key: cord- - xmxcm authors: walden, andrew p; clarke, geraldine m; mckechnie, stuart; hutton, paula; gordon, anthony c; rello, jordi; chiche, jean-daniel; stueber, frank; garrard, christopher s; hinds, charles j title: patients with community acquired pneumonia admitted to european intensive care units: an epidemiological survey of the genosept cohort date: - - journal: crit care doi: . /cc sha: doc_id: cord_uid: xmxcm introduction: community acquired pneumonia (cap) is the most common infectious reason for admission to the intensive care unit (icu). the genosept study was designed to determine genetic influences on sepsis outcome. phenotypic data was recorded using a robust clinical database allowing a contemporary analysis of the clinical characteristics, microbiology, outcomes and independent risk factors in patients with severe cap admitted to icus across europe. methods: kaplan-meier analysis was used to determine mortality rates. a cox proportional hazards (ph) model was used to identify variables independently associated with -day and six-month mortality. results: data from patients admitted to centres across countries was extracted. median age was years, % were male. mortality rate at days was %, rising to % at six months. streptococcus pneumoniae was the commonest organism isolated ( % of cases) with no organism identified in %. independent risk factors associated with an increased risk of death at six months included apache ii score (hazard ratio, hr, . ; confidence interval, ci, . - . ), bilateral pulmonary infiltrates (hr . ; ci . - . ) and ventilator support (hr . ; ci . - . ). haematocrit, ph and urine volume on day one were all associated with a worse outcome. conclusions: the mortality rate in patients with severe cap admitted to european icus was % at six months. streptococcus pneumoniae was the commonest organism isolated. in many cases the infecting organism was not identified. ventilator support, the presence of diffuse pulmonary infiltrates, lower haematocrit, urine volume and ph on admission were independent predictors of a worse outcome. community acquired pneumonia (cap) is common, affecting between and individuals per , of the adult population each year [ , ] and is the commonest cause of sepsis, severe sepsis and septic shock [ ] . between and % of patients require hospital admission [ , , ] of whom to % will be admitted to an icu [ ] [ ] [ ] . hospital and icu admission rates for cap are increasing for all ages [ ] . an ageing, more vulnerable population, earlier recognition of deteriorating patients and better availability and use of intensive care beds may in part explain this increase. a number of investigators have examined the clinical and microbiological factors that might affect the outcome from severe cap [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , but these studies have often been relatively small, with considerable heterogeneity in both the inclusion criteria and outcome measures. as a consequence reported mortality rates have varied and there has been uncertainty regarding the most important risk factors for death. a number of more recent, larger studies have focussed on identifying patients with cap at increased risk of severe sepsis and death, as well as those who may require ventilator or vasopressor support [ , [ ] [ ] [ ] . one of these studies provides outcome data at days for the smaller subgroup of patients with severe sepsis admitted to the icu [ ] , and another [ ] reports microbiological findings and -day mortality in a subgroup of patients admitted to the icu. the aim of the study reported here was to define the clinical characteristics, microbiological aetiology, outcomes and independent risk factors for mortality in a large, contemporary cohort of patients with severe cap admitted to icus across europe. by using such a large database with clear censor data for mortality we hoped to overcome some of the deficiencies of previous studies. the genosept study was conceived by the european critical care research network (eccrn), the research arm of the european society for intensive care medicine (esicm) with the aim of defining genetic influences on the host response and outcomes in patients with sepsis. genosept is a pan-european study that has recorded comprehensive phenotypic data and obtained dna from a large cohort of patients admitted to icu with sepsis due to cap, peritonitis, meningococcal disease or pancreatitis. ethics approval was granted nationally, for individual centres, or for both. written, informed consent was obtained from all patients or a legal representative. patients reported here were recruited into genosept from centres across countries (see additional file for contributors) over a -year period between september and october . inclusion criteria were as follows: admission to a high dependency unit (hdu) or icu with cap, and age over years. the diagnosis of cap was defined as a febrile illness associated with cough, sputum production, breathlessness, leucocytosis and radiological features of pneumonia acquired in the community or within less than days of hospital admission [ ] . the diagnosis of sepsis was based upon the international consensus criteria published in [ ] . patients were further sub-classified according to the criteria for severe sepsis and septic shock. exclusion criteria were as follows: patient or legal representative unwilling or unable to give consent; patient under yrs of age; patient pregnant; advanced directive to withhold or withdraw life-sustaining treatment or admitted for palliative care only (please see also additional file ). patients were observed until death or for a maximum of months. in those who had died between icu discharge and -month follow-up the date of death was recorded. specific data was recorded in the electronic case report form (ecrf) to allow calculation of the acute physiology and chronic health evaluation ii (apache ii) and sequential organ failure assessment (sofa) scores [ , ] . the infectious diseases society of america/american thoracic society (idsa/ats) criteria were used for the diagnosis of severe cap [ ] . co-morbidities were recorded according to the modified charlson scoring system [ ] . chest radiograph appearances were recorded as: ) lobar, ) localised or ) diffuse bilateral. investigators were also asked to consider the differential diagnosis of cardiogenic pulmonary oedema in those with diffuse pulmonary infiltrates. microbiological investigations were performed according to local policies and practices. investigators recorded the microbiological findings, including the organism(s) isolated, the source of the organism and the use of serology. mortality at days and at months were chosen as primary endpoints. univariate analysis was performed using a cox proportional hazards model, adjusted for age and gender. variables considered by the investigators to be clinically relevant were chosen for analysis (see additional file ). a test for proportional hazards using the schoenfeld residuals was performed, and for covariates indicating evidence of non-proportionality, spline smooth estimates of time-dependent hazard ratios (hrs) with point-wise confidence bands were calculated [ ] . variables that were significant in the univariate analysis after bonferroni adjustment for multiple testing (p-value < . /k where k is the number of variables tested) were entered into a multivariate cox proportional hazards model to determine independent risk factors for death. a final set of predictors for each of -day and -month mortality was selected from these variables via a stepwise cox proportional hazards regression model. r software version . . was used for all data analysis. between september and october , , patients were enrolled. four individuals were excluded because of missing or inconsistent data. patient characteristics are shown in table . on admission, , patients ( %) met idsa/ats criteria for severe cap, on major criteria and on minor criteria. median age was years (range to , iqr to ): % were male, % were caucasian and % mediterranean, and patients were hospitalised for more than hours prior to icu admission. of these the mean time from hospital admission to icu admission was . days. median length of stay in the icu was days (iqr to ); median length of stay in hospital was days (iqr to ) ( table ) . a total of ( %) patients had one or more co-morbid conditions, with cardiac and respiratory disease affecting and patients, respectively. chronic obstructive pulmonary disease was documented in ( . %) patients, diabetes mellitus in . % and a chronic neurological condition in . %. on the day of admission ( %) patients required mechanical ventilation, with the number increasing to patients ( %) within the first week of admission ( table ). median duration of mechanical ventilation was days: patients ( %) satisfied the criteria for septic shock. the median duration of inotrope/vasopressor support was days. renal replacement therapy was required during the first week of admission in % of patients. median sofa score on admission was (iqr to ) and median apache ii score was (iqr to ). chest radiograph appearances were recorded as lobar consolidation in . %, patchy localised consolidation in . % and diffuse, bilateral changes in . %. a total of ( . %) patients had died within months of enrolment, ( . %) in the icu, in hospital after icu discharge and between hospital discharge and months following icu admission. the in-hospital mortality rate was . % and the -day mortality rate was . % (see table and figure ). mortality was higher in mechanically ventilated patients, ( . % at days and . % at months) and in patients with septic shock receiving haemodynamic support with inotropes or vasopressors ( . % and . % respectively). the standardised mortality ratio derived from the apache ii score was . ( % ci . , . ) [ ] . no causative organism was identified in over a third of patients (table ) . streptococcus pneumoniae (pneumococcus) was the most commonly isolated organism ( % of cases), positive microbiology was obtained from lung secretions/lavage in % of cases; blood culture in %; urinary antigen testing in %; blood serology in %; pleural fluid in . % and other methods in %. bacteraemia was present in ( %) of patients and pleural infection/empyema in ( %). pneumococcus was the commonest organism causing bacteraemia and empyema, accounting for episodes ( %) and episodes ( %) respectively. atypical organisms and viruses were rarely identified. isolation of staphylococcus aureus, presence of septic shock, need for mechanical ventilation and renal replacement therapy all showed a strong association with outcome (table ) . the factors most strongly associated with -day mortality were the apache ii score calculated on day (hr = . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the considerable heterogeneity in admission policies, study design, guidelines compliance [ ] , and severity scoring in these studies probably accounts for the wide range of reported mortality rates and makes meaningful comparisons difficult. most of these studies have used icu admission rather than severity scores to indicate severe disease. only three studies [ , , ] defined censor points for death, which is important as in-hospital mortality increases following icu discharge by between and % [ ] . admission practices in different countries may also lead to large ranges in mortality. take for instance one study of patients admitted to a spanish respiratory icu in the s the mortality rate was % but with rates of mechanical ventilation and septic shock of % and % respectively [ ] , whereas in a uk study published in the mortality rate was %, with mechanical ventilation and septic shock rates of % and % respectively [ ] . the mortality rates reported here are more in keeping with other recent, large cohorts. the capuci group analysed patients admitted to over spanish icus between and and found icu mortality rates of % with associated apache ii scores of [ ] . they included both immunocompetent and immunosuppressed patients. in the immunocompetent individuals the rate of death at icu discharge was slightly lower at %, a figure that is closer to the % seen in the genosept cohort, (in which immunocompromised patients were [ ] . in the port study, of , patients were admitted to the icu with an in-hospital mortality rate of . % [ ] . the standard censor point for most interventional icu studies is days, although it is recognised that there is a significant attrition rate post icu discharge. it is also well-recognised that in cap patients there is an increased death rate in the months following discharge [ ] , and in patients with sepsis there is significant excess mortality for at least five years [ ] . in one study, the death rate of icu patients between days and months was % in patients with sepsis, similar to the % seen in icu patients without sepsis [ ] and the % found in the present study. this compares to an increase in mortality from . % at days to . % at days in the subgroup of icu patients in the port study [ ] and an increase from . % to . % at months in the genims cohort of icu patients [ ] . although the microbiological methodology was not standardised, our findings are consistent with previous studies of severe cap. notably, streptococcus pneumoniae accounted for % of all cases and no aetiological agent was identified in over a third [ ] . within the genosept cohort the rate of streptococcus pneumoniae was higher than previously reported and was mirrored by a decrease in the number of cases where no aetiological agent was identified, suggesting that detection rates may have improved, rather than there being a true increase in all values are significant at a type i error rate of % after a bonferroni correction to take account of the multiple testing of variables (a p-value < . was considered to be statistically significant). results are adjusted for age and sex. all day- variables unless specified otherwise. rrt, renal replacement therapy; mv, mechanical ventilation; niv, non-invasive ventilation; sbp, systolic blood pressure; map, mean arterial pressure. incidence. pneumococcal antigen testing in urine and other bodily fluids has become the standard of care in many institutions and has good positive and negative predictive value both in hospitalised cap patients [ ] and in those admitted to icu [ ] . amongst the patients with confirmed pneumococcal pneumonia in the present study, a total of positive results were obtained. of these ( %) were positive urinary antigen tests and ( %) were based on positive blood serology. further evidence to support this apparent increase in detection rates is provided by a recent study that reported detection rates of % for streptococcus pneumoniae, with % of cases being diagnosed using antigen testing [ ] . in comparison, the bts study from reported a rate of streptococcus pneumoniae infection of %, with positive antigen testing in only % of patients [ , ] . in hospitalised patients with cap, as many as to % may involve a viral infection, the virus being the only organism isolated in % [ ] . failure to respond to standard antimicrobial therapy means that more patients with viral pneumonia are likely to be admitted to icu. certainly patients with co-morbidities have a higher incidence of viral infection. in the present study viral infections were rarely identified. this raises the question as to whether a more aggressive search for viral pathogens should be conducted in all ventilated patients, coupled with more frequent and targeted use of antiviral therapy. multivariate analysis identified four variables (apache ii score, haematocrit, mechanical ventilation and ph) that were independently associated with outcome at both days and months the need for mechanical ventilation was related to a worse outcome at both days and months, consistent with other data showing respiratory failure to be an independent predictor of mortality in many categories of critically ill patients [ , ] . the persistence of this relationship for up to months reflects the fact that many patients who have received ventilator support will continue to have significant neuromuscular weakness and be at risk for a prolonged period after discharge from the icu [ ] . it may be that over-aggressive use of intravenous fluids, reflected in a dilutional reduction in haematocrit worsens lung injury and thus prolongs the need for mechanical ventilation. conservative fluid management has been associated with better outcomes, albeit in the later phases of critical illness [ ] . a key element of early goal-directed therapy in patients with sepsis is blood transfusion to maintain the haematocrit, perhaps accounting for the positive association between better outcomes and a higher haematocrit in the present, and other studies [ ] . similarly the positive independent relationship between a higher ph on admission and a better outcome may reflect more effective early resuscitation. although there was no association between the admission p:f ratio and outcome, diffuse bilateral changes on the chest radiograph (suggesting a diagnosis of acute lung injury/acute respiratory distress syndrome) independently predicted a worse outcome at months. this is consistent with other studies showing a mortality rate for ards much higher than that seen in our cohort of patients with cap [ ] . urine volume, renal failure and the need for renal replacement therapy were associated with worse outcome in the univariate analysis and there was a clear independent association between urine output and mortality at months. acute kidney injury (aki) has been shown to be independently associated with higher icu and in hospital mortality rates [ , ] . the need for ongoing renal support in those with aki is estimated to be %, perhaps explaining the association with outcome at months. other studies have attempted to determine independent risk factors for death from cap. for example, the presence of septic shock has been associated with odds ratios for risk of death ranging from to but inevitably with wide confidence intervals due to the small numbers of patients included in these analyses [ , , , , ] ; also the lack of a consistent censor point complicates interpretation of these findings. we found an association between septic shock and outcome on univariate analysis but this effect was not seen in multivariate analysis, perhaps reflecting improvements in the acute management of shock. this study has two important limitations. firstly participating centres were at liberty to decide which patients they would enrol; subjects were not, therefore, enrolled consecutively, thereby introducing a potential for selection bias. also there was considerable variation in the number of patients recruited in each country and some centres contributed only small numbers of patients. nevertheless there was a wide range of ages, severity of physiological derangement and co-morbidities, whereas apache ii scores and ventilation rates were similar to previous studies, suggesting that a significant, systematic selection bias is unlikely. secondly, microbiological protocols were not standardised. on the other hand our observations therefore reflect current approaches to microbiological diagnosis in routine clinical practice across europe. the icu mortality rate in this contemporary cohort of patients admitted to icus across europe with severe cap was %, rising to % at hospital discharge and % at months. streptococcus pneumoniae was the commonest cause of cap, but in many cases the infecting organism was not identified. the need for ventilator support, and the presence of diffuse bilateral infiltrates on the chest radiograph, as well as lower haematocrit, urine volume and ph on admission to icu were independent predictors of a worse outcome. prospective study of the aetiology and outcome of pneumonia in the community incidence of community-acquired pneumonia in the population of four municipalities in eastern finland understanding the inflammatory cytokine response in pneumonia and sepsis: results of the genetic and inflammatory markers of sepsis (genims) study community-acquired pneumonia: the annual cost to the national health service in the uk severe community-acquired pneumonia. epidemiology and prognostic factors prognostic factors of pneumonia requiring admission to the intensive care unit the british thoracic society research committee and the public healthlaboratory service: the aetiology, management and outcome of severe community-acquired pneumonia on the intensive care unit increasing hospital admissions for pneumonia combination antibiotic therapy with macrolides improves survival in intubated patients with community-acquired pneumonia aetiology and outcome of severe community-acquired pneumonia impact of management guidelines on the outcome of severe community acquired pneumonia the outcome of community acquired pneumonia treated on the intensive care unit severe communityacquired pneumonia. etiology, epidemiology, and prognosis factors. french study group for community-acquired pneumonia in the intensive care unit etiology of community-acquired pneumonia: impact of age, comorbidity, and severity severe community-acquired pneumonia. etiology, prognosis, and treatment a five-year study of severe community-acquired pneumonia with emphasis on prognosis in patients admitted to an intensive care unit a predictive model for the treatment approach to community-acquired pneumonia in patients needing icu admission severe community-acquired pneumonia: factors influencing need of intensive care treatment and prognosis a three-year study of severe community-acquired pneumonia with emphasis on outcome a new diagnostic approach to the patient with severe pneumonia antibiotic prescription for community-acquired pneumonia in the intensive care unit: impact of adherence to infectious diseases society of america guidelines on survival severe community-acquired pneumonia: assessment of microbial aetiology as mortality factor the british thoracic society and the public health laboratory service: community-acquired pneumonia in adults in british hospitals in - : a survey of aetiology, mortality, prognostic factors and outcome severe community-acquired pneumonia: use of intensive care services and evaluation of american and british thoracic society diagnostic criteria severe sepsis in community-acquired pneumonia: when does it happen, and do systemic inflammatory response syndrome criteria help predict course? chest australian community-acquired pneumonia study c, grayson ml: smart-cop: a tool for predicting the need for intensive respiratory or vasopressor support in community-acquired pneumonia sccm/esicm/accp/ats/sis international sepsis definitions conference apache ii: a severity of disease classification system the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults a new method of classifying prognostic comorbidity in longitudinal studies: development and validation modeling survival data: extending the cox model communityacquired pneumonia on the intensive care unit: secondary analysis of , cases in the icnarc case mix programme database inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis long-term mortality and quality of life in sepsis: a systematic review quality of life of survivors from severe sepsis and septic shock may be similar to that of others who survive critical illness community-acquired pneumonia in europe: causative pathogens and resistance patterns evaluation of the immunochromatographic binax now assay for detection of streptococcus pneumoniae urinary antigen in a prospective study of community-acquired pneumonia in spain evaluation of the binax now streptococcus pneumoniae urinary antigen assay in intensive care patients hospitalized for pneumonia viral infection in adults hospitalized with community-acquired pneumonia: prevalence, pathogens, and presentation canadian critical care trials group: one-year outcomes in survivors of the acute respiratory distress syndrome comparison of two fluid-management strategies in acute lung injury sepsis in european intensive care units: results of the soap study beginning and ending supportive therapy for the kidney (best kidney) investigators: acute renal failure in critically ill patients: a multinational, multicenter study effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients submit your next manuscript to biomed central and take full advantage of: • convenient online submission • thorough peer review • no space constraints or color figure charges • immediate publication on acceptance • inclusion in pubmed, cas, scopus and google scholar • research which is freely available for redistribution the genosept project was supported by the european critical care research network and the european society of intensive care medicine. we would like to acknowledge all the co-investigators and research nurses who were involved in the project. a list of their names can be found in the additional file . the mortality rate from severe cap in patients admitted to icu is % at six months streptococcus pneumonia remains the most commonly isolated organism no microbiological diagnosis is found in a third of patients the need for mechanical ventilation is a strong predictor of a poor outcome ph, haematocrit, urine output and diffuse changes on chest radiography all predict a worse outcome authors' contributions apw prepared the database for analysis, prepared the first copy of the manuscript and coordinated all manuscript revisions; gmc performed the primary statistical analysis, helped in the writing of the manuscript and provided the tables and figures; smck assisted in preparation of the database for analysis and helped in writing and reviewing the manuscript; ph helped with the preparation of the database for analysis and helped in writing and reviewing the manuscript; acg helped in the design of the genosept project and in the writing an reviewing of the manuscript; jr helped in the design of the genosept project and in writing and reviewing the manuscript; j-dc helped in the design of the genosept project and in writing and reviewing the manuscript; fs helped in the design of the genosept project and in writing and reviewing the manuscript; csg helped in the design of the genosept project and in writing and reviewing the manuscript; cjh helped in the design of the genosept project and in writing and reviewing the manuscript. all authors read and approved the final manuscript. andrew p walden and geraldine m clarke contributed equally as joint first authors. key: cord- -m ujhhsc authors: koekkoek, w. a. c.; menger, y. a.; van zanten, f. j. l.; van dijk, d.; van zanten, a. r. h. title: the effect of cisatracurium infusion on the energy expenditure of critically ill patients: an observational cohort study date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: m ujhhsc background: both overfeeding and underfeeding of intensive care unit (icu) patients are associated with worse outcomes. a reliable estimation of the energy expenditure (ee) of icu patients may help to avoid these phenomena. several factors that influence ee have been studied previously. however, the effect of neuromuscular blocking agents on ee, which conceptually would lower ee, has not been extensively investigated. methods: we studied a cohort of adult critically ill patients requiring invasive mechanical ventilation and treatment with continuous infusion of cisatracurium for at least h. the study aimed to quantify the effect of cisatracurium infusion on ee (primary endpoint). ee was estimated based on ventilator-derived vco( ) (ee in kcal/day = vco( ) × . ). a subgroup analysis of septic and non-septic patients was performed. furthermore, the effects of body temperature and sepsis on ee were evaluated. a secondary endpoint was hypercaloric feeding (> % of ee) after cisatracurium infusion. results: in total, patients were included. mean ee before cisatracurium infusion was kcal/day and kcal/day after cisatracurium infusion. multivariable analysis showed a significantly lower ee after cisatracurium infusion (md − . kcal ( % ci − . to − . ; p = . ) in all patients. this difference was statistically significant in both sepsis and non-sepsis patients (p = . and p = . ). non-sepsis patients had lower ee than sepsis patients (md − . kcal; % ci − . to − . , p = . ). body temperature and ee were positively correlated (spearman’s rho = . , p < . ). hypercaloric feeding was observed in patients. conclusions: our data suggest that continuous infusion of cisatracurium in mechanically ventilated icu patients is associated with a significant reduction in ee, although the magnitude of the effect is small. sepsis and higher body temperature are associated with increased ee. cisatracurium infusion is associated with overfeeding in only a minority of patients and therefore, in most patients, no reductions in caloric prescription are necessary. targeting optimal nutrition concerning energy goals is essential in critically ill patients, as both underfeeding and overfeeding have been associated with increased morbidity and mortality [ ] . ideally, the target is based on energy expenditure (ee). however, due to the pathophysiological response to critical illness, iatrogenic interventions, and differences in body composition, ee is highly variable in and between critically ill patients [ ] . frequent monitoring of ee may circumvent this problem and help to adjust the optimal amount of calories on an individual basis. at present, indirect calorimetry is considered the gold standard. however, frequently, this technique is not available and often unfeasible [ ] . to optimize nutritional targets without frequent monitoring of ee, it is essential to know which factors are associated with either an increase or decrease in ee. specific conditions expected to influence ee have been studied such as sepsis [ ] [ ] [ ] , burns [ , ] , trauma [ , ] , cerebrovascular accidents [ , ] , pregnancy [ ] , body temperature [ ] , administration of sedatives [ ] , and therapeutic hypothermia [ , ] . an increased ee has been reported in patients with sepsis, trauma, burns, fever, and pregnancy. therapeutic hypothermia and the administration of sedatives are associated with a decrease in ee [ ] . however, limited information is available on the effects of neuromuscular blocking agents (nmbas) on ee. furthermore, it is not known whether nmba administration affects the ee in sepsis patients similarly compared with non-sepsis patients and in relation to the baseline temperature. this study aimed to quantify the effect of cisatracurium infusion on ee of adult critically ill patients. also, we analyzed the effects of body temperature and sepsis on ee. secondary endpoint was hypercaloric feeding as a consequence of muscle relaxation. we performed a retrospective observational study in patients treated with cisatracurium at the mixed medicalsurgical adult intensive care unit of the gelderse vallei hospital, ede, the netherlands, between january , , and october , . patients were included when they met with the following inclusion criteria: adult critically ill patients (≥ years) requiring invasive mechanical ventilation and treatment with cisatracurium for at least h. exclusion criteria were pregnancy, hypothermia induced by therapeutic temperature management, burns, and malignant hyperthermia because these conditions have a substantial effect on ee. patients were also excluded when data on vco were incomplete. in patients with multiple icu admissions during the study period, data from readmissions were excluded. an icu admission was considered readmission when the patient was admitted within months from the primary icu admission. cisatracurium is the nmba of choice for sustained neuromuscular blockade during critical illness in gelderse vallei hospital. cisatracurium was administered when indicated according to the international clinical practice guidelines for the sustained neuromuscular blockade in the adult critically ill patient [ ] . an infusion was started at doses of μg/kg per minute and then adjusted by assessment of the train-of-four (tof) using a peripheral nerve stimulator (tof-watch® s, dublin, ireland). according to the hospital protocol, tof measurements were performed every hour, and dosage adjustments were made to achieve a tof level of or lower. the electrodes of the tof-watch® were placed on the other wrist daily to prevent skin lesions. the primary endpoint was the total ee, expressed as kcal/day, which was measured before and during cisatracurium infusion. indirect calorimetry was not routinely available during the study period. ee was, therefore, estimated by an adjusted version of weir's equation using the ventilator-derived vco (eevco ). eevco = . × vco (l/min) / respiratory quotient + . × vco (l/min) × . the respiratory quotient was considered to be a fixed value of . [ ] [ ] [ ] . the mechanical ventilator measured the vco (hamilton-s , hamilton medical ag, bonaduz, switzerland), and every minute, data are automatically sent to our electronic patient data management system (metavision; imdsoft metavision®, tel aviv, israel). for each patient, the vco was collected during the h before and during the h after the start of cisatracurium infusion. when patients were not admitted to the icu h before the start of cisatracurium infusion, the parameters of the available hours were used. the eevco was calculated every h using the mean vco measurements from the previous h. secondary endpoint was hypercaloric feeding (> % of ee) after cisatracurium infusion. we also evaluated icu length of stay (los) and in-hospital mortality in patients receiving hypercaloric versus regular or hypocaloric feeding. the world health organization/food and agricultural organization of the united nations (who/fao) formulas were used to calculate caloric and protein targets by our computerized feeding protocol [ ] . according to bmi, the actual (bmi < ), corrected (bmi - ; regression to bmi of ), or ideal body weight (bmi > ; regression to bmi in women and bmi . in men) was used. an addition to the resting ee (ree) of % was used to correct for disease activity [ ] . most parameters were routinely collected into an extensive icu database during standard clinical care. data extraction was performed using sas enterprise guide queries (version . hf ) searching our patient data management system (metavision; imdsoft metavision®, tel aviv, israel, and neozis®, electronic medical record, mi consultancy, katwijk, the netherlands). data to calculate the charlson comorbidity index (cci) [ ] were obtained from the quality management system for hospital mortality registration. data verification was performed manually. collected data were de-identified and stored on a secure hospital computer. there were no identifiable paper documents. descriptive data are reported as means and standard deviation (sd) or median and interquartile range in case of skewed distributions, or as frequencies and percentages when appropriate. for the primary analysis, comparing the ee before and after cisatracurium infusion, a general linear mixed model analysis for repeated measures was performed with an autoregressive covariance structure. in this analysis, we corrected for body temperature, sedative and noradrenaline dosages, ph, peep, and fio and repeated measurements. we performed a subgroup analysis of septic and nonseptic patients. we also evaluated the effects of body temperature on ee with the pearson or spearman rank correlation tests. the effects of sepsis on ee were analyzed through general linear mixed models, correcting for the following confounders: cisatracurium, temperature, nutric score, gender, bmi, admission type, and repeated effects. finally, we evaluated the effect of hypercaloric feeding vs. normocaloric and hypocaloric feeding on in-hospital mortality and icu length of stay (los) by chi-square test and one-way anova, respectively. a p value of < . was considered statistically significant. the data analyses were performed using ibm corp. spss statistics for windows (version . , released new york, usa). during the study period, patients were admitted to the icu, of which received cisatracurium for at least h and therefore were eligible for inclusion. we excluded patients according to the exclusion criteria. in total, patients were enrolled in this study (fig. ) . baseline characteristics and nutritional parameters are shown in tables , , and . the median age was . years, and . % were female. the median sofa and apache ii scores on admission were and , respectively. most patients were septic ( . %) and admitted to the icu because of medical reasons ( %). a median icu and hospital los of and days were found. the in-hospital mortality was . %. the mean ee was kcal/day before cisatracurium infusion (= control period) and kcal/day during cisatracurium infusion resulting in a mean difference of in the subgroup of sepsis patients, cisatracurium reduced ee from kcal/day to kcal/day (mean difference of − . kcal; % ci − . to − . ; p = . ). in the subgroup of non-sepsis patients, cisatracurium reduced ee from kcal/day to kcal/day (mean difference − . kcal; % ci − . to − . ; p = . ). in both analyses, adjustment for body temperature, sedative and noradrenaline dosages, ph, peep, and fio were performed. a significant non-linear positive association between body temperature and ee was found (spearman's rho = . , p < . ; fig. ). mean ee was kcal ( % ci - ) in nonseptic patients and kcal ( % ci - ) in septic patients (p = . ). in mixed-model multivariable analysis, a significantly lower ee was observed in nonseptic patients than in septic patients (mean difference − . kcal, % ci − . to − . ; p = . ). only seven patients ( . %) received > % of their caloric target (estimated by eevco ) on the first day of cisatracurium infusion. twenty patients ( . %) received between and % of their caloric target, while patients ( . %) were fed hypocalorically (< % of caloric target). because of the small number of patients with hypercaloric intake, no associations between hypercaloric intake and icu los or mortality were calculated. we studied the effect of cisatracurium infusion on ee in a cohort of adult critically ill patients. cisatracurium infusion lowered ee as estimated by the vco method by . %. nmbas act by interfering with the binding of acetylcholine to the motor endplate in the synaptic cleft of the neuromuscular junction, thereby ultimately preventing muscle contraction. indications for the continuous infusion of nmbas during critical illness comprise severe acute respiratory distress syndrome (ards) (pao /fio < ), overt shivering during therapeutic hypothermia, and other life-threatening situations associated with profound hypoxemia, respiratory acidosis, or hemodynamic compromise in case of failure of other measures such as deep sedation [ ] . cisatracurium is one of the most widely used nmbas for continuous infusion as it can also be used in patients with hepatic or renal insufficiency [ ] . due to the blocking of muscle contractions and as a consequence of the subsequent lower muscular heat production, nmbas should conceptually reduce ee. however, this hypothesis has not been studied in icu patients with the previously described indications for the use of continuous nmba infusion. overall, only one earlier study has evaluated the effects of nmbas on ee in adults, reporting a significant increase in ee of . % after discontinuation of pancuronium in patients with severe head injury [ ] . additionally, one study investigated the effects of nmba infusion (vecuronium, pancuronium, and atracurium) in critically ill children reporting a significant reduction of . % of ee h after infusion of nmbas [ ] . we observed a non-linear positive association between body temperature and ee. four small previous studies reported an association between body temperature and ee in critically ill patients [ , , ] . a reduction of . % of ee per °c decrease at temperatures below °c and an increase of . % per °c at temperatures above °c have been reported [ , ] . we observed a higher ee in septic patients than in nonseptic patients. this was in line with our expectations based on previous studies in which ee in septic patients was - % of ee in non-septic patients [ ] . however, a recent observational study in patients found no differences in ee between septic and nonseptic patients ( vs. kcal/day) [ ] . this is the largest cohort of critically ill patients in which the effects of nmbas on ee have been studied. the effects of nmbas, especially cisatracurium, in this specific patient population have not been studied before. a large number of patient variables were available with few missing data, providing enough data to perform rigorous multivariable and repeated measure analyses. however, our study has several limitations. indirect calorimetry was not routinely available during the study period. therefore, ee was calculated using vco obtained from the mechanical ventilator. calculation of ee from vco has been demonstrated to be more accurate than predictive equations, but less than indirect calorimetry. finally, limitations related to the retrospective design may potentially have introduced bias and residual confounding. as cisatracurium reduces ee, reduction of caloric intake after the start of nmbas should be considered, especially in those patients that are on full feeding or considered to reach this target soon, because they are at risk of hypercaloric feeding and associated harm. before we designed the study, we expected, due to the drop in ee induced by the nmba, that some of the patients would be overfed. based on the results, we noticed that a reduction of ee by nmba could induce an almost % overfeeding risk in individual patients. in daily practice, this did not occur as the patients were not on nutrition target. thus, for most patients, adjustment may not be necessary as in our analysis the reduction of ee found was only . % and hypercaloric feeding was only present in . %, while most other patients were fed ( . %) hypocalorically after initiation of cisatracurium infusion. although not the focus of our present study, it should be noted that the recent rose trial, studying the effect of early neuromuscular blockade ( -h continuous infusion of cisatracurium) with concomitant heavy sedation, compared with usual care, did not result in a significant mortality difference at days in patients with moderate to severe acute respiratory distress syndrome in contrast to an earlier rct [ , ] . this trial was stopped early at the second interim analysis for futility. this study may lead to reevaluation of the use of nmbas in severe respiratory failure. our data suggest that continuous infusion of cisatracurium in mechanically ventilated icu patients is associated with a significant reduction in ee as estimated by the vco method, although the magnitude of the effect is small. sepsis and higher body temperature are associated with increased ee. cisatracurium infusion is associated with overfeeding in only a minority of patients, and therefore, in most patients no reductions in caloric prescription are necessary. resting energy expenditure, calorie and protein consumption in critically ill patients: a retrospective cohort study the use of indirect calorimetry in the intensive care unit introducing a new generation indirect calorimeter for estimating energy requirements in adult intensive care unit patients: feasibility, practical considerations, and comparison with a mathematical equation energy expenditure in different patient populations on intensive care: one size does not fit all resting energy expenditure and oxygen consumption in critically ill patients with vs without sepsis predicting energy expenditure in sepsis: harris-benedict and schofield equations versus the weir derivation reliability of resting energy expenditure in major burns: comparison between measured and predictive equations energy expenditure in patients with severe head injury: controlled normothermia with sedation and neuromuscular blockade resting energy expenditure in critically ill patients with spontaneous intracranial hemorrhage variations in resting energy expenditure: impact on gestational weight gain quantitative analysis of the relationship between sedation and resting energy expenditure in postoperative patients resting energy expenditure and substrate oxidation rates correlate to temperature and outcome after cardiac arrest -a prospective observational cohort study clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient validation of carbon dioxide production (vco ) as a tool to calculate resting energy expenditure (ree) in mechanically ventilated critically ill patients: a retrospective observational study ventilator-derived carbon dioxide production to assess energy expenditure in critically ill patients: proof of concept can calculation of energy expenditure based on co measurements replace indirect calorimetry? crit care effects of implementation of a computerized nutritional protocol in mechanically ventilated critically ill patients: a single-centre before and after study insights into energy requirements in disease a new method of classifying prognostic comorbidity in longitudinal studies: development and validation identifying critically-ill patients who will benefit most from nutritional therapy: further validation of the "modified nutric" nutritional risk assessment tool use of cisatracurium in critical care: a review of the literature effect of neuromuscular blockade on energy expenditure in patients with severe head injury effect of neuromuscular blockade on oxygen consumption and energy expenditure in sedated, mechanically ventilated children effect of cooling on oxygen consumption in febrile critically ill patients optimal temperature for the management of severe traumatic brain injury: effect of hypothermia on intracranial pressure, systemic and intracranial hemodynamics, and metabolism early neuromuscular blockade in the acute respiratory distress syndrome neuromuscular blockers in early acute respiratory distress syndrome springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors wish to thank johannes kars, data specialist, and dick van blokland, icu it application specialist, for their support with data collection. all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, key: cord- -w r oetd authors: kanafani, zeina a.; zahreddine, nada; tayyar, ralph; sfeir, jad; araj, george f.; matar, ghassan m.; kanj, souha s. title: multi-drug resistant acinetobacter species: a seven-year experience from a tertiary care center in lebanon date: - - journal: antimicrob resist infect control doi: . /s - - - sha: doc_id: cord_uid: w r oetd background: acinetobacter species have become increasingly common in the intensive care units (icu) over the past two decades, causing serious infections. at the american university of beirut medical center, the incidence of multi-drug resistant acinetobacter baumannii (mdr-ab) infections in the icu increased sharply in by around %, and these infections have continued to cause a serious problem to this day. methods: we conducted a seven-year prospective cohort study between and in the icu. early in the epidemic, a case-control study was performed that included mdr-ab cases diagnosed between and and uninfected controls admitted to the icu during the same time. results: the total number of patients with mdr-ab infections diagnosed between and was . there were also patients with mdr-ab colonization without evidence of active infection between and . the incidence of mdr-ab transmission was . cases/ icu patient-days. the majority of infections were considered hospital-acquired ( %) and most consisted of respiratory infections ( . %). the mortality rate of patients with mdr-ab ranged from % to %. conclusion: mdr-ab infections mostly consisted of ventilator-associated pneumonia and were associated with a very high mortality rate. infection control measures should be reinforced to control the transmission of these organisms in the icu. multidrug-resistant organisms (mdro) have significant infection control implications and are currently affecting the clinical course of patients in tertiary care centers. acinetobacter baumannii is of particular importance. the organism is widely distributed in nature and survives on moist and dry surfaces [ , ] . worldwide, multidrug-resistant a. baumannii (mdr-ab) has become a significant cause of hospitalacquired infections (hai) and hospital-acquired colonizations (hac) resulting in high morbidity and mortality [ ] in patients admitted to the intensive care units (icu) over the past two decades [ ] . strict adherence to infection control practices and environmental disinfection have been effective in controlling outbreaks [ ] . appropriate strategies and practices must therefore be implemented to prevent the growing transmission of mdr-ab. in line with the worldwide emergence of mdr-ab, similar trends have been observed at various centers in lebanon. although national studies are lacking, the available evidence suggests rapidly falling susceptibility rates to carbapenems (from . % in to . % in at selected hospitals) [ ] , and a predominance of oxa- and ges- with upstream insertion sequence isaba ( % of isolates in a study from centers) [ ] . at the american university of beirut medical center (aubmc), hai and hac caused by mdr-ab initially increased in the icu in from - cases to - per month. these infections were mostly associated with invasive devices such as ventilators, central venous catheters, and urinary catheters. investigations carried by the infection control and prevention program (icpp) identified multiple factors that contributed to the transmission of mdr-ab. we herein describe our experience at the aubmc with mdr-ab over a -year period and the infection control measures that were implemented to control the spread of this organism in the icu. aubmc is a -bed teaching tertiary care center functioning as a referral center at the national and regional levels. the icu consists of a medical and surgical unit with a nine-bed capacity. three single-and three double-bed rooms are spread around a central nursing station. the icu population consists of high-risk patients with multiple comorbidities, as well as patients following major surgical procedures. the beds in the double rooms are maintained at a distance of m and separated by textile curtains. a -year prospective cohort study was conducted in the icu with systematic attempts to assess present practices and to introduce new interventions to contain the transmissions of mdr-ab in the unit. all icu patients were evaluated examining the risk factors attributed to the transmission of mdr-ab hai or hac. the icu team routinely collected specimens from newly admitted patients for baseline bacteriological studies and all patients were placed under contact isolation. a standardized screening method was adopted, where cultures were obtained from deep tracheal aspirates (dta), urine, oropharyngeal, axillary, umbilical, perianal, and rectal areas. the icpp team reviewed the culture results on daily basis to advise on the isolation status of patients through daily surveillance rounds. patients identified with mdr-ab were kept on contact isolation. cultures were repeated on weekly basis until discharge. all mdr-ab hai and hac were periodically discussed with the icu staff for feedback and interventions. furthermore, environmental cultures were obtained following the identification of clusters or outbreaks from the direct environment of the patient and from the medical equipment used inside the icu cubicle. repeated cleaning and disinfection was performed for all surfaces or equipment identified to be contaminated with mdr-ab. a nested retrospective case-control study from january till june was performed in the icu and the respiratory care unit (rcu) to analyze patient related risk factors leading to mdr-ab transmissions. controls were randomly selected from patients admitted to the icu and the rcu during the same study period but who did not have a positive screening culture for mdr-ab. moreover, cases consisted of patients with one or more cultures growing mdr-ab (either colonized or infected). for patients with multiple mdr-ab culture results, only the first positive culture was considered. the data were entered into a database using ibm® spss® statistics version . according to the centers for disease control and prevention (cdc), a multidrug-resistant pathogen is defined as one that is resistant to one or more classes of antimicrobial agents, including carbapenems [ ] . in this study, mdr-ab was defined as an isolate that is resistant to all tested antimicrobial agents except colistin and tigecycline [ ] . a culture positive for mdr-ab was considered to represent colonization when patients showed no evidence of infection. as for the case definition, patients with at least one clinical/ surveillance specimen positive for mdr-ab were defined as cases of transmission of mdr-ab colonization or infection that was not present on admission. such patients were considered to have acquired mdr-ab during their icu stay. for device-associated infections, the definitions were subject to considerable variation since based on the updates issued by the cdc and when the reports published by the national nosocomial infections surveillance (nnis) system were updated and replaced by the national healthcare safety network (nhsn). all infections were classified using the cdc definitions of the corresponding year using laboratory and clinical criteria. infection control staff collected data on central line-associated primary bloodstream infections (clabsi), ventilator-associated pneumonias (vap), and urinary catheter associated urinary tract infections (cauti) in patients admitted to the adult icu. corresponding icu denominator data consisting of patient-days and device-days were also collected by infection control staff for the same calendar month [ , ] . a cluster was defined as an aggregation of mdr-ab cases (more than cases), closely grouped in time and place. when the number of cases in the cluster exceeded transmissions, it was considered an outbreak. acinetobacter isolates were identified using the maldi-tof platform for identification. all isolates were tested using the disk diffusion method based on the clinical and laboratory standards institute (clsi) breakpoints. the colistin sensitivity testing was made based on vitec- bio system and disk diffusion according to the method reported by galani et al. in study [ , ] . a written informed consent was not needed for our study as the information was obtained from the daily surveillance rounds of the icpp team. the medical records of patients were routinely reviewed as part of the ongoing icpp work. patients were not contacted and medical records were not retrieved a second time to write the manuscript. over the years, statistics were collected and stored for statistical analysis and periodic reports within the institution. all figures included in the manuscript were retrieved from the preexisting icpp files without having to perform a review of patient records. furthermore, the available statistics did not include any identifiable information to maintain patient confidentiality. a total of cases infected with acinetobacter spp. (carbapenem-sensitive and resistant acinetobacter isolates) and controls (uninfected patients) were included. the mean age of the infected patients was . ± . years with a male predominance (male:female ratio of : ). culture specimens consist mostly of respiratory secretions ( %), followed by wound ( %), blood ( %), and urine ( %). moreover, the microbiological distribution of the isolates was predominated by one species, namely acinetobacter baumannii complex ( isolates, %) with the other % distributed between a. junii ( isolates, . %) and a. lwoffi ( isolate, . %). in addition, patients ( %) had carbapenem-resistant isolates, of which were tested against colistin and found to be susceptible. most infections were deemed to be hospitalacquired ( %) with only % being community-acquired. furthermore, underlying comorbidities such as diabetes mellitus, renal insufficiency, chronic obstructive pulmonary disease (copd), and malignancy were significant risk factors for developing an acinetobacter infection. in addition, patients who had undergone surgical interventions and those who received antibiotics within days prior to admission were at significant risk for developing an acinetobacter infection (p < . ) ( table ). all complications due to acinetobacter infections, except for acute respiratory distress syndrome (ards), were encountered more with resistant strains as compared to sensitive ones, but none of these complications was of statistical significance ( table ) . the total number of patients with acinetobacter infections diagnosed between and was (table ). there were also patients with mdr-ab colonization without evidence of active infection between and . prior to , screening of patients on admission to the icu was not performed. the mean age of the patients was . years (range - ) with a male predominance ( . %). the mean length of icu stay was . days (range - days). outliers for patients staying for more than days (maximum recorded length of stay was months) were documented but were not included in the calculation of the mean length of stay ( patients). the most common site of infection among the isolates was the respiratory tract ( . %), followed by surgical wound ( . %), blood ( . %), urine ( . %) and others ( . %) ( table ). the most common colonization site among the cases was the respiratory tract ( . %) followed by skin colonization ( . %). the mortality rate ( %) in the icu was associated with old age, trauma, cancer, multiple comorbidities, and invasive device use. during the outbreak period from december to december , patients out of ( . %) admitted to the icu became colonized or infected with mdr-ab, with patients from the surgical icu having slightly less risk than those from the medical icu. the overall colonization pressure (number of mdr-ab patient-days × /total number of patient-days) of mdr-ab between and was . cases per icu patient-days (range (table ). in addition, the average length of stay for mdr-ab patients admitted to the icu was . days (range - ) with the average length of stay till the acquisition of mdr-ab being . days (range - ). the all-cause mortality rate of patients dying with mdr-ab infection/ colonization was high and ranged between % and %. given the fact that the patients were critically ill, calculating the attributable mortality was challenging. moreover, the icpp took several control measures to help break the transmission cycle of the organism. hand hygiene, universal screening and isolating all newly admitted patients played a key role in containing the outbreaks. furthermore, the change in cleaning protocols and the extensive focus on educating healthcare workers limited the spread of mdr-ab to other hospital wards. didecyldimethylammonium chloride (ddac) was adopted for cleaning and disinfection of floors, walls, surfaces, and medical devices. this disinfectant and detergent has bactericidal and fungicidal activity, in addition to being active on hcv, hiv- , and influenza virus at a dilution of . % ( ml in l of water). table summarizes the clusters and outbreaks encountered throughout the study period along with control measures that were undertaken by the icpp: sampling environmental culture swabs from patients' environment and equipment was conducted throughout the study period. as a result, positive cultures were recovered from samples taken from the ventilators, the portable x-ray and the nitric oxide machines. by molecular typing, these isolates were found to be identical to the bacteria isolated from the patients. these pieces of equipment were thought to play a major role in the outbreak. subsequently, icpp proposed new protocols for the process of placing patients on assisted respiratory therapy and issued detailed procedures for cleaning and disinfection of ventilators. cultures were taken from additional environmental sources including the water, the faucets, and the air conditioning outlets in the rooms and failed to yield any acinetobacter growth. other sources that were identified during the investigation of later outbreaks included leaking mattresses and pillows, which were thought to be also possible total reservoirs for mdr-ab. all leaking mattresses and pillows were discarded and replaced by new ones. the program adopted tracking the mdr-ab colonization pressure (cp) and reporting it on a monthly basis. in fact, during the same study period, mdr-ab cp was relatively high and correlated with the high crude numbers of mdr-ab infections and colonizations. by that time, transmissions of mdr-ab had become endemic. additional steps that became standard of care in the nursing units included the implementation of the bundles for device-associated infections (vap, clabsi, and cauti bundles) as recommended by the institute for health care improvement, proper monthly training for healthcare workers especially in the critical care units, adoption of a "bare below elbow" outfit for all icu workers, and daily presence of the icpp team members in the icus. all these measures were essential to containing the spread of mdr-ab inside the icu. the addition of close-circuit television (cctv) cameras was also instrumental in identifying health care personnel breaches during the evening and night shifts. these cameras had an additive effect and contributed to the control of the epidemic. over the past decade, acinetobacter spp. have been increasingly associated with hospital infections and colonizations. our study describes several outbreaks caused by mdr-ab between and . our initial case control study of acinetobacter infections, between and , revealed that most of the infected patients were elderly, with a male predominance, similar to the study by abbo et al. [ ] . positive cultures consisted mostly of respiratory secretions, followed by wound, blood, and then urine; findings comparable to an international study [ ] . acinetobacter baumannii was the predominant isolated species with only few isolates of a. junii and a. lwoffi. at the beginning of the study about half of the isolates were carbapenem resistant, of which around half were found to be susceptible to colistin. most of the infections were considered hospital-acquired with a small percentage being community-acquired infections. as in previously reported studies [ ] , patients infected with acinetobacter had several risk factors including underlying comorbidities such as diabetes mellitus, renal insufficiency, copd, and malignancy. furthermore, surgical interventions and prior antibiotic treatment within days before admission were also found to be significant risk factors for developing an acinetobacter infection in concordance with a study by playford et al. [ ] . in this study, we compared infections with susceptible versus resistant isolates and found that there was a trend towards more sepsis, respiratory failure, icu admission, and prolonged hospital stay in infections with mdr-ab strains. however, acute respiratory distress syndrome (ards) was seen in both groups. similar findings were seen in another study in the icu from china [ ] . in the prospective study conducted between and , there was also a predominance of male gender, with a mean age of years comparable to our case-control study. the mean length of stay in the icu was around days, however, outliers for patients staying for more than days were documented. during this period, carbapenem resistance among acinetobacter isolates increased steadily, with prevailing mdr-ab towards the end of . this was likely due to the significant increase in carbapenem use at aubmc, in view of the rising incidence of extended spectrum beta lactamase producing enterobacteriacae [ ] . the most common site of infection among the patients with acinetobacter infections was found to be the respiratory tract, followed by surgical wound, blood, and urine as reported in other studies [ ] . similarly, the most common colonization site between and was the respiratory tract followed by skin colonization. acinetobacter infections have been associated with increased mortality in several published reports. in our study, the all-cause mortality rate of patients with mdr-ab infection/colonization was high, but it was difficult to calculate the attributable mortality due to the fact that many patients were critically ill with multiple comorbid conditions. higher mortality rates were seen in older patients, those with trauma, cancer, multiple comorbidities, and invasive device use. in addition, during the study period, the average length of stay for mdr-ab patients admitted to the icu increased. patients with acinetobacter incurred greater financial costs than those who did not have acinetobacter transmissions. it is estimated that a single ventilatorassociated pneumonia (vap) or central line-associated bloodstream infection (clabsi) due to mdr-ab may result in weeks of additional hospitalization with its incurred added cost. the average cost of icu stay, at our medical center, for one patient with mdr-ab infection can reach $ per day. for an extended icu stay of weeks, the patient's bill can be up to $ , . because of the poor outcome of the acinetobacter infections and the incurred increased morbidity, hospital stay and cost of infected patients, the icpp adopted a series of control measures since december . for example, in view of published supportive evidence [ ] , the use of the h o vaporizer for room disinfection after discharges of colonized or infected patients was initiated in . although in this report, the acinetobacter contamination in the icu environment was found to be a cause of recurrent mdr-ab clusters or outbreaks, lack of proper hand hygiene and lack of adherence to proper infection control practices were thought to play a major role in the spread of this organism. audits conducted by the icpp team as well as anonymous audits led to the identification of several breaches by the health care providers that were promptly addressed. the nursing director and the chief of staff office issued warnings for health care workers with repeated acts of non-compliance. finally, changes in the reporting of data, namely the introduction of the cp measure as an important predictor of infection and colonization [ ] , helped in standardization and benchmarking of infection rates. our study has limitations. patient-level antibiotic treatment data were not available. therefore, patient outcome could not be analyzed based on treatment received. colonized patients were not followed after discharge from the icu. the only outcome available for these patients was the overall mortality rate. attributable mortality was not assessed because of multiple confounding variables such as underlying illnesses, invasive procedures, cancer patients, etc. another limitation is that some of the data were obtained retrospectively and could not be re-verified. finally, the fact that multiple interventions were implemented at the same time in an effort to control the epidemic prevented the analysis of the effect of each measure by itself. in conclusion, at our center, mdr-ab infections mostly caused ventilator-associated pneumonia and were associated with a very high mortality rate. acinetobacter can colonize several environmental sources including respirators, mattresses and others. it is an organism that is difficult to eradicate and easy to spread in the icu setting. adherence to proper infection control measures is key in controlling the transmission and spread of these organisms in the icu. effect of biofilm formation on the survival of acinetobacter baumannii on dry surfaces influence of relative humidity and suspending menstrua on survival of acinetobacter spp. on dry surfaces multidrug-resistant acinetobacter infection mortality rate and length of hospitalization criteria for patient admission to an intensive care unit and related mortality rates healthcare infection control practices advisory c. management of multidrug-resistant organisms in health care settings surveillance of antimicrobial resistance in lebanese hospitals: retrospective nationwide compiled data heterogeneity of carbapenem resistance mechanisms among gram-negative pathogens in lebanon: results of the first cross-sectional countrywide study multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance national healthcare safety network report, data summary for , device-associated module national healthcare safety network (nhsn) report, data summary for colistin susceptibility testing by etest and disk diffusion methods evaluation of the etest method for detecting colistin susceptibility of multidrug-resistant gramnegative isolates in vietnam multidrug-resistant acinetobacter baumannii concurrent outbreak of multidrugresistant and susceptible subclones of acinetobacter baumannii affecting different wards of a single hospital nosocomial imipenem-resistant acinetobacter baumannii infections: epidemiology and risk factors carbapenem-resistant acinetobacter baumannii in intensive care unit patients: risk factors for acquisition, infection and their consequences multidrug resistant acinetobacter baumannii: risk factors for appearance of imipenem resistant strains on patients formerly with susceptible strains a reflection on bacterial resistance to antimicrobial agents at a major tertiary care center in lebanon over a decade acinetobacter spp. as nosocomial pathogens: microbiological, clinical, and epidemiological features efficiency of hydrogen peroxide in improving disinfection of icu rooms colonization pressure and risk factors for acquisition of imipenem-resistant acinetobacter baumannii in a medical surgical intensive care unit in brazil not applicable. the study did not require any external funding. the data that support the findings of this study are available from the infection control and prevention program at the american university of beirut medical center but restrictions apply to the availability of these data due to institutional policies on data sharing. authors' contributions zk designed the study and analyzed and interpreted the patient data. nz collected the patient data and obtained the environmental cultures; rt collected the patient data; js collected the patient data; ga performed the microbiological testing; gm performed the microbiological testing; sk designed and oversaw the conduct of the study. all authors read and approved the final manuscript.ethics approval and consent to participate informed consent was not obtained for the purpose of this study as all data emanated from the routine daily work of the infection control and prevention program. not applicable. the authors declare that they have no competing interests. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. • we accept pre-submission inquiries • our selector tool helps you to find the most relevant journal submit your next manuscript to biomed central and we will help you at every step: key: cord- -pw coi v authors: ballus, josep; lopez-delgado, juan c.; sabater-riera, joan; perez-fernandez, xose l.; betbese, a. j.; roncal, j. a. title: surgical site infection in critically ill patients with secondary and tertiary peritonitis: epidemiology, microbiology and influence in outcomes date: - - journal: bmc infect dis doi: . /s - - - sha: doc_id: cord_uid: pw coi v background: surgical site infection (ssi) remains a significant problem in the postoperative period that can negatively affect clinical outcomes. microbiology findings are typically similar to other nosocomial infections, with differences dependent on microbiology selection due to antibiotic pressure or the resident flora. however, this is poorly understood in the critical care setting. we therefore aimed to assess the incidence, epidemiology and microbiology of ssi and its association with outcomes in patients with severe peritonitis in the intensive care unit (icu). methods: we prospectively studied consecutive patients admitted to our surgical icu from to with a diagnosis of secondary or tertiary peritonitis. we collected the following data: ssi diagnosis, demographics, acute physiology and chronic health evaluation (apache) ii score, simplified acute physiology score (saps) ii score, type of surgery, microbiology, antibiotic treatment and outcomes. microbiological sampling was done by means of swabs. results: we identified episodes of ssi in patients ( . %) aged . ± . years, of which episodes occurred in men ( . %). the mean apache ii and saps ii scores were . ± . and . ± . respectively. the mean icu and hospital stays were . ± . and . ± days respectively. pseudomonas spp. (n = , . %), escherichia coli (n = , . %) and candida spp. (n = , . %) were the most frequently isolated microorganisms, but gram-positive cocci (n = , . %) were also frequent. microorganisms isolated from ssis were associated with a higher incidence of antibiotic resistance ( . %) in icu patients, but not with higher in-hospital mortality. however, patients who suffered from ssi had longer icu admissions (odds ratio = . , % confidence interval . – . , p = . ). conclusions: the incidence of ssi in secondary or tertiary peritonitis requiring icu admission is very high. physicians may consider antibiotic-resistant pathogens, gram-positive cocci and fungi when choosing empiric antibiotic treatment for ssi, although more studies are needed to confirm our results due to the inherent limitations of the microbiological sampling with swabs performed in our research. the presence of ssi may be associated with prolonged icu stays, but without any influence on overall mortality. the skin is the main barrier against bacterial infection of internal tissues, and surgical wounds create a physical disruption to that barrier. the movement of bacteria across the skin barrier can lead to surgical site infections (ssi), one of the most frequent infectious complications of surgical procedures, with the potential risk for adverse outcomes [ ] . ssi involves different inflammatory responses that range from low to high clinical significance [ ] , with that following abdominal surgery being a typical example associated with increased morbidity and mortality [ ] [ ] [ ] [ ] . worse still, ssi can spread to surrounding areas and vital deep structures, often requiring debridement or drainage [ , ] . consequently, the treatment of ssi leads to increased costs, especially when we consider the high number of surgical procedures and their complexity in a typical referral hospital [ ] [ ] [ ] [ ] . peritonitis, which is defined as inflammation of the serous membrane that covers the abdominal cavity and their organs, is classified into primary (spontaneous), secondary (process-related pathology in the visceral organs) and tertiary (persistent or recurrent after initial adequate surgical treatment). secondary and tertiary peritonitis are associated with higher morbidity with mortality rates of - % [ , ] . tertiary peritonitis usually occurs in icu settings at least - h following adequate treatment of secondary peritonitis, and has a mortality rate of - % [ ] . centers for disease control and prevention (cdc) estimates that the risk of ssi associated with abdominal surgery ranges from approximately to %, depending on the type of surgery [ , , , ] . ssi is classified into several categories: clean ( %), clean-contaminated ( %), contaminated ( %) and dirty ( %) [ , ] . stratification before surgery could help identify at-risk patients suitable for surveillance [ ] . despite the marked influence of ssi associated with severe peritonitis on public health and clinical practice, it has been poorly addressed in the literature, even in the icu setting. this study therefore aimed to describe the incidence, epidemiology, microbiology and outcomes of ssi in patients admitted with secondary or tertiary peritonitis to the icu of a tertiary referral hospital. this prospective, observational study was carried out at from january to december . at the time this study was performed, the hospital universitari de bellvitge (hub) was a tertiary hospital with general care beds and icu beds. we included all consecutive patients from any type of abdominal surgery who required icu admission beyond h for secondary or tertiary peritonitis. all patients received standard preoperative hygiene care and antibiotic prophylaxis at anaesthetic induction consistent with our institutional protocols for elective and emergency surgery [ ] . ssi was defined using the cdc definition [ ] and diagnosis was by the responsible physicians, based on clinical criteria. any purulent drainage from a surgical incision with signs of inflammation of the surrounding tissue was considered an ssi, whether microorganisms were isolated in cultures or not. the infection had to present at the surgical site within days of surgery [ ] [ ] [ ] . the study was approved by the institutional ethics committee of our hospital (comité d' Ètica i assajos clínics de hub (ceic); ethics and clinical assays committee of hub), and informed consent was waived due to the observational design. in all patients, the decisions regarding icu admission and treatment were made by the treating physician. data were recorded from the medical registry of each patient in real time, using a standardised questionnaire, and collected in a database. the following information was recorded on admission: demographic data, medical history and comorbidities, surgical indication and type of surgery (elective or emergency), surgical technique, intraoperative variables (number of drains inserted), microbiologic findings, arterial lactate on admission and treatment characteristics. during their icu stay, we also recorded the following: need for vasopressor drugs, mechanical ventilation and renal replacement therapy (rrt) and; any new microbiological findings, including the appropriateness, changes and resistance to antibiotic treatment. illness severity was quantified with the acute physiology and chronic health evaluation (apache) and simplified acute physiology score (saps) scoring systems during the first h of icu admission for all patients. after icu discharge, follow-up was planned to collected data on in-hospital mortality and patients were followed until discharge from icu or until resolution. the surgical teams collaborated with icu physicians to control the ssi, using simple washouts or serial debridements when appropriate. we obtained tissue samples and exudate samples, and direct needle aspiration was used when needed, in collaboration with the surgical team. the microbiological samples were obtained under conditions as sterile as possible in order to avoid colonizers of the superficial wound. the deepness of tissue sample was evaluated based on ssi characteristics. if necessary, drainage was performed, and any necrotic tissue was debrided and foreign material removed. intensive irrigation with saline solution was employed when necessary to facilitate mechanical debridement [ ] . we provided rational antibiotic therapy based on local guidelines and after consultation with an infectious disease physician. for diagnosis purposes, microbiological samples were sent to the laboratory as swabs in culture media for semiquantitative aerobic and anaerobic cultures. to isolate anaerobes, specimens were inoculated into columbia blood agar plates enriched with hemin and menadione, incubated in an anaerobic chamber at °c, and specimens were gram stained at and h for direct examination. statistical analysis was conducted using pasw statistics . (spss inc., chicago, illinois, usa). continuous data are expressed as mean ± standard deviation and categorical data are expressed as percentages. comparisons between groups with non-normal distributions were by two-sample t-tests or mann-whitney u tests after applying the one-sample kolmogorov-smirnov test. the χ -test was used to evaluate categorical variables. multivariable analysis was done to assess the influence of ssi and other ssi-related factors, such as the microbiology results, on mortality and outcomes. odds ratios (ors) and % confidence intervals (cis) are quoted as appropriate. a p-value of . was considered statistically significant in all cases. of the patients hospitalised for secondary or tertiary peritonitis in our icu, we identified episodes of ssi in patients. the ssi rate of . % was higher in icu compared with the rest of hospitalized patients who underwent major abdominal surgery (n = / ; . %) during the study period (p < . ). patient characteristics, inflammatory response, type of surgery and outcomes are shown in table . the mean duration of hospitalisation prior to surgery was . ± . days. urgent abdominal surgery comprised %- % of all abdominal surgeries performed at our hospital, showing a difference in the type of surgery in comparison with icu patients (p = . ). the types of surgery (based on the anatomical location) of the different identified ssi episodes are shown in fig. . all patients were monitored with a central venous catheter, arterial catheter and urinary catheter, and all patients were on vasoactive drugs or inotropic support. in the studied population, we identified positive culture isolates: ( . %) were from ssis, ( . %) were from intra-abdominal abscesses, ( . %) were from positive blood cultures (blood cultures) and ( . %) were from other cultures. the microbiology results for isolates from ssi are shown in table , with a preponderance of escherichia coli (n = , . %) and pseudomonas aeruginosa (n = , . %), while gram-positive cocci and candida spp. were also frequent at rates of . % (n = ) and . % (n = ) respectively. antibiotic resistance to two or more antibiotics occurred in . % (n = ), with rates of extended spectrum beta-lactamase-producing enterobacteriaceae (n = ) and pseudomonas aeruginosa carbapenem-resistant (n = ) of . % and . % respectively, but with low rates of typical multi-resistant microorganisms such as acinetobacter baumanii ( . %, n = ) and methicillin resistant staphylococcus aureus (mrsa) ( . %, n = ). the microorganisms isolated from intra-abdominal abscesses were the same of those isolated in ssi samples in the . % of the patients (n = ) with similar rates of of multi-resistant bacteria. no relationship was established between the intraabdominal abscesses and the occurrence of ssi based of clinical and surgical evaluation. based on the culture antibiograms, . % of patients received appropriate antibiotic treatment. the most commonly used antibiotics are shown in table , with the use of multiple, simultaneous or sequential antibiotics being used in . % of the cases (n = ). a mean of . antibiotics was used per ssi, with treatment lasting ± days. total mortality was . % (n = ), from which . % (n = ) correspond to icu deaths. although ssi was not associated with higher mortality in our population when confounders, such as variables that reflected disease severity, were included in the multivariate analysis, it was associated with a longer icu stay (or = . , % ci: . - . ; p = . ). indeed, mortality was lower in the group with ssi (or = . , % ci . - . ; p = . ). the need for rrt (or = . , % ci: . - . ; p = . ) and prolonged icu stay (or = . , % ci: . - . ; p < . ) were associated with higher in-hospital mortality. this study provides data on the incidence and microbiology of ssis for a large cohort of critically ill patients admitted with secondary or tertiary peritonitis to a surgical icu. it confirms that there was a high incidence of ssi in those patients. the main findings of our study were that ssi was associated with a prolonged icu stay, but that it had little impact on the overall in-hospital mortality in our population. the development of postoperative ssi is known to have been multifactorial, arising from a complex relationship between host and environmental factors [ , ] . host risk factors for ssi include morbid obesity, disease severity, advanced age, low blood-protein levels and malnutrition, diabetes, malignancy and sepsis, while other risk factors that include susceptibility include immunosuppression, smoking and having a distant infection site [ ] . pre-existing morbidity, the time of surgery and the type of ssi may also play key roles in the development of ssis [ ] . thus, an increasingly elderly population with a greater number of comorbidities significantly increases the risk of developing an ssi [ , ] . critically ill patients represent an increasing proportion of the inpatient population that will undoubtedly lead to greater diagnostic and management challenges, especially given that most ssis in the icus are nosocomial [ ] . ssis are most common in high-risk patients, with an incidence of about . % [ , ] . antibiotic prophylaxis reduces postoperative morbidity and length of hospital stay, which positively affects ssirelated costs [ ] . wounds with a risk of infection below % do not generally require antibiotic prophylaxis, but notable exceptions include the placement of a prosthesis, cardiovascular surgery and neuro-surgery [ ] . up to % of all elective surgical patients may develop an ssi, with rates as high as % being common in contaminated or dirty surgical procedures [ ] . in our study, the majority of procedures were considered dirty or contaminated, and many of the critically ill patients had markedly decreased serum protein concentrations. together, these may ultimately explain our higher ssi rate. our higher rates may also reflect the inherent risks of tertiary care institutions and the severity of our cohort. therefore, our results may not be applicable to secondary and non-referral hospitals. an ssi can increase hospital stay by about six days and can add - % to hospital costs, even leading to death; therefore, prevention and control should be an [ , ] . ssis may occur following any surgical incision, even after the use of minimally invasive techniques, so ssis need to be reported through systematic monitoring programmes for nosocomial infection [ ] . we showed that patients suffering from ssi in our cohort had longer icu stays. however, we do not think this was simply a surrogate of higher illness severity in the ssi group because of the comparable severity scores between groups. the dominant causative microorganisms and treatment options have changed over time. today, most common pathogens are resistant to common antibiotics [ ] with the need for a high index of suspicion, prompt operative intervention, appropriate antibiotic treatment and proper resuscitation [ ] . hypovolemia and hypothermia create peripheral vasoconstriction that leads to poor tissue perfusion, which facilitates the development of ssi in the presence of necrotic tissue, foreign bodies, hematomas and seromas [ ] . the microbiology of intra-abdominal infections also varies depending on the source of infection, prior use of antibiotics, the site of infection and if it is community acquired or nosocomial. besides the host and wound factors, physicians should be aware of the increase in high-virulence species, such as staphylococcus aureus and streptococcus pyogenes. in addition, escherichia coli, bacteroides fragilis and other gram-negative, anaerobic pathogens are common in large bowel perforations [ ] . nosocomial intra-abdominal infections often involve microorganisms such as pseudomonas spp., enterococcus spp. and fungi [ ] . in our population, there was an increased presence of multidrugresistant pathogens and fungal ssi rates when compared with other series [ , ] . this could be explained by the higher antibiotic pressure, use of broad-spectrum antibiotics, illness severity and prolonged treatment periods. indeed, concomitant treatment for peritonitis compounded matters. we also showed higher reliance on total parenteral nutrition (tpn) because enteral nutrition was poorly tolerated and we opted to initiate it early to avoid hypoalbuminemia, which is a risk factor for fungal infection and ssi in critically ill patients [ ] . however, we concede that tpn is a risk factor for all types of fungal infection in icu, especially among surgical patients [ ] . the increasing trend to reduce hospital stays by implementing innovative surgical techniques (particularly minimally invasive and endoscopic procedures) makes it necessary to ensure that accurate measurement and monitoring of adverse events can take place after discharge. without doing so, we cannot establish the real impact of ssi on morbidity and mortality [ , , ] . control measures with an emphasis on the education of healthcare professionals, such as frequent hand washing and the need to isolate patients with multi-resistant bacteria in cluster units, are necessary to reduce ssi rates [ ] . although the total elimination of ssi is not possible, a reduction in the rate of infection to a minimum should be achievable, even in critically ill patients [ ] . our study presents certain limitations. the most important is that we used for microbiological sampling a skin swabs instead of the "gold standard" for culture of skin, which are tissue biopsy or aspiration sampling of infected tissue. we could have obtained colonizer microorganisms that are not responsible for the infection and cultures may be misleading organisms in the deep tissue infection. thus, our results should be considered cautiously and more studies are needed to confirm them. secondly, this was a single-centre observational study and our results cannot be extrapolated to other less severely ill populations. among the strengths of this study are the large sample size, the prospective entry of all data and the use of postoperative scores, which are not used in contemporary studies, even though their importance in risk stratification has been emphasised over recent decades. furthermore, this investigation was conducted at a large tertiary referral hospital with a high level of complexity over a four-year period. in summary, the incidence of ssi was very high in patients with secondary or tertiary peritonitis requiring icu admission. when they prescribe antibiotic therapy, physicians should consider that microorganisms isolated from patients with ssi are more likely to include multidrugresistant pathogens, including pseudomonas spp., grampositive cocci and fungi, although more studies are needed to confirm our results due to the inherent limitations of the microbiological sampling with skin swabs performed in our research. despite the presence of an ssi may be associated with prolonged icu stays, we did not find any effect on the in-hospital mortality in our population. abbreviations ssi: surgical site infection; icu: intensive care unit; apache: acute physiology and chronic health evaluation; saps: simplified acute physiology score; rrt: renal replacement therapy; tpn: total parenteral nutrition; ards: acute respiratory distress syndrome in adults. there is no funding support or conflicts of interest for the present paper. authors' contributions jb was involved in the conception and design of the research, acquisition of data and wrote the paper. jcld performed partial statistical analysis, acquisition of data and wrote the paper. jsr contributed to the design of the research and acquisition of data. xlpf supervised and performed statistical analysis. ajb was involved in the conception, design of the research and interpretation of data. jar was involved in the design of the research and supervised the writing of the present manuscript. all authors read and approved the final version of this manuscript. epidemiology and microbiology of surgical wound infections risk factors for and epidemiology of surgical site infections surgical wound infection: a general overview the epidemiology of chest and leg wound infections following cardiothoracic surgery surgical site infections: epidemiology and prevention the epidemiology of intra-abdominal flora in critically ill patients with secondary and tertiary abdominal sepsis intensive care unit management of intra-abdominal infection risk factors for severe sepsis in secondary peritonitis surgical infections in the critically ill risk factors for wound infection after surgery for colorectal cancer cdc definitions of nosocomial surgical site infections, : a modification of cdc definitions of surgical wound infections surgical wound infection: epidemiology, pathogenesis, diagnosis and management apache ii: a severity of disease classification system implications of , consecutive surgical infections entering year adverse impact of surgical site infections in english hospitals national nosocomial infections surveillance system (nnis): description of surveillance methods microbiological diagnosis of intra-abdominal infections overview of the etiology of wound infections with particular emphasis on community-acquired illnesses a risk factor analysis of healthcare-associated fungal infections in an intensive care unit: a retrospective cohort study fungal infections in icu patients: epidemiology and the role of diagnostics continuous, -year wound infection surveillance: results, advantages, and unanswered questions the authors wish to thank the icu nurses and all members of the general surgery department for their contribution to the study and for their care of the patients reported in this paper. key: cord- -i ztypg authors: chow, eric j.; doyle, joshua d.; uyeki, timothy m. title: influenza virus-related critical illness: prevention, diagnosis, treatment date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: i ztypg annual seasonal influenza epidemics of variable severity result in significant morbidity and mortality in the united states (u.s.) and worldwide. in temperate climate countries, including the u.s., influenza activity peaks during the winter months. annual influenza vaccination is recommended for all persons in the u.s. aged months and older, and among those at increased risk for influenza-related complications in other parts of the world (e.g. young children, elderly). observational studies have reported effectiveness of influenza vaccination to reduce the risks of severe disease requiring hospitalization, intensive care unit admission, and death. a diagnosis of influenza should be considered in critically ill patients admitted with complications such as exacerbation of underlying chronic comorbidities, community-acquired pneumonia, and respiratory failure during influenza season. molecular tests are recommended for influenza testing of respiratory specimens in hospitalized patients. antigen detection assays are not recommended in critically ill patients because of lower sensitivity; negative results of these tests should not be used to make clinical decisions, and respiratory specimens should be tested for influenza by molecular assays. because critically ill patients with lower respiratory tract disease may have cleared influenza virus in the upper respiratory tract, but have prolonged influenza viral replication in the lower respiratory tract, an endotracheal aspirate (preferentially) or bronchoalveolar lavage fluid specimen (if collected for other diagnostic purposes) should be tested by molecular assay for detection of influenza viruses. observational studies have reported that antiviral treatment of critically ill adult influenza patients with a neuraminidase inhibitor is associated with survival benefit. since earlier initiation of antiviral treatment is associated with the greatest clinical benefit, standard-dose oseltamivir ( mg twice daily in adults) for enteric administration is recommended as soon as possible as it is well absorbed in critically ill patients. based upon observational data that suggest harms, adjunctive corticosteroid treatment is currently not recommended for children or adults hospitalized with influenza, including critically ill patients, unless clinically indicated for another reason, such as treatment of asthma or copd exacerbation, or septic shock. a number of pharmaceutical agents are in development for treatment of severe influenza. annual seasonal influenza epidemics of variable severity result in significant morbidity and mortality in the united states (u.s.) and worldwide [ ] [ ] [ ] . in temperate climate countries, including the u.s., influenza activity peaks during the winter months whereas in tropical regions influenza activity may be more variable [ ] [ ] [ ] . most persons with symptomatic influenza virus infection have self-limited uncomplicated upper respiratory tract illness. one study estimated that during - , approximately . % of the u.s. population experienced symptomatic influenza each year [ ] . however, complications may result in severe illness, including fatal outcomes. during - , an estimated . - million medical visits, , - , hospitalizations, and , - , deaths were associated with influenza each year in the u.s. [ ] . another study estimated that , - , influenza-related intensive care unit (icu) admissions occur annually in the u.s. [ ] . there are an estimated , - , respiratory deaths attributed to seasonal influenza each year worldwide [ ] . here, we review strategies for prevention, diagnosis, and treatment of influenza virus infections in the icu (table ) . influenza vaccination is the primary method for preventing influenza and reducing the risk of severe outcomes. in the u.s., the advisory committee on immunization practices (acip) recommends annual influenza vaccination for all persons aged months and older and prioritizes those at higher risk for influenza complications [ ] . high-risk groups include adults aged > years [ , ] , children aged < years (particularly those aged < years) [ , ] , pregnant women (up to weeks postpartum) [ ] [ ] [ ] [ ] , persons with certain chronic medical conditions, native americans/alaska natives, and residents of nursing homes and other long-term care facilities (table ) . studies have specifically highlighted that those with chronic pulmonary, cardiovascular, renal, hepatic, neurologic, hematologic or metabolic disorders, immunocompromised persons, children and adolescents receiving aspirin-or salicylate-containing medications and who might be at risk for experiencing reye syndrome with influenza virus infection, and those who are extremely obese (bmi > ) are at increased risk for influenza-related complications [ , [ ] [ ] [ ] [ ] [ ] . many studies evaluated risk factors for severe influenza during the h n influenza pandemic. adult icu patients with influenza a(h n )pdm virus infection were primarily non-elderly, were obese [ ] [ ] [ ] [ ] [ ] , and had higher odds of death, invasive mechanical ventilation, acute respiratory distress syndrome (ards), septic shock, and multi-lobar pneumonia when compared with seasonal influenza patients [ , ] . in children, independent risk factors for influenza a(h n )pdm -related mortality included chronic neurologic condition or immune compromise, acute myocarditis or encephalitis, and early presumed mrsa co-infection of the lung [ ] . female gender was also identified as a risk factor; however, there was no gender difference in overall mortality. bacterial coinfection was identified in approximately one third of fatal influenza a(h n )pdm cases in the largest autopsy case series [ ] . bacterial co-infections in the interpandemic period are also common in critically ill influenza patients [ ] . one study identified past or current tobacco use as a risk factor associated with icu admission [ ] . a recent multicenter cohort study reported that mortality was higher in immunosuppressed patients with influenza a(h n )pdm than in immunocompetent patients [ ] . severity of influenza seasons varies from yearto-year based on the predominant influenza viruses, and between seasonal and pandemic influenza [ , ] . one study reported that patients with influenza a(h n ) pdm had higher odds of severe disease than patients with either influenza a(h n ) or influenza b virus infections [ ] . however, influenza b virus infection has been shown to increase the odds of in-hospital mortality in children compared with influenza a virus infection [ ] . influenza vaccination is recommended each fall for all persons aged > months in the u.s. and should continue • there are an estimated , - , seasonal influenza-associated respiratory deaths every year worldwide. • annual influenza vaccination is the primary method of preventing influenza and influenza-related complications, especially in high-risk persons. • influenza molecular diagnostic testing is recommended for all patients requiring hospitalization with suspected influenza. • influenza antiviral treatment should be started as soon as possible in hospitalized patients with suspected influenza, including critically ill patients, and should not be delayed while awaiting results of influenza diagnostic tests. • enterically administered oseltamivir is recommended for influenza patients except for those with contraindications (e.g., gastric stasis, ileus, malabsorption). • repeat virologic testing in lower respiratory tract specimens may be required to determine therapeutic endpoints in ventilated patients with influenza • corticosteroids are not recommended for the routine treatment of influenza except when indicated for treatment of underlying medical conditions (e.g., copd or asthma exacerbation) or septic shock. [ ] , and reducing in-hospital mortality and icu admissions for those aged - years and > years compared to unvaccinated individuals [ ] . one study reported that duration of icu hospitalization was reduced a half-day in patients aged - years who had received influenza vaccination compared with unvaccinated patients [ ] . a study across all age groups in spain reported influenza ve of % in reducing the risk of severe influenza requiring hospitalization [ ] . a southern hemisphere study reported influenza ve of % in reducing influenza-associated icu admissions among adults [ ] while a study in spain showed an adjusted influenza ve of % in preventing icu admission and death [ ] . despite the benefits of influenza vaccination, there continues to be low vaccine coverage among adults admitted to the icu who often have a high prevalence of high-risk comorbidities [ , ] . in children, low influenza vaccination coverage has also been reported among those admitted to pediatric icus, even among those with underlying high-risk conditions [ ] . full influenza vaccination was shown to result in a % reduction in pediatric icu admissions compared to unvaccinated or partially vaccinated influenza patients [ ] . furthermore, one study showed that influenza ve was % in reducing the risk of mortality in children aged months to years in the u.s. [ ] . these data further emphasize the benefits of influenza vaccination in reducing severe influenza complications, especially in high-risk persons. persons with uncomplicated influenza typically experience acute onset of respiratory symptoms (cough, rhinorrhea, congestion), myalgias, and headache with or without fever. during influenza season, clinicians should also consider influenza when there is only fever present or in patients who are afebrile and have respiratory symptoms [ ] . complications of influenza vary by age, underlying comorbidities or high-risk conditions such as pregnancy, and immune function; elderly and immunocompromised persons may not always manifest fever. critically ill patients may be admitted with respiratory or multi-organ failure, exacerbation of an underlying condition such as chronic lung disease [ , ] , heart failure [ ] , or other extrapulmonary complications including stroke, encephalopathy, or encephalitis [ , , ] . influenza testing is recommended for all patients requiring hospitalization with suspected influenza, including those admitted to the icu during influenza season with acute respiratory illness and community-acquired pneumonia, without a clear alternative diagnosis. furthermore, all individuals requiring critical care outside of influenza season should be tested for influenza if there is a possible epidemiological link to an individual with recent influenza, such as travel to areas with influenza activity or exposure to an institutional influenza outbreak. special consideration should be given to elderly and immunocompromised patients, as influenza virus infection may not present with typical acute respiratory illness signs and symptoms (e.g., absence of fever). the infectious diseases society of america (idsa) influenza clinical practice guidelines also recommend influenza testing for patients at high risk of complications such as exacerbation of chronic cardiopulmonary disease [ ] . diagnosis of influenza should be made as soon as possible in critically ill patients, and initiation of antiviral treatment should not be delayed while awaiting results of diagnostic tests. studies have reported an increase in mortality of icu patients with influenza a(h n )pdm virus infection when diagnosis was delayed [ ] , and shorter hospital length of stay when antiviral treatment was initiated within h of admission [ ] . several kinds of influenza diagnostic tests are available in clinical settings with variable sensitivities and specificities, including antigen detection assays, and molecular assays (nucleic acid detection) using respiratory tract specimens (table ) . within each of these testing categories, there is a wide range of available tests with varying diagnostic accuracy, and understanding the limitations of each diagnostic tool will allow the clinician to properly interpret their results. most studies of influenza diagnostic accuracy have been conducted on specimens from patients with uncomplicated influenza, and few have assessed the performance of influenza tests in critically ill patients. the idsa guidelines recommend molecular influenza assays for testing respiratory specimens from all hospitalized patients with suspected influenza because of their high sensitivity, specificity, and time to results ( min to several hours) [ ] . the use of rapid influenza molecular diagnostic testing can result in better outcomes for patients and reduce the amount of resources required to care for patients in the emergency room [ ] . serology and viral culture are not recommended for clinical decision making, because timely results will not be available to inform clinical management. serology requires collection of appropriately paired acute and convalescent sera performed at specialized public health reference laboratories, and results based upon a single serum specimen are not interpretable [ ] . although viral culture can confirm the presence of infectious virus with very high sensitivity and specificity, it must be performed at public health laboratories and requires - days to yield results. a recent meta-analysis reported that influenza antigen detection tests that produce rapid results had very high specificities (> %), but sensitivities were highly variable compared with rt-pcr [ ] . rapid influenza diagnostic tests (ridts) without an analyzer device had only moderate sensitivity ( - %), ridts that utilize an analyzer device (digital immunoassays) had moderately high sensitivity ( - %), and rapid influenza molecular assays (nucleic acid detection) had high sensitivity ( - %) [ ] . low sensitivity of ridts for detecting influenza virus in icu patients has been reported [ ] . recently, a systematic analysis of rapid influenza molecular tests from studies reported pooled sensitivity and specificity of . % and . %, respectively [ ] . therefore, antigen detection assays, such as rapid influenza diagnostic tests and immunofluorescence assays, are not recommended for hospitalized patients with suspected influenza because of their lower sensitivities, unless molecular assays are not available [ ] . negative results for influenza based on tests with low sensitivity (e.g., ridts, immunofluorescence assays) should not be used to make clinical decisions. instead, negative test results should be followed up with reverse transcription polymerase chain reaction (rt-pcr) or other influenza molecular assays to confirm results, and antiviral treatment should continue until results are available. preferred respiratory specimens for influenza testing in hospitalized patients without lower respiratory tract disease include nasopharyngeal, mid-turbinate nasal, or combined nasal-throat swabs. collection of lower respiratory tract specimens should be considered in hospitalized patients with suspected influenza if upper respiratory tract specimens are negative and a positive test would result in a change of clinical management [ ] , because viral replication in the lower respiratory tract may be ongoing and prolonged after virus is no longer detectable in the upper respiratory tract [ , ] . influenza a(h n )pdm virus in particular has been shown to have affinity for infecting the lower respiratory tract [ , ] . in hospitalized patients receiving invasive mechanical ventilation in whom influenza is suspected, but not yet diagnosed, influenza testing should be performed on endotracheal aspirate specimens instead of those collected from the upper respiratory tract [ ] . molecular testing, including rt-pcr for influenza viruses can also be performed on bronchoalveolar lavage (bal) fluid if collected for the testing of other pathogens. blood, plasma, serum, cerebrospinal fluid, urine, and stool samples have very low diagnostic yield and are not recommended for influenza testing [ ] . diagnostic test results on specimens collected from non-respiratory sites should not be used for clinical decision making even for patients with extra-pulmonary complications of influenza. novel influenza a viruses are typically of animal origin, differ antigenically and genetically from currently circulating seasonal influenza a viruses (including h n pdm and h n subtypes) and have infected at least one person. novel influenza a viruses can cause a wide clinical spectrum of illness, ranging from asymptomatic infection, uncomplicated illness, to fulminant pneumonia, ards, and multi-organ failure [ ] and human infection with a novel influenza a virus is of public health concern. in the u.s., human infection with a novel influenza a virus is nationally reportable to the centers for disease control and prevention; globally, treatment of severe influenza presents multiple challenges. the mainstay of therapy for patients with influenza is initiation of antiviral medication as soon as possible after illness onset [ ] . currently available fdaapproved antiviral medications include neuraminidase inhibitors (nais) (e.g., oral oseltamivir, inhaled zanamivir, and intravenous peramivir); cap-dependent endonuclease inhibitor (baloxavir marboxil); and adamantanes (e.g., amantadine and rimantadine) ( table ). nais and baloxavir have activity against both influenza a and b viruses. adamantanes only have activity against influenza a viruses and are not recommended for treatment of influenza due to widespread resistance among currently circulating strains of seasonal influenza a viruses. notably, fda-approved antiviral medications for treatment of influenza are approved for early treatment of uncomplicated influenza in outpatients based upon randomized placebo-controlled clinical trials conducted among previously healthy outpatients. meta-analyses of randomized placebo-controlled clinical trials of early oseltamivir treatment of influenza in pediatric and adult outpatients have reported clinical benefit in reducing duration of illness and risk for some complications associated with influenza [ , ] . no completed randomized, placebo-controlled trials of antiviral treatment have been conducted in hospitalized influenza patients to establish the efficacy of oseltamivir or other nais. a number of observational studies have reported clinical benefit of neuraminidase inhibitors in hospitalized patients, including reduction in duration of hospitalization and risk of death, including in icu patients [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . additionally, a systematic review of published reviews/meta-analyses reported survival benefit of nai treatment in hospitalized patients [ ] , although another meta-analysis of observational studies did not [ ] . in particular, a large pooled individual patient-level meta-analysis of observational studies from countries identified a % reduction in risk of mortality in critically ill adults and those aged ≥ years old when comparing early nai treatment (< h) with later treatment (> h), and a % reduction in mortality risk between influenza patients receiving early nai treatment and those who did not receive nais [ ] . the mortality risk reduction of nai treatment at any time versus no treatment was % for critically ill patients aged ≥ years old; while a similar reduction in mortality was identified in critically ill children aged < years, the result was not statistically significant [ ] and was likely underpowered because death is less common in hospitalized children with influenza than in adults. although studies have shown the greatest clinical benefit when antivirals are started within days of illness onset, some observational studies have shown clinical benefit of neuraminidase inhibitors when started up to days following symptom onset [ , , , ] . the large metaanalysis mentioned above also identified a significantly reduced mortality risk reduction ( %) in critically ill patients aged ≥ years old who received nai treatment > h after symptom onset compared with those who did not [ ] . a cohort study of early versus late oseltamivir treatment reported a significant reduction in mortality and median duration of icu hospitalization in severely ill patients with influenza a(h n ), but not a(h n pdm ) or b virus infection in greece [ ] . one french study reported delays in initiation of oseltamivir treatment prescribed to hospitalized influenza patients and suggested empiric administration of oseltamivir treatment in the emergency department for patients being admitted with lower respiratory tract disease during influenza season [ ] . overall, based upon available observational data to date in hospitalized patients with influenza, including icu patients, initiation of neuraminidase inhibitor antiviral treatment is recommended as soon as possible for hospitalized patients with suspected or confirmed influenza. data on optimal dosing and duration of therapy with neuraminidase inhibitors are limited in critically ill influenza patients. enterically administered oseltamivir is the preferred treatment for most hospitalized patients, given the lack of data for intravenous peramivir in this population. the use of inhaled zanamivir is not recommended in in critically ill patients due to the lack of data in hospitalized patients and the risk of bronchospasm in patients with underlying lung disease. studies indicate that oseltamivir administered orally or via oro/naso-gastric tube is well absorbed in critically ill patients and reaches plasma levels comparable to those in ambulatory patients [ ] . similarly, several observational studies indicate that enteric oseltamivir reaches comparable plasma concentrations to non-critically ill patients in those receiving extracorporeal membrane oxygenation (ecmo) and renal replacement therapy [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , although dosing should be reduced in patients with significant renal impairment. there is scant evidence that increased nai dosing (e.g., twice daily dosing) in critically ill patients provides additional clinical benefit than standard dosing [ , [ ] [ ] [ ] [ ] [ ] . of note, studies also suggest that increased oseltamivir dosing does not provide additional clinical benefit in obese adults, including extreme obesity (bmi > ) [ , ] . duration of therapy can be difficult to define, as prolonged influenza viral replication and shedding from the both upper and lower respiratory tract can occur in critically ill patients [ , ] . for this reason, it may be beneficial to continue antiviral therapy beyond days, and repeat virologic testing may be beneficial in determining appropriate therapeutic endpoints [ ] . continuing antiviral treatment in critically ill patients until virus is not detectable in the lower respiratory tract may also help reduce the pro-inflammatory dysregulated cytokine response triggered by influenza virus infection and reduce nosocomial influenza virus transmission to healthcare personnel in the icu. consultation with a specialist with training in infectious diseases for the potential emergence of antiviral resistant virus infection should be considered for icu patients with evidence of persistent influenza viral replication after nai treatment, particularly in severely immunocompromised patients [ , ] . for patients who cannot tolerate or absorb enteric oseltamivir due to gastric stasis, malabsorption, or other gastrointestinal processes, intravenous peramivir may be an alternative [ , ] ; however, studies have not identified an advantage for intravenous peramivir in comparison with enteric oseltamivir [ ] . notably, a randomized trial conducted in three influenza seasons found similar clinical outcomes between iv peramivir and enteric oseltamivir in hospitalized adult influenza patients [ ] ; a separate trial did not identify significant additional clinical benefit of peramivir in combination with standard-of-care therapy (which often included an nai) [ ] . a more recent, multicenter randomized controlled trial also found similar clinical benefit between enteric oseltamivir and intravenous peramivir in hospitalized influenza patients [ ] . in , a novel antiviral agent, baloxavir marboxil, was fda-approved for early treatment of uncomplicated influenza in outpatients aged ≥ years old. baloxavir acts via inhibition of the influenza virus cap-dependent endonuclease, a different mechanism than the neuraminidase inhibitors, and can treat nai-resistant influenza virus infections. randomized controlled trials of single-dose oral baloxavir showed similar clinical benefit to days of twice-daily oral oseltamivir [ ] . however, because these studies were limited to patients with uncomplicated influenza, the role of baloxavir monotherapy or in combination with an nai for treatment of hospitalized influenza patients is unclear. specifically, optimal dosing, duration of therapy, and appropriate endpoints have yet to be determined for baloxavir treatment of hospitalized influenza patients. in the outpatient rct, patients treated with single-dose baloxavir showed significant reduction in influenza viral levels in the upper respiratory tract at h compared with those receiving placebo or oral oseltamivir [ ] . however, it is unknown whether this reduction in influenza viral shedding correlates with reduced transmissibility. a potential concern for the use of baloxavir in critically ill patients is the rapid development of resistance observed during the outpatient clinical trials [ ] . a trial to assess the efficacy and safety of baloxavir in combination with oseltamivir versus oseltamivir monotherapy in hospitalized influenza patients is currently enrolling participants [ ] . there are no completed randomized clinical trials of adjunctive corticosteroid treatment in influenza patients. a trial of corticosteroid therapy was planned during the h n pandemic, but was halted due to limited number of enrolees [ ] . one observational study in china during the h n pandemic reported that administration of parenteral glucocorticoids within h of illness onset tripled the risk of developing critical illness or death from influenza a(h n )pdm virus infection [ ] . a re-analysis of prospectively collected data on influenza patients admitted with primary influenza pneumonia to icus in spain during - using propensity scoring matching reported that corticosteroid use was significantly associated with icu mortality [ ] . meta-analyses of observational studies have concluded that that corticosteroid treatment of hospitalized influenza patients does not result in better outcomes and may be associated with adverse outcomes including increased mortality [ ] [ ] [ ] . similarly, a retrospective observational study conducted on critically ill children during the h n pandemic found that high-dose (equivalent to mg/kg per day of methylprednisolone) corticosteroid treatment was associated with mortality in the icu, although a causative relationship was not determined [ ] . a selection of individual observational studies in critically ill children and adults have also reported potential association between corticosteroid treatment and adverse influenza outcomes [ , , ] . a recent cochrane review of available observational studies suggested increased mortality when adjunctive corticosteroid therapy is used for influenza patients; however, the available evidence was of low quality and the authors suggest interpreting these results with caution [ ] . multiple studies have reported that corticosteroid treatment is associated with prolonged influenza viral shedding in hospitalized patients [ ] [ ] [ ] , including in sporadic human infections with avian influenza a(h n ) virus in china [ ] , and increased rates of secondary bacterial and fungal co-infections [ , ] , which may lead to adverse clinical outcomes. however, there is some evidence to suggest that the increased risk attributed to corticosteroid treatment is a result of bias in observational studies. a large, retrospective study of critically ill adults in canada found an increased risk of mortality in patients receiving corticosteroids; however, after adjusting for time-dependent differences between groups, no significant differences in mortality were observed with corticosteroid treatment [ ] . moreover, potential differences between low-dose and medium-/ high-dose corticosteroid treatment are not well understood. one observational study of hospitalized patients with viral pneumonia due to avian influenza a(h n ) virus infection in china reported that high-dose, but not low or moderate-dose corticosteroids, was associated with increased -day and -day mortality [ ] . currently, on the basis of available observational data to date, adjunctive corticosteroid treatment is not recommended for children or adults hospitalized with influenza, including critically ill patients, unless clinically indicated for another reason, such as treatment of asthma or copd exacerbation or septic shock [ ] . further studies are required to understand the clinical benefit or harms associated with corticosteroid treatment of critically ill influenza patients. although neuraminidase inhibitors (oseltamivir) are currently recommended for antiviral treatment of influenza in hospitalized patients based on observational studies, including in critically ill patients, there are a number of novel strategies and products for treating influenza in various stages of development. one approach under investigation is triple-combination antiviral drug (tcad) therapy, which combines amantadine, ribavirin, and oseltamivir for treatment of influenza in critically ill and high-risk patients. unfortunately, studies to date have not shown a benefit of tcad over oseltamivir monotherapy [ ] [ ] [ ] . several novel antiviral compounds are in various stages of investigation, including small-molecule polymerase inhibitors such as pimodivir [ ] and favipiravir [ ] . a number of monoclonal and polyclonal antibodies, targeted against a variety of influenza viral proteins, are also in development [ ] [ ] [ ] [ ] . similarly, convalescent plasma has shown potential benefit in the treatment of severe influenza, and further trials are underway [ ] [ ] [ ] . another area of intense interest is the modification of the host antiviral response to influenza virus infection. there are ongoing preclinical and clinical studies of a variety of other immunomodulatory agents for treatment of influenza, including celecoxib [ ] , statins, etanercept, pioglitazone, azithromycin [ ] , and interferons [ ] . influenza vaccination can reduce the risk of complications from influenza, including reducing illness severity and the risks of hospitalization, icu admission, and death. the elderly, young children, pregnant women, and those with underlying medical conditions are most at risk for severe complications of influenza. a diagnosis of influenza should be considered in critically ill patients admitted with complications such as exacerbation of underlying chronic comorbidities, community-acquired pneumonia, and respiratory failure during influenza season. influenza molecular assays are recommended for testing upper respiratory tract specimens in patients without signs of lower respiratory tract disease. however, because critically ill patients with lower respiratory tract disease may have cleared influenza virus in the upper respiratory tract, but have prolonged influenza viral replication in the lower respiratory tract, an endotracheal aspirate (preferentially) or bronchoalveolar lavage fluid specimen (if collected for other diagnostic purposes) should be tested by molecular assay. antiviral treatment with standard-dose oseltamivir delivered orally or enterally by oro or naso-gastric tube is recommended as soon as possible for patients with suspected influenza without waiting for testing results. corticosteroids should not be routinely administered for treatment of influenza and should only be given for other indications (e.g., exacerbation of asthma or chronic obstructive pulmonary disease, or septic shock), because of the risk for prolongation of influenza viral shedding and ventilator-associated pneumonia in critically ill influenza patients with respiratory failure. future directions for treatment of influenza in critically ill patients include novel antiviral compounds, combination antiviral treatment with drugs with different mechanisms of action, immunomodulatory agents, and strategies for multimodality, combination antiviral, and host-directed immunomodulatory therapies. endnotes these risk factors are included in the u.s. cdc's advisory committee on immunization practices recommendations for influenza vaccination. this may also apply to indigenous people from other countries, including indigenous australians and first nations people. burden of medically attended influenza infection and cases averted by vaccination -united states, / through / influenza seasons estimates of global seasonal influenza-associated respiratory mortality: a modelling study estimated influenza illnesses, medical visits, hospitalizations, and deaths averted by vaccination in the united states influenza seasonality in the tropics and subtropics -when to vaccinate? burden of influenza in ecologically distinct regions of peru: household active surveillance of a community cohort dynamics of influenza in tropical africa: temperature, humidity, and co-circulating (sub)types. influenza other respir viruses seasonal incidence of symptomatic influenza in the united states estimating influenza disease burden from population-based surveillance data in the united states prevention and control of seasonal influenza with vaccines: recommendations of the advisory committee on immunization practices-united states excess pneumonia and influenza associated hospitalization during influenza epidemics in the united states, - impact of epidemic type a influenza in a defined adult population the burden of influenza in young children the underrecognized burden of influenza in young children pandemic influenza a(h n ) virus illness among pregnant women in the united states pregnancy as a risk factor for severe outcomes from influenza virus infection: a systematic review and meta-analysis of observational studies severe h n influenza in pregnant and postpartum women in california pandemic influenza a (h n ) virus infection in postpartum women in california influenza-associated pediatric deaths in the united states neurologic disorders among pediatric deaths associated with the pandemic influenza influenza-and rsv-associated hospitalizations among adults populations at risk for severe or complicated influenza illness: systematic review and meta-analysis risk factors for severe outcomes following influenza a (h n ) infection: a global pooled analysis intensive care adult patients with severe respiratory failure caused by influenza a (h n )v in spain critical illness from pandemic influenza a virus and bacterial coinfection in the united states critical care services and h n influenza in australia and new zealand critically ill patients with influenza a(h n ) in mexico critically ill patients with influenza a(h n ) infection in canada seasonal influenza a h n pdm virus and severe outcomes: a reason for broader vaccination in non-elderly. at-risk people plos one critically ill children during the - influenza pandemic in the united states pandemic influenza a (h n ): pathology and pathogenesis of fatal cases in the united states influenza virus and factors that are associated with icu admission, pulmonary co-infections and icu mortality smoking may increase the risk of hospitalization due to influenza clinical characteristics, evolution, and treatment-related risk factors for mortality among immunosuppressed patients with influenza a (h n ) virus admitted to the intensive care unit complications among adults hospitalized with influenza: a comparison of seasonal influenza and the h n pandemic influenza-associated intensive-care unit admissions and deaths -california patients hospitalized with laboratoryconfirmed influenza during the - influenza season: exploring disease severity by virus type and subtype influenza b hospitalizations are associated with mortality in children effect of influenza vaccination on the prognosis of hospitalized influenza patients influenza vaccination modifies disease severity among community-dwelling adults hospitalized with influenza does influenza vaccination modify influenza severity? data on older adults hospitalized with influenza during the - season in the united states influenza vaccine effectiveness in preventing outpatient, inpatient, and severe cases of laboratory-confirmed influenza influenza vaccine effectiveness in preventing influenza-associated intensive care admissions and attenuating severe disease among adults in new zealand the working group on surveillance of severe influenza hospitalized cases in catalonia. influenza vaccine effectiveness in reducing severe outcomes over six influenza seasons, a case-case analysis, spain, / to / high intensive care unit admission rate for - influenza is associated with a low rate of vaccination epidemiological features of influenza in canadian adult intensive care unit patients effectiveness of influenza vaccine against life-threatening rt-pcr-confirmed influenza illness in us children influenza vaccine effectiveness against pediatric deaths clinical practice guidelines by the infectious diseases society of america: update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenzaa viruses are frequently present as the infecting agent in acute exacerbations of chronic obstructive pulmonary disease in patients presenting to hospital infection in severe asthma exacerbations and critical asthma syndrome effect of influenza on outcomes in patients with heart failure the hidden burden of influenza: a review of the extra-pulmonary complications of influenza infection. influenza other respir viruses delay in diagnosis of influenza a (h n )pdm virus infection in critically ill patients and impact on clinical outcome early oseltamivir after hospital admission is associated with shortened hospitalization: a five-year analysis of oseltamivir timing and clinical outcomes the impact of rapid molecular diagnostic testing for respiratory viruses on outcomes for emergency department patients diagnostic accuracy of novel and traditional rapid tests for influenza infection compared with reverse transcriptase polymerase chain reaction: a systematic review and meta-analysis rapid-test sensitivity for novel swine-origin influenza a (h n ) virus in humans rapid molecular tests for influenza, respiratory syncytial virus, and other respiratory viruses: a systematic review of diagnostic accuracy and clinical impact studies rt-pcr, and other molecular assays for diagnosis of influenza virus infection novel influenza a viruses and pandemic threats centers for disease control and prevention. influenza antiviral medications: summary for clinicians oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials efficacy and safety of oseltamivir in children: systematic review and individual patient data meta-analysis of randomized controlled trials benefit of early treatment with oseltamivir in hospitalized patients with documented influenza a (h n ): retrospective cohort study oseltamivir shortens hospital stays of critically ill children hospitalized with seasonal influenza: a retrospective cohort study antivirals for treatment of influenza: a systematic review and meta-analysis of observational studies neuraminidase inhibitors for critically ill children with influenza impact of neuraminidase inhibitor treatment on outcomes of public health importance during the - influenza a(h n ) pandemic: a systematic review and meta-analysis in hospitalized patients effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza a h n pdm virus infection: a meta-analysis of individual participant data effectiveness of antiviral treatment in preventing death in severe hospitalised influenza cases over six seasons impact of early oseltamivir treatment on outcome in critically ill patients with pandemic influenza a safety and effectiveness of neuraminidase inhibitors for influenza treatment, prophylaxis, and outbreak control: a systematic review of systematic reviews and/or meta-analyses outcomes of adults hospitalised with severe influenza treatment with neuraminidase inhibitors for critically ill patients with influenza a (h n )pdm effect of early oseltamivir treatment on mortality in critically ill patients with different types of influenza: a multi-season cohort study analysis of delays in the prescription of oseltamivir in hospitals and potential for improvement enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (h n ) influenza pharmacokinetics of oseltamivir and oseltamivir carboxylate in critically ill patients receiving continuous venovenous hemodialysis and/or extracorporeal membrane oxygenation the pharmacokinetics of oseltamivir and oseltamivir carboxylate in a critically ill pediatric patient receiving extracorporeal membrane oxygenation and continuous venovenous hemodialysis high levels and safety of oseltamivir carboxylate plasma concentrations after nasogastric administration in critically ill children in a pediatric intensive care unit pharmacokinetics of oseltamivir carboxylate in critically ill patients: each patient is unique impact of extracorporeal membrane oxygenation and continuous venovenous hemodiafiltration on the pharmacokinetics of oseltamivir carboxylate in critically ill patients with pandemic (h n ) influenza oseltamivir pharmacokinetics in critically ill adults receiving extracorporeal membrane oxygenation support pharmacokinetic changes of antibiotic, antiviral, antituberculosis and antifungal agents during extracorporeal membrane oxygenation in critically ill adult patients a prospective intervention study on higher-dose oseltamivir treatment in adults hospitalized with influenza a and b infections comparison of highdose versus standard dose oseltamivir in critically ill patients with influenza oseltamivir dosing in critically ill patients with severe influenza effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial a randomized study of standard versus double dose oseltamivir for treating influenza in the community oseltamivir and oseltamivir carboxylate pharmacokinetics in obese adults: dose modification for weight is not necessary oseltamivir pharmacokinetics in morbid obesity (optimo trial) delayed clearance of viral load and marked cytokine activation in severe cases of pandemic h n influenza virus infection viral clearance and inflammatory response patterns in adults hospitalized for pandemic influenza a(h n ) virus pneumonia end points for testing influenza antiviral treatments for patients at high risk of severe and life-threatening disease neuraminidase inhibitor resistance in influenza: a clinical perspective single dose peramivir for the treatment of acute seasonal influenza: integrated analysis of efficacy and safety from two placebo-controlled trials intravenous peramivir for treatment of influenza in hospitalized patients comparison of efficacy of intravenous peramivir and oral oseltamivir for the treatment of influenza: systematic review and meta-analysis a clinical trial of intravenous peramivir compared with oral oseltamivir for the treatment of seasonal influenza in hospitalized adults evaluation of intravenous peramivir for treatment of influenza in hospitalized patients efficacy and safety of intravenous peramivir compared with oseltamivir in high-risk patients infected with influenza a and b viruses: a multicenter randomized controlled study baloxavir marboxil for uncomplicated influenza in adults and adolescents characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil a phase iii, randomized, double-blind placebo-controlled, multicenter study to evaluate the efficacy and safety of baloxavir marboxil in combination with standard-of-care neuraminidase inhibitor in hospitalized participants with severe influenza designing and conducting a randomized trial for pandemic critical illness: the h n influenza pandemic early use of glucocorticoids was a risk factor for critical disease and death from ph n infection corticosteroid treatment in critically ill patients with severe influenza pneumonia: a propensity score matching study effect of corticosteroid therapy on influenza-related mortality: a systematic review and meta-analysis corticosteroids for the treatment of human infection with influenza virus: a systematic review and meta-analysis the effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis early corticosteroids in severe influenza a/h n pneumonia and acute respiratory distress syndrome corticosteroid treatment in critically ill patients with pandemic influenza a/h n infection: analytic strategy using propensity scores corticosteroids as adjunctive therapy in the treatment of influenza antiviral treatment for patients hospitalized with severe influenza infection may affect clinical outcomes prolonged viral shedding in pandemic influenza a(h n ): clinical significance and viral load analysis in hospitalized patients viral loads and duration of viral shedding in adult patients hospitalized with influenza factors associated with prolonged viral shedding in patients with avian influenza a(h n ) virus infection neuraminidase inhibitors, superinfection and corticosteroids affect survival of influenza patients use of early corticosteroid therapy on icu admission in patients affected by severe pandemic (h n )v influenza a infection the influence of corticosteroid treatment on the outcome of influenza a(h n pdm )-related critical illness adjuvant corticosteroid treatment in adults with influenza a (h n ) viral pneumonia oseltamivir, amantadine, and ribavirin combination antiviral therapy versus oseltamivir monotherapy for the treatment of influenza: a multicentre, double-blind, randomised phase trial combination therapy with amantadine, oseltamivir and ribavirin for influenza a infection: safety and pharmacokinetics triple-combination antiviral drug for pandemic h n influenza virus infection in critically ill patients on mechanical ventilation phase b study of pimodivir (jnj- ) as monotherapy or in combination with oseltamivir for treatment of acute uncomplicated seasonal influenza a: topaz trial phase efficacy and safety study of favipiravir for treatment of uncomplicated influenza in adults -t us bethesda: national library of medicine study to evaluate the efficacy and safety of intravenous vis in aaddition to oseltamivir (tamiflu®) compared with oseltamivir alone in hospitalized adults with influenza a infection requiring oxygen support a study of mhaa a in combination with oseltamivir versus oseltamivir in participants with severe influenza a infection efficacy and safety of treatment with an anti-m e monoclonal antibody in experimental human influenza polyclonal and monoclonal antibodies for the treatment of influenza immune plasma for the treatment of severe influenza: an open-label, multicentre, phase randomised study convalescent plasma treatment reduced mortality in patients with severe pandemic influenza a (h n ) virus infection hyperimmune iv immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe influenza a(h n ) infection a randomized controlled trial on the treatment of severe influenza a infection anti-inflammatory effects of adjunctive macrolide treatment in adults hospitalized with influenza: a randomized controlled trial the role of adjuvant immunomodulatory agents for treatment of severe influenza not applicable. no external funding was received. the authors were supported by their work at the centers for disease control and prevention (cdc). not applicable. the findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the centers for disease control and prevention. key: cord- - kw v rm authors: vuillard, constance; pineton de chambrun, marc; de prost, nicolas; guérin, claude; schmidt, matthieu; dargent, auguste; quenot, jean-pierre; préau, sébastien; ledoux, geoffrey; neuville, mathilde; voiriot, guillaume; fartoukh, muriel; coudroy, rémi; dumas, guillaume; maury, eric; terzi, nicolas; tandjaoui-lambiotte, yacine; schneider, francis; grall, maximilien; guérot, emmanuel; larcher, romaric; ricome, sylvie; le mao, raphaël; colin, gwenhaël; guitton, christophe; zafrani, lara; morawiec, elise; dubert, marie; pajot, olivier; mentec, hervé; plantefève, gaëtan; contou, damien title: clinical features and outcome of patients with acute respiratory failure revealing anti-synthetase or anti-mda- dermato-pulmonary syndrome: a french multicenter retrospective study date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: kw v rm background: anti-synthetase (as) and dermato-pulmonary associated with anti-mda- antibodies (amda- ) syndromes are near one of the other autoimmune inflammatory myopathies potentially responsible for severe acute interstitial lung disease. we undertook a -year retrospective multicenter study in french icus in order to describe the clinical presentation and the outcome of patients admitted to the icu for acute respiratory failure (arf) revealing as or amda- syndromes. results: from to , patients ( males; median age [ st– rd quartiles – ] years, no comorbidity %) were admitted to the icu for arf revealing as (n = , %) or amda- (n = , %) syndromes. muscular, articular and cutaneous manifestations occurred in patients ( %), ( %) and ( %) patients, respectively. seventeen of them ( %) had no extra-pulmonary manifestations. c-reactive protein was increased ( [ – ] mg/l), whereas procalcitonine was not ( . [ . – . ] ng/ml). proportion of patients with creatine kinase ≥ n was % (n = / ). forty-two patients ( %) had ards, which was severe in %, with a rate of % (n = / ) of extra-corporeal membrane oxygenation requirement. proportion of patients who received corticosteroids, cyclophosphamide, rituximab, intravenous immunoglobulins and plasma exchange were %, %, %, % and %, respectively. icu and hospital mortality rates were % (n = / ) and % (n = / ), respectively. patients with amda- dermato-pulmonary syndrome had a higher hospital mortality than those with as syndrome (n = / , % vs. n = / , %; p = . ). conclusions: intensivists should consider inflammatory myopathies as a cause of arf of unknown origin. extra-pulmonary manifestations are commonly lacking. mortality is high, especially in amda- dermato-pulmonary syndrome. identifying the cause of acute respiratory distress syndrome (ards) is a crucial step for initiating a targeted treatment and improving prognosis [ , ] . however, two recent studies [ , ] showed that % of patients with ards according to the berlin criteria [ ] lacked exposure to "common" risk factors (e.g., pneumonia, acute pancreatitis, aspiration of gastric content or extra-pulmonary sepsis) with no etiology eventually retrieved in % of them [ ] . for such atypical ards, a comprehensive diagnostic work-up, including specific immunologic tests, is recommended [ ] so that to identify immune causes, typically amenable to specific therapeutic interventions (e.g., corticosteroids). yet, an ancillary analysis [ ] of an international, multicenter, prospective cohort study [ ] reported that such immunological examinations were performed in only % of ards without common risk factors. anti-synthetase (as) and anti-melanoma differentiation-associated gene (amda- ) syndromes are near one of the other autoimmune inflammatory myopathies [ ] potentially responsible for rapidly progressive interstitial lung disease leading to acute respiratory failure and ards [ ] [ ] [ ] [ ] . as and amda- dermatopulmonary syndromes may be clinically indistinguishable one from another, with almost three-quarter of patients with amda- dermato-pulmonary syndrome exhibiting the clinical attributes of the as syndrome [ ] . when arf is the initial presentation of as or amda- syndromes [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] or when extra-respiratory manifestations, such as muscular, cutaneous or articular signs are lacking [ , [ ] [ ] [ ] [ ] [ ] , the diagnosis is challenging, especially in the intensive care unit (icu) setting, where many other reasons of acute respiratory failure (arf) can be discussed. to the best of knowledge, a number of case reports of arf revealing autoimmune inflammatory myopathies have been previously reported, but an extended case series has not been published as yet. therefore, we undertook this retrospective study in order to: ( ) describe the clinical features and the outcome of patients admitted to the icu for arf revealing either an as or an amda- dermato-pulmonary syndrome, and; ( ) identify predictive factors of hospital mortality. we conducted a -year multicenter retrospective noninterventional study in icus in france from january , , to december , . all patients older than years were included if they met the following criteria: ( ) admitted to the icu for arf not related to cardiogenic pulmonary edema; ( ) no common ards risk factor, among pneumonia, acute pancreatitis, aspiration of gastric content, extra-pulmonary sepsis, multiple transfusions, major trauma, pulmonary vasculitis, drowning, severe burns, identified according to the berlin definition [ ] ; ( ) immunologic test performed during icu stay, which was positive for anti-synthetase (jo- , pl , pl , oj, ej, ks, zo, yrs/tyr/ha) or anti-mda- autoantibodies; and ( ) no alternative diagnosis for arf. it is worth notifying that in the present study the diagnosis of as or amda- dermato-pulmonary syndromes had to be made during the icu stay. therefore, those who had a diagnosis of as or amda- made before icu admission were not included. the investigator of each participating center was responsible for the identification of the patients, either from the hospital medical reports, using the function "research the files in which the key words mda- or antisynthetase or myositis occurs" of microsoft windows ® , or through a search using the international classification of diseases ( th revision) following codes: m (autoimmune myositis), m (myositis), m (polymyositis) and m (dermatomyositis). the clinical charts of all identified patients were anonymized before sending to the main investigators (dc and cv). clinical charts were reviewed in order to check the inclusion criteria. the following data were collected on a standardized anonymized case record form: demographic characteristics (age, gender), severity scores upon icu admission (sequential organ failure assessment [ ] and simplified acute physiology score ii [ ] ), main comorbidities, delay between first respiratory sign and icu admission, clinical examination (respiratory and extra-respiratory manifestations) and laboratory findings at the time of icu admission (blood leukocytes and platelets counts, serum procalcitonine, c-reactive protein, creatine kinase and creatinine levels, pao /fio with fio calculated according to the following formula [ , ] : fio = oxygen flow in liter per minute × . + . when standard oxygen was used), radiological findings on chest x-ray and ct scan, cytological and bacteriological analyses of broncho-alveolar lavage (bal) fluid, type of positive autoantibodies (jo- , pl , pl , oj, ej, ks, zo, yrs/tyr/ ha or amda- ), immunosuppressive treatments received (corticosteroids, cyclophosphamide, rituximab, basiliximab, tacrolimus, cyclosporine, methotrexate, intravenous immunoglobulins or plasma exchange), organ supports in the icu (invasive mechanical ventilation, extra-corporeal membrane oxygenation (ecmo), renal replacement therapy, vasopressors), icu and hospital length of stay, icu and hospital mortality. written reports of chest ct scan performed at the time of icu admission were sent to the main investigators (dc and cv) in order to individualize elementary lesions (ground-glass attenuation, alveolar consolidation, septal thickening, pleural effusion, pneumothorax, pneumomediastinum and mediastinal lymphadenopathy) and their location (lower or upper lobe predominance). signs of lung fibrosis (honeycombing, traction bronchiectasis and reticulations) were also collected. cytological analyses of bal fluid collected at the time of icu admission were reported, as well as results of open lung, skin or muscle biopsies, if performed. continuous variables are reported as median [ st- rd quartiles] and compared by the mann-whitney u test. categorical variables are reported as counts and percentage points in groups and compared by using the fisher's exact test. survival curves of patients with amda- and as syndromes were drawn using the kaplan-meier method and compared using the log-rank test. all tests were two-sided, with p < . indicating statistical significance. the statistical analysis was performed by using the rstudio software version . . (www.rstud io.com). from january , , to december , , patients fulfilled the inclusion criteria, including ( %) with as syndrome (jo- n = / ( %); pl n = / ( %); pl n = / ( %); ej n = / ( %)) and ( %) with amda- dermato-pulmonary syndrome. all the patients with amda- dermato-pulmonary syndrome were admitted after january , . demographical characteristics, main comorbidities and clinical manifestations are given in table . most of the patients had no comorbidity (n = / , %). median sapsii and sofa scores at the time of icu admission were and [ ] [ ] [ ] [ ] [ ] [ ] , respectively. the median delay between first respiratory sign and icu admission was days. most of the patients had central temperature > °c (n = / , %). myalgia, arthralgia/arthritis and cutaneous manifestations occurred in % (n = / ), % (n = / ) and % (n = / ) of patients, respectively. about one-third of patients (n = / , %) had no extra-pulmonary manifestation, in a similar proportion in amda- and as groups. biological data at the time of icu admission and radiological findings are reported in table . c-reactive protein levels (n < mg/l) were increased ( mg/l), while procalcitonine levels (n < . ng/ml) were not ( . [ . - . ] ng/ml). the rate of patients having creatine kinase plasma levels greater than times the upper limit of normal laboratory range was % (n = / ) in the whole population, and only % (n = / ) in the as group. the median pao /fio ratio at icu admission was [ - ] mmhg. most patients (n = / , %) had bilateral condensations on chest x-ray, with a predominantly lower location (n = / , %) ( table ). all patients underwent a lung ct scan, which showed ground-glass attenuation in % (n = / ) and alveolar condensation in % (n = / ). signs of lung fibrosis were observed in % (n = / ), while % (n = / ) had mediastinal lymphadenopathies. bal fluid analyses were available in % (n = / ) of patients and are summarized in table . the cell count was [ - ] × /ml, and percentages of lymphocytes, neutrophils and macrophages were % , % and % , respectively. bal was performed before antibiotic therapy in only / ( %) patients and was negative for lung infection in every patient. there was no correlation between bal findings and elementary lesions observed on chest ct scan. in particular, the proportion of patients with > % bal neutrophils did not differ between patients with or without elementary lesions of lung fibrosis on chest ct scan (n = / , % vs. n = / , %, p = . ). an open lung biopsy was performed in ( %) patients and depicted findings consistent with organizing pneumonia (n = ), usual interstitial pneumonitis (n = ) and diffuse alveolar damage (n = ) ( table ). a total of patients ( %) had a muscle (n = ) or a skin (n = ) biopsy performed during the icu stay. all muscle biopsies revealed findings consistent with an inflammatory myositis, while skin biopsies were either normal (n = ) or revealed findings consistent with lichenoid dermatitis (n = ) or with dermatomyositis (n = ) ( table ) . most patients (n = / , %) received an antimicrobial therapy upon icu admission (table ). all patients received steroids, after a median delay of [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days following the icu admission. other immunosuppressive treatments administered are reported in table . almost all patients (n = / , %) had ards, categorized as severe (pao /fio ≤ mmhg with peep ≥ mmh o) in % (n = / ), with % (n = / ) of them requiring ecmo. icu and hospital mortality rates were % (n = / ) and % (n = / ), respectively. patients with amda- dermato-pulmonary syndrome had a higher icu mortality than those with as syndrome (n = / , % vs. n = / , %; p < . ). among the icu survivors, ( %) were diagnosed with a cancer (colorectal n = , pharyngeal n = , melanoma n = ) during the [ - ] days post-icu stay follow-up. compared to patients who survived at the hospital discharge, those who died were more likely to have an amda- autoantibody (n = / , % vs. n = / , %; p = . ), had a higher rate of ground-glass attenuation table demographical and clinical manifestations of patients with acute respiratory failure revealing anti-synthetase syndrome or dermato-pulmonary syndrome associated with anti-mda- antibodies amda- anti-mda- antibodies, as anti-synthetase, arf acute respiratory failure, hiv human immunodeficiency virus, icu intensive care unit, iqr inter-quartile range, saps simplified acute physiology score, sofa sepsis-related organ failure assessment chronic respiratory failure ( ) ( ) ( ) . congestive heart failure ( ) ( ) ( ) . chronic kidney failure active solid cancer or malignant hemopathy ( ) ( ) ( ) . table ). after adjustment on syndrome (anti-synthetase or amda- dermato-pulmonary syndrome), the presence of ground-glass attenuations on chest ct scan was no longer associated with in-hospital mortality (p = . ). the kaplan-meier graph showed a lower probability of survival days after icu admission in patients with amda- antibody than in patients with as antibody (fig. ; p < . log-rank test). we are herein reporting the first large cohort of patients admitted to icu for arf revealing either as or amda- dermato-pulmonary syndrome. the main findings are: ( ) clinical manifestations may be nonspecific with the absence of extra-pulmonary manifestations of inflammatory myositis in one-third of patients; ( ) hypoxemia is severe with a high rate of severe ards and rescue maneuvers; and ( ) hospital mortality is high, especially in dermato-pulmonary syndrome associated with amda- autoantibodies. as and amda- -associated dermato-pulmonary syndromes are two near each of the other inflammatory myopathies that may be responsible for severe acute interstitial lung diseases [ ] [ ] [ ] . the diagnosis is easy to consider when extra-pulmonary manifestations are present. in as syndrome, the main extra-pulmonary manifestations include myositis with elevated creatine kinase levels, non-erosive arthritis, raynaud's phenomenon and thick cracked skin over the tips and sides of the fingers called "mechanic's hands" [ ] [ ] [ ] [ ] [ ] [ ] . however, there is a wide heterogeneity in clinical manifestations depending on the causative as autoantibody [ , ] . in amda- -associated dermato-pulmonary syndrome, the cutaneous manifestations (skin ulcerations or necrosis, facial erythema, mechanic's hands, periungual telangiectasia, gottron's papules, raynaud's phenomenon) are in the forefront [ , , ] and usually contrast with the absence of clinical signs of myositis (clinically "amyopathic myositis"). demographical and clinical findings in our patients were in line with those recently reported in non-icu patients with as [ , , ] or with amda- dermato-pulmonary syndromes [ ] . both in as and amda- dermato-pulmonary syndromes, extra-pulmonary manifestations may be lacking [ , ] rendering the diagnosis difficult to make. in our series, more than one-third of patients had no extra-pulmonary manifestations with a similar proportion in as and amda- patients. this rate contrasts with the % rate recently reported [ ] in patients with amda- dermato-pulmonary syndrome, reflecting the lack of training of intensivists for the clinical assessment of these patients and highlighting the need for a multidisciplinary approach. considering the high proportion of patients lacking extra-pulmonary manifestations, the clinical presentation may mimic that of a "bilateral pneumonia without microbiological documentation. " hence, % of our patients received antibiotic therapy at icu admission. the presence of an intense inflammatory syndrome with increased c-reactive protein levels contrasting with the lack of elevation of serum procalcitonine could help intensivists appreciating the probability of an infectious process, this dissociation being highly suggestive of a non-infectious inflammatory process. in our series, bal was performed in % of patients. unlike a recent work [ ] showing that a lymphocytic bal fluid was associated with better icu survival in ards patients with no common risk factor, our study failed to identify any predictive role of bal cytology on hospital survival. bal fluid analysis does not seem a useful diagnostic tool for as or amda- dermato-pulmonary syndromes, but should nevertheless be performed to rule out an alternative diagnosis, such as diffuse alveolar hemorrhage or active infection. all included patients underwent chest ct scan. interestingly, ct chest findings predominate in the lower lobes, which is consistent with a previous report [ ] . ct scan signs of lung fibrosis have been recently shown to be associated with a poor outcome in patients with arf related to interstitial lung diseases [ ] . in our study, ct scan signs of lung fibrosis were not associated with hospital mortality, probably because of a lack of adequate power. while ground-glass opacities are usually considered as potentially reversible lung lesions during idiopathic pulmonary fibrosis [ , ] , these lesions were associated with in-hospital mortality in our study, probably because they were more frequently observed during amda- dermato-pulmonary syndromes. indeed, this association was no longer observed after adjustment on the type of positive antibody (anti-synthetase or amda- ). our series underlines the severity of as and amda- dermato-pulmonary syndrome, since % of patients fulfilled the berlin criteria for ards [ ] , categorized as severe (pao /fio ≤ mmhg with peep ≥ mmh o) in % of cases. anti-mda- dermato-pulmonary syndromes exhibited a significantly higher mortality than as syndromes, with almost all these patients dying in the icu of refractory ards despite a high rate of ecmo ( %). moreover, amda- patients had a much higher mortality than those with severe ards included in the lung safe study [ ] , highlighting the irreversibility of lung lesions despite immunosuppressive treatments. these results are in line with previous series, showing that refractory ards is the leading cause of mortality in amda- patients [ ] . whether our patients had a true ards (i.e., presence of diffuse alveolar damage (dad), the histological hallmark of ards) or simply fulfilled the berlin criteria while having a non-dad histology is unknown. in fact, the berlin definition of ards is not fully reliable for diagnosing dad, and several non-dad histological entities (such as lung fibrosis, organizing pneumonia, diffuse alveolar hemorrhage or lung tumoral infiltration) have been reported in patients fulfilling the clinical and radiological criteria for ards [ , [ ] [ ] [ ] . regarding the onset of lung injury, the berlin definition of ards stipulates that "respiratory signs should occur (or worsen) within days after an exposure to a common ards risk factor" (e.g., pneumonia, acute pancreatitis, aspiration of gastric content or extra-pulmonary sepsis). in our patients, the absence of a common risk factor for ards according to the berlin definition together with delay between first respiratory sign and icu admission exceeding days ( days) advocate more for an ards mimicker rather than for a real ards. however, a recent histological study revealed that % of patients with an acute decompensation of as syndrome due to jo- autoantibody exhibited histological lesions of dad [ ] . in non-icu patients, the prognosis of inflammatory myopathies depends on the severity of lung involvement [ , , , ] . treatment of interstitial lung disease associated with as and amda- dermato-pulmonary syndromes is not standardized and based on case reports. numerous immunosuppressive therapies are available (e.g., cyclophosphamide, methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, rituximab, basiliximab, intravenous immunoglobulins or plasma exchange) [ , , , , , ] , but high-dose corticosteroids remain the first-line therapy. our study underlines the wide variations in the choice of immunosuppressive treatment even if the association corticosteroids-cyclophosphamide was administered in almost over patients. patients with amda- received significantly more immunosuppressive drugs highlighting a higher severity. of note, % of icu survivors developed cancer, in line with previous series of as patients [ ] . our study suffers from several limitations. first, we included a limited number of patients, inherent to the rarity of the disease. however, this is the first series on arf revealing as or amda- syndromes in an icu context and our findings are consistent with previous reports. this limited number of patients precluded performing multivariable analyses and thus did not allow for adjusting the observed association between some variables and mortality with potential confounders. second, the relationship between positive as or amda- autoantibody and arf is not proven. we therefore cannot exclude that some patients had a fortuitously positive autoantibody and that inflammatory myopathy was not the cause of arf. however, this hypothesis appears unlikely since an alternative diagnosis for arf had to be excluded, and all patients were treated with immunosuppressive therapies underlining the high degree of clinician's suspicion. third, because the patients were recruited over a -year period in centers, icu procedures were inevitably heterogeneous. fourth, the prevalence of amda- dermato-pulmonary syndromes may have been underestimated during the study period since detection of amda- autoantibody was first described in [ ] and was therefore routinely available only from in most of participating centers. last, several classical predictors of mortality related to ventilation (tidal volume or driving pressure [ ] ) were not available as a result of a long-term retrospective design. considering the high proportion of patients lacking extra-pulmonary manifestations and the nonspecific presentation mimicking that of a bilateral communityacquired pneumonia, we believe that arf related to autoimmune inflammatory myopathies may be underdiagnosed. hence, de prost et al. recently showed that the diagnostic work-up performed in ards patients with no common risk factor was not comprehensive, with only % of patients having immunological tests [ ] . the lack of screening for as or amda- autoantibodies is probably one of the reasons why these diseases are underestimated. therefore, when the etiology of arf appears unclear, we recommend a more aggressive diagnostic work-up [ ] , including immunological tests in order to identify patients amenable to specific therapies. a careful assessment of extra-pulmonary manifestations, such as cutaneous or articular signs, is crucial. while the presence of extra-pulmonary manifestations is highly suggestive, the -week delay between first respiratory signs and icu admission, the absence of an obvious etiology for arf, the presence of bi-basal consolidations on chest x-ray with an intense inflammatory process, contrasting with a low procalcitonin level together with the lack of microbiological documentation are the main clues to consider the diagnosis of as or amda- syndromes in a patient without extra-pulmonary manifestation. to better assess the relevance of these signs, further prospective studies aiming at systematically screen for autoantibodies in ards without risk factors are needed. once the diagnosis is made, the management is difficult and requires a multidisciplinary approach involving intensivists, pulmonologists, internists and rheumatologists in order to decide the best-individualized therapeutic strategy. intensivists should consider inflammatory myopathies, such as anti-synthetase syndrome and dermato-pulmonary syndrome associated with anti-mda- antibodies, as a cause of acute respiratory failure when the etiology appears unclear. extra-pulmonary manifestations are commonly lacking and an isolated lung involvement may reveal the disease. hospital mortality is high, especially in amda- dermato-pulmonary syndrome. abbreviations ards: acute respiratory distress syndrome; arf: acute respiratory failure; as: anti-synthetase; amda- : anti-mda- autoantibody; bal: broncho-alveolar lavage; dad: diffuse alveolar damage; ecmo: extra-corporeal membrane oxygenation; icu: intensive care unit. dc had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. dc made substantial contribution to the study design, data collection and analysis and manuscript writing. cv contributed to data collection and interpretation, and drafting of the manuscript. mpc, ndp, ad, j-pq, sp, gl, mn, gv, mf, rc, gd, em, nt, yt-l, fs, mg, eg, rl, sr, rlm, gc, cg, lz and em contributed to patients identification in each center, data collection and manuscript writing. md contributed to the data analysis, statistical analysis and manuscript revision. ndp, cg, op, hm and gp contributed to the manuscript writing and revision, and provided important intellectual content. all authors read and approved the final manuscript. service de réanimation, centre hospitalier universitaire de grenoble alpes, avenue maquis du grésivaudan, la tronche, france. service de réanimation médico-chirurgicale, centre hospitalier universitaire avicennes -assistance publique hôpitaux de paris, rue de stalingrad, bobigny, france. service de réanimation service de réanimation médico-chirurgicale service de réanimation médico-chirurgicale, centre hospitalier du mans, avenue rubillard, le mans, france. service de réanimation médicale unité de réanimation et de surveillance continue, service de pneumologie et réanimation médicale, groupe hospitalier pitié-salpêtrière, - bd de l'hôpital a contributive result of open-lung biopsy improves survival in acute respiratory distress syndrome patients do we need ards? acute respiratory distress syndrome mimickers lacking common risk factors of the berlin definition etiologies, diagnostic work-up and outcomes of acute respiratory distress syndrome with no common risk factor: a prospective multicenter study acute respiratory distress syndrome: the berlin definition diagnostic workup for ards patients epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries anti-melanoma differentiation-associated protein -associated dermatomyositis: expanding the clinical spectrum interstitial lung disease and anti-jo- antibodies: difference between acute and gradual onset dermato-pulmonary syndrome associated with mda- antibodies a novel dermato-pulmonary syndrome associated with mda- antibodies: report of cases and review of the literature. medicine (baltimore) interstitial pneumonia with autoimmune features: an additional risk factor for ards? ann intensive care acute interstitial lung disease revealing antisynthetase syndrome acute respiratory distress syndrome secondary to antisynthetase syndrome is reversible with tacrolimus acute respiratory distress syndrome as the initial clinical manifestation of an antisynthetase syndrome adult respiratory distress syndrome in polymyositis patients with the anti-jo- antibody severe respiratory failure as a presenting feature of an interstitial lung disease associated with anti-synthetase syndrome (ass) interstitial lung disease with autoantibodies against aminoacyl-trna synthetases in the absence of clinically apparent myositis clinical profiles and prognosis of patients with distinct antisynthetase autoantibodies two cases of interstitial pneumonia with anti-jo- antibodies in the absence of myositis pulmonary fibrosis with predominant cd lymphocytic alveolitis and anti-jo- antibodies clinical manifestations of anti-synthetase syndrome positive for antialanyl-trna synthetase (anti-pl ) antibodies: a retrospective study of cases the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine a new simplified acute physiology score (saps ii) based on a european/north american multicenter study delivered oxygen concentrations using low-flow and high-flow nasal cannulas early identification of acute respiratory distress disorder in the absence of positive pressure ventilation: implications for revision of the berlin criteria for acute respiratory distress syndrome interstitial lung disease associated with the idiopathic inflammatory myopathies: what progress has been made in the past years? antisynthetase syndrome clinical and serological aspects of patients with anti-jo- antibodies-an evolving spectrum of disease manifestations myositis specific autoantibodies: changing insights in pathophysiology and clinical associations polymyositis, pulmonary fibrosis and autoantibodies to aminoacyl-trna synthetase enzymes clinical manifestations and outcome of anti-pl positive patients with antisynthetase syndrome sensitivity and specificity of anti-jo- antibodies in autoimmune diseases with myositis comparison of long-term outcome between anti-jo -and anti-pl /pl positive patients with antisynthetase syndrome the mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to mda (cadm- ): a retrospective study clinical features and outcomes of interstitial lung disease in anti-jo- positive antisynthetase syndrome acute respiratory failure in critically ill patients with interstitial lung disease idiopathic pulmonary fibrosis: predicting response to therapy and survival idiopathic pulmonary fibrosis: a composite physiologic index derived from disease extent observed by computed tomography comparison of the berlin definition for acute respiratory distress syndrome with autopsy the role of open-lung biopsy in ards open lung biopsy in nonresolving acute respiratory distress syndrome commonly identifies corticosteroid-sensitive pathologies, associated with better outcome the pulmonary histopathologic manifestations of the anti-jo- trna synthetase syndrome interstitial lung disease in polymyositis and dermatomyositis the diagnosis and treatment of antisynthetase syndrome basiliximab may improve the survival rate of rapidly progressive interstitial pneumonia in patients with clinically amyopathic dermatomyositis with anti-mda antibody antisynthetase syndrome and malignancy: our experience autoantibodies to a -kd polypeptide, cadm- driving pressure and survival in the acute respiratory distress syndrome the authors declare that they have no competing interests. the study was approved by institutional review board of the french society for respiratory medicine in september (cepro - ), which waived informed consent. this study did not receive funding from external or internal sources. key: cord- - krf yxz authors: li, xi; huang, yongbo; xu, zhiheng; zhang, rong; liu, xiaoqing; li, yimin; mao, pu title: cytomegalovirus infection and outcome in immunocompetent patients in the intensive care unit: a systematic review and meta-analysis date: - - journal: bmc infect dis doi: . /s - - - sha: doc_id: cord_uid: krf yxz background: cytomegalovirus (cmv) infection is common in immunocompetent patients in intensive care units (icus). however, whether cmv infection or cmv reactivation contributes to mortality of immunocompetent patients remains unclear. methods: a literature search was conducted for relevant studies published before may , . studies reporting on cmv infection in immunocompetent patients in icus and containing × tables on cmv results and all-cause mortality were included. results: eighteen studies involving immunocompetent patients admitted to icus were included in the meta-analysis. the overall rate of cmv infection was % ( %ci – %, i( ) = %, n = ) and the cmv reactivation was % ( %ci – %, i( ) = %, n = ). the odds ratio (or) for all-cause mortality among patients with cmv infection, compared with those without infection, was . ( %ci . – . , i( ) = %, n = ). moreover, upon exclusion of studies in which antiviral treatment was possibly or definitely provided to some patients, the association of mortality rate with cmv infection was also statistically significant (or: . , %ci . – . , i( ) = %, n = ,). for cmv seropositive patients, the or for mortality in patients with cmv reactivation as compared with patients without cmv reactivation was . ( %ci . – . , i( ) = %, n = ). patients with cmv infection required significantly longer mechanical ventilation (mean difference (md): days ( % ci – , i( ) = %, n = )) and longer duration of icu stay (md: days ( % ci – , i( ) = %, n = )) than patients without cmv infection. when analysis was limited to detection in blood, cmv infection without antiviral drug treatment or reactivation was not significantly associated with higher mortality (or: . , %ci . – . , i( ) = %, n = ; or: . , i( ) = %, n = ). conclusion: critically ill patients without immunosuppression admitted to icus show a high rate of cmv infection. cmv infection during the natural unaltered course or reactivation in critically ill patients is associated with increased mortality, but have no effect on mortality when cmv in blood. more studies are needed to clarify the impact of cmv infection on clinical outcomes in those patients. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. human cytomegalovirus (cmv) is a prototypic member of the β herpes virus subfamily [ ] . the prevalence of cmv seropositivity in human populations is roughly - % [ ] [ ] [ ] and highest amongst older people [ ] . cytomegalovirus infection induces innate immune responses (eg. natural killer cells) and adaptive immunity (eg. cd +/cd + t cells). however, the virus can evade host detection by expressing genes that interfere with both the innate and adaptive immune systems. eventually, cmv is able to establish latency in which either the host fails to eliminate the virus or the virus cannot replicate. however, cmv can become reactivated during periods of host immune suppression [ ] . it is well known that cmv infection is common in canonical immunodeficiency patients, such as those with human immunodeficiency virus infection, solid organ or stem cell transplantation and patients undergoing chemoor radiotherapy [ ] [ ] [ ] . with the development of more sensitive detection method, the rate of cmv detection is high in intensive care units (icus) [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . however, so far, there is no convincing research to support the use of antiviral treatment when critically ill but immunocompetent patients present with cmv infection. furthermore, whether cmv is a contributor or simply a bystander to the severity of illness remains under debate [ ] [ ] [ ] . whether cmv infection is associated with increased mortality in immunocompetent icu patients remains controversial [ ] [ ] [ ] [ ] . a previous meta-analysis published in demonstrated that cmv infection was associated with a higher mortality rate, nearly twice that observed in patients without cmv infection [ ] . however, this study did not consider the influence of antiviral drugs on clinical outcomes. moreover, many clinical studies about cmv have been reported in recent years. thus, to acquire a better understanding of the potential role of cmv infection in contributing to mortality in critically ill patients, especially those not receiving antiviral agents and cmv detected in blood, we performed a meta-analysis of data available in the literature, focusing on the outcome in immunocompetent icu patients with cmv infection. a literature search for relevant publications included within the electronic databases pubmed, embase and the cochrane library was performed using combinations of the keywords "cytomegaloviruses", "salivary gland viruses", "herpes virus", "cytomegaloviral infection", "hhv ", "intensive care", "critical care", "critical illness", "mechanical ventilation", and "pulmonary ventilator". all searches were updated on may , . no language restriction was enforced. we also consulted relevant reference articles and searched using google scholar. two researchers (lx and hyb) performed data extraction independently, and any discrepancies were addressed by discussion and reevaluation until consensus was achieved. observational studies were eligible if they reported on cmv infection in immunocompetent patients in the icu, and if a × table could be constructed based on cmv results and all-cause mortality. all patients were over years of age. the systematic review included only studies in which all patients were tested for cmv. an episode of cmv infection was defined by one of the examination cmv viral culture, polymerase chain reaction (pcr), cmv antigen (pp ) in blood, tracheal aspirates, urine, or a combination of these. a case was defined by the presence of reactivation, where the patient had cmv infection and was seropositive. immunocompetent patients were defined as those patients who did not receive a solid organ or hematopoietic stem cell transplant, did not receive immunosuppressive treatment, did not have human immunodeficiency virus infection, did not have primary immunodeficiency, and did not receive chemotherapy or radiotherapy before icu admission. we obtained information on basic study characteristics (author, year of publication, country of origin, study period, setting, and study design), characteristic population, the site and detection method of sample, cmv seropositivity, cmv infection incidence, all-cause mortality, length of icu/hospital stay, length of mechanical ventilation, and administration of antiviral drugs. the newcastle-ottawa scale, developed for evaluating the quality of observational studies (additional file : table s ) [ ] , was used to assess the validity of included studies. continuous variables are reported as mean or median values and categorical variables are reported as n (%). meta-analytic pooling was performed for outcome variables with a logit transformation approach, reporting results as summary point estimates ( % confidence interval, ci). we used the mantel-haenszel method to obtain odds ratios (ors) and % ci. when only the median, range, or interquartile range of length of mechanical ventilation and the length of icu stay were reported, we used simple formulas to estimate the mean and standard deviation [ ] . between-study heterogeneity was examined using the i measure of inconsistency and the chi-square test of heterogeneity. to evaluate publication bias, we constructed a funnel plot and used the egger test. sensitivity analyses of the begg's test were additionally conducted to ascertain the robustness of our findings. all meta-analyses were performed with r software (version . . for windows) and spss (ibm, armonk, ny, usa). the initial database search identified potentially relevant studies. following this, assessment of the full text yielded studies suitable for analysis. another publication was incorporated after examining references from the extracted articles [ ] . consequently, our meta-analysis consisted of articles (fig. ) , including one case-control [ ] and cohort studies [ - , - , ] . most studies were conducted in the united states and europe, except one cohort study in egypt [ ] , and were published between and (table ) . overall, the studies were well done, with a median score of (range - ) on the newcastle-ottawa scale for appraising the quality of observational studies. a total of patients were included, having been admitted to the icu for a variety of reasons, with a median age of years. the median period of prospective studies was months, ranging broadly from to months. all studies used cmv blood assays, and studies also assayed sputum samples. most studies indicated that the frequency of sample collection was once a week. in our analysis, the methods used to assess cmv infection were virus culture, pp antigen detection and pcr detection of cmv dna in ten, three and two studies, respectively, and combinations of two diagnostic methods in the remaining three studies. as shown in fig. , the overall detection rate of cmv was % ( % ci - %, i = %, n = ). as compared with patients without cmv infection, the all-cause mortality of patients with cmv infection was significantly higher (or: . ; % ci . - . , i = %, n = ) (fig. a) . when analysis was limited to cmv detection in blood, there was still statistical significance in mortality rate between patients with cmv infection (or: . , % ci . - . , i = %, n = ) compared with patients without infection (additional file : figure s ). to rule out the impact of antiviral drugs on patients with cmv infection, four studies in which patients received antiviral drugs during their icu stay and eight studies that did not specify the use of antiviral drugs were excluded. the remaining six studies of patients without antiviral treatment during the course of icu stay were analyzed [ , , , , , ] . the difference in mortality rates between patients with cmv infection remained significant (or: . , % ci . - . , i = %, n = ) compared with patients without infection (fig. b) . when analysis was limited to cmv detection in blood, there was no statistical significance in mortality rate between patients with cmv infection (or: . , % ci . - . , i = %, n = ) as compared with patients without infection (additional file : figure s ). the mean difference in mechanical ventilation days and duration of icu stay was an increase of days ( % ci - , i = %, n = ) and days ( % ci - , i = %, n = ), respectively, between patients with and without cmv infection ( fig. a and b) . when analysis was limited to cmv detection in blood, there was still a statistically significant difference in length of mechanical ventilation and icu stay between patients with cmv infection as compared with patients without infection (md: days ( % ci - , i = %, n = ) and md: days ( % ci - , i = %, n = )), respectively (additional file : figure s and additional file : figure s ). the cmv seropositivity rate, which represents previous infection, was % ( % ci - %, i = %, n = ) in immunocompetent icu patients (fig. a) . patients with cmv reactivation, which represents cmv detected among seropositive patients, was % ( % ci - %, i = %, n = ) (fig. b) . the or for mortality in patients with cmv reactivation as compared with patients without cmv reactivation was . ( % ci . - . , i = %, n = ) (fig. c) . but for patients of cmv infection in blood, the reactivation was not associated with higher mortality (or: . , % ci . - . , i = %, n = ) (additional file : figure s ). we also analyzed the rate of cmv and mortality thought categorized by the detection methods (additional file : figure s , additional file : figure s : additional file : figure s and additional file : figure s ). we used the egger test to detect publication bias. there was no publication bias either in the overall cmv prevalence analysis (t = . , p = . ) or in the all-cause cmv mortality analysis (t = − . , p = . ). we also used begg's test to detect sensitivity analysis, and the results showed that the analyses were robust. in this meta-analysis, we have demonstrated that cmv infection frequently present in critically ill immunocompetent patients at icu admission. the overall rate of cmv infection was %, which was higher than the % presented in a previous meta-analysis [ ] , because eight recent studies detecting cmv infection by pcr assay were included in our meta-analysis [ - , , ] . polymerase chain reaction has been demonstrated to be the most sensitive method of cmv detection [ ] , but even so, the cmv infection rate may still be underestimated because we chose only the studies containing × tables on cmv results and all-cause mortality. we excluded studies where either the rate of cmv infection or mortality was zero and we also excluded some studies with a % infection rate that used early monitoring of cmv, often fewer than days after admission to the icu [ , [ ] [ ] [ ] . we believe this could have led to underestimation of the cmv infection rate because the transition to cmv infection requires time for the complete lytic virus cycle to develop from the latent phase [ ] . we found that the detection rate of cmv by culture, pp and pcr was , and %, respectively. desachy for cmv infection were obtained in a median of days by pcr compared with days by pp antigen detection after onset of sepsis [ ] . therefore, pcr facilitates earlier diagnosis of an episode of cmv infection than any other method. we then analyzed the association between cmv positivity and mortality, stratified by detection method. we also found that patients with cmv infection detected by pcr had higher mortality than patients without cmv infection (or: . , % ci . - . , i = %, n = ). however, when compared with other methods, the association with mortality was marginally less strong using pcr. we may think that viral burden of cmv is determinant of pathogenesis, and higher cmv loads is correlated with progression of some cmv infection disease [ , ] . the presence of cmv seropositivity, representing previous infection, was found in % of immunocompetent icu patients and the incidence of cmv reactivation was high, observed in % of seropositive patients in our meta-analysis. there are several factors that might explain the high prevalence. first of all, the rate of cmv seropositivity increases with advancing age [ ] and in our analysis, the median age was years. second, to inhibit the reactivation of cmv, as many as % of all peripheral cd + and cd + t cells are constantly required for immune surveillance to maintain functional latency [ ] . sepsis is associated with immunoparalysis, as apoptosis of cd + and cd + t cells is increased [ , ] . furthermore, some patients in the icu may be immunosuppressed after trauma and major surgery [ ] . in addition, treatments commonly received in the icu, such as massive transfusion, corticosteroids, or catecholamines may transiently compromise host immunity [ ] . it has also been reported that the use of heart-lung machines can lead to temporary systemic immunosuppression [ ] . therefore, patients in the icu may show transient immunoparalysis [ ] , potentially resulting in the observed cmv reactivation. third, some inflammatory cytokines including tumor necrosis factor alpha and interleukin- β, can stimulate reactivation of latent cmv [ ] . thus, significant numbers of immunocompetent patients harboring latent virus are susceptible to cmv reactivation during critical illness. when the mortality analysis was limited to cmv detection in blood, cmv infection without antiviral drug treatment or reactivation was not significantly associated with higher mortality. this maybe explained that the presence of high peripheral levels of functional cmv-specific cd + and cd + t cells in immunocompetent patients, which can suppress cmv during episodes of reactivation [ ] . it was observed that cmv infection was not associated with mortality in cmv colitis. in steroid-refractory patients with ulcerative colitis, cmv was found in the colon by histopathology, which is also not associated with adverse clinical outcomes [ ] . indeed, there has been no research to demonstrate that immunocompetent critically patients with cmv infection could benefit from antivirus therapy. and there are a number of side effects of antiviral drugs, such as hematologic complications (neutropenia, anemia and thrombocytopenia), renal dysfunction, mental disorders [ ] . therefore, giving antiviral drugs to critically ill patients should be considered cautiously in terms of advantage-disadvantage ratio. to address this issue, there are two ongoing, blinded, randomized placebo-controlled clinical trials of an antiviral drug with activity against cmv in critically ill patients in the icu (nct , nct ). patients with sepsis have the highest incidence of cmv infection [ ] . early in 's, bacterial sepsis was considered to trigger cmv reactivation [ ] . the reactivation associated with sepsis was consequence of inflammatory stimulation, transient immune compromise, and maybe involving some component of epigenetic regulation of viral dna [ ] . there are five limitations in this study. first, we observed large heterogeneity in many of our analyses. however, little or no heterogeneity was observed in the meta-analysis of mortality outcome. second, most studies were not blind, thus reducing the reliability of the results. third, lack of sufficient data on clinical parameters (eg: severity of illness, cause of icu admission, comorbidity) meant that stratified analyses based on such clinical characteristics were not possible. fourth, the definition of the state of cmv infection was inconsistent and maybe restrictive to capture the dynamics of cmv infection. as such, we could not conduct meta-analysis with outcome data and this is a major limitation of our meta-analysis. finally, one [ ] cannot discount the effect of unmeasured confounders given the observational nature of the body of evidence comprising this meta-analysis. cytomegalovirus: pathogen, paradigm, and puzzle seroprevalence of cytomegalovirus (cmv) and risk factors for infection in adolescent males cytomegalovirus seroconversion rates and risk factors: implications for congenital cmv cytomegalovirus seroprevalence in the united states: the national health and nutrition examination surveys impairment of cytomegalovirus and host balance in elderly subjects human cytomegalovirus immunity and immune evasion pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients cytomegalovirus replication kinetics in solid organ transplant recipients managed by preemptive therapy importance of cytomegalovirus viraemia in risk of disease progression and death in hiv-infected patients receiving highly active antiretroviral therapy cytomegalovirus seroprevalence as a risk factor for poor outcome in acute respiratory distress syndrome* reactivation of multiple viruses in patients with sepsis the impact of cytomegalovirus infection on mechanically ventilated patients in the respiratory and geriatric intensive care units cytomegalovirus reactivation and associated outcome of critically ill patients with severe sepsis cytomegalovirus infection in severe burn patients monitoring by real-time polymerase chain reaction: a prospective study virological and immunological features of active cytomegalovirus infection in nonimmunosuppressed patients in a surgical and trauma intensive care unit active cytomegalovirus infection is common in mechanically ventilated medical intensive care unit patients increased mortality in long-term intensive care patients with active cytomegalovirus infection cytomegalovirus reactivation in critically ill immunocompetent patients active cytomegalovirus infection in patients with septic shock cytomegalovirus infection in critically ill patients: associated factors and consequences occult herpes family viral infections are endemic in critically ill surgical patients human cytomegalovirus infections in nonimmunosuppressed critically ill patients high incidence of active cytomegalovirus infection among septic patients occult herpes family viruses may increase mortality in critically ill surgical patients incidence and morbidity of cytomegaloviral infection in patients with mediastinitis following cardiac surgery sepsis and cytomegalovirus: foes or conspirators? cytomegalovirus and mortality in critical care patients: another piece of the puzzle cytomegalovirus in the intensive care unit: pathogen or passenger? prevalence and mortality associated with cytomegalovirus infection in nonimmunosuppressed patients in the intensive care unit critical evaluation of the newcastle-ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses estimating the mean and variance from the median, range, and the size of a sample cytomegalovirus reactivation in a general, nonimmunosuppressed intensive care unit population: incidence, risk factors, associations with organ dysfunction, and inflammatory biomarkers cytomegalovirus reactivation and mortality in patients with acute respiratory distress syndrome cytomegalovirus load in whole blood is more reliable for predicting and assessing cmv disease than pp antigenaemia selective reactivation of human herpesvirus variant a occurs in critically ill immunocompetent hosts reactivation of human herpesvirus type in multiple organ failure syndrome evaluation by polymerase chain reaction of cytomegalovirus reactivation in intensive care patients under mechanical ventilation cytomegalovirus infection in patients with bacterial sepsis diagnostic approaches to cytomegalovirus infection in bone marrow and organ transplantation a real-time taqman pcr for routine quantitation of cytomegalovirus dna in crude leukocyte lysates from stem cell transplant patients broadly targeted human cytomegalovirus-specific cd + and cd + t cells dominate the memory compartments of exposed subjects sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy sepsis: a roadmap for future research acquired immunologic deficiencies after trauma and surgical procedures immunologic abnormalities in patients receiving multiple blood transfusions pediatric cardiac surgery with cardiopulmonary bypass: pathways contributing to transient systemic immune suppression sir isaac newton, sepsis, sirs, and cars lipopolysaccharide, tumor necrosis factor alpha, or interleukin- beta triggers reactivation of latent cytomegalovirus in immunocompetent mice cytomegalovirus in inflammatory bowel disease: pathogen or innocent bystander? treating hsv and cmv reactivations in critically ill patients who are not immunocompromised: con our findings suggests that there is a high incidence of cmv seropositivity and cmv infection in critically ill patients without immunosuppression. this study suggest that cmv infection without antiviral drug treatment or reactivation in critically ill patients is associated with increased mortality, and is not associated with mortality when cmv infection is detected in blood. further research is necessary to determine the full role of cmv in this vulnerable patient demographic. additional file : table s . the newcastle-ottawa scale (pdf kb) additional file : figure s availability of data and materials all data generated or analyzed during this study are included in this published article.authors' contributions lx conducted the literature search, extracted data, performed statistical analysis, and drafted the manuscript. hyb conducted the search, extracted the data, and revised the manuscript. xzh performed the statistical analysis and edited the manuscript. zr conducted the literature search and extracted data. lxq interpreted the data. mp designed the study, interpreted data, and revised the manuscript. lym conceived and designed the study and revised the manuscript. all authors have read and approved the final manuscript. key: cord- -k p fr authors: olive, david; georges, hugues; devos, patrick; boussekey, nicolas; chiche, arnaud; meybeck, agnes; alfandari, serge; leroy, olivier title: severe pneumococcal pneumonia: impact of new quinolones on prognosis date: - - journal: bmc infect dis doi: . / - - - sha: doc_id: cord_uid: k p fr background: most guidelines have been proposing, for more than years, a β-lactam combined with either a quinolone or a macrolide as empirical, first-line therapy of severe community acquired pneumonia (cap) requiring icu admission. our goal was to evaluate the outcome of patients with severe cap, focusing on the impact of new rather than old fluoroquinolones combined with β-lactam in the empirical antimicrobial treatments. methods: retrospective study of consecutive patients admitted in a -bed general intensive care unit (icu), between january and january , for severe (pneumonia severity index > or = ) community-acquired pneumonia due to non penicillin-resistant streptococcus pneumoniae and treated with a β-lactam combined with a fluoroquinolone. results: we included patients of whom received a β-lactam combined with ofloxacin or ciprofloxacin and combined with levofloxacin. twenty six patients ( . %) died in the icu. three independent factors associated with decreased survival in icu were identified: septic shock on icu admission (aor = . ; % ci . - . ; p = . ), age > yrs. (aor = . ; % ci . - . ; p = . ) and initial treatment with a β-lactam combined with ofloxacin or ciprofloxacin (aor = . ; % ci . - . ; p = . ). conclusion: our results suggest that, when combined to a β-lactam, levofloxacin is associated with lower mortality than ofloxacin or ciprofloxacin in severe pneumococcal community-acquired pneumonia. streptococcus pneumoniae is the leading causative agent of community-acquired pneumonia (cap). despite new antimicrobial agents and advances in supportive measures, attributable mortality linked to pneumococcal pneumonia remains unchanged and dramatically high when patient are admitted in intensive care units (icu) [ ] . most guidelines have been proposing, for more than years, a combination of a β-lactam with either a quinolone or a macrolide as empirical, first-line therapy of severe cap requiring icu admission [ ] [ ] [ ] [ ] [ ] [ ] [ ] . although a recent study demonstrated combination antibiotic therapy to be associated with a higher survival rate than monotherapy in patients with severe cap and shock [ ] , the rationale for this combination was not to increase efficacy but rather to routinely provide coverage of all common pathogens causing severe cap and particularly, s. pneumoniae and legionella species. in our icu, we followed until the french recommendations [ ] . most patients received an empirical therapy based on a β-lactam-fluoroquinolone combination. before , fluoroquinolones used were ofloxacin and ciprofloxacin. levofloxacin replaced these quinolones since its addition to the hospital formulary. such a replacement was comforted by the ers, french and idsa guidelines published between and [ ] [ ] [ ] . we wished to determine outcomes of patients treated with a combination of β-lactam plus fluoroquinolone for severe pneumococcal pneumonia. this homogenous modification of severe cap antibiotic management in our icu gives us the further opportunity to assess the influence of a fluoroquinolone with enhanced activity against s.pneumoniae. firstly, we retrospectively collected all consecutive patients aged > years who were admitted into our icu ( -bed medical and surgical intensive care unit in a -bed general hospital) between january and january for severe community-acquired pneumonia (cap) and who received a definite diagnosis of pneumococcal pneumonia. secondly, we selected patients who received, as initial antibiotic treatment, a β-lactam plus a fluoroquinolone, used with an appropriate dosage by iv route. thirdly, patients were divided into two groups according to the fluoroquinolone used, group a for ofloxacin or ciprofloxacin, group b for levofloxacin. the study protocol was submitted to the institutional review board for university hospital of lille which gave an approval with waiver of informed consent, in agreement with french regulations concerning such retrospective studies. cap was defined by the following criteria observed at initial presentation or occurring within h following hospitalization: acute onset of signs and symptoms of lower respiratory tract infection and a new pulmonary infiltrate found on the hospital admission chest radiograph. we excluded patients coming from nursing homes or hospitalized within days prior to developing pneumonia or hospitalized > h in general medical wards before icu admission, and those with radiographic abnormalities attributed solely to any other known cause (i.e., pulmonary embolus, lung carcinoma or congestive heart failure). the decision for admission to our icu was made, in all cases, by the attending physicians. however, only patients having a pneumonia severity index (psi) score ≥ were included in this study [ ] . streptococcus pneumoniae was considered as the causative agent of cap when a s. pneumoniae strain was isolated from > blood culture or when validated sputum (< squamous epithelial cells and > polymorphonuclear cells per low-power field) or tracheobronchial aspirates cultures grew with > cfu/ml s. pneumoniae. patients having cap due to a penicillinresistant strain of s. pneumoniae (mic > mg/l) were excluded from our study. appropriate drug dosages were defined in the french recommendations as: amoxicillin > mg/kg/d, cefotaxime > mg/kg/d, ceftriaxone > mg/kg/d, piperacillin > mg/kg/d, ofloxacin = mg/ h, ciprofloxacin = mg/ h, levofloxacin = mg/ h [ , , ] . these drug dosages for β-lactams, ofloxacin and ciprofloxacin were unchanged during the study period. thus, doses used in both groups were similar. within h of admission, all patients underwent clinical, radiological and biological tests. briefly, we recorded age, gender, underlying clinical characteristics and initial vital signs. chronic respiratory insufficiency was assessed combining the usual clinical and radiological criteria and the coexistence of ventilatory impairment assessed either before or after icu stay. immunosuppression was defined as recent use of immunosuppressant or systemic corticosteroids (i.e., prednisolone > . mg/kg/day for more than month), human immunodeficiency virus infection, neutropenia (absolute neutrophil count < . cells/mm ), organ transplantation with ongoing immunosuppressant, cancer chemotherapy within the past months, or asplenia. shock was defined as a sustained (> h) decrease in the systolic blood pressure of at least mm hg from baseline or a resultant systolic blood pressure < mm hg after adequate volume replacement and in the absence of any antihypertensive drug [ ] . severity of illness at admission to icu was assessed using the simplified acute physiology score ii (saps) ii [ ] , the sepsis-related organ failure assessment (sofa) score [ ] and the logistic organ dysfunction (lod) score [ ] . we also calculated the psi at icu admission [ ] . for all patients, information on the following therapeutic topics instituted within hours following icu admission was recorded: supportive measures such as mechanical ventilation or hemodialysis, use of vasopressor drugs, hydrocortisone, drotrecogin alfa (activated), or intensive insulin therapy. the effectiveness of initial antimicrobial therapy was assessed within h after treatment as follows: a lack of clinical improvement days after treatment initiation (worsening or persistent fever or hypothermia, worsening of pulmonary infiltrates or of respiratory function assessed by pao /fio ) defined an ineffective treatment. on day , day and day , body temperature, and sofa score were determined. during the patient's stay in the icu, occurrence of complications was recorded. we distinguished sepsis-related complications (secondary septic shock, acute respiratory distress syndrome or development of multiple organ failure), hospital-acquired lower respiratory tract (ha-lrt) superinfections and icu-related complications (i.e., upper gastrointestinal bleeding, catheter-related infection, deep venous thrombosis and pulmonary embolism). multiple organ failure (mof), acute respiratory distress syndrome (ards) and ha-lrt were defined according to usual criteria [ ] [ ] [ ] . durations of mechanical ventilation, treatment with vasopressor drugs, and icu length of stay were noted. finally, patient mortality was evaluated on d- , and at the time of icu discharge. descriptive analyses were performed in order to check and resume data. characteristics of patients in each group were compared. continuous variables were compared using the student's t test. categorical variables were compared using chi-square test or fisher's exact test when chi-square was not appropriate. differences between groups were considered to be significant for variables yielding a p value < . . a stepwise logistic regression including variables collected within the first hours of icu stay and associated with a p value < . in bivariate analysis was performed. adjusted odd-ratios were computed using a logistic regression analysis including the independent predictors of mortality. the kaplan-meier product limit method and the log-rank test were used to construct and compare survival curves for patients in each group. all statistical analyses were performed using the sas software, v . . during the study period, patients with severe cap were admitted in our unit. among them, ( %) patients exhibited a severe pneumococcal pneumonia and, finally, we identified patients treated with a β-lactam combined with a fluoroquinolone, including men ( . %) and women ( . %). the mean age was . ± . years. s. pneumoniae was identified in blood cultures in patients ( . %). infection was polymicrobial in patients ( . %). causative pathogens associated with s. pneumoniae were haemophilus influenzae (n = ), methicillin susceptible staphylococcus aureus (n = ), enterobacteriaceae (n = ), streptococcus spp. (n = ) and moraxella catarrhalis (n = ). all pathogens were susceptible to at least one drug (β-lactam and/or fluoroquinolone) received by the patients. thirty-eight patients ( . %) were classified as group a. β-lactams used were a third generation cephalosporin (n = ; . %), amoxicillin ± clavulanic acid (n = ; . %) and piperacillin-tazobactam (n = ; . %) combined with ofloxacin (n = ; . %) or ciprofloxacin (n = ; . %). thirty-two patients ( . %) were classified as group b. β-lactams used were a third generation cephalosporin (n = ; . %), amoxicillin ± clavulanic acid (n = ; . %) and piperacillin-tazobactam (n = ; . %) combined with levofloxacin. main patients' characteristics on icu admission are reported table . most characteristics were similar in the two groups. however, underlying chronic respiratory insufficiency and bacteremia were more frequent in group b patients. main therapeutics instituted during icu stay, evolution of severity scores, and occurrence of complications are reported table . the most significant differences between the two groups of patients were the more frequent use of drotrecogin alpha, intensive insulin therapy and hydrocortisone in group b patients. on day , ( %) patients had died, ( . %) in group a and ( . %) in group b (p = . ). overall, patients died in the icu, ( . %) in group a vs. ( . %) in group b (p = . ). so, difference in mortality rates was only significant during the first days of icu stay (figure ). in group a, in-icu mortality was % ( / ) when ofloxacin or ciprofloxacin were combined with a third generation cephalosporin and . % ( / ) when combined with another beta-lactam, respectively (p = . ). in group b, it was . % ( / ) when levofloxacin was combined with a third generation cephalosporin and . % ( / ) when combined with another beta-lactam (p = ). results of icu-discharge survival prognosis bivariate analysis, including factors present on icu admission, are reported table . all underlying diseases (excepted chronic heart failure), mechanical ventilation, use of a third generation cephalosporin combined with a fluoroquinolone, and bacteraemia on icu admission did not appear as significant prognostic variables in this analysis. among the bacteremic patients, mortality was higher in group a patients ( . %) than group b patients ( . %), but the difference was not statistically significant ( / vs. / ; p = . ). among the patients with septic shock on icu admission, mortality was higher in group a patients ( %) than in group b patients ( %), but the difference was not statistically significant ( / vs. / ; p = . ). among variables collected during the icu stay, use of hydrocortisone, intensive insulin therapy, haemodialysis and occurrence of ha-lrt superinfections did not appear as significant prognostic variables. conversely, improvement on d , sofa > on d , d , and d , and occurrence of sepsis-related complications were significantly associated with outcome at icu discharge (table ) . according to the results of the bivariate analysis, the following variables were entered in the stepwise analysis: chronic heart failure, age > yrs, acute respiratory failure requiring mechanical ventilation, septic shock on icu admission, use of hydrocortisone, haemodialysis, psi score = , saps ii > on d , lod > on d , the main finding of this retrospective analysis is that levofloxacin plus a β-lactam appears to be associated with improved survival compared to ofloxacin or ciprofloxacin plus a β-lactam in severe pneumococcal cap. empirical antibiotic regimen for icu-treated severe cap has long been recommended to cover the most common severe cap pathogens (s. pneumoniae, s. aureus and h.influenzae), atypical pathogens and most relevant enterobacteriaceae species. levofloxacin is a fluoroquinolone active against most of these pathogens, especially s. pneumoniae with or without decreased penicillin susceptibility [ , ] . its clinical activity in cap has been well documented in various clinical trials in europe and the usa [ , ] . some studies demonstrated the efficacy of levofloxacin used as monotherapy in severe cap, compared to ceftriaxone plus erythromycin or cefotaxime plus ofloxacin [ , ] . nevertheless, experts continue to propose, for icu-treated severe cap, an empirical antibiotic regimen based on an anti pneumococcal β-lactam combined with either a macrolide or a fluoroquinolone. since respiratory fluoroquinolones with enhanced activity against s. pneumoniae (levofloxacin, moxifloxacin or gemifloxacin) became available, they replaced second generation fluoroquinolones (ofloxacin or ciprofloxacin) in the guidelines [ ] [ ] [ ] . this fluoroquinolone generation shift has never been clearly justified and, to our knowledge, no clinical study has compared these different quinolones combined with a β-lactam in severe cap. our results suggest that, when severe cap causative agent is s. pneumoniae, a combination levofloxacin plus β-lactam is associated with lower mortality than a combination ofloxacin or ciprofloxacin plus β-lactam. these results could be surprising as all patients received an appropriately dosed β-lactam active against s. pneumoniae and as numerous strains of s. pneumoniae remain in vitro susceptible to ofloxacin or ciprofloxacin. however, there might be bacteriological and clinical data explaining our results. a synergy between β-lactams and levofloxacin against s. pneumoniae has been reported [ ] . conversely, synergy was rarely observed between the combination of cefotaxime and ofloxacin [ ] . recent clinical studies suggest that combination therapies could improve the prognosis of pneumococcal pneumonia: waterer et al. retrospectively studying patients with severe bacteremic pneumococcal pneumonia demonstrated that a single effective therapy was an independent predictor of mortality (aor = . ) [ ] . baddour et al. performed a prospective, multicenter, international study including adult patients with s. pneumoniae bacteremia [ ] . although the -day mortality was not significantly different for all patients receiving monotherapy versus combination ( . % vs. . %), a combination of in vitro active agents was associated with a significantly lower mortality than a single active agent ( . % vs. %; p = . ). the present work has numerous limits. the most important is probably major treatment differences among the two groups. patients were recruited during a long period ( - ), during which therapies such as hydrocortisone, drotrecogin alfa (activated), or intensive insulin therapy were introduced. management of septic shock and ards has changed following results of large international studies [ , ] . as most changes in management of patients with multiple organ failures overlap with our antibiotic policy changes, our results might be biased. indeed, hydrocortisone use and intensive insulin therapy were more frequent in group b than in group a. however, these factors were not significantly associated with icu survival in bivariate analysis and hydrocortisone use, in multivariate analysis, was not an independent prognostic factor. moreover, there is no evidence suggesting a survival benefit by most adjunctive therapies in patients with cap [ ] and the benefit of intensive insulin therapy in medical icu and/or low-dose steroids is now highly questionable [ , ] . similarly, the use of cephalosporin is more frequent in group b than in group a. however, the use of a third generation cephalosporin rather than amoxicillin has no impact on prognosis. this is not surprising as, to our knowledge, no clinical study demonstrated a third generation cephalosporin to be superior to amoxicillin for non penicillin-resistant s. pneumoniae cap as far as drug dosage is adequate. finally, some important prognostic parameters such as the time elapsed between admission and the first dose of antibiotic were not taken into account in our study. before , we did not have computerized data charts thus, exact time of admission and antibiotics admission, particularly for patients transferred from other departments/hospitals cannot be obtained. our study suggests that levofloxacin combined with a β-lactam is associated with improved survival in comparison with ofloxacin or ciprofloxacin combined with a β-lactam in severe pneumococcal patients admitted in the icu. this combination, proposed by current guidelines as empirical treatment of severe cap patients admitted in icu could improve their prognosis. obviously, only a prospective, randomized, double-blind trial could confirm this result. list of abbreviations aor: adjusted odd ratio; ards: acute respiratory distress syndrome; cap: community-acquired pneumonia; ci: confidence interval; ha-lrt superinfections: hospital-acquired lower respiratory tract superinfections; icu: intensive care unit; lod score: logistic organ dysfunction score; los: length of stay; mof: multiple organ failure; mv: mechanical ventilation; psi: pneumonia severity index; saps: simplified acute physiology score; sofa: sepsis-related organ failure assessment; sd: standard deviation. epidemiological features and prognosis of severe community-acquired pneumococcal pneumonia quatrième conférence de consensus en thérapeutique anti-infectieuse de la société de pathologie infectieuse de langue française: les infections des voies respiratoires management of community-acquired lower respiratory tract infection in the adult. recommendations by the french language society of pneumology with collaboration of the french language society of infectious pathology, from the recommendations of the practice guidelines for the management of community-acquired pneumonia in olive et al. bmc infectious diseases infectious diseases society of america guidelines for the management of adults with community-acquired pneumonia. diagnosis, assessment of severity, antimicrobial therapy, and prevention european society of clinical microbiology and infectious diseases: guidelines for the management of adult lower respiratory tract infections xve conférence de consensus en thérapeutique anti-infectieuse: prise en charge des infections des voies respiratoires basses de l'adulte immunocompétent consensus guidelines on the management of community-acquired pneumonia in adults group: combination antibiotic therapy improves survival in patients with community-acquired pneumonia and shock a prediction rule to identify low-risk patients with communityacquired pneumonia international sepsis definitions conference: sccm/esicm/accp/ats/sis international sepsis definitions conference a new simplified acute physiology score (saps ii) based on a european/north american multicenter study the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure: on behalf of the working group on sepsis-related problems of the european society of intensive care medicine the logistic organ dysfunction system: a new way to assess organ dysfunction in the intensive care unit age, chronic disease, sepsis, organ system failure, and mortality in a medical intensive care unit the american-european consensus conference on ards cdc definitions for nosocomial infections levofloxacin. a review of its antibacterial activity, pharmacokinetics and therapeutic efficacy in-vitro activity of levofloxacin against streptococcus pneumoniae with various levels of penicillin resistance a multicenter, randomized study comparing the efficacy and safety of intravenous and/or oral levofloxacin versus ceftriaxone and/or cefuroxime axetil in treatment of adults with community-acquired pneumonia a multicenter, open-label, randomized comparison of levofloxacin vs azithromycin plus ceftriaxone in hospitalized adults with moderate to severe communityacquired pneumonia multicenter, open-label, randomized study to compare the safety and efficacy of levofloxacin versus ceftriaxone sodium and erythromycin followed by clarithromycin and amoxicillin-clavulanate in the treatment of serious communityacquired pneumonia in adults caulin e, for the levofloxacin study group: comparison of levofloxacin and cefotaxime combined with ofloxacin for icu patients with community-acquired pneumonia who do not require vasopressors cefotaxime acts synergistically with levofloxacin in experimental meningitis due to penicillin resistant pneumococci and prevents selection of levofloxacin-resistant mutants in vitro in vitro interaction between ofloxacin and cefotaxime against grampositive and gram negative bacteria involved in serious infections monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia international pneumococcal study group: combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia the acute respiratory distress syndrome network: ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock adjunctive therapies for community-acquired pneumonia: a systematic review intensive versus conventional glucose control in critically ill patients edusepsis study group: effectiveness of treatments for severe sepsis pre-publication history the pre-publication history for this paper can be accessed here severe pneumococcal pneumonia: impact of new quinolones on prognosis. bmc infectious diseases the writers thank g. moran for collaboration in the writing of this paper. authors' contributions do collected data and helped to draft the manuscript., hg participated in the design of the study, collected data and helped to draft the manuscript, pd performed the statistical analysis., nb collected data and helped to draft the manuscript, ac collected data and helped to draft the manuscript, am collected data and helped to draft the manuscript, sa collected data and helped to draft the manuscript, and ol contributed to the design of the study and wrote the manuscript. all authors read and approved the final manuscript. the authors declare that they have no competing interests. key: cord- -s udpwxq authors: seifi, najmeh; safarian, mohammad; nematy, mohsen; rezvani, reza; khadem-rezaian, majid; sedaghat, alireza title: effects of synbiotic supplementation on energy and macronutrients homeostasis and muscle wasting of critical care patients: study protocol and a review of previous studies date: - - journal: trials doi: . /s - - - sha: doc_id: cord_uid: s udpwxq background: an extreme and persistent dysbiosis occurs among critically ill patients, regardless of the heterogeneity of disease. dysbiosis in critically ill patients may make them prone to hospital-acquired infections, sepsis, multi-organ failure (mof), energy homeostasis disturbance, muscle wasting, and cachexia. modulation of gut microbiota through synbiotics can be considered as a potential treatment for muscle wasting and macronutrient homeostasis disturbances. methods: this is a prospective, single-center, double-blind, parallel randomized controlled trial with the aim to evaluate the effects of synbiotic supplementation on energy and macronutrient homeostasis and muscle wasting in critically ill patients. a total of hemodynamically stable, adult, critically ill patients who receive enteral nutrition via a nasogasteric tube (ngt) in the – h after admission to critical care will be included in this study. eligible patients will be randomly assigned to receive lactocare (zisttakhmir) capsules mg every h or a placebo capsule, which contains only the sterile maize starch and is similar to synbiotic capsules for days. the synbiotic and placebo capsules will be given through the nasogastric tube, separately from gavage, after feeding. discussion: gut microbiota modulation through synbiotics is proposed to improve clinical prognosis and reduce infectious complications, ventilator dependency, and length of icu stay by improving energy and macronutrient homeostasis and reducing muscle protein catabolism. trial registration: iranian registry of clinical trials, irct n . registered on march . the gut microbiota refers to the commensal microorganisms that reside in our gastrointestinal tract (git) with a symbiotic relationship [ ] . gut microbiota has a significant role in host metabolism and homeostasis [ , ] . a disturbance in this microbial community, which leads to an unhealthy state, is called dysbiosis [ ] . over the past decade, emerging evidence has demonstrated the role of intestinal dysbiosis in the pathogenesis of various conditions, such as infectious, immune, and metabolic diseases [ ] , while it has not been studied extensively in critical illness. an extreme and persistent dysbiosis occurs among critically ill patients, regardless of the heterogeneity of disease. the extreme dysbiosis in patients under critical care is due to the stress of critical illness, multiple antibiotics and additional pharmacological interventions, and highly processed enteral/parenteral nutrition [ , ] . dysbiosis in critically ill patients may make them prone to hospital-acquired infections, sepsis, multi-organ failure (mof), energy homeostasis disturbance, muscle wasting, and cachexia [ , , ] . the majority of patients in the intensive care unit (icu) have had a severe illness, trauma, or major surgery, and accordingly they are unable to manage their nutritional demands. although nutritional support is a daily practice in the icu, many patients still suffer from malnutrition due to lack of intake or uptake of nutrients [ ] . the prevalence of malnutrition in the icu within developed and developing countries is reported as . % and . %, respectively [ ] . malnutrition is independently associated with longer icu stay, more icu readmissions, and a higher incidence of infections and risk of mortality [ ] . a greater degree of malnutrition is also associated with a higher risk of -day mortality [ ] . malnutrition further tends toward acute or chronic loss of muscle bulk and function [ ] . the gut microbiota and their derived metabolites play an essential role in the absorption, storage, and consumption of energy derived from the diet [ , ] . previous studies suggest that modulating gut microbiota by novel therapeutics, such as prebiotics, probiotics, or synbiotics, can have an effect on gastrointestinal tolerance and complications of enteral nutrition, which eventually lead to the regulation of energy intake. recently, tuncay et al. showed that enteric formula with prebiotic content in patients under neurocritical care was associated with a significant increase in total feed volume and energy intake and a non-significant tendency to achieve a target dose of nutrition more frequently and earlier [ ] . malik et al. also found that in patients in the icu, receiving enteral formula supplemented with probiotics led to a faster return of gut function (tolerated feeding of % of their estimated required calories for h consecutively) [ ] . however, sanaie et al. demonstrated that daily energy and protein intake in patients receiving probiotic supplements on the icu were not significantly different from the group receiving placebo [ ] . in the critical care setting, diarrhea is the most obvious complication of enteral nutrition (en), which is associated with the inadequacy of energy and macronutrient intake [ ] . previous systematic reviews have confirmed the significant benefit of probiotics in the reduction of diarrhea in hospital patients overall. but a recent meta-analysis focused on patients in the icu found no benefit of probiotics in preventing or treating diarrhea [ ] . besides, in the dysbiosis state of critical illness, microbial products that reach distant organs like brain, adipose tissue, and liver, favor the development of immune-mediated diseases and metabolic alterations [ ] . gut microbiota metabolites like short-chain fatty acids (scfas) can also influence the immune system and host metabolism, which regulates energy homeostasis [ ] . thus, gut microbiota modulation may be beneficial in the regulation of immune and metabolic responses and energy homeostasis. muscle wasting, characterized by loss of muscle mass and strength, is associated with negative health outcomes such as functional disability, greater risk of infections, delayed recovery, poor life quality, and mortality [ ] . the gut microbiota have been reported to influence muscle metabolism. the molecular mechanisms of this gut-muscle axis remain to be identified. gut microbiota influence amino acid bioavailability and are sources of different metabolites, such as conjugated linoleic acid, acetate, and bile acids, which modulate muscle metabolism [ ] . various pathogen-associated molecular patterns (pamps) activate the transcription factor nuclear factor kappa light chain enhancer of activated b cells (nf-kb) through toll-like receptors (tlrs) and modulate the production of proinflammatory cytokines, which can induce muscle atrophy [ ] (fig. ) . modulation of gut microbiota through prebiotics, probiotics, or synbiotics can be considered as a potential treatment for muscle wasting and cachexia. in mouse models of leukemia, restoring lactobacillus species by oral supplementation with lactobacillus reuteri - and lactobacillus gasseri , reduces inflammatory cytokines and expression of muscle atrophy makers [ ] . in another study, bindels et al. showed that prebiotic supplementation in leukemic mice could contribute to delaying anorexia and fat mass sparing by inducing a metabolic shift in adipose tissue [ ] . in the mouse models of cancer cachexia, administration of a synbiotic supplement including inulin-type fructans and live l. reuteri - was associated with restoration of the gut barrier and immune function, thus reducing cachexia. it also prolonged survival [ ] . varian et al. also showed that probiotic administration in leukemic mice could inhibit cachexia by reducing systemic inflammation [ ] . considering the extreme dysbiosis in critically ill patients and related energy and macronutrients homeostasis disturbance and muscle wasting, prompted us to evaluate the effect of synbiotic supplementation on the elimination of this condition. to our knowledge, this is the first study to investiage the effect of synbiotic supplementation on muscle wasting in critically ill patients. the primary objective is to evaluate the effects of synbiotic supplementation on energy and macronutrient homeostasis and muscle wasting in patients under critical care. the secondary objective is to evaluate the effects of synbiotic supplementation on infectious complications and length of hospital and icu stay in patients under critical care. this is a prospective, single-center, double-blind, parallel randomized controlled trial that will be conducted in edalatian medical icu, emam reza hospital, mashhad, iran. the study protocol was written following the standard protocol items: recommendation for interventional trials (spirit) checklist (additional file ). participants must meet all the inclusion criteria to participate in this study: adults aged - years; admitted to the icu; hemodynamically stable within - h after admission; requiring exclusive enteral nutrition (en) via a nasogastric tube (ngt); not taking any kind of microbial cell preparations (prebiotics probiotics, synbiotics); estimated length of icu stay more than days; and provision of written consent. all candidates meeting any of the exclusion criteria at baseline will be excluded from study participation: pregnancy or lactation; any contraindication to en; any contraindication to insertion of the ngt; receiving immunosuppressive treatment, radiotherapy, or chemotherapy; hematologic disease; acquired immune deficiency syndrome (aids); transplant recipient; known allergy to microbial cell preparations; cancer or autoimmune diseases; artificial heart valve or congenital heart valve disease; estimated length of icu stay less than days; gastric disease; or gastrointestinal tract (gi) tract surgery. before the screening procedure, informed consent will be obtained from every participant who meets the inclusion criteria. first, we will describe the purpose of the study, the procedures involved, the length of time the subject is suspected to participate, any possible disadvantages or discomforts, the benefits of the study to society and individuals, and the person to contact for answers to further questions. we will also emphasize that participation is voluntary, and refusal or withdrawal will not cause any loss of benefits that they are entitled to receive. then the participants or their legal guardian will read and sign two copies of the written form. if, the informed consent was obtained from the patient's guardian because of the patient's lack of competence to consent and then later in the study the patient subsequently became competent as required, consent will be regained. after providing their written consent, patients are randomly allocated in a : ratio to the intervention or control group (a or b). patients will be randomized through a stratified sequential randomization plan generated online. randomization will be stratified by disease severity (acute physiology and chronic health evaluation (apache) ii, - and - ). for allocation concealment, we will use sealed opaque envelopes; inside each there is a carbon paper and the a or b card. to avoid probable selection bias, we will write the patient's name on the envelope before opening it. all patients, researchers, and medical staff will be blinded to the allocation to either synbiotic or placebo capsules. an available third party, the secretary of the icu, will be aware of whether a or b is allocated the synbiotic supplement. in the case of any complication associated with the intervention allocated, the medical staff will refer to the secretary for details. interventions, administration, and duration all eligible patients will receive standard hospital gavage as en through the ngt in the - h after admission to the icu. according to the recent european society of parenteral and enteral nutrition (espen) guideline on clinical nutrition in the icu [ ] , continuous rather than bolus en is preferred because it causes less diarrhea, but there is no difference in other outcomes. another systematic review showed that bolus feeding is associated with lower aspiration rate and better calorie attainment [ ] . it also provides a greater stimulus for protein synthesis [ ] . considering these data and the availability of bolus en in our hospitals we applied this method. in the absence of an indirect calorimeter, the simple weight-based equation of - kcal/kg/day in the acute flow phase and - kcal/kg/day in the anabolic flow phase is preferred for measurement of calorie requirements. for overweight and obese patients, ideal body weight: . × height (cm) − (male) (or − (female) is suggested as a reference weight [ ] . to avoid overfeeding, the en target will be prescribed within days in patients with high nutritional risk and within days in patients with low nutritional risk according to the modified nutrition risk in critically ill (nutric) score. the flow charts in figs. and will be used for initiation and continuation of en. in the intervention group, patients will receive lactocare (zisttakhmir) capsules mg every h for days. each capsule contains lactobacillus casei . × colony-forming units (cfu), lactobacillus acidophilus . × cfu, lactobacillus rhamnosus . × cfu, lactobacillus bulgaricus . × cfu, bifidobacterium breve × cfu, bifidobacterium longum × cfu, streptococcus thermophilus . × cfu, and fructooligosaccharides (fos). the probiotics capsule will be given through the ngt, separately from gavage, after feeding. patients in the control group will receive a placebo capsule, which contains only sterile maize starch and is similar to probiotic capsules. the liquid preparations ready for gavage through the ngt are also similar in color and odor. the pharmaceutical company will provide synbiotic and placebo capsules in distinct boxes identified as a or b. synbiotic capsules can be stored at room temperature for - weeks but the best condition for keeping this product is in the refrigerator at - °c. unused study products will be returned to the company supplying them. concomitant interventions will be: -it is common that patients under critical care receive at least one antibiotic during their icu stay. acute physiology and chronic health evaluation ii nutrition risk in critically ill on the other hand, it is believed that antibiotics have bacteriostatic or bactericidal effects on both pathogenic and non-pathogenic bacteria. so, it is recommended that probiotic and antibiotic administration be separated by at least h hours [ ] . -considering their analgesic and sedative properties, opioids are widely used in patients under critical care. opioids are believed to suppress the immune system and delay gi peristalsis [ ] . delayed peristalsis can increase bacterial translocation out of the gi tract [ ] . -prevention of gi tract (git) stress ulcers, through h receptor blockers or proton-pump inhibitors, is common in critical care practice. increase in gi -it is believed that the elevated level of catecholamines in patients under critical care, as prescribed exogenously beside endogenous production, can impair the immune system [ ] . these drugs are routinely administered in critical care practice, so we will record and consider them as conflicting factors. as the researcher will administer the capsules to the patients through the ngt, adherence assessment is not required. the schedule of evaluations is shown in table . as shown in fig. , calorie achievement goals are set according to the patients' modified nutric score. in everyday visits, we will evaluate gi signs and symptoms (e.g. vomiting, diarrhea, abdominal distention) and gastric residual volume (grv). if there is no sign or symptom of intolerance and grv is less than ml, en will be increased by %. otherwise, we will approach as fig. . energy homeostasis (calorie intakeestimated calorie requirement) will be recorded each day. mid-arm circumference, which is an available anthropometric measurement tool, will be evaluated twice a week. as all patients receiving en should be monitored for some clinical and laboratory variables, we set our monitoring approach as reported by berger mm, et al. [ ] , monitoring nutrition in the icu, clinical nutrition ( ). concomitant medications, pressure ulcers, infectious complications, and other adverse events will be recorded every day. the apache ii and sequential organ failure assessment (sofa) will be scored on days , , and . before and after the intervention, fasting blood and -h urine samples will be obtained. urine urea nitrogen, -methyl histidine, and creatinine will be measured in urine samples. fasting blood glucose, insulin, c-reactive protein (crp) and endotoxins will be measured in fasting blood samples. despite the ample evidence supporting the safety of probiotics in critically ill patients, there are case reports of risks and suggested theoretical risks related to probiotic administration. the most important is the risk of bacteremia and fungemia in high-risk populations, which may be associated with improper use and unintended contamination of central-line catheters [ ] . to avoid risk of bacteremia we will not include a high-risk population, such as patients who have recently had major surgery, or patients with short bowel syndrome, fig. . abbreviations: alt alanine aminotransferase, ast aspartate aminotransferase, apache ii acute physiology and chronic health evaluation ii, cl chloride, cr creatinine, gcs glasgow coma scale, grv gastric residual volume, k potassium, mg magnesium, na sodium, nutric nutrition risk in critically ill, p phosphorus, prealb pre-albumin, sofa sequential organ failure assessment, tg triglyceride heart valve disease, artificial heart valve, or patients who are immunocompromised. we will also pay careful attention to the proper administration and handwashing protocols. gene transfer and over-stimulation of the immune system are other suggested theoretical risks, on which there is not yet any evidence in humans [ ] . if intervention-related side effects exceed the level reported by previous studies, we will stop the intervention and present the results to the ethics committee of mashhad university of medical sciences (mums) for further decision making. if adverse events are caused by the study intervention, the researcher and medical team will provide timely and proper treatment to participants. data will be analyzed using the intention-to-treat approach. we did not find any similar study that has evaluated our primary objectives. so, we considered one of the main secondary objectives to estimate the required sample size. mahmoodpoor and co-workers [ ] reported the icu stay in two study groups as . ± and . ± . days. considering alpha error of . and power of %, the required sample size allowing for % dropout is patients in each group. the primary outcomes are . energy homeostasis (calorie intake-estimated calorie requirement) . protein catabolism (nitrogen balance) -nitrogen balance is a measure of the net change in total body protein. it is the difference between nitrogen eliminated from the body and nitrogen ingested in the diet. a positive or neutral nitrogen balance shows that protein stores are increased or maintained, while a negative nitrogen balance indicates protein mass is decreasing. the practical method for estimating nitrogen balance supposes that total nitrogen loss is equal to urinary urea nitrogen excretion plus g/day additional loss from non-urinary urea nitrogen, gastrointestinal, and insensible losses [ , ] . to measure the nitrogen balance, during the -h urine collection, the total intake of protein will be recorded to calculate nitrogen intake: -h urine samples will be immediately delivered to the laboratory to measure urea nitrogen. - mh is exclusively found in muscle proteins, and after protein degradation, it is rapidly excreted in the urine without further reutilization or metabolization. so, measuring urinary mh, after at least day of a meat-free diet, can be used as a biomarker of muscle protein breakdown [ , ] . after a -day meat-free diet, -h urine will be collected. urine samples will be centrifuged for min at ×g. the supernatant will be collected and stored at − °c for a maximum of months. the elisa method will be used for mh detection. -since -h urinary creatinine estimates the total pool of muscle proteins, muscle protein turnover can be calculated from the mh/creatinine excretion ratio [ ] . a -h urine sample will be delivered to the laboratory to immediately measure creatinine by the enzymatic method. -free glycerol is an important index of lipid metabolism. when the body uses stored fat as the energy supply, glycerol and fatty acids are released into the circulation. the absence of glycerol kinase in the adipocyte decreases triacylglycerol resynthesize and supports hepatic gluconeogenesis [ ] . after obtaining the overnight fasting blood sample, the serum will be separated. the serum sample will be stored at − °c for further measurement of free glycerol by enzymatic colorimetric method. . glucose homeostasis (fasting blood sugar (fbs), insulin) . inflammatory status (crp, neutrophil/lymphocyte ratio (nlr)) -nlr is an available measurable marker used to measure systemic inflammation. -intestinal gram-negative bacteria are the major source of lipopolysaccharides (lps), which are referred to as endotoxins. in the case of reduced intestinal barrier integrity due to dysbiosis, luminal endotoxins can enter the circulation [ ] . endotoxin activity assay (eaa) will be used to determine endotoxin levels in whole blood. the secondary outcomes are: . enteral feeding tolerance (abdominal examination and grv measurement) . clinical prognosis (apache and sofa score) . nutritional status (nutric score) . infectious complications incidence . pressure ulcer incidence and grade . ventilator-dependent days . length of icu stay . length of hospital stay . -day mortality data will be analyzed using spss for windows version . and medcalc statistical software version . . (medcalc software bvba, ostend, belgium; https://www. medcalc.org; ). descriptive (frequency, percentage, mean, standard deviation) and inferential analysis (student t test, paired sample t test, repeated measures analysis of variance (anova)) will be performed. any covariates will be controlled by ancova or binary logistic regression. all tests will be two-tailed and a p value < . will be considered as statistically significant. data collection will be supervised by the primary investigator. in addition, % of electronic data will be checked randomly with paper questionnaires and any discrepancies will lead to a % double-checking of electronic data. any outliers will be checked against patient medical records. in the intestinal tract, gut microbiota control different immune and endocrine functions [ ] . they have a major role in the absorption, storage, and consumption of energy derived from the diet [ , ] . outside the intestine, they also modulate cell metabolism, energy homeostasis, systemic inflammation, appetite and food intake [ , ] . on the other hand, a few clinical studies, modulating gut microbiota in patients under critical care demonstrated a faster return of gut function and earlier achievement of the nutritional target dose [ , ] . therefore, we expect that our patients in the intervention group will have a better enteric feeding tolerance and also more desirable energy homeostasis. animal studies have shown that modulation of gut microbiota by prebiotics, probiotics, or synbiotics can reduce cachexia and muscle mass sparing [ ] [ ] [ ] [ ] . the underlying mechanisms remain to be identified. gut microbiota influence amino acid bioavailability and are a source of different metabolites such as conjugated linoleic acid, acetate, and bile acids that modulate muscle metabolism. gut microbiota are also a source of pamps, which activate the transcription factor nf-kb through toll-like receptors (tlrs) and cause muscle wasting. gut microbiota also modulate production of proinflammatory cytokines, which can induce muscle atrophy [ ] . we expect that synbiotic intervention in patients under critical care reduces muscle protein degradation and turnover. as malnutrition and muscle wasting in these patients are associated with negative health outcomes, gut microbiota modulation will improve the clinical prognosis and reduce infectious complications, ventilator dependency, and length of icu stay. recruitment was started on march and is estimated to be completed by october . recruitment was ongoing at the time of submission. this is the last protocol version (number , january ). additional file . standard protocol items: recommendation for interventional trials (spirit) checklist: recommended items to address in a clinical trial protocol and related documents. the support provided by mashhad university of medical sciences (mums) to conduct this study is highly acknowledged. participants' study information will be stored at the security site. all laboratory specimens, data collected, and reports will be identified by a coded id number. we will attempt to release the full study protocol and results as soon as possible, regardless of the magnitude or direction of effect. the anonymized data set and statistical code may be available from the corresponding author on reasonable request. authors' contributions ns and ms initially conceptualized and designed the study. ms, as, mn, and rr upgraded the protocol design and contributed to obtaining initial funding. the manuscript was written by ns and reviewed by all members. mkr was responsible for design optimizing and statistical analysis. all authors read and approved the final manuscript. this research will be funded by the vice chancellery for research of mashhad university of medical sciences (mums), and all study stages will be undertaken under its supervision. the datasets generated and/or analyzed during the current study are not publicly available due to ethical considerations, but may be available from the corresponding author on reasonable request. ethics approval and consent to participate ethical approval was obtained from ethical committee of mums. the ethical approval code is ir.mums.medical.rec. . . the informed consent will be obtained from all study participants or their legal guardian. any modification to protocol which may impact on the conduct of the study, will be approved by ethical committee of mums prior to implementation. gut microbiota in health and disease current understanding of the human microbiome the role of the microbiome in human health and disease: an introduction for clinicians the impact of probiotics' administration on glycemic control, body composition, gut microbiome, mitochondria, and other hormonal signals in adolescents with prediabetesa randomized, controlled trial study protocol gut microbiota: an integral moderator in health and disease role of the microbiome, probiotics, and 'dysbiosis therapy' in critical illness the re-emerging role of the intestinal microflora in critical illness and inflammation: why the gut hypothesis of sepsis syndrome will not go away muscle wasting: the gut microbiota as a new therapeutic target? gut barrier dysfunction and microbial translocation in cancer cachexia: a new therapeutic target malnutrition in critically ill patients in intensive care units association between malnutrition and clinical outcomes in the intensive care unit: a systematic review association between malnutrition and -day mortality and intensive care length-ofstay in the critically ill: a prospective cohort study diagnostic criteria for malnutrition-an espen consensus statement gut microbiota, nutrient sensing and energy balance gut microbiota and energy balance: role in obesity use of standard enteral formula versus enteric formula with prebiotic content in nutrition therapy: a randomized controlled study among neuro-critical care patients microbial cell preparation in enteral feeding in critically ill patients: a randomized, doubleblind, placebo-controlled clinical trial effect of a multispecies probiotic on inflammatory markers in critically ill patients: a randomized, double-blind, placebocontrolled trial probiotic and synbiotic therapy in critical illness: a systematic review and meta-analysis the immune system bridges the gut microbiota with systemic energy homeostasis: focus on tlrs, mucosal barrier, and scfas muscle loss: the new malnutrition challenge in clinical practice restoring specific lactobacilli levels decreases inflammation and muscle atrophy markers in an acute leukemia mouse model non digestible oligosaccharides modulate the gut microbiota to control the development of leukemia and associated cachexia in mice synbiotic approach restores intestinal homeostasis and prolongs survival in leukaemic mice with cachexia beneficial bacteria inhibit cachexia espen guideline on clinical nutrition in the intensive care unit effectiveness of continuous enteral nutrition versus intermittent enteral nutrition in intensive care patients: a systematic review intermittent versus continuous feeding in critically ill adults treatment of opioid-induced gut dysfunction bacterial translocation: overview of mechanisms and clinical impact gastric acid reduction leads to an alteration in lower intestinal microflora probiotics in the critical care unit: fad, fact, or fiction? monitoring nutrition in the icu effect of a probiotic preparation on ventilator-associated pneumonia in critically ill patients admitted to the intensive care unit: a prospective double-blind randomized controlled trial assessment of protein and energy nutritional status. nutritional management of renal disease nitrogen balance and protein requirements for critically ill older patients clinical usefulness of urinary -methylhistidine excretion in indicating muscle protein breakdown the influence of dietary habits and meat consumption on plasma -methylhistidine-a potential marker for muscle protein turnover lipolysis in adipocytes understanding intestinal lipopolysaccharide permeability and associated inflammation interaction between obesity and the gut microbiota: relevance in nutrition role of gastrointestinal hormones in feeding behavior and obesity treatment publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations no personal identifying information will be published. the authors declare that they have no competing interests. key: cord- -hrkj y o authors: villa, gianluca; amass, timothy; giua, rosa; lanini, iacopo; chelazzi, cosimo; tofani, lorenzo; mcfadden, rory; de gaudio, a. raffaele; omahony, sean; levy, mitchell m.; romagnoli, stefano title: validation of end-of-life scoring-system to identify the dying patient: a prospective analysis date: - - journal: bmc anesthesiol doi: . /s - - -y sha: doc_id: cord_uid: hrkj y o background: the “end-of-life scoring-system” (ending-s) was previously developed to identify patients at high-risk of dying in the icu and to facilitate a practical integration between palliative and intensive care. the aim of this study is to prospectively validate ending-s in a cohort of long-term critical care patients. materials and methods: adult long-term icu patients (with a length-of-stay> days) were considered for this prospective multicenter observational study. ending-s and sofa score were calculated daily and evaluated against the patient’s icu outcome. the predictive properties were evaluated through a receiver operating characteristic (roc) analysis. results: two hundred twenty patients were enrolled for this study. among these, . % died during the icu stay. ending-s correctly predicted the icu outcome in . % of patients. sensitivity, specificity, positive and negative predictive values associated with the previously identified ending-s cut-off of . were . , . , and . %, respectively. roc-auc for outcome prediction was . for ending-s and . for sofa in this cohort. conclusions: ending-s, while not as accurately as in the pilot study, demonstrated acceptable discrimination properties in identifying long-term icu patients at very high-risk of dying. ending-s may be a useful tool aimed at facilitating a practical integration between palliative, end-of-life and intensive care. trial registration: clinicaltrials.gov identifier: nct ; first registration august , . being aware of the value of palliative care services to help meet the families' and patients' needs and align therapy to the prognosis of the patient balanced with their preferences and values [ , ] . beyond those clearly at the final stages of irreversible diseases (i.e. end-of-life), all patients admitted in the icu require an early integration between a comprehensive palliative approach and intensive care treatment [ , ] . the probability of dying of each critical care patient should be evaluated early on at the icu admission and continuously reassessed during the entire icu length of stay; the amount of palliative care treatments should thus be integrated accordingly [ ] . although excellent scoring systems are available in the icu for prognostic and clinical monitoring purposes (e.g. acute physiologic assessment and chronic health evaluation, apache, and sequential organ failure assessment score, sofa [ ] ), an accurate identification of end-of-life patients in the icu is still cumbersome [ ] [ ] [ ] . as example, the usefulness of several scores (e.g. the apache score) is mainly validated at the icu admission, when the patients' responsiveness to intensive care treatments is not clear yet. other scoring systems (e.g. the sofa score) are well validated to monitor the organ dysfunctions over time in the icu; nevertheless, the requirement of biochemical data for the scoring calculation may limit their routine use/daily application [ ] . finally, the requirement for, and to what degree, palliative care should be integrated with intensive care for all icu patients is often not objectively defined and instead determined by individual physician's perspective [ , ] . the "end-of-life scoring-system" (ending-s) was previously developed to: ) identify patients at very high risk of dying in the icu and ) facilitate a practical integration between palliative, end-of-life and intensive care treatments [ ] . in a pilot study, ending-s presented acceptable calibration and discrimination properties in identifying patients at very high risk of dying in the icu, with a receiver operating characteristic-area under the curve (roc-auc) analysis equal to . ( %ci, . to ) and agreement between the predicted probability and the observed frequency of death in the icu (p > . at hosmer-lemeshow test) were preliminarily observed [ ] . the aim of this observational study is to prospectively validate ending-s in a cohort of critical care patients with an icu length of stay longer than days. this observational prospective study was performed in three icus: rhode island hospital's medical icu (providence ri), rush medical center's medical icu (chicago il) and azienda ospedaliera universitaria careggi's surgical and medical icu (florence italy). the institutional review boards of each center reviewed and approved the protocol (clinicaltrials.gov identifier: nct ; first retrospective registration: august , ). written consent for analysis and publication of clinical data was obtained from all consentable patients. if the patient was not able to sign consent forms at the study enrollment, permission for analysis and publication of clinical data was obtained from a surrogate or waived in accordance with local ethics committee. all adult patients admitted in the icu from september to march were considered eligible for the study. patients admitted to the icu for end-of-life care were excluded. in order to consider only the long-term icu patients, those with an icu length of stay shorter than days were excluded from the analysis. data abstraction forms were prospectively completed for all eligible patients. in particular, ending-s and sofa scores were calculated daily from the icu day to the icu discharge for each enrolled patient. in accordance with the previous paper [ ] , ending-s score was calculated as: where days of mv/icu los expresses the ratio between the current days in which the patient requires mechanical ventilation (mv) and the current icu length of stay (los, quantitative variable), days of vasoactive drugs/icu los expresses the ratio between the current days in which the patient requires vasoactive drugs and the current icu length of stay (quantitative variable), sepsis expresses a septic condition (dichotomous variable: if currently affected, otherwise ), icu los expresses the current icu length of stay (quantitative variable). the icu patients' management has not changed according to the value of ending-s observed. according to the patients' outcome, the enrolled population was divided into two groups, either "survived" or "died". death in the icu being used as a surrogate to identify those icu patients that had been at the end of their life prior to death. for "died" patients, maximization of palliative care and end-of-life care are thus certainly required. for "survived" patients, a certain form of palliative care is required according to the patients' multidimensional evaluation and expected prognosis, but very unlikely these patients require end-of-life care. the association between the daily values of ending-s and patients' outcome at the icu discharge was tested through a logistic regression analysis (or, % ci). the ending-s predictive properties were evaluated with a roc analysis. the effectiveness of ending-s cut-off . was previously validated for prediction of death during the icu stay. the positive predictive value (ppv), negative predictive values (npv), sensitivity and specificity of ending-s were calculated. similarly, the association between the daily values of sofa score and patients' outcome was tested through a logistic regression analysis. the effectiveness of sofa score was assessed for prediction of death during the icu stay. in the absence of a specific cut-off point, only a roc analysis was performed for this scoring system. continuous parameters observed in the population are reported as median [interquartile range] or mean ± standard deviation (sd), where appropriate; dichotomous parameters are expressed as crude number and percentage. a pvalue of . has been considered for statistical significance. data was analyzed using stata . software (stata corp, , lakeway drive college station, , , texas, us). nine hundred and eleven patients were prospectively screened for this multicenter study. among these, patients had an icu length of stay longer than days and thus prospectively enrolled and considered for the analysis. the enrollment procedures are reported in fig. . among the enrolled patients, . % ( / ) died during the icu stay, while . % ( / ) survived and were discharged from the icu. the patients' characteristics, for both survivor and death groups, are reported in table . among patients who died, of ( . %) had ending-s values higher than . (true positive), while the remaining ( . %) had at least an ending-s < . during the icu stay (false negative). however, among patients who survived to icu discharge, of ( . %) had ending-s values smaller than . (true negative), while the remaining ( . %) had at least an ending-s ≥ . during the icu stay (false positive). given these characteristics, ending-s correctly predicted for patients ( / sensitivity and specificity associated with ending-s cut-off of . were . and . %, respectively; positive and negative predictive values were and . %, respectively. roc-auc of . was found for ending-s in this validation set (fig. , panel a) , % ci [ . - . ]. fig. the enrollment process. over the entire population potentially eligible for this prospective study, patients were excluded because admitted in the icu for comfort measure only (cmo), for lack of family members (required for the qualitative analysis of the study, data not presented), or because pregnant or prisoner. in order to consider only "long term" icu patients, those with an icu length of stay (los) < days were excluded. finally, patients refused to be enrolled in this observational study, forms were not completed for patients ( consent form and clinical data forms) and patients were excluded because not english or italian native speaking considering daily values of sofa score both for survived and not survived patients, a mean sofa score of . ± . was observed for patients who died, while ± . was observed for patients who survived at the icu discharge. a roc-auc of . ( %ci . - . ) was found for daily values of sofa score in predicting icu death (fig. , panel b) . in this observational study, the previously defined ending-score was prospectively tested in a cohort of critical care patients with an icu length of stay longer than days in order to validate its discriminative effect in identifying patient at very high risk of dying in the icu. the comparison between the icu outcome observed for every enrolled patient and that expected according to the ending-s cut-off of . reveals a direct association between ending-s and patients' icu outcome p < . ). in particular, every incremental increase in ending-s value increased the or estimate of death in the icu by . . compared with discrimination properties showed by ending-s in the pilot study, less efficient characteristics were observed in this prospective validation. indeed, a roc-auc of . ( %ci, . - . ) was observed in similar to the roc-auc, the sensitivity and specificity values previously observed in the pilot study are reduced in this external validation study [ ] . the identification of end-of-life patients is quintessential for an adequate integration between qualitative and intensive care treatments during the icu stay [ , ] . notably, palliative care should not be considered as an alternative for the intensive care in these patients; this care should instead be concomitantly made available for the patients and their family early on from the icu admission [ ] . the importance of palliative care with respect to intensive care should be proportional with the probability that the patient is at very high risk of dying in the icu and in accordance with the specific patient and family needs. identification of the patient at very high risk of dying is not the only limitation for palliative care integration in the icu [ ] . indeed, the "relative amount" of palliative care that should be considered adequate for a specific patient in a specific moment during the icu stay is difficult to define. most of data in literature show that the management of palliative and end-of-life care is still determined by the physician's subjective experiences, religion, level of expertise and other nonobjective and unquantifiable variables [ , , [ ] [ ] [ ] . used beside other tools and comprehensive clinical evaluations, this objective tool, able to accurately identify dying patients and to suggest the adequate ratio between qualitative and intensive care for those patients at very high-risk of dying in the icu, might help the physician appropriately integrate palliative care in the icu [ ] . assuming that the progression toward end-of-life should be characterized by an increasing presence of palliative care in the global management of the patient, the probability of being at very high risk of death in the icu can be used as an indicator of the percentage need of palliative and mainly end-of-life care integration. treatments based on patients' and families' needs (i.e. targeted on communication, psychological, social personal and/or spiritual well-being), should be progressively prioritized within the efforts of the health care team. in these terms, evaluating the ending-s and sofa score might also be potentially useful for guiding palliative care integration in the icu (fig. ) . while sofa does outperform ending-s, ending-s may still be considered clinically useful when compared to a sofa score in two ways. first, the negative predictive value of ending-s of . % suggests that an ending-s score less than . is clinically valuable in aiding clinicians in identifying patients that are likely to survive. combining this with the fact that an ending-s score does not require any laboratory data as the sofa score does, ending-s can be calculated every day, easily, on each patient. sofa score requires laboratory data which was often missing in this cohort limiting the usefulness of a sofa score in providing daily prognostic information. another important difference between ending-s and sofa score is in the variation during the icu length of stay of clinically stable patients who spend their end-oflife period in the icu before dying. although in critical condition, several patients have high and unchanged values of sofa score over time, specifically before dying. thus, a prognostic tool only based on sofa score would not change, failing to alert the physician to the increasing amount of palliative and end-of-life care required for that patient. on the other hand, as ending-s is influenced by the progression of days spent in the icu, it increases over time even in absence of clinical changes. this suggests that, by virtue of staying in the icu, patients could require a progressively increasing amount of qualitative care over time. there are several limitations in this study; among these, the use of icu mortality as a surrogate to identify end-of-life is the most important. the aim of ending-s is to identify those patients likely being at very high risk of dying in the icu and suggest the physician to appropriately consider palliative care integration for these patients. interestingly, an objective definition of end-of- for each patient, the higher the ending-s or sofa score, the higher the probability of icu death, the higher the amount of palliative care interventions (in green) that should be integrated with intensive care treatment (in blue). palliative care and intensive care should not be mutually exclusive; they should instead integrate each-other during the entire course of the patient's disease from the diagnosis and the initial organ dysfunction to the occurrence of multiorgan failure and end-of-life condition (within the dashed line). an appropriate scoring system should be characterized by a slope in score/ outcome probability able to promote intensive care and palliative care integration continuously, and across different levels of patient's severity life status is still lacking in clinical practice, even for patients who are not hospitalized [ ] . for this reason, as in other papers [ , ] , the outcome observed at the icu discharge has been used as a surrogate for end-of-life condition for patients both enrolled in the pilot study and for those enrolled in this prospective validation. notably, despite death in the icu certainly being associated with the end-of-life of patients, icu survival does not necessarily exclude the end-of-life condition or the requirement of palliative care [ ] . unfortunately, a systematic follow-up for patients discharged from the icu is lacking in this study. another important conceptual limitation refers to the exclusive use of the patient's prognosis to guide the palliative care/intensive care integration. several authors agree that palliative care should be based on needs of patients and their family instead of being exclusively based on patients' prognosis. a comprehensive qualitative evaluation should be integrated on ending-s parameters to further improve its role in guiding palliative care. issues such as patients and family needs, perception of the disease, communication between family members and with health care providers should be considered and analyzed with this aim. although values observed in the pilot study resulted in a slightly overestimated prediction model, acceptable discrimination properties have been demonstrated for ending-s in identifying patients at very high risk of dying with an icu stay longer than days. although sofa score was more effective and accurate in predicting patients' death in the icu, the ending-s score offers the benefit of not requiring laboratory data, a strong negative predictive value for icu death, and daily changes by including length of stay. these factors may allow ending-s to be meaningfully integrated into daily practice and aid in the integration between palliative, end-of-life and intensive care. nevertheless, further prospective validations and comparisons between edning-s and other standardized score are necessarily to better characterize the clinical application of this tool. end-of-life decision-making and quality of icu performance: an observational study in italian units use of intensive care at the end of life in the united states: an epidemiologic study* the right choice at the right time end of life care in italian intensive care units: where are we now? minerva anestesiol family care rituals in the icu to reduce symptoms of post-traumatic stress disorder in family members-a multicenter, multinational, before-and-after intervention trial implementing primary palliative care best practices in critical care with the care and communication bundle organ dysfunction scores in icu end-of-life decision making in the intensive care unit a practical tool to identify patients who may benefit from a palliative approach: the caring criteria medical futility: predicting outcome of intensive care unit patients by nurses and doctors--a prospective comparative study development of end-oflife scoring-system to identify critically ill patients after initial critical care who are highly likely to die: a pilot study instruments for the identification of patients in need of palliative care: a systematic review protocol of measurement properties physicians ' perceptions of the value of prognostic models : the benefits and risks of prognostic confidence effect of a quality-improvement intervention on end-of-life care in the intensive care unit: a randomized trial meeting standards of high-quality intensive care unit palliative care: clinical performance and predictors developing guidelines that identify patients who would benefit from palliative care services in the surgical intensive care unit end-of-life practices in european. units: the ethicus study end-oflife practices in european intensive care units: the ethicus study hospital variation and temporal trends in palliative and end-of-life care in the icu palliative care in the cardiac intensive care unit predictors of death in an intensive care unit: contribution to the palliative approach tt -fatores preditores de óbito em unidade de terapia intensiva: contribuição para a abordagem paliativista early palliative care reduces end-of-life intensive care unit (icu) use but not icu course in patients with advanced cancer publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. we have the following interests: gv received from baxter honoraria for lectures, from pall international support for travel expenses, hotel accommodations, and registration to meetings. sr received from baxter, orion pharma, and vygon honoraria for lectures, from icu medical, msd and medtronic grants for consultancy, form baxter, bbraun, pall international, and vygon support for travel expenses, hotel accommodations, and registration to meetings. cc received support for meetings (travels, hotel accommodations, and/or registration) by bbraun, astellas, msd, pfizer, pall international, baxter, and orion pharma, for lectures by orion pharma. ardg received research grants from msd italia, baxter, pall international. there are no patents, products in development or marketed products to declare. this does not alter our adherence to all the journal policies. authors' contributions g. v.: this author substantial helped to conception and design, acquisition of data, analysis and interpretation of data; t. a.: this author was accountable for all aspects of the work thereby ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved; r. g.: this author helped to conception and design, acquisition of data; i. l.: this author helped to conception and design the study; c. ente cassa di risparmio di firenze (grant number . ), the "cox foundation" (grant number: na), the "philip and irene toll gage foundation" (grant number: na) and the national heart lung and blood institute (nhlbi grant number: t hl ) have economically supported the feasibility and management of this study through research grants aimed at study coordination, statistical analysis and recruitment of investigators for this study. the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. the datasets analysed during the current study are available from the corresponding author on reasonable request. the institutional review boards of each center reviewed and approved the protocol; in particular the "comitato etico area vasta toscana centro" approved the study protocol for the azienda ospedaliero universitaria careggi in florence, the internal review board of the rhode island hospital approved the study protocol in providence and the internal review board of the rush university medical center approved the study protocol in chicago. (clinicaltrials.gov identifier: nct ). written consent for analysis and publication of clinical data was obtained from all consentable patients. if the patient was not able to sign consent forms at the study enrollment, permission for analysis and publication of clinical data was obtained from a surrogate or waived in accordance with local ethics committee. all methods of consent were approved by the appropriate ethics committees. not applicable. key: cord- -n d fw f authors: ong, david s. y.; spitoni, cristian; klein klouwenberg, peter m. c.; verduyn lunel, frans m.; frencken, jos f.; schultz, marcus j.; van der poll, tom; kesecioglu, jozef; bonten, marc j. m.; cremer, olaf l. title: cytomegalovirus reactivation and mortality in patients with acute respiratory distress syndrome date: - - journal: intensive care med doi: . /s - - -z sha: doc_id: cord_uid: n d fw f purpose: cytomegalovirus (cmv) reactivation occurs frequently in patients with the acute respiratory distress syndrome (ards) and has been associated with increased mortality. however, it remains unknown whether this association represents an independent risk for poor outcome. we aimed to estimate the attributable effect of cmv reactivation on mortality in immunocompetent ards patients. methods: we prospectively studied immunocompetent ards patients who tested seropositive for cmv and remained mechanically ventilated beyond day in two tertiary intensive care units in the netherlands from to . cmv loads were determined in plasma weekly. competing risks cox regression was used with cmv reactivation status as a time-dependent exposure variable. subsequently, in sensitivity analyses we adjusted for the evolution of disease severity until onset of reactivation using marginal structural modeling. results: of ards patients, ( %) were cmv seropositive and reactivation occurred in ( %) of them. after adjustment for confounding and competing risks, cmv reactivation was associated with overall increased icu mortality (adjusted subdistribution hazard ratio (shr) . , % ci . – . ), which resulted from the joint action of trends toward an increased mortality rate (direct effect; cause specific hazard ratio (hr) . , % ci . – . ) and a reduced successful weaning rate (indirect effect; cause specific hr . , % ci . – . ). these associations remained in sensitivity analyses. the population-attributable fraction of icu mortality was % ( % ci – ) by day (risk difference . , % ci . – . ). conclusion: cmv reactivation is independently associated with increased case fatality in immunocompetent ards patients who are cmv seropositive. electronic supplementary material: the online version of this article (doi: . /s - - -z) contains supplementary material, which is available to authorized users. abstract purpose: cytomegalovirus (cmv) reactivation occurs frequently in patients with the acute respiratory distress syndrome (ards) and has been associated with increased mortality. however, it remains unknown whether this association represents an independent risk for poor outcome. we aimed to estimate the attributable effect of cmv reactivation on mortality in immunocompetent ards patients. methods: we prospectively studied immunocompetent ards patients who tested seropositive for cmv and remained mechanically ventilated beyond day in two tertiary intensive care units in the netherlands from to . cmv loads were determined in plasma weekly. competing risks cox regression was used with cmv reactivation status as a time-dependent exposure variable. subsequently, in sensitivity analyses we adjusted for the evolution of disease severity until onset of reactivation using marginal structural modeling. results: of ards patients, ( %) were cmv seropositive and reactivation occurred in ( %) of them. after adjustment for confounding and competing risks, cmv reactivation was associated with overall increased icu mortality (adjusted subdistribution hazard ratio (shr) . , % ci . - . ), which resulted from the joint action of trends toward an increased mortality rate (direct effect; cause specific hazard ratio (hr) . , % ci . - . ) and a reduced successful weaning rate (indirect effect; cause specific hr . , % ci . - . ). these associations remained in sensitivity analyses. the although the burden of cytomegalovirus (cmv) disease has been well established in immunocompromised patients [ ] , cmv viremia has also been described in intensive care unit (icu) patients without known prior immune deficiency. this almost exclusively results from systemic viral reactivation, and incidence rates of up to % have been reported in critically ill cmv seropositive subjects [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . furthermore, cmv reactivation in critically ill patients has been associated with a prolonged duration of mechanical ventilation [ , , [ ] [ ] [ ] [ ] [ ] , an increased length of stay in the icu [ , , , , ] , and excess mortality [ , , [ ] [ ] [ ] . nevertheless, it remains uncertain whether these findings imply that cmv reactivation is a truly independent risk factor with respect to these observed poor clinical outcomes because most studies that have assessed these associations did not adequately account for all possible sources of bias. as a consequence, cmv viremia might merely be a marker of illness severity, contributing only little to the overall burden of disease. to achieve an accurate estimation of the true effect of cmv reactivation on clinical outcome, it is crucial in observational studies to adjust for the time-dependent occurrence of cmv reactivation and the evolution of disease severity prior to its onset. moreover, the presence of competing events should be taken into account when follow-up time is censored [ ] . for instance, when icu mortality is the outcome, then icu discharge is a competing risk that prohibits the event of interest from occurring first. patients with acute respiratory distress syndrome (ards) often have a long and complicated disease course in the icu, which portends a particular risk for viral reactivations [ , ] . despite the uncertainties regarding the clinical relevance of cmv disease in immunocompetent critically ill patients, it is etiologically plausible that virus reactivation adds to the pulmonary pathology in patients with ards. in experimental murine studies, cmv reactivation caused exacerbated and prolonged cytokine and chemokine expression in lung tissues, which eventually led to increased pulmonary fibrosis compared to controls [ ] . in a clinical study of open lung biopsies in ards patients with prolonged respiratory failure or in whom microbiological cultures remained negative, cmv pneumonia was found in % of cases [ ] . both findings suggest that cmv-related pulmonary pathology may be causally linked to the clinical disease course following ards onset, especially in the most severely ill patients who require prolonged mechanical ventilation. if cmv reactivation does contribute to poor clinical outcome in these patients, either prophylaxis or pre-emptive therapy with (val)ganciclovir may be considered. the aim of this study was to estimate the proportion of deaths that can be attributed to systemic reactivation of cmv in ards patients who are latent carriers of the virus. some results of this study have been previously reported in the form of an abstract [ ] . the present study was conducted within the framework of the molecular diagnosis and risk stratification of sepsis (mars) cohort (clinicaltrials.gov identifier: nct ) for which the institutional review board approved an opt-out method of informed consent (protocol number - c) [ ] . we prospectively included consecutive adults who presented with ards to the mixed icus of two tertiary care hospitals in the netherlands between january and december and required mechanical ventilation beyond day of icu admission. since data collection for our study started before publication of the berlin definition in , ards was defined according to the american-european consensus conference criteria [ ] : that is, the diagnosis required an acute onset of symptoms, the presence of bilateral infiltrates on chest radiography, a pulmonary artery occlusion pressure less than mmhg and/or the absence of left ventricular dysfunction, and pao /fio ratio (p/f) less than . we excluded patients who had received (val)ganciclovir, (val)acyclovir, cidofovir, or foscarnet in the week before icu admission and those with known immunodeficiency [ ] . immunodeficiency was defined as a history of solid organ or stem cell transplantation, infection with the human immunodeficiency virus, hematological malignancy, use of immunosuppressive medication (more than . mg prednisone per kilo for more than months, more than mg prednisone per day for more than week, or equivalent), chemotherapy/radiotherapy in the year before icu admission, and any known humoral or cellular immune deficiency. leftover plasma, which was harvested from blood samples obtained daily as part of routine patient care, was stored at - °c within h after blood draw. cmv serostatus was determined by an enzyme immunoassay (enzygnost cmv/igg, siemens healthcare diagnostic products, marburg, germany). subsequently, in seropositive patients only, viral loads in plasma were determined by real-time taqman cmv-dna polymerase chain reaction [ ] . cmv loads were determined on a weekly basis for a maximum of days following study inclusion (i.e., day of icu admission). for intermediary days, on which quantitative pcr was not performed, we estimated viral loads by log-linear imputation. cmv reactivation was defined as a viral load of at least international units per milliliter (iu/ml), as calibrated according to the cmv world health organization (who) standard. screening for cmv was not part of routine clinical practice in either participating hospital. neither serology results nor viral loads measured as part of our study were made available to the treating physicians, and none of the included patients therefore received antiviral treatment directed against cmv. mortality was the outcome of primary interest in this study and was defined as death on mechanical ventilation before day (i.e., day following study inclusion). successful weaning, which is a competing event of the primary outcome, was defined as complete liberation from mechanical ventilatory support on two or more consecutive days before day . we considered distal end points more likely to be amenable by pre-existing comorbidities, as well as specific end-of-life practices, bed availability, and other local factors. nonetheless, in a subsequent sensitivity analysis, we used discharge and death in icu as alternative end points. for our primary analyses we used cox proportional hazards modeling, in which mortality and successful weaning were considered as competing events and cmv reactivation status was fitted as a time-dependent variable. possible confounders that were screened included all patient characteristics and therapeutic interventions listed in table , and some markers of disease severity: acute physiology and chronic health evaluation apache acute physiology and chronic health evaluation, ards acute respiratory distress syndrome, copd chronic obstructive pulmonary disease, icu intensive care unit, peep positive end expiratory pressure, p/f partial pressure of oxygen in arterial blood to fraction of inspired oxygen ratio (apache) iv score, presence of septic shock, partial pressure of oxygen in arterial blood to fraction of inspired oxygen ratio, and positive end expiratory pressure (peep) setting. to account for possible confounding, we included baseline covariables that showed differences between the reactivated and non-reactivated groups at a p value of less than . , and changed the crude effect estimates for either mortality or weaning by more than %. we included only the strongest (possible) confounders by using these two criteria combined in order to avoid statistical overfitting (i.e., incorporating too many variables given the limited number of events). the two possible outcomes are interrelated as increased mortality may negatively impact the duration of mechanical ventilation. a competing risks analysis accommodates for this by providing two measures of association. first, the cause-specific hazard ratio (cshr) estimates the direct effects of cmv reactivation on each outcome of interest (i.e., mortality on the ventilator and successful weaning). second, the subdistribution hazard ratio (shr) estimates the risk of dying from reactivation at a given time-point, while accounting for the competing risk of successful weaning. to obtain direct estimates of cumulative risks in terms of the shr we used the fine and gray model [ ] . finally, to estimate the populationattributable fraction of mortality due to cmv reactivation, we used a multi-state model (fig. s ), which accounts for the time of reactivation [ ] . confidence intervals were calculated by bootstrap resampling [ , ] . despite these efforts to accurately assess the effect of cmv reactivation on clinical outcomes, residual confounding may still remain, because markers of illness at baseline (which we included in all multivariable analyses) may no longer be representative of the disease state at the time of reactivation onset. thus, we performed a sensitivity analysis using marginal structural modeling to adjust for the evolution of disease severity prior to the onset of cmv reactivation (see also supplementary material) [ , ] . such analysis first involves estimation of the daily probabilities of cmv reactivation using a multivariable logistic regression model that includes markers of disease severity on a daily basis. these probabilities are used to calculate an inversed probability weight that is then included as a summary measure of all relevant covariables in the final cox regression model. however, because marginal structural modeling requires many assumptions that are difficult to be checked, we considered this a sensitivity analysis only. data were analyzed with sas . (cary, nc, usa) and r . . software (r foundation for statistical computing, vienna, austria; packages ''etm'', ''mstate'', ''ipw''). we enrolled patients with ards who required mechanical ventilation for more than days (fig. s ). of these were excluded because of known prior immunocompromise or antiviral treatment and two were excluded because of missing samples. subsequently, ( %) patients tested seropositive for cmv and were thus included in the study. ards was of primary pulmonary origin in ( %) of these cases, whereas the remainder was of secondary etiology (e.g., associated with non-pulmonary sepsis, major surgery, or blood transfusion). cmv reactivation cmv reactivation occurred in ( %) of the included patients (table ). these patients more frequently hadat the time of icu admission-concurrent septic shock, higher apache iv scores, and renal insufficiency compared to patients who never had cmv reactivation. in addition, a larger proportion of these patients were receiving high dose corticosteroid therapy during the first days in icu. the median time from icu admission to onset of reactivation was . days (interquartile range (iqr) - ). within the subgroup of patients acquiring cmv reactivation the proportion of individuals having relatively high viral loads (at least iu/ml) increased over time (fig. ) . in a patient population that is selected by an icu stay of at least weeks, the proportion with cmv viremia is as high as of patients ( %). on day after study inclusion (this was days following icu admission) ( %) patients had died, the quantitative pcr results were calibrated according to the cmv who standard; viral loads greater than or equal to iu/ml were denoted 'high reactivation'. viral loads of - iu/ml were denoted 'low reactivation', and undetectable loads or viral loads below iu/ml were denoted 'no reactivation' ( %) were successfully weaned, and ( %) remained still on mechanical ventilation (table ). in crude analyses, patients with cmv reactivation had both a longer duration of mechanical ventilation ( (iqr - ) vs. (iqr - ) days; p \ . ) and higher mortality ( of ( %) vs. of ( %) patients; p \ . ) compared to subjects without reactivation. table shows the results of the various cox survival regression analyses. baseline variables associated with reactivation status (at p \ . ) which changed the crude effect estimate by more than % included the apa-che iv score, use of high dose corticosteroid therapy, and peep setting. in the primary multivariable adjusted analysis, cmv reactivation was no longer statistically associated with either increased mortality or a reduced rate of successful weaning. however, simultaneous effects on both the daily rates of death and weaning did reveal a significant association with overall mortality when competing risks were accounted for (shr . , % ci . - . ). as a post hoc sensitivity analysis, we then used marginal structural modeling to assess potential residual confounding by differences in the evolution of disease severity prior to cmv reactivation between both groups, but found very similar results (table ) . changing the definitions of our primary end points to include all deaths in the icu (irrespective of mechanical ventilation status) and discharge (rather than successful weaning) also did not change these findings (table s ). furthermore, the independent association with mortality remained among subgroups of patients receiving and not receiving high dose corticosteroid therapy; shr . ( % ci . - . ) and . ( % ci . - . ), respectively (table s ). corticosteroids were mostly used for the treatment of concurrent septic shock ( of cases). figure shows the predicted mortality in a hypothetical population of ards patients in which all cmv reactivation is prevented, compared to true (observed) mortality in the study population. the population-attributable fraction of icu mortality due to cmv reactivation was estimated at % ( % ci - %) by day , which translates into an absolute mortality difference of . % ( % ci . - . ). data are presented as hazard ratios with % ci. the causespecific hazard ratio (cshr) estimates the direct effect of cmv reactivation on clinical outcome (i.e., successful weaning or death on mechanical ventilation). the subdistribution hazard ratio (shr) is a summary measure of both separate cause-specific hazards and estimates the overall risk of dying from cmv reactivation while taking into account the competing event of successful weaning a apache iv score, use of high dose corticosteroid therapy, and peep setting b time-dependent covariables included the risk, injury, failure, loss and end-stage kidney disease (rifle) score, sequential organ failure assessment (sofa) score, presence of septic shock, and use of high dose corticosteroid therapy, which were all measured on a daily basis until h prior to reactivation onset in order to explore possible causal pathways for the observed association between cmv reactivation and death, we performed a post hoc descriptive analysis of the trajectories of organ dysfunction, pulmonary and inflammatory markers over time following reactivation. in short, we compared the patients having cmv reactivation with non-exposed patients who were matched on baseline characteristics and their length of stay in icu at the onset of reactivation (table s ). in summary, the total burden of organ dysfunction was slightly higher in patients at the start of cmv reactivation compared to matched non-exposed control subjects, although individual markers of pulmonary dysfunction and inflammation were similar. more importantly, there was a clear trend towards resolution of organ dysfunction over time in nonexposed subjects that was less pronounced in patients having cmv reactivation. however, it should be emphasized that these findings should be interpreted very carefully because of the presence of informative censoring (i.e., patients who die or get discharged do not further contribute to average scores on the group level). cmv reactivation in ards patients increased the overall risk of death on the ventilator through the combined effect of subtle alterations in both the daily rates of death and successful weaning. after accounting for multiple sources of confounding, the absolute mortality that can be attributed to cmv reactivation was estimated to be . % by day following study inclusion. previous findings of excess mortality have triggered debate whether antiviral prophylaxis should be used [ , ] . however, a greater understanding of pathophysiology and clinical risk factors is necessary to select the optimal target population for such strategies. in our study, reactivation rates were % in ards patients overall and % among those with concurrent septic shock. the latter finding might be explained by the increased severity and duration of immune suppression that may be observed in patients with septic shock, including a pronounced depletion of t cells [ , ] . indeed, a recent study investigating the potential use of antiviral prophylaxis based on the screening of ards patients for cmv seroprevalence found that such a strategy is unlikely to be beneficial overall, but suggested a possible benefit in a post hoc subgroup of patients with septic shock [ ] . as the proportion of patients with cmv reactivation increased in time, altering the minimal length of stay in the icu as a criterion may also improve the selection of a high-risk target population. until then, a pre-emptive treatment strategy (by which patients would be screened for cmv and treated only if reactivation occurs) seems more attractive because the number of patients exposed to the toxicity of (val)ganciclovir would be reduced by %. however, the effects of pre-emptive compared to prophylactic treatment on relevant patient outcomes are most likely lower, as treatment is initiated only after reactivation has already begun. intervention trials comparing prophylaxis, pre-emptive treatment, and wait-andsee strategies are necessary before any evidence-based recommendations regarding the clinical management of cmv reactivation in critically ill patients with ards can be made. our study has several strengths. first, observations were nested within a large prospective data collection initiative that included consecutive patients, thereby minimizing selection bias [ ] . all ards events were diagnosed by dedicated trained observers, which minimizes information bias. moreover, we used a highly sensitive method of quantitative real-time pcr for cmv detection. most importantly, we used advanced methodologies to account for both competing risks and timedependent information in an attempt to produce unbiased estimates of the independent association between cmv reactivation and clinical outcome. this methodological approach was mainly necessary because of two reasons. first, cox regression analysis requires that censoring of survival time must be non-informative, but in our study this was clearly not the case since ards patients who are weaned and discharged from the icu alive are in a better health state than those who remain on the ventilator beyond that time point [ , ] . furthermore, when icu mortality is the event of interest, then discharge must be regarded as a competing event as it precludes this outcome from being observed [ ] . the use of the subdistribution hazard model provides a general solution to this informative censoring. second, the median time to cmv reactivation in our cohort was . (iqr - ) days. if ignored, such delays may cause distortion (termed immortal time bias) as nonexposed time observed before the onset of reactivation will be wrongfully attributed to the exposed time at risk, resulting in underestimation of effects associated with cmv reactivation [ , ] . time-dependent fitting of cmv reactivation status in our regression models resolved this issue. our study also has several limitations. first, even the use of advanced methodology cannot rule out the possibility of unmeasured confounding in an observational study. therefore, it remains somewhat uncertain whether the excess mortality that we observed can be fully attributed to cmv reactivation, or whether other unknown factors-including other viral reactivations [ , ]-may also be involved. second, the principle of multivariable analysis to adjust for confounders is to statistically 'force' exposed and non-exposed patients to be similar in all aspects of disease aside from their reactivation status. however, in a dynamic icu setting, during which critically ill patients continuously deteriorate and improve over time, it is very difficult to verify whether such adjustment was successful. we performed marginal structural modeling as a sensitivity analysis to assess the possible impact of variations in the evolution of disease severity between patients on our effect estimates, yet found very similar results as in our primary analysis. third, we measured systemic cmv reactivation in plasma but did not collect information about concurrent viral loads in the lungs. this study, therefore, provides no insight into either the prevalence or relevance of pulmonary cmv reactivations. of note, previous studies have shown that pulmonary reactivation may occur without the concurrent viremia [ , , ] . furthermore, we focused exclusively on the occurrence of reactivation while patients were on mechanical ventilation (primary analysis) or in the icu (sensitivity analysis), as we considered these to be the most relevant time windows to potentially treat or prevent cmv reactivation in the icu. however, because of this deliberate focus we cannot provide information about possible episodes of reactivation that may have occurred later. likewise we did not investigate the occurrence of reactivations after day in the icu. thus, this study only provides insight into the short-term effects of systemic cmv reactivation in ards patients in settings in which screening or antiviral prophylaxis is not part of routine clinical practice. in conclusion, systemic reactivation of cmv in immunocompetent ards patients is common and independently associated with death in the icu. these findings support the need for future studies to better predict cmv reactivation as well as to evaluate the efficacy of treatment strategies directed against cmv reactivation in these patients. human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments active cytomegalovirus infection is common in mechanically ventilated medical intensive care unit patients virological and immunological features of active cytomegalovirus infection in nonimmunosuppressed patients in a surgical and trauma intensive care unit looking for biological factors to predict the risk of active cytomegalovirus infection in nonimmunosuppressed critically ill patients cytomegalovirus seroprevalence as a risk factor for poor outcome in acute respiratory distress syndrome pulmonary cytomegalovirus reactivation causes pathology in immunocompetent mice a contributive result of openlung biopsy improves survival in acute respiratory distress syndrome patients cytomegalovirus reactivation in critically ill patients with acute respiratory distress syndrome interobserver agreement of centers for disease control and prevention criteria for classifying infections in critically ill patients the american-european consensus conference on ards. definitions, mechanisms, relevant outcomes, and clinical trial coordination diagnosing herpesvirus infections by real-time amplification and rapid culture a proportional hazards model for the subdistribution of a competing risk attributable mortality due to nosocomial infections. a simple and useful application of multistate models use of multistate models to assess prolongation of intensive care unit stay due to nosocomial infection the time-dependent bias and its effect on extra length of stay due to nosocomial infection marginal structural models and causal inference in epidemiology attributable mortality of ventilator-associated pneumonia: a reappraisal using causal analysis treating hsv and cmv reactivations in critically ill patients who are not immunocompromised: pro treating hsv and cmv reactivations in critically ill patients who are not immunocompromised: con sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy transient cd -memory contraction: a potential contributor to latent cytomegalovirus reactivation adjusting for time-varying confounding in the subdistribution analysis of a competing risk modeling the effect of time-dependent exposure on intensive care unit mortality immortal time bias in critical care research: application of timevarying cox regression for observational cohort studies effectiveness of inhaled corticosteroids in chronic obstructive pulmonary disease: immortal time bias in observational studies coreactivation of human herpesvirus and cytomegalovirus is associated with worse clinical outcome in critically ill adults immunological insights into the pathogenesis of active cmv infection in non-immunosuppressed critically ill patients detection of herpesvirus ebv dna in the lower respiratory tract of icu patients: a marker of infection of the lower respiratory tract? acknowledgments we thank huberta dekker (department of medical microbiology, university medical center utrecht, the netherlands) for her logistical support in this project, and the participating icus and research nurses of the two medical centers for their help in data acquisition. this work was supported by the center for translational molecular medicine (http://www.ctmm.nl), project mars (grant i- ). jk received a personal fee from becton-dickinson. the sponsor did not play a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.the mars consortium also includes the following per- key: cord- -mig zt p authors: delgado-rodríguez, miguel; castilla, jesús; godoy, pere; martín, vicente; soldevila, nuria; alonso, jordi; astray, jenaro; baricot, maretva; cantón, rafael; castro, ady; gónzález-candelas, fernando; mayoral, josé maría; quintana, josé maría; pumarola, tomás; tamames, sonia; sáez, marc; domínguez, angela title: prognosis of hospitalized patients with h n influenza in spain: influence of neuraminidase inhibitors date: - - journal: j antimicrob chemother doi: . /jac/dks sha: doc_id: cord_uid: mig zt p background: the h n influenza pandemic strain has been associated with a poor prognosis in hospitalized patients. the present report evaluates the factors influencing prognosis. methods: a total of patients hospitalized with h n influenza in hospitals (nationwide) in spain were analysed. detailed histories of variables preceding hospital admission were obtained by interview, validating data on medications and vaccine with their attending physicians. data on treatment and complications during hospital stay were recorded. as definition of poor outcome, the endpoints of death and admission to intensive care were combined; and as a further outcome, length of stay was used. results: the mean age was . years (sd . years). there were deaths and admissions to intensive care (combined, ). the use of neuraminidase inhibitors was reported by patients ( . %). the variables significantly associated with a poor outcome were diabetes (or = . , % ci = . – . ), corticosteroid therapy (or = . , % ci = . – . ) and use of histamine- receptor antagonists (or = . , % ci = . – . ), while the use of neuraminidase inhibitors (or = . , % ci = . – . ) was protective. neuraminidase inhibitors within the first days after the influenza onset reduced hospital stay by a mean of . days ( % ci = . – . ). conclusions: the use of neuraminidase inhibitors decreases the length of hospital stay and admission to intensive care and/or death. influenza a pandemic h n virus infections began to spread in spain during spring . reports suggested high mortality in children and adults associated with the new virus in mexico , and argentina, as well as in previously healthy young people. analysis of cases hospitalized in the usa showed a mortality rate of %, with % of patients being admitted to the intensive care unit (icu). a study of patients infected with the pandemic virus strain admitted to spanish icus found a mortality rate of %, somewhat lower than in latin american countries. these findings suggest that the h n virus is more virulent than previous strains. as there was no specific targeted vaccine giving protection against the h n influenza virus available at the beginning of the outbreak, health authorities began to recommend administration of neuraminidase inhibitors to reduce transmission and/or complications. various studies have suggested that these drugs are also effective in reducing the severity of the infection. , , we reviewed nationwide spanish data on hospitalized patients with h n influenza a in order to: (i) evaluate the frequency of adverse outcomes during hospitalization; and (ii) identify the factors influencing poor/good outcome, including the use of neuraminidase inhibitors shortly after the onset of symptoms. we carried out a multicentre study in hospitals from seven spanish regions (andalusia, catalonia, castile and leon, madrid, navarre, the basque country and valencia). between july and february we selected hospitalized patients with influenza syndrome, acute respiratory infection, septic shock or multiple organ failure in whom influenza virus a (h n ) infection was confirmed by real-time reversetranscription pcr (rt-pcr) from nasopharyngeal swabs; haemagglutinin (ha) sequencing was performed. we excluded patients who had nosocomial infection, defined as pandemic virus infection in a patient that appears ≥ h after admission for another cause. all information collected was treated as confidential, in strict observance of legislation for observational studies. the study was approved by the ethics committees of the hospitals involved, following the declaration of helsinki principles. written informed consent was obtained from all patients included in the study. during the pandemic flu all patients suspected of having the disease, either in outpatient clinics or hospitals, were diagnosed by rt-pcr of samples from nasopharyngeal swabs. within the next h, hospitalized patients were interviewed at the centre. of these, rejected participation and were excluded because flu had been acquired after hospital admission. the following demographic variables and pre-existing medical conditions were recorded for all study participants: age, sex, ethnicity, educational level, smoking, alcoholism, pregnancy in women aged - years, history of pneumonia in the previous two years, chronic obstructive pulmonary disease (copd), asthma, cardiovascular disease, renal failure, diabetes, hiv infection, disabling neurological disease, cancer, transplantation, morbid obesity (body mass index ≥ ), use of neuraminidase inhibitors before hospital admission (and their timing relative to the onset of symptoms, verified after contacting the prescribing general practitioner), use of other medications in the days before hospital admission (corticosteroids, antibiotics etc.) and treatment received during hospitalization (medications, catheters and mechanical ventilation). for each vaccine, a case was considered vaccinated if the vaccine had been received ≥ days before the onset of symptoms. data were collected during hospital admission and the clinical chart was also reviewed after discharge. the outcome variables were admission to an icu, in-hospital death and length of hospital stay (in days). given that the number of deaths was very low, a combined endpoint was classified as 'poor outcome': icu admission and/or in-hospital death. bivariate comparisons were made using pearson's x test for categorical variables and student's t-test for continuous variables. as a measure of association, the relative risk (or) and % ci were calculated. logistic regression was applied in the multivariate analysis for dichotomous adverse outcomes. to determine the variables to be included in the multivariate analysis, the procedure described by sun et al. was followed. intermediate variables were discarded. we ran two stepwise models, one backward and another forward, including variables with p, . . , we constructed a list of predictors of mortality identified in other studies. using information from stepwise models and the list of predictors, a saturated model was built, and by using a heuristic approach, variables that did not change the coefficient of the bundles by more than % were discarded, in order to construct a parsimonious model retaining all important confounders. to analyse the impact of different variables on the length of hospital stay, patients who died were excluded from these analyses. given that hospital stay did not follow the normal curve, natural logarithms were used. firstly, to select potential variables related to length of stay, we used cox regression in the same fashion as described above for the logistic regression analysis. the variables selected by this model were tested by including other potential candidates according to the logistic regression analyses. secondly, an analysis of covariance was applied to estimate the adjusted means of hospital length of stay. all analyses were made using the stata /se package (college station, tx, usa). there were a total of patients [ ( . %) were female, of which ( %) were pregnant]. the mean age was . years (sd . ) and % were aged , years. the use of neuraminidase inhibitors was reported by patients ( . %), with oseltamivir being administered in all cases but two (zanamivir). during hospitalization, patients ( . %) were admitted to the icu and died ( . %), of whom were not receiving intensive care. no death occurred in pregnant women, of whom only one was admitted to the icu. the timings of the use of neuraminidase inhibitors before hospital admission were: patients in the first h after the onset of symptoms, between - h and after h ( table ) . the relationship between study variables and icu admission/ in-hospital death is shown in table . in the univariate analyses, age, most comorbidities (copd, diabetes, liver failure and cardiovascular disease), ex-smoking, corticosteroid therapy and histamine- receptor antagonists were associated with an adverse outcome during hospitalization. in the multivariate models, the variables significantly associated with a poor outcome were diabetes (or¼ . , % ci¼ . - . ), corticosteroid therapy (or¼ . , % ci ¼ . - . ) and use of histamine- receptor antagonists (or ¼ . , % ci ¼ . - . ). use of neuraminidase inhibitors was protective (or ¼ . , % ci ¼ . - . ). pneumonia at admission, copd, ex-smoking and liver failure showed a trend to association. delgado-rodríguez et al. the trend analysis for age in the multivariable analysis yielded a p value of . , with advanced age associated with a higher risk of adverse outcome. when the timing of treatment with neuraminidase inhibitors after the onset of influenza was analysed, the benefit was confined to administration within the first h after the onset of symptoms. table shows the variables associated with length of hospital stay. the use of neuraminidase inhibitors within the first days after the onset of influenza reduced hospital stay by a mean of . days (from . to . , p, . ), whereas delayed administration was associated with an increase in hospital stay. pneumonia diagnosed at admission was clearly associated with longer hospital stay, as were comorbidities (copd, neurological impairment and cardiovascular disease) and some therapies (proton pump inhibitors). we found that traditional risk factors associated with hospitalization in patients with influenza (copd and corticosteroid therapy before admission) were also found in our patients. likewise, the use of neuraminidase inhibitors reduced the probability of adverse outcomes during hospital stay and significantly shortened the length of stay. this study is observational and can be affected by several limitations. kumar has recently highlighted the drawbacks of observational studies in estimating the benefits of early viral treatment in the prognosis of flu. we agree that selection bias is difficult to avoid. immortal time bias or survival-durationrelated selection bias imply that the late use of antivirals may be related to a better prognosis, whereas in fact our results suggest the opposite. our results show no benefit of late neuraminidase treatment. in israel, a retrospective cohort study documented a higher rate of complications after admission. severe complications (excluding hypoxia and uncomplicated pneumonia) occurred more frequently with late oseltamivir. in the same way, a spanish study of icu patients showed that icu length of stay, days of mechanical ventilation and mortality were reduced in patients receiving early treatment versus late treatment with oseltamivir. these reports do not give comparisons with flu patients without antiviral treatment. the mortality rate in our study ( . %) was low in comparison with other studies. this may be due to the fact that our patients were not all admitted to the icu, , and did not all have pneumonia at hospital admission. even so, the mortality rate was clearly lower than that found in the usa at the beginning of the pandemic ( %) or the . % reported in canada. likewise, the rate of icu admission ( . %) was lower than that found in the usa ( %) and canada ( %), although it was similar to the % reported in new zealand maoris. some form of selection bias cannot be completely ruled out as our study patients had to be interviewed to collect data on the use of medications before admission and other risk factors related to disease severity. in a study carried out in catalonia (north-east spain), of cases hospitalized, . % were admitted to the icu. in contrast, in andalusia (southern spain), out of hospitalized cases ( %) were admitted to an icu. in another spanish study of patients admitted to the icu, the mortality rate was %. taken together, these data suggest that patients who died shortly after admission were not picked up by our study. the predisposing factors for a higher probability of adverse outcome during hospitalization were broadly similar to those found in other studies. , in one international series of patients with community-acquired pneumonia, male sex and obesity were predictors of mortality, although we did not find similar results. we found a significant association between reductions in icu admission/death and the administration of neuraminidase inhibitors within the first h after the onset of symptoms, similarly to the findings of jain et al. and other studies. , in these reports none of the pregnant women who died had taken neuraminidase inhibitors within the first two days after the onset of illness. early use of neuraminidase inhibitors was associated with shorter hospital stay. other reports have found no relationship between antiviral treatment and hospital stay. in summary, we found that early treatment with neuraminidase inhibitors had a beneficial effect on outcomes during hospital de torrecá rdenas), a. morillo (hospital virgen del rocío) hospital virgen de las nieves), m. zarzuela (hospital puerta del mar). valencia community: j. blanquer (hospital clínico de valencia), m. morales (hospital doctor peset) hospital vall d'hebró n), f. calafell (universitat pompeu fabra the basque country: u instituto de salud carlos iii (ministry of science and innovation, national institute of health carlos iii), programme of research on influenza a/h n (gr / ) and agency for the management of grants for university research (agaur, /sgr ). the funders had no role in the study design severe respiratory disease concurrent with the circulation of h n influenza pneumonia and respiratory failure from swine-origin influenza a (h n ) in mexico pediatric hospitalizations associated with pandemic influenza a (h n ) in argentina hospitalized patients with h n influenza in the united states h n influenza virus infection during pregnancy in the usa california pandemic (h n ) working group. severe h n influenza in pregnant and postpartum women in california inappropriate use of bivariable analysis to screen risk factors for use in multivariable analysis simulation study of confounder-selection strategies the impact of confounder selection criteria on effect estimation early versus late oseltamivir treatment in severely ill patients with pandemic influenza a (h n ): speed is life benefit of early treatment with oseltamivir in hospitalized patients with documented influenza a (h n ): retrospective cohort study impact of early oseltamivir treatment on outcome in critically ill patients with pandemic influenza a critical care services and h n influenza in australia and new zealand predicting mortality in hospitalized patients with h n influenza pneumonia risk of severe outcomes among patients admitted to hospital with pandemic (h n ) influenza hospitalizations for pandemic (h n ) among maori and pacific islanders behaviour of the pandemic h n influenza virus in andalusia, spain, at the onset of the - season critically ill patients with pandemic influenza a (h n ) infection in spain: factors associated with death clinical and epidemiologic characteristics of an outbreak of novel h n (swine origin) influenza a virus among united states military beneficiaries antiviral therapy and outcomes of influenza requiring hospitalization in ontario h n influenza and hospitalization other members of the ciberesp cases and controls in pandemic influenza working group none to declare. key: cord- - r in gw authors: giannella, maddalena; rodríguez-sánchez, belen; roa, paula lópez; catalán, pilar; muñoz, patricia; de viedma, darío garcía; bouza, emilio title: should lower respiratory tract secretions from intensive care patients be systematically screened for influenza virus during the influenza season? date: - - journal: crit care doi: . /cc sha: doc_id: cord_uid: r in gw introduction: influenza is easily overlooked in intensive care units (icus), particularly in patients with alternative causes of respiratory failure or in those who acquire influenza during their icu stay. methods: we performed a prospective study of patients admitted to three adult icus of our hospital from december to february . all tracheal aspirate (ta) samples sent to the microbiology department were systematically screened for influenza. we defined influenza as unsuspected if testing was not requested and the patient was not receiving empirical antiviral therapy after sample collection. results: we received ta samples from patients. influenza was detected in patients and was classified as unsuspected in ( . %) patients, and as hospital acquired in ( %) patients. suspected and unsuspected cases were compared, and significant differences were found for age ( versus median years), severe respiratory failure ( . % versus %), surgery ( . % versus %), median days of icu stay before diagnosis ( versus ), nosocomial infection ( . % versus . %), cough ( . % versus . %), localized infiltrate on chest radiograph ( . % versus %), median days to antiviral treatment ( versus ), pneumonia ( . % versus . %), and acute respiratory distress syndrome ( % versus . %). multivariate analysis showed admission to the surgical icu (odds ratio (or), . ; % confidence interval (ci), . to . ; p = . ) and localized infiltrate on chest radiograph (or, . ; % ci, . to . ; p = . ) to be independent risk factors for unsuspected influenza. overall mortality at days was %. icu admission for severe respiratory failure was an independent risk factor for poor outcome. conclusion: during the influenza season, almost one third of critical patients with suspected lower respiratory tract infection had influenza, and in . %, the influenza was unsuspected. lower respiratory samples from adult icus should be systematically screened for influenza during seasonal epidemics. influenza is a common cause of admission to the intensive care unit (icu) during the influenza season and influenza pandemics [ ] [ ] [ ] [ ] . however, it may be overlooked, particularly in patients with clinical manifestations that can be explained by alternative infectious or noninfectious causes [ ] . furthermore, influenza may not be suspected when respiratory function deteriorates or fails in patients already admitted to the icu. at present, information on influenza acquired during icu stay is scarce and incomplete [ ] . timely knowledge of the presence of influenza virus in patients admitted to the icu has obvious epidemiologic, diagnostic, and therapeutic advantages [ ] . we assessed the burden of influenza in adult icus and the number of overlooked cases when the routine diagnostic workup was applied during the influenza season. we screened all tracheal aspirates sent to the microbiology department for the diagnosis of lower respiratory tract infection, even when not requested by the attending physician. our hospital is a , -bed tertiary referral teaching institution caring for a population of approximately , inhabitants. it has three different adult icus (medical, surgical, and cardiac surgery) with a total of beds. from december , , through february , , all tracheal aspirate (ta) samples obtained from adult patients (≥ years) admitted to our icus and sent to the microbiology department were systematically screened for influenza virus. icu admission criteria and management for all patients, including the need for intubation and for obtaining ta samples, were not standardized, and decisions were made at the discretion of the attending physician. patients with laboratory-confirmed influenza, by realtime reverse transcriptase polymerase chain reaction (rt-pcr) on ta and nasopharyngeal samples, were prospectively followed up by an infectious diseases specialist and treated with oseltamivir, mg/day, for to days. clinical and microbiology data were recorded in a preestablished protocol and entered into a database. the study was approved by the ethics committee of the "fundación para la investigación biomédica del hospital gregorio marañón." the requirement for informed consent was waived because we applied an excellent diagnostic technique to improve the quality of patient care without any negative impact. our objectives were to determine the incidence of influenza among adult icu patients with a ta sample obtained during the influenza season, and to demonstrate the frequency of unsuspected cases and the rate of hospital-acquired episodes. the variables recorded were age, sex, classification of the severity of underlying conditions according to the charlson comorbidity index [ ] , type of icu, date and cause of icu admission, apache ii score [ ] on admission to the icu, date of onset of influenza symptoms, clinical manifestations and radiologic findings at diagnosis, date of ta sample collection, other samples tested for influenza and result, date of initiation of antiviral treatment, complications (septic shock, acute respiratory distress syndrome (ards)), outcome including mortality within days after influenza diagnosis, and length of icu and hospital stay. we defined the diagnosis of influenza as unsuspected when influenza testing was not explicitly requested or had not been previously requested in other samples, such as nasopharyngeal swabs, and the patient was not receiving empirical antiviral treatment immediately after sample collection. influenza was classified as community acquired if the flu syndrome (fever, chills, malaise, sore throat, rhinorrhea, cough, dyspnea, myalgia, nausea, and diarrhea) began before or during the first hours of hospital admission. the infection was classified as hospitalacquired, if symptoms started after the first hours [ ] . as for causes of icu admissions, severe respiratory failure was defined as severe hypoxemia (pao < mm hg) refractory to high-flow oxygen therapy (fio , %) with a venturi mask. as for underlying conditions, chronic obstructive pulmonary disease was defined according to the criteria of the global initiative for chronic obstructive lung disease [ ] . immunosuppressed patients were those with hematologic malignancy (with or without bone marrow transplantation), hiv infection, inflammatory diseases under biologic or immunosuppressive treatment and solid organ transplant. as for influenza vaccination, we considered patients who had been vaccinated against influenza within months before admission. pneumonia was defined according to the current idsa/ats guidelines [ ] . ards and septic shock were defined by using standard criteria [ , ] . samples for microbiologic diagnosis were taken by endotracheal aspiration with a f sterile probe to a depth of cm from the distal end of the endotracheal tube. the secretions obtained were collected in a sterile container (lukens specimen container; sherwood medical, tullamore, ireland) and transported in sterile packages to the microbiology laboratory for gram staining and bacterial and viral procedures. standard bacterial procedures included quantitative culture performed on blood agar, chocolate agar, mcconkey agar, and, when required, legionella agar (bcye) [ ] . positive samples were defined as those with bacterial counts ≥ cfu/ml of each significant microorganism. the microorganisms were identified and antimicrobial susceptibility testing performed by using an automatic system (microscan; dade behring, sacramento, ca, usa). breakpoints were determined after the clinical and laboratory standards institute (clsi) guidelines [ ] . unless proven otherwise, we considered as nonpathogenic the isolation (at any concentration) of the following microorganisms: viridans-group streptococci, enterococcus spp., coagulase-negative staphylococcus, neisseria spp., corynebacterium spp., and candida spp. samples were collected in viral-transport medium (copan c; copan innovation, brescia, italy). a μl aliquot was stored at °c for no longer than hours until analysis. the rest of the sample was stored at - °c for further amplification and sequencing. rna was extracted in a nuclisens easymag system (biomérieux, boxtel, the netherlands) by following the manufacturer's instructions. pandemic influenza a ph n was detected by real-time reverse transcriptase polymerase chain reaction (rt-pcr) by following the who/cdc protocol in a stratagene mx thermocycler (stratagene, la jolla, ca, usa). those samples rendering indeterminate results (low-fluorescence signal or high ct values) were tested again with the realtime ready inf a/h n detection set (roche diagnostics, mannheim, germany). influenza b was detected by using the realtime ready influenza b detection set (roche diagnostics). h n and seasonal h n strains were detected as described elsewhere [ ] . relative dna was quantified by combining the rt-pcr methods described with the detection of a housekeeping gene with real-time rt-pcr, as described by the cdc. this method allowed normalization of the initial amount of rna present in each sample [ ] . categoric variables appear with their frequency distribution. nonnormally distributed continuous variables are expressed as the median and interquartile range (iqr). the association between categoric variables was evaluated by using the χ test or fisher exact test; the association between continuous variables was evaluated by using the mann-whitney u test. a logistic binary model was used to analyze the independent risk factors for unsuspected influenza and -day mortality. variables with p ≤ . in the univariate analysis were entered into the multivariate model. the level of significance was set at p < . for all the tests. the statistical analysis was performed by using spss . . during the study period, patients were admitted to our adult icus. overall, one or more ta samples were obtained from patients, and a microbiologic diagnosis was made in of them (see figure ). bacterial infection was diagnosed in patients, and the frequencies of the pathogens isolated were as follows: staphylococcus aureus, . %; enterobacteriaceae, . %; pseudomonas aeruginosa, . %; streptococcus pneumoniae, . %; and acinetobacter baumannii, . %. a diagnosis of viral infection only was made in patients: with influenza virus, one with adenovirus, and one with herpes simplex virus. aspergillus fumigatus was the only microorganism isolated in three patients. the remaining eight patients initially had coinfection with influenza virus and the following microorganisms: s. aureus, three; s. pyogenes, one; s. pneumoniae, one; a. baumannii, one; p. aeruginosa, one; and aspergillus fumigatus, one. during the study period, the overall incidence of influenza in the adult icus of our hospital was . cases per icu admissions. the incidence of influenza among the patients with at least one ta sample sent to the microbiology department was . cases per icu patients. the reasons for admission to the icu and the characteristics and outcome of the patients with influenza are shown in table . influenza was unsuspected in ( . %) patients and hospital-acquired in ( %) patients. at the time of influenza diagnosis, all patients but one were intubated. among patients with co-infection, the reasons for admission to the icu were as follows: surgery, five; respiratory failure, one; cardiac arrest, one; and decompensated cirrhosis, one. influenza was classified as hospital acquired in five ( . %) of them, and pneumonia was diagnosed in seven ( . %) patients. overall, viral infection was diagnosed in patients, and in ( . %) of them, influenza was detected. influenza was due to the pandemic influenza a h n strain in ( %) patients, influenza b in three ( . %) patients, and influenza a h n in one ( . %) patient. in of the patients, influenza testing was performed simultaneously in the ta and nasopharyngeal samples. the upper respiratory tract sample failed to detect influenza in . % of cases. overall, the median relative viral load at diagnosis was . (iqr, . to . ) . this tended to be higher in patients with suspected influenza ( table ) . patients with suspected influenza were compared with those with unsuspected influenza ( table ). the univariate analysis revealed significant differences for age ( versus years; p = . ), medical icu ( . % versus %; p = . ), admission to the icu for severe respiratory failure ( . % versus %; p = . ), length of icu stay before the influenza diagnosis ( (iqr, to ) versus (iqr, to ) days; p = . ), classification as having hospital-acquired influenza ( . % versus . %; p = . ), cough ( . % versus . %; p = . ), localized pulmonary infiltrate on radiograph ( . % versus %; p = . ), median days to initiation of antiviral therapy after onset of symptoms ( (iqr, to ) versus (iqr, . to ) days; p = . ), pneumonia ( . % versus . %; p = . ), and development of ards ( % versus . %; p = . ). mortality at days after the influenza diagnosis was . % and % (p = . ) in patients with suspected and unsuspected influenza, respectively. multivariate analysis showed the independent risk factors associated with unsuspected influenza to be admission to the surgical icu (or, . ; %ci, . to . ; p = . ) and localized pulmonary infiltrate on radiograph (or, . ; %ci, . to . ; p = . ). longer icu stay before the diagnosis of influenza was also associated with unsuspected influenza but was not significant (table ) . overall mortality at days after influenza diagnosis was %. the univariate analysis of the risk factors for mortality is shown in table . nosocomial acquisition of influenza was associated with better outcome ( . % versus . %; p = . ). the only independent risk factor for -day mortality in the multivariate analysis was severe respiratory failure as the reason for admission to the icu (or, . ; %ci, . to . ; p = . ). during the influenza season, almost one third of patients hospitalized in our adult icus and with suggestion of lower respiratory tract infection had influenza. influenza was unsuspected in . % and hospital acquired in %. patients with unsuspected influenza were more frequently admitted to the icu for surgery, had a localized infiltrate on chest radiograph, and stayed longer in the icu before being diagnosed with influenza. antiviral treatment was initiated later in patients with unsuspected influenza, although mortality was similar in both groups. overall mortality at days after the influenza diagnosis was %; however, it was lower in patients with nosocomial influenza. severe respiratory failure as the cause of admission to the icu was the only independent factor associated with poor outcome. acute febrile respiratory illness is a common cause of respiratory failure and admission to the icu [ ] [ ] [ ] . in most cases, the etiology is bacterial, although viruses have been implicated in almost % of cases [ ] . during the pandemic, the rate of icu admission for respiratory failure among hospitalized patients with a confirmed diagnosis of influenza a (h n v) ranged from % to % [ ] [ ] [ ] [ ] [ ] . however, no studies have investigated the rates of bacterial and viral etiologies among patients admitted to the icu with suggestion of lower respiratory tract infection during the pandemic. here, we demonstrated that, after the pandemic influenza season, the etiology was viral in . % of patients admitted to the icu with suggestion of lower the etiology of acute febrile respiratory illness causing respiratory failure is often unknown at admission to the icu [ ] . about half of the cases are diagnosed as bacterial pneumonia shortly after admission, with a small number of cases found to be viral pneumonia when the initial bacterial studies are negative [ ] . detection of influenza virus often depends on specific epidemiologic risk factors and clinical suspicion. the combination of fever, malaise, and cough was shown to have a % positive predictive value during the pandemic and seasonal epidemics [ , ] ; however, these criteria may be not accurate in icu patients, because other etiologies, or conditions like as postsurgery sedation, may confound the diagnosis [ ] . in our study, influenza was unsuspected in . % of cases. suspicion of influenza was lower in older patients, in those admitted to the icu for surgical conditions, in those who stayed for a longer time in hospital and icu, and in those who did not have a cough and diffuse pulmonary infiltrates. the direct consequence of overlooked influenza was a significant delay in the initiation of antiviral treatment. definitive diagnosis of influenza is by detection of the virus in culture or rt-pcr with a nasopharyngeal aspirate/swab or lower respiratory tract sample [ , ] . because viral shedding peaks at hours after the onset of illness and declines thereafter, testing of lower respiratory tract samples in patients with compromised lung parenchyma may be more beneficial [ , , ] . accordingly, we found that the upper respiratory tract sample did not reveal influenza in . % of cases. diagnostic viral load tended to be higher in patients with suspected influenza, possibly as a result of the earlier diagnosis of influenza after onset of symptoms in this group compared with patients with unsuspected influenza. hospital-acquired influenza is a well-recognized problem [ , ] . nosocomial outbreaks of pandemic and seasonal influenza have been documented in various settings, including icus, pediatric wards, transplant units, medical wards, and surgical wards [ ] [ ] [ ] [ ] [ ] . however, few sporadic cases of hospital-acquired influenza have been reported during surveillance activities [ ] . in a study including , patients hospitalized with the pandemic influenza a in hospitals in the united kingdom, the authors identified ( %) cases of sporadic nosocomial influenza [ ] . these comprised adults and children. most had serious underlying illnesses and were admitted to nonmedical areas, as in our study. unexpectedly, we found that the -day mortality rate was lower in patients with hospital-acquired influenza. this figure can be associated with viral factors, such as lower virulence of the influenza strains circulating in the hospital, or with host factors, such as older age and surgical conditions. overall, -day mortality was high ( %), and admission to the icu for severe respiratory failure was an independent risk factor for death. these data are consistent with those of martin-loeches et al. [ ] , who showed that patients from the postpandemic influenza ph n period had an unexpectedly high mortality rate. early administration of antiviral therapy has been associated with better outcome in critically ill patients [ ] . in our study, although the timing to initiation of antiviral treatment was longer among patients with unsuspected influenza, a trend to lower mortality was seen in this group compared with patients with suspected influenza. a possible explanation of this finding could be that: suspected and unsuspected groups were epidemiologically very different, and the median relative viral load was lower in the unsuspected group; thus, epidemiologic and viral factors could influence the outcome in the two groups independently of the timing of antiviral treatment. conversely, the benefit of testing will not be necessarily to the patient in terms of improved outcome due to early therapy, but more likely to preventing the nosocomial transmission of influenza. our study is limited in that the small number and heterogeneity of patients diminishes the power of our data analysis. we performed the study during the postpandemic period ( to ), when the prevalence of the pandemic influenza a h n strain was still high. findings could vary between one influenza season and another, depending on the characteristics of the prevalent influenza virus stain. we did not perform a costeffectiveness analysis, although the finding of a longer icu and hospital stay in patients with unsuspected influenza suggests a potential favorable impact on care management. we could not perform an analysis of the possible routes of transmission of the nosocomial cases. however, we can exclude with sufficient certainty the occurrence of an outbreak for the following reasons: (a) the cases of hospital-acquired influenza were distributed uniformly between the three icus (postsurgery icu, six; medical icu, five; and postcardiosurgery icu, two); (b) no case of influenza was recognized among the healthcare staff during the study period; (c) the preventive measures included vaccination of staff, respiratory isolation, and droplet-contact precautions, as recommended by the centers for disease control and prevention [ ] . we showed that influenza is a common cause of acute respiratory illness among patients admitted to the icu during seasonal epidemics, and that it is often overlooked, and it could lead to a delay in the initiation of antiviral treatment and possible nosocomial transmission of influenza. microbiology departments should systematically investigate the presence of influenza in respiratory samples obtained from icu patients during the seasonal epidemic. • the incidence of influenza in the adult icu during the influenza season is high. • the diagnosis of influenza is often overlooked in icu patients. among patients with unsuspected influenza, the timing to initiation of antiviral treatment was longer, and the rate of hospital-acquired influenza was higher compared with that of patients with suspected influenza. • microbiology departments should systematically investigate the presence of influenza in respiratory samples obtained from icu patients during the seasonal epidemic. abbreviations apache: acute physiology and chronic health evaluation; ards: acute respiratory distress syndrome; ats: american thoracic society; cdc: centers for disease control; copd: chronic obstructive pulmonary disease; icu: intensive care unit; idsa: infectious diseases society of america; iqr: interquartile range; rt-pcr: reverse transcriptase-polymerase chain reaction; ta: tracheal aspirate; who: world health organization. case mix, outcome and length of stay for admissions to adult, general critical care units in england, wales and northern ireland: the intensive care national audit & research centre case mix programme database febrile respiratory illness in the intensive care unit setting: an infection control perspective acute febrile respiratory illness in the icu: reducing disease transmission severe febrile respiratory illnesses as a cause of mass critical care nosocomial influenza: new concepts and practice morbidity during hospitalization: can we predict it? apache ii: a severity of disease classification system incubation periods of acute respiratory viral infections: a systematic review the gold guidelines: a comprehensive care framework infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults the american-european consensus conference on ards: definitions, mechanisms, relevant outcomes, and clinical trial coordination surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock guidelines for performance of respiratory tract cultures performance standards for antimicrobial susceptibility testing: fifteenth informational supplement typing (a/b) and subtyping (h /h /h ) of influenza a viruses by multiplex real-time rt-pcr assays prolonged viral shedding in pandemic influenza a h n : clinical significance and viral load analysis in hospitalized patients acute respiratory distress syndrome and pneumonia: a comprehensive review of clinical data critically ill children with pandemic influenza (h n ) in pediatric intensive care units in turkey outcomes from pandemic influenza a h n infection in recipients of solid-organ transplants: a multicentre cohort study hospitalized children with pandemic influenza a (h n ): comparison to seasonal influenza and risk factors for admission to the icu pandemic influenza a (h n ) virus hospitalizations investigation team: hospitalized patients with h n influenza in the united states hospitalized patients with pandemic influenza a (h n ) virus infection in the united states efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial neuraminidase inhibitor flu treatment investigator group does this patient have influenza? when should a diagnosis of influenza be considered in adults requiring intensive care unit admission? results of population-based active surveillance in toronto implications of antiviral resistance of influenza viruses intensive care adult patients with severe respiratory failure caused by influenza a (h n )v in spain nosocomial influenza in children influenza in the acute hospital setting nosocomial outbreak of influenza virus a (h n ) infection in a solid organ transplant department a nosocomial outbreak of pandemic influenza a(h n ) in a paediatric oncology ward in italy outbreak of novel influenza a (h n ) in an adult haematology department and haematopoietic cell transplantation unit: clinical presentation and outcome nosocomial pandemic (h n ) pandemic and post-pandemic influenza a (h n ) infection in critically ill patients impact of early oseltamivir treatment on outcome in critically ill patients with pandemic influenza a should lower respiratory tract secretions from intensive care patients be systematically screened for influenza virus during the influenza season? critical care :r . submit your next manuscript to biomed central and take full advantage of: • convenient online submission • thorough peer review • no space constraints or color figure charges • immediate publication on acceptance • inclusion in pubmed, cas, scopus and google scholar • research which is freely available for redistribution we thank thomas o'boyle for his help with the preparation of the manuscript. this study was partially financed by the programa de centros de investigación biomédica en red (ciber) de enfermedades respiratorias cb / / . maddalena giannella (cm / ) is contracted by the fis. all the authors made a substantial contribution. eb, dgdv, pc, and pm assisted in the conception and design of the study, revised the manuscript critically, and gave the final approval of the version to be published. mg, br, and plr were responsible for data acquisition, analysis, and interpretation. mg drafted the manuscript. members of gang study group revised and approved the study design and assisted in the data acquisition. all authors read and approved the final manuscript. the authors declare that they have no competing interests. key: cord- - prli s authors: vahedian-azimi, amir; bashar, farshid r.; khan, abbas m.; miller, andrew c. title: natural versus artificial light exposure on delirium incidence in ards patients date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: prli s nan we read with interest the study by smonig et al. on the impact of natural light (nl) exposure on delirium-associated outcomes in mechanically ventilated (mv) intensive care unit (icu) patients [ ] . in this single-center, prospective, observational study, the authors report an improvement in the secondary outcomes of hallucination incidence and haloperidol administration for agitation. no difference in delirium incidence or duration, mv duration, self-extubation, icu or hospital length-of-stay (los), or mortality was observed [ ] . we request clarification on whether the cumulative doses of haloperidol differed. smonig's findings differ from our observations. we have conducted a longitudinal cohort study of , icu patients with acute respiratory distress syndrome (ards) on mv from icus ( mixed, surgical, medical) from academic medical centers [ , ] . here, we report the results of a retrospective secondary analysis of patients from the mixed medical-surgical icus of two academic hospitals to assess the impact of nl exposure on delirium incidence. each icu had the same layout including beds; with adjacent windows allowing for nl (circadian pattern), and positioned m from the nearest window (artificial light: al). delirium was defined according to the dsm-iv-tr [ ] , and was assessed three times daily by the bedside nurse and researcher (kappa agreement coefficient . - . ) using the confusion assessment method for the icu (cam-icu) [ ] . we performed both unadjusted and adjusted logistic regression accounting for: year, diagnosis, age, sex, vital signs, illness severity (apache-ii score), development of ventilator-associated pneumonia, microbiology results, presence of an multiple drug resistant pathogens, mv duration, los (icu, hospital), and survival. we found that al patients had a . -and . times greater incidence of delirium by unadjusted and adjusted logistic regression, respectively. methodological differences in delirium definition, screening method and frequency, criteria for nl group, and population studied may contribute to the outcome heterogeneity across studies (table ) [ , [ ] [ ] [ ] [ ] . six studies utilized a validated delirium screening tool (table ) , whereas one did not [ ] , and one included (as a positive) any patient treated with haloperidol (regardless of screen result) [ ] . furthermore, two studies required a positive delirium screen on ≥ consecutive days to be classified as delirium [ , ] . moreover, the light exposure definitions vary considerably across studies. three studies compare patients in rooms with or without windows [ , , ] , whereas in two studies, all patients have nl exposure to differing degrees [ , ] . the assessed patient populations differ as well. whereas we found improved delirium outcomes in ards patients, who often have greater illness severity and longer icu los than the general icu patient population, no difference was observed in other icu populations [ , [ ] [ ] [ ] . our data suggest that further investigation in defined icu sub-populations may provide an opportunity to better identify those likely to benefit from nl exposure. such studies should capitalize on transparency using clear and reproducible of key variables including the definitions of delirium and nl exposure. based on the current level of evidence, it would be premature to discard a therapeutic role for nl exposure in critically ill patients. impact of natural light exposure on delirium burden in adult patients receiving invasive mechanical ventilation in the icu: a prospective study post-icu psychological morbidity in patients with ards and delirium impact of religiosity on delirium severity among critically ill shi'a muslims: a prospective multicenter observational study diagnostic and statistical manual of mental disorders (dsm-iv-tr) fourth edition (text revision) evaluation of delirium in critically ill patients: validation of the confusion assessment method for the intensive care unit (cam-icu) delirium and effect of circadian light in the intensive care unit: a retrospective cohort study effect of intensive care unit environment on in-hospital delirium after cardiac surgery do windows or natural views affect outcomes or costs among patients in icus? intensive care unit environment may affect the course of delirium publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. the authors that contributed to study design were ava, frb and acm. study implementation and data abstraction was performed by ava and frb. data analysis was performed by ava and acm. manuscript writing and revision were performed by acm amk, and ava. all authors read and approved the final manuscript. key: cord- -ta i ata authors: nair, girish b; niederman, michael s title: year in review : critical care - respiratory infections date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: ta i ata infectious complications, particularly in the respiratory tract of critically ill patients, are related to increased mortality. severe infection is part of a multiple system illness and female patients with severe sepsis have a worse prognosis compared to males. kallistatin is a protective hormokine released during monocyte activation and low levels in the setting of septic shock can predict adverse outcomes. presepsin is another biomarker that was recently evaluated and is elevated in patients with severe sepsis patients at risk of dying. the centers for disease control and prevention has introduced new definitions for identifying patients at risk of ventilator-associated complications (vacs), but several other conditions, such as pulmonary edema and acute respiratory distress syndrome, may cause vacs, and not all patients with vacs may have ventilator-associated pneumonia. new studies have suggested strategies to identify patients at risk for resistant pathogen infection and therapies that optimize efficacy, without the overuse of broad-spectrum therapy in patients with healthcare-associated pneumonia. innovative strategies using optimized dosing of antimicrobials, maximizing the pharmacokinetic and pharmacodynamic properties of drugs in critically ill patients, and newer routes of drug delivery are being explored to combat drug-resistant pathogens. we summarize the major clinical studies on respiratory infections in critically ill patients published in . critically ill patients with respiratory infections have been the continued focus of investigation over the last several years. infections, mostly nosocomial, are a major cause of mortality in hospitalized patients related to an increased risk of infection with multi-drug resistant (mdr) pathogens and the widespread use of indiscriminate broad-spectrum antibiotics. the frequency and epidemiology of mdr pathogens show regional variation, however, with several studies pointing out that the risk of mdr pathogens in healthcare-associated pneumonia (hcap) is variable and hence there is a need for accurate risk scoring in this category of patients. obtaining meaningful data and monitoring trends of preventative strategies have become ever more important, with the centers for disease control and prevention (cdc) recently publishing new surveillance definitions. newer biomarkers are becoming part of the increasing armamentarium in the field of critical care medicine and antibiotic stewardship using biomarkers has been studied robustly. antibiotic use in the critically ill, with dosing to attain better pharmacokinetic and pharmacodynamic results, was part of several research studies. we summarize the findings from the major clinical research studies published in on respiratory infections, with a focus on infections in critically ill patients. respiratory infection continues to be the most common cause of sepsis and septic shock. the past decade has seen increased awareness in recognizing patients with sepsis and several guidelines, including the 'surviving sepsis campaign' , have published a detailed framework on the approach to patients with severe sepsis. in a large, prospective, french, multicenter, observational study as part of the episs study cohort, investigators examined the epidemiology of septic shock in , patients [ ] . in this study, . % of patients had respiratory tract infection as the cause of septic shock and . % required invasive mechanical ventilation (mv), with gram-negative bacilli being the most common pathogens identified. although most patients received initial appropriate antibiotic therapy (n = ), the in-hospital mortality rate was still high, up to . %. a higher sequential organ failure assessment (sofa) score, age and chronic health status score and the presence of immunosuppression were independent risk factors for short-term mortality. in a follow-up study of the same cohort of patients, -month mortality was . %. severity of illness, indicated by a higher sofa score early after septic shock, impacted mortality the most, while co-morbid conditions such as cirrhosis, nosocomial infection and age influenced mortality after hospitalization [ ] . in another prospective observational cohort of , patients with severe sepsis, phua and colleagues studied the characteristics and outcomes of patients with a positive microbial culture ( . %) compared with those whose culture was negative ( . %) [ ] . respiratory infection was the most common cause of sepsis in both groups, and a lung source was determined as the primary cause of sepsis more often in patients with a negative culture than in patients with a positive culture ( . % versus . , p < . ). of all the pathogens identified, infection with pseudomonas aeruginosa (pa) was associated with increased mortality (odds ratio (or) . , % confidence interval (ci) . to . , p = . ). patients with culture-negative sepsis had fewer comorbidities; these patients were more often women and had lower severity of illness than those with culture-positive sepsis. although patients with positive culture had higher mortality, it was not an independent predictor of mortality on logistic regression analysis. sakr and colleagues [ ] studied the influence of gender on , patients with severe sepsis and found the frequency of severe sepsis and septic shock was lower in women than in men ( . % versus . %, p = . ) and the overall icu mortality was not different in both sexes ( . % versus . %, p = . ). in the subset of patients with severe sepsis, however, female patients had worse survival than men ( . % versus . %, p = . ). further studies on the impact of gender-specific hormonal and immunologic profile differences may uncover an explanation for these findings. cognitive dysfunction has been noted in patients following severe illness. in a study including , participants, the authors tested the hypothesis that a bidirectional relationship exists between pneumonia and dementia, with subclinical changes in cognition increasing the risk of pneumonia hospitalization and an accelerated decline in cognitive dysfunction occurring after pneumonia [ ] . three trajectories were identified longitudinally based on teng's modified mini mental state examination -no decline, minimal decline and severe decline. a low cognitive score prior to hospitalization increased the risk of pneumonia -a point lower modified mini mental state score increased the hazard of pneumonia by . %. patients who had at least one episode of pneumonia had a higher risk of developing subsequent dementia than those without pneumonia (hazards ratio . , % ci . to . , p = . ). of the total population, . % had severe sepsis and similar cognitive decline as was seen with pneumonia. neurotoxicity related to elevated cytokine levels and other co-morbid conditions with severe illness, such as delirium, could be a plausible explanation for the cognitive decline. however, the population in this study who developed pneumonia were slightly older and had abnormal scores on mini mental state examination and potentially were identified earlier in their course with longitudinal screening. enteral feeding is the desired mode of nutritional supplementation in critically ill patients, but patients receiving enteral nutrition may have gastroparesis and gastroesophageal reflux, putting them at risk for aspiration; therefore, measurement of gastric residual volume (grv) is recommended in ventilated patients. reignier and associates [ ] in a randomized, non-inferiority, open-label, multicenter trial studied whether grv monitoring every hours and adjusting enteral feeding rates if the volume exceeded ml would prevent ventilator-associated pneumonia (vap). in this study, there was no difference in vap incidence between patients who had grv measured (n = ) compared with the group (n = ) who did not ( . % versus . %), and all the clinical outcomes, including mortality, were similar in both groups. patients in whom grv was not measured had a higher incidence of vomiting, but also a higher proportion of this group achieved the calorie target and had lower use of prokinetic agents. although the study was done well, it was underpowered to determine the harmful effects related to vomiting and included mostly patients in the medical icu and excluded patients with gastrointestinal bleeding. in a meta-analysis of randomized controlled trials including , patients, alhazzani and colleagues [ ] reviewed the risk of pneumonia in patients receiving small bowel feeding compared to gastric feeding. small bowel feeding was associated with reduced risk of pneumonia (relative risk . , % ci . to . , p = . ), but there was no difference in mortality, ventilator days or icu length of stay (los) between the two groups. the study is limited, however, because the individual trials had small sample sizes, included severe pancreatitis patients and patients not in the icu and used variable definitions of pneumonia. insertion of the small bowel feeding tube can be technically difficult if done blindly and may need additional training with fluoroscopy and endoscopy procedures. even though oropharyngeal bacterial translocation seems a likely cause of the development of vap, it is unclear if monitoring gastric reserve volume or advancing the feeding tube to the small intestine clearly prevents vap. another identified risk factor for ventilator-associated respiratory infection (including vap and ventilator-associated tracheobronchitis) is iatrogenic immune suppression (or . ), a risk factor that has frequently been excluded in prior studies [ ] . shorr and colleagues [ ] studied the factors leading to -day readmission in culture-proven non-nosocomial pneumonia patients who survived to discharge following initial hospitalization to any of the nine participating hospitals in the same geographical area. the readmission rate was . % (n = ) within the -day period and was related to non-pneumonia causes such as chronic obstructive pulmonary disease ( %) and congestive heart failure (chf) ( %). while pneumonia accounted for only . % (n = ) of readmissions, patients with hcap were re-admitted more often than those with communityacquired pneumonia (cap) ( . % versus . %, p < . ) and had more comorbid conditions. the four independent variables associated with readmission on logistic regression analysis were long-term care admission prior to index hospitalization (or = . , p = . ), immunosuppressed state (or = . , p = . ), previous antibiotics (or = . , p = . ) and previous -day hospitalization (or = . , p = . ). these data suggest that readmission rates differ among groups of patients with pneumonia, and that patients with hcap and those with baseline poor functional status have a higher likelihood of being readmitted than uncomplicated cap patients. clinical algorithms based on biomarkers help with antibiotic de-escalation and possibly limit antibiotic over-exposure in patients with pneumonia, but their use in clinical practice has been variable. procalcitonin (pct), an inflammatory hormokine, is elevated in bacterial infection and helps with antibiotic stewardship, and risk stratification, particularly for respiratory infections. presepsin (scd -st) is another novel biomarker (soluble amino-terminal fragment of the cluster of differentiation (cd) marker protein cd ) in sepsis that is released into the circulation during monocyte activation. kallistatin is an endogenous serine proteinase inhibitor that has a strong affinity to tissue kallikrein and is thought to have a protective role with a higher consumption in patients with severe sepsis. in a prospective observational study of severe cap patients admitted to icu, lin and colleagues [ ] determined the prognostic value of serum kallistatin and its correlation to other biomarkers; healthy patients were included as controls. plasma kallistatin and antithrombin iii were significantly lower on days and in patients who did not survive ( %) compared to those who did, possibly indicating greater consumption of these factors in the severely ill. the plasma kallistatin levels were significantly reduced in patients with septic shock and in those who developed acute respiratory distress syndrome (ards). a cutoff level of day kallistatin < . μg/ml can discriminate between survivors and non-survivors with an area under the curve (auc) of . , p = . ( figure ). thus, decreased plasma kallistatin level on day of icu admittance is independently associated with mortality and severity of disease in cap patients in this study. in a multicenter, case-control study, masson and colleagues [ ] compared presepsin and pct levels in survivors and nonsurvivors who were admitted to icu with severe sepsis. the presepsin levels were significantly higher on day of enrollment in patients who died compared with survivors and remained significantly elevated on day as well. presepsin was independently associated with short-term icu and -day mortality and had good prognostic accuracy similar to the sofa score for long-term mortality at days. pct on the other hand was not related to mortality and the levels declined on day in both survivors and non-survivors. chf may cause gut translocation of bacteria and potentially lead to elevated pct levels. wang and colleagues [ ] studied the diagnostic value of serum pct levels in , patients with different types of chf. patients were grouped into chf (n = , ), chf with infection (n = , ), infection only (n = , ) and healthy controls (n = ). the pct levels in patients with chf were significantly elevated compared with healthy controls, while those with infection and chf had higher levels than both the infection alone and chf alone group ( figure ). in patients with increasing severity of chf, the positive predictive value of pct decreased significantly ( . in class ii chf with infection to . in class iv chf). if the pct was negative, however, the finding was good for ruling out infection in class iv chf patients (negative predictive value of ). hence, elevated pct should not be taken at face value in patients with chf and a higher cutoff should be used to define infection, depending on the severity of heart failure. in a meta-analysis of seven studies including , patients, prkno and colleagues [ ] studied the safety of using a pct-based regimen in patients with severe sepsis or septic shock. the -day mortality based on results from four included studies was not different between the pct-based regimen and standard treatment groups, but the pct group had a shorter duration of antimicrobial therapy based on five included studies. the studies included in the meta-analysis had substantial differences in design and cutoff values for pct and included both medical and surgical patients, but the common theme was that therapy based on pct leads to more de-escalation and a shorter duration of antibiotic therapy, with no adverse impact on mortality. the stop antibiotics on guidance of procalcitonin study (saps) is an ongoing, multicenter, randomized dutch study of daily pct versus standard therapy , currently finishing enrollment, and will be the largest icu-based trial evaluating the early stopping of antibiotics based on pct [ ] . healthcare bundles in the form of daily goal sheets and educational sessions have been shown to reduce the incidence of vap and related complications, but variable practices and different vap definitions limit their use. the cdc recently introduced a step-wise approach for 'objective' surveillance of ventilator-associated events and includes ventilator-associated complications (vacs), infection-related ventilator-associated complications (ivacs), as well as possible and probable vap. muscedere and associates [ ] studied the clinical impact and preventability of vacs and ivacs using prospectively collected data on , patients from another series and determined the relationship to vap. over four study periods, vacs developed in . % of patients (n = ), ivacs in . % (n = ) and vap was noted in . % (n = ); patients had both a vac or ivac and vap. patients who had vacs were more likely to develop vap than those who did not have vacs ( . % versus . %, p < . ). patients with vacs or ivacs had significantly more ventilator days, hospital days, and antibiotic days and higher hospital boxes represent interquartile range, and whiskers the th and th percentiles in each category. hf, heart failure; pct, procalcitonin. adapted from wang and colleagues [ ] . mortality compared with patients who did not develop vacs or ivacs. when prevention efforts were undertaken, they were able to reduce the incidence of vacs and vap, but not ivacs, over subsequent periods. in another study, hayashi and colleagues [ ] compared patients with vacs to without vacs and noted that patients who developed vacs had a longer icu los ( versus days), duration of mv ( versus days) and use of antibiotics but no difference in overall icu mortality and hospital los. vac definitions identified a 'potential vap' (a vac with positive culture of respiratory pathogens in respiratory specimens plus antibiotic prescription with intention to treat as vap) in . % of cases, but it was not specific for vap and included atelectasis in . % of patients, acute pulmonary edema in . %, and ards in . %. using electronic records to identify complications related to ventilation is easy and identifies sick patients, but many patients with vap were not identified in both studies and therefore vacs and ivacs may be different diseases with different pathobiological causes than vap. sinuff and associates [ ] studied the impact of a -year multi-faceted intervention via educational sessions supplemented with reminders and led by local opinion leaders on improving concordance with vap prevention and treatment guidelines and assessed sustainable behavior changes in the icu. over time, there was more improvement in prevention strategies than in therapy approaches, and, overall, a significant increase in guideline concordance (aggregate concordance (mean (standard deviation)): . % ( . ), . % ( . ), . % ( . ), . % ( . ); p = . ). they also observed a reduction in vap rates (events/ patients: ( . %), ( . %), ( . %), ( . %); p = . ) over the study period, but icu mortality and length of icu stay were unchanged, despite adjustments for age and sofa score. the best concordance rate achieved was only . % and highlights the potential barriers to guideline implementation and variable practices that exist within the community despite multiple reinforcements. in another study, including patients, investigators using data from electronic medical records compared the incidence and outcomes in vap patients using various definitions, including the new cdc ventilator-associated event algorithm, before and after a vap bundle was introduced in their institution (pre-bundle period january to december (n = ); post-bundle period january to december (n = )) [ ] . unlike the previous study, vap and vac incidence remained unchanged and was not affected by the implementation of the vap bundle despite good compliance. however, mortality adjusted for severity of illness was less in the post-bundle period ( % versus %, p < . ), although the duration of mv, icu and hospital los did not change post-bundle introduction. the lack of reduction in vap and vac incidence could have been due to continuous quality improvement interventions that were already underway prior to guideline implementation, but interestingly the newer ventilator-associated event definitions did not recognize vap in all patients, similar to findings from the studies by muscedere and colleagues [ ] and hayashi and colleagues [ ] discussed above. luna and associates [ ] , in a prospective study of ventilated patients, analyzed if an antibiotic prescription strategy based on routine endotracheal aspirate (eta) culture was better than empiric antibiotic therapy for vap, as outlined by the american thoracic society (ats)/infectious disease society of america (idsa) guidelines. eighty-three patients had vap and the eta and bronchoalveolar lavage (bal) cultures had concordance in only culture pairs. sensitivity for eta to predict a bal-obtained pathogen was . % ( / microorganisms cultured) and was better if done within days of vap onset and in recurrent vap. antibiotic decisions made according to the ats/idsa guidelines led to appropriate therapy in . % of patients compared with . % based on eta culture, with fewer antibiotic days using the eta-based culture. hence, using a strategy for vap diagnosis and treatment decisionmaking based on eta cultures alone could result in inappropriate therapy but possibly helps with de-escalation and leads to fewer antibiotic days. recent studies have confirmed the significant heterogeneity among hcap patients and also that the risk for mdr pathogens has regional differences. in a study including patients with cap and with hcap, the authors compared the performance of pneumonia severity index (psi) and curb- risk scores for predicting -day mortality [ ] . hcap patients were sicker, had more frequent icu admission, longer length of icu stay and higher mortality than cap patients in this cohort. the discriminatory power for -day mortality, using both psi and curb- , was lower in hcap patients than cap patients (auc for psi = . , curb- = . in hcap group versus auc for psi = . , curb = . ; p = . ). thus, both scoring systems were less effective for predicting mortality in hcap than in cap patients, but if used, the psi scoring system performed better than curb- . in a prospective study including , patients ( cap and hcap), shindo and associates [ ] determined the risk factors for pathogens resistant to macrolides, beta-lactams and respiratory fluoroquinolones (cap-drps). hcap patients had a higher frequency of cap-drps than cap patients ( . % versus . %) and a higher -day mortality rate ( . % versus . %). independent risk factors for cap-drps were similar in both cap and hcap groups, and included prior hospitalization, immunosuppression, previous antibiotic use, gastric acid-suppressive agents, tube feeding, and non-ambulatory status. the higher the number of risk factors, the greater the chance of cap-drps (auc . , % ci . to . ). they also identified risk factors for methicillin-resistant staphylococcus aureus (mrsa), which included dialysis within days, prior mrsa isolation within the past days, antibiotics in the past days, and gastric acid-suppressive therapy. however, the presence of a high frequency of resistant pathogens in this study group limits generalization and further studies are needed for external validity of the model. in another study, aliberti and colleagues [ ] used probabilistic risk scores for prediction of mdr pathogens in two independent cohorts admitted to the hospital from the community (n = , ) to validate the previously reported shorr and aliberti risk scores. the prevalence of mdr pathogens was . % in barcelona and . % in edinburgh and the two scores performed consistently better than the traditional hcap classification in both centers. maruyama and colleagues [ ] , in a prospective study of patients (cap = , hcap = ), applied a therapeutic algorithm based on the presence of mdr risk factors (immunosuppression, hospitalization within the last days, poor functional status indicated by a barthel index score < , and antibiotic therapy within the past months) and severity of illness (need for icu admission or requiring mv) to determine its impact on outcomes. hcap patients with no or one risk factor were treated with cap therapy and those with two or more risk factors were treated with a hospital acquired pneumonia regimen based on the ats/idsa guidelines. hcap patients with two or more risk factors had a higher incidence of mdr pathogens and higher mortality than cap patients ( . % versus %, p < . , and . % versus . %, p = . , respectively). although only % of hcap patients received broad-spectrum antibiotics, using the algorithm the majority ( . %) received appropriate therapy for the identified pathogens. thus, using this approach, broad-spectrum antibiotic use can be limited, even in patients with hcap. lacroix and associates [ ] investigated the role of early fiberoptic bronchoscopeguided distal protected small volume bronchoalveolar lavage (mini-bal) in hcap patients. mini-bal helped identify causative pathogens more efficiently than blood culture ( . % versus . %, p < . ), up to % in patients who did not receive prior antibiotics. thus, a strategy based on mini-bal might help with early identification, but the authors did not compare length of antibiotic days, development of resistance or mortality between an empiric regimen and patients who had mini-bal. the practicality of this approach in the non-intubated hcap population needs to be validated. sicot and colleagues [ ] evaluated the characteristics of patients with panton-valentine leucocidin (pvl) community-acquired s. aureus pneumonia from a french registry, based on methicillin resistance. both pvl-mrsa (n = , %) and pvl-methicillin-sensitive staphylococcus aureus (pvl-mssa; n = , %) occurred in younger patients (median age . years) with no underlying comorbidities. airway hemorrhage was more frequent in pvl-mssa necrotizing pneumonia compared with pvl-mrsa ( . % versus . %, p = . ) but there was no significant difference in mortality ( . % versus . %), icu admission, severity of disease or use of antibiotics between the two groups. interestingly, methicillin resistance was not associated with increased mortality, but patients with airway hemorrhage had a three-fold increase in -and -day mortality (or . and . , respectively) and patients treated with an anti-toxin regimen (clindamycin, linezolid, or rifampicin) had a better chance of survival (mortality rate . % versus . %, p < . ) even though the timing of therapy was not available. this study is one of the largest series on necrotizing community-acquired staphylococcal infection and shows that, despite the resistance pattern, pvl-associated s. aureus infection can be a severe disease with high mortality in young patients from the community and that the use of anti-toxin therapy in suspected patients is associated with a potential survival advantage. choi and associates [ ] studied the role of viruses in patients with severe pneumonia ( with cap and with hcap) using rt-pcr and bal fluid ( . %) or nasopharyngeal swab ( . %). of the patients, . % (n = ) had positive bacterial culture, . % (n = ) had viral infections, and . % (n = ) had bacterialviral co-infections. rhinovirus was the most commonly identified virus ( . %), followed by parainfluenza virus ( . %) and human metapneumovirus ( . %). bacterial coinfection was more common with parainfluenza and influenza viruses and less common with respiratory syncitial virus and rhinoviruses. there was no difference in mortality between each group, but of those patients with viral infection, rhinovirus was associated with the highest mortality ( . %), followed by influenza virus ( . %). this is an interesting study and shows that polymicrobial infection with viruses and bacteria is not uncommon in patients with severe pneumonia. however, some study participants had antibiotics prior to bal and therefore the negative bacterial cultures may not have been an accurate finding. in contrast to the discussion above, bacterial infection commonly complicates viral respiratory infection and is often associated with higher morbidity and mortality. muscedere and colleagues [ ] evaluated the risk of coexistent or secondarily acquired bacterial respiratory tract or bloodstream-positive cultures in patients with influenza a (h n ) infection during the outbreak. they noted that % of patients (n = ) had at least a positive blood or respiratory culture during their icu stay ( . % had co-existent and . % had icu-acquired infection; . % had both) despite almost all patients receiving antibiotics. patients with any positive culture had higher morbidity with more days on the ventilator, longer icu and hospital los and higher hospital mortality ( . % versus . %, p = . ). the interesting finding from this study is that influenza infection (h n ) is not as mild as previously thought; the majority of icu patients required mv and the morbidity and mortality were high even in patients without bacterial co-infection. hung and colleagues [ ] in a double-blind, randomized controlled trial evaluated the use of hyperimmune iv immunoglobulin (h-ivig) fractionated from convalescent plasma of patients who had h n infection (n = ) versus normal iv immunoglobulin (n = ) in patients with severe h n infection. patients who received h-ivig had significantly lower viral loads post-treatment and, if treatment was given within days of onset, had mortality benefit (or . , % ci . to . , p = . ). although the study is limited by a relatively small sample size, the h n antibody present in the convalescent h-ivig, if used early, offers potential benefit in the treatment of h n infection. the ats/idsa guidelines recommend antibiotic therapy based on the risk for mdr pathogens with early onset infection (within days of admission), generally using a narrow-spectrum antibiotic regimen. restrepo and colleagues [ ] examined the microbial cultures of vap patients from large prospective, randomized, open-label studies, classifying patients as early-(< days since hospitalization, n = ) and late-onset vap (> days, n = ). late-onset vap patients had a higher overall frequency of gram-negative pathogens ( . % versus . %, p = . ) and more significant antibiotic exposure in the prior month ( . % versus . %, p < . ). however, both early-and late-onset vap patients had similar rates of mdr pathogens ( . % and . %, respectively, p = . ). investigators from the eu-vap study divided patients with microbiology-confirmed nosocomial pneumonia into two groups; group was early-onset with no mdr risk factors (n = ) and group was early-onset with mdr risk factors or late-onset pneumonia [ ] . the presence of severe sepsis/septic shock (or = . ) and pneumonia that developed in a center with greater than a % prevalence of resistant pathogens (or = . ) was independently associated with the presence of resistant pathogens in group patients. these findings suggest that most patients with vap are at risk for mdr pathogens, and that very few can safely receive narrow-spectrum empiric therapy. tumbarello and associates [ ] analyzed the impact of multi-drug resistance on outcomes in patients admitted to icu with culture-confirmed pa pneumonia. forty-two cases ( %) involved mdr pa, and ( . %) were colistin-only susceptible pa. the initial antimicrobial regimen was inadequate in patients ( . %) and more often inadequate among those with mdr pa. patients who had initial inappropriate antibiotics had a higher mortality than those who had appropriate therapy ( . % versus . %, p = . ) and mdr pa patients treated with empiric combination therapy had a lower risk of initial inappropriate antibiotics than those treated with monotherapy. in a similar study, pena and colleagues [ ] looked at the impact of mdr in patients with pa vap, of which cases were caused by mdr strains, ( %) of which were extensively drug-resistant. as with the previous study, vap patients with susceptible pa received adequate empiric antibiotic coverage more often, both empiric and definitive, than patients with mdr pathogens ( % versus %, p < . ). although inadequate antibiotics were an independent risk factor for early mortality (or . , p = . ) and patients with susceptible strains had more adequate coverage, those with inadequate therapy had a higher mortality that could be related to severity of illness more than to resistance. the outcomerea data on pa pneumonias include pa-vap episodes with multi-drug resistance defined as resistance to two antibiotics (piperacillin, ceftazidime, imipenem, colistin, and fluoroquinolones) [ ] . mdr was not related to treatment failure or relapses but was associated with longer icu los. fluoroquinolone use prior to the first episode was associated with increased risk of treatment failure probably related to the induction of resistance, but when used in the treatment regimen, fluoroquinolones decreased the risk of treatment failure. in another study of confirmed pseudomonal pneumonia patients, serotypes o and o were more prevalent, but mortality was higher with o ( %) and lower with o ( %); clinical resolution tended to be better with o ( %) compared with other serotypes. higher acute physiology and chronic health evaluation ii score was associated with worse outcomes among all serotypes [ ] . clinically feasible and simple to use predictors of icu outcome in patients with icu-acquired pneumonia are important in clinical practice. in a prospective observational study, esperatti and colleagues [ ] determined the usefulness of a set of predictors of adverse outcomes (paos) in icu-acquired pneumonia patients and determined their correlation with serum inflammatory markers and clinical prognostic scores. the paos were determined to hours after starting antibiotics (evolutionary criteria), and were considered positive if there was: ) no improvement in partial pressure of oxygen in arterial blood/fraction of inspired oxygen ratio since the onset of pneumonia and in the absence of other causes of worsening oxygenation; ) requirement for intubation despite antibiotics for hours; ) persistence of fever or hypothermia together with purulent secretions; ) a % or greater increase in pulmonary infiltrates on chest radiograph; ) development of septic shock or multi-organ dysfunction not present on day . fifty percent of patients had at least one pao, and had a higher -day mortality ( % versus %, p = . ), less mean ventilator-free days ( versus , p = . ) and elevated serum inflammatory markers such as pct and c-reactive protein compared with those who did not have any paos. the trend remained significant in patients who developed vap, as well as those who had nonventilator icu-acquired pneumonia. the failure to improve oxygenation (partial pressure of oxygen in arterial blood/ fraction of inspired oxygen) and a worsening sofa score over days were independently associated with mortality in a multivariate analysis. the ats/idsa guidelines recommend using combination antibiotic therapy in patients with severe cap admitted to the icu. adrie and colleagues [ ] examined the impact of dual (β-lactam plus macrolide or fluoroquinolone (n = )) versus monotherapy (β-lactam alone (n = )) in immunocompetent severe cap patients, using a large prospective database. they found no significant difference in -day mortality between patients who had dual therapy compared to monotherapy, and in those who received dual therapy, there was no survival advantage between the macrolide and fluoroquinolone subgroups (subdistribution hazard ratio . , % ci . to . , p = . ). interestingly, patients who had initial adequate antibiotic therapy had a survival advantage (subdistribution hazard ratio . , % ci . to . . , p = . ) and those who received dual therapy had a higher frequency of initial adequate antibiotics, which did not translate into improved survival. further, subgroup analysis did not reveal a survival benefit even in patients with septic shock or streptococcus pneumoniae infection receiving dual therapy, but dual therapy did not increase the development of mdr pathogens or nosocomial pneumonia. in a similar study including , hospitalized patients, guideline concordant therapy (defined as macrolides/β-lactams or respiratory fluoroquinolone monotherapy) did not have a mortality benefit compared with discordant therapy, but a composite endpoint of death or icu admission was lower in the concordant group ( . % versus . %; adjusted or . , % ci . to . , p < . ) [ ] . most patients received levofloxacin monotherapy in the guideline-concordant group ( %) and there was no significant difference in mortality between patients who received macrolide/β-lactam antibiotics versus those who had fluoroquinolone/β-lactams (adjusted or . , % ci . to . , p = . ). the findings from these studies contradict previous reported studies, but lack of randomization and possible misclassification bias limits interpretation. antibiotic dosing in critically ill patients is challenging due to deranged drug metabolism and elimination that can lead to suboptimal dosing. extended infusion of antibiotics with a time-dependent killing mechanism, such as beta-lactams, has been proposed as a means to overcome the pharmacokinetic/pharmacodynamic (pk/pd) alterations in severely ill patients in order to optimize the time that drug concentration exceeds the minimum inhibitory concentration (mic) of the target organism. carlier and colleagues [ ] studied the effect of augmented renal clearance on extended infusion of meropenem or piperacillin/tazobactam (pip/tazo) in patients with sepsis and normal creatinine clearance [ ] . patients received a loading dose ( g for meropenem and . g for pip/tazo) followed by extended infusion usually over hours every hours for pip/tazo and hours for meropenem. only % of patients achieved a predefined pk/pd target, and of patients who had augmented renal clearance ( %), the majority did not achieve the target ( %). augmented renal clearance with a clearance > ml/ minute was an independent predictor of not achieving the pk/pd target, but the study was not designed to look at outcome and treatment failures, and the pk/pd target may have been set too high. dulhunty and colleagues [ ] , in a double-blind randomized controlled trial, compared continuous versus intermittent bolus dosing of pip/tazo, meropenem, and ticarcillin-clavulanate in patients with severe sepsis. patients in the intervention arm received active infusion and placebo boluses and controls received placebo infusion and active boluses. the concentration exceeded the mic more often in the intervention group than in controls ( . % versus . %, p = . ; most with meropenem and least with ticarcillinclaculanate) and the patients in the intervention group had a higher clinical cure rate, but there was no difference in icu or hospital los or mortality. the study reinforces the dosing options available for critically ill patients based on pk characteristics, but did not have the statistical power to determine a mortality benefit, although there was a trend towards better survival in the intervention arm. with the growing development of resistance to beta-lactams, aminoglycosides are advocated for patients with severe sepsis as part of combination therapy, especially with pa infection and the bactericidal activity of aminoglycosides is dependent on peak concentration (cpeak) relative to mic. as noted above, the concentration of aminoglycoside can change in critically ill patients due to variations in drug clearance. in a study of patients with severe sepsis ( % with lung infection) requiring amikacin, investigators used therapeutic drug monitoring and dose adjustments to optimize serum concentration [ ] . microbiological eradication and clinical cure were higher in patients who achieved initial optimal cpeak/mic and were proportionately higher with higher target concentration. patients who achieved the target concentration after days had a worse clinical cure and microbiological eradication than those who achieved this goal on the first day. renal failure was seen in % of patients and was more likely in those with impaired clearance and higher minimum concentration. inhalation antibiotics have the potential advantage of achieving high alveolar concentrations with minimal systemic side effects. in a matched : case control study, tumbarello and colleagues [ ] studied aerosolized colistin (given via jet nebulizer or ultrasonic nebulizer) as an adjunctive treatment to intravenous therapy with the same drug in vap patients with positive cultures for gram-negative mdr pathogens susceptible only to colistin. patients receiving aerosolized therapy in conjunction with intravenous colistin had a higher clinical cure rate compared with controls ( . % versus . %, p = . ) and fewer days on the ventilator after onset of vap ( versus days, p = . ), but no difference in overall mortality or icu los. also, there was no difference in the rate of new-onset kidney failure between the two groups. the study results are in contrast to previous reports with aerosolized colistin providing only modest benefits. in this study the medication was delivered in the majority of patients using conventional ventilators with jet nebulizers and the local concentration of antibiotics could not be determined. in view of the reported increased incidence of drug-resistant pathogens causing vap and the potential treatment alternative with aerosolized colistin, further randomized controlled studies are needed prior to generalization of the results. in a study looking at factors influencing antibiotic de-escalation in patients admitted to icu with sepsis, only . % of patients had the number of antibiotics reduced or switched to a narrower spectrum [ ] . however, there was no difference in mortality rate, icu los or duration of mv between patients who had de-escalation compared with those with no de-escalation. in those patients who did not have de-escalation, % had no de-escalation despite meeting criteria. narrowspectrum initial antibiotic therapy (or . , % ci . to . , p < . ) and infection with an mdr bacteria (or . , % ci . to . , p = . ) were factors preventing de-escalation. duration of antibiotic treatment for nosocomial pneumonia is not clearly defined, and previous studies have shown that a short duration may be as clinically effective as a longer duration (> days) and more cost-effective. a meta-analysis of four randomized controlled trials (including patients) comparing short ( to days) with long ( to days) duration regimens in patients with vap showed no difference in mortality, icu los or mv between the two groups, and more antibioticfree days in the short course group [ ] . there was a trend towards more relapses due to non-fermenting gram-negative bacilli in the shorter duration antibiotic cohort. in another observational study, including suspected vap patients with negative bal results, investigators compared the effects of early discontinuation (antibiotics stopped within day of final negative quantitative bal culture results) with late discontinuation of antibiotics (more than day after negative final bal cultures) [ ] . there was no difference in mortality between early discontinuation ( . %) and late discontinuation ( . %) patients (p = . ). clinical resolution as noted by clinical pulmonary infection score was similar in both groups and patients with late discontinuation had a longer duration of antibiotic therapy ( versus days, p < . ). interestingly, patients with early discontinuation developed less frequent superinfections compared with late discontinuation patients ( . % versus . %, p = . ). these results add credence to the value of de-escalation for vap patients and to the possibility that longer antibiotic courses may cause microbial persistence and selection pressure leading to the development of microbial resistance. prophylactic systemic antibiotics have a role in preventing early-onset vap in closed head injury patients. valles and colleagues [ ] evaluated the role of single-dose antibiotics within hours of intubation (ceftriaxone g intravenously; g ertapenem in those with hypersensitivity to beta-lactam; mg levofloxacin in those with anaphylaxis to beta-lactam) in the prevention of early-onset vap or ventilator-associated tracheobronchitis in comatose patients. they compared patients who received prophylaxis to historical cohorts. the patients who received prophylaxis had fewer microbiologically confirmed cases of vap ( % versus . %, or . , p = . ), less mv days, and shorter icu los. however, there was no difference in mortality or hospital los between the two groups. although there was no increased incidence of mdr pathogens in the prophylaxis group with lateonset vap, the study patients did not have surveillance cultures and hence the rate of colonization is unknown. prophylactic antibiotic at the time of intubation in high-risk patients at risk for vap is an interesting concept and further prospective randomized controlled studies are required prior to generalization of the results. statins have possible anti-inflammatory and immunomodulatory effects and their use in patients with pneumonia had previously been reported to lead to beneficial outcomes. papazian and associates in a double-blind, parallel-group study, randomized vap patients (defined as having a clinical pulmonary infection score > ) to receive simvastatin ( mg) or placebo [ ] . the authors planned to enroll , patients, but the study was stopped prematurely because of futility after enrolling in the intervention arm and in the control group. there was no significant difference in -day mortality ( % absolute increase with simvastatin) or other secondary outcomes, including duration of mv, coronary events, ards, or adverse side effects between the two groups. however, of those patients naive to prior statin use, the -day mortality was higher in the placebo arm ( % versus %, p = . ). although this trial was underpowered to highlight any marginal beneficial effects of statins, the results are similar to another recent trial exploring the role of statins in sepsis that also did not find any difference in levels of interleukin- , but possible beneficial effects in continuing chronic statin therapy [ ] . probiotics may restore non-pathogenic gut flora and the value of their use in critically ill patients has been inconclusive. barraud and associates [ ] conducted a meta-analysis including randomized studies with , patients to evaluate the use of probiotics (most with lactobacillus sp.) in the icu. probiotic use did not have a significant impact on mortality or the duration of mv. however, probiotic use resulted in a significant decrease in nosocomial pneumonia even after adjustment for heterogeneity (or . , % ci . to . ) and also led to a shorter icu los. use of probiotics could potentially prevent gastric colonization by pathogenic bacteria and might explain the beneficial effects seen with icu-acquired pneumonia. whether this should be added to vap prevention measures is still to be determined and will need further large trials, with vap as the primary end point. respiratory infections remain the most common cause of sepsis and septic shock, with gram-negatives being slightly more common than gram-positives. some patients have sepsis with negative cultures and these patients may have a better prognosis than those with positive cultures. severe infection is part of a multiple system illness, and some recent data have examined the relationship of pneumonia to cognitive impairment, showing that infection can lead to cognitive decline, possibly related to inflammatory cytokines, while at the same time patients who develop pneumonia may be more cognitively impaired than those without pneumonia. many episodes of pneumonia result from gastric aspiration, but recent investigations have shown that development of vap could not be prevented even with enteral feeding and close attention to gastric residual volume. one alternative is to place feeding tubes directly into the small bowel, which may reduce pneumonia risk but not have an impact on mortality. biomarkers may help us guide the need for therapy, the duration of therapy for pneumonia, and the prognosis for survival, but most data have been collected with serum pct measurements. recent studies suggest that kallistatin is a protective hormokine, and that, in the setting of septic shock, low levels may predict adverse outcomes such as ards and death. another biomarker, presepsin, is elevated in severe sepsis patients who die. pct has been used to separate patients with infection from those without infection, but in the presence of chf new data suggest that low levels may rule out infection, but that severe heart failure itself can falsely elevate levels. the diagnosis of vap remains confusing, and new data have shown the limited value of the cdc definition of vacs. vacs include a number of non-infectious diagnoses, and many patients with vap do not have a vac. some data suggest that vacs can be prevented, but there are also studies showing that the currently available ventilator bundles cannot prevent them. in the management of cap and vap, it is important to account for mdr pathogens in empiric therapy. outside the hospital, there are patients who develop hcap and many of these are also at risk for mdr pathogens. new studies have suggested strategies to identify patients at risk for resistant pathogen infection, and therapies that optimize efficacy, without the overuse of broad-spectrum therapy. the optimal therapy of mdr pathogens is being explored, but for mrsa cap, the use of anti-toxin therapy may improve outcome. in vap, the role of resistance in determining outcome is uncertain, but most studies suggest an interaction between drug susceptibility and disease severity. optimizing the therapy of mdr pathogens is being explored in a number of ways, including the use of modified dosing regimens, and inhaled antibiotics for pneumonia. our enhanced understanding of altered renal clearance in severe infection has led to renewed efforts to provide enough antibiotic to seriously ill patients, and to avoid the use of too low a dose of an effective agent. in the future, we will continue our efforts at pneumonia prevention, but this will require a continued understanding of disease pathogenesis, the use of prevention bundles and the application of standard therapies in novel ways (as demonstrated with studies of statins). note: this article is part of a collection of year in review articles in critical care. other articles in this series can be found at [ ] . acute respiratory distress syndrome cap: community-acquired pneumonia; cdc: centers for disease control and prevention; chf: congestive heart failure; ci: confidence interval peak concentration; eta: endotracheal aspirate; grv: gastric residual volume; hcap: healthcare-associated pneumonia; h-ivig: hyperimmune iv immunoglobulin; idsa: infectious disease society of america; ivac: infection-related ventilator-associated complication mdr: multi-drug resistant; mic: minimum inhibitory concentration methicillin-sensitive staphylococcus aureus; mv: mechanical ventilation; ofa: sequential organ failure assessment; or: odds ratio pao: predictors of adverse outcome; pcr: polymerase chain reaction pct: procalcitonin; pip/tazo: piperacillin/tazobactam; pk/pd: pharmacokinetic/pharmacodynamic; psi: pneumonia severity index pvl: panton-valentine leucocidin; rt: reverse transcriptase; vac: ventilator-associated complication; vap: ventilator-associated pneumonia the epidemiology of septic shock in french intensive care units: the prospective multicenter cohort episs study profile of the risk of death after septic shock in the present era: an epidemiologic study characteristics and outcomes of culture-negative versus culture-positive severe sepsis the influence of gender on the epidemiology of and outcome from severe sepsis bidirectional relationship between cognitive function and pneumonia effect of not monitoring residual gastric volume on risk of ventilator-associated pneumonia in adults receiving mechanical ventilation and early enteral feeding: a randomized controlled trial small bowel feeding and risk of pneumonia in adult critically ill patients: a systematic review and meta-analysis of randomized trials suspected ventilator-associated respiratory infection in severely ill patients: a prospective observational study readmission following hospitalization for pneumonia: the impact of pneumonia type and its implication for hospitals plasma kallistatin levels in patients with severe community-acquired pneumonia presepsin (soluble cd subtype) and procalcitonin levels for mortality prediction in sepsis: data from the albumin italian outcome sepsis trial procalcitonin testing for diagnosis and short-term prognosis in bacterial infection complicated by congestive heart failure: a multicenter analysis of , cases procalcitonin-guided therapy in intensive care unit patients with severe sepsis and septic shock -a systematic review and meta-analysis stop antibiotics on guidance of procalcitonin study (saps): a randomised prospective multicenter investigator-initiated trial to analyse whether daily measurements of procalcitonin versus a standard-of-care approach can safely shorten antibiotic duration in intensive care unit patients -calculated sample size: patients the clinical impact and preventability of ventilator-associated conditions in critically ill patients who are mechanically ventilated toward improved surveillance: the impact of ventilator-associated complications on length of stay and antibiotic use in patients in intensive care units implementation of clinical practice guidelines for ventilator-associated pneumonia: a multicenter prospective study temporal trends of ventilator-associated pneumonia incidence and the effect of implementing health-care bundles in a suburban community is a strategy based on routine endotracheal cultures the best way to prescribe antibiotics in ventilator-associated pneumonia? performances of prognostic scoring systems in patients with healthcare-associated pneumonia risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia multidrug-resistant pathogens in hospitalised patients coming from the community with pneumonia: a european perspective a new strategy for healthcare-associated pneumonia: a -year prospective multicenter cohort study using risk factors for multidrug-resistant pathogens to select initial empiric therapy evaluation of early mini-bronchoalveolar lavage in the diagnosis of health care-associated pneumonia: a prospective study methicillin resistance is not a predictor of severity in community-acquired staphylococcus aureus necrotizing pneumonia -results of a prospective observational study viral infection in patients with severe pneumonia requiring intensive care unit admission the occurrence and impact of bacterial organisms complicating critical care illness associated with influenza a(h n ) infection hyperimmune iv immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe influenza a (h n ) infection comparison of the bacterial etiology of early-onset and late-onset ventilator-associated pneumonia in subjects enrolled in large clinical studies potentially resistant microorganisms in intubated patients with hospital-acquired pneumonia: the interaction of ecology, shock and risk factors clinical outcomes of pseudomonas aeruginosa pneumonia in intensive care unit patients impact of multidrug resistance on pseudomonas aeruginosa ventilator-associated pneumonia outcome: predictors of early and crude mortality pseudomonas aeruginosa ventilator-associated pneumonia. predictive factors of treatment failure pseudomonas aeruginosa serotypes in nosocomial pneumonia: prevalence and clinical outcomes validation of predictors of adverse outcomes in hospital-acquired pneumonia in the icu initial use of one or two antibiotics for critically ill patients with community-acquired pneumonia: impact on survival and bacterial resistance impact of guideline-concordant antibiotics and macrolide/beta-lactam combinations in patients hospitalized with pneumonia: prospective cohort study meropenem and piperacillin/tazobactam prescribing in critically ill patients: does augmented renal clearance affect pharmacokinetic/pharmacodynamic target attainment when extended infusions are used? continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial therapeutic drug monitoring of amikacin in septic patients effect of aerosolized colistin as adjunctive treatment on the outcomes of microbiologically documented ventilator-associated pneumonia caused by colistin-only susceptible gram-negative bacteria factors influencing the implementation of antibiotic de-escalation and impact of this strategy in critically ill patients short-vs long-duration antibiotic regimens for ventilator-associated pneumonia: a systematic review and meta-analysis early antibiotic discontinuation in patients with clinically suspected ventilatorassociated pneumonia and negative quantitative bronchoscopy cultures efficacy of single-dose antibiotic against early-onset pneumonia in comatose patients who are ventilated effect of statin therapy on mortality in patients with ventilator-associated pneumonia: a randomized clinical trial a multicenter randomized trial of atorvastatin therapy in intensive care patients with severe sepsis impact of the administration of probiotics on mortality in critically ill adult patients: a meta-analysis of randomized controlled trials cite this article as: nair and niederman: year in review : critical care -respiratory infections the authors declare that they have no competing interests.author details key: cord- -l er authors: richard, jean-christophe marie; pham, tài; brun-buisson, christian; reignier, jean; mercat, alain; beduneau, gaëtan; régnier, bernard; mourvillier, bruno; guitton, christophe; castanier, matthias; combes, alain; tulzo, yves le; brochard, laurent title: interest of a simple on-line screening registry for measuring icu burden related to an influenza pandemic date: - - journal: crit care doi: . /cc sha: doc_id: cord_uid: l er introduction: the specific burden imposed on intensive care units (icus) during the a/h n influenza pandemic has been poorly explored. an on-line screening registry allowed a daily report of icu beds occupancy rate by flu infected patients (flu-or) admitted in french icus. methods: we conducted a prospective inception cohort study with results of an on-line screening registry designed for daily assessment of icu burden. results: among the centers participating to the french h n research network on mechanical ventilation (reva) - french society of intensive care (srlf) registry, icus belonging to seven large geographical areas voluntarily participated in a website screening-registry. the aim was to daily assess the icu beds occupancy rate by influenza-infected and non-infected patients for at least three weeks. three hundred ninety-one critically ill infected patients were enrolled in the cohort, representing a subset of % of the whole french pandemic cohort; % were mechanically ventilated, % required extra corporal membrane oxygenation (ecmo) and % died. the global flu-or in these icus was only . %, but it exceeded a predefined % critical threshold in icus for a total of weeks. flu-ors were significantly higher in university than in non-university hospitals. the peak icu burden was poorly predicted by observations obtained at the level of large geographical areas. conclusions: the peak flu-or during the pandemic significantly exceeded a % critical threshold in almost half of the icus, with an uneven distribution with time, geographical areas and between university and non-university hospitals. an on-line assessment of flu-or via a simple dedicated registry may contribute to better match resources and needs. in the fall of , the reported incidence of patients infected with the pandemic influenza a(h n ) virus in france exceeded the usual incidence of seasonal flu [ , ] . notification of all patients infected with a(h n ) virus became mandatory from july to november but later was restricted to intensive care unit (icu) admissions because of a large and rapid increase in the number of cases [ ] . taking into account observations made during the early stage of the pandemic in other countries [ ] [ ] [ ] (especially in the southern hemisphere [ ] [ ] [ ] [ ] [ ] ), the french ministry of health organized the response to the pandemic according to the possible needs of seven regions, so-called 'defense areas', in order to regulate the supply of equipment ( figure ). the purpose of this plan was to distribute resources equitably across regions while avoiding any shortage in icu beds. extracorporal membrane oxygenation (ecmo) devices and icu ventilators were distributed in the reference centers of each defense area to cover the french territory. a % rate of icu bed occupancy by flu patients in a region was indicated as a critical threshold to consider cancellation of scheduled surgical activities. at the same time, we recorded data corresponding to the cohort of icu patients through a large research network on mechanical ventilation (reva-srlf registry) [ ] . in addition, we designed a dedicated website screening registry to prospectively assess the specific burden related to the a(h n ) pandemic in icus recruited on a voluntary basis. we proposed that a relatively simple screening registry would be able to give a much more exact picture of the respective burden on the different icus, geographical areas, and university versus non-university centers. here, we report the exact rate of icu bed occupancy by flu-infected patients (flu-or) during the pandemic in a representative subset of french icus. the french reva-srlf registry was a multi-center prospective observational survey based on a website registry, and several results of this registry have been published elsewhere [ ] [ ] [ ] . in brief, from november (week - ) through january (week - ), out of icus participating in the general registry (representing one fourth of all french icus) accepted an invitation to participate in a website screening registry to do a daily assessment of the rate of icu bed occupancy by influenza-infected and non-infected patients. sixty-nine icus belonging to either referral university hospitals ( icus) or general hospitals ( icus) eventually completed the daily screening for at least three consecutive weeks and admitted at least one a(h n )-infected patient and were kept for the present analysis. twenty icus that, for organization reasons or for lack of a(h n ) patients, did not complete three consecutive weeks were excluded from the analysis. recording of patients' data in the registry was approved by the national commission for protection of patients' rights and electronic data recording. the study was approved by the ethics committee of the french society of intensive care (srlf). informed consent was waived in agreement with the observational design of the study. suspected infection was proven by means of a polymerase chain reaction eventually completed by serologic analysis. when positive, the patient was considered a 'confirmed case'. a typical clinical flu presentation associated with a negative test was considered a 'suspected case' when no other etiology was found. suspected as well as confirmed cases were enrolled in the present study. admission data consisted of dates and times of admission to the hospital and icu; age; sex; pregnancy status; fatal underlying disease defined within the mccabe [ ] classification; the simplified acute physiology score iii (saps iii) [ ] , which is a severity score ranging from to ; immunosuppression and its cause; history of chronic respiratory disease, diabetes, or chronic heart failure; weight and height; and pregnancy. a follow-up during the icu hospitalization, including time and duration of ventilation, antiviral and corticosteroid use, use of rescue therapy including ecmo, and the cause of death, was also performed. a specific website registry (screening registry) was designed in order to do a daily assessment of the occupancy rate related to the management of a(h n ) nonventilated or ventilated patients. isn't 'in order to daily assess the occupancy rate...' better? baseline information on the number of available beds, ventilators, and staffing was collected. for each participating unit, a customized table representing the number of available beds on each day of the week was displayed on the website ( figure ). each available bed was characterized by using a specific code on a daily basis to identify whether it was occupied or used by a non-infected patient or a flu-infected patient; the ventilation status (mechanically ventilated or not) of each patient was also coded. the number of available beds could be modified each day in case of the closing or opening of additional beds. online completion of the registry required less than minutes per day for a -bed icu and usually was performed every morning after checking the patients' status during the first round. to facilitate postponed data recording, a table corresponding to the week in progress was available on the website for printing. the website was designed by a professional who paid great attention to the user-friendliness of the interface. each participating center received a weekly electronic update to provide information on the evolution of the pandemic and encourage completion of the registry. when needed, reminders were automatically displayed on the website. based on these data, the icu bed flu-or was computed as the number of bed-days per week occupied by flu patients divided by the total number of bed-days occupied per week and was expressed as a percentage. a weekly flu-or was calculated for each participating icu and for each defense area in the course of the pandemic, differentiating ventilated from non-ventilated patients. we also differentiated flu-or observed in university hospitals from that in non-university hospitals. data collected were directly downloaded as electronic .xls files from the reva web registry. the data management and the analysis were performed by cb-b, tp, and j-cmr. the database was completed when needed after direct contact with the icu physicians. duplicate notifications were systematically checked, and patients transferred from one participating icu to another were counted as a single admission. descriptive statistics included frequency analysis -percentages and corresponding % confidence intervals (cis) -for categorical variables and means and standard deviations or medians and interquartile ranges (iqrs) for continuous variables. differences in medical and demographic characteristics according to outcomes or in flu-or between types of hospitals were tested by using a chi-squared test for categorical variables and a student t test for continuous parametric variables. all statistical tests were two-sided, and p values of . or less denoted statistical significance. statistical analysis was performed with r software packages [ ] . three hundred ninety-one patients with a(h n ) were admitted from september to february in the icus participating in the screening registry and were included in this study. among them, ( %) had a confirmed influenza a infection. this subset of patients represents . % of the whole cohort of french influenza-infected adult icu patients [ ] ; they had the same overall characteristics, except for a higher rate of immunosuppression (table ) . tables and show the baseline characteristics and main risk factors for flu recorded in these patients according to survival or to the intensity of ventilatory support. mechanical ventilation was provided to ( %) patients, ( %) fulfilled criteria for acute respiratory distress syndrome, and ( %) required additional ecmo. the mortality rate of the whole cohort was %. figure shows the distribution of the icus participating in the screening registry across the seven defense areas as well as the distribution of icu beds belonging figure shows the weekly and maximal flu-or in the seven defense areas. the peak of the pandemics varied across the different geographical defense areas as illustrated by the profiles of the mean flu-or in each region ( figure ). the maximal flu-or observed in any icu in each region is also indicated. a flu-or of above % was recorded in individual icus, for a total of weeks out of the accumulated weeks of screening across the icus: . % of the screening weeks ( % ci of . % to . %). the percentage of screened weeks with flu-or of above % varied between defense areas from . % (east) to . % (north). the pooled flu-or calculated over the whole study period (including university and non-university hospital) for the entire country was . % and varied across the seven defense areas from . % (east) to . % (southeast). at each week, this rate was significantly higher in university hospitals than in non-university hospitals (figure ). during the pandemic period, none of the participating hospitals used the threshold level of % icu bed occupancy rate to modify hospital admission policy or bed availability. in this prospective observational study using a dedicated online screening registry designed to assess the daily burden of the a(h n ) influenza pandemic on french icus, we found important variations in the actual influenza burden between geographical areas, university and nonuniversity hospitals, and time. in several individual icus, our screening registry has permitted us to observe peak occupancy rates greatly exceeding those calculated by averaging data observed in the largest defense areas. our findings suggest that the organization of future pandemic response plans can greatly benefit from online data obtained in almost real time [ , ] . a dedicated online registry able to assess the week-by-week flu-or in each icu may help to better distribute resources according to the actual needs. even if icus were encouraged to do a daily assessment of the presence of patients with a (h n ), we chose to report the calculation per week first to be consistent with the french organization and the national institute for public health surveillance (niphs), which displayed the time course of the pandemic weekly, and also to simplify data notification for participating centers. in fact, in collaboration with the niphs, we developed a strong communication strategy via the reva website to simplify and therefore encourage rigorous notification. flu-ors calculated per week in the present study were comparable to and often higher than those observed in the southern hemisphere. over the -month pandemic period in australia and new zealand [ ] , the anzics (australian and new zealand intensive care society) investigators reported that an average of . % of available icu bed-days were occupied by patients with h n infection, whereas the peak percentage ranged from . % to % [ ] . in our study, . % of the beds of enrolled icus were occupied by influenza-infected patients during the whole study period, and a maximum flu-or recorded per week in individual icus reached %. inclusion of the icus that had not admitted any patients with a(h n ) would have lowered global flu-or but would not have changed the maximal flu-ors that we observed. the icu length of stay, however, may have impacted the flu-or since a large difference between the two reports was observed: the median durations of icu stay were . days (iqr of to ) in the anzics study and days (iqr of to ) in french icus. uneven time and regional distribution may also impact the flu-or calculations. in the anzics investigation, the number of days that icu beds were occupied by infected patients per region was calculated by multiplying the total number of patients by their length of stay. this approach allowed us to estimate a peak flu-or per region but not per individual icu. the results of our registry show that this can greatly underestimate true peak activities in some icus. this is of particular importance since h n burden changed rapidly over time and from one icu to the other. the web-based screening registry specifically developed for our study allowed a daily assessment of the icu occupancy rate in individual icus with an accuracy similar to that in larger regions. for example, observations reported from the paris area ( figure ) showed that the maximal flu-or significantly differed from the weekly flu-or calculated within all icus belonging to that region. overall, our observations suggest that an accurate estimation of the influenza burden on icus requires a daily and real-time flu-or assessment, which seems feasible in view of our findings. in anticipation of the flu surge, health authorities decided that, in order to alleviate the pressure on icu beds, planned surgery activity should be cancelled when flu-or exceeded %. we contacted each participating icu and confirmed that no canceling of scheduled surgery had been decided although flu-or exceeded % in many icus. such peak activities occurred for more than weeks among units. future analysis may help to refine this threshold and thus may have to take into account how long it is exceeded. the magnitude of a pandemic and its consequences on the organization of a health-care system depend on several parameters and are notoriously difficult to predict [ , ] . therefore, experiences reported during the first waves throughout the world were useful to better elaborate forecasts taking into account different attack rates and epidemic wave durations [ , ] . data gathered in canada during the first wave were applied to a variety of second-wave models to determine its impact on icu and ventilator demand [ , ] . an attack rate of greater than % can result in significant shortages in icu beds and ventilators [ ] . retrospective estimations showed that attack rates in europe [ ] , north america, and australia did not exceed % during each of the pandemic waves [ ] . the overall impact also greatly depends on the durations of mechanical ventilation and icu stay. high attack rate combined with a short epidemic duration and long expected duration of mechanical ventilation represents the worst scenario in terms of bed occupancy rate and thus the maximal burden. given a % attack rate with a similar clinical presentation, french icu resources in university hospitals would probably have been overwhelmed, according to our observations. a weakness of our study is that only a subset of french icus participated in the screening. our cohort represented % of the whole french cohort reported during the same period to the health ministry. the distribution of the subset of university and non-university hospitals participating in this study within the seven areas (except in the northern area) suggests that french icu health-care resources were reasonably well represented (figure ). this is supported by the comparability of baseline characteristics of patients within the present cohort to those of the entire french cohort (table ) [ ] . general inferences that can be made from this study are limited because of the difficulties in extrapolating from one health-care system to another. but regardless of the system, the primary goal here was to be able to assess, as closely to reality as possible, the related burden of an epidemic, and such an assessment was made possible by the specific screening registry. revisiting the pandemic plans in light of emergent findings is certainly a key issue to be able to cope with further pandemic waves. our observations suggest that the specific activity related to critically ill h n -infected ( ) ( ) ( ) ( ) ( ) saps iii, mean (sd) ( ) ( ) ( ) . ( ) . ( ) duration of ventilation in days, median (iqr) ( - ) ( - ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) length of stay in icu in days, median (iqr) ( - ) ( - ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) obesity, number ( patients varied widely according to time, regions, and individual icus as well as within larger areas. we report maximal icu flu-ors that significantly exceed the % predefined critical threshold. the website registry described here and tested during the first pandemic wave in france allowed a real-time awareness of bed utilization and capacity. • a simple online registry permits us to accurately describe specific h n icu burden in real time. • icu burden related to h n -infected patients varied widely according to time, regions, and individual icus. • in most icus, the maximal rate of bed occupancy by patients with flu exceeded the predefined % critical threshold. • online assessment of flu-or in the icu may help to better match resources and needs in case of new h n pandemics. chausseret; ch d'annonay: v. cadiergue; ch d'armantières: c. canevet mourvillier; gh diaconesse croix saint simon flu-or) in university and non-university hospitals after all seven 'defense areas' were pooled together. for each week of the pandemic (from week of to week of ), national flu-or of university intensive care units (icus) (blue columns) was higher than that of non-university icus (red columns). *p < . . richard et al sens: d. tonduangu; hopital de hautepierre f. blot; ch de versailles: m. henri-lagarrigue institute for biomedical research, boulevard gambetta, rouen, , france. department of intensive care bis rue la nouë bras de fer, nantes, france. service de réanimation médicale chemin des bourelly, marseille, , france. service de réanimation médicale early estimates of pandemic influenza a(h n ) virus activity in general practice in france: incidence of influenza-like illness and age distribution of reported cases real-time comparative monitoring of the a/h n pandemic in france adult intensive-care patients with pandemic influenza a(h n ) infection h n influenza in the united states epidemiology of pandemic influenza a(h n ) deaths in the united states europe's initial experience with pandemic (h n ) -mitigation and delaying policies and practices outbreak of swine-origin influenza a (h n ) virus infection -mexico update: novel influenza a (h n ) virus infection -mexico epidemiological and transmissibility analysis of influenza a(h n )v in a southern hemisphere setting: peru influenza a (h n )v in the southern hemisphere-lessons to learn for europe? h n influenza in australia and new zealand severe h n influenza infection in adults: the french experience. réanimation early corticosteroids in severe influenza a/h n pneumonia and acute respiratory distress syndrome can procalcitonin help identify associated bacterial infection in patients with severe influenza pneumonia? a multicentre study french experience of a/h n v influenza in pregnant women gram negative bacteremia: i. etiology and ecology saps -from evaluation of the patient to evaluation of the intensive care unit. part : objectives, methods and cohort description the r project for statistical computing real-time epidemic forecasting for pandemic influenza modelling the impact of an influenza a/h n pandemic on critical care demand from early pathogenicity data: the case for sentinel reporting potential intensive care unit ventilator demand/capacity mismatch due to novel swine-origin h n in canada mortality and morbidity burden associated with a/h n pdm influenza virus pandemic a(h n ) influenza: review of the southern hemisphere experience impact of pandemic (h n ) influenza on critical care capacity in victoria critically ill patients with influenza a(h n ) infection in canada triaging for adult critical care in the event of overwhelming need a lower than expected adult victorian community attack rate for pandemic (h n ) interest of a simple on-line screening registry for measuring icu burden related to an influenza pandemic the reva registry was funded in part by the french ministry of health, the inserm-institut des maladies infectieuses, and the srlf. these funding sources had no role in the collection, analysis, or interpretation of the data.the authors acknowledge the help of isabelle bonmarin and claire fuhrman (french niphs, st maurice, france) for cross-checking notification forms. we thank didier potelune and catherine giguet (one science corporation, paris, france) and adrien constan (reva) for their contributions to the website design. we are indebted to the staff of the icus for their active contributions to the study. reva correspondents for each participating center are listed in the list of contributors. we thank warren datziel for proofreading and english language editing. authors' contributions j-cmr helped to conceive of the study and participated in its design and coordination, helped to design the website registry and to coordinate data management, and participated in the editing of the manuscript. tp helped to conceive of the study and participated in its design and coordination, helped to coordinate data management, and participated in the editing of the manuscript. cb-b helped to conceive of the study and participated in its design and coordination and helped to design the website registry and to coordinate data management. am helped to conceive of the study and participated in its design and coordination and helped to design the website registry. lb helped to conceive of the study and participated in its design and coordination, helped to design the website registry, and participated in the editing of the manuscript. gb helped to design the website registry and actively participated in the study as a reva correspondent from the six most active centers. jr and br (president and member of the srlf, respectively) helped and encouraged participating centers to complete the screening registry. bm, cg, mc, ac, and ylt actively participated in the study as reva correspondents from the six most active centers. all authors read and approved the final manuscript. the authors declare that they have no competing interests. key: cord- -gsbbjb y authors: de jonghe, b.; cook, d.; sharshar, t.; lefaucheur, j.-p.; carlet, j.; outin, h. title: acquired neuromuscular disorders in critically ill patients: a systematic review date: journal: intensive care med doi: . /s sha: doc_id: cord_uid: gsbbjb y objective: to summarize the prospective clinical studies of neuromuscular abnormalities in intensive care unit (icu) patients. study identification and selection: studies were identified through medline, embase, references in primary and review articles, personal files, and contact with authors. through duplicate independent review, we selected prospective cohort studies evaluating icu-acquired neuromuscular disorders. data abstraction: in duplicate, independently, we abstracted key data regarding design features, the population, clinical and laboratory diagnostic tests, and clinical outcomes. results: we identified eight studies that enrolled patients. inception cohorts varied; some were mechanically ventilated patients for ≥ days, others were based on a diagnosis of sepsis, organ failure, or severe asthma while others were selected on the basis of exposure to muscle relaxants, or because of participation in muscle biochemistry studies. weakness was systematically assessed in two of the eight studies, concerning patients with severe asthma, with a reported frequency of and %, respectively. electrophysiologic and histologic abnormalities consisted of both peripheral nerve and muscle involvement and were frequently reported, even in non-selected icu patients. in a population of patients mechanically ventilated for more than days, electrophysiologic abnormalities were reported in % of cases. two studies showed a clinically important increase ( and days, respectively) in duration of mechanical ventilation and a mortality twice as high in patients with critical illness neuromuscular abnormalities, compared to those without. conclusions: prospective studies of icu-acquired neuromuscular abnormalities include a small number of patients with various electrophysiologic findings but insufficiently reported clinical correlations. evaluation of risk factors for these disorders and studies examining their contribution to weaning difficulties and long-term disability are needed. abstract objective: to summarize the prospective clinical studies of neuromuscular abnormalities in intensive care unit (icu) patients. study identification and selection: studies were identified through medline, embase, references in primary and review articles, personal files, and contact with authors. through duplicate independent review, we selected prospective cohort studies evaluating icu-acquired neuromuscular disorders. data abstraction: in duplicate, independently, we abstracted key data regarding design features, the population, clinical and laboratory diagnostic tests, and clinical outcomes. results: we identified eight studies that enrolled patients. inception cohorts varied; some were mechanically ventilated patients for ³ days, others were based on a diagnosis of sepsis, organ failure, or severe asthma while others were selected on the basis of exposure to muscle relaxants, or because of participation in muscle biochemistry studies. weakness was systematically assessed in two of the eight studies, concerning patients with severe asthma, with a reported frequency of and %, respectively. electrophysiologic and histologic abnormalities consisted of both peripheral nerve and muscle involvement and were frequently reported, even in non-selected icu patients. in a population of patients mechanically ventilated for more than days, electrophysiologic abnormalities were reported in % of cases. two studies showed a clinically important increase ( and days, respectively) in duration of mechanical ventilation and a mortality twice as high in patients with critical illness neuromuscular abnormalities, compared to those without. conclusions: prospective studies of icu-acquired neuromuscular abnormalities include a small number of patients with various electrophysiologic findings but insufficiently reported clinical correlations. evaluation of risk factors for these disorders and studies examining their contribution to weaning difficulties and long-term disability are needed. bolton and colleagues [ ] . since then the number of retrospective studies [ ± ] , and editorials [ ± ] on this phenomenon have increased considerably. many narrative reviews [ ± ] have also been published, mostly focusing on historical features, specific populations, and/or pathophysiological mechanisms. clinicians have suspected that weakness and a variable constellation of physical signs, such as sensory abnormalities and/or decreased deep tendon reflexes may be explained on the basis of neuromuscular disease acquired in the intensive care unit (icu). electrophysiologic and histologic examinations have revealed abnormalities involving sensory and/or motor peripheral nerves, the neuromuscular junction, and muscle fibers. a landmark review article published recently [ ] outlined the major conditions of critical illness neuromuscular abnormalities (cinma) ( table ) . critical illness polyneuropathy characterized by primary axonal degeneration of motor and sensory fibers is the most common manifestation of cinma [ ] . the weakness tends to occur following prolonged treatment of sepsis and may represent the neural manifestation of multiple organ failure (mof). the second most fully described syndromes are purely motor deficits comprising muscle atrophy restricted to type ii fibers [ , ] , muscle fiber necrosis [ ] , and even motor axonopathy [ ] . these motor syndromes are observed in patients recovering from respiratory failure such as in acute asthma or the acute respiratory distress syndrome (ards). high and prolonged doses of corticosteroids and/or non-depolarizing neuromuscular blockers are thought to be strongly associated with these neuromuscular abnormalities, although pathophysiologic mechanisms remain to be established. the remaining condi-tions are less well described. necrotizing myopathy associated with rhabdomyolysis revealed by high creatine phosophokinase plasma levels has been described in patients with multiple injuries and severe sepsis [ ] . severe muscle proteolysis has been observed after prolonged immobilization, regardless of the cause of immobilization, and is often worsened by malnutrition [ ] . in addition, prolonged neuromuscular blockade [ ] or metabolic disturbances such as hypophosphatemia, hypomagnesemia, hypermagnesemia, hypokalemia, and hypocalcemia [ , ] can precipitate or aggravate weakness. cinma appears to be a syndrome related to various conditions, rather than a specific disease related to a specific condition. in whichever context it occurs, cinma may be responsible for prolonged mechanical ventilation and increased length of icu stay. although a search for definitive risk factors, pathophysiologic mechanisms, and preventive interventions will be important in directing future research, determining the clinical spectrum of the disease is the first step in such a research program. the goal of this systematic review was to appraise critically and summarize the prospective clinical studies of icu-acquired neuromuscular disorders, describing the frequency, clinical features, and outcomes related to critical illness and neuromuscular abnormalities. to identify prospective studies, we searched two computerized databases from january to september . for medline and embase, we used the following text words and key words: critical care, intensive care, critical illness, neuropathy, polyneuropathy, myopathy, neuromyopathy, neuromuscular, muscular, prospective studies. we had no language restrictions. the titles (and the abstracts, when available) in the medline and embase printouts and the reference lists of all primary articles and review articles were reviewed independently in duplicate. any additional relevant articles were identified and retrieved. the following selection criteria were applied to the full manuscripts by two of the authors (b. d. j. and d. c.) independently: studies had to enroll critically ill adult patients presenting acquired peripheral nervous system and/or muscular and/or neuromuscular transmission abnormalities, described clinically and/or electrphysiologically and/or histologically, involving limbs and/or respiratory muscle, in prospective cohort studies. a priori, we excluded retrospective studies, case series, and studies concerning central nervous system (cns) abnormalities. in duplicate, data were abstracted concerning the population, findings on clinical examination, the results of neuromuscular tests, and clinical outcome. potential confounding pharmacotherapy which could affect the frequency of cinma was also extracted: corticosteroids, neuromuscular blockers, aminoglycosides, and metronidazole. the first two types of drugs have been been frequently associated with the occurrence of cinma in icu patients with acute asthma or ards. the last two are commonly used antibiotics, which are known to worsen neuromuscular transmission in patients with myasthenia gravis (aminoglycosides) or to induce polyneuropathy after prolonged administration (metronidazole). for each study, in- formation reflecting the validity of the study was also extracted. this included: ( ) description of the cohort; ( ) time of inclusion of patients in the study; ( ) duration of follow-up; ( ) whether any clinical or electrophysiologic or histologic examination was initially planned, percentage of patients in whom this examination was performed; ( ) comprehensive description of the clinical examination, if any; ( ) description of the electrophysiologic examination if any. these criteria are presented for each study in tables and . because very sparse data concerning risk factors were available in these studies, risk factor could not be comprehensively summarized in this review. disagreements between reviewers concerning design characteristics and raw data abstraction were resolved by discussion and consensus. the database search yielded seven potentially relevant studies, and reference review yielded an additional two. one study enrolling patients both retrospectively and prospectively, in which it was not possible to distinguish between the two types of patient selection, was excluded [ ] . two case series were also excluded [ , ] , and also one prospective study enrolling exclusively patients with cns disease [ ] . total agreement was reached regarding study selection. the characteristics of the eight studies included are reported in table [ ± ]. the sample size of these investigations ranged from to . although some of the same patients were probably reported in different articles [ , ] , the total number of patients reported in these studies was , of whom had cinma (or were suspected of having cinma) and of whom were controls. inclusion criteria for patients were mechanical ventilation for > days in three studies [ ± ], diagnosis of sepsis or organ failure in two [ , ] , diagnosis of severe asthma [ ] , exposure to vecuronium [ ] , or participation in muscle biochemistry studies [ ] . two investigators specified that patients were enrolled in a consecutive manner [ , ] . most excluded patients with previous neuromuscular disease [ ± , ± ], previous central neurologic disease [ ± ] , or potential risk factors for neuromuscular disease such as diabetes, alcoholism, human immunodeficiency virus, malignancy, and renal failure [ , , ] . some studies also described the use of pharmacotherapy suspected of impairing neuromuscular function, including neuromuscular blockers, corticosteroids, aminoglycosides, and metronidazole [ , ± , ] . only three of the eight studies included a formal clinical evaluation of cinma focused on the physical examination in a percentage of patients specified by the investigator (table ) . all had an initial clinical assessment. two had unscheduled [ , ] and one regularly scheduled [ ] further evaluations. electrophysiologic examination was performed systematically in five studies [ , , ± ] , and in a subset of patients in two others [ , ] . electrophysiologic evaluation generally included sensory and motor nerve conduction studies and needle electromyography (emg). however, evaluation of neuromuscular transmission was available in only one study [ ] . diaphragmatic emg was conducted in one study which included phrenic nerve stimulation [ ] . two investigations reported muscle biopsies in all patients [ , ] , but in one other this was only performed in selected patients, mostly because of lack of consent from patients or relatives [ ] . the frequency of weakness in the three cohort studies which specified how many patients were assessed for clinical neurologic function [ , , ] is reported in table . in the two that enrolled patients with asthma and/ or who had received vecuronium, the frequency was and %, respectively [ , ] . in the study that enrolled mechanically ventilated patients with mof it was % [ ] , although only % were clinically evaluated. among the three cohort studies enrolling non-selected icu patients, none described the frequency of weakness or other clinical parameters, probably because of impaired consciousness in most of the patients. muscle atrophy was reported in / patients in whom polyneuropathy was subsequently diagnosed on emg [ ] and in / in another study [ ] . deep tendon reflexes were reported as decreased or absent in all patients with polyneuropathy in one study [ ] and in / in a second [ ] . electrophysiologic and histologic abnormalities were variable across studies but were generally detectable in the majority of patients (table ). in none of the four cohort studies of patients with organ failure were both emg and muscle biopsy systematically performed. in two studies in which emg was systematically performed [ , ] , abnormalities were found in and % of patients, respectively. the most frequent finding was axonal neuropathy (ªcritical illness polyneuropathyº). in the two other studies, where muscle biopsy was performed [ , ] , primary muscle disease (atrophy not related to denervation and/or muscle necrosis) was found in % of patients and was frequently associated with signs of denervation due to axonopathy [ ] . in the two kupfer [ ] douglass [ ] coakley [ ] leijten et al. [ ] leijten et al. [ ] berek et al. [ ] time of initial assessment after icu admission (days) [ , ] , the emg, although not systematically performed, showed only a myopathic pattern in one study [ ] and signs of muscle denervation in % of patients in the other [ ] . in this last study, prolonged neuromuscular blockade probably accounted for the clinical weakness in % of the patients. in one large cohort study of non-selected icu patients, in which electrophysiologic examination was systematically performed, % had electrophysiologic abnormalities [ ] . summarizing the clinical outcomes in these studies is difficult because the duration and completeness of follow-up was variable and not reported in detail. duration of paralysis was reported in two studies [ , ] . in one enrolling patients with acute asthma [ ] , the duration of paralysis ranged between days and months, except for two patients with prolonged neuromuscular blockade in whom weakness resolved within h. in the second, performed in an unselected icu population [ ] , the duration of weakness ranged from weeks to year. duration of mechanical ventilation in cinma patients was available in three studies [ , , ] (mean duration, respectively, , , and days) with extremes ranging from week to more than days. the duration of mechanical ventilation was significantly longer than in non-cinma patients in two of those investigations [ , ] . length of icu stay was not reported in any study. two compared mortality between cin-ma and non-cinma patients ( vs % [ ] and vs % [ ] ), suggesting that detection of emg abnormalities could have prognostic value in patients ventilated for more than days. in the eight studies included in this systematic review, diverse patient populations were enrolled. six studies described patients with sepsis and/or mof [ , , , ] and patients who had previously received neuromuscular blockers and/or corticosteroids [ , ] . as so many different circumstances can lead to cinma, more information about frequency of cinma in nonselected icu patients would be of interest. however, only two cohort studies [ , ] were conducted in a non-selected population. the main clinical feature of cinma is weakness. only two cohort studies, enrolling a total of patients and including asthmatic patients who had received corticosteroids and/or neuromuscular blockers, systematically evaluated weakness [ , ] . drawing strong conclusions about the frequency of this clinical sign of weakness is thus difficult. the frequency of cinma in a general icu population still remains unclear. large cohort studies are needed to address this issue. severity of weakness was described in only one investigation [ ] , using the categories mild, moderate, or severe. by contrast, electrophysiologic and/or histologic assessments were performed in all but one study [ ] . these studies confirm the high frequency of electrophysiologic abnormalities in selected populations (mof or asthma), as in non-selected patients. in leijten et al.'s investigation [ ] , % of patients mechanically ventilated for more than days had electrophysiologic abnormalities. correlations with clinical findings were not specified. although emg and muscle biopsies were never performed systematically in the same study, unsuspected primary muscle involvement was found in patients with weakness associated with multiple organ dysfunction or sepsis, in which peripheral nerve abnormalities are usually described. this could reflect a direct effect of sepsis on muscle fiber, or of concurrent pathologies such as disuse proteolysis and malnutrition. conversely, axonal abnormalities may be encountered in patients treated with corticosteroids and neuromuscular blockers in whom primary muscle abnormalities are expected. thus, no specific electrophysiologic or histologic pattern corresponding to a specific condition was reported. icu-acquired axonopathy, although possibly influenced by pre-icu diseases, can be confidently detected on electrophysiologic examination. this test may be a useful for the diagnosis and could help further epidemiologic studies. however, the importance of peripheral neurologic abnormalities detected when patients are still in a coma, as was frequently the case in these studies, is unclear. early systematic detection of electrophysiologic abnormalities in icu patients might have prognostic value, since these abnormalities are associated with a high mortality [ , ] . however, the difficulty of obtaining electrophysiologic evaluation in icu patients may preclude this systematic approach in daily practice. the importance of the histologic examination in assessing weakness in the icu setting also needs to be better understood. primary muscle involvement is unlikely to be definitively determined without muscle biopsy, but this may be refused because the test is invasive and has no proven therapeutic implications at present. two studies comprehensively reported the comparative duration of mechanical ventilation between cin-ma and non-cinma patients [ , ] , showing prolonged mechanical ventilation in cinma patients, the difference reaching statistical significance in one investigation [ ] . however, establishing the potential contribution of cinma to weaning difficulty is challenging. only one study cited here described a correlation between limb and respiratory muscle weakness [ ] . superficial diaphragmatic emg is unreliable [ ] , needle diaphragmatic emg is risky in ventilated patients [ ] , and phrenic nerve stimulation is difficult to perform in many icus. these problems may account for the dearth of information concerning the attribution of cinma to diaphragmatic weakness and delayed liberation from mechanical ventilation. two cohort studies enrolling patients with mof reported a comparative mortality between cinma patients diagnosed on electrophysiologic examination and non-cinma patients, both of them showing a higher mortality in cinma patients [ , ] . although none of these differences were significant, possibly due to sample sizes that were too small, electrophysiologic diagnosis of cinma could thus be a risk factor for mortality in icu patients with mof. it is not clear whether this finding reflects a higher initial severity of illness in cinma patients or a specific contribution to mortality. further large, matched case-control studies could help to address this point. the optimal type of investigation required to evaluate the natural history of a disease and its impact on patients in the short and long term is a prognosis study. such studies describe inception cohorts at a similar point in time and follow them prospectively to provide clinical outcome data using specific criteria systematically applied to all patients [ ] . among the prognosis studies cited in this review, the inception cohorts were well described, but the patients were identified at different points in the history of their illnesses. many were evaluated while comatose, precluding careful evaluation of weakness. the duration of clinical follow-up, when mentionned, was variable but tended to be short, precluding long term assessment of function and survival. finally, the sample sizes in these studies were small, making confidence intervals around these estimates highly variable. however, individually and in aggregate, these studies have helped to describe the problem of cinma and have provided useful information for intensivists. risk factors for cinma were not summarized in this review for many reasons. although six of the studies reported risk factor analysis [ ± , , ] , these were mainly performed to explain electrophysiologic or histologic results, but not to predict which factors were associated clinical abnormalities such as weakness or paralysis. moreover, many studies excluded patients with potential risk factors such as diabetes mellitus, alcohol abuse, or renal failure, possibly leading to a selection bias for risk factor analysis. future studies should focus on clinically important problems such as failure to wean from mechanical ventilation and length of icu stay in the short term, and post-icu and posthospital disability in the long term. ideally, reproducible measurements using bedside tests and objective scales should be incorporated at regular intervals. potential risk factors for weakness should be carefully documented, including dosing of drugs that may exacerbate or cause weakness. electrophysiologic tests should incorporate studies of neuromuscular transmission to diagnose conditions exacerbated by non-de-polarizing neuromuscular blockers and aminoglycosides. in patients agreeing to muscle biopsy, histologic examination may be the only way to evaluate accurately muscle involvement, which may be underappreciated by physical or emg examination. a consensus conference may be useful in which multidisciplinary experts could explore whether endorsement of a specific classification system would allow readers to make comparisons across studies and facilitate communication among clinicians and scientists. a common set of definitions may also promote multicenter studies, thereby creating a database of sufficient size to generate stable incidence estimates, to identify accurately risk factors, and to determine clinical and economic sequelae. better understanding of the mechanisms and predictors of cinma might help to target preventive therapy (e. g., minimizing exposure to paralytic agents) and encourage rigorous evaluation of potential therapeutic interventions (e. g., intensive physiotherapy, including nerve and/or muscle electrostimulation, intravenous immunotherapy [ ] , and other innovative approaches). severe myopathy after status asthmaticus polyneuropathy in critically ill patients critical illness polyneuromyopathy after artificial respiration prolonged paralysis after treatment with neuromuscular junction blocking agents acute myopathy of intensive care: clinical, electromyographic and pathological aspects persistent paralysis in critically ill patients after long-term administration of vecuronium neuromuscular conditions in the intensive care units the expanding spectrum of critical illness polyneuropathy neuromuscular blockade in the intensive care unit: more than we bargained for critical illness polyneuropathy. a review of the literature, definition and pathophysiology sepsis and the systemic inflammatory response syndrome: neuromuscular manifestations acute myopathy associated with combined use of corticosteroids and neuromuscular blocking agents neuromyopathies secondaires en rØanimation acute quadriplegic myopathy: a complication of treatment with steroids, nondepolarizing blocking agents, or both acute myopathy during treatment of status asthmaticus with corticosteroids and steroidal muscle relaxants neuromuscular disorders in intensive care unit patients treated with pancuronium bromide. occurrence in a cluster group of seven patients and two sporadic cases, with electrophysiologic and histologic examination a syndrome of acute severe muscle necrosis in intensive care unit patients muscle proteolysis induced by a circulating peptide in patients with sepsis or trauma hypophosphatemia-associated respiratory muscle weakness in a general inpatient population neurologic manifestations of fluid and electrolyte disturbances acute respiratory failure neuropathy: a variant of critical illness polyneuropathy neuromuscular causes of prolonged ventilator dependency critical illness polyneuropathy: clinical findings and outcomes of a frequent cause of neuromuscular weaning failure critical illness myopathy and neuropathy peripheral nerve function in sepsis and multiple organ failure necrotizing myopathy in critically-ill patients prolonged weakness after long-term infusion of vecuronium bromide myopathy in severe asthma preliminary observations on the neuromuscular abnormalities in patients with organ failure and sepsis the role of polyneuropathy in motor convalescence after prolonged mechanical ventilation critical illness polyneuropathy in multiple organ dysfunction syndrome and weaning from the ventilator polyneuropathies in critically ill patients: a prospective evaluation comparison of diaphragmatic emg centroid frequencies: esophageal versus chest surface leads pneumothorax. complication of needle emg of thoracic wall users' guides to the medical literature. v. how to use an article about prognosis. evidence-based medicine working group effects of early treatment with immunoglobulin on critical illness polyneuropathy following multiple organ failure and gram-negative sepsis key: cord- -x q f authors: pottecher, julien; noll, eric; borel, marie; audibert, gérard; gette, sébastien; meyer, christian; gaertner, elisabeth; legros, vincent; carapito, raphaël; uring-lambert, béatrice; sauleau, erik; land, walter g.; bahram, seiamak; meyer, alain; geny, bernard; diemunsch, pierre title: protocol for traumadornase: a prospective, randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patients date: - - journal: trials doi: . /s - - - sha: doc_id: cord_uid: x q f background: acute respiratory distress syndrome continues to drive significant morbidity and mortality after severe trauma. the incidence of trauma-induced, moderate-to-severe hypoxaemia, according to the berlin definition, could be as high as %. its pathophysiology includes the release of damage-associated molecular patterns (damps), which propagate tissue injuries by triggering neutrophil extracellular traps (nets). nets include a dna backbone coated with cytoplasmic proteins, which drive pulmonary cytotoxic effects. the structure of nets and many damps includes double-stranded dna, which prevents their neutralization by plasma. dornase alfa is a us food and drug administration-approved recombinant dnase, which cleaves extracellular dna and may therefore break up the backbone of nets and damps. aerosolized dornase alfa was shown to reduce trauma-induced lung injury in experimental models and to improve arterial oxygenation in ventilated patients. methods: traumadornase will be an institution-led, multicentre, double-blinded, placebo-controlled randomized trial in ventilated trauma patients. the primary trial objective is to demonstrate a reduction in the incidence of moderate-to-severe hypoxaemia in severe trauma patients during the first days from % to % by providing aerosolized dornase alfa as compared to placebo. the secondary objectives are to demonstrate an improvement in lung function and a reduction in morbidity and mortality. randomization of patients per treatment arm will be carried out through a secure, web-based system. statistical analyses will include a descriptive step and an inferential step using fully bayesian techniques. the study was approved by both the agence nationale de la sécurité du médicament et des produits de santé (ansm, on october ) and a national institutional review board (cpp, on november ). participant recruitment began in march . results will be published in international peer-reviewed medical journals. discussion: if early administration of inhaled dornase alfa actually reduces the incidence of moderate-to-severe hypoxaemia in patients with severe trauma, this new therapeutic strategy may be easily implemented in many clinical trauma care settings. this treatment may facilitate ventilator weaning, reduce the burden of trauma-induced lung inflammation and facilitate recovery and rehabilitation in severe trauma patients. trial registration: clinicaltrials.gov, nct . registered on december . aerogen (ireland) will provide nebulizers to study centres at an estimated value of k€. after validation from its scientific committee, the traumadornase study is supported by a k€ grant from the french ministry of health (phrci- -s ). severe trauma remains a major socio-economic burden worldwide [ , ] . indeed, it is the third cause of fatality overall, the first cause of fatality and invalidity in the - age group and the first cause of disabilityadjusted life years (dalys). aside from civilian and military trauma cases, terrorist attacks have added new threats [ ] . while the first peak of trauma-associated mortality happens within the very first hours from exsanguination and severe central nervous system injuries, secondary deaths are triggered by multi-organ failure (mof) and acute respiratory distress syndrome (ards) in the intensive care unit (icu) [ ] . the taxonomy of ards was recently refined by the last berlin definition [ ] , which also distinguished three levels of increasing hypoxaemia severity (mild/moderate/ severe) based on the ratio of partial arterial oxygen tension (pao ) over inspired oxygen fraction (fio ). patients who develop moderate-to-severe ards in the icu have a worse prognosis compared to mild ards patients, including increased mortality rates ( % vs. %), impaired functional recovery, compromised quality of life and cognitive dysfunction [ ] . severe trauma definitely remains a significant risk factor for hypoxaemia, implicating both direct and indirect lung injuries [ ] . notwithstanding improvements in prehospital care, resuscitation and mechanical ventilation, the incidence of hypoxaemia in trauma patients has remained consistently high during the last years [ ] [ ] [ ] [ ] . in the most severely injured trauma patients (injury severity score (iss) [ ] above ) requiring blood transfusion, the incidence of hypoxaemia may exceed %. indeed, a recent analysis of the prommtt registry underlines that the incidence of moderate-to-severe hypoxaemia could be as high as % [ ] . in trauma patients, ards increases the duration of mechanical ventilation, icu and hospital lengths of stay, incidence of ventilation-acquired pneumonias, healthcare-associated costs and mortality [ ] . pathophysiology of trauma-associated hypoxaemia and acute respiratory distress syndrome as previously stated [ ] , severe trauma may contribute to hypoxaemia by both direct injuries (lung contusion, aspiration) and indirect injuries (non-thoracic trauma, musculoskeletal injuries, haemorrhagic shock, transfusionassociated acute lung injury [ , ] ). whatever the mechanism implicated, inflammation is a key player [ ] [ ] [ ] . indeed, tissue injury triggers a massive and short-lived release of damage-associated molecular patterns (damps) [ ] , which bind both toll-like receptors (tlrs) [ ] and receptors for advanced glycation end products (rage) [ , ] , which recruit and activate neutrophils, resulting in a widespread systemic inflammatory response [ ] . the molecular structure of damps is diverse but the most potent are made of double-stranded dna [ ] , either fully (e.g. mitochondrial dna [ ] [ ] [ ] ) or partly (e.g. nucleosomes [ ] , high mobility group box- (hmgb ), heat shock proteins (hsp)). once bound to neutrophils, damps induce profound conformational changes in these cells (netosis), which trigger both non-self pathogen killing [ ] and self tissue injury [ , ] . indeed, netosis refers to the release of neutrophil extracellular traps (nets), composed of a backbone (decondensed chromatin fibres) coated with antimicrobial granular and cytoplasmic proteins, such as myeloperoxidase, neutrophil elastase (ne) and αdefensins [ , ] . the detrimental effects of excessive net release are particularly important to ards, because nets can expand more easily in the pulmonary alveoli, causing extensive lung injury [ ] and hypoxaemia. moreover, while unbound ne is usually rapidly inactivated when released into plasma, dna-bound ne is protected from neutralization by plasma [ ] . double-stranded dna thus constitutes the backbone of both damps and nets, and prevents nets from plasma neutralization. extracellular dna is physiologically broken up by endogenous deoxyribonucleases (dnases [ , ] ), which may become overwhelmed by a massive influx of both damps and nets. this is exacerbated as the activity of endogenous dnases is reduced in severe trauma patients ( . ± . u/ml) compared to healthy controls ( . ± . u/ml; p < . [ ] ). however, an fda-approved recombinant dnase has been commercially available since (dornase alfa, pulmozyme; roche, basel, switzerland and genentech, san francisco, ca, usa) and prescribed for the treatment of pulmonary exacerbations in cystic fibrosis patients. as dornase alfa is usually administered via the intratracheal route (aerosols), its biological actions and pharmacokinetic properties could be an excellent prerequisite for a clinical breakthrough in trauma-induced hypoxaemia. indeed, dornase alfa was shown to reduce trauma-induced lung injury in mice [ ] , to fight against sepsis-induced ards [ , ] and to reduce mechanical ventilation-induced lung injury [ ] , which are traditional "second hits" for lung damage in ventilated trauma patients. in a small, randomized clinical trial, aerosolized dornase alfa was also shown to improve oxygenation in mechanically ventilated icu patients with lobar atelectasis [ ] . the primary objective of the traumadornase study is to demonstrate a reduction in the incidence of moderateto-severe hypoxaemia from % to % in severe trauma patients during the first icu days by providing aerosolized dornase alfa once during the first icu days as compared to equivalent provision of placebo (nacl . %). the secondary objectives are to demonstrate, using aerosolized dornase alfa as compared to placebo, an improvement in static lung compliance, a reduction in mechanical ventilation duration or an increase in ventilation-free icu days, a reduction in the length of icu stay, a reduction in the hospital length of stay, a reduction in the incidence of multi-organ failure, a reduction in the incidence of ventilator-associated pneumonia (vap) and a reduction in mortality at day . this will be an investigator-initiated, institution-led, multicentre, double-blinded, placebo-controlled, parallel-group, superiority, randomized trial in ventilated, trauma icu patients. randomization will be carried out through a secure web-based randomization system, stratified by the centre and the presence of severe traumatic brain injury (glasgow coma score < on scene). the study will be conducted in seven french participating hospitals, both university-affiliated and non-universityaffiliated. inclusion criteria will be checked before inclusion in the study. the inclusion criteria are as follows: the exclusion criteria are as follows: pregnancy or breast-feeding opposition from the patient or his/her relatives protected major (guardianship) contraindication to the use of dornase alfa known intolerance to dornase alfa patient whose life expectancy is less than h, according to the treating physician "do not resuscitate" order who will take informed consent? { a} inclusion will be feasible after patient approval, relative approval or emergency consent procedure (according to french law [ ] ). subsequent confirmation of consent will be obtained from the relatives and from the patient as soon as possible. the consent forms are available from the corresponding author on request. after primary haemostasis and emergent surgical interventions, patients will be randomized in the icu within h. in the case of emergent surgical intervention before icu admission, a maximum delay of h will be tolerated from hospital admission (trauma bay) to study drug administration. day will be considered the day of icu admission. additional consent will be required for the collection of biological specimens in ancillary studies, which will be stored for a maximum duration of years. the comparator will be normal saline (nacl . %, . ml, administered through the aerogen solo device). nacl is neutral regarding damps, nets and occurrence of either hypoxaemia or ards, and therefore is considered a placebo. treatment with either dornase alfa or placebo will be administered using aerosol (aerogen solo) in the ventilation circuit once per day (average treatment length: min) for the first days. the aerogen device was shown to optimize dornase alfa deposition in the distal lung airways [ , ] . dornase alfa has an excellent safety profile and aerosolized nacl . % has a neutral effect on lung physiology. the variables under study will be gathered every day and recorded on the electronic clinical research form (cleanweb; telemedicine technologies s.a.s., boulogne billancourt, france). for safety purposes, patient variables will be closely monitored before, during and within the first postadministration hour: lowest spo , maximal value and maximal increase in peak inspiratory airway pressure, maximal value and maximal increase in plateau airway pressure, extreme values of heart rate and mean arterial pressure, skin erythema, urticaria and variations in central temperature exceeding °c. during the first days, at least one blood gas analysis and chest x-ray will be performed every day at : a.m. to compute the primary endpoint: presence or absence of ards and severity of hypoxaemia according to the berlin definition. additional blood gas analysis will be allowed and the worst daily pao /fio ratio will be considered. on days , and , additional blood samples ( ml on each day) will be drawn into edta tubes, centrifuged and stored (− °c) for subsequent analysis of damps (mitochondrial dna by qpcr; hmgb , hsp and srage by elisa) at the end of enrolment. whole blood samples will be drawn (days , and ) for extemporaneous quantification of nets on fresh blood using a flow cytometric assay [ ] in patients at the strasbourg centre. in the case of an adverse event following treatment administration (desaturation, bronchospasm, anaphylactic reaction), treatment will be immediately discontinued and the second treatment dose will not be given on day . in each centre, boxes containing both full and empty treatment vials will be returned to the pharmacy responsible for clinical studies. for every included patient, a sheet will be completed (date, hour, nurse in charge) and signed for every study treatment preparation, administration and clinical surveillance. for safety purposes, patient variables will be closely monitored before, during and within the first postadministration hour: lowest spo , maximal value and maximal increase in peak inspiratory airway pressure, maximal value and maximal increase in plateau airway pressure, extreme values of heart rate and mean arterial pressure, skin erythema, urticaria and variations in central temperature exceeding °c. at least one blood gas analysis and chest x-ray will be performed every day at : a.m. to compute the primary endpoint: presence or absence of ards and severity of hypoxaemia according to the berlin definition. additional blood gas analysis will be allowed and the worst daily pao /fio ratio will be taken into account. daily care for the included patients will be protocolized according to good clinical practices, especially concerning respiratory care (semi-recumbent position, protective mechanical ventilation ( - ml/kg predicted body weight), peep > cmh o, plateau pressure < cmh o, close tracheal cuff pressure monitoring, early enteral feeding ( ml on day ), glucose control and protocolized sedation based on both cpot and rass scores [ ] ). adherence to guidelines will be checked in every centre for every patient. patients will be followed until day for the record of study outcomes. every concomitant care will be allowed except aerosols during study drug administration. post-trial care is not planned. patients who suffer harm from trial participation will be cared for in the intensive care unit. should prejudice linked to study participation occur, financial compensation will be provided by the insurance (société hospitalière d'assurances mutuelles-sham, rue edouard rochet, , lyon cedex , france; contract number: . ) contracted by the promotor (hôpitaux universitaires de strasbourg). at months, the respiratory status will be assessed using the modified mrc dyspnoea questionnaire [ , ] and a chest x-ray. the primary endpoint will be the incidence of moderate-to-severe hypoxaemia (pao /fio < , according to the berlin definition [ ] ) in severe trauma patients (iss > ) during the first icu days. the pao /fio ratio will be computed at least once daily ( : a.m.) together with the supine chest x-ray and the worst daily pao /fio value will be taken into account to define hypoxaemia severity. in ards patients, the severity of hypoxaemia allows for its classification according to the berlin definition and is strongly associated with mortality, length of recovery and quality of life [ , ] . the following secondary endpoints will be recorded: static lung compliance (ml/cmh o) (measured at least once daily at : a.m. during the first days) duration of mechanical ventilation (h) from icu admission to first extubation success (> h without reintubation) length of icu stay (h) length of stay in the hospital (days) incidence of multi-organ failure (a sofa score of or more in at least two organ systems [ ] ), assessed daily during the first days incidence of vap according to both the american thoracic society (ats) [ ] and the center for disease control and prevention (cdc) [ ] definitions, assessed daily during the first days the effects of dornase alfa and normal saline will be assessed according to the plasma concentrations of damps (mitochondrial dna, hmgb- , hsp , srage) and nets (strasbourg centre only) divided into quartiles at day , day and day . it is anticipated that trauma patients with the highest blood concentrations of either damps or nets will develop the most severe complications (including hypoxaemia and ards). the time course of damp and net blood concentrations will also be analysed according to treatment group to unveil a potential quicker decrease in patients randomized in the dornase alfa group. the total duration of participation in the study will be days. the forecast study duration is months from first to last patient recruitment (table ) . the sample size was determined to be subjects per arm (i.e. subjects in total). dornase alfa is expected to reduce the incidence of moderate-to-severe hypoxaemia from . to . . considering a reasonable standard deviation of . , and using bayesian techniques [ ] , subjects per arm were estimated to show a difference of more than . (instead of the expected . ). clinical examination includes physical examination (auscultation of the chest, central body temperature, positive end-expiratory pressure and inspired oxygen fraction levels) and recording of utstein criteria [ ] b diagnostic tests include arterial blood gases, chest x-ray, leukocyte and platelet counts, creatinine, blood urea nitrogen, bilirubin and quantitative lung bacteriologic samplings (bronchoalveolar lavage fluid or protected specimen brush) in the case of suspected lung infection c blood withdrawal: ml of blood on day , day and day d study treatment will be given on day and day assuming % loss to follow-up, this number was increased to subjects per arm, although these subjects will not be replaced. patients will be recruited in seven french participating hospitals, both university-affiliated and non-universityaffiliated and admitting severe trauma patients: taken as a whole, more than patients per year fulfil the inclusion criteria, allowing for an inclusion ratio of one patient included out of seven patients admitted to one of the participating centres. randomization will be conducted over a dedicated, password-protected, ssl-encrypted website (cleanweb; telemedicine technologies s.a.s.) to allow immediate and concealed allocation. allocation will also be stratified by centre and the presence of severe traumatic brain injury (glasgow coma score < on scene). the experimental study drug and placebo will be provided in identical boxes, allowing double-blind administration. the logistics of the trial fluid distribution to each of the seven participating centres that are anticipated to be recruiting will be coordinated by the pharmacy of the coordinating centre (hôpitaux universitaires de strasbourg). the allocation sequence will be computer-generated (cleanweb; telemedicine technologies s.a.s.). patients will be enrolled by registered investigators, who will also assign patients to a treatment consisting of either dornase alfa or placebo. trial participants, care providers, outcome assessors and data analysts will remain blinded after assignment to interventions, until the final analysis. unblinding is permissible whenever an adverse event occurs, via immediate request to the poison centre of the study coordinator hospital (hôpitaux universitaires de strasbourg) h per day and days per year. the procedure for revealing a participant's allocated intervention during the trial includes an explicit mention in the patient record. clinical research associates will ensure that patient inclusion, data collection, registry and rapport are in line with the protocol, and that the study is conducted in accordance with the good clinical practice guidelines. furthermore, clinical research associates will check the following variables: patient initials, date of birth, sex, signed consent form, eligibility criteria, date of randomization, treatment assignment, adverse events and study endpoints. the data monitoring committee is institution-based and independent from potential industrial sponsors. a dedicated card will be given to any included patient and participation in the traumadornase trial will be explicitly mentioned during transfer to another ward or hospital during handovers. data will be collected in each centre by clinical data technicians on an electronic case report form (cleanweb; telemedicine technologies s.a.s.) using double password-protected computers. pre-specified lists, range of values and drop-down menus in the electronic case report form will facilitate data entry and prevent writing errors. study documents will be deidentified, stored in each recruitment centre and kept for at least years in a locked, secure office, according to french law. all personnel involved in data analysis will be masked. only the principal investigators and the statisticians will have access to the final data set. people with direct access to the data will take all necessary precautions to maintain confidentiality. all data collected during the study will be rendered anonymous. only initials and inclusion number will be registered. plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use { } on days , and , additional blood samples ( ml on each day) will be drawn into edta tubes, centrifuged and stored (− °c) for subsequent analysis of damps (mitochondrial dna by qpcr; hmgb , hsp and srage by elisa) at the end of enrolment. in patients included in the strasbourg centre, whole blood samples will be drawn (days , and ) for extemporaneous quantification of nets on fresh blood using a flow cytometric assay [ ] . the remaining biological specimens will be stored in . -ml aliquots at "biomax" biobank, statistical analyses will include a descriptive step and an inferential step using fully bayesian techniques. the estimates will use markov chains to monte carlo integrations (mcmc), choosing prior distributions to be nearly conjugated situations. unless the diagnoses for convergence give clues to the contrary, we will use three markov chains with separated starting points, a burn-in of , for each chain and , more iterations with a thinning of for building a total sample of , iterations on which the monte carlo integrations are used to retrieve characteristics of posterior distributions. the analyses will be carried out using r software (with ad hoc packages) and openbugs. sensitivity analyses will be systematically conducted, considering three scenarios with different priors: a default non-informative prior (e.g. jeffreys prior), then an optimist prior and, finally, a pessimist prior. in the descriptive step, all of the variables collected will be summarized: number and frequency for qualitative variables (ordinal and categorical) and minimum, quantiles ( . , , , and . ), maximum, mean and standard deviation for quantitative variables (discrete and continuous). for variables gathered over time, these descriptions will be provided globally and at each time. this description will be enriched by inference to extrapolate the observed quantities on the sample. for quantitative variables, we will assume a normal likelihood combined with a normal prior on the mean (mean and variance ) and γ on the precision (inverse of variance) with parameters . and . , and therefore mean . and variance . for binary variables (for which one proportion needs to be estimated), we will assume a binomial likelihood and a β prior on the proportion (jeffreys prior with parameters . and . , and thus mean . and variance . ). for categorical variables with more than two categories, we will assume a categorical likelihood together with a dirichlet prior (jeffreys prior with all parameters at . ). the aim of this study is to show that the frequency of moderate-to-severe hypoxaemia is lower in the dornase alpha group than in the placebo group. the main variable is then dichotomous "moderate-to-severe hypoxaemia yes/no", modelled in a logistic mixed regression. we will assume that this variable is bernoulli distributed with parameter π. the logit of this parameter (linear predictor) is additively written as: where: α is a grand mean, with mean normal prior (the variance in this normal is , corresponding to a low informative prior) i(g i = ) is a dummy covariate coded for the group of subject i ( for the dornase alpha group and for the placebo group)the prior on the parameter of this covariate is the same normal as that for the grand mean β i is a (random) subject effect, on which is assumed a normal prior with mean and low variance (e.g. ) because the linear predictor is on the logit scale, the probability for moderate-to-severe hypoxaemia will be obtained by monitoring the back-transformation of the logit. this regression model without covariates except group will be completed for taking into account potential confounding variables. in the model, the entire set of these variables will be added and, secondly, selected using stochastic search variable selection (ssvs) [ ] . in such a model, the prior distribution on each parameter is a mixture of two mean normal distributions, one with low variance and the other with high variance: if the posterior weight on this second normal is strongly around , then the prior on the parameter is essentially driven by a normal distribution whose mean is centred on ; this is the clue for a "non-significant" parameter. the secondary analyses will be conducted as the main analysis with a regressive model, testing the difference of a parameter between the two groups. only the likelihood model will be changed to take into account the type of variable studied: γ distribution for continuous variables such as length of stay and duration of ventilation. dichotomous variables such as -day mortality will be studied with logistic regression. no statistical procedure for replacing missing values will be used. all variables and subjects will be considered in the descriptive analyses, but, for inference, % missing data or more will result in rejection of the variable or individual. an interim analysis will be performed after inclusion of the first patients. these preliminary data will be available to the data safety and monitoring board (see later for details), which will have the ability to stop the trial for either futility or harm. analyses will be performed in intention to treat. to verify the impact of possible deviations from the protocol, these analyses will be supplemented by an analysis per protocol. subgroup analyses will be conducted according to the glasgow coma scale on site (score either ≤ or > ). methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data { c} no statistical procedure for replacing missing values will be used. all variables and subjects will be considered in the descriptive analyses, but, for inference, % missing data or more will result in rejection of the variable or individual. plans to give access to the full protocol, participant-level data and statistical code { c} the protocol is available on the clinicaltrials.gov website (https://clinicaltrials.gov/ct /show/nct ?term= traumadornase&draw= &rank= ). study documents will be de-identified, stored in each recruitment centre and kept for at least years in a locked, secure office, according to french law. all personnel involved in data analysis will be masked. only the principal investigators and the statisticians will have access to the final data set. composition of the data monitoring committee, its role and reporting structure { a} the data safety and monitoring board (dsmb) will include dr laure peyro-saint paul (drug monitoring specialist), prof. bernard asselain (methodologist and biostatistician), prof. catherine paugam-burtz (anaesthesiologist and intensive care physician), prof. samir jaber (anaesthesiologist and intensive care physician) and prof. boris jung (intensive care physician). the dsmb, independent from the study sponsor and principal investigator, including three intensive care physicians, one methodologist and one drug safety specialist, will meet after inclusion of the first patients to assess the safety of dornase alfa administration in ventilated trauma patients. the safety variables under study are detailed in the "interventions" section. the dsmb will meet subsequently after further incremental inclusions of patients. the dsmb charter was signed by all of its members. adverse events and unintended effects of the trial intervention or trial conduct will be declared to the promotor within h of occurrence. moreover, the dsmb will meet after inclusion of the first patients to assess the safety of dornase alfa administration in ventilated trauma patients. the safety variables under study are detailed in the following. for safety purposes, patient variables will be closely monitored before, during and within the first post-administration hour: lowest spo , maximal value and maximal increase in peak inspiratory airway pressure, maximal value and maximal increase in plateau airway pressure, extreme values of heart rate and mean arterial pressure, skin erythema, urticaria and variations in central temperature exceeding °c. the dsmb will meet subsequently after further incremental inclusions of patients. in every centre, an audit will be performed by the direction de la recherche clinique des hôpitaux universitaires de strasbourg after inclusion of the first patient, then yearly and after enrolment of the last patient. plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) { } important protocol modifications will be communicated to investigators, irb and trial registries via e-mail. every protocol amendment will be first submitted to the irb and, after validation, transmitted to investigating centres, which will acknowledge receipt. the results of the study will be released to the participating physicians, referring physicians and medical community no later than year after the completion of the trial, through presentation at scientific conferences and publication in peer-reviewed journals. eligible authors will meet all four requirements of the icmje guidelines: substantial contributions to the conception or design of the work; or the acquisition, analysis or interpretation of data for the work drafting the work or revising it critically for important intellectual content final approval of the version to be published agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved to the best of our knowledge, traumadornase is the first large-scale study to evaluate the usefulness of inhaled dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in a population of severe trauma patients, who will also benefit from other lung-protective measures. the benefits are expected to include a reduction in both duration of mechanical ventilation and stay in the icu, lower costs of hospital stay, fewer days on mechanical ventilation and a reduction in the selective pressure on multidrug-resistant bacteria. in order to keep management practices as standardized as possible, we decided to limit the number of investigating centres to seven university-affiliated and non university-affiliated hospitals, all of which are recognized in the field of trauma care and treat more than severe trauma patients per year. these centres belong to the traumabase network (www.traumabase.eu), which promotes multicentre clinical research on trauma and ensures consistent recording of clinical data according to the traumabase registry guidelines. these seven centres also share the same standards of care and, except for pitié-salpêtrière centre, belong to the same region of france (grand est). from a translational point of view, the study will challenge the hypothesis that breaking up the doublestranded dna backbone of both damps and nets with dornase alfa may reduce inflammation and netinduced epithelial and endothelial cell injuries in the lungs of trauma patients. dornase alfa is a long-standingfda-approved mucolytic agent used in cystic fibrosis patients. its safety profile and limited side effects make it an appropriate candidate to curb damp-induced, net-mediated inflammation. as we will use high-end vibrating mesh nebulizers, which provide excellent lung deposition and drug bioavailability, we expect that dornase alfa will be deposited within the depth of the lung parenchyma, where it may be the most useful. the incidence of moderate-to-severe hypoxaemia is the primary study endpoint. a % basal incidence of moderate-to-severe hypoxaemia may appear overstated to some experts, but it must be underlined that only severe trauma patients will be included and that a % incidence was reported in the last randomized promtt trial [ ] , in the era of damage-control resuscitation [ ] . a % absolute reduction seems ambitious for a single intervention. however, previous studies using dornase alfa in animal lung injury models and in ventilated patients suffering atelectasis demonstrated striking results [ , [ ] [ ] [ ] [ ] ] . because fluid loading regimens and transfusion strategies are based on local written protocols, they may act as potential confounding variables. however, this will be controlled by the stratification of the randomization at the centre level and adjustment of statistical analyses in cases of differences between groups. in conclusion, this trial is the first multicentre, randomized controlled, double-blinded study adequately powered to test the hypothesis that aerosolized dornase alfa reduces the incidence of moderate-to-severe hypoxaemia in mechanically ventilated severe trauma patients. protocol version . was approved by the national institutional review board on november . the study started on march and is expected to last until september ( -month inclusion period plus month participation period). after validation from its scientific committee, the traumadornase study was funded by the french ministry of health. fédération hospitalo-universitaire omicare, centre de recherche d inserm umr_s neurophysiologie respiratoire expérimentale et clinique, ap-hp, groupe hospitalier pitié-salpêtrière charles foix, département d'anesthésie réanimation réanimation chirurgicale et traumatologique, samu , rue cognacq-jay, reims, france. hôpitaux universitaires de strasbourg, nouvel hôpital civil, laboratoire central d'immunologie, place de l'hôpital, strasbourg cedex service de physiologie et d'explorations fonctionnelles disability-adjusted life years (dalys) for diseases and injuries in regions, - : a systematic analysis for the global burden of disease study the toll of death and disability from traumatic injury in the united states-the "neglected disease" of modern society, still neglected after years icu specialists facing terrorist attack: the nice experience distribution of the probability of survival is a strategic issue for randomized trials in critically ill patients acute respiratory distress syndrome: the berlin definition functional disability years after acute respiratory distress syndrome acute respiratory distress syndrome incidence of adult respiratory distress syndrome in trauma patients: a systematic review and meta-analysis over a period of three decades clinical predictors of early acute respiratory distress syndrome in trauma patients the acute respiratory distress syndrome following isolated severe traumatic brain injury heterogeneous phenotypes of acute respiratory distress syndrome after major trauma the injury severity score revisited application of the berlin definition in prommtt patients: the impact of resuscitation on the incidence of hypoxemia acute lung injury and the acute respiratory distress syndrome in the injured patient potential contribution of mitochondrial (mt) dna damage associated molecular patterns (damps) in transfusion products to the development of acute respiratory distress syndrome (ards) after multiple transfusions transfusion-related acute lung injury: the work of damps a genomic storm in critically injured humans sterile inflammation: sensing and reacting to damage microbial recognition and danger signals in sepsis and trauma plasma levels of danger-associated molecular patterns are associated with immune suppression in trauma patients toll-like receptors in the vascular system: sensing the dangers within the hmgb /rage axis triggers neutrophil-mediated injury amplification following necrosis the hmgb -rage inflammatory pathway: implications for brain injury-induced pulmonary dysfunction trauma surgery . advances and future directions for management of trauma patients with musculoskeletal injuries circulating mitochondrial damps cause inflammatory responses to injury clinical immunology: culprits with evolutionary ties elevated levels of plasma mitochondrial dna damps are linked to clinical outcome in severely injured human subjects plasma mitochondrial dna levels in patients with trauma and severe sepsis: time course and the association with clinical status circulating histones are mediators of trauma-associated lung injury neutrophil recruitment and function in health and inflammation neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones role of neutrophil extracellular traps following injury neutrophil extracellular traps in pulmonary diseases: too much of a good thing molecular mechanisms of net formation and degradation revealed by intravital imaging in the liver vasculature dnasei protects against paraquat-induced acute lung injury and pulmonary fibrosis mediated by mitochondrial dna reduced deoxyribonuclease enzyme activity in response to high postinjury mitochondrial dna concentration provides a therapeutic target for systemic inflammatory response syndrome targeting neutrophils to prevent malaria-associated acute lung injury/acute respiratory distress syndrome in mice mitochondrial dna damage associated molecular patterns in ventilatorassociated pneumonia: prevention and reversal by intratracheal dnase i mitochondrial dna damage-associated molecular patterns mediate a feedforward cycle of bacteria-induced vascular injury in perfused rat lungs mechanical ventilation induces neutrophil extracellular trap formation inhaled dornase alfa (pulmozyme) as a noninvasive treatment of atelectasis in mechanically ventilated patients french legal approach to clinical research aerosol delivery of recombinant human dnase i: in vitro comparison of a vibrating-mesh nebulizer with a jet nebulizer a technical feasibility study of dornase alfa delivery with eflow flow cytometric assay for direct quantification of neutrophil extracellular traps in blood samples hospital-acquired pneumonia in icu evaluation of clinical methods for rating dyspnea the body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease reversal of trauma-induced coagulopathy using first-line coagulation factor concentrates or fresh frozen plasma (retic): a single-centre, parallelgroup, open-label, randomised trial infectious diseases society of america. guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia complications of mechanical ventilation-the cdc's new surveillance paradigm bayesian and mixed bayesian/likelihood criteria for sample size determination variable selection via gibbs sampling the prospective, observational, multicenter, major trauma transfusion (prommtt) study: comparative effectiveness of a time-varying treatment with competing risks local dornase alfa treatment reduces nets-induced airway obstruction during severe rsv infection publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors are greatly indebted to barbara jung and mathias candusso, clinical research associates, for writing the study draft. the authors thank jo-ann elicia west, msc, an independent consultant in cartigny l'epinay, france, for providing editorial support, which was funded by hôpitaux universitaires strasbourg, direction de la recherche clinique et des innovations, strasbourg, france in accordance with good publication practice (gpp ) guidelines (http://www.ismpp.org/gpp ). jp conceived the study, coordinated its design, drafted and wrote the manuscript. jp, en, mb, ga, sg, cm, eg, vl, rc, bu-l, es, wgl, sb, am, bg and pd read and were involved in critical appraisal and revision of the manuscript. es provided statistical expertise. all authors approved the final manuscript prior to submission. aerogen (ireland) will provide nebulizers to the study centres (estimated value: € , ). after validation from its scientific committee, the traumadornase study is supported by a € , grant from the french ministry of health (phrci- -s ). funders will have no role in the study's design, collection, management, analysis and interpretation of data, writing of the report and the decision to submit the report for publication conception or in the data analysis. name and contact information for the trial sponsor: ms nathalie portier, french ministry of health, girci est, chu de dijon, , rue paul gaffarel, bp , dijon cedex, france. only the principal investigators, the dsmb and the statisticians will have access to the final data set. the data sets used and analysed during the current study will be available from the corresponding author on reasonable request, after publication of the main core article. the clinical trial will adhere to the principles of the declaration of helsinki and to the clinical trials directive / /ec of the european parliament on the approximation of the laws, regulations and administrative provisions of the member states relating to the implementation of good clinical practices in the conduct of clinical trials on medicinal products for human use. ethical aspects of this research project have been approved by the french agence nationale de la sécurité du médicament et des produits de santé (ansm, on october ) and a national institutional review board (cpp, on november ), which covers all participant sites. the trial will be monitored by the research monitoring officers of strasbourg university hospital. significant changes to the protocol will be submitted for approbation by the national institutional review board. prior consent of the subject will not be possible in most cases due to traumatic brain injury, haemorrhagic shock or prehospital sedation requirements. therefore, consent of the subject's legally acceptable representative will be requested. a consent form specifically designed for the subject's legally acceptable representative will be provided with documented approval or favourable opinion of the institutional review board in order to protect the rights, safety and well-being of the subject and to ensure compliance with any applicable regulatory requirements. consent to participation in the study by the patient's relatives will be solicited, according to the requirements of the ethics committee. in cases where neither patient consent nor relative's consent is available within the -h inclusion timeline, the subject will be included following the emergency consent procedure (according to french law [ ] , code de la santé publique, article l - ). subsequent confirmation of consent will be obtained from the relatives and the patient as soon as possible. although it is not anticipated, owing to the trial design, publication of any personal information about a patient will require her/his consent. the authors declare that they have no competing interests. key: cord- -d qj b authors: vincent, jean-louis; abraham, edward; annane, djillali; bernard, gordon; rivers, emanuel; van den berghe, greet title: reducing mortality in sepsis: new directions date: - - journal: crit care doi: . /cc sha: doc_id: cord_uid: d qj b considerable progress has been made in the past few years in the development of therapeutic interventions that can reduce mortality in sepsis. however, encouraging physicians to put the results of new studies into practice is not always simple. a roundtable was thus convened to provide guidance for clinicians on the integration and implementation of new interventions into the intensive care unit (icu). five topics were selected that have been shown in randomized, controlled trials to reduce mortality: limiting the tidal volume in acute lung injury or acute respiratory distress syndrome, early goal-directed therapy, use of drotrecogin alfa (activated), use of moderate doses of steroids, and tight control of blood sugar. one of the principal investigators for each study was invited to participate in the roundtable. the discussions and questions that followed the presentation of data by each panel member enabled a consensus recommendation to be derived regarding when each intervention should be used. each new intervention has a place in the management of patients with sepsis. furthermore, and importantly, the therapies are not mutually exclusive; many patients will need a combination of several approaches – an 'icu package'. the present article provides guidelines from experts in the field on optimal patient selection and timing for each intervention, and provides advice on how to integrate new therapies into icu practice, including protocol development, so that mortality rates from this disease process can be reduced. sepsis is the tenth most common cause of death in the us [ ] . a recent us study reported that severe sepsis accounts for in excess of , deaths annually from a total population of approximately , patients-a mortality rate of approximately % (with published studies quoting a range of - %) [ ] . this persistent, high mortality rate is clearly unacceptable, given that it ranks sepsis above some of the higher profile causes of in-hospital death, including stroke ( - % risk of death in the first days) and acute myocardial infarction (ami) ( % risk of death in the first days) [ ] . moreover, the actual number of deaths associated with the condition may be even higher than current estimates suggest. many sepsis patients have at least one comorbidity and deaths are often attributed to these conditions rather than to sepsis [ ] [ ] [ ] . unfamiliarity with the signs and symptoms of sepsis may further hinder accurate diagnosis. there are many possible reasons for this high mortality. sepsis is certainly a complex disease state; the pathophysiology is only now beginning to be unraveled, and it is complicated by heterogeneous presentation (possible signs of sepsis are presented in table ). while none of these signs alone is specific for sepsis, the otherwise unexplained presence of these signs should signal the possibility of a septic response. many cases of sepsis are recognized late, and patients are often inappropriately treated before entering the intensive care unit (icu) by physicians unfamiliar with the signs and symptoms of the condition. furthermore, treatment may be initiated by any of a number of physicians (anesthetists, hematologists, intensivists, infectious disease specialists, pulmonologists, and emergency physicians). there are presently various defined supportive strategies for treating patients with sepsis, but improvements are needed to reduce the unacceptably high mortality rate. moreover, as with other areas of medicine, the application and integration of new but proven strategies for reducing morbidity and mortality into clinical practice has been slow. encouraging new data have recently been presented on new approaches to the management of patients with sepsis. many of these approaches attempt to modulate or interrupt the sepsis cascade and to address the cause of multiorgan dysfunction. although many of these approaches are in early phases of development (e.g. antibodies to tumor necrosis factor [tnf] alpha, bactericidal permeability increasing protein, high-flow hemofiltration to remove circulating inflam-matory mediators, platelet-activating factor acetyl hydrolase, and antielastases), other approaches are more advanced and are already beginning to impact on outcomes in the icu. at a roundtable discussion in london in june , professor jean-louis vincent brought together five experts to discuss more effective implementation of five exciting new interventions in the icu setting to decrease the unacceptable burden of mortality in patients with severe sepsis. each of the roundtable panelists is a highly respected physician in the world of sepsis and critical care medicine. the interventions discussed encompassed low tidal volume in patients with acute lung injury (ali)/acute respiratory distress syndrome (ards) (edward abraham), early goal-directed therapy (egdt) (emanuel rivers), drotrecogin alfa (activated) (gordon bernard), moderate-dose corticosteroids (djillali annane), and tight control of blood sugar (greet van den berghe). the purpose of the roundtable discussion was to provide guidance for clinicians on the integration of new interventions into the icu to reduce the mortality in sepsis, on appropriate patient selection for these interventions, and on appropriate timing of these interventions. the present review reports the discussions and recommendations of the panel. the overall -day mortality in the icu is typically ~ % [ ] . the -day mortality in the population with severe sepsis, defined as sepsis with organ dysfunction, is - %. it is clear from this figure that severe sepsis contributes disproportionately to the overall -day mortality in the icu and compares unfavorably with some of the higher profile acute killers in hospital (e.g. stroke and ami) [ ] . despite the general improvements in medicine overall, this mortality rate has remained essentially unchanged for the past years. this has contributed to a feeling of pessimism among table possible signs of sepsis (adapted from [ intensivists and other medical professionals regarding treatment prospects for severe sepsis, and a reluctance to rapidly incorporate new interventions into clinical practice [ ] . although the sepsis mortality rates are unacceptable, they camouflage some significant developments that are and have been occurring for hospital patients, for the general icu population and, particularly, for those with severe sepsis. direct comparison of mortality rates among patients with identical acute pysiology and chronic health evaluation (apache) scores in the placebo arm of anti-tnf or anti-endotoxin studies published - years ago [ ] [ ] [ ] with more recent studies [ , ] , demonstrates that the mortality rate is much lower in more recent studies. interestingly, this decrease was apparent even before the five interventions discussed in the present article were published, reflecting improvements in the general supportive care of sepsis patients. indeed, the panel contends that mortality from septic shock has already been reduced. some patients who in the recent past would have died from severe sepsis or septic shock do not reach the icu now because they are well managed on the wards, in the emergency department, and even during preoperative and postoperative care. for example, those sepsis patients that receive prompt antibiotic therapy have a - % lower mortality rate than those who receive antibiotic therapy later in their care [ ] . progress is also being made in diagnosing sepsis: more patients are being tested to identify the source of infection and the pathogens involved, supportive care measures have been improved (e.g. hemodynamic support), and other measures have been put in place to reduce the incidence of nosocomial infections (e.g. reducing the need for pulmonary artery catheters by using echo techniques to assess cardiac function). there has also been a realization of the importance of specially trained intensive care physicians in the icu. it has been internationally recognized that changing the icu from an 'open format', whereby patients are cared for by their admitting physician, to a 'closed format', whereby patients are managed by appointed intensivists, reduces mortality rates [ ] . although the mortality rate is beginning to decline, it still remains unacceptably high. furthermore, the number of patients with severe sepsis and septic shock is increasing; people are living longer, and there has been a rise in the number of immunocompromised patients due to aggressive cancer therapy and the increased prevalence of hiv. in-hospital ami-associated mortality rates averaged approximately - % in the s [ ] . this clearly unacceptable mortality rate was addressed by the development of a number of new pharmacological and mechanical interventions together with improvements in supportive care. in the landmark second international study of infarct survival trial, published in , , suspected ami patients were treated with either streptokinase or aspirin, with both drugs, or with neither. the mortality rate in the combination group of this trial was %, compared with . % in those patients given neither streptokinase nor aspirin [ ] . cardiologists have effectively implemented multiple pharmacologic and supportive care interventions to reduce mortality in ami from - % to % and lower. not satisfied with this already remarkable figure, they are trying to reduce it further. physicians treating patients with sepsis are clearly faced with a very different situation to those treating patients with ami, and so direct comparisons are not possible. however, several factors have contributed to the success of ami therapy and possibly to the lack of such success in sepsis (table ) . sepsis is undoubtedly complicated. however, many of the lessons that have been learned through effective application of therapies in other disease states can be applied to severe sepsis. furthermore, the encouraging data that are beginning to appear in the literature indicate that sepsis may not be as intractable to treat as once thought. the following sections provide salient information on five interventions that have shown a significant positive impact on mortality rates in sepsis, severe sepsis, septic shock, or sepsis-related diseases in recent clinical trials. the interventions were presented at the roundtable by one of the principal investigators of the key trial of the intervention. each section concludes with recommendations for the integration of the particular intervention into clinical practice. the traditional approach in patients with ali/ards is to ventilate using tidal volumes between and ml/kg body weight, almost twice the average tidal volume at rest ( - ml/kg body weight), and to maintain a low positive endexpiratory pressure (peep). the purpose of this approach is to achieve normal values for the ph and partial pressure of arterial carbon dioxide. however, this method leads to high inspiratory airway pressures and to excessive stretch of the aerated lung. in , tremblay et al. examined the effect of ventilation strategy on lung inflammatory mediators in the presence and absence of a pre-existing inflammatory stimulus in sprague-dawley rats [ ] . in both stimulated and nonstimulated groups, the presence of inflammatory mediators (tnf-α, il- β, il- , il- , macrophage inflammatory protein , and ifn-γ) was highest in those rats ventilated with a large tidal volume and zero peep. furthermore, in a study by ranieri et al. in [ ] , the concentration of inflammatory mediators hours after randomization of the groups was significantly lower in the lung-protective strategy group (tidal volume, . ± . ml/kg) than in the control group (tidal volume, . ± . ml/kg) (p < . ). following on from the positive results in the tremblay et al. trial [ ] , a small study ( patients) was carried out by amato et al. in brazil [ ] . the mortality rate was % in patients given 'protective' ventilation (peep above the lower inflection point on the static pressure-volume curve, tidal volume < ml/kg ideal body weight, driving pressures < cmh o above the peep value, permissive hypercapnia, and preferential use of pressurelimited ventilatory modes) compared with % in patients on conventional ventilation (p < . ). this impressive reduction in mortality was tempered by the higher than normal mortality level in the control group, prompting the national institutes of health-funded acute respiratory distress syndrome network to set up a similar, larger ( patients), prospective, multicenter, randomized trial in the us [ ] . for a summary of the protocol used in this study, see appendix . the trial was stopped after the fourth interim analysis because the use of lower tidal volumes was found to be associated with a significantly reduced mortality (p = . for the difference in mortality between groups). the primary endpoints were mortality prior to hospital discharge with unassisted breathing and ventilator-free days (days alive, off mechanical ventilation, between enrollment and day ). both of these endpoints were achieved (figs - ). in addition, patients receiving a tidal volume of ml/kg ideal body weight had increased organ failure free days and lower il- levels. ali is seen in - % of patients with sepsis [ ] . although the approach has only been tested in patients with ali/ards, a tidal volume of ml/kg ideal body weight is at the lower end of the range of physiologic ventilation. hence, this approach should be suitable for most patients in the icu setting. furthermore, as many patients with severe sepsis or septic shock progress to frank ali/ards, the panel believes that low tidal volume therapy is a valid option in these patients, and an option that may indeed prevent the development of ali/ards. although patient selection in the clinical trial specified both blood gas and lung infiltrate criteria, at least % of patients in the general icu setting meet the criteria for blood gas but table a comparison of acute myocardial infarction (ami) and sepsis market issues significant publicity surrounding and general awareness lack of understanding among physicians and the of the condition; large trials general public diagnosis a relatively straightforward and relatively common complicated by a long list of signs and symptoms diagnosis (electrocardiogram, enzymes, troponin), and and few objective tools for validation one that can be made by generalists, not just cardiology specialists generally single organ disease (notable exception when often chronic or acute comorbidities complicated by cardiogenic shock) generalists have been taught to recognize the signs sepsis patients often come 'second hand' from a and symptoms of ami; initial treatment is usually specialist who may not be appropriately trained to provided by emergency physicians, who are trained diagnose, manage, and refer patients with sepsis to treat these patients mortality prior to hospital discharge in patients receiving a tidal volume of and ml/kg ideal body weight. acidosis is more likely to develop in patients with severe lung problems rather than in those exhibiting milder disease when tidal volumes are kept low. however, acidosis is seldom a clinical problem and rarely requires administration of bicarbonates. one of the issues with low tidal volume therapy is that the patients are often more uncomfortable, at least initially, when they are being ventilated with a tidal volume of ml/kg ideal body weight. the patients tend to exhibit tachypnea and may become more agitated. sedation is generally required, but the ventilator setting can be maintained. of more concern is that icu staff may consider a respiration rate of /min to be a sign of something more serious and may attempt to terminate the intervention. education of staff is clearly essential. the strategy assessed in this trial not only includes ventilation with a low tidal volume, but also the provision of extrinsic peep. there may be some concern that an increased respiratory rate may result in intrinsic peep and hemodynamic problems (e.g. decreased cardiac filling, decreased cardiac output, and diminished blood pressure). the panel believes that auto peep was not an issue in the acute respiratory distress syndrome network study. in addition, in the groups with low tidal volume, at least % more oxygen was required to maintain the fraction of inspired oxygen (fio ), suggesting that there was very little auto peep occurring. when mechanical ventilation is indicated for treatment of patients with ali/ards, the tidal volume should be limited tõ ml/kg ideal body weight. goal-directed therapy represents an attempt to adjust the cardiac preload, afterload, and contractility to balance systemic oxygen delivery with oxygen demand. in patients with severe sepsis and septic shock, such an approach would seem eminently reasonable as part of general supportive measures to restore and maintain adequate cellular perfusion and to prevent organ dysfunction. in the setting of the icu, however, supranormal and normal approaches have met with little or no success [ , ] . it is possible that, by the time these therapies are applied in the icu, any such intervention may have been too late. hence, the focus has shifted towards hemodynamic optimization in the early presentation of disease, such as in the emergency department. a prospective, randomized, predominantly blinded study was initiated by the early goal-directed therapy collaborative group to examine the results of hemodynamic interventions in the emergency department [ ] . in this study, patients were randomly assigned to either hours of egdt or to standard therapy prior to admission to the icu. baseline characteristics (including the adequacy and duration of antibiotic therapy) in the egdt and standard therapy groups were not significantly different. the vital signs, resuscitation endpoints, organ dysfunction scores, and coagulation-related variables were similar in these groups at baseline [ ] . however, there were some important differences between the treatment groups (see table ). available online http://ccforum.com/content/ /s /s proportion of patients alive and off the ventilator having been ventilated with a tidal volume of and ml/kg ideal body weight. median number of ventilator-free days in patients receiving a tidal volume of and ml/kg ideal body weight. patients randomized to egdt received the same therapy but, in addition, were monitored for the endpoint of central venous oxygen saturation (scvo ) > %. egdt patients were given more intravenous fluids (including blood transfusions) and more inotropic support (mostly dobutamine). for more information on the protocol used in this study, see appendix . key data are presented in table . the in-hospital mortality was . % in the group assigned to egdt and was . % in the group assigned to standard therapy (p = . ), indicating that egdt provides significant benefits in improving outcomes in patients with severe sepsis and septic shock. during the interval from to hours, patients assigned to egdt exhibited a more significant improvement in mean scvo ( . ± . % versus . ± . %), in lactate concentration ( . ± . mmol/l versus . ± . mmol/), in base deficit ( . ± . mmol/l versus . ± . mmol/l), and in ph ( . ± . versus . ± . ) than patients assigned to standard therapy (p ≤ . for all comparisons). during the same period, the mean apache ii scores were significantly lower, indicating less severe organ dysfunction, in the patients assigned to egdt than in those patients assigned to standard therapy ( . ± . versus . ± . , p < . ). the protocol was based predominantly on guidelines published in by the society of critical care medicine [ ] . however, these guidelines have not been universally followed in clinical practice since their publication. an increasing number of critically ill patients are presenting to, and being treated in, emergency departments [ , ] . this is present-ing significant resource challenges in the emergency department environment. the inability to institute egdt may thus not be a conscious decision by the clinician not to follow the society of critical care medicine guidelines. emergency medicine in general may have to develop and formulate the cost-benefit analysis to support or implement such care in this environment in order to improve outcomes. there are sufficient evidence-based data to recommend that all patients with severe sepsis or septic shock should receive early and aggressive resuscitation based on this egdt protocol (see appendix ) . it is important that the interventions are individualized to each patient. a negative or positive value indicates how the control group therapy compares with the treatment group. a p < . , b p = . , c p = . , d p = . , e p = . . egdt, early goal-directed therapy. it is possible to identify patients with profound global myocardial dysfunction who are hence at risk of impaired perfusion. these patients, almost % of those in the egdt group, received dobutamine during the first hours because myocardial suppression was diagnosed. once myocardial dysfunction is corrected (and compliance improved), these patients become more suitable for volume loading, so this group received almost . liters more fluids in the first hours than the control patients. therefore, although vasopressor use was similar in the first hours, patients in the egdt group were more aggressively weaned off these agents during this period, resulting in fewer patients in this group entering the icu on vasopressors than in the control group. the lack of aggressive volume loading in the control group led to greater use of vasopressors in patients over the subsequent hours. in spite of more volume loading, the egdt group received less mechanical ventilation over the subsequent hours than in the standard treatment group. why was cardiovascular collapse a significant cause of death in the control group? cryptic shock (shock with normal vital signs) is a frequent occurrence in early severe sepsis and septic shock. despite resuscitation to the goals for mean arterial blood pressure and cvp, almost % of control patients continued to exhibit global tissue hypoxia (decreased scvo and increased lactate levels); in these patients, there was a twofold increase in hemodynamic deterioration, requiring more mechanical ventilation, pulmonary artery catheterization, and vasopressor use in the subsequent hours. how do severe sepsis and septic shock differ hemodynamically in the early stages compared with that classically described in the icu? patients presenting with early sepsis and septic shock are characterized by hypovolemia (low cvp), normal to increased blood pressures, and decreased cardiac output (decreased central venous oxygen saturation and low cardiac index). this is in contrast to icu patients who are euvolemic, have high scvo , and have elevated cardiac indices [ ] . what are the most important ways in which egdt can improve outcomes? the key factors are early detection of high-risk patients in cryptic shock, early reversal of hemodynamic perturbations and global tissue hypoxia, prevention of acute cardiovascular collapse, and the possibility of preventing the inflammatory aspects of global tissue hypoxia that accompany the inflammation or infection. severe sepsis and septic shock patients should receive early aggressive therapy to restore and maintain oxygen availability to the cells. there should also be generous use of fluids and inotropic agents titrated by appropriate hemodynamic monitoring. background a large number of observational studies have shown that patients with sepsis have severe depletion of protein c [ , ] . a number of studies have also shown the association of protein c depletion with high mortality in sepsis [ ] [ ] [ ] . furthermore, baboon studies have demonstrated that treatment with activated protein c prevents death from live escherichia coli infusions [ , ] . activated protein c exerts a number of actions. anticoagulant action includes the inactivation of coagulation factors va and viiia, and the inhibition of the formation of thrombin. profibrinolytic action allows the activity of tissue plasminogen activator (endogenous tissue plasminogen activator), by inactivating plasminogen activator inhibitor and thrombin activatable fibrinolysis inhibitor. finally, anti-inflammatory action reduces il- (in vivo) and proinflammatory cytokines (in vitro). the specific mechanisms by which drotrecogin alfa (activated) exerts its effect on survival in patients with severe sepsis are not completely understood. the efficacy of drotrecogin alfa (activated) (recombinant human activated protein c) in reducing mortality in patients with severe sepsis was investigated in a large multicenter, blinded, placebo-controlled, randomized, phase iii clinical trial, the protein c worldwide evaluation in severe sepsis (prowess) trial [ ] . all patients in the prowess trial received standard supportive care in addition to either drotrecogin alfa (activated) or placebo. for a summary of the protocol used in the prowess study, see appendix . the overall mortality in patients treated with drotrecogin alfa (activated) was . % compared with . % in patients receiving placebo, an absolute risk reduction of . % (p = . ) (see fig. ). the absolute risk reduction in patients with high risk of death defined by an apache ii score ≥ was . % (p < . ). the absolute risk reduction in patients with high risk of death defined by multiple organ failure was . % (p = . ). no substantial differences in drotrecogin alfa (activated) treatment effects were observed in subgroups defined by gender, ethnic origin, or infectious agent. can drotrecogin alfa (activated) be used in patients on dialysis for pre-existing renal failure, a category that was specifically excluded in the prowess trial? no pharmacokinetic data were available on drotrecogin alfa (activated) in patients on chronic dialysis when the prowess trial began, so such patients were excluded from the trial. subsequent research has shown that the pharmacokinetics of drotrecogin alfa (activated) are not substantially changed in patients on chronic dialysis. the design of the prowess trial allowed a maximum of hours between the onset of first organ dysfunction and the receipt of drotrecogin alfa (activated) (a -hour window was allowed for receipt of the drug following the first confirmation of first organ dysfunction, which in turn had to have been present for no more than hours). the treatment effect of drotrecogin alfa (activated) was consistent across all time intervals from meeting the entry criteria to the receipt of the study drug. treatment with drotrecogin alfa (activated) thus does not appear to be as time critical as interventions such as tissue plasminogen activator in stroke or myocardial infarction. because most of the experience with drotrecogin alfa (activated) was based on organ failure times less than hours, treatment should not be delayed when an appropriate candidate is identified. the time window employed in the prowess trial should allow a full history to be taken and other tests to be performed to determine the bleeding risk. as with all anticoagulants, drotrecogin alfa (activated) is associated with a risk of severe bleeding. during the infusion period in the prowess trial, the bleeding rates were . % in the drotrecogin alfa (activated) group versus . % in the placebo group (p = . ). the risk of bleeding was fairly constant across most subgroups. however, severe thrombocytopenia (< , /mm ) was commonly associated with serious bleeding and intracerebral hemorrhage. patients at high risk of death in the prowess trial were most likely to benefit from drotrecogin alfa (activated). in the prowess trial, the apache ii score was the most effective predictor of risk of death and likelihood of benefit from drotrecogin alfa (activated), particularly in those patients with an apache ii score ≥ . in the prowess trial, the number of organ dysfunctions was also an important indicator that supported an association between likelihood of benefit from drotrecogin alfa (activated) and risk of death. two or more organ dysfunctions identify a population that responds well to therapy, and is a practical measurement. the panel believes that acute respiratory failure or hypotension unresponsive to fluid challenge should suggest the use of drotrecogin alfa (activated). however, coagulopathy, a platelet count < , /mm , acidosis, or low urine output alone should not suggest its use. a very large international study of , patients will be started in late to investigate the efficacy of drotrecogin alfa (activated) in patients with a single organ failure and/or apache scores < . the decision on whether to administer the drug should ultimately depend on whether the patient meets the selection criteria. a patient presenting in the emergency room with acute respiratory failure or acute cardiovascular decompensation should receive appropriate treatment there. the drawback to treatment in the emergency room is that there may not be sufficient time in which to evaluate the patient's bleeding risks. delaying treatment for a few hours will enable more tests to be performed and a fuller history to be taken, both of which will provide a better indication of whether drotrecogin alfa (activated) is appropriate. the dose is always the same ( µg/kg/hour), regardless of the type of organ failure or the degree of sepsis severity. in addition, the -hour window of treatment is always the same so that interruptions of treatment are made up at the end to maintain a total of hours of treatment. twenty-eight-day survival in patients treated with drotrecogin alfa (activated) or placebo: all-cause mortality. do patients require any laboratory testing before they receive drotrecogin alfa (activated)? no laboratory testing was carried out in the prowess trial, and subgroup analysis identified no biochemical marker that conclusively indicates treatment. for example, treatment-associated reductions in mortality were observed in patients with normal protein c levels and in those with low protein c levels. clinical criteria are recommended for the initiation of therapy. aspirin ( mg/day) was allowed in the prowess trial. patients on glycoprotein iib/iiia inhibitors were excluded because no data were available regarding drug interactions and pharmacokinetics. use of these types of agents is likely to increase the risk of bleeding with drotrecogin alfa (activated) therapy. the anticipated benefits must therefore be weighed against the potential risks. in the prowess trial, efforts were made to correct the international normalized ratio towards normal if it was greater than at any time during infusion of drotrecogin alfa (activated). approximately one-third of patients in the prowess trial received steroids at the same time as drotrecogin alfa (activated). there was no interaction with steroid use, presumably because the mechanism of action of steroids is so different from that of activated protein c. hence, steroids should be used if they are needed, and if the patient qualifies for drotrecogin alfa (activated) the two should be used together. drotrecogin alfa (activated) should be considered for use in all adult patients with recent onset severe sepsis or septic shock, and a high risk of death. the value of steroids in the treatment of patients with severe sepsis and septic shock has been fiercely debated for some time. although a number of well-designed, randomized, controlled trials failed to show any benefits of steroid therapy in terms of improved survival in patients with severe sepsis (reviewed in [ , ] ), with mortality increased in many as a result of an increased incidence of nosocomial infections, these trials were primarily investigating the efficacy of short courses of high-dose steroids. the question of whether lower doses of steroids may provide benefit in these patients has only recently been addressed. there is a relatively strong rationale for considering the use of steroids in patients with refractory septic shock. relative adrenal insufficiency is common in patients with refractory septic shock ( - % of patients) [ ] . in addition to such relative adrenal insufficiency and the blunted response to corticotrophin, a large body of evidence indicates that sepsis and refractory septic shock are characterized by peripheral tissue resistance to corticosteroids [ , ] . in septic patients, this can be evidenced in a variety of ways. first, global cortisol binding, which carries cortisol from the adrenal glands to the tissues, decreases in patients with severe sepsis [ ] . second, the number and binding affinity of glucocorticosteroid receptors may be reduced in patients with sepsis and severe sepsis [ ] , leading to a decrease in the conversion of cortisone to its active form, cortisol, particularly by il- levels in the tissues. finally, data have been published demonstrating that moderate doses of steroids may restore cell sensitivity to vasopressors [ ] . this may reduce the intensity of the inflammatory response and decrease organ dysfunction. low-dose steroid treatment is also well tolerated [ ] . this body of evidence prompted the initiation of a phase iii randomized, controlled trial performed in centers in france with patients [ ] . the aim of the trial was to determine whether moderate-dose corticosteroid therapy affected survival in patients with refractory septic shock and adrenal insufficiency. all patients had to be treated with vasopressor agents and mechanical ventilation. for a summary of the protocol used in this study, see appendix . patients were stratified according to their response to the adrenocorticotrophic hormone (acth) test. nonresponders were defined by an increment in cortisol levels < µg/dl or < nm/l after challenge with µg cosyntropin. of the patients included, there were nonresponders to the corticotropin test (placebo, patients; steroids, patients). a significant survival benefit was demonstrated among nonresponders receiving moderate-dose corticosteroids. there were deaths in the placebo group ( %) and deaths in the steroid group ( %) (hazard ratio, . ; % confidence interval, . - . ; p = . ). no beneficial effects were observed in the subset of patients who were classified as responders. hence, in this paradigm, the acth test serves as a useful prognostic measure. since a beneficial effect was observed in the total population, however, the need for an acth test can be challenged and further studies are required. if an acth test is performed, corticosteroid administration can be started before results are received. moderate-dose corticosteroids should be administered to patients with established refractory septic shock. what is the optimal dose for this intervention? hydrocortisone should be given daily at a dose of - mg. fludrocortisone should be given daily at a dose of µg. what is the optimal duration for this intervention? moderate doses of steroids should be given for days. hydrocortisone can be administered as serial boluses or as a continuous infusion. it may be that rebound phenomena at treatment discontinuation are more frequent when hydrocortisone is given as a continuous infusion. in addition, in the phase iii randomized trial, hydrocortisone was given as serial boluses. the phase iii randomized trial has shown that the combination of hydrocortisone and fludrocortisone increased survival. in addition, sepsis is more frequently associated with a mineralocorticoid deficiency than a glucocorticoid deficiency. hence, fludrocortisone should be added to hydrocortisone. administration of moderate-dose corticosteroids should be considered in cases of refractory septic shock, particularly in those with relative adrenal insufficiency. it is recommended that an acth test be carried out before starting the intervention. hyperglycemia, caused by insulin resistance in the liver and muscle, is a common finding in icu patients. it can be considered an adaptive response, providing glucose for the brain, red cells, and wound healing, and is generally only treated when blood glucose increases to > mg/dl (> mmol/l). previous studies have shown that high levels of insulin-like growth factor binding protein (a very good marker of lack of hepatic insulin effect) predict mortality [ , ] . patients with high insulin-like growth factor binding protein also tend to have the lowest insulin levels, indicating that beta cell function is impaired and, therefore, not enough insulin is being produced. these results indicate that hyperglycemia may not always be adaptive and that it should be treated to avoid the onset of specific complications. nevertheless, conventional wisdom in the icu has been that hyperglycemia is beneficial and that hypoglycemia should be avoided. the hypothesis that hyperglycemia (> mg/dl, > . mmol/l) predisposes to specific icu complications, prolonged intensive care dependency and death was tested in a prospective, randomized, controlled trial [ ] . for a summary of the protocol used in this study, see appendix . thirty-five of the patients ( . %) in the intensive insulin group died in the icu, compared with patients ( . %) in the conventional therapy group. for further mortality data on both the length of hospital stay and the cause of death, see tables and . for morbidity data, see figure . tight control of blood sugar, as outlined in appendix , requires a strict protocol for insulin administration and repeated determination of blood sugar. this is yet to be proven, and is the subject of an ongoing study. because medical patients tend to stay in the icu longer than surgical patients, the results from this study indicate that this intervention would be even more favorable to medical icu patients. however, one needs to be careful with application of the algorithm in certain disease states, especially severe hepatic dysfunction and renal failure. no, all carbohydrates are included. see appendix for guidelines on feeding. the level was chosen because it is in the physiologic range for healthy people. as well as its effect on glycemia, insulin has been shown to inhibit tnf-α and macrophage inhibitory factor (when infused concomitantly with glucose). this has led to some doubts as to whether the effect in this study was due to normalization of blood glucose levels. however, multivariate analysis of all the risk factors for mortality, including severity of illness on admission, indicated that blood glucose determines the outcome; there was a % increase in risk of death per mg/dl increase in blood glucose. it is not yet possible to determine this. although it was blood glucose levels that were measured, the effects of insulin may in fact be on free fatty acids, as they change in parallel with s blood glucose. one of the key mechanisms may be prevention of hypertriglyceridemia and high concentrations of free fatty acids. it is strongly advisable to tightly control blood sugar close to physiologic levels, especially in surgical patients. implemen-tation of this recommendation requires a well-defined icu protocol. the interventions discussed in the present article have been applied in different patient populations and at different times in the course of the disease (see table ). it is essential for physicians to understand that these therapies are not mutually exclusive. optimal patient management may require a combination of approaches: mechanical ventilation to preserve lung function, hemodynamic support to maintain adequate scvo , intensive insulin therapy to normalize blood sugar, steroids to provide adequate immunosuppression, and drotrecogin alfa (activated) to prevent the systemic coagulopathy characteristic of severe sepsis and, hence, to preserve organ function. a sound understanding of the indications and contraindications of these interventions will guide appropriate intervention. similarly, the timing of therapy needs to be closely monitored. education in the signs and symptoms of sepsis and severe sepsis should prompt early initiation of therapy. many of the interventions discussed in this article were tested at specific available online http://ccforum.com/content/ /s /s multiple organ failure, no sepsis focus multiple organ failure, with sepsis focus most important effects on morbidity [ ] . cvvh, continuous venovenous hemofiltration; icu, intensive care unit; nnt, number needed to treat; rrr, relative risk reduction. despite the wealth of data to support the approaches discussed, it is clear that uptake of these interventions into clinical practice has been slow. although there may be practical reasons for this, it would appear in many cases to involve either unfamiliarity with the data or a reluctance, or at least inertia, to change established practices (witness the necessity of proving that hypoglycemia is beneficial in icu patients despite no good evidence to the contrary). the icu has changed in the past years; there are more tools to use and more interventions to implement. despite application of new methods, however, outcomes have changed very little and certainly not in proportion to the changes that were expected based on the results from clinical trials. efficient integration of new interventions into the wider icu population is clearly essential. the panel believes that optimal use of existing therapies and the integration of proven new therapies will reduce mortality rates. further positive results from new trials with improved trial designs should encourage intensivists to incorporate new interventions into their practice. protocols are essential to ensure efficient integration of new therapies and to improve outcomes on the wards. morris predicted in a recent paper that an increase in compliance with evidence-based recommendations through the use of protocols would decrease error and would enhance patient safety [ ] . however, a complete treatment protocol is only effective when each ward (inside and outside of the icu) has the trained staff to implement it, and when a skilled intensive care physician is available to lead the team. training and education of staff is essential. all five of the interventions discussed in this article have generated convincing evidence for their use, and they hold out hope for reducing mortality in patients with sepsis, severe sepsis and septic shock. yet, despite compelling data, the application of these interventions has yet to become routine practice in most icus. it is our hope that this article will enable physicians to understand how best to apply these therapies in clinical practice; from appropriate patient selection and timing of therapy, to combining different approaches for optimal patient management. a willingness to embrace new interventions, coupled with the development and implementation of rigorous protocols to ensure appropriate use, will improve outcomes and lead to a substantial reduction in mortality in these patients. • a respiratory rate ≥ breaths/min or a partial pressure of arterial carbon dioxide ≤ mmhg, or the use of mechanical ventilation for an acute respiratory process. • a white cell count ≥ , /mm or ≤ /mm , or a differential count showing > % immature neutrophils. patients should meet at least one of the following five criteria: • pregnancy or breastfeeding. • aged younger than years or weight > kg. • platelet count < , /mm . • conditions that increase the risk of bleeding: • surgery requiring general or spinal anesthesia within hours before the infusion, the potential need for such surgery during the infusion, or evidence of active bleeding postoperatively; • a history of severe head trauma requiring hospitalization, intracranial surgery, or stroke within months before the study, or any history of intracerebral arteriovenous malformation, cerebral aneurysm, or mass lesions of the central nervous system; • a history of congenital bleeding diatheses; gastrointestinal bleeding within weeks before the study unless corrective surgery had been performed; or • trauma considered to increase the risk of bleeding. • a known hypercoagualable condition including: • resistance to activated protein c; • hereditary deficiency of protein c, protein s, or antithrombin iii; • presence of anticardiolipin antibody, antiphospholipid antibody, lupus anticoagulant, or homocysteinemia; or • recently documented (within months) or highly suspected deep-vein thrombosis or pulmonary embolism. • patient's family or physician, or both, not in favor of aggressive treatment of the patient, or the presence of an advanced directive to withhold life-sustaining treatment. • patient not expected to survive days because of an uncorrectable medical condition, such as poorly controlled neoplasm or other end-stage disease. • moribund state in which death is perceived to be imminent. • human immunodeficiency virus infection in association with a last known cd cell count ≤ /mm . • history of bone marrow, lung, liver, pancreas, or smallbowel transplantation. • chronic renal failure requiring hemodialysis or peritoneal dialysis (acute renal failure was not an exclusion criterion). • known or suspected portosystemic hypertension, chronic jaundice, cirrhosis, or chronic ascites. • acute pancreatitis with no established source of infection. • participation in an investigational study within days before treatment. • use of any of the following medications or treatment regimens: • unfractionated heparin to treat an active thrombotic event within hours before the infusion (prophylactic treatment with a dose of unfractionated heparin of up to , u/day was permitted); • low molecular weight heparin at a higher dose than recommended for prophylactic use (as specified in the package insert) within hours before the infusion; • warfarin (if used within days before study entry and if the prothrombin time exceeded the upper limit of the normal range for the institution); • acetylsalicylic acid at a dose of more than mg/day within days before the study; • thrombolytic therapy within days before the study (thrombolytic agents permitted for the treatment of thromboses within a catheter); • glycoprotein iib/iiia antagonists within days before study entry; • antithrombin iii at a dose of more than , u within hours before the study; • protein c within hours before the study. drotrecogin alfa (activated) should be given at a dose of µg/kg/hour for hours. infusion should be interrupted hour prior to any percutaneous procedure or major surgery, and should be resumed and hours later, respectively, in the absence of bleeding complications. there was an -hour time window from shock onset to check for eligibility and to perform a short acth test (blood samples before and and min after a µg intravenous bolus of tetracosactrin). patients were then randomly assigned to receive mg hydrocortisone as an intravenous bolus every hours and one µg tablet of fludrocortisone through a nasogastric tube once a day, or their respective placebos. treatments were given for days, and patients were followed up for year. on admission, patients should receive continuous intravenous glucose ( - g over hours). after hours, total parenteral, combined parenteral and enteral, or total enteral feeding should be instituted: - nonprotein kcal/kg/day with a balanced composition ( . - . g nitrogen/kg/day and - % nonprotein calories in the form of lipids). total enteral feeding should be attempted as early as possible. national vital statistics reports epidemiology of severe sepsis in the united states: analysis of incidence, outcome, and associated costs of care the task force on the management of acute myocardial infarction of the european society of cardiology epidemiology of sepsis: an update severe sepsis and septic shock. definitions, epidemiology, and clinical manifestations gram-negative sepsis: a dilemma of modern medicine sepsis definitions. lancet infect dis use of the sofa score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study improved survival of patients with acute respiratory distress syndrome (ards): - [concepts in emergency and critical care treatment of gram-negative bacteremia and septic shock with ha- a human monoclonal antibody against endotoxin. a randomized, double-blind, placebo-controlled trial treatment of gram-negative bacteremia and shock with human antiserum to a mutant escherichia coli the tnfα α mab sepsis study group: monoclonal antibody to human tumor necrosis factor alpha (tnfα α mab): efficacy and safety in patients with the sepsis syndrome lenercept study group: lenercept (p -tumor necrosis factor receptor fusion protein, ro - , tenefuse) patients with severe sepsis or early septic shock. a randomized double-blind placebo-controlled multicenter phase iii trial with patients recombinant human protein c worldwide evaluation in severe sepsis (prowess) study group: efficacy and safety of recombinant human activated protein c for severe sepsis current concepts: treating patients with severe sepsis need for intensivists in intensive care units randomised trial of intravenous streptokinase, oral aspirin, both, or neither among , cases of suspected acute myocardial infarction: isis- (second international study of infarct survival) collaborative group injurious ventilatory strategies increase cytokines and c-fos m-rna expression in an isolated rat lung model effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. the acute respiratory distress syndrome network airway and lung in sepsis elevation of systemic oxygen delivery in the treatment of critically ill patients a trial of goal-oriented hemodynamic therapy in critically ill patients. svo collaborative group early goal-directed therapy collaborative group: early goal-directed therapy in the treatment of severe sepsis and septic shock task force of the american college of critical care medicine, society of critical care medicine: practice parameters for hemodynamic support of sepsis in adult patients in sepsis critical care in the emergency department: a physiologic assessment and outcome evaluation critical care provided in an urban emergency department a hemodynamic comparison of early and late phase severe sepsis and septic shock low levels of protein c are associated with poor outcomes in severe sepsis protein c, protein s, c b-binding protein in severe infection and septic shock prognostic value of protein c concentrations in neutropenic patients at high risk of severe septic complications van der voort e: protein c and s deficiency in severe infectious purpura of children: a collaborative study of cases. intensive care med epidemic meningioccemia and purpura fulminans with induced protein c deficiency protein c prevents the coagulopathic and lethal effects of escherichia coli infusion in the baboon the endothelial cell protein c receptor aids in host defense against escherichia coli sepsis corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature steroid controversy in sepsis and septic shock: a meta-analysis a -level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blinded, singlecenter study prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome: evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids patterns of corticosteroidbinding globulin and the free cortisol index during septic shock and multitrauma adrenal insufficiency during the late stage of polymicrobial sepsis reversal of late septic shock with supraphysiologic doses of hydrocortisone effect of a treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock reactivation of pituitary hormone release and metabolic improvement by infusion of growth hormone-releasing peptide and thyrotropin-releasing hormone in patients with protracted critical illness a paradoxical gender dissociation within the growth hormone/insulin-like growth factor i axis during protracted critical illness bouillon r: intensive insulin therapy in the critically ill patients decision support and safety of clinical environments. qual saf health care the roundtable discussion was supported by an unrestricted educational grant from eli lilly and company. jlv, ea, gb and er are consultants to eli lilly and company. all authors received an honorarium/grant for participating in this meeting. inclusion criteria • partial pressure of arterial oxygen/fio ≤ mmhg. • bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph.• no clinical evidence of left atrial hypertension, pulmonary artery wedge pressure ≤ mmhg if measured. • positive pressure ventilation via endotracheal tube. inclusion criteria patients must have a known infection or a suspected infection, as evidenced by one or more of the following:• white cells in a normally sterile body fluid.• perforated viscus.• radiographic evidence of pneumonia in association with the production of purulent sputum. • a syndrome associated with a high risk of infection (e.g. ascending cholangitis). patients should meet at least three of the following four criteria:• a core temperature ≥ °c ( . °f) or ≤ °c ( . °f).• a heart rate ≥ beats/min, except in patients with a medical condition known to increase the heart rate or those receiving treatment that would prevent tachycardia.available online http://ccforum.com/content/ /s /s the study included all mechanically ventilated patients entering the icu: predominantly surgical patients, with some neu-rological patients (the icu in which the trial took place also sees such patients). medical icu patients (e.g. those with chronic obstructive pulmonary disease or oncologic or hematological disorders) were not included as they are not treated in the unit where the study was conducted. however, septic patients that were initially surgical but then came back from the ward with sepsis were included.only those patients who were moribund or had do-notresuscitate status at icu admission were excluded from the trial. if blood glucose ≥ mg/dl (≥ . mmol/l), infuse with insulin to maintain normoglycemia ( - mg/dl, . - . mmol/l). do not exceed iu/hour. adjust insulin dose based on measurements of whole-blood glucose in undiluted arterial blood, performed at - hour intervals, based on the following algorithm: adjust the dose in proportion to the observed change in blood glucose level (if blood glucose decreases by % then the insulin dose should be decreased by % and checked within the next hour). appendix table provides information on the appropriate action depending on the blood glucose level. the numerical instructions provided in appendix table are a guide; insulin dosage should always be done with common sense, proportionate to the previous changes in blood glucose observed upon previous changes in dosage.available online http://ccforum.com/content/ /s /s appendix table appropriate action depending on blood glucose level key: cord- -u dfp gf authors: toubiana, julie; courtine, emilie; tores, frederic; asfar, pierre; daubin, cédric; rousseau, christophe; ouaaz, fatah; marin, nathalie; cariou, alain; chiche, jean-daniel; mira, jean-paul title: association of rel polymorphisms and outcome of patients with septic shock date: - - journal: ann intensive care doi: . /s - - -z sha: doc_id: cord_uid: u dfp gf background: crel, a subunit of nf-κb, is implicated in the inflammatory response observed in autoimmune disease. hence, knocked-out mice for crel had a significantly higher mortality, providing new and important functions of crel in the physiopathology of septic shock. whether genetic variants in the human rel gene are associated with severity of septic shock is unknown. methods: we genotyped a population of icu patients with septic shock and icu controls for two known polymorphisms of rel; rel rs and rel rs . outcome of patients according to the presence of rel variant alleles was compared. results: the distribution of rel variant alleles was not significantly different between patients and controls. among the septic shock group, rel rs *t minor allele was not associated with worse outcome. in contrast, rel rs *g minor allele was significantly associated with more multi-organ failure and early death [or . ; % ci ( . – . )]. conclusion: in a large icu population, we report a significant clinical association between a variation in the human rel gene and severity and mortality of septic shock, suggesting for the first time a new insight into the role of crel in response to infection in humans. despite continued efforts and significant advances in critical care medicine, septic shock remains a significant health problem with a mortality rate around % [ , ] . septic shock is defined as sepsis accompanied by cardiovascular failure that is often a part of multiple organ dysfunction syndrome (mods) [ ] . thus, septic shock represents an extreme manifestation of the host inflammatory response to severe infection. transcription of inflammatory mediators such as cytokines, chemokines, adhesion molecules and reactive oxygen species is strongly activated by the transcriptional factor nf-κb and contributes to the development of mods [ , ] . nf-κb is an ubiquitous family of inducible dimeric homodimer or heterodimer transcriptional factors composed by five members: rel (c-rel), rela (p ), relb, nf-κb (p /p ) and nf-κb (p /p ) [ ] . the role of rela in severe infection is well established, as it is highly recruited to the promoter of pro-inflammatory genes in non-survivors of septic shock [ , ] . the crel subunit was the least studied member of the rel family, but seems to have also a critical role in the antimicrobial host defense. indeed, in vivo studies revealed that crel is required for macrophage activation [ , ] , adaptive immunity [ ] and the control of lymphocyte proliferation [ , ] . crel is also a key regulator of numerous cytokines: il- , il- , il- , il- , il- , il- , il- , il- , ifn-γ, ifn-β, ifn-λ, mip -α and gm-csf [ , [ ] [ ] [ ] [ ] [ ] [ ] . more recently, in a murine model of polymicrobial sepsis, rel deficiency led to an increased mortality, an enhanced systemic inflammatory response and a sustained depletion of spleen lymphoid dendritic cells [ ] [ ] [ ] [ ] ] . furthermore, whole blood transcriptomics showed that crel targets inflammatory and survival genes during sepsis [ , ] . moreover, genetic variants within the rel locus have been associated with inflammatory diseases or autoimmunity in europeans [ ] . even if no study reports the importance of crel in human sepsis, these elements highlight the potential importance of crel for nf-κb targeted-immunomodulation in severe infections. recently, the role of genetic factors influencing the susceptibility to or the severity of severe sepsis has been extensively studied. several single nucleotide polymorphisms (snps) have been characterized in genes of nf-κb pathway proteins. for instance, snps in tlrs [ ] [ ] [ ] , tirap [ ] , irak [ , ] , iκb [ ] and nf-κb inducing kinase (nik) [ ] genes have been associated with severity of sepsis. however, the association between genetic variants in nf-κb subunits and severe infections has been poorly reported. hence, the present study aims to test the hypothesis of an association between clinically significant rel genetic variants and severity of septic shock in a large cohort of well-defined intensive care unit (icu) patients. this study was conducted prospectively in three medical icus in france. all three icus share similar severe sepsis management protocols based on international guidelines from the surviving sepsis campaign for management of severe sepsis/septic shock [ ] . the septic shock group was defined by usual criteria [ ] . briefly, patients were eligible for inclusion into the septic shock group (ss) if they had, within their stay in icu, a clinical evidence of infection with two of four sirs criteria (fever (> . °c) or hypothermia (< °c); tachycardia (> beats/min); tachypnea (> breaths/min) or need of mechanical ventilation; white cell count > × /l) and if, after an adequate fluid resuscitation, they required vasopressor infusion (norepinephrine, epinephrine or dopamine > μg/kg/min) to maintain a mean arterial pressure higher than mmhg. exclusion criteria included comorbidities highly associated with death in ss [ ] : age above years, cardiac failure (nyha class iii or iv), liver insufficiency (child c), bone marrow aplasia or leucopenia not related to septic shock (white blood cell count < . × /l), immunosuppression (hiv, current immunosuppressive therapy including steroids with equivalent prednisone > . mg/kg per day) or ongoing cancer with undergoing treatment. the control group (c) was composed of patients hospitalized simultaneously in the three icus for other reasons than infection and who did not develop sepsis nor required any inotropic or vasopressor agents during their icu stay. similar exclusion criteria were used for the control and the ss groups. patients were followed up throughout their icu stay, and clinical and biological characteristics were prospectively collected: age, gender, sapsii score and previous medical history of severe infection requiring hospitalization. for the ss group, characteristics of current infectious episode were also collected: primary sites of infection, infection-related microorganisms, development of multi-organ dysfunction syndrome (mods) (defined as the presence of more than two organ system failures occurring simultaneously icu stay) [ ] , mechanical ventilation requirement estimated by ventilator-free day (vfd: time without mechanical ventilation within the icu period censured to days) [ ] and icu mortality. to minimize confounding factors due to ethnical differences, all patients selected in the study were caucasians and had european origins. the institutional review board of cochin hospital, paris, france, approved the study, and informed consents have been obtained from the patients or their relatives. two previously described snp have been analyzed. the snp rs is a a → g transition located in the second intron of rel gene on chromosome (chromosomic location ). the snp rs is a g → t transition located in the fourth intron of rel gene (chromosomic location ). all genetic analyses were performed blinded from the clinical data. genomic dna was extracted from mononuclear cells using magna pure compact automate (roche diagnostics ® ). dna extracts were then quantified and stored in code-barr tubes ( dcypher, abgene ® ) to maintain anonymous status of the patients all along the study. real-time pcr allelic discrimination assays were realized by taqman ® method on abi (applied biosystems ® ). probe and primer combinations were designed to discriminate the two rel snps (rs and rs ). quality control for genotyping was performed by automatic sequencing patients carrying the different rel genotypes in order to confirm allelic discrimination results and also by re-genotyping % of the entire cohort. all dna samples showing discrepancy between the two analyses were definitively sequenced (n = ). all data were analyzed by spss v . and "r" v softwares. both snps were tested for hardy-weinberg disequilibrium to check for stratification. in order to calculate the Šidák multiple testing correction, we first evaluate the effective number of independent tests (called meff ) in the analysis by using the methodology proposed by li and ji [ ] . this method aims to prevent from overcorrection due to possible linkage disequilibrium (ld) between the snps. power calculation has been based on the frequency of the variant allele in the control population as proposed by hattersley et al. [ ] . hence, for an incidence of the variant allele of % in the control population and a power at %, a % increase in the case population with a type i error of %, individuals in each group appear to be sufficient to detect genetic susceptibility to ss (http://www.stat.ubc.ca/~rollin/stats/ssize/b .html). for the second study assessing the prognostic value of the variant alleles in ss group, given the frequency of the variant genotype, and an expecting mortality rate at - % in the ss subgroup group, we considered that ss patients were sufficient for a power at . (type i error at . ) to identify a % difference in genotype frequency. descriptive results of continuous variables were expressed as median and interquartile range reflecting population distribution. variables were tested with chisquare test for categorical data (sex, multi-organ failure, primary sites of infection, microorganisms, genotypes) and with mann-whitney u test for numerical data (age, sapsii, vfd). a multivariate logistic regression model was used to determine the respective role of rel genotypes for susceptibility to ss and to icu mortality. confounding factors with a p value < . were included in this model. continuous variables were included without any transformation, and genotypes were considered as a factor (dichotomous unordered variate) to avoid the implicit dose effect when coding the genotypes , and according to the number of mutated alleles carried. results were expressed as odds ratio (or) and % confidence interval (ci), and variable with p value < . was defined as statistically significant. the total enrolled caucasian population was composed by septic shock patients (ss) and controls (c). in the c group, enrolled icu patients were admitted for various non-infectious reasons (metabolic: %, neurological: %, respiratory: %, cardiovascular: % and surgical: %) and did not develop severe sepsis and did not require vasopressor infusion during their icu stay. c patients were younger than ss patients ( vs . years, respectively, p = . ), and females were more represented in c group ( and %, for c and ss, respectively, p = . ). mortality rate and occurrence of mods in the c group were and %, respectively. all ss patients received norepinephrine or epinephrine as first vasopressor. the main site of infection was the lung ( %); microorganisms were identified in % of the cases, mainly gram-positive bacteria. median sapsii value of and high percentage of patients with multiple organ dysfunctions ( %) underlined the severity of the septic shock population. the icu mortality rate of the ss group was %. hardy-weinberg proportions were comparable to expected percentages regarding rel variants: rel rs (p = . ) and rel rs (p = . ) in favor of homogeneity of population ethnicity. to determine whether rel rs and rs snps were associated with septic shock susceptibility, genotype frequencies were determined for ss and c patients. as reported in table , no significant difference was found between the two groups. moreover, these incidences were similar to those reported in the hapmap database-reported genotype distribution for european population (http:// www.ncbi.nhm.nih.gov/projects/snp/snp_viewtable. cgi?pop= ). among the ss patients, general clinical characteristics were not significantly different between patients carrying rel minor allele and patients homozygous for major allele on both rel-analyzed loci ( table ). in order to study the link between rel snps and septic shock severity, we compared acute respiratory distress syndrome (ards) and mods frequencies, and vfd value between patients carrying rel rs *g and rs *t minor alleles and in those homozygous for the major alleles. as given in table , vfd values were table ]. for multiple testing correction, we calculated a meff of . [ ] leading to a corrected p value of . . a similar trend was observed for ards (p = . , table ). in ss group, mortality was not significantly different between patients carrying rel rs *t minor allele and homozygous for the major allele of this snp ( . vs. . %, for minor and major alleles, respectively, p = . ). in contrast, the presence of the rs *g minor allele was significantly associated with a higher mortality rate ( vs. %, for minor and major alleles, respectively, p = . ) (fig. ) the present study showed that septic shock patients carrying the rs *g minor allele had an over risk of mods and mortality. in contrast, no association was found between the rel rs *t allele and the severity of septic shock. this study was the first to investigate the importance of two polymorphisms within rel gene in a large european population of septic shock patients. several human studies have suggested that these variants may have an effect on the inflammatory balance, as they have been associated with inflammatory and autoimmune diseases. indeed, the intronic rs snp in the rel gene was associated with susceptibility to rheumatoid arthritis [ ] [ ] [ ] and psoriasis [ ] . the intronic rs snp was linked to a higher risk of crohn's disease, ulcerative colitis [ ] and celiac disease [ , ] and primary sclerosing cholangitis [ ] . genome-wide studies have also found that rel locus was associated with psoriasis [ , ] , rheumatoid arthritis [ ] , ulcerative colitis [ , ] and hodgkin's lymphoma [ ] . however, functional and structural effects of these polymorphisms are still unknown and need to be investigated. given that variant alleles are located on an intronic site, it is possible that these polymorphisms affect transcriptional efficiency of rel gene or these variants may be in strong linkage disequilibrium with a variant inside a neighbor gene. the higher rate of mortality observed in ss patients carrying rs *g might be linked to a higher inflammatory state, as they also developed more frequently mods. they also tend to have more ards and lower vfds however not significant, but this is most likely underpowered, as vfds are not normally distributed. mortality in septic shock was partially related to hyperactivation of nf-κb [ , ] . in this setting, previous genetic studies on several gain of function snps in genes of receptors and signaling molecules upstream of nf-κb, such as tlr and irak [ , ] , showed a significant association with severity of sepsis. these genetic factors might unbalance the fine-tune regulation toward a hyperinflammatory deleterious state. however, the exact role of crel on inflammatory processes is less understood in humans. recent studies have shown that crel could be involved in autoimmunity, such as inflammatory arthritis [ ] and autoimmune encephalomyelitis [ ] . more recently, crel was shown to have a key role in antimicrobial defense processes. rel−/− mice are more susceptible to leishmania major [ ] or toxoplasma gondii infections [ ] , to viral infection by influenza virus [ ] , to bacterial infection by listeria monocytogenes [ ] and to polymicrobial sepsis [ ] . crel is probably important in pro-/ anti-inflammatory balance as rel−/− mice seemed to have an enhanced inflammatory response [ ] . the study design quality is important for a right interpretation of genetic association studies [ ] . we tried to follow closely these quality criteria. first, it is important to select a snp of a protein involved in the physiopathology of the disease. as already mentioned, rel seems to be an interesting gene to study because nf-κb plays a central role in physiopathology of sepsis, and recent studies show the importance of crel in this context. however, one important limit of our study is the absence of data regarding the functional effect of these two snps. functional data are needed to improve our understanding of how rs *g variant of rel is related to sepsis severity. second, the population homogeneity has been controlled by limiting the study on european patients without severe comorbidities. the third item is probably one of the more controversial in the sepsis field: choice of a clearly defined phenotype to avoid confusion factors. thus, we have selected only patients with septic shock whose diagnosis and treatment are standardized [ ] , and these patients had no major comorbidity or immunosuppressive treatment, severe autoimmune diseases in particular, that could have been confounding the results. however, it is impossible to rule out effects of confounding factors or gene-environment interactions in our results, and septic shock is heterogeneous with regard to the source of infection. sample size is essential for statistics quality in association study but is difficult to achieve in pure septic shock population. at our knowledge, our cohort is one of the largest ever published populations in this topic and is large enough to diminish type i error. it is important to consider that after correction for multiple testing, our result only reached near significance. Šidák/ bonferroni correction assumes, however, that markers are independent, whereas the snps studied here are in ld and are therefore not truly independent from each other. as a result, though we tried to take into account ld by the calculation of meff, the adjustment is likely to overcorrect in this case. we therefore consider that our preliminary results would need a validation in independent cohorts. finally, this genetic association study is limited to one gene. genome-wide association studies (gwas) are now discovering new unsuspected genes that might have an impact on sepsis outcome [ ] . the association between rs *g allele and severity of septic shock brings a new perspective on the role of crel subunit of nf-κb in severe infections in humans. better understanding of the genetic effects of nf-κbdependent inflammatory pathways is essential for further research on modulation of nf-κb activity by specific inhibitors, such as small molecule inhibitors of crel, as an adjuvant treatment for sepsis [ , ] . further studies are needed to investigate the functional role of this rel polymorphism on the inflammatory processes observed in sepsis and to validate these encouraging results in independent cohort. abbreviations mods: multiple organ dysfunction syndrome; il: interleukin; ifn: interferon; snp: single nucleotide polymorphisms; icu: intensive care unit; ss: septic shock group; c: control group; vfd: ventilator-free day; ards: acute respiratory distress syndrome; ld: linkage disequilibrium; tlr: toll-like receptor. severe sepsis and septic shock epidemiology of severe sepsis surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock nf-kappa b activation as a pathological mechanism of septic shock and inflammation the two nf-kappab activation pathways and their role in innate and adaptive immunity characterization of elements determining the dimerization properties of relb and p predictive value of nuclear factor kappab activity and plasma cytokine levels in patients with sepsis role of nfkappab in the mortality of sepsis the rel subunit of nf-kappab-like transcription factors is a positive and negative regulator of macrophage gene expression: distinct roles for rel in different macrophage populations cutting edge: identification of c-rel-dependent and -independent pathways of il- production during infectious and inflammatory stimuli mice lacking the transcription factor subunit rel can clear an influenza infection and have functional anti-viral cytotoxic t cells but do not develop an optimal antibody response multiple hemopoietic defects and lymphoid hyperplasia in mice lacking the transcriptional activation domain of the c-rel protein genomewide analysis of gene expression in t cells to identify targets of the nf-kappa b transcription factor c-rel the roles of c-rel and interleukin- in tolerance: a molecular explanation of self-nonself discrimination il- rescues the hyporesponsiveness of c-rel deficient b cells independent of bcl-xl, mcl- , and bcl- interferon regulatory factor- activates il- and il- promoters in cooperation with c-rel regulation of the il- gene by the nf-kappab transcription factor c-rel regulation of ifn-lambda promoter activity (ifn-lambda /il- ) in human airway epithelial cells nuclear factor kappab subunits relb and crel negatively regulate toll-like receptor -mediated beta-interferon production via induction of transcriptional repressor protein yy critical role of crel subunit of nf-kappab in sepsis survival the c-rel transcription factor in development and disease toll-like receptor polymorphisms affect innate immune responses and outcomes in sepsis a common dominant tlr stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease relevance of mutations in the tlr receptor in patients with gram-negative septic shock a mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis irak functional genetic variant affects severity of septic shock variant irak- haplotype is associated with increased nuclear factor-kappab activation and worse outcomes in sepsis ikappab genetic polymorphisms and invasive pneumococcal disease a single nucleotide polymorphism in nf-kappab inducing kinase is associated with mortality in septic shock surviving sepsis campaign guidelines for management of severe sepsis and septic shock definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis incidence, risk factors, and outcome of severe sepsis and septic shock in adults: a multicenter prospective study in intensive care units. french icu group for severe sepsis statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix what makes a good genetic association study? confirmation of association of the rel locus with rheumatoid arthritis susceptibility in the uk population encoding a member of the nf-kappab family of transcription factors, is a newly defined risk locus for rheumatoid arthritis genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci an investigation of rheumatoid arthritis loci in patients with early-onset psoriasis validates association of the rel gene genetic analysis of innate immunity in crohn's disease and ulcerative colitis identifies two susceptibility loci harboring card and il rap coeliac disease-associated risk variants in tnfaip and rel implicate altered nf-kappab signalling improving the estimation of celiac disease sibling risk by non-hla genes three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for il , rel, and card a genome-wide association study identifies new psoriasis susceptibility loci and an interaction between hla-c and erap genome-wide association identifies multiple ulcerative colitis susceptibility loci ulcerative colitis-risk loci on chromosomes p and q found by genome-wide association study a genome-wide association study of hodgkin's lymphoma identifies new susceptibility loci at p . (rel), q . and p (gata ) nuclear factor-kappab activation in peripheral blood mononuclear cells in children with sepsis distinct roles for the nf-kappab (p ) and c-rel transcription factors in inflammatory arthritis critical roles of c-rel in autoimmune inflammation and helper t cell differentiation genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study the ikk nf-kappa b system: a treasure trove for drug development a small-molecule c-rel inhibitor reduces alloactivation of t cells without compromising antitumor activity this study was supported by national grant from the ministry of health (phrc ), grant from carisma (cochin association for research in inflammation, sepsis and molecular advances), grant from srlf (société de réanimation de langue française) and grant from sfar (société française anesthésie réanimation. these funding organizations played no role in the design, execution and publication of the study. jt and jpm participated in the design of the study and the interpretation of the data. jdc, ac, pa, nm and cd participated in the recruitment of patients; ec and jt in the redaction and revision of the manuscript; and ft checked the statistics. cr and fo performed the genotyping experiments. all the authors reviewed the manuscript. all authors read and approved the final manuscript. the authors declare that they have no competing interests. key: cord- -flo j authors: andrews, peter; azoulay, elie; antonelli, massimo; brochard, laurent; brun-buisson, christian; dobb, geoffrey; fagon, jean-yves; gerlach, herwig; groeneveld, johan; mancebo, jordi; metnitz, philipp; nava, stefano; pugin, jerome; pinsky, michael; radermacher, peter; richard, christian; tasker, robert; vallet, benoit title: year in review in intensive care medicine, . i. respiratory failure, infection, and sepsis date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: flo j nan respiratory monitoring measurement of lung volume has always been a concern in patients receiving mechanical ventilation (mv), and complex methods have been proposed for clinical investigation. patroniti et al. [ ] described a simplified helium dilution technique to measure end-expiratory lung volume and compared it to computed tomography (ct) in mv patients. the authors specifically studied the accuracy and precision of the method. a simple rebreathing gas was used to deliver at least ten usual tidal volumes. the agreement between the two methods was found very acceptable for clinical purposes. it was noted, however, that the higher the amount of hyperinflated tissue, the greater was the underestimation of lung volume by the helium dilution method. it has been well demonstrated that a frequent cause of repeated lung volume loss is endotracheal suctioning. this can induce derecruitment in patients with acute respiratory distress syndrome (ards). the effects of such maneuver were tested in ten patients with only mild to moderate lung failure by fernandez et al. [ ] . three techniques were compared with or without preoxygenation. the authors found that reduction in lung volume during suctioning was similar with the quasiclosed and closed systems but significantly higher with the open system. they also observed that in these patients without severe lung disease these changes were transient and rapidly reversible within min. alveolar consolidation is best diagnosed by ct. lichtenstein et al. [ ] , continuing their assessment of the usefulness of lung ultrasound examination in the icu, assessed its value in patients in whom ct had confirmed alveolar consolidation. only were not diagnosed by ultrasound; conversely, ultrasound was positive in only one of control patients without alveolar consolidation on ct. at least in the author's hands, this technique seems to constitute a reliable tool for this diagnosis. measurement of respiratory mechanics usually describes the respiratory system in terms of elastance, compliance and time constant. in an elegant study, kondili et al. [ ] divided tidal expiration in different phases based on the analysis of expiratory flow-volume curves in ten patients with acute exacerbation of chronic obstructive pulmonary disease (copd). they showed that the end of expiration is characterized by a lengthening of time constants, and that the addition of external positive endexpiratory pressure decreases resistance at the end of expiration and shortens time constants, thus facilitating equilibration between the external pressure and the alve-olar pressure. although we already knew the effects of external positive end-expiratory pressure in such patients, this new method of exploration sheds new light on its mechanisms. a part of expiratory resistances can be caused by the endotracheal tube itself. in many cases its contribution is not huge. however, more and more studies suggest that over the course of mv the inner diameter of the tube may progressively decrease due to the permanent deposits of secretions. using the acoustic reflectometry method boquØ et al. [ ] prospectively assessed the inner volume reduction of endotracheal tubes, used in patients, and found this reduction to be extremely frequent. in almost one-fourth of the patients the real diameter of the tube was smaller than mm. the clinical implications of such findings may be important, and further studies are needed on this topic. intra-abdominal hypertension may have important clinical consequences in terms of both respiratory function and intra-abdominal organs function its prevalence, however, is not known. it is thus the great merit of this multicenter collaborative -day prevalence study by malbrain et al. [ ] in icus of six countries to evaluate its frequency in a cohort of patients. based on a definition of abnormal intra-abdominal pressure of mmhg or higher, its prevalence was %, while % of the patients had abdominal compartment syndrome with a pressure of mmhg or higher. the only risk factor was the body mass index, while the effects of massive fluid resuscitation and renal and coagulation impairment were at the limit of statistical significance. last, intrahospital transport poses an important risk to icu patients. continuous monitoring as well as presence of qualified staff and well maintained equipment are probably essential to minimize incidents. the australian incident monitoring study in intensive care received reports describing incidents over a -year period [ ] . they tried to identify all contributing factors, of which % were system-based and the others were humanbased. in % of the incidents there were significant adverse outcomes. a number of factors were also identified as having prevented or limited harm. these problems are often underestimated or underreported and deserve great attention. an editorial by shirley and bion [ ] accompanied this paper. acute respiratory distress syndrome epidemiological characteristics and outcomes from acute lung injury (ali) vary across studies. this variability depends on definitions, subpopulations included in studies, comorbidities, and the severity of the disease per se. brun-buisson and coworkers [ ] studied the current occurrence and causes of ali and ards, the relationships and respective outcome of mild ali (pao /fio between and mmhg) and ards (pao /fio equal to or below mmhg), and the factors associated with survival. a -month inception cohort (february-march ) of individuals with ali among , patients who were admitted for at least h in an intensive care unit (icu) was scrutinized. data pertain to ten european countries and icus. among patients initially having mild ali ( %) went on to ards. there were with mild ali while had ards. crude icu and hospital mortality rates were . % and . % (p< . ) for mild ali and . % and . % (p= . ) for ards. initial mean tidal volume and positive end-expiratory pressure were . € . ml/kg and . € . cmh o in ards patients. air leaks were detected in . % of subjects. in multivariate analysis mortality was associated with age, immunoincompetence, simplified acute physiology score (saps) ii, logistic organ dysfunction score, and early air leak. the authors concluded that ali is frequent, that there is a continuum between ali and ards, and that there is a substantial difference in mortality, being much higher in ards. an editorial comment by rubenfeld and christie [ ] accompanies this article, which also has an erratum [ ] . a pao /fio ratio below mmhg is one of the diagnostic criteria of ards according to the american-european consensus conference, yet this ratio is affected by a number of factors such as ventilator settings and fio per se. ferguson and colleagues [ ] analyzed the impact on enrollment in a trial of high-frequency oscillatory ventilation and the potential effects on study outcome when screened ards patients were placed on standard ventilator settings. these settings were pressure control ventilation to achieve a tidal volume - ml/kg predicted body weight ensuring peak inspiratory pressures below cmh o, fio and positive end-expiratory pressure cmh o. forty-one consecutive patients were included. after institution of standard settings, in patients ( %) the pao /fio was persistently below mmhg and the remainder ( patients, %) had a pao /fio above mmhg min after the changes were implemented. the change in fio was the main reason for these changes in pao /fio . the icu mortality rate was significantly greater in those with persistent ards than in those with the transient form, . % vs. . % respectively (p= . ). the authors concluded that their findings are important for trial design because of the observed differences in outcome, and proposed the use of standardized ventilator settings for patient enrollment. china has seen enormous economic growth, yet the country's demographic characteristics differ substantially from those in the western world. the epidemiological characteristics of ards in china are largely unknown. lu and coworkers [ ] performed a -month survey ( ) ( ) in icus in university hospitals in shanghai. the aim was to investigate the incidence, causes, and outcome of ards in adult patients who were treated in the icu for at least h. a total of , admissions were registered during this period, and patients ( %) were diagnosed as having an ards. the most common predisposing factors for ards were pneumonia ( %) and sepsis of nonpulmonary origin ( %). twenty-seven patients were not intubated. in those who received invasive mv the most frequently used ventilatory mode was synchronized intermittent mandatory ventilation ( %). in hospital mortality rate for ards patients was . %. the majority of ards patients who died ( %) did so because of multiple organ dysfunction, whereas % died because of refractory respiratory failure. the authors concluded that reassessment of respiratory and intensive care management and implementation of effective therapeutic interventions are required. severe acute respiratory syndrome severe acute respiratory syndrome epidemics, whose causative agent is a coronavirus, carries a mortality rate of about - % in young patients and about % in the elderly. gomersall and coworkers [ ] undertook a retrospective, observational cohort study of the first patients who were admitted to the icu of a hong kong university hospital because of respiratory failure. the aim was to describe the clinical course and outcome of these patients and to investigate factors associated with prognosis. their median acute physiology and chronic health evaluation (apache) ii score was (interquartile range - ). at days patients ( %) were alive and not undergoing mv, ( . %) were receiving mv, and had died ( . %). seven of ventilated patients ( . %) developed barotrauma despite a low tidal volume (mean tidal volume . € . ml/kg predicted body weight) and low-pressure strategy (mean positive end-expiratory pressure . € . cmh o, and peak airway pressures of . € . cmh o in those who did not develop barotrauma and . € . cmh o in those who did not develop it). variables associated with poor outcome on univariate analysis were age, severity of illness, lymphocyte count, decreased steroid dose, positive fluid balance, chronic disease or immunosuppresion, and nosocomial sepsis. the authors concluded that mortality is high for this syndrome, it causes severe respiratory failure with little organ failure, and there is a high incidence of barotrauma in those requiring mv. endotracheal extubation is the final step in weaning from mv. a failed tracheal extubation entails a worse prognosis. traditional weaning indices are poor predictors of extubation outcomes. data suggest that patients with neurological diagnoses, lack of adequate cough, and fre-quent endotracheal suctioning are at increased risk of extubation failure. salam and coworkers [ ] objectively assessed the impact of neurological status, cough strength, and volume of endotracheal secretions on extubation outcomes. in patients who had passed a spontaneous breathing trial they measured cough peak flow, endotracheal secretions and ability to complete four simple tasks (open eyes, follow with eyes, grasp hand, and stick out tongue). fourteen patients ( . %) failed the first extubation. patients with a cough peak flow equal to or below l/min were more likely to fail extubation than those with a cough peak flow higher than l/min [risk ratio (rr) . , % confidence interval (ci) . - . ]. patients with secretions of more than . ml/h were more likely to fail than those with fewer secretions (rr , % ci - . ). patients unable to complete the tasks were more likely to fail than those who completed the commands (rr . , % ci . - . ) . the presence of any two of those risk factors had a sensitivity of % and specificity of % in predicting extubation failure. the authors concluded that these simple, inexpensive, and reproducible methods provide a useful clinical approach to guide the extubation process. an editorial by epstein [ ] comments further on this article. periextubation pain has received little attention in icu patients. acute pain arouses clinical manifestations related to sympathetic system activation, and can lead to deleterious cardiovascular effects. gacouin and coworkers [ ] assessed the intensity of pain at extubation time using a visual analogue scale in of a total of extubated patients for a period of year. pain was significantly associated with a saps ii above (p= . ), duration of mv of days or more (p= . ) and intubation not performed in the operating room (p= . ). severe pain was reported by % of patients. pain resolved within h after extubation in the majority of patients. duration of mv for days or longer was the only independent risk factor for pain of at least moderate intensity [odds ratio (or) . , % ci . - . , p= . ]. the authors concluded that periextubation pain is frequent and should be considered for treatment. unplanned, deliberate self-extubation of the trachea may affect patients' outcomes and clinical resources. moons and coworkers [ ] developed a risk assessment tool to categorize patients at risk of deliberate tracheal self-extubation. patients admitted in seven icus of a large referral tertiary center and who had been intubated for more than h were followed for months. in this period cases of unplanned extubations occurred. clinical and demographic characteristics were compared to those of randomly selected control patients. incidence of unplanned extubations was . % (density incidence . per ventilation days). incidence was lower in surgical icus ( . %) compared with medical icus ( . %). fifteen cases ( . %) required reintubation. multiple logistic regression indicated that patients with a low sedation level and higher degree of consciousness were at higher risk for deliberate self-extubation. the authors concluded that appropriate reduction in sedation when patients are weaned, a timely extubation, and increased surveillance when high risk is recognized may reduce the number of unplanned extubations. the recent international consensus conference in intensive care medicine on the use of niv in acute respiratory failure [ ] clearly stated that, "the addition of nppv to standard medical treatment of patients with acute respiratory failure may prevent eti, and reduce the rate of complications and mortality in patients with hypercapnic "pump" failure." concerning episodes of "lung failure" the same document concluded that "the use of niv may be also an appropriate treatment in selected patient populations with acute "lung" failure. single studies have demonstrated noninvasive mv (niv) to be an adequate alternative to conventional ventilatory support or better therapeutic strategy than standard therapy plus oxygen in such patients. more studies are required to confirm these findings. in the year four studies were published in intensive care medicine to improve understanding of and perhaps expand the indications for niv and to highlight some methodological problems. continuous positive airway pressure (cpap) has been considered a very effective treatment of acute respiratory failure (arf) due to cardiogenic pulmonary edema (cpe). l'her et al. [ ] compared the physiological and clinical effects of cpap and those of standard medical therapy in a subset of very old patients (> years) in whom the application of any form of mv is sometimes denied. within h cpap led to decreased respiratory rate and improved oxygenation compared to baseline, whereas no differences were observed in the medical treatment group. seventeen patients of this latter group developed severe complications vs. only four of the cpap group. early -h mortality was significantly lower in the ventilated patients, but overall hospital mortality not. the authors concluded that cpap promotes early clinical and physiological improvement in elderly patients during episodes of arf due to cpe, without affecting overall mortality. while niv has been considered the first line treatment to prevent intubation in copd patients during an episode of hypercapnic arf, little is known about its effectiveness as "real" alternative to invasive mv when the criteria for emergency intubation are met. in a matched case control study performed in copd patients with very severe arf (ph . , paco mmhg) squadrone et al. [ ] , evaluated the efficacy of noninvasive (case) vs. invasive mv (control). mortality rate, duration of mv, and length of icu and hospital stay did not differ between the two groups, but the niv group had fewer complications and a tendency to be weaned earlier from ventilation. intubation rate in the case group was %, but this subset of patients had similar outcomes as those of the control group. those with successful niv had lower mortality rate and shorter icu and hospital stay than the patients who received intubation. in copd patients with very advanced hypercapnic arf niv thus has a high rate of failure but nevertheless provides some advantages compared to invasive ventilation. indeed a subgroup analysis suggested that the delay in intubation was not deleterious in the subset of patients who failed niv. patients with severe chronic pulmonary diseases often suffer from coexistent pathologies and are also likely to develop extrapulmonary complications. scala and coworkers [ ] assessed the impact of those comorbidity on short-and long-term outcomes of niv in hypercapnic arf of copd patients. they divided patients (ph . , paco mmhg) into failure (n= ) or success group (n= ) according to whether niv avoided intubation. the prevalence of chronic and acute comorbidities was, respectively, % and %, most of the cases being cardiovascular. both niv failure and -month mortality were greater in patients with than in those without comorbidities. multiple regression analysis predicted niv failure by acute comorbidity and forced expiratory volume in s, while death at months was predicted by having more than a single acute comorbidity of noncardiovascular origin and worst pre-existing activities of daily living. the presence of comorbidities is common in copd patients requiring niv, and their presence influences the outcomes of the patients. technical aspects of niv include not only the types of interfaces, ventilators, and ventilatory modes employed but also some "marginal factors" that may interfere with patient well-being. it is now clear, for example, that loud sounds can contribute to patient discomfort during the icu stay. cavaliere et al. [ ] studied the noise intensity in ten healthy volunteers undergoing niv with two different levels of pressure support ( and cmh o), using the helmet with and without heat and moisture exchanger filter, full face mask, and a nasal mask. inside the helmet the noise intensity exceeded db, which was significantly higher than that during facial and nasal ventilation ( db). noise intensity was not affected by the level of pressure applied or by the presence of filters. the level of discomfort was similar using the four different settings. the authors concluded that niv helmet is associated with significantly greater noise than nasal and facial masks, but that it is equally comfortable in the short-term setting. weaning and postextubation failure weaning difficulties occur in a relatively small percentage of ventilated patients; however, patients undergoing prolonged mv are more prone to develop complications and therefore dramatically increase the costs of care. great attention should be paid to early identification of patients who are likely to fail weaning and to predicting those who may develop postextubation respiratory failure. three studies assessed the causes of weaning failures or the effectiveness of physiological indices in predicting weaning or postextubation failure. paresis acquired during the icu stay (icuap) is recognized as a major event that often occurs during the management of patients with prolonged critical illness. it has also been shown that the duration of mv is an independent predictor of icuap. de jonghe et al. [ ] studied a prospective cohort of patients without preexisting neuromuscular disease and ventilated longer than days to determine whether icuap is an independent risk factor of prolonged weaning after awakening. the presence of icuap was defined as an medical research council score lower than . patients who developed icuap ( / , %), had a significantly longer weaning time ( days vs. days). in multivariate analysis the two independent predictors of prolonged weaning were icuap and the presence of copd. the authors concluded that icuap was the strongest independent predictor of prolonged mv, and that the prevention of icuap should result in shorter weaning time. only few of the studies that have investigated the utility and accuracy of some weaning indices were blinded. conti and coworkers [ ] evaluated the most popular weaning indices in a blinded fashion (i.e., the physicians making decisions about the weaning were always unaware of the predictive values). the study had two steps: patients' data were first used to select the cutoff values for weaning predictors (i.e., minimal false classification); these values were prospectively validated in a cohort of other patients. the variables recorded during the first min after discontinuation of ventilation were: vital capacity, tidal volume, pressure in the first ms of an occluded inspiration (p . ), minute ventilation, respiratory rate, maximal inspiratory pressure (mip), rapid shallow breathing index (f/vt), p . /mip, and p . f/vt. the receiving operating characteristic curve showed that the tests had no ability in discriminating between success and failure. the authors concluded that the most common evaluated indices are poor predictors of weaning outcome. the breathing pattern in normal persons displays a certain variability, which is maintained by a central neural mechanism and the feedback loops of arterial chemoreceptors and lung vagal sensory receptors. deviations in breathing pattern variability (bpv) from the normal level have been found in individuals under pathological con-ditions. bien et al. [ ] investigated whether potential changes in bpv predict weaning from mv in postoperative patients recovering from systemic inflammatory response syndrome (sirs). the analysis employed to assess the bpv during a -min period of pressure support ventilation at cmh o, was the pointcare plot, which is a scattergram that dynamically analyzes breathing pattern on real-time, breath-to-breath basis. the coefficient of variation and sd, indicators of the dispersion of data points in the plot, were significantly lower in the patients who failed the weaning attempt than in those who did not. a low bpv is associated with a high incidence of weaning failure, and this variability may potentially serve as a weaning predictor. p . has been proposed as a predictor of weaning parameter, despite results that have been somewhat controversial. fernandez and coworkers [ ] although catheter-related infection (cri) rates have decreased due to improved infection control techniques and devices, cri remains the major cause of nosocomial bacteremia in icus. preventive strategies and new devices opposing colonization continue to be tested. four randomized controlled trials (rct) on this topic have been published in intensive care medicine this year. langgartner et al. [ ] examined central venous catheters (cvcs) and investigated whether skin disinfection during cvc insertion with an alcohol plus chlorhexidine ( . %) solution followed by povidone-iodine provides greater protection against cvc colonization and infection than either one of the antiseptics alone. they found that catheter colonization rates were reduced fivefold (from % with povidone-iodine alone to . %) with the successive application of both antiseptics. mo-lecular typing of organisms confirmed that most cvc colonization originated from the skin insertion site. the sample size of this study was, however, too small to confirm a reduction in infection rates. in another rct including cvcs carrasco et al. [ ] compared heparin-coated triple-lumen catheters to chlorhexidine-sulfadiazine coated ones, a comparison which had not been performed previously. colonization was found in of heparin-coated catheters in of chlorhexidine and silver sulfadiazine coated catheters (p= . ). the incidence of cvc-related bloodstream infections (bsis) did not differ [ finally, brun-buisson et al. [ ] tested the new generation of antiseptic-coated catheters (with enhanced chlorhexidine-silver sulfadiazine coating on both the internal and external aspect of the cvc) vs. nonimpregnated cvcs in a rct enrolling patients. significant colonization of the catheter occurred in ( . %) and ( . %) patients, respectively, in the noncoated and coated groups ( vs. . per , catheter-days, p= . ), and cvc-related bsis occurred in ( ) and ( ) patients in the noncoated and coated groups, respectively ( . vs. per , catheter days, p= . ). in all these trials antimicrobial-impregnated catheters were associated with a significant reduction in catheter colonization and a trend to reduction in infection episodes, but not of bsi. it is noteworthy that all these trials have relatively low definite rates of cvc-related bsi in the control groups. in this context it is difficult to demonstrate efficacy of antimicrobial-impregnated catheters unless the sample size of the study is adequately powered. the potential for increased risk of colonization of antibiotic-impregnated catheters with candida spp. needs confirmatory evidence. safdar and maki [ ] provided additional evidence in support of the predominant pathogenesis of short-term cvc-related infection by analyzing the combined results of two trials ( , catheters) testing preventive strategies aimed at minimizing catheter colonization at the skin entry site. the pathogenesis of infection was confirmed by dna typing of organisms. the overall cvc-related bsi rate was . / , catheter-days. in the pooled control groups of the two trials cvc-related bsis occurred ( . per , catheter-days), in % of which infections were extraluminally acquired, % intraluminally derived, and % indeterminate. in contrast, cvc-related bsis in the treatment groups were most often intraluminally derived ( %, p= . ). the authors concluded that most cvc-related bsis were extraluminally acquired and derived from the cutaneous microflora. therefore strategies achieving successful suppression of cutaneous colonization can substantially reduce the risk of cvc-related bsi associated with short-term cvcs. it is noteworthy that about % of cvcs removed because of suspected infection prove not to be infected. to limit wasteful removal of catheters rijnders et al. [ ] tested in a small rct whether a "watchful waiting" strategy in which selected patients with low to moderate suspicion of cvc infection were observed without removal of the cvc is safe and allowed to retain the cvc. hemodynamically stable patients without proven bacteremia, insertion site infection, or intravascular foreign body were randomized to a standard-of-care group (in which all cvcs were changed as planned) or the watchful waiting group (in which cvcs were changed only when bacteremia or hemodynamic instability subsequently occurred). of patients with suspected cri, patients met exclusion criteria ( of whom were shown to be bacteremic, including , %, with cvc-related bsi), and ( %) were randomized. all cvcs were changed in the standard group vs. of in the watchful waiting group ( % reduction, p< . ), with no difference in bacteremia rate or outcome of patients. the authors concluded that the use of a simple clinical algorithm permits a substantial decrease in the number of unnecessarily removed cvcs, without increased morbidity. in an accompanying editorial, brun-buisson [ ] emphasizes the value of this conservative approach in selected patients with low/moderate suspicion of cvc infection and comments on the potential value of additional tests (skin site insertion swab culture, paired blood culture) to assist the clinical decision making in this conservative approach. to identify factors associated with hospital outcome of adult patients with infective endocarditis (ie) mourvilliers et al. [ ] retrospectively reviewed patients admitted over an -year period to their referral center icu. the overall hospital mortality rate was %. in patients with native valve ie (n= ) variables associated with outcome by multivariate analysis included septic shock (or . , % ci . - . , p= . ), cerebral emboli (or , % ci . - . , p= . ), immunocompromised state (or . , %ci . - . , p= . ), and cardiac surgery (or . , % ci . - . , p= . ). in those with prosthetic valve ie (n= ) the variables included septic shock (or . , % ci . - . , p= . ), neurological complications (or . , % ci . - . , p= . ), and immunocompromised state (or . , % ci . - . , p= . ). the authors concluded that ie is associated with a high mortality rate in patients requiring icu admission; although early complications make optimal medical and surgical management decisions often difficult, surgical treatment appears to improve outcome of patients. in a questionnaire survey of french intensivists azoulay et al. [ ] addressed the difficult and unresolved question of the interpretation of a lower respiratory secretion sample positive for candida spp. as expected, physicians' attitudes varied widely. although a majority felt that positive samples for candida reflect colonization only in nonimmunocompromised patients, one-fourth ( %) were inclined to provide antifungal therapy; a majority ( %) felt that repeating samplings at various sites to calculate the "colonization index" was necessary. the authors concluded that additional studies are needed to improve our understanding of respiratory tract candida colonization and infection in nonneutropenic mv patients and to determine the indications for preemptive antifungal therapy in this population. misset et al. [ ] report the results of a -year infection control quality improvement program, based on published guidelines to reduce nosocomial infection rates in their medical-surgical icu. mean device-related infection rates (per , procedure-days) were: ventilator-associated pneumonia (vap) . , urinary tract infection (uti) . , cvc colonization . , and cvc-related bsi . . during the -year study period there was a significant decline in uti and cvc-related infection rates and an increase in time to infection, but not of vap rates. the authors concluded that uti and cvc-related infections can be reduced through a continuous quality-improvement program based on surveillance of nosocomial infections. to identify factors associated with high use of antimicrobials, meyer et al. [ ] reported results from the first years in icus of the sari program, a surveillance system of antimicrobial use in a german icu network set up in . the mean antimicrobial use density (ad) was , ddd/ , patient-days and was correlated with length of stay. penicillins plus b-lactamase inhibitor (ad . ) and quinolones ( . ) were the antimicrobials most used. length of stay was an independent risk factor for an ad above the % percentile of the total amount of antimicrobials used (or . per day) as well as for higher use of carbapenems (or . per day) and extended-spectrum penicillins (or . per day). high use of glycopeptides and quinolones (ad > % percentile) was correlated with cvc. the authors suggested that the sari data could serve as a benchmark by which to improve the quality of antimicrobial drug administration in icus and for international comparison. two large epidemiological studies of severe sepsis syndromes were published this year. to provide an updated epidemiology of severe sepsis, brun-buisson et al. [ ] reported the results of a -week inception cohort study of severe sepsis and shock conducted in randomly selected french icus. of , patients admitted ( . %) had severe sepsis or shock, % of which cases were icu acquired. the median saps ii and sequential organ failure assessment (sofa) at onset of severe sepsis were and , respectively. mortality was % and . % at and days after sepsis, and . % of patients remained hospitalized at months. chronic liver and heart failure, acute renal failure and shock, saps ii at onset of severe sepsis and -h total sofa scores were the independent risk factors most strongly associated with death. the authors concluded that whereas the attack rate of severe sepsis has increased in french icus over the past decade, its mortality appears to have decreased, suggesting improved management of patients. finfer et al. [ ] reported a prospective populationbased, inception cohort, incidence study conducted in multidisciplinary icus of hospitals in australia and new zealand, including , consecutive icu admissions. a total of patients- . ( % ci . - . ) per icu admissions-had episodes of severe sepsis. the icu and -day mortality rates were . % and . %, respectively, and . % of patients died in hospital. the authors estimated the incidence of severe sepsis in adults treated in australian and new zealand icus at . ( . - . ) per , inhabitants and concluded that the population incidence found in this prospective study falls in the lower range of recent estimates from retrospective studies in the united states and the united kingdom. in an accompanying editorial moss [ ] highlights questions concerning the interpretation of epidemiological surveys and recent changes in the epidemiology of sepsis. finkielman et al. [ ] report a -year, single-center, retrospective study of patients (mean age years) with septic abortion, a relatively rare condition nowadays. their apache ii mean score was . on admission. acute renal failure developed in % ( of ) of patients, disseminated intravascular coagulation in % ( of ) , and septic shock in % ( of ) . blood cultures were positive in % ( of ). twelve patients died ( %). the authors concluded that, when requiring icu admission, this preventable event remains associated with high morbidity and mortality. the diagnostic value of c-reactive protein remains controversial. sierra et al. [ ] reexamined this question in a prospective observational study of patients with sirs ( having subsequently confirmed and without confirmed infection) and normal control subjects. median c-reactive protein values on day were lower in healthy subjects ( . mg/dl, % ci . - . ), patients with acute myocardial infarction ( . mg/dl, % ci . - . ), and those with noninfectious sirs ( . mg/dl, % ci . - . ), than in those with sepsis ( . , % ci . - . , p< . ). a c-reactive protein threshold value of mg/dl had a . % sensitivity and . % specificity for predicting sepsis. the authors concluded that determination of serum c-reactive protein can be used as an early indicator of infection in patients with sirs. to determine the clinical impact of the recently available highly active antiretroviral therapy (haart) on icu admissions and outcome in patients infected with human immunodeficiency virus (hiv) vincent et al. [ ] compared patients admitted during a pre-haart era ( - ; n= ) and the haart era ( - ; n= ) . during the latter % of patients admitted to the icu had not or only little benefited from the availability of haart: % had no history of antiretroviral therapy, and % had failed to respond to antiretroviral. the icu admission rate of hospitalized hiv-infected patients increased rather than decreased compared with the pre-haart era (haart . % vs. pre-haart . %, p= . ). after adjustment for significant prognostic covariates icu survival was unchanged between the two periods (adjusted or . , % ci . - . ), but month survival had improved (adjusted or . , % ci . - . , p= . ). the authors concluded that the icu admission rate of hiv-infected patients remains high in the haart era, possibly because of underutilization of therapy and limited access to health care. as indicated by yu and singh [ ] , "over studies have been published in peer-review journals in the past years dealing with management of ventilator-associated pneumonia (vap)." however, no consensus exists to date on the best way for identifying patients with true lung infection, for selecting early appropriate antimicrobial therapy, or for avoiding unnecessary use of antibiotics. controversies regarding the management of patients suspected of developing vap have been nourished by numerous studies comparing different bacteriological di-agnostic techniques, or clinical to bacteriological evaluation, and/or evaluating the clinical pulmonary infection score (cpis) recently proposed as the first step of a "clinical strategy" [ ] . elatrous et al. [ ] conducted a prospective study in patients clinically suspected of episodes of vap to compare quantitative cultures of endotracheal aspirates (eta) and plugged telescoping catheter. pneumonia was diagnosed on positive cultures (! cfu/ml) of the latter. the authors reported a good correlation between the two techniques for identifying bacterial species and differentiating between positive and negative cultures of the plugged telescoping catheter by using a diagnostic threshold for eta of cfu/ml. they calculated a sensitivity of % and a specificity of % for eta. with the usual and widely used threshold of cfu/ml for eta, results were less good, with a poor agreement between the two techniques (k= . ). the authors concluded that eta quantitative cultures are adequate techniques to identify pathogenic organisms in significant concentration in the lower respiratory tract but not to diagnose vap since quantitative cultures of the plugged telescoping catheter are not a "gold standard" and even not a "silver standard" to differentiate lung infection from heavy colonization of the lower respiratory tract. mentec et al. [ ] reported the results of a multicenter prospective study conducted in five french icus that enrolled patients with suspected vap, including with "confirmed" vap (based on the classification of the international consensus conference on the clinical investigation of vap [ ] ). four diagnostic techniques were compared: blind tracheal aspirates, blind protected telescoping catheter (blind ptc), bronchoscopic ptc, and bronchoscopic bronchoalveolar lavage (bal). the authors found that direct examination of secretions obtained with blind ptc, bronchoscopic ptc, and bal are of similar value for diagnosing vap and choosing appropriate initial treatment. in contrast, they underlined that blind and bronchoscopic ptc had diagnostic values comparable to that reported with bal only when the collected sample contains visible secretions; in the entire population, the areas under receiver operating characteristic curve were significant smaller with the three techniques ( . , p= . for blind tracheal aspirates; . , p= . for blind ptc; . , p= . for bonchoscopic ptc) than with bal ( . ). these two studies have the usual limitations of studies evaluating new diagnostic methods: the absence of clear and definitive definition of the disease, here the absence of a gold standard. several published studies have tried to determine such a gold standard-experimental studies, animal studies, postmortem studies [ ] -and suggested that only the combination of histological examination and quantitative cultures of lung tissue gives arguments strong enough to validate or eliminate the diagnosis of pneumonia in patients treated with mv for more than days. dupont et al. [ ] designed a study in patients with vaps to assess the impact on the duration of mv and the use of antibiotic treatment of the results of a diagnostic technique: the percentage of infected cells in liquid obtained with bal, i.e., the value of direct examination. in clinical practice the time of direct examination of pulmonary secretions is a very important issue since it corresponds to the time of the differentiation between infected and noninfected patients, the decision to treat or not, and the choice of initial antimicrobial therapy. the authors confirmed a strong relationship between the percentage of infected cells and the results of quantitative cultures of bal. they also found two factors negatively associated with the percentage of infected cells: the duration of mv before the onset of vap ( . € . % before the th day, . € . % between the th and the th day; and . € . % after days of mv; p= . ) and the ongoing use of antibiotics. they suggested that this diagnostic criteria should be analyzed with caution in patients receiving prior antibiotic therapy with clinical suspicion of late-onset vap. schurink et al. [ ] examined the accuracy of the cpis for diagnosing vap and evaluated interoberver variability in its calculation. they compared the scores of a slightly modified cpis with results of quantitative cultures of bal in patients suspected of vap. the diagnosis of vap was based on a positive bal (quantitative cultures growth ! cfu/ml). for patients the cpis was calculated by two investigators. vap was diagnosed in patients. when using cpis higher than to diagnose vap, the sensitivity of the score was % and the specificity only %. with a cutoff of points the diagnostic values were lower (sensitivity %, specificity %). in addition, a major limitations was identified by the authors, compromising the wide use of cpis in clinical practice, since the level of agreement between observers in measuring individual cpis ( vs. > ) was poor. they concluded that the low specificity and sensitivity of cpis, combined with a considerable interobserver variability, do not permit to base a diagnostic strategy on such a score. luyt et al. [ ] confirmed this observation in a retrospective cohort study conducted in patients included in the "invasive strategy" group of the french multicenter randomized trial comparing two strategies (invasive vs. clinical) in the management of patients suspected of having vap [ ] . cpis was calculated retrospectively with the data collected for the initial study on days and and was compared between patients with bacteriologically confirmed vap (n= ) or not (n= ). on day cpis was similar in the two groups ( . € . vs. . € . with and without vap, respectively, ns). on day the patients ( %) had a cpis higher than . based on the algorithm described by singh et al. [ ] these patients would have required prolonged antimicrobial therapy. compared with a strategy based on bronchoscopy, patients without bacteriologically confirmed vap would have been unnecessarily treated, and patients with vap would have not received antibiotics after day for a total of % of patients incorrectly managed. for more than years clinical evaluation including temperature, macroscopic aspect of tracheal secretions, leukocytosis, and chest radiography has been repeatedly identified as at least a nonoptimal way to diagnose pneumonia in patients treated with mv [ ] . cpis, which is no more than the quantification of a clinical evaluation, does indeed constitute significant progress, particularly when it is included in a management algorithm [ ] . as indicated by yu and singh [ ] in their editorial, the use of such an algorithm based on cpis resulted in limiting the number and duration of antibiotics, reducing incidence of infections due to multiresistant bacteria, shortening duration of stay, and lowering -day mortality rate. it is therefore possible to reduce antibiotic use without deleterious consequences for mv-treated patients treated with clinical signs suggesting the development of vap. furthermore the authors clearly stated that excessive broad-spectrum therapy leads to greater emergence of multiply-resistant organisms and increases mortality and morbidity. limiting the use of antibiotics in patients with cpis lower than is a very important first step of a "revisited" strategy. yu and singh reported important data concerning this strategy. during the years following the implementation of the singh protocol they had not experienced "a single case of a patient with an invasive infection leading to death in a patient with cpis < receiving day monotherapy." thus the relevant questions are: is this patient developing vap? does the patient require antibiotics? to answer to these questions, it is possible to propose at least two new randomized trials: first, according to the authors, a comparison of a shortcourse monotherapy vs. no antibiotics in patients with low (< ) cpis and, second, a comparison of the singh protocol with a bacteriological strategy already evidenced as superior to the "classic" clinical strategy [ ] . adequacy of initial antibiotic therapy is recognized as a major prognostic factor in patients with vap [ ] . this statement seems obvious; it is also the rationale for giving broad-spectrum antibiotics in all patients with clinical suspicion of vap, ignoring the risk of emergence of resistance, over morbidity and mortality associated with the absence of control of antibiotic prescriptions. thus the relationship between appropriateness of treatment and outcome needs to be clarified. clec'h et al. [ ] conducted a study in patients with bacteriologically confirmed vap to test the hypothesis of a link between adequacy of treatment, severity of illness at vap onset, and outcome. the rate of ade-quate antibiotic therapy was . % on day and % on day . no significant difference in mortality was observed with and without adequate initial treatment in the entire population. however, in patients ( %) with low severity level (defined by a logistic organ dysfunction score ), inadequate therapy was clearly associated with higher icu mortality ( %, vs. % in patients appropriately treated, p= . ). pending confirmatory studies these results potentially have major impact on the management of patients suspected of having vap: the appropriate choice of antibiotic(s) is of particular importance in the group of patients with low severity level at the time of the onset of clinical signs of infection. it is reasonnable to perform accurate bacteriological investigations in this population to guide the choice of initial treatment. development and correct evaluation of new antibiotics is one of the cornerstones for improving therapeutic management in patients with vap. one current and increasing difficulty is the treatment of infections due to multiresistant bacteria such as pseudomonas aeruginosa, acinetobacter spp., stenotrophomonas maltophilia, blactamase secretor enterobacteriaceae, and methicillinresistant staphylococcus aureus (mrsa). to date the treatment of mrsa is based on the use of glycopeptides. linezolid, a new oxazolidinone, is a potential alternative to vancomycin for the treatment of severe infections due to mrsa. kollef et al. [ ] reported the results of a retrospective analysis of a subgroup of patients enrolled in two randomized double-blind trials comparing mg linezolid to g vancomycin every h. among patients with suspected gram-positive vap, had vap due to mrsa. in this subgroup clinical cure rates were . % with linezolid (vs . % with vancomycin, p= . ), bacterial eradication rates . % (vs . %, p= . ), and survival rates . % (vs . %, p= . ). logistic regression analysis identified linezolid as one of the independent factors associated with survival in patients with mrsa vap (or . , p= . ), with apache ii score of or less, presence of pleural effusion, and absence of bacteremia. in their editorial ioanas and lode [ ] suggested that linezolid may already be a better choice than vancomycin in vap due to mrsa. the major reason is that vancomycin is a "modest drug" for the treatment of lung infection due predominantly to the extremely poor penetration of vancomycin in the epithelial lining fluid and to the frequent inadequate serum levels. however, linezolidresistant strains of s. aureus have already been reported in the united states and united kingdom. as a conclusion, the authors recommended that (a) linezolid be used with caution and (b) parallel strategies such as antibiotic rotations, restricted use of antibiotics, hygiene measures and cohorting be adapted to diminish antibiotic-selective pressure and to decrease infections by resistant s. aureus. to design strategies of prevention of vap, valles et al. [ ] conducted a study to identify routes and patterns of colonization with p. aeruginosa. ninety-eight intubated patients ventilated longer than days were investigated; authors collected samples from the tap water of the room, stomach, oropharynx, subglottic secretions, trachea, and rectum at the time of intubation and three times per week. they observed colonization in . % of patients and tracheal colonization in . %. ten patients had tracheal colonization at intubation, and four developed vap. p. aeruginosa was isolated in . % of samples of the room's tap water; however, identified pulsotypes were rarely associated with vap. the authors concluded that colonization with p. aeruginosa was endogenous and exogenous. as a consequence they suggested the combination of prophylactic measures avoiding airway colonization and infection control measures to reduce crosscontamination. subglottic suctioning and semirecubent positioning have been proposed to prevent vap [ ] . girou et al. [ ] designed a randomized trial to evaluate the impact of the two measures on tracheal colonization in patients receiving long-term mv. oropharyngeal and tracheal secretions were collected daily ( samples in the eight patients of the suctioning group and in the ten patients of the control group). comparing patients receiving these measures to patients receiving standard care and supine position, the authors identified no differences in bacterial counts in the trachea ( . log cfu/ml in the suctioning group vs. . log cfu/ml in the control group), colonization on day ( % vs. %, respectively), or in the daily bacterial count in the oropharynx and in the trachea. vap rate was similar in both groups. they concluded that continuous subglottic suctioning and semirecubent position do not reduce tracheal colonization in long-term mv patients. the true impact of such prophylactic measures needs to be evaluated more precisely. in contrast to community-acquired pneumonia, lung inflammatory response has been poorly investigated in patients with vap. millo et al. [ ] examined whether cytokine concentrations change in the lungs of patients with vap. they investigated the lungs by using nondirected bronchial lavage and performed serial cytokines and cytokine inhibitors measurements in patients with vap and patients without vap. they observed no modifications in plasma concentrations of cytokines and cytokine inhibitors. in nondirected bronchial lavage fluid the concentrations of tumor necrosis factor a, tumor necrosis factor a receptor , and interleukins a, b, and increased significantly in patients with vap. the authors concluded that cytokines and cytokine inhibitor production are compartmentalized in the lung of patients who develop vap. el-solh et al. [ ] evaluated the impact of inadequate antimicrobial therapy on procoagulant and fibrinolytic activity in patients with bacteriologically confirmed vap and control patients treated with mv. seven patients were not treated appropriately; thrombin-antithrombin complex, prothrombin activation fragment, and plasminogen activator inhibitor type levels were higher than in those who received adequate treatment. despite antibiotic adjustment on day thrombin-antithrombin complex levels remained elevated and were correlated with p/f ratio. such a procoagulant activity was accompanied by a local depression of fibrinolytic capacity. no correlation was found between the bacterial burden and the homeostatic derangements. the authors suggested that the lung inflammatory response in patients with inadequately treated vap induces a local procoagulant activity associated with hypoxemia. lung volume in mechanically ventilated patients: measurement by simplified helium dilution compared to quantitative ct scan changes in lung volume with three systems of endotracheal suctioning with and without preoxygenation in patients with mild-tomoderate lung failure ultrasound diagnosis of alveolar consolidation in the critically ill pattern of lung emptying and expiratory resistance in mechanically ventilated patients with chronic obstructive pulmonary disease endotracheal tube intraluminal diameter narrowing after mechanical ventilation. use of acoustic reflectometry prevalence of intra-abdominal hypertension in critically ill patients: a multicentre epidemiological study incidents relating to the intra-hospital transfer of critically ill patients. an analysis of the reports submitted to the australian incident monitoring study in intensive care intra-hospital transport of critically ill patients: minimising risk epidemiology and outcome of acute lung injury in european intensive care units. results from the alive study the epidemiologist in the intensive care unit epidemiology and outcome of acute lung injury in european intensive care units. results from the alive study screening of ards patients using standardized ventilator settings: influence on enrollment in a clinical trial a -months clinical survey of incidence and outcome of acute respiratory distress syndrome in shangai intensive care units short-term outcome of critically ill patients with severe acute respiratory syndrome neurologic status, cough, secretions and extubation outcomes putting it all together to predict extubation outcome. intensive care med assessment of peri-extubation pain by visual analogue scale in the adult intensive care unit: a prospective observational study. intensive care med development of a risk assessment tool for deliberate self-extubation in intensive care patients international consensus conferences in intensive care medicine: non-invasive positive pressure ventilation in acute respiratory failure. organised jointly by the american thoracic society, the european respiratory society, the european society of intensive care medicine, and the societe de reanimation de langue francaise, and approved by the ats board of directors noninvasive continuous positive airway pressure in elderly cardiogenic pulmonary edema patients noninvasive vs invasive ventilation in copd patients with severe acute respiratory failure deemed to require ventilatory assistance co-morbidity and acute decompensations of copd requiring non-invasive positive-pressure ventilation noise exposure during noninvasive ventilation with a helmet, a nasal mask, and a facial mask does icu-acquired paresis lengthen weaning from mechanical ventilation? a prospective, blinded evaluation of indexes proposed to predict weaning from mechanical ventilation breathing pattern variability: a weaning predictor in postoperative patients recovering from systemic inflammatory response syndrome extubation failure: diagnostic value of occlusion pressure (p . ) and p . -derived parameters combined skin disinfection with chlorhexidine/propanol and aqueous povidone-iodine reduces bacterial colonisation of central venous catheters. intensive care med evaluation of a triple-lumen central venous heparin-coated catheter versus a catheter coated with chlorhexidine and silver sulfadiazine in critically ill patients benefits of minocycline and rifampin-impregnated central venous cathetersa prospective, randomized, double-blind, controlled, multicenter trial central venous catheters coated with minocycline and rifampin for the prevention of catheter-related colonization and bloodstream infections. a randomized, double-blind trial prevention of intravascular catheter-related infection with newer chlorhexidine-silver sulfadiazine-coated catheters: a randomized controlled trial the pathogenesis of catheter-related bloodstream infection with noncuffed short-term central venous catheters watchful waiting versus immediate catheter removal in icu patients with suspected catheter-related infection: a randomized trial suspected central venous catheter-associated infection: can the catheter be safely retained? infective endocarditis in the intensive care unit: clinical spectrum and prognostic factors in consecutive patients practices in non-neutropenic icu patients with candida-positive airway specimens a continuous quality-improvement program reduces nosocomial infection rates in the icu surveillance of antimicrobial use and antimicrobial resistance in intensive care units (sari). i. antimicrobial use in german intensive care units. intensive care med episepsis: a reappraisal of the epidemiology and outcome of severe sepsis in french intensive care units adultpopulation incidence of severe sepsis in australian and new zealand intensive care units a global perspective on the epidemiology of sepsis the clinical course of patients with septic abortion admitted to an intensive care unit c-reactive protein used as an early indicator of infection in patients with systemic inflammatory response syndrome characteristics and outcomes of hiv-infected patients in the icu: impact of the highly active antiretroviral treatment era excessive antimicrobial usage causes measurable harm to patients with suspected ventilator-associated pneumonia shortcourse empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit: a proposed solution for indiscriminate antibiotic prescription diagnosis of ventilatorassociated pneumonia: agreement between quantitative cultures of endotracheal aspiration and plugged telescoping catheter blind and bronchoscopic sampling methods in suspected ventilatorassociated pneumonia. a multicentre prospective study patient selection for clinical investigation of ventilator-associated pneumonia. criteria for evaluating diagnostic techniques ventilatorassociated pneumonia variation of infected cell count in bronchoalveolar lavage and timing of ventilator-associated pneumonia clinical pulmonary infection score for ventilator-associated pneumonia: accuracy and inter-observer variability value of the clinical pulmonary infection score for the identification and management of ventilator-associated pneumonia invasive and non-invasive strategies for management of suspected ventilator-associated pneumonia. a randomized trial efficacy of adequate early antibiotic therapy in ventilator-associated pneumonia: influence of disease severity clinical cure and survival in gram-positive ventilator-associated pneumonia: retrospective analysis of two double-blind studies comparing linezolid with vancomycin linezolid in vap by mrsa: a better choice? intensive care med patterns of colonization by pseudomonas aeruginosa in intubated patients: a -year prospective study of : isolates using pulsed-field gel electrophoresis with implications for prevention of ventilator-associated pneumonia the prevention of ventilator-associated pneumonia airway colonisation in longterm mechanically ventilated patients. effect of semi-recumbent position and continuous subglottic suctioning compartmentalisation of cytokines and cytokine inhibitors in ventilator-associated pneumonia procoagulant and fibrinolytic activity in ventilator-associated pneumonia: impact of inadequate antimicrobial therapy key: cord- -daxz yhp authors: haeberle, helene; prohaska, stefanie; martus, peter; straub, andreas; zarbock, alexander; marx, gernot; zago, manola; giera, martin; koeppen, michael; rosenberger, peter title: therapeutic iloprost for the treatment of acute respiratory distress syndrome (ards) (the thilo trial): a prospective, randomized, multicenter phase ii study date: - - journal: trials doi: . /s - - - sha: doc_id: cord_uid: daxz yhp background: acute respiratory distress syndrome (ards) is caused by rapid-onset (within hours) acute inflammatory processes in lung tissue, and it is a life-threatening condition with high mortality. the treatment of ards to date is focused on the prevention of further iatrogenic damage of the lung rather than the treatment of the initial inflammatory process. several preclinical studies have revealed a beneficial effect of iloprost on the control of pulmonary inflammation, and in a small number of patients with ards, iloprost treatment resulted in improved oxygenation. therefore, we plan to conduct a large multicenter trial to evaluate the effect of iloprost on ards. methods: the therapeutic iloprost during ards trial (thilo trial) is a multicenter, randomized, single blinded, clinical phase ii trial assessing the efficacy of inhaled iloprost for the prevention of the development and progression of ards in critically ill patients. one hundred fifty critically ill patients suffering from acute ards will be treated either by nebulized iloprost or nacl . % for days. blood samples will be drawn at defined time points to elucidate the serum levels of iloprost and inflammatory markers during treatment. mechanical ventilation will be standardized. in follow-up visits at days and as well as months after enrollment, functional status according to the barthel index and a health care-related questionnaire, and frailty (vulnerable elders survey) will be evaluated. the primary endpoint is the improvement of oxygenation, defined as the ratio of pao( )/fio( ). secondary endpoints include -day all-cause mortality, sequential organ failure assessment scores during the study period up to day , the duration of mechanical ventilation, the length of intensive care unit (icu) stay, ventilator-associated pneumonia, delirium, icu-acquired weakness, and discharge localization. the study will be conducted in three university ards centers in germany. discussion: the results of the thilo trial will highlight the anti-inflammatory effect of iloprost on early inflammatory processes during ards, resulting in the improvement of outcome parameters in patients with ards. trial registration: eudra-ct: - - . registered on april . clinicaltrials.gov: nct . registered on june . acute respiratory distress syndrome (ards) is defined as pulmonary compromise with bilateral pulmonary infiltrates associated with moderate to severe hypoxemia [ ] . the public health impact of ards is considerable, and it is estimated that approximately , cases of ards occur annually in germany. the estimated mortality ranges from to % and depends on the severity of the associated hypoxemia [ ] . patients surviving ards treatment also show reduced functional capacity in their everyday life following hospitalization [ , ] . therefore, there is a pressing need to develop further ards treatment strategies with a view to ultimately improving patient outcomes. the bilateral pulmonary infiltrates that can be identified on chest radiography reflect the diffuse inflammatory changes within the lung that are caused by acute inflammation within the pulmonary tissue and the alveolar space. the initial inflammatory process is induced by the activation of the innate immune response by the binding of microbial products (pathogen-associated molecular patterns [pamps]) or cell injury-associated endogenous molecules (danger-associated molecular patterns [damps] ) to pattern recognition receptors (prrs). therefore, the common causes of ards are trauma, sepsis, pneumonia, blood transfusion, or aspiration into the lungs. after the initial activation of the innate immune response, innate immune effector mechanisms, such as the formation of neutrophil extracellular traps (nets), are activated, which further aggravate the alveolar injury [ ] . the resulting increased permeability of the microvascular barrier results in the extravascular accumulation of protein-rich fluid that accumulates within the alveolar space. the increased permeability is also linked to the transfer of leukocytes (mostly neutrophil granulocytes) and erythrocytes into the alveolar space in ards, as well as to the presence of proinflammatory-regulated cytokines that increase the inflammatory burden within the lung [ ] . as a result, dysregulated inflammation, the accumulation of leukocytes and platelets, and altered permeability of alveolar barriers remain the central pathophysiologic problems in ards [ , ] . the treatment of ards to date is focused on the prevention of further iatrogenic damage of the lung through lung-protective mechanical ventilation, neuromuscular blockade, and conservative fluid management [ ] . recent clinical trials have focused on the role of ventilation strategies in the prevention or treatment of ards using noninvasive ventilation devices or prone positioning [ , ] . although these strategies have shown a positive effect on patient oxygenation and symptoms, they do not interfere with the underlying pathophysiological changes of ards. several interventions have tried to use a potential anti-inflammatory strategy for the treatment of the existing intra-alveolar inflammation or to intervene in the development of intra-alveolar inflammation. for this, patients were treated with aspirin, simvastatin, and surfactant, but the tested treatments failed and did not have any significant effect [ ] [ ] [ ] . considerable evidence in preclinical models shows that the use of iloprost for the treatment of ards and pulmonary inflammation might be of significant benefit. in small animal models, investigators showed that iloprost improves endothelial barrier function and reduces the detrimental signs of pulmonary edema [ ] . it also reduces the pulmonary sequestration of leukocytes and platelets, which is a central disease mechanism underlying the development of ards [ ] . this evidence could be transferred into different models of lung injury, showing positive evidence for the reduction of pulmonary inflammation in a pressure-induced model of lung injury [ ] . the anti-inflammatory effect was attributed to the cyclooxygenase- (cox- ) system and the involvement of lipoxin a [ ] . ras-related protein (rap- ) might also be involved in the protective role of iloprost [ ] . this positive anti-inflammatory effect of iloprost on the pulmonary tissue was also demonstrated in several models of ischemia-reperfusion (ir) injury. furthermore, ir injury can also result in ards and pulmonary failure. iloprost was able to reduce this pulmonary compromise in several preclinical studies [ ] [ ] [ ] [ ] . the anti-inflammatory effect of iloprost was also shown in large animal models of lung injury using porcine models of ards [ ] [ ] [ ] . here, again, iloprost showed an anti-inflammatory effect. in addition, the shunt fraction could be reduced, which resulted in improved oxygenation and improved pulmonary dynamics, which is essential for the reinstitution of spontaneous ventilation during and following ards [ , , [ ] [ ] [ ] . this shows that the preclinical data identified a beneficial effect of iloprost on ards. so far, only one study on inhaled iloprost in adult patients with ards has been conducted, although an application of inhaled iloprost is noted in the guidelines of the association of the scientific medical societies (awmf) for the treatment of ards [ ] . the awmf guidelines indicate that the use of ards can be considered, especially in patients with severe ards who are mechanically ventilated and not selfconsenting [ ] . thilo is a multicenter, randomized, single blinded clinical phase ii trial assessing the efficacy of inhaled iloprost in the development and progression of ards in critically ill patients. based on the risk of pulmonary hemorrhage, which is very rare-especially in patients with ards-the study medication was unblended. for safety reasons, after treatment of patients (day after last dose investigational medicinal product [imp] patient ) within the study, an interim analysis for an increased risk for pulmonary hemorrhage ≥ grade iii according to common terminology (toxicity) criteria for adverse events (ctcae) version . in the treatment (iloprost) arm will be performed and the results discussed with the data and safety monitoring board (dsmb). the study was ap- the target population for this clinical trial is adult critically ill patients with ards. patients will be included in the trial if they present with ards as defined by the berlin definition (table and [ ] ) and meet the inclusion criteria. the trial population will consist of both sexes. one hundred fifty intensive care patients with ards will be included in the study at the department of anesthesiology, eberhard karls university tübingen, germany; the department of intensive care and intermediate care, university hospital rwth aachen, germany; and the department of anesthesiology, university hospital münster (ukm), münster, germany. patients meeting the following criteria will be included: age ≥ years, pao /fio ≤ , bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph, need for positive pressure ventilation via an endotracheal tube or noninvasive ventilation and no clinical signs of left atrial hypertension detected via echocardiography, or if measured, a pulmonary arterial wedge pressure (pawp) less than or equal to mmhg. the term "acute onset" is defined as follows: the durations of the hypoxemia criterion and the chest radiograph criterion must be ≤ h at the time of randomization. patients must be enrolled within h of ards onset and no later than days from the initiation of mechanical ventilation. the exclusion criteria are defined as follows: subject age < years; time interval more than days since the initiation of mechanical ventilation; more than h since the onset of ards; patient, surrogate, or physician not committed to full intensive care support; positive pregnancy test at the time of screening; and contraindications against iloprost. these are defined as conditions in which the effects of iloprost on platelets might increase the risk of hemorrhage (e.g., active peptic ulcers, trauma, intracranial hemorrhage), severe coronary heart disease, myocardial infarction (within the last months), decompensated heart failure, severe arrhythmias, unstable angina pectoris, pulmonary arterial hypertension caused by the occlusion of pulmonary veins, cerebrovascular events (e.g., transient ischemic attack, stroke) within the last months, and congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to pulmonary hypertension. patients who received iloprost treatment for any indication within h prior to enrollment in the clinical trial or patients who were on thrombin inhibitors or nitric oxide (no) within the previous h before study randomization were also excluded. additionally, patients dependent on the sponsor, investigator, or their employees were not included in the study. the imp is iloprost (ventavis®; drug code sub mig; atc code b ac ), manufactured by berlimed s.a., madrid, spain (for bayer pharma ag, germany). it will be used as a concentrate for use in nebulizers and will be administered by inhalation three times a day ( μg per administration). the administration of the drug will occur at the same time each day ± h. in cases of severe adverse effects, the dosage will be reduced to μg once a day (morning). other dose modifications or temporary cessation of the study drug will not be allowed. iloprost is usually dissolved in . % sodium chloride (nacl), which is used to keep the ventilator circuit moist as standard of care. therefore, in the control group, nacl . % will be used to keep the airway circuit moist, which is the standard of care for the treatment of patients with pulmonary insufficiency [ ] . considering the pharmacokinetic and dynamic profile of iloprost, we have suggested an approach of an application of three times per day, with a dose of μg, which seems to be an average dose in the trials reported up to now. the rationale behind this was that iloprost also exerts an anti- inflammatory effect that may last up to h [ ] [ ] [ ] [ ] [ ] . therefore, an administration of iloprost three times a day would allow a significant time frame per day to be covered by anti-inflammation due to this drug. the duration of days was included in the trial because the pathophysiology of ards develops within the first few days and is progressive during that period. randomization lists will be generated at the biostatistical center. based on these lists, numbered envelopes will be provided and used for randomization. relevant additional medications and treatments such as vasopressors, inotropes, anti-infective agents, inhalative therapy or sedation, steroids, and immunosuppressive therapy administered to the subjects on entry to the trial or at any time during the trial are regarded as concomitant medications and treatments and must be documented on the appropriate pages of the case report form (crf); these data will be grouped according to class of medication. depending on the substance, the documentation varies in details (e.g., dosing). this study will consist of the following consecutive phases: study entry, treatment, and follow-up. the time points and trial procedures are listed in table . all patients included in this trial will receive standard care for ards according to the ards network, with special consideration of lung-protective ventilation strategies. in this trial, patients with ards present an emergency situation, such as the diagnosis of ards requiring intensive care unit (icu) admission and ventilation therapy, which does not allow for any delay of diagnostic workup or therapy. additionally, due to severe symptoms, the vast majority of patients who meet the eligibility criteria for the trial are assumed to be unable to give consent in the acute admission phase, and legally authorized representatives (lars) might not be available in most cases. this is also in line with local regulations: e.g., § of the german drug law allows the start of a treatment in an emergency situation without prior consent if the immediate treatment is necessary to save the patient's life, recover the patient's health, or ease the patient's suffering. in this situation the consent of an independent physician not directly involved in the study conduct will be sought before the beginning of any study-related activity. the consent has to be obtained as soon as the patient is able to give consent or a lar is available. independently, personal consent will be obtained from each patient after recovering consciousness and competence for decisionmaking or by a legal representative in cases recovering is not achieved during the study duration (i.e., day ). when possible, however, the patient or his legal representative is to be informed both in writing and verbally by the investigator before any study-specific procedure is iloprost or nacl . % (control) x x x x x clinical assessment including outcome x x x x x x x x x laboratory testing x x x x x x x x adverse/serious adverse event monitoring x x x x x x x plasma biomarkers x x x x x x barthel index x x x x sofa score x x x x x x x x health-related questionnaire x ves x performed. each patient or his legal representative will be informed about the modalities of the clinical study in accordance with the provided patient information. informed consent from the patient will be obtained using a form approved by the ethics committee (ec) of the universitätsklinikum tübingen or the local ec if the patient is treated in a collaborating institution. the treatment group will receive μg of nebulized iloprost three times per day for days in addition to standard care. iloprost will be measured in blood samples to determine the serum levels within this setting. the control group will receive nebulized . % nacl with an equal volume three times per day for days. after days, the trial treatment will be complete (fig. ) . blood samples will be drawn at defined time points for a variety of biomarkers to better assess the associations among coagulation, inflammation, and iloprost treatment. key cointerventions (infection control, aspiration precautions, fluids, and transfusion) will be standardized across all patients. mechanical ventilation will be standardized (see additional file ). hospital survivors will undergo a brief follow-up phone survey to assess functional status (barthel index), a health-related questionnaire, and the vulnerable elders survey (ves) to assess frailty months after enrollment. the patients will be visited daily until day or until discharge from the icu, which could be beyond day . if discharged, the next visit will be on day ; if patients are still in the icu, there will still be daily visits until this time point. data will be collected according to the study procedure until then. each visit will consist of a clinical examination, a blood sample, assessment of the functional capacity through the barthel index, and assessment of the severity of illness through the sequential organ failure assessment (sofa) score. all data will be recorded on an electronic case report form (ecrf); this will be used as a visit diary. blood samples will be drawn at defined visits for a variety of biomarkers to better assess the associations among coagulation, inflammation, and iloprost treatment (table ) . the primary objective and endpoint is to assess the effect of iloprost on the improvement of oxygenation (pao /fio ratio) in patients with ards. as secondary objectives, the absolute incidence of the following parameters will be determined: fig. trial protocol and intervention scheme. after screening and determination of eligibility, patients will be included after a maximum of h after the onset of ards. within this time period, screening, consent, and randomization will be initialized. in addition, lung-protective ventilation will be instituted. after randomization, iloprost × μg (intervention) or nacl . % (control) will be administered for days through a standard ultrasound nebulizer. daily recordings will be made with respect to the development of the pao /fio ratio and the severity of ards, organ failure, lung injury, and potential adverse events. the treatment with iloprost or nacl ( . %) will be stopped after days. the follow-up period will then continue up to days and months to determine the outcome, quality of life, and pulmonary/secondary organ function overall survival in the -day follow-up period ( day all-cause mortality) duration of mechanical ventilation support icu length of stay ventilator-associated pneumonia pulmonary hemorrhage gastrointestinal hemorrhage pulmonary embolism hospital discharge or d laboratory testing blood count x a x a x a x a x a x a x b x c x x procalcitonin x a x a x a x a x a x a x b x c x x il- x a x a x a x a x a x a x b x c x x pao /fio x a x a x a x a x a x a x b x c hemoglobin x a x a x a x a x a x a x b x c x x hemostasis parameters x a x a x a x a x a x a x b x c x x renal parameters x a x a x a x a x a x a x b x c x x ventilation support including ventilation parameters x a x a x a x a x a x a x a prone positioning x a x a x a x a x a x a x a ecmo x a x a x a x a x a x a x a relaxation x a x a x a x a x a x a x a high-frequency ventilation x a x a x a x a x a x a x a tracheotomy hemodynamic parameters x a x a x a x a x a x a x b x x x vasopressor therapy x a x a x a x a x a x a x a inotrope therapy x a x a x a x a x a x a x a fluid balance x a x a x a x a x a x a x a transfusion of red blood cells x x x x x x x b x x x transfusion of thrombocytes x x x x x x x b x x x anticoagulation infection x x x x x x x b x x x anti-infective therapy x x x x x x x b x x x the exploratory objectives are -month survival, quality of life (qol) assessed with a short-form survey (sf ), functional status (barthel index), and frailty (ves) assessed by phone follow-up interview. the following parameters will be used to determine the treatment efficacy: improvement of oxygenation (pao /fio ) on a daily basis in relationship to baseline overall survival in the -day follow-up period decrease in duration and severity of ards sofa scores: to be calculated based on data in hospital records duration of mechanical ventilation support: documentation in hospital records icu length of stay: documentation in hospital records ventilator-associated pneumonia: documentation of microbiological findings in hospital records incidence of barotrauma: documentation of ventilator parameters in hospital records reduced morbidity assessed through sofa score, also according to the incidence of complications and increased functionality assessed through the barthel index delirium: documentation (e.g., confusion assessment method for the icu [cam-icu]) in hospital records icu-acquired weakness: documentation in hospital records discharge location: documentation in hospital records, phone call. the demographic parameters at enrollment include age, sex, race, icu admission diagnosis, and comorbidities (such as diabetes, existing malignancy, any kind of pre-existing pulmonary disease, and hypertension). the main clinical data obtained during the icu daily assessment are as follows: laboratory data: blood count, procalcitonin, interleukin (il)- , creatinine, urea, partial thromboplastin time (ptt), d-dimers, international normalized ratio (inr), aspartate aminotransferase (ast), alanine aminotransferase (alt), albumin, cholinesterase (che), brain natriuretic peptide (bnp) weekly assessments of the icu will include the following: differential blood count creatinine clearance ecmo post-oxygenator pao sofa score assessment at discharge chronic renal failure at discharge hepatic failure at discharge length of stay in the icu length of stay in the hospital discharge from hospital to a nursing home discharge from hospital to home discharge from hospital to a rehabilitation unit residence in nursing home at months the final assessment will consist of the following: days of ecmo support ventilator days tracheotomy need for mechanical ventilation at home incidence of pulmonary hemorrhage defined by an indication for blood transfusion, radiological finding, or a decrease in oxygenation incidence of barotrauma incidence of pleural drainage incidence of pulmonary embolism defined by the following parameters: new hypotension sign of right ventricular failure on echocardiography biomarkers computed tomography (ct) scan (optional) incidence of gastrointestinal bleeding defined by the following parameters: upper gastrointestinal bleeding, blood vomiting, lower gastrointestinal bleeding, melena, indication for blood transfusion, endoscopic diagnosis/intervention incidence of cerebral hemorrhage defined by the following parameters: impairment as measured by the glasgow coma scale, ct scan infections: incidence of positive blood culture, pneumonia, wound infection, peritonitis, surgical intervention due to infection, bacterial infection, fungal infection, viral infection, or multidrugresistant gram-negative bacteria (mrgn) infection anti-infective therapy: generic, duration, incidence of changing anti-infective therapy due to inadequate treatment incidence of surgical intervention. the trial case report form (crf) is the primary data collection instrument for the trial. for this project, electronic crfs (ecrfs) will be used. entered data will be subjected to plausibility checks directly implemented in the crf, monitoring, and medical review. the trial master file, the crfs, and other material supplied for the conduct of the study will be retained by the sponsor/ clinical research organization (cro) according to applicable regulations and laws. the investigator(s) will archive all trial data (source data and investigator site file [isf], including the subject identification list and relevant correspondence) according to the international conference on harmonization of technical requirements for registration of pharmaceuticals for human use (ich) consolidated guideline on good clinical practice (gcp) and local laws or regulations. the study population will consist of the following: those to be assessed for eligibility (n = ); those to be assigned to the trial (n = ); those to be analyzed (n = in the intention-to-treat [itt] analysis, other endpoints n = ). the sample size and power consideration refers to evaluable patients, and it is assumed that the power will not be decreased in the analysis of the itt population using multiple imputation. furthermore, baseline adjustment will not be taken into account, which leads to a conservative sample size estimation. in a previous study on iloprost with patients, an increase from ± to ± was observed for the pao /fio , which was significant at the . level [ ] . recalculation shows that the intraindividual standard deviation must have been considerably smaller, as a p value of . corresponds to an effect size of . (intraindividually) and thus to an intraindividual standard deviation of approximately in this study. in our study, we can show effect sizes of . assuming error degrees of freedom, taking into account day for baseline adjustment and days for the study center (inquiry, power %, level of significance . , twosided t test). if we assume the recalculated standard deviation from the previous study in our study (which is still conservative due to the linear baseline adjustment used in our study), an (interindividual) effect size of . corresponds to a difference of approximately in the pao /fio ratio in the treatment arm compared to the control arm. this seems to be a reasonable and relevant effect. the primary endpoint of pao /fio at day after the baseline will be analyzed daily using a baseline adjusted analysis of covariance model with the last measurement of the pao /fio ratio before treatment as the baseline, with the study arm as a second-level factor. the study center will be included in the analysis as a nuisance factor. additionally, an interaction term between baseline and treatment will be included in the model if this term is significant. in the case of interaction, the main effect will be retrieved for the arithmetic mean of the baseline values using the centered variable for pao /fio . multiple imputation will be applied in the itt population of patients receiving at least one dose of treatment or the control. statistical analysis of the prespecified secondary endpoints will be performed with descriptive and exploratory statistical methods according to the scale and observed distribution (absolute and percentage frequencies, chi-square tests, logistic regression models for categorical variables; means and standard deviations, medians, and quartiles, or ranges with t tests or mann-whitney tests and linear regression models for continuous variables; kaplan-meier curves, log-rank tests, and cox proportional hazard models for censored data). the p values will be reported but should not be considered part of the confirmatory analysis. planned subgroup analyses will be performed according to the following: sex and race (only for subgroups larger than subjects) patients with increased pulmonary arterial pressure direct vs. indirect lung injury age stratified by decades. for safety reasons, after the enrollment of patients (day after last dose imp patient ), an interim analysis of the following will be performed: . an increased risk of pulmonary hemorrhage ≥ grade iii according to ctcae version . in the treatment (iloprost) arm . levels of imp in the serum. the results will be discussed with the dsmb. the dsmb has to assess whether the results allow continuation of the study as planned. moreover, after treatment of a total of patients (day after the last dose imp patient ), an interim analysis of an increased risk of pulmonary hemorrhage ≥ grade iii according to ctcae version . in the treatment (iloprost) arm will be performed, and the results will again be discussed with the dsmb. the dsmb must assess whether the results allow continuation of the study as planned. moreover, in the following situations, a premature termination of the trial must be considered: . substantial changes in risk-benefit considerations . new insights from other trials . insufficient recruitment rate. the biometric report will be delivered according to the sop bi of the statistical center (ikeab). in summary, the report will contain sections on the statistical methodology, preprocessing of data, and the descriptive, exploratory, and confirmatory analyses. it will be reviewed by the principal investigator (pi) before presenting the final version. to date, there is no pharmacologic intervention to treat or prevent the development of lung injury or ards. iloprost-containing medications are well recognized epidemiologically as an effective therapeutic agent for the treatment of moderate to severe pulmonary hypertension. iloprost has been shown to exert antiplatelet and anti-inflammatory actions in small clinical observation studies and several preclinical laboratory examinations. however, the use of iloprost for the treatment of ards is not novel; it has been used in small studies before. indeed, we propose in this study to systemically evaluate the application of iloprost in a randomized controlled trial (rct) to identify the potential use and benefit of iloprost in ards. the composite endpoint was chosen, as it is likely to be more sensitive than just -day mortality to detect an effect signal. although it is not a double-blinded strategy, the recorded objectives will help support or refute our hypothesis that iloprost reduces lung inflammation during early ards. this study includes some possible pitfalls, like the single-blinded design. however, due to randomization and based on the close data acquisition, we will be able to minimize bias. however, in addition to the effect of iloprost on lung inflammation, this study will also be a resource for information about clotting issues in terms of the systemic and local anticoagulation effects of iloprost in lung tissue, and also in other compartments besides the lung. although iloprost is used frequently in pulmonary hypertension, there are currently no data about iloprost concentration in the blood after inhalative treatment. in addition, iloprost may have a positive effect on lung compliance during acute ards as well as during resolution, since it has been shown to have a lasting positive effect on fibrosis in the lung and other tissues in animal models [ , ] . in one-lung ventilation, iloprost seems to reduce intrapulmonary shunts, resulting in better oxygenation [ , ] . in this context, the analysis of ventilator-free days or time on ecmo may reveal important information. further on, intravenous application of iloprost may improve microcirculation, resulting in better kidney recovery in patients with sepsis [ , ] . patients with ards frequently show multiorgan failure. therefore, the comparison of incidence and time frame for extracorporeal therapy may give insights on the effect of inhaled iloprost on microcirculation in other organs. therefore, iloprost may positively influence the outcome of ards patients by at least one of the effects described above. this study will be the first to describe the effects of iloprost on inflammation, fibrosis, bleeding events, and oxygenation organ failure and anticoagulation during a continuous time frame of at least days in critically ill patients. the berlin definition of ards: an expanded rationale, justification, and supplementary material the american-european consensus conference on ards. definitions, mechanisms, relevant outcomes, and clinical trial coordination long-term outcomes after ards long-term assessment of lung function in survivors of severe ards the acute respiratory distress syndrome the acute respiratory distress syndrome leitlinie invasive beatmung und einsatz extrakorporaler verfahren bei akuter respiratorischer insuffizienz effect of noninvasive ventilation delivered by helmet vs face mask on the rate of endotracheal intubation in patients with acute respiratory distress syndrome: a randomized clinical trial prone positioning improves survival in severe ards: a pathophysiologic review and individual patient meta-analysis effect of aspirin on development of ards in at-risk patients presenting to the emergency department: the lips-a randomized clinical trial simvastatin in the acute respiratory distress syndrome rosuvastatin for sepsis-associated acute respiratory distress syndrome iloprost improves endothelial barrier function in lipopolysaccharide-induced lung injury iloprost attenuates traumarelated pulmonary sequestration of leucocytes and platelets lung endothelial barrier protection by iloprost in the -hit models of ventilator-induced lung injury (vili) involves inhibition of rho signaling protective role of cyclooxygenase (cox)- in experimental lung injury: evidence of a lipoxin a -mediated effect rap mediates protective effects of iloprost against ventilator-induced lung injury the effects of iloprost on lung injury induced by skeletal muscle ischemia-reperfusion iloprost ameliorates post-ischemic lung reperfusion injury and maintains an appropriate pulmonary et- balance protective effects of levosimendan and iloprost on lung injury induced by limb ischemia-reperfusion: a rabbit model effects of alprostadil and iloprost on renal, lung, and skeletal muscle injury following hindlimb ischemia-reperfusion injury in rats donor pretreatment using the aerosolized prostacyclin analogue iloprost optimizes post-ischemic function of non-heart beating donor lungs inhalative pre-treatment of donor lungs using the aerosolized prostacyclin analog iloprost ameliorates reperfusion injury cardiopulmonary effects of iloprost in experimental acute lung injury preischemic iloprost application for improvement of graft preservation: which route is superior in experimental pig lung transplantation: inhaled or intravenous? aerosolized iloprost for severe pulmonary hypertension as a bridge to heart transplantation iloprost improves gas exchange in patients with pulmonary hypertension and ards aerosolized prostacyclins for acute respiratory distress syndrome (ards) the effects of iloprost and alprostadil on ischemia-reperfusion injury in preventing inflammation, tissue degeneration, and apoptosis in rat skeletal muscle increased neutrophil mediator release in patients with pulmonary hypertension-suppression by inhaled iloprost assessment of the vasodilator response in primary pulmonary hypertension. comparing prostacyclin and iloprost administered by either infusion or inhalation pharmacokinetics and pharmacodynamics of the prostacyclin analogue iloprost in man effects of hyperbaric oxygen and iloprost on intestinal ischemia-reperfusion induced acute lung injury iloprost reverses established fibrosis in experimental right ventricular failure effects of iloprost on bleomycin-induced pulmonary fibrosis in rats compared with methyl-prednisolone the effects of iloprost on oxygenation during one-lung ventilation for lung surgery: a randomized controlled trial iloprost preserves renal oxygenation and restores kidney function in endotoxemia-related acute renal failure in the rat intravenous iloprost to recruit the microcirculation in septic shock patients? publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations supplementary information accompanies this paper at https://doi.org/ . /s - - - . authors' contributions pr and hah drafted the current manuscript. mg, az, mk, pm, and sp critically reviewed and revised the draft report. all authors have read and approved the final version, which was also approved by the sponsor. this study is financed by the akf (applied clinical research) program ( - - ) for the faculty of medicine of the university of tübingen. the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. the thilo trial protocol was approved by the ethics committee of the university of tübingen, germany (protocol number / amg ) on june . the local ethics committee at each site will approve the study protocol (approvals already in place are shown in additional file ). any modifications to the protocol will be immediately communicated to all responsible authorities. all patients, or their legal representative, must give written informed consent. not applicable. the authors declare that they have no competing interests. key: cord- -obrq q authors: benghanem, sarah; mazeraud, aurélien; azabou, eric; chhor, vibol; shinotsuka, cassia righy; claassen, jan; rohaut, benjamin; sharshar, tarek title: brainstem dysfunction in critically ill patients date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: obrq q the brainstem conveys sensory and motor inputs between the spinal cord and the brain, and contains nuclei of the cranial nerves. it controls the sleep-wake cycle and vital functions via the ascending reticular activating system and the autonomic nuclei, respectively. brainstem dysfunction may lead to sensory and motor deficits, cranial nerve palsies, impairment of consciousness, dysautonomia, and respiratory failure. the brainstem is prone to various primary and secondary insults, resulting in acute or chronic dysfunction. of particular importance for characterizing brainstem dysfunction and identifying the underlying etiology are a detailed clinical examination, mri, neurophysiologic tests such as brainstem auditory evoked potentials, and an analysis of the cerebrospinal fluid. detection of brainstem dysfunction is challenging but of utmost importance in comatose and deeply sedated patients both to guide therapy and to support outcome prediction. in the present review, we summarize the neuroanatomy, clinical syndromes, and diagnostic techniques of critical illness-associated brainstem dysfunction for the critical care setting. the brainstem is the caudal portion of the brain that connects the diencephalon to the spinal cord and the cerebellum [ ] . the brainstem mediates sensory and motor pathways between the spinal cord and the brain and contains nuclei of the cranial nerves, the ascending reticular activating system (aras), and the autonomic nuclei. it controls the brainstem reflexes and the sleepwake cycle and is responsible for the autonomic control of the cardiocirculatory, respiratory, digestive, and immune systems. brainstem dysfunction may result from various acute or chronic insults, including stroke, infectious, tumors, inflammatory, and neurodegenerative diseases. in the context of critical illness, the brainstem can be susceptible to various insults that can be categorized as structural and non-structural origin. brainstem dysfunction can then contribute to impairment of consciousness, cardiocirculatory and respiratory failure, and thus increased mortality [ ] [ ] [ ] [ ] . in the present review, we describe brainstem functional neuroanatomy, clinical syndromes, and assessment methods before addressing the concept of critical illnessassociated brainstem dysfunction. the brainstem can be categorized into three major parts: midbrain, pons, and medulla oblongata ( figs. and ) . the brainstem contains both gray and white matter, with the basilar artery representing the vascular supply. the gray matter includes the nuclei of the cranial nerves (anterior part), the aras (posterior part), the extrapyramidal and the central autonomic nervous system (ans). this gray matter controls brainstem reflexes, arousal, automatic movements, and homeostasis, respectively. the white matter is composed of ascending sensory pathways and descending pyramidal and extrapyramidal pathways (table ) . brainstem pathology should be considered in cases of (a) sensory or motor deficits combined with cranial nerve palsy, (b) impairment of consciousness, (c) dysautonomia, or (d) neurological respiratory failure. the pyramidal and extrapyramidal tracts connect the upper motor neurons and the extrapyramidal nuclei with the lower motor neurons located in either the brainstem or the spinal cord [ ] . while the former controls voluntary movement, the latter is involved in reflexes, motion, complex movements, and postural control (tables and ). upper motor neuron damage can lead to symptoms, ranging from hemiparesis to the locked-in syndrome, which is typically characterized by intact awareness, quadriplegia, anarthria, and absence of eye movements except for preserved vertical gaze. it usually results from bilateral pontine white matter lesions [ ] . characteristic clinical features of brainstem lesions include ipsilateral cranial nerve palsies or cerebellar signs combined with contralateral motor deficits. brainstem lesions may present with abnormal movements, such as hemichorea, hemiballism, dystonia, tremor, asterixis, pseudo-athetosis, and non-epileptic myoclonus [ ] ( table ) . bilateral motor corticobulbar tract lesion may present with swallowing impairment, dysphagia, dysphonia, velo-pharyngo-laryngeal impairments, uncontrollable crying/laughing episodes, and emotional lability (i.e., pseudobulbar affect; table ). a brainstem lesion of the posterior column-medial lemniscus pathway and the spinothalamic tract results in a contralateral proprioceptive/touch and temperature/pain deficit, respectively. the testing of the cranial nerves and brainstem reflexes is described in table . abnormal spontaneous eye position and movements may be encountered in patients with brainstem lesions and can be seen in comatose patients. assessment of pupillary size allows the diagnosis of third nerve lesion (i.e., mydriasis) or horner's syndrome (i.e., myosis, ptosis, enophtalmia, and anhidrosis). pupillary light, corneal, oculocephalic, and gag reflexes are routinely assessed in the critical care setting. the oculovestibular responses and oculocardiac are less frequently tested, except to determine brain death. the absence of brainstem reflexes and spontaneous breathing is a prerequisite for the diagnosis of brain death [ ] . automated pupillometry could improve the assessment of the pupil light reflex and thereby its prognostic value [ ] . corneo-mandibular reflexes can be detected in acute brain injury, but its prognostic relevance remains controversial. finally, assessments of primitive reflexes are less relevant in the icu context but can (table ) . when suspecting brainstem lesions, mri will have the highest yield to further localize and characterize brainstem lesions [ ] (table ). evoked potentials may be also useful for detecting a brainstem lesion. eeg [ ] may be supportive in patients with abnormal movements and disorders of consciousness, and cerebrospinal fluid (csf) analysis for those with suspected inflammatory or infectious diseases. the aras controls the sleep-wake cycle and includes several nuclei mainly located in the pontine and midbrain tegmentum [ ] (table , figs. and ): the rostral raphe complex, the parabrachial nucleus, the laterodorsal tegmental nucleus, the locus coeruleus (lc), the nucleus pontis oralis, the basal forebrain, and the thalamus. monoaminergic neurons are directly linked to the cortex and are inhibited during deep sleep. cholinergic pedunculopontine and laterodorsal tegmental nuclei are indirectly connected to the cortex via the thalamus and remain active during rapid eye movement sleep. these pathways are modulated by hypothalamic neurons [ ] . disorders of consciousness can be organized between acute and subacute or chronic [ ] . acute impairments of consciousness include coma which is defined as a "state of unresponsiveness in which the patient lies with eyes closed and cannot be aroused to respond appropriately to stimuli even with vigorous stimulation" [ ] . the association of a prolonged non-responsive coma with a complete cessation of brainstem reflexes and functions suggests the diagnosis of brain death which is defined as an irreversible loss of all functions of the entire brain. delirium is defined as an acute and fluctuating disturbance of consciousness, including attention and impairment of cognition, associated with motor hyperactivity or hypoactivity [ , ] . delirium has been associated with long-term cognitive impairment, functional disability in icu survivors, and hospital mortality [ ] . brainstem dysfunction could account for some features of delirium, such as fluctuations in arousal and attentional impairment that could be related to aras and to ponto-mesencephalic tegmentum dysfunction, respectively. other states of acute impairment of consciousness include clouding of consciousness and stupor, but they are less frequently used [ ] . subacute or chronic disorders of consciousness include the vegetative state (vs, also called unresponsive wakefulness syndrome) defined as state of unresponsiveness in which the patient shows spontaneous eye opening without any behavioral evidence of self or environmental awareness [ ] . the minimally conscious state (mcs) is defined as state of severely impaired consciousness with minimal behavioral evidence of self or environmental awareness, characterized by the presence of non-reflexive behavior (visual pursuit, appropriate motor response to painful stimulus) or even intermittent command following indicating a cortical integration [ , ] . the vs and mcs are related to a preservation of brainstem arousal functions but with persistent impairment of supratentorial networks implicated in consciousness [ ] . stimulation of the aras may improve consciousness in vegetative or mcs patients [ ] . in addition to deep brain stimulation, vagal nerve stimulation, which probably modulates the activity of the nucleus of the tractus solitarius and the dorsal raphe, has shown promising results [ ] . in addition to these classical syndromes, other consciousness impairments have been described. peduncular lesions can cause hallucinations [ ] which may be encountered in icu patients. more generally speaking, it is likely that brainstem dysfunctions account for a portion of the sleep-wake cycle impairments experienced by icu patients. brainstem lesions can induce cognitive deficits including impaired attention, naming ability, executive functioning, and memory impairment [ ] , ascribed to a disruption of interconnection between the frontal- subcortical system and the brainstem [ ] . finally, deep sedation is a pharmacologically induced coma, and its mechanisms of action involve the brainstem gaba and n-methyl-d-aspartate (nmda) receptors [ ] . assessments of consciousness are based on neurological examination to confirm the diagnosis, determine the underlying cause, and evaluate the prognosis. in clinical practice, this assessment most commonly relies on the glasgow coma scale (gcs) [ ] . focusing on the brainstem in particular, the four (full outline of un-responsiveness) score is to be preferred as it includes the corneal, pupil light, and cough reflexes and respiratory patterns [ ] . in comatose patients, pupil sizes and reactivity can be suggestive of particular etiologies, such as drug overdose (myosis for opioids or mydriasis for tricyclic anti-depressants). in comatose brain-injured patients, brainstem reflex assessment is crucial to detect a uncal or downward cerebellar (tonsillar) herniation [ ] . while the absence of corneal and pupillary light reflexes is strongly associated with poor outcome in post-anoxia, their prognostic value is less validated in other causes [ ] . patients with severe critical illness may be comatose due to sedation, which in clinical practice can be assessed using the rass (richmond agitation sedation scale) [ ] . in deeply sedated patients (i.e., rass − or − ), the brainstem reflexes assessment sedation scale (brass) might be useful to assess the effect of sedatives on the brainstem and potentially detect a brainstem dysfunction [ ] ( table ). the cam-icu and icdsc are appropriate to monitor delirium [ , ] . finally, in vs and mcs patients, the coma recovery scale-revised has also been validated [ ] . coma due to structural brainstem lesions is predominantly related to pedunculo-pontine tegmental lesions, usually detected on mri [ ] (table ) . neurophysiological tests may be useful to assess the neurological prognosis in patients with impairment of consciousness. somatosensory evoked potentials (ssep) assess conduction from peripheral nerves (n ) to the somatosensory cortical (n ) regions passing through the brainstem (p ). brainstem auditory evoked potentials (baep) are described in table [ ] . interestingly, sedation increases latencies and decreases amplitudes of evoked potentials in a dose-dependent manner but does probably not change the amplitudes with low to moderate doses used in icu [ ] . the intracranial conduction time and intrapontine conduction time are assessed by measures of the p -n inter-peak latency on ssep and the iii-v interpeak latency on baep [ ] . the prognostic value of baep has been explored in various causes of coma [ ] [ ] [ ] . after cardiac arrest, the predictive value of baep for poor outcomes is limited [ ] . however, in traumatic brain injury, preserved baep are associated with a good outcome [ ] . wave i can disappear if the auditory nerve is injured (traumatic or hypoxic injuries) [ ] . reactivity on eeg to auditory, visual, or nociceptive stimuli is important to assess after cardiac arrest because its absence is associated with poor outcome [ , ] . absent reactivity can result from a thalamus-brainstem loops and aras dysfunction [ ] [ ] [ ] [ ] . the electrophysiological measurement of the blink reflex (table ) is a way to study the trigemino-facial loop [ ] , but its prognostic value in comatose patients remains insufficiently supported [ ] . the ans plays a key role in homeostasis and allostasis by controlling vital functions and the immune system [ ] and is composed of sympathetic (e.g., noradrenergic) and parasympathetic (e.g., cholinergic) systems. sympathetic effects originate from the spinal cord (d to l ), while parasympathetic neuronal cell bodies are present in the nuclei of cranial nerves iii (edinger westphal nuclei), vii, ix, and x and the sacral spinal cord (s to s ). activation of the parasympathetic nervous system results in a decrease in heart rate (hr) and blood pressure (bp), and an increase in gastrointestinal tonus, vesical detrusor contraction, and myosis. activation of the sympathetic system results in opposite effects. cortical input can modulate responses in the ans [ ] as well as various receptors throughout the body, including the baroreceptors [ ] . brainstem injury may cause dysautonomic symptoms, which can be life-threatening [ ] (table ) . cardiac arrhythmias frequently occur after brainstem stroke and are associated with increased mortality [ ] . an intracranial hypertension-induced midbrain insult can impair parasympathetic control and thereby induce adrenergic storm. in brain death, there is a disappearance of the vasomotor tone and an impairment of myocardial contractility [ ] . as exhaustive discussions of tests that allow testing of the ans are beyond the scope of this review, we will focus on cardiovascular tests degenerative/atrophic injury mri magnetic resonance imaging, tdm tomodensitometry, csf cerebrospinal fluid, ecg electrocardiogram mri results according to etiologies: vascular injury: diffusion and flair-weighted sequence hyperintensity restricted to a vascular territory hemorrhage: swi/t * sequence hypointensity inflammatory: diffuse or multifocal white matter lesions on t -and flairweighted sequences, with or without contrast enhancement inflammatory nmo (mri of optical nerve and medullary mri): extensive and confluent myelitis on more than three vertebrae and optical neuritis with possible contrast enhancement traumatic injury: hyperintensity on diffusion sequence, diffuse axonal injuries on dti (diffusion tensor imaging) sequence, hemorrhage lesions on t */swi metabolic: t hyperintensity specifically involves the central pons infectious: abscess/nodes with contrast enhancement paraneoplastic: limbic encephalitis with temporal diffusion and flair hyperintensity tumor: mass with possible necrosis, contrast enhancement and oedema revealed by a flair hyperintensity around tumor degenerative injury: brain and brainstem atrophy (colibri sign) absence of grimacing to pain and absence of ocr absence of grimacing to pain and presence of ocr ocr: oculocephalic reflex brass is a clinical score that has been developed for scoring brainstem dysfunction in deeply sedated, non-brain-injured, mechanically ventilated, critically ill patients and ranges from to the brass has prognostic value, as -day mortality proportionally increases with the brass score applicable to icu patients. standard monitoring allows for the detection of variations in hr and bp that can be suggestive of dysautonomia. however, the lack of apparent changes in cardiovascular signals does not rule out dysautonomia, which can be then assessed with the hr and bp spectral analysis. high frequency (hf) band (i.e., . to . hz) variability of the hr is thought to predominantly reflect parasympathetic tone, while low frequency (lf) variability (i.e., . to . hz) is primarily mediated by sympathetic activity. the lf/hf ratio reflects the sympathovagal balance. therefore, spectral analysis allows studying the sympathetic, parasympathetic, and baroreflex activities both at rest and during stimulation [ ] . if the valsalva maneuver, the cold pressure test, and the pharmacological tests (with yohimbine or clonidine) allow testing the ans, their use in icu is very limited. conversely, pupillometry is much more applicable for assessing dysautonomia in icu. thus, patients with dysautonomia present a pupil dilatation at resting state and a slow redilatation time [ ] . there are two types of muscles that play a major role in the respiratory system, dilatator muscles of the superior airway that are innervated by the brainstem via cranial nerves (motor neurons present in the v, vii, and xii nuclei) and contractor/pump muscles (diaphragm, intercostal, sternocleidomastoid, abdominal muscles) that are innervated by spinal motor neurons. they are controlled by bulbospinal (automatic command) and corticospinal (voluntary command) pathways. the respiratory drive originates from neurons of the latero-rostro-ventral medulla oblongata, which includes the pre-botzinger complex and the parafacial respiratory group that control inspiration and expiration, respectively [ ] ( table ) . this center receives various inputs to automatically adjust the respiratory drive to metabolic and mechanic changes [ ] . metabolic inputs are mediated by both peripheral (aortic and carotid) and central (medulla oblongata and lc) chemoreceptors [ ] . the mechanical inputs are mediated by mechanoreceptors localized in the pulmonary parenchyma, bronchial wall, and muscle. at the level of the pons, the pedunculopontine tegmentum, the lc, the lateral parabrachial and kölliker-fuse nuclei are involved in the automatic respiratory control [ ] ( table ) . automatic and voluntary control of respiratory motor neurons can be injured together or separately. for instance, automatic control is impaired in central congenital and acquired hypoventilation syndrome (i.e., ondine syndrome), while voluntary control is preserved [ ] . acquired hypoventilation syndrome can result from brainstem tumoral, traumatic, ischemic, and inflammatory injuries [ ] , which implies the need for long-term mechanical ventilation. ventilator management may be significantly affected by brainstem lesions, and importantly, clinical features of neurological respiratory dysfunction are related to the localization of brainstem injury. the more caudal the lesion is, the more it is associated with an impairment of the respiratory drive. midbrain injuries do not usually affect the respiratory rate (rr). injuries to the upper pons increase the tidal volume and decrease the rr, while injuries of the lower pons are associated with respiratory asynchrony (e.g., ponto-peduncular injury). ataxic breathing (irregular pauses and apnea periods) and central apnea are observed in rostro-ventral medulla oblongata injuries and associated with poor outcomes. central neurogenic hyperventilation results from activation of the medullary respiratory center. finally, yawning or refractory hiccups may be seen with lesions of the posterolateral medulla oblongata [ ] . swallowing impairment contributes also to the difficulty of weaning mechanical ventilation and can be an indication for a tracheostomy. there are various structural and non-structural causes of neurological respiratory dysfunction, including infratentorial lesions, drug toxicity, heart failure, and sepsis [ ] [ ] [ ] . diagnosis relies on standard assessments of brainstem lesions can result in absent or delayed peaks iii and v, prolonged iii-v and i-v inter-peak latency, or a reduced i/v amplitude ratio (< . ) delay or absence of r indicates a facial /trigeminal nerve injury. r can be delayed in comatose patient and is also bilaterally delayed or absent in wallenberg's syndrome (with a r preserved) respiratory function (e.g., ventilator curves, tidal volumes (vt), and rr in mechanically ventilated patients) but also on assessing the ventilatory response to hypercapnia (e.g., during a t-piece trial). an electromyogram of the respiratory muscles, notably the diaphragm, provides relevant information on the central drive. this technique may be helpful in patients that are impossible to wean from mechanical ventilation. as a caveat, it may be at times difficult to differentiate central respiratory dysfunction from critical illness neuropathy/myopathy. emg and nerve conduction studies may help with the distinction, but limited assessments of every respiratory muscle group and available at highly specialized units limit this approach [ ] . in mechanically ventilated patients, spirography can be performed (with the vt/inspiration duration (ti) ratio reflects the ventilatory command intensity) as well as the occlusion pressure measurement (i.e., p . ). the latter reflects the "unconscious"/central respiratory command, but variability of its measurements limits routine application. the leading causes of primary brainstem dysfunction are summarized in table and major differential diagnosis of brainstem dysfunction in table . in the following section, we will discuss evidence for brainstem dysfunction encountered in critically ill patients beyond primary brainstem dysfunction. the "brainstem dysfunction" hypothesis originates from our study on usefulness of neurological examination in non-brain-injured critically ill patients who required deep sedation. these patients have usually a severe critical illness and therefore a higher risk to develop severe secondary brain insult [ , ] . furthermore, protracted deep sedation is still required in more than % of critically ill patients [ ] and has been reported to be associated with increased mortality [ ] . we found that assessment of brainstem reflexes was reproducible in this population [ , ] . we also found that routinely used sedative and analgesic agents such as midazolam and fentanyl do not impair pupillary light, corneal, and cough reflexes in % of cases but depress oculocephalic response and grimacing to painful stimulation (absent in and %, respectively) [ , , ] . the cessation of brainstem reflexes results from the combining effects of critical illness (i.e., secondary brain insult), sedative, and analgesic agents. it is interesting to note that guedel observed more than years ago that sedative drugs abolish brainstem reflexes according to a sequential pattern (the loss of consciousness, followed by the cessation of brainstem reflexes in a rostro-caudal way until apnea) [ ] . in deeply sedated non-brain-injured critically ill patients, the cessation of brainstem responses follows two distinct patterns. the first is characterized by a depression of whole brainstem responses (similar to guedel's description), and the second is characterized by a preferential impairment of the corneal reflex, the pupillary light reflex, and to a lesser extent the cough reflex, with paradoxical preservation of the oculocephalic response. the latter profile is associated with the severity of critical illness and the depth of sedation. interestingly, this pattern cannot be ascribed to a unique focal brainstem lesion which most likely relies on a functional rather than a structural origin. this suggests that some neuroanatomical centers are more sensitive to deep sedation, critical illness, or both. opioids might also contribute to brainstem dysfunction, as they depress the aras, respiratory centers, and brainstem reflexes (notably pupillary light and cough reflexes). however, morphine infusion rates did not differ in our study between the two cessation patterns of brainstem reflexes [ ] . to assess brainstem reactivity in deeply sedated critically ill patients, we developed the brass [ ] ( table ). the principle of the brass development is not in agreement with the traditional paradigm of jackson, which states that the brainstem reflexes are abolished in a rostro-caudal way. it thus differs from the four score [ ] , which conditions the assessment of the cough reflex to the cessation of the pupillary light and corneal reflexes. besides improving the prediction of mortality in deeply sedated patients, the assessment of brainstem reflexes, with help of either the brass or the four score, might prompt the icu physician to perform a brainstem imaging. it is however likely that the processes involved in critical illness-related brainstem dysfunction are radiologically assessable. neurophysiological tests provide further arguments for brainstem dysfunction in critically ill patients without primary brainstem injury. for instance, eeg is not reactive in % of patients with sepsis [ , ] , knowing that absence of reactivity can result from a dysfunction of the aras [ ] [ ] [ ] [ ] . middle latency baep responses and ssep latencies were increased in % and % of deeply sedated non-brain-injured critically ill patients, respectively [ ] , indicating an impairment of the brainstem conduction. interestingly, mean values of these latencies did not differ from those recorded in deeply sedated brain-injured patients. critical illness is also associated with decreased variability in hr and bp, with an impaired sympathetic tone and baroreflex [ , ] and also with a reduced tidal volume variability [ ] that can correlate with weaning failure. since most of these findings concerned sedated patients, one may argue that sedative agents might be involved as a revealing or aggravating underlying insults. this hypothesis is further supported by the fact that increase in evoked potential latencies cannot be only ascribe to sedation since long-term swallowing disorders [ ] and aspiration pneumonia are more frequent in sepsis survivors [ ] . thus, a multimodal assessment of brainstem dysfunction in critical illness is warranted. the undergoing multicenter proretro study (clinicaltrials.gov: nct ) aims to evaluate a multimodal approach based on neurological examination and neurophysiological tests. neuroimaging and neuropathological studies show that the brainstem is prone to vascular, inflammatory, and excitotoxic insults [ ] . for instance, sepsis can be associated with impaired autoregulation of cerebral blood flow and microcirculatory dysfunction, which may compromise the brainstem perfusion. second, a multifocal necrotizing leukoencephalopathy involving the brainstem can be secondary to an intense systemic inflammatory response [ ] . finally, the neuro-inflammatory process can culminate in neuronal apoptosis, which is evidenced in brainstem autonomic nuclei in patients who died from septic shock or in experimental sepsis [ ] . interestingly, it has been shown that apoptosis of autonomic nuclei can induce hypotension in septic rat [ ] . both humoral and neural pathways can induce a neuroinflammatory process. the former involves the area postrema (fig. ) , which allows the diffusion of circulating inflammatory mediators into the brainstem; the latter involves mainly the vagal nerve, which mediates the transmission of peripheral inflammatory signals to the brainstem [ , ] . autonomic brainstem nuclei are regulated by these two pathways, which then play a major role in the control of systemic inflammatory response. finally, metabolic processes can be involved. it is well known that electrolyte disturbances but also renal and liver failure impair brainstem responses, as illustrated by centro-pontine myelinolysis or by usefulness of four score in hepatic encephalopathy [ ] . the predictive value of the neurological examination findings and neurophysiological responses has been assessed in critically ill patients. there is a proportional relationship between the brass value and mortality. interestingly, absence of a grimacing response associated with preserved oculocephalic responses is the most predictive of mortality [ ] , suggesting that prediction is better when first based on a combination of signs, and second, a decoupling process between the upper and lower part of the brainstem is involved [ ] . the absence of eeg reactivity and of ssep p response and increased p -n ssep latencies are associated with increased mortality [ , , ] . impaired hr variability and decreased sympathetic control are associated with mortality and organ failure [ ] . there are arguments for a relationship between delirium and brainstem dysfunction. the drugs currently used for treating delirium are involving brainstem receptors. thus, neuroleptics are antagonists of the dopamine d and serotoninergic ht a receptors that are prevalent in the brainstem [ ] . dexmedetomidine is a selective agonist of alpha- receptor, notably at the level of the lc [ ] . the role of the brainstem in patients with delirium is supported by these pharmacological data and further supported by neuropathological findings that demonstrate hypoxic and ischemic insults of the pons in delirious patients [ ] . absent oculocephalic responses and delayed middle-latency baep have been associated with delayed awakening or delirium after sedation discontinuation [ ] . in neuroanatomical point of view, it is likely that cessation of the oculocephalic response reflects a dysfunction of the aras while cessation of the cough reflex reflects a dysfunction of the cardiovascular and respiratory autonomic nuclei. finally, if conceivable, we do not know to what extent brainstem dysfunction contributes to long-term post-icu mortality and functional disability. another contributing factor of the brainstem dysfunction in critical illness course might be the impaired sympatho-vagal control of the inflammatory response. the vagus nerve first senses and modulates peripheral inflammation, constituting the so-called cholinergic reflex [ ] ; second, it senses the microbiota metabolites, being a major component of the gut-brain axis [ ] ( table ). the adrenergic system controls the immune system, with alpha and beta- receptors being proinflammatory and beta- receptors anti-inflammatory [ ] . it is therefore conceivable that a brainstem-related neuro-immune impairment can contribute to infection, organ failure, or death by facilitating a maladapted immune response. the modulation of the cholinergic reflex by α nachr agonists and by vagal nerve stimulation has been proposed in sepsis and critical illness to improve peripheral immune response and reduce organ dysfunction [ ] . in addition to its peripheral immune effects, cholinergic modulation and vagal stimulation can promote anti-inflammatory microglial polarization [ ] . however, we shall remind that rivastigmine, a cholinesterase inhibitor, is deleterious in critically ill patients. vagal nerve stimulation is also proposed in refractory status epilepticus [ ] and consciousness disorders [ ] , suggesting its potential but not yet demonstrated effect in critical illness-related encephalopathy. beta-blockers reduce the mortality in cardiac diseases by attenuating the deleterious effects of sympathetic hyperactivation and increasing the vagal tone [ ] . in sepsis, betablockers improve hr control, reduce systemic inflammation, and decrease mortality, acknowledging that their routine use is not yet warranted [ , ] . brainstem dysfunction can present with central sensory and motor deficits, cranial nerve palsies and abnormal brainstem reflexes, disorders of consciousness, respiratory failure, and dysautonomia. clinical examination is essential for detecting a brainstem dysfunction that may be supported by neuroimaging, electrophysiological, autonomic, and respiratory assessments. brainstem dysfunction mainly results from secondary insult and might contribute to critical illness-related mortality, organ dysfunction, immune dysregulation, delayed awakening, and delirium. the assessment of the brainstem should then be included in the routine neuromonitoring of critically ill patients. the brainstem: anatomy, assessment, and clinical syndromes inappropriate sympathetic activation at onset of septic shock: a spectral analysis approach brainstem responses can predict death and delirium in sedated patients in intensive care unit apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock neuroanatomy and physiology of brain dysfunction in sepsis magnetic resonance imaging differential diagnosis of brainstem lesions in children locked-in syndrome movement disorders after stroke brain death: the european perspective pupillometry in anesthesia and critical care recommendations for the use of electroencephalography and evoked potentials in comatose patients neuroanatomical correlates of brainstem coma hypothalamic regulation of sleep and circadian rhythms the diagnosis of stupor and coma delirium as a predictor of long-term cognitive impairment in survivors of critical illness delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (cam-icu) unresponsive wakefulness syndrome: a new name for the vegetative state or apallic syndrome reply: response to « minimally conscious state or cortically mediated state? » the minimally conscious state: definition and diagnostic criteria practice guideline update recommendations summary: disorders of consciousness: report of the guideline development, dissemination, and implementation subcommittee of the american academy of neurology; the american congress of rehabilitation medicine; and the national institute on disability, independent living, and rehabilitation research electromagnetic brain stimulation in patients with disorders of consciousness restoring consciousness with vagus nerve stimulation altered functional connectivity in lesional peduncular hallucinosis with rem sleep behavior disorder a clinical research study of cognitive dysfunction and affective impairment after isolated brainstem stroke general anesthesia, sleep, and coma validation of a new coma scale: the four score european resuscitation council and european society of intensive care medicine guidelines for post-resuscitation care : section of the european resuscitation council guidelines for resuscitation monitoring sedation status over time in icu patients: reliability and validity of the richmond agitation-sedation scale (rass) brainstem response patterns in deeply-sedated critically-ill patients predict -day mortality intensive care delirium screening checklist: evaluation of a new screening tool the influence of therapeutics on prognostication after cardiac arrest prediction of « awakening » and outcome in prolonged acute coma from severe traumatic brain injury: evidence for validity of short latency seps prognostic value of evoked potentials and clinical grading in primary subarachnoid haemorrhage early impairment of intracranial conduction time predicts mortality in deeply sedated critically ill patients: a prospective observational pilot study the potential role of auditory evoked potentials to assess prognosis in comatose survivors from cardiac arrest the combined monitoring of brain stem auditory evoked potentials and intracranial pressure in coma. a study of patients the depression of the auditory nerve-brain-stem evoked response in hypoxaemia--mechanism and site of effect neurological prognostication of outcome in patients in coma after cardiac arrest value of eeg reactivity for prediction of neurologic outcome after cardiac arrest: insights from the parisian registry reactivity of dogs' brain oscillations to visual stimuli measured with noninvasive electroencephalography disruption of brain-heart coupling in sepsis early standard electroencephalogram abnormalities predict mortality in septic intensive care unit patients value and mechanisms of eeg reactivity in the prognosis of patients with impaired consciousness: a systematic review late blink reflex changes in lateral medullary lesions. an electrophysiological and neuro-anatomical study of wallenberg's syndrome blink reflexes in severe traumatic coma overview of the anatomy, physiology, and pharmacology of the autonomic nervous system baroreflex sensitivity: mechanisms and measurement correlation of cardiac arrhythmias with brainstem compression in patients with intracerebral hemorrhage physiologic changes during brain stem death--lessons for management of the organ donor assessment of autonomic function in humans by heart rate spectral analysis pupil findings in a consecutive series of patients with generalised autonomic neuropathy pre-bötzinger complex: a brainstem region that may generate respiratory rhythm in mammals looking for inspiration: new perspectives on respiratory rhythm effects of hypercapnia and hypocapnia on ventilatory variability and the chaotic dynamics of ventilatory flow in humans brainstem integration of arousal, sleep, cardiovascular, and respiratory control the cerebral cost of breathing: an fmri case-study in congenital central hypoventilation syndrome central alveolar hypoventilation syndromes persistent hiccups (singultus) as the presenting symptom of lateral medullary syndrome does high-dose buprenorphine cause respiratory depression?: possible mechanisms and therapeutic consequences creactive protein is elevated in heart failure patients with central sleep apnea and cheyne-stokes respiration a mechanism of central sleep apnea in patients with heart failure dyspnea and surface inspiratory electromyograms in mechanically ventilated patients early sedation with dexmedetomidine in critically ill patients historical vignettes: dr. arthur ernest guedel - the relationship of the four score to patient outcome: a systematic review reduced breathing variability as a predictor of unsuccessful patient separation from mechanical ventilation acute and long-term dysphagia in critically ill patients with severe sepsis: results of a prospective controlled observational study readmission diagnoses after hospitalization for severe sepsis and other acute medical conditions multifocal necrotizing leukoencephalopathy in septic shock dysfunction of the mitochondrial respiratory chain in the rostral ventrolateral medulla during experimental endotoxemia in the rat neural mechanisms of inflammation-induced fever signaling the brain in systemic inflammation: role of sensory circumventricular organs four score, a reliable score for assessing overt hepatic encephalopathy in cirrhotic patients heart rate variability as predictor of mortality in sepsis: a prospective cohort study antipsychotic use and diagnosis of delirium in the intensive care unit dexmedetomidine: what next? brain autopsy findings in icu patients previously suffering from delirium: a pilot study the vagus nerve and the inflammatory reflex--linking immunity and metabolism the vagus nerve at the interface of the microbiota-gut-brain axis adrenergic regulation of innate immunity: a review stimulation of the α nicotinic acetylcholine receptor protects against sepsis by inhibiting toll-like receptor via phosphoinositide -kinase activation activation of the α nicotinic receptor promotes lipopolysaccharide-induced conversion of m microglia to m vns for refractory status epilepticus heart rate control with adrenergic blockade: clinical outcomes in cardiovascular medicine. vasc health risk manag systematic review of use of β-blockers in sepsis the effect of beta-adrenergic blockade on inflammatory and cardiovascular responses to acute mental stress publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank the reviewers for their comments and suggestions to improve our manuscript. authors' contributions sb, am, br, and ea drafted the manuscript. jc, crs, vb, and ts critically revised the manuscript for important intellectual content. all authors read and approved the final manuscript. availability of data and materials not applicable ethics approval and consent to participate key: cord- -oep grwq authors: li, yuting; li, hongxiang; zhang, dong title: comparison of t-piece and pressure support ventilation as spontaneous breathing trials in critically ill patients: a systematic review and meta-analysis date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: oep grwq background: the effect of alternative spontaneous breathing trial (sbt) techniques on extubation success and other clinically important outcomes is uncertain. a systematic review and meta-analysis was performed to clarify the preferable sbt (t-piece or pressure support ventilation [psv]). methods: we searched the pubmed, cochrane, and embase databases for randomized controlled trials (rcts) from inception to the st of july . we included rcts involving adult patients (> years) who underwent at least two different sbt methods. all authors reported our primary outcome of successful extubation rate and clearly compared ps versus t-piece with clinically relevant secondary outcomes (rate of reintubation, icu and hospital length of stay, and icu and hospital mortality). results were expressed as odds ratio (or) and mean difference (md) with accompanying % confidence interval (ci). results: ten rcts including patients were included. the results of this meta-analysis showed that there was no significant difference in the successful extubation rate between the t-piece group and ps group (odds ratio [or] = . ; % ci, . – . ; p = . ; i( ) = %). in addition, compared with the ps group, the t-piece group showed no significant difference in the rate of reintubation (odds ratio [or] = . ; % ci, . – . ; p = . ; i( ) = %), icu mortality (odds ratio [or] = . ; % ci, . – . ; p = . ; i( ) = %), hospital mortality (odds ratio [or] = . ; % ci, . – . ; p = . ; i( ) = %), icu length of stay (mean difference = − . ; % ci, − . to . ; p = . ; i( ) = %), and hospital length of stay (mean difference = − . ; % ci, − . to . ; p = . ; i( ) = %). conclusions: t-piece and psv as sbts are considered to have comparable predictive power of successful extubation in critically ill patients. the analysis of secondary outcomes also shows no significant difference in the rate of reintubation, icu and hospital length of stay, and icu and hospital mortality between the two groups. further randomized controlled studies of sbts are still required. t-piece and psv as sbts are considered to have comparable predictive power of successful extubation in critically ill patients. further randomized controlled studies of sbts are still required to confirm our results. mechanical ventilation is often required in patients with critical illness, but after recovery from the acute illness, several problems can impair the successful separation of the patient from the ventilator [ ] . weaning from mechanical ventilation is one of the most important and challenging problems for most intensive care unit (icu) patients. it is well known that weaning failure is associated with longer use of mechanical ventilation, higher infection rate, longer icu stay, longer hospital stay, and higher mortality rate [ ] . a spontaneous breathing trial (sbt) is most often performed to assess the ability of a patient to sustain spontaneous breathing when extubated [ ] . the most common modes of sbt are t-piece ventilation and pressure support ventilation (psv), lasting between min and h [ ] [ ] [ ] . discontinuation of mechanical ventilation should be accomplished when the patient's ability to breathe unassisted is identified. both premature and delayed ventilator discontinuation are associated with significant morbidity. daily spontaneous breathing trials (sbts) are the current evidence-based standard of care in determining the time of ventilator discontinuation. when patients are ready to wean, the weaning process should be initiated with the first sbt as soon as possible. nevertheless, about - % of the patients will be re-intubated even if they are able to tolerate (or pass) the sbt [ ] . a recent meta-analysis suggested that patients undergoing ps (vs t-piece) sbts appear to be % more likely to be extubated successfully and, if the results of an outlier trial are excluded, % more likely to pass an sbt [ ] . another meta-analysis found that psv might be superior to t-piece with regard to weaning success for simple-towean subjects. for the prolonged-weaning subgroup, however, t-piece was associated with a shorter weaning duration [ ] . a latest large-scale multicenter randomized controlled trial found that an sbt consisting of min of psv, compared with h of t-piece ventilation, led to significantly higher rates of successful extubation [ ] . moreover, the latest american thoracic society guidelines for weaning recommend psv sbts with moderate-quality evidence [ ] . thus, further research is needed to determine the best approach for sbts. in this study, we conducted a meta-analysis, which extracted results from published randomized controlled trials (rcts) to evaluate the effectiveness and safety of two strategies, a t-piece and psv, for weaning adult patients with respiratory failure that required mechanical ventilation, measuring extubation success and other clinically important outcomes. this systematic review and meta-analysis is reported according to the preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines [ ] . ethical approval was not necessary for this study because it was a review of the published literature. we searched the pubmed, cochrane, and embase databases for rcts from inception to the st of july using the following search terms: spontaneous breathing trial, t-piece, t-tube, pressure support ventilation, pressure support, weaning, ventilator weaning, mechanical ventilation. the search was slightly adjusted according to the requirements of the different databases. the authors' personal files and reference lists of relevant review articles were also reviewed. the flow chart of the search strategies is summarized in fig. . the primary outcome was successful extubation rate, and successful extubation was defined as remaining free of invasive mechanical ventilation h after the first sbt [ ] . secondary outcomes were rate of reintubation among patients who were extubated after the sbt, icu, and hospital length of stay, and icu and hospital mortality. weighted means were calculated based on the number of patients in each study. the inclusion criteria were as follows: ( ) randomized controlled trials; ( ) adult patients (> years) who underwent at least two different sbt methods; ( ) all authors reported our primary outcome of successful extubation rate; ( ) clearly comparing ps versus t-piece with clinically relevant secondary outcomes. we excluded nonrandomized controlled trials and studies without clear comparisons of the outcomes. in addition, we excluded studies evaluating sbt methods in patients with tracheotomy and in patients receiving noninvasive ventilation. two reviewers (yl and hl) independently performed quality assessment using the cochrane collaboration's tool for assessing risk of bias [ ] . the specific elements were adequacy of the methods used to minimize bias through: ( ) randomization sequence (selection bias), ( ) allocation concealment (selection bias), ( ) blinding of study personnel and participants (performance bias), ( ) blinding of outcome assessors (performance bias), ( ) complete reporting of data without arbitrarily excluded patients and with low to minimal loss to follow-up (attrition bias), ( ) selective reporting bias, and ( ) other sources of bias. satisfactory performance, unclear performance, and unsatisfactory performance of each domain from the tool is denoted by green, yellow, and red colors respectively. the risk of bias summary is presented in fig. ; the risk of bias graph is presented in fig. . statistical analyses were performed using review manager version . (revman, the cochrane collaboration, oxford, uk). risk ratio (rr) with % confidence intervals (ci) was calculated for dichotomous variables. as to the continuous variables, mean difference (md) and % ci was estimated as the effect result. a random-effects model was used to pool studies with significant heterogeneity, as determined by the chi-squared test (p < . ) and inconsistency index (i ≥ %) [ ] . some of the selected continuous variables were represented by the median (interquartile range). we calculated their mean and standard deviation according to the sample size with a calculator [ ] , and then performed meta-analysis. a p value < . was set as the threshold of statistical significance. the search strategy identified studies, and the data were from rcts comprising patients (table ) [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the characteristics of the included studies are shown in table . a total of eligible studies were published between and . among these studies, studies were conducted in spain, studies were conducted in croatia, studies were conducted in brazil, study was conducted in korea, study was conducted in switzerland, study was conducted in thailand, and study was conducted in china. of these studies, three were multi-center studies [ , , ] and seven were single-center studies [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the interventions of ps and t-piece included in the meta-analysis are outlined in table . a total of rcts including patients were included, and the successful extubation rate was about . % ( / in the t-piece group and / (fig. ) . a funnel plot was used to assess the publication bias (fig. ) . five of included studies were analyzed to assess the rate of reintubation. the rate of reintubation was about . % ( / in the t-piece group and / in the ps group). there was no statistically significant difference in the rate of reintubation between groups (odds ratio [or] = . ; % ci, . - . ; p = . ; chi = . ; i = %) (fig. ) . three of the included studies were analyzed to assess the icu mortality. there was no statistically significant difference in the icu mortality between groups (odds ratio [or] = . ; % ci, . - . ; p = . ; chi = . ; i = %) (fig. ) . three of included studies were analyzed to assess the hospital mortality. there was no statistically significant difference in the hospital mortality between groups (odds ratio [or] = . ; % ci, . - . ; p = . ; chi = . ; i = %) (fig. ) . four of included studies were analyzed to assess the icu length of stay. there was no statistically significant (fig. ). four of included studies were analyzed to assess the hospital length of stay. there was no statistically significant difference in the hospital length of stay between groups (mean difference = − . ; % ci, − . to . ; p = . ; chi = . ; i = %) (fig. ). this systematic review and meta-analysis of ten unique rcts including patients compared tpiece and pressure support ventilation as spontaneous breathing trials in critically ill patients. we found that the overall successful extubation rate was about . % and there was no significant difference of successful extubation rate between the t-piece group and ps group. extubation failure may occur because of upper-airway obstruction, ineffective cough, and excessive respiratory secretions that cannot be managed by the patient [ ] . another potential reason for extubation failure is loss of positive pressure in the chest after extubation in subjects weaned to psv [ ] . psv allows patients to retain control over respiratory rate and timing, inspiratory flow rate, and tidal volume. in addition, physicians can modulate a satisfactory workload for the patients by monitoring breathing frequency and accessory muscle activity during psv. because of these potential advantages, the value of psv as a technique to gradually withdraw ventilator support is generally recognized for patients who have weaning difficulties [ ] . sklar et al. [ ] recently pointed out that psv significantly reduces the work of breathing and pressure-time product compared to the t-piece, which could, in turn, more closely represent the post-extubation scenario. however, noninvasive mechanical ventilation (niv) dissemination as an adjunctive for extubation makes clinical interpretation of these data difficult [ ] . the major finding of our study suggests that both spontaneous breathing using t-piece and psv are suitable methods for successful extubation of patients with critical illness from mechanical ventilation. the main goal of a weaning trial is to identify patients who are able to breathe without a ventilator with the minimum risk of extubation failure and its potential complications [ ] . daily screening of respiratory function by sbt is associated with a shorter duration of mechanical ventilation [ ] . after a successful sbt and extubation, to % of patients require reintubation, and reintubation is associated with higher mortality [ , ] . in this meta-analysis, the reintubation rate was not significantly different between the groups (about . %), which is lower than the % in the first study by esteban et al. [ ] and similar to the % in their second study [ ] . conversely, the reintubation rate was higher than in a study by perren et al. [ ] ( % for short sbts and % for long sbts), but that study has a singlecenter design and the small sample size precludes direct comparison. hospital mortality and icu mortality were not statistically significant different between groups. icu or hospital mortality may be not directly related to the sbt technique which is the intervention that is applied for a very short period during the course of icu admission. patient mortality is associated with prolonged intubation or unsuccessful weaning and they significantly increased medical costs because of extended hospitalization. besides this, we also found that hospital length of stay and icu length of stay were not statistically significant different between groups. this finding can be explained by the reintubation rate, apache ii score at admission, and the overall successful extubation rate, which were not significantly different between the groups. a variety of workers have indicated that continuous positive airway pressure of cm h o, typically considered as minimal support, decreases patient work of breathing by as much as %. pressure support of cm h o also decreases patient work of breathing by to % [ , ] . the vast majority of patients can cope with a to % increase in work of breathing at the point of extubation, but a fragile patient may not [ ] . the small population of marginal patients will likely require reintubation. reintubation is associated with a significant mortality rate. it is necessary to look for the high-risk patient and treat all patients as vulnerable and assess their ability to breathe. our meta-analysis has several characteristics: ( ) we conducted a systematic search of several databases to identify all rcts comparing t-piece and psv sbt techniques in weaning subjects. ( ) we employed standardized techniques to assess risk of bias and overall quality of evidence. this meta-analysis is associated with several limitations. first, the number of included studies is small. further randomized clinical trials should be conducted in order to assess whether or not psv is safer and more effective compared to the t-piece method for achieving relevant clinical outcomes among adult patients with at least h of invasive ventilation. second, many of the secondary outcomes such as hospital length of stay or hospital mortality were not included in all of the studies examined in this meta-analysis. third, the rate of sbt success is also very important because successful extubation after passing the sbt will be also related to upper airway patency and adequacy of secretion clearance. only if the patients have the above conditions can they pass the sbts. however, not all of included studies showed this data. fourth, there was substantial heterogeneity among the included studies. therefore, our findings should be interpreted with caution. t-piece and psv as sbts are considered to have comparable predictive power of successful extubation in critically ill patients. the analysis of secondary outcomes also shows no significant difference in the rate of reintubation, icu and hospital length of stay, and icu and managing the apparent and hidden difficulties of weaning from mechanical ventilation extubation failure after successful spontaneous breathing trial: prediction is still a challenge! respir care effort to breathe with various spontaneous breathing trial techniques. a physiologic meta-analysis mechanical ventilation international study group. characteristics and outcomes in adult patients receiving mechanical ventilation: a -day international study characteristics and outcomes of ventilated patients according to time to liberation from mechanical ventilation evolution of mechanical ventilation in response to clinical research outcomes of extubation failure in medical intensive care unit patients trials directly comparing alternative spontaneous breathing trial techniques: a systematic review and meta-analysis spontaneous breathing trials with t-piece or pressure support ventilation effect of pressure support vs t-piece ventilation strategies during spontaneous breathing trials on successful extubation among patients receiving mechanical ventilation: a randomized clinical trial liberation from mechanical ventilation in critically ill adults: executive summary of an official preferred reporting items for systematic reviews and meta-analyses: the prisma statement cochrane handbook for systematic reviews of interventions the exact distribution of cochran's heterogeneity statistic in one-way random effects meta-analysis estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range extubation outcome after spontaneous breathing trials with t-tube or pressure support ventilation. the spanish lung failure collaborative group effect of an additional -hour t-piece trial on weaning outcome at minimal pressure support extubation after breathing trials with automatic tube compensation, t-tube, or pressure support ventilation comparison of pressure support and t-tube weaning from mechanical ventilation: randomized prospective study chronic obstructive pulmonary disease and weaning of difficult-to-wean patients from mechanical ventilation: randomized prospective study comparison of pressure support ventilation and t-piece in determining rapid shallow breathing index in spontaneous breathing trials comparison of proportional assist ventilation plus, t-tube ventilation, and pressure support ventilation as spontaneous breathing trials for extubation: a randomized study an open label randomized controlled trial to compare low level pressure support and t-piece as strategies for discontinuation of mechanical ventilation in a general surgical intensive care unit pressure-support ventilation or t-piece spontaneous breathing trials for patients with chronic obstructive pulmonary disease -a randomized controlled trial weaning from mechanical ventilation outcome of reintubated patients after scheduled extubation effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously weaning from the ventilator and extubation in icu risk factors and outcomes for airway failure versus non-airway failure in the intensive care unit: a multicenter observational study of extubation procedures spanish lung failure collaborative group. effect of spontaneous breathing trial duration on outcome of attempts to discontinue mechanical ventilation protocol-directed weaning from mechanical ventilation: clinical outcome in patients randomized for a -min or -min trial with pressure support ventilation extubation and the myth of "minimal ventilator settings pressure-time product during continuous positive airway pressure, pressure support ventilation, and t-piece during weaning from mechanical ventilation physiologic basis of mechanical ventilation not applicable. this work was supported by the project of natural science foundation of jilin province (no. jc). all data generated or analyzed during this study are included in this published article. authors' contributions yl searched the scientific literature and drafted the manuscript. hl contributed to the conception and design and data interpretation. hl also helped to collect the data and performed the statistical analyses. dz contributed to the conception and design, data interpretation, manuscript revision for critical intellectual content, and supervision of the study. all authors read and approved the manuscript.ethics approval and consent to participate not applicable. not applicable. the authors declare that they have no competing interests. key: cord- -mu u bvj authors: wiesen, jonathan; komara, john j; walker, esteban; wiedemann, herbert p; guzman, jorge a title: relative cost and outcomes in the intensive care unit of acute lung injury (ali) due to pandemic influenza compared with other etiologies: a single-center study date: - - journal: ann intensive care doi: . / - - - sha: doc_id: cord_uid: mu u bvj background: critical illness due to h n influenza has been characterized by respiratory complications, including acute lung injury (ali) or acute respiratory distress syndrome (ards), and associated with high mortality. we studied the severity, outcomes, and hospital charges of patients with ali/ards secondary to pandemic influenza a infection compared with ali and ards from other etiologies. methods: a retrospective review was conducted that included patients admitted to the cleveland clinic micu with ali/ards and confirmed influenza a infection, and all patients admitted with ali/ards from any other etiology from september to march . an itemized list of individual hospital charges was obtained for each patient from the hospital billing office and organized by billing code into a database. continuous data that were normally distributed are presented as the mean ± sd and were analyzed by the student’s t test. the chi-square and fisher exact tests were used to evaluate differences in proportions between patient subgroups. data that were not normally distributed were compared with the wilcoxon rank-sum test. results: forty-five patients were studied: in the h n group and in the noninfluenza group. mean ± sd age was similar ( ± and ± years, respectively, p = . ). h n patients had lower apache iii scores ( ± vs. ± , p = . ) and had higher pplat and peep on days , , and . hospital and icu length of stay and duration of mechanical ventilation were comparable. sofa scores over the first weeks in the icu indicate more severe organ failure in the noninfluenza group (p = . ). hospital mortality was significantly higher in the noninfluenza group ( vs. %, p = . ). the noninfluenza group tended to have higher overall charges, including significantly higher cost of blood products in the icu. conclusions: ali/ards secondary to pandemic influenza infection is associated with more severe respiratory compromise but has lower overall acuity and better survival rates than ali/ards due to other causes. higher absolute charges in the noninfluenza group are likely due to underlying comorbid medical conditions. the spread of a novel h n strain of the influenza a virus represents the first pandemic of the st century and the first influenza pandemic since [ ] . compared with seasonal influenza, this strain was more prevalent in younger-aged individuals, obese patients, and pregnant women [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . severe cases of pandemic h n resulted in respiratory failure thought to be secondary to direct cell damage and systemic cytokine release resulting in acute lung injury (ali) or acute respiratory distress syndrome (ards) requiring prolonged ventilatory assistance and the frequent use of rescue therapies [ , , , [ ] [ ] [ ] [ ] [ ] . limited data exist that compare the clinical differences between ali in h n patients and ali arising from other etiologies. furthermore, whereas a number of studies have assessed different aspects of the economic impact of the recent pandemic [ ] [ ] [ ] [ ] , few have focused on the health care cost of the pandemic, particularly the utilization of limited icu resources. we report the severity, clinical outcomes, and hospital charges of ali/ards secondary to pandemic influenza a infection compared with ali/ards from other etiologies during a similar period of time. based on clinical bedside observations and published reports [ , , ] , we hypothesize that ali/ards secondary to pandemic influenza is associated with similar icu outcomes but increased resource utilization and higher hospital charges due to the frequent need for rescue interventions and prolonged ventilatory assistance. the study was approved by the human investigation committee of the cleveland clinic foundation (ccf) (institutional review board approval # - ) as a retrospective, single-center study at the ccf medical icu. patients were identified from a unit-based acute lung injury screening database (cleveland clinic is one of the centers participating in the ardsnetwork) and the h n patient log maintained during the fall-winter season of - . patients were included if they met criteria for ali (pao /fio ≤ ; acute bilateral infiltrates; positive pressure ventilation via endotracheal tube; and no clinical evidence of left atrial hypertension or congestive heart failure) between the months of september to march -the time that influenza infection was most prevalent. diagnostic methods for influenza a virus detection consisted of rapid antigen testing, polymerase chain reaction (rtpcr), and viral culture from nasopharyngeal swabs, tracheal aspirates, and bronchioalveolar lavage specimens. the patients were grouped into two categories: those with laboratoryproven h n infection; and those in whom h n was not clinically suspected. only patients with confirmed infection were included in the influenza group to ensure that the clinical course of the disease was accurately captured. patients were excluded from the study if they did not meet the above criteria for ards, or if clinical suspicion pointed to a likely pandemic viral infection with negative diagnostics. a research electronic data capture (redcap) database was constructed with a complete listing of the patient's demographic and clinical information, including age, gender, height, weight, body mass index (bmi), presenting symptoms, past medical history, primary reason for admission to the icu, vital signs, presence of vasopressors, laboratory values, ventilator settings and respiratory parameters, acute physiology and chronic health evaluation (apache) iii and sequential organ failure assessment (sofa) scores on admission to the micu, number of intubated days, duration of icu and hospital stay, mortality, and rescue therapies (namely inhaled nitric oxide, proning, high-frequency oscillatory ventilation, and extracorporeal membrane oxygenation [ecmo]) [ ] . the data collection was de-identified and collected in accordance with hipaa guidelines. as part of the routine micu respiratory therapy protocol, mechanical ventilation parameters are recorded every hours. all patients are managed according to a mechanical ventilation protocol that incorporates the use of nonconventional modes when a lung protective strategy on conventional modes failed to provide adequate oxygenation. the following criteria were used to define the analyzed parameters: ) mode of ventilation: the mode of ventilation that was used for the longest time for a given day; ) pao /fio : worst daily ratios were recorded; ) plateau pressure (pplat): for patients on volume control ventilation the airway pressure was measured after a -second inspiratory hold without concomitant active inspiratory efforts, and for patients on pressure control ventilation (pcv) the highest total system pressure (peep + inspiratory pressure) was recorded; ) positive end expiratory pressure (peep): the value corresponding to the highest peep for the day was recorded; ) tidal volume (vt): the largest daily volume was recorded. respiratory data were captured on the first day of intubation (day ) and then on subsequent days , , and of mechanical ventilation. there were no differences in ventilator protocols or management between the two groups. an itemized bill of individual charges for each patient was obtained from the hospital billing office and was organized by billing code into the following categories: room/board, pharmacy, supplies, laboratory, radiology, surgical (including procedures performed under general anesthesia), blood products, respiratory services, dialysis, and miscellaneous (which included some professional fees, nonsurgical procedures and phlebotomy, and diagnostics not included in the other categories, such as electroencephalograms, electrocardiograms, echocardiograms, cardiac catheterizations, and vascular studies). the values represent the hospital charges for the aforementioned services rather than the actual reimbursement, which may be subject to more variability. the single-center nature of the study removes interfacility differences in clinical and billing practices. continuous data that were normally distributed are presented as the mean ± sd and were analyzed by the student's t test. the chi-square and fisher exact tests were used to evaluate differences in proportions between patient groups. in instances where the data were not normally distributed, the groups were compared with the wilcoxon rank-sum test. differences were considered statistically significant if the p value was < . . fifty-one patients were identified in the acute lung injury screening database between september and march . twenty-two met criteria for ali and did not have confirmed or suspected h n infection and were thus included in the noninfluenza group (ali/ards secondary to noninfluenza etiologies). thirty-six patients in the h n patient log had confirmed influenza a testing. of those, had ali requiring mechanical ventilation (mv) during their micu stay and were included in our analysis. demographics, presenting symptoms, past medical history, and acuity on admission are shown in table . patients in the influenza group tended to be younger with a higher bmi. patients in the influenza group presented more often with lower respiratory infection ( vs. %, p = . ) and had increased requirement for mechanical ventilation on admission to the icu ( vs. %, p = . ). on the other hand, the noninfluenza group had a higher propensity to present with shock requiring vasopressors ( vs. %, respectively, p = . ). the primary cause of ali in the h n group was pneumonia (n = ), whereas in the noninfluenza group the etiologies were more varied, including pneumonia (n = ), sepsis (n = ), aspiration of gastric contents (n = ), transfusion reaction (n = ), and other (n = ). whereas seven patients ( %) in the h n group were considered healthy, only one patient ( %) in the noninfluenza group had no comorbid medical conditions on admission to the icu (table ) . this difference is reflected in the lower mean apache iii score on admission to the icu in the h n group ( ± vs. ± , p = . ), despite similar sofa scores ( . ± . and . ± . , p = . ). there were no statistically significant differences between the two groups for initial laboratory data, including white blood cell count, platelets, serum creatinine, bilirubin, and creatinine kinase. the number of patients who developed acute renal failure that required dialysis throughout their icu stay was the same (n = ) in both groups. sofa scores on days , , , and of mechanical ventilation indicate that patients in the noninfluenza group had more severe organ failure during their icu stay (p = . ; table ). table shows oxygenation index and mechanical ventilation related parameters on days , , , and . there was a nonsignificant trend toward worsening hypoxia in the h n group, despite significantly higher peep and pplat on days , , and . tidal volumes were comparable throughout. plateau pressures in the h n group were high due to the relative decrease in pulmonary compliance in h n -related lung injury. four patients in both groups were ventilated with airway pressure release ventilation (aprv). more patients in the influenza group required rescue therapies on day of mechanical ventilation ( vs. , respectively, p = . ); however, similar numbers of patients in both groups required rescue therapies over the duration of mv ( and patients, respectively). rescue therapies in the h n group included inhaled no (n = ), ecmo (n = ), prone ventilation (n = ), and high-frequency ventilation (n = ), and in the noninfluenza group only inhaled no (n = ) and prone ventilation (n = ). mechanical ventilation days were comparable between groups ( ± vs. ± days for groups i and ii, respectively, p = . ) as were -day ventilator-free days ( ± . and . ± , p = . ). four patients in the h n group and seven in the noninfluenza group underwent a tracheostomy procedure. hospital and icu los were comparable (median ± iqr: ± vs. . ± . and ± vs. ± . days for the influenza group and ii, respectively, wilcoxon p = . and . ). mortality was significantly higher for patients in the noninfluenza group ( vs. %, p = . ). interestingly, a kaplan-meier curve of icu mortality (figure ) indicates that patients in the h n group were more likely to be discharged alive from the icu when the length of stay was greater than days, despite a trend toward higher mortality within the first weeks. even though all charges were higher in the noninfluenza group, only the difference in blood products utilized in the icu was significant ( ± vs. ± thousands of u.s. dollars, wilcoxon p < . ; table ). differences in icu charges in pharmacy (p = . ), supplies (p = . ), radiology (p = . ), and miscellaneous (p = . ) were large but not significant due to considerable variation. the proportion of charges in each of the major categories was similar between the groups (figure ). the average total icu cost per patient ( ± vs. ± thousands of u.s. dollars, wilcoxon p = . ) and the average icu cost per patient per day ( ± vs. ± thousands of u.s. dollars, wilcoxon p = . ) tended to be higher in the noninfluenza group. the fall of heralded the influx of patients suffering from severe hypoxic respiratory complications secondary to the pandemic h n influenza to icus across the country. due to the severity of pulmonary disease that many of these patients experienced, perception among treating clinicians was that these patients would have a all values expressed as mean ± sd. using mixed models, the overall p value comparing the influenza and noninfluenza groups is . . the trend over time was not significant (p = . ). worse outcomes and consume more resources, as measured by hospital charges, than patients who developed ali from other etiologies. we demonstrated that, contrary to what was perceived, pandemic influenza a ali/ ards was associated with a lower acuity and, consequently, lower hospital mortality that ali/ards from other etiologies, and had a similar icu and hospital los. icu and total hospital charges reflected a trend toward higher overall charges for room and board, blood products, pharmacy, and overall charge per patient in the noninfluenza group. in accordance with other descriptive reports of pandemic influenza [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , patients who tested positive for h n infection, tended to be young (no patients > years old), obese ( had bmi > kg/m ), and in relatively good health ( % with no comorbid medical conditions). there were no pregnant patients in either group. compared with other studies of pandemic influenza patients who required mechanical ventilation, sofa scores (mean . ) were similar, although apache ii ( ± ) scores were higher [ ] [ ] [ ] [ ] , , , ] . the degree of respiratory compromise in our patients was more severe than other reports judging by the higher peep requirements and longer duration of mechanical ventilation, which was roughly double that reported in other studies [ ] [ ] [ ] , , , , , ] . plateau pressures in these studies were not consistently reported. however, despite significantly longer ventilation duration and prolonged icu and hospital stays, the mortality in our cohort was not higher than that seen in other studies, which ranged from - % in patients who required mechanical ventilation [ ] [ ] [ ] , , , , , ] . looking at the different patient characteristics between groups, it may be tempting to postulate that the higher rate of patients with pulmonary ards in the h n group, in contrast to prevalent nonpulmonary ards in the noninfluenza group, would correlate with a higher peep response among the latter [ ] . our findings suggest the contrary. patients in the h n group had higher mean plateau pressure, likely indicative of lower compliance. the similarity of pao /fio ratios in the two groups may be a reflection of higher peep values used in the h n group for lung recruitment, rather than being indicative of comparable degrees of lung injury. although assessing recruitability from this retrospective analysis is difficult and may be inaccurate, the higher peep used and the implication of lower compliance observed are predictors of potentially recruitable lung [ ] . these observations support the recent call for a reevaluation of the ali and ards criteria to account for this heterogeneity in the patient population [ ] . a number of important differences between the two cohorts emerged as well. as expected, the noninfluenza group was older, had more comorbid medical conditions, and less often presented to the icu with respiratory failure. the degree of ventilator support was significantly higher in the h n group on days , , and , and there was a trend to more severe hypoxemia during that time as well. nevertheless, the use of use of aprv and rescue therapies was comparable in both groups. despite more severe respiratory compromise, h n patients did not have longer time on the ventilator, longer icu or hospital stays, or higher mortality. although sofa scores were similar, the noninfluenza group had significantly higher apache iii scores, likely secondary to points assigned to comorbid medical conditions. the high acuity of illness, as well as the presence of severe comorbidities, such as solid and hematologic oncologic conditions ( patients), chronic renal insufficiency ( patients), and cirrhosis of the liver ( patients), likely contributed to the poor outcomes in the noninfluenza group. conversely, despite more severe respiratory compromise, patients in the h n group were more likely to recover due to their younger age and better overall health histories. the % mortality in the noninfluenza group was much higher than typically reported in clinical trials, with one notable exception [ ] . however, reports from tertiary care centers involving patient cohorts with similar underlying comorbid conditions have reported equally high mortality rates [ ] . our observation brings up an interesting point, namely the difference between the reported mortality in clinical trials and the observed mortality in a similar clinical condition affecting patients that would have been excluded from such trials due to coexisting comorbidities. a kaplan-meier plot of icu mortality (figure ) indicates that although patients in the h n group were less likely to survive the first days of icu care, those that did survive past day were more likely to be discharged alive from the hospital. patients in the noninfluenza group were unlikely to survive if their icu length of stay exceeded weeks. ards is among the most expensive conditions encountered in the icu [ ] . in , bellamy and oye described the charges of patients with ards, with the most expensive being room and board ( %), clinical laboratory ( %), pharmacy ( %), and inhalation therapy and ventilation ( %) [ ] . twenty-five years later, our study indicates that the aforementioned categories continue to represent the most expensive charges incurred by ards patients in the icu. the overall similarity of charges in room and board and respiratory therapy between the two groups is likely indicative of the comparative durations of hospitalization and mechanical ventilation. interestingly, despite higher ventilatory requirements and more severe hypoxemia in the h n group, respiratory charges were similar between the two groups, suggesting that the high cost of maintaining a patient on mechanical ventilation is independent of the degree of ventilator support necessary. thus, respiratory charges are more likely a reflection of duration of mechanical ventilation rather than the degree of ventilator support necessary. absolute icu charges for room and board, blood products, pharmacy, radiology, average daily charge, and overall charge per patient were larger in the noninfluenza group. icu charges for blood products in the noninfluenza group were greater by a factor of four, and pharmacy charges double that of the h n group. this finding is likely a reflection of the higher prevalence of underlying comorbid medical conditions in the noninfluenza group, such as malignancy and cirrhosis, which require expensive medications and predispose to anemia. moreover, the high mortality in this cohort likely precluded even higher hospital charges. nevertheless, the h n cohort amassed charges of similar magnitude to the most ill and expensive patients in the icu, indicating the abundant health care resources consumed by severe pandemic influenza infection. there are a number of limitations to our study. as a retrospective chart review rather than a prospective investigation, the information was culled from sources that were at times incomplete. second, the study contained a relatively small number of patients, and measures taken to ensure internal validity of each group, such as limiting the influenza group to confirmed h n infection and the noninfluenza group to the duration of the influenza season, further limited its size. additionally, whereas our study provides descriptive information relevant to the patient population of our institution and tertiary referral centers with similar acuity, other icus may be exposed to a different cohort of patients. on the other hand, as a single-center study, potential differences in clinical and billing practices could be minimized. although a comprehensive charge profile of each patient was generated, trends in the timing of charges could not be obtained. finally, the hospital charge data were mined from an extensive database divided by charge coding, and therefore, some charges may have been mislabeled or inappropriately categorized. our study provides interesting observations about the clinical course, outcomes, and cost of the h n influenza pandemic. although patients with severe pulmonary complications of pandemic influenza infection have poor oxygenation and require significant ventilatory support and rescue therapies, their younger age and tendency to have fewer comorbid medical conditions contribute to their improved prognosis compared with patients with ali from other causes. both groups of patients consume enormous amounts of hospital resources, and physicians and policy makers must be aware of this when future pandemics arise. world now at the start of influenza pandemic california pandemic (h n ) working group: severe h n influenza in pregnant and postpartum women in california pediatric hospitalizations associated with pandemic influenza a (h n ) in argentina critical care services and h n influenza in australia and new zealand extracorporeal membrane oxygenation for influenza a(h n ) acute respiratory distress syndrome critically ill patients with influenza a(h n ) in mexico intensive care adult patients with severe respiratory failure caused by influenza a (h n )v in spain critically ill patients with influenza a(h n ) infection in canada pandemic (h n ) : epidemiological, clinical and prevention aspects hospitalized patients with h n influenza in the united states pandemic (h n ) influenza writing committee of the who consultation on clinical aspects of pandemic (h n ) influenza, bautista e, chotpitayasunondh t: clinical aspects of pandemic influenza a (h n ) virus infection clinical management of pandemic influenza a(h n ) infection h n : viral pneumonia as a cause of acute respiratory distress syndrome ventilator management for hypoxemic respiratory failure attributable to h n novel swine origin influenza virus hospitalized patients with h n influenza infection: the mayo clinic experience clinical findings and demographic factors associated with icu admission in utah due to novel influenza a(h n ) infection the macroeconomic impact of pandemic influenza: estimates from models of the united kingdom, france, belgium and the netherlands cost-effectiveness analysis of hospital infection control response to an epidemic respiratory virus threat economic consequences to society of pandemic h n influenza -preliminary results for sweden effectiveness and cost-effectiveness of vaccination against pandemic influenza (h n ) research electronic data capture (redcap)-a metadata-driven methodology and workflow process for providing translational research informatics support severe refractory hypoxaemia in h n ( ) intensive care patients: initial experience in an asian regional hospital lung recruitment in patients with the acute respiratory distress syndrome epidemiology and outcomes of acute lung injury effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome adult respiratory distress syndrome: hospital charges and outcome according to underlying disease variable costs of icu patients: a multicenter prospective study relative cost and outcomes in the intensive care unit of acute lung injury (ali) due to pandemic influenza compared with other etiologies: a single-center study the authors declare that they have no competing interests.authors' contributions jw and jk were responsible for the data input. jw and jg composed the manuscript. hw provided editorial assistance. ew provided the statistical analysis. all authors read and approved the final manuscript. submit your manuscript to a journal and benefi t from: convenient online submission rigorous peer review immediate publication on acceptance open access: articles freely available online high visibility within the fi eld retaining the copyright to your article submit your next manuscript at springeropen.com key: cord- -mgrxo j authors: lee, james c.; diamond, joshua m.; christie, jason d. title: critical care management of the lung transplant recipient date: - - journal: curr respir care rep doi: . /s - - - sha: doc_id: cord_uid: mgrxo j lung transplantation provides the prospect of improved survival and quality of life for patients with end stage lung and pulmonary vascular diseases. given the severity of illness of such patients at the time of surgery, lung transplant recipients require particular attention in the immediate post-operative period to ensure optimal short-term and long-term outcomes. the management of such patients involves active involvement of a multidisciplinary team versed in common post-operative complications. this review provides an overview of such complications as they pertain to the practitioners caring for post-operative lung transplant recipients. causes and treatment of conditions affecting early morbidity and mortality in lung transplant recipients will be detailed, including primary graft dysfunction, cardiovascular and surgical complications, and immunologic and infectious issues. additionally, lung donor management issues and bridging the critically ill potential lung transplant recipient to transplantation will be discussed. since the modern era of lung transplantation began in with the first series of successful human lung transplants [ ], there have been remarkable advances in this potentially lifesaving procedure for thousands of patients with end-stage lung and pulmonary-vascular diseases. however, the overall survival rates of lung transplant recipients in comparison to other solid organ transplant recipients is lagging, due in part to the unique technical, immunogenic, and infectious aspects of transplanting human lungs [ ] . in more recent eras, survival has improved, largely due to improvements affecting the early post-transplant period [ ] . despite these improvements, early morbidity and mortality remain important limiting factors for long term success; therefore, early recognition and management of problems that arise before and after lung transplantation in the intensive care unit setting are key to the long term success of the recipient. this review aims to summarize the most important aspects of the critical care management of the lung transplant recipient in the peri-operative time period [ ] [ ] [ ] [ ] . donor management in the icu the continued relative lack of supply of organs in contrast to the increasing demand for lung transplantation has spurred interest in expanding the traditionally accepted definition of the "ideal" lung donor, whose criteria of age < , pao > , minimal smoking history, and clear chest x-rays have contributed to lung acceptance rates of less than % [ ] . one avenue to expand the pool beyond this seemingly restrictive definition is the use of "extended donors" with liberalized selection criteria. some transplant centers have shown that the use of these donors have comparable shortterm outcomes to "ideal donors." other centers have described prolonged icu stays and increased early mortality with the use of donor lungs with infiltrates and/or purulent secretions [ ] [ ] [ ] [ ] [ ] . aggressive donor management by the team caring for a potential lung donor may result in the improvement of the function of "extended" donor lungs closer to the range of "ideal" organ and thus increasing lung donor conversion rates [ ] [ ] [ ] . a protocol-based approach for the management of potential organ donors, and particularly the ventilator management of potential lung donors, is an effective way to standardize variation in practice styles in the community as well as improve donor conversion rates. the university of texas at san antonio showed that with protocols designed to incorporate standardized lung recruitment maneuvers, aggressive donor fluid management, and aspiration-reduction precautions, rates of lung procurement can be significantly increased. of actual donors during a year protocol period, % were lungs from patients initially considered poor donors [ ] . a similar experience in quebec showed that simple lung recruitment protocols can be instituted safely and effectively to increase procurement rates and organ availability, of particular importance in large geographic areas with limited donors [ ] . education of intensivists on care of the brain dead patient is key, as proper management of such patients may affect both procurement rates as well as lead to improved immediate post-transplant outcomes. reviewed recently by naik and angel [ • ], brain death elicits hemodynamic instability, activation of inflammatory pathways, and endocrine dysfunction that can profoundly impacts the quality and function of the donated lungs. in conjunction with an active local donor procurement organization, active donor management is necessary to treat these homeostatic derangements. mascia et al. showed in a survey of icus in italy, that there is a clear tendency towards maintaining potentially injurious ventilatory management strategies and not performing recruitment maneuvers after the pronouncement of brain death [ ] . this same group also recently demonstrated beneficial effects of employing lung protective ventilatory strategies (tidal volume - mg/kg predicted body weight, peep - cm h o) on potential lung donors in a randomized controlled trial compared to conventional ventilatory parameters (tidal volume - mg/kg predicted body weight, peep - cm h o) [ ] . of patients enrolled into the study, % of donors from the lung protective ventilator strategy group went on to donate lungs vs. % of conventional ventilatory strategy group. six month outcomes of lung recipients from both groups did not differ [ ] . the management of the predisposing advanced lung diseases in lung transplant candidates who become acutely ill while awaiting lung transplantation can pose a challenge to the critical care practitioner. given the sometimes unpredictable nature of donor availability, the icu care of such patients has the potential to be prolonged, during which time-sensitive issues such as nutritional status, functional capacity, and infection avoidance in an effort to maintain listing eligibility become the focus of care. since the institution of the lung allocation score (las) in in the u.s. [ ] , the concept of net survival benefit as a balance of risk of death on the waitlist vs. chance of survival at year has driven organ allocation, often assigning the highest scores to patients who are acutely ill and mechanically ventilated. traditionally, requirement for mechanical ventilation had been viewed as a contraindication for active listing at most lung transplant centers due to the fear for poor outcomes. as described by mason et al., after querying the united network for organ sharing for lung transplantation from october through january , these fears are not unfounded [ ••] . the authors showed that of , transplants performed, patients were on mechanical ventilation and were on extracorporeal membrane oxygenation (ecmo) at the time of transplantation, both factors that contribute to the highest las scores. survival rates at , , , and months were significantly worse in both mechanical ventilation and ecmo supported; patients; for example, year survival was % for the ecmo bridged patients vs. % for the unsupported patients. those patients that received mechanical ventilation tended to be younger, have higher oxygen requirement, poorer renal function, and diagnoses other than emphysema such as cystic fibrosis. of note, the increase in mortality seen in patients with pre-operative mechanical ventilation or ecmo support seemed to be limited to the early time period after lung transplant; patients who required aggressive support pretransplant who survived the first months had comparable long-term survival to those not requiring pre-transplant support [ ••] . therefore, these historical administrative data suggest that improvements in the pre-operative morbidity of these procedures, such as reducing sedation, paralytics, or immobility in the pre-operative critical-ill patients, could lead to reasonable long-term outcomes. in recent years, pre-operative life support of the potential recipient has evolved. the concept of "bridging to transplantation" involves the use of mechanical support systems to sustain a patient in respiratory failure until the lung transplant can be performed, often with concurrent aggressive rehabilitation and physical therapy if at all possible [ ••, ] . similar to advances in mechanical circulatory support in heart transplantation, technical advances in the redesign of circulatory pumps, membrane oxygenators, and venous catheters has now made less invasive ecmo support feasible without immobilizing or paralyzing the patient in most cases. smaller, bilumen catheters, introduced into the jugular vein and the inferior and superior vena cava to drain venous blood and simultaneously provide oxygenated blood into the right atrium [ ] , may potentially allow patients to be awake, nonventilated, and ambulatory during ecmo support. as this field is rapidly evolving, further research will need to be done on selection of appropriate patients [ , •, - ] . the immediate post-operative period in the icu remains the most critical for the lung transplant recipient, requiring continuous hemodynamic monitoring, often maximal ventilatory support, and close observation of chest tube output for evidence of bleeding or other surgical complications. aggressive peri-operative antibiotic coverage is employed, often tailored to pre-transplant culture data, with consideration of induction immunosuppression. often, newly instituted transplant medications have the potential for unforeseen side effects on the kidneys, central nervous system, and other organs. the following sections highlight the most important critical care issues in the post-operative lung transplant recipient. a comprehensive list of peri-operative complications is listed in table . the various etiologies of respiratory failure following lung transplantation have been reviewed [ ••, , ] and will also be addressed in sections below. the most frequent and significant cause of early mortality after lung transplantation is primary graft dysfunction (pgd), a form of injury to the allograft resulting in large part from ischemia-reperfusion injury from the transplant process itself. pgd affects up to % of all lung transplants, and it leads to prolonged mechanical ventilation and icu length of stay, poor functional outcomes, and an increased risk of bronchiolitis obliterans syndrome (bos) [ , ] . in its most severe form, pgd presents as diffuse alveolar infiltrates in the allograft in the absence of cardiogenic pulmonary edema, infection, or cellular rejection that can lead to refractory hypoxia. several clinical risk factors for pgd have been described, to which malnutrition the icu physician should be attuned in order to assess the possibility of pgd in the critically ill lung transplant recipient. these include donor characteristics such as female gender, african-american race, extremes of donor age, elevated pulmonary arterial systolic pressure at the time of transplant, obesity and pre-existing diagnoses of pulmonary arterial hypertension and idiopathic pulmonary fibrosis [ ] [ ] [ ] [ ] . surgical and intra-operative risk factors for pgd include blood product administration, single transplant procedure and use of cardiopulmonary bypass [ ] [ ] [ ] [ ] [ ] . as most prior studies are hampered by small numbers, several of these risk factors have been inconsistently reported. ongoing multi-centered prospective studies are underway to better understand the clinical risk factors for severe pgd. treatment of pgd is supportive. other potentially reversible etiologies (table ) should be ruled-out utilizing the information available to the icu physician such as pulmonary arterial catheter measurements, cvp, radiographs, bronchoscopy, and echocardiography. mechanical ventilator support should be continued while simultaneously avoiding excessive colloid or crystalloid administration. diuresis should be initiated with blood pressure support if needed, as the lung parenchyma is damaged with evidence of capillary leak [ ] . theoretical benefits of lung protective ventilator strategies (low stretch, high peep) are extrapolated from the ards literature. as a rescue therapy, pressurecontrolled ventilation modes may be preferentially utilized to minimize barotrauma and airway/anastomosis complications. inhaled nitric oxide, while not proven to be effective in preventing pgd [ ] , may have benefit in improving oxygenation, reducing mean pulmonary arterial pressure, and increasing mean systemic arterial pressure in the first - h after transplant [ ] . ventilator management of pgd in single lung transplants with copd can be challenging. acute hyperinflation and significant v/q mismatch can occur, perhaps necessitating dual-lumen independent lung ventilation which can be logistically challenging for the icu staff. in severe and refractory cases, ecmo has been applied in those pgd cases not responsive to traditional mechanical ventilation. in the university of pittsburgh published their experience with ecmo in heart-lung and lung transplant recipients over a year period. of patients, . % required ecmo, instituted within the first days after transplant; of patients were successfully weaned off ecmo. thirty day-, year-, and year-survival in this group was %, %, and % respectively [ •] . in this severely ill population, it has been shown that late institution of ecmo, or inability to wean off ecmo, has led to near universal poor outcomes [ •, ] . most recently, hartwig et al. have investigated whether the use of venovenous ecmo and improvements in icu technology have affected outcomes. at a center where venovenous ecmo was the routine treatment for severe pgd, over a year period of time, of patients required ecmo. patients were able to be weaned from ecmo % of the time, and survival was better than in previous reports: %, %, and % at day, year and years, respectively. while encouraging, the authors did notice worse allograft function in ecmo survivors at years [ ••] . this study illustrates that with evolving technology and increased experience, venovenous ecmo may be successfully utilized in very select cases of profound respiratory failure following lung transplantation. the lung transplant recipient with elevated pulmonary arterial pressures at the time of transplant or an underlying diagnosis of pulmonary arterial hypertension requires particularly close attention immediately after lung transplantation. the proper care of such patients begins prior to surgery, as the anesthesiologist should be vigilant to avoid sudden rises in pulmonary vascular resistance and subsequent right heart failure [ •]. intra-operative transesophageal echocardiography can be a useful tool to evaluate right ventricular function. pulmonary vasodilators such as inhaled nitric oxide, milrinone, and inhaled prostacyclin can reduce right ventricular afterload and expedite recovery of the rv in the post-operative state [ • ]. most transplant recipients will require vasopressors during the surgical procedure, and it is not uncommon to return to the icu with vasopressors being administered with the expectation of quick weaning of such agents. fluid management should be aimed at maintaining cardiac output but also minimizing pulmonary edema with active use of pulmonary arterial catheter measurements or echocardiography if available. arrhythmias after lung transplant are typically supraventricular in origin and are common, ranging between % and %. older patients seem particularly at risk for this complication [ ] . in a recent review of lung transplant recipients, atrial fibrillation occurred in % of patients within days after surgery, with a mean onset at . +/- days. mean icu stay and hospital stays are lengthened when atrial arrhythmias are experienced [ ] . in the icu, hemodynamically significant arrhythmias should be treated aggressively with cardioversion when indicated; otherwise, medical management will usually suffice. if these issues persist, consideration should be given to antiarrhythmic administration such as amiodarone, as well as initiation of anticoagulation. when bleeding complications are concurrent, this can be problematic. the propensity for intra-operative bleeding in lung transplant recipients can often be anticipated prior to the surgical procedure, with proper precautions taken. recipients with an underlying history of heart disease with coronary stents in place may chronically be on antiplatelet agents such as clopidogrel, which will increase the risk of bleeding substantially. additionally, patients with severe pulmonary hypertension may be on warfarin therapy that requires reversal. the explantation of native lungs can also lead to substantial bleeding; scarred lung parenchyma may be fibrotic and adherent to pleural surfaces, or inflamed and associated with chronic foci of infection such as in sarcoidosis or cystic fibrosis patients. other infections such as aspergillomas with reactive pleural involvement sometimes pose a prohibitive risk for bleeding during the explantation of native lungs and can lead to operative demise if significant. in the post-operative setting, bleeding risk must be monitored through serial laboratory studies, chest tube drainage measurements, and radiographs. rapidly enlarging effusions or "white out" of a lung field may indicate a significant pleural bleed, which may not be appreciated based on recorded output alone should the chest tube malfunction or be improperly positioned. differences in size matching present special challenges for management of the lung transplant recipient. lung transplant recipients with fibrotic lung diseases will tend to have smaller thoracic cavities for their height, and because of this, there may be difficulties finding properly size-matched donors. donor lungs may be volume reduced intraoperatively using linear stapling, though potential complications from this type of procedure include air leaks and bronchopleural fistula formation [ ] . if lungs are too big for the chest cavity in the immediate postoperative period, the team may choose to delay chest closure if the median sternotomy approach is used, for instance. in the post-operative state, patients with open chests require specialized nursing attention and broadened antibiotic and antifungal coverage. size mismatches of donor lungs that are too small for a thoracic cavity may lead to persistent pleural effusions and high chest tube output. in these situations, chest wall remodeling may occur over time or the recipient may be left with chronic post-operative effusions. vascular anastomotic complications can lead to severe and sudden compromise in the lung transplant recipient. fortunately, these are rare, but may carry high mortality. pulmonary arterial stenosis or thrombus formation typically presents with hypotension and evidence of right heart failure. pulmonary venous thrombosis, usually in proximity to the pulmonary vein-left atrial anastomosis typically presents with hypotension and either lobar or diffuse pulmonary edema with refractory hypoxemia (fig. ) [ ] . because of the rarity of these conditions, diagnosis can be difficult and requires a high index of suspicion. urgent transesophageal echocardiography should be performed at the bedside for patients with a rapid change of course for diagnosis before potential surgical intervention. thrombolysis is a high-risk intervention that can be considered for pulmonary vein thrombosis [ ] ; however, management usually involves surgical re-exploration. in the immediate post-operative state, the bronchial anastomoses are prone to complications due to the bronchial circulation being sacrificed during the transplant procedure. this relative ischemia may then be exacerbated by intra-or post-operative hypotension or other hemodynamic fluctuations, making the anastomosis susceptible to necrosis, dehiscence, and infection. frank bronchial dehiscence is rare, on the order of %; partial dehiscence can be addressed with the temporary placement of self-expanding wire stents to encourage granulation tissue growth and healing [ ••, , ] . in most lung transplant programs, it is the general practice to sacrifice the bronchial arterial supply when implanting the newly transplanted lung. in spite of concerns that bronchial artery revascularization (bar) prolongs ischemic time and increases operative risk of bleeding, centers who routinely employ bar argue for potential benefits of fewer airway complications and reduced bos risk [ ] [ ] [ ] [ ] . before bar can be advocated for widespread use, extension of these techniques to a broader range of centers with consistent surgical competency needs to be addressed. hyperacute and acute rejection hyperacute rejection is a distinct and rare form of lung rejection and is described mostly in case reports [ ] [ ] [ ] [ ] [ ] [ ] . it is characterized by an early and rapid onset, minutes to hours after reperfusion, and is the result of preformed recipient antibodies causing profound allograft dysfunction via mechanisms such as complement activation from abo incompatibility or unrecognized significant anti-hla antibodies to the donor. clinically, one sees pink frothy sputum, profound hypoxemia, and pathologically a coagulopathy with fibrin and platelet thrombi formation within minutes to hours of reimplantation. the first case report appeared in as described by frost et al. and illustrates the typical presentation: the patient described was a single lung recipient who tolerated a few hours of hyperacute rejection [ ] . the patient had a history of two pregnancies, no blood transfusions, and a calculated pra was approximately %. three hours after implantation a donor specific class i antibody to b was identified. the patient underwent treatment with plasmapheresis, cytoxan, and ultimately the allograft was removed and the patient relisted for re-transplant. the recipient died days later before another donor could be identified [ ] . other case reports detail patient survival after suspected hyperacute rejection with similarly aggressive immunosuppression regimens [ ] . although traditionally thought not to occur in the days following transplantation, acute cellular rejection can be seen as early as a week after transplant, and it can make treatment of other icu complications difficult. for instance, during treatment of profound infections in critically ill lung transplant recipients, targeted immunosuppression levels may be lowered or agents stopped altogether in efforts to allow the patient to fend off the current infection. beyond the initial hospitalization, acute cellular rejection is a common occurrence especially in the first year post-transplant, monitored with surveillance bronchoscopy with transbronchial biopsies. the initiation of several immunosuppressive agents in the early post-operative period not only predisposes the transplant recipient to infectious complications, but can cause transient renal dysfunction that may be exacerbated by other concurrent medical complications. the calcineurin inhibitors tacrolimus and cyclosporine are the main culprits for acute renal dysfunction. these agents induce vasoconstriction of the afferent renal arteriole leading to reduction of renal blood flow and glomerular filtration rate. if the critically ill lung transplant recipient experiences peri-operative hypotension, aggressive diuresis for pgd, and is on numerous potentially other nephrotoxic medications, renal dysfunction may be prolonged and severe, leading to serious long-term complications. in a series of lung and heartlung transplant recipients surviving at least months, . % had a decrease in kidney function, and end stage renal disease occurred in . % at a median duration of months [ ] . infectious complications are a frequent and important cause of morbidity and mortality in the post-operative lung transplant recipient. in addition to the relatively high levels of immunosuppression required by lung transplant recipients, the lungs are unique when compared to other solid organ transplants in that they are continually exposed to the external environment, thereby putting the allografts at risk for many more potential infectious insults. this section will focus on the infectious issues surrounding the care of the lung transplant recipient in the immediate post-operative time period. pre-transplant culture data are vitally important when caring for lung transplant recipients in the icu. ideally patients with underlying suppurative lung diseases such as bronchiectasis or cystic fibrosis will have recent culture data with which to guide immediate antibiotic therapy choices in the post-operative period. organisms such as multi-drug resistant pseudomonas species, methicillin resistant staph aureus, rapidly-growing nontuberculous mycobacteria (ntmb), and fungal organisms will directly impact peri-operative antibacterial and antifungal choices and will likely affect treatment duration as well. in patients with cystic fibrosis, the sinuses and upper respiratory tract may be a reservoir for ongoing infections and therefore aggressive antibiosis and prolonged therapy is often necessary. cultures taken intra-operatively, from bronchoscopy performed after bronchial anastomoses are completed, as well as pleural and chest wall cultures can be very useful as well. the former provide up-to-date sampling of the potential donor flora, which can be used in conjunction with cultures obtained from the donor site to help guide antibiotic therapy. chest cavity cultures can be helpful in recipients with structurally abnormal lungs (e.g. cavitary lesions) or parenchymal pulmonary nodules that may be suspicious for chronic infections such as aspergillus species or ntmb. culture data from the organ donor may potentially affect post-transplant care in the icu. as lung donors are ventilator-dependent, tracheal aspirate cultures are routinely performed, as well as blood and urine cultures. however, such information may not be readily available at the time of transplant, so any significant change in postoperative course or concern for progressing infection in the recipient should prompt an investigation into the results of donor cultures. empiric broad spectrum perioperative antibiotic prophylaxis is often employed, but the decision to continue such treatment is on a case-bycase basis, often impacted by information derived from donor culture results. viral infections in the post-operative state are rare, but conceivably can either be transmitted via the donor or result from an early or subclinical respiratory virus in the recipient at the time of surgery and induction immunosuppression. recipients may have been exposed to community acquired viruses such as respiratory syncytial virus, adenovirus, parainfluenza, and influenza, which may become clinically apparent in the peri-operative period as fulminant respiratory or systemic infections. in contrast, although cmv is a commonly seen viral pathogen in post-transplant patients, overwhelming cmv infection is rare in the immediate post-operative state in the modern era. most centers will institute cmv prophylaxis of varying duration depending on the cmv status of the donor and recipient. due to the wide variety of common and opportunistic infections to which the lung transplant population is susceptible, it is often prudent for the icu practitioner to employ the expertise of transplant infectious disease specialists to help manage such cases. in addition, the presence of a dedicated transplant pharmacist as part of the multidisciplinary team is helpful in monitoring for significant medication interactions that affect serum drug levels and for side effects such as nephrotoxicity. the care of the lung transplant recipient in the immediate post-operative period is a complex undertaking that requires a multidisciplinary team led by the icu practitioner working in conjunction with the transplant medical and surgical teams. the lung transplant recipient is at risk for several categories of complications. with donor supply shortages and increasing numbers of patients awaiting transplant, the scenario of employing more extended criteria lungs in increasingly critically ill recipients at the time of transplant is becoming more likely. great care must be taken to reduce the impact of immediate post-operative morbidity on long term outcomes in this population. disclosure no potential conflicts of interest relevant to this article were reported. lung transplantation for pulmonary fibrosis. toronto lung transplant group the registry of the international society for heart and lung transplantation: twentyeighth adult lung and heart-lung transplant report management of the patient undergoing lung transplantation: an intensive care perspective critical care aspects of lung transplantation lung transplantation: donor and recipient critical care aspects perioperative management in lung transplantation a review of lung transplant donor acceptability criteria outcomes of extended donor lung recipients after lung transplantation successful transplantation of marginally acceptable thoracic organs extended donor lungs: years experience in a consecutive series marginal donor lungs: a reassessment liberalization of donor criteria in lung and heart-lung transplantation availability of lungs for transplantation: exploring the real potential of the donor pool lung donor selection and management donor selection and management impact of a lung transplantation donor-management protocol on lung donation and recipient outcomes pulmonary recruitment protocol for organ donors: a new strategy to improve the rate of lung utilization special issues in the management and selection of the donor for lung transplantation ventilatory and hemodynamic management of potential organ donors: an observational survey effect of a lung protective strategy for organ donors on eligibility and availability of lungs for transplantation: a randomized controlled trial lung allocation in the united states large registry review of united states experience with lung transplantation of patients on mechanical respiratory support bridges to lung transplantation active rehabilitation and physical therapy during extracorporeal membrane oxygenation while awaiting lung transplantation: a practical approach use of bicaval dual-lumen catheter for adult venovenous extracorporeal membrane oxygenation extracorporeal membrane oxygenation as a bridge to lung transplant: midterm outcomes extracorporeal membrane oxygenation in awake patients as bridge to lung transplantation ambulatory venovenous extracorporeal respiratory support as a bridge for cystic fibrosis patients to emergent lung transplantation primary lung transplantation after bridge with extracorporeal membrane oxygenation: a plea for a shift in our paradigms for indications double lumen bi-cava cannula for veno-venous extracorporeal membrane oxygenation as bridge to lung transplantation in non-intubated patient successful lung retransplantation after extended use of extracorporeal membrane oxygenation as a bridge good recent general overview of pulmonary complications following lung transplantation respiratory failure after lung transplantation update of early respiratory failure in the lung transplant recipient primary graft dysfunction primary graft dysfunction: definition, risk factors, short-and long-term outcomes clinical risk factors for primary graft failure following lung transplantation effect of donor age and ischemic time on intermediate survival and morbidity after lung transplantation risk factors for primary graft dysfunction after lung transplantation risk factors for early primary graft dysfunction after lung transplantation: a registry study effect of cardiopulmonary bypass on early graft dysfunction in clinical lung transplantation plasma levels of receptor for advanced glycation end products, blood transfusion, and risk of primary graft dysfunction cardiopulmonary bypass is associated with early allograft dysfunction but not death after double-lung transplantation early lung allograft function in twin recipients from the same donor: risk factor analysis lung transplant for interstitial lung disease: outcomes for single versus bilateral lung transplantation report of the ishlt working group on primary lung graft dysfunction part vi: treatment a randomized trial of inhaled nitric oxide to prevent ischemia-reperfusion injury after lung transplantation effects of inhaled nitric oxide following lung transplantation extracorporeal membrane oxygenation for primary graft dysfunction after lung transplantation: long-term survival institution of extracorporeal membrane oxygenation late after lung transplantation -a futile exercise? improved survival but marginal allograft function in patients treated with extracorporeal membrane oxygenation after lung transplantation anesthetic management for lung transplantation atrial fibrillation, atrial flutter, or both after pulmonary transplantation systemic recombinant tissue plasminogen activator lysis for left atrial thrombus formation after single-lung retransplantation endobronchial stent placement for the management of airway complications after lung transplantation short-term deployment of self-expanding metallic stents facilitates healing of bronchial dehiscence lung transplant airway hypoxia: a diathesis to fibrosis? airway complications after lung transplantation can be avoided without bronchial artery revascularization bronchial blood supply after lung transplantation without bronchial artery revascularization bronchial artery revascularization in lung transplantation: techniques, experience, and outcomes hyperacute rejection in single lung transplantation-case report of successful management by means of plasmapheresis and antithymocyte globulin treatment fulminant hyperacute rejection after unilateral lung transplantation hyperacute rejection of a pulmonary allograft. immediate clinical and pathologic findings hyperacute rejection after single lung transplantation: a case report hyperacute rejection following lung transplantation hyperacute rejection after lung transplantation caused by undetected low-titer anti-hla antibodies predictors of renal function following lung or heart-lung transplantation key: cord- - b vjhgn authors: hick, john l.; christian, michael d.; sprung, charles l. title: chapter . surge capacity and infrastructure considerations for mass critical care date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: b vjhgn purpose: to provide recommendations and standard operating procedures for intensive care unit (icu) and hospital preparations for a mass disaster or influenza epidemic with a specific focus on surge capacity and infrastructure considerations. methods: based on a literature review and expert opinion, a delphi process was used to define the essential topics including surge capacity and infrastructure considerations. results: key recommendations include: ( ) hospitals should increase their icu beds to the maximal extent by expanding icu capacity and expanding icus into other areas; ( ) hospitals should have appropriate beds and monitors for these expansion areas; hospitals should develop contingency plans at the facility and government (local, state, provincial, national) levels to provide additional ventilators; ( ) hospitals should develop a phased staffing plan (nursing and physician) for icus that provides sufficient patient care supervision during contingency and crisis situations; ( ) hospitals should provide expert input to the emergency management personnel at the hospital both during planning for surge capacity as well as during response; ( ) hospitals should assure that adequate infrastructure support is present to support critical care activities; ( ) hospitals should prioritize locations for expansion by expanding existing icus, using postanesthesia care units and emergency departments to capacity, then step-down units, large procedure suites, telemetry units and finally hospital wards. conclusions: judicious planning and adoption of protocols for surge capacity and infrastructure considerations are necessary to optimize outcomes during a pandemic. abstract purpose: to provide recommendations and standard operating procedures for intensive care unit (icu) and hospital preparations for a mass disaster or influenza epidemic with a specific focus on surge capacity and infrastructure considerations. methods: based on a literature review and expert opinion, a delphi process was used to define the essential topics including surge capacity and infrastructure considerations. results: key recommendations include: ( ) hospitals should increase their icu beds to the maximal extent by expanding icu capacity and expanding icus into other areas; ( ) hospitals should have appropriate beds and monitors for these expansion areas; hospitals should develop contingency plans at the facility and government (local, state, provincial, national) levels to provide additional ventilators; ( ) hospitals should develop a phased staffing plan (nursing and physician) for icus that provides sufficient patient care supervision during contingency and crisis situations; ( ) hospitals should provide expert input to the emergency management personnel at the hospital both during planning for surge capacity as well as during response; ( ) hospitals should assure that adequate infrastructure support is present to support critical care activities; ( ) hospitals should prioritize locations for expansion by expanding existing icus, using postanesthesia care units and emergency departments to capacity, then stepdown units, large procedure suites, telemetry units and finally hospital wards. conclusions: judicious planning and adoption of protocols for surge capacity and infrastructure considerations are necessary to optimize outcomes during a pandemic. the type of the mass casualty event (mce) is a major determinant of the demands on a hospital. for h n influenza, the impact on icu services varied considerably. the proportion of icu beds occupied by patients with h n peaked at - % in australia and new zealand [ ] , but icu services in mexico were overwhelmed, and many patients required ventilation outside icus [ ] . used for events of any scale and for both sudden (e.g., bomb detonation) or gradual events (e.g., pandemic influenza). . scope: using examples and general recommendations, provide templates for intensive care unit (icu) and isolation area expansion including consideration of central system capacity expansion (such as oxygen). recent recommendations have called for institutions to prepare for at least a % increase in icu capacity beyond baseline during a pandemic or catastrophic disaster [ ] . this level of expansion of space and services is not achievable without significant prior planning/preparedness activities. institutions should define their own capacities and capabilities. defining specific limitations (e.g., shortage of available ventilators), sources to mitigate these shortfalls (e.g., national stockpile, institutional cache) and a strategy for accepting/using outside resources to expand capacity is critical to response success. this document cannot account for operational planning details at individual institutions, but aims to provide a brief, general overview of key issues to be addressed during events requiring critical care surge capacity generation. hospitals should create their own specific plans according to hospital size, role in the community and the hazards recognized in the community. hospitals may refer to recent articles for surge capacity frameworks [ , ] and crisis patient care decision frameworks [ , ] . . goals and objectives: describe the basis for institutional standard operating procedures (sop) for icu and isolation space expansion using templates. provide recommendations for expansion of oxygen capacity and continuity of infrastructure operation. . mass casualty event: an event generating a large number of victims that does not generate demand exceeding the facility or community resources. . disaster: an event generating large numbers of victims that exceed usual hospital and/or community resources and requires changes in the usual practices to meet demand (usually short term). usually implies temporary communications and resource shortfalls and a temporary lack of situational awareness. note that a mce is not equivalent to a disaster, and increased capacity and preparedness increase facility surge capacity for larger patient volumes before a mce becomes a disaster. . crisis standard of care: a substantial change in usual health care operations and the level of care it is possible to deliver, made necessary by a pervasive (e.g., pandemic influenza) or catastrophic (e.g., earthquake, hurricane) disaster. this change in the level of care delivered is justified by specific circumstances and is formally declared by government entities. the formal declaration that crisis standards of care are in operation enables specific legal/regulatory powers and protections for health care providers in the necessary tasks of allocating and using scarce medical resources [ ]. . surge capacity: three functional components of surge capacity exist (fig. ) [ , ] . a. conventional: using usual patient care spaces, resources and practices. b. contingency: using adapted areas of the facility for icu services (procedure areas, post-anesthesia care, operative suites, stepdown units) including adaptations to standard staffing and resource practices to provide functionally equivalent medical care, with minimal increase in risk to the patient. c. crisis: providing sufficient care under the circumstances with significant changes to standard staffing and resource practices (e.g., using an oxygen-saturation monitor with high/low rate alarms instead of usual cardiac and other monitors, tiered staffing so one nurse/physician with critical care expertise supervises several staff with lesser degrees of training that provide the bedside care) that may significantly impact patient morbidity and mortality. . an incident management system (hospital incident command system or alternative nationally compliant system) [ , ] is in place at the facility. this assures that in addition to using appropriate incident command positions and terminology that the process of management by objectives and utilization of formal and practiced planning cycles to generate incident action plans (iap) for the next operational period is followed. the hospital emergency executive control group coordinates these activities (see chap. : coordination and collaboration of interface units). . coordination agreements and systems with neighboring/regional health care facilities are put in place [ ] by the local, regional or national emergency executive control group (see chap. : coordination and collaboration of interface units). these may cross jurisdictional and even national boundaries. the importance of resource-balancing across multiple institutions cannot be overemphasized. during a single-site event, expedient patient transfer to those facilities with resources provides the best care possible, and during a pervasive event (such as a pandemic), s inter-facility coordination assures a consistent standard of care across a given region. 'regions' are usually defined functionally for hospitals rather than geographically (as is the case for emergency management), and planning should include usual referral partners regardless of geographic boundaries. . the hospital has an icu, operating rooms, postanesthesia care, stepdown/intermediate care units and procedure areas (may include respiratory/gastrointestinal procedure rooms or outpatient surgery/procedure areas) [ ] [ ] [ ] . the hospital has prepared for mces including stockpiling equipment, medications and basic supplies [ , ] . this should include planning for special populations regardless of the hospital's role in the community (for example, a hospital that does not usually provide burn or pediatric care may have to provide care for these patients during an incident that overwhelms or damages usual community resources). . the hospital has one ventilator per critical care bed [ ] but can obtain limited additional ventilators within - h. lines of authority . the hospital incident manager [ ] has overall decisionmaking authority to implement surge capacity or any other systematic decisions involved in the response. depending on the organization of the system, the hospital incident manager optimally may answer to (or at least coordinate with) an over-arching governmental entity and be providing institutional direction informed by higher level situational awareness and objectives. critical care staff (unit nursing supervisor or physician depending on availability) at hospitals should be prepared to act within their authority to: a. inform the incident manager about the status and capacity of icu services and their resource needs. these updates should occur as soon as possible after event declaration and be updated every few hours until the influx of patients has stabilized (after a no-notice event) at which point twice-daily reporting is likely to be sufficient unless specific circumstances require an update. unless temporary, requires state empowerment, clinical guidance, and protection for triage decisions and authorization for alternate care sites/techniques. once situational awareness has been achieved, triage decisions should be as systematic and integrated into institutional process, review and documentation as possible. institutions consider impact on the community of resource use (consider ''greatest good'' versus individual patient needs, e.g., conserve resources when possible), but patient-centered decision making is still the focus. institutions (and providers) should make triage decisions balancing the availability of resources to others and the individual patient's needs-shift to community-centered decision making s e. change staffing patterns and hours to provide the most appropriate coverage based on the demands of the incident. . critical care surge capacity-critical care is expanded across a continuum of physical space reflected below from conventional to crisis capacity. the institutional plan should provide for a phased expansion of critical care appropriate to the incident demands. hospitals should be able to increase their icu beds to the maximal extent by expanding icus and other areas with appropriate beds and monitors. increases beyond % over usual capacity are unlikely with the current h n virus. future mutations, outbreaks or mce may require maximum feasible expansion of capacity. this maximal feasible number will vary between institutions and countries, and be determined by the number of excess icu patients, the usual icu bed proportion of the total population and the maximum feasible expansion. as noted above, one group recommended a % expansion target, but many facilities may not be able to reach this target [ ] and should consider phased expansion to double capacity. a. conventional: involves spaces usually used for critical care. occupancy and staffing of existing beds is request additional staffing as needed for post-anesthesia care ( beds), pre-induction ( beds) and special procedures/outpatient surgery unit ( beds up to beds) . move stable icu patients to step-down units, move step-down and rule-outs to non-monitored beds as appropriate . transfer patients from monitored to non-monitored beds as appropriate . staff gastroenterology laboratory and cardiac outpatient area if required . move cots to pre-designated discharge holding area/waiting areas for holding patients pending transfers and clearing rooms . assess with planning chief need to activate regional transfer plan and for additional/follow-on staff and material resources crisis care . add cots or stretchers, transfer stable critical care patients with less resource demand to medicine floors (medical units are preferred by location to surgery, neurology, pediatric floor beds due to location) according to demand based on surge capacity worksheet . note additional beds created in units and halls do not have dedicated monitoring systems. call bioelectronics for any additional spares and ask that they pull accident & emergency (a&e) orthopedic area monitors, crash cart monitors, and depending on needs may move portable monitors from surgery/procedure areas. may need to make request to other facilities or discontinue cardiac/invasive monitoring to decrease demand. can also use saturation monitor for high/low rate alarm-respiratory care can assist re-allocation of saturation monitors . assess situation with planning section chief-as above-if internal/external transfers will not allow patients to move off cots within h then: decompression/demobilization in conjunction with incident manager prepare patient lists for transfer-focus on those that are stable or with resource needs that are difficult to meet in the current environment but do not preclude transfer. as more resources and staff become available and transfers are made to other institutions, transition critical care back to contingency and then conventional locations, restoring normal operations and care locations note that these represent a small portion of an overall surge capacity plan (which itself is a portion of the institutional emergency operations plan) and should be tailored to the needs of the facility maximized, including moving appropriate patients to step-down care from icu (facilitated by having preexisting 'bump lists'), increasing staffing through callbacks and holding staff as needed. this should be coupled with hospital-wide implementation of the same strategies of maximal bed use including 'surge discharge' that prioritize floor patients for early discharge or movement to other holding areas/hall beds per unit protocol so that adequate space can be created for icu patient transfers [ , ] . discharge holding areas should be pre-identified, and processes for patient assessment and rapid discharge should be in place if patients are to move efficiently between the emergency department (ed)/accident and emergency (a&e), operating suites, icus and inpatient floors. for example, a lounge or waiting area may be designated as an area where patients designated for early discharge can be moved while awaiting final orders, medications and transportation in order to more quickly make these beds available for incoming patients. this is of particular utility in a 'no-notice' or sudden event. during a more prolonged event, selective admission and surgical strategies (deferring elective procedures and selective scheduling of other procedures) will be of prominent value in maintaining maximal critical care resources. b. contingency: utilizes spaces that can provide comparable services to true icu beds with supervising staff that have critical care skills. this would include use of pre-and post-anesthesia care units (pacu), operating suites (especially in procedure areas), procedure rooms [gastroenterology (gi), respiratory, interventional radiology], step-down units/monitored units and potentially emergency department beds (though competing priorities for use will impact incident manager decisions about which spaces to use). the overall objective is to concentrate care for the least stable and most critically ill in the conventional critical care areas and move those that are more stable or with lower resource requirements to other areas of care. key infrastructure features include the ability to provide usual cardiac and oxygen saturation monitoring, intravenous medications and drips and mechanical ventilation [ ] [ ] [ ] . in preparing hospitals for a crisis, locations should be prioritized in the following order: expanding existing icus, postanesthesia care units and emergency departments to capacity, then step-down units, large procedure suites, telemetry units and finally hospital wards [ ] . infection control personnel should create a phased plan to accommodate larger numbers of patients with highly infectious diseases as this may be different than planning for patients that do not require isolation. hospitals should balance icu needs and the potential decreasing benefits of increasing icu capacity (because of excess workload) with other hospital needs that may suffer more as services are depleted. staff for these areas (anesthesia, surgery, critical care, emergency) should have a high degree of comfort managing the critically ill, at least on a short-term basis. hospital incident 'worksheets' should be developed that map and prioritize care areas for use based on ability to monitor the patient rooms, proximity to existing critical care or step-down units, and institution-specific factors (for example, pacu and pre-anesthesia care first, followed by conversion of step-down unit to icu level care, etc.) ( table ) . staff and equipment considerations should be pre-planned so that critical care staff can supervise overall care for critical patients while reducing their hands-on patient care responsibilities ('increasing the altitude of supervision' to oversee a larger number of patients) [ , ] . ventilators are expensive and difficult to stockpile, but contingency plans at the facility and government (local, state, provincial, national) levels should provide for some additional ventilators. planned criteria for re-distribution of equipment (use of oxygen saturation monitors restricted to those that are on ventilators or on high-flow oxygen, for example, with spot checks for others) or conservation of equipment (what medications should be given by pumps vs. those that can safely be given by gravity flow) may facilitate implementation during an event [ , ] . prioritization of support services (minimizing tests ordered, laboratory and radiology restricting services to essential tests and diagnostics, use of alternative diagnostics-for example, ultrasound rather than computed tomography for abdominal imaging) is also required and should be institution-wide. restrictions on utilization of diagnostics (laboratory, radiology) should increase with demand in pre-planned phases. the phased response for h n may last several weeks [ , ] . c. crisis: provision of 'sufficient' critical care in areas that are not designed for high-intensity care, for example, using floor beds with an oxygen saturation monitor (with high/low rate and low saturation alarms) for a patient on a ventilator and using staff that do not have significant training in critical care to provide basic care (basic nursing care, vital signs monitoring, etc.) with an even higher 'altitude' of the critical care nurses and physicians supervising these providers (e.g., critical care nursing and physician staff round on the patients at scheduled intervals to provide guidance to the primary nursing and physician staff and are available for consultation/questions). should demand exceed resource capacity for specific equipment (e.g., ventilators, extra-corporeal membrane oxygenation equipment), with no resources expected and no transfers possible [ , ] , triage processes should be implemented that have been pre-planned to the extent possible and are consistent with the community standard of care and any state, provincial or national guidance. central system considerations . oxygen a. remodeling or building projects at a hospital should consider incorporating oxygen ports (or extra ports) into patient rooms, meeting rooms, etc., to facilitate conversion to patient care areas or the accommodation of additional beds in usual areas. however, safety considerations are paramount, as these systems may not be used often and yet still require regular inspection and testing. multi-patient regulators are available that can serve multiple patients on variable oxygen flow rates from a single wall port, and these may be useful for providing cohort care, particularly in flat-space areas such as meeting rooms, etc. though this does not provide critical care, it can open beds up that can be used for critical care and thus is a valuable part of planning. b. hospitals should carefully consider limitations of the oxygen supply. even if enough ventilators or oxygen flow meters are available such that every bed in the hospital would have one, the oxygen systems for most hospitals were not designed to provide such a supply and maintain pressure within the system. continued supply and re-supply of liquid oxygen may be another limiting factor. hospitals should examine their oxygen delivery and storage systems for vulnerabilities. often, there are many potential points of failure within these systems with little redundancy or recovery. it may be to the institution's advantage to duplicate liquid oxygen systems, ideally separated geographically, or at least equipped to allow an interface with a trailerbased liquid oxygen system should the primary fixed delivery system fail. . suction/compressed air: suction and compressed air lines are a lower priority for incorporation into congregate care spaces (those providing low acuity non-ambulatory patient care); however, at least compressed air (and ideally suction) should be available for any spaces where mechanical ventilation is a consideration (i.e., patient rooms). hand-held and battery-operated suction units are available and may have utility, though the availability of wall suction is far preferable because of superior performance. . utilities a. electricity: emergency generators at most hospitals do not have the capacity to power outlets in all patient rooms sufficiently for the monitors, ventilators and pumps necessary for critical care. further, heating, air conditioning and ventilation systems (including negative flow systems) may not be included or adequately powered with emergency power circuits. critical care staff should identify which systems and outlets are included in emergency power, which are not and what the maximum load is (just because outlets are marked for emergency use does not mean that the generators can support the electrical draw if many of these outlets are used at once). the hospital should plan with jurisdictional emergency management the types and quantities of generators necessary to effectively run the facility should primary power fail and have the necessary adaptors available to wire temporary generators into the hospital system [ ] . b. water: clean water is required for many health care activities, including large volumes for hemodialysis. hospital planners may be unaware of the water needs for critical care activities and should work with critical care to forecast needs and identify suppliers and an operating procedure. c. continuity of operational planning: the ability of the institution to provide critical care depends on the maintenance of the operating infrastructure. water and utilities are separated from these because of the specific considerations above, but the availability of lighting, communications, information technology, fire suppression, heating/ventilation/air conditioning, nutrition services, laboratory, radiology and many other support and infrastructure services is not assured and critical care planners should be familiar with planning for maintaining general hospital operations during outages and other incidents [ , ] . functional roles and responsibilities of the internal personnel and interface agencies or sectors (these should be defined prior to the event and the specific actions to be taken listed in job action sheets or other resources that the care providers and incident management team can reference during an event) with resource acquisition (particularly for non-medical supplies such as security personnel for traffic control, etc.), coordinates the response on the jurisdictional level, and depending on the regional construct may assist with arranging patient transfers. this group assists with emergency medical services and other patient transportation resources. b. health care systems: provide mutual aid including resources and staff to disproportionately affected hospitals. depending on regional constructs, these systems ideally have a coordinating entity that establishes priorities of response and resource assignments, coordinates patient transfers, and works with other stakeholder agencies to obtain necessary staff, resources and emergency declarations. hospital personnel should understand how these systems work in their area and practice using them prior to an event [ , ] . logistics support and requirements necessary for the effective implementation of the sop incident management framework, institutional mobilization (disaster) plan, pre-existing phased implementation plans for capacity expansion, materials and resources appropriate to the plans (scope determined by institutional commitment and financial resources) and mechanism for monitoring, requesting and receiving resources [ ] [ ] [ ] are required. development/adaptation of facility plans should include administrative and critical care stakeholders, review and vetting with other affected department staff [accident facilities should establish temporary anteroom/changing area off hallway ( h). facilities should isolate ventilation to unit and change to % supply, % exhaust. step-down care may be provided in micu prior to transfer to floor negative pressure rooms . open surgery and procedure center as isolation stepdown/critical care isolation area in consultation with incident manager if necessary ([ patients or more anticipated). ventilation is already exhausted from this area; elective surgical volumes should be reduced during event. use locker rooms as clean/infectious transition zones for ppe donning/doffing. may use operating suites for icu level care in cooperation with anesthesia. capacity beds including in waiting/recovery and operating room/procedure rooms . ppe used by staff continuously in infectious area crisis patient care (catastrophic event, e.g., pandemic influenza) . using the standard surge capacity worksheet as a tool, determine with incident management which patient care areas to use as infectious patient cohort care depending on the current and anticipated event scope. cohort areas to may expand and contract during the course of the event . facilities should assist with construction of temporary anterooms for ppe changing adjacent to each cohort area and assure exhaust ventilation for these areas. supply may not be able to be manipulated for large areas . hospital should implement access control and staff screening/monitoring plans . ppe used by staff continuously in infectious/cohort area, potentially hospital-wide depending on scope of the event and transmissibility sample core infectious disease critical care capacity elements for 'city hospital.' note that this plan reflects specific adaptations for the facility and that each facility should identify a phased approach to these patients. space concerns are only one element of an overall infectious disease response plan and guidance for specific disease management, infection control, staff screening, behavioral health, visitor and access control policies, emergency department screening and cohorting, and patient transport planning (use of elevators, etc.) policies all should be included in the institutional plan city hospital sop for critical care management of a special pathogen: this guideline applies only to pathogens that are transmitted by airborne or suspected airborne routes and have a high likelihood of transmission and severe morbidity/mortality (may include sars, pandemic influenza, some hemorrhagic fevers). these patients require careful and comprehensive use of personal protective equipment (ppe) by staff caregivers s & emergency (a&e), operating room, stepdown units, and procedure areas, laboratory and radiology services, etc.], and preparedness activities supporting the sop (materials acquisition, planning). the initial development of the critical care surge plan should include a draft, with discussion, revision and a feedback cycle to the facility stakeholders. once a draft plan is complete, a tabletop exercise should test basic assumptions of the plan with revision as needed. initial orientation and training of staff on procedures should follow, and the plans should then be tested as realistically as possible in a functional exercise. after each exercise or event, an after-action review should identify areas for improvement and corrective actions. the sop should be redrafted as needed based on the experiences, or additional preparedness/planning activities may need to occur. education on these changes is conducted, and the plan exercised again. too often hospital disaster exercises stop with the patients being processed through the ed/a&e and do not require inpatient decision-making. effective augmentation of critical care services at a hospital requires substantial planning prior to the event, with integration of planning efforts across multiple services at the hospital and the engagement of community and government partners. development of a phased critical care expansion plan addressing staff, space and supplies in conjunction with hospital administration and emergency management personnel should be a priority with the ongoing h n influenza pandemic. conflict of interest none. critical care services and h n influenza in australia and new zealand critically ill patients with influenza a(h n ) in mexico task force for mass critical care. definitive care for the critically ill during a disaster: a framework for optimizing critical care surge capacity: from a task force for mass critical care summit meeting surge capacity concepts for health care facilities: the co-s-tr model for initial incident assessment refining surge capacity: conventional, contingency, and crisis capacity providing mass medical care with scarce resources: a community planning guide. prepared by health systems research, inc., under contract no. - - . ahrq publication no. - . agency for healthcare research and quality federal emergency management agency-department of homeland security medical surge capacity and capability: a management system for integrating medical and health resources during large-scale emergencies augmentation of hospital critical care capacity after bioterrorist attacks or epidemics: recommendations of the working group on emergency mass critical care task force for mass critical care. definitive care for the critically ill during a disaster: medical resources for surge capacity: from a task force for mass critical care summit meeting healthcare facility and community strategies for patient care surge capacity hospital bed surge capacity in the event of a mass-casualty incident inpatient disposition classification for the creation of hospital surge capacity: a multiphase study patient care strategies for scarce resource situations task force for mass critical care. definitive care for the critically ill during a disaster: a framework for allocation of scarce resources in mass critical care: from a task force for mass critical care summit meeting electrical blackouts in hospitals and the need for reassessment of the electrical infrastructure and more powerful standby generation continuity of operations (coop) programs continuity of operations planning for public health and medical services. national disaster medical system training summit airborne infectious disease management: methods for temporary negative pressure isolation association for healthcare resource and materials management, health industry distributors association, health industry group purchasing association ( ) medical-surgical supply formulary by disaster scenario standards and guidelines for healthcare surge during emergencies-hospital operational tools manual key: cord- -nki sasr authors: vidaur, loreto; totorika, izarne; montes, milagrosa; vicente, diego; rello, jordi; cilla, gustavo title: human metapneumovirus as cause of severe community-acquired pneumonia in adults: insights from a ten-year molecular and epidemiological analysis date: - - journal: ann intensive care doi: . /s - - -y sha: doc_id: cord_uid: nki sasr background: information on the clinical, epidemiological and molecular characterization of human metapneumovirus in critically ill adult patients with severe community-acquired pneumonia (cap) and the role of biomarkers identifying bacterial coinfection is scarce. methods: this is a retrospective epidemiological study of adult patients with hmpv severe cap admitted to icu during a ten-year period with admission psi score ≥ . results: the . % of the patients with severe cap due to human metapneumovirus were detected during the first half of the year. median age was years and . % were male. the genotyping of isolated human metapneumovirus showed group b predominance ( . %). all patients had acute respiratory failure. median apache ii and sofa score were and . , respectively. the % were coinfected with streptococcus pneumoniae. . % of the patients had shock at admission and % underwent mechanical ventilation. seven patients developed ards, three of them younger than years and without comorbidities. mortality in icu was . %. among survivors, icu and hospital stay were . and days, respectively. plasma levels of procalcitonin were higher in patients with bacterial coinfection ( . vs . ; p < . ). the levels of c-reactive protein, however, were similar. conclusion: human metapneumovirus was associated with severe cap requiring icu admission among elderly patients or patients with comorbidities, but also in healthy young subjects. these patients often underwent mechanical ventilation with elevated health resource consumption. while one out of four patients showed pneumococcal coinfection, plasma procalcitonin helped to implement antimicrobial stewardship. electronic supplementary material: the online version of this article ( . /s - - -y) contains supplementary material, which is available to authorized users. human metapneumovirus (hmpv) is a worldwide distributed enveloped virus with a rna genome closely related to respiratory syncytial virus. hmpv belongs to the paramyxoviridae family, in the genus metapneumovirus, first identified in the netherlands in [ ] . based on genetic and antigenic variability, hmpv strains have been classified in two groups or lineages (a and b) and four sublineages (a , a , b and b ) [ ] [ ] [ ] . the virus has been reported as a common respiratory pathogen in childhood, associated mainly with upper but also with lower respiratory tract infections [ , ] . during the annual epidemics, hmpv has been associated with a significant number of hospital admissions in young children [ ] [ ] [ ] [ ] . respiratory tract infections caused by hmpv during adulthood are less prevalent and less serious than those open access *correspondence: loretovidaurtello@gmail.com critical care department, donostia university hospital-biodonostia health research institute, san sebastian, guipuzcoa, spain full list of author information is available at the end of the article in childhood. however, the presence of hmpv has been detected in - % of adult patients admitted due to a community-acquired pneumonia (cap) [ , ] and has been associated with asthma and chronic obstructive pulmonary disease exacerbation [ ] [ ] [ ] . the same as with other common respiratory viruses, hmpv is usually associated with non-severe pneumonia, whereas risk factors like immunosuppression, specific comorbidities-chronic lung disease, heart disease, blood disorders-elderly and living in long-term care facilities are associated with a higher risk of severe viral pneumonia [ , ] . nevertheless, recent studies suggest that hmpv infection is an underappreciated cause of critical illness, also in previously healthy patients [ ] [ ] [ ] [ ] . severe community-acquired pneumonia (scap) is a known infectious complication of respiratory viruses including hmpv. in these cases, clinical presentation, evolution and treatment differ depending on the pathogens involved, hmpv alone or hmpv coinfected with a bacteria. some biomarkers have been studied as diagnostic markers to discriminate between viral or bacterial pneumonias and help physicians to decide not to start or when to withdraw the antibiotic therapy [ , ] . the main objective of this study was to describe the clinical and epidemiological characteristics of adults with severe pneumonia caused by hmpv who required intensive care unit (icu) admission, over a long period of time. secondary objectives were to characterize the epidemiological and molecular viral diversity and to compare the value of c-reactive protein (crp) and procalcitonin in identifying bacterial coinfections. this is a ten-year, retrospective epidemiological study with inclusion of patients with cap due to hmpv admitted in a -bed icu in the north of spain. in , this icu assisted a referral population of , inhabitants older than years. all patients older than years from july to june admitted in the icu by cap with admission psi score ≥ were considered eligible. during the first years of the study, samples to detect respiratory viruses were obtained occasionally in patients with cap. however, it turned the standard of care in the icu after influenza pandemic. to be included, cases meet two of the following three criteria upon admission: (a) severe acute respiratory failure (pao /fio < ), (b) multilobar radiological involvement or (c) systolic arterial pressure < mmhg. acute respiratory distress syndrome (ards) was diagnosed as an acute diffuse lung injury with increased vascular permeability, bilateral radiographic opacities and hypoxemia not fully explained by cardiac failure or fluid overload following the berlin criteria [ ] . exclusion criteria: subjects with nosocomial pneumonia or admitted due to non-respiratory infection (non-severe coincidental infection) and patients with pneumonia during the preceding months (persistence of viral rna in respiratory samples). patients were recruited from the computerized records of the microbiology department, and the medical records were revised by two clinical investigators (it, lv). the recorded clinical variables were socio-demographic (age and sex), comorbidities, the charlson comorbidity score and clinical symptoms at admission [ ] . radiological and analytic findings at admission and during the evolution, coinfections, antibiotic therapy, the presence of shock or need of mechanical ventilation, icu and hospital stay were also recorded. the detection of hmpv in respiratory samples was made by reverse transcription polymerase chain reaction (rt-pcr), in house monoplex until july [ ] , real-time commercial multiplex (luminex xtag respiratory viral panel [usa]) until july and seegene anyplex ™ ii rv /allplex ™ respiratory panel [republic of korea] since then. the extraction of nucleic acids was made using an automatic biorobot m extractor (qiagen gmbh, hilden, germany) until july and the nuclisens ® easy-mag platform (bio-mèrieux sa, marcy l'etoile, france) from that date. the genotyping of hmpv was performed with a rt-pcr followed by sequencing [ ] . blood cultures, streptococcus pneumoniae and legionella pneumophila antigenuria (alere binaxnow, scarborough, me, usa), and pharyngeal exudates with viral transport media to evaluate respiratory viruses were assessed in all the patients included in the study. coinfection was considered when hmpv was isolated with other viral or bacterial pathogens at the same time. discrete variables were expressed as counts (percentage) and continuous variables as medians and - % interquartile ranges (iqrs). differences in continuous variables were analyzed by the mann-whitney u test or the kruskall-wallis test when appropriate. qualitative variables were analyzed by the chi-square test with yate's correction when necessary. the threshold for clinical significance was p < . . data analysis was performed using spss for windows . . (spss, chicago, il, usa). the obtained clinical samples and the medical intervention of the patients were ordered by the clinician attending each patient. the study was approved by the ethics committee for clinical research of the health area of gipuzkoa (spain). informed consent was waived due to the retrospective nature of the study. during the study period, respiratory samples were sent from the icu to the microbiology service to study viral etiology, hmpv being identified in patients ( . %). studied samples were mainly pharyngeal exudates ( . %), but also tracheal aspirates ( . %), bronchoaspirates ( . %), bronchoalveolar lavages ( . %) and sputum ( . %), where bacterial culture was also performed. five patients with hmpv were excluded because admission causes were other than respiratory infection. cases were detected every year except in (n = - ). the highest prevalence was in and (fig. ) . twenty-six of the patients with respiratory infection due to hmpv ( . %) were detected during the first half of the year and ( . %) in march-april. hmpv circulated every year later than influenza virus, being the epidemic peak of both infections separated by a period of - months. in fact, the % of cases ( / ) of hmpv infections in patients admitted to icu occurred out of the influenza epidemic period ( table ) . genotyping of hmpv was performed in cases, being ten cases of hmpv group a ( . %) and of hmpv group b ( . %). the viral strains belonged to sublineages a (n = ; . %), b (n = ; . %) and b (n = ; . %). group a strains predominated until ( . %), while later, the most frequent was genotype b ( %). after excluding seven patients with bacterial coinfection, there were not significant differences in the genotype of hmpv between six patients who developed ards ( % genotype b) and who did not ( % genotype b). at icu admission, all patients had acute respiratory failure and received empiric antibiotic therapy. median apache ii score was , and median saps iii and sofa scores were . [iqr . - . ] and . [iqr . - . ], respectively. median age of the included patients was years [ - % iqr . - . ], and . % of them were under years old ( with less than two comorbidities). the . % (n = ) of the patients were male. main symptoms at admission were cough ( . %), dyspnea ( . %), fever ( . %) and purulent respiratory secretions ( . %). nineteen patients ( . %) had major comorbidities such as immune compromise (n = ), asthma (n = ) or chronic respiratory disease (n = ) ( table ) . seven patients (none died) had coinfection with streptococcus pneumoniae. three episodes were coinfected with viral pathogens: human parainfluenza virus type (hpiv ), human rhinovirus and cytomegalovirus (last one in an immunosuppressed patient). predominant radiologic pattern in patients with hmpv infection and without coinfection was the interstitial alveolar pattern ( . %), while in the patients with streptococcus pneumoniae coinfection, the alveolar pattern was predominant ( . %). eight patients had pleural effusion at admission, and two more developed it during the icu stay. pleural effusion was bilateral in four patients and massive (> l) in three cases. seventeen ( . %) patients had shock at admission, fourteen ( %) underwent invasive mechanical ventilation (median . days [iqr - . ]) due to acute respiratory failure and four were tracheostomized due to prolonged mechanical ventilation. severe complications were frequent, highlighting acute renal failure in patients ( . %), of which two required renal replacement therapy; cardiac failure or cardiogenic shock in eight patients ( . %); and ards in seven cases ( %) (two of them in patients with bacterial coinfection) ( table ). three patients who developed ards were younger than years ( , and years, respectively) without major comorbidities or bacterial coinfection. all of them underwent invasive mechanical ventilation due to acute respiratory failure (one had coinfection with hpiv ). the main clinical and epidemiological characteristics of the patients are summarized in the supplementary material (additional file : table s , additional file : table s ). the majority of the patients ( . %) had lymphocytopenia (< /ml) at admission ( our study gives new insights on the molecular epidemiology of hmpv pneumonia admitted to the icu over years. hmpv was consistently detected in cap admitted to the icu, with an annual incidence ranging . - case/ , inhabitants older than years per year. molecular characterization of hmpv revealed group dominance of subgroup b. hmpv infection presented seasonal distribution, with / of cases detected in late winter-early spring each year. the % of the studied patients were younger than years without comorbidities. hmpv cap often presented as acute respiratory failure with bilateral opacities and half of icu subjects underwent mechanical ventilation. lymphocytopenia and pleural effusion were common at admission. plasma procalcitonin was a sensitive tool to identify coinfection with bacteria ( %), which contributes to antimicrobial stewardship. these findings suggest the need to implement hmpv diagnosis tests in subjects with cap developing acute respiratory failure. two out of three patients of this study had shock at admission, half of them underwent mechanical ventilation, one out of four developed ards and one out of seven died during the clinical course, suggesting that hmpv is responsible for scap in adults. these data are concordant to that observed in the only study with a wide range of patients with hmpv infection in critically ill patients, in which % of the patients required mechanical ventilation, % developed ards and the mortality was % [ ] . moreover, there are sporadic reports of - patients with hmpv infection acquired in the community and acute respiratory failure who required icu admission [ ] [ ] [ ] . in a large prospective study of icu patients requiring invasive mechanical ventilation, hmpv was more frequently detected in patients admitted by severe respiratory infection than in patients with other causes, suggesting a causal role of hmpv in the development of severe respiratory infection [ ] . most of the patients of this study had major comorbidities at admission, mainly chronic respiratory failure and immunosuppression, being those patients and the elderly the most susceptible to develop severe hmpv infections [ , , ] . however, % of the patients were younger than years old and one out of three did not have major comorbidities, being similar to cap related to other etiologies. interestingly, three patients ( . %) were young adult patients without comorbidities and without bacterial coinfection that developed ards pointing out a main role of hmpv in the etiology of severe respiratory infections requiring mechanical ventilation. in the cohort of patients of hasvold et al. [ ] , % of the patients had only minor comorbidities and were not immunosuppressed. one out of four episodes of severe acute respiratory infection was coinfected with bacteria, similar to that observed in other series [ , ] . streptococcus pneumoniae, one of the bacterial species most frequently involved in post-viral super-infections [ ] , was the main isolated bacterial pathogen. in these episodes, procalcitonin has been reported to discriminate between viral episodes and those with bacterial coinfection [ ] , in contrast with crp. some studies have recommended different cutoff points of procalcitonin to discontinue early antibiotic therapy in patients with community-acquired therapy, being . ng/ml and, mainly . ng/ml the most recommended [ , ] . none of the patients with documented bacterial coinfection in this study had a procalcitonin level lower than ng/ml which supports the early discontinuation of antibiotic therapy in this group of patients with low plasma levels of procalcitonin. the results of this study, about procalcitonin plasma determinations, could help to develop personalized medicine in patients with cap, helping physicians to early discrimination between viral or bacterial pneumonia and antimicrobial stewardship [ ] . three different genotypes of hmpv were associated with severe cap requiring icu admission, which supports that all of them are able to cause severe infections in adult patients. the low number of cases of the three different hmpv lineages, the presence of coinfections and the retrospective nature of the study made impossible to analyze the clinical pattern and the evolution of the patients based on the genotype of the infecting hmpv. however, to date, there are no significant differences in the evolution or clinical manifestation between different genotypes of hmpv in adults in the outpatient setting [ ] . this study has some limitations and therefore, the results should be evaluated cautiously. the hmpv infection was diagnosed by oropharyngeal swab samples more than in low respiratory tract samples, mainly in non-intubated patients. the detection of a viral pathogen in respiratory samples of a patient with acute respiratory infection can be coincident and not related to icu admission. the retrospective design of the study can underestimate the actual incidence of hmpv infection because some patients admitted because of acute respiratory infection could not be investigated for viral etiology. however, from the influenza pandemics, nasopharyngeal swab samples with respiratory viral detection are routine of care being collected in the % of patients with scap admitted to icu. finally, three different molecular techniques were used, with potential selection bias due to the differences in sensitivity of these techniques. in conclusion, our study confirms that hmpv, a respiratory virus causing bronchiolitis and pneumonia in children, was associated with severe cap requiring icu admission among elderly patients or patients with comorbidities, but also in healthy young subjects. these patients often underwent mechanical ventilation with long icu and hospital stays, associated with elevated health resource consumption. the results of this study agree with recent observations [ ] suggesting a shift in the paradigm of severe pneumonia, recommending that viral infection (and specifically hmpv) should be ruled out when complicated with acute respiratory failure. while one out of four patients showed pneumococcal coinfection, plasma procalcitonin levels helped to implement antimicrobial stewardship. additional file : table s . main characteristics of immunocompetent adult patients admitted to the intensive care unit due to a severe community-acquired pneumonia associated with human metapneumovirus infection (guipuzcoa, basque country, spain, - ). table s . main characteristics of immunosuppressed adult patients admitted to the intensive care unit due to a severe community-acquired pneumonia associated with human metapneumovirus infection (guipuzcoa, basque country, spain, - ). ards: acute respiratory distress syndrome; apache ii: acute physiology and chronic health evaluation ii; cap: community-acquired pneumonia; copd: chronic obstructive pulmonary disease; crp: c-reactive protein; hmpv: human metapneumovirus; icu: intensive care unit; psi score: pneumonia severity index; saps iii: simplified acute physiology score iii; scap: severe communityacquired pneumonia; sofa: sequential organ failure assessment. a newly discovered human pneumovirus isolated from young children with respiratory tract disease human metapneumovirus: lessons learned over the first decade genetic diversity of human metapneumovirus over consecutive years in australia burden of human metapneumovirus infection in young children hospitalization rates for human metapneumovirus infection among to year olds in gipuzkoa human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children a -year experience with human metapneumovirus in children aged < years systematic review of respiratory viral pathogens identified in adults with community-acquired pneumonia in europe community-acquired pneumonia requiring hospitalization among u.s. adults human metapneumovirus infections in adults: another piece of the puzzle human metapneumovirus infection plays an etiologic role in acute asthma exacerbations requiring hospitalization in adults human metapneumovirus infection in adults with community-acquired pneumonia and exacerbation of chronic obstructive pulmonary disease severe viral pneumonia in adults: what is important for the icu physician? an outbreak of severe respiratory tract infection due to human metapneumovirus in a long-term care facility linssen cf. human metapneumovirus in bronchoalveolar lavage fluid of critically ill patients with suspected pneumonia human metapneumovirus infections on the icu: a report of three cases viral infection in patients with severe pneumonia requiring intensive care unit admission the role of human metapneumovirus in the critically ill adult patient infection biomarkers in primary care patients with acute respiratory infections-comparison of procalcitonin and c-reactive protein serum procalcitonin measurement and viral testing to guide antibiotic use for respiratory infections in hospitalized adults: a randomized controlled trial acute respiratory distress syndrome: the berlin definition validation of a combined comorbidity index seasonal distribution and phylogenetic analysis of human metapneumovirus among children in osaka city respiratory viruses in invasively ventilated critically ill patients-a prospective multicenter observational study postviral complications. bacterial pneumonia procalcitonin (pct) levels for ruling-out bacterial coinfection in icu patients with influenza: a chaid decision-tree analysis effect of procalcitonin guided guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the pro-hosp randomized controlled trial procalcitonin guidance of antibiotic therapy in community acquired pneumonia: a randomized trial towards precision medicine in sepsis: a position paper from the european society of clinical microbiology and infectious diseases the role of human metapneumovirus genetic diversity and nasopharyngeal load on symptom severity in adults lv made substantial contribution to the conception and design of the work, the acquisition, analysis and interpretation of the data and has drafted the work. it made substantial contribution to the conception and design of the study, analysis and interpretation of the data. dv, mm, jr and gc made substantial contributions to the interpretation of the data and substantively revised it. all authors read and approved the final manuscript. the authors declare that there has not been any source of funding for the research. the datasets supporting the conclusions of this article are included within the article (and its additional file). the study was approved by the ethics committee for clinical research of the health area of gipuzkoa (spain). informed consent was waived due to the retrospective nature of the study. not applicable. the authors declare that they have no competing interests. key: cord- -lc fqhb authors: barbier, françois; coquet, isaline; legriel, stéphane; pavie, juliette; darmon, michael; mayaux, julien; molina, jean-michel; schlemmer, benoît; azoulay, Élie title: etiologies and outcome of acute respiratory failure in hiv-infected patients date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: lc fqhb objective: to assess the etiologies and outcome of acute respiratory failure (arf) in hiv-infected patients over the first decade of combination antiretroviral therapy (art) use. methods: retrospective study of all hiv-infected patients (n = ) admitted to a single intensive care unit (icu) for arf between and . results: arf revealed the diagnosis of hiv infection in ( . %) patients. causes of arf were bacterial pneumonia (n = ), pneumocystis jirovecii pneumonia (pcp, n = ), other opportunistic infections (n = ), and noninfectious pulmonary disease (n = ); the distribution of causes did not change over the -year study period. two or more causes were identified in patients. the patients on art more frequently had bacterial pneumonia and less frequently had opportunistic infections (p = . ). noninvasive ventilation was needed in patients and endotracheal intubation in . hospital mortality was . %. factors independently associated with mortality were mechanical ventilation [odds ratio (or) = . , p < . ], vasopressor use (or, . ; p = . ), time from hospital admission to icu admission (or, . per day; p = . ), and number of causes (or, . ; p = . ). hiv-related variables (cd count, viral load, and art) were not associated with mortality. conclusion: bacterial pneumonia and pcp remain the leading causes of arf in hiv-infected patients in the art era. hospital survival has improved, and depends on the extent of organ dysfunction rather than on hiv-related characteristics. acute respiratory failure (arf) is the leading reason for intensive care unit (icu) admission in hiv-infected patients, with bacterial pneumonia and pneumocystis jirovecii pneumonia (pcp) accounting for most cases [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . effects of hiv infection that predispose patients to lung infections include depletion of alveolar cd t cells, impairment of humoral immunity, and functional alterations of granulocytes and alveolar macrophages [ , ] . changes in the causes of arf were reported shortly after the introduction of combination antiretroviral therapy (art) [ , , ] . the drop in hiv rna levels and increase in cd t-cell counts induced by art were associated with a reduced incidence of opportunistic infections and an increase in life expectancy [ , ] . as a result of both primary prophylaxis and art, the percentage of arf cases due to pcp dropped from % to - % [ , , , ] . however, most of the available studies of arf in hiv-infected patients were conducted before , at a time when art was not yet widely used, and more recent data are scarce [ ] [ ] [ ] . thus, the possible influence of art advent on the causes and outcomes of arf in hiv-infected patients is not fully understood. the objectives of this study were to determine whether the causes and outcome of arf in hiv-infected patients have changed in the first decade following the advent of art, and to assess the effect of art use on these variables. to this end, we reviewed the medical charts of all hiv-infected patients admitted to our icu for arf between and . this retrospective study was conducted in the medical icu of the saint-louis hospital, a -bed university hospital in paris, france. all hiv-infected patients admitted for arf between january and december , were included, unless they were receiving treatment for hematological malignancies or solid tumor. in patients with multiple admissions for arf during the study period, only the first icu stay was evaluated. arf was defined as a respiratory rate of more than breaths/min and respiratory distress symptoms, pao on room air of less than mm hg, or need for invasive or noninvasive mechanical ventilation (mv). of note, admission policies of hivinfected patients remained identical throughout the study period in our icu and consisted in broad admission for arf, regardless of hiv-related history. the ethics committee of the french society for critical medicine approved the study. eligible patients were screened by independent query of the entire icu database by of the investigators. the medical charts of the included subjects were then reviewed by intensivists including a pulmonologist and an infectious disease specialist. both the icu charts and the charts from the infectious diseases department supplying hiv follow-up were reviewed. the characteristics of the hiv infection shown in table were collected. aids-defining illnesses before icu admission were defined according to the latest statement of the centers for disease control and prevention (cdc) [ ] . art was defined as a combination of or more antiretroviral drugs belonging to at least classes among the following: protease inhibitors, nucleoside reverse transcriptase inhibitors, and nonnucleoside reverse transcriptase inhibitors [ ] . we defined patients as receiving art if the medication was prescribed for more than days. however, patients whose medical charts from the infectious disease department indicated poor compliance with the prescribed art regimen were classified as not receiving art. poor compliance was defined as stationary viral load despite fully active antiretroviral therapy and no evidence of viral resistance according to available genotyping data, or no drug taken for more than months. the demographic data, co-morbidities, and icu stay characteristics reported in tables and were collected. life-sustaining treatments used in the icu were recorded. the sepsis-related organ failure assessment (sofa) score was calculated in each patient and used to define extrarespiratory failures within the first h of the icu stay [ ] . the cause of arf was determined by consensus among all icu clinicians. four nonmutually exclusive diagnostic categories were used: bacterial pneumonia documented clinically and/or microbiologically, pcp, opportunistic lung infections other than pcp and bacterial pneumonia, and noninfectious diseases. clinically documented bacterial pneumonia was defined as an appropriate history and response to empiric antimicrobial therapy with focal pneumonia on chest x-ray, and either septic shock or predominantly neutrophils on bronchoalveolar lavage (bal) fluid examination, but no bacterial pathogen isolated. the diagnosis of pcp required documentation of p. jirovecii on respiratory samples. the diagnostic strategy, which has been described elsewhere [ ] , included blood cultures, saline-induced sputum (is) for p. jirovecii testing, expectorated sputum for bacteria and mycobacteria, bal, distal protected specimen (dps), pleural fluid culture, legionella pneumophila serogroup i urinary antigen, and cryptococcus neoformans antigenemia. results are reported as medians and quartiles ( th- th percentiles) or numbers and percentages. to provide a global overview of survival trends over time, the study period was subdivided into subperiods, i.e., to , to , and to . we sought to assess potential changes over time in term of icu admissions, frequency of inaugural arf, respective incidences of the causal groups, and survival. patient characteristics were compared according to the use of art and the causes of arf using the chi-square test or fisher's exact test, as appropriate, for categorical variables, and the nonparametric wilcoxon's rank-sum test or the kruskal-wallis test for continuous variables. to investigate association between patient characteristics, use of art, and hospital death, we first performed univariate analyses to look for a significant influence of each variable on hospital mortality by logistic regression, estimating the odds ratio (or) with a % confidence this work was presented in part at the american thoracic society international conference, - may , toronto, canada (abstract no. ) [ ] . interval (ci). variables listed in table were entered into a backward, stepwise multiple logistic regression model in which hospital mortality was the outcome variable of interest. all tests were -sided, and p values smaller than . were considered statistically significant. analyses were done using the statview software package version . (sas institute, cary, nc). . %, and . % for the same subperiods, respectively, p = . ) (fig. ) . at icu admission, patients were on art overall ( . %), without significant changes over the study period. no significant differences were found in terms of demographic characteristics, hiv risk factors, and co-morbidities when patients receiving art were compared with those who did not (table ) . admission through the emergency room occurred in ( . %) patients. severity of organs failures at icu admission, assessed by the sofa score, did not differ significantly table ) . at least cause of arf was found in patients ( . %). infection was far more common than noninfectious pulmonary disease. table lists the definitive diagnoses. half the patients had bacterial pneumonia, streptococcus pneumoniae being the most common pathogen. septic shock occurred in ( . %) patients with bacterial pneumonia. the second most common cause of arf was pcp, which was identified in about one-third of patients overall and in two-thirds of patients with newly diagnosed hiv infection. pneumonia due to other opportunistic pathogens was diagnosed in ( . %) patients, with mycobacterium complex tuberculosis being the most common pathogen (n = ). table compares patient characteristics across the etiological groups. patients on art were more likely to be admitted for bacterial pneumonia or noninfectious pulmonary disease than other patients (p = . ). aidsrelated causes were significantly more prevalent in the group with newly diagnosed hiv infection (p \ . ). neither the distribution of causes nor the prevalence of aids-related diagnoses changed significantly over the study period. two or more causes were found in patients ( . %). bacterial pneumonia was present concomitantly with pcp in patients, other opportunistic infections in patients, and noninfectious pulmonary disease in patients. among the patients with pcp, ( . %) also had other opportunistic infections, including who had cytomegalovirus (cmv) reactivation with cytological evidence of cmv pneumonia on bronchoalveolar lavage (bal) fluid. most of the noninfectious pulmonary diseases were related to co-morbidities; examples were pulmonary edema related to heart failure and hypercapnic arf related to chronic obstructive pulmonary disease. factors independently associated with a diagnosis of pcp were diagnosis of hiv infection at icu admission (or, . ; ci, . - . ; p = . ), time from respiratory symptom onset to icu admission (or, . per day; ci, . - . ; p = . ), and pcp prophylaxis (or, . ; ci, . . , p = . ). steroids were given to all patients with pcp and pao less than mm hg on room air and/or mv (n = ). niv was used in ( . %) of the patients with pcp, of whom only subsequently required tracheal intubation. invasive mv was used in ( . %) patients with pcp. pneumothorax occurred in patients with pcp, including patient who was receiving mv. overall in-hospital mortality was . % (n = , including deaths in the icu), and remained consistent through the study period. survival rates were not statistically different between the etiological groups, even if mv was required ( table ). significant results hiv human immunodeficiency syndrome, icu intensive care unit, pcp pneumocystis jirovecii pneumonia, iris immune restorationinduced syndrome, arf acute respiratory failure, copd chronic obstructive pulmonary disease, aids acquired immunodeficiency syndrome a clinically documented bacterial pneumonia was defined as an appropriate history and response to empiric antimicrobial therapy with focal pneumonia on chest x-ray, and either septic shock or predominantly neutrophils on bal fluid examination, without documented bacterial pathogen b including co-infection with haemophilus influenzae (n = ) and staphylococcus aureus (n = ) c including co-infection with streptococcus pneumonia (n = ) and s. aureus (n = ) d including the two co-infections with s. pneumoniae and h. influenzae e including rhodococcus equi (n = ), toxoplasma gondii (n = ), cryptococcus neoformans (n = ) and aspergillus fumigatus (n = ) of univariate analysis are listed in table . most of variables associated with short-term prognosis reflected severity of organs failures, at admission or during the icu stay. when etiological parameters were tested, only pseudomonas aeruginosa pneumonia (or, . ; % ci, . - . ; p = . ) and cmv pneumonia (or, . ; % ci, . . ; p = . ) were found to be univariately linked to in-hospital mortality. kaposi's sarcoma was also associated with a poor prognosis (or, . ; % ci, . - . ), but the analysis was underpowered (n = , p = . ). by multivariate analysis ( this study reports the causes and short-term outcome of arf in hiv-infected patients admitted to the icu during the first years after the advent of art. the . % hospital mortality rate is consistent with earlier evidence of recent survival gains among critically ill hiv-infected patients [ , ] . however, in the latest series from the san francisco general hospital ( - and - ) , almost % of hiv-infected patients with arf died before hospital discharge, and arf was among the critical illnesses associated with the worst outcomes in hiv-infected patients [ , ] . comparable findings were obtained in the early art era [ , , , ] . the lower mortality rate in our patients cannot be ascribed to lesser disease severity. severity of organ dysfunction was comparable to earlier studies, with onethird of patients requiring invasive mv and one-fourth requiring vasopressor support. differences in terms of hiv-related characteristics, such as cd cell count and hiv viral load, should be taken into account for the comparison of short-term outcome between other recent series [ , [ ] [ ] [ ] and ours. nevertheless, and as in these previous studies, we found that these variables were not independent predictors of in-hospital mortality. the introduction of art does not explain the improved survival in our study. fewer than one-third of our patients were on art at icu admission, in keeping with other studies [ , , , , ] , and this percentage showed no significant changes over the study period. it has been shown that the use of art, together with the cd t-cell count, influences long-term outcomes of hivinfected patients after icu discharge [ , ] . our data suggest, however, that art may have no influence on short-term survival of hiv-infected patients admitted to the icu for arf. similarly, no independent influence of art on short-term outcome was noted in studies of hiv-infected patients admitted to the icu for any reason [ , ] . in our study, art use was associated with nonopportunistic causes of arf and cd t-cell counts were significantly lower in patients with opportunistic infections. however, it should be noted that among the patients with newly diagnosed hiv infection, cd counts and viral load were available in only and patients, respectively. nevertheless, the severity of organ failure at admission, as reflected by the sofa score, was not different between patients receiving art and those who did not. moreover, survival was not significantly different across the etiological groups, and hiv-related causes were not independently associated with death before hospital discharge. thus, improved outcomes in patients with opportunistic pulmonary infections, mainly pcp, may contribute to explaining the lack of a survival advantage in patients on art. pcp was an independent predictor of death in most of the previous studies of critically ill hiv-infected patients, particularly when mv was needed or pneumothorax occurred, with hospital mortality rates ranging from % to % [ , , , [ ] [ ] [ ] [ ] [ ] [ ] . thus, the fact that pcp was slightly more frequent in other recent series [ , ] could have contributed to the better overall survival in our cohort. however, the mortality rate in our patients with pcp was the lowest reported to date, and this cause was associated with the best short-term outcome. this difference cannot be ascribed to differences in steroids use, as steroids have been extensively prescribed to treat severe pcp since the early s [ ] . recent improvements in the survival of hiv-infected patients with pcp are related to advances in respiratory support modalities, such as the routine use of pressure support ventilation [ ] and protective ventilation for intubated patients with pcp [ , ] , who consistently meet criteria for acute lung injury or acute respiratory distress syndrome (ards). by multivariate analysis, independent predictors of hospital mortality included a need for invasive mv, a need for vasopressors, a longer time from hospital admission to icu admission, and the presence of more than cause of arf. transfer of hiv-infected patients from another ward to the icu has been associated with higher mortality rates than icu admission from the emergency room [ ] . in another study, early intensive management improved the prognosis of patients with severe bacterial sepsis [ ] . in our cohort, half the patients had arf due to bacterial pneumonia, including . % with septic shock. in two-thirds of the patients with bacterial pneumonia, faster icu admission from the emergency room may have allowed earlier initiation of appropriate sepsis management. thus, the lower hospital mortality rate compared to earlier studies [ , , ] , most notably in patients with bacterial pneumonia, may be partly ascribable to the policy of prompt icu admission from the emergency department at our hospital. furthermore, our aggressive diagnostic strategy supplied the etiology of arf in nearly all our patients. establishing the etiological diagnosis has been shown to improve survival [ ] . thus, our results suggest that hospital mortality of hiv-infected patients with arf depends chiefly on the severity of organ failure at admission and during the icu stay and that improvement in-hospital survival results primarily from advances in intensive care practices, as opposed to improvement in immune status and use of art. our results support earlier evidence that bacterial pneumonia is now a major cause of arf among hivinfected patients [ , , ] . art reduces the risk of bacterial pneumonia during aids [ ] , although hivinfected patients with mild cd t-cell depletion remain at increased risk [ ] . this may explain why, despite art advent, bacterial pneumonia was the most frequent cause of arf in our study. two studies found a decrease in the incidence of pcp-related arf early in the art era [ , ] . in our cohort, pcp was diagnosed in one-third of patients overall and was even more common among patients with previously unknown hiv infection. that incidence of pcp remains high is in keeping with recent series from san francisco and london, where pcp was the most common etiology [ , ] . the fact that more than half the cases of pcp occurred in patients who were aware of their hiv infection suggests inadequate compliance with pcp prophylaxis. poor compliance may explain why the frequency of pcp remained unchanged throughout the study period, although the frequency of inaugural arf tended to decrease. the proportion of noninfectious non-hiv-related causes of arf was considerably higher than in studies done before the advent of art [ , , ]. the immune system reconstitution and increased life expectancy obtained with art expose the patients to exacerbations of co-morbid conditions unrelated to hiv infection, such as chronic obstructive pulmonary disease or chronic heart failure. this observation is the main change in clinical and etiological patterns induced by art. our study has several limitations. first, it has the limitations inherent in its retrospective design. second, we defined the use of art and pcp prophylaxis as adherence to these treatments, as opposed to their prescription. we cannot exclude that some patients were misclassified as adherent or nonadherent by the infectious diseases physicians. difficulties with the evaluation of adherence occur in all studies of hiv-infected patients, even those conducted prospectively. third, our study was done in a single icu, which may have led to patient selection bias. the population admitted to an icu depends on local policies of admission and influences both etiological and outcome patterns [ ] . however, hiv infection is not considered a reason for refusing admission at our icu, and the characteristics of our population are consistent with those of patients in other studies [ , ] . in conclusion, hospital mortality of hiv-infected patients with arf depends mainly on the number and severity of organ failure at admission and during the icu stay and is not influenced by the extent of immune deficiency. hospital survival has improved when compared with studies from the pre-art era, which is not ascribable to the advent of highly active antiretroviral therapy. we believe that this evolution results from global progresses in intensive care practices, such as early icu transfer from the emergency department or other hospital wards, niv for pcp, and aggressive management of bacterial sepsis, even if our study was not designed to measure the individual effects of these procedures. finally, we found that bacterial pneumonia was the most common cause of arf in hiv-infected patients, even if pcp remains a major cause of life-threatening respiratory failure, most notably in patients whose hiv infection was previously unknown. respiratory disease trends in the pulmonary complications of hiv infection study cohort. pulmonary complications of hiv infection study group predictors of shortand long-term survival in hiv-infected patients admitted to the icu impact of haart advent on admission patterns and survival in hivinfected patients admitted to an intensive care unit intensive care in patients with hiv infection in the era of highly active antiretroviral therapy intensive care of patients with the acquired immunodeficiency syndrome: outcome and changing patterns of utilization reappraisal of the aetiology and prognostic factors of severe acute respiratory failure in hiv patients outcomes of intensive care for patients with human immunodeficiency virus infection clinical course, prognostic factors, and outcome prediction for hiv patients in the icu. the pip (pulmonary complications, icu support, and prognostic factors in hospitalized patients with hiv) study pulmonary complications of hiv infection infectious lung complications in patients with hiv/ aids characteristics and outcomes of hiv-infected patients in the icu: impact of the highly active antiretroviral treatment era epidemiology of human immunodeficiency virus-associated opportunistic infections in the united states in the era of highly active antiretroviral therapy highly active antiretroviral therapy decreases mortality and morbidity in patients with advanced hiv disease intensive care of human immunodeficiency virus-infected patients during the era of highly active antiretroviral therapy survival for patients with hiv admitted to the icu continues to improve in the current era of combination antiretroviral therapy improved survival for hiv infected patients with severe pneumocystis jirovecii pneumonia is independent of highly active antiretroviral therapy survival of hiv-infected patients in the intensive care unit in the era of highly active antiretroviral therapy acute respiratory failure (arf) in hiv-infected patients: trends in etiologies and prognostic factors on the first decade of highly active antiretroviral therapy (haart) (abstract no. ) revised surveillance case definitions for hiv infection among adults, adolescents, and children aged \ months and for hiv infection and aids among children aged months to \ years--united states guidelines for using antiretroviral agents among hivinfected adults and adolescents the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure aids-related pneumocystis carinii pneumonia in the era of adjunctive steroids: implication of bal neutrophilia critical care of immunocompromised patients: human immunodeficiency virus aetiology and prognostic factors of patients with aids presenting life-threatening acute respiratory failure mechanical ventilation for pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome: is the prognosis really improved improvements in outcomes of acute respiratory failure for patients with human immunodeficiency virus-related pneumocystis carinii pneumonia a controlled trial of early adjunctive treatment with corticosteroids for pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome california collaborative treatment group noninvasive ventilation for treating acute respiratory failure in aids patients with pneumocystis carinii pneumonia low tidal volume ventilation is associated with reduced mortality in hiv-infected patients with acute lung injury meta-analysis of acute lung injury and acute respiratory distress syndrome trials early goaldirected therapy in the treatment of severe sepsis and septic shock bacterial pneumonia in hospitalized patients with hiv infection. the pulmonary complications, icu support and prognostic factors of hospitalized patients with hiv (pip) study the importance of bacterial sepsis in intensive care unit patients with acquired immunodeficiency syndrome: implications for future care in the age of increasing antiretroviral resistance management of patients with hiv in the intensive care unit effect on antiretroviral therapy on the incidence of bacterial pneumonia in patients with advanced hiv infection pyogenic bacterial lower respiratory tract infection in human immunodeficiency virus-infected patients variations in intensive care unit utilization for patients with human immunodeficiency virus-related pneumocystis carinii pneumonia: importance of hospital characteristics and geographic location acc/aha key data elements and definitions for measuring the clinical management and outcomes of patients with chronic heart failure: a report of the american college of cardiology/american heart association task force on clinical data standards (writing committee to develop heart failure clinical data standards): developed in collaboration with the standards for the diagnosis and treatment of patients with copd: a summary of the ats/ers position paper staging of chronic kidney disease: time for a course correction acknowledgments we thank antoinette wolfe for english revision of the manuscript. this study was supported by a grant from the assistance-publique hôpitaux de paris (aom ), a nonprofit institution.conflict of interest statement all of the authors declare that they have no conflict of interest. key: cord- - d l bn authors: antonelli, massimo; azoulay, elie; bonten, marc; chastre, jean; citerio, giuseppe; conti, giorgio; de backer, daniel; lemaire, françois; gerlach, herwig; groeneveld, johan; hedenstierna, goran; macrae, duncan; mancebo, jordi; maggiore, salvatore m.; mebazaa, alexandre; metnitz, philipp; pugin, jerôme; wernerman, jan; zhang, haibo title: year in review in intensive care medicine, : i. brain injury and neurology, renal failure and endocrinology, metabolism and nutrition, sepsis, infections and pneumonia date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: d l bn nan recent experimental evidence suggests that matrix metalloproteinases (mmps) are implicated in the pathophysiology of traumatic brain injury (tbi) by increasing blood-brain barrier permeability and exacerbating posttraumatic edema. mmps are zinc-dependent and cell surface-associated endopeptidases that cleave all extracellular matrix (ecm) components, including collagen, laminin, and proteoglycans. the mmps and their potential deleterious effects are tightly regulated at transcriptional and post-transcriptional levels through proform activation and by mmp tissue inhibitors (timps) two members of this family have a very specific and marked activity against gelatin and are termed gelatinases. in vitro studies have demonstrated that the secretion of gelatinases is significantly increased in cortical cultures when mechanical injury is simulated. in human tbi, data about the presence of gelatinases in the brain extracellular fluid (ecf) and their temporal profile, both in plasma and ecf, are still lacking. sahuquillo's group [ ] examined the acute profile of mmp- and mmp- in the plasma of patients with moderate or severe tbi and, more interestingly, in the brain extracellular fluid (ecf). high levels of gelatinases were found in plasma and brain ecf in the early phase of tbi, indicating that both local and systemic trauma-induced upregulation of gelatinases in the acute phase might play an important role in the pathophysiology of tbi and could be a future therapeutic target. after admission in intensive care units (icu), clinicians are often challenged with the contemporary management of intracranial priorities and extra-cranial complications. the incidence and severity of non-neurological organ dysfunction in acute neurological patients has been studied analyzing the database from the observational sepsis occurrence in acutely ill patients (soap) study in icu [ ] . the data comes from cases, % of the , patients in the soap database, admitted with a neurological diagnosis, % with traumatic brain injury and % with cerebrovascular accident. neurological patients developed icu-acquired sepsis and respiratory failure more frequently than the other patients, and length of stay, icu and hospital mortality were higher compared with non-neurological patients. multivariate logistic analysis showed that cardiovascular failure, hepatic failure, and ali/ards were factors independently associated with a higher risk of death in the icu. one of the main intracranial therapy targets in the acute phase is high intracranial pressure (hicp). mauritz [ ] described icp use in a sample of , severe tbi from a registry of patients admitted to austrian icus between and . mauritz aimed to investigate reasons why patients did or did not receive icp monitoring and to describe factors influencing hospital mortality after severe tbi. the ad hoc created statistical model explains only % of the variance of the use of icp monitoring, but clearly showed that severity and age are importantly associated with icp monitoring. the more severe, as the less injured, cases were less likely to be submitted to icp. that is likely to reflect a clinical judgment concerning who can benefit from invasive monitoring. an evaluation of potential salvageability is part of the decisional analysis. interestingly, no clear, standardized definition of ''salvageability'' is available. older patients are less often monitored. the second aim of the paper was to analyze the impact of several predictors, including icp monitoring, on mortality at hospital discharge. the study confirms a clear association between the number of cases treated by center per year and better outcome. this supports the benefit of centralization, as shown in tbi and other neurological non-traumatic pathologies. finally, an additional result was that the subgroup with the highest rate of icp monitoring had the lowest mortality suggesting a utility of monitoring and treating high icp. due to potential complication icp related, even if minor in good hands, non-invasive methods of icp measuring are appealing. between others, the relationship between optic nerve sheath diameter (onsd) and icp in neurocritical care patients has been explored [ ] . a significant relationship between onsd and icp was recorded. changes in icp were strongly correlated with changes in onsd. enlarged onsd was a suitable predictor of elevated icp. even if the studied cohort was limited, non-invasive measurements were correlated with invasive icp. this method, once validated in a wider number of patients, could be used as a screening test when raised icp is suspected. stocchetti [ ] quantified, in a prospective study of consecutive tbi patients, the occurrence of hicp refractory to conventional medical therapy. in this tbi subset more aggressive therapies, as profound hyperventilation, barbiturates, decompressive craniectomy, are currently used. hicp is frequent; patients had at least day of icp [ mmhg . early surgery was necessary for cases, and standard medical therapy [sedation, mannitol, cerebrospinal fluid (csf) withdrawal, paco [ ] [ ] [ ] [ ] [ ] [ ] was used in patients. reinforced treatment (paco - mmhg, induced arterial hypertension, muscle relaxants) was used in cases ( %), and second-tier therapies in ( %). surgical decompression and/or barbiturates were used in of cases ( %). six-month outcome was favorable (good recovery or moderate disability) in cases ( %). hicp was associated with worse outcome. outcome for cases who had received second-tier therapies was significantly worse ( % favorable at months, p = . ). therefore, hicp is frequent and is associated with worse outcome. the indications for surgical decompression and/or barbiturates seem restricted to less than % of severe tbi. the use of hyperventilation and the adherence to international guidelines after tbi have been studied [ ] analyzing data coming from european centers, participating in the brainit initiative (http://www.brainit.org). one hundred and fifty-one patients and , abgs, representing , ventilation episodes (ve), were included in the analysis. patients without elevated intracranial pressure (icp \ mmhg) manifested a statistically significant higher paco ( ± . mmhg) in comparison to patients with elevated icp (c mmhg ( ± . mmhg). intensified forced hyperventilation (paco b mmhg) in the absence of elevated icp was found in only ve ( %). early prophylactic hyperventilation was used in , ve ( %). during forced hyperventilation simultaneous monitoring of cerebral oxygenation was used in only %. overall adherence to current guidelines seems common, but early prophylactic hyperventilation and the use of additional cerebral oxygenation monitoring during forced hyperventilation are not followed exposing the patient to potential iatrogenic complications. after the acute phase, hormonal disturbances have been described both in tbi and in subarachnoid hemorrhage patients. maiya [ ] retrospectively studied acute anatomical changes in the pituitary gland in tbi patients undergoing magnetic resonance imaging (mri) during the acute phase. mri scans from normal healthy volunteers were used as controls. the pituitary glands were significantly enlarged in the tbi group. twelve of the cases ( %) demonstrated focal changes. in approximately % of patients acute tbi was associated with pituitary gland enlargement with specific lesions. mri of the pituitary may provide useful information about the mechanisms involved in post-traumatic hypopituitarism. the neuro-intensive care and emergency medicine (nicem) section of the european society of intensive care medicine (esicm) developed a document on neuromonitoring in neuro-intensive care [ ] . the questions discussed and addressed in this manuscript were: ( ) who should have icp monitoring and for how long? ( ) what icp technologies are available and what are their relative advantages/disadvantages? ( ) should cpp monitoring and autoregulation testing be used? ( ) when should brain tissue oxygen tension [pbro( )] be monitored? ( ) should structurally normal or abnormal tissue be monitored with pbro( )? ( ) should microdialysis be considered in complex cases? this articulated paper provide useful information to clinicians working in nicu and also to those developing specialist nicu services within their hospital practice. the paper by schlenk [ ] in patients with subarachnoid hemorrhage suggests, as indicated by strong [ ] in the accompanying editorial, that great caution is needed in choice of a target range for plasma glucose if tight glycemic control with insulin is undertaken. the authors in a prospective, nonrandomized, single-center study, explored whether hyperglycemia exerts deleterious effects via cerebral energy metabolism and the effects of cerebral high/low glucose in patients with aneurysmal subarachnoid hemorrhage. in all patients a microdialysis catheter was inserted. cerebral low-glucose episodes and high-glucose episodes occurred independently of blood glucose levels. during high-glucose episodes cerebral microdialysate levels were normal, while cerebral low glucose, occurring more frequently in symptomatic patients, was associated with severe cellular distress, i.e., increase in lactate/pyruvate ratio, glutamate, glycerol and with unfavorable outcome. cerebral low glucose was associated with severe metabolic distress and may present a target for therapy to improve clinical outcome. tight glycemic control could be deleterious in this neurological population. electrical activity in icu/epilepsy legriel [ ] studied icu patients with status epilepticus (se). median seizure time was min and patients had seizures longer than min. the most common causes of se were cerebral insult in % and anticonvulsant drug withdrawal in % of patients. no cause was identified in % of patients. median time from se to treatment was . the se was refractory in % patients. hospital mortality was %. by multivariate analysis, independent predictors of -day mortality were age, gcs at scene, continuous se, symptomatic se and refractory se. further studies are needed to evaluate the possible impact of early maximal anticonvulsant treatment on outcomes. an increasing interest is rising re-evaluating the utility of monitoring cerebral electrical activity. this is done, usually, with continuous eeg system even if other, simpler, approaches are explored. walsh [ ] prospectively assessed whether the entropy module, a device to measure hypnosis in anesthesia, is a valid measure of sedation state in critically ill patients. four hundred and seventyfive trained observer assessments were made and compared with concurrent entropy numbers. entropy of the frontal eeg does not discriminate sedation state adequately for clinical use in icu patients. morandi [ ] and coworkers undertook a multinational effort to identify conflicts in terminology and phenomenology of delirium to facilitate communication across medical disciplines and languages. the evaluation of the terminology used for acute brain dysfunction was determined conducting communications with authors from academic communities throughout countries/regions that speak the variants of the romanic languages included into this manuscript. interestingly only % use the term delirium to indicate the disorder as defined by the dsm-iv as an acute change in mental status, inattention, disorganized thinking and altered level of consciousness. attempts towards standardization in terminology, or at least awareness of differences across languages and specialties, will help cross-talk among clinicians and researchers. cheung [ ] surveyed the same topic in canadian icus with a response rate of . %. when an etiological cognitive dysfunction diagnosis was obvious, - % responded with the medical diagnosis to explain the cognitive abnormalities; only - % used the term ''delirium''. in contrast, where an underlying medical problem was lacking, % of respondents diagnosed ''delirium''. non-pharmacological and pharmacological management varied considerably. commonly selected pharmacological agents were antipsychotics and benzodiazepines, followed by narcotics, non-narcotic analgesics, and other sedatives. canadian intensivists diagnose delirium based upon the presence or absence of an obvious medical etiology. looking for delirium scoring methods, plaschke [ ] assessed the agreement between the delirium ratings of two independent delirium assessment methods: the confusion assessment method for the icu and the intensive care delirium screening checklist (icdsc). after excluding permanently unconscious patients with b on the richmond agitation sedations scale (rass), delirium was identified in of the patients ( %). the patients who were included were tested in paired but researcher-independent ratings of delirium by both scoring methods. the kappa coefficient determined over days of icu stay was . , indicating good agreement. soja [ ] implemented delirium monitoring, test reliability, and monitor compliance of performing the confusion assessment method for the intensive care unit (cam-icu) in trauma patients. following a webbased teaching module, bedside nurses evaluated patients daily for depth of sedation with the rass and for the presence of delirium with the cam-icu. on randomly assigned days, evaluations by nursing staff were followed by evaluations by an expert evaluator to assess compliance and reliability of the cam-icu in trauma patients. overall agreement (kappa) between nurses and expert evaluator was . . the survey revealed that nurses were confident in performing the cam-icu, realized the importance of delirium, and were satisfied with the training that they received. defining the etiology of hyponatremia in acute neurological patients is a sometime an intriguing challenge. brimioulle [ ] assessed whether hyponatremia is associated with the syndrome of inappropriate antidiuretic hormone secretion (siadh) or with cerebral salt-wasting syndrome (csws). measurement of blood, plasma, and red blood cell volumes to discriminate siadh and csws. renal, adrenal and thyroid functions were normal in all patients. average blood, plasma, and red blood cell volumes were , and ml/kg in control patients and , and ml/kg in hyponatremic patients, respectively. the adequate blood volumes in hyponatremic patients confirmed the diagnosis of siadh and did not support the concept of csws. hausfater [ ] studied the effect of non-exertional heatstroke on serum procalcitonin (pct) levels in patients with defined heatstroke during the august heat wave in france were analyzed; -day mortality was recorded. among the patients included, ( %) were admitted to an intensive care unit (icu). at days, patients ( %) had died. median pct value was . lg/l and ( %) patients had pct above . lg/l (pct?). temperature above or equal to °c was the only variable significantly associated with fatal outcome. median pct values were similar between survivors and non-survivors (p = . ). high serum pct levels was observed in heatstroke without concomitant bacterial infection. the pct was not a valid mortality predictor in heatstroke, but could be an indicator of the severity of illness. the use of a single dose of etomidate to facilitate laryngeal intubation is still widespread in spite of the demonstration of the potential of the drug to inhibit the last step in cortisol synthesis in the adrenal cortex. the recent corticus study also shows the in vivo capability of the drug to suppress acth-cortisol responses, at least in septic patients. the clinical consequences, however, remain unclear, in spite of awareness of the problem for decades. the paper by vinclair et al. [ ] somewhat adds to the evidence in describing the in vivo effects of etomidate in non-septic patients in the course of time, in terms of ratios of circulating b-deoxycortiol to cortisol, reflecting in vivo activity of the last enzymatic step in cortisol synthesis potentially inhibited by etomidate. the results suggest, in the absence of a control group, that the ratio increases after etomidate administration and is associated with a diminished rise in circulating cortisol upon acth. the etomidate effect has waned in % of patients after h. again, the clinical consequences remain unclear. adrenal insufficiency has been recently observed in critically ill patients with liver cirrhosis and severe sepsis. du cheyron et al. [ ] thus postulated that hyperreninemic hypoaldosteronism may be common and may have an impact on outcome in patients with acute on chronic liver failure. the authors thus investigated the relation between the adrenal production of gluco-and mineralo-corticoids, inflammatory status and outcome in critically ill patients with liver cirrhosis. they included consecutive patients with liver cirrhosis and applied a corticotropin stimulation test within h following icu admission. hyperreninemic hypoaldosteronism syndrome was defined as basal renin over aldosterone ratio (rra) higher than . they found impaired adrenal function in ( %) patients. patients ( %) presented with an rra [ . patients with rra [ exhibited greater disease severity and organ dysfunction scores at baseline, but risk-adjusted mortality rates were not different between the two groups. renin and il- plasma concentrations were positively correlated. a cox regression analysis revealed hyperreninemic hypoaldosteronism syndrome, il- higher than pg/ml and severe renal failure to be independent predictors of -day mortality. the authors concluded that adrenal dysfunction was common in critically ill cirrhotic patients. hyperreninemic hypoaldosteronism syndrome was related to a greater pro-inflammatory status and degree of acute organ failure, and was independently associated with a worse prognosis. in attempts to prevent harmful acute kidney injury (aki) and acute renal failure (arf) in the critically ill, control of intraabdominal hypertension may contribute. to this end, accurate measurements of intraabdominal pressure are warranted. malbrain and colleagues [ ] compared ( observers) manual foley catheter, and automated spiegelberg catheter and cimon Ò -balloon catheter measurements with the applied hydrostatic pressure in a -l container. the measurements (between - cm h o) were very close to each other. it is therefore suggested that manual are as good as automated measurements (and vice versa). other preventive measures may include drug treatments and in this context heemskerk et al. [ ] report on the interesting potential of inhibiting no-induced soluble guanylate cyclase by methylene blue (mb) administration. in a small (n= , uncontrolled) series of (refractory) septic shock patients, they suggested on the basis of a decrease in no metabolites and excretion of renal tubular injury markers in the urine that mb ( mg/kg over h) was able to decrease renal tubular damage and increase renal function parameters. however, the outcome benefits of such treatment warrant further study. the results obtained may thus increase our mechanistic rather than therapeutic insight. when aki/arf has nonetheless developed, renal replacement therapy must be initiated, the type, timing and dosing of which continues to be subject of debate. in a randomized study on septic patients (n= / ) with need for renal replacement, high volume ( ml/kg per h) was compared with low volume ( ml/kg per h) hemofiltration [ ] . the former treatment resulted in less norepinephrine requirements to maintain mean arterial blood pressure and urine output tended to increase. there was no effect on renal recovery/survival in this small, but unique (randomized!) study, while the effect on hemodynamics confirms observational data. extracorporeal therapy with polymyxin-b to scavenge endotoxin in severely septic patients has been tried before. in the study by cantaluppi et al. [ ] however, the technique was used to evaluate its effect on circulating proapoptotic factors in gram-negative sepsis (n= pmx-b, n= standard care) that could play a role, among others, in the development of organ damage such as aki/ arf. there were some indications that this therapy indeed worked in this preliminary mechanistic study. circulating proapoptotic factors on cultured renal cells diminished, as well as sofa/rifle scores, proteinuria and tubular enzymes. the data suggest a role of apoptosis in the development of sepsis-related aki/arf. when clinicians have decided on the basis of likelihood of resuming endogenous renal function, to discontinue renal replacement therapy, some patients later again need such treatment. this issue has been addressed retrospectively by wu et al. [ ] from taiwan, who, not unexpectedly, found that, among others, oliguria, high age and sofa, and a long period of prior need for renal replacement predicted its recurrent need (in %, within days). indeed, some patients may have only partial recovery of renal function or remain on renal replacement therapy even months after the initial insult. moreover, aki/arf is a risk factor for chronic renal failure over decades. the paper thus again nicely illustrates that aki/ arf with need for renal replacement therapy is not a benign disorder and the future challenge, of course, is to find ways to promote full recovery and limit (recurrent) need for renal replacement therapy. two physiological reviews and notes have dealt with renal failure, as part of a cardio-renal syndrome and as a basis for renal replacement therapy [ , ] . the authors extend the link between heart and kidney beyond congestive heart failure and also indicate a more aggressive approach in the use of different renal therapies. hemofilter circuits used for extracorporal renal replacement therapy have an expected lifespan of - h. however, they often clot prematurely which impairs azotemic control and has also effects on costs and nursing workload. antithrombin (at) deficiency has been associated with hemofilter thrombosis (ht) in patients with sepsis. lanquetot et al. [ ] investigated whether there was an association between at level activity and ht occurrence during early continuous hemofiltration. they included consecutive patients following cardiopulmonary bypass. subjects were grouped according to the appearance of one or more episodes of hemofilter thrombosis. morbidity and mortality did not differ significantly between the two groups. the authors found initial at activity to be low in both groups. on the following days at activity was lower in the ht group but was not found to be a predictor of ht in multivariate analysis. the authors concluded that the potential interest of monitoring at levels to adapt anticoagulant strategy needs to be analyzed in larger series of patients. during there has been a number of studies over tight glucose control. honiden et al. [ ] reported in a prospective observational study that early tight glucose control, within h from icu admission, was associated with a better outcome in terms of mortality, ventilator free days, and length of stay. also after the use of stepwise regression analysis, the differences between the two groups remained associated with the timing of the tight glucose control. the result calls for a prospective randomized trial to address the timing of tight glucose control. two studies report of the advantages of a computerized algorithm to facilitate and to increase success rate of tight glucose control. pachler et al. [ ] evaluated their algorithm in a small randomized study. they found a mean blood glucose value within the target range and a lower hyperglycemic index in the group using a computerized algorithm, but also a shorter sampling interval. safety was evaluated by hypoglycemia, which was inconclusive, with overall only one hypoglycemic event in the ? patients. in a questionnaire, nurses were in favor of the computerized algorithm. vogelzang et al. [ ] report from a large observational study that the hypoglycemia rate was low ( . %) and that target level was reached faster and with fewer samples when the computerized algorithm was used. lapichino et al. [ ] investigated if tight glucose control affected no-metabolism as reflected by the circulating levels of asymmetricdimethylarginine. in a prospective study of patients in septic shock they found no difference attributable to tight glucose control in clinical outcome parameters or in asymmetric-dimethylarginine. mean blood glucose were versus mg/dl, respectively, in the two groups. ornithine transcarbamylase deficiency is a rare disorder usually diagnosed in childhood, which may also have an adult onset and which gives encephalopathy and obscure unconsciousness. panlaqui et al. [ ] report of a case and point out the possible treatment with hemodia-filtration, protein elimination, and ammonia scavenging medications. the possibility of recovery with correct diagnosis and treatment makes awareness of such a rare condition important. nguyen et al. [ ] used manometry to study gastric motility. in a small case-control study they showed that critically ill patients have an impaired motility both in the antrum and pyloric region. furthermore, the synchronization between the two regions was also impaired in the critically ill patients. using gastric scintigraphic data nguyen et al. [ ] also report from a small observational study that the mode of sedation may influence gastric emptying. patients kept on midazolam and morphine had a significantly slower gastric emptying as compared to patients kept om propofol. the result clearly calls for a larger prospective randomized study. the cumulated energy deficit in icu patients primarily on enteral nutrition, which has been reported in several studies, is mainly related to underfeeding during the initial week of icu stay. desachy et al. [ ] report of a prospective randomized study in consecutive patients given enteral nutrition introduced stepwise or all at once. success rate in terms of calories delivered was significantly better in the groups given the full dose of enteral nutrition from start. that group had a larger fraction of gastric residues [ ml, but the rate of adverse events necessitating complementary parenteral nutrition was similar in the two groups. adverse effects related to the use of prokinetic therapy was reported by nguyen et al. [ ] in an observational study of consecutive patients receiving erythromycin, metoclopramide or the combination of the two. patients given the combination had a higher rate of diarrhea, but no single patient had a positive toxin test for clostridium difficile. the role of immuno-modulating diets (imds) in critically ill patients is controversial. marik and colleagues [ ] in the november issue published a meta-analysis to determine the impact of imds on hospital mortality, nosocomial infections and length of stay (los) in critically ill patients. by using the medline, embase, cochrane register of controlled trials as data source, were selected randomized control trials (rcts) that compared the outcome of critically ill patients receiving an imd or a control diet. twenty-four studies (with a total of , patients) were included in the meta-analysis; studies included icu patients, burn patients and trauma patients. four of the studies used formulas supplemented with arginine, two with arginine and glutamine, nine with arginine and fish oil (fo), two with arginine, glutamine and fo, six with glutamine alone and three studies used a formula supplemented with fo alone. overall imds had no effect on mortality or los, but reduced the number of infections. mortality, infections and los were significantly lower only in the icu patients receiving the fo imd. the authors concluded that an imd supplemented with fo improved the outcome of medical icu patients (with sirs/sepsis/ards). imds supplemented with arginine with/without additional glutamine or fo do not appear to offer an advantage over standard enteral formulas in icu, trauma and burn patients. the ratio of omega- to omega- polyunsaturated fatty acids in the diet is suggested to have implications on the severity of the inflammatory response. friesecke et al. [ ] randomized consecutive patients on parenteral nutrition, also stratified for sirs or not, to receive a standard fat emulsion or a fish-oil enriched emulsion rich in omega- polyunsaturated fatty acids. endpoints were interleukin and monocyte hla-dr as well as a number of morbidity/mortality parameters. no differences in any of the parameters studied were seen, which illustrates the difficulty to reproduce the promising results from animal studies in a relevant clinical material. regulation of the activity of transcription factor nf-kappab is an important therapeutic effect of the major omega- fatty acids in fo, eicosapentaenoic and docosahexaenoic acid (epa and dha). using the articles obtained by a pubmed research, singer and colleagues [ ] reviewed three aspects of nf-kappab/inflammatory inhibition by fish oil: ( ) the inhibition of the nf-kap-pab pathway at different levels, ( ) the production of resolvin d and protectin d that are potent, endogenous, dha-derived lipid mediators that attenuate neutrophil migration and tissue injury in peritonitis and ischemia-reperfusion injury, ( ) the modulation of vagal tone with potential anti-inflammatory effects. the authors concluded that whether the pleiotropic actions of epa/dha contribute to fo's therapeutic effect in sepsis remained to be shown. in the january issue, in conjunction with critical care medicine was published the controversial guidelines for management of severe sepsis and septic shock with the intent of providing an update to the original surviving sepsis campaign clinical management guidelines, ''surviving sepsis campaign guidelines for management of severe sepsis and septic shock,'' published in [ ] . the authors used the grade system to guide assessment of quality of evidence from high (a) to very low (d) and to determine the strength of recommendations. key recommendations, listed by category, include: early goal-directed resuscitation of the septic patient during the first h after recognition ( c); blood cultures prior to antibiotic therapy ( c); imaging studies performed promptly to confirm potential source of infection ( c); administration of broad-spectrum antibiotic therapy within h of diagnosis of septic shock ( b) and severe sepsis without septic shock ( d); reassessment of antibiotic therapy with microbiology and clinical data to narrow coverage, when appropriate ( c); a usual - days of antibiotic therapy guided by clinical response ( d); source control with attention to the balance of risks and benefits of the chosen method ( c); administration of either crystalloid or colloid fluid resuscitation ( b); fluid challenge to restore mean circulating filling pressure ( c); reduction in rate of fluid administration with rising filling pressures and no improvement in tissue perfusion ( d); vasopressor preference for norepinephrine or dopamine to maintain an initial target of mean arterial pressure [ or = mm hg ( c); dobutamine inotropic therapy when cardiac output remains low despite fluid resuscitation and combined inotropic/vasopressor therapy ( c); stress-dose steroid therapy given only in septic shock after blood pressure is identified to be poorly responsive to fluid and vasopressor therapy ( c); recombinant activated protein c in patients with severe sepsis and clinical assessment of high risk for death ( b except c for post-operative patients). in the absence of tissue hypoperfusion, coronary artery disease, or acute hemorrhage, target a hemoglobin of - g/dl ( b); a low tidal volume ( b) and limitation of inspiratory plateau pressure strategy ( c) for acute lung injury (ali)/acute respiratory distress syndrome (ards); application of at least a minimal amount of positive endexpiratory pressure in acute lung injury ( c); head of bed elevation in mechanically ventilated patients unless contraindicated ( b); avoiding routine use of pulmonary artery catheters in ali/ards ( a); to decrease days of mechanical ventilation and icu length of stay, a conservative fluid strategy for patients with established ali/ ards who are not in shock ( c); protocols for weaning and sedation/analgesia ( b); using either intermittent bolus sedation or continuous infusion sedation with daily interruptions or lightening ( b); avoidance of neuromuscular blockers, if at all possible ( b); institution of glycemic control ( b) targeting a blood glucose \ mg/dl after initial stabilization ( c); equivalency of continuous veno-veno hemofiltration or intermittent hemodialysis ( b); prophylaxis for deep vein thrombosis ( a); use of stress ulcer prophylaxis to prevent upper gi bleeding using h blockers ( a) or proton pump inhibitors ( b); and consideration of limitation of support where appropriate ( d). recommendations specific to pediatric severe sepsis include: greater use of physical examination therapeutic end points ( c); dopamine as the first drug of choice for hypotension ( c); steroids only in children with suspected or proven adrenal insufficiency ( c); a recommendation against the use of recombinant activated protein c in children ( b). the authors concluded that evidenced-based recommendations regarding the acute management of sepsis and septic shock are the first step toward improved outcomes for this important group of critically ill patients. the field of biomarkers for systemic inflammatory response syndrome (sirs) and sepsis is continuously evolving. the role of osteopontin, a protein with cell signaling functions in the interstitium upon inflammation, has been studied as a sepsis marker, by vaschetto et al. [ ] in sirs/sepsis patients (vs. controls). the investigators demonstrated that circulating osteopontin could be used as a marker of il- release and of sepsis (vs. sirs), even though the levels were elevated in sirs (vs. control) as well. osteopontin appeared capable of increasing il- secretion by macrophages in vitro. it is unclear how specific the findings were for microbial infection, however. dulhunty et al. [ ] reported on a multi-center study (n = , patients) done in australia and new zealand to answer the question whether severe non-infectious sirs differs from severe sepsis in the icu, regarding epidemiological issues. even though mortality rates were similar, severe non-septic sirs was more common and more often associated with neurological abnormalities and causes of death, than severe sepsis. this study adds to the idea that infection per se is not a major determinant of patient outcome, in contrast to the response of the body to either non-infectious or infectious threats. interactions of inflammatory mediators (or biomarkers) in sepsis remain immensely complex. de kruif et al. [ ] demonstrated that some of these biomarkers are dose-dependently inhibited by corticosteroid treatment, and variations in the gene expression of interleukins and appeared to be different between septic icu patients, non-septic bacteremic patients and healthy controls [ ] . and patients undergoing elective cardiac surgery, preoperative levels of apolipoprotein ci were associated with increased perioperative levels of tnfalpha in patients experiencing endotoxemia [ ] . payen and colleagues [ ] assessed blood leucocytes gene profiling in the course of the septic shock recovery period and tested the relation between encoding gene expression and protein level in septic shock patients. gene expression levels were studied on a dedicated microarray of genes involved in inflammatory processes. the time-related gene expression study showed significant changes in ten genes. among them, s a and s a had a reduced expression over time compared with d , whereas cd 's expression increased. by rt-qpcr, the s a plasma levels decrease in parallel with the gene expression decrease. the cd gene expression evolution significantly correlated with hla-dr monocyte expression. moreno and coworkers [ ] wished to evaluate the value of the piro concept in septic patients. piro stands for predisposition, infection, response and outcome. the predictive value for outcome of premorbid factors, together with infectious features in the icu and the subsequent changes in sequential organ failure assessment (sofa) were evaluated. the saps database was used for this purpose, on , patients with signs of infection in the icu [ h. sepsis, severe sepsis and septic shock were defined according to standard criteria. hospital mortality was %. predictive factors were scored as the saps piro score which appeared to have excellent (even somewhat better than the saps model) predictive value for mortality. the conclusion of the authors is that piro components independently contribute to outcome prediction. thereby, the study is one of the first to argue in favor of the clinical validity as well as the practicability or usefulness of the piro concept. early identification of septic patients at high risk of death may provide an opportunity to change the treatment strategy to improve the outcome. because plasma midregional pro-atrial natriuretic peptide (mr-proanp) concentrations have recently emerged as a valuable tool for individual risk assessment in such a setting, seligman et al. investigated the prognostic role of this marker in consecutive patients who developed vap [ ] . the study demonstrated that mr-proanp levels were significantly higher in vap patients dying within days when compared to survivors. in multivariate logistic regression models of predictors of death including age, sex, apache ii, and blood creatinine, mr-proanp levels on the day of diagnosis of vap and on day turned out to be the only parameters that remained as independent predictors. lipoproteins, and in particular high-density lipoproteins (hdl), have been demonstrated to play an important role in modulating inflammation and the response to infection. because apolipoprotein ci (apoci) protects against the development of murine bacterial sepsis and is virtually completely depleted in human sepsis, its timecourse in patients with severe sepsis may predict survival. this hypothesis was confirmed in a small pilot study performed by berbee et al. [ ] . upon hospitalization, apoci levels were approximately times lower than normal values in septic patients. remarkably, apoci levels remained low in non-survivors, whereas apoci levels gradually increased to normal levels in survivors. during the host response to infection and the development of sepsis and shock, vasopressor-insensitive hypotension (shock) may supervene for which the clinician may consider adjunctive therapy with hydrocortisone. kaufmann et al. [ ] again demonstrated in patients with septic shock that hydrocortisone treatment decreases vasopressor requirements and circulating il- . moreover, this therapy preserved opsonization (zymosan)-dependent neutrophil functions, while suppressing spontaneous hydrogen peroxide release (flow cytometry). the (small) study was placebo-controlled. these data may help our understanding of the mechanism of action of steroid therapy in septic shock and suggest that hydrocortisone has no major immunosuppressive effects on neutrophils limiting host defences. severe sepsis and septic shock are serious complications of hematological malignancies. vandijck and colleagues [ ] compared characteristics and outcomes in icu patients with hematological malignancies and severe sepsis/septic shock who had or had not received recent intravenous chemotherapy. among the patients, there were patients with severe sepsis and with septic shock; ( %) had received recent intravenous chemotherapy. in-hospital, and -month mortality rates were . versus . %, and . versus . % in patients with and without recent chemotherapy, respectively. by multivariate analysis, previous chemotherapy was protective. after adjustment with a propensity score for recent chemotherapy, chemotherapy was not associated with outcome. activated protein c for severe sepsis patients is a controversial therapy. in the study of kalil and sun [ ] , the authors aimed to respond to two questions. the first was, what is the current probability that activated protein c is not better than the control? and, if the current probability is not small, then the second question was, how many patients will be needed for the activated protein c confirmatory trial? to give an adequate response to these questions, the authors used a bayesian statistical approach. the p value commonly used in frequentist statistical methods only tell us how likely we will observe the reported data when the null hypothesis is true, but does not tell us the actual probability of treatment effect. bayesian methodology, however, can provide this actual (or current) probability. to do this, all available data is selected for the prior probability. the prior distributions were defined as severe skeptic, moderate skeptic, mild skeptic and enthusiastic. the authors found that, except for the enthusiastic analysis, the current probabilities that activated protein c is not better than the control are not small (range, . - . ). the number of patients needed for a confirmatory trial ranged between and , . the authors concluded that a confirmatory trial with about patients with severe sepsis and high risk of death can provide a convincing answer for moderate and mild skeptic physicians regarding the efficacy of the drug. in a special article published in the november issue finfer et al. [ ] report on the ongoing new trial of activated protein c for persistent septic shock. the authors, members of the steering committee of the trial, fully discuss the potential benefits and harm of this drug and provide in-depth explanations about organizational issues and the sponsor's role, the design and the goals of this ongoing study, the safety monitoring and the analysis and report of the data. a full disclosure of the conflicts of interest is provided in the esm file accompanying this article, together with the complete study protocol. because its particular characteristics, this article is accompanied by editors' comments [ ] , and two editorials: one providing an european view on this issue [ ] , the other providing a north-american view [ ] . intravascular-device related infections remain among the most frequent infectious complications of intensive care treatment. yet, the absolute risk on infection per catheter per day is low, hampering the analysis of intervention studies aimed to reduce this incidence. in a large study by gowardman et al. [ ] , the incidence density of tip colonization ( . / , catheter days) was almost ten times as high as that of catheter-related infection ( . / , catheter days). in another observational study, the incidence density of arterial catheter colonization was . per catheter days, and the relative risk of colonization increased in time [ ] , as did the risk for central venous catheter-related infection in a spanish multi-center study [ ] . indeed, bacterial growth on the tip of catheters has been used as a proxy for catheter-related infections. in a prospective study, souweine and coworkers [ ] determined that in patients without a clinical suspicion of catheter-related infection, the chance of bacterial growth on the tip was . % ( . per , catheter days) and that administration of antibiotics at the time of removal was associated with a lower risk of tip colonization. therefore, proportions of patients on antibiotics at the time of line removal should be taken into account when using this proxy as an endpoint. all predictions are difficult, especially when they involve the outcome of infections and sepsis. yet, several studies aimed to identify accurate prognostic factors. an increment of c-reactive protein of mg/l increased the odds of death after icu-discharge with . ( % ci . - . ) after adjustment for age, apache ii score predicted mortality and delta sofa with an area under the receiver operating characteristic curve of . ( % ci . - . ) [ ] . in icu patients, high loads of herpes simplex type i virus in bronchoalveolar lavage fluid were associated with mortality. boer and coworkers [ ] developed a prognostic model for the presence of posttraumatic stress syndrome after abdominal sepsis, that included age, length of icu stay and having traumatic memories of the icu or hospital stay [ ] . the numbers of studies evaluating genetic associations with outcome is now rapidly increasing. angiotensinconverting enzyme insertion/deletion polymorphism was not associated with outcome in sepsis and ards (villar et al. [ ] ). selective decontamination of the digestive tract (sdd) is a frequently used infection prevention measure in some countries. in sdd, non-absorbable antibiotics are applied topically and it has been assumed that detectable systemic levels of these agents, such as tobramycin, will not be reached. however, detectable serum levels of tobramycin were measured in % of patients receiving both sdd and cvvh. one patient had a toxic level of mg/l [ ] . in a randomized cross-over study, langgartner and coworkers [ ] demonstrated that appropriate bacterial concentrations of meropenem in patients on continuous renal replacement therapy could be achieved with continuous infusion, with similar areas under the curve but longer times above the mic as with intermittent bolus injection. water sinks are considered as relevant sources for many bacterial species, including pseudomonas aeruginosa. in a non-outbreak setting, these bacteria were isolated from % of samples taken from u-bends and in % of those from tap water. yet, based upon genotyping, only of patients was colonized by a p. aeruginosa clone also isolated from water samples [ ] . candida infections remain a crucial issue in the icu. in a -year national perspective observational study conducted in adult french icus bougnoux and colleagues [ ] determined the concomitant incidence, molecular diversity, management and outcome. the study enrolled with nosocomial candidemia and/or candiduria. the mean incidences of candidemia and candiduria were . and . / , admissions, respectively. eight percent of candiduric patients developed candidemia with the same species. the mean interval between icu admission and candidemia was . ± . days, and . ± . days for candiduria. c. albicans and c. glabrata were isolated in . and % of blood and . and . % of urine candida-positive cultures, respectively. fluconazole was the most frequently prescribed agent. crude icu mortality was . % for candidemic and . % for candiduric patients. seventy-five percent of the patients were infected with a unique c. albicans strain; cross-transmission between seven patients was suggested in one hospital. no difference in susceptibility and genetic background were found between blood and urine strains of candida species. it is difficult to judge the quality of care in different icus. objective and reproducible criteria are badly needed, but hampered by the absence of a gold standard. najjar-pellet and coworkers [ ] proposed a scoring system based upon variables that might serve as a tool for quality assessment in future studies. one quality variable, not included in the previously mentioned scoring system, is the recognition of rare diseases, such as, for instance acute disseminated encephalomyelitis (adem). in a retrospective multi-center study of years sonneville and coworkers [ ] describe the characteristics of adem patients needing icu admission. adem is not a benign disease, as % of the patients died and % had persistent functional sequelae. p damas and colleagues [ ] in an observational single-center study assessed the temporal relationship between icu-acquired infection (iai) and the prevalence and severity of organ dysfunction or failure (od/ f). almost , patients hospitalized for more than days during a -year observation period were studied: did not acquire iai, of whom had infection on admission (ioa); did acquire iai, of whom had ioa. the saps ii and sofa score of the first h were significantly higher in patients with than in those without iai. sofapreinf of iai patients was also higher than the sofamax of patients without iai both in patients with ( . ± . vs. . ± . ) and those without ioa ( . ± . vs. . ± . ). sofapreinf represented . % of the value of sofamax in patients with iai. sofapreinf increased significantly with the occurrence of sepsis, severe sepsis, or septic shock during icu stay. the authors concluded that icuacquired infections are significantly associated with hospital mortality; but thir contribution to od/f sems minor. aminoglycosides are broad-spectrum antibiotics active against most pathogens responsible for ventilator-associated pneumonia (vap), even those with multidrugresistance patterns. however, the systemic use of this antibiotic class is limited by its toxicity and poor penetration into the lung. aerosol administration offers the theoretical advantage of achieving high antibiotic concentrations at the infection site and low systemic absorption, thereby avoiding renal toxicity. however, some uncertainties persist regarding the real usefulness of such a mode of administration, since during mechanical ventilation (mv), high amounts of the particles dispersed by conventional nebulizers remain in the ventilatory circuits and the tracheobronchial tree before reaching the distal lung. in a study carried out in subjects with healthy lungs, ehrmann et al. [ ] showed that, using an optimized nebulization technique with a vertical spacer placed underneath a vibrating mesh nebulizer, doses of mg/kg amikacin were associated with serum concentrations equal to or less than those obtained after intravenous infusion of mg/kg amikacin. because amikacin systemic pharmacokinetics reflect deposition of the nebulized drug in the distal pulmonary parenchyma, these data strongly support the hypothesis that optimized nebulization of antimicrobial agents may permit to obtain very high lung parenchyma concentrations during a sufficiently long period of time for achieving bactericidal activity. despite advances in prophylactic perioperative antibiotic therapy, post-operative pneumonia is a feared complication following major surgery and is associated with an icu mortality of - %. one of the major predisposing factors is insufficient target-site concentration of antibiotics used for prophylaxis. because ventilation/perfusion mismatch due to atelectasis may also influence antibiotic distribution to lung tissue, hence increasing the risk of post-operative pneumonia, hutschala et al. compared the penetration of levofloxacin into the lung of two groups of patients, using microdialysis probes to sequentially determine in vivo lung tissue levels. the first group consisted of five patients who underwent coronary artery bypass grafting (cabg) with cardiopulmonary bypass (cpb) (atelectasis model), and the second one, of five patients operated with the offpump coronary artery bypass grafting (opcab)-technique [ ] . in the opcab-group, the median of the maximum concentration of levofloxacin in lung tissue was significantly higher compared with the cpb-group, establishing that atelectasis formations lead to critically lower lung tissue concentrations of levofloxacin in nondependent parts of lung tissue. such data emphasizes the necessity of direct interstitial antibiotic measurement to re-evaluate commonly accepted prophylactic and therapeutic antibiotic dosages in various clinical settings and pulmonary diseases associated with the formation of atelectasis. to favorably impact the outcome of patients with severe nosocomial sepsis, antibiotic therapy covering the offending pathogen has to be initiated without delay, which implies administration within h of clinical deterioration. in patients at risk for infection with multidrug resistant (mdr) pathogens, the clinician has to resort to broad-spectrum antimicrobials, which are themselves linked with the emergence of multi-drug resistance. the potential value of systematic endotracheal tracheal surveillance cultures as a tool to predict involvement of mdr microorganisms in vap was studied by two independent groups of investigators [ , ] bacterial colonization of the respiratory tract frequently persists, even when a patient receives antimicrobial treatment, and even though the colonizing bacteria are, in vitro, susceptible to the antibiotics. to test the hypothesis that antibiotics with presumed efficacy, based on in vitro susceptibility testing, reduce the likelihood of persistence of respiratory tract colonization, compared to antibiotics presumed to be ineffective or when no antibiotics were administered at all, visscher et al. [ ] analyzed endotracheal aspirate cultures performed during icu stay in a large cohort of mechanically ventilated icu patients. systemic antibiotics were administered on , ( %) of patient days. antibiotic use was associated with non-persistence for all pathogens, except acinetobacter species and p. aeruginosa. relative risks for non-persistence (as compared to ineffective or no antibiotics) ranged from . ( % ci . - . ) for h. influenzae to . ( . - . ) for acinetobacter species. pathogen-specific characteristics, such as the ability of biofilm formation of p. aeruginosa, or patient-specific characteristics, such as the severity of underlying disease or immune paralysis, could both be involved, but further studies are needed to elucidate this matter. unlike mycobacterium tuberculosis, nontuberculous mycobacteria (ntm) exist in the environment and can be isolated from clinical specimens in the absence of true infection. in patients with complicated and critical conditions, such as those admitted to icu, the clinical significance of ntm in respiratory specimens and the prognostic impact of ntm pulmonary infection are even more difficult to understand than in stable patients. therefore, shu et al. conducted a retrospective study including all medical icu patients with ntm being isolated from respiratory specimens within a period of . years to evaluate the clinical significance of the presence of ntm and compare the demographic characteristics, clinical manifestations, and outcome in patients with ntm pulmonary infection with those with ntm colonization and control subjects whose respiratory samples were culture-negative for mycobacteria [ ] . among the , patients admitted to medical icus, ntm were isolated from ( . %) patients. of them, ( %) were considered ntm pulmonary infection. within days after icu admission, significantly more patients with ntm infection died than those with ntm colonization and control subjects ( vs. vs. %, p \ . ). therefore, keeping a high suspicion when ntm is isolated and using careful consideration when starting anti-ntm treatment should be emphasized. in the absence of a clinically available gold standard, vap is usually diagnosed according to a combination of criteria, such as systemic signs of infection, abnormalities on chest radiograph, and microbiological identification of pathogens; however, each of these criterions combines high sensitivity with low specificity. in an attempt to raise diagnostic accuracy, luyt et al. [ ] assesses the predictive capacity for the diagnosis of vap of serum procalcitonin levels before and on the day it is suspected. among the suspected episodes vap was confirmed by quantitative bronchoalveolar lavage cultures in and refuted in . on day a . ng/ml procalcitonin threshold had % sensitivity but only % specificity for diagnosing vap. between ''before'' and day , procalcitonin increased in and % of patients with and without vap, respectively. thus, crude values and procalcitonin rise had poor diagnostic value for vap in this particular setting and should not be used to initiate antibiotics when vap is clinically suspected. mixed results were also observed by el solh et al. [ ] when they examined the potential role of serum and alveolar soluble triggering receptor expressed on myeloid cells (strem- ) as a biological marker of pulmonary aspiration syndromes. while circulating levels of strem- were comparable between those with aspiration syndromes and controls, the alveolar levels of strem- were higher in patients with culture-positive pulmonary aspiration compared with those culture-negative pulmonary aspiration (p \ . ). a cut-off value of pg/ml for alveolar strem- achieved a sensitivity of % and a specificity of % with an area under the curve of . . because cells and secretions recovered by bronchoalveolar lavage (bal) can be microscopically examined immediately after the procedure to detect the presence or absence of intracellular or extracellular bacteria in the lower respiratory tract, this technique is particularly well suited to provide rapid identification of patients with pneumonia. however, it is commonly assumed that prior antimicrobial therapy can dramatically decrease its sensitivity. in order to re-assess the influence of antibiotics on the value of various bal cytological parameters in diagnosing vap, linssen et al. [ ] studied episodes of clinically suspected vap in patients. there was no difference in areas under the curve (aucs) of receiver operating characteristic curves between patients with and without antibiotic therapy for any parameter studied. the most prominent aucs were: total cell count, . ; percentage polymorphonuclear neutrophils, . ; and percentage infected cells, . . based on these data, it appears that the percentage of infected cells in balf can be reliably used for diagnosing vap in patients receiving antibiotic therapy, provided that the introduction of the new antibiotics was recent (less than h). prevention vap remains a major problem in intensive care units and effective preventive measures are eagerly searched for. the presence of an endotracheal tube (ett) not only compromises the natural barrier between the oropharynx and trachea, but also provides a protected environment for pathogens since a biofilm develops on its inner and outer surfaces. in an attempt to prevent bacterial colonization of the lower respiratory tract in patients requiring mechanical ventilation, berra et al. [ ] developed a polyurethane ett coated with silver sulfadiazine. in a second study, the same group of investigators randomized adult patients to be intubated with a standard non-coated ett, or with a silver sulfadiazine-coated ett [ ] . coating with silver sulfadiazine prevented bacterial colonization of the ett and was associated with a thinner mucus layer. although preliminary, these data support the hypothesis that an endotracheal tube coated externally and internally with a potent antiseptic product such as silver could exert a sustained antimicrobial effect within the proximal airways and block biofilm formation at its surface. moderate and severe traumatic brain injury induce early overexpression of systemic and brain gelatinases extracranial complications in patients with acute brain injury: a post-hoc analysis of the soap study monitoring of intracranial pressure in patients with severe traumatic brain injury: an austrian prospective multicenter study noninvasive assessment of intracranial pressure using ocular sonography in neurocritical care patients refractory intracranial hypertension and ''secondtier'' therapies in traumatic brain injury the use of hyperventilation therapy after traumatic brain injury in europe: an analysis of the brainit database magnetic resonance imaging changes in the pituitary gland following acute traumatic brain injury nicem consensus on neurological monitoring in acute neurological disease hyperglycemia and cerebral glucose in aneurysmal subarachnoid hemorrhage the management of plasma glucose in acute cerebral ischaemia and traumatic brain injury: more research needed outcomes in critically ill patients with status epilepticus an assessment of the validity of spectral entropy as a measure of sedation state in mechanically ventilated critically ill patients understanding international differences in terminology for delirium and other types of acute brain dysfunction in critically ill patients recognition and labeling of delirium symptoms by intensivists: does it matter? comparison of the confusion assessment method for the intensive care unit (cam-icu) with the intensive care delirium screening checklist (icdsc) for delirium in critical care patients gives high agreement rate(s) implementation, reliability testing, and compliance monitoring of the confusion assessment method for the intensive care unit in trauma patients hyponatremia in neurological patients: cerebral salt wasting versus inappropriate antidiuretic hormone secretion is procalcitonin a marker of critical illness in heatstroke? duration of adrenal inhibition following a single dose of etomidate in critically ill patients hyperreninemic hypoaldosteronism syndrome, plasma concentrations of interleukin- and outcome in critically ill patients with liver cirrhosis in vitro validation of a novel method for continuous intra-abdominal pressure monitoring short-term beneficial effects of methylene blue on kidney damage in septic shock patients a pilot randomized study comparing high and low volume hemofiltration on vasopressor use in septic shock polymyxin-b hemoperfusion inactivates circulating proapoptotic factors risk factors of early redialysis after weaning from postoperative acute renal replacement therapy cardiorenal syndrome: refining the definition of a complex symbiosis gone wrong renal replacement therapies: physiological review antithrombin level and circuit thrombosis during hemofiltration after cardiopulmonary bypass early versus late intravenous insulin administration in critically ill patients tight glycaemic control by an automated algorithm with time-variant sampling in medical icu patients computerassisted glucose control in critically ill patients tight glycemic control does not affect asymmetric-dimethylarginine in septic patients acute hyperammonemic encephalopathy in adult onset ornithine transcarbamylase deficiency diminished functional association between proximal and distal gastric motility in critically ill patients the effects of sedation on gastric emptying and intra-gastric meal distribution in critical illness initial efficacy and tolerability of early enteral nutrition with immediate or gradual introduction in intubated patients risk of clostridium difficile diarrhoea in critically ill patients treated with erythromycin-based prokinetic therapy for feed intolerance immunonutrition in critically ill patients: a systematic review and analysis of the literature fish oil supplementation in the parenteral nutrition of critically ill medical patients: a randomised controlled trial antiinflammatory properties of omega- fatty acids in critical illness: novel mechanisms and an integrative perspective surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock serum levels of osteopontin are increased in sirs and sepsis does severe non-infectious sirs differ from severe sepsis? results from a multi-centre australian and new zealand intensive care unit study the influence of corticosteroids on the release of novel biomarkers in human endotoxemia the human response to infection is associated with distinct patterns of interleukin and interleukin expression preoperative apolipoprotein ci levels correlate positively with the proinflammatory response in patients experiencing endotoxemia following elective cardiac surgery gene profiling in human blood leucocytes during recovery from septic shock sepsis mortality prediction based on predisposition, infection and response prognostic value of midregional pro-atrial natriuretic peptide in ventilator-associated pneumonia plasma apolipoprotein ci correlates with increased survival in patients with severe sepsis stress doses of hydrocortisone in septic shock: beneficial effects on opsonizationdependent neutrophil functions impact of recent intravenous chemotherapy on outcome in severe sepsis and septic shock patients with hematological malignancies how many patients with severe sepsis are needed to confirm the efficacy of drotrecogin alfa activated? a bayesian design design, conduct, analysis and reporting of a multi-national placebocontrolled trial of activated protein c for persistent septic shock c for persistent septic shock science, medicine and industry: are we getting out of the black hole in sepsis research? once is not enough: clinical trials in sepsis influence of insertion site on central venous catheter colonization and bloodstream infection rates indwelling time and risk of colonization of peripheral arterial catheters in critically ill patients risk factors and prognosis of catheter-related bloodstream infection in critically ill patients: a multicenter study do antibiotics administered at the time of central venous catheter removal interfere with the evaluation of colonization? c-reactive protein concentration as a predictor of in-hospital mortality after icu discharge: a prospective cohort study herpes simplex virus load in bronchoalveolar lavage fluid is related to poor outcome in critically ill patients factors associated with posttraumatic stress symptoms in a prospective cohort of patients after abdominal sepsis: a nomogram angiotensinconverting enzyme insertion/deletion polymorphism is not associated with susceptibility and outcome in sepsis and acute respiratory distress syndrome systemic tobramycin concentrations during selective decontamination of the digestive tract in intensive care unit patients on continuous venovenous hemofiltration pharmacokinetics of meropenem during intermittent and continuous intravenous application in patients treated by continuous renal replacement therapy the role of water fittings in intensive care rooms as reservoirs for the colonization of patients with pseudomonas aeruginosa candidemia and candiduria in critically ill patients admitted to intensive care units in france: incidence, molecular diversity, management and outcome quality assessment in intensive care units: proposal for a scoring system in terms of structure and process acute disseminated encephalomyelitisin the intensive care unit: clinical features and outcome of adults intensive care unit acquired infection and organ failure pharmacokinetics of high-dose nebulized amikacin in mechanically ventilated healthy subjects the impact of perioperative atelectasis on antibiotic penetration into lung tissue: an in vivo microdialysis study systematic surveillance cultures as a tool to predict involvement of multidrug antibiotic resistant bacteria in ventilator-associated pneumonia screening for resistant gram-negative microorganisms to guide empiric therapy of subsequent infection throat and rectal swabs may have an important role in mrsa screening of critically ill patients effects of systemic antibiotic therapy on bacterial persistence in the respiratory tract of mechanically ventilated patients nontuberculous mycobacteria pulmonary infection in medical intensive care unit: the incidence, patient characteristics, and clinical significance usefulness of procalcitonin for the diagnosis of ventilator-associated pneumonia triggering receptors expressed on myeloid cells in pulmonary aspiration syndromes influence of antibiotic therapy on the cytological diagnosis of ventilator-associated pneumonia antimicrobialcoated endotracheal tubes: an experimental study internally coated endotracheal tubes with silver sulfadiazine in polyurethane to prevent bacterial colonization: a clinical trial key: cord- -sw qbbj authors: aylward, ryan e.; van der merwe, elizabeth; pazi, sisa; van niekerk, minette; ensor, jason; baker, debbie; freercks, robert j. title: risk factors and outcomes of acute kidney injury in south african critically ill adults: a prospective cohort study date: - - journal: bmc nephrol doi: . /s - - - sha: doc_id: cord_uid: sw qbbj background: there is a marked paucity of data concerning aki in sub-saharan africa, where there is a substantial burden of trauma and hiv. methods: prospective data was collected on all patients admitted to a multi-disciplinary icu in south africa during . development of aki (before or during icu admission) was recorded and renal recovery days after icu discharge was determined. results: of admissions, the mean age was . years and mean saps score was . . comorbidities included hypertension ( . %), hiv ( . %), diabetes ( . %), ckd ( . %) and active tuberculosis ( . %). the most common reason for admission was trauma ( %). aki developed in ( . %). male gender, illness severity, length of stay, vasopressor drugs and sepsis were independently associated with aki. aki was associated with a higher in-hospital mortality rate of . % vs . % in those without aki. age, active tuberculosis, higher saps score, mechanical ventilation, vasopressor support and sepsis were associated with an increased adjusted odds ratio for death. hiv was not independently associated with aki or hospital mortality. ckd developed in of ( . %) patients with stage aki; none were dialysis-dependent. conclusions: in this large prospective multidisciplinary icu cohort of younger patients, aki was common, often associated with trauma in addition to traditional risk factors and was associated with good functional renal recovery at days in most survivors. although the hiv prevalence was high and associated with higher mortality, this was related to the severity of illness and not to hiv status per se. acute kidney injury (aki) is commonly encountered in the intensive care unit (icu) [ ] , but with a widely variable reported incidence due to non-standardization of its definition [ ] . regardless of the definition used, aki is a well-recognized independent risk factor for mortality, is associated with substantial morbidity and is a current major cause for global concern [ ] [ ] [ ] [ ] . furthermore, aki requiring dialysis is now recognized as a risk factor for end stage kidney disease in the long term [ , ] and is associated with poor long-term quality of life after icu discharge [ , ] . aki has been well characterized in high income (hi) countries and appears to be increasing in incidence [ , [ ] [ ] [ ] . however, there is a marked paucity of data from african icu's concerning the incidence, aetiology and effect of aki on mortality and functional renal recovery, where the prevalence of hiv and trauma is high and where resources are often limited [ , , ] . renal replacement therapy is an expensive [ ] and scarce resource in south africa [ ] and in particular, in the rest of sub-saharan africa [ , ] . the international society of nephrology has boldly called for by : the elimination of preventable deaths from aki by [ ] . timely diagnosis and prevention remain the most important strategies. accordingly, understanding the epidemiology of aki in lower and middle income (lmi) countries must be a key step in tackling this problem. our aim therefore, was to describe the epidemiology of aki in patients admitted to our south african multidisciplinary icu, where there is currently a high prevalence of hiv and traumaassociated admissions. we sought to characterize the factors associated with the development of aki, the effect of hiv on aki as well as survival and to report on the -day renal function outcome of all who developed aki. an observational prospective design was used. cohorts were divided into those who did and did not develop aki (prior to and/or after admission to the icu) as well as by hiv status where known. all patients older than years admitted to the livingstone hospital icu between january and january were included. patients who died within h of being admitted to icu, those who were brain-dead awaiting organ harvesting, and patients with known or presumed end stage kidney disease were excluded from the study. the livingstone hospital adult icu is a tertiary service, closed, multi-disciplinary -bed unit serving a catchment area of . million people. the hospital is government-funded and is located in the nelson mandela bay metropole in south africa where . million people live in an urban setting, . % of whom live in informal shack dwellings and . % of whom are unemployed. the balance of , people live in surrounding rural areas within a radius of km [ ] . full time consultant supervision is provided by two intensivists and two nephrologists. the provision of dialysis is also government-funded and not restricted within the icu or by hiv status. however, general prognosis and current resource limitations are taken into consideration prior to the admission of any patient to the icu [ ] . the modality of dialysis is chosen by the treating consultant based on clinical status with a preference for intermittent haemodialysis or sustained low efficiency daily dialysis (sledd) due to cost constraints. continuous renal replacement therapy (crrt) is reserved for severely haemodynamically unstable patients and for those with raised intracranial pressure. referring disciplines include medicine, trauma, general surgery, urology, neurosurgery, orthopaedics, obstetrics and gynaecology. elective cardiology and cardio-thoracic surgery have their own dedicated icu. obstetrics also has their own high care although patients with advanced organ dysfunction are referred to our unit. aki was diagnosed and staged according to the kidney diseases improving global outcomes (kdigo) definition [ ] . a normal serum creatinine not older than days was assumed to be the baseline where available, as recommended [ ] . the cause of aki was determined by the treating intensivist/nephrologist and more than one cause could be assigned. aki was recorded as resolved once creatinine improved to the known or presumed baseline. if renal function had not recovered by hospital discharge, patients were followed up for at least days following icu discharge or until renal recovery. patients who had not recovered their renal function by this time were deemed to have chronic kidney disease (ckd). approval for the study (protocol number: / ) was granted by the walter sisulu university human research ethics unit. since we were conducting a nonexperimental study that would not influence clinical decision-making or patient management, the need for study participant consent was waived by the ethics unit. demographic data including age, sex, race and details related to co-morbidities were recorded. for patients known with hiv, a premorbid cd count and viral load was recorded, where available. the simplified acute physiology score (saps ) [ ] was calculated within the first hour of icu admission. the sequential organ failure assessment (sofa) [ ] was calculated h after admission and every third day thereafter, or sooner if the patient's condition deteriorated. vasopressor and mechanical ventilation requirements were also recorded. cause of aki, renal replacement modality and creatinine on admission, peak and discharge were recorded for patients in the aki cohort. sepsis was defined using sepsis- criteria [ ] . data were exported from the research electronic data capture (redcap) hosted at the university of cape town [ ] and analyzed with rstudio, (version . . ). hypothesis tests were considered significant if the two-sided p-value < . . continuous data were tested for normality using the kolmogorov-smirnov, shapiro-wilk, anderson-darling and pearson's chi-squared tests. normally distributed data are reported as means (standard deviation) and skewed data as medians (interquartile range). discrete data are presented as numbers (percentages). the student's t-test and the mann-whiteney u test were used to compare continuous data and the chisquare and fischer's exact test were used for discrete data, as appropriate. missing outcome data (n = ) were analysed using multiple imputation. hazard ratios for mortality by aki and hiv status were calculated using the cox proportional hazards model. multivariate logistic-regression models were used to determine associations of developing aki and dying. variables by bivariate analysis with an alpha level < . between aki and non-aki cohorts as well as known predictors for aki (age, sex, hypertension, active malignancy and admission saps score) were included in the model. kdigo stages , and were compared to patients who did not develop aki as reference. a total of patients were admitted to the icu during the study period and were excluded from the analysis; fig. details the reasons for exclusion. vital status after icu discharge could not be established for patients due to in-patient transfers to other hospitals and the unavailability of further records; six were in the aki cohort, and outcomes were imputed. in-hospital mortality was . % while mortality in icu was . %. the most common diagnoses admitted were: assault ( %), motor and pedestrian vehicle accidents ( %), acute abdomen ( %), pneumonia ( %; including cases later identified as tuberculosis) and self-inflicted drug/toxin overdose ( . %). admissions included surgical emergencies (n = , . %), medical emergencies (n = , . %), surgical elective cases (n = , %) and obstetric emergencies (n = , . %). table shows the baseline characteristics of all patients admitted to the icu and by aki status. aki developed in patients ( . %), . % of whom were diagnosed with aki on admission to the icu. the maximum kdigo stage was stage in ( . %), stage in ( . %) and stage in ( . %) patients respectively. figure shows the main causes identified for developing aki. herbal ingestion was only documented in patients and patients were exposed to antituberculous drugs (rifampicin and isoniazid). of the hiv positive patients who developed aki, had received tenofovir prior to aki diagnosis. histology was obtained in situations where the cause of aki was not clear or the clinical course of the patient was unclear. kidney biopsies were performed in patients ( % of the aki cohort), only of whom had hiv which showed interstitial hiv associated nephropathy. the others were in hiv negative subjects; showed features of mesangiocapillary glomerulonephritis, of which was crescentic and had features of ascending pyelonephritis. risk factors associated with aki are presented in table . on multivariate analysis, male gender, increased sofa and/or saps score, increased length of stay, the need for vasopressor drugs and eighty-eight patients were dialyzed ( . % of patients with stage aki, . % of the cohort with aki and . % of the entire cohort), . % of whom were fig. ). the most common indications for dialysis initiation were life-threatening hyperkalaemia ( . %), uraemic symptoms such as encephalopathy or seizures ( . %) and refractory metabolic acidosis ( . %). the development of aki was associated with a higher in-hospital mortality rate of . % compared to . % in those without aki (hazards ratio . , % ci . ; . ; logrank p < . (fig. ) ). further, the odds of dying increased stepwise with increasing kdigo aki stage (fig. ) in the aki cohort, an increased adjusted odds ratio for death was observed with increasing age, active tuberculosis, higher saps score, receipt of mechanical ventilation, receipt of vasopressor support and in those with sepsis (table ) . hiv infection was associated with worse survival in those with aki (fig. ) . however, on multivariate analysis, hiv was not found to be an independent risk factor for mortality (table ) . patients with hiv and aki were more severely ill on admission with mean saps score (sd) of . ( . ) versus . ( . ), p = . and sofa (iqr) of ( ; ) versus ( ; ), p = . . they also had a higher likelihood of having active tuberculosis [or ( %ci) = . ( . ; . ), p = . ]. the median premorbid cd count was significantly lower in those with aki than without ( . cells/microliter versus cells/microliter, p = . ) but viral suppression was similar in both groups (viral load log . vs . respectively, p = . ). although icu length of stay was less in hiv patients with aki (median icu days vs , p = . ), the proportion of patients with hiv who died within the first h was higher at . % compared to . % in those who were hiv negative, p = . . this is the largest prospective african study of aki in critically ill adults with an hiv seropositive rate of . %. similar studies include reports from morocco (n = ) [ ] , the democratic republic of congo (drc, n = ) [ ] and egypt (n = ) [ ] . however, only the drc study reported hiv prevalence, which was low at . %. consistent with other lmi countries, patients were younger than in hi country cohorts (mean age . years) with lower comorbidity rates [ , , , [ ] [ ] [ ] [ ] , mostly of black african ethnicity, and were representative of the local community that we serve [ ] . as in other african [ ] [ ] [ ] and hi country [ ] icubased studies, aki was very common in our cohort and affected nearly two thirds ( . %) of all patients admitted to the icu. aki was associated with male gender, higher severity of illness, more sepsis, longer icu stay and the need for vasopressors. pre-existing ckd was negatively associated with aki but reflects an admission bias against very ill patients with ckd to the unit due to a lack of resources to continue with chronic renal replacement therapy in most. increased age, severity of illness, sepsis, mechanical ventilation, the use of vasopressors and the presence of tuberculosis were independently associated with mortality in those with aki. furthermore, increasing stage of aki showed a stepwise increase in the risk of mortality. although our unit admits emergency medical as well as elective surgical cases, just over a quarter of all admissions were trauma related, reflecting the alarmingly high levels of interpersonal violence and road traffic accidents prevalent in south africa. in , interpersonal violence and road injury combined were the second leading cause of death and disability adjusted life years lost in south africa, after hiv which was the leading cause [ ] . consequently, a large proportion of aki was attributable to hypovolaemic shock ( . %) and rhabdomyolysis ( . %) in keeping with the degree of trauma-related admissions. two recent retrospective studies in south africa also highlighted aki in trauma victims as a major contributor to morbidity and mortality [ , ] . this reflects a major change in the epidemiology of aki in south africa where older reports have not highlighted trauma as a major cause of aki [ , , ] and has important public health implications for health administrators. sepsis was also a common precipitant of aki at . % which is similar to that reported in other lmi country studies in the critically ill [ , , ] . herbal and traditional medicine use is not a prominent cause of aki in our region compared with prior reports from other regions [ , ] . tropical diseases such as malaria are not endemic in our region and are therefore also not common precipitants of aki. severe aki (kdigo stage ) was common, affecting . % of all those with aki and . % of all admissions. the number of patients dialyzed ( . % of all admissions) was slightly lower than in the large acute kidney injury-epidemiologic prospective investigation (aki-epi) study where . % of all admissions were dialyzed [ ] and may be explained by local practice to usually delay the initiation of dialysis until more classic indications exist. notwithstanding this fact, most patients requiring dialysis were initiated early (within h of icu admission) reflecting the advanced state of organ dysfunction at admission and late presentation that is common in lmi countries [ ] . although the aki-epi study was multinational, only patients from africa were included. continuous renal replacement therapies are available in our center but cost in excess of times more than intermittent dialysis. as such, crrt is reserved for specific indications and the rate of crrt use was much lower in our study at . % compared to . % in the aki-epi study. of those who developed aki and survived, a significant proportion of patients with stage aki did not recover renal function fully ( . %). south africa has a very high hiv burden of . million people living with hiv as well as the largest number of people on antiretroviral therapy in the world [ ] . the hiv seropositive rate of . % in our cohort is consistent with the known background prevalence of hiv in our province of . % in adults aged - when measured in [ ] . this is vastly different to a retrospective study in a south african medical icu in [ ] where only three patients ( . %) in the aki cohort were hiv positive. in our study, active tuberculosis was very common, affecting in of all admissions. this is likely in part due to the high prevalence of hiv, but also due to the high reported background incidence of tuberculosis in the community of cases/ per year [ ] . whilst tuberculosis was not associated with aki per se, it was independently associated with mortality. many cases of active tuberculosis were diagnosed during icu admission through microbiological means and many were not the primary cause of admission. hiv infection was associated with higher mortality, as well as the presence of sepsis and active tuberculosis. it was also associated with increased severity of illness and the need for emergency admission. length of stay was shorter for those with hiv, but reflects earlier mortality in those with increased severity of illness. as in other studies in the post-haart era [ , , [ ] [ ] [ ] , it would appear from our data that traditional predictors of mortality such as higher severity of illness are implicated in predicting mortality and not hiv status, cd count, viral suppression nor the use of haart. proportionally few ( . %) hiv positive patients that developed aki were receiving tenofovir-based haart at the time of icu admission. although there was little difference in viral suppression between groups, the cd count was significantly lower in the group that developed aki thereby placing patients at risk for the immune reconstitution inflammatory syndrome (iris) [ ] . while tenofovir has been shown to be nephrotoxic [ ] , we hypothesize that the pathogenesis of aki in at least some of our hiv patients was related to the often recent initiation of haart with the development of an unmasking tuberculosis-associated iris [ ] and consequent tuberculosis sepsis syndrome with associated aki. this has previously been reported [ ] and is likely to be under-recognized. this study needs to be viewed in the context of its limitations. we may have underestimated the incidence of aki since we were unable to reliably utilize the kdigo urine output criterion for diagnosis as patients admitted to the icu were not always weighed or catheterised. secondly, . % of all patients admitted to the icu were not tested for hiv. all patients who were able to consent were encouraged to have an hiv test; however, patients that were moribund or confused were not tested for hiv without indication or consent. on the other hand, to our knowledge, this is the largest published prospective cohort of critically ill adults with hiv and aki [ ] . the study was inclusive of all major disciplines with the exception of cardiothoracics and the loss to follow up was low at . %. standardised criteria for the diagnosis of all stages of aki were used and -day renal recovery data was obtained. in this large prospective multidisciplinary icu cohort of younger patients in a lmi country with a high hiv prevalence and many trauma related admissions, aki was frequently encountered, and was associated with a high mortality, but good functional renal recovery in most survivors. while hiv infection was associated with higher mortality, this was due to increased severity of illness, not hiv status per se. epidemiology of acute kidney injury in critically ill patients: the multinational aki-epi study timing and outcome of aki in critically ill patients varies with the definition used and the addition of urine output criteria incidence, outcomes, and comparisons across definitions of aki in hospitalized individuals small acute increases in serum creatinine are associated with decreased long-term survival in the critically ill acute kidney injury: an increasing global concern raising awareness of acute kidney injury: a global perspective of a silent killer five-year risk of end-stage renal disease among intensive care patients surviving dialysis-requiring acute kidney injury: a nationwide cohort study acute kidney injury and chronic kidney disease as interconnected syndromes six-month outcome in acute kidney injury requiring renal replacement therapy in the icu: a multicentre prospective study health-related quality-of-life among survivors of acute kidney injury in the intensive care unit: a systematic review the intensive care medicine agenda on acute kidney injury intensity of continuous renal-replacement therapy in critically ill patients intensity of renal support in critically ill patients with acute kidney injury epidemiology of acute kidney injury in africa nephrology in africa-not yet uhuru cost and mortality associated with postoperative acute kidney injury an effective approach to chronic kidney disease in south africa. south african medical journal =. suid-afrikaanse tydskrif vir geneeskunde acute kidney injury among adult patients with sepsis in a low-income country: clinical patterns and short-term outcomes clinical characteristics and -day outcomes of intermittent hemodialysis for acute kidney injury in an african intensive care unit international society of nephrology's by initiative for acute kidney injury (zero preventable deaths by ): a human rights case for nephrology provincial profile: eastern cape the critical care society of southern africa consensus guideline on icu triage and rationing (conictri) kdoqi us commentary on the kdigo clinical practice guideline for acute kidney injury choice of reference serum creatinine in defining acute kidney injury saps --from evaluation of the patient to evaluation of the intensive care unit. part : development of a prognostic model for hospital mortality at icu admission the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine developing a new definition and assessing new clinical criteria for septic shock: for the third international consensus definitions for sepsis and septic shock (sepsis- ) research electronic data capture (redcap)--a metadata-driven methodology and workflow process for providing translational research informatics support epidemiology of acute kidney injury in moroccan medical intensive care patients: a regional prospective, observational study acute kidney injury is a powerful independent predictor of mortality in critically ill patients: a multicenter prospective cohort study from kinshasa, the democratic republic of congo risk, predictors, and outcomes of acute kidney injury in patients admitted to intensive care units in egypt the contrasting characteristics of acute kidney injury in developed and developing countries health and health care in south africa- years after mandela acute kidney injury on presentation to a major trauma service is associated with poor outcomes a prospective study of the demographics, management and outcome of patients with acute kidney injury in cape town renal failure in hiv-positive patients-a south african experience acute dialysis in hiv-positive patients in cape town nephrotoxins in africa acute kidney injury associated with the use of traditional medicines the fifth south african national hiv prevalence, incidence, behaviour and communication survey acute renal failure in the medical icu still predictive of high mortality. south african medical journal =. suid-afrikaanse tydskrif vir geneeskunde nationwide and regional incidence of microbiologically confirmed pulmonary tuberculosis in south africa, - : a time series analysis acute kidney injury among hivinfected patients admitted to the intensive care unit hiv-positive patients in the intensive care unit: a retrospective audit. south african medical journal =. suid-afrikaanse tydskrif vir geneeskunde clinical characteristics, outcomes and risk factors for death among critically ill patients with hiv-related acute kidney injury a practical approach to the diagnosis and management of paradoxical tuberculosis immune reconstitution inflammatory syndrome tenofovir nephrotoxicity: acute tubular necrosis with distinctive clinical, pathological, and mitochondrial abnormalities tuberculosis-associated immune reconstitution inflammatory syndrome and unmasking of tuberculosis by antiretroviral therapy acute kidney disease due to immune reconstitution inflammatory syndrome in an hiv-infected patient with tuberculosis the outcome of hiv-positive patients admitted to intensive care units with acute kidney injury springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to thank all the rotating doctors who helped collect data. noline van vuuren was invaluable in data checking and cleaning. authors' contributions ra wrote the protocol, collected and cleaned data and wrote the manuscript. evdm assisted with the protocol, consultancy and manuscript writing. sp cleaned data and performed the statistical analysis. mvn collected and cleaned data. je assisted with consultancy, following up patients in the renal unit and appraisal of the final manuscript. db assisted with data collection, consultancy and appraisal of the final manuscript. rf assisted with the protocol, consultancy, manuscript writing and follow up of patients in the renal unit. all authors approved the final version of the manuscript. the authors gratefully acknowledge roche south africa for an unrestricted research grant that was used to fund data capturing, analysis, presentation and publication of the study (ref: sa/nonp/ / ). the funder did not contribute to the design, conduct of the study, analysis or interpretation of results. not applicable. the authors declare that they have no competing interests.author details adult critical care unit, livingstone hospital, port elizabeth, south africa. key: cord- -n vxazst authors: papazian, laurent; klompas, michael; luyt, charles-edouard title: ventilator-associated pneumonia in adults: a narrative review date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: n vxazst ventilator-associated pneumonia (vap) is one of the most frequent icu-acquired infections. reported incidences vary widely from to % depending on the setting and diagnostic criteria. vap is associated with prolonged duration of mechanical ventilation and icu stay. the estimated attributable mortality of vap is around %, with higher mortality rates in surgical icu patients and in patients with mid-range severity scores at admission. microbiological confirmation of infection is strongly encouraged. which sampling method to use is still a matter of controversy. emerging microbiological tools will likely modify our routine approach to diagnosing and treating vap in the next future. prevention of vap is based on minimizing the exposure to mechanical ventilation and encouraging early liberation. bundles that combine multiple prevention strategies may improve outcomes, but large randomized trials are needed to confirm this. treatment should be limited to days in the vast majority of the cases. patients should be reassessed daily to confirm ongoing suspicion of disease, antibiotics should be narrowed as soon as antibiotic susceptibility results are available, and clinicians should consider stopping antibiotics if cultures are negative. ventilator-associated pneumonia (vap) is defined by infection of the pulmonary parenchyma in patients exposed to invasive mechanical ventilation for at least h and is part of icu-acquired pneumonia. vap remains one of the most common infections in patients requiring invasive mechanical ventilation. despite recent advances in microbiological tools, the epidemiology and diagnostic criteria for vap are still controversial, complicating the interpretation of treatment, prevention, and outcomes studies. vap imposes a significant economic burden. a recent cost evaluation from the usa estimated that the attributable cost of vap to be $ , ( % ci $ , -$ , ) [ ] . we will focus this review on current understanding of the epidemiology, diagnosis, prevention, and treatment of ventilator-associated pneumonia. other conditions such as ventilator-associated tracheobronchitis are not detailed. incidence vap is reported to affect - % of patients receiving invasive mechanical ventilation for more than days, with large variations depending upon the country, icu type, and criteria used to identify vap [ ] [ ] [ ] . vap rates in north american hospitals have been reported to be as low as - . cases per ventilator-days [ ] . european centers, however, report much higher rates. the eu-vap/cap study, for example, reported an incidence density of . vap episodes per ventilator-days [ ] . lower-middle-income countries also report higher rates compared to us hospitals and highincome countries in particular ( . vs . per ventilator-days; p = . ) [ ] . these large discrepancies are at least in part explained by differences in definitions, differences in how definitions are applied, diagnostic limitations of all definitions, and differences in microbiological sampling methods [ ] . the daily risk of vap peaks between days - of mechanical ventilation, whereas the cumulative incidence is closely related to total duration of mechanical ventilation [ , ] . the centers for disease control and prevention's national healthcare safety network (nhsn) has reported large decreases in the incidence of vap for both medical and surgical icus over the past years [ ] . these results were not confirmed, however, by an analysis using a stable definition for vap conducted by the medicare patient safety monitoring system (mpsms) from through [ ] . the incidence of vap was roughly % throughout the study period in a selected population of patients of at least years with principal diagnoses of acute myocardial infarction, heart failure, pneumonia, and selected major surgical procedures [ ] . these discrepancies suggest the possibility of variations in how surveillance criteria are applied and support the use of more objective surveillance parameters [ ] . comprehensive research to identify novel diagnostic biomarkers could be of interest in this context. incidence rates greatly vary based on the studied population. for example, vap rates as high as . / ventilator-days have been reported in cancer patients [ ] . a high incidence is also reported in trauma patients ( . % in one series of patients) [ ] , explained at least in part by the alteration of immune function after major traumatic injury, aspiration resulting from brain injury and lung contusion [ ] . the increased incidence observed in chronic obstructive pulmonary disease (copd) patients might be explained by prolonged duration of invasive mechanical ventilation (muscular weakness), high incidence of microaspiration and bacterial colonization (defective mucociliary clearance), and altered local and general host defense mechanisms [ ] . acute respiratory distress syndrome (ards) is also associated with a high risk of vap. even with the use of lungprotective strategies, incidence as high as % has been reported [ ] among ards patients in general and % in patients receiving extra-corporeal membrane oxygenation (ecmo) [ ] . age does not appear to be particularly associated with risk of pneumonia in ventilated patients. a secondary analysis of a european cohort study [ ] reported . vaps per ventilation days in middle-aged ( - years) patients, . in old patients ( - years) , and . in very old patients (≥ years). logistic regression analysis was unable to identify a higher risk of vap among elderly patients [ ] . in contrast, male gender is generally recognized as an independent risk factor for vap [ ] . the most important risk factor for vap, however, is likely the underlying medical conditions of mechanically ventilated patients including their comorbidities and severity of illness. accounting for difference in patient populations and vap definitions is crucial for the implementation of suitable surveillance programs, analyzing differences in vap rates between different icus, and evaluating potential therapeutic approaches, and prevention strategies. the systematic use of incidence density as a parameter to evaluate vap epidemiology would also be helpful to reach these latter objectives. although all-cause mortality associated with vap has been reported to be as high as %, there is still considerable controversy regarding the extent to which vap contributes to death in icu patients. in contrast, vap has been consistently associated with prolonging duration of both mechanical ventilation and icu stay. different methods have been used to evaluate the attributable mortality of vap. observational cohort studies done in the nineties reported conflicting results [ , ] . however, these studies included heterogenous populations and were not prospective [ ] . as the risk of acquiring vap is not constant throughout the duration of mechanical ventilation (the risk is higher during the first days), there is a risk of bias due to icu mortality and discharge acting as competing endpoints (the sickest patients may have very short lengths of stay because of early death). more sophisticated statistical approaches have therefore been used, such as multistate and competing risks models, to estimate the attributable mortality of vap. a competing risk survival analysis, treating icu discharge as a competing risk of icu mortality among patients treated in french icus, reported that the icu mortality attributable to vap was very low, about % on day and . % on day [ ] . in ards patients, crude mortality rates of up to . % have been reported in patients with vap versus . % in patients without vap (p = . ) [ ] . however, after adjusting for confounding factors, vap was no longer associated with icu death [ ] . even after using a multistate approach controlling for the same risk factors, the occurrence of a bacterial vap was not associated with the risk of icu death [ ] . this is consistent with recent reports in cancer patients [ ] and in traumatic brain injury patients [ ] , in which vap was not associated with death. another approach to limit the risk of biases related to the presence of confounding factors is to use randomized-controlled trials evaluating the preventive effects on vap and mortality. based on aggregate data from randomized studies on vap prevention, the estimated attributable mortality rate of vap was % [ ] . a similar approach using individual patient data for meta-analysis, including patients from vap prevention trials, estimated an attributable mortality of %, with higher mortality rates in surgical icu patients and in patients with mid-range severity scores at admission (i.e., acute physiology and chronic health evaluation scores [apache ] - and simplified acute physiology score [saps ] scores of - [ ] in contrast, attributable mortality was close to zero in trauma patients, medical patients, and patients with low or high severity of illness scores [ ] . antimicrobial resistant pathogens may increase the mortality rates associated with vap although this is controversial [ , ] }. in summary, vap is associated with prolonged duration of mechanical ventilation and prolonged icu stay, whereas mortality is mainly driven by patients' underlying conditions and illness severity. future studies should focus on more homogeneous groups of patients in order to better elucidate the differential contributions of underlying disease, type, and number of organ failures and pathogen identity and resistance profile to the risk of death associated with vap. the organisms associated with vap vary according to many factors including duration of mechanical ventilation, length of hospital and icu stays before vaps, timing and cumulative exposure to antimicrobials, the local ecology, and the occurrence of any potential epidemic phenomena in a given icu. usual gram-negative microorganisms involved in vap are pseudomonas aeruginosa, escherichia coli, klebsiella pneumoniae, and acinetobacter species; staphylococcus aureus is the major gram-positive microorganism [ ] [ ] [ ] [ ] [ ] [ ] . it is generally recognized that early-onset vap (within the first days of hospitalization) in previously healthy patients not receiving antibiotics usually involves normal oropharyngeal flora, whereas late-onset vap (occurring after at least days of hospitalization) and vap in patients with risk factors for multidrug resistant (mdr) pathogens are more likely to be due to mdr pathogens [ ] . however, mdr pathogens may be isolated in early-onset vap, mainly in the presence of certain risk factors such as antimicrobial exposure within the preceding days [ ] [ ] [ ] . some reports have found comparable rates of mdr pathogens in patients with early-versus late-onset vap [ , , ] . other risk factors for mdr pathogens generally recognized include prior colonization or infection with mdr pathogens, ards preceding vap, acute renal replacement therapy prior to vap, and the presence of septic shock at time of vap [ ] . the recent international guidelines of the european respiratory society, european society of intensive care medicine, european society of clinical microbiology and infectious diseases and asociación latinoamericana del tórax suggested that additional risk factors should be taken into account such as high local rates of mdr pathogens, recent prolonged hospital stay (> days of hospitalization) and previous colonization with mdr pathogens [ ] . resistance to third-and fourth-generation cephalosporins in enterobacteriaceae strains due to the expression of acquired extended-spectrum β-lactamases (esbls) and/ or ampc β-lactamases is a major worry [ ] . the spread of carbapenemase-producing strains is also a growing concern. mdr isolates of pseudomonas aeruginosa are increasingly prevalent [ ] ; one-half to two-thirds of acinetobacter baumannii strains causing vap are currently carbapenem-resistant [ ] . colistin resistance has increased following rising rates of colistin consumption to treat extensively drug-resistant (xdr) organisms [ ] . vap may be caused by multiple pathogens which can complicate the therapeutic approach [ , , ] . fungi rarely cause vap [ ] . candida spp. is the most common yeast isolated in respiratory samples [ ] . colonization of the lower respiratory tract by candida spp. affects up to % of mechanically ventilated patients and could be associated with an increased risk of bacterial vap, most notably caused by pseudomonas aeruginosa [ ] . however, available data do not support a direct role of candida spp. as a vap-causative pathogen [ ] . in a recent report, the relationship between candida spp. colonization and bacterial vap was prospectively evaluated in patients presenting with multiple organ failure [ ] . whereas patients ( . %) had tracheal colonization with candida spp., no association with bacterial vap was found [ ] . aspergillus spp. (mainly aspergillus fumigatus) may be involved in some late-onset vap, particularly in patients with a recent history of influenza [ ] . a recently proposed clinical algorithm assessed the relevance of positive cultures and might be helpful for clinicians to decide whether to treat or not [ ] . finally, respiratory viruses including influenza, respiratory syncytial virus, and others may be responsible for vap [ ] [ ] [ ] [ ] . the herpesviridae herpes simplex virus (hsv) and cytomegalovirus (cmv) can cause viral reactivation pneumonia in immunocompromised and nonimmunocompromised mechanically ventilated patients. histopathological evidence of hsv bronchopneumonitis has been reported in up to % of mechanically ventilated patients with worsening respiratory status [ ] . cmv reactivation is observed in - % of critically ill patients, especially in those with multi-organ failure and prolonged icu stays [ , ] . histologically proven cmv pneumonia has been reported in ards patients with persistent clinical deterioration and negative bronchoalveolar lavage bacterial culture [ ] [ ] [ ] [ ] . other viruses have been identified in mechanically ventilated patients, but their pathogenicity needs to be confirmed [ , ] . vap diagnosis is traditionally defined by the concomitant presence of the three following criteria: clinical suspicion, new or progressive and persistent radiographic infiltrates, and positive microbiological cultures from lower respiratory tract specimens [ , , , ] . the first step to diagnose vap is clinical suspicion. many criteria for suspecting vap exist (fever, leukocytosis, decline in oxygenation…), but their usefulness, alone or in combination, is not sufficient to diagnose vap [ ] . scores have been proposed to help improve diagnostic accuracy, the most used being the clinical pulmonary infection score (cpis) developed by pugin et al. [ ] : the original description of this score is based on variables (temperature, blood leukocytes, tracheal secretions aspect, oxygenation, radiographic infiltrates, and semiquantitative cultures of tracheal aspirates with gram stain), and patients with a score above are at risk of having vap. one randomized study found that using cpis to determine when to stop antibiotics led to less antibiotic consumption compared to a clinical strategy of fixed durations of antibiotics [ ] . however, using cpis to determine when to start antibiotics may be associated with undue antibiotic use due to its low specificity, particularly as compared to obtaining lower respiratory tract specimens for culture [ ] . therefore, recent guidelines do not recommend cpis to diagnose vap [ , ] . vap should rather be suspected in patients with clinical signs of infection, such as at least two of the following criteria: new onset of fever, purulent endotracheal secretions, leukocytosis or leucopenia, increase in minute ventilation, decline in oxygenation, and/or increased need for vasopressors to maintain blood pressure. these signs are not specific for vap, however, and can often be observed in the many conditions that mimic vap (e.g., pulmonary edema, pulmonary contusion, pulmonary hemorrhage, mucous plugging, atelectasis, thromboembolic disease, etc.). although almost all definitions for suspecting (and diagnosing) vap include radiographic criteria (new or progressive and persistent infiltrates), it is well known that chest x-rays are neither sensitive nor specific for vap [ , , ] . figures and display two patients for whom radiological criteria were falsely negative ( fig. ) or not contributive (fig. ) . computed tomography (ct) scan may be a good alternative since it is more sensitive; however, a strategy based on systematic lung ct-scan has obvious drawbacks, the main issues being feasibility, maintaining patient safety during transport, and availability. lung ultrasound has recently been proposed as a diagnostic aid for vap; however, data on its sensitivity and specificity are lacking [ ] . biomarkers such as c-reactive protein, procalcitonin or soluble triggering receptor expressed on myeloid cells (strem- ) have been proposed as diagnostic markers for vap; however, they lack accuracy and their use is, to date, not recommended for vap diagnosis [ , , [ ] [ ] [ ] [ ] . more research is needed to identify sensitive and specific biomarkers that could help the clinician to diagnose vap, identify the causative pathogen, and guide antibiotic therapy. a translational approach, with application of genomic, proteomic, and metabolomic methodologies, may be helpful in improving our understanding of the pathophysiology of vap and helping identify judicious biomarkers or profiles that could help clinicians [ ] . in summary, there is no single clinical criterion, biomarker or score that is accurate enough to diagnose vap. therefore, vap should be considered whenever there are new signs of respiratory deterioration potentially attributable to infection (e.g., fever, purulent sputum, leukocytosis, worsening oxygenation, unexplained hypotension, or increasing vasopressor requirements), with or without new or progressive pulmonary infiltrates. once vap is suspected, the second step of the diagnostic workup is to perform microbiological sampling (fig. ) . recently, scientific societies from north america and europe proposed recommendations to diagnose vap [ , ] (table ). the european guidelines [ ] suggested obtaining distal quantitative samples before antibiotic treatment, since it is known that, if samples are obtained after starting antibiotic treatment, the results may be altered or emerge as negative. the use of distal quantitative cultures, which may be more specific than blind (non-directed) sampling techniques, may help to reduce overutilization of antibiotics particularly if clinicians only start antibiotics in patients with positive gram stains, positive cultures, or suspected septic shock [ ] . direct examination and gram staining use are controversial. the american guidelines [ ] suggest that a high-quality gram stain from a respiratory specimen with numerous and predominant organisms provides further support for the diagnosis of vap. the absence of microorganisms on gram stain, however, does not reliably exclude vap, and so it is important to also review culture results. the limited sensitivity and specificity of gram stain are another reason why we need to identify additional rapid diagnostic strategies including biomarkers and rapid microorganism identification and susceptibility assays. presentations of diagnostic sampling techniques for vaps are sometimes confusing. invasive techniques are those which are distal and directed by bronchoscopy, such as bronchoalveolar lavage (bal), protected specimen brush (psb) or lung biopsies (an uncommon sampling method). blind mini-bal using a plugged fig. chest x-rays and ct-scan of a -year-old man who developed ventilator-associated pneumonia. chest x-ray performed the day vap was suspected seems normal (a), whereas the ct-scan performed the same day showed consolidation of the left inferior lobe (b, d). bronchoalveolar lavage yielded enterobacter aerogenes. the next day, chest x-ray showed progression of pulmonary infiltrates (c). vap diagnosis based on chest x-ray would have been delayed telescopic catheter (or blind protected specimen brush) is a non-directed sampling technique which is not always distal (because there is no confirmation of the correct placement of the tip of the catheter) and which is considered as "non-invasive" even though bleeding and pneumothoraces are possible complications. these "invasive techniques" also present several disadvantages: the need for qualified personnel to perform these procedures (even though it is now a conditional skill to become an intensivist in many countries), potential risks for the patient (hypoxemia, barotrauma, bleeding), and the associated costs especially when using disposable bronchoscopes. however, the use of bronchoscopic bal combined with quantitative cultures may achieve more reliable identification of causative agents with a higher specificity than qualitative sampling methods and allows sufficient fluid return to perform complementary analyses (i.e., cytology, albumin levels, viruses identification, galactomannan determination, procollagen iii in ards patients). qualitative cultures obtaining using proximal sampling methods such as endotracheal aspirates may overestimate the presence of bacteria potentially lead to unnecessary antibiotics use, and promotion of antibiotic resistance. however, they can be performed more quickly and simply compared to bronchoscopy, with fewer complications and resources (fig. ) . a metaanalysis of randomized trials comparing invasive microbiological sampling techniques with quantitative cultures versus noninvasive sampling methods with either quantitative or semiquantitative cultures did not find any differences in patients' outcomes [ , ] . a common dilemma is the question of whether to start antibiotics when invasive quantitative culture results are negative or below the diagnostic threshold for patients with suspected vap. the infectious diseases society of america (idsa)/american thoracic society (ats) guidelines suggest withholding antibiotics in such cases so long as they are clinically stable [ ] . this strategy might be associated with less unnecessary antibiotic use, which should reduce antibiotic-related adverse events (such as clostridium difficile emergence and rising antibiotic resistance) and costs. however, intensivists should always use their clinical judgment to temper this decision if there is other compelling evidence of pulmonary infection, if the patient received antimicrobial therapy prior to microbiological sampling, if there is associated septic shock, if the patient is immunocompromised, and/or if the patient fails to improve despite managing potential non-infectious causes of clinical deterioration. although not recommend by the recent guidelines, some patients may receive antibiotics before microbiological sampling, results of this latter being therefore negative many times. in such cases, giving a full course ( days, see below) of antibiotics may expose the patient to prolonged undue antibiotics and may promote antibiotic resistance. therefore, our recommendation is to reevaluate the patient at - h; if the clinical course is favorable, and the likelihood of infection is low, antibiotics could be stopped. another solution is to use procalcitonin to stop antibiotics at - h if the procalcitonin level is < . ng/ml or has decrease of more than % as compared to the peak value [ , , ] . another common situation is a patient who receives antibiotics for more than h at the time of microbiological sampling (whatever the indication, for an extrapulmonary infection for example). if microbiological results are negative, that suggests that the patient does not have vap. therefore, no new antibiotics should be started, and the decision on what to do with the current antimicrobial treatment should be based on the initial indication. one of the challenges in diagnosing vap, whatever the technique used (endotracheal aspirates or bronchoscopic-guided bal), is to decrease the time from sampling to pathogen identification. indeed, it currently takes at least - h using conventional microbiological methods to identify the pathogen(s) responsible for infection and its (their) sensitivity to antimicrobial treatment (fig. ) . during that time, empiric broad-spectrum fig. chest x-ray of a -year-old woman with h n influenzaassociated acute respiratory distress syndrome ("white lungs"). she developed fever, leukocytosis, purulent tracheal secretions and bronchoalveolar lavage (obtained during fiber optic bronchoscopy) yielded pseudomonas aeruginosa. chest x-ray was unchanged (same chest x-ray since week) and obviously not useful for suspecting/diagnosing ventilator-associated pneumonia antibiotics are often given [ , , ] . one of the key issues in antimicrobial stewardship is to decrease the consumption of broad-spectrum antibiotics [ ] both by limiting their prescription and shortening their duration. over the past few years, molecular methods have been developed to decrease the time between sampling organism identification, and determination of antibiotic susceptibilities. for example, the use of polymerase chain reaction (pcr) to detect bacterial dna can shorten the time of organism identification and susceptibilities, but it is restricted to specific pathogens and resistance mechanisms, for example meca to detect methicillin resistance in staphyloccocus aureus strains [ ] . although this technique is not available to determine resistance patterns for pathogens commonly responsible for vap such as pseudomonas aeruginosa [ ] or it requires a positive culture to detect resistance mechanisms [ ] , it is routinely used in many places to allow for very early de-escalation and narrowing of antimicrobial treatment in specific situations, for example to withdraw or withhold anti-mrsa antibiotics (fig. ) . recently, new tools using multiplex pcr directly applied to fresh (bronchoscopic) samples have been developed to identify pathogens. some tests screen just for the main pathogens responsible for vap, and some of them also screen for selected resistance mechanisms. the pneumonia application of the unyvero system (curetis ag, holzgerlingen, germany) allows testing for different bacteria and one fungus, including those most frequently responsible for vap, as well as resistance markers, directly in clinical specimens, with a turnaround time of to h [ ] . recent studies have evaluated this new technique as compared to conventional microbiological methods and found a concordance rate fig. schematic representation of vap diagnosis and treatment. clinical suspicion of vap refers to the association of some of the following criteria: fever, purulent sputum, leukocytosis, impaired oxygenation, unexplained hypotension or shock, new (or progression of ) pulmonary infiltrates on chest x-ray (not always observed). empirical treatment takes into account the underlying disease and its severity, the presence of risk factors for multiple-drug-resistant pathogens (antibiotic therapy in the previous days, hospital stay > days, septic shock at vap onset, ards prior to vap onset, acute renal replacement therapy prior to vap onset, previous colonization with mdr pathogen) and local pattern of antimicrobial susceptibility. immunocompromised patients, patients with empyema, lung abscess or necrotising pneumonia should receive prolonged antimicrobial course [ ] between the two techniques of - % for pathogen identification, and of - % for identifying resistance [ ] [ ] [ ] [ ] . however, this kind of technique is limited by the risk of over-detection, i.e., detection of dna of nonviable organisms, detection of pathogens at non-pathogenic thresholds, and the detection of non-pathogenic organisms (i.e., colonizers rather than invaders). this kind of technique will probably facilitate major advances in the management of vap in the near future, allowing clinicians to tailor antibiotics within a few hours (fig. ) . however, improvements in the breadth and sensitivity of the technique as well as studies evaluating the safety and efficacy of rapid diagnostics to improve the suitability and duration of antimicrobial treatment as well as impacts on patients' outcomes are needed before it can be routinely recommended. the clinical signs used to diagnose vap are neither sensitive nor specific either alone or in combination. even lung biopsies are not definitive because of the uneven distribution of lung lesions and variability in pathologists' interpretations. as such, it is highly unlikely that there will be a worldwide consensus on how best to define and conduct surveillance. this bespeaks the critical need for further research to develop and validate new diagnostic tools to support surveillance, prevention, and treatment studies as well as quality improvement initiatives. this need is particularly acute in the usa where regulators and legislators have considered including hospitals' vap rates in benchmarking and reimbursement policies. in this context, the us centers for disease control and prevention developed the concept of ventilator-associated events (vae), a surveillance strategy designed to broaden the focus of surveillance to encompass multiple causes of respiratory deterioration in ventilated patients, not just pneumonia, to make surveillance more objective, and to allow for the possibility of automated surveillance using electronic clinical data. the definition includes subcriteria to try to identify the subset of vaes that might be infection-related and which might be due to pneumonia in particular, but there are no data to suggest that vae definitions are any more (or less) accurate than traditional surveillance definitions [ ] . while lower respiratory tract surveillance cultures may help to predict the involvement of mdr microorganisms in patients that develop vap and thus decrease unnecessary broad-spectrum antibiotics use, there are no clear data that this strategy improves clinical outcomes or lowers costs [ , ] . consensus diagnostic criteria that can be objectively applied are needed to compare incidence rates between hospitals and countries for the purposes of public health planning and reimbursement. many of our presumptions about how best to prevent vap have recently been challenged. oral care with chlorhexidine and stress ulcer prophylaxis may be harmful, new data affirm the long-held fear that selective oral and should patients with suspected vap be treated based on the results of invasive sampling (bal, psb, blind mini-bal) with quantitative culture results, noninvasive sampling (endotracheal aspiration) with quantitative culture results, or noninvasive sampling with semiquantitative culture results? recommendation we suggest noninvasive sampling with semiquantitative cultures to diagnose vap, rather than invasive sampling with quantitative cultures and rather than noninvasive sampling with quantitative cultures (weak recommendation, low-quality evidence) if invasive quantitative cultures are performed, should patients with suspected vap whose culture results are below the diagnostic threshold for vap (psb with < cfu/ml, bal with < cfu/ml) have their antibiotics withheld rather than continued? recommendation noninvasive sampling with semiquantitative cultures is the preferred methodology to diagnose vap; however, the panel recognizes that invasive quantitative cultures will occasionally be performed by some clinicians. for patients with suspected vap whose invasive quantitative culture results are below the diagnostic threshold for vap, we suggest that antibiotics be withheld rather than continued (weak recommendation, very low-quality evidence) we suggest obtaining distal quantitative samples (prior to any antibiotic treatment) in order to reduce antibiotic exposure in stable patients with suspected vap and to improve the accuracy of the results. (weak recommendation, low quality of evidence) we recommend obtaining a lower respiratory tract sample (distal quantitative or proximal quantitative or qualitative culture) to focus and narrow the initial empiric antibiotic therapy. (strong recommendation, low quality of evidence) digestive decontamination may not be effective in icus with high baseline rates of antibiotic resistance, and subglottic secretion drainage may not shorten duration of mechanical ventilation or icu length-of-stay as was once thought [ ] [ ] [ ] [ ] [ ] . the practices most consistently associated with earlier extubation and/or lower mortality rates are those focused on limiting exposure to invasive mechanical ventilation by avoiding intubation and speeding extubation [ ] . interpreting the vap prevention literature is challenging because many initiatives have been reported to lower vap rates, but the limitations of vap diagnostic tools and criteria make it difficult to discern the true effect of prevention strategies [ ] . unless and until we develop sensitive and specific markers for the presence or absence of vap, providers are advised to consider more objective outcomes when evaluating the potential merits of proposed prevention strategies [ ] . these include duration of mechanical ventilation, icu length-of-stay, ventilator-associated events, antibiotic utilization, and mortality. comparing prevention measures' impacts on vap rates versus more objective outcomes can sometimes lead to surprising discrepancies. for example, meta-analyses of randomized trials of oral care with chlorhexidine suggest this intervention may lower vap rates but increase mortality [ , ] . we will use this lens to briefly review common vap prevention strategies. several recent trials evaluated the potential benefits of modifying endotracheal tube cuff shapes and/or materials to minimize seepage of microbe-laden fluids across the cuff and into the lungs. unfortunately, neither tapered cuffs nor ultrathin polyurethane proved to be any better than conventional cylindrical cuffs or polyvinyl fig. current and potential future workup processes for identification of pathogens responsible for vap. to date, it takes - h. to identify pathogen responsible for ventilator-associated pneumonia (vap) and its susceptibility to antibiotics (purple boxes), delaying the definitive, targeted treatment at that time (green boxes). awaiting these results, physicians prescribe empiric broad-spectrum antimicrobial treatment. the use of specific, targeted polymerase chain reaction (pcr) may allow shortening this time to - h., but for specific pathogens and specific resistance mechanisms. a potential future workup process will be to use multiplex pcr (blue box) to identify within less than h pathogens responsible for vap and their resistance to antimicrobials chloride at preventing vap or improving objective outcomes [ ] [ ] [ ] [ ] . likewise, manually monitoring cuff pressures every h to minimize inadvertent drops in endotracheal tube cuff pressure was no better at preventing vap, decreasing length-of-stay, or lowering mortality in a recent single center study compared to checking cuff pressures only at intubation, following frank tube migration, or detection of a cuff pressure leak [ ] . a meta-analysis of three randomized trials of automated cuff pressure monitoring did report significantly lower vap rates with automated cuff pressure systems, but the analysis was limited by small numbers, substantial heterogeneity, and limited evaluation of secondary outcomes [ ] . subglottic secretion drainage has repeatedly been associated with lower vap rates in both individual randomized trials and meta-analyses but does not appear to shorten the time to extubation, icu length-of-stay, prevent ventilator-associated events, or lower mortality rates [ ] . earlier meta-analyses did suggest a possible impact on time to extubation and icu discharge but were confounded by ambiguous study results and high levels of heterogeneity [ , ] . two studies have reported an association between subglottic secretion drainage and less antibiotic utilization, but a third did not [ ] [ ] [ ] . recent studies have also called into question the effectiveness and safety of oral chlorhexidine. there is no association between oral care with chlorhexidine and lower vap rates on meta-analysis of double-blind randomized trials [ ] . more concerningly, some meta-analyses and observational studies have reported that oral care with chlorhexidine may increase mortality rates, perhaps because some patients may aspirate some of the antiseptic triggering acute lung injury [ , , , , , ] . a cluster randomized de-adoption study is currently underway to better characterize the safety and effectiveness of oral chlorhexidine for ventilated patients [ ] . elevating the head of the bed to prevent reflux of gastric secretions into the lungs is the most commonly practiced intervention to prevent vap [ , ] but is supported by surprisingly few randomized trials. a cochrane review of randomized trials enrolling patients did report collectively fewer clinically suspected vaps in patients randomized to head-of-bed elevation, but no effect on microbiologically confirmed vap and no effect on objective outcomes [ ] . some investigators have hypothesized that putting patients in the lateral trendelenburg may be a better way to prevent vap by recruiting gravity to carry oral secretions away from the lungs. a recent study confirmed this hypothesis, but the trial was terminated early due to a surfeit of adverse events among patients randomized to lateral trendelenburg [ ] . selective oral and digestive decontamination is one of the very few preventative strategies in critical care that has repeatedly been associated with lower mortality rates [ , ] . this strategy is widely practiced in the netherlands, but practitioners elsewhere have been loath to adopt antibiotic decontamination for fear that it might promote antibiotic resistance, particularly in icus with high baseline rates of antibiotic-resistant bacteria and antibiotic utilization. ironically, oral and digestive decontamination may actually decrease overall antibiotic utilization presumably by decreasing the incidence of infections requiring treatment [ ] . nonetheless, a recent cluster randomized trial of oral and digestive decontamination in icus with high baseline rates of antibiotic resistance and antibiotic utilization found no significant impact on bloodstream infections or mortality [ ] . probiotics may protect patients from vap by modulating the microbiome and inhibiting colonization with invasive pathogens. some randomized trials have reported lower vap rates, but this signal is not present on meta-analysis restricted to double-blinded studies [ ] . a large multicenter study is currently underway [ ] . stress ulcer prophylaxis has been associated with higher vap rates in some observational studies and in a recent meta-analysis of randomized trials [ , , ] . a large randomized trial of pantoprazole vs placebo, however, reported no difference between arms in pneumonia rates [ ] . at the same time, stress ulcer prophylaxis had a relatively modest effect on gastrointestinal bleeding rates ( . % vs . %) and no impact on transfusion requirements or mortality rates. additional large randomized trials are underway. the prevention practices that have most consistently been associated with improving objective outcomes for ventilated patients have been those focused on avoiding intubation and minimizing exposure to invasive ventilation by using high flow oxygen or noninvasive ventilation as alternatives to intubation, lightening sedation, using spontaneous breathing trials to prompt early extubation, and early mobilization [ , ] . these interventions appear to be synergistic insofar as minimizing sedation facilitates mobilization and early extubation. observational studies of quality improvement collaboratives have reported that bundling these practices together is associated with earlier extubation and lower mortality rates [ ] [ ] [ ] [ ] . it will be important, however, to confirm these findings in randomized trials given the many potential sources of bias in observational studies [ ] . table summarizes current knowledge about vap prevention. intravenous (iv) antimicrobial therapy is the cornerstone of vap treatment. physicians face a dilemma, however, between avoiding ineffective treatment, inappropriate initial antimicrobial treatment being associated with increased mortality [ ] ; and on the other hand, reducing the consumption of broad-spectrum antibiotics, the latter being associated with increased bacterial resistance [ ] . therefore, treatment of vap should be a two-step process: the first step is empiric treatment, the choice and immediacy of treatment being driven by disease severity (i.e., mortality risk) and risk factors of mdr pathogens; and the second step is definitive treatment, for which clinicians should try to avoid overuse of antibiotics. the choice and timing of antimicrobial agents used should take into account four parameters: severity of the current illness, type and number of underlying diseases and their severity, risk factors for mdr pathogens, and the local pattern of antimicrobial susceptibility. risk factors for mdr pathogens include high (> %) local prevalence of pathogen resistance, antibiotic therapy in the previous days, hospital stay > days, septic shock at vap onset, ards prior to vap onset, acute renal replacement therapy prior to vap onset and previous colonization with mdr pathogens [ , ] . in non-immunocompromised patients with early-onset vap and no risk factors for mdr pathogens (as defined above), monotherapy with narrow-spectrum antibiotic (non-pseudomonal third generation cephalosporin) can be used (table ) [ ] (this situation is not mentioned in the idsa/ats guidelines [ ] ). in other situations, initial empiric treatment should include a broad-spectrum β-lactam targeting pseudomonas aeruginosa and/ or esbl-producing enterobacteriaceae (ceftazidime, cefepime, piperacillin-tazobactam or a carbapenem) plus a non-β-lactam antipseudomonal agent, such as aminoglycosides (amikacin or tobramycin) or fluoroquinolones (ciprofloxacin or levofloxacin) ( table ). the choice of the β-lactam agent should take into account previously used antibiotics, local pattern of susceptibilities and patient colonization with mdr pathogen. for example, a carbapenem should be preferred in patients colonized with esbl-producing enterobacteriaceae. indeed, although carbapenem are overprescribed in esbl carriers, - % of vap episodes in these patients are due to an esblproducing enterobacteriaceae, and it seems difficult not head-of-bed elevation [ ] may lower rates understudied, few and contradictory randomized trials tapered endotracheal tube cuffs and ultrathin polyurethane [ , ] no impact in vivo studies document persistently high rates of subclinical aspiration despite the theoretical advantages of these designs automated endotracheal tube cuff pressure monitoring [ ] may lower rates understudied, merits further evaluation subglottic secretion drainage [ ] may lower rates extensively studied but despite lower vap rates no impact on duration of mechanical ventilation, icu length-ofstay, ventilator-associated events, or mortality. unclear impact on antibiotic utilization [ , , ] may increase vap rates observational studies and some meta-analyses suggest higher vap rates but a recent large randomized trial found no impact vap prevention bundles [ ] likely lower vap rates extensively studied, almost exclusively in before-after and time-series analyses. may be associated with lower mortality rates. most benefit likely from minimizing sedation and encouraging early extubation to take into account this pathogen in the empirical antimicrobial treatment [ , ] . moreover, it has been shown that % of infection-related ventilator-associated complications were neither vap nor attributable to a documented icu infection [ ] , indicating that efforts should be concentrated on the diagnostic strategy, to use carbapenems only in patients with true infection, and to withhold carbapenems when the likelihood of infection is low. the use of new beta-lactam agents (ceftazidimeavibactam, ceftolozane-tazobactam, meropenemvaborbactam, imipenem-relebactam) in the empirical treatment of vap should probably be reserved in patients colonized with mdr/xdr pathogens, such as carbapenem-resistant enterobacteriaceae or xdr pseudomonas aeruginosa susceptible only to these drugs. the idsa/ats guidelines recommend empiric coverage of methicillin-resistant staphylococcus aureus (mrsa) in patients who received antibiotics in the preceding days or those hospitalized in units with high (> %) or unknown mrsa prevalence among vap patients [ ] . european guidelines state that mrsa coverage should be considered if the unit has > % of staphylococcus aureus respiratory isolates as mrsa [ ] . a recent study performed in the usa showed that among patients with hospital-acquired pneumonia (not specifically vap) in hospitals with mrsa prevalence > %, only % grew mrsa on respiratory specimen culture, indicating that potentially % would have been over treated by using the hospital-wide prevalence of mrsa instead of the vap-specific prevalence of mrsa [ , ] . moreover, mrsa vap prevalence is low in several countries [ ] . therefore, the empiric use of an anti-mrsa agent should be restricted to units with high (> %) incidence of vap secondary to mrsa, or in patients already colonized by mrsa. one of the goals for clinicians should be to avoid overuse of antibiotics. first, antibiotics should be stopped if no pathogen is retrieved. indeed, many episodes of suspected vap are not vap [ ] . second, in patients with bacteriologically proven vap, antibiotics should be narrowed once culture results and susceptibility tests are [ ] . in patients with esbl-producing enterobacteriaceae vap susceptible to piperacillin-tazobactam, the use of this drug could be discussed as an alternative to carbapenem since results of the merino trial may be disputable [ ] [ ] [ ] [ ] . moreover, the place of new betalactam agents (ceftolozane-tazobactam, ceftazidimeavibactam) as carbapenem-sparing agents remains to be determined, since their impact on emergence of antimicrobial resistance as compared to carbapenem is not known. their use should be reserved as last resort agents in mdr/xdr difficult to treat pathogens (carbapenemresistant enterobacteriaceae, xdr pseudomonas aer-uginosa…). last, antimicrobial therapy can be safely switched to monotherapy once pathogens responsible for infection are identified and susceptibility results have been obtained, even for non-fermenting gramnegative bacilli such as pseudomonas aeruginosa [ ] . indeed, the usefulness of combination therapy is mostly to increase the likelihood of appropriateness of treatment rather than improving the prognosis of patients. therefore, double antipseudomonal coverage in patients with pseudomonas aeruginosa vap with uncomplicated course should be avoided once susceptibility tests are available [ , ] . both european and us guidelines recommend that the duration of antimicrobial treatment for vap should not exceed days in most patients, including those infected with non-fermenting gram-negative bacilli (pseudomonas aeruginosa, acinetobacter spp….) [ , , , ] . longer course may be appropriate for immunocompromised patients and are likely necessary for patients with empyema, lung abscess, or necrotising pneumonia [ ] . shortening duration of antimicrobial below days is currently not recommended [ , , , ] , but some authors have demonstrated that treatment duration can be customized based on procalcitonin kinetics and have been able to treat some patients for < days using this strategy [ , , ] . nebulisation of antibiotics has grown in recent years, but the ideal candidates to receive this treatment are not well defined [ ] . to date, nebulized antibiotics cannot be recommended as an alternative to the intravenous route, partly because data are lacking on this indication, partly because - % of patients with vap have concurrent bacteraemia, and partly because multiple and repeated daily use of nebulisation may prolong duration of mechanical ventilation [ , ] . the use of nebulised antibiotics as an adjunctive treatment (i.e., in addition to effective intravenous therapy) is also not recommended; two recent randomized-controlled trials failed to demonstrate superiority of nebulised antibiotics (amikacin alone or combined with fosfomycin) over placebo in patients with vap due to "traditional pathogens" [ , ] . the use of nebulised antibiotics should therefore be restricted to patients with vap to xdr-gram-negative pathogens susceptible only to colistin or aminoglycosides [ ] . indeed, three meta-analyses found that in patients infected with such pathogens, the use of nebulised colistin combined with iv colistin led to better outcomes compared to iv colistin alone [ ] [ ] [ ] . whether or not nebulised antibiotics may decrease emergence of bacterial resistance, as suggested by two studies performed in patients with ventilator-associated tracheobronchitis, remains to be determined [ , ] . the use of pathogen-specific antibodies as an adjunctive or preventive treatment is currently under investigation. aerucin (aridis ® ) is an igg mab that binds to the pseudomonas alginate exopolysaccharide involved in cellular adhesion. a phase , placebo-controlled, double-blind study to assess its safety and efficacy as adjunctive therapy to standard antibiotics in patients with p aeruginosa hap/vap (nct ) has been performed recently, but results are not yet available. recent studies have evaluated the usefulness of antibodies to neutralize or inhibit specific s. aureus or p. aeruginosa virulence factors [ ] . the purpose of this kind of strategy is to reduce the risk for developing vap in patients colonized by these pathogens. results of these studies are promising, since a phase trial targeting pseudomonas aeruginosa virulence factors showed trend toward lower rate of infection due to this pathogen [ ] , and the recently released results of the saatelite study, that evaluated an antibody against staphylococcus aureus virulence factor, found also trend toward lower incidence of staphylococcus aureus pneumonia [ ] . although this strategy is more preventive than curative, the usefulness of these anti-virulence agents as adjuvant to antibiotics remains to be evaluated. there is no definitive answer to this question. the recent pth trial suggested that acyclovir does not change the number of ventilator-free days in patients presenting with hsv oropharyngeal reactivation disease [ ] . intriguingly, however, the same study reported a near significant decrease in mortality among patients randomized to acyclovir [ ] . antiviral prophylaxis using valganciclovir or valacyclovir was able to decrease blood reactivation in a randomized study involving patients [ ] . however, the valacyclovir arm was halted prematurely because of higher mortality by days without clear explanation [ ] . in another interventional trial, ganciclovir prophylaxis did not reduce plasma interleukin levels in critically ill cmv-seropositive adults [ ] . the ganciclovir group did, however, have more ventilator-free days in both the intention-to-treat population and in the sepsis subgroup [ ] . more research is needed to evaluate the precise clinical consequences of viral reactivations and whether and how they should be managed. despite a lot of research, vap remains one of the most frequent icu-acquired infections and is associated with an increased mortality. which sampling method to use is still a matter of controversy. emerging microbiological tools will likely modify our routine approach to diagnosing and treating vap in the next future. large randomized trials are needed to confirm that bundles that combine multiple prevention strategies may improve outcomes. treatment should be limited to days in the vast majority of the cases. further research is needed to identify and assess new therapeutic approaches. health care-associated infections: a meta-analysis of costs and financial impact on the us health care system guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia effect of not monitoring residual gastric volume on risk of ventilator-associated pneumonia in adults receiving mechanical ventilation and early enteral feeding: a randomized controlled trial effect of oropharyngeal povidone-iodine preventive oral care on ventilator-associated pneumonia in severely brain-injured or cerebral hemorrhage patients: a multicenter, randomized controlled trial national healthcare safety network report, data summary for , device-associated module nosocomial pneumonia in icus in europe: perspectives from the eu-vap/cap study a systematic review and meta-analysis of ventilator-associated pneumonia in adults in asia: an analysis of national income level on incidence and etiology impact of diagnostic criteria on the incidence of ventilator-associated pneumonia incidence of and risk factors for ventilator-associated pneumonia in critically ill patients ventilator-associated pneumonia and icu mortality in severe ards patients ventilated according to a lung-protective strategy national healthcare safety network report, data summary for , device-associated module trend in ventilator-associated pneumonia rates between developing a new, national approach to surveillance for ventilator-associated events: executive summary ventilator-associated pneumonia and bloodstream infections in intensive care unit cancer patients: a retrospective -year study on prospectively monitored patients ventilator-associated pneumonia is more common and of less consequence in trauma patients compared with other critically ill patients chronic obstructive pulmonary disease and the risk for ventilator-associated pneumonia nosocomial infections during extracorporeal membrane oxygenation: incidence, etiology, and impact on patients' outcome prevalence, risk factors, and mortality for ventilator-associated pneumonia in middle-aged, old, and very old critically ill patients healthcare-associated infections surveillance network of i ( ) trends of incidence and risk factors of ventilator-associated pneumonia in elderly patients admitted to french icus between nosocomial pneumonia in ventilated patients: a cohort study evaluating attributable mortality and hospital stay effect of ventilator-associated pneumonia on mortality and morbidity ventilator-associated pneumonia and mortality: a systematic review of observational studies attributable mortality of ventilator-associated pneumonia: a reappraisal using causal analysis incidence, risk factors, and outcomes of ventilator-associated pneumonia in traumatic brain injury: a metaanalysis estimating the attributable mortality of ventilator-associated pneumonia from randomized prevention studies attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies resistance patterns and outcomes in intensive care unit (icu)-acquired pneumonia. validation of european centre for disease prevention and control (ecdc) and the centers for disease control and prevention (cdc) classification of multidrug resistant organisms assessment of severity of icu-acquired pneumonia and association with etiology nosocomial pneumonia in the intensive care unit acquired during mechanical ventilation or not epidemiology and outcomes of ventilator-associated pneumonia in a large us database ventilator-associated pneumonia (vap) with multidrug-resistant (mdr) pathogens: optimal treatment? microbial cause of icu-acquired pneumonia: hospital-acquired pneumonia versus ventilator-associated pneumonia microbial etiology and prognostic factors of ventilator-associated pneumonia: a multicenter retrospective study in shanghai management of adults with hospitalacquired and ventilator-associated pneumonia: clinical practice guidelines by the infectious diseases society of america and the american thoracic society the impact of onset time on the isolated pathogens and outcomes in ventilator associated pneumonia potentially resistant microorganisms in intubated patients with hospital-acquired pneumonia: the interaction of ecology, shock and risk factors comparison of the bacterial etiology of early-onset and lateonset ventilator-associated pneumonia in subjects enrolled in large clinical studies international ers/ esicm/escmid/alat guidelines for the management of hospitalacquired pneumonia and ventilator-associated pneumonia: guidelines for the management of hospital-acquired pneumonia (hap)/ventilatorassociated pneumonia (vap) of the comparison of septic shock due to multidrug-resistant acinetobacter baumannii or klebsiella pneumoniae carbapenemaseproducing k. pneumoniae in intensive care unit patients multidrug-resistant pseudomonas aeruginosa and mortality in mechanically ventilated icu patients asian network for surveillance of resistant pathogens study g ( ) high prevalence of multidrugresistant nonfermenters in hospital-acquired pneumonia in asia high incidence of mdr and xdr pseudomonas aeruginosa isolates obtained from patients with ventilator-associated pneumonia in greece, italy and spain as part of the magicbullet clinical trial incidence and outcome of polymicrobial ventilator-associated pneumonia antibiotic treatment of hospital-acquired pneumonia: is it different from ventilator-associated pneumonia? histopathologic and microbiologic aspects of ventilator-associated pneumonia impact of candida species on clinical outcomes in patients with suspected ventilator-associated pneumonia outcomerea study g ( ) candida colonization of the respiratory tract and subsequent pseudomonas ventilator-associated pneumonia impact of bronchial colonization with candida spp. on the risk of bacterial ventilator-associated pneumonia in the icu: the fungibact prospective cohort study invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study a clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients outbreak of adenovirus type severe pneumonia in a french intensive care unit viral infection is not uncommon in adult patients with severe hospital-acquired pneumonia impact of respiratory viruses in hospital-acquired pneumonia in the intensive care unit: a single-center retrospective study respiratory viruses in invasively ventilated critically ill patients-a prospective multicenter observational study herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation cytomegalovirus reactivation in critically ill immunocompetent patients effect of ganciclovir on il- levels among cytomegalovirus-seropositive adults with critical illness: a randomized clinical trial a contributive result of openlung biopsy improves survival in acute respiratory distress syndrome patients cytomegalovirus. an unexpected cause of ventilatorassociated pneumonia cytomegalovirus reactivation in icu patients open-lung biopsy in patients with acute respiratory distress syndrome epidemiology of multiple herpes viremia in previously immunocompetent patients with septic shock reactivation of multiple viruses in patients with sepsis does this patient have vap? brief summary of french guidelines for the prevention, diagnosis and treatment of hospital-acquired pneumonia in icu does this patient have ventilator-associated pneumonia? diagnosis of ventilator-associated pneumonia by bacteriologic analysis of bronchoscopic and nonbronchoscopic "blind" bronchoalveolar lavage fluid short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. a proposed solution for indiscriminate antibiotic prescription value of the clinical pulmonary infection score for the identification and management of ventilatorassociated pneumonia the radiologic diagnosis of autopsy-proven ventilator-associated pneumonia lung ultrasound for diagnosis and monitoring of ventilator-associated pneumonia soluble triggering receptor expressed on myeloid cells and the diagnosis of pneumonia blind protected specimen brush and bronchoalveolar lavage in ventilated children usefulness of procalcitonin for the diagnosis of ventilator-associated pneumonia biomarker kinetics in the prediction of vap diagnosis: results from the biovap study the current status of biomarkers for the diagnosis of nosocomial pneumonias invasive and noninvasive strategies for management of suspected ventilator-associated pneumonia. a randomized trial quantitative versus qualitative cultures of respiratory secretions for clinical outcomes in patients with ventilator-associated pneumonia quantitative versus qualitative cultures of respiratory secretions for clinical outcomes in patients with ventilator-associated pneumonia effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis procalcitonin (pct)-guided antibiotic stewardship: an international experts consensus on optimized clinical use antibiotic stewardship in the intensive care unit development of a real-time staphylococcus aureus and mrsa (sam-) pcr for routine blood culture clinical impact of rapid polymerase chain reaction (pcr) test for group b streptococcus (gbs) in term women with ruptured membranes evaluation of curetis unyvero, a multiplex pcr-based testing system, for rapid detection of bacteria and antibiotic resistance and impact of the assay on management of severe nosocomial pneumonia comparison of unyvero p pneumonia cartridge, in-house pcr and culture for the identification of respiratory pathogens and antibiotic resistance in bronchoalveolar lavage fluids in the critical care setting point-of-care multiplex pcr promises short turnaround times for microbial testing in hospital-acquired pneumonia-an observational pilot study in critical ill patients assessment of the multiplex pcr-based assay unyvero pneumonia application for detection of bacterial pathogens and antibiotic resistance genes in children and neonates value of lower respiratory tract surveillance cultures to predict bacterial pathogens in ventilator-associated pneumonia: systematic review and diagnostic test accuracy meta-analysis early antibiotic treatment for bal-confirmed ventilatorassociated pneumonia: a role for routine endotracheal aspirate cultures oropharyngeal decontamination with antiseptics to prevent ventilator-associated pneumonia: rethinking the benefits of chlorhexidine stress ulcer prophylaxis in intensive care unit patients receiving enteral nutrition: a systematic review and meta-analysis decontamination strategies and bloodstream infections with antibiotic-resistant microorganisms in ventilated patients: a randomized clinical trial subglottic secretion drainage and objective outcomes: a systematic review and meta-analysis ventilator bundle compliance and risk of ventilator-associated events clinical significance of upper airway virus detection in critically ill hematology patients eight initiatives that misleadingly lower ventilatorassociated pneumonia rates strategies to prevent ventilator-associated pneumonia in acute care hospitals: update reappraisal of routine oral care with chlorhexidine gluconate for patients receiving mechanical ventilation: systematic review and metaanalysis selective digestive or oropharyngeal decontamination and topical oropharyngeal chlorhexidine for prevention of death in general intensive care: systematic review and network meta-analysis randomized intubation with polyurethane or conical cuffs to prevent pneumonia in ventilated patients bestcuff study g, the boreal n ( ) impact of taperedcuff tracheal tube on microaspiration of gastric contents in intubated critically ill patients: a multicenter cluster-randomized cross-over controlled trial randomized pilot trial of two modified endotracheal tubes to prevent ventilator-associated pneumonia prevention of ventilator-associated and early postoperative pneumonia through tapered endotracheal tube cuffs: a systematic review and meta-analysis of randomized controlled trials frequent versus infrequent monitoring of endotracheal tube cuff pressures continuous control of tracheal cuff pressure for vap prevention: a collaborative meta-analysis of individual participant data subglottic secretion drainage for the prevention of ventilatorassociated pneumonia: a systematic review and meta-analysis continuous aspiration of subglottic secretions in the prevention of ventilator-associated pneumonia in the postoperative period of major heart surgery prevention of ventilator-associated pneumonia and ventilator-associated conditions: a randomized controlled trial with subglottic secretion suctioning intermittent subglottic secretion drainage and ventilatorassociated pneumonia: a multicenter trial associations between ventilator bundle components and outcomes effects of chlorhexidine gluconate oral care on hospital mortality: a hospital-wide, observational cohort study protocol for a multi-centered, stepped wedge, cluster randomized controlled trial of the de-adoption of oral chlorhexidine prophylaxis and implementation of an oral care bundle for mechanically ventilated critically ill patients: the choral study what us hospitals are currently doing to prevent common device-associated infections: results from a national survey infection prevention practices in japan, thailand, and the united states: results from national surveys semi-recumbent position versus supine position for the prevention of ventilatorassociated pneumonia in adults requiring mechanical ventilation randomized, multicenter trial of lateral trendelenburg versus semirecumbent body position for the prevention of ventilator-associated pneumonia which multicenter randomized controlled trials in critical care medicine have shown reduced mortality? a systematic review selective digestive and oropharyngeal decontamination in medical and surgical icu patients: individual patient data meta-analysis effect of selective decontamination on antimicrobial resistance in intensive care units: a systematic review and meta-analysis probiotics for the prevention of ventilator-associated pneumonia: a meta-analysis of randomized controlled trials probiotics: prevention of severe pneumonia and endotracheal colonization trial-prospect: a pilot trial efficacy and safety of stress ulcer prophylaxis in critically ill patients: a network metaanalysis of randomized trials risks and benefits of stress ulcer prophylaxis for patients with severe sepsis executive summary: clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the icu the effects of active mobilisation and rehabilitation in icu on mortality and function: a systematic review ventilator bundle and its effects on mortality among icu patients: a meta-analysis improving hospital survival and reducing brain dysfunction at seven california community hospitals: implementing pad guidelines via the abcdef bundle in , patients caring for critically ill patients with the abcdef bundle: results of the icu liberation collaborative in over , adults staged implementation of awakening and breathing, coordination, delirium monitoring and management, and early mobilization bundle improves patient outcomes and reduces hospital costs rethinking ventilator bundles clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia understanding resistance frequency, associated factors and outcome of multi-drug-resistant intensive care unit-acquired pneumonia among patients colonized with extended-spectrum beta-lactamaseproducing enterobacteriaceae infection-related ventilator-associated complications in icu patients colonised with extended-spectrum beta-lactamase-producing enterobacteriaceae potential impact of hospital-acquired pneumonia guidelines on empiric antibiotics. an evaluation of veterans affairs medical centers effect of piperacillin-tazobactam vs meropenem on -day mortality for patients with e. coli or klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial antibiotics for ceftriaxone-resistant gram-negative bacterial bloodstream infections use of non-carbapenem antibiotics to treat severe extended-spectrum beta-lactamase-producing enterobacteriaceae infections in intensive care unit patients a multinational, preregistered cohort study of beta-lactam/beta-lactamase inhibitor combinations for treatment of bloodstream infections due to extended-spectrum-betalactamase-producing enterobacteriaceae effect of adequate single-drug vs combination antimicrobial therapy on mortality in pseudomonas aeruginosa bloodstream infections: a post hoc analysis of a prospective cohort influence of empiric therapy with a beta-lactam alone or combined with an aminoglycoside on prognosis of bacteremia due to gram-negative microorganisms german study group competence network s ( ) effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial comparison of vs days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (prorata trial): a multicentre randomised controlled trial use of nebulized antimicrobials for the treatment of respiratory infections in invasively mechanically ventilated adults: a position paper from the european society of clinical microbiology and infectious diseases nebulized ceftazidime and amikacin in ventilatorassociated pneumonia caused by pseudomonas aeruginosa aerosol therapy for pneumonia in the intensive care unit a randomized trial of the amikacin fosfomycin inhalation system for the adjunctive therapy of gram-negative ventilator-associated pneumonia: iasis trial inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with gram-negative pneumonia (inhale): a double-blind, randomised, placebo-controlled, phase , superiority trial nebulized antibiotics for ventilator-associated pneumonia: a systematic review and meta-analysis intravenous combined with aerosolised polymyxin versus intravenous polymyxin alone in the treatment of pneumonia caused by multidrug-resistant pathogens: a systematic review and meta-analysis the role of aerosolized colistin in the treatment of ventilator-associated pneumonia: a systematic review and metaanalysis aerosolized antibiotics and ventilator-associated tracheobronchitis in the intensive care unit reduction of bacterial resistance with inhaled antibiotics in the intensive care unit new strategies targeting virulence factors of staphylococcus aureus and pseudomonas aeruginosa safety and pharmacokinetics of an anti-pcrv pegylated monoclonal antibody fragment in mechanically ventilated patients colonized with pseudomonas aeruginosa: a randomized, double-blind, placebo-controlled trial suvratoxumab reduces staphylococcus aureus pneumonia in high-risk icu patients: results of the saatellite study acyclovir for mechanically ventilated patients with herpes simplex virus oropharyngeal reactivation: a randomized clinical trial safety and efficacy of antiviral therapy for prevention of cytomegalovirus reactivation in immunocompetent critically ill patients: a randomized clinical trial prevention of intensive care unit-acquired pneumonia probiotics for preventing ventilator-associated pneumonia in mechanically ventilated patients: a meta-analysis with trial sequential analysis key: cord- -ocnce z authors: torres, antoni; chalmers, james d.; dela cruz, charles s.; dominedò, cristina; kollef, marin; martin-loeches, ignacio; niederman, michael; wunderink, richard g. title: challenges in severe community-acquired pneumonia: a point-of-view review date: - - journal: intensive care med doi: . /s - - -y sha: doc_id: cord_uid: ocnce z purpose: severe community-acquired pneumonia (scap) is still associated with substantial morbidity and mortality. in this point-of-view review paper, a group of experts discuss the main controversies in scap: the role of severity scores to guide patient settings of care and empiric antibiotic therapy; the emergence of pathogens outside the core microorganisms of cap; viral scap; the best empirical treatment; septic shock as the most lethal complication; and the need for new antibiotics. methods: for all topics, the authors describe current controversies and evidence and provide recommendations and suggestions for future research. evidence was based on meta-analyses, most recent rcts and recent interventional or observational studies. recommendations were reached by consensus of all the authors. results and conclusions: the idsa/ats criteria remain the most pragmatic tool to predict icu admission. the authors recommend a combination of a beta-lactam/beta-lactamase inhibitor or a third g cephalosporin plus a macrolide in most scap patients, and to empirically cover pes (p. aeruginosa, extended spectrum beta-lactamase producing enterobacteriaceae, methicillin-resistant s. aureus) pathogens when at least two specific risk factors are present. in patients with influenza cap, the authors recommend the use of oseltamivir and avoidance of the use of steroids. corticosteroids can be used in case of refractory shock and high systemic inflammatory response. during recent decades, the number of patients requiring intensive care management due to severe community-acquired pneumonia (scap) has increased globally, especially among the elderly, patients with comorbidities and the immunocompromised [ ] . a large populationbased surveillance study on hospitalized cap patients found that % of patients required intensive care unit (icu) admission, with % of them needing mechanical ventilation [ ] . scap hospital mortality is still high, ranging from % to more than % [ , ] . since delays from hospitalization to icu admission have been related to increased mortality [ ] , several scoring systems have been evaluated in order to promptly identify patients requiring intensive care management and to guide empiric antibiotic therapy [ ] . streptococcus pneumoniae remains the main pathogen responsible of cap, regardless of age and comorbidities [ ] . however, approximately % of cap are caused by antibiotic-resistant pathogens [ ] . furthermore, the implementation of multiplex polymerase chain reaction (pcr) techniques has identified respiratory viruses, mainly influenza virus and rhinovirus, as important cap causative pathogens [ ] . early adequate antibiotic administration is crucial in scap management [ ] ; however, the optimal strategy is still far from being established. initial antimicrobial therapy lacking activity against the offending pathogens has been associated with greater mortality [ ] . the cluster rct from postma et al. [ ] showed the same efficacy when comparing beta-lactam monotherapy with betalactam plus macrolide or quinolone. the constant debate regarding the superiority of β-lactam plus macrolide compared to β-lactam plus fluoroquinolones in scap is still open [ ] . septic shock is the most lethal complication of scap. corticosteroids are recommended in refractory septic shock, although some controversies still remain. due to the emergence of pathogens outside the core microorganisms of cap [ ] , new antibiotics are urgently needed. in this point-of-view review paper, a group of experts discuss the current main controversies regarding scap: severity scores, pathogens outside the core microorganisms of cap (pes pathogens), viral scap, empirical treatment, septic shock and the potential role of new antibiotics. all the topics include four sections: the current controversy, the evidence, suggested recommendations and suggestions for future research. the evidence was based on meta-analyses, most recent rcts and recent interventional or observational studies that the panel considered important for the question. recommendations were reached by consensus of all the authors and are summarized in table . severity assessment is an essential component of the initial evaluation of cap patients [ ] . to date, there is no consensus on the optimal assessment tool or how it should be applied in clinical practice [ , ] . some "real-world" problems may complicate the interpretation of studies that investigate scores for icu admission prediction [ ] . in one study, / of patients presenting to hospital had advanced directives or do not attempt resuscitation (dnar) orders in place that made icu admission inappropriate [ ] . second, many studies include patients who require mechanical ventilation or vasopressor treatment at admission in "prediction" studies, making a prediction score moot [ ] . third, the number of adult icu beds [ ] , the threshold for icu admission and the characteristics of patients admitted to icu are highly variable across different healthcare systems. finally, there is still relatively little evidence that implementation of severity tools into clinical practice results in improved outcomes [ ] . the two most widely used severity assessment tools in cap, the pneumonia severity index (psi) and the curb score, perform well to predict -day mortality, but are less useful in identifying scap requiring icu admission [ ] . this reflects the strong influence of age on both scoring systems, and the low value provided to respiratory failure and other organ dysfunctions which are often a major driver of icu admission. alternative scoring systems have been proposed that are more focused on organ dysfunction. the idsa/ats criteria (table ) predict both mortality and future requirements for mechanical ventilation and vasopressor support as a surrogate of icu admission [ ] . simplification of these criteria with the removal of less common organ dysfunctions is possible without losing prognostic accuracy. lim et al. [ ] conducted a before and after implementation study in which the idsa/ats criteria were used to triage patients. this resulted in a reduced mortality (from . to . %), an increased use of icu resources ( . % of patients admitted to the icu vs.. a group of experts discuss current controversies regarding severe community-acquired pneumonia and provide a summary of recommendations. the idsa/ats criteria remain the most pragmatic and robust tools to predict patients requiring icu admission we recommend empirically covering pes pathogens in scap when at least two specific risk factors are present we recommend the use of prompt therapy with oseltamivir in patients with influenza cap and avoidance of the use of steroids. zanamivir can be used in cases of treatment failure and/or confirmed oseltamivir resistance we recommend a combination of a beta-lactam/beta-lactamase inhibitor or a third g cephalosporin plus a macrolide in most scap patients patients with scap and septic shock should be managed with current practice guidelines. corticosteroids can be used in cases of refractory shock and high systemic inflammatory response based on available data, new antibiotics providing existing limitations in empiric therapy (including macrolide resistant species and mrsa) are needed . % previously) and reduced delayed icu admissions. similar criteria are included in the smart-cop tool [ ] . recently, it has been shown that sepsis- criteria can also help to identify patients at risk of icu admission, although disease-specific tools still have the best discrimination for mortality [ ] . the idsa/ats criteria remain the most pragmatic and robust tools for predicting patients requiring icu admission. major criteria identify patients requiring immediate icu care, while minor criteria (either the simplified or standard version) identify patients with a higher likelihood of requiring icu care and benefiting from more aggressive therapy or closer observation [ , , ] . psi and curb should not be used to guide icu care as they can be misleading. biomarkers such as c reactive protein, proadrenomedullin, procalcitonin and others have been suggested to provide additional information about cap prognosis [ , ] . none are currently fully validated and ready for implementation in clinical practice. we need data demonstrating the utility of severity scores to predict a complicated course of cap, to help improving patient allocation (need for icu admission) and to identify patients likely to respond to specific therapies, including corticosteroids or macrolides [ ] [ ] [ ] . finally, we need data demonstrating a lower mortality rate when these scoring systems are used. guidelines for cap recommend empiric therapy for pathogens outside the core microorganisms of cap, including methicillin-resistant s. aureus (mrsa), p. aeruginosa and other drug-resistant gram-negatives, in selected patients with severe illness [ ] . however, the incidence of these pathogens in cap is low and often varies with geography and patient characteristics. the healthcare-associated pneumonia (hcap) definition is not a good predictor of these pathogens [ ] . identifying patients at higher risk could avoid the overuse of broadspectrum empiric therapy. in one study of icu-admitted cap patients, one in six pseudomonas were resistant to third-generation cephalosporins with antipseudomonal activity. common pathogens included e. coli ( . %), p. aeruginosa stenotrophomas maltophilia ( . %) and acinetobacter baumannii ( . %) [ ] . in one review, the incidence of gram-negative cap was estimated to be between and %, but not all these organisms were resistant and not all patients were in the icu [ ] . shindo et al. reported . % of cap and . % of hcap caused by drug-resistant pathogens [ ] ; however, the number of patients treated in icu was not stated. similarly, in another study, . % of cap and . % of hcap were caused by pathogens outside the core microorganisms of cap, but only of were treated in icu [ ] . one recent development is the concept of pes (p. aeruginosa, extended-spectrum beta-lactamase producing enterobacteriaceae and mrsa) pathogens. pes pathogens have been identified in % of cap patients with an etiologic diagnosis, with p. aeruginosa being the most common; - % of patients with pes pathogens required icu admission, more often than those without these pathogens [ ] . in another study of cap patients, pes pathogens were found in . % patients but icu admission was needed in only . % cases, a rate similar to those without pes pathogens [ ] . risk factors for pes pathogens have been identified, although most studies are not specific to icu patients (table ). webb et al. divided risk factors into therapyrelated (extrinsic factors), patient-related (intrinsic factors) and those related to selective antibiotic pressure [ ] . in one study, risk factors were prior antibiotic therapy, gastric acid-suppressive therapy, tube feeding and non-ambulatory status [ ] , while in another study were cap severity, prior antibiotic therapy, recent hospitalization, poor functional status, dialysis and immune suppression [ ] . in a study of bacteremic cap due to pes pathogens, risk factors for these pathogens were prior antibiotic therapy, low c-reactive protein (crp) and the absence of pleuritic chest pain [ ] . some studies have focused on risks for specific pathogens. a multinational study of patients found p. aeruginosa in . % and antibiotic-resistant p. aeruginosa in % [ ] . risk factors for p. aeruginosa were in another study, risk factors for p. aeruginosa cap included male sex, chronic respiratory diseases, lower crp and higher psi. however, the only risk factor for antibiotic-resistant p. aeruginosa was prior antibiotic therapy [ ] . risk factors for mrsa included many of the above plus chronic dialysis, prior mrsa infection/colonization, recurrent skin infections and severe comorbidities [ , ] . the studies that investigate risk factors for pes pathogens often use the term "multidrug resistent" (mdr), although they include indistinctly mdr and non-mdr microorganisms, mainly p. aeruginosa. in this manuscript we decided to use the acronym pes because we believe it reflects better the need for a different antibiotic treatment covering these pathogens (carbapenems +/linezolid) compared to the standard one required for the "core" cap pathogens. we recommend covering pes pathogens when specific risk factors are present, including prior antibiotic therapy, recent hospitalization, recent p. aeruginosa or mrsa infection or colonization, poor functional status and immune suppression. when patients have at least risk factors, the frequency of pes pathogens can exceed %, thus requiring empiric therapy against these pathogens. [ , ] . we need prospective studies using invasive sampling methods and new molecular diagnostic tests in a population of cap patients treated exclusively in icu. we need to identify patients at higher risk of pes pathogens through accurate scoring systems and to determine a threshold above which empiric therapy for these pathogens is justified. finally, we need to be aware of scap microbiology future changes induced by influenza and pneumococcal vaccination, in both adults and children. before the appearance of influenza pandemics, respiratory viruses were uncommonly diagnosed and affected essentially patients with comorbidities [ ] . in fact, influenza virus a is the most frequent respiratory virus identified, followed by human rhinovirus, human respiratory syncytial virus (rsv) and influenza b virus. rsv is now recognized as a significant problem in the elderly, persons with cardiopulmonary diseases and immunocompromised hosts [ ] . a major controversy in patients with suspected severe viral cap (svcap) is twofold: the use of unnecessary antibiotics when the primary cause of pneumonia is viral without co-infection, and possible treatments with antiviral agents. currently, recommendations for patients with svcap are focused on rapid recognition of the pathogen and antiviral treatment with neuraminidase inhibitors (nais). recommendations regarding nais administration are controversial. the cochrane review of the topic in concluded that oseltamivir did not reduce hospitalizations and complications due to influenza [ ] . two systematic reviews and meta-analyses found that benefits in patients who were otherwise healthy did not outweigh its risks [ , ] . however, another meta-analysis found that oseltamivir was effective in the prevention of influenza at individual and household levels. in critically ill patients, observational studies have found a benefit to a prompt use of oseltamivir [ ] . on the other hand, zanamivir has been proposed by different guidelines, especially in immunosuppressed patients, based on a potential antiviral resistance to oseltamivir among circulating influenza viruses that is currently low [ ] . inhaled zanamivir is not recommended because of the lack of data regarding its use in patients with severe influenza disease. the use of corticosteroids has re-emerged in patients with scap based on recent randomized control trials (rct) and systematic review and meta-analysis [ , ] . in patients with svcap, the use of corticosteroids has not been associated with survival benefit but with an increased risk of nosocomial infections [ ] . a recent observational study found that corticosteroid administration as adjuvant therapy to standard antiviral treatment in critically ill patients with severe influenza pneumonia was associated with increased icu mortality [ ] . regarding rsv, not many treatment options are available, while a phase b rct of presatovir for the treatment of rsv in lung transplant recipients has been recently published with no positive results. we suggest maintaining an active communication with sentinel national and continental centers, and a local routine surveillance program in hospital settings [ ] . we advocate diagnosing svcap in accordance with a seasonal activity pattern. we encourage prompt treatment with oseltamivir in patients with svcap within the first h from influenza diagnosis. we recommend not using zanamivir regularly and only on the basis of treatment failure and confirmed oseltamivir mutations. a rct has not demonstrated a superior effect of zanamivir compared to oseltamivir; all treatments had a similar safety profile in hospitalised patients with severe influenza [ ] . we recommend avoiding the use of steroids in patients with svcap due to futile effect and an increased risk of super-infections in all subgroups of patients including the immunosuppressed. in cases of rsv, there is no available treatment at the present time. the best preferable evidence to determine the effect of nais should come from rcts. currently, only very few patients with high severity rates and a psi above have been enrolled in rcts for scap [ ] . in addition, in patients with infections, performing a rct with or without antibiotics will foremost be inappropriate and unethical. although there is sufficient evidence that antivirals decrease viral loads, their use in scap is still a matter of controversy [ ] . studies analyzing the timing of nais administration could provide further positive results. regarding the use of corticosteroids, a rct could be conducted in svcap patients with high inflammation and severity. no rct has specifically targeted scap. only one allowed enrollment of mechanically ventilated patients, while the rest specifically excluded scap patients [ ] . conversely, epidemiologic data suggest that scap patients may have a different etiologic spectrum than patients hospitalized outside the icu [ , ] , including a high incidence of viral infection. therefore, whether antibiotics appropriate for non-icu patients are safe and efficacious in scap is unclear. moreover, rapid diagnostic tests offer the possibility for specific treatment. if they demonstrate high sensitivity for atypical pathogens, fluoroquinolone monotherapy may even be superior to macrolides. whether other effects of macrolides are beneficial in cases other than s. pneumoniae is debatable, and beta-lactams are clearly not needed for atypicals. the controversy is threefold: ( ) is beta-lactam/macrolide combination therapy superior to other beta-lactam treatments? ( ) are additional antibiotics required for pes pathogens? and ( ) is prolonged antibiotic therapy needed for all patients with only positive viral testing? non-interventional trials suggest that beta-lactam/macrolide combination therapy is associated with lower mortality, especially in patients with pneumococcal bacteremia [ ] . however, the study by postma et al. [ ] found no difference in -day mortality when comparing beta-lactam alone with beta-lactam/macrolide or quinolones. the study exhibits two important limitations: first, % of patients had no chest x-ray confirmation; second, most patients had a low-grade severity pneumonia, as measured by the psi scale. another rct study [ ] found a lower rate of readmissions and a higher rate of clinical cure only in patients with psi categories iv and v pneumonia receiving beta-lactam plus macrolide. observational studies of beta-lactam/quinolone combination therapy for scap suggest better outcome than beta-lactam monotherapy. one prospective study found combination therapy with an early quinolone was slightly superior to a cephalosporin alone [ ] . three theories support the benefit of empirical macrolide combination: ( ) better coverage of atypical pathogens, including legionella, ( ) suppression of exotoxin production from s. pneumoniae [ ] , and ( ) host immunomodulatory effects. the latter two clearly differentiate between macrolides and quinolones, although both are effective against atypical pathogens. the underlying assumption that most of these culture-negative cases are s. pneumoniae is questionable with greater use of the highlyeffective conjugate pneumococcal vaccines [ ] . some data support the use of quinolones for proven severe legionella [ ] . methicillin-sensitive strains are likely covered adequately with standard empirical therapy. however, empirical coverage of mrsa for all scap patients does not improve outcomes [ ] . gross hemoptysis, leukopenia, skin rashes, and rapidly progressive or necrotizing infiltrates are relatively distinctive for the toxigenic community-acquired strain [ ] . observational studies suggest a better outcome with the use of antibiotics that interfere with ribosomal synthesis, such as linezolid or clindamycin [ ] . whether more rapid killing associated with the cephalosporin ceftaroline obviates the need for toxin suppression is unknown [ ] . patients with scap who are at risk for pathogens usually considered nosocomial represent a therapeutic dilemma. unfortunately, piperacillin/tazobactam, the most commonly prescribed antibiotic for suspected drug-resistant pathogens, has recently been shown to have adverse outcomes in patients with e. coli and k. pneumoniae bloodstream infection and ceftriaxone resistance [ ] . in cases of svcap, the overwhelming majority of patients receive empirical antibiotics despite infrequently documented bacterial superinfection. short-course prophylactic antibiotics may prevent bacterial superinfection while prolonged courses predispose to nosocomial infections, disrupting gut and lung microbiomes. it is worth pointing out that some scap cases require longer antibiotic administration. these include scap caused by s. aureus, patients with pleural effusions, pulmonary abscess and, patients with initial inadequate antibiotic treatment. we recommend a combination of a beta-lactam/betalactamase inhibitor or a third g cephalosporin plus a macrolide for most scap patients. legionella, if documented, should be treated with a quinolone. empirical linezolid should be reserved to patients with risk factors for community-acquired mrsa. empirical broader spectrum therapy for gram-negative pathogens should be limited to patients with several risk factors for pes pathogens. we need a rct of usual treatment (cephalosporin/ macrolide) with additional empirical coverage for pes pathogens versus pathogen-specific therapy based on rapid diagnostic testing. we need interventional studies investigating the duration of scap antibiotic treatment according to procalcitonin and rapid molecular diagnostic techniques. finally, we need a rct of short-course antibiotic therapy for scap patients with only viral detection on molecular testing. pneumonia is the most common cause of septic shock [ ] . despite improvements in the overall survival from severe sepsis, mortality from scap remains high-up to % in some studies [ ] . reasons for this discrepancy remain unclear, but it suggests the possibility that scap represents a unique subset of septic shock that deserves a unique set of guidelines for management. the high mortality in scap, despite early and adequate antibiotic treatment, may be a result of inadequate infection control and/or dysregulated inflammatory responses. the latter possibility raises the perennial question in the management of scap of whether or not to employ systemic corticosteroid therapy. current strategies to manage patients with scap and shock include the identification of pathogens using available diagnostics [ ] , early and appropriate (including combination) antimicrobial administration [ ] , hemodynamic resuscitation [ ] , and, for some patients, appropriate management of acute respiratory failure or ards [ ] . two recent rcts, the adrenal and the approc-chss, supported the use of adjunct corticosteroid therapy in septic shock (table ) , both studies demonstrating a reduction in the number of vasopressor-and ventilatordependent days [ , ] . in these studies, % and % of patients had pulmonary infections, respectively. the approcchss demonstrated a small mortality benefit, a feature some authors attributed to the inclusion of mineralocorticoids in the treatment protocol. however, this finding may be better explained by the higher baseline mortality in the latter trial, which would fit with the general trend in steroid trials dating back to (including the french trial, hypress, and corticus), which showed the greatest benefit of therapy in the sickest populations [ ] [ ] [ ] . a recent network meta-analysis of septic shock studies supported with strong evidence the role of corticosteroids in shock reversal [ ] . the use of steroids in scap (with or without shock) remains controversial [ , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , although many studies have shown significant reductions in length of stay and time to clinical stability. increasing evidence suggests that patients with strong inflammatory responses, such as those with highly elevated crp, may represent a subset of scap patients who would benefit from such corticosteroid treatment [ ] . conversely, corticosteroid use in patients with versus cap has been related to increased mortality [ ] . there is currently insufficient evidence to support other adjuvant therapies in scap, such as immunoglobulins, g-csf or statins [ ] . patients with scap and shock should be managed according to current practice guidelines. adjunctive therapy, including systemic corticosteroids, should be reserved for scap patients with refractory septic shock or with high systemic inflammatory response (as measured by crp). studies are still needed to clarify why scap mortality remains high despite improvements in overall sepsis outcomes. host inflammatory responses (both of the lung and systemic) require better characterization to determine the potential role of immune modulators in scap. finally, additional studies are needed to better assess patients' immune phenotype and to determine who should receive steroids and other immunosuppressive therapies. treatment success in scap rests on prompt delivery of antibiotics targeting the likely causative organisms. an important controversy is whether existing antibiotics are adequate therapies or whether new antimicrobials are needed. initial inappropriate empiric therapy in scap is primarily driven by the failure to cover a specific pathogen (e.g., mrsa) or the presence of a resistant bacterial pathogen (e.g., macrolide-resistant s. pneumoniae) [ ] . the need to empirically cover both "typical" bacterial pathogens (s. pneumonia, haemophilus influenza, mmsa) and "atypical" pathogens (mycoplasma pneumoniae, legionella [ , ] . based on the available data, it appears that new antibiotics providing coverage for the currently existing limitations in empiric therapy are needed (table ) . lefamulin is a novel semisynthetic pleuromutilin that inhibits bacterial growth by binding to the peptidyl transferase center of the s ribosomal subunit [ ] . pleuromutilins are not typically affected by resistance to other antibiotic classes (including macrolides, fluoroquinolones, and tetracyclines). two phase trials (leap intravenous to oral lefamulin; leap -oral only) have demonstrated comparable (non-inferior) outcomes to moxifloxacin (https ://inves tors.nabri va.com/stati c-files / c b - cc- -b d -d ea c d b (accessed july ). omadacycline is from the aminomethylcycline class created by chemical modification of minocycline. it inhibits protein synthesis by binding to the s ribosomal subunit. chemical modifications enable it to be active against the two main forms of bacterial resistance to the tetracyclines: efflux and ribosomal protection. results from the phase optic trial comparing once-daily oral and intravenous omadacycline to oral and intravenous moxifloxacin demonstrated noninferiority (https ://globe newsw ire.com/news-relea se/ / / / / /en/parat ek-annou nces-posit ive-phase - -study -of-omada cycli ne-in-commu nity-acqui red-bacte rial-pneum onia.html (accessed july ). delafloxacin (baxdela ™ ) is a potent fluoroquinolone with structural differences allowing it to move better than other fluoroquinolones through an acidic medium facilitating transmembrane passage into bacteria. delafloxacin has a high affinity for both topoisomerase iv and dna gyrase targets, giving it activity against gram-positive and gram-negative bacteria, as well as anaerobes and intracellular microorganisms [ ] . the results of a phase trial comparing delafloxacin to moxifloxacin for hospitalized patients with cap are awaited. solithromycin (solithera ™ ) is a fourth-generation macrolide and the first fluoroketolide in clinical development. solithromycin has potent in vitro activity against the most common cap pathogens, including fluoroquinolone-resistant isolates of s. pneumoniae. two phase trials of oral and intravenous to oral therapy for cap demonstrated comparable results to moxifloxacin [ ] . however, due to concerns over potential liver toxicity, the fda recommended that the company initiate a new clinical study to better evaluate the drug's safety profile in patients. nemonoxacin is a novel nonfluorinated quinolone with a wide antimicrobial spectrum covering gram-positive cocci and gram-negative bacilli, including the common cap pathogens. one published phase trial and two unpublished phase trials suggest that nemonoxacin is non-inferior to levofloxacin for the treatment of cap [ , ] . ceftaroline fosamil (teflaro ™ ) is an n-phosphonoamino water-soluble prodrug cephalosporin with the active form, ceftaroline, possessing broad-spectrum in vitro antimicrobial activity. the spectrum of activity includes typical cap bacterial pathogens and its high affinity for pbp a allows coverage of mrsa [ ] . the high superiority of ceftaroline compared to ceftriaxone in bacterial pneumonia was demonstrated in the focus and trials [ ] . the current role of the new antibiotics in scap is almost unknown, since the majority of them have not been studied in this specific subgroup of patients. ceftaroline could be added to the list of beta-lactams for the empirical or targeted treatment of scap. we need observational and/or rct studies of new antibiotics in the specific scap population. non-traditional agents, such as monoclonal antibodies, that may minimize or avoid the emergence of resistance should also be explored. scap is a major challenge in icu due to its high mortality, complications, short and long-term consequences. however, the optimal care is still not well standardized. scap remains a small section of general cap recommendations, and performing interventional and rcts in this subgroup of patients may be difficult. in this point-of-view review paper, we provide literature evidence, suggested recommendations and suggestions for future research regarding six seminal questions of scap management: ( ) who needs to be admitted to icu? ( ) when should pes pathogens be suspected? ( ) how should severe viral cap be managed? ( ) what is the optimal empirical antibiotic treatment for scap? ( ) when should corticosteroids in scap with septic shock be used? and ( ) what is the current evidence regarding new antibiotics and the pipe-line for coming years? ten-year trends in intensive care admissions for respiratory infections in the elderly communityacquired pneumonia requiring hospitalization among u.s. adults communityacquired pneumonia as an emergency condition predictors of severe sepsis among patients hospitalized for communityacquired pneumonia community-acquired pneumonia on the intensive care unit: secondary analysis of , cases in the icnarc case mix programme database new sepsis definition (sepsis- ) and community-acquired pneumonia mortality. a validation and clinical decision-making study estimating the burden of pneumococcal pneumonia among adults: a systematic review and meta-analysis of diagnostic techniques community-acquired pneumonia due to multidrug-and non-multidrug-resistant pseudomonas aeruginosa severe community-acquired pneumonia: current management and future therapeutic alternatives impact of antibiotic therapy in severe community-acquired pneumonia: data from the infauci study antibiotic treatment strategies for community-acquired pneumonia in adults is beta-lactam plus macrolide more effective than beta-lactam plus fluoroquinolone among patients with severe community-acquired pneumonia?: a systemic review and meta-analysis risk factors associated with potentially antibiotic-resistant pathogens in communityacquired pneumonia severity scores and community-acquired pneumonia. time to move forward severity assessment tools to guide icu admission in community-acquired pneumonia: systematic review and meta-analysis -hospital deaths among adults with community-acquired pneumonia validation of the infectious diseases society of america/ american thoratic society minor criteria for intensive care unit admission in community-acquired pneumonia patients without major criteria or contraindications to intensive care unit care rocket science and the infectious diseases society of america comparison of medical admissions to intensive care units in the united states and united kingdom idsa/ats minor criteria aid pre-intensive care unit resuscitation in severe community-acquired pneumonia simplification of the idsa/ats criteria for severe cap using meta-analysis and observational data smart-cop: a tool for predicting the need for intensive respiratory or vasopressor support in community-acquired pneumonia markers of neutrophil extracellular traps predict adverse outcome in community-acquired pneumonia: secondary analysis of a randomised controlled trial initial inflammatory profile in community-acquired pneumonia depends on time since onset of symptoms severity assessment scores to guide empirical use of antibiotics in community acquired pneumonia infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults predicting risk of drugresistant organisms in pneumonia: moving beyond the hcap model are third-generation cephalosporins unavoidable for empirical therapy of communityacquired pneumonia in adult patients who require icu admission? a retrospective study the respiratory threat posed by multidrug resistant gram-negative bacteria risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia a therapeutic strategy for all pneumonia patients: a -year prospective multicenter-cohort study using risk factors for multidrug resistant pathogens to select initial empiric therapy risk factors for drug-resistant pathogens in immunocompetent patients with pneumonia: evaluation of pes pathogens bacteraemia and antibioticresistant pathogens in community acquired pneumonia: risk and prognosis burdenand risk factors for pseudomonas aeruginosa community-acquired pneumonia: a multinational point prevalence study of hospitalised patients global initiative for meticillin-resistant staphylococcus aureus pneumonia (glimp): an international, observational cohort study increased incidence of co-infection in critically ill patients with influenza frequency of respiratory virus infections and next-generation analysis of influenza a/ h n pdm dynamics in the lower respiratory tract of patients admitted to the icu neuraminidase inhibitors for preventing and treating influenza in healthy adults and children oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials global update on the susceptibility of human influenza viruses to neuraminidase inhibitors and status of novel antivirals effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial corticosteroids for pneumonia the pharmacological management of severe influenza infection-'existing and emerging therapies corticosteroid treatment in critically ill patients with severe influenza pneumonia: a propensity score matching study neces-sari-ly? intravenous zanamivir or oral oseltamivir for hospitalised patients with influenza: an international, randomised, double-blind, double-dummy, phase trial placebo-controlled trials of treatments for communityacquired pneumonia: review of the literature and discussion of feasibility and potential value critics attack chief medical officer's advice to use antivirals for flu comparison of levofloxacin and cefotaxime combined with ofloxacin for icu patients with community-acquired pneumonia who do not require vasopressors severe community-acquired pneumonia: characteristics and prognostic factors in ventilated and non-ventilated patients effectiveness of combination therapy versus monotherapy with a third-generation cephalosporin in bacteraemic pneumococcal pneumonia: a propensity score analysis beta-lactam monotherapy vs. beta-lactam-macrolide combination treatment in moderately severe community-acquired pneumonia: a randomized noninferiority trial clarithromycin alone and in combination with ceftriaxone inhibits the production of pneumolysin by both macrolide-susceptible and macrolide-resistant strains of streptococcus pneumoniae polysaccharide conjugate vaccine against pneumococcal pneumonia in adults the association of antibiotic treatment regimen and hospital mortality in patients hospitalized with legionella pneumonia empiric therapy directed against mrsa in patients admitted to the intensive care unit does not improve outcomes in community-acquired pneumonia factors predicting mortality in necrotizing community-acquired pneumonia caused by staphylococcus aureus containing panton-valentine leukocidin methicillin resistance is not a predictor of severity in community-acquired staphylococcus aureus necrotizing pneumonia-results of a prospective observational study integrated analysis of focus and focus : randomized, doubled-blinded, multicenter phase trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-acquired pneumonia effect of piperacillin-tazobactam vs. meropenem on -day mortality for patients with e coli or klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial patients with community acquired pneumonia admitted to european intensive care units: an epidemiological survey of the genosept cohort determining best outcomes from community-acquired pneumonia and how to achieve them the use of polymerase chain reaction amplification for the detection of viruses and bacteria in severe community-acquired pneumonia delays from first medical contact to antibiotic administration for sepsis surviving sepsis campaign: international guidelines for management of sepsis and septic shock management of ards in adults adjunctive glucocorticoid therapy in patients with septic shock hydrocortisone plus fludrocortisone for adults with septic shock hydrocortisone therapy for patients with septic shock effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock effect of hydrocortisone on development of shock among patients with severe sepsis: the hypress randomized clinical trial corticosteroids in septic shock: a systematic review and network meta-analysis corticosteroid therapy for severe community-acquired pneumonia: a meta-analysis corticosteroids in patients hospitalized with community-acquired pneumonia: systematic review and individual patient data metaanalysis efficacy of corticosteroid treatment for severe community-acquired pneumonia: a meta-analysis adjunctive therapies for community-acquired pneumonia: a systematic review corticosteroids in the treatment of community-acquired pneumonia in adults: a meta-analysis corticosteroid therapy for patients hospitalized with community-acquired pneumonia: a systematic review and meta-analysis adjunctive systemic corticosteroids for hospitalized community-acquired pneumonia: systematic review and meta-analysis adjunctive corticotherapy for community acquired pneumonia: a systematic review and meta-analysis efficacy and safety of corticosteroids for community-acquired pneumonia: a systematic review and meta-analysis corticosteroids as adjunctive therapy in the treatment of influenza nonantibiotic adjunctive therapies for community-acquired pneumonia (corticosteroids and beyond): where are we with them? a case series of macrolide treatment failures in community acquired pneumonia the effect of macrolide resistance on the presentation and outcome of patients hospitalized for streptococcus pneumoniae pneumonia macrolide-resistant mycoplasma pneumoniae prevalence and clinical aspects in adult patients with communityacquired pneumonia in china: a prospective multicenter surveillance study in vitro activity of lefamulin tested against streptococcus pneumoniae with defined serotypes, including multidrug-resistant isolates causing lower respiratory tract infections in the united states in vitro activity of delafloxacin against contemporary bacterial pathogens from the united states and europe spotlight on solithromycin in the treatment of community-acquired bacterial pneumonia: design, development, and potential place in therapy a randomized, double-blind, multicenter phase ii study comparing the efficacy and safety of oral nemonoxacin with oral levofloxacin in the treatment of communityacquired pneumonia managing community acquired pneumonia in the elderly-the next generation of pharmacotherapy on the horizon ceftaroline fosamil for the treatment of community-acquired pneumonia: from focus to capture key: cord- - bcq jnm authors: fernando, shannon m.; mathew, rebecca; hibbert, benjamin; rochwerg, bram; munshi, laveena; walkey, allan j.; møller, morten hylander; simard, trevor; di santo, pietro; ramirez, f. daniel; tanuseputro, peter; kyeremanteng, kwadwo title: new-onset atrial fibrillation and associated outcomes and resource use among critically ill adults—a multicenter retrospective cohort study date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: bcq jnm background: new-onset atrial fibrillation (noaf) is commonly encountered in critically ill adults. evidence evaluating the association between noaf and patient-important outcomes in this population is conflicting. furthermore, little is known regarding the association between noaf and resource use or hospital costs. methods: retrospective analysis ( – ) of a prospectively collected registry from two canadian hospitals of consecutive icu patients aged ≥ years. we excluded patients with a known history of af prior to hospital admission. any occurrence of atrial fibrillation (af) was prospectively recorded by bedside nurses. the primary outcome was hospital mortality, and we used multivariable logistic regression to adjust for confounders. we used a generalized linear model to evaluate contributors to total cost. results: we included , patients, and ( . %) had noaf during their icu admission. while noaf was not associated with increased odds of hospital death among the entire cohort (adjusted odds ratio [aor] . [ % confidence interval [ci] . – . ]), an interaction was noted between noaf and sepsis, and the presence of both was associated with higher odds of hospital mortality (aor . [ % ci . – . ]) than either alone. patients with noaf had higher total costs (cost ratio [cr] . [ % ci . – . ]). among patients with noaf, treatment with a rhythm-control strategy was associated with higher costs (cr . [ % ci . – . ]). conclusions: while noaf was not associated with death or requiring discharge to long-term care among critically ill patients, it was associated with increased length of stay in icu and increased total costs. atrial fibrillation (af) is the most common cardiac dysrhythmia, with a lifetime risk of in among older adults [ ] . development of af has been associated with stroke, myocardial infarction, heart failure, and death [ ] . in the intensive care unit (icu), patients often present with pre-existing af; however, some icu patients may develop new-onset af (noaf) in the context of critical illness [ ] . unlike af seen in non-critically ill patients, noaf is often thought to be a consequence of critical illness pathophysiology and treatment, including inflammation, electrolyte disturbances, or proarrhythmic medications, namely vasopressors and inotropes [ ] . incidence of noaf in the general icu varies markedly; however, most studies suggest that - % of patients will develop this complication during their icu stay [ ] [ ] [ ] . the clinical importance of critical illness-associated noaf is a matter of ongoing uncertainty [ ] . af in and of itself may contribute to clinical decompensation through hemodynamic compromise [ ] . alternatively, noaf may simply represent a marker of increased illness severity, and may identify patients at increased risk of death without acting causally to worsen prognosis. some cohort studies have identified an independent association between noaf and mortality [ ] [ ] [ ] , while others have not [ , ] . whether this relationship is seen among all critically ill patients, or limited to select subgroups, is unknown. furthermore, the factors associated with death among patients with noaf are unknown. equally important is the relationship between noaf, and subsequent icu resource use and costs [ , ] . since the icu is a major source of hospital expenditure, considerable effort has been dedicated to understand the contributors to cost, in order to drive policy and optimize resource utilization [ ] . with regard to noaf, little is known regarding the degree of impact on cost expenditures. we primarily sought to evaluate the association between noaf and outcomes, resource utilization, and costs among critically ill adult patients. given the prognostic importance of noaf among patients with sepsis [ , ] , we secondarily aimed to evaluate the association between incidence of noaf and associated outcomes and resource utilization among critically ill patients with suspected infection, sepsis, and septic shock. we obtained ethics approval for this study from the ottawa health science network research ethics board (protocol - h). we studied icu patients from two hospitals within the ottawa hospital network (ottawa, on). these hospitals have approximately combined icu admissions per year. these are combined medical and non-cardiac surgical icus. we retrospectively examined prospectively collected data from the ottawa hospital data warehouse, a health administrative database used in previous studies [ ] [ ] [ ] [ ] . from hospital admission, data is gathered daily from each patient and stored in the data warehouse. data quality assessments are executed routinely, and quality-assurance initiatives are conducted regularly to ensure completeness and accuracy. we included all consecutive patients ≥ years of age, admitted to one of the two icus between january and december . sample size was determined pragmatically, on the basis of available patients in the data warehouse. we also examined pre-specified subgroups of patients, including those with suspected infection, sepsis, and septic shock, as based on the third international consensus definitions for sepsis and septic shock (sepsis- ) [ ] [ ] [ ] . "suspected infection" was defined as concomitant administration of oral or parenteral antibiotics, and sampling of body-fluid cultures, as performed previously [ , ] , and in keeping with the sepsis- definitions [ ] . "sepsis" was defined as suspected infection and an increase in the sequential organ failure assessment (sofa) score by greater than points [ , ] . finally, "septic shock" was defined by sepsis in addition to initiation of vasopressors or a serum lactate ≥ . mmol/l [ , ] . we obtained all data from the ottawa hospital data warehouse. we abstracted demographic data, comorbidities, elixhauser comorbidity score [ ] , and multiple organ dysfunction score (mods) [ ] at the time of icu admission. the elixhauser comorbidity score is generated from comorbidities stored in the data warehouse, and the association between this index and hospital mortality has been previously validated in our database [ ] . the "most responsible diagnosis" was recorded at death or discharge, based upon international classification of diseases, version (icd- , july ). we also noted whether there was presence of a "no cardiopulmonary resuscitation (cpr)" directive at the time of icu admission. we collected outcome data from admission until either the point of discharge from hospital or hospital death. we determined patient costs using the case-costing system of the ottawa hospital data warehouse, as done previously [ , , ] . total hospital costs include both direct and indirect sources. direct costs refer to all hospital expenses with fee codes linked to the patient identifier. indirect costs refer to any overhead operational fees associated with provided service. the ottawa hospital uses a standardized case-costing methodology, developed by the ontario case costing initiative, and based upon the canadian institute for health information management guidelines [ ] . costs were indexed to canadian dollars using consumer price indices [ , ] . the primary outcome was hospital mortality. secondary outcomes included discharge directly from hospital to long-term care (among survivors to hospital discharge originally from home), hospital readmission within days of hospital discharge among survivors, icu length of stay (los), hospital los, resource utilization (including invasive and non-invasive mechanical ventilation, and renal replacement therapy), and total hospital costs. for each patient, the occurrence of any af was prospectively recorded by bedside nurses for the purposes of quality assurance. the date and time of af, as captured by the bedside nurse, was stored in the data warehouse. patients identified through this method were then evaluated by a single investigator (smf), to confirm the diagnosis. since there is no consensus definition for noaf [ ] , we followed pre-existing definitions from the literature [ , ] . noaf was defined as either ( ) af ≥ h in duration, as noted by bedside telemetry (routinely evaluated in charts where electrocardiograms were not completed); ( ) af < h in duration, but captured on electrocardiogram; or ( ) af initiating pharmacologic therapy or electrical cardioversion. all bedside ecgs, along with final interpretation by an attending cardiologist are stored in patient records. "sustained" af was defined as failure to convert to sinus rhythm h following the onset of any pharmacological treatment or electrical cardioversion. we excluded patients with a previously documented or known history of af, as determined at the time of hospital admission and stored in the data warehouse. we performed all statistical analyses using r (version . . ) and ibm spss (version . ). we present data as mean values, with standard deviation (sd), or medians, with interquartile range (iqr), where appropriate. student's t test (parametric values), mann-whitney test (non-parametric values), and χ (for categorical values) were performed to determine between-group differences. in keeping with existing guidelines, we did not perform pairwise comparisons of baseline characteristics [ ] . to adjust for measured confounders in the association between new-onset af and outcomes of interest, we followed recommendations for observational studies in the critically ill [ ] . as per these recommendations, confounders were determined a priori, on the basis of their likelihood of influencing both the presence of noaf and mortality and not acting as mediators or colliders in the association between af and mortality, as based upon existing clinical knowledge evaluating the association between noaf and mortality in critically ill patients [ , ] . in accordance with these recommendations [ ] , we used multivariable logistic regression modeling to adjust for important continuous (age, mods at icu admission, elixhauser comorbidity index) and categorical (sex, individual comorbidities, "no-cpr" directive on admission, location prior to icu admission, and most responsible diagnosis) variables. as recommended, variables on the causal pathway and potentially contributing to noaf (e.g., vasoactive medications) were not included [ ] . we evaluated for possible synergy between noaf and sepsis through the use of an interaction term in the primary model, as performed previously [ ] . if a statistically significant interaction term was found between noaf and sepsis, we then represented this with a four-level categorization. we assessed variation in total hospital costs using a multivariable generalized linear model with gamma distribution and log link [ , ] . we present adjusted odds ratios (aors) and cost ratios (crs) with % confidence intervals. a p value of ≤ . was considered statistically significant. a total of , patients were admitted to the participating icus from to (fig. ). of these, patients ( . %) had a known or documented history of af prior to icu admission, and were excluded. a further patients ( . %) were excluded because of missing outcome data. we included , patients in the analyses. of these patients, ( . %) had noaf while in the icu. baseline characteristics of patient with and without noaf are shown in table . noaf patients were older (mean age . years vs. . years), had higher severity of illness (mean mods . vs. . ), and higher comorbidity burden. patient outcomes are depicted in table . median time from hospitalization to development of noaf was day (iqr - ), and ( . %) of noaf patients had sustained af lasting longer than h. multivariable logistic regression analyses examining in-hospital mortality among the entire cohort, and among subgroups with suspected infection (n = , table ), sepsis (n = , . % of "suspected infection" population), and septic shock (n = , . % of "sepsis" population) are included in additional files , , and : tables s -s , respectively). following adjustment for confounding variables, noaf was not associated with higher hospital mortality among all icu patients (aor . [ % ci . - . ]). however, noaf was associated with higher hospital mortality among icu patients with suspected infection (aor . [ % ci . - . ]), sepsis (aor . [ % ci . - . ]), and septic shock (aor . [ % ci . - . ]). a statistically significant interaction was seen between noaf and presence of sepsis, and the presence of both was associated with higher odds than either alone (additional file : . patients with noaf had prolonged median icu los ( days vs. days, p < . ) and median total hospital los ( days vs. days, p < . ). among patients with noaf, factors associated with increased risk of hospital mortality included increasing age, increased mods score, history of chf (as identified in the data warehouse), and sustained af (additional file : table s ). comparisons of resources used between patients with and without af are shown in table . no differences were seen in the use of invasive ( . % in those with noaf vs. . % in those without noaf, p = . ) or non-invasive ventilation ( . % in those with noaf vs. . % in those without noaf, p = . ). vasoactive medication use was higher among patients with noaf ( . % vs. . %, p = . ). in terms of treatment strategy for noaf, ( . %) patients received antiarrhythmic medical therapy (i.e., amiodarone, procainamide, or flecainide), while ( . %) received therapy with a beta-blocker, calcium channel blocker, or digoxin. a total of patients ( . %) received a combination of the above therapies. finally, comparisons of patient costs between patients with and without noaf are shown in table table s ). among patients with noaf (additional file : table s ), significant predictors of total hospital costs include total hospital or icu los, use of invasive mechanical ventilation or renal replacement therapy, and use of antiarrhythmic medical therapy (as compared to beta-blocker, calcium channel blocker, or digoxin treatment). we identified noaf in . % of critically ill adults, in keeping with known prevalence rates [ ] . we found no association between noaf and increased hospital patients with noaf had prolonged icu and hospital los, and noaf was a predictor of increased total costs. mechanical ventilation, renal replacement therapy, and use of antiarrhythmic therapy were significant predictors of total cost in noaf patients. taken together, our study identifies important novel associations between noaf and outcomes among critically ill patients, and also describes the economic impact of noaf. hospital mortality among critically ill adults is high, and therefore, identification of prognostic factors associated with increased risk can be helpful to clinicians in escalating or tailoring therapy. identification of these factors may also be helpful in discussions with patients and families regarding goals of care. noaf is often thought to be a marker of illness severity [ ] ; however, the evidence examining the association between noaf and hospital mortality remains uncertain [ ] . in our large cohort of critically ill adults, we did not find such an association. however, evaluation of subgroups of patients with suspected infection, sepsis, and septic shock did find an independent association between noaf and hospital mortality potentially suggesting that the consequences of noaf in the patient with sepsis may differ from other populations. important physiologic changes occur during sepsis that make the atrial substrate vulnerable to noaf [ ] , and patients with sepsis have a nearly sixfold risk of developing af, as compared to other populations [ ] . our findings identifying an independent association between noaf and mortality from sepsis are supportive of existing literature, and potentially suggest that survival in this population may be improved through the prevention and treatment of noaf [ ] . importantly, unlike previous studies, we defined sepsis and septic shock using the most recent sepsis- definitions, indicating that noaf has potential implications in these populations, and demonstrate an interaction between the presence of noaf and sepsis. in keeping with the sepsis- focus of sepsis as infection with concomitant organ dysfunction, noaf may indeed represent sepsis-defining cardiac dysfunction [ ] . as such, noaf during sepsis might mediate mortality and may not simply be a marker of illness severity, as is seen in other disease processes [ ] . if noaf does represent a marker of illness severity, then its presence may be considered an important indicator of deterioration among critically ill patients. therefore, identification of factors associated with mortality among icu patients who develop noaf remains an important area of ongoing research [ ] . unsurprisingly, a history of heart failure was associated with hospital mortality among patients with noaf in our cohort, suggesting that these patients may be more susceptible to the hemodynamic effects of noaf. our results also found that sustained af following h of treatment was also associated with higher hospital mortality. therefore, sustained af may represent a particular ominous marker of illness severity among critically ill adults, and clinicians should act cautiously in those patients with noaf and persisting af. we additionally evaluated the association between noaf and hospital resource use and cost. identification of factors associated with such outcomes remains an important focus in critical care research [ ] . few differences were found with regard to resource utilization between patients with and without noaf. however, patients with noaf did have prolonged icu and hospital los, which translated into higher costs. the presence of noaf was also a significant predictor of costs among our cohort, and this was independent of other important factors more commonly associated with cost, including renal replacement therapy and mechanical ventilation [ ] . this prolonged los was also manifested in increased laboratory, pharmacy, and nursing costs. despite higher costs, patients with noaf had higher unadjusted mortality, which translated into significant differences in cost per survivor (a proxy indicator of cost-effectiveness). among patients with noaf, treatment with antiarrhythmic medication (as compared to beta-blockers, calcium channel blockers, or digoxin) was associated with higher cost, but decrease in mortality. while this study was not designed to test the efficacy of therapeutic agents for noaf, the little evidence that exists on this topic seems to suggest no beneficial effect of any particular agent [ , ] . this is in keeping with our results. we did not find evidence of difference in mortality associated with antiarrhythmic agents, but did note increased cost. this is likely attributable to the expense of these drugs [ ] , and the fact that they often cannot be administered outside of a monitored setting and therefore may prolong icu los. however, it must be stressed that the efficacy of these agents can only be appropriately tested in a randomized trial, and while equipoise exists, decisions related to agents for treatment of noaf must be made on a case-by-case basis. we used a large multicenter database of patients with prospective identification of noaf, and provide novel data related to hospital mortality, resource utilization, and cost. we also closely followed recommendations for control of confounding in observational studies [ ] . however, our study has important limitations. most importantly, our database lacks the granularity to investigate other potential factors that may influence outcome from noaf, such as underlying cardiac function, pulmonary artery catheterization, rate of af, timing of af (particularly in relation to onset of critical illness), use of anticoagulation, and incidence of other arrhythmias. some outcome data, such as incidence of stroke, were not available. we additionally excluded patients with existing af on the basis of known or documented af, but it is possible that patients may have had pre-existing af and not known, due to absence of symptoms [ ] . overall, this lack of granularity represents an important limitation in our study. second, patients were included on the basis of prospective identification by nursing staff. while similar methods have been used at other institutions [ ] , it is possible that cases of noaf were missed using this methodology, particularly if af was brief and transiently lifetime risk for development of atrial fibrillation: the framingham heart study impact of atrial fibrillation on the risk of death: the framingham heart study atrial fibrillation in the icu new-onset atrial fibrillation in adult critically ill patients: a scoping review incidence and prognosis of sustained arrhythmias in critically ill patients epidemiology and management of atrial fibrillation in medical and noncardiac surgical adult intensive care unit patients incidence, predictors, and outcomes of new-onset atrial fibrillation in critically ill patients with sepsis. a cohort study new-onset atrial fibrillation in the critically ill atrial fibrillation is an independent predictor of mortality in critically ill patients epidemiology and outcome of new-onset atrial fibrillation in the medical intensive care unit why is it so hard to stop doing things that are unwanted, non-beneficial, or unsustainable? de-implementing low value care in critically ill patients: a call for action-less is more approach to economic analysis in critical care incident stroke and mortality associated with new-onset atrial fibrillation in patients hospitalized with severe sepsis long-term outcomes following development of new-onset atrial fibrillation during sepsis sepsis- septic shock criteria and associated mortality among infected hospitalized patients assessed by a rapid response team outcomes and costs of patients admitted to the icu due to spontaneous intracranial hemorrhage outcomes of older hospitalized patients requiring rapid response team activation for acute deterioration frailty and invasive mechanical ventilation: association with outcomes, extubation failure, and tracheostomy the third international consensus definitions for sepsis and septic shock (sepsis- ) assessment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (sepsis- ) sepsis definitions task f. developing a new definition and assessing new clinical criteria for septic shock: for the third international consensus definitions for sepsis and septic shock (sepsis- ) frailty and associated outcomes and resource utilization among older icu patients with suspected infection comorbidity measures for use with administrative data multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome a modification of the elixhauser comorbidity measures into a point system for hospital death using administrative data emergency department disposition decisions and associated mortality and costs in icu patients with suspected infection patterns of health care use in a high-cost inpatient population in ottawa, ontario: a retrospective observational study strengthening the reporting of genetic association studies (strega): an extension of the strengthening the reporting of observational studies in epidemiology (strobe) statement control of confounding and reporting of results in causal inference studies. guidance for authors from editors of respiratory, sleep, and critical care journals using generalized linear models to assess medical care costs regression models for analyzing costs and their determinants in health care: an introductory review incidence and prognostic impact of newonset atrial fibrillation in patients with septic shock: a prospective observational study when rhythm changes cause the blues: new-onset atrial fibrillation during sepsis new-onset atrial fibrillation as a sepsis defining organ failure mediation analysis of high blood pressure targets, arrhythmias, and shock mortality daily cost of an intensive care unit day: the contribution of mechanical ventilation costeffectiveness of defibrillator therapy or amiodarone in chronic stable heart failure: results from the sudden cardiac death in heart failure trial (scd-heft) asymptomatic or "silent" atrial fibrillation: frequency in untreated patients and patients receiving azimilide novel method of atrial fibrillation case identification and burden estimation using the mimic-iii electronic health data set long-term impact of newly diagnosed atrial fibrillation during critical care: a south korean nationwide cohort study publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations resolved. third, we only had data related to outcomes prior to hospital death or discharge. existing data suggest deleterious long-term outcomes in patients who develop noaf during critical illness [ , ] . unfortunately, we were unable to evaluate this in our cohort. finally, while our data are derived from two hospitals, they exist within the same city and therefore are susceptible to bias from local practices. while noaf was not associated with hospital mortality among all critically ill patients, it was associated with mortality in subgroups of patients with suspected infection, sepsis, and septic shock. among patients with noaf, sustained af was associated with higher risk of hospital mortality. finally, patients with noaf had higher costs than patients without noaf, and noaf was a predictor of increased total costs among all icu patients. supplementary information accompanies this paper at https://doi.org/ . /s - - - .additional file : table s . generalized linear model with gamma distribution and log link for total cost for entire study cohort (n = , ). generalized linear model with gamma distribution and log link for total cost for entire study cohort (n = , ). additional file : table s . generalized linear model with gamma distribution and log link for total cost for patients with new-onset atrial fibrillation (n = , ). generalized linear model with gamma distribution and log link for total cost for patients with new-onset atrial fibrillation (n = , ). authors' contributions smf, rm, bh, br, and kk designed the study. smf and kk gathered the data. smf, rm, bh, br, lm, ajw, mhm, ts, pd, fdr, pt, and kk analyzed the data, interpreted the data, and wrote the manuscript. all authors read and approved the final manuscript. none received. the datasets generated and analyzed are not publicly available due to patient privacy considerations, but are available from the corresponding author on reasonable request.ethics approval and consent to participate ethics approval for this study was obtained from the ottawa health sciences research ethics board. not applicable. the authors declare that they have no competing interests.author details key: cord- -rqd b s authors: daneman, nick; rishu, asgar h.; pinto, ruxandra; arabi, yaseen; belley-cote, emilie p.; cirone, robert; downing, mark; cook, deborah j.; hall, richard; mcguinness, shay; mcintyre, lauralyn; muscedere, john; parke, rachael; reynolds, steven; rogers, benjamin a.; shehabi, yahya; shin, phillip; whitlock, richard; fowler, robert a. title: a pilot randomized controlled trial of versus days of antibiotic treatment for bloodstream infection on non-intensive care versus intensive care wards date: - - journal: trials doi: . /s - - - sha: doc_id: cord_uid: rqd b s background: the optimal treatment duration for patients with bloodstream infection is understudied. the bacteremia antibiotic length actually needed for clinical effectiveness (balance) pilot randomized clinical trial (rct) determined that it was feasible to enroll and randomize intensive care unit (icu) patients with bloodstream infection to versus days of treatment, and served as the vanguard for the ongoing balance main rct. we performed this balance-ward pilot rct to examine the feasibility and impact of potentially extending the balance main rct to include patients hospitalized on non-icu wards. methods: we conducted an open pilot rct among a subset of six sites participating in the ongoing balance rct, randomizing patients with positive non-staphylococcus aureus blood cultures on non-icu wards to versus days of antibiotic treatment. the co-primary feasibility outcomes were recruitment rate and adherence to treatment duration protocol. we compared feasibility outcomes, patient/pathogen characteristics, and overall outcomes among those enrolled in this balance-ward and prior balance-icu pilot rcts. we estimated the sample size and non-inferiority margin impacts of expanding the balance main rct to include non-icu patients. results: a total of patients were recruited over site-months (mean . patients/site-month, median . , range . – . patients/site-month). the overall recruitment rate exceeded the balance-icu pilot rct (mean . patients/site-month, p < . ). overall protocol adherence also exceeded the adherence in the balance-icu pilot rct ( / , % vs / , %, p = . ). balance-ward patients were older, with lower sequential organ failure assessment scores, and higher proportions of infections caused by escherichia coli and genito-urinary sources of bloodstream infection. the balance-ward pilot rct patients had an overall -day mortality rate of / ( . %), which was comparable to the -day mortality rate in the icu pilot rct ( / , . %) (p = . ). simulation models indicated there would be minimal sample size and non-inferiority margin implications of expanding enrolment to increasing proportions of non-icu versus icu patients. conclusion: it is feasible to enroll non-icu patients in a trial of versus days of antibiotics for bloodstream infection, and expanding the balance rct hospital-wide has the potential to improve the timeliness and generalizability of trial results. trial registration: clinicaltrials.gov, nct . registered on september , . (continued from previous page) indicated there would be minimal sample size and non-inferiority margin implications of expanding enrolment to increasing proportions of non-icu versus icu patients. conclusion: it is feasible to enroll non-icu patients in a trial of versus days of antibiotics for bloodstream infection, and expanding the balance rct hospital-wide has the potential to improve the timeliness and generalizability of trial results. trial registration: clinicaltrials.gov, nct . registered on september , . keywords: bacteremia, bloodstream infection, critical care, intensive care, duration of treatment the world health organization has declared antibiotic resistance a global public health threat, based on rising rates of resistant pathogens and diminishing rates of new antibiotic development [ ] . antimicrobial stewardship is a cornerstone of efforts to counter this threat. however, evidence-informed stewardship treatment decisions for patients with life-threatening illnesses such as bloodstream infections are challenging because little evidence exists for the optimal duration of treatment. among patients with suspected bloodstream infections, broad-spectrum antibiotics must be initiated empirically because early adequate empiric treatment is associated with improved survival [ , ] . due to the rising prevalence of resistant organisms, the tailoring or deescalation of these empiric regimens is not possible even when blood culture and susceptibility results become available. patients must then remain on broad-spectrum agents for their full treatment course [ ] . therefore, shortening total treatment durations may be the most feasible approach to minimize patient-level and societallevel antimicrobial harms [ ] . our systematic review, national practice survey, and observational studies have documented a lack of evidence to guide optimal treatment durations for bloodstream infections, wide variation in clinical practice, and collective equipoise for a trial of versus days of antibiotic treatment for patients with bloodstream infections [ ] [ ] [ ] . through the bacteremia antibiotic length actually needed for clinical effectiveness (balance) pilot randomized controlled trial (clinicaltrials.gov nct ) we documented the feasibility of this trial design among patients in intensive care units (icus) [ ] . these patients served as a vanguard for the balance main trial (clini-caltrials.gov nct ), which has recruited more than patients across a growing number of icu sites and countries. the canadian critical care trials group (ccctg) and australian & new zealand intensive care society clinical trials group (anzics ctg) began the bal-ance trial in the icu setting. as the majority of patients with bacteremia are cared for on general medical and surgical wards, we began to explore hospital-wide expansion to the full population of hospitalized patients with bacteremia as a means to improve the generalizability and timeliness of the balance rct. we first conducted a distinct balance pilot trial focused on patients admitted to general hospital wards at the balance central study site. we then expanded this approach to several community and academic hospitals participating in the balance trial (clinicaltrials.gov nct ). the objectives of this multi-centre balance-ward pilot rct were three-fold: ( ) to test the feasibility of ward (non-icu) recruitment into this trial; ( ) to compare the patient, pathogen, and outcome characteristics among patients enrolled in the balance-ward pilot rct to characteristics in the prior balance-icu pilot rct; and ( ) to estimate the sample size and noninferiority margin impacts of merging the balance-ward pilot with the balance main trial. we conducted a pilot rct of versus days of antibiotic treatment for patients with bloodstream infection, which was identical to our prior balance-icu pilot rct [ , ] , except that it focused on patients admitted to general medical and surgical wards. in this balance-ward pilot trial, as per the prior balance-icu pilot trial focused on critically ill patients, randomization was determined through a central, web-based system (http://www. randomize.net) with variable block sizes of four to six patients, stratified by site. the intervention related only to the duration of treatment, with patients randomized : in parallel to versus days of treatment. all other aspects of care (antibiotic selection, doses, intervals, routes of delivery, and timing of hospital discharge) were at the discretion of the clinical team. participant and clinician blinding and placebo controls were not used given the diversity of pathogens and underlying foci of infection, but allocation concealment was maintained until the seventh day of treatment to mitigate selection bias and differential treatment. the central study team and statistician were blinded to treatment group. the balance-ward pilot trial was registered separately on clinicaltrials.gov (nct ), with unique ethics approval at all participating sites, so that enrolled patients could be kept distinct from the main trial until completion of the pilot and evaluation of feasibility. the balance-ward pilot trial was launched at sunnybrook health sciences centre (shsc) in october , and then after year extended to five other active bal-ance sites, including the ottawa hospital (toh), kingston general hospital (kgh), hamilton general hospital (hgh), st. joseph's health centre (sjhc) toronto, and north york general hospital (nygh). the inclusion criteria differed, by definition, from the prior balance pilot rct [ , ] in that we considered all adult patients with a blood culture reported as positive with a pathogenic bacterium while on a non-icu ward rather than reported as positive while in an icu. however, the exclusion criteria were unchanged from the balance pilot rct: previously enrolled patients, those with neutropenia, organ transplantation, prosthetic valves, endovascular grafts, suspected or documented syndromes requiring prolonged treatment (endocarditis, osteomyelitis, undrained abscess, unremoved prosthetic infection), patients with a single positive culture of a common contaminant organism, or bloodstream infection with staphylococcus aureus, staphylococcus lugdunensis, or fungal organisms. potentially eligible patients were identified through microbiology laboratory reports of positive blood cultures. the site research coordinator screened the medical records of these patients to confirm that they met all inclusion criteria, and no exclusion criteria, and then provided patients with study information materials. consenting patients could be enrolled any time up to the seventh day of adequate antibiotic treatment [ ] . as per the original balance-icu pilot rct, the coprimary feasibility outcomes were ( ) recruitment rates and ( ) adherence to treatment protocol. protocol adherence was defined as receipt of ± days of antibiotics or ± days of antibiotics for patients randomized to shorter versus longer duration treatment, respectively. we did not target a specific protocol adherence rate to consider the trial feasible, but sought to determine whether the protocol adherence rate would exceed the rate seen in the balance icu pilot rct ( %) [ ] . as with the balance icu pilot rct, we expected that there would be some patients for whom clinicians would continue antibiotic treatment beyond the assigned duration because of concerns of new infection, persistent infection, or previously unrecognized deep-seated infection. these were counted as protocol deviations. the target recruitment rate was an average of one patient per site per month to consider including ward enrolments in the bal-ance main trial. the panel of secondary clinical outcomes (e.g., length of stay, mortality, antibiotic-free days, clostridiodes difficile, and antibiotic resistant organisms) were identical to those collected in the original balance pilot rct [ , ] . included among these secondary outcomes was the planned primary outcome from the main balance rct, -day mortality. antibiotic-free days were calculated as the number of days alive and not on any antibiotics in the time period from collection of the index blood culture to days after this date; patients that died prior to day were assigned antibiotic-free days. treatment adherence and clinical outcomes were recorded by the site research coordinator, via chart review and discussion with the clinical team if needed. patients were followed throughout the hospital stay to a -day maximum, with capture of baseline characteristics and outcome information on the same electronic case report form used for the balance main trial. ninety-day mortality was collected via follow-up phone call days from the index bacteremia. there were no interim analyses or stopping rules within this pilot rct. as with our initial balance pilot rct, we planned a priori to maintain blinding of treatment assignment in the balance-ward pilot rct [ ] . a feasibility pilot rct is not powered to identify clinically important differences in safety or efficacy endpoints, but rather this is the goal of the balance main rct. we analyzed the balance-ward pilot rct results as a single cohort, describing overall rates of recruitment per site per month and overall protocol adherence as the coprimary feasibility outcomes of interest. next, we compared these feasibility outcomes to those achieved during our initial balance-icu pilot rct [ ] . poisson regression was used to compare recruitment rates per month in the icu versus non-icu pilots; chisquare test was used to compare protocol adherence. to further evaluate the difference between the two pilot rcts we compared baseline patient characteristics, pathogens, foci of infection, and clinical outcomes among ward and icu patients; the chi-square test or fischer's exact test were used to compare categorical variables, while a t-test or the wilcoxon rank sum test were used to compare continuous variables. the wilson score method was used to determine % confidence intervals. p values were not adjusted for multiple comparisons. if the balance-ward pilot demonstrated feasibility, we planned to consider merging the ward-based protocol with the icu-based protocol of the balance main trial. therefore, we estimated the percentage of recruited patients that would be enrolled from icu versus non-icu wards as a function of the percentage of sites expanding to hospital-wide enrolments. next, we estimated the impact on overall trial sample size and noninferiority margins as a function of the proportion of anticipated icu versus ward enrolments at the time of trial completion. for these calculations we estimated the day mortality for ward patients using outcome data from this ward pilot rct, and we estimated the mortality for icu patients from up-to-date data from the ongoing balance main rct. at the time the ward pilot was completed, patients had been enrolled and reached the -day endpoint in the balance main trial. we sought to enroll a minimum of patients (to equal the sample size of our balance-icu pilot) [ ] , but to improve generalizability of the balance-ward pilot trial we planned to continue enrolment until successful enrolment of at least one patient at all five additional non-central study sites. recruitment extended from october to december . a total of non-icu patients diagnosed with bacteremia on hospital wards were screened for study eligibility, of whom ( %) were deemed eligible for enrolment (fig. ) . the most common reasons for noneligibility among the excluded patients were single positive cultures with contaminant organisms ( ), syndromes with well-defined requirement for prolonged treatment ( ), and s. aureus bacteremia ( ). of eligible patients, / ( %) were enrolled and randomized (fig. ) ; this percentage ranged from to % across participating sites (table ) . a total of patients were recruited over sitemonths (mean . patients/site-month; table ). the recruitment rate varied across the six participating sites: hospital a ( . patients per month, over . months), hospital b ( . patients/month, over . months), hospital c ( . patient/month, over . months), hospital d ( . patients per month, over . months), hospital e ( . patients/month, over month), and hospital f ( . patients/month, over . months) ( table ). the overall recruitment rate significantly exceeded the recruitment rate in the balance-icu pilot rct ( . patients/sitemonth vs . patients/site-month, p < . ). the overall adherence to treatment duration protocol was / ( %), with minimal variation across study sites: shsc / , sjhc / , toh / , kgh / , nygh / , hgh / (table ) . overall protocol adherence significantly exceeded the adherence achieved in the balance-icu pilot rct ( / , % vs / , %, p = . ). patients enrolled in the balance-ward pilot rct were older than those enrolled in the icu pilot rct (median (iqr) ( - ) vs ( - ) years, p = . ), but had a lower sequential organ failure assessment (sofa) score ( ( - ) vs ( - ), p < . ) on the day blood cultures were collected ( table ) . a greater proportion of the bacteremias in non-icu ward patients were community-acquired ( vs %, p < . ), and a greater proportion were due to genito-urinary sources of infection ( vs %, p < . ) and/or e. coli as a causative pathogen ( vs %, p < . ) ( table ) . however, a broad variety of pathogens was still implicated in the non-icu infections ( pathogens among the patients), and the top ten pathogen list was similar to the top pathogens seen in the balance-icu pilot rct (table ) . as per a priori plans, we did not examine clinical outcomes separated by treatment duration arm in this pilot rct. the balance-ward pilot rct patients had an overall -day mortality rate of / ( . %, % ci . - . %), which was similar to the -day mortality rate in the icu pilot rct ( / , . %, % ci . - . %) (p = . ; table ) and mortality estimates from the main balance rct as of patients enrolled ( / , . %, % ci . - . %). the patients in the balance-ward pilot had a shorter median (iqr) length of hospital stay ( ( - ) vs ( - ) days, p < . ) and more antibiotic-free days by day ( ( - ) vs ( - ), p < . ) ( table ). only one patient was lost to follow-up at days, but there are ongoing efforts to ascertain final vital status for this patient. assuming average enrolment rates in the icu based on up-to-date data from the balance main trial, as well as ward enrolment rates from this balance-ward pilot rct, we are able to estimate how the final proportion of icu versus non-icu patients will vary according all data are presented as n (%) or medians (interquartile ranges) unless otherwise specified a one patient in the ward-pilot group and one patient in the icu-pilot group have unknown comorbidities b a total of different bacterial species were isolated among the index blood cultures of the icu patients; a total of different species were isolated among the ward patients sofa sequential organ failure assessment to the proportion of sites that choose to expand enrolment onto non-icu wards (fig. ) . even under scenarios in which three-quarters of sites expand to non-icu wards, the final study population will still be comprised of nearly half icu patients (fig. ) . assuming a -day mortality rate of . % among bal-ance ward patients and . % among balance-icu patients (based on most up-to-date data from the main balance trial), merging ward patients into the main trial would result in an overall mortality rate of % if there were equal numbers of ward and icu patients. figures and depict the sample size and noninferiority margin implications of merging ward patients into the balance rct as a function of the final percentage of ward patients enrolled. in the prior balance-icu pilot rct we demonstrated that it was feasible to enroll icu patients into a trial of versus days of treatment for bloodstream infection [ ] , thereby providing the vanguard patients for the multinational, multicentre balance main rct. in this subsequent balance-ward pilot rct, we have confirmed that it is feasible to enroll patients cared for on general hospital wards and have clarified the viability and implications of expanding the balance main rct to include hospital-wide patients with bacteremia. the balance-ward pilot rct documented feasibility with respect to both co-primary outcomes of recruitment rate and protocol adherence. we achieved mean recruitment rates of . patients per site-month; the median recruitment rate per site per month was lower ( . ) but still met our feasibility target. similarly, we achieved protocol adherence rates of %, which exceeded the % adherence rates in the icu population. on the basis of these co-primary outcomes it appears feasible that the balance rct could be extended from icus to include non-icu patients. the increased recruitment rate on the wards can be attributed to the larger number of bacteremic patients than those who are in the icu. the superior protocol adherence rates on the general wards may be due to the lower severity of illness and lower risk of secondary nosocomial infections among these patients with shorter lengths of hospital stay and fewer indwelling devices such as endotracheal tubes and central venous catheters. as expected, there were some measurable differences in critically ill patients with bacteremia enrolled in the initial balance pilot compared to the patients on the wards who were enrolled in this pilot. the latter were older, had lower severity of illness at baseline, and more commonly had community-acquired bacteremia, genitourinary sources of infection, and e. coli as a causative pathogen. on the one hand, merging non-icu patients with icu patients into a single trial could be viewed as mixing two heterogeneous populations together. on the other hand, combining these patients together could be considered as reflecting a broader population of patients all data are presented as medians and interquartile ranges unless otherwise specified a based on up-to-date data from the first icu patients enrolled in the balance main rct b one patient loss to follow-up for -day outcome (but ongoing efforts underway to ascertain vital status) with bloodstream infection, yielding more generalizable trial results. the icu and non-icu pilot trial patients were both infected with a diverse range of gram negative and gram positive bacterial pathogens, and each included patients with a diverse range of host comorbidities. typically a trial based on a specific diagnosis (e.g., pulmonary embolism, myocardial infarction) would be conducted across the full spectrum of severity, including those patients admitted to icu and non-icu wards. conceptually, enrolling both non-icu and icu patients captures the full spectrum of bacteremic illness, and the patients are only dichotomized by the location of care within the hospital. the -day mortality rate in this pilot rct ( . %) was similar to the mortality rate seen in a recently published rct of patients allocated to versus days of antibiotics for patients with gram negative bacteremia conducted on non-icu wards in three centers in israel and italy [ ] . as expected, the -day mortality rate was lower than that seen in our prior balance-icu pilot rct ( %) [ ] . the mortality difference between non-icu and icu patients is even wider than the icu pilot data suggest, because a more updated mortality estimate from the balance main trial suggests that the mortality has risen to . %. at a fixed non-inferiority margin of %, adding non-icu ward patients in the study would decrease our total sample size requirement (fig. ) ; maintaining our sample size target would enable us to reduce the achievable absolute non-inferiority margin (fig. ) . it is important to note that our % non-inferiority margin is already much smaller than the noninferiority margins used in recent trials of antibiotic treatment duration in patients with serious bacterial infections [ ] [ ] [ ] [ ] , and is also much lower than the us federal drug administration recommendation of noninferiority margins for ventilator-associated pneumonia [ ] . therefore, we have opted to maintain our current overall sample size target (n = ) for the balance main trial. our balance-ward pilot rct enrolled patients in six sites, and so we cannot be certain that the recruitment and adherence results would be generalizable to all of the sites involved in the balance main rct. however, the generalizability is bolstered by inclusion of a mix of both community and academic hospitals, as well as sites with long-standing versus recent involvement in the ccctg. another limitation is that we cannot predict whether expansion to include non-icu enrolment will lead to a compensatory decrease in icu recruitments by diluting study teams' efforts across broader clinical units. in our six pilot rct sites, though, we did not see reductions in icu recruitments. as balance is expanded hospital-wide, we will assess the interplay of icu and non-icu recruitment rates over time. the low rate of enrolment of eligible ward patients, and wide variation across sites, suggests that further efforts may be necessary to foster enrolments, including educating ward clinicians about the pre-rct work which has documented practice heterogeneity and collective clinical equipoise. the balance-ward pilot rct experience suggests that sites with infectious diseases engagement on the study team achieve much higher recruitment rates and percent enrolment of eligible patients, and so this will be crucial for future sites considering hospitalwide recruitment. we will also need to track eligible non-enrolled patients, along with recruitment rates and protocol adherence, as a site-specific metric throughout the conduct of the trial. the balance steering committee and ccctg have guided us in conducting step-wise pilots of the bal-ance rct protocol in the initial icu population, and now in this non-icu population, once again confirming the feasibility of the balance trial design on general hospital wards. we have carefully reviewed the onegroup findings (maintaining allocation concealment) with the ccctg and the balance international steering committee, both of which have strongly endorsed the option for participating balance sites to extend enrolments hospital-wide. given the success of this non-icu pilot, no other protocol changes are required to facilitate inclusion of non-icu patients in the balance main trial. a detailed statistical analysis plan involving the entire cohort will be published before the trial is completed; randomization will be stratified by icu and non-icu ward location, and a subgroup analysis will be conducted. the subgroup analyses, by definition, will not be powered to achieve the same non-inferiority margin as the overall balance trial population. however, the achievable non-inferiority margins within the icu and non-icu subgroups will still be less than the noninferiority margins used in recent landmark antimicrobial minimization studies involving patients with serious bacterial infections [ , [ ] [ ] [ ] . we anticipate that the final balance trial results will be more generalizable to the full population of patients admitted to hospital with bloodstream infections, and yet will include a majority of critically ill patients, ensuring that the data are relevant to our sickest of patients. in doing so, we hope that balance will provide an evidence foundation for the treatment of a broad range of patients with non-s. aureus bacteremia, and allow us to maximize the benefits while minimizing the harms of antimicrobial treatments for bloodstream infections. departments of critical care medicine and anesthesiology, pain management and perioperative medicine systematic review and meta-analysis of the efficacy of appropriate empiric antibiotic therapy for sepsis duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock effect of piperacillin-tazobactam vs meropenem on -day mortality for patients with e. coli or klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial shortening antibiotic treatment durations for bacteremia duration of antibiotic therapy for bacteremia: a systematic review and meta-analysis antibiotic treatment duration for bloodstream infections in critically ill patients: a national survey of canadian infectious diseases and critical care specialists duration of antimicrobial treatment for bacteremia in canadian critically ill patients versus days of antibiotic treatment for critically ill patients with bloodstream infection: a pilot randomized clinical trial bacteremia antibiotic length actually needed for clinical effectiveness (balance): study protocol for a pilot randomized controlled trial the design and interpretation of pilot trials in clinical research in critical care seven versus fourteen days of antibiotic therapy for uncomplicated gram-negative bacteremia: a noninferiority randomized controlled trial comparison of vs days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial trial of short-course antimicrobial therapy for intraabdominal infection partial oral versus intravenous antibiotic treatment of endocarditis guidance for industry hospital-acquired bacterial pneumonia and ventilator asssociated bacterial pneumonia: developing drugs for treatment. - - . ref type: online source springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to acknowledge the extraordinary efforts of the research coordinators at each participating site in screening and enrolling eligible patients, including kanthi kavikondala, miranda hunt, shelley acres, rebecca porteous, irene watpool, alexandra sabev, nevena savija, katrina fimiani, alexandra lostun, and rizani ravindran. we also like to acknowledge the crucial contributions of lisa buckingham and nicole zytaruk at the clarity methods centre in helping to develop the electronic case report form and database. we thank allan garland and kirsten feist for providing internal manuscript review within the ccctg.authors' contributions nd and raf conceived and designed the study, obtained funding, developed the statistical analysis plan, database development, drafted the manuscript, and are responsible for overall management and supervision. ahr participated in the study design, helped develop paper and electronic crf and web randomization and drafting of the manuscript. rp contributed to the study design, provided statistical and methodological expertise, and helped draft the manuscript. ya, epbc, rc, md, djc, rh, sm, lm, jm, rp, sr, br, ys, ps, and rw participated in the study design, contributed to writing grant applications, and helped in reviewing and revising the manuscript for intellectual content. all the authors have reviewed and approved the manuscript for publication. the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.ethics approval and consent to participate key: cord- -q ydi authors: koyama, kansuke; katayama, shinshu; tonai, ken; shima, jun; koinuma, toshitaka; nunomiya, shin title: biomarker profiles of coagulopathy and alveolar epithelial injury in acute respiratory distress syndrome with idiopathic/immune-related disease or common direct risk factors date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: q ydi background: altered coagulation and alveolar injury are the hallmarks of acute respiratory distress syndrome (ards). however, whether the biomarkers that reflect pathophysiology differ depending on the etiology of ards has not been examined. this study aimed to investigate the biomarker profiles of coagulopathy and alveolar epithelial injury in two subtypes of ards: patients with direct common risk factors (dards) and those with idiopathic or immune-related diseases (iards), which are classified as “ards without common risk factors” based on the berlin definition. methods: this retrospective, observational study included adult patients who were admitted to the intensive care unit (icu) at a university hospital with a diagnosis of ards with no indirect risk factors. plasma biomarkers (thrombin–antithrombin complex [tat], plasminogen activator inhibitor [pai]- , protein c [pc] activity, procalcitonin [pct], surfactant protein [sp]-d, and kl- ) were routinely measured during the first days of the patient’s icu stay. results: among eligible patients with ards, were excluded based on the exclusion criteria (n = ) or other causes of ards (n = ). of the remaining patients, were identified as having dards and as having iards. among the iards patients, tat (marker of thrombin generation) and pai- (marker of inhibited fibrinolysis) were increased, and pc activity was above normal. in contrast, pc activity was significantly decreased, and tat or pai- was present at much higher levels in dards compared with iards patients. significant differences were also observed in pct, sp-d, and kl- between patients with dards and iards. the receiver operating characteristic (roc) analysis showed that areas under the roc curve for pc activity, pai- , pct, sp-d, and kl- were similarly high for distinguishing between dards and iards (pc . , p = . ; pai- . , p = . ; pct . , p = . ; and sp-d . , p = . vs. kl- . , respectively). conclusions: coagulopathy and alveolar epithelial injury were observed in both patients with dards and with iards. however, their biomarker profiles were significantly different between the two groups. the different patterns of pai- , pc activity, sp-d, and kl- may help in differentiating between these ards subtypes. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. acute respiratory distress syndrome (ards) comprises acute-onset respiratory failure, which is characterized by hypoxemia and radiographic bilateral lung opacities that result from various direct or indirect injuries to the pulmonary parenchyma or vasculature [ ] . the most recent berlin definition provides common risk factors for ards, which are classified as direct factors (e.g., pneumonia, aspiration of gastric contents) or indirect factors (e.g., nonpulmonary sepsis, major trauma, pancreatitis) [ ] . some patients presenting with ards, however, lack exposure to common risk factors, resulting in the condition called an ards "imitator" or "mimic" [ , ] . in a large cohort study, gibelin et al. reported a . % prevalence of ards without a common risk factor [ ] . a secondary analysis of the lung safe study confirmed that . % of ards patients had no common risk factors that were identified when ards was recognized [ ] . these ards patients who lacked exposure to common risk factors can be categorized as having immune, idiopathic, drug-induced, and malignant diseases [ , ] . connective tissue disease-associated interstitial lung disease (ctd-ild) is considered to be a main cause of immune-related forms of ards. ctd-ild may precede the clinical and laboratory manifestations of ctd and therefore could present as lone ards [ ] . acute onset or acute exacerbation of idiopathic interstitial lung diseases may refer to idiopathic forms of ards. although no risk factors or causes are identified in this subgroup of ards, recent studies have shown that many patients with idiopathic interstitial pneumonia have clinical features that suggest an underlying immune process, indicating that the pathobiology of idiopathic and immunerelated diseases may partially overlap [ , ] . early identification of these subsets of ards based on the pathophysiology is of clinical interest and may lead to the development of specific therapeutic intervention. however, the lesions of these idiopathic and immune-related ards may be mostly limited to the lung, and it is often difficult in the acute phase to distinguish between idiopathic/immune-related diseases and ards with common direct risk factors, based solely on the clinical findings. activation of coagulation and alveolar epithelial injury are the hallmarks of ards (fig. ) [ , ] . the biomarkers may reflect activation and injuries of different cell populations in the lung and thereby help to improve the understanding about pathogenic processes and to improve diagnostics. thrombin-antithrombin complex (tat) levels are increased in ards patients, reflecting tissue factor-and contact phase-mediated activation of coagulation cascade and excessive thrombin generation. thrombin and proinflammatory cytokines activate endothelial cells, leading to expression of plasminogen activator inhibitor (pai)- , which inhibits fibrinolysis. the levels of natural anticoagulants such as protein c (pc) are reduced because of increased consumption, impaired synthesis, and mostly capillary leakage that results from endothelial damage. surfactant protein (sp)-d and a membrane glycoprotein kl- are also increased in the plasma of ards patients, reflecting type ii alveolar cell injury [ , ] . the alterations in biomarkers that indicate thrombin generation, inhibited fibrinolysis, decreased anticoagulant, and epithelial injury are distinctive patterns of ards. however, whether these biomarker profiles may differ depending on the ards etiologies has not been examined. the aim of this study was to examine the profiles of the plasma biomarkers that reflect coagulopathy and alveolar epithelial injury in patients with idiopathic/immune-related ards (iards) and in those with common direct risk factors (dards). we investigated the baseline levels and time courses of hemostatic and type ii pneumocyte biomarkers and compared the discriminative ability of those biomarkers between iards and dards. we also evaluated the biomarkers in patients with unilateral pneumonia who were admitted during the same period for reference purposes. this single-center, retrospective, observational study was conducted at a -bed medicosurgical intensive care unit (icu) at jichi medical university hospital (tochigi, japan). medical records for all patients admitted to the icu between april and march were reviewed. adult patients admitted because of ards without indirect risk factors or unilateral pneumonia who underwent invasive mechanical ventilation within h of admission were included in the study. exclusion criteria were age < years, > week of respiratory disease progression before icu admission, previously known interstitial pneumonia or ipf, or a diagnosis of pneumocystis pneumonia. we also excluded patients with bone marrow failure, decompensated liver cirrhosis or failure, a history of chemotherapy, therapeutic anticoagulation, or blood transfusion during the preceding weeks. the institutional research ethics committee at jichi medical university approved this study and waived the requirement for informed consent because of the study's retrospective design. the ards without indirect risk factors was diagnosed according to the berlin definition with the following criteria: within week of new or worsening respiratory symptoms, bilateral lung opacities were found on chest radiography, and the pao /f i o ratio was ≤ mmhg with a positive end-expiratory pressure of ≥ cmh o. additionally, no cardiac failure or fluid overload and no common indirect risk factors for ards, such as nonpulmonary sepsis, major trauma, or pancreatitis could be found [ ] . direct lung injury risk factors were defined as pneumonia, aspiration of gastric contents, pulmonary contusion, inhalation injury, and near drowning, based on the berlin definitions. patients with vasculitis were classified as having ards without common risk factors because vasculitis is not pathologically characterized by diffuse alveolar damage (dad). the diagnosis of pneumonia was based on infectious diseases society of america/american thoracic society consensus guidelines combined with clinical data and microbiological diagnostic testing (including a blood culture, sputum culture, or culture of endotracheal aspirate, and a urinary antigen test for streptococcus pneumoniae and legionella pneumophila) [ , ] . bronchoalveolar lavage (bal) fluid for gram staining and culture, direct fluorescence assay for pneumocystis jirovecii, and a rapid influenza a/b diagnostic test (immunochromatographic assays for specific influenza viral antigens) were also performed, as needed. ards without common risk factors were separated into four etiological groups, as described below [ ] . idiopathic ards was defined as the absence of any ards etiology including common risk factors despite a comprehensive diagnostic work-up, or acute presentation of idiopathic interstitial pneumonia [ ] . immunerelated ards was defined as an acute presentation of ctd-ild as defined in accordance with established ctd criteria (e.g., american college of rheumatology criteria [ ] ) during hospitalization, or hypersensitive pneumonitis [ ] . malignancy-associated ards was defined as requiring cytological or pathological evidence of hematological or solid malignancy. drug-induced ards was defined as previous exposure to a drug that is known to be a pneumonia inducer in the absence of any other risk factor for ards [ ] . descriptive data (including demographic, diagnostic, clinical, and laboratory data) were collected from the electronic medical records of all eligible patients. initial severity indices, including the acute physiology and chronic health evaluation (apache) ii and simplified acute physiology score (saps) ii, were calculated on the day of icu admission [ , ] . sequential organ failure assessment (sofa) scores were calculated during the first days [ ] . clinical outcomes were assessed according to icu days, ventilator-free days, and allcause -and -day mortality. for the patients with idiopathic and immune-related ards, bal fluid cytological analysis and autoimmunity tests were extracted from the medical charts when available. at our institute, the biomarkers of coagulation and type ii pneumonocytes are routinely measured for the patients who are admitted to the icu with respiratory failure and/or with suspected sepsis. plasma biomarkers were measured at the time of icu admission (icu day ) and on icu days - . coagulation and fibrinolytic markers included global markers (platelet count, immature platelet fraction, prothrombin time-international normalized ratio [pt-inr], fibrin degradation product [fdp]), markers of thrombin generation (tat), markers of anticoagulant activity (pc activity), and markers of fibrinolytic activity (plasmin-α -plasmin inhibitor complex [pic], pai- ). global markers were assayed using an xe- hematology analyzer (sysmex, kobe, japan) and a cs- i automatic coagulation analyzer (sysmex). berichrom assays (siemens healthcare diagnostics, tokyo, japan) were used to assay pc activity. the tat/pic test f enzyme immunoassay (sysmex) was used to measure tat and pic levels. the pai- was measured using the tpai test (mitsubishi chemical medience, tokyo, japan). surfactant protein (sp)-d, kl- , c-reactive protein (crp), and procalcitonin (pct) were measured using the sp-d kit enzyme immunoassay (yamasa, chiba, japan), presto ii kl- chemiluminescent enzyme immunoassay (sekisui medical, tokyo, japan), crp-hg latex immunoassay (eiken kagaku, tokyo, japan), and brahms pct chemiluminescent enzyme immunoassay (roche diagnostic, tokyo, japan), respectively. differences in clinical characteristics and laboratory data among the groups were analyzed using the χ test or fisher's exact test for categorical variables and the wilcoxon rank-sum test or kruskal-wallis test with/without steel-dwass pairwise comparisons for continuous variables, as appropriate. changes in the biomarker concentrations over time in the groups were compared with multiple analysis of variance. a multivariate logistic regression model based on a forward stepwise method was used to identify the best combination of coagulation biomarkers to diagnose iards. receiver operating characteristic (roc) curve analysis was performed to calculate the area under the receiver operating characteristic curve (auc) of the biomarkers at day to evaluate the discriminative capacity between the two groups. all p values were two-tailed, and p < . was considered to indicate statistical significance. data were analyzed using jmp version (sas institute, tokyo, japan). overall, ards patients with no indirect risk factors were admitted to the icu during the study period. among them, were excluded based on the exclusion criteria: history of known interstitial pneumonia, ; pneumocystis pneumonia, ; hematological malignancy with bone marrow failure, ; liver failure, ; anticoagulation therapy, ; inconclusive diagnosis, ; and insufficient data, . data from the remaining patients were included in the study. in addition, patients who were admitted to the icu with unilateral pneumonia during the same period were enrolled for comparison. among the patients with pulmonary ards, had been exposed to direct lung injury risk factors and had not been exposed to any of the common risk factors. the direct risk factors of lung injury included pneumonia ( ; . %), aspiration ( ; . %), and drowning ( ; . %). the ards patients without common risk factors were classified as idiopathic ( ; . %), immunerelated ( ; . %), malignancy-associated ( ; . %), and drug-induced ( ; . %). table shows the baseline characteristics and outcomes of the study patients with iards and dards and those with unilateral pneumonia. patients with dards were more severely ill, with higher apache ii, saps ii, and sofa scores on icu admission compared with patients with iards. the pao /f i o ratio on admission and the severity of ards, however, were not different between patients with dards and those with iards. ventilator-free days, length of icu stay, and mortality were also similar for the two groups. the distribution of pathogens in patients with dards and those with pneumonia are shown in additional file : table s . in patients with dards, the most common causative microorganisms were klebsiella pneumoniae ( . %), followed by streptococcus pneumoniae ( . %) and methicillin-susceptible staphylococcus aureus ( . %). among the patients with iards, ( . %) were diagnosed with idiopathic ards and ( . %) with immune-related ards, which included the following: rheumatoid arthritis (n = ), dermatomyositis (n = ), systemic lupus erythematosus (n = ), scleroderma (n = ), microscopic polyangiitis (n = ), granulomatosis with polyangiitis (n = ), and hypersensitivity pneumonitis (n = ). table shows the bal findings and autoantibodies in patients with iards. in about half of these patients (idiopathic, . %; immune-related, . %), neutrophils and lymphocytes were both elevated in bal fluid, showing a mixed cellular pattern (defined as neutrophil > % and lymphocyte > % on bal differential cell counts). antinuclear antibody was positive (with > : titers) in . %, and anticyclic citrullinated peptide antibody was positive in . % of the patients with immune-related ards. notably, . % of the patients with idiopathic ards were positive for autoantibodies against aminoacyl-trna synthetase. data are expressed as the median (interquartile range) or n (%) ihd ischemic heart disease, chf chronic heart failure, copd chronic obstructive pulmonary disease, ckd chronic kidney disease, cvd cerebrovascular disease, apache acute physiology and chronic health evaluation, saps simplified acute physiology score, sofa sequential organ failure assessment, peep positive end-expiratory pressure *comparison between patients with direct risk factor-associated ards and idiopathic/immune-related ards **comparison among the three groups. italic numbers indicate statistical significance groups. the tat levels were increased in the three groups, but those levels were much lower in iards patients compared with dards patients on day ( . pct levels (marker of infection) on day were increased in the dards and pneumonia patients but were lower than the reference value for infection in patients with iards. however, levels of crp, a widely used marker of inflammation and mechanistically downstream of il- , were not different among the three groups. the markers of type ii pneumocyte injury, sp-d, and kl- were markedly increased in patients with iards compared with those with dards or pneumonia (figs. and ) . to compare the abilities of the plasma biomarkers to distinguish between ards subtypes, we conducted a roc curve analysis to calculate the aucs of biomarkers for coagulation, infection, and pneumocytes ( in this retrospective analysis of ards subtypes, we evaluated the changes in coagulation and alveolar epithelial cell biomarkers over time in patients with iards and dards. tat and pai- levels were increased in patients in both ards subgroups, but a significantly higher increase in those biomarkers were observed in patients with dards. additionally, pc activity decreased in dards, whereas that in iards was normal or even increased. there were also significant differences in pct, sp-d, and kl- levels between the two groups on the day of icu admission. these results suggest that each iards and dards may have its distinct patterns of plasma biomarkers, which could help to differentiate between these ards subgroups. alterations in coagulation and fibrinolytic abnormalities have been observed in animal models of lung injury and in human patients with ards or ild [ ] [ ] [ ] . chambers reported that uncontrolled activation of the coagulation cascade might contribute to the development of fibrosis in both ards and ipf, suggesting that coagulopathy is pivotal as a common pathophysiological factor in these diseases [ ] . in our study, increased coagulation (suggested by increased tat) and suppressed fibrinolysis (suggested by elevated pai- levels) were observed in patients with dards but were less prominent in iards patients. these results are in line with gunther et al.'s study that showed enhanced procoagulant and depressed fibrinolytic capacities were greater in patients with ards than in those with pneumonia or in healthy controls [ , ] . in addition, there were significant differences in coagulation inhibition or the levels of natural anticoagulant between dards and iards. to the best of our knowledge, this is the first study to show differences in the coagulation profile between ards with and without common risk factors, or ards mimics. the pathophysiology accounting for these different coagulopathic patterns has not been identified. one explanation might be that inflammation and coagulopathy fig. changes in coagulation biomarkers during days - in the intensive care unit (icu) for patients with iards, dards, or pneumonia. pt-inr, prothrombin time-international normalized ratio; fdp, fibrin degradation products; tat, thrombin-antithrombin complex; pic, plasmin-α plasmin inhibitor complex; pai- , plasminogen activator inhibitor- . data are expressed as the mean, with the % confidence interval shown by the error bars are relatively limited to the lung in iards, whereas dards is a more systemic disease. although the cause of dards is direct lung injury, indicators of systemic involvement, reflected in the apache ii or sofa scores, were significantly higher in patients with dards compared with those with iards. another possible mechanism might be explained by the different pathological findings of iards and dards. lorente et al. showed that ards patients with dad had higher pt-inr and lower platelet counts than ards patients without dad [ ] . pc activities were within the normal range or even increased in iards patients, whereas those in dards patients remained significantly decreased throughout the observational period. these results are somewhat consistent with the meta-analysis conducted by terpstra et al., which showed that the pc level was decreased in ards and was associated with increased odds for an ards diagnosis [ ] . in the presence of sepsis or ards, anticoagulation pathways, such as the pc system, are impaired because of increased consumption, decreased protein synthesis, extravasation from vessels, and degradation by several proteolytic enzymes. particularly, extravascular leakage resulting from endothelial damage may be the main mechanism during the acute phase [ , ] . decreased pc activity in dards patients, therefore, may reflect systemic endothelial dysfunction. in contrast, bargagli et al. reported that pc activity increased during acute exacerbation of usual ip but was normal in stable usual ip or nsip [ ] . they postulated that increased pc activity was associated with upregulation of the fibrinolytic response to a procoagulant state caused by fibrosis. although the pathophysiological mechanisms of altered pc activity in patients with ards have not been clarified, our findings indicate that the differences in the anticoagulant response to increased coagulation may be useful for distinguishing the ards etiologies. we analyzed idiopathic and immune-related ards within the same category, although these two disorders are classified as having different etiologies. idiopathic interstitial pneumonias (iips) are diffuse inflammatory lung diseases that are grouped together with similar clinical, radiological, and histopathological features. the diagnosis of an iip is based on the exclusion of known causes of ip, such as drugs, environmental exposure, or ctds [ ] . ctd-ilds are the lung manifestation of ctds, where the underlying mechanism is systemic autoimmunity. thus, the diagnosis is based on specific extra-thoracic features of ctds with/without the existence of autoantibodies. recent studies have shown, however, that some patients with ild have certain clinical features that suggest an underlying autoimmune process, although they do not fully meet the diagnostic criteria for any characterizable ctd. the european respiratory society/american thoracic society task force on undifferentiated forms of connective tissue disease-associated interstitial lung disease proposed the term "interstitial pneumonia with autoimmune features" for such diseases [ ] . in our study, approximately % of the idiopathic ards patients were diagnosed as having antisynthetase syndrome without myositis or arthritis and % were positive for anticyclic citrullinated peptide antibody. the biomarker profiles were similar in patients with idiopathic ards and those with immune-related ards, which indicates overlapping pathophysiology of coagulopathy and epithelial injury in these two subsets. sp-d and kl- , which are glycoproteins secreted by type ii alveolar epithelial cells, are widely used as potential surrogate markers of alveolar injury, or alveolitis. the roles of sp-d and kl- are well established for improving diagnostic accuracy, predicting the prognosis, or predicting the risk of acute exacerbation, especially in patients with nsip or ipf [ , , ] . sp-d and kl- are also known to be elevated in ards patients [ , ] , but no published reports have compared the biomarker levels according to different ards etiologies. using data from korea and the usa, park et al. showed that plasma sp-d levels were there were some potential limitations to our study. first, this was a retrospective, observational study conducted at a single center with a relatively small population. a large validation study is needed to confirm our results. second, we could not perform serological tests for non-influenza respiratory viruses, such as the respiratory syncytial virus or human metapneumovirus. although we ruled out the common ards risk factors and known causes of interstitial pneumonia (e.g., drugs, environmental agents, ctds) to diagnose idiopathic ards, we could not completely exclude the possibility of viral infections or environmental antigen exposures, which could subside spontaneously. third, we could perform bal for only about half of iards patients, which may not be generalizable to the whole population. finally, we did not measure the biomarkers in the bal fluid. although systemic markers are easier to obtain and the bal procedure may not always be possible because of the risk of respiratory and hemodynamic complications, the biomarkers in the bal fluid would more specifically reflect the regional pathophysiology in the alveoli. further studies are needed to evaluate the pathogenic processes of these biomarkers from the pulmonary compartment to the circulation. changes in the biomarkers of coagulopathy and alveolar epithelial injury were observed in both patients with dards and with iards, but those biomarker profiles were significantly different between the two groups. pai- and pc activity, as well as pct, sp-d, and kl- , discriminated well between dards and iards on the day of icu admission. these preliminary findings indicate that the biomarker profiles may help to understand the pathogenic processes and improve the prompt differentiation between ards subtypes. additional file : table s . distribution of microorganisms in patients with dards or pneumonia. (docx kb) acute respiratory distress syndrome acute respiratory distress syndrome: the berlin definition acute respiratory distress syndrome mimics: the role of lung biopsy acute respiratory distress syndrome without identifiable risk factors: a secondary analysis of the ards network trials acute respiratory distress syndrome mimickers lacking common risk factors of the berlin definition etiologies, diagnostic work-up and outcomes of acute respiratory distress syndrome with no common risk factor: a prospective multicenter study rare respiratory diseases in the icu: when to suspect them and specific approaches serological and morphological prognostic factors in patients with interstitial pneumonia with autoimmune features research statement: interstitial pneumonia with autoimmune features interstitial pneumonia with autoimmune features: an additional risk factor for ards? ann intensive care blood platelets and sepsis pathophysiology: a new therapeutic prospect in critical ill patients? ann intensive care a review of pulmonary coagulopathy in acute lung injury, acute respiratory distress syndrome and pneumonia comparative study of kl- , surfactant protein-a, surfactant protein-d, and monocyte chemoattractant protein- as serum markers for interstitial lung diseases plasma biomarkers for acute respiratory distress syndrome: a systematic review and meta-analysis* management of adults with hospital-acquired and ventilator-associated pneumonia: clinical practice guidelines by the infectious diseases society of america and the infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias rheumatoid arthritis classification criteria: an american college of rheumatology/ european league against rheumatism collaborative initiative recent advances in hypersensitivity pneumonitis drugassociated acute lung injury: a population-based cohort study apache ii: a severity of disease classification system a new simplified acute physiology score (saps ii) based on a european/north american multicenter study the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine acute respiratory distress syndrome and diffuse alveolar damage. new insights on a complex relationship coagulation, fibrinolysis, and fibrin deposition in acute lung injury tissue factor expression and fibrin deposition in the lungs of patients with idiopathic pulmonary fibrosis and systemic sclerosis procoagulant signalling mechanisms in lung inflammation and fibrosis: novel opportunities for pharmacological intervention? bronchoalveolar hemostasis in lung injury and acute respiratory distress syndrome alveolar fibrin formation caused by enhanced procoagulant and depressed fibrinolytic capacities in severe pneumonia. comparison with the acute respiratory distress syndrome acute respiratory distress syndrome in patients with and without diffuse alveolar damage: an autopsy study decreased plasma activity of antithrombin or protein c is not due to consumption coagulopathy in septic patients with disseminated intravascular coagulation decreased antithrombin activity in the early phase of trauma is strongly associated with extravascular leakage, but not with antithrombin consumption: a prospective observational study serum analysis of coagulation factors in ipf and nsip idiopathic pulmonary fibrosis: from epithelial injury to biomarkers--insights from the bench side pneumocyte biomarkers kl- and surfactant protein d reflect the distinct findings of high-resolution computed tomography in nonspecific interstitial pneumonia pathophysiology and biomarkers of acute respiratory distress syndrome plasma surfactant protein-d as a diagnostic biomarker for acute respiratory distress syndrome: validation in us and korean cohorts we appreciate the assistance of the nursing staff at the intensive care unit at jichi medical university hospital, tochigi, japan. we thank nancy schatken, bs, mt (ascp), and jodi smith, phd, from edanz group (http://www. edanzediting.com/), for editing a draft of this manuscript. authors' contributions kk contributed to the conception and design, data acquisition, analysis and interpretation of the data, and writing and drafting of the manuscript. sk and kt contributed to the patient recruitment, data acquisition, analysis, and review of the manuscript. tk and js helped review the draft manuscript. sn supervised the study and reviewed the manuscript. all authors read and approved the final manuscript. the study was not funded. the dataset generated and/or analyzed during the current study is not publicly available because of patient-related confidentiality, but is available from the corresponding author upon reasonable request. this study was approved by the institutional research ethics committee of jichi medical university. informed consent was waived based on the study's retrospective, observational design, which preserves the confidentiality of personal information. not applicable. the authors declare that they have no competing interests. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -kjcbbgse authors: brun-buisson, c. title: the epidemiology of the systemic inflammatory response date: journal: intensive care med doi: . /s sha: doc_id: cord_uid: kjcbbgse objective: to examine the incidence, risk factors, aetiologies and outcome of the various forms of the septic syndromes (the systemic inflammatory response syndrome [sirs] sepsis, severe sepsis, and septic shock) and their relationships with infection.¶design: review of published cohort studies examining the epidemiology of the septic syndromes, with emphasis on intensive care unit (icu) patients.¶results: the prevalence of sirs is very high, affecting one-third of all in-hospital patients, and > % of all icu patients; in surgical icu patients, sirs occurs in > % patients. trauma patients are at particularly high risk of sirs, and most these patients do not have infection documented. the prevalence of infection and bacteraemia increases with the number of sirs criteria met, and with increasing severity of the septic syndromes. about one-third of patients with sirs have or evolve to sepsis. sepsis may occur in approximately % of icu patients, and bacteraemic sepsis in %. in such patients, sepsis evolves to severe sepsis in > % of cases, whereas evolution to severe sepsis in non-icu patients is about %. severe sepsis and septic shock occur in %– % of ward patients and %– % or more icu patients, depending on the case-mix; % of patients with severe sepsis have shock. there is a graded severity from sirs to sepsis, severe sepsis and septic shock, with an associated -d mortality of approximately %, %, %– %, and %– %, respectively. mortality rates are similar within each stage, whether infection is documented or not, and microbiological characteristics of infection do not substantially influence outcome, although the source of infection does. while about three of four deaths occur during the first months after sepsis, the septic syndromes significantly impact on long-term outcome, with an estimated % reduction of life expectancy over the following five years. the major determinants of outcome, both short-term and long-term, of patients with sepsis are the severity of underlying diseases and comorbidities, the presence of shock and organ failures at onset of sepsis or evolving thereafter. it has been estimated that two-thirds of the overall mortality can be attributed to sepsis.¶conclusions: the prevalence of sepsis in icu patients is very high, and most patients have clinically or microbiologically documented infection, except in specific subset of patients. the prognosis of septic syndromes is related to underlying diseases and the severity of the inflammatory response and its sequelae, reflected in shock and organ dysfunction/failures. abstract objective: to examine the incidence, risk factors, aetiologies and outcome of the various forms of the septic syndromes (the systemic inflammatory response syndrome [sirs] sepsis, severe sepsis, and septic shock) and their relationships with infection. design: review of published cohort studies examining the epidemiology of the septic syndromes, with emphasis on intensive care unit (icu) patients. results: the prevalence of sirs is very high, affecting one-third of all in-hospital patients, and > % of all icu patients; in surgical icu patients, sirs occurs in > % patients. trauma patients are at particularly high risk of sirs, and most these patients do not have infection documented. the prevalence of infection and bacteraemia increases with the number of sirs criteria met, and with increasing severity of the septic syndromes. about onethird of patients with sirs have or evolve to sepsis. sepsis may occur in approximately % of icu patients, and bacteraemic sepsis in %. in such patients, sepsis evolves to severe sepsis in > % of cases, whereas evolution to severe sepsis in non-icu patients is about %. severe sepsis and septic shock occur in %± % of ward patients and %± % or more icu patients, depending on the case-mix; % of patients with severe sepsis have shock. there is a graded severity from sirs to sepsis, severe sepsis and septic shock, with an associated -d mortality of approximately %, %, %± %, and %± %, respectively. mortality rates are similar within each stage, whether infection is documented or not, and microbiological characteristics of infection do not substantially influence outcome, although the source of infection does. while about three of four deaths occur during the first months after sepsis, the septic syndromes significantly impact on long-term outcome, with an estimated % reduction of life expectancy over the following five years. the major determinants of outcome, both short-term and long-term, of patients with sepsis are the severity of underlying diseases and comorbidities, the presence of shock and organ failures at onset of sepsis or evolving thereafter. it has been estimated that two-thirds of the overall mortality can be attributed to sepsis. conclusions: the prevalence of sepsis in icu patients is very high, and most patients have clinically or microbiologically documented infection, except in specific subset of patients. the prognosis of septic syndromes is related to underlying diseases and the severity of the inflammatory response and its sequelae, reflected in shock and organ dysfunction/failures. similarly to ards [ ] the definition of septic syndromes has caused much controversy and debate in the past decade. many of these controversies have stemmed from the frustration accumulated following the repeatedly negative results of new therapeutic interventions aiming at controlling the inflammatory response associated with infection. hence the suggestions that new definitions were needed, that would allow a quicker and simpler identification of septic patients for accrual into randomised trials of new therapies [ ] and that would help derive more consistent and comparable results from epidemiological studies and clinical trials. while the ultimate goal of showing the efficacy of these pharmacological interventions remains elusive, the definitions elaborated then and now in widespread use did provide the impetus for conducting several epidemiological studies aimed at better characterising the septic syndromes and their sequelae. in this paper, we shall review these studies and summarise the current understanding of the clinical and microbiological epidemiology of the septic syndromes, their interplay, and outcomes of patients affected. finally, we shall discuss the implications of this information for conducting clinical trials. the term ªsepsisº has long been used interchangeably with bacteraemia, severe sepsis or even septic shock, undoubtedly a source of some confusion and difficulty in putting together results from published studies. in the us expert panel from the american college of chest physicians and the society of critical care medicine [ ] produced a consensus statement on the suggested definitions to characterise the various stages of the associated inflammatory response and help in differentiating infectious from non-infectious processes. while the recent definitions are centred on the documentation of infection, they aim at encompassing all potential clinical presentations of infection and its consequences. the principles followed in elaborating the definitions were that: ( ) infectious (and some non-infectious) processes, whatever their cause, elicit a common systemic response which, although of variable intensity, is the expression of common pathophysiologic pathways resulting from the expression and interaction of various humoral and cellular mediators and cytokines; ( ) sepsis and related terms should be reserved for infectious processes; and ( ) there is a continuum between the various stages of this response to infection (table ) . although the definitions do provide a framework for classifying patients ± a useful achievement for enrolling patients into clinical trials ± a persisting and unresolved problem facing clinicians in clinical practice is that the definitions are in part retrospective (based on the documentation of infection) and do not actually help them solve the major clinical issue when faced with a septic patient, which is to differentiate infectious from non-infectious processes. another critique of this classification has been that its broad-based approach, intended to identify patients early in the course of the infectious process, did not in fact help physicians, and especially intensivists, to better characterise patients exhibiting the least severe presentations of the septic syndromes. in other words, the high sensitivity of the definition is counterbalanced by a rather low specificity. finally, even the sensitivity of the definitions has been questioned, as there are unquestionably infected patients that do not meet sepsis criteria. nevertheless, several large epidemiological studies conducted after this conference have contributed to s sepsis-induced hypotension, persisting despite adequate fluid resuscitation, ( , ) and manifestations of hypoperfusion as listed in . hypotension, sepsis-induced a decrease in systolic blood pressure to < mm hg, or of > mm hg from baseline, in the absence of other cause for hypotension ( ) ( ) the sirs may be caused by a variety of insults in addition to infection, including but not limited to trauma and status post-major surgery, acute pancreatitis, and burns ( ) an adequate fluid challenge is usually considered as at least ml fluid infused rapidly, and persisting hypotension as one persisting for > hour ( ) patients on inotropic/vasoactive agents may not be hypotensive at time of evaluation our better understanding and characterisation of the epidemiology and relationships to infection of the various stages of the inflammatory response, and of their outcome. in reviewing these, we will use definitions recommended by the expert panel [ ] and will use the term ªseptic syndromesº to refer to all stages of the inflammatory response to infection. evaluations of the incidence of sepsis have initially focused on the most indisputable evidence for infection, i. e., bacteraemia. the incidence of bacteraemia has been increasing steadily over the years. in , the us national center for health statistics reported that the rate of bacteraemia had increased from . / , to . / , hospital discharges between to [ ] . much ± if not all ± this change is caused by the increasing importance of nosocomial infection. at one tertiary-care institution, the rate of nosocomial bacteraemia has increased steadily from . / , to . / , discharges between and [ ] . in the french multi-center study conducted in in public or public-affiliated hospitals [ ] we recorded an overall incidence rate of bacteraemia of . ( ci . to . ) per , admissions; this rate was more than eight-fold higher in icus ( / , ) than in wards ( . / , ) ( table ) . of the bacteraemic episodes recorded in this study, % occurred in icus, % in medical wards, and % in surgical wards. extrapolating these results to the whole country would give a figure of approximately , bacteraemic episodes occurring annually, of which , would occur in icus. so far, the most comprehensive study on the clinical significance of the early stages of the septic syndromes was conducted by rangel-fausto et al. at the university of iowa hospital and clinics [ ] . this study was performed in three icus (medical, surgical, and cardiovascular) and wards of a -bed teaching hospital including icu beds. the incidence of sirs, sepsis, and severe sepsis and septic shock was assessed during a -month period, including a follow-up period of up to days. of the patients admitted during the study period, s data are reported with % confidence intervals in brackets, when available. na = not available ( ) -month incidence study in hospitals in france; ( ) survey at academic medical centres in the us; ( ) incidence study at one academic centre in the netherlands; ( ) prevalence survey at one academic medical centre in the us; ( ) prevalence survey at n hospitals in italy; ( ) incidence of bacteremic sepsis only at one academic medical centre in switzerland a incidence/ , admissions; b incidence/ , patient-days ( %) met at least two criteria for sirs at some point in their hospital stay [ < ]. the major finding from this study was that medical or surgical icu patients met or more sirs criteria during > % of their unit stay, whereas patients in the cardiovascular icu met such criteria during slightly over one-half of their unit stay, and patients from other wards from % to % of their stay. it should be noted however, that the wards surveyed likely housed a population at unusually high risk of sepsis, as indicated by the two prevalence surveys done to complement the incidence study. in these surveys including all hospital wards, the prevalence of sirs was about twice higher ( % and %) in the wards participating in the incidence study than that recorded in the other wards ( % and %) ( table ). the prevalence of sepsis was of %± % in the latter wards, and that of severe sepsis and shock was similar in both surveys in the two categories of wards, respectively at %± %, and %. of the episodes of septic syndromes (i. e., at least sirs) recorded in the incidence study, ( . %) were classified as sepsis, ( . %) as severe sepsis, and ( . %) as septic shock [ ] . patients with infection were classified as having culture-proven or culture-negative sepsis. it is noteworthy that less than % of all episodes were microbiologically documented, although this proportion increased from % when patients only met criteria for sirs, to % in patients presenting with shock. importantly, this study confirmed the expected natural progression between the different stages of septic syndromes: % and % of patients having or sirs criteria, respectively developed culture-proven sepsis by day , and % of those with criteria subsequently developed sepsis, while % of those with sepsis developed severe sepsis, a median of only day after sepsis; conversely, only % of patients presenting with severe sepsis developed septic shock, and this occurrence was delayed by a median of days after severe sepsis [ , ] . the authors also noted an increasing prevalence of eventual organ dysfunctions (respiratory, renal, disseminated intravascular coagulation and shock) with increasing number of sirs criteria. of note, % of patients meeting four sirs criteria developed shock at some point in time. although there were some minor differences in risk of organ failures depending on the stage examined, the overall rate of organ failures was similar within each stage (as well as mortality) whether infection was confirmed or not, to the notable exception of acute renal failure, which was more frequent at all stages in the presence of confirmed infection. several conclusions can be drawn from this study: . the incidence of sirs is very high in icu patients, and its recognition cannot help in accurately identifying patients who will prove to be infected or those at higher risk of the more severe stages. this is confirmed by the fact that only about one-third to onehalf of patients meeting sirs criteria were subsequently proven to have confirmed (i. e., microbiologically proven) sepsis; the prevalence of infection, however, increases with the number of sirs criteria met. however, this conclusion must be tempered by the fact that many patients with sirs were thought to have infection, and were thus administered empirical antimicrobial therapy, which likely interfered with the documentation of infection; the actual proportion of non-infectious sirs or ªsevere sirsº in this study is unknown. . there is indeed a continuum between the different stages of the inflammatory response from sirs to sepsis, severe sepsis and shock. however, only about one-third of patients presenting with sirs have confirmed sepsis and about one-fourth will evolve to severe sepsis. conversely, sepsis (microbiologically confirmed) appears at high risk of evolving rapidly to severe sepsis, as shown by the % proportion of cases subsequently developing severe sepsis, of which one-half will occur within one day of sepsis. . whether infection is confirmed or not, the outcomes are similar in terms of organ dysfunctions and mortality, within each corresponding stage (with the possible exception of renal failure). in another large study, sands [ ] have evaluated patients with severe trauma during the first hours in the sicu; ( %) had sirs. when stratifying patients on the presence of multiple organ dysfunction (mods), these authors found that the rate of sirs was much higher in patients with mods ( / , %) than in patients without ( / , %). the occurrence of mods appeared related to the severity of injury, the volume of blood and fluid replacement, but not to the presence of infection: infection rates were % and %, respectively, in patients with and without mods. as expected in this particular population, sirs appeared as an extremely frequent and non-specific finding, irrespective of the presence of infection. likewise, muckart and bhangwanjee assessed the incidence of the septic syndromes in penetrating or blunt trauma [ ] . of patients followed-up, ( %) fulfilled sirs criteria: % had sirs only and % sepsis; % had severe sepsis and % severe sirs; and % had septic shock and % non-documented septic shock. documentation of infection was more frequent with penetrating trauma. in the italian multicenter study conducted in ± in icus [ ] , % of patients had sirs on admission; at any time during the study, sirs only was recorded in % of patients, sepsis in another %, severe sepsis in . %, and septic shock in %. overall, % of patients had one of the septic syndromes, of which more than two-thirds were non-microbiologically documented sirs. similarly to the study from iowa [ ] the investigators noted that a substantial proportion of patients evolved from an earlier stage on admission to a more severe one: % of patients with sirs evolved to sepsis, but only < % to severe sepsis, while % of patients with sepsis evolved to severe sepsis or shock. severe sepsis and septic shock these syndromes are of much more concern to intensivists than sirs, given their more severe outcome, and the poor specificity (and suboptimal sensitivity) of the latter. a closer view of the overall incidence of these two severe syndromes, which are easier to characterise in the icu, has been provided by two multicenter multi-institutional hospital-wide studies. in the french bacteraemia/sepsis study, including hospitals on the one hand [ ] and icus on the other [ ] both surveyed during a -month period, the overall incidence of severe sepsis and shock (including clinically and microbiologically documented infection) was of / of all hospital admissions, but only of . / in medical/surgical wards and / in icus ( table ). of note, nearly half the episodes were of nosocomial origin. in the parallel larger icu survey, severe sepsis or shock occurred in % icu admissions; % of the episodes were microbiologically docu-mented. the attack rate was higher in larger ( > beds) than smaller hospitals ( . vs. . / admissions). septic shock occurred in . / icu admissions. in the study by sands et al. [ ] sepsis was noted in % icu patients and severe sepsis (defined in that study as sepsis + one of seven criteria for organ dysfunction) occurred in % of icu admissions, a figure very close to the rate recorded in france in large hospitals. while nearly % sepsis episodes occurred in non-icu patients, only % episodes of severe sepsis occurred in such patients, and % were recorded in icu patients [ ] . the relationship between bacteraemia and sepsis has been specifically studied in the french bacteraemia/sepsis multicenter survey [ ] . data from this study indicate that only % bacteraemic episodes occurred in icus, while % occurred in wards, including % in medical wards, and % in surgical wards. sepsis was recorded in % of bacteraemic episodes, severe sepsis in %, of which % were associated with septic shock ( % of all bacteraemic episodes). however, the prevalence of severe sepsis during bacteraemia was much higher in icus than in medical/surgical wards ( % vs. % of bacteraemic episodes, p < . ), emphasising the much higher risk of organ dysfunction and shock during bacteraemia in critically ill patients. conversely, the prevalence of bacteraemia during severe sepsis was estimated at % by kieft et al. [ ] at % in the french multicenter study [ ] and at . % of episodes in the study conducted by sands et al. [ ] . rangel-frausto et al., recorded bacteraemia in % of patients with sepsis, % of those with severe sepsis, and % of patients with septic shock [ ] . in non-icu patients, the prevalence of bacteraemia during severe sepsis was estimated at %, compared to % in icu patients [ ] . likewise, sands et al., found a prevalence of bacteraemia during severe sepsis of % in non-icu patients and of % in icu patients [ , ] . these data indicate that, although icu patients are at much higher risk of severe sepsis than ward patients, bacteraemic severe sepsis is proportionally less often encountered in icu than in non-icu patients. factors associated with bacteraemia at the onset of sepsis have been examined in the study conducted by sands et al. [ ] . independent predictors of bacteraemia during sepsis were: a suspected or documented focal infection, absence of antibiotic therapy, presence of liver disease, of a hickman catheter, altered mental status, and focal abdominal signs. infection caused by staphylococci were associated with hemodialysis and mechanical ventilation, while gram-negative infection were associated with the use of tpn, the absence of antibiotic therapy, the presence of a hickman catheter, of focal abdominal signs, and of chills [ ] . the prediction rules derived from these data performed reasonably well, although the rates of bacteraemia in the highest-risk groups varied from only % to %, depending on the source and micro-organisms involved. host factors identified (by multivariate analysis) as independently associated with severe sepsis among the admissions to the icus participating in the french bacteraemia/sepsis study were: age, male sex, admission to a large ( > beds) hospital, a medical or unscheduled surgical admission, presence of chronic liver insufficiency, of immunodepression, and of severe underlying disease [ ] . there was no difference in these risk factors when excluding patients with non-documented severe sepsis (i. e.,`severe sirs') from the cohort. this question was specifically addressed in the french multicenter study of patients with bacteraemia [ ] . by cox regression analysis, independent factors associated with severe sepsis during bacteraemia were increasing age ( > years), sources other than the urinary tract, an intravascular catheter, or primary bacteraemia. organisms involved were not associated with the occurrence of severe sepsis, nor was the severity of the underlying disease. in another retrospective study of patients that had been included in the va corticosteroids trials [ ] (of whom % had uncomplicated sepsis, % met criteria for severe sepsis and % for septic shock), independent risk factors for the development of severe sepsis or shock were age, gastro-intestinal tract disease, liver disease, haematological disorders, spinal cord injury, and drug abuse. as already mentioned, only a limited fraction of patients presenting with one of the septic syndromes have microbiologically documented infection. in patients meeting criteria for sirs, only % were found by rangel-fausto et al., to have documented infection (i. e., sepsis), and % had culture-negative, but clinically documented, infection; the proportion of documented infection rose to only % in patients with severe sepsis, and to % in patients with septic shock [ ] . higher rates of infection were similarly found in the more severe forms of septic syndromes in other studies: clinically or microbiologically documented infection was recorded in % of episodes in patients meeting clinical criteria for severe sepsis by sands et al. [ ] and in % of episodes recorded by brun-buisson et al. [ ] ; in these two studies, % and % of patients had microbiologically documented infection, and % and % had clinically documented infection, respectively. therefore, only a small fraction of patients presenting with clinically suspected severe sepsis ( %± %) had no infection clinically or microbiologically documented. the four major sources of infection in patients with severe sepsis, in descending order, are the respiratory tract, the abdomen, the urinary tract, and primary bacteraemia [ , ] ; these sources account for > % of cases of severe sepsis (table a) . this distribution differs somewhat from that observed in patients with bacteraemic sepsis, where the urinary tract is the major source of infection (table b), reflecting the lower risk associated with this source in causing severe sepsis, as already mentioned. of note, there is no major difference in the distribution of sources of infection when one compares microbiologically documented cases to clinically documented cases, except for a higher proportion of urinary tract infection and catheter infection in the former group. microbial epidemiology of sepsis, severe sepsis or shock the microbiological features of the septic syndromes may depend in part on the population studied and setting. bacteraemia may be taken as the reference syndrome for looking at microbial aetiologies of sepsis. it should be recalled that major changes have occurred in the past two decades in the epidemiology of bacteraemia. these include increasing rates overall, and a growing importance of gram-positive organisms over the years, especially among nosocomial episodes, which account for most of the recent increased rates [ ] . much of this increasing role of gram-positive organisms is due to catheter-related infections and primary bacteraemia. as a result, gram-positives now outweigh gramnegative among bacteraemic episodes ( % vs %), as shown in the french multicenter study (table ) [ ] . in severe sepsis, however, the proportion of grampositives and gram-negatives appear similar, reflecting the lower risk of severe sepsis associated with infection caused by coagulase-negative staphylococci [ ] ; in non-bacteraemic severe sepsis, however, gram-negative organisms appear to predominate [ ] . again, there was no major difference in the distribution of organisms when comparing bacteraemic episodes associated with sepsis only or with severe sepsis, except for a marginally higher proportion of polymicrobial infection (table ). these data suggest that the microbiologic characteristics of infection are not a major determinant of the clinical presentation and intensity of the host response to infection. this notion is also consistent with the fact that it appears quite difficult to predict bacteraemia in patients presenting with clinical sepsis [ ] . it is apparent that the classification into three major syndromes (sepsis, severe sepsis, and sepsis shock) reflects a grading in prognosis of patients affected, and this is clearly an important outcome of the current classification. there are, however, wide variations in mortality rates reported in cohorts of patients with septic s * p < . for comparison of sources between episodes of bacteremic sepsis and bacteremic severe sepsis. data from [ ] ; reproduced with permission syndromes, especially for hospital-wide data. in the study by rangel-fausto et al. [ , ] the -day mortality of the different stages from sirs to septic shock was %, %, %, and % for sirs, sepsis, severe sepsis and septic shock, respectively. in the study conducted by sands et al. [ , ] the -day mortality of patients with severe sepsis and septic shock was %. in the french multicenter study, the -day mortality was % in patients with bacteraemic sepsis ( % in ward patients), and of % in patients with bacteraemic severe sepsis or shock [ ] . in studies restricted to icu patients, mortality rates were slightly more consistent across studies. pittet et al., reported a -day and hospital mortality rate of bacteraemic sepsis of % and %, respectively [ ] ; % of these patients had severe sepsis, as assessed by the presence of organ dysfunction at onset or secondarily. brun-buisson et al., reported a -day mortality of % in icu patients with bacteraemic sepsis, % of whom had severe sepsis or shock [ ] ; overall, mortality was % at days after severe sepsis among icu patients, of whom % had septic shock [ ] . it is apparent that the mortality rate for a given stage upon inclusion is dependent in large part on the proportion of patients rapidly evolving to a more severe stage. knaus et al., have shown that a wide range of mortality risk could be observed in patients classified as having sepsis or even shock [ ] . further insight into a better characterisation of outcome for septic patients has been provided by studies looking at mortality risk adjustment through risk factors analyses and models specific to septic patients. as for all icu patients, there are two major determinants of outcome for septic patients: the severity of underlying disease, and the severity of acute illness. severity of underlying disease has been assessed via several indexes or systems, such as the simple (and robust, but somewhat subjective) three-classes index developed by maccabe et al., for bacteraemic patients [ , ] or a comorbidity scoring index, a system primarily developed for adjusting the risk of nosocomial infection [ ] ; finally, general scoring systems such as the apache ii include comorbidities, expressed as pre-existing organ dysfunction for the four major organ systems (respiratory, cardiovascular, renal, and liver), or include a few major comorbidities such as in the saps ii (aids, metastatic cancer, and haematological malignancy) [ ] . a more complete assessment of pre-existing conditions can probably be obtained by ascribing a weighted score to diagnosis and comorbidities, as used in the apache ii and iii scoring systems [ ] . stratifying patients by risk class according to one of the general scores provides a more accurate risk prediction of outcome for septic patients than a simple stratification in one of the stages of sepsis [ ] . further analysis of the performance of these scores in septic patients have led to the development of customised scores, either through the integration of additional variables [ ] or through modification of the weighting of variables included in the original score [ ] . the use of such customised models in risk prediction in the context of clinical trials to accurately compare predicted to observed mortality and derive the efficacy of new therapies in subgroups of patients has, however, been disappointing [ , ] . it is apparent that the general scores, whether or not customised, principally reflect the severity of acute physiologic disturbances when measured at time of sepsis; in other words, they reflect the severity of organ dysfunction associated with sepsis. two studies have examined risk factors for short-term mortality in a predefined cohort of icu patients with sepsis or severe sepsis [ , ] . in the french multicenter study [ ] several factors recorded at onset of sepsis were found associated with early mortality of patients with severe sepsis: the maccabe index (or = . and for ultimately and rapidly fatal underlying disease, respectively), and bacteraemia (or = . ); however, the three most important independent risk factors for early mortality were the saps ii (or = . per unit of score, p = . ), the presence of shock (or = . , p = . ), and the presence of more than one organ system failures, as defined according to knaus et al. [ ] (or = . and or = . for or > organ failures, respectively; p = . ). later mortality after severe sepsis was also associated with the saps ii, and the number of organ system failures, but also with other factors related to underlying diseases, such as pre-existing liver or cardiovascular failure or the maccabe index, the admission category, and presence of multiple sources of infection. in patients with bacteraemic sepsis, pittet et al. [ ] also found that the apache ii score measured at the time of sepsis was highly predictive of mortality (and a better predictor than apache ii measured on icu admission). these authors also noted that prior antimicrobial therapy and hypothermia were associated with a poorer prognosis. organ dysfunctions were also strongly associated with mortality; however, only those recorded after the onset of sepsis were associated with mortality in that study [ ] . this surprising finding may have been due to the limited power of the study. therefore, in addition to a general severity score, and one assessing prior comorbidities such as the mac-cabe score, organ dysfunctions at onset of sepsis and developing after its onset appear as the major determinants of the short-term outcome of septic patients. whether customised models for sepsis perform better than the above combination of three major determinants has not been formally tested on a large cohort of patients, and remains unknown. an interesting approach would be to incorporate a score of organ dysfunction in the prognostic assessment of patients with sepsis. these refined scoring systems for organ dysfunction/failures [ , , ] which allows identification of organ dysfunction in a graded manner and at an earlier stage, would likely allow a more precise description of prognostic factors and of the interrelations between the various organ dysfunctions and their respective impact on outcome. however, from the viewpoint of mortality prediction, it is unlikely that these scores perform better than the general (or customised) scoring systems. most studies and clinical trials have focused on -day or hospital mortality, a relatively short-term view, which does not provide a complete picture of the impact of sepsis on life expectancy, an important consideration for cost-benefit studies of the impact of new therapies. admittedly, most deaths usually occur early in severe sepsis. for example, % and % of all deaths had occurred by day and by day , respectively, in the french multicenter study [ ] and in the study by pittet et al. [ ] . however, % of patients remained in the hospital for more than days in the former study, and the median hospital stay of survivors was days, with lengths of stay ranging from to days [ ] . these data suggest that it would be advisable to assess the outcome of sepsis at least after rather than months after sepsis. similarly, sands et al. reported that the crude mortality of patients with severe sepsis was % at days and % at five months post-discharge [ ] . sasse et al. [ ] reported a crude -day and hospital mortality rate of % and %, respectively, in icu patients with bacteraemic sepsis, and of % and % respectively at months and year after admission; it should be emphasised that in this particular study, % of patients each had hiv infection or malignancy. finally, rangel-frausto et al., reported a -day crude mortality of % in the cohort of patients meeting at least sirs criteria; an additional patients died during the ensuing months, and more between and months follow-up [ ] . the overall crude mortality rate at months was therefore of % in patients meeting at least sirs criteria. however, the relative part of sepsis and other host factors in the overall mortality is unknown. perl et al., have addressed part of the problem by examining factors associated with late mortality after sepsis in a cohort of patients with severe sepsis entered in one clinical trial of anti-endotoxin antibodies [ ] . in that study, the crude mortality of patients was % at month, % at months, and % at months; after a mean follow-up of months, % patients had died. when examining factors associated with mortality at those different points in time after sepsis, they found that all models included the severity of underlying disease (maccabe classification) and a combined index of comorbidities, in addition to vasopressors (or shock) and ventilator use (or ards). therefore, pre-existing illness and comorbidities, in addition to shock and organ failures (i. e., ards), are also confirmed as important predictors of long-term outcome in this study. an elegant study by quartin et al. [ ] has provided some more insight into the problem of long-term mortality attributable to sepsis. these authors have estimated the increased risk of mortality attributable to sepsis over a -year follow-up period in patients qualifying for sepsis and entered into a clinical trial of corticosteroid therapy, as compared to a control cohort of non-septic hospitalised patients, after adjustment on risk factors for death in the control cohort. after years, ( %) of the septic patients had died. the authors estimated that septic patients had an increased mortality risk persisting beyond one month and over the five years following sepsis; the increased risk was apparent in all stages of septic syndromes. the median predicted life expectancy was years among septic patients. the average life expectancy cost of sepsis was estimated at . years and the median survival among -day survivors was reduced from . to . years. in the septic population, there were ( %) more deaths than predicted from controls within the first month, ( %) more within one year, and ( %) more within years; thus, the overall mortality attributable to sepsis was % at one year. sepsis also appears to significantly affect the quality of life of survivors. in the study by perl et al. [ ] survivors had lower scores than normal by functional status and general health perception scales. it is quite clear from the above epidemiological information that sirs criteria are much too non-specific to be used for the selection of patients. including patients characterised only by these criteria would only result in augmenting the`background noise', by introducing a large population having a < % risk of sepsis, and a low risk of mortality. one would like sepsis or its more severe forms to be used as criteria for inclusion. however, physicians remain with the dilemma that there is no reliable method for identifying patients having sepsis among those presenting with clinical criteria for sirs/ sepsis. in this respect, the new classification has not provided a significant advance in identifying at-risk patients. it is noteworthy that all recent clinical trials have actually used criteria for severe sepsis or shock in their inclusion criteria. if this classification is used, and there is a need for studying patients at an early stage of infection, then a more in-depth analysis of risk factors for sepsis or its more severe forms in patients with sirs patients is needed. septic shock remains a major prognostic factor and, importantly, is readily available for stratification at inclusion of patients into clinical trials. a general severity score (original or customised) could also be used, or better, an organ dysfunction score, depending on objectives and end-points pursued in the trial. consideration should also be given to major underlying conditions, using a simple index, such as the maccabe score. it is apparent that the systemic response to infection, not infection itself, is the major determinant of the outcome of patients. mortality remains the reference endpoint. this simple and robust end-point is validated by the fact that mortality remains high, at least in the most severe forms of the septic syndromes, and by the estimated attributable mortality which is also very high, and likely accounts for two-thirds of the overall mortality, especially of the short-term mortality. since sepsis has also substantial effects on long-term survival, a longer than usual follow-up (i. e., months to year) should be used, at least if some possible delayed effects of therapy on survival are expected. using mortality as an end-point implies that factors other than sepsis itself, which have a significant impact on patients' survival, are accounted for in the survival analysis. these factors include, (but may not be limited to) the severity of the underlying disease, the presence of comorbidities, and the severity of haemodynamic disturbances and other organ dysfunction at inclusion. the importance of underlying conditions is highlighted by the relatively low spontaneous life expectancy associated with underlying illness and comorbidities in most patients with sepsis. it has been suggested that the assessment of organ dysfunction/failure, especially via a grading score could be used as a substitute for mortality. this debate is at present unsettled. clearly, organ dysfunctions are strongly (linearly) related to mortality, and there is no obvious advantage from using such a score instead of mortality. using organ failure-free days, as suggested when dealing with one organ system dysfunction such as ards, may be misleading, as death may still occur relatively late after onset of sepsis. at present, organ failure scores are best used as adjustment variables at onset of sepsis and their assessment over time should be viewed as explanatory observations in an attempt to provide better insight into the physiological effects of interventions. the american-european consensus conference on ards: definitions, mechanisms, relevant outcomes and clinical trials coordination definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis increase in national hospital discharge survey rates for septicemia ± united states nosocomial bloodstream infections. secular trends in rates, mortality, and contribution to total hospital deaths bacteremia and severe sepsis in adults: a multicenter prospective survey in icus and wards of hospitals the natural history of the systemic inflammatory response syndrome the dynamics of disease progression in sepsis: markov modeling describing the natural history and the likely impact of effective antisepsis agents epidemiology of sepsis syndrome in academic medical centers systemic inflammatory response syndrome, sepsis, severe sepsis and septic shock: incidence, morbidities and outcomes in surgical icu patients role of systemic inflammatory response syndrome and infection in the occurrence of early multiple organ dysfunction syndrome following severe trauma american college of chest physicians/ society of critical care medicine consensus conference definitions of the systemic inflammatory response syndrome and allied disorders in relation to critically injured patients the italian sepsis study: preliminary results on the incidence and evolution of sirs, sepsis, severe sepsis and septic shock incidence, risk factors, and outcome of severe sepsis and septic shock in adults. a multicenter prospective study in intensive care units predicting bacteremia in patients with sepsis syndrome the sepsis syndrome in a dutch university hospital. clinical observations the departement of veterans affairs sepsis cooperative studies group ( ) magnitude and duration of the effect of sepsis on survival bedside prediction of mortality from bacteremic sepsis. a dynamic analysis of icu patients wagner dp ( ) evaluation of definitions for sepsis gram-negative bacteremia.iv. re-evaluation of clinical features and treatment in patients long-term survival and function after suspected gram-negative sepsis importance of pre-existing comorbidities for prognosis of septicemia in critically ill patients a new simplified acute physiology score (saps ii) based on a european-north american multicenter study the clinical evaluation of new drugs for sepsis: a prospective study design based on survival analysis the icu scoring group ( ) customized probability models for early severe sepsis in adult intensive care patients the phase iii rhil- ra sepsis study group ( ) recombinant human interleukin- receptor antagonist in the treatment of patients with sepsis syndrome: results from a randomized prognosis in acute organ system failure the icu scoring group ( ) the logistic organ dysfunction system: a new way to assess organ dysfunction in the intensive care unit multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome use of the sofa score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study long-term survival after intensive care unit admission with sepsis key: cord- -q wy e authors: delannoy, p.-y.; boussekey, n.; devos, p.; alfandari, s.; turbelin, c.; chiche, a.; meybeck, a.; georges, h.; leroy, o. title: impact of combination therapy with aminoglycosides on the outcome of icu-acquired bacteraemias date: - - journal: eur j clin microbiol infect dis doi: . /s - - -z sha: doc_id: cord_uid: q wy e pharmacodynamic studies report on the rapid bactericidal activity of aminoglycosides, conferring them as being of theoretical interest for bacteraemia treatment. we assessed this issue in a retrospective study of patients with intensive care unit (icu)-acquired bacteraemias. to determine the impact of aminoglycosides in antimicrobial combination on the outcome of patients with bacteraemia, we performed a monovariate analysis and a logistic regression analysis comparing patients treated with or without aminoglycosides. forty-eight bacteraemias in patients were included. eighteen patients received aminoglycosides. baseline characteristics as well as adaptation and adequation of antibiotherapy did not differ in patients who did or did not receive aminoglycosides. patients who received aminoglycosides had longer time alive away from the icu ( . ± . ( [ – ]) vs. . ± . ( [ – ] days; p = . ) and free from mechanical ventilation ( . ± . ( [ – ] vs. . ± . ( [ – ] days; p = . ) on day . the icu mortality was % in the aminoglycoside group versus % (p = . ). in the multivariate analysis, patients treated with aminoglycosides were times less likely to die than those treated without aminoglycosides (confidence interval [ci] = [ . – . ]; p = . ). our study supports the hypothesis that combination short-term antibiotherapy with an aminoglycoside for icu-acquired bacteraemias could increase survival. combination antimicrobial therapy with beta-lactams plus aminoglycosides (ags) was widely used in the s and s. the advent of broader spectrum beta-lactams and reports on ag toxicity were the basis of the current controversy on combination therapy. meta-analysis failed to demonstrate improved outcomes in patients treated with antibiotic combinations over those receiving monotherapy [ ] [ ] [ ] [ ] and resulted in a decreased use of combination therapy. however, it remains frequently used in intensive care units (icus) due to the theoretical advantages of rapid bacterial killing and extending the spectrum of activity in the era of multidrugresistant microorganisms. bacteraemia is a severe infection associated with increased morbidity and mortality [ ] [ ] [ ] . hospital-acquired bacteraemias are more often due to drug-resistant organisms. a delay in the administration of active antibiotics has been linked to an increased risk of death. ags exhibit concentration-dependant activity, allowing for maximum efficacy with once-daily, short-duration therapy, which offers the added benefit of decreased toxicity. moreover, the pharmacologic properties of ags could be beneficial in the specific subgroup of critically ill patients presenting with icu-acquired bacteraemia. we performed a retrospective study to evaluate the impact of ags in antimicrobial combination on icu-acquired bacteraemia in our universityaffiliated icu [ ] [ ] [ ] [ ] . eligible patients were those who developed icu-acquired bacteraemia from january to july during their stay in the icu of tourcoing hospital, france. patients were recruited though the icu ongoing database and the microbiology laboratory records. neither approval of the ethics committee nor informed consent was required, considering our study was retrospective. the aim of the study was to evaluate the impact of ags in antibiotic combination on the outcome of patients with icu-acquired bacteraemia. for each bacteraemia, the following covariates were collected: age, gender, comorbidities (cardiac disease, diabetes mellitus, chronic obstructive pulmonary disease [copd], chronic hepatic failure, chronic renal failure, haematologic malignancies, non-haematologic malignancies). patients were considered as being on immunosuppressive treatment if they had received corticosteroids ( mg/d for at least two weeks), cytotoxic therapies or radiotherapy in the last three months. organ transplant patients, human immunodeficiency virus (hiv)positive patients and patients with splenectomy or neutropaenia (granulocyte count < / mm ) were considered to be immunocompromised. we collected all antibiotics administered during the month before bacteraemia. icu-acquired bacteraemia was defined as any bacteraemia occurring in our unit more than h after admission. coagulase-negative staphylococci were considered if two successive blood cultures were positive with the same antibiogram. the source of infection was classified as follows: lower respiratory tract, intra-abdominal, genitourinary tract, catheter-related infection, endocarditis, meningitis, cutaneous infection, primary bacteraemia or other. secondary bacteraemia was defined as an episode developing after a documented infection with the same microorganism at another body site [ ] . the severity of illness was evaluated with the simplified acute physiology score (saps ii) [ ] and the sepsisrelated organ failure assessment (sofa) score [ ] . we considered organ dysfunction if the score was greater . haemodynamic instability was defined as a need for vasopressive drugs to maintain adequate blood pressure and respiratory failure was noted when pao /fio < with ventilatory support was required. acute renal dysfunction was defined by a serum creatinine > mg/l or urine output < ml/d, acute hepatic dysfunction by an increase in bilirubin level > mg/l, neurologic failure by glasgow coma scale score < . platelet count < , /mm was considered as a coagulopathy. we collected biological data including leukocyte and platelet counts, ph, urea, creatinine, pao /fio , prothrombin time, bilirubin and c-reactive protein (crp). variables collected on antibiotherapy were as follows: time from the first positive blood culture to first antibiotic administration and antimicrobial agents used. the administration schedule of ags was recorded. following local guidelines, we performed peak serum dosages and trough dosages for patients with initial renal impairment. a trough over μg/ml was considered to be toxic. antibiotic therapy was considered as adapted if it followed the recommendations and adequate if it included at least one antibiotic active in vitro on the isolated pathogen [ ] . we also recorded the use of activated protein c, hydrocortisone, intensive insulin therapy, and need for mechanical ventilation or renal replacement therapy (rrt). the sofa score evolution was recorded on days and following bacteraemia. we investigated whether the patient had developed infection-related complications, such as septic shock, acute respiratory distress syndrome (ards), renal failure, disseminated intravascular coagulopathy or hepatic dysfunction. to evaluate the renal function, we used the risk, injury, failure, loss of kidney function and end-stage kidney disease (rifle) criteria [ ] . patients were considered as having acute kidney injury when the rifle class increased to injury or failure after bacteraemia. we also searched for any other hospital-acquired infection and bacteraemia recurrence. the primary endpoint was -day survival. secondary endpoints were number of days without mechanical ventilation, without vasopressive drugs, without rrt and with icu discharge on day from bacteraemia. to evaluate the impact of ags on patients' outcomes, we compared patients with or without ags in their empirical antibiotic regimen for bacteraemia through a monovariate analysis. comparisons between groups were performed using the chi-square test or fisher's exact test for categorical parameters. continuous variables were analysed using wilcoxon's test. differences between groups were considered to be significant for variables yielding a p-value less than . . all significant parameters in the monovariate analysis were evaluated in the multivariate logistic regression analysis. all analyses were performed using sas software version . . between january and july , we identified icuacquired bacteraemias in patients. of the overall population, % were male, the mean age was years ± , the mean saps ii on the bacteraemia day was ± and the mean sofa score was . ± . . the baseline characteristics did not differ in patients who did or did not receive ags (table ) . the most frequent portal of entry was a catheter-related bacteraemia ( %). the most frequent microorganisms were staphylococcus aureus ( %) and enterobacteriaceae ( %). no polybacterial bacteraemia was observed. the bacteriological data are presented table . all but three patients received a beta-lactam as the primary therapy. eighteen patients ( . %) received combination therapy with an ag ( with amikacin and six with gentamicin). patients with ags received a mean of . ± . ag injections. ags were more frequently administered in gram-negative than in gram-positive bacteraemias ( vs. %, p . ). two patients developed acute renal failure in the ag group versus three in the non-ag group (p ). in the ag group, % of patients received at least two antibiotics active on the isolated pathogen, whereas this was only % in the other group (p< . ). the most frequent combination in the ag group was beta-lactam with ags (n ) for eight enterobacteriaceae, for five methicillin-susceptible s. aureus and for one coagulase-negative staphylococcus bacteraemias. the other combination in the ag group was glycopeptides plus ag for one coagulase-negative staphylococcus bacteraemia. in the non-ag group, combinations were beta-lactam plus quinolone (n ) and beta-lactam plus colistin (n ) for enterobacteriaceae bacteraemias, and one association of beta-lactam with linezolid for methicillin-susceptible staphylococcus. no difference was found between the two groups in the management and the occurrence of complications (table ). antibiotherapy delay was not different between the two groups and the adaptation and adequation of antibiotherapy reached % in both groups. patients who received ags had longer time alive away from the icu ( . ± . ( [ - ]) vs. . ± . ( [ - ]); p . ) and free from mechanical ventilation ( . ± . ( [ - ]) vs. . ± . ( [ - ]); p . ) on day . the icu mortality was % in the ag group and % in the non-ag group (p . ). the occurrence of another nosocomial infection, complications of bacteraemia and sofa score evolution did not differ between the two groups. the univariate analysis identified five variables associated with a higher mortality: -hepatic failure (p . ) -oliguria (p . ) -no ag (p . ) -no vancomycin (p . ) -sofa score ≥ (p . ) these variables were included in a logistic regression multivariate analysis model. two independent risk factors for mortality were identified: we found a survival benefit with the use of combination therapy with ags for icu-acquired bacteraemias. ags have unique characteristics among antimicrobial agents. they exhibit extremely rapid bacterial killing, have a demonstrated synergy with beta-lactams on some bacteria and have a prolonged post-antibiotic effect [ ] . in the icu, inadequate empirical antibiotic therapy is associated with an increased mortality risk in patients with ventilator-associated pneumonia and bacteraemia. with the increasing occurrence of drugresistant microorganisms, both community-and hospitalacquired, icu physicians often use empirical combination therapy to increase the initial spectrum coverage. in our study, the rates of appropriate antibiotic treatment in the two groups were not statistically significant and do not explain our main result [ ] [ ] [ ] [ ] . the bacteraemias' portals of entry, similarly, could not explain our results. catheter-related bacteraemias were usually associated to a low mortality rate and were more frequent in the group without ags. the major adverse effects of ags are dose-dependent nephrotoxicity and ototoxicity. in our study, the rates of adverse events were not increased by ags. ag nephrotoxicity is influenced by the administration schedule, the duration of treatment and individual variability. the risk of nephrotoxicity is lower for once-daily ag dosing than for traditional twiceor thrice-daily dosing. our dosing regimen, drug level monitoring and duration of treatment are strictly adherent to our institution's guidelines. we only use once-daily high dosing, with a maximum of days treatment duration. this might explain the lack of observed adverse events [ , ] . icu patients with or without bacteraemia have an increased volume of distribution. the usual dosages of betalactams might be less effective. these patients would be the most likely to benefit from the enhanced bactericidal activity offered by a beta-lactam-ag combination therapy. most studies do not support a benefit for combination therapy. the comparison of ag/beta-lactam combination with betalactam monotherapy has been the subject of numerous studies and meta-analysis. paul et al., in , reviewed , patients from clinical trials [ ] . combination therapy did not prevent the emergence of antimicrobial resistance and did not affect patient outcomes. acute kidney injuries were mostly found in the combination group. paul et al. found the same conclusions in another meta-analysis published in [ ] . furno et al., in , performed a similar meta-analysis focussing mostly on immunocompromised patients [ ] . among , septic episodes with , bacteraemias, their conclusions were similar. safdar et al. found a significant survival advantage with ags for bacteraemia caused by pseudomonas aeruginosa in comparative non-randomised studies [ ] analysed in a meta-analysis. the meta-analysis by bliziotis et al. concluded that combination therapy lacks benefit with respect to the selection of drug-resistant organisms, superinfection, treatment failure and mortality [ ]. leibovici et al., reviewing all of the previously mentioned meta-analyses, concluded to a lack of interest of the beta-lactam ag combination [ ] . however, it has been objected [ ] that most studies included suffered from limitations weakening this interpretation: the studies were heterogeneous and rarely compared the same beta-lactam in both arms. the latter means that it is difficult to relate the difference in efficacy to the ag and not the betalactam. furthermore, the studies mainly used outdated ag administration schedules, such as thrice-daily administration, long treatment duration and lack of serum monitoring. these are related to treatment toxicity, which was counted as treatment failure in many studies. finally, bliziotis et al. suggested that once-daily ag therapy combined with a beta-lactam could have a beneficial effect on the development of resistance compared with beta-lactam monotherapy and should be the subject of further research. recently, a systematic review of randomised trials focussing on the clinical implications of beta-lactam-ag synergy recommended avoiding the routine use of beta-lactam-ag combination therapy. in a subgroup of bacteraemic patients, they did not find any survival advantage for combination therapy [ ] . our study focussed on the most severe patients, i.e. icu patients with hospital-acquired bacteraemia who need more rapidly active treatment than less severe patients. our study has several limitations that should be taken into account. first, this study is retrospective and low-powered. second, our groups were statistically homogeneous, except for greater hepatic failure in patients without ag. this failure, a major prognostic factor associated with a high mortality, could have biassed our study. third, we considered a very specific clinical scenario: icu-acquired bacteraemias. fourth, except for methicillin-resistant s. aureus, we observed only rarely drug-resistant organisms. however, considering the susceptibility pattern of drug-resistant bacteria now observed in our icu, this would probably enhance our results. mostly, treatment with ag permitted to reach an % rate of effective bi-therapy instead of only % without ag. the debate about aminoglycoside (ag) interest is not closed. our study suggests that short-term combination beta-lactams plus ags therapy in intensive care unit (icu)-acquired bacteraemia could reduce mortality. this should be confirmed in future prospective randomised trials. effect of aminoglycoside and beta-lactam combination therapy versus beta-lactam monotherapy on the emergence of antimicrobial resistance: a meta-analysis of randomized, controlled trials does combination antimicrobial therapy reduce mortality in gram-negative bacteraemia? a meta-analysis monotherapy or aminoglycoside-containing combinations for empirical antibiotic treatment of febrile neutropenic patients: a meta-analysis community-acquired bloodstream infection in critically ill adult patients: impact of shock and inappropriate antibiotic therapy on survival nosocomial bacteremia in critically ill patients: a multicenter study evaluating epidemiology and prognosis. spanish collaborative group for infections in intensive care units of sociedad espanola de medicina intensiva y unidades coronarias (semiuc) antibiotic use and impact on outcome from bacteraemic critical illness: the bacteraemia study in intensive care (basic) beta-lactams with or without aminoglycosides a prospective randomized study comparing once-versus twice-daily amikacin dosing in critically ill adult and paediatric patients once-daily dosing of aminoglycosides: review and recommendations for clinical practice prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity a new simplified acute physiology score (saps ii) based on a european/north american multicenter study the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine promoting appropriate antimicrobial drug use: perspective from the centers for disease control and prevention acute renal failuredefinition, outcome measures, animal models, fluid therapy and information technology needs management of infections caused by gram-negative bacilli: the role of antimicrobial combinations mortality and morbidity attributable to inadequate empirical antimicrobial therapy in patients admitted to the icu with sepsis: a matched cohort study impact of inappropriate antibiotic therapy on mortality in patients with ventilator-associated pneumonia and blood stream infection: a meta-analysis benefit of empirical appropriate antibiotic treatment: thirty-day mortality and duration of hospital stay impact of adequate antibiotic empirical therapy on the outcome of patients admitted to the intensive care unit with sepsis aminoglycoside nephrotoxicity: modeling, simulation, and control aminoglycoside nephrotoxicity: do time and frequency of administration matter? beta lactam antibiotic monotherapy versus beta lactamaminoglycoside antibiotic combination therapy for sepsis aminoglycoside drugs in clinical practice: an evidence-based approach clinical implications of β-lactam-aminoglycoside synergism: systematic review of randomised trials key: cord- - hul lw authors: antonelli, massimo; azoulay, elie; bonten, marc; chastre, jean; citerio, giuseppe; conti, giorgio; de backer, daniel; lemaire, françois; gerlach, herwig; groeneveld, johan; hedenstierna, goran; macrae, duncan; mancebo, jordi; maggiore, salvatore m.; mebazaa, alexandre; metnitz, philipp; pugin, jerôme; wernerman, jan; zhang, haibo title: year in review in intensive care medicine, : iii. paediatrics, ethics, outcome research and critical care organization, sedation, pharmacology and miscellanea date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: hul lw nan increasingly in paediatric intensive care, as in the adult sphere, the intensivist's focus is increasingly guided towards not only reducing mortality but also to ensuring that survival is morbidity-free. baghurst et al. [ ] reported on the applicability of sequential control charts for monitoring of the quality of paediatric intensive care using risk-adjusted probabilities of death estimated by the paediatric index of mortality version (pim ). a total of , patient records submitted to the australia and new zealand paediatric intensive care registry from picu's were used in the report. during the -year monitoring period the investigators demonstrated that their methodology was able to detect one 'alarm' for poor picu performance and one 'alarm' for better than expected picu performance. in their paper, the authors present a detailed description of sequential analysis methodologies and describe their potential prospective use as tools for monitoring the performance of intensive care units. they caution that 'alarms' for poor or excessively good performance are arbitrarily set and are not necessarily indicative of 'real' problems. alarms should, however, act as triggers for investigation to ascertain whether the data is sound and if so whether true clinical over or underperformance exists. numa et al. [ ] undertook a study to determine whether outcomes were influenced by time of admission to an australian tertiary paediatric intensive care unit without h per day in-house intensivist cover. evening, night and weekend cover by staff intensivists was provided mainly by telephone with discretionary return to hospital to support resident paediatric staff. the authors found that a lack of in-house intensivist was not associated with any increase in riskadjusted mortality or increased length of stay. they attribute these findings to a combination of relatively experienced junior staff and the effectiveness of telephone backup and discretionary attendance from intensivists after hours. two studies in looked at the quality of survival of children after undergoing intensive care. in a case-control study, elison et al. [ ] reported on a detailed neuropsychological follow-up of children, with mean age . ± . years, tested a mean of . ± . months following hospital discharge. they detected the presence of impaired memory and attention in children following acute illness and links between memory anomalies and emotional/behavioural problems. these findings, if replicated in a larger study, are very important to children and their parents and teachers. knoester et al. [ ] also reported on early neurocognitive sequelae of intensive care but in addition reported information on physical outcomes. they determined that % of children had detectable physical sequelae months after picu discharge. whilst % of sequelae were attributed to previously unknown illness, % were acquired of which % were related to complications of picu procedures. finally, in the area of patient safety and quality, burmester et al. [ ] reported on the apparent benefit of the introduction of a structured prescription education programme and standardised prescription template in a paediatric cardiac icu. the total number of prescription errors fell from a baseline of . % of prescriptions to . % after the implementation of the measures and this was associated with a small but statistically significant reduction in the incidence of adverse drug events. weight-based variations in drug dosing are often quoted as a factor in the known high incidence of drug errors in paediatric practice. disappointingly, tenfold miscalculations which are particularly common and dangerous in children if the decimal point is misplaced during calculations showed no improvement with the studied interventions. this report highlights the need for regular ongoing education in critical care units which typically have high prescription volumes and often see high turnover of staff, particularly 'junior' prescribers such as resident medical staff. the high mortality of septic shock in children was confirmed in a paper from wolfler et al. [ ] who reported a prospective observational study across italian paediatric intensive care units conducted over a period of year. during the study , children were admitted to the participating picu's. the incidence of severe sepsis was . % and that of septic shock . %, with associated mortalities of . and . %, respectively. in march the journal published a landmark paper from de oliveira et al. [ ] . they studied children with septic shock who were resuscitated according to accm/pals guidelines [ ] with or without scvo goal-directed therapy. in this randomised controlled trial, there was a significant difference in mortality rate with use of accm/ pals haemodynamic support guidelines for septic shock between patients with or without scvo guided therapy. patients who received therapies directed to the goal of scvo [ % were given more fluid, red blood cells and inotropic support after the initial resuscitation, with a resulting . -fold reduction in mortality. this study supports the incorporation goal-directed therapy using the endpoint of a scvo c % within accm/pals guidelines the use of which provided a significant beneficial impact on the outcome of children and adolescents with septic shock in this study. recently the use of vasopressin and vasopressin analogues, potent vasoconstrictors, has been reported in the management of vasodilatory shock in children. jerath reported a retrospective study of the use of vasopressin in a series of children in a multidisciplinary picu. haemodynamics appear to have been favourably influenced, but the authors noted adverse effects on renal function and lower platelet counts associated with vasopressin use. yildizdas et al. [ ] performed a randomised non-blinded comparison of the use of the vasopressin analogue terlipressin in a group of children with refractory septic shock. although terlipressin had no beneficial effect on mortality rate in this study, its use was associated with increased mean arterial pressure, improved oxygenation, decreased length of stay in the picu and had a beneficial effect on survival time among nonsurvivors. despite these interesting early reports, the place of vasopressin and its analogues in the management of shock states in children is not yet established. until blinded, randomized, and placebo-controlled studies are conducted in children with septic shock and in other shock states which compare the use of vasopressin-like drugs to standard treatments such as noradrenaline, their use should be considered only a rescue therapy of last resort. with increased experience, improved surgical techniques, and advances in postoperative care and immunosuppressive therapy, paediatric intestinal transplantation is already into the medical mainstream. in this article, hauser and coll [ ] reviewed the literature on intensive care of paediatric intestinal transplantation as well as their own experience. this article covers the following areas: the indications for intestinal transplantation, the management of critically ill children awaiting intestinal transplantation, the operative procedure, the postoperative management. this last area deals with the intestinal graft, the liver graft, the cardiovascular, respiratory and renal support, the electrolyte and haematologic management, the pain and infection control, the rejection and other alterations in graft function, the nutritional support, the problems of high stomal output, the immunosuppressive treatment, the outcomes and the upcoming challenges. the authors concluded that transplant teams accept patients with higher morbidity and higher risks for complications and indicate that many of these patients would benefit from earlier referral for transplant evaluation before severe complications develop. sedation and analgesic practices vary widely in both adult and paediatric intensive care. however, relatively little high quality evidence supports current paediatric practice. lamas et al. [ ] investigated the utility of the bispectral index (bis), auditory-evoked responses (aep) and ramsay and comfort clinical scales in the assessment of sedation in critically ill children. simultaneous recordings were obtained. in children in whom neuromuscular blockade was not being used, correlation between the four methods was moderate or good. however, only bis and aep were found to be potentially reliable in those children who were both sedated and subject to neuromuscular blockade. the authors concluded that their results support the finding that the clinical scales do not evaluate the level of sedation accurately in critically ill children with neuromuscular relaxation, leading to a higher risk of over or undersedation. they suggest that in these children, bis and the aep index methods may provide a better assessment of the level of sedation. however, they caution that lack of correlation between these two methods in children with neuromuscular relaxation and the absence of a reference method to evaluate sedation in the relaxed patient means that their results must be interpreted carefully. further studies are needed. recently, akcan-arikan et al. [ ] have described a modified version of the rifle criteria for paediatric patients (prifle). their proposed prifle criteria are based on a decrease in estimated creatinine clearance (eccl),and urine output is based on body weight. plötz et al. [ ] independently evaluated the prifle criteria in a cohort of children in a european picu. sixty children ( %) developed acute kidney injury (aki) according to prifle criteria of whom six required renal replacement therapy. the authors conclude that prifle criteria may guide the early identification of patients at risk of aki and therefore guide early initiation of therapy, with potential to avoid progress from 'risk' to injury'. hoover and colleagues reported a series of children on ecmo for respiratory failure who received cvvh for [ h and compared these to ecmo/non-cvvh casematched control children. significant findings included a faster time to desired caloric intake and reduced furosemide use in cvvh treated children. although no obvious survival benefit related to use of cvvh was demonstrated, the association of cvvh on ecmo with improved fluid balance and nutritional management was compelling. performing optimal cardiovascular monitoring in critically ill children is a considerable challenge. the journal published four papers in which address various aspects of this challenging field. durand et al. [ ] investigated whether the measurement of respiratory variations in aortic blood flow velocity (d v peak ao), systolic arterial (d sap) pressure and pulse pressure (d pp) could accurately predict fluid responsiveness in ventilated children. standardised volume challenges were given to children with preserved ventricular function. aortic blood flow was analysed by transthoracic pulsed doppler. whilst a positive correlation was found between d v peak ao and volume expansion-induced gain in stroke volume, measurements of d sap pressure and d pp were of little value in predicting responses to fluid augmentation in ventilated children. in a preliminary study, knirsch et al. [ ] compared the measurement of cardiac output using the ultrasound cardiac output monitor (uscom) with pulmonary artery catheterderived thermodilution cardiac output in a group of children undergoing cardiac catheterization. the main finding was that cardiac output measured with uscom did not reliably represent absolute values measured by pulmonary artery catheter thermodilution, with a mean percentage error higher than %. the limitations of transthoracic pulsed doppler cardiac output measurement in comparison to cardiac output measurement by the thermodilution technique has been recognized [ ] . a number of user-dependent technical factors have been shown to influence ultrasound-derived measurements in other studies in a variety of situations. in addition, possible inaccuracy in algorithm-derived aortic valve diameter used in calculation for cardiac output from flow can introduce systematic error. many of these limitations are negated if serial measurements are used to derive trends in aortic flow rather algorithm-derived 'absolute' cardiac outputs. frey et al. [ ] brought clarity to the interpretation of aspects of the photoplethysmographic wave which is displayed by most pulse oximeters. they demonstrate that it may be used to derive additional haemodynamic information in some selected situations when, for instance, arterial blood pressure monitoring is not available. the advantages of this method are its widespread use, non-invasiveness and continuity. the authors suggest that haemodynamic deterioration, whether suddenly occurring or slowly evolving over time, may be detected by this method. there is only minimal reference to photoplethysmography monitoring in the paediatric literature. three studies published in relate to aspects of the care of children undergoing cardiac surgery using cardiopulmonary bypass. tissières et al. [ ] described the use of the biomarker n-terminal brain natriuretic peptide (n-probnp) and troponin i in children following valvular surgery. their results demonstrated that n-probnp was superior to troponin i in reflecting clinical and echocardiographic postoperative recovery. furthermore the authors suggest that preoperative n-probnp reflected postoperative myocardial functional capacity, thus potentially helping in the early identification of patients who are at risk of chronic cardiac dysfunction. another biomarker, plasma angiopoetin- (angpt- ), a vascular growth factor, was found by giuliano et al. [ ] to independently predict cardiac icu length of stay in a series of children palliative or corrective cardiac surgery. the angiopoietins are a family of vascular growth factors that are necessary for both developmental and pathological angiogenesis. angpt- promotes increased vascular permeability and inflammation and has been shown to be increased in adults with congestive heart failure and the acute coronary syndrome. the authors conclude that angpt- appears to be an important biomarker of adverse outcome following cpb. further studies pertaining to the role of angpt- in the pathophysiology of capillary leak syndrome following cpb are warranted. at a more practical level, the study reported by ross-russell et al. [ ] is a large prospective report of the measurement of phrenic nerve latency in children before and after cardiac surgery. phrenic nerve injury being a relatively common and clinically important complication of cardiothoracic surgery). the authors ascertained an incidence of phrenic nerve injury associated with surgery of %. injury was associated with an increased duration of postoperative ventilation ( vs. h, p \ . ). of particular interest in this report is medium term follow-up which shows that one-third children recovered function within months and a further one-third within months. two papers recently published in the journal shed further light on the mechanisms of paediatric respiratory disease. a paper by plunkett et al. [ ] addressed the question of whether the d allele of the i/d polymorphism of the angiotensin converting enzyme (ace) gene is associated with increased susceptibility to acute hypoxaemic respiratory failure (ahrf) in critically ill children. previous reports have linked the d allele of the ace gene to susceptibity for ards in critically ill adults and bronchopulmonary dysplasia in pre-term infants. in a single centre prospective study, ahrf developed in . % of critically ill children. there was no significant difference in the frequency of the d allele between patient groups with and without ahrf. the authors suggest that this may suggest differences in the pathogenesis of paediatric ahrf and adult ards. phospholipases a is an enzyme widely distributed in the body and was the focus of a report from de luca et al. [ ] . the enzyme is primarily involved in the turnover of membrane phospholipids and lipid digestion. in addition phospholipase a is involved in inflammation pathways through the formation of eicosanoids and other inflammatory mediators. in the lungs the secretory form of the enzyme (spla ) is produced mainly by alveolar macrophages and secreted into the alveoli. spla has been shown to be involved in lung inflammation and surfactant degradation and it may play a role for spla in the development of acute respiratory distress syndrome (ards). de luca et al. provide evidence that spla is present in high concentrations in bronchoalveolar lavage fluid obtained from neonates with pneumonia and hyaline membrane disease. in this study, spla levels correlated negatively with dynamic compliance and positively with indices of poorer oxygenation. it appears therefore that the enzyme plays a role in the pathogenesis of respiratory failure in neonates. respiratory disease caused by the respiratory syncytial virus (rsv) accounts for almost % of admissions to picu's [ ] . rsv disease is characterised by inflammation of the small airways with raised airways resistance, air-trapping and pulmonary consolidation, disproportionately effects young infants due primarily to their poor respiratory muscle reserve. icm recently published three papers describing different ventilatory strategies for infants with rsv disease. javouhey et al. [ ] used noninvasive ventilation as their primary form of respiratory support in infants. they applied continuous positive airway pressure (cpap) at - cm h o with additional bi-level positive pressure ventilation of - cm h o as required. compared to an immediately prior historical cohort of infants with the disease, the intubation rate was significantly lower ( vs. % p \ . ). berner and colleagues [ ] adopted a different strategy, successfully using high frequency oscillatory ventilation whilst allowing spontaneous breathing in a group of infants with rsv. these two strategies are essentially delivering physiologically similar therapy, maintaining spontaneous ventilation and relying on cpap to maintain lung volume and reduce the work of breathing. the suggestion that cpap is clinically effective in rsv bronchiolitis possibly through reduced work of breathing in babies with rsv bronchiolitis was first made by beasley addressed similar issues in two related papers investigating the mechanics of breathing in children with severe croup and the effect of nebulization of epinephrine on measures of airway obstruction [ ] . respiratory mechanics were studies in infants with severe croup. patients were found to maintain minute ventilation by means of large increases in mean intrathoracic pressure required to overcome inspiratory flow limitation. nebulised epinephrine was found to result in short-lived improvement in some but not all patients with croup. both inspiratory and expiratory airway resistance fell in patients responding to nebulised epinephrine. oesophageal pressures in both studies were measured via a feeding tube and were found to be satisfactory for quantification of the acute response to nebulised epinephrine whereas flow measurements were unhelpful. finally two clinical reports address areas of the management of acute respiratory failure in children where significant differences from adult practice are evident. pathan et al. [ ] reported a series of children categorised as receiving 'paediatric extra-corporeal life support' in a single institution from the inception of their ecls programme in july until december . clinical selection criteria operated during the study were those of severe respiratory failure failing to respond to conventional management and in whom recovery was believed to be reasonably possible. survival to hospital discharge was with % surviving to year. severity of pulmonary dysfunction pre-ecmo and the presence of shock predicted higher risk of mortality. kneyber et al. [ ] raise the important question of whether we know the true incidence of the acute respiratory distress syndrome in children, or whether it is under-recognised. they retrospectively reviewed mechanically ventilated children admitted to two regional dutch paediatric icu's. chest radiographs were screened for the presence of bilateral infiltrates, pao /fio ratios calculated and left ventricular dysfunction ruled out by echocardiography. forty-one ( . %) of children met criteria for ards giving a population-based incidence of ards of . per , per year. the incidence of paediatric ards is low compared to adults, but the authors suggest that many cases of ards are categorised by their underlying diseases such as viral infections, leading to significant underreporting of ards. this may be particularly important when planning randomised -controlled trials, as significant underestimation of the effected population could lead to erroneous trial designs or abandonment of trials at the planning stage due to perceived difficulty in recruiting subjects in a timely and cost-effective manner. bachmann et al. [ ] investigated the level of adoption of paediatric ventilation technologies from the participants at two international conferences. the authors used the approach of rogers' which addresses both differences among individuals and characteristics of the innovation [ ] . the authors concluded that whilst evidence of outcomes is the most relevant factor for assessment of potentially beneficial technologies, other factors that encourage adoption of mediocre technologies, or that retard adoption of potentially beneficial technologies, must be understood and acknowledged. in a concise review, truog [ ] reminds us the specificities and issues in paediatric clinical research. universal requirements for ethical research are on one hand the respect of subject's autonomy and on the other the protection against harm (the risk-benefit ratio). respect of autonomy for a child under implies that investigators, whenever possible, seek his-her assent, besides the parental authorization. protection is achieved via a drastic limitation of the risks children can be exposed during a trial: in the us, the threshold is a ''minimal risk'' for healthy children and a ''minor increase over minimal risk'' for diseased ones. then, dr truog proposes a threestep approach of evaluation of paediatric research protocols. the basic concept here is the so-called ''component analysis'': the research protocol has to be broken in several components, those part of standard care and those which are necessary for research, in addition to care. each of these components are separately analysed in terms of risk/benefit balance. however, appreciation of ''minimal risk'' is always debatable, and it is the essential role of the research ethics committee (recs, or irbs in the us) to define it on a case to case basis. minneci et al. [ ] review a few recent randomized clinical trials performed on severely ill patients (the arma trial comparing a low and a lage vt in ards, the trial assessing the effect of growth hormone in icu patients and the tricc trial, on the level of blood transfusion, also in icu patients) and emphasise the crucial importance of the control group. they convincingly show that most of the controversies which followed the publication of some of them stemmed from the inappropriate design of control groups. a well designed control group has two main functions: the first one is to protect the patients enrolled in the trial, and the second is to guarantee the external validity of the conclusions of the research. if the new therapy is to replace the existing standard, it has to have been tested against this standard. authors' recommendations are that a control group should not be historical, needs to represent current care and should be enrolled along with the new treatment group. of course, in all large trials involving severely ill patients, a dsmb will monitor safety by comparing the intervention group to this control group. special difficulties are commonplace in critical care research: patients populations are frequently heterogeneous, syndromes are dealt with, instead of diseases (septic shock, ards.), many treatments are delivered with titration: vt, peep, catecholamines, blood transfusion, making the design of a control group extraordinary arduous (one size does no fit all.). zamperetti and latronico [ ] give a rather grim view of the regulatory aspects of clinical research in italy. basically, directive / /ec has been literally translated and transposed in the italian legislation, thus creating a ''legal representative'', which has not been defined, at the difference of nearly all eu member states. in consequence, decisions for any specific protocols depend on local rec, with no coordination or common guidelines. similarly, a waived or deferred consent in emergency research may or may not be possible, depending of the local rec, which may base its decision on directive , which prohibits it, or the oviedo convention, which makes it possible. a clear description of the convention of human rights and biomedicine (oviedo) of the council of europe is provided by elmar doppelfeld [ ] . the mechanisms by which states and governments, members or not of the eu, sign and ratify the conventions and protocols produced by the council of europe are described, as well as the links between the european commission and the council (not obvious to all.). concerning research on severely ill patients (a vulnerable population), special provisions are written in the additional protocol. conditions for waiving consent (emergency) and for designation of surrogate decisionmakers in case of incapacity are specified. research on incompetent persons when no direct benefit is provided is possible, under some specific provisions. charles sprung et al. [ ] published in icm their seventh paper derived from the huge ethicus database. this study has demonstrated a large gradient from northern to southern regions in europe as to the end of life decisions in icus. it was certainly tempting to see whether physician's values could explain these discrepancies. clearly, the lesser degree of end of life decisions in the south corresponds to more paternalistic views, as expressed by a more frequently cited ''unresponsiveness to therapy'', a lesser degree of documentation of their decisions and also a lesser consideration for patients' ''best interest''. however, all investigators, irrespectively of their location, gave a low priority to patient or family request. the authors conclude that ''.there is room (in europe) for greater engagement with patients and their families to promote patient autonomy in the end of life decision-making process''! end of life decisions are influenced by the religious affiliation of physicians, despite the delimitation of religion from ''acculturation'' is not always clear-cut. this was another important demonstration by the ethicus study [ ] . bulöw et al. [ ] review the world's major religions' points of view on end of life decisions in the icu. the jewish perspective gives a fascinating insight into a new israeli law which deals with the prohibition by halacha of withdrawing mechanical ventilation. surprisingly enough, the islamic perspective is not far from the catholic tradition (the moral of intention, for instance), but the authors take the precaution to indicate that in different countries, ''recognized religious scholars'' may have the last word. ''death rattle'' is a common occurrence after ''terminal'' extubation, at the end of life. it may destabilize families and jeopardize an otherwise well conducted withdrawal of life support in the icu. erwin kompanje et al. [ ] provide an excellent overview of the phenomenon and give guidelines on how to prevent and to treat it. this is probably one of the most useful recommendations in a crucial subject, though usually ignored. the icm series on national legislations on end of life in icus, which started in , continued in with austria [ ] , along with the guidelines produced by the austrian association of intensive care medicine [ ] and spain [ ] . cabre et al. [ ] have described the legal framework for end of life decision in spain. as in other european countries, the spanish society is currently concerned by controversies as to limitation of care in emergency departments or icus, a debate obscured by the absence of a clear delimitation between euthanasia and the withdrawal of life support. it is good news to learn that the court of justice of madrid finally cleared the physicians involved in the ''leganés case'' [ ] from any wrongdoing. a very interesting initiative, which should be replicated elsewhere, is the choice of end of life decisions as an indicator of good quality of care by the spanish society of critical care, the semicyuc. servillo and striano [ ] tell us how in italy, as in spain, end-of-life care gives fierce debates, further enhanced by the strong influence of the catholic church in such matters. dr riccio, an anaesthetist involved in the welby case has also been relaxed by justice. the debate is now focused on the introduction in the italian law of ''advanced directives''. as in other countries where laws are mute on end of life decisions, the role of professional societies (the siaarti in italy) is crucial in guiding physicians and in protecting them occasionally. sexual dysfunction seems to be highly prevalent not only in the community, but also after critical illness. although patients report sexual function to be important, symptoms of sexual dysfunction after major illness are seldom evaluated by medical practitioners. ulvik et al. [ ] thus studied sexual dysfunction in trauma patients - years after discharge from the icu, using a questionnaire. the cohort comprised of consecutive trauma patients over years of age admitted to their icu in the period - , of which were eligible. the response rate was with % highly satisfactory. patients were asked to describe their sexual life both, prior to the icu admission and presently. half of the patients reported sexual function to be unchanged, % impaired, and % even to be better than before the trauma. erectile dysfunction was found to contribute in % of men younger than years and % of men years or older. age, being single, injury severity score, and depression were associated with a poor sexual function. the authors concluded that due to the high incidence and also the possible impact on individual quality of life, sexual function should be regularly evaluated at least in trauma patients. the saps risk-adjustment system, developed from a world-wide multicenter study, has been published in . as for all severity of illness systems, external validation studies are needed to proof the prognostic performance in settings different than the one the score has been developed from. ledoux et al. [ ] undertook a prospective study in their institution to evaluate the performance of saps and to compare it to two other systems, namely apache ii and saps ii. they included consecutively to the icu admitted patients over an month period. with respect to discrimination, apache ii performed worse than saps ii and saps models. calibration was unsatisfactory again for apache ii and for the general saps model, whereas it was satisfactory for saps ii and the saps model with the central european equation. the authors concluded, that the saps admission score and its model for central and western europe was more discriminative and better calibrated than apache ii, but it was not significantly better than the saps ii. since this study presents as a single centre study with a low patient number, the results have to be viewed with caution. multicenter studies with higher patient numbers are required to determine the prognostic ability of a risk-adjustment system. intra-abdominal hypertension (iah) has only in the past decade received attention as a potential source of problems for critically ill patients. several recent studies have highlighted the possible impact of increased intra-abdominal pressure on renal function. dalfino et al. [ ] studied the relationship between iah and acute renal failure (arf) in critically ill patients. they included all patients who were consecutively admitted during a -month period. iah was defined as a iap [ = mmhg in at least two consecutive measurements performed at -h intervals. arf was defined according to the failure class of the rifle criteria. almost a third of their patients developed iah. arf developed in % of their patients, with a significant difference between the two groups: . % in the iah versus . % in the non-iah group (p \ . ). shock and low abdominal perfusion pressure were predictive factors for the development of arf. a cut-off point of mmhg had the best predictive power for the development of arf. although raw hospital mortality was significantly higher in patients with iah, risk-adjusted mortality rate was not different between the two groups. the authors concluded, that iah is clearly an independent and strong predictor for the development of arf. however, the contribution of impaired systemic hemodynamics should also be taken into account. the impact on mortality of early coagulation disorders after severe burn injury was addressed by lavrentieva et al. [ ] . in this single centre prospective study conducted on patients with severe thermal burn injury the -day mortality rate was %. the presence of overt dic was related to mortality (or = . ). antithrombin, protein s, plasminogen activator inhibitor , and sofa score on day , protein c on day , and thrombin/antithrombin complexes on day revealed a good prognostic value for icu mortality. the authors concluded that the severe thermal injury is associated with the early activation of coagulation cascade, presence of dic, organ failure, and increased mortality. bedside adherence to clinical practice guidelines may influence the outcome. the dissemination of medical knowledge is essential and practice surveys are important to assess practices of health-care professionals and develop strategies for more effective actions. the tecla study [ ] with a multicenter, -day crosssectional design assessed adherence to clinical recommendations for three interventions routinely used in critical care medicine. a total of patients hospitalized in the participating icus in countries were enrolled. red blood cell transfusion (n = ) was performed appropriately in patients ( %), while among the patients who received no transfusion ( %) had a valid indication. setting of tidal volume in acute respiratory distress syndrome, assessed in patients, was deemed appropriate in cases ( %). prescription of stress ulcer prophylaxis (n = ) was appropriate in only patients ( %), while among the patients who were not treated ( %) had an indication. the survey concluded that the implementation of recommendations varies across different domains of care, being suboptimal in some contexts. wheeler et al. [ ] carried out an audit to quantify the variability in the concentration of drug infusions prepared in an adult intensive care unit. they also established whether there was a relationship between the quality of syringe labelling and drug preparation. they collected discarded syringes containing midazolam, insulin, norepinephrine, dopamine, potassium or magnesium. residual solutions were sampled, concentrations were measured, and syringe labels were awarded a score for labelling quality based on an -point scale. the majority of the infusions differed from the expected concentration by more than %. magnesium infusions were least likely to be properly labelled. there was a positive correlation between quality of syringe labelling and drug preparation. after the introduction of a new electrolyte prescription chart, magnesium and potassium preparation significantly improved but there was still substantial variability. the authors conclude by a plea for the use of pre-prepared syringes or standardized drug preparation and labelling systems. scientific societies have published position papers recommending certain critical care pharmacy activities. in a brief report leblanc et al. [ ] described the activities of international pharmacists who had a significant portion of their duties dedicated to critical care to increase the awareness of pharmacist roles to the critical care team. the authors analyzed data obtained in a website based survey. the majority of respondents ( . % of a total of pharmacists) attended medical rounds and . % were involved in research. the majority of pharmacists ( . %) were involved in drug monitoring (mainly aminoglycosides and vancomycin). a few prepared intravenous medications or total parenteral nutrition, and . %, respectively. authors conclude that critical care pharmacists participate in a wide range of activities and they expect that the involvement of the pharmacist in critical care teams will increase. in a prospective multicentre study, takala et al. [ ] tested the feasibility of three software-driven critical care protocols. they applied software-driven protocols for cardiovascular management, sedation, and weaning during the first icu-days in cardiac surgery and septic patients. protocol use was discontinued in % of patients by the treating clinician and in % for technical/ administrative reasons. this study advocates that multiple software-driven treatment protocols can be simultaneously applied with high acceptance and rapid achievement of primary treatment goals (initial hemodynamic stability, sedation targets, weaning time). in a prospective observational study, perren et al. [ ] assessed whether cross-checking of the physician icu transfer report by icu nurses may reduce transfer report errors. about patients were randomly selected at discharge from the icu and physician icu transfer reports were cross-checked by nurses using defined review criteria. about ( %) transfer reports were affected by at least one error which was classified as simple ( %), serious ( %) or critical ( %). thirty-five ( %) transfer reports were considered potentially harmful. among intercepted errors, were prescription errors ( % of all prescriptions), involved proposed procedures, and were deficient in updating diagnoses. only the number of medications included in the transfer report was associated with the occurrence of at least one critical/serious error. calzavacca et al. [ ] identified risk factors for mortality in patients receiving one or more medical emergency team reviews during daytime hours over a -year-period. delayed medical emergency team activation and not-for resuscitation orders were the only factors that showed an independent association with mortality. ospina et al. [ ] in a comprehensive literature review analysed which monitoring techniques have been shown to improve outcomes in icu patients, concluding that there is no broad evidence that any form of monitoring improves outcomes in the icu. through an highly sensitive search in the cochrane central register of controlled trials (central) and medline, for prospective, randomized controlled trials (rcts) conducted in adult patients in the icu and the operating room (major surgical procedures), the authors focused on the impact of monitoring on outcome. of , potential articles, evaluated the impact of monitoring. forty studies were related to hemodynamic monitoring, to respiratory monitoring, and to neurological monitoring. positive non-mortality outcomes were observed in of hemodynamic studies, of respiratory, and in all neurological studies. mortality was evaluated in hemodynamic studies, but a beneficial impact was demonstrated in only . for respiratory monitoring, seven studies evaluated mortality, but only three of them showed an improved outcome. in a qualitative study, mc adam et al. [ ] described the contributions to care that family members perform while their loved one is at high risk of dying in the icu. interviews with relatives were recorded and three independent raters coded transcripts. work roles that family members take on while their loved one is in the icu consisted of active presence, patient protector, facilitator, historian, coach, and voluntary caregiver. these multiple roles performed by relatives are often not valued or go unrecognized by icu health care providers. giannini et al. [ ] investigated visiting policies in italian icus. median daily visiting time was min and % of icus had one daily visiting slot. there were restrictions on number ( % of units) and type ( %) of visitors and on child visits ( %). policies were not modified for child patients in % of icus, nor for a dying patient in %. no waiting room was provided by % of icus. gowning procedures were required for visitors in % of units. in % of icus informative material on the unit was provided to the family on patient admission. regional area and volume of admissions significantly influenced visiting hours. one-third of icus were being rethinking their policies. verdon et al. [ ] evaluated the level of burnout in members of the nursing team. % showed a high level of burnout. among concerns reported by the nurses, only the lack of patients' co-operation, the organization of the service and the rapid patient turnover were independently associated with a high level of burnout. weinert and sprenkle [ ] assessed the impact of sedative exposure on icu recall and symptoms of posttraumatic stress disorder in patients receiving mechanical ventilation. they interviewed patients who required [ h of mechanical ventilation months after icu discharge. eighty patients were also interviewed at months. icu recall was greater for events occurring at the end of critical illness; however, % of subjects had amnesia for the entire icu course. posttraumatic stress disorder prevalence was % at months and % at months. recall of a delirious memory during critical illness was associated with more severe posttraumatic stress symptoms. neither icu recall nor posttraumatic stress symptoms were associated with the intensity of sedative administration during mechanical ventilation. posttraumatic stress symptoms were lowest in patients either the most awake during mechanical ventilation or the least awake. in a prospective, randomised, single-blinded, controlled study, röhm et al. [ ] compared sevoflurane and propofol in terms of recovery times from sedation. a total of patients after elective coronary artery bypass graft surgery received either sevoflurane (n = ) or propofol (n = ) for short-term postoperative sedation in the icu. mean extubation times from termination of sedation (the primary outcome) were significantly shorter with sevoflurane than with propofol ( vs. min). the length of icu stay was comparable in both groups, but hospital length of stay was significantly shorter in the sevoflurane group. costs for sedation per patient were similar in both groups. suchyta et al. [ ] compared mortality and discharge disposition in critically ill patients with and without drug or alcohol dependence and patients with and without psychiatric disorders. they found that patients with drug or alcohol dependence were at higher risk for icu admission compared to the general population. however, the prevalence of psychiatric disorders was significantly lower than in the general population. drug or alcohol dependence predicted shorter hospital length of stay. in a retrospective review of patient records over years in french city hospitals lapostolle et al. [ ] evaluated patients with an elevated serum digitalis concentration (digoxin [ . ng/ml or digitoxin [ ng/ml), following chronic or acute exposure. of these, ( %) had received antidotal therapy with fab fragments. five independent factors were associated with the use of antidotal therapy: acute overdose (or . ), fab fragment availability in the hospital ( . ), serum potassium ( . ), and heart rate ( . ). mortality was significantly lower in fab-treated ( %, / ) than untreated patients ( %, / ). the authors concluded that antidotal therapy is underused in patients with an elevated digitalis concentration and the use of identical criteria for antidotal treatment after acute and chronic poisoning should help optimize outcomes. vandijck et al. [ ] compared characteristics and outcomes in icu-patients with haematological malignancies and severe sepsis/septic shock who had or had not received recent intravenous chemotherapy. among the patients, there were patients with severe sepsis and with septic shock; ( %) had received recent intravenous chemotherapy. in-hospital, and -month mortality rates were . versus . %, and . versus . % in patients with and without recent chemotherapy, respectively. by multivariate analysis, previous chemotherapy was protective. after adjustment with a propensity score for recent chemotherapy, chemotherapy was not associated with outcome. in a review article [ ] on organ dysfunction in hemophagocytic lymphohistiocytosis créput et al. provides an overall overview on this entity and aims at helping clinicians to maintain a high level of suspicion regarding the diagnosis. the parts covered in this review are: the clinical and laboratory features, the cytology and histology aspects, the etiologies, the pathophysiology, the prognosis and mortality, and the therapeutic approach. the authors concluded that the management of the hemophagocytic lymphohistiocytosis requires a multidisciplinary team, and the high mortality in patients with no etiological diagnosis requires aggressive investigation and treatment. payen et al. [ ] assessed blood leucocytes gene profiling in the course of the septic shock recovery period and tested the relation between encoding gene expression and protein level in septic shock patients. gene expression levels were studied on a dedicated microarray of genes involved in inflammatory processes. the time-related gene expression study showed significant changes in ten genes. among them, s a and s a had a reduced expression over time compared with d , whereas cd 's expression increased. by rt-qpcr, the s a plasma levels decrease in parallel with the gene expression decrease. the cd gene expression evolution significantly correlated with hla-dr monocyte expression. in a fascinating mini-series foresti et al. [ ] and bauer et al. [ ] reviewed the role and pathophysiological mechanisms of the heme oxygenase-carbon monoxide system (ho-co) and the challenging potential use of co as therapeutic agent. in the past decade, the use of co gas in pre-clinical experimental models of disease has produced some remarkable data indicating that its therapeutic delivery to mammals could alleviate inflammatory processes and cardiovascular disorders. however, the inherent toxic nature of co cannot be ignored, knowing that inhalation of uncontrolled amounts of this gas can ultimately lead to serious systemic complications and neuronal derangements. from a clinical perspective, a key question is whether a safe and therapeutically effective threshold of co can be reached locally in organs and tissues without delivering potentially toxic amounts through the lung. the advent of co-releasing molecules (co-rms), a group of compounds capable of carrying and liberating controlled quantities of co in cellular systems, could be a plausible alternative in the attempt to overcome the limitations of co gas. although in its infancy and far from being used for clinical applications, the co-rms technology is supported by very encouraging biological results. the application of risk-adjusted control charts using the paediatric index of mortality for monitoring paediatric intensive care performance in australia and new zealand after-hours admissions are not associated with increased risk-adjusted mortality in pediatric intensive care neuropsychological function in children following admission to paediatric intensive care: a pilot investigation surviving pediatric intensive care: physical outcome after months interventions to reduce medication prescribing errors in a paediatric cardiac intensive care unit incidence of and mortality due to sepsis, severe sepsis and septic shock in italian pediatric intensive care units: a prospective national survey accm/pals haemodynamic support guidelines for paediatric septic shock: an outcomes comparison with and without monitoring central venous oxygen saturation clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock terlipressin as a rescue therapy for catecholamine-resistant septic shock in children pediatric intestinal and multivisceral transplantation: a new challenge for the pediatric intensivist assessing sedation in critically ill children by bispectral index, auditory-evoked potentials and clinical scales modified rifle criteria in critically ill children with acute kidney injury pediatric acute kidney injury in the icu: an independent evaluation of prifle criteria respiratory variations in aortic blood flow predict fluid responsiveness in ventilated children cardiac output measurement in children: comparison of the ultrasound cardiac output monitor with thermodilution cardiac output measurement a comparison of thermodilution and pulsed doppler cardiac output measurement in critically ill children clinical applications of photoplethysmography in paediatric intensive care value of brain natriuretic peptide in the perioperative follow-up of children with valvular disease the effect of epinephrine by nebulization on measures of airway obstruction in patients with acute severe croup predictors of outcome for children requiring respiratory extra-corporeal life support: implications for inclusion and exclusion criteria acute respiratory distress syndrome: is it underrecognized in the pediatric intensive care unit? factors effecting adoption of new neonatal and pediatric respiratory technologies diffusion of innovations ethical assessment of pediatric research protocols the importance of usual care control groups for safety monitoring and validity during critical care research clinical research in critically ill patients: the situation in italy council of europe in the field of bioethics: the convention on human rights and biomedicine and other legal instruments reasons, considerations, difficulties and documentation of end-of-life decisions in european intensive care units: the ethicus study the importance of religious affiliation and culture on end-of-life decisions in european intensive care units the world's major religions' points of view on end-of-life decisions in the intensive care unit anticipation of distress after discontinuation of mechanical ventilation in the icu at the end of life endof-life decisions in austria's intensive care units recommendations on therapy limitation and therapy discontinuation in intensive care units: consensus paper of the austrian associations of intensive care medicine end-of-life care in spain: legal framework opiates at the end of life in an emergency department in spain: euthanasia or good clinical practice? end-oflife: still an italian dilemma sexual function in icu survivors more than years after major trauma saps admission score: an external validation in a general intensive care population intraabdominal hypertension and acute renal failure in critically ill patients early coagulation disorders after severe burn injury: impact on mortality bedside adherence to clinical practice guidelines in the intensive care unit: the tecla study variability in the concentrations of intravenous drug infusions prepared in a critical care unit international critical care hospital pharmacist activities development and simultaneous application of multiple care protocols in critical care: a multicenter feasibility study from the icu to the ward: cross-checking of the physician's transfer report by intensive care nurses a prospective study of factors influencing the outcome of patients after a medical emergency team review what type of monitoring has been shown to improve outcomes in acutely ill patients? unrecognized contributions of families in the intensive care unit visiting policies in italian intensive care units: a nationwide survey burnout in a surgical icu team post-icu consequences of patient wakefulness and sedative exposure during mechanical ventilation short-term sevoflurane sedation using the anaesthetic conserving device after cardiothoracic surgery substance dependence and psychiatric disorders are related to outcomes in a mixed icu population assessment of digoxin antibody use in patients with elevated serum digoxin following chronic or acute exposure understanding organ dysfunction in hemophagocytic lymphohistiocytosis impact of recent intravenous chemotherapy on outcome in severe sepsis and septic shock patients with hematological malignancies gene profiling in human blood leucocytes during recovery from septic shock the heme oxygenase-carbon monoxide system: regulation and role in stress response and organ failure use of carbon monoxide as a therapeutic agent: promises and challenges key: cord- -sgi hq authors: ely, e.; gautam, s.; margolin, r.; francis, j.; may, l.; speroff, t.; truman, b.; dittus, r.; bernard, g.; inouye, s. title: the impact of delirium in the intensive care unit on hospital length of stay date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: sgi hq study objective: to determine the relationship between delirium in the intensive care unit (icu) and outcomes including length of stay in the hospital. design: a prospective cohort study. setting: the adult medical icu of a tertiary care, university-based medical center. participants: the study population consisted of patients admitted to the icu, of whom received mechanical ventilation. measurements: all patients were evaluated for the development and persistence of delirium on a daily basis by a geriatric or psychiatric specialist with expertise in delirium assessment using the diagnostic statistical manual iv (dsm-iv) criteria of the american psychiatric association, the reference standard for delirium ratings. primary outcomes measured were length of stay in the icu and hospital. results: the mean onset of delirium was . days (s.d.± . ), and the mean duration was . ± . days. of the patients, ( . %) developed delirium, and of these ( . %) developed the complication while still in the icu. the duration of delirium was associated with length of stay in the icu (r= . , p= . ) and in the hospital (r= . , p< . ). using multivariate analysis, delirium was the strongest predictor of length of stay in the hospital (p= . ) even after adjusting for severity of illness, age, gender, race, and days of benzodiazepine and narcotic drug administration. conclusions: in this patient cohort, the majority of patients developed delirium in the icu, and delirium was the strongest independent determinant of length of stay in the hospital. further study and monitoring of delirium in the icu and the risk factors for its development are warranted. patients in the intensive care unit (icu) are at very high risk for the development of delirium due to factors such as multi-system illnesses and comorbidities, the use of psychoactive medications, and age. among general medical or surgical patients, the frequency of delirium varies from % to % [ , , ] . these demographic data reflect non-icu patients and there are, unfortunately, sparse data concerning the demographics of delirium in the icu [ , ] and even less on its impact on outcomes among medical icu patients. the incidence of acute respiratory failure requiring mechanical ventilation rises tenfold from the age of ± years [ ] , resulting in greater numbers of elderly patients treated in our icus [ , ] . without appropriate preventive and management strategies, the aging of the population will likely result in an increased burden of delirium among mechanically ventilated patients across the country [ , , ] , a factor which could strongly effect discharge rates to nursing homes following hospital discharge [ , ] . while recent studies have selected delirium and pharmacologic issues (which are inter-related) as two of the top three most important target areas for quality of care improvement in vulnerable older adults [ ] , nearly all delirium investigations have excluded medical icu patients who are often receiving prolonged sedation on mechanical ventilators [ , , , , , ] . likewise, recent systematic reviews and clinical practice guidelines of sedation practices and consequences in the icu have not even mentioned delirium [ , , ] . as the medical community strives to advance many facets of care for both younger and older patients treated in the icu, it is imperative that we improve our understanding of the frequency and duration of delirium on outcomes in the icu. in this investigation of medical icu patients, we assessed for the development of delirium in the icu and the presence of persistent cognitive deficits at the time of hospital discharge. the main goal of this study was to determine the impact of delirium on commonly monitored clinical outcomes such as length of stay in the icu and in the hospital. the study population included both ventilated and non-ventilated adult medical icu patients admitted to the vanderbilt university medical center. fifty-three consecutive patients were enrolled into the study out of the patients admitted to the icu during the study period. exclusion criteria defined a priori included a history of chronic dementia, psychosis, mental retardation, or other neurologic diseases that would confound the diagnosis of delirium (e.g., cerebrovascular accident with residual cognitive impair-ment), and patient or family refusal to participate. twelve patients were excluded due to underlying chronic dementia or psychosis, and there were three refusals, leaving the patients who were enrolled. five patients were never evaluated by the reference standard geriatric or psychiatric specialist and were therefore excluded from further analysis. this left patients upon which to base the current report. the institutional review board approved this study, and informed consent was obtained from the patient and/or the surrogate. two study nurses enrolled patients each morning and recorded baseline demographics, severity of illness data using the acute physiology and chronic health evaluation (apache) ii score [ ] , activities of daily living [ ] , and risk factors for delirium derived from data in the literature [ , , , , , , , , ] . the modified blessed dementia rating scale (mbdrs) [ ] was used to screen for dementia via family or surrogate interviews. this use of the mbdrs is consistent with its original intent, as it was validated as a dementia screening instrument by comparing the structured mbdrs surrogate interview with the patients' neuropathologic findings at autopsy. the surrogates also completed a set of global questions (rated on a ± scale) that were related to their perceptions of the presence or absence of dementia and the likelihood of the development of delirium. while no patients with documented chronic dementia were enrolled in this investigation, it is possible that patients with mild dementia were admitted to the icu without a prior diagnosis. to account for the possibility of such baseline cognitive deficits, we defined a priori a subgroup of patients as having ªpossible mild dementiaº at enrollment if any of the following three criteria were met: ( ) the geriatric psychiatric expert rated them as demented; ( ) they had an mbdrs [ ] of or greater (lower than the usual cutoff of or greater, thereby increasing sensitivity for detection of dementia); or ( ) a rating on the question answered by the surrogate of or greater out of as ªpossibly having dementia.º once enrolled, patients were followed daily until hospital discharge (see reference standard evaluations below). at the time of hospital discharge, the patients completed the folstein mini-mental state examination (mmse) [ ] , geriatric depression scale [ ] , sf- [ ] , and maugeri respiratory foundation- (mrf- ) [ ] quality of life instruments. the sf- is summarized using mental and physical component scores, which range from to ( = optimal). the mrf± is a disease-specific quality of life instrument designed for use in patients with chronic respiratory diseases [ ] , and it is scored from to with lower numbers indicating better quality of life ( = optimal) based on respiratory disability. all cognitive assessments were conducted in the afternoon between p.m and p.m. the geriatric or psychiatric experts served as the reference standard by completing the dsm iv [ ] criteria for delirium (see appendix) or a rating for a more severely impaired sensorium such as stupor or coma. these latter states were defined as follows: ( ) stupor ± difficult to arouse, unaware of some or all elements in the environment, or not spontaneously interacting with the interviewer; becomes incompletely aware and inappropriately interactive when prodded strongly; and ( ) coma ± unarousable, unaware of all elements in the environment, with no spontaneous interaction or awareness of the interviewer, so that the interview is difficult or impossible even with maximal prodding. our two experts (one a geriatrician with extensive experience in delirium assessment [ , , , , ] and the other a geriatric psychiatrist with years of experience on a busy in-hospital consult liaison service) performed independent patient evaluations. they were allowed the flexibility of utilizing any and all means of patient evaluation, testing, and data gathering (i.e., chart review, lab data, and nursing notes), thus maximizing their ability to arrive at a reference standard rating of cognitive functioning. this included speaking with family members, the patient's bedside clinical nurse (as opposed to study nurse), and any others who observed the patient's behavior and thinking that day. the delivery of psychoactive medications (e.g., sedatives and analgesics) was not interrupted or modified for the purposes of the delirium assessments, but was left strictly in the hands of the managing clinicians who were not co-investigators. the managing clinicians and the treatment team were blinded to the reference standard evaluations. for multiple linear regression analysis, the independent or explanatory variable was the duration of delirium in days that had begun in the icu (i.e., ªicu-onsetº delirium). the dependent or response variables chosen for the multiple regression analysis were length of stay in icu, length of stay in hospital, folstein mmse score, depression as measured by the gds, and quality of life as measured by sf and mrf- forms. covariates used in the analysis included age, gender, apache ii, and number of days of psychoactive drug use. for this investigation, psychoactive drug days were counted as any day on which a patient received either a narcotic or a benzodiazepine either iv or po (recognizing, of course, that numerous other drugs are implicated to have deliriogenic features). days were rounded to the nearest digit. since the histogram of hospital stay showed a skewed distribution, the data were transformed using the log scale. the transformed variable was approximately normally distributed. the correlation of each of the outcome variable (e.g., icu length of stay and hospital length of stay) was calculated with each of the covariates in univariate analysis. the relationship between delirium and outcome adjusted for covariates was examined using multiple linear regression analysis. statistical significance was defined as a p value < . . severity of illness was described using the apache ii score [ ] . statistical analysis was performed using sas version (sas institute, cary, n. c., usa). the reference standard geriatric or psychiatric experts evaluated a total of patients in this investigation. the mean age of the population was (mean s. d.), and ( %) were mechanically ventilated on enrollment ( table ). the distribution by race was % caucasian, % african-american, and % hispanic. severity of illness as measured by apache ii was a mean of . . . the mbdrs mean score was . . , well below the level of typically used to predict the presence of baseline dementia. using a liberal definition of ªpossible mild dementiaº as defined in methods, there were only ( %) patients with this condition. patients had a variety of admission diagnoses as outlined in table . the prevalence of each risk factor in the population is presented in table . the mean number of identified risk factors for delirium in these patients was , with a range of ± risk factors present. the most frequent risk factor present in this cohort was the use of benzodiazepines or narcotics in of patients ( %), although the dose and frequency of administration were not recorded for this study. table prevalence of risk factors for delirium in icu cohort. the list of risk factors for delirium was derived from the literature using the references listed below. visual or hearing impairments were determined by patient or family report and by subjective (not formal) evaluation. malnutrition was recorded if patient had a low prealbumin, cholesterol below mg/dl, or received no feeds for > h in the hospital. sleep disturbances are an obvious risk factor, but this was not objectively tracked for this study [ , , , , , , , , ] risk factor frequency, n (%) [ ] . the geriatric depression scale yields a score from to , with a score of or higher indicates possible depression with % sensitivity and % specificity [ ] . the short form- is a generic quality of life instrument that is widely used and scored according to a mental and physical component score, each with a range of values from to ( = optimal) [ ] . the maugeri respiratory foundation- is a disease-specific quality-of-life instrument designed for use in patients with chronic respiratory diseases [ ] , and it is scored from to with lower numbers indicating better quality of life ( = optimal) based on respiratory disability were having trouble with at least three of the following: forgetting names more than before, feeling absent minded, forgetting what they were going to say, or having difficulty maintaining concentration even on topics interesting to them. simple linear regression (univariate analysis) showed that both icu stay and hospital stay were significantly correlated with duration of delirium and psychoactive drug days, while apache ii score, age, and gender were not ( table ). the duration of delirium with onset in the icu was associated with length of stay in the icu (r = . , p = . ) and in the hospital (r = . , p < . ). the duration of delirium also correlated with the duration of benzodiazepine or narcotic use (r = . , p = . ), but less well with apache ii (r = . , p = . ) and age (r = . , p = . ). the development of delirium was poorly correlated with other outcomes including folstein mmse (r = ± . , p = . ), sf- (r = ± . , p = . ), and mrf- (r = . , p = . ). the results of the multiple linear re-gression analysis are displayed in table . using multiple regression analysis, delirium with onset in the icu was the strongest predictor of length of stay in the hospital (p = . ) even after adjusting for severity of illness, age, gender, race, and days of psychoactive drug utilization. the model's adjusted r for delirium in relation to the length of icu stay was . , and for the length of hospital stay the adjusted r was . . delirium complicates the hospital stay of more than ± million elderly patients per year in the u. s., involving over . million in-patient days and accounting for at least $ billion in medicare expenditures [ , , , , , ] . medical icu patients are among the sickest patients in our entire health care system and consume substantial resources with median costs of $ , to $ , per patient [ ] , and costs per quality adjusted life-year ranging from $ , to $ , depending upon prognostic strata [ ] . it is not known whether delirium contributes independently to poor outcomes. we have conducted a delirium investigation in the icu us- [ ] , drug days = number of days that a patient received psychoactive medications designated in methods b delirium with onset in the icu (i.e., ªicu-onsetº delirium), duration measured in days. the adjusted r for delirium in relation to the icu stay was . , and for the hospital stay the adjusted r was . table multiple linear regression model: predictors of lengths of stay in icu and hospita* ing reference standard evaluators and found that delirium occurred in % of all patients and was the strongest predictor of length of stay in the hospital even after adjusting for severity of illness and other covariates. the prevalence of delirium in this investigation was four times higher than the control rate of delirium a recently reported cohort of medical patients [ ] . the fact that delirium was an independent determinant of length of stay sends an important message to the icu community that this poorly monitored yet extremely common complication of icu stay should achieve a high priority for future study. in the icu setting, as in terminal cancer patients [ ] , it will be important to determine if delirium is merely a marker of illness and physical frailty, an avoidable iatrogenic complication, or an independent contributor to poor neurological outcomes and survival. the development of delirium in non-icu patients has an associated in-hospital mortality of ± % [ , , , ] . francis and kapoor [ ] found that -year mortality in patients having experienced delirium was % versus % in controls. in addition, a -site epidemiological delirium study showed that delirium was an important independent predictor of the combined outcome of death or nursing home placement [ ] . in this investigation, we found that icu patients had an inordinately high number of risk factors to develop delirium. while benzodiazepines and narcotics were the most prevalent risk factor in this cohort (administered to % of patients), numerous other risk factors must be considered, as we found that their use explained only % (i.e., r = . ) of the variation in duration of delirium. in fact, the mean number of risk factors per patient was . clinical prediction rules have repeatedly shown that it is possible to stratify patients into risk groups depending upon the number of risk factors present [ , , , ] . patients with three or more of these risk factors have been considered ªhigh riskº for delirium [ , , , ] , and in icu patients, this magnitude of risk is nearly universal. in practical terms, the risk factors for delirium can be divided into three categories [ , , , , , , , , ] : ) the acute illness itself; ) host factors including age or chronic health problems; and ) iatrogenic or environmental factors. modifications of risk factors in the icu such as the use of psychoactive drugs, maintenance of sleep/wake cycles, attempts at prevention of malnutrition, optimization of the use of restraints, and adjustments in care to account for visual or hearing impairment could help improve the incidence and/or duration of delirium [ ] . this observational investigation did not address treatment of delirium, but we believe that two important concepts warrant mentioning: ) in delirious patients, a search for all reversible precipitants is the first line of action; and ) symptomatic treatments should be considered when available and not contraindicated (e.g., haloperidol). in two important and recently reported clinical trials, dose reductions of narcotics and benzodiazepines have been shown to improve outcomes in the icu for mechanically ventilated patients [ , ] , but the effects on delirium or long-term cognitive impairment were not measured. a major limitation of our ability to determine the best therapy for delirium has been that standard delirium assessment instruments [ , , ] were not validated for use in intubated, non-verbal patients. prior to routine monitoring of delirium in the icu population, better instruments need to be developed for nurses or other icu personnel to measure delirium as an outcome for investigations and quality assurance [ , ] . delirium remains unrecognized by the clinician in as many as ± % of patients experiencing this complication [ , ] , and it may be attributed incorrectly to dementia, depression, or just an ªexpectedº occurrence in the critically ill, elderly patients [ ] . in addition, the term ªdeliriumº has not been used to categorize the types and degrees of cognitive impairment found in septic patients in the icu, with the default, all-inclusive term of ªseptic encephalopathyº (encompassing delirium, stupor, and coma) being used instead [ , , , ] . it is important for the medical community (especially those who care for critically ill patients in the icu) not only to distinguish delirium from other degrees of cognitive impairment, but also to recognize that subtypes of delirium exist. these subtypes of delirium are classified by psychomotor activity as either hypoactive, hyperactive, or mixed [ , ] . when patients are allowed to emerge from the effects of sedation, they may do so peacefully or in a combative manner. on one extreme are the ªpeacefulº patients, who are often assumed erroneously to be thinking clearly. these patients with hypoactive or quiet delirium represented % of all episodes of delirium in our investigation. this subtype is manifested as decreased mental activity and inattention, and is frequently overlooked by physicians and nurses [ , , ] . many clinicians expect delirium to present with agitation or hallucinations, features that are not required for the diagnosis. failing to recognize deficits in cognitive function places these fragile patients at risk for aspiration and reintubation [ , , ] . when patients are in a combative state, they are usually referred to as having ªintensive care syndromeº or ªicu psychosis,º which is the hyperactive subtype of delirium [ , , , ] . these terms may be a potentially dangerous misnomer, because they imply that increased psychomotor activity and hallucinations are an expected outcome in the icu [ , , , , , ] . in this cohort, hyperactive delirium was present in only % of the episodes of delirium. this investigation has several limitations. most importantly, the size and the duration of follow-up should be extended in future cohorts to better determine the role of delirium on mortality. in addition, future studies of larger cohorts including more elderly icu patients with diverse causes of respiratory failure should assess neuropsychological function beyond the icu stay in order to determine the prevalence of and risk factors for persistent deficits. recent data on long-term outcomes after the acute respiratory distress syndrome (ards) demonstrated impaired neuropsychological function in % of patients at one-year follow-up [ ] . we did not find an association between delirium and impaired quality of life in our study, yet this may represent another limitation of either the size of the study or the quality of life instruments chosen. for example, the mrf- has not been used previously in an icu cohort (it was chosen because it has both disease-specific questions for respiratory patients as well as those related to cognitive impairment). recently, data has begun to emerge regarding quality of life measures following icu care [ , , ] , including the role of sedatives and neuromuscular blocking agents in psychiatric disorders after icu care [ ] , but no data are available for delirium. our risk factor analysis, while thorough in comparison to previous icu delirium studies, lacked sleep monitoring and employed simple methods to track psychoactive drug use. future studies should track both of these risk factors in a more detail. while this investigation did not find a striking correlation between age and delirium, the cohort contained a relatively young population and the study was not powered to evaluate this relationship. lastly, sepsis itself should be tracked as an independent risk factor for delirium in icu cohorts, considering the aforementioned entity of septic ªencephalopathy,º which often includes delirium. in conclusion, we have shown that delirium developing in the icu was a strong predictor of length of stay in the hospital. this investigation should raise awareness of delirium as a complication of stay in the icu for critically ill patients. this complication may be modifiable and deserves further study. monitoring delirium in the icu in patients receiving mechanical ventilation may be a future priority in the icu, especially as the age of icu patients continues to increase, thereby introducing older patients who are vulnerable to this complication. reference standard evaluations were performed by the geriatric or psychiatric experts using all available information including patient examinations and interactions, nurse and family interviews, physicians' and nurses' notes, laboratory values, and any other chart data present. a. disturbance of consciousness (i.e., reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention. b. a change in cognition (such as memory deficit, disorientation, language disturbance) or the development of a perceptual disturbance that is not better accounted for by a preexisting, established, or evolving dementia. c. the disturbance develops over a short period of time (usually hours to days) and tends to fluctuate during the course of the day. d. there is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by one of the following: i. the direct physiological consequences of a general medical condition. ii. the direct result of medication use or substance intoxication (substance intoxication delirium). iii. the direct result of a withdrawal syndrome (substance withdrawal delirium). iv. the direct result of more than one of the above etiologies (delirium due to multiple etiologies). the diagnosis of cognitive impairment involves careful observations of the abilities of the patient and knowledge of the patient's former level of functioning. in order to identify all cases cognitive impairment, we have adopted the following measures: ) the above dsm criteria and mental status definitions will be consistently employed; ) a geriatric psychiatrist's evaluation will be conducted to determine which of these criteria are met by the patient. this will involve a bedside evaluation and screening for cognitive and attention deficits; ) lastly, interviewing the family and nurse who provide the majority of patient care will establish baseline functioning and identify fluctuations [ ] . a multicomponent intervention to prevent delirium in hospitalized older patients delirium: the occurrence and persistence of symptoms among elderly hospitalized patients intensive care syndrome. intensive intensive care unit psychosis revisited: understanding and managing delirium in the critical care setting acute respiratory failure in the united states: incidence and -day survival intensive care ± : change in patient characteristics, nursing workload and outcome intensive care for critically ill elderly: mortality, costs, and quality of life. review of the literature mechanical ventilation in a cohort of elderly patients admitted to an intensive care unit the prognostic significance of delirium in older hospital patients evaluation of delirium in critically ill patients: validation of the confusion assessment method for the intensive care unit (cam-icu) delirium: a symptom of how hospital care is failing older persons and a window to improve quality of hospital care selecting target conditions for quality of care improvement in vulnerable older adults a clinical prediction rule for delirium after elective noncardiac surgery the relationship of postoperative delirium with psychoactive medications clarifying confusion: the confusion assessment method the dilemma of delirium: clinical and research controversies regarding diagnosis and evaluation of delirium in hospitalized elderly medical patients sedation in the intensive care unit sedation in the intensive care unit practice parameters for intravenous analgesia and sedation for adult patients in the intensive care unit: an executive summary apache ii: a severity of disease classification system studies of illness in the aged-the index of adl: a standardized measure of biological and psychosocial function post-operative delirium: predictors and prognosis in elderly orthopedic patients the impact of postoperative pain on the development of postoperative delirium a predictive model for delirium in hospitalized elderly medical patients based on admission characteristics intensive care delirium; the effect of outside deprivation in a windowless unit delirium in hospitalized elderly the association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects mini-mental state a practical method for grading the cognitive state of patients for the clinician screening for depression in elderly primary care patients cross-validation of item selection and scoring for the sf- health survey in nine countries: results from the international quality of life assessment project analysis of factors that characterise health impairment in patients with chronic respiratory failure diagnostic and statistical manual of mental disorders, th edn. american psychiatric association, washington prognosis after hospital discharge of older medical patients with delirium delirium in older patients drug-induced delirium the cost of respiratory care in mechanically ventilated patients with chronic obstructive pulmonary disease outcomes and cost-effectiveness of ventilator support and aggressive care for patients with acute respiratory failure due to pneumonia or acute respiratory distress syndrome occurrence, causes, and outcome of delirium in patients with advanced cancer does delirium contribute to poor hospital outcomes? a three-site epidemiologic study american psychiatric association ( ) practice guideline for the treatment of patients with delirium precipitating factors for delirium in hospitalized elderly persons: predictive model and interrelationship with baseline vulnerability effect of a nursing implemented sedation protocol on the duration of mechanical ventilation daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation a symptom rating scale for delirium further analyses of the delirium rating scale delirium in the mechanically ventilated patients: validity and reliability of the confusion assessment method for the icu (cam-icu) neurologic complications of critical medical illnesses pathophysiology of septic encephalopathy: a review the spectrum of septic encephalopathy: definitions, etiologies, and mortalities relationship between symptoms and motoric subtype of delirium an empirical study of delirium subtypes effect of failed extubation on the outcome of mechanical ventilation independent effects of etiology of failure and time to reintubation on outcome for patients failing extubation clinical characteristics, respiratory functional parameters, and outcome of a two-hour t-piece trial of patients weaning from mechanical ventilation does ªicu psychosisº really exist? neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome outcome, functional autonomy, and quality of life of elderly patients with a long-term intensive care unit stay short form : a valid and reliable measure of health-related quality of life quality of life in intensive care unit survivors: a place for outcomes research in critical care intensive care unit drug use and subsequent quality of life in acute lung injury patients key: cord- -cnwg dnn authors: gutierrez, guillermo title: artificial intelligence in the intensive care unit date: - - journal: crit care doi: . /s - - -y sha: doc_id: cord_uid: cnwg dnn this article is one of ten reviews selected from the annual update in intensive care and emergency medicine . other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate . further information about the annual update in intensive care and emergency medicine is available from http://www.springer.com/series/ . the past century has witnessed a massive increase in our ability to perform complex calculations. the development of the transistor in the s, followed by the silicone integrated circuit, accelerated those capabilities and gave rise to what is commonly known as moore's law. according to this principle, the number of transistors packed into a dense integrated circuit doubles every years. the corollary is that computation speed also doubles at -year intervals. figure is a graphical interpretation of moore's law, showing an exponential increase in computational power, in terms of calculations per second that can be purchased with $ (constant us, ) . according to that graph, computing power has increased by a factor of from the mechanical analytical engine of the early s to today's core i quad chip found in personal laptop computers. the growth in computing power was made possible by the relentless downsizing of integrated circuits, with some components being produced in the sub- nm range. as we approach the physical limits of silicone chip downsizing, other materials are being developed. a likely candidate is the carbon nanotube, composed of a single sheet of carbon atoms arranged in a hexagonal pattern. when rolled into itself, the sheet becomes a tube approximately nm in diameter, capable of forming different circuit elements. this nascent technology, along with the development of quantum computing, assures the durability of moore's law well into the future. as processors grew in power, and personal computers became ubiquitous appliances, the stage was set for the development of the internet, a digital network that morphed from the arpanet, a communication structure designed by the u.s. advanced research projects agency (arpa) to transfer information among computers located at remote distances. the internet promoted the free dissemination of software and provided the impetus for computer scientists to develop powerful algorithms aimed at simulating human intelligence. according to the encyclopedia britannica, artificial intelligence (ai) refers to a system "endowed with the intellectual processes characteristic of humans, such as the ability to reason, discover meaning, generalize, or learn from past experience." ai computer systems are able to perform tasks normally requiring human intelligence and that are considered "smart" by humans. ai systems act on information, such as controlling a self-driving automobile or influencing consumer shopping decisions. in the area of medicine, ai has been used in drug discovery, personalized diagnostics and therapeutics, molecular biology, bioinformatics, and medical imaging. ai applications are also capable of discerning patterns of disease by scrutinizing and analyzing massive amounts of digital information stored in electronic medical records. in a recent proposal aimed at regulating ai software in medical devices, the u.s. food and drug administration states that "artificial intelligence-based technologies have the potential to transform healthcare by deriving new and important insights from the vast amount of data generated during the delivery of healthcare every day" [ ] . human intelligence is defined by the mental capability to think abstractly, use reason to solve problems, make plans, comprehend complex ideas, and learn from experience [ ] . much of human intelligence involves pattern recognition, a process that matches a visual or other type of stimuli, to similar information stored in our brains. although endowed with abstract thinking and capable of sublime leaps in imagination, humans have a limited capacity for memory. it is estimated that the brain cannot store more than four "chunks" of short-term memory at any one time [ ] . moreover, humans find it difficult to think in terms of n-dimensional spaces or visualize patterns embedded into large quantities of data. conversely, computers have vast memory storage, excel at handling multidimensional problems and can discern even small or "fuzzy" associations within massive data collections. the use of computers to guide the treatment of critically ill patients is not a new concept. with uneven results, computerized systems have been proposed in the past to monitor icu patients [ ] , manage patients on mechanical ventilators [ , ] , guide care in patients with acute respiratory distress syndrome (ards) [ ] , and manage arterial oxygenation [ ] . these early computer systems were programmed with highly specific and sequential if/then/else logical expressions that assessed the validity of a condition based on accepted physiological principles and/or clinical experience (fig. ). according to these expressions, if a given condition was judged to be "true," then the program executed instruction , else, it executed instruction . ai is based on a fundamentally different approach to traditional computer programming. instead of instructing the computer to evaluate a given condition, or to perform a specific task according to detailed programmed instructions, ai algorithms, in a manner similar to the way children absorb knowledge, learn from exposure to numerous examples. ai algorithms establish their own rules of behavior and can even improve on their "intelligence" by incorporating additional experiences resulting from the application of these rules. machine learning is a subset of ai in which machines learn or extract knowledge from the available data, but do not act on the information. machine learning combines statistical analysis techniques with computer science to produce algorithms capable of "statistical learning." broadly speaking, there are two types of machine learning structures: supervised and unsupervised (fig. ) . the objective of supervised machine learning is to develop an algorithm capable of predicting a unique output when provided with a specific input. in other words, the machine is shown examples of input (x) and its corresponding output (y), such that y = f(x). machine learning is predicated on large sets of data containing myriad examples that relate one or several input variables to a single output. the expectations are that the resulting algorithm will deliver accurate predictions when exposed to new and never before seen data. supervised learning requires a great deal of human effort when building large datasets to train and test the algorithm. there are two major types of supervised learning: regression and classification. most clinicians are familiar with regression analysis, a statistical technique producing a mathematical expression relating one input variable to another (linear regression) or many input variables to one dependent variable (multiple regression). in regression analysis, the output is a continuous function of the input. in other words, the predicted variable will change in concert with the input variables. regression is used commonly to test hypotheses involving causal relationships, with the choice of model being based on its significance and goodness of fit. classification supervised learning is a form of pattern recognition designed to predict a single, nonnumerical output, or "class," from a predefined list of possibilities. classifier algorithms are trained with many lines of data, with each line having several input variables and one desired output. for example, a model designed to identify a breed of dog may be trained with data listing their traits or characteristics, e.g., height, type of hair, and length of tail. each line will be associated with a specific breed. once trained, the model can be asked to predict the dog breed when given new set of input variables. two important steps are needed to build a classifier model. the first is to establish the number of classes the model will be required to identify. the second is to identify the number of variables required to describe the classes. fewer variables and classes require less training data and result in simpler and more accurate models. the simplest classification model is the binary kind, in which the model is asked to choose between a "yes" and a "no" answer. classes may consist of physical objects (chair, table, etc.), medical conditions (e.g., sepsis, ards, chronic obstructive pulmonary disease [copd], etc.), clinical or physiological observations (e.g., different types of arrhythmia or ventilator asynchronies). each class is associated with a number of input variables common to all classes. in machine learning parlance, input variables are known as "features," with each line of data, or "instance," containing several features and a single class. let us say we want to develop a classifier algorithm to identify five different kinds of animal (fig. ) . in this example, each line of data has one animal class and several features to describe the animal's characteristic, such as sea or land dwelling, fish or mammal. this is a very simple example having only one instance per class. the model, therefore, would be totally inadequate if its purpose were to differentiate among different dog or cat breeds. in that case, many more instances would be needed to describe different types of dogs and cats. the more specific one wishes to be, the more features are needed to describe the classes. on the other hand, increasing the number of features results in complex models that require greater computing power and longer time to run, a condition termed "the curse of dimensionality." an important guiding principle in machine learning is the truism that "less is best." in mathematical terms, a feature matrix contains n features and m instances, and it is associated with an m length classification vector: perhaps the most important step in developing a machine learning model is to have a clear definition of the problem and to determine its suitability for machine learning. the next step is to determine the size of the feature matrix and the classification vector (fig. ) . whereas humans develop generalized concepts on the basis of just a few examples, training a machine learning algorithm requires large quantities of data. the creation of a large feature matrix with its classification vector is accomplished by gathering as many instances as possible. once satisfied that we have collected an adequate number of examples to be presented to the computer, we split the feature matrix into a "training" dataset, for model development, and a "test" dataset. the data are split by a random process that assigns instances from the original data to each dataset. a common practice is to use % or % of the data for training and the remainder for testing. the purpose of the "test" dataset is to assess the algorithm's accuracy when exposed to never before seen data. accuracy is defined as the percentage of correct answers made by the algorithm on the unknown "test" dataset. should accuracy fall below a chosen expected value, we can choose to gather more "training" data or to use another type of machine learning algorithm altogether. several types of classifier algorithms may be used to create the machine learning model. among them are decision trees, random forests, k-nearest neighbors, and many others (fig. ) . a popular type of classifier algorithm is the neural network, modeled on the way human neurons are thought to process information. the basic element of the neural network, the perceptron, produces a single binary output from several inputs. a neural network results from the interacting of several perceptrons. advanced machine learning systems encompassing several layers of stacked complex neural networks are called deep learning. it is beyond the purpose of this chapter to describe the theory and application of these algorithms (listed in fig. ), but the reader interested in pursuing this line of investigation can access "scikit-learn" (https://scikitlearn.org/stable/), an open source machine learning library written with the python programming language (https://www.python.org/). this library of programs makes it relatively easy to develop classification supervised machine learning algorithms. when building a classifier model, it is imperative to generalize its utility to make accurate predictions using both the "training" and the "test" datasets. one should beware of models of high complexity that may conform closely to the "training" set, but have poor accuracy when applied to the "test" dataset, a phenomenon called "overfitting." in this type of machine learning, no instructions are given to the algorithm on how to process the data. instead, the computer is asked to extract knowledge from a large set of unclassified data with no known output or a set of rules. given the lack of label information, a major challenge for the investigator when evaluating an unsupervised algorithm is how to determine the utility of the results, or whether the right output has been achieved. unsupervised algorithms, however, can be very useful in exploratory attempts to understand large collections of data. the techniques most commonly used are clustering, anomaly detection, and dimensionality reduction. in clustering, algorithms are asked to identify or partition large data sets into subsections and patterns sharing similar characteristics. in anomaly detection the algorithm is asked to detect atypical patterns in the dataset, such as searching for outliers. dimensionality reduction is useful when analyzing data having many features, or dimensions. these algorithms may be able to present the data in a simpler form, summarizing its essential characteristics and making it easier for humans or other machine learning algorithms to understand. an important point to keep in mind is that no machine learning algorithm, regardless of its accuracy, is the only possible choice for a model. other algorithms may be capable of providing a good fit and derive additional useful inferences from the data. for those wishing to delve deeper into the development of machine learning models, a good source of information is the book by müller and guido [ ] and the website (https://www.geeksforgeeks.org/learning-model-building-scikit-learn-pythonmachine-learning-library/). there are numerous opportunities in the hospital setting to apply ai. unsupervised machine learning techniques have been used to explore massive amounts of data encoded in electronic medical records. models have been developed to obtain important information in a patient's chart [ ] and identify high-cost patients [ ] . supervised machine learning algorithms, given their potential for automated pattern recognition of images, have proven their utility in radiology [ ] and histopathology [ ] . machine learning has been used extensively in the fields of surgery, as it pertains to robotics [ ] , in cardiology [ ] for early detection of heart failure [ ] , and in cancer research to classify tumor types and growth rates [ ] . although the introduction of machine learning to the icu is in its infancy, several studies have already been published describing the application of this technology in the management of the critically ill patient. some have used large population datasets to predict length of stay, icu readmission and mortality rates, and the risks of developing medical complications or conditions such as sepsis and ards. other studies have dealt with smaller datasets of clinical and physiological data to aid in the monitoring of patients undergoing ventilatory support. houthooft et al. [ ] trained a support vector machine model to forecast patient survival and length of stay using data from , patients. the model's area under the curve (auc) for predicting a prolonged length of stay was . . this is in contrast to a clinical study showing the accuracy of physicians to be only % when predicting icu length of stay [ ] . a hidden markov model framework applied to physiological measurements taken during the first h of icu admission also predicted icu length of stay with reasonable accuracy [ ] . the problem of icu readmission was investigated with a neural network algorithm applied to the medical information mart for intensive care iii (mimic-iii) database. this is an open source, freely available database collected from patients treated in the critical care units of the beth israel deaconess medical center between and . the algorithm was able to identify patients at risk of icu readmission with . sensitivity and auc of . [ ] . awad et al. [ ] applied several machine learning algorithms, including decision trees, random forest, and naïve bayes to , first admission mimic-ii data to predict icu mortality. features included demographic, physiological, and laboratory data. these models outperformed standard scoring systems, such as apache-ii, sequential organ failure assessment (sofa), and simplified acute physiology score (saps), a finding that was confirmed by the same group in a follow-up study using time-series analysis [ ] . a swedish system using artificial neural networks applied to > , first-time icu admissions also showed superior performance in predicting the risk of dying when compared to saps- [ ] . machine learning models have also been proposed to predict mortality in trauma [ ] and pediatric icu patients [ ] . the abovementioned icu survival models, while offering improved performance when compared to standard mortality prediction scoring systems, are somewhat cumbersome to use, require a large number of variables and have yet to be tested prospectively. yoon et al. [ ] developed a method to predict instability in the icu based on logistic regression and random forest models of electrocardiogram (ekg) measures of tachycardia, reporting an accuracy of . and auc of . . the publication of the study is accompanied by an excellent and highly recommended editorial by vistisen et al. [ ] that thoroughly analyzes the strengths and pitfalls of machine learning methods as predictors of complications in the icu. a recent study applied a random forest classifier to over , electronic health records of hospitalized patients to predict the occurrence of sepsis and septic shock. although the algorithm was highly specific ( %), it only had a sensitivity of %, severely limiting its utility [ ] . other studies have been published describing the use of machine learning models in generating patient-specific risk scores for pulmonary emboli [ ] , risk stratification of ards [ ] , prediction of acute kidney injury in severely burned patients [ ] and in general icu populations [ ] , prediction of volume responsiveness after fluid administration [ ] and identification of patients likely to develop complicated clostridium difficile infection [ ] . whereas present day mechanical ventilators work exceedingly well in delivering air to diseased lungs, they are "feed-forward" or open loop systems where the input signal, or mode of ventilation, is largely unaffected by its output, the adequacy of ventilation. as such, ventilators lack the capacity to assess the patient's response to the delivered breath. a desirable solution is the development of the autonomous ventilator, a device that could monitor the patient's response to ventilation continuously, while adjusting ventilatory parameters to provide the patient with a comfortable, optimally delivered breath. although we are far from this ideal device, significant strides are being made toward making it into a reality. over the past decade, there has been considerable interest in detecting and classifying patient-ventilator asynchrony, a phenomenon indicating the degree of coupling or response of the patient to ventilatory support [ ] . machine learning methods of detecting patient-ventilator asynchrony have been based on morphological changes of the pressure and flow signals. chen et al. [ ] developed an algorithm to identify ineffective efforts from the maximum deflection of the expiratory portion of airway pressure and flow. ineffective effort was present in % of the patients enrolled in their study. analysis of breaths yielded sensitivity and specificity for the detection of ineffective efforts > %. an algorithm developed by blanch at al [ ] . compared a theoretical exponential expiratory flow curve to actual flow tracings. a deviation exceeding % was considered indicative of ineffective effort. they compared the predictions of the algorithm in a random selection of breaths obtained from patients, to those made by five experts and reported . % sensitivity and . % specificity with . % predictive value. as proof-of-concept, this group also reported monitoring airway signals in mechanically ventilated patients and were able to predict the probability of an asynchrony occurring from one breath period to the next using a hidden markov model [ ] . the system used in these trials has been commercialized as better care®, and it is capable of acquiring, synchronizing, recording, and analyzing digital signals from bedside monitors and mechanical ventilators [ ] . rhem et al. [ ] and adams et al. [ ] developed a set of algorithms to detect two types of asynchrony associated with dynamic hyperinflation, double triggering, and flow asynchrony. based on a learning database of breaths from patients, they developed logical operators to recognize double triggering based on bedside clinical rules. dynamic hyperinflation was identified from the ratio of exhaled to inhaled tidal volume. the algorithms were validated with data drawn from another patient cohort (n = ), resulting in sensitivity and specificity > %. sottile at al [ ] . evaluated several types of machine learning algorithms, including random forest, naïve bayes, and adaboost on data recorded from mechanically ventilated patients with or at risk of ards. they chose features based on clinical insight and signal description and were able to determine the presence of synchronous breathing, as well as three types of patientventilator asynchrony, including double triggering, flow limited and ineffective triggering, with an auc > . . the authors did acknowledge that their algorithm does not identify all types of patient-ventilator asynchrony, in particular premature ventilator terminated breaths, or cycling asynchronies. gholami et al. [ ] trained a random forest classifier algorithm from a training data set produced by five experts who evaluated breath cycles from mechanically ventilated patients to evaluate cycling asynchronies. patients were ventilated with pressurecontrolled volume ventilation. the model accurately detected the presence or absence of secondary synchrony with a sensitivity of %. mulqueeny et al. [ ] used a naïve bayes machine learning algorithm with features, including measures of respiratory rate, tidal volume, respiratory mechanics and expiratory flow morphology to a dataset of breaths manually classified by a single observer, resulting in an accuracy of %, but a sensitivity of only %. loo et al. [ ] trained a convolutional neural network with abnormal and normal breathing cycles aimed at developing an algorithm capable of separating normal from abnormal breathing cycles, reporting . % sensitivity and . % specificity. the accuracy of a machine learning algorithm is judged by its ability to correctly predict the unseen test dataset. models are created and tested with instances culled from the same data population, and it is common to find reports of algorithms having very high accuracy scores in the machine learning literature. given a judicious selection of features, a sufficiently large number of instances, and a wise choice of algorithm, the most likely outcome will be a highly accurate model. if the data are true and verifiable, the model's predictions are also bound to be reliable. on the other hand, when a model trained with untested or faulty data is presented with data drawn from the same population, the predictions are likely to be accurate but totally unreliable. as some have succinctly put it, rubbish in, rubbish out. this begs the question of what are the limits of model reliability. whereas ai is able to consider numerous variables and minimize human bias in data classification, it cannot insure model reliability. therefore, the greatest challenge when creating a clinical machine learning model lies in identifying the gold standard to be used in the classification. a great deal of what we see and do in medicine is highly subjective, and unanimity of opinion is seldom found among intensivists. for example, a study [ ] on interobserver reliability of clinicians in diagnosing ards according to the berlin definition found only a moderate degree of reliability (kappa = . ). the main driver of the variability was the interpretation of chest radiographs. similar findings were noted in clinicians evaluating optic disk photographs for glaucoma (kappa . - . ) [ ] . it is therefore unlikely that model reliability in the icu will ever exceed - %, even in the best of hands. experienced intensivists excel at collecting, classifying, and analyzing snapshots of clinical information to expeditiously reach a diagnosis and decide on treatment options. in the data-intensive environment of today's icus, however, intensivists must cope with a relentless flow of information, some of it useful, most of it not. according to a thoughtful essay by alan morris [ ] , intensivists must contend with no less than variables when caring for patients on ventilatory support. the ability to catalog, correlate, and classify these variables on a continuous basis lies well beyond the capabilities of even the most knowledgeable and perceptive of clinicians. the judicious application of ai technology can be of assistance in helping us deal with information overload. machine learning algorithms have been used to analyze data stored in electronic medical records to predict icu mortality and length of stay. they also have furthered our understanding of populations who may be at risk of disease progression or likely to experience medical complications. these retrospective studies, useful as they may be in the early identification and stratification of patients, represent only the low-lying fruit in ai research. a more difficult task, but perhaps one with far greater potential, is the development of intelligent machine learning monitors capable of continuously assessing the human response to critical illness with a high degree of certainty. the development of such monitors will provide the knowledge and experience needed for the creation of the semi-autonomous icu, an environment where intelligent machines provide most of the care delivered today by humans. the full potential of ai will be realized once it becomes a trustworthy clinical adjunct to intensivists. by helping us cope with information overload, ai endowed machines may allow our faculties of reflection, imagination, and compassion to come to the fore when caring for fellow humans in distress. the future of ai in the icu is indeed bright. as with all new technologies, there will be zealots and pharisees, ups and downs, elations and disappointments, as well as thorny ethical quandaries. i have no doubt, however, that ai is here to stay, and it behooves us to become familiar with this technology for the betterment of our patients. proposed regulatory framework for modifications to artificial intelligence/ machine learning (ai/ml)-based software as a medical device (samd) mainstream science on intelligence: an editorial with signatories, history, and bibliography chunks in expert memory: evidence for the magical number four integrated computer systems for monitoring of the critically ill assessment of the ability to manage patients on mechanical ventilators using a computer model a microprocessor based feedback controller for mechanical ventilation computerized management of patient care in a complex, controlled clinical trial in the intensive care unit performance of computerized protocols for the management of arterial oxygenation in an intensive care unit introduction to machine learning with python: a guide for data scientists piloting electronic medical record-based early detection of inpatient deterioration in community hospitals big data and machine learning in health care artificial intelligence in radiology deep learning as a tool for increased accuracy and efficiency of histopathological diagnosis surgical robotics beyond enhanced dexterity instrumentation: a survey of machine learning techniques and their role in intelligent and autonomous surgical actions artificial intelligence in cardiology using recurrent neural network models for early detection of heart failure onset image-based classification of tumor type and growth rate using machine learning: a preclinical study predictive modelling of survival and length of stay in critically ill patients using sequential organ failure scores icu physicians are unable to accurately predict length of stay at admission: a prospective study improving length of stay prediction using a hidden markov model analysis and prediction of unplanned intensive care unit readmission using recurrent neural networks with lon short term memory early hospital mortality prediction of intensive care unit patients using an ensemble learning approach predicting hospital mortality for intensive care unit patients: time-series analysis artificial neural networks improve and simplify intensive care mortality prognostication: a national cohort study of , first-time intensive care unit admissions machine learning models of survival prediction in trauma patients a deep learning model for real-time mortality prediction in critically ill children predicting tachycardia as a surrogate for instability in the intensive care unit predicting vital sign deterioration with artificial intelligence or machine learning a machine learning algorithm to predict severe sepsis and septic shock: development, implementation, and impact on clinical practice development and performance of the pulmonary embolism result forecast model (perform) for computed tomography clinical decision support machine learning for patient risk stratification for acute respiratory distress syndrome artificial intelligence and machine learning for predicting acute kidney injury in severely burned patients: a proof of concept machine learning versus physicians' prediction of acute kidney injury in critically ill adults: a prospective evaluation of the akipredictor machine learning for the prediction of volume responsiveness in patients with oliguric acute kidney injury in critical care using machine learning and the electronic health record to predict complicated clostridium difficile infection patient-ventilator asynchrony during assisted mechanical ventilation detecting ineffective triggering in the expiratory phase in mechanically ventilated patients based on airway flow and pressure deflection: feasibility of using a computer algorithm validation of the better care® system to detect ineffective efforts during expiration in mechanically ventilated patients: a pilot study predicting patient-ventilator asynchronies with hidden markov models creation of a robust and generalizable machine learning classifier for patient ventilator asynchrony development and validation of a multialgorithm analytic platform to detect off-target mechanical ventilation the association between ventilator dyssynchrony, delivered tidal volume, and sedation using a novel automated ventilator dyssynchrony detection algorithm replicating human expertise of mechanical ventilation waveform analysis in detecting patient-ventilator cycling asynchrony using machine learning automated detection of asynchrony in patient-ventilator interaction mat-nor mb. a machine learning model for real-time asynchronous breathing monitoring interobserver reliability of the berlin ards definition and strategies to improve the reliability of ards diagnosis agreement among clinicians in the recognition of patterns of optic disk damage in glaucoma human cognitive limitations. broad, consistent, clinical application of physiological principles will require decision support publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none.author's contributions single author review by guillermo gutierrez, md, phd who has read and approved of the final manuscript. availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. key: cord- -hm tvkt authors: rasulo, frank a.; togni, tommaso; romagnoli, stefano title: essential noninvasive multimodality neuromonitoring for the critically ill patient date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: hm tvkt this article is one of ten reviews selected from the annual update in intensive care and emergency medicine . other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate . further information about the annual update in intensive care and emergency medicine is available from http://www.springer.com/series/ . technology has made huge progress within the field of medicine, where newer and more sophisticated devices have been created to assist clinicians in daily practice. many of these instruments have become either less invasive or noninvasive. such is the case for neuromonitoring, where it is now possible to apply multimodality noninvasive monitoring to derive a great deal of information necessary for both therapeutic and prognostic purposes. multimodal evaluation becomes paramount when dealing with brain injury, whether it be traumatic or nontraumatic. such is the case for monitoring of brain stem reflexes, cerebral hemodynamics, and brain function. brain stem reflexes can be evaluated through a clinical neurological exam. however, this is not always possible, due to drugs or impossibility of evoking the reflexes for inaccessible areas of the scalp or head. yet, there are reflexes that require a more precise evaluation in order to be useful. such is the case for the automated pupillary response to light, which can be done with extraordinary accuracy using pupillometry devices. cerebral hemodynamics, most commonly represented by cerebral blood flow (cbf), intracranial pressure (icp), and cerebral perfusion pressure (cpp), can now be evaluated with a good level of reliability using brain ultrasound. cerebral function can be evaluated using electrophysiological monitoring, which has become easily applicable also by neurointensivists, in part due to the development of more user-friendly devices. these three components represent the concept of essential noninvasive multimodality neuromonitoring, which we describe in this chapter. one of the most important parameters to evaluate when performing a clinical neurological examination of the brain stem reflexes is the pupillary light reflex. the pupil constricts when the light signal is carried to the tectal plate in the midbrain, then to the edinger-westphal nucleus, and then to the eye where it causes the motor fibers to contract, visualized clinically by pupil constriction. the pupillary light reflex, along with size and size differences between pupils (anisocoria), provides information regarding the functional status of both the optic and the oculomotor nerves. until recently, evaluation of the pupils was performed through simple observation of the pupil's reaction to light evoked by flashlights. similarly, the pupil's diameter and anisocoria were assessed by an approximate estimation. however, manual examination of the pupillary light reflex is subject to large inter-examiner discrepancies, as high as %, particularly when miosis is present. the discrepancy may be further increased in the presence of other confounding factors such as alcohol, drugs, or hypothermia [ ] . couret et al. observed an error rate of % and a % failure rate in the detection of anisocoria even for pupils of an intermediate size ( - mm) [ ] . larson et al. demonstrated that there was a complete failure in detecting the pupillary light reflex when manual examination was performed when the reflex amplitude was < . mm [ ] . the examiner would score the initial diameter of the pupil, followed by light stimulation. reactivity was described as present or absent, or briskly reactive versus sluggishly reactive. recently, automated infrared pupillometry has been introduced into clinical practice, quickly gaining popularity due to its quantitative precision, low cost, noninvasiveness, bedside applicability, and easy-to-use technology, contributing to a modern precision-oriented approach to medicine. with the event of this new technology, it is now possible to add important prognostic and diagnostic information to clinical practice when dealing with the patient with brain injury of various origins. a few devices are available on the market and are composed of an infrared light-emitting diode, a digital camera that captures the outer border of the iris and senses the reflected infrared light, a data processor, and a screen display showing measured variables in response to the light stimulation, in both a numerical and a graphical format (fig. ). the measured variables are size, asymmetry, constriction change to light stimulation, latency, and constriction and dilation velocity. the average reported values are shown in table . clinicians have been checking the pupils of patients with suspected or known brain injury or impaired consciousness for over years. the use of the automated pupillary light reflex has been applied in various forms of brain injury for both prognostic and diagnostic reasons. its use as a prognostic tool has been mostly studied in the comatose post-cardiac arrest patient. rossetti et al. showed that bilateral absence of the standard manual pupillary light reflex at day following cardiac arrest was a strong predictor of poor outcome [ ] . however, these patients may be under opioid sedation and the pupillary light reflex may be subject to confounding effects, therefore reducing the prognostic accuracy. behrends et al. [ ] were the first to show that quantitative pupillometry had strong prognostic predictive value during cardiopulmonary resuscitation (cpr) in in-hospital cardiac arrest patients and strong correlations between return to spontaneous circulation and quantitative pupillary were also demonstrated by yokobori et al. [ ] . pupillometry has been shown to be equally accurate in predicting poor -year outcome compared to absent reactivity on the eeg and bilaterally absent n waves on sseps [ , ] . one multicenter study recently compared quantitative automated pupillary light reflex and neurological pupillary index (npi; using the neuroptics npi- , neuroptics, laguna hills, ca) to manual pupillary light reflex in comatose cardiac arrest patients and found that an npi ≤ , performed between days and following cardiac arrest, was % specific for an unfavorable -month neurological outcome when compared to manual pupillary light reflex [ ] . pupillary light reactivity is a well-described prognostic variable in the setting of severe head injury. the literature is full of evidence demonstrating that alterations of the pupillary pupil dilation to pain pupillary dilation reflex (%) * * pupillary pain index * * depends on intensity of stimulation [ ] [ ] [ ] [ ] plr pupillary light reflex light reflex, pupil size, and/or anisocoria are correlated with outcome following traumatic brain injury (tbi) [ ] . in fact, neurosurgeons triage patients to surgical evacuation of mass lesions or conservative therapy according to the pupillary status [ ] . it has also been shown that patients who undergo prompt treatment after a new pupil abnormality, whether it be medical or surgical, have a better outcome [ ] . in patients with acute traumatic epidural hematoma and glasgow coma scale (gcs) score < , anisocoria was present in % of patients and reducing the surgery interval to < min was associated with a better outcome [ ] . tbi patients with a gcs = and fixed, dilated pupils had no chance of survival, whereas patients with a gcs = with pupils that were not fixed or dilated had an excellent survival rate [ ] . intracranial hypertension is associated with decreased npi, and patients with elevated icp had an improvement in npi values after treatment with osmotic therapy. therefore, pupillometry has the potential as a noninvasive tool to assess the efficacy of osmotic therapy [ ] . stevens et al. performed a prospective observational study on patients with tbi requiring invasive icp monitoring and showed a weak relationship between icp events and a preceding npi event. the strength of this trend appeared to diminish post-decompressive surgery [ ] . jahns et al. assessed patients with severe tbi with abnormal lesions on head computed tomography (ct) imaging who underwent parenchymal icp monitoring and repeated npi assessment through four consecutive measurements over intervals of h prior to sustained elevated icp > mmhg and found that episodes of elevated icp correlated with a concomitant decrease in npi. sustained abnormal npi was in turn associated with a more complicated icp course and worse outcome [ ] . vassilieva et al. assessed the feasibility of automated pupillometry for the detection of command following in patients with altered consciousness. they enrolled healthy volunteers and patients with a wide range of neurological disorders who were asked to engage in mental arithmetic [ ] . fourteen of ( %) healthy volunteers and of ( . %) neurological patients fulfilled pre-specified criteria for command following by showing pupillary dilations during or arithmetic tasks. none of the five sedated and unconscious icu patients passed this threshold. therefore, automated infrared pupillometry combined with mental arithmetic appears to be a promising paradigm for the detection of covert consciousness in unresponsive patients with brain injury and may have potential in the future of providing a tool that can reveal covert consciousness in patients in whom standard investigations have failed to detect signs of consciousness (fig. ). objective nociceptive assessment and optimal pain management have gained increasing attention and adequate nociceptive monitoring remains challenging in noncommunicative, critically ill adults. in the intensive care unit (icu), routine nociceptive evaluation in mechanically ventilated patients is usually carried out through scales such as the behavior pain scale (bps). however, this assessment is limited by medication use (e.g., neuromuscular blocking agents) and the inherent subjective character of nociceptive evaluation by third parties. since pupillary reflexes are submitted to controlled regulation by the autonomic nervous system, pupillometry allows the assessment of pain in patients subjected to painful stimulation. in fact, pupillary constriction is mediated by the parasympathetic system, whereas dilation is mediated by the noradrenergic sympathetic fibers that are under the influence of stimuli, including stress and pain. a painful stimulus would typically evoke a pupillary dilation reflex. the potential for application of pupillometry for pain evaluation becomes even greater when dealing with the unconscious patient, during general anesthesia for example, where pain assessment scores have no value. several studies have suggested the use of pupillometry in noncommunicative icu adults. paulus et al. demonstrated that pupillary dilation reflex evaluation may predict analgesia requirements during endotracheal aspiration [ ] . moreover, this method may be able to reveal different levels of analgesia and could have discriminatory properties regarding different types of noxious procedures [ ] . recently, scientific interest has been directed toward the use of specific protocols for pupillary dilation reflex assessment because of their low stimulation currents. the pupillary pain index protocol suggested in our approach has been previously investigated in anesthetized adults, revealing a significant correlation between pupillary dilation reflex and opioid administration [ ] . furthermore, sabourdin et al. demonstrated that pupillary dilation reflex can be used to guide individual intraoperative remifentanil administration and therefore reduce intraoperative opioid consumption and postoperative rescue analgesia requirements [ ] . bedside ultrasonography is becoming increasingly widespread in modern medicine, especially in the intensive care setting where this kind of resource is easily accessible and always available to physicians. brain ultrasonography is a safe, noninvasive way to assess brain anatomy, pathology, and intracranial blood flow. transcranial doppler was first introduced in by aaslid et al. to record flow velocity in basal cerebral arteries [ ] . advances in technology introduced transcranial colorcoded duplex ultrasonography which allows us to assess anatomical features of the brain, rather than just identify brain vessels blindly. brain ultrasonography can be applied in different settings, even outside of neurosurgical icus: stroke units, enabling physicians to assess the effectiveness of a fibrinolytic therapy, and operating rooms for monitoring cbf during carotid vascular surgery are just some examples of its potential. despite being less reliable compared to ct scans and magnetic resonance imaging (mri), transcranial colorcoded duplex ultrasonography is a useful tool to monitor intracranial lesions, such as hematomas, which might cause a midline shift. it might even enable the clinician to assess the ventricles and parenchyma in selected patients with a good acoustic window [ ] . there are four main acoustic windows accessible for brain ultrasonography, usually performed with a - . mhz probe (fig. ): . transtemporal approach: between the tragus and the lateral orbit wall, with the probe marker facing toward the eye. the first landmark is the contralateral skull, which is normally around cm deep. the midbrain (fig. left panel) appears as a hypoechoic shaped heart in the middle of the scan. once found, the power doppler can be selected to explore the circle of willis. this approach is generally used to identify midline shifts (when scanning the third ventricle, which appears as a hypoechoic band between two hyperechoic lines, as shown in fig. ) and assess blood flow (fig. ). . transorbital approach: through transorbital ultrasonography it is possible to assess the optic nerve sheath diameter (fig. ) , as well as blood flow in the ophthalmic artery. occipital approach: the landmark for this approach is cm below the external occipital protuberance, aiming forward and superiorly (toward the eyes), starting with a large scale ( - cm); the anatomic landmarks which can be seen with ultrasound are the clivus (hyperechoic structure) and the foramen magnum (hypoechoic). using the power doppler function, it is possible to scan for both vertebral arteries ending the basilar artery (fig. ). submandibular approach: the submandibular window allows assessment of the extracranial and intracranial or extradural segment of the internal carotid artery. the probe should be placed at the angle of the mandible, directed slightly medially and posteriorly. the internal carotid artery can usually be identified at a depth of - mm. the optic nerve sheath diameter is a good surrogate measurement for icp [ ] ; cutoffs > . cm correlate well with an icp > mmhg. this noninvasive, quick, repeatable way to assess icp carries a sensitivity of . and therefore a good level of diagnostic accuracy to quickly detect increased icp [ ] . using a linear probe placed transversally over the closed eyelid of the patient, the clinician can scan the optic nerve behind the eye, as a hypoechoic structure extending posteriorly from the retina. measurements of its diameter should be taken mm from the globe perpendicularly (as shown in fig. ) , using an electronic caliper. the rationale behind this technique is related to the anatomy of the optic nerve, which originates directly from the central nervous system (cns) and is surrounded by the meningeal sheaths and cerebrospinal fluid (csf): increases in icp shift csf into this space, which increases in diameter. this easy and repeatable technique carries one important pitfall, which is the artifact created by the retinal artery. this vessel runs close to the nerve and might appear as a hypoechoic bump that is particularly difficult to distinguish from the optic nerve. when any suspicion arises, color doppler mode should be used to evaluate the presence of blood flow. icp can be estimated using brain ultrasonography, through a transtemporal approach, assessing blood flow in the middle cerebral artery. the formula used was first introduced by czosnyka et al. in [ ] , originally to estimate cpp noninvasively: the third ventricle appears as a hypoechoic band between two hyperechoic lines where map is the mean arterial pressure, fvd the diastolic flow velocity, and fvm the mean flow velocity. however, given that map-icp=cpp, the formula can be written as evidence shows that this method can accurately exclude intracranial hypertension in patients with acute brain injury. the best icp threshold estimated was . mmhg, which carried a sensitivity of % and a specificity of . % [ ] . another useful tool to consider while estimating icp using this technique is the pulsatility index. this is calculated as the difference between systolic and diastolic flow velocities, divided by the mean velocity. many studies have supported the interpretation of the pulsatility index as a tool to reflect distal cerebrovascular resistances, attributing a higher pulsatility index to higher cerebrovascular resistances [ ] . however, the pulsatility index is not dependent solely on cerebrovascular resistances, but its value is the result of an interplay between cerebrovascular resistances, cpp, and compliance of the arterial bed. some authors consider this parameter as less reliable for estimation of icp [ ] , and it should therefore be used together with other noninvasive methods for estimation of icp (transcranial color-coded duplex ultrasonographyoptic nerve sheath diameter, as already described). vasospasm after aneurysmal subarachnoid hemorrhage (sah) is the main cause of delayed cerebral ischemia and is associated with severe mortality and morbidity. guidelines agree on the importance of monitoring blood flow velocities noninvasively [ ] . transcranial doppler and transcranial color-coded duplex ultrasonography play a pivotal role in the detection of this complication after aneurysmal sah. monitoring mean flow velocities is not enough, as an increase in flow velocity does not necessarily imply arterial narrowing. to differentiate this from cerebral hyperemia, lindegaard et al. [ ] introduced a ratio between either the middle cerebral artery fig. the circle of willis, as scanned from a transtemporal approach in a patient who underwent a decompressive craniectomy. the different shapes of the arterial flows are shown in the picture fig. the optic nerve sheath diameter can be measured using a transorbital approach fig. an occipital approach to assess vertebral and basilar blood flow. landmarks are the hyperechoic clivus and hypoechoic foramen magnum or the anterior cerebral artery and the internal carotid artery, using a threshold of as a diagnostic criterion. a lindegaard ratio of or above was diagnostic for vasospasm, a lindegaard ratio of less than indicated hyperemia, and a lindegaard ratio of was highly predictive of severe vasospasm. a blunt increase in flow velocities of cm/s or more within h is also predictive of vasospasm. in , a modified lindegaard ratio was published for the assessment of basilar vasospasm as a ratio between basilar artery and extracranial vertebral artery, using a cutoff of to differentiate between vasospasm and hyperemia [ ] . midline shift can be effectively determined using the transtemporal window, axial plane on ultrasound. the main landmarks are the contralateral skull bone and the mesencephalon, and once those are found and centered in the image, the probe can be tilted cranially °until the third ventricle appears in the middle of the scan (diencephalic plane), as two parallel hyperechoic lines in the middle of the field, according to the technique described by seidel et al. in [ ] . having identified the third ventricle, the clinician should use an electronic caliper to measure the distance between the ventricle and the inner part of the skull bone, bilaterally. the difference between the two measurements divided by two is the estimation of the midline shift. this relates well with the midline shift measured on ct scan (compared with the bland-altman method), regardless of the cause of the shift (spaceoccupying lesion, hematoma) [ ] (fig. ) . digital subtraction angiography is considered the gold standard for the confirmation of cerebral circulatory arrest and brain death. however, it requires transport of a hemodynamically unstable patient to the radiology suite to perform an invasive procedure. cbf can be assessed using transcranial doppler. increased icp blunts diastolic flow velocities and, when icp equals the diastolic arterial blood pressure, flow velocity becomes zero. when icp increases even further, there is a backflow of blood during the diastolic phase. this phenomenon is called reverberating flow, after diastolic peak blood flows in the opposite direction, and can be assessed with transcranial doppler. brunser et al. reported that power mode transcranial doppler had high sensitivity and specificity for diagnosis of brain death, respectively % and % (flow velocity was assessed in the middle cerebral artery using a transtemporal approach) [ ] (fig. ). precision medicine represents "a new era of medicine through research, technology, and policies that empower patients, researchers, and providers to work together toward development of individualized care." with these words, barack obama, former president of the united states, launched the precision medicine initiative on january , . funds were dedicated to creating treatments tailored to individual patients' biologic (genetic and molecular) profiles. interestingly, current attempts toward standardization of care-protocols, checklists, algorithms, evidence-based medicine, guidelines, consensus papers, and enhanced recovery after surgery programs-challenge precision medicine. while protocols provide guidelines derived from strong evidence that decreases standard variability of care, eventual personalization discovered through clinical algorithms may provide better outcomes [ ] . drug response to sedatives and hypnotics is just one example of interindividual variability related to pharmacogenomics. in this light, identification of the correct dose of sedatives for optimal sedation in the icu, through proper monitoring and within specific institutional protocols, matches well with the concept of precision and personalized medicine. intensivists continuously monitor their patients' organs and systems during the icu stay: of the cardiovascular system using invasive and noninvasive methods; the respiratory system using blood gas and ventilator curve analysis; and renal function using urine output, creatinine, and biomarker levels. the brain is the main target of the sedatives frequently administered to critically ill patients, but no monitor is usually applied to monitor their effect on brain electrical activity, at least outside the neuro-icu. the main reason for this reality is that electroencephalography (eeg) [ ] is a complex investigation system that few intensivists can interpret. technological evolution has developed a variety of fig. reverberating flow in a patient with severe brain injury who developed an isoelectric encephalogram trace minutes after this recording and was confirmed brain dead a few hours later (simplified) eeg-derived indices that can be used to make this information more available. use of processed eeg indices has been shown to improve intraoperative anesthetic titration during anesthesia but also sedation in the icu: bispectral index [bis, medtronic, boulder, co), e-entropy (ge healthcare, helsinki, finland), narcotrend (narcotrend gruppe, hannover, germany), masimo sedline (sedline, masimo corp, irvine, ca), and neurosense (neurowave systems, inc., cleveland heights, oh) are a few examples of the tools now available on the market (fig. ). there is as yet no evidence for superiority of one device over the others and differences in trace visualization, shape and characteristics of the sensor, institutional habits, and budgets are the main reasons for operator choice [ ] . a detailed description of the eeg signal recording and processing is beyond the aim of this chapter, and the reader is referred to dedicated articles [ ] . briefly, subcortical regions (e.g., the thalamus) produce small potentials that cannot be identified from electrodes placed on the scalp because an electric field decreases in strength by the square of the distance from its source (fig. ) . however, because of the close and continuous interconnection between superficial and deep brain structures, surface eeg reflects the states of both cortical and subcortical areas. dedicated monitors that automatically elaborate the frontal eeg trace are needed because a full-montage eeg during sedation requires cumbersome equipment and specialized training, not available to all intensivists. moreover, a frontal processed eeg trace is considered reliable for the purposes of anesthesia/sedation monitoring even if some clinical conditions (see later) eventually require some knowledge of basic eeg principles. processed eeg monitors deliver three main pieces of information: ( ) the raw trace, ( ) the numerical index of anesthesia/sedation depth, and ( ) the d spectrogram (fig. ) . the reader is referred to dedicated articles for details about the specific parameters [ ] . processed eeg was originally intended for the management of the anesthetic state during surgery to avoid accidental awareness and to titrate sedation in critically ill patients where clinical scales represent the gold standard. the inclusion of processed eeg into many multiparametric icu monitors reflects the perceived need for icu caregivers to use a comprehensive approach in the management of sedated patients. deep sedation is clearly associated with poor short-and long-term outcomes in critically ill patients: prolonged mechanical ventilation and cognitive and psychological complications all increase hospital and icu length of stay and mortality [ ] . although light sedation, with patients being able to communicate and cooperate at any time, represents a modern target of sedation and a standard of care in icus, moderate-to-deep sedation (e.g., a richmond agitation-sedation scale [rass] ≤ ) may be needed in a nonnegligible number of patients, including those with alcohol weaning syndromes complicated by uncontrolled agitation; complex ventilator-patient desynchrony; refractory status epilepticus; intracranial hypertension; patients receiving neuromuscular blocking agents; postsurgical patients requiring hemodynamic, temperature, or bleeding stabilization; post-cardiac arrest therapy (post-resuscitation care); or tbi. in these categories of patients, clinical scales (e.g., rass, riker sedation-agitation scale [sas]), unless they represent standardized assessment of sedation levels, cannot be applied. moreover, they are commonly evaluated every - h, and may not detect periods of inadequate sedation occurring between assessments, whereas processed eeg is a continuous method of analysis. in addition, clinical scale assessment is performed by disturbing sedated or sleeping patients (processed eeg does not require modification of the sedation state) and can never identify phases of burst suppression or isoelectric traces (total suppression) [ ] , which are associated with negative outcomes (e.g., delirium occurrence, prolonged mechanical ventilation, mortality). in this context, in a post hoc analysis of a prospective observational study performed in icu patients under mechanical ventilation, burst suppression occurred in % of the cases and was an independent predictor of increased risk of death at months [ ] . processed eeg values can vary greatly in patients sedated in the icu because, unlike those undergoing painful surgery, patients in the icu may not experience strong stimulation and therefore require relatively low levels of sedation, appearing calm with bis values of around - . clinical procedures, spontaneous patient arousal, physiological sleep cycles, noise, and nursing activities may cause sedation levels to fluctuate. what is important to consider is that muscle activity (mainly) and electric devices (less frequently) may interfere with the ability of the system to process the raw trace, leading to falsely increased sedation indexes [ ] . in order to limit this sort of artifact the companies are improving their devices keeping them more "resistant" to emg interference. in a change from the previous version published in , the recent international guidelines on sedation practice in the icu [ ] (clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the icu) report that processed eeg monitoring systems, although best suited for sedative titration during deep sedation or for patients who receive neuromuscular blockade, may also have potential benefits in lighter sedation states and that processed eeg monitoring, compared with the standard clinical scales, may improve sedative titration [ ] . using processed eeg systems as an objective guide for sedative dosing in critically ill patients can decrease the medical complications of oversedation, such as depressed cardiac contractility and hypotension. there are few studies on processed eeg monitoring in the icu. the first was a prospective trial that randomized patient sedation to be assessed using the ramsay scale or bis monitoring during propofol sedation that was stopped every h [ ] . a nurse-guided ramsey score of was the target in controls, and a bis value of - was the target for the study group. a reduction in propofol of % was obtained in the bis group versus controls. the second study [ ] was a prospective randomized trial in which patients sedated with morphine and midazolam were randomized to sedation titration based on a bis > versus clinical assessment. no difference was found in the total amount of administered sedative drugs, length of mechanical ventilation, or icu length of stay. in a recent study on trauma patients, use of bis resulted in a decrease in sedation and analgesia use, decrease in agitation, less failure to extubate, and fewer tracheostomies, with an approximate -day decreased length of stay [ ] . beyond its use for sedative titration purposes, processed eeg may have some additional applications in icu patients, including identification of subclinical/ unrecognized seizures or seizures occurring when neuromuscular blocking agents are administered. nevertheless, depending on the frequencies of the ictal waveforms, processed eeg may have variable values that only skilled intensivists are able to read on the raw eeg trace to successfully understand this clinical condition. processed eeg monitors can also be used to guide therapy aimed at minimizing cerebral metabolism rate to reach predefined levels of burst suppression [ ] . a significant proportion of critically ill patients with altered mental status have nonconvulsive subclinical seizures and nonconvulsive status epilepticus [ ] . continuous eeg assessment for nonconvulsive subclinical seizures and nonconvulsive status epilepticus in patients with altered mental status can be indicated in patients with a history of epilepsy, fluctuating level of consciousness, acute brain injury, recent convulsive status epilepticus, stereotyped activity such as paroxysmal movements, nystagmus, twitching, jerking, hippus, and autonomic variability [ ] . nonconvulsive subclinical seizures, seizures with little or no overt clinical manifestations, can be detected with eeg monitoring. noninvasive neuro-multimodality monitoring is now possible. we present an essential bundle of noninvasive neuromonitoring composed of pupillometry, brain ultrasound, and processed eeg. although some of these noninvasive tools are not yet reliable enough to completely substitute invasive monitoring, they do represent an important adjunct for the clinician in both neuroanesthesia and neurocritical care environments. we have only described the basic features and the potential that transcranial color-coded duplex doppler and brain ultrasonography have to offer to the clinician. bedside ultrasounds are becoming increasingly popular with clinicians because they are quick, reliable, and repeatable. while not yet being a substitute for invasive icp monitoring, ultrasound can give the clinician useful information when indications for such invasive devices are blurred or contraindicated (liver failure, anticoagulation). moreover, it has become a mainstay for the early detection of vasospasm in patients with aneurysmal sah. in the emergency department, expanding focused assessment with sonography in trauma (fast) assessment to brain ultrasound may enable the physician to become aware of increased icp even before the patient is transported for a ct scan, and prompt early neuroprotective medical intervention. eeg is a fundamental tool for monitoring human brain electrical activity during changing states of consciousness like sleep, sedation, or general anesthesia. processed eeg may contribute to help anesthesiologists and intensivists optimize drug doses in individuals with different pharmacogenomics and clearance of sedatives. processed eeg devices are not simple plug-and-play units providing a wellinterpretable dimensionless number. they require a global knowledge of technology and of eeg tracings to avoid misinterpretation, especially when muscle activity interferes with the processing algorithm. the use of processed eeg in the icu could be much more complex than during anesthesia in the operating rooms. nevertheless, processed eeg monitors offer advantages in the management of patients under moderate and deep sedation and in patients receiving neuromuscular blocking agents to avoid both awareness and burst suppression. some pathological states, such as seizures or altered eeg states (iatrogenic burst suppression or areflexic coma), may be revealed by processed eeg and trigger a complete eeg examination. pupil examination: validity and clinical utility of an automated pupillometer reliability of standard pupillometry practice in neurocritical care: an observational, double-blinded study pupillometric analysis of the 'absent light reflex neurological prognostication of outcome in patients in coma after cardiac arrest infrared pupillometry to detect the light reflex during cardiopulmonary resuscitation: a case series quantitative pupillometry and neuronspecific enolase independently predict return of spontaneous circulation following cardiogenic out-of-hospital cardiac arrest: a prospective pilot study quantitative versus standard pupillary light reflex for early prognostication in comatose cardiac arrest patients: an international prospective multicentre double-blinded study variation in monitoring and treatment policies for intracranial hypertension in traumatic brain injury: a survey in neurotrauma centers participating in the center-tbi study infrared pupillometry during uncal herniation prognosis and clinical relevance of anisocoria-craniotomy latency for epidural hematoma in comatose patients use of admission glasgow coma score, pupil size, and pupil reactivity to determine outcome for trauma patients effects of osmotic therapy on pupil reactivity: quantification using pupillometry in critically ill neurologic patients optical pupillometry in traumatic brain injury: neurological pupil index and its relationship with intracranial pressure through significant event analysis quantitative pupillometry for the monitoring of intracranial hypertension in patients with severe traumatic brain injury automated pupillometry to detect command following in neurological patients: a proof-of-concept study pupillary reflex measurement predicts insufficient analgesia before endotracheal suctioning in critically ill patients reflex pupillary dilatation in response to skin incision and alfentanil in children anaesthetized with sevoflurane: a more sensitive measure of noxious stimulation than the commonly used variables pupillary dilation reflex and pupillary pain index evaluation during general anaesthesia: a pilot study pupillometry-guided intraoperative remifentanil administration versus standard practice influences opioid use: a randomized study noninvasive transcranial doppler ultrasound recording of flow velocity in basal cerebral arteries transcranial color-coded duplex sonography fir bedside monitoring of central nervous system infection as a consequence of decompressive craniectomy after traumatic brain injury non-invasive intracranial pressure assessment in brain injured patients using ultrasound-based methods optic nerve sheath diameter on computed tomography is correlated with simultaneously measured intracranial pressure in patients with severe traumatic brain injury cerebral perfusion pressure in head-injured patients: a noninvasive assessment using transcranial doppler ultrasonography the accuracy of transcranial doppler in excluding intracranial hypertension following acute brain injury: a multicenter prospective pilot study transcranial doppler pulsatility in vasodilation and stenosis consensus summary statement of the international multidisciplinary consensus conference on multimodality monitoring in neurocritical care cerebral vasospasm after subarachnoid hemorrhage investigated by means of transcranial doppler ultrasound basilar vasospasm diagnosis: investigation of a modified "lindegaard index" based on imaging studies and blood velocity measurements of the basilar artery transcranial color-coded duplex sonography for evaluation of midline-shift after chronic-subdural hematoma evacuation (temase): a prospective study accuracy of power mode transcranial doppler in the diagnosis of brain death standardized care versus precision medicine in the perioperative setting: can point-of-care testing help bridge the gap? a primer for eeg signal processing in anesthesia electroencephalography and brain oxygenation monitoring in the perioperative period the technology of processed electroencephalogram monitoring devices for assessment of depth of anesthesia electroencephalogram signatures of loss and recovery of consciousness from propofol sedation depth and long-term mortality in mechanically ventilated critically ill adults: a prospective longitudinal multicentre cohort study bispectral index can reliably detect deep sedation in mechanically ventilated patients: a prospective multicenter validation study presence of electroencephalogram burst suppression in sedated, critically ill patients is associated with increased mortality different conditions that could result in the bispectral index indicating an incorrect hypnotic state clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the icu a randomized evaluation of bispectral index-augmented sedation assessment in neurological patients the impact of bispectral index monitoring on sedation administration in mechanically ventilated patients utility of bispectral index in the management of multiple trauma patients can bis monitoring be used to assess the depth of propofol anesthesia in the treatment of refractory status epilepticus? prevalence of nonconvulsive status epilepticus in comatose patients continuous electroencephalogram monitoring in the intensive care unit publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations each author (far, tt, sr) has made substantial contributions to the conception, design of the work, drafted the work and substantively revised it. all authors, (far, tt, sr) have approved the submitted and final version of the manuscript (and any substantially modified version that involves the author's contribution to the study) all authors, (far, tt, sr) have agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature. publication costs were funded by the corresponding author's private university funds (university of brescia, italy). ethics approval and consent to participate not applicable. not applicable. the authors declare that they have no competing interests.author details key: cord- -zhessjqh authors: bawazeer, mohammed; amer, marwa; maghrabi, khalid; alshaikh, kamel; amin, rashid; rizwan, muhammad; shaban, mohammad; de vol, edward; hijazi, mohammed title: adjunct low-dose ketamine infusion vs standard of care in mechanically ventilated critically ill patients at a tertiary saudi hospital (attainment trial): study protocol for a randomized, prospective, pilot, feasibility trial date: - - journal: trials doi: . /s - - - sha: doc_id: cord_uid: zhessjqh background: a noticeable interest in ketamine infusion for sedation management has developed among critical care physicians for critically ill patients. the pain, agitation/sedation, delirium, immobility, and sleep disruption guideline suggested low-dose ketamine infusion as an adjunct to opioid therapy to reduce opioid requirements in post-surgical patients in the intensive care unit (icu). this was, however, rated as conditional due to the very low quality of evidence. ketamine has favorable characteristics, making it an especially viable alternative for patients with respiratory and hemodynamic instability. the analgo-sedative adjunct ketamine infusion in mechanically ventilated icu patients (attainment) trial aims to assess the effect and safety of adjunct low-dose continuous infusion of ketamine as an analgo-sedative compared to standard of care in critically ill patients on mechanical ventilation (mv) for ≥ h. methods/design: this trial is a prospective, randomized, active controlled, open-label, pilot, feasibility study of adult icu patients (> years old) on mv. the study will take place in the adult icus in the king faisal specialist hospital and research center (kfsh&rc), riyadh, saudi arabia, and will enroll patients. patients will be randomized post-intubation into two groups: the intervention group will receive an adjunct low-dose continuous infusion of ketamine plus standard of care. ketamine will be administered over a period of h at a fixed infusion rate of μg/kg/min ( . mg/kg/h) in the first h followed by μg/kg/min ( . mg/kg/h) in the second h. the control group will receive standard of care in the icu (propofol and/or fentanyl and/or midazolam) according to the kfsh&rc sedation and analgesia protocol as clinically appropriate. the primary outcome is mv duration until icu discharge, death, extubation, or days post-randomization, whichever comes first. discussion: the first patient was enrolled on september . as of october , a total of patients had been enrolled. we expect to complete the recruitment by december . the findings of this pilot trial will likely justify further investigation for the role of adjunct low-dose ketamine infusion as an analgo-sedative agent in a larger, multicenter, randomized controlled trial. trial registration: clinicaltrials.gov: nct . registered on august . current controlled trials: isrctn . registered on february . sedation and analgesia management are both integral components of care in the intensive care unit (icu). although benzodiazepines have been the mainstay therapy for sedation in critically ill patients, their use has declined in recent years, with favoring of nonbenzodiazepines, such as propofol and dexmedetomidine. this change in practice is based on studies demonstrating the association between the sustained use of benzodiazepines and increased mechanical ventilation (mv) duration, icu length of stay (los), and development of delirium. a paradigm shift has therefore occurred in the management of patients' sedation in the icu. maintenance of light levels of sedation in adult patients in the icu has been recommended to improve patient clinical outcomes, such as shorter duration of mv and shorter icu los [ ] . a noticeable interest in ketamine infusion for sedation management in critically ill patients has developed among critical care physicians [ ] . the pain, agitation/sedation, delirium, immobility, and sleep disruption (padis) guideline suggested low-dose ketamine as an adjunct to opioid therapy for reducing opioid consumption in post-surgical adults admitted to the icu (i.e., conditional recommendation, very low quality of evidence) [ ] . in a single-center, double-blind, randomized controlled trial (rct) of icu post-abdominal surgery patients, adjunctive ketamine was associated with a reduced intake of morphine. however, there were no differences in patients' self-reported pain intensity [ ] . ketamine was administered as . mg/kg intravenous (iv) push followed by infusion of μg/kg/min ( . mg/kg/h) × h, then μg/kg/ min × h ( . mg/kg/h). the incidence of side effects (i.e., nausea, delirium, hallucination, hypoventilation, pruritus, and sedation) did not differ between the ketamine and opioidalone groups. based on this generally positive icu rct, the padis panel made a conditional recommendation for the use of low-dose ketamine as an adjunct to opioids to optimize acute post-operative pain management in critically ill adults (refer to supplementary table : previous ketamine trials in the icu setting) [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . because of an increased focus on ensuring that pain is appropriately controlled in patients before using sedative-hypnotic medications (also known as the analgo-sedation approach), ketamine has gained attention for its unique pharmacologic properties that could address both the analgesic and sedative requirements. ketamine could result in decreased duration of mv while providing optimal levels of sedation [ ] . similar to dexmedetomidine, ketamine has a non-gabaergic mechanism of action [ ] . it induces rapid sedation and analgesia through dual mechanisms mediated by inhibition of the n-methyl-d-aspartate receptor and activation of the opioid μand κ-receptors [ ] . ketamine is also saudi food and drug authority (fda)-approved for the induction of anesthesia and has been used for acute and chronic pain in sub-anesthetic dose, post-operative opioid sparing, rapid sequence intubation, and procedural sedation and analgesia [ ] . additionally, ketamine has favorable characteristics, including bronchodilation, preservation of cardiac output, increase in blood pressure, minimal effects on bowel motility, and maintaining of respiratory drive and airway reflexes while actively weaning from mv; these features make it an especially viable alternative for patients with respiratory and hemodynamic instability [ ] . although commonly used sedatives are effective, they have side effects including benzodiazepine-associated delirium, opioid-induced constipation, and the negative hemodynamic effect caused by propofol and dexmedetomidine [ , [ ] [ ] [ ] . the most frequently observed adverse effects associated with ketamine when used to maintain sedation include tachycardia ( . %), hypertension ( %), paradoxical agitation (up to %), and hypersalivation ( %) [ ] . although there is limited literature on adults, as many as % of pediatric patients who receive ketamine for continuous sedation experience the emergence phenomenon, including vivid hallucinations and delirium during or after ketamine use [ ] . when ketamine is used for procedural sedation in adults (usually administered as a relatively high dose, - mg/kg repeated q - min to maximum mg), up to % of patients may develop the emergence phenomenon [ ] . risk factors for delirium with ketamine include prior history of psychiatric disorders, dementia, and the use of a high dose in procedural sedation [ ] . the development of the emergence phenomenon can cause patients to transiently require higher amounts of other sedatives, usually benzodiazepines. however, ketamine-based analgo-sedation in mv patients administered as a subanesthetic/sub-dissociative/low dose results in similar numbers of delirium-and coma-free days as those in non-ketamine-based regimens, as shown in a retrospective cohort study conducted by shurtleff et al. at an academic medical center [ ] . ketamine infusion in this trial was μ g/ kg/min ( . mg/kg/h) titrated using μ g/kg/min every min up to a maximum of μ g/kg/min ( . mg/kg/h). the authors found that the number of days alive without delirium or coma was days (interquartile range [iqr] - days) with ketamine and days (iqr - days) with a non-ketamine medication (p = . ). delirium occurred in of the patients ( %) with ketamine and in of the patients ( %) with the non-ketamine drug (p = . ). similarly, the rct cited by the padis guideline showed that the incidence of side effects (i.e., delirium and hallucinations) did not differ between the ketamine and opioid-alone groups [ ] . at king faisal specialist hospital and research center (kfsh&rc), continuous infusions of sedatives and analgesics are prescribed at the physician's discretion and titrated to achieve richmond agitation-sedation scale (rass) and pain scores; the infusions are performed with a nurse-driven protocol. the protocol promotes analgesia-first sedation (with fentanyl) and recommends propofol as the first-line agent when sedation is required. patients receive a daily spontaneous awakening trial (sat) paired with a spontaneous breathing trial (sbt). the rass and the confusion assessment method for the icu (cam-icu) are routinely used to assess the level of sedation and the presence of delirium, respectively. ketamine, registered by the ministry of health of saudi arabia, is a kfsh&rc hospital formulary medication and is listed in the kfsh&rc icu pain and sedation protocol as an option for patients with severe bronchospasm. however, the order or the combination that could be most effective with ketamine is unclear (refer to supplementary figure : kfsh&rc new sedation protocol for adult icus). as stated previously, the padis guideline listed ketamine as a conditional recommendation, with very low quality of evidence (limited high-level evidence). most trials listed in supplementary table are in surgical icu settings, retrospective in nature, or are rcts focused on comparing ketamine to placebo or two study drugs (e.g., ketamine vs opioid). however, most patients in the icu are sedated with a combination of drugs. moreover, most trials had a limited focus on patientcentered outcomes, such as duration of mv or icu los, as the primary outcome favoring surrogate outcomes, such as sedation scores and changes in analgesics and sedatives [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . to help further delineate ketamine's role as a maintenance analgo-sedation agent in the icu, further rcts need to be conducted to compare the effects of ketamine to those of other analgesics and sedatives on reducing the duration of mv, icu los, and delirium occurrence. recently, there was a prospective, double-blinded, multicenter rct (kemimof) in critically ill patients > years old and requiring sedation for > h in the icu, in uganda. patients were randomized to receive either ketamine-midazolam or morphinemidazolam given as premixed -ml syringes for infusion. the primary outcome measures were duration of mv, incidence of hypotension, and incidence of delirium. the trial was terminated on august with pending results. limitations of this trial are the use of premixed syringes, which are not typically used in adult icu sedation practice, and the focus on comparing two study drugs (ketamine vs morphine) [ ] . robust clinical outcome data and comprehensive assessments of adverse events (aes) associated with ketamine use in mechanically ventilated patients are limited, leaving a significant knowledge gap, which has been reflected in the wide variation in the use of ketamine as a sedative agent in icus. this is also highlighted in a recent systematic review and meta-analysis by manasco et al. [ ] . therefore, we propose a prospective, randomized, active controlled, open-label, pilot, feasibility study to assess the effect and safety of analgo-sedative ad-junct ketamine infusion in mechanically ventilated icu patients (the attainment trial) compared to standard of care alone. we hypothesized that low-dose ketamine infusion will reduce the duration of mv with an acceptable safety profile compared to standard of care. the findings of this pilot trial will likely justify further investigations on the role of adjunct low-dose ketamine infusion as an analgo-sedative and inform the design of a large multicenter rct with sufficient power to detect differences in clinical outcomes. the primary objective the primary objective is to study the feasibility and effect of adjunct low-dose ketamine infusion on mv duration compared to the standard of care alone in critically ill patients. secondary objectives are to study the effect of adjunct low-dose ketamine infusion on the following: . the cumulative dose of pain and sedative medications . the incidence of dexmedetomidine use postrandomization . the number of patients within rass and pain score goals . the hemodynamic status in terms of vasopressor therapy requirement . icu and hospital los . tracheostomy, unplanned extubation, and reintubation rates . the incidence of delirium and rate of positive cam-icu assessment . the rate of antipsychotic use for icu-acquired delirium . the rate of hypersalivation and frequent suctioning . the rate of using physical restraint . mortality rate at days. the attainment trial is a prospective, randomized, open-label, active controlled, parallel group, pilot, feasibility, phase study of adult patients admitted to the kfsh&rc adult icus, riyadh, saudi arabia. this trial is approved by the institutional review board (irb) of the kfsh&rc. the trial is registered in clinicaltrials.gov: nct , current controlled trials: isrctn , and saudi food and drug authority: sctr # . the protocol adheres to the standard protocol items: recommendations for interventional trials (spirit) guidelines (see supplementary file and supplementary table ). the inclusion criteria are as follows: adult patients (> years old) on mv admitted to one of the following icus: medical, surgical, or transplant/oncology icu intubated within the previous h expected to require mv for more than h expected to be on the kfsh&rc icu sedation and pain protocol no objection from the icu attending physician for enrollment the exclusion criteria are: patients with a history of dementia or psychiatric disorders or those on any antipsychotic or antidepressant medications at home pregnancy age < years old expected to need mv < h known hypersensitivity to ketamine patients with expected targeted rass score of − , e.g., patients on continuous infusion neuromuscular blockade patients on dexmedetomidine as the primary sedative prior to randomization patients with cardiogenic shock, acute decompensated heart failure, or myocardial infarction history of end-stage liver failure (child-pugh score c) proven or suspected primary neurological injury (traumatic brain injury, ischemic stroke, intracranial hemorrhage, spinal cord injury, anoxic brain injury, brain edema) patients with persistent heart rate (hr) > beats per minute (bpm) or systolic blood pressure (sbp) > mmhg patients identified as do not resuscitate (dnr) or those expected to die within h patients on extracorporeal membrane oxygenation (ecmo) patients with refractory status epilepticus who are receiving ketamine infusion proven or suspected status asthmaticus. the study is conducted according to good clinical practice guidelines. the study protocol as well as the informed consent have been approved by the research ethics committee (rec) and clinical research committee (crc) at kfsh&rc with research advisory council (rac) number . once an eligible patient is identified, study investigators start the consenting process to explain the objectives of the trial and its potential risks and benefits to the patient's surrogate decision-maker. a verbal consent from a guardian/next of kin over the phone is considered to allow randomization and initiation of timely intervention when written authorization cannot be secured in sufficient time (within h of intubation). verbal consent is documented in medical records to indicate the research subject's acceptance to participate in the study. a prospective written consent is obtained thereafter from the patient (if extubated) or the patient's guardian/next of kin once they become available. patients will be randomized into two groups: the intervention group will receive an adjunct low-dose continuous infusion of ketamine plus the standard of care in the icu. ketamine will be administered over a -h period at a fixed infusion rate of μg/kg/min ( . mg/kg/h) for the first h followed by μg/kg/min ( . mg/kg/h) in the second h. the control group will receive the standard of care in the icu, where propofol and/or fentanyl and/or midazolam will be given according to the kfsh&rc icu sedation and analgesia protocol as clinically appropriate. other aspects of care in both groups, including rass goal, sat, sbt, mobilization, and non-pharmacological interventions to promote comfort and facilitate sleep, will be left to the discretion of the icu attending physician. please refer to fig. : study methodology. the intervention may be stopped in the following situations (see table for more details): the icu team deemed that excessive sedation is persisting after holding or decreasing the other sedatives (propofol and/or fentanyl and/or midazolam) and the patient is not in target rass. adverse effects: persistent tachycardia with hr > for ≥ h, persistent hypertension with sbp > for ≥ h, uncontrolled agitation (removing tubes and lines) and combative behavior. patient died or goals of care changed to comfort care. patient is weaned off sedation and/or extubated. patients will be randomly assigned to one of two study groups in a : ratio by a computer-generated randomization list created by an independent biostatistician; no stratification will be performed. our initial screening and eligibility assessment is done by bedside icu nurses who are blinded to treatment assignment. to further ensure allocation concealment, access to the randomization will be restricted to a pharmacist (third party and not part of the study) to whom principal investigators refer at a distance (by telephone) to know the assigned treatment. the study investigators and study participants during the recruitment and consenting process will be blinded to the treatment assignment. once the consenting process is complete, the principal investigators will contact the pharmacist (third party) for patient table intervention stopping rules and protocol deviation events action regarding the intervention (ketamine) action regarding the study procedure (data collection and data analysis) completed h ketamine will be discontinued (intended duration for this trial is h). continuation of ketamine or other analgesics and sedatives for more than h will be left to the treating physicians, but will not be related to the research purpose subject will be included in the data analysis positive cam-icu score for delirium and hallucination within the first h ketamine will be continued, and delirium treatment (nonpharmacological and antipsychotic use) will be left to the treating physicians. in cases of uncontrolled agitation (removal of tubes and lines and combative behavior) within the first h, ketamine will be discontinued (refer to protocol deviation below) subject will be included in the data analysis (safety outcome data) use of physical restraint within the first h ketamine will be continued unless uncontrolled agitation (removal of tubes and lines and combative behavior) within the first h, in which case ketamine will be discontinued (refer to protocol deviation below) subject will be included in the data analysis (safety outcome data) hypersalivation and frequent suctioning within the first h ketamine will be continued and management of hypersalivation will be left to the treating physicians subject will be included in the data analysis protocol deviation (patient did not complete the intended duration of the trial (i.e., h) ketamine will be discontinued all information will be removed and not included in the analysis (modified intentionto-treat principle) patient extubated and sedation weaned off within the first h ketamine will be discontinued subject will be included in the data analysis if the icu team believed the patient is not in target for rass within the first h when the patient is deemed to be excessively sedated after receiving ketamine and other sedatives (propofol and/or fentanyl and/or midazolam), the other sedatives will be held first (or decreased) and ketamine will be continued until the subject reaches the team's desired rass goal. in situations where excessive sedation persisted and the patient is not yet in target rass, then ketamine will be discontinued when the patient is deemed to be agitated after receiving ketamine and other sedatives (propofol and/or fentanyl and/or midazolam), the other sedatives will be increased, use as needed boluses, or add dexmedetomidine. the decision to continue or discontinue ketamine infusion will be left to the discretion of the treating physicians subject will be included in the data analysis persistent tachycardia with hr > for > h within the first h if the icu treating physicians believes that ketamine is the primary causative factor, ketamine will be discontinued and patient will be followed up for h. detailed documentation will be carried out in the medical record for adverse event, severity of event, recovery from event, group allocation, and relation to study protocol subject will be included in the data analysis ketamine will be discontinued subject will be included in the data analysis (safety outcome data) physician decline after randomization ketamine will be discontinued subject will be included in the data analysis a in cases of death (either within the first h, until icu or hospital discharge, or days after randomization, whichever comes first), detailed documentation will be carried out in the medical record for the cause of death, group allocation, and relation to study protocol allocation and initiation of the trial intervention. group allocation will be concealed until after randomization. the study interventions will continue for h from the time of randomization. patients and medical charts will be followed at baseline prior to randomization and at h and h post-randomization. medical charts will also be followed to document the outcomes at days, or until death, whichever comes first. please refer to fig. for the schedule of enrollment, interventions, and assessments. the study investigators and study participants during the recruitment and consenting process will be blinded to the treatment assignment. once the trial intervention starts, the treating team and study investigators will not be blinded to the trial intervention for practical and safety purposes (open label). the study statistician is blinded to the treatment allocation, and the study investigators will remain blinded to the results until the conclusion of the study. the principal investigators will ensure enrollment of patients as quickly as possible after h post-intubation. patients intubated for more than h will be excluded to eliminate early contamination or confounders. the primary outcome is median duration of mv: the number of calendar days from intubation date to extubation date, until icu discharge, death, or days post-randomization, whichever comes first. this outcome was chosen as a patient-centered outcome and based on the mechanistic plausibility data that showed ketamine possibly has a bronchodilatory effect and maintains respiratory drive and airway reflexes [ , , ] . because duration of mv is highly influenced by mortality, the median ventilator-free days to day post-randomization will be calculated as a co-primary outcome [ ] . see the statistical methods in "data analysis." secondary clinical outcomes . proportion of patients achieving the rass goal and pain score goal within the first h after randomization . proportion and median vasopressor requirements in the first h after randomization . median change in mean arterial pressure (map) and hr in the first h after randomization . icu and hospital los: number of calendar days (median, iqr) from randomization to discharge date from the icu or hospital . proportion of tracheostomy, unplanned extubation (self-extubation), and re-intubation within days post-randomization . proportion of patients starting on antipsychotics and positive cam-icu score to assess the incidence of delirium h after randomization. the presence of delirium will also be confirmed through a psychiatrist consultation . proportion of physical restraint h after randomization . proportion of patients with frequent suctioning in the first h after randomization (defined as interval between suctioning episodes h or less) . mortality rate at the time of hospital discharge or days after randomization, whichever comes first. secondary feasibility outcomes: . proportion of screened patients . proportion of eligible patients enrolled . enrollment rate (i.e., number of enrollments per month) . protocol compliance. data will be collected in the kfsh&rc research electronic data capture (redcap) platform. each subject will be given a unique subject id number (database numbers and all identifiers will be removed). a subject id key will be used to match the subjects' medical record numbers and will be kept in a password-protected file that is accessible to the principal investigators. access to the redcap data will be limited to the principal investigators and co-investigators involved in data collection only. access to redcap requires authentication (username and password) for secure maintenance of the data. all investigators are kfsh&rc employees and have access to the electronic medical record (power chart). all collected information will be stored in a secure manner, and all patient data will be kept confidential. to ensure consistency in data collection, training sessions will be held by the principal investigators for all research co-investigators involved in data collection prior to study commencement. additionally, the principal investigators will conduct educational sessions for icu physicians and icu nurses, which will include the study protocol, and periodic follow-up educational sessions to provide feedback and ensure optimal compliance with the study protocol. there will be periodic internal audits of data entry accuracy and compliance by the principal investigators. this will allow us to identify any protocol deviations and provide an opportunity for feedback to the co-investigators involved in data entry. range edits and value checks will be incorporated into the redcap software to minimize the potential for data entry errors. moreover, printed copies of de-identified case report forms will be submitted to the rac at the kfsh&rc any time upon committee request and will be reviewed upon the receipt of the progress report by june (the date specified originally upon irb approval of the study protocol). the following data will be collected: age, gender, weight, mode of mv at baseline, percentage of renal replacement therapy at baseline, lactate level at baseline, and severity of illness as estimated by sequential organ failure assessment (sofa) score and acute physiology and chronic health evaluation (apache ii) score, with higher scores indicating higher severity of illness [ ] . moreover, we will collect icu type, baseline analgesics, sedatives, vasopressor requirements, and pre-deliric delirium risk score, which is a delirium prediction model specifically designed for adult critical care patients h after icu admission. this model will be used to predict the factors that may influence delirium risk prior to randomization [ ] . we will also collect rass, pain, and cam-icu scores at baseline and at and h post-randomization. the rass is a scale used to assess the depth of sedation on a scale of − to + , with a negative value indicating deeper sedation and positive values indicating increased agitation [ ] . the cam-icu is a valid and reliable delirium assessment tool. patients with a rass score of − or lower will be excluded from cam-icu assessment, as they cannot participate in the exam [ ] . we will calculate the modified clinical pulmonary infection score (cpis) to differentiate secretions caused by patients' underlying lung pathology (ventilator-associated pneumonia [vap]) vs ketamine-associated hypersalivation [ ] . we will also record the proportion of eligible participants enrolled, rates of recruitment, protocol deviations, and aes. the sample size calculation associated with the specified (required) number of patients to be recruited is based on the study by buchheit et al. [ ] . in their study, the median time from initiation of ketamine to extubation was . days (iqr . - . ). as time from initiation of ketamine to extubation is bounded below by zero, and assuming that the distribution is skewed toward larger times, a lognormal distribution was assumed to be appropriate for modeling such times. we additionally assumed that the distribution of times from intubation to extubation for patients who are not treated with ketamine is lognormal, with median . and iqr from . to . . the hypothesis of interest is h : m = m vs ha: m ≠ m , where m is the median time for those treated with ketamine, and m is the median time for those not treated with ketamine. here the times are distributed with lognormal distributions, and the respective iqrs are . - . for ketamine-treated patients and . - . for those not treated with ketamine. a simulation analysis was carried out with simulated patient times under each of the above two distributional scenarios, i.e., intubation to extubation times under a lognormal of . and . - . (median and iqr) and intubation to extubation times under a lognormal of . and . - . (median and iqr). this was followed by calculation of the level of significance by the wilcoxon rank sum test (i.e., the associated p value). by repeating this simulation , times, . % of the simulations had a p value less than . . this shows that the power of a design with ketamine-treated and non-ketaminetreated patients should (with at least % probability) demonstrate that the time from intubation to extubation is one day less for those treated with ketamine. it is recognized that non-compliance and dropouts may occur. hence, the study has been designed to recruit ketamine-treated and untreated subjects for analyses (i.e., total sample size ). the median ventilator-free days will be calculated as calendar days with no ventilator support to day post-randomization. participants who die before day are assigned zero free days. data will be analyzed using the modified intention-to-treat principle and will comprise data from all patients who undergo randomization, with the exception of those who withdraw consent, have an unknown primary outcome, or are identified as ineligible after randomization. the shapiro-wilk test for normality will be used to assess the distribution of all outcome variables. chi-square and t tests (or wilcoxon rank sum) will be used to compare categorical data and continuous data, respectively. all data will be presented as median and iqr, if not normally distributed (or count and percentages, if categorical). univariate and multivariate regression analyses will be used to identify risk factors and predictors for delirium. statistically significant factors in the univariate analysis (≤ . ) will be included in the multivariate analysis. adjustments for the analysis will be accounted for with the bonferroni technique. a prespecified sub-group analysis of the primary outcome will be conducted on the following variables: age > vs age < sofa score > vs < apache ii > vs < ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (pf ratio > vs pf ratio < ) surgical vs medical admission. we will strive to obtain full data on every patient to allow an intention-to-treat analysis. if there is missing information as patients withdraw from the study before completion of the follow-up period, it will be handled in the normal fashion of survival analysis (censored observation). imputation (based on regression model) will be considered in case of incomplete information about key covariates. sensitivity analyses with such excluded patients will be conducted and compared with an imputed values model. each of the analyses will be redone to test each hypothesis and verify the robustness of the conclusion. statistical analyses will be performed using sas/ jmp, v. . (sas institute, cary, nc, usa). the study statistician is blinded to the treatment allocation, and study investigators will remain blinded to the results until the conclusion of the study. the principal investigators will meet weekly to perform periodic internal audits of data accuracy, review enrollment rates, and oversee and coordinate the study in general. this will allow them to identify any protocol deviations and provide an opportunity for feedback to the other co-investigators. an independent rac at the kfsh&rc will serve as a safety monitoring committee which includes faculty with expertise in various disciplines engaged in human subjects' research from the hospital and research center, and also community members. consultants with special expertise might be invited to assist from time to time with complex issues. the committee will undertake periodic reviews at the discretion of the chair, and an expedited review is done for all serious unexpected adverse events (suaes), including death. the committee has the authority to suspend or halt recruitment if necessary. refer to supplementary file for the form used to report suaes and death by the study investigators within h of occurrence. all death cases reviewed so far have been due to the underlying disease, with participation in the trial not being a contributing factor. any clinically significant worsening in a study participant's condition based on clinical judgement compared to the baseline status at the time of randomization will be recorded as an ae in our progress report to be sent to the rac by june (the date specified originally upon irb approval of the study protocol). this is applied whether or not the ae is considered to be related to the study treatment. in addition, this study is registered at the saudi food and drug authority (fda), which provides independent input regarding the safety of interventions. since this is an investigator-initiated, single-center, pilot, feasibility trial, periodic reviews are basically focused on monitoring safety. no formal interim analysis of efficacy will be undertaken due to possible small numbers that might preclude determination of a statistically significant difference in outcomes between the arms. no stopping rules or external independent data safety monitoring committee (dsmc) are specified. we believe the administration of sedative agents is standard of practice in the icu to minimize a patient's discomfort while on mv (see supplementary figure : kfsh&rc new sedation protocol for adult icus). hence, the expected adverse effects will not exceed what is encountered during daily practice (e.g., benzodiazepine-associated delirium, opioid-induced constipation, hemodynamic instability associated with propofol and dexmedetomidine, ketamine-associated sympathetic stimulation " tachycardia and increase in blood pressure," and possible delirium). nonetheless, an external and independent dsmc will be considered moving forward to a multisite rct. as detailed in the patient information and consent form, any injury or complication occurring as a result of trial participation is to be reported to the study team, who will arrange all necessary medical treatment. trial disseminationthe trial registration and dissemination information is as follows: to the best of our knowledge, our pilot study is the first rct that compares adjunct low-dose ketamine infusion to standard of care alone in critically ill patients. it is conducted in a mixed icu cohort (medical, surgical, transplant, and oncology icu settings), focused on patient-centered outcomes as a primary outcome (duration of mv), and addresses the fact that most patients in the icu are sedated with a combination of drugs. randomization, blinded study participants and study statistician, and adherence to the modified intention-to-treat principle will limit potential sources of bias. another strength of this pilot study is the narrow randomization window (within h post-intubation), which was chosen based on prior literature that showed early initiation of an intervention increases the ability of the intervention to influence the outcome, be more informative for clinicians, and have a greater power to detect an effect on important outcomes, such as duration of mechanical ventilation and long-term outcomes [ ] [ ] [ ] . moreover, we elected to record the vasopressor requirements, cumulative sedatives and analgesics, number of patients within rass and pain score goals, and delirium incidence h post-randomization to avoid the presence of confounders if measured > h after ketamine infusion, similar to the study by groetzinger et al. [ ] . a concern was raised about the under-dosing of ketamine compared to icu ketamine studies. various dosing regimens of ketamine continuous infusion for sedation are described in the literature. a recent systematic review described the existing data regarding ketamine dosing for adjunct sedation in small cohorts of primarily neurologically injured patients [ ] . the included studies describe dosing regimens up to . μ g/kg/min ( . mg/kg/h), which is substantially higher than the doses prescribed in our cohort. as most patients in the review had a neurological injury, sedatives were administered to maintain deep sedation, and often with background benzodiazepine infusion or even barbiturate anesthesia [ ] . on the other hand, groetzinger and colleagues used continuous infusion ketamine for adjunct sedation in a population of mechanically ventilated, critically ill adults targeting light sedation; ketamine was infused at a median starting dose of . - . μ g/kg/min ( . - . mg/kg/h) for a median of . days. the maximum doses of ketamine in individual patients experiencing adverse drug reactions (such as tachyarrhythmia) ranged from . - μ g/kg/min ( . to . mg/kg/h), necessitating discontinuation of the infusion [ ] . we aimed to describe our experience using ketamine as an adjunct low-dose sedative in an era that emphasizes light sedation in a complex, mechanically ventilated, critically ill population, specifically patients with medical illnesses, or following complicated surgical procedures. therefore, we chose in our pilot study the dosing regimen based on the rct cited by the padis guideline, which is comparable to the dosing regimen described in the study of groetzinger et al. we believe this represents the safest dose as an adjunct analgo-sedative agent to decrease the risk of side effects, i.e., delirium, hallucinations, and tachycardia, through its sympathetic stimulation [ , , ] . limitations of our pilot study include the open-label design, as it has a process of multiple interventions related to the pain and sedation protocol. therefore, the icu treating team and the study investigators will know to which arm the study participants are randomized. moreover, we will not collect data on other pain medications such as morphine and hydromorphone, as those medications are rarely used, per the kfsh&rc adult sedation protocol, compared to fentanyl. another limitation is exclusion of patients in status asthmaticus or status epilepticus and patients placed on ecmo, as the dosing regimen of ketamine in those conditions is different than the regimen we used herein as an adjunct analgo-sedative agent. this may limit the external validity of this trial, although the population described in our cohort is relevant to many critically ill patients. since we were interested in describing ketamine infusions as part of a light sedation strategy, we have excluded patients for whom the rass goal is − , such as those receiving continuous infusion neuromuscular blockade. additionally, the safety profile described in our cohort is not generalizable to higher doses of ketamine used to achieve deep sedation. in conclusion, the findings of this pilot trial will contribute to a better understanding of adjunct low-dose ketamine infusion as an analgo-sedative agent and test the feasibility for a larger multicenter, randomized, double-blind, placebo-controlled trial with an adequate power to determine the effect of ketamine infusion as an analgo-sedative agent on clinical outcomes-mirroring other major sedation-related rcts [ , , [ ] [ ] [ ] . future trials addressing cardiac assessment and hemodynamic metrics in a more protocolized way would be a great addition. for example, studies could assess metrics such as measurement of cardiac index (ci), stroke volume (sv), pulse pressure variation (ppv), and stroke volume variation (svv) estimated by arterial pulse pressure waveform analysis (e.g., with the vigileo monitor) at baseline (prerandomization) and at and h afterward (post-randomization), considering other potential confounders and adjunct interventions to evaluate whether these findings are direct consequences of ketamine or independent changes related to the severity of critical illness and the cumulative effect of adjunct interventions (i.e., antimicrobials, steroids, fluid administration, and blood products). lastly, it would be optimal to assess some patient-reported outcomes for those who developed an emergence reaction or delirium. the active engagement of patients and family members has been highlighted recently in the icu literature, and this would be a great addition to consider in a future multicenter trial through completing an icu diary or a survey days post-icu discharge among icu survivors [ ] . as of october , a total of patients have been enrolled. we expect to complete the recruitment by december . the trial was first approved on july (protocol v ) and opened to recruitment on september (protocol v ). the protocol was amended on september (protocol v ) requesting initial waiver of consent, as we faced difficulty with the patient enrollment and consenting prior to randomization due to inability to reach the legal surrogate (not answering the phone for verbal consent) or the emotional factor with the legal surrogate, especially during the first h postintubation and icu admission. however, our research ethics committee mandated the informed consent prior to randomization. another protocol amendment (protocol v ) on february reflected the clarifications that were made in the revised version. clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the icu continuous infusion ketamine for adjunctive sedation in medical intensive care unit patients: a case series the effects of small-dose ketamine on morphine consumption in surgical intensive care unit patients after major abdominal surgery low-dose ketamine in chronic critical illness continuous infusion ketamine for adjunctive analgosedation in mechanically ventilated, critically ill patients impact of ketamine use on adjunctive analgesic and sedative medications in critically ill trauma patients safety of sedation with ketamine in severe head injury patients: comparison with sufentanil comparison of ketamine-versus nonketamine-based sedation on delirium and coma in the intensive care unit impact of low-dose ketamine on the usage of continuous opioid infusion for the treatment of pain in adult mechanically ventilated patients in surgical intensive care units low doses of ketamine reduce delirium but not opiate consumption in mechanically ventilated and sedated icu patients: a randomized doubleblind control trial ketamine infusion for adjunct sedation in mechanically ventilated adults ketamine for analgosedation in the intensive care unit: a systematic review ketamine use in the intensive care unit role of ketamine in acute postoperative pain management: a narrative review consensus guidelines on the use of intravenous ketamine infusions for chronic pain from the american society of regional anesthesia and pain medicine, the american academy of pain medicine, and the american society of anesthesiologists early goaldirected sedation versus standard sedation in mechanically ventilated critically ill patients: a pilot study the spice iii study protocol and analysis plan: a randomized trial of early goal-directed sedation compared with standard care in mechanically ventilated patients early sedation with dexmedetomidine in critically ill patients (spice iii) ketamine continuous infusions in critically ill infants and children adverse events associated with ketamine for procedural sedation in adults comparing clinical outcomes between ketaminemidazolam and morphine-midazolam for continuous sedation in icu patients ketamine sedation in mechanically ventilated patients: a systematic review and metaanalysis reappraisal of ventilator-free days in critical care research the third international consensus definitions for sepsis and septic shock (sepsis- ) development and validation of pre-deliric (prediction of delirium in icu patients) delirium prediction model for intensive care patients: observational multicentre study psychometric properties of the arabic version of the confusion assessment method for the intensive care unit (cam-icu) diagnosing pneumonia during mechanical ventilation the clinical pulmonary infection score revisited dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the mends randomized controlled trial dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial (sedcom) nonpharmacologic interventions to prevent or mitigate adverse long-term outcomes among icu survivors: a systematic review and meta-analysis we thank the icu physicians, icu nurses, icu nurses' clinical educators, icu satellite pharmacists, and the pharmacy automation team at kfsh&rc for their support to this study. we are thankful to the saudi critical care trials group for providing feedback for the study proposal. we also thank the research staff, and the participants and their families. without their collective generosity, this trial would not have been possible. supplementary information accompanies this paper at https://doi.org/ . /s - - - . authors' contributions mb and ma conceived and designed the study and the analytical plan, drafted the manuscript, critically revised the manuscript for important intellectual content, and registered the trial at saudi fda, clinicaltrials.gov, and isrctn. dr. mb and dr. ma contributed equally as first authors, have full access to all of the data in the study, and take responsibility for the integrity of the data, study supervision, accuracy of the data analysis, and approval of the final version of the study protocol to be published. km acquired, analyzed, and interpreted the data, critically revised the manuscript for important intellectual content, and approved the final version to be published. mh acquired, analyzed, and interpreted the data, critically revised the manuscript for important intellectual content, and approved the final version to be published. ra, mr, ka, and ms acquired, analyzed, and interpreted the data and approved the final version to be published. ed participated in sample size calculation, analysis or interpretation of data, submission of the documents to the saudi fda, and approval of the final version to be published. we confirmed that the authorship followed the uniform requirements for manuscripts submitted to biomedical journals. all authors read and approved the final manuscript. research centre, p.o box , riyadh , tel: + - - - ext . this trial is investigator-initiated, and all study authors are employees at king faisal specialist hospital and research center (kfsh&rc), which has not provided any research grant for this particular project. all authors are expected to volunteer their time and use local resources to conduct the study. the study drug ketamine is provided to the kfsh&rc pharmaceutical care division through hikma pharmaceuticals, which has no role in the design or conduct of the trial, analysis of the data, or writing or review of the manuscript. email: ora@kfshrc.edu.sa. all data in the study protocol are included in this published article and its supplementary information files. the study is conducted according to good clinical practice guidelines. the study protocol and informed consent were approved by the research ethics committee and clinical research committee at kfsh&rc with research advisory council number . once an eligible patient is identified, study investigators start the consenting process to explain the objectives of the trial and its potential risks and benefits to the patient's surrogate decision-maker. a verbal consent from a guardian/next of kin over the phone is considered to allow randomization and initiation of timely intervention when written authorization cannot be secured in sufficient time (within h of intubation). verbal consent is documented in medical records to indicate the research subject's acceptance to participate in the study. a prospective written consent is obtained thereafter from the patient (if extubated) or the patient's guardian/next of kin once they become available. not applicable. the authors declare that they have no competing interests. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -raayrjmd authors: flattres, aurelien; aarab, yassir; nougaret, stephanie; garnier, fanny; larcher, romaric; amalric, mathieu; klouche, kada; etienne, pascal; subra, gilles; jaber, samir; molinari, nicolas; matecki, stefan; jung, boris title: real-time shear wave ultrasound elastography: a new tool for the evaluation of diaphragm and limb muscle stiffness in critically ill patients date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: raayrjmd background: muscle weakness following critical illness is the consequence of loss of muscle mass and alteration of muscle quality. it is associated with long-term disability. ultrasonography is a reliable tool to quantify muscle mass, but studies that evaluate muscle quality at the critically ill bedside are lacking. shear wave ultrasound elastography (swe) provides spatial representation of soft tissue stiffness and measures of muscle quality. the reliability and reproducibility of swe in critically ill patients has never been evaluated. methods: two operators tested in healthy controls and in critically ill patients the intra- and inter-operator reliability of the swe using transversal and longitudinal views of the diaphragm and limb muscles. reliability was calculated using the intra-class correlation coefficient and a bootstrap sampling method assessed their consistency. results: we collected images. longitudinal views of the diaphragm (icc . [ . – . ]), the biceps brachii (icc . [ . – . ]) and the rectus femoris (icc . [ . – . ]) were the most reliable views in a training set of healthy controls. intra-class correlation coefficient for inter-operator reproducibility and intra-operator reliability was above . for all muscles in a validation set of healthy controls. in critically ill patients, inter-operator reproducibility and intra-operator and reliability iccs were respectively . [ . – . ], . [ . – . ] and . [ . – . ] for the diaphragm; . [ . – . ], . [ . – . ] and . [ . – ] for the biceps brachii and . [ . – . ], . [ . – . ] and . [ . – ] for the rectus femoris. the probability to reach intra-class correlation coefficient greater than . in a , bootstrap sampling for inter-operator reproducibility was respectively %, % and % for the diaphragm, the biceps brachii and the rectus femoris respectively. conclusions: swe is a reliable technique to evaluate limb muscles and the diaphragm in both healthy controls and in critically ill patients. trial registration: the study was registered (clinicaltrial nct ). survivors of critical illness have severe long-term functional disability [ ] . following the intensive care unit (icu) stay, the quality of life and return to pre-icu admission daily activities are impaired [ ] [ ] [ ] . both diaphragm and limb muscles are affected [ , [ ] [ ] [ ] [ ] . limb muscle weakness is one of the greatest issues linked with disability and poor outcomes in survivors [ , [ ] [ ] [ ] [ ] . diaphragm weakness has also been associated with poor outcome such as dependency on mechanical ventilation, prolonged icu length of stay and mortality [ , [ ] [ ] [ ] . muscle weakness is related to muscle mass but beyond mass, loss of muscle function and muscle quality without atrophy has been observed in the elderly and in chronic hemodialysis patient populations, [ , ] a condition labeled as dynapenia. at the icu bedside, ultrasonography (us) is an inexpensive, user-friendly, nonvolitional and non-invasive tool widely used by intensivists. us has been suggested to be a reliable tool to approximate muscle mass by measuring the cross-sectional area and muscle thickness [ , ] and to also approximate muscle quality by grey-scale analysis of the muscle echogenicity [ , ] . however, subcutaneous tissue and muscle edema and inflammation, frequently observed in the critically ill, can make the grey-scale analysis difficult to interpret. moreover, diaphragm contractions during spontaneous breathing and passive stretch during mechanical ventilation may also make ultrasonography more difficult to perform in the critically ill patients than in healthy controls able to block their breathing cycle. shear wave ultrasound elastography (swe) is a method of us imaging based on the detection of shear wave propagation through the tissue. by using inversion algorithms, this method maps the waves into elastograms and determines stiffness of the tissue by measuring the shear modulus value [ ] . swe has been established as an excellent diagnostic method for liver fibrosis, breast cancer and thyroid cancer [ ] . in skeletal muscles, it provides a spatial representation and quantifiable measurement of the mechanical properties and an approximate of the muscle fibrosis and the activity of the disease in chronic myopathy [ ] as well as a surrogate of diaphragm force production in healthy volunteers during isovolumetric inspiratory efforts [ ] . although swe muscle analysis may provide new data about muscle quality during critical illness, it has never been evaluated in the very specific critically ill population which is exposed to severe structural muscular alterations. we therefore designed the present study with the aim of determining the reliability and reproducibility of swe measurements for limb muscles and the diaphragm in both healthy subjects and in critically ill patients. we conducted the ultramuscle prospective observational study at a medical icu of the university hospital of montpellier, france. institutional ethical approval was obtained ( -cler-mtp- - ), and the study was registered (clinicaltrial nct ). because the ultramuscle study was part of an image databank storage, consent was waived according to french law. we followed the strobe guidelines for observational studies [ ] . we enrolled adult healthy subjects and consecutive adult critically ill patients. inclusion criteria for the critically ill patients were at least one organ failure (organ failure being defined by a sepsis-related organ failure assessment (sofa) score [ ] equal or greater than for the organ considered) and an expected length of icu stay of at least days. non-inclusion criteria were pregnancy, a history of neuromuscular disease (myasthenia gravis, chronic myopathy or neuropathy), spinal cord injury, recent intracranial disease, transfer from another icu, age below and refusal to participate in the trial. we first enrolled healthy subjects as a training set to assess inter-operator reproducibility for each view and to determine the best view (longitudinal vs transversal) for the biceps, the rectus femoris and the diaphragm. we then enrolled an additional validation set of healthy subjects to assess both inter-and intra-operator reliability for each muscle. then we enrolled consecutive critically ill patients during the last weeks of november , to assess both the inter-and intraoperator reliability for each muscle using the best views determined in healthy controls. shear wave elastography imaging procedure general procedure an aixplorer ultrasonic scanner (supersonic imagine, aix-en-provence, france) was used with a - mhz linear transducer (sl - ; supersonic imagine) in swe mode with musculoskeletal pre-set. all biceps, rectus femoris and diaphragm images were performed by two operators: an expert with years of experience in the field of skeletal muscle ultrasound in the icu and a novice who was not familiar with muscular ultrasound. both were trained by the supersonic imagine engineer before enrolling the first participant. all acquired images and data were stored and analysed secondarily as recommended by nijholt et al. using osirix dicom viewer software (pixmeo, geneva, switzerland) [ ] . healthy controls and patients were assessed in supine position, with their knees in passive extension and neutral rotation, and their arms by their sides and with forearms supinated and elbows at °of flexion. conscious subjects were instructed to remain relaxed, to breathe as quietly as possible throughout the procedure, and to maintain an apnea at functional residual capacity for swe acquisition. for mechanically ventilated patients, an end-expiratory pause was applied during swe acquisition and the absence of diaphragm contraction was assessed using ventilator curves and ultrasound realtime images. the absence of movements and limb muscle contraction was also clinically carefully checked in the critically ill patients. we collected all measurements in triplicate, from the three muscles on the right side and at a resting position: diaphragm, biceps brachii and the rectus femoris. to enable repeat ultrasound assessments at the same location, a mark was drawn on the subject's arm, leg and chest during the first measurement procedure, and was used by the two operators for all measurements. during image acquisition, transducers were placed with minimal compression on top of a generous amount of coupling gel to avoid distortion of the underlying tissue [ ] . for all muscles, we collected both a transversal view that refers to the transducer being positioned perpendicular to the fibers and a longitudinal view that refers to the transducer being positioned parallel to the fibers. for the diaphragm views, the transducer was placed at the zone of apposition at the th- th intercostal space between the right anterior and midaxillary lines to better identify the three-layered structure. all diaphragm views were acquired at the end of expiration when the muscle is the thinnest. all peripheral muscle images were acquired after s of motionlessness assessed clinically. for the biceps brachii views, the transducer was placed perpendicular to the long axis of the arm on its anterior surface, over the mid-distance of the long head of the biceps brachii. for the rectus femoris images, the transducer was placed perpendicular to the long axis of the thigh on its anterior surface, at three fifths of the distance from the anterior superior iliac spine to the superior patellar border. in biomechanics, stiffness is defined by the proportional relationship between the stress (the external force or compression) and strain (deformation) applied to it. transmission of a longitudinal pulse leads to tissue displacement, which is detected by pulse echo ultrasound and allow the measurement of the shear wave velocity [v in m s − ]. the shear wave velocity v is proportional to the shear modulus (μ expressed in kpa) using the formula: μ = ρ.v (where ρ is the tissue density, equals to kg m in the human body). hard tissues have a higher μ and v than soft ones. we performed the measurements at the middle portion of each muscle belly avoiding tendons, aponeurosis and fascial tissues to avoid measurement biases. when activating the swe mode, a color-coded box representing the region of interest was super-imposed on the image (fig. ) . swe images were continuously acquired at a sampling rate of hz during apnea at the end of expiration for healthy subjects, or during an end-expiratory pause for mechanically ventilated patients. an elastography real-time -s cine loop was stored. we then offline manually drew the widest region of interest possible (labeled as a "q-box trace") in a homogenous frozen image to average the shear modulus measurement into the drawn q-box and to carefully exclude the surroundings tissue from the measurement. descriptive statistics are reported as numbers (%), mean ± standard deviation (sd) or median (and interquartile [ - %] ). kolmogorov-smirnov test was used to test normality. differences in mean shear modulus (kpa) were compared using student's t test, mann-whitney test or wilcoxon matched pairs signed rank test, as appropriate. between-operator reproducibility and within-operator reliability were calculated using an analysis of variance intra-class correlation coefficient (icc). an icc is measured on a scale of to ; represents perfect reliability with no measurement error, whereas indicates no association. measurement reliability was classified as follows: - . "poor agreement", . - . "moderate agreement", . - . "good agreement", . - "excellent agreement". the best icc measured in the training set in the healthy controls was used to perform the measurements in both the validation set in the healthy controls and in the critically ill patients. to look for a minimum icc value of . with an % power and the significance level set at p < . , we calculated that pairs of measures would be necessary for each muscle. because this is the first study performed in the critically ill by intensivists and taking into the risk of uninterpretable images, we chose to increase this number by % ( measures). the healthy controls cohort was split into a training and a validation set ( - measures) and we enrolled consecutive critically ill patients ( - measures). finally, we used a bootstrap sampling method to assess the consistency of our findings. statistical analysis was conducted using graphpad, prism (graphpad software, la jolla, ca, usa) and r software version . . (https:// www.r-project.org/). we collected us examinations in healthy controls and in critically ill patients. clinical characteristics are reported in table . in the training set obtained from healthy controls, we compared swe measurements collected from transversal and longitudinal images in the diaphragm, the biceps brachii and the rectus femoris by the two operators. figure is an illustration of the images obtained for the three evaluated muscles. the training set allowed us to determine that the best interoperator reliability was obtained with the longitudinal views for the diaphragm and the biceps brachii. no significant difference in inter-operator reliability was observed between the transversal and the longitudinal views for the rectus femoris (table ) . figures and show how the images were obtained for the three evaluated muscles. in the validation set obtained from healthy controls, swe measurements were analysed. inter-operator and intra-operator reliability, measured on triplicates for each muscle were excellent, the median icc being above . for each muscle for both the novice (intra-operator ) and expert (intra-operator ) operator (table ) . bland and altman analysis confirmed the excellent inter and intra-operator reliability of the measurements (fig. ) . we then enrolled critically ill patients (table ) and analysed images. global shear modulus in kpa was . (± . ), . (± . ) and . (± . ) for diaphragm, biceps brachii and rectus femoris respectively. no significant differences were found between the novice and expert operators as shown in the bland-altman graphs (fig. ) . the average inter-operator reproducibility was excellent for the three muscles with iccs being above . . the intra-operator reliability of the swe measurements was also excellent, icc being above . ( table ). the inter-operator reliability of the swe measures was assessed using bootstrap resampling with replacement ( , samples) to the measures performed on the critically ill patients. the probability to reach good to excellent iccs between operators (above . ) for diaphragm, biceps brachii and rectus femoris in a , bootstrap sample was %, % and % respectively. this study shows that intra-and inter-operator reliability of shear modulus evaluation, a parameter of muscle quality in limb muscles and the diaphragm in both healthy controls and in critically ill patients, is excellent. us evaluation of critically ill patients at the bedside has been largely adopted by intensivists because it is easily available, non-expensive and non-invasive and it can be used as a monitoring tool during the icu stay. therefore, besides its large indications in cardiovascular or respiratory management, it has also often been described to evaluate limb muscle and diaphragm mass in weak patients during the icu stay [ , [ ] [ ] [ ] [ ] [ ] . very few us studies have however focused on parameters that reflect muscle quality. in a landmark study, puthucheary et al. critically ill patients that changes in vastus intermedius but not rectus femoris echogenicity over time were correlated with physical function tests collected at icu awakening and at icu discharge [ ] . beyond quantitative analysis of the muscle mass, non-invasive tools are urgently needed to provide measurable parameters of limb and respiratory muscle quality. real-time nonvolitional tools, available at the bedside such as swe, would provide targets for clinical trials aiming at improving quality of life and autonomy in survivors of critical illness [ ] . because different pathologic and healthy tissues reveal a similar echogenicity pattern and similar grey-scale but different shear modulus values, sonoelastographic techniques such as swe measurement might be a promising tool to evaluate and to monitor muscle quality and in vivo contractile property changes over time [ , ] . for instance, high shear modulus is associated with muscle stiffness in cerebral palsy or in late duchenne's myopathy [ ] , while low shear modulus is associated with atrophy in a gne chronic myopathy [ ] . moreover, shear modulus but not echogenicity is associated with muscle fibrosis. no study has ever been performed to evaluate shear modulus measurement feasibility and reliability in the critically ill population at high risk of muscle edema. we report herein that shear modulus measurement was reliable and easy to learn for both expert and novice non-radiologist operators working with critically ill patients. few others have assessed inter-operator and intra-operator reliability in measuring muscle shear modulus and have reported similar results. tas et al. reported in healthy subjects an excellent intra-operator reliability and inter-operator reproducibility for rectus femoris (icc above . ) [ ] . dorado-cortez et al. reported better reliability and reproducibility for shear wave velocity measured in longitudinal plane than transverse plane in healthy lower limb muscles [ ] . du et al. found a good agreement for shear modulus reproducibility in patients with parkinson's disease, and a significant difference in biceps brachii stiffness between healthy controls ( ± kpa), mildly symptomatic patients ( ± kpa) and remarkably symptomatic patients ( ± kpa) [ ] . to assess the muscle globally and to avoid intramuscular heterogenous measurements, we chose to use the largest square possible as the region of interest. in the present study, we explored both the limb muscles and the diaphragm, the main inspiratory muscle. nowadays, since specific phrenic nerve stimulation tools to explore critical illness-associated diaphragm weakness are not routinely available at the bedside [ , ] (and diaphragmatic biopsies are very difficult to obtain in humans [ , , ] ), non-invasive tools to explore the diaphragm using us is more and more popular. us may help by approximating diaphragm mass by measuring fig. bland-altman plot of the difference of shear modulus between operators in healthy subjects thickness as well as approximating diaphragm contractile activity by measuring the excursion and the thickening fraction [ ] . a pioneer study by goligher has reported that during critical illness and mechanical ventilation, the diaphragm thickness may decrease (supposedly because of atrophy), but may not change during the stay or may increase (supposedly because of myotrauma) [ , ] . since diaphragmatic shear modulus has been associated with diaphragmatic function in spontaneously breathing volunteers [ ] , shear modulus analysis of the diaphragm in the critically ill may pave the way towards a non-invasive better understanding of diaphragm quality changes during critical illness. our study presents limits that should be discussed. first, we did not perform muscle biopsies to correlate shear modulus to pathology. however, most of the studies that have evaluated swe in muscles did not show pathology data either [ , ] . second, precautions must be taken into consideration when shear modulus is measured. position of the patient, muscle contraction and pressure applied to the muscle by the probe do indeed influence the shear modulus value [ , , ] . we therefore took extreme precautions to limit any measurement bias and used an excessive amount of gel, did not apply any pressure to the muscle during the evaluation and used triplicates to calculate the mean shear modulus. we also paid extra attention to measure the shear modulus in muscles with no contractions and at the end of the expiration for the diaphragm. in the healthy controls, we report a diaphragm shear modulus above the range observed by bachasson et al. [ ] . two main differences should be noted between the two studies. we performed the measurements in the supine position rather than the semi-recumbent position which may have impaired the diaphragm to completely relax at the end of the expiration. we designed the present study as a real-life bedside study and did not use a pneumotachograph or a transdiaphragmatic pressure monitoring. therefore, even after taking extra precautions to measure the shear modulus at the end of expiration with no diaphragm contraction, it is possible that some of the measurements were performed above the functional residual capacity. however, because both intra-operator reliability and inter-operator reproducibility icc were very high, our results suggest that shear wave elastography is a feasible technique to describe diaphragm ultrastructure. diaphragm biopsies using critically ill animal models may help assessing the accuracy of the shear wave elastography technique in phenotyping diaphragm weakness. to limit the influence of muscle anisotropy on the measured value, we chose to use a large square as the region of interest to measure the signal. third, we used shear modulus measurement rather than shear wave velocity. all commercially available us elastography systems are based on the prerequisite assumption that the material is elastic, incompressible, homogenous and isotropic, with a density which equals g/cm . the muscle tissue is however anisotropic and shear modulus should therefore be used as a variation during the course of the disease. our study shows for the first time that a non-volitional, non-invasive ultrasonographic evaluation of muscle abbreviations: icc intra-class coefficient correlation, kpa kilopascals, sd standard deviation. icc are presented with % confidence interval stiffness and contractile properties using shear modulus measurement is reliable in the critically ill population for both the limb muscles and the diaphragm. swe is an us tool that should be investigated in a larger population of critically ill patients to assess whether it might serve as a tool to identify different patient's phenotypes of muscle weakness. abbreviations icc: intra-class correlation coefficient; icu: intensive care unit; sd: standard deviation; sofa: sepsis-related organ failure assessment; swe: shear wave ultrasound elastography; us: ultrasonography; μ: shear modulus the recover program: disability risk groups and -year outcome after or more days of mechanical ventilation long-term cognitive impairment and functional disability among survivors of severe sepsis predictors of return to work in survivors of critical illness diaphragmatic dysfunction in patients with icu-acquired weakness and its impact on extubation failure rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans leaky ryanodine receptors contribute to diaphragmatic weakness during mechanical ventilation acute skeletal muscle wasting in critical illness functional disability years after acute respiratory distress syndrome acute outcomes and -year mortality of intensive care unitacquired weakness. a cohort study and propensity-matched analysis early mobilization and recovery in mechanically ventilated patients in the icu: a bi-national, multi-centre, prospective cohort study respective contribution of intensive care unit-acquired limb muscle and severe diaphragm weakness on weaning outcome and mortality: a post hoc analysis of two cohorts diaphragm dysfunction on admission to the intensive care unit. prevalence, risk factors, and prognostic impact-a prospective study diaphragm weakness in mechanically ventilated critically ill patients diaphragm dysfunction during weaning from mechanical ventilation: an underestimated phenomenon with clinical implications mechanisms of chronic muscle wasting and dysfunction after an intensive care unit stay. a pilot study physical inactivity and protein energy wasting play independent roles in muscle weakness in maintenance haemodialysis patients quantitative neuromuscular ultrasound in intensive care unit-acquired weakness: a systematic review muscle ultrasound from diagnostic tool to outcome measure--quantification is the challenge reliability of a novel ultrasound system for gray-scale analysis of muscle supersonic shear imaging: a new technique for soft tissue elasticity mapping efsumb guidelines and recommendations on the clinical use of ultrasound elastography. part : clinical applications skeletal muscle in healthy subjects versus those with gne-related myopathy: evaluation with shearwave us--a pilot study diaphragm shear modulus reflects transdiaphragmatic pressure during isovolumetric inspiratory efforts and ventilation against inspiratory loading the strengthening the reporting of observational studies in epidemiology (strobe) statement: guidelines for reporting observational studies the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine the reliability and validity of ultrasound to quantify muscles in older adults: a systematic review shear-wave elastography: basic physics and musculoskeletal applications ultrasonography in the intensive care setting can be used to detect changes in the quality and quantity of muscle and is related to muscle strength and function muscle mass, strength and functional outcomes in critically ill patients after cardiothoracic surgery: does neuromuscular electrical stimulation help? the catastim randomized controlled trial evolution of diaphragm thickness during mechanical ventilation. impact of inspiratory effort mechanical ventilation and diaphragmatic atrophy in critically ill patients: an ultrasound study the course of diaphragm atrophy in ventilated patients assessed with ultrasound: a longitudinal cohort study skeletal muscle ultrasound in critical care: a tool in need of translation shear wave sonoelastography of skeletal muscle: basic principles, biomechanical concepts, clinical applications, and future perspectives noninvasive assessment of muscle stiffness in patients with duchenne muscular dystrophy shear wave elastography is a reliable and repeatable method for measuring the elastic modulus of the rectus femoris muscle and patellar tendon: shear wave elastography of the rectus femoris muscle and patellar tendon ultrasound shear wave velocity in skeletal muscle: a reproducibility study ultrasound shear wave elastography in assessment of muscle stiffness in patients with parkinson's disease: a primary observation rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans diaphragm muscle fiber weakness and ubiquitinproteasome activation in critically ill patients critical illness-associated diaphragm weakness diaphragmatic myotrauma: a mediator of prolonged ventilation and poor patient outcomes in acute respiratory failure diaphragmatic shear modulus at various submaximal inspiratory mouth pressure levels the effect of unit, depth, and probe load on the reliability of muscle shear wave elastography: variables affecting reliability of swe publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to thank claudine gniadek, rn, and the members of the medical and nursing team for their participation in the present study. we also thank julie carr, md, for her advices writing the manuscript. authors' contributions af and ya performed all the measurements, analysed the results and participated to the manuscript editing, sn contributes to the result analysis and to the manuscript editing, fg, rl and ma contributed to the study design and patient enrolments, kk contributed to the study design and to the manuscript editing, pe and gs reviewed some of the measurements and participated to the result analysis, sj contributed to the study's design, result analysis and manuscript editing, nm performed the statistical analysis, sm reviewed some of the measurements and participated to the result analysis, bj designed the study, participated to the manuscript editing and approved its final version. all authors read and approved the final manuscript. this study has received funding by departmental resources, the medical school of the montpellier university (yassir aarab, young researcher grant) and the regenhab fhu (aurelien flattres, phd grant). the authors of this manuscript consent to share the collected data to others. data are provided to qualified investigators free of charge. required documents to request data include a summary of the research plan, request form and irb review. datasets will be shared after careful examination by the study board of investigators. data will be available months after the main publication and indefinitely.ethics approval and consent to participate institutional ethical approval was obtained ( -cler-mtp- - ), and the study was registered (clinicaltrial nct ). because the ultramuscle study was part of an image databank storage, consent was waived according to french law. not applicable. the ultrasound equipment aixplorer was made available for the study by supersonic imagine s.a. (aix-en-provence, france). the supersonic company did not have any access to the study's design, the results and the manuscript editing. the authors declare that they have no competing interests. key: cord- -dy v asg authors: bissell, brittany d.; laine, melanie e.; thompson bastin, melissa l.; flannery, alexander h.; kelly, andrew; riser, jeremy; neyra, javier a.; potter, jordan; morris, peter e. title: impact of protocolized diuresis for de-resuscitation in the intensive care unit date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: dy v asg objective: administration of diuretics has been shown to assist fluid management and improve clinical outcomes in the critically ill post-shock resolution. current guidelines have not yet included standardization or guidance for diuretic-based de-resuscitation in critically ill patients. this study aimed to evaluate the impact of a multi-disciplinary protocol for diuresis-guided de-resuscitation in the critically ill. methods: this was a pre-post single-center pilot study within the medical intensive care unit (icu) of a large academic medical center. adult patients admitted to the medical icu receiving mechanical ventilation with either ( ) clinical signs of volume overload via chest radiography or physical exam or ( ) any cumulative fluid balance ≥ ml since hospital admission were eligible for inclusion. patients received diuresis per clinician discretion for a -year period (historical control) followed by a diuresis protocol for year (intervention). patients within the intervention group were matched in a : ratio with those from the historical cohort who met the study inclusion and exclusion criteria. results: a total of patients were included, in the protocol group and receiving standard care. protocolized diuresis was associated with a significant decrease in -h post-shock cumulative fluid balance [median, iqr − (− – ) ml vs (− – ) ml; p < . ]. in-hospital mortality in the intervention group was lower compared to the historical group ( . % vs . %; p = . ) and higher icu-free days (p = . ). however, no statistically significant difference was found in ventilator-free days, and increased rates of hypernatremia and hypokalemia were demonstrated. conclusions: this study showed that a protocol for diuresis for de-resuscitation can significantly improve -h post-shock fluid balance with potential benefit on clinical outcomes. early intravenous (iv) fluid resuscitation is a necessary tool to improve hemodynamic stability and organ perfusion and possibly decrease mortality in critically ill patients admitted to the intensive care unit (icu) [ , ] . however, the benefit of continued fluid administration after the first - h is unclear. paradoxically, a positive fluid balance secondary to excess fluid accumulation has been associated with diverse and persistent detriment on a multitude of organ systems [ ] . perpetuating clinical harm has been demonstrated on pulmonary and renal function, as well as important clinical outcomes such as mortality and length of stay [ ] . despite the growing body of evidence supporting the adverse aspects of positive fluid balance, fluid overload remains common in icu patients [ ] . one approach to correcting fluid balance is shifting focus onto the post-or de-resuscitation period with appropriate diuresis, or renal replacement therapy (rrt) in those non-responsive to diuresis, once hemodynamic stability is achieved [ ] . effective diuresis may be challenged by many hindrances. an overall lack of standardization exists in identification of fluid-overloaded patients as optimal transition times between fluid resuscitation and fluid removal are not clear, and clinical signs of fluid overload are delayed relative to onset of organ damage [ ] [ ] [ ] . standard of care diuretic treatment regimens may be inadequate via sustained delays in initiation from shock resolution or inadequate dosing and follow-up. additionally, apprehension for side effects can be seen, including serum creatinine rises and new onset acute kidney injury (aki). however, the preponderance of adverse event data surrounding these medications is found in non-critical care populations, frequently non-translatable to patients in the icu [ ] . previous protocols guiding volume removal in the critically ill can be found in specific populations including acute decompensated heart failure, aki, or rrt weaning, with protocolized approaches often improving clinical outcomes versus standard of care [ ] [ ] [ ] . further, while limited evidence is available steering diuretic deresuscitation in the broad icu population, protocols have relied upon dated monitoring parameters, including central venous or pulmonary artery occlusion pressures [ ] [ ] [ ] . in this study, we aimed to evaluate the impact of a novel diuresis protocol utilizing common bedside monitoring parameters and simplified loop diuretic dosing on cumulative fluid balance over the first h following hemodynamic stability, as compared to standard of care. this was a pilot study to evaluate a service line level change in diuresis practice. patients requiring mechanical ventilation with a net-positive or -even cumulative fluid or clinical signs of fluid overload determined via chest x-ray or physical exam between april , , and april , , received the diuresis protocol (see additional file ). inclusion and exclusion criteria are summarized in additional file . patients were assessed for inclusion and exclusion daily while in the icu. in order to approximate an experimental design using observational electronic health record (ehr) data, each patient visit within the intervention group was matched to three patient visits meeting the above inclusion and exclusion criteria from the historical time period of all medical icu admits between january and december who received furosemide. diuresis practices in the historical group were non-protocolized and left to physician discretion. patients who met the inclusion criteria from the historical cohort who were not matched with a patient from the intervention group were excluded from the analysis to prevent significant heterogeneity between groups. patient identification occurred by the clinical pharmacist days per week in collaboration with the medical team. after identification of appropriate patients for inclusion a net h fluid balance (ranging from − ml to − ml) was established during interdisciplinary rounds which was divided into three shift goal fluid balance targets to assess at -h intervals. upon establishment of goal, diuretic orders were entered, with dose selection based on previous diuretic exposure and baseline renal function. orders included conditional diuretic orders if shift fluid balance targets were not met, basic metabolic panels, goal parameters, and hold parameters for adverse events (see additional file ). combination diuresis was permitted once the maximum dose of furosemide was reached ( mg iv) or potential hypernatremia. available options included metolazone mg oral or chlorothiazide mg iv in instances when no enteral access was available. indications for continuous infusion diuresis included a lack of response to mg or failure of sustained diuretic response resulting in failure to achieve goal fluid balance. in order to ensure appropriate compliance during overnight hours with decreased staffing ratios, an order set was created requiring nursing evaluation of urine output at the designated intervals. conditional medication orders could be activated by the bedside nurse based on individual patient response and pharmacistdriven goal parameters. diuresis hold parameters were established to minimize adverse events. the overall management of patients outside of diuresis protocol was left to physician discretion. given the paucity of evidence surrounding diuresis in this population, investigators involved in this study performed an interim analysis to promote a quality improvement corollary to the protocol. a data monitoring committee (dmc) was formed for data analysis after % of chronologic study completion. the dmc consisted of the division chief, independent statistical committee (isc), and non-committee physicians, pharmacists, and nursing. approximately months from protocol initiation, the isc performed data extraction which was brought forward to the dmc, without statistical analysis. a protocol modification occurred per the request of the dmc (see additional file ). this study protocol and modification were approved by the institutional review board. as this project was considered a quality improvement initiative, a waiver of informed consent was granted. the primary outcome of this study was the net cumulative fluid balance h following shock resolution. secondary outcomes included icu mortality, icu length of stay, hospital length of stay, ventilator-free days, incidence of aki (defined by kdigo criteria), and the incidence of a severe metabolic disturbance including hypokalemia, hypernatremia, or de novo metabolic alkalosis, defined as a potassium < mmol/l, sodium > mmol/l, or bicarbonate > mmol/l with a ph of > . , respectively. ventilator-free days were defined as the number of days from day to day in which a patient was able to breathe without assistance with death as a competing risk with an assignment of zero free days. for time-dependent interventions, medication administration record medication scans were utilized for medication-related times, respiratory therapy documentation was utilized for ventilator therapy, while admission, transfer, and discharge orders were collected for durations of stay. from our previous study of diluent change in the medical icu, the average fluid balance in our patients at h was positive . ± . l [ ] . based on these data, we calculated a sample size of patients in each group to achieve a ≥ -l decrease in fluid balance at h postshock, maintaining an % power and an alpha of . . continuous data were assessed for distribution and evaluated via t test or mann-whitney u, as appropriate. chi-square or fisher's exact were utilized for categorical data. data for analysis was pulled by a data analyst and validated with prospectively collected data, with discrepancies resolved by the analyst. the same inclusion and exclusion criteria used to enroll patients in the protocol were applied to selection of the control patients in the pre-protocol group. mahalanobis distance matching was used to measure similarities of each patient in the control and protocol group. age, gender, insurance type, home county classification, admission source, diagnosisrelated group (drg) weight, sequential organ failure assessment (sofa) score at time of diuresis initiation, baseline serum creatinine prior to first dose of furosemide, pre-diuretic fluid balance, time from ventilator to first diuretic administration, pre-diuretic vasopressor administration, chronic obstructive pulmonary disease (copd) diagnosis, and acute respiratory distress syndrome (ards) diagnosis were used as matching variables in the distance calculation. nearest neighbor matching was then used to select the three control visits "closest" to each protocol visit, based on the distance calculation. the utilization of drg was chosen by data analysis experts to bolster the validity of the severity of illness scores between groups. further, a test of interaction was performed for patient enrollment pre-and post-protocol modification regarding the magnitude of difference on h fluid balance. a logistic regression model was defined a priori to be built for all-cause mortality. forward selection was utilized with variables included in the model if p < . in the univariate analysis or if deemed biologically plausible and clinically relevant. these initial variables incorporated into the model included sofa score, drg weight, age, intervention versus standard therapy assignment, mechanical ventilation time to initiation of first dose of furosemide, net cumulative fluid balance prior to furosemide, and vasoactive therapy. if the intervention group was not to be identified as a significant covariate, it was predetermined that such would be manually entered into the final model to ascertain the point estimate. collinearity was assessed with the use of variance inflation factors while goodness of fit was assessed with the hosmer-lemeshow test. given the potential for pertinent changes in clinical practice that are unrelated to the protocol, an interrupted time series was performed. further, given the subjective nature of the inclusion criterion clinical signs of fluid overload determined via chest x-ray or physical exam, a subgroup analysis was performed including only those included based on objective volume status (net positive cumulative fluid balance at furosemide start). a subgroup was also collected for pre-and post-protocol amendments to assure no significant impact on clinical outcome. over the study period, patients met criteria for inclusion upon screening, of which, were excluded based on pre-defined exclusion criteria (fig. ) . a total of standard therapy patients who met study criteria were matched : to patients in the intervention group (n = ), for a total of study patients. the matching procedures resulted in balanced groups, based on the pre-defined variables used in the matching algorithm (table ). further, no major difference in other baseline clinical criteria was found with the exception of a higher arterial ph in the intervention group, as well as a higher incidence of rhabdomyolysis on admission (see additional file ). no difference was demonstrated in the utilization of concomitant medications, other than a higher incidence of use of intravenous anti-viral medications in the protocol group (table ) . regarding diuretic exposure, the diuresis protocol group received a higher dose of furosemide upon initiation, day - , and cumulatively; however, diuretic dosing and patient response was variable (fig. ). more patients in the protocol group received concomitant metolazone or acetazolamide therapy, while the standard therapy group had more adjunctive albumin use. the median (iqr) fluid balance within this study at -h post-shock resolution was ml (− - ) vs − ml (− - ) in the historical and interventional cohorts, respectively (p < . ) ( table ) . there was also a significant difference in -and -h fluid balance in the intervention group when compared to the historical cohort. the test of interaction demonstrated no statistical significance regarding those enrolled in the protocol before or after modification (see additional file ), and the subgroup analysis excluding those patients based on subjective clinical criteria (physical exam findings, concern for pulmonary edema) showed similar findings (see additional file ). in the interrupted time series accounting for potential practice variation over time, no significance was demonstrated relative to time before or after intervention (see additional file ). however, a significant difference was demonstrated in -h post-shock fluid balance with protocol use (see additional file ). for the secondary outcomes, while patients had an additional ventilator-free day in the intervention group, this difference was not statistically significant. within the intervention cohort, there was a statistically significant increase in the rate of electrolyte disturbances, primarily driven by an increase in hypernatremia and hypokalemia, despite higher total potassium replacement in the intervention group. in-hospital mortality in the intervention group was lower compared to the historical group ( . % vs . %; p = . ). there was also a higher rate of icu-free days, with these patients having more days free of icu care (p = . ). in multivariable analysis, protocolized therapy was associated with a % ( - %) decreased odds of hospital mortality after adjustment for sofa, fluid balance upon furosemide initiation, time on mechanical ventilation prior to furosemide therapy, and age (see additional file ). given known limitations of serum creatinine as a marker of kidney function during acute illness, a post hoc analysis was performed of rrt dependence at discharge. rrt dependence at discharge was found to be significantly higher in the standard therapy cohort compared to the protocol group. regarding protocol compliance, a total of patient days on protocol were available for evaluation. the most common indication for a furosemide hold was due to protocol discontinuation (see additional file ). a total of deviations occurred within the patient days, for a decrease in dosing frequency prior to protocol modification, for doses administered despite hold criteria, missed nursing activations of conditional orders, and inappropriate holds, of which for unknown reasons, for nursing concern regarding furosemide interval, and for urine output. eighteen patient days required a dose adjustment per protocol, of which were driven by conditional orders. this study was the first to evaluate a volume deresuscitation protocol utilizing pharmacologic diuresis in the medical intensive care unit. this study has several strengths, including the protocol with easily obtainable bedside monitoring parameters within the ehr, the multi-disciplinary approach to protocol development, fig. selection of patients for study population utilization, and modification, frequency of monitoring, and selection of matching parameters. several potential confounders on -h fluid balance were matched between groups, systematically decreasing between-group difference. further, results of the interrupted time series showed no significant difference in slopes of fluid balance over time, while the association between improved -h post-shock fluid balance and intervention group remained significant (fig. ) . we demonstrated a significant decrease in h cumulative fluid volume with the addition of a diuresis protocol in the critically ill. this correlates with previous protocols within acute respiratory distress syndrome and heart failure which demonstrated improved volume status with strategized diuresis without an increase in kidney failure [ , ] . unlike studies within the heart failure population, our protocol prioritized intermittent dosing to decrease intravenous access concerns and protocolized electrolyte and safety monitoring [ ] . with such, a significant increase in the rate of hypernatremia and hypokalemia was seen within the intervention group. no statistically significant difference in duration of mechanical ventilation wean was found. this does not correlate with previous evidence within the critically ill population, demonstrating increased ventilator-free days with conservative volume management [ ] . comparatively, while our study utilized more specific titration strategies and common bedside monitoring parameters, this was a single-center, nonrandomized study and likely underpowered to detect a difference in ventilator duration. key considerations to this study include a decrease in mortality and increased icu-free days in the intervention group. known correlates of mortality within the sepsis population, including baseline weight and admission source, were included as parameters within the regression model [ ] [ ] [ ] . the variables previously correlated with mortality were accounted for in the matching criteria of this cohort. studies demonstrate that almost ubiquitous organ dysfunction has been associated with positive volume status in the icu. it is possible that the implication of volume de-resuscitation seen in the current study could be casually linked with mortality, in line with a vast number of previous studies demonstrating the impact of fluid status on survival rates aside of its effect on ventilator days; however, this study can only show correlation given the nature of its design. particularly, patients in the intervention group also had a decrease in rrt dependence at discharge. rrt receipt prior to hospital discharge has been associated with progression to end stage renal disease, cardiovascular disease, and increased mortality [ , ] . regarding ventilator days, ventilation wean procedures are not standardized at this institution. daily spontaneous breathing trials are performed in all patients who meet criteria; however, extubation orders are left to provider discretion. this lack of ventilator wean protocolization may have affected ventilator-free days between groups. however, reintubation rates were in alignment with previous studies with ranges . - . % and were not significantly different between groups which supports relative uniformity on wean strategies [ ] . further of note, changes to the institutional nursingdriven electrolyte replacement protocol occurred midimplementation (see additional file ). the protocol modification sought more aggressive potassium replacement; however, nursing adherence was not evaluated. as follow-up potassium evaluations were mandated with protocol implementation, it is possible that incidences of hypokalemia were increased secondary to more frequent monitoring relative to the historical cohort; however, frequency of serum potassium collections were not recorded. in regard to rates of hypernatremia, providers were permitted to request continuation of furosemide despite elevated sodium levels, likely resulting in the subsequent increased rate of metolazone use in the intervention group. there was a significant difference in cumulative fluid balance that was likely due to higher furosemide exposure in the intervention group, as demonstrated in previous protocols of furosemide in acute kidney injury [ ] . the significant increase in episodes of hypernatremia and hypokalemia are predictable and reversible within this strategy. if replicated in future randomized trials, improvements in icu length of stay and mortality may take precedence over concern for electrolyte abnormalities. future protocol designs should account for these episodes of hypernatremia and hypokalemia with creation of more explicit electrolyte replacement rules. further, electrolyte derangements may be of greater consideration in an alternative icu population, including cardiothoracic/cardiology critical care. patient-specific factors should be taken into consideration with implementation of this protocol. a key limitation to this study is the lack of randomization and blinding. given the nature of the protocol, blinding to the medical staff was not possible. a pre-and post-intervention study was chosen given the lack of blinding. it was anticipated that an overall change in practice may occur over the study timeframe given increased awareness of the detrimental effects of fluid overload and approach to diuretic dosing in critically ill patients, a phenomenon recently found in management of septic shock [ , ] . however, given the limited time lapse between the historical group and protocol implementation and lack of emergence of guidelines regarding volume de-resuscitation, changes in overall approaches to care based on external factors were unlikely. to limit potential bias further, patients were matched on a large number of relevant variables and objective outcome measures were utilized, with the exception of the drg weight. however, the authors opted for inclusion of this variable versus international classification of disease coding given its consideration for up to eight diagnoses, including the primary diagnosis, and up to six procedures performed during the stay, likely increasing its objectiveness versus retrospective chart review. regardless, it is still possible for potential residual confounders on illness severity to have been missed. given that volume overload and positive fluid balance may be markers of severity of illness rather than a parameter for early diuresis intervention, the differences in mortality and length of stay must be replicated in a larger, randomized controlled trial for confirmation. worth nothing, true blinding in a randomized controlled trial would likely be unfeasible by nature of the protocol design and a parallel design could subject the trial to potential for a significant hawthorne effect. protocol modifications in the study may also be seen as a potential limiting factor. however, in the subgroup analysis performed, protocol inclusion did not appear to significantly impact the primary result. additionally, the inclusion rate appeared relatively low at %. recent studies have demonstrated small recruitment rates within the critically ill [ , ] . a significant portion of our patients were excluded for active vasoactive therapy or aki. clinical inertia is a consideration, particularly given this protocol's pilot nature. further, consideration must be made for a lag in adaptation, particularly in times of low staffing. lastly, the selection of outcome parameters is worth mentioning. we evaluated -h net cumulative fluid balance in accordance with previous literature; however, evidence suggests that fluid balance documentation is not always accurate. the utilization of ehr flowsheets decreases potential for error in icu documentation. the frequency in documentation required via the protocol aligns with standard of care within the icu. recent studies have challenged the validity of net cumulative fluid balance in the icu and its relationship to body weight or clinical signs of fluid overload [ , ] . because this practice is not tightly protocolized, we did not utilize body weight as a monitoring parameter. however, it is possible that this study demonstrated that a pharmacist-driven diuresis protocol of volume de-resuscitation was significantly associated with a lower cumulative fluid balance at h post-shock. the addition of the diuresis protocol was likely effective for a multitude of reasons, including the overall increased awareness of avoidance of volume overload and tailored diuresis utilization, the standardization of doses and follow-up monitoring, as well as an increase in furosemide dosing as demonstrated in this study. however, with increased dosing of furosemide, increased rates of adverse events were found, namely hypernatremia and hypokalemia. risk versus benefit of active volume de-resuscitation and electrolyte fluctuations must be considered. the increased mortality and decreased number of icu-free days in the standard therapy group are hypothesis-generating, particularly given the lack of difference between-groups in ventilator-free days. using a diuresis protocol for volume de-resuscitation, we demonstrated a significant decrease in net cumulative fluid balance at h following shock resolution, with potential benefit on clinical outcomes including renal recovery, mortality, and icu length of stay. although this study supports the implementation of a diuresis protocol in the icu, larger randomized controlled trials are needed to confirm or refute the potential benefits of de-resuscitation, through protocol-driven diuresis, on important patient centered outcomes, such as icu length of stay, ventilator-free days, and in-hospital mortality, as suggested by observed associations in the present study. supplementary information accompanies this paper at https://doi.org/ . /s - - - . additional file . supplementary digital content this file includes relevant study protocols, definitions, as well as subgroup analyses and additional informational tables beyond manuscript content. higher fluid balance increases the risk of death from sepsis: results from a large international audit fluid volume, fluid balance and patient outcome in severe sepsis and septic shock: a systematic review fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice fluid overload in patients with severe sepsis and septic shock treated with early goal-directed therapy is associated with increased acute need for fluidrelated medical interventions and hospital death pharmacological management of fluid overload fluid overload fades away! time for fluid stewardship fluid-management strategies in acute lung injury--liberal, conservative, or both? relevance of changes in serum creatinine during a heart failure trial of decongestive strategies: insights from the dose trial successful weaning from continuous renal replacement therapy. associated risk factors the effect of low-dose furosemide in critically ill patients with early acute kidney injury: a pilot randomized blinded controlled trial (the spark study) a diuretic protocol increases volume removal and reduces readmissions among hospitalized patients with acute decompensated heart failure protocol-guided diuretic management: comparison of furosemide by continuous infusion and intermittent bolus frusemide administration in critically ill patients by continuous compared to bolus therapy comparison of two fluidmanagement strategies in acute lung injury insidious harm of medication diluents as a contributor to cumulative volume and hyperchloremia: a prospective, open-label, sequential period pilot study icu admission source as a predictor of mortality for patients with sepsis does obesity protect against death in sepsis? a retrospective cohort study of , adult patients unexplained mortality differences between septic shock trials: a systematic analysis of population characteristics and control-group mortality rates high incidence of transition to esrd in patients discharged with dialysis dependent aki: the cleveland clinic experience. presented in poster format at kidney week predictors of long-term prognosis in acute kidney injury survivors who require continuous renal replacement therapy after cardiovascular surgery a comparison of four methods of weaning patients from mechanical ventilation. spanish lung failure collaborative group early goal-directed therapy in the treatment of severe sepsis and septic shock goal-directed therapy for septic shock -a patient-level meta-analysis recruitment and retention of participants in randomised controlled trials: a review of trials funded and published by the united kingdom health technology assessment programme effect of hydrocortisone on development of shock among patients with severe sepsis: the hypress randomized clinical trial fluid balance in critically ill patients. should we really rely on it? estimation of fluid status changes in critically ill patients: fluid balance chart or electronic bed weight? publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to thank the physician and nursing staff and leadership who played an integral part in the implementation and improvement of the project.authors' contributions bb and ml designed the protocol. af, bb, ml, and mt assisted in the patient enrollment and data collection. af, bb, ml, mt, and jp collected the data. ak and jr assisted in the statistical analysis and retrospective data collection. jn and pm assisted with the protocol implementation and paper design. all authors read and approved the final manuscript. financial support for this study was provided by the american society of health-systems pharmacists foundation new investigator grant. the datasets during and/or analyzed during the current study are available from the corresponding author on reasonable request. ethics approval and consent to participate this work was performed at the university of kentucky healthcare. institutional review board approval was received (medxp protocol ). not applicable. the authors declare that they have no competing interests.author details key: cord- -w esk authors: moreno, gerard; rodríguez, alejandro; reyes, luis f.; gomez, josep; sole-violan, jordi; díaz, emili; bodí, maría; trefler, sandra; guardiola, juan; yébenes, juan c.; soriano, alex; garnacho-montero, josé; socias, lorenzo; del valle ortíz, maría; correig, eudald; marín-corral, judith; vallverdú-vidal, montserrat; restrepo, marcos i.; torres, antoni; martín-loeches, ignacio title: corticosteroid treatment in critically ill patients with severe influenza pneumonia: a propensity score matching study date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: w esk purpose: to determine clinical predictors associated with corticosteroid administration and its association with icu mortality in critically ill patients with severe influenza pneumonia. methods: secondary analysis of a prospective cohort study of critically ill patients with confirmed influenza pneumonia admitted to icus in spain between june and april . patients who received corticosteroid treatment for causes other than viral pneumonia (e.g., refractory septic shock and asthma or chronic obstructive pulmonary disease [copd] exacerbation) were excluded. patients with corticosteroid therapy were compared with those without corticosteroid therapy. we use a propensity score (ps) matching analysis to reduce confounding factors. the primary outcome was icu mortality. cox proportional hazards and competing risks analysis was performed to assess the impact of corticosteroids on icu mortality. results: a total of patients with primary influenza pneumonia were enrolled. corticosteroids were administered in ( . %) patients, with methylprednisolone the most frequently used corticosteroid ( / [ . %]). the median daily dose was equivalent to mg of methylprednisolone (iqr – ) for a median duration of days (iqr – ). asthma, copd, hematological disease, and the need for mechanical ventilation were independently associated with corticosteroid use. crude icu mortality was higher in patients who received corticosteroids ( . %) than in patients who did not receive corticosteroids ( . %, p < . ). after ps matching, corticosteroid use was associated with icu mortality in the cox (hr = . [ % ci . – . ], p < . ) and competing risks analysis (shr = . [ % ci . – . ], p = . ). conclusion: administration of corticosteroids in patients with severe influenza pneumonia is associated with increased icu mortality, and these agents should not be used as co-adjuvant therapy. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. pneumonia caused by the influenza a(h n )pdm virus infection may lead to life-threatening acute respiratory failure (arf) and acute respiratory distress syndrome (ards). antiviral therapy is the cornerstone of treatment for influenza pneumonia [ ] [ ] [ ] ; in addition, intravenous corticosteroids have been used as co-adjuvant therapy in patients with arf/ards to modulate lung inflammation and improve clinical outcomes [ ] [ ] [ ] [ ] [ ] . however, no randomized clinical trials have investigated the potential benefit or harm of corticosteroid therapy for arf/ards due to acute influenza pneumonia. during the h n pandemic, corticosteroids were widely used despite contradictory [ , ] , unfavorable [ , [ ] [ ] [ ] , or inconclusive [ , ] available data. a recent cochrane review [ ] concluded that co-adjuvant corticosteroid therapy was associated with increased mortality in patients with influenza pneumonia. however, the data were derived from observational studies of very low quality and with several methodological limitations, including other clinical indications of corticosteroids as a major potential concern. thus, it is impossible to be sure that patients who were treated with corticosteroids did not have other corticosteroid indications or were not more severely ill in the first place. we have previously reported that corticosteroid therapy does not improve survival in patients with primary viral pneumonia [ ] . however, in that observational study, we assessed the effects of corticosteroid therapy on survival between patients who were and were not treated, but we did not apply a statistical method that would have balanced all the variables between the two groups. therefore, the aim of the present study was to identify the factors associated with corticosteroid use and its impact on intensive care unit (icu) mortality using propensity score (ps) matching analysis in icu patients with influenza pneumonia. preliminary results of this analysis were presented in the th international symposium on intensive care and emergency medicine [ ] . this was a secondary analysis of prospective and observational cohorts of critically ill subjects admitted to icus in spain (which represents approximately % of the country's icus) between june and april . data were obtained from a voluntary registry created by semicyuc (sociedad española de medicina intensiva, crítica y unidades coronarias). all consecutive cases admitted to the icu were collected. the study was approved by the joan xxiii university hospital ethics committee (irb# ). patient identity remained anonymous, and the requirement for informed consent was waived due to the observational nature of the study, as reported elsewhere [ , [ ] [ ] [ ] [ ] [ ] . inclusion criteria participants included patients admitted with fever (> °c); respiratory symptoms consistent with cough, sore throat, myalgia, or influenza-like illness; acute respiratory failure requiring icu admission; and microbiological confirmation of viral a, b, or c infection identified by reverse transcription polymerase chain reaction (rt-pcr) at icu admission. data were reported by the attending physician reviewing medical charts and radiological and laboratory records. the attending physician ordered all tests and procedures related to patient care. exclusion criteria patients receiving corticosteroids as rescue therapy (due to shock) or due to chronic obstructive pulmonary disease (copd)/asthma exacerbation were excluded (see definition below). children < years old were not enrolled in the study. patients with non-pulmonary influenza infection and those with healthcareassociated pneumonia were also excluded. the following variables were recorded at icu admission: demographic data, comorbidities, time from illness onset to hospital admission, time to first dose of antiviral delivery, microbiological findings, and laboratory and chest radiological findings at icu admission (all the collected variables are reported in e- table of the supplementary material). to determine illness severity, the acute physiology and chronic health evaluation (apache) ii score [ ] was estimated for all patients within h of icu admission. organ failure was assessed using the sequential organ failure assessment (sofa) scoring system [ ] , also at icu admission. the indication of corticosteroid treatment was clearly reported in the case report form and was confirmed by the medical records. community-acquired pneumonia (cap) was defined in accordance with current american thoracic society and infectious diseases society of america guidelines (ats/ idsa) [ ] . the rt-pcr test for influenza was carried out in accordance with the guidelines of the centers for disease control and prevention (cdc) [ ] . primary viral pneumonia was defined as acute respiratory failure and unequivocal alveolar opacities involving two or more lobes, with negative respiratory and blood bacterial cultures during the acute phase of influenza virus infection at icu admission [ ] . systemic corticosteroids have been widely used as co-adjuvant therapy in patients arf/ards due to influenza pneumonia to modulate lung inflammation, despite controversy on clinical outcomes. our findings provide solid evidence to support the association of corticosteroids administration with increased icu mortality in critically ill patients with influenza pneumonia. copd "exacerbation" was defined according to copd exacerbation guidelines of the european respiratory society/ats [ ] as increased respiratory symptoms, particularly dyspnea, cough, and increased sputum purulence without pulmonary infiltrates in chest x-ray. copd patients with pulmonary infiltrates in chest x-ray were considered as cap and were included in the present analysis. asthma exacerbation was defined as acute or subacute episodes characterized by a progressive increase in one or more typical asthmatic symptoms (dyspnea, coughing, wheezing, and tightness of the chest [ ] without infiltrates in the chest x-ray. asthmatic patients with pulmonary infiltrates in chest x-ray were considered as cap and were included in the present analysis. community-acquired respiratory co-infection (carc) was considered in patients with confirmation of influenza virus infection showing recurrence of fever, increase in cough and production of purulent sputum plus positive bacterial/fungal respiratory or blood cultures at icu admission [ , ] . refractory septic shock was defined in accordance with the surviving sepsis campaign guidelines [ ] ; that is, patients in whom adequate fluid resuscitation and vasopressor therapy are unable to restore hemodynamic stability. ventilator-associated pneumonia was defined according to the new ats/idsa guidelines [ ] among icu patients who developed a new pneumonic event while mechanically ventilated for at least h after clinical presentation. corticosteroid treatment: we considered the primary indication recorded by the treating physician as coadjuvant treatment for viral pneumonia. corticosteroid therapy was defined as corticosteroid administration at icu admission (within the first h). patients receiving corticosteroids as rescue therapy (due to shock) or due to copd/asthma exacerbation were excluded (see exclusion criteria). obese patients were defined as those with a body mass index (bmi) of > kg/m . the icu admission criteria and treatment decisions for all patients, including the decision to intubate and type of antibiotic, antiviral, or corticosteroid therapy administered, were not standardized between centers and were left to the discretion of the attending physician, according to the spanish society of intensive care recommendations [ ] . primary to determine whether corticosteroid use was associated with icu mortality. in addition, the primary outcome was examined in eight pre-specified subgroups defined according to the following baseline characteristics: ( ) severity of illness (apache score < vs. ≥ ), ( ) intensity of organ dysfunction (sofa < vs. ≥ ), ( ) presence of shock upon icu (yes vs. no), ( ) need for mechanical ventilation (mv) upon icu admission (yes vs. no), ( ) inflammatory response to c-reactive protein (crp < vs. ≥ mg/dl), ( ) presence of bacterial coinfection (yes vs. no), ( ) chronic lung disease such as copd (yes vs. no), and ( ) asthma (yes vs. no). the cutoff for continuous variables was determined according to our population median value. secondary to determine risk factors associated with corticosteroid use. icu length of stay (los) and mv days were also examined in survivors between groups receiving and not receiving corticosteroid therapy. discrete variables were expressed as counts (percentage) and continuous variables as means with standard deviation (sd) or medians and interquartile range - % (iqr). for patient demographics and clinical characteristics, differences between groups were assessed using the chi-squared test and fisher's exact test for categorical variables, and the student t test or the mann-whitney u test for continuous variables. to investigate the association between baseline (icu admission) variables and corticosteroid use, a multivariate analysis (binary logistic regression) was performed. the multivariate model comprised factors of clinical interest and all significant covariates in the univariate analysis. the results are presented as odds ratios (or) and % confidence intervals (ci). model integrity was examined using standard diagnostic statistics and plots and goodness of fit for each model for all outcomes, and was assessed with the hosmer-lemeshow test. after this first approach, we generated a full-matching ps analysis in order to minimize the effect of a corticosteroid treatment selection bias and to control for potential confounding factors (additional information about the ps full-matching analysis can be found in the electronic supplementary material) [ ] . this allowed us to study two comparable (almost identical) cohorts: ( ) the corticosteroid-treated group and ( ) the control group, comprising patients who did not receive corticosteroid treatment. ps matching analysis attempts to compare outcomes between patients who have a similar distribution of all the covariates measured. an attractive feature of this approach is that it uses the entire sample. using the ps methodology, all patients were assigned a weight between and ; this propensity-matched cohort was generated by choosing the best weight balance. this method optimizes the post-weighting balance of covariates between groups and, in this way, approximates the conditions of random site-of-treatment assignment. to assess our ps adjustment, we checked for adequate overlap in propensity scores between groups with a crossvalidation model. to do so, we divided the patients in the database into two subsets: (a) a "training set" with patients ( %), and (b) a "validation set" with patients ( %). after the matching, a kaplan-meier survival plot was generated to track icu mortality over time for corticosteroid-treated and untreated patients. in addition, cox proportional hazards regression models were fitted to assess the impact of corticosteroids on icu mortality. the results are presented as hazard ratios (hr) and % ci and adjusted survival plots. because cox hazard survival analysis is not satisfactory for describing icu patient mortality over time [ ] , we performed a competing risks analysis to confirm our results. first, we computed the cumulative incidence function (cif) of death over time. at time t, the cif defines the probability of dying in the icu by that time t when the population can be discharged alive. the cif was estimated from the data using the cmprsk package developed by gray [ ] . we used the fine and gray model [ ] , which extends the cox model to competing risks data by considering the sub-distribution hazard (for instance, the hazard function associated with the cif). the strength of the association between each variable and the outcome was assessed using the sub-hazard ratio (shr), which is the ratio of hazards associated with the cif in the presence of and in the absence of a prognostic factor. in order to avoid spurious associations, the variables that we entered in the regression models were those with a relationship in the univariate analysis (p < . ) or a plausible relationship with the dependent variable. data analysis was performed using spss for windows version . (ibm corp., armonk, ny, usa). mixed-effects models were performed with r (cran.r-project.org). a total of patients with confirmed influenza pneumonia were enrolled at icus in spain during the study period ( ) ( ) ( ) ( ) ( ) ( ) . of these, ( . %) met the inclusion criteria and were included in the study (fig. ) . among patients with corticosteroid therapy, ( . %) received methylprednisolone, ( . %) prednisolone, and three ( . %) dexamethasone. for all patients who received therapy with corticosteroids due to pneumonia, this was initiated within the first h of icu admission. patients received a median (interquartile range [iqr]) daily dose equivalent to ( - ) mg of methylprednisolone, and the median duration of corticosteroid treatment was ( - ) days. the frequency of corticosteroid treatment by study period was . % in , . % in , % in , and . % in . considering the period as baseline, we observed that only in was there a significant reduction (p = . ) in the indication of corticosteroid treatment as co-adjuvant therapy for pneumonia. no differences in the rate of ventilator-associated pneumonia were observed between patients with (n = , . %) and without (n = , . %) corticosteroid therapy. clinical characteristics of patients and their distribution in the two groups are shown in table fig. flowchart of all excluded and included patients who received corticosteroid therapy were sicker according to the apache ii score, more obese, and more likely to have asthma, copd, and hematological diseases than those who did not receive treatment. mv use, serum procalcitonin concentrations, and icu mortality rate were higher in patients who received corticosteroids. there were no significant differences between groups regarding icu los or mv days. no other differences were found between the groups. overall mortality was . % ( / ). to determine factors associated with corticosteroid use, a stepwise logistic regression model was performed. apache ii score, asthma, copd, obesity, hematological disease, and mv were the independent variables included in the model. as shown in table , mv (or = . ), asthma (or = . ), copd (or = . ), and hematological disease (or = . ) were independently associated with corticosteroid use. table , supplementary material). ps matching was applied, and control and treated patients were matched. the summaries of balance for unmatched and matched data are shown in table (and e- fig. in the supplementary material). the apache ii score, sofa score, delay at icu admission, number of quadrants infiltrated in chest x-ray, serum lactate dehydrogenase (ldh), white blood cell (wbc) count, continuous renal replacement therapy (crrt), serum crp, mv, shock, chronic heart disease, human immunodeficiency virus (hiv/aids), primary viral pneumonia, bacterial co-infection, and corticosteroid use were the variables included in the logistic regression analysis of the ps model. the discriminatory power of the model (e- fig. , supplementary material) was good, with an area under the receiver operating characteristic curve of . ( % ci . - . , p < . ). the accuracy of the predictive model (training set) with respect to the validation set was . . e- figure (supplementary material) shows the kaplan-meier estimates of the mortality rate during icu admission, differentiating between patients with and without corticosteroid use. the cumulative survival was lower in patients with corticosteroid therapy than in untreated patients (log-rank test . , p < . ). when we excluded patients with carc, the results were similar (log-rank test . , p = . ; supplementary material) . however, in patients with carc, only a trend towards higher mortality related to corticosteroid treatment was observed p = . ; supplementary material) . finally, to determine the impact of corticosteroid use on icu mortality, a cox regression analysis adjusted for apache ii and potential confounding factors (see e- fig. in supplementary material) was performed. the survival plot (fig. ) showed that the use of corticosteroids was significantly associated with a higher icu mortality rate (hr . [ % ci . - . ], p < . ). when a multivariate fine and gray regression model was used (fig. and e- table in the supplementary material), corticosteroid use remained as a factor associated with mortality (shr = . [ % ci . - . ], p < . ). our results strongly suggest that administration of corticosteroids as co-adjuvant therapy to standard antiviral treatment in critically ill patients with severe influenza pneumonia is associated with increased icu mortality. this negative effect was evident in all subgroups considered and after careful adjustments, including a ps matching analysis. to assess the potential effects of corticosteroids on these severely ill patients, we limited our analysis to a well-defined cohort of icu patients with severe influenza pneumonia, and excluded those with other indications for corticosteroid use. the effect analysis of corticosteroids was restricted to early administration (within the first h of icu admission) in order to avoid the inclusion of patients receiving rescue therapy and to reduce the effects of time-dependent confounders. we found that mv, asthma, copd, and hematological disease were independently associated with corticosteroid use. severe acute lung injury following influenza infection is characterized by uncontrolled local and systemic inflammation [ ] [ ] [ ] . this damage is caused by an excessive host innate response with exaggerated migration of macrophages, neutrophils, and pro-inflammatory cytokines, leading to classic exudative diffuse alveolar damage, severe necrotizing bronchiolitis with predominantly neutrophilic inflammation, and intense alveolar hemorrhage [ ] . corticosteroids have several anti-inflammatory, immunomodulatory, and vascular properties, including inhibition of pro-inflammatory cytokines, reduction of leukocyte trafficking, stimulation of apoptosis in t-lymphocytes, and maintenance of endothelial integrity and vascular permeability. therefore, they may represent an option for adjunctive therapy; however, although they are frequently prescribed in critically ill patients with influenza pneumonia, their potential benefits and harms are controversial [ , , , , ] . three recent systematic reviews and meta-analyses [ ] [ ] [ ] concluded that corticosteroid therapy is significantly associated with mortality, even in the subgroup of patients with influenza hospitalized in or outside the icu. these systematic reviews recognize similar limitations such as the heterogeneity of the studies, lack of sufficient data on indication for corticosteroids, dosage, therapy timing, type of corticosteroid use, and severity of illness. a recent cochrane review [ ] reported an association between corticosteroid therapy and increased mortality. however, all studies included were observational (only seven studies included patients admitted to the icu) and of very low quality due to confounding by indication. therefore, it was impossible to determine whether additional corticosteroid therapy is indeed harmful in patients with influenza infection. several observational studies have evaluated the impact of corticosteroids on mortality in patients with influenza infection [ - , , , , - ] , and have offered conflicting perspectives. observational studies are potentially susceptible to bias and do not provide robust results. despite these weaknesses, however, observational data are representative of current clinical practice, and applying modern methods such as ps matching may help in evaluating the effects of certain interventions in clinical settings and may help to guide decision-making. to the best of our knowledge, only one study has used an analysis similar to ours in patients with influenza infection. in critically ill patients, kim et al. [ ] analyzed the effect of corticosteroid treatment on -day mortality with a similar methodology to ours, applying multivariate adjustment (controlling for variables that differed between the two groups and incorporating the ps) and ps matching ( : ). sixty-five pairs were generated, and the -day mortality rate was higher in the corticosteroid group ( % vs. %, p = . ). these data are in concordance with our results; however, the mortality rate in our patients was substantially lower. this discrepancy might be due to several factors, including differences in severity of illness, endpoint observational period (icu mortality vs. -day mortality), and early recognition vs. standard of care. interestingly, kim et al. reported that half of the patients treated with corticosteroids received hydrocortisone, a non-standard co-adjuvant treatment of pneumonia. the authors did not report the treatment indication for corticosteroid therapy; thus many patients in this cohort may have received corticosteroids for a reason other than influenza-induced acute lung injury. in contrast, our population comprised only patients treated with corticosteroids as an co-adjuvant therapy for severe viral pneumonia, excluding patients with other indications for corticosteroids (such as shock). therefore, with a homogeneous group of critically ill patients, and after carefully controlling for important confounders through a ps matching analysis and competing risks analysis, we provide robust evidence to support the association between corticosteroid administration and increased mortality. interestingly, the subgroup analysis showed that, in contrast to patients with asthma, copd patients treated with corticosteroids had a higher risk of icu mortality than those without corticosteroid therapy. we are not able to explain this finding using our database because we did not collect data on the degree of copd severity. copd patients may be at an advanced stage of disease. this condition, and other uncontrolled confounding factors, may explain the higher mortality among copd patients even after excluding patients with copd exacerbation. the main strengths of this study are the homogeneous and uniform population, the high number of critically ill patients included in our multicenter study, data regarding the kind/indication of corticosteroid treatment, and the carefully executed analysis to resolve confounding factors including the presence of competing risks. however, we recognize some limitations. first, our results were obtained in a homogeneous population of patients with influenza pneumonia and cannot be extrapolated to other populations. second, we did not review the duration of viral shedding or appearance of drug-resistant virus in either group. third, ps matching analysis may also be a limitation, because this method may not reflect the possible biases in observational studies, and some residual confounding may persist. however, as ps matching analysis can balance the population and reduces observational bias, it is the best evidence available for physicians. fourth, data on mv of patients were not recorded. lung-protective ventilation is the standard of care for patients with acute lung injury/ards because of the evidence that it decreases mortality. although we did not provide data regarding ventilation of patients, it is broadly accepted in this country that applying protective ventilation improves results and is one of the national quality indicators. finally, we did not record data about muscle weakness or metabolic alterations related to corticosteroid treatment. in a homogeneous group of critically ill patients with severe influenza pneumonia, after adequate adjustment by ps matching and competing risks, co-adjuvant corticosteroid therapy was significantly associated with increased icu mortality. our data strongly suggest that corticosteroids should not be used as co-adjuvant therapy in patients with influenza pneumonia. the online version of this article (https ://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. higinio martín hernández hospital nuestra señora del andaluz ojeda anzález hospital virgen vega, salamanca) nicolás hidalgo andrés cataluña: rosa mª catalán (hospital general de joaquim ramón cervelló hospital dos leonel lagunes (hospital vall angels pascual diago (hospital verge de la cinta hospital san camil carmen lomas fernández, josé julián berrade (hospital m. broggi hospital virgen del puerto galicia: mª lourdes cordero complejo hospitalario de madrid: frutos del nogal sáez, m blasco navalpotro, ricardo díaz abad, josé luis flordelis lasierra josé mª molina (hospital nuestra señora de miriam díaz cámara eduardo morales fdez. de la reguera (hospital central de la defensa murcia: sofía martínez (hospital isabel cremades navalon, martín vigil velis (hospital universitario reina sofía noemí llamas fernández (hospital general universitario rafael méndez navarra: enrique maraví-poma, i jimenez urra, laura macaya redin, a tellería (hospital virgen del camino noelia artesero garcia, laura macaya (complejo hospitalario navarra-uci a) complejo hospitalario navarra uci b) tomás rodríguez (hospital de basurto iratí garrido santos (hospital de higinio martín hernández (hospital galdakao valencia: josé blanquer, nieves carbonell, josé ferreres franco abilio arrascaeta llanes hospital de la ribera, valencia) andorra: antoli ribas (hospital nuestra señora de meritxell effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza a h n pdm virus infection: a meta-analysis of individual participant data impact of neuraminidase inhibitors on influenza a(h n ) pdm -related pneumonia: an ipd meta-analysis impact of early oseltamivir treatment on outcome in critically ill patients with pandemic influenza a the illegitimate crusade against corticosteroids for severe h n pneumonia adjuvant corticosteroid treatment in adults with influenza a (h n ) viral pneumonia* impact of corticosteroid treatment and antiviral therapy on clinical outcomes in hematopoietic cell transplant patients infected with influenza virus early corticosteroids in severe influenza a/h n pneumonia and acute respiratory distress syndrome methylprednisolone infusion for life-threatening h n -virus infection corticosteroid therapy in intensive care unit patients with pcrconfirmed influenza a (h n ) infection in finland h n influenza a virus-associated acute lung injury: response to combination oseltamivir and prolonged corticosteroid treatment corticosteroid treatment in critically ill patients with pandemic influenza a/h n infection analytic strategy using propensity scores corticosteroid therapy in patients with primary viral pneumonia due to pandemic (h n ) influenza use of early corticosteroid therapy on icu admission in patients affected by severe pandemic (h n )v influenza a infection corticosteroids as adjunctive therapy in the treatment of influenza (review) corticosteroid treatment in patients with severe influenza pneumonia: a propensity score matching analysis characteristics of patients with hospital-acquired influenza a (h n )pdm virus admitted to the intensive care unit impact of obesity in patients infected with influenza a(h n ) patients with influenza a (h n )pdm admitted to the icu. impact of the recommendations of the semicyuc pandemic and post-pandemic influenza a (h n ) infection in critically ill patients severe pandemic (h n )v influenza a infection: report on the first deaths in spain apache ii: a severity of disease classification system the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine infectious diseases society of america/american thoracic society consensus guidelines on the management of communityacquired pneumonia in adults world heal organization asthma exacerbations: origin, effect, and prevention increased incidence of co-infection in critically ill patients with influenza community-acquired respiratory coinfection in critically iii patients with pandemic influenza a(h n ) virus surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock management of adults with hospital-acquired and ventilatorassociated pneumonia: clinical practice guidelines by the infectious diseases society of america and the recommendations of the infectious diseases work group (gtei) of the spanish society of intensive and critical care medicine and coronary units (semicyuc) and the infections in critically ill patients study group (geipc) of the spanish society of infectiou optimal full matching for survival outcomes: a method that merits more widespread use evaluating mortality in intensive care units: contribution of competing risks analyses a proportional hazards model for the subdistribution of a competing risk organizing pneumonia in patients with severe respiratory failure due to novel a (h n ) influenza clinical aspects and cytokine response in severe h n influenza a virus infection h n : viral pneumonia as a cause of acute respiratory distress syndrome glucocorticosteroid in treatment of severe pneumonia early use of glucocorticoids was a risk factor for critical disease and death from ph n infection effect of corticosteroid therapy on influenza-related mortality: a systematic review and meta-analysis do corticosteroids reduce the mortality of influenza a (h n ) infection? a meta-analysis corticosteroids for the treatment of human infection with influenza virus: a systematic review and meta-analysis early corticosteroid treatment for severe pneumonia caused by h n influenza virus systemic corticosteroids and early administration of antiviral agents for pneumonia with acute wheezing due to influenza a (h n ) pdm in japan effect of low-tomoderate-dose corticosteroids on mortality of hospitalized adolescents and adults with influenza a (h n ) pdm viral pneumonia the authors are grateful to michael maudsley for language editing and eudald correig for the statistical analysis.getgag (grupo español de trabajo gripe a grave) study group investigators. andalucía: pedro cobo (hospital punta de europa, algeciras); javier martins (hospital santa ana motril, granada); cecilia carbayo (hospital torrecardenas, almería); emilio robles-musso, antonio cárdenas, javier fierro author contributions gm, ar, jsv, iml, ed and at conceived and designed the study. all authors, apart from mr, lfr, jg, and as, contributed to the acquisition and local preparation of the constituent database. gm, ar, ec, st, iml, ed, jgm, ls, and jcy contributed to database creation and standardization, design of statistical analyses, and data analysis. gm, ar, lfr, jg, jsv, ed, mb, st, jg, jcy, as, jgm, ls, mvo, jmc, mvv, mir, at, and iml made important intellectual contributions and actively participated in the interpretation of the data and wrote the paper. all authors contributed to critical examination of the paper for important intellectual content and approval of the final manuscript. this study was supported in part by grants from semicyuc (spanish society of critical care) and the ricardo barri casanovas foundation. the study sponsors had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. the corresponding authors (ar/gm) had full access to all the data in the study and final responsibility for the decision to submit for publication. all named authors declare that they have no conflicting interests. the institutional review board of joan xxiii hospital approved the original study (irbref# ). key: cord- -w dc h authors: ríos, fernando g; estenssoro, elisa; villarejo, fernando; valentini, ricardo; aguilar, liliana; pezzola, daniel; valdez, pascual; blasco, miguel; orlandi, cristina; alvarez, javier; saldarini, fernando; gómez, alejandro; gómez, pablo e; deheza, martin; zazu, alan; quinteros, mónica; chena, ariel; osatnik, javier; violi, damian; gonzalez, maria eugenia; chiappero, guillermo title: lung function and organ dysfunctions in patients requiring mechanical ventilation during the influenza a (h n ) pandemic date: - - journal: crit care doi: . /cc sha: doc_id: cord_uid: w dc h introduction: most cases of the influenza a (h n ) infection are self-limited, but occasionally the disease evolves to a severe condition needing hospitalization. here we describe the evolution of the respiratory compromise, ventilatory management and laboratory variables of patients with diffuse viral pneumonitis caused by pandemic influenza a (h n ) admitted to the icu. method: this was a multicenter, prospective inception cohort study including adult patients with acute respiratory failure requiring mechanical ventilation (mv) admitted to icus in argentina between june and september of during the influenza a (h n ) pandemic. in a standard case-report form, we collected epidemiological characteristics, results of real-time reverse-transcriptase--polymerase-chain-reaction viral diagnostic tests, oxygenation variables, acid-base status, respiratory mechanics, ventilation management and laboratory tests. variables were recorded on icu admission and at days , and . results: during the study period patients with diffuse viral pneumonitis requiring mv were admitted. they were ± years of age, with acute physiology and chronic health evaluation ii (apache ii) scores of ± , and most frequent comorbidities were obesity ( %), previous respiratory disease ( %) and immunosuppression ( %). non-invasive ventilation (niv) was applied in ( %) patients on admission, but % were later intubated. acute respiratory distress syndrome (ards) was present throughout the entire icu stay in the whole group (mean pao( )/fio( ) ± ). tidal-volumes used were . to . ml/kg (ideal body weight), plateau pressures always remained < cmh( )o, without differences between survivors and non-survivors; and mean positive end-expiratory pressure (peep) levels used were between to cm h( )o. rescue therapies, like recruitment maneuvers ( to %), prone positioning ( to %) and tracheal gas insufflation ( %) were frequently applied. at all time points, ph, platelet count, lactate dehydrogenase assay (ldh) and sequential organ failure assessment (sofa) differed significantly between survivors and non-survivors. lack of recovery of platelet count and persistence of leukocytosis were characteristic of non-survivors. mortality was high ( %); and length of mv was ( to ) days. conclusions: these patients had severe, hypoxemic respiratory failure compatible with ards that persisted over time, frequently requiring rescue therapies to support oxygenation. niv use is not warranted, given its high failure rate. death and evolution to prolonged mechanical ventilation were common outcomes. persistence of thrombocytopenia, acidosis and leukocytosis, and high ldh levels found in non-survivors during the course of the disease might be novel prognostic findings. on april , a novel influenza a (h n ) virus emerged in mexico and spread rapidly across the world [ , ] . as of june , more than countries had reported confirmed cases of infection with pandemic influenza a (h n ) virus, including at least , deaths [ ] . unlike seasonal influenza, in which hospitalizations occur among patients younger than and older than years, or in those with underlying diseases [ ] , this novel virus affected otherwise healthy young and middle-aged adults and obese individuals [ , ] . patients with previous respiratory disease, immunocompromised hosts and pregnant women were affected as frequently as with seasonal influenza [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . although a mild form of the disease was prevalent, it soon became evident that the influenza a (h n ) virus could also provoke severe, acute respiratory failure requiring admission to the intensive care unit (icu) for mechanical ventilation [ ] , which was reflected in the severe pathological injury found at autopsy [ ] . the argentinian population was greatly affected during the pandemic, with a total of , , cases of influenza-like illness requiring , hospitalizations. of the , confirmed cases of patients infected with the new strain, died [ ] . this represents a death rate per infection of . % in hospitalized cases; an intermediate figure compared to . % in brazil, . % in chile, and approximately % in uruguay, colombia and venezuela [ ] . it should be noted that these numbers reflect great uncertainty, particularly with regard to case diagnosis. lack of testing of mild disease and difficulties due to laboratory overload have also been well described [ , ] . these general problems have been acknowledged by experts [ ] . the severity of disease was rapidly perceived by health authorities and scientific societies. hence, a committee of experts of the argentinian society of intensive care medicine decided to focus on the most acutely ill patients: those presenting with diffuse viral pneumonitis requiring mechanical ventilation. they designed an epidemiological study, recently-published, to determine risk factors and outcomes [ ] ; this is one of many series up to the present that have described epidemiological and clinical aspects of the influenza a (h n ) pandemic [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . there remains, however, a paucity of data published on physiological evolution during icu stay [ ] . this present study, concurrently planned with the first by the same committee of experts, thus aims to provide such information. our objectives were: first, to characterize alterations of oxygenation, respiratory mechanics and the use of mechanical ventilation; second, to explore compliance with protective lung ventilation; and, finally, to assess the evolution of laboratory findings and organ dysfunctions throughout the course of the disease. this was a multicenter, inception cohort study that included patients aged > years admitted to the icu with a previous history of influenza-like illness, evolving to acute respiratory failure that required mechanical ventilation during the winter in the southern hemisphere. these patients had confirmed or probable disease caused by the influenza a (h n ) virus and were included in the registry of cases of the argentinian society of intensive care medicine (sati), created to characterize local aspects of the pandemic. on june , a form to collect online epidemiological data was posted on the official sati website. a detailed description and analysis of this information was recently published [ ] . there was also an optional, more comprehensive casereport form to complete, developed by experts of the sati's respiratory committee for recording certain prespecified variables throughout icu stay, which included mechanical ventilation (mv), respiratory mechanics, oxygenation, blood chemistry and organ failure variables. this information was collected over days and is analyzed in the present study. patients were characterized as confirmed, probable or possible cases of influenza a (h n ) [ ] according to the findings in the respiratory samples collected on admission. some specimens, however, were not analyzed because laboratories soon became overloaded, especially at the beginning of the pandemic. as of september , the weekly update of the ministry of health reported that in patients ≥ years with influenzalike illness, the influenza a (h n ) virus had displaced other respiratory viruses in . % of the samples processed [ , ] . as a result of this, probable and suspected cases were considered as caused by the novel virus and were so included in the study. we collected dates of hospital and icu admission, and of mv onset; demographics; risk factors for influenza a; actual weight; height; severity of illness (acute physiology and chronic health evaluation ii, apache ii), organ failures (sequential organ failure assessment, sofa); type of mv used, as noninvasive (niv) and invasive; and date of intubation. ideal body weight (ibw, ml/kg) and body mass index (bmi) were calculated; obesity was defined as a bmi > . at mv onset (day ) and on days , and , until death or discharge, whichever occurred first, we recorded: ( ) mv-related variables. ( ) mv modes: volume-controlled ventilation (vcv); pressure-controlled ventilation (pcv); bilevel mode; pressure support ventilation (psv); other. ( ) tidal volume (vt, in ml/kg of ibw) ( ) pressures: peak, plateau pressures, total positive end-expiratory pressure (peep) and driving pressure (plateau pressure -peep), in cmh o. the main outcome measure was hospital mortality; secondary outcomes were length of mv, of icu (losicu) and of hospital (loshosp) stays. in case of missing observations, local study coordinators were contacted to provide the corresponding values. proportions were calculated as percentages of existing data. no assumptions for missing data were made. statistical analysis was performed with spss . (spss inc., chicago, il, usa). data were analyzed for the entire population; for the subgroups of survivors vs. non-survivors; and for patients receiving niv on admission vs. those who did not. descriptive statistics used were: mean ± standard deviations (sd) and median and - % interquartile ranges (iqr) for continuous data of normal and non-normal distribution, respectively; and percentages for categorical data. differences between subgroups were analyzed with unpaired t test, mann-whitney u test, and chi-square tests, as appropriate. a p-value of <. was considered statistically significant. a kaplan-meier curve was constructed to evaluate survival over the follow-up period. over time, normally distributed data were analyzed with two-way repeated measures of anova. at the pre-specified time points, differences within the entire group and subgroups, and between subgroups, were tested using paired and unpaired t tests, respectively. in non-normally distributed data, differences over time within the entire group and the subgroups were analyzed with friedman's and wilcoxon tests. comparisons between subgroups at the pre-specified time points were tested with mann-whitney u test. the bonferroni correction was used to adjustments for multiple comparisons. the local institutional review boards waived the need for informed consent, given the general lack of knowledge on the clinical and outcome characteristics of the ongoing pandemic and to the non-interventional study design. general characteristics (table ) between june and august , the sati's online registry included patients admitted to icus with confirmed/probable/possible diffuse viral pneumonitis caused by influenza a (h n ), with acute respiratory failure requiring mv ( ) . of these, consecutive patients admitted to icus were followed over time, and are presented in this study. to address any potential concern that unconfirmed cases could belong to a different population of patients, we performed a sensitivity analysis of clinical and outcome characteristics data after exclusion of these patients. the results of this analysis did not differ from those of the primary assessments, so the patients are considered for evaluation. briefly, patients were middle-aged, with no gender preponderance; they had a history of symptoms of nearly one-week duration and were ventilated at [ to - ] day after hospital admission. pre-existent respiratory diseases, obesity, and diseases causing immunosuppression were the most frequent comorbid conditions; and prevalence of pregnancy was higher than in the general population, as expected [ ] . non-survivors were sicker on admission; duration of previous symptoms was longer; and organ failures were more severe. obesity and immunosuppression were significantly more frequent as predisposing conditions. ninety-three patients survived ( %) (see figure ). (table ) during the study period, the entire group had vt values between . to . ml/kg of ibw, with plateau pressures remaining always < cmh o. non-survivors displayed a trend towards lower vt and higher plateau pressures, which differed significantly from survivors only at day . intermediate peep levels were used, and decreased in survivors from day onwards. driving pressures were similar over time in all patients; only at admission did non-survivors exhibit higher values. pao /fio increased significantly over time in all patients and in survivors. it remained, however, < in the whole group throughout the entire icu stay due to non-survivor values. non-survivors displayed significantly lower pao /fio at all time points. lung infiltrates (in quadrants) peaked at day ( . ± . vs. . ± at day , p < . ) and then decreased during the study in the entire group, especially at day ( . ± . , p < . vs. day ), which reflected the improvement in survivors ( . ± . at day vs. . ± . at day , p < . ). in figure , the utilization of ventilation modes and rescue therapies in the entire group are shown. briefly, pcv use equaled vcv at day , preceded by deterioration in oxygenation and respiratory mechanics: pao / fio ± vs. ± , (p = . ); paco ± vs. ± mmhg (p = . ); ph . ± . vs. . ± . (p = . ), and plateau pressures of ± vs. ± cmh o (p = . ). recruitment maneuvers became significantly more common in non-survivors at day ( %, vs. % in survivors; p = . ), as did prone positioning ( %, vs. %; p = . ). after that, only prone positioning remained significantly more used in nonsurvivors (at day : %; vs. %, p = . ; and at day : %; vs. %, p = . ). six patients received tracheal gas insufflation; only one survived. neuromuscular blockers were prescribed in % of patients on admission; and their use was subsequently more frequent in non-survivors (day : % vs. %, p = . ; and day : % vs. %, p = . ). the main causes of death were refractory hypoxemia ( %); followed by multiorgan dysfunction syndrome ( %) and shock ( %). prolonged mechanical ventilation and long icu and hospital stays were frequent (table ) . tracheostomy was performed in patients ( %) at day [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . acid-base variables and fluid balance (table ) arterial ph increased over time in the whole cohort and in both subgroups, perhaps secondary to general resuscitation measures. despite this, non-survivors displayed significantly lower ph at all time points, owing to changes in base excess on days and , and to pco elevations thereafter. respiratory rates remained unchanged, only increasing at day in non-survivors; nevertheless, this corresponded to the highest pco values, indicating the more severe respiratory compromise. bicarbonate paralleled ph behavior. changes in fluid balance did not show clear trends: only at day they decreased significantly, expressing survivors' behavior. forty-nine patients ( %) underwent a trial of niv on admission; they were significantly less ill and had a lower incidence of immunosuppression. oxygenation and outcome variables were similar to those of patients not receiving niv. sixty-one percent of patients (n = ) receiving niv survived; duration of niv was of ( to ) hours. there were no differences between survivors and nonsurvivors in the duration of the procedure, or in the type of interface or respirator used. of note, most patients on niv ( out of ; %) had to be intubated and ventilated invasively for hypoxemic failure. characteristics associated to niv success/failure are shown in table . niv was also used for treating post-extubation respiratory failure in of patients ( %), with success (reintubation not needed) in cases ( %). the most consistent changes over time were found in platelet count, which increased significantly in the whole cohort (p < . for days , and vs. day ), secondary to elevations in survivors. at all time points, platelets differed between survivors and non-survivors. conversely, white blood cell count showed a progressive creatine-kinase and markers of liver injury (alanine/ aspartate aminotransferases, serum bilirubin; not shown) were mildly elevated and displayed no substantial changes. on the contrary, lactate-dehydrogenase levels were significantly higher in non-survivors throughout the study. creatinine levels were stable over the period, but were significantly higher in non-survivors on days and . finally, sofa score diminished over time in all patients (p < . for days and vs. day ), as a result of the decrease in survivors. sofa was significantly lower in survivors throughout the study. in figure , the differences between survivors and non-survivors are displayed. we report on a large, prospective cohort of influenza a (h n ) patients that were mechanically ventilated for acute respiratory failure due to diffuse pneumonitis during the pandemic in argentina. though most were middle-aged, previously healthy adults, patients with preexistent lung disease, immunosuppression, obesity and pregnancy were also affected. mortality was high and evolution to chronic critical illness was common, as shown by prolonged mechanical ventilation, high needs of tracheostomy, and lengthened icu and hospital stays. patients had characteristically a history of protracted symptoms and displayed severe compromise of oxygenation compatible with ards throughout the study period, which only improved in survivors. at all time points, pao /fio differed significantly between survivors and non-survivors, requiring higher fio and peep in this last subgroup. yet the levels of applied peep were only in the intermediate range, similar to mean values of . cmh o of peep in an international study on mechanical ventilation [ ] , which may explain the relatively high fio used in our study. driving pressures were similar in both subgroups most of the time, suggesting an intention to limit alveolar excursion as part of a protective strategy. it is striking that, as has been described in similar studies on mechanical ventilation performed during the influenza a (h n ) pandemic [ , ] , tidal volumes used were between . and . ml/kg ibw, certainly higher than the ml/kg demonstrated as being lungprotective [ ] . indeed, barriers to implementing lowtidal volume have been identified and might explain physician behavior [ ] . despite this, plateau pressures did remain below cmh o [ ] , indicating that lung compliance might have been preserved. perhaps clinicians focused on plateau pressures rather than on tidal volumes [ ] since it still remains unclear which should be limited to avoid ventilator-induced lung injury [ ] . we, like others [ , , , ] , could not find differences in utilized tidal volumes between survivors and non-survivors. even so, non-survivors tended to display lower values, probably reflecting physician efforts to intensify protective ventilation strategies in the most severely compromised. some researchers [ , ] have suggested that allowing higher tidal volumes in a population of young and previously healthy patients with strong ventilatory drive might reveal an attempt to restrain heavy sedation and neuromuscular blocker use. notwithstanding this, we believe that these findings may also represent clinicians' inadequate prescription, as described in other scenarios [ ] . not unexpectedly, vcv was the most common ventilator mode used. pcv use increased throughout the study period, peaking at day . this is in contrast with the recently identified trend towards decreased pcv utilization. transition to pcv mode was associated with preceding physiological worsening, so clinicians might have perceived pcv utilization as part of a global lungprotective strategy [ ] . refractory hypoxemia was the main cause of death. as in other studies [ , , ] , rescue therapies were frequently applied, with utilization highest hours after admission. recruitment maneuvers and prone positioning were the primary adjuvants utilized; ecmo and hfov are currently not available in argentina. a table oxygenation and acid-base variables, and fluid balance in all patients, and in survivors and non-survivors. prolonged mechanical ventilation course was frequent as reported elsewhere [ ] . niv was the first ventilation approach in % of cases, with % later requiring invasive ventilation, as has been documented in other studies [ , , ] . these common experiences should caution against delaying proper ventilatory support in this group, given that rapid deterioration is common. a recent meta-analysis suggests that niv does not decrease the need for intubation, so evidence to support its use in severe ards is questionable [ ] . in our study, improved outcomes with niv could be due to milder disease, evidenced by apache ii. the small number of patients that were not intubated precludes a statistical analysis; however, they were younger, with less severe disease and better oxygenation. significant changes in fluid balance were late and reflected changes in survivors. negative fluid balances could never be obtained, perhaps suggesting a continuing need for hemodynamic support: % of patients presented with shock [ ] . on the whole, fluid balances remained between those achieved by "liberal" and "conservative" strategies of the fluids and catheters treatment trial, depending on the day evaluated [ ] . thus far, it is not clear whether the negative fluid balance has a causal role in improving outcome in ali/ards, or if it simply expresses the global recovery of patients. another important finding was that arterial ph consistently and significantly differed between survivors and non-survivors, as described elsewhere [ , ] . during the first hours acidosis had a major metabolic component, likely as a sign of hemodynamic impairment. after the first week, respiratory acidosis ensued, indicating either the effects of protective ventilation, or merely deterioration due to progressive shunt, profound ventilation/perfusion mismatch and increased deadspace. with respect to blood chemistry, the usual findings of thrombocytopenia, leukocytosis and mildly elevated creatine-kinase blood levels were present [ , ] . regrettably, the lymphocyte count was not recorded. in viral infections, thrombocytopenia occurred frequently. although the mechanisms by which the influenza a (h n ) virus causes thrombocytopenia are unknown, its lack of resolution is a marker of poor prognosis. both leukocytosis and leucopenia have been found in hospitalized patients with influenza a (h n ) [ , ] ; in our study, persistent leukocytosis was associated with increased mortality. ldh elevations have been previously described in fatal cases [ ] , which corresponded to our finding of higher ldh levels in non-survivors at all time points. such elevations have also been reported in seasonal influenza [ ] . in experimental studies, increased ldh is a marker of human fetal membrane cell apoptosis induced by influenza virus [ ] . finally, multiorgan failure was frequent, and predictably more severe in non-survivors. this study has several strengths: first, the clinical characteristics and time course of pandemic influenza a (h n ) are thoroughly described and analyzed. second, data were collected prospectively in consecutive patients and with a standardized casereporting form, representing a large, nationwide cohort. third, temporal patterns of mechanical ventilation use, acid-base and blood chemistry variables, as well as fluid balance and organ failures, are carefully analyzed. prognostic implications are highlighted. finally, we present the largest experience with niv use during the pandemic. study limitations include the focus on mechanically ventilated patients, excluding less severe cases also admitted to the icu. many cases could not be confirmed because laboratories were overwhelmed with clinical samples, which is also described elsewhere [ , ] . data about transmission to healthcare workers were not recorded, especially regarding niv. currently, most information about its use during an epidemic relies upon expert opinion [ ] . in patients with diffuse viral pneumonitis caused by the influenza a (h n ) virus admitted to the icu and followed over time, ards was the rule, requiring high ventilation support and frequent use of rescue therapies. death, organ failures, and evolution to prolonged mechanical ventilation were common. in most cases, noninvasive ventilation failed to prevent endotracheal intubation. finally, elevated ldh levels, lack of recovery of platelet count and persistent acidosis and leukocytosis in non-survivors behaved as prognostic findings. • in influenza a (h n ) patients, hospital admission with prompt indication of mechanical ventilation -a marker of severe disease -was associated with a history of symptoms of nearly one-week duration. • an initial niv trial was not effective to avoid intubation in most patients; thus, this ventilation approach should likely be discarded in this setting. • mortality and morbidity were frequent: death was common and was mainly caused by persistent, refractory hypoxemia. prolonged mechanical ventilation and icu and hospital stays were typical. • ph, platelet count, ldh and sofa differed significantly between survivors and non-survivors over time. lack of recovery of platelet count and persistence of leukocytosis might be markers of poor prognosis. • every effort should be done to increase adherence to protective ventilation in the real world. abbreviations ali: acute lung injury; ards: acute respiratory distress syndrome; bmi: body mass index; cxr: plain chest x-ray film; ibw: ideal body weight; icu: intensive care unit; ldh: lactate dehydrogenase assay; los: length of stay; mv: mechanical ventilation; niv: non-invasive ventilation; pao /fio : relation between patient arterial po and inspired oxygen fraction used; pcv: pressure-controlled ventilation; peep: positive end-expiratory pressure; psv: pressure support ventilation; rr: respiratory rate; rt-pcr: real-time reversetranscriptase-polymerase-chain-reaction; sati: argentinian society of intensive care; sofa: sequential organ failure assessment; vcv: volumecontrolled ventilation; vt: tidal volume. the registry of the argentinian society of intensive care department intensive care, hospital general de agudos velez sarsfield, calderón de la barca , (c ahh) department critical care department intensive care, hospital lagomaggiore, gordillo s/n department intensive care mar del plata, argentina. intensive care unit, hospital universidad abierta interamericana, portela , (c aab) group on influenza: pneumonia and respiratory failure from swine-origin influenza a (h n ) in mexico pandemic (h n ) -update . weekly update influenza-associated hospitalizations in the united states intensive care patients with severe novel influenza a (h n ) virus infection-michigan critically ill patients with influenza a (h n ) infection in canada critically ill patients with influenza a (h n ) in mexico critical care services and h n influenza in australia and new zealand pandemic influenza a (h n ) virus hospitalizations investigation team: hospitalized patients with h n influenza in the united states h n ) working group: factors associated with death or hospitalization due to pandemic influenza a(h n ) infection in california intensive care adult patients with severe respiratory failure caused by influenza a (h n ) in spain influenza a pandemics: clinical and organizational aspects: the experience in chile national influenza a pandemic (h n ) clinical investigation group of china: clinical features of the initial cases of pandemic influenza a (h n ) virus infection in china registry of the argentinian society of intensive care sati: pandemic influenza a (h n ) in argentina: a study of patients on mechanical ventilation novel influenza a (h n ) pregnancy working group: h n influenza virus infection during pregnancy in the usa severe respiratory disease concurrent with the circulation of h n influenza pathology in fatal novel human influenza a (h n ) infection influenza pandémica (h n ) . república argentina worldwide statistics of the h n influenza a pandemic practical lessons from the first outbreaks: clinical presentation, obstacles, and management strategies for severe pandemic (ph n ) influenza pneumonitis writing committee of the who consultation on clinical aspects of pandemic (h n ) ventilator management for hypoxemic respiratory failure attributable to h n novel swine origin influenza virus guidance on case definitions to be used for investigations of novel influenza a (h n ) cases influenza pandémica (h n ) . república argentina. influenza pandémica (h n ) . report of the epidemiological week direccion de estadisticas e informacion de salud. sistema estadístico de salud. serie -número evolution of mechanical ventilation in response to clinical research the acute respiratory distress syndrome network: ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and acute respiratory distress syndrome barriers to providing lung-protective ventilation to patients with acute lung injury tidal volume reduction in patients with acute lung injury when plateau pressures are not high. ards clinical trials network express) study group: positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial anzueto a: tidal volume in mechanical ventilation: the importance of considering predicted body weight pressure-and volume-limited ventilation strategy group: evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome the multicenter trail group on tidal volume reduction in ards: tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome mechanical ventilation in critically ill patients with influenza a (h n ) mechanical ventilation in critically ill patients with influenza a (h n ) the finnali study on acute respiratory failure: not the final cut effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome is there a role for noninvasive ventilation in acute respiratory distress syndrome? a meta-analysis the national heart, lung, and blood institute acute respiratory distress syndrome (ards) clinical trials network: comparison of two fluidmanagement strategies in acute lung injury metabolic correlates of oxygen debt predict posttrauma early acute respiratory distress syndrome and the related cytokine response osatnik j: incidence, clinical course, and outcome in patients with acute respiratory distress syndrome swine influenza (h n ) pneumonia: clinical considerations influenza pneumonia: a descriptive study lactate dehydrogenase leakage as a marker for apoptotic cell degradation induced by influenza virus infection in human fetal membrane cells should noninvasive ventilation be considered a high-risk procedure during an epidemic? on the role of non-invasive (niv) to treat patients during the h n influenza pandemic lung function and organ dysfunctions in patients requiring mechanical ventilation during the influenza a (h n ) pandemic the authors declare that they have no competing interests. key: cord- - qi aibx authors: van de groep, kirsten; nierkens, stefan; cremer, olaf l.; peelen, linda m.; klein klouwenberg, peter m. c.; schultz, marcus j.; hack, c. erik; van der poll, tom; bonten, marc j. m.; ong, david s. y. title: effect of cytomegalovirus reactivation on the time course of systemic host response biomarkers in previously immunocompetent critically ill patients with sepsis: a matched cohort study date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: qi aibx background: cytomegalovirus (cmv) reactivation in previously immunocompetent critically ill patients is associated with increased mortality, which has been hypothesized to result from virus-induced immunomodulation. therefore, we studied the effects of cmv reactivation on the temporal course of host response biomarkers in patients with sepsis. methods: in this matched cohort study, each sepsis patient developing cmv reactivation between day and (cmv+) was compared with one cmv seropositive patient without reactivation (cmvs+) and one cmv seronegative patient (cmvs−). cmv serostatus and plasma loads were determined by enzyme-linked immunoassays and real-time polymerase chain reaction, respectively. systemic interleukin- (il- ), il- , il- , interferon-gamma–induced protein- (ip- ), neutrophilic elastase, il- receptor antagonist (ra), and il- were measured at five time points by multiplex immunoassay. the effects of cmv reactivation on sequential concentrations of these biomarkers were assessed in multivariable mixed models. results: among cmv+ patients, could be matched to cmvs+ or cmvs− controls or both. the two baseline characteristics and host response biomarker levels at viremia onset were similar between groups. cmv+ patients had increased ip- on day after viremia onset (symmetric percentage difference + % versus − % when compared with cmvs+ and + % versus + % when compared with cmvs−) and decreased il- ra (− % versus % and − % versus + %, respectively). however, multivariable analyses did not show an independent association between cmv reactivation and time trends of il- , ip- , il- , or il- ra. conclusion: cmv reactivation was not independently associated with changes in the temporal trends of host response biomarkers in comparison with non-reactivating patients. therefore, these markers should not be used as surrogate clinical endpoints for interventional studies evaluating anti-cmv therapy. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. cytomegalovirus (cmv) reactivation is observed in - % of intensive care unit (icu) patients without known prior immune deficiency [ ] [ ] [ ] and is associated with increased morbidity and mortality [ ] [ ] [ ] . in a previous study, we estimated that the population-attributable fraction of icu mortality due to cmv reactivation was % in patients with acute respiratory distress syndrome (ards) [ ] . in a subsequent study among patients with septic shock, we found an effect of cmv reactivation on icu mortality only in patients with concurrent epstein-barr virus reactivation [ ] . although multiple studies point toward a causal relationship, definitive proof that cmv reactivation worsens clinical outcome is lacking, as most data are also compatible with a scenario in which cmv reactivation is merely a marker of immune suppression in this patient group. based on previous studies in icu patients, there is a clear pathophysiological link between inflammation and immune suppression on the one hand and the subsequent risk of cmv reactivation on the other [ ] [ ] [ ] [ ] [ ] . markers reflecting impaired functioning of natural killer cells and cytotoxic t cells were predictive of cmv reactivation [ , ] . furthermore, bacterial sepsis and corticosteroids have been identified as clinical risk factors for cmv reactivation [ , , ] . however, less is known about the reverse association and thus the effects of cmv reactivation on the immune system. direct cytotoxic effects of cmv on organs have been observed primarily in immunocompromised hosts [ ] but also in previously immunocompetent patients in the icu [ ] . moreover, indirect immune-modulating effects are assumed to play a role in the pathogenicity of cmv [ , [ ] [ ] [ ] . in vitro analysis revealed multiple mechanisms encoded within the genome of cmv that may contribute to a non-specific inhibition of both cellular and humoral immunity [ ] . observational clinical studies yielded conflicting results comparing levels of multiple inflammatory markers in patients with and without cmv reactivation [ , , ] . however, these studies analyzed biomarker responses only immediately upon icu admission and thus could not assess potential immunological effects due to the onset of cmv reactivation. nevertheless, cytokine levels were used as a primary (surrogate) endpoint in a recent placebo-controlled randomized control trial in which prophylactic antiviral treatment with ganciclovir failed to reduce interleukin- (il- ) levels [ ] . hence, definite proof of immune-modulating effects induced by cmv remains to be demonstrated. naturally, such an effect can be demonstrated only after onset of cmv reactivation. therefore, this longitudinal study aimed to investigate whether the temporal course of seven host response biomarkers, including both pro-and anti-inflammatory cytokines, in previously immunocompetent icu patients with sepsis differs between patients with and without cmv reactivation. this matched cohort study was performed among patients who had been included in two previous studies conducted within the molecular diagnosis and risk stratification of sepsis (mars) cohort [ , ] . for this study, we included sepsis patients who presented with either concomitant ards or septic shock to the mixed icus of two university medical centers in the netherlands between january and june and had remained in the icu beyond day . exclusion criteria were cmv seronegative patients with cmv viremia (thus a primary infection) during their icu stay and known immunodeficiency or anti-viral treatment in the week before icu admission. the institutional review boards of both study centers approved an opt-out method of informed consent (protocol number - c). from this parent cohort, we selected patients with an onset of cmv reactivation between day and in the icu. these patients with viremia were matched to two control groups consisting of patients without viremia on any day of icu admission. first, we matched patients with reactivation in a : ratio to cmv seropositive patients without reactivation (further referred to as "primary comparison"). second, we matched patients with reactivation in a : ratio to cmv seronegative patients without cmv viremia (further referred to as "secondary comparison"). this secondary comparison was intended mainly to confirm results of the primary comparison; the rationale was that any finding suggestive for an effect of cmv reactivation should also become apparent when compared with seronegative patients who are not at risk for cmv reactivation. matching criteria to reduce confounding were length of stay until reactivation (determines t = ), sequential organ failure assessment (sofa) score at t = (± points), age (± years), sex, and high-dose corticosteroid use during days prior to t = (that is, more than mg hydrocortisone or equivalent). patients were also matched on hospital and calendar day of icu admission (± days) in order to reduce possible influences of variation in sample workup and biobank storage duration [ ] . the optimal matching result was retrieved by selecting the largest sample size after random iterations of the matching procedure. leftover plasma, obtained daily as part of routine patient care, was stored at − °c and used to determine cmv serostatus at icu admission. subsequently, cmv load in blood was measured weekly, and for intermediary days, on which quantitative polymerase chain reaction was not performed, we estimated viral loads by log-linear imputation (see electronic supplementary materials of [ ] ). cmv viremia was defined as at least international units (iu) per milliliter. this cutoff value was similar to the ones used in previous studies [ , ] . results of cmv viral load measurements in plasma performed for this study were not made available to the treating physicians, and none of the included patients received anti-cmv treatment. to map the immune response, we measured a panel of host response biomarkers in samples derived from five time points: day of viremia onset (t = ), days prior (t = − ), and after viremia onset at day , , and (sample availability depended on length of stay in the icu). a multiplex luminex immunoassay was performed by using edta plasma and included the following proteins: il- , il- , il- , tumor necrosis factor-alpha (tnf-α), tnf-related apoptosis-inducing ligand (trail), interferon-gamma (ifn-γ), ifn-γ-induced protein- (ip- ), neutrophilic elastase, granzyme-b, il- receptor antagonist (ra), and il- . based on the results of a pilot run using samples obtained from ards patients without sepsis at icu admission (whom were not included in this study), we excluded ifn-γ, tnf-α, trail, and granzyme-b from the final panel because the levels of these biomarkers were below the lower limit of detection in more than % of the samples. of note, in this pilot run, cmv reactivation was not associated with detectability of the four excluded biomarkers. measurements of biomarkers were performed by using an in-house developed and validated multiplex immunoassay (iso certified) based on luminex technology (xmap, luminex, austin, tx, usa). the assay was performed as described previously [ ] . in short, thawed edta plasma samples ( μl) were diluted : in high performance elisa (hpe) buffer (sanquin, the netherlands) and centrifuged through filtration columns to remove debris. then non-specific heterophilic immunoglobulins were pre-absorbed from all samples with heteroblock (omega biologicals, bozeman, mt, usa). next, samples were incubated with antibody-conjugated magplex microspheres for -h at room temperature with continuous shaking and this was followed by -h incubation with biotinylated antibodies and -min incubation with phycoerythrin-conjugated streptavidin diluted in hpe buffer. acquisition was performed with the flexmap d system (bio-rad laboratories, hercules, ca, usa) in combination with xponent software version . (luminex). data were analyzed by -parametric curve fitting using bio-plex manager software, version . . (bio-rad laboratories). univariable analyses were performed to compare patients and disease characteristics for matched groups with and without cmv reactivation using chi-squared, wilcoxon rank sum, or fischer exact tests as appropriate. measured host response markers were natural log-transformed concentrations in picograms per milliliter for all analyses. symmetric percentage differences were calculated for each patient at the different time points. this delta percentage reflects the relative change from the measurement days prior to cmv reactivation until the follow-up measurement [ ] . we performed additional multivariable analyses by using generalized linear mixed models to assess the effect of cmv reactivation on the time course of each individual biomarker. in the mixed model analyses, we assessed whether baseline biomarker levels were comparable between matched groups (that is, coefficient for cmv reactivation) as well as the effect of cmv on the course of the biomarker levels over time (that is, coefficient for interaction term between time and cmv reactivation). a priori we chose to model the established immune markers il- and il- . based on the observed divergence in the symmetric percentage differences over time between groups, we conducted the multivariable analyses also for the pro-inflammatory chemokine ip- and the anti-inflammatory cytokine il- ra. since not all cmv reactivation patients were included in both comparisons, we performed separate mixed model analyses for the primary and secondary comparisons. thus, in total, eight models were built (for each of the four biomarkers in each of the two comparisons). for each model, sofa score at t = (that is, the day of reactivation) and age were included as confounders since we used a range (instead of an exact value) as matching criteria for these co-variables. for the fixed part of th emodels a polynomial term for time was evaluted (that is, quadratic time effect). furthermore, a random intercept and a rondom slowe were evaluted for each model. restricted maximum likelihood estimation (reml) was used to generate unbiased variance estimates for the final models [ ] . different ways to model the time course for each host response marker were compared by using the likelihood ratio test and akaike's information criterion. to take multiple testing into account and reduce the risk of spurious findings, we performed all statistical testing against a p value of . and used a confidence interval of %. bonferroni adjustment was deemed inappropriate and too conservative as the different measurements performed over time within a single patient and hence the tests were highly correlated with each other. analyses were performed by using either sas enterprise guide . (sas institute, cary, nc, usa) or r version . . (r foundation for statistical computing, ; used packages "lme ", "lmetest"). forty-five ( %) of eligible patients with cmv reactivation during icu day - could be included after matching (fig. ) . twenty-eight patients were matched to a seropositive patient as well as a seronegative, nine to only seropositive, and eight to only seronegative, respectively. this resulted in a study population of unique patients, divided into a primary comparison (that is, with cmv reactivation matched to cmv seropositive without reactivation) and a secondary comparison (that is, with cmv reactivation matched to cmv seronegative). patient and disease characteristics at icu admission were comparable between matched groups and are presented in table . in the patients with cmv reactivation, median peak level of cmv dna load was iu/ml (interquartile range (iqr) - ). median length of stay in the icu until reactivation was days (iqr - ), which was influenced by the used inclusion criterion (that is, viremia onset between day and in the icu). of the unique sepsis patients included, ( %) presented to the icu with septic shock and ( %) patients had ards during the first week of icu admission. in the primary comparison, the median icu length of stay was days (iqr - ) for patients with cmv reactivation versus days (iqr [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] for subjects without reactivation (p = . ). this was days (iqr - ) versus days (iqr [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in the secondary comparison (p = . ), respectively. hospital mortality was % for patients with cmv reactivation and % for the matched patients without reactivation in the primary comparison (p = . ). in the secondary comparison, this was % versus % (p = . ), respectively. baseline levels of measured host response markers were comparable between patients with and without reactivation, both at t = − (that is, days prior to viremia onset) and at t = (that is, day of reactivation onset) ( table ). in general, this remained the case for each marker up to days after cmv reactivation; the exceptions were median il- levels (which were significantly higher on day ) and median il- levels (which were significantly lower on day ) in patients with cmv reactivation compared with controls (additional file : table s ). however, these differences were not consistent across both primary and secondary comparison. time trends of various markers within patients were described by symmetric percentage differences relative to their levels days prior to cmv viremia onset (fig. for primary comparison, additional file : figure s for secondary comparison). for ip- and il- ra, differences in time trends were observed between patients with and without reactivation in both comparisons. patients with cmv reactivation had a more pronounced increase of ip- (median percentage difference of % versus − %) and decrease of il- ra (median percentage difference of − % versus %) on day after viremia onset compared with cmv seropositive patients without reactivation. for the secondary comparison, with cmv seronegative patients, similar differences in trends were observed for ip- (+ % versus + %) and il- ra (− % versus + %), respectively. of importance, sample size decreased over time because of death or icu discharge with a minimum of per patient group after days (additional file table s ). in the multivariable mixed model analyses, cmv reactivation did not significantly affect the baseline levels of il- , ip- , il- , and il- ra (table ) . a significant decrease over time was observed in all patients for il- in both the primary and secondary comparison and for il- in the primary comparison only, respectively. however, cmv reactivation did not significantly affect the time trend of any of the four analyzed biomarkers. we performed an explorative study to compare time trends of host response biomarkers in patients with reactivation that were matched to non-reactivating control patients who were either seropositive or seronegative for cmv. although we initially observed differential trends of il- ra and ip- in the crude analysis, these differences did not remain in the linear mixed model analysis the hypothesis of an immune-modulating effect of cmv is based on the observation of increased mortality and morbidity in patients with viremia without organ manifestation of cmv disease [ , ] . proposed mechanisms of such indirect pathogenicity are autoantibody production, enhanced inflammation, vascular damage, and cmv-induced immunosuppression [ ] . based on this hypothesis and an observed association between plasma markers and mortality in patients with ards [ ] , il- was used as a surrogate endpoint in a recent randomized controlled trial that evaluated the safety of preventive antiviral treatment in icu patients [ ] . our finding that cmv reactivation is not associated with modified il- dynamics questions the suitability of il- as an endpoint in clinical trials evaluating preventive therapy for cmv reactivation in icu patients. furthermore, time trends of other immunological biomarkers were not robustly affected by cmv reactivation. our study has several strengths. first, to our knowledge, this is the first study with serial measurements of the immune response following (instead of prior to) cmv reactivation. second, our study design included two matched control groups. because of the used matched cohort design, we could include only out of patients with cmv reactivation but this loss was compensated by the ability to include controls that were more comparable to those patients. sepsis patients in the icu are known to be very heterogeneous [ , ] ; thus, the matching reduced in theory both confounding and unwanted variation by extraneous factors. third, by using mixed model analyses, we accounted for correlation of measurements performed within one patient by the use of random effects, which increased the statistical power to identify differences between patient groups. moreover, this type of analysis takes into account the considerable loss to follow-up of patients and allowed us to estimate an average trend over time based on available data. our study also has some limitations. first, this was an explorative study evaluating multiple host response biomarkers. we chose a lower p value threshold of significance in order to decrease the risk of spurious findings due to multiple testing, but false-negative findings remain an accessory risk to keep in mind also when considering our study sample size. unfortunately, a formal sample size calculation for this kind of statistical analysis was not possible. nevertheless, we postulate that possible immunomodulating effects of cmv reactivation il- . ( . - . ) . ( . - . ) . . ( . - . ) . ( . - . ) . ip- . ( . - . ) . ( . - . ) . seem at most to be rather limited in these patients because no large differences in biomarker levels between matched groups were observed. second, we analyzed host response biomarkers as standalone markers, which is probably a simplification of the complex immune response. however, large sample sizes are required to perform more advanced network analyses, and the integration of time series in such analyses, to our knowledge, has not been conducted before. we also measured only the plasma concentrations. since cmv pneumonitis could be an important mediator of the pathological effect of cmv reactivation in critically ill patients, bronchoalveolar lavage samples may be additionally informative but were not available [ , ] . finally, we did not evaluate all potentially relevant biomarkers for cmv reactivation; thus, future studies are needed before an immunomodulating effect of cmv can be ruled out with certainty as an important pathological mechanism in previously immunocompetent icu patients. this study could not demonstrate an independent immunomodulating effect of cmv reactivation in patients with sepsis. this finding does not lend support for the use of immunological markers as surrogate endpoints for clinical outcome in interventional studies of prophylactic or pre-emptive cmv therapy in icu patients. additional file : table s . absolute levels of host response markers during follow-up by cytomegalovirus (cmv) reactivation status. figure s . ethics approval and consent to participate all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional or national research committee (or both) and with the helsinki declaration and its later amendments or comparable ethical standards. for this study, an opt-out informed consent method was approved. not applicable. cytomegalovirus reactivation in a general, nonimmunosuppressed intensive care unit population: incidence, risk factors, associations with organ dysfunction, and inflammatory biomarkers cytomegalovirus reactivation and associated outcome of critically ill patients with severe sepsis cytomegalovirus reactivation in critically ill immunocompetent patients prevalence and mortality associated with cytomegalovirus infection in nonimmunosuppressed patients in the intensive care unit association between cytomegalovirus reactivation and clinical outcomes in immunocompetent critically ill patients: a systematic review and meta-analysis cytomegalovirus infection in critically ill patients: a systematic review cytomegalovirus reactivation and mortality in patients with acute respiratory distress syndrome epidemiology of multiple herpes viremia in previously immunocompetent patients with septic shock active cytomegalovirus infection is common in mechanically ventilated medical intensive care unit patients interferon-gamma production by natural killer cells and cytomegalovirus in critically ill patients evaluation of cytomegalovirus (cmv)-specific t-cell immunity for the assessment of the risk of active cmv infection in non-immunosuppressed surgical and trauma intensive care unit patients human cytomegalovirus infections in nonimmunosuppressed critically ill patients cytomegalovirus reactivation in icu patients human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments a contributive result of open-lung biopsy improves survival in acute respiratory distress syndrome patients cmv in critically ill patients: pathogen or bystander cytomegalovirus-induced immunopathology and its clinical consequences reactivation of multiple viruses in patients with sepsis the 'indirect' effects of cytomegalovirus infection virological and immunological features of active cytomegalovirus infection in nonimmunosuppressed patients in a surgical and trauma intensive care unit effect of ganciclovir on il- levels among cytomegalovirus-seropositive adults with critical illness: a randomized clinical trial cytokine assays: an assessment of the preparation and treatment of blood and tissue samples effect of anticoagulants on circulating immune related proteins in healthy subjects statistics notes: percentage differences, symmetry, and natural logarithms using the general linear mixed model to analyse unbalanced repeated measures and longitudinal data lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury why have clinical trials in sepsis failed? unexplained mortality differences between septic shock trials: a systematic analysis of population characteristics and control-group mortality rates immunological insights into the pathogenesis of active cmv infection in non-immunosuppressed critically ill patients we thank the department of medical microbiology and the multiplex core facility of the laboratory for translational immunology for their logistical support and performance of measurements, the participating icus and research nurses of the two medical centers for their help in data acquisition, and all members of the molecular diagnosis and risk stratification of sepsis all authors declare that they have no conflicts of interest related to the subject matter. key: cord- -s le ugm authors: dimopoulos, g.; karabinis, a.; samonis, g.; falagas, m. e. title: candidemia in immunocompromised and immunocompetent critically ill patients: a prospective comparative study date: - - journal: eur j clin microbiol infect dis doi: . /s - - - sha: doc_id: cord_uid: s le ugm the purpose of this study was to compare the risk factors, clinical manifestations, and outcome of candidemia in immunocompromised (ic) and nonimmunocompromised (nic) critically ill patients. data were collected prospectively over a -year period ( / – / ) from patients in a -bed, medical–surgical intensive care unit (icu). eligible for participation in this study were patients who developed candidemia during their icu stay. patients under antifungal therapy and with a confirmed systemic fungal infection prior to the diagnosis of candidemia were excluded. cultures of blood, urine, and stool were performed for all patients in the study, and all patients underwent endoscopy/biopsy of the esophagus for detection of candida. smears and/or scrapings of oropharyngeal and esophageal lesions were examined for hyphae and/or pseudohyphae and were also cultured for yeasts. during the study period, , patients were hospitalized in the icu, % for primary medical reasons and % for surgical reasons. after application of the study’s inclusion and exclusion criteria, patients with candidemia ( ic and nic) were analyzed. total parenteral nutrition was more common in ic than in nic patients ( / [ %] vs / [ %], p = . ). oropharyngeal candidiasis was detected in of ( . %) ic patients and in of ( . %) nic patients (p = . ). esophageal candidiasis was also more common in ic than in nic patients ( / [ %] vs / [ %], p = . ). among the ic patients, all except died, resulting in a crude mortality of %; among the nic patients, died, resulting in a crude mortality of % (p > . ). autopsy was performed in two ic and in six nic patients, with disseminated candidiasis found in one ic patient. oropharyngeal and esophageal candidiasis are frequent in ic patients with candidemia. in contrast, this coexistence is rare in nic critically ill patients with candida bloodstream infections. a high mortality was noted in both ic and nic critically ill patients with candidemia. cases, the yeast's portal of entry is the gut, yet in other patients, especially those with central venous catheters (cvcs), skin is the most likely culprit [ , ] . candidemia may occur in both immunocompromised (ic) and nonimmunocompromised (nic) patients. the development of candidemia, however, strongly implies immunodeficiency, since it often occurs in ic patients and, more specifically, in - % of those with myeloproliferative disorders or leukemia and in up to % of patients with aids [ ] . in immunocompetent patients, candida esophagitis is quite rare and is associated with certain predisposing factors, such as use of h -receptor antagonists, antacids, prior vagotomy producing hypochlorydria, administration of antibiotics and systemic or inhaled corticosteroids, functional or mechanical obstruction of the esophagus, malnutrition, metabolic disorders, and alcoholism [ ] [ ] [ ] . however, it is unclear if candida esophagitis is unusual in the general population because its occurrence in that setting has never been investigated prospectively. no study to date has been specifically designed to compare risk factors, manifestations, and outcome of candidemia in ic and nic critically ill patients. thus, we performed the present study to assess possible clinically significant differences between ic and nic patients with candidemia receiving care in the icu setting. this was a prospective study that was conducted over years (february -january ) in a -bed, medical-surgical icu in a tertiary hospital in greece. the "g. gennimatas" general hospital in athens is a -bed general hospital that mainly serves the north-northeastern part of athens. the study protocol was approved by the hospital's ethics committee. because of the patients' inability to give informed consent for participation in the study, consent was obtained from their next of kin. eligible for participation in the study were patients who had been hospitalized for > h and had developed candidemia during their icu stay. blood cultures were ordered at the discretion of the attending physicians, when clinically indicated. patients with severe thrombocytopenia (platelets < , /μl) or coagulopathy were excluded because our study included a biopsy procedure. patients receiving or who had received prior antifungal therapy the last month before the icu admission and patients with a confirmed systemic fungal infection prior to the diagnosis of candidemia also were excluded because the focus of the study was to be a population with icu-acquired canidemia. one of the authors (g.d.) collected the data in a standard manner and was responsible for the follow-up of the patients during the study period. patients were evaluated in terms of age, acute physiology and chronic health evaluation-ii (apache ii) and sequestrial organ failure assessment (sofa) scores, mean duration of icu stay, main predisposing factors for fungal infection development, and clinical outcome. for the purposes of the study, patients without underlying malignancy or neutropenia (leukocyte count > , /μl and neutrophil count > , /μl) and with human immunodeficiency virus (hiv) seronegative status who had not received corticosteroids orally, intravenously, or by nebulization within the last days prior to icu admission were defined as nonimmunocompromised (nic). patients who received systemic corticosteroids for icu indications, such as sepsis or adult respiratory distress syndrome (ards), after their icu admission were classified in the nic group. the study population did not include transplant patients, since our center is a trauma-oriented general hospital. oral thrush was clinically diagnosed by the presence of typical creamy lesions and whitish plaques or pseudomembranes in the oropharyngeal mucosa and on the tongue. a complete laboratory evaluation, which included a hemogram as well as biochemical and coagulation profiles, urinalysis, serologic testing for hiv, radiological studies, and an electrocardiogram, was performed. blood, urine, and stool cultures, in addition to cultures of scrapings obtained from the oropharynx, were performed for all study patients. oropharyngeal scrapings were also immediately examined microscopically for the presence of yeasts and/or hyphae/pseudohyphae, using % potassium hydroxide. the investigational work-up for invasive candidiasis in our patients (other than blood cultures, esophageal endoscopy, and oral scrapings) included (a) identification of predisposing factors, (b) surveillance cultures to detect possible colonization, (c) eye exam, and (d) ct scans of the suspected site of infection. all endoscopies were performed by the same gastroenterologist. endoscopies were performed during the first h after the diagnosis of candidemia, using a pentax eg videoscope. during endoscopy, brushing specimens and tissue biopsies were obtained for microbiological and histological examination. candida esophagitis was diagnosed by the presence of visible esophageal lesions (white plaques with hyperemia and edema, linear and nodular elevated plaques with ulceration, plaques with increased friability of the mucous membrane) using a modified kodsi method and was verified by biopsy showing hyphae in histological sections and/or candida growth on agar plates [ , ] . additionally, the brushing specimens were evaluated immediately for yeasts and hyphae/pseudohyphae after the addition of % potassium hydroxide and were cultured on sabouraud dextrose agar plates for candida growth. biopsy samples were fixed with % formalin and paraffin followed by acid-schiff staining to detect mucosal invasion by the fungus. cultures were considered positive if there was growth of candida on sabouraud dextrose agar plates. yeasts were identified using the api c aux system (biomérieux, marcy l'etoile, france). candidemia was defined by at least one positive blood culture for candida spp., and candiduria by a urine culture with candida spp. growth of ≥ cfu/ml. candidemia was identified using bactalert (biomérieux, usa). table shows the number of sites (besides blood) colonized by candida spp. disseminated candidiasis was diagnosed when candida was identified by culture and/or biopsy from two or more organs. we used candida id agar (biomérieux) to discriminate between candida albicans, candida non-albicans, and candida tropicalis. additionally, we used the germ-tube method and the api c (assimilation of carbohydrates) for identification of all species of candida. ic and nic patients were compared for certain variables of interest by mann-whitney u test, chi-squared test, and fisher exact test. the level of significance was set at p< . . during the study period, , patients were hospitalized in the icu, % for primary medical reasons and % for primary surgical reasons. twenty-four patients ( ic and nic) met the eligibility criteria. of these, ( %) were ng cultures with no growth medical patients and ( %) surgical patients. their demographic and clinical characteristics are shown in table . among the ic and nic patients, ( %) and ( %) were females, respectively (p> . ). the median age of the ic and nic patients was years (range - ) and years (range - ), respectively (p> . ). the median duration of icu stay for ic and nic patients was . and . days, respectively (p> . ). among the nine ic patients, all had underlying primary medical pathology, since three had leukaemia/lymphoma, three aids, and one each had liver cirrhosis complicated by septic shock, pneumonia following chemotherapy for lung cancer, and rheumatoid arthritis complicated by pneumonia. none of the patients in the study with leukemia/lymphoma received chemotherapy during the study or for weeks prior to the diagnosis of candidemia. the patients with lung cancer and rheumatoid arthritis (patient nos. and in ic group, table ) received treatment with glucocorticosteroids. among the nic patients, the underlying diagnosis was pneumonia/ards in , trauma/head injury in , peritonitis in , pancreatitis in , and pulmonary embolism in . six of the nic patients had surgical pathology: three with trauma/head injury and three with peritonitis. most patients with pneumonia had community-acquired infection but needed icu admission due to respiratory failure. patient numbers and in the nic group (table ) developed ventilator-associated pneumonia. the mean time from icu admission to the isolation of candida from blood specimens was days (range - days). the mean time between drawing blood specimens for culture and isolation of candida was days. the presence of known predisposing factors for development of candidiasis in these patients is shown in table . the ic patients with candidemia had higher mean apache ii ( ± vs ± ) and sofa ( ± vs ± ) scores during icu admission compared to the nic patients (p= . for both scores). in addition, the administration of total parenteral nutrition was more common in ic patients (p= . ). oropharyngeal candidiasis was detected in of ( . %) ic patients and in of ( . %) nic patients (p= . ). in the ic patients, the diagnosis of oral thrush was confirmed prior to the icu admission, while in the single nic patient with oral thrush, the diagnosis was established on the eighth icu day. four of the nine ( %) ic patients and none of the nic patients presented with esophageal candidiasis (p= . ). all patients with esophageal candidiasis manifested symptoms (mainly odynophagia; dysphagia in one patient) before icu admission, but the diagnosis table shows the results of the fungal cultures in ic and nic patients. c. albicans was isolated from the blood in of ( . %) ic patients and in of ( . %) nic patients, while non-albicans candida spp. were isolated in the remaining patients of the two study groups (p> . ). among nic patients, c. tropicalis was isolated from the blood of three patients and candida krusei and candida parapsilosis from one patient each. among ic patients, c. krusei, c. parapsilosis, candida dubliniensis, and candida lusitaniae were isolated from the blood of one patient each. the same candida spp. were isolated in at least two different body sites in eight of ten nic patients and in four of five ic patients with candidemia due to c. albicans. there was one patient (table ) who had concomitant and persistent methicillin-resistant staphylococcus aureus (mrsa) bacteremia during the icu hospitalization. patients with c. albicans candidemia received fluconazole mg every h intravenously and patients with non-albicans candidemia liposomal amphotericin b intravenously (mean duration of therapy, . days; range - days). no statistically significant difference in clinical outcome was detected between nic and ic patients with candidemia. among the nine ic patients, all except two (patient nos. and ; table ) died, resulting in a crude mortality of %. among the nic patients, (patient nos. , , , , , , , , and ; table ) died, resulting in a crude mortality of % (p> . ). when ic and nic patients were combined, the mortality among patients with primary medical pathology and patients with surgical pathology was identical, at %. more specifically, of the patients with medical pathology ( ic and nic), ( ic and nic) died, while of the patients with surgical pathology (all nic) died. autopsy after consent was performed in eight patients (two ic and six nic) and showed disseminated candidiasis in one ic patient (oropharyngeal, esophageal, and gastric candidiasis). the main findings of our study of critically ill patients with candidemia are that ic patients had higher apache ii and sofa scores and were more likely to receive total parenteral nutrition than nic patients. in addition, oropharyngeal and esophageal candidiasis was considerably more common in ic than in nic icu patients with candidemia. of importance, a high mortality was noted in both ic and nic critically ill patients with candidemia. the recent advances in intensive care have improved the survival of critically ill patients at the cost of the emergence of nosocomial infections of the bloodstream and other sites. candidemia is the most common hematogenous fungal infection and the fourth most common bsi overall in the usa, accounting for % of all nosocomial bsis [ ] . in greece, there are no relevant data from large multicenter studies regarding candidal bsi, although there are data from a single-center study reporting that . - . % of bsis during a -year period ( - ) were due to candida spp. [ ] . risk factors for invasive candidiasis in the icu have been defined by several studies and include a prolonged hospital stay; the use of broad-spectrum antibiotics, corticosteroids or other immunosuppressants; the administration of total parenteral nutrition, hemodialysis or multiple blood transfusions; prolonged mechanical ventilation; diabetes mellitus; gastrointestinal perforation or surgery; and pancreatitis [ , [ ] [ ] [ ] [ ] ] . candida spp. colonize the gastrointestinal tract of healthy individuals and, although they are most frequently recovered from the oropharynx, they have also been isolated from the stool of - % of healthy adults [ ] . colonization of the gastrointestinal tract or the oropharynx with candida spp. has been shown to invariably precede hematogenous or systemic disease, although in recent years the improved survival of burn victims and the widespread use of cvcs has allowed direct invasion of the bloodstream by candida spp. that colonize the skin [ , ] . candida colonization as a risk factor is still controversial. it has been studied as a predictor of invasive candidiasis in the icu setting; in fact, a "colonization index" has been proposed to predict invasive candidiasis in icu patients, although guidelines for identifying patients who would best benefit from antifungal prophylaxis are not established [ , ] . it is unclear, however, whether differences exist between ic and nic patients in the way candidemia and/or systemic candidiasis is acquired in relation to the presence of prior mucosal candidiasis. one of the purposes of the present prospective clinical study was to assess a possible correlation between the development of candidemia and/or systemic candidiasis and the pre-existence of oropharyngeal or esophageal candidiasis in critically ill patients. we showed that oropharyngeal and esophageal candidiasis was rare in nic critically ill patients with candidemia, but often the two entities coexisted in ic patients. a prior diagnosis of oral thrush due to candida spp. in conjunction with a candida-positive stool culture was a sensitive marker for the presence of esophageal candidiasis. the development of candida esophagitis is a two-step process that includes colonization of the esophagus and invasion of the epithelial layer. when the intraluminal concentration of candida spp. is high, the fungus is able to transmigrate the wall of the digestive tract and gain access to the circulation, a process known as persorption [ ] . in nic patients, this process, although rare, has been associated with certain predisposing factors and as-yetunknown mechanisms of infection [ ] . the nic patients in our study developed candidemia during their icu hospitalization, and none manifested esophageal candidiasis, although one developed oral thrush. our autopsy findings, which showed that six nic patients had no organ involvement, suggest that candidemia probably resulted from transient fungal translocation across the gastrointestinal tract without affecting the mucosal membranes. however, we performed autopsies in only % of the nic patients. a correlation between oral thrush and esophageal candidiasis has been shown in a number of studies in ic patients with aids or cancer [ ] [ ] [ ] . in our study, the simultaneous diagnosis of oral thrush and a stool culture positive for candida spp. in ic patients was associated with a % specificity and a positive predictive value for development of esophageal candidiasis. the lack of correlation between candidemia/systemic candidiasis and mucosal candidiasis in nic in comparison to ic patients can likely be explained by the defective primary defense mechanisms against tissue invasion and dissemination that are common in ic patients. we would like to emphasize that oral candidiasis that presents as erythematous candidiasis (in the absence of other specific symptoms and signs) could be difficult to diagnose in critically ill patients and might be occasionally misleading because (a) tubes and other devices placed in the oral cavity are themselves able to produce mild inflammatory lesions, and (b) the increased respiratory secretions and, often, the regurgitated enteral nutrition content may cause inflammation of the oral mucosa. the clinical characteristics of the eligible nic and ic patients of the study were well balanced between the groups, except for the more frequent use of parenteral alimentation and the higher apache ii scores in the ic patients. total parenteral nutrition has been a known risk factor for bsi due to candida spp., and its use has recently been associated with candidemia due to c. parapsilosis in both children and adults [ , ] . interestingly, candidemia due to c. parapsilosis in non-neutropenic patients with an intravenous hyperalimentation catheter has a low mortality rate and a good prognosis [ ] . in our study, c. parapsilosis was isolated from the blood cultures of two patients, one nic and one ic, making it the third most common candida sp. encountered, after c. albicans ( blood isolates total; in nic patients) and c. tropicalis ( blood isolates, all in nic patients). the nic patient with c. parapsilosis candidemia in our series had charcot disease complicated by pneumonia, but she survived. the other patient with c. parapsilosis candidemia had aids and succumbed to his disease. the higher apache ii scores in our ic patients are suggestive of an increased severity of the underlying critical illness. lower (< points) apache ii scores have been associated with a higher probability of survival in a multicenter study of non-neutropenic critically ill patients with candidemia [ ] , and higher apache iii scores have been associated with increased mortality in cancer patients with candidemia in a study of episodes at the m.d. anderson cancer center [ ] . c. albicans was the candida sp. most commonly isolated from the blood of our patients ( of isolates, or . %), followed by c. tropicalis ( isolates, or . %), c. parapsilosis ( isolates, or . %), c. krusei ( isolates or . %), c. dubliniensis, and c. lusitaniae ( isolate each, or . %). in one patient (table ) , persistent mrsa bacteremia was observed concomitantly with candidemia. there are sporadic reports indicating a small but significant proportion of patients who have icu-acquired candidemia concomitantly with bacteremia [ ] . in our patients, fungemia due to c. tropicalis was not preceded by colonization with the same species. it is well known that c. tropicalis, part of the normal human mucocutaneous flora, is a major cause of septicemia/disseminated candidiasis, mainly in patients with lymphoma, leukemia, and diabetes [ ] . accordingly, a possible explanation for the development of c. tropicalis candidemia in our patients could be the uncontrolled diabetes combined with the severe septic syndrome. we did not have any cases of candidemia due to candida glabrata, a common pathogen in the usa and israel [ , ] . this finding is in accordance with the data of the sentry antimicrobial surveillance program, which surveyed episodes of bsi due to candida spp. in patients hospitalized in european icus. overall, % of the bsis due to candida spp. were attributable to c. albicans, followed by c. parapsilosis ( %), c. glabrata ( %), c. tropicalis ( %), c. famata ( %), c. krusei ( %), and candida inconspicua ( %) [ ] . with regards to c. albicans, our figures are very close to both european [ ] and american studies. for example, trick et al. [ ] , who described the secular trend of hospitalacquired candidemia among icu patients in the usa during - , found that among cases of monomicrobial and polymicrobial candidemia, c. albicans was isolated in and %, respectively. the high crude mortality among our patients ( % for nic and % for ic) was not unexpected, given the severity of their underlying diseases, and is comparable to the mortality rate for adults with candidemia reported by lark et al. [ ] ( %), gudlaugsson et al. [ ] ( %), karlowsky et al. [ ] ( %), colombo et al. [ ] ( %), and pappas et al. [ ] ( %). although we saw no difference in outcome between medical and surgical patients, others have described a poorer outcome for medical patients with candidemia [ ] . in our study population, patients with ards and sepsis were classified in the nic group because we believe that these patients have a temporary immunosuppression (if they survive), while the patients classified in the ic group had a certain degree of chronic immunosuppression, despite the differences in the underlying disease. the patient with alcoholic cirrhosis and sepsis (table ) was classified in the ic group because he had received glucocorticosteroids due to exacerbations of chronic obstructive pulmonary disease for months before admission to the icu. the design of the study did not allow for all patients admitted to the icu to be evaluated for the presence of oropharyngeal and esophageal candidiasis. additionally, we focused on a subset of patients with icu-acquired candidemia without prior systemic fungal infection who had not been exposed to prophylactic antifungal drugs. since, by definition, the term "icu-acquired candidemia" means that the fungal infection is acquired in the icu, we excluded from our study those patients with previous invasive fungal infection . we should acknowledge that our study has several limitations. first, we were unable to pinpoint the exact time of onset of the esophageal candidiasis, especially since oral thrush was already present before admission to the icu. due to obvious ethical reasons, we evaluated our patients for esophageal candidiasis with endoscopy only once. thus, we do not know if the esophagus was involved before or after the icu admission. second, it is unclear if the esophageal candidiasis resulted from hematogenous spread of the fungi in the esophagus, or if the bloodstream involvement was directly related to the oral thrush or the esophageal candidiasis. third, we did not focus on the treatment administered to patients with candidemia, although we did report that patients with c. albicans and non-albicans candidemia received fluconazole and liposomal amphotericin b intravenously, respectively. fourth, we do not have readily available data on the length of stay of all patients who received care in the icu or the total number of cases of candidemia in the icu, including those excluded, to know how common candidemia is among icu patients. fifth, there are no readily available data regarding the type of therapy and the removal of cvcs and the influence of either factor on outcome in the two patient groups studied. sixth, the sample of our study population is relatively small (study population from a single center) and thus does not permit a powerful statistical analysis; unfortunately, various practical reasons prevented us from incorporating data from other large icus into our study. finally, we do not have readily available data on mics because the laboratory usually reported the results for an isolate as either "susceptible" or "not susceptible" to fluconazole. in conclusion, we compared various characteristics, including risk factors, manifestations, and outcome of ic and nic icu patients with candidemia. we found that oropharyngeal and esophageal candidiasis frequently coexisted with candidemia in ic patients. prospective, clinical studies are needed to better define the value of avoiding colonization and/or of treating oropharyngeal and esophageal candidiasis for the prevention of systemic disease in selected critically ill patients. nosocomial bloodstream infections in united states hospitals: a three-year analysis system report, data summary from predominant pathogens in hospital infections new approaches to the risk of candida in the intensive care unit risk factors for candidal bloodstream infections in surgical intensive care unit patients: the nemis prospective multicenter study. the national epidemiology of mycosis survey nosocomial fungal infections: candidemia candidemia in allogeneic blood and marrow transplant recipients: evolution of risk factors after the adoption of prophylactic fluconazole epidemiology of nosocomial fungal infections risk factors for candidemia in cancer patients: a case-control study candidemia in cancer patients: a prospective, multicenter surveillance study by the invasive fungal infection group (ifig) of the european organization for research and treatment of cancer (eortc) the role of the gastrointestinal tract in hematogenous candidiasis: from the laboratory to the bedside revisiting the source of candidemia: skin or gut? esophageal infections: etiology, diagnosis, and management invasive candidiasis following cimetidine therapy candida overgrowth in gastric juice of peptic ulcer subjects on short-and long-term treatment with h -receptor antagonists esophageal candidiasis as a complication of inhaled corticosteroids candida esophagitis: a prospective study of cases esophagitis in the immunocompromised host: role of esophagoscopy in diagnosis national surveillance of nosocomial blood stream infection due to candida albicans: frequency of occurrence and antifungal susceptibility in the scope program secular trend of antimicrobial resistance of blood isolates in a newly founded greek hospital in: bodey gp (ed) candidiasis: pathogenesis, diagnosis and treatment incidence of candida in hospital inpatients and the effects of antibiotic therapy candida colonization and subsequent infections in critically ill surgical patients rules for identifying patients at increased risk for candidal infections in the surgical intensive care unit: approach to developing practical criteria for systematic use in antifungal prophylaxis trials fungaemia and funguria after oral administration of candida albicans oropharyngeal candidiasis as a marker for esophageal candidiasis in patients with cancer prospective evaluation of oropharyngeal findings in human immunodeficiency virusinfected patients with esophageal ulceration presumptive clinical criteria versus endoscopy in the diagnosis of candida esophagitis at various hiv- disease stages hematogenous infections due to candida parapsilosis: changing trends in fungemic patients at a comprehensive cancer center during the last four decades emergence of candida parapsilosis as the predominant species causing candidemia in children for the study group of fungal infection in the icu ( ) candidemia in nonneutropenic critically ill patients: analysis of prognostic factors and assessment of systemic antifungal therapy risk factors and predictors of outcome in patients with cancer and breakthrough candidemia infections with candida spp. in critically ill patients are primarily related to the length of stay in the intensive care unit candidiasis: pathogenesis, diagnosis and treatment secular trend of hospital-acquired candidemia among intensive care unit patients in the united states during - epidemiology of candidemia-a nationwide survey in israel international surveillance of blood stream infections due to candida species in the european sentry program: species distribution and antifungal susceptibility, including the investigational triazole andechinocandin agents. sentry participant group (europe) four-year prospective evaluation of nosocomial bacteremia: epidemiology, microbiology, and patient outcome attributable mortality of nosocomial candidemia, revisited candidemia in a canadian tertiary care hospital from to high rate of nonalbicans candidemia in brazilian tertiary care hospitals a prospective observational study of candidemia: epidemiology, therapy, and influences on mortality in hospitalized adult and pediatric patients candidemia in critically ill patients: difference of outcome between medical and surgical patients key: cord- -tciwtxud authors: singh, nina; gayowski, timothy; wagener, marilyn m.; marino, ignazio r. title: outcome of patients with cirrhosis requiring intensive care unit support: prospective assessment of predictors of mortality date: journal: j gastroenterol doi: . /s sha: doc_id: cord_uid: tciwtxud determinants of outcome and the utility of the child-pugh score and the acute physiology and chronic health evaluation (apache) ii score as predictors of outcome were prospectively assessed in consecutive patients with cirrhosis requiring intensive care unit (icu) management. overall mortality in the icu was % ( / ). child-pugh scores did not differ between survivors or nonsurvivors ( . versus . , p = . ), however apache ii scores (p = . ), acute physiology scores (p = . ), and karnofsky scores (p = . ) were significant predictors of outcome. by univariate analysis, requirement of mechanical ventilation analysis (p = . ), duration of mechanical ventilation (p = . ), pulmonary infiltrates (p = . ), infections (p = . ), gastrointestinal bleeding (p = . ), and serum creatinine ≥ . mg/dl (p = . ) were significantly associated with mortality. by logistic regression analysis only pulmonary infiltrates (p = . ) and renal dysfunction (p = . ) were independent predictors of mortality. when controlled for the severity of illness (apache ii scores), the mortality in patients with cirrhosis caused by alcohol was significantly lower than that in patients with liver disease not caused by alcohol (p = . ). our study not only identified predictors of poor outcome in patients with cirrhosis requiring icu care but also provided data that may have implications for optimal timing for transplantation. intensive care unit (icu) care is an integral part of the management of patients with complications of cirrhosis. a number of medical complications, e.g., hepatic encephalopathy, coagulopathy predisposing to hemorrhage, variceal bleeding, pulmonary edema, infections, or cardiac complications, may prompt admission to the icu in patients with endstage liver disease. these critically ill patients also comprise a significant proportion of those who eventually undergo liver transplantation. factors that adversely influence survival in critically ill patients have been assessed in a number of medical conditions, including hematologic malignancies, bone marrow and organ transplantation, - and respiratory diseases. child-pugh scores were initially developed for the assessment of hepatocellular functional reserve in patients undergoing surgical treatment for variceal bleeding, and have since been widely used for the assessment of the severity of illness in patients with endstage liver disease. , child-pugh scores predicted outcome in a retrospective study of patients with cirrhosis and chronic liver disease admitted to the icu. however, these criteria have not been uniformly shown to be optimal predictors of survival in patients with cirrhosis and were of limited value for discriminating the highrisk patients for transplantation. , acute physiology and chronic health evaluation (apache) scores were determined to be of prognostic significance in a study in icu patients with cirrhosis; however, neither child-pugh scores nor etiology of liver disease were assessed in that study. no study, to our knowledge, has prospectively evaluated child-pugh scores and apache scores concurrently as predictors of outcome in critically ill patients with cirrhosis. pervious studies on icu outcome in patients with endstage liver disease were conducted prior to the routine testing of hepatitis c virus (hcv). , [ ] [ ] [ ] hcv has emerged as a significant cause of cirrhosis and is one of the leading indications for liver transplantation; an estimated . million people in the united states have chronic hcv infection and each year - chronically infected patients with hcv die of liverrelated complications. we prospectively followed consecutive patients with cirrhosis requiring icu care at our institution over a year period. the primary objectives of this study were: to determine the outcome and the prognostic factors associated with poor outcome in patients with cirrhosis admitted to the icu and to determine whether standardized severity-of-illness scoring systems, e.g., child-pugh score and apache ii scores, predicted the outcome in these patients. the study samples comprised patients with cirrhosis referred to the liver transplant service of the pittsburgh veterans affairs medical center between january, and december, . consecutive patients requiring icu admission at any time between their referral and transplantation or death were considered as an icu admission. for the purpose of this study, each icu admission was considered a separate patient, as reported previously. all icu admissions were followed until discharge from the icu or until death. the following variables were recorded for each patient on admission to the icu: age, sex, etiology of liver disease, data of hospital admission, data and reason for icu admission, presence of co-morbid illness (diabetes, hypertension, heart disease, malignancy, renal failure), and child-pugh score. admission vital signs, karnofsky score, and laboratory data (complete blood count, bun, creatinine, total bilirubin, alkaline phosphatase, alanine aminotransferase, gamma glutamyl transpeptidase, prothrombin partial thromboplastin times, serum cholesterol, albumin, and electrolytes) were also recorded. the apache scoring system is the most widely employed severity-of-illness scale in the icu studies. the apache ii score was calculated at the time of the icu admission by adding the acute physiology score (aps), chronic health points, and age points. it has also been shown that preadmission functional status of the patient is an important determinant of the outcome in critically ill patients. , we employed the karnofsky performance score to assess the functional status of the study patients. during the icu stay, the following variables were recorded: invasive procedures (requirement for pulmonary artery catheter, arterial line, tracheostomy, endoscopy, bronchoscopy); total parenteral or enteral nutrition; inotropic or vasopressor support; requirement for and duration of mechanical ventilation; dialysis; infections; and presence of pulmonary infiltrates and their etiology. the criteria for diagnosing nosocomial pneumonia, adult respiratory distress syndrome, pulmonary edema, and peritonitis were as previously reported. statistical analysis. patient demographics and laboratory values were entered into a database (prophet, bbn systems and technologies, cambridge, ma, usa). contingency tables were analyzed using the or fisher exact test. continuous variables were compared using the t-test or mann-whitney test. multivariate logistic regression analysis was done in stepwise fashion with variables being entered to the equation if the significance level was less than . and removed from the equation if greater than . . the pool of variables available for analysis was chosen from variables that were significant by univariate analysis and considered to be of clinical importance (factors that could possibly be altered by management in the icu). there were icu admissions in patients with cirrhosis during the study period; patients had admission, patients had admissions, patient had admissions, and patient had admissions to the icu. the mean age of the patients was years (range, - years). the underlying liver diseases in these patients are outlined in table . comorbid illnesses included diabetes mellitus in % ( / ), hypertension in % ( / ), coronary artery disease in % ( / ), and malignancy in % ( / ) of the patients. the reasons for icu admission were hepatic encephalopathy, % ( / ); gastrointestinal bleeding, % ( / ); status postsurgical procedure; % ( / ); hypotension/sepsis, % ( / ); respiratory distress, % ( / ); and miscellaneous, % ( / ), i.e., chest pain , platelet transfusion reaction , seizure , and disseminated intravascular coagulation . the duration of icu stay ranged between and days (mean, days); % of the patients had an icu length of stay greater than days and % stayed for days or more. the study patients had been hospitalized a mean of days (range, - days) before being admitted to the icu. overall, % ( / ) of the icu admissions were associated with death. mortality was % ( / ) in patients table ) . respiratory rate and pulse rate on admission did not differ significantly between survivors and nonsurvivors; however, nonsurvivors were significantly more likely to have an abnormal temperature (p ϭ . ) and abnormal blood pressure (p ϭ . ) than survivors. mental status was not a predictor of outcome; coma scores (part of apache ii scores) and percentage of patients with ; p ϭ . ), bun ( . mg/dl versus mg/dl; p ϭ . ), and white blood count ( . versus . /mm ; p ϭ . ) and significantly lower hematocrit ( % versus . %; p ϭ . ) compared with survivors. mortality was significantly higher in patients with renal impairment, i.e., creatinine more than . mg/ dl ( % versus %; p ϭ . ). forty-three percent ( / ) of the patients required mechanical ventilation. requirement for mechanical ventilation and duration of mechanical ventilation were significant predictors of mortality. seventyfour percent of the nonsurvivors, compared with % of the survivors, required mechanical ventilation (p ϭ . ). patients who died had significantly longer ventilatory support (mean, days versus day; p ϭ . ). twenty percent ( / ) of the patients required dialysis. patients requiring dialysis had significantly greater severity-of-illness (apache ii scores, . versus . ; p ϭ . ), were more likely to develop pulmonary infiltrates in the icu ( % versus %; p ϭ . ), and were more likely to have had hypotension at any time during the icu stay ( %, / versus %, / ; p ϭ . ). pulmonary infiltrates developed in % ( / ) of the patients. the etiology of pulmonary infiltrates was pulmonary edema in % ( / ), acute respiratory distress syndrome in % ( / ), atelectasis in % ( / ), pneumonia in % ( / ), and pulmonary fibrosis in % ( / ). patients developing pulmonary infiltrates were more severely ill, i.e., had higher apache ii scores (p ϭ . ), had longer icu length of stay (p ϭ . ), and were more likely to have renal impairment, i.e., creatinine more than . mg/dl (p ϭ . ). when controlled for the severity of illness, the patients with pulmonary infiltrates were significantly more likely to die than those without pulmonary infiltrates (p ϭ . ). infections occurred in % ( / ) of the patients and bacteremia in % ( / ) of the patients; % ( / ) of the survivors versus % ( / ) of the nonsurvivors developed infections (p ϭ . ). spontaneous bacterial peritonitis accounted for % ( / ) of all infections in the icu and was caused by culture-negative neutrocytic ascites in % of the episodes, neutrocytic ascites in % of the episodes, and bacteriascites in % of the episodes. the etiologic agents of bloodstream infections were staphylococcus aureus ( %, / , including one patient with endocarditis), klebsiella pneumoniae ( %, / ), citrobacter freundii ( %, / ), enterococci ( %, / ), and pseudomonas aeruginosa ( %, / ). one patient (receiving corticosteroids) had fungemia caused by candida albicans. patients experiencing infections were more likely to have had gastrointestinal bleeding (p ϭ . ), creatinine more than . mg/dl (p ϭ . ), and to have required dialysis (p ϭ . ). mortality was higher in infected ( %, / ) versus noninfected ( %, / ) patients (p ϭ . ). when pulmonary infiltrates, infections, renal impairment, and gastrointestinal bleeding were entered into a logistic regression model, only pulmonary infiltrates (p ϭ . ) and renal dysfunction (p ϭ . ) were independent predictors of mortality. mortality was % when all the above four variables were present and % when none of the above was present. mortality rate was % when pulmonary infiltrates and gastrointestinal bleeding were present and % when pulmonary infiltrates and renal dysfunction existed. when controlled for the apache ii scores (apache ii more than ), % ( / ) patients with alcoholic cirrhosis versus % ( / ) of the patients with cirrhosis not caused by alcohol died (p ϭ . ). eighty-three percent of the patients without alcoholic cirrhosis had viral hepatitis (hcv % and hbv %). serum creatinine ( . versus . mg/dl), bilirubin ( . versus . mg/dl), and frequency of gastrointestinal bleeding ( % versus %) were not different between patients with cirrhosis caused by alcohol versus nonalcoholic cirrhosis; however the patients with nonalcoholic cirrhosis were more likely to have required mechanical ventilation ( % versus %, p ϭ . ) and to have pulmonary infiltrates ( % versus %, p ϭ . ). assessment of prognosis has become increasingly important in the medical management of critically ill patients. such data can serve to elucidate factors that portend an unfavorable outcome, but more importantly, identify those variables that may be potentially modifiable or amenable to intervention. in critically ill patients with cirrhosis, such data also have implications regarding optimal timing of transplantation. mortality in these critically ill patients in our study was %. child-pugh scores failed to predict the outcome, whereas apache ii scores, aps scores, and functional status of the patient (karnofsky score) were more accurate predictors of outcome. the lack of predictive accuracy of child-pugh scores is probably because extrahepatic severity-of-illness variables, e.g., renal function, vital signs, and pulmonary status, are not measured by child-pugh scores, although these scores do assess a number of different criteria related to the liver disease. of routinely available liver functions tests assessed, only bilirubin and prothrombin time, and not aminotransferases, alkaline phosphatase, albumin, or cholesterol were significant predictors of outcome. the prognostic significance of hyperbilirubinemia and elevated prothrombin time has also been recognized in patients with other medical conditions requiring icu care. in a study assessing outcome in icu patients treated with hemodialysis for acute renal failure, serum bilirubin and prothrombin time were significantly associated with mortality; hyperbilirubinemia was an independent predictor of mortality. bilirubin was also a significant predictor of outcome in transplant recipients requiring icu care and of early graft failure in liver transplant candidates undergoing transplantation. we observed a high incidence of renal dysfunction in our patients with cirrhosis admitted to the icu. renal impairment (creatinine more than . mg/dl) was present in % of the patients, and % of the patients required dialysis. patients requiring dialysis were significantly more ill (as assessed by apache ii scores). however, when controlled for the severity of illness, renal impairment (p ϭ . ) and dialysis (p ϭ . ) remained significantly associated with mortality in the icu. the grave prognostic association of renal failure in endstage liver disease was also emphasized in a recent spanish study. renal impairment after spontaneous bacterial peritonitis in cirrhosis was reported to be the most significant predictor of hospital mortality. these data have important implications regarding timing of transplantation. patients with endstage liver disease and renal impairment are at high risk for mortality. however, transplantation should ideally be undertaken before renal failure and the requirement for dialysis ensue. pretransplant renal dysfunction was an independent predictor of early graft failure after liver transplantation , and pretransplant dialysis has been identified as a significant risk factor for early posttransplant mortality and infectious morbidity. [ ] [ ] [ ] [ ] nearly one-third of our patients with cirrhosis in the icu experienced infections. spontaneous bacterial peritonitis (sbp) and bacteremia have been reported in %- % and %- % of patients with cirrhosis, respectively. our incidence of sbp ( %) and bacteremia ( %) was therefore somewhat higher than that reported in cirrhotic patients in general. this was likely reflective of the fact that our patients represented a subgroup of most critically ill patients with liver disease. although mortality was higher in the infected patients, infections were not an independent predictor of mortality. escherichia coli, klebsiella, and enterococcus were the most frequent causes of culture-positive sbp or spontaneous bacteremia; however, culturenegative neutrocytic ascites was the most frequently observed variant of sbp. patients with gastrointestinal bleeding, renal impairment, and those requiring dialysis were at significantly higher risk for infections in the icu. gastrointestinal hemorrhage has been shown to impair the reticuloendothelial function and facilitate bacterial translocation across the gut. , likewise, the association of renal failure with infections is well recognized. in % ( / ) of our patients, a unique presentation characterized by marked leukocytosis (in the absence of any documented infection) with eventual progression to multiple organ system failure, was observed. the white blood cell count of these patients ranged from . to . /mm (mean, . /mm ). the mortality in these patients ( %) was comparable to that of patients with documented infections in the icu ( %). we hypothesize that this clinical presentation may likely be caused by enhanced production and decreased metabolism of cytokines, e.g., tumor necrosis factor-alpha and interleukin ( l)- , which have been demonstrated in patients with endstage liver disease. a systemic inflammatory response syndrome in patients with cirrhosis of the liver, in the absence of infections, has recently been described, with leukocyte activation in the peripheral blood of patients with cirrhosis and systemic inflammatory response syndrome correlated with the serum levels of l- . mental status has been shown to be a significant predictor of outcome in icu patients in a number of clinical settings, e.g., patients with acute renal failure requiring dialysis and transplant recipients. , although encephalopathy was the predominant reason for icu admission in our patients, no association between the presence or absence of encephalopathy, the degree of encephalopathy (stage i, ii, or iii) or coma scores (apache) was demonstrated in our study. these findings may likely reflect the reversible nature of hepatic encephalopathy with appropriate management in patients with liver disease. an intriguing finding in our study was that, when controlled for the severity of illness (apache ii scores), the mortality in patients with cirrhosis caused by alcohol was significantly lower than that in patients with liver disease not caused by alcohol ( % versus %; p ϭ . ). although child-pugh scores, serum bilirubin, creatinine, or the incidence of gastrointestinal bleeding was not different, the patients with liver disease not caused by alcohol may have been more debilitated, as indicated by a significantly greater requirement for mechanical ventilation and a higher incidence of pulmonary infiltrates. nevertheless, the association of underlying liver disease with outcome has also been noted in transplant recipients. higher graft and patient survival was observed in patients undergoing liver transplantation for cholestatic and alcoholic liver disease compared with other liver diseases, including hepatitis. the vast majority of our patients with nonalcoholic liver disease had viral hepatitis caused by hepatitis c virus. it has been proposed that hepatitis c virus is an immunodulatory virus. greater infectious morbidity in patients with hepatitis c virus compared with patients without hepatitis c virus infection has been documented in transplant recipients. in the nontransplant setting, t-cell-derived cytokine levels were significantly higher in patients with hepatitis c virus compared with normal controls. whether differences in cytokine profile, level, or expression were contributory variables to differential disease severity in patients with and without viral hepatitis in our study remains speculative. despite the high mortality in critically ill patients with cirrhosis, icu support is not entirely futile in these patients. of patients in this study who underwent liver transplantation, the -year survival was % ( / ), the mean karnofsky score of these transplant recipients at year being . in conclusion, among critically ill patients with cirrhosis, the mortality in the icu was %. child-pugh scores, compared to apache iii scores, were less than optimal predictors of the outcome. pulmonary infiltrates and renal impairment were identified as independently significant medical complications that predicted mortality in our patients. future studies validating our findings are warranted, since these data have implications not only for prognosis but for the selection of candidates and timing of transplantation. intensive therapy for life threatening medical complications of hematological malignancy outcome of recipients of bone marrow transplant who require intensive-care unit support mortality during intensive care after orthotopic liver transplantation intensive care unit management in liver transplant recipients: beneficial effect on survival and preservation of quality of life mortality in intensive care patients with respiratory disease; is age important? in: child cg (ed) the liver and portal hypertension transection of the oesophagus for bleeding oesophageal varices prog-nosis of patients with cirrhosis and chronic liver disease admitted to the medical intensive care unit child-pugh score and liver transplantation prognostic value to child-turcotte criteria in medically treated cirrhosis intensive care unit admissions with cirrhosis: risk-stratifying patient groups and predicting individual survival prediction of mortality in cirrhosis of the liver survival and prognostic indicators in compensated and decompensated cirrhosis prognostic assessment of acute complications of bone marrow transplantation requiring intensive therapy apacheacute physiology and chronic health evaluation: a physiologically based classification system ventilator-associated pneumonia, a multivariate analysis the clinical evaluation of chemotherapeutic agents in cancer the american-european consensus conference on ards: definitions, mechanisms, outcomes, and clinical trial coordination causes of fever and pulmonary densities in patients with clinical manifestations of ventilator-associated pneumonia culture-negative neutrocytic ascites: a variant of spontaneous bacterial peritonitis estimation of the multivariate logistic risk function: a comparison of the discriminant function and maximum likelihood approaches risk factors influencing survival in acute renal failure treated by hemodialysisl assessing risk in liver transplantation. special reference to the significance of a positive cytotoxic crossmatch renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors, and prognosis the preoperative assessment of risk in liver transplantation. a multivariate analysis in cases of the uw era risk factors and predictive indexes of early graft failure in liver transplantation risk factors associated with mortality and infectious morbidity after liver transplantation tumor necrosis factor alpha and interleukin plasma levels in infected cirrhotic patients leukocyte activation in the peripheral blood of patients with cirrhosis of the liver and sirs, correlation with serum interleukin- levels and organ dysfunction acute renal failure treated by hemofiltration: factors affecting outcome hepatitis c virus and organ transplantation increased infections in liver transplant recipients with recurrent hepatitis c virus hepatitis immunoregulatory cytokines in chronic hepatitis c virus infection: pre and posttreatment with interferon alpha perioperative risk factor assessment in liver transplantation prognostic value to preoperatively obtained clinical and laboratory data in predicting survival following ortotopic liver transplantation infectious complications in liver recipients on tacrolimus: prospective analysis of consecutive liver transplants spontaneous bacterial peritonitis sequential changes in reticuloendothelial system after acute hemorrhage hepatic reticuloendothelial protection against bacteremia in experimental hemorrhagic shock key: cord- -qpjvmwmp authors: kinikar, aarti avinash; kulkarni, rajesh k.; valvi, chhaya t.; mave, vidya; gupte, nikhil; khadse, sandhya; bhardwaj, renu; kagal, anju; puranik, shaila; gupta, amita; bollinger, robert; jamkar, arun title: predictors of mortality in hospitalized children with pandemic h n influenza in pune, india date: - - journal: indian j pediatr doi: . /s - - - sha: doc_id: cord_uid: qpjvmwmp objective: to analyse the factors associated with increased mortality among indian children with h n . methods: data were abstracted from available hospital records of children less than y of age, who were admitted to sassoon general hospital in pune, india, with confirmed pandemic h n influenza infection from august through january . logistic regression analysis was used to identify clinical characteristics associated with mortality. results: of pediatric cases admitted with influenza like illness (ili), ( . %) had confirmed h n influenza infection. the median age of hin cases was . y; ( %) had an associated co-morbid condition. median duration of symptoms was d (interquartile range (iqr), – d). all h n cases received oseltamivir and empiric antimicrobials on admission. intensive care unit (icu) admission was required for ( %) children, and ( %) required mechanical ventilation.fifteen children ( %) died; mortality was associated with presence of diffuse alveolar infiltrate on admission chest radiography (odds ratio (or) , %ci : . – ; p < . ), use of corticosteroids in ards in children who required mechanical ventilation (or . , %ci: . – . ; p = . ), spo( ) < % on admission (or . , % ci: . – . ; p < . ) and presence of ards (or . , % ci : . – . ; p < . ). necropsy from all children who died showed ( %) had ards pattern and necrotizing pneumonitis, diffuse hemorrhage and interstitial pneumonia (n = each, %) with gram positive organisms consistent with severe viral and bacterial co-infection. conclusions: hypoxia, ards and use of corticosteroids in children with ards who were mechanically ventilated were the factors associated with increased odds of mortality. necropsy also suggested bacterial co-infection as a risk factor. on may , the first indian case of h n was confirmed. subsequently, one of india's largest documented h n outbreaks occurred in pune, with the first pediatric case reported in july . subsequently, sassoon general hospital (sgh), pune established a separate isolation ward and icu for suspected h n patients. to date, data on the current pandemic suggests that children under y of age represent almost half of all h n influenza cases, with many having at least one underlying medical condition, particularly asthma [ ] [ ] [ ] [ ] . in published reports, the majority of hospitalized children received antivirals; however, they appear to have significant mortality [ ] . a recent publication reported that factors independently associated with in-hospital mortality in adults and children were, requirement for invasive ventilation at intensive care unit (icu) admission, older age and presence of any co-existing conditions [ ] . understanding the factors associated with increase morbidity and mortality among indian children with h n could identify opportunities to prevent deaths due to present and future influenza pandemics in india. therefore, the authors analyzed the factors associated with mortality, among children admitted to the largest public hospital in pune, during the h n pandemic. sassoon general hospitals (sgh)-byramjee jeejeebhoy medical college (bjmc) is a large maharashtra government tertiary care public and teaching hospital, which serves pune city (city with population of approximately million) and surrounding peri-urban and rural areas. available hospital records were retrospectively reviewed for children with pcrconfirmed h n infection, who were less than y of age on admission to sgh and were admitted between august and january to the pediatric swine flu isolation icu and ward. children were admitted to icu if they had severe respiratory distress or hemodynamic instability requiring continuous monitoring and icu care. pathological specimens from children who died were reviewed for histopathological changes and secondary bacterial infections by gram staining. clinical and demographic data were extracted from available hospital records, using a standardized case report form (crf). the crf's were quality assured for completeness and accuracy and were entered via single data entry in a ms access database. the following data were collected: demographic characteristics like age, gender and location of residence; clinical characteristics on admission including duration of symptoms, co-morbid illnesses; clinical findings at presentation; and hospital course including use of antibiotics, corticosteroids and antiviral drugs, requirement of bubble continuous positive airway pressure (cpap)or mechanical ventilation, presence of co-infections, laboratory and radiologic findings. the primary outcome of the study was in-hospital mortality. necropsy data were available and included in the analysis for all children who died. tissue sections of lung and liver were formalin fixed, paraffin embedded and hematoxylin and eosin stained. gram staining of lung tissue blocks was also performed on all lung necropsy specimens. no personal patient identifiers were extracted on the crf's. all children admitted with ili, underwent nasopharyngeal (np) aspirate or swab specimen collection for the presence of h n specific viral nucleic acid on the day of hospitalization. influenza-like illness was defined by the documentation of fever (temperature > °f), and/or cough or sore throat, with any of the following symptoms: myalgia or arthralgia, respiratory distress, or vomiting or diarrhea. patient specimens were analyzed at the national institute of virology (niv), a world health organization (who)certified national reference virology laboratory in pune, india within h of collection. reverse-transcriptase pcr assay was performed according to the protocol recommended by the u.s. centers for disease control and prevention (cdc) [ ] . for the purposes of this analysis, a child was defined as infected with h n influenza based on laboratory confirmation of the presence of h n specific viral nucleic acid in nasopharyngeal specimen collected on hospitalization. the study was reviewed and approved by the ethics committee of sgh and the institutional review board (irb) of the johns hopkins university school of medicine. an epidemic curve of children presenting to the hospital with ili, and among those with pcr confirmed h n was created. demographic and clinical characteristics, on admission and in hospital, were summarized as a whole and also stratified by age categories less than y, - y and more than y. categorical variables were summarized using frequencies, and non-normal continuous variables using medians and iqr. categorical and continuous data across age categories were compared at % level of significance, using a fisher's exact test and nonparametric analysis of variance (kruskal-wallis test) respectively. the primary outcome of the study was mortality defined as in hospital death. logistic regression was used to identify risk factors for mortality. all analysis was done using stata software version . . between august and january , a total of patients with ili were admitted to the h n ward and icu, of which ( %) were children < y old. ninetytwo children ( %) had pcr-confirmed h n influenza infection. epidemic curve shown in fig. , suggests an initial peak in late august and september (wk - ). subsequently, there was a waxing and waning in the number of cases followed by another mild increase in the number of h n cases beginning in november and continuing through january . among the h n -confirmed cases, ( %) were males and the median age was . y (iqr . - ), with ( %) cases less than y of age. thirteen ( %) cases had a confirmed h n positive contact. table shows the demographic and clinical characteristics including signs and symptoms on admission and in-hospital, stratified by age. an underlying co-morbid condition was noted in ( %) of h n cases: congenital heart disease (n= ), asthma (n= ), diaphragmatic hernia (n= ), seizure disorder (n= ) and gastroesphageal reflux disease (n= ). coinfections were noted in ( %) of h n cases: hiv (n= ), dengue (n= ), tuberculosis (n= ), malaria (n= ) and typhoid (n= ). nutritional assessment at admission revealed that % of the h n cases had adequate nutrition and % had moderate acute malnutrition as per who growth standards [ ] . all h n cases received the antiviral drug oseltamivir on admission at the dosage recommended by the cdc [ ] . the median time from illness onset to initiation of oseltamivir was d and ( %) children received oseltamivir within h of symptom onset. two ( %) had received oseltamivir prior to admission. on admission, all children who were subsequently confirmed to have h n were also empirically started on broad spectrum antibiotics ( rd generation cephalosporin), and ( %) received vancomycin, although all children had received antibiotics prior to admission by an outside provider. bacterial co-infections isolated from blood cultures and/ or endotracheal aspirates were identified in ( %) children; gram-negative infections included acinetobacter baumanii (n= ), pseudomonas aeruginosa (n= ), citrobacter freundii (n= ) and escherichia coli (n= ), and gram positive infections included coagulase-negative staphylococci spp. (n= ) and methicillin resistant staphylococcus aureus (n= ). the most common clinical complications observed were acute respiratory distress syndrome (ards) (n= , %), empyema (n= , %), and encephalitis (n= , %). eighty-eight ( %) h n cases required icu care. all received oxygen therapy on admission. thirty six ( %) required ventilatory support on admission; ( %) received non invasive ventilation (nasal bubble cpap) and ( %) received mechanical ventilation. among icu admitted cases, the median time from symptoms onset to initiation of oseltamivir was d (range, - d). a short course of corticosteroids was administered to ( %) children. among icu-admitted cases, ( %) died, of which ( %) died within the first h of hospital admission. all children (n= ) who received non-invasive ventilation (bubble cpap) survived. the median age of children who died was y (iqr, - . y) and the median time from onset of symptoms to death was d (iqr, - d). the median duration of hospital stay among those who died was d (iqr, - d). among those who survived and were on mechanical ventilation, the median duration of hospital stay was significantly higher than those who died ( d vs. d, p . ). the duration of symptoms before admission was significantly lower in those who survived on assisted ventilation compared to those who died (median d vs. d, % ci : . - . ; p . ). mortality was associated with spo < % at admission (or . , %ci: . - . ; p< . ); presence of diffuse alveolar infiltrate (dai) on admission (or , %ci: . - . ; p< . ) and presence of ards on admission (or , %ci: . - ; p< . ) ( table ) . there was a strong trend with late presentation to hospital icu intensive care unit; anemia hb less than mg/dl; thrombocytopenia platelets less than /dl; leucopenia white blood cells less than , /dl; gerd gastro-esophageal reflux disease; ards/ali acute respiratory distress syndrome/acute lung injury defined as diffuse alveolar infiltrate along with pao /fio ratio less than and respectively. a defined as % increase from baseline creatinine. (admission to the hospital ≥ h of symptom onset) being associated with -fold increased odds of mortality; however this was not statistically significant (p= . ).however, late presentation to the hospital combined with need for mechanical ventilation on admission was associated with statistically significant increased risk of mortality (or , %ci: . - . ; p< . ).lastly, there was also a strong trend with the presence of co-morbid condition being associated with an almost -fold increased odds of mortality (or, . , %ci: . - ; p= . ). fourteen ( %) children admitted to icu received oseltamivir within h of symptom onset and survived while one of the children who died, received oseltamivir within h of symptom onset. pneumonia on admission was seen in all the children and was associated with higher mortality if presented with diffuse alveolar infiltrate. secondary bacterial infections particularly, nosocomial infection was associated with higher mortality; however this was not statistically significant (or . , % ci: . - . ; p= . ). necropsy performed on all children who died showed ards pattern (n= ) (fig. a) , necrotizing pneumonitis (n= ), diffuse hemorrhage (n= ) and interstitial pneumonia (n= ) consistent with severe viral and/or bacterial infection (table ) . a polymorphonuclear infiltrate was seen in cases (fig. b) , suggestive of a secondary bacterial infection. further gram staining of lung tissue blocks showed presence of gram positive infection in ( %) patients. liver necropsy revealed varied pathology ranging from fatty changes to sub massive necrosis (data not shown). since the beginning of the present pandemic in pune, india, until st january ; adult and pediatric patients with influenza-like illness were screened at various screening centers (unpublished report from niv, pune, india) and , ( %) underwent nasopharyngeal swab testing. of these, ( %) were confirmed to have h n infection and ( . %) were in the - y age group. the authors evaluated the risk factors associated with mortality in their setting and found that lower admission o saturation, corticosteroid treatment in children with ards requiring mechanical ventilation, diffuse alveolar infiltrate and presence of ards was associated with increased mortality in children with pandemic h n influenza infection. in addition, the authors found a trend towards late presentation to the hospital and bacterial coinfection also being associated with increased risk of mortality (though these were not statistically significant). the present case series of hospitalized children with h n influenza infection during the h n india pandemic depicts the severity of illness seen in hospitalized young children. h n infection caused significant pneumonia and ards, and resulted in icu admissions and deaths in % and % of children, respectively. the reported influenza-like presentations such as fever, cough, sore throat, and myalgia as well as gastrointestinal symptoms in the present setting was comparable to previous reports of h n in children [ ] [ ] [ ] . neurological symptoms and complications such as, altered mentation and seizures along with influenza like symptoms were also noted in the present study and were similar to what has been previously reported [ ] . high-income settings have reported obesity in a significant proportion of adults and children with h n infection [ ] [ ] [ ] . in contrast, the authors did not find an association between nutritional status and risk of h n illness in the present hospitalized cohort; nutritional assessment in the present center revealed that % of those children admitted were neither obese nor undernourished by standard anthropometric measurements. in contrast to reports from the developed world [ ] [ ] [ ] [ ] of the current h n pandemic, underlying medical conditions were lower in the present case series. asthma only accounted for % in the present group, whereas in other studies it has been reported to be % or higher [ ] [ ] [ ] [ ] . hiv has been associated with h n in published reports [ ] and the authors identified % of their children co-infected with hiv, which is higher than the population prevalence of hiv in children in the authors' area (unpublished data). nevertheless, the presence of a co-morbid condition showed a trend towards increased mortality in the present series. all children received oseltamivir and empiric antimicrobials on admission to the present center. although the present data shows that survival and deaths among children who have received oseltamivir within h of symptom onset is not statistically significant, the authors recommend early initiation of oseltamivir under pandemic situation. in spite of receiving antimicrobials prior to admission and upon admission, % had confirmed bacterial co-infection during the course of their hospitalization. this included both gram negative and gram positive organisms and is consistent with previous reports [ ] . the presence of secondary bacterial infection showed a trend towards increased mortality by fold. dengue [ ] and hiv [ ] co-infection with h n has been recently reported, but for the first time, the present case series is reporting coinfections like malaria, tuberculosis and typhoid fever in patients with confirmed h n infection. however, these co-infections were not associated with increased mortality in the present cohort. the mortality rate of % noted in the present study is consistent with prior reports of current pandemic for children [ ] [ ] [ ] . the authors found that lower admission o saturation, diffuse alveolar infiltrate on admission, corticosteroid treatment in children with ards requiring mechanical ventilation and presence of ards was associated with increased mortality in children with pandemic h n influenza infection. the fact that mechanical ventilation was required on admission in patients who died, suggests that these children presented late in the course of their illness. late presentation to the health care system remains a major challenge in influenza pandemics and is frequently associated with poor outcomes, including higher risk of mortality. mass media and community efforts during a pandemic need to emphasize earlier presentation to health care centers equipped to address pandemic influenza with special care taken to transfer critically ill patients in well equipped ambulances. necropsy performed on the children who died demonstrated presence of ards pattern, necrotizing pneumonitis, and diffuse alveolar hemorrhage as the probable cause of mortality. the histological findings are similar to that a recent report [ ] . the gram staining of lung tissue blocks in the present series revealed that more than half had an underlying gram positive bacterial infection suggestive of alveoli filled with dense exudate of polymorphs with scanty mononuclear cell, fibrin deposition, intra alveolar hemorrhage, necrosis of alveolar wall with micro abscess formation and marked congestion of alveolar capillaries streptococcal and staphylococcal infections. cdc has reported bacterial co-infection in almost one third of all fatal h n cases in united states and majority of these infections were streptococcal and staphylococcal infections [ ] . the present study had a potential limitation. since sgh was the only referral center for critically ill patients with suspected h n infection in pune, india during the early pandemic, the patients represented the most critically ill children in the community with h n and are not representative of the typical cases of childhood h n in the community. the authors' experience in india suggests that mortality may be associated with late presentation to tertiary care centers and severe illness at presentation, including severe respiratory distress and ards. in addition, secondary bacterial infection may also be clinically significant contributor to mortality. in resource-constrained settings such as the present one, the authors recommend early referral and admission of critically ill children, prompt initiation of empirical oseltamivir and broad spectrum antibiotics in order to have better outcomes. hospitalized patients with h n influenza in the united states critically ill patients with influenz a (h n ) in mexico critically ill patients with influenza a(h n ) infection in canada the australia and new zealand extracormembrane oxygenation (anz ecmo) influenza investigators. extracorporeal membrane oxygenation for influenza a (h n ) acute respiratory distress syndrome pediatric hospitalizations associated with pandemic influenza a (h n ) in argentina critical care services and h n influenza in australia and new zealand rtpcr) protocol for detection and characterization of swine influenza who child growth standards: length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-forage: methods and development. geneva: world health organization updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the - season clinical characteristics of paediatric h n admissions in birmingham surveillance for pediatric deaths associated with pandemic influenza a (h n ) virus infection: united states neurologic complications associated with novel influenza a (h n ) virus infection in children pandemic influenza a (h n ) in hiv- -infected patients bacterial coinfections in lung tissue specimens from fatal cases of pandemic influenza a (h n )-united states co-infection with dengue virus and pandemic (h n ) virus clinical profile of h n positive hiv-infected children lung pathology in fatal novel influenza a (h n ) infection contributions all authors participated in data analysis and manuscript preparation.conflict of interest none.role of funding source none. key: cord- -k kca zl authors: kamel, toufik; helms, julie; janssen-langenstein, ralf; kouatchet, achille; guillon, antoine; bourenne, jeremy; contou, damien; guervilly, christophe; coudroy, rémi; hoppe, marie anne; lascarrou, jean baptiste; quenot, jean pierre; colin, gwenhaël; meng, paris; roustan, jérôme; cracco, christophe; nay, mai-anh; boulain, thierry title: benefit-to-risk balance of bronchoalveolar lavage in the critically ill. a prospective, multicenter cohort study date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: k kca zl purpose: to assess the benefit-to-risk balance of bronchoalveolar lavage (bal) in intensive care unit (icu) patients. methods: in icus, we prospectively collected adverse events during or within h after bal and assessed the bal input for decision making in consecutive adult patients. the occurrence of a clinical adverse event at least of grade , i.e., sufficiently severe to need therapeutic action(s), including modification(s) in respiratory support, defined poor bal tolerance. the bal input for decision making was declared satisfactory if it allowed to interrupt or initiate one or several treatments. results: we included bal in patients [age years (interquartile range (iqr) – ); female gender: ( . %); simplified acute physiology score ii: (iqr - ); immunosuppression ( . %)]. bal was begun in non-intubated patients in ( . %) cases. sixty-seven ( . %) patients reached the grade of adverse event or higher. logistic regression showed that a bal performed by a non-experienced physician (non-pulmonologist, or intensivist with less than years in the specialty or less than bal performed) was the main predictor of poor bal tolerance in non-intubated patients [or: . ( % confidence interval . – . ); p = . ]. a satisfactory bal input for decision making was observed in ( . %) cases and was not predictable using logistic regression. conclusions: adverse events related to bal in icu patients are not infrequent nor necessarily benign. our findings call for an extreme caution, when envisaging a bal in icu patients and for a mandatory accompaniment of the less experienced physicians. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. bronchoalveolar lavage (bal) performed during fiberoptic bronchoscopy can help in diagnosing a vast array of lung diseases [ , ] . in the intensive care unit (icu), it is often performed in patients with acute respiratory failure. the main risk brought by fiberoptic bronchoscopy in the critically ill is the worsening of hypoxemia [ ] [ ] [ ] , but in the few studies focused on fiberoptic bronchoscopy tolerance and comprising a significant number of bal performed in icu patients, bal has been considered well tolerated in most of the cases [ ] [ ] [ ] [ ] [ ] [ ] [ ] . meanwhile, as less invasive diagnostic methods exist or are emerging (high-resolution ct scan imaging, molecular microbiological diagnosis on nasopharyngeal swab, or on tracheal aspirates, etc.), the real utility of bal for the diagnosis of pulmonary diseases encountered in the icu may be questioned. in immunocompromised patients who represent a large proportion of patients undergoing bal in the icu, the diagnostic yield of bal was reported to be rather low compared to a less invasive approach [ ] . therefore, estimating the benefit-to-risk balance of bal in the critically ill would be an appreciable adjunct for decision making, when bal is envisaged. the objectives of this prospective, non-interventional, multicentre cohort study were to count and describe the adverse events observed during and after bal in the critically ill to estimate the proportion of patients for whom the bal fluid analysis allowed therapeutic decision(s) and to search for predisposing factors for either harm or benefit. the study took place in french medical-surgical icus (from public, university-affiliated [n = ] or non-university hospitals [n = ]) from april , to october , , complied with french law for observational studies, was approved by the comité de protection des personnes (approval number: . . ) and was registered with clinicaltrials.gov (nct ). patients or next-of-kin and physicians who performed the bal gave informed consent. patients were included if ( ) they had an indication to undergo a bal as decided by their attending intensivist, ( ) cellular analysis of bal fluid by a pathologist was planned, and ( ) consent had been obtained. pregnant women and patients under years of age were excluded. mini-bals, bals performed without bronchoscopy and bal without cellular analysis by a pathologist were not allowed. patients were included at time of their first bal during the icu stay. each center was asked to include at least patients and a maximum of patients. we planned to include patients and bals (see online resource for sample size considerations). data were recorded using paper case report forms filled in by local investigators and/or study nurses and then digitalized in the coordinating center (orléans). there was no on-site monitoring, but centers could be queried for clarification after centralized checking of data for completeness and consistency. the study was strictly non-interventional and physicians were asked not to modify their usual practice. we recorded the specialty (pulmonologist or intensivist) of the physician performing the bal. the physician's experience in terms of years in the specialty (< ; - ; > years) and of number of bal performed (< ; - ; > ) was recorded. we defined the physician performing the bal as an "experienced physician" when he/she was a pulmonologist or when he/ she was an intensivist with the greatest experience (i.e., > years in the specialty or > bal performed), considering that pulmonologists, by virtue of their specialty, are sufficiently trained in the practice of bal. we collected patients' characteristics at inclusion, including demographics, time spent in icu before bal, existence of acute respiratory failure before bal or not, according to the attending intensivist's judgment, simplified acute physiology score (sapsii) [ ] , tobacco use, underlying respiratory diseases, immunosuppression, and use of anticoagulant or antiplatelet therapy. we recorded the indication(s) of bal, vital signs before bal (respiratory rate [rr], heart rate [hr], blood pressure [bp]), and arterial blood gases, blood lactate, and pulse oximetry (spo ) within the past h. type of respiratory support used, body temperature, bp, hr, rr, and spo were collected at the beginning of bronchoscopy and at , , , and h, thereafter. the amounts of fluid instilled for bal and recovered were recorded. if sampled, arterial blood gases corresponding to the lowest pao /inspired fraction of oxygen (fio ) ratio within h after bal were also recorded. for patients under oxygen therapy other than high-flow nasal cannula oxygen therapy (hfnc), the fio value was derived from oxygen flow rate [ ] . in the critically ill, bronchoalveolar lavage (bal) is an aid for decision making in less than % of the cases and is associated with frequent, sometimes serious adverse events. adverse events and bronchoalveolar fluid of poor quality are observed more frequently, when bal is performed by the less experienced physicians. bal respiratory tolerance was first assessed by recording the need for modification(s) in respiratory support as previously described [ ] from the beginning of bronchoscopy to h after, including need of tracheal intubation, increase by more than % in oxygen flow rate, or use of hfnc in patients under standard oxygen therapy, increase by more than % in gas flow rate or fio in patients initially under hfnc, need of non-invasive ventilation (niv) in patients who initially had no mechanical respiratory support and increase by more than % in inspiratory pressure support or in positive end-expiratory pressure or in fio , in patients initially treated by niv. we added to this list the following events: increase by more than % in inspiratory pressure support or in positive end-expiratory pressure or in fio , or need of extracorporeal membrane oxygenation therapy in patients initially treated by invasive mechanical ventilation, and need for switching from pressure support mode to volume-controlled mode in patients with mechanical respiratory support. in addition, the investigators were asked to declare all clinically significant drops in spo and all other clinically significant events occurring during the h following the beginning of the bronchoscopy/bal procedure. all events were categorized in five grades of increasing severity (see table ). pathologists assessed the quality of the bal fluid. a bal fluid containing more than % of bronchial (squamous or ciliated epithelial) cells or less than , cells/ml or that was judged non interpretable for other reasons was said of "poor quality". otherwise, the bal fluid was considered of "good quality". the attending intensivists were asked, after having collected all analyses made on bal fluid, to categorize the bal according to the highest degree of usefulness it had reached: class , of no help; class , in line with (but not definitively confirming) a diagnosis already mentioned; class , suggesting a diagnosis not previously envisaged; class , allowing to interrupt one or several treatments; or class , bringing definitive diagnosis and/or allowing the initiation a new therapy. categorical variables are expressed as counts and percentages. continuous variables are expressed as median and interquartile range (iqr) or mean and sd. variables were compared between groups using χ test, fisher exact test, kruskal-wallis rank sum test, mann-whitney u test, one-way analysis of variance, or t test when appropriate. for multivariable analyses, missing values were replaced using multiple imputation by chained equations, and imputed datasets were pooled and analysed. multivariable logistic regressions with centers handled as random effect variable were used to identify predictors of "poor tolerance" (defined as the occurrence of at least one adverse event of grade or higher during the h-period of the study), and of "good usefulness" (degree of usefulness of class or ) (see online resource for detailed methods of variables/models selection). regarding bal tolerance, predictors were also searched in the framework of an ordinal regression model (proportional odds model) [ ] with mixed effects, using the highest grade of adverse event reached by each patient (as defined in table ) as an ordered categorical outcome. odds ratios (or) are given with their % the time courses of rr, hr, bp, and spo , from bal time (h ) to h after bal, were compared between types of respiratory support used at time of bal in the framework of distinct linear mixed models, adjusting for initial pao /fio ratio and sapsii, and patients handled as random effect. in these analyses, p values were adjusted for multiple comparisons using the tukey's test. all analyses were conducted using r software . . (http://www.r-proje ct.org). a two-side p value < . indicated statistical significance. among the bal performed during the study period, bal in patients were included (fig. other characteristics of patients and bal are exposed in table . a total of ( . %) patients needed modification of the respiratory support within the h after the beginning of bal, including eight ( . %) intubations in the hfnc/niv group and one ( . %) in the standard oxygen therapy group. percentages of patients needing change in the type of respiratory support are shown in table s online resource . a total of adverse events of any grade were observed (table ) . sixty-seven ( . %) patients reached the grade of adverse event or higher in the whole population. more patients in the hfnc/niv group ( (fig. ). in non-intubated patients, the percentage of grade adverse events was . % ( / ) when bal was performed by a non-experienced physician versus . % ( / ) otherwise, but the difference did not reach statistical significance due to small subsets sizes. logistic regression showed a strong interaction between the variables "invasive mechanical ventilation" and "experienced physician" (p < . ) (table s ). in the subset of non-intubated patients, a bal performed by a "non-experienced physician" was significantly associated with an increased risk of grade adverse events occurrence (or: . [ . - . ]; p = . ) (table s ) . logistic regression disclosed no significant predictor of grade adverse events in the invasive mechanical ventilation group (data not shown). proportional odds model analysis performed on the whole population also showed a strong interaction between the variables "invasive mechanical ventilation" and "experienced physician" (p < . ) (table s ). in the subset of non-intubated patients, a bal performed by a non-experienced physician was significantly associated with an increased risk of adverse events (or: . [ . - . ]; p = . ) and spo below % within h before bal, when entered as restricted cubic splines, placed the patients at risk of adverse events of grade or higher ( figure s ). no fig. study flow chart. a among the bronchoalveolar lavages (bal) performed during the study period, we did not record whether they comprised cellular analysis by a pathologist or if they were mini-bal or bal performed with or without bronchoscopy. b patient recruitment exceeded the expected, because we anticipated a number of non-workable case report forms h more than one indication could be present for each bal i significantly higher than in the nasal high-flow oxygen therapy or non-invasive ventilation group (p < . ), and then in the invasive mechanical ventilation group (p = . ) j h indicates the time at which bal has began k experience in years in the specialty and in terms of number of bal performed are detailed in table s of the online resource l we defined the physician performing the bal as an "experienced physician" when he/she was a pulmonologist or when he/she was an intensivist with the greatest experience (i.e., > years in the specialty or > bal performed) - . ]; p = . ) and the amount of bal fluid (in ml) recovered handled as a linear predictor (or . [ . - . ] per ml increase; p < . ), were statistically significant predictors of a bal fluid of good quality (table s ). transforming the amount of bal fluid in restricted cubic splines to take into account potential non-linearity gave a slightly better model fit and showed a biphasic relationship between the amount of bal fluid recovered and the probability of obtaining a bal of good quality (fig. ) . the same biphasic relationship was also founded in intubated patients ( figure s ), in non-intubated patients ( figure s ) , and in patients for whom the bal was not performed only for suspicion of hospital-acquired lung infection ( figure s ). no statistically significant predictor of a bal of good quality could be identified in patients for whom a suspicion of hospitalacquired lung infection was the sole indication of bal (data not shown). diagnoses retained for explaining the lung disease that justified the performance of bal are exposed in tables s , s , s , and s in the online resource . bal input was classified in class (not useful) in patients out of ( . %) ( counts and percentages of grade adverse event(s) during or after bal according to physician's experience and type of initial respiratory support. ns not significant. we defined the physician performing the bal as an "experienced physician" when he/she was a pulmonologist or when he/she was an intensivist with the greatest experience (i.e., > years in the specialty or > bal performed) there were / ( . %) bal classified as of good usefulness (i.e., class or ) in the whole population. this frequency was not statistically different between intubated and non-intubated patients at time of bal or between patients with bal performed only for suspicion of hospital-acquired lung infection or not (table s ). the quality of the bal fluid collected was not statistically associated with the bal usefulness: . % ( / ) of bal judged of good quality were classified in class or , versus . % ( / ) when bal was not judged of good quality by the pathologist (p = . ). multivariable logistic regression did not identify statistically significant predictors of a bal of class or (data not shown), either in the whole population or in pre-specified subsets. linear mixed model analysis showed that baseline and further spo values were lower in the standard oxygen group than in the two other types of respiratory support. other details of analyses are reported in figure s . in this multicenter cohort of critically ill patients, numerous adverse events were observed during or after bal and grade adverse events affected . % of the study population. the association of the noninvasiveness of respiratory support used with a bal performed by a nonexperienced physician was a strong predictor of adverse events occurrence. the experience of the physician performing the bal and the amount of bal fluid recovered were the main predictors of a bal fluid judged as of good quality by the pathologist. the bal input for decision making was satisfactory (i.e., allowed discontinuing a treatment and/or initiating a new one) in less than % of the cases. even when bal was indicated only for suspicion of hospital-acquired lung infection, a case where bal fluid quality might have less importance since most often mainly microbiological information is expected, the bal input was satisfactory in % ( / ) of the cases. interestingly, among the non-intubated patients with the most severe respiratory failure, for whom clinicians had judged standard oxygen therapy was not sufficient, only ( . %) had bal performed under niv, while the remaining patients had bal performed under hfnc therapy. in high-risk patients, niv for fiberoptic bronchoscopy with bal has been shown feasible [ , ] and recently, in one small-size randomized trial, safer than hfnc therapy [ ] . in counterpart, hfnc therapy has been shown safer than niv in patients with severe hypoxemic respiratory failure [ ] and has the advantage to be easy to use for care providers. this probably explains the predominant use of hfnc therapy in our study cohort. however, while some recent studies suggested that hfnc is safe for performing fiberoptic bronchoscopy and bal [ ] [ ] [ ] , large randomized trials are still needed. in the present study, adverse events collected were more frequent than in several previous studies [ ] [ ] [ ] [ ] ] . this discrepancy may be due to differences in methods used for collecting and defining adverse events. however, while the non-comparative design of this study does not allow firm conclusions regarding the cause-effect relationship between bal and the collected adverse events, the high frequency of adverse events should prompt caution when performing bal in icu patients, especially in non-intubated patients. the high frequency of adverse events might account for the increased hospital mortality recently observed in non-ventilated immunocompromised patients who underwent a bronchoscopy as compared to those who did not [ ] . given the high frequency of adverse events we observed in non-ventilated table s in online resource ) was used. the amount of bal fluid recovered was transformed in cubic splines to account for non-linearity. the biphasic shape of the figure shows that below ml of bal fluid recovered, the estimated probability declines in parallel with the amount of fluid recovered patients, one may wonder if systematically intubating the sickest patients (e.g., those with profound hypoxemia) could not be a safer option for performing bal. however, although this is a common concern in icus, to our knowledge, no comparative trial has yet been conducted to answer this question. it is worth noting that in the few available prospective studies focused on bal tolerance that showed rather low adverse event rate [ ] [ ] [ ] , bronchoscopies and bal were mostly performed by pulmonologists [ ] or by experienced icu physicians [ , ] . the present study highlights the importance of the physician's experience and training, which have often been emphasized in recommendations [ , , ] for bronchoscopy but have never been demonstrated for icu patients undergoing bal so far. although we could not show a direct link between the quality of the bal fluid recovered and the diagnostic yield of bal, the fact that the variable "experienced physician" was also a strong predictor of a bal of good quality suggests that the greater the experience of the physician performing the bal, the better the chance of performing a safe and useful bal. previous studies have reported that the diagnostic yield of bal was within the range of - % in icu patients [ , , ] . in line with these results, using a pragmatical classification in an unselected population, we found that the bal showed good usefulness for decision making in one half of the cases. additionally, we found that the bal input for decision making was not easily predictable. this uncertainty associated with the bal input for decision making again justifies the caution with which bal should be performed to ensure the best possible benefit-to-risk balance. although the bal usefulness of % observed in this study may appear rather low compared to the number of adverse events brought about, it should be placed in perspective with other diagnostic, invasive procedures such as open lung biopsy. in a recent meta-analysis in acute respiratory distress syndrome patients [ ] , open lung biopsy was reported to yield definitive diagnosis in nearly % of the cases, allowing to change therapy in %, while causing complications in %, resulting in a more favorable benefit-to-harm ratio than the one we observed for bal. however, great variability of diagnostic yield ( - %), impact on therapy ( - %) and complications ( - %) of lung biopsy existed between the published cohort studies [ ] , preventing any definitive conclusion. moreover, as those studies were mostly retrospective, it is highly probable that many adverse events were not collected. therefore, prospective studies that could help in deciding which procedure is riskier or more beneficial to patients are still lacking. in addition, although open lung biopsy may have proved beneficial to some immunosuppressed patients such as after bone marrow transplantation [ ] , it cannot reasonably be offered to all patients for whom bal currently appears to be the most appropriate diagnostic tool, either because it may be disproportionate for patients with low severity of disease or because surgical procedures are a real challenge for cancer patients with pancytopenia. undoubtedly, if there is one alternative to the bal that could be less risky for immunosuppressed patients, it is the combination of non-invasive tests on sputum, nasopharyngeal secretions, urine, and blood that may dramatically restrict the number of patients for whom bal is absolutely needed [ ] . this might become increasingly true in view of the current development of molecular diagnostic tools [ ] [ ] [ ] , the knowledge acquired in chest highresolution computed tomography imaging [ , ] , and perhaps future progress in the human volatilome analysis [ ] . this study has several limitations. first, because we did not study any control group in parallel, the adverse events collected cannot be attributed to bronchoscopy or to the bal with certainty. however, all the events collected are known side effects of bronchoscopy or bal and the close temporal relationship between bal and adverse events suggests that a non-negligible part of these events were related to the bal. second, we did not record the anesthesia regimen used during bronchoscopy and could not differentiate local from general anesthesia. some adverse events (e.g., hypotension) probably were side effects of intravenous anesthesia. anyway, our aim was to record, in real-life conditions, adverse events possibly related to the bal procedure, of which anesthesia is an integral part [ ] . conversely, the occurrence of adverse events such as hypertension, agitation, cough, or bronchospasm, at least in intubated patients, may reflect suboptimal anesthesia and leaves room for improvement. this suggests that in addition to an experienced physician performing the bal, the systematic presence of a second physician adjusting anesthesia, adapting ventilatory support and taking care of the hemodynamic status, might improve the patient safety. third, as there are no published specific classifications of adverse events and of diagnostic yield of bal, we used our own classifications. regarding the adverse events (table ) , it is noteworthy that the main predictor of adverse events identified (non-experienced physician performing a bal in a non-intubated patient), not only was strongly associated with grade adverse events, but also by proportional odds model analysis was associated with an increased probability of observing any grade of adverse event above a certain value versus observing any grade of adverse event below the same value. in our view, this would tend to validate the adverse events classification we proposed. fourth, we used a "home-made" classification of the bal input for decision making. this may have introduced bias in the estimation of the diagnostic yield of bal. in particular for the diagnosis of ventilator-associated pneumonia, it is possible that the culture of the bal fluid identified a microorganism already identified by other means (e.g., tracheal aspirate with semi-quantitative culture) and did not lead to modification of the antibiotic regimen already in place. although some may argue that in this case the diagnostic yield of bal might have been declared as very good, there is an ongoing debate about the bacteriological samples to be used for accurately diagnosing ventilatorassociated pneumonia [ , ] . also, in some instances despite no formal respiratory diagnosis was retained, the input of bal was classified as class (i.e., the best possible) by the attending intensivists, because bal not only has allowed ruling out some diagnoses, but also allowed trying another treatment such as diuretics or corticosteroids. this may have slightly distorted the classification of the bal input. fifth, in the french icus involved in this study, the bronchoscopy and bal could be performed either by pulmonologists or intensivists. therefore, our results may not be found in countries, where performing bronchoscopy is a prerogative exclusively reserved for pulmonologists. our findings suggest that in real-life conditions, adverse events during or following bal in icu patients are not infrequent nor necessarily benign. the lack of experience of the physician performing the bal was identified as the main predictor of clinically significant adverse events in non-intubated patients. on the other hand, the diagnostic yield of bal could be considered satisfactory in less than one half of the cases. altogether, these findings call for an extreme caution when considering the indication of bal in icu patients and for a mandatory accompaniment of the less experienced physicians. the online version of this article (https ://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. avenue molière, strasbourg cedex, france. chu d' angers service de réanimation médicale et de médecine hyperbare, , rue larrey, angers cedex , france. chru de tours-hôpital bretonneau service de réanimation polyvalente, bis médecine intensive réanimation, réanimation des urgences chu la timone -pole rush, rue saint pierre rue du lieutenant-colonel prudhon, argenteuil cedex université de poitiers, rue de la milétrie, poitiers, france. ch de la rochelle-hôpital saint-louis service de réanimation polyvalente, rue du docteur schweitzer, la rochelle cedex , france. service de médecine intensive réanimation, chu de nantes-hôtel dieu, bd. jean monnet, nantes cedex british thoracic society bronchoscopy guideline group et al ( ) british thoracic society guideline for diagnostic flexible bronchoscopy in adults: accredited by nice arterial hypoxemia induced by fiberoptic bronchoscopy use of bronchoalveolar lavage to diagnose bacterial pneumonia in mechanically ventilated patients safety of bronchoalveolar lavage in the critically ill, mechanically ventilated patient safety of bronchoalveolar lavage in patients with adult respiratory distress syndrome fiber optic bronchoscopy in patients with acute hypoxemic respiratory failure requiring noninvasive ventilation-a feasibility study safety of performing fiberoptic bronchoscopy in critically ill hypoxemic patients with acute respiratory failure bergmans dc ( ) clinical course and complications following diagnostic bronchoalveolar lavage in critically ill mechanically ventilated patients indications, clinical outcomes and complications of flexible bronchoscopies the diagnostic yield, safety, and impact of flexible bronchoscopy in non-hiv immunocompromised critically ill patients in the intensive care unit diagnostic strategy for hematology and oncology patients with acute respiratory failure: randomized controlled trial a new simplified acute physiology score (saps ii) based on a european/north american multicenter study aarc clinical practice guideline ( ) in-vitro ph and blood gas analysis and hemoximetry. american association for respiratory care analysis of ordinal categorical data noninvasive positive-pressure ventilation vs. conventional oxygen supplementation in hypoxemic patients undergoing diagnostic bronchoscopy continuous positive airway pressure during fiberoptic bronchoscopy in hypoxemic patients. a randomized double-blind study using a new device high-flow nasal cannula oxygen versus non-invasive ventilation in patients with acute hypoxaemic respiratory failure undergoing flexible bronchoscopy-a prospective randomised trial high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure effectiveness and safety of highflow nasal cannula oxygen delivery during bronchoalveolar lavage in acute respiratory failure patients high-flow nasal oxygen for bronchoalveolar lavage in acute respiratory failure patients prospective experience of high-flow nasal oxygen during bronchoscopy in patients: a feasibility study efraim investigators and the nine-i study group et al ( ) diagnosis and outcome of acute respiratory failure in immunocompromised patients after bronchoscopy guidelines for competency and training in fiberoptic bronchoscopy. section on bronchoscopy endoscopy working group of the french society of pulmonary medicine et al ( ) diagnostic flexible bronchoscopy. recommendations of the endoscopy working group of the french society of pulmonary medicine surgical lung biopsy in adult respiratory distress syndrome: a meta-analysis diffuse pulmonary infiltrates after bone marrow transplantation: the role of open lung biopsy multiplex platforms for the identification of respiratory pathogens: are they useful in pediatric clinical practice? molecular quantification of bacteria from respiratory samples in patients with suspected ventilator-associated pneumonia rapid quantification of staphylococcus aureus from endotracheal aspirates of ventilatedpatients: a proof-of-concept study noninfectious pulmonary complications after hematopoietic stem cell transplantation: practical approach to imaging diagnosis infection in immunocompromised hosts: imaging the human volatilome: volatile organic compounds (vocs) in exhaled breath, skin emanations, urine, feces and saliva management of adults with hospital-acquired and ventilator-associated pneumonia: clinical practice guidelines by the infectious diseases society of america and the the international ers/esicm/ escmid/alat guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: guidelines for the management of hospital-acquired pneumonia (hap)/ventilatorassociated pneumonia (vap) of the the authors declare that they have no conflicts of interest in relation to this study. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- - f g t y authors: labeau, s. o.; conoscenti, e.; blot, s. i. title: less daily oral hygiene is more in the icu: not sure date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: f g t y nan the interest in research on oral care in intensive care unit (icu) patients has emerged largely from the s onward after years of being a rather ignored topic in health science. since, the focus has been on its potential contribution to preventing pneumonia by eliminating contaminated oral pathogens that might invade the lower respiratory tract. accumulating evidence of the effectiveness of oral care with chlorhexidine gluconate (chg) in preventing ventilator-associated pneumonia (vap) or postoperative pneumonia [ , ] has led to adopting chg oral care as the gold standard for intubated patients. recently, however, potential adverse effects of chg on the oral mucosa [ ] and reduced bacterial susceptibility [ ] have been reported, as well as an even more alarming potential association of chg oral care with an increased risk of mortality [ ] [ ] [ ] [ ] . although the latter association results from retrospective studies or meta-analyses, righteous calls for caution and for a thorough re-evaluation of the established gold standard have been launched [ , ] . it is not unlikely that the findings presented above could instigate questioning the safety of oral care in the icu. additionally, doubt could be casted on its value as the beneficial effect on the risk of vap of other oral hygiene measures not involving chg, such as swabbing and toothbrushing, is not supported by the evidence [ ] . oral care does, however, not need to reduce the risk of pneumonia to be pivotal. as in healthy individuals, mouth care is an indispensable basic hygiene requirement for each icu patient, intubated or not. appropriate oral care counters discomfort caused by xerostomia, a sore mouth or ulcerated lips, and promotes oral health by preventing caries and decay of teeth, bacterial or candidal stomatitis, gingivitis, and periodontitis which has been associated with systemic diseases such as bacteraemia, rheumatoid arthritis and cardiovascular diseases, including stroke [ ] . oral health is therefore just as important an endpoint of oral care as vap prevention. a potential risk reduction in pneumonia should rather be considered as a favourable side effect of oral care and not as the primary goal. moreover, oral care aiming at oral health does not necessarily involve chg use. toothpaste and an appropriate brush adequately clean teeth and gums. the oral cavity can be cleansed mechanically and/or chemically with non-chg containing mouthwashes, and saliva substitutes, stimulants and moisturizing gels are not chgbased [ ] . there are no substantiated arguments to question the legitimacy of oral care for safety concerns due to potential chg-associated harm. the above plea for proper daily oral care may not seem to leave room for doubting the viewpoint that less daily oral care in the icu could be more. however, there are no evidence-based standards available to date that define the interventions, methods and frequency to provide icu patients with optimal oral health. in the clinical environment, this lack of evidence is reflected by a huge variety of practices that differ between, and even within, healthcare facilities, and of oral care protocols that are based on expert opinion only. it seems obvious that toothbrushing is an essential component of these protocols owing to its potential to effectively decrease dental plaque reservoirs [ ] , but the rationale for the incorporation of some other interventions is far less obvious, e.g. the use of foam sticks and specific oral care solutions. while lacking proof of evidence of their effectiveness, these interventions are not rarely costly and labour-intensive. as such, and until solid evidence will determine best *correspondence: sonia.labeau@hogent.be practices, many oral care protocols could benefit from critical reconsideration aiming at a rational downsizing of unsubstantiated resources without affecting the quality of care. from this perspective, less daily oral care in the icu could indeed be more. as a striking example, the most appropriate frequency of oral care is a well-known matter of debate. since there is no evidence for choosing one frequency over another, intervals vary extensively among protocols, both for intubated and non-intubated patients. protocols generally include an intervention (toothbrushing and/or swabbing and/or oral moistening) minimally twice a day. particularly for intubated patients, the suggested regimens range widely, i.e. from two times daily up to six times daily. to change such generic, costly and demanding care routines into individualized care that is tailored to the patients' specific needs it might be suggested to use an oral assessment score to determine mouth care regimes. most assessment tools have, however, been developed for use in the care-dependent elderly. recently, ames and colleagues [ ] developed an assessment scale specifically for critically ill intubated and non-intubated patients that, moreover, includes an interpretation of the timing of oral care based on the score. although the authors report no measures of reliability or validity of the instrument, their tool might be a first step towards better matching timing and frequency of oral care to the specific needs of individual icu patients and to turn 'more' into a 'less' of at least equal quality. we warmly invite researchers to contribute to the acquisition of evidence-based insights in what should be recommended as optimal oral hygiene in the icu in order to eliminate expensive but redundant interventions from daily practice and to provide patients with optimal oral health. well-designed, appropriately sampled multicenter trials are needed to tackle what we consider to be research priorities in this field (table ) [ ] . additionally, we welcome all further evidence clarifying the contribution of oral care interventions to the prevention of pneumonia and the current concerns regarding the safety of chg oral care. in conclusion, the current state of the science does not allow to determine whether less daily oral hygiene could indeed be more. while awaiting solid evidence that will elucidate this uncertainty, we consider an individualized oral care approach that takes into account the patients' risk profile and ability to maintain oral health themselves the best option. optimal frequency for various aspects of daily oral hygiene (teeth brushing, moisturizing, mouthwash) outcome: oral health as measured through specific, valid and reliable oral assessment tools for intubated and non-intubated icu patients, respectively valid and reliable oral assessment tool needs to be developed first. then, separate randomized controlled trials or multiple armed rcts or factorial design. cave, the latter rely on the assumption of no interaction between treatment arms best practices for icu patients with specific oral needs best oral hygiene practices for patients with, e.g. dental prostheses, following maxillofacial surgery, oral health problems, … multidisciplinary cooperation with dental professionals prevention of ventilator-associated pneumonia with oral antiseptics: a systematic review and meta-analysis reappraisal of routine oral care with chlorhexidine gluconate for patients receiving mechanical ventilation: systematic review and meta-analysis oral mucosal adverse events with chlorhexidine % mouthwash in icu decreased susceptibility to chlorhexidine affects a quarter of escherichia coli isolates responsible for pneumonia in icu patients effects of chlorhexidine gluconate oral care on hospital mortality: a hospitalwide, observational cohort study selective digestive or oropharyngeal decontamination and topical oropharyngeal chlorhexidine for prevention of death in general intensive care: systematic review and network meta-analysis associations between ventilator bundle components and outcomes ventilator-associated events: prevalence, outcome, and preventability oral care with chlorhexidine: beware! chlorhexidine use in adult patients on icu oral hygiene care for critically ill patients to prevent ventilator-associated pneumonia relationship between periodontal infections and systemic disease oral care of intubated patients effects of systematic oral care in critically ill patients: a multicenter study research priorities in oral care for endotracheallyintubated patients all authors declare that they have no conflicts of interest. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- - stfqrd authors: robba, chiara; galimberti, stefania; graziano, francesca; wiegers, eveline j. a.; lingsma, hester f.; iaquaniello, carolina; stocchetti, nino; menon, david; citerio, giuseppe title: tracheostomy practice and timing in traumatic brain-injured patients: a center-tbi study date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: stfqrd purpose: indications and optimal timing for tracheostomy in traumatic brain-injured (tbi) patients are uncertain. this study aims to describe the patients’ characteristics, timing, and factors related to the decision to perform a tracheostomy and differences in strategies among different countries and assess the effect of the timing of tracheostomy on patients’ outcomes. methods: we selected tbi patients from center-tbi, a prospective observational longitudinal cohort study, with an intensive care unit stay ≥ h. tracheostomy was defined as early (≤ days from admission) or late (> days). we used a cox regression model to identify critical factors that affected the timing of tracheostomy. the outcome was assessed at months using the extended glasgow outcome score. results: of the included patients, ( . %) had a tracheostomy. age (hazard rate, hr = . , % ci = . – . , p = . ), glasgow coma scale ≤ (hr = . , % ci = . – . at ; p < . ), thoracic trauma (hr = . , % ci = . – . , p = . ), hypoxemia (hr = . , % ci = . – . , p = . ), unreactive pupil (hr = . , % ci = . – . at ; p < . ) were predictors for tracheostomy. considerable heterogeneity among countries was found in tracheostomy frequency ( . – . %) and timing (early – . %). patients with a late tracheostomy were more likely to have a worse neurological outcome, i.e., mortality and poor neurological sequels (or = . , % ci = . – . , p = . ), and longer length of stay (los) ( . vs. . days, p = . ). conclusions: tracheostomy after tbi is routinely performed in severe neurological damaged patients. early tracheostomy is associated with a better neurological outcome and reduced los, but the causality of this relationship remains unproven. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. tracheostomy can facilitate weaning in long-term ventilated patients, potentially shortening the duration of mechanical ventilation and intensive care unit (icu) stay, and reducing complications from prolonged tracheal intubation, such as ventilator-associated pneumonia (vap) and tracheal lesions [ ] . in patients who require icu care after a tbi, the main indications for tracheostomy include failure to wean invasive mechanical ventilation, absence of protective airway reflexes, impairment of respiratory drive, and difficulties in managing secretions [ ] . the proportion of tbi patients who might benefit from a tracheostomy, and the most appropriate timing for the procedure [ ] are still undefined, and relevant biases confound the limited, mainly retrospective, available data on this issue. moreover, policies and clinical practice vary among different centres, and the optimal indications for tracheostomy remain uncertain [ ] . conventionally, tracheostomies performed in the first week are classified as early, while tracheostomies performed later than days are defined as late [ ] . the ideal timing for a tracheostomy is uncertain since the evidence on the advantages of early over late tracheostomy is conflicting, and no real differences in mortality have been identified between early and late tracheostomy so far [ , ] . to obtain insights into tracheostomy in patients who had suffered a tbi, we analysed data from the icu stratum of the center-tbi study [ ] . this study aims to describe the characteristics of those tbi patients who undergo a tracheostomy and the current state of its timing; to identify the factors involved in performing the procedure and the different strategies between countries, and to assess the effect of the timing on patients' outcome. the collaborative european neurotrauma effectiveness research in traumatic brain injury (center-tbi study, registered at clinicaltrials.gov nct ) is a longitudinal prospective collection of tbi patient data across centres in europe between december , , and december , , as previously described [ , ] . the medical ethics committees approved the center-tbi study in all participating centres, and we obtained informed consent according to local regulations. we performed a pre-planned analysis focusing on tracheostomy practice in the center-tbi cohort during the icu stay (esm ). the project was preregistered on the center-tbi proposal platform in december and approved by the center-tbi proposal review committee (esm document ) before starting the analysis. this report complies with the strengthening the reporting of observational studies in epidemiology (strobe) reporting guidelines (esm table s ). for this analysis, the inclusion criteria were: • a clinical diagnosis of tbi with an indication for a brain computed tomography scan (ct); • presentation to the hospital within h (hrs) postinjury; • icu admission with a length of stay (los) ≥ h. exclusion criteria were: • death in the first h; • short icu los (< h). these exclusion criteria were defined to exclude patients in whom tracheostomy was never likely to have been considered, either because of extremely severe injury and rapid death, or those in whom the injury was not severe enough. detailed data were collected on pre-injury factors and patient's characteristics, injury details, glasgow coma scale (gcs), pre-hospital care, clinical care, post-acute care, and outcome, with a total of over unique data fields, with many fields collected serially over time (e.g., physiological variables in the icu stratum). hypoxemia was defined as a documented partial pressure of oxygen (pao ) < kpa ( mmhg), oxygen saturation (sao ) < %, or both; hypotension was defined as a documented systolic blood pressure < mmhg. the aim of this study is threefold: . describe the patients' characteristics and timing of tracheostomy in tbi patients; . identify the factors related to the decision to perform a tracheostomy and differences in strategies among different countries; . assess the effect of the timing of tracheostomy on patients' outcomes. tracheostomy after tbi is commonly performed in the most severe neurological damaged patients. early tracheostomy is associated with shorter icu length of stay and with a trend of a better outcome. the primary endpoint was the patients' functional outcome assessed by the extended glasgow outcome score (gose) at months. an unfavourable outcome was defined as gose ≤ , which takes into account both poor neurological outcome and mortality together. all responses were obtained by study personnel from patients or from a proxy (where impaired cognitive capacity prevented patient interview), during a face-to-face visit, by telephone interview, or by postal questionnaire at months (range - months) after injury [ ] . all outcome evaluators had received training in the use of the gose. we also registered mortality at months, and the icu and hospital los. continuous variables are described with median and interquartile range (iqr), or mean and standard deviation (sd), as appropriate, and categorical data were reported as absolute and relative frequencies. the nature of the variables guided the choice of the test for the comparison among groups. a cox regression model was used to identify the key factors that affected the decision and timing of tracheostomy during icu stay. time origin was icu admission, and patients who did not receive the procedure were censored at discharge from icu or at death, whichever occurred first. a frailty term was included to account for centre-specific effects. variables significant in the univariate analysis, and others judged clinically relevant, were initially identified, and the selection of the covariates for the final model (including age, gcs, pupillary reactivity, hypoxemia, thoracic, and facial trauma) was based on the likelihood ratio test (lrt) and akaike information criterion (aic). assumptions regarding the proportionality of the hazards and the linearity of effects were investigated using the schoenfeld test and the martingale residuals, respectively [ ] . for variables violating the proportional hazards assumption, the time dependence of the effect was adjusted by including a term for the interaction of the variable and time [ ] . the country-and centre-specific incidence rate of late, early, and no tracheostomy was estimated from a proportional odds model, adjusting for patient characteristics associated with a tracheostomy, and including a random intercept for country and centre. the median odds ratio (mor) was also calculated as a measure of variability between centres [ ] . the role of timing of tracheostomy on different outcomes was explored on the subset of patients who underwent a tracheostomy. the time to the procedure was evaluated both as a discrete (i.e., days from icu admission) and as a categorical variable (i.e., ≤ vs. > days) [ ] . a logistic regression model was applied to the odds of an unfavourable gose (gose ≤ ), while we performed a cox model on the -month mortality from icu admission, with patients contributing to the risk set from the day of tracheostomy. death from any cause was the event of interest, and patients alive at months from icu admission were censored. a linear regression model was used for the evaluation of los in both icu and hospital. los was calculated from icu admission (and from tracheostomy) to discharge or death in icu, with a sensitivity analysis that excluded patients who died in icu or hospital. all analyses were adjusted for known outcome predictors in the core impact model (i.e., age, gcs at arrival, and pupillary reactivity) [ ] . we used a multivariate imputation by chained equations in all the multivariable models to deal with missing values in the predictors, generating imputed datasets [ ] . analyses on complete cases were also performed to check consistency in the results. model diagnostics were performed in all the imputed datasets, and final decisions were taken based on the findings of the majority of datasets. all the tests conducted were two-sided with a significance level of %. the analyses were conducted in r (version . . , r core team, ) [ ] . of the consecutive patients requiring icu care, (from countries and centres) had an icu los ≥ h. of these, subjects ( . % of the study cohort, . % of the overall icu population) underwent a tracheostomy and were included in the analysis (esm figure s ). details regarding the screening and enrolment process are described in the main center-tbi manuscript [ ] . patients' characteristics at icu admission are summarized in table (both overall and stratified by whether or not they received a tracheostomy). patients who received or did not receive a tracheostomy were similar in terms of age, sex, pre-injury american society of anaesthesiologists' physical status (asaps) score, mechanism of injury, and pre-injury clinical history. patients receiving tracheostomy more frequently had lower median gcs at arrival (median vs. , p < . ), and abnormal pupillary reactivity (at least one unreactive pupil in . % vs. . %, p < . ). moreover, patients who underwent tracheostomy had a higher rate of early hypoxemia ( . % vs. . %, p = . ), early hypotension during their icu stay, patients receiving tracheostomy more frequently underwent the placement of an intracranial pressure (icp) monitoring device ( . % vs. . , p < . ), and suffered from ventilator acquired pneumonia (vap; . % vs. . %, p < . ), and respiratory failure ( . % vs. . %, p < . ) ( table ) . of the patients included in the study, ( %) received a withdrawal of treatment: ( . %) were not tracheotomised, and ( . %) had undergone a tracheostomy. the median (iqr) time to tracheostomy of the patients was ( - ) days from icu admission, with ( . %) of the patients receiving tracheostomy on the day of icu admission and the last procedure performed after days in icu (esm figure s and figure s ). details on the characteristics of the tracheotomised patients are reported separately for early ( patients, . %) and late ( patients, . %) procedures in table the results of the cox regression model for the tracheostomy procedure are reported in table . age had a statistically significant impact, indicating a % increase in the hazard of tracheostomy for each year increase in age (hr = . , % ci = . - . , p = . ). the hazard for requiring a tracheostomy was significantly lower in patients with gcs > vs. those with gcs ≤ (p < . ) and the hr increased linearly after icu admission, with the hr at , and days from admission calculated as . ( % ci = . - . ), . ( % ci = . - . ), and . ( % ci = . - . ), respectively. the effect of pupillary reactivity was also not constant in time, and the hr estimates indicate that patients with at least one unreactive pupil have a higher hazard (p < . ) as compared to those with both reacting pupils, with an hr at , and days from admission of . ( % ci = . - . ), . ( % ci = . - . ) and . ( % ci = . - . ). the hazard of tracheostomy was . times higher in patients with thoracic trauma as compared to those without ( % ci = . - . , p = . ), while the two timing groups did not show a significant difference in the incidence of facial trauma (hr = . , % ci = . - . , p lrt = . , and p = . ). finally, hypoxemia was associated with an increased hazard of undergoing a tracheostomy (hr = . , % ci = . - . , p = . ). the findings of the model on complete cases were consistent (esm table s ). we observed a considerable heterogeneity among countries in the decision to perform a tracheostomy (with adjusted tracheostomy rates ranging from . to . %) and in the timing for tracheostomy (with the incidence of late tracheostomy ranging from . to . %, and early tracheostomy from to . %) (fig. a) . furthermore, individual centres within the same country showed different adjusted percentages of early vs. late tracheostomy (fig. b) . in the vast majority of centres, a delayed procedure was more likely to happen than an early one, and only in two institutions, the policy was to opt exclusively for an early strategy. moreover, the variability in the centre-specific rate of late tracheostomy was more pronounced than the early rate. the crude rates observed at country and centre levels are shown in esm figure s . we used the mor to quantify between-centre differences and found that even after correction for patient characteristics, there was a . -fold difference in the odds of tracheostomy between centres with the highest and lowest tracheostomy rates. the univariate analyses (esm table s ) showed no significant effect of early vs. late tracheostomy on icu mortality, -month mortality, or -month gose (p = . , p = . , and p = . , respectively). however, patients who received a late tracheostomy had a statistically significant longer mean los in icu ( . vs. . days, p < . ) and in hospital ( . vs. . days, p = . ) when measured from the point of icu admission. these differences were abolished when los was measured from tracheostomy (mean los in icu for early vs. late tracheostomy: . days vs. . days, p = . ; mean los in hospital: . days vs. . days, p = . ). the adjusted regression analyses demonstrated an association between an early tracheostomy and a better neurological outcome captured by the gose (table ) . patients with a late tracheostomy were more likely to have a worse neurological outcome (model : or = . , % ci = . - . , p = . ), and the analysis using day to tracheostomy as a continuous variable (model ) showed that every day of delay in performing the multivariable cox analysis on mortality at months found that tracheostomy performed after week was not associated with a significant increase of the hazard of mortality (hr = . , % ci = . - . ; p = . ). however, model showed that each increase of a day in the timing of tracheostomy was associated with a % increase in the hazard of mortality (hr = . , % ci = . - . , p < . ). late tracheostomy in model was associated with an increase in the mean icu los of . days ( % ci = . - . , p < . ), and an increase in hospital los of . days ( % ci = . - . , p < . ); each days deferral in tracheostomy was associated with a -day increase in icu los, and a day increase in hospital los. los after tracheostomy in icu was shorter in the late tracheostomy group (− . days, p = . ), while the hospital los was similar between the two groups (esm table s ). similar results were obtained when excluding icu deaths (data not shown). sensitivity analyses on all the outcomes considering complete data gave consistent results (esm table s ). at our knowledge, this analysis based on prospective observational data from center-tbi [ ] is the most extensive assessment of the practice of tracheostomy in tbi patients, across centres and countries in europe. our main findings are: • tracheostomy is commonly performed in tbi patients in icu, and is most frequently undertaken after the first week in icu; • the likelihood of receiving a tracheostomy increases significantly with age, the severity of neurological injury (expressed as lower gcs and pupillary abnormalities), extra-cranial injury (particularly thoracic trauma), and early secondary insults (such as hypoxemia); • there are significant variations in tracheostomy rates across countries and centres in europe; • when assessed as a discrete variable, later tracheostomies are associated with an increase in unfavourable outcome and los. we found that tracheostomy was frequent amongst tbi patients in the icu. the procedure was undertaken in . % of our study cohort, which is more frequent than in studies in general icu cohorts, where past literature reports rates of about % [ , ] . this increased need for tracheostomy in the tbi population is attributable to a higher rate of extubation failure and the need for prolonged protection of the airways secondary to neurological injury. in general icu patients, tracheostomy is most commonly performed after days from admission [ , ] , with only a quarter of tracheostomies delivered on or before day [ ] . in contrast, only % of our tbi cohort underwent tracheostomy later than days from admission, and in %, tracheostomy was undertaken before day . the risk of receiving a tracheostomy was related to the severity of the neurological injury, quantified using gcs and pupillary reactivity at admission, and the presence of early secondary insults (such as hypoxemia). non-neurological drivers of the decision to perform a tracheostomy include age and the occurrence of thoracic trauma, which may adversely affect respiratory weaning and extubation success. while the effect of non-neurological factors and hypoxemia on the risk of receiving tracheostomy was constant over time, the cox model indicated that both gcs and pupillary reactivity had a time-dependent effect, with an increased impact on the hr of tracheostomy with increasing time from admission. these findings suggest that both the initial severity of the neurological injury and probably its trajectory, play a role in the decision process. the result that the median time to tracheostomy was days post-admission probably reflects a change in treatment targets. in the initial phase, the aim is to manage acute intracranial emergencies, and tracheostomy at this stage could increase intracranial pressure and adversely affect the outcome. once this phase is complete, cessation of sedation, weaning from ventilator support, and initiation of rehabilitation become key treatment targets. this timing of tracheostomy also prevents the use of the procedure in patients with lesser severities of injury, who might achieve successful extubation, and in those who have a rapidly progressive course and succumb early to their injuries. this process of selection still leads to tracheostomy at an earlier stage than commonly observed in non-tbi patients but allows the selection of a cohort most likely susceptible to the potential benefits of the procedure on the patients' outcomes [ , ] , by dealing with ongoing failure to protect the airway and the consequent risk of extubation failure [ ] [ ] [ ] [ ] . however, the approach to tracheostomy was by no means uniform across icus that contributed to center-tbi. we found substantial between-country and between-centre differences in the incidence and timing of tracheostomy, which persisted even after adjustment for covariates. our results suggest that the current, local medical practices influence the decision to perform a tracheostomy, along with the ethical and legal implications context, clinical expertise, and costs relating to the procedure and equipment, replicating past findings in the general icu population [ , , ] . the literature suggests that early tracheostomy may potentially reduce hospital stay, duration of mechanical ventilation and mortality rates [ , , , ] . in a propensity-matched cohort study on tbi patients, early tracheostomy (≤ days) was associated with shorter mechanical ventilation duration ( vs. days, rr = . , % ci = . - . ), icu and hospital los (rr = . , ci = . - . , and rr = . , % ci = . - . ), but did not affect mortality [ ] . while the results of a cochrane meta-analysis in general icu patients [ ] showed a possible mortality benefit from a tracheostomy, our data replicate smaller studies that specifically addressed tbi. khalili et al. [ ] found that, in a cohort of tbi patients, early tracheostomy resulted in lower icu and hospital los ( . vs. . days, p = . ; and . vs. . days, p = . , respectively), but did not affect mortality. a meta-analysis by mccredie et al. [ ] concluded that early tracheostomy might reduce the long-term mortality, duration of mechanical ventilation, and los. however, waiting longer, i.e., excluding patients probably improving or dying for brain damage, leads to fewer tracheostomy and similar short-term outcomes. each increase of day in tracheostomy timing was significantly associated with a % increase in the risk of an unfavourable outcome with a % increase in the hazard of death. while this association may suggest a benefit from an earlier tracheostomy, we should be cautious about assigning causality to this association, since there may be competing confounds. patients with more severe injury may have had a more prolonged need for therapies directed toward limiting the intracranial damage evolution (thus delaying tracheostomy) or might have a worse expected outcome (leading to a higher number of attempts to withhold tracheostomy). in our cohort, patients who received late tracheostomy had a statistically significant longer mean los in icu (by nearly week) and in hospital (by about days), with each days deferral in tracheostomy associated with about and days' increase in los in icu and hospital, respectively. in this direction also goes the interval between tracheostomy and discharge from icu, which is shorter in the "later tracheostomy" group, along with the information that withdrawal of treatment is more frequent in patients without tracheostomy. mortality in the icu of tracheotomised patients was minimal (esm figure s ). although we used robust statistical methods and covariate adjustment, unidentified residual confounders may have affected our analyses. moreover, although center-tbi banked detailed data on many aspects of injury, clinical care, and outcome, some key characteristics, such as those related to mechanical ventilation and respiratory complications, were not recorded. the observational nature of our study only allows us to report associations and cannot test the causal relationships between factors and tracheostomy practice. patients with tbi undergo a tracheostomy, more often than in general icu populations. several patient-and injury-related factors are associated with the decision to perform a tracheostomy in this group of patients. however, an analysis that adjusts for these covariates still shows substantial between-centre differences, which probably reflect inadequate evidence, a lack of consensus, and the absence of strong guidelines in this setting. the later performance of tracheostomy is associated with increased los and worse functional neurological outcome, but the causality of this relationship remains unproven. randomized controlled trials exploring the effect of tracheostomy and its timing on patients' outcomes are warranted. a prospective, randomized, study comparing early percutaneous dilational tracheotomy to prolonged translaryngeal intubation (delayed tracheotomy) in critically ill medical patients evidence-based guidelines for the use of tracheostomy in critically ill patients liberation of neurosurgical patients from mechanical ventilation and tracheostomy in neurocritical care effect of early versus late or no tracheostomy on mortality and pneumonia of critically ill patients receiving mechanical ventilation: a systematic review and meta-analysis early versus late tracheostomy for critically ill patients results of early and late surgical decompression and stabilization for acute traumatic cervical spinal cord injury in patients with concomitant chest injuries effect of early versus late tracheostomy or prolonged intubation in critically ill patients with acute brain injury: a systematic review and meta-analysis case-mix, care pathways, and outcomes in patients with traumatic brain injury in center-tbi: a european prospective, multicentre, longitudinal, cohort study collaborative european neurotrauma effectiveness research in traumatic brain injury (center-tbi): a prospective longitudinal observational study structured interviews for the glasgow outcome scale and the extended glasgow outcome scale: guidelines for their use analysing survival data from clinical trials and observational studies a brief conceptual tutorial of multilevel analysis in social epidemiology: using measures of clustering in multilevel logistic regression to investigate contextual phenomena impact database of traumatic brain injury: design and description multiple imputation with multivariate imputation by chained equation (mice) package ) r: a language and environment for statistical computing epidemiology and patterns of tracheostomy practice in patients with acute respiratory distress syndrome in icus across countries trends in tracheostomy for mechanically ventilated patients in the united states rate of reintubation in mechanically ventilated neurosurgical and neurologic patients: evaluation of a systematic approach to weaning and extubation outcome of mechanically ventilated patients who require a tracheostomy experience with traumatic brain injury: is early tracheostomy associated with better prognosis? a meta-analysis of the influencing factors for tracheostomy after cervical spinal cord injury stroke-related early tracheostomy versus prolonged orotracheal intubation in neurocritical care trial (setpoint): a randomized pilot trial discontinuing mechanical ventilatory support early tracheotomy versus prolonged endotracheal intubation in unselected severely ill icu patients indications for and timing of tracheostomy early tracheostomy versus prolonged endotracheal intubation in severe head injury multicenter, randomized, prospective trial of early tracheostomy tracheostomy timing in traumatic brain injury: a propensity-matched cohort study gc ideated and supervised the project, participated in the data analysis, drafted the manuscript, and the supplementary tables, discussed the findings with all the authors, collected the cois. cr ideated the project, participated in the data analysis, drafted the manuscript, and the supplementary tables. fg and sg analysed the data, drafted the manuscript, and the supplementary tables. ci was an active part of the manuscript drafting and revision. dm proofread the manuscript to ensure its compliance with standard scientific english' rules. all co-authors gave substantial feedback on the manuscript and approved the final version of it. this article is reported as per strengthening the reporting of observational studies in epidemiology (strobe) reporting guidelines (www.strob e-state menen t.org) (electronic supplementary material esm ). data used in the preparation of this manuscript were obtained in the context of the collaborative european neurotrauma effectiveness research in traumatic brain injury (center-tbi study, registered at clinicaltrials.gov nct ), a large collaborative project, supported by the framework program of the european union ( ). additional funding was obtained from the hannelore kohl stiftung (germany), from onemind (usa) and from integra lifesciences corporation (usa). the funder had no role in the design of the study, the collection, analysis, and interpretation of data, or in writing the manuscript. conflicts of interest gc is editor-in-chief of intensive care medicine. gc reports grants, personal fees as speakers' bureau member and advisory board member from integra and neuroptics; personal fees from nestle and ucb pharma, all outside of the submitted work. dkm reports grants from the european union and uk national institute for health research, during the conduct of the study; grants, personal fees, and non-financial support from glaxosmithkline; personal fees from neurotrauma sciences, lantmaanen ab, pressura, and pfizer, outside of the submitted work. the other authors declare that they have no competing interests. the data supporting the findings in the study are available upon reasonable request from the corresponding author (gc) and are stored at https ://cente r-tbi.incf.org/_ cf e d c b d eb ef . imaging data can be found at https ://cente r-tbi.incf.org/_ cf d bd bb b b e, data on vitals values at https ://cente r-tbi.incf.org/_ cf d ce bb b b f, while data regarding medications can be found at https ://cente r-tbi.incf.org/_ cf d e d bb b b . the medical ethics committees of all participating centers approved the center-tbi study, and informed consent was obtained according to local regulations. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -c c rfzi authors: gordon, sharon m.; jackson, james c.; ely, e. wesley; burger, candace; hopkins, ramona o. title: clinical identification of cognitive impairment in icu survivors: insights for intensivists date: - - journal: intensive care med doi: . /s - - -y sha: doc_id: cord_uid: c c rfzi background: a growing body of research has demonstrated the presence of ongoing cognitive impairment in large numbers of icu survivors. objective: this review offers a practical framework for practicing intensivists and those following patients after their icu stay for the identification of cognitive impairment in icu survivors. conclusions: early detection of cognitive impairment in critically ill patients is an important and achievable goal, but overt cognitive impairment remains unrecognized in most cases. however, it can be identified by objective (test scores) or subjective evidence (clinical judgment, patient observation, family interaction). approximately , patients are hospitalized in intensive care units (icus) each day in the united states [ ] . while research is limited regarding cognitive outcomes in patients who survive critical illness, these patients are at risk for physical, emotional, and neurocognitive morbidity [ , , , , ] . although additional research is necessary to address crucial questions regarding cognitive impairment in icu survivors, early reports are worrying, and in some respects parallel early reports of cognitive impairment following coronary artery bypass grafting (cabg). two decades ago studies on cabg and cognitive outcome were in their infancy and received relatively little attention [ ] . since that time over investigations [ ] have studied the effects of cabg on cognition and have documented the existence of pervasive and frequently severe cognitive deficits in - % of patients following surgery [ ] . the cognitive impairment reported in icu survivors is similar to that observed following elective cabg surgery [ ] and following carbon monoxide poisoning [ ] . current data suggest that approximately one-third or more of icu survivors develop ongoing and persistent cognitive impairment [ ] . among specific populations of icu survivors such as patients with acute respiratory distress syndrome (ards) the prevalence of persistent cognitive impairment is even greater and may be as high as % at year [ ] and % at years [ ] (table ) . while cross-study comparisons are difficult due to differences in study design (e.g., prospective vs. retrospective), definition of sequelae, neurocognitive tests administered, time to follow-up, patient population, and disease severity, the potential ramifications of these findings are significant, particularly if cognitive impairment goes unidentified. the purpose of this report is to highlight the problem of cognitive impairment following icu survival, to assist clinicians in identifying probable cognitive impairment in icu patients through objective as well as clinically oriented strategies, and to provide guidelines for referral of cognitively impaired patients to specialists in cognitive evaluation and rehabilitation. for a discussion of research issues with icu survivors, please refer to our companion article in this issue. defining cognitive impairment this review uses key terms that are widely understood in psychiatric, neurology, and neuropsychological settings but may be less familiar to intensivists. the term cognitive impairment, as defined here, refers to clinically significant abnormalities in one or more brain functions including memory, attention, mental processing speed, executive function, visual spatial abilities, and intellectual function. cognitive impairment can be mild, moderate, or severe and can limit an individual's ability to think, reason, and/or perform everyday tasks. the term cognitive decline refers to deterioration in cognitive abilities from baseline and is not necessarily synonymous with cognitive impairment as it does not imply an absolute level of functioning. for example, a person with an intelligence quotient in the superior range might experience significant cognitive decline and still function within the normal range, therefore not being characterized as cognitively impaired. however, this type of decline can cause significant disruption in the everyday life of a person who is used to performing at high levels in occupational and vocational areas. such was the case of the person quoted in the opening paragraph. alternatively, slight decline in a person with below average intelligence could result in the diagnosis of cognitive impairment but have a minor impact on everyday function. the impairment experienced by patients following icu hospitalization should not be equated with common dementias, such as alzheimer's disease and vascular dementia, which are typically age related, largely irreversible, progressive in nature, and characterized by significant impairments in memory and at least one other sphere of mental activity [ , ] . in contrast to common dementias, there is only limited information regarding the clinical course of icu-related cognitive impairment. for example, cognitive functioning appears to improve in many icu survivors from hospital discharge to year; however, significant numbers ( %) of icu survivors remain impaired at year [ ], with little improvement during the nd [ ] . the cognitive impairment experienced by many icu survivors varies widely with regard to severity and should be thought of as acquired disease or an exacerbation of a preexisting disease (depending upon the individual patient's situation). acquired cognitive impairment can range from mild to severe. for example, jackson et al. [ ] reported that after excluding those with detectable pre-icu baseline cognitive impairment % of patients suffered from persistent cognitive impairment of a severity similar to the cognitive impairments observed in mild to moderate dementia. although the nature of deficits differs across studies, it appears that impairment is particularly pervasive in areas of memory, visuoconstruction, processing speed, and executive functioning (fig. ) . the cause and risk factors for the development of cognitive impairment following icu hospitalization are largely unknown, although the risk factors for cognitive impairment following cardiac surgery are well documented and include advanced age, lower premorbid intelligence, cerebrovascular and peripheral-vascular disease, and hypoxia [ , ] . researchers have hypothesized that the presence of certain factors such as sepsis and ards and its associated hypoxemia [ ] , the development of delirium [ ] , and the use of sedative and narcotic medications are associated with the development of cognitive impairment after critical illness, although such mechanisms are in need of further exploration. although between one and three of every four patients experience cognitive impairment following icu treatment [ , ], little is known regarding the functional and financial impact of such impairment in these patients. cognitive impairment is generally associated with inability to return to work, decreased quality of life and independence, and generalized functional decline; an important caveat to this observation, however, is that many investigations on the consequences of cognitive impairment have been carried out in populations with alzheimer's disease, and may not be directly applicable to icu survivors [ , , , ] . cognitive impairment resulting from a host of illnesses and medical syndromes including human immunodeficiency virus, ards, trau-matic brain injury, and bacterial meningitis are associated with decreased quality of life [ , , , ] . even mild forms of cognitive impairment can be extremely problematic and may lead to significant difficulties in activities of daily living such as impaired driving, money management, and performance of basic household functions (e.g., cleaning, cooking, organizing) [ , , ] . the specific economic consequences of cognitive impairment following a stay in the icu are not yet known. however, in the general population the economic consequences of cognitive impairment are substantial and depend on factors such as the severity and nature of impairment, rate of decline, and the setting in which care is provided (e.g., nursing home vs. private residence) [ ] . for example, a -point decrease on the mini mental state examination (mmse) is associated with a $ , per year increase in overall healthcare expenditures [ ] . the "per-patient societal cost burden" of even mild forms of cognitive impairment is estimated to be over $ , per year [ ] . the costs associated with traumatic brain injury are less well known, but it appears that the wages of individuals returning to work after a brain injury decline by approximately % per year [ ] . should the icu team strive towards early identification of cognitive impairment? a consensus is emerging among neurologists, psychiatrists, and other specialists regarding the importance of early identification of cognitive impairment [ ] . the failure to identify cognitive impairment can have serious implications for patients in a variety of functional domains. for example, a person may return to work based on the erroneous assumption that he or she is "perfectly fine," only for the patient to encounter difficulties performing at the previous level due to problems with memory and disorganization. these difficulties may be wrongly attributed to "laziness" or lack of motivation and may result in the termination of employment. situations such as this are not inevitable and can often be avoided if a patient's cognitive impairment is identified as such. the identification of cognitive impairment is valuable not only to patients but also to their families and caregivers as it enables them to mobilize necessary resources before the onset of a crisis such as inability to care for self or children and to function independently. the lack of early identification of cognitive impairment delays referral for cognitive rehabilitation, which has been shown to improve cognitive function [ ] . cognitive rehabilitation may be appropriate for individuals with cognitive impairment due to a wide variety of causes (e.g., traumatic brain injury, cerebrovascular accident, hypoxia) and is considered to be effective in improving neuropsychological abilities such as attention/ concentration, memory, and executive function [ ] . despite the importance of early identification of cognitive impairment, studies consistently demonstrate that physicians fail to recognize (or assess) cognitive impairment in - % of patients in non-icu clinical practice settings [ , ] . recent data suggest that cognitive impairment is rarely evaluated in icu patients [ ] and may be overlooked in one of every two cases [ ] . reasons for limited recognition of cognitive impairment include time constraints, perception of limited treatment options, and limited knowledge regarding how to perform cognitive screening [ ] . intensivists and those caring for patients after the icu stay should be aware that there are excellent brief screening tools that can be readily used in the midst of a busy day by themselves or other members of the icu team ( table ). these measures are simple to use and do not require specialized training to administer. while the early identification of cognitive impairment is very important, the approaches to identification vary widely depending on the setting. assessing patients in various hospital and outpatient settings presents various challenges and may require the use of different tools. patients can be assessed at various stages of their illness as they move from the icu to acute care and then to the outpatient setting. cognitive impairment in these different settings can be identified in a variety of ways and can be based on objective data (e.g., test scores) or more subjective evidence (e.g., clinical judgment, patient observation, family interaction). the following section suggests a logical approach at each stage and consider advantages and limitations of tools that can be used in each setting. how do you identify cognitive impairment in critically ill icu patients? in many instances intensivists are the providers best positioned to identify possible acute cognitive impairment in critically ill patients. although it is unlikely that they have the time to assess these patients individually, evaluations can be performed by nurses and other allied healthcare professionals such as psychologists, social workers, and speech therapists [ , ] . however, due to multiple factors in icu settings such as mechanical ventilation, related communication difficulties, the high prevalence of delirium, and patient fatigue, formal in-depth assessment of critically ill patients is often not possible. sometimes the only assessment possible in such populations is related to detection of delirium, which can be rapidly and reliably assessed with the intensive care delirium screening checklist [ , ] or the confusion assessment method for the intensive care unit (cam-icu) [ , ] . for free downloads of material used to monitor delirium in the icu (including translations into multiple languages) the reader is referred to the educational website: http://www.icudelirium.org. if patients are not delirious, their cognitive function can be quickly evaluated using the mmse or another brief cognitive screening tool. the detection of delirium may be important in light of evidence suggesting an association between delirium and an increased risk of cognitive impairment and other adverse outcomes (although much remains to be discovered about this association) [ ] . how do you identify cognitive impairment following icu stay in hospitalized patients? when patients are discharged from the icu to rehabilitation or general hospital units, their cognitive status may improve, and they may be more able to interact with an evaluator or clinician. at this point neuropsychological assessment may be appropriate and the completion of such testing more realistic. in cases where cognitive screening is possible numerous suitable instruments are available [ ] . the mmse is widely considered the "gold standard" among screening tools and consists of items ( possible points) that assess a range of global abilities including orientation, memory, and attention [ ] . a score of or below on the mmse indicates the presence of moderate to severe cognitive impairment, but it should be noted that the test is susceptible to the effects of age and education and can be more reliably scored using age and education adjusted norms [ ] . other screening tools that are equally "user friendly" and, in some cases require even less time to administer are available ( table ). in general, cognitive screening instruments require little if any specialized training to administer and score, and depending on the instrument the administration time varies from to min. while the sensitivity and specificity of these instruments vary, they generally have acceptable reliability and validity and are effective at identifying moderate to severe cognitive impairment. they are less sensitive in the detection of mild forms of cognitive impairment [ ] . while more comprehensive and sophisticated instruments exist, using them with hospitalized patients may be impractical as they can be quite lengthy and may require specialized training to administer. moderate or severe forms of cognitive impairment can frequently be identified without the use of psychometric instruments or questionnaires and through reliance on more subjective methods [ , , ] . these methods include the use of clinical judgment, the direct observation of patients, and interaction with families. the perceptions of family members can be very helpful as parents, spouses, or children are often aware of even minor changes in a patient's functional abilities or personality. the following is a list of warning signals, or "red flags," that can suggest possible cognitive impairment in hospitalized or icu patients: -personality changes -increased apathy -loss of social inhibitions, display of socially inappropriate behavior with staff -increased irritability or suspiciousness toward family, visitors, or medical team -outbursts of inappropriate or unprovoked anger -memory complaints -difficulty learning new facts and information about one's medical condition -persistent word finding problems -inability to recall conversations with medical staff and recent events in the hospital such as visits by staff, family, or friends -inability to remember having eaten or what was eaten at meal time -executive dysfunction -difficulty following nurses', physicians', or therapists' directions -problems with planning and decision making related to such things as discharge planning -confusion when trying to perform multiple tasks -functional deficits -difficulty looking up telephone numbers or using the telephone or other equipment such as the television and hospital bed -decline in self-care not attributable to physical problems or limitations -inability to find one's room -inability to follow a conversation -difficulty following through with tasks caution should be exercised when drawing conclusions about cognitive functioning based on in-hospital assessments as performance may be adversely affected by factors such as fatigue and residual effects of sedative and narcotic medications. how do you identify cognitive impairment following icu stay in the outpatient clinic? patients typically return to outpatient clinics approx. - months after hospital discharge for routine follow-up. by then patients have recovered from any transient cognitive dysfunction (e.g., delirium, effects of medications) and may be functioning at levels that reflect their new baseline. generally, individuals have begun to resume their normal activities and may experience previously nonexistent functional limitations due to acquired cognitive impairment. it may be beneficial to repeat the mmse and compare the current score with those obtained during the patient's hospitalization. improvement in cognitive function is expected and a decline of more than points (or a score below the standard cutoff of ), as well as the presence of persistently abnormal scores, suggests the need for further evaluation, as the mmse is a relatively stable, reliable measure and resistant to large fluctuations in scoring in the absence of actual neuropsychological change [ ] . it is also appropriate to assess activities of daily living such as bathing and dressing or, more importantly, instrumental activities of daily living (iadls) such as cooking, following a recipe, and balancing a checkbook (which can be significantly affected by even minor neuropsychological changes) [ , ] . formal assessments of functional abilities can be carried out with instruments such as the pfeffer et al. [ ] functional activities questionnaire (faq) and the lawton and brody [ ] instrumental activities of daily living (table ) or by asking simple, targeted questions. for example, clinicians can inquire about a patient's ability to perform complex tasks such as using a telephone or a remote control, following a complex recipe, making a grocery list, or managing money or medications [ ] . an important factor to evaluate is the presence of change and the degree to which the current level of function is different from prehospital levels. poor performance on measures of functional ability are not proof of cognitive impairment but can assist a practitioner in determining whether a patient should be referred for a more comprehensive neuropsychological assessment [ ] . many icu survivors experience significant affective symptoms such as depression and anxiety [ ] . the prevalence and severity of affective disorders including symptoms of depression and anxiety in icu survivors range from less than % to % [ , , , , ] . depression has been reported to occur in up to % of icu survivors [ ], and it is estimated that % have clinically significant anxiety [ ] . indeed, it may be that the high rates of depression among icu survivors are related to the cognitive impairment they experience, although this has not been evaluated in icu cohorts. affective disorders such as depression as well as posttraumatic stress disorder and anxiety may adversely affect test performance, especially if severe [ , ] . moderate to severe depression may result in decreased effort and low motivation that may decrease neuropsychological test scores in cognitive domains such as psychomotor speed or attention [ , ] , whereas moderate to severe anxiety may result in increased distractibility and blocked thoughts or words [ , ] . in some cases severe depression may mimic symptoms of cognitive impairment, although important differences exist between these conditions. in general, individuals with depression retain the ability to learn and do not forget as rapidly, do not display significant decrements in language, are inconsistent with regard to orientation to time and date and are typically more self-aware than their cognitively impaired counterparts [ , , ] . a variety of instruments are available for use in the assessment of affective function (table ). those for assessing depression include the geriatric depression scale-short form (gds-sf) [ ] , the beck depression inventory (bdi) [ ] , the center for epidemiologic studies depression scale (ces-d) [ ] , and the hospital anxiety-depression scale (hads) [ ] . anxiety can be assessed using the hads [ ] or the beck anxiety inventory (bai) [ ] . recent guidelines ( ) for dementia screening developed by the united states preventative services task force recommend that clinicians assess cognitive function whenever cognitive impairment or deterioration is suspected [ ] . in keeping with this recommendation (given the high rates of cognitive impairment in icu survivors), it would be ideal yet impractical to screen all icu survivors at hospital discharge and subsequent follow-up visits. therefore this is not recommended. an alternative approach is to screen only those individuals with an increased likelihood of developing cognitive impairment, although, as discussed above, only limited research has assessed causal mechanisms and risk factors of cognitive impairment following critical illness. more general evi- , , , , , , , ] . cognitive screening using a tool such as the mmse or mini-cog should be performed on any individuals who answer affirmatively to questions about memory difficulties, display impaired iadls, or have signs of cognitive impairment including ongoing delirium or memory/ orientation problems (e.g., confusion, repeating the same question, losing things such as glasses, forgetting familiar names, getting lost), social problems (e.g., neglect of appearance, nutrition, hygiene, loss of interest in hobbies, social withdrawal), and/or behavioral problems (e.g., wandering, irritability, agitation, apathy) should undergo cognitive screening using a tool such as the mmse. although screening at hospital discharge may result in a high false-positive rate because of the transient effects of medication and acute illness, it is important to track the patient's cognitive status during the weeks to months following icu and hospital discharge. when patients are thought to have cognitive impairment, they should be referred to a clinical neuropsychologist for consultation and further neuropsychological evaluation. although few neuropsychologists are actively involved in the assess-ment and management of survivors of critical illness at the present time, they are the appropriate professionals to assess cognitive function in these patients. it should be noted that neuropsychologists might be unavailable in small hospitals or rural areas. neuropsychologists are typically employed in neurology, rehabilitation medicine, or psychiatry departments in most moderately sized or large medical centers. in cases where neuropsychologists are unavailable, it is appropriate to refer patients to a clinical psychologist, as they are trained in performing basic cognitive evaluations. the adverse effects of critical illness on cognitive functioning are being increasingly studied and recognized by both clinicians and investigators. although much remains unknown, it appears that a significant percentage of critically ill patients and survivors experience cognitive impairment affecting quality of life and overall daily functioning. intensivists, particularly those that follow patients after icu discharge, are uniquely positioned to initiate cognitive screening and subsequent referral of critically ill patients and survivors. cognitive screening is simple, quick, and of great potential benefit, particularly in the early detection of cognitive impairment and should be widely incorporated in relevant clinical settings. future needs in pulmonary and critical care medicine quality-adjusted survival in the first year after the acute respiratory distress syndrome pulmonary function and health-related quality of life in survivors of acute respiratory distess syndrome healthrelated quality of life after acute lung injury the relationship between cognitive performance and employment and health status in long-term survivors of the acute respiratory distress syndrome: results of an exploratory study the epidemiology of dementia: alzheimer's disease and vascular dementia behavioral neurology neuropsychological sequelae following acute respiratory distress syndrome: two year outcome predictors of cognitive decline following coronary artery bypass graft surgery postoperative hypoxia is a contributory factor to cognitive impairment after cardiac surgery the association between delirium and cognitive decline: a review of the empirical literature cognitive impairment, dementia and quality of life in patients and caregivers a follow-up study of change in quality of life among persons with dementia residing in a long-term care facility the influence of cognitive impairment and psychiatric symptom on daily functioning in nursing facilities: a longitudinal study quality of life in patients with traumatic brain injury-basic issues, assessment and recommendations neurocognitive impairment influences quality of life in hiv-infected patients receiving haart cognitive impairment in adults with good recovery after bacterial meningitis factors associated with perceived quality of life many years after traumatic brain injury instrumental activities of daily living: a stepping stone towards alzheimer's disease diagnosis in subjects with mild cognitive impairment? fitness to drive in older drivers with cognitive impairment impaired financial abilities in mild cognitive impairment: a direct assessment approach estimating the relationship between disease progression and cost of care in dementia costs of mini mental state examination-related cognitive impairment societal costs of vascular cognitive impairment in older adults financial and vocational outcomes year after traumatic brain injury practice parameter: early detection of dementia: mild cognitive impairment (an evidence based review) efficacy of neuropsychological rehabilitation for mild-moderate traumatic brain injury evidence based cognitive rehabilitation: recommendations for clinical practice do general practitioners miss dementia in elderly patients documentation and evaluation of cognitive impairment in elderly primary care patients underrecognition of preexisting cognitive impairment by physicians in older icu patients diagnosing dementia: perspectives of primary care physicians older people with dementia in acute settings screening for cognitive impairment in the older adult intensive care delirium screening checklist: evaluation of a new screening tool delirium in an intensive care unit: a study of risk factors evaluation of delirium in critically ill patients: validation of the confusion assessment method for the intensive care unit (cam-icu) delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (cam-icu) brief screening tests for dementia mini-mental state a practical method for grading the cognitive state of patients for the clinician population-based norms for the mini-mental state examination by age and education level early identification of alzheimer's disease and related dementias deciphering the d's: cognitive decline, delirium, depression and dementia-a review the initial recognition and diagnosis of dementia the mini-mental state examination: a comprehensive review functional deficits in patients with mild cognitive impairment: prediction of ad measurement of functional activities in older adults in the community assessment of older people: self-maintaining and instrumental activities of daily living diagnostic evaluation of elderly patients with mild memory problems the performance of instrumental activities of daily living scale in screening for cognitive impairment in elderly community residents psychological problems following icu treatment anxiety, delirium, and pain in an intensive care unit neuropsychological sequelae in ards survivors health-related quality of life and posttraumatic stress disorder in survivors of the acute respiratory distress syndrome ptsd symptoms and cognitive performance in recent trauma survivors cognitive deficits in major depression the subcortical dysfunction model of memory deficits in depression: neuropsychological validation in a subgroup of patients motivational effects on neuropsychological functioning: comparison of depressed versus nondepressed individuals relationships among anxiety, defensiveness, sex, task difficulty, and performance on various neuropsychological tasks anxiety and cognitive functioning: a multifaceted approach rate of forgetting in dementia and depression unawareness of deficits in neuropsychological syndromes differentiating dementia from pseudo-dementia early in the clinical course: utility of neuropsychological tests geriatric depression scale (gds): recent evidence and development of a shorter version radloff ls ( ) the ces-d scale: a self report depression scale for research in the general population the hospital anxiety and depression scale an inventory for assessing clinical anxiety: psychometric properties united states preventive services task force ( ) screening for dementia: recommendation and rationale impact of diabetes on cognitive function among older populations: a population based cohort study cognitive impairment and mortality in elderly patients with heart failure cognitive impairment and decline are associated with carotid artery disease in patients without clinically evident cerebrovascular disease cognitive functioning in patients with chronic obstructive pulmonary disease and mild hypoxemia compared with patients with mild alzheimer disease and normal controls progressive neuropsychologic impairments and hypoxemia: relationship in chronic obstructive pulmonary disease postoperative hypoxia is a contributory factor to cognitive impairment after cardiac surgery evaluation of tests of central nervous system performance after hypoxemia for a model of cognitive impairment quality of life, emotional, and cognitive functioning following acute respiratory distress syndrome neuropsychological sequelae in survivors of ards compared with critically ill control patients acute respiratory distress syndrome and long term cognitive impairment: a case study neuropsychological impairments following hanta virus pulmonary syndrome clock-drawing: is it the ideal cognitive screening test? the mini-cog: a cognitive vital signs measure for dementia screening in multilingual elderly screening for dementia in the outpatient setting: the time and change test screening for dementia with the memory impairment screen the gpcog: a new screening test for dementia designed for general practice tics telephone for cognitive status, professional manual. psychological assessment resources key: cord- - v zchf authors: deemer, kirsten; zjadewicz, karolina; fiest, kirsten; oviatt, stephanie; parsons, michelle; myhre, brittany; posadas-calleja, juan title: effect of early cognitive interventions on delirium in critically ill patients: a systematic review date: - - journal: can j anaesth doi: . /s - - -z sha: doc_id: cord_uid: v zchf purpose: a systematic review of the literature was conducted to determine the effects of early cognitive interventions on delirium outcomes in critically ill patients. source: search strategies were developed for medline, embase, joanna briggs institute, cochrane, scopus, and cinahl databases. eligible studies described the application of early cognitive interventions for delirium prevention or treatment within any intensive care setting. study designs included randomized-controlled trials, quasi-experimental trials, and pre/post interventional trials. two reviewers independently extracted data and assessed risk of bias using cochrane methodology. principal findings: four hundred and four citations were found. seven full-text articles were included in the final review. six of the included studies had an overall serious, high, or critical risk of bias. after application of cognitive intervention protocols, a significant reduction in delirium incidence, duration, occurrence, and development was found in four studies. feasibility of cognitive interventions was measured in three studies. cognitive stimulation techniques were described in the majority of studies. conclusion: the study of early cognitive interventions in critically ill patients was identified in a small number of studies with limited sample sizes. an overall high risk of bias and variability within protocols limit the utility of the findings for widespread practice implications. this review may help to promote future large, multi-centre trials studying the addition of cognitive interventions to current delirium prevention practices. the need for robust data is essential to support the implementation of early cognitive interventions protocols. study designs included randomized-controlled trials, quasi-experimental trials, and pre/post interventional trials. two reviewers independently extracted data and assessed risk of bias using cochrane methodology. principal findings four hundred and four citations were found. seven full-text articles were included in the final review. six of the included studies had an overall serious, high, or critical risk of bias. after application of cognitive intervention protocols, a significant reduction in delirium incidence, duration, occurrence, and development was found in four studies. feasibility of cognitive interventions was measured in three studies. cognitive stimulation techniques were described in the majority of studies. conclusion the study of early cognitive interventions in critically ill patients was identified in a small number of studies with limited sample sizes. an overall high risk of bias and variability within protocols limit the utility of the findings for widespread practice implications. this review may help to promote future large, multi-centre trials studying the addition of cognitive interventions to current delirium prevention practices. the need for robust data is essential to support the implementation of early cognitive interventions protocols. objectif une revue systématique de la littérature a été réalisée afin de déterminer les effets des interventions cognitives précoces sur l'évolution du delirium chez les patients en état critique. source des stratégies de recherche ont été mises au point pour explorer les bases de données medline, embase, joanna briggs institute, cochrane, scopus et cinahl. les études éligibles devaient décrire l'application d'interventions cognitives précoces pour la prévention ou le traitement du delirium dans un contexte de soins intensifs. les types d'études retenues incluaient des études randomisées contrô lées, des études quasi expérimentales et des études pré-/post-interventionnelles. en se fondant sur la méthodologie cochrane, deux réviseurs ont extrait les données et évalué le risque de biais de manière indépendante. constatations principales quatre cent quatre citations ont été extraites. sept articles ont été retenus pour le compte rendu final. six des études incluses présentaient un risque global de biais majeur, élevé ou critique. après l'application des protocoles d'interventions cognitives, quatre études ont noté une réduction significative de l'incidence, de la durée, de la survenue et de l'apparition de delirium. trois études ont mesuré la faisabilité des interventions cognitives. la majorité des études décrivaient les techniques de stimulation cognitive. conclusion nous sommes parvenus à identifier quelques études ayant des tailles d'échantillon limitées décrivant des interventions cognitives précoces chez les patients en état critique. un risque global élevé de biais et de variabilité au sein des protocoles limite toutefois l'utilité de ces observations pour leurs applications dans la pratique. ce compte rendu pourrait susciter l'intérêt de chercheurs pour réaliser des études d'envergure et multicentriques examinant l'ajout d'interventions cognitives aux pratiques actuelles de prévention du delirium. le besoin de données robustes est crucial pour soutenir la mise en oeuvre de protocoles précoces d'interventions cognitives. keywords cognitive interventions Á delirium Á icu delirium Á ocupational therapist Á delirium prevention delirium is an acute neurologic disorder marked by inattention and a fluctuating course of altered level of consciousness that can occur as a result of medical illness, medical treatment (e.g., pharmacotherapy), and withdrawal of substances (e.g., alcohol). , delirium rates in the intensive care unit (icu) vary widely ( - %). , , intensive care unit delirium is associated with increased morbidity, mortality, healthcare costs, and a longer duration of mechanical ventilation. [ ] [ ] [ ] [ ] [ ] [ ] prolonged delirium in the icu is a risk factor for the development of post-intensive care syndrome characterized by new or worsened impairments in physical, cognitive, and mental health. [ ] [ ] [ ] in addition, delirium is an independent predictor of cognitive impairment and is associated with poor functional and cognitive recovery following critical illness. , best practice guidelines place emphasis on detection and severity measurement of icu delirium using validated tools such as the confusion method assessment for the icu (cam-icu) or the intensive care delirium scoring checklist (icdsc). such tools underpin research endeavors, and more importantly, the diagnosis and potential treatment of delirium. in general, pharmacologic management has not been proven to prevent or shorten the duration of delirium in critically ill patients; in fact, evidence shows certain medication classes should be avoided because of the risk of potentiating delirium (e.g., benzodiazepines, anticholinergics, tricyclic antidepressants, and first generation antihistamines). , while antipsychotic medications have no proven efficacy, dexmedetomidine may decrease the duration of delirium when compared with placebo in mechanically ventilated patients with agitated delirium. , repeated standardized tasks specifically focusing on the cognitive domains. , maintenance or restoration of cognitive functions. , spaced information retrieval. tasks resembling activities of daily living. digit span, memory tasks, picture guess, difference searching. tailoring of task difficulty to the individual. individual or group settings. cognitive stimulation engagement in range of group activities and discussions to enhance cognitive and social functioning. maintenance or restoration of cognitive functions. reality orientation. discussions within group environment including reminiscence therapy. recreational activities. memory training. cognitive rehabilitation individualized approach to improve functional ability and autonomy. targeting everyday functioning to optimize residual cognitive abilities. , improve functioning in the everyday context. development and enhancement of new strategies to overcome cognitive obstacles such as use of memory aids (e.g., calendars or diaries). emerging evidence points towards the benefits of nonpharmacologic interventions for the prevention and management of delirium. , cognitive interventions are evidenced-based strategies targeting cognitive domains impacted by delirium such as orientation, memory, abstract thinking, and executive function. , traditionally used in alzheimer's disease, dementia, stroke and traumatic brain injury, cognitive interventions encompass the clinically distinct concepts of cognitive training, cognitive stimulation, and cognitive rehabilitation (table ) . [ ] [ ] [ ] cognitive training involves guidance with standardized tasks that focus on specific domains (i.e., memory or executive function) and can occur in individualor group settings. cognitive stimulation improves general cognitive and social functioning by engaging patients in a range of group activities (i.e., reality orientation, word searches, or board games). [ ] [ ] [ ] in practice, cognitive training and stimulation exercises may overlap, and include memory training using visual imagery and metacognitive training using self-awareness and selfregulation approaches to recover executive functioning. , , finally, cognitive rehabilitation is an individualized approach to improve functional ability and autonomy with a focus on optimizing residual cognitive abilities. , the cognitive reserve theoryinterventions targeting remaining cognitive reserve to stimulate activity-dependent neuroplasticity-underlies the use of cognitive interventions in elderly dementia patients with delirium. , similarly, cognitive interventions in critically ill patients with delirium, or those at risk of developing delirium, may stimulate neuronal plasticity thereby enhancing cognitive function. , recent clinical studies assessed various nonpharmacological interventions combined with physical rehabilitation for delirium prevention. [ ] [ ] [ ] this systematic review will focus on the elements of early cognitive interventions and their effects on delirium outcomes such as incidence, duration, and severity in critically ill patients. methodology for this review conformed to the preferred reporting items for systematic reviews and meta-analysis (prisma) guidelines ( figure ). the populations of interest were critically ill or intensive care patients. we defined the intervention as any therapies, strategies, or rehabilitation exercises directed at improving patient cognition or the domains of cognition. examples of interventions included repeated tasks, games, skills, or questions such as orientation exercises in both writing and/ or verbal exercises. we sought to find studies comparing patients who received the intervention and those that did not, and reported on our primary outcome of interestdelirium. this review included original research articles such as randomized-controlled trials (rct), quasiexperimental trials (i.e., non-rct), observational trials, and pre/post intervention trials describing the application of cognitive interventions early in the icu stay, as well as reporting on the burden (i.e., incidence, prevalence, severity) of delirium according to validated tools such as the cam-icu or icdsc. english language publications studying either pediatric or adult critically ill populations were chosen. editorials, commentaries, review articles, case studies, non-interventional study designs, and grey literature were excluded. non-english articles were excluded. articles focusing only on cognitive interventions following hospital discharge (i.e., outpatients) were excluded as we sought to assess interventions applied early during critical illness. search strategies were developed by k.d. and reviewed by a health sciences librarian. the search was conducted using medline, embase, joanna briggs institute, cochrane, scopus, and cinahl databases. medical subject heading (mesh) terms and key words were used including three key concepts: cognitive interventions, delirium prevention, and critical care. limitations included english language articles. there were no date restrictions. search terms were detailed according to database mesh terms (appendix a). the initial search was conducted by the primary investigator (k.d.). search results were managed using endnote. screening methods and data extraction two reviewers (k.d. and j.p.) manually screened in duplicate titles and abstracts for predetermined inclusion and exclusion criteria. titles and abstracts lacking sufficient information for inclusion were reviewed in fulltext form. disagreements were resolved by a third-party reviewer (k.z.). articles were chosen for full-text review after assessment of inclusion criteria for study population, study comparison, and study outcomes. subsequently, two investigators (k.d. and j.p.) independently reviewed full-text articles for final data extraction and analysis. interrater reliability was measured using cohen's kappa (j) where b indicates no agreement and indicates perfect agreement. data extraction data extraction was conducted independently and in duplicate by two reviewers (k.d. and k.z.) using a data extraction table that included study methodology, population, objectives, country of origin, specific cognitive interventions conducted, the healthcare professionals conducting interventions, outcomes measured (e.g., delirium incidence, severity and duration), study limitations, and key findings. two authors (k.d. and k.z.) independently assessed all rcts using the cochrane collaboration's risk of bias tool as described in the cochrane handbook for systematic reviews of interventions. the following six domains were analyzed: random sequence generation; allocation concealment; blinding of participants; personnel and outcome assessors; how incomplete outcome data were addressed; selective outcome reporting; and other sources of bias (such as baseline imbalances). each domain was judged as ''low'', ''high'', or ''unclear'' risk by a using a specific set of criteria outlined in the handbook. conclusions regarding the overall risk of bias were derived from the individual domain judgements and the effect on the primary outcome. randomized-controlled trials judged to be at high risk of bias were deemed to have high risk for one or more key domain. similarly, all three non-rcts were independently assessed using the risk of bias in non-randomized studies of interventions (robins-i) tool by k.d. and k.z. the robins-i is the preferred tool of the cochrane scientific committee and uses seven domains to assess risk: bias due to confounding; bias in selection of participants into the study; bias in classification of interventions; bias due to deviations from intended interventions; bias due to missing data; bias in measurement of outcomes; and bias in selection of the reported result. individual domains are graded as ''low-'', ''moderate-'', ''serious-'' or ''critical-'' risk of bias or ''no information''. an overall risk of bias judgement (low, moderate, serious, or critical) is ascertained after each domain is addressed. non-randomized-controlled trials with serious or critical risk of bias in a key domain were judged overall as having a serious or critical risk of bias. disagreements in risk of bias results for both rcts and non-rcts were reviewed by a third author (s.o.) and final consensus was reached after discussion. results are presented in both synthesized (tables and ) and descriptive formats (appendix b). a narrative format was chosen for the presentation of findings. a meta-analysis was not pursued because of heterogeneity of interventions, outcomes, and study designs. the search yielded articles; duplicate articles were eliminated leaving for further consideration ( figure ). of these, two hundred and thirty-three articles were removed after title and abstract review for failure to meet inclusion criteria (good agreement was met after title and abstract review; j = . ), leaving publications. following full-text review, articles were excluded as they did not meet criteria for study design, article type, or lacked a study focus of cognitive interventions applied early during a period of critical illness (full agreement was met after full-text review; j = . ). our literature search yielded seven articles for in-depth analysis (table ) . no articles were excluded from the final review and data extraction based on risk of bias judgement. all articles were published between and , included patients over yr of age, and were conducted in single-centre mixed medical/surgical icus. four articles were rcts, [ ] [ ] [ ] [ ] one was a pre-post intervention trial, and two were multi-phase prospective observational studies. , three studies were conducted in the united states , , ; with the remainder in chile, australia, italy, and the netherlands. table risk of bias summary of randomized-controlled trials + = indicates a low risk of bias; -= indicates high risk of bias; ? = indicates unclear risk of bias. brummel et al. mitchell et al. munro et al. six of seven studies included in this review were deemed to have either a critical, serious, or high risk of bias. [ ] [ ] [ ] [ ] [ ] [ ] only one article was assessed as low risk in all domains (tables and ). we chose to include one study which had an overall critical risk of bias because it focused on the individual elements of cognitive interventions. one rct did not include enough information to determine if patient allocation was properly concealed or if there was blinding of personnel, participants, or outcome evaluators. therefore, performance bias was possible and the overall judgement of bias was deemed unclear. of the studies that reported delirium outcomes, two were judged as having serious bias and one as having an unclear risk of bias (tables and ). [ ] [ ] [ ] notably, moderate to serious bias was detected in all three non-rcts within the domain of outcome measurements. [ ] [ ] [ ] two studies did not adequately describe a difference in personnel assessing outcomes and those delivering the intervention (appendix b). , delirium outcomes four of the seven studies reported results on delirium outcomes after cognitive interventions (table ) . , [ ] [ ] [ ] there was wide variation in the types of outcomes reported (i.e., delirium incidence, duration, occurrence and development; delirium-free days; delirium severity; and time to develop delirium). alverez et al. conducted an rct of elderly icu patients and reported a reduced delirium incidence ( % in the control group vs % in experimental group) after implementation of an occupational therapy led cognitive intervention protocol that included stimulation, rehabilitation, and training exercises (p = . ). rivosecchi et al. included cognitive stimulation in a non-pharmacological delirium prevention bundle, and reported a reduced incidence of delirium between phase i ( . %) and phase ii ( . %) of the study (p = . ). additionally, a reduction in delirium duration was reported by alverez et al. showed a significant reduction in the occurrence of delirium ( % phase i vs % in phase ii) after introducing a cognitive simulation protocol that included orientation, environmental, acoustic, and visual interventions (p = . ). while controlling for dementia, apache ii, and mechanical ventilation, rivosecchi et al. concluded patients were less likely to develop delirium after administration of a non-pharmacologic bundle that included music, exposure to daylight, table risk of bias summary in non-randomized-controlled trials colombo et al. rivosecchi et al. wassenaar et al. of patients experiencing delirium, exposure to reorientation protocol did not significantly change mortality. a reorientation strategy was associated with a reduced incidence of delirium. mitchell et al. delirium-free days. mean delirium-free days: . in family voice group, . in unknown voice group, and . in the control group (p = . ). patients exposed to recorded voice messages from family members had more deliriumfree days. it is feasible to provide cognitive training exercise to critically ill patients; patients found this to be a positive experience. also measured delirium severity using a delirium rating scale and there was no significant difference in mean delirium scores ( points in control group vs points in experimental group, p = . ). there was no significant difference in the mean time until development of delirium as reported by rivosecchi et al. between phase i ( . hr) and phase ii ( . hr) (p = . ). the remaining three studies, although underpowered to assess delirium outcomes, assessed the feasibility of interventions or estimated an appropriate sample size for future studies (table ) . , , for example, brummel et al. showed that early cognitive therapy in critically ill patients is not only feasible but also safe and appropriate for both mechanically and non-mechanically ventilated patients ( % of patients received early cognitive therapy on at least one study day; % of possible cognitive therapy sessions were completed). mitchell et al. showed that a family-oriented cognitive intervention is feasible and acceptable but a low family recruitment rate was reported ( %). finally, wassenaar et al. showed the feasibility of nursing-led cognitive training exercises that are practical and non-burdensome (nursing median likert scale: . - . ; patient median likert scale range: . - . ). cognitive intervention protocols consisted of either training, stimulation, rehabilitation, or a combination of all three (table ) . two studies utilized all three categories of cognitive interventions, which accounted for more varied protocols targeting several cognitive domains. , the majority of studies (six) included cognitive stimulation (i.e., orientation activities and environmental stimulation). [ ] [ ] [ ] [ ] cognitive training exercises were employed in three studies and included memory and visuospatial construction games and games targeting enhancement of attention. , , specific cognitive domains were targeted because of common impairments seen in delirium. these domains were identified in five studies and included orientation, memory, visual perception, problem solving, executive function, attention, and processing speed (table ) . , , , , two studies titrated their cognitive intervention protocol according to the level of sedation of the patient (as assessed by the richmond agitation and sedation scale [rass], appendix c) that permitted staged advancement of task difficulty. , neither study mentioned cognitive interventions that were attempted in patients showing the deepest levels of sedation (i.e., rass - to - ). healthcare professionals (physicians, occupational therapists, nurses) were involved in delivering cognitive interventions in a majority of studies (table ) . [ ] [ ] [ ] [ ] [ ] [ ] nevertheless, mitchell et al. studied interventions conducted by family members in the form of orientation, cognitive, and sensory stimulation. the participation of family in cognitive interventions was considered in three studies and included direct patient interactions such as participating in activities of daily living, voice-recorded messages, and orientation exercises (table ) . , , discussion impact of cognitive intervention on delirium outcomes we found insufficient evidence to support the use of early cognitive interventions in the prevention or management of delirium in critically ill patients. only seven small studies were identified examining early cognitive interventions in critically ill patients. four articles variably reported a reduction in delirium incidence, duration, occurrence, severity, and an increase in delirium-free days. , [ ] [ ] [ ] the remaining three studies only considered the feasibility of implementing a prevention program and did not report on delirium outcomes. , , furthermore, six of seven studies identified in our review had a serious, high, or critical risk of bias, which impacts conclusions on delirium outcomes. the implementation of cognitive interventions in critically ill patients is relatively new; there were no publications prior to that met our inclusion criteria. delirium can have serious negative consequences in icu patients, and as of yet there are no specific interventions-pharmacologic or non-pharmacologicthat reliably prevent its development. , nevertheless, there is an emerging body of evidence that suggests the utility of multimodal delirium prevention programs that includes the incorporation of a non-pharmacologic, multidisciplinary team approach. , , , for example, early rehabilitation reduces the number of patients who develop delirium and shortens duration of delirium when it manifests. , incorporating early rehabilitation using a multimodal, multidisciplinary approach improves the management of delirium. , , the ''abcdef'' bundle consists of assessment, prevention and management of pain; both spontaneous awakening and breathing trials; choice of sedation/analgesia; delirium monitoring and management; early mobility; and family engagement and empowerment. higher bundle compliance is associated with improved survival and more delirium-free days. specific interventions such as minimizing restraint use, reducing noise, increasing daylight exposure, and promoting orientation and sleep are non-pharmacologic options for delirium prevention as part of a multimodal bundle. the application of individual components of delirium prevention bundles in critically ill patients (specifically early physical and occupational therapy with a focus on functional mobility and activities of daily living) have shortened the duration of delirium. notably, it has been deemed safe and feasible to conduct physiotherapy even on patients receiving advanced life support treatments such as extracorporeal membrane oxygenation. nevertheless, studies of other non-pharmacologic therapies such as early cognitive interventions are lacking. among the studies we identified, there was wide variation in the specific components of cognitive intervention protocols, which limits generalizability of their findings and comparison of their effects. only two articles contained protocols that included cognitive stimulation, training and rehabilitation strategies based on the rationale that several cognitive domains are affected by delirium and should be targeted for therapy. , this review found a limited number of studies with small sample sizes and overall high risk of bias. therefore, it is not reasonable to draw conclusions regarding the specific type, dose, or component of cognitive interventions or if they would be efficacious in delirium prevention and management. this is especially true given the heterogeneity of populations reported across studies. further study is necessary to test a standardized cognitive intervention protocol that may encompass cognitive stimulation, cognitive training, and cognitive rehabilitation exercises. additionally, appreciation of the patient's baseline cognitive and premorbid status is necessary to tailor cognitive interventions appropriately in diverse critically ill populations. two studies discussed titration of cognitive interventions according to a standardized agitationsedation scale. , nevertheless, neither study mentions cognitive interventions at the deepest levels of sedation. not uncommonly, icu patients require various medications for sedation and analgesia, and it is not clear whether cognitive interventions at various levels of sedation can be of benefit with regard to delirium outcomes. in a systematic review of adult critical care survivors diagnosed with post-traumatic stress disorder, post-traumatic responses were strongly linked to the development of delusional memories, which are more likely to develop in patients who are deeply sedated. , future research may reveal whether delusional memories can be ameliorated using cognitive interventions, and whether these interventions should be considered at all levels of sedation. a variety of healthcare professionals were identified in the delivery of cognitive interventions in the majority of studies; however, direct family involvement with cognitive interventions was considered in three studies. , , such involvement dovetails nicely with changing attitudes regarding family participation in patients treated in a critical care setting. our review indicates that family participation in delirium prevention strategies can complement those performed by nurses and other healthcare professionals. family member participation may be particularly beneficial because of the personalized nature of cognitive stimulation, knowledge of the patient, and familiarity of voice. , additionally, family members may personally benefit from being able to directly participate in patient care and so gain a sense of purpose and control. family involvement in the care of critically ill patients is an underutilized resource that certainly merits further consideration and study. while one identified study deemed cognitive interactions feasible and nonburdensome to nursing, future methodologically-robust research may determine if these interventions are indeed feasible for a variety of patient populations, sedation levels, nursing workloads, and severity of illnesses. assessment of the combination of input from healthcare providers and family members is essential before providing recommendations that could be tailored to resources available within individual icus. feasibility studies included in this review may assist with protocol development of future rcts, such as the study by mitchell et al. who provided a sample size estimate of ( % power; p = . ). additional studies are needed to elucidate the value of a standardized, multimodal cognitive intervention protocol combined with pharmacologic delirium prevention measures to determine the effect on delirium in critically ill patients. this systematic review has several limitations. the studies included in this review were deemed to have critical, serious, or high risk of bias, limiting overarching conclusions on the effects of cognitive interventions. additionally, the majority of articles were pilot or feasibility studies; therefore, it would be premature to form conclusions on delirium outcomes. cross study conclusions regarding cognitive interventions were not possible because of the large variation in populations of critically ill patients included in the studies (e.g., ventilation status, ages, and severity of illness). there was considerable variation in the types of cognitive interventions used; therefore, it is not possible to compare these and recommend any single intervention or protocol. this review studied only english articles so there may be additional evidence available that we did not include. finally, our review may be further limited by the databases we interrogated; while we searched six major databases, additional relevant studies may be available from sources not indexed in these chosen databases. early cognitive intervention for delirium prevention and management is a relatively new focus of research and insufficient evidence is available supporting its use critically ill patients. larger, multi-centre trials that study standardized cognitive intervention protocols are needed to examine the effects on delirium outcomes in a range of icu populations, levels of sedation, and healthcare professionals. it is anticipated that a considerable level of resources, training, and support would be required to implement additional non-pharmacologic interventions into current delirium prevention bundles. author contributions brittany myhre, michelle parsons, stephanie oviatt, kirsten deemer, and juan posadas contributed to all aspects of this manuscript, including study conception and design; acquisition, analysis, and interpretation of data; and drafting the article. kirsten fiest contributed to the conception and design of the study in addition to editing. karolina zjadewicz contributed to the analysis of data and contributed to the conception and design of the study. funding statement :none. editorial responsibility ithis submission was handled by dr. steven backman, associate editor, canadian journal of anesthesia. appendix a search strategy for effect of early cognitive interventions on delirium in critically ill patients pre-specified primary and secondary outcomes reported in pre-specified way. free of other bias low the study appears to be free of other sources of bias. high high risk of bias in one or more key domain. mitchell et al. adequate random sequence generation low random component in the sequence generation process described. allocation concealment unclear insufficient information to determine if patient allocation was concealed from participants and investigators. blinding of participants high family members filled out their own data slips to track whether intervention was conducted or not. high not possible to blind outcome assessors. unclear authors did not adequately address how data set was completed when only % of data slips were completed by family members. low pre-specified primary and secondary outcomes reported in pre-specified way. free of other bias high low family compliance in data slip completion; skewed detection of intervention. high high risk of bias in one or more key domain. munro et al. adequate random sequence generation low random component in the sequence generation process described. allocation concealment unclear insufficient information to determine if patient allocation was concealed from participants and investigators. unclear insufficient information on who delivered interventions or if personnel were blinded. unclear insufficient information on the blinding of outcome assessors. incomplete outcome data addressed no missing outcome data. free of selective outcome reporting low a priori determined primary and secondary outcomes appropriately reported. the study appears to be free of other sources of bias. unclear unclear risk of bias in one or more key domain. colombo et al. confounding moderate all known important confounding domains appropriately measured and controlled for; serious residual confounding not expected. all eligible participants for the trial were included. low intervention status well-defined and intervention definition is based solely on information collected at the time of intervention. deviation from intended intervention low any deviations from intended intervention reflected usual practice. no flow chart. insufficient information regarding potential for missing data. nursing provided both the interventions and the outcome measures. moderate congruence between outcome measures and analyses specified in protocol but cannot be compared with a well conducted randomized control trial. serious serious risk of bias in at least one key domain. rivosecchi et al. confounding serious lack of control for delirium-inducing medication use. patient exposure was higher in phase ii of study and was not considered in regression analysis. selection of participants serious % and % of patients were unable to be assessed upon admission into phase and , respectively, because of illness severity. they may have been at higher risk for delirium. low intervention status well-defined; intervention definition based solely on information collected at the time of intervention. deviation from intended intervention low any deviations from intended intervention reflected usual practice. missing data low data were reasonably complete. the outcome was assessed by assessors aware of the intervention received by study participants because of the study type (i.e., pre/post intervention trial). reported results corresponded to intended outcomes, analysis, and sub-cohorts. overall judgement serious serious risk of bias in at least one key domain. wassenaar et al. confounding serious enrollment of patients if the rass was - to ? and stable. intervention feasibility not tested in sicker patients so questionable generalizability of findings. sampling of enrolled patients to test the intervention was based on the presence and absence of delirium diagnosis. low intervention status well-defined and intervention definition is based solely on information collected at the time of intervention. low no apparent deviations. any deviations from intended intervention reflected usual practice. missing data low data were reasonably complete. authors do not distinguish that patient burdensome ratings (using a likert scale) were conducted by a separate outcome assessor than those performing the cognitive intervention. reported results corresponded to intended outcomes, analysis, and sub-cohorts. overall judgement critical critical risk of bias in at least one key domain. light sedation briefly awakens with eye contact to verbal stimuli (\ sec) - moderate sedation movement or eye opening to verbal stimuli but no eye contact - deep sedation no response to voice, but movement or eye opening in response to physical stimulation v unarousable no response to voice or to physical stimulation - delirium in critically ill patients delirium in the intensive care unit delirium in the intensive care unit and long-term cognitive and psychosocial functioning: literature review prevalence and risk factors for development of delirium in surgical and trauma intensive care unit patients delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit outcome of delirium in critically ill patients: systematic review and meta-analysis delirium duration and mortality in lightly sedated, mechanically ventilated intensive care patients delirium as a predictor of long-term cognitive impairment in survivors of critical illness delirium in the intensive care unit implementation of the pain, agitation, and delirium clinical practice guidelines and promoting patient mobility to prevent post-intensive care syndrome clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the icu delirium management in the icu effect of dexmedetomidine added to standard care on ventilator-free time in patients with agitated delirium: a randomized clinical trial clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit practical protocol for implementing cognitive stimulation in persons with delirium superimposed on dementia cognitive training and cognitive rehabilitation for people with early-stage alzheimer's disease: a review cognitive training and cognitive rehabilitation for persons with mild to moderate dementia of the alzheimer's or vascular type: a review efficacy of cognitive rehabilitation in alzheimer disease: a -year follow-up study evidence-based cognitive rehabilitation: updated review of the literature from occupational therapists use of cognitive interventions for clients with alzheimer's disease a framework for cognitive interventions targeting everyday memory performance and memory selfefficacy an intervention for delirium superimposed on dementia based on cognitive reserve theory early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial early physical medicine and rehabilitation for patients with acute respiratory failure: a quality improvement project the effect of a multicomponent multidisciplinary bundle of interventions on sleep and delirium in medical and surgical intensive care patients the prisma statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration interrater reliability: the kappa statistic cochrane handbook for systematic reviews of interventions robins-i: a tool for assessing risk of bias in non-randomised studies of interventions occupational therapy for delirium management in elderly patients without mechanical ventilation in an intensive care unit: a pilot randomized clinical trial feasibility and safety of early combined cognitive and physical therapy for critically ill medical and surgical patients: the activity and cognitive therapy in icu (act-icu) trial a family intervention to reduce delirium in hospitalised icu patients: a feasibility randomised controlled trial delirium prevention in critically ill adults through an automated reorientation intervention -a pilot randomized controlled trial the implementation of a nonpharmacologic protocol to prevent intensive care delirium a reorientation strategy for reducing delirium in the critically ill. results of an interventional study feasibility of cognitive training in critically ill patients: a pilot study the richmond agitation-sedation scale: validity and reliability in adult intensive care unit patients pharmacologic management of delirium in the icu: a review of the literature pharmacological interventions for the treatment of delirium in critically ill adults. cochrane database syst rev improving hospital survival and reducing brain dysfunction at seven california community hospitals: implementing pad guidelines via the abcdef bundle in , patients effectiveness and safety of the awakening and breathing coordination, delirium monitoring/management, and early exercise/mobility (abcde) bundle safety and feasibility of early physical therapy for patients on extracorporeal membrane oxygenator: university of maryland medical center experience literature review of post-traumatic stress disorder in the critical care population patients' perceptions of and emotional outcome after intensive care: results from a multicentre study perceptions of family members, nurses, and physicians on involving patients' families in delirium prevention the abcdef bundle in critical care comparison of cognitive intervention strategies for older adults with mild to moderate alzheimer's disease: a bayesian meta-analytic review acknowledgements we would like to acknowledge helen lee robertson, mlis, liaison librarian, clinical medicine health sciences library, university of calgary for her guidance in our search strategies. key: cord- -nck f ny authors: ling, lowell; joynt, gavin m.; lipman, jeff; constantin, jean-michel; joannes-boyau, olivier title: covid- : a critical care perspective informed by lessons learnt from other viral epidemics date: - - journal: anaesth crit care pain med doi: . /j.accpm. . . sha: doc_id: cord_uid: nck f ny nan the world is closely watching the outbreak of respiratory illness associated with the novel beta coronavirus sars-cov- . the first cases were reported in wuhan, hubei province, china [ ] . at the time of writing the number of reported cases of the resulting disease, covid- , is already over , and shows no immediate signs of stabilisation. although the majority remain in wuhan and hubei province, cases have been reported in all provinces of china and over countries across the globe. the aim of this editorial is to review the management of critically ill patients with covid- infection. initially termed -ncov, sequencing showed that now officially named sars-cov- is - % similar to bat severe acute respiratory syndrome related coronaviruses found in chinese horseshoe bats [ , ] . in addition, it is about % akin to severe acute respiratory syndrome coronavirus (sars-cov) and % related to middle east respiratory syndrome coronavirus (mers-cov). the latter two coronaviruses have their immediate origins from civets and camels, respectively [ , ] . although it is uncertain how covid- transmission from animals to humans occurred, epidemiological studies suggested an intermediary wild animal host sold in the huanan seafood wholesale market [ ] . currently, while human to human transmission is certain, the mechanism of transmission remains controversial [ , , ] . although it is likely that covid- transmission is primarily via droplets and fomite contact, airborne transmission events cannot yet be excluded. transmission via the faecal-oral route remains a possibility as sars-cov- rna, but not live virus, has been detected in stool [ ] . molecularly, like sars-cov, the sars-cov- virus likely uses ace- as entry receptor, which is highly expressed in the lung and gastrointestinal tract [ ] [ ] [ ] . initial symptoms are non-specific and include fever, cough, sore throat, rhinorrhea, myalgia or fatigue, sputum and headache [ , ] . patients typically complain of dyspnea one week after symptom onset, and some progress to develop acute respiratory distress syndrome. the median time from presentation to mechanical ventilation is . days, and while initial reports from the chinese epicentre suggest that between to % of hospitalised patients require icu admission [ , , ] , this rate appears to be lower, approximately %, in hong kong and singapore (personal observation ll/gmj). other organ dysfunctions reported in these cohorts include acute kidney injury ( %) and septic shock ( - . %). patients requiring icu care were older and had more comorbidities than those that did not. as of th february , only deaths have been reported outside china, but the mortality of covid- reported in initial hospitalised cohorts in china ranges from . to % [ , , ] . these findings should be interpreted in context since the hospitalised cohorts may have a significantly higher mortality than community patients with mild symptoms who may not seek hospital care. infection is confirmed by positive test to sars-cov- by realtime rt-pcr, isolation in cell culture of sars-cov- from clinical specimens, or rising serum antibody concentrations. if laboratory confirmatory tests are not available, clinical and epidemiological criteria such as those advocated by the us centers for disease control and prevention (cdc) may be used (https://www.cdc.gov/ coronavirus/ -ncov/hcp/clinical-criteria.html?cdc_aa_ refval=https% a% f% fwww.cdc.gov% fcoronavirus% f -ncov% fclinical-criteria.html). based on current best evidence, supportive treatment and organ support remain the focus of icu care. specific treatments such as the use of corticosteroids to control the inflammatory response, and antivirals, particularly the combination of lopinavir/ritonavir and ribavirin have been used, but are unproven to improve outcomes [ ] . the cautionary experience of sars-cov provided a lesson of the desperate pursuit to find effective treatment. during this outbreak, the use of highdose corticosteroids (> g methylprednisolone in the acute phase of disease) used to modulate the immune response was not conclusively shown to improve outcomes, but resulted in devastating steroid induced complications [ ] . as respiratory failure is the predominant complication of covid- , attention to the delivery of appropriate lung protective anaesth crit care pain med xxx ( ) xxx-xxx infection control outbreak sars-cov- strategies during mechanical ventilation and prevention of hospital acquired infections is likely to contribute to improved outcomes in critically ill patients. lack of clear knowledge of the mechanisms of covid- transmission makes it difficult to develop evidence-based infection control protocols to prevent transmission to healthcare workers (hcw) and other patients. certainly, icu hcw are at particularly high risk of nosocomial transmission because of potential exposure to aerosolised respiratory secretions during intubation, tracheal suctioning, bronchoscopy and respiratory circuit disconnection, as well as environmental contamination [ ] [ ] [ ] [ ] . thus, it is currently prudent to assume higher precautionary measures in icu than those currently recommended by the cdc (respiratory droplet and contact precautions). suspected or confirmed cases should ideally be isolated in a negative pressure airborne infection isolation room (aiir) with sufficient air changes (> /h) and personnel trained to use personal protective equipment (ppe) for airborne precautions. all support and sanitary staff, often forgotten, should also receive appropriate ppe and infection control training, particularly as there may be a risk of faecal transmission [ ] . if full airborne precautions are not possible due to limited facilities or overwhelming numbers of cases, other measures that may decrease risk of nosocomial transmission include cohorting of patients in dedicated wards, or physical separation, supported by disciplined use of ppe, universal contact and droplet precautions and adequate ward ventilation [ , [ ] [ ] [ ] . encouragingly, with strict ppe protocols combined with rigorous implementation, the reported risk of staff contracting sars-cov in one icu was low, despite suboptimal physical space, ventilation and complete absence of aiir facilities [ ] . limited data suggests that the use of high-flow nasal oxygen (hfno) may prevent intubation in severe hypoxemic respiratory failure [ ] . within the icu, and with hcw protected by high-level ppe (including an n mask), non-invasive ventilation (niv) and hfno use during sars-cov and influenza epidemic was not clearly associated with an increased risk in hcw [ , ] . however, a recent meta-analysis demonstrated that there may be an increased risk of viral transmission to hcw who treated patients receiving niv [ ] . since the mode of covid- transmission remains unclear and mortality benefit of hfno and niv in severe pneumonia is unproven, we do not currently recommend their use in suspected or confirmed cases of covid- . if used, patients must be closely monitored in icu or high care areas, and airborne respiratory precautions strictly adhered to. the timing and decision to intubate patients with covid- should be made on a case-by-case basis. the threshold for intubation may be lower in covid- since use of high-flow nasal oxygen (hfno) or non-invasive ventilation may potentially increase the risk of transmission to hcw [ ] . disease transmission risk of viral respiratory infections during intubation has been shown to be high [ , ] , and therefore early, controlled intubation may also increase the safety margin of intubation and by allowing adequate preparation time for this high-risk procedure. airborne precautions should be applied throughout. some additional measures to reduce transmission risk include intubation in an aiir, and limiting non-essential staff to reduced exposure time [ , ] . placing bacterial/viral filters in circuits and between the mask and bag valve mask (bvm) resuscitator during manual mask ventilation may serve to reduce viral particle dispersion into the atsmopshere [ ] . intubation in covid- patients should be performed by those experienced in airway management to increase first-pass success [ , ] . video laryngoscopy improves intubation rates and allows the operator to be further away from the patient's oropharynx [ ] . standard use of rapid sequence induction to avoid or minimise bvm ventilation may be preferable as bvm was previously associated with sars-cov nosocomial infection [ ] . pre-oxygenation under these conditions using a well-sealed bvm with appropriately placed viral filter is recommended. directly connecting the ventilator circuit to the et tube immediately after intubation, rather than the bvm resuscitator, eliminates the need to reconnect and facilitates expired gas scavenging. in-line ''closed suctioning systems'' should be used to maintain a closed circuit. the increased transmission of sars-cov to hcw previously reported during cardiopulmonary resuscitation (cpr) was likely due to virus aerosolisation during bvm ventilation [ ] . preventive measures may include using apnoeic oxygenation during cpr, or careful two-person bvm ventilation to allow an effective face seal by two handed mask holding (with inline bacterial/viral filter), and early intubation when indicated. the use of mechanical cpr devices to replace hcw cpr may reduce the risk of facemask leakage for the hcw, and decreases their own minute ventilation, thus potentially reducing the risk of disease transmission. for patients already receiving mechanical ventilation in icu, the ventilator may be set to volume control, with a large negative pressure trigger and high-pressure alarm setting to avoid a need for disconnection and change to manual bvm ventilation. one of the greatest challenges in emerging epidemics is uncertainty amongst hcw about transmission risks, and fear of becoming a victim of the outbreak disease. icu is a high-risk area where a larger number of ''high transmission risk'' procedures are performed. clear concise communication and leadership are critical to tackle stress, fear, fake news and mistrust during the crisis [ ] . staff morale is vulnerable and emotional support should be proactively made available. frontline staff must be made to feel safe by constant exposure to clear protocols and rigorous training. expansion of critical care beds to cope with increased numbers of patients by opening more icu beds, and converting wards and other monitored areas for icu provision is often recommended in outbreak disaster plans. however, experience from sars-cov showed that rapid and excessive expansion may overwhelm staff, lead to excess infections in hcw, and compromise care [ ] . thus, expansion should be matched by safe staffing to guarantee an appropriate quality of care and staff safety, which necessarily limit expansion. it has been suggested by an expert consensus group with first-hand experience of outbreak expansion that this is realistically limited to a maximum of - % of baseline capacity [ ] . alternatively, restricting normal critical care to provide only core and essential provisions, may allow greater expansion and more patients to have limited life sustaining interventions under conditions of limited resources [ ] . should these measures be overwhelmed, individual patient triage and appropriate rationing of icu care will be required to provide greatest benefit for the editorial / anaesth crit care pain med xxx ( ) xxx-xxx greatest number of patients [ , ] . a structured triage approach incorporating triage admission criteria that can adapt to the scale of crisis, are fluid and adaptable depending on the evolution of the outbreak and change in response to resource pressures is necessary. a process of development and implementation that provides transparency, an appeal mechanism, documentation of decisions and that is culturally and socially sensitive is recommended [ ] . the epicentre of the epidemic in china provided an early warning for europe to allow the preparation of preventive measures, and specific organisational processes were rapidly adopted. patients returning from china, and in particular from hubei province are quarantined for days. anyone who develops symptoms that could suggest a coronavirus infection are encouraged to call a single emergency number and if covid- is suspected, they are managed at their location by a specialised medical team equipped with ppe to prevent viral contamination, and when necessary, hospitalised in an intensive care unit. in icus suspected and confirmed cases are isolated with protective measures against staff contamination and placed in specific rooms with a negative pressure airflow. based on the experience of sars-cov and h n influenza outbreaks, seriously ill patients are referred to specialised units that have ecmo capability if required. although one -year old chinese tourist with co-morbidities has died in hospital, the majority of patients who have tested positive for sars-cov- to date have not yet shown signs of severe respiratory failure and some have been discharged from hospital after the contagious period. currently, icus continue to manage patients with severe h n influenza, utilising ecmo when indicated, and are therefore well prepared for the treatment of severe contagious viral infections. should community outbreaks occur globally, the management of critically ill patients with covid- infection will be challenging. the lack of specific treatment is compounded by uncertainties about its mode of transmission and clinical outcomes. given these knowledge gaps, it becomes essential that as much robust highquality evidence as possible is gathered in the early stages of the disease. a strong appeal is made for the icu community to come together globally, and for the contribution of data by all icus to local, regional and international databases. covid- patients pose risks to icu staff, but the precise magnitude of this risk is currently unclear. adequate precautions, good hand hygiene, plentiful supplies of properly fitted n- masks and other essential ppe, filters for circuits, clear and robust protocols, teamwork and communication are all needed to address these concerns. icu management teams have the responsibility to make these needs known to relevant authorities to ensure proper forward planning and adequate procurement. painful lessons were learned from the recent sars-cov and influenza epidemics. it is time to apply what we have learned, and rise to the challenge of covid- . the authors declare that they have no competing interest. clinical features of patients infected with novel coronavirus in wuhan, china a familial cluster of pneumonia associated with the novel coronavirus indicating person-toperson transmission: a study of a family cluster genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding animal origins of the severe acute respiratory syndrome coronavirus: insight from ace -s-protein interactions enzootic patterns of middle east respiratory syndrome coronavirus in imported african and local arabian dromedary camels: a prospective genomic study epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study importation and human-to-human transmission of a novel coronavirus in vietnam early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia first case of novel coronavirus in the united states angiotensinconverting enzyme is a functional receptor for the sars coronavirus a pneumonia outbreak associated with a new coronavirus of probable bat origin the digestive system is a potential route of -ncov infection: a bioinformatics analysis based on single-cell transcriptomes clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china osteonecrosis of hip and knee in patients with severe acute respiratory syndrome treated with steroids factors associated with transmission of severe acute respiratory syndrome among health-care workers in singapore which preventive measures might protect health care workers from sars? detection of airborne severe acute respiratory syndrome (sars) coronavirus and environmental contamination in sars outbreak units aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review clinical management and infection control of sars: lessons learned ventilation of wards and nosocomial outbreak of severe acute respiratory syndrome among healthcare workers investigation of a nosocomial outbreak of severe acute respiratory syndrome (sars) in toronto, canada transmission of sars to healthcare workers. the experience of a hong kong icu effect of high-flow nasal cannula oxygen therapy in adults with acute hypoxemic respiratory failure: a meta-analysis of randomized controlled trials transmission of severe acute respiratory syndrome during intubation and mechanical ventilation high-flow nasal therapy in adults with severe acute respiratory infection: a cohort study in patients with influenza a/h n v factors associated with nosocomial sars-cov transmission among healthcare workers in hanoi can breathing circuit filters help prevent the spread of influenza a (h n ) virus from intubated patients? influence of residency training on multiple attempts at endotracheal intubation mechanical ventilation in an airborne epidemic videolaryngoscopy versus direct laryngoscopy for adult patients requiring tracheal intubation possible sars coronavirus transmission during cardiopulmonary resuscitation clinical review: sars -lessons in disaster management report of the select committee to inquire into the handling of the severe acute respiratory syndrome outbreak by the government and the hospital authority expanding icu facilities in an epidemic: recommendations based on experience from the sars epidemic in hong kong and singapore augmentation of hospital critical care capacity after bioterrorist attacks or epidemics: recommendations of the working group on emergency mass critical care critical care triage. recommendations and standard operating procedures for intensive care unit and hospital preparations for an influenza epidemic or mass disaster triage: care of the critically ill and injured during pandemics and disasters: chest consensus statement key: cord- -g q gpp authors: nan title: neurocritical care society th annual meeting date: - - journal: neurocrit care doi: . /s - - - sha: doc_id: cord_uid: g q gpp nan eighty-five patients were enrolled, underwent therapeutic hypothermia, and had a poor outcome. baseline characteristics did not differ between groups, except for the use of sedatives: % of hypothermia versus % of normothermia patients (p= . ). corneal reflex, motor response and neuron specific enolase (nse), performed sub optimally in both the hypothermia and normothermia groups. however, all predictors accurately predicted poor outcome (fpr %) in patients without sedation regardless of whether they received hypothermia *numbers indicate percentages ( % ci). ‡ data not available for all patients. sedation is a confounder in the prognostication of comatose survivors after cpr. patients treated with hypothermia are more likely to receive sedation in proximity of their -hour neurological examination. hypothermia did not affect the accuracy of predictors of poor neurological outcome in this limited data set. methods: continuous eegs performed in a pediatric icu were transformed into -channel cdsa and aeeg displays. neurophysiologists and eeg technologists were trained to identify seizures using cdsa and aeeg. participants were then presented with only the cdsa or aeeg displays and asked to mark events that they suspected to be seizures. their performance was compared to seizures previously identified using the conventional - channel eeg recording. the eeg recordings contained discrete seizures over hours. the sensitivity for seizure identification and false-positive rates across all recordings are shown below. values are median (range). false-positive rate (# / hour) sensitivity (%) false-positive rate (# / hour) . ( . - . ) . ( . - . ) . ( . - . ) . ( . - . ) for individual recordings, however, the median sensitivity for seizure identification varied from % to %, and the median false-positive rate varied from /hour to . /hour. factors reducing the sensitivity included focal and low amplitude seizures. factors increasing the false-positive rate included movement and electrode artifacts, and non-ictal eeg waveforms such as periodic epileptiform discharges and a burst-suppression pattern. cdsa and aeeg are equally sensitive and specific tools for seizure identification among critically ill children. their performance is likely even better in a clinical context, when reviewers have access to the underlying raw eeg. these findings support the use of cdsa and aeeg as screening tools, with the caveat that low amplitude and focal seizures are liable to be missed using these techniques. intermountain medical center, salt lake city, utah, united states, johns hopkins hospital, baltimore, md, united states recent studies suggest that glucose variability is an important predictor for mortality in a mixed critically ill population, however, the relationship of glucose variability with sich remains ill defined. we sought to evaluate the relationship between glucose variability on in-hospital mortality during the acute phase of sich. we performed a retrospective chart review of consecutively admitted patients with sich with a minimum of glucose readings during the first -icu days. data extracted included: patient characteristics, clinical features, glucose values/insulin use, and outcomes. blood glucose indices assessed over the days included: average glucose levels (glucavg), standard deviation of glucose (glucsd), coefficient of variance (gluccv), and peak glucose (glucmax). statistical assessment of the glucose indices was assessed in relationship to in-hospital mortality. there were a total of glucose readings in patients with an overall mortality of %. univariate analysis showed the only significant baseline patient characteristics were lower admission gcs and higher apache ii in the nonsurvival group. admission glucose ( ± vs. ± ; p= . ), glucavg ( ± vs. ± ; p= . ), glucsd ( ± vs. ± ; p< . ), gluccv ( ± vs. ± ; p= . ), and glucmax ( ± vs. ± ; p= . ) were significantly higher in the nonsurvival compared to the survival group (mg/dl, respectively). logistic regression analysis showed that significant predictors for in-hospital survival include admission gcs (or . ; % ci . - . ; p< . ), glucsd (or . ; % ci . - . ; p< . ), and gluccv (or . ; % ci . - . ; p= . ). findings from this study suggest that a large variability of glucose during the acute phase of sich is associated with higher in-hospital mortality. the variability appears to be a more important predictor for outcomes than admission glucose or average glucose levels. the proportion of deaths was higher among patients in the intensive arm but this was not statistically significant ( % vs. %, p= . ). when good versus poor outcome at months was dichotomized to mrs score - versus - , respectively, there was no difference in outcome between the two groups ( . % vs. % had a poor three month outcome, p = . ). there was also no difference in icu or hospital los or days on mechanical ventilation. hypoglycemia (< mg/dl) and severe hypoglycemia (< mg/dl) was more common in the intensive arm ( % vs. %, p= . ) and ( % vs %), respectively. there was no benefit to intensive insulin therapy in this small critically ill neurologic population. previous studies of glycemic control in non-neurologic icu patients have shown conflicting results. this is the first glycemic control study specifically examining critically ill neurologic patients and functional outcome. given these results and the increased resources required to implement intensive insulin therapy, it cannot be recommended over conventional control. to improve organ donation conversion rates, neurointensivists at a level ii trauma, community hospital and the local organ procurement organization (opo) decided to diminish decoupling. decoupling is when the explanation of brain death by the physician is separated from the request for organ donation by the family support coordinator (fsc). the fsc is not present for the final explanation of declaration of brain death and the physician familiar to the family, typically, is not present for the request. we were concerned that in the transition of physician to fsc, conversion was being lost. data was retrospectively reviewed from - when decoupling was still occurring and compared to data thus far from where the physician and fsc were present together for both the final explanation of brain death (by physician) and request for organ donation (by fsc). we also compared data from two similar local hospitals that have not changed decoupling. all first person consent donors were removed from the data. in - , our hospital's conversion rate of eligible to actual donors was % and % respectively. in the first six months of , where decoupling was diminished, the conversion rate was %. the conversion rates for two other local hospitals of similar potential and patient mix were % ( ), % ( ) , and % ( ) (community based hospital); and % ( ), % ( ) , and % ( ) (university based hospital). the presence of the physician familiar to the family during the organ donation request may enhance organ donation conversion in non-first consent potential donors. physicians should consider working with the opo and fsc to try this process especially if conversion rates for organ donation are low. previous studies suggest that dynamic autoregulation in the posterior cerebral artery (pca) is less efficient compared to the middle cerebral artery (mca). we examined the role of cerebral vasodilation due to metabolic activation (i.e. visual stimulus) on autoregulatory characteristics in the two vascular territories. blood flow velocity (bfv) in the pca and mca and mean arterial pressure (map) were measured continuously in healthy volunteers ( ± years) while seated with eyes open. additional subjects ( ± years) were examined with eyes closed and open. cerebrovascular resistance index (cvr i ) was calculated as the ratio of map to mean bfv in the pca and mca arterial territories. autoregulation was assessed using transfer function gains in both the pca and mca territories in the low ( . - . hz), high ( . - . hz) and cardiac (~ hz) frequency ranges. the effects of vascular territory (pca vs. mca) or visual activation (eyes-closed vs. eyes-open) on bfv, map, endtidal co , cvr i , and transfer function coherence, gains, and phases were assessed by using a repeated-measures two-way anova, respectively. with eyes open, gains were significantly higher in the pca compared to the mca in the low (pca: . ± . vs. mca: . ± . , p= . ) and high (pca: . ± . vs. mca: . ± . , p= . ) frequencies. opening eyes increased bfv and reduced cerebrovascular resistance index in the pca but not mca. this vasodilation in the pca was associated with increased gain in the low (autoregulatory) frequency while mca gain did not change (pca: . ± . vs. . ± . , mca: . ± . vs. . ± . , p= . ). dilation of the pca territory during visual cortex activation resulted in increased pca transfer function gain without changing mca gain. thus, impaired autoregulation in the pca reported in previous literature is likely the result of metabolic vasodilation and not an inherent difference in the autoregulatory characteristics of the posterior circulation. various scales have been devised for the prediction of vasospasm following aneurysmal rupture. all such tools require the measurement of sah burden by computed tomography to predict the likelihood of symptomatic vasospasm. especially prominent in these scales is their reliance upon a subjective assessment of clot thickness which allows for variability in grading across raters. the current study seeks to compare the inter-rater reliability of the fisher and newer frontera scales when a rigid definition of thick clot is used. cases of subarachnoid hemorrhage were randomly selected from our radiographic archives. initial head cts were independently reviewed by two raters and a score for both the fisher and frontera scale was assigned to each study. the following criteria were established to characterize thick clot: . hemorrhage in any major cistern appearing on two contiguous slices; . hemorrhage occupying > % of any major cistern on a single cut; . contiguous hemorrhage with a density approximating that of bone. hemorrhage was scored as "thick" if any two of the three criteria were met. the degree of agreement in scores between raters was then assessed by way of the spearman's rho and cohen's kappa for inter-rater reliability. for both the fisher and frontera scales, a high degree of inter-rater reliability was demonstrated with rho values of . (p=. ) and . (p. ) respectively. when cohen's kappa was employed, respective values of . and . were obtained. these kappa values, which reflect the use of a stringent definition for thick subarachnoid hemorrhage, were stronger than those previously reported by ah. kramer et.al. with the use of a stringent definition for thick subarachnoid hemorrhage, an assessment of subarachnoid clot burden can be made that shows a high degree of reliability across observers. although ventilator-associated pneumonia (vap) carries significant mortality there is scarce data on vap in the neurosurgical intensive care unit (nsicu). we sought to determine the clinical factors associated with vap in the nsicu. we analyzed all admissions to the nsicu requiring mechanical ventilation for at least hours to determine factors associated with vap. we collected demographics, medical history, admission diagnosis, admission glasgow and four coma scale, tracheostomy need, ventilator days, length of stay, and mortality. for statistical analysis we performed fishers exact test (categorical variables) and students t-test (continuous variables). we used the centers for disease control vap definition. we analyzed admissions to the nsicu over one year. the sample was comprised of males and females with a median age of ( - ). the median gcs was ( - ) and the median four scale was ( - ). the median length of stay was days . diagnosis included subarachnoid hemorrhage ( %), head trauma, ( %) intracranial hemorrhage ( %), subdural hematoma ( %), spinal cord injury ( %), neoplasms ( %), and others ( %). the incidence of vap was . %. mortality was significantly higher (p < . ) among patients with vap ( %) than in non-vap patients ( %). there was no difference in clinical risk factors, admission diagnosis, and need for tracheostomy. the mean age of vap patients was and that of non-vap patients was . age < was associated with vap (p< . ). the only clinical variables associated with vap were mechanical ventilation for > days and four score < (p = . and . respectively). in the nsicu vap is frequent and carries significant mortality. duration of mechanical ventilation and four coma score predict vap. poster blood pressure decreases due to general anesthesia for intra-arterial therapy for acute ischemic stroke are associated with decreased functional relative hypotension after large vessel stroke is associated with poor outcome. general anesthesia (ga) causes peripheral vasodilation and cardiac depression, leading to a decrease in systemic blood pressure. in initial analysis of the merci registry-a prospective, uncontrolled cohort of patients treated with the merci retriever-functional outcome after stroke was worse in those patients intubated for the procedure as compared with those in whom conscious sedation or deep sedation was performed. we hypothesized that the poor functional outcomes in intubated patients resulted from decreased systemic blood pressure. the study population consisted of all patients enrolled at our institution in the merci registry from october to july . during the study period, all ia stroke interventions were performed under ga. data regarding demographics, stroke severity (nihss on presentation), recanalization (tici grade), and functional outcome at days (modified rankin scale; mrs) were prospectively collected. we retrospectively reviewed the blood pressures on presentation, prior to intubation and after intubation. : patients were identified; of these, had adequate records of blood pressure before and after intubation as well as day follow-up assessments. the average age was and % were male. compared with pre-intubation baseline, significant reductions in sbp ( . vs . , p<. ) and map ( . vs . , p<. ) were observed following intubation. controlling for well established predictors of outcome (nihss, age, location of vessel occlusion, and recanalization), the first sbp and dbp recorded immediately after intubation were significantly correlated with mrs (p= . , p= . ) with lower measurements associated with poor functional outcomes. blood pressure declined significantly as a result of general anesthesia, and lower sbp and dbp following intubation were associated with worse functional outcomes. these findings suggest that blood pressure should be aggressively supported in acute stroke patients treated undergoing ia mechanical thrombectomy. posttraumatic vasospasm (ptv) is an under-recognized cause of ischemic damage following traumatic brain injury (tbi), but little is known about its pathogenesis and risk factors. although ptv significantly differs from aneurysmal vasospasm [ , ] , it shares certain characteristics [ ] [ ] [ ] [ ] that may provide insight into its pathogenesis. in particular, the risk of aneurysmal vasospasm is increased in patients with fever [ ] [ ] [ ] [ ] [ ] [ ] or leukocytosis [ - ], but these relationships have not been previously explored in ptv. a review of consecutive patients with tbi yielded patients with severe tbi that survived beyond hours. eight patients developed clinically significant posttraumatic vasospasm (csptv), defined as unexplained decline in neurological function or brain tissue oxygenation with ct angiogram evidence of arterial vasospasm. temperature and serum leukocyte counts were compared in severe tbi patients with and without ptv. admission temperature was significantly higher in patients that developed csptv ( . . ºc vs. . . ºc, p= . ), and fever on admission (t> ºc) was associated with significantly increased likelihood of vasospasm (or= . ). csptv did not occur in patients with hypothermia (t< ºc) on admission, while % of those with fever (t> ºc) developed csptv. admission leukocyte count was significantly higher in patients that developed csptv ( . . k/mm vs. . . k/mm , p= . ). . % of patients with leukocytosis on admission (wbc> k/mm ) developed csptv, compared to . % of patients without leukocytosis. hyperthermia on admission correlates with increased likelihood of developing clinically significant ptv. serum leukocyte count on admission is higher in patients who subsequently develop csptv, suggesting that activation of inflammatory pathways and/or early infection may be involved in the pathogenesis of vasospasm. the observation that csptv did not occur in patients with admission temperatures below ºc suggests a possible protective role for early hypothermia. subarachnoid hemorrhage (sah) frequently causes stunned myocardium (sm). the predictors of sm and its impact on clinical course and outcome are not fully defined. we evaluated consecutive sah patients enrolled in the sah outcomes project from february -june . patients were excluded due to history of cardiac disease, were excluded due to non-aneurysmal sah. sm was defined as wall motion abnormalities +/-elevated troponins. demographic, clinical, and outcome data was compared between those with and without sm. results: % (n= ) of patients were hunt & hess (hh) grade - . modified fisher score was >= in % (n= ). sm was diagnosed in % (n= ). on univariate analyses, sm was associated with loss of consciousness (loc) at onset, hh grade, hijdra score, posterior aneurysm location, female gender, tobacco non-use, bmi, ivh, systolic bp, heart rate (hr), glucose, and wbc count. in a logistic regression accounting for race and age, female gender (p= . ), loc at onset (p< . ), posterior aneurysm location (p= . ), hr (p= . ), systolic bp (p= . ), hh grade (p< . ) & tobacco non-history (p= . ) were independent predictors of sm. sm was associated with in-hospital development of fever, hyperglycemia, pneumonia, anemia, seizures, global cerebral edema (gce), sodium dysregulation, and arrhythmia. after accounting for age & gender, arrhythmia (p< . ), fever (p= . ), and gce (p< . ) were independently associated with sm. after adjusting for gender, age and known risk factors for poor outcome, sm was an independent predictor of mrs > and death at months. chronic brain atrophy is regionally specific and is regionally associated with reductions in oxidative brain metabolism but not ischemia. the temporal lobe exhibit the greatest extent of atrophy, which may be related to the extent of initial trauma. leão's spreading depression (sd) of electrocorticographic (ecog) activity describes a propagating wave of neuronal/astroglial depolarization in cerebral grey matter. sd occurring in normally perfused cortex may be benign, but similar peri-infarct depolarizations (pid) cause ischemic lesion growth. here we present results of a pilot study to determine the association of depolarizations with clinical outcome in traumatic brain injury (tbi). at five hospitals, subdural electrode strips were placed in patients who required craniotomy for surgical management of tbi. sd and pid events were identified by criteria of fabricius et al. (brain : - , ) in ecog recordings made during intensive care for a median duration of hr. six-month egos scores were dichotomized to good ( - ; n= ) and poor ( - ; n= ) outcomes. in / ( %) patients, depolarizations occurred. of these, were sd type, were pid, and were mixed. the proportion of poor outcomes was % ( / ) in patients with no depolarizations, compared to % ( / ) in patients with sd and % ( / ) for patients with pid. the occurrence of pid and either type of depolarization were both significantly associated with worse outcomes (fisher exact test, p= . and , p= . , resp.), while sd alone was not ( , p= . ). there was no association of pupil reactivity ( , p= . ), gcs motor score ( , p= . ), pre-hospital hypotension ( , p= . ), or subarachnoid hemorrhage ( , p= . ) with outcome. ages of patients with good ( ± s.d.) vs. poor ( ± ) outcome did not significantly differ (p= . ). these data suggest that depolarization activity is significantly associated with poor outcome, with predictive power at least as great as established outcome predictors. prevention of depolarizations by pharmacologic or physiologic therapy may represent a novel strategy to improve tbi outcomes. an increased sample size is required for improved statistical power and to determine the independence of depolarizations from co-variates. introduction: vasospasm (vs) represents a substantial source of morbidity and mortality in patients with subarachnoid hemorrhage (sah). transcranial ultrasound (tcus) velocities indicating vs in the anterior cerebral artery (aca) are not well established. the purpose of this study is to identify aca velocities that correlate to ipsilateral aca infarction. the aca mean velocities of consecutive sah patients undergoing routine twice daily tcus were prospectively collected. the maximum (max), minimum (min), and first (fir) mean velocity value for each vessel was determined, as were the ratios for max/min and max/fir. this process was performed for the entire group, and then for only patients having at least days of readings. determination of aca territory infarction was made by evaluation of serial head ct scans performed up to day following the ictus. velocity comparisons were made between patients having and those not having aca territory infarctions on ct. for the entire group, data was available for vessels, of which had associated infarction. max velocity was somewhat greater in patients with aca infarctions ( cms/s vs cms/s, p=. ), and min velocities were substantially greater ( cms/s vs cms/s, p=. ). the group having at least days of tcus constituted vessels, of which had associated infarction. max velocity was again somewhat greater ( cms/s vs cms/s, p=. ) and min velocity was again significantly greater ( cms/s vs cms/s, p=. ). no correlation was observed for fir, max/min, or max/fir. patients ultimately developing aca infarctions have greater min velocities and tend to have greater max velocities. since only the use of max velocities is practical, our findings suggest that velocities between - cms/s may identify those vessels at risk for infarction, which is consistent with the available literature. cerebral infarction following subarachnoid hemorrhage (sah) contributes to morbidity and mortality. vasospasm (vs) has traditionally been considered the main cause, yet recent literature suggests other potential etiologies. anterior cerebral artery (aca) infarctions may result in permanent deficits of intellect and behavior. the purpose of this study is to document the prevalence of aca infarctions and to characterize the etiology of these infarctions in patients with aneurysmal sah. consecutive sah patients underwent review of cerebral ct scans as close to weeks after the ictus as possible so as to identify sah related aca infarctions. earlier scans were reviewed in patients found to have aca infarctions to determine the timing of the infarction. vs related infarctions were defined as those beginning at least days after the ictus. infarcts occurring less than days after the ictus were considered to be non-vs related. imaging was available for patients ( aca territories). overall, . % of patients developed aca infarctions in . % of aca territories. of these, only . % of patients and . % of territorial infarcts were deemed likely due to vasospasm. most aca infarct patients ( %) had aca/acomm aneurysm ruptures. of patients with aca infarction and aca/acomm aneurysms, % had infarcts within the first days (p=. ). all bilateral aca infarctions with aca/acomm aneurysms had infarctions within days of the ictus. aca infarctions are not rare in patients with sah. patients with aca/acomm aneurysms were more likely to have aca infarcts in the acute phase, prior to the usual onset of vs. the etiology of these infarctions remains to be determined, but may be related to vessel thrombosis at the time of hemorrhage, procedural/operative complications, or early vs. telemedicine holds promise as a technology-intensive method of providing rapid acute neurology expertise to local hospitals with available ct scanning, and has been proposed as a way to increase access to limited specialty expertise in a cost-effective manner. we here report the experience of a multi-state telemedicine company, working in joint effort with academic hospitals, providing acute neurological consultations to community-based hospitals. specialists on call (soc) is a california-based telemedicine company providing / specialist physicians consultations to urban, suburban and critical access hospitals via videoconferencing technology. neurological consultations are conducted by board-certified neurologists. consults requests are responded within minutes. initially, the specialists discusses the case by telephone and in a second step, the video-conference is started. teleneurological exam is conducted following established and validated guidelines, especially for nihss. recommendations and further steps are discussed with patients, family members and consulting physician. between january and may , a total of teleneurology consults were performed, among community hospitals in states. only hospitals had over beds ( and ), the rest ranged between and beds. stroke was the diagnosis in cases ( . %), of which ( %) were acute ischemic events (aie) (stroke or tia) and ( %), intracranial hemorrhages. ( . % of aie) received thrombolytic therapy with intravenous tpa. seizure was the diagnosis in patients ( . % of the total) and other diagnosis (including headache, dizziness, vertigo and chronic pain) in ( . %) patients. telestroke consultation can be useful in increasing the use of intravenous tpa at community hospitals without access to adequate on-site stroke expertise. besides thrombolytic decisions, teleconsultation can improve the care of other neurocritical conditions, including seizures, or intracerebral hemorrhage and triage to centers with neurocritical-care capability. increased intracranial pressure (icp) is associated with poor outcome in acute brain injury. in this study we examined how episodes of increased icp (> mmhg; > minutes) affected brain metabolism. twenty-one patients (mean age . + . years) with severe brain injury (gcs< ) were studied prospectively. lactate, pyruvate, and glucose were measured each hour using cerebral microdialysis (cma). brain oxygen (pbto ), mean arterial pressure (map), icp and cerebral perfusion pressure (cpp) were recorded continuously. linear mixed effects models were used to examine the relationship between episodes of increased icp and the lactate:pyruvate ratio (lpr). there were episodes of increased icp, episodes of compromised pbto (< mmhg) and episodes of brain hypoxia (pbto < mmhg). median icp ( % - % iqr) was greater during brain hypoxia ( . [ . ] vs. . [ . ]; p < . ). gee models indicated that icp > mmhg was associated with more than double the odds of brain hypoxia (or= . ; % ci: . , . , p= . ) or compromised pbto (or= . ; % ci: . , . , p= . ). however the frequency of increased icp (> mmhg) was similar among patients with compromised pbto (p= . ) or brain hypoxia (p= . ) compared to normal pbto . only half the patients with brain hypoxia had increased icp. elevated lpr (> ) was rare (n= [ . %] of icp episodes). median lpr ( % - % iqr) was greater during episodes of brain hypoxia than normal pbto ( . ( . ) vs. . ( . ), p< . ) and only slightly greater in episodes with compromised pbto compared to corresponding episodes with normal pbto ( . ( . ) vs. . ( . ), p= . ). lpr did not increase when icp was > mmhg. evidence for brain energy dysfunction is very rare when icp is > mmhg and any icp effect on lpr may be indirect and depend on pbto . rafael badenes, pablo gonzalez, laura alcover, armando maruenda, javier belda hospital clinico universitario, valencia, spain this was a pilot study to compare the cerebral neurochemical changes in patients with traumatic brain injury (tbi) who underwent conventional blood glucose level (bgl) control and intensive bgl control with continuous titrated insulin. this prospective, randomized study was conducted in traumatic brain injury patients in a surgical and trauma intensive care unit. patients admitted over an -month period with tbi were prospectively divided into two groups according to the method used for bgl control: the 'intensive' group consisted of patients who underwent continuous titrated insulin infusion to maintain a lower normoglycemic level of - mmol/l, and the 'conventional' group consisted of patients whose bgl was maintained at between . and . mmol/l using conventional 'sliding scale' bolus subcutaneous insulin administration. data on cerebral haemodynamics, interstitial brain oxygenation (ptio( )) and neurochemical monitoring were collected via microcatheters inserted in the penumbral region. we analyzed cerebral microdialysis samples. in patients treated with intensive insulin therapy, there was a reduction in microdialysis glucose by % of baseline concentration compared with a % reduction in patients treated with a conventional blood glucose level control. intensive insulin therapy was associated with increased incidence of microdialysis markers of cellular distress, elevated glutamate ( +/- % vs. +/- %, p<. ), elevated lactate/pyruvate ratio ( +/- % vs. +/- %, p<. ) and low glucose ( +/- % vs. +/- %, p<. ), and increased global oxygen extraction fraction. cerebral microdialysis glucose was lower in nonsurvivors than in survivors ( . +/- . vs. . +/- . mmol/l, p < . ). intensive glycaemic control using insulin induced a decrease of cerebral glucose and an increase in microdialysis markers of cellular distress. in patients with severe brain injury, tight systemic glucose control is associated with increased mortality. brain tissue oxygen (bto ) monitoring is used in severe traumatic brain injury (tbi) patients. how cerebral hypoxia should be treated and its response to treatment is not clearly defined. we examined which medical therapies restore normal bto in tbi patients. severe tbi (gcs less than ) patients were enrolled in a prospective observational cohort study. intracranial pressure (icp), cerebral perfusion pressure (cpp) and bto were monitored. episodes of cerebral hypoxia (bto less than mmhg) and medical interventions and therapies that improved bto were identified. three hundred seventy nine episodes of cerebral hypoxia were recorded and treated in forty nine patients (mean age +/- years). medical management successfully reversed % of the cerebral hypoxia episodes. ventilator manipulation, cpp augmentation, and sedation were the most frequent interventions. increasing fio restored bto % of the time. cpp augmentation and sedation were effective in % and % cerebral hypoxia episodes, respectively. icp reduction using mannitol was effective in % of treated episodes. phenylephrine was the most frequent vasopressor administered and improved bto % of the time. other interventions including head repositioning, airway suctioning, and blood transfusions, were effective in %, %, and % treated episodes, respectively. successful medical treatment of cerebral hypoxia was associated with improved outcome. survivors had a % rate of response to treatment (n= ) and nonsurvivors had a % rate of response (n= ; p= . ). cerebral hypoxia occurs in tbi patients despite traditional practices to maintain cpp. medical interventions other than those to treat icp and cpp can improve bto , increasing the number of therapies for severe tbi in the icu. poster intravenous dantrolene for the treatment of cerebral vasospasm after subarachnoid hemorrhage -final results of a prospective phase i cerebral vasospasm (cvsp) after subarachnoid hemorrhage (sah) is the major cause of disability and death. treatment options are limited. dantrolene blocks ryanodine receptor-mediated intracellular calcium release from the sarco-endoplasmic reticulum. it attenuates cerebral vasoconstriction, potentates the action of nimodipine on cerebral vessels and is neuroprotective in animal models. we performed a prospective phase i study examining the safety and effects of a single-dose of dantrolene on cvsp after sah. in an irb approved, prospective, open-label single-blinded phase i study, sah patients with elevated transcranial doppler (tcd) velocities and lindegaard indices suggesting cvsp were enrolled. after baseline tcds by a single, trained operator, patients receive a one-time infusion of dantrolene over minutes with dose escalation (first five patients . mg/kg, the following five patients . mg/kg). infusions, ventilator and ventriculostomy settings were kept unaltered, so that physiological data could be followed. hr, bp, icp, cpp, cvp and body temperature were recorded at infusion start (time ), every min during the infusion and with every tcd thereafter. serum abg, chem and osmolarity were measured at time and min, and lfts at time and hrs. tcds were repeated at , and min after time . statistical analysis was performed with repeated measures anova for the physiological values and change ( ) in systolic, mean and diastolic tcd in the vessel in cvsp from time , followed by post-test bonferroni's multiple comparison test with bonferroni p-value adjustment for significant findings. laboratory values were analyzed by wilcoxon matched pairs test. ten patients (n= each group with . mg/kg and . mg/kg dantrolene) were enrolled. over the entire study period, hr, map, dbp, icp, cpp and body temperature remained stable, except for sbp which decreased (p= . ). posttest bonferroni's multiple comparison test with p-value adjustment (p= . ) showed a trend towards a difference between time points and min (mean - . mmhg), and and min (mean - . mmhg), although this was not significant. significantly different laboratory changes were na (mean - . meq/l, p= . ), cl (mean - . meq/l, p= . ) and alkaline phosphatase (mean - . mg/dl, p= . ); the degree of change, however, was considered clinically insignificant. none of the other laboratory values changed. systolic and mean tcd velocities decreased significantly over time compared to time (systolic p= . ; diastolic p= . ; mean p= . ). post-anova linear trend testing indicates the magnitude of change: systolic (slope - . , p= . ); diastolic (slope - . , p= . ) and mean tcd (slope - . , p= . ). a one-time infusion of dantrolene appears safe, although the mild changes in na, cl and alkaline phosphatase warrant monitoring. most importantly, transaminases did not change. dantrolene decreases tcd velocities over time, presumably due to inhibition of cerebral vasoconstriction. we have insufficient data to comment on the duration of this effect. our results warrant further study with repeated or continuous dantrolene dosing for treatment or prevention of cvsp after sah or other vasoconstriction syndromes. status epilepticus carries a mortality rate up to %. newer, intravenously (iv) applicable antiepileptic agents might be powerful adjunctive therapies. we report our experiences with iv levetiracetam in a prospective patient cohort with status epilepticus. we treated patients with convulsive status epilepticus with an institutional protocol consisting of iv lorazepam followed by iv phenytoin, iv levetiracetam as third line agent or second line agent if there were contraindications for iv phenytoin, and iv propofol and/or midazolam as fourth line agents. primary outcome was treatment success of iv levetiracetam. secondary outcome measures were time to treatment success, modified rankin scale (mrs) at and months, and complications. of the patients had cerebral structural abnormalities, an infection, and hyponatremia as underlying etiology for status epilepticus. median age was (range - ) years, patients were male. baseline gcs was ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . levetiracetam successfully treated status epilepticus in patients. median time to treatment success was ( - ) minutes in all patients. at months patients had died, support had been actively withdrawn in patients. the mrs was in patients, in patients, in patient, in patients, in patients and in patients. at months, patient with a mrs of had progressed to . the most common complications included hyperglycemia ( %), hypotension ( %), acute renal failure ( %), anemia ( %), thrombocytopenia ( %), urinary tract infection ( %), and seizure recurrence ( %). levetiracetam offers a feasible alternative strategy to break status epilepticus as adjunctive third line therapy in a paucity of patients before administration of sedatives with a broad spectrum of adverse effects and needs to be studied in a standardized trial. stroke is the third leading cause of death in industrialized nations.the treatment pathway for ischemia is often determined by assessing the extent of permanent damage aided by imaging modalities such as mri.diffusion weighted imaging (dwi) is an accepted mri technique that is sensitive to water diffusion.the restriction of water in damaged cells is used as a surrogate measure of cell death.although cells may have taken on water,this surrogate measure may be inaccurate,frequently leading to overestimation of the severity of ischemia.measures of sodium are reported to be more accurate indicators of cell death and can also be used to determine stroke onset time because of a linear relationship between ischemia and sodium concentration.we have developed a multinuclear coil and radiofrequency current source that permit simultaneous high-speed proton and sodium imaging so that treatable ischemia can be better ascertained. an -channel,broadband,radiofrequency,phased array and current source were built enabling targeted,accelerated,and simultaneous spectroscopic imaging of water,helium,and sodium on a . t ge mr scanner.it was tested on phantoms of known sodium and water concentrations and in rats with known inhaled helium concentrations. high quality imaging of protons and sodium in phantom models of known sodium concentration were obtained.additionally, high quality helium imaging in rats demonstrated the ability of the system to image other nuclei and proved the quantitative and qualitative imaging capabilities of the array in vivo. mars imaging provides a new, simultaneous multinuclear approach to determine the extent of ischemia quickly and quantitatively.high quality images with this system can be obtained in humans with the same hardware and can be used with standard . t mr scanners. septic shock is often associated with relative vasopressin (avp) deficiency that may be related to impaired avp synthesis and release by the neurohypophyseal system, which includes the neurohypophysis and magnollecular neurons of the paraventricular and supraoptic nuclei. neurohypophyseal system has never been assessed in human septic shock and only partially in experimental sepsis. we investigated avp synthesis and release by the neurohypophyseal system in septic rats and in human septic shock. design: ex vivo human and animal study. setting: university research laboratory in the human study, post-mortem examination of the neurohypophyseal system was performed in patients who died from septic shock (n= ) or other causes (n= ). in the experimental study, sepsis was induced by fecal peritonitis in conscious, fluid-resuscitated male adult wistar rats. rats either early died spontaneously from septic shock in average at hours (septic early death, n= ) or were sacrificed in average hours after induction of sepsis (septic, n= ). post-mortem examination was performed in both groups. comparisons were made against sham operation controls (n= ). avp protein and mrna were assessed by immunohistochemistry and in-situ hybridization. in both septic shock patients and septic rats with early death, the avp content in the neurohypophyseal and supraoptic magnocellular neurones was decreased while it was increased in the paraventricular magnocellular neurones. no significant change was observed in avp mrna expression in either paraventricular or supraoptic magnocellular cells. in septic shock, avp post-transcriptional synthesis and transport are altered in the supraoptic and paraventricular magnocellular neurones, respectively. this suggests that supraoptic and paraventricular nuclei are liable to distinct pathogenic mechanisms, which may account for relative avp deficiency. introduction: dual brain death (dbd) examination has been historically followed to determine irreversible brain damage. a policy was introduced in our hospital to utilize single brain death examination (sbd) including an apnoea test and a confirmatory test for cerebral blood flow in patients with catastrophic neurological injuries to determine brain death. we investigated if organ procurement would be affected by sbd. the database of gift of life (the designated organ recovery organization for michigan), was screened for our institution patients meeting brain death criteria between jan and july . for each patient, age, sex, primary cause of mortality, number of brain death examinations performed, type of confirmatory tests used to declare brain death, medical exclusions for organ donation and number of organs procured was obtained. continuous variables were analyzed using the student t-test and categorical variables using fischer's exact test with p values set at . . seventy patients met brain death criteria between january and july and were excluded due to incomplete records. there was no difference between the age and sex composition between the two groups. twenty seven patients were diagnosed with brain death using sbd while were diagnosed using dbd. twenty four patients with sbd and with dbd were eligible for organ donation (p= . ). each of eligible sbd and dbd patients donated organs (p= . ); organs were procured from each group (p= . ). single brain death examination did not preclude the rate of organ donation in our patient cohort. dual brain death examination can be substituted by a single brain death examination along with a confirmatory test for cerebral blood flow in patients with catastrophic neurological injuries without affecting the rate of organ donation. this may result in a less time delay before declaring death and minimize physician workload. etiologies for spontaneous intracerebral hemorrhage (ich) or intraventricular hemorrhage (ivh) vary. mri can often identify underlying vascular lesions, but conventional catheter angiography remains the gold standard. guidelines for the use of catheter angiography are non-specific. we aimed to determine the diagnostic yield of catheter angiography in addition to mri in patients with ich or ivh who met pre-defined criteria. consecutive patients with spontaneous ich or ivh were enrolled. in addition to non-contrast brain ct and laboratory testing, all patients underwent gadolinium enhanced mri/mra. catheter angiography was pursued if the following criteria were met: . lobar ich or isolated ivh and age years or . deep ich and no history of hypertension and age years or . any other indication based on the opinion of the treating neurointensivist. of prospectively enrolled patients, ( %) met criteria for catheter angiography. seven were excluded from angiography because a definitive ich cause was established by mri and because of a coagulopathy explaining the ich. forty-four ( %) patients underwent catheter angiography, which identified the ich etiology in ( %). in of these, the diagnosis was already suspected based on mri, but in cases catheter angiography increased the diagnostic confidence. in one patient a small avm was diagnosed by angiography alone. thirteen patients ( %) had both contrast angiography and pathology. of these, had a vascular abnormality as the cause of the ich. five of these were diagnosed by angiography. in one patient the pathology showed an avm while the angiogram and the mri were negative. two patients with cavernous malformations were diagnosed by mri alone. the diagnostic yield of catheter angiography in spontaneous ich or ivh is limited if patients also undergo gadolinium enhanced mri/mra. patients with anticoagulation-related intracerebral hemorrhage (ich) commonly are treated with fresh frozen plasma (ffp) for anticoagulation reversal. one risk of ffp is thought to be related to volume overload and pulmonary edema (ped). however, this has neither been validated, nor quantified compared with the natural risk following ich. we hypothesized that patients with anticoagulation-related ich are at higher risk of ped in-hospital, and that this increased risk would be related to dose of ffp used. retrospective review of a prospectively collected cohort of consecutive patients with primary ich presenting to a single center between august -may . of included patients, % were male, and mean age was +/- years. % were on warfarin at presentation, with a median inr of . (iqr . - . ). of these patients, % received ffp, at a median dose of (iqr - ) units. overall, patients ( . %) developed ped, at a median time of (iqr - ) days after presentation, and these patients showed a longer hospital length of stay [median (iqr - ) days vs. (iqr - ) days, p= . ]. anticoagulated patients were at higher risk of developing ped during hospitalization ( % vs. %, p= . ). patients receiving ffp were also at higher risk than those who did not ( % vs. %, p< . ). in multivariable analysis with a cox proportional hazards model, use of ffp was an independent predictor of developing ped (hr . per unit given, % ci . - . ), and the effect of warfarin fell out of the analysis when ffp was included. patients with anticoagulation-related ich are at increased risk of ped during hospitalization, accounted for by ffp use. each additional unit of ffp confers an approximately % increased risk of this complication. ventilator associated pneumonia (vap) is an infrequently studied morbidity in neurointensive care, despite high historical rates ranging from . to . infections per device days. in comparison, mean rates in medical icu's have been substantially lower: . - . . in our neurocritical care unit (nccu), vap incidence was initially near the national nosocomial infection surveillance (nnis) th percentile for neurosurgical icus ( . infections per ventilator days) necessitating an evidence-based performance improvement initiative to reduce vap rates. prospective surveillance study of vap incidence in a -bed nccu over a month period. vap rates were defined by national healthcare safety network (nhsn) criteria. interventions included an aggressive hand hygiene campaign, use of the ventilator bundle, oral care every hours, and introduction of the hi/lo endotracheal tube. ventilator bundle compliance was assessed. : patient days with a total of ventilator days were monitored. in september , concomitant to an acinetobacter outbreak, vap rates were infections per ventilator days. by january , hand hygiene compliance had increased from to % and rates were . following institution of frequent oral care in combination with the emphasized vap bundle, by may , rates had decreased to . at this point, all new intubations performed in the unit employed the hi/lo ett. by june , vap incidence decreased to . infections per ventilator days (< th nnis percentile). compliance with components of the ventilator bundle ranged from % to %. despite caring for patients at high risk of vap, concerted efforts with multiple evidence-based performance measures and interventions can significantly reduce the incidence of infection. feedback with compliance may be essential to maintain low vap rates. the use of hmg-coa reductase inhibitors (statins) has increased among subarachnoid hemorrhage (sah) patients for cerebral vasospasm prophylaxis. statins increase risk of myopathy, but additional factors may also be causative. myopathy rates in this group of critically ill patients are not well characterized. sah patients were prospectively entered into an institutional database; those with myopathy were retrospectively identified. serum creatine kinase (ck), aldolase (at time of suspected myopathy diagnosis), and catecholamines (at admission), muscle biopsy results, and medication administration records were evaluated. four ( . %) of aneurysmal sah patients treated between jan , through july , were newly diagnosed with myopathy. two were hunt/hess , and each: grade and . one was fisher , others were fisher . all had symptomatic hydrocephalus, were treated endovascularly with paralysis paraprocedurally, given simvastatin mg daily within hours of sah (none had prior statin use). all were insulin resistant, requiring high dose sliding scale insulin. two received steroids. all had elevated catecholamines. maximum ck levels (u/l) were , , , and , respectively. aldolase was checked and elevated in patients. the forth underwent muscle biopsy revealing necrotic fibers; this patient had the lowest maximum ck. the myopathy rate in this cohort is times higher than that reported in healthy patients treated with statins. since all sah patients did not receive statins, this rate is underestimated and much higher than reported in other trials evaluating statins in sah, assuming risk is solely attributable to statins. the contribution of other etiologic variables (critical illness, paralytic, steroid) is not clear, and potentially are additive. aldolase may be an additional means of identifying subclinical cases. these findings need to be confirmed and pathogenic factors better elucidated. neurocritical care is a relatively new discipline and its practitioners come from a variety of backgrounds. salaries are likely to differ based on primary appointment, geographic location, practice setting, and time spent on clinical effort. it is not known how many neurointensivists practice full-time critical care, and it is likely that many also have responsibilities as consultants, researchers and administrators. a survey will be emailed to all members of the neurocritical care society. information that will be collected regarding salary, icu directorship, primary appointment, practice setting, hospital type, geographic location, percent effort on clinical responsibilities, sources of income including salary incentives, patient population, board certification and subspecialty training, etc. the results will be reported at the meeting and compared to the previous survey done by the authors. the information gathered in this survey enhances the understanding of the current practice of neurocritical care throughout the united states. this data may be valuable to neurointensivists during contract negotiations, to hospital administrators trying to assess the feasibility of hiring a neurointensivist, and to neurologists-in-training as a way of generating interest in neurocritical care as a career choice. therapeutic hypothermia (th) is being implemented with an increase for multiple indications in the neuro-icu. the risk of developing renal dysfunction with th is thought to be low, but is not clearly defined in neurologic patients. retrospective chart review of prospectively identified patients. per institutional th protocol, patient's goal temperature was c. baseline serum creatinine (cr) level and creatinine clearance (crcl) were obtained and followed at least daily during th and rewarming. data was evaluated for changes in cr and crcl during and following th induction and any impact these changes had on treatment. thirty five patients received th (for post-cardiac arrest and intracranial pressure control related to subarachnoid haemorrhage, intracerebral haemorrhage or traumatic brain injury). maintenance of goal temperature varied from to hours. nine ( %) had an increase in cr and crcl within normal limits; of these, occurred following induction, occurred during th maintenance, and during rewarming. three ( %) patients had an elevation in cr above normal limits; all of these elevations arose after beginning rewarming, and none led to chronic renal failure. there was a direct relationship in the change in cr and crcl (p< . ). of the patients who had an abnormal change in cr, had an abnormal change in crcl. overall, % of the patients demonstrated some form of elevation in cr and decrease in crcl. no patient experienced clinically significant changes in renal function requiring changes in therapy. this cohort experienced changes in renal function that were not associated with clinical relevance. the majority of changes occurred during th or rewarming and were not chronic. any contribution of th induced muscle injury to cr changes would need to be assessed with future study. initial hematoma size, coagulopathy, and hypertension are recognized predictors of hematoma progression in intracerebral hemorrhage (ich). we aimed in our study to assess if the absolute number of wbc and/or increase in the wbc number within hours of progression can predict hematoma progression. data of consecutive patients with primary, supratentorial ich, admitted within h of onset were reviewed, identifying patients with progression (wp) and no progression (np). hematoma progression was defined as % increase of hematoma size, subsequent intraventricular bleeding or increase of the preexistent amount of intraventricular blood. we compared the two groups for demographic data, risk factors, admission neurological status, neurological deterioration occurence, and wbc, coagulation profile, and blood pressure (bp) at admission or within hours of hematoma progression, using univariate and multivariate analysis. we identified cases (np) and (wp). baseline variables were similar, except for the systolic bp that was higher in wp than in np group ( + mmhg versus + mmhg, p= . ). neither wbc at admission ( . + . x /mm versus . + . x /mm , p= . ) nor the variation of the wbc admission -within h of progression ( . + . x /mm versus . + . x /mm , p < . ) was significantly different between the np and wp groups. neurological deterioration and mortality were more frequent in the wp than np group ( % versus %, p< . ; % versus %, p= . respectively). logistic regression showed that the change in wbc from admission to within hours of progression and systolic bp were associated with hematoma progression (wald statistic . , p< . ; wald statistic . , p < . ). the variation of wbc within hours of progression and systolic bp seem to be independent predictors of hematoma progression. heparin-induced thrombocytopenia (hit) is a dreaded complication of heparin related products. we analyzed the risk factors and outcomes of subarachnoid hemorrhage (sah) patients in whom hit was suspected and either confirmed as present or absent by platelet factor (pf ) antibody test. all patients with presumed aneurysmal, non-traumatic sah and a pf test were identified through the massachusetts general hospital's research patient database. charts, laboratory values and images were analyzed retrospectively. we identified patients with sah who were tested for hit. of these patients, ( %) had a positive antibody test. there was no difference between mean platelet nadirs of hit+ and hit-patients, vs. th/mm , respectively. univariate analysis identified gender, magnesium prophylaxis, fisher group , clipping vs. coiling, presence of angiographic spasm, number of vasospasm treatments and day of hit testing as potential risk factors associated with hit. a multivariate analysis showed that female gender (or . , %ci . - . ), greater number of vasospasm treatments (or . , %ci . - . ), later day of hit testing (or . , % . - . ) increased the risk of hit and coiling reduced the risk compared to clipping (or . , %ci . - . ). those patients in whom hit was present had more infarcts on ct, longer icu and hospital stays and worse modified rankin scores on discharge. the presence of hit in sah has adverse consequences and is more likely in female patients, who have undergone aneurysm clipping and require more than one endovascular vasospasm treatment. coagulopathy-associated intracerebral hemorrhage (cich) leads to over % mortality and is associated with secondary thromboembolic (te) complications. rapid coagulopathy reversal improves cich outcome. activated factor viia (fviia) rapidly reverses coagulopathy and causes local hemostasis, but is associated increased te. we examine a large case series of cich patients treated with fviia to determine te rates in this population all cich patients are treated with standardized protocol with emergent intravenous vitamin k, fresh frozen plasma (ffp), and are eligible for fviia mcg/kg. we identified consecutive fviia-treated cich patients from database from - and identified patients. were excluded for no identifiable coagulopathy or fviia use for severe trauma. were analyzed. we collect data on diagnosis, coagulopathy etiology, history of ischemic heart disease (cad) and te. we examined the incidence of troponin elevation, ekg changes, symptomatic coronary ischemia, venous thrombosis, and stroke following fviia use. subjects had average age . years. over % had abnormal ekg on presentation. % fviia-treated cich patients had history of venous thrombosis (dvt) or pulmonary embolism (pe), % had cad, % had atrial fibrillation, and % stroke. troponin elevation above . ng/ml developed in % patients. only / patients developed clinically symptomatic cardiac ischemia. % developed dvt/pe, and / ( . %) developed ischemic stroke. there is a trend towards correlation of cad history with degree of troponin elevation (p= . ). coagulopathy-associated ich patients have high burden of prior ischemic heart disease and venous thromboembolism. though low level troponin elevations occur, incidence of fviia-related symptomatic cardiac ischemia, stroke, or venous thrombosis is low in fviia-treated cich patients. this low incidence justifies a prospective controlled study to evaluate risk versus benefit of fviia use for emergent coagulopathy reversal in cich. assessing neurological function is important in critical illness, but in sedated patients neurological examination is considered to be non interpretable. this prospective multicentre observational study assessed neurological responses in critically ill patients who required to be sedated with midazolam (± subfentanyl). their relationship with -day mortality and altered mental status (delirium or coma within three days after sedation discontinuation) was also assessed. daily neurological examination included the glasgow coma scale, the assessment to intensive care environment score (atice), eye position and movement, pupil size and response to light, corneal reflex, oculocephalic response, grimace to noxious stimuli and cough reflex. at awakening, mental status was assessed with using atice or confusion assessment method for the icu ( neurological examination is interpretable and may be useful for prediction of outcome of critically ill sedated patients. daniel evans , gail tudor , deborah cushing , jeffrey florman , david seder maine medical center, portland, me, united states, husson college, bangor, me, united states, we evaluated complication rates, outcomes, and the cost of care of patients with good-grade (hunt and hess grades i-iii) aneurismal subarachnoid hemorrhage (ggsah) admitted directly to an intermediate care unit (imc). retrospective chart review of all ggsah admitted to a tertiary referral center from to . we recorded demographics, vital signs, and pertinent aspects of the hospital course. a multivariate logistic regression model including hunt and hess grade was employed to evaluate for association between admission location and radiographic or clinical vasospasm or infarction. among ggsah admissions to imc or the intensive care unit (icu), mortality was . %. thirty-three grade i patients ( %), grade ii patients ( %), and grade iii patients ( %) were admitted directly to imc. none of these patients died, and ( %) suffered cerebral infarction. factors associated with imc admission were lower hh grade (p< . ), gcs of (p< . ), and no ventricular drain placement (p=. ). age, medical comorbidities, and clipping vs. coiling were not associated with admission location. eight patients ( %) admitted to imc were subsequently transferred to icu. patients admitted to icu were more likely to die ( % vs. %, p=. ), to suffer respiratory failure ( % vs %, p=. ), and fever ( % vs %, p=. ). in multivariate logistic regression, imc admission was unrelated to vasospasm or infarction. admission to icu was associated with higher median patient charges ($ , . vs. $ , . , p< . ). we found no evidence that imc admission (primarily among hunt and hess i and ii patients) was associated with increased morbidity, and the in-hospital mortality rate of imc admissions over years was zero. given the higher cost of care among patients admitted to icu, it may be appropriate to consider imc admission for selected patients. wei xiong, matthew koenig, xiaoxu kang, xiaofeng jia, adrian puttgen, nitish thakor, romeryko geocadin johns hopkins university, baltimore, md, united states neurologic injury from cardiac arrest (ca) continues to be a significant problem, in part due to the lack of real-time monitoring of brain injury and recovery. somatosensory evoked potentials (sep) are a reliable marker of poor outcome because they are relatively resistant to physiologic and therapeutic perturbations. we tested the hypothesis that early recovery of cortical sep would be associated with better outcome after resuscitation from ca. sixteen adult male wistar rats were subjected to asphyxial cardiac arrest. half underwent mins of asphyxia (group ca ) and half underwent mins (group ca ). continuous seps from median nerve stimulation were recorded from these rats for hours immediately following ca. additional serial seps were recorded at , , and hours after ca. clinical recovery was evaluated using the neurologic deficit scale ( - , normal = ), which was performed at , , and hours after ca (primary outcome measure). all rats in group ca survived to hours, while only rats in group ca survived to that time. mean nds values in the ca group at , , and hours after ca were . , . , and . ; while in group ca , they were . (pvalue . ), . (p-value . ), and . (p-value . ), respectively. the n (first negative peak at approximately ms) amplitude differed significantly between the two groups within hour after ca. rats that suffered longer ca durations showed later recovery of n . the n latency was similar between the two groups. although early recovery of n showed a trend towards better -hour nds scores, this was not significant. a smaller n peak was consistently observed to recover earlier in all rats, which may represent the thalamic component of sep. the delayed recovery of n is associated with longer ca times in rats. early recovery of n shows a trend towards better outcomes. n , which may represent thalamic activity, reappears much earlier than cortical responses (n ), suggesting thalamocortical desynchrony in early recovery. sep after ca is a dynamic and promising tool to monitor early neurologic recovery after ca. evidence suggests a role for inflammation in vasospasm after subarachnoid hemorrhage (sah). recent studies suggest that systemic inflammation may lead to vasospasm. to test the hypothesis that systemic inflammation worsens vasospasm we evaluated the effect of lps on vasospasm. c bl/ j mice received either ug/animal lps i.p., or saline. hours later, animals had either sah induction or sham surgery. in a separate group, neutrophils were depleted prior to lps administration. to test whether neutrophils in the csf from the sah are required for vasospasm, we injected blood from lps-sensitized, neutrophil-depleted mice to the csf of lps-sensitized, non-depleted mice and the converse (adoption studies). at hours post injection, animals were perfused with saline, formalin and india ink, and the brains were removed for quantitative evaluation of basal cerebral vasculature for vasospasm. the mean differences in diameter of mca segments at mm distal to bifurcation were compared. a separate set of animals were perfused with saline and formalin for immunohistochemical staining of neutrophils and microglia. in saline-injected animals with sah, the mean vessel diameter was significantly smaller compared to the salineinjected sham group. there was no difference in the means of vessel diameter between saline-or lps-injected sham groups. lps injection in the animals with sah exacerbated the vasospasm. neutrophil depletion prior to lps ameliorated vasospasm. neutrophil extravasation into the brain and microglial activation was increased in the lps group compared to controls but was reversed by neutrophil depletion. in the adoption studies, depletion of neutrophils in the csf blood ameliorates vasospasm but neutrophil depletion in the systemic circulation did not. systemic inflammation induced by lps exacerbates vasospasm. the effect is reversed by neutrophil depletion in the csf. this suggests that inflammation in the brain is a more important contributor than systemic inflammation in vasospasm. malnutrition in the intensive care setting is associated with increase mortality presumably secondary to increased infections. acute ischemic and hemorrhagic stroke patients in the icu often experience a delay of enteral nutrition due to delays in swallowing evaluation and diagnostic procedures that require a period of food abstinence. serum albumin levels are often used as markers for malnutrition. this study was retrospective analysis of patients admitted from january/december with the diagnosis of ischemic or hemorrhagic stroke. the goal of the study was to determine the association between albumin levels less than . mg/l during the first hours of icu admission and mortality. t-tests were used to identify significant difference between means. chi-square tests were used to examine the distribution of categorical variables across discharge statuses. after identifying variables that were significantly different, a logistic model was built to determine if admission day albumin levels are independently associated with mortality. there was no difference in mean serum albumin levels between non-survivors ( . mg/l) or survivors ( . mg/l (p= . )). there was no difference between non-survivors and survivors in day albumin levels or in the change from day to day . a logistic model controlling for age and dyslipidemia (factors significantly or marginally significantly elevated in non-survivors) showed that admission day albumin was not an independent predictor of outcome. in our study, there was no correlation between serum albumin levels and mortality. we did not analyze the incidence of infections in this study population. this study validates the may critical care medicine guidelines on nutrition support in the icu. they concluded that albumin was not a valid nutrition assessment tool in the icu. future studies should examine the relationship between hypoalbuminemia, prealbumin levels and the incidence of infections in the stroke patient population. tnf-is an inflammatory cytokine that plays a central role in promoting the cascade of events leading to an inflammatory response. recent studies have suggested that tnf-may play a key role in the formation and rupture of cerebral aneurysms, and that the underlying cerebral inflammatory response is a major determinate of outcome following subrarachnoid hemorrhage (sah). we studied comatose sah patients who underwent multimodality neuromonitoring with intracranial pressure (icp), cerebral microdialysis, and brain tissue oxygen (pbto ) as part of their clinical care. continuous physiological variables were time-locked every hours and recorded at the same point that brain interstitial fluid tnf-was measured in brain microdialysis samples. significant associations were determined using generalized estimation equations. each patient had a mean of brain tissue tnf-measurements obtained over an average of hours of monitoring. tnf-levels rose progressively over time. predictors of elevated brain interstitial tnf-included higher brain interstitial fluid glucose levels ( = . , p< . ), intraventricular hemorrhage ( = . , p< . ), and aneurysm size > mm ( = . , p< . ). there was no relationship between tnf-levels and the burden of cisternal sah; concurrent measurements of serum glucose, or lactate-pyruvate ratio. brain interstitial tnf-levels are elevated after sah, and are associated with large aneurysm size, the burden of intraventricular blood, and elevation brain interstitial glucose levels. experimental studies have demonstrated that tumor necrosis factor-(tnf-) plays a crucial role in the onset of hemolysis-induced vascular injury and cerebral vasoconstriction [ ] . we hypothesized that tnf-measured from brain interstitial fluid would correlate with the severity of vasospasm following aneurysmal subarachnoid hemorrhage (asah). from a consecutive series of asah patients who underwent cerebral microdialysis (md) and evaluation of vasospasm by computed tomographic angiogram (cta) or digital subtraction angiography (dsa), tnf-levels from md were measured at hour intervals from sah days - using enzyme-linked immunosorbent assay (elisa). a blinded attending neuroradiologist independently evaluated each cta and dsa and assigned a vasospasm index (vi). five patients had vi< and patients had a vi> , where the median vi was (range - ). median log tnf-area under the curve (auc) was . (pg/ml)*day (interquartile range . - . ) for the vi< group, and . (pg/ml)*day (interquartile range . - . ) for the >= group (p< . ). in this small series of poor-grade asah patients, the area under the curve of tnf-levels from sah days - correlates with severity of radiographic vasospasm. further analysis in a larger population is warranted based on our preliminary findings. mild therapeutic hypothermia (th, - ºc) reduces mortality and improves neurologic outcomes after ventricular fibrillation cardiac arrest (ca). the relationship between time to achieve th and outcomes remains undefined. we hypothesized that a shorter interval from ca to achieve th would be associated with improved neurologic outcome. we retrospectively reviewed all subjects with in-or out-of-hospital ca treated with th between november and april at our institution. the time to target temperature was defined as the interval between witnessed ca and first measurement of hypothermia ( ºc) and further categorized as early (< hours) or delayed (> hours). outcomes were assessed at the time of death or discharge by the cerebral performance category score (cpc). good neurologic outcome was defined as cpc or . fisher's exact test was used to assess the univariate relationship between time to target temperature and neurological outcome. patients were treated with th after in-hospital ( %) and out-of-hospital ( %) ca. subjects that did not reach target temperature or with unwitnessed ca were excluded. of the remaining patients, % ( / ) survived to discharge and % ( / ) achieved a good neurologic outcome. five patients ( / ) reached early target temperature; % ( / ) of those had a good neurological outcome. % ( / ) of subjects with delayed target temperature achieved a good neurological outcome. the univariate relationship between time to target temperature and neurological outcome was statistically significant (p= . ). attaining th within hours of in-or out-of-hospital ca is associated with a greater likelihood of a good neurological outcome at discharge. time from ca to achieved th should be included as a clinically important covariate in future studies of predictors of outcome after ca. cerebral autoregulation tests have gained importance for the assessment of patients with a variety of brain disorders. in critically ill patients, testing of dynamic autoregulation is safe and practical, but the ability to respond to steady state change in blood pressure is probably more clinically relevant. the purpose of this study was to compare static autoregulation testing with two different dynamic autoregulation tests (cuff deflation and carotid compression tests) in patients with severe traumatic brain injury. twenty-two studies were performed in tbi patients. changes in middle cerebral artery flow velocity (mcafv) were observed by transcranial doppler. static autoregulatory index (sari) was determined from the steady-state response of mcafv to phenylephrine-induced rise in blood pressure. dynamic autoregulatory index (dari) was determined by the cuff deflation method as described by aaslid ( ) and the transient hyperemic response ratio (thrr) was calculated as described by smielewski ( ) . these dynamic tests were performed in triplicate at baseline prior to inducing hypertension with phenylephrine, and the values were averaged to give a single index value. since the anatomy of the brain injury varied from patient to patient, the autoregulatory indices were summarized for the worst and best sides of the brain based on the appearance of the initial ct scan. the sari averaged . + . on the side of the brain that was more injured, and . + . on the less injured side. thrr was closely correlated with the sari, both on the side that was more injured (r=. , p=. ) and on the less injured side (r=. , p=. ). the dari was significantly correlated with sari only on the side that was more injured (r=. , p=. ). these data suggest the ability of dynamic autoregulation to predict static autoregulation may vary with the type of test chosen. published guidelines from the american society for gastrointestinal endoscopy considers peg tube placement a high-risk procedure for bleeding and recommends discontinuation of clopidogrel, to days before peg placement. unfortunately the perioperative time period is associated with increased ischemic events, length of stay (los) in the hospital and resource consumption. this is a retrospective review of prospectively collected data that sought to examine the safety of peg tube placement in patients while on clopidogrel alone or in combination with aspirin. patients admitted into our neuro-icu who met the set criteria during the period january to july were included in the study. mean duration on antiplatelet therapy prior to peg placement was days. one patient had a new stroke during hospitalization, unrelated to the procedure. no post-operative complications, bleeding or neurologic changes were noted in any of the patients. relevant blood indices remained largely unchanged. although peg tube placement is considered a high-risk procedure for bleeding, in the absence of pre-existing bleeding disorder it may be safe to perform this procedure in patients taking clopidogrel. there may be no need to consider reversion to aspirin alone, in those on combination therapy. timely placement of peg tubes in this subgroup of patients may reduce their los and decrease the risk of new ischemic events. introduction: hunt and hess grade sah is accompanied by high rates of mortality and severe disability. mortality in these patients is driven by withdrawal or limitation of care. some patients do enjoy good functional outcomes. we seek to describe the frequency and predictive factors for good outcome following grade sah. we will also describe risk factors for limitation of care following grade sah. we identified consecutive patients with sah and worst hunt and hess grade of within hours of admission (mean age years; % female) in a prospectively collected registry of aneurysmal sah patients. the frequency of good outcome (modified rankin through ) at months was calculated. we performed univariate analysis of pre-admission and admission characteristics to identify associations with good outcome. independent risk factors were identified through multiple logistic regression analyses. we performed a multivariate analysis of risk factors for limitation of care. good functional outcome occurred in ( %) of patients. white ethnicity (or . %ci . - . ), employment at the time of sah (or . %ci . - . ), lack of limitation of care (or . %ci . - . ), and normal papillary reactivity on admission (or . %ci . - . ) were independently associated with good outcome. in a subgroup of patients in whom care was not limited, ( %) had good outcomes; white ethnicity(or . %ci . - . ), employment status(or %ci . - . ), and absence of fever(or . %ci . - . ) independently predicted good outcome. among patient characteristics analyzed, admission gcs(p< . ) predicted limitation in care. a substantial proportion of patients with grade sah who receive full medical support enjoy a good recovery at months. age, pre-morbid co-morbidity, and clinical and radiographic measures of hemorrhage severity do not predict good outcome in our study, but socioeconomic factors may. intracerebral hemorrhage (ich) is the most lethal type of stroke. hypertensive ich (hich) is the most frequent ich subtype. we aimed to evaluate predictors of -day mortality after hich. retrospective cohort. this study was approved by our irb. we found patients with hich amongst patients admitted to our hospital from july to june . mortality was % (n = ). thirty-two patients ( %) were male, and ( %) were black. mean age was ± years ( patients were years). initial pulse pressure ± mm hg, and mean gcs score was ± . mean ich volume was ml (range, . to ml) measured on first head ct scan with the use of the abc/ method, and patients ( %) had intraventricular hemorrhage (ivh). fifty-five patients ( %) had supra-and patients had infra-tentorial ich. the mean ich score (hemphill, et al. stroke. ; : - ) was . points (range, to points). one of patients with ich score of , and patients with scores of or died. in univariable logistic regression modeling, all independent predictors used to develop the ich score, except age years (p = . ), were associated with day mortality: initial gcs (p = . ), ich volume (p = . ), ivh (p = . ), and infra-tentorial ich (p = . ), and the ich score (p = . ) accurately predicted mortality at days. in multivariable logistic regression analysis, only gcs alone was predictive of -day mortality. the roc/auc analysis demonstrated that gcs was a powerful predictor of mortality with an auc = . . gcs was the most powerful predictor of mortality. our study suggests that gcs is a powerful predictor of -day mortality after hich. further research is warranted. pneumocephalus is found in % of postcraniotomy computed tomographies of the head (ctoh) and is considered a benign complication of surgery. occasionally, however, it may lead to lethargy, headache and, if under tension, signs of elevated intracranial pressure or brain herniation. high percentage supplemental oxygen is frequently used as a treatment, but data regarding its effectiveness are very limited. postcraniotomy patients admitted to the neuro-intensive care unit with pneumocephalus received % fio on-off every hours for at least hours (treatment subgroup). during the off period, this subgroup, as well as the controls remained on room air (or % fio if mechanically ventilated). the assignment to each subgroup was based on the neurosurgeon's preference. the intracranial air volume on the ctoh was measured before and after the intervention via an image j analysis package. twenty-two treated patients and controls (mean age and years, and % women, respectively) were identified. the most common diagnoses were subdural hematoma (in % vs % for the treatment and control subgroups, respectively) and tumor ( % in both). there was no difference in the number of ventilated patients or in those with external ventricular drainages, in the lapsed period between the initial and final ctoh and the initial and final volume of air between the two subgroups. the percentage of air volume change (after adjustment for the lapsed time) and the rate of air absorption were significantly higher in the treated group ( % vs %, p = . and . . %/hour vs . . %/hour, p = . , respectively). this pilot study suggests that intermittent oxygen administration in patients with craniotomy decreases the pneumocephalus volume and increases the rate of intracranial air absorption. in a recent publication (wijdicks et al. neurology. oct ; ( ): - ), the safety of apnea testing in the declaration of brain death was evaluated at a single tertiary care center. one major conclusion was that apnea testing was safe in hemodynamically compromised patients in most circumstances and rarely aborted. determinants of apnea test completion failure are unknown. we calculated the alveolar-arterial oxygenation gradients (a-a gradient) in the previously studied cohort. arterial blood gas values were obtained prior to the initiation of apnea testing. patients that completed the procedure during the declaration of brain death were compared to those whose studies were aborted. statistical analysis was performed using nonparametric wilcoxon rank-sum test. of the original patients studied, a-a gradients were calculated for patients. seven of these patients had aborted apnea testing because of hypoxemia and/or hypotension. seventy-nine percent of patients that completed apnea testing had gradients larger than mm hg compared to % in those whose study was aborted, % versus % with gradients greater than mm hg, and % versus % with gradients greater than mm hg. the a-a gradient median values for completed and aborted apnea tests were mm hg (range: - - ) and mm hg (range: - ), respectively (p value= . ). the apnea test can be performed safely in most hemodynamically compromised individuals with large a-a gradients undergoing brain death evaluation. a larger percentage of patients that failed completion of apnea testing had significantly greater a-a gradients. predicting apnea test failure with this respiratory parameter warrants further validation in a larger population. cerebral glucose metabolism and energy production are affected by serum glucose levels. the objective of this study was to assess whether serum glucose variability and the ratio of cerebral-to-serum glucose are associated with cerebral metabolic distress and outcome after severe brain injury retrospective cohort study conducted in a neurological intensive care unit of a university hospital. we studied consecutive comatose patients with subarachnoid or intracerebral hemorrhage, traumatic brain injury, or cardiac arrest who underwent cerebral microdialysis and intracranial pressure monitoring.continuous insulin infusion was used to maintain target serum glucose levels of - mg/dl. general linear models of logistic function utilizing generalized estimating equations were used to relate these predictor variables to cerebral metabolic distress (defined as a lactate/pyruvate ratio [lpr] ) and mortality. the ratio of brain-to-serum glucose was calculated every to hours. daily serum glucose variability was expressed as the standard deviation (sd), mean amplitude glycemic excursion (mage), and glycemic lability index (gli) of all serum glucose measurements. a total of neuromonitoring hours and days were analyzed. after adjustment for glasgow coma scale scores, cerebral perfusion pressure, and serum glucose levels, brain/serum glucose ratios below the median ( . ) were independently associated with increased risk of metabolic distress (adjusted or= . [ . - . ], p< . ). increased serum glucose variability was also independently associated with higher risk of cerebral metabolic distress (adjusted or= . [ . - . ], p< . for sd and adjusted or= . [ . - . ], p= . for mage). low brain/serum glucose ratios and all three measures of increased serum glucose variability were also independently associated with in hospital mortality after adjusting for age and apache-ii scores (all p . ) reduced brain/serum glucose ratios and increased serum glucose variability are associated with cerebral metabolic distress and increased hospital mortality after severe brain injury. in critically-ill neurological patients, cerebral perfusion may be optimized by manipulating cerebral perfusion pressure and cardiac output. the objective of this study was to investigate the relationship between cardiac output (co) response to a fluid challenge and changes in brain tissue oxygen pressure (pbto ) in patients with severe brain injury prospective observational study conducted in a neurological intensive care unit of a university hospital. normal saline ( ml) or albumin % ( ml) boluses were given according to a standardized fluid management protocol. the relationship between co and pbto was analyzed using generalized estimating equations with an exchangeable correlation structure we studied fluid challenges administered to consecutive comatose patients that underwent multimodality monitoring with co, intracranial pressure (icp), and pbto . diagnoses included subarachnoid hemorrhage (n= ), intracerebral hemorrhage (n= ), cardiac arrest (n= ), traumatic brain injury and status epilepticus (n= each). of the fluid boluses analyzed, ( %) resulted in a % increase in co. median absolute (+ . vs+ . mmhg) and percent ( % vs %) changes in pbto were greater in co responders than in non-responders. in a multivariable model, a co response was independently associated with pbto response (adjusted or . , %ci . - . , p= . ) after adjusting for mean arterial pressure, icp and end-tidal co . stroke volume variation showed a good ability to predict co response with an area under the roc curve of . and a best cutoff value of %. bolus fluid resuscitation resulting in augmentation of co can improve cerebral oxygenation after severe brain injury little current data exists regarding outcome, cost and length of stay after subdural hemorrhage (sdh). we sought to examine predictors of discharge disposition, icu and hospital length of stay (los) and direct, indirect, icu, surgical and imaging charges for sdh. a retrospective review was conducted of acute, chronic and subacute sdh patients, aged > years admitted to our hospital between - . disposition was characterized as dead or poor (discharged to a nursing home, hospice, subacute or chronic care facility). multivariable logistic regression analysis was performed to identify predictors of each outcome variable. of sdh patients, the median age was . ( - ), and the median admission glasgow coma scale (gcs) was ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . the sdh was characterized as acute in ( %), subacute in ( %), chronic in ( %) and acute, subacute and chronic in ( %). craniotomy was performed in ( %) of patients, burrhole drainage in ( %) of patients and both in ( %) of patients. death occurred in ( %) of patients and poor outcome in ( %). significant predictors of death or poor outcome included age, admission gcs and hospital los (all p< . ). surgery was protective against poor outcome (odds ratio [or] . , % confidence interval [ci] . - . , p= . ). median hospital los was ( - ) days and median icu los was ( - ) days. both were associated with gcs (all p< . ). median total direct charges for hospitalization were $ , ($ -$ , ). icu and hospital los were significant predictors of direct charges, overhead, imaging and surgical charges (all p< . ). herniation, sdh thickness, type of sdh, type of surgery and gender did not predict discharge disposition, cost or los. despite good admission neurological status, death or poor discharge outcome is common after sdh. though surgery mitigates against poor discharge disposition, los and charges remain high. sathees thayapararajah, bryan young, irene gulka, ahmed al-amri, sujit das lhsc, university of western ontario, london, on, canada introduction: acute fulminant hepatic failure (afhf) is common in tertiary care centers with transplant facilities. cerebral edema frequently threatens the lives of such patients. we reviewed cases of afhf in the neuroicu, noting the incidence of cerebral edema with ct scans and factors associated with mortality. patients were captured through hmri classification of acute liver/hepatic failure. chart review included tabulation of: demographics, inr; serum bilirubin, creatinine, albumin; in-hospital mortality. ct scans were re-read with blinding to clinical information and catalogued for changes in sulcal markings, ventricular size and gray-white differentiation (gwd). inclusion criteria: age greater than years, encephalopathy, hepatic failure within weeks of onset of liver disease, ct scans of head performed. acetaminophen toxicity was the most common etiology ( cases). twelve patients had cerebral edema on ct, including of the with acetaminophen toxicity. decreases in sulcal markings and ventricular size preceded conspicuous alterations in gwd. fourteen died, including all with cerebral edema. none of the hematological or biochemical variables correlated significantly with mortality. acetaminophen toxicity is a common cause of afhf; this combination has a strong association with cerebral edema. early development of cerebral edema occurs in almost all the afhf cases with acetaminophen overdose and can be detected in its early stages. this facilitates management for prevention of fatal brain herniation. afhf patients develop the changes on brain parenchyma within hours of onset of symptoms, during grade i-ii encephalopathy, most strikingly with aod. levetiracetam is increasingly being considered for seizure prophylaxis following tbi. although its acquisition cost is higher than phenytoin, the complete cost of therapy remains unknown as levetiracetam does not require therapeutic drug monitoring and has less pharmacokinetic variability. we developed a cost-minimization model to compare total costs associated with phenytoin and levetiracetam when used for seizure prophylaxis following tbi. five scenarios were tested based on drug, initial method of administration (iv vs. po) and whether or not po conversion occurred. factors considered in the analysis were drug costs, monitoring costs and likelihood of achieving a therapeutic concentration. treatment duration consisted of days. for arms that included po transition, po therapy began after day . decision trees were developed and a single-payoff method was used to identify the least costly scenario. hospital acquisition costs using us dollars were used to assess all costs. the scenario associated with the lowest cost was iv phenytoin followed by po levetiracetam ($ /patient). this was followed by iv levetiracetam transitioned to po levetiracetam ($ ), iv phenytoin transitioned to po phenytoin ($ ), iv phenytoin ($ ) and iv levetiracetam ($ ). the factor associated with the most variability in the model was timing of po transition. a two-way sensitivity analysis which altered timing of po transition revealed iv phenytoin followed by po levetiracetam as the least costly scenario except when iv to po transition occurred after day . in this scenario, iv levetiracetam followed by po levetiracetam was preferred. iv phenytoin followed by po levetiracetam will result in the lowest overall cost when used for a total -day course in patients with tbi. this illustrates the importance of considering all costs associated with a therapy when evaluating the total cost of medication therapy. the joint commission accreditation standards require hospitals to develop policies which address donation after cardiac death (dcd). optn/unos published the "model elements" for dcd protocols that describe suitable dcd candidates to primarily have "non-recoverable and irreversible neurological injury" resulting in ventilator dependency; a description we suspected to be highly inaccurate. we sought to more accurately clinically characterize those considered dcd eligible to facilitate constructive improvement of relevant policies and processes. local opo quarterly audits over months identified patients who were considered eligible for dcd and died within the requisite minutes of treatment withdrawal (dcdep). all cases were reviewed to determine the frequency/nature of any neurological abnormalities and whether they were "non-recoverable and irreversible." we also characterized the mechanism of respiratory failure and death. ( %) of dcdep had an identified neurological injury. only / ( %) had "non-recoverable and irreversible neurological injuries. / ( %) of dcdep were seen by a neuro-specialist, and / ( %) had brain imaging. / ( %) had a neurological injury that could compromise ventilatory drive, and at least / ( %) died of airway compromise with variable approaches to palliative care regarding sedation and oral airway usage. . % of dcdep had no neurologic injury. . only patients ( %) had neurologic injuries that could be correctly characterized as "non recoverable and irreversible" leading to "ventilatory dependency." . airway compromise is an important cause of death in dcdep and demands better uniformity of palliative care to assure equivalent treatment of dying patients independent of "donor status." . the published "model elements" for dcd protocols do not accurately represent the patient population. ventilator-associated pneumonia (vap) is the most common nosocomial infection among medical intensive care unit (icu) patients and associated with increased mortality and length of stay (los). neurologic disease is a risk factor for vap development, but the relationship between vap and outcomes in neurologic patients remains largely unknown. all mechanically-ventilated patients over a two-year period with neurovascular disease were included. data collected included patient demographics, dates of admission and discharge, los, and ventilator hours. vap was defined using standard published criteria. comparisons between neurologic patients who did and did not develop vap were made using univariate and multivariate analysis. of intubated neurovascular patients, ( . %) developed vap. compared with those who did not develop vap, those with vap were younger ( . ± . versus . ± . , p= . ), had increased los ( . ± . days versus . ± . , p< . ), and more ventilator hours ( ± versus . ± , p< . ). there was no difference in mortality between patients with and without vap ( . % versus . %, p= . ). vap was not an independent predictor of mortality in a multivariate model (or . , p= . ). subsequent case-control analysis of patients with and without vap demonstrated an increase in transports for cross-sectional head imaging ( . transports versus . , p= . ). vap in neurocritical care patients is associated with increased los and ventilator hours, but does not lead to increased mortality, contrary to prior studies in medical icu patients. the significance and frequency of vap in neurologic patients is different from patients in other icus because reasons for intubation vary. neurologic patients with vap have more imaging-related transports compared to controls, suggesting an association with ventilator disconnections. introduction: ich causes the highest mortality of all strokes. admission to a neuro-icu has been associated with reduced mortality following ich. this is leading to several hospitals routinely transferring ich patients to hospitals with neuro-icus. however, delays in optimizing management prior to and during transfer often leads to deleterious consequences. our objective was to compare functional outcomes in ich patients admitted to our neuro-icu directly from our ed with inter-hospital transfer admissions. records of consecutive spontaneous supratentorial ich patients admitted to our neuro-icu were reviewed. patients with ich related to trauma or underlying lesions (brain tumors, aneurysms, avm) were excluded. we compared outcomes at discharge in patients admitted directly from our ed and inter-hospital transfers (iht) using dichotomized modified rankin scale. other factors potentially impacting outcomes such as age, ich volume, ivh volume and admission gcs were included in the multiple logistic regression analysis. patients were included in the analysis (ed . %; iht . %). there were no significant differences between the groups in mean age (ed . +/- . ; iht . +/- . , p . ), ich volume (ed . +/- . ; iht . +/- . , p . ), ivh volume (ed . +/- . ; iht . +/- . , p . ) and gcs (ed . +/- . , iht . +/- . ; p . ). . % ed patients had good outcomes at discharge compared to . % iht. this difference was statistically significant following univariate (p= . , % ci= . - . ) and multivariate analysis (p= . , % ci= . - . ). odds (adjusted) of ed admissions having good outcomes was times higher than inter-hospital transfers. ich patients brought to the neuro-icu directly from our ed had significantly better outcomes than inter-hospital transfers. although this could possibly be caused by delays in optimizing ich management, other equally plausible hypotheses need to be prospectively tested. isis duran, storm liebling, michael moore, andrew naidech northwestern university, chicago, united states hospital acquired pneumonia (hap) is a significant cause of morbidity and mortality. hap increases costs, impacts quality metrics and will soon be designated as a medicare "never event". the us centers for disease control have published standard guidelines for the diagnosis of pneumonia, but few confirmatory data exist. we sought to determine the inter-rater reliability of diagnosing pneumonia by cdc criteria in patients admitted for brain hemorrhage. patients with intraparenchymal or subarachnoid hemorrhage admitted to our neuro/spine icu in were included in this irb-approved study. utilizing cdc criteria, pneumonia was diagnosed prospectively by a neurointensivist and institutional infection control (ic) personnel. following a thorough review of the electronic medical records, chest radiographs, and microbiology results, a neurocritical care fellow and a pulmonary critical care attending physician made an independent retrospective assessment of the diagnosis. analysis of the inter-rater reliability of the diagnosis of pneumonia was performed using kappa statistics. one hundred three patients were identified. the male:female ratio was : . pneumonia was diagnosed in patients by ic personnel, by the neurointensivist, by the fellow, and by the pulmonologist. overall inter-rater reliability was poor, with a median kappa value of . [ . - . ]. the highest inter-rater agreement was between the fellow and the pulmonologist (kappa= . ), while the lowest was between the pulmonologist and ic personnel (kappa= . ). the diagnosis of hap by cdc criteria, despite highly trained reviewers and clear diagnostic criteria, had poor interrater reliability in a sample of high risk patients. the diagnosis of hap should not be a measure of quality of care, nor should it be used as a determinant of payment unless the inter-rater reliability can be markedly improved. recent studies have reported excess hospitalization costs for aneurysm coiling compared to clipping after subarachnoid hemorrhage (sah). we aimed to compare categories of charges, length of stay (los), and discharge disposition in patients who underwent surgical versus endovascular aneurysm repair. a retrospective review was conducted of spontaneous sah patients between / - / . charges captured in the hospital database and were categorized as direct, overhead, icu, surgical and radiographic/angiographic. analysis was adjusted for age, hunt-hess grade, aneurysm size, aneurysm location and los. discharge disposition and los were compared between clipped and coiled patients using logistic regression or mann whitney u-nonparametric test. of sah patients, ( %) were clipped and ( %) were coiled. coiled patients were significantly older ( versus years; p= . ), and had larger aneurysms ( versus mm; p= . ). there were no differences in hunt-hess grade, aneurysm location, or modified fisher score. compared to coiled patients, median radiographic/angiographic charges were lower in the clipped group ($ versus $ , , adjusted or [aor] . , % ci . - . , p< . ), but median surgical charges were higher ($ , versus $ , aor , % ci - , , p< . ). total median direct charges were similar ($ , for clipped versus $ , for coiled patients, p= . ), as were icu direct charges ($ , versus $ , , p= . ) and overhead ($ , versus $ , , p= . ). median icu los ( days for each group) and hospital los ( days for each group) were similar as were discharge dispositions after adjusting for age, hunt-hess grade and aneurysm size: % of clipped patients died versus % of coiled patients (p= . ) and % versus % had a poor discharge disposition (p= . ). though surgical and radiographic/angiographic charges differed between sah patients who had surgical versus endovascular repair, icu charges, overhead and total direct charges were similar as were icu and hospital los and discharge disposition. osmotic diuretics and hypertonic saline (hs) are commonly used to treat traumatic brain injury (tbi). the untoward effects of mannitol, including hypotension, rebound intracranial hypertension, decreased potency and effect duration have lead to research of alternative treatments. hypertonic saline has been increasingly used to treat cerebral edema, however, efficacy and safety of repeated boluses has not been established. this preliminary prospective trial assesses the ability of single ml . % saline bolus to lower icp without losing potency while maintaining hemodynamic stability. thirty-five individual boluses of . % saline were given in tbi patients (aged - ) during a -month period. included tbi patients sustained icp elevation (> mmhg x minutes) despite full sedation, paralytics, temperature control and minimal stimulation. starting at bolus initiation, icp, cerebral perfusion pressure (cpp), heart rate (hr), systolic blood pressure (sbp), sodium level (na), and serum osmolality (sosm) were recorded regularly for hours. if repeated boluses were given in the same patient (icp re-elevated > mmhg x minutes), recording of parameters was restarted at a new zero time-point to assess the effect of each bolus individually. statistical analysis included power analysis, normalization testing, anova (analysis of variance) and scheffe test. within minutes of administration a statistically significant decrease in icp was sustained up to hours (power > %, p< . ). mean icp at initiation declined from mmhg to < mmhg by minutes (> % reduction, p< . ). the mean cpp before treatment increased from mmhg to mmhg by minutes ( % rise, p< . ). mean hr and sbp remained constant. sodium levels ranged from to and sosm from to . small volume . % saline boluses can be used repeatedly in patients with tbi to significantly lower icp and improve cerebral perfusion. repeated boluses resulted in a sustained magnitude and duration of icp reduction up to hours. introduction: intraventricular hemorrhage (ivh) can result from different etiologies all are intracranial in location. in this unique case we describe a case of ivh secondary to an extracranial vascular source. retrospective chart analysis for a patient that was taken care of at our institution's neurocritical care unit with cerebellar hemorrhage. patient was a year old male who presented with severe headache and imbalance. ct scan revealed a cerebellar hemorrhage and minimal intraventricular hemorrhage. patient underwent suboccipital craniectomy with evacuation of the hematoma. patient had an external ventricular drain (evd) placed in the or through the occipital horn. patient recovered over the following few days with minimal neurological deficits. suddenly patient suffered from a profuse bleeding from the scalp site of the evd. bleeding was controlled by pressure and suture. next day patient suffered from a similar episode. during the control of the bleeding the patient deteriorated neurologically and had to be intubated. patient ct scan showed massive intraventricular hemorrhage. angiography revealed an occipital artery pseudoaneurysm that was the cause of the bleeding and probably resulted from the evd insertion. the aneurysm was coiled without complication and patient was discharged later to long term care facility. pseudoaneurysms of the external carotid artery branches could result from trauma induced during evd insertion. in the presence of evd tract the hemorrhage that occurs from these pseudoaneurysms could track along under pressure to cause intracranial hemorrhage. this is an unusual and unfortunate experience that we wanted to raise awareness about. veena yashaswi, ravi patel, adham kamel, jonathan naysan, juliuse gene latorre, tara ramachandran, ziad el-zammar, yahia lodi upstate medical university, syracuse, ny, united states surgical treatment of fusiform intracranial aneurysm is extremely difficult and associated with poor outcome. endovascular stent-assisted treatment of fusiform intracranial aneurysm without sacrificing the parent artery has been introduced into clinical practice recently as an alternative option. objective: the objective of our study is report our experience of stent-assisted treatment of fusiform intracranial aneurysm. consecutive patients who underwent stent-assisted treatment for fusiform intracranial aneurysm were enrolled from to . patient's demographics including the hunt & hess grade, fished scale, location and size of aneurysm including the rate of radiographic evidence of aneurysm occlusion were collected. additionally a days outcome measurement was obtained using glasgow outcome scale (gos). five female patients, median age years (ranges to ) with five unruptured symptomatic intracranial fusiform aneurysms were treated with neuroform stent. four of which required staged coiling in addition to stenting and one required stenting only. three aneurysms were located at the internal carotid artery (two at the carotid bifurcation, one at the origin of ophthalmic artery) one at the middle cerebral artery and one at the vertebral artery. there was no intraoperative or post operative complication related to the stent-assisted treatment. immediate near complete occlusion was observed in one and subtotal occlusion in cases. in months follow-up angiography, complete occlusion of aneurysm was observed in patients (vertebral artery and carotid bifurcation ), near complete occlusion in two (carotid ophthalmic one and carotid bifurcation one) and subtotal in one (middle cerebral artery). good outcome was observed in all cases (gos ). endovascular stent-assisted repair not only provides a safe alternative option for the treatment of intracranial fusiform aneurysm, but also improve progressive occlusion of aneurysm with good outcome. wilson cueva, obi iwuchukwu, fernando goldenberg, agnieszka ardelt, jeffrey frank university of chicago medical center, chicago, il, united states hyperammonemia is a well recognized precipitant of cerebral edema (ce) and an important cause of death in acute liver failure. however, isolated hyperammonemia can occur in patients with enzymatic deficiencies important for ureagenesis. extreme hyperammonemia from newly diagnosed ureadysgenesis in adults has been reported, most often leading to disabled outcome or death from ce. we present the clinical, therapeutic and outcome details of two patients with newly symptomatic ureadysgenesis-induced hyperammonemia who developed profound ce and intracranial hypertension (ich). both are the only survivors ever reported with their degree of extreme hyperammonemia (peak and mcg/dl) with normal neurological outcome. case- : a healthy year-old male developed seizures followed by profound encephalopathy associated with ammonia level of mcg/dl without liver failure. case- : after a successful lung transplant, a year-old man developed severe encephalopathy associated with ammonia level of mcg/dl without liver failure. ornithine transcarbamylase deficiency was discovered in case and acquired glutamine synthetase deficiency was suspected in case . steroids provoked symptomatology in both cases leading to severe ce and ich. both required intracranial pressure monitoring, cerebral perfusion pressures directed therapy, promotion of ammonia clearance (cvvhd, lactulose), catabolism limiting treatments (hypothermia, insulin administration, infection control, nourishment), protein restriction, and the use of alternative pathway therapy. both patients fully recovered. -hyperammonemia should be suspected in patients presenting with unexplained ce even in the absence of liver failure. -multidimensional contemporary neurocritical care strategies can optimize survival and improve functional outcome from this historically disabling and deadly condition. -extreme hyperammonemia should not deter aggressive proactive management in these patients now that we report normal neurological outcome in these unique survivors. we is a known neurological complication of thiamine deficiency. although it usually manifests among alcoholics, na patients with either malabsorption, poor dietary intake, severe vomiting or increased metabolic demands are prone to develop we. we present three clinical cases in whom typical brain mri and pathology findings led to the diagnosis of na-we. case- : year-old na female became comatose after a two months history of severe vomiting secondary to a gastrointestinal disease. case- : year-old na female with breast cancer became comatose in the setting of weeks history of severe vomiting after chemotherapy. case- : year-old na female became comatose status-post cardiac arrest of very short duration, not enough to explain the severity of the encephalopathy. severe alteration of the level of consciousness without focal deficits was the prominent clinical finding in all patients; nystagmus was present in case . brain mri showed t /flair signal abnormalities in bilateral mamillary bodies, thalamus and periaqueductal area in cases and and an autopsy in case revealed findings consistent with we. despite intravenous thiamine supplementation, cases and did not improve clinically and eventually expired. case had complete neurological recovery within the first hours of treatment with intravenous thiamine. -we should be considered in all patients with unexplained confusion or deteriorating mental status even in the absence of a prior history of alcohol abuse. -in the presence of atypical or incomplete clinical picture of we, appropriate brain mri findings can help establishing the diagnosis. -early diagnosis of we is critical given that the success of the treatment depends on the urgent thiamine supplementation. -failure to recognize and treat we may result in devastating neurological outcome. arterial venous carbon dioxide removal (avco r) is a technique that uses a pumpless extracorpeal circuit for carbon dioxide removal. avco r has been used in adult and pediatric patients with severe hypercapnea. the system is placed at bedside using the seldinger technique to cannulate the femoral vessels. normally this system requires anticoagulation but can be performed without anticoagulation. case reports of avco r used to control ph and pco after neurotrauma. a male suffered extensive head injury after mvc progressing to brain death. organ harvest was planned. because of extensive lung injury complicated by hypercapnea and academia, donor viability was in jepody with paco rising to and ph of . . avco r was placed for ph and carbon dioxide control. the paco and ph promptly corrected to and . . after a brain death exanimation he remained on avco r until organ harvest. a male presented with a cervical injury at the c- level. imagining showed cervical fractures, disc herniation and cord contusion involving c- to t- .the patient developed respiratory distress. chest x-ray revealed ards. in aprv the ph was . and pco of . the patient had a subsequent cardiopulmonary arrest. after successful resuscitation avco r was started. within hours the ph and pco were . and without manipulation of the ventilator settings. he was on aco r for days and eventually weaned off mechanical ventilation after surgical decompression and fusion and discharged to rehabilitation. neither case required anticoagulation. . avco r is a simple extracorpeal technique that can be used to manage life threatening hypercapnea in patients with critical neurologic illness or injury . the technique can be inserted at bedside and used without anticoagulation continuous renal replacement therapy (crrt) is preferred over intermittent hemodialysis (ihd) in patients with acute brain injury (abi) due to increased intracranial pressure (icp) seen during ihd [ , ] . despite the preference for crrt in this patient population limited data is available on icp changes during therapy. there is some support for the early stability of icp for patients with fulminant hepatic failure that underwent continuous arteriovenous hemofiltration [ , ] . retrospective observational study (over a year period) of patients with abi and icp monitoring whom also underwent crrt. icp and fluid volumes were analyzed for the hours before and after initiation of crrt. four patients met criteria. table- describes the sample population. three patients had developed refractory intracranial hypertension (rih) prior to initiation of crrt ( in pharmacologic coma) and patient developed intracranial hypertension on ihd that resolved with crrt. no changes in medications were made in the hours prior to starting crrt except pentobarbital coma was initiated one patient six hours prior to crrt without lowering of icp. no attempts were made to lower icp in the hours following crrt. a decline in icp was seen at , , and hours following initiation of crrt in rih patients ( given the decrease in icp at one hour and relatively small percentage of total fluid balance removed, it seems unlikely that fluid removal or improved systemic oxygenation decreased icp. early improvement in icp may be due to removal of cytokines and myocardinal depressants seen with ultrafiltration and membrane absorption which is maximal during the first hour of filter use due to filter charge [ ] . given the mortality and morbidity associated with rih, further research is warranted. isoflurane, an inhalational anesthetic, is an alternative treatment for refractory status epilepticus (rse). it is effective, has rapid onset of action, and is easily titrated to produce burst-suppression patterns on the electroencephalogram. little is known regarding potential human toxicities caused by isoflurane. we present two cases of prolonged rse treated with prolonged high dose isoflurane who developed abnormal t hyperintensity lesions on magnetic resonance imaging (mri), which improved after taper or discontinuation of isoflurane. we report two patients with prolonged refractory status epilepticus who were treated with prolonged high-dose isoflurane (defined as an average end tidal concentration > . % for seven or more days) and developed new changes on brain mri. we collected demographic information, daily dosing of all antiepileptic medications and anesthetics received. we reviewed and analyzed the results of serial mri scans. patient one had prolonged rse for days and was treated with isoflurane for days with . % concentrationhours. patient two, currently hospitalized, has had rse for at least days and was treated with isoflurane for days with . % concentration-hours. in both patients, serial brain mris showed progressive t signal hyperintensity involving bilateral thalami, cerebellar hemispheres, and cerebellar vermis after treatment with - weeks of high dose isoflurane. these findings improved following taper and/or discontinuation of isoflurane. these cases raise the possibility that isoflurane is neurotoxic when used in high doses for prolonged time periods. though we cannot be certain of the exact cause of brain lesions, the timing of their appearance after isoflurane initiation and subsequent improvement after taper or discontinuation suggest a possible association with isoflurane. further studies are needed to clarify the safety of prolonged isoflurane use in rse cerebral edema is common in severe brain injury and can lead to harmful elevations in intracranial pressure (icp). hyponatremia, typically associated with excess levels of vasopressin (adh), frequently complicates acute brain injury and can worsen edema and icp. conivaptan, a vasopressin-receptor antagonist, has been shown to correct hyponatremia in these high-risk patients by inducing loss of free water (aquaresis). it is unknown whether raising sodium with a bolus of conivaptan can also acutely reduce icp. we prospectively assessed the change in serum sodium (na + ), icp, and cerebral perfusion pressure (cpp) after a bolus of conivaptan was given for the treatment of hyponatremia in a patient with cerebral edema associated with traumatic brain injury (tbi). a -year old suffered severe tbi with left carotid dissection, complicated by hemispheric infarcts and worsening edema. conivaptan mg iv was given as a bolus when na + rapidly dropped to meq/l. its aquaretic effect peaked between and hours after the dose, with hourly urine outputs of ml/hour. eight hours postadministration, na + had risen to meq/l. icp had been stable at - mm hg for several hours prior and remained in this range for the first hours after conivaptan, but then fell to mm hg at hours, remaining mm hg after hours. cpp, initially stable at - mm hg, rose to mm hg after hours. a single bolus of conivaptan not only resulted in rapid correction of hyponatremia but also a significant fall in icp temporally associated with peak aquaresis. confirmation of this novel osmotic effect is required, as is further delineation of the role of such agents in the management of brain edema. financial support: the authors have received speaking honoraria from astellas pharma. seizures are a known complication of aneurysmal subarachnoid hemorrhage (sah). they can increase cerebral metabolic demand and lead to cardiopulmonary compromise. this could be detrimental in the setting of delayed cerebral ischemia (dci), when brain tissue is vulnerable to further reductions in oxygen delivery or increases in demand. an association between seizures and worsening ischemia could influence the decision to use antiepileptic drug (aed) prophylaxis in patients with vasospasm. case report of a patient who developed irreversible neurological deficits and cerebral infarction immediately after a seizure in the setting of initially stable vasospasm with dci. a year-old woman developed confusion, aphasia, and right hemiparesis on day after sah. angiography confirmed severe anterior circulation vasospasm. the patient responded to hypertensive therapy with almost complete resolution of her ischemic neurological deficits. on day , however, she had a single generalized seizure and required intubation after brief oxygen desaturation. she had a concurrent drop in blood pressure, necessitating an increase in previously stable dose of vasopressors post-ictally she developed recurrent aphasia and worsening hemiparesis which did not resolve despite further hemodynamic augmentation. subsequent head cts revealed new infarcts in the left anterior and middle cerebral artery territories. she had received prophylactic phenytoin for only the first days of her icu stay per our sah protocol. aed prophylaxis is typically used early after sah when risk is high and a seizure may precipitate aneurysmal rebleeding. this case illustrates how a seizure occurring later, in the setting of vasospasm, can lead to decompensation of dci with potential for irreversible infarction. therefore, patients with vasospasm may benefit from extended duration of prophylaxis to prevent such complications. dural sinus thrombosis is a rare cause of stroke. anticoagulation is the preferred treatment; however, some patients experience rapidly progressive neurological deficits and poor outcomes despite adequate anticoagulation. mechanical thrombectomy via a trans-femoral approach is an effective alternative treatment, but technical limitations can make this approach impossible in some patients. we report two cases in which angiojet® (medrad-interventional/possis) thrombectomy was performed via a transjugular approach. in the first patient, trans-jugular access was preferred due to the presence of bilateral deep vein thromboses in the femoral and iliac veins and an inferior vena cava filter. in the second patient, the trans-femoral approach was impossible due to the length of the catheter ( cm xmi), which was insufficient to access to the anterior two thirds of the superior sagittal sinus via a trans-femoral approach. in both patients, the trans-jugular access was obtained utilizing direct ultrasound and fluoroscopic guidance. a stabilizing guidewire was placed to deliver the angiojet® catheter to the superior sagittal sinus. the first patient was a year-old woman with heparin-induced thrombocytopenia, a large intracranial hemorrhage and refractory increased intracranial pressure. the second patient was a year-old man who presented with dehydration and a rapidly declining neurological exam. in both patients, antegrade blood flow was restored within the dural sinuses after mechanical thrombectomy via the trans-jugular approach. computed tomography scans after thrombectomy did not show evidence of increased hemorrhage and there were no complications from the procedure. the first patient died despite successful thrombectomy from other complications of her underlying disease. the second patient made a full recovery. mechanical thrombectomy has been shown to be a successful treatment for dural sinus thrombosis for patients with progressive symptoms despite adequate anticoagulation. the trans-jugular approach is a valuable alternative variation of mechanical thrombectomy in patients who have contraindications to the trans-femoral approach. we retrospectively reviewed data from patients with stbi admitted to the neuroscience icu (nsicu) of an urban tertiary care level trauma center who had a cerebral oxygen monitor (licox ) in place and were administered inhaled nitric oxide (ino) per institutional protocol. data were collected from bedside flow sheets. two patients met inclusion criteria. patient # was admitted after a motor vehicle collision with stbi and pulmonary contusions. she developed adult respiratory distress syndrome (ards) on hospital day # requiring ino at ppm. prior to ino therapy, pbto was . mm hg, pao = mm hg and icp = cm h o; within hours of ino initiation, pbto climbed to mm hg (+ %), pao rose to (+ %), and icp remained cm h o (+ %). patient # sustained a stbi and pulmonary contusions after a motorcycle collision. he developed ards on hospital day # requiring ino at ppm. prior to ino therapy pbto was . mm hg, pao = mm hg and icp = cm h ; within hours of ino initiation, pbto rose to mm hg (+ %), pao rose to mm hg (+ %) and icp climbed to cm h o (+ %). patients admitted to the nsicu after stbi may develop complex physiologic derangements, including ards. the use of ino may benefit both cerebral and pulmonary dysfunction, and may warrant further investigation. amar dhand, kazuma nakagawa, wade smith, tarik tihan university of california, san francisco, san francisco, ca, united states introduction: ventricular free wall rupture is a fatal complication of myocardial infarction (mi). although described in mi patients who receive thrombolytic therapy, this complication is not well known in ischemic stroke patients who receive intravenous (iv) t-pa. here, we report a patient who had cardiac rupture and hemopericardium immediately following iv t-pa administration. case report. a -year-old woman with history of coronary artery disease presented with acute onset of left hemiparesis and right gaze preference (nihss ). ct angiography showed right middle cerebral artery (mca) occlusion at the bifurication, a filling defect in the left atrial appendage suggestive of left atrial thrombus, and right segmental pulmonary embolism. an electrocardiogram showed st elevations in the v -v distribution with initial troponin i level of . ug/l. iv t-pa was administered hour from symptom onset. one hour after completing t-pa infusion, the patient suddenly became unresponsive, bradycardiac, and rapidly demonstrated an asystolic arrest. given the established dnr/dni status, she was not resuscitated. autopsy study showed subacute myocardial infarction ( - days old), rupture of the anterolateral wall of the left ventricle, and cc of hemopericardium. pathological study of the brain showed an old hemorrhagic infarction in the left occipital lobe, evidence of remote hypoxic/ischemic injury and % occlusion of the basilar artery, but no evidence of intracranial hemorrhage. this case report illustrates a fatal cardiac complication of iv thrombolytic therapy that was used for acute ischemic stroke treatment in the setting of subacute myocardial infarction. the speculated mechanism of this phenomenon is alteration of collagen metabolism by thrombolytic therapy. although mi is not an absolute contraindication for iv t-pa administration, clinicians should be aware that cardiac rupture may occur when iv t-pa is given to patients with concomitant stroke and mi. anti-nmda-receptor encephalitis (nmdare) is a rare autoimmune encephalitis associated with antibodies that antagonize nmda receptors. although nmdare is an uncommon disorder, we present confirmed cases treated in our neuro-icu over months. we report three cases of nmdare including the first reported case during pregnancy. all patients were women between and years of age. all had a prodrome of psychiatric symptoms and had orofacial and limb dyskinesias at presentation. each developed progressive unresponsiveness, required mechanical ventilation secondary to hypoventilation and had autonomic instability. one required a transvenous pacer for symptomatic bradycardia. all were evaluated for ovarian teratoma. all underwent oopherectomy. two were found to have ovarian teratomas by pathology. patients were treated with a combination of ivig, steroids and plasma exchange. all patients improved and were discharged from the hospital to inpatient rehabilitation. one patient was weeks pregnant at admission. she delivered via cesearean section at weeks gestation. the neonate had mildly increased tone but appeared otherwise healthy and was discharged home at days. the csf of the neonate was negative for nmda antibodies. nmdare is a reportedly rare cause of encephalitis which may be more common than reported. it has characteristic features that should not go unrecognized. high suspicion for ovarian teratoma is appropriate. imaging may not accurately differentiate between benign cysts and teratoma. oopherectomy for any ovarian abnormality may be reasonable, given poor correlation of pathologically confirmed teratoma with radiographic imaging. this is the first reported case of nmdare during pregnancy. nmda receptors play an important role during fetal development and the long-term sequelae for children exposed to nmdar antibodies in utero are unknown. csf hypovolemia is typically diagnosed in patients presenting with positional headaches. however, severe intracranial hypotension and brain sagging may cause orthostatic coma. we present a case that illustrates this uncommon presentation. a yr old male who presented with acute onset of headache, nausea, vomiting and disequilibrium. extensive diagnostic work-up, including head ct, mri/mra and lp, was initially unremarkable. his headaches became progressively worse with a prominent postural component. a csf leak was suspected at the lumbar level diagnosed with ct myelogram and treated with a blood patch at the outside hospital with temporary resolution of his symptoms. a repeat mri/mra revealed bilateral subdural hematomas without mass effect and diffuse dural enhancement, consistent with decreased csf pressure. due to worsening level of consciousness, the patient underwent urgent evacuation of the left subdural without any change in his mental status subsequent imaging showed reaccumulation of the hematoma. over the next few days, the patient became increasingly stuporous and had an acute respiratory decline requiring intubation. the patient was subsequently transferred to our institution. head mri revealed dramatic sagging of the brain showing the pontomedullary junction at the opening of the foramen magnum. there was reproducible improvement in his cognitive status and cheyne stokes breathing with trendelenburg positioning. he underwent a repeat ct myelogram which showed a csf leak at t and possibly at c -c . the csf leaks were repaired with localized blood patches with significant improvement in his neurological exam. csf hypovolemia may cause coma from distortion and downward displacement of the thalamus-brainstem structures. evacuation of subdural fluid collections-typically without mass effect-may be detrimental in these patients contributing to further reduction of csf volume. instead, identification and treatment of the responsible csf leak is curative. infection with human immunodeficiency virus (hiv) has been associated with the development of intracranial aneurysms. although the pathogenesis of aneurysm formation in hiv infected patients is unclear, one purported mechanism is direct invasion of cerebral vessels by the virus itself. here, we report a unique case of an hiv infected patient whose intracranial aneurysm rapidly enlarged during a period of anti-retroviral therapy non-adherence. case report. a year-old hiv infected female (cd count cells/ml) was admitted with a subarachnoid hemorrhage. cerebral angiography revealed a dilating vasculopathy of multiple large intracranial vessels along with fusiform aneurysms of the right and left proximal anterior cerebral arteries (aca). a saccular aneurysm measuring x . mm arose from the right fusiform aca aneurysm and was successfully treated with endovascular coiling. four weeks later, the patient was re-admitted with a decreased level of consciousness. head ct revealed recurrent subarachnoid hemorrhage. the patient had not adhered to her anti-retroviral therapy and her cd count upon re-admission was cells/ml (hiv load copies/ml). cerebral angiography revealed enlargement of the previously coiled aneurysm which now measured x x . mm. infectious vasculitides were excluded with serum and cerebrospinal fluid (csf) testing, including negative blood and csf cultures, negative serum and csf antibodies for syphilis, and negative serum antibodies and csf polymerase chain reaction for varicella zoster virus. the co-occurrence of rapid aneurysmal enlargement with non-adherence to antiretroviral therapy suggests an elevated hiv burden may accelerate vasculopathy. rapid enlargement and re-rupture of intracranial aneurysms may be seen in hiv infected patients with an elevated viral burden. identifying the unique clinical and radiological features of hiv vasculopathy may lead to earlier recognition and novel therapeutic approaches. patients with de novo refractory status epilepticus are often referred to as having norse. the clinical course is often prolonged (range: - days), and morbidity and mortality is high ( %). cjd is a rare cause of refractory convulsive and non-convulsive status epilepticus. we describe here a patient with norse who had probable sporadic cjd. year old, kg, caucasian female with a past medical history of systemic hypertension, pulmonary hypertension, and prior pulmonary mai complex presented to the er with delirium and accelerated hypertension. initial examination revealed encephalopathy. patient had generalized tonic clonic seizures, with rapid progression to status epilepticus which was refractory to dilantin ( mg tid), keppra ( mg bid), phenobarbitone ( mg tid), midazolam ( mcg/kg/min), and propofol ( mcg/kg/min) infusion. she was then put in pentobarbital coma ( m/kg/hr) for hours, and was found to be refractory to withdrawal of pentobarbital. on day of her status epilepticus the patient had an episode of massive pulmonary hemorrhage and went into pea, from which she couldn't be revived. workup for norse including mri brain, ct chest, abdomen and pelvis, failed to reveal any evidence of stroke, press, neoplasm, meningo-encephalitis. paraneoplastic antibody panel was negative. toxicology, metabolic, haematological, vascular, and immunological workup was negative. csf analysis revealed a wbc of , protein and glucose and protein - - was positive. to our knowledge this is the first case report of norse complicating cjd. norse complicating cjd is associated with high mortality. our case is also unique for its acute onset, absence of myoclonus, and absence of extra pyramidal features commonly seen in cjd. in patients with refractory status epilepticus with no obvious cause, cjd should be considered in the differential diagnoses. predicting recovery after cardiac arrest continues to challenge neurointensivists. updated aan practice parameters add two new evidence-based elements to traditional clinical examination criteria ) absence of bilateral n response on sseps and ) neuron-specific enolase (nse) > µg/dl as measured within days. concurrently moderate hypothermia has emerged as an efficacious therapy, with the possibility of modifying the predictive power of criteria established independent of such intervention. case: a year old woman undergoing breast lumpectomy was resuscitated following interoperative asystole. rosc was secured by mins; but she arrived to nsicu comatose with only minimal pupillary and corneal reflexes. moderate hypothermia with target temperatures of - o c was achieved by hours and maintained for hours before slow re-warming. at hours, n s were bilaterally present, but nse was µg/dl. brain mri at day was normal. over weeks she remained comatose with absent motor response requiring aggressive therapy for bouts of refractory non-convulsive status epilepticus. she continued to have intermittent transient myoclonic movements months after cardiac arrest. eye opening without awareness of surroundings began at icu week with gradual return to consciousness. subsequently she has made slow steady improvement, conversing appropriately with memory of family names and past experiences. now months post-arrest on the inpatient rehabilitation unit she moves all extremities with - / muscle strength. her most recent fim score is . prognostication after cardiac arrest remains complex. application of hypothermia may alter the validity of predictors established previously. confounders and convergent evidence must be considered over any single data point. as in the past, time remains the final arbiter of certainty. near infrared spectroscopy is a non-invasive method of monitoring cerebral oxygenation. by employing time and spatial resolution of several light wavelengths, cortical blood flow, volume and oxygenation can be quantified (cerebral oximetry). we present a case utilizing cerebral oximetry in a patient with cerebral vasospasm after subarachnoid hemorrhage (sah) with concurrent use of brain tissue partial pressure of oxygen (pbto ) monitoring. a year old woman developed severe diffuse vasospasm following sah. we monitored intracranial pressure (icp) as well as tissue oximetry (pbto ) via licox (integra) catheter placed in the distribution of the left mca. over a -hour period during the third day of vasospasm, cerox (ornim) monitoring was applied over the left fronto-temporal area to evaluate the relationship between pbto and non-invasive cerebral oximetry. there were episodes of pbto desaturation (< mmhg for > mins) over the period of dual monitoring. over % of these pbto desaturations were preceded by > % decline in cerox values from baseline. there were episodes of cerebral oximetry desaturation (< % for > mins). less than % of cerox desaturations were temporally related to a decline in pbto to less than mmhg. hemoglobin was stable at mg/dl and icp was well controlled (< mmhg) during the entire hours. in this subject, desaturations of pbto appeared to be related to desaturations by non-invasive cerebral oximetry; the converse was not the case. perhaps cortical oxygen desaturations (cerox) occur with increased frequency compared to subcortical oxygen desaturations (pbto ) in diffuse vasospasm after sah. cerox monitoring may provide an enhanced understanding of oxygen delivery and utilization during periods of ongoing cerebral ischemia. further studies are required to substantiate these findings. status epilepticus refractory to conventional anti-epileptic drugs typically carries a poor prognosis, but patients may recover well if seizures can be stopped. case reports suggest that electroconvulsive therapy (ect) may stop seizures in patients with refractory status epilepticus, and we sought to examine its effectiveness in a series of patients. three consecutive patients with refractory status epilepticus at our institution were treated with ect after other therapies had failed. all patients were women, with age ranging from to years, and none had a significant medical history. extensive diagnostic testing was unrevealing, and all patients were empirically treated for infectious and autoimmune encephalitis. ect was begun because of ongoing seizures despite potent combinations of conventional anti-epileptic drugs, multiple trials of complete eeg suppression with anesthetic agents, and trials of more infrequently used therapies such as inhaled anesthetic agents and ketamine. ect stopped seizures in of patients. one patient recovered completely, and in outpatient follow-up had a normal neurological examination and a score of on the mini mental state examination. the second patient was left with mild cognitive impairment and epilepsy, but returned to independent living. in the third patient, seizures continued despite ect, and care was withdrawn at the family's request. autopsy revealed evidence of active meningoencephalitis despite treatment with antiviral therapy and high-dose steroids. ect stopped seizures in of patients with refractory status epilepticus. our results and those of prior case reports suggest that ect may be an effective therapy for refractory status epilepticus, and warrants further study for this indication. wendy wright, bill asbury, susan samuel, jane gilmore, owen samuels emory university hospital, atlanta, ga, united states conivaptan, an avp-receptor antagonist, has been used in neurocritical care patients to treat euvolemic hyponatremia. therefore, it would stand to reason that the aquaretic effect of conivaptan could also be used to induce a state of therapeutic hypernatremia. therapeutic hypernatremia is one of the standard modalities for the treatment of cerebral edema. conivaptan bolus +/-continuous infusion was administered to three patients with cerebral edema in the neurocritical care unit. all patients were initially treated with conventional measures to induce therapeutic hypernatremia, yet were not meeting the desired serum na goal. conivaptan was used in these patients to augment the effects of hypertonic saline. one patient received a single mg bolus of conivaptan in addition to . % nacl and his [na] increased an average of meq/l. one patient received a single mg bolus in addition to . % nacl + % nacl + nacl tablets + fludrocortisone and his [na] increased an average of meq/l. a third patient received conivaptan boluses + infusion in addition to % nacl and his [na] increased an average of meq/l. fluid balances were not adversely affected in any of these patients. conivaptan added to hypertonic saline therapy appears to be a rational strategy for achieving therapeutic hypernatremia in patients with cerebral edema without adversely affecting fluid balance. further study is needed to assess the effects of conivaptan on intracranial pressure, cerebral perfusion pressure and intravascular volume. financial support: dr. wright has served as a consultant for astellas pharma us delayed cerebral ischemia from vasospasm is an under-recognized, yet potentially treatable cause of morbidity and mortality in meningitis. while cerebral vasospasm has been documented via transcranial doppler sonography in patients with meningitis, few reports document vasospasm by cerebral angiography in this population. we report two patients who suffered neurological decline resulting from angiographically documented vasospasm during treatment for meningitis. the first patient was a -year-old woman who developed acute aphasia and hemiplegia during treatment for meningitis. formal cerebral angiography demonstrated left anterior circulation vasospasm. she was treated with verapamil into the left internal carotid artery and aggressive hypervolemia and hypertension. within hours, she was neurologically normal. the second patient was a postpartum woman with meningitis who presented with aphasia and hemiplegia. magnetic resonance imaging showed areas of diffusion restriction consistent with her examination. although she initially made clinical improvement with antibiotic therapy and was discharged, she re-presented days later with severe left anterior circulation vasospasm and massive left hemisphere stroke and later died. in our cases, as well as those described by the tcd literature, neurological decline and vasospasm occurred within days from the diagnosis of meningitis. this suggests that the "window" for vasospasm secondary to meningitis may be similar to that of vasospasm from sah. the development of focal neurologic symptoms in patients with meningitis should prompt radiographic evaluation for vasospasm. current treatment algorithms do not include the routine use of cerebrovascular imaging during treatment for meningitis, and thus this potentially treatable complication may be under diagnosed. prospective studies evaluating cerebrovascular complications in acute meningitis using neuroimaging coupled with directed hypervolemichypertensive therapies should be undertaken and may lead to a reduction in the persistently high morbidity and mortality associated with this common disease. opsoclonus-myoclonus syndrome (oms) is typically associated with a paraneoplastic syndrome or viral encephalitis. various locations, including the crerebellum, have been proposed as anatomic correlations to this syndrome. oms as a result of posterior reversible encephalopathy syndrome (pres) has not been previously described. a yo man with past medical history of poorly control hypertension, hyperlipidemia, and peripheral neuropathy presented with confusion and visual difficulties. initial exam demonstrated a fever of , bp= / (max / ), and lethargy. laboratory studies revealed acute renal insufficiency (ari) (cr= . ) and rhabdomyolysis (cpk= ). mri showed faint hyperintensities in the cerebellum and paieto-occipital subcortical areas (image ). the patient subsequently developed agitation with diffuse multifocal myoclonus and pronounced opsoclonus. repeat mri (image ) showed extensive hyperintensities in the subcortical hemispheres bilaterally and in the cerebellum, consistent with pres (image ). eeg showed diffuse slowing, and lp showed elevated protein ( mg/dl). csf cultures, vdrl, lyme antibody, listeria antibodies, west nile virus pcr, hsv pcr, and jc virus pcr were all negative. ct scan with contrast of the chest, abdomen and pelvis, revealed no neoplasms. results of serum paraneoplastic antibodies are pending. elevations in spep and upep were determined to be due to monoclonal gammopathy of unknown significance. we present a unique case of pres presenting as oms. involvement of the cerebellum may have been causative in this case. the most likely explanation for the development of pres was hypertension with ari. the acute onset, negative viral studies and body ct scan, resolution of symptoms with control of hypertension and reversal of ari, and the characteristic mri findings all supported pres as the cause of oms. we describe the clinical, imaging, and follow-up details of two patients who developed bsevad in the peripartum period to enhance the early recognition of this uncommon but important and potentially disabling complication. both patients were initially misdiagnosed with post-dural puncture headaches (pdph). both patients were in their thirties (ages and ), had epidural anesthesia, and developed their symptoms within days of delivery. patient # developed postural headache within hours of delivery, and patient # developed severe neck pain and bioccipital headache days after delivery. both received epidural blood patch for presumptive diagnosis of pdph without any significant relief. patient # developed nausea, vomiting, and ataxia days postpartum with a follow-up mri revealing acute bilateral cerebellar infarcts and a unilateral pontine infarct. patient # performed unusual physical positions during her pushing phase of labor (drawing provided). initial neuroimaging with ct, mri brain in both were reported as normal. however, -vessel cerebral angiography in both patients revealed bsevad. both patients did well with medical therapy without sequelae. the risk factors, diagnostic clues, and therapeutic considerations are discussed. . bsevad is a rare peripartum complication. . bsevad presents with clinical features that resemble pdph but have some distinguishing features to facilitate differentiation. . bsevad can lead to stroke similar to non peripartum cerebral arterial dissections. . early recognition of this rare complication can potentially lead to protecting patients from devastating posterior circulation strokes. the late-onset form of pompe's disease presents generally with limb girdle weakness. respiratory failure develops later and is the most frequently reported cause of death. we describe a case of late onset pompe's disease emphasizing the need to incorporate this rare entity into the differential diagnosis of patients with ventilatory failure a year old man presented with progressive weakness and shortness of breath. - years previously he noticed gradual lower extremity weakness. he began having difficulty breathing while lying flat. he was admitted to the neuroicu due to progressive respiratory failure. neuromuscular junction disease, neuropathy and typical myopathies were excluded. emg: normal nerve conduction studies. needle exam showed complex repetitive discharges, myotonic discharges and fibrillation potentials consistent with a myopathic process. muscle biopsy: myopathic changes associated with features of a vacuolar myopathy with abnormal glycogen accumulation and markedly increased acid phosphatase reactivity consistent with acid maltase deficiency. dried blood spot serum assay for acid -glucosidase was undetectable. pompe's disease is a rare condition that is now recognized as a treatable entity. therefore, it should be included in the differential diagnosis of adult patients with gradually progressive myopathy and respiratory muscle weakness. its treatment, enzyme replacement with recombinant human alpha-glucosidase (rhgaa), although not yet fda-approved for patients over years of age, has shown significant clinical benefit when started early in the course of the disease. owing to the success of therapeutic hypothermia (th) post cardiac arrest, additional indications are now being explored. this case report documents successful application of th for treatment of refractory intracranial hypertension due to poor grade subarachnoid hemorrhage (sah) without the need for decompressive hemicraniectomy. a -year-old male (da) became unconscious after complaining of a bad headache. in the ed, da was listed as unresponsive to all stimuli. ct revealed a hunt/hess grade sah. an aneurismal clipping was performed the following day. on day , he experienced severe vasospasm not amendable to angioplasty and refractory to osmotherapy, cerebrospinal fluid drainage, and mild hyperventilation. at one point the intracranial pressures exceeded mmhg and his left pupil became fixed and dilated. a ct showed extensive edema and a worsening midline shift. it was then decided to initiate th in anticipation for worsening vasospasm. once the target temperature of degrees c was achieved, the icp stabilized. attempts to re-warm on days and led to increases in icp therefore aborted. finally, on day (th day ), da was re-warmed successfully. ct results that originally showed a large area of edema and midline shift was resolved. da was extubated day , a vp shunt was placed on day and discharged to home after a rehabilitation stay with a good neurological recovery on day . considering the mortality of a high grade sah can exceed %, we believe th contributed significantly to a good neurological outcome. a recent study described the need for a decompressive hemicraniectomy prior to attempting mild hypothermia. our case report documents successful application without invasive surgery and may be an option for others. amaurosis is an uncommon complication of pregnancy encountered by neurologists. two common causes of blindness in during the peripartum period are: ( ) reversible posterior leukoencephalopathy syndrome (rpls), and ( ) preeclampsia. case report: a -year old woman delivered twins at -weeks because of severe preeclampsia. in the early postpartum period, she developed altered mental status, and by postpartum day # , she was responsive only to first name, unable to follow commands, and increasingly combative. blood pressures were elevated up to mmhg systolic, and mmhg diastolic. she had limited vision by absence of blink response to confrontation bilaterally. head ct and eeg were unremarkable. based on findings on cerebral magnetic resonance imaging (mri), a diagnosis of hypertensive encephalopathy was made. however, the occipital lobes are clearly spared. her condition substantially improved, and by postpartum day she was able to cooperate with visual acuity and funduscopic examinations. visual acuity was / bilaterally. bilateral fundi showed discrete patches of retinal whitening located between the arterioles and venules, few retinal hemorrhages, and normal optic discs .by discharge, her blood pressure and mental status were at baseline, her vision improved to / , and repeat mri showed resolution of the earlier findings. cause of blindness in this patient was related to purtscher's retinopathy. we believe that this is the first documented case of a patient with a hypertensive encephalopathy and purtscher's retinopathy. this observation indicates that transient visual loss in the setting of elevated systemic blood pressures does not have to be cortical in nature. continuous eeg monitoring of neurocritical care patients is becoming more common. over % of critically ill patients with altered sensorium are diagnosed with non-convulsive seizures or status epilepticus. as continuous eeg is increasingly used with critically ill patients, it is important for practitioners to recognize artifacts that may mimic clinically relevant pathologic discharges. we describe a newly discovered artifact from an invasive hemodynamic monitoring device. seven patients who had a ref/ox (edwards lifesciences) continuous cardiac output pulmonary artery catheter (cco) placed for hemodynamic monitoring and were simultaneously monitored with continuous eeg were retrospectively identified. all patients were cared for in a bed neuroscience icu in an urban level trauma center. all eegs were interpreted by a board certified epileptologist. all patients' eegs demonstrated a distinctive artifact believed to be associated with the cco catheter. this artifact has not been previously described with other pulmonary artery catheters. the eeg was characterized by an intermittent high amplitude, narrow complex, spike-like artifact followed by a high amplitude slow wave. it is hypothesized that this signal results from current flow to the thermal element of the catheter. neurocritical care patients frequently undergo multi-modality monitoring. this newly identified eeg artifact with cco monitoring has an appearance that may be confused with epileptic spike/wave discharges or burst suppression. the impact of this potential artifact generated by the use of cco devices requires further characterization. as neurocritical care patients increase in complexity and are subjected to more invasive monitoring, the identification of new eeg artifacts may become more common. the diagnosis of gullian-barre syndrome (gbs) is based on a combination of clinical and laboratory features. gbs typically presents as a monophasic, subacute, symmetrically, predominantly motor neuropathy. in rare cases, gbs can present with acute quadriparesis and cranial nerve involvement. we report two cases of patients who presented in a state mimicking brain death with complete dysfunction of efferent nerves which turned out to be fulminant gbs. two cases with rapidly progressive weakness presented to our institution with very rapid deterioration requiring mechanical ventilation. over a very short course of time, both patients became paralyzed with complete absence of brainstem reflexes. brainstem function tests were performed as part of full neurological examination which revealed that both patients had non-reactive mydriasis with complete internal and external ophthalmoplegia. rest of the neurological exam including deep tendon reflexes showed no reponse. due to lack of identifiable cause of patient s condition, further diagnostic test were carried out. both patient s underwent csf analysis which revealed evidence of albuminocytological dissociation. a diagnosis of severe guill i a n-barre syndrome with involvement of peripheral and cranial nerves was suspected. electrophysiological studies were performed that showed this was suggestive of severe, axonal, sensorimotor peripheral polyneuropathy with profuse ongoing denervation in bulbar, cervical and lumbosacral innervated muscles. extensive laboratory evaluation including gq b antibody were carried out. after prolonged course, both patients made some functional recovery. both these cases proved that in rare cases, gbs can present with signs of coma and absent brainstem reflexes. brain-death protocols require that before the declaration of brain-death, an etiology needs to identified that could explain the clinical picture and all reversible causes are excluded. these cases illustrate the importance of electrophysiologic, laboratory and imaging studies in patients with suspected brain death where a cause is not clearly determined. hyperperfusion syndrome is a serious complication after carotid revascularization procedure associated with poor outcome, developing between day to days after procedure. in addition to increased cerebral blood flow, clinical manifestation include headache, seizure and intracerebral hemorrhage. equally rare is stent thrombosis especially in patients who were adequately treated with antiplatelets prior to procedure. distinction between the two condition requires prompt diagnosis to achieve good outcome. case report and medical record review m presented with acute l hemiparesis and was treated with iv tpa. nihss was on admission and after hours. ct brain did not show any acute infarction. cerebral angiogram showed % r ica stenosis.the patient underwent r carotid stenting on day . postprocedure map was maintained between - mmhg using oral and iv antihypertensive agents. hours post procedure the patient developed l hemiparesis, dysarthria, right gaze preference and l hemianopia. blood pressure was augmented to map - mmhg while en route to ct/mri and angiography for suspected acute stent occlusion. patient's hemiparesis worsened. ct brain showed unilateral subtle r hemispheric edema but no hemorrhage. mri showed patchy dwi along r hemisphere with subtle cortical and meningeal enhancement. emergent angiography showed patent stent. blood pressure was immediately controlled to map - mmhg and patient improved. within hours, patient was ambulatory. repeat ct brain did not show any acute infarction. months after discharge, he was asymptomatic. hyperperfusion syndrome can develop even with relatively controlled blood pressure post-carotid revascularization. emergent vascular imaging is necessary to differentiate acute stent occlusion from hyperperfusion syndrome so that appropriate measures may be done. when aggressively managed, symptoms associated with hyperperfusion syndrome are fully reversible if not associated with hemorrhage. fulminant hepatic failure (fhf) or diffuse anoxic injury can lead to the development of cerebral edema and increased intracranial pressure. hypothermia has been utilized in both clinical scenarios in attempt to prevent the development cerebral edema and manage elevated intracranial pressure. in this case, we sought to determine a correlation between brain and core temperatures in specifically in intravascular therapeutic hypothermia (iht) this observation was conducted in a year-old woman with grade iii hepatic encephalopathy (he) due to fhf. iht using coolgard® icy catheter (zoll medical) was started immediately as the patient progressed to grade iii he. esophageal and foley temperature probes were utilized for recording core body temperature. monitoring of brain temperature and intracranial pressure was conducted via licox® system (integra). goal temperature range for iht was between - ° c. brain and core temperatures were recorded hourly during iht which was a period of hours. data was collected and plotted to show correlation between the three temperatures over time. measurements were obtained over the course of hours to log temperatures. the results showed: brain temperature: y=- . x + . . r = . . bladder temperature: y = - . x + . . r = . . esophageal temperature: y = - . x + . . the results show a direct linear correlation between brain, esophageal, and bladder temperatures accurate correlation between brain and core temperatures was demonstrated during ihs. further investigation using larger number of subjects is needed to confirm this. the cerebral circulation is normally pulsatile except for short periods of time in patients subjected to extracorporeal circulation, commonly used during cardiac surgery. a new generation of left ventricular assist devices (lvad) generates continuous, non-pulsatile blood flow. in patients with implantable continuous flow lvad (cflvad), peripheral arterial pulsatility will exist as long as the native heart is capable of maintaining enough contractility to generate some stroke volume during systole. we explored the intracranial circulation with transcranial doppler (tcd) in patients that had a cflvad implanted and were neurologically intact. doppler insonation was performed through the routine temporal and occipital bone windows and proximal intracranial vessels were surveyed. transthoracic echocardiogram was performed in all patients to assess the lv function. / patients ( %) that had some preservation of the native heart function exhibited an intracranial flow pattern consisting of: high end diastolic flow velocity, very low pulsatility index and sometimes a sinusoidal wave appearance coincident with the native heart's systolic contraction. / patients ( %) that had extremely poor heart contractility exhibited a distinctive pattern of continuous flow where it was impossible to distinguish between systolic and diastolic flow. with the advent of new mechanical cardiac support for patients with end-stage heart failure, new peripheral and cerebral blood flow patterns develop and clinicians need to be aware of these distinctive and novel findings. this scenario opens an enormous opportunity to understand and better characterize a new physiological situation. it could also limit the usefulness of bedside tcd as a complementary method for the diagnosis of cerebral circulatory arrest given the lack of pulsation, known generator of the isolated systolic spikes or the "to and fro" pattern considered pathognomonic findings of the absence of intracranial circulation. edgar samaniego , gregory kapinos the advanced cardiovascular life support (acls) and advanced trauma life support (atls) provider courses are excellent resuscitation tools directed towards respiratory and hemodynamic stabilization, nevertheless, survival rates with good neurological outcome are dismal. the neurological content of acls and atls training manuals was reviewed. an advanced neurological life support (anls) course is proposed based on the deficiencies of acls and atls (table) . the neurological content of acls is % and covers only ischemic stroke, with no mention of hemorrhagic stroke or other neurological emergencies. the neurological content of atls is %, with a brief description of intracranial hemorrhages, increased intracranial pressure and spinal cord injuries management. both courses overlooked frequent devastating neurological emergencies like status epilepticus, anoxic encephalopathy, acute paralysis and meningitis. many basic concepts of neurological critical care management are missing in advanced resuscitation courses. we advocate the creation of an anls provider course to improve neurological outcomes of patients who undergo resuscitation. animal studies have shown that even a temperature elevation of one degree celsius can worsen neuronal injury after brain ischemia. since the skull acts as a thermal insulator, we hypothesized that decompressive hemicraniectomy lowers brain temperature by facilitating the heat convection from the brain to its surrounding air. fifty patients with severe brain injury (tbi= , ich= ) requiring continuous brain temperature monitoring (licox, integra lifesciences, plainsboro, nj) from january to march were retrospectively studied and grouped into "hemicraniectomy" (n= ) or "no hemicraniectomy" group (n= ). the core body (t core ) and brain (t br ) temperature measurements were recorded at -min intervals over ± icu days. as a surrogate marker for the degree of external heat loss from the brain, t br-core was calculated as the difference between t br and t core with each recording. t-tests were used to initially assess the difference between groups. then, in order to account for clustering of observations in individual patients, generalized estimating equations (gee) were used to assess association of hemicraniectomy with t br-core , adjusting for core body temperature and diagnosis. ). however, after adjusting for intraindividual variability using gee, only higher core body temperature, but not hemicraniectomy, was associated with difference in t br-core (p= . for t core ; p= . for hemicraniectomy). this suggests that the t br-core temperature difference is larger at higher body temperature. substantial variability exists in the brain-to-body temperature gradient across patients and core body temperatures. however, this difference is not due to the presence of a hemicraniectomy. the assumption is often made that young people would want decompressive hemicraniectomy after a large stroke as a life-saving measure. however, this assumption favoring aggressive life-saving treatment, and the perception of quality of life after neurological disability, have not been adequately studied. we conducted a cross-sectional questionnaire-based survey that consisted of demographic information (age, sex, race, marital and family status, religion, income, education level, access to healthcare), and attitude towards neurological disability (based on the highest acceptable modified rankin scale (mrs) that they would be "willing to live with"). young adults in the los angeles county were surveyed and grouped by whether or not they would want hemicraniectomy after a large stroke despite a high likelihood of disability. findings from the two groups were compared using student's t-test and chi-square test. logistic regression analysis was used to determine the factors predicting willingness to accept decompressive hemicraniectomy. in this pilot study, young adults (mean age: ± ) were surveyed. the highest acceptable mrs ( - ) participants felt "willing to live with" were: . % ( ), . % ( ), . % ( ), . % ( ), . % ( ), . % ( ) . despite a high likelihood of severe disability, of ( %) reported they would undergo hemicraniectomy after a severe stroke. neither the demographic factors nor the highest acceptable mrs were associated with the willingness to seek aggressive treatment and hemicraniectomy. the results from our preliminary study support the commonly held assumption that young adults are generally willing to accept decompressive hemicranietomy as a life-saving measure. however, a substantial subset (~ %) were not willing to accept this aggressive measure, which emphasizes the importance of discussing the individual's previously stated wishes, even in the young population. further study in larger populations is needed to better characterize the factors impacting young adults' decisions regarding aggressive care. . ) , but a trend was noted for ne levels (p=. ), and a significant correlation was seen for dhpg (p=. ). our study supports the theory of a cns mediated adrenergic mechanism for nc, based on the presence of increased csf levels of ne and its dhpg metabolite. recent studies have suggested that recurrent stroke during aspirin treatment might have been caused by biochemical aspirin resistance (bar). we hypothesized that patients with bar would develop early recurrent ischemic lesions (erils) on diffusion-weighted imaging (dwi) more than those without bar. we included consecutive patients who: ) were admitted to our center within hours of stroke onset; ) had a final diagnosis of acute ischemic stroke, confirmed by dwi, or tia; ) underwent follow-up dwi within seven days after initial dwi; ) received aspirin therapy; and ) underwent tests for bar. aspirin was administered to patients soon after initial imaging study. bar was measured using the veryfynow rapid platelet function assay-aspirin (accumetrics inc., san diego, ca). an aru was defined as bar. erils were defined as new lesions on followup dwi with decreased apparent diffusion coefficient, which were not detected on initial dwi scans. the bar is associated with the development of erils during the first week after development of ischemic stroke. this suggests that increased thrombogenicity is one of important mechanisms of erils and that aggressive antiplatelet therapy is warranted during the acute phase. in this study we examined the effects of mannitol % on brain metabolism and brain tissue oxygenation (pbto ) in severely brain-injured patients with intracranial hypertension. twenty-two episodes of raised intracranial pressure (> mm hg) resistant to standard therapy that required infusions of mannitol were prospectively studied in comatose patients with multimodality monitoring of intracranial pressure (icp), pbto , and microdialysis. we compared mean arterial blood pressure (map), icp, cerebral perfusion pressure (cpp), pbto , and brain lactate, pyruvate, and glucose using cerebral microdialysis, for hours preceding and hours after hyperosmolar therapy. time series data were analyzed using a multivariable general linear model (glm) utilizing generalized estimating equations (gee) for model estimation to account for within-subjects and betweensubjects variations over time. g/kg of % mannitol solution led to a maximal reduction of icp at minutes (from ± to ± mm hg, p < . ). cpp increased at a peak of minutes (from ± to ± mm hg, p = . ) after mannitol infusion was started, whereas map and pbto did not change significantly. compared to lactate-pyruvate ratio (lpr) at the time of osmotherapy ( ± ,) , mannitol resulted in a an % decrease over hours (to ± , p = . ). brain glucose levels remained unaffected. mannitol effectively reduces icp and augments cpp, and appeared to benefit oxidative metabolism as measured by the lpr. twenty-eight comatose sah patients that underwent multimodality monitoring with intracranial pressure and microdialysis were studied. mc was defined as lactate/pyruvate ratio (lpr) and brain glucose < . mmol/l. time series data were analyzed using a multivariable general linear model with a logistic link function for dichotomized outcomes. multimodality monitoring included hours of observation (mean ± hours per patient). in exploratory analysis, serum glucose significantly decreased from . mmol/l ( mg/dl) hours before to . mmol/l ( mg/dl) at the onset of mc (p< . ). reductions in serum glucose of % or more were associated with new onset mc (adjusted odds ratio [or] . , % confidence interval [ci] . - . ). this association was independent of the absolute serum glucose level. in a second model we chose an elevation of the lpr by % or more as the outcome variable. again, reductions in serum glucose of % or more were independently associated with an lrp rise (adjusted or . , % ci . - . ). all analyses were adjusted for significant covariates including glasgow coma scale and cerebral perfusion pressure. acute reductions in serum glucose, even to levels within the normal range, may trigger brain energy metabolic crisis and lpr elevation in poor-grade sah patients. hyponatremia develops in up to one-third of patients after subarachnoid hemorrhage (sah), and is usually attributed to cerebral salt wasting or siadh. our goal was to identify risk factors for hyponatremia after sah, and to determine its impact on outcome. we analyzed consecutive sah patients enrolled in the columbia university sah outcomes project between july and june . hyponatremia was defined as sodium level meq/l occurring at any point during hospitalization. multivariate analysis was performed to identify risk factors for hyponatremia. functional disability was evaluated at discharge and months with the modified rankin scale (mrs, score - ) and barthel index (bi, score < ) the frequency of hyponatremia in or cohort was % ( / ). hyponatremia developed on median post bleed day with most cases occurring between days and . logistic regression adjusted for gender and initial hunt- hyponatremia occurs in % of sah patients, is predicted by older age, fever, renal failure and hydrocephalus, and is associated with reversible functional disability at discharge. failure to correct hyponatremia my potentially interfere with rehabilitation and recovery after sah. previous studies have reported that younger patients have a higher incidence of clinical deterioration from vasospasm after subarachnoid hemorrhage. we sought to determine the relationship between age, with the incidence of vasospasm defined by angiographic, tcd, or clinical criteria. we analyzed consecutive sah patients enrolled in the columbia university sah outcomes project between july and june . vasospasm was assessed using angiography and/or a mean flow velocity greater than cm/s in any vessel. symptomatic vasospasm was defined as clinical deterioration (i.e. a new focal deficit, decrease in level of consciousness, or both) and asymptotic vasospasm included a new infarct on ct that was not visible on the admission or immediate postoperative scan. a tcd velocity greater than cm/s was observed in % of patients and of the patients that had follow-up angiography performed ( %), % of those patients had vessel narrowing consistent with angiographic vasospasm. in contrast symptomatic vasospasm was observed in only % of all patients with % of patients suffering infarction attributed to vasospasm. in total % of patients had either symptomatic vasospasm or asymptomatic infarction from vasospasm. multivariable logistic regression revealed that after accounting for disease severity (hunt & hess) , modified fisher score, gender, and history of smoking, younger age was significantly related to the occurrence of angiographic (or: . , % ci: . - . ) and tcd> cm/s (or: . , % ci: . - . ) spasm, but was not significantly associated with symptomatic vasospasm (p=. ) or delayed infarction from vasospasm (p=. ). our data support the findings that younger patients are more likely to experience vasospasm defined by tcd and angiography than older patients, but in our cohort we did not observe a higher incidence of clinical vasospasm or infarction. aggressive treatment of tcd-based and angiographic vasospasm with intra-arterial vasodilators or balloon angioplasty may mitigate the effect of age. post-traumatic vasospasm (ptv) occurs in - % of patients with severe traumatic brain injury (tbi), and is an independent predictor of neurological outcome. although ptv incidence has been associated with injury severity, there are conflicting reports regarding patterns of intracranial hemorrhage that may correspond with development of posttraumatic vasospasm. some authors report that subarachnoid hemorrhage or subdural hematoma is necessary to develop ptv, while others have reported significant ptv in the absence of these lesions. we performed a review of prospectively collected ct scan data from consecutive head injured patients treated at a tertiary level i trauma center. rotterdam ct score data was reviewed from all patients in the tbi registry, and admission head ct scans from patients with severe tbi (gcs ) with (n= ) and without (n= ) clinically significant ptv (csptv) were re-evaluated by a 'blinded' investigator. csptv was defined as demonstrated neurological decline with ct angiographic evidence of arterial vasospasm. rotterdam ct score significantly correlated with the development of csptv(p= . ). the components of this score were further investigated. we found no correlation between epidural hematoma, subdural hematoma, midline shift, or cisternal compression and the development of csptv. the presence of intraparenchymal hemorrhage (p= . ) and cisternal subarachnoid hemorrhage (p= . ), however, significantly correlated with risk of csptv. all cases of csptv were diffuse in anatomic distribution, and, therefore, did not correlate with side of maximal injury. rotterdam ct score, intraparenchymal and cisternal subarachnoid hemorrhage on admission ct are significantly correlated with the incidence of csptv. this suggests that risk of cerebral vasospasm following traumatic brain injury is increased not only in subarachnoid hemorrhage, but also intraparenchymal hemorrhage, and that rotterdam ct score may be a useful metric for assessing risk of csptv in severe tbi patients. we reviewed patients from a tertiary level trauma center tbi registry and identified patients with clinically significant ptv (csptv), defined as demonstrated neurological decline with ct angiographic evidence of arterial vasospasm. patient charts were reviewed to characterize the natural history, treatment and efficacy of treatment in csptv. treatment strategies for patients with csptv included observation, "triple-h" therapy, oral statins, intra-arterial verapamil infusion and tba. the decision to pursue intra-arterial therapy was based on severity of spasm and clinical exam. observation alone was used in patients with mild, diffuse spasm on cta and rapid clinical improvement (n= ), whereas those with persistent signs of spasm all underwent medical therapy (n= ). intra-arterial verapamil infusion was used in patients with moderate to severe spasm (n= ). tba was performed in patients who had severe and diffuse spasm (n= ). in all cases, therapy was effective in reducing (n= ) or reversing (n= ) ptv. three month functional outcome data revealed no significant differences between patients with and without csptv. treatment of ptv is effective in reducing or reversing arterial vasospasm. a variety of therapies exist, which should be chosen based on clinical exam and the degree and distribution of spasm. although it is unknown if treatment improves outcome, our data suggest that patients with csptv have similar outcomes to those without csptv when they are adequately treated. a clinical pathway is presented to aid in the screening, diagnosis, and treatment of ptv. tracheostomy and gastrostomy are common procedures in patients suffering neurologic insults. we report our current data of these procedures performed simultaneously at bedside by a neurointensivist using percutaneous techniques. database of all tracheotomies, gastrostomies and combined procedures performed by the neuro-critical care team was retrospectively analyzed. also, satisfaction surveys by nursing and house staff were employed to reassess and refine the service. all procedures were completed at bedside in the neurointensive care or other intensive care units utilizing two critical care fellows, an intensive care nurse and a respiratory therapist under the direction of the neurocritical care attending. the team followed each patient daily and reported any complication until discharge. complications were categorized as major (requiring additional surgical intervention) or minor (no additional surgical intervention). to date the team has performed over combined percutaneous tracheostomy and gastrostomiesin patients with primary neurologic pathology. there were two major complications and five minor complications reported. the neurologic pathology was mixed as was the,age and weight ranges combined tracheostomy and peg tube placement can be performed safely by a neurointensivist complications rates are low and no catastrophic events reported. attendings, house staff and nursing supports the continuation of this programs the neuro-critical care service now performs the majority of these procedures in our institution based on the success of the service, non-neurologic related services are consulting the neuro-critical care team to perform these procedures. introduction: traumatic brain injury (tbi) is a complex disease state that includes disruption of the blood-brain barrier (bbb) and inflammatory changes. angiopoietins are a family of growth factors integral in maintaining endothelial integrity and controlling inflammation. angiopoietin i (ang ) induces phosphorylation of the tie ligand enhancing endothelial integrity. angiopoietin ii (ang ) inhibits this action. in animal models, ang is up regulated in tbi while ang appears unchanged. injury models in other tissues suggest that the ratio of ang to ang may be significant. little is known about their role in humans with tbi. we collected csf from patients with tbi ( patients) and compared it controls ( patients). individual levels and ratios were compared. each non-tbi csf had < cells/um, negative gram stain and cultures and normal protein and glucose levels. csf samples were collected from the tbi group within hours of drainage placement.. ang and ang were analyzed using an elisa method and reported in pg/ml. the levels of ang in the control group and tbi group were not significantly different (p value of . ). there was significant increase in ang- in the tbi group (p = . ). comparing the ratios of ang and ang , ang was times higher ( : ) in the control group than in the in the tbi group ( . : ). this data correlates with animal data that shows an increase in ang after tbi. this data further demonstrates a significant change in the ratio of ang to ang after tbi. what happens over time and how this relates to severity and prognosis is yet to be investigated. restoring an ang- to ang- ratio to normal may be a therapeutic strategy worthy of investigation. external ventricular drains (evd) and intracranial pressure monitoring equipment are used frequently in neuroscience intensive care units. because of the potential for the development of nosocomial infection prevention is important. current practice varies from using no antibiotics to continuous antibiotics while devices are in place. there is inadequate foundation to support a particular practice. to define practice patterns, a survey was sent to > , neurosurgeons, critical care, neurocritical care, and infectious diseases specialists. the same survey was also submitted to members of the neurocritical care society but filtered to exclude redundancy. ten percent of practitioners solicited responded to the survey. eighty seven percent of respondents were from north america, followed by asia, europe, and south america. twothirds practiced in academic centers and had > years experience. seventy seven percent of respondents were neurosurgeons, followed by neurocritical care, infectious diseases, and critical care. o % peri-operative abx o % use none. one third of respondents use antibiotic coated evd's there are differing practices among the specialties surveyed. a majority of the respondents use abx for the duration the devices are in place. there are differences in practice among respondents based on specialty, geography, years of practice and type of practice. eighty percent of respondents think a randomized trial comparing abx strategies is needed. retrospective chart review of prospectively identified patients. per institutional protocol, patients were cooled to a nadir of c. baseline prothrombin time (pt), partial thromboplastin time (ptt) and platelet count were obtained and followed at least daily during th and rewarming. data was evaluated for the development of new abnormalities following th induction. thirty six patients received th for various clinical indications, including cardiac arrest and intracranial pressure control (related to subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, and traumatic brain injury). duration of goal temperature maintenance varied from hours to hours. after induction of th, / ( . %) showed abnormal pt, / ( . %) had abnormal ptt, and / ( . %) patients developed thrombocytopenia (platelet count < , /µl). in those developing abnormalities, normalization was not seen for any parameter within hrs of rewarming. overall, % of the patients demonstrated some form of new abnormality following th, none of which had clinically significant bleeding episodes. overall, -day mortality was %; no mortality was attributable to th. we concur with the previously reported findings that th is associated with coagulation abnormalities. a high proportion of patients were found to demonstrate such abnormalities, which persisted following rewarming; the exact clinical significance of these findings is not clear. in addition to this standard laboratory testing, changes in radiographic imaging may serve as a more sensitive adjunctive measure to evaluate the significance of th related coagulopathy. transtentorial herniation (tth) is a clinical syndrome consisting of pupillary dilatation with loss of pupillary light reflex and decreased level of consciousness in the setting of a large intracranial mass lesion. reversal of tth is defined as return of pupillary light reflex with or without immediate improvement in level of consciousness. the role of renal function in the mechanism of hypertonic therapy remains unclear. we evaluated the efficacy and safety of . % saline in tth in patients with end-stage renal disease (esrd) on hemodialysis. patients with clinically defined tth and esrd on hemodialysis treated with . % saline ( to ml) were included in the analysis of a retrospective cohort. of subjects over years, we identified patients with esrd that had tth events. lesions were related to stroke (n= ), intracerebral hemorrhage (n= ), and subdural hemorrhage (n= ). all patients received a . % saline bolus, along with mannitol ( % of events), hypertonic saline maintenance fluids ( %), ventriculostomy (n= ), and hemicraniectomy (n= ). clinical reversal of tth occurred in / events ( %); of patients survived to discharge. in patients, icp recording of tth events showed a reduction from icp of . mmhg (mean sem) with tth to . . mmhg (p= . ) one hour after the . % saline bolus. serum sodium increased from . mmol/l to . mmol/l hours after . % saline bolus (p= . ). no patients were undergoing hemodialysis at the time of the tth event, and the post-infusion serum creatinine did not change. treatment with . % saline was associated with rapid clinical reversal of tth and reduction in icp in this small cohort of patients with esrd. this finding supports that hypertonic saline may be effective in cases of esrd. introduction: intubated patients with subarachnoid hemorrhage (sah) may spontaneously hyperventilate despite minimal ventilatory support. the impact of this is unclear, although hypocapnea may be harmful in traumatic brain injury. we set out to determine the incidence of spontaneous hyperventilation in patients with sah and its association with clinical outcomes. we identified consecutive, intubated patients with spontaneous sah from clinical databases ( ) ( ) ( ) . demographics, clinical and ventilation data (for the first days post-bleed) were collected. hypocapnea was defined as an arterial pco <= mmhg. primary outcomes were ( ) the presence of symptomatic vasospasm (defined by both angiographic vasospasm and clinical symptoms); ( ) death in the intensive care unit. associations between hypocapnea and outcomes were explored with multivariate analysis. we identified patients with sah and a median duration of ventilation of days [iqr - ]. hypocapnea was observed on at least one day in patients ( %), and patients ( %) had at least pco < mmhg. all hypocapnea was associated with alkalemia. ventilatory support was minimal (cpap or ps cm h o) in % of hypocanea measurements. sedation normalized pco in % of cases, and use of neuromuscular blockade was rare. median duration of hypocapnea (at least one pco <= mmhg each day) was days [iqr - ]. duration of hypocapnea was associated with increased odds of symptomatic vasospasm (or . for each day with hypocapnea; p= . ) after adjusting for fisher ct grade. duration of hypocapea was not associated with icu mortality after adjustment for apache ii and wfns grade (p= . ). the incidence of spontaneous hyperventilation is high in intubated patients with sah, despite minimal ventilator support. duration of hypocapnea was independently and statistically significantly associated with symptomatic vasospasm. few studies have evaluated physician-family interactions and decision-making in the neurocritical care unit (nccu). we sought to determine if the icu team's use of a structured checklist for family conferences (fc) would improve family satisfaction. we conducted a prospective pilot pre-and post-intervention study. we designed an -item checklist of key content for fc conducted with the intent of making significant patient management decisions. phase i was observational, with a nurse covertly documenting the key content covered during the fc. phase ii was interventional. we asked the icu team to use the checklist during fc to cover all key content. a family member and the icu team member completed an immediate post-fc written survey, and the fs-icu , a family satisfaction survey, was mailed to the family months after nccu discharge. families enrolled ( phase i; phase ii), with patient age ± years, apache iii score ± and nccu los ± days. patients died ( -pi; -pii). median key content covered was items in phase i and items in phase ii (p= . ). in phase ii, icu team member self-report of key content was higher than documented content ( vs. items; p= . ). post-fc survey scores increased from . (phase i) to (phase ii) (p= . ). the fs-icu decision-making subscale median score was . in phase i and in phase ii (p= . ). use of a fc checklist in the nccu marginally improved coverage of key elements in family conferences, however post fc family satisfaction was improved. further evaluation of the influence of checklists on patient outcomes and family satisfaction for family conferences in the nccu is warranted. h. adrian püttgen , jai madhok , xiaofeng jia , anil maybhate johns hopkins university medical institutions, baltimore, md, united states, johns hopkins university school of medicine, baltimore, md, united states, johns hopkins university, baltimore, md, united states sep's represent the brain's response to sensory electrical stimulus. current clinical methods require averaging a large number of sep waveforms for meaningful prognostication. automated sep monitoring could be used as a noninvasive bedside tool for conditions that severely affect somatosensory conduction due to elevating intracranial pressure (icp) such as cerebral oedema or intracerebral haemorrhage. adult wistar rats were used in this pilot study. to model intracranial hypertension, a latex micro-balloon ( µl maximum volume) was surgically inserted into the epidural space via a burr hole on the left hemisphere ( mm off the sagittal suture). using a micro-pump, the balloon was slowly inflated with water at µl/min for two min periods with a min pause. seps were recorded after electrically stimulating the hind limb at . hz. icp was recorded using a transducing catheter inserted in the subdural space over the right hemisphere. balloon inflation was accompanied by a steady increase in the icp. the increase in icp beyond a certain level was accompanied by the sudden disappearance of sep's within a few seconds ( to sweeps). in our pilot experiments, the peak to peak amplitude of the sep dropped steeply from about + µv to + µv before a complete and sudden disappearance when the balloon volume reached approx. + µl. this pilot study demonstrates the effect of an intracranial mass on the integrity of the somatosensory pathway. the finding of a threshold of lesion magnitude after which further expansion causes a dramatic disappearance of sep points to the possibility of using continuous sep for monitoring rapidly evolving mass lesions such as cerebral oedema or intracerebral haemorrhage. we studied the feasibility of intracortical electroencephalography (ice) including quantitative eeg (qeeg) analysis for the detection of vasospasm in a series of poor-grade sah patients. from a consecutive series of sah patients who underwent ice placement, the alpha/delta ratio ( - hz/ - hz; adr) was calculated at twenty second intervals from the ice and scalp eeg recordings. percent changes between averaged values over - hours of the baseline eeg and the eeg prior to angiography were calculated. the entire continuous qeeg recording for each patient was then reviewed to determine optimal automated alarm criteria. ice recordings revealed an improved signal-to-noise ratio when compared to surface eeg recordings. the adr calculated from the ice decreased between baseline eeg and follow-up eeg on average by % (mean adr decrease . ± . to . ± . ) for those with vasospasm (n= ) compared to % ( . ± . to . ± . ) for those without vasospasm (n= ). a sustained decrease in the adr by at least % from baseline for a minimum of hours occurred in patients with vasospasm - days before angiographic confirmation of vasospasm. this was not seen in patients without angiographic vasospasm. eeg recordings from ice are promising to reliably detect vasospasm in severely brain injured sah patients. absence of artifact allows for automated qeeg analysis of ice recordings. raising the head-of-bed (hob) js a very important step in taking care of critically ill patients, particularly in the neurocritical care, as it influences abdominal pressure, decreases incidence of pneumonia associated with aspiration secondary to the decrease in gastroesophageal reflux and reduces intracranial pressure, improving cerebral perfusion pressure. nevertheless, this relatively simple maneuver is still not widely applied. after explaining the goals of raising the hob individually, each health-care worker (hcw) attending in our -bed neurocritical care service was requested to position the hob between and degrees. as our beds are able to measure hob angulation, it was later conferred. after this simple procedure, hcw were again explained and a folder was distributed. it contained a questionnaire and pictures of hob at , , and degrees. later on, they were again requested to position hob at the adequate position. the first poll revealed that out of participating nurses did not or only partially knew the reasons hob should be positioned between and degrees and almost % of the attempts resulted in failures. among physicians, . % only partially knew the reasons. they could rightly position hob in % of the attempts. after the questionnaire, every and each one of the hcw could name the reasons of hob positioning and almost % of the attempts resulted in right results. hcw should be constantly reminded the importance of simple tasks in the care of neurocritical patients. hob elevation should not be regulated by random trials. automatic beds are very important devices, particularly when some features are present, such as hob angulation and, even though it could seem an expensive device, it will finally allow cheaper and less risky expenditures. posterior reversible encephalopathy syndrome (pres) can be caused by hypertensive crisis and is often associated with rapid fluctuations in blood pressure (bp). the role of these bp changes in the pathogenesis of pres has not been formally studied. we sought to analyze the relationship between blood pressure (bp) fluctuations and the occurrence of pres. consecutive hospitalized patients who developed pres were compared with randomly selected controls matched for age, gender, and history of hypertension. systolic bp (sbp) and diastolic bp (dbp) were collected every hours for hours before developing pres symptoms. sbp, dbp, mean arterial pressure (map), and pulse pressure (pp) changes over a -hour window was summarized for each individual by calculating an m value as described by service et al ( ) . m values were compared using wilcoxon signed rank test. tests were two sided and p values less than . were considered statistically significant. we analyzed the bp profiles in cases of pres and controls. median age of pres patients was years (range - ). of them ( %) had pre-existing hypertension. hypertensive encephalopathy was considered the etiology of pres in patients ( %). at symptomatic onset of pres, mean sbp was ± mmhg (range - ), dbp ± mmhg (range - ), map ± (range - ), and pp ± (range - ). while bp was higher in pres cases, hypertension severity was variable and bp fluctuations were not significantly more common than in controls (p values for sbp, dbp, map, pp were . , . , . , . , respectively). bp fluctuations do not appear to be more common in hospitalized patients who develop pres compared with matched controls. other predisposing factors must therefore contribute to the development of pres. technologies allowing emergent detection of focal cerebral hypoxia would be of great utility in the treatment of ischemic stroke by facilitating diagnosis, tracking reperfusion, and identifying re-thrombosis. non-invasive brain oxymetry using near-infrared reflectance spectroscopy (nirs) technology incorporated into the invos device (somanetics, troy, mi), provides direct measurement of regional oxyhemoglobin saturation (rso ) within the cerebral cortex. this study utilized the invos device to determine the predictive value of cortical rso monitoring in the assessment of ischemia in patients presenting with large hemispheric strokes. patients exhibiting acute ischemic strokes involving proximal mca or ica occlusions on ct angiography were enrolled prospectively. the invos device was applied according to the manufacturer's recommendations. rso data was recorded at s intervals for at least hr in each patient. concomitant vital signs, hgb, oxygen saturation, pao , and paco were collected. three out of patients underwent emergent cerebral angiography. a neuroradiologist, blinded to the invos results, evaluated all ct, ct perfusion, and cerebral angiography studies. ct perfusion imaging confirmed large hemispheric strokes in all patients. mean time from symptom onset to start of rso monitoring was hours (range = - ). data analysis consistently demonstrated mean ro saturation levels on the ischemic hemisphere to be either the same or higher than that of the non-ischemic hemisphere. rso levels were independent of bp, hgb, oxygen saturation, pao or paco levels. cerebral angiography demonstrated significant collateral flow over the affected hemisphere despite deep large vessel occlusions. these findings suggest that nirs technology has limited utility in the assessment of patients with acute ischemic stroke. patency of cortical collaterals and increased tissue oxygen extraction during ischemia, among other factors, may offset a decrease of cortical rso within the affected hemisphere. venous thromboembolism is a common problem in critically ill patients. neurosurgical patients even though at higher risk; often do not receive timely pharmacological thromboprophylaxis for fear of bleeding risks. recent literature points towards the safety and efficacy of early prophylaxis (scd's + heparin/lovenox); however this has not been tested extensively in a randomized controlled trial. a retrospective chart review of patients with a primary diagnosis of subarachnoid hemorrhage (sah), intracerebral hemorrhage (ich), and subdural hematoma (sdh) admitted from january to june was conducted for icd- codes of dvt and or pe, and for presence of associated risk factors. all patients received intermittent compression devices (scd's) on all patients from time of admission to time of discharge, surveillance doppler ultrasound evaluation of both lower extremities once every week, and doppler screening of symptomatic upper extremities. overall incidence of dvt was . % (n= ). the incidence of dvt was . % in sah, . % in ich, and . % in sdh. the incidence of pe was . %.the presence of intraventricular hemorrhage was seen in . % of patients with sah who had dvt. this study shows almost double the incidence of dvt than reported in the recent literature. picc line and central lines were associated with higher incidence of dvt.the timing of the diagnosis of dvt falls in a time window where intracranial bleeding risks from anti-coagulation are far less than in the acute stage. this study will provide us a unique cohort of patients whom we can compare in a prospective manner to patients who will receive subcutaneous heparin along with scd's in the future, since we are changing our policy to implement heparin thromboprophylaxis. the presence of intraventricular hemorrhage (ivh) is predictive of worse outcomes following aneurysmal subarachnoid hemorrhage (sah) [ ] . however, the amount of ivh can vary considerably. no previous studies have assessed the association between actual hematoma volume (in ml) and subsequent complications or outcomes. we performed a cohort study involving consecutive patients with concomitant sah and ivh. with investigators blinded to subsequent events, ct scans were graded using two systems. first, to determine the volume of ivh, we used the ivh score, recently shown to correlate exceptionally well with computerized volumetric assessment [ ] . second, to examine the relative amount of subarachnoid blood, we applied the sah component of the hijdra score [ ] . using logistic regression to adjust for sah score and other potential confounders, we assessed the association between ivh volume and poor neurological outcomes (glasgow outcome scale - ), as well as symptomatic vasospasm and delayed infarction. compared with patients who had a favourable outcome, those with poor outcomes had significantly larger baseline ivh volumes (mean . ml vs. . ml, p= . ). in the multivariable analysis, ivh volume remained an independent predictor of poor neurological outcome (or per ml: . , . - . , p= . ). patients in the highest quartile for ivh volume were far more likely to progress to poor outcomes compared with those in the lowest quartile (or . , . - . , p= . ). in contrast, ivh volume was not associated with either vasospasm or delayed infarction. interobserver agreement in the determination of ivh score was good. volume of ivh is a strong, independent predictor of death and poor neurological recovery, even when one adjusts for the amount of concomitant subarachnoid blood. future studies should assess whether measures aimed at accelerating the clearance of ivh (e.g. intraventricular thrombolysis) can modify this association. andrew naidech, kimberly levasseur, storm leibling, rajeev garg, michael shapiro, michael ault, sherif afifi, hunt batjer northwestern university, chcago, il, united states while many icus have implemented protocols for tight glucose control, there are few data on relative hypoglycemia and neurologic outcomes. we addressed the hypothesis that lower glucose leads to worse neurologic outcomes after subarachnoid hemorrhage (sah). one hundred seventy-two ( ) consecutive patients were treated with a protocol designed to achieve serum glucose - mg/dl. we prospectively ascertained patients on admission and recorded medical history and clinical events. glucose measurements from the hospital laboratory were electronically retrieved. (a separate analysis of bedside glucose results found similar results.) cerebral infarction was prospectively documented with neuroimaging. outcomes were assessed with the modified rankin scale (mrs) at days, days and months. worse neurologic injury at admission (p< . ) and a history of diabetes (p= . ) were associated with increased glucose variance. patients with radiographic cerebral infarction ( ± vs. ± mg/dl, p= . ), symptomatic vasospasm ( ± vs. ± mg/dl, p= . ) and angiographic vasospasm ( ± vs. ± mg/dl, p= . ) had lower nadir glucose, but maximum and mean glucose were not different. glucose < mg/dl was earlier and more frequent in patients with worse functional outcome (p< . ). progressive reductions in nadir glucose were associated with increasing functional disability at months (p= . ) after accounting for neurologic grade and mean glucose. severe hypoglycemia (< mg/dl) occurred in one patient. in patients with sah, nadir glucose below the < mg/dl is associated with cerebral infarction, vasospasm, and worse functional outcomes in multivariate models. protocols for target glucose - mg/dl effectively control hyperglycemia, but may place patients with sah at risk for vasospasm, cerebral infarction and poor outcome even when severe hypoglycemia does not occur. andrew naidech, rajeev garg, storm liebling, kimberly levasseur, micheal macken, stephan schuele, hunt batjer northwestern university, chicago, il, united states there are few data on the effectiveness and side effects of anti-epileptic drug (aed) therapy after intracerebral hemorrhage (ich). we tested the hypothesis that aed use is associated with more complications and worse outcome after ich. we prospectively enrolled patients with ich and recorded aed use as either prophylactic or therapeutic along with clinical characteristics. aed administration and free phenytoin (pht) serum levels were retrieved from the electronic medical record. patients with depressed mental status underwent continuous eeg monitoring. outcomes were measured with the nih stroke scale and modified rankin scale (mrs) at days or discharge, and the mrs at days and months. we constructed logistic regression models for poor outcome at months with a forwardconditional model. seven ( %) patients had a clinical seizure, five on the day of ich. pht was associated with more fever (p= . ), worse nih stroke scale at days ( [ - ] vs. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , p= . ) and worse mrs at days, days and months. in a forward-conditional logistic regression model pht prophylaxis was associated with an increased risk of poor outcome, or . ( . - . ) p= . , entering after admission nih stroke scale and age. excluding patients with a seizure did not change the results. levetiracetam was not associated with demographics, seizures, complications, or outcomes. pht was associated with more fever and worse outcomes after ich. posterior reversible leukoencephalopathy syndrome (pres) is characterized by seizures, headache, encephalopathy and visual disturbances associated with reversible vasogenic edema on brain imaging. status epilepticus (se) has been infrequently described as an initial manifestation of pres. the clinical and radiological features of patients with pres and se have not been well described. patients with se were identified from a mostly prospectively collected database of patients (n= ) with pres. we collected data on general demographics, clinical presentation, history of epilepsy, peak systolic and diastolic blood pressures, and predisposing conditions. brain mris were analyzed independently by two neuroradiologists for lesion location and distribution, severity, presence of hemorrhage and presence of restricted diffusion. of patients with pres, ( %) presented with se. only had a prior history of epilepsy. mean peak sbp was mm hg ( - ) and mean dbp was mm hg ( - ). etiologies of pres included hypertension (n= ), cytotoxic medications (n= ), sepsis (n- ) and other (n= ). renal failure was present in ( %) cases and ( %) had pre-existing chronic kidney disease. twelve patients ( %) had a history of autoimmunity. among patients with brain mri, ( %) demonstrated mild edema and ( %) had moderate-severe edema. the cortex was involved in only patients ( %). almost all had edema in the parietal-occipital region (n= , %). when compared with the rest of our pres cohort, we did not identify any significant clinical or radiological predictors of se. se is not an infrequent presentation of pres. its occurrence is not correlated with the severity of radiologic edema and the great majority of patients actually lack cortical involvement. recognition that pres may present with se is important because, besides anticonvulsants, appropriate treatment requires identifying and treating the underlying cause of pres. hypervolemia is known to lead to peripheral and pulmonary edema however the effect on intracranial pressure (icp) following traumatic brain injury (tbi) is unclear. there is no direct evidence in humans linking hypervolemia independently to elevated icp. compelling evidence suggests that fluid restriction should be avoided and limited evidence suggest significant hypervolemia may be associated with worse outcome following tbi [ ] . the use of fluids and vasopressors to elevate cerebral perfusion pressure (cpp) > mmhg has been to shown to increase the risk of pulmonary complications (but not clearly effect icp) following tbi and is not recommended by guidelines [ , , ] . despite this, some ancillary monitoring protocols recommend elevating cpp to treat episodes of cerebral hypoxia. retrospective observational cohort study of severe tbi patients admitted over a -year period to a neuro-trauma unit. data extracted: characteristics; fluid balance; development of refractory intracranial hypertension (rih); pulmonary complications; use of vasopressors; ancillary monitoring. patients with unsurvivable injuries, early withdrawal of care or the development of refractory intracranial hypertension (rih) within hours were excluded. forty-one patients with mean age . ; % male; % automobile accidents; % polytrauma; average best gcs of . (a subgroup presented with higher gcs with declined secondary to neurological injury). rih was associated with lower fluid balance but not hypervolemia (overall q = %, iq = %, q = %). an early low fluid balance and hypervolemia both are associated with more pulmonary complications. the use of vasopressors, and to a lesser extent licox monitoring is associated with a higher incidence of pulmonary complications and possibly rih. [tables - ] % ( / ) % ( / ) % ( / ) q = first quartile, iq = interquartile, q = fourth quartile; rih = failure of first tier therapy by brain trauma foundation; pulmonary complications = ards or pulmonary edema with p/f ratio < ; use of vasopressors = for > hours and > hours to maintain cpp > mmhg following severe tbi hypovolemia should be avoided as it's associated with increased icp and pulmonary complications [ ] . extreme hypervolemia should be avoided, if possible, to minimize pulmonary complications. ancillary monitoring protocols should be used with caution, as the components that may improve outcome versus those that may harm are incompletely defined. without correction for patient demographics, severity of illness, and head ct findings further conclusions cannot be made. invasive mechanical ventilation is required in one third of patients with guillain-barré syndrome (gbs). there are few early indicators of subsequent progression to respiratory failure. adrenal function has rarely been studied in patients with gbs. we assessed the relationship between plasma cortisol level and gbs related complications, notably respiratory failure. plasma cortisol levels were measured before (t ) and minutes (t ) after corticotrophin test in gbs patients at admission, ( %) of which were ventilated within hours from admission, ( %)ventilated after the th hour and ( %) never ventilated. the volume of subarachnoid hemorrhage (including intraventricular blood) following aneurysmal rupture is associated with the development of vasospasm. intraventricular catheters (ivc) facilitate cerebral spinal fluid (csf) drainage and may reduce the incidence or severity of vasospasm but little evidence exists from which clinicians may determine the best practice. the purpose of this study was to provide the foundation for designing a trial that will explore how different methods of csf drainage may impact outcomes in these patients. this observational pilot study enrolled adult sah patients. data was collected through chart abstraction. attending neurosurgeons determined whether each patient's ivc was primarily left open to drain csf resulting in intermittent icp monitoring (drain-first group), versus an ivc that was primarily set to monitor icp resulting in intermittent csf drainage at a set pressure threshold (monitor-first group). subjects were primarily female ( %), mean years old. subjects in the drain-first group (n= ) and the monitor-first group (n= ) had similar hunt/hess (p= . ) and fisher scores (p= . ). although there are no statistically significant differences between groups, this pilot study was not designed to test a hypothesized difference. the monitor-first group had lower mean csf output ( vs ml/day), lower rates of vasospasm ( % vs %), lower incidence of complication ( % vs %), shorter length of stay ( vs days), and lower modified rankin scores at discharge ( . vs . ). this observational study suggests that the method of ivc management may impact clinical outcomes. although the monitor-first group method appears to be favourable, it is difficult to attribute differences in a non-randomized trial. a larger randomized controlled clinical trial is now in progress. introduction: subarachnoid hemorrhage (sah) patients whose initial angiogram does not locate a bleeding source are often classified as having perimesencephalic hemorrhages. however, many patients do not fit into this benign picture and are non-perimesencephalic, angiogram-negative sah (npan-sah). though the conventional angiogram remains the gold standard for diagnosis, multiple non-invasive imaging tests, beyond a second angiogram, are often performed in the acute evaluation of npan-sah. with irb approval, we retrospectively reviewed non-traumatic sah patients admitted to our institution from january , to june , . hunt-hess and fisher scores, in-hospital complications, and imaging data were abstracted from medical charts. non-perimesencephalic angiogram-negative sah has a worse prognosis compared to perimesencephalic sah. additional non-invasive neuroimaging provided no diagnostic yield in either patient population. guidelines suggest an ideal time from injury to surgical decompression of less than four hours in patients with acute traumatic subdural or extradural haematoma. previous audits at our centre showed this standard was not consistently achieved. we looked for a relationship between the length of this time interval and adverse neurological outcome at six months. we retrospectively reviewed all patients with acute traumatic subdural (asdh) or extradural (aedh) haematoma transferred to our neurosurgical centre over a three year period (december -november ) for emergency surgical decompression. we identified the time elapsed from presentation at the emergency department to commencement of surgical decompression. we then assessed neurological function at six months post surgery using a glasgow outcome score. we were able to include patients in our study ( asdh, aedh). the mean time from presentation to surgery was : hours. at six months . % of patients had a good neurological outcome (gos - ), . % had a poor outcome . of those presenting with gcs < , % had a good outcome compared to % of those with an admission gcs of or above. achieving definitive surgery within four hours of presentation, let alone injury remains elusive. we were unable to associate prolonged length of transfer time with worse neurological outcome at six months. our study was retrospective and the numbers were small. our unit accepts a significant number of patients from outside its normal referral area, meaning there may already be a significant delay in many cases. in most cases there was no single identifiable reason for delay and a few cases showed that transfer could be achieved very rapidly. sah patients who had hunt-hess grades - , a ventriculostomy, and tcus performed for at least days were included in this study. csf ml was collected from each patient during the first hours and assayed by hplc for levels of epinephrine (epi), norepinephrine (ne), and dihydroxyphenylglycol (dhpg). mca vs was defined as a mean velocity (mv) > cms/s with a mca/ica ratio of > at any time. analyses were calculated on a per-case and per-vessel basis. of the initial patients included, were excluded due to incomplete data as a result of early mortality or absent bone windows. from the remaining patients, had only ipsilateral bone windows, resulting in a total of vessels amenable to insonation. mean age was yo, and % were female. ct scores (frontera et al.) were = %, = %, = %, & = %. on a per-case basis, patients with mca vs were younger ( yo vs yo, p=. ), but no correlation was observed between mca vs and adrenergic levels. on a per-vessel basis, hh grade tended to correlate with mca vs (p=. ), but again no association was observed between mca vs and adrenergic levels. no connection was seen between csf adrenergic levels and mca vs. our study is limited by small numbers, but our findings are consistent with the available literature whereby the association between the sympathetic nervous system and vs remains uncertain. marek mirski hospital of the university of pennsylvania, philadelphia, pa., united states, johns hopkins medical institutions, baltimore, md., united states dexmedetomidine is an alpha- adrenoreceptor agonist with sedative, analgesic and anxiolytic properties approved for the intubated adult patient in the icu setting. it possesses well described attributes for the neurological population; a rapid ability to sedate and awaken the patient allowing continuing neurologic assessment and no relevant respiratory depression. properties including neuroprotection, cardioprotection and renoprotection have been proposed and investigated in various settings. demonstrated clinical benefits in the icu neuroscience setting are just emerging. this synopsis reviews the literature in regards to clinical studies conducted to evaluate dexmedetomidine in the neurosciences. characteristics of the studies were categorized by study design, setting, patient population, and comparisons to other agents. human clinical studies were identified through a search of pubmed from - . key words include dexmedetomidine, nicu, neurocritical care and cea. study designs include randomized, observational, retrospective and case series. twenty-seven studies were included in the final analysis. the majority are case-studies or anecdotal and the literature consists of mostly surgical patients vs. the icu population. the leading hypothesis is that dexmedetomidine is safe and efficacious in the neurosurgical population and may provide neuroprotection. consistent findings are the attenuation of hemodynamic and endocrine response, smoother extubation and facilitation of neurological assessment. dexmedetomidine has gained popularity in applications beyond its labeled indication and dosage, in various icu's, and in special populations. the literature points to gained acceptance and favorable conditions for sedation without toxicity on cns parameters and a rapidity of onset and offset. there is brevity of literature which demonstrates positive outcomes in the neuroscience setting and the primary data does not represent level or evidence. more studies should be done to validate this drug for common use as there appears to be great advantages in the neuroscience population. the hijdra scale was developed to quantify the volume of blood following aneurysmal subarachnoid hemorrhage (asah). we investigated the relationship of hemorrhage quantity utilizing the hijdra scale and aneurysm size among patients with asah. we prospectively followed up a cohort of sah patients annually to document outcome events after obtaining informed consent. we abstracted demographic, clinical, and past medical history data by chart review on a subset of patients with documented asah after excluding those with cryptogenic, traumatic, and non-aneurysmal sah. the primary outcome of interest, hemorrhage quantity, was analyzed as both an ordinal measure (small, moderate, large) using tertiles and a dichotomous measure using the median. proportional odds logistical models for ordinal response measures and simple logistical regression for dichotomous responses were constructed to investigate the relationship between hemorrhage quantity and aneurysm size. from / to / a total of patients were enrolled in the rush university sah database. of these, we identified patients with documented asah; % were female; % white, % black, % hispanic; and the mean age was ± years. the mean ruptured aneurysm size was . mm and the median hijdra score was (range - ). we found no relationship between ordinal (p= . ) and dichotomous (p= . ) hemorrhage quantity and aneurysm size. no relationships were found between hemorrhage quantity and age, sex, race, apache ii score, and history of anti-platelet use. there was a trend for significance among patients with a past medical history of hypertension and having large hemorrhage quantity (or . , . - . ; p= . ). we found no relationship between aneurysm size and quantity of hemorrhage among patients with asah. future studies should focus on clinical variables such as hypertension and their role in hemorrhage quantity. stroke is the third leading cause of death in the united states. among the stroke subtypes intracerebral hemorrhage (ich), subarachnoid hemorrhage (sah), and ischemic stroke (is), ich and sah are associated with the highest mortality, followed by is. most deaths due to stroke occur within the first days, though it is unclear if any specific stroke subtype carries a significantly higher risk of early mortality (within the first hours from presentation) when compared to the other subtypes. with irb approval, we retrospectively reviewed stroke patients transferred to our institution between november and april who died during hospitalization. we collected data including primary diagnosis, confirmed by ct or mri, and time from presentation to our institution to death from any cause. among the in-hospital stroke deaths, ich was the diagnosis in ( %), sah in ( %), and is in ( % amongst in-hospital stroke deaths, ich was the stroke subtype associated with the highest likelihood of early mortality. this may indicate the severity of the disease process and a lack of effective early therapeutic measures available for ich. cerebral vasospasm is a common complication of sah and remains a major cause of death and disability after aneurysm rupture. the enos promoter (- t>c) cc genotype has been associated with a three-fold increased risk of angiographic cerebral vasospasm, however, its effect on adverse neurologic outcomes after sah has yet to be determined. we hypothesize that enos genotype would predict worse outcome, likely through its effect on risk of vasospasm. subjects included patients with confirmed aneurysmal sah enrolled in a longitudinal cohort study. we analyzed data from subjects for whom we had genotype information as well as -month follow-up assessment. patients who died prior to follow-up were excluded. univariate analyses used chi-square, wilcoxon ranksum or students t-test for the individual predictor variables. modified rankin scale score (mrs) was our primary outcome. logistic regression analysis for poor outcomes (mrs > ) included genotype and adjusted for age, sex, race/ethnicity, and hunt-hess grade. of the subjects, % were dependent or severely disabled (mrs > ) at months. older age, higher hunt hess grade and presence of vasospasm were associated with poor outcomes. the enos (- t>c) cc genotype was associated with mrs> with an adjusted or of . ( %ci . - . ). our results support a trend between enos (- t>c) cc genotype and -month poor functional outcome (mrs> ). although these results are not as robust as the association with angiographic cerebral vasospasm, it demonstrates the ability to integrate genetic information with clinical outcomes. limitations are primarily the small sample size and ability to adequately adjust for all clinical factors that could influence outcome. whether the effect on outcome of enos genotype is related to cerebral vasospasm risk will require further study. therapeutic hypothermia has been utilized in various brain injury models, including aneurysmal subarachnoid hemorrhage (sah). hypothermia has been used to treat refractory cerebral edema or severe vasospasm in this setting. however, there is very little data on hypothermia as a prophylactic measure before potential complications of sah have occurred. we evaluated the safety and feasibility of prophylactic hypothermia in patients with aneurysmal sah. we conducted a retrospective chart review of patients admitted with aneurysmal sah at a tertiary stroke center from july , to june , , who were also treated with induced hypothermia. only patients who had hypothermia initiated prior to symptomatic vasospasm onset were included. a total of out of patients were treated prophylactically with mild hypothermia ( - degrees celsius). three patients presented with hunt and hess grade i-iii, and seven patients with grade iv-v sah. average time at initiation of hypothermia was on sah day (range day - ). six ( %) patients underwent treatment of aneurysm by endovascular coiling or surgical clipping within hours of symptom onset. the average duration of hypothermia was days (range - days). nine ( %) patients developed evidence of vasospasm on computed tomography angiography or transcranial doppler. five ( %) patients survived to discharge. causes of death included irreversible global hypoxia from cardiac arrest ( ), severe refractory cerebral vasospasm ( ), and malignant mca infarction ( ) . all four patients with grade v sah died. when these patients were excluded, of the remaining patients, ( %) survived to discharge, and ( %) died. prophylactic hypothermia may be effective and safe in selected patients with aneurysmal sah. additional studies are needed to further define timing and parameters for therapeutic hypothermia in this setting. melatonin and pinoline are indolamines which have shown an antioxidative direct and indirect protection effect in vitro and in vivo models. fourteen -week-old male, c b mice underwent reversible middle cerebral artery occlusion ischemia ( . hours) followed by hr of reperfusion. the animals received pinoline ( mg/kg i.p.; n= ), melatonin ( mg/kg i.p.; n= ) or vehicle (n = ) at ischemia, immediately upon reperfusion, and at and . hr post-ischemia. another three animals in each group received the same doses but were sacrificed at . hours and used for protein oxidation quantification by western blot. rectal temperature, surgical time, time to ischemia and time to reperfusion were recorded continuously. initial neurological damage by modified stroke score was grossly assessed at ischemia, reperfusion, and at hr. infarction volume was quantified using , , -triphenyltetrazolium chloride (ttc) staining, digital photography, and imaging analysis software. means (± sd) were calculated and compared using student's t-test or anova. p . was set as statistically significant. total hemispheric infarction volume was reduced in the pinoline and melatonin-treated mice compared with the nontreated group ( ± % vs. ± %; p < . ) and ( ± % vs. ± %; p < . ) respectively. pinoline score was . vs. . in the control group at h. no statistical difference was observed in the melatonin group. optical net intensity ratio was statistically significance at cortical level on the kd band in the melatonin and kd on the pinoline groups. pinoline and melatonin treatment appeared to confer neuroprotection on a cerebral ischemia in vivo model. although its anti-ischemic mechanism needs to be elucidated, both molecules are potent free radical scavenging properties may offer a potential therapy. manisha gupte, jay joshi, sayona john, shyam prabhakaran, vivien lee rush university medical center, chicago, il, united states the "weekend effect" phenomenon suggests that admission day of the week is an independent predictor of mortality. we evaluated the effect of weekend admission on sah in-hospital mortality at a single academic center. with irb approval, we retrospectively reviewed consecutive sah patients admitted to our institution from august , to june , . weekend was defined as saturday or sunday. data was collected on day of the week admission, in-hospital mortality, aneurysm type and treatment. ct images were reviewed by the study neurologist and scored for fisher grade. of sah patients admitted to our institution, ( %) were female. the mean age was . years (range, to ). ct brain fisher score was as follows: fisher ( %), fisher ( %) and fisher ( %). the cerebral aneurysm distribution was acom ( %), pcom ( %), mca ( %), multiple ( %), and angiogram negative ( %). surgical clipping was performed in ( %) and endovascular treatment was performed in ( %). the overall sah in-hospital mortality rate was %. weekday admission accounted for %, and weekend admission occurred in %. age, fisher grade, and treatment modality were not significantly different between weekday versus weekend admission. the mean time from admission to treatment of aneurysm was . days and did not differ significantly by weekend versus weekday admission (p . ). mortality rate was % for sah patients admitted on a weekend versus % for sah patients admitted on a weekday (p . ). the weekend effect does not appear to be a significant factor in mortality outcomes of sah patients. the time to definitive aneurysm treatment does not appear to be impacted by weekend admission. the ich score is a simple clinical-radiographic scale in patients with intracerebral hemorrhage (ich) that helps estimate -day mortality. we hypothesize that the ich score can be applied to patients with warfarin ich (w-ich) to help estimate thirty-day mortality. anemia is a highly prevalent condition among hospitalized patients. we hypothesize that patients with acute cerebrovascular disease and anemia on admission have poor prognosis in terms of death, length of stay and disposition. a retrospective analysis of patients admitted to our institution with acute stroke (ischemic, hemorrhagic, subarachnoid hemorrhage) between october and march was performed. they were dichotomized based on hematocrit levels of < , >/= for women and < and >/= for men using the who definition of anemia. covariates used include diagnosis, demographic information and past medical history. the best admission hematocrit cutoff points for distinguishing between those with increased risk of death, disposition to snf (skilled nursing facility), increased los (length of stay) were identified. of the patients, ( . %) were female with a mean age of . years. of these patients ( . %) were anemic. ten patients died and nine were dispositioned to snf. while the relationship between disposition and anemic status was not significant (p= . ), there was evidence that those who died were more likely to be anemic (p= . ). los did not differ statistically between anemic and those without anemia. none of the variables were statistically significant on univariable analysis for mortality. anemia on admission did not predict death, disposition to snf or los, but there was a tendency that patients who died were more likely to be anemic. the admission hematocrit cutoff point for distinguishing risk of death, disposition to snf was slightly lower and increased los was higher than the who definition of anemia. abciximab, a glycoprotein iib/iiia receptor inhibitor (gpiib/iiia), is used during neuroendovascular procedures both to prevent and treat ischemic sequelae. experience with abciximab in this setting is limited and major bleeding complications, including fatal intracranial hemorrhage (ich), are of particular concern. we report our multicenter experience with ich following administration of abciximab during neuroendovascular procedures. we identified neuroendovascular procedures in which abciximab was used at three academic institutions from november through april . cases of periprocedural ich were identified and pertinent demographic, historical, procedural, laboratory, and radiographic data were collected. clinical outcome was measured by the glasgow outcome scale (gos) either at death or discharge. abciximab was used in neuroendovascular procedures; ich cases ( . %) were identified. procedures performed and indications for abciximab use varied. route of abciximab administration included iv bolus only (n= ), ia bolus and iv infusion (n= ), iv bolus and iv infusion (n= ), and iv infusion without preceding bolus (n= ). all patients but one received periprocedural antiplatelet, anticoagulant, or thrombolytic agents. all ich were detected within hours of abciximab administration, (except patient ; hours); were detected within hours. ich patterns varied and included subarachnoid hemorrhage (sah) with intraventricular hemorrhage (ivh) (n= ); intraparenchymal hemorrhage (iph) with ivh (n= ); sah, ivh, and iph (n= ); and a combination of sah, ivh, iph, and subdural hemorrhage (n= ). four patients died following ich (i.e. gos score of ); gos scores at discharge for the remaining cases were (n= ), and (n= ). ich was common ( . %) after neuroendovascular procedures using abciximab and was associated with a % mortality. future management strategies should focus on earlier recognition of gpiib/iiia-related-ich; development of direct gpiib/iiia antidotes; comparisons with shorter-half-life gpiib/iiia drugs; and identification of optimal abciximab dose and route. cerox is a novel noninvasive brain and tissue oxygen saturation monitor based on nirs and ultrasound technology. the purpose of this prospective observational study of patients with both traumatic and non-traumatic brain injuries is to determine if the cerox correlates with existing measures of cerebral oxygen metabolism which are currently used as part of regular care in the management of patients with severe brain injury. we enrolled patients with severe brain injury (tbi = , ich = ) who had at least one invasive cerebral oxygen monitor in addition to an intra-cranial pressure monitor. cerox adhesive patches were placed bilaterally over the frontal regions of the scalp and optical probes were attached to the patch clips. monitoring with cerox continued for up to days. high density physiological data, e.g., map, brain tissue oxygen, jugular venous saturation, icp, were collected at q minute intervals into our neurocritical care database. physiological data were then merged with cerox measurements. ten patients requiring invasive neuromonitoring were enrolled during this -month study period. the duration of noninvasive recording was - days (mean= days) with maximum length of uninterrupted recording being -hours. cerox measurements ranged from - . % (mean = %) on the left and - % (mean = . %) on the right. in this group of patients, the brain tissue oxygen tension ranged from . - . mm hg, the jugular venous saturation was . - % and the cerebral blood flow varied from . - ml/ gm/min. continuous monitoring with cerox is safe and feasible in neurocritical care setting. it has the potential of providing information about cerebral metabolism needed for close monitoring and management of patients with severe brain injury deep vein thrombosis (dvt) is a common complication of intracerebral hemorrhage (ich) and has been associated with immobility in the lower extremities. [ ] atherosclerotic risk factors (hypertension, diabetes mellitus (dm) and hypercholesterolemia) are associated with arterial thrombosis and have been postulated play a role in venous thrombosis. [ ] we hypothesized that a history of atherosclerotic risk factors increases the risk of dvt in ich patients. retrospective analysis of patients diagnosed with spontaneous ich at our institution between january and december was performed. demographics, history of hypertension, dm or hypercholesterolemia; systolic blood pressure at presentation; presence of immobility or hemiparesis and diagnosis of dvt were collected. logistic regression analysis was used to predict the risk of dvt. of patients with spontaneous ich were immobile and were selected for analysis. all patients had sequential compression devices applied on admission. the overall incidence of dvt diagnosed by lower extremity doppler was % and pulmonary embolism was . %. mean time to diagnosis of dvt was . (sd . ) days. after stepwise logistic regression analyses, significant predictors of dvt in immobilized ich patients were, history of hypercholesterolemia (or . p= . ) and sbp on admission > (or . p= . ). immobilized ich patients with a history of hypercholesterolemia were three times more likely to develop dvt. a sbp > on admission was five times more likely to predict dvt. thus atherosclerotic risk factors may play a role in the pathophysiology of dvt in immobilized ich patients, suggesting a possible etiopathologic link between arterial and venous thrombosis. acute ischemic stroke due to the occlusion of the internal carotid artery (ica) is associated with malignant stroke and poor outcome. without revascularization of ica perfusion to the middle cerebral artery (mca) and anterior cerebral artery (aca) is not possible. objective: objective of our study is to evaluate the technical feasibility of emergent carotid artery revascularization using stent and to evaluate the impact of stenting in distal cerebral perfusion. from an established stroke database consecutive patients with acute ischemic stroke who underwent emergent carotid stenting and thrombolysis/clot retrieval of the mca and aca from july to december were enrolled. patients' demographics including presenting national institute of health stroke scale (nihss), degree of revascularization, hemorrhagic conversion and days outcome data using glasgow outcome scale (gos) were collected. successful ica stenting was possible in / ( %) patients. the average age of patients was years (ranges - ) and average nihss was (ranges - ). carotid stenting facilitated successful revascularization of the mca and aca using tpa and merci clot retriever device in patients ( . %), ( %) of which has achieved complete recanalization in the mca and aca. in complete recanalization group a point or higher nihss improvement was observed in / ( . %) patients. symptomatic intracranial hemorrhage was observed in . % patients. seven of patients who achieved complete recanalization had a good outcome. five of patients who did not achieve complete recanalazation of the mca and aca died and had nihss . nihss was associated with incomplete recanalization of the mca and aca with poor outcome. emergent carotid revascularization is not only technically feasible in patients with acute ischemic stroke due to the carotid occlusion, but it also facilitates successful renalization of the mca and aca. further study is necessary. stent-assisted coiling of wide neck intracranial aneurysm requires therapeutic dose of antiplatelets to prevent stent thrombosis. stent-assisted coiling of the ruptured intracranial aneurysms also requires a loading of both loading dose of aspirin and plavix. objective: to report any potential complication associated with the use of both aspirin and plavix in stent-assisted coiling of ruptured wide neck intracranial aneurysm. consecutive patients who underwent stent-assisted coiling for ruptured wide neck intracranial aneurysm were enrolled from to . patient's demographics including the hunt & hess grade, fished scale, use of ventriculostomy catheter, location and size of aneurysm were collected. any complication such rupture of aneurysm, ventriculostomy associated hemorrhage or systemic bleeding was recorded. additionally a days outcome measurement was obtained using glasgow outcome scale (gos). results: patients with mean age of ± underwent stent-assisted coiling. a loading dose of plavix ( mg to mg) and aspirin mg were given prior to stent placement. patients received ventriculostomy catheter, cases before and cases after the procedure. there was no intraoperative ruptured of aneurysm or hemorrhage related to ventriculostomy or systemic hemorrhagic event. there were two episodes of stent thrombosis; one was an asymptomatic which developed during stent-assisted coiling procedure and resolved spontaneously, the other was symptomatic required intra-arterial administration of thrombolytic. there was no mortality and good outcome was observed in % of patient. stent-assisted coiling of the ruptured wide neck intracranial aneurysm using therapeutic dose of aspirin and plavix is not associated with increased bleeding complication such as rupture of aneurysm or intracranial hemorrhage related to ventriculostomy. however, the thromboembolic events remain the main challenge in stent-assisted coiling of ruptured intracranial wide neck aneurysm. therefore, antiplatelets should not be withheld prior to a stent-assisted coiling of ruptured wide neck aneurysm. we have used mild therapeutic hypothermia in patients with severe traumatic brain injury. in this study we investigated the effects of hypothermia on brain tissue oxygenation. brain tissue oxygen tension (pbto ) in addition to intracranial pressure (icp), cerebral perfusion pressure (cpp), and jugular venous saturation (sjo ) were monitored in consecutive patients with a glasgow coma scale score of to (ages to years). patients were cooled to a target temperature of . o c. patients with good recovery and moderate disability on the glasgow outcome scale were regarded as having favorable outcomes. a retrospective review of a six-month period in a university nccu was performed where patients were treated according to the above hypothesis. anticoagulation was usually started with heparin units sq q hr within the first hours and increased to units sq q hr after hours. anticoagulation was increased in many cases to enoxaparin mg sq q hr after another hours. of the patients who received care during the six-month period, patients ( . %) were diagnosed with lower extremity dvt that were asymptomatic in % of the cases. ivcf's were placed in patients ( % of those with dvt). two patients were diagnosed with pulmonary emboli (. %). there were no fatal pulmonary emboli. there were no significant bleeding complications or ivcf complications. surveillance lower extremity venous dopplers every - days, scd's, cs's, and escalating doses of anticoagulation as is tolerated and safe lower the risk of dvt in this high risk population and identify early asymptomatic dvt. fatal pe can be prevented with ivcf placement and more aggressive anticoagulation as permitted by the diminishing risk of bleeding as time passes from the acute injury. heparin induced thrombocytopenia (hit) is a common yet under-recognized condition in the neuro icu. it is caused by an autoimmune reaction to heparin-platelet factor (pf ) complexes which causes activation of platelets and leads to thrombosis. patients with aneurysmal subarachnoid hemorrhage treated by endovascular means are exposed to large doses of unfractionated heparin and therefore may be at high risk for hit. the medical records of consecutive patients with aneurysmal sah were reviewed. diagnosis of hit was made by clinical determination. clinically diagnosed hit is common in the sah population. patients with hit are at higher risk for cerebral infarction, in-hospital mortality and disability. a high suspicion for hit is appropriate in patients with aneurysmal sah treated by endovascular means. mild hypothermia ( - °c) has been investigated in a variety of neurologic diseases and disorders. since the s research has shown that hypothermia provides vital neuroprotection after sustaining brain/spine injury from a trauma, stroke, or cardiac arrest. hypothermia reduces increased icp and improves neurologic outcomes. [ ] [ ] [ ] [ ] translation of the research to clinical practice poses many challenges such as determination of the most effective method of cooling, maintaining hypothermia, and slowly re-warming back to normothermia. a neuro hypothermia protocol was instituted in march . patients underwent mild hypothermia using a hydrogel-pad cooling system. this retrospective study analyzed the data related to induction start times and associated variables (bmi and bsa) and sought to determine whether any correlation existed between the variables and degree/hour induction to goal temperature - + . °c. additionally, data was collected related to hours at °c and assessment of device control of ascent rate to °c. using the pearson correlation coefficient and the bonferroni standard correction method, patient charts were reviewed and data assessed to determine the statistical relevance of several variables: gender-males, age , bmi . , bsa . , induction start temperature . , target temperature . , hour to target temperature . , and temperature descent of . degrees/hour. it was determined that there was a significant statistical association between temperature changes (degrees/hour) and bmi/bsa values. the p-values for the bmi was determined to be . and the bsa . . target temperatures were maintained at °c with minimal variances. the ascent to °c was controlled at . °c/hour for the brain injured patients and . °c/hour for the spinal cord injured patients. the final analysis of the data revealed that an individual's bmi and bsa does directly affect both the induction of hypothermia and the controlled re-warming back to the targeted normothermic goal. mechanical ventilation is associated with worse outcome after intracerebral (ich) and subarachnoid hemorrhage (sah). we sought to examine the predictors of duration of mechanical ventilation. we prospectively identified patients with spontaneous ich and sah who required invasive mechanical ventilation. ventilator settings and measurements were recorded daily from the initiation of ventilation. complications were prospectively recorded. data are presented as mean +/-sd or n(%) when appropriate. variables for multiple linear regression were chosen with a stepwise algorithm (in order of decreasing significance). patients with aneurysmal sah of all clinical grades were prospectively studied. regional anterior alpha power was quantitatively analysed. we assessed alpha power and variability using the product of standard deviation and mean power over a -hour duration, repeated along a window sliding by minutes and graphically displayed. an independent clinician predicted the status of patients as improvement, deterioration or no change from the previous day. this was first done using only clinical data. ceeg trends prior to that day were then presented and another prediction made. results were compared with the true clinical states that were determined independently. clinical evolution in patients who were treated for vasospasm was correlated with daily mean alpha power. coiling followed by clot evacuation is associated with a faster time to aneurysm protection and similar outcome, los, and cost as clipping and evacuation. this may be a viable alternative treatment strategy. using cdsa, icu nurses were the most sensitive at identifying seizures, however they also demonstrated the highest false-positive rate. neurophysiologists and eeg technologists demonstrated slightly lower sensitivity, and much lower false-positive rates. however, on individual eeg recordings performance varied greatly, with group median sensitivities ranging from at % to %. neurophysiologists, eeg technologists and bedside nurses demonstrated comparable performance in seizure identification using cdsa. the observed differences in sensitivity and false-positive rates between different groups of reviewers are smaller than the variability in their performance on individual eeg recordings. coagulation disorders are common after traumatic brain injury (tbi), and may contribute to morbidity and mortality ( ) . these disorders are complex and dynamic over time, making clinical evaluation of coagulation status of the patients difficult ( ) . thromboelastography (teg) has been suggested as a tool for rapid assessment of such states. teg is a test of clot formation and lysis, providing a holistic assessment of clot formation time and strength. it is an easy to perform, point of care test that enables clinicians to differentiate hypo or hypercoagulability, and the factors contributing to each, and evolution over time. the aim of this work is to show the contribution of teg to the evaluation of coagulopathies in patients with isolated tbi. we have retrospectively inspected teg records and routine coagulation studies from patients with isolated tbi, and checked for signs of either bleeding tendency or signs of hypercoaguilation ten patients with isolated traumatic brain injury were evaluated using teg. reasons for tests included workup of suspected bleeding, assessment of hypercoagulable states, or planned invasive procedures. three of these patients showed increased ly , indicating thrombolysis, and two patient showed prolongation of the r value, indicating prolonged clotting time. two patients showed increased maximal amplitude (ma), indicating a hypercoagulable state. thromboelastography is a useful adjunct tool in the assessment of coagulation status in isolated tbi patients, and may help in clinical decision making in such patients. further work, relating thromboelastography results, prognosis and management are warranted. christine hartney, kathryn keim, diane sowa, richard temes rush university medical center, chicago, il, united states the objective of this study was to compare differences in resting energy expenditure (ree) results of critically ill neurology patients based on gender, body mass index (bmi) class and race. this study was a retrospective chart review of patients admitted to the neurosciences intensive care unit at an urban medical center who were started on enteral nutrition support. the research methods received approval from the institutional review board for human studies. the differences between gender, bmi class and race may not have been detected as a limitation of the sample size. research is needed to further explore the relationship among gender, bmi class and race and use of established predictive equations for the critically ill neurology patient. many critically ill neurologic and neurosurgical patients undergo a significant change in functional status or require end-of-life care. therefore, palliative care is an integral part of care provided by neurocritical care physicians and midlevel providers. at times, the needs of the patients and families can overwhelm these clinicians, whose focus is often on curative measure, so there may be a benefit to integrating a formal palliative care consultation service into the neuroicu. an anonymous survey was conducted among the four neuro icu physicians and nine nurse practitioners regarding the integration of a palliative care consult service into the neurocritical care service. the survey consisted of seven "yes" or "no" questions and a write-in section for comments. all providers thought that it was helpful to have the palliative care consult team in the icu, and that they provided added support not just for families, but to the physicians and nurse practitioners. / respondents stated that palliative care was only appropriate for families that wanted to decelerate care. only / responded that they were aware of the existence of formal criteria that were designed to trigger the consultation of the palliative care team. feelings were mixed regarding nurse-driven consults, with only respondents feeling that this was appropriate. in general, the formal palliative care consult service was felt to be a welcome addition. clearly, the existence of formal criteria to trigger a palliative care consult had not been emphasized enough to physician and midlevel providers, and the concept of nurse-driven consults was not accepted by the majority of number of providers. additional comments obtained will be used to improve the process by which palliative care services are obtained. most clinical trials in traumatic brain injury (tbi) have failed to demonstrate a therapeutic benefit. one factor implicated in these failures is an inadequate estimate of the smallest clinically meaningful beneficial effect -the minimal important difference (mid). in this study we surveyed the neurocritical care society (ncs) membership to determine an mid for tbi clinical trials. a survey approved by the ncs research committee was developed to assess the mid that would lead physicians to recommend a new therapy for tbi patients. the survey was distributed online to all ncs members with a -week response period. there were responses ( . %) from ncs members. respondents included neuro-intensivists ( . %), neurologists ( . %), and neurosurgeons ( . %); % were in academic practice on average . years. two-thirds ( . %) cared for to severe tbi patients monthly and . % had participated in tbi clinical trials. one third believed that % of patients would consent to minimal risk trials. the preferred primary outcome measures were mortality, glasgow outcome score (gos), and gos extended, while the sf- , neuropsychological measures and sliding dichotomy were the least preferred. the preferred secondary outcome measures were intracranial pressure (icp) control, therapeutic intensity level (for icp) and repeat imaging. organ dysfunction scores and biomarkers were least preferred. a reduction in unfavorable outcome of % (iqr - %) was reported as the mid needed to introduce a new therapy. mid rather than "number needed to treat" was the preferred method to describe trial efficacy. in this ncs survey, the preferred primary outcome measure for tbi trials was mortality or gos. a % reduction in unfavorable outcome is considered the mid. this information can be used to help define sample size for future tbi clinical trials. compare the quality and sensitivity of electroencephalography signals (eeg) obtained with a disposable template system to eeg obtained by certified eeg technicians. prospectively acquired eeg data were obtained in hour blocks (matched pairs) from leads placed by a certified eeg technician vs. those placed using a disposable template system (brainet®). quality measures included start and end recording of impedance, elapsed time from physician's order to first recorded eeg, and a blinded subjective evaluation of data quality. all segments of data were de-identified and will be read by a blinded reviewer highly experienced in eeg interpretation. analysis from the first subjects of a subject trial is presented here. average impedances in the brainet® group were within recommended guidelines, but were slightly higher than technician applied leads. groups had similar impedance variance, lead failure rates, and maximal difference in impedance at the beginning and at the end of the hour blocks. the difference in mean time to first eeg for the brainet® group ( mins) vs. technician applied leads ( mins) was statistically significant (p< . ). evaluation of sensitivity is pending collection of the remaining data sets. preliminary analysis indicates the use of a disposable template system that allows a non-technician healthcare provider to place eeg leads is feasible and safe. no significant differences in eeg quality during hours of recording were found, and use of brainnet® leads was associated with a significant reduction in the time from order to the first page of eeg data. this preliminary assessment does not allow for conclusions about the overall quality and sensitivity of disposable template leads; the complete set of eeg segments needs to be collected and undergo blinded review. outcome following aneurysmal subarachnoid hemorrhage (sah) is related to various demographic and clinical factors. biomarkers are an increasingly employed means for determining outcome in neurologically injured patients. the purpose of this study is to correlate cerebrospinal fluid (csf) adrenergic compound and metabolite levels to clinical and outcome measures. consecutive sah patients with ventriculostomy had csf collected ml within d of onset. csf was assayed for epinephrine (epi), norepinephrine (ne), and dihydroxyphenylglycol (dhpg) by hplc. levels were compared to various demographnic, clinical, and radiological measures, and to mortality at days. mean age was yo and % were female. hh grade was in %, in %, and in %. no correlation was found for age, but women had greater dhpg levels ( pg/dl vs pg/dl, p=. ). dichotomized hh score demonstrated greater epi levels in g / patients compared to g patients ( pg/dl vs pg/dl, p=. ). patients who died had also greater epi levels ( pg/dl vs pg/dl, p=. ) yet lower dhpg levels ( pg/dl vs pg/dl, p=. ), but regression analysis incorporating hh grade eliminated these associations. in sah, women demonstrate greater elevations in the ne metabolite dhpg, and greater elevations in epi are present in hh grade / patients. patients who die have greater csf epi levels which appears related to the severity of the disease. gail pyne-geithman, opeolu adeoye, jordan bonomo, carolyn koenig, jed hartings, lori shutter university of cincinnati, cincinnati, oh , united states as in clinical neurocritical care (ncc) practice, effective ncc basic science research requires organized interdisciplinary collaboration. the purpose of this abstract is to share our experience in building a basic science collaborative to facilitate the efforts of others and foster discussion regarding engagement of basic scientists in the neurocritical care society (ncs) and ncc research efforts. our institution is active in interdisciplinary ncc clinical practice and fellowship training, in addition to conducting various clinical trials relevant to ncc. collaborating with the clinicians is a core of basic scientists who are working to integrate their funded research into the fabric of care in the neurosciences icu. the composition of the team is truly interdisciplinary, spanning multiple clinical and basic science departments and colleges within our institution. frequent meetings among ncc physicians, surgeons, research nurses in the division of clinical trials and basic scientists have resulted in fruitful collaborations in teaching, research and funding. clinical responsibilities of fellows and residents limits time for bench research, so joining an existing project allows time and resources to be used productively. ncc fellows are teamed with a basic science mentor, and these collaborations often continue beyond the tenure of the fellowship. the basic scientists benefit, as current basic research needs to have translational potential to the clinical setting. basic scientists attend clinical rounds, reinforcing the benefits of truly translational research. gaining a reputation for quality research that enables consistent funding and earns respect from the ncc community requires engagement and input of basic scientists. individual institutions can solicit interested basic scientists to join in their research planning and execution and augment the training of residents and fellows, thus preparing the next generation of research-trained clinicians. the methodist hospital, houston, texas, united states the purpose of this study was to evaluate the association between tight glucose control and the incidence of ventriculitis in neuro intensive care unit with evds the hospital's computer system was used to identify patients admitted between january , and december , to the neuro icu with documented evd placement. patients' years of age or older and deemed to require insulin therapy by the admitting physician were included in the study. we excluded patients if they had evd placement or documented csf infections before admission to the unit, were treated with antibiotics a week prior to admission, and length of icu hospitalization less than seven days. the primary outcome measure was evd related infection. the secondary outcome measures were in hospital and icu length of stay and in hospital death the association between glucose control and positive csf cultures was described using the morning blood glucose for seven consecutive days stratified based on the number of blood glucose readings that fell between - mg/dl. the binary logistic regression model showed that patients with a higher percent of readings in tight blood glucose range were more likely to have cns infection (odds ratio . ; p <. ). the secondary outcomes could not be measured because we did not have enough readings to stratify our data into categories contrary to our hypothesis, the results from our study suggest a possible association between tight blood glucose and an increase in evd related infections. at this time we are unable to make recommendations based on these results given the inherent limitations of our study ; i.e., small sample size, retrospective design, single centered and single morning blood glucose reading to assess glucose control following aneurismal subarachnoid hemorrhage (sah) half the patients' die and only one third of survivors make a full recovery. the optimal hemoglobin (hgb) after sah, however, is uncertain. higher-goal hgb and more red blood cell transfusion (rbct) lead to worse outcome in general critical care. clinical series suggest that rbct may increase vasospasm risk and exacerbate outcome after sah. however other studies suggest that a higher hgb may be associated with better outcome and less cerebral infarction after sah. we now will examine the hypothesis that patient outcome after sah is better when an hgb level of . g/dl rather than an hgb of g/dl triggers transfusion. we propose a multi-center, prospective, phase iii randomized, clinical trial involving adults admitted to university based nicus within hours of sah.. eligible sah patients will be randomly assigned to one of two treatment groups, ) restrictive (hgb of . g/dl) or ) liberal (hgb of . g/dl) transfusion triggers stratified by center and sah severity. the primary objective is to determine if sah subjects who have a restrictive transfusion trigger during the first days of care, are more likely to have a favorable -month outcome than subjects transfused with a liberal trigger. the trial is designed to detect an overall absolute difference of % in the proportion of favorable outcomes (glasgow outcome score of good or moderate disability). secondary objectives include: ) determine if a restrictive policy is associated with less vasospasm. ) examine the relationship between hgb and month outcome and cerebral infarction. the number of randomized subjects is expected to be . the number of randomized subjects is expected to be . to date centers have agreed to participate. this group will receive administrative, statistical and data coordinating support from the university of pennsylvania center for clinical epidemiology and biostatistics. the proposal is under review at the nih. background: brain death (bd) is diagnosed clinically by documentation of coma, absence of brainstem reflexes, and apnea unresponsive to hypercarbia. in argentina (like other countries) other confirmatory tests are required as a part of the diagnostic criteria. the utility of cta with cerebral perfusion was reported by qureshi in and then evaluated by combes et al and they found % false negative rate for the test; moreover, greer et al reported one case of false positive. in spain, otero has reported a sensitivity of % in a series of patients who had cta and ct perfusion. accuracy of cta and ctp must be assessed. we propose that cta and ctp is a reliable confirmatory test for bd, with particular interest in cases where barbiturates or other cns depressant drugs difficult to diagnose clinically or by electrophysiological studies. prospective multicenter study to determine the accuracy diagnostic of brain death with cta & ctp in patients with suspicion of bd according clinical criteria (cc) defined by neurological criteria, apnea test; compared with electrophysiological methods and tcd evaluation. all adults of at least years of age who meet the cc of bd. intensive care unit, emergency department, neurocritical care unit, stroke unit in hospitals with availability of tcd, eeg and multi-row ct hours. in patients with cc of bd, we will be performing ctp and then cta. all the case will be made an eeg and tcd evaluation main outcome measure: evidence of cerebral circulatory arrest. absence of cerebral perfusion sensitivity and specificity, ppv and npv for cta & ctp compared with cc, eeg & tcd. accuracy of cta & ctp in patients with recent utilisation of cns depressor or nm blockers to confirm bd before eeg and tcd. complications rate associated with the use of contrast. renal failure post contrast use. we need at least patients to to achieve a sample size that allows the analysis of sensitivity, specificity and construction of roc. not started. funding is needed to support the project. quantitative diffusion-weighted imaging mri (dwi) in comatose post-cardiac arrest survivors holds promise as a prognostic tool. between and days more than % of brain volume with an adc value < x - mm /sec identifies poor outcome patients with % specificity and % sensitivity (ann neurol ; : - ). this threshold needs validation in an external dataset. we hypothesize that the capacity for recovery of consciousness in comatose cardiac arrest survivors can be predicted with quantitative dwi. multicenter observational study of dwi mris in comatose cardiac arrest survivors obtained between and days after the arrest. patient data will be recorded using a web-based data entry form including baseline characteristics, neurological examinations, results of neurophysiological testing, cause of death, and -day outcome. patients may be entered retrospectively and prospectively. brain dwi scans will be blindly analyzed centrally and an outcome measure (survival versus death or vegetative at days) will be assigned. patients who remain comatose after cardiac arrest and who have undergone dwi between and days after the arrest. main outcome measure: the specificity of the predefined dwi threshold (adc of x - mm /sec) for prediction of poor outcome (defined as death or failure to recover consciousness at days). the sensitivity of the predefined dwi threshold in comparison with the -hour neurological examination and, if available, sseps and peak serum levels of neuron specific enolase. assuming a % survival rate, and % specificity of dwi for poor outcome, patients are needed to achieve a % false positive rate for poor outcome with a % confidence interval of to %. centers are invited to participate. several investigators have expressed interest. background: there have been several randomised controlled clinical trials of weaning from mechanical ventilation which has shown quicker weaning and shorter ventilation time in abrupt discontinuation of mechanical support as opposed to gradual step-wise withdrawal. however, there have been no substantial trials of ventilatory weaning in acute brain injury patients or those with neuromuscular diseases. the neurocritically ill patient on mechanical ventilation will require slower step-wise weaning from mechanical ventilation. multicenter, randomized, non-blinded phase trial feasibility and safety trial. all patients in the neurocritical care unit expected to be on mechanical ventilation for more than days. routine scheduled post-operative patients and patients transferred from outside hospitals already on mechanical ventilation for more than hours will be excluded. neurocritical care unit. patients will be randomized to slow step-wise simv wean versus pressure support wean on cpap. length of time on mechanical ventialtion pneumonia, urgent re-intubation, hypoxia from previous studies in the medical intensice care units, patients, half with acute brain injury, half with neuromuscular diseases. despite the use of appropriate antimicrobial therapies, the morbidity and mortality associated with bacterial meningitis remains high. cerebrovascular complications from meningitis, including vasospasm, have been shown to contribute to this poor outcome. several series have reported tcd velocity elevation correlates with clinical decline and occurs in up to % of patients with bacterial meningitis. to date no systematic large trial has been completed to detect or treat this complication. . phase ii: clinically significant vasospasm in bacterial meningitis results in higher mortality compared with those with normal tcd velocities. . phase iii goal directed therapy: triple h, intra-arterial verapamil and angioplasty will increase survival in patients with bacterial meningitis at high risk for vasospasm. patients admitted to the icu with the diagnosis of bacterial meningitis. phaseii: bacterial meningitis enrolled within hours of diagnosis. subjects receive baseline cta of head/neck, daily tcds, angiography when mean velocities > , daily nihss, mortality rate at one month, and mrs at months. significant vasospasm will be defined as angiographic vasospasm with corresponding increased nihss of at least points. phaseiii: target population from phase ii. all subjects will undergo testing and data collection as outlined in phase ii. subjects randomized to aggressive vasospasm treatment vs. standard-care. in the treatment group, vasospasm will be treated with goal-directed therapy. one month mortality. independent predictors of the presence of vasospasm. rankin score at months. phase ii and iii: inference of portions (alpha . , beta . , delta . , n= subjects) current status: big idea. the outcome of devastating neurologic disease like massive ischemic stroke, intracranial hemorrhage, status epilepticus, and subarachnoid hemorrhage is presumed to be poor. mortality in studies may be influenced by premature withdrawal of care, and not by natural history or chronic complications. if these patients are given maximal supportive care chronically, their outcome will be better than expected based upon commonly accepted morbidity/mortality. randomized, controlled non-blinded clinical trial. patients with devastating neurologic conditions as listed above who require mechanical ventilation (mv) and feeding tube placement (tf). neurocritical care unit of major tertiary care centers as part of a multi-center trial. families are offered usual standard of care-either withdrawal of care or full supportive care. for those not certain about which course to take, enrolment is offered. the trial would necessarily require initial full supportive care such as tracheostomy and feeding tube placement. the patients are randomized to one of two treatment regimens: ) aggressive, long-term supportive care involving treatment of intercurrent medical complications and full resuscitation; ) basic supportive care including mv and tf but not involving these aggressive measures. modified rankin scale at one, two, and five years. continued need for mv/tf, barthel index, correlation with initial hospital care in a specialized neurocritical care unit. assuming a % event rate (severe disability or mortality) in the control group and expecting a % relative risk reduction (about % absolute risk reduction), the estimated sample size with an % power and an alpha of . is patients total ( in each arm). proposal status. how to structure randomization in concert with ethical principles and which supportive measures can be ethically restricted must be determined. intervention: continuous veno-venous hemofiltration via femoral access with total effluent rate of ml kg - h - , blood flow rate between - ml/min, high permeability glycerine free polyethersulfone membrane, filter change every hours, pre-filter replacement fluids: prismasate bgk / / . (osmo ) and sodium-citrate anticoagulant. fluid management per attending physician. minimum duration of hours with termination after - hours of icp control or at hours. secondary outcome measures: change in icp at hours and every hours thereafter; neurological outcome (glasgow outcome scale score dichotomized unfavorable ( , , ) / favorable ( , )); cytokine removal and complications. power analysis: a sample of size will be obtained to attain a power of . at % level of significance current status: idea phase renal replacement therapy in the patient with acute brain injury renal replacement therapy for the patient with acute traumatic brain injury and severe acute kidney injury early changes in intracranial pressure during haemofiltration treatment in patients with grade hepatic encephalopathy and acute oliguric renal failure continuous arteriovenous hemofiltration in patients with hepatic encephalopathy and renal failure cytokine removal during continuous hemofiltration in septic patients fluid thresholds and outcome from severe brain injury adult respiratory distress syndrome: a complication of induced hypertension after severe head injury prevention of secondary ischemic insults after severe head injury combination therapy with hypothermia for treatment of cerebral ischemia clinical study of mild hypothermia treatment for severe traumatic brain injury management of pitfalls for the successful clinical use of hypothermia treatment multicenter trial of early hypothermia in severe brain injury guidelines for the management of severe traumatic brain injury. rd edition none s neurocrit care early decompressive craniectomy for patients with severe traumatic brain injury and refractory intracranial hypertension--a pilot randomized trial renal replacement therapy for the patient with acute traumatic brain injury and severe acute kidney injury continuous renal replacement therapy for refractory intracranial hypertension introduction: many authors suggest using pentobarbital when elevated intracranial pressure or seizures are refractory to other agents. due to the lack of outcome data after the use of this agent, we investigated the outcomes of patients treated with pentobarbital over the past five years. patients were identified using a pharmacy database that tracks inpatient medication dispensing at our tertiary referral center. all patients, older than , cared for in adult icus, who received pentobarbital between and were included. inpatient mortality was compared between patients older and younger than as well as those who required vasopressors using fisher's exact test. twenty-two patients received pentobarbital. the mean patient age was (sd= ). just over half ( %) were men. pentobarbital was used in % of the patients to treat intracranial hypertension; the remainder were treated for refractory status epilepticus. the most frequent underlying disorders were toxic-metabolic disease processes.fourteen patients ( %) died in the hospital. care was withdrawn in %. of the patients ( %) who were alive at the time of discharge: ( %) were discharged to acute rehabilitation, ( %) to an extended care facility, ( %) to sub-acute rehabilitation, ( %) to hospice, and ( %) to home.hypotension, renal failure, and pneumonia were common ( - %) in patient receiving pentobarbital. there was no significant association between inpatient mortality and reason for pentobarbital use. age and need for vasopressors were not significantly associated with in hospital mortality. pentobarbital use was associated with significant morbidity and mortality (greater than %), but % of patients were discharged home or to acute rehabilitation facilities. further study is needed to better clarify the risks and benefits of pentobarbital to treat refractory intracranial hypertension and status epilepticus. the neurologic mechanism leading to unresponsiveness after acute traumatic brain injury is not well understood. posturing reflex examination in evaluating comatose patients is ubiquitous. the reliability of this practice has not been systematically evaluated. from the trauma service registry at a level trauma center, all admissions between from / / to / / where the patient had a head component of the abbreviated injury score > were identified. from this group of , patients, the records of the patients with a glasgow coma scale (gcs) on presentation and a brain ct scan performed in the ed were evaluated. ct scans were scored for injury by location and the motor component of the gcs (gcs m ) was noted from ed documentation. the study population was young (mean age . ) and predominantly male ( %). the gcs m was (indicating extensor posturing or no response) for patients and > (indicating flexor response or better) for patients. on univariate analysis, intra-axial injury above the thalamus did not correlate with the gcs m ( with gcs m , with gcs m > , p= . ). a second analysis of intra-axial injury above the midbrain again showed no reliable correlation with gcs m ( with gcs m , with gcs m > , p= . ). patients with extensor or worse exams were less likely to have a glasgow outcome score > ( ( %) with gcs m , ( %) with gcs m > , p= . ). gcs m responses of flexor or worse did not reliably correlate with injuries at the level of the thalamus or below. however, lower gcs m was still associated with poor gos. this study points to a need for reinvestigation into the neuroanaotmic basis for posturing and unresponsiveness to enhance the understanding and improve acute management of these patients. jeff chen, sandy cecil, patrick chen, susan rowland, sarah callaway, david adler legacy emanuel medical center, portland, oregon, united states since the cma cerebral microdialysis analyzer received fda approval for clinical use in in the united states, cerebral microdialysis has gained increasing acceptance as an adjunct in the multimodality monitoring of the brain after traumatic brain injury, subarachnoid hemorrhage, and stroke. we describe a single institutional four year experience with cma and recent iscus flex . the cma and iscus flex analyzers, cma pump, and cma microdialysis catheters were obtained from cma microdialysis (solna, sweden). perfusion fluid cns (artificial csf) was perfused at . ul/min, and samples collected hourly. lactate, pyruvate, glucose, glycerol, and glutamate levels were entered into the icu pilot program along with neurophysiologic parameters to analyze relationships/trends. all cerebral microdialysis catheters were implanted by board certified attending neurosurgeons at a single community-based hospital. catheters were implanted directly into the brain via a mm diameter corticectomy at the time of craniotomy. catheters were placed via twist drill hole/bolt when craniotomies were not performed. status epilepticus (se) affects , americans yearly. - % of cases fail initial therapy. refractory cases requiring midazolam, pentobarbital, or propofol fail in - % of patients. outcome is independent of the anaesthetic agent or extent of eeg suppression. hypothermia (ht) in rodent models of se abates epileptic discharges and neuronal death. case reports demonstrate ht as an effective adjunctive or primary treatment for refractory se (rse). ht effectively treats rse. multicenter, randomized, non-blinded phase iia trial of ht in rse evaluating target temperature and duration. inclusion criteria: rse patients failing initial benzodiazepines and phenytoin treatment, > yo, and > o c upon admission. exclusion criteria: immunosuppression, active infected, unstable cardiac rhythm, coagulopathy, se secondary to cardiac arrest/anoxia, active chf, pregnancy, in-place ivc filter, or dnr/dni status. eeg monitored patients with rse will be randomized. controls will be managed at the intensivist's discretion. remaining patients will be varied by ht duration ( hr v hr) and target temperature ( - o c v - o c). initially, seizure will be treated with midazolam while endovascular cooling catheters are placed, and a cold saline bolus is given. at goal temperature, midazolam will be weaned to off or the lowest dose necessary for absence of seizure activity. anaesthetic medication requirements and seizure burden (i.e. seizure frequency, duration, and number), from achieving goal temperature until icu discharge, as compared with control. total iv anaesthetic icu duration vasopressor/inotrope requirements modified rankin score at discharge infectious, device, and coagulopathic complications power analysis: > patients (> each arm) would be % powered to detect a % difference in ht vs control (alpha= . ), and a % difference of each arm vs control (alpha= . ), in the primary outcome measures of anaesthetic and seizure burden. a phase i study is underway at washington university and henry ford hospital. this study remains unfunded. traditional dogma has mandated that brain injured patients with a glasgow coma score of < need to remain intubated for airway protection. recent prospective studies have suggested that in brain injured patients with intact airway reflexes, prolonged intubation leads to an increase in nosocomial pneumonias and worse outcomes. a recent randomized trial suggested randomization of brain injured patients into early and delayed extubation is safe and feasible. brain injured patients with a gcs < and intact airway reflexes will not have worse outcomes if extubated early compared to a similar extubation group with delayed extubation until their gcs becomes > . multi-center non blinded randomized phase trial. a non inferiority trial of immediate versus delayed extubation accounting for a . change in modified rankin scores would require patients in each treatment arm for % power. immediate extubation in stable brain injured patients with intact airway reflexes as evaluated by an airway care score. hospital discharge modified rankin score. hospital and icu length of stay, nosocomial pneumonias, reintubations. all intubated adult patients with severe brain injury defined as a gcs< are potentially eligible. exclusion criteria includes: patients < , lack of surrogate informed consent, intubation for therapeutic interventions, anticipated medical or neurological worsening, intubation for airway edema, or prolonged intubation > weeks. a feasibility trial has been completed and published. the study is in search of centers and funding. outcome of patients with ich is dismal. the majority of patients succumb in the first hours to the effect of the hemorrhage causing tissue shifts and herniation. furthermore, many are comatose, ventilator-dependent because of alteration of consciousness brought upon by pressure on midline diencephalic structures. both early hemostatic therapy and surgical evacuation failed to improve outcome simple yet large decompression with durotomy in patients with large, unilateral hypertensive capsulo-ganglionic ich preceded by administration of rfviia for stabilization of clot and thereby prevention of hematoma growth upon decompression should result in less hematoma expansion (safe), reduce pressure on midline structure, and improve mentation and overall outcome study design: randomized, controlled but not blinded, feasibility and safety multi-center trial patients with spontaneous, hypertensive large ( ml) ich located in the putamen and internal capsule with evidence of mass effect on midline structure ( mm septum pellucidum shift), who are not moribund (decerebrate posturing, absent pupillary light and oculocephalic reflexes), and who present within hours from onset of bleed are eligible to be enrolled. patients should have no contraindication to receiving rfviia. patients are screened upon arrival to the er or nicu if transferred directly there intervention: mcg/kg rfviia is given prior to patients undergoing a large, fronto-temporo-parietal decompressive craniotomy with durotomy without clot evacuation. further care like blood pressure control and osmotic therapy will not be standardized. hematoma expansion, improvement in midline shift by % deterioration by points on nihss within first hours following decompression, good outcome at months (mrs ), icu and hospital los, days on mechanical ventilation with a beta level of . and alpha . , an assumed hematoma expansion rate of % in the non intervention group (fast trial placebo group hematoma growth rate) and % in the intervention group, patients are needed to be randomized not initiated yet cerebral vasospasm (cv) after aneurysmal subarachnoid hemorrhage (asah) remains a significant cause of morbidity. intravenous nicardipine has been previously studied clinically as a neuroprotectant, and shown to decrease the incidence of angiographic and symptomatic vasospasm in asah, and has the potential to avoid rescue intraarterial rescue therapy and the resultant complications. hypertensive hypervolemic vasodilatory hhvd for cv will result in a reduction in duration cv, fewer delayed ischemic neurologic deficits (dinds) and better functional outcome. randomized placebo controlled trial of hhvd versus hh therapy. patients with asah, ages - , without a history of coronary artery disease (cad), ischemic cardiomyopathy, neurodegenerative disorder, or chronic kidney disease not on hemodialysis. intervention: hhvd therapy using norepinephrine and continuous nicardipine infusion at mg/hr initiated at the onset of cerebral vasospasm, for a duration of days. intracranial hypertension (ih) is the most powerful predictor of poor outcome in severe tbi. indomethacyn (im) is a cox inhibitor with a potent vasoconstrictive effect in cerebral arterioles that has been used in tbi, avm's and intracranial neoplasm. there is a little of evidence that supports its utility in the treatment of ih with special emphasis in type a waves in patients with an impaired cerebral vasoreactivity, improving both cerebral perfusion and response to other second-tier therapeutic tools. however, large, prospective, randomised and controlled studies have not yet been performed to confirm its benefit in patients with tbi the im could be effective to treat refractory ih in severe tbi with impaired cerebral autoregulation and poor response to other therapeutic strategies. im can improve indices of cerebral haemodinamics and cerebral oxygenation decreasing neuronal ischemic damage. this therapeutic approach can reduce til to control intracranial pressure, also the length-of-stay in icu can be reduced too. im can improve long term functional outcome in severe tbi. multicenter, randomized controlled trial to evaluate the efficacy and safety of im in patients with severe tbi that presents intracranial hypertension which have reached a therapeutic intensity level that includes second-tier therapies (ie,deccompresive craniectomy, controlled hypothermia, etc) all patients (older than years old) that presents with glasgow coma scale or <, with icp above torr and with any evidence of hyperaemia (tcd, sjvo , avdo etc) or increased cbv (ct perfusion, etc) despite standard therapy (includes mechanical ventilation, evacuation of intracranial mass, profound sedation, osmotherapy, etc). intensive care unit or neurocritical care unit or neurotrauma unit at a hospital that has multimodal monitoring modality (icp, cpp, etco or pco , sjvo or ptio , tcd etc) and neuroimaging with evaluation of cbv (ct perfusion, etc) indomethacyn . - . mg/kg at loading dose, followed by continous infusion . - . mg/kg/hr or placebo in patients who develop high icp despite standard therapy for icp control. icp control (reduction of icp below torr or torr in dc), normalization of cerebral oxygenation (avdo , sjvo or ptio ). improvement of cerebral perfusion measured by cuantitative or cualitative methods neurological outcome (egos) at discharge, , , and days. overall mortality at month , and qol at month , and evidence of long-term ischemic damage we need a sample of at least patients to find statistically significative difference between intervention and placebo group. not started. financial supports is needed. hyperglycemia is very common in acute brain injury (abi) from ischemic stroke, hemorrhage or trauma and is associated with poor outcome. tight glucose control is effective in improving outcome in medical/surgical icu but its role in abi is uncertain. studies investigating brain metabolism using microdialysis showed increased brain metabolic crisis with tight glycemic control. currently the optimal glucose control for patients with acute brain injury is unclear. aggressive hyperglycemia management will result in improved outcome in abi compared with standard glucose management. multicenter, randomized, single-blinded phase ii feasibility and safety trial. inclusion criteria: patients admitted to icu for management of abi with high likelihood of requiring at least hours of intensive care. absence of health care proxy to sign consent. patient with do not resuscitate and do not intubate orders on admission history of allergy or known contraindication to insulin moderate to severe baseline disability (pre-abi modified rankin scale or greater) severe terminal concurrent medical illness with expected survival of less than three months. neurocritical care unit. treatment arm will receive continuous insulin infusion targeting blood sugar level - mg/dl. control group will receive subcutaneous insulin injection and/or insulin infusion targeting blood sugar level - mg/dl. modified rankin scale at months rate of medical complications, including infection, new neurologic abnormality, hypoglycaemia and in-hospital mortality.length of icu, hospital stay. based on our retrospective study with expected good clinical outcome of % and % relative difference in outcome between groups, the study will need patients in each arm with % power and % two-sided alpha level. protocol complete. for submission for funding. rebleeding on the first day following asah is as high as - %, and approximately half of these occur within hrs of onset. unanticipated delays in asah diagnosis and result in failure to secure aneurysms during the period of maximal rebleeding. a novel approach of acute antifibrinolysis (< h duration) has demonstrated safety, however, there have been no trials powered to demonstrate a difference in long-term outcome. therefore, a clinical trial evaluating the impact of -aminocaproic acid (eaca) on outcome following asah is warranted. acute treatment with intravenous eaca will improve twelve-month outcome in patients with asah. neurological emergency treatment trials (nett)-based multi-center, randomized, double-blind, placebo-controlled phase-iii trial. all adult asah patients presenting to nett facilities will be screened for enrollment. patients must receive study drug within h of asah onset. those with aneurysm-negative sah, anticipated treatment within h, or recent thromboembolic disorder will be excluded. subjects will be enrolled and treatment initiated in the emergency department and continued during transfer and the referral-center intensive care unit. patients will receive an intravenous placebo or eaca. a g loading dose, will be followed by infusion of g/hr, to a maximum h. favorable -month modified rankin score( - ) the barthel and lawton scales(disability scales), sip(quality-of-life scale), and a psychometric battery(cognitive/intellectual domains) will be assessed as secondary outcomes. known sequelae of asah and antifibrinolytic therapy including rebleeding, vasospasm, hydrocephalus, and thrombotic complications will be tracked. based on a analysis with = . and a power of %, subjects will be randomized. this calculation is based on conservative estimates from past studies that demonstrate % increase in favorable outcome for patients receiving acute eaca. based on a analysis with = . and a power of %, subjects will be randomized. this calculation is based on conservative estimates from past studies that demonstrate % increase in favorable outcome for patients receiving acute eaca. additionally, there are also associated nonlinear hospital system factors, hi, probably accounting for positive preclinical and single center studies, followed by multicenter failure. the severity regression equation can now be described asthis leads to the notion that the current widely accepted methods of evaluating single facet therapy to attenuate such multifaceted complex problems is generally a fruitless waste of public resources which has produced innovation paralysis.preclinical studies have demonstrated the potential for dramatic breakthrough level neuroprotection with a multifaceted approach but a rational systematic method for introduction of multifaceted therapeutic bundles is needed. multifaceted neuroprotective bundles can be used to demonstrate robust neuroprotection. can the plan-do-study-act (pdsa) qi method be used to incrementally add and evaluate individual facets of neuroprotective therapeutic bundles? single center pdsa therapeutic bundle development followed by multicenter randomized trial of a therapeutic bundle. patients with acute tbi or brain ischemia syndromes setting: ed, or, and icu multi mechanism multifaceted therapy incrementally and sequentially implemented during active post insult secondary pathophysiologic processes. surrogates for functional outcome with sequentially added facets in a therapeutic bundle ongoing evaluation of functional neurologic outcome. none yet background: refractory intracranial hypertension (rih) is associated with death or poor neurological outcome in - % of patients and clinical equipoise often exists among management [ ] . for patients with cerebral edema or intracranial hypertension who require renal replacement therapy, continuous (crrt) modes are preferred due to limited data showing improved intracranial stability over traditional intermittent hemodialysis (ihd). this is attributed to better cardiovascular stability, less rapid fluid shifts, bicarbonate and osmolality changes as well as more biocompatible, and highly permeable membranes [ ] . anecdotal reports have suggested improvement in intracranial pressure (icp) [ and verbal] during crrt and we have observed this in patients (table , figure - patients with persistent disorders of consciousness, defined as the absence of response to simple orders, days after the event unexplained by sedation. signed informed consent. inclusion of tbi and non tbi comatose patients (ischemia, sah, hematoma and cerebral anoxia). neuroicu. mri under mechanical ventilation. inclusions during years. follow up at months and one year by phone interview. electronic crf. multimodal mri with mrs (pons and csi) and dti under mechanical ventilation. controls per center. predictability of dichotomized gos at year using a composite index combining clinical data and quantified indicators from mrs (naa/cr in specific brain regions) and dti. design of specific algorithms according to the etiology of coma. with subjects, % of power to detect a variable with an or by standard deviation of . ( = %, bilateral test, proportion of patients with poor outcome = %, nquery advisor® . ). % of lost to follow-up within year and % of drop-out. total tbi to be included = . same reasoning for non tbi patients. founded in france €. european actively including patients following a similar protocol. patients already included (tbi patients, anoxia , intracerebral hematoma , sah , arterial ischemia ). mortality rate at one year %.financial support: none key: cord- -jfp uumb authors: papali, alfred; adhikari, neill k. j.; diaz, janet v.; dondorp, arjen m.; dünser, martin w.; jacob, shevin t.; phua, jason; romain, marc; schultz, marcus j. title: infrastructure and organization of adult intensive care units in resource-limited settings date: - - journal: sepsis management in resource-limited settings doi: . / - - - - _ sha: doc_id: cord_uid: jfp uumb in this chapter, we provide guidance on some basic structural requirements, focusing on organization, staffing, and infrastructure. we suggest a closed-format intensive care unit (icu) with dedicated physicians and nurses, specifically trained in intensive care medicine whenever feasible. regarding infrastructural components, a reliable electricity supply is essential, with adequate backup systems. facilities for oxygen therapy are crucial, and the choice between oxygen concentrators, cylinders, and a centralized system depends on the setting. for use in mechanical ventilators, a centralized piped system is preferred. facilities for proper hand hygiene are essential. alcohol-based solutions are preferred, except in the context of ebola virus disease (chloride-based solutions) and clostridium difficile infection (soap and water). availability of disposable gloves is important for self-protection; for invasive procedures masks, caps, sterile gowns, sterile drapes, and sterile gloves are recommended. caring for patients with highly contagious infectious diseases requires access to personal protective equipment. basic icu equipment should include vital signs monitors and mechanical ventilators, which should also deliver noninvasive ventilator modes. we suggest that icus providing invasive ventilatory support have the ability to measure end-tidal carbon dioxide and if possible can perform blood gas analysis. we recommend availability of glucometers and capabilities for measuring blood lactate. we suggest implementation of bedside ultrasound as diagnostic tool. finally, we recommend proper administration of patient data; suggest development of locally applicable bundles, protocols, and checklists for the management of sepsis; and implement systematic collection of quality and performance indicators to guide improvements in icu performance. around the world differ in available resources, and our working group [ ] and others [ ] have different definitions what an icu entails. in this chapter, we aim to answer seven questions basic prerequisites for quality intensive care in resource-limited settings: ( ) which healthcare professionals should provide care in icus in resourcelimited settings? ( ) how should these healthcare professionals be trained? ( ) how should electricity be supplied to icus in resource-limited settings? ( ) how should oxygen be supplied to icus in resource-limited settings? ( ) which hygienic facilities are fundamental in icus in resource-limited settings? ( ) which technical equipment should be available in icus in resource-limited settings? ( ) which quality measures to improve care should be implemented in icus in resourcelimited settings? we provide a series of simple, pragmatic recommendations for optimizing icu infrastructure and organization in resource-limited settings, with a focus on adult icus (table . ). understanding the great variability of technical, material, and human resources within and between these environments, each institution must determine the utility of implementing these recommendations based on local capabilities. in resource rich settings, intensive care medicine has evolved into a multidisciplinary and team-based approach. involvement of icu physicians and other healthcare professionals results in better outcomes and reduces costs of care [ , ] . postgraduate training in the specialty of intensive care medicine is becoming more commonplace for icu physicians, icu nurses, and even allied healthcare professionals in most high-income countries [ , ] ; training in intensive care medicine is commonly available for physicians from different medical specialties. most training programs last at least year and end with a national or international examination [ ] . accreditation and certification in different sub-specialties (e.g., neuro-intensive care) or examination techniques (e.g., echocardiography, lung ultrasound) can be achieved in some countries [ ] . studies in resource-rich settings show that the physician-staffing model in use affects outcomes of critically ill patients [ ] [ ] [ ] . in comparison to a so-called open icu model, in which physicians from outside the icu remain directly responsible for the care of their patients, a so-called closed icu model, in which one or more physicians, usually trained in intensive care medicine, and exclusively based within the icu, become responsible for the critically ill patients, results in lower mortality rates, shorter length of stay, and reduced costs of care [ ] . studies in resource-rich settings also show that the nurse-staffing model affects outcomes of critically ill patients [ ] . more nurses available per icu bed improves survival rates, particularly for patients at a high risk of dying [ ] , reduces postoperative [ ] and infectious complications like ventilator-associated pneumonia [ ] , and prevents medication errors [ ] . a higher nurse-to-patient ratio is also independently associated with a better compliance with, for example, sepsis care bundles [ ] . notably, a higher nurse-to-patient ratio prevents burnout of nurses [ ] . studies in resource-rich settings also suggest that the presence of allied healthcare professionals like pharmacists [ ] , respiratory or physical therapists [ ] , and dieticians [ ] within a multidisciplinary icu team improves patient outcomes [ ] . furthermore, proactive communications with infectious disease specialists or microbiologists favorably affect antibiotic use and costs [ ] . finally, so-called telemedicine in icus in resource-rich settings, mainly to solve the problem of physician shortages during nighttime hours and in some icus with low-intensity staffing [ ] , has been shown to improve early identification of patients who deteriorate [ ] and increases the number of interventions [ ] , but the effect on icu outcomes remains controversial [ ] and costs of required technological infrastructure are high [ ] . there is minimal evidence from resource-limited settings that icu outcomes improve after changing from an "open icu model" to a "closed icu model." one equipment acquisition of technical equipment should be guided by local availability and feasibility of routine maintenance (ug). we recommend basic vital signs monitors (including electrocardiogram, respiratory rate, oscillometric blood pressure, and pulse oximetry) available for each icu bed ( c). we recommend that icus have one or more mechanical ventilators available ( c). these mechanical ventilators should also deliver noninvasive ventilatory modes, measure tidal volume and airway pressures, and support oxygen delivery ( b). we suggest that icus providing invasive ventilatory support have the ability to measure end-tidal carbon dioxide ( c) and to perform blood gas analysis ( c). we recommend that icus have point-of-care capabilities for measuring blood glucose (e.g., glucometers) ( b). we recommend that icus have capabilities for measuring blood lactate levels ( b). we suggest that icus have available point-of-care ultrasound devices ( c) and that key clinical staff undergo formal ultrasound training ( c) quality we recommend maintaining patient records and icu documentation in accordance with national regulations and requirements ( d). we suggest that icus develop locally applicable bundles, protocols, and checklists to improve quality of care ( c). we suggest that icus systematically collect quality and performance indicators and participate in national/international benchmarking projects ( c) abbreviations: icu intensive care unit, ug ungraded before-after study from thailand showed a % absolute mortality reduction (from . to . %, p = . ) and shortening of length of stay of . days (− . to − . , p < . ) in a surgical icu [ ] . the reduction in mortality was greatest in patients with a length of stay > h ( . vs. . %, p < . ). a prospective before-after study in a large university hospital in turkey demonstrated a . -fold reduction of in-hospital mortality after introduction of the "closed icu model" [ ] . the survival effects were most prominent in patients requiring mechanical ventilation. postgraduate training programs in intensive care medicine for physicians have been established in selected resource-limited settings such as india [ ] , ethiopia [ ] , brazil [ ] , china [ ] , and south africa [ ] , but the literature fails to report on outcome changes after its establishment. no studies have been published from resource-limited settings evaluating patient outcomes related to nurse-to-patient ratios. evidence from resource-limited settings confirms the benefits of including pharmacists into the multidisciplinary icu team on patient outcomes [ ] . studies from china, thailand, jordan, egypt, and vietnam demonstrated consistent reductions in medication costs [ ] [ ] [ ] and adverse events [ ] after involvement of a pharmacist in daily icu practice. no studies on the effects of including physicians from other backgrounds (e.g., infectious disease specialists) or allied healthcare professionals (e.g., psychologists, case managers, social workers, respiratory therapists, dieticians, or physical therapists) into icu teams in resource-limited settings were identified by our search. data on implementation of telemedicine in resource-limited icus is minimal despite reports of successful implementation in areas with a scarcity of specialists [ ] . only one study, performed in india in patients with acute myocardial infarction, showed a reduction in mortality following implementation of telemedicine [ ] . despite the trends indicating that a "closed icu model" improves patient outcomes in resource-limited icus, human resources are inconsistently available in most of these settings. the number of physicians per inhabitants is substantially lower in low-and middle-than high-income countries [ ] . this leaves many hospitals in resource-limited areas with a critical shortage of physicians, particularly during off-hours, weekends, and holidays. from the authors' experience, in some hospitals, a physician is completely absent during nighttime. patient care is then, for example, overseen by mid-level providers, such as clinical officers. no systematic data on the availability of physicians specialized in intensive care medicine have been published for resource-limited settings. there also are no studies detailing the relevance of icu training methods typically found in resource-rich settings amid the different cultural and disease pattern contexts of resource-limited settings. despite the availability of specialty training programs in selected countries, regional data and the experience of the authors suggest that intensive care specialists are unavailable in many icus in resource-limited settings [ ] . some icus in sub-saharan africa are, for example, run and staffed by "anesthetic officers" (non-physicians with specific training in certain elements of anesthesia) in close cooperation with surgeons, internal medicine specialists, and pediatricians [ ] [ ] [ ] [ ] . the number of nurses per inhabitants is substantially lower in low-and middle-than in high-income countries [ ] . consequently, the number of nursing staff is limited in many icus in resource-limited settings [ ] . limited availability of nursing staff in resource-limited icus naturally leads to low nurse-to-patient ratios of often : or higher, particularly during off-hours and weekends. it can be assumed that similar associations between nurse-to-patient ratios and outcomes exist in resource-limited and resource-rich settings. however, given the general shortage of nursing staff, especially those trained in intensive care nursing, it is highly questionable whether cutoff values for nurse-to-patient ratios established in resource-rich setting specific guidelines (e.g., : ) can be extrapolated to icus in resource-limited settings. allied healthcare professionals, such as physiotherapists and dieticians, are usually unavailable in many, if not most, resource-limited icus [ ] . if these healthcare professionals are available in the hospital or even the icu, they are, in the experience of the authors, often not trained or experienced in caring for the critically ill patient. accordingly, dedicated critical care pharmacists are uncommon in many resource-limited icus [ ] , and even if available, their presence during icu rounds, where benefits are strongest [ ] , is limited [ ] . in addition, high staff-related costs may strain or exceed tight budgets of hospitals and be another reason why a multidisciplinary icu model appears less feasible in resourcelimited than in resource-rich settings. in the absence of dedicated icu staff, family members often assume an important role in caring for the patient. increasing global internet connectivity and the ubiquity of mobile phones could facilitate low-cost icu telemedicine and translate to rapid and accessible icu consultative services in some resource-limited settings [ ] . however, related implementation and maintenance costs, unavailability of stable internet coverage in many rural or remote areas, and questions of credentialing and accountability for out-ofcountry-based telemedicine providers remain ongoing challenges. author experience suggests that telemedicine links between "sister hospitals," one in a resource-limited setting and one in a resource-rich setting, may provide meaningful collaboration and educational opportunities on both sides. finally, we could not identify any safety considerations to the implementation of a multidisciplinary team approach in icus in resource-limited settings. we suggest that, if possible, icus use a closed-format model where physicians specifically trained or experienced in intensive care medicine direct patient care ( b). we further suggest that icus be staffed with nurses who are trained in intensive care nursing ( c). wherever available, allied healthcare professionals (e.g., pharmacists) should be part of an icu team (ungraded). currently, no recommendation on icu telemedicine in resource-limited settings can be made. the care of the critically ill patient substantially differs from noncritically ill patients and thus requires specific training of all healthcare professionals involved due to the complex care requirements. high-performing icus are typically staffed with icu physicians and nurses and allied health professionals who, in addition to general training, have pursued further training in intensive care. regulatory bodies in these settings frequently consider specialty certification as a prerequisite to permanently work in an icu. however, formal intensive care specialty training programs are rare or nonexistent in resource-limited settings. this lack of specialty education is likely to translate into limited knowledge about the pathophysiology and diagnostic and therapeutic management of critically ill patients [ ] . it remains unclear how healthcare professionals working in icus in resource-limited settings, where no established regional or national specialty education programs in intensive care medicine exist, should be trained. the majority of studies from resource-limited settings describe small-scale, focused training courses in individual institutions and pre-and post-course tests of knowledge. four investigations, one in ghana [ ] and three in sri lanka [ ] [ ] [ ] , were about regional or national training programs for physicians, icu nurses, and physical therapists. dedicated courses in trauma and intensive care-and emergency medicine-related procedures improve knowledge in "best clinical practice" of healthcare professionals working in icus in resource-limited settings [ , ] . focused training programs that use well-established training models, such as the "fundamental critical care support" course, facilitated immediate knowledge gain, especially in junior clinicians or those with limited practical experience taking care of critically ill patients [ ] . however, data on influences on patient care and longterm knowledge retention are limited. intensive care-specific courses also demonstrated benefit in allied health professionals in resource-limited settings [ ] . a national train-the-trainers program for critical care nursing in sri lanka was structured as seven educational blocks over a period of months [ ] . using didactics, simulation, and small group learning, by , this program trained nurses and faculty and allowed local trainers eventually to take command of course directorship. in ghana, a countrywide continuing medical education course in acute trauma management was developed, and targeting general practitioners in rural hospitals showed significant knowledge retention and critical procedural skills improvement even year after course completion [ ] . in locations where institutional, regional, or national courses are unavailable, the use of mobile health technology to facilitate intensive care education and training is of great interest. a pilot study in haiti showed that non-physician ultrasound learners, linked to ultrasound instructors in the united states via mobile phone video chat technology, can learn how to obtain clinically useful ultrasound images [ ] . validated e-learning methodologies are also in use to enhance critical care education and capacity in cambodia, although specific outcomes have yet to be declared [ ] . among nearly all available studies from resource-limited settings, a universal theme is partnerships between an institution based in a resource-limited and one in a resource-rich setting. these partnerships, when successful, can evolve from simple facility-to-facility ventures [ ] to more longitudinal, systems-based programs [ ] . whether approached vertically (institution-based) or horizontally (systemsbased), partnerships also permit local personnel in resource-limited settings to advance knowledge or develop specific skill sets while remaining in their setting. in many cases, the goal is for the resource-limited settings partner to administer the program independently. one successful example of such a horizontally integrated program is the east african training initiative, a pulmonary/critical care fellowship training program in addis ababa, ethiopia [ ] . in partnership with the ethiopian ministry of health, international professional societies, nongovernmental organizations, and a consortium of universities in europe and north america, a growing cadre of domestically trained intensive care physicians is now assuming leadership roles in icu education and clinical care in the country, where only a few years ago no such opportunities existed. a similar project has been established successfully to train nurses in emergency and critical care medicine in ethiopia [ ] . dedicated and sustainable partnerships at national and international levels incorporating both vertical and horizontal planning, such as the east africa training initiative, require funding, enormous coordination, and sustained buy-in from numerous parties with diverse interests. consequently, such partnerships are likely less feasible and more expensive to establish; however, they are more likely to have lasting success. partnerships between individual institutions in resource-limited settings and professional societies in high-income countries are also possible but may lack sustainability. a serious risk to such partnerships is "brain drain," the emigration of well-trained and specialized healthcare workers from resource-limited to resource-rich settings or from low-and middle-income to high-income countries [ ] . solutions to the "brain drain" are complex and must involve systematic national programs to facilitate return of well-educated emigrated healthcare professionals to their home countries. small-scale initiatives, such as intermittent, institution-level icu training courses like the "fundamental critical care support" course and others, are least likely to provide long-term benefit given their temporary nature. the teaching content may be difficult to implement in some resource-limited settings. furthermore, start-up costs for formal courses, especially the ones developed in high-income countries, may exceed local budgets [ ] . focused critical care teaching courses, such as basic for developing health systems, which is free and nonproprietary, have been developed and adjusted to resource-limited healthcare systems [ , ] . remote education via telemedicine may play a role in the future to reduce costs and improve availability of training options. we could not identify any published safety concerns to the implementation of educational interventions in icus in resource-limited settings. we suggest that all healthcare professionals working in icus be specifically trained in the care of the critically ill patient ( c). unless national or regional specialty training programs in intensive care medicine are available, we suggest that training of icu physicians, nurses, and allied healthcare professionals occurs through longitudinal, multimodal programs coordinated by partnerships between ministries of health, national and international professional societies, nongovernmental organizations, as well as institutions with well-established programs in icu training ( d). we recommend that such icu training programs adhere to validated, international standards of intensive care medicine, but that they be adapted to local needs and resources ( c). modern icus provide around-the-clock, life-sustaining therapies often by the use of electricity-driven machines such as mechanical ventilators, syringe pumps, or extracorporeal therapies. unexpected power cuts interrupt these therapies and may result in significant harm to or death of critically ill patients. consistent and reliable electrical power supply is therefore a key logistical requirement of every icu. however, electricity supply in resource-limited settings is often inconsistent. major challenges include wide voltage fluctuations, which are deleterious to electricity-driven medical equipment. in many resource-limited settings, electrical power cuts occur on a regular basis and backup electrical sources are frequently absent. in a survey of health centers in african countries, only . % of facilities were reported to have a reliable electricity supply and . % had a backup power source such as a generator. the same survey showed that . % of healthcare facilities did not have any electricity supply [ ] . from personal experiences of one of the authors (ap) in , the national public hospital in south sudan sometimes had to function without electricity for days, limiting hospital services to dispensing medications and making already hot inpatient wards unbearable since fans were not working. basic clinical services during these periods were performed by flashlight in the evening and not at all at night. ensuring continuous electric supply is therefore imperative for icus to function effectively. voltage surges can be attenuated by installing voltage stabilizers into the main electrical supply line(s) of the icu. power cuts can be bridged by backup electrical sources, including batteries. although multiple technical options exist (including solar power sources), fuel-or diesel-driven generators are the most commonly available technical solution in resource-limited settings. it is important to install an electrical backup source that provides adequate electrical power to supply essential medical apparatus in the icu (e.g., mechanical ventilators, oxygen concentrators, syringe pumps delivering catecholamine agents) and other important machines (e.g., air compressor supporting the pressurized air system). even when such backup power supplies are available, the time delay between mains power cut and startup of the backup supplies can be a limiting factor. since even brief power cuts cause electrical equipment to shut down, backup sources that start automatically and immediately are crucial. using battery-equipped equipment with short ( - min) automatic emergency electrical supply can help to mitigate patient harm. if backup sources must be started manually, protocols must be in place to guide icu workers how to act in response to abrupt interruptions of life-sustaining therapies. such protocols should ideally focus on three steps in a descending priority: (a) compensation of stopped mechanical ventilators (e.g., by manual bagging), (b) compensation of stopped catecholamine infusions (e.g., by injecting adrenaline into gravity infusions with titration of drops per minute), and (c) compensation of interrupted oxygen supply if oxygen concentrators are used for oxygen supply (e.g., by activating backup oxygen cylinders). it is important that these protocols can be implemented during daylight and nighttime (e.g., availability of functioning flashlights is essential) and that the icu staff, particularly the nurses and nurse assistants, is adequately trained to implement them. periodic mock "drills" may help to ensure smooth implementation in the event of an actual event. solar power has great potential for icus in resource-limited settings, especially given that many of these settings are located in tropical, sunny environments. solar panel installation was associated with a significant reduction in mean inpatient pediatric mortality in a single-center, retrospective, before-and-after observational study in sierra leone [ ] . an observational, proof-of-concept study in uganda also demonstrated improvements in physiologic variables related to respiratory failure after solar panels were installed to power oxygen concentrators in a pediatric icu [ ] . these improvements were consistent even on cloudy days. the greatest barrier to ensure adequate electrical supply to an icu in a resourcelimited setting is financial. while voltage stabilizers are not costly and are readily available even in resource-limited settings, generators and other backup power sources are expensive, especially with automatic bridging functions. diesel generators large enough to function through sustained power cuts require steady supply of fuel, which itself can be cost-prohibitive or in short supply. another commonly faced challenge is maintenance of these systems, which requires technical expertise. particularly during nighttime when technicians are not readily available, the icu/ hospital staff needs to be familiar with activation of the available backup power source if activation does not occur automatically, a situation that poses logistical and safety challenges when the primary concern is stabilization of critically ill patients. when exposed to extreme weather conditions, generator malfunctions can occur and require skilled local technicians for repair. a stable electricity supply is an essential infrastructural component of an icu (ungraded). we recommend that icus use voltage stabilizers in case voltage fluctuations endanger the function of electrical medical equipment ( d). we recommend that adequate backup electrical sources be available to bridge power cuts ( c). we suggest that these backup electrical sources take over electricity supply automatically allowing for (near) continuous functioning of life-sustaining medical equipment ( d). we recommend that icus with no adequate backup electrical source have protocols in place guiding icu staff how to bridge life-sustaining therapies during power cuts ( d). the world health organization considers oxygen fundamentally important and lists it on page one of the essential medication list [ ] . in , the lancet commission on global surgery revealed that approximately one quarter of hospitals surveyed in resource-limited countries lack sufficient oxygen supply [ ] . this analysis reinforced previous data reporting similar deficiencies in multiple resource-limited settings across the world [ , , ] . since severity of hypoxemia correlates with mortality [ ] and often goes undiagnosed in resource-limited settings [ ] , ensuring adequate oxygen supply to icus in resource-limited settings is of critical importance. there are three commonly used methods to supply icus in resource-limited settings with oxygen: oxygen cylinders, oxygen concentrators, and centralized, piped oxygen systems [ ] . oxygen cylinders provide pressurized oxygen at variably high flow rates but-depending on their size-only do so for a limited period. they do not require electrical power supply but do require pressure regulators and flowmeters to deliver oxygen safely to the patient. oxygen cylinders are purchased or rented from supply companies and refilled at central distribution points, often making long transportation times to (remote) healthcare facilities necessary. they are generally easy to use, but problems include oxygen leakage from the adaptors (varying from to % of the entire cylinder oxygen content), difficulty moving due to size and weight, and sometimes confusion with the local color coding system [ ] . oxygen concentrators are devices which purify oxygen (> %) from ambient air by absorbing nitrogen onto zeolite membranes. most concentrators deliver oxygen flow rates of up to l/min. while this is typically enough to deliver oxygen noninvasively to (one to three) moderately unwell neonates or small children, it may not be enough in critically ill older children or adult patients. in contrast to oxygen cylinders, oxygen concentrators depend on a continuous electrical power supply. they also require technical maintenance including regular filter changes. not all models of oxygen concentrators are technically suitable for sustained use in a tropical environment [ ] . centralized, piped oxygen systems typically deliver pressurized oxygen through wall outlets to bed spaces in the icu. these systems are supplied by either a liquid oxygen tank, an oxygen concentrator, or several large oxygen cylinders. proper functioning of centralized oxygen systems depends on adequate engineering expertise and technical maintenance. specifically, pipeline conditions (presence and severity of gas leak) and diameter (to ensure adequate gas flow), compatible wall outlets, and the presence of shutoff valves must be considered. all three modes of oxygen supply to an icu require the presence of a backup oxygen source in case of premature emptying (e.g., oxygen cylinders, centralized oxygen system supported by oxygen cylinders), electrical power cuts (e.g., oxygen concentrators), or technical defects (e.g., oxygen concentrators, centralized oxygen system). in many resource-limited settings, oxygen cylinders are used as backup oxygen systems. most modern mechanical ventilators depend on pressurized air and oxygen supply. although oxygen cylinders may be used, doing so may require frequent exchange, particularly at high minute volumes or inspiratory oxygen concentrations. therefore, centralized, pressurized oxygen and air systems appear most practical to run these types of ventilators. selected types of mechanical ventilators and the majority of noninvasive (home) ventilators generate their driving pressure by internal air compressors and do not depend on a pressurized gas supply. when using these ventilators, oxygen can be delivered to the y-piece or the inspiration tubing using either an oxygen cylinder or an oxygen concentrator. oxygen concentrators are unable to serve as a pressurized oxygen source to run mechanical ventilators but can be used to enrich the oxygen concentration of inspiratory breaths delivered by compressor-driven ventilators. although the latter practice results in unclear inspiratory oxygen concentrations, the oxygen flow of the oxygen concentrator can be titrated to achieve a desired blood oxygen saturation. taking the aforementioned conditions into account, the choice of the most appropriate method to supply an icu with oxygen depends on site-specific requirements and conditions. a non-icu study from the gambia found that cylinders were better than concentrators due to local factors at out of hospitals studied. the authors suggested that concentrators are most advantageous when electrical power is reliable; cylinders may be preferable when power supply is erratic but only when weighed against substantial transportation and delivery costs [ ] . additionally, oxygen concentrators cannot be used to run mechanical ventilators that depend on a pressurized oxygen source as they generate insufficient oxygen flows and pressures. installation and maintenance of oxygen systems in an icu in a resource-limited setting face multiple challenges. while oxygen cylinders are commonly available, also in remote areas, oxygen concentrators are often not locally available and can only be purchased in metropolitan areas or from overseas. although some materials to set up centralized oxygen systems are ubiquitously available (e.g., copper pipes), key parts, such as wall outlets or liquid oxygen tanks, are not. copper pipes are also prone to theft [ ] . maintenance of all oxygen supply systems is frequently impeded by financial constraints and a shortage of workers with sufficient training, equipment, and technical experience [ ] . a before-after study evaluated the feasibility and outcome effects of improved oxygen delivery on case fatality rates of children with pneumonia admitted to five hospitals in papua new guinea. after introduction of pulse oximeters to detect hypoxemia and installation of oxygen concentrators, the risk of death for a child with pneumonia was reduced by % [risk ratio . (ci %, . - . ) compared to the time period before oximeters and oxygen concentrators were made available]. the implementation costs were estimated to be usd $ per patient treated, usd $ per life saved, and usd $ per disability-adjusted life year averted [ ] . multiple studies from resource-limited settings demonstrated greater cost reductions with oxygen concentrator systems compared to cylinders and generators. in papua new guinea, the overall -year cost estimate for cylinders, capable of producing , l/day, was approximately usd $ , when compared to three oxygen concentrators (usd $ , ) and an oxygen generator system (usd $ , ), both capable of producing , l/day, [ ] . in the gambia, annual costs for cylinders at one hospital were usd $ , vs. usd $ , for concentrators with h availability of grid power [ ] . a different -year, singlecenter analysis from the gambia estimated that installation of oxygen concentrators with a reliable backup power supply saved % on oxygen supply costs compared to cylinders (assuming l/min flow rate). when accounting for air leaks and the estimated costs of backup power supply maintenance, the authors estimated total savings of usd $ , over years [ ] . given regional variations in supply chains, local engineering and maintenance capabilities, electrical power supply, and other factors, these cost analyses cannot be applied uniformly to other resourcelimited settings. a decision support algorithm to determine the best mode of oxygen supply to an individual icu in a resource-limited setting has been suggested by some authors [ ] . oxygen is an essential medication for critically ill patients, and an adequate oxygen supply is a crucial infrastructural component of an icu (ungraded). we recommend that icus in resource-limited settings choose the type of oxygen supply (concentrators, cylinders, centralized system) based on site-specific conditions and requirements ( b). we suggest that, when feasible, oxygen be supplied by centralized, piped systems to icus when mechanical ventilators are used ( d). while healthcare-acquired infections are prevalent throughout the world, the burden is highest in resource-limited settings. the world health organization estimates that healthcare-associated infection rates are roughly times higher in low-and middle-income countries compared to high-income countries [ ] . in icus specifically, a meta-analysis reported an overall incidence of icu-associated infections of . per patient days in developing countries. this was three times greater than the prevalence reported from the united states. surgical site infections were most common, but device-associated infections were highly prevalent as well [ ] . healthcare-associated infections can be transmitted via myriad mechanisms. many, if not most, can be prevented easily with simple measures. however, lack of hygienic facilities, insufficient training of staff, and lack of administrative oversight (e.g., by hospital-level and national-level infection control measures) are likely to contribute to the deleteriously high rates of nosocomial infection rates in icus in resourcelimited settings [ ] . in line with findings from resource-rich settings, several studies originating in resource-limited settings suggest that hand hygiene is the most effective method of reducing healthcare-acquired infections. healthcare workers can contaminate hands and medical devices with even a single contact with the patient or his/her immediate surroundings. contaminant transfer to other patients and healthcare workers is common if hand hygiene is inadequate or not performed [ ] . innumerable challenges to improving hand hygiene in resource-limited settings have been identified, but reasons vary from location to location [ ] . convincing evidence indicates that implementation of multimodal hand hygiene programs can not only improve hand hygiene compliance but also reduce icu-acquired infection rates. a prospective observational study involving icus in resource-limited countries demonstrated a significant . % overall increase in hand hygiene compliance after implementation of a multidimensional hand hygiene program involving administrative support, supply availability, education and training, workplace reminders, process surveillance, and performance feedback [ ] . these findings have been replicated in geographically diverse locations including india [ ] , china [ ] , and mexico [ ] . a prospective study in six colombian icus demonstrated a significant reduction ( . % annually during the -year study period) in central line-associated bloodstream infections after introduction of a targeted hand hygiene program that included installation of alcohol-based hand rub dispensers adjacent to each icu bed and regular feedback to healthcare workers [ ] . in a vietnamese tertiary icu, the combination of hand hygiene and antimicrobial mixing reduced mrsa infections significantly, but not the incidence of the four hospital-acquired gram-negative infections studied. several large studies from resource-limited and resource-rich countries reported superior efficacy of hand rubbing with alcohol-based solutions over handwashing with antiseptic soap to reduce hand contamination. a study including three egyptian icus and a renal dialysis unit found that hand rubbing with alcohol-based liquids or gels resulted in a higher reduction of bacterial counts on the hands of icu staff compared to handwashing with soap and water ( - % vs. %, p < . ) [ ] . these results are in line with the findings of a randomized controlled trial conducted in french icus that observed a % reduction in bacterial hand contamination when using alcohol-based hand rub compared to soap and water [ ] . during the west african ebola virus disease outbreak, chlorine-based hand hygiene was commonly used following patient encounters in ebola treatment centers and in affected communities. this practice is supported by an observational study conducted in ebola treatment centers in sierra leone demonstrating elimination of ebola virus rna from contaminated personal protective equipment following treatment with locally produced chlorine solutions [ ] . although this study did not determine whether detection of ebola rna on personal protective equipment translated to an increased risk of infection, it can be inferred that reducing contamination is likely to decrease the risk of iatrogenic infection. although frequent hand hygiene with chlorine-based solution may increase skin irritation, the severity of irritation is little different than with use of soap and water and alcohol-based solutions based on a randomized trial comparing different handwash regimens [ ] . non-sterile, clean examination gloves function as a protective barrier for medical staff who potentially encounter blood, body fluids, or other possibly infectious material. the bacterial bioburden of non-sterile examination gloves is very low [ ] and does not differ between newly opened and nearly empty boxes [ ] . a randomized controlled trial performed in us icus reported that the total bacterial colony counts of gloved hands were not different if hand hygiene was performed before non-sterile examination gloves were donned or not, suggesting that hand hygiene before donning non-sterile gloves is unnecessary [ ] . several studies, however, indicate that contaminated examination gloves can spread bacterial pathogens from healthcare workers to patients [ ] . furthermore, examination gloves do not avoid bacterial contamination of healthcare workers' hands due to microlesions [ ] . based on these results, the who emphasizes that wearing gloves does not replace the need for subsequent hand hygiene [ ] . reuse of medical examination or surgical gloves is commonplace in many resource-limited settings [ref] , but the limited studies available suggest that reprocessing and reuse of disposable gloves may be harmful to patients and healthcare professionals. a laboratory-based study from kenya comparing sterility and physical integrity of reprocessed plastic surgical gloves compared to new, sterilized surgical gloves demonstrated alarmingly reduced physical integrity and sterility of the reprocessed gloves [ ] . a before-after study from pakistan found that the use of (plastic) shoe covers by medical staff and visitors was not helpful in preventing infections with common icu pathogens or improving the outcome of critically ill patients [ ] . further infection control measures such as fogging and spraying of disinfectants, the use of disinfection or sticky mats, and routine use of face masks or caps by icu staff or visitors have not been shown to influence infection rates in icus [ ] . no trials from resource-limited settings on the routine use of gloves, gowns, and aprons to prevent nosocomial or cross infection in critically ill patients were identified. three large randomized trials from the united states concluded that the universal use of gloves and gowns for all patient contact compared with usual care (adequate hand hygiene and use of gloves in case of contact with blood, body fluids, or other contaminants) did not reduce adverse events or the transmission rate of multiresistant bacteria [ ] [ ] [ ] . similarly, a cochrane meta-analysis primarily consisting of studies from resource-rich settings could not identify evidence that overgowns used by staff or visitors are effective in limiting death, infection, or bacterial colonization in infants admitted to neonatal wards or intensive care units [ ] . critically ill patients with known or suspected airborne, droplet, or contact infections require specific hygienic precautions. although no randomized controlled trials were identified by our literature search, (cohort) isolation of patients with airborne (e.g., mycobacterium tuberculosis) or droplet infections (e.g., influenza virus, measles, varicella zoster virus, neisseria meningitidis, coronavirus) in separate rooms is recommended by international and national guidelines both in resource-rich and resource-limited settings [ , ] . in addition to standard hygienic measures, adequate hand hygiene in particular, the use of masks has been recommended to protect healthcare workers caring for (critically ill) patients with acute respiratory infections. despite surrogate exposure studies indicating that n respirators are associated with less filter penetration and inward leakage than surgical masks, large clinical trials and meta-analyses failed to show that n respirators are superior to surgical masks in protecting healthcare workers against influenza during routine care [ ] [ ] [ ] . the centers for disease control and prevention recommends use of n disposable, powered air-purifying, or self-contained breathing apparatus respirators for healthcare workers caring for patients with tuberculosis [ ] . in addition to isolation, patients with highly contagious infectious diseases, such as viral hemorrhagic fever or smallpox infection, require specific hygienic precautions. in its latest guidelines on personal protective equipment for use in a filovirus disease outbreak, the world health organization recommends the use of face shields or goggles, a fluid-resistant head cover and surgical mask, double gloves, and protective body wear, as well as waterproof aprons and boots, in addition to regular on-duty clothing [ ] . a large before-after study in north america showed that the use of full-barrier precautions during insertion of central venous catheters, in addition to adequate hand hygiene when handling catheters, significantly reduced the risk of central venous catheter-related bloodstream infections by up to % over the -month study period [ ] . full sterile barrier precautions include the use of a cap, mask, sterile drapes, a sterile gown, and sterile gloves following adequate skin preparation and hand hygiene; these components have not been studied separately. other observational studies confirmed these findings and suggest that the rate of central venous catheter-related bloodstream or other device-related infections can be minimized with the use of appropriate hygienic precautions [ ] [ ] [ ] [ ] [ ] . no randomized controlled trials from resource-limited or resource-rich settings on the architectural design of icus to prevent transmission of microbial pathogens were identified by our search and a previous review of the literature [ ] . a prospective study from the united kingdom reported that isolation of patients colonized or infected with methicillin-resistant staphylococcus aureus in single rooms or cohorted bays did not reduce cross infection as long as adequate hand hygiene measures were maintained [ ] . in contrast, studies suggest that isolation of critically ill patients in rooms that are poorly visualized by staff is likely related to a higher risk of death [ ] . national and international guidelines recommend isolation of patients with highly contagious infectious diseases (e.g., tuberculosis, influenza, measles, rubeola infection, varicella zoster infection, hemorrhagic virus disease) or severe immune suppression (e.g., neutropenia, burns, transplant) [ , ] . atmospheric pressure in isolation rooms should be controllable to target negative pressure when isolating patients with airborne infections and positive pressure when caring for patients who require protective isolation [ , ] . a survey-based study of icus in resourcelimited asian countries (bangladesh, india, nepal, pakistan, and the philippines) found that did not have single rooms and did not have negative pressure rooms [ ] . a study from peru reported that upper-room ultraviolet lights and negative air ionization prevented most airborne tuberculosis transmission detectable by guinea pig air sampling [ ] . these observations have recently been confirmed by a study from south africa suggesting that upper-room ultraviolet light is an effective, lowcost intervention for use in tuberculosis infection control in high-risk clinical settings [ ] . regarding the architectural design of new or newly renovated icus, consensus-based guidelines published by the indian society of critical care medicine recommend the installation of filter-containing central air-conditioning systems with a minimum of six total air changes per room per hour (filter efficiency % down to μm); clearly demarcated routes of traffic flow through the icu; adequate space around and between beds; an adequate number of washbasins; a separate medication preparation area; separate areas for clean, soiled, and waste storage/disposal; and adequate toilet facilities [ ] . alcohol hand rub dispensers are recommended to be placed at the icu entry and exits and at every bed space and workstation [ ] . despite the clear evidence that the use of alcohol-based hand rub solutions reduces the risk of infection transmission [ ] , commercial alcohol-based hand rubs are often unavailable in resource-limited settings [ ] . a study from egypt suggests that locally prepared alcohol-based hand rubs are similarly effective to commercial products [ ] , so local preparation of these products may be feasible and potentially more affordable than purchase of foreign-made products, with recipes readily available [ ] . locally produced chlorine-based handwashing solutions are also effective for decontamination in ebola virus disease [ ] , but careful attention must be paid to varying shelf lives among solutions of differing chemical composition, especially in hot environments [ ] . hand hygiene dispensers are commonly used to supply icu workers in resource-rich countries with alcohol-based hand rub solutions. these dispensers are, however, often unavailable or restricted to the operating theaters in hospitals in resource-limited settings. in addition, they depend on regular refilling by dedicated staff, which may be problematic in understaffed icus. in the absence of adequate hand hygiene dispensers, small pocket bottles containing alcohol-based hand rub solutions can be carried, used, and refilled by each icu worker (fig. . ) . a multifaceted hand hygiene program (including upgrading hand hygiene facilities, provision of alcohol-based hand rub at point of care, hand hygiene campaigns, continuous hand hygiene education) not only reduced the incidence of hospital-acquired infections in vietnamese icus but also proved to be costeffective [ ] . although a cluster-randomized, crossover trial in rural kenya failed to show differences in surgical site infections between handwashing with alcohol or soap and water ( . vs. %) in patients undergoing clean or clean-contaminated surgery, the use of alcohol-based hand rubbing solutions was as feasible and affordable (€ . vs. € . per week) as handwashing with soap and water [ ] . religious beliefs do not influence the use of alcohol-based hand rub solutions for hand hygiene but may impact implementation effectiveness [ ] . respirator masks are often unavailable and underused in resource-limited settings where acute respiratory infections are highly prevalent. given cost concerns and the unclear scientific benefit of using n respirators compared with surgical masks [ ] , it appears advisable that if n respirators are in short supply they should be reserved to protect healthcare workers caring for patients with tuberculosis or other airborne infectious diseases or when caring for patients with dropletspread infections during aerosol-generating procedures or when caring for patients in very hot and humid environments for long periods when surgical masks may become wet and ineffective (e.g., during the ebola epidemic). importantly, cloth a b masks are prone to moisture retention and poor filtration when reused [ ] . as suggested by a randomized controlled trial, they should not replace surgical masks in high-risk situations [ ] . one striking challenge during the most recent ebola virus disease epidemic was the shortage of personal protective equipment faced by healthcare workers caring for diseased patients in west africa, as global fears of a disease spread rose and resource-rich countries filled their stocks with protective body suits. since single-use, disposable sterile gowns and drapes, commonly used for invasive procedures in icus in resource-rich settings, are expensive and mostly unavailable in resource-limited countries, autoclavable gowns and cloths may be used instead for the majority of common icu illnesses. for ebola virus disease, the who emphasizes use of disposable personal protective equipment [ ] . we recommend that icus have available an adequate number of and easily accessible facilities for handwashing/hand hygiene ( a). we recommend hand hygiene after each patient contact with an alcohol-based solution ( a) or, for ebola virus disease specifically, with chlorine-based solution ( c). in case alcohol-based solutions are unavailable, we recommend using soap and water for handwashing ( a). alcohol hand rub solutions may be produced locally and carried in small bottles by each healthcare worker (ungraded). we recommend that non-sterile, clean examination gloves for self-protection of medical staff be available ( c). importantly, gloved hands can equally transmit infectious pathogens and that the use of gloves does not replace the need for subsequent hand hygiene (ungraded). we recommend the availability of masks, caps, sterile gowns, sterile drapes, and sterile gloves for invasive procedures such as insertion of central venous catheters ( a). we recommend that icus and hospitals in areas where highly contagious infectious diseases (e.g., tuberculosis, ebola virus disease) are endemic have rapid access to adequate quantities of personal protective equipment as recommended by the world health organization and the centers for disease control and prevention ( c). we suggest that hospitals develop individual policies and procedures for reuse of disposable personal protective and other medical equipment ( c). when icus are renovated or newly built, we suggest compliance with national and international best-practice recommendations on icu architectural design ( d). the very nature of an icu warrants a higher reliance on technical equipment, devices, and other technologies compared to the general medical ward. irrespective of the geographic location or level of resource limitation, technical equipment constitutes an essential component of icu-level patient care. what specific types of technical equipment are essential, however, remains undetermined. in resourcelimited settings, multiple challenges in terms of equipment procurement and maintenance exist [ ] . for example, can the technical equipment run with frequent electric current interruptions? how reliable are the supply chains to obtain or replace the equipment and are local technicians available for repairs? is donated equipment relevant in the local context and are clinicians educated on how to use it [ ] ? given these considerations, resource-limited hospitals and health systems must find and fund equipment purchase or donation sustainably and in the most targeted manner possible. no large clinical trial has so far shown a reproducible survival benefit related to the use of a single monitoring device in critically ill patients. monitors improve the care of the critically ill only if healthcare staff make timely and appropriate changes in the therapeutic management based on data from monitors. in view of the fact that pathologic deviations of vital signs such as heart rate, respiratory rate, arterial blood pressure, and arterial oxygen saturation are associated with an increased risk of organ dysfunction and death [ ] [ ] [ ] [ ] , especially in settings where artificial life support is inconsistently available [ ] [ ] [ ] [ ] [ ] [ ] [ ] , it appears sensible to measure these parameters continuously or at regular intervals. a prospective, before-and-after interventional study including icu patients in a tanzanian university hospital reported that a vital signs-directed therapy improved the acute management of patients with abnormal vital signs. while overall in-hospital mortality was unchanged before and after the intervention, critically ill patients with arterial hypotension experienced a lower post-implementation mortality ( . vs. . %, p = . ; number needed to treat . ) [ ] . no conclusive evidence-either from resource-limited or resource-rich settings-was identified to answer the question whether noninvasive or invasive blood pressure measurement is superior in critically ill patients. while a study performed in critically ill patients in an emergency department in a resource-rich country reported inaccuracy of oscillometric blood pressure measurements at hypotensive blood pressure ranges [ ] , a prospective multicenter study from france found a good discriminative power of noninvasive blood pressure measurements to identify arterial hypotension (mean arterial blood pressure < mmhg) and track arterial blood pressure in patients with shock [ ] . a survey among us intensivists observed that % and % of respondents reported using noninvasive blood pressure measurements in hypotensive patients and patients on vasopressor support, respectively [ ] . a recent cochrane meta-analysis could not identify convincing evidence that the use of pulse oximetry conveys a significant survival benefit in perioperative patients [ ] . however, a large, multicenter, before-and-after intervention study from papua new guinea observed a survival benefit associated with the systematic use of pulse oximetry to monitor and treat children with pneumonia, when coupled with a reliable oxygen supply [ ] . in settings where blood gas analyzers are unavailable, the plethysmographic oxygen saturation relative to the inspiratory oxygen concentration (spo / fio ratio) can be used for decision-making and continuous monitoring [ , ] . a systematic review of the literature evaluated the benefit associated with the use of portable ultrasound devices in low-and middle-income countries [ ] . although several reports were identified describing the successful diagnosis, triage, and management of patients with complex, life-threatening conditions with the use of pointof-care ultrasound, no randomized controlled trial has so far evaluated the impact of ultrasound-guided diagnosis and treatment in resource-limited settings. a haitian-us study demonstrated that tele-mentoring of non-physicians performing ultrasound in a resource-limited setting was feasible and adequate to make clinical decisions in the majority ( %) of cases [ ] . our literature search did not identify any randomized controlled trials evaluating the effects of mechanical ventilators on mortality in critically ill patients both in resourcelimited and resource-rich settings. however, mortality of patients with hypoxemia who do not receive mechanical ventilatory support is extremely high, suggesting that mechanical ventilation associates with a survival benefit [ ] . observational evidence from icus in vietnam suggest that general intensive care measures, including mechanical ventilation, can improve clinical outcomes [ , ] . a structured icu training program that included modules on mechanical ventilation improved overall icu mortality in two of three icus in india, nepal, and bangladesh [ ] . reports from india and africa confirm the feasibility of noninvasive ventilation in resource-limited settings [ , ] . a randomized controlled trial including four rural hospitals in ghana found that continuous positive airway pressure application by local nurses significantly reduced respiratory rate and was not associated with complications in children with respiratory distress [ ] . a randomized controlled trial that was stopped early including bangladeshi children with severe pneumonia and hypoxemia found that the use of bubble continuous positive airway pressure reduced the risk of treatment failure and death compared with standard lowflow oxygen therapy [ ] . these results were confirmed by studies from india and malawi [ , ] . no randomized controlled trials on the use of end-tidal carbon dioxide monitoring in resource-limited settings were identified. studies from both resource-limited and resource-rich settings prove that end-tidal carbon dioxide measurement is a reliable technique to verify endotracheal tube placement and an adequate tool to monitor mechanical ventilation [ ] [ ] [ ] . although differences between arterial and end-tidal carbon dioxide values are common and vary individually [ , ] , the trends over time appear helpful to guide mechanical ventilation, particularly when arterial blood gas analyzers are unavailable [ ] [ ] [ ] . renal replacement therapy improves short-and long-term survival of patients with severe acute renal injury [ , ] . recommendations regarding renal replacement therapy for critically ill patients in resource-limited settings are discussed in another chapter in this book [ ] . abnormal blood glucose levels and increased blood lactate levels have both been associated with increased mortality in the critically ill in resource-limited and resource-rich settings [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . a ugandan multicenter study recorded an incidence of hypoglycemia of . % among sepsis patients. in this study, hypoglycemia was an independent risk factor for in-hospital mortality and could not be adequately predicted by clinical examination [ ] . hypoglycemia is a well-known complication of malaria, particularly in children [ ] and those treated with quinine [ ] . although our literature search did not reveal a randomized controlled trial showing that measurement of blood glucose is associated with improved outcome, it is sensible to assume that detection of dysglycemic episodes is associated with improved care. while studies from resource-limited settings suggest that results of point-of-care methods to measure blood glucose levels are closely correlated with those of laboratory measurements [ , ] , some studies from resource-rich settings have highlighted inaccuracies of point-of-care devices in lower blood glucose ranges [ ] . a recent international multicenter study, however, demonstrated that bedside blood glucose monitoring systems were acceptable for use in critically ill patient settings when compared to a central laboratory reference method [ ] . similarly, lactate levels as measured by a point-of-care blood lactate analyzer reliably predicted mortality in ugandan sepsis patients [ ] , as well as febrile children in tanzania [ ] . no randomized controlled trials from resource-limited settings were identified evaluating the outcome effects of lactate measurements or lactate-guided interventions in critically ill patients. although limited by insufficient information size, a meta-analysis with sequential analysis of randomized controlled trials originating in resource-rich countries suggested that the use of lactate clearance as a goal to guide resuscitation was associated with a reduction in the risk of death in adult patients with sepsis [ ] . similar to glucose and lactate measurement, our literature search failed to find studies demonstrating improved outcomes for arterial or venous blood gas measurement. a swiss prospective observational study demonstrated that lower ph was an independent predictor of -month mortality in emergency department patients presenting with dyspnea, but arterial blood gas analysis itself had very limited diagnostic value [ ] . according to international consensus definitions developed in high-income countries, measurement of the partial pressure of oxygen is required to diagnose the acute respiratory distress syndrome (ards) [ ] . similar recommendations have been made for sepsis-induced ards diagnosis in resource-limited settings [ ] , supported by observational evidence to show that patients with increasing severity of ards as determined by the arterial partial pressure of oxygen to fraction of inspired oxygen ratio have higher mortality and higher noninvasive ventilation failure rates [ ] . the availability of vital signs monitors, mechanical ventilators, renal replacement devices, and point-of-care tools in icus varies substantially between resourcelimited regions [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . several studies suggest that hospitals in middle-income countries and metropolitan areas of low-income countries have more technical equipment available than healthcare facilities in low-income countries and rural areas [ ] [ ] [ ] [ ] [ ] . except for remote areas [ , ] , the availability of vital signs monitors and glucometers appears consistently high; point-of-care laboratory facilities and renal replacement equipment are strikingly unavailable in certain areas [ ] [ ] [ ] . common challenges of installing and maintaining technical equipment in icus in resource-limited settings are high investment costs depending on the regional availability of medical retailers, the need for reliable electrical power supply, disposable materials (e.g., ecg electrodes, printer paper), as well as technical maintenance and repair in case of device malfunction or breakdown [ ] . a mathematical model based on cost-effectiveness threshold and the results of previous studies concluded that the perioperative use of pulse oximeters is cost-effective in resource-limited settings [ ] . in addition to challenges faced with installation and maintenance of vital signs monitors and as previously described, mechanical ventilators additionally require a reliable oxygen and/or (pressurized) gas supply as well as structured training of healthcare staff. in contrast to invasive mechanical ventilation, noninvasive mechanical ventilation appears to be feasible and safe in resource-limited settings after short, structured education of icu staff [ , ] . a study from india even reported that the use of noninvasive mechanical ventilation to treat patients with acute exacerbations of chronic obstructive pulmonary disease in non-icu wards was both feasible and cost-effective [ ] . although continuous positive airway pressure and/or high-flow oxygen devices may be implemented in clinical practice with relatively low implementation costs and a concise staff training, its maintenance may consume high amounts of oxygen, particularly when used at high inspiratory oxygen concentrations in adults. oxygen requirements in children are substantially lower due to lower minute ventilation. whereas both the implementation and maintenance costs to run point-of-care glucometers in the icu are low, other point-of-care laboratory facilities (e.g., blood gas analyzers, including lactate measurements) critically depend on the local availability of (costly) supply materials (e.g., reactive agents), reliable electrical supply, as well as regular maintenance by skilled laboratory or medical technicians. although cassette-based blood gas analyzers show a comparable accuracy to traditional blood gas analyzers [ ] and require less technical maintenance, they are associated with much higher costs, particularly when large amounts of blood samples are analyzed. separate point-of-care devices measuring blood lactate levels have been suggested as cheaper alternatives to blood gas analyzers in resourcelimited settings [ , ] . moreover, availability of blood gas analyzers is severely limited [ ] , and contemporary evidence from resource-rich and resource-limited settings suggest that arterial blood gas measurement may not be necessary to diagnose and to improve outcomes for ards [ , ] . acquisition of technical equipment should be guided by local availability and feasibility of routine maintenance (ungraded). we recommend that icus have basic vital signs monitors (including electrocardiogram, respiratory rate, oscillometric blood pressure, and pulse oximetry) available for each icu bed ( c). we recommend that icus have one or more mechanical ventilators available ( c). these mechanical ventilators should also deliver noninvasive ventilatory modes, measure tidal volume and airway pressures, and support oxygen delivery ( b). we suggest that icus that provide invasive ventilatory support have facilities available to measure end-tidal carbon dioxide ( c) and to perform blood gas analysis ( c). we recommend that icus have point-of-care capabilities for measuring blood glucose (e.g., glucometers) ( b). we recommend that icus have capabilities for measuring blood lactate levels ( b). we suggest that icus have available point-of-care ultrasound devices ( c) and that key clinical staff undergo formal ultrasound training ( c). the sepsis and intensive care literature is replete with examples of poor quality care [ ] . the great challenge is how best to improve quality of care for critically ill patients in resource-limited settings when faced with countless financial, resource, and administrative constraints. a significant limitation is that sparse epidemiologic data detailing sepsis presentation and management in resource-limited settings have been published [ ] . without these data, it is difficult, if not impossible, to identify effective interventions that work at the population level. various authors have developed general roadmaps for the future [ ] , but specific interventions demonstrating convincing improvements in intensive care in resource-limited settings are still lacking. regular documentation of the patient's history of care is a medicolegal requirement in almost all healthcare systems. medical records are the integral repository of the patient's disease course, healthcare planning, and documentation of communications with other healthcare providers, the patient, and his/her family. furthermore, medical records are used to assess compliance of care with institutional, national, or international guidelines and regulations. although electronic data documentation has become commonplace in many icus in resource-rich settings and resulted in improved accuracy and legibility of documents, a meta-analysis failed to show that implementation of electronic medical records has a substantial effect on relevant icu outcomes such as mortality, length of stay, or costs of care [ ] . although introduction of a daily goal form can improve communication between icu healthcare professionals and possibly reduce icu length of stay [ ] [ ] [ ] [ ] [ ] , a large, randomized, controlled, multicenter trial from a resource-limited setting failed to reproduce beneficial effects of a multifaceted quality improvement intervention with daily checklists, goal setting, and clinician prompting on in-hospital mortality of critically ill patients [ ] . a multitude of quality improvement methods to implement and translate scientific evidence into clinical care have been published. education, audit and feedback, protocols, bundles of care, and checklists are common tools studied to improve the quality of icu and sepsis care. most reports originate in resource-rich settings. a large nationwide educational effort to implement international sepsis guidelines using two care bundles was associated with improved guideline compliance and lower hospital mortality in spain [ ] . these results were confirmed by several other reports [ , ] , indicating that a higher compliance with international sepsis guidelines was directly and significantly associated with improved survival [ ] [ ] [ ] . a large prospective interventional study in uganda found that a bundled protocol to implement early monitored sepsis management improved survival of patients with severe sepsis in two hospitals [ ] . a small observational cohort study in haiti demonstrated improved process measures in septic care after implementation of a simplified sepsis protocol developed by the world health organization, although there was no mortality effect [ ] . similarly, two hospitalwide, protocol-based quality improvement programs significantly reduced the rate of catheter-associated urinary tract and catheter-associated bloodstream infections in thailand [ , ] . checklists have been implemented successfully to optimize sepsis care [ ] and high-risk procedures [ ] in critically ill patients in resourcerich settings. a large international quality improvement project based on checklists to minimize preventable deaths, disability, and complications in critically ill patients is underway and includes several icus based in resource-limited settings [ ] . benchmarking is another accepted quality improvement concept in healthcare to identify performance gaps and to improve the quality of care based on anonymous comparison of quality indicators with other institutions and services. although multiple benchmarking projects and icu registries exist in resource-rich countries, no evidence currently supports that they translate into improved patient outcomes. a reduction in the standardized mortality ratio in dutch icus occurring concurrently with the dutch national benchmarking activities suggests that benchmarking of icu performance indicators is a promising tool to improve quality of icu care [ ] . quality and performance indicators of icus have been published by national and international societies in both resource-rich and resource-limited settings [ ] [ ] [ ] . while several national and international icu registries and benchmarking projects exist in resource-rich countries [ ] , only a few national icu registries exist in resource-limited settings, such as sri lanka [ ] and malaysia [ ] . similarly, internal and external clinical audits have been suggested as promising methods to improve quality of icu care in resource-rich countries [ , ] , but consistent data from resource-limited settings are lacking. although implementation of protocols, bundles, and checklists into clinical practice requires a variable amount of funding, preliminary results of studies from resource-limited settings suggest that these interventions may prevent adverse events and complications [ , ] . a delicate and important challenge of implementing protocols, care bundles, and checklists into clinical practice in icus in resourcelimited settings is the lack of safety data. different disease pathologies, as well as absent treatment options (e.g., airway protection and mechanical ventilation), could well explain why certain interventions that were shown to improve patient outcome in resource-rich settings increased morbidity and mortality in resource-limited settings [ , [ ] [ ] [ ] . this underlines the urgent need to test the efficacy and safety of adjusted care bundles and protocols to improve care of critically ill and sepsis patients in settings where resources are constrained [ , ] . another consideration is that quality control measure implementation may divert financial resources from clinical care. although long-term reduction savings may occur due to avoidance of adverse events, the up-front expenditure may prove burdensome. we recommend maintaining patient records and icu documentation in accordance with national regulations and requirements ( d). we suggest that icus develop locally applicable bundles, protocols, and checklists to improve quality of care ( c). we suggest that icus systematically collect quality and performance indicators and participate in national/international benchmarking projects ( c). we provide a series of simple, pragmatic recommendations for optimizing icu infrastructure and organization in resource-limited settings. understanding the great variability of technical, material, and human resources within and between these environments, each institution must determine the utility of implementing these recommendations based on local capabilities. given the paucity of evidence, there remains a clear need for additional studies from resource-limited settings. open access this chapter is licensed under the terms of the creative commons attribution . international license (http://creativecommons.org/licenses/by/ . /), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons license and indicate if changes were made. the images or other third party material in this chapter are included in the chapter's creative commons license, unless indicated otherwise in a credit line to the material. if material is not included in the chapter's creative commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. what is an intensive care unit? a report of the task force of the world federation of societies of intensive and critical care medicine global intensive care working group of the european society of intensive care medicine. current challenges in the management of sepsis in icus in resource-poor settings and suggestions for the future multidisciplinary critical care and intensivist staffing: results of a statewide survey and association with mortality do intensivist staffing patterns influence hospital mortality following icu admission? a systematic review and meta-analyses an international survey of training in adult intensive care medicine the educational environment for training in intensive care medicine: structures, processes, outcomes and challenges in the european region the impact of open versus closed format icu admission practices on the outcome of high risk surgical patients: a cohort analysis ats ad hoc committee on icu organization. an official american thoracic society systematic review: the effect of nighttime intensivist staffing on mortality and length of stay among intensive care unit patients economic implications of nighttime attending intensivist coverage in a medical intensive care unit standards for nurse staffing in critical care units determined by: the british association of critical care nurses, the critical care networks national nurse leads, royal college of nursing critical care and in-flight forum nurse staffing, medical staffing and mortality in intensive care: an observational study postoperative complications: does intensive care unit staff nursing make a difference? heart lung staffing level: a determinant of late-onset ventilator-associated pneumonia sentinel events evaluation (see) study investigators. errors in administration of parenteral drugs in intensive care units: multinational prospective study influence of full-time intensivist and the nurse-to-patient ratio on the implementation of severe sepsis bundles in korean intensive care units bed-to-nurse ratios, provision of basic nursing care, and in-hospital and -day mortality among acute stroke patients admitted to an intensive care unit: cross-sectional analysis of survey and administrative data do we need a pharmacist in the icu? physical therapist-established intensive care unit early mobilization program: quality improvement project for critical care at the university of california san francisco medical center implementation of dietitian recommendations for enteral nutrition results in improved outcomes impact of regular collaboration between infectious diseases and critical care practitioners on antimicrobial utilization and patient outcome physician staffing patterns and clinical outcomes in critically ill patients: a systematic review collection of annotated data in a clinical validation study for alarm algorithms in intensive care-a methodologic framework prompting physicians to address a daily checklist and process of care and clinical outcomes: a single-site study the effect of telemedicine in critically ill patients: systematic review and meta-analysis does telemonitoring of patients--the eicu--improve intensive care? health aff (millwood) the impact of closed icu model on mortality in general surgical intensive care unit effect of closed unit policy and appointing an intensivist in a developing country icus worldwide: critical care in india the east african training initiative. a model training program in pulmonary and critical care medicine for low-income countries organization and staffing of intensive care units in brazil clinical review: critical care medicine in mainland china icus worldwide: an overview of critical care medicine in south africa effectiveness of pharmaceutical care in an intensive care unit from china. a pre-and post-intervention study impact of pharmacist's interventions on cost of drug therapy in intensive care unit abu-oliem as. impact of clinical pharmacist on cost of drug therapy in the icu effect of critical care pharmacist's intervention on medication errors: a systematic review and meta-analysis of observational studies telemedicine acceptance and implementation in developing countries: benefits, categories, and barriers eicu reduces mortality in stemi patients in resource-limited areas global supply of health professionals mortality in children under five receiving nonphysician clinician emergency care in uganda mortality related to acute illness and injury in rural uganda: task shifting to improve outcomes emergency and critical care services in tanzania: a survey of ten hospitals helfen berührt" study team. anesthesia and its allied disciplines in the developing world: a nationwide survey of the republic of zambia critical care nursing practice and education in rwanda what is an intensive care unit? a report of the task force of the world federation of societies of intensive and critical care medicine on-ward participation of a hospital pharmacist in a dutch intensive care unit reduces prescribing errors and related patient harm: an intervention study critical care in resource-poor settings: lessons learned and future directions tele-medicine and point-ofcare ultrasound: a new paradigm for resource-constrained settings a "three delays" model for severe sepsis in resourcelimited countries the development of continuing education for trauma care in an african nation capacity building for critical care training delivery: development and evaluation of the network for improving critical care skills training (nicst) programme in sri lanka nursing intensive care skills training: a nurse led, short, structured, and practical training program, developed and tested in a resource-limited setting the effect of a practical icu workshop on the knowledge, attitudes and skills of physiotherapists in sri lanka evaluation of trauma and critical care training courses on the knowledge and confidence of participants in kenya and zambia evaluation of fundamental critical care course in kenya: knowledge, attitude, and practice remote tele-mentored ultrasound for non-physician learners using facetime: a feasibility study in a low-income country bolstering medical education to enhance critical care capacity in cambodia surgical capacity building in uganda through twinning, technology, and training camps establishing an anaesthesia and intensive care partnership and aiming for national impact in tanzania. glob health development of emergency medicine and critical care masters program for nurses at addis ababa university, school of medicine basic for developing healthcare systems a systematic review of short courses for nonspecialist education in intensive care influenza preparedness in low-resource settings: a look at oxygen delivery in african countries effect of solar panels on inpatient paediatric mortality in a district hospital in sierra leone (abstract) solar-powered oxygen delivery: proof of concept geneva: world health organization global surgery : evidence and solutions for achieving health, welfare, and economic development sepsis in haiti: prevalence, treatment, and outcomes in a port-au-prince referral hospital hypoxaemia among children in rural hospitals in papua new guinea: epidemiology and resource availability--a study to support a national oxygen programme oxygen as an essential medicine: under-and over-treatment of hypoxemia in low-and high-income nations prevalence of undiagnosed hypoxemia in adults and children in an under-resourced district hospital in zambia oxygen supplies for hospitals in papua new guinea: a comparison of the feasibility and cost-effectiveness of methods for different settings implementation and -year follow-up of an uninterrupted oxygen supply system in a hospital in the gambia oxygen concentrators for use in tropical countries: a survey meeting oxygen needs in africa: an options analysis from the gambia improved oxygen systems for childhood pneumonia: a multihospital effectiveness study in papua new guinea clean care is safer care: the first global challenge of the who world alliance for patient safety burden of endemic health-care-associated infection in developing countries: systematic review and meta-analysis implementation of infection control in health facilities in arua district, uganda: a cross-sectional study healthcare worker and family caregiver hand hygiene in bangladeshi healthcare facilities: results from the bangladesh national hygiene baseline survey who guidelines on hand hygiene in health care: a summary first global patient safety challenge clean care is safer care impact of the international nosocomial infection control consortium (inicc) multidimensional hand hygiene approach over years in cities of limited-resource countries from latin america the impact of the international nosocomial infection control consortium (inicc) multicenter, multidimensional hand hygiene approach in two cities of india impact of the international nosocomial infection control consortium (inicc) multidimensional hand hygiene approach in five intensive care units in three cities of impact of the international nosocomial infection control consortium (inicc) multidimensional hand hygiene approach during years in hospitals in mexican cities effectiveness of a hand hygiene promotion strategy using alcohol-based handrub in intensive care units in colombia comparative study on efficacy of different alcohol hand rubs and routine hand wash in a health-care setting efficacy of handrubbing with alcohol based solution versus standard handwashing with antiseptic soap: randomised clinical trial environmental contamination and persistence of ebola virus rna in an ebola treatment center seeking clearer recommendations for hand hygiene in communities facing ebola: a randomized trial investigating the impact of six hand washing methods on skin irritation and dermatitis is the use of boxed gloves in an intensive care unit safe? bacterial count comparisons on examination gloves from freshly opened boxes versus nearly empty boxes and from examination gloves before treatment versus after dental dam isolation is hand hygiene before putting on nonsterile gloves in the intensive care unit a waste of healthcare worker time?-a randomized controlled trial contamination of examination gloves in patient rooms and implications for transmission of antimicrobialresistant microorganisms what is the use? an international look at reuse of single-use medical devices the microbial and physical quality of recycled gloves to determine the effect of wearing shoe covers by medical staff and visitors on infection rates, mortality and length of stay in intensive care unit proven and unproven methods in hospital infection control in intensive care units benefits of universal glove and gown primary investigators. the effect of universal glove and gown use on adverse events in intensive care unit patients universal glove and gown use and acquisition of antibiotic-resistant bacteria in the icu: a randomized trial intervention to reduce transmission of resistant bacteria in intensive care gowning by attendants and visitors in newborn nurseries for prevention of neonatal morbidity and mortality guidelines for prevention of hospital acquired infections world health organization. guidelines on core components of infection prevention and control programmes at the national and acute health care facility level effectiveness of n respirators versus surgical masks in protecting health care workers from acute respiratory infection: a systematic review and meta-analysis physical interventions to interrupt or reduce the spread of respiratory viruses surgical mask vs n respirator for preventing influenza among health care workers: a randomized trial guideline for isolation precautions: preventing transmission of infectious agents in healthcare settings world health organization. personal protective equipment for use in a filovirus disease outbreak: rapid advice guideline an intervention to decrease catheter-related bloodstream infections in the icu implementing a multifaceted intervention to decrease central line-associated bloodstream infections in seha (abu dhabi health services company) intensive care units: the abu dhabi experience a multicenter, phased, cluster-randomized controlled trial to reduce central line-associated bloodstream infections in intensive care units* eradicating central line-associated bloodstream infections statewide: the hawaii experience decreasing centralline-associated bloodstream infections in connecticut intensive care units achieving zero central line-associated bloodstream infection rates in your intensive care unit does the architecture of hospital facilities influence nosocomial infection rates? a systematic review isolation of patients in single rooms or cohorts to reduce spread of mrsa in intensive-care units: prospective twocentre study relationship between icu design and mortality asian critical care clinical trials group. structure, organization, and delivery of critical care in asian icus upper room ultraviolet light and negative air ionization to prevent tuberculosis transmission institutional tuberculosis transmission. controlled trial of upper room ultraviolet air disinfection: a basis for new dosing guidelines guidelines for prevention of hospital acquired infections guide to local production: who-recommended handrub formulations shelf-life of chlorine solutions recommended in ebola virus disease response cost-effectiveness of a hand hygiene program on health care-associated infections in intensive care patients at a tertiary care hospital in vietnam cluster-randomized, crossover trial of the efficacy of plain soap and water versus alcohol-based rub for surgical hand preparation in a rural hospital in kenya muslim health-care workers and alcoholbased handrubs current practices and barriers to the use of facemasks and respirators among hospital-based health care workers in vietnam a cluster randomised trial of cloth masks compared with medical masks in healthcare workers infection prevention and control (ipc) guidance summary: ebola guidance package an approach to prioritization of medical devices in low-income countries: an example based on the republic of south sudan determining the utility and durability of medical equipment donated to a rural clinic in a low-income country mortality rates increase dramatically below a systolic blood pressure of -mm hg in septic surgical patients association of arterial blood pressure and vasopressor load with septic shock mortality: a post hoc analysis of a multicenter trial international study on microcirculatory shock occurrence in acutely ill patients assessment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (sepsis- ) diagnosing acute respiratory distress syndrome in resource limited settings: the kigali modification of the berlin definition hypoxaemia as a mortality risk factor in acute lower respiratory infections in children in low and middle-income countries: systematic review and meta-analysis prevalence and predictors of hypoxaemia in respiratory and non-respiratory primary diagnoses among emergently ill children at a tertiary hospital in south western nigeria single deranged physiologic parameters are associated with mortality in a low-income country severely deranged vital signs as triggers for acute treatment modifications on an intensive care unit in a lowincome country sepsis carries a high mortality among hospitalised adults in malawi in the era of antiretroviral therapy scaleup: a longitudinal cohort study dynamic measurement of hemodynamic parameters and cardiac preload in adults with dengue: a prospective observational study vital signs directed therapy: improving care in an intensive care unit in a low-income country accuracy of oscillometric blood pressure measurement according to the relation between cuff size and upper-arm circumference in critically ill patients tracking hypotension and dynamic changes in arterial blood pressure with brachial cuff measurements results of a survey of blood pressure monitoring by intensivists in critically ill patients: a preliminary study pulse oximetry for perioperative monitoring the use of the pulse oximetric saturation/fraction of inspired oxygen ratio for risk stratification of patients with severe sepsis and septic shock ventilatory support of patients with sepsis or septic shock in resource-limited settings the use of portable ultrasound devices in low-and middle-income countries: a systematic review of the literature impact of improved vaccination programme and intensive care facilities on incidence and outcome of tetanus in southern vietnam neonatal tetanus in vietnam: comprehensive intensive care support improves mortality impact of a structured icu training programme in resource-limited settings in asia non-invasive ventilation for children with acute respiratory failure in the developing world: literature review and an implementation example noninvasive mechanical ventilation: an -month experience of two tertiary care hospitals in north india a randomized clinical trial evaluating nasal continuous positive airway pressure for acute respiratory distress in a developing country bubble continuous positive airway pressure for children with severe pneumonia and hypoxaemia in bangladesh: an open, randomised controlled trial use of nasal bubble cpap in children with hypoxemic clinical pneumonia-report from a resource limited set-up efficacy of a lowcost bubble cpap system in treatment of respiratory distress in a neonatal ward in malawi continuous end-tidal carbon dioxide monitoring in pediatric intensive care units the use of end-tidal carbon dioxide monitoring to confirm endotracheal tube placement in adult and paediatric intensive care units in australia and new zealand the role of an anaesthetist in a field hospital during the cholera epidemic among rwandan refugees in goma end-tidal to arterial carbon dioxide partial pressure difference during craniotomy in anaesthetised patients a comparison of the end-tidal-co documented by capnometry and the arterial pco in emergency patients utility of end-tidal carbon dioxide monitoring in critically ill children weaning with end-tidal co and pulse oximetry comparison of noninvasive measurements of carbon dioxide tension during withdrawal from mechanical ventilation acute tubular necrosis; analysis of one hundred cases with respect to mortality, complications, and treatment with and without dialysis acute renal failure (arf) in developing countries: which factors actually influence survival european society of intensive care medicine (esicm) global intensive care working group and the mahidol-oxford research unit (moru) mild hypoglycemia is independently associated with increased risk of mortality in patients with sepsis: a -year retrospective observational study the impact of early hypoglycemia and blood glucose variability on outcome in critical illness lactate measurements in sepsis-induced tissue hypoperfusion: results from the surviving sepsis campaign database serum lactate is associated with mortality in severe sepsis independent of organ failure and shock early lactate clearance is associated with improved outcome in severe sepsis and septic shock point-ofcare lactate testing predicts mortality of severe sepsis in a predominantly hiv type -infected patient population in uganda point-of-care measurement of blood lactate in children admitted with febrile illness to an african district hospital lactic acidosis and hypoglycaemia in children with severe malaria: pathophysiological and prognostic significance clinical features and prognostic indicators in paediatric cerebral malaria: a study of comatose malawian children raised venous lactate and markers of intestinal translocation are associated with mortality among in-patients with hiv-associated tb in rural south africa an evaluation of serial blood lactate measurement as an early predictor of shock and its outcome in patients of trauma or sepsis hypoglycemia at admission is associated with in hospital mortality in ugandan patients with severe sepsis clinical features of severe malaria associated with death: a -year observational study in the gambia artesunate versus quinine for treating severe malaria comparison of bedside and laboratory blood glucose estimations in critically ill children with shock performance of point-of-care diagnostics for glucose, lactate, and hemoglobin in the management of severe malaria in a resource-constrained hospital in uganda accuracy of accuchek glucose measurement in intensive care patients bedside glucose monitoring-is it safe? a new, regulatory-compliant risk assessment evaluation protocol in critically ill patient care settings early lactate clearance-guided therapy in patients with sepsis: a meta-analysis with trial sequential analysis of randomized controlled trials value of arterial blood gas analysis in patients with acute dyspnea: an observational study acute respiratory distress syndrome: the berlin definition acute respiratory distress syndrome: predictors of noninvasive ventilation failure and intensive care unit mortality in clinical practice non-cardiopulmonary monitoring in thai-icu (icu-resource i study) cardiopulmonary monitoring in thai icus (icu-resource i study) mechanical ventilators availability survey in thai icus (icu-resource i study) prioritizing essential surgery and safe anesthesia for the post development agenda: operative capacities of district hospitals in low-and middle-income countries nationwide survey on resource availability for implementing current sepsis guidelines in mongolia availability of critical care resources to treat patients with severe sepsis or septic shock in africa: a self-reported, continent-wide survey of anaesthesia providers identifying resource needs for sepsis care and guideline implementation in the democratic republic of the congo: a cluster survey of hospitals in four eastern provinces management of potentially life-threatening emergencies at primary level hospitals in mongolia: results of a prospective, observational multicenter study a nationwide census of icu capacity and admissions in mongolia worldwide access to treatment for end-stage kidney disease: a systematic review equipment donation to developing countries peri-operative pulse oximetry in low-income countries: a cost-effectiveness analysis costeffectiveness analysis of a low-cost bubble cpap device in providing ventilatory support for neonates in malawi-a preliminary report cost-effectiveness of noninvasive ventilation for chronic obstructive pulmonary disease-related respiratory failure in indian hospitals without icu facilities performance of cassettebased blood gas analyzers to monitor blood glucose and lactate levels in a surgical intensive care setting the handheld blood lactate analyser versus the blood gas based analyser for measurement of serum lactate and its prognostic significance in severe sepsis healthcare infrastructure capacity to respond to severe acute respiratory infection (sari) and sepsis in vietnam: a low-middle income country clinical characteristics and outcomes are similar in ards diagnosed by oxygen saturation/fio ratio compared with pao /fio ratio a survey on critical care resources and practices in low-and middle-income countries current challenges in the management of sepsis in icus in resource-poor settings and suggestions for the future impact of the electronic medical record on mortality, length of stay, and cost in the hospital and icu: a systematic review and metaanalysis improving communication in the icu using daily goals improving nurse-physician communication and satisfaction in the intensive care unit with a daily goals worksheet improving communication in a pediatric intensive care unit using daily patient goal sheets use of a daily goals checklist for morning icu rounds: a mixed-methods study a daily goals tool to facilitate indirect nursephysician communication during morning rounds on a medical-surgical unit effect of a quality improvement intervention with daily round checklists, goal setting, and clinician prompting on mortality of critically ill patients: a randomized clinical trial improvement in process of care and outcome after a multicenter severe sepsis educational program in spain bundled care for septic shock: an analysis of clinical trials impact of sepsis bundle strategy on outcomes of patients suffering from severe sepsis and septic shock in china mortality reduction and long-term compliance with surviving sepsis campaign: a nationwide multicenter study the surviving sepsis campaign bundles and outcome: results from the international multicentre prevalence study on sepsis (the impress study) surviving sepsis campaign: association between performance metrics and outcomes in a . -year study the impact of early monitored management on survival in hospitalized adult ugandan patients with severe sepsis: a prospective intervention study* treatment outcomes after implementation of an adapted who protocol for severe sepsis and septic shock in haiti effectiveness of multifaceted hospitalwide qualityimprovement programs featuring an intervention to removeunnecessary urinary catheters at a tertiary care center in thailand effectiveness of a catheter-associated bloodstream infection bundle in a thai tertiary care center: a -year study canadian association of emergency physicians sepsis treatment checklist: optimizing sepsis care in canadian emergency departments a standardized rapid sequence intubation protocolfacilitates airway management in critically injured patients checklist for early recognition and treatment of acute illness: international collaboration to improve critical care practice will benchmarking icus improve outcome? prospectively defined indicators to improve the safety and quality of care for critically ill patients: a report from the task force on safety and quality of the european society of intensive care medicine (esicm) the german quality indicators in intensive care medicine -second edition quality indicators for icu: isccm guidelines for icus in india swedish intensive care registry national intensive care surveillance: a critical care clinical registry and bed availability system for sri lanka malaysian registry of intensive care improving quality in intensive care unit practice through clinical audit raising the standard: a compendium of audit recipes for continuous quality improvement in anaesthesia. royal college of anaesthetists a multifaceted intervention for quality improvement in a network of intensive care units: a cluster randomized trial simplified severe sepsis protocol: a randomized controlled trial of modified early goal-directed therapy in zambia mortality after fluid bolus in african children with severe infection key: cord- -at nvda authors: de weerdt, annick; janssen, bram g.; cox, bianca; bijnens, esmée m.; vanpoucke, charlotte; lefebvre, wouter; el salawi, omar; jans, margot; verbrugghe, walter; nawrot, tim s.; jorens, philippe g. title: pre-admission air pollution exposure prolongs the duration of ventilation in intensive care patients date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: at nvda purpose: air pollutant exposure constitutes a serious risk factor for the emergence or aggravation of (existing) pulmonary disease. the impact of pre-intensive care ambient air pollutant exposure on the duration of artificial ventilation was, however, not yet established. methods: the medical records of patients, admitted to the intensive care unit (icu) of the antwerp university hospital (flanders, belgium), who were artificially ventilated on icu admission or within h after admission, for the duration of at least h, were analyzed. for each patient’s home address, daily air pollutant exposure [particulate matter with an aerodynamic diameter ≤ . µm (pm( . )) and ≤ µm (pm( )), nitrogen dioxide (no( )) and black carbon (bc)] up to days prior to hospital admission was modeled using a high-resolution spatial–temporal model. the association between duration of artificial ventilation and air pollution exposure during the last days before icu admission was assessed using distributed lag models with a negative binomial regression fit. results: controlling for pre-specified confounders, an iqr increment in bc ( . µg/m( )) up to days before admission was associated with an estimated cumulative increase of . % in ventilation duration ( % ci . – . ). significant associations were also observed for pm( . ), pm( ) and no( ), with cumulative estimates ranging from . to . %. conclusion: short-term ambient air pollution exposure prior to icu admission represents an unrecognized environmental risk factor for the duration of artificial ventilation in the icu. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. the usual outdoor traffic-related air polluting suspects comprise gaseous (e.g., nitrogen dioxide (no )) and particulate pollutants generated by combustion processes. particulate matter (pm) is a heterogenic mixture of solid and liquid particles of organic and inorganic substances, drifting in the air. mostly, sulfate, nitrates, ammonia, sodium chloride, black carbon, mineral dust and water are present, though heavy metals, polycyclic aromatic hydrocarbons, bacteria, viruses and even pollen can also be found [ ] . relevant to human health, inhalable particles are categorized by aerodynamic diameter: equal or less than (≤) µm (pm ), ≤ . µm (pm . ) or ≤ . µm (pm . ). black carbon (bc), a component of pm . formed through incomplete combustion processes, is often used-in addition to no -as a proxy of trafficrelated air pollution. the smaller the particle, the deeper the penetration in the respiratory system, leading to inflammatory reactions on the alveolar level, resulting in cytotoxicity and possible mutagenesis [ , ] . as such, ambient air pollution constitutes a serious risk factor not only for the emergence of respiratory infections, but also for the development of reduced pulmonary function and/or aggravation of existing pulmonary disease (e.g., asthma, cystic fibrosis, chronic obstructive pulmonary disease [copd]) [ ] [ ] [ ] [ ] . in analogy with the recent finding that patient preadmission medical and sociodemographic characteristics (e.g., medication use, immune status, frailty) can influence the course and outcome and even the degree of respiratory failure during intensive care unit (icu) admission [ ] [ ] [ ] , we investigated the association between short-term exposure to residential ambient air pollution and the duration of mechanical ventilation in icu patients. a detailed description of the methods is provided in an electronic supplement. we conducted a large-scale cohort study in the -bed tertiary icu of the antwerp university hospital (flanders, belgium). medical records of , patients, admitted from june , , up to and including april , , were analyzed for all modes of artificial (invasive and noninvasive) ventilation within h of admission. clinical data were primarily retrieved from the patient data management system (pdms) (metavision, imdsoft, düsseldorf, germany), while personal information (e.g., smoking status) was retrieved from other medical records. our study was approved by the ethical committee of the university of antwerp/antwerp university hospital (airpollutic trial, / / ). a total of patients were mechanically ventilated within the first h of admission for the duration of at least h. after exclusion of patients living outside of belgium (n = ), removal of patients with no data on smoking status (n = ) and elimination of children (< age years) (n = ), our final study population comprised patients (fig. ) . we obtained relevant demographic and clinical data in every patient and used the simplified acute physiology score (saps ) as a validated score for severity of illness [ ] . we also obtained information on apache iv [ ] . ventilation duration was calculated by summing the duration (in hours) of all consecutive (invasive and noninvasive) ventilation episodes during the same icu admission and was rounded to the nearest number of whole days. residential addresses were geocoded with arcgis software. residential pm . , pm , bc and no exposure levels (µg/m ) were modeled for each patient's address using a high-resolution spatiotemporal model [ ] . the model takes into account land cover data obtained from satellite images (corine land cover data set) and pollution data from fixed monitoring stations in combination with a dispersion model [ ] . we calculated the daily concentrations of air pollutants at the patient's residential address up to days before admission (lag to lag , with lag representing the day of admission). for a sensitivity analysis, we calculated the annual average air pollution levels (as a proxy for long-term exposure). short-term health effects of environmental stressors may become apparent only a few or more days after exposure, implying that exposures during several days (lags) before the effect on human health should be considered. instead of testing associations with lagged exposures in separate models, distributed lag (nonlinear) models [dl(n) ms] provide a flexible methodology to capture the temporal pattern of the association by entering different lags in one and the same model. the primary study outcome short-term ambient particulate and gaseous air pollution exposure prior to icu admission significantly prolongs the duration of mechanical ventilation irrespective of preexisting lung disease or icu admission diagnosis. this finding suggests that optimizing air quality could influence icu-related morbidity. was the duration of ventilation in days. the association between ventilation duration and air pollution exposure was investigated by negative binomial regression, using a separate model for each of the four pollutants. potential delayed effects of air pollution on ventilation duration up to days before icu admission (lag to lag ) were allowed by using dlnms [ ] , with lag representing the day of admission, lag the day before admission and so on. the exposure-response function was modeled using a natural cubic spline with df. seasonality and longterm trends were modeled using a natural cubic spline of time (day of the study period) with df per year. models were additionally adjusted for indicator variables for day of the week and for known determinants of duration of ventilation such as sex, age (modeled with a natural cubic spline with df ), bmi (kg/m ), disease severity (saps ), smoking status (non-smoker/active smoker), origin of the patient before icu admission (emergency department/ other) and admission diagnosis (non-respiratory/respiratory non-infectious respiratory infectious). in a secondary analysis, we adjusted our models for apache iv. in an effort to account for exposure misclassification in patients who were admitted to the hospital some days before icu admission (e.g., days at home, days in the hospital, then icu admission), we performed an analysis where we combined the daily exposure values derived at the home address with the daily exposure values derived at the hospital. alternatively, we excluded patients coming from another hospital icu to account for possible exposure misclassification (resulting in n = ). in another secondary analysis, we accounted for possible confounding due to respiratory comorbidities by excluding all patients with preexisting lung disease including copd and asthma (resulting in n = ) and by excluding all patients with preexisting respiratory and neuromuscular comorbidities (n = ). we then further restricted the study population to patients who left the icu alive (n = ) to account for early death. finally, to differentiate between short-and long-term effects, we added annual average air pollution levels (as a proxy for long-term exposure) to our main model. reported estimates represent the lag-specific and cumulative (lag - days) percentage change (with % confidence intervals [ci]) in ventilation duration for an interquartile range (iqr) increase in air pollution exposure. all analyses were performed with the statistical software r (r foundation for statistical computing, vienna, austria) using the "dlnm" package [ ] . demographic and clinical characteristics of the adult patients are summarized in table . . % of our study population were years or older. there were more men ( . %) than women ( . %), and nearly one-third ( . %) of our population were smokers. approximately % of our population was admitted with a non-respiratory diagnosis, only . % with a non-infectious respiratory disease and . % with a respiratory infection. the mean (± sd) ventilation duration was (± ) days with median ( th- th percentiles) daily air pollution exposures up to days before admission were . ( . - . ) μg/m for bc, . ( . - . ) μg/m for pm . , . ( . - . ) μg/m for pm and . ( . - . ) μg/m for no ( table ). the majority of participants lived in the province of antwerp, relatively close to the antwerp university hospital, where we observed the highest levels of pm . exposure in belgium (figure electronic supplement) the lag-specific dlm estimates of the association between ventilation duration and air pollutant exposures up to days before the icu admission are shown in fig. . the effect of all examined components of air pollution on ventilation duration was found to be acute, with significant effect estimates at lag (except for no ) and estimates close to zero after lag . an iqr ( . µg/ m ) increment in bc exposure up to days before icu admission was associated with a . % ( % ci . to . ) longer mechanical ventilation duration ( table ) . the corresponding estimates for pm . , pm and no were . % ( % ci . - . ), . % ( % ci . - . ), and . % ( % ci . - . ), respectively. correcting our models for apache iv or using data where we took into account possible exposure misclassification had a little effect on our estimates for all pollutants except that the estimates of pm . did not reach significance anymore (table ). excluding patients who had been hospitalized in another hospital icu, days prior to admission to our icu, also did not change our effect estimates substantially (table ). restricting our analysis to patients without preexisting copd and asthma resulted in stronger associations for all pollutants: . % ( % ci . - . ) for bc, . % ( % ci . - . ) for pm . , . % ( % ci . - . ) for pm , and . % ( % ci . - . ) for no even after excluding all patients with respiratory and neuromuscular comorbidities. further restricting the study population to patients without preexisting comorbidities, leaving the icu alive, resulted in a further increase in cumulative effect estimates for bc and no and similar (although no longer significant) estimates for pm . and pm . to differentiate between short-and long-term effects, we added annual average air pollution levels (as a proxy for long-term exposure) to our main model but found it not to be associated with the duration of ventilation. in our study of icu patients, requiring mechanical ventilatory support for a diversity of reasons, ventilation duration was significantly associated with pre-admission exposure to bc, pm . , pm and no . for an iqr higher air pollution exposure up to days before admission, the duration of ventilation was estimated to be . - . % longer. our data were obtained in a large and diverse icu population, and the relationship between air pollution exposure and duration of ventilation was shown irrespective of preexisting lung disease or icu admission diagnosis. it has been shown that medical and sociodemographic characteristics [ , , ] already present prior to icu admission contribute to the occurrence and severity of organ failure including respiratory failure as well as the outcome in the critically ill. however, pre-admission environmental factors have hardly been studied in this context, or studies have found no effect (i.e., sunlight exposure prior to icu admission has been found not to influence the incidence of icu-acquired delirium) [ ] . we are the first to report on the effect of pre-admission air pollution exposure on the duration of mechanical ventilation. the findings of this study are of critical public health importance because of the ubiquity of ambient air pollution. short-term ambient particulate air pollution is independently associated with daily all-cause, cardiovascular and respiratory mortality [ , ] . as such, air pollution has important molecular and physiological effects on the lung, an organ frequently failing in the critically ill. a few recent studies have demonstrated some effects of air pollution on the occurrence of (only) the acute respiratory distress syndrome (ards) and associated mortality. long-term ozone and pm . exposure are associated with an increased risk for ards among older adults in the usa [ ] and in patients at risk for ards (e.g., trauma patient, active smoker) [ ] . rush et al. [ ] described how chronic exposure to high levels of ozone and pm results in higher mortality rates in ards patients, and most recently, reilly et al. [ ] added long-term exposure to low to moderate levels of sulfur dioxide, no and carbon monoxide to the risk factors for ards in trauma patients. our results indicate the acute effects of air pollution on ventilation duration. significant associations were observed for lag , representing the day of icu admission, but positive estimates (close to significance for bc and pm . ) were also observed for lag . a similar lagged pattern (lag and lag ) has been shown in a recent study investigating the association between the short-term effect of ambient air pollution (pm and pm . ) and hospital admission for respiratory diseases [ ] . the mechanism of this lagged pattern is not completely understood, but (pulmonary and/or systemic) oxidative stress and inflammation might be plausible biological mechanisms. for example, in a prospective panel study, increased blood levels of c-reactive protein and icam- were observed for an increase in pm and ultrafine particles with a delay of - days [ ] . in individuals of the framingham heart study, elevated exposure to relatively low levels of ambient air pollution for a few days was associated with higher levels of biomarkers of systemic inflammation (including c-reactive protein, interleukin- and tumor necrosis factor receptor ) [ ] . therefore, it is reasonable to assume that acute air pollution-induced inflammation processes occur, at least in the lung, since this is the primary site of inflammation. the effects of air pollutants on the lung originate from extracellular activation of the inflammatory response and/or oxidative stress-mediated inflammation in airway epithelial cells [ ] . known detrimental effects of airway inflammation comprise a reduction in pulmonary function, increased airway reactivity with hypersecretion of mucus and alterations in mucociliary activity [ ] . the latter will of course contribute to a protracted exposure of the airway epithelium to toxic particles, thus generating a prolonged inflammatory response. we hypothesize that inflammatory reactions on the alveolar, airway and/or pulmonary capillary level result in gas exchange impairment, thus contributing to the lengthening of ventilation duration. the estimates represent the cumulative percentage change in ventilation duration for an iqr (μg/m ) increment in the air pollutant up to days before the icu admission all models were adjusted for long-term trends and seasonality, age, sex, bmi, smoking habit, saps , day of the week, icu origin and admission diagnosis a including preexisting copd, asthma and all other respiratory comorbidities modern critical care does not only focus on the prevention of primary ventilation-associated morbidities such as ventilator-associated pneumonia or barotrauma [ , ] but also tries to prevent long-term sequela related to prolonged mechanical ventilation by the use of short-acting sedatives and daily appraisal of the need for mechanical ventilation. indeed, duration of ventilation-related conditions such as cognitive impairment, depression, neuro-myopathy and pulmonary function alterations (e.g., reduced diffusion capacity) can persist in the icu survivor, resulting in a long-term need of medical, psychological and/or physiotherapeutic care, causing considerable economic burden [ , ] . our data thus represent a novel and potentially modifiable environmental risk factor, which, if improved, will not only ameliorate the post-icu quality of life but might also reduce health care costs. the incentive to "clear the air" will gain even more importance in the future, considering the projected increase in an aging [ ] population who are even more at risk for air pollution-related respiratory diseases due to an age-related defective mucociliary function in combination with decreased muscle strength, compromising the ability to clear inhaled particles [ , ] . our study was conducted in the northern part of flanders (belgium), where levels of air pollutants continued to decrease between and . in , the annual levels of air pollutants in our study population nearly reached the who standards for pm . ( . vs. µg/m ) and for pm ( . vs. µg/m ) and even dived under the limit for no ( . vs. µg/m ) (table electronic supplement) [ ] . the european union (eu) air quality directives are less stringent (annual limits μg/m for pm . , µg/m for pm and no ) than the who guidelines. in light of the fact that we found significant effects on duration of ventilation at air pollution levels well below the eu limits, our findings support a further down-revision of the current eu air pollution directives in the direction of the who guidelines. our findings need to be interpreted within the context of its strengths and limitations. although we used validated exposure models, there might be some exposure misclassification. for example, we interpolated daily exposure levels at the residence without taking the amount of exposure at the address of employment or the time spent indoors into account. however, considering the higher age and expected preexisting health problems in our study population, we may assume that a considerable portion of time before admission was spent at the home address. furthermore, a number of patients had been admitted to our hospital some days before icu admission, thus generating some exposure misclassification. however, it is reasonable to assume that the exposure misclassification is random, resulting in an underestimation of effect estimates [ , ] . moreover, our findings stayed robust after accounting for possible exposure misclassification and excluding patients coming from another hospital icu. in terms of validity of the exposure model, we showed that the estimated long-term residential exposure correlates with the internal nanosized carbon load in urine [ ] . secondly, we recognize the multifactorial character of ventilation duration, but we wish to emphasize that the use of short-acting sedatives, lung-protective ventilation and spontaneous breathing trials has been the mainstay of icu ventilation care in the antwerp university hospital before, during and after the study period. any differences in duration of ventilation are therefore not attributable to physician-specific particularities, but a priori to (preexistent) patient characteristics. additionally, our findings were robust after adjusting for apache iv, excluding all patients with preexisting lung disease (copd and asthma) or other comorbidities and even after excluding the patients that died in the icu to account for the competing risk of early mortality. thirdly, due to patient heterogeneity in the intensive care and random exposure misclassification-which cannot be ruled out in epidemiology-we observed relatively wide confidence intervals around our estimates. finally, we could not retrieve information on socioeconomic status (ses). although ses is important in long-term exposure outcomes, it is less likely to be an important confounder in acute exposure studies as no relation between shortterm temporal differences in air pollution exposure and ses is expected. our results add to the growing body of evidence that links air pollution exposure to respiratory health. our study is the first to examine the effect of pre-admission ambient air pollution on duration of artificial ventilation in the icu. our results suggest that a further optimization of air quality could influence icu-related morbidity and-although not directly studied-icu-related health costs. our study also demonstrates that exposure to "low-level" air pollution prior to mechanical ventilation is clinically relevant. accounting for exposure misclassification excl. respiratory a , neuromuscular comorbidities & deaths air quality guidelines for particulate matter, ozone, nitrogen dioxide and sulfur dioxide inhaled pollutants: the molecular scene behind respiratory and systemic diseases associated with ultrafine particulate matter the impact of pm . on the human respiratory system global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, - : a systematic analysis for the global burden of disease study short-term exposure to air pollution: associations with lung function and inflammatory markers in non-smoking, healthy adults impact of air pollution on cystic fibrosis pulmonary exacerbations: a case-crossover analysis an association of particulate air pollution and traffic exposure with mortality after lung transplantation in europe prehospital aspirin use is associated with reduced risk of acute respiratory distress syndrome in critically ill patients: a propensityadjusted analysis preadmission oral corticosteroids are associated with reduced risk of acute respiratory distress syndrome in critically ill adults with sepsis the impact of frailty on intensive care unit outcomes: a systematic review and meta-analysis saps -from evaluation of the patient to evaluation of the intensive care unit. part : development of a prognostic model for hospital mortality at icu admission acute physiology and chronic health evaluation (apache) iv: hospital mortality assessment for today's critically ill patients spatial interpolation of air pollution measurements using corine land cover data validation of the mimosa-aurora-ifdm model chain for policy support: modeling concentrations of elemental carbon in flanders distributed lag non-linear models distributed lag linear and non-linear models in r: the package dlnm quality of life before intensive care unit admission is a predictor of survival effect of preadmission sunlight exposure on intensive care unit-acquired delirium: a multicenter study ambient particulate air pollution and daily mortality in cities climate change, global warming, and intensive care impact of long-term exposures to ambient pm . and ozone on ards risk for older adults in the united states long-term ozone exposure increases the risk of developing the acute respiratory distress syndrome association between chronic exposure to air pollution and mortality in the acute respiratory distress syndrome low to moderate air pollutant exposure and acute respiratory distress syndrome after severe trauma short-term effects of ambient pm and pm . air pollution on hospital admission for respiratory diseases: case-crossover evidence from shenzhen, china air pollution and markers of inflammation and coagulation in patients with coronary heart disease short-term exposure to ambient air pollution and biomarkers of systemic inflammation: the framingham heart study pro-inflammatory effects and oxidative stress in lung macrophages and epithelial cells induced by ambient particulate matter interactions of oxygen radicals with airway epithelium ventilator-associated pneumonia: present understanding and ongoing debates long-term complications of critical care risk factors for persistent cognitive impairment after critical illness, nested case-control study ageing europe-looking at the lives of older people in the eu the aging lung the effect of oxidative stress polymorphisms on the association between long-term black carbon exposure and lung function among elderly men epidemiology in medicine air pollution and risk of stroke: underestimation of effect due to misclassification of time of event onset children's urinary environmental carbon load. a novel marker reflecting residential ambient air pollution exposure? key: cord- -u ecibta authors: haviland, kelly; tan, kay see; schwenk, nadja; pillai, manju v.; stover, diane e.; downey, robert j. title: outcomes after long-term mechanical ventilation of cancer patients date: - - journal: bmc palliat care doi: . /s - - -x sha: doc_id: cord_uid: u ecibta background: the probability of weaning and of long-term survival of chronically mechanically ventilated cancer patients is unknown, with incomplete information available to guide therapeutic decisions. we sought to determine the probability of weaning and overall survival of cancer patients requiring long-term mechanical ventilation in a specialized weaning unit. methods: a single-institution retrospective review of patients requiring mechanical ventilation outside of a critical care setting from to and from january to december , , was performed. demographic and clinical data were recorded, including cancer specifics, comorbidities, treatments, and outcomes. overall survival was determined using the kaplan-meier approach. time to weaning was analyzed using the cumulative incidence function, with death considered a competing risk. prognostic factors were evaluated for use in prospective evaluations of weaning protocols. results: between and , patients required mechanical ventilation outside of a critical care setting with weaning as a goal of care. the cumulative incidence of weaning after discharge from the intensive care unit was % at days, % at days, % at days, % at days, and % at days. the median survival was . years ( % ci, . to . ) for those not weaned and . years ( % ci, . to . ) for those weaned. overall survival at year and years was and % among those weaned and and % among those not weaned. during , patients at our institution required mechanical ventilation outside of a critical care setting, with weaning as a goal of care. overall, with a median follow-up of days (range, – days; average, days), % of patients requiring long-term mechanical ventilation ( of ) are alive. conclusions: cancer patients can be weaned from long-term mechanical ventilation, even after prolonged periods of support. implementation of a resource-intensive weaning program did not improve rates of successful weaning. no clear time on mechanical ventilation could be identified beyond which weaning was unprecedented. short-term overall survival for these patients is poor. prolonged mechanical ventilation ranks sixtieth among the reasons for hospitalization but third for total charges generated (us$ billion in ) and first for charges per patient [ ] . patients requiring long-term mechanical ventilatory support are part of a group of patients often referred to as "chronically critically ill," and they often share other medical conditions, including recurrent infections, neuromuscular dysfunction (due to both disuse and medication), cognitive changes (such as delirium), and pain and other problems. as such, they represent a group of patients with profoundly recalcitrant medical conditions. the outcomes achieved by medical care of patients requiring mechanical ventilation have been incompletely characterized with regard to the likelihood of both weaning and survival, and even less so with regard to quality of life during the time these patients remain alive. cancer patients requiring long-term mechanical ventilation have been the subject of only two previous studies. shih and colleagues reviewed cancer patients who required mechanical ventilation for > days in taiwan from to . half of these patients survived < . months, and the -year overall survival was % [ ] . in taiwan, care may not be withdrawn, limiting the application of this work to other populations in which care may be withdrawn if it is believed to be futile. soares et al. performed a retrospective review of a single institution's experience with cancer patients requiring > days of mechanical ventilation via tracheostomy in an intensive care unit (icu), essentially all of whom required mechanical ventilatory support [ ] . however, the duration of the need for mechanical ventilation was not provided. the hospital and -month survivals were and %, respectively, for patients in this study. in , the surgical advanced care unit (sacu) was opened at memorial hospital, memorial sloan kettering cancer center (msk). among other clinical programs, the sacu offers a comprehensive program aimed at weaning patients from long-term mechanical ventilation. this weaning program is multidisciplinary (including internists, pulmonologists, specialized nps, respiratory care, rehabilitation, social work, case management), with a high level of nursing staffing (one rn for two patients) and dedicated physical facilities (rooms designed to accommodate ventilated patients). since , the sacu staff care for approximately patients each year who require long-term mechanical ventilation. to measure whether the creation of a dedicated weaning program altered the outcomes seen in this patient population, we performed a single-institution retrospective study of cancer patients requiring long-term mechanical ventilation who were cared for in a specialized intermediate care weaning unit. the goal of this study was to characterize the results achieved, focusing on the likelihood of weaning and on overall survival. two patient cohorts were examined. the first group was cared for between and , a period that was chosen so that a comparison between patients receiving care before and after creation of a dedicated weaning unit could be performed. the second group was cared for between january and december , a period chosen because it represents contemporary practice and provides sufficient time for clinical follow-up to estimate long-term outcomes. design, setting, and eligibility criteria after a waiver of authorization (wa - ) was obtained from the institutional review board at memorial sloan kettering cancer center, we performed a retrospective review of a single institution's experience with all patients treated with prolonged mechanical ventilation with weaning as a goal of care after icu discharge, subject to intensivist discretion, between and and between january and december . pediatric (< years of age) and neurological patients were not included. during the initial years of the study period ( - ), the primary responsibility for care of patients treated with prolonged mechanical ventilation after icu discharge was by the service that had initially admitted the patient to the hospital on their primary floor. in , the surgical advanced care unit (sacu) was created. under the sacu program, all patients treated with prolonged mechanical ventilation after discharge from the icu were transferred to the care of the general medicine service. a coordinated program of care was delivered, organized around daily rounds attended by the sacu nurse practitioners and registered nurses, the general medicine attending, and the pulmonary medicine attending, as well as representatives from the previous primary service, respiratory therapy, physical therapy, occupational therapy, social work, and case management. demographic and clinical data were recorded, including cancer specifics, comorbidities, treatments, and outcomes. the data fields collected and definitions used are listed in the supplemental materials. weaning as a goal of care was determined from a subjective review of the daily determinations made by the treating team of attending physicians. successful weaning was defined as removal from all mechanical ventilatory support for h. patient demographic and clinical characteristics were summarized using descriptive statistics. by use of the kaplan-meier method, overall survival was calculated from the time of icu discharge until the date of death or was censored on the date of last clinical contact. weaning status was treated as a time-dependent covariate: all patients began as "not weaned" upon icu discharge, and the weaning status changed to "weaned" on the date of first documentation of weaning, if applicable. comparisons of overall survival by group were made using the log-rank test. cox regression was used for univariable and multivariable analyses to estimate the hazard of death based on weaning statuses, with adjustment for demographic and clinical variables. factors included care in the sacu, age on initiation of ventilatory support outside of the icu, sex, cancer status (active versus no evidence of disease), tumor histology (solid versus liquid), and number of days on mechanical ventilation while in the icu. time to weaning, defined as the number of months between icu discharge and first documentation of successful weaning, was analyzed using a competing risks approach. death without having been weaned was treated as a competing risk event. cumulative incidence functions for each competing event were calculated using competing risks methodology [ ] . fine and gray's competing risk regressions for the subhazard ratio [ ] were used to evaluate any patient, tumor, or treatment characteristic that was associated with the incidence of weaning. we derived the conditional probability of weaning in the presence of a competing risk (death without having been weaned) in a period, assuming the surviving patient was not yet weaned at the beginning of the period [ ] . analyses were conducted using r . . (r development core team, vienna, austria) and stata (statacorp, college station, tx). all statistical tests were -sided, and p < . was considered to indicate statistical significance. between january , , and december , , patients were mechanically ventilated at memorial hospital outside of a critical care unit (excluding pediatric and neurological patients, who were treated in separate, specialized programs). of the patients, were treated with weaning as a goal of care; the remainder were treated with palliative intent. for the purposes of this study, to achieve uniformity in the study populations, patients who had not been admitted to the icu were excluded from the analyses, resulting in patients included in the study cohort. the demographic and clinical characteristics of the patients with weaning as a goal of care are summarized in table . in total, % of the patients either had known active malignancies or were being actively treated with antineoplastic therapy. a majority of the patients with cancer ( %) had solid tumors. the median followup for this cohort was . months (range, < month to . years); for patients in this cohort who died, the median follow-up was . months (range, < month to . years). of the patients in the study cohort, ( %) were weaned from mechanical ventilation. of all the cancer patients with weaning as a goal of care and requiring days of mechanical ventilation after icu discharge, % were eventually weaned. of patients requiring days of mechanical ventilation after icu discharge, % were eventually weaned (table ). figure shows the cumulative incidence of weaning since icu discharge, along with the curve for the competing risk of death without weaning. the median ( th to th percentile) duration on ventilators since icu discharge, for patients who were weaned, was ( to ) days; for those who were not weaned, this was ( to ) days. the probability of a surviving patient being weaned by a certain time (i.e., if the patient had neither died nor been weaned) after icu discharge was % at days, % at days, and % at days ( table ). patients who either had active disease or were receiving antineoplastic therapy were approximately % less likely to be weaned at any given time point, compared with patients who did not have active disease or who were not undergoing treatment (table ) . patients with solid tumors were not significantly more likely to be weaned than patients with liquid tumors (p = . ). the median survival for patients who had weaning as a goal of care but who were not weaned was . years ( % ci, . to . ), compared with . years for those who were weaned ( % ci, . to . ). the year overall survival for patients who were not weaned was % ( % ci, to %), compared with % for patients who were weaned ( % ci, to %) (p < . ) ( figs. and ) . the -year overall survival for patients who were weaned was % and for patients who were not weaned was %. when weaning status was used as a time-varying covariate, the hazard of death for patients who were able to be weaned was . times that for those who were not able to be weaned ( % ci, . to . ) (p < . ); conversely, the hazard of death for patients who were not weaned was . times higher than that for patients who were successfully weaned ( % ci, . to . ) (p < . ). among the univariable cox proportional hazards models, weaning status was the only factor that was significantly associated with overall survival (table ) , so a multivariable analysis was not performed. the second cohort of patients examined were cared for between january and december , . during this interval, there were unique patients admitted to sacu for ventilator management. six of patients were admitted to sacu more than once. the median hospital length of stay (los) for the patients was days (average, days; range, - days). the median sacu los for all patients was days (average, ; range, - days). thirty percent of patients who were in the sacu on ventilator for > days were subsequently able to be weaned. the discharge status of the patients was as follows. thirty-eight percent of patients ( of ) were discharged alive from the hospital. eight percent of patients ( of ) were discharged to home. thirty percent of patients ( of ) were discharged to a long-term care facility or hospice. sixty-one percent of patients ( of ) died while inpatients at msk. at last follow-up, the status of patients discharged from msk was to home, to hospice, to a rehabilitation facility, and unknown from chart review. the most frequent disposition of patients with sacu los ≥ days ( patients) was death at msk ( patients). of the patients with sacu los ≥ days, patients were weaned and was not weaned. overall, with a median follow-up of days (range, - days; average, days), % of patients requiring long-term mechanical ventilation at msk ( of ) are alive. we found that the -year and -year overall survival for patients who were weaned were and %. the -year and -year overall survival for patients who were not weaned were and %. again, the -year overall survival for weaned patients in our study was similar to survival rates in previous reports including non-cancer patients. engoren et al. [ ] , in , reported a -year overall survival of %. bigatello [ ] , in , reported a similar -year overall survival, of %. similar outcomes have been reported in more recent studies: in a retrospective multicenter review from , carson et al. [ ] fig. overall survival of weaned and not weaned cancer patients. weaning status was entered as a time-dependent covariate. all patients were discharged from icu while on mechanical ventilation and thus were not weaned at icu discharge; the patient's status was changed to "weaned" at the date of the first recorded weaning efforts to improve long-term outcomes after prolonged mechanical ventilation have been reported. daly et al. [ ] reported a prospective randomized trial of patients cared for either by a disease management team (dmt)-including nurse practitioners, a geriatrician, and a pulmonologist-or by the primary service alone. care by the dmt extended to months after hospital discharge. unfortunately, neither mortality, need for rehospitalization, nor time to rehospitalization was significantly improved in the dmt care group. this emphasizes the recalcitrance and intractability of the medical problems experienced by this patient population. similarly, for the patients that compose our study population, at first, care was directed by the original admitting service, with weaning directed by the critical service as a consult service. in , we created the sacu, which consolidated all patients requiring mechanical ventilation outside of an icu to one floor with dedicated ventilator rooms, including monitoring, and a cadre of nurse practitioners who were physically present on the floor - . all mechanically ventilated patients were transferred to the general medicine service, which coordinated care during daily rounds ( days a week) with representatives from nursing (both registered nurses and sacu-dedicated nurse practitioners) as well as pulmonary medicine, respiratory therapy, rehabilitation medicine (i.e., physical and occupational therapy), and social work services. the outcomes of patients cared for in the sacu, despite this coordination of care and expenditure of resources, were not significantly different from the outcomes of patients cared for before the creation of the sacu. it is possible that our weaning program was more effective than our data suggest because of other factors that are difficult to account for. for example, during this same time, the memorial hospital icu implemented multiple other care plans directed at improving the likelihood of weaning while in the icu, including sedation holidays [ ] and mobilization while on mechanical ventilatory support [ ] . it is likely that these programs led to earlier successful weaning of more patients while they were admitted to the icu and that the remaining patients, who were discharged from the icu to sacu care while on mechanical ventilation, represented a sicker patient population with more recalcitrant medical conditions. our study provides information on the likelihood of weaning and on survival for cancer patients requiring long-term mechanical ventilation. it is our hope that this information can be provided to patients and their families to assist in clinical decision-making. specifically, with the goal of guiding care in mind, we examined whether an inflection point for success in weaning associated with the duration of weaning might be found. for example, an early period characterized by a high success fig. the cumulative incidence of weaning after icu discharge and of the competing risk of death without weaning. the cumulative incidence of weaning was % at days after icu discharge time-varying covariate: weaning status changed from "not weaned" to "weaned" on the date of first documentation of weaning post-icu discharge rate in weaning might be followed by a plateau in weaning success, such that transition to a care plan for longterm ventilatory support could be made. no such inflection point seems apparent, and if it does exist, it seems likely to occur between and days (fig. ) . our study also does not provide what may be more important information: the likely quality of life during a patient's remaining life. multiple studies have noted diminished quality of life [ , [ ] [ ] [ ] , including persistent significant cognitive deficiencies [ , ] , after care that included prolong mechanical ventilation. in general, these outcomes are not anticipated by patients and their caregivers. cox et al. [ ] found that, at the time of initiation of ventilation, % of patients and caregivers expected the patient to be alive at year, % expected good functional status, and % expected a good quality of life. after a year, only % of patients were alive, and of these survivors only % had a good functional status and % had a good quality of life. taken together, these findings suggest that palliative care teams should be included in the overall management of patients requiring long-term mechanical ventilation [ ] . future research could include collecting detailed information about patient quality of life and then examining whether providing patients and their families detailed information about the quality and duration of life that is likely to be experienced by a patient alters the clinical decisions patients and families make. supplementary information accompanies this paper at https://doi.org/ . /s - - -x. abbreviations dmt: disease management team; icu: intensive care unit; sacu: surgical advanced care unit outcomes of prolonged mechanical ventilation incidence, life expectancy and prognostic factors in cancer patients under prolonged mechanical ventilation: a nationwide analysis of , cases during short-and long-term outcomes of critically ill patients with cancer and prolonged icu length of stay regression modeling of competing crude failure probabilities a proportional hazards model for the subdistribution of a competing risk competing risks: a practical perspective hospital and long-term outcome after tracheostomy for respiratory failure outcome of patients undergoing prolonged mechanical ventilation after critical illness a multicenter mortality prediction model for patients receiving prolonged mechanical ventilation trial of a disease management program to reduce hospital readmissions of the chronically critically ill removing the critically ill patient from mechanical ventilation effect of early rehabilitation during intensive care unit stay on functional status: systematic review and meta-analysis survival and quality of life: short-term versus long-term ventilator patients morbidity, mortality, and quality-of-life outcomes of patients requiring >or= days of mechanical ventilation quality of life after prolonged intensive care brain dysfunction: another burden for the chronically critically ill expectations and outcomes of prolonged mechanical ventilation palliative care of the chronically critically ill patient publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. authors' contributions kh had full access to all of the data in the study and takes responsibility for the integrity of the data collected. kh, rd, kst performed the data analysis. rjd, kh, kst, ns, mvp, and des contributed substantially to the study design, and interpretation, writing of the manuscript, and final approval of the manuscript. this study was funded, in part, by nih/nci cancer center support grant p ca . the datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.ethics approval and consent to participate a waiver of approval (wa - ) was obtained from the institutional review board at memorial sloan kettering cancer center. not applicable. the authors declare that they have no competing interests.author details key: cord- -hy xmtiq authors: walz, alice; canter, marguerite orsi; betters, kristina title: the icu liberation bundle and strategies for implementation in pediatrics date: - - journal: curr pediatr rep doi: . /s - - - sha: doc_id: cord_uid: hy xmtiq purpose of review: we briefly review post-intensive care syndrome (pics) and the morbidities associated with critical illness that led to the intensive care unit (icu) liberation movement. we review each element of the icu liberation bundle, including pediatric support data, as well as tips and strategies for implementation in a pediatric icu (picu) setting. recent findings: numerous studies have found children have cognitive, physical, and psychiatric deficits after a picu stay. the effects of the full icu liberation bundle in children have not been published, but in adults, bundle implementation (even partial) resulted in significant improvement in survival, mechanical ventilation use, coma, delirium, restraint-free care, icu readmissions, and post-icu discharge disposition. summary: although initially described in adults, children also suffer from pics. the icu liberation bundle is feasible in children and may ameliorate the effects of a picu stay. further studies are needed to characterize the benefits of the icu liberation bundle in children. the landscape of pediatric intensive care has changed immensely since the advent of the first pediatric intensive care units (picus) in the s and s [ ] . through advances in mechanical support, medications, and procedures, mortality has been greatly reduced [ ] , but many pediatric survivors of critical illnesses will experience long-term disabilities, higher readmission rates, and overall poorer health status [ ] [ ] [ ] [ ] [ ] [ ] . such knowledge of the harm of an icu stay, initially described in the adult icu population, led the movement to reevaluate icu clinical practice patterns and culture. with increasing awareness of the long-term detriments of an icu stay, the term post-intensive care syndrome (pics) was coined to describe the combination of negative cognitive, psychological, and physical effects after critical illness [ , •] . pics has been described in children as well, although the true incidence is difficult to determine [ , ] . studies have shown up to % of children may display negative psychological and behavioral outcomes in the first year following picu discharge including ongoing fears, changes in memory, attention span, cognitive functioning, self-esteem, or self-confidence, and a large proportion of picu survivors may suffer from posttraumatic stress symptoms [ ] [ ] [ ] . several studies have described significant motor deficits and exacerbation of baseline physical disabilities in children post-icu stay [ , , ] . a systematic review published in found studies documenting deficits in all three pics domains in picu survivors [ ] . although these pediatric cohort studies have found significant morbidities, it is difficult to compare data and estimate a true incidence due to varied outcomes scales and measures [ ] . in addition to patient deficits, parents or family members of critically ill children can experience depression or post-traumatic stress disorder (ptsd) symptoms as well [ , ] . given these findings, recent focus has shifted from solely improving mortality to better understanding and preventing the long-term psychologic, social, and physical impairment experienced by critically ill patients and their families. a compelling body of literature, mostly adult, surfaced to support several changes in clinical care to ameliorate pics and the effects of an icu stay. the icu liberation collaborative was a quality improvement initiative hosted by the society of critical care medicine among hospitals ( adult and pediatric) formed to implement and assess changes in clinical practice aimed at improving patient outcomes. the collaborative worked to integrate the icu liberation bundle, also known as the abcdef bundle, in the care of their patients to mitigate the effects of an icu stay [ •] . bundle implementation resulted in substantial improvements among adult icu patients [ ••, ] . in two large multicenter studies at varied types of icus [ ••, ] , even partial bundle implementation resulted in improvement in survival, mechanical ventilation use, coma, delirium, restraint-free care, icu readmissions, and post-icu discharge disposition. furthermore, the data supported a dose-response relationship, in which a higher proportion of bundle compliance correlated with improved clinical outcomes. although pediatric data is limited, these results have further supported the use of the abcdef bundle in all icu patients, including picu patients. the icu liberation bundle, also known as the abcdef bundle (table ) , is an evidence-based guideline to liberate patients from the harmful effects of an icu stay. this large-scale quality improvement strategy offers guidance for the daily care of critically ill patients that can reduce pain, agitation, and delirium, in an effort to prevent physical, psychological, and cognitive morbidities that limit or prolong recovery. the components of the bundle include assessment, prevention, and management of pain; both spontaneous awakening and breathing trials; choice of sedation and analgesia; delirium assessment, prevention and management; early mobility and exercise; and family engagement and empowerment. pain and agitation are prevalent issues for pediatric patients during critical illness, and the overall goal of pain management within the picu should be to maintain children in a calm, comfortable state that minimizes pain, but in which the patient is also able to remain alert and lucid during recovery. a key first step in managing pain is to correctly assess a patient's pain level. self-report is a reliable indicator of pain; however, it has been shown that a large proportion of pediatric patients in the picu are unable to self-report their pain [ ] . the heterogenous ages and developmental levels of the patients, in addition to the use of invasive support, can make adequate pain assessment challenging. to ameliorate this, a reliable and valid pain scale, appropriate for different ages, should be used for assessing pain and titrating medications when self-reporting is not possible. the choice of pain scale used will depend on patient age and the verbal and cognitive capacity of the patient. in pediatrics, validated pain scales include the face, legs, activity, crying, consolability (flacc) scale for nonverbal children to years of age [ ] , the individualized numeric rating scale (nrs) for nonverbal cognitively impaired children aged years and older [ ] , and the wong-baker faces pain scale (faces) for verbal children years or older [ ] . in each of these scales, a score of to can be assigned, with higher scores indicating more pain. in addition to the use of medications to treat acute pain, nonpharmacologic interventions should be considered as adjuncts. examples include repositioning, distraction, increasing caregiver presence, heat/cold compresses, or the use of massage therapy, music therapy, and child life therapy [ ] [ ] [ ] . tips for implementation start by choosing a validated assessment tool to systematically evaluate levels of pain (in pediatrics, this includes the nrs, faces, and flacc scales) and incorporate this into daily nursing assessments. discuss among key stakeholders how higher pain scores should be addressed with medications and nonpharmacologic interventions and be sure to include reassessment of pain scores after intervention. prolonged mechanical ventilation is associated with increased patient morbidity and mortality and there is evidence that reducing the duration of mechanical ventilation through ventilator weaning protocols can improve clinical outcomes [ , •] . therefore, it is imperative to recognize early those patients who are ready for discontinuation of mechanical family engagement and empowerment respiratory support. a spontaneous breathing trial (sbt) is a systematic clinical assessment of the respiratory pattern, adequacy of gas exchange, hemodynamic stability, and subjective patient comfort that can be used to prompt consideration for ventilator discontinuation [ , ] . in practice, systematic usage of sbt leads to earlier discontinuation of mechanical ventilation and it has been shown that up to % of critically ill adult patients who tolerated sbt were able to be successfully extubated [ ] . while similar outcome data for sbt does not yet exist in pediatrics, and there remains controversy over both the optimal technique to perform an sbt and the criteria defining a successful sbt, investigation is currently underway in pediatrics. patients requiring mechanical ventilation are often maintained on continuous sedative infusions; thus, it is important to pay attention to the effects of sedation on respiratory drive and how the level of sedation may affect a patient's success of liberation from mechanical ventilation. deep sedation has been associated with longer duration of mechanical ventilation and reduced -month survival [ ] . one such option to systematically assess a patient's sedation requirements and ability to be more awake while mechanically ventilated is through a trial of daily sedation interruption, or a "sedation holiday." this daily sedation interruption is often referred to as a spontaneous awakening trial (sat). a sat used alone or paired together with sbt has been shown to lead to earlier discontinuation of mechanical ventilation, decreased icu length of stay, and improved -year survival in critically ill adult patients [ •, ] . tips for implementation start by forming a multidisciplinary team of physicians, respiratory therapists (rt), and registered nurses (rn) to agree on selection criteria that would allow patients to begin sbt trials, set the criteria that determine trial failure, and determine what next steps will be for patients who have passed the sbt. once agreed upon criteria are established, trial a huddle each morning to discuss which of the current patients in the picu meet criteria. be sure to coordinate the sat/sbt trial with rn/rt availability. over time, consider tracking the percentage of patients that qualify for sat/sbt who pass and are able to be successfully extubated. the use of deep sedation has been shown to be associated with worse short-term and long-term outcomes [ , ] . whenever feasible, the goal of sedation should be to have our patients be as close to alert and calm as safely possible. numerous adult studies have demonstrated significant benefit in optimizing pain treatment in critically ill patients versus only providing sedatives. this practice, termed "analgosedation," has been shown to decrease duration of mechanical ventilation and shorten icu length of stay in adults [ ] . as new drugs emerge and we continue to learn about the detrimental effects of long-term sedation and neuromuscular blockade, sedation and analgesia for our patients become an increasingly important and complex choice. the first choice when determining a sedative and analgesic regimen for a critically ill patient is to choose the degree/depth of sedation targeted. the richmond agitation sedation scale (rass), the state behavioral scale (sbs), and the comfort behavioral scale (comfort-b) are validated sedation scales for use in pediatrics, with the rass and the comfort-b having the advantage of having been validated in both intubated and non-intubated patients [ ] [ ] [ ] . once the depth of sedation is chosen, it is important to focus on the selection of specific sedative and analgesic medications. in the last decade, an overwhelming amount of data has shown that benzodiazepines are independently associated with the incidence of delirium [ •, ] . in light of this evidence, benzodiazepines should not be used as a first-line sedative in critically ill children. the use of dexmedetomidine has increased in the picu over the last decade and may shorten length of mechanical ventilation as well as lower opioid requirements and incidence of delirium [ , ] . one emerging area of interest in the last decade has been the use of sedation protocols. the randomized evaluation of sedation titration for respiratory failure (restore) trial showed that protocolized sedation was feasible and led to fewer days of opioid administration and exposure to fewer sedative classes and that patients were more often awake and calm. however, protocolized sedation was not found to reduce the duration of mechanical ventilation and did increase days with any report of pain and agitation [ ] . subsequent studies of nurse-driven sedation protocols have continued to show its safety and efficacy, as well as its ability to reduce benzodiazepine administration, shorten duration of mechanical ventilation, and decrease the occurrence of withdrawal symptoms [ , ] . tips for implementation start by incorporating a validated tool for sedation in the nursing assessment and educate key stakeholders (nursing, residents/fellows) on the benefit of analgosedation. incorporate and discuss sedation targets/ goals at least daily on rounds. form a multidisciplinary team to develop and implement a sedation protocol; addressing analgesia first and avoiding benzodiazepines are the first-line choice of sedative. delirium is a prevalent and serious complication of critical illness. this complication affects - % of critically ill children in the picu [ •, , ] , with an even higher prevalence in children following cardiac surgery and cardiopulmonary bypass [ , ] and in children requiring extracorporeal membrane oxygenation support [ ] . the development of delirium in critically ill children has been shown to be associated with increased morbidity and mortality, longer duration of mechanical ventilation, increased length of stay, as well as higher resource utilization and medical cost [ ] [ ] [ ] . there are three motoric subtypes of delirium: hyperactive, hypoactive, and mixed-type delirium. in critically ill children, the hypoactive subtype is by far the most common. hypoactive delirium is characterized by inattention, decreased responsiveness, and lethargy, and without standardized use of validated pediatric delirium screening tools is the most likely to be missed or misdiagnosed as oversedation. there are three validated screening tools for use in critically ill children: the pediatric confusion assessment method for the intensive care unit (pcam-icu) and the preschool confusion assessment method for the icu (pscam-icu), the cornell assessment of pediatric delirium (capd), and the sophia observation withdrawal symptoms-pediatric delirium (sos-pd) scale [ , , , ] . the use of these screening tools is paramount to the assessment and diagnosis of delirium in critically ill children. in the last decade, modifiable and nonmodifiable risk factors for the development of pediatric delirium have been identified. younger children, especially under the age of , are at higher risk of delirium, as are children with underlying developmental delay, preexisting conditions, and higher severity of illness at picu admission [ •, , ] . the use of benzodiazepine has been shown to be an independent risk factor for the development of delirium, with a dose-response effect [ , , ] . a recent study found that children receiving benzodiazepines had over three times the likelihood of becoming delirious, after controlling for cognitive status, mechanical ventilation, and opiate use [ ] . other potentially modifiable risk factors include the use of restraints [ •] , anticholinergic medications [ , ] , and red blood cell transfusions [ ] . delirium has multifactorial etiologies and triggers; it can develop as a complication of the underlying illness and organ dysfunction, and be precipitated by sedation, uncontrolled pain, withdrawal, sleep disruption, and the abnormal icu environment and immobility. the clinical symptomatology of delirium can be difficult to distinguish from pain and iatrogenic withdrawal syndrome, which makes the use of a validated screening tool paramount in its diagnosis (fig. ) . preventing and managing delirium therefore starts with a careful identification of triggers and the underlying etiology. there is a paucity of evidence to truly guide the prevention and management of pediatric delirium. studies in adult icu patients have shown that implementation and adherence to the abcdef liberation bundle had a significantly lower risk of delirium [ ••] . recent studies in adults have shown that antipsychotics are not effective in significantly decreasing the duration of delirium [ ] . antipsychotics can be helpful for symptomatic management when a child continues to experience delirium despite the optimal management of the underlying illness and minimizing iatrogenic triggers. although this represents offlabel use, quetiapine was shown to be safe and effective in a randomized controlled trial [ ] , and case studies suggest the same for risperidone and olanzapine [ ] [ ] [ ] . tips for implementation start by choosing a validated screening tool for delirium and integrating it into the nursing assessment. avoid unnecessary sedation and avoid the use of benzodiazepines whenever possible. once delirium is diagnosed, a careful evaluation of inciting events and etiology is warranted. the off-label use of atypical antipsychotics can be helpful in symptomatic management if delirium persists. icu-acquired weakness is a well-described phenomenon in adults [ ] [ ] [ ] and children [ ] [ ] [ ] [ ] . early mobility (em) [ ] , the practice of physical and occupational therapy early during critical illness, is used to prevent and treat icuacquired weakness. biopsies in adults with septic shock suggest early mobility may maintain muscle fibers and lessen the muscle atrophy associated with critical illness [ ] . adult studies have shown several other benefits of em, including decreased delirium incidence, decreased icu length of stay, decreased hospital length of stay, decreased ventilator days, and earlier attainment of activities of daily living [ ] [ ] [ ] [ ] . varied developmental stages and a broad spectrum of ages can make em more challenging in pediatrics [ ] . in addition to protocolization and equipment barriers, many studies have found staff perceptions to be a significant barrier [ , ] . however, a systematic review of pediatric em studies and over patients found only % of patients had any type of adverse event related to em, suggesting em is also safe in the picu population [ ] . staff perceptions may be amenable to change with education and development of a multidisciplinary protocol [ ] . em outcomes data in pediatrics is sparse, but several studies have demonstrated feasibility [ , - , •] . two pediatric studies have found significant clinical benefits related to em. in a single-center pre-post cohort of pediatric liver transplant patients, implementation of an em program resulted in faster ambulation and shorter hospital length of stay [ •]. simone et al. instituted delirium screening, protocolized sedation, and an em protocol in a staged approach in single-center picu and noted decreased incidence of delirium after implementation of em [ •] . further studies are needed to elucidate the clinical benefits of em in the picu population. tips for implementation engage key stakeholders early and build a multidisciplinary committee (i.e., physical therapy, occupational therapy, nursing, respiratory therapy, administration, physicians and nurse practitioners or physician assistants, child life specialists, speech therapists) to create, champion, and implement a unit-wide protocol. protocols should take into consideration unit-and hospital-specific needs and resources, and always make patient safety a priority. engage bedside staff with education, hands-on experience, and success stories to encourage protocol adherence. patient-and family-centered care (pfcc) is not a novel concept to pediatricians, as it is a core value in the field of pediatrics given the importance of family engagement to the successful care of children. pfcc is rooted in the understanding that involving patients and families in their own care or their loved one's care is a mutually beneficial experience that will result in improved patient satisfaction, decreased patient anxiety, confusion, and agitation, and potentially higher quality care and safer care [ ] [ ] [ ] . the core pfcc values in the icu liberation bundle are keeping patients and families informed, actively involving patients and families in decision-making, actively involving patients and families in self-management, providing both physical comfort and emotional support to patient and families, and maintaining a clear understanding of patients' concepts of illness and cultural beliefs [ ] . tips for implementation form a patient and family counsel to help identify areas for improvement and guide change. consider a family survey to understand baseline family engagement in your picu. common ways to institute pfcc include open visitation policies, family-centered rounds, allowing family presence during codes, providing education to families on how they can participate in care, encouraging families to be part of your unit's safety culture, providing icu diaries, and practicing shared decision-making to create a partnership between the icu team and families. implementation of the abcdef bundle can be daunting since it requires a multidisciplinary collaborative approach and a real culture change. a recent review on the existing barriers to abcde bundle implementation in adult icu identified four distinct domains: ( ) patient-related, ( ) clinician-related, ( ) protocol-related, and ( ) icu contextual barriers [ ] . these domains are consistent with domains of the consolidated framework for implementation research (cfir), a widely-used framework in implementation science [ ] . each picu will likely face different barriers within each domain, and the first step to implementation should be to identify our own unit's barriers. one of the most common hurdles to protocol implementation is provider buy-in. bedside providers may have concerns about patient safety (especially for early mobility and the use of an analgosedation model) and may think that the risk it poses outweighs potential benefits. with effective education on the safety and feasibility of bundle implementation [ , ] and ongoing feedback to providers with up to date data on how usage of the bundle is helping their patients, providers can feel empowered and motivated to lead bundle reliability performance. involving multidisciplinary bedside providers and other key stakeholders early on during protocol design is also essential to ensure protocol feasibility and will help buy-in. another frequently encountered barrier to protocol implementation is resource limitations, especially the availability of personnel such as physical and respiratory therapists, and equipment. support and engagement of senior health care executive can help secure and allocate the appropriate resources. the support of these groups is vital to the success of abcdef bundle implementation and function, as they can play an important role in motivating teams, helping to solve complex problems involving culture change within the hospital and icu environment [ ] . a summary of these and other commonly encountered barriers can be found in table . while the improvements in clinical outcomes using the icu liberation bundle in the critically ill adult population is promising, similar outcome data for bundle implementation in pediatrics is lacking. further emphasis should be placed on investigating the effect the icu liberation bundle, as well as each individual bundle element, has on survival and morbidity related to critical illness in pediatrics. similarly, pics may be a significant issue for survivors of pediatric illness and their families, but no unified scales exist in the literature to be able to truly quantify the incidence of this problem. unified outcomes scales are needed in order to better understand both the factors that predispose patients to developing pics as well as improve long-term outcomes from those affected by pics after hospital discharge. as the survivorship of patients in the picu increases, more focus will need to be placed on improving post-icu functional status with intentional after-icu support and interventions. one novel and developing approach to improving the lives of survivors of critical illness is the development of icu follow-up clinics. this outpatient support has been used as part of post-icu recovery models for some adult units after icu discharge, though its impact on recovery remains largely unknown. this intervention has not been adopted widely, nor has it been studied extensively in the pediatric population. with advances in technology and the availability of telemedicine services, future research should explore whether a model for icu follow-up can further improve the after-icu recovery for critically ill pediatric patients and their families. medical advancements have led to a steady increase in survival among pediatric patients suffering from critical illness, though morbidity related to long-term physical, cognitive, and psychological effects persists for many pediatric patients and their families after hospital discharge. use of systematic care bundles such as the icu liberation bundle may further improve survival in pediatric patients as well as decrease the incidence of pics. widespread icu liberation bundle implementation in pediatrics with systematic outcome monitoring low prioritization and competing priorities and analysis will be essential for further advances in outcomes for pediatric survivors of critical illness. conflict of interest the authors declare that they have no conflict of interest. human and animal rights this article does not contain any studies with human or animal subjects performed by any of the authors. a history of pediatric critical care medicine three decades of pediatric intensive care: who was admitted, what happened in intensive care, and what happened afterward. pediatr crit care med functional outcomes and physical impairments in pediatric critical care survivors: a scoping review. pediatr crit care med outcome at months after admission for pediatric intensive care: a report of a national study of pediatric intensive care units in the united kingdom long-term function after pediatric critical illness: results from the survivor outcomes study * . pediatr crit care med pediatric intensive care outcomes: development of new morbidities during pediatric critical care. pediatr crit care med relationship of illness severity and length of stay to functional outcomes in the pediatric intensive care unit: a multi-institutional study risk factors for acquiring functional and cognitive disabilities during admission to a picu. pediatr crit care med the abcdef bundle in critical care the abcdef bundle: science and philosophy of how icu liberation serves patients and families conceptualizing post intensive care syndrome in children -the pics-p framework characteristics of postintensive care syndrome in survivors of pediatric critical illness: a systematic review children's psychological and behavioral responses following pediatric intensive care unit hospitalization: the caring intensively study patterns of post-traumatic stress symptoms in families after paediatric intensive care posttraumatic stress disorder in children and their parents following admission to the pediatric intensive care unit: a review. pediatr crit care med functional recovery in critically ill children, the "weecover" multicenter study the association between parent ptsd/depression symptoms and child ptsd symptoms: a meta-analysis caring for critically ill patients with the abcdef bundle improving hospital survival and reducing brain dysfunction at seven california community hospitals: implementing pad guidelines via the abcdef bundle in patients pain assessment practices in the pediatric intensive care unit the flacc: a behavioral scale for scoring postoperative pain in young children pain assessment in nonverbal children with severe cognitive impairments: the individualized numeric rating scale (inrs) pain in children: comparison of assessment scales. okla nurse distraction using the buzzy for children during an iv insertion relief of pain and anxiety in pediatric patients in emergency medical systems pain outcomes in a us children's hospital: a prospective cross-sectional survey ventilator-associated lung injury efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (awakening and breathing controlled trial): a randomised controlled trial effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously evidence-based guidelines for weaning and discontinuing ventilatory support: a collective task force facilitated by the american college of chest physicians; the american association for respiratory care; and the american college of critical medicine early intensive care sedation predicts long-term mortality in ventilated critically ill patients daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation practice patterns and outcomes associated with early sedation depth in mechanically ventilated patients: a systematic review and meta-analysis analgosedation: a paradigm shift in intensive care unit sedation practice validity of the richmond agitation-sedation scale (rass) in critically ill children assessment of sedation levels in pediatric intensive care patients can be improved by using the comfort "behavior" scale. pediatr crit care med state behavioral scale: a sedation assessment instrument for infants and young children supported on mechanical ventilation. pediatr crit care med delirium and benzodiazepines associated with prolonged icu stay in critically ill infants and young children benzodiazepines and development of delirium in critically ill children dexmedetomidine improves the outcomes in paediatric cardiac surgery: a metaanalysis of randomized controlled trials outcomes of dexmedetomidine treatment in pediatric patients undergoing congenital heart disease surgery: a meta-analysis long-term outcomes after protocolized sedation versus usual care in ventilated pediatric patients implementation of a nurse-driven sedation protocol in a picu decreases daily doses of midazolam. pediatr crit care med nurse-driven pediatric analgesia and sedation protocol reduces withdrawal symptoms in critically ill medical pediatric patients delirium in critically ill children: an international point prevalence study * diagnosing delirium in critically ill children: validity and reliability of the pediatric confusion assessment method for the intensive care unit the preschool confusion assessment method for the icu delirium is a common and early finding in patients in the pediatric cardiac intensive care unit delirium in children after cardiac bypass surgery delirium in the pediatric cardiac extracorporeal membrane oxygenation patient population: a case series cost associated with pediatric delirium in the icu patterns of postoperative delirium in children* delirium and mortality in critically ill children cornell assessment of pediatric delirium construction of the sophia observation withdrawal symptomsscale (sos) for critically ill children benzodiazepines and development of delirium in critically ill children: estimating the causal effect delirium in the pediatric hematology, oncology, and bone marrow transplant population. pediatr blood cancer anticholinergic medication burden in pediatric prolonged critical illness: a potentially modifiable risk factor for delirium. pediatr crit care med association between transfusion of rbcs and subsequent development of delirium in critically ill children haloperidol and ziprasidone for treatment of delirium in critical illness evaluation of the safety of quetiapine in treating delirium in critically ill children: a retrospective review an evaluation of risperidone dosing for pediatric delirium in children less than or equal to years of age antipsychotic treatment of delirium in critically ill children: a retrospective matched cohort study olanzapine reduces delirium symptoms in the critically ill pediatric patient intensive care unit-acquired weakness icu-acquired weakness icu-acquired weakness and recovery from critical illness intensive care unit acquired weakness in children: critical illness polyneuropathy and myopathy icu-acquired weakness is associated with differences in clinical outcomes in critically ill children. pediatr crit care med muscle weakness in critically ill children thigh ultrasound monitoring identifies decreases in quadriceps femoris thickness as a frequent observation in critically ill children. pediatr crit care med bench-to-bedside review: mobilizing patients in the intensive care unit -from pathophysiology to clinical trials impact of very early physical therapy during septic shock on skeletal muscle early physical medicine and rehabilitation for patients with acute respiratory failure: a quality improvement project early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial goal directed early mobilization reduces icu length of stay and improves functional mobility: an international multi center, randomized, controlled trial (soms trial) preventing icu subsyndromal delirium conversion to delirium with low-dose iv haloperidol: a doubleblind, placebo-controlled pilot study development and implementation of an early mobility program for mechanically ventilated pediatric patients changes in provider perceptions regarding early mobility in the picu. pediatr crit care med early mobilization in critically ill children: a systematic review picu up! pediatr crit care med early exercise in critically ill youth and children, a preliminary evaluation: the weecycle pilot trial early protocolized versus usual care rehabilitation for pediatric neurocritical care patients: a randomized controlled trial mobilization therapy in the pediatric intensive care unit: a multidisciplinary quality improvement initiative implementation of an icu bundle: an interprofessional quality improvement project to enhance delirium management and monitor delirium prevalence in a single picu pediatric cohort study showing physical improvement in pediatric liver family presence: visitation in the adult icu. crit care nurse family-centered care in the pediatric intensive care unit. pediatr clin n am patient-and family-centered care: leveraging best practices to improve the care of hospitalized children. pediatr clin n am identifying barriers to delivering the awakening and breathing coordination, delirium, and early exercise/mobility bundle to minimize adverse outcomes for mechanically ventilated patients: a systematic review fostering implementation of health services research findings into practice: a consolidated framework for advancing implementation science common challenges to effective abcdef bundle implementation: the icu liberation campaign experience. crit care nurse publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- - lcjw authors: de waele, jan j.; schouten, jeroen; beovic, bojana; tabah, alexis; leone, marc title: antimicrobial de-escalation as part of antimicrobial stewardship in intensive care: no simple answers to simple questions—a viewpoint of experts date: - - journal: intensive care med doi: . /s - - -z sha: doc_id: cord_uid: lcjw antimicrobial de-escalation (ade) is defined as the discontinuation of one or more components of combination empirical therapy, and/or the change from a broad-spectrum to a narrower spectrum antimicrobial. it is most commonly recommended in the intensive care unit (icu) patient who is treated with broad-spectrum antibiotics as a strategy to reduce antimicrobial pressure of empirical broad-spectrum therapy and prevent antimicrobial resistance, yet this has not been convincingly demonstrated in a clinical setting. even if it appears beneficial, ade may have some unwanted side effects: it has been associated with prolongation of antimicrobial therapy and could inappropriately be used as a justification for unrestricted broadness of empirical therapy. also, exposing a patient to multiple, sequential antimicrobials could have unwanted effects on the microbiome. for these reasons, ade has important shortcomings to be promoted as a quality indicator for appropriate antimicrobial use in the icu. despite this, ade clearly has a role in the management of infections in the icu. the most appropriate use of ade is in patients with microbiologically confirmed infections requiring longer antimicrobial therapy. ade should be used as an integral part of an icu antimicrobial stewardship approach in which it is guided by optimal specimen quality and relevance. rapid diagnostics may further assist in avoiding unnecessary initiation of broad-spectrum therapy, which in turn will decrease the need for subsequent ade. antimicrobial de-escalation (ade) is a strategy to decrease the spectrum of the empirical antimicrobial regimen a few days into the treatment [ ] . multiple definitions have been used in the past but there appears to be consensus that ade refers to stopping one or more components of combination therapy, changing an antimicrobial for another molecule with a narrower spectrum or a combination thereof (fig. ) [ ] . table provides an overview of the terminology commonly used in this context. ade was introduced in the intensive care unit (icu) at the beginning of the century with the rationale that it may prevent the harm from (extremely) broad-spectrum empirical regimens [ ] . those were becoming increasingly necessary due to the emerging and mounting phenomenon of antimicrobial resistance (amr) [ ] . many studies have looked at ade in the icu. most were observational and published from centers with a particular interest in antimicrobial stewardship programs (asp). ade appears to be safe, but while improved outcomes are frequently reported, selection bias is prevalent: ade is more frequently used in patients who are clinically improving [ ] . we should be careful not to infer causation between ade and improved clinical outcomes [ ] . regardless of the definition used or the intervention studied, it should be very clear that overall antimicrobial consumption is linked to amr, irrespective of the class of antibiotics. decreasing antibiotic exposure should, therefore, be the priority of any asp [ ] . in this manuscript, we aim to highlight recent insights into ade, its value in asps and the practical application as well as discuss the controversies and fig. schematic overview of the timeline of antimicrobial therapy including antimicrobial de-escalation, with the pivotal and companion antimicrobial components of the empirical regimen and most common changes within a short antibiotic course for critically ill patients with an infection. 'antifungals' refer to antimicrobials targeting fungal pathogens, 'anti-mrsa' to antimicrobials targeting methicillin-resistant staphylococcus aureus, 'anti-difficult to treat pathogens' to antimicrobials targeting resistance in gram-negative pathogens, 'atypical/intracellular targeted' refers to a second antibiotic commonly prescribed for community-acquired pneumonia, 'antitoxin effect' to antimicrobials administered for the suppression of toxin and cytokine production, and 'synergistic effect' to most commonly an aminoglycoside given as combination therapy in patients with septic shock table definition of terms adequate antimicrobial therapy antimicrobial therapy active against the pathogen responsible for infection, administered at the dose, route and mode in accordance to best current practices broad-spectrum therapy antimicrobial therapy aimed at covering all relevant pathogens potentially causing the infectious episode narrow-spectrum therapy antibiotic with activity exclusively against one specific pathogen or a more limited group of pathogens combination therapy two or more antibiotics aimed at . covering the identified or suspected pathogen(s) with more than one antibiotic to hasten pathogen clearance using antimicrobials with different mechanisms of action or . broadening antimicrobial spectrum collateral effects of the antimicrobials administered to the patient, including downstream effects on the patient's microbiota favouring the acquisition, selection and overgrowth of multidrug-resistant bacteria pivotal antibiotic antibiotic that is central to the regimen, usually a beta-lactam antibiotic for gram-negative severe infections companion antibiotics antibiotics added to the regimen to broaden the spectrum to pathogens not covered by the pivotal agent. commonly glycopeptides and/or aminoglycosides, which are interrupted most of time after a short exposure ( days) pitfalls related to the topic. for an overview of recent studies, we refer to the esicm/esgcip position statement on this topic [ ] . ade aims to reduce broad-spectrum antimicrobial exposure, and as a result decrease the emergence of amr, without impairing patient outcomes [ ] . a randomised clinical trial comparing continuation or de-escalation of the pivotal or main antimicrobial found a decrease in broad-spectrum antimicrobial use in the de-escalation group, while the mortality rate was similar in both groups [ ] . reducing antimicrobial exposure is essential in any asp, as antimicrobial use has an important impact on the gut where overgrowth of organisms resistant to antimicrobials significantly impacts the intestinal microbiome. inadequate empirical therapy has been associated with an increased mortality rate in septic shock [ ] . ade indirectly legitimises the use of broad-spectrum empirical therapy, as it suggests that-once the causative pathogen has been identified and the susceptibility is known-therapy can be scaled down. therefore, ade would limit any further harm to the microbiome, inflicted by broad-spectrum agents and would thus allow for a broad-spectrum empirical safety net as well as for the application of antimicrobial stewardship principles. observational studies and meta-analyses have suggested improved outcomes associated with ade [ , ] , but as mentioned before, any causal effect is not likely to be present. finally, as discussed elsewhere, ade may be associated with cost saving, since it allows reducing the use of expensive antimicrobials for short durations and using older and less expensive drugs for the continuation of treatment [ ] . the dark side of de-escalation ade was welcomed as a remedy to mitigate the effects of empirical broad-spectrum agents with the assumption that short courses of those agents have little impact on the development of amr. however, this assumption has given us an unwarranted sense of safety that ade would prevent the ecological consequences of extremely broad-spectrum empirical antimicrobial treatment regimens. these regimens are often considered lifesaving and necessary in patients with severe infections especially in the setting of high prevalence of amr. recent research, however, has clearly shown that amr appears earlier than expected in the course of treatment, probably within the first few days [ ] . thus, ade should not be used as an excuse for the indiscriminate prescription of broadspectrum antimicrobial regimens. when analysing the influence of this sense of safety that ade has on our prescribing behaviour, we need to consider two other issues. first, although none of the involved studies was designed to assess its effect on total duration of therapy, ade has been associated with an increase in the total duration of antimicrobial therapy [ ] . there may be multiple possible explanations for this finding, including potential "errors in counting total days of therapy" and the perception that narrow-spectrum antimicrobials are harmless and can be continued for longer periods of time [ ] . second, the risk of using ade as an excuse to continue antimicrobials in the absence of infection is likely to cause more harm than stopping all antimicrobials alltogether. on one hand, narrower agents will still cause the emergence of amr, and on the other, continuing antimicrobials in the absence of infection may decrease the quality of diagnostic decision-making [ ] . finally, the broad-and narrower spectrum antimicrobials may differ in their pharmacokinetics resulting in insufficient concentrations at the site of infection and pk/pd target attainment, often with a disadvantage for narrowspectrum antibiotics [ ] . ade is often presented as an effective strategy to reduce amr, but no direct associations were found between ade and ecological impact in icu patients. in an observational comparative study, de bus et al. did not find associations between de-escalation and emergence of multidrug-resistant (mdr) pathogens [ ] . similar findings were reported in a randomised clinical trial comparing ade and continuation of the pivotal antimicrobial [ ] . small but significant differences in carbapenemresistant acinetobacter spp. colonisation were observed after carbapenem de-escalation [ ] . large numbers of patients are probably required to find a difference in terms of amr, suggesting a limited overall ecological impact. in brief, the level of evidence showing that ade reduces amr is low. ade, at least for the pivotal agent, is defined by the switch from a broad-spectrum antimicrobial to a narrower spectrum antimicrobial. however, "grading" of antimicrobials according to spectrum is not an easy task. a french group proposed a six-rank consensual classification of beta-lactam antibiotics. despite several delphi rounds, no consensus was reached to differentiate piperacillin/tazobactam, ticarcillin/clavulanic acid, fourth-generation cephalosporin and antipseudomonal third-generation cephalosporin. the group could not find an agreement on the delay within which ade should be performed and on whether or not the shortening of antimicrobial therapy duration should be included in ade definition [ ] . in parallel, a group of experts from the us developed a numerical score to measure the spectrum of antimicrobial regimens [ ] . the classification that was obtained using a delphi consensus procedure based on clinical scenario's differed from the one reported by the french group. piperacillin-tazobactam was the worst ecological antimicrobial for the us group, whereas imipenem was selected by the french group. this discrepancy underlines how difficult it is to assess the ecological impact of antimicrobials, and thereby to define ade. ade implicitly involves the use of more than one antimicrobial: either the number of antimicrobials is reduced in patients who receive combination antimicrobial therapy initially, or patients are administered two different antimicrobials sequentially. although we generally assume that ade is beneficial, there may also be downsides to the use of multiple antimicrobials, even for short periods of time. first, when one antimicrobial is replaced by another with a narrower spectrum, it should be considered that two antimicrobials may cause more harm than one. for example, when empirical treatment with meropenem is switched to levofloxacin, this may be considered as narrowing of the spectrum, but that patient is exposed to two courses of short duration antimicrobial therapy with a different -and potentially-cumulative damaging effect on the microbiome. short exposure to broad-spectrum antimicrobials already results in early disruption of intestinal microbiome [ ] . it has been demonstrated that as little as day of exposure to imipenem is enough to result in amr [ ] . for each day of additional exposure to cefepime or piperacillin/tazobactam, the risk of mdr emergence increases with % [ ] . furthermore, antibiotics have been found to persist for up to h at low concentrations after discontinuation [ ] and these low concentrations are at high risk for the emergence of resistance. second, combining antimicrobials in empirical therapy aims at broadening the spectrum of therapy, reducing amr or creating synergy between drugs; although this was documented in experimental studies, the latter two effects were never confirmed in vivo. while the reduced number of antimicrobials after ade may appear advantageous, one should question the true need for multiple antimicrobials in the first place [ ] . better risk stratification, the use of rapid diagnostic techniques and the use of surveillance cultures are all strategies that could avoid the use of multiple antimicrobials empirically [ ] . finally, the impact of combining different antibiotic classes on the intestinal flora is largely unknown [ ] . recent studies have shown differential effects according to the antimicrobial activity against anaerobes, with a four times higher risk of gut colonisation with ceftriaxone resistant gram-negative bacteria after being exposed to anti-anaerobe antimicrobials [ ] . a better insight into the effect of different antimicrobials is needed to understand the dynamics that are relevant in ade. in most practice guidelines for asp, ade appears as a recommended stewardship objective [ ] . in the us, a survey showed that prior authorisation for selected antimicrobials, antimicrobial reviews with prospective audit and feedback, and guideline development were common strategies in asps [ ] , while ade was not explicitly reported as a major component. in a french survey, reassessment of antimicrobial prescriptions, but not specifically ade, appears as a major element of asp for most respondents [ ] . in nine dutch hospitals, ade was not yet included in asp, although responders disclosed that the intervention was required in the future program [ ] . of the two most evidence-based asp interventions (post-prescriptional review and prior authorisation [ ] ), post-prescriptional review (which may include ade) gained some advantage over the latter because of its larger effect on reducing antimicrobial use [ ] . in the light of pitfalls of ade mentioned before, post-prescriptional review by an expert remains essential for good antimicrobial practice. however, reviewing antimicrobial use only after prescription may equally stimulate unnecessary initial broad-spectrum empirical treatment. it is becoming increasingly clear that duration of therapy can be reduced to - days for most infections in icu patients [ ] , with specific exceptions such as some pathogens (e.g. s. aureus), patient conditions (immunosuppression) or inadequacy of source control. this development certainly questions the indication for ade. if cultures become available - h after the start of therapy, what is the expected benefit of changing wellinstituted therapy for more days? apart from the considerations discussed earlier, getting ade done properly in daily practice (collect cultures, correctly interpret cultures, instigate change of therapy in concordance with prescribers, prevent a time gap without effective antimicrobial therapy, adapting dose due to different pk properties of new antimicrobial, etc.) can be a challenge with little apparent benefit. however, this does not mean in any way that cultures should not be taken. for many reasons other than ade (such as potentially inappropriate therapy, duration of therapy, mic determination, complications, follow-up, epidemiology), appropriate sampling remains pivotal to asps in icu. rapid diagnostics (different molecular technology sepsis panels, metagenomics), another component of asp, undoubtedly will change the way we will use antimicrobials in the future. for example, an observational retrospective study suggested that the use of a rapid test detecting mrsa within the first hour after bronchial sampling was associated with a reduction of empirical vancomycin or linezolid [ ] . an ongoing multicentre randomised clinical trial evaluates the use of a rapid diagnostic test detecting early the presence of esbl in patients with suspected infections to enterobacteriaceae [ ] . rapid diagnostics would also give more opportunities for watchful waiting and not start broad-spectrum antimicrobial therapy, thereby eradicating ade practice in subgroups of patients [ ] . especially in patients without shock, this could probably be done safely. unfortunately, there are still a lot of uncertainties regarding the use of these tests to allow their routine use in septic icu patients. individualisation of antimicrobial treatment based on risk assessment and rapid diagnostics may be a less appealing strategy in institutions with high resistance rates. it is certainly easier to avoid carbapenems in hospitals where amr rates are low. moreover, rapid diagnostic techniques are often unavailable in low-and middle-income countries where an already higher resistance burden leads to a vicious circle of increasing amr and indiscriminate broad-spectrum empirical treatment. in these settings where control of amr is most urgently needed [ ] -in spite of its limitations-ade may still be felt as one of the few options to decrease broad-spectrum antimicrobial use. counterintuitively, promoting ade may cause an increase in broad-spectrum antibiotic use as an unexpected side effect in these settings [ ] . ade has been proposed repeatedly as an important objective for asp in hospitals. it has been selected in a rand-modified delphi procedure among experts as of key quality indicators (qi) to measure and improve appropriate use in hospital [ ] and clinimetric properties have been tested in a large group of hospitalised patients [ , ] . furthermore, it has been associated with reduced mortality, hospital length of stay and cost reduction in a systematic review, although the lack of a clear definition hampers interpretation of this association [ ] . as a result, ade has become an essential quality metric to evaluate the success of an asp. for measurement purposes, "appropriate ade" has been operationalised as the number of patients in whom empirical antimicrobials have been changed to a less broad-spectrum regimen (numerator) divided by all patients who were started on empirical therapy on admission (denominator). the score of the indicator is expressed as a percentage. in routine hospital practice, performance on key qis is regarded as increasingly important as hospitals are often publicly and financially punished by healthcare authorities or health insurance companies if they do not meet expectations. as asps are now considered essential for the quality and safety of hospital care, it is likely that qis related to asp will come under increasing scrutiny in the following years. a higher percentage of "appropriate ade" will be regarded as one of the elements of a more successful implementation of an asp. however, due to the ongoing discussion about the definition of appropriate ade, it remains extremely difficult to judge and compare hospitals on this specific qi: when is ade actually considered appropriate, which are definitions and cut-off points? here are two examples of how misinterpretation and unwanted effects of mandatory ade reporting could play out: . if broad-spectrum antimicrobial therapy is prescribed for a patient with nosocomial pneumonia, e.g. with meropenem and vancomycin and it is changed by simply stopping vancomycin on day , this will count as ade, even if the pivotal antimicrobial (meropenem) remains unchanged. this (undesirable) course of events would still be considered ade and add to a higher percentage of hospital-wide "appropriate ade". . on the other side, patients who are prescribed (relatively) narrow-spectrum antimicrobial therapy (e.g. starting with flucloxacillin for a suspected s. aureusrelated skin and soft tissue infection) and need not be changed once cultures become available, are 'punished' as no ade has taken place while best medical practice has been followed. in summary, it becomes easy to achieve good qi results while performing poor antimicrobial stewardship. even worse, starting narrower spectrum therapy is discouraged and broad-spectrum empirical is encouraged (as this will increase ade performance metrics). a high performance on a qi for ade may only reflect an overuse of empirical broad-spectrum antimicrobials. clearly, the opportunities to de-escalate are largely determined by empirical therapy and, therefore, using ade as an isolated quality measure should be discouraged. identifying the pathogen responsible for infection is critical for ade, which relies on an accurate interpretation of microbiological results in the context of clinical presentation of infection. a crucial necessity is to obtain cultures from relevant sites before antibiotics are administered, as the absence of cultures or negative cultures has been associated with non-ade [ ] . the challenge and complexity of this process in routine practice are often underestimated in recommendations and guidelines. first, all samples are not equal: samples obtained from sterile sites have a different role compared to samples obtained from superficial sites: e.g. positive blood cultures are more relevant than samples collected from skin wound or through a drain. in this context, respiratory samples are the most challenging to interpret in the absence of quantitative cultures or other diagnostic approaches that allow discrimination between infection and colonisation. clearly, defining ventilator-associated pneumonia as well as hospitalacquired pneumonia remains difficult and may be an obstacle to ade. second, infective pathogens should be discriminated from colonising pathogens, in the absence of accurate biomarkers. third, all pathogens are not equal: identification of s. aureus is more significant than that of coagulase-negative staphylococci, although this should be modulated by the clinical context. in brief, there are some situations in which the confidence in a sample and its clinical relevance are higher compared to some other situations. here, the resulting strategy will rely strongly on the microbiological result. to resolve this issue, an excellent interaction between intensivists, surgeons, radiologists, microbiologists and infectious diseases physicians is required. while ade is sometimes conducted in patients in whom no microbiological samples were available [ ] , obtaining samples before initiating any antimicrobial treatment should be a general rule, and the quality and relevance of these samples are critical. our purpose is not to exclude ade as a part of asp's, and we remain convinced that ade has great value. as discussed above, until the validation and large-scale use of rapid diagnostic techniques is a reality, ade-or rather streamlining antimicrobial therapy-will remain essential. based on the microbiological results available and clinical course of the patient, we recommend a clinical strategy that integrates ade while acknowledging the inherent limitations of this approach. the planned duration of antimicrobial therapy is also to be considered when antimicrobial therapy is reevaluated (fig. ) . for short courses of antimicrobial therapy ( days or less), continuing the empirical treatment, if appropriate, can avoid sequential use of different antimicrobials and thus multiple impacts on the microbiome. another option, which should always be considered is stopping the antimicrobial treatment. indeed, in patients who are improving, e.g. in whom the sofa score decreased during the first - h, the need for continuing treatment beyond day should be debated for a significant number of infections. a seminal randomised clinical trial suggested that, in patients with non-severe no growth re-consider diagnosƟcs fig. antimicrobial management strategies integrating antimicrobial de-escalation in clinical practice pulmonary infiltrate, a course of days of ciprofloxacin was as efficient as a prolonged treatment [ ] . the feasibility of ultra-short course of antimicrobial treatments has been suggested in an observational study comparing patients with ventilator-associated pneumonia treated for - days and treated for > days, the outcomes of two groups being similar [ ] . for longer courses of antimicrobial therapy ( days or more), ade should probably be a recommended strategy, particularly if high-quality and clinically relevant samples are available. its presumed effects on amr and cost are relevant in these conditions. for intermediate-duration antimicrobial therapy ( - days), decisions should be tailored according to institutional asp recommendations. ranking antibiotics according to the local epidemiology and available drugs probably is more important than trying to obtain an international consensus on how antibiotics should be classified. in patients with confirmed infection and who are deteriorating, a single integrated recommendation is impossible. in our opinion, the first step is to rule out other-infectious and non-infectious-causes of shock. the second step is to confirm the adequacy of source control and dosing of antimicrobial(s). only then, the empirical antimicrobial treatment can be either maintained, escalated, de-escalated or stopped. in patients with negative cultures, another cause of organ dysfunction should be considered. if the mechanism is non-infectious, the antimicrobial treatment can be stopped; if another source of infection is found, new samples are required, and antimicrobials should be adapted to the new clinical picture. in conclusion, ade has become more clearly defined and understood, but until now, a demonstrable impact on amr is lacking. ade should not be used as a 'carte blanche' for the unrestricted use of (very-) broad empirical antimicrobial therapy and it is important to recognize that it may have unexpected and unwanted side effects. the impact of ade on the microbiome needs further study while one should consider that sequential exposure to two different antimicrobials may not necessarily be better than to one. we advocate against the use of ade as a qi in the icu. in the meantime, ade should clearly be regarded as an important component of asps. when applying ade, planned duration of therapy, as well as sample quality and relevance need to be incorporated in the decision-making process. efforts should also be aimed at optimising empirical therapy, which may reduce the need for ade later on; this is where rapid diagnostic techniques may have an important role. a systematic review of the definitions, determinants, and clinical outcomes of antimicrobial de-escalation in the intensive care unit antimicrobial deescalation in critically ill patients: a position statement from a task force of the european society of intensive care medicine (esicm) and european society of clinical microbiology and infectious diseases (escmid) critically ill patients study group (esgcip) international conference for the development of consensus on the diagnosis and treatment of ventilator-associated pneumonia antimicrobial resistance and antibiotic stewardship programs in the icu: insistence and persistence in the fight against resistance. a position statement from esicm/escmid/waaar round table on multi-drug resistance efficacy and safety of antimicrobial de-escalation as a clinical strategy rationalizing antimicrobial therapy in the icu: a narrative review de-escalation versus continuation of empirical antimicrobial treatment in severe sepsis: a multicenter non-blinded randomized noninferiority trial adequate antibiotic therapy prior to icu admission in patients with severe sepsis and septic shock reduces hospital mortality collaborative approach of individual participant data of prospective studies of de-escalation in non-immunosuppressed critically ill patients with sepsis de-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock emergence of imipenem-resistant gram-negative bacilli in intestinal flora of intensive care patients clinical outcomes of carbapenem de-escalation regardless of microbiological results: a propensity score analysis comparison of vs days of antibiotic therapy for ventilatorassociated pneumonia in adults: a randomized trial a simulation study reveals lack of pharmacokinetic/pharmacodynamic target attainment in de-escalated antibiotic therapy in critically ill patients impact of de-escalation of beta-lactam antibiotics on the emergence of antibiotic resistance in icu patients: a retrospective observational study safety and clinical outcomes of carbapenem de-escalation as part of an antimicrobial stewardship programme in an esbl-endemic setting de-escalation sg ( ) elaboration of a consensual definition of de-escalation allowing a ranking of β-lactams development of an antibiotic spectrum score based on veterans affairs culture and susceptibility data for the purpose of measuring antibiotic de-escalation: a modified delphi approach impact of antimicrobial therapy on the gut microbiome duration of exposure to antipseudomonal β-lactam antibiotics in the critically ill and development of new resistance persistence of piperacillin concentrations after treatment discontinuation: in cauda venenum empirical mono-versus combination antibiotic therapy in adult intensive care patients with severe sepsis-a systematic review with meta-analysis and trial sequential analysis rapid diagnostic test and use of antibiotic against methicillin-resistant staphylococcus aureus in adult intensive care unit carbapenems and alternative β-lactams for the treatment of infections due to extended-spectrum β-lactamase-producing enterobacteriaceae: what impact on intestinal colonisation resistance antibiotics with activity against intestinal anaerobes and the hazard of acquired colonization with ceftriaxone-resistant gram-negative pathogens in icu patients: a propensity score-based analysis clinical practice guidelines for creating an acute care hospitalbased antimicrobial stewardship program: a systematic review essential resources and strategies for antibiotic stewardship programs in the acute care setting implementation of antibiotic stewardship programmes in french icus in : a nationwide cross-sectional survey what is the more effective antibiotic stewardship intervention: preprescription authorization or postprescription review with feedback optimal duration of antibiotic treatment in gram-negative infections multicentre randomised controlled trial to investigate usefulness of the rapid diagnostic βlacta test performed directly on bacterial cell pellets from respiratory, urinary or blood samples for the early de-escalation of carbapenems in septic intensive care unit patients: the blue-carba protocol when not to start antibiotics: avoiding antibiotic overuse in the intensive care unit preventive and therapeutic strategies in critically ill patients with highly resistant bacteria development of quality indicators for antimicrobial treatment in adults with sepsis applicability of generic quality indicators for appropriate antibiotic use in daily hospital practice: a cross-sectional point-prevalence multicenter study current evidence on hospital antimicrobial stewardship objectives: a systematic review and meta-analysis short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. a proposed solution for indiscriminate antibiotic prescription ultrashort-course antibiotics for patients with suspected ventilator-associated pneumonia but minimal and stable ventilator settings the authors declare that they have no competing interests. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -afcmln w authors: olsen, markus harboe; jensen, helene ravnholt; ebdrup, søren røddik; topp, nina hvid; strange, ditte gry; møller, kirsten; kondziella, daniel title: automated pupillometry and the four score — what is the diagnostic benefit in neurointensive care? date: - - journal: acta neurochir (wien) doi: . /s - - -y sha: doc_id: cord_uid: afcmln w introduction: the glasgow coma scale (gcs) and visual inspection of pupillary function are routine measures to monitor patients with impaired consciousness and predict their outcome in the neurointensive care unit (neuro-icu). our aim was to compare more recent measures, i.e. four score and automated pupillometry, to standard monitoring with the gcs and visual inspection of pupils. methods: supervised trained nursing staff examined a consecutive sample of patients admitted to the neuro-icu of a tertiary referral centre using gcs and four score and assessing pupillary function first by visual inspection and then by automated pupillometry. clinical outcome was evaluated months after admission using the glasgow outcome scale-extended. results: fifty-six consecutive patients (median age years) were assessed a total of times. of the patients with at least one gcs score of , had a favourable outcome. all seven patients with at least one four score of ≤ had an unfavourable outcome, which was best predicted by a low “brainstem” sub-score. compared to automated pupillometry, visual assessment underestimated pupillary diameters (median difference, . mm; p = . ). automated pupillometry detected a preserved pupillary light reflex in patients, in whom visual inspection had missed pupillary constriction. discussion: training of nursing staff to implement frequent monitoring of patients in the neuro-icu with four score and automated pupillometry is feasible. both measures provide additional clinical information compared to the gcs and visual assessment of pupillary function, most importantly a more granular classification of patients with low levels of consciousness by the four score. patients in the neurointensive care unit (neuro-icu) often have impaired consciousness, either due to their brain injury or because of iatrogenic interventions such as sedation. standardised evaluation is essential to monitor clinical improvement or deterioration and response to treatment. the widely used glasgow coma scale (gcs) was originally introduced as a tool to assess levels of consciousness in patients with acute head trauma, but is now used in most patients with impaired consciousness [ ] . however, the gcs has several limitations. most importantly, its reliance on verbal output confounds the assessment of consciousness in patients with aphasia, the locked-in syndrome and those who are intubated [ , ] . in contrast, the full outline of unresponsiveness (four) score does not rely on verbal assessment and includes a detailed assessment of brainstem function (table ) [ ] . the four score, introduced in [ ] , has been extensively tested for validity, reliability, reproducibility and prognostic value, primarily in patients with traumatic brain injury but also in a broader neuro-icu population [ ] . in general, in patients with impaired consciousness, the four score allows a finer gradation of consciousness levels but has, primarily due to the missing verbal sub-score, a disadvantage in patients with only a minimally impaired consciousness. in the same vein, visual inspection of pupillary function is a routine measure to monitor patients with impaired consciousness and predict their outcome [ ] , but its main disadvantage is the low interrater reliability [ ] , whereas automated infrared pupillometry using a handheld device allows for objective and quantitative measurement of pupillary function [ , ] . in this feasibility study, we aimed to assess how the four score and automated pupillometry add meaningful clinical information in a regular neuro-icu setting, compared to gcs and visual inspection of pupils. to this end, we enrolled a consecutive cohort of patients admitted to the neuro-icu and trained nursing staff to monitor patients using the four score and automated pupillometry. these assessments were used to analyse ( ) if the four score results in a more granular evaluation of different levels of consciousness, ( ) how well visual inspection of pupillary function reflects results from automated pupillometry and ( ) if nursing staff can be trained to collect four scores and perform automated pupillometry in a true-to-life neuro-icu setting. from june to september , trained nursing staff examined a consecutive sample of patients with acute brain injury admitted to the neuro-icu of a tertiary referral centre. fiftysix consecutive patients ( males, median age years; iqr, - ; range, - ) with aneurysmal subarachnoid haemorrhage ( %), intracerebral haematoma ( %), traumatic brain injury ( %) or other neurological or neurosurgical conditions ( %) were assessed. the nursing staff was taught the theoretical underpinnings and practical application of the four score during hour lectures, and they learned to assess pupillary diameters and light responses first by visual inspection and then by automated pupillometry (npi ® neuroptics pupillometer, irvine, usa). following this, the nursing staff assessed patients in the neuro-icu under supervision before initiation of the main observational study period. lectures and training were carried out by board-certified anaesthesiologists and a neurologist with expertise in neurocritical care. the ethics committee of the capital region waived the need for informed consent because data were collected as part of clinical routine (ref. number ). patients were first dichotomized according to their lowest gcs score, so that one group consisted of patients with a gcs score of at least once during icu admission, and the other group comprised all other patients. we then dichotomized patients according to their pupillary function; i.e. patients who at least once had one or two non-responsive pupils were allocated to one group and the remaining patients to the other. each pupil was counted as one assessment (i.e. two pupillary assessments per one assessment of consciousness level). patients assessed more than times were examined by at least two of the five trained nurses. clinical outcome was evaluated months after admission, based on notes from electronic patient charts, using the glasgow outcome scale-extended (gose), and patients were again dichotomized according to their outcome (favourable, gose - ; unfavourable, gose - ). in [ ] addition, we performed logistic regression to analyse gcs and four scores without dichotomization. to interpret results from our observational study in the context of the medical literature, we did two systematic searches of pubmed and medline (march , ) with publications from and forward. the first search was a combination of "(four or (full outline of unresponsiveness))" and "pupillometry", which resulted in entries. following screening of abstracts, we did not identify any relevant publications. the second search combined "(four or (full outline of unresponsiveness))" with "((glasgow coma scale) or (gcs))", resulting in entries. entries were screened for adult patients with acute brain injury in an intensive care setting, which yielded relevant publications. data handling and statistical analyses were done using r (r . . , r development core team [ ] , vienna, austria). univariate logistic regression was used to analyse the cut-off of four score before a significant increase in gcs was observed. the absolute difference between visual evaluation and automated pupillometry for pupillary size was compared using the student's t test. data are presented as either median, iqr and range or percentage, unless otherwise stated. fifty-six patients were assessed a median of five times (iqr, - ; range, - ; total number of assessments, gcs/four score, ; visual inspection/automated pupillometry, ). the minimum interval between assessments was h. nineteen of the patients ( %) achieved a favourable outcome (gose ≥ ). the median gcs was (iqr, - ; range, [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , and the median four score was (iqr, - ; range, - ). assessments with a gcs of corresponded to a median four score of (iqr, - ; range, - ); similarly, gcs - corresponded to a median four score of (iqr, - ; range, - ) (fig. ) . gcs scores > were only obtained with four scores of or higher (fig. ) . of the patients who at least once had a gcs score of - , ( %) had a favourable outcome. in comparison, % of patients with gcs - achieved a favourable outcome as well ( table ). in contrast, % of patients with a four score > achieved a favourable outcome, whereas none of the patients with at least one four score of ≤ had a favourable outcome. preserved brainstem reflexes seemed to be the main driver of favourable outcomes according to the four score. visual inspection underestimated pupillary diameter as compared to automated pupillometry by . mm (iqr, . - . ; range, - . ; p = . , wilcoxon signed-rank test) ( fig. a and b) , whereas assessment of pupillary constriction by visual inspection was binary (present or absent), automated pupillometry provided quantitative data with an overall median pupillary constriction of . mm (iqr . - . ; range - . ). in of the pupils ( %) where visual inspection suggested absence of pupillary constriction, automated pupillometry confirmed this observation (median constriction mm; iqr: - . ; range: - . ) (fig. c) . however, in the remaining pupils (from patients), where visual inspection suggested absence of pupillary constriction, automated pupillometry revealed a preserved pupillary light reflex. furthermore, pupils (from patients), where visual inspection suggested intact pupillary constriction, did not constrict when examined with automated pupillometry. visual inspection suggested absence of pupillary constriction at least once in patients ( pupils in total), ( %) of which had an unfavourable clinical outcome. absence of pupillary constriction by automated pupillometry was noticed at least once in patients ( pupils), and of them had an unfavourable outcome ( %) ( table ). frequent bedside monitoring is essential to identify clinical deterioration in critically ill patients and to evaluate treatment responses. our results suggest that the four score and automated pupillometry provide additional clinical information and prognostic information compared to the gcs and visual inspection of the pupils, especially in assessments where the gcs score is . moreover, we found that training of nursing staff is feasible to implement automated pupillometry and the four score for frequent bedside monitoring in the icu. a gcs score of is considered less predictive of outcome [ ] . patients with a gcs of for a prolonged period during their stay in the neuro-icu are difficult to monitor for subtle changes in their clinical condition [ ] . this may occur because a gcs of is frequently associated with iatrogenic causes such as sedation rather than the underlying neurological condition. indeed, in our study a gcs score of was the most common result ( % of assessments) and corresponded to a wide range of four scores (from to ). these patients varied widely in terms of presence or absence of brainstem reflexes, which indicates that the four score allows for a more granular classification of patients with severely impaired consciousness levels. fig. scatter plot illustrating the relationship between gcs score and four score, again showing that patients with a gcs score of may score very differently on the four (from to ). the graph depicts mean and % confidence intervals of gcs scores for every four score (black line). asterisks (***) indicate significant difference (p < . ) from baseline (four score of ) using logistic regression. gcs, glasgow coma scale; four, full outline of unresponsiveness the four score has a high interrater reliability, which has been confirmed for patients with tbi [ , , , ] , as well as patients in general icus [ , , ] and neuro-icus [ , , ] . the validity of the four score renders it a good predictor of patient outcome. validity studies have assessed the four score at a specific time point during icu admission to define the best cut-off between favourable and unfavourable outcome, showing that the four score compares favourably as a predictor [ , , , ] . results from our cohort are well in line these findings, as no patient with a four score of ≤ had a favourable outcome, while having a gcs of was comparable with the rest of the cohort in terms of favourable outcome ( % vs. %). in contrast to most previous reports, we went further and frequently repeated assessments which allow us to conclude that more information can be obtained with repeated four scores in patients with the lowest level of consciousness, as compared to the gcs. in other words, very low four scores are more informative and carry a much more sinister prognosis than very low gcs scores. frequent evaluation of pupillary function is valuable to monitor intracranial pressure (icp) clinically. evidence of fluctuations of pressure levels in certain intracranial compartments fig. a pupillary size and difference in size for every pupil assessed, i.e. the summarised numerical differences (n = ). on average, visual inspection slightly underestimates pupillary size compared to automated pupillometry. b comparison of every assessment of pupils assessed as mm and below. this graph shows that in an individual patient, visual inspection may over-or underestimate pupillary sizes compared to automated pupillometry. c pupillary constriction recorded by automated pupillometry in mm categorized by conclusions from visual inspection. although visual inspection can suggest absence of pupillary constriction, automated pupillometry may still show that pupils do constrict. auto. pupil., automated pupillometry; vis. eval., visual evaluation; Δsize = difference in size measured; constr., constriction; poss., possible (as opposed to global icp), often missed by a monitoring pressure transducer, is sometimes revealed by pupillary function. reliable estimations of pupillary size and contractibility are therefore needed. in this study, we showed that estimation of pupillary size and constriction by visual inspection can be very different from what is measured using automated pupillometry. like the four score, pupillary constriction served as a valuable outcome predictor, irrespective of the mode of assessment. automated pupillometry is more precise and can reveal pupillary constriction below . mm (in contrast to visual inspection), although the additional prognostic value in this study appeared relatively limited [ ] . still, whenever visual evaluation suggests that pupils appear not to constrict to light, automated pupillometry should be used to corroborate this, which would help avoiding wrong conclusions, including those related to prognosis. at the same time, it is important to be aware that automated pupillometry can occasionally miss a pupillary light reflex in very sluggish pupils [ ] . compared to visual inspection, however, automated pupillometry does provide detailed quantitative information such as the speed of pupillary constriction, the percentage change of pupillary diameters and dilation velocity [ , , , ] . the potential of these data as surrogate markers for the assessment of sedation, evolving brainstem damage, intracranial hypertension or consciousness levels should be investigated in future studies. moreover, automated pupillometry might be valuable when it is mandatory to confirm the absence of pupillary function such as during brain death determination prior to organ donation. to sum-up, our pupillary function data corroborate previous publications suggesting the overall superiority of automated pupillometry over visual evaluation of pupillary size in the neuro-icu [ ] , although for clinical routine we would suggest using both methods as they complement each other. restated, automated pupillometry should be added to visual inspection of pupils rather than replacing it. the major limitation of the present study is the low sample size. we pragmatically included a true-to-life, heterogenous cohort of patients with acute brain injury and did not adjust for factors such as sedation, disease aetiology or localization of brain damage. since visual inspection of pupillary size and automated pupillometry were not obtained at the exact same timepoints (but for obvious reasons a few seconds apart), some of the difference between the methods could be artificial, e.g. because of changing ambient light intensity, although we made all efforts to exclude such confounders. despite these caveats, we were able to show that the gcs has relatively limited value as a prognostic marker in the neuro-icu and for monitoring subtle changes in the neurological status, as compared to the four score, and that automated pupillometry adds valuable quantitative information as compared to visual inspection of pupils. training of nursing staff to implement frequent monitoring with the four score and automated pupillometry is feasible in the neuro-icu. both measures provide additional clinical information compared to the gcs and visual inspection of pupils, in particular a much more granular distinction by the four among unresponsive patients with a gcs score of . this corroborates earlier data showing that the four score performs better than the gcs for the prognostication of icu mortality, probably because the respiratory and brainstem reflex components of the four score reflect morbidity better than does the verbal part of the gcs [ ] and, as stated previously, because low gcs scores are frequently iatrogenic, e.g. due to sedation and neuromuscular blocking agents. finally, compared to visual inspection of pupils, automated pupillometry allows a much finer quantification of pupillary function, the clinical value of which needs to be addressed more in detail in future studies. the full outline of unresponsiveness (four) score and its use in outcome prediction: a scoping systematic review of the adult literature the current significance of the four score: a systematic review and critical analysis of the literature predictive value of glasgow coma score and full outline of unresponsiveness score on the outcome of multiple trauma patients validation of a new neurological score (four score) in the assessment of neurosurgical patients with severely impaired consciousness the relationship of the four score to patient outcome: a systematic review validity of the four score coma scale in the medical intensive care unit quantitative pupillometry for the monitoring of intracranial hypertension in patients with severe traumatic brain injury neuro/trauma intensive care unit nurses' perception of the use of the full outline of unresponsiveness score versus the glasgow coma scale when assessing the neurological status of intensive care unit patients neurologist versus machine: is the pupillometer better than the naked eye in detecting pupillary reactivity a comparative study of glasgow coma scale and full outline of unresponsiveness scores for predicting long-term outcome after brain injury pupil examination: validity and clinical utility of an automated pupillometer predictive validity and inter-rater reliability of the persian version of full outline of unresponsiveness among unconscious patients with traumatic brain injury in an intensive care unit four score predicts early outcome in patients after traumatic brain injury prognostic value of automated pupillometry: an unselected cohort from a cardiac intensive care unit interrater reliability of pupillary assessments influence of strategic cortical infarctions on pupillary function a systematic review assessing the current state of automated pupillometry in the neuroicu clinical monitoring scales in acute brain injury: assessment of coma, pain, agitation, and delirium a french validation study of the coma recovery scale-revised (crs-r) glasgow coma scale versus full outline of unresponsiveness scale for prediction of outcomes in patients with traumatic brain injury in the intensive care unit risk factors and outcomes of critically ill patients with acute brain failure: a novel end point assessment of coma and impaired consciousness. a practical scale automated pupillometry to detect command following in neurological patients: a proof-of-concept study validation of a new coma scale: the four score comparison of the full outline of unresponsiveness score and the glasgow coma scale in predicting mortality in critically ill patients* further validation of the four score coma scale by intensive care nurses publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors' contributions mho-concept and design of the study, analysis of data, important intellectual content, writing of the manuscript, approval of final manuscript; hrj, sre, nht-data acquisition, important intellectual content, approval of final manuscript; dgs, km-important intellectual content, approval of final manuscript; dk-concept and design of the study, analysis of data, important intellectual content, writing of the manuscript, approval of final manuscript. conflict of interest all authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licencing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.ethical approval all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the helsinki declaration and its later amendments or comparable ethical standards. key: cord- -v m l wz authors: nan title: neurocritical care society (th) annual meeting date: - - journal: neurocrit care doi: . /s - - - sha: doc_id: cord_uid: v m l wz nan in this exploratory analysis, csf levels in the progesterone treated group were variable and not as supratheraputic compared to serum levels. this study highlights an additional factor that needs to be considered in the designing of clinical trials in tbi. not only does the heterogeneity of the injury and subsequent outcome measures need to be refined, but the biomarker of pk levels also needs to be analyzed in csf as well as serum to determine if the treatment is reaching the target organ, the brain. arctic ground squirrels (ags) are extreme hibernators capable of withstanding months of freezing temperatures by suppressing metabolic rate. hibernation is characterized by hypoxia and low cerebral blood flow and interrupted by bouts of arousal in which perfusion is quickly restored. curiously, ags do not experience reperfusion injury which is hypothesized to be reflected in altered transcriptional signatures in an in vitro model of reperfusion injury. to investigate the influence of ischemia/reperfusion on ags neuronal stem and neural progenitor cells (nsc/npcs), we exposed ags and murine nsc/npcs to control conditions, hypoxia, oxygen and glucose deprivation or glucose deprivation alone or following return to normal conditions to model reperfusion. cell viability and cell cycle state were assessed by automated cytometry; metabolic phenotype by in vitro oxygen consumption and extracellular acidification rate. to determine novel genes involved in ags resilience to reperfusion injury, a cdna library was constructed in a mammalian expression vector and introduced into murine nscs that were then assayed for viability after ischemia/reperfusion. ags nsc/npcs demonstrated marked resistance to ischemia/reperfusion injury compared to murine nsc/npcs. this survival phenotype is associated with suppressed mitochondrial oxidation and altered cell cycle regulation. ags genes regulating mitochondrial function strongly modulated murine nsc/npc viability following ischemia/reperfusion injury. a dynamic ability to suppress mitochondrial oxidation may underlie resilience to reperfusion injury in ags by promoting a quiescent cell cycle phenotype. development of therapeutic agents suppressing mitochondrial oxidation may induce a protective phenotype and promote survival following reperfusion injury. high throughput imaging of motor system connectivity in the mouse brain. stroke results in profound alterations to architecture in the brain, particularly the corticospinal tract (cst). some plasticity may contribute to functional recovery, while other changes may be maladaptive. studies of cst connectivity have been limited by standard imaging methods which do not allow visualization and analysis of global axonal connectivity in the brain. we employed two novel imaging methods to visualize axonal projections to forelimb musculature. first, a pseudorabies viral (prv) vector carrying green fluorescent protein (gfp) was injected into the left forelimb flexor in naïve - week-old c mice. prv was transported retrogradely and transynaptically, labeling neurons in the motor cortex and other regions of interest. whole slide imaging was performed using an automated slide scanner (nanozoomer, hamamatsu photonics k.k., hamamatsu city, japan) producing images of serial coronal sections, allowing visualization of multiple levels of the brain in a single slide image. for serial two-photon tomography (stpt), utsw whole brain microscopy facility used a tissuecyte imaging system (tissue vision, somerville, ma) which uniquely performs automated sectioning and fluorescent imaging of the brain to produce -dimensional images with micronlevel resolution. this allows for unprecedented visualization of axonal connectivity in the whole brain. we have imaged motor systems in the brain of uninjured mice using two different methods, each with distinct benefits. whole slide imaging allows for quantification of regions of interest in the brain on a single slide, while stpt produces a highly detailed image that improves our understanding motor systems in -d space. future directions will investigate changes in connectivity following stroke injury and during recovery, allowing a greater understanding of the complexity of plasticity and how it contributes to beneficial and pathological circuit remodeling after injury. andexanet alfa (anxa) is a modified recombinant factor xa (fxa) derivative that sequesters direct fxa inhibitors and reverses their anticoagulation effects. non-specific prothrombin complex concentrates (pccs) have been proposed as potential reversal strategies. the objective of these studies was to compare -factor (bebulin) and -factor (kcentra®) pccs, approved for reversal of warfarin, with anxa in reversing anticoagulation effects of rivaroxaban in a rabbit model of bleeding. nzw rabbits were treated with rivaroxaban (iv, mg/kg) and min later, either pccs ( -factor pcc: or mg/kg; -factor pcc: , , or iu/kg) or anxa ( or mg/rabbit) was administered iv. liver injury was then induced with -cm incisions following laparotomy, and blood loss was measured for min. plasma concentrations of unbound (active) and total rivaroxaban, as well as pharmacodynamic (pd) parameters (anti-fxa activity, pt, and aptt) were determined. anxa reduced blood loss in rivaroxaban-anticoagulated rabbits to levels seen in non-anticoagulated rabbits. in rabbits treated with anxa, anti-fxa activity and unbound rivaroxaban were reduced dosedependently by > % and > %, respectively, within minutes, and both parameters correlated with reduction in blood loss. in contrast, -factor or -factor pccs had no significant effect on any of these markers in rivaroxaban-anticoagulated rabbits. anxa effectively reversed the anticoagulation activity of rivaroxaban in a rabbit model of bleeding. in contrast, pccs showed no reversal activity as assessed by blood loss or pd markers. these results suggest that use of non-specific pccs as reversal agents for direct fxa inhibitors are not likely to be as effective as specific reversal agents that target fxa inhibitors. investigation of anxa vs. pcc to reduce hematoma expansion in models of intracranial hemorrhage is warranted. outcomes after resuscitation from cardiac arrest (ca) remain poor. preventable secondary injury from ongoing brain tissue hypoxia (bth) may worsen injury burden. unfortunately, markers to allow individualized, real-time care optimization are lacking. we performed a randomized crossover trial in a swine model of opioid-induced ca to ) determine the prevalence of bth with standard care (stdc), and ) test whether neuromonitor-guided goal-directed care (ngdc) can prevent bth. female swine ( - kg) were anesthetized with propofol and fentanyl. we placed femoral arterial and venous sheaths, a continuous cardiac output pulmonary artery catheter (edwards lifescience) and a right frontal intracranial access bolt (hemedex) with probes for brain tissue oxygen (pbto ), pressure (raumedic), microdialysis (mdialysis ), cerebral blood flow (cbf) (hemedex), and an -contact electroencephalographic depth electrode (adtech). we induced apnea with mcg/kg fentanyl, extubated the animal and began acls min after apnea. after h stabilization, animals with return of spontaneous circulation (rosc) were randomized to three alternating h care blocks: stdc (mean arterial pressure> mmhg, oxygen saturation - %, cardiac output> % baseline) or ngdc (pbto > mmhg, cbf> ml/ g/min). animals were euthanized at h post-rosc. our primary outcome was the effect of care block on pbto , which we analyzed at min resolution using generalized estimating equations with robust standard errors. overall, of animals achieved rosc after ± min. pbto was higher during ngdc than stdc (p< . ) and did not differ during ngdc from pre-arrest. pbto was < mmhg more during stdc than ngdc ( % of minutes vs %, p< . ). cbf was lower during ngdc than stdc (p< . ), and lower in both arms than pre-arrest (both p< . ). brain tissue hypoxia was common in this cardiac arrest model and prevented by neuromonitor-guided goal-directed care. lower cbf and higher pbto during goal-directed care implies preserved hypoxic cerebral vasodilation and diffusion-limited oxygen delivery. future work will incorporate electroencephalographic and metabolic injury markers. sage- is a proprietary formulation of the endogenous neurosteroid allopregnanolone, being studied as a potential adjunctive therapy for the treatment of super-refractory status epilepticus (srse) . srse refers to a condition of persistent seizures that have failed treatment with first-, second-and third-line treatments. in preclinical models, prolonged seizures reduce the surface expression of synaptic gabaa receptors, exacerbating neuronal excitability and limiting target sites for gabaergic treatments (eg. benzodiazepines). here we present preclinical data describing the pharmacological properties of sage- that support its further development as a potential treatment for srse. gaba-evoked currents were examined in vitro with whole cell patch clamp recordings in cells expressing -pilocarpine model of refractory status epilepticus (pouliot ) was used to examine in vivo anticonvulsant activity. sage- or pentobarbital was administered intravenously minutes after the onset of pilocarpine-induced seizures, a time point when benzodiazepines are ineffective in animal models (pouliot ). sage- potentiated both synaptic-vitro, with ec s of nm and nm, respectively. the concentration-gabaa receptors by sage- was , -fold more potent than that observed with pentobarbital alone. when sages were also observed in the rat model of rse. when sub-active doses of sage- and pentobarbital were combined, electrographic seizure activity was significantly reduced. in vitro, sage- potently modulated both synaptic-type and extrasynaptic-type gabaa receptors, and the maximal potentiation at these receptors was further augmented by the co-application of pentobarbital. this enhanced in vitro potency and maximal effect at gabaa receptors provides further support for the development of sage- as a potential treatment for srse. vasospasm has long been considered the primary mechanism underlying delayed cerebral ischemia (dci) in subarachnoid hemorrhage (sah), but increasing evidence shows that other processes such as cortical spreading depressions and inflammation. we propose that abnormal neural activity in the form of epileptiform abnormalities, we term ictal-interictal continuum abnormalities (iicas), may contribute to dci. these abnormalities may increase metabolic demands in injured brain tissue, thereby contributing to metabolic crisis and secondary neuronal injury. here, we investigate whether the presence of iicas predict dci development. we analyzed eeg reports from icu patients with moderate-severe non-traumatic sah. continuous eeg data was recorded with daily review to identify electrographic seizures and interictal patterns. we tallied daily seizures, sporadic epileptiform discharges, lateralized or generalized periodic discharges (lpds and gpds), and lateralized or generalized rhythmic delta activity (lrda and grda). delayed cerebral ischemic events were also marked. cumulative distribution curves and iica-to-dci time plots were calculated. iicas are more prevalent in patients who develop dci, especially when they begin several days after the onset of sah. all iica types except generalized rhythmic delta activity occur more commonly in patients who develop dci. in particular, iicas that begin later in hospitalization correlate with increased risk of dci (lrda day , ed day , lpds day , gpds day ) most iicas also precede the onset of dci. we next trend features of discharges to identify those most closely associated with dci and will present our preliminary findings. iicas represent a new marker for identifying early patients at increased risk for dci. moreover, iicas might contribute mechanistically to dci and therefore represent a new potential target for intervention to prevent secondary cerebral injury following sah. up to % of patients resuscitated from cardiac arrest remain in a coma, and the ability to predict longterm neurologic recovery in these patients is limited. quantitative analysis of electroencephalography (qeeg) is objective and may facilitate outcome prediction. consecutive patients with hypoxic-ischemic coma were enrolled. continuous eeg was obtained on all patients. eeg was post-processed and analyzed by fourier transform. spectral analysis was conducted on artifact-free contiguous -minute eeg epochs from each hour. whole band ( -- hz) --suppression ratio were computed as quantitative metrics of eeg for the entire eeg recording, and then statistically compared during the last hours of eeg. sedation, level of arousal, and body temperature were also analyzed. good outcome (good neurologic outcome, gno) was defined as consciousness recovery at any point in the acute hospitalization. ten subjects were included in the study, with ceeg durations ranging from - hours of recording. the mean age was . years ( - ). there were significant differences in alpha power ( . ( . - . ) vs . ( . - . ), median (iqr), p< . , gno vs poor neurologic outcome [pno] ), delta power ( . ( . - . ) vs . ( . - . ), median (iqr), p= . , gno vs pno), burst suppression ratio ( . ( . - . ) vs . ( . - . ), median (iqr), p= . , gno vs pno), and multiple measures of variability between gno and pno patients. quantitative spectral analysis of continuous eeg may be predictive of consciousness recovery in patients with hypoxic-ischemic coma. higher alpha power, lower burst suppression ratio, and higher variability were all correlated with good outcome. because the media plays an important role in educating the public and impacting public perception on medical topics, we sought to evaluate whether mainstream media provides education or misinformation to the public about brain death through review of articles on two recent highly publicized brain death cases: ) the jahi mcmath case, in which a teenage girl was declared brain dead and her family refused to allow organ support to be discontinued; and ) the marlise muñoz case, in which a pregnant woman was declared brain dead and the hospital refused to terminate organ support until they were ordered to do so by a judge. media websites of using the search terms, "jahi mcmath" and "marlise muñoz." each article was evaluated to determine whether it contained ) teaching points, or ) misinformation, defined as misleading, incomplete, or incorrect information. we reviewed unique articles. the subject was referred to as being "alive" or on "life support" in % ( ) of the articles, % ( ) of which also described the subject as being brain dead. a definition of brain death was provided in % ( ) of the articles. only % ( ) of the articles noted that organ support should be discontinued after brain death declaration unless a family has agreed to organ donation. reference was made to wellarticles and % ( ) of these implied both patients were in the same clinical state. mainstream media provides poor education to the public on brain death. because public understanding of brain death impacts organ and tissue donation, it is important for physicians, organ procurement organizations, and transplant coordinators to improve public education on this topic. neurocrit care ( ) :s -s post-operative hemorrhage: a possible predictor of delirium in brain tumor patients post-operative delirium after brain tumor resection is frequent, difficult to manage, and may increase chart review of patients admitted to the neurologic intensive care unit (nicu) after brain tumor resection. we also evaluated the effect of agitated delirium on length of stay. medical records of nicu admissions form - were reviewed to identify cases and controls. cases were defined as patients with no pre-existing neuropsychiatric history who experienced significant agitated delirium post-operatively, defined by requirement for treatment with neuroleptics (quetiapine or dexmedetomidine) < hours after surgical resection. we compared these patients to a control group comprised of randomly selected patients admitted after brain tumor resection who did not experience agitated delirium. in a multifactors: sex, age, tumor location, pathology, postpost-operative hemorrhage, use of steroids and prophylactic anti-epileptics, particularly levetiracetam. there were cases and controls. multivariate analysis revealed male sex (o.r . ; % ci . - . ; p= . ) and a post-operative course complicated by hemorrhage within the resection cavity (o.r . ; % ci . - . ; p< . ) as significant predictors of agitated delirium. the icu length of stay was significantly longer in those with agitated delirium ( . ± . days vs. . ± . days; p< . ). neurointensivists caring for post-operative patients with brain tumor may consider resection site ctor for developing agitated delirium. future studies may investigate -operative bleeding and delirium and the long term outcome of these patients. cardiac arrest is a leading cause of death and disability, and predicting outcome in these patients is a challenge. optic nerve sheath diameter (onsd) on brain ct correlates closely with intracranial pressure. therefore in this study we studied correlation between onsd measured on the initial brain ct in patients after cardiac arrest and outcome. this is a retrospective study of patients with cardiac arrest admitted to the medical intensive care unit at our hospital between and . pati arrest were included. demographics, neurological status on arrival and day and outcomes were collected. onsd on brain ct was measured bilaterally mm behind the optic nerve head and averaged for each patient. a total of patients were included. mean age was ± . years, patients ( %) were male. patients ( %) suffered out-of-hospital cardiac arrest. mean glasgow coma scale (gcs) on admission was . ± . (range - ; median ). return of spontaneous circulation (rosc) time was . ± . intervention. patients ( . %) underwent therapeutic hypothermia. patients ( . %) had seizures. average modified ( . %) had a good outcome (mrs - ). average duration from rosc to ct was . ± . days. mean onsd in patients with gcs - at day was . ± . mm, while in those with gcs - at day , onsd was . ± . mm (p= . ). mean onsd in patients with mrs - at discharge was . ± . mm, while in those with mrs - was . ± . (p= . ). there does not appear to be a significant correlation between the onsd o cardiac arrest and outcome at day . traumatic brain injury (tbi) is a major public health problem. while the association between subarachnoid hemorrhage and systolic dysfunction (sd) has been established, the effect of tbi on the incidence of early sd in previously healthy patients following moderate-severe tbi, and ) to describe the longitudinal change in we conducted a prospective cohort study among mild and moderate-severe tbi patients admitted to a level trauma center with these inclusion criteria: ) age < years, ) no severe non-tbi injuries, ) no prior cardiac disease, and ) minimal comorbidities. transthoracic echocardiograms were performed at < hours, - days, and - days following tbi. systolic function was assessed using fractional shortening (fs), and sd was defined as fs< %. descriptive statistics were used to compare the mild and moderate-severe tbi groups. multivariable linear regression was used to compare fractional shortening between groups. patients were studied ( mild tbi and moderate-severe tbi). both groups were young ( . years mild tbi and . years moderate-severe tbi) and mostly male ( % mild tbi and % moderatesevere tbi). early sd was present in ( %) moderate-severe tbi patients and ( %) mild tbi patients (p< . ). on multivariable regression, moderate-severe tbi was associated with an absolute . % reduced fs compared to mild tbi ( % ci . % - . %, p= . ). all patients with early sd recovered to normal systolic function by - days injury ( figure ). sd is common early after moderatehospitalization. tbi severity is independently associated with worse systolic function. early echocardiography is a safe, applicable, and feasible procedure following tbi and may aid clinicians with hemodynamic management post tbi. sophie samuel. department of pharmacy. memorial hermann medical center, houston, tx, usa. paroxysmal sympathetic hyperactivity (psh) is a neurological condition that occurs most frequently after traumatic brain injury (tbi). sympathetic hyperactivity can manifest as increased heart rate, blood pressure, respiratory rate, temperature, sweating and posturing activity. in , a consensus statement and probability of diagnosis. the objective of this study is to report the incidence, frequency and severity of psh symptoms in the acute setting after tbi using the new diagnostic criteria. this was a retrospective study from july -august . included were all adult patients admitted to a tertiary care intensive care unit with a primary diagnosis of tbi and a length of stay longer than days. symptoms were recorded. the most frequent symptom was tachycardia ( %), followed by tachypnea ( %), hypertension ( %), symptoms occurring simultaneously and % had symptom - ) vs ( - ); p= . ] and at day ; [ ( - ) vs ( - ); p< . .] medications often used to control symptoms included, anti-pyretics, opioids, beta--- ) vs ( - ); p= . ], but no difference in mortality. symptoms of sympathetic hyperactivity were seen commonly after tbi in the acute setting. using a admitted with a hospital length of stay greater than days. hypertonic saline (hts) appears to be more effective than mannitol in reducing raised intracranial pressure (icp) after severe traumatic brain injury (tbi). in this study we investigated which agent had superior combined effects on icp and cerebral perfusion pressure (cpp). the brain trauma foundation tbi-patients who received only hts were identified and matched with patients who received mannitol only ( : and : match). the two groups were matched for age, pupillary reactivity, glasgow coma scale (gcs), ct abnormality, craniotomy and occurrence of hypotension on day . univariate analysis was performed to compare combined average and duration of icp> mmhg (icphigh) and cpp< mmhg a total of patients with severe tbi, who received only hts were identified and matched with ( : ) and ( : ) patients who received mannitol only. in the : group hts patient was excluded, as there was no corresponding match in mannitol group. the mean age, gcs, incidence of abnormal pupils, hypotension, abnormal ct, craniotomy and day of icp insertion were similar in the groups. there was no difference in number of days of icp monitoring (p= . , . ; : , : groups). osmolar doses were comparable; all patients in hts group received % hts except one who received . %. in : match, number of days with cpplow ( . ± . vs. . ± . , p= . ) was significantly lower in the hts group. in p= . ) were significantly lower in the hts group. these results were reproduced in the : analyses. hts is superior in its combined effect on icp and cpp after severe tbi when compared to mannitol. statins constitute a class of medications commonly used in the treatment of elevated cholesterol. however, in experimental studies statins also have other non-cholesterol mediated mechanisms of action, which may have neuroprotective effects. the purpose of this study was to determine if administration of atorvastatin for days after injury would improve neurological recovery in patients with mild traumatic brain injury (mtbi). the hypothesis was that atorvastatin administration would reduce post-concussion symptoms and also -injury would be safe. patients with mtbi were placebo for days starting within hours of injury. assessments of post-concussion syndrome, postthe rivermead post-concussion symptoms questionnaire at months was the primary outcome. enrollment in the trial was stopped early because of difficulty in recruiting sufficient numbers of subjects. patients with mtbi were enrolled; patients received atorvastatin and received placebo. the mean rivermead score was . for the atorvastatin group compared to . for the placebo group at months post-injury [f( , ) = . , p=. )]. the change in the rivermead score between baseline and months was also analyzed. the mean change in score was a decrease of . for the atorvastatin group and . for the placebo group [f( , )=. , p=. ]. no serious adverse events occurred, and there was no significant difference in the incidence of adverse events in the two treatment groups. atorvastatin administration for days post-injury was safe, but there were no significant differences in neurological recovery after mtbi with atorvastatin. association between comorbidities, nutritional status, and anticlotting drugs and neurological outcomes in geriatric patients with traumatic brain injury an essential part of the management of traumatic brain injury (tbi) is the mitigation of secondary insults to the brain such as sustained increases in intracranial pressure (icp). it would be beneficial to be able to predict increased icp so as to facilitate safe transport of patients. given the role of neuro-inflammation in increases in icp. after admission. receiver operating characteristic (roc) curves were used to compare the predictive elevation of icp above or mmhg for min or more in the following hours. serum samples from patients were matched to subsequent hour periods of monitoring.. ni-vs the predictive capacity of a combined model of ni-vs and il level over ni-vs alone in predicting icp elevation to > mmhg ( . vs . , p mmhg ( . vs . p < . ). levels when combined with physiological data. even without invasive monitoring, predictions about measurements. head injury neuroworsening (nw) after traumatic brain injury (tbi) is a major cause of added morbidity, however, there is no reliable way to predict nw. we hypothesized that autonomic nervous system dysfunction (ans) measured by analysis of plethysmograph variability (ppgv) in the first hour after presentation may predict nw in the initial hours after tbi. and head abbreviated injury score(ais)> . patients with systemic trauma were excluded. nw was defined as any of the following occurring in the first hours: new asymmetric pupillary dilatation (> mm), point gcs decline, interval worsening of ct scan as assessed by the marshall score, or requirement for neurosurgical intervention. the beat-to-beat variation of the ppg, and ppg morphologic features were calculated to quantify the ans impact on the physiological status. multivariate stepwise logistic regression was used to develop predictive models of nw. there were patients (mean age years old, gcs , iss , % women) who met criteria between december and may . nw occurred in ( %) patients. ppgv analysis at (ppg ) and (ppg ) minutes post-admission demonstrated predictive capability for nw(p< . ). ppgv was able to better discriminate nw as compared to a baseline model of age, sex, initial vs (roc . v. . , p= . ). ppgv better discriminated future nw as compared to the model of age, sex, admission vs and gcs (roc . v . ,p= . ), and marginally better than a model combining admission vs, gcs, and marshall score on ct(roc . v . ,p= . ). ans dysfunction assessed by continuous ppg waveform analysis in the first hour represents a nonclinical factors to more accurately predict nw, potentially leading to automated algorithms for earlier therapeutic interventions. tanzania severe traumatic brain injury (tbi) is the number one cause of death and disability among young adults worldwide. formulation and subsequent adherence to the brain trauma foundation (btf) guidelines has been associated with reduced mortality after severe tbi. in this study we studied epidemiology and treatment of severe tbi at a tertiary referral hospital in tanzania in reference to the btf guidelines. patients with tbi hospitalized at bugando medical centre, a tanzanian tertiary referral hospital were recorded in a prospective registry. demographics, cause of trauma, clinical characteristics, hospital care, and mortality were recorded for days and on the day of discharge. between september and october , of patient . %) were hospit pressure (icp) monitoring were not performed for any patient. thirty-eigh - pre-hospital and routine icu care, ct imaging, blood pressure and icp monitoring are underutilized or unavailable in the management of severe tbi in the tertiary referral hospital setting. tbi associated mortality is significantly higher than that in high-income countries. improving outcomes after severe tbi will require concerted investment in pre-hospital care as well as improvement in availability of neuroimaging, icu resources and expertise in multidisciplinary care. establishment of comprehensive traum elevated intracranial pressure (icp) is thought to mediate secondary brain injury by decreasing cerebral perfusion pressure (cpp) and reducing cerebral blood flow. clinical trials targeting icp thresholds have not demonstrated benefit. we hypothesized that stratifying elevations in icp based on their effect on cpp would be feasible with the use of continuous, time-resolute neuromonitoring data. we studied a convenience sample of five patients undergoing intracranial neuromonitoring after severe traumatic brain injury per our institutional protocol. patients had a parenchymal icp monitor time-synced with continuous arterial blood pressure. waveform data were recorded into moberg cns monitors, and second-bywere identified and their duration was measured along with cpp. elevations were stratified into those that exhibited a reciprocal decrease in cpp (icp[neg] ) and those with stable or elevated cpp (icp [preserved] ). the mean patient age was ; three were male. a total of individual elevations in intracranial pressure were observed over a monitoring duration of , minutes. we found icp elevations that reciprocally decreased cpp (icpneg) were identifiable using bedside neuromonitoring devices, and that these elevations resulted in a cpp drop of nearly mmhg, despite a similar maximum icp despite a shorter duration. the majority of these icp elevations occurred in patients with poor outcome, and may represent a target for aggressive icp lowering therapy. mild traumatic brain injury (mtbi) is defined as an initial glasgow coma scale (gcs) - . current recommendations include a follow-up computed tomography (ct) scan of the head prior to discharge. often, imaging and neurological exam remains stable, questioning the role of routine repeat imaging. a retrospective chart review was completed on tbi patients evaluated at a level trauma center between august and december . inclusion criteria included: initial gcs - , blunt head injury, and available repeat imaging. exclusion criteria included gcs < , penetrating trauma, those that required immediate surgery, or those without repeat imaging. a total of patients were included in the analysis. statistics were done with mann-u whitney or chi-square testing. age was . ± years. there were males and females. the most common mechanism was falls ( . %), followed by motor-vehicle collision ( . %), motor-cycle accident ( . %), assault ( . %), pedestrian--related ( . %). polytrauma occurred in . %, better, . % were stable, . % were worse. only patients ( . %) exhibited neuro-exam changes, where patients received repeat imaging which ultimately demonstrated stable findings. ultimately, only one patient required a neurosurgical procedure, an external ventricular drain, due to significant decline. age, gender, mechan neuro-exam changes. on the other hand, neuro-exam changes significantly correlated with ct changes (p = . ). repeat imaging tend to show worse findings when associated with neurological changes. on the other hand, results for repeat imaging were variable without neurological changes and generally did not alter repeat imaging is only warranted for neurological changes that may necessitate a neurosurgical procedure. create a meaningful tool, we explored family members' and physicians' perspectives on prognosis communication during goals-of-care discussions for citbi patients employing mixed-methods. we conducted semi-structured interviews with citbi surrogate decision-- trauma centers, and attending physicians representing geographic (northeast,mid-atlantic,south,west,midwest] and subspecialty diversity (neurocritical care,neurosurgery,trauma,palliative care). two independent reviewers analyzed transcribed interviews using deductive and inductive approaches (nvivo-software). the sample size was determined by theme saturation. prognosticated outcomes expressed as percentages, and % preferred prognosis in a "more direct" manner. surrogates favored percentages because they were "more clear, more concise, and less confusing". in contrast, % of physicians stated that they do not use precise percentages when discussing prognosis in citbi due to distrust in the predictive accuracy of existing data: "better have damn good data to do that with, and most often, we do not." physicians also voiced concern over families' judgment…they become simplified and [these numbers are] used against you later." the dissimilar preferences for the use of percentages and numbers during prognostication represent an important difference between surrogates and physicians. these findings have a direct impact on the design of a goals-of-care sdm tool for citbi. a future goals-of-care decision aid will require iterative decompressive craniectomy (dc) is not a new procedure, however, it has gained momentum in recent years, in the management of refractory intracranial hypertension. however, the timing of dc has not been -based guidelines for the optimal timing of dc has resulted in a wide variability in practice patterns. in most instances, dc has been performed based on neurosurgical evaluation of the patient with or without intracranial pressure (icp) monitoring and evidence of increased shown variable outcomes in emergency (within hours of injury) neurosurgical procedure in traumatic brain injury (tbi). the purpose of this study was to evaluate the impact of emergency dc on in-hospital mortality following blunt tbi. craniectomies performed on patients with a blunt mechanism of head injury within twenty-four hours of admission, were included in the study. in-hospital mortality was the main outcome of interest. patients qualified for the study. patients ( %) underwent a craniectomy within hours (emergency group)and patients ( %) had craniectomy performed between > hours hours to hours following hospital arrival (late group). propensity matched analysis identified pairs of patients in both groups. the mean standardized differences were less than % after matching. there were no significant differences in mortality [odd ratio . , ci ( . [ . , % ci (- . , . ), p= . ] and length of stay between the groups [hazard ratio, . , % ci ( . , . ], p= . ]. no difference was seen on in-hospital mortality between patients operated within hours versus patients operated between and hours of admission. spreading depolarizations (sds) are pathological waves of neuronal depolarization that occur in % of patients with traumatic brain injury (tbi) who require surgical treatment of focal lesions. the incidence of sds in non-surgical tbi i (deeg) placed at bedside via burrhole. we hypothesized that the incidence of sds recorded using deeg in non-surgical patients would be similar to that documented in surgical tbi. -penetrating tbi who did not require urgent neurosurgery on admission. all patients underwent bedside burrhole placement of intracranial pressure, tissue oxygen, regional blood flow and deeg monitors via a single quad-lumen bolt per institutional protocol. data were recorded on moberg cns with dc-coupled amplifiers. over a -- ; % male; gcs range - ) underwent monitoring for a mea - . hours, beginning . hours (median, quartiles: . -( %) monitoring devices were placed in nonpatients had focal pathology in the monitored lobe, w died, including those with sds. there were no significant hematomas or infections related to invasive neuromonitoring. the incidence of sds detected with deeg placed in non-dominant frontal lobe was lower than previously reported with injury-targeted placement of subdural strips in surgical tbi patients. this may be due to targeting to injured periinnate incidence of sd in patients with non-surgical or more diffuse injuries. targeted placement of subdural electrodes through burr holes may be warranted in non-surgical tbi patients. university of utah general surgery, salt lake city, ut, usa. traumatic brain injury (tbi) is a prevalent condition that is responsible for a significant amount of disability and healthcare expenditures. clinicians can and do use the impact prognostic calculations to inform o examine self-reported individual and institutional use of the impact prognostic calculations in an effort to identify trends and effects on treatment. we conducted an international and multidisciplinary survey examining self-reported awareness and use of the impact prognostic calculator. factors associated with awareness and use of the calculator including provider specialty, years in practice, personal and institutional volume of tbi patients treated, and institutional trauma level were als voluntary and anonymous survey in an email. study data was collected and managed using redcap. respondents ( . %) were aware of the calculator, only . % ( ) said that they often, and . % ( ) said they sometimes used it. volume of tbi cases and specialty both were positively associated with awareness and use of the calculator. providers often or sometimes used calculator, . % ( ) stated that it had some influence on their care for the patients. . % used the information to better of care and % used it to provide more aggressive care. of those aware, still only slightly more than half ( %) used it. the use of the impact calculator was mainly to better communicate with patient family, but a portion, . % and % of providers, said it influenced their care in other ways. these results provide direction to increase awareness and use of the impact prognostic calculations. the brain trauma foundation guidelines suggest individualizing cerebral perfusion pressure (cpp) goals based on tissue oxygenation (pbto ), pressure reactivity (index; prx), and metabolism (lactate-pyruvate ratio; lpr). our objectives were to investigate practices pertaining to bedside hemodynamic and neuromonitoring in tbi patients, and to analyze differences among "neurointensivists" (nis; defined as clinical electronic survey of items including a tbi case-scenario; endorsed by sccm ( , recipients) and esicm (on-line newsletter) in . chi-square test was used to compare proportions of responses between nis and ois with a significance p< . . there were responders ( % completion rate); ( %) were classified as ois and ( %) as nis. use of neuromonitoring-derived variables to optimize cpp in patients with severe tbi, for the entire cohort: pbto ( %), transcranial doppler(tcd) ( %), jugular venous bulb ( %), ct perfusion(ctp) ( %), prx ( %), and lpr ( %). nis use more pbto ( % vs. %, p= . ) and ctp ( . % vs. . %, p= . ). more nis have a hemodynamic protocol ( . % vs. . %, p= . ) for tbi, use more arterial waveform analysis ( % vs. %, p= . ), and bedside ultrasound ( % vs. . %, p= . ), while more ois monitor mixed venous oxygen saturation ( . % vs. %, p= . ). in the case scenario of raised icp, low pbto , and preserved pressure autoregula (vasopressor use . % nis vs. % ois, p= . ). "neurointensivists" employ more hemodynamic and neuromonitoring to patients with tbi. intracranial pressure and cpp remain cornerstones of management, however the use of other physiologic variables -specific pp goals. the predominant experience of penetrating traumatic brain injury (ptbi) derives from battlefield settings, but the civilian experience in western settings in patients treated after is limited to only small and single-center studies. as a result, outcome predictors of civilian ptbi in modern trauma and neurocritical care settings are poorly defined. the aim of this study was to identify predictors associated with survival in a contemporary, large, diverse two-center ptbi cohort, and to develop a parsimonious survival prediction score for civilian ptbi. our cohort comprised ptbi patients retrospectively identified from the local trauma registries at two u.s. level- trauma centers, of which one was predominantly urban and the other predominantly rural. predictors of in-hospital and -month survival identified in univariate and multivariable logistic regression were used to develop the simple surviving penetrating injury to the brain (spin) score. at hospital discharge and -months post ptbi was . %. motor glasgow coma sub-score, pupillary reactivity, self-inflicted injury, transfer from other hospital, female sex, injury severity score and inr were independently associated with survival (all p< . ; area-under-the-curve . ). important radiological factors associated with survival were also identified but their addition to the full multivariable would have resulted in model overfitting without much gain in the area-under-the-curve. we developed the spin score, a logistic regressionafter ptbi. while external validation is warranted, this clinical survival prediction tool may provide important information to guide families and physicians during intervention-and goals-of-care decision- real-time visualization of the cumulative pressure and time dose of intracranial pressure in individual traumatic brain injured patients. the 'dose' of intracranial hypertension, a summary measure of duration and intensity of elevated intracranial pressure (icp) episodes, is associated with worse outcome in traumatic brain injury ( retrospective analysis of minute-by-minute icp monitoring data from a large multicenter database of tbi population-based color-coded plots by güiza et al, where 'bad' icp episodes are red, and 'good' icp episodes are blue. the icp insult currently experienced by the patient, together with his icp episodes of the previous hours, and the cumulative icp burden since icu admission, are shown. when playing these minute-by-minute snapshots consecutively, an animation is created showing the current and cumulative burden of icp of the patient. we present the clinical course of patients, with good outcome (gos ), and who died (gos ). clinical trials aiming at aggressively treating icp below a fixed threshold of mmhg have given thresholds, could present a new way to define secondary injury by icp, and a future target for therapy. the proposed method visualizes the current and cumulative time and pressure burden of icp for individual patients, which could help a neuro-intensivist in identifying when a patient is currently in a state of potentially harmful elevated icp, or when his outcome is at a turning point. acute blood pressure variation and mortality in severe traumatic brain injury we retrospectively evaluate temperations ( hematomas) from april to march operated by one young neurosurgeon. during the operation, we made sure to put the burr hole the highest, not to drainage tube into the right position. we scaled the amount of hematoma by hand free roi using head ct before operation and also the next day to evaluate the improvement rate. the recurrence rate was . % ( cases). the average amount of air contaminated was . ml and the improvement rate was . %, both of which didn't relate to the recurrence. no relevance among the recurrence rate, the amount of air contaminated and the hematoma improvement rate could be found. though the amount of air contaminated during temperation doesn't relate to the recurrence rate, it was useful to scale the hematoma improvement rate and the amount of air in order to objectively assess the d recurrence became less, which suggest that we need to investigate the operation for chronic sundial hematoma further after we operate more. the aim of this prospective observational study was to evaluate if trans-cranial doppler (tcd) ultrasonography can be used as an inference tool of cerebral hypoxic episodes in patients with moderate to severe traumatic brain injury. recruited patients had serial tcd studies to assess blood flow velocity of the middle cerebral artery (mca). measurements were done on bilateral mcas as soon as logistically possible after the insertion of pbto monitoring, once a day for a total of days, and during dynamic challenge tests when feasible. multiple physiologic parameters were registered concomitantly with each tcd measurement, with a particular focus on determinants of pbto and potential confounding factors. we studied consecutive patients with a total of tcd studies, of which ( %) were performed - . h) after tbi. when considering all readings, we found no correlation between pbto and mca's readings > h. for value level, icp, and cpp. to correlate with brain tissue hypoxia and could be use as a screening tool to help minimise timesensitive secondary injury during that period. otherwise, vmean is not correlated to pbto . a precise assessment of brain condition after severe traumatic brain injury (tbi) is crucial to reduce secondary injuries and sequelae. multimodal neuromonitoring permits to assess multiple systemic and brain parameters, but these data are complex to interpret continuously, especially in the overwhelmed environment of intensive care unit (icu). computerized decision support systems (cdss) can assist the clinicians in optimizing care. this study aims to evaluate an algorithm for classifying the cerebral condition, as a first step in the development of a cdss. the study was approved by the local research ethics committee. patients with severe tbi (glasgow coma score < ) with a monitoring of intracranial pressure and brain tissue oxygenation pressure were eligible. data were extracted from the existing icu electronical medical records (semi solutions médicales). an incremental learning fuzzy minparameters online was implemented. the different cerebral status categories included: control condition, ntracranial hypertension. previously validated and published datasets were used to train the system. the system was then tested with the patients' data and compared to a classification made by two clinical experts. eight -hour recording periods from adults with severe tbi were analyzed. the pathophysiological status was appropriately classified by the cdss in (median) % (interquartile: - %) of time. every critical event was detected, but brief misclassifications were frequently observed during the transition periods. in this preliminary cohort of patients with severe tbi, the cdss was able to adequately classify the brain condition in a large proportion of time, but some errors occurred during brief transitional periods. further training of the cdss with a larger dataset may improve the system accuracy, which should be tested in a larger patient population. mild traumatic brain injury (tbi) is a commonly seen pathology at trauma centers. neurosurgical consultation is a routine practice; however, the vast majority do not require surgical intervention or invasive monitoring during the entirety of their hospital stay. in certain trauma centers, neurologycentered neurocritical care solely evaluate and manage mild tbi. we provide a retrospective analysis of this practice at our level trauma center. a retrospective chart review was completed on tbi patients evaluated at a level trauma center between september and december . inclusion criteria included; initial gcs - , blunt head injury, available repeat imaging, and management by neurology-centered neuro-intensivists. exclusion criteria included gcs < , penetrating trauma, those that needed immediate surgery, those with neurosurgical consultation, and those without available imaging. a total of patients were included in the final analysis. age was . ± years. there were males and females. the most common mechanism was falls ( . %), followed by motor-vehicle collision ( . %), motor--related ( . %), assault ( . %), and pedestrian- . % were stable, . % were worse. only patients ( . %) exhibited neuro-exam changes, where patients received repeat imaging which ultimately demonstrated stable findings. no patients required a neurosurgical procedure. average hospital stay was . ± . days. neurology-centered neuro-intensivists can manage mild tbi appropriately without official neurosurgical consultation. this practice can streamline tbi management and potentially reduce hospital costs. bulic, natasha n. renda, may m. kim-tenser, gene g. sung, benjamin b. emanuel. usc, los angeles, ca, usa. measurements of optic nerve sheath diameter (onsd) using bedside ultrasound (us) have been shown to correlate with clinical and radiologic signs and symptoms of increased intracranial pressure (icp). eleven patients ( males, females) with traumatic brain injury (tbi) and gcs< were evaluated. all patients had extraventricular drainage (evd) monitors, right and left. three patients had right decompressive hemicraniectomy, had left hemicraniectomy, had suboccipital craniectomy and did not have decompression. a total of examinations were obtained with invasive icp measurements, pulsatility indices (p balance were recorded. twenty-nine ocular uss were performed on individual patients. in ons assessments, bilateral onsd was . mm, while icp was mmhg, however, later developed icp mmhg within hours. another patient had bilateral ons . mm, while icp was mmhg, however, later developed icp of > mmhg within hours. two patients had bilateral ons measurement> . mm with corresponding icp > mmhg all patients with onsd mmhg had ons > . mm. although, patients with ons > . mm and icp mmhg within the next h. there was no correlation between pi on tcd, thus tcd was not useful in this dataset. there was no correlation between increased temperature or elevated blood pressure with icp> mmhg. this small sample size suggests that onsd may predict future icp elevations, however, a larger sample size is needed to confirm these results. the precise threshold differentiating normal and elevated intracranial pressure (icp) is variable among individuals. in the context of several pathophysiologic conditions, elevated icp leads to abnormalities in global cerebral functioning and impacts the function of cranial nerves (cns), either or both which may contribute to ocular dysmotility. the purpose of this study is to assess the impact of elevated icp on eye watching a -second continuously playing video moving around the perimeter of a viewing monitor. pupil position was recorded at hz and metrics associated with each eye individually and both eyes together were calculated. linear regression with generalized estimating equations was performed to test performed at icp levels ranging from - to mm hg in twenty-three patients (twelve female, eleven male, mean age . years) on fiftycorrelating with cranial nerve function linearly decreased with increasing icp (p-value mm hg was . . intracranial pressure. increasingly elevated icp was associated with increasingly abnormal eye tr physiologic impact of elevated intracranial pressure. this represents a new non-invasive automatable means for assessing the physiologic impact of elevated icp. use of shared decision--of-care decisions in critically-ill traumatic brain injury (citbi) offers the hope to decrease variation and bias in goals-of-care discussions. sdm guidelines demand the inclusion of an evidenceand acceptance of the "international-mission-for-prognosis-and-analysis-of-clinical-trials-in-tbi"(impact)-model by physicians holding such discussions with citbi families. we conducted a mixed-methods study with semi-structured interviews in attending physicians representing geographic (northeast,mid-atlantic,south,west,midwest) and subspecialty diversity (neurocritical care, neurosurgery, trauma, palliative care). we explored methods of prognosis derivation and communication, citbi outcome model use, and, specifically, awareness and perceived utility of the impact-model. we analyzed transcripts in nvivo-software with the investigator-triangulated-inductive--approach. theme saturation determined the final sample size. overall, % of physicians use the impact-model, % were not aware of it, and % don't rely on any tbi outcome models. positive impact-model views included: "helpful in getting an idea where your confidence should be"; "to ground physicians a little bit"; "reduces the variability of prognosis that a large some participants "do not thin only"; "those calculators are about populations; they're not about individuals, use of those calculators for this purpose is a perversion of the original construct". we identified substantial physician variability in the awareness of, use, and attitude toward the impactmodel, which crucially informs the development and successful implementation of future goals-of-care sdm tools in citbi. the analyses of acute subdural hematoma using acute subdural hematoma (asdh) is associated with cerebral contusion and laceration of bridging veins following a head injury, however a few cases of asdh without head injury had been reported. the purpose of this study was to detect the difference of traumatic asdh and non-traumatic one. cases of asdh hospitalized at our institute from march to march were retrospectively reviewed. traumatic groups were patients ( . %), and non-traumatic groups were patients ( . %). the results were statistically analyzed by logistic regression to use the various factors: age, gender, glasgow coma scale (gcs) score, the presence of light reflection, danti--coagulation agents, neurological outcome and so on. neurological outcome was evaluated using glasgow outcome scale, and it was classified into two groups: the good prognosis group (gr, md) and the poor prognosis group (sd, vs, d). traumatic groups were mean age . ± . years, and were comprised of males and females. non-traumatic groups were mean age . ± . years, and were comprised of male and females. there were significant difference in patients` characteristics, the presence of light reflection, d-dimer and neurological outcome (p < . ). non-we will be described the detail of them and collect further cases in the future. traumatic brain injuries (tbi) are of significant importance due to increased morbidity and mortality. we retrospectively analysed tbis to assess clinical profile and factors predicting in-hospital mortality. electronic database at a private, urban tertiary care centre was screened ( to ) to include all tbi -hospital mortality outcome were assessed. mean age of population was . ± . years with . % being males. most injuries ( %) resulted from road traffic accidents (rtas). bleeding from either ear, nose or throat (ent) was most common presentation ( . %) followed by vomiting ( . %) and convulsions ( . %). on presentation, severe brain d subdural ( . %) haematoma was most common followed by sub-arachnoid ( . %), extradural ( . %) and intracerebral ( . %). threatened airway was observed only in . % cases. bony trauma ( %) followed by face ( . %) ,chest ( . %), and spine injuries ( . %) were associated injuries. in-hospital in-hospital mo . , . ; p< . ), tachycardia (or . , % ci . , . ; p= . ) and with development of hyponatremia (or . , % ci . , . ; p< . ) or fever (or . , % ci . , . ; p= . ) during hospitalization. ventilator support was necessary in ( %) cases out of which ( %) died. hospital stay (days) did not vary significantly in survivors and non-survivors ( . ± . vs . ± . , p= . ). development of hyponatremia or fever and requirement of assisted ventilation were associated with -hospital mortality. casey we established a team that included attending physicians, fellows, advanced practice providers (app), specific guidelines. we surveyed staff regarding team communication and discussion of qsis during rounds. we designed a dgt that defined team member roles, structured communication patterns, and prompted standard discussion of qsis. following implementation, we evaluated team compliance with the dgt, as well as rates of catheter-associated urinary tract infections (cauti) and ventilatorassociated pneumonias (vap). % respiratory therapists). for most qsis, a minority of staff reported that these were always addressed during morning rounds (% staff indicating qsi "always" addressed: % pressure ulcers, % code status, % cam icu, % mobility goal, % central line catheter removal, % urinary catheter removal, % dvt prophylaxis plan, % ventilator weaning). shared understanding of daily goals between nurses and physicians was reported by % of staff, with a significant difference between nurse %), p = . . dgt audits spanning patient days demonstrated median compliance greater than % for discussion of all qsis. there was an % reduction in cautis ( % ci %, %), p = . , and a trend towards reduction in vap that was not significant. team discussion of qsis can be enhanced by dgts. by promoting adherence to evidence-based best practice, dgts may reduce hospital-associated infections. follow-up is ongoing to determine the impact of dgts on clinical outcomes and team communication. catheter-associated urinary tract infection (cauti) is the most common health-care associated infection accounting for > , nosocomial infections annually (gould, ) . according to the center for disease control, cautis are also a leading cause of secondary blood stream infection resulting in development related to cognitive, motor, and sensory deficits. neuroicu's goal was to eliminate cautis, defined as a rate of zero. with initial efforts ( ( catheter days (titsworth et al, . in february, neuroicu launched a patient-centered quality improvement effort to further reduce cautis. the neuroicu interdisciplinary comprehensive unit safety program (cusp) performed an extensive literature review of evidence based best practices specific to urinary catheter management. a preexisting, staff nurse driven urinary catheter management protocol was revised to better fit the needs of the neurocritical care population, including assessment of and interventions for acute and chronic scan assessments to every hrs, revision of urinary d-ofconducted daily rounds to evaluate the necessity and management of indwelling urinary catheters. after three months of implementation, compliance with use of the neuroicu's urinary catheter management algorithm (ucma) was greater than %, urinary catheter utilization was reduced from % to %, and cauti rates were reduced to zero. implementing a neurocritical care patient-centered, interdisciplinary approach to urinary catheter management significantly impacted urinary catheter utilization, cauti rates, and unit culture. dedicated neurointensivists have previously been shown to improve various outcome measurements in patient and family satisfaction. the purpose of this study is to evaluate the impact of newly appointed neurointensivists on quality outcome measures in a nsicu. this is an observational cohort study of adult patients (> years) in a -bed nsicu at an academic, tertiary care center evaluating quality outcome measures pre-and post-neurointensivists. outcome measurements include catheter associated urinary tract infection (cauti), central line blood stream infection (clabsi), ventilator associated pneumonia (vap), patient acuity, mortality, and length of stay (los). patient satisfaction questionnaires from discharged patients were compared to historical controls. tentiveness of doctors; ) recommend the hospital to others. statistics include -sample binomial and n- chi-squared (categorical) and t-test (continuous). for questionnaire data, considered significant. total patient days occurred pre-and days post-neurointensivist coverage. patient acuity decreased . % (p= . ). cauti ( %, p= . ), clabsi ( %, p= . ), central line days ( . %, p< . ), ventilator days ( . %, p= . ), and vap ( %, p= . ) also decreased. these saved the hospital an estimated $ , based on health services advisory group data. questionnaires were returned. patient satisf on physicians' attentiveness (p= . ). patients recommending the hospital to others increased % (p= . ). dedicated neurointensivists positively impact quality outcome metrics, particularly significantly improving patient satisfaction. future studies should evaluate the direct impact of neurointensivists on medicare reimbursement from improved patient satisfaction. bertan hallacoglu, tanmayi t. oruganti, chandran c. seshagiri. research & development, boston, ma, usa. cephalogics has developed a wearable diffuse optical tomography (dot) imaging device to help clinicians monitor perfusion and oxygenation from multiple brain regions on the bedside in disease states the system to changes in cerebral tissue oxygenation (scto ) induced by hyperventilation in a pig and human subjects. dot sensor was positioned on the pig's head along the sagittal line, and the second sensor was positioned on the hind leg muscle for monitoring systemic tissue oxygenation (ssto ). dot measurements were performed continuously during baseline ( mins, paco = mmhg), transient hypercapnia ( mins, paco = mmhg), and recovery ( min, paco = mmhg) periods controlled by the respiratory rate of the ventilator. dot data were recorded to a laptop for off-line analysis. sto -sd) were computed for comparison of results across measurements. the approach was also investigated in three human volunteers, who were instructed to hyperventilate during dot recordings. -- %), consistent with reports of reduced cerebral blood flow during hypocapnia. in contrast, ssto estimates - %), indicating elevated systemic perfusion. both parameters fully recovered to baseline values during the recovery period. scto response to hyperventilation in human volunteers were consistent with the results in pig. hypercapnia induced reduction in scto was noninvasively imaged in human subjects and a pig despite the large scalp-cortex distance in pig. the results of this study demonstrate the sensitivity of the cephalogics' dot system to scto values and its ability to separate scto from systemic perfusion. brittany doyle, michael m. rogers, daiwai d. olson, venkatesh v. aiyagari. ut southwestern, depts. of neurological surgery, neurology and neurotherapeutic, dallas, usa. multidisciplinary rounds play a pivotal role in optimizing care in the neurosciences critical care unit (nccu). care providers were frustrated with inconsistency and the need for manual data entry to conduct multidisciplinary rounds. the purpose of this project was to develop an integrated computerized form that incorporated "smart" features within epictm. the nccu nursing council collaborated with the physicians to design a standardized system-based approach to multidisciplinary rounds, and the elements that would be addressed within each system. input was collated from nursing, neurology, neurosurgery, pharmacy, and critical care into a paper version which was beta tested before the epic tool was officially rolled out. the rounds template is now a perpetually editable note with fields that include drop-down menus, copy--populate with up-to-date data (e.g., icp values, lab values). while there was a learning curve to the use and un -led rounds became much more efficient, comprehensive, and less frustrating for the entire healthcare team. within four months, nursing management saw the benefit of such a standardized tool for clear communication and the tool also became the standard for nurse-to-nurse handover at change of shift. efficient and orderly presentation of information during multidisciplinary rounds is greatly assisted by the use of a standardized electronic tool. having all of the current, relevant data available in a single location has greatly improved the quality of nurse-led neurocritical care rounds. this tool can be replicated and customized to the needs and patient populations of other units and hospitals. the degree of burst suppression on continuous critical care eeg (cceeg) monitoring is used to guide dosing of intravenous anesthetic drugs (ivads) in the treatment of refractory elevated intracranial pressure (icp) and refractory status epilepticus (se). however, medication titration is performed only as frequently as cceeg review (potentially as little as - times a day). quantitative eeg (qeeg) may provide a continuous, objective assessment of the level of burst suppression that would allow for more precise and rapid titration of ivads. compared software-generated qeeg burst suppression ratio (qeeg bsr) with three raw eeg variables as determined by two board-certified neurophysiologists (r and r ): bursts per minute (bpm), total burst duration per minute (bd) and average inter-burst interval (ibi) for one minute segments per patient. a total of eeg segments were analyzed. agreement between readers was very high for the three raw eeg variables: bpm, bd and ibi (correlation coefficient . , . , and . , respectively). the best correlation was observed between bd and qeeg bsr (- . for both r and r ). the correlation between bpm and qeeg bsr (- . r and - . r ) and ibi and qeeg bsr ( . r and . r ) was not as strong. left and right hemispheric qeeg bsr did not differ statistically from the generalized qeeg bsr (p= . and . , respectively) despite the presence of focal intracranial pathology. the depth of therapeutic burst suppression can be accurately assessed by generalized qeeg bsr. although cceeg bursts per minute is the most commonly used cceeg metric of burst suppression, it shows a lesser correlation with qeeg bsr than total burst duration per minute. there is little operational data on optimal neuro-icu physician staffing. this prospective study evaluated the introduction of night-time in-hospital neurocritical care fellows (ncfs) in an urban academic hospital. the goal was to determine if the new staffing model enhances patient care and provider and patient satisfaction. irb approval was obtained. the new staffing model was rolled out on - - . providers (ncfs; neurology residents and attendings; neurosurgery residents, physician assistants, advanced practice nurses and attendings; neuro-icu nurses) were surveyed. a pre-roll out survey of providers' perceptions of the existing model (night-time ncf coverage from home with on-call in-hospital neurology residents and neurosurgery physician assistants or residents, not dedicated to the neuro-icu) was administered prior to new model roll-out. two follow-up surveys, a separate night-shift nurses survey, and patient (or surrogate) surveys were administered between - - and - - . surveys were electronic and responses were voluntary and anonymous except for the night-shift nurses survey which was paper, required, and anonymous. response rates were % (pre-roll out), % (first follow-up), and % (second follow-up). % of providers indicated pre-roll out that night-time in-hospital ncfs would be beneficial; % (first follow-up) and % (second follow-up) indicated satisfaction with the new staffing model. major reasons for satisfaction included: physician response to emergencies, physician -nurse communication, and patient outcome. the reason for dissatisfaction was decreased educational opportunity for residents. % of night-shift nurses reported preference for the new model. % of patients (or surrogates) agreed to participate: % reported satisfaction with the care they received in the icu; dissatisfaction was not more than % of providers were satisfied with a new staffing model featuring night-time in-hospital ncfs. additional studies are necessary to determine optimal neuro-icu physician staffing with increasing patient and treatment complexity and decreasing resources. therapeutic plasma exchange (tpe) is a first-line therapy for guillain-barre syndrome, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy and polyneuropathy associated with paraproteinemias. tpe is also a second-line therapy for neuromyelitis optica, chronic focal encephalitis, and acute multiple sclerosis. the therapy is also used in autoimmune encephalopathies, refractory status care service has provided a neurointensivist run tpe program using membrane-based technology with the gambro® prismaflex system. a benefit of a neurointensivist managed membrane -based service is lower direct costs compared to centrifugal-based therapies. since a consultation to another service (often available during business hours) is avoided, delays in therapy can be reduced (potentially further decreasing costs) and the therapy is also available for emerging indications such as refractory status epilepticus. this review is of the initial patients treated with tpe in our neurocritical care unit between april and may . all patients were treated with % albumin with a targeted exchange of . to . plasma volumes. overall dosing, timing, indications as well complication were reviewed. indications for therapy included guillain-barre syndrome, myasthenia gravis, autoimmune encephalitis, refractory status epilepticus, autoimmune vasculitis, and parainfectious transverse myelitis. all patients received a minimum prescription of . plasma volumes and had the therapy started sooner than historical controls. no changes in nurse staffing were required for the therapies and we report no bleeding, infectious or access related complications. mild coagulopathy was seen in most patients after previously not available. a neuro-intensivist lead tpe program is feasible and safe. the therapy can be delivered more timely and can be offered for a wider variety of indications. a cost analysis of the program is now underway. specialty neurocritical care improves hospital length of stay and mortality in patients with critical neurologic illness. however, clinical practices are often informed by studies focused on mortality or gross functional outcome. both staff and family members face uncertainty about neurological outcome, which performing detailed followup for all patients admitted to the university of cincinnati neurosciences intensive care unit (nsicu). all patients admitted during a twotrained outcome scale-extended (gose), cognitive outcome using the teleph and quality-of-life using the euro-qol. we assessed the duration of each follow-up call in order to determine feasibility. n= patients were admitted to the nsicu; mean age was ; % were male. overall follow-up was obtained in %; % of survivors were contacted. disposition from nsicu included: home ( %), acute rehab ( %), long-term care ( %), hospice ( %). in-hospital mortality was %. median gose (iqr) was ( - ) and median mrs (iqr) was ( -- . an average of : (mm:ss) was required for each assessment; comprehensive assessments required : . overall, a total time of approximately hours was required for patients. our pilot study demonstrated feasibility of following patients admitted to the nsicu. these findings have the potential to guide in-hospital care and out-of-hospital resources when used as a quality improvement metric, and to provide valuable information for retrospective research. our neurocritical care unit restructuring provided an opportunity to revise our staffing model. the prior model ratio of : resulted in at least one nurse experiencing a : ratio when high acuity patients -specific data to support a higher staffing. prospective observational study of nursing time using the -item therapeutic intervention scoring system (tiss- ) and manual timing of discrete nursing interventions including off-unit transport. baseline data was obtained to include measures of nursing experience. measures of central tendency and regression analysis was performed using sas v . . the average time to complete a neurologic assessment was . minutes; the average time to chart a neurologic assessment was . minutes. for time spent off the unit the average time spent traveling to ct was < minutes, average time spent in mri was minutes twice a day, average time in ir was . minutes. we found that nursing experience was not associated with patient acuity, duration of assessment, nor time spent doc ents. assessment time was associated with documentation time. moreover, higher acuity was a predictor of both assessment time and documentation time. the data were used to support an increased acuity model with nurses having planned : ratio. neurologic critical are patients require more hands on nursing care and time spent in diagnostic testing than an average critical care patient. neurocritical care units staffing ratios should be adjusted to provide time to ensure nursing care is complete. melissa panter, sonja s. stutzman, daiwai d. olson, venkatesh v. aiyagari. utsouthwestern/neurocritical care, dallas, usa. venous access is a basic yet critical component of care. determining which venous access devices (vad) to use depends on the type, duration, and frequency of infusion. prolonged continuous infusion of drugs or fluids, benefit from midline peripheral catheter (midline) or a peripherally inserted central catheters (picc). midlines are safe and effective but use is declining in favor of piccs, which have similar insertion costs and added benefits, such as the delivery of toxic drugs harmful to peripheral veins. however, an infection associated with a picc is classified as a central line associated blood stream infection which has important financial implications for the hospital. therefore, it is important that the type of vad be specifically tailored based on -physician collaborative study to design and test a decision support tool to assist clinicians in determining the appropriateness of the piccs vs midlines for patients. this study has three phases. first, a retrospective chart review of vad decisionexamine the current degree of appropriateness for each type of vad for each specific patient scenario. next, we will design a decision support tool to help decide which vad should be used. the tool will be developed based on expert clinician, pharmacist review and a review of the literature. finally, we will their patients. the first phase of the study is ongoing and we will present the results of the retrospective part of the study and the decision support tool at the annual neurocritical care society meeting. a decision support tool to guide clinicians choosing between different types of vad will help improve current clinical practice and patient outcomes. clinical trials in neurocritical care require a predictable set of baseline, monitoring, treatment, and clinical outcomes data. however, interoperability standards restrict automated real-time streaming of this data, resulting in inefficiencies performing clinical trials, preventing real-time clinical trial oversight and constraining collaborative research. we investigated available data systems and developed a conceptual e. examining current traumatic brain injury interventional trials, we considered technical interoperability -based clinical trial oversight and collaborative analytic research. we elaborated a vendor-neutral interoperability schema for data extraction, repositories, analysis, annotation, and visualization. the proposed conceptual solution is described. nodes of data acquisition include: ) continuously streaming devices including physiologic monitors and infusion pumps; ) discrete data from highpenetrance ehr and laboratory platforms; and ) biospecimen, radiology, and clinical outcomes repositories. an application program interface performs function calls to utilize individual episodes of data. a data management system queries and manages multiple patient records for batch processing of ondemand or prefor real-time or post-hoc assessment of raw and derived parameters (e.g., percent time in target range or on-protocol compliance). we enumerate the variety of current nodes requiring interoperability interfaces, and propose an open standard to promote a highly efficient platform for n -based clinical research, featuring automated case report form data extraction, a programmable interface for oversight and early warning detection, and a platform for annotation and crowdsourcing of novel algorithms. this conceptual architecture for a modular, vendor-neutral, data collection and management system for -based clinical trials in neurocritical care and offer new functionality for real-time oversight and collaborative analytics. improving cancer is a devastating illness; with a rise in brain and spine tumors specialized care is more important that ever. with advances in technology and treatment strategy, those too ill to previously receive care reased acuity has translated to the need for higher levels of hospital care. recognizing the unique expertise required to care for this emerging population, the decision was made to merge neurology and oncology specialties within critical care. the purpose of this poster is to describe the admission criteria, patient population, utilized technology, staffing model, and patient outcomes of a newly created neuro-oncology critical care unit (nccu). in january , a bed neurocritical care unit was opened in a midwestern academic medical center. six of the beds housed within this bed unit were designated and budgeted to the oncology medical center. separate nursing staff and management teams were created to support the care within the unit while maintaining close collaboration with university hospital nccu nursing teams. while nursing teams are distinct, nurse practitioners, neurointensivist, and other multidisciplinary team members are shared between both services. to evaluate the benefit of patient diagnosis, care needs, nccu length of stay (los), number of ventilator acquired pneumonias (vaps), urinary tract infections (utis), and central line acquired bloodstream infections (clabsis). at the time of this submission, specific results are still being tabulated. merging access to academic research trials and oncologic and neurointensive specialists, this has created an environment that promotes care reflective of the most up to date evidence based practice. through the utilization of creative staffing and focused onboarding, this unit has been able to treat this subspecialized population holistically utilizing a multidisciplinary approach to minimize hospital acquired complications and los. in , the neurocritical care society (ncs) published a consensus statement in support of multimodal neuromonitoring, emphasizing the essential need for systems to integrate data in meaningful ways to t barrier to the integration of data from multiple group on neurocritical care informatics was established in ; it includes experts from the clinical and research side of neurocritical care and representatives from medical device manufacturers. through an open meeting and continued discussion, a recommendation document "medical device connectivity" was produced. its objective is to provide guidance to medical device manufacturers desiring to design a communication protocol that allows external systems to acquire data from their devices. our research on this project uncovered a high percentage of errors in medical device protocols as well as undocumented characteristics and safety issues. the group developed recommendations for providing robust communications as well as address usability and safety concerns. the document outlines the content that should be transmitted which includes device identification, protocol version identification, patient identifier, events, alarm conditions, system status, data labels, and units. finally, it must be thoroughly documented and validated by the manufacturer. multimodal monitoring (which requires medical device connectivity) reportedly improves quality of care through reduction of errors and increased detection of adverse events. however, widely adopted connectivity are on the horizon. in the meantime, the document created in this project will provide guidance for manufacturers in their communications protocol development. in doing so, they will then further the ncs's recommendations on device connectivity for multimodal monitoring. warfarin-related intracranial hemorrhage (ich) is associated with increased mortality due to higher rates of hematoma expansion. current guidelines recommend rapid anticoagulation reversal using intravenous vitamin k and prothrombin complex concentrate (pcc). previous studies show high prevalence of incomplete anticoagulation reversal with -factor pcc. we therefore sought to assess the impact of pcc type in reversing warfarin in ich patients. this was a retrospective study of ich patients ( traumatic and non-traumatic) with warfarinassociated coagulopathy who were admitted to a level ii trauma center between january and september and received at least one dose of -factor or -factor pcc. post-pcc inr of £ . was considered successful inr reversal. multivariable model using logistic regression was performed to assess the impact of pcc type on successful inr reversal after adjusting for age, sex, bmi, and baseline inr. overall, the prevalence of successful inr reversal was . %. there was a higher proportion of patients with successful inr reversal in those who received -factor pcc than -factor pcc ( . % vs. . %, respectively, p= . ). in the multivariable model, -factor pcc (or . ; % ci: . to . ) and baseline inr (or per unit of inr . ; % ci: . - . ) were independent predictors of successful inr reversal. the change in inr post-pcc was significantly greater in those who received -factor pcc than -factor pcc ( . ± . vs. . ± . respectively, p< . ). -factor pcc more reliably reversed warfarin in ich patients compared to -factor pcc. cortical spreading depolarizations (csds) as highly active metabolic event commonly occur in patients with intracerebral hemorrhage (ich) and may contribute to secondary brain injury. fever is an independent predictor for unfavorable outcome after ich and may trigger csds. here, we investigated the dynamics of brain-temperature (tbrain) relative to csds and core-temperature (tcore). twenty comatose patients with ich and multimodal electrocorticograpy (ecog) monitoring were prospectively enrolled. a subdural ecog strip was placed adjacent to the evacuated ich. a combined intracranial pressure (icp) and tbrain probe was inserted in the white matter ipsilateral to the ich. monitoring data were averaged to -minute-means for longitudinal analysis and to one-hour-means. -burden was defined as % of temperature > . ° c per -hours. data were analyzed using gee-models and are presented as median and interquartile range (iqr). during hours ( hours [ -csds occurred in clusters. baseline tcore and tbrain were . °c ( . - . ) and . °c ( . - . ), respectively. tbrain but not tcore significantly increased minutes preceding the csds by a median of . °c ( . -- . ]; p< . ) but not tcore (p= . ) was higher during clusters compared to episodes of single csds. csds probability was highes or= . per %; tcore: p< . ; or= . per %) independent of map and icp. csds were triggered during episodes of fever. our data suggest an association between csds and cerebral heat production, especially during clusters. integration of ecog monitoring in trials investigating prophylactic normothermia after ich may help to understand the potential beneficial effect of this intervention. anticoagulation reversal is recommended for patients with intracerebral hemorrhage (ich) on vitamin k antagonists. we propose a window for reversal of vitamin k antagonists, in which ich volume remains below the average growth in a control population on follow up imaging a retrospective review of neuro icu patients at henry ford from - was conducted on patients with the icd code for diagnosis of ich. inclusion criteria: brought to ed at onset of symptoms, either not on anticoagulation or were on warfarin with therapeutic inr, and had received pcc administration. fifty eight total patients were identified. patients were approximately matched for gcs on admission, ich w - cc difference in volume estimation. forty-seven control patients were identified: mean age ( - ), gcs on admission ( - ), sbp , ich volume on admission . cc, ich volume on repeat scan . cc, change in ich volume . %, and mean time between initial and stability scans was minutes. eleven patients on vkas were identified who underwent reversal with -factor pcc. mean age ( - ), gcs on admission ( - ), sbp , ich volume on admission . cc, ich volume on repeat scan . cc, and time between scans was minutes. average inr on presentation was . . all patients on warfarin patients who had pcc administered before minutes ( ) had a mean change in ich volume of . %. patients who had reversal completed after the minutes ( ) had a mean change in ich volume of . %. (p value= . ). we propose a potential "recommended reversal time" of less than minutes for vitamin k antagonists in our institution. limitations of study include small sample size. the full outline of unresponsiveness (four score) is a validated scale that provides the essentials of a coma examination by incorporating motor response, eye opening and eye movements, brainstem reflexes, and respiratory pattern. we incorporated the four score into the existing ich score and consecutive patients admitted to our institution from - with spontaneous ich were reviewed. using patient age, hemorrhage location, hemorrhage volume, evidence of intraventricular extension and gcs, the ich score was calculated. the four score was then incorporated into the ich score as a substitution for the gcs (ich-four score). the ability of the two scores to predict mortality at month was then compared. in total, patients met inclusion criteria. the median age was years (iqr - ) and ( . %) were male. overall mortality at one month was . % (n= ). the area under the roc curve was . ( % ci . - . ) for the ich score, and . ( % ci . - . ) for the ich-four score. for ich scores of , , and , one-month mortality was . %, . %, . % and . %. in the ich-four score model, mortality was . %, . %, . % and . % for scores of , , and , respectively. the ich score and the ich-four score predict -month mortality with comparable accuracy. as the four score provides additional clinical information regarding patient status, it may be a reasonable substitute for the gcs into the ich score. depressive symptoms in patients with intracerebral hemorrhage (ich) are common and are associated with worse outcomes. it is not well described how often depressive symptoms are appropriately ascertained and treated in a multicenter cohort, and whether this is a potential target for improving outcomes. we retrieved diagnostic codes from four university health systems across chicago (multicenter cohort). separately, we prospectively screened for depressive symptoms (nih patient reported outcomes measurement information system, promis, t score ), in patients at one prospectively assessed cohort center at one, three and twelve months after ich onset. we compared detection rates of depressive symptoms between the two samples. diagnostic codes for depressive symptoms up to three months after ich onset were recorded in of ( . %) of the multicenter cohort versus of ( . %) in the prospectively screened cohort (or . , % ci . - . , p < . ). results were similar considering depressive symptoms up to months after ich, of patients in the multicenter ( . %) versus of prospective patients ( . %; or . , % ci . - . , p < . ). in the multicenter cohort less than % of patients months of ich onset. the prevalence of depressive symptoms in survivors of ich is more common than would be suggested treated and ssris may be an under-utilized therapeutic option. vitamin k antagonist (vka)are associated with higher mortality than primary ich. prompt reversal of international normalized ratio (inr) with prothrombin complex concentrate (pcc) may promote hemostasis and decrease hematoma impact of an electronic order set designed to standardize and facilitate more timely reversal of coagulopathy in vka-associated ich. we identified all adults that received pcc for vka-associated ich from june to march at ucsf medical center, which included a period before and after an electronic order set became available in . we abstracted baseline demographics and clinical data from electronic medical records. the primary outcome was time from radiographic identification of ich to administration of pcc. secondary outcomes included pcc dosing accuracy based on actual weight and baseline inr as well as time from pcc order to follow-up inr. we identified patients that received pcc for vka-associated ich, including patients before and patients after the order set became available. baseline demographics and clinical features were similar. order set use was associated with a significant decrease in the time from identification of ich on imaging to the administration of pcc (median vs. minutes; p= . ), more accurate doses delivered ( . % vs . %; p< . ), and a shorter time from the pcc order to follow-up inr (median vs minutes, -hospital mortality were similar in the two groups. an electronic order set for administering pcc for vka-associated ich was associated with significantly faster time to pcc administration and increased accuracy in dose administered. andrew naidech, alan a. long, kathryn k. muldoon, rajbeer r. sangha. northwestern medicine, chicago, il, usa. crucial to identify patients. both active contrast extravasation ("spot sign") and lower platelet activity have been associated with hematoma growth. we tested the hypothesis that patients with a spot sign had lower platelet activity. we prospectively identified patients with acute ich, measured platelet activity on admission, routinely obtained ct angiography and graded the presence or absence of a spot sign. we limited the analysis to patients who underwent ct angiography within hours of ich symptom onset. platelet activity was measured with the verifynow-asa (accumetrics, ca). non-normally distributed data were compared with the mann-whitney test, and binary variables with chi-squared or logistic regression. - . years, % were women and % had a history of hypertension. sixteen ( . %) had a positive spot sign. a spot sign was associated with lower platelet activity ( [ - ] vs. [ - ] aru, p= . , where <= aru indicates an aspirin effect). of patients with a spot sign, had platelet activity <= aru. platelet activity <= aru was associated with increased odds of a spot sign (or . , % ci . - . , p= . ). the presence of a spot sign on ct angiography was associated with lower platelet activity, suggesting a hematoma growth. introduction: clot dissolution is a biochemical process catalyzed by enzymatic proteins, requiring a specific temperature range for optimal function. clear iii, a randomized, double-blinded, placebocontrolled trial tested whether extraventricular drainage (evd) plus intraventricular alteplase improved outcome by removing ivh compared to evd plus saline. methods: retrospective assessment of prospectively collected temperature data q h over first days post randomization. blinded assessment o functional outcome (mrs - ). results: median (interquartile range) daily temperature was . ( . , . )°c and did not differ between - (vs. at days [ . ( . , . ) vs. . ( . , . ), p . °c was significantly associated with faster ivh clot lysis rate (spearmans rho . ; p= . ), but despite significantly higher temperatures, patients with mrs - (vs. mrs - ) had significantly lower average percentage ivh removal at day ( . ± . %vs. . ± . %, p< . ) and ( . ± . % vs. . ± . %, p= . ). temperature functional outcome of . ( %ci: . - . ) and . ( %ci: . - . ) at and days respectively, and was an independent predictor of poor functional outcome at day , but not after adjustment for early infection and other severity predictors. associated with faster clot lysis rate, but also with poor functional outcome. negative associations with of ich patients, patients ( %) had waich and received kcentra. the inr ranges were: . - . in patients ( %), . - . in ( %), . - . in ( %) and > . in patients ( %). within minutes of -minute repeat inr ranges were . - . and . - . , respectively. ffp was administered to ( %), ( %), ( %) and ( %) patient in each group for a persistently elevated inr. at h post-pcc, inr reversal occurred in %, % (rest had inr . ), %, and %, respectively. at h and one had dic following pcc administration. in this small case series of waich patients, inr correction with kcentra was adequate except for those with inr . - prevalence of stroke following craniotomy or craniectomy for spontaneously intracranial hemorrhage intensive care resources, particularly, neuroscience intensive care resources are limited and costly. in most institutions in the country, all intracerebral hemorrhage (ich) patients are admitted to the neuroscience intensive care unit. we sought to identify what criteria will allow us to determine which primary intracerebral hemorrhage patients will not need admission to an intensive care unit (icu). we studied retrospectively patients with primary ich from january to the end of dec . we reviewed multiple admitting characteristics: demographics, hematoma volume, location of hemorrhage, any brain compression, blood pressure, respiratory status, inr, glasgow coma score (gcs). the reasons for neuroscience intensive care unit admission requirements are the need for mechanical ventilation, hydrocephalus, increased intracranial pressure, low gcs score, hematoma expansion, or the unit, and who did not require any icu care intervention. this group had the following characteristics: supratentorial ich, ich volume . we called this criteria the "non-admission criteria for patients with primary intracerebral hemorrhage". patients were identified as primary ich. patients ( . %) fulfilled the non-admission criteria to the neuro-intensive care unit. of patients patients ( . %) discharged home, patients to acute rehab facility ( . %), patients discharged to snf ( . %), patient died ( . %); elderly patient with existing dnr comfort care orders. none of the patients had to be readmitted to neuroscience intensive care unit, and none required neurosurgical procedure. we propose that ich patients that fulfill the non-admission criteria do not have to be admitted to an icu and can safely be monitored in a step down unit this represented about % of ich patients at our tertiary academic medical center. future prospective studies are required to validate the criteria. joseph r. blunck, justin j. shewmaker. saint lukes hospital / pharmacy, kansas city, mo, usa. current guidelines recommend the use of -factor prothrombin complex concentrate (pcc) rather than fresh frozen plasma for reversal of warfarin-related intracranial hemorrhage (wrich). there is no consensus regarding an optimal pcc dosing strategy, but limited data suggest that pcc dosing should be based on weight and international normalized ratio (inr). in november of , our health system implemented a wrich reversal protocol with a -factor pcc dosing nomogram that utilized fixed-dose options of , above or below . the purpose of this study is to evaluate the effectiveness and safety of this simplified -factor pcc dosing protocol. patients given -factor pcc for wrich reversal in our health system were retrospectively identified with billing codes. chart review was completed to evaluate the primary endpoint of achieving a post treatment evidence of a venous thromboembolic event, time to goal -hospital mortality. we identified wrich patients from november through april that were reversed with our simplified -factor pcc dosing protocol. seventy-seven ( . %) patients achieved a post reversal goal -six ( . %) patients received a pcc dose equivalent to rounded pi dosing and the mean (sd) dose difference between groups was ( ) units vs. ( ) units, protocol vs. pi dosing, respectively. one patient ( . %) had a thromboembolic event that occurred days post reversal. a simplified -factor pcc dosing protocol is a safe and effective strategy for wrich reversal. -hospital, year and year mortality, and has been influences functional outcomes. we sought to evaluate the association between cci and outcomes in patients with primary intracerebral hemorrhage (ich). patients admitted to our center with primary-ich from - were included. demographic and clinical data were collected. the primary outcome measures were the proportion of patients with discharge mrs (dmrs) of - , death and poor discharge disposition (any disposition other than home or inpatient-rehabilitation). crude and adjusted logistic regression were used to evaluate the association between cci and outcomes. patients were identified. there were ( . %) patients with a cci of or , ( . %) patients with a cci of - , and ( . %) with a cci of or greater. while the continuous cci was not significantly associated with a dmrs of - (or . , % ci . - . , p= . ), it was associated with disposition. the odds of poor disposition increased % with each increase in cci (or . , % ci . - . , p= . ). the odds of death increases % with each point increase in cci (or . , % ci . - . , p= . ). after adjusting for baseline ich score, cci remains significantly associated with poor disposition (or . , % ci . - . , p= . ), however the association between cci and death was not statistically significant (or . , % ci . - . , p= . ). in contrast to previous studies, cci was not associated with poor short-term functional outcome or inhospital mortality in ich patients after adjusting for ich score. however, it was significantly associated with poor discharge disposition. this suggests that cumulative comorbidities only predict disposition in ich, because the ich score strongly impacts poor functional outcome and in-hospital mortality. accurate assessment of renal function remains a unique challenge in patients with intracerebral hemorrhage (ich). mathematical estimates of creatinine clearance (crcl) routinely used are often inaccurate in this setting. subsets of critically ill patients have been shown to exhibit a hyperdynamic response leading to an enhanced renal clearance. no studies exist evaluating the directly measured creatinine clearance of patients with ich. this was a single-center prospective observational study of adult patients with ich admitted to the nsicu between january and july . eight-hour urinary creatinine clearances were performed daily to directly measure crcl until the patient no longer had a foley catheter or the patient left the nsicu. urinary -gault equation. statistical significance was defined as p-value < . . thirty patients with ich were enrolled in the study. the study sample was % male with a mean age of ± . years. the median admission ich score was (iqr - ) with a mean ich volume of ± . ml. the median admission gcs was . (iqr - ) and median admission sofa score was . (iqr -additionally, the mean urinary crcl was significantly higher than the estimated crcl each individual study patients with ich consistently experienced urinary crcl greater than estimated crcl predicted based on -gault equation. as renally eliminated medications are routinely dosed based on mathematical estimates of renal function, further study is needed to optimize medication regimens in this patient population to prevent underexposure. the cognitive reserve hypothesis suggests that variations in patient pre-morbid status such as education, occupation and brain morphology influence outcome. this has been extensively validated in patients with alzheimer's disease. an important component of cognitive reserve is brain morphology, which can be quantified with measures such as whole brain-or gray matter volume. this study examines use of novel measures of brain morphology to measure cognitive reserve in patients with sdh. patients with ct-documented sdh were screened. we identified patients who had a clinically indicated post-morbid mri, telephone interview for cognitive status (tics) and barthel index (bi) at discharge and follow-up. mri was used to measure several volumes such as whole brain-, gray matter-, left vs right caudate-, hippocampal and intraventricular csf volume using a freesurfer pipeline. primary outcome measures were tics at and bi at months results: -up. regional - ) (sd), ---- at discharge and - . at follow-up ( -- . ) at mo. we found a positive correlation between intraventricular csf volume and bi at mo (r = . , p= . ). there was also a significant correlation between left caudate volume and bi at months. brain morphology did not correlate with tics outcome at months. quantitative imaging can be used to predict functional outcomes in patients with intracranial hemorrhages. as we continue enrollment we hope to generate meaningful no and brain tumors. christian hernandez, vivien v. lee, bichun b. ouyang, torrey t. birch. rush university medical center/department of neurological sciences, chicago, il, usa. it remains unclear which patients with intracerebral hemorrhage (ich) benefit from surgical hematoma evacuation, and the patient factors associated with the decision to pursue surgical intervention are largely early surgical intervention for ich and to investigate if an age bias exists at our institution. one hundred and twenty consecutive patients who were admitted to the neurosciences intensive care unit with primary ich between april and january were retrospectively reviewed. multivariate regression analysis was used to analyze if select patient factors were associated with the decision to pursue early surgical intervention. in total patients were analyzed; patients ( %) were female (mean age . ± . ), patients ( %) had supratentorial ich, and patients ( %) underwent hematoma evacuation. in univariate analysis age, race, and gender were not significantly a intervention. the only factors associated with hematoma evacuation were gcs score and ich volume. after controlling for significant variables, multivariate analysis showed that the only factor associated with surgical intervention was ich volume (or . , p= . ) . surgical intervention did not affect discharge disposition (p= . ), but was associated with a longer length of stay ( vs days, p= . ). in this analysis, ich volume was the only predictor of hematoma evacuation in patients with primary ich. age and sex did not influence patient selection for surgical intervention. surgical treatment did not affect patient disposition at discharge, but was associated with longer hospitalizations. further investigation is needed to determine which patients with ich benefit most from early hematoma evacuation. studied. we investigate factors associated with admission systolic blood pressure (sbp), including hemorrhagic transformation (ht) and discharge outcome. this is a retrospective study of consecutive ais patients presenting from april to march . demographic and clinical data were collected. admission sbp was divided into three tiers: . the primary outcome measure was in-hospital mortality. seven hundred seventy six patients were included (meanwere patients with sbp> ( . %), with sbp - ( . %), and with sbp were ry of hypertension ( . %; p . premorbid use of antihypertensives did not differ among the three groups. there were no differences in proportion of ht ( . % vs. . % vs. . %; p= . ). although patients treated with iv-tpa were evenly distributed among tiers ( . % vs. . % vs. . %), more patients with sbp had mrs - (p= . ). compared to sbp was associated with lower odds of in-hospital mortality (or . , %ci= . - . , p= . ). this remained significant after adjusting for age and nihss (or . , %ci . - . , p= . ). normal presenting sbp (< ) in patients with ais was associated with worse discharge functionaloutcome and higher in-hospital mortality. these differences may be related to other associated medical conditions such as pre-existing heart failure. further research is needed to define the ideal range to maintain sbp after ais. between april and february , patients with non-traumatic, non-aneurysmal and nonmalignant parenchymal cerebral icb were identified. the associations of nihss at presentation (nihssp), nihss at hours (nihssd ), size of icb, comorbidities, and infection with los were investigated retrospectively. the mean age for the patients was . ± . years and % were male while most patients were white ( %). the most prevalent comorbidity was hypertension ( % nihssd is a useful measure of los and should be collected for patients with icb. nihssd at upper teens present most challenges to discharge and should be the aggressive focus for discharge planners. incidence of infection and ventilator need is high in this population, adding to the challenges. although oral factor xa inhibitors (fxai), used for the prevention and treatment of venous racranial hemorrhage (ich) than warfarin in clinical studies, intracranial bleeding is still associated with high morbidity and mortality. moreover, there are no specific guidelines for managing these bleeds other than empirical institution-based hemorrhage protocols. there is a need to understand the real-world management, outcomes, and resource utilization of fxai-associated major bleeding in order to potentially improve morbidity and mortality in these patients. five us medical centers participated in a retrospective study of patients admitted to the hospital with lifethreatening bleeding on or after january while on apixaban, rivaroxaban, or low molecular weight heparin (lmwh). baseline characteristics, treatment patterns, outcomes, and resource utilization were assessed. ich patients were reviewed and are reported specifically. this interim report includes major bleed patients, including ich. the majority of ich were hypertensive [ ( %)], ( %) were on concomitant anti-platelet with fxai, ( %) were diabetic and e ich was spontaneous ( %) and trauma ( %). in the management of ich bleeding, % of patients received clotting factors (e.g. pcc), whereas % received interventions (e.g. radiological embolization). within days of discharge, ( %) died, of which occurred during the admission. for the patients who did not die, length of hospitalization was . ( . - . ) days, with only discharged patient restarting on an anticoagulant. this study provides a real-world picture of patients receiving fxais or lmwh, experiencing lifethreatening intracranial bleeds. despite efforts to restore hemostasis, mortality remains high and substantial healthcare resources are expended. this highlights the need to develop specific strategies for managemen prophylactic seizure medications are not recommended by guidelines for patients with intracerebral hemorrhage, yet are prescribed to nearly % of them. there are few data on disparities in their use. we tested the hypothesis that there are differences in the administration of seizure medication, specifically we electronically retrieved information from patients who were diagnosed with intracerebral hemorrhage from healthlnk, a multi-center electronic repository in chicago, il, from - ("multicenter cohort"). from through , we prospectively identified patients with intracerebral hemorrhage at one site ("prospective cohort"). there were , patients in the multicenter cohort from four sites. the use of levetiracetam varied with -americans (or . , % ci . - . , p< . ). in the prospective cohort (n= ), hematoma location, older age, depressed consciousness, larger hematoma volume and no alcohol abuse were -americans to receive levetiracetam (or . , % ci . - . , p= . ). african-americans were more location was independently associated with levetiracetam administration (p< . ) disparities in the use of levetiracetam and they are confounded by hematoma location, a datapoint not typically available in administrative datasets. deviation from guidelines for the use of seizure medications is common and rational, and any impact on outcomes is uncertain greater gains in late recovery for intracerebral hemorrhage patients with more debilitating initial injury. multiple intracerebral hemorrhage (ich) studies have examined differences between discharge and month outcome. however, few studies have examined late recovery specifically between -and month endpoints. the aim of this study was to identify potential factors predicting late recovery in ich patients. twenty-four patients diagnosed with primary ich at yale-new haven hospital were prospectively enrolled between july , and july , . outcomes were assessed using barthel index (bi) at discharge, months, and months. repeated-measures regression analysis was conducted using age, admission glasgow coma scale (gcs), ich volume, intraventricular extension, and ich location, to compare outcomes at discharge, months, and months. there was a significant improvement across time points (p = . ), with follow-up testing showing improvement between discharge and months (p < . ), discharge and months (p = . ), and months and months (p = . ). regression testing resulted in a significant relationship of time (p = . ), time x gcs (p = . ), time x ich volume (p < . ), time x ich location (p < . ). plots show increased late recovery (i.e., between and months) for patients with lower gcs scores, larger ich volume, and deep ich location. patients with more devastating initial ichs show greater gains in late recovery between and months. these results suggest initial disability at months may not represent overall recovery and support continual follow-up out to one year. while extensive studies have examined the outcomes of intracerebral hemorrhage (ich) patients under the age of , few studies have examined outcomes in an elderly cohort (> years). the aim of this case-control study was to determine the independent effects of age on outcome after ich. nineteen ich patients prospectively identified at yale-new haven hospital above the age of were matched against patients below age , based on ich location (lobar, deep, cerebellar, brainstem), ich volume (> cc), presence of intraventricular hemorrhage (ivh), and admission gcs ( - , - , - ). the matched groups were compared via univariate analysis to examine differences in morbidity while there was no difference in pre-ich disability (mrs > ; p > . ), at months elderly patients exhibited higher morbidity (mrs > , p = . ). despite these differences, there were no differences in overall mortality between groups at discharge or at months and no differences between barthel index at months. despite greater morbidity as defined by mrs, elderly patients with ich do not significantly differ from younger patients in mortality rates or ability to perform activities of daily living at discharge and months. these results may warrant further studies to provide more accurate prognostication after ich in elderly populations. hypertension after intracerebral hemorrhage (ich) is associated with hematoma expansion, morbidity and mortality. there are currently no recommendations to standardize the critical care approach to acute blood pressure (bp) management in ich. we performed a large retrospective cohort study to examine practice variability in bp management in acute ich. care center using local get with the guidelines data. we abstracted time-stamped clinical variables including all documented bp measurements, and medications administered, as well as hematoma location from the electronic medical record. all acute ich patients are admitted to the neuroicu and comanaged by neuro-intensivists and vascular neurologists. we used descriptive statistics to summarize overall population and treatment characteristics. - ) years, and % were female. and % other. electronic medical record data were available in subjects, of which ( %) received continuous infusion for bp control within hours of admission ( % nicardipine, % clevidipine). a systolic bp goal was charted in ( %) and ranged from to mmhg. these goals were modified in % during the same admission ( % increased, % decreased). overall, unique oral antihypertensives were administered ( % received a beta-an ace inhibitor, and % a diuretic). hypertension requiring continuous antihypertensive infusion is common after ich. there is high practice variability in bp targets and choice of antihypertensive medications. a prospective study of a systematic and protocolized approach to antihypertensive medication use in ich is necessary to determine if reducing practice variability improves outcomes. intracranial hemorrhage (ich) has long been thought to be a devastating consequence in the setting of end-stage liver disease. due to its association with abnormal coagulation, the prognosis is thought to be poor, and frequently leads to withdrawal of care. our aim with this study was to assess the true overall mortality rate of ich in end-stage liver disease and compare it to mortality of ich in the general population. all patients > years of age admitted to mayo clinic from to with a subsequent diagnosis of non-traumatic ich and end-stage liver disease were identified. patients presenting with primary epidural, subdural, intraventricular, or subarachnoid hemorrhage were excluded. using actuarial methods, day, day, and year mortality rates were calculated. patients with simultaneous diagnosis of ich and end-stage liver disease were identified. of the patients were female ( %) and patients were male ( %). the mean age at diagnosis was years. the mean systolic blood pressure in the mortality cohort was mmhg, compared to mmhg in the survival cohort. the day, day, and year mortality rates were %, %, and % respectively. ich associated mortality in end-stage liver disease does not significantly differ when compared to ich mortality in the general population. the mean systolic blood pressure at presentation did not specifically correlate with an increased incidence of ich associated mortality. these findings are important in the practice of neurocritical care, confirming that poor prognostication and expedited withdrawal of care should be reconsidered. future directions will include mortality adjusted by hemorrhage location, size, and presence of intraventricular extension. kcentra® (human prothrombin complex concentrate) is the first fda-approved non-activated -factor prothrombin complex concentrate for the urgent reversal of vitamin k antagonist agents in adults with acute major bleeding. the recommended dosing is based upon the units of factor ix, which can vary within each vial (range from vial size to reduce waste and some based upon the exact factor ix content. this variation in dosing may be associated with complications in care and has never been evaluated. underdosing of the medication can lead to suboptimal response and overdosing the medication can cause thromboembolic events. the purpose of this observational trial is to assess the current prescribing practices of kcentra® in neurocritical care unit patients across the united states and evaluate the impact on patient response and safety. additionally we plan to characterize current approaches to repeat dosing. this was a retrospective observational study of adult patients across centers who received kcentra for reversal of warfarin-related bleeding between january , and december , . descriptive statistics and tests for comparison will be utilized to evaluate differences in dosing, outcome, and the occurrence of adverse events. statistical significance will be defined as p-value < . . data collection is ongoing but the full results will be presented during the meeting. result of this study will document the real-world use of kcentra® in patients with severe life threatening bleeding and assess the impact of variations in prescribing practices on patient responses. there is a paucity of data regarding this topic and combining data from multiple neurocritical care units will be timely in identify optimal dosing strategies. perihematomal edema (phe) associated with intracerebral hemorrhage (ich) has been suggested to have an impact on both mortality and functional outcomes in spontaneous, supratentorial ich. there have been no studies examining the impact of phe in infratentorial hemorrhage. the aim of this study was to evaluate the impact of absolute phe volume as well as phe expansion rate in cerebellar hemorrhages at the time of discharge and at months. patients diagnosed with primary cerebellar ich at yale new haven hospital were prospectively enrolled between july , and july , . patients were evaluated using mrs and bi at discharge and months. ich and edema volumes on ct were measured using a semi-automated threshold based approach and phe expansion rate was the difference between initial and follow-up phe volumes divided scale (gcs), ich volume, intraventricular (ivh) volume, edema (phe), and phe expansion rate from baseline to first follow up ct scan before decompression ( h window). at discharge, patients with higher morbidity (mrs > ) exhibited higher ich volume (p = . ) and phe volume (p = . ) on admission ct and a trend for greater rates of phe expansion (p = . ). these differences were not significant at months and when adjusted for ich volume. plots suggest an association between higher phe rate and lower bi scores at months. phe may have a clinically significant impact in patients with cerebellar ich at time of discharge, but these results are limited by a small sample size. these results warrant further studies and suggest therapies to ameliorate edema may be a treatment option for cerebellar ich. yahia thrombolysis and adjunctive stent retriever thrombectomy (srt) is associated with better perfusion and outcomes. despite benefit, % to % of patients had poor outcomes. thrombectomy in ais with lao within hours is performed as secondary after iv thrombolysis, which may be associated with delay. the purpose of our study is to evaluate the safety, feasibility, recanalization rate and outcome of primary str within hours without intravenous thrombolytic in ais from lao. srt as an alternative to iv rtpa. consecutive patients who underwent primary srt for lao within patients with lao; mean age . ± . years and mean nihss ± ; chose primary srt after informed consent. near complete (tici b in ) complete (tici in ) was observed in all ( %) patients. recanalization from symptoms and groin puncture was . ± . and . ± . minutes respectively. immediate post-thrombectomy, hour and day nihss score was . ± . , . ± . and . ± . respectively. asymptomatic perfusion related hemorrhage developed in patients ( %). days outcomes; mrs %, mrs . %, and mrs . %. our study demonstrates that primary srt in ais from lao occlusion is not only safe and feasible, but associated with complete recanalization and good outcome. further study is required. currently, no reliable predictive tools are available to determine which patients with a large hemispheric infarction (lhi) will progress to cerebral herniation (ch). we sought to determine whether continuous measurements of blood pressure variance (bpv), heart rate variance (hrv), and entropy within hours of admission would enhance the ability to predict future ch in lhi patients. patients presenting within hours of onset from an internal carotid artery (ica) or middle cerebral artery and november . patients with ch were matched : by age and nihss with patients who did not have ch. shannon entropy and standard deviation were used to measure the instability of hr and between groups. a model predicting ch utilizing the admission factors of age, gender, nihss, intraarterial (ia) therapy, and thrombolysis was compared to an admission model enhanced with bpv, hrv and entropy hours after admission. data from patients were analyzed (median age years old, median nihss , % women). there were no differences in the proportion of patients with a left hemisphere syndrome ( %), undergoing ia therapy ( %) or thrombolysis ( %) between groups. ch was observed a median of days after the ictus. at hours after admission, median measures of bpv, hrv and entropy were significantly higher in the ch group (p< . ). a model of admission factors enhanced with physiologic data was better able to predict ch than a model with admission factors alone (roc: . v. . , p= . ) poster early recognition of which patients with large hemispheric infarction (lhi) will develop malignant cerebral however, the early time-course of edema has not been adequately studied. we applied volumetric in the first hours, prior to development of midline shift (mls). we identified lhi patients with scans within six hours of onset and subsequent scans early ( - while all recently published endovascular stent-retriever randomized clinical trials (rcts) were positive, their designs differed considerably particularly with regard to the extent of intravenous rt-pa use prior to thrombectomy. here, we assessed whether rt- we adapted a method previously published by us to develop a pooled outcome model relating percent utilization of rt-presenting > , subjects and a range of - % utilization of rt-pa. we correlated percent rt-pa and baseline - ) and mortality. this model includes ± p<. statistical interval surfaces to assess whether a trial's outcomes surpasses the variability of the pooled sample (neurology : - , ) . stent retriever rcts were compared against the model. the mrs model showed excellent fit: r-square= . , p< . . each stent retriever trial's outcomes exceeded mrs improvement varied dramatically according to %rt-pa, with the greatest improvement in those with % rt-pa use. when we included all case series and testing their outcomes at their baseline nihss and percent rt-pa use, shortest overall treatment times also related to improved outcomes (p=. ). mortality trends were similar in that lowest mortality was seen in those trials with highest rt-pa use and the trial with higher than expected mortality had the lowest rt-pa use. an outcome model including % iv rt-pa permitted analysis of stent-retriever therapy compared to a large sample. best outcomes were related to higher rt-pa utilization and shorter treatment times, suggesting a strong treatment interaction between modalities. based on these results, until studied prospectively, iv rt-pa, if administered rapidly, should not be bypassed prior to thrombectomy. intra-arterial mechanical thrombectomy (iamt) is currently considered the standard therapy for acute thrombectomies performed under general anesthesia (ga) may adversely affect functional outcomes. we report our experiences with iamt performed routinely under ga at the montreal neurological hospital (mnh). this is a retrospective analysis of adult patients admitted to the mnh from january to april with ais from proximal intracranial occlusions of the anterior cerebral circulation. all patients were assessed both clinically and radiologically. forty-two patients underwent iamt for ais. twenty-eight patients were included for analyses ( had procedures under conscious sedation, had missing months assessment). clinical outcomes were (mrs) outcomes (mrs --good and poor outcome groups respectively. sixty-eight percent of the good outcome group received iv tpa, as compared to % in the poor outcome group. patients in the good outcome group were also more % in the poor outcome group]. intraprocedural map drops below mmhg observed in patients in the good outcome group versus non in the poor outcome group. in our small retrospective single centre study about thrombectomy for ais under ga, our -month outcomes are comparable to larger studies where thrombectomies were done under conscious sedation. pending the results of ongoing prospective trials about the use of ga during iamt for ais, our results do not support the reservations derived from recently published retrospective data on the use of ga in this context. conservative initial management of young adults with severe hemispheric stroke in a comprehensive stroke center reduces decompressive craniectomy rates pooled european trial results of early decompressive craniectomy (dc) did not require radiographic mass effect at the time of dc. early surgery for supratentorial cerebral hemorrhage does not improve recovery or survival compared to initial conservative medical management. early vs delayed dc for hemispheric a prospective inpatient neurosurgical database from october to march was queried for neurocritical care admissions for hemispheric - under irb approval. a retrospective chart review was conducted using a structured questionnaire using the electronic medical record. we identified patients who met the inclusion criteria for the pool were managed with medical treatment only (mto) with average maximal septal shift of . mm and pineal shift of . mm. twelve patients ( %) underwent dc with average maximal septal shift of . mm and group, mto, and dc were respectively: mr - % vs % vs %; mr - % vs % vs %, and death % vs % vs %. four patients in the mto group declined dc; died and one survived with mr of . no patients developed brainstem herniation prior to referral for decompressive craniectomy. surgical complications death or survival with severe disabilities. time of recanalization since symptoms is a strong predictor of outcome in patients who underwent stent retriever thrombectomy from middle cerebral artery occlusion. hours since symptoms have not been clearly investigated especially, those with large artery occlusion (lao) and underwent stent retriever thrombectomy (srt) . objective: to identify the predictors of outcome in ais patients from middle cerebral artery (mca) occlusion with large clot burden (lcb > mm) and underwent srt, who recanalize less than hours versus more than hours since symptoms. software was used to analyze the data. ais patients who underwent srt in mca; age . ± . years and mean admission nihss ± . complete (tici ) and partial (tici b) recanalization was observed in . % and . % respectively onset was ± minutes. presenting nihss of . dropped to , and at immediate, hours and days post srt respectively. good univariate analysis, recanalization time, immediate and hours post srt nihss were predictors of outcome (p-value= . , . and . respectively). in multivariate analysis, time of recanalization since symptoms (p-value= . ) and baseline mrs (p-value= . ) continued to be the predictors of good outcome. our study demonstrates that patients with lao from mca who recanalize less than hours of symptoms onset have good chance of good outcome compared to those who recanilize more than hours. therefore, all ais patients with lao should offer early srt to achieve a good functional outcome. further studies are required. jennifer a. frontera. neurological institute, cleveland clinic, cleveland, oh, usa. prospectively collected data of heartmate ii (n= ) and heartware (n= ) lvad patients from a single blood stream infection [bsi]), specific pathogens mann-whitney u, chi--wise logistic regression analyses. of patients, lvad infection occurred in ( %) including: bsi in ( %), wound infection in infect p< . ). driveline and wound infection were not a - . , associated with bsi (aor . , %ci . - . , p= . ). there was no association with any specific infectious pathogen. precautions to mitigate i demonstrate a causal relationship. the frequency of dysphagia is greater than %. the early clinical evaluation of swallowing disorders can help define approaches and avoid oral feeding, which may be detrimental to the patient. the aim of this study was to identify predictive clinical factors associated with enteral tube feeding in acute ischemic our database were reviewed. clinical early ct score (asp association. of the patients, used enteral feeding tubes ( . %). the mean age ( . years -sd . ), mean gcs ( . -sd . ), mean nihss ( . -sd . ), and aspect score ( . -sd . ) were significantly higher in the tube group. logistic regression showed that only age (odds ratio [or], . ; % confidence interval [ci], . - . . p= , ), nihss score (or, . ; % ci, . - . , p= , ) and nihss (dysarthria) subscore (or, . ; % ci, . - . , p= , ) were independent predictors of enteral tube feeding. a - in conclusion, combining information about age, nihss, nihss subscore, may be a useful predictor kyushu university, fukuoka, japan. tissue plasminogen activator (te designed and developed an information and communication ipads, pcs, and bigdepartments before the patient's arriva number of calls is reduced. we compared the number of times that emergency room (er) nurses called for computed tomography (ct) or magnetic resonance imaging (mri) between before and after the system introduction. before this system, er nurses called for ct or mri an average . and . times, respectively; after system introduction, the average number of times decreased to . and . , respectively. therefore, this system -pa. also, it automatically records the transitions between could improve treatment times for iv tclinical trial to confirm the tool's efficacy. an important and controversial issue of peri-(est) is the management of sedation and airway. according to retrospective data the widely favored intubation and general anesthesia (ga) appears associated with worse functional outcome compared to "conscious sedation" (gs) in the non-intubated state. siesta is a prospective, monocentric, outcome assessor-blinded, : randomized, parallel-group interventional study comparing non-intubated vs. intubated patients receiving est for acute ischemic endpoint is the improvement of the national institute of health s enrolment of the intended patients has been completed. sixty of the recruited patients are female these patients, % received pre-procedural rtpa. seventy-eight patients were randomized to cs, ( %) of these had to be converted to ga during the procedure. we will present preliminary results of the study, including the primary endpoint improvement in nihss after hours and selected secondary endpoints. the aim of this study is the prospective randomized investigation of potential advantages of the non- in young chung. departments of neurology , seoul national university bundang hospital, seongnam, korea, republic of. cerebral edema during therapeutic hypothermia us hypothermia. the authors retrospectively reviewed patients with large hemispheric infarction who were treated with therapeutic hypothermia and hyperosmolar therapy from to . patients who were dead or underwent hemicraniectomy was defined as failure of therapeutic hypothermia. infarction size was measured as sum of restricted area in diffusion weighted imaging which were performed on admission. b -ct was carried out regularly after onset of therapeutic hypothermia. shift of septum pellucidum, pineal gland and choroid plexus calcification were measured in b-ct. seventeen patients were enrolled after exclusion of patients whose b-ct was inadequate to evaluate. ten patients were successfully treated with therapeutic hypothermia (group success, n= ). six patients were dead and patient had hemicraniectomy (group failure, n= ). initial infarction size between two groups was not significantly different. both septum pellucidum shift (sds) and pineal gland shift (pgs) were significantly different in groups on . ± . days after onset of therapeutic hypothermia (mean sds . vs. . mm ; mean pgs . vs. . mm). specificity and positive predictive values for the failure calcification shift was not significantly different in groups during therapeutic hypothermia. degree of progression of cerebral edema on . ± . days after onset of therapeutic hypothermia helps to excellent in predicting fatal outcome. the main limitation of this study include its retrospective singlecenter nature, which may limit generalizablility of the study. aminocaproic acid for reversal of tissue plasminogen activator (tpa) related hemorrhagic transformation in acute ischemic stroke. -thrombolytic ich. aminocaproic acid (aca) inhibits binding of plasminogen to fibrin, hence inhibiting fibrinolytic property of tpa. there is limited report a case series of aca use for reversal of post-tpa ht. we reviewed the and identified patients treated with iv tpa. patients with post-tpa ht who received iv aca were identified. data on demographics, clinical characteristics, nihss, ich score, new thrombotic events during hospitalization, and hospital and intensive care unit (icu) length of stay (los) were collected. a total of patients developed post-tpa ich, of which received aca. % of patients were male, mean age of . ± . years. patients received tpa within a mean time of ± minutes from symptom onset, pre-tpa mean nihss was . ± . . mean time for ht after tpa administration was . ± . hours, with a hematoma volume of . ± . mm . in addition to aca, % received cryoprecipitate, % platelets, and % fresh frozen plasma transfusions. % of patients had no hematoma expansion and % developed a new thrombotic event. mean hospital los was ± days and mean icu los was ± days. at the time of discharge % had an mrs of , % mrs and % mrs . in this retrospective case series % of patients had hematoma expansion despite receiving aca, while % had a new thrombotic event. further research is warranted to determine the utility of aca for the treatment of post-tpa ht. large vessel occlusion (lvo). while studies have analyzed difference in blood clot constructs, limited data is available understanding the effect of prior anti-platelet use on endovascular therapy (evt) for ias patients with lvo in the middle cerebral artery (mca). we aimed to determine if prior anti-platelet use had effect on evt procedure time, recanalization rate, and functional outcome measured by the modified a retrospective chart review was conducted of consecutive ais patients who underwent evt of lvo of mca at the university of kansas medical center from - . outcomes were measured using total procedural and fluoroscopy time, procedural recanalization score using the modified thrombolysis in cerebral infarction score (tici), time to recanalization, incidence of sich, and -month mrs. univariable and multivariable analysis were performed. . for all) were similar between antiplatelet use versus those without. in separate multivariable models (adjusting for all significant variables), antiplatelet use was not associated with tandem ica occlusion, total procedure time, fluoroscopy time, good recanalization, or -month mrs. no impact was found of prior antioutcomes in ais patients undergoing evt. these findings should be further confirmed in a larger database and prospective cohort study. the study evaluated the effect of a neurology-specific heparin infusion protocol with more frequent ptt monitoring and a narrower goal ptt range ( . x normal) on rate of hemorrhagic or thromboembolic events. this is a retrospective cohort study evaluating patients before (october -september ) and after (october -september ) implementation of a neurology-specific heparin infusion protocol. all patients > years old receiving intravenous heparin with a diagnosis of acute ischemic st evaluated for inclusion. primary outcomes are time to first therapeutic ptt and time to therapeutic ptt range. secondary outcomes include rate of intracranial hemorrhage, rate of thromboembolic events, protocol compliance, number of subtherapeutic and supratherapeutic ptt values, time to initiation of oral anticoagulation, duration of heparin infusion, and number of heparin titrations. time to therapeutic ptt range was . hours in the pre-protocol group (n= ) and . hours in the post-protocol group (n= ) (p= . ). number of ptt values per patient was . in the pre-protocol group and . in the post-protocol group, of which . % and . % were therapeutic, respectively. percentage of supratherapeutic ptt values was . % and %, respectively (p= . ). time to first ptt, time to first therapeutic ptt, and percentage of subtherapeutic ptt values were not significantly different. assessment of secondary clinical outcomes is ongoing. our neurology-specific heparin protocol resulted in a faster time to therapeutic ptt range with a higher percentage of therapeutic ptt values and fewer supratherapeutic ptt values. investigation regarding change in incidence of hemorrhagic and thromboembolic complications is ongoing. hospital moyses deutsch, in the southern city of são paulo is indicated for the use of rtpa intravenously ctive to demonstrate experience the use of intravenous retrospective study, in all cases of isch to february . protocol indicates the use of alteplase patients with inclusion criteria, the period between the onset of symptoms and hospital admission up to . hours and no contraindication to the use of thrombolytics, nihss calculated on admission and hours after thrombolysis. computed tomography (ct) on admission and after hours.evaluation required by neurological telemedicine hospital israelita albert einstein shortly after the conclusion of the tc cranio. trough has been triggered in cases. time between onset of symptoms and drug administration, patients less than minutes, patients between and minutes, patients - minutes .the average nihss at admission was , with patients showed a reduction of or more the points nihss score within the first hours. patient non-symptomatic intracranial hemorrhage and symptomatic intracranial hemorrhage and deaths during the period. all patients receiving alteplase in the recommended time interval and underwent ct cranio control. some cases were not triggered by the evaluation of neurology telemedicine. there was improvement in nihss score similar percentage observed in reference studies. the protocol implementation has been adequate excellent support of telemdicina neurology team. good profitability of time and therapeutic efficacy. the mortality that correlated with the severity of patients and the nihss admission. this data ratifies the intracerebral hemorrhage (ich) is approximately % and non-ich bleeding over %. hypofibrinogenemia occurs in approximately % of tpa-treated patients and i cryoprecipitate is often used to restore fibrinogen levels, despite limited published evidence. cryoprecipitate has several limitations, including the need for abo matching, thawing, and concerns regarding potential transmission of viral pathogens. riastap, a purified fibrinogen concentrate, is a promising alternative to cryoprecipitate for the reversal of hemorrhage post-tpa. the objective of this study was to evaluate the safety and efficacy of riastap for the treatment of post-tpa hemorrhage. a single-center retrospective observational analysis was conducted to evaluate patients who received riastap for the treatment of postmeasure was reversal of hypofibrinogenemia. hypofibrinogenemia was defined as a fibrinogen level < hospital mortality. eleven patients were included in our analysis. the average dose of riastap administered was , units. five patients had hypofibrinogenemia prior to riastap administration, with a mean fibrinogen level (iqr to ). the six patients who were not hypofibrinogenemic at baseline had minimal effect on fibrinogen levels post-- . to ). one patient was diagnosed with a deep vein thrombosis days post-riastap administration and no infusion reactions were reported. in-hospital mortality occurred in . % of our patient population. riastap administration successfully and safely treated hypofibrinogenemia in patients with post-tpa hemorrhage. casey catheter-associated urinary tract infections (cauti) are the most prevalent hospital-acquired infections (hai), and account for more than , cases annually and , deaths per year. cauti is the most common hai in neuroscience intensive care units ( immobility and urinary retention. we implemented a team-driven multimodal quality improvement initiative to reduce cauti and catheter-utilization rates in the nsicu. we convened a multidisciplinary cauti prevention team including nurses, advance practice providers, physicians, and infection control specialists. we developed a cauti surveillance program that involved review cauti and catheter utilization rates. we applied root cause analysis to target improvement opportunities, and implemented interventions including best-practice catheter insertion techniques, modification of bowel regimen, and guidelines for timing of catheter removal. we also implemented a daily goals tool to prompt standardized team communication surrounding catheter removal on morning interdisciplinary rounds. we performed poisson generalized linear model analyses, controlling for linear time trends and testing with sandwich errors. we analyzed data before and after implementation of interventions, spanning a time period of months. -- . ), as did mean catheter days per -- . ). we observed a % reduction in cauti rate adjusted by catheter days ( % ci %, %), p = . . there was an % reduction in catheter utilization rate adjusted by patient days ( % ci %, %), p = . . a team-driven multimodal approach to cauti reduction resulted in significant decreases in cauti and catheter utilization rates in the nsicu. team-driven interventions enhance communication and shared -up is ongoing to evaluate sustainability. non-neurological complications involving a single or multiple organ systems during intensive care in critically ill patients of traumatic brain and spine injuries is significant cause of poor prognosis but often not well managed. the aim of this study was to assess the frequency of such complications in neuro icu and assess their impact on morbidity and mortality. a prospective observational study on patients of varied demographic profile admitted in neuro icu over a period of months for injury and associated multisystem involvement was conducted. significant predefined parameters addressing the non-neurological complications occurring during their icu stay were recorded including disturbances and bleeding complications. the study period was from admission to the icu till the discharge from the icu or demise. % of patients developed respiratory complications in the form of chest infiltrate ( %) and atelectasis ( . %). . % of patients suffered from cardiovascular complications. % of patients had dyselectrolytemia, commonest being hypernatremia due to hypovolemia ( %). sepsis was observed in . %. bleeding diathesis and acute renal injury were observed in % & . % of patients respectively. % of the patients succumbed to injury out of which . % was due to non -neurological cause. further results will be discussed in detail with inferences at the meeting. intensivists in neuro icu must consistently assess and treat the non-neurological complications in traumatic brain and spine-injured patients and deliver appropriate care to bring down the mortality and morbidity and improve outcome. neurocrit care ( ) :s -s transcranial doppler (tcd) is a useful ancillary test in neurologic critical care for monitoring patients at with elevated intracranial pressure and cerebral vascular resistance. the normal values of cerebral blood flow velocity and pis are significantly distorted by nonpulsatile blood flow, as in patients on venoarterial extracorporeal membrane oxygenation (va-ecmo) circulation. this analysis evaluates changes in pi measurements in patients on va-ecmo following cerebral vasodilation, vasoconstriction, increased intracranial pressures, or cerebral circulatory arrest. data from tcds in patients on va-ecmo in the cedars sinai medical center cardiac surgical icu were reviewed. mean pis were calculated for each patient using gosling's pi formula. the values obtained were compared with ejection fractions (ef) obtained within hours of tcd. pis were globally low or absent in all tcds. the non-demonstrable pi seen in one patient is from severely diminished cardiac function, resulting in tcds were performed at the initiation and conclusion of va-ecmo cannulation. the pi values for these tcds correlated directly with changes in efs. also, an abrupt rise in pi to normal value was seen with placement of a total artificial heart and return of pulsatile circulation. we demonstrate that patients on mechanical circulatory support demonstrate low-absent pis on tcds. ion or cerebral circulatory arrest. moreover, rising pis in patients with improving cardiac function should not be confused with elevated intracranial pressures. venous thromboembolism (vte) prophylaxis in underweight patients with neurologic injury remains unaddressed by recent guidelines and primary literature. this study aimed to describe vte prophylaxis strategies employed in this population and compare the impact of underweight and non-obese patients on thrombotic and bleeding events. underweight and non--care unit from september , to july , were retrospectively identified. underweight was defined as a body -obese as a bmi . excluded if they received > vte prophylaxis regimen, had an icu length of stay < hours, or received vte prophylaxis for < hours. patients were stratified to non-obese and underweight groups and subsequently matched : , on age and diagnosis. prophylaxis regimen, prevalence and type of the most common regimen in the underweight (n= ) and non-obese (n= ) groups was unfractionated (ufh) units subcutaneously every hrs ( . % vs. . %; p= . ). only underweight patients received ufh units subcutaneously every hrs ( . % vs. . %; p< . ). non-obese and underweight patients had no difference in the proportion of overall bleeding ( . % vs. . % p= . ) and thrombotic events ( . % vs. . % p= . ) while receiving vte prophylaxis. further analyses revealed a statistically significant difference in the proportion of underweight patients that developed intracranial hematoma expansion while receiving prophylaxis versus non-obese patients arge dispositions were seen between groups. current practice does not reflect a consistent dose reduction for neurologically-injured, underweight patients. caution should be considered when using increased doses of ufh in neurologically-injured patients. continued assessment of vte prophylaxis is needed to confirm these findings. patients in the neuro intensive care unit (nicu) commonly need vasopressor infusions for various reasons. the traditional approach is to insert central venous catheters (cvc) for this purpose. cvcs carry among others. phenylephrine is a commonly used vasopressor in the nicu. the purpose of this study was to evaluate the safety of phenylephrine infusion through peripheral intravenous catheter (iv). retrospective review of consecutive patients admitted to the neuro icu and administered phenylephrine infusion through peripheral iv line. one hundred patients, mean age years (sd ± ) were included in the analysis. fifty-four ( %) were men. eightydisease. the most common indications of phenylephrine were hemodynamic augmentation ( %), multifactorial transient post-operative hypotension ( %) and hypotension due to other causes ( %). most common location of iv line was proximal upper extremity ( % antecubital, % forearm) with gauge of the iv line between ( %) and ( %). average maximum rate of phenylephrine infusion duration of hours (sd ± , range to ). central line was eventually placed in % due to physician preference and in another % due to a change of vasopressor to norepinephrine. there were any complications. infusion of phenylephrine through peripheral iv appears safe when used in moderate doses for the short term and can be considered in lieu of placing a central line solely for this purpose. this may reduce the complications associated with central lines. osmotic therapy continues to be standard care in the medical management of cytotoxic cerebral edema. the long term use of monotherapy is often limited by side effect profile. the combination of low dose mannitol and hypertonic saline may provide synergistic effect by combining mechanisms of action, while limiting dose-related toxicities of either agent. we investigated safety and efficacy endpoints for combination therapy. a single-center retrospective cohort study from august to december . identified patients were administered combination mannitol and hypertonic saline for > hour duration. the primary outcome criteria, sodium fluctuation, and central pontine myelinolysis. patients (mean age ± , % male) were identified. underlying neurological injury included % brain injury. % had neurosurgical management. the average number of mannitol doses given was , and the average duration of hypertonic saline was hours. the range of mannitol dose was . - . percentage of osmotic therapy doses were held for pred mannitol, % held hypertonic saline). aki occurred in ( %) patients ( -stage aki, -stage central pontine myelinolysis. low dose combination osmotic therapy was tolerated with no central pontine myelinolysis and rare sodium fluctuations; however transient low grade aki was common. further study is needed to evaluate the relative efficacy of single and combination osmotic therapy in the neurocritical care population. clinical characteristics of nonconvulsive status epilepticus diagnosed by simplified continuous eeg monitoring at an emergency intensive care unit. the clinical characteristics of nonconvulsive status epilepticus (ncse) presenting in icu in japan is limited. our institute provides a noninvasive monitoring system of two-channel simplified continuous eeg (seeg) for the bedside monitoring of cerebral activities. the present study aimed to elucidate the clinical characteristics of ncse in patients with altered mental status (ams). this single-center retrospective study comprised patients who were hospitalized between march , and september , at the emergency intensive care unit (icu) of the kagawa university hospital. primary outcome was the ncse incidence. the secondary outcome was the comparison of duration of icu stay, hospital stay, and a favorable neurological outcome (fo), as assessed using the tal between the groups with and without ncse. fo and poor neurological outcomes (po) were defined as mrs scores of - and - , respectively. simplified continuous electroencephalogram (seeg) was monitored in patients (median age, years; . % males) with acute ams. ncse was observed in ( . %) of the patients with ams. rates of fo, duration of icu stay, and hospital stay were not significantly different between the ncse and non-ncse groups (p = . , p = . , and p = . , respectively). approximately % of the patients with ams admitted to emergency icus developed ncse. the outcomes of ams patients with and without ncse did not differ significantly when appropriate medical attention and antiepileptic drugs were initiated. seeg monitoring may be recommended in patients with ams in emergency icu to obtain early detection of ncse followed by appropriate intervention. approximately , people per year will need mechanical ventilation secondary to neurological injury resulting in significant mortality. delaying liberation in neurologically impaired patients otherwise ready for liberation is a source for significant hospital charges. there is no clear guideline to suggest one spontaneous breathing trial (sbt) over another in predicting the liberation success. zero pressure support and zero positive end expiratory pressure (peep) or zeep is a traditional method assessing patient's readiness for mechanical ventilation liberation. however, neurologically injured patients with was to assess mechanical ventilation liberation in patients who failed zeep and subsequently passed pressure support trial. retrospective analysis of liberation in intubated patients in a neurosciences intensive care unit. all patients were initially challenged with zeep. if passed, patients were liberated from mechanical mcnemar's exact test. p value < . was considered significant. adult (> years old) patients were included. the majority of patients were successfully liberated from mechanical ventilation using minute zeep trial alone (n= , . %). eleven ( . %) patients failed . %) required reintubation. ten ( . %) this study shows that the majority of patients can be successfully liberated from mechanical ventilation successful liberation from mechanical ventilation. neurocrit care ( ) :s -s vancomycin establishey using nonmem software by the department of pharmacy of nanjing drum tower hospital in neurosurgical intensive care unit patients. according to the patient's gender, age, body weight, serum creatinine (scr), serum albumin (alb), the actual measured value. during the period from march to march , patients including male and female, whose age is ± years old ( - years old), were grouped and copies of blood concentration of vancomycin were measured. the average concentration was . m the actual measured value (r= . , p< . ), the mean absolute percentage error (mape) was . . neurosurgical intensive care unit patients for drug value prediction and drug dosage guidance. but because of coma, the body weight estimation has errors (about %). the renal function sometimes changed by contrast agent and diuretic drug has an impact on predictive results. by adjusting methods, accurate prediction rate increased to nearly %. xi liu-deryke, sindhuri s. avula, jason j. vilar. florida hospital orlando/pharmacy department, orlando, fl, usa. little data exists concerning clevidipine in this population. large variations in bp during the first hours is an independent predictor for poor outc aneurysmal subarachnoid hemorrhage (asah) admitted to neuroscience intensive care unit from january through december were identified retrospectively. patients were included if they received clevidipine or nicardipine for initial acute bp management, and bp goal was defined by the prescribers. bp variability was measured by standard deviation (sd) of mean arterial pressure (map) over the first hour of therapy. seventy three patients were included in the analysis (clevidipine n= ; nicardipine n= ). admission and % asah. baseline map between clevidipine and nicardipine group was comparable ( vs. mmhg). the number of bp recordings was similar between groups (clevidipine vs. nicardipine ; p= . ) and the average time to goal was minutes and minutes, respectively (p= . ). the average map during the first hours was similar (clevidipine vs. nicardipine mmhg; p= . ). although not statistically significant, clevidipine group had a higher percentage of bp above goal compared to nicardipine group ( . % vs . %; p= . ). there was no significant difference in bp variability between clevidipine and nicardipine group (sd . vs. . mmhg; p= . ). our study did not find a difference in bp variability between clevidipine and nicardipine following acute long corrected qt interval (qtc) has been associated with malignant ventricular arrhythmias specifically present in neuro intensive care unit (nicu) patients. in addition to medical causes, acute neurologic insult has been shown to cause multiple neuro-cardiac manifestations including qtc prolongation. prevalence ge and surgical icu patients which have different disease processes compared to nicu. retrospective review of consecutive patients admitted to the neuro icu and having abnormal qtc interval. ninety-five patients, mean age years (sd ± ) were included in the analysis. fifty four ( %) were men. average duration of hospitali ( %), subdural hemorrhage ( %), and cerebral hemorrhage ( %). fiftycardiovascular disease, % had abnormal ejection fraction. thirty-seven patients ( %) needed abnormalities were observed throughout the hospitalization and patients frequently received qtc prolonging drugs. mean qtc was ms (sd ± , range - ). there were episodes ( %) of nonsustained ventricular tachycardia which did not lead to any immediate consequences. one patient had cardiac arrest following anesthesia for hemicraniectomy. initial rhythm was asystole followed by fine ventricular fibrillation and therefore could not be clearly attributed to prolonged qtc. there were no episodes of tdp. -sustained ventricular tachycardia was observed without leading to cardiac arrest. no episodes of tdp were observed in these patients. deep venous thrombosis (dvt) of the lower extremities is a common cause of morbidity and mortality among neurologically injured patients. the data on incidence and prevalence rates of dvt among high medical or surgical intensive care unit with very limited information on patients in neuro-intensive care units (nicu). the aim of the present study is to assess the incidence and prevalence of deep vein thrombosis among patients admitted with acute neurologic injury. our institution routinely conducts ultrasound screening within hours of admission and -month period. data was abstracted and analyzed to assess the prevalence of dvt in this period. we excluded patients presenting with superficial vein thrombosis, hematoma and chronic venous scarring. over a period of one year; the prevalence of dvt was . % (n= ). of the cases that were diagnosed with dvt; more than one-half ( . %) presented with dvt at the time of admission. patients ( . %) acquired dvt during hospitalization. majority of the patients with dvt at the time of admission are caucasian males with mean age and mean saps ii score of . , ranging between and . prevalence of dvt at the time of presentation to the neuro icu is relatively high. further research is s neurocrit care ( ) :s -s practice guidelines recommend that practitioners should not prescribe prolonged prophylactic systemic antibiotics (ppsa) after neurosurgical procedures, even if drains are left in place. we sought to evaluate ) current practice patterns related to ppsa administration to neurosurgical patients with drains and devices and ) practitioner perception about the need for ppsa in this population. we surveyed members of the neurocritical care society on use of ppsa (defined as maintenance antibiotics after the time of insertion) and personal perception about the need for ppsa in patients with intraparenchymal monitors, subdural drains, subgaleal dra -pratt spinal drains, and lumbar drains. of respondents, routine institutional use of ppsa was reported by fewest respondents reported use with subgaleal drains and the most respondents reported use with -pratt spinal drains with instrumentation. respondents had varying personal opinions on the need while the lowest ( %) was for patients with subgaleal drains. it is on the use of ppsa in patients with neurosurgical drains is necessary to optimize patient care. transition to comfort measures only (cmo) in an intensive care unit (icu) is a common but delicate process that requires a well-organized multi-disciplinary and multi-professional care model. the goal of this survey was to understand potential deficiencies and inconsistencies in the transition to cmo in order to develop a process to improve the quality of care provided to patients at their end-of-life. after obtaining irb approval, a web-based questionnaire was distributed to attending physicians, residents, fellow trainees, bedside nurses, respiratory therapists and spiritual care team members, who deliver care to patients in neurological, medical, trauma-surgical, and burn intensive care units at the university of washington's harborview medical center. overall survey response was . % ( out of ). the concept that transition to cmo is a multidisciplinary process was not universal with only . % of all bedside nursing and respiratory therapists feeling invited and actively engaged in the discussion about cmo. the majority of respondents ( %) encountered at least one 'less than ideal' transition to cmo. deficiencies identified included gaps d interprofessional conflict ( . %). most participants ( %) agreed that a formalized process might reduce round the transition to cmo. we identified several barriers towards an optimal, collaborative transition to cmo in icus at a large academic medical center, highlighting the need for a formalized process. such a process would ensure communication between various disciplines and professions, and offer healthcare providers opportunities for dialogue to address all the issues resulting in a smooth transition to cmo. dexmedetomidine's propensity to cause bradycardia is well documented in non-neurocritically ill patients. e units (icu) when defined as heart rate (hr) < bpm. neurocritically ill patients have been excluded from all randomized trials. the aim of this study is to assess the development of bradycardia in patients with neurologic injury who have received dexmedetomidine for sedation in the icu. was done via nursing driven protocol with no loading doses. primary outcome was the incidence of bradycardia (hr < bpm) during first administration. secondary outcomes were percent decrease in hr from baseline and time to event analysis using cox regression. mortality in the icu was collected. a total of patients were included ( % male, mean age years, mean saps ii ). the most bradycardia occurred in patients ( . %). the average maximum dose was higher in patients who infusion duration did not vary. baseline hr was lower in bradycardic patients ( ± bpm vs. ± bpm, p= . ) and a larger mean percent decrease in baseline hr was observed ( . % ± . vs. . % ± . ). median time to first bradycardic event was hours [ . - . ] which was significantly impacted by baseline hr (hazard ratio . ; % ci, . - . ; p= . ). mortality was significantly lower in patients who developed bradycardia, . vs. . % (p= . ). these data indicate that bradycardia associated with dexmedetomidine occurs considerably among the neurocritically ill. future assessment of clinicall development would further contribute to the limited data of dexmedetomidine use within this patient population. medical complications after subarachnoid hemorrhage. medical complications occur frequently after subarachnoid hemorrhage (sah). their impact on outcome has been previously described, but was not validated in international series of sah. we evaluated consecutive patients admitted to a tertiary hospital in brazil with sah from january - ) at discharge. we calculated the frequency of medical complications according to prespecified criteria and eva of poor outcome. thirty-six% had a poor outcome; mortality was . %. the most frequent complications were hyperglycemia ( %), fever ( %), pneumonia ( . %), hypotension (< mm hg systolic) treated with vasopressors ( . %) and venous thromboembolism ( . %). hyperglycemia (odds ratio [or], . ; % confidence interval [ci], . - . ; p= . ) significantly predicted poor outcome after adjustment for age and hunt-hess grade. hyperglycemia affected more than one third of patients with sah and was significantly associated with poor functional outcome. critical care strategies directed at maintaining normoglycemia may improve outcome after sah. s neurocrit care ( ) :s -s blood pressure (bp) can be measured in critically-ill patients using non-invasive (oscillometric) blood pressure (nibp) and intra-arterial blood pressure (iabp) monitoring. the accuracy of nibp compared to the "gold standard," aibp, has been questioned. nibp monitors generally tend to over-read at low values and under-read at high values compared to iabp. previous studies exploring nibp-iabp correlations have generally been performed on patients not receiving continuous infusions of vasoactive medications. since many critically-ill patients receive vasopressors and antihypertensive agents, we wanted to study the relationship between simultaneously-measured nibp and iabp recordings in this patient population. we prospectively identified patients (n= , target n= ) admitted to a neurosciences icu, who had simultaneous iabp and nibp monitoring while receiving intravenous infusions of manually abstracted via retrospective chart audit. covariate and demographic variables were also abstracted and entered into an electronic spreadsheet. statistical analysis performed using sas v . . initial results from subjects ( % caucasian, % male, mean age . years, mean bmi . ), observations. independent-samples t-tests showed a significant difference between nibp vs iabp readings: ([sbp: m= vs mmhg respectively; p mmhg ( . %)]. bland-altman plots demonstrated good inter-method agreement between nibp-iabp measures (when visually excluding outliers) and -aibp sbp differences at higher blood pressures. preliminary analysis indicates a statistically significant difference between nibp-iabp readings for patients on vasoactive medications. yet when visually excluding outliers, there is good inter-method agreement. data from the entire cohort will be available for presentation at the ncs annual meeting and will be helpful in choosing appropriate bp monitoring methods for patients on vasoactive infusions. new-onset refractory status epilepticus (norse) is an important syndrome often associated with a poor outcome. the aim of the present study was to review norse cases in our hospital and to determine the main factor that may improve patient outcomes. we retrospectively reviewed our hospital medical records and database of electroencephalograms (eegs) over a years period (may -may ). in our facility, we performed -h continuous eeg monitoring using the international - system. of the monitored patients, we excluded those who were meningitis, herpes encephalitis, and history of epilepsy. we discussed their causes and neurological outc (go) was defined as a mrs score of - , whereas a poor neurological outcome (po) was defined as a score of - . moreover, we attempted to determine the main factor that influenced the neurological outcomes. we identified patients who had undergone eeg, and identified six norse patients among them. the on arrival was . all patients were diagnosed with limbic encephalitis and all had nonconvulsive status treatments, such as steroids, were delayed in all po patients. on the basis of our data, the cause of all norse cases was limbic encephalitis. in po patients, definitive treatments, such as pulse steroid therapy, were delayed. this is a relatively small study. further research is needed to identify the factors which could improve outcomes. multi-drug resistant organisms (mdro) are an increasing concern in health systems. pathogens such as pseudomonas aeruginosa, acinetobacter baumanii, and carbapenamase-producing enterobacteriaceae hold highest mortality rates especially when the central nervous system is involved. when mdros are cultured treatment options are becoming limited and reliance on medications such as colistin and aminoglycosides is becoming more prevalent. however, penetration of these therapies into the central nervous system is concerning therefore local administration is a potential concomitant therapy. this study was a retrospective chart review from to for all patients with documented mdros who received intraventricular colistin. seven patients from to met inclusion criteria. the average age of the patients included was years old, were males, and the median length of intensive care unit stay was days. the dose of colistin used for each patient was mg via intraventricular route. the duration of therapy ranged from - days and all cerebrospinal fluid cultures were sterile at days after administration of colistin. each patient received concomitant systemic antibiotics while receiving intraventricular colistin. six of the seven the use of intraventricular colistin was not associated with any reported adverse events. the use of intraventricular colistin was associated with positive clinical outcomes with no reported adverse effects. myasthenic crisis: epidemiology, economics and opportunities for change -a single center retrospective analysis. avinash b. kumar, vikram v. tiwari, kevin k. scharfman, justin j. calabrace. vanderbilt university medical center, nashville, tn, usa. myasthenia gravis (mg) patients are admitted to the icu for myasthenic crises characterized by immunoglobulin (ivig) or plasmapheresis and supp and care flow maps of patients admitted to our institution this is an irb-approved, retrospective cohort study of patients admitted to a tertiary neuro icu. we included adult (age > years), with a diagnosis of mg who received plasmapheresis or ivig therapy. the demographics and clinical data were summarized for patients in the ivig and plasmapheresis cohorts. we also compared the icu and hospital los and in addition the hospital cost data for patients in both cohorts. the final cohort included hospital encounters for individual patients ( female) admitted between - . the mean age on admission was . ± . y. there was no significant difference between c ventilation; the median duration of mv was . d (range - ). the median readmission rate was . ± . . ). patients had multiple crisis readmissions (> ). this cohort was socially challenged ( divorced, analysis included patients ( in ivig cohort and in plasmapheresis cohort). the mean hospital costs (variable direct-technical) in ivig cohort was approx. $ more than the plasmapheresis cohort. there was no statistically significant difference between in the limited financial analysis. . % of patients were either medicare or medicaid patients, . % wer the disease burden on patients and hospitals of this orphan condition are significant and continues beyond the icu. evidence based care pathways need to be explored for the management of this high resource utility disease. botulism is a rare potentially fatal and treatable disorder caused by a bacterial-produced toxin that affects the presynaptic synaptic membrane resulting in a characteristic neuromuscular dysfunction. it is caused by either the ingestion of the toxin or the bacteria, inhalation, or wound infection. we present our we report consecutive cases of botulism presenting to university medical center of el paso. medical records where reviewed to obtain demographic information, clinical presentation, treatment and outcome. in popping and had abscesses in the administration areas. by history the most common %, ophthalmoplegia %, ptosis %. interestingly enough, in those patients with the documentation the pupils were reactive in %. all patients required mechanical ventilation and all were treated with the trivalent antitoxin. thirteen patients were disc derivatives (mostly -monoacetylmorphine and -monoacetylmorphine) was associated with the development of botulism. its presence in the us-mexican border is not surprising since is frequently produced in latin america. its association with the development of botulism should be recognized early to allow a prompt diagnosis and treatment with the antitoxin. a clinical feature worth noting is the presence of normal pupillary light reflex in nearly half of patients thus a normal pupillary response should not be used as a finding to exclude botulism. in clinical trials limits the discovery of effects that may be particularly relevant to underrepresented populations. clear iii, a presented an opportunity to evaluate african american (aa) enrollment. investigators across u.s. hospitals screened , patients over a -year period: % aa; . % asian; . % native american; . % pacific islander; . % white; . % mixed race; and . % not reporting. the mean age for aas was younger at . (sd: . ) vs. . (sd: . ) for whites (p= . ). the randomized-to-screened ratio for aas was . vs. . % for other racial groups (p< . ). higher . %, p= . ); northeast ( . % vs. . %, p< . ); south ( . % vs. %, p= . ); and west ( . % vs. . %, p=nonsignificant). african americans were less frequently excluded due to non-hypertensive etiology ( . % vs. %, p< . ), not having ventricular drainage ( . % vs. . %, p= . ), dnr status ( . % vs. . %, p= . ) and unstable bleeding ( . % vs. . %, p= . ); and more frequently excluded for prior disability ( % vs. . %, p= . ), larger hemorrhages ( . % vs. . %, p= . ), and by investigator decision ( . % vs. . %, p< . ). of the patients who refused consent, aas accounted for . % vs. . % of whites. in an unadjusted logistic model, the odds ratio for successful enrollment of aas was . (p< . ) vs. whites, and . (p< . ) after adjustment for age and hispanic ethnicity. the age < , - and - subgroups maintained higher adjusted odds ratios than whites at . (p< . ), . (p< . ) and . (p< . ) respectively; the above subgroup was not significantly different. others have reported difficulty enrolling aas into clinical trials. clear iii suggests this may be a misperception s neurocrit care ( ) :s -s pipeline that utilizes machine-learning algorithms to integrate clinical data and quantitative eeg (qeeg) trends, providing continuous estimation of prognosis. a collaboration involving two academic centers in the u.s. assembled a retrospective clinical and eeg database of adult subjects with cardiac arrest and return of spontaneous circulation who underwent continuous eeg monitoring. four qeeg features were included in the model: regularity, tsalis entropy, alpha-to-delta ratio, and voltage < uv. only the first hours of eeg data were evaluated in this analysis. poor outcome was defined as cerebral performance category of - at discharge. ten fold cross validation resampling method was utilized, and model performance evaluation metrics were area under roc curve (auc), sensitivity, and specificity. the algorithm provided an hourly estimation of poor clinical and eeg data was available for a total subjects. mean age was . years and overall mortality was . %. one hundred and twenty subjects ( . %) had poor outcome. our multiparametric qeeg method achieved optimal performance for mortality prediction at hours (auc . ), with a sensitivity of % and specificity of %. optimal poor outcome prediction performance was achieved at hours (auc . ), with a sensitivity of % and specificity of %. at a false-positive rate of %, the sensitivity for poor outcome was %. alpha-delta ratio and voltage < uv were independently associated with mortality and poor discharge outcome at hours (p< . ). employment of machine-learning methods in qeeg analysis allows early and robust outcome prediction in cardiac arrest. this approach has potential to facilitate real-time individualized prognostication in cardiac arrest. secondary brain injury may be a significant barrier to survival following extracorporeal membrane oxygenation (ecmo) for, otherwise reversible, cardiorespiratory failure. prevalence of brain injury phenotypes on neuroimaging were described in our prior wor neurological injury on outcomes in adult patients on ecmo. a retrospective cohort of ecmo-treated adults. clinical and outcome data was obtained from electronic chart abstraction of clinical and physi of decannulation. % (n= ) of ct scans and % (n= ) of mris had abnormal findings. intracranial hemorrhage was seen in % patients with neuroimaging. in addition, % of mris revealed diffuse significant difference in survival to hospital discharge and mean modified with or without neuroimaging during ecmo ( % vs. %, p= . ; mrs, . ± . vs. . ± . , p= . ). however, in the group undergoing neuroimaging, normal scans were associated with better survival to hospital discharge ( % vs. % p< . ) and lower mrs ( . ± . vs. . ± . , p= . ). ( . %) of survivors who did not get neuroimaging and ( %) of those who got neuroimaging achieved abilty to perform independent adl at discharge (p= . ). all patients with ability to perform independent adl in neuroimaging group had normal scans. ( %) of survivors who did not get neuroimaging and ( %) of those who got neuroimaging were discharged home (p= . ). all surviving patients in the neuroimaging group who were discharged home had normal scans. secondary brain injury in ecmosurvival and functional outcomes. a prospective study has been planned to better understand mechanisms mediating this effect. neurocrit care ( ) :s -s re-verse ad is an ongoing, phase , cohort study evaluating the extent to which idarucizumab, a humanized fab fragment specifically reverses dabigatran's anticoagulation effect in patients with serious bleeding or requiring urgent interventions. dabigatran is a direct acting oral anticoagulant approved for -valvular atrial fibrillation and venous thromboembolism treatment and prevention. in re-ly, dabigatran and mg bid were associated with significantly lower annualized rates of intracranial hemorrhage (ich) than warfarin ( . %, . % and . %, respectively). nonetheless, the mortality rate with ich in the context of any anticoagulation remains high, probably reflecting the effect of hematoma expansion. whether idarucizumab improves clinical outcome in dabigatran-treated patients this analysis of the first patients enrolled in re-verse ad focuses on patients with ich. patients presenting with ich were given intravenous idarucizumab g as two . g bolus infusions administered effect, based on central laboratory determination of dilute thrombin time (dtt) or ecarin clotting time (ect). we compared the clinical outcome of this re-verse ad interim analysis with dabigatran-treated ich patients in re-ly. in this interim analysis, patients with dabigatran-associated ich were enrolled in re-verse ad. complete reversal of anticoagulation was observed by dtt and ect within minutes of idarucizumab administration. preliminary results from this interim analysis indicate that the mortality rate of ich patients re-ly. idarucizumab reversed anticoagulation in ich patients and appears to improve mortality rates in dabigatran-treated patients with ich versus historical controls from re-ly. results from additional patients in re-verse ad will provide further information on the effects of idarucizumab reversal in patients with ich. ****permission was not granted to print this abstract**** s neurocrit care ( ) :s -s callie electroencephalography (eeg) has clinical and prognostic importance for comatose survivors of cardiac arrest. recent interest in quantitative eeg (qeeg) analysis has grown. the qualitative effects of sedation ing effects of sedatives on qeeg are poorly characterized in anoxic injury. we hypothesize that sedation would decrease amplitude-integrated eeg would predict neurological recovery. we routinely monitor comatose post-arrest patients with eeg for this prospective study, we included consecutive eeg-monitored patients who had protocolized sedation interruptions, excluding those with contraindications to interruption such as seizure or hemodynamic instability. we used persyst v to quantify sr, aeeg, and adr and calculated medians for min immediately prior to sedation interruption and the last min of interruption. we used nonparametric tests to determine if the qeeg signal changed pre-to post-and whether this differed by outcome (cerebral performance category - at hospital discharge vs - ). of screened subjects, met inclusion criteria (median age years, % male). sedation regimens varied ( propofol; fentanyl; midazolam). median duration of sedation interruption was min, and did not differ by sedative type. pre-interruption, higher adr and aeeg and lower sr predicted favorable outcome. post-interruption, sr decreased (median change - . , iqr: - . to ), aeeg increased ( . , (p= . ), but aeeg and adr changes did not differ by outcome. in acute anoxic brain injury, sedation increases sr and decreases aeeg. larger decreases in sr with sedation interruption predict worse outcomes, which may reflect a susceptibility of deafferentated cortex to suppress in response to sedation. ashley r. hedges, gary g. davis, brianne b. wolfe, erin e. lingenfelter, gregory g. hawryluk, safdar s. ansari. university of utah hospital and clinics, salt lake city, ut, usa. for patients presenting with subarachnoid hemorrhage (sah) or traumatic brain injury (tbi), levetiracetam has begun to emerge as a preferred alternative to phenytoin for seizure prophylaxis following initial presentation. however, the optimal dose of levetiracetam has not been determined. a retrospective review of electronic medical records identified patients that received levetiracetam for seizure prophylaxis for sah or tbi in a level one trauma center from may , to october , . the goal of this research was to quantify the combined seizure incidence (including both clinically observed seizures and those confirmed by electroencephalogram) in patients receiving levetiracetam mg twice daily compared to levetiracetam > mg total daily dose. among patients captured, % were male, with a mean age of years old. for patients receiving seizure incidence was observed, . % vs . %, in patients receiving levetiracetam mg twice daily this was observed despite no difference in potential confounders, includ trend towards increased levetiracetam failure rates was observed in the lower dosing scheme of mg twice daily. t electroencephalograms ordered ( vs , p= . ). no difference in adverse effects were observed our project suggests that patients may benefit from a standardized levetiracetam dosing scheme of mg twice daily. treating intraventricular hemorrhage (ivh) with a fibrinolytic (ivf) therapy such alteplase via a catheter is becoming an increasingly popular intervention. with the conclusion of the clear iii trial a larger cohort of patient data is available to update past meta analyses. mortality and good functional outcome after thrombolytic treatment was reviewed in patients with hypertensive ivh. a literature search was performed from to march to collect all literature on ivh treatment with ivf. seventeen papers meeting our inclusion and exclusion criteria were collected for further analysis. ivh patients with vascular abnormalities and traumatic injuries were excluded. mortality and functional outcome was assessed to compare ivf treated and control groups in all publications. there was a significant difference in mortality favoring the treatment group at days, days and days ( %ci, . - . ; p= . ; %ci, . - . ; p= . ; %ci, . - . ; p= . ). pooling mrs and gos good functional outcomes, there was a significant difference favoring the treatment group at , , and days ( %ci, . - . ; p= . ; %ci, . - . ; p= . ; %ci, . - . ; p= . ). there was a non-significant trend in mrs scores favoring the treatment group. a significant difference in gos score favoring the treatment group was found at , , , and days ( %ci, . - . ; p= . ; %ci, . - . ; p= . ; %ci, . - . ; p= . ; %ci, . - . ; p= . ). treatment of hypertensive ivh with thrombolytic may improve functional outcome and reduce mortality compared to control groups as early as days, a trend that continues to days for mortality and days for functional outcome. different effect sizes are generated when different functional outcome tools, such as mrs and gos, are used. an aging population and increasing use of anticoagulants and antiplatelet agents to prevent ischemic hematoma (ssdh) and sdh related to trauma (tsdh). we sought to study the association of antiplatelet agent and warfarin use in sdh patients admitted to our neurosurgical icu. warfarin were studied. neurosurgical methods of sdh evacuation and re-evacuation were studied as well as hemostatic factors such as international normalized ratio (inr) within the first hrs, blood products and hemostatic agents given to reverse coagulopathy or antithrombotic effects. demographic information such as age, gender and comorbidities were noted and indication for antithrombotic agent. we excluded major trauma (level ) associated with sdh at our center. from january to may , we admitted sdh patients, of which . % required evacuation ( -> , mean = . ), and on ( %) underwent redo evacuation (range in days -(date range - days). hour inr rates in warfarin related sdh were all < . except for . of these , only one patient required re-operation. mort in our patient population, sdh was associated with a need for evacuation in . % of all patients, of which a higher rate of reagents. mortality was also higher in the warfarin associated sdh patients. consecutive patie complications were prospectively enrolled. medical critical care attendings (micu), neurocritical care attendings (nicu), residents (res), and nurses (rn) predicted the following: ) -month functional -month quality of life (qol). patients were followed up at months and their functional status and qol were compared to the predicted values. functional outcomes were dichotomized to good (mrs - ) vs. poor (mrs - ). (of ) patients had -month mrs predicted by all provider groups. fifty-four ( %) patients had good outcome and ( %) had poor outcome. the micu, nicu, res, and rn providers had similar predictive values ( % ci) for accurately predicting good outcome ( % ( - ), % ( - ), % ( - ), and % ( - ), respectively). nicu was most accurate in identifying poor patient outcome, % ( - ), followed by micu % ( - ), rn % ( - ), and res % ( - ) (p= . , . , and < . , respectively). when patients who transitioned to comfort measures only (n= ) were excluded from the analysis, the nicu team was more accurate at predicting poor outcome. fifty-three survivors had qol predicted by all provider groups. the accuracy of qol predi neurocritical care attendings are better than healthcare providers without neurological training at predicting poor -month functional outcome in neurocritical care patients. however, the overall predictive accuracy for -month mrs and qol was similar between healthcare provider teams. there are significant limitations in providers' ability to predict long-term functional outcomes. patients with severe acute brain injury (sabi) raise important palliative care considerations associated with sudden, devastating injury and uncertain prognosis. the goal of this study was to explore how family members, nurses and physicians experience the palliative and supportive care needs of patients with sabi receiving care in the neurosciences intensive care unit (neuro-icu). design: semi-structured in-person interviews were audiotaped, transcribed, and analyzed using thematic analysis. setting: thirty-bed neuro-subjects: forty-seven interviews were completed regarding patients receiving care in the neuro-icu with family members (n= ), nurses (n= ) and physicians (n= ). hope varied depending on the par away, generally in the process of conveying prognosis, while families expressed hope as an action that supported coping with their loved one's acute illness and its prognostic uncertainty. ( ) participants described the loss of personhood through brain injury, the need to recognize and treat the brain-injured patient as a person, and the importance of relatedness and connection, including personal support of families by clinicians. in their pursuit to recognize and preserve personhood, physicians used stories from patients and families to inform them about patient identities, while nurses focused on providing supportive, empathetic care to patients and families. support for hope and preservation of personhood challenge care in the neuro-icu as identified by families and clinicians of patients with severe acute brain injury. specific practical approaches can address these challenges and improve care to meet the needs of patients and families in the neuro-icu. despite increasing evidence that early mobilization strategies are effective, we showed patients were not adequately mobilized in two argentinean hospitals. we implemented a progressive-mobility protocol and examined its feasibility, safety and applicability in our neurocritical patients. prospective observational implementation study of a progressive-mobility protocol for neurocritical patients admitted to icus of two university hospitals in argentina. all patients were evaluated twice daily for level of movement and clinical stability. patients progressed as tolerated from passive movement implementation baseline to icu patients admitted in months - after implementation began (two month start-up phase not analyzed). there were pre-implementation patients with assessments ( % post-operative, % traumatic -implementation patients with measurements ( % postpopulations: median age years ( % ci - ), nearly % were men. mobilization was . times - . ) after protocol implementation. two thirds of pre-implementation patients ( . %) were not mobilized compared with only . % post-implementation (p< . ). among mechanically ventilated patients, . % of pre-implementation assessments showed no mobilization vs. . % post. post-implementation patients with an endotracheal tube had a lower rate of mobilization ( . %) than ventilated patients with a tracheostomy ( . %). passive movement, turns and full assistance to sit up and transition out of bed to chair was achieved for . % and . % achieved higher levels ( , , ) . mobility sessions with the physical therapist were < minutes in % of the cases. no mobility-related adverse events occurred. mobilized following protocol implementation. this prospective study demonstrated that early and progressive mobility among neurocritical care patients in argentina is feasible and safe. psychiatry, geriatrics, and oncology have adopted comprehensive approaches to predict outcomes accounting for important constructs such as spirituality and resilience. critical illness often occurs as a sudden catastrophic event leaving patients with significant long-term cognitive, behavioral and neurological disturbances. impact of resilience and spirituality on recovery in this setting has not been investigated. we have designed a study to validate two important scales, connor davidson resilience scale- and brief rcope spirituality scales for surrogate responders. hours with one or two surrogate responders will be included. this prospective cohort study will collect demographic, laboratory and radiographic data in a redcap database. for every patient enrolled, the cd-risc-and a behalf, themselves, and for each other. each patient will complete two resilience and two spirituality scale cd-risc and three spirituality scales . the scales will be administered to the patient ,if possible, prior to discharge; at months and at months. if patient ing followup. cars study has screened patients in days, enrolling patients. common diagnoses include subarachnoid hemorrhage ( ), cns malignancy ( ), intracranial hemorrhage ( ), unruptured aneurysm ( ), subdural hematoma ( ). based on current enrollment, this unique methodology for surrogate validation of scales is feasible. by august , an anticipated subject will be recruited. surrogate validation of quantitative measurements of resilience, spirituality can provide new insight into prognostication and patient centered critical care. active family engagement in the intensive care unit (icu) could improve patients' and families' experience with care, interactions with the healthcare team, and outcomes. this study examined the perceptions and attitudes of family members regarding increased engagement with passive mobilization of neurocritical care patients. an educational video on passive mobilization of icu patients was developed to engage family members to participate as valued members of the healthcare team. an anthropologist and a nurse or physician (study team) invited family of neurocritical care patients in an academic medical center icu in argentina their perceptions of engagement with care. a multidisciplinary team ( mds, rns, anthropologists) completed the analysis. thirty-two family members ( % female) of icu patients participated. the study team observed and the family participants reported to be positively surprised by: the format of learning by video that was different from how they usually received daily information; the information in the video was more detailed than anything previously taught; the invitation to watch the video and engage in patient's care was new and unexpected as was the opportunity to provide opinions on how to improve the video instruction. a newly authorized them to touch the patient and participate in care. they reported increased hope about prognosis and perceived an improved relationship with the healthcare team. only one family member considered the video irrelevant. family members' attitudes and perceptions toward this low cost approach to engagement were positive. this approach to teaching and engagement may help humanize the complex icu environment. - % of americans believe in the concept of miracles. we hypothesize that a belief in miracles leads to consultation rate of palliative care. addressing a patient or family's belief in miracles and understanding what a miracle signifies early in the neuro- the critical illness resilience and spirituality (cars) study is a prospective cohort study currently -icu at mount sinai hospital with an expected length of stay of at least hours and surrogate responders. as part of the study, all recruited patients and their families primary outcome is tracheostomy and peg tube placement. secondary outcomes include length of stay, full code status, and palliative care consultation. these groups will be matched with regards to the disease specific sever regression will be used to compare rates of the primary and secondary outcomes. the cars study has screened patients screened and enrolled patients so far. of those enrolled, the most common diagnoses include subarachnoid hemorrhage ( ), cns malignancy ( ), intracranial hemorrhage ( ), unruptured aneurysm ( ), subdural hematoma ( ). this is an ongoing study, we anticipate recruiting patients by the end of august, . belief in miracles could potentially influence continuation of aggressive measures in a shared decisionparadigm in the neuro-icu. mary m. barden, teddy t. youn, carolina c. maciel, sonya s. zhou, david d. greer. department of neurology, yale-new haven hospital, yale school of medicine, new haven, ct, usa. withdrawal of life-sustaining therapy (wlst) for predicted poor neurological outcome is a common cause of death among post-cardiac arrest patients. recent guidelines recommend against wlst before hours post-arrest. early wlst perpetuates a self-fulfilling prophecy that may contribute to premature death in some patients who otherwise would have survived with good neurological recovery. a retrospective cohort of resuscitated cardiac arrest patients from january to march at a single tertiary academic medical center was reviewed. patients were evaluated for outcomes at hospital discharge and (when applicable) the timing of and reason for wlst. prognostic indicators including clinical examination, electrophysiology, and neuroimaging were analyzed and findings were compared to day of wlst. of patients, ( %) had wlst due to perceived poor neurological prognosis. median day of wlst for this reason was post-arrest day . when stratified according to treatment with targeted temperature management (ttm), the median day of wlst remained day for both ttm-treated and non ttm-treated groups. of patients with wlst, the phrase "no chance for meaningful recovery" was used in documentation for ( %), mri results were cited as indicative of poor neurological prognosis for ( %), and pupillary light reflex was present day post-arrest (or day post-complete rewarming) in ( %). in a retrospective cohort of resuscitated cardiac arrest patients, wlst for predicted poor neurological outcome was the most common cause of death. the median day of wlst was post-arrest day . many patients with wlst had present pupillary reflexes on day post-arrest (or day post-complete wlst in the setting of indeterminate prognostic indicators undermines accurate neurological prognostication of post-cardiac arrest patients and perpetuates a self-fulfilling prophecy of poor outcome. brain injury global hypoxic ischemic brain injury (hibi) is a major cause of death and disability worldwide. invasive monitoring of brain function enables goal-directed treatment strategies that optimize cerebral physiology, reduce secondary brain injury (sbi), and potentially improve outcomes. we report a series of patients with hibi where intracranial monitors were placed to guide clinical management. retrospective analysis of patients with hibi cared for at a large academic center over a year period. all patients received therapeutic hypothermia (th) to °, continuous eeg monitoring, and had a bundle of invasive monitors placed through a multi-lumen cranial bolt. the full bundle consisted of an icp monitor, brain oxygen (pbto ) monitor, cerebral blood flow (cbf) probe, and cerebral microdialysis probe. patients received the full bundle, while the others received a partial bundle. patients were treated using a tiered algorithm designed to optimize cerebral physiological parameters. precipitants of hibi included cardiac arrest ( patients), airway occlusion during anesthesia induction ( patient), and hanging ( patient). mean patient age was years. average time between initial injury and probe placement was hours. average duration of monitoring was . days. no adverse events occurred after monitor placement. episodes of deranged cerebral physiology-including intracranial hypertension, brain hypoxia, cerebral glycopenia, metabolic crisis, and reduced perfusion leading to treatment changes occurred in of patients. they occurred up to days after initial injury, and in all cases would have otherwise been clinically silent. of patients died in the hospital. the surviving patients all regained consciousness and were discharged to acute rehabilitation facilities. we did not find invasive intracranial monitoring after hibi appears safe and identifies physiological states associated with sbi. goal directed treatment utilizing multi-modality monitoring in hibi merit further study. is associated with worse patient outcomes; however, it can be difficult to reliably detect. delirium prevention is therefore a potentially beneficial strategy and is most effective in patients who are at high to evaluate whether the advanced practice providers (app's) would both use the dps and also find the dps easy to use. during a --bed neurocritical care unit at a large -stratify consecutive admissions of patients with ais a descriptive statistics. the apps completed a -item questionnaire that included the system usability scale (sus) and open-ended questions to determine the usability of the dps, as well as to assess for facilitators and barriers for the use of the dps. no individual patient data was collected. patients admitted with ais and ich (n= ) were assessed by the app's using the dps. compliance with dps use was of apps (n= ). the sus score ( . ) was mid-point between "acceptable" and "excellent." facilitators and barriers for use of the dps were identified. the dps was easy to use and was consistently used by the app's. adoption of the dps with this patient population can be a first step to identify the most atthis vulnerable population. the intensive care unit is a complex learning environment with variability in a number of external factors. prior studies of neurology residency training in the neurological intensive care unit have focused on general exposure. this study aims to evaluate resident perception of neurocritical care training. an online survey was sent to program directors and neurocritical care members for distribution to neurology residents. the survey consisted of free-text or selection style questions that focus on resident perception of neurocritical training. statical analysis for group differences was completed with t or fisher exact tests a total of responses ( . % response rate) was obtained. of those responders, completed a freetext question regarding needed improvements to neurointensive care training. % responded with needs for educational changes, and these responders did not differ from other responder in average required practitioners ( % vs % p= . ), and neurocritical care attendings ( % vs % p= . ). this is the first study to examine neurology residents' concerns with neurocritical care rotations. there is little neurocritical care educational materials focused to neurology residents, but the emergency assess the neurocritical care educational training priorities during neurology residency are warranted. our institute had several cases of conflict come to light in the evaluation of patients being evaluated for death by neurological criteria. provider understanding and awareness of clinical guidelines was found to be low across all sub-specialties. it was deemed important to follow appropriate procedures based on published guidelines and a standardized process to provide appropriate care for each patient, optimize icu resource utilization and strengthen provider and public trust. due to medical, legal and ethical issues involved , an institutional standard was called for . -specialties about discrepancies, we revised the institutional policy to reflect emphasis of educational gaps and reflect the latest published guidelines and practice updates . we created an education module , a standardized template in electronic medical to allow escalation in case of conflicts . the project led to increased participation and satisfaction amongst the clinical providers in the icus when n education source to evaluate patients with a consistent approach based on published practiced parameters. we observed a trend in decrease in length of stay and variance for brain dead patients since donation referrals as well timely initiation and effectiveness of family discussions in irreversibly confirming this is in a survey model. a standard care pathway towards evaluation of patients with death by neurological criteria can be successfully implemented at an institutional level in a tertiary care academic medical center. establishing and maintaining optimal brain perfusion is a crucial endpoint for resuscitation and postcardiac arrest care. a recently fda-approved device that employs laser and pulsed doppler now provides clinicians with the cerebral flow index (cfi), a non-invasive measure of brain perfusion. we sought to determine if cfi provided by the ornim c-flow device can be used as a simple and valid measurement of brain perfusion after resuscitation in cardiac arrest patients. we performed a single-center prospective observational inception cohort study of adult patients with cardiac arrest starting in october . comatose patients with sustained return of spontaneous circulation (rosc) within minutes of maneuvers were included. the ornim cflow was connected as soon as feasible after rosc. clinicians were blinded to cfi values. primary outcome was survival at discharge and secondary outcome was neurological assessment using the cerebral performance categories (cpc) scale at discharge. a total of patients have been enrolled as of may . half ( . %) were out-of-hospital arrests and neurological outcome (cpc or ). mean interval between arrest and start of monitoring was hours with a mean duration of hours. adequate signal was available . % of the monitoring time. mean cfi in survivors was . , compared to . in non-survivors (p value . ). patients with good neurological outcome at discharge also had a higher mean cfi, although the small sample size precludes any conclusion. our results demonstrate that cerebral perfusion monitoring using the ornim cflow after cardiac arrest is feasible. it also suggests that higher cfi might be associated with survival at discharge. as enrollment progresses and more data are collected, further insight on the potential role of cfi as a neuromonitoring tool might emerge. tuberculous meningitis (tbm) is the most devastating form of tuberculosis, yet rates of neurological complications and mortality are uncertain in high-income countries. we used administrative claims data on all admissions at nonfederal hospitals to identify adult patients with tbm in california between -- , and florida between - . our outcomes of interest were mortality and the fo seizure, hydrocephalus requiring a ventriculoperitoneal shunt, vision impairment, and hearing impairment. kaplan-meier survival statistics were used to assess the cumulative rates of neurological complications and death. we identified patients with tbm, of whom . % ( % ci, . - . %) developed at least one neurological complication or died. more than two-thirds of these complications occurred during the initial hospitalization for tbm. individual neurological complications were not uncommon: the cumulative rate of - . %), the rate of seizure was . % ( % ci, . - . %), and the rate of ventriculoperitoneal shunting was . % ( % ci, . - . %). vision impairment occurred in . % ( % ci, . - . %) of patients and hearing impairment occurred in . % ( % ci, . - . %). the mortality rate was . % ( % ci, . - . %). nd death even in high-income countries such as the united states. neuropalliative care in peru: emergence from the conspiracy of silence the development of palliative care in peru remains limited, particularly for non-oncologic services such as palliative and end-of-life care in patients, families, nurses and physicians in a specialized neurological institute in lima, peru. we used a mixed methods approach consisting of surveys and qualitative, semi-structured interviews that were recorded, transcribed and analyzed using thematic analysis. surveys identified a substantial need for palliative care in the neurological institute ( % of doctors and of do emerged from qualitative interviews evolved around communication about end-of-life choices in neurologic disease. knowledge about advance directives was limited among both clinicians and families, and prognosis, and who should tell them. however, the perception that a physician should be honest, and that suffering and pain should be avoided at all times was unanimous. barriers to transparency in patientphysician communication included ( ) expectation of cure with medical treatment; ( ) families' trust in god training in communication, symptom management and end-of-life care; and ( ) a paternalistic culture. participants identified several challenges specific to palliative care in neurologic disease. in a country without a palliative care training program and no legal basis for advance directives, families and clinicians are emerging from a culture of silence about serious diagnoses and end-of-life care choices. our findings emphasize the need for palliative care education for neurology providers and the public in peru. a trained physician must perform the brain death examination in a systematic fashion in order to recognize and prevent potential sources of error. given the infrequency at which brain death presents in a hospital setting, clinicians may not always have the opportunity to observe a brain death examination during their training. in this study, we plan to evaluate the effect of medical specialty and expertise on documentation errors. we performed a retrospective chart review of brain death examinations between jan. to july st at the university of pittsburgh medical center presbyterian. physician specialty and training level, documentation errors, and confirmatory tests such as cerebral blood flow (cbf), electroencephalography (eeg), and computed tomography angiography (cta) were collected from medical records. exams. ams carried out. the most common completion of documentation by at least one examiner. attending physicians, residents and fellows were responsible for % ( neurology and neurosurgery residents have limited exposure to the brain death examination. regardless communication with patients and their families is of central concern in healthcare. however, evidence shows that it is often poorly addressed, especially at times of rapid health status changes and periods of clinical uncertainty. acute neurological emergencies pose an inherently unique challenge in communication. while emerging studies have addressed communication gaps and strategies to improve them in various critical care settings, none have assessed this issue in acute neurological emergencies ongoing irb approved prospective observational study in a bed neurocritical care unit in tertiary care academic medical center all patients admitted to the unit and all clinical providers participating in their care screened for inclusion. direct observation of discussions between clinical providers and families by a questions addressing the satisfaction, understanding of treatment options, impact on health care decisions and ways to improve communication five patients have been enrolled in the study, so far. the results are analyzed for concordance between tween answers is considered between all participants for general satisfaction with the communication (as well as family's understanding of treatment options explained to them by the physician. some disagreement on the impact of the discussion on health care decisions. qualitative domains identified by families as areas of good ical radiographic images. domains identified as needing improvement included explanation of medical circumstances and need for private room for discussions. we observed general satisfaction with communication. further enrollment will help elucidate any definitive areas of improvement and impact of communication on health care decisions. laith maali, sheema s. khan, mahmoud m. ismail, rhys r. brooks, vishnumurthy v. shushrutha hedna. the university of new mexico, albuquerque, nm, usa. cerebral venous thrombosis (cvt) usually accounts for < in their demographics, etiology, clinical features, radiological presentation, and mortality have not been previously explored. a systematic search was performed for publications in pubmed usi thrombosis", "cerebral vein thrombosis" and "cortical vein thrombosis". a total of relevant studies were abstracted with strict selection criteria and a total of patients' data were used for the final analysis. linear correlation was used for our descriptive analysis. cases reported were europe- , asia- , north america- , africa- , australia- and south america- . overall male to female ratio was : . , among clinical characteristics headache was the most common symptom and hematological factors were the most common etiology. location of the thrombosis was described mostly in the transverse sinus. intercontinental differences in relation to demographics, etiology, clinical features, radiological presentation, and mortality were identified. cvt can have significant disparity in their demographics, etiology, clinical features, radiological presentation, and mortality when compared from one continent to another. it is important for the worldwide physicians to recognize these differences and to follow the most recent guidelines, diagnostic methods and treatment to insure the best outcome and prognosis. timely communication is critical for high quality care in the intensive care unit(icu). published literature in surgical icus quotes up to % of patient caregivers receive prognostic information with mean prognostic interval . ± . days since icu admission prognostication in acute neurological injuries is challenging and uncertainty may delay communication. we assess occurrence and timeliness of goals of care communication in a neurocritical care unit prospective observational study by surveying nurses in a bed neurocritical care unit in tertiary level eriod. data was also collected during daily morning multidisciplinary huddle and verified by verbally surveying the nurses. survey results were analyzed for patients and patient encounters. in . % encounters , the nurses felt the patient's treatment plan matched patient-centered goals of care in . % encounters, a provider family discussion had occurred in the last hours. within the st hours of icu admission, . % patients were identified to need goals of care discussion in the multidisciplinary huddle, only . % had such a discussion. for patients needing goals of care addressed, a discussion occurred on an average . ± . days since icu admission. dichotomized by age, . % patients younger than years old had a discussion , if one was needed, while only % older than years had one. when dichotomized by gender, . % of males and . % of females had a provider discussion. . % females compared to % of males received a discussion on goals of care if identified as needed within st hours of icu admission. our data shows timely communication of goals of care in the neurocritical care unit with a mean time comparable to published literature. however, there appear to be demographic disparities that warrant further research. cerebral vasomotor reactivity reflect prognosis after cardiac arrest sungeun lee. ajou university school of medicine / department of neurology, suwon, korea, republic of. neurological prognostication after cardiac arrest is a difficult problem. since several studies reported good effect of target temperature management (ttm), prognostication after cardiac arrest was delayed and became complex. recently, some reports presented that impaired cerebral autoregulation was correlated with neurologically poor outcome. the aim of this study was to determine whether vasomotor reactivity (vmr) test by transcranial doppler (tcd), reflecting cerebral hemodynamic status, affected accuracy of neurological prognostication in post cardiac arrest patients. since january , patients were enrolled after cardiac arrest. patients who performed vmr test during ttm period were included and patient with unstable vital sign or malignant findings in brain ct, such as massive subarachnoid hemorrhage or severe brain edema, or poor temporal windows. primary outcome was cerebral performance category scale (cpc) at discharge. vmr test used breath-holding method during seconds. carbon d analysis. other conventional prognostication test, such as eeg, sep, et al., was performed after hours from rewarming time. we divided patients between good (cpc - ) and poor (cpc - ) outcome group and compared results from prognostic test between two groups. potential, and electroencephalography after hours from rewarming time were presented favorable results in good outcome group. (p< . ) vmr during breath-holding technique during ttm period also was more increased in good outcome group at right ( . ± . % vs. . ± . %, p< . ) and left ( . ± . % vs. . ± . %, p< . ) middle cerebral arteries. the present study shows that vasomotor reactivity is preserved in patients with neurological good outcome. to evaluating cerebral hemodynamic status by vmr test seems to be useful tool for early prognostication after cardiac arrest. michelle l. lozano, susan s. yeager. the ohio state university wexner medical center, columbus, oh, usa. as the numbers and opportunities for advanced practice providers (apps) in neurocritical care units (nccus) has increased, the integration of these providers into the health care setting has become a greater challenge. currently no data exists to support h comfort levels before and after completion orientation. this prospective, pre and post observational study was sent to newly hired nccu apps within an academic medical center. a one hundred-item survey was created to evaluate self-reported experience cus. baseline data was collected from each app. next, apps were integrated into the nccu utilizing a three month orientation program which fused a series of didactic, simulated, and precepted experiences. after e survey tool. student's t test statistics were utilized to compare before and after experience and comfort levels with items identified as necessary to perform in the nccu app role. as utilization of apps in the nccu becomes more prevalent, integration processes need developed to practice. a structured approach enables identification of high priority areas to assist with initial and and comfort levels. results indicate that further education and exposure to items such as neurologic imaging may be helpful. limitations of this study include subjective data from a small, self-reported, single institutional sample. further research of larger, more diversified sample representation is needed to validate whether these results can be generalized to other nccus. yasuhiro kuroda, kenya k. kawakita, toru t. hifumi. department of emergency medicine, kagawa university, miki, japan. brain damage after return of spontaneous circulation (rosc) varies among studies and patients despite an established modality enabling proper evaluation. evaluation of brain injury after rosc is needed for the determination of the inclusion criteria of neurocritical care, especially of targeted temperature management. literatures are reviewed and summarized. the association between admission glasgow coma score (gcs) motor score and neurologic outcome after rosc (day ) is an independent predictor of good neurologic outcome at days in patients sustaining out-of-hospital cardiac arrest who receive therapeutic hypothermia: gcs motor score , n= ( . %); score - , n= ( . %); score - , n= ( . %), p< . (hifumi ). recently no significant differences of neurologic outcome at days after hospital admission was observed between mild therapeutic hypothermia and control in the subgroup of gcs motor score or . these data show that initial gcs motor score examination immediately after rosc can at least provide baseline objective prognostic data for decisions by healthcare professionals. neurological signs such as gcs, brain stem reflex, respiratory status, and degree of shivering are potential variables that can be incorporated into a predictive model for a more precise evaluation of brain injury in cardiac arrest survivors undergoing ttm. effect of targeted temperature management should be evaluated depending on the brain injury in pcas. cydni n. williams, jennifer j. wilson. oregon health and science university, department of pediatrics, portland, or, usa. -level estimates of et utilization in pediatric ais, and explore demographic and clinical characteristics, associated interventions, and outcomes. retrospective cohort analysis of the kids' inpatient database evaluated et utilization in children with ais and age > days, identified by diagnosis and procedure codes. analyses were weighted for national estimates and compared with chi-square and t-tests. among pediatric ais patients, ( %) received et. anterior circulation occlusions were seen in % of et patients. et patient age ranged versus %, p<. ) was more common and seizure was less common ( % et versus %, p=. ) in et patients. average age was higher with et ( versus years, p<. ). other patient demographics, hospital characteristics, and critical care procedures were similar. thrombolytic agents (tpa) were common with et ( % et versus % overall). intracranial hemorrhage was similar ( % et versus %, p= . ), and varied by tpa ( % et with tpa, % tpa only, % et only, % neither). there was a nonsignificant trend toward poor outcome (death, discharge to nursing facility, tracheostomy, or gastrostomy) was seen between poor outcome and et ( % et versus %, p=. ). et in pediatric ais is uncommon, utilized mostly in older children and those with paresis. though hemorrhage was uncommon, this data suggests caution with et and tpa combination. associations between et and poor outcome may reflect disease severity bias. more research on outcomes with et in pediatric ais is needed. luis p. lee, michael m. leoncio, balagangadhar b. totapally. nicklaus children's hospital / pediatric critical care department, miami, fl, usa. and cerebral edema is the most serious complication leading to morbidity and mortality. we queried a nationally representative database to determine epidemiologic data of cerebral edema in children with dka. an analysis of the healthcare cost and utilization project's kids inpatient database for the year was performed. the database was filtered using icd- diagnosis codes for dka ( . , . , . , . ) and cerebral edema ( . ) from the age of month to years. we examined these procedures, outcome and mortality rates. sample weighing was employed to produce national estimates. chi-square test, mann whitney u test and binary regression analysis were performed using spss to analyze the data. a total of , patients with dka were discharged during . females were %. racial distribution - ) years. cerebral edema was present in ( . %) children. the overall mortality rate was . %, but the mortality rate in children who developed cerebral edema was higher at . % (or: ; % ci: - ). mortality was higher in children who had a major operative procedure ( . % vs . %; or , % ci: - ) and in those with medicaid compared to private insurance ( . % vs . % p= . ) and lower in number of chronic conditions, and hospital charges were significantly higher among non-survivors but there was no difference in the age. the overall mortality rate in children admitted with dka is . %. cerebral edema prevalence is . % and it increases mortality significantly. mullai baalaaji, sunit s. singhi, muralidharan m. jayashree, arun a. bansal. pediatric intensive care unit, department of pediatrics, pgimer, chandigarh, india. near-infrared spectroscopy (nirs), a non-invasive modality to measure regional cerebral oxygenation (rso ), is being increasingly used to monitor cerebral tissue oxygenation. we studied relationship of rso with cerebral perfusion pressure (cpp) and intracranial pressure (icp) in children with acute cns infections to determine if rso could be used as non-invasive surrogate for cpp. in a prospective observational study we enrolled children, aged < years, with raised icp due to acute cns infections after approval by institutional ethics committee. they were monitored simultaneously for rso of both frontal-- c, covidien-iic), invasive blood pressure, and icp using intraparenchymal fibre-optic catheter (codman). linear trends and correlation coefficients were used to define relation of rso with icp and cpp. a total of paired values of rso , icp and cpp were analysed. the linear trends during the first hours revealed no significant correlation between changes in rso and changes in icp and cpp from baseline (r = . , . for icp and cpp respectively). however, the trend was not uniform - % patients had no correlation between rso and cpp, % showed a positive correlation and % showed a negative correlation. subgroup analysis revealed that strength of correlation between rso and - . ,p mmhg and normal cpp were . ( . - . ,p % respectively. rso has complex interaction with icp and cpp; the changes in icp and cpp could not predict changes in rso . however, the odds for normal cpp was significantly higher when rso > % and this cut-off could be used as a non-invasive target for age appropriate cpp. refractory status epilepticus is persistent seizure activity despite treatment with one first-line and one second-line anti-epileptic medication, while seizure activity > hours is considered super-refractory. functional outcome for children with these conditions is not well defined. this study describes functional outcome for children with refractory and super-refractory status epilepticus proposing that prognosis will be variable with high mortality. survivors will be and technology dependence. this retrospective chart review evaluated children age - years who received pentobarbital infusion at texas children's hospital pediatric intensive care unit from - for status epilepticus. outcome was defined using pediatric cerebral performance category score (pcpc) at time of discharge and at the most recent clinical evaluation per the medical record. additional measures included mortality, need for medical technology (tracheostomy or gastrostomy tube), seizure burden, and number of seizure medications at discharge. children met inclusion criteria. in-hospital mortality was %, secondary to withdrawal of support ( %), brain death ( %), or cardiac arrest ( %). highest mortality occurred in acute hypoxic ischemic injury (p= . ). of survivors, % returned to baseline pcpc at discharge while % demonstrated tracheostomy and children underwent gastrostomy tube placement. seizures persisted at discharge for most patients with no prior frequency. most children required additional home seizure medications. long-term follow-up was documented for survivors up to years after discharge. % demonstrated improved pcpc and % showed decline including additional deaths. mortality in this population was high. functional outcome in survivors was variable. some children returned to neurologic baseline by time of discharge and for those who did not, continued functional improvement was possible over time. their s -injury. in addition to standard anatomic imaging, mr sequences obtained "often or always" included: diffusion--perfusionpediatric tbi subjects received an acute mri within days post-injury. fifteen adapt sites, accounting for over % of adapt enrollment, committed to recruit adapt subjects for a non-sedated mri scan at one year post -tbi. conclusion: collection of - acute mri scans from the subjects enrolled in adapt to study associations between acute mri findings and functional outcome is potentially feasible. allowing for % mortality and % recruitment rate, recruitment of - adapt subjects from adapt sites for a follow-up mri to study relationships between advanced mri measures and neurocognitive function is potentially feasible and would represent the largest such study conducted to date. antimicrobial prescribing practices and antibiotic resistance following neurosurgical drain placement: a single-center observational study andrea j. passarelli, hasan h. alhasani. christiana care health system department of pharmacy, newark, de, usa. the use of systemic antibiotics for the duration of neurosurgical drain placement has not been associated with reduced rates of drain related infection (dri) and may contribute to the development of antimicrobial resistance and clostridium difficile infection (cdi). we sought to describe antimicrobial prescribing practices, incidence of dri, and development of antimicrobial resistance and cdi after neurosurgical drain placement at our institution. this was a single center study including adult patients status post ventriculostomy or ventriculoperitoneal shunt or ommaya reservoir, and use of an antibiotic impregnated drain. bacterial cultures and c. difficile pcr during the index admission and days post-discharge were collected. antibiotic resistance was defined as an organism resistant to the prophylactic agent. prolonged prophylaxis was defined as antibiotics continued for > hours after drain placement. eighty-one patients with drains were included. the median duration of prophylaxis was . days and cefazolin was most commonly prescribed agent ( %). three of patients with evds developed dri. prolonged vs. perioperative prophylaxis. of non-dris % were resistant to the prophylactic agent used. e. coli, k. oxytoca, and s. aureus had higher rates of resistance to cefazolin compared to our institutional antibiogram, although not statistically significant. no patients developed cdi. the use of prolonged prophylaxis was not associated with a reduced reduction in dri. most bacterial isolates were resistant to the prophylactic agent used. we suggest that antibiotic prophylaxis for neurosurgical drain placement be limited to one preoperative dose within minutes of the procedure the objectives of this study are to evaluate our institution's practice for initiating seizure prophylaxis postoperatively and establish a standard of care. adult patients who underwent cerebrovascular surgery from august to july were screened for study inclusion. patients who received lev postoperatively were compared to those who did not receive lev. clinical seizures and data were obtained from retrospective review of electronic medical records. the primary outcome was seizure occurrence in the first days after surgery. secondary outcomes of the patients included in the study, there were in the no lev group and in the lev group. two seizures occurred in the no lev group while no seizures occurred in the lev group ( vs , p= . ). there were no differences between surgery type, intraoperative blood loss or proportion of asah. of the patients with asah, % were not on lev and seizure occurred. of patients with intraparenchymal or intraventricular extension, % were not on lev. average length of stay was prolonged for the lev group ( vs days, p< . ). the majority of patients did not receive lev postoperatively and there was no difference in seizure developing a standardized approach for initiating lev may decrease variability in practices and streamline postoperative care. post-operative pain control after craniotomy: a meta-narrative review craniotomy is commonly performed for the treatment of a variety of conditions including brain tumors, aneurysms, and vascular malformations. despite significant advances in the quality and efficacy of neuroanesthetic care, there are no evidence-based guidelines for the management of post-operative pain after craniotomy. uncontrolled poststay, increased hospital care costs, and poor health-dencebased clinical decision rules, clinicians often rely on institutional or expert-based opinions to guide their decisionon opioid use, there an urgent need to evaluate existing pain management protocols. hence, we conducted a meta-narrative to evaluate heterogeneity in current practices regarding management of postoperative pain after craniotomy. a meta-narrative review was performed utilizing th terms "pain" and "craniotomy". a total of articles and systematic reviews were resulted. inclusion criteria were studies from - , randomized controlled trials, retrospective studies, systematic reviews, case reports, case series published in english were included. of these, articles and systematic reviews were included in the final analysis. there is a paucity of randomized controlled trials to develop evidence based peri-operative pain management protocols in craniotomy patients. there is evidence to suggest that scalp infiltration with local anesthetic may improve post-operative pain scores immediately after surgery. the perioperative use of nonsteroidal anti-inflammatory medications may improve pain scores without a subsequent increase in management of post-operative pain after craniotomy remains a challenging problem for clinicians and patients. there is an urgent need to conduct well designed randomized controlled trials to guide perioperative pain management in craniotomy patients and to use opioid sparing techniques for improving patient outcomes. symptomatic plateau waves are characterized by paroxysmal neurological symptoms suggestive of elevated intracranial pressure such as depressed level of consciousness, pupillary dilatation, and dysautonomia in a patient with an intracranial mass lesion. cli seizures, syncope, or new brain injury. noninvasive cerebral blood flow can be measured using ultrasound-tagged infrared spectroscopy; continuous eeg is sensitive to changes in blood flow. we report two patients without invasive intracranial pressure monitoring who demonstrated changes in blood flow and eeg during symptomatic plateau waves. case series. case was a year-old man with fungal ventriculomeningitis. after a prolonged hospital course, he developed an entrapped th ventricle and began to experience periods of complete unresponsiveness with anisocoria, clonus, and tachy-or bradycardia lasting between and minutes. episodes resolved after decompression and ventricular stent placement. case was a year-old woman with intraventricular meningioma who underwent partial resection with entrapment of the right lateral ventricle. on post-operative day she developed multiple episodes of unresponsiveness, diaphoresis, clonus, tachy-or bradycardia lasting to minutes, culminating in a persistent episode requiring urgent craniotomy. in both patients, ceeg was started to assess for seizures and ornim device was used to characterize blood flow. in each, symptomatic plateau waves were accompanied by decreased blood flow, followed by attenuation of faster frequencies on the ceeg. symptomatic plateau waves may be characterized noninvasively by using surface measurements of blood flow and ceeg. this case series demonstrates that decreases in bifrontal blood flow lead to depressions in ceeg during these symptomatic plateau waves. noninvasive measurement of blood flow in conjunction with ceeg provides an adjunct to invasive icp monitoring in patients with mass lesions at an open--sseefficacy of sage- , a proprietary formulation of allopregnanolone, in patients with super-refractory status epilepti line agents (tlas) while sage-(none attributed by the safety committee to sage- ). post-hoc analyses evaluated the pharmacological effects of sage- and the effect of sage- administration in the context of multiple antiepileptic drugs (aeds), pressors, and tlas. here we examine the hemodynamic properties of sage- in the study patients, with the goal of further understanding the clinical context of sage- administration in this critically ill population. burst suppression we maintenance of the tla. key exclusion criteria were anoxic brain injury and very short life expectancy. at enrollment, patients received an average of . aeds and . tlas with an average status epilepticus duration of . days. hemodynamic measurements (heart rate, systolic and diastolic blood pressure) were collected at screening, pre-dose, during sage- treatment ( , , , minutes; , , , , , , , hours) and followwas examined. twenty-five patients received treatment with sage- . during the study, mean changes in hemodynamic parameters from baseline were limited, both for patients receiving the standard (n= patients) and high (n= patients) sage- dose. regarding hemodynamic parameters, sage- was well tolerated in the srse patients studied, suggesting for further study that sage- may not elicit immediate or sustained hemodynamic changes in srse patients. real-world studies regarding use of benzodiazepines in pre-hospital and emergency department (ed) was to analyze benzodiazepine usage patterns in se by emergency medical services (ems) and the ed of an inner-city hospital. and september to ems and hospital ed were reviewed. the associated outcomes of interest were endotracheal intubation, hospital admission, and seizure recurrence. data was analyzed via descriptive statistics. of patients analyzed, ( . %) had a history of epilepsy. benzodiazepine utilization varied; ems preferred midazolam ( . %) while the ed used lorazepam most often ( . %). benzodiazepine dosages used were lower than recommended; median dose of midazolam administered by ems was only mg and median dose of lorazepam in the ed was mg. patients received . ± . benzodiazepine doses on average. seizure activity was aborted with benzodiazepines alone in ( . %) patients and recurred in ( . %). twenty-three ( . %) patients were intubated, all post-arrival. there was no observed correlation between number of benzodiazepine doses given and baseline characteristics, decision to intubate, or incidence of seizure recurrence. all patients were admitted and ( . %) were admitted to the icu. we observed consistent underdosing of benzodiazepines used for the treatment of se by both ems and the ed. there was lower than expected achievement of seizure cessation and intubation rates were higher than reported in previous studies. further investigation is needed to identify the barriers to optimal benzodiazepine selection and dosing for se patients at our institution. super-refractory status epilepticus (srse) refers to a condition of persistent seizures that have failed treatment with first-, second-and third-line treatments. sage- , a proprietary formulation of the endogenous neuroactive steroid allopregnanolone (a potent positive allosteric modulator of synaptic and extrasynaptic gabaa receptors in animal models), is being developed for the treatment of patients with srse who have not responded to standard treatment regimens. -sse- was an open-label, phase - in patients with srse. the present analysis explores the pk properties of sage- over the course of the trial. sage- was administered as a -day continuous intravenous infusion to patients with srse and receiving third line agents (tlas) for seizure or burst suppression. patients received either a standard dosing regimen (n= ) or a high dose regimen (n= ) and were subsequently weaned off tlas and sage- . the standard dose was chosen, based on a modeling approach, to achieve a mean plasma exposure roughly equivalent to the highest endogenous concentrations measured in the third trimester of pregnancy (~ nm). since women tolerate this endogenous level without apparent adverse effects, mean (sd) steadyand for the high dose regimen wa -state concentrations were approximately dose proportional between the standard and high doses, indicating that clearance was dose-independent of infusion to allow determination of half-life or volume of distribution. in this study of patients with srse, sage- clearance was not dose-dependent and plasma concentrations were in line with target exposures. jennifer a. creed, christa c. swisher. duke university medical center / department of neurology, durham, nc, usa. ****permission was not granted to print this abstract**** seizures after resuscitation from cardiac arrest predict worse outcomes, but there is no evidence that treating seizures improves outcomes. we leveraged existing practice variation to compare the effectiveness of aggressive electroencephalography (eeg) and antiepileptic drug (aed) use to infrequent spot eeg and aed use. we performed a retrospective cohort study including comatose post-arrest patients at two academic centers from - . the same critical care group staffs both, but center uses continuous eeg (ceeg) monitoring and aggressively treats malignant eeg patterns while center uses infrequent spot eegs and rarely treats with aeds. we classified each patient's daily eegs from admission until death, malignant," or "not performed." we abstracted covariates and outcomes from our prospective registry, e rhythm, arrest location, survival to discharge and functionally favorable survival. we used multi-level mixed-effects logistic models to test for an association of center with outcomes after adjusting for eeg and clinical covariates. we included subjects (center : , center : ). center subjects were younger, arrested more often out-of-hospital and had higher illness severity (all p< . ). overall, ( %) center subjects were eeg-monitored (median days (iqr - d)), ( %) had a malignant pattern observed and median of d (iqr - d), ( %) had malignant patterns observed (less frequent myoclonic status epilepticu center comparisons). in multilevel modeling, there was no significant center effect on outcomes. after cardiac arrest, treatment at a center using aggressive ceeg monitoring and aed treatment is not associated with better outcomes at discharge. phenytoin dosing adjustment for obesity may not be necessary effective loading with weight-based dosing of phenytoin for therapeutic levels is necessary in several emergent settings. practices for dosing obese patients, those > . x ideal body weight (ibw) vary, including using total body weight (tbw), adjusted body weight (adjbw; correction factor . ), and the abernathy formula (correction factor . ). our objective was to determine whether dose adjustments were necessary for obese patients. charts were reviewed retrospectively from two tertiary medical centers from september to august . we included all admitted patients older than years of age, initiated on iv fosphenytoin for any reason, with therapeutic post-load level (total phenytoin of -in pre-mean weight-based loading doses were compared for obese and non-obese patients who achieved postload levels in the therapeutic and high therapeutic range (total level - , free . - . ), using welch's two-sample t-tests. a total of patients, non-obese and obese, met inclusion criteria, including non-obese and obese patients who achieved high therapeutic levels, desired for ongoing status epilepticus. the mean -obese and . ( % ci: . , . ) for obese patients (t = . , p = . ). dose to achieve high therapeutic levels was . ( % ci: . , . ) for non-obese and . ( % ci: . , . ) for obese patients (t = . , p = . ). our results suggest that adjustment calculations of fosphenytoin loading dose for obese patients may not be necessary, thus can all patients into high therapeutic range, especially desirable in status epilepticus, while not harmful in other patients. stephen sage- is a proprietary formulation of allopregnanolone. sage- was studied in an open-label nical study of patients with super-refractory status epilepticus (srse). the primary - . - in resolving srse in these patients. to further understand the specific patient and treatment-related parameters which may affect outcomes in this study, we performed a post-hoc analysis on the completed data set. in this open-label, single-treatment with sage- . key efficacy outcome measures were: ) successful wean off of tla(s) after hour ; and ) subsequent successful taper off sage- after hour , without recurrence in the hour period following treatment. a total of patients received open-label treatment with sage-sage- . response rate appeared consistent across varying patient demographics (gender, age, ethnicity) and baseline treatment regimens. overall, % of patients experienced at least serious adverse event (sae) and patients died during the trial. no saes and no deaths were attributed by the safety committee to sage- administration. there was little evidence of a relationship between response rate and patient demographics (gender, -trial supports further investigation of sage- in srse, and can inform inclusion criteria for future trials. the clinical efficacy and safety of sage- in the treatment of srse is being evaluated further in an ongoing phase , randomized, placebo-controlled trial. jocelyn y. cheng. drexel university college of medicine, philadelphia, pa, usa. in catastrophic neurologic injury, withdrawal of care (woc) is often considered. while woc is based on the perception of poor prognosis, the question of whether it creates a self-fulfilling prophecy has been raised. though studied in traumatic brain injury epilepticus (se) is unclear. the goal of this study was to describe the final cause of death in adults with se, and determine the impact and associated clinical characteristics of woc on mortality rates. a single-center retrospective study at an urban academic medical center was conducted between age;gender;glasgow coma scale (gcs);acute physiology and chronic health evaluation-ii (apache-ii);history of epilepsy;etiology of se;refractory se (rse);in-hospital mortality; and cause of death. -tests were used as appropriate. binary logistic regression analysis adjusted for covariates, and p < . was considered significant. of subjects, male, mean age years, there were ( . %) in-hospital deaths, ( %) due to woc. the remaining causes were cardiogenic(n= , %) and respiratory(n= , . %), with sepsis, brain death and seizures individually comprising . %(n= each). excluding woc, in-hospital mortality fell to -group without cardiac arrest (ca), inof which %(n= ) was due to woc; mortality decreased t the total cohort, there was no significant difference in baseline characteristics excepting metabolic seizure were more common in woc subjects. metabolic etiology (or: . ,p= . ) and ca (or: . ,p= . ) remained significantly associated with woc after univariate but not multivariate adjustment. withdrawal of care is a major determinant of mortality in se, and is associated with metabolic dysfunction clinical decision- an open--sse- ) evaluated the safety and efficacy of sage- , a proprietary formulation of allopregnanolone, in patients with super-refractory status epilepticus (srse). entry criteria were designed to maximize patient treatment opportunities. the objective of this post-hoc analysis was to demonstrate sage- activity despite heterogeneity of srse causes and high comorbidity burden. d-line agent (tla; with anoxic brain injury or very short life expectancy were excluded. - years) and mean status epilepticus duration was . days (range - days). probable srse causes included infection, hemorrhage, worsening cgi-s score. all patients required - tlas and - aeds at baseline. up to weans from tlas were sage- at the end of da six patients ( %) died from underlying srse cause or associated comorbid conditions. no saes were attributed by the safety committee to sage- . mean numbers of baseline wean attempts, comorbid conditions, and srse episode duration were comparable between responders and non-responders. activity despite the heterogeneity of cause of srse and comorbidity burden. delayed neurologic deterioration (dnd) from vasospasm is associated with poor outcome after subarachnoid hemorrhage. continuous eeg (ceeg) monitoring has lead to detection of eeg patterns of uncertain clinical significance -ictal-interictal continuum (iica). these have been associated with acute brain injury but variably predict outcome. we describe the types and prevalence of iica eeg patterns in patients who develop angiographic vasospasm and discharge outcomes retrospective study of adult patients with non-traumatic subarachnoid hemorrhage admitted at emory university hospital neuro-icu from january -february who underwent ceeg. ceeg were recorded using - electrode placement and interpretation of the iica eeg patterns using the american clinical neurophysiology society research terminology. in sah patients, ( %) were female and hypertensive ( %). majority had poor grade sah ( % hh grade , % grade and % grade ). moderate to severe angiographic vasospasm were detected in ( %) patients . days after admission. ceeg was initiated . days after admission. periodic discharges (pds) occurred in ( %) patients, ( . %) of which were generalized and ( . %) lateralized. rhythmic delta activity (rda) occurred in ( . %) with ( . %) generalized. stimulus induced rhythmic discharges (sirpids) were seen in ( . %) and electrographic seizures in ( . %) patients. vasospasm was common in patients with any iica patterns ( . % vs. . % p= . ), pds ( . % vs. . % p= . ) and rdas ( . % vs. . % p= . ). rdas were common in patients with discharge mrs - ( . % vs. . % p= . ) and pds were equally seen across all outcomes ( % vs. % p= . ). the observed trends were not statistically significant. iicas such as pds and rdas were common in patients who developed vasospasm but seen equally with a larger sample size is needed to support these findings. ncs and (ncse) have been reported in - % of critically ill patients. whether patients with ncse should be treated as aggressively as patients with convulsive status remains controversial. this study sing on its correlation with patients' outcome and possible predictors. in this retrospective study n= patients underwent ceeg at mount sinai neurological and neurosurgical icu (nsicu). ceeg data according to acns guidelines was collected. outcome was evaluated by mortality, glasgow outcome scale (gos), glasgow coma scale (gcs). we compared seizures were detected in % of subjects and % experienced of cg (p= . or . ci . of cg (p= . , or . , . considering clinical predictors, only gaze deviation and subtle facial movements were significant (p= . or . , p= . , . mortality and mean hospitalization length were not different. outcome was significantly different in nsicu with mean gcs being in ng and in cg (s for p= . ), but was not significantly different at discharge, as mean gos was in ng and . in cg (p= . ). our findings show that patients' history of epil rstand prognostication in these patients. raquel farias-moeller, archana a. pasupuleti, luca l. bartolini, amy a. kao, brittany b. cines, jessica j. carpenter. children's national health system, washington, dc, usa. super refractory status epilepticus (srse) ensues when there is no improvement of seizure control in response to anesthetic therapy or seizure recurrence after reduction of anesthetic agents. there is no consensus on standard of care for srse. ketogenic diet (kd) has reported success but technical challenges exist including inability to feed patients, concomitant steroid use, persistent acidotic states and ur step-by-step approach to initiation and continuation of kd in the picu. patients with srse who had kd initiation in the picu were identified from a prospective neurocritical care database with irb approval. data from the hospital course was supplemented by review of the electronic medical record. descriptive analysis was performed. neurointensivists used our step-by-step guideline to start patients on kd. nine children with srse who had kd initiated in the picu were identified. the mean age was . years (sd . ). median number of days to start kd from detection of seizures was . mean time nine children remained on the kd for months or longer. the median number of aeds trialed before kd was started was [iqr - ] and the median number of continuous infusions was [iqr - ]. after initiation of kd most patients were weaned off continuous we demonstrated the feasibility of a practical approach to initiation of kd in the picu for children with srse. these children were successfully weaned off continuous anesthetic infusions. larger studies, both in children and adults, are needed to determine the effectiveness, safety and tolerability of kd in the management of srse as well as its ease of implementation. although overall mortality of status epilepticus is high, baseline patient characteristics and co-morbidities may help to predict outcomes and shape treatment decisions. two previously published scores exist to predict outcomes: the status epilepticus severity score (stess) and the epidemiology-based mortality score in status epilepticus (emse). however, a comparison of the two scores has not previously been completed in an american population. we hypothesize that both scores will adequately predict the primary outcome of in-hospital death. we performed a retrospective analysis of all cases of status epilepticus admitted to the neuro-critical collected data on age, comorbidities, eeg findings, and seizure history. the primary outcome was inhospital death. a sensitivity and specificity analysis was completed, in addition to a student's t-test for a comparison of the two scores. forty-six patients were admitted to the nccu for management of status epilepticus during june and january , of which experienced in-hospital death. the median age of the sample was , with approximately half of the sample ( . %) having or more comorbidities. the two most common etiologies were cryptogenic (n= ) and acute cerebrovascular events (n= ). while the sensitivity of both emse and stess were very high ( % and % respectively), the specificities were very low ( . % and . % respectively). a student's t-test between those who experienced in-hospital death and those who did not was only significant for emse at the p< . level (p= . ). the specificity of emse and stess for our external validation did not correlate with previous studies; however, both tools are sensitive. the emse and stess may be useful to predict outcomes of status epilepticus in populations with few comorbid conditions, but are less helpful when patients have multiple medical problems. in , the acns published critical care eeg terminology in an effort to improve clinical research and management of patients requiring continuous eeg (ceeg) monitoring. we sought to understand the familiarity of providers in our neurocritical care (ncc) program with this terminology two years after implementation at our institution. we administered a question web-based survey to ncc fellows, advanced practice providers (apps), tanding of acns terminology, and clinical eeg application. there were attending physicians, ncc fellows, and apps. attending physicians and apps had a median of (range: , ) and years (range: . , ) experience since most recent post graduate training, respectively. all data is reported for apps and physicians respectively as percentage correct. highest rated component of the ceeg report that influenced patient management was "conversation with lected by . % of apps and % of physicians. set forth by the acns and highlight the importance of communication between ncc providers and epileptologists as well as areas of potential education for providers of all training levels. carbamazepine (cbz), an oral antiepileptic drug (aed), is a potent inducer of cytochrome p (cyp) (eg, phenytoin, fosphenytoin, phenobarbital, valproic acid, levetiracetam, or lacosamide) to reduce the -drug metabolism (reduced efficacy or toxicity). an iv cbz formulation has been developed; study ov- (nct ) evaluated bioequivalence and a (nct ) evaluated tolerability. both studies were similarly designed. eligible adult patients received a stable oral cbz regimen ( daily dosage (divided doses q h) during the confinement period (ov- : -or -min infusions q h for days, patients in the -min group were eligible to receive four -to -min infusions on day ; a: -min infusions q h for days, then one -min infusion on day ). oral cbz was resumed for days ( a: days). bioequivalence of iv to oral cbz was evaluated in ov- ; tolerability data were pooled. in ov- , -min iv cbz infusions were within the %- % bioequivalence range vs oral cbz; min infusions exceeded the upper limit for maximum plasma concentration. in both trials, patients switched to iv cbz ( -min: n= ; infusion was dizziness ( %); infusion-site reactions ( %) were the only new aes experienced by patients vs oral cbz. seizure control was maintained during the switch. to avoid potential drug toxicity reactions, it is beneficial to maintain patients on cbz. iv cbz administered as multiple -min infusions was bioequivalent to oral cbz. iv cbz was well tolerated. treatments for aneurysmal subarachnoid hemorrhage (asah) remain inadequate. eg- is a sustained release formulation of nimodipine for intraventricular delivery in order to avoid dose-limiting -label, dose escalation study of a single intraventricular dose of eg- that was designed to determine the maximum tolerated glasgow outcome scale (www.clinicaltrials.gov identifier: nct ). subjects with asah repaired by clipping or coiling were randomized within hours of asah to eg- or oral nimodipine if they were world federation of neurological surgeons grade to and had a ventricular catheter. cohorts of subjects received , , , , or mg eg- ( per cohort) or oral nimodipine ( per cohort). plasma nimodipine concentrations were sustained for days. the maximum concentration, steady state concentration and area under the curve for the first days increased with increasing dose of egbetween males and females. plasma nimodipine concentrations following eg- administration did not exceed plasma concentrations of oral nimodipine mg every hours at steady state. cerebrospinal fluid nimodipine concentrations with eg- were orders of magnitude higher than in plasma or with oral nimodipine. subjects treated with eg- (n= ) had a median intensive care stay . days less and hospital length of stay . days less than subjects treated with enteral nimodipine (n= , table) . intraventricular eg- produced sustained, dose-dependent nimodipine plasma concentrations and shortened intensive care and hospital length of stay. improved clinical outcome support conduct of a pivotal phase study of eg- . increasing exposure to ionizing radiation for medical diagnostics and treatment has raised questions about possible long term effects. this study describes the effective dose of ionizing radiation exposure in patients with aneurysmal subarachnoid hemorrhage (asah). thirty-five asah patients admitted to a university hospital between jan , and december , , greater than years old, and discharged alive were included. the primary objective was to calculate the mean total effective dose of ionizing radiation (tedir) in asah patients. secondarily, the number of asah patients with a calculated tedir greater than the annual and cumulative maximal permissible radiation dose (mprd) as described by the national council of radiation protection and measurements (ncrp) and the international commission on radiological protection (ircp) was determined. factors associated with greater than maximal exposure limits were evaluated. tedir exposure ranged from . - . millisievert (msv), with a mean (sd) of . ( . ) msv. seven , the presence of vasospasm (p< . ), external ventricular drain (evd) (p < . ), or ventriculo-peritoneal shunt (vps) (p< . ) were statistically significant factors for increased tedir in asah. demographic data, previous medical history, and location of aneurysm were not statistically significant. univariate analysis representing the degree to which tedir increases for each of these factors revealed hh class ( or ) . (p< . ), vasospasm . (p< . ), evd . (p< . ), vps . (p< . ). in multivariate analysis representing the degree in which the tedir increases, only vasospasm . (p< . ) and evd . (p< . ) were statistically significant factors. following asah, patients with severe disease requiring vasospasm treatment and shunting are at warranted. patients with aneurysmal subarachnoid hemorrhage (sah) have high morbidity and mortality related to cerebral ischemia and infarction. in this study we explored the reversibility of reduction in cerebral blood flow (cbf) after sah. we conducted a retrospective analysis using prospectively collected ct perfusion (ctp) data from sah patients. patients were grouped as good (hunt hess - ) and poor grades . ctp data were compared at baseline ( - days after aneurysm rupture) and follow-up (> days). cbf at baseline was comparable between good and poor grade patients ( . ± . vs. . ± . -up there was an improvement from baseline in both groups ( . ± . and . ± . respectively, p= . ). however, in hypoperfused areas, rcbf was significantly lower in poor grade patients compared to good grade ( . ± . vs. . ± . , p= . ) and significantly lower than global cbf in both groups (p< . ). at follow-up, only poor grade patients demonstrated an increase in rcbf ( . ± . , p= . ) while in good grade patients, rcbf remains unchanged ( . ± . , p= . ). the absolute improvement in rcbf was significantly greater in poor grade patients ow-up in both groups was not statistically different in the two groups (p= . ) but significantly lower than global cbf (p< . ). regional hypoperfusion occurs after sah. in good grade patients there is no recovery in rcbf while in poor grade patients there is partial recovery implying a biphasic response with a reversible and an irreversible reduction in rcbf. this has not been previously described in the literature and may implicate two distinct mechanisms responsible for rcbf reduction after sah. aneurysmal subarachnoid hemorrhage (asah) is an important cause of morbidity and mortality, with patients susceptible to a variety of medical complications. external ventricular drains (evds) are commonly used for intracranial pressure monitoring and csf drainage; however, this puts asah patients -associated infections (vais). many preventative strategies have been proposed and implemented over the last years. using the nationwide inpatient sample (nis) database, this study examines trends in evd usage, vai rates, and mortality over a -year period. in this retrospective analysis, data from the nis was obtained for the period of january , through december , using international classification of diseases, th revision (icd- ) codes. analysis was performed using sas . surveymeans. primary outcomes of interest were rates of evd use, vai and in-patient mortality, as well as hospital length of stay. during the study period, there were , asah admissions, with evd placement reported in . % of cases. there was no change in either evd use or rate of vai (mean vai rate of . % over the years). no change in hospital length of stay was observed. from january , to december , , despite a variety of vai-preventative strategies advocated for and implemented, the national vai rate in asah patients has not changed; however, mortality has declined by a mean arr of . % per year over the study period. this may reflect improved neurointensive care provided to this critically ill population. stable vai rates may reflect incomplete adoption of effective preventative strategies, or use of ineffective o study has previously examined these trends in asah. the purpose of this study was to determine the effect of routine use of dexamethasone on delayed cerebral ischemia and poor outcome (death and severe disability) after aneurysmal subarachnoid hemorrhage (asah). this is a single center, observational cohort study comparing patients with asah admitted to a tertiary referral center from to . a variation in practice patterns for the use of dexamethasone - mg every hours after asah exists in our institution depending on neurosurgeon preference. patients were followed prospectively for the occurrence of complications including delayed cerebral ischemia (dci), e (bad outcome defined as a mrs of - ) and months (bad outcome defined as mrs of - ). out of the patients, ( %) patients received dexamethasone during the first hours of admission. significant factors associated with steroid use were females ( % v %;p= . ) and aneurysm clipping verses coiling ( % v %;p< . ). there was no difference in hh, fisher grade, incidence of infections, or incidence of dci ( % v %;p= . ). steroid use was significantly associated with bad outcome at discharge ( % v %;p= . ), but no difference at months ( % v %;p= . ). when examined separately for coiled and clipped patients similar trends were found in both subgroups. steroid use was associated with a longer hospital length of stay (los). in multivariable regression analysis steroid use was significantly associated with worse outcome (or . ;p< . ) when controlled for age, hh grade and type of surgical intervention. the study did not detect any benefit in the use of steroids in reducing the incidence of delayed cerebral ischemia in acute aneurysmal subarachnoid hemorrhage. however, steroid use was significantly associated with longer los, and worse functional outcome at discharge. antiplatelet therapy for the prevention of peri-coiling thromboembolism in high risk patients with ruptured intracranial aneurysms thromboembolic events (tee) during or after coiling of intracranial aneurysms is the most frequent procedural complication, resulting in permanent neurologic disability in a subset of patients. in unruptured aneurysm patients, there is evidence supporting the use of periprocedural antiplatelet therapy to prevent tee. whether patients with ruptured aneurysms and subarachnoid hemorrhage should also be given peri-coiling antiplatelet therapy is less clear. we reviewed a prospective registry of endovascularly treated aneurysm patients to delineate angiographic features associated with periprocedural tee. we then performed a controlled before-andangiographic feature associated with tee) to evaluate whether selective aspirin administration would reduce the rate of periprocedural thromboembolism without increasing major hemorrhagic complications. small parent artery diameter, an incorporated branch, intraprocedural thrombus formation, and parent rate of periprocedural tee, from . % in the control group to . % in the aspirin-treated group (p = . ). tee reduction in the aspirin-treated group continued to be statistically significant even when ith tee in other large studies with an adjusted or of . ( % ci . - . ). there were no major systemic hemorrhagic -bleed, symptomatic intracranial hemorrhage, or major external ventricular drain (evd)-associated hemorrhage (p = . ). significantly reduce the rate of peri-coiling tee without increasing major systemic or intracranial hemorrhages. neurocrit care ( ) :s -s muhammad k. athar, umer u. mukhtar, umer u. shoukat, david d. boorman, fred f. rincon, matthew m. vibbert, syed s. shah, jacqueline j. urtecho, jack j. jallo. thomas jefferson university hospital, philadelphia, pa, usa. fever is frequent in patients with subarachnoid hemorrhage (sah). differentiating infectious fever from central fever can be challenging. it is important to diagnose the cause of fever in the neurological intensive care unit (nicu) because of the detrimental effects of fever on brain injured patients. we hypothesized that procalcitonin (pct) could be useful to distinguish central fever from infectious fever in patients with sah. prospective, chart review study conducted in the nicu between december and september . was clinical infection defined as positive cultures (blood, urine, sputum, mini bal, csf, and c. difficle toxin) or infiltrate on chest x-ray within days of onset of fever. sixty-twenty-- . , and had pct > . . out pct > . . using multiple logistic regression, pct between . - . had an odds ratio of . ( % ci . - . ), pct > . had an odds ratio of . , and a maximum temperature odds ratio of . (ci . - . ). using pct > . alone had an odds ratio of . ( % ci . - . ). -pv: . % with a sample prevalence of . %. roc curve area: . %. fever in sah patients. the test has high specificity and npv so it can be a valuable toll to rule out infectious fever in nicu. intraventricular hemorrhage (ivh) due to subarachnoid hemorrhage (sah) has been associated with fever, hydrocephalus, and shunt dependence. the modified graeb score (mgs) as an enhanced measure of intraventricular hemorrhage has been shown to correlate wit intracerebral hemorrhage (ich) as well as shunt dependency in sah. we evaluated the mgs's association to complications during hospital stay and impact on functional independence at discharge in sah patients. retrospective review was performed of prospectively collected data for consecutive sah patients enrolled into the university of maryland recovery after cerebral hemorrhage (reach) study. hunt and hess (hh) grade, global cerebral edema (gce), and infarct on admi team of neurointensivists. mgs was calculated from each patient's admission ct scan and dichotomized according to a cutoff value based on the median value for our sample. clinical complications during each admission were recorded, and independence of performing adl's was obtained from physical and occupational therapy notes. statistical analysis was performed using univariate and multivariate logistical regression. ninety-eight sah patients from july to november were reviewed for this study. mgs was calculated in patients and dichotomized based on a median cutoff value of . hh, gce, and admission infarcts were not found to be significantly associated with high mgs. on univariate analysis, elevated mgs was significantly associated with hospital acquired infections (uti, pneumonia, and sepsis, p< . ), fever (p= . ), hypotension (p= . ), hypernatremia (p= . ), symptomatic vasospasm (p< . ), and new i independence with adl's (p= . ). severity of ivh as measured by mgs is associated with multiple in-hospital complications. the mgs can be used as an independent predictor of loss of independence of adl's on discharge for patients with sah. ed cerebral ischemia (dci) and brain injury following subarachnoid hemorrhage (sah). while systemic corticosteroids may mitigate inflammation and promote fluid and salt retention following sah, there is limited evidence on the impact of corticosteroid administration on outcomes following sah. corticosteroids are frequently administered in clinical practice following sah for the management of post-operative cerebral edema and refractory headache. our goal was to examine the impact of corticosteroid use following sah on the occurrence of dci and poor functional outcome at discharge. retrospective analysis of data from a single center sah registry on patients admitted between - who survived > hours. a logistic regression model was created with multiple potential predictors of outcome and steroid use, and with corticosteroid use as the response variable. patients were divided into quartiles based on the propensity score. the impact of corticosteroid use on the outcome of interest (dci then poor functional outcome at discharge) was then determined while controlling for the propensity score quartile. co-variates in analysis included age, gender, ethnicity, history of diabetes or statin use, aneurysm location, aneurysmal vs non-aneurysmal bleed, treatment modality, hunt hess, modified fisher. a total of patients with aneurysmal and nonaneurysmal sah were included in this analysis. corticosteroids were administered in ( . %). dci occurred in ( . %). poor outcome (mrs> at discharge) occurred ( . %). following propensity score analysis, corticosteroid use was not associated with dci (p= . ) but was associated with a significant reduction in poor outcomes at discharge (p= . , or . , % ci . - . ). corticosteroid use following sah was not associated with a reduction in dci but was associated with an approximately % reduction in the odds of poor functional outcome at discharge. a clinical trial of corticosteroids initiated in the early period following sah may be warranted. besides the impact of the initial bleeding, cv remains the leading cause for mortality and morbidity after successful cian therapy? data of patients with cian were analyzed with regard to onset of multimodal neuromonitoring, if one or both hemispheres were monitored and for the integration of neuromonitoring values in decision months after sah using the glasgow outcome scale (gos). ct-scans were reviewed for infarctions at time of discharge. patients were in the favourable outcome group (gos - ), patients showed unfavourable outcome (gos - ). in patients of the gos - group neuromonitoring was implanted in the hemisphere with the highest transcranial doppler (tcd) values. additional monitoring was installed contralaterally if tcds increased. in of those patients, contralateral pbto values were ischemic and angiography revealed severe cv in the non cian treated hemisphere. ct scans of those patients revealed significant infarctions in the hemisphere that was not initially monitored. the patients with gos - were monitored bilaterally at early timpo small infarctions but no territorial infarct was seen at discharge. a delay in bilateral multimodal neuromonitoring might facilitate delayed cerebral ischemia (dic). this might be due to a delayed detection of a mismatch between oxygen supply and consumption. in addition severe cv is not always detectable in tcd and might thus be diagnosed too late to initiate a successful cian therapy. in contrast, new severe cv or relaspses of cv after stop of cian therapy are detected efficiently if bilateral neuromonitoring is in place and the values are acted upon accordingly. the effects of short versus longer duration prophylaxis of levetiracetam on cognitive / functional outcomes in aneurysmal subarachnoid hemorrhage and risk of development of delayed seizures tamara majic, dela d. amoussou, chrystal c. reed, asma a. moheet. cedars sinai medical center, los angeles, ca, usa. chart review performed on patients admitted from january to december with asah, who received levetiracetam seizure prophylaxis mg bid or greater for < days versus days or more. we compared the length of icu stay, delta gcs at discharge, mrs ( vs days), and incidence of delayed seizures -- . ; p < . ) lengths of icu stay for short-duration levetiracetam therapy was -- . for long-duration (p< . ). length of icu stay in low dose -- . days (p < . ). preliminary data for early and late onset seizures delayed seizures occurred with longer duration prophylaxis preliminary data suggests delayed cerebral ischemia was universally present in patients with delayed seizures. the incident rate of dci was higher in patients with early seizures ( %) vs without seizures ( %) between low dose and high dose, and between short duration and long-duration levetiracetam therapy. length of icu stay is shorter in subjects treated with low dose levetiracetam vs high dose, which may suggest that a low dose levetiracetam may have a lower adverse effect profile. the presence of delayed ischemia may warrant a longer duration prophylaxis. the longer duration prophylaxis does not seem to reduce the incidence of delayed seizures, although a longer duration of study is warranted. in spite of improvements in mortality and physical disability for aneurysmal subarachnoid hemorrhage for 'delayed brain injury' often attributable to the direct neurotoxic and neuroinflammatory influence of the initial hemorrhage burden. these processes can result in global brain atrophy and commonly manifests as new cognitive disability including deficits with memory, executive function, and language. heparin exerts a wide range of interactions postulated to antagonize multiple pathophysiological mechanisms implicated in asah. here we review low-dose iv heparin (ldivh) as a promising treatment for preventing 'delayed brain injury' in asah survivors and inform on a new multi-center randomized trial. recent studies evaluating ldivh in asah are reviewed. the astroh study is an open-label, blindedadjudication, randomized phase ii trial. the primary efficacy outcome is mean montreal cognitive assessment (moca, - , normal - ) scores at the -day follow-up and patients will be enrolled over years at academic medical centers. the primary safety outcome is any major bleeding or clinically relevant non-major bleeding. one-year outcomes are also being assessed. ldivh significantly reduced neuroinflammation, demyelination, and transsynaptic apoptosis in a rat sah model. in a retrospective study ldivh patients were compared to well-matched controls. ldivh subjects had % clinical vasospasm and % vasospasm related infarction compared to % and % respectively in controls (p= . and p= . ). in another retrospective cohort study ldivh patients (n= ) had mean moca of . compared to . in controls(n= ) (p= . ). multivariate analysis confirmed ldivh positively influenced moca scores when controlling for factors that negatively influenced cognition. the astroh study is active and enrolled its first subject in april, . ldivh is a promising treatment for asah and is currently being investigated in a multi-center randomized trial (astroh), nct . gastrointestinal bleeding (asah) patients and to determine the effect of gib on in-hospital complications and outcomes. gib in asah patients and to determine the effect of this complication on other in-hospital complications and outcomes. the incidence of gib in asah hospitalizations (n= , ) was , per , patients with . % requiring blood transfusions. multivariate independent predictors of gib included: age - gib in asah is uncommon and is influenced by patient demographics and preexisting comorbidities and significantly increases disability and mortality. twenty-six consecutive asah patients undergoing multimodal neuromonitoring including cmd were studied. interventions of full-strength enteral nutrition (en) after > hours without any feeding preceding en were identified. parameters of systemic and cerebral metabolism and insulin dose were timeand analyzed together with continuous variables to study the effect of en on brain metabolism (glucose, lactate, pyruvate and glutamate). out of interventions in total, were excluded because of simultaneous parenteral supplementation or missing values, leaving interventions in patients eligible for analysis. the mean en--glucose significantly increased from perfusion pressure (cpp), baseline serum and brain glucose levels, the baseline metabolic profile [brain metabolic di and independent of the insulin dose given during the intervention. the increase of cmd-glucose was strongly dependent on the delta increase of serum glucose (median during the intervention (p< . ). although probe location influenced absolute cmd-glucose-levels (p< . ), significant increases were even observed in perilesional brain tissue (p< . ). no change in cmd-lactate, cmd-pyruvate, cmd-lpr or cmd-glutamate levels were observed (p over . ). brain glucose levels increased during enteral feeding independent of cpp, baseline glucose levels, insulin administration, and probe location. despite this increase, no additional metabolic improvement was observed. the clinical benefit of interventions ta needs to be investigated in a prospective approach. mean platelet volume (mpv) is a common daily laboratory investigation in subarachnoid hemorrhage diseases and is postulated to signify increased systemic thrombogenicity. similarly, diabetics have elevated mpv suggestive of associated vasculopathic complications through increased thrombogenicity. with non-aneurysmal sah (nasah) as compared to aneurysmal sah (asah). hence, we investigated if vasculopathy. we reviewed charts of patients admitted with the diagnosis of sah between january and december . we compared proportions using fisher's exact tests, and constructed roc curves to find threshold values for admission mpv that had the best combination of sensitivity and specificity to predict nasah versus asah. of the patients who met the inclusion criteria were asah. diabetic patients who presented with diabetic patients, a threshold value for mpv of . fl yielded the best combination of sensitivity and specificity to predict asah vs nasah (auc= . ; % ci . , . ). using this threshold, sah is more -similar mpv association was not observed among diabetic patients presenting with sah. mean mpv at admission did not differ between diabetic patients who presented with asah ( . fl) and those who presented with nasah ( . fl, p= . ). nonng with sah. aneurysmal subarachnoid hemorrhage (asah) is associated with mortality rates up to %, and up to one half of survivors suffer from long term neurologic disability. though several clinical scores have been developed to predict in-hospital mortality and long term outcomes, there is no universally accepted score. create a new predictive model. we conducted a retrospective chart review of patients admitted with asah to a single neurocritical care unit from september to february . we excluded patients with non-aneurysmal sah (including trauma, avms, and mycotic aneurysms). demographic and clinical variables collected included age, admission gcs, admission apache ii score, hunt and hess score, presence of delayed cererbral ischemia, and hospital acquired infections. our outcome measure was glasgow outcome scale at discharge. we created a penalized logistic regression model to determine predictors of outcome. we assessed performance by estimating the area under the roc curve (auc). of patients reviewed, met inclusion criteria. the mean age of the cohort was years. . % (n= ) of patients were female. the mean apache ii score on admission was . (median . ). majority of patients (n= , . %) had a discharge gos of . a combination of predictors performed optimally: age, admission apache ii, gcs, use of mechanical ventilation and presence of hospital acquired infections. the mean auc of the model was %. at the point of maximum-accuracy on the roc curve, the sensitivity was %, and specificity was %. clinical features at admission and during hospitalization can predict outcomes in patients with asah. clinical characteristics from the first few days of the hospital admission, such as hospital acquired infections, can be added to existing models, to improve outcome prediction scores. subarachnoid hemorrhage (sah) patients may experience supply-demand mismatch of cerebral metabolism from seizures, vasospasm, cortical spreading depolarization, hydrocephalus, or cerebral edema. previous studies have focused on non-neuronal measures of cerebral autoregulation. we examine the impact of various neurocritical interventions by examining anecdotally identified intracranial eeg (ieeg) responses considered clinically impactful as well as systematic examination of repeated interventions within patients. sah patients of hunt-hess grade - underwent ) clinical multimodality neuromonitoring utilizing brain tissue oxygen cerebral oximetry, cerebral blood flow, spencer depth electrode, and fiberoptic icp through a quadconsent using time-synchronized monitoring (cns- , moberg research). we reviewed clinician anecdotes of treatment responses to vasopressors, endovascular vasodilators, anti-seizure pharmacotherapy, nimodipine, and ventriculostomy adjustments. we then assessed each patient's response to multiple grouped interventions using spectral features including alpha-to-delta ratio (adr) normalized to pre-intervention baseline (nadr). paired t-tests and scatter plots, respectively, demonstrated the impact of interventions and blood pressure on nadr. patients had available post-sah ieeg data over months. of patients with post-procedural brain responded with an increase in ieeg alpha activity power. two patients developed a decline in adr associated with asah-related vasospasm, one who had eeg improvement after endovascular spasmolysis. two patients developed scalp-negative ieeg seizures, both electroclinically improving with anti-seizure pharmacotherapy. grouped interventions showed heterogeneous responses to vasopressors and one patient with a significant, repeated response. nimodipine had no consistent discernible peri-dose impact on nadr. we display scatter plots showing the peri-intervention patient-specific correlation between mean arterial pressure and nadr. patients with aneurysmal sah may develop neuronal impairment rescuable by neurocritical care interventions. our data show these responses are patient-and statemodels of dynamic sah pathophysiology. introduction: (dci), may be an important determinant of outcome following subarachnoid hemorrhage (sah). potentially, early treatment measures such as control of intracranial pressure, blood pressure management and initiation of nimodipine may mitigate ebi. our objective was to study the impact of delayed presentation to medical care on the occurrence of dci and poor outcomes following sah. retrospective analysis from a single center sah registry. patients admitted between and for nontraumatic sah, who survived more than hours were eligible for inclusion. [vr ] the explanatory variable of interest was time from symptom onset to diagnostic ct, dichotomized at hours. covariates included age, gender, ethnicity, hunt-hess grade, modified fisher grade, hypertension, aneurysm location and treatment modality. the primary outcome of interest was poor functional outcome at discharge (defined as models were constructed with the outcomes of interest as the response variables. a total of patients were included. the median time to diagnosis was . hours (interquartile range . - . ). twenty-four patients ( . %) presented greater than hours from onset. poor functional outcome at discharge occurred in ( . %) and dci in ( . %). multivariate analysis revealed no association between delayed presentation and either dci (p = . ) or poor functional outcome at discharge (p = . ). hours from symptom onset to diagnosis as a continuous variable also did not reveal a significant association with dci or poor functional outcome. delayed presentation to medical care beyond hours is not associated with either dci or poor functional outcome at discharge following subarachnoid hemorrhage. a treatment bundle including extracorporeal cardiopulmonary resuscitation (ecpr) combined with targeted temperature management (ttm) may improve outcome of cardiac arrest (ca) patients, however, prognostication for these patients still remains challenging. we sought to examine the prognostic value of amplitude-integrated electroencephalogram (aeeg) for ca patients during ecpr and ttm. this was a single-center, retrospective analysis of adult ca patients treated with ecpr and ttm under aeeg monitoring with subhairline montage. intra-arrest cooling was immediately initiated with cold fluid infusion and extracorporeal cooling method and maintained at °c for h. patents underwent intraaortic balloon pumping (iabp) and percutaneous coronary intervention (pci) if needed. neurological outcome was assessed with the cerebral performance category (cpc) scale at hospital discharge. ecpr was conducted in patients (age . [ - ] years, % male) amongst ca or post-ca comatose patients since november . the initial cardiac rhythm was refractory ventricular fibrillation in , pulseless electrical activity in , and asystole in . the cause of ca was cardiogenic; underwent pci and needed iabp support. collapse-to-ecpr time was . min. initial aeeg patterns were; flat trace (n= ); low voltage (n= ); suppression-burst (sb) (n= ); electrographic status epilepticus (ese) recovery (cpc - ). their aeeg pattern was continuous in , low voltage in , and ese in . among rn of spontaneous circulation. patients with ese recovered after antiepileptic administration. ecpr was withdrawn in patients based on clinical and prolonged flat aeeg findings. continuous aeeg adds early prognostic information for ca patients with ecpr under ttm. the suppression ratio (sr) is a processed eeg variable estimating the percent of an eeg epoch ( - ) that is suppressed. sr has been associated with neurologic outcome after several types of brain injury and using different technologies including full montage eeg recordings and simplified processed eeg monitors. we compared sr during targeted temperature management (ttm) after cardiac arrest, using two independent blinded assessment tools. a convenience sample of adult patients treated with ttm after cardiac arrest were enrolled to compare and the full montage continuous eeg using natus equipment with persyst magicfor . seconds). machine times were recorded to synchronize, and sr results were recorded once for each subject at a time without stimulation or artifact using correlation and altman-bland analysis. adults were enrolled in this study with a median age of years, ( %) were male. during sr - ) for persyst sr . ( . - ). comparing medtronic and persyst sr, the spearman correlation was . (p< . ), and altman bland testing revealed a bias of . with % limits of agreement - . to . . bedside estimation of suppression ratio during ttm after cardiac arrest showed excellent agreement when measured with the medtronic bispectral index monitor and the full montage natus ceeg monitor though the impact of therapeutic hypothermia on neurological outcomes remains controversial, there is strong evidence that pyrexia is detrimental. posthypothermia fever experienced by cardiac arrest patients is of particular concern. this abstract examines the ability of an esophageal heat transfer device (ehtd) to maintain core temperature below °c in critical care patients, with a focus on posthypothermia fever in post cardiac arrest (pca) patients. de-identified data for subjects who received temperature management using an ehtd were collected with a condition appropriate for active temperature management. core temperature readings for each patient were recorded at least hourly; if measurements were recorded more frequently, temperature over an hour span was averaged. patient data was analyzed to determine what proportion of measurements were above °c. data from a total of patients was collected, including post-cardiac arrest patients and fever reversal cases. a total of core temperature measurement events (over an average of . h per patient) were included in the analysis. ( . %) were below °c, recorded measurements exceeded °c, and no data were recorded for time points. of the measurements recorded posthypothermia, ( . %) remained below °c. esophageal temperature modulation using an ehtd appears to be an effective method for fever prevention and reduction. visual representations of the pca subset showed an upward trend in temperature after - hours of maintaining target temperature, but before active cooling ended. this suggests that many of these patients might have become febrile in the absence of active temperature management. achieving and maintaining normothermia (nt) after subarachnoid hemorrhage (sah) or intracerebral hemorrhage (ich) often requires surface or intravascular cooling devices that are associated with a significant burden of shivering. we describe a new, closed loop esophageal cooling device (ecd: -- . c) and the shiver burden during the maintenance of nt. we enrolled mechanically-ventilated patients with sah or ich with refractory fever (> . c). temperature and bedside shivering assessment scale (bsas) were recorded every minutes for the time above c, median bsas and cumulative number of anti-shivering interventions per patient was recorded prospectively. all patients received magnesium, buspirone, and acetaminophen as baseline anti -shivering interventions. ten patients ( ich, sah) were enrolled between october and april . the median gcs at initiation was ( ---- . m , and % were women. there was a temperature reduction at minutes (mean . c to . c, p= . ) and % of patients achieved nt (median time = . hrs.; range: . - hours). nt was maintained for median -- %) time above > e time. the median number of total shiver interventions per patient was ( - ) throughout the ttm time period. no device related complications were noted. the ecd successfully achieved and maintained nt with a low shiver burden and may be a feasible option for nt in this critically-ill population. we present a case of toxic leukoencephalopathy in a young woman taking a thermogenic dietary supplement. a year old female with unremarkable pmh except being on a diet drug "remuvik" presented with a day history of severe headache, blurry vision, photophobia, phonophobia, nausea, vomiting and brief intermittent hand spasms. neurological exam was notable for mild right finger-to-nose ataxia and diffuse hyperreflexia. initial mri demonstrated extensive bilaterally symmetric t hyperintensities of the corpus callosum and periventricular white matter. csf profile was unremarkable. labs were unremarkable except for serum sodium of meq/l. approximately hours later, patient became unresponsive with bilaterally fixed-dilated pupils and decerebrate posturing. she was intubated and gms of mannitol was emergently administered with concern for cerebral edema. iv lorazepam was also given. a stat ct head showed diffuse cerebral edema. an external ventricular drain was placed emergently and % nacl was started. continuous eeg was negative for seizures. next day she started following commands and on day she was discharged home with normal neurological exam. given her presentation and mri findings, she was diagnosed with acute toxic leukoencephalopathy due to thermogenic diet pill "remuvik". patient had been taking the diet drug for months and had lost lbs. the main ingredients in remuvik are listed as resveratrol, caffeine-free green tea and l -carnitine while the remaining ingredients are unknown. similar presentation with another diet drug "thermatrim" has been previously reported. these products are not fda regulated and are easily available to the general public. the acute cerebral edema with decompensation was thought to be due to hyponatremia caused by remuvik. while the mechanism of leukoencephalopathy is not well understood and further investigation is needed, spreading awareness is the key to prevent serious adverse effects of such unregulated products. baclofen is a frequently used muscle relaxant. we report a case of, low dose baclofen causing reversible gped's (generalized periodic epileptiform discharges). on review of literature, baclofen toxicity/overdose has been associated with burst suppression patterns on eeg, with one case report of baclofen toxicity causing gped's. to the best of our knowledge there have not been reports of low dose baclofen induced significant eeg changes. case reportthe patient is an year old woman, with poor baseline functional status from advanced dementia and limb contractures, on coumadin for old dvt/pe, with sub-therapeutic inr, was admitted with new onset seizures secondary to venous infarcts over bilateral parieto-occipital areas, due to extensive venous sinus thrombosis. she was monitored on continuous video eeg and initiated on antiepileptic medications, vimpat and dilantin. eeg recording initially demonstrated occasional sharp waves, maximal in the left frontal region. however, because of excessive emg artifact caused by hypertonia, the patient was started on baclofen mg. within hours patient's mental status deteriorated and eeg recording demonstrated gped's with periods of suppression. due to concern for drug adverse reaction, baclofen was discontinued. the eeg reverted to pre-baclofen pattern, while her mental status slowly improved. she was provided supportive care and ultimately discharged to a rehabilitation facility. in this elderly dementia patient, with low seizure threshold from the acute cerebral insult, low dose of baclofen was enough to induce encephalopathy and gped's. the absence of any metabolic disturbances along with rapid resolution of clinical and electroencephalographic abnormalities after discontinuation of the drug supports the hypothesis that these findings may be the direct cerebral toxic effect of baclofen. iatrogenic encephalopathy with baclofen should be considered in the differential for elderly patients with low cognitive reserve rotational vertebrobasilar insufficiency, also called bow hunter's syndrome after the symptom-inducing head position adopted when aiming a bow, is a rare cause of posterior circulation ischemia. we present a case of an -year-old woman who presented to barnes-jewish hospital with several days of episodic vertigo and gait instability. two weeks prior to presentation she had fallen and struck her head. imaging revealed a complex c fracture as well as an odontoid fracture with posterior displacement. she began having positional spells characterized by loss of consciousness, gaze deviation, fencer posturing, and sonorous breathing. review of clinical records and literature review. the spells were initially highly concerning for seizures. the patient was monitored on continuous video eeg, however no seizures were detected during typical spells. a ct angiogram revealed an occluded right vertebral artery at the level of c with diminutive vs. absent posterior communicating arteries isolating the posterior circulation. subsequent mr angiography revealed a patent right vertebral artery with no evidence of stroke. catheter cerebral angiography demonstrated a patent left vertebral artery. turning the head degrees during the procedure, however, elicited a typical spell and completely occluded the left vertebral artery. the patient underwent occipitocervical fusion, but unfortunately suffered a multifocal posterior circulation stroke and was discharged with hospice care. we present an unusual case of rotational vertebrobasilar insufficiency that mimicked a classic sezure semiology and presented several diagnostic dilemmas in the icu. in this case, traumatic injury resulted in likely bilateral positional vertebral artery occlusion with resultantly profound brainstem ischemia. bow hunter's syndrome should be considered in all cases of positional neurological spells, particularly in the setting of neck injury. optic nerve sheath diameter (onsd) measurement using ultrasound has been proposed as a reliable method for non-invasive assessment of intracranial pressure (icp). we report a case of using onsd to monitor icp in a tbi patient with elevated icp undergoing medical treatment with acetazolamide. we hypothesize that a difference in onsd could be detected with ultrasound before and after treatment. patient is a year old man with mild tbi due to assault. his head ct reveals a long calvarial fracture extending along the superior sagittal suture line and posteriorly into the left parietal bone, as well as a large epidural hematoma overlying the frontoparietal vertex near midline, and causing inferior displacement and extrinsic compression of the superior sagittal sinus. his physical exam reveals a young man with right orbital ecchymosis who is sleepy but easily arousable with a gcs of and no motor deficits. dilated fundus exam by ophthalmology reveals grade - papilledema consistent with elevated icp. the patient complains of persistent headaches and nausea that is unremitting. acetazolamide was started to decrease icp. we measured onsd with a sonosite ultrasound device prior to start of acetazolamide and days afterwards. two measurements were taken on each eye, one in the horizontal and vertical orientation each. the average onsd was . mm on the right eye and . mm on the left eye prior to initiation of treatment. on the day after treatment onsd was . mm on the right and . mm on the left eye. the patient's headache improved and nausea resolved. the next day onsd was . mm on the right and . mm on the left eye. headache and nausea completely resolved. this case report affirms that ultrasound measurement of onsd could be used reliably to assess icp noninvasively during the course of treatment for elevated icp. manoj k. mittal. kansas university medical center/ neurology, kansas city, ks, usa. timing of brain death evaluation could be crucial in maintaining organ perfusion for donation. a new bedside cerebral blood flow monitor (cflow monitor from ornim) has not been previously studied for determining the timing of brain death examination. we present here a case illustrating the role of bedside blood flow monitoring in determining the timing of brain death evaluation. a year-old-woman presented with acute right middle cerebral artery stroke and bilateral internal carotid artery occlusions. she was not a candidate for intravenous thrombolysis or endovascular therapy due to unknown time of symptoms onset. her initial nihss was (right gaze deviation, mild aphasia, mild dysarthria, left facial droop, left hemiparesis, left sided decreased sensation and neglect). day- , she got intubated for hypoxic respiratory failure. day- , ct head showed cerebral edema with midline shift of mm. patient was not a decompressive hemicraniectomy candidate. day- , patient was comatose. day- , patient lost bilateral pupillary reflex. ct head showed worsening midline shift of mm with right uncal herniation, bilateral anterior cerebral artery and left posterior cerebral artery stroke, and brainstem compression. day- , bedside cerebral blood blood flow monitoring was started with right sided cerebral blood flow index (cfi) of and left side cfi of . patient met criteria for brain death except that she was still breathing over the ventilator. patient was extubated for comfort measures. after minutes patients stopped breathing. her cfi dropped < bilaterally. patient underwent cardiac arrest after minutes and then both cfi were < . patient was not a candidate for organ donation. bedside cerebral blood flow monitoring may assist in determining the timing of brain death evaluation in comatose patients with imminent brain death. patients with cfi < may be considered for brain death evaluation. our finding needs further confirmation. aneurysmal subarachnoid hemorrhage patient. icus are high cost in the u.s., comprising about % of the us gdp. pressure is being placed on hospitals and intensivists to reduce costs, including earlier palliative care engagement to shorten length of stay.. as the u.s. migrates to a value-based system, further pressure will be made on reducing prolonged and expensive icu interventions, similar to quality adjusted life year (qaly) cutoff values to justify costs. a young year old man presented with worst headache of his life, and was found comatose by ems and referred to our neuroicu. he had a . cm giant basilar asah with intraventricular hemorrhage. the aneurysm was coiled endovascularly with external ventricular drain placed. he required therapeutic hypothermia, osmotherapy, induced hypertension and balloon angioplasty and intraarterial verapamil for refractory basilar and bilateral middle cerebral artery vasospasm. he had refractory intracranial pressure from global cerebral edema and around post-operative day # required bifrontal craniectomy. later percutaneous tracheostomy, peg tube, and ventriculoperitoneal shunting were performed. his total costs exceeded $ , u.s. dollars. one year later, his modified rankin scale was zero, and he went to college. his qaly (quality adjusted life year) for the rest of his year was . given a utility of . his physicians felt he should live to a normal life expectancy of years of age, q is quality of life weight = (perfect health, utility = ), l is residual life expectancy = more years. his qal-expectancy , is about life-years gained which divided over his life span is about $ , /year and less than the current cms reported value of $ , per year. this case exemplifies how high cost care can be delivered to deliver cost-effective, high quality care and underscore the need for integrated high-complexity neuroicu care. early mobility in the intensive care unit setting is associated with a number of positive effects including improved quality of life. though there is a strong body of evidence supporting early mobility in medical intensive care units, the benefits of very early mobilization after acute stroke are yet unclear as early hemodynamic variability in patients with impaired cerebral auto regulation is of concern. another potential barrier to early mobilization is the presence of an external ventricular drain (evd) for cerebrospinal fluid diversion and intracranial pressure (icp) monitoring. this case demonstrates hemodynamic and icp responses to progressive, device assisted mobility interventions during the acute phase of intracerebral hemorrhage (ich) in the setting of persistent elevations of icp requiring two evds. a year-old man was admitted to the neuroscience critical care unit with an acute thalamic ich and intraventricular hemorrhage requiring placement of two evds. starting on day following ich onset, the patient underwent progressive mobilization following the johns hopkins nccu activity and mobility algorithm. range of motion exercises were performed initially, progressing to supine cycle ergometry followed by incremental verticalization using the tilt table (sara combilizer®arjo huntleigh inc.,il). blood pressure, heart rate, oxygen saturation, and icp were recorded before, during and after the mobility interventions. no adverse neurologic effects were noted during these mobility interventions. recorded hemodynamic variables and icp remained within the set goals throughout. moreover the patient was able to tolerate degrees of verticalization on the tilt table. progressive, device assisted early mobilization was feasible when titrated by skilled healthcare professionals in a critically ill hemorrhagic stroke patient with evds. studies on larger patient samples are needed to improve our understanding of the hemodynamic and neurophysiologic responses to establish safety of progressive early mobilization of critically ill patients with acute stroke. anand venkatraman, ayaz a. khawaja, angela a. shapshak. university of alabama at birmingham / department of neurology, birmingham, al, usa. we describe a case of a patient with uncontrolled hypertension (htn) and prior intracranial hemorrhage (ich) who developed an intracranial hemorrhage shortly after consuming redline, a heavily-caffeinated energy drink. a -year old caucasian male with prior history of ich and chronic untreated htn was transferred to our service for evaluation of . x . cm ich in the left thalamus. blood pressure had been elevated in the emergency room there and he had been started on a nicardipine infusion. nih stroke scale was . ich score was . admission labs were normal. urine drug screen was negative. on questioning, patient revealed that symptoms had started within hours of consumption of bottle of redline, an energy drink. he was not a regular user but did consume it whenever he needed to get a lot of work done. mri of the brain did not show any vascular malformation or other lesion. multiple remote hemorrhages were seen in the subcortical areas. we stared lisinopril and weaned off his nicardipine infusion. he was discharged with minimal deficits. the high caffeine content is the most likely component of the drink that led to the ich, given that high caffeine consumption is linked to increased risk of hemorrhagic strokes. caffeine also has effects on platelet aggregation and endothelial function that could raise stroke risk. generalizability is limited by the fact that the patient had uncontrolled htn and prior ichs. however, given that % of adults in the usa have uncontrolled htn, and given that ich account for - % of all strokes, a large population is at risk. to our knowledge this is the first report of intracranial hemorrhage following consumption of an energy drink. consumers must exercise caution, especially in the setting of uncontrolled risk factors. elena schmidt, varada v. nair, gene g. latorre. suny upstate university hospital / department of neurology, syracuse, ny, usa. often times medications given in emergency cases have unintended consequences, sometimes posing even more harm than the reason for their administration. we report a case of a young lady with history of anaphylactic reaction who received i.m. epinephrine after developing allergic reaction to antibiotic, resulting in bilateral intracerebral hemorrhage (ich). our case is of a year old female with history of anaphylactic reaction who had been recently started on cephalexin for orbital cellulitis. she was sent to ed after having a syncopal event in the doctor's office. while in ed, the patient was administered . mg of : , epinephrine i.m. because of suspected anaphylactic reaction. shortly after, she complained of nausea, vomiting and developed right sided weakness and numbness. immediate ct head revealed two areas of ich, within the left parietal and right occipital lobes. extensive work-up ensued, with cta head and neck (negative for vessel anomalies), cerebral dsa (negative for vasculitis), mri brain w/wo contrast (negative for malignancy or amyloid angiopathy), ct thorax and abdomen (negative for malignancy). serum studies for vasculitis work-up were also unrevealing. echocardiogram did not show evidence for chronic hypertension such as lv hypertrophy. although there have been reports in the literature of spontaneous intracranial hemorrhage (intraparenchymal or subarachnoid) after various ways of epinephrine administration, in our patient's case, the extensive work-up done to exclude other etiologies stands out. this strengthens the hypothesis that epinephrine, causing an acute spike in blood pressure, ultimately led to spontaneous ich. in addition, the case of our patient is unique in that she developed two areas of ich, in a location typical for posterior reversible encephalopathy syndrome (pres), a syndrome known to be caused by significant elevation in blood pressures, suggesting a common underlying pathophysiology. careful consideration of indications should occur before administering such potentially harmful treatments. "last known normal" (lkn) time remains the standard for determining the onset of acute ischemic stroke and appropriateness of providing acute therapies. as older adults become more familiar with social media platforms, these applications may become a source of recognizing when a patient was lkn. we report an year-old woman who was "found down" at home. the patient lived independently, and was able to crawl to a telephone for help. on arrival to the emergency department, she had a right middle cerebral artery syndrome with an nih stroke scale of . she had a decreased level of arousal and severe dysarthria which precluded assessment of her lkn. the patient's son reported that he had last seen her normal hours prior, placing her outside the time window for acute therapies. however, the patient's granddaughter reported that the patient had been logged into facebook < hour prior to her admission "chatting" and commenting on photos. "timestamps" of comments left on photos by the patient provided exact times of the patient's activity. the only logical means of being able to perform these relatively high-functioning tasks would have been if the she was normal at the time of posting, thereby establishing her lkn. the patient was treated with systemic t-pa followed by endovascular therapy for a proximal m occlusion. the patient had rapid improvement of her stroke symptoms. she was discharged home with an nih stroke scale of . this patient's recent use of the social media was critical in determining the patient's lkn, leading to lifesaving acute stroke therapy. providers should be aware that social media may serve as a useful source of symptom onset information. in this case, it led to good outcome and discharge home. bilateral recurrent artery of heubner (rah) infarctions have been seldomnly reported in the literature. even more so for those cases that have occurred subsequent to neurosurgical extensive resections of large invasive olfactory groove meningioma. rah, a branch of the anterio-inferior cerebral artery, supplies anterior limb of the internal capsule, anterior caudate, putamen and globus pallidus. infarction typically results in contralateral paresis of the arm and face. other symptoms can occur i.e. choreiform movements, abulia, attention disorder, impaired memory, apathy, decreased spontaneity, depression, dementia etc. we present a case of bilateral rah infarcts as a complication of a large olfactory groove meningioma resection. we did an extensive chart review of our patient during post-operative neurointensive care unit stay, rest of the hospital stay and discharge follow up at month. our patients brain mri done as a part of routine post-operative imaging showed bilateral caudate head infarcts in the territory of rah. post-operative exam was significant for a left hemianopsia and right super quadrantopsia with color desaturation. patient did not experience any new weakness or movement related problems. he did have changes in cognition (forgetfulness & irritability) along with a subjective loss of sense of smell but these were consistent with his pre-op assessment. olfactory groove meningioma's comprise % of all intracranial meningiomas, are slow growing and tend to engulf and compress neighboring structures. most common complications of olfactory groove meningioma resections are post-operative cerebral edema, csf leak, seizures, cns infections, hydrocephalus and rarely brain ischemia. bilateral rah infarction, although rare has been reported in literature in association with vascular anomalies and other stroke risk factors. cerebral infarction involving the aca territories remains a known adverse complication of large olfactory groove meningioma resections, but bilateral infarcts due to these have not been reported before. angioinvasive aspergillus associated stroke in an immunocompetent host. aspergillus vasculitis is an under-recognized cause of stroke in immunocompetent hosts, especially when other risk factors are present. we present a case of autopsy proven angioinvasive aspergillus causing strokes in an immunocompetent host, and review the characteristic imaging findings to aid diagnosis. -year-old female developed cardiogenic shock after three-vessel-coronary artery bypass grafting (cabg) using saphenous vein grafts requiring intra-aortic balloon pump placement. this was complicated by aortic dissection, and she underwent replacement of the ascending aortic arch. refractory cardiogenic shock ensued for which she underwent placement of veno-arterial extracorporeal membrane oxygenation. postoperatively, she was noted to be in coma, and a non-contrast ct of the brain showed small multiple small ischemic strokes bilaterally. with persistent multi-organ failure, she was ultimately transitioned to comfort care and passed. autopsy revealed multiple perivascular petechial hemorrhagic infarcts involving white matter, deep gray matter and cerebellum on gross specimen. histopatholgic study showed aspergillus associated acute and chronic inflammation of blood vessel, and surrounding gliosis. aspergillus was also found in coronary grafts and kidneys. aspergillus associated cerebral vasculitis was considered less likely, as cabg, extracorporeal membrane oxygenation (ecmo) device-related thrombosis and acute mi were the leading differentials for stroke here, and no obvious immunosuppression was evident. cerebral aspergillosis can occur from direct spread from sinus infections or through hematogenous mode, and seemed to have originated from coronary grafts in this case. aspergillus has a predilection for posterior circulation arteries, and lacunar-type infarcts or petechial hemorrhages within the midbrain, thalami, or corpus callosum are characteristic. these findings should raise suspicion for aspergillus, especially without objective evidence of other mechanisms of stroke. early initiation of anti-fungal therapy may improve the likelihood of survival, and confirmatory testing in the form of blood vessel imaging, csf analysis and fungal blood cultures should be performed in suspected cases. autoimmune ganglionopathy: a rare cause of cardiac arrest kelly braun. neurological institute, cleveland clinic, cleveland, oh, usa. autoimmune autonomic ganglionopathy is a rare disorder characterized by pandysautonomia that occurs as a result of autoantibodies to ganglionic nicotinic acetylcholine receptors. we describe a year old male with autoimmune ganglionopathy previously treated with ivig who suffered cardiac arrest and anoxic brain injury as a complication of this disorder. the patient had a history of multiple autoimmune diseases (dm , autoimmune hepatitis, hashimoto's thyroiditis, celiac disease, antiphospholipid syndrome and ulcerative colitis). to alleviate his pre-syncopal lightheadedness related to dysautonomia, he would typically kneel and place his head on his folded arms. the patient was found unresponsive in this position in pea arrest. he underwent cpr followed by therapeutic hypothermia ( °c x h). the initial exam off sedation showed an obtunded patient with intact pupillary and corneal reflexes, but no tracking or command following. though he moved all extremities spontaneously, the movements were not purposeful and had a choreiform quality. notable labs were an elevated achr ganglionic neuronal antibody ( . nmol/l on hospital day and . nmol/l on hospital day ; normal < . nmol/l). mri brain showed symmetric diffusion restriction and flair changes throughout the brainstem, thalami and cerebellum, however there was no cortical diffusion restriction. eeg showed generalized intermittent rhythmic slowing, which was maximal bifrontally. he was treated with methylprednisolone mg daily for days and transitioned to prednisone mg daily. at the time of discharge to an acute rehabilitation facility, the patient followed most simple commands and moved all of his extremities against resistance, though he was noted to have diffuse hypotonia. to our knowledge, this is the first reported case of cardiac arrest attributed to autoimmune autonomic ganglionopathy. while rare, this is a serious complication of this syndrome. bibhukalyani das, shantanu s. shubham. institute of neurosciences kolkata, kolkata, india. global burden of tuberculosis is still high particularly in developing world. india is the largest tb burden country accounting for / th of the global incidence.cns tuberculosis is the most severe form of infection with microbacterium tuberculosis.emergence of mdr(multi drug resistant) tuberculosis has compounded the risk and adverse outcome. fatality rate of mdr tb meningitis is % with significant functional impairment in most of the survivors. mortality > % if patient is hiv positive. we report a case of yrs old girl from eastern india case of mdr -cns tuberculosis with a protracted clinical course of years. she developed a whole range of complications including hydrocephalus, optochiasmatic arachnoiditis with secondary optic atrophy, multiple tuberculomas, cerebellar and brainstem tubercular abscesses and siadh with hyponatraemia. our case is notable for few rare complications in the form of transverse sinus thrombosis secondary to chronic meningitis necessitating oral anticoagulation . the patient also developed various side effects of long term att such as -(i) att induced hepatitis. (ii) moxifloxacin induced seizures and re-adjustment of antiepileptics due to interaction with antitubercular drugs. she was managed with antitubercular drugs ( first line drugs) along with second line drugs (amikacin, levofloxacin, cycloserine, ethionamide) her clinical course was complicated by obstructive hydrocephalus requiring evd, vp shunt and shunt revision . developed acute sdh possibly secondary to shunt and required surgical drainage . later she developed posterior fossa tubercular abscess and needed craniectomy. pus from tubercular abscess grew mtb resistant to rifampicin and isoniazid. so the patient was maintained on second line drugs, ultimately succumbed to hospital acquired pneumonia. cns tuberculosis if associated with multiple medical, surgical complications, impose real critical care challenges compounded by mdr which often encountered in a developing country like india. megan lange, rebecca r. horrell. university of maryland medical center, neurocritical care unit, baltimore, md, usa. super-refractory status epilepticus, defined as seizures persisting despite anesthetics, is associated with high morbidity and mortality. here we present two cases of super-refractory status epilepticus intractable to aggressive therapies, including but not limited to anesthetics, electroconvulsive therapy, and immunotherapy. in both cases, the patients developed sepsis and cardiac arrest following prolonged hospitalizations with subsequent termination of seizure activity and improvement in electroencephalogram findings and neurologic exams. a review of the literature revealed a variety of publications describing super-refractory status epilepticus as a result of sepsis or cardiac arrest, but there is limited data describing either complication as therapeutic for status epilepticus. we propose that the systemic effects associated with profound sepsis, or the brief electrographic silence occurring in the setting of cardiac arrest could have played a role in halting seizures in these patients. we describe two theories regarding the potential mechanism by which cardiac arrest or sepsis could play a role in termination of seizures. exploration into specific mediators involved in these conditions and their relationship to status epilepticus could uncover therapeutic targets. targeted therapies could demonstrate promise in effectively treating super-refractory status epilepticus, thereby improving morbidity and mortality rates. ticagrelor is approved for prevention of cardiovascular events in adults with acute coronary syndrome (acs) . we present a patient with sah who developed thrombus during coiling procedure that was treated with abciximab followed by ticagrelor and aspirin, with potentially devastating consequences. a -year-old male presented after sudden onset severe headache. imaging revealed sah from a ruptured basilar tip aneurysm. the patient was neurologically intact with mild confusion, but declined during transfer and required intubation. an external ventricular drain was placed for hydrocephalus. during cerebral angiogram with coil embolization, a thrombus formed on the coil. intra-arterial abciximab was used with resolution of thrombus. he was extubated post procedure. aspirin and ticagrelor ( mg twice daily) were prescribed. the following day, the patient became increasingly lethargic with an increased respiratory rate ( s). he reported no perception of increased work of breathing. portable chest radiograph demonstrated only mild pulmonary edema. he did not have an oxygen requirement. venous blood gas demonstrated a ph . with a pco of , suggesting a respiratory alkalosis. transcranial dopplers demonstrated normal velocities, but the patient was considered for cerebral angiogram given a high concern for vasospasm with his neurologic exam. ticagrelor was stopped the following day. the patient's tachypnea and mental status rapidly improved. ticagrelor reversibly inhibits the platelet p y adenosine phosphate receptor and is indicated for prevention of cardiovascular events in adults with acs. in patients with both cerebral hemorrhage and a need for antithrombotic therapy, this reversible agent may become more widely used. dyspnea is a known side effect of ticagrelor, occurring in . % of patients (p< . ). dyspnea causes respiratory alkalosis and the resulting hypocapnea results in vasoconstriction. in this case, mental status change after administration of ticagrelor suggests that patients at risk for vasospasm may be particularly vulnerable to its side effects. over the past years, the americas have experienced waves of emerging and re-emerging arboviruses that cause neuroinvasive disease, including west nile virus, chikungunya virus, zika virus, and dengue virus. these viruses pose great challenges for traditional candidate-based infectious disease diagnostics that already fail to identify a causative pathogen in approximately % of encephalitis cases. we present the case of a year-old girl with a history of renal transplant managed with mycophenolic acid, tacrolimus and prednisone who presented to an emergency department with two days of high fevers, chills, upper back, neck pain and rash followed by encephalopathy. one month prior to presentation she attended summer camp by a lake in the angeles national forest, california. her hospital course was complicated by status epilepticus. cerebrospinal fluid (csf) analysis demonstrated a mixed neutrophilic and lympocytic pleocytosis. mri of the brain demonstrated symmetric t hyperintensities and edema in the bilateral thalami and leptomeningeal enhancement in the thalamus, cerebellum, brainstem, cervical spine and caudal equine. an extensive diagnostic work-up for infectious causes of encephalitis was performed and only identified epstein-barr virus. research protocol. unbiased mds of rna extracted from her csf and processed through a custom bioinformatics pipeline identified west nile virus. subsequently, convalescent serum serologies confirmed west nile virus infection. this case provides a first proof-of-principle that mds can detect even low level arbovirus burden in the csf of a patient with acute meningoencephalitis. given the rapidly changing landscape of viral causes of encephalitis in the americas, the ability of mds to comprehensively detect a huge array of microbes with a single assay may make it an optimal method for early identification of emerging causes of viral encephalitis, including in the transplant patient population. cladophialophora bantiana is a dematiaceous mold with a predilection for causing central nervous system infection, particularly in normal hosts. there is no standard therapy and mortality rates from this disease remain extremely high approaching %. here we describe a case involving a year-old immunocompetent man who presented with new onset seizures. brain imaging revealed bifrontal ring enhancing lesions concerning for abscess.the patient underwent surgical debridement of the lesions and bilateral intracavitary treatment with amphotericin b using ommaya reservoirs for several months. after approximately months of treatment which included surgical debridement , oral voriconazole and intracavitary amphotericin b, our patient is off all antifungals and no longer receiving intracavitary treatment. he remains fully functional with a nonfocal neurologic exam, being monitored with serial brain mris. due to rare incidence of cerebral phaeohyphomycosis, there are no clinical trials to help formulate standardized treatment guidelines despite its high mortality . this case places emphasis on an early aggressive multimodal approach for treatment of cerebral phaeohyphomycosis using a combination of surgical debridement, intracavitary antifungal injection, and oral antifungal therapy. does neurocritical care need to improve outreach to non-neuro specialties? firas abdulmajeed, mb. chb, bart b. nathan, md, fcns. university of virginia/ department of neurology, charlottesville, va, usa. the number of neuro-critical care(ncc) fellowship positions has been increasing yearly. the number of applicants has plateaued over the last years, leaving many programs with unfilled fellowship positions. the demand for neurointensivists is on the rise. trainees have come from neurology traditionally, with a limited number from internal medicine (im). we hypothesize that the relative paucity of im fellows was in part due to insufficient knowledge of ncc. we surveyed im residency programs in the united states, asking program directors to forward our survey to their residents. on another survey, ncc fellowship directors were asked: ) how many trainees and how many faculty hires from im and/ or em have they had within the last five years internal medicine residencies survey results: we obtained individual responses, responses were complete. how long is the ncc fellowship? n= % year % years % years residents of what specialty can apply to a ncc fellowship? n= . % (neurology, neurosurgery, anesthesiology, im and em) % neurology only % neurology, neurosurgery and anesthesia knowledge of san francisco matching system? n= % yes. % no do you know about the application cycle for the ncc match? n= % yes. % no knowledge of emergency neurological life support? n= % yes % no ncc fellowships' directors survey results: of the programs responded fellows with im/em background that were trained within the last years: / neuro-intensivists with im/em background hired: / im residents appear to have little knowledge of ncc fellowship. a lack of awareness of enls could affect the quality of care provided for neurological emergencies. additionally, for the specialty to grow and fill unmatched fellowship positions,current training and outreach strategies to non-neurology trainees may need to be improved somatosensory evoked potentials (sseps) are a sensitive, minimally invasive technique used to identify injury from the posterior columns of the spinal cord to the somatosensory cortex. the role of sseps as a neuromonitoring tool, in the neuroicu has not been well established. we present a case using sseps as a neuromonitoring tool illustrating electrical improvement along with clinical and radiographical improvement in a symptomatic chiari i malformation. year old female who was months postpartum after vaginal delivery with epidural analgesia presented with headaches, diplopia and nausea/vomiting. after arrival to er, she acutely developed flaccid quadriparesis with ophthalmoplegia and loss of airway while awake and following commands. given the concern for intracranial hypotension, we administered mannitol, hyperventilated and placed in trendelenburg position. head ct showed cisternal effacement in the setting of a likely pre-existing chiari malformation with cerebellar tonsillar. decompressive surgery was not an option initially given her dysautonomia and neurologic instability whenever the patient was not in trendelenburg. during her prolonged course, she had two mris of her brain and spinal cord which showed chiari i malformation with syrinx at c and presyrinx down to t . there was cervical spine venous engorgement and csf block at the level of the foramen-magnum. she was evaluated with serial sseps which initially showed low amplitude n response that improved with her clinical improvement. ssep is a minimally invasive method to electrically assess the somatosensory pathway integrity from the spinal cord, brainstem and cortex. given its sensitivity to the function of the dorsal columns of the spinal cord and medial lemniscus of the brainstem, sseps may be a useful monitoring adjunct to follow the evolution of posterior fossa lesions in patients that may not tolerate other means of monitoring and/or transportation, such as mri. review of prospectively maintained patient database identified one case of status epilepticus in a patient with cns-ptld. we present a case report with literature review. a -year old hispanic woman with a history of renal transplant years prior, presented with episodic confusion and gait ataxia progressing over two weeks. she was on immunomodulation with mycophenolate. patient had witnessed periods of behavioral arrest. continuous electroencephalography (ceeg) demonstrated right temporal sharps and - second epochs of bi-frontal - hz activity, some of which were associated with non-stereotyped movements of her left shoulder and trunk, suggestive of se. she received benzodiazepines followed by levetiracetam (renal dose) and phenytoin load for seizure control. mri brain without contrast demonstrated multifocal infiltrative t -hyperintense white matter lesions, most prominent in right temporal lobe. csf analysis demonstrated rbc, (l %) wbc, protein, glucose, culture and gram stain were negative. there were unmatched csf bands with an unremarkable cytology. csf pcr was positive for ebv and viral load was detected at copies/nl. other csf microbial assays including jcv were negative. stereotactic right temporal brain biopsy demonstrated areas of necrosis, axonal disruption, loss of myelin with polytypic plasma cells, cd and cd positive b cells and cd positive t cells on immunohistochemistry consistent with a diagnosis of polymorphic ptld. despite treatment with dexamethasone and rituximab, patient continued to remain critically ill and eventually received palliative measures. among transplant recipients, pcns-ptld is rare but debilitating with varied neurological presentation. high degree of suspicion, early diagnosis and treatment are paramount for survival. cortical myoclonus caused by activation of cortical areas subjacent to multiple subdural hematomas is an unusual mechanism of epilepsy. we report the case of a patient with an extra axial bleeding and myoclonic seizures evaluated with ictal fdg-pet. case report a year old male was admitted to our hospital because of worsening symptoms of cardiac failure of chagasic etiology. due to hemodynamic instability he was treated with the placement of an intraortic balloon pump. sixteen days after hospital admission, he presented intermittent generalized myoclonic jerks. on initial examination he was alert and oriented to time and place, had preserved strength in all limbs, although presenting with very frequent clusters of myoclonus. initial investigation with a head ct showed multiple foci of extra axial bleeding, distributed over the frontal and parietal areas. the electroencephalogram (eeg) confirmed the suspected diagnosis of myoclonic seizures, exhibiting generalized polispike-slow wave complex. due to the multiplicity of bleeding sites, with no obvious reason for spontaneous bleeding other than regular anticoagulation, the patient was submitted to a whole-body fdg-pet in order to exclude the possibility of dural metastatic implants. fdg-pet showed areas of cortical hypermetabolism adjacent to the bleeding foci, probably reflecting an epileptogenic mechanism of cortical activation. there was no evidence of hypermetabolism directly over the extra-axial areas of bleeding, what ruled out the hypothesis of dural metastasis. a diagnosis of spontaneous subdural hematomas associated to anticoagulation was given after all other causes were excluded. the patient was treated with sodium valproate and had sustained improvement of the myoclonic seizures. the bleeding areas were eventually reabsorbed, but the patient died from complications of cardiac failure. our report is the first to illustrate the mechanism of cortical activation leading to epileptic status in a patient with multiple subdural hematomas detected by ictal fdg-pet. to present a case of early onset myoclonic status epilepticus (mse) after cardiopulmonary arrest with incomplete resolution of myoclonus and good cognitive outcome. a year-old man presented status post cardiopulmonary arrest and cpr in the field with return of spontaneous circulation (rosc) after arrival to the hospital and cardioversion. the patient was intubated and treated with therapeutic hypothermia, but developed clinical mse with normal eeg within hours. he was aggressively managed with propofol, levetiracetam, and fentanyl. initial mri demonstrated diffuse hypoxic ischemic injury. mri on the th day of admission demonstrated improvement but a new white matter lesion in the splenium of the corpus callosum. after multiple unsuccessful attempts to discontinue fentanyl and days of treatment, the patient was given a poor prognosis based on the aan mse practice parameters and was placed on do not escalate care orders. propofol was slowly decreased; however the patient improved significantly throughout hospitalization with improved language and cognitive examination and only mild residual reflex myoclonus at the time of discharge. mri imaging had completely resolved by the th day of hospitalization. the patient's final diagnosis is lance-adams syndrome of action myoclonus incompletely controlled with levetiracetam. aggressive and prolonged treatment including therapeutic hypothermia in young patients with early onset mse was effective despite aan practice parameters. this patient survived with good cognitive outcome and with relatively modest deficits. further research is needed to assess whether improvements in intensive care unit capabilities over the past decade may contribute to improved outcome in young patients with cardiac arrest and whether practice parameters should be revised. at the start of this protocol, the serum sodium was and one-hour urine output was liter. this protocol was continued for hours. endocrinology was consulted and recommended changing to ddavp. serum sodium was [np ] and one-hour urine output cc prior to first dose of ddavp university of washington, department of surgery, seattle, wa, usa. earlier feeding results in improved outcomes in adults with severe traumatic brain injury (tbi) and in the overall pediatric intensive care unit (picu) population. current practices of nutrition initiation in children with tbi are not well described. this multicenter study evaluated timing and factors associated with nutrition initiation in children admitted to picus with tbi. we hypothesize that severely brain injured patients would have a delay in initiation of enteral nutrition. we retrospectively analyzed the multicenter pediatric trauma assessment and management database (ptam) from . patients with severe tbi were defined as glasgow coma scale (gcs) < with n in this group was compared injury, abdominal procedures were compared between the two groups. chi square and fisher exact tests were used for dichotomous variables; non-parametric tests were used for continuous variables. multivariable regression analysis with a stepwise procedure was performed to ascertain the best set of variables associated with delayed initiation of enteral nutrition. of patients admitted to the five ptam picus with severe tbi, ( %) were fed < hours from admission. patients with gcs < were fed a median . hours from admission (iqr . - . ) compared to . hours (iqr . regimen, higher injury and illness severity scores and lower minimum gcs were significantly associated with feeding initiation > hours. on multivariable analysis, scheduled bowel regimen, higher prism score and lower minimum gcs were significantly associated with nutrition initiation > hrs. lower gcs is independently associated with delayed initiation of enteral nutrition in children with tbi, independent of severity of injury or abdominal injury. all patients that suffered ca within hours of sah onset were identified from a prospectively collected characteristics, and outcomes of those with and without ca in the setting of sah using binary logistic regression. only % (n= ) of sah patients had ca within hours of the bleed. % (n= ) of those with ca had f these patients died while in the hospital. three patients had a ventricular fibrillation (vfib) arrest, and one of these patients (n= ), and half of these patients survived. % of patients were comatose after the arrest, most of which underwent cooling (goal temperatures - ). % of deaths in our cohort were from withdrawal of life support (n= ). increased aneurysm size (or . for each mm, % ci . - . ), amount of sah (or . , , and global cerebral edema (or . , ci . - . ) were associated with noncomatose patients and those with vfib arrests may have a better prognosis. acute herniation at the time of bleeding as indicated by large volume sah and global cerebral edema may be the underlying mechanism of most early cardiac arrest in sah patients. early identification of delayed cerebral ischemia (dci) following aneurysmal subarachnoid hemorrhage (sah) could allow more effective intervention. statistical methods that predict dci using variables collected routinely during icu care such as trends in vital signs and laboratory values have shown promise in recent studies. however, these studies have not all employed methods to guard against model overfitting. in this study we use cross validation to obtain minimally-biased estimates of the value of passively collected icu variables for predicting dci. early identification of delayed cerebral ischemia (dci) following aneurysmal subarachnoid hemorrhage (sah) could allow more effective intervention. statistical methods that predict dci using variables collected routinely during icu care such as trends in vital signs and laboratory values have shown promise in recent studies. however, these studies have not all employed methods to guard against model overfitting. in this study we use cross validation to obtain minimally-biased estimates of the value of passively collected icu variables for predicting dci. dci occurred in % of patients. penalized logistic regression selected features for inclusion in the final predictive model, derived from gcs, heart rate, mean aterial blood pressure, respiratory rate, spo , ventricular drainage, and sodium data. the mean auc of the model was %. potentially clinically relevant (sensitivity, specificity) points on the roc curve included ( , )% and ( , )%. dci occurred in % of patients. penalized logistic regression selected features for inclusion in the final predictive model, derived from gcs, heart rate, mean aterial blood pressure, respiratory rate, spo , ventricular drainage, and sodium data. the mean auc of the model was %. potentially clinically relevant (sensitivity, specificity) points on the roc curve included ( , )% and ( , )%. subarachnoid hemorrhage (sah) remains a highly morbid disease leading to > -related year of life lost before age . mechanisms of sah-related early brain injury and vasospasm remain microrna (mir)- a is released in response to hypoxia and promotes angiogenesis. we hypothesize that higher levels of mir- a is associated with outcome in human sah. functiona -up every months. good functional outcome is defined as mrs % reduction in caliber of any vessel on post-sah day cerebral angiogram. in sah subjects we compared csf and plasma mir- a by quantitative pcr on post-sah days , and between outcome groups. data are normalized using log-transformation and then compared using student's t- study population has mean age of . % has hunt and hess (hh) grade > . good outcome at months is associated with higher plasma mir- a levels on post-sah day (p= . ) and day (p= . ). after adjusting for important predictors of outcome (hh grade; age), plasma mir- a on post-sah day remains strongly associated with outcome (p< . ). plasma mir- a levels were not associated with vasospasm. mir- a is present in csf and is elevated in sah compared to controls (p< . ), but csf mir- a showed no association with functional outcome or vasospasm status. higher plasma mir- a level at post-sah day is independently associated with -month sah outcome. mechanistic experiments are necessary to determine whether mir- a expression is neuro-protective in sah. validation studies in larger, independent cohorts are necessary to validate mirna- a as a accurate assessment of renal function remains a unique challenge in patients with aneurysmal subarachnoid hemorrhage (asah). mathematical estimates of creatinine clearance (crcl) routinely used are often inaccurate in this setting. patients with asah have been shown to exhibit a hyperdynamic response leading to an enhanced renal clearance. no studies exist evaluating the directly measured creatinine clearance of patients with asah over time. this was a single-center prospective observational study of adult patients with asah admitted to the nsicu between january and july . eight-hour urinary creatinine clearances were performed daily to directly measure crcl until the patient no longer had a foley catheter or the patient left the nsicu.-gault equation. statistical significance was defined as p-value < . . fifty patients with asah were enrolled in the study. the study sample was % female with a mean age of . ± . years. the median hunt and hess grade was (iqr - ) and the median modified fisher grade was (iqr - ). additionally, the median admission gcs was . (iqr - ) and median admission sofa score was (iqr - ). the mean urinary crcl over the study period was . ± . patients with asah consistently experienced urinary crcl greater than estimated crcl predicted based on -gault equation. as renally eliminated medications are routinely dosed based on mathematical estimates of renal function, further study is needed to optimize medication regimens in this patient population to prevent underexposure. agitated delirium is frequently encountered after acute brain injury, but data is limited in patients with nces of agitation in these patients. via records of antipsychotic or dexmedetomidine administration, and agitation was confirmed via chart study team. outcome was assessed at months using interview for cognitive status (tics), and lawton-iadl score. agitation developed in of patients ( . %) and was most common in the first hours after admission, and in patients with hunt and hess grades and . agitated patients were significantly more in half of these patients a complication appeared to occur within hours of the onset of agitation. patients with agitation had increased icu and hospital lengths of stay, but this was not significant after controlling for other predictors of length of stay. for patients with hunt and hess grades - , agitation was not independently associated with functional impaired at months compared to those without agitation after controlling for other predictors (lawton > ; p = . , or . , % ci . - . ). patients with sah frequently experience agitation requiring medical treatment, especially early in their clinical course, and especially in non-comatose patients with higher clinical grades. agitation is also associated with the development of multiple hospital complications, and may have an independent impact on long-term outcomes. seizures after subarachnoid hemorrhage (sah) are a frequent complication. sah patients are typically prescribed prophylactic anti-epileptic drugs (aed) for three to seven days. phenytoin has fallen out of favor as aed prophylaxis due to its association with worsened outcome as well as drug interactions. newer aeds including levetiracetam are more commonly used despite an incomplete understanding of their effect on outcome. retrospective analysis was performed of prospectively collected data for consecutive sah patients enrolled into the university of maryland recovery after cerebral hemorrhage (reach) study between -hess (hh) and modified fisher score (mfs) was adjudi a team of neurointensivists. retrospective analysis of cumulative dose of levetiracetam was divided into groups of low-dose (= , mg) using the median as a cutoff. concordance and discordance was noted. pearson chi-square was used. association of levetiracetam dose and quetiapine use as a surrogate of in-hospital delirium was also investigated. multi-variate logistic regression was used to determine predictors of ability to perform activities of daily living (adls) in survivors. asah patients from july to november were reviewed for this study. cumulative levetiracetam dose was calculated in patients and dichotomized into high-dose (>= , mg) or lowdose groups. hunt-hess was found to be significantly associated with high-dose levetiracetam. on multivariate analysis, high-there is a trend towards increased use of quetiapine in the high-dose levetiracetam group. full analysis will be provided at time of presentation. an extended course of levetiracetam is an independent predictor of loss of independence in activities of daily living after sah. there is also a trend toward increased delirium. larger, prospective studies are necessary for a more complete understanding of the impact of seizure prophylaxis on functional outcome after subarachnoid hemorrhage. myocardium: a case series and review of the literature. intra-aortic balloon pump (iabp) counterpulsation has been used to maximize cerebral blood flow in patients with subarachnoid hemorrhage (sah), refractory vasospasm and evidence of cardiac dysfunction. neurogenic stunned myocardium (nsm) pr lv dysfunction. we present cases with sah, vasospasm and iabp placement, including cases with nsm. we also reviewed the literature with the goal of examining the safety of iabp for cardiac dysfunction after sah, outcomes and selection criteria for its use. we searched for cases of sah and iabp placement at the university of kansas medical center (kumc) from to . patients met criteria and all had a secured aneurysm, refractory vasospasm and echocardiograms prior to iabp placement. we collected demographics, vitals, ekg, troponin, medications, iabp and icu complications, discharge and follow-up mrs. however, at follow-r outcome. literature review identified patients -up. our results indicate that patients that have iabp placement in the setting of sah, vasospasm and cardiac dysfunction may have a good outcome if they are younger, have evidence of reversible nsm and avoid icu complications including pe, uti and sepsis. the patients level of mobility and independence at discharge may not be indicative of overall functional improvement. a significant complication of non-traumatic sub-arachnoid hemorrhage (nt-sah) is the development of delayed cerebral ischemia associated with cerebral vasospasm. milrinone, an inotrope and a phosphodiesterase inhibitor, has been used intravenously, intra-thecally and intra-arterially as a delayed cerebral ischemia treatment and prophylaxis. the purpose of the current study is to systematically review the available evidence on its efficacy for that indication. articles from medline, embase, cochrane library, clinicaltrials.gov, reference lists of relevant articles, and gray literature were searched. study selection criteria were used and strength of evidence was graded. neurological outcomes and side effects were assessed. of articles identified, studies met the selection criteria and analyzed. the level of evidence varied and was generally low. this systematic review helped determine the current state of evidence for the efficacy and safety of milrinone in the management of delayed cerebral ischemia in the context of nt-sah. the available evidence is promising but of generally low quality suggesting the need for a randomized controlled trial. blood lactate variability: a strong independent predictor of neurological outcomes in patients with aneurysmal subarachnoid hemorrhage blood lactate levels during intensive care unit (icu) management of patients with aneurysmal subarachnoid hemorrhage (sah) can be used as an indicator of not only volume status but also aerobic glycolysis caused by excessive catecholamine levels and impaired lactate clearance. to determine whether blood lactate variability (lv) can predict neurological outcomes in patients with sah, we assessed the standard deviation (sd) of blood lactate level of each patient during icu stay. we retrospectively reviewed all patients at the age of years or older who were consecutively hospitalized in kagawa university hospital with sah and at least five arterial lactate measurements between january , and may , . patients were divided into two groups with a mean lactate to identify independent predictors of unfavorable neurological outcome. unfavorable neurological outcomes occurred in . % of a total of patients. in both groups, there were increases in unfavorable neurological outcomes with increasing sd of lactate (quartile , %; that sd of la correlated with unfavorable neurological outcomes (p < . ). multiple logistic regression analysis showed that sd of lactate (odds ratio, . ; % confidence interval, . - . , p < . ), age, and h&k grade were independent predictors. this study demonstrated that increased lv was an independent predictor of unfavorable neurological outcomes in patients with sah. the main causes of mortality and morbidity after aneurysmal subarachnoid hemorrhage (saha) are rebleeding and delayed cerebral ischemia secondary to cerebral vasospasm. the use of milrinone, an inotropic and vasodilator agent, is described in as one option to treat vasospasm in patients with refractory symptoms. our objective was to describe the experience of our neurocritical care service with the use of milrinone in accordance with the montreal protocol for patients with refractory vasospasm. a retrospective study based on data obtained from medical records of patients suffering from saha and refractory vasospasm treated with milrinone from february to february . from saha patients admitted to our hospital during the study period, were identified with refractory were female and % of patients were pre-hypertensive. a total of % of the patients had hunt-hess scores between - and % scored or in the modified fisher scale. vasosespam was identified after -- . days. in % of the patients hypertension was induced with norepinephrine as an initial treatment. the mean duration of the treatment - . days. two cases were treated with intra-arterial milrinone and angioplasty. the most common adverse event during the use of milrinone was hypotension ( %). death occurred in patients. favorable functional outcome at the discharge was observed in % of the cases. in conclusion, the use of milrinone seems to be a safe option in the treatment of delayed cerebral ischemia secondary to vasospasm, especially in services where the availability of endovascular treatment is not a routine. (sah). however, pathomechanism and etiology of this elevation leading to poor outcomes remains uncertain. this study investigated the effect of troponin elevation on multi-organ dysfunction and outcomes in patients with sah. admitted to the neuroscience intensive care unit from july to january . among patients, patients were eligible for inclusion with investigation of serum troponin level at admission. troponin elevation (> elevation were older ( . ± . vs . ± . years; p < . ) and more often had a loss of consciousness ( . % vs . %; p < . ), symptomatic hydrocephalus ( . % vs . %; p = . ), and a higher hunt-hess score ( . ± . vs . ± . ; p < . ) and modified fisher score ( . ± . vs . ± . ; p < . ) at ictal period. during hospitalization, patients with troponin elevation more often had a respiratory failure ( . % vs . dysfunction ( . % vs . %; p = . ) and more often treated with vasopressure ( . % vs . %; p = . ) and longer duration of mechanical ventilation ( . ± . vs . ± . day; p = . ) than those without troponin elevation. troponin elevation in the acute stage of sah is associated with multi-organ dysfunction. thus troponin to mitigate early brain damage in subarachnoid hemorrhage (sah), we have been treating world federation of neurological surgeons grade (wfns) grade patients with therapeutic hypothermia (th) for days immediately after onset. management after rewarming was problematic since fever in sah is associated with vasospasm and poor outcome. we studied the feasibility and safety of endovascular cooling to maintain prophylactic normothermia following initial th in patients with severe sah. th (core body temperature . °c) was initiated, using surface cooling, immediately after the diagnosis of wfns grade sah was made. the ruptured aneurysm was surgically clipped as soon as feasible. around postoperative day , after rewarming to °c, an endovascular catheter with cooling balloons jugular vein and connected to xp® temperature management system (asahi kasei zoll medical corp.) for days. prospectively collected data were analyzed. . days. nine patients developed shivering with increased temperature and were given acetaminophen and dexmedetomidine. there was no evidence of vasospasm or additional cerebral infarction during endovascular cooling, and no catheter-related sepsis or thromboembolic event. after removal of the cooling catheter, vasospasm-related cerebral infarction and fatal bacterial meningitis related to spinal drainage occurred. three-month outcomes were good recovery (n= ), moderate disability (n= ), severe disability (n= ); vegetative state (n= ), and death (n= ). elimination of fever burden in the first days after onset was safe and feasible with combined surface and endovascular cooling in patients with wfns grade sah. disease processes. this study examines: ) the relationship between admission lactate and the clinical and radiographic severity of asah, and ) whether levels predict outcomes including vasospasm, delayed cerebral ischemia (dci), and inpatient mortality. this is a retrospective analysis of consecutive asah patients with lactate drawn on admission.compared to those with normal levels. differences between groups were compared using chi-square tests for categorical variables, and independent t-tests for continuous variables. spearman correlations were calculated between lactate levels and mean values for continuous variables. elevations in lactate were associated with admission gcs, hunt & hess (hh) grade, fisher score, serum white blood cell count (wbc), troponin i (tn), glucose, and ventilator-free days (vfd). positive correlation was found between lactate and hh, fisher score, wbc, tn, and glucose. an inverse correlation existed between lactate and gcs, and vfd. compared to survivors, non-survivors had significantly higher lactate levels. all results were considered significant with a p-value < . . no association between lactate and the development of vasospasm or dci was found. higher admission serum lactate is positively correlated with hh grade, fisher score, serum wbc, tn and glucose, but negatively correlated with admission gcs and vfd. presence of an elevated lactate was also predictive of inpatient mortality. this is the first report of correlation between early lactate and asah severity, and conflicts with prior results suggesting an association between lactic acid and the development of dci. further studies are needed to determine whether lactate elevations relate to hypovolemia, acute inflammatory response, elevated sympathetic outflow, or other cause. with malignant cerebral infarction with high osmotic pressure therapy. some patients need decompressive hemicraniectomy or expire due to cerebral herniation after ttm. hence this study was performed to determine associated factors in case of failure of ttm in patients with malignant cerebral infarction. from january to december , a study was performed in patients with malignant cerebral infarction occurred within hours at neurological intensive care unit. all patients were diagnosed hyperosmotic fluid therapy and ttm. we defined failure of ttm to cases treated by decompressive hemicraniectomy or death due to brain herniation. a total of patients, ttm were failed in patients. failures of ttm were common in patients without recanalization after thro ( fever occurs in - % of critically ill neurological patients, and small temperature elevations are correlated to increased morbidity. it is therefore crucial to acutely control the temperature of such patients. systems currently available are resource intensive and not always readily available in units, resulting in delays in treatment. emcools pads and are composed of multiple cooling units filled with graphite and water, with an adhesive underside that allows for efficient heat transfer. pads are stored at - c, and are available for immediate use. the retrospective analysis of the emcool device included all subjects that had the device applied in the neuroscience intensive care unit (nsicu), with consistent temperature data recorded. preliminary subarachnoid hemorrhage ( %), intracerebral hemorrhage ( %), subdural hemorrhage ( %), and pituitary tumor ( %). all subjects were febrile ( treatment period. the bedside shivering assessment scale was recorded at each application. c, t avg = . c) drop in temperature at mins c) achieved at mins. unconscious patients displayed a much higher rate of cooling at t as c). of the total subjects, % had shivering events upon application (bsas ), device. preliminary results show the emcools pads are an effective and safe method to control temperature elevations in neurologically critically ill patients. all even numbered posters will present on friday all odd numbered posters will present on saturday all poster sessions are in prince george exhibit hall a from : pm superior sagittal sinus thrombosis (ssst) accounts for only . - % of all strokes, with a traumatic etiology representing an uncommon occurrence. current guidelines advocate treating ssst with anticoagulation regardless of etiology, though efficacy is controversial and not yet studied in the traumatic brain injury (tbi) patient population. we recognize the importance of alternate treatment modalities of post-traumatic ssst, particularly surgical alternatives, and the dilemmas faced with anticoagulation therapy in the trauma population. we report a case of a -year-old male admitted with ssst who suffered severe tbi secondary to a pedestrian versus automobile collision. imaging demonstrated bifrontal and right temporal lobe hemorrhagic contusions, scattered subarachnoid hemorrhage, diffuse cerebral edema, multiple nondepressed skull fractures, and ssst. on post trauma day two, the patient clinically deteriorated; an external ventricular device (evd) was placed, and therapeutic heparin drip was started, despite the presence of intracranial hemorrhage and risk of evd-related hemorrhage. the patient developed refractory elevated intracranial pressure (icp) mandating initiation of pentobarbital to achieve burst suppression on continuous electroencephalography (ceeg) and serial administration of . % hypertonic bolus and mannitol for two weeks. hemicraniectomy and endovascular treatment were entertained though not pursued due to anticipated complications associated with concomitant anticoagulation therapy. anticoagulation was briefly interrupted for evd removal on post trauma day . he was extubated on post trauma day and transitioned to warfarin. repeat imaging showed complete recanalization of the superior sagittal sinus. the patient was discharged to inpatient rehabilitation after a -day hospital course. management of ssst secondary to tbi remains controversial as these patients present with multiple confounding factors, further complicated by the lack of treatment guidelines. further studies are needed to determine which independent or combined medical and surgical treatment modalities will decrease morbidity and mortality in this patient population. takotsubo cardiomyopathy (tc) is known to occur in patients with subarachnoid haemorrhage (sah) but is rarely reported in patients with traumatic brain injury (tbi). here we present a tbi patient with complicated clinical course developing severe tc and compared to previously published reports. case report and literature review. a years-old-woman was admitted to our tertiary care hospital because of tbi with admission glasgow coma scale score of . computed tomography (ct) scanning of the brain revealed an acute subdural hematoma and traumatic sah over left hemisphere and a small left frontal hemorrhagic contusion. six hours later she deteriorated and head-ct showed significant progression of right frontal hemorrhage with intraventricular expansion and a midline shift. hematoma evacuation was immediately performed. postoperatively the patient developed cardiogenic shock necessitating an increasing dose of noradrenaline, neosynephrine and dobutamine to achieve a cerebral perfusion pressure of > mmhg. echocardiography demonstrated severe left ventricular myocardial dysfunction suggestive for tc, supported by raised troponin-t and nt-probnp levels and abnormalities in ecg. continuous infusion of levosimendan was added and maintained for hours which led to stabilization allowing noradrenalin to be decreased the following days. repeated echocardiography days later showed normalized cardiac function. the patient's condition gradually improved and was extubated after days fully awake with mild left facial-brachial weakness. here we present a complicated case of tc with tbi developing cardiogenic shock within hours of admission. we will compare the patient's tc characteristics and clinical course with published cases (n = ) of tc with tbi. further studies of tc in patients with tbi and the utility of levosimendan is warranted. management of post-operative central diabetes insipidus (di) is focused on replacing urine output with free water. this may not always be sufficient, and desmopressin (ddavp) is needed. the use of ddavp, however, is known to cause profound changes in sodium particularly if the triphasic response postpituitary surgery is occurring. herein, we report a case using a dilute vasopressin bolus protocol in managing hypovolemia in acute, post-operative, central di. case report comparing two protocols for di management. statistical analysis was performed on serum sodium, urine specific gravity, and urine output using student t-test. p< . was considered significant. anti-programmed cell death (pd- ) antibodies are an effective treatment option for nsclc and other cancer entities. anti pd- antibodies including nivolumab can induce immune-related adverse events (iraes) in a number of organ systems. neurological iraes can be life-threatening and necessitate appropriate investigation and management by a neurologist. myasthenic syndromes have rarely been described. here we present a case of a man who developed a lambert eaton myasthenic syndrome thought to be a nivolumab-related immune adverse event. a -year-old man on nivolumab for metastatic nsclc developed asymmetrical ptosis followed by facial diplegia, dysarthria and dysphagia and fatigable limb weakness. he had clinical features of lambert eaton myasthenic syndrome with striking truncal, shoulder and pelvic girdle fatigable weakness that demonstrated a temporary increase in strength during the first few contractions. he developed neuromuscular respiratory failure requiring noninvasive positive pressure ventilation. his muscle reflexes were initially absent and after repeated attempts could be elicited. his mri brain was normal, csf was within normal limits and his serum and csf antibodies against ach receptors, musk and voltage gated calcium channels were negative. he weakened after an initial mg/kg dose of prednisone. plasma exchange resulted in a significant improvement of his weakness and the ability to wean the patient off noninvasive positive pressure ventilation. it is important to recognize that neurologic immune-related adverse events associated with nivolumab can cause lambert eaton myasthenic syndrome. early recognition and aggressive treatment with plasma exchange can be life-saving. neuroendocrine tumor (net) of middle ear is extremely rare. many names have been ascribed to these seemingly benign neuroendocrine lesions including middle ear adenoma (mea), adenomatous tumor and carcinoid tumor (ct). 'neuroendocrine adenoma' has also been used to better describe the histologic nature of these tumors. here we present the first case of carcinoid tumor of middle ear (ctme) complicated by dural sinus thrombosis and bony metastasis. a year old man presented with right sided facial palsy for hours and progressive hearing loss for months. physical examination revealed perforated right tympanic membrane with visible purulent material. ct scan of the head showed a small right cerebellar infarct. the mri demonstrated right cerebellar hemorrhagic venous infarct and a heterogeneous middle ear mass extending into the internal auditory canal. mrv revealed thrombus in the right sigmoid and transverse sinus.cervical spine mri revealed diffuse osseous metastases .the histology and immunohistochemistry (ihc) after surgical resection was consistent with ctme. proliferation rate of> % was seen by ki staining. he suffered massive intracranial bleed on heparin therapy and passed away. the nets of head neck region are divided in categories based on histology and ihc. ) well differentiated ct, / hpfs and ki- > %. although regional metastasis is not uncommon, only cases of distant metastasis have been reported in the past. our patient was diagnosed to have atypical carcinoid but the ki- was > % which is consistent with small cell cancer. the new classification system that takes the ihc and presence of metastasis into consideration to classify these tumors is much more clinically relevant. more research is necessary to find out the biological markers for better prognostication of this rare cancer. sung m. cho.neurological institute, cleveland clinic, cleveland, oh, usa. acute transverse myelitis is an acquired inflammatory spinal cord disorder, which can be due to infection, autoimmune disorders, or malignancy, however, the cause is often unknown despite an extensive workup. we describe a rare case of acute transverse myelitis caused by coxsackie b /b virus. a -year-old male with no past medical history presented with a viral prodrome of flu-like symptoms followed by severe headache, neck stiffness, photophobia, encephalopathy and paraplegia. mri of the brain with contrast was unremarkable, but mri of the spine showed an extensive longitudinal, nonenhancing t cord signal change from c -t without hemorrhagic components. lumbar puncture revealed rbc, wbc, protein, and glucose ( mg/dl serum glucose). extensive serum and csf work-up was negative for hiv, wnv, ebv, cmv, lyme, vzv, hsv, nmo antibody, ace, paraneoplastic panel, cytology, cryptococcus, and csf bacterial and fungal cultures. ct chest and blind transbronchial needle lymph node biopsy were negative for sarcoidosis. serum coxsackie b ( : ) and b (> : ) antibody titers were significantly elevated. the patient was treated with intravenous methylprednisolone mg for days along with plasmapheresis for sessions. the patient had improvement in lower extremity strength during his hospital stay and was discharged to a rehab facility on a steroid taper. at one-month follow up, the patient had complete recovery of lower extremity strength as well as bowel and bladder function and was ambulatory. at -month follow-up, mri and csf studies were markedly improved. transverse myelitis due to coxsackie has been reported in serotypes b , b , a , a , however only three cases of b or b related transverse myelitis have been reported and this is the first case, to our knowledge, with both b and b related transverse myelitis. external ventricular drains (evds) are necessary for select patients admitted to the neurointensive care unit (nicu). evds are critical to the management of diseases such as subarachnoid hemorrhage, traumatic brain injury, and acute hydrocephalus. we report a case of a woman with poor-grade aneurysmal subarachnoid hemorrhage who experienced inadvertent intraventricular non-iodinated contrast injection during vasospasm evaluation with ct angiography. we provide a review and analyses of adverse evd related injections reported in the literature and summarize management recommendations. a pubmed search was performed for unintended evd injections from to . unique cases were selected and classified by the type of inadvertent injection and location of the event. acute management was categorized by the use of evd manipulation, lumbar drain placement, and supportive medical therapies. cases involving ventriculoperitoneal shunts, ommaya reservoirs, or other intrathecal device systems were excluded. a total of seven unique cases were identified, four involving contrast administration and three involving medication administration. the sentinel event in five cases occurred outside of the nicu. acute management with evd manipulation was employed in six cases; three of these cases also used lumbar drains. three cases necessitated intubation. our patient received prophylactic dexamethasone and levetiracetam, underwent immediate evd manipulation, and placement of a lumbar drain. continuous eeg monitoring and daily head cts were performed until intraventricular clearance was noted at hours. acute management of inadvertent intraventricular injections entails immediate evd manipulation and possible lumbar drain placement to facilitate rapid csf clearance of injected substances. intubation may be required immediately depending on exposure. inadequate distinction between compatible drain tubing and relative inexperience of providers managing the evds likely contributed to the errors in these cases. the increased incidence of these events outside of the nicu suggests additional safety measures may be warranted when patients with evds travel off-unit. an unusual presentation of isolated brain abscess in non-traumatic convexal subarachnoid hemorrhage: a case report to present a unique case of isolated brain abscess presenting as non-traumatic convexal subarachnoid hemorrhage (csah) six days before radiologic signs could be seen. to our knowledge only one other case of csah due to brain abscess has been reported thus far. a -year old man with no past medical history or prior trauma presented with acute onset of transient left hemianesthesia lasting ten minutes. computed tomography (ct) of the head revealed csah. we were presented with a diagnostic dilemma when magnetic resonance imaging (mri) of the brain, magnetic resonance angiography (mra) of the head and neck, magnetic resonance venography (mrv) and conventional angiography failed to show the cause of csah. the patient was discharged in a stable condition, but returned six days later with worsening symptoms, including left hemiparesis. repeat mri with contrast revealed a cerebral abscess in the same location as the prior csah. csah without clear evidence of trauma due to abscess is a rare occurrence. we suggest in cases of csah where imaging techniques present no abnormalities, follow-up imaging within seven days should be considered. jonathan marehbian, diane d. chan, david d. greer.yale new haven hospital, department of neurology, new haven, ct, usa. spinally-mediated reflex movements can be present in brain dead patients. however, abnormal movements have long been a challenge in the clinical determination of brain death. in this report, we describe delayed plantar extension with noxious nail bed stimulation that has not been previously described in brain death. a -year-old male suffered severe anoxic brain injury following respiratory failure due to heroin overdose. his clinical exam and apnea testing were consistent with brain death with the exception of a reproducible delayed plantar extension with noxious nail bed stimulation. ancillary testing with technetium m nuclear scan (spect) demonstrated no cerebral blood flow, confirming that the finding was spinally-mediated. novel movements are important to document in order to aid in the timely determination of brain death, and to avoid unnecessary and potentially confounding ancillary testing. the mechanism underlying delayed plantar extension is likely spinally mediated. vascular perforation during a neuroendovascular procedure is an unexpected and feared complication, which can lead to fatal outcomes. a prompt recognition and initiation of treatment are paramount. endovascular strategies to address this complication have been widely described. however, the goals of therapy in the neurointensive care unit (neuroicu) remain unclear. we report two cases in which endovascular strategies associated with aggressive intensive care resulted in a good clinical outcome at discharge. case report. vessel perforation occurred in patients during neuroendovascular interventions: a left-carotid stenting and an ica-aneurysm embolization with balloon-assisted coiling. once contrast extravasation was demonstrated, heparin was immediately reversed and endovascular strategies were performed to minimize the complications. sah was present in the initial head ct in both cases. in the neuroicu, targets of therapy were a) systolic blood pressure (sbp) < mmhg, b) mechanical ventilatory support, and c) seizures and vasospasm prophylaxis with phenytoin and nimodipine respectively. one of the patients developed mild hydrocephalus and left upper extremity weakness, with mri showing tiny right hemispheric strokes, while the other one, did not show any focal deficit. both patients were discharged home few days later with mrs of and , respectively. iatrogenic vascular perforation is an uncommon complication that occurs secondary to inadequate manipulation of the catheter, guide wire, devices, or forceful contrast injection. clinical care strategies aim to prevent fatal outcomes. we recommend reversing heparin; provide an adequate ventilatory support, maintain a strict control over the sbp, and seizure and vasospasm prophylaxis. but, larger studies are required to determine the standard of care since endovascular therapy is rapidly becoming first-line of treatment for neurovascular conditions. cerebral hyperperfusion syndrome (chs) symptoms range from severe unilateral headache to seizures, focal symptoms and intracerebral hemorrhage, usually occurring follow carotid endarterectomy (cea)/ carotid stenting (cas). we describe a case of a patient who developed chs after spontaneous recanalization of carotid intra-stent thrombosis. case report. years old african american male who had recently placed left cervical stent was transferred to baptist medical center with new evidence of intra-stent thrombosis. he was started on heparin drip and sbp was augmented with levophed for sbp> . two days later, the patient developed excruciating headache followed hours later by acute onset of right upper extremity and face twitching associated with severe hypertension. the bp was controlled, protamine was given to reverse heparin and keppra was loaded to treating seizures. cta at this time showed recanalization of carotid in-stent stenosis and ctp confirmed hyperperfusion of frontal and parietal lobe with neither evidence of new ischemic area nor bleeding. fortunately, inspite a delay in diagnosis by hours, patient did not suffer intracranial hemorrhage. most patients who develop chs will have complete recovery if it is discovered and treated early.aggressive prophylactic blood pressure control is the main treatment. for those who are diagnosed late and those progressing to ich, the prognosis can be devastating with mortality rates up to %. considering the importance of blood pressure control in the cerebral hemodynamic, studies have been done, trying to find a better tool to predict the best bp target in order to prevent chs. near infrared spectroscopy (nirs) is a non-invasive and reliable technique that monitor the cerebral hemodynamic. had nirs been deployed during anticoagulation, the diagnosis of cerebral hyperperfusion syndrome would have been made at the onset of headaches and would have avoided the development of seizures and potentially a life threatening hemorrhage. the triphasic response: water imbalance after neurosurgery : a case reportbibhukalyani das, indranil i. ghosh.institute of neurosciences kolkata, kolkata, india. water balance disorders after neurosurgery are well recognized, but detailed reports of the triphasic response are scarce. we describe a -year-old woman, who developed the triphasic response with hyper and hyponatraemia after resection of craniopharyngeoma. a -year-old female (no previous medical history, no medication, normal electrolytes and endocrine parameters) with mri showing s/o craniopharyngeoma underwent neurosurgery using a subfrontal approach to resect the craniopharyngeoma while leaving the pituitary stalk intact (according to the surgical notes). within a few hours of an uneventful postoperative recovery she started having polyuria and hypoosmolar urine with hypernatremia. being normoglycaemic and not on any diuretics a diagnosis of central diabetes insipidus was made treated with desmopressin nasal spray and drinking water ad libitum. improvement occurred over the next postoperative day when desmopressin was discontinued. on the third day she developed with hypoosmolar hyponatremia along with seizure treated with % saline and fuid restriction. two days later polyuria returned and was ultimately discharged with desmopressin tablets and advice to take fluids ad libitum. na this case illustrates the dramatic and sudden changes in water balance that may occur after neurosurgery. the pathophysiology of the triphasic response appears to be early hypothalamic dysfunction, subsequent release of vasopressin from the degenerating pituitary and, finally,depletion of vasopressin stores. it has been difficult to identify patients at risk, but predisposing factors appear to relate both to the disease (macroadenoma, microadenoma, craniopharyngioma) and to the surgery (degree of manipulation). successful prevention probably involves a psychological switch by not waiting until frank dysnatraemia has developed, but to act as soon as urine output and tonicity change. this requires an index of suspicion for treating and consulting physicians and specific instructions to nursing staff, especially in nonintensive care settings. refractory status epilepticus (rse) has high mortality and is difficult to treat. when traditional therapies fail ketamine may be considered. ketamine is associated with limited reports of adverse cardiac events during anesthesia, but not during treatment for rse. we evaluated occurrences of cardiac arrhythmias associated with ketamine. retrospective chart review of neurocritical care patients in a tertiary academic medical center who received ketamine infusion for rse between october and april . ten patients were admitted to a neurologic intensive care unit and received ketamine infusion for rse. etiology of rse included autoimmune/infectious process ( ), ischemic stroke ( ) and subarachnoid hemorrhage ( ). of the ten patients who received ketamine, three had documented cardiac events without prior cardiac history. one patient remained clinically stable and did not require intervention. another patient required escalating doses of ketamine infusion (maximum mg/kg/hr) for rse secondary to presumed leptomeningeal disease, had an asystolic event and expired. the third patient was on low dose ketamine ( . mg/kg/hr) for rse secondary to subarachnoid hemorrhage, and developed multiple arrhythmias including recurrent episodes of asystole. once ketamine was discontinued the patient stabilized. arrhythmias are not uncommon in critically ill patients, but this is the first report of cardiac arrest associated with the use of ketamine for rse. although sympathomimetic properties of ketamine may provide vasopressor sparing effects, which reduce the need for vasopressors to counteract the hypotension commonly seen with other anesthetics used in rse, it may put patients at risk for cardiac arrhythmias. in addition, ketamine has direct negative ionotropic effects and may raise pulmonary artery pressures. caution should be employed when ketamine is used in rse in patients with other independent risk factors for cardiac events. a year-old veterinary technician with headache and fever for days presented with altered mental status and myoclonic jerking. initial lp showed white cells and elevated protein ( mg/dl). recurrent clinical seizures occurred for days prior to transfer to our institution. his exam demonstrated diffuse hyperreflexia and coma; eeg demonstrated up to . hz frontally-predominant rhythmic delta but no unequivocal seizures. extensive workup revealed no evidence of infectious, toxic, or immune-mediated encephalitis. mri demonstrated bithalamic injury and a region of questionable periventricular nodular heterotopia in the right parietal region. subsequently, he developed recurrent clinical and unequivocal electrographic seizures from the right parieto-occipital region. five periods each lasting > hours of anesthesia-induced eeg burst suppression failed to stop seizures, qualifying him as super-refractory status epilepticus. after weeks of failure to wean from anesthetia, invasive monitoring for seizure localization was carried out using strips and depth electrodes. multiple seizures were recorded, localizing to the medial occipital lobe, which was subsequently resected along with the region of pathologyconfirmed heterotopia. seizures gradually improved, requiring anti-seizure drugs and a ketogenic diet. he regained consciousness with preserved higher cognitive functions (language, memory) and personality months later as his antiseizure drugs were successfully decreased. his motor recovery was limited by critical illness myoneuropathy. new-onset focal super-refractory status epilepticus may respond to surgical resection in extreme cases. close collaboration with a multidisciplinary team of epileptologists and neurosurgeons can lead to resolution of seizures and eventually recovery. in patients with leptomeningeal metastases (lm) and elevated intracranial pressure (icp), transient neurologic events secondary to plateau waves -temporary elevations in icp -may occur. there is a paucity of clinical reports correlating video-eeg with definite or presumed plateau waves in patients with lm. case report and literature review. pubmed was queried for 'leptomeningeal metastases and eeg', 'leptomeningeal metastases and plateau waves' and ' leptomeningeal metastases and intracranial pressure'. a -year-old woman was transferred to our hospital for further care of a pituitary microadenoma noted on outside imaging. she had a history of hodgkin lymphoma treated with radio-chemotherapy. during her admission, she developed episodes of confusion and video-eeg monitoring was initiated. while there were no electrographic seizures, several events, between to minutes in duration, of delayed or absent verbal responses, eye rolling, staring and alternating gaze preferences to both sides were noted. all these coincided with abrupt onset of marked background slowing, evident through generalized - hz delta, mixed with some theta frequencies. review of outside and repeat imaging with mri of the brain with contrast revealed brain and leptomeningeal metastases. cerebrospinal fluid examination showed raised opening pressures and malignant cells, leading to a subsequent diagnosis of primary signet ring cell cancer. we found one additional report describing video-eeg correlates of presumed plateau waves in patients with lm. our clinical description of transient neurologic events in this patient adds to the current literature of paroxysmal manifestations owing to raised icp in patients with lm. awareness of this clinical phenomenon may serve as a surrogate of raised icp before clinical signs of the same develop in patients with lm. it may also help delineate the cause of raised icp due to cns metastases in a patient with a corresponding history of cancer. background: terson's syndrome is the development of intraocular hemorrhage (ioh) in association with subarachnoid hemorrhage (sah). we report a case of terson's syndrome and review the literature. case report: a yr woman presented with severe neck pain and somnolence. ct imaging showed fisher grade sah with aneurysms in the right internal carotid and posterior communicating arteries. she developed low pressure hydrocephalus treated with ventriculostomy. on hospital day she developed vision loss. ophthalmologic examination demonstrated bilateral vitreous hemorrhages with near complete fundoscopic resolution by day . over the next months she underwent pars plana vitrectomy (ppv) of the left eye two times. current vision od / , os / . discussion: the incidence of terson's syndrome among patients with sah is documented to be between - %. in prospective studies, ioh was found in up to % of patients with sah compared to only % in retrospective studies suggesting under-reporting. this is likely because ioh is found more often in higher severity bleeds where patients cannot self-report visual loss due to decreased loc. patients with ioh are more likely to have worse neurologic outcomes and die more often than those with lower grade bleeds without the development of ioh. along with fundoscopy, hand held ultrasound may be used for bedside diagnosis. erm development is the most common intraocular complication from terson's syndrome and occurs in - % of patients. complete or near complete return of visual acuity is less likely without surgical intervention. visual acuity has been show to recover better and faster if ppv is performed within days. there is no literature on incidence of visual loss after acute phase of sah. conclusions: routine evaluation with imaging and fundoscopy may help in detecting ioh sooner in the clinical course and has the potential to decrease long-term morbidity. iatrogenic underfeeding in critically ill patients is often unrecognized and underestimated. an international prospective study of critical care units showed patients received only . % and . % of prescribed calorie and protein needs. the inability to initiate enteral nutrition within - hours of icu admission or frequent interruptions of the enteral regimen lead to insufficient nutrient delivery and a compounding energy deficit. an increase in infectious complications is associated with negative energy balance in patients with subarachnoid hemorrhage (sah). a quality initiative project was developed at mayo clinic florida to measure time to reach enteral nutrition target and common interruptions of enteral nutrition. the target subjects were mechanically ventilated patients in medical and transplant icu; however the quality measure has recently extended to the neurocritical care unit. data collected included clinical diagnosis, sofa and apache ii score, subjective global assessment (sga) score, nutric score, enteral tube type and regimen, and reason and duration for interruption of nutrition. a year old subject with sah and posterior fossa avm resection was deemed low nutrition risk with sga score a and nutric score . enteral nutrition was initiated via nasoenteric tube within hours of intubation. target enteral goal rate was reached within hours. the patient received % of calorie/protein needs of the days. the most common enteral interruption was for procedure; primarily head ct, for longest duration of minutes. the interruption of enteral nutrition in neurocritical care patients is likely unavoidable due to procedures. these disruptions, however, need not result in iatrogenic underfeeding. neurocritical care units may utilize volume-based enteral protocols to allow nurses to compensate for lost nutrition with increased enteral rate. neurogenic pulmonary edema is challenging to manage in the context of aneurysmal subarachnoid hemorrhage (asah) due competing priorities between organ systems. we present a case of refractory neurogenic pulmonary edema due to asah necessitating extracorporeal membrane oxygenation (ecmo). case report. a year-old female with a history of hypertension and diabetes presented neurologically intact with hh f asah due to a left posterior communicating artery aneurysm. she underwent coil embolization on sah day and remained intubated after the procedure due to development of flash pulmonary edema. transthoracic echo demonstrated normal left ventricular function. on sah day after unplanned extubation, she was temporized on noninvasive ventilation until reintubation the following day. she progressed to severe ards requiring high-dose sedatives and paralytics which obscured her neurologic exam. on sah day , a day course of intrathecal nicardipine was initiated for elevated left mca transcranial doppler velocities. on sah day , her respiratory status further declined and veno-venous ecmo was initiated as rescue therapy after head ct did not demonstrate new hemorrhage or infarct. throughout the day ecmo course, a low-dose heparin infusion was utilized along with vasopressors to optimize cerebral perfusion pressure (cpp). she was decannulated on sah day . surveillance ct head demonstrated left-sided ischemic infarcts in multiple vascular territories. on sah day , she was discharged to an outside facility for ventilator weaning. upon discharge, she was alert and followed commands with her left arm, however she was aphasic without movement of her other extremities. veno-venous ecmo was performed in an asah patient after coil embolization. although the patient did not develop intracranial hemorrhage, her course was complicated by severe vasospasm and delayed cerebral ischemia (dci). while ecmo is a rescue therapy for severe hypoxemia, its effect on cpp remains uncertain and may potentiate dci. key: cord- -i q gsu authors: nan title: (th) european congress of trauma and emergency surgery: may – , antalya, turkey date: - - journal: eur j trauma emerg surg doi: . /s - - -z sha: doc_id: cord_uid: i q gsu nan introduction and aims: although liver is well protected by the thoracic cage, it is a frequently injured organ especially by penetrating traumas and also rarely by blunt traumas. retroperitoneally located pancreas and duodenum injury with or without liver injury occur rarely but they are seriously life threatening injuries. for these reasons we aimed to investigate the traumatic liver, duodenum and pancreas injuries as a whole. materials and methods: cases of blunt and penetrating traumas occured in our district are included in this study. in these patients parameters of sex, age, etiology, admission time, stability and physical status on admission, concurrent organ injury, operation type, gradings of injuries, were investigated. results: cases ( , %) suffered from liver injury, while cases ( , %) suffered from hepaticopancreaticoduodenal injury. cases ( %) were caused by penetrating injuries. cases of liver injury group had isolated liver injury whereas cases of the group has additional thoracic injury, cases had great vessel injury, case had orthopedic injury and lastly case had head injury in addition to the liver injury. in the combined hepatic injury group mortality rate was , %. conclusions . in hepatoduodenopancreatic injury group blunt and penetrating injury rates are equal. . duodenum-pancreas injuries occur rarely. liver,with injury rates of cases in this study, is the most frequently injured organ. . mortality rate is higher in the subgroups of patients who admitted to hospital late, and who had concurrent thoracic, orthopedic, and head trauma. background: the incidence of blunt bowel and mesenteric injury (bbmi) has increased recently in blunt abdominal trauma and this is possibly due to an increasing number of high speed motor accidents and the use of seat belts. objective: in this study we sought to identify the factors determining the time of surgical intervention and how they affect the outcome of the patient with bbmi. this was achieved by reviewing our experience as a major victorian trauma service in the management of bowel and mesenteric injuries and how this compares to current literature. methods: a retrospective study reviewing consecutive patients who presented to the alfred trauma centre with blunt bowel and mesenteric injuries over years. results: of the patients with bbmi % were male, % were female. % of the patients underwent a laparotomy, % of patients were treated conservatively and % were diagnosed post-mortem. the times from admission to laparotomy were: - h %, - h %, - h %, - h %, - h %, more than h %, respectively. fast (focused abdominal sonography for trauma) was done in and % of this group had a positive fast. while % of patients had a negative fast and % of patients had an equivocal fast. % overall group did not have a fast. computerised tomography (ct) scans were undertaken preoperatively in % of the patients and showed: free gas ( %), bowel wall thickening ( %), fat and mesenteric stranding or hematoma ( %) and free fluid with no solid organ injury ( %). conclusion: the timing of surgical intervention is mostly determined by the clinical examination and the helical ct scan findings in bbmi. fast lacks in sensitivity and specificity in identifying bowel and mesenteric trauma. delayed diagnosis of more than h has significantly higher bowel related morbidity but not mortality. predictors for the selection of patients for abdominal ct after blunt trauma: a proposal for a diagnostic algorithm introduction and objectives: gastrointestinal and mesenteric injuries (gimi) are not common in trauma, and their diagnosis is frequently delayed. our aims were to determine the reliability of ct scan and to assess the clinical significance of a delayed diagnosis. methods: retrospective analysis of cases confirmed at laparotomy. patients were identified at the severe trauma registry of our hospital, between and . results: we found ( , %) gimi out of patients with abdominal trauma, in a registry with . severe trauma cases included. the mean iss and niss were of and , respectively. mortality was of ( , %) patients, of them unexpected. a ct scan was performed in ( %) cases, and only in were there signs suggestive of a gimi. surgery was delayed for more than h in ( %) patients, the most common reason being a false negative result in the ct scan. there was no significant increase of morbidity or mortality in the delayed diagnosis group. conclusion: the overall incidence of gimi was high in our registry ( % in penetrating and . % in blunt trauma). several factors such as the initial lack of symptoms, a low diagnostic sensitivity of the ct ( % false negatives), and the nonoperative management of solid organ injuries, have contributed to a delayed diagnosis in one of every five patients in our series, but this has not led to a significant increase in septic complications in this group. author to editor: ct scan diagnosis of gastrointestinal injuries continues to be a matter of concern. there is controversy on the clinical significance of a delayed diagnosis of small bowel injuries management of rectal injury: reappraisal of old techniques introduction and objectives: due to immunological functions, conservation of injured spleen following abdominal trauma is very important. for this reason nonoperative management (nom) in the last years has been accepted as the ideal treatment in those patents who are hemodynamically stable and do not require a laparotomy; however in case of multiple abdominal solid organ injuries (soi) nom is controversial. methods: we report on a case of a -years-old patient with spleen and renal injury subsequent to blunt abdominal trauma. ct scan revealed a ois iv injury (third degree in graz classification) and an ois iv renal injury. since chances for successful spleen angioembolization were judged poor by radiologist, a laparotomy and partial spleen resection with preservation of one-third of the spleen was performed. immediately after surgery, angioembolization of the renal injury was successfully performed. results: a contrast enhanced ultrasound (ceus) performed on day and day after trauma revealed a hypertrophy of the residual spleen with diffuse distribution of contrast agent in the spleen parenchyma, confirming functional activity of the organ. morphological and functional evolution of left kidney was normal. conclusions: sequential treatment (surgical preservation of the most injured organ followed by immediate angiographic embolization) could be a valid option in case of multiple abdominal soi; furthermore, ceus is an interesting new tool to determine functional activity of residual spleen. introduction: precise timing of cholecystectomy procedure after biliary pancreatitis is still controversial. the major drawback of interval cholecystectomy is the recurrence of pancreatitis within the interval of - weeks. early cholecystectomy (performed prior to discharge), however, have the disadvantages of increased technical difficulty and conversion rates. methods: we reviewed patients with recurrent biliary pancreatitis among a total number of cases of biliary pancreatitis in-between january and january . results: the mean age was . (range - ), and male-to-female ratio was . ( : ). seventeen patients (% ) had a history of previous cholecystectomy. of these patients, (% ) have had early cholecystectomy, and (% ) have had interval cholecystectomy. the rest of the patients (% , n = ) consists of those who have been scheduled for interval cholecystectomy but have had a recurrent episode during the -week interval (% , n = ) or after the -week interval (% , n = ). conclusion: the majority of patients with biliary pancreatitis do not have any recurrent episodes even if they do not have a surgical or an endoscopic treatment. according to our data, however, an influenced percentage of recurrent pancreatitis develops in patients who do not have early cholecystectomy. therefore, we prefer early cholecystectomy in means of reducing the risk of recurrent pancreatitis during or after the -week interval. introduction and aim: nonoperative management (nom) of splenic injury is currently the most common management strategy in hemodynamically stable trauma patients. aim of this study was to asses if the success rates of - % described, mainly in the north-american literature could be confirmed. methods: we conducted a retrospective study of all patients older than year with blunt splenic injury who were admitted to a level i trauma center. a total of patients were identified with blunt splenic injury during the -year study period ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . results: the majority were young men; mean age was years. thirty-three ( %) patients underwent immediate surgical management. sixty-seven ( %) patients were treated with planned nom and ( %) patients underwent angiography and embolization (a&e). we did not encounter early complications following a&e. fourteen patients failed observation due to ongoing bleeding. of these, were treated with splenectomy and three with a&e. the splenic salvage rate after observation was %. the splenic salvage rate after a&e was %. four of the five patients with a rebleeding after initially a&e underwent splenectomy and one patient was treated with reembolization. the overall mortality rate was . %. none of the patients died as a result of splenic injury treatment failure. conclusion: nonoperative management in blunt splenic injuries in our trauma center is a well-tolerated treatment with a success rate of %. the splenic salvage and mortality rate is comparable with the literature which is mainly based on north-american studies. mannheim peritonitis index (mpi) is a scoring system with prognostic significance. we applied mpi to patients with perforative peritonitis (on patients in sri ramachandra medical college) to validate the scoring method. it is a specific score with accuracy and allows prediction of prognosis. aim of the study ( ) to study the incidence and aetiology of perforative peritonitis. ( ) to study the demographics of the study population. ( ) to analyse if mannheim peritonitis index (mpi) is a valid scoring method. p-possum (p < . ) scores in the index surgery. malignancy was the most frequent initial diagnosis in patients with spp and benign diseases in tp. there were no differences on the interval between operations ( ± days tp vs. . ± days spp; p = . ) neither in the number of previous laparotomies (p = . ). tp was associated to emergency index surgery (p = . ) and icu hospitalization (p < . ), mechanical ventilation (p = . ) and vasoactive drugs (p = . ). there were no differences in any of the clinical and biochemical parameters analyzed, neither in sirs (p = . ) or p-possum scores after relaparotomy (p = . ). we found no differences regarding mean hospital stay ( days tp vs. days spp; p = . ) and mortality rate ( % in spp vs. % in tp; p = . ). conclusions: although certain differences exist, the clinical course of postoperative peritonitis seems to depend more on factors other than their secondary or tertiary origin. background and aim: patients with primary acs will often develop a secondary acute respiratory distress syndrome (ards). mechanic pressure is mainly responsibe in pulmonary findings in acs. we aimed the role of aspiration of gastric contents into lower airways in pulmonary complications of acs. methods: the rats were initially divided into five groups (group i-v), and then these groups were divided again into two groups if they are unfed (group ia-va) or fed (group ib-vb). in animals in group i-v intraperitoneal pressure (iap) was applied as follows: , , and cm h o by instillation of isotonic saline solution. results: total scores of lung histopathologic findings were concordant with the degree of iab. when the total scores of histopathologic findings in lungs were compared for each applied iab with control group, the scores were higher in fed animals than unfed animals. histopathologic findings in lungs were observed when increased-iap to mmhg ( cmh o) which was accepted as cut-off value. the comparison of the scores of histopathologic findings in two groups in which the applied iab was lower then the cut-off value were not significantly different from the control group. however comparison of the scores of histopathologic findings equal to or above mmhg were significantly higher then the control group. conclusion: our results show that that pulmonary aspiration related with passive regurgitation in acs has a substantial influence on histopathologic findings seen in this disorder. editor to self: secilmiş bildiri emergency surgery and delayed abdominal closure: results in cases carlos mesquita, marco serô dio, francisco castro-sousa emergency and general surgery departments, coimbra university hospital, coimbra, portugal delayed abdominal closure (dac), in emergency surgery, must be economical, fast to execute and easy to maintain, allowing second look and definitive closure, with minimal prejudices to the abdominal wall. as an alternative to the vacuum closure systems, the aa have been utilising the rotondo and schwab technique (iatsic-dstc course), by the interposition of a plastic towel between abdominal contents and wall. dac has been utilised in patients ( male, female, - ) , median age of ( - ). in five, after abdominopelvic packing for hypovolemic shock conditions. in , after mediastinal and peritoneal decontamination procedures and lavage for septic situations with actual or potential compartment syndrome: three from acute necrotizing pancreatitis, six from dehiscent digestive sutures and two from strangulated hernias. four patients died in the open abdomen situation, one from pancreatitis and three from dehiscent sutures. primary abdominal closure has been possible in : in the cases of packing and in of the of the cases of sepsis. in one case of pancreatitis it has been possible a secondary closure. dac is now accepted like a safe procedure in damage control and compartment syndrome conditions which contributes to ameliorate the results in life threatening situations. than %. this report describes our experience with vacuum assisted closure (vac-)therapy in the management of efs in an oa. materials and methods: nine patients with seventeen high output efs in an oa were treated with vac-therapy from january till january . the abdominal wound was covered with fatty gauzes. small efs were covered with a patch of hydrophilic polyvinylalcohol foam. the entire abdominal wound was covered with polyurethane foam which promotes granulation and seals of the oa preventing further spillage of enteric contents. continuous negative pressure at - mm hg was applied. for large fistulas with protruding mucosa a hole was cut within the polyurethane foam and an ostomy bag was placed over the fistula mouth. surgery with enterectomy was planned - weeks later. results: the vac-dressing was changed every days. three efs closed spontaneously. time between onset of fistulisation and surgery was days (median days). no additional fistulas occured. one patient died postoperatively. conclusions: although previously considered a contraindication to vac-therapy, the oa with efs can be managed with vac-therapy. a taylored application of the foam and a reduced negative pressure seem to allow a safe and reliable way to manage efs. partial enterectomy and abdominall closure is possible after several weeks. introduction: it was the aim of the study to analyze the potential value of microdialysis in the rectus abdominis muscle (ram) compared with conventional monitoring parameters currently in clinical use for the detection of the abdominal compartment syndrome (acs). methods: pigs were anaesthesized, mechanically ventilated and continuously monitored. microdialysis was performed in different abdominal organs, the ram and cervical muscle (distant reference) for glucose, lactate, lactate-pyruvate ratio (lpr) and glycerol. iah was maintained for h. three groups were analysed: control (a), iah mmhg (b) and mmhg (c).cardiopulmonary parameters, urinary output, blood gas analysis and venous lactate were recorded. results: mean arterial pressure and abdominal perfusion pressure remained above clinically defined thresholds during the experiments for groups a and b. in contrast, group c demonstrated a persistent decrease below these thresholds. significant reduction of urinary output was only seen in group c. lactate levels also remained within physiological range in all groups. in contrast, microdialysis revealed a significant increase of lpr in all monitored organs in groups b and c, indicating ischemia and energy failure. of interest, lpr in the ram showed a significant increase already after h of iah in group b. conclusion: microdialysis of the ram detected local metabolic derangements in animals with iah of mmhg while clinically established monitoring tools failed to show organ dysfunction/tissue ischemia. our data suggest that continuous microdialysis in the ram may represent a promising tool for early detecting iah-induced metabolic derangements before manifestation of clinically apparent acs. introduction: to avoid morbidity associated with open abdomen, subcutaneous linea alba fasciotomy (slaf) was introduced for management of abdominal compartment syndrome (acp) in severe acute pancreatitis (sap). we analyzed the efficacy and safety of slaf as a surgical decompressive technique. methods: a retrospective study of a -year period identified patients with sap and acs undergoing slaf. mean age was (range - ) years, were male and had alcohol-induced sap. slaf was performed - days post-admission, in / cases within h. results: the mean (range) preoperative intra-abdominal pressure (iap) was ( - ) mmhg and immediate postoperative iap ( - ) mmhg. the mean decrease was ( - ) mmhg and the decompressive effect was considered sufficient in / cases. two of these developed recurrent acs and required completion laparotomy, as did the with insufficient effect ( - days post-slaf). the mean preoperative sofa score was ( - ) and ( - ) - days postoperatively, the decrease was > in patients with successful slaf. eventually four patients underwent necrosectomy, two following sufficient slaf. the overall mortality and morbidity rates were / and / , no complications were attributed to slaf itself. mean hospital stay was ( - ) days. of the survivors, fascial closure was achieved in two, and planned hernia in four (two with split-thickness skin graft and two with post-slaf hernia). conclusion: slaf is a safe decompressive technique in sap-related acs. it is effective in about - % of cases, but some require completion laparotomy and/or necrosectomy later on. methods: between march and december , patients were managed with vac technique (kci, san antonio). the mean age was . ( - ) , and m/f sex ratio was / . indications were severe abdominal sepsis in patients, mechanical obstruction due to colorectal cancer in patients, pancreatitis in patients, posttraumatic abdominal compartment syndrome patients, evisseration in patients, enterocutaneous fistule in patients. results: as morbidity there were fistulaes and intraabdominal abscess in all patients. four of the patients were died with concomitant disease. there was no mortality related using vac system. thirty five patients ( %) was underwent a delayed primary closure, five underwent secondary healing by granulation, and four underwent split thickness skin grafting. surgical outcomes of severe hepatic injury were retrospectively reviewed. (methods) among patients with hepatic injury treated between and , patients who underwent surgery were included. the study period was divided into early ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) , middle ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) and late ( ) ( ) ( ) ( ) ( ) phases, and type of injury, surgical procedure performed and patients' outcome were retrospectively reviewed. (results) ( ) percentage of patients undergoing surgery: % ( / ) underwent surgery in the early phase, % ( / ) in middle and % ( / ) in late phase. ( ) timing of surgery: the numbers of patients underwent laparotomy in er, urgent laparotomy in or, and delayed laparotomy (after h) were ( %), ( %) and ( %) in early phase; ( %), ( %) and ( %) in middle; and ( %), ( %) and in late phase, respectively. ( ) surgical procedures performed: for type iiib (jast grading) cases, hepatectomy was performed in % and hepatorrhaphy was performed in %, giving a mortality rate of % in early phase, . % in middle and % in the late phase. for iiib + ivc/hv cases, hepatectomy was performed in all patients, giving a mortality rate of % in early phase, % in middle and . % in late phase. (discussion) with the increase in nonsurgical management, surgical treatment for hepatic injury is performed preferably in patients requiring immediate response, such as laparotomy in er. the surgical outcome of hepatic injury has been improving, with a survival rate of approximately % for type iiib cases and % for iiib + ivc/hv cases. rifat tokyay, tolga taymaz amerikan hastanesi, istanbul, turkey objective: the aim of this study was to assess the unexpected returns (ur) within month of the adult patients and the pediatric trauma patients initially seen in the _ istanbul american hospital emergency department. design: all urs between . . - . . were recorded. initial diagnosis, final diagnosis, initial treatment, final treatment, reason for readmission, and last medical condition were noted. results: eighty eight urs were recorded. final diagnosis of of these patients were surgical. forty one of these surgical patients had ur due to error in diagnosis and five due to error in treatment. fifty two of these patients returned on the same day or the next day, between nd and rd days, between th and th days and between th and th days. male to female ratio was to . three of the patients were pediatric trauma patients, were between - years, and were over . missed final diagnosis were: acute cholecystitis ( ), acute appendicitis ( ), missed fractures ( ), pneumothorax ( ) liver mass ( ), urethral stone ( ), ectopic pregnancy ( ), diverticulitis ( ), subarachnoid bleeding ( ), others ( ). conclusions: acute cholecystitis, acute appendicitis, and missed fractures were the most frequent surgical causes of urs after emergency department discharges. liberal utilization of abdominal sonography and abdominal ct scan may reduce missed acute abdomen in abdominal pain patients and appropriate radiological imaging and meticulous evaluation of the x-rays may reduce unnoticed spinal, pelvic and facial fractures in trauma patients. editor to self: seçilmiş bildiri olabilir introduction and aim: bacteremia sepsis and septic shock might develop rapidly for the patients with infection in bile path. early diagnosis, surgical treatment and antibiotherapy decrease mortality. in this study, the relation between choledocholithiasis, cholangitis and pancreatitis and treatment methods have been evaluated. method: the demographic features, the treatments, the intensity of the illness and mortality rate of the patients in afyon kocatepe university general surgery clinic between the years background: enterocutaneous fistula continues to be a serious surgical problem. they are related with major electrolyte imbalances, malnutrition and delayed tissue healing. our recent experience with enterocutaneous fistulas is reviewed hereby. methods: we analyzed the charts of all patients with enterocutaneous fistula from january to december . fistulas were assessed for localization, type, output, etiology, use of somatostatin analog and fibrin glue, nutritional support, type of surgical intervention, wound vac, and endoscopic findings. results: we identified patients. fistulas were localized as gastroduodenal in five patients, jejuno-ileal in seven, and colonic in eight. there were enterocutaneous and entero-atmospheric fistulas. endoscopy was performed in patients. output was low (< ml) in , whereas high (> ) in patients. seventeen patients developed fistulas due to iatrogenic reasons, six patients had an underlying malignancy, and three patients developed fistulas after pancreatitis. somatostatin analogs were used in patients. conservative treatment was performed in patients, primary surgical intervention in patients, and secondary surgical intervention in patients. fibrin glue was used in patients and was of benefit to . healing was achieved in patients ( %) after mean . days (range - ). two ( %) patients were died. conclusion: there appears to be no strict rule for treatment of enterocutaneous fistulas. liberal use of endoscopy, fibrin glue as well as restorative surgical intervention all play a major role, and should be employed selectively on an individual basis in the management of enterocutaneous fistulas. aim: in this study we aimed to evaluate the patients whose admitted to neurosurgery and anesthesiology intensive care unit (naicu) between and . matherial and methods: the patients whose admitted to naicu between january and january evaluated retrospectively. diagnosis, age, gender, mortality rate, staying day in icu of the all patients were determined. head traumas were obtained in trauma and multitrauma patients. results: total number of the patients those are admitted to naicu were , and of them because of head trauma ( . %). of the cases were pure head traumas ( . %) or politraumas accompanied with head traumas (ht).the rate of ht was . % of all traumas.there were men, women. mean age of men were . and women were . . staying icu were obtained as . days. the mortality rate was found as . % ( cases). operated cases were ( . %) and the cases followed without any operation were ( . %). mortality rate between operated cases were . % ( ) and nonoperated cases were . % ( ) . ht cases were evaluated by glascow coma scale (gcs) as severe (gcs £ ),intermediate ,moderate (gcs ‡ ).the cases which had gcs £ were ( . %). operated cases were ( . %) and of them dead ( . %). the mortality rate of operated cases ( cases) which had gcs = - were . % ( cases). the number of cases were which had gcs ‡ and the mortality rate of operated cases ( cases) were . % ( cases) at this group. the mortality rate of nonoperated cases ( cases) were . % ( cases). conclusion: the higher rate was ht cases when the trauma patients evaluated and mortality rate of nonoperated trauma patients were higher then operated trauma cases. author to editor: this study send for giving knowledge about traumas which admitted to kocatepe university school fo medicine at a period of months. introduction and aim: this study has been carried out to compare conservative and surgical treatment for the acute pancreatic. method: the treatment processes and radiologic outlook of the patients with acute pancreatitis in afyon kocatepe university general surgery clinic between the years and have been observed retrospectively. results: the average age of the patients with acute pancreatic is and . % of them were women. while conservative treatment was applied on patients, surgical treatment was applied on patients. while the etiologic reason was based on a known source for the . % of the patients, no reason was found for the . % of the patients. ercp was applied for six patients within the scope of conservative treatment. necrotizing pancreatitis existed in five patients. surgical debritment and abdominal washing were applied for four of the patients. acute pancreatitis were diagnosed for the . % of the patients after tomography. one of the patients which had surgical treatment died ( . %). there was no mortality for the patients having conservative treatment. there was not a substantial distinction between the two treatment methods in terms of mortality. ten of the patients had laparoscopic cholecystectomy, ten of the patients had open cholecystectomy (one of the patients with abdominal washing), one of the patients had choledochal exploration with t tube drainage and open abdomen. conclusion: the conservative treatment should be prefered though the treatment ways of acute pancreatitis under discussion. there is not a distinction between the tow methohds in terms of mortality. mü nevver moran, emre gundogdu, ismail bilgiç, hayrettin dizen, mehmet mahir Ö zmen department of surgery, ankara numune teaching and research hospital, ankara, turkey our aim was to compare to efficiancy of different scoring systems as a prognostic indicator in acute pancreatitis. medical records of patients ( female) with mean (range) age of ( - ) years who are diagnosed as acute pancreatitis during years were evaluated according to age, sex, etiologic factors, sirs, apache ii, balthazar scores and ranson scores at admission and at h in order to evaluate the correlation with mortality. the commonest cause was gallstone seen in ( %) cases followed by idiopathic in ( %), alcohol in ( %) and other in ( %). there were ( , %) cases with mortality and ( %) patients underwent operation. in survivors mean (sd) age was ( ) years, sirs score was . ( ) , ranson scores at admission was . ( . ) , ranson scores at h was . ( . ), apache ii score was . ( . ), balthazar scores was . ( . ). in the nonsurvivors group of ( , %) cases, the mean age (sd) was ( ). admission sirs score was . ( . ), apache ii score was ( . ), ranson score was . ( . ), ranson scores at h was . ( . ). when both groups were compared sirs score, apache ii score at the admission and ranson score at h were found to be statistically significant (p < . , p = . , and p = . , respectively), and no differences observed in reference to balthazarscore, hospital stay and icu stay (p > . ). although admission sirs score, apache-score and h ranson score were all found to be important prognostic indicators, sirs seems better and most promising indicator as it is easy to use and not requires sophisticated tests. normal in patients ( %). the appendix was divided by endo-loop in %, intracorporeal suturing in % and endo gia in % of the patients. the meso-appendix division was performed by endoclip ( %), ligasure ( %) and bipolar cautery ( %) . conversion to open procedure rate was ( %). mean operating time was min ( - ). mean hospital stay was . days . major complications were as follows: right iliac artery injury (n = ), bladder injury (n = ), post operative bleeding (n = ), intraabdominal abscess (n = ), appendiceal stump leakage (n = ). minor complications were trocar site infection (n = ) and mechanical bowel obstruction (n = ).there was no mortality. conclusion: la is associated with considerably decreased morbidity and might be considered as the treatment of choice in aa. hakan yanar, cemalettin ertekin, korhan taviloglu, ali fuat kaan gö k, emre sivrikö z, gü lay sarıçam, recep gü loglu trauma and emergency surgery service, istanbul university, istanbul faculty of mediine, istanbul, turkey background: gastrointestinal stenting is increasingly employed to relieve passage. it provides a palliation in inoperable cases or anastomotic strictures. in left-sided colonic and rectal obstruction, it allows decompression for a definitive surgery to be performed. methods: between may and december , patients with acute mechanical intestinal obstruction were treated with endoscopic stenting. localization of malignancy, stenting complications, and surgical interventions were assessed. results: there were a total of patients undergoing gastrointestinal stenting. sixteen patients received gastroscopic stents, four patients with esophageal, eight patients with gastric, four patients with duodenal tumors. stenting failed in five patients ( %), and surgery was required in four patients. nine patients were referred to adjuvant oncologic treatment. fourteen patients received colonoscopic stents; in one patient with a left-colon, in nine patients with sigmoid colon, and in four patients with rectal tumors. stenting failed in seven patients ( %), and six patients were operated emergently with a need for stoma in two patients. ten patients were referred to adjuvant oncologic treatment. no patient was died related with procedure. conclusion: gastrointestinal stenting is a useful adjunct in the treatment of patients presenting with acute mechanical intestinal obstruction for palliation as well as for decompression before definitive surgical therapy. introduction and objectives: internal hernia (ih) is a rare entity which occurs due to the protrusion of an intraabdominal viscus through a normal or abnormal mesenteric or peritoneal aperture. ih can either be acquired through a trauma or surgical procedure, or constitutional and related to congenital peritoneal defects. intestinal obstruction due to ih is very dangerous and lethal because it may be silent, and delay in diagnosis may cause severe abdominal conditions. in this report, we aimed to present patients with ih. methods: seventeen patients who were admitted to our clinic with the diagnosis of ih between january and january were included. patients' demographic data, type of the hernias, type of surgical procedures, length of hospital stay, and prognosis of the patients are evaluated retrospectively. results: there were nine male, eight female patients. mean age of the patients was . years ( - ) . postsurgical ih were seen in eight, paraduodenal in four, transomental in one, sigmoid mesocolon hernia in one patient, and the remaining three hernias were not classified. laparotomy was performed in patients, laparoscopy in and conversion to open surgery in patient. small bowel perforation was found in three patients. seven patients underwent intestinal resection and anastomosis. mean length of postoperative hospital stay was . days ( - ). there was no mortality. conclusion: ih is a rare cause of small bowel obstruction in adults and often present with complications. a high index of suspicion may lead to early surgical intervention and reduce morbidity and mortality. introduction: esophageal perforation is a serious surgical condition in which delay for surgery results in high mortality. application of covered stents is an alternative for emergency surgery. the aim of this study is to analyze the results of esophageal stent application retrospectively. the clinical data and outcome of patients diagnosed and treated for esophageal perforation by endoscopic stent application between february and december were evaluated. results: the mean age of these patients was ( - ) and male to female ratio was / . causes of perforation was mediastinal abscess (n ¼ ), metal stent application (n ¼ ), and balloon dilatation (n ¼ ). stents were applied immediately after perforation in three patients. remained three patients were referred from other institutions and the mean time of delay was h ( - ). perforations were at proximal (n ¼ ) middle (n ¼ ) and distal esophagus (n ¼ ). self expanding covered metal stents were applied in an appropriate position to bridge perforation area in a fashion to cover minimally cm distal and proximal normal esophageal mucosa to all patients under fluoroscopic control. no contrast leak was observed immediately after application and h later. patients were interned and observed under intravenous fluid and antibiotic therapy. except one patient developing transient subcutaneous emphysema no complication was observed. all perforations were closed and the stents were removed at the end of fourth week. conclusion: at the early phase of esophageal perforations covered esophageal stent application can be a better alternative to surgery. introduction: upper gi bleedings are serious conditions which may be life threatening. in seriously bleeding cases the failure of the endoscopic interventions makes surgical intervention necessary. the aim of this study is to present the success rate of endoscopic interventions for upper gi bleeding performed by surgeons. methods: clinical data and the outcome of endoscopic interventions made to of , upper gi bleeding patients admitted to a large community hospitals single surgical endoscopy center between january and september were analyzed retrospectively. results: hemostasis with endoscopic interventions was achieved in ( . %) at initial (n ¼ ) or at second endoscopy (n ¼ ). patients underwent emerging surgery. there was no mortality at the patients treated by endoscopic interventions where as seven patients died after surgery ( . %). conclusion: the outcome of surgery is poor in upper gi bleeding. thus maximum effort should be given to achieve homeostasis by endoscopy. the success rate of endoscopic interventions in this study performed by surgeons is extremely high and satisfying. naomi beks, mariëlle van gameren, sander ten raa, armand van kanten, gert roukema emergency department, maasstad ziekenhuis, rotterdam, the netherlands analgesia use at the emergency department, how evidence-based do we work when dealing with patient with acute abdominal pain? based on a pilot at our emergency department we concluded that it is still common practice to withheld a patient with acute abdominal pain from analgesia till examined by a surgeon or resident. this in contrary to evidence presented in literature which show no negative effect of analgesia use on accuracy of diagnosis in patients with acute abdominal pain. a total of inquiries were send to nurses, physicians and surgeons working at the emergency department of teaching hospitals in the netherlands. we questioned their standard policy on analgesia use in acute abdominal pain. a total of completed inquiries were retrieved, resulting in a response rate of %. there is a difference between the response of nurses and doctors, versus %, respectively. compared to nurses, doctors are more optimistic about the moment analgesia is given. remarkable is the result that % of patients do not receive any analgesia even after examination by a surgical resident and % of the patients have to wait till they are examined by a surgeon is outshining. patients are still withheld from analgesia till a resident or surgeon examines them even though this is not evidence-based medicine. there is no consensus in the netherlands on analgesia use in patients with acute abdominal pain in the emergency department setting. a national guideline for patients with acute abdominal pain is recommended. introduction and objectives: the benefits of laparoscopic appendectomy remain debated in literature. methods: this is a monocentric, retrospective study to evaluate the differences between open and laparoscopic appendectomy for length of hospital stay, wound infection, major complications. retrospective surgical site infection rate evaluation has been possible only for in hospital stay, no further clinical data has been collected regarding outpatient follow-up. results: from january to october we reviewed patients undergoing surgery for acute appendicitis. patients underwent laparoscopic appendectomy ( . %) (group a), patients open appendectomy ( . %) (group b). two different surgical teams, one for laparoscopy and one for laparotomy, performed the procedures. complicated (perforated or gangrenous) appendicitis were in group a ( . %) and in group b ( . %). mean hospital stay group a was . days, . (p = n.s.) group b. mean hospital stay in complicated appendicitis group (a + b) was . days, in uncomplicated (a + b) was . days (p < . ). laparoscopic appendectomy was associated with lower wound infection rate (group a . % vs. group b . %) (p < . ). infection rate in complicated appendicitis (a + b) was . %, in uncomplicated cases (a + b) was . % (p < . ). no mortality in both groups has been observed. one conversion in laparoscopic group was reported. no cases of deep surgical site infection have been observed. conclusions: laparoscopic appendectomy seems to be associated to a lower rate of wound infection. length of hospital stay and rate of major complication seems to be related to gangrenous or perforated appendicitis and not to the surgical technique. significantly lower on postoperative third and seventh day, respectively. conclusions: in this model of general peritonitis, mb significantly reduced adhesion formation. mb is blocking the tnf alpha early postoperative days. early blocking of the activity of tnf-alpha after peritonitis resulted in lower rates of adhesion formation macroscopically. the tnf-alpha can be an important factor for postoperative adhesion formation. results: laparoscopic surgery was performed in patients due to peptic ulcer perforation. seventy-five patients ( %) underwent laparoscopic repair alone or laparoscopic repair with omentoplasty. in the remaining patients ( %), the procedure was converted to laparotomy. amongst ( men / women) patients who were included into the study, the mean age was . ( - ) . in patients ( %, / ) preoperative diagnosis was unclear and the patients were taken to operating theater due to acute abdomen. in all patients, but one, the duodenal defect was repaired by primary suturing; in one patient, simply intra-abdominal lavage and drainage were performed because the omentum was found to seal the defect. omentoplasty was performed in ( %) patients. one and two abdominal drains were used in ( %) and ( %), respectively. mean hospital stay was . ( - ) days. morbidity was % (n = ). early morbidity included bile leakage in three patients, postoperative intra-abdominal bleeding in one. one patient had trocar site hernia. one patient ( -year-old female) died on postoperative day due to sepsis in the intensive care unit. conclusion: laparoscopic primary repair is a safe and efficient method in peptic ulcer perforation. akın tarım, sedat yıldırım, cem aydogan, gö khan moray, mehmet haberal department of general surgery, baş kent university, ankara, turkey introduction: approximately % of multiple trauma patients sustain concomitant burns. complicated management issues arise in these patients as burn and trauma care often conflict. the purpose of this study was to describe the different types of burn injuries seen in burn patients with additional forms of trauma, and to report the survival rate for this patient group. methods: in this retrospective study, patients were admitted to our center with concomitant burns and trauma from - . this study retrospectively analyzed the types of burn injury, extent of burns, types of other trauma associated with the burns, and outcomes. results: of this study group, were male. average age was . ± . . mechanisms included motor vehicle collisions, electrocutions with subsequent falls, one plane crashes, lpg or oxygen tube explosions and other type of explosions. average burn size was . ± . %. the most common traumatic injury was fracture and head injury ( ). management of fractures in burn patients and resuscitation in head injured burn patient represented the most common conflicts in patient care. there were deaths in this series. conclusion: burns are a rare but significant complication in the trauma patient. outcomes are dependent on rapid trauma evaluation as well as effective resuscitation and wound management. given the complexities of their problems, these patients necessitate a balanced multidisciplinary approach to maximize their potential for full recovery. thoughtful compromise between trauma and burn priorities is frequently necessary. introduction: fournier's gangrene (fg) is a rapidly progressive, polymicrobial, synergistic necrotizing fasciitis. in this study we aimed to determine the risk factors effective on the prognosis of the disease. methods: the files of consecutive patients operated for fg during - were investigated retrospectively. the surviving and mortal groups of patients were compared for demographic data, etiological factors and treatment modality besides length of hospital stay and treatment cost. results: the mean age of the patients was . years and female/ male ratio was / . mortality was seen in ( . ) patients and significantly high in female ( . %) (p = . ). the most frequent comorbid disease was diabetes ( . %), etiological factor was perianal abscess ( . %) and etiological source was anorectal region ( . %); and they did not affect the mortality. the most frequent cultivated microorganism e.coli ( . %) was significantly high in the mortal group (p = . ). imipenem was the antibiotic used in all of the patients. the mean number of debridements was , and intestinal diversion was utilized for . % of the patients. fecal decontamination ( . %) of the patients was performed by surgical ( ) and nonsurgical ( ) methods. the length of hospital stay in surviving group ( . days) was higher than the mortal group ( . days) (p = . ). there was no difference between two groups of patients for the length of hospital stay (p > . ). conclusion: female gender, duration of complaint prior to treatment, fournier gangrene severity point and cultivated microorganism (e.coli) were the factors affecting the mortality. aim: post-traumatic coronary aneurysms (ptca) are extremely rare. we report an asymptomatic ptca in a young patient. case: -year-old male, with no significant previous history. admitted intubated and ventilated after a car runover. he had cerebral, thoracic, abdominal, pelvic and lower extremity trauma. initial assessment disclosed eight left fractured ribs with associated pneumothorax; fast was negative, head ct normal. thoracic ct reveled small bilateral hemothoraces and pulmonary contusion, with no evidence of vascular lesions. he also had a fibular, clavicle, and pelvis fracture. control angio-ct at day showed pleural and pericardial effusions and raised the suspicion of left descending ptca, subsequently confirmed with mri. the patient remained asymptomatic with normal ekg and cardiac enzymes throughout this period. a coronariogram confirmed the ptca, that had undergone spontaneous thrombosis, with no further treatment required. discussion: coronary aneurysms (true or false) may occur after blunt thoracic trauma. ptca normally result from controlled rupture post myocardial infarction or cardiac contusion, with gradual wall rupture. although in this patient the diagnosis was made without any clinical manifestation, suspicion is the main key for diagnosis. aneurysms must be considered as a differential diagnosis in patients with thoracic trauma history associated with arterial emboli, congestive heart failure, arrhythmia, chest pain or dyspnea. conclusion: every trauma victim must be exhaustively evaluated. in any case a careful follow-up must be made in thoracic and abdominal trauma victims to decrease the possibility of missing injuries. aim: acute mesenteric ischemia (aim) continues to be highly morbid cause of emergency. early diagnosis and treatment may reduce severity of the disease. the aim of this study is to investigate causes for morbidity and mortality in ami patients. materials and methods: this retrospective study has patients of ami. the patients were classified according to their age, sex, clinical and laboratory findings, comorbidity, etiology, operative procedures, complications. and effect of these causes on mortality and survival was investigated. the results were statistically evaluated. results: of patients were male and were female. mean age was . for females and . for males. the most common symptom was abdominal pain. only one third of patients had diagnosed correctly before operation. amylase was high in % of patients. plain abdominal graphy showed air-fluid levels in all patients. mortality rate was high in patients aging over years (p < . ). there were no relationship between mortality and gender. the patients those who had massive small bowel and colon resection developed high mortality rates ( %). resection of ileocaecal valve also increased the mortality. five patients all of whom developed perforation died. majority of survivors had surgical intervention during first h of ischemic attack. the patients those died due to perforation had delayed surgical intervention. • there is no benefit of routine laboratory findings in early diagnosis of ami. • massive intestinal resection, absence of ileocaecal valve and stomal procedure increased mortality rate. • delay in diagnosis and treatment also caused high mortality. cem aydogan , yahya ekici , ebru sakallıoglu , sedat belli , mahir kırnap , emin tü rk , mehmet haberal department of generel surgery, baş kent university, ankra, turkey institute of burn, fire and natural disaster, baş kent university, ankara, turkey introduction: more than % of all burn patients can be managed on an ambulatory basis. appropriate management of minor burns minimizes further damage. methods: the epidemiology, demographics, and outcomes of ambulatory acute burn patients were reviewed at our center between and . patients who were in aba referral criteria were excluded from the study. results: the patients' mean age was . ± . years (range, - years) . the percentage of patients whose first admission was to our center was . %; the percentage of those referred from another center was . %. scald burns were the most frequently reported cause of burns ( . %). the house was the most frequently reported place at which the burns occurred ( . %). the percentage of stoverelated burns was . %. the upper extremities ( %) and lower extremities ( %) were the most frequently reported places on which the burns occurred. mean tbsa affected and superficial partial thickness burned area were . ± . % and . ± . %. the mean follow-up and the mean number of dressings applied to the burns were . ± . days (range - days) and . ± . (range - ). four patients ( . %) needed skin grafting, and two patients ( . %) were hospitalized for debridement without grafting. conclusions: close follow-up is important in minor burns to minimize further damage. burn centers must play an active role in the care of all burns. the devastating effects of burns can be prevented and decreased by educational programs. stove-related burns remain a problem in turkey. results: mean age was . ± . years. the percentage of the male patients was . %. the mean tbsa affected was . ± . %. the percentages of high voltage electricity injury, lightning injury, and lowvoltage current injury were . , . , and . %, respectively. place of employments ( . %) and outdoors ( . %) were the most frequently reported places at which the burns occurred. the burns mostly occurred in urban areas ( . %).upper and lower extremities were the most frequently affected regions. the percentages of the patients who underwent debridement, grafting, amputation and fasciotomy were . , . , . , and , %, respectively. the percentage of patients who had additional trauma other than electric burn injury was . %. mean hospital stay of patients was . ± . days. the mortality rate was . %. majority of the patients died from septic complications ( . %) conclusion: aggressive multidisciplinary treatment modalities and early debridment, grafting and/or flaps are very important. special considerations are required for public education about electricity and its hazardous effects. governmental supports are needed both in prevention and in therapy. ahmet erkilic, harun analay, sabri mehmet barazi, halil Ç eliksö z, bayram rü zgar burn center, av.cengiz gö kçek general hospital, gaziantep, turkey early staged excision and autogenous skin grafting or temporarily wound coverage with biologic dressing or allograft until autogenous donor sites are available is now conventional treatment for fullthickness burns. typically, tangential excision is performed with a handheld knife thus it may be difficult to control bleeding from the wound bed and difficult to assess the suitability of underlying for accepting a graft. a hydrosurgery system -versajet Ò is available that can be used for tangential burn wound excision. this device offers an easy and more precise way of excising eschar and is particularly useful excising nonviable tissue from the concave surfaces of hands and feet, as well as the eyelids and ears. totally, hydrosurgical tangential excision (hte) were performed for patients with burn, in our burn center in one and half year. several times performing were needed . % of patients (n = ). wounds of patients with - % total burned body surface were covered autogenous skin grafts subsequent to hte. more extensive wounds were covered with biologic dressings temporarily and wounds as soon as suitable autogenous skin grafting was performed. at this interval, burn wounds were shrunk average - % and donor skin poverty was increased. frequently, delaying to excision and coverage of burn wounds may be awful. early excision and early coverage of the burn wounds must be a golden standard for the current treatment of the burns. also hte is becoming a candidate to golden standard at burn treatment. introduction: in our previous study, we examined the treatment results of burn patients older than years, and found a significant increase in mortality with increasing age groups. the aim of the present study was to reevaluate this patient group and also compare these results with the previous study period of to . patients and methods: one-hundred and fifteen patients older than years were admitted to our burn unit during the last years. these patients were divided to three groups with respect to their ages (group a: - years, group b: - years, and group c: older than years). demographic properties of patients, etiology, and extend of burn injury, co-morbidity, length of hospital stay, and mortality rates were recorded. results: during the last years, demographic properties and etiology of burn injury did not changed significantly. however overall survival rate increased from . to % and ld values for burn injury are significantly increased in all age groups. length of hospital stay is significantly decreased in all age groups, especially in group b (from . to . days). co-morbidities did not change over time and sepsis is the leading cause of death in patients ( %). conclusion: in our burn unit, treatment results in patients older than years showed a significant improvement during the last years. introduction and objectives: patients who has weakness of mental and motor functions are under more risk than normal burned injured population. we would like to focus on burn injured cases that have co-exiting morbidities. methods: comorbid patients who applied to burn unit due to burn between january and july were taken into evaluation. comorbid etiologies were seizures ( case), mental retardation ( case) and down syndrome ( case), respectively. results: during follow-up period, one of the cases had aggrevated petit mal convulsion due to devastating effect of burn injury. in one case there was grade pressure sore and urethral infection who was paraplegic patient. weight loss was observed on a geriatric case that had seizure due to insufficient nutrition. conclusion: burn injured cases that have comorbidity, special care, and additional measures should be taken. psychological, neurological or geriatric causes are the factors that affect the recovery of burn defects and success of operation. detailed evaluation of coexisting disorder and additional care are the key points of the comorbid burn patient. aim: the present study was aimed to evaluate the gender differences of burned children in clinical course and outcome. methods: children (aged - ) admitted to our burn center between august and january were retrospectively evaluated. total burn surface area (tbsa), levels of some acute phase markers, grafting need, and hospitalization time were analyzed. results: sixty three patients [ ( . %) males, ( . %) females] were included in this study. the mean age was respectively . ± . years and . ± . years in males and females (p = . ). the mean tbsa burned respectively . ± . % and . ± . % in males and females (p = . ). the mean wbc count in admission was significantly higher in males than females ( . ± . x - /l vs. . ± . x - /l, p < . ), but there was not any significant difference between females and males in crp count. (p = . ). skin graft operation was performed in ( . %) of males and in ( . %) of females (p = . ) and also, we did not find any significant difference between males and females in hospitalization time ( . ± . days vs. . ± . days, p = . ). conclusion: although many studies have showed that critically ill females have a better outcome than critically ill males, any significant difference was not observed between burned male children and burned female children in most of the clinical parameters, except white blood cell counts. introduction and objectives: the goal of our study was to evaluate the preparedness of hospital physicians, emergency physicians and paramedics in the eu and the usa for a mass casualty incident. methods: an online survey which contained questions was sent to the head of the department of trauma-surgery, emergency medicine and to paramedics by e-mail. among other things we questioned: existence of a hospital emergency-and disaster plan and the yearly exercise of the plan. coordination with the local rescue service as well as existence of decontamination facilities were asked for. replies were analysed statistically with the one-way analysis of variance (anova) test and the turkey-kramer multiple comparisons test. results: altogether, assistant and emergency doctors as well as paramedics answered. % were not conscious of the details of the disaster plan of her hospital while % did not know the plan at all. % of the interviewed doctors did not know her area of responsibility in the case of an internal emergency. % of the interviewed know what to do in case of an mci. % of the interviewed doctors and % of the paramedics did not know her area of responsibility at the treatment of patients contaminated chemically, nuclearly or biologically. conclusions: the preparedness for doctors and paramedics in hospitals and in the preclinical rescue service in the eu and the usa on a mci (mass casualty incident) are insufficient. the emergency medical education of doctors and paramedics should be adapted to the terrorist threats disaster preparedness of chief physicians and hospitals in germany, the eu and the usa for a mass casualty incident introduction and objectives: the goal of our study was to evaluate the preparedness of hospitals in the eu and the usa for a mass casualty incident. methods: an online survey which contained questions was sent to the chief physician of hospitals by e-mail. things we questioned: existence of a hospital disaster plan and the yearly exercise. coordination with the local rescue service as well as existence of decontamination facilities. replies were analysed statistically. results: altogether, senior consultants, of this senior consultants from germany as well as senior consultants from the usa and the eu, answered. all people claimed to have a hospital disaster plan. % of the german hospitals made an exercise of the plan with tabletop exercises. however, % of chief physicians in the usa and the eu made an exercise of the plan regularly with table top exercises. % of the hospitals in the brd did not have any decontamination possibility of nbc (nuclear, biological, chemical) contaminated patients, while % of the hospitals had this possibility on the spot in the eu and the usa. conclusions: the exercise of the hospital disaster plan in germany is insufficient, compared with the hospitals in the eu and the usa. furthermore the german hospitals are badly equipped in the worldwide comparison to decontaminate patients on the spot. we demand for an increase of the ''exercises'' of the hospital disaster plan (also by tabletop exercises) as well as an improved equipment for the decontamination of the injured. in the two big earthquakes that occurred in the north-west of turkey in in short intervals within less than months there were approximately , cases of death and around , were injured. there were several other deadly earthquakes in the whole world the same year. main survival factors in the post-disaster period are prevention from injuries as well as detecting the location of the survivors and the rescued. the reality of the situation of persons who lost their lives in such traps, the severely injured, and the ones who survived must be analyzed. rational prevention methods against possible crush injuries due to collapsing buildings have been con-sidered in the light of the field and simulation experience we gained and suggestions have been presented to reduce mortality and morbidity. our work has been conducted with the aid of medicine based on proof, appropriate observation as well as sampling and experimental methods. a global approach concerning worst case scenario led by earthquakes has been proposed taking into consideration the different models of behavior in different countries and societies to increase the chance of survival to a maximum and to reduce injuries to a minimum level. due to unlimited possibilities of travelling nowadays, it is not possible to estimate the place, the country or the circumstances under which a person could experience a disaster. carlos alberto godinho cordeiro mesquita ordem dos mé dicos, colé gio de competê ncia em emergê ncia mé dica, lisbon, portugal in portugal there are three official ways to differentiate: specialty (vertical), subspecialty (vertical) and competence (transversal). doctors may access to a subspecialty or a competence as a second step, after a specialty. portuguese medical association (ordem dos mé dicos, om) is the official entity that regulates all the medical and surgical activities in portugal, being his duty to protect the public interest. doctors must be registered with to practise medicine or surgery. om also sets the standards and outcomes for basic medical education. after graduating from medical school and completing their foundation training, doctors usually complete a third and even a fourth stage of postgraduate training, whose standards are set by the colleges. these are responsible for promoting the development of postgraduate medical education and training for all, establishing standards and requirements and making sure they are met across the country. emergency medicine exists as a competence since and goes behind the prehospital acute care. this college is strongly interested in the development of an autonomous college of competence on emergency surgery (trauma surgery included) and it exists, since , an official national working group on emergency surgery education (grupo de trabalho para a formaçã o específica em cirurgia de emergê ncia), with representatives of general surgery ( ), neurosurgery ( ), orthopaedics ( ), thoracic ( ), vascular ( ) , urological ( ) and paediatric surgery ( ) . the general surgeons, iatsic members and dstc instructors, also integrate and lead the national steering committee for dstc, after a recently signed memorandum of understanding. author to editor: the point of the situation, from an organisational point of view, about trauma and emergency surgery education in portugal and the importance for the relationship with portuguese speaking doctors around the world introduction and objectives: practical training in emergency medicine should be an important part of undergraduate education, as every physician should be able to handle medical emergencies. however, adequate practical training is time and personal consuming. this work seeks to determine whether medical students (peer to peer education) can be trained as course instructors in emergency medicine training and if there are differences in the training outcome. methods: the undergraduate training consists of both basic life support (bls) and advanced cardiac life support (acls) courses. after both courses, students have to pass a multiple choice test and have to complete a course evaluation. during the instructor training, all candidates, students and physicians were trained together with theoretical and practical training and were furthermore supervised during their first courses. results: until now, bls and acls trainings were conducted of which % (bls) and % (acls) were run by medical students. there were no significant differences in the written examinations nor in the course evaluations ( = very good to = unsatisfactory) between courses by staff ( . for bls and . for acls) or medical students as trainers ( . for bls and . for acls, respectively). conclusions: peer to peer education can be a useful tool in the manpower consuming practical training in emergency medicine without influencing the learning outcomes or the evaluation. background: non-invasive pelvic ring stabilization (pelvic binding, pb) in shocked patients is recommended by state and institutional guidelines regardless the fracture pattern. the purpose of this study was to determine the adherence to the guidelines, radiological efficacy of the technique, and identification of potential adverse effects associated. methods: analysis of the prospective database of a level trauma center on high-energy unstable pelvic fractures. collected data included patient demographics, physiology, fracture classification, application, and timing of pb, associated injuries and outcomes. pre and post-pb radiographs were compared to evaluate the changes in fracture position. the potential effects of pb on soft tissue complications were assessed by independent experts. results: during the -month study period a total of pb was performed on patients with high-energy unstable pelvic ring injuries. stable patients were less likely to get pb ( %) than shocked patients ( %). the adherence to guidelines was %. analyzing fracture types (ao/ota classification) of shocked patients the adherence was: b %, b %, b %, c %, c %, c %. better radiological appearance was detected in b %, c %, c %, c % types. one femoral artery, four bladder and three rectum injuries were identified in patients with pb applied. there were no association between the complications and the pb. introduction and objectives: in our country, the vast majority of circumsicion is stil not done by physicians. in this study, we evaluated the patients who treated for circumsicion complications in our clinic. methods: a total of children who treated for cicumsicion complication in our clinic between and were evaluated. results: mean age during circumsicion was . months ( - years). out of had not been circumsiced by physicians. complication was bleeding in patients, burred penis in , complete glanular amputation in , and urethral fistula in patient. one suture was enough to control bleeding for the majority of patients with this complications, while general anesthesia required for treating other complications. conclusions: significant number of children still undergo circumsicion between and years old (fallic period) in our country. the vast majority of complications occur when circumsicion is not done by physicians; significant number of these complications require revision under general anesthesia. as a result, circumsicion is still a challenging both public and social problem in our country, and results in high morbidity because the majority is not done by experienced hand. arda demirkan , salih ekinci , onur polat , serdar gü rler , mü ge gü nalp , semih baskan department of emergency, ankara university, ankara, turkey department of general surgery, ankara university, ankara, turkey objective: multiple trauma involves at least two systems of body which abdomen, extremities, chest and head-neck. the aim of this study is to show relationship between the severity of injury and electrolyte changes in multiple trauma patients. method: this is a prospective study which adult multiple trauma patients ( male and female) were studied. the median age was . (range - ) . in all cases, serum sodium, potassium and calcium levels and injury severity score (iss) were obtained on admission to emergency department after trauma. severity of injury was estimated with iss. degree of association between variables was evaluated by spearman's correlation coefficient test. results: the mean sodium levels was . mmol/l, the mean potassium levels was . mmol/l, the mean calcium levels was mg/ dl. there was a negative correlation between calcium and iss, and this is statistically significant (p = . ). while other serum electrolytes (sodium and potassium) did not change according to iss. conclusion: electrolyte abnormalities often occurs in critical ill patients, this imbalance has a prognostic importance particularly in multiple trauma patients. electrolyte changes determinated in early period and appropriate resuscitation is indispensable. we suggest that low calcium levels can be considered for the severe injury. this condition may be related to interrupted calcium mechanism in critical trauma patients. introduction and objectives: preparation is essential to meet the challenge of optimal care for a sudden unexpected surge of casualties due to a major incident. by definition, requirements exceed standard care facilities in qualitative and or quantitative respect and interfere with regular patient care. to meet the growing demand for disasterpreparedness a permanent facility to provide structured, prepared relief in such situations was developed. we describe this facility. objectives: the aim of this study is to find out the effects of melatonin on the erythrocyte and kidney malodyaldehyde (mda) and superoxide dismutase (sod) levels in radiocontrast nephropathy. methods: in this study, new zealand type rabbits were included. the test subjects were divided into four groups six rabbits in each (control, sham, hydration and melatonin groups). blood samples of all subjects were taken in beginning of study. renal tissue was obtained in the control group. the rest received ml diatrizoat sodium intravenously. hydration group was given ml/kg/day iv bolus . % nacl. melatonin group was given mg/kg iv melatonin four times with the same dose isotonic. it was blood and renal tissue samples were taken at the th and nd hours. mda levels were determined with ohkawa method, sod enzyme activity was studied with ransod (randox,uk) superoxide dismutase assay kit. results: the mean renal sod value of the melatonin group ( . ± . nmol/g) was significantly higher than in the sham ( . ± . nmol/g), control ( . ± . nmol/g) and hydration groups ( . ± . nmol/g) (respectively p = . , . , . ). the mean renal mda value of melatonin group ( . ± . nmol/g) was significantly lower than sham ( . ± . nmol/g) and hydration groups ( . ± . nmol/g) (p = . , . respectively). conclusion: melatonin has a curative effect on the lipid peroxidation caused by the contrast substance in the kidney. in preventing nephropathy resulting from contrast substance, giving melatonin together with hydration can be more effective than giving hydration alone in the clinic. in addition, all datasets entered with voice recognition were complete and available in the system as soon as the patient left the trauma bay. compared to the retrospective cohort % of the patients had incomplete data concerning the vital parameters. conclusion: the introduction of voice recognition technology real time produces more accurate data more quickly. we are convinced that high tech technology will increasingly assist the trauma surgeon and if we are correct it looks like the prediction of don trunkey will come true viz: ''the current possibilities for using digital resources within medical care are merely limited by our own imagination'' introduction and aims: despite the improvements in the diagnosis and treatment, mortality rates are still high following urgent operation for perforated peptic ulcer (ppu). in this study, we analyzed the factors affecting the survival of the patients operated for ppu. materials and methods: the records of the patients operated due to ppu between january and january were analyzed. age, sex, american society of anesthesiology (asa) score, alcohol consumption, smoking, nonsteroidal antiinflammatory drug (nsaid) usage, the time passed from the onset of symptoms to operation, history of previous peptic ulcer disease, diameter and localisation of the ulcer, surgical technique, length of stay, postoperative complications and mortality rates were determined. results: the mean age was and asa score was . primary suture and omentoplasty was the selected procedure in patients while gastrostomy was added to primary suture to another patients. twenty nine patients received primary suture, truncal vagotomy and gastroenterostomy and seven underwent resection. the mean length of stay was days. three patients suffered from atelectasis and pneumonia, one from empyema, eight from surgical site infection and four from leakage. twenty three of the patients experienced respiratory failure and died of multi organ deficiency ( . %). age and asa score were found as factors significantly affecting survival. abdominal cocoon (idiopatic sclerosing encapsulating peritonitis) is a rare disease of the peritoneum which refers to a condition where there is a total or partial encasement of the small bowel by a dense fibrous membrane. the abdominal cocoon is probably a developmental abnormality, largely asymptomatic, and is found incidentally at laparotomy or autopsy. it is an unusual cause of intestinal obstruction. pre-operative diagnosis cannot be often made correctly. complete recovery is expected after removal of the membrane surgically. a -year-old man presented with abdominal pain, swelling and vomiting of two day's duration. there was no history of peritonitis, abdominal surgery or tuberculosis. physical examination of the abdomen revealed a distended abdomen, hypoactive bowel sounds, tenderness and rigidity in the whole abdomen. a tender lump was palpated in the right lower quadrant. routine laboratory workup revealed a total leukocyte count of cells/ml, and normal serum chemistry. pa x-ray of the chest normal. plain abdominal x-ray showed few air-fluid levels. contrast-enhanced abdomen-pelvis computed tomography showed a dilatation up to . cm in small intestine. emergency laparotomy was performed through a right paramedian incision. in exploration, small bowel was observed to be dilated, its mesentery was edematous and the whole small and large bowel was covered by a dense whitish and approximately mm thick membrane. the membrane was partially removed, and adhesiolisis of the intestinal loops was performed without bowel resection. after surgery, the patient was tolerated diet without any complication and was discharged, on hospital day . methods: the data of al-ain hospital trauma registry were prospectively collected over a period of years ( ) ( ) ( ) ( ) . all trauma patients who were admitted to intensive care unit (icu) were included in the study. univariate analysis was used to compare gender, age, nationality, mechanism of injury, systolic blood pressure and gcs on arrival, the need for ventilation, presence of head or chest injuries, ais for both the chest and head injuries and the iss. significant factors were then entered into a direct logistic regression. results: there were patients ( males). mean (range) age was year. . % were uae nationals. the two most common mechanisms of injury were road traffic collisions ( . %) followed by fall from height ( . %). the median (range) iss was . the mean (sd) icu stay was . ( . ) days while the mean (sd) hospital stay was . ( ). the overall mortality was . %. significant factors that have affected mortality included gcs (p < . ), mechanism of injury (p = . ), age (p = . ) and iss (p = . ). the best gcs that predicted mortality was . while the best iss that predicted mortality was . conclusions: rta is the most common cause of serious trauma in uae followed by falls. gcs is the most significant factor that predicted mortality in icu trauma patients. introduction: glutamine is an antioxidant which enhance glutathione levels. in this study our goal is to assess the safety and efficacy of parenteral glutamine on antioxidant capacity and organ dysfunction in septic patients. methods: prospective, randomized study of the septic patients admitted to the surgical intensive care unit (icu). patients were randomized to receive either glutamine (group glu, n = ) or glutamine + n-acetylcysteine (group nac, n = ) or a control supplement-placebo (group pla, n = ) parenterally up to days. organ dysfunction and clinical outcomes were assessed by daily total sequential organ failure assessment (sofa) score over the -day study period. serum total antioxidant capacity (tac) was measured by cuprac method. also we evaluated procalcitonin (prc) and c-reactive protein (crp) levels as infection markers on days , , , and . results: there was no significant differences between the patients' ages, apache ii, sofa scores and infection markers on the day of admission. group glu and nac showed a significant decline of daily total sofa score (glu: p < . , nac: p < . , pla: p = . ) and crp levels (glu: p < . , nac: p < . , pla: p < . ). but prc levels decreased significantly over time just in group glu (glu: p < . , nac: p = . , pla: p = . ). on the other hand, serum tac measurements were not significant. the mean icu length of stay were glu: ± . , nac: . ± . , pla: . ± . (glu/nac: p < . , glu/pla: p < . ), but in group glu the overall mortality was significantly lower than nac and pla groups (glu: %, nac: %, pla: %). conclusion: in septic patients, parenteral supplementation with glutamine results in significantly better recovery of organ function compared with nac and pla. we coud not find any significant relationship between tac levels and clinical outcomes. background: acute renal failure (arf) requiring renal replacement therapy in icu setting is related to high mortality. the purpose of the study is to assess any indicators of improved survival. materıal and methods: retrospective study of trauma patients, who underwent haemodialysis over a period of years (patients with penetrating, blunt trauma and burns). information on pre-hospital and in-hospital resuscitation, trauma scores and physiological scores and daily icu records were collected. the majority of patients were initially dialysed with cvvhd and later on with sled. results: of the patients, died and overall mortality was . %. this was highest in the group of burn patients ( %). survival in all patients irrespective of mechanism of injury was unrelated to rts, iss, apache ii and triss. the duration of haemodialysis be-tween the three different trauma mechanism groups was not significantly different. age is not a significant predictor of survival. patients with polyuria at time of initiation of haemodialysis had not a better outcome than those who were oliguric/anuric/normouric. conclusions: arf in trauma patients has a low survival rate. controversial conclusions have been presented in the literature. in our study, none of the parameters reported in previous publications to affect survival was proven as correct, although our number of patients was comparable to that of other studies. as we are still at an early stage of understanding the predictors and the behaviour of renal failure in the trauma patients there is a need for the planning multicentric prospective studies. weaning from mechanical ventilation constitutes a dynamic process, and represents one of the most challenging decisions in the management of critically ill patients. success of weaning depends on multiple factors, and wrong decisions result either in prolonged mechanical ventilation, or reintubation and nosocomial pneumonia. many mathematical indexes have been described and used for decision making with varying successes. we have developed a multiparameter fuzzy-logic decision support system for prediction of success of weaning from mechanical ventilator. after fuzzifying relevant numerical variables, this system evaluates the appropriateness of perfusion, arterial blood gases, mechanical properties, and gas exchange, and converts these to a weaning probability. system has been designed using jfuzzylogic package and uses mamdani center of gravity algorithm for defuzzification. after optimization system has been tested over a software that creates random clinical scenarios within a range that can represent challenging patients. for each scenario jabour' weaning index, rapid shallow breathing index (rsbi) and pressure time index have also been calculated and compared with fuzzy-logic system. results indicate that currently used indexes and especially rsbi, disregard many important parameters and shown a potential to fail in many critical scenarios (in % of simulations). additionally we would like to discuss the potential of fuzzy-logic in clinical decision support, and design and optimization issues. trauma scoring systems used for uniform reporting and evaluation of trauma outcomes include physiologic, anatomic and combined systems. these systems have already been evaluated and shown to have accurate performance. we proposed a possible effect of response to resuscitation on the performance of trauma scoring. data necessary for calculation of iss, rts, triss and ascot systems have been retrospectively collected from the records of last consecutive trauma patients admitted to our surgical critical care unit. score and mortality prediction calculations have been performed over a software developed in our department, at three time points, at admission to er, after h of resuscitation, and at icu admission. additionally a fuzzy-logic inference system which uses physiologic variables as input has been designed for trauma related mortality prediction and applied to the same dataset. performances of scoring systems and fuzzy-logic inference system have been evaluated. results indicated that all systems have good discrimination, but variable calibration characteristics. for all systems evaluated response to resuscitation has effected system performance and scores and predicted mortality values calculated after resuscitation have shown better discrimination. fuzzy-logic inference system designed has shown discrimination characteristics comparable but not better then the other systems, which indicate the importance of inclusion of specific organ injuries in trauma scoring and mortality prediction. daily monitoring of immune/inflammatory status is a fundamental procedure in the icu. in small animal disease models such a surveillance is challenging given the limited blood volume available. to validate a new method for daily immuno-inflammatory monitoring in critically ill (septic) mice, we followed their short/longterm survival, organ function and inflammatory status. furthermore, the reliability of complete blood count (cbc) differential was tested in re-suspended blood cell pellet. female of- and cd- mice were subjected to cecal ligation and puncture (clp). ll blood samples were collected (facial vein puncture) from half of each strain daily for days or on day only. additionally, ll (diluted : ) volume was collected (of- only) and divided to compare cbcs in whole versus resuspended blood. there were no differences in / -day clp mortality. for both strains, changes in circulating interleukin- and chemical parameters (alt, ldh, bun, glucose) were comparable between sampled subgroups. ll sampling in of- mice caused a decrease of % in rbc and % in hb (both p < . ). in cd- animals, both rbc and hb showed a similar decrease of % (p > . ). platelet and wbc counts were unaffected. cbc comparison displayed a high correlation for all cell types (r > . , slope > . ) except lymphocytes (r > . ,slope > . ). this was reproduced in non-clp mice. the results indicate the minimal biological effect of daily sampling upon septic mice. cbc differential from resuspended pellet is highly reliable. this newly validated facial vein punture sampling protocol allows multi-directional monitoring in mouse models of critical illness such as acute peritonitis. introduction: a comparison of the amount of procalcitonin (pct) with that of c-reactive protein (crp) during various types of and severities of multiple trauma., and their relation to trauma-related complications, was performed. the aim of this study was to describe the amount of and the time course of pct and crp induction in patients with various types of and severities of high-velocity trauma. background: to provide a score to predict the risk of early mortality after single craniocerebral gunshot wound (gsw) based on three clinical parameters. methods: all patients admitted to baragwanath hospital, johannesburg, south africa, between october and may for an isolated single craniocerebral gsw were retrospectively evaluated for the documentation of (a) blood pressure on admission, (b) inspection of the bullet entry and exit site, and (c) initial consciousness (n = ). results: conscious gsw victims had an early mortality risk of . %, unconscious patients a more than fourfold higher risk ( . %). patients with a systolic blood pressure between and mmhg had a . % risk of mortality. hypotension (< mmhg) doubled this risk ( . %) and severe hypertension ( mmhg) was associated with an even higher mortality rate of . %. patients without brain spilling out of the wound (''non-oozer'') exhibited a mortality of . %, whereas it was twice as high ( . %) in patients with brain spill (''oozer''). by logistic regression a prognostic index (pi) for each variant of the evaluated parameters could be established: non-oozer: , oozer: , conscious: , unconscious: , £rrsys < mmhg: , rrsys < mmhg: , rrsys mmhg: . this resulted in a score ( - ), by which the individual risk of early mortality after gsw can be anticipated. conclusions: three immediately obtainable clinical parameters were evaluated and a score for predicting the risk of early mortality after a single craniocerebral gsw was established. gunshot wounds to the head are associated with poor outcome. we reviewed data to identify prognostic factors. we performed a retrospective study of all patients admitted to a level trauma center with isolated gunshot injury to the head during six and half years. data collected included demographics, mechanism of injury, prehospital and resuscitation room data, and initial ct scan characteristics. the primary outcome measure was the glasgow outcome scale (gos). seventy-two patients with isolated gunshot wounds to the head were admitted. overall mortality was %. the mortality for patients with an initial gcs of < was versus % for those with initial gcs > (p < . ). fifty percent had pupillary abnormalities on arrival at the emergency department. mortality in this group was versus % in those with normal pupillary reflexes (p = . ). elevated plasma lactate was associated with nonsurvival. thirteen percent of survivors were assessed as able to live independently after their injury. civilian gunshot injury to the head is related to high mortality. indicators of outcome are the admission gcs score, pupillary abnormality, metabolic acidosis, and ct pattern of severe injury. introduction and objectives: the aim of this study is to compare the effects of the mannitol and melatonin on the levels of blood and brain malondialdehyde (mda). methods: in the study, new zealand type rabbits were used. the test subjects were divided into four groups; sham (n = ), control (n = ), mannitol (n = ) and melatonin (n = ) groups. blood cerebrum tissue samples were taken to research for mda in the control group. head trauma was applied with feeney method to the rabbits in the other groups. venose blood samples were taken before and after trauma to observe mda. mg/kg melatonin was given to the melatonin group, and g/kg mannitol was given to mannitol ( %), between and in ( . %), and between and in patients ( . %). mortality rate was % (n = ). patients who died had significantly higher iss (p < . ), lower gcs, (p < . ), and higher head ais (p < . ). conclusions: road traffic collision is the leading cause of head injury in our setting. in this study population, head injury was severe, more than one fifth of the cases were admitted to the icu, and gcs was below in %. patients who died had significantly higher iss, lower gcs, and higher head ais. backgrounds and objectives: benefits of emergency burr-hole craniotomy (or evacuation) for patients with critical head trauma remained unclear. our study objective is to compare the effectiveness of burr-hole craniotomy to decompressive craniotomy using data from a large-scaled, multicenter and nationwide registry of hospitalized trauma patients in japan. materials and methods: among a total of records registered in japan trauma data bank, we selected patients with critical head trauma which were scored as ais (critical injury on the abbreviated injury scale) on head and underwent either of burr-hole craniotomy or decompressive craniotomy. parameters of the trauma injury severity score (triss) were used to adjust the baseline trauma severity. univariate analysis and multivariate logistic regression analysis estimated the relative risk of inhospital death. results: a total of zygomatic and/or orbital fractures were identified with subtarsal ( %), subciliary ( %), transconjunctival ( %) incisions, and laceration ( %). the risk of ectropion was highest in subciliary incisions ( . %, p = . ), however, only one case required operative management. entropion was found in two cases after transconjunctival incisions (p = . ); both required operative management. lid edema was present in . % of subtarsal and . % of subciliary incisions (p = . ). one hypertrophic scar was seen with the subtarsal and two cases with the subciliary approach (p = . ). conclusions: lower eyelid malposition occurs after any lower eyelid incisions for facial fracture repair. ectropion is most commonly seen in subciliary incisions, while entropion is rare. a subtarsal incision has a low risk of malposition, however is associated with hypertrophic scars. although choice of incision can be based on surgeon preference, a thorough patient discussion must include potential complications with each approach. in traumatology things happen quickly, data are often incomplete and therefore misleading and there is also pressure for quick decision. in dealing with the matter we distinct among wrong decisions based on insufficient data and errors due to systemic faults or individual incompetence or negligence. possible systemic faults are at every level of treatment: taking history, clinical examination, diagnostics, decision making, treatment procedures and even rehabilitation. most analysed errors occured when patient was handed over to another team or another level of treatment. haste and insufficient or inadequate report leads to wrong assumptions and -if that is not discovered in time -to wrong treatment. on personal level usual mistake was being satisfied when one injury was found and others were missed to insufficient exam or diagnostics. dealing with unfamiliar drugs lead to overdosage and sometimes death of the patient. to avoid such disasters extra training was added to medical school and medical students systematically approach the subject. at the emergency department adherence to protocols is encouraged, especially in cases of unresponsive patients. on hospital level enough time should be provided for attending physicians to make thorough rounds. this should provide much needed redundancy in the age of maximum efficiency. unfortunately we feel it is still not possible to implement measures of self-reporting as known by the airline industry due to inadequate law regulation! author to editor: measures for preventing medical errors in trauma department is showed. background and aim: missed injuries adversely affect patient outcome and damage physician, as well as institutional, credibility. autopsies are useful in uncovering missed injuries or undiagnosed conditions that contribute to death after injury. the aim of this paper is to analyze and compare medical documentation and autopsies findings in searching for missing injuries in trauma fatalities treated in our hospital. patients and methods: we analyzed data for patients died after trauma in years period (january st, -december st, introduction: immune suppression is a compensatory mechanism in acute inflammation e.g. following trauma. multiple mechanisms underlying this phenomenon include decreased cytokine production, shifts in cytokine balance and unresponsive adaptive immunity. we show in a model of acute inflammation that neutrophils, apart from their established pro-inflammatory characteristics, possess multiple mechanisms mediating immune suppression. methods: healthy male volunteers were given ng/kg e. coli lipopolysaccharides intravenously. blood was taken at various time points. neutrophils were stained with antibodies and isolated by facs. neutrophil receptor-expression, phagocytosis and oxidase were measured. lymphocytes were cultured in the presence of neutrophil subsets and cd /cd or pha. proliferation was measured by incorporation of h. results: distinct neutrophil subsets were identified. - h after administration of lps % of neutrophils displayed a two to threefold decreased expression in innate immune receptors, decreased phagocytosis and oxidase production. another neutrophil subset ( %) inhibited lymphocyte proliferation by % (in the presence of cd /cd or pha) in a : ratio independent of il- , tgfb, arginase or indoleamine - . instead direct delivery of h o appeared to be the mechanism of immune suppression. conclusion: in acute inflammation neutrophils utilize multiple mechanisms mediating immune suppression. firstly refractory neutrophils appear in the circulation. secondly another population of circulating neutrophils effectively suppresses adaptive immunity. these observations dictate an important role for neutrophil-mediated immune suppression following conditions such as trauma, contributing to the susceptibility to infections seen in these patients. sham-group) received a single intraperitoneal injection of either zinc protoporphyrin (znpp), an ho inhibitor, hemin, an ho- inducer, or vehicle. h later, rats were anesthetized and subjected to hts, including bleeding, laparatomy, and reperfusion (inadequate and adequate phase) and were sacrificed h later. ho- mrna was determined by real-time pcr and ho activity was determined in liver homogenate. free iron was measured by electron paramagnetic resonance spectroscopy in nonhomogenized liver tissue. ho- mrna was elevated only in the hts-group pretreated with znpp versus the sham-group. ho activity was increased in all hts groups compared to sham groups, with the most distinctive increase seen in the hemin pretreated groups. plasma bilirubin values showed a similar increase in the groups pretreated with hemin. no significant difference was found in free iron concentration among all groups. our data show that changes of ho activity prior to hts are not associated with elevated free iron, late after reperfusion, suggesting that free iron released from ho is efficiently deactivated. introduction: cells of the innate immune system are essential in the development of inflammatory complications. the activation status of this system can be determined by analyzing expression activation markers on neutrophils in peripheral blood. our research group previously showed that a combination of these receptors, the 'priming score', reflected the inflammatory status of individual patients. hypothesis: systemic activation of the innate immune system attracts functional neutrophils into damaged tissues. dysfunctional neutrophils stay behind in the circulation, causing a paralyzed innate immune system and increased susceptibility to late onset sepsis (> days objectives: our study objective is to stratify risk factors of the second (within hours) and third peak (within days) of trauma death independently. materials and methods: , records from japan trauma data bank were retrospectively analyzed. as outcomes for the analysis, we defined the early and delayed death as deaths within days and those after days, respectively. based on the framework of trauma injury severity score (triss), coded glasgow coma scale (cgcs), coded systolic blood pressure (csbp), coded respiratory rate (crr), injury severity score (iss) and coded age (cage) were used as independent variables to determine the outcomes using proportional hazard analysis. conclusions: in our observation, statistically-significant risk factors of early and delayed trauma death differed. physiological severity largely affected the second peak. in contrast, the third peak mainly correlated to anatomical severity and elderly in age compared to risk for the second peak. especially, an initial hypotension might no longer affect the third peak of trauma death independently. regression analysis including all the parameters of rts as explanatory variables showed the odds ratios of categorical sbp variables predicting the inhospital death. results: a total of , records matched the inclusion criteria. score- , , , , a and b in sbp subcategory consisted of , , , , , , and patients, respectively. inhospital mortality of score- , , , , a and b were , , , , and %, respectively. after adjustment for rts, the odds ratios for the inhospital death of score- , , , , a and b were . , . , . , . , . (reference) and . , respectively. isolated head trauma were more frequent in score- b compared to score- a ( vs. %, p < . ). conclusion: a trauma patient with systolic hypertension ‡ mmhg is scored points in sbp category under rts rule, however, exposed to higher mortality rate similar to patients with points in sbp subcategory and maybe related to isolated head trauma. author to editor: to whom it may concern: we have received a e-mail replied from abstractagent.com which alert the exceed in limitations of abstract submission. the e-mail noticed us, the presenting author of this abstract (akira endo) posted or more abstract as a presenting author, however, the authors of ''increased mortality in trauma patients with systolic hypertension'' believed that akira endo in department of accdm, tmdu, japan surely posted this abstract only. the name ''akira endo'' is common in japan. we suppose that ''akira endo'' of the other institutes were doublecounted. editor to self: seçilmiş bildiri background: the united arab emirates (uae) is developing rapidly, with many foreign construction, farm, and industrial workers at risk of injury. aims: to assess external causes, risk factors, severity, and anatomical region of work-related injuries using a trauma registry. methods: surgical admissions / to / were recorded in the registry at the main trauma hospital in al-ain region, population , . prevention-related variables were analyzed using spss and severity quantified by injury severity scores (iss). results: there were work-related injury hospitalisations, equating to an incidence of about / , workers/year. males accounted for %, ages - years %, and nonnationals %, with % of workers from the indian sub-continent. external causes included falls %, falling objects %, powered machines %, animals %, burns %, and other %. at least % of falls were from relatively high levels. median iss was for all six main external causes. extremities were most frequently injured. mean hospitalisation was . days. % (n = ) were admitted to the intensive care unit and % (n = ) died after admission. conclusions: main external causes were proportionately much more frequent than in industrialised countries, and admissions prolonged. priorities include effective countermeasures for falls from height and falling objects, and for machinery injuries. improved work injury data, access to occupational health services, specific regulations and frequent inspections at all construction sites, workshops, and farms, together with appropriate penalties for safety violations, are essential to reduce incidence and severity of occupational injury among vulnerable migrant workers in the uae. introduction and objectives: immobilization of the spine in trauma patients at risk of spinal damage is performed using a rigid long spineboard or vacuum mattress both during pre-hospital and inhospital care. however, disadvantages of these immobilization devices in terms of discomfort and tissue-interface pressures have guided the development of a new soft-layered long spineboard. we compared tissue-interface pressure and degree of comfort during immobilization on a rigid spineboard, a vacuum mattress and a newly developed soft-layered long spineboard. methods: in this randomized cross-over trial, volunteers were immobilized sequentially on all three devices for min per device. tissue-interface pressures were measured using an xsensor pressure mapping device, including the peak pressure and the peak pressure index (ppi). comfort was rated on a visual analogue scale (vas) after min and after min of immobilization. results: tissue-interface pressures were significantly higher on the standard long spineboard and the vacuum mattress than on the softlayered long spineboard. ppi for the sacrum on the soft-layered long spineboard was significantly lower than on both other devices, with an average ppi close to normal diastolic blood pressures. the participants reported significantly more comfort on the soft-layered long spineboard compared to the rigid long spineboard, both after and min (p < . ). conclusion: using the soft-layered long spineboard, which imposes less pressure on the tissue and provides better comfort than the standard long spineboard and the vacuum mattress, means buying time to optimize the patient's treatment while minimizing tissue damage. background: trauma and emergency surgery models differ all across europe. no definitive model was accepted and work and surgical emergency load are different in each region. we performed a cohort study to analyze the impact of emergency (including trauma) surgery in the general surgical practice at a portuguese university hospital. methods: data on emergency surgical cases and admissions to the surgical service over a -month period were collected and analyzed; this included patient demographics, referral sources, diagnosis, operation, and length of stay (los conclusion: emergency workload represents a significant part of the work for the general surgeons. the emergency surgical cases and admissions had a significant impact in the mortality rates of the general surgery admissions. resource planning and training should be based on more comprehensive, prospective data such as these. background: the long-term health outcomes and costs of helicopter emergency medical services (hems) assistance remain uncertain. the aim of this study was to investigate the cost-effectiveness of hems assistance versus emergency medical services (ems). methods: a prospective cohort study was performed at a level i trauma centre. quality of life measurements were obtained at year after trauma, using the euroqol- d as generic measure. health outcomes and costs were combined into costs per quality-adjusted life year (qaly). results: the study population receiving hems assistance was more severely injured than that receiving ems assistance only. the incremental costs for intramural care were e , for hems treated patients compared with patients treated by ems only, which was mainly determined by the costs of the intensive care stay and the used diagnostics. finally, the costs for hems assistance instead of ems assistance were e , per qaly. the sensitivity analysis showed a cost-effectiveness ratio between e , and e , . conclusion: the costs per qaly for helicopter emergency medical services in the netherlands remain below the acceptance threshold. therefore, hems should be considered as cost-effective. author to editor: this study describes the long-term health outcomes and costs of helicopter emergency medical services (hems) assistance. it investigates the cost-effectiveness of hems assistance versus emergency medical services (ems), and may serve as a reference for future quality of life and cost-effectiveness studies on the subject of hems and severely injured patients introduction: in usual multi-trauma care (utc) each partner has its own ''autonomous'' treatment perspective. clinical evidence, however, suggests that an integrated multi-trauma rehabilitation approach ('supported fast-track multi-trauma rehabilitation service': sftrs), featuring earlier transfer to a specialised trauma rehabilitation unit; earlier start of 'non-weight-bearing' training and multidisciplinary treatment; early individual goal-setting; co-ordination of treatment between trauma-surgeon and physiatrist, may be more (cost-)effective. the feasibility of a multi-centre trial examining the (cost-)effectiveness of sftrs was assessed. methods: data from multi-trauma patients (iss ‡ , complex multiple extremity injuries or complex pelvic fractures) were inventoried. patient characteristics, trauma severity, quality of life, health status, anxiety and depression, and cognitive functioning were assessed in two dutch trauma centres providing utc or sftrs. results: no differences in patient characteristics', trauma severity or discharge destination were found between sftrs and utc. discharge destination was 'home' ( . %), 'rehabilitation clinic' ( . %), 'nursing home' ( . %), 'other hospital' ( . %), 'unknown' ( . %). . % of patients died. however, hospital length-of-stay differed: . (sd: . ) days (sftrs) and . (sd: . ) days (utc). conclusion: adequate patient numbers may be recruited, baseline patient characteristics did not differ between collaborating centres, hospital length-of-stay was reduced in sftrs and adequate patient follow-up is possible. based hereupon, a nonrandomised multi-centre clinical trial started. (isrctn ). the trauma-region of north-west netherlands has consensus criteria for mobile medical team (mmt) scene dispatch. the mmt can be dispatched by the ems-dispatch centre or by the on-scene ambulance crew and is transported by helicopter or ground transport. although much attention has been paid to improve the dispatch criteria, the mmt is often cancelled after being dispatched. the aim of this study was to assess the cancellation rate and the noncompliant dispatches of our mmt, and to identify factors associated with this form of primary overtriage. methods: we conducted a retrospective case review of consecutive mmt-dispatches during a months period. by means of chart review, data pertinent to prehospital triage, patient's condition onscene and hospital course were collected and analyzed. all dispatches were evaluated by using the mmt-dispatch and mission appropriateness criteria results: median age was . years and . % of the patients was male. of these, patients were trauma victims ( . % blunt trauma). after being dispatched, the mmt was cancelled times ( . %). statistically significant differences between assists and cancellations were found for overall mortality, mean rts, gcs, and iss, mean hospitalization and amount of icu admissions (p < . ). almost % of all dispatches were neither appropriate, nor met the dispatch criteria. fourteen ( %) missions were appropriate, but did not meet the dispatch criteria. conclusions: nearly a half of mmt-dispatches were cancelled and almost % did not meet the dispatch criteria. dispatch criteria for the mobile medical team in our trauma-region need further refinement and compliance. the ''traumax Ò '' hip screw plate is a new device that allows the treatment the fractures both of the neck and the trochanteric area of the femur, expected subtrochanteric area. this plate conserves the characteristics of a dynamic hip screw (compression of the fracture site, good positioning of the pieces of bone, integrity of gluteus muscles) more specific characteristics: this device is modular, allows to choose the length of the barrel adapted to the length of the head screw, the diaphysal screws are locked by a tech nut according to the patented ''surfix'' system. the locked screw gives a good stability even if the bone has a poor density and allows to use a short plate that preserves the piercing lateral vessels of the femur. this short modular screw plate can be implanted by a cm minimal invasive approach using a particular instrumental pipe. during the presentation we will report the results of a prospective study colligating cases of ten french hospitals. a preliminary study of consecutives cases gives prominence to a few blooding with an average of ml, a operative time of an average of mn, a xr exposing time of an average of s. healing bone has been obtained in all cases. the head screw has been placed at the center or just below in %. no complication dues to the plate has been reported; in all cases only one approach has been used. aim: to assess moderate-term outcomes of silastic joint replacements of the first metatarsophalangeal joint. methods: the patients ( feet) that had silastic implants inserted were reviewed at an average of years and months (ranging months to years and months). the mean patient age was years. these patients answered a subjective questionnaire, had their feet examined clinically and radiographically and a pre-operative and post-operative aofas score was calculated for each. results: the questionnaire revealed that every patient described that their pain had decreased after surgery and feet ( %) were completely pain free. there was a significant improvement in patients' subjective pain scores after surgery (t value £ . ). preoperatively, the mean pain score for all feet was . , whereas post-operative the mean pain score was . . the mean aofas score before surgery was . . this increased to a mean score of . after surgery (p £ . ). this again is a significant improvement. no patient was dissatisfied with the outcome with their surgery. conclusion: these moderate term results are encouraging, with good subjective and objective results. however, long-term follow-up will be required to assess the longevity of this implant • theatre staff should be trained for proper application and cleaning of the exsanguinators • alcohol wipes are good alternative to current practice and should be used for decontamination • we must wash our hands before and after its use • we should use plastic bag over the limb first before using the exsanguinators it is presented one new minimally invasive method for closed fracture reduction and one extramedullary selfdynamisable internal fixator developed by the author. there is no contact between bone and internal fixator in fracture area. it has been widely investigated biomechanically. in clinical use it has been applied to , patients in treatment of femoral fractures. the age of patients was from to years. this internal fixator is applied by two small incisions. reduction is achieved using standard traction table or using special reduction device. this reduction device provides possibility of reduction with minimal using of fluoroscopy or even, after more experience without using of any imaging technique as fluoroscopy, ultrasound or computer navigation. received clinical results are promising, as it has been shown early callus formation and radiological union within the - months. it has been allowed to patients early full weight bearing. during the treatment it has been confirmed working of self-dynamisation concept, which probably all together with d configuration resulted in unexpectedly quick fracture healing. follow up was months ( - ). according to results obtained, it can bee concluded that new biological internal fixator is suitable for minimally invasive technique, without opening of fracture site. it can be used as primary method or soon after external fixation if damaging control concept used. ( ) ( ) ( ) ( ) ( ) and followed-up for a minimum of years formed the study population. a retrospective review of data from electronic patient record (epr), clinical coding, clinic and gp letters was made. age, residential placement, garden's classification of fracture, mode of injury, associated comorbidities, pre-admission mobilisation status, allergies, addictions and anticoagulation status details were collected. an indepth study was conducted to look into delays for surgery, length of stay in hospital, complications and treatment of these complications. reasons for re-admissions, re-operations and comorbidities developing as a result of these interventions was critically analysed. results: the mean age of patients was years (range - years). the incidence of non-union was % and avascular necrosis at year was %. revision surgery was performed in ( %) cases. complications were more principally in patients who had end-stage renal failure ( %), diabetes mellitus ( %), osteoporosis ( %), and steroid use ( %). conclusion: the complications and revision surgery rate was high in patients with particular co-morbidities despite being undisplaced. comorbidities and patient's age were also strong predictors of healing in addition to fracture configuration. outcome of hip fractures is influenced by complex interplay of multiple factors and not only by radiographic appearance. methods: this is a -year of retrospective study. we had included patients to our study ( females and males) with the average age of . . we used bryan and morrey classification system and included type i and type iii fractures. results: there were type i and three type iii fractures. associated injuries were two dislocations with one mcl injury and two radial nerve symptoms. all the patients had orif with screw and two patients had supplementation of fixation with wires. most patients were mobilized early in weeks time. nine of them treated with miniacutrak screw fixation, four with herbert screws and one lag screw (ao miniscrew). the approach was mainly postero-lateral but for five patients, it was antero-lateral. all patients were clinically and radiologically assessed. average time for radiological union was weeks. on the other hand, one patient had revision fixation because of failure of metalwork. additionally, one patient had capsular release for contraction and another one had removal of screw for prominence of metalwork. average follow-up was . months ( - months). mayo elbow score was excellent for seven patients, good for three patients, and fair for three patients. one patient could not be fully scored due to learning difficulties. we recommend open reduction and internal fixation for all type and type fractures so that function can be regained early. objectives: to report the outcome and comparison of calcaneum fracture managements for intra-articular fractures. methods: a prospective study of the patients with intra-articular calcaneum fractures in the foot&ankle unit of a busy trauma hospital. all the patients were followed up with the calcaneal fracture score. we compared the outcome of surgical management sanders type (group a) and type (group b) fractures with conservative treatment (group c) at years and assessed the medium term outcomes of groups a and b. group c were a consecutive series of patients recruited to the study later than a and b, hence the smaller number in that group. results: patients were included in our study. there were in group a, in group b, and in group c. mean follow-ups for the groups were a = years, b = . years, and c = . years. mean -year scores for the groups were a = . , b = . , and c = . , with statistically significant differences between groups a and c (p = . ), and between groups b and c (p = . ), but no significant difference between groups a and b. at medium-term follow-up (> years), the scores for group a and b were . and . , respectively. there were deep, superficial infections and metalwork removals in total. conclusion: on comparing the medium term outcome to the -year one, group a showed some improvement and group b stayed the same. in this series, contrary to published articles, there was a better outcome at years with surgical treatment than conservative treatment. author to editor: all the authors have agreed with content of the abstract. there was not any conflict of interest for this study. objective: to assess the effectiveness of mobile angiography with a digital subtraction angiography (dsa) technology directly into the emergency room (er) for blunt trauma patients with pelvic injury. materials-methods: this is a retrospective review of a cohort of blunt trauma patients with pelvic injury treated after the direct availability of mobile angiography by trained trauma surgeons into the er for resuscitation. data was collected including demographics, hemodynamic variables, resuscitation intervals form admission through completion of hemostasis, metabolic factors (ph and body core temperature), mortality and transcatheter arterial embolization (tae) related complications. results: twenty-nine patients underwent tae in the er. mean age, shock index, and injury severity score were ± years old, . ± . , and ± , respectively. the interval from the decision to perform tae through initiation of tae and the interval from the decision to perform tae through completion of tae were ± min and ± min, respectively. the mean dbody core temperature (bt) from admission through completion of tae was - . ± . °c. and the mean dph from admission through completion of tae was . ± . . there were clinically significant correlations between dbt and resuscitation interval, and between dph and resuscitation interval. tae was successfully performed in all cases and mortality was %. no tae-related complications were observed. conclusion: immediate availability of mobile angiography into the er by trained trauma surgeons was effective to shorten the time required to restore normal physiology of trauma patients with pelvic injury without leaving the er for resuscitation. introduction: tgf-b is a regulatory protein, involved in fracture healing. the purpose of this study was to investigate the role of tgf-b in human fracture healing, and to verify whether tgf-b is a reliable marker of nonunion. methods: serum samples of patients with long bone fractures were collected over a period of months. patients were assigned to groups: first group contained patients with physiological fracture healing. eleven patients with nonunions formed the second group. healthy volunteers served as controls. results: in patients with physiological healing serum concentrations were initially high. serum concentrations then decreased rapidly after weeks and reached a plateau between weeks and . thereafter, another continuous slight increase of the concentrations was observed between weeks and . in patients with impaired fracture healing tgf-b serum concentrations were initially similar to those with normal healing. a significant increase of the concentration was observed between weeks and , followed by a continuous decline of the serum levels for the remainder of the observation period. significant differences between the concentrations in both groups were observed at weeks and . tgf-b as marker would have detected patients with nonunions at weeks after fracture with a sensitivity of % and a specificity of %. distal metaphyseal radial fractures are extremely common fractures in children (% , ). high rates of displacement occurs during conservative treatment. the aim of this study was to determine the effect of kirschner wire application after closed reduction of radial metaphyseal fractures with high risk of redisplacement. in this retrospective study cases were studied in two groups. in group (n = ), k-wire applied after closed reduction. in group (n = ), only cast was applied following closed reduction. the mean follow-up was months. the compared clinical and radiological parameters were; pain, limb deformity, range of motion of the wrist, angulation of the fracture site, radial distal epiphyseal angle and severity of translation. redisplacement rate was % in group and % in group . this shows, kirschner wire fixation had a positive effect in continuity of the initial reduction (p = . ). age (p = . ), gender (p = . ), reduction quality (p = . ) had no effect on redisplacement. concerning the severity of translation, the risk of redisplacement increases in stage ( - %) and stage (> %) fractures (p = . ). concomitant complete ulnar fracture had also redisplacement risk (p = . ). redisplacement risk increases when the distance of fracture line to epiphyseal line was between and mm (p = . ). there was no significant difference between two groups after last evaluation based on radiological parameters and clinical results (p > . ). as a conclusion; this study shows that kirschner wire fixation prevents redisplacement in early follow-up of first weeks but there is no superiority after months follow-up in distal metaphyseal fractures of children. patients in group c showed the best functional results, the greatest ankle range of motion, the fastest full bearing, the fastest walking on toes and heels, and the shortest duration of physical limitations (walking on uneven ground and sports activities) (p < . for all). in group b, there were two reruptures, in group c one, and in group a there were no reruptures. good functional results and a relatively small number of postsurgical complications advocate the usage of surgical techniques. the best and fastest functional recovery was attained in the group treated with the original technique of percutaneous fixation with two embracing and crossed loops. open surgical reconstruction is indicated only in the case of rerupture after percutaneous suturing. introduction: there are different techniques for arthrodesis of endstage arthrosis of the ankle-joint. internal fixation is the favoured method in many institutions. we retrospectively examined the technique and clinical results of external fixation in a triangular frame. patients/methods: from to a consecutive series of patients with end-stage arthritis of the ankle joint was treated. mean age at the index-procedure was . years, patients were male ( . %). via a bilateral approach the malleoli and the joint-surfaces were resected. an ao-fixator was applied with steinmann-nails. follow-up examination at mean . years included a standardised questionnaire and a clinical examination including the criteria of the aofas-score and radiographs. results: in two cases, due to contracture a pes equinus position had to be accepted. in two cases a further bone transplant was performed at and weeks for unsatisfactory bony union. after mean . weeks, radiographs confirmed satisfactory union and the fixator was removed. in four patients a nonunion of the anklearthrodesis developed ( . %). the mean aofas score improved from . to . points. statistical analysis of the insurance status showed that patients insured under a workers injury compensation scheme had a mean score of . compared to . for the remaining (p = . ). discussion: nonunion rates and clinical results of arthrodesis by triangular external fixation of the ankle joint do not differ to internal fixation methods in literature comparison. the complication rate and the reduced patient comfort reserve this method mainly for infected arthritis and complicated soft tissue situations. implants with multidirectional locked screws have theoretical advantages in the treatment of periprosthetic fractures. in osteoporotic bone they provide a high stability. we concluded a retrospective study of a consecutive series of the outcome of vancouver b and c femoral injuries using two specific locked-implants. from to we treated patients with a periprosthetic fracture of the femur with a locked plate. the mean age at the index procedure was . years, patients were female ( %). in cases ( . %) we saw a hip endoprosthesis, in cases ( . %) a knee endoprosthesis and in cases both ( . %). outcome measures were intra-and postoperative complications, bony union, degree of mobility and social status, barthel-mobility-index and ''stand-up&go'' test. union occurred in cases ( . %) after the index procedure. twice the implant failed, we saw four general complications. the mean duration until full weight bearing status in these patients was . weeks. at follow-up patients ( %) had maintained the same social status as before the fracture. regarding the mobility status patients ( %) had regained their previous level, patients walking without aid before now required a cane and patients a walking frame. the mean barthel-index was points of . the mean stand-up&go time was measured as seconds. conclusion: overall failure rates of osteosynthesis after periprosthetic fractures of up to % are reported ( ). with . % implant related failures and % general complications, the presented methods achieve bony union and mobility in a high percentage of cases. arthroscopic-assisted percutaneous figure introduction: we describe a new arthroscopic-assisted reduction and percutaneous tension band wiring technique for patella fractures that combines the advantages of minimally invasive surgery and stable internal fixation. surgical technique: we reduce the fracture percutaneously by towel clips with the patient in the supine position. we insert two . mm kirschner (k) wires in a caudocranial direction under arthroscopic control. we do four stab incisions to assign the inferolateral (il) and inferomedial (im), superolateral (sl) and superomedial (sm) portals besides the k wire tips. we insert a trocar with its cannula from sl portal to sm portal under the k wires. we take the trocar out and leave the cannula inside. we run -gauge cerclage wire through the cannula in sl to sm direction. we take out the cannula. we perform exactly the same steps directed from sm portal to il portal, from il portal to im portal, and from im portal to sl portal, respectively. finally near the sl portal, wires are secured with a single knot. we check the fixation by c scope. results: radiographic consolidation was achieved in all five patients at an average of months. all patients returned to the activity level previous to fracture. conclusion: this technique presents advantages over open techniques. it is minimally invasive and cosmetically pleasing, permits visualization of reduction and stability, allows concomitant intraarticular pathology to be exposed, and facilitates early rehabilitation. although we did not attempted yet, we believe that even comminuted fractures can be fixed with this technique. ( ) timing of the procedure, ( ) accurate technique, ( ) stable implants for early mobilisation. in this study we present our experience in the treatment of ftp with locking plates trying to define the role of a medial plate. materials and methods: from to we treated patients with a ao c ftp by orif with locking plates. indications for a medial plate were: involvement of the medial joint surface, coronal fracture of the medial plateau and irreducible dislocated medial condyle. all the patients have been followed up clinically with the lysholm and rasmussen scores and radiographically until consolidation. results: all fractures united. one patient underwent knee amputation for septic complication. the mean lysholm score was ''fair'' while the rasmussen score was ''good'', that means that the subjective result was worse than the objective one. patients treated by double plating had a worse clinical result that was not dependent on the quality of reduction. we had three cases of malalignment, one rsd, two superficial infections, two transient nerve palsy. conclusion: complications in our series were frequent and the clinical results not particularly good. the right timing and an accurate surgical technique are essential for a good reduction, newer implants control effectively the fragments but the high energy of the trauma remains the major determinant of the bad outcome of these fractures. introduction: the high percentage of failure of fixation systems in periprosthetic fractures depends on the technical difficulty of the procedure, the presence of the cement mantle and the poor quality of the remaining bone. the lcp system offers an enhanced stability that reduce the implant mobilization, and preserves the bone vascularity, fastening the healing time. we present our results in the treatment of periprosthetic fractures with lcp. materials and methods: consecutive patients with vancouver b fractures were operated on using . lcp. a standard open reduction of the fracture through a lateral approach was used. patients were evaluated clinically and radiologically for a mean follow up time of . months. results: all the fractures united except two where a narrow . plate and too many cerclage wires around the fracture were used. all the patients showed at fu an hhs over points. the anatomical reduction of the fracture led to a faster healing. conclusions: the effect of the position of screws and cerclages in relation to the plate and fracture are discussed. the authors conclude that lcp system, has to be considered the golden standard in the osteosynthesis of vancouver type b periprosthetic hip fractures, permitting early weight bearing and healing in physiological time. it is better to avoid narrow . plates and cerclages at the fracture site. suggestions on the plate length and screw and cerclages position are given depending on the fracture type and length. the role of the anatomical prosthesis in the treatment of proximal humeral fractures ló ránt bardó cz, jános csotye pá ndy ká lmá n county hospital, gyula, hungary, traumatology introduction and objectives: we would like to present the results of the treatment of proximal humeral fractures with endoprosthesis. methods: between and we operated patients with endoprosthesis for proximal humeral fractures. were delta prosthesis, the results of these operations are the subject of an other presentation. patients were treated with anatomical shoulder prosthesis. the results of these were controlled by personal examination (constant score, x-ray) and by the base of the clinical documentation. was hemi-and total endoprosthesis. in cases the operation was acute and in cases for chronic cases. the average follow up time was . month. we categorized our patients in different groups, based on the fracture type and the time of the surgery. results: we compared the cs of the operated shoulder with the contralateral one in each patient group. we have to accentuate the importance of patient cathegorization, because the results can be analyzed properly only on base of these. on the x-rays the prosthesis were in good place, we found no evidence of losening. conclusions: when the indication is good, the prosthetic procedure is the choice for acute or chronic fractures of the proximal hunerus, and the results are good. we confirmed the statistically significancy of the efficacy of the treatment methods between the same analyzed groups. aim: to discover if how often lateral x-ray change the management of fracture neck of femur fractures as an adjunct to the standard ap film. method: orthopaedic consultants and registrar grade orthopaedic surgeons were asked to decide the management of neck of femur fracture solely from an ap film. at a second sitting the same films were shown in a different order in conjunction with the associated lateral hip x-ray. the surgeons were asked to comment on the adequacy of the lateral x-ray and their choice of management using the both films to make a decision. results: less than half of the lateral hip x-ray were adequate when reviewed on the monitors and very few operative decisions were changed with the addition of the lateral x-ray. conclusion: a standard ap film is usually sufficient to plan management in a fractured neck of femur fracture and the additional time, money, and discomfort of obtaining lateral films does not seem justified in these circumstances. an sermon, stefaan nijs, barbara bosch, paul broos department of traumatology, university hospitals gasthuisberg, leuven, belgium introduction: humeral head fractures extending into the shaft often are a challenge to the surgeon. although they are a rather rare entity, they often occur in osteoporotic bone and are difficult to stabilize. however, because of their intra-articular extension, a perfect reduction and stable osteosynthesis is needed. methods: between august and august , patients with a combined shaft and humeral head fracture were operated in our department. a long philos plate was used in all cases through an extended deltopectoral approach. postoperatively, immediate mobilization was allowed. mean follow-up time was months. results: there were three preoperatively existing radial nerve palsies of which two completely and one partially recuperated postoperatively. there occurred no radial nerve palsies which did not exist preoperatively. revision surgery was necessary in two patients because of hardware failure and secondary fracture displacement within the first week after surgery. in both cases, again a long philos plate was used. all fractures were radiographically healed within months; there were no cases of avascular necrosis of the humeral head. most of the patients were subjectively satisfied with the functional result although mobilization of the shoulder was only moderate in nearly half of the cases. conclusion: in conclusion we can say the use of long philos-plates for the treatment of combined shaft and humeral head fractures gives good results when carried out by experienced hands. osteosynthesis with the use of locked nails is an efficacious method for the treatment of long bone fractures and nonunions of extremities. however, it is contraindicated in case of infection. one way to obviate this problem is to coat implants with antibiotic-loaded bone cement. the objective of this work was to evaluate the efficiency of antibiotic cement-coated interlocking nails for osteosynthesis of long bones in case of infection (infected nonunions) or at high risk of its development (severe open fractures). in - , nails with antibacterial cement coating were used to treat patients including ones with severe open long bone fractures (gustilo-anderson type iiia-iiib). these fixators were employed both at admittance of the patients (with an isolated injury) and within - days after it (in case of polytrauma). patients of this group underwent one-step surgery combining osteosynthesis and the closure of soft-tissue defects with local muscular flaps. in patients with infected nonunions of long bones, osteosynthesis was performed after seeding fistula discharge for microflora. none of the patients in the group with severe bone fractures suffered deep suppuration and all achieved consolidation of fractures. one case of recurrent infection associated with extensive necrosis of bone was documented in the group of patients with infected nonunions. the remaining patients had resolution of signs of infectious process, and their nonunions consolidated. the use of antibiotic cementcoated interlocking nails is a promising method for osteosynthesis of long bones in case of infection and at high risk of its development. author to editor: severe open fractures and infected nonunions are one of the most difficult problems in trauma orthopedic surgery. we had only one treatment option for this pathology down to resent times. it was an external fixator, but it has many disadvantages. in we start using antibiotic cement-coated interlocking nail, and we have promising first results. this results we would like to present in eurotrauma . hawar akrawi, david gordon hargreaves department of trauma and orthopaedics, southampton university hospitals nhs trust, southampton, the united kingdom introduction: we describe our clinical experience with a new posterior approach for reconstruction of distal intercondylar fractures of humerus. the maserati approach comprises of a midline proximal triceps split in conjunction with elevation of medial and lateral edges of triceps from the condylar ridges. this approach gives adequate access for accurate reduction and internal fixation of distal and intraarticular humeral fractures. methods: a single consultant series of patients with distal humerus fractures (ao grade -a to -c) were treated using the maserati approach and distal humeral locking plates over -year period at level trauma centre. all cases were reviewed. there were female and male patients with age range from to year. average follow-up was months. these patients were assessed for: . accuracy of reduction of fracture fragments. . complications i.e. infection, triceps weakness, triceps lag and fracture union. . elbow function as per the mayo elbow performance score (meps). results: nine patients had anatomical reduction. no cases of infection or nonunion. one case of delayed union. none of the patients exhibited triceps lag or weakness. the meps was - (mean ). discussion: the maserati approach is a safe approach that provides good access to the articular surface of elbow without compromising the triceps muscle. triceps continuity is preserved, allowing early rehabilitation without the possible co-morbidities associated with other posterior elbow approaches (non-union of olecranon, triceps weakness or triceps lag). author to editor: dear sir/madam, i will be very grateful if you could offer me the opportunity to give a podium presentation about this innovative approach. patients with distal humeral fractures are difficult to manage and with oral presentation, i will be able to demonstrate clearly, with media presentation, the full advantage of this new approach. results: improvement of the neurological deficit was observed in cases. ct control at least of years follow up shows good bone integration of the iliac crest bone in majority of the cases. two patients experienced temporary neurological symptoms, which showed complete remission. the endoscopic procedure for reconstruction of the anterior load-bearing spinal column developed to a standard concept in trauma management. the minimal morbidity of the operative approach, good visualisation of the operative field and angle stable implant make it possible to restore the anterior column on a safe technique. full weight bearing (painless) ranged (un) - (ø ) and (rn) - (ø ) weeks. x-ray healing ranged (un) - (ø ) and (rn) - (ø ) weeks. there was one patient with delay union( weeks) in un group. there were any infection; loss of reduction; re-operation and nonunion in both groups. discussion: we started this study because many studies before preferred reamed nailing but we have long term experience with undreamed nail with the comparable results (retrospective analyze). our hypothesis is that the biological advantages of undreamed nail should display if the perfect technical performance is done. conclusion: there are no significant differences between un and rn groups in our study in this time. we expect recruiting more than patients by the year end and during next years we will be able evidence the data completely. this work was supported by the research project moofvz septic arthritis following acl reconstruction péter frö hlich zentralinstitution for sportsmedicine, budapest, hungary infection after arthroscopic anterior cruciate ligament reconstruction is an uncommon complication, which could be a danger not only for joint function, but also for the joint integrity. we have to differentiate by the clinical recognition of this complication from swelling caused by other conditions (for example suffusion). there is no standardized opinion and method in the field of arthroscopic or open procedure, or necessity of aggressive graft removing. from a consecutive case series of , patients, who underwent anterior cruciate ligament reconstruction between and . we report on patients with postoperative septic complication. of these were extraarticular, and intraarticular manifestation. our protocol is based on infection severity classification modified by gä chter. reliability and significance level of diagnostic criteria (clinical evaluation, laboratory tests, synovial fluid analysis, and bacterial culture) were analyzed. the outcome was determined by early recognition and consequent treatment. there is only one patient, whose acl tendon graft has to be removed. the ikdc score shows the following result: a: , b: , c: , d: , it proved to be similar to the multicenter studies. in the last years we have no more postoperative infection following acl reconstruction by the application our protocol. we will review this protocol. introduction: early fixation of long bone fractures in the multiple injured patient has been recognized as beneficial in minimizing secondary lung and remote organ failure. although early fracture fixation is expedient in px with multiple injury etc may be associated with post-traumatic systemic complication. in this study all pz from a consecutive series of trauma patients with truama team activation admitted between / and / to department of emergency of niguarda hospital in milan were included when they fulfilled all of the following criteria: directly admitted, iss of more than , and survival of more than h. patients with fracture of long bones and/or pelvis with a clear indication for operative treatment and the necessity of immediate fracture stabilization where treat according with dco. all other patients fulfilling the inclusion criteria with minor fracture or thus not requiring immediate fixation formed the control group. iss, rts and ps was calculated at the admission and reevaluated later by the trauma leader. all injury was classified with ao and gustilo classification conclusion: the goals of dco include stopping ongoing injury including local soft-tissue injury and remote organ injury secondary to local release of inflammatory mediators further thought to prevent pulmonary complications by allowing patients to avoid the enforced supine position. this study was conducted retrospectively to evacuate the effectiveness of the trauma team organization and to evaluate the concept of dco by immediate external fracture fixation and consecutive conversion osteosynthesis with regards to time saving, effectiveness and safety. introduction: injury of the soft tissue results in a release of numerous cytokines, which activate fibroblasts of the surrounding tissue to proliferate and to undergo a phenotypic transdifferentiation into contractile myofibroblasts (mfs). in this study we analyzed the hypothesis, that human joint capsule mfs are specifically regulated by the cytokine ifn-c via the modulation of alpha-smooth muscle actin (a-sma) which is responsible for the contractile phenotype. methods: joint capsules were obtained from patients undergoing orthopaedic surgeries. to investigate the functional effect of ifn-c, we cultured mfs in a three-dimensional ( d)-collagen gel contraction model. an alamarblue assay in combination with the collagen gels was established to analyze the viability and the proliferative capacity of mfs upon ifn-c treatment. the effect of ifn-c stimulation on the gene expression levels of the specific mf markers a-sma and collagen i is going to be determined by real-time pcr (rt-pcr). this part of the study is in progress. results: mfs cultured in the presence of ifn-c show a reduced proliferative capacity. moreover, the addition of ifn-c reveals a dose-dependent decrease of collagen gel contraction. these effects were specifically blocked by a neutralizing ifn-c antibody. first results of rt-pcr analysis show an inhibition of a-sma and collagen i gene expression by ifn-c. conclusions: ifn-c reduces mf viability and contractility in a dosedependent way, presumably by down-regulating mf specific genes. this study suggests that ifn-c might be effective in attenuating the contraction of soft tissue in fibrocontractive disorders. with an average age of . years old were included and a retrospective database study was performed. the outcome parameters we analysed were the radiological outcome, the functional outcome and the prevalence of complications. results: the fracture healed in an accurate anatomical position in all patients treated with esin ( %). seven patients ( , %) suffered from irritation around the entrance opening and in four patients ( . %) the pen migrated medially. in eight cases ( , %), this resulted in a reoperation, consisting of remodelling, reposition or removal of the pen. in two cases we saw a refracture after removing the pen. the overall complication rate was . %. dash scores showed an average functional outcome of . points (range: - ) at . months follow-up. conclusion: operative treatment with esin in dislocated midclavicular fractures offers good mid-term radiological results and a good dash score. the overall prevalence of complications was . % and in . % a re-operation was required. the results found in the available literature showed a re-intervention rate of %. prospective randomised research is required in order to determine the right surgical indications and to find out what the long-term results of this relatively new method of fixation are. aim: our main aim was to find out whether there is a place for nonoperative treatment as a definitive primary option in patients with significant medical co-morbidity. methods: we did this audit in collating information on , hip fracture patients across nhs hospitals in england. out of , ( . %) patients were treated conservatively. results: there were males and females patients managed conservatively in our study. during hospitalisation, became bedridden and died. among these patients, were deemed physically unfit for surgery by anaesthetists and by medical consultants. the decision was made by orthopaedic consultants in ten cases and by multidisciplinary team in four cases. five patients refused surgery and five patients were palliative due to terminal illnesses. patients who did not proceed to surgery had significantly higher mortality rates (overall mortality rate %) suggesting that they were physiologically much worse group of patients. conclusion: as the average life span of our population increases, some hip fractures are now treated nonoperatively because of the possibility of severe or fatal complications due to surgery. often, refusal of surgery by the patient or the patients' family obligates the need for nonoperative treatment. it might be acceptable not to opt for the surgery if the patients are medically very high risk because of these reasons (e.g. acute cardiac event, severe aortic stenosis, multiorgan failure etc). the burden of patients with pubic rami fractures seems to be increasing. more patients with pubic rami fractures are admitted to hospital due to the absolute increase in the number of elderly people. although pubic ramus fractures are generally considered a benign fracture for its inherent stability experience indicated that this fracture is accompanied with a high morbidity and mortality. in a case-control study patients aged over years old with an isolated single fracture of the pubic rami admitted to the hospital were compared for morbidity and mortality to age-and gender matched hospitalized patients without fractures. data was acquired by the patient files. during years patients, with a median age of . (range: - ) years, were admitted with a median length of stay of days (range: - ). the mortality rates of patients with isolated pubic rami fractures at , , and years were significantly higher in the patient group compared to our control group, being: . , . and . %, respectively (p < . ). one third of the mortality is explained by cardiovascular events. during hospital admission a complication rate of . % was found, which was mainly caused by infectious diseases, including urinary tract infection and pneumonia. thirty-three percent of the patients (temporarily) went to a nursing home, because of the incapability to mobilise independently. in conclusion, patients admitted to the hospital for an isolated pubic ramus fracture have significant morbidity and mortality both during hospital admission and during -year follow-up. purpose: comminute fractures of the radial head are challenging to treat with open reduction and internal fixation. radial head arthroplasty is an alternative treatment. the purpose of this study was evaluating our results of a closely followed cohort of patients in whom an unreconstructible radial head fracture had been treated with modular pyrocarbon/metallic prosthesis. methods: from may to september , patients were operated for traumatic injuries in elbow. there were female and male with mean age ( - years). the follow-up was a mean of months ( - months). fractures of the radial head have been classified by mason with a subsequent modification by johnston. the indication for a radial head replacement are comminuted type iii fractures in cases, type iv in cases, and monteggia variant with olecranon and radial head fractures in cases. results: by using the mayo elbow score, patients had good/ excellent results, with fair and poor outcomes. patients showed an average arc of motion from - º to º. complications were three implant dislocations, needed to remove the implant. asymptomatic radiographic heterotopic ossification in elbow was showed in one case and bone lucencies were found in seven cases. we had not seen persistent instability, infection, synostosis, loosening, severe degenerative changes or impingement. conclusion: the treatment of unreconstructible comminute radial head fracture with noncemented pyrocarbon radial head implant usually gives an optimal result depending on the severity of the initial injury and the presence of associated injuries. methods: this retrospective clinical study is a follow-up examination of bony avulsion fractures of the intercondyloid eminence in adults and adolescents treated in our hospital in the last years. after the medical history was recorded, the course of the accident and type of injury was documented (classification according to meyers and mckeever) . also the type of treatment (conservative, arthroscopic surgery or open surgery) and accompanying injuries were analysed. the clinical follow-up examination took place after more than months after the trauma. during the face-to-face interview, physical and radiological examination, the knee function, and especially the stability of the knee-joint were assessed. furthermore the clinical outcome was determined using the lachmann-test and the lysholm-knee-score. results: the patient group consisted of male and female patients aged - years. the patients showed subjective and functionally predominant good to very good results. despite subjective stability and absence of pain, in some patients remained a mild hyperlaxity of the anterior cruciate ligament. conclusion: fractures of the intercondyloid eminence are a rare but serious injury of the knee. the correct diagnosis, classification, and curative treatment of the fracture is indispensable for the flawless function and stability. an individual approach is necessary in every patient. distal radius fractures are typical and frequent fracture of elderly woman with reduced bone density. the angle stable plate, often also multidirectional is today the most common stabilisation device. because of the introduction of bulky and bended implants as the micronail or targon dr we decided to test the xs radius nail witch is a , mm or , mm straight nail and witch is introduced after guide wire placement and over drilling with a cannulated drill of the same diameter. it is locked parallel to the joint in different directions with angular stability with threaded wires. methods: radius sawbones were osteotomised corresponding to a a fracture and stabilised with a angle stable plate ( ) and xs nail ( ). , alternating load cycles from - n were performed and the deformation was registered. also a fe analysis with the msc patran/marc software were performed. both types of osteosynthesis showed good stability. the deformation of the xs group however was % lower. also the calculated deformation in the fe study was % lower. also deformation amplitude was lower with . mm compared to . mm in the plate group. the differences however were not significant. both devices show good biomechanical results. the xs nail has the advantage of mainly intraosseus position, simple operation technique with introduction over a guide wire from the proc. styloideus radii and over drilling with a cannulated drill of the same size. the exposure of the n rad.superf. must be performed. first clinical evaluation is presented. angioembolization in severe pelvic fractures: experience of a tertiary centre in united arab emirates results: twelve patients (all males) having a median (range) age of ( - ) years were studied. five were vehicle drivers, four passengers, two pedestrians, and one fall from height. seven had abdominal tenderness while four had abdominal guarding. median (range) systolic blood pressure before angioembolization was ( - ) mmhg and ( - ) mmhg after embolization. nine patients had unilateral internal iliac artery embolization, one had embolization of the pubic bone artery, one had pudendal artery embolization, and one had bilateral iliac embolization and liver embolization. six patients had external fixation of the pelvis after the angioembolization. three patients had a laparotomy, the first had intraperitoneal urinary bladder rupture which was repaired, the second had pelvic packing and diverting colostomy for a severe perineal wound, the third had a liver injury and died on the table. one patient had a thoracotomy with interposition aortic thoracic graft. eleven were admitted to the icu having a median (range) icu stay of ( - ) days. the overall median (range) hospital stay was ( - ) days. only one patient died ( . %). conclusions: angioembolization of severe pelvic fractures with haemorrhage was successful in % of cases and played an important role in the initial management of severe pelvic fractures with haemorrhage. there were nine female and eight male patients passed with a mean age of . years. the knees were assessed at regular intervals and the mean follow-up period was . months (range - ). after initial assessment to confirm absence of trochlear dysplasia, the technique involves plication of the medial retinaculum with a nonabsorbable suture passed percutaneously using a long curved needle under arthroscopic vision and a small incision to bury the knot from the plication. post operative rehabilitation was done with flexion restricted to °for the first weeks followed by a gradual return to normal range of movements with vastus medialis obliquus strengthening exercises. results: patients reported good outcomes with no further episodes of dislocations. one patient who had persistent patellar instability requiring further distal bony-realignment procedure to achieve stability. none of the patients had major complications. conclusion: we report good results with this relatively simple technique of medial retinacular plication and would advocate it as an effectiveless invasive surgical option for patients with recurrent patellar instability in the absence of major trochlear abnormality or significant mal alignment. in a lateral (group a) and in a prone position (group b) with no significant difference in age ( . / . years) as well as pre-and insurgery parameters; no patients were excluded. the complication rate was analyzed by medical records, the radiographic outcome by plain x-rays and ct scans after an average of months postoperatively. comparison of the two patient groups utilized t-tests or chisquare testing of pearson as determined by number of data points for each variable assessed. results: the adequacy of fracture reduction had significantly poorer findings according to matta in a (p = . ), resulting in a significantly higher post-traumatic arthrosis rate (p = . ) defined as helfet iii or iv. no revision surgery was needed; no infection was detected in any group whereas iatrogenic nerve damages ( temporary, persistent) were found only in a. there was no significant difference concerning extensive blood loss, femoral head necrosis, epstein grades, heterotopic ossification classified by brooker and secondary surgery needed. conclusions: due to gravity the femoral head in the lateral position may constrain reduction leading to an inferior radiographic outcome. purpose: the incidence of fracture neck of femur (nof) has been increasing worldwide, due to an aging population. the commonest forms of analgesia are opioids and in some units regional blockade. but regional block is skill dependent and opiates are known to have many side effects. paracetamol is an analgesia that is safe and has an excellent side-effect profile within standard doses. intravenous paracetamol has a far higher predictable bio-availability than oral, within standard dosage. this study is to assess the suitability of using intravenous paracetamol as an alternative. method: prospective study: a change in protocol resulted in all nof's admitted under the care of the senior author being prescribed regular intra-venous paracetamol within standard dosage. prn opioids were available for breakthrough pain. nof's admitted under the care of other consultants remained on the established protocol. opioid usage and pain scores ( - ) were measured. results: results of patients were collected, in intravenous paracetamol group and in the original protocol group. there is a % reduction in opiate usage in the intravenous paracetamol group (p value = . ). there is only a . difference in average pain score between groups (p value = . ). conclusion: the use of regular intra-venous paracetamol results in a significant reduction in the need for opioid analgesia. the pain relief within this group was comparable to that in the control group. a simple change in analgesia protocol to a safer, more predictive agent can result in an improved pre/postoperative period. author to editor: funding: the study received no funding from any source. external fixation has already became on the end of last century as routine temporarily method of fracture bone fixation, especially in the light of damage control. but out of damage control, external fixation has been accepted in many developed countries as routine temporarily method in treatment of complex articular fractures (knee, ankle, elbow). the main reason was absence (night time, weekend) of experienced surgeon who can treat these complex particular fractures, as during the night. sometimes, the skin problem can prolong such fixation for three or more weeks. however, external fixation of tibia and distal radius can be method of choose for definitive treatment not only in open but in closed fractures as well. it becomes justified when high mobile and relatively simple external fixation devices have been developed allowing addition correction of reduction. in this paper, we want to present possibility of using already applied, external fixation device as temporarily method. about week after external fixation done (on femur or tibia) we developed technique existing external fixator to be used as a reduction device. once, desirable fracture reduction achieved, internal fixation is very easy and we do not need fluoroscopy control for reduction, just for internal device fixation by minimally invasive method. using this method, we already treated patients with femur fractures and with tibia fractures. from results obtained it can be concluded that external fixator developed by mitkovic is suitable to function as accurate fracture reduction device providing condition for simple minimally invasive internal fixation. results: with the antegrade nailing technique the mean postoperative constant score was . (flexion . °m abduction . °, pain . ). the elbow extension was free in . %. a correct axial alignment was found in %, in % we found a varus deviation of °- °. in % the nail perforated. in complications there was one prolonged bone healing, one pseudarthrosis and one infection. two thirds of the patients were very satisfied with the outcome. in the retrograde nailing technique the mean postoperative constant score was . (flexion . °, abduction . °, pain . ). the elbow extension was free in . %. only % of the patients showed a mild discomfort at the operative approach at the elbow. a correct axial alignment was found in %, in % we found a varus deviation of °- °. in % patients showed a postoperatively detected fracture in the supracondyle region. . % of the patients were very satisfied with their outcome. conclusion: the retrograde nailing technique is a save and sufficient method for treating humeral shaft fractures, especially because the rotator cuff is not disturbed. introduction and objectives: the bony bankart lesion is an avulsion fracture of the glenoid that usually occurs after anterior shoulder dislocation. this injury is frequently missed and often creates shoulder instability. therefore, open reduction and internal fixation (orif) of the fragment is recommended. in this study we looked at shoulder function, instability and pain after this operation. postoperative x-rays were reviewed on anatomical reduction. patients and methods: between and , bankart fractures were operated. they were classified according to ideberg. sixteen patients had an ideberg type b fracture and three a type . these patients received questionnaires with a number of validated scoring systems. we used the ases, rowe shoulder score and the dash questionnaire. results: the response was %. all respondents did get a stable shoulder after surgery. two patients regularly experience mild pain. the average rowe score was . (range - ). the average ases score for adl was (maximum score , adl unlimited). the median dash score on the quality of life was . (where means no loss of quality of life). there was a clear positive relationship between the radiological postoperative congruency of the joint, the shoulder function and quality of life. introduction: traumatic dislocation is the most severe form of ligament injury of knee.the purpose of this study is to report our cases in past years. methods: between and , knees in men and women; patients were treated for traumatic knee dislocation in our trauma center. the mean age was ( - ) years at the time of injury. the mechanism of injury were motor vehicle accident in , fall from high in and industrial accidents in patients. patients had additional extremity trauma. vascular injury detected in knees who required immediate reconstruction by vascular surgeons. the orthopaedic stabilization of the initial injury was bridging external fixation in knees included all vascular injuries. patients had fibular nerve palsy. in knees medial collateral ligament, in knees lateral collateral ligament, in knees anterior cruciate ligament, in knees posterior cruciate ligament and in knees posterol ateral corner lesions were diagnosed. one had tuberositas tibia avulsion. multiligament reconstruction was performed on a delayed basis in patients for a minimum of ( - ) month after the injury all patients had functional rehabilitation for a mean ( - ) weeks. results: at an average follow-up of . ( - ) years they were examined for stability and range of motion. all knees having multiligament reconstruction and of the patients in whom nonsurgical treatment was undertaken were stable. patients having multiligament reconstruction had slightly lower knee range of motion hypothesis: computed tomography (ct) is more accurate than bone scintigraphy for diagnosis of a radiographically occult scaphoid fracture. methods: in a study period of year, consecutive patients with a suspected scaphoid fracture but no fracture on scaphoid radiographs were evaluated with ct within h of injury and bone scintigraphy between and days after injury. the reference standard for a true (radiographic occult) scaphoid fracture was either ( ) diagnosis of fracture on both ct and bone scintigraphy, or ( ) in case of discrepancy, clinical and/or radiographic evidence of a fracture. results: ct showed scaphoid and other fractures. bone scintigraphy showed scaphoid and other fractures. according to the reference standard there were nine scaphoid fractures. the prevalence of true scaphoid fractures among suspected fractures was therefore %. ct had a sensitivity of %, specificity of %, accuracy of %, a positive predictive value (ppv) of % and a negative predictive value (npv) of %. the prevalence corrected ppv was % and the prevalence corrected npv was %. bone scintigraphy had a sensitivity of %, specificity of %, accuracy of %, a positive predictive value of % and a negative predictive value of %. the prevalence corrected ppv was % and the prevalence corrected npv was %. summary: this study could not confirm that early ct imaging is superior to bone scintigraphy for suspected scaphoid fractures. bone scintigraphy remains a highly sensitive and reasonably specific study for the diagnosis of an occult scaphoid fracture introduction: the therapeutic management of scaphoid fractures is still surrounded by controversy. immobilisation for non-or minimal displaced scaphoid fractures results in a union rate of more than %. functional outcome is often measured using clinical examination and radiological consolidation. however, the indication of how successful the treatment has been is the functional outcome of the patient. functional outcome of upper-extremity fractures can be measured reliably using the dash (disabilities of the arm shoulder and hand) outcome measure. materials-methods: consecutive patients with non-or minimally displaced scaphoid fractures, treated conservatively, were included. the trauma mechanism, treatment modality, diagnostic modalities, duration of cast immobilization and complications were analysed for all patients. functional outcome was measured using the dash outcome measure. results: patients showed good clinical and radiologic outcome after weeks of cast immobilization with a mean dash of . . six patients consolidated within weeks with a mean dash of . . three patients with four fractures took more than weeks to achieve clinical and radiologic consolidation and had a mean dash of . . the dash questionnaires showed statistically significant differences between patient age, fracture location and duration of cast immobilization. conclusion: conservative treatment of non-or minimally displaced scaphoid fractures results in good functional outcome after weeks of cast immobilization, particularly in young patients with distal or waist scaphoid fractures. objective: pedicle screw instrumentation is the most common procedure in stabilizing fractures of the throracolumbar spine, but yields an immanent potential for iatrogenic damage due to malpositioned pedicle screws. methods-materials: patients undergoing posterior instrumentations were included. preoparative ct scans were used to determine fracture level and classification. postoperative ct scan were evaluated for screw positions of all pedicle screws. cobb angles were compared to calculate the degree of reduction. the position of all pedicle screws was determined according to the classification proposed by zdichavsky. results: pedicle screws were assessed. pedicle screws were classified as optimal (ia, %), ib, iia, iib, iiia and iiib. malpositions were more often the more cranial pedicle instrumentation was performed ( % increase per level, p < . ). malpositions (ib-iiib) occurred more often on the right side of the patient (p < . ). the mean reduction was °. discussion: this study confirms the hitherto felt but unproven suspicion that malpositioning occurs more often in the upper thoracic spine. even more remarkably is the side-dependency in malpositioning. we attribute the higher rate of malpositioned screws on the right side of the patient to the circumstance that the surgeon usually stands on the left side of the patient and visual control of the direction of the pedicle screw during insertion is probably more difficult on the opponent side. we recommend envisioning this fact and -if navigation is not used -changing the position during the procedure. background: u-shaped sacral fractures are rare and highly unstable pelvic ring injuries. surgical stabilization may facilitate early mobilization and reduce mortality. however, limited evidence has prevented the development of a standard treatment algorithm. furthermore, little is known about the quality of life in these patients. purpose: to assess the injury characteristics, choice of treatment and quality of life of patients with u-shaped sacral fractures. methods: eight patients with u-shaped sacral fractures were identified over a -year period. neurological outcome was classified by gibbons' criteria. quality of life was evaluated using the euroqol- d questionnaire. results: there were five women and three men; the median age was years. the injury severity score ranged from to . definitive internal fixation was established after to days. percutaneous iliosacral screws were used in two patients with relatively stable fractures. transsacral plate osteosynthesis was used in one patient with minor displacement. triangular osteosynthesis with transsacral plating was used in four patients with multilevel sacral fractures, highly unstable fractures or traumatic spondylolysis l -s . one patient with an associated l fracture received a triangular osteosynthesis without transsacral plating. early partial weight bearing was encouraged whenever possible. follow-up ranged from to months (median months). four patients kept severe bowel and/ or bladder dysfunction. in the euroqol- d, pain, mood disorders and mobility problems prevailed. conclusion: u-shaped sacral fractures are rare and complex injuries. operative stabilization is tailor-made on the individual fracture characteristics. outcome is dominated by neurological deficits, pain, mood disorders and mobility problems. background: traumatic amputations are important causes of acute stress disorder and post-traumatic stress disorder. in this study, we aimed to present traumatic amputated patients needed more psychiatric support than the other trauma patients during the hospitalization period in the orthopaedics and traumatology clinic and in the later periods more post-traumatic stress disorder could be observed in this patient group. patients and methods: twenty-two traumatic amputated patients who have been treated in our clinic were evaluated retrospectively. during the early post-traumatic period, between the nd and th day, it was observed whether they needed any psychiatric support treatment. after the th month of the trauma, the patients were referred to the psychiatry department, and it was evaluated whether they needed any psychiatric support treatment by measuring the 'post-traumatic stress disorder scale' (tssb-Ö ). results: twenty-one (% . ) of twenty-two patients were male, one (% . ) of them was female. introduction: intramedullary nailing is challenging in proximal tibia fractures, associated with high rates of malalignment. to date, no studies report the potential of lateral tibia nail insertion to correct primary valgus malalignment, commonly seen in proximal quarter fractures. materials and methods: fresh-frozen cadaver lower extremities were used to simulate an ao/ota -a fracture. six nails (expert tibial nailing system, synthes, salzburg, austria) were inserted at the lateral third, six nails at the middle third and six nails at the medial third of the lateral tibia plateau. after nail insertion, alignment in the coronal plane was recorded. results: mean varus malalignment was dependent on the entry point at the lateral tibia plateau. mean varus malalignment was °if nails were inserted at the lateral third, °at the middle third and °after nail insertion at the medial third. if nails were inserted from the medial third, valgus malalignment was recorded in two specimens. discussion: the effect of correction of coronal malalignment in proximal tibia fractures is dependent on the point of nail entry at the lateral plateau. primary valgus deformation up to °can be corrected by inserting tibia nails at the lateral third of the lateral tibia plateau. surgeons should be aware of possible varus deformity and valgus malalignment despite lateral nail insertion. introduction: treatment of patients with distal radial fractures is primarily based on radiologic parameters. however, correlation between these parameters and functional outcome is questionable. objective: determine the value of radiological parameters for the appropriate treatment of patients with distal radial fractures. methods: a retrospective analysis was performed for a consecutive series of patients with conservatively treated distal radial fractures. axial radial shortening, radial displacement, radial angle, dorsal angle, and dorsal displacement were measured on the postero-anterior and lateral x-rays. functional outcome was measured using the quick dash-score (qds). minimal follow up was months. the radiological findings of patients who met the criteria for conservative treatment were compared to those of patients that met the current criteria for operative treatment (dorsal angulation > °, radial angle > °, radial displacement > mm, radial shortening > mm and step off > mm) but who had been treated conservatively instead. results: in a -year period patients were treated conservatively for a distal radial fracture. the qds was performed in ( %) patients. male female ratio was : , the average age was years (range - ). the mean qds was (sd ± ; range - ). age and female sex associated negatively with the qds. none of the radiologic findings was associated with the qds. half of the patients met the current criteria for operative treatment. the qds of this group corresponded however with that of the correctly conservatively treated patients. introduction: conservative treatment is generally preferred for simple elbow dislocations. in this study, the clinical and radiological results of conservative treatment are retrospectively evaluated. the patients were treated with closed reduction, plaster splint and brace. methods: dislocations of all patients were towards posterior and the average length of immobilization was . days ( - days) after closed reduction. the patients were assessed clinically for range of motion, instability, and atrophy after . months of mean follow up. mayo elbow performance score (meps) was used to evaluate functional outcome. standard elbow x-rays were evaluated for degeneration, heterotopic ossification, and concentric reduction. results: the average age of the patients was . ( - ) years. none of the patients had muscular atrophy. four patients ( . %) reported mild pain with heavy activity. six patients ( . %) had neurological complaints related with ulnar nerve. the average flexion arc and average rotational arc were °and °, respectively. the differences between the contralateral elbow motions were . °for flexion arc and . °for rotational arc. four patients ( %) had minimal residual instability. three patients ( . %) had mild radiographic signs of arthrosis and patients ( . %) showed minimal-mild degree of heterotopic ossification. an average score of . was obtained using meps. only four patients ( %) considered themselves fully recovered. conclusion: closed reduction and immobilization is a universal method for simple elbow dislocations. however, although functional scores were excellent, most of the patients did not consider themselves fully recovered. anterior odontoid screw fixation (aosf) is a valuable treatment after of, reported union rates in the elderly vary between and % when assessed on plain radiographs. in this study union-rates in of treated with aosf in patients aged ‡ years were revisited and risk factors for non-union analyzed. retrospective data review of a prospectively gathered c -fracture patients treated with aosf for of and age ‡ years were included for study. asides demographics and common injury characteristics, injury radiographs and ct-scans were assessed for fracture displacement, type, atlantodental osteoarthritis and particularly focussing on the square surface of of. follow-up ct-scans were assessed for technical failures, odontoid union, number of screws in aosf, square surface of screws used and the related healing surface. there were male ( . %) and female ( . %) patients with a mean age of . ± . years at injury ( - y). mean follow-up with ct-scans was . ± . months ( . - . mo). intervall injury to aosf was . ± . days ( - days). mean square surface of fractures was . ± . mm ( . - . mm ) and mean osseus healing surface was . ± . % ( . - . %). ct-based analysis revealed osseus union in nine ( %), while the remaining nine patients ( %) revealed non-union. in two patients, symptomatic non-union indicated posterior fusion of c - . union-rate significantly correlated with increased fracture surface (p = . ). observable was the trend that using two screws for aosf correlated with increased fusion-rate compared to one screw (p = . ). lifethreathening hemorrhage is often seen in pelvic ring fractures. efficient treatment of this hemorrhage is critical for survival in these patients. the purpose was to analyse the causes of death in hemodynamically unstable patients with a pelvic ring fracture and to determine if standardized treatment will reduce mortality. retrospectively, all data were reviewed of hemodynamically unstable patients with a pelvic ring fracture in the period / / till / / . of all patients, the pathway of treatment was analysed and compared with the standardized treatment protocol in our clinic. all injuries were categorized in injuries in airway, breathing, circulation and disability according to atls Ò principles. death was classified as directly related to the pelvic fracture if the patient required massive transfusions, died within h after admission and had no other body area injury with ais ‡ responsible for persistent hemorrhagic shock. we reviewed the data of patients. / patients died ( %). these patients were significant older and had a significant higher iss and shock class than survivors. two patients died of pulmonary trauma ( %), patients ( %) died of exsanguination(c) and patients ( %) died due to major head trauma. in patients ( %) there was a combination of injuries, which caused death. thus, overall hypovolemic shock contributed to mortality in cases. only in three patients death could be directly related to hemorrhage from the pelvis. two nonsurviving patients ( %) were not treated according to our standardized treatment protocol. in the survivor group this was only one patient. there is no consensus on the treatment of the acute total achilles tendon rupture. treatment modality is chosen on the basis of patient characteristics or the preference of the attending surgeon. using ultrasound, the distance between the two tendon ends in equinus position can be measured. this could form the basis for decision making between conservative-and surgical treatment. this cohort study consists of consecutive patients, between january and january . using ultrasound, patients were assigned to a surgicalor conservative treatment group. a gap of more than mm in maximal equines position was an indication for surgical treatment. seventy-two patients, men and women, received a conservative treatment. in patients the achilles tendon was primarily sutured. in the surgical group the post operative treatment was identical to the conservative treatment. the male-female ratio did not differ significantly (p = . ). the average age was years. sports caused % (n = ) of all injuries. the surgical group showed six re-ruptures versus nine in the conservative group (p = . ). on average, a rerupture occurs after days. no significant difference in major and minor complications (p = . ). outpatient treatment was needed days for the surgical treatment group versus days for the conservative treatment group (p = . ). ultrasound measured distance between the two ends of the achilles tendon in equinus in an acute total rupture can be used as a selection method in making a decision between surgical and conservative treatment. introduction: missile wounds induced by aviation bomb splinters pertain to grave injuries, due to large wound area and high risk of complications. material-methods: patients with large defects, in of casescombined with long bone fractures caused by missile injuries were treated by us in the period of august-november in . every cases were subjected to radical primary debridement with complete drainage. after relevant preparation for soft tissue plastic repair (involving primary radical debridement, primary external fixation, complex drug therapy and repetitive regular debridement) the following repair procedures were undertaken: in four cases, soft tissue defects were covered via rotation of local flaps. in three cases, defects were covered through transplantation of free skin grafts. in four cases, large soft tissue defects were overlayed by vascularized thoraco-dorsal (ld flap). in two of these, bone defect repair was simultaneously performed applying avascular graft taken from hip bone crista. results: in seven cases, transplanted flaps adhered perfectly, without trophic or infective complications. in one case, rotated local flap necrotized due to interrupted perfusion, which was subsequently replaced by free skin transplant. in five cases, fracture consolidation was completed in - months. in remaining two cases (after bone defect repair), consolidation process still proceeds with satisfying rate. conclusion: transplantation of vascularized thoraco-dorsal flap is especially effective for covering large soft tissular defects. soft tissular plastic repair has the double advantage of defect reconstructive ability and prevention from secondary infections, with additional stimulation of bone tissue regeneration. introduction: shoulder arthroplasty remains a valuable treatment for complex fractures of the proximal humerus. however the success of anatomical arthroplasty is mainly dependent of anatomical healing of the tuberosities. even with specific prostheses and fixation techniques in - % of cases anatomical healing is not achieved. using a nonfracture specific trauma prosthesis we achieved better elevation and abduction; however endorotation, exorotation, subjective shoulder rating and complication rate did score poorer than in anatomical arthroplasty. we assumed that the impossibility to refixate the lesser and greater tuberosity fragment, and subsequently the subscapularis and infraspinatus-teres minor tendons, are the main cause for this observation material-methods: we developed a fracture specific reversed shoulder prosthesis allowing for anatomical refixation of the tuberosities. we included patients in the reversed fracture arthroplasty group. function is scored using the constant murley-score. radiographically we evaluate for evidence of scapular notching. complications are recorded. we compare our results to an historical series of delta iii prostheses. results: at months the mean constant score is . points. there was no case of notching. there was one complication, an early infect. the mean constant score in the delta group was points. there was notching present in % of cases. in the delta group there were five reoperations in three patients because of dislocation. conclusion: there is a strong trend to better functional outcome using the fracture specific design. there are less complications and less notching. the possibility to refixate the tuberosities leads to better results. introduction: as fractures of the femur are severe injuries and patients mostly suffer from extensive pain they quickly attract the physician's attention in the emergency room. the literature has shown that injuries to the ipsilateral knee can occur accompanying such injuries. in most cases, these injuries though were diagnosed on delay. excluding cases in which a knee injury was apparent already on admission, we sought to investigate the number and severity of initially undetected lesions to the knee accompanying a femoral shaft fracture and give an overview of the literature. methods: charts and x-rays of patients treated for a femoral shaft fracture from january until december were reviewed. patients, in whom any other injury of the affected limb apart from a midshaft femoral fracture was initially diagnosed, were excluded. also patients, in whom an injury to the knee had been diagnosed on admission, were excluded. results: fifty-three patients with midshaft femoral fractures were available for analysis. an injury to the knee was diagnosed in cases ( %). there was one partial tear of the posterior cruciate ligament and two grade lesions of the medial meniscus. all lesions were conservatively treated. the shoulder is the most mobile joint of the human body. it has a great range of movement that takes place in all three cartesian planes. this is a complex phenomenon. there is considerable controversy over an ideal method for the functional assessment of shoulder joint complex. various methods have been used but they are often inaccurate and unreliable. thus, a better technique, that is reliable as well as repeatable, is required to measure the movements. the aim of this study is to assess the shoulder movement by fastrak Ò and vicon Ò systems and to compare their repeatability. methods-materials: the functional movement of the shoulder joint was assessed by fastrak Ò and vicon Ò systems. a difference between the two systems was determined and a comparison of repeatability was carried out. a population of healthy male volunteers were asked to perform six different tasks that covered all the movements occurring at the shoulder. these tasks were repeated twice on each side on two different days. the measurements were recorded and a custom-made programme, prepared for each system separately, calculated the angles. results: the recorded data was analysed using repeated measure analysis of variance. it was found that the coefficient of repeatability of fastrak Ò was better than the vicon Ò system for each task and there was no significant difference (p < . ) between the two sides. conclusion: the fastrak Ò system is better than the vicon Ò system for assessing shoulder movements. it can be used in clinical practice. ( - ). we applied sarmiento cast without any padding or little padding immediately. we encouraged the patients moving their arms. the treatment ends upon the presence of a bone callus and absence of pain at the fracture site. during the whole therapy the skin condition is monitored and emphasis is put on the prevention of reflex sympathetic dystrophy. we evaluate the result of the treatment with a focus on the any restriction of the range of motion of joints and the presenting any angulation of the humeral shaft. average follow up time was months ( - ). all fractures were healed without any major problem and we did not face any nonunion and no major angulations axis of the humerus. average union time was months ( - ). the results of nonsurgical treatment of the humerus mid and distal thirds shaft fractures are reported as a less complicated way and have a higher rate of union. this method is practical, efficient, cheap, and safe, if a good cooperation with patients is established and close observation is done. ( ). the aim of this study is to evaluate the surgical anatomical aspects of the minimally invasive hip surgery procedure in cadavers. methods: the mis approach was performed on four specially embalmed cadavers. all cadavers had a normal 'range of motion' of the hip joint. the difference in muscle length and work space were measured in all leg positions. additionally the difference in muscle tension in anterior and posterior luxation was compared with regard to the accessibility of the femoral shaft. results: the length of the medial-and minimal gluteal muscles is reduced in abduction. a difference of more than cm was found between °to °abduction and full abduction. the working space ( . · cm), is limited in the maximum ( °) abduction position. posterior luxation gives a better femoral shaft approach and less/ none muscle tension/damage compared to anterior luxation. the optimal approach to the femoral neck during mis of the hip is achieved during °- °abduction of the ipsilateral leg combined with °retroflexion. the best femoral shaft approach for prosthesis insertion is the posterior luxation. no additional damage, excluding the skin and fascia incision, was seen during posterior luxation. posterior luxation and exorotation of the leg enables straight and direct access to the femoral shaft compared to the access obtained during anterior leg luxation. background: it has been stated that acromial morphology plays an important role in the etiology of rotator cuff pathology. the system most widely used to describe the morphology is the bigliani classification. recently nyfeller introduced the acromial index. we wanted to examine whether there is a correlation between these two parameters and the presence of a rotator cuff tear or an impingement syndrome. methods: we assessed both parameters in four groups of patients each. the first group consisted of patients with operatively treated rotator cuff tears (average age . years) and the second group of patients known with impingement syndrome but documented intact rotator cuff (average age . ). for both groups, an age and gender matched control group was constructed. results: type three acromions were significantly more prevalent in the rotator cuff tear group than in the control group (p < . ). the average acromial index was . + . in the rotator cuff tear group and . + . in the rotator cuff control group, which is not statistically significant (p = . ). in the impingement group, the acromial index was . + . and . + . in the impingement control group. this difference was found to be statistically significant (p < . ). conclusions: patients with a rotator cuff tear appear to have more frequently bigliani type three acromion than age and gender matched, asymptomatic patients. there is no correlation between acromial index and acromial type or age. objective: extracorporeal membrane oxygenation (ecmo) is rarely used successfully in trauma. transfusion related acute lung injury (trali) is also rare in plasma containing blood product transfusion. methods: this is a case report of a trauma patient with life-threatening trali following trauma that was rescued successfully using ecmo. a year old patient was struck by an automobile and suffered a grade ii splenic injury, grade iv-v right renal injury as well as multiple orthopedic injuries. an attempt at angiographic embolization failed as the patient required multiple transfusions and became progressively hypotensive. the patient underwent emergent nephrectomy but rapidly became hypoxic with the pao becoming less than mmhg for over an hour. despite aggressive attempts at ventilation and oxygenation, the endotracheal tube was filled with fluid and hypoxia pursued despite low right heart filling volumes. rescue ecmo was instituted with successful oxygenation. after h the patient recovered from trali and was able to have ecmo discontinued. the patient was weaned off the ventilator within days and the patient had full recovery. the patient did not suffer any hypoxic brain insult. conclusions: although it is often thought that ecmo is unsuccessful in trauma patients, this case demonstrates its potential use in trauma patients. author to editor: will also present as poster findings: a total number of patients (all male; . ± . ) were found. injuries were resulting from gun shot fires (n = ; . %) or stab wounds (n = ; . %). injury sites within the heart were the right atrium (n = ; . %), the right ventricle (n = ; . %), the left atrium (n = ; . %), and the left ventricle (n = ; . %) (more than one site was observed in patients). the accompanying injuries were observed in the spleen (n = ; . %), the lung (n = ; . %), the liver (n = ; . %), and the stomach (n = ; . %). in ( . %) patients emergent thoracotomy was clinically decided with suspicious findings of hypovolemic shock or cardiac injury including low blood pressure, jugular fullness, deeply heard heart sounds, filiform pulse, narrowing of pulse pressure. the rest patients (n = ; . %) were operated after major blood drainage from tube thoracostomy. all the injuries were repaired with sutures, and pericardial fenestration was done in all. mortality was observed in two cases ( . %). patients with penetrating regional wounds should be suspected for penetrating cardiac injuries, since immediate surgical intervention may decrease the risk of mortality. introduction: the use of ''pan-ct'' is discouraged in settings of high imaging demand. this study compared clinical and plain chest film findings to determine need for, and results of, chest ct. methods: during recent month period, patients sustained blunt chest injury either isolated or in setting of multisystem trauma. data was tabulated by a combination of prospective and retrospective analysis. initial injury assessment followed atls protocol. supine chest film, followed by chest ct, were performed in all patients and compared with clinical findings. results: significant clinical findings were defined as tachypnea, decreased air entry, chest wall tenderness and initial oxygen saturation less than %. the presence of two or more of these clinical findings occurred in patients ( %). ct findings in this group included multiple rib fractures ± flail chest, sternal fractures, pneumothoraces, hemthoraces, and pulmonary contusions. higher ais and need for interventions occurred in this group. the co-existence of tachypnea and desaturation correlated with the need for tube thoracostomy in / patients( %) - pre-ct, post ct. conclusions: in patients with blunt chest injury, the presence of two or more of the clinical signs -tachypnea, decreased air entry, chest wall tenderness, oxygen saturation < % -is associated with: ( ) significant chest injury demonstrated on chest ct; ( ) higher correlation with ct findings than plain films alone; and ( ) introduction: complex regional pain syndrome (crps) sustained after trauma has a great negative impact on rehabilitation and activities of daily living. treatment is most often unrewarding. aim: to analyze prospectively the efficacy of endoscopic thoracic sympathectomy (ets) in reducing pain and disability associated with crps. patient and methods: over a -year period, patients ( females and males; mean age . ± . ) with posttraumatic crps underwent unilateral ets. the median duration of crps symptoms before ets was . months (range: . - ) . the sympathetic chain was resected from the second to fifth rib. mean postoperative follow-up was . ± . months (range: - . ). pain was assessed, at rest (passive) and during movement (active), using a visual analogue scale (vas) from to . results: one patient ( . %) had a hydrothorax and three patients ( %) complained about contralateral compensatory hyperhydrosis. at month (n = ), months (n = ), months (n = ) and year (n = ) after ets, there was a significant decrease in passive and active vas (p < . ). ten out of patients ( , %) needed less analgesics after surgery, and seven ( %) did not need analgesics at all. the mean sleep duration improved significant from . ± . h preoperatively to . ± . h postoperatively (p < . ). overall, patient satisfaction was % ( out of patients). conclusion: ets is efficient for decreasing pain and improving quality of life, and therefore should be considered in the treatment of crps. author to editor: complex regional pain syndrome (also known as sudeck or reflex sympathetic dystrophy) is a complex disease that trauma surgeons frequently encounter in the post-traumatic period. endoscopic thoracic sympathectomy is not well known among trauma surgeon, although it is an good option in relieving the pain and improving the quality of life. monitoring is accomplished with chest x-ray (cxr), but ultrasound (us) is nowadays established as more sensitive than cxr in detection of ptx. patients and methods: from october , thoracic views for detection of ptx are systematically included in the efast protocol during primary survey for every trauma patients (pts) admitted to our level i trauma center. among hospitalized pts, a selective usguided aspiration for small ptx was applied in three pts (two with a slow reabsorption time, one in a pt requiring hyperbaric oxygen therapy for a soft tissue infection of the leg). in supine position, delimitation of the area of anterior ptx was done with a linear probe, searching for lung points in adjacent intercostal spaces. under local anesthesia, a fr catheter was inserted in the ptx and aspiration monitored in real time by us, until restoration of sliding lung. the day after, after confirmation of normal gliding lung, two pts were discharged and one deemed suitable for hyperbaric oxygen therapy. discussion: small traumatic ptx is generally monitored without treatment. in some pts, drainage is however required, but the procedure is blind if performed on the basis of cxr findings. us allows to precisely define the site and the limits of ptx, insert a small catheter in the right area, monitoring reexpansion of the lung and complete aspiration of ptx and shortening recovery. background and objectives: occult diaphragmatic injuries are associated with significant mortality, if the diagnosis is delayed. we report our experience in diagnostic and therapeutic thoracoscopy in a selected group of patients with penetrating thoracoabdominal injuries. methods: the patients who underwent thoracoscopic management of thoracoabdominal stab injuries between june and june were included into the study. the data were retrospectively analyzed. results: eighteen selected patients with thoracoabdominal stab injuries were managed by thoracoscopy. the procedures were performed under general (n = ) or local anesthesia (n = ). diaphragmatic injuries were repaired by intracorporeal sutures in seven cases and bleeding was controlled in another two cases by electrocautery coagulation. the procedures were simply diagnostic in nine patients. the mean operating time and hospital stay were . min and . days, respectively. there was neither intraoperative or early postoperative complication, nor mortality. in a patient who had intra thoracic adhesions due to prior tuberculosis, unmentioned by the patient preoperatively, adequate exploration could not be achieved during thoracoscopy. the procedure was converted to laparoscopy and laparoscopic gastric and diaphragmatic repairs were performed. conclusion: thoracoscopy seems to be a safe, quick and efficient method in the diagnosis and treatment of diaphragmatic wounds, due to thoracoabdominal penetrating injuries. the nonoperative management is gradually more used in abdominal stab injuries and surgeons can resort to thoracoscopy and laparoscopy as a minimally invasive, diagnostic and therapeutic tool. trauma surgeons should be aware of the benefits of thoracoscopy and must have sufficient skills to carry out this technique. summary: generating acute lung injury by smoke inhalation and analyzing a method to pursuit standardized smoke. methods: a standardized glass, measures of cm width, cm length and cm height used as a closed area. we established a valf system under the glass which allows air inside but does not let it outside. with a hole above the glass, we attached the system to pomp with a hose. and the pomp was attached to a cm radial length balloon by another hose. we put a four ampere electricity owen in to glass and put g cotton to the oven. we burned the cotton for s in the closed area and we fullfilled the balloon with smoke by the pomp in s. rabbits were entubated after being anestesized. we waited seconds for the smoke to reduce down to room tempe rature to avoid thermal damage. after that, we seperated the balloon from the pomp and put it right through rabbits by ambulant air flow and inhalated in min.this procedure repeated for each rabbit. after the procedure ended,the entubation tubes were pulled away and the rabbits were left to spontaneous respiration. rabbits were allowed to standart rabbit bait and water at the th hour. results: we think we used a standardized smoke inhalation model in this study. methods: ten wistar rats were anesthetized and heparinised before the femoral artery was pierced to initiate bleeding. rats were than randomized to control and study groups. mph was poured into the bleeding site and a mass was placed on it. after s, the mass was removed and assessment of hemostasis was done. if bleeding ceased the test was scored as ''passed at s''. if not, additional dose of mph and compression was reapplied for an additional s. if bleeding has stopped after the second application, the test was scored as ''passed at s''. if not, the same procedure was repeated for the last additional s. if bleeding stopped now test was scored as passed at s. similar sequence of trials was done in the control group but without mph. the difference between bleeding periods in two groups was observed. results: application of mph resulted in complete cessation of bleeding in four of five and one of five rats at and s, respectively. in the control group hemostasis could not be achieved in all five rats, even at s. the statistical difference between the groups was significant (p < . ( . - . year) with supracondylar humeral fractures were treated operatively. according to gartland ( %) were type-ii, ( %) were type-iii. at the time of arrival at emergency department, four ( %) children sustained vascular impairment with pink pulseless extremity persisting after reduction. in three cases, a cubital approach was performed. two arteries showed a major lesion (one direct suture, one saphenus vein graft), and one artery showed an entrapment. all lesions showed a normal postoperative pulsation. another three ( %) children sustained a complete paralysis of the radial nerve. these cases were conservatively treated with complete neural restitution. conclusions: urgent anatomical reduction and fixation are crucial. in persisting vascular impairment after reduction, surgical exploration for the restoration of arterial patency should be performed, even in the presence of a pink hand. conversion to open surgical repair was needed in one case due to retroperitoneal bleeding from the iliac arteries. early postoperative mortality was observed in ( %) patients; due to massive coagulation disorder and hemodynamic instabiliy in postop st day and th day. mean follow-up was months (range - months). late mortality was not observed. overall reintervention rate was % (n = ); proksimal re-stenting was needed due to type endoleak in one patient. embolectomy for crossfemoral bypass was needed in one other patient after stenting for aneurysmal abdominal aortic rupture, this patient underwent re-crossfemoral bypass surgery later on. introduction: dislocations of and fractures around the knee are accompanied by injuries of the regional vessels to a certain extent. in any case of suspicion at the scene of accident an immediate transport to an adequate trauma center is the precondition for successful limb salvage. methods: between and , patients with arterial injury after dislocation of or fractures around the knee have been treated. retrospective analysis was performed in order to acquire epidemiologic data. furthermore we investigated the sufficiency of preoperative management and diagnostics. we explored peri-and postoperative complications, such as compartment syndrome, secondary thrombosis, infection and number of revision surgeries and related the data to the final follow up after and months. results: arterial injury was found in four cases of knee dislocation, in seven cases of proximal tibial fracture, and in nine cases of distal femur fracture. seven patients underwent acute angiography, since the year all patients were assessed with cta. seventeen cases were treated with venous interposition, one with a venous patch, and two with direct suture. fasciotomy was performed in all cases. limb salvage was successful in cases. in seven cases secondary amputation was necessary, six of these patients were polytraumatized. discussion: sufficient time management is crucial for the survival of vessel injured extremities, as the time of ischaemia must not exceed h. perfect interdisciplinary coordination and the establishment of specific algorithms are needed in order to decrease the risk of complications and amputations of lower extremities. the survey on the epidemiology of car-motor related accidents in children in kashan, iran iman ghaffarpasand, maneli dorudian tehrani department of surgery, kashan medical university, kashan, iran introduction: the most common cause of death in children is accident and reinforced a lot of taxes on the society. kashan has the second position in trauma ranking of iran so we studied this important issue in the children. methods and material: in this descriptive study, data has been gathered by trained hospital nurses during month in traumatic patients refered to -bed teaching hospital, kashan. the main method is questionnaire filling by direct interviewing. findings: among cases of trauna ( . %) of them was children below years old that cases ( . %) were due to car accident, cases ( . %) were due to motor accident and rest of them ( . %) were pedestrian accident. boys involved . times as girls the most injuries happened was head-injury ( . %). conclusion: these finding suggest that we have to pay more attention to this age group specially - because of the high rate of their involvement. finally as you see the last but not the least, these findings emphasise on protective cap wearing for every persons. managing blunt splenic injury in a level ii trauma center: the laparoscopic option background: the past decades treatment modality of blunt splenic trauma was a point of discussion. where nowadays explorative laparotomy remains the standard of care for hemodynamic unstable patients, treatment of hemodynamic stable patients is less uniform. in this stable population maximum conservative approach seems preferable, though level evidence is still absent. failure of the conservative pathway is backed up by percutanous angioembolisation or laparoscopic salvation. the evolution to minimal invasive access makes laparotomy as a primary care for hemodynamic stable isolated splenic injury superfluous. methods: this paper discusses the initiation of explorative laparoscopy and successive splenectomy in two patients scoring a grade iii posttraumatic splenic injury. grading was based on ct scan imaging using the spleen injury scale defined by the american association for the surgery of trauma (aast). conservative treatment was abandoned because of moderate hemoperitoneum and continuing need for transfusion. results: an uncomplicated laparoscopic splenectomy was performed in both patients. perioperative spleen preserving measures failed because of the extent of the parenchymal lesion. conclusion: performing laparoscopic splenectomy seems a good procedure when conservative treatment for splenic injury fails. this accounts for a rural level ii trauma center where the accommodation to perform safe angioembolisation is missing, knowing that laparoscopic splenectomy is not a straight forward procedure but is made easier because of the growing skills of our surgeons. hepatic portal venous gas (hpvg) is often associated with serious intra-abdominal pathology like ischaemic bowel disease and necrotizing enterocolitis, with reported mortality rates above %, with most requiring urgent operation. however, hpvg has been reported seen on ultrasound or computed tomography (ct) scans immediately after blunt trauma, followed by spontaneous resolution. gastric pneumatosis (gp) has rarely been reported as a trauma-related entity. the combination of hpvg and gp after blunt trauma has been described in very few patients. we report the case of a -year-old woman who presented with an edh requiring craniotomy and an initial abdominal ct scan showing only an ois grade liver injury. a transient increase in serum amylase combined with abdominal distension led to a repeat abdominal ct scan h post injury to rule out pancreatic and duodenal injuries, revealing gp and hpvg. endoscopy demonstrated mucosal erythema of the posterior gastric wall from the fundus to the pylorus. however, the clinical status of the patient was benign, and did not mandate surgical intervention. the patient was treated nonoperatively with nasogastric decompression and antibiotic coverage, and underwent a successful recovery with no abdominal complications. to our knowledge, only one other adult patient has been described with hpvg and gp occurring after an initial normal abdominal ct scan. a gastric resection was performed, and operative treatment was recommended for this combination of entities in trauma patients. our patient shows that treatment strategies in these cases probably should be guided by the clinical status of the patient. introduction and aims: while the number of colorectal injuries due to penetrating trauma are increasing, increased traffic accident rates also cause the number of blunt rectal injuries associated with trauma in traffic accidents to be increased. rectal injuries occur rarely. because of post operative septic complications, morbidity and mortality rates are high. early admission, stability, operation type all play important roles in the fate of the patient. we aimed to investigate these criteria in our patients who have colorectal injuries. material-method: cases who had penetrating or blunt trauma in our district during last years were included in this study. aim of this study is to present three cases with torsion of omentum, that often resemble acute cholecystitis or appendicitis, and the diagnosis is made at the time of exploratory laparotomy. case description: the first case, a -year-old men, presented with a -day history of right hypocondrial abdominal pain, fever and vomiting. the pain increasing in severity while the patient is standing and relieved in supine position. laboratory findings were normal, except for mild leucocytosis ( , /cc). the patient underwent u/s examination, which showed an encysted mass in the right abdomen. a mass, originating from the omentum, was revealed after laparotomy. the mass was excised and an appendectomy was also performed. the second patient, a -year-old female, was admitted in our department with abdominal pain, associated with vomitus. a mild leucocytosis ( , /cc) was observed. an u/s was carried out, which revealed a mass · cm lying besides a stone-free gallbladder. the patient underwent diagnostic laparoscopy and a cystic mass, which was twisted, was resected using bipolar forceps. sixteen of all laparotomies did not reveal any internal organ lesion. of these laparotomies with negative findings, had been operated for stabbing injury and had been operated for gunshot injury. twenty-one cases had single organ injury; whereas, multiple organs were affected in cases. frequencies of organ injuries were as follows: small intestine, colon, stomach, liver, diaphragm, spleen, kidney, and pancreas. the mean duration of hospitalization was . ± days. after surgery, four cases needed intensive care unit; therefore, they were referred to a higher-level healthcare center. among cases whom the treatment was completed in our institution, had complication. conclusion: penetrating abdominal injuries mostly occurred in young males and stabbing injuries were more common. most penetrating injuries can be treated at secondary care centers. however, they should be referred to a higher-level institution after the initial intervention, when necessary. background: both nonoperative management (nom) of blunt hepatic trauma and the damage control laparotomy are significant advances in the management of massively injured trauma victims. methods: this study is a retrospective evaluation of patients admitted with liver trauma during . of them required early surgical procedures, damage control surgery and followed nom. patients were stratified by age, mechanism of injury, ais, initial blood pressure, heart rates, and blood transfusion volume. initial outcome data included major complications, intensive care unit and hospital length of stay, and mortality. readmission data including the number of admissions, surgical procedures, and hospital length of stay were then analyzed. the average age of the study group was , years. almost all of these patients were males ( , %) and car crash was the main mechanism involved ( , %). liver injuries were frequently an element of multiple trauma and was associated with cranio-cerebral trauma ( , %) and spleen lesion ( , %). the overall mortality during the first admission was , %, yet . % attributable to the liver trauma and only . % after damage control. conclusions: damage control surgery offers a simple effective alternative to the traditional surgical management of complex or multiple injuries. phase i can be done at a local hospital before transfer to a major trauma center for resuscitation and definitive repair. reasonable surgical procedures based on classification of liver injuries and damage control principles increase the survival rate of severe liver trauma. background: at our department, a simple scoring system based on three criteria (blood pressure below , be below - . and body temperature below °c) has been used to determine the suitability of individual patients as candidates for dcs. objectives: the present study was undertaken to establish a valid strategy for the treatment of severe pancreatic injury and to test the validity of the scoring system used at our department for identifying suitable candidates for dcs. subjects and methods: the subjects of the study were patients with the grater and equal of grade iii (organ injury scale (ois))pancreatic injury treated surgically (type iii in cases and iv or v in cases). results: resection of the pancreatic body and tail was performed in both the groups to treat type iii injury, and all of the cases with type iii injury had favorable outcomes. among the cases with type iv or v injury, all of those patients satisfying two or fewer than two of the criteria of the dcs scoring system survived dcs, while two patients satisfying all the three criteria of the dcs scoring system died after dcs. the two patients who underwent pancreatic duct-forming surgery needed prolonged hospitalization. discussion: our results suggest that dcs should be selected in cases where at least one of the three criteria of the dcs scoring system is satisfied. as a procedure for radical operation, resection of the distal pancreas may be recommended for type iii, and pancreatoduodenectomy for type iv or v. author to editor: our results suggest that dcs should be selected in cases where at least one of the three criteria (systolic pressure below , severe hypothermia with body temperature below °c, and acidosis with be below - . ) of the dcs scoring system is satisfied. this dcs score is accords with the score of another abstract (abs ref ). we did not show the details of the score in another abstract ( ). please refer in our another abstract (ref iatrogenic and traumatic lesions involving common hepatic duct and duodenum can be treated with a primary and contemporary reconstruction, at the condition of hemodynamic stability. we propose a technique which include the following steps: cholecystectomy with intraoperative cholangiography; transection of the common bile duct above the tear, oversewing its distal part; kocherization of the duodenum; a cm long roux-en-y jejunal loop is constructed and brought up retrocolically in the right sub-hepatic space, orientating its antimesenteric side towards the corresponding duodenal wall; termino-lateral hepatico-jejunostomy with a transanastomotic temporary stent in case of small biliary duct's size; a side-to-side jejuno-duodenostomy performed cm distally; a feeding jejunostomy. we remark the following advantages of this procedure: ( ) the rouxen-y biliary diversion reduces the risks of stenosis and cholangitis, frequent after a direct repair of the common bile duct; ( ) an adequate distance between the biliary and duodenal anastomosis prevent entero-biliary reflux; ( ) the duodeno-jejunal anastomosis appears more appropriate, considering the complications after direct repair of large duodenal tears. more aggressive options, such as duodeno-cephalo-pancreatectomy, pancreas-preserving-duodenectomy and segmental duodenal resection, must be considered more risk solutions. introduction: the liver is the most commonly affected organ in abdominal trauma. in our department, the majority of traumatic liver injuries are treated conservatively. this option involves the monitoring of possible complications, such as late rupture, hemobilia, arterio-venous fistula, pseudo-aneurysm, biloma and abscess formation. case: a year-old patient was admitted after a m fall. established diagnoses were: multiple facial fractures, right pneumothorax with pulmonary contusion, right renal artery thrombosis and grade hepatic laceration. the patient was discharged on the st post-trauma day (ptd), after an uneventful course. on the st ptd, he was readmitted for abdominal pain. thoracoabdominal ct revealed an intra-hepatic arterio-venous fistula. angiographic superselective embolization was performed, and the patient was discharged following a control abdominal ct scan that showed resolution of the fistula. he was again readmitted on the th ptd, with abdominal pain, jaundice and gastrointestinal bleeding. an abdominal ultrasound raised the possibility of hemobilia, confirmed by upper endoscopy. a new angiography did not reveal any active bleeding, and an abdominal ct showed satisfactory evolution of the liver lesion. the patient was discharged on the th ptd, asymptomatic. at month follow-up, the patient presents no complaints, other than a new-onset arterial hypertension of renovascular origin. conclusion: arteriovenous fistulae and hemobilia are relatively uncommon sequelae of abdominal trauma. however, these diagnoses should be actively sought in the presence of abdominal pain, especially when associated with jaundice and gastrointestinal bleeding. a multidisciplinary approach is essential for a successful treatment. diaphragmatic hernias constitute frequent complications after thoracic and abdominal trauma ( . - %), especially on the left side ( %) and the diagnosis is frequently delayed. clinical presentation is variable and may include respiratory distress and abdominal pain, frequently attributed to intestinal obstruction, pancreatitis, biliary colic or peptic disease. the authors present a case report of a right diaphragmatic hernia diagnosed years after a thoracoabdominal blunt trauma. the male patient, years old, was admitted in the emergency room with epigastric pain, bloating, slight abdominal distension with months of evolution and recent worsening. he suffered a previous thoracoabdominal trauma years ago, consecutive to a downfall of about eight meters high with lumbar vertebrae fracture (l ) and was submitted to conservative treatment in an orthopaedic ward; x-ray signs of diaphragmatic hernia were unrecognized. actual chest x-ray revealed an elevated right hemidiaphragm and presence of abdominal content in the right hemithorax. mr demonstrated a right hemidiaphragmatic rupture and the presence of abdominal content in the thoracic cavity. patient was operated by laparoscopic approach; a diaphragmatic hernia grade iii (a.a.s.t. classification) was observed and submitted to prosthetic repair. postoperative period was uneventful. patient remains asymptomatic with no signs of recurrence after years. this case is paradigmatic of the difficulty of immediate diagnosis of diaphragmatic hernias, especially at the right hemidiaphragm. high index of clinical suspicion is needed for its early recognition in context of blunt trauma. laparoscopic treatment revealed to be safe and efficient, with the known advantages of minimally invasive procedures. results: their ages were between and , were male and were female. the type of injury was penetrating in , blunt in and blunt and penetrating in patient. in patients, the left kidney was injured, in the injury was at right kidney and in injuries was bilateral. the average transport time to hospital was min ( min- days). one hundred and seventeen out of patients were explored immediately as they hemodynamically unstable position. remaining patients were evaluated with ultrasonography, intravenous urography and computerised tomography. sixty four of these patients were followed conservatively. the injuries in patients followed conservatively were in patient's grade , in grade , in grade . renal units of patients were operated. nephrectomy was done in , nephropathy was done in and renal artery repairing was done in patient. conclusion: nephrectomy and mortality were high because of the long transport time, frequent high grade and high rate of associated organ injuries. rojnoveanu gheorghe sigmoid volvulus is seen more frequently at elderly ages and early diagnosis and treatment decreases its mortality and morbidity rate. we reviewed sigmoid volvulus cases treated in our clinic. patients hospitalized and treated due to diagnosis ofsigmoid colonic volvulus in dr. lü tfi kırdar kartal education and training hospital during - were analysed. treatment modalities, morbidity and mortality rates were analysed. patients were male, were female. mean age was ( - ). sigmoid colon resection and end colostomy was done to patients, sigmoid colon resection and end to end anastomosis was done to patients and nonoperative colonoskopic decompression was applied to patients with sistemic illness and they were prepared for elective sigmoid colon resection and end to end anastomosis. in one patient with anastomosis, anastomotic leakage was detected and end colostomy was applied. two emergently operated patients with sistemic illness died. mortality rate was% . in conclusion, sigmoid volvulus patients with sistemic illness should be prepared to elective surgery with colonic decompression. we think that the best treatment for early diagnosed cases is sigmoid colonic resection and end to end anastomosis. introduction: onset of world war ii, the report concerning diverting colostomy declared reduced mortality rates for colon injury, compared to world war i. in spite that nearly years has passed away, although all therapeutic options, this method -used for the management for colon injury -still include some controversial points. methods: ninety-five patient's characteristics were compared in two groups (patients with or without diverting stoma). clinical findings and patient's characteristics, injury mechanism, localisation of the wound, blood transfusion requirements, fecal contamination, colon injury score (cis), penetrating abdominal trauma index (pati score), evidence of shock, morbidity rate, mean hospital stay, main and additional surgical procedures of patients who admitted to our clinic from to were reviewed retrospectively. results: we have no mortality in both groups, except the first postoperative h. diversion colostomy was performed in patients and primary repair in patients. median hospital stay for primary repair and diversion groups were and days, respectively, (p < . ). respiratory system, septic complications, clinical anastamosis leakage and other complications were similar in both groups. conclusions: although all articles that prompt primary repair, this approach includes some inconvenient points. it is acceptable in military or war originated injuries. diversion mostly is necessary in wounds, related to highly potent and energic fragments. nevertheless, nearly all of the civilian colonic injuries can be treatment with primary repair without diversion since the mechanism of the wound is different than war injuries. dogan gö nü llü , oguz Ç atal , nilü fer yazgan yıldırım , tayfun yucel , ferda nihat kö ksoy taksim trainig and research hospital, _ istanbul, turkey background: the management of haemodynamic stable penetrating injuries of the flank has not been well defined; laparoscopic exploration, closed abdominal examination and triple contrast computed tomography (ct) are alternative modalities. our aims are to explain our experiences in these cases. methods: we reviewed the patients with isolated penetrating flank trauma admitted between and . the flank was defined as area between the anterior and posterior axillary lines, inferior to the fifth intercostal space superior to the iliac crest. results: there were haemodynamic stable patients ( gunshot and stab injuries). there were three patient groups: laparotomy (g ) (n = ), laparoscopy (g ) (n = ) and only closed clinical observation with triple contrast ct scan (g ) (n = ). patients in the g were gunshot injuries; the other two gunshot injuries were tangential and were included in the g . in the g there were four left diaphragmatic injuries, all repaired laparoscopically. one patient with splenic laceration and another with small bowel injury were converted to an open exploration. there were eight negative laparoscopies ( / ).two patients of g ( / ) with negative tomography were submitted to laparotomy after day of closed observation. the mean length of hospitalization in the groups was respectively . , . and . days. introduction: intra and retro abdominal hemorrhage are common following blind and penetrating abdominal trauma. liver, spleen and kidneys are known to be prone to injury and to bleed after an abdominal trauma. hepatocellular carcinoma is a well known disease. however, a renal mass from a primary origin in the liver is rare. this paper presents a patient, who was treated with right nephrectomy for traumatic bleeding from a ruptured renal mass. end diagnosis was metastatic hepatocellular carcinoma. case: the patient was -years-old man. he had no positive medical and surgical history, and no complaint. he was referred to emergency service after traffic accident. during his initial assessment abdominal rigidity and tenderness were found, which were accompanied with tachycardia and hypotension even after fluid resuscitation. fast revealed that there was free fluid in his abdomen, so we decided to operate him. at laparotomy we observed a bleeding tumoral mass in the right kidney and in his liver. he was treated with right nephrectomy and irregular hepatectomy. pathologic examination demonstrated a metastatic hepatocellular carcinoma. conclusion: hepatocellular carcinoma is a well known disease with its common acute complications such as rupture and bleeding. in this case, we observed hcc metastasis to the right kidney although the patient had no medical and surgical history including hcc. bleeding was induced after a blind trauma, was treated with resection. gall bladder (gb) injuries either following penetrating or blunt abdominal trauma is a rare entity and usually misdiagnosed with a delay in diagnosis. the incidence of gb injury is reported to range between . and . % among the surgically treated patients following abdominal trauma. cholecystectomy is the definitive treatment even in severe contusion of a nonperforated gb. simple suture repair or cholecystostomy are also advocated as alternative surgical interventions by some authors. gb is afforded significant anatomic protection from external trauma, since it is partially embedded in the relatively massive liver parenchyme, cushioned by the surrounding omentum and intestines, and shielded by ribcage. clinical symptoms may be minimal or nil initially but gradual clinical deterioration, related to spillage of bile into the peritoneal cavity, can follow. bilous fluid taken by paracentesis or diagnostic peritoneal lavage can only be helpful after a delay as abdominal computed tomography. an year-old male was admitted to our emergency department for the fifth time because of penetrating abdominal trauma of at the right upper quadrant by a knife in a -day-period. he was hospitalized in three of them and operated on at last, because of acute abdomen, since paracentesis revealed bile coloured free abdominal fluid in addition to abdominal guarding, leucocytosis( , /mm ), and fever.the ultimate ultrasonography and computed tomography revealed large amount of free fluid (bile) and minimal intrahepatic hematoma. at laparotomy; full-cut hepatic and cholecystic perforation (both anterior and posterior surfaces) resulted in cholecystectomy. he was discharged on the fourth postoperative day. since almost all reports about the delayed rupture of gb are usually unrecognized gb perforations,a diagnostic delay can only be avoided by a high clinical index of suspicion. sixty-three patients were treated conservatively, whereas patients had laparotomy and patients underwent angiography. of patients transported by ambulance or helicopter, % arrived at the emergency unit within min after prehospital alert. in % the time on scene were longer than min. in this group only % were diagnosed by ct within min after arrival to the emergency unit. conclusion: low volume in trauma care results in substandard handling time. in hospitals with a low volume exposure to trauma, the prehospital response teams and surgeons achieves limited experience, especially in penetrating trauma. exchange programs must be emphasised. author to editor: this study describes the complete workload in primary handled trauma patients in a typical nothern european universtyhospital with very low incidence of penetrating trauma and low volume of blunt trauma. our trauma registry covers % of patients admitted to the hosptial. it is the only hospital in the area, and patients do not bypass the system and are treated elsewhere. the study will point out that prehosptial responsetime and inhosptial procedures are is acceptable, but emergencyroom handlingtime is to long, due to lack of practice. national or european exchange programs for surgical trauma care must be practiced. introduction: explosives create and energize particles that act as projectiles prone to further fragmentation in the body. these fragments may result in secondary injuries. this has been repeatedly described in the orthopedic and neurosurgical literature. in this paper we demonstrate that such a process is also possible for abdominal injuries during or after fascial penetration. material-method: in all abdominal wall injuries, despite negative physical examination of conscious and alert patients we used local wound exploration as a standard approach. finding a full thickness fascial defect, we assumed an intraperitoneal injury and performed laparotomy. result: using this method, we found hollow organ injuries in of ( . %) patients. in ( . %) of these patients at laparotomy, we found multiple, projectile induced injuries in a sprayed distribution. these injuries were found far from the trajectory, in the absence of bone fragmentation. the mean number of peritoneal defects was . , however, for each peritoneal defect, we found an average of . intraabdominal injuries when through and through injuries were excluded. conclusion: local wound exploration is an accurate indicator of possible intraabdominal injuries. although fragments of projectiles would be expected to be distributed along the trajectory, meticulous exploration of abdomen is mandatory because this is not always true. despite a single peritoneal defect, there may be multiple intraperitoneal injuries due to further fragmentation of the projectile. introduction and objectives: nonoperative management of penetrating abdominal stab wounds has been established as standard care recently. it decreased negative laparotomy rate without any increase in morbidity and mortality. in this study we evaluated the outcome of patients managed due to penetrating abdominal stab wounds. intraabdominal injury due to blunt abdominal trauma usually presents acutely. in the absence of peritoneal irritation findings or shock the patients may be treated conservatively. delayed small bowel obstruction after blunt trauma is very rare clinical entity. it may be caused by subclinical bowel perforation, localized bowel ischemia or mesenteric vascular injury. we present a years old man of blunt abdominal trauma that was treated nonoperatively. despite the success medical treatment, months later, the patient presented with abdominal pain and vomiting. the radiologic studies suggested a mechanical intestinal obstruction. at the operation a conglomerated terminal ileal segment causing obstruction was found and the patient is treated by a resection and primary anastomosis. the operative findings may be explained by a subclinical perforation at the time of the trauma. this kind of complication should be suspected in patients with post traumatic patients which presents with signs of intestinal obstruction in weeks after the trauma. nevin kanan, ayfer Ö zbaş department of surgical nursing, istanbul university, florence nightingale school of nursing, ankara, turkey with traumatic injury, kidneys can be thrust against the lower ribs, resulting in contusion and rupture. up to % of patients with renal trauma have associated injuries of other internal organs. injuries may be blunt (automobile and motorcycle crashes, falls) or penetrating (gunshot wounds). approximately - % of all renal trauma cases are blunt trauma injuries; penetrating renal trauma accounts for the remaining - %. blunt renal trauma is classified into one of four groups which are contusion, minö r laceration, majö r laceration and vascular injury. • with a contusion of kidney, healing may take place with conservative measures (i.e. bed rest) • if minö r laceration is present, the patient is hospitalized and kept on bed rest until the hematuria clears. • depending on the patient's condition and the nature of the injury, major lacerations may be treated through surgical intervention or conservatively (bed rest, no surgery) • vascular injuries require immediate exploratory surgery because of the high incidence of involvement of other organ systems and the serious complications that may result if these injuries are untreated. the patient is often in shock and requires aggressive fluid resuscitation. for the management of patient with renal trauma, nursing diagnoses are: • inefective tissue perfusion (renal) related to interruption of arterial flow • anxiety related to physical injury • acute pain related to physical injury • impaired urinary elimination related to renal damage and shock background: penetrating abdominal buckshot wounds are believed to necessitate emergent laparotomy to rule out any hollow or solid organ injury. recently, nonoperative management has been suggested in selected patients. this paper aims to present two cases with penetrating abdominal buckshot wounds, treated nonoperatively. materials-methods: a chart review has been conducted for patients operated in our institution for abdominal buckshot wounds. demographics, evaluation tools and follow-up parameters has been analyzed and documented. results: a total number of two patients (both male; and years old) were found. both were shot on their left thoracolumbar regions. left and bilateral chest tubes were necessitated after initial examinations, but both denied any abdominal tenderness, although computed tomography showed multiple abdominally located pellets. gastroscopy (n = ), echocardiography (n = ), intravenous pyelography (n = ) were necessitated for further evaluation, but showed no abnormality. the patients were followed up with routine abdominal examinations, vital signs and routine laboratory tests and discharged from the hospital on days and after uneventful recovery periods. discussion: patients with penetrating abdominal buckshot wounds may be followed with nonoperative management instead of routine laparotomy. objective: treatment procedures in cases who were operated due to colon injuries were investigated in this study. material-methods: thirty-two cases who were operated due to colon injuries in our clinic between and were investigated retrospectively. cases were investigated with regard to age, sex, type of trauma, hemodynamic condition, interval between injury and surgery, additional organ injury, transfusion volume, injury site and severity, faecal contamination, surgical procedures, postoperational complications and mortality and factors affecting morbidity and mortality were determined. colonic injury severity scale (ciss), abdominal trauma index (ati) and flint classification were used for evaluating severity of colon injury,severity of additional organ injury and faecal contamination, respectively. systolic blood pressure less than mmhg on admission was referred to as ''shock''. results: males comprised out of cases and mean age was . (range: - ) years. twenty-five cases were injured due to penetrating trauma and left colon injury was the most common ( cases) type of injury. additional intraabdominal organ injury and extraabdominal injury were observed in and cases, respectively. mean interval between injury and surgery was . (range . - ) h. fifteen cases received blood transfusion. five cases had shock on admission. seven cases received stoma surgery while all cases with flint grade more than iii or ati score higher than received colostomy. only cases with high ciss score received resection and anastomosis surgery. complications were observed in cases while mortality occurred in two cases due to hemorrhagic shock. conclusion: routine primary repair cannot always be performed in colon injuries since many factors affect the decision for type of surgery. primary repair may be performed safely in hemodynamicallystable cases with ati score less than and flint grade i-ii. seat belt syndrome is defined as a seatbelt sign associated with lumber spine fracture and bowel perforation. an isolated rectal perforation due to seatbelt syndrome is extremely rare. there is only one case reported in the danish literature and non in the english literature. hereby, we report a -years old male who was a front seat restrained passenger involved in a head-on collision. he has presented with lower abdominal and back pain. seat belt mark was seen transversely across the lower abdomen. initial trauma ct scan was normal except for burst fracture of l vertebra which was operated by internal fixation on the same day of admission. the patient continued to have abdominal pain and distention which became clear on the third day. repeated abdominal ct scan on the third day has shown free intraperitoneal air. exploratory laparotomy has revealed a perforation of the proximal part of the rectum below the recto sigmoid junction. hartmann's procedure was performed with end colostomy. the abdomen was left open and temporarily closed using saline iv bags sandwiched between layers of steri-drape. peritoneal toileting was performed four times under general anesthesia with gradual closure of the abdominal fascia over a period of weeks. postoperatively, the patient had urinary retention due to a quada equina injury although he could walk. the presence of seat belt sign and a lumber fracture should rise to the possibility of a bowel injury. author to editor: seat belt syndrome is defined as a seatbelt sign associated with lumber spine fracture and bowel perforation. an isolated rectal perforation due to seatbelt syndrome is extremely rare. there is only one case reported in the danish literature and non in the english literature. hereby, we report such a case. fuat ipekçi, muharrem karaoglan, hü seyin toptay, hasan Ş ahin department of general surgery, tepecik education hospital, izmir, turkey introduction and aims: meckel's diverticulum results from incomplete degeneration of omphalomesenteric duct. it is usually diagnosed incidentally during appendectomy; however, sometimes perforation or bleeding may lead the surgeon to the diagnosis. we aimed to investigate the frequency of meckel's diverticulum during emergency laparotomy performed for acute appendicitis and clinical and pathological characteristics of the patients with meckel's diverticulitis and appendicitis. material-method: the material consisted of , patients who admitted to our hospital and treated by appendectomy during a -year interval between the years and . of these patients ( , %) were male and remaining ( , %) were female. all patients were investigated for meckel's diverticulum weather they have acute appendicitis or not. results: meckel's diverticulum was found during out of , appendectomies ( . %). of the cases, were asymptomatic but four patients were symptomatic with inflamed diverticulitis. of these four patients two have normal appendix and other two have secondary appendicitis due to meckel's diverticulitis. all four symptomatic cases were treated by diverticulectomy and appendectomy. all asymptomatic cases were treated by appendectomy alone. no mortality or major morbidity was detected. conclusions: despite of its rarity ( . % in our appendectomy series), meckel's diverticulum must be searched weather the appendix is normal or inflamed. introduction: illegal drug smuggling is a widespread problem. drug packs carried inside body cavities may leak its contents and be dissolved inside the body and signs of toxicity (aka. body packer syndrome) become evident. this case was reported to represent the very first proven patient in turkey. case: a year-old man were brought in the emergency department (ed) from the airport because of severe tremor, palpitation, restlessness associated with hypertension and tachycardia. the patient was cooperative and oriented. on examination, his blood pressure (bp) was / mmhg, pulse rate /bpm, whereas other systems were unremarkable. he was put on cardiac monitor and infusion of glycerol trinitrate was instituted ( mcg/min). urinary toxicologic screen was positive for cocaine and benzodiazepine. after admission to the ed he complained of epigastric distension and abdominal pain and admitted that he had swallowed cocaine packs. his abdominal xrays showed gas-fluid levels and opaque round-shaped mass images. a nasogastric catheter was inserted and gastric contents (approximately , ml) were drained. he was consulted with surgery clinic with a diagnosis of an ileus due to swallowed packs. he was hospitalized in the surgical ward. after supportive treatment and repeated enema applications he excreted cocaine packs in days. he was discharged following clinical stabilization and abdominal x-rays were repeatedly normal. conclusion: toxicologic analysis must be employed in patients who are suspected to have intoxication, to identify life-threatening drugs and vasoactive substances. advanced imaging methods must be exercised to exclude bowel obstruction in these patients. background: pseudoaneurysm is a well recognized complication of pancreatitis. angioembolization is considered to be the first option of treatment. to our knowledge, the case we hereby report is the first one with successful re-angioembolization. case: a -year-old man, with aids, history of cns toxoplasmosis, chronic pancreatitis with pseudocyst secondary to alcohol abuse, was hospitalized for pneumonia. during his hospitalization, he developed abdominal pain and hypotension. after resuscitation, ct angiogram of the abdomen revealed active bleeding into a pseudo-aneurysm, near the head of the pancreas, measuring . x . cm and arising from superior and inferior pancreaticoduodenal arteries. this was confirmed by angiogram. angioembolization distal and proximal to the bleeding area was performed using coils. eight days later, the patient became hypotensive and dropped his hemoglobin again. he was taken for an emergency laparotomy which revealed a cm pancreatic pseudocyst with hemorrhage. the pseudocyst was opened through the medial wall of the duodenum, ligation of the bleeding intracystic vessels, and cysto-doudenostomy were performed. his postoperative course was uneventful and he was discharged home on postoperative day . five days later he was readmitted with hematemsis and anemia. celiac angiogram revealed bleeding from the gastrodoudenal artery which was embolized. he died months later due to hiv nephropathy without any evidence of re-bleeding. objectives: any sort of discomfort in the abdominal cavity that lasts less than week is defined as acute abdominal pain. the purpose of the study was to evaluate the outcome of hospitalized patients with unspecified acute abdominal pain following initial clinical and laboratory evaluation. method: from january to december , patients with acute unspecified abdominal pain were admitted to surgery department. gender, age, definite diagnosis, time from hospitalization to surgery and hospital length of stay were retrospectively reviewed. results: fifty-six of the patients with acute unspecified abdominal pain were females ( %) and were males ( %), median age was years (range - ). while definite diagnosis was confirmed in patients ( %), the initial diagnosis was not changed in patients ( %). distribution of new diagnoses were appendicitis (n = ), gastroenteritis (n = ), genitourinary disorder (n = ), familial mediterranean fever (n = ), inflammatory bowel disease (n = ), mesenteric adenitis (n = ), peptic ulcus perforation (n = ), constipation (n = ), diverticular disease (n = ), pneumatosis intestinalis (n = ), hepatobilier disease (n = ) and intra abdominal tumor (n = ). depending on the cause of abdominal discomfort, patients ( %) required surgical intervention. median time from hospitalization to surgery was h (range - the use of temporary skin substitutes (tss) is a useful technique in the treatment of full-and partial thickness burn wounds affecting a large body surface area. early excision of the eschar is mandatory. but if we cannot find sufficient donor site, tss using seems to best choice. the ideal tss must be has some properties: adherence, control of water loss, safety, flexibility, stability on wound surfaces, bacterial barrier, and ease of application, ease storage and cost effectiveness. case report: a -year-old girl was admitted to our burn center with deep flame burns affecting face, thorax, upper and lower extremity ( %). she underwent an early burn excision on day post-burn day. the whole area excised with hydrosurgically was covered with biobrane Ò and compressive dressing. seven days after we removed biobrane from the upper and lower extremities and grafted the wound bed. face healed spontaneously under the tss and tss covering the thorax was rest intact. after days thoracic tss was removed and grafted and we covered the thorax with biobrane Ò over the grafts again. after days a second grafting was needed. patient was discharged from the hospital th post-burn day. the use of biobrane Ò as a tss after burn wound excision was satisfactory, because it enabled us to delay auto grafting until we were sure of good conditions in the wound bed. also it proved to be a good dressing over the meshed autografts. it reduces the healing time and improved the quality of grafts. introduction: endoscopic examination of the colon during the diagnostic or treatment purposes, perforation incidence is reported between . and . %. determination of risk factors may decrease the incidence with early recognition of the serious complications of surgery may reduce interference. method: we have examined retrospectively the patients in whom colon perforation appeared due to endoscopic analysis of colon carried out at endoscopy unit between january and december . results: total colonoscopy and rectosigmoidoscopy were applied to , patients. in patients ( . %) perforation was observed. the median age was . ( - ), m/f: / . all colonoscopys were made for diagnosis; anemia in two, hemorrhodial disease in one, subileus in two, anal prolapsus in one, right colon tumor suspation in one patients. one sigmoid polypectomy was applied, diverticulosis disease of the colon in two patients, dolichocolon in one, one previous pelvic surgery were observed. perforation zone was observed in sigmoid colon in all patients. four patients were diagnosed in the process of colonoscopy ( . %), were diagnosed in - h ( . %), was diagnosed days later. laparotomy was applied to all patients. perforation zones of patients were fixed primarily and these patients were discharged as cured. one patient who was applied to diversionary ostomy was reoperated due to abdomen collection. no mortality was observed. conclusion: colonoscopic perforation is a rare, serious complication. sigmoid colon is the location where the perforations are mostly observed. although primary fixation is generally efficient in cases of early diagnosis, morbidity increases seriously due to late diagnosis. with more than one stomas. eleven patients were discharged with planned ventral hernias. primary abdominal closure succeeded in four patients. fasciitis due to severe peritonitis and stomas prevented primary closure. eighteen of patient died during treatment, were discharged. sixteen of patients with more than one bag were died, five survived (mortality . %). conclusions: morbidity and mortality were higher in patients with more than one stoma than patients with single stoma. second stoma has a negative effect on primary fascial closure. fasciitis due to severe peritonitis also prevents fascial closure. acute diaphragmatic hernia after minimally invasive esophagectomy the aim of this study was to evaluate the disease profile and mortality ratio of patients presenting with acute abdomen. four hundred fifty eight patients who underwent surgery with the diagnosis of acute abdomen were analyzed retrospectively. the effects of age, sex, american society of anesthesiology (asa) class, accompany disease, admission time after the onset of the symptoms, follow up interval before the operation on mortality and length of hospital stay were evaluated. male/female ratio was . , and mean age was . . main causes were biliary system disease ( . %), intestinal obstruction ( . %), peptic ulcer perforation ( %) and acute appendicitis ( . %). median asa class was and . % of the patients had at least one preexisting disease. mortality ratio was . %. asa class, age, preexisting diseases other than malignity, period between the onset of symptoms and admission, follow-up time was significantly effective on mortality. background: resveratrol is a strong antioxidant with antiinflammatory effects. we aimed to investigate the effects of resveratrol on oxidative injury, histopathology and bacterial translocation in induced i/r injury in rats. methods: female wistar-albino rats were randomly allocated into four groups; sham-operated group(laparotomy without i/r injury), i/ r group (laparotomy plus min of ischemia followed by min of reperfusion), alcohol group (only . % ethyl alcohole . ml/day intraperitoneally for both days before surgery and min before ischemia), resveratrol group ( mg/kg resveratrol intraperitoneally both days before surgery and min before ischemia. intestinal tissue samples were obtained for investigation of tissue levels of malondialdehyde (mda), nitric oxide (no), superoxide dismutase (sod), myeloperoxidase (mpo) and histopathologic evaluation bacteriological translocation (bt) in mesenteric lymph node (mln), liver and spleen was also studied. results: resveratrol significantly decreased mda, no and mpo levels in i/r injury (p < . ). sod activity of resveratrol-treated group was significantly lower than sham group and significantly higher than i/r and i/r + alcohol groups (p < . ). histopathologically, the median intestinal injury score in i/r and i/r + alcohol groups was significantly higher than in sham and resveratrol-treatment groups (p < . and p < . , respectively). the incidence of bt differred between the groups i/r and i/r + alcohol in mlm, spleen and liver (p < . ). nevertheless, the treatment with resveratrol reduced bt to mln, spleen and liver, compared to other i/ r groups (p < . gastrointestinal stromal tumors (gists) represent rare neoplasms of the gastrointestinal tract. here we describe a case with gist and thrombocytosis presenting as an acute abdomen. our knowledge, the co-existence of gist and thrombocytosis has not been reported so far. case: a -year old female was admitted to the emergency room with epigastric pain and vomiting over duration of days. physical examination showed abdominal distension, rebound tenderness, and a palpable rlq mass. the laboratory findings were, wbc: . /l, plt · - /l and c-reactive protein . mg/l. a computed tomography scan of the abdomen showed conglomerate of small bowel. the abdominal exploration showed that a · · cm mass was located on small intestine. the mass was completely resected and enteroenterostomy was performed. the histological examination demonstrated whirling sheets of spindle cells which were stained positively for cd (c-kit) and cd , mitotic index > / hpf, while smooth muscle actin and vimentin were focally positive, and keratine, desmin, s- protein were negative. this specific immunophenotype characterized gist. during the post operative follow up, platelets were above normal levels · - /l. therefore, bone marrow biopsy was performed. hiperplasia in megakaryocytes were found. the patient was negative for bcr-abl and philadelphia chromosome. discussion: here we describe a case with gist and thrombocytosis presenting as an acute abdomen. ten percent to % of these tumors are biologically aggressive; signs of malignant potential are metastases and invasion. the current treatment for localized disease is surgical resection. co-existence of thrombocytosis and gist has never been reported. laboratory tests showed no abnormality except white blood cell count of /ll.plain abdominal x-ray and ct did not show any abnormal findings including free air (fig. ) . endoscopic examination of the stomach revealed an ingested toothpick protruding from the prepyloric antrum (fig. ) . the toothpick was deeply fixed into the antral wall. the whole toothpick . cm in length was removed using a loop without damage to the gastrointestinal wall, bleeding or any other complication. after endoscopic removal of the toothpick, her epigastralgia resolved. on the second hospital day, the patient was asymptomatic. medical therapy with proton pump inhibitor was stopped and she was discharged on the third hospital day. conclusion: accidental ingestion of foreign bodies is common and in general harmless. a perforation of the gastrointestinal tract by ingested foreign bodies is rare, occurring in less than % of ingested bodies like toothpicks are involved in less than . %. occasionally, the passage of the swallowed item may stop at one of the anatomic bottlenecks of the gastrointestinal tract, which may lead to perforations that may require operative or endoscopic interventions. results: we analyzed the number, causes and rates of emergency operations. the total number of emergency operations was , and , , for the first and second groups, respectively. we observed an % decrease in number of emergency operations for the second group. we also observed that the cause of majority ( % for the first group, % for the second) of the emergency operations was acute abdomen and the rate between the groups did not change. lower extremity amputation and strangulation hernia operations decreased and %, respectively. the number of operations which are caused by ileus and acute cholecystitis increased and %, respectively. conclusions: difference in distribution of emergency operations between two groups was statistically insignificant. however, we observed both an increase and a decrease in small numbers of some subgroups. it is believed that this is related to the change in patient profile and technological improvements in surgery. aim: we hypothesized that one of the most widely used anesthetic agents, propofol, may reduce inflammatory processes, and organ injury induced with cecal and ligation puncture study design: bacterial peritonitis was induced in rats by cecal ligation and puncture. the rats were randomly assigned to three groups. group (n = ) received propofol, group (n = ) received intralipid, group (n = ) was control, which did not receive any injection. all animals were killed days later so we could assess the adhesion score. tissue antioxidant levels were measured in -g tissue samples taken from the abdominal wall. results: the adhesion score was significantly lower in the propofol group than in the control group (p < . ). the catalase levels were higher in the intralipid and control groups than the propofol groups. conclusions: intraperitoneal propofol reduced the formation of postoperative intra-abdominal adhesions without compromising wound healing in this bacterial peritonitis rat model. propofol also decreased the oxidative stress during peritonitis approximately, min after the onset of the operation, a sudden decrease in end-tidal carbon dioxide from to mmhg was noticed. soon after, both systolic arterial pressure and heart rate decreased dramatically. arterial blood gas measurements showed that pco was mmhg at that moment. surgery and insufflation of gas was stopped, ephedrine mg was given intravenously and ventilation with % o was started. trendelenburg position was achieved immediately. a catheter was introduced through the right juguler vein to the right atrium rapidly and - ml gas bubble was withdrawn. soon, hemodynamic measures were recovered. since substantial amount of blood in the peritoneum was noticed, conversion to laparotomy with subcostal incision was performed. at exploration, through and through tear of mm in inferior vena cava was detected. the defect was sutured with / polypropylene. anesthesiologist and surgeon must be aware of this dangerous complication. the emphasis is given to the prevention and prompt recognition of this event to the use of available tools in the management of cardiovascular complications. aim: obstructive jaundice, develops accompanied with high morbidity and mortality rates. the absence of bile in bowels leads to bacterial translocation and ultimately to endotoxemia and septice-mia. _ in our study, observing changes on bowel level during obstructive jaundice and examining its contribution to bacterial translocation have been aimed. material-methods: the study has been carried out at _ istanbul university _ istanbul faculty of medicine experimental medical research center (detam) with approval of _ istanbul university _ istanbul faculty of medicine ethical board for animals. two groups out of male wistar albino rats have been formed. one hour after injecting d-xylose to first group the rats were put to sleep (anesthetized) and specimens of tissue (liver, spleen, mesenteric lymph nodes) and blood were taken for microbiological and biochemical examinations. in the second group an obstructive jaundice has been established by ligation of common bile ducts. the same specimens were obtained after days. findings: in the first group no proliferation on tissue and blood cultures were detected. an obstructive jaundice has been shown in biochemical investigation of blood. d-xylose was found to be . ± . mg/dl. in the second group, proliferation, of mainly e. coli, were detected on cultures and d-xylose was found to be . ± . mg/dl. statistically significant increases were assigned between groups, between tissue and blood cultures (p < . ) and d-xylose values (p < . ). results: detecting statistically significant increases in d-xylose levels in the second group leads to the conclusion that increases in bowel permeability plays an important role in bacterial translocation. conclusions: while wound infections were higher in open appendectomy procedure group, surgical time was higher in laparoscopic procedure group. the achievement of optimal results will be based on increasing surgical laparoscopic experience. objectives: intraabdominal hypertension (iht) in intensive care units is a common problem. investigation of the effects of dexmedetomidine on respiratory system in rats with iht was aimed. patients and methods: adult wistar-albino male rats were anaesthetized by rata ''ksalazin/ketamin'' combination. experimental model of iht( - mmhg) was induced via pressure cuff. rats were left to spontaneous respiration for h prior to randomly division into four groups. the first group underwent no process (control group). in sf group; cc of . % nacl,in the third group; . lg/kg dxmt and in the last, . lg/kg dxmt were intravenously administered. thereafter min passed to observe the effects of dxmt. the rats were killed via cervical dislocation prior to surgery. lung tissues were fixed in % formalin and stained with he. whereas the other cross sections were stained with tunel method,the rest were stained with anti-caspase , , and anti-fas/fasl antibodies for immunohistochemical analysis. results: histological changes in group were the less. there were no atalectatic changes in the same group. pnl infiltration and interalveolar thickness were higher in the . lg/kg dxmt group than others. in indirect immunohistochemical studies, in the . lg/kg dxmt group, immunoreactivity of caspase and were increased. however, the caspase- immunoreactivity was less than caspase- . these results supported that . lg/kg dxmt administration led apoptosis, even though to be delayed, to start and showed that extrinsic pathways was used through apoptotic pathways. it was concluded that low dose of dxmt caused to delay in apoptosis in the lungs. results: a total of microorganisms were responsible for the cris, of which ( . %) were gram-positive bacteria, ( , %) were gram-negative bacteria and ( . %) were candida species. isolated from the microorganisms were: klebsiella pneumoniae ( %), acinetobacter ( . %), enterobacter ( . %), rroteas mirabilis ( . %) pseudomonas aeroginosa ( %), staphylococcus ( . %). patients ( . %) developed crbsis and in patients with positive blood cultures cris were negative. in our study, femoral venous access was associated with a significantly higher incidence of cri and crbsi than jugular and subclavian access; and jugular access was associated with a significantly higher incidence of cri and crbsi than subclavian access conclusion our results suggest that the order for punction, to minimize the cvc-related infection risk, should be subclavian (first order), jugular (second) and femoral vein (third). introduction and objectives: undescended testis is a risk factor for the testicular carcinoma, especially a seminoma. seminoma can be seen at any age, but it is considerably rare in elderly patients. we describe a patient who presented with acute abdomen secondary to an ileum perforation due to the involvement of seminoma. case: a year-old man complaining with right lower abdominal pain and a palpabl mass with a -week history was evaluated. an abdominal computed tomography was showed a large, solid, welldefined intraabdominal mass, measured about · ·x cm in right quadrant of lower abdomen. an exploratory laparotomy was adjudged to perform. whilst the preoperative investigations for surgery were continued, the patient admitted to the emergency service with acute abdomen symptoms, which was started suddenly. he had peritoneal irritation signs. he underwent an urgent laparotomy and a large mass located on terminal ileum mesenter through the retroperiton was detected. dilated ileum segments with omentum wrapped along the antimesenteric border of the distal ileum was found. on separating omentum from ileum, perforation along the antimesenteric border was noted. extended right hemicolectomy and an end ileostomy was performed. histopathologic examination revealed a classical seminoma with extensive tumor necrosis and showed evidence of vascular invasion. conclusions: undescended testes should be considered in men with an intraabdominal groin mass and should be aware of its potential complications. department with diagnosis of acute cholecystitis and on exploration giant gallbladder with giant stone and gallbladder adenocarcinoma. case: a years old female was applied to emergency department with abdominal pain, nausea and vomiting. on physical examination, right upper quadrant tenderness and defence were detected. murphy sing was positive and gallbladder was palpable on subcostal space. in laboratory tests, white blood cell count was , /mm , glucose was mg/dl and liver function tests were minimally elevated. in hepatobiliary ultrasonography, the gallbladder was hidropic ( · cm) and there was a stone ( cm in diameter) and a mass ( · cm) in the gallbladder.cholecystectomy operation was performed. acute cholecystitis + cholelithiasis + adenocarcinoma were reported in the histopathological evaluation. conclusion: the carcinomas of the gallbladder were associated with gall stones in - % of the patients. we concluded that the presence of the symptoms in our patient was delayed due to the magnitude of the gallstone and the excessive size of the gallbladder. perforation of the gallbladder by trans-gastric migration of a sewing needle _ ingestion of foreign bodies is a common problem, especially in the elderly, pediatric, and psychiatric population, but fortunately, most of them pass spontaneously and uneventfully within week.the perforation and migration of ingested foreign objects into the abdominal cavity is very rare and usually leads to a laparotomy. perforation of the stomach by sewing needle with migration to the gallbladder is extremely rare, and none cases have been reported in the literature. a -year-old woman was admitted because of abdominal pain and a history of a swallowed sewing needle month ago. she had been followed-up at her local hospital and referred to our hospital because of the failure of progression of the foreign body. physical examination showed right upper quadrant tenderness, guarding, and a positive murphy's sign. blood analysis showed increased white blood count. she was submitted to abdominal plain x-rays, which revealed a radio-opaque objects in the liver area with the form of the sewing needles. the patient was clinically stable, and a semi-urgent laparotomy was planned. at laparotomy the needle was in the gallbladder and that the end of the needle could be palpated and the site of gastric perforation. removal of the intra gallbladder needle did not cause any problem. we was performed cholecystectomy and primary gastroraphy. the postoperative period was uneventful and the patient was discharged on seventh day of the operation. if there is a history of sewing needle ingestion and failure of progression and also signs of an acute abdomen, the surgeon must carefully evaluate gallbladder. introduction: sigmoid volvulus is an unusual intestinal obstruction form ( ) . it is most common in the middle aged, elderly, institutionalized or neuropsychiatric patients ( ). patients and methods: twenty-one sigmoid volvulus patients were reviewed retrospectively between and .the recorded data were age,gender,admission symptoms,physical examination,radiological, and operative findings, surgical procedure, postoperative complications, mortality, and hospital stay.there were male and female patients. the mean ages of the patients was . years ( - ).the most common symptoms in acute abdomen patients were pain, and tenderness. abdominal distension were the most recorded sign in patient without peritonitis. the mean admission time was . days ( - ). five patients had a history of sigmoid volvulus ( %). leukocytosis and high fever were found in ( %) patients. radiological evaluation of the patients revealed sign of intestinal obstruction (n = , %),frimann-dahl sign (n = , %) and bilateral free air under diaphragm due to perforation of the twisted sigmoid colon (n = , . %). no patient underwent contrast enema examination of the colon. the mean hospital stay was . days ( - days) . two patients without signs of peritonitis were treated by sigmoidoscopy and operated on elective course.patients with signs of acute abdomen were operated urgently. the patients had several associated diseases such as atherosclerotic heart disease, diabetes mellitus, hypertansion, chronic obstructive pulmonary disease, cerebrovascular disease. eight patients ( %) died due to sepsis. morbidity rate was %. wound infection, evisseration pneumonia, and acute renal failure were found in ( %) patients. the principal strategy in treatment of sigmoid volvulus is early nonoperative detorsion followed by elective surgery consist of colectomy and anastomosis on well-hydrated patient. urgent laparotomy is indicated in case of peritonitis. sigmoidopexy is an alternative option but it is usually ineffective and has high recurrence rate. results: ten men and four (six) female were enrolled in the study. mean age was years (range - ). e.coli and acinetobacter were the common organisms cultured. all patients were treated with a common approach of resuscitation, broad spectrum antibiotics, and wide surgical excision. objectıves: acute appendicitis is one of the most common nonobstetric surgical pathology. clinical symptoms and findings are masked due to anatomical and physiological changes of peregnancy, so diagnose and treatment of acute appendicitis in pregnancy generally late. the curent study reported the cases which were diagnosed acute appendicitis in pregnancy and promptly operated in our general surgery clinic. material-methods: we evaluated sixteen cases' data between october and october who admitted to emergencey department with abdominal pain, vomiting, nausea and anorexia complaints and diagnosed as acute appendicitis in pregnancy and operated. results: the average of the cases were . (range - ) and thirteen of them were second, two of them were third and one of them was in the first trimester. the time interval between the onset of the complaints and operation was . (range - ) days. upon physical examination, there were rebound tenderness present in cases, muscular rigitide in three cases, right lower quadrant pain in nine cases and widely irration of all abdominal guadrant in four cases. there were not any maternal mortality and morbity after operation, however in only one case fetal mortality was observed inevitable abortion due to vaginal bleeding. conclusion: in our cases acute appendicitis was diagnosed frequently in the second of the pregnancy with abdominal pain symptoms and rebound tenderness findings. recognition is important because early diagnose and prompt surgical intervention can reduce maternal and fetal mortality and morbity in acute appendicitis. introduction and objectives: conservative management of penetrating trauma has been mainly advocated in centres with a high incidence and large experience with those injuries. our aim was to assess the preventable death rate in our patient population, and the failure rate of conservative management. introduction and objectives: the data about role of amelogenin that is an extracellular matrix protein, during the healing process of the gastrointestinal anastomosis is lacking. in this study, the effects of amelogenin treatment on normal and ischemic colon anastomosis were evaluated. methods: adult male wistar albino rats weighing - g, were divided into four weight-matched groups: normal colon anastomosis group (n = ); amelogenin treated normal colon anastomosis group (n = ); ischemic colon anastomosis group (n = ); amelogenin treated ischemic colon anstomosis group (n = ). sufficient equal volume of amelogenin to entirely cover the anastomosis area had been applied. all animals were killed on postoperative day . bursting pressure levels were measured. peri anastomotic colon tissue hydroxyproline, catalase (cat), cu-zn superoxide dismutase (sod), glutathione (gsh), malondialdehyde (mda) and nitric oxide (no) levels were assessed to evaluate oxidative stress. results: bursting pressure levels of the ischemic colon anastomosis group is significantly lower than the normal colon anastomosis, the amelogenin treated normal colon anastomosis and the amelogenin treated ischemic colon anastomosis groups respectively (p = . , p = . , p = . ). hydroxyproline level of the amelogenin treated normal colon anastomosis group is significantly lower than the normal colon anastomosis and the ischemic colon anastomosis groups respectively (p = . , p = . ). gsh level of the ischemic colon anastomosis significantly lower than the amelogenin treated normal colon anastomosis group and the amelogenin treated ischemic colon anstomosis group respectively (p = . , p = . ). conclusions: amelogenin treatment could support the physical strength of ischemic colon anastomosis and effect oxidant/antioxidant response positively. introduction: meckel's diverticulum is the most common congenital anomaly of the gastrointestinal tract, occuring in - % of the population. in the majority of patients, meckel's diverticulum is asymptomatic. we report our experience with the management of complicated meckel's diverticulum in adults. methods: between april and january , the data of seven patients ( males and females) aged - years who underwent surgery due to complications of mechel's diverticulum was retrospectively evaluated. results: of the seven patients, three presented with acute surgical abdomen, two had abdominal pain mimicking acute appendicitis, one had incarcerated incissional hernia, and one had intussusception. intraoperative diagnoses were as follows; littre's hernia in one, ileoileal intussusception due to meckel's diveticulum in one, diverticulitis in two, perforation of the diverticulum in three patients. while diverticulectomies were performed in five patients, two had small bowel resections. in addition to, appendectomy was performed in four patient. all the patient had an uneventful recovery except one, who experienced a postoperative wound infection. the hospital stay was - days. ectopic gastric mucosa was found in two cases. in one case, neuroendocrine tumor was detected in the appendix. conclusions: meckel's diverticulum is an uncommon cause of acute abdominal disease in adults. meckel's diverticulum presents distinctive challenges to a clinician, as it is prone to varied complications such as intestinal obstruction, diverticulitis, perforation. the diagnosis of meckel's diverticulum is difficult to establish preoperatively, and index of suspicion is necessary in patients with an acute abdominal illness. introduction: pneumatosis cystoides intestinalis is a pathologhy which is rarely incidentally seen and is characterised with submucosal or subserosal air cysts. there is no surgical indication in asymptomatic cases. surgical treatment is needed in the development of complication or the possibility of risk. a patient who is hospitalized with diagnosis of pyloric stenosis and is detected pneumatosis cystoides intestinalis incidentally at the operation is presented. case: year old male was admitted our emergency department with vomiting weight loss complaints. pyloric stenosis was diagnosed by radiologic and endoscopic examination. he was hospitalized and acute abdominal signs developed. free air was detected in radiologic examination. surgery was performed. pyloric stenosis and pneumotosis cystoides intestinalis in jejenum were diagnosed. biopsy specimen was obtained from the cysts in jejunal serosa. subtotal gastrectomy, gastrojejunostomy and bilateral truncal vagotomy were performed for the pyloric stenosis. result and discussion: there is no surgical indication in asymptomatic cases. pneumotosis cystoides intestinalis commonly accompony pyloric stenosis and perforation of the cysts may bring out acute abdominal symptoms. knowing this pathology, we may avoid unnecessary emercent laparotomies. aim: in urgent surgical procedures for peptic ulcer perforation, there is considerable postoperative morbidity and mortality. this study aimed to describe and analyze the risk factors that determine beforehand morbidity and mortality in cases with perforated peptic ulcer. materıals-methods: age, sex, co-morbid diseases, symptom duration, abdominal air, amount of intra-abdominal liquid, location and diameter of perforation, operation, and the mannheim peritonitis index (mpi) score were prospectively analyzed in cases. significant risk factors that cause morbidity and mortality were determined through a statistical study. results: the study sample consisted of a total of cases ( males and females) with a mean age of (range - ). duodenum and stomach perforations were detected in and . % of the cases. in cases ( . %), a total of complications were detected. the mortality rate was . %. statistical analyses revealed significant relationships between morbidity and > age (p = . ), co-morbid disease (p = . ), perforation location (p = . ), type of operation (p = . ), and mpi score (p = . ). the factors significant for mortality included > age (p = . ), co-morbid disease (p = . ), > h of symptom duration (p = . ), > cc intra-abdominal liquid (p = . ), a perforation diameter of > . cm (p = . ), omentopexy (p = . ), and a mpi score of > (p = . ). conclusion: factors such as age, co-morbid disease, prolonged perforation duration, amount of intra-abdominal liquid, perforation diameter, type of surgical operation, and mpi score were significant for mortality. the present study found that primary suture is a safe procedure for cases with peptic ulcer perforation. introduction: the presence of foreign objects in the rectum is a rare encountered situation. these objects are usually inserted transanally or swallowed as foreign objects. this study was conducted to investigate the results of patients admitted to our clinic with a rectal foreign body. methods: data of patients who admitted to our clinic between and were evaluated retrospectively results: mean age of the population was . . the foreign object was taken out in the proctological position in patients. in patients these methods failed and laparatomy was performed and the objects were taken out transanally without colotomy. in three patients symptoms and signs of peritonitis were significant at admission and all of them were lost because of rectum perforation followed by septic shock. distribution of foreign objects was: six deodorant lids, five glass bottles, two aubergine, a glass, a salt cellar, a piece of plastic pipe, a vibrator, a plastic cover, a chocolate cover, a chicken bone, a fish bone, needles, a spiral, coins and key, a piece of thermometer, teeth prosthesis and soap. mortality was seen in three patients. the presence of foreign objects in the rectum is a rare encountered situation which should always be kept in mind for differential diagnosis. most of these objects can be taken out transanally. if this fails, all efforts must be shown to take it out without opening the colonic lumen. because of potential complications, the surgeon must be careful during intervention. median age of the alive was . median leukocyte number at the moment of appliance was . , median debridement . and median inpatient stay were determined as days. median age of the dead . median leukocyte number at the moment of appliance was . , median debridement . and median inpatient stay were determined as days. the most common reason of the aetiology was determined as perinal abscess. diversionary ostomy was applied to six patients. chronic kidney failure, and type diabetes was exist in four patients of dead-group. in addition, in one patient type diabetes and hypertension was observed. conclusion: chronic kidney failure related to hemodialysis and high level of lekucyte number at the moment of appliance are the important prognastic factors of deaths related to fg. computed tomography (ct) has become the mainstream of evaluating all hemodynamically stable patients with acute problems when the attending doctor, is urging for diagnosis. basing a diagnosis solely on radiological data sometimes ignoring medical history and physical examination may lead to unexpected errors. wrong interpretation of radiological images or images with equivocal findings which may delude the radiologist and technical errors (artifacts) are all potential sources of mistakes. the aim of this study is to draw attention to the danger of the modern imaging diagnostic modalities to misguide the treatment of patients who need emergency care. we present some cases we faced in our clinic where radiological images showed pathologic entities which in fact did not exist (false positive errors) but forced us to inappropriate treatment. two patients underwent negative laparatomies with imaging diagnosis of a ruptured gallbladder in one case and free air under the diaphragm in the other. a patient with a severe head injury and a ct scanning showing pneumocephalous was transferred to a tertiary centre to be proved on repeated images that initial diagnosis was mistaken due to a wrong calibration of the gantry. imaging findings do not necessarily represent reality. almost always surgeons rely on ct scans for treatment decisions. it is a hard task for a surgeon to question or ignore the pictures to treat a patient based on medical history and physical examination. experience of radiologist is essential and close cooperation with the attending surgeon is needed to avoid radiological misfindings in emergency cases. author to editor: to be presented as a poster. a full text is available on demand. intentional own insertion of rectal foreign bodies in a married, claimed to be straight male, using antidepressive medicaments because of sexual orientation disorder, resulted in resurgery with the same reason of mechanical intestinal obstruction after years in the same surgery clinic by the same surgery team as an emergency intervention. failure of the nonoperative measures under local, spinal and general anesthesia led to the surgical treatment of the -year-old patient in and , who is now years old during the second event. large bottles were removed through laparotomies and colotomies followed by primary repair to reverse the ongoing ileus, which resolved on the th postoperative days in both events. a surgeon who is called to see a patient with retained foreign body should answer whether the patient had rectal perforation and whether the foreign body could be removed transanally without regional or general anesthesia with or without surgical intervention. in case of children; habitually self inserting objects in her vagina or sexually aggressive behaviour with others, e.g. for a boy ''humping'' toys in sexual positions can be a behavioural indicator of child sexual abuse or assault. hence message is: if in a patient perforation of sigmoid colon or rectum history after anal insertion of foreign body in an otherwise healthy adult becomes habitual,the patient should be send to psychiatric counselling. discussion of the nonoperative measures to remove rectally inserted objects is also an utmost important opportunity constituting the largest part of the report of the present case. necrotizing fasciitis is a highly morbid and mortal condition. as a result of aggressive debridement, wide tissue defects occur. wound cleaning from infective material, granulation process and grafting of wound requires a long time. recently, a vacuum assisted therapy system has begun to use for this kind of wounds. this study discuss the treatment result of vacuum assisted therapy (vac Ò therapy tm ) in two patients with giant abdominal wall defect in view of current literature. case : a years old man had an operation because of an accident on railway. at the time of admission there was a wide defect with necrotizing fasciitis on the right lombar region and anterior abdominal wall. there was a full thickness defect about · cm after an aggressive debridement. it was successfully treated with vac and the patient has been discharged after tissue grafting on the postoperative day . case : a years old man had an operation because of an accident. he was admitted at postoperative day . he underwent an aggressive debridement because of necrotizing fasciitis. the skin, rectus abdominus, transversus abdominus, internal and external oblique muscles and some part of quadriceps femoris on the left side was excised. the sacroiliac joint was also broken and pubis was separated. vac abdomen has been applied on two different sites and the wound has become available for grafting after days of therapy. as a conclusion, vacuum assisted therapy provides safe and accelerated wound healing, improves proper tissue granulation in patients with giant abdominal defect. introduction: bogota bag (bb) is a device used for the temporary closure of the abdominal wall (aw). despite its potential benefits, their use is not widespread and remains controversial in the present. aım: to describe our experience in its management for the temporary closure of the aw in emergency situations. methods: for a period of years, bb has been used in patients (pts), with an average age of . years. six had a secondary peritonitis, one tertiary peritonitis, two haemoperitoneum and one a compartment syndrome established. the technique consisted of the placement of a bag of sterile serum, stitched to the skin with nonabsorbable material. results: the average of bags placed by year was . . no morbidity was associated with the placement and/or replacement of bb. the average time of hospitalization was . days and the average time of income in the icu was . days. in pts, the bag was replacement one or more times. the average number of surgical interventions by patient during the income was . . the average time of permanence of the patient with the bag was . days. sixty percent of patients are alive today. objectıves: the aim of the current study is to assess the role of ultrasonography in the management of acute appendicitis. methods: ultrasonography was performed to patients with acute appendicitis suspicion between and . appendectomy was performed to patients with acute appendicitis diagnosis according to clinical examination after ultrasonography. patients who had a diagnosis different from acute appendicitis with clinical examination were observed. the histopathological findings of patients with appendectomy were compared with their usg findings. results: of patients had acute appendicitis diagnosis by ultrasonography. hystopathological examination showed acute appendicitis in of these patients. patients did not have acute appendicitis. usg showed that patients did not have acute appendicitis. ten of these patients showed gynecological pathology, and six of them showed urinary pathology, and they were all treated appropriately. in eight patients the appendicitis findings became evident in clinical observation; resulting in appendectomy, and histopathological examination showed acute appendicitis. forty patients showed improvement at follow up. no spesific treatment was needed. misdiagnosis rate was determined as . %. the sensitivity, specificity, positive predictive value, negative predictive value and accuracy percentage of ultrasonography in the diagnosis of acute appendicitis was . , . , . , . and . %, respectively. conclusion: ultrasonography has a high degree of accuracy in the diagnosis of acute appendicitis. however, we also conclude that ultrasonography results should always be interpreted in combination with clinical findings. background: hydatid cyst disease is frequent in some regions of the world, including our country turkey, and is most commonly located in the liver and lungs. the hydatid cysts may rupture spontaneously or as a result of trauma. herein, we describe a rare case of retrovesical hydatid cyst which was resulted from rupture of spontaneous rupture of liver hydatic cyst intraperitoneally. case: fifty-four years old male was admitted to emergency department with complaints of frequent urination and abdominal pain lasting for days. there was general abdominal tenderness on physical examination. there was no history of trauma or operation. in his abdominal ultrasonography and tomography there were primary cyst ( · cm), ruptured cyst ( · cm) and retrovesically located cyst ( · cm). indirect hemagglutination test was positive for echinococcus granulosus ( / , ) . laparotomy was performed and all the cysts were excised by partial cystectomy. there was no postoperative complication. the patient was externalized on postoperative th day with albendazol treatment. conclusion: retrovesical localization of hydatic cyst is a very rare. these cysts mostly occur as a result of surgical inoculation caused by inadequate surgery or free intraperitoneal rupture of primary hydatic cyst. in endemic regions, possibility of hydatic cyst should be kept in mind in differential diagnosis of intrapelvic cysts and masses. background: wegener's granulomatosis (wg) is a systemic necrotizing vasculitis of unknown etiology characterized mainly by involvement of the upper airways, lungs, kidneys and may rarely involve the gastrointestinal tract. intestinal involvement may be asymptomatic. we herein report a wg with massive lower gastrointestinal hemorrhage due to colonic involvement. case: the patient complained of dyspnea which started months ago, fatigue, generalized arthralgia and myalgia together with loss of sensation on right upper extremity was applied to emergency and hospitalized by internal medicine department. physical examination revealed a very ill-looking patient, there were positive lung findings for wg and c-anca was positive. we consulted the patient because of hematochesia with abrupt drop of hemoglobin and platelet count. on colonoscopy whole mucosa was full with fresh blood from sigmoid to anal canal. on angiography multiple foci of bleeding were demonstrated on descending and sigmoid colon. embolectomy was not performed because of multiple foci. hemoglobin decrease continued and his clinical condition deteriorated; an explorative laparotomy and total left colectomy was performed. his melena persisted for days but hemoglobin was maintained at after units transfusion after operation. conclusion: we herein report a case with clinical wg who developed a gastrointestinal hemorrhage and treated by surgery. the uremic state and cytotoxic agents given to patients may detoriated the gastrointestinal bleeding. immunosuppressive therapy might exacerbate gastrointestinal complications. the clinicians should be aware of this situation, therefore treatment of these must be performed in centers where angiography and endoscopy are available. background: the aim of this study is to determine the strength and proceeded efficiency of mda, sod, and catalase levels that are indicators of oxidative stress in generalized peritonitis. material-methods: this study was conducted as prospective and randomized with patients who applied at dicle university, department of general surgery between march-september . patients were composed as group (n = ); generalized peritonitis, group (n = ); laparotomy under elective conditions and not present peritonitis; group (n = ) as control group. in order to measure limits of mda, sod, crp and catalase, blood samples were drawn from the patients in group and group on before operation day (bod), st and rd days. the mda values of group on before operation day, st and rd days were compared to group and , the difference were found statistically meaningful. statistical differences noticed between group and mda values on bod, st and rd days. statistical differences were noticed between catalase values measured bod and rd days when group and values compared to group . the sod values of group and group on day were compared to group , meaningful statistical difference was found. statistically meaningful difference was found between the sod values group and on st day. conclusion: values of sod, mda and catalase were noticed usable parameters for the following and detection of severity of generalized peritonitis sinan cumhur karakoç, gü rkan yetkin, _ ismail ethem akgü n, mehmet uludag, bü lent Ç itgez, hamdi Ö zş ahin, cabbar kartal general surgery departmet, Ş iş li etfal training hospital, istanbul, turkey objectıve: we aimed to evaluate the effects of early cholecystectomy on morbidity and patient comfort in patients with acute biliary pancreatitis. methods: patients who underwent cholecystectomy for acute biliary pancreatitis in our clinic between and were evaluated retrospectively. the patients were divided into three groups as early, late and elective cholecystectomy cases. fındıngs: patients who had undergone cholecystectomy operation in the first days until the administration to hospital were classified as the first group (early cholecystectomy). patients who had undergone cholecystectomy between the nd and th weeks until the administration to hospital were classified as the second group (late cholecystectomy). patients who had undergone cholecystectomy after weeks were classified as the third group (elective cholecystectomy). in group , no patient had pancreatitis attacks; of patients in group had recurrent pancreatitis attack in the preoperative period and treated in our clinic. in order of these data, age, height, weight, gender, sgot, sgpt, amylase, bilirubin and the time for waiting for the operation were compared and evaluated statistically. the time for waiting for the operation was found to be p > . , and it was shown to be significant. results: there is a tendency to perform cholecystectomy in patients with acute biliary pancreatitis, after the acute attack is resolved. we believe that the early cholecystectomy prevents the patient from the additional morbidity in patients with acute biliary pancreatitis, by showing this with a statistically significant result in our study. traumatic right sided diaphragmatic hernia is clinically rare and may present with complications in a later period. on the right side presence of liver is thought to be a protective factor for both development of diaphragmatic injury itself and for its complications. we present a case of right sided diaphragmatic hernia due to blunt trauma, which was asymptomatic for years and has been presented with intestinal obstruction. the patient, years of male, has presented with intestinal obstruction and abdominal pain which has been relieved after nasogastric decompression. despite conservative treatment patient has not shown further improvement and has been operated on a semi-elective basis. significant part of small and large bowel, distal portion of stomach, and almost whole of liver had been herniated and reduced by right thoracoabdominal approach. cm wide defect in diaphragm has been repaired with prolene mesh, laparotomy has not been closed and bogota bag has been applied. in the early postoperative period transaminase levels have increased , u, and ct-angiography has revealed patchy areas of low per-fusion in both lobes of liver. after therapeutic anticoagulation liver function has recovered completely, abdomen is closed and oral feeding commenced. at the th postoperative day respiratory insufficiency has occured after witnessed aspiration of gastric contents, followed by multiple organ failure. this case represents a quite late presentation of right sided traumatic diaphragmatic hernia, for which treatment was complicated. this case clearly shows the importance of detailed evaluation and timely treatment of all traumatic diaphragmatic hernias. cem ibis, dogan albayrak, fedayi calta, eren taskin, mehmet ali yagci, ahmet hatipoglu, irfan coskun department of general surgery, medical faculty, trakya university edirne, turkey introduction: amyand hernia is first described by claduis amyand in london in an year old male. it is a rare condition and described as appendix vermiformis in the hernia sac. we present a case of an incarcerated inguinal hernia with appendix vermiformis inside. case: sixty nine years old male with bulging and pain in the right inguinal region is evaluated. right inguinal hernia was detected. after opening the hernia sac, the appendix and ceacum were observed. lichtenstein procedure was performed. the patient was discharged in the second postoperative day. discussion: although the incidence of appendix vermiformis in the hernia sac is . - %, the incidence of acute appendicitis in the hernia sac is . - . % in various reports. the treatment of amyand hernia is related to the appendix found inside. the application of appendectomy to normal appendix in routine hernia repair procedure is controversial due to infection risk. we do not routinely perform prophylactic appendectomy in such patients. we thought that a patient tailored approach is more acceptable. introduction and objectives: hydatid disease is typically asymptomatic. it can become symptomatic due to expansion, rupture or pyogenic infection. rupture of the cyst is the most common complication, followed by secondary infection, jaundice, and anaphylaxis. methods: in this study, we analyzed demographic and clinical characteristics of the cyst hydatic patients who admitted the emergency service due to complications of the cyst hydatic. the medical records of patients, with a final diagnosis of complicated cyst hydatic were reviewed for demographic information, admission symptoms, laboratory findings, evaluation techniques, and outcome. results: ten patients ( men, women) with final diagnosis of complicated ce (cystic echinococcosis) included the study. all of the patients had abdominal pain. while the pain was diffuse in the entire abdomen in seven patients, it was located in the right upper quadrant in three patients. patient's complaints were nausea, vomiting, jaundice, ileus and urticaria. the clinical signs and symptoms of hc rupture are not always severe, but hydatid fluid can irritate, which can cause peritonitis as occurred in our series of patients, all of whom had acute abdominal signs. in this study, % of the patients with ruptured ce had abdominal pain. thus, the clinical presentation of ce rupture is not always silent. the severe clinical presentation and infrequency of ce perforation has been held partially responsible for the misdiagnosis by the surgeon. conclusion: in conclusion; complicated hc may be admitted to emergency service with different clinical pictures especially in endemic regions and must be considered in differential diagnosis. background: to evalute the changes in the pattern of iatrogenıc bılıary injury and consequentıal effects on treatment strategy and outcome. methods: seventy-three patıents treated for iatrogenıc bılıary injury (ibi) between july and november at a tertıary care center in izmir, turkey were retrospectıvely analysed. results: underlyıng diseases were; missed tumor (n: , . %), biliary surgery (n: , %) and hydatıc dısease (n: , , %). in recent years wıth a gradual increase in the avaılabılıty of endoscopıc and radiologial expertise the majorıty of patıents underwent extensıve preoperatıve diagnostic and therapeutıc procodures includıng endoscopıc retrograd panceratography for cases( . %) and percutaneus transhepatıc cholangıography for cases( %). defınıtıve surgery was performed in all patıents except ( . %) of them. roux-en-y hepatıco-jejunostomy was the primary reconstructıon technıque and performed for cases ( %). there was only one ( . %) hospıtal mortalıty. restenosıs developed in ( . %) cases and was reoperated. percutaneus baloon dilatation was faıled in three patıents as a fırst treatment optıon. none of patıents died of dısease related causes durıng the follow-up perıod. conclusion: increased experınece in laparoscopıc biliary surgery might be caused to attempt more challengıng cases and increased bılary tract injurıes. tolga kafadar, ercan gedik, sadullah girgin, bilsel baç, _ ibrahim halil taçyıldız department of general surgery, dicle university, diyarbakir, turkey the aim our study was to determine the independent risk factors affecting patients with upper gastrointestinal hemorrhage who underwent surgery. materials and methods: the medical records of patients with upper gastrointestinal hemorrhage who underwent operation were reviewed for variables including age, gender, shock, association with co-morbidity, pulse rate, hemoglobin levels, white blood cell count, serum urea, creatinine, sodium and potassium levels, time of opera-tion, number unit of blood transfusion, rockall risk score and length of hospital stay. in order to determine the independent risk factors mortality and morbidity, we carried out entered logistic regression analysis. results: morbidity and mortality rate were . % ( patients) and . % ( patients), respectively. the independent risk factors affecting morbidity were serum albumin level [odds ratio (or) = . , % confidence interval (ci) = . - . , p = . ] and rockall score ‡ (or = . , ci = . - . , p = . ), and the independent risk factors affecting mortality were advanced age (or = . , ci = . - . , p = . ), and high rockall score (or = . , ci = . - . , p = . ). conclusion: to decrease the postoperative morbidity and mortality rates in patients with ugih requiring surgery, patients preoperative risk factors should be demonstrated. we believe that establishment of interventional indication on time and evaluation of intraoperative surgical region and technique in combination with the patient-and disease-related factors in patients requiring surgery would help reduce morbidity and mortality rates. blunt thoracic trauma leads to various clinical conditions, such as hemothorax, pneumothorax, pulmonary contusion, and respiratory tract hemorrhage. especially, respiratory tract hemorrhage resulting from pulmonary contusion is so critical to require a clinical challenge. of our experienced survivors, trauma victims (male / , - years old) with blunt thoracic trauma associated with motorcycle accident were transferred to our emergency departments. they similarly suffered respiratory failure (average respiratory rate of ) and hypotension (average shock index of . ) on arrival. immediate after the rapid-developing respiratory failure in relation to lung contusion and endobronchial bleeding, bronchial blockade device and extracorporeal membrane oxygenation (ecmo) were urgently introduced at an average of and min, respectively, and achieved rapid resolution of their respiratory crisis. all of them withdraw from ecmo within days. pulmonary contusion sometimes follows fatal progress, and we consider that quick bronchus blockade and ecmo introduction is the key of survival. emergency departments (ed) in greece are incorporated to the departments of the hospital and are divided in two major areas: one for internal medicine and one for general surgery. every patient has free access to the (ed). the workload and the conditions treated in ed in greece are geographically and social -economically depended. the national health system is represented by one hospital for each prefecture. the general hospital of trikala, is categorized as an urban hospital, with beds, and is covering a population of approximately , people, living in the town and in villages situated in the surrounding mountain area. the department of general surgery is stuffed by general surgeon specialists and seven residences. during , , patients were examined in the surgical ed. in this study we analyze the characteristics of the patients, the number and causes of admissions in the various departments of our hospital and also the transferals to a tertiary center. aim: pneumotosis cystoides intestinalis is a rare entity, and may be associated with pyloric stenosis. materıals-methods: data of a patient operated for pyloric stenosis and pneumotosis cystoides intestinalis in our institution are presented. results: patient was a year-old addicted male, and his body mass index was . kg/m . he had been suffering from nausea/vomiting, bloating and constipation for a few months. a gastroscopic examination revealed atonic gastric dilatation, duodenal ulcer and related pyloric stenosis, and positive serology for helicobacter pylori. an eradication treatment in conjunction with long term proton pomp inhibitors were given, however the patient readmitted to our department with worsening symptoms including vomiting, pain and weight loss after months. repeated gastroscopies and gastric meal x-ray examination revealed pyloric stenosis and the patient decided to have an operation instead of repeated medical treatment. during laparotomy, subserosal foamy air bubbles were observed on the serosal wall of ileum. a partial resection of ileum was necessitated for the suspicion of perforation. vagotomy with finney pyloroplasty was performed in order to cure the pyloric stenosis. the postoperative period was uneventful and the patient was discharged from the hospital on day . the patient has not have a recurrence, gained weight and have no problem since years postoperatively. conclusion: pneumocytosis cystoides intestinalis may be observed in the presence of a pyloric stenosis and necessitates resection if any doubt for perforation is present. granulosus. in this study, a rare appearance of the disease is presented as an abscess located in the retroperitoneal space. results: the patient was years-old male with several comorbidities admitted to our emergency department with fever and left lumbar pain. he had had operated for hepatic hydatid disease years before the admission. physical examination revealed local tenderness and slight hyperemia on his left lumbar region. his laboratory findings showed leucocytosis, and a computed tomography demonstrated a huge retroperitoneal abscess located between spleen and pelvic entrance and denied any pathological finding regarding to the left kidney or adrenal gland. since the general condition of the patient did not allow an operation under general anesthesia, the abscess was drained through a cm long incision located on the hyperemic area under local anesthesia. after complete removal of the abscess and daughter cysts, a drain was left behind, and removed on day . the patient was discharged out of hospital on day , after an uneventful recovery period. discussion: to best to our knowledge, this is the first hydatid disease case presented as a retroperitoneal abscess in the literature. hydatid disease may be kept in mind as a differential diagnosis in the presence of a cystic retroperitoneal mass in endemic regions. ali uzunkö y , zekeriya sayın harran university school of medicine department of general surgery, sanliurfa, turkey osm ortadogu hospital, sanliurfa, turkey introduction and objectives: giant true splenic artery aneurism is rare lesions. these aneurisms have risk of rupture and bleeding. we have performed a giant true splenic artery aneurism. case: the case is a year old female patient. she applied to hospital with complaints of abdominal pain. at the physical examination, there were a moderate splenomegaly and a pulsatile mass in the left upper abdomen. it was shown a giant splenic aneurism at the abdominal computed tomography and colour doppler ultrasonography. colour-doppler abdominal ultrasonography showed about mm splenic artery aneurism. computed abdominal tomography showed a hypo dense mass situated anterior and superior to the pancreas tall and corpus extending up to the splenic helium. the diagnosis was confirmed by ct angiography. the patient was performed with general anaesthesia and left subcostal incision. at the exploration, splenic arterial dilatation and aneurismal sac was shown and aneurysmectomy with splenectomy was performed. there was no complication intraoperatively and postoperatively. the patient was discharged at the postoperative fifth day. there was no complaint at the control examination at the fifteenth day after discharging. conclusions: although giant splenic artery aneurism is rare, but they have risk of rupture and bleeding. there are two options for treatment of these lesions. one of them is aneurysmectomy. it is frequently performed with splenectomy. other option is embolisation. in our opinion, surgery for giant splenic artery aneurism is performed successfully without important complication. author to editor: saved by lookus introduction: an association between the administration of paracetamol and relative hypotension in critically ill patients has been reported by the staff working in the surgical and trauma intensive care unit of istanbul faculty of medicine. methods: a prospective, observational study was undertaken to investigate the effect of paracetamol on systemic blood pressure in two groups of critically ill patients. a dose of mg of paracetamol was administered intravenously to both groups in min time. blood pressure, heart rate were recorded at baseline, at the end of infusion and then at , , min after administration. the differences occured over the observation period was measured by friedman analyse. results: twenty-eight patients with sepsis, were enrolled to group- (anti-pyretic effect) and postoperative patients were enrolled to group- (analgesic effect). analysis of data from all patients showed that systolic arterial pressure (sap) and mean arterial pressure (map) were reduced significantly over the observation period in both groups (sap:p < . for both, map:group- p < . , group- p < . ). sap and map in group- and group- decreased by an average of approximately and % respectively. however, no significant decrease in dap was noted in group- . conclusions: utilization of the intravenous paracetamol for febrile and/or postoperative patients caused a significant decrease in systemic blood pressure after administration. this drug-induced hypotension was clinically relevant to control the required blood pressure. thus, clinicians should be aware of this potential effect, especially in critically ill patients. yazile sayın faculty of health, surgical nursing division, cumhuriyet university, sivas, turkey background: pain is considered one of the most important symptoms which guide diagnosis, treatment and nursing care in the emergency departments. aım: to discuss pain evaluation by nurses in emergency departments and to attract attention towards nurses' responsibility for pain evaluation. methods: qualitative and quantitative data from studies on pain evaluation by nurses were evaluated. results: all studies reviewed showed that about three fourths of the nurses in the emergency departments did not make pain evaluation based on the standards (using pain rating scales, reporting the conditions likely to affect pain evaluation etc.). the nurses included in studies assigned significantly lower scores for pain than the researchers(p < . ;p < . ). all studies revealed the following reasons why triage nurses did not play an effective role in pain evaluation: insufficient knowledge, the idea that doctors are responsible for pain evaluation, doctors not appreciating the value of pain data provided by nurses, insufficient cooperation among members of the health staff, work overload, time constraints, errors in reporting data on pain evaluation and conflicting attitudes and beliefs concerning pain evaluation. it has been reported that only - % of the patients presenting with pain to emergency departments received effective pain management. the most important reason for this low rate has been shown to be deficiencies in pain evaluation due to insufficient multidisciplinary cooperation. conclusion: it can be concluded that nurses in emergency departments are not efficient enough to use interventions which help to evaluate pain for effective pain management. introduction: diverticulosis of the colon is a common condition. complications of diverticulitis often require surgery. perforated diverticulitis may rarely present with spreading superficial sepsis. case: male, years, history of chronic depression. admitted in the emergency department after a -day history of abdominal pain in the left lower quadrant (llq), associated with asthenia, anorexia and weight loss, without diarrhea, constipation or fever. the patient examination showed edema and thickening of the abdominal wall with swelling and redness in the llq. blood chemistry revealed leukocytosis with neutrophilia and elevated c-reactive protein. a diabetic ketoacidosis was diagnosed. the abdominal ct confirmed abdominal necrotizing fasciitis with an abscess, without other intra-abdominal changes. the patient was then submitted to emergency surgery with debridement of the necrotising fasciitis and drainage of the abscess. he was admitted to the icu. further debridement was necessary h later. at d , fecal contamination of the wound was detected, leading to a subsequent laparotomy with identification of a sigmoid inflammatory mass attached to the site of the fistula's external orifice. a hartmannprocedure was performed (histology confirmed the diagnosis of perforated diverticulitis). the patient developed a sirs complicated with a right-side necrotizing pneumonia requiring multiple antibiotic treatment and pulmonary decortication. death occurred at the th hospitalization day. conclusion: necrotising fasciitis as a consequence of perforated diverticulitis is an uncommon but potentially lethal condition requiring prompt surgical intervention. when accessing an abdominal necrotising fasciitis without recognisable source, an elevated index of suspicion is necessary to link it to complicated diverticulitis. fatih baş ak, kü rş ad Ö ztü rk tc sb bozkir community hospital introduction: care of trauma patients may be difficult in small community hospitals. these hospitals are usually staffed by a small number of general practitioners and, perhaps, a general surgeon, and a significant number of trauma cases are brought to them. the records of minor and major trauma patients who admitted to bozkir community hospital between june and december were evaluated. mortality and transfer rate were recorded. general surgeon was not present in first months. the rates of last months when general surgeon has been present were calculated separately. results: trauma patients were admitted in first months ( . %) of these were transferred to larger centers. treatment of remaining ( . %) patients continued in our hospital. mortality rate of first months was . %. three patients requiring immediate surgery died because of absence of general surgeon. patients were admitted in last months. ( . %) of these were transferred to larger centers. mortality rate of last months was . %. three gunshot wound and one penetrating cardiac wound patients were saved with emergent surgery. conclusions: regardless of the sophisticated techniques for dealing with trauma that exist in larger centers, it is the staff of smaller hospitals that often shoulder the initial burden of trauma care. transfer rate is between and % of all trauma cases. our hospital is . h away from larger centers. presence of general surgeon in last months mainly affected the care of patients that requiring immediate surgical attention. metin kement, hakan acar, ilhami soykan barlas, uygar dü zci, cem gezen burn center, kartal education and research hospital, istanbul, turkey aim: fecal contamination which may result in septicemia, graft loss and wound healing delay is the most serious problem for burns in perineal, gluteal and upper thigh regions. temporary fecal containment devices can be used for diverting feaces from burned area. the aim of this study was to evaluate early results of using of these devices in our burn center. methods: twelve patients, who were applied temporary fecal containment devices in our burn center, were retrospectively evaluated in this study. results: ( . %) of the patients were male.the mean age was . ± . year.the mean tbsa burned was . ± . %. ( %) of the patients had burn in all three regions (perine, gluteus and upper thigh). three ( %) of the patients had burn in upper thigh. and ( %) of the patients had burn in gluteal region. the devices were placed intra-rectally on the first admission days of all patients.the mean application time was . ± . days. except minimal fecal leakage in ( . %) patients, any complication was not observed in our cases. local infection confirmed by tissue culture was observed in ( . %) patients including two patients with fecal leakage. besides, in one of these four patients, septicemia was developed and managed successfully with antibiotics and supportive treatment in intensive care unit of our center.one patient with % burn was died on days of application due to multiple organ failure. conclusion: temporary fecal containment devices aim to protect patients' wounds from fecal contamination by diverting feaces. if the safety of these device is proved in further studies, they may reduce the necessities of diverting stoma operation in burn patient. metin kement, ilhami soykan barlas, uygar dü zci, hakan acar, cem fazlı gezen burn center, kartal education and research hospital, istanbul, turkey aım: reactive thrombocytosis which develops secondary to infection, trauma, malignancy or surgery is the most common ethiology of thrombocytosis. although thrombocytosis is a benign and self-limiting condition in most cases, it may result in some thrombotic and hemorrhagic complications. the aim of this study was to evaluate the reactive thorombocytosis in burn patients. material: thrombocyte counts was retrospectively evaluated in consequent burn patients admitted to our burn center between august and january . the correlations between thrombocyte counts and demographic data, total body surface area burned (tbsa), hospitalization time and levels of some acute phase markers also analysed. results: the mean thrombocyte counts were respectively . ± . /mm , . ± . /mm on admission day and second day (p < . ). the number of patients with thrombocytosis was ( . %) in admission, ( %) of them were children. the rate of thrombocytosis was / ( . %) in children,whereas the rate of thrombocytosis was only / ( . %) in adults (p < . ). the mean thrombocyte counts in children and adults were respectively . ± . /mm , . ± . /mm in admission (p < . ). the mean wbc count was significantly higher in patients with thrombocytosis than patients with normal thrombocyte count (p < . ), but there was not any significant difference in crp count (p = . ). and also,we did not find any significant difference between patients with thrombocytosis and patients with normal thrombocyte count in tbsa and hospitalization time (p = . and . , respectively) conclusion: reactive thrombocytosis is seen more frequently in burned children than burned adults and mostly unrelated to degree of burn. background: electrical injuries are related with multiple organ dysfunction as well as high morbidity and mortality. pulmonary compromise is rare, if compared to other organ dysfunctions related with electrical injuries. in this study, we presented a case with pulmonary hemorrhage associated with electrical injury. case: a -year-old previously health man was brought to our emergency department (ed), h following the accident, with electrical injury. initial examination findings were blood pressure / mmhg, heart rate /min, respiratory rate breath /min. glasgow coma score was . decreased breath sounds, bilateral rales and wheezing were determined. there were small necrotic wounds (typical contact injury) on the first finger of left hand and under the right foot of patient. there was no trauma in thoracic wall. blood gas analysis revealed respiratory and metabolic acidosis. the inr and platelet levels were normal. when chest radiograph and thoracic computed tomography were assessed, air bronchograms and symmetric consolidations were determined in the both lungs. patient was intubated and fresh blood was aspirated from endotracheal tube. mechanical ventilatory support was performed the patient due to lung hemorrhage and respiratory failure. patient died after h of admission in the ed. conclusion: multiple organ dysfunction and necrotic skin lesions could be occurred in electrical injuries. electrical injuries on the chest may cause lung infarction because of the direct effect of the electrical current and vascular embolism. possibility of lung injury should be investigated after electrical injury especially in patients with respiratory failure. nebahat yıldız , aysel gü rkan , _ imren aş ar , ayş e hale uysal trauma and emergency surgery service,istanbul university, istanbul faculty of mediine, istanbul, turkey health science of faculty marmara universty, istanbul, turkey introduction and objectıve: the outcome of burn treatment is measured not only by mortality and morbidity, but also by post-burn psychological factors. the purpose of this study was to investigate whether difference in length of hospitalization exist between burn patients with and without mental health problems and if so, why. methods: the descriptive study was retrospective review of patient with burn injuries who had received care at one burn unit in the istanbul from october to december . socio-demographic features of patients, burn criteria (kind, depth, size, location), duration of hospital stay, and psychological problems were tabulated. results: psychological impairment was found in of hospitalized burn patient. there were acute stress disorder in fifteen patient, anxiety in nine, adjustment disorder together with anxiety in eight, depression in seven, post-traumatic stress disorder in six patient. fortyone ( . %) patient had burns which were between i and ii degree and ( . %) patient had burns which were between ii and iii degree. in patient, burned area has been % or more. patients with psychologocal impairment were longer hospital stay and intensive care unit than patients without psychologocal impairment. sixty-four ( . %) patients with psychologocal impairment had been discharge either getting better or recovering completely but unfortunately ( . %) patients died. conclusion: the presence of psychological problems in burn patients have an impact on their burn care. psychological interventions can contribute towards successful outcomes. introduction and objectives: major burns can cause disseminated intravascular coagulation (dic) and is a serious clinical problem. we would like to present dic cases whose burn rate is % according to total body surface area (tbsa) which developed after late postoperative period. methods: two cases over %, nd and rd degree burn injury admitted to our facility. first case who was year old female developed s. aureus and second case was years old female developed p. aeruginosa sepsis which was confirmed by blood culture. in first case dic developed at postburn day and in second case at postburn day. in both cases dic developed after postsurgery day . results: on patients, bleeding points, as leaking, were detected on all over burn areas. at the same period thrombocyte values decreased sharply ( . k/ul). increase in prothrombin time (pt) ( . second) and active partial thromboplastin time (aptt) ( second) values, decrease in fibrinogen levels was observed. cases were discharged from hospital in th day, without any problem. patient was taken for iu erythrocyte suspension and iu platelet suspension in this time totally. conclusion: dic occurs in early period of burning; but it can be formed in later periods, even after defects were recovered by operation. rapid establishment of dic table just before the discharging term from hospital is an unusual and interesting situation. the patients in our study can be accepted as an example of the necessity of observing coagulation parameters in every periods of burn damage. methods: sphere project handbook reviewed by experts in the field of each section, the terms of our country's adaptation has been made. within the framework of the project dissemination, sphere workshops have been organized in various provinces. the ppt slides were adapted to turkey's needs. the project's outcomes have been observed through the pre-post tests and the workshop evaluation forms. results: expert review and the end of the first study, with a high risk of disaster in our country, the handbook was understood to be necessary and useful. in addition to this, the control lists in details but useful and also, the summary tables are useful to take a decision in emergencies. it is also understood that preliminary results from the project is compatible with literatur data. conclusions: developed in each country is adapting to the local experience of the sphere, significant experience with disasters in our country the right to contribute are welcome. indeed, the first application of the new approach by the sphere project's coordination center is monitored with interest. introduction: ( ) initial assessment of trauma patients is a period with a high frequency of treatment protocol deviations and an elevated number of avoidable complications. ( ) the majority of medical errors are diagnostic or cognitive, whereas operative technical complications accounted for less than %, and ( ) general surgery residents (gsr) do not feel well-trained on the management of major trauma patients. aim: describe initial experience with one approach to foster quality improvement in trauma care modifying the method by which we train surgeons. methods: we integrated in the gsr program, simulation based training sessions with other educational tools as lectures and workshops. the scenario objectives were based on research data indicating major deficiencies in trauma care (tc). we incorporated team training and crisis resource management sessions. to review trauma life support diagnostic and therapeutic standardized protocols we run scenarios to train initial assessment, and head, thoracic and abdominal trauma. after every clinical case, residents participated in a video assisted debriefing session leaded by a specialized instructor. an evaluation interview was made after the course. results: all resident viewed the experience as a ''very good'' training modality. many of them felt their time was better spent in the simulator session than in the operating room, and wanted to do it more often or in a scheduled way. some of them complained about evaluating the mannequin and the equipment when compared to the one in their actual work setting. conclusions: integrating patient simulation with traditional surgical training may strength the approach to tc education. introduction: pulmonary embolism is a life-threatening condition and its diagnosis is generally based on clinical suspicion. case: a years old male had been admitted to another hospital with acute dyspnea and syncope and after initial evaluation he had immediately been undergone an operation due to epidural hematoma. he was referred to our emergency department with early diagnosis of acute coronary syndrome after operation because intraoperative and postoperative tachycardia could not be controlled. in his physical examination gcs: , arterial blood pressure / mmhg, heart rate /min and breath rate /min. ecg, echocardiogram and thorax ct findings complied with pulmonary embolism. venous doppler ultrasonograpy findings complied with chronic deep venous thrombosis. thrombolytic or antiaggregant medication could not be started because of epidural hematoma operation. at postoperative h low molecular weight heparin and at h warfarin was administered. in follow-up period his symptoms regressed and there was no complication due to epidural hematoma surgery. he discharged from hospital at day . conclusion: in trauma patients, one of the important issues that have to be considered during clinical evaluation is the primary reason leading to trauma. in this case, the investigation for syncope etiology revealed the haemorrhage and thrombus diagnosis concomitantly. these two diagnoses have opposite treatment strategies and due to this condition we had difficulty in management of the patient. although there are intracranial haemorrhage cases due to pulmonary embolism treatment (thrombolytic or antiaggregant), a similar case report cannot be found in the available literature. introduction and objectives: different societies have different type of snake bites. _ in our actually series, two patient from u.k. and seven patients from south-eastern part of turkey presented with lıke compartment syndrome result of was bitten by a snake to their fingers. methods: four of nine patients applied to our clinic at the day of event, the other five were referred to us after the emergency treatments have been done. all bites were over or distally to the pip joint. after being bitten by snake, patients admitted to our accident and emergency department because they had like as compartment syndrome on the forearm. two of the patients were referred to us very late stage and one of them had partial necrosis and the other had total necrosis already. none of patients had signs of systemic envenoming. results: two patients with local swelling and no other symptoms were discharged. coverage of the defects were performed with full thickness skin grafting in two patients, cross-finger flap in one patient, reverse dorsal digital arter flap in one patient and dorsal interosseous metacarpal flap in two patients. one patient had amputation. none of patients had fasciotomy. conclusions: this study represents the clinical effects and current approaches for the treatment of snake bites to distal finger. all patients presented with compartment syndrome like symptoms on the hand or forearm. these patients should be followed-up very closely. final wounds should be closed either with skin grafts or local flaps. simultaneously, systemic envenoming should be considered. the aim was to evaluate the geriatric patient with abdominal pain in emergency department (ed). methods: the preliminary retrospective study included the period between january and june , , ankara. data were achieved from registration notebooks, manually. the patients separated within age to three groups as - , - , and over. the finalization of management, hospitalization, operation rate, mortality were studied. results: there were ( . %, annually) patients. the mean age was . ± . ( - ), the mean hospitalization duration was days ( - ). the sex and the age of patients can be seen in table . . % (n = ) of them discharged from ed. abdominal ct and usg usage were . % (n = ), . % (n = ) in ed. . % (n = ) patients had both ct and usg. abdominal ct and usg results are showed in tables , . finalization of patient management was demonstrated in table . the operation rate for all patients was . % (n = ). general surgery hospitalization and operation rate were . and . % (n = , n = ). the mortality rate was . % (n = ) in admission. there were not any significant difference between the groups of - and - according to sex, finalization, ct, usg utilization, operation rate (p = . , p = . , p = . , p = . , p = . ) with spss x test, while the number of advanced geriatrics was unsuitable for statistics. conclusions: females and the - age group were common with a complaint of abdominal pain in ed. most of them had hospitalization indications and the primary yard was general surgery with brid ileus. mortality rate was lower than % introduction: nontraumatic epigastric and left upper caudran pain is a common complaint in emergency department. it can include lifethreatened various reasons as cardiac, respiratory, and serious gastrointestinal problems, rarely. case: a year old man had an emesis with recurrent epigastric and left upper caudran pain admitted as second turn to ed in h. physical examination except a slight epigastric sensitiveness, ekg, urine test and biochemical tests, complet abdominal ultrasonography, x-rays were nonspesific on the first day. wbc was . on cbc. his complaints relieved with semptomatic treatment with an mg ranitidine, mg metoclopramide, serum sale on his observation and discharged with suggestions. in second admission with nonspecific physical examination findings, computerized tomography (ct) revealed splenic unenhanced parenchymal areas consistent with splenic infarcts. computerized tomography angiography (cta) showed a small aneurysm of the celiac trunk, a characteristic pattern of caliber irregularities and arterial wall thickening of the splanchnic arteriesincluding splenic artery, common hepatic, right and left hepatic arteries-, suggesting splanchnic arterial mediolysis (figures and are presented with permission of patient's written consent). he was hospitalized to general surgery and started low molecular weight heparin. as clinical and radiologic findings were degrated, he was discharged without an operation. conclusions: splanchnic (segmental) arterial mediolysis is a rare noninflammatory vascular disease of the abdominal splanchnic arteries with slight symptoms. ct for vasculary and internal organs should be performed to diagnose in recurrent complaints beside observing the physical findings. introduction: it is well documented that healing of peptic ulcer perforation (pup) is possible with conservative therapy in selected cases. thus a spontaneously closed pup diagnosed at exploration may not require surgical repair. methods: study included three patients in which diagnostic laparoscopy suggested spontaneously closed pup between and . suggestion criteria were; fibrin cloth on duodenum with or without subhepatic fluid collection, no visible perforation, otherwise normal exploratory findings. omentum minus was dissected and cautiously observed. the stomach was filled with ml diluted methylene blue fluid via nasogastric tube, operation table was tilted to right and up, a gentle pressure on the stomach was made with the shaft of laparoscopic irrigator to fasciculate the passage while the descending section of duodenum was compressed with the shaft of a grasper. duodenum was cautiously observed for min to detect dye leakage in all patients. if no leak was observed, operation was terminated after abdominal irrigation and inserting a catheter to the subhepatic area. therapy for pup was given postoperatively. results: all patients were male and the mean age was ( - ), no leak of dye was observed at operation. nasogastric tube was removed and food intake was allowed at postoperative second day. all patients were discharged on third day. conclusion: although the perforation site is almost always identified at operation, to meet a spontaneously closed pup is also possible. irrigation and drainage alone may be sufficient for these cases after blue dye test as described in this study. the complicated appendix with/without abscess was delivered through the umbilical incision for an open technique safely. this gave our patients the maximum benefits of the minimally invasive surgery with better visualization, reducing equipment needs, less postoperative pain, rapid discharge, no postoperative infections, and excellent cosmetic results. all patients were quite satisfied during follow-up. conclusions: it is concluded that hybrid appendectomy seems to be feasible and reliable for children with complicated appendicitis not suitable for conventional laparoscopic technique. vata was successfully accomplished with obvious advantages, and avoided conversion to the open fashion. background: appendicectomy remains the most frequent emergency operation. the management of these patients varies between surgeons and hospitals. at our centre, it was a routine to review post operative children at months. aims: is to evaluate the need for a routine follow up in children who had appendicectomy. methods: it is a retrospective observational study for consecutive patients between and . a parallel questionnaire was sent to the parents of all the children. results: the average age was . years. % of the patients were found to have normal appendices. % of the patients were discharged within days. % of the patient had intravenous antibiotics for day and % were discharged with oral antibiotics. % had a routine follow up appointment in months time. in % of cases there was no change in the management. on the questionnaire % of the parents thought they were given enough information regarding the procedure. in terms of routine follow ups, % of the parents found it very useful while % found it a little or not useful. conclusion: this study shows that there is no change of the management or a clinical need for the routine follow up. however the patients and their families like to keep a follow up appointment. it is more convenient for the patients and their family to arrange other sorts of follow up like a phone call conversation or a general practitioner follow up. yavuz savaş koca, mustafa ugur, celal Ç erçi, recep Ç etin department of general surgery, sü leyman demirel university, isparta,turkey the aim of this study was to evaluate the disease profile and mortality ratio of patients presenting with acute abdomen. four hundred fifty eight patients who underwent surgery with the diagnosis of acute abdomen were analyzed retrospectively. the effects of age, sex, american society of anesthesiology (asa) class, accompany disease, admission time after the onset of the symptoms, follow up interval before the operation on mortality and length of hospital stay were evaluated. male/female ratio was . , and mean age was . . main causes were biliary system disease ( . %), intestinal obstruction ( . %), peptic ulcer perforation ( %) and acute appendicitis ( . %). median asa class was and . % of the patients had at least one preexisting disease. mortality ratio was . %. asa class, age, preexisting diseases other than malignity, period between the onset of symptoms and admission, follow-up time was significantly efective on mortality. reliability of ultrasonography for diagnosing acute appendicitis aylin hande gö kçe , acar aren , feridun suat gö kçe , hakan Ö zkan , alper dursun Ş agban , _ ibrahim aydın , gü rhan Ç elik , gü rol kö roglu s.b. _ istanbul eg itim ve araş tırma hastanesi, istanbul, turkey balıklı rum hastanesi, istanbul, turkey purpose: abdominal ultrasonography is the most commonly used diagnostic tool for diagnosing acute appendicitis,which is one of the most common causes of acute surgical abdomen. _ in this study, we examined the reliability of ultrasonography for diagnosing acute appendicitis. in this prospective study we performed abdominal ultrasonography on patients admitted to our surgical emergency department and diagnosed as acute surgical abdomen according to the physical examination and laboratory findings during . these patients were surgically treated by appendectomy and the materials were pathologically examined. results: patients were admitted to this study. of these patients ( . %) were diagnosed as acute appendicitis, and ( . %) of them diagnosed differently. ( . %) of patients diagnosed as acute appendicitis on ultrasonography examinations were reported as acute appendicitis on histopatological examination. ( . %) of patients diagnosed differently on ultrasonography examination were reported as acute appendicitis on histopathological examination. conclusion: the sensivity of abdominal ultrasonography for diagnosing acute appendicitis is high ( %), but the specificity is low (p = . ). we calculated that the specificity is . , positive predictive value is . , negative predictive value . , accuracy is . . abdominal ultrasonography is a helpful diagnostic tool for diagnosing acute appendicitis.however, it should not be seen superior to anamnesis and physical examination findings. poisoning: a case report background: mushroom poisoning is an important clinical problem which may cause serious complications and death. acute pancreatitis is a rare complication of mushroom poisoning. in this study, we presented a case that developed liver damage and acute pancreatitis following wild mushroom ingestion. case: sixty-six years old women admitted to emergency department with complaints of nausea, vomiting and abdominal pain. it was learned that patient was ingested wild mushroom before h of admittance and her complaints were started after - h of ingestion. in initial examination, general appearance and vital signs of patients were normal and there was epigastric discomfort. laboratory findings were leukocyte , /ll ( . - . ), aspartate aminotransferase u/l ( - ), alanine aminotransferase u/l ( - ), amylase u/l ( - ), lipase , u/l ( - ) on admission. liver and pancreas was determined as normal in abdomen ultrasonographic examination. computerized tomography of the abdomen showed minimal peripancreatic fluid. the patient was observed in emergency intensive care unit and symptomatic therapy was performed. hepatic transaminases and pancreatic enzymes were decreased progressively during the observation. the patient was discharged from the hospital after days clinical course, without complication. conclusion: mushroom poisoning and acute pancreatitis have similar gastrointestinal symptoms and sings. therefore, possibility of acute pancreatitis as well as other organ dysfunctions should be investi-gated in patients with mushroom poisoning. early recognition and appropriate therapy for acute pancreatitis and mushroom poisoning may lead to an improved prognosis and complications. mehmet mustafa altıntaş , , ayhan Ç evik , , yekin Ö zcabı , , gü lay dalkılıç , , hü seyin ekinci , , nejdet bildik , dr. lü tfi kırdar kartal education and training hospital, istanbul, turkey general surgery clinic, istanbul, turkey diagnostic emergency laparoscopy is very helpful in diagnosing acute abdomen and evaluating abdominal trauma. parallel to developments in laparoscopic techniques, its emergency applications are increasing. we reviewed our diagnostic emergency laparoscopy procedures applied to patients with acute abdomen and could not be diagnosed after h of follow-up. we applied diagnostic emergency laparoscopy to patients in dr. lü tfi kırdar kartal education and training hospital during - . in patients laparoscopy indication was undiagnosed acute abdomen. there were four acute appendicitis, two peptic ulcus perforation, two small bowel necrosis, one perforated hepatic hydatid cysts, one iatrogenic urinary bladder perforation, one postlaparoscopic cholecystectomy bile fistula and non-surgical adnexial pathologies. diagnostic emergency laparoscopy was performed in five patients with penetrating abdominal injury. there were small bowel injury in two patients, colonic injury in two patients and no injury in one patient. diagnostic emergency laparoscopy was performed in four patients with blunt abdominal injury. there were grade splenic laceration in two patients, grade liver injury in one patients and intraabdominal bleeding in one patient. in conclusion, diagnostic emergency laparoscopy is a suitable technique in undiagnosed acute abdomen patients which could not be diagnosed after physical examination, laboratory, radiology and follow-up and helps surgeon to diagnose the disease. also diagnostic emergency laparoscopy performed by experienced surgeons prevents negative laparotomy especially in abdominal trauma patients. mehmet ali yagcı, atakan sezer, ahmet rahmi hatipoglu, irfan coskun, zeki hoscoskun, aydın altan department of general surgery, trakya university school of medicine, edirne, turkey introduction: appendectomy is known as the most common nonobstetrical operative procedure in pregnant women with an estimated frequency of / , of all pregnancies.pregnancy continues to obscure the accurate diagnosis of acute appendicitis due to gestational physiological changes.diagnostic delay increases the incidence of perforation, hence increasing maternal and fetal morbidity and mortality. patients and results: four patients of appendicitis during pregnancy were concluded in study between to may ( table ). the mean age was (range - ). three patients presented during three trimester and one in first trimester.the mean time interval of symptoms to the admission is h (range - ).abdominal pain, vomiting, and nausea are the most common complaints.rebound was the main sign observed in all patients.fever was noted in two patients. mean value of wbc count was , per l (range , - , ). ultrasonographic examination was performed to all patients with the diagnosis of acute appendicitis.three patients were operated under general anesthesia and one under regional anesthesia. paramedian incision was applied to three patients and mcburney to the other one. the exploration findings were two perforated, one phlegmonous appendicitis and a normal appendix. no maternal or fetal mortality occured. cesarean section was performed on -week pregnancy during appendectomy due to early onset contractions. adhesiolysis was performed in same case because of postoperative ileus. conclusion: the accurate diagnosis of appendicitis during pregnancy requires a high level of suspicion and clinical skills. delay of operation correlates to more inflammatory changes in the appendix and to higher maternal and fetal complication rates. early laparotomy with appropriate preoperative diagnosis will reduce the fetal and maternal morbidity and mortality. introduction: paraesophageal hernias occur most commonly in elderly and account for % in all hiatal hernias [ ] . although the fundus or corpus of the stomach are most commonly the contents of a paraesophageal hernia, we reported a case in which the gastric fundus and corpus incarcerated in the paraesophageal space, followed by perforation. case: -year-old woman admitted to state hospital following sudden onset of abdominal pain.previously she was diagnosed as esophageal hiatal hernia. on physical examination, abdominal distension with mild tenderness was recognized. pulse rate and blood pressure were per min and / mmhg. the initial laboratory investigations revealed wbc , per ml, urea mg/ dl, creatinine . mg/dl. chest graphy revealed unusual gas shadow in the left thorax (fig. ) . ct demonstrated intraperitoneal free air, ascites, and the prolapsed stomach in the left thorax (fig. ). an urgent laparotomy was performed revealing dirty ascites.the gastric fundus and corpus were incarcerated in paraesophageal space (fig. ) . a perforation mm in size was recognized in the fundus. the perforation was sutured primary and cruroraphy was performed. the patient required respiratory support and died on the th postoperative day due to multiple organ failure and septic shock. conclusion: the contents of paraesophageal hernia commonly include the gastric fundus or corpus. paraesophageal hernias can cause lethal complications, including gastric obstruction, strangulation, perforation, and hemorrhage. paraesophageal hernias can usually be repaired easily, even using the most recent laparoscopic technique ( ). thus, because of the very serious potential complications inherent in cases such as ours that can result from an untreated paraesophageal hernia, we recommend that elective repair be carried out, even in asymptomatic patients. introduction and objectives: the solitary fibrous tumor (sft) of peritoneum, especially arising in lesser omentum is extremely rare. we report a case of lesser omentum soliter fibrous tumor, causing pain and abdominal fullness with its mass effect. case: a -year-old male was admitted to our hospital, due to an intraabdominal mass lesion, epigastric pain, abdominal fullness and vomiting episodes. on physical examination, a hard, non-tender mass was palpated in the epigastric region. computed tomography (ct) showed, an approximate . · . · . cm sized solid mass with fibrous capsula between left liver lobe and stomach. at laparotomy, a yellowish brown solid tumor with hard consistency was found on the lesser omentum. the tumor was not adhered to the adjacent structures and could be resected completely. postoperative course was uneventful and no recurrence was determined during follow up. results: histopathologic examination diagnosed the mass as a sft. the tumoral cells were spindle-shaped and did not present mitotic activity or atipies and showed very low proliferation index with ki (< %) and immunohistochemical positivity for cd and negativity for c-kit (cd ), actin, and s- . conclusion: although sft are rare, especially in the abdomen of adults, are generally benign but malignant cases have been reported. in our case, the tumor has a benign character shows neither mitotic activity nor nuclear atypical. this is the third case of soliter fibrous tumor of the lesser omentum described in the english literature. introduction and aims: a single hamartomatous adenoma of stomach is rare. gastric hamartomatous polyps are usually multiple, familial and assosciated with other syndromes. they are also associated with chronic helicobacter pylori infection, acid hypersecretion and predisposition to gastric cancer. this is the first case of gastric hamartoma which is coexistent with duodenal ulcer perforation. case: a -year old male admitted to our hospital with complaints of stomach ache, nausea and vomitting. because there was free air under right subdiaphragmatic surface on chest x-ray, an emergency operation was performed. there was a perforated ulcer on the first part of duodenum and a large quantity of bile mixed with blood in the abdominal cavity. on further exploration a tumoral mass which was about cm in diameter was found on the stomach corpus. because of possibility of malignancy, a subtotal gastrectomy including the perforation zone was performed. histologically the tumor was well circumscribed and it consisted of uniform, clear cells. at first, it was thought to be metastatic lesion from kidneys or other organs. in this context, all body was scanned however no pathology has been identified. later on, the tumor was approved to be hamartomatous adenoma and helicobacter pylori was positive. postoperative course was entirely uneventful. objectıve: the aim of this work is to determine the level of apoptosis, which is believed to hold an important role in septicemia process that affects mortality and morbidity in obstructive jaundice, in lingers of rats that were experimentally subjected to obstructive jaundice. materials and methods: the experimentals were separated into two goups of eight. choledoch was isolated in each group and while surgery was ended at this level in the control group, choledoch was tied with - silk from two different places and cut between ligatures full fold. experiment animals were operated for the second time in the postoperative seventh day for liver sampling and sacrificationaimed histological analysis through the old incision with anaesthesia provided. to exhibit the p expression immunohistochemically, anti-p clone do- was used as the primer antibody and hrp as the secondary antibody. samples taken for the determination of apoptosis were painted by the tunel method. fındıngs: in the evaluation of apoptotic cells in liver cells, apoptotic cells were observed to widely exist in the liver tissue and it was determined that they exhibited dense accumulation in some regions. in the immunohistochemical evaluation made for evaluation of p expression in hepatocytes, p -positive hepatocytes were determined to exist quite widely in the tissue samples taken from the livers of rats in the experiment group. result: consequently, in this study we determined that in the obstructive jaundice group, both apoptotic index and, as a result of the immunohistochemical studies, p expression increases in the liver. introduction: the risk of leakage from an anastomosis is higher in large intestine. in emergent colon operations primary anastomosis is avoided especially on the left colon, and multi-step procedures are preferred if there is a dirty abdomen. the aim of this experimental study was to compare different suture materials in left colonic anastomosis in presence of peritonitis. metods: this study was conducted on wistar-albino rats by dividing them in groups of equal numbers. after median laparotomy, the whole layer of left colon was cut cm over the pelvic peritoneum and fecal contamination was performed. one day later, the abdomen was opened again under general anesthesia. the abdomen was washed with sf before starting colonic anastomosis. for colonic anastomosis; vicryl + silk was used in the st group rats, pds was used in the nd group rats, and coated vicryl plus antibacterial suture and silk was used in the rd group rats. results: tissue hydroksiproline, anastomosis bursting pressures and histopathologic findings on the anastomosis line were evaluated on the th postoperative day. the highest anastomosis bursting pressure was found in group iii (p < . ). the highest tissue hydroksiproline level was found in group iii (p < . group i-iii, group ii-iii). when histopathologic findings were evaluated by comparing three groups, the healing of the intestine tissue score was found to be highest in group iii (p < . , groups i-iii). conclusion: consequently, it was observed that using antibacterial suture increased resection safety in the presence of peritonitis and anastomosis safety in primary anastomosis. introduction and objectives: the chance of finding the vermiform appendix within an inguinal hernia occurs in approximately one percent of the cases, and is known as amyand's hernia. appendicitis within an inguinal hernial sac is rare. materials and methods: we present two amyand's hernia cases: one with a vermiform appendix and one with a perforated appendicitis. case : an -years-old man presented with a years history of bilateral inguinal mass. ultrasound examination described a hernia which contains mobile bowel segments inside, on the right side. the appendix was obsereved edematous and hyperemic in the hernial sac. an appendicectomy was done. further exploration of the bowels revealed a meckel diverticulitis which was managed by a wedge resection. case : a -years-old woman presented with one week history of an inguinal mass, pain and anorexia. abdominal computerized tomography demonstrated an incarcerated right-sided inguinal hernia.the hernia sac was filled with the perforated appendix. appendicectomy was carried out. results: postoperative recovery was uncomplicated, the patients were discharged without any complication. discussion: acute appendicitis or perforation of the appendix within the hernia sac simulates perforation of the intestine, and does not have specific symptoms or signs. preoperative clinical diagnosis is very difficult and the diagnosis is made intraoperatively. since the absence of any pathognomonic radiological features, the value of preoperative computed tomography is limited. treatment of hernial appendicitis is an appendicectomy with suture hernial repair. the management of a non-inflamed appendix is debatable. the usual practice covers reduction of the appendix, and mesh repair. in the immediate post-operative period the patient had a high output jejunostomy and was dependent on total parenteral nutritional support. a bishop-koop procedure was performed on day and by day , the patient was completely independent of any adjuvant nutritional therapy. five months from primary surgery colostomy was closed. introduction and objectives: the management of pancreatic pseudocysts which occur after blunt abdominal trauma in children is still controversial. in this study, we present our experience therapeutic approach of pancreatic pseudocysts that occur after trauma. methods: we evaluated patients with traumatic pancreatic pseudocysts who admitted to our clinic between and . we performed ultrasonography, computerize tomography (ct) and blood amylase level for all patients. results: there were eight males and one female. the average age was . years (range - years). the mechanism of injury was bicycle handle bar injury in four, falls in three, assault in one and motor vehicle accident in one patient. abdominal pain was the most common symptom. the median size of cysts was . cm (range - cm). the time interval between trauma and pancreatic pseudocysts was days (range - days). of the nine patients, four ( . %) occurred in less than weeks. all patients were initially followed up conservatively. three patients ( %) were successfully treated conservatively, while patients ( %) required intervention either by percutaneous radiological drainage ( ), cystogastrostomy ( ) and external drainage with laparotomy ( ). complication developed in two patients (septic shock, persistent hyperamylasemia). no patient died. conclusion: traumatic pancreatic pseudocysts may occur short after traumatic injury in children. all patients with traumatic pancreatic pseudocysts should be managed by conservative approach initially. however, if the cyst is cause of gastric outlet obstruction or the size of cyst is bigger than cm, interventional management may be required. introduction: splenic abscess is a rare entity,with a frequency of . - . % in autopsy series.mortality rate is still high, up to %, and can potentially reach % among patients who do not receive antibiotic treatment. case : year-old woman presented with fever and left upper abdominal pain for days. hepatomegaly and tender splenomegaly were present.ct of the abdomen revealed · cm hypoechoic lesion in the spleen (fig. ) . initial laparoscopic approach was performed but failed due to inappropriate anatomy. conventional splenectomy was done and at exploration there was · cm abscess in spleen. the patient was dischared on the eighth day of operation. case : yearold woman admitted with femoral artery thrombosis.thromboembolectomy and leg amputation was performed by cardiovascular surgeons.she was consultated with fever and left upper abdominal pain on the second day of operation. ct of the abdomen revealed a · cm mass with air fluid levels in the spleen (fig. ) . splenectomy was performed and a · cm abscess was observed in spleen.the patient died on the second day of operation due to sepsis. a proximal stoma after resection of the perforated small bowel and colon, closure of the distal stump in case of severe generalized peritonitis without the possibility to perform a primary anastomosis. a loop ileostomy to prevent bacterial translocation in case of pancreatitis. retrospective analysis of clinical data of patients admitted between and for emergency operation requiring laparotomy and the construction of one or more small-bowel stomas. patients had ileostomies created for temporary fecal diversion after emergency surgery including bowel obstruction was the most frequent cause of peritonitis ( cases),followed by anastomotic leakage and peritonitis ( ), acute mesenteric infarction ( cases), intestinal perforation ( cases), strangulated incisional hernia ( cases), acute abdomen of crohn disease ( cases), peritonitis carcinomatosa and frosen pelvis ( cases), mean age was . years (range - ), being males and females. overall mortality was % ( patients). patients died on the first days postoperatively. indications, morbidity, mortality and problems involving the ileostomies in emergency abdominal surgery urgency are herein discussed. in the majority of patients with acute abdomen doing ileostomies,lacking of vital capacity of bowel wall as well as insufficiency of previously laid sutures were revealed, which forced a surgeon to resort to resection; in such cases the method of choice for decompression should be the application of ileostomy. postoperative jaundice is often multifactorial. a precipitating or causative factor may be identified but seldom can a specific therapy be offered. the late complications were mainly presented by the biliary ducts cicatricial stricture, the jaundice and cholangitis recurrency. in this report, we described an extremely rare case of a -year-old woman presenting with pain in the right upper quadrant, jaundice, and weight loss in whom a whipple procedure was performed. usg and mr cholangiography showed that dilatation of intrahepatic and extrahepatic bile ducts and hepaticojejunostomy line. mrcp also showed that, there was a closed jejunal loop related with hepaticojejunostomy. obstruction by local tumor recurrence and infiltration of the efferent jejunal conduit between the proximal hepaticojejunostomy and the duodenojejunostomy led to closed loop syndrome and jaundice. frozen sections by direct incisional biopsy revealed a recurrent tumor invasion. a previously unreported late complication after whipple resection of the head of the pancreas was recognized as ''closed efferent loop syndrome'' mimicking obstructive jaundice. the case was accepted as inoperable because of tumor invasion to the jejunum, transverse colon, and surrounding tissue. roux-en y type jejunojejunostomy was performed. the patient had an uneventful postoperative course. introduction: the form of mechanical asphyxia where respiration is prevented by the external pressure on the body: a large weight compressing the chest or abdomen, wedging of the body within a narrow space death in large crowds is traumatic asphyxia. case: a -year-old man was found compressed by a motorboat in the garage while he was working for installation of the boat. the face, neck and upper part of the chest were congested and many petechiae were observed on the conjunctivae. ecchymotic bruises were observed on the right cervical, lower chest, upper abdominal regions and open fracture of the right humerus, ecchymotic abrasion on right anterior superior iliac spine line were detected. subcutaneous haemorrhages in the chest wall and bleeding without subcutaneous haemorrhage in the inferior part of the right sternocleidomastoid region were observed during the internal examination. fractures of the right third and fifth ribs which were accompanied by bleeding in the surrounding soft tissues and muscles, and ecchymoses over the right sixth rib without any fracture were also observed. macroscopic examination of the lungs revealed congestion, subpleural superficial bleeding areas and histopathological examination showed hemorrhagic alveolar oedema. all the internal organs and big vessels were intact. there was no hemorrhage in the thoracal and abdominal cavity. toxicological analysis was negative. conclusions: in the presented case, the impact cause of the chest compression was distinctly determined by the autopsy and criminal investigation. death was reported as asphyxia by the thorax compression without other lethal factors. purpose: the purpose of this prospective study was to evaluate safety of early surgical interventions in the repairment of animal bites with tissue injuries. materials and methods: tissue repairment and/or reconstruction were done, total in patients. of them were dogs', of them were horses' or donkeys' biting between the years - . wound sterilization and debridement were made before repairment. rabies and tetanus prophylaxis were done for all patients. tissue repairments after animal biting were made early and promptly. patients having animal injuries, apart from biting were not included in the study. results: of the patients were male and of them were female. the minimum age of the patient was . and the maximum was , and the average age was . in cases head-neck, in eight cases extremities and in two cases body were biting areas. horses' or donkeys' bitings were seen particulary in ears. in these animals' biting tissue lose was emphased. we prefered primary saturation in cases, skin greft in ten cases and repairment with flap in five cases. finger amputation was required in one of the patients. total ear reconstruction was done gradually in a patient. no infections observed in patients after the surgical interventions. conclusion: we concluded that, early tissue repairments may done after wound sterilization and debridement, safely. treatment plan. multidetector computed tomography (mdct) imaging is an improving and being a widely used method recently in many areas of medicine. it is possible to evaluate the peripheric vascular structures, anatomic variations or vascular pathologies with mdct angiography (mdcta). methods: the arcuate foramen is an anatomical variant of the atlas vertebra: anterior and posterior osseous bridges or ponticles can arch over the vertebral artery, to a greater or lesser degree, transforming the arterial groove into a canal. dissection of the vertebral artery leading to thrombotic occlusion or ischaemia from narrowing of the arterial lumen has been described in trauma. there are fistula between a dural branch of the spinal ramus of a radicular artery and an intradural medullary vein in spinal vascular malformations. mdct angiography is feasible and is an alternative technique in diagnosis spinal vaskü ler malformations. the craniovertebral junction (cvj) is a funnel-shaped structure comprised of the clivus and foramen magnum and the upper two cervical vertebrae. the most frequent neoplastic lesions of the craniovertebral junction are meningiomas, neurinomas, chordomas, paragangliomas, epidermoids, dermoids and chondrosarcomas. conclusion: in this presentation, pathologies seen in craniocervical junction (congenital variation, trauma, vascular malformation and tumor) were discussed with figures and compared with the literature. introduction and objectıves:small bowel obstruction (sbo) is very rare. although the diagnosis is straightforward, some patients with intermittant and low-degree symptoms could be misdiagnosed as psychiatric disease. we presented here a patient with intermittant symptoms of ileus treated as psychiatric disease case: a year old male patient was referred from phsyiciatry clinic to our department with complaints of weight loss, nausea and malnutrition. his medical history revealed a laparoscopic appendectomy months ago. he emphasized that his complaints started shortly after the operation and increasingly got worse. he was admitted to hospital days after operation with symptoms of ileus and managed conservatively. the intermittant abdominal pain and nausea continued. since the pain was intensified after meals, patient refused eating. during the period of months he lost kg of weight. after numerous radiological and endoscopic investigations patient was referred to psychiatry due to persistent anorexia. after short psychiatric medication, he was referred to our surgical unit. multislice abdominal computerized tomography and and enteroclysis of small bowel clearly demonstrated an obstruction in the jejunal segment of the intestine. at laparotomy, small bowel obstruction was detected and segmental resection was performed. postoperative period was uneventful and patient was discharged from hospital on postoperative day . conclusions: the diagnosis of anorexia and nausea due to sbo is relatively difficult. the patients were sometimes misdiagndosed as having psychiatric disease. before starting psychiatric medication, they must be reevaluated for all putative causes of sbo. introduction: endoscopically placed biliary stents are a well-established procedure for the treatment of benign and malignant biliary disease. duodenal perforation may occur at the time of insertion of a biliary endoprosthesis or following endoscopic manipulation of such a stent. methods: we report a case of duodenal perforation complicating stenting for biliary fistula in surgery for hepatic hydatid cyst. case: a -year-old man was admitted to a local hospital following the sudden onset of abdominal pain,distension with nausea and vomiting. he developed a biliary fistula after surgery for hepatic hydatid cyst months ago. endoscopically placed biliary stent was performed for the treatment of biliary fistula at the same hospital months ago.on examination, marked abdominal distension with mild tenderness was recognized. his pulse rate and blood pressure were /min and / mmhg, respectively. abdominal x-ray showed two foreign body images and subdiaphragmatic free air. emergency laparotomy revealed dirty ascites and perforation of the third portion of the duodenum by the plastic stents. the second stent was found at pericecal area. after extraction the plastic stents and irrigation with isotonic sodium chloride solution, the site of perforation in the duodenum was primary reparing and triple tube placement performed. conclusion: endoscopic retrograde cholangiopancreatography (ercp) is considered to be the most difficult endoscopic procedure in gastrointestinal endoscopy, and is associated with potentially severe and sometimes life-threatening complications such as duodenal perforation. surgical statistics indicate the importance of early diagnosis and treatment for duodenal perforation. introduction and objectives: ticks play an important role in transmitting several infectious agents, such as viruses, bacteria, spirochetes, rickettsia, and parasites. in this study, we analysed the demographic and clinic characteristics of the patients who admitted to emergency service due to tick bite. methods: in this study, patients were selected from cases of tick bite admitted to the department of emergency medicine of ankara numune hospital during the - periods. detailed histories and some blood tests of patients were taken, and the body of the tick grasped gently avoiding to inject more salivary toxins. results: totally patients admitted to hospital in this period. the most frequent symptoms at administration were malaise, myalgia, and fatigue. hemorrhagic manifestations were observed in patients and bleeding was from multiple sites in patients. other symptoms were watery diarrhoea, skin eruption, macular rash, and petechia-ecchymosis. in the comparison of the clinical features and laboratory results of the surviving and the patients who died, we found that the rates of fever during hospitalization, confusion, neck stiffness, bleeding from multiple sites and presence of petechia/ecchymosis were higher in the patients who died than in the surviving ones. additionally, the mean values of alt, ast, lhd, ck, ptt, international normalized ratio (inr), and urea were also higher and mean plt counts were lower in the patients who died. conclusion: the acute tick-bite reactions show special histologic features, which are unquestionably related to the particular morphology and physiology of the mouthparts of these arthropods. results: totally patients ( men and women) were evaluated. the mean age was . ( - ) years and the mean follow up period was ( - ) months. the localization of the hernias were as follows: inguinal hernias, seven femoral hernias, two umblical hernias, two paraumblical hernias, one epigastric hernia and one inguinal + femoral hernia. all of these strangulated hernias were treated with prosthetic graft repairing. in addition to these hernia repairs, in the same operation sessions three hydrocele repairs, three omentum resections, two partial small intestine resection and anastomosis, one lymphadenectomy, one orchiectomy and one laparotomy were done when necessary. in the early post operative period four patients died because of other diseases not related with the surgical procedures or hernia itself. wound infections were observed in three patients and they were treated with antibiotics and anti inflammatory drugs. we report a rare case of ileal perforation caused by an ingested cm long fork. a -year-old man presented to the emergency department with exhaustion, weight loss and abdominal pain. he had been having pain in the abdomen, nausea and vomiting for the previous days. the patient had received psychiatric treatment, and started to experience weight loss and exhaustion - months previously. no conclusions could be drawn from physical examination for abdominal tenderness and defence. direct x-ray showed an appearance conforming to a fork in the intestine and subdiaphragmatic free gas. the patient was sent for emergency surgery, with a diagnosis of ileal perforation and foreign-body ingestion. most of the ingested foreign bodies that reach the stomach pass through the alimentary tract without complication. perforation occurs in, % of all cases of foreign-body ingestion, usually in the oesophagus. other sites where perforation can occur are the pylorus, the duodenum, the duodenojejunal flexure, the ileocaecal region and any site of congenital anomalies. long, thin or sharp objects, as seen in our case causing ileal perforation. foreign-body ingestion is a possibility to be borne in mind at presentations to the emergency department, especially those with symptoms described in psychiatric cases. appendicectomy is a common emergency operation, its major complications are uncommon. most complications of appendicectomy occur in the early postoperative period and easy amenable to treatment with conservative medical therapy. appendicitis, usually a benign disease, can have its prognosis worsened in case of postoperative fistula. the latter occurs rarely after open appendicectomy but accounts for % of the morbidity rate. schloffer tumor (inflamatory granuloma or abscess in the abdominal wall at the operative scar) is rare complication that usually develop months to years postoperatively and late postoperative enterocutaneous fistula has been described in literature as a rare complication of acute appendicitis. we describe one such case where the patient presented with a tender mass under the incision site six months later after appendicectomy. findings of computed tomography were demonstrated thickening in the abdominal wall and abdominal wall abscess like schloffer tumor. abscess was drained. there were not produced any microorganisms in the wound culture. after conservative therapy healing was completed in a short period. one year later, the patient was admitted with complaints. on the examination, passage of undigested food particles through a sore in the appendicectomy incision site. computed tomography were demonstrated fistula tract extending from appendicectomy site to skin. enterocutanous fistula was occured at the appendicectomy incision year later after operation and successfully treated with en-block fistulectomy and right hemicolectomy. postoperative course was uneventfull. patient discharged from hospital at seventh day after operation. objective: vascular insufficiency may lead to hypoxic injury in intestines. the lesions in the colon are called ischemic colitis. mesenteric ischemia is more prevalent in patients getting hemodialysis. in this study we report hemodialysis patients admitted to the emergency department because of acute abdominal symptoms. case year old woman was chronic hemodialysis patient admitted to the emergency room with acute onset abdominal pain.the initial diagnosis was acute appendicitis and she underwent laparotomy. peroperatively isolated cecum necrosis was seen. right hemicolectomy and ileotransversostomy was performed. she died days after surgery because of sepsis. case year old man was chronic hemodialsysis patient admitted to the er because of abdominal pain persisting for h. with an initial diagnosis of acute abdomen a median incision was performed. peropertively widespread peritoneal adherences and isolated cecum necrosis were seen. cecum was resected and side to end ileocolostomy was performed.he died days after his first operation. case year old man was chronic hemodialysis patient admitted to the er with pain localizing to right inferior abdomen. with an initial diagnosis of acute appendicitis laporotomy through a mc burney incision was performed. there was · cm cecum necrosis. cecum resection and end colostomy and ileostomy was performed. the patient was discharged days after the operation without any problem. discussion: ischemic necrosis of cecum is a rare variant of ischemic colitis. in hemodialysis patients requiring colon resection due to ischemic colitis, primary anastamosis should be avoided, diversion stomies should be preferred. agitation is a non-specific constellation of comparatively unrelated behaviours that possess a risk to the safety of the patient or caregiver, impedes the process of care giving or impairs a person's function. the management of agitated trauma patient contains hospital, prehospital, in emergency department and inside of the hospital transports. the reasons of the agitation hypoxia, hypoglycemia, hypovolemia, pain, traumatic brain injury, anxiety disorder, drug and alcohol abuse, psychiatric disorders. pain management has had a limited role in the management of trauma patients, primarily because of the concern that side effects (decreased ventilatory drive and vasodilatation) of narcotics may aggravate preexisting hypoxia and hypotension. health professionals should monitor pulse oxymetry and serial vital signs if any narcotics are administered to a trauma patient. small doses of benzodiazapine sedatives should be titrated cautiously because of the potential side effects of hypotension and ventilatory depression. to control agitated patients with traumatic brain injury include haloperidol, midazolam, and propofol. in the emergency setting, they are most often indicated to control agitated or psychotic behavior that constitutes an imminent danger to the patient or others. to control agitated patients should be a part of the trauma management. we present a protocol for trauma team. there were males ( . %) and females ( . ). eighty percent of the patients were between and years of age. the overall mortality was . % ( patients). eighty percent of deaths occured in comatose patients (p < . ). comatose state, precence of focal motor signs, respiratory irregularities and hypertansion-bradycardia, pupillary changes were determined as the bad prognostic factors. a midline shift greater than mm, hematoma volume greater than ml, accompanying intracerebral and extracranial traumatic pathologies significantly increased the mortality rate. there was no significant statistical correlation between the outcome and the age, sex of the patient, trauma-to-operation interval, thickness, localization and origin of edh and aetiology. results: the primary factor on outcome is glasgow coma scale scores of the patients at the time of surgery. therefore early surgery is crucial in the management of edh which is a dynamic process. introduction: in this study, we have evaluated the incidence and clinical characteristics of the patients for traumatic brain injury (tbi)-associated coagulopathy after tbi retrospectively. methods: retrospective study of all patients admitted to the trauma and emergency surgery intensive care unit (icu) from january through december with tbi. criteria for tbi-coagulopathy (tbi-c) included a clinical condition consistent with coagulopathy in conjunction with a platelet count < , mm and/or international normalized ratio (inr) > . and/or activated partial thromboplastin time (aptt) > s and/or prothrombin time (pt) > . s. the following potential risk factors were included to identify independent risk factors for tbi-c and its association with mortality, age, mechanism of injury (blunt (b) or penetrating (p)), glasgow coma scale (gcs), injury severity scale (iss), presence of polytrauma, icu length of stay (icu-los). results: a total of patients met study criteria. tbi-c occured in . % (n: ) of all patients (b: . %, p: . %). in patients with tbi-c, mean age was . ± . years. the averages of gcs was . ± . , iss was . ± . , icu-los was . ± . days, polytrauma was considered . % (n: ) and the overall mortality was . %(n: ) in patients with tbi-c. conclusions: in our study, tbi-c occured more frequently among patients sustaining blunt versus penetrating injuries. to our knowledge, tbi patients are at considerable risk of developing coagulopathy and anesthesiologists should be aware of this life-threatening syndrome, especially in tbi patients with blunt injuries. erythropoietin (epo), glycoprotein hormone, is a mainly produced by the kidney that stimulates proliferation, growth and differentiation of erythroid precursors in the bone marrow. recently, anti-inflammatory, neuroprotective, antiapopitotic, angiogenic and vasodilatator effects of epo have been also determinated. the purpose of this study was to investigate the effects of rhuepo in reducing the severity of experimental spinal cord injury (sci). ninety adult sprague-dowley rats weighted g (± ) were used for the study. through a dorsal incision, t - laminectomies performed in prone position and clip compression had made for ischemic injury as tator method. the rats divided in three groups. systemic l ( , u/kg) rhuepo had given h before the trauma in the first group, min. later after the injury in the second group and the third was the control group. the rats were killed with high dose intraperitoneal ketamin h later after the injury. the histological examination of injured spinal cord specimens for the potential neuroprotective effects of rhuepo was done. further more the axial spine sections stained with ttc (triphenyl tetrazolium chloride). the ischemic areas were evaluated with a imaging calculation program. we use wet-dry method for determination of ischemic tissue edema. we concluded that administrating a single dose rhuepo ( , u/ kg) has potential neuroprotective effect on experimental spine injury by reducing severity of inflammation and tissue edema in the secondary ischemic area. it has known both early surgery and high dose steroid treatment prevents the neurological function and viability caused of the traumatic secondary spine injury. we present surgically treated a traumatic rotation-compression spinal cord injury caused by a motor vehicle accident. the patient referred to our clinic h after the injury. at the time of admission, he had a localized pain at the thoracic - vertebrae level, loss motor and sensorial function under the level t classified as asia grade a. he was incontinent. in the radiological evaluation we found loss of height at the thoracic th and th vertebrae body, serious spinal column injury include t - burst fracture, laminas and facet joints fractures with three colon damage (denis f). we detected the spinal instability criteria in . we did not see penetrating injury or primary spinal cord injury signs but spinal canal tightness for percent in ct and mri scans. we took the patient to surgery in unusual classical surgery timing. first, decompressing surgery applied to the t - laminas and posterior stabilization with transpedicular screw-rot system. one day after the first operation, t and t corpectomy applied for anterior stabilization with cage-screw system. mega dose steroid had given also before the first surgery. postoperatively early neurological evaluation, he had asia grade c, after second month asia grade d without incontinence. in our opinion the decompressing surgery that applied in h in the patients without complete primary spine injury, has a positive neurological feedback. introduction: it is a rare occurrence with the rate of % in the subjects with spinal infestation cyst hydatic echinococcus granulosus. intradural hydatic cyst is relatively rare when compared with other spinal hydatic cysts. we are presenting here a -year-old female case who applied to emergency service with backache and paralysed legs and was diagnosed with spinal intradural extramedullary hydatic cyst. case: a -year-old female patient applied to emergency service with complaints of a backache started two days ago, paralyses in both legs and being unable to walk. in her neurological examination, a complete motor power loss in the lower extremities and bilateral sensation loss compatible with t dermatoma were detected. in the torako-lomber spinal magnetic resonance imaging (mri), multiple cystic characterized nodular lesions having peripheral contrast with regular contour including right neural foramen and paravertebral zone at the level of t -t and l in the intradural distance were determined. the patient was diagnosed with common spinal intradural extramedullary hydatic cyst exhibiting bone involvement. as the lesion was very broad had paraplegia, we did not consider operation. conclusions: hydatic cyst infestation is a benign disease. if it is not diagnosed early and treated when it involves in some systems rarely as it did in this study, the results can be serious. diagnosis should be confirmed quickly with increasingly common advanced radiological diagnosis methods. the aim in these cases is to eradicate the cysts surgically, however, chemo-therapy and percutaneous drain methods have become more significant recently. introductıon: several guidelines advocate multiple chest radiographs during primary resuscitation of trauma patients. several local hospital protocols include a repeat radiograph before leaving the trauma resuscitation room (tr). the purpose of this study was to determine the value of routine repeat radiograph. methods: one year data of all radiological imaging in our tr were prospectively collected for all patients presented to the tr of the hospital. we counted and assessed the radiographs and classified our findings as either 'new injury detected', 'presence of intervention equipment', or 'deterioration of previously detected injury'. results: in total, patients were included. more than % had two radiographs. eight ( . %) new injuries without clinical relevance were found on the repeat radiograph after an initial normal radiograph. in total patients ( %), had a repeat radiograph to verify the effect of an intervention or position of equipment. in patients ( %) with two abnormal radiographs, newly diagnosed injuries (n = ) or deterioration of known injuries (n = ) were found. in patients ( %) the results of the repeat radiograph had no clinical consequences. conclusıon: our study supports a strategy of omitting a routine repeat radiograph in trauma patients whose initial radiograph is normal. introduction and objective: the neck region is affected in only about - % of all trauma cases, and isolated neck injuries, especially from a blunt mechanism, is even more rare. our objective was to assess the incidence, disability from spinal cord injuries, and preventable deaths in our patients with isolated neck trauma. material and methods: patients were identified at the severe trauma registry of our hospital, between and . the triss method was used to assess preventable deaths. results: we found ( . %) patients with neck injuries out of . patients included in our registry, ( %) from blunt (bnt) and ( %) from penetrating trauma (pnt). only ( %) bnt and ( %) pnt were isolated. the mean iss of the bnt and pnt groups was of ± and ± . , respectively. in the bnt group, ( %) patients had spinal fractures (with spinal cord injuries with permanent disability), had airway injuries and a vascular injury. in the pnt group, patient had a spinal fracture, had vascular injuries and airway injuries. overall mortality was of ( %) patients, in each group, and only one of them was deemed preventable. conclusions: isolated neck trauma is a rare cause of disability and preventable death in our area. most penetrating injuries have a lowto-moderate degree of anatomic severity (ais £ ). for each group. however about applications increased gradually with a peak at o'clock in all groups. patients treated at ed were mostly stricken ( . %) and the busy period was between - h with two peaks at and o'clock. totally, patients were hospitalized mostly in group iii ( . %) regardless of cause (p < . ). patients referred to another hospital were frequently in group iii ( . %) and also in group iv ( . %). mortality was slightly high in group iii. however higher rate ( . %) was seen among patients in group ii. conclusion: midnight hours seemed safe in terms of mortality and severity of trauma. whether the reason for a higher transportation rate at night hours is the severity of trauma or sedation of ed staff is not clear. introductıon: in this study we aimed to investigate and compare the features of child and adult injuries due to bicycle accidents admitted to our emergency department. patients and methods: the study was carried out retrospectively by searching the files of patients admitted to the emergency department due to bicycle accidents, in the emergency department and archive records between the dates of january and december . the patients were divided into two groups as adults and children. age and sex of patients, season or month of injuries, place and mechanism of injury, injury site of the body, diagnosis and treatment modalities, discharge and hospitalization rates were evaluated. results: totally patients were included in the study. % of the patients were in child age group, % were adults. it was determined that number of accidents increased especially in the summer months. . % of accidents concerning children and all of adult accidents occurred in the streets. falling down from the bicycle was the most common injury mechanism in children ( %) and adults ( %). head and neck region was the most common body site subjected to the injury both in children ( %) and adults ( %). % of child patients and % of adult patients were discharged after emergency department follow up and treatment. there was a significant difference between two groups with respect to injury severity. conclusıon: as a conclusion most of the injuries due to bicycle accidents happen in children, in the streets, in summer months and school vacations. conclusıons: road traffic collision is a major cause of trauma and death in al-ain city. seatbelt compliance is alarmingly low and should be enforced. introduction and objectives: the controversy between the ''scoop and run'' versus the ''stay and play'' approach in severely injured trauma patients has been an ongoing issue for decades. the present study was undertaken to investigate whether changes in prehospital care for patients with severe traumatic brain injury in the netherlands, have improved outcome. methods: in this retrospective study, files were analysed for all patients admitted to one of six hospitals in the limburg region in the netherlands with a gcs < on admittance over the period january -december . all patients had proven traumatic brain damage on ct or mri. relevant prehospital and clinical data from a similar study conducted years ago were compared to data from the present cohort. the main outcome was mortality. results: the two research groups had similar characteristics. in the historic cohort, basic life support (bls) and the 'scoop and run' method in patients with major traumatic brain injury (tbi) was common, with an average time on scene of . min. nowadays, prehospital care is performed mainly on the level of prehospital advanced life support (als), with average time on scene about four times as long as in the historic cohort. however, the overall mortality rate for the current cohort compared to years ago has not decreased. conclusion: despite more on-site als in major tbi nowadays, there was no reduction in mortality. the team is provided to be ready all the time by making monthly and yearly national education exercises. these exercises are planned with two methods: ( ) as demonstration during education ( ) by creating extraordinary condition simulations aim: _ interpret the support of exercises plans on umke operational agility and to accomplish next plans through this way. material -method: umke teams are divided into two parts after geting their basic educations. first group is planned to exercise in education room with demonstrations. the second is planned to exercise the extraordinary situation simulations in which people(not from the groups) made up and acted as injured and moulage is also used in this group. after the exercises, results are compared according to the criteria for assessment. in the first group's demonstrations it is worked by giving roles to team members in the education atmosphere with existing equipments (chair, table, ladder…). in the second group, worked with the moulaged volunteers and extraordinary situation simulations just like the real(wreck, avalanche, fire…) the results are considered statistically by t test. findings: according to the assessment criterias the first group's average point is . and the second is found as . . (p < . ). discussion and result: exercises in a form of extraordinary situations effected team's performance, operational success and involvement positively. planning the exercises with this data will increase the quality of the educations which planned in the future. nurhan babaoglu, tayfun cucioglu, gö khan akbulut national medical rescue team, ministery of health, afyonkarahisar, turkey entry: umke designed as serving medical rescue in extraordinary circumstances. they carries their approaching skills to the top by managing regional and national exercises. the teams in different cities coordinate and share their knowledge and agility by this exercises. aim: after the workshop oriented educations, criteria are needed to improve and decide the affect of the exercises as numerical which supplies standardization of the teams. material-method: teams are evaluated according to criteria and graded from to . after the exercises, results and the importance of criteria shared with teams. month later same teams evaluated again in exercises. criteria: ( ) equipment ( ) team accordance and work discipline ( ) security and to define work risks ( ) approach to the injured ( ) evaluate the injured people ( ) convert the theory to practise ( ) usage of materials correctly and in proper place ( ) packaging ( ) taking out the injured safely ( ) cleanness of the materials and control of medical bag findings: after antalya umke basic education, team's evaluated and average score was . . this results shared with teams and in next exercises in isparta mean score founded as . . (p < . ) discussion and result: when the evaluation criteria and results shared with the teams, it is confirmed that the teams react better in ongoing situations. it is considered that it will also increase the quality and effectiveness of the education. the criteria for evaluation going to help standardization which can be used by all medical rescue teams will provide a common manner between the groups. hasan Ç elik, gö khan akbulut, nurhan babaoglu, tayfun cucioglu national medical rescue team, ministry of health, afyonkarahisar, turkey umke teams are established in in cities in order to act in disasters and extraordinary circumstances as a medical rescue team. members are chosen among the volunteered medical crew. the team's mission is to support the search and rescue teams medically in extraordinary circumstances. team starts with the first intervention and maintain the stabilization of the injured person before the transport so that prevents the second insult. working principles was not obvious during the establishment phase and this caused chaos at the beginning. by designating the teams responsibilities work distribution reached to the standard. national medical rescue team is consisting of medical personnel who are named as leader, logistic, pigeon, squirrel and courier. the team leader who is chosen from doctors who has experienced in disaster medicine and have knowledge about leadership, provides a common manner and motivation among the team. also directs the intervention to the injured person and coordinates with search and rescue teams just after the fast arrive in extraordinary circumstances. squirrel communicates with injured at first and starts his intervention with the direction of the leader. logistic is responsible for all equipment (spin board, medical bags…). courier provides the equipment transportation between logistic and squirrel. pigeon is responsible for photographing, recording and communicating with the center. this organization type performed in regional and national practises from to and also in train accident in kü tahya. _ it helped maintaining standardization and acquired successful results. author to editor: bu yazıyı ulusal medikal kurtarma ekiplerini (umke) tanıtmak amacıyla hazırladık. eg er uygun gö rü rseniz, umke yi tanıtıcı bir stand açıp medikal çantamızı ve dig er kullandıg ımız malzemeleri tanıtabiliriz. ayrıca bu gü ne kadar katıldıg ımız (pakistan depremi, isparta uçak kazası, kü tahya tren kazası) afet, tatbikat ve eg itimlerimizi(ameliyathane konteynırımızı) power point olarak sunabiliriz. helicopter use as a part of trauma care introductıon: rapid transport and persistence of prehospital care is crucial to decrease the mortalities and morbidities of combat related injuries. hence, helicopters are effectively used by the military although they are austere environments that offer limited space, equipment and resources for the crew and requires higher level of skills for prehospital trauma care. materıal-method: the data were collected from consequent casualties, by the helicopter medical team (a surgeon, anesthesiology technician and a paramedic). during the flight, we triaged the casualties according to wound characteristics (severity, mechanism, location), physiological parameters, and provided basic life support stated by trauma resuscitation course (trk). we transmitted these findings to the military trauma center to provide hospital preparedness. result: injury mechanisms were % explosives and % highvelocity weapons. time to hospital admittance was < min after the injury. most frequent sites of injury (ais - ) were extremities ( %) and thorax ( . %); the frequency of ‡ anatomical site injury was %. capillary refill rates were; < seconds . %, > seconds . %. mean sao , gcs, hr, respiratory rate values were . ± . , . ± . , . ± . , . ± . , respectively. during uninterrupted care, ( %) intubations were performed and % of casualties were operated upon admittance without any onboard mortalities. conclusion: the high energy and lethality of the wounding agents in combat render the helicopter evacuations indispensible. additionally, civilian major trauma patients may benefit from expeditious transport to the closest trauma centers or from rural inaccessible areas within the 'golden hour of trauma'. the most important steps for the treatment of the combat injury causalities are to stop or reduce bleeding and to start fluid resuscitation. peripheral intravenous (iv) line placement is one of the most important procedure in the battlefield conditions. most of the time, fluid resuscitation would be the only available medical treatment for the injured combatant because of the prolonged evacuation period in the battlefield. also, this procedure would be very difficult and time consuming especially under hostile gunfire. excessive blood loss and hypotension may cause the peripheral venous collapse and makes the procedure more difficult. here we described a simple method to make this procedure easier. we offer the forward medical team personal to perform the upper extremity peripheral venous mapping of the combatant before the operation. the medical providers (doctor or paramedic) who would perform the first medical intervention would examine the upper extremities of baddy just before the operation. the medical care provider should determine the suitable situations for the iv line placement. then he should remark the both site of the appropriate vein by camouflage paintings, leaving the probable angiocath insertion sites non-painted. we believe that this method would make the peripheral iv line placement easier and faster for the forward medical team personal in the war conditions. one probable disadvantages of this method is the negative psychological effect on the combatant that makes them to estimate the risk of wounded in a few hours. introduction and objectives: ambulance and emergency care technicians are the key personnel for pre-hospital care of trauma. this study reviews the work anxiety states of some of the students in ambulance and emergency care technicians department, vocational school of health services, marmara university by comparing it with those of the students in radiology department of the same school. methods: this study was developed as a sectional type of study and was conducted on volunteer students from the above mentioned departments. the data were analyzed using the spss . software and employing the frequency distribution, t-test for individual groups, and unidirectional variance analysis methods. results: the study group of subjects was . % female and . % male. . % of the subjects expressed anxiety over their employment in the future; . % of them expressed no work anxiety. the work anxiety points of the subjects were compared in terms of their genders, academic years and departments, and said comparison did not reveal any statistically significant difference (p > . ). conclusions: the work anxiety state is one of the major factors having an impact on professional success, and is a negative state having an impact on one's performance, success and, in turn, psychological state. it would be proper to study the issue of work anxiety by obtaining psychological support, and to cooperate with the actors in this sector to develop solutions. it is concluded that further studies should be conducted on work anxiety and its reasons. in general, emergency patients should be transported to the closest appropriate hospital. if the emergency medical services have identified a specific hospital with better resources to treat seriously injured patients, the patient should be transported to that institution, bypassing closer hospitals. the cooperation is expected between the hospitals, and the development of formal transfer agreements, describing all of the legal, economic, and medical aspects of the relationship are encouraged. ideally, the entire trauma system in a city should be designed on the basis of need and existing resources, with all affected parties involved in the planning, development, and implementation. the goal of the system is to match the needs of an injured patient to the resources of the available facilities so that optimal and cost-effective care is achieved. we conduct six essential questions for the preparation of trauma. is there a legal authority to formally designate hospital's trauma response in your city? what sources were used as a basis for standards of the trauma response in your service area? were the number of hospitals identified for your service area limited based on the results of needs assessment? what type of transport practice occurs in your service area when a field assessment identifies a trauma patient with severe injuries that threaten loss of life or limb? is a trauma registry present in your service area? is there a designated trauma advisory committee that evaluates the performance of trauma care delivery within your service area? we evaluated the role of primary hip arthroplasty (consisting of both total hip replacements and hemiarthroplasty) in these comminuted, osteoporotic or neglected fractures. these patients at-risk were in need of a single definitive surgical plan for early ambulation and preventing complications. typically these patients were elderly with poor mobility and had multiple other medical condition to be able to withstand multiple surgeries. there was a need to obtain the best results with the single, rapid procedure for pain relief and early ambulation. excellent to very good results were obtained in about % of these patients. good results were obtained in about % of these patients and poor results in about %. most of the poor results were the outcomes of complicated medical conditions rather than the failure of the orthopaedic procedure itself. we advocate arthroplasty in neglected, osteoporotic or severely comminuted per-trochanteric fractures for immediate mobilization and optimising outcomes. the role of intra-articular steroids or hyaluronic acid injections in early arthritis may be warranted and perhaps safe. but for patients waiting for a knee replacement these can prove positively dangerous. a meta-analysis has revealed that intra-articular injections given in patients waiting for a knee replacement procedure is fraught with dangers. apart from a high risk of post-operative infection and failure of the procedure, several other side-effects or complications make this risky. there is a higher-than-average chance of quadriceps tendon rupture, delayed wound healing, superficial infections and slower rehabilitation. in comparison hyaluronic injections have been found efficacious in the short term and do not contribute to complications normally attributed to steroids. thus intra-articular injections should be used with caution, repeated injections are best avoided and are certainly contraindicated if a procedure is anticipated to be performed within six months. introduction: pediatric forearm fractures are common. the majority has satisfactory outcome. but poor results do occur and malunion can compromise rotation. we belief that the angulation of the fracture depends on the action of the body and that we can reduce the fracture by completing the action. this way we can perceive a stable anatomic reduction without internal fixation. methods: we undertook a prospective study of distal forearm fractures in children. we included children with a non-displaced angulated metaphyseal distal forearm fracture. the angulation was between °and °.we all reduced them by completing the action of the body. this means a volar angulated fracture is reduced by pronation of the hand and a dorsal angulated fracture is reduced by supination. after the reduction they were casted in an upper-arm cast in pronation or supination depending of the reduction manoeuvre. afterwards the all received weeks of upper-arm cast and weeks of lower-arm cast. results: they all healed without loss of reduction and without further treatment. they all had full recovery of function. conclusıon: non-displaced angulated metaphyseal distal forearm fractures in children can be treated conservatively by closed reduction and plaster cast. background: vascular endothelial growth factor (vegf) plays an important role in the bone repair process as a potent mediator of angiogenesis and influences directly the osteoblast differentiation. inhibiting vegf suppresses angiogenesis and callus mineralization in animals. however, no data exist on systemic expression of vegf with regard to delayed or failed fracture healing in humans so far. methods: one hundred fourteen patients with long bone fractures were included into the study. serum samples were collected over a period of months following a standardized time schedule. vegf serum concentrations were measured. patients were assigned to groups according to their course of fracture healing. the first group contained patients with physiological fracture healing. eleven patients with delayed-or non-unions formed the second group of the study. in addition, healthy volunteers served as controls. results: an increase of vegf serum concentration within the first weeks after fracture in both groups with a following decrease within months after trauma was observed. serum vegf concentrations in patients with impaired fracture healing were higher compared to the patients with physiological healing during the entire observation period. however, statistically significant differences were not observed at any time point between both groups. vegf concentrations in both groups were significantly higher than those in controls. conclusıon: the present results show significantly elevated serum concentrations of vegf in patients after fracture of long bones especially at the initial healing phase indicating the importance of vegf in the process of fracture healing in humans. first, dsbls is applied to . cm proximal to most prominent point of medial malleol of tibia. the dsbls was inserted parallel to the joint surface in frontal and horizontal plane. after the dsbls is applied the selected nail is inserted. reamed imn is used for the tibias with narrow isthmus ( ). the success of di is checked following the insertion of nail with set screw on the dslbs. the unsuccessful attempts are repeated after the reason is removed. the di of tibias were successful and were unsuccessful at the first attempt. in unsuccessful cases, the nails were at the posterior ( ), anterior ( ) and lateral ( ) collum femoris fractures accounts . - % of all fractures. however it is very rare in children ( %). in this study we evaluated pediatric patients who were operated due to collum femoris fracture in terms of avascular necrosis and functional outcome. age of the patients ranged from to . there were seven girls and five boys. two of the patients were admitted to the emergency department due to a fall from height, therefore they had multi system trauma. the remaining ten patients had isolated collum femoris fracture. fractures was classified according to delbet classificaion; seven transcervical and five cervicothrochanteric. locking plate-screw fixation was applied to one patient, other fractures were fixed with two or three cannulated screws. open reduction was applied to four patients and closed reduction to eight. five of the cases were operated in the first h of the fracture, however the remaining seven patients were operated after the first h ( - days) due to late admission. range of motion of the hip joint was limited in only one patient who had polytrauma and operated after the first h. there were three avascular necrosis as acomplication. all of them operated after the first h and all the fracture types were cervicotrochanteric. open reduction was applied to two patients and closed reduction to one. pediatric collum femoris fractures are rarely seen in children but treatment is challenging and open to complications. fracture type, surgical methods, did not effect the outcome, but timing of surgery did. author to editor: in this study we discussed the outcome of pediatric collum femoris fractures, which is a very rare fracture in orthopaedic experience. surgical management of humerus shaft fractures is an increasing interest nowadays. we want to discuss the outcome of conservative, open reduction and internal plate fixation (or _ if) and intramedullary nailing (imn) methods in adults ( - years old). patients had conservative treatment with modified custom made sarmiento brace and of them had union with °- °of malunion. none of the nine have complains and the avarage union duration is weeks ( - ). one patients did not tolerate bracing and undergone surgery. patients had or _ if and had gone second operation for nonunion and had elonged wound drainage. all the fractures healed eventually with in weeks ( - ). no neurovascular complication was observed. patients had imn treatment and had delayed union up to months, had undergone reoperation with or _ if for non-union, had intraoperative fracture of elbow and had shoulder problems with impingement and rotatory cuff problems. avarage union duration was found weeks ( - ). surgical treatment is getting more popular for long bones nowadays. early return of work and social life, anatomic reduction, using no sling or such devices and easy follow up protocols are the facts that popularising the surgical management. but in our series, we had seen multiple types complications that are as high as they are mentioned in literature. with the experience of those patients that had been treated with in this year, conservative treatment methods have to be conserned firstly in suitable and tolerable patients for us. intoduction and objectives: correction of sagittal deformity is important in thoracolumbar burst fractures. the clinical maneuvers needed for reduction and the assessment of correction of the fractured vertebra is not well described. in this prospective series we used the length of the interspinous ligaments as reduction parameter. our aim was to evaluate the efficacy of this assessment technique in achieving good correction. methods: from to patients (m/f / , mean age . ) with unstable thoracolumbar burst fractures were treated by posterior fusion with a standard construct by a single surgeon. all patients were treated with segmental posterior instrumentation with two levels above and two levels below the fracture level fixation by means of pre-contoured rods and distraction technique. with these maneuvers the length of the injured level was tried to be equalized to the mean of upper and lower levels. anterior column was assessed by radioscopy. preoperative and postoperative radiographs were analyzed and local kyphosis (lk), farcy's sagittal index (fsi) and compression percentage (cp) were measured. results: the preoperative lk decreased from . °to . °, fsi decreased from . °to . °and cp decreased from to . . after a minimum follow-up time of years all patients continue to do well with no statistically significant decrease in these parameters. conclusions: assessment of thoracolumbar burst fracture reduction with pre-contoured rods and distraction technique can be made safely by intraoperative measurement of the length of the interspinous ligaments. case: an -year old lady was admitted in our emergency department with a neer -part fracture of the right proximal humerus caused by a fall. she was operated on and received a shoulder hemiarthroplasty. during cementation of the stem the patient became bradycard and acute respiratory arrest occurred. she was resuscitated, but eventually died h postoperatively. postmortem examination revealed embolic bone marrow occluding the pulmonary capillaries. comment: pulmonary embolus after upper extremity surgery is a rare complication. fatal pulmonary embolus is even more rare. when reviewing literature there is no previous case of fatal pulmonary embolus caused by fat emboli described. fat embolism syndrome was first described by zenker in , but its frequency today is still unclear. usually it presents as a multisystem disorder. the most often and most seriously affected organs are the lung, brain, cardiovascular system and skin. it is a self-limiting disease, therefore treatment should be mainly supportive. purpose: lack of knee flexion is a possible complication in severe femur fractures. two different techniques for the treatment of this problem were applied. materıals-methods: from to , patients with severely arthrofibrotic knees were managed with two different operative techniques. the mean age of the patients at the time of the operation was years. we recorded the clinical outcome of patient using judet quadricepsplasty with a follow-up of months, and of two patients using extra-articular mini-invasive quadricepsplasty and intra-articular arthroscopic lysis of adhesions during the same anesthesia session with a mean follow-up of months. all patients were evaluated according to the criteria of judet and the hospital for special surgery knee-rating system. results: the average maximum degree of flexion increased from °p reoperatively to °at the time of the most recent follow-up. according to the criteria of judet, the result was good for knees, and fair for one. the average hospital for special surgery knee score improved from points preoperatively to points at the time of the most recent follow-up. a superficial wound infection occured in one patient. conclusions: if you select the appropriate cases, the judet procedure and mini-invasive operation for the severely arthrofibrotic knee can be used to increase the range of motion and enhance functional outcome. purpose: floating knee and elbow injuries are complex injuries. the types of fractures, soft tissue and associated injuries make this a challenging problem to manage. we present the outcome of these injuries after surgical management. materials and methods: two patients with floating knee injuries(classified by blake and mcbryde) and one patient with floating elbow injuries were managed over an average of months. both fractures of the floating knee injury and the three fractures of the elbow injury were surgically fixed using different modalities. the associated injuries were managed appropriately. assessment of the end result used the karlströ m criteria after bony union. results: mechanism of injury was road traffic accidents in two patients (floating knee) and falling from height for one patient (floating elbow). there were associated injuries, patient was tipiia, patient was tipiib. both these patients had intramedullary nailing for femur fractures. patient had ilizarov external fixation for segmenter tibia fractures, patient had a proximal medial plate for proximal tibia fracture. patient had plates afıxed to all fractures.complications were knee stiffness and delayed union of femur in a patient (second operation required). the bony union time average from weeks for femur fractures, weeks for tibia, weeks for upper extremities. according to the karlstom criteria the end results was acceptable. the average elbow score was / (good). patients with tibial bio-screw fixation there is insufficient evidence from randomized trials to determine the optimal intervention in patients with displaced four-part fractures of the proximal humerus: head preserving surgery with problem to obtain and maintain reduction until bone healing, implant failure, avn of the head, ha with > % tuberosities related complications-resorption, displacement, rsa with high complication rate, moderate function due to restricted rotation and insufficient long-time follow-up. in our presentation we will discuss: • new rsa designs, which improve function and lessen complication rates • question of tuberosities fixation to rsa in proximal humeral fractures • literature overlook of rsa in proximal humeral fractures the goal of rsa is to minimize shoulder immobilization and to start functional rehabilitation immediately. indications are same as for ha + tuberosity osteoporosis and comminution + week or absent rc. decision for if, ha or rsa is often intraoperative. tuberosities fixation is debatable (prolonged immobilization, prosthesis dislocation). functional results are more consistent than in ha, but complication rate is higher (it may be lowered by new prosthesis designs). frequent ct scanning due to incomplete -view x-ray imaging of the cervical spine background: conventional c-spine imaging is still widely used, despite increasing replacement by ct scanning. the aim of this study was to analyze the frequency of incomplete c-spine x-rays ( -view series) in blunt trauma patients. methods: during a -year period we analyzed the frequency and value of -view series of the c-spine. secondary we assessed the reasons for subsequent ct scanning after the -view series according to the following classification: inevaluability, incomplete -view series, evaluation of findings on -view series or for unexplained, persistent clinical symptoms. furthermore we evaluated predictors for incompleteness. results: c-spine injuries were diagnosed in blunt trauma patients ( . %). patients ( %) had their c-spine cleared based on the nexus criteria. patients were primarily evaluated with view series and patients primarily with ct scanning. within the population with primarily -view series ( %) were repeatedly incomplete and ( %) were inevaluable. in the major part of the incomplete -view series no apparent reason could be determined. however, the presence of clavicular fractures (resulting in incomplete radiographs in vs. % without a fracture; p < . ) and rib fractures ( vs. %; p = . ) were associated with incomplete -view series. conclusion: in more than a third of the patients primarily assessed with -view series, the results are incomplete or inevaluable necessitating ct scanning. therefore, the diagnostic value of -view series is questionable. in patients with clavicular and rib fractures -view series can be omitted and primary ct scanning is advised. the treatment of open distal tibia fractures is still discussed controversially and they are a great challenge for surgeons. it is still not clear if there should be initial stabilization with an external fixator or primary osteosynthesis with an intramedullary nail or plate. we retrospectively examined patients with ii°and iiia°open distal tibia fractures which were treated during the last years in our level one trauma center. we treated male and female patients with an average age of years. ten patients were treated with an external fixator and patients were treated with an intramedullary nail or plate osteosynthesis in acute surgery. the patients, firstly treated with an external fixator, were stabilized with reamed intramedullary nailing in eight cases and with locked plating in two cases after wound closure. there was no difference in the duration until bony union in any groups. fewer unplaned revisions (n = ) and no deep osseous infections were found in those patients treated with an external fixator in the acute phase of the injury. patients treated with a definitive osteosynthesis underwent unplaned revisions in six cases and developed deep osseous wound infections in four cases. we therefore recommend that initial treatment with an external fixator should be preferred and after consolidation of the soft tissue, the definitive stabilization should be done with a stabile osteosynthesis system. author to editor: this topic remains of a high interest among trauma surgeons, especially now, that angle stable intramedullary fixation systems run the market. fractures of the clavicle shaft are common and have been typically addressed to nonoperative treatment. but favorable results with the precontured anatomic plates are facilitating surgeons for primary surgical treatment. this study reports the surgical results of adult clavicle shaft fractured patients (age range - ) that had been operated with in last months. all fractures were displaced and none of them was open nor had neurovascular injury. avarege healing time was found weeks ( - weeks). all patients had anatomic reduction postoperatively. of the patients fracture site was grafted with dbm. of patients had sterile wound drainage which was lasted for weeks postoperatively (all were grafted with dbm), of them re-operated ( of them for early implant failure and early implant removal for plate disturbance) and one patient was operated for times ( of them was in another center) for early implant failure, nonunion,wound problems and neurovascular complications. of was healed eventually. of patients were satisfied with the treatment and had a full range of motion at final follow-up and were able to return to pre-injury occupational and activity levels. nonoperative treatment of displaced shaft fractures may be associated with a higher rate of nonunion and functional deficits. however, our study shows that surgical treatment also has high complication rates. there is currently considerable debate about the benefits of primary operative treatment of these injuries because it remains difficult to predict which patients will have these complications. platelet rich plasma (prp) is applied in orthopaedic, maxillofacial and plastic surgery with variable outcome. different growth factors and cytokines are stored in platelets, including platelet derived growth factor (pdgf), contributing to the potential positive effects of prp. the aim of our study was to investigate the properties of pdgf administered locally in a rat femoral non-union model. in our experiment a critical sized osteotomy was performed in the rat femur, which was filled with a spacer, inhibiting bone formation for a period of weeks. in a second operation this spacer was removed and the test item was applied into the defect. we compared the pdgf group (d = ng, c = lg/ml of pdgf in fibrin matrix) with the fibrin alone and blank control groups. four weeks after the second operation, specimens were analysed by x-ray, lct imaging and histology. in group pdgf we found a lct confirmed union in of specimens and the lct evaluated bone volume was median . mm (q = . / q = . ). in the control groups there was a bony bridge in of fibrin and in of blank specimens. the bone volumes were median . mm (q = . /q = . ) fibrin and median . mm (q = . /q = . ) blank, respectively. we did not find a strong tendency for new bone formation in the group treated with pdgf. in our model we observed even a tendency to inhibit bone regeneration for pdgf. introduction and objectıves: hand traumas are one of the most common encountered complex traumas. closing the defects on either dorsal or palmar side of the hand is sometime difficult because of limited local tissue and to provide a tissue the tendon glides underneath. in spite of high risk of donor side morbidity and sacrificing a major artery of the hand, radial forearm flap is the most frequent choice to close the defects at this region. method: in a year time, five patients with severe hand traumas who admitted to our clinic, treated with perforator based three radial artery and two ulnar artery adipose-fascial forearm flaps. the adipose-fascial island flap was raised on one or two of these perforators without sacrificing a major vessel.the flap was transposed to defect region and covered with stsg. in all five patients' donor side was closed primarily. results: the biggest flap size was · cm. there was no flap loss except one patient who had partial flap necrosis and it healed secondarily. the donor side was healed uneventfully in all the patients. there was no tendon adhesion. conclusıon: perforator based radial or ulnar artery adipose-fascial flap is a safe and reliable method for closing defects on the hand. it has both less donor side deformity and fascial component of the flap provides better tendon gliding and less tendon adhesion. however, it requires more experience to raise adipose-fascial flap. introduction and objectıves: one of the most common causes of the lower extremity defect in adult is a road traffic accident. the most challenging issues is to close the defect on the / of lower extremity because local tissue is very limited and mostly damaged due to high energy injury. we investigated the difficulties of how we close the defect on one third of the lower extremity particularly in children, in our unit. method: in a year time, patients under years old admitted to our unit. all patients had gustillo iiib injury and the biggest size of the defect was · cm. one patient had different lesions on the heel the other was on the anterior aspect of tibia. after radical debridement, the wound closed with alt free flap with in first week of admission. different defects on a lower extremity were closed with alt and vastus lateralis muscle free flap with a single pedicle. result: the biggest flap size was · cm. an average pedicule length was . cm and the diameter of the vessel was . cm the average operation time was h min. one flap had partial necrosis and healed secondarily. they had uneventful recovery and discharged on average postoperative days. conclusıon: in children even less than years age, one of the good and suitable options for closing the defect on the one third of the lower extremity is alt as a free flap. stable odontoid fractures can be treated with external immobilization using, e.g., a philadelphia collar (pc) or a halo thoracic vest (htv). it is important to delineate the capacity of both orthoses, halo and philly, for immobilization of the atlantoaxial complex (aac), e.g., for their use in odontoid fracture care. in this in-vivo biomechanical comparison volunteers (mean age = . ± . ) were subjected to flexion-extension radiographs immobilized in a modified htv and a pc. radiographs were analyzed for the segmental rotation angle of c - in sagittal plane (sra c - ) and the absolute rotation angle of c - (ara c - ). separation angles (rsra c - and rara c - ) were calculated from flexion-extension views. concerning restriction of subaxial sagittal plane motion, the htv was more effective than the pc. the difference for the rara c - between the pc (mean . °) and htv (mean . °) yielded significance (p = . ). but, concerning restriction of flexion-extension at the aac, there was no statistical significant difference for the rsra c - between the pc and htv (p = . ). pc (mean . °) was superior to the htv (mean . °) in restricting sagittal motion at c - . in comparison to normals atlantoaxial motion was restricted by . % (pc) and . % (htv). the current study demonstrated that there was no significant difference in restriction of sagittal motion at c - between the pc and htv. in light of the current biomechanical data and a selected review of literature it is concluded that the use of a pc is sufficient for the treatment of stable odontoid fractures. introductıon: although most ankle injuries are associated ligamentous structures, some types of fractures mimic to ligamentous sprain and misdiagnosed as well. most of the ankle sprains undergo radiographic examination and some of type fractures easily are missed even x-ray. the aim of this study is to evaluate the missed talar neck fractures and to emphasize the missed fractures. materıals-methods: misdiagnosed cases were included in the study. average age at the time of trauma was ( - ). all cases evaluated prospectively. if the patients had ankle sprain and their initial x-rays show no evident of fracture, they were involved in the study. the diagnosis of the fracture was figured out by control x-ray, ct scan and mri (except case). all patients were evaluated by the scoring system of american orthopaedic foot and ankle society (aofas introductıon and objectıves: treatment of proximal humeral fractures remains controversial, because of complexity of this kind of fractures. the purpose of this study is to present our first experience using angular stable fixation in and part proximal humeral fractures method: in last mounts we treated patients with this method, men and women (mean age ). anterior approach was performed in every case (mis technique in two cases), and every patients underwent to early rehabilitation. periodical clinical and radiographic control were performed. results: short term results are good with satisfaction of the patient, no pain and acceptable range of motion. we have case of deep infection that need revision surgery and antibiotic treatment. preoperative diagnosis of appendiceal diverticulitis is rare. the incidence of appendiceal diverticulitis ranges from . to . %. % of the diverticulitis of colon cases appear above years of age, and they are mostly in the left colon. case: a year-old male, who had a -year history of episodic right lower quadrant abdominal pain was admitted to the surgical emergency department for worsening of his complaints. the physical examination was only notable for right lower quadrant abdominal tenderness. laboratory findings was normal. on ultrasonography examination signs of acute appendicitis was noted. as the radiological findings did not match with the clinical status of the patient, he was followed up. later, acute abdominal symptoms appeared, and the patient was admitted to the operating theatre. two cm long nodules were seen on the appendix preoperatively. appendectomy was done. the patient was discharged on the first postoperative day. the histopatological examination revealed acute appendicitis signs and two mm long diverticula one of which is inflamed in the middle and the other in the distal part of the specimen were reported. conclusıon: the most common cause of acute appendicitis in adult population is fecaloid. lymphoid hyperplasia, carsinoid tumors, mucosel, parasites, fruit and vegetable seeds are other causes. although appendiceal diverticulitis is rare, clinicians should be aware of its occurrence and tendency for appendiceal perforation. introduction and objective: traumatic intracranial hematoma is the most common complication of the head injury requiring emergency intervention. as most of them are located supratentorially, they can be seen less frequently in the posterior fossa. this study aims to evaluates the clinical, radiological and surgical aspects of traumatic posterior fossa hematomas in patients who were treated at our center. methods: the records of patients with of traumatic posterior fossa hematomas that had been treated at our center between and were reviewed. results: of the cases, had cerebellar hematomas and had epidural hematomas. fall was the most common cause, followed by animal kick, assault and traffic accident. diagnosis and management decisions were determined by cranial computed tomography scans. surgical intervention was performed in cases. the outcome was good in patients. three patients died who had low gcs at admission and additional cranial lesion. conclusions: patients with occipital trauma should be evaluated immediately using cranial computed tomography scans. early diagnosis of traumatic hematomas and prompt surgical intervention in those having mass effect provide good results. introduction: transcranial stab wounds made with a knife mostly produce a classic slot skull fracture and underlying tract hematoma, and often cause severe neurological deficits. an unusual case with combined pareses of oculomotor and trochlear nerves due to penetrating stab wound to the brain is presented. methods: a -year-old boy was admitted to our clinic after an altercation that resulted in the patient sustaining stub wound to his head. results: he was conscious. neuro-ophthalmic examination showed that the left eye had limited adduction, supraduction, and infraduction, incomplete convergence and left sided ptosis with dilated pupil. an emergency computed tomographic scan of his brain was obtained, which revealed a left slot fracture at the squamous portion of the temporal bone of the anterior cranial fossa and a frontotemporal intracerebral stub tract hematoma. he underwent emergent surgery. fractured bone pieces and lacerated brain tissue were removed. neurological deficits remained unchanged at months follow-up. conclusions: cranial nerve injury related to the knife wound to the brain is very rare. the penetration site, depth of penetration and trajectory of the object are important in occurring of this injury. prognosis seems to be poor in these cases. introductıon: large number of knee x-rays are done incidentally for patients presenting with knee trauma in accident and emergency. using only one lateral view knee x-ray as a screening tool would reduce the cost by % as per a. verma et al., an interesting proposition. method: we investigated the validity of lateral view knee x-rays alone as a screening tool for detecting fractures around the knee in acute knee trauma. randomly picked x-rays were reviewed. the ap and lateral views were interpreted by a consultant radiologist and the findings used as gold standard for the study. the lateral views alone were independently interpreted on two different occasions by the (a) radiographer (b) emergency nurse practitioner accident & emergency (c) middle grade doctor accident and emergency (d) consultant orthopaedic surgeon. results: there was significant inter observer variation in sensitivity which ranged from to % with the highest sensitivity being achieved by the radiographer. the specificity was generally high with a range from to %. though there was a high validity in the case of the radiographer the sensitivity for the other observers was low. conclusıon: though there could be a significant saving in terms of resources and unnecessary radiation by doing lateral views alone as opposed to the routine ap & lateral views as first line x-rays, we do not recommend using the lateral views alone as a safe screening tool in knee trauma because of high inter observer variation in sensitivity. tk gullett, charalambous p. charalambous, ajay sahu, matt j. ravenscroft stepping hill hospital, stockport, uk introductıon: in distal biceps tendon ruptures, re-attachment to the radial tuberosity should ensure an adequate tendon to bone surface contact to achieve a sound repair and fast tendon to bone healing. method and technique: we are describing a l-configuration reattachment of distal biceps tendon rupture, using a single anterior transverse incision at the cubital fossa crease. each pair of sutures from the most distal anchor is passed through the distal part of the tendon. one strand of each pair is passed in a zig zag fashion through the tendon whilst the other strand is simply passed straight through the tendon in a posterior to anterior direction. the four strands of the proximal anchor are passed so that they form two mattress sutures through the proximal part of the tendon. tightening is then performed in a specific sequence with initially pulling on strand a and b to bring the tendon down to bone and then tightening these to the corresponding suture strand of their pair. the two pairs of sutures are then tied to each other. this second anchor tightening ensures that the tendon is brought down onto the bone in an l configuration increasing the contact surface area between tendon and bone. results: we have used this technique in patients till now with excellent results and no re-ruptures. discussion: our technique is simple to perform and provides a sound repair with a large surface area of contact between tendon and bone. results: out of a % (n = ) response rate, respondents ( male, female) were included in the study. we excluded people with previous hip, knee or back problems. in our study, the symptom scores that is lysholm, oxford and visual analogue scale for pain and function did not show any significant decline with age. on the other hand, the scores measuring activity levels that is tegner and ucla scales declined significantly with increasing age. our normal scores were far ahead of age-matched post operative scores following total knee replacement. there was no difference between males and females. the symptom scores declined with increase in medical problems. conclusıon: our age matched scores were superior to post operative total knee replacement (tkr) scores from the njr. this furthered our motive to create a set of reference knee scores in the normal population which could be used by other studies to compare their results and help improve postoperative outcomes. mesenchymal stem cells (mscs) are multipotent stromal cells that have extensive proliferative potential and the ability to undergo multilineage differentiation. traditionally, osteogenic differentiation of mesenchymal stem cells has been studied in cells isolated from bone marrow and iliac crest. however, these harvest techniques are associated with several problems, including donor morbidity, pain, and limited amount of cells. only a few years ago, adipose tissue has been identified as another source of mulitpotent mscs, which are referred to as adipose derived stem cells (adscs). the aim of our study was to provide a comparative analysis of primary osteoblasts from the iliac crest and osteogenic differentiated mscs from adipose tissue, using osteoblast-specific protein expression. in patients the cells were differentiated into the osteoblast lineage using osteogenic medium (adobs). primary osteoblasts were isolated from iliac crest specimens in patients undergoing osteosynthesis with spongioplasty (female: , male: , mean age ± . ). phenotype marker expression of osteoblast-specific proteins osteocalcin, alkaline phosphase, type i collagen, and cbfa- (runx- ) was analyzed up to days following incubation using rt-pcr, western blot, and immunocytochemistry. additionaly, the following surface proteins of adscs were analyzed: nucleostemin, cd , cd , cd , cd , cd , and cd . rt-pcr analysis revealed that the non-differentiated adscs contained different types of stromal cells with a large variety of cd marker expression. surface protein expression (cd) did not differ significantly in cells isolated from either fat tissue or bone. author to editor: saved by lookus. background: at our department, classification of the responsiveness to fluid resuscitation and a simple and practical damage control surgery (dcs) scoring system have been used to determine the efficacy of the treatment strategy in trauma patients. cases and methods: we examined out of hepatic injury patients, excluding cardiopulmonary arrest cases. the present study was undertaken to establish a valid strategy for the treatment of hepatic injury, and further improvement of the survival rate was evaluated based on the grater and equal of grade iv [organ injury scale (ois)] hepatic injury necessitating emergency room laparotomy. result: interventional radiology (ivr) treatment cases were all stable or responder patients and all survived with effective hemostasis. transient responder or non responder patients that needed hemostasis were treated by emergency laparotomy, and all the cases that eventually expired needed dcs. the mean injury severity score (iss) was . and the mean probability of survival (ps) was . , and hemostasis treatment was started within a mean of . min, yielding a survival rate of . % in the cases with grater and equal grade iv (ois) liver injury that needed emergency room laparotomy. conclusion: our criteria for deciding the therapeutic strategy based on the response to the initial fluid resuscitation seemed to be useful from the viewpoint of hemostasis for liver injury. the key to securing quality regional trauma care is to designate a trauma care hospital as a trauma center and to transport severely injured patients to the center as rapidly as possible. author to editor: we show that our classification of the responsiveness to fluid resuscitation and a simple and practical damage control surgery (dcs) scoring system is very effective for liver injury strategy. fractures of the proximal femur are, more than ever, an important challenge in the field of traumatology. the gamma-nail, a combination of advantages of the sliding screw with the intramedullary nail, represents an efficient technique in the management of these fractures. a series of fractures of the proximal femur in which this nail was used is reported. the average age of patients was . years (range - years). . % ( patients) of the cases were female. the average duration of the operation recorded was min. in all cases closed reduction was achieved. the mean healing time was . weeks in . % of the cases. there were two cases of delayed consolidation but no pseudarthroses. postoperative complications occurred in cases ( . %). one case of migration of the proximal screw was the most important complication. the most frequent complications ( cases) were seromas and hematomas of the surgical wound, which resolved satisfactorily in all cases. superficial infections ( cases) also evolved favorably, once the appropriate antibiotic treatment had been instituted. no breakages or failures due to implant fatigue were seen. the patient's recovery after suffering the fracture and the operation was evaluated and the % ( patients) recovered their previous walking ability. the overall mortality was . % ( patients) with of the deaths occurring while in hospital. in conclusion, this preliminary study has shown that gamma-nail can be safely used by the average surgeon in the average hospital to treat a common and sometimes difficult fracture. valerio ranieri, loris trenti, aldo rossi, antonio manenti departement of general surgery, university of modena and reggio emilia, modena, italy a years old nigerian woman, at the end of the nd pregnancy, was submitted to a caesarean section for uterine atony. post-operative thrombo-prophylaxis was given. from pod , fever, abdominal pain and increasing tenderness in the right lower quadrant with leucocytosis appeared. ultrasonography showed only small amount of fluid in the douglas pouch, while a contrast-enhanced ct and a rmn revealed a dishomogeneus cylindrical mass of . cm in diameter extending from the right parauterine space towards the duodenum, suggestive of thrombosis of the ovarian vein. laparotomy followed: uterus, ovaries, appendix and bowels were normal. after mobilizing the right colon the ovarian pedicle appeared enlarged and firm; it was dissected, starting from the vena cava, and completely excised preserving the adnexa. post-operative course was uneventful. histology confirmed a suppurative thrombophlebitis; the haematological study ruled out any coagulation abnormality. the patient completed a months low-molecular-weight-heparin treatment. ovarian vein suppurative thrombophlebitis can seriously complicate a caesarean section, till to require a surgical treatment. the imaging is essential for a prompt diagnosis. purpose: to prospectively study the mechanism, distribution of injury, and outcome of patients hospitalized with camel bite injury. methodology: all patients admitted to al-ain hospital with a camel bite were prospectively studied over years (october -october . mechanism of injury including behavior of the camel, distribution and severity of injury, patient's demography, and outcome were studied. results: all patients were males having a median (range) age of ( - ). almost half of them were pakistani. twenty-five were camel caregivers while five were camel riders. seven patients were raised up by the camel's mouth and thrown to the ground while the other patients were only bitten. majority of the injuries were in the upper limb ( ) followed by the head and neck ( ). / upper limb injuries had associated fractures. two patients who were bitten at the neck were admitted to the icu. one of them died due to massive left-brain infarction and the other had complete quadriplegia due to spinal cord injury. the median hospital stay was days. one patient died ( %). conclusıon: the behavior of the camel is occasionally unpredictable and the canine teeth of the camel, which are long, can cause severe penetrating trauma despite the small puncture on the skin. care should be taken when handling the camel. author to editor: dear colleague: this is the only prospective clinical study of camel bites in the literature that took us years to collect. the data is very unique and is of great interest. fikri abu-zidan gastrointestinal cytomegalavirus infections occurs predominantly in immunocompromised patients.involvement of the gastrointestinal tract in acquired immunodeficiency syndrome (aids) patients is frequent. however the prevalence of cytomegalovirus appendicitis is exceedingly rare. case: a year-old male infected with the human immunodeficiency virus, who had chronic abdominal pain with subsequent development of acute right lower quadrant tenderness was admitted to the surgical emergency department. his physical examination revealed no other finding than a mass in the right lower quadrant. his abdominal ultrasonography and abdominal ct revealed a plastron appendicitis. so he was hospitalized for medical treatment and discharged after days of treatment. his control abdominal ultrasonography and ct at the second month showed that plastron appendicitis persisted, therefore the patient was rehospitalized. he was discharged after days of medical treatment. after months the patient experienced severe abdominal pain. appendectomy was performed and histopathogic examination revealed a cytomegalovirus infection. the problems related to diagnose cytomegalovirus appendicitis and therapeutic management of cytomegalovirus infections are discussed. conclusion: aggressive use of ultrasound and abdominal computed tomographic scanning, along with early surgical intervention, is recommended. introduction: spontaneous intramural hematoma of intestine due to anticoagulan therapy is an unusual reason for acute abdomen. the first symptom is usually severe abdominal pain, nausea and vomiting. the most useful radiographic methods is computed tomography. the treatment approach is conservative and surgical. we present four patients treated our clinics due to intramural hematom. two patients are treated surgically and two patients are treated conservatively. material and method: we carried out four patients diagnosed and treated for intramural hematoma of small intestine between and years in haydarpasa numune training and research hospital second surgery department. we examine in this patients age, sex, etiologcy, hematologic parameters, the treatment approach (conservative and surgery), hospitalization times. results: the mean age of the patients was . years (range - ). all patients were male. the etiological factor was warfarin treatment due to aort valve replacement in three patient and ischemic cerebral disease in one patient. laboratuary parameters were elevated leukocyte counts in all patients. two patients was treated by surgical treatment due to intestinal obstriction and ishemia two patient was treated conservatively (nasogastric decompression and total parenteral nutrition). median hospitalization time was . day ( - ). discussion: when patients using anticoagulan therapy applied to emergency unit with abdominal pain, physicians must remember intramural hematoma as reason of acute abdomen. first choice is conservative treatment however cases of acute abdomen with intestinal obstriction and ischemia require surgical intervention. introductıon: motorcycle accidents continue to be a source of severe injury. the joy and exhilaration of riding motorcycles brings with it the risk of morbidity and mortality associated with these accidents. case: it concerns a -year-old man that in / / entered the emergency room after suffering a motorcycle accident. at the admission he had pain, swelling and deformity of the left knee. radiographs showed tibial plateau fracture type vi of schatzker. he was submitted to surgical treatment with open reduction and ostheosynthesis with liss plate and was orientated to rehabilitation. six months after, the fracture was healed in correct alignment, had normal gait, normal knee range of motion and returned to work. eight months after surgery he suffered another motorcycle accident with left leg trauma, radiographs showed a supracondylar femoral fracture type .a ao-asif and diaphyseal tibial fracture below the plate. he underwent surgical treatment with open reduction and osteosynthesis of the supracondilyan femoral fracture with lcp plate, extraction of the liss plate and ostheosynthesis with diaphyseal lcp plate. eleven weeks postoperatively, he was able to walk without crutches. five months after had normal range of motion of the left limb and was working. conclusıon: tibial plateau fractures are serious injuries and stable fixation without compromising the soft-tissue envelope is often difficult but with the liss plate we can achieve fixation of an associated metaphyseal/diaphyseal fracture component with minimal approach. multiple consecutive fractures are an important source of limb deformity and impairment, which we could prevent in this case. introduction: the optimum management of non-united humeral diaphyseal fractures remains unclear. a number of implants are available utilising varying operative philosophies and balancing operative complication risks. we present two cases of humeral shaft non-union treated with an intramedullary compression nail, a technique which is previously unreported. cases: case : a year old male with a closed fracture of the humeral diaphysis ( -a ). initial failed open reduction and internal fixation with an anterior placed . mm dynamic compression plate (dcp) was subsequently revised to a posterior . mm dcp plus bone graft months later. one year post revision, the fracture had failed to unite and was referred to the senior author. he underwent a stage reconstruction with the t humeral intramedullary nail in compression mode. at month review the fracture had united and at years postoperatively he had full range, pain free shoulder and elbow movement. case : a year old female with a closed diaphyseal humerus fracture ( -a ) treated conservatively in a u slab and functional brace developed a mobile, painful non-union. she underwent the same procedure as above and at months the fracture had united. she was pain free and had full range of elbow movement. shoulder movement was restricted due to co-existing glenohumeral osteoarthritis. conclusion: key tenets of fracture and non-union surgery include the ability to obtain stability and compression. this paper describes the first reported use of an intramedullary nail in compression mode for humeral diaphyseal non-union. fingertip amputations are the most common type of amputation injury in the upper extremity and they are important because of an often disproportionately long period of convalescence. different surgical procedures are available for reconstruction, but none is absolutely satisfactory. twenty-two cases ( patients) of fingertip amputation have been treated by primary skin closure using the v-y plasty (tranquilli-leali). there were men and women. the average age was . years. the procedure was carried out under regional anaesthesia using a tourniquet. all devitalized tissue was excised and the bone was smoothed. a triangular flap with a distal base was developed. the width of the base should be the same as the amputated edge of the nail or the nailbed, and the length should be a little longer than the width. the flap was mobilized and sutured to the nail or the nailbed. finally the volar gap was closed. the average follow-up period was months, ranging from to months. all of the flaps survived and achieved normal or adequate two-point discrimination. two patients had some loss of distal interphalangeal joint extension and five patients had cold hypersensitivity. rapid return to work was possible in most cases. the technique is simple and presents an excellent method for fingertip reconstruction in allen type i, ii and iii injuries. bilateral anterior shoulder dislocation is rare, and his aetiology is via various traumatic insults, atraumatic occurrences, and through extreme muscular contractions like epilepsy. in epileptic seizures is more common to occur posterior bilateral dislocation. the aim of this work is to describe a rare case of anterior bilateral shoulder dislocation after a convulsive crisis. it concerns a case of a -year-old male, with alcoholism history, who entered the emergency room in / / with a generalized tonic-clonic seizure. after, he had bilateral shoulder deformity and swelling. radiographs demonstrated a bilateral anterior shoulder luxation and bilateral greater tuberosity fracture. the dislocation was reduced and both shoulders were immobilized. month later, radiographs showed bilateral reduction maintenance and bilateral greater tuberosity fracture deviation. the patient had extremely restriction of active and passive ranges of motion in both shoulders: in the left had º of active external rotation and º of abduction; in the right º of active external rotation and º of abduction. at this moment surgical procedure was done with bilateral open reduction and osteosynthesis with ''phylus'' plate and was orientated to physical rehabilitation. at the month follow up, he had significantly improved both shoulders range of motion, and returned to the normal daily activities and months later returned to work. displaced fractures of the greater tuber-osities after shoulder dislocation may result in motion limitation and functional disability. open reduction and stable fixation allows for early passive motion of the joint and early return to activities of daily living. introduction and objectıves: direct inoculation, hematogenous spread or underlying medical illness which can predispose a patient easily for osteomyelitis are the causes of a vertebral infection. this case report represents a vertebral osteomyelitis of a patient seen after spine trauma. case: an year-old girl was admitted to our out-patient clinic with a history of progressive back pain. her inflammatory markers were high, physical examination revealed only spinous tenderness to palpation and she had a spine trauma history when she was at nine. radiological evaluation demonstrated lumbar and mild anterior compression, an incomplete intervertebral fusion and endplate irregularities with an intact spinal cord. bilateral sequential transpedicular drainage from l vertebra was performed without any complication. she has a pain free course of months with negative inflammatory markers. conclusions: the management of vertebral osteomyelitis is often challenging and in case of continuing pain and progressive kyphosis, surgical treatment is indicated. beside aggressive surgical procedures, minimally invasive techniques can be an option for the treatment of such cases. . instead of standard screws with diameter of mm using screws with diameter of . mm . instead of , diameter cannulated tunnel using , mm cannulated tunnel results: in use of this new modified method the time of surgery is shorter, the percutaneous surgical technique is simplified, the blooded lose is minimalizied, the surgery can be performed by two persons: the surgeon and the scrub nurse and few special instruments required. conclusion: based on our results we recommend this modified minimal invasive percutaneous osteosynthesis in case of garden iii femoral neck fractures, in garden iv one, especially immobile patients and patients with poor general conditions (asa score iv). introduction: pelvic fracture is one of the serious skeletal injuries, resulting in substantial mortality. the large amount of kinetic energy necessary to fracture the bony pelvis often leads to concomitant thoracoabdominal injury. pelvic fracture and combined injuries need effective initial resuscitation. however, it is hard to predict the mortality due to the complexity of multiple injuries. therefore, the introduction and objectıves: in this study, we aimed to investigate the distribution of the diagnosis in patients who underwent urgent surgical intervention in the operating room. methods: distribution of the diagnosis in patients who underwent an orthopaedic urgent intervention in the year are evaluated retrospectively from the medical records. results: patients with orthopaedic complaints [ male, female; mean age . ( - ) years] were operated on urgently in the year . patients ( shoulder, hip and lisfranc dislocations) had traumatic acute joint dislocation in which closed reduction was unsuccessful without general anestesia, one had supracondylar humeral fracture, one had distal femoral epiphyseal type ii fracture, one had isolated radial shaft fracture with neurovascular injury, one had t spinal fracture dislocation with paraplegia, one had type iii acromiaclavicular ligament rupture, one had quadriceps muscle laceration due to knife wound, one had tendo calcaneus rupture and one had patellar tendon rupture with medial meniscal injury due to knife injury. the mean time from admission to operation was found . h (range - ). conclusıon: it was concluded that the closed reduction of joint dislocations under general anestesia were the major group in orthopaedic urgent intervention. why ankle should be reduced urgently? shahzad sadiq, tariq mahmood worcester acute hospital, worcester, uk fracture dislocation of ankle is common orthopaedic emergency. it is paramount that to avoid soft tissue damage, the ankle is reduced as soon as possible. despite all efforts ankle dislocations could lead to significant blister formation. we reviewed a case series in which ankle joint was reduced with external fixator until skin healing methods: the cases who were admitted to our emergency department between august and and were exposed to traumatic extremity amputation were studied. the medical records such as age, sex, education level, occupation, the way trauma occurred, the affected anatomic zones, performed interventions and hospitalization duration parameters were evaluated. results: the data of subjects were evaluated in this study. mean age was , the rate of female/male was / . . there was a reverse correlation between the education level and occurrence prevalence. . % of the cases were laborers, . % various free self employed and . % were farmers. according to their occurrences, industrial accidents . %, pinching finger in the doorway . % and home accidents . % formed the first three rank. hand finger amputation was . %, toe amputation . % and others were . %. while cases were treated at the emergency service and discharged, cases were referred to related clinics. five cases were referred to other centers and two subjects willingly left our clinic. the mean length of stay was . days. conclusıons: traumatic amputation concerns particularly the young and the people in active work life. since the majority of the cases have hand injuries, they are striking because they cause workforce lose in addition to cosmetic and functional defects. introduction: distal radius fractures are one of the most common injuries regardless of age group. due to their localization they pose a serious threat to the fine wrist movements. for most of the patients the perfect functional result is of a vital importance. open reduction and stable osteosynthesis may help to produces desired outcome. methods: we have compared distal radius radius fractures treated with open reduction and stabilization with . mm synthes lcp and treated with synthes , mm lcp. we have compared the functional results, neurological damage and patient comfort with questionare form. measurements from x-rays were also compared. we have included patients of age between and years, with distal radius fracture. of them with intraarticular fracture. results: intraarticular fractures of distal radius treated with synthes . mm lcp show better functional results compared to synthes . mm lcp. there is no relevant difference depending on used material in extraarticular fractures. conclusıons: we recommend the use of synthes . lcp for intraarticula distal radius fractures for its greater diversity and abillity to stabilize even a small fragments. introduction and objectives: surgical treatment of fractures by using resorbable implants is not too expanded alternative to classical steel or titanium implants. indication for using are intraarticular and periarticular fractures at first of all. the most advantage is no necessary of implants extraction. another one is propagation of load callus during the degradation of material. possibility of making profitable ct and nmr is indispensable.in this paper author presents experiences with using of resorbable screws. methods: at our department there are resorbable cortical screws . , . and . mm bionx made from polyamide polymer with minimal stronghold for weeks and total absorption after years. this screws are determinated for cancellous bones in periarticular areas. we are using them in cases of fracture posterior wall of acetabulum, distal humeral intraarticular fractures, radial head. it can be used for treatment children¢s fractures too. the follow up is same like in ''classical'' osteosynthesis. results: there were no infection's complications, no malfunction screws in our group of patients. the postoperative and ambulatory treatment including physiotherapy was same like in group with classical osteosynthesis. the only one failure was during surgery -we have wraped screw four times because of insufficient pre-drilling and using too much power during insertion. we could recommend resorbable screws as suitable alternative in some type of surgical treatment intraarticular fractures at most. the indication have to be well look over and way of using has to be well understand as well as careful manipulation during surgery. the benefits are no metal material, no extraction in future and profitable ct and nmr. heart valve lesions in blunt cardiac trauma -mechanism, diagnosis and treatment robert lipovec, granc gregorcic department of cardiac surgery, university clinical center maribor, maribor, slovenia because of the variation in diagnostic criteria, cardiac involvement in blunt chest trauma is estimated at approximately %. in contrast to cardiac contusion which is often difficult to validate, traumatic valvular lesions are usually associated with some degree of hemodynamic impairment. patients with positive findings on clinical examination, ecg, cxr and troponine should be screened for valvular lesions by transthoracic echocardiography. blunt injury to cardiac valves can lead to progressive ventricular failure often requiring surgical management. patients with structural damage to the left sided heart valves usually require immediate surgical repair, while right sided valvular lesions can be managed in a delayed fashion. the management is based on type of structural injury and hemodynamic compromise. valvular reconstruction is usually attempted, if possible. the paper outlines historical perspective, mechanisms of injury as well as our experience with diagnosis and treatment of traumatic valvular lesions. two case reports are presented. one patient had a traumatic mitral chords rupture and the other had a tricuspid papillary muscle rupture. both cases were diagnosed immediately and surgically corrected. the ruptured mitral valve was urgently replaced. the tricuspid valve was repaired by delayed surgery. patients in al-ain city, united arab emirates . %, respectively. only the difference between group iia and iib was found to be statistically significant. dıscussıon: rib fractures increase the pain and have a negative effect on breathing during postoperative course. ineffective breathing may cause athelectasis, fever and infection which is associated with increased morbidity. the incidence of rib fractures are higher in anatomical resections in whom the thoracic cavity should be opened widely. a longer incision and step to step opening of the thoracic cavity may decrease the incidence of this undesirable complication. objectıve: this case report describes a surgical method to treat multiple rib fractures by using arch bars. case: a year old male patient was admitted to emergency unit with bilateral flail chest, bilateral multiple rib fractures, bilateral hemopneumothorax and pulmonary contusion. the patient was initially tachypneic and had a shallow breathing. because of the respiratory arrest he was intubated. physical examination revealed crepitation from subcutaneous and oseeous tissues especially on the left hemithorax. after left sided tube thoracostomy cc hemorrhagical drainage and massive air leak was observed. ct scan showed bilateral rib fractures extending from the first to the eleventh ribs, bilateral hemopneumothorax and bilateral pulmonary contusion (picture , ). therefore tube thoracostomy was also administered on the right hemithorax and cc hemorrhagical drainage and air leak occured. because of the thoracic deformity, persistant hemorrhagical drainage and air leak from the left hemithorax, the patient underwent exploratris thoracotomy and damaged pulmonary parenchyma was repaired. multiple rib fractures which damaged the thoracic wall stability severely were fixed by using arch bars (picture ). the patient required mechanical ventilation for days postoperatively. the latest ct scans of pulmonary parenchyma and thoracic wall after arch bar application are seen in pictures and . conclusıon: in this case the conventional rib fixation procedures with kirschner wires or plate plaques could not applied because of multiple small fractured segments. despite various materials suggested in literature, the use of arch bars to repair flail segments with multiple small pieces are not mentioned. tariq siddiqui, kimball maull the trauma center at hamad, hamad general hospital, doha, qatar introductıon: intrathoracic fluid following blunt chest trauma is almost always blood, and derangement in the patient's cardiorespiratory status is directly related to the volume of blood accumulated in the pleural space and the associated compression of pulmaonary parenchyma. tension chylothorax in the setting of bilateral chylothoraces is a rare cause for such a condition. a year old man fell from a height of three meters and presented with back pain. examination disclosed abrasion and tenderness over the right paraspinal area. he was discharged home. four days later, he returned in severe respiratory distress -hypertensive, with rapid pulse, tachypneic and with peripheral cyanosis. there were no breath sounds on the right side and decreased air entry on the left, and bedside ultrasound showed fluid in the right chest. chest x-ray confirmed complete opacification of the right hemithorax and loss of the costo-phrenic angle on the left side. a right tube thoracostomy yielded , ccs of pinkish-white fluid with immediate improvement in cardiorespiratory status. computed tomography disclosed bilateral th and th rib fractures, spinous process fracture of the th thoracic vertebra and bilateral effusions. a left chest tube brought back ccs of additional similar fluid. diliatation of the cisterna chyli in the abdomen with collapse of the thoracic duct were confirmed by mri. conclusıons: post-traumatic tension chylothorax causing cardiorepiratory compromise is rare. in this report, the patient responded to chest tube decompression and dietary measures without complication. author to editor: this report is complimented by excellent illustrations, including ct and mri findings, showing the anatomy of the injury… conducive to poster display. introduction: blast lung injury (bli) is a unique injury rarely seen in the civilian population. our objective was to assess its severity, prognosis and associated injuries as compared to victims with chest wall trauma following explosions. material and methods: retrospective study of victims of the march terrorist bombings in madrid who were treated at the closest hospital. we compared the group with pure bli (bilateral infiltrates in a butterfly pattern, and absence of chest wall fractures) (group i) with that of patients with peripheral infiltrates and chest wall fractures (group ii). results: of patients included in the registry, ( %) had thoracic injuries. ( %) were included in group i, and ( %) in group ii. the mean iss in groups i and ii was of . ± and . ± . , respectively. among the critical patient population in both groups (n = ), those belonging to group ii were in need of a longer period of ventilatory support and had more ventilator-associated pneumonias. in group i, the most frequent associated injuries were tympanic perforation ( . %), º- º burns ( . %) and abdominal trauma ( %). in group ii, º- º burns ( %), followed by tympanic perforation ( %) and skeletal trauma ( %). one patient died in each group ( . vs. . %). conclusions: pure bli patients had a greater degree of anatomic severity, had more severe burns and abdominal trauma than patients with lung infiltrates and thoracic wall fractures. overall prognosis was excellent in both groups. aım: aim of the study was to determine the rate of injuries detectable by ultrasonography in patients suffering from blunt thoracic trauma. materıals-methods: this study include the patients suffering from blunt thoracic trauma who have not any pathological findings in routine radiological diagnostic procedures. ultrasonography of the thorax was prospectively performed in patients with blunt chest trauma additionally to the routine radiological diagnostic procedures. ultrasound findings referring to the rate of detection of fractures, pneumothorax, pleural effusions, lung contusions, haematomas of the lung and chest wall was performed. results: we studied consecutive patients suffering from blunt thoracic trauma who has any pathological findings in routine radiological diagnostic procedures. the findings detectable by ultrasonography were the following: pleural effusion %, haemopneumothorax %, haematoma of the chest wall %, contusion of the lung %. conclusıon: rib fractures and pleural effusions are commonly diagnosed by ultrasonography in patients with blunt thoracic trauma. this study showed that ultrasonography may have superiority to chest-x-ray in diagnosis of rib fractures, pneumothorax, haemothorax, haematomas of the chest wall and pulmonary contusions in blunt thoracic trauma patients. Ş adiye emircan , Ö zlem kö ksal , fatma Ö zdemir , halil Ö zgü ç department of emergency medicine, uludag university, bursa, turkey department of general surgery, uludag university, bursa, turkey aım: the purpose of this study is to define the epidemiologic properties of patients that have been subject to thorax injuries and general body traumas, analyze their condition when they are brought to our emergency department, to determine the correlation of physiological and anatomical risk factors with the mortality rate, and to ensure early diagnosis of severe trauma. methods: trauma cases that had been subject to general body trauma have been retrospectively examined in this study. epidemiological properties of the cases have been determined, their initial condition during initial admission to emergency department have been analyzed, and cases have been assessed in terms of mortality developments. survival probabilities and unexpected mortality rates have been computed using trauma revised score-injury severity score (triss) methodology. results: mortality rates was . %. univariance analysis revealed that hypotension, age, pathologic respiration pattern, blunt injury, accompanying injury, abdominal trauma, high injury severity score (iss), low glascow coma scale (gcs), revised trauma score (rts), triss were the factors affecting mortality. in logistic regression analysis, presence of blunt injuries, triss < , iss > and gcs < have been found independent prognostic factors. strongest factor indicating mortality has found to be triss. in presence of factors affecting mortality, patients with thorax trauma should be evaluated as being of high risk group and therefore diagnosis and treatment strategies must be aggressive. case analysis based on triss model shall further reveal the mistakes that may be made in patient care and may improve patient care. introductıon: penetrating thoracal and cardiac wounds are asssociated with high mortality. we aimed to present our experience in such cases. materıals-method: twenty three patients with penetrating thoracal stab injury, between and , were investigated retrospectively. gender, age, injured areas, extent of thoracal damage, accompanying organ damages and outcomes of these patients were evaluated. results: all patients, except one, were male with a mean age of . years (between and years). in patients penetrating abdominal injury accompanied thorax trauma and one of these patients died peripoeratively. patients out of thoracal trauma had an additional cardiac stab wound and half of them were only pericardial injury. one of these cases went into emergency coronary artery bypass surgery due to lad injury. only four patients required intensive care postoperatively and four patients were lost perioperatively all of which had additional cardiac injury. conclusıon: the overall mortality rate was %, but mortality of patients with additional cardiac stab injury was higher, with a rate of %. suspect of cardiac injury should be considered in patients who are injured close around cardiac area and one should intervene quickly both in diagnosis and treatment. introduction: abdomen and thorax blunt and penetrating injuries, common cases of emergency surgery, cause less complication with proper analysis and surgical intervention. material and method: we retrospectively evaluated patients operated due to thoraco-abdominal blunt and penetrating trauma in _ istanbul training and research hospital last year. results: median age was . ( - ) and all were male. patients were operated due to blunt abdomen in , penetrating abdomen injury in , abdomen and thorax penetrating injury in by general surgeons. abdominal exploration in ( . %) were negative laparotomy. background: we described a patient with dysfunctions of all the nerves and ruptured brachial artery and vein due to closed injury caused by spontaneously reduced dislocation of the elbow. case: a -year-old man fallen down onto his left elbow with small skin erosion and a large area with ecchymosis on the elbow presented. left radial and ulnar pulses were nonpalpable but no sign of acute ischemia was noticed. he had drop hand and could minimally make flexion, opposition, abduction and adduction of fingers. strength of fingers, wrist flexion and thumb adduction were weak. radiography was normal. emergent surgical exploration was performed with prediagnosis of severe closed soft tissue injury and vascular damage. brachial artery and vein had complete disruption with rupture of brachial muscle and the anterior joint capsule. elbow joint could be posteriorly dislocated. artery and vein were repaired with saphenous vein graft. median and ulnar nerves had normal appearance. at postoperative th hour nerve injuries showed complete recovery. he could have normal range of motion in the wrist and hand. sensorial examination was normal. he had a well perfused arm. conclusıon: spontaneously reduced dislocations of the elbow can be sometimes missed. large hematoma and neurologic dysfunction in closed injury of the elbow indicate severe trauma of joint also in case of normal bone structure in radiography. immediate diagnosis and operative treatment of brachial artery injury is mandatory. closed elbow dislocation and multiple nerve injuries may have good results with conservative treatment. we present the case of a y male, with his left lower limb severely damaged by a caterpillar vehicle. he was admitted in the er about min after the accident. he presented with exposed fractures of the femur and leg bones, extensive soft tissue and muscle damage, class iii shock, and an umbilical clamp in the exteriorized femoral artery in the thigh, placed by a fireman in site. the mess (mangled extremity severity score) calculated for this patient was . after the initial assessment in the er the patient was transfered to the or. he had a complete transection of the femoral artery and vein with a severe ischemic foot. despite the mess score, a vascular and bone repairs have been considered. two temporary shunts were placed in both femoral vessels (artery and vein) followed by external fixation of the femur and leg fractures. the definitive vascular repair of the artery and vein was made with autologous saphenous vein after the bone fixation. some damaged skin and necrotic soft tissues were removed, and the reminder skin was only proximated. the limb was functionally and anatomically preserved, with no obvious neurologic deficit, despite subsequent debridements and skin grafts. the authors concluded that in similar cases: introductıon: trauma is responsible for . million of death, % of them in young people. vascular injuries of the upper extremity represent % of all peripheral vascular lesions, the majority of them at the braquial artery. objectıve: report a case of chemical injury of braquial artery. methods: -year-old man was admitted in the emergency room with third degree sulphuric acid burn in the middle third of arm ( % of total body surface area). the radial and ulnar artery pulses were palpable. at the th day after injury, haemorrhage was noted and disruption of braquial artery was clear. a braquial-radial reversed long saphenous vein interposition graft was performed. after surgery palpable radial and ulnar pulses were present, without evidence of nerve injury. results: the chemical burns severity depends on the concentration, properties of the agent and the duration of skin contact. sulphuric acid causes coagulation necroses, with thrombus formation in the microvasculature. its corrosive properties are accentuated by exothermic reaction with water. its burns are more serious than those compared with strong acids, and, as observed in this case, it causes frequently third-degree injuries. besides this, it has the ability to cause continuing tissue destruction, from th hour to th day after injury. this fact could explain why there was no artery lesion at the admission but at the th day. conclusıon: sulphuric acid burn is potential devastating and tend to be prolonged in time, obliging to a continuous monitoring and multidisciplinary approach. introduction and objectıves: the medicolegal studies show that the most frequent mechanisms of the lethal major vascular injuries were stab wounds followed by gunshot wounds and blunt trauma. during the blunt traumas, simple lethal major vascular injuries without any fracture are seen rarely. we experienced a case of common femoral artery and vein transection as a cause of death without any femoral fractures which were caused by blunt trauma. case: during the transportation of wood blocks, a wooden log fell from the truck over the forester, -year-old man. he sustained a crush injury and died in the emergency service on the same day of the trauma. it was learnt that no medical intervention was performed on the case. ecchymotic bruises on the left abdominal-pelvic, femoral, right inguinal, genital region, deformation under the right knee were observed during the autopsy. it was determined that there was a traumatic transection on the left common femoral artery and vein, which was accompanied by massive bleeding in surrounding soft tissues and muscles without any fracture of the left femur. all the internal organs were intact and showed paleness. death was due to internal hemorrhage caused by the transection of the femoral artery and vein. conclusıons: during the examination of the cases who were exposed to the blunt trauma, peripheral vascular injury must be investigated without any delay. if vascular injury was determined in the early times after the trauma, surgical and medical treatment could be performed successfully and the case could survive. introductıon: traumatic internal carotid artery dissection is a rare and grave cause of embolic strokes occurred especially in young age group. if it is not diagnosed early and required treatment is not given, thrombosis can be a serious trouble with permanent neurological deficit and high mortality rate up to %. case: we presented a delayed diagnosed traumatic carotid artery dissection in a year-old female case. there were no ischemic infarct findings in the cerebral ct on admission, but there were cerebral infarct findings in the cerebral ct taken twice because of the left hemiplegia noticed days later when the patient regained her consciousness. we made the diagnosis of the case, forwarded to our emergency service with acute cerebral infarct diagnosis, certain through arterial doppler ultrasonography, cerebral mri, diffusion mri and mr angiography. we did not consider invasive treatment since the neurological damage was permanent and dissection grade was iv according to angiography findings. we did not administrate anticoagulant treatment considering that the patient can turn her ischemic infarct into hemorrhagic infarct. the case was discharged within a week and advised physiotherapy. conclusıon: although the advances in diagnostic methods, diagnosis with traumatic carotid artery dissection is still missed out or delayed as in the case we presented. early diagnosis enables permanent neurological damage to be decreased or vanished. however, the vital factors for early diagnosis are the obtained anamnesis to direct to radiological examinations, detailed physical examination and high clinical doubts. introduction: acute arterial occlusion is a serious clinical condition resulting death of patient or related organs. these are usually older patients with a lot of comorbid conditions. method: _ in our clinic, we retrospectively examined the records of patients who underwent surgical treatment for acute arterial occlusion between january and december . mean age of patients was . years. ( %) of these patients were female, and ( %) were male. embolic occlusions were found in an upper extremity in ( %) patients and in a lower extremity in ( %). the most common source of these emboli was cardiac origin. atherosclerosis, trauma and arterial catheters were the other causes of emboli. ( %) of patients were admitted less than h preoperatively, ( %) were admitted - h preoperatively, ( %) were admitted after a delay of longer than h preoperatively. ( %) of patients were in sinus rythm, ( %) were in atrial fibrillation preoperatively. motor dysfunction of extremity was found in ( %) of patients preoperatively. diagnosis was based on the findings of physical examinations and emergent doppler ultrasonography. any other invasive evaluation was not performed to decrease acute occlusive ischemic period. surgical intervention had performed immediately results: the overall mortalıty rate was % ( ). _ in ( . %) of patients, after setting of demarcation line, amputation was performed. conclusıon: early diagnosis, catheter embolectomy and use of anticoagulation are very important therapeutic modalities for limb salvage and reduction of morbidity and mortality. there was a comorbidity in all patients and cardiac disease and hypertension were the most common ones. the most common laboratory abnormalities were leukocytosis, hypoalbuminemia, hyperamylasemia. there was superiory vasculary necrosis in patients, inferior vasculary necrosis in one patient.one patient had nonocclusive mesenteric ischemia. segmentery resection was performed to patients. abdominoperineal resection was performed to the patient with inferior mesenter artery occlusion. we performed duodenotransversostomy on two patients and only laparotomy on two patients. reoperation was required in five patients. causes of death was multiorgan insufficiency in seven cases, cardiac death in two cases.one patient died due to short intestine syndrome. results: the patient was discharged on postoperative th hours without any complications. conclusıon: single incision laparoscopic appendectomy is a safe and effective technique that can be performed in well experienced centers success. jorge pereira, luis filipe pinheiro surgery department, sã o teotó nio hospital, viseu, portugal trauma represents one of the most important causes of death and disability of today. the exponential growth of the major cities, the continuous building of roads and the uprising of terrorism, foresee that trauma will keep is importance as a major cause of disease. recently, the management of the trauma patient as been modified, with the introduction of the atls method. this fact has produced great improvement, proven and reproducible, decreasing mortality and morbidity of trauma. the teaching of this new method, albeit its good results, has not seen many changes over the years. however, in recent days, we have seen the introduction of new computer technologies in teaching. this methods use simulation, e-learning and even interaction as learning techniques. taking advantage of the mentioned techniques, the authors produced an animated video, using computer-animated drawings that allow demonstrations difficult to reproduce in real life. using simple software and computer video editing, the authors invite you to watch a trauma patient in the emergency room, since his arrival to the end of the primary survey, watching demonstrations of life saving techniques and the stabilization of the patient. the authors present a video of a young male, years of age, ± kg victim of a motorcycle crash, with a fall over cut branches of trees, min before his admission in the e.r. he sustained an impalement with a stick in the fourth right anterior para-sternal space. at admission he was conscious, gcs = , bp = / , hr = /m, sato = %, hemodynamically normal. breath sounds slightly diminished in the left. a left anterolateral thoracotomy as been done, as well a left subcostal lararotomy, since the stick also had penetrated the left hemidiaphragm. the patient had no significant thoracic or abdominal injuries despite the violence of the trauma mechanism. the ''foreign body'' was successfully removed by combined abdominal and thoracic route, and a left chest tube was put in place. the patient recovered very well and was discharged in the eighth day. author to editor: ''english'' corrections are welcome, please! berker bü yü kgü ral, mehmet bekerecioglu al-marashda , amgad elsherif , hani o. eid , fikri m univariate analysis was used to compare patients who died and those who survived. significant factors were then entered into a backward stepwise likelihood ratio logistic regression. results: out of , patients of the registry, patients ( . %) had chest trauma with a mean (sd) age of . ( . ) years. ( %) were males . ( . %) got injured in the street or highway, ( . %) at work place, and ( . %) at home. the main mechanism of injury was road traffic collision in ( %) fall from height in ( . %). ( . %) were admitted to icu. the median (range) iss was ( - ). ( . ) of patients got isolated chest injury, ( . %) had head injury, ( %) lower limb injury, ( . %) upper limb injury iatrogenic rib fractures during thoracotomy: comparision of posterolateral and anterolateral thoracotomies operations for thoracic trauma, extended lung resections and re-thoracotomies were excluded. posterolateral thoracotomy incision was performed for group i ( patients; . %), and anterolateral thoracotomy incision for group ii ( patients; . %). groups were also divided into two groups for the type of resection the percentages for rib fractures for group ia, ib, iia, and iib were . , . , . , and . damage control principles can a be used in all surgical fields . general surgeons must have experience in vascular repair skills . the reperfusion of the limb joão filipe coutinho vasconcelos , sandrina braga , pedro brandão , daniel brandão , miguel maia , joana ferreira , paulo barreto , vítor martins , a. guedes vaz , leonor rios vila nova de gaia, portugal department of plastic surgery rectal prolapse describes the protruding of the entire rectum or some parts of the rectum from anus. it is caused by the weakening of the ligaments and muscles that hold the rectum in place.it is associated with advanced age, long term constipation or diarrhea, childbirth, previous surgery, and sphincter paralysis. trauma may cause sphincter paralysis and can be associated with rectal prolapse. it usually begins with prolapse of the rectum during defecation or val salva movement and usually progresses to a chronic stage. long term prolapse can cause ulcerations, bleeding and in some cases perforation if not reducted. a -year-old male presented with rectal prolapse, bleeding, abdominal pain. he stated that he could not replace the prolapsed segment for days and has been suffering for years since after he fell from a tree and he had massive bleeding during the last h. physical examination revealed that a cm segment of the rectum was prolapsed with the whole layers. there were ischemic and necrotic areas and active bleeding from the mucosa. reduction trial was not successfull. emergent laparotomy was performed. bimanual reduction failed.thus transanal intervention, with sigmoid resection was performed. end colostomy was preferred. no complications occurred the following months and colorectal anastomosis was performed with a preventive ileostomy. although rectal prolapse is usually a benign condition it may cause fatal complications such as perforation, necrosis if not reduced for a long time and surgery should be performed promptly in these cases.ing to the age, diagnosis, treatment results, mortality rates between the years of and . results: summarised in the table .in conclusion, the most of our multitrauma cases caused by traffical accidents, were young. the mortality rate % for multitrauma cases, the percentage of multitrauma cases were . % of all intensive care patients. preventing the accidents is as much important as treatment strategies for multitrauma cases. arif tü rkmen, ertan gü nal, mehmet bekerecioglu, berker bü yü kgü ral department of plastic and reconstructive surgery, gaziantep university school of medicine, gaziantep, turkeyintroduction and objectıves: as personal problems dealing with health, jobs, financial status and the family problems increasing, more suicide attempt subjects are consulted in emergency rooms day-byday. although gunshots to the oro-facial region form - % of the total victims, it is important that seconder deformities resulted with aesthetic, functional and psychological problems were usually encountered after primary surgery. this study reviews cases of self-inflinct gunshot injuries of face and our experiences in early and late managements over a -year period.methods: this study is based on subjects who attempted suicide resulting in extensive facial deformities, not in death between and . demographic details, mechanism and direction of injury, early and late management and seconder deformities were recorded. results: after establishing the airway control and completing the primary survey, all patients underwent debridement and bleeding control. reconstruction of maxillofacial fractures were performed in patients on the day of admission and the remaining within days of injury. following procedures as scar revisions, rhinoplasty, mandible reconstruction, ectropion operations or coverage of palatal defects etc. were performed after earliest months from primary operation.conclusıons: after stabilization of life-threatening injuries, the goals of early management are regenerate of anatomic form and function to include dental occlusion and mouth opening to prevent scarring, contractures of mobile structures and ankylosis. seconder operations required for aesthetic and functional problems should be performed earliest after month from primary operation that all the scar formations and wound healing's were completed. background: injuries of maxillofacial region in patients with polytrauma are frequent but are rarely treated primarily. in order to achieve satisfactory treatment results trauma treatment team must include a maxillofacial surgeon.materıal-methods: the study shows treatment results of polytraumatized patients with maxillofacial injuries. dominant trauma was: maxillofacial in %, craniocerebral in %, locomotor in %, thoracic in % and abdominal in % of cases. treatment of maxillofacial trauma was in % of cases surgical and in % conservative. treatment of other traumas was operative in % and conservative in % of patients. results: early mortality rate was %. four exitus were recorded during the first h, exitus on the th day and exitus on the th post-trauma day. dominant trauma was in exitus craniocerebral, in exitus thoracic and in exitus severe locomotor. long-term treatment results in remaining patients were: for maxillofacial regiongood in patients ( %), satisfactory in patients ( %) and poor in patients ( %); for other regions -good in patients ( %), satisfactory in patient ( %) and poor in patients ( %). conclusıon: existing maxillofacial trauma in polytraumatized patients usually directs treatment toward conservative methods.reasons for this are insufficient number of maxillofacial surgeons in trauma teams and delay of surgical treatment of other present traumas due to difficult anesthesia application. unfortunately, conservative treatment approach induces inadequate treatment results from both functional and esthetic point of view. however, as revealed by hospitalization, transportation, and mortality data, women were exposed to more severe trauma. in addition, poisoning and fall caused more death. the rate of mortality of women seems to be less when compared to literature. conclusıon: bicyclists in non-fatal frontal crashes with cars suffered the most serious injuries from the impact to bonnet and windshield, likely due to highest energy transformation. bicycle helmets, collision mitigation system that alerts the driver or automatically brakes the car, and external airbags protecting the bicyclists from hitting bonnet and windshield, may reduce injuries.author to editor: this is a complete analysis of mechanism of injury in crashes carfront versus bicyclist. journals were completed with traffic notes from police at scene, patents own history of the crash from the injury database and furthermore interview. the catch area is welldefined with no other hospitals in the area and total cover of all injuries in the database. this gives a good picture of the dynamics of the the crash and mechanism of injury. or street ( ais +). third impact in patients gave injuries ( head/neck) at windshield ( ais +) or street ( ais +). thirteen persons, who hit the street as the fourth impact point, sustained three injuries (zero ais +) as contusions of the pelvis and lower back. conclusıon: pedestrians in non-fatal frontal crashes with a car suffered the most serious head injuries at second impact in bonnet, windshield or street. safer passageways for pedestrians might preclude the crash. mechanisms preventing the pedestrian of hitting the bonnet and windshield, may reduce the injuries. author to editor: this is a complete analysis of mechanism of injury in crashes carfront versus pedestrian. journals were completed with traffic notes from police at scene, patients own history of the crash from the injury database and furthermore interview. the catch area is welldefined with no other hospitals in the area and total cover of all injuries in the database. this gives a good picture of the dynamics of the the crash and mechanism of injury. one of the primary characteristics which professions possess is to make the members of a profession have autonomy in decision making and practice. nursing practice is evaluated in relation to professional practice standards and guidelines, rules, etc… application of professional standards requires that nurses use critical thinking for the good of individuals or groups. critical thinking also requires the use of scientifically based and practiced-based criteria for making clinical judgments. these criteria may be practice based on standards developed by clinical practice guidelines developed by individual clinical agencies. for example, intensive care units (icus) are designed to meet the special needs of acutely and critically ill patients. a patient is generally admitted to the icu for one of three reasons. the patient may be physiologically unstable, at risk for serious complications and require intensive and complicated nursing support. despite the emphasis on caring for the patient who can survive death is common in icu patients. it is reported that % of patients admitted to icus will die, and another % may leave the icu but will not survive to discharge. this suggests a need for caution and coordination of care when transferring patients from icus to general units. in this article, the practice guideline which titled ''patient appropriateness for adult icu admissions and discharge'' will be discussed. the terminology for pelvic fractures and its recent modifiers are confusion to the trainee to say the least. we surveyed orthopaedic trainees in the latter part of their surgical rotations. the same set of radiographs were shown to all trainees and their classifications recorded. the same set of radiographs were shown to the trainees again after a period of days. we found significant inter-observer variability ( %) and wide intra-observer variability ( %). though trainees were adept at identifying basic fractures patterns and identifying individual column or lip/wall fractures the complex fracture patterns seems to generate different answers from the same observer at different times. the ct scan was the most effective tool identified for accuracy of the fractured fragments but the more complex assignments resulted in the trainees grouping them differently. results: twenty-one fractures ( . %) healed without complication including five fractures where external fixation was converted into internal one. the mean time to union was . ( - ) months. there were two pin-track infections, two deep infections, and only one nonunion. the femur length was equal to the healthy side in cases, and was shorter by - cm in five cases. mean active knee flexion was °. knee flexion was more than °in patients. conclusions: external fixation is a useful technique for the stabilization of severe open and close highly comminuted femoral shaft fractures. it is safe procedure to achieve temporary rigid stabilization of femur fracture in critical polytraumatized patients before delayed internal fixation (damage control orthopedics). purpose of this study was to determine the factors predicting mortality.methods: a retrospective study was performed on cases of pelvic fracture who visited to emergency department from january to june . data were collected regarding demographic characteristics, mechanism of injury, injury severity score (iss), abbreviated injury score (ais), simplified acute physiologic score ii (saps ii), transfusion requirements, fluid requirements, the finding of angiography, hemoglobin, platelet, prothrombin time ( fractures were managed by using an intraarticular, chevron-shaped olecranon osteotomy in all patients. methods: the mean age was . years. a straight posterior surgical incision was performed. a thin oscillating saw was used to begin the olecranon osteotomy. a small osteotome was then inserted and the osteotomy was completed through the subchondral bone. the posterior elbow capsule was incised. the olecranon fragment and the triceps muscle were reflected proximally to expose the distal humeral articular surface. osteotomy fixations were performed with two intramedullary kirschner wires and dorsal tension band in patients. in four patients, an intramedullary screw and a tension band were used for fixation. results: at the final control, the jupiter classification system was used for the evaluation of the patients. eighty one percent of the patients revealed good and excellent results at the long-term followup. none of the patients showed osteotomy nonunion. the most frequent complication was skin problem due to subcutaneous prominence of the implants.conclusions: the goals of treatment of distal humerus fractures are anatomic articular restoration and rigid fixation. olecranon osteotomy provides good visualization for rigid fixation especially in type c distal humeral articular fractures. this is a useful method for excellent anatomic reduction of the articular surface. conclusions: there could be some steps during primary treatment for discussion. but real mistake was vacillation and delay of reosteosynthesis and spongioplasty even it was cause by risk for infection and possible failure of flap. our case demonstrate that sometimes too much care could be hurtful. introductıon: the population who applied to the public emergency services due to the injuries related to butchering the sacrificial animals during the feast of sacrifice were evaluated. materıals-method: eighty-nine patients who admitted to the emergency services in kirikkale during the feast of sacrifice in were evaluated according to age, sex, application day and time, state of experience, type and mechanism of injury and medical treatment. results: the age average was ± and % of them were male. eighty-eight percent of the patients admitted in the first day. seventy percent of the injuries were penetrating injuries and % of them were blunt. the average time passed after the trauma was min. almost half of the cases were wounded with a knife, % were wounded unintentionally by the others and % of the cases were due to hit of animals. fifty-seven percent of the patients had butchering experience before. ninety-one percent of the cases were hand injuries. thirty percent of the cases had fractures. nine percent of all cases had tendon injury, % of the cases were treated primarily skin suturation. conclusıon: the injuries related to butchering of the sacrificial animals sometimes can be serious. in extremity injuries, the number of tendon cuts and bone fractures can not be underestimated. both equipments and medical staff support for the injured people should be provided and preliminary arrangements should be done during the feast of sacrifice. every butchering job in this period should be given to professionals. introduction: osteoporotic fractures of the trochanteric area are often treated with a gamma-nail or similar implants utilizing a screw applied into the femoral head. one of the main problems of these techniques is the cut out in the femoral head. we biomechanically evaluated a novel technique of cement augmentation of the bed of the screw in a standardised osteoporotic bone model and its capability to reduce the cut out rate. material and methods: utilizing a polyurethane-foam osteoporotic model that has been previously described (specific gravity . g/cm ), a biomechanical testing of a neck of femur screw (tgn, stryker, duisburg, germany) was performed. the screw was implanted according to manufacturers instruction, the migration characteristics were then biomechanically tested (zwick testing machine) with a static stepwise load increase ( n). first these tests were performed without, in a second series with the augmentation of a fast hardening biopolymer (corthoss, orthovita, usa). each series was repeated five times. the transfer from a stable to an unstable condition was biomechanically determined. results: on average the applied load at the moment of failure with critical cut out was n for the non-augmented screws. with augmentation, the average load was , n, the difference was statistically significant.discussion: it appears in biomechanical testing that augmentation of the femoral head can improve the load bearing capabilities and thereby possibly reduce the rate of cut-out failure in osteoporotic bone. we proceed now with further biomechanical testing, grant of the local ethics committee for human testing has been applied for. introductions and objectıves: the aim of this study was to examine the relationship between childs' favourite cartoon stars who can fly and falling down from a high place in two cases. methods: in this paper we presented two similar cases who were seen with a history of falling down from a high place. the first case was a -year old girl who fell down from the third floor of their apartment. on her examination it was learned that she wanted to fly like her favourite magical cartoon star girls. the second case was a -year old boy who fell down from the second floor. while falling down he was screaming to his friends that he was flying.results: on the physical examination of the first case, deformity and crepitation in right femur were found. x-rays showed right femur distal epiphysis salter harris type iv fracture. she was hospitalized due to the pneumothrax in pediatric surgery intensive care unit. the procedure of closed reduction and fixation with multiple kirschner wires was performed under general anestesia. closed body fracture in the left femur was found in case ii. introductıon: the purpose of this study was to compare the biomechanical properties of different possibilities of screw placement in multidirectional palmar fixed-angle plate in distal radius osteotomy cadaver model under loading conditions. methods: an extra-articular fracture was created in pairs of fresh frozen human cadaver radii. the specimens were randomized into four groups. all radii were plated with a volar fixed-angle plate. there were different possibilities of screw placement in the distal fragment:group a: screws were used in the distal row of the plate. group b: screws were used alternately in the distal and proximal row. group c: screws were used in the proximal row. group d: screws were used filling all screws holes in the distal and proximal row of the plate.the proximal fragment was fixed with screws each. the specimens were loaded with n under dorsal and volar bending and with n axial loading. results: group d had the highest stiffness of n/mm under axial compression and was statistically significant stiffer than the other groups. group b had a stiffness of n/mm followed by group a with n/mm. group c showed only a stiffness of n/mm. there were no statistically significant differences under dorsal and volar bending.conclusıons: occupying all screw holes in the distal fragment offered the highest stability. using only the proximal row with screws showed an unstable situation. it is therefore recommended to use at least screws in the distal fragment. perilunate dislocations are the most common type of carpal dislocation. they can be produced by high-energy injuries. the population primarily at risk is male young adults. in perilunate dislocations, the proximal articular surface of the lunate retains contact with the distal radius. the dorsal-perilunate/volar-lunate dislocation is more common. we performed a retrospective study of perilunate dislocations from to . a total of were reviewed. mean age of the patients was . (range - ). all the patients were male. the trauma mechanism was fall from height in and motor vehicle accident in . all the dislocations were dorsal-perilunate/volar-lunate dislocations. all the dislocations were together with ipsilateral scaphoid fractures. all were closed injuries and all were reduced by closed reduction maneuvers. percutaneous pinning was applied for the dislocation and scaphoid fractures. mean follow-up time was months (range - months). when compared with the non-injured wrist, there was limited range of movement in only one patient.no limitation of range of motion in the other patients could be obtained. the patients did not have pain and instability. radiologically no arthrosis of the wrist could be obtained but in all patients there was scaphoid pseudoarthrosis. functional range of motion of the wrist after a perilunate dislocation is independent of the concomitant scaphoid fractures. bostjan sluga, tomaz malovrh traumatology department, university clinical centre, ljubljana, sloveniainfective complications of tibia fractures result in nonunion, bone defects and soft tissue envelope impairment. several methods of treatment have been described to deal with bone defect including callus distraction, fibula transfer, muscle flap and bone grafting. there are many possibilities to encourage bone healing; bone morphogenic proteins, platelet rich plasma, electrical, ultrasound or shockwave stimulation and hyperbaric oxygen therapy. a patient with both tibias infected nonunion is presented. high energy trauma primarily and inadequate debridement secondarily were probably the cause of the healing complications. a middle-age man was injured in a gas explosion and suffered comminuted closed fractures of both distal tibias. after an immediate external fixation we operated him on the th day after the injury, anatomical reduction and internal fixation on both sides was done. an infection developed after weeks. ankle joint arthrodesis was necessary on one side and implant removal, repetitive debridement with bone grafting on the other. we could not cure the infection and the fracture did not heal. after years, operations, days of ciprofloxacin, days of gentamicin, days of vancomycin, days of implanted gentamicin antibiotic beds and the use of cultivated autogenous steam cells clinically evident nonunion was still present. surgery was performed again, a resection of cm of bone and callus distraction with an unilateral frame. despite a fast progress in knowledge and improvement of methods, a radical debridement, preservation or reconstruction of soft tissue coverage, systemic and local antibiotic therapy and appropriate stabilization is still a keystone in infected nonunion treatment. some people who live in some regions of our country trust in bonesetter's skills more than these ones of professional orthopaedist in the hospitals. the fact that some bonesetter's particular skills to cure the non-operative back pain seems to make them credible on closed reduction too. in this case report, right humerus proximal body fractures due to falling were discussed. the case was -year-old male. in the treatment of this case, velpau bandage, closed reduction and plaster cast-splint has been applied after that he was called to the clinic control, but he did not come to control. the parents of the case were aware of the fact he cannot raise enough the right upper extremity and he was taken along to the hospital. from his anamnesis, it has been learnt that the bonesetter has removed the castsplint and, tried to perform closed reduction. actual physical examination showed that there was an arm pain, crepitation and deformity. a diagnose has been made: there was an union right humerus proximal body fractures, so he has to be hospitalised. under general anaesthesia, closed reduction and bandage velpeau were applied. on the rd day of the hospitalisation, the case was externed and was advised to come for a polyclinic control. because of the importance of epiphysis lines of bones and of other complications from the upper extremities fractures, the treatments have to be performed by the orthopaedists or in accordance with them. about this medical issue, families should be made conscious by healthy authorities. there were women and men. the mean age was . years (range - years) and mean follow-up period was months (range - months). posterior kocher-langenbeck approach was used at patients and ilioinguinal approach was used at two patients.results: there were both column, posterior column with posterior wall, transverse with posterior wall and posterior wall fractures. anatomic reduction was obtained at patients and adequate reduction at patients according to matta criterias. harris scoring system revealed excellent at , good at , moderate at and bad at patients. over % of these patients had satisfactory function. there were any pulmonary embolism, deep infection or nonunion detected. one of four patients whom had developed osteoarthritis, managed with total arthroplasty. postoperative sciatic nerve injury was developed at one patient. conclusıon: secondary arthrosis, nonanatomic reduction, unstable fixation and nerve injuries were associated with poor results. our clinical experience for acetabulum fractures were similar to that reported previously at the literature with over % of satisfactory results sedat kocak, birsen ertekin, esma erdemir, abdullah sadik girisgin, basar cander introduction and objectives: quadriceps muscle tears are usually seen in middle-aged and older people. particularly people with chronic diseases (such as diabetes mellitus, renal failure and gout) are prone to develop quadriceps muscle ruptures. we present a case of partial rupture of the quadriceps muscle in a -year-old girl after intramuscular injections. we thought that this patient could be the youngest patient reported with a quadriceps muscle rupture. methods: patient presented to our clinic with left knee pain, limitation in knee flexion and a localized palpable swelling at the anterolateral side of thigh. there was no blunt trauma but it happened while she jumping on the sofa. in her detailed history we learnt that she had a serious upper tract respiratory infection a week ago and used some parenteral antibiotics (twice a day, intramuscular clindamycine for days).results: plain radiographies were normal. mri showed a partial tear of the vastus lateralis muscle matching with the injection sites. the patient was placed in a long leg half-cast which was maintained for weeks. she treated with conservative treatment successfully.conclusions: mr imaging is useful to diagnose and differentiate in this pathology. multiple intramuscular injections may contribute to damage muscles and make them prone to tears with muscle contractions. quadriceps muscle ruptures in children can be treated successfully with conservative treatment. twenty year old female attempted suicide by jumping from a four story high building, resulting in multiple fractures of the limbs and a complex fracture of the body of the fourth lumbar vertebra (l ) resulting in paralysis of the inferior limbs. the l fracture was treated by a neurosurgeon with the extraction of the body of the vertebra, insertion of a cage device and arthrodeses of the third and fifth vertebras using a metal plate and screws, thereby stabilizing the affected segment and decompressing the medullar channel. the approach was achieved by a general surgeon using the technique of localio, that consists in a paramedian incision of the abdomen and the dissection of the retroperitoneal space without entering the abdominal cavity, dissecting and isolating the left ureter and the main vascular structures (iliac vessels and the left iliolumbar vein) in order to allow a good exposure of the three vertebra bodies involved. the patient recovered the complete function and control over the limbs, resulting no neurological sequelae from the fracture. it is of major importance that this procedure be performed by a multidisciplinary team of surgeons, involving a neurosurgeon and a general surgeon, in this way achieving a better result and a lower risk of complications. josef märz department of surgery, regional hospital karlovy vary, czech republicabdominal ultrasonography or ct were applied to ( . %) patients with blunt trauma and ( . %) patients with penetrating trauma. one ( . %) negative laparotomy was applied to patients with blunt trauma. to splenic injuries was splenectomy. sigmoid perforation, diaphragm rupture, bladder rupture were observed and were fixed primarily. one patient died during surgery due to liver and vena cava injuries. patients with penetrating injury were operated due to firearm injury in ( %) and stab wound in ( %), mortality was not. negative laparotomy was applied to ( . %) patients. multiorgan injury was observed in patients. tube thoracostomy was inserted to patients. of the intestine injuries and stomach injury was fixed primarily. two resection and anastomose and three diversionary ostomy were done. conclusion: proper examination must be considered according to the formation of trauma. _ imaging methods have been used less in penetrating trauma, and negative laparotomy is reported to be applied more than in cases of blunt traumas introductıon: chest tube insertion is frequently used by thoracoabdominal surgeons in urgent conditions. occasionally, this invasive procedure may be associated with lethal complications in inexperienced hands. in this study, we analyzed patients with visceral and/or diaphragmatic injuries due to chest tube insertions. methods: six patients with diaphragmatic and visceral injuries subsequent to chest tube insertions between and were evaluated. the diagnosis was established with roentgenogram, biochemistry of the fluid drained from the chest tube and confirmed with computerized tomography in all patients. results: pleural effusion accompanying respiratory distress was the main indication for chest tube insertion in all patients. in five patients, coexistent gastric perforations with diaphragmatic ruptures were detected, also the esophagus was additionally perforated in one patient. partial gastrectomies were performed in three patients, whereas total gastrectomy in one and primary repair required in two patients respectively. five of the patients died from septic complications. the only survived patients with early diagnosis and primary repair was discharged from the hospital on the th day. conclusıon: penetration of a drainage tube through viscera is a wellrecognized but seldom reported phenomenon. in the majority of patients with diaphragmatic rupture, abnormalities can be found at initial chest radiography. if transdiaphragmatic herniation is missing, diaphragmatic rupture is difficult to diagnose by chest radiography alone. computed tomography is often necessary to reveal the correct diagnosis. early diagnosis and treatment are extremely important in the management of these patients. bronchobiliary fistula is a rare condition, arising as a complication of hydatid disease of the liver, hepatic tuberculosis, hepatic malignancy, chronic pancreatitis, hepatic trauma or surgery. conservative treatment is directed at non-surgical approaches of relieving biliary obstruction to allow for normal flow of bile into the duodenum via endoscopy or percutaneous routes. however in complicated cases which failed conservative non-surgical therapy, surgical intervention is usually required. we report a -year-old man who presented with bilioptysis from a bronchobiliary fistula resulting from firearm injury after days. for his current admission, the patient reported a -day history of cough productive of yellow-green sputum coupled with fevers and malaise.this was successfully treated surgically with a right medial lobectomy and t-tube drainage. paget-von schroetter syndrome(pss) refers to spontaneous thrombosis of the subclavian vein and constitutes . - % of all venous thromboses. it is prevalent among young and healthy adult males who engage in sports. a -year-old male presented with pain and swelling of the left arm after a sequence of intense, repetitive weight lifting exercises. upon questioning, he disclosed that he had been engaged with weight lifting for a long time and had complaints for a while. bases on these findings, upper-extremity effort thrombosis was suspected. contrast-enhanced mr angiography revealed near-complete occlusion of the proximal left subclavian vein and collateral formations in the distal were observed. color doppler us showed a heterogeneous thrombotic mass that filled almost the entire proximal segment of the left subclavian vein thrombosis extended into the proximal segment of the left internal jugular vein. furthermore, extensive venous collateral formations were present the left proximal cervical localization. both mr angiographic and sonographic findings were consistent with pss. as the patient had already developed extensive venous collaterals, no surgical intervention was performed. instead, treatment with lowmolecular weight heparin and anticoagulants, was initiated and was continued along with the follow-up for bleeding parameters. as of years clinical follow-up the patient is doing well, and treatment is continued with oral anticoagulants and acetylsalicylic. pss should be considered in the differential diagnosis of effort induced upper extremity pain and swelling. conservative non-operative treatment is acceptable and can be successfully used with favorable long-term outcomes. although, blunt trauma of the extremities is a common diagnosis in emergency clinics, compartment syndrome associated with vascular injury following blunt trauma may be difficult to diagnose. urgent diagnosis and treatment of compartment syndrome is of particular importance for limb salvage or even to save the patients' life. years old male patient was referred to emergency clinic due to blunt trauma of the right lower extremity. right thigh was echimotic and swollen. pallor, coldness and severe pain were present at the lower part of the trauma level. distal pulses were not palpable. acute compartment syndrome of the right thigh was diagnosed that led to an emergent operation. intraoperatively, popliteal artery rupture was diagnosed and repaired with end-to-end anastomosis. fasciotomies were performed at the anteromedial and anterolateral portions of the right leg and anteromedial part of the thigh for the treatment of compartment syndrome. in early postoperative period, distal pulses were palpable. preoperatively present pallor and coldness improved in the first few h. fasciotomies were closed with skin grafts at the th postoperative day. patient was discharged at the th postoperative day with palpable distal pulses and failure of dorsal flexion of the right ankle representing mild neurological injury. possible vascular injury should be kept in mind in a patient with compartment syndrome following blunt trauma of extremities. success of surgical repair depends on the early diagnosis and treatment. late repair may result in neurological complications or even the loss of extremities.conclusıon: acute mesenteric ischemia is highly mortal emergency which should always be suspected in elderly patients with cardiac disease suffering from abdominal pain. acute ischemia of the lower member after injury by firearm -case report patient with years, male sex, admitted at the urgency department after injury of the left lower member by firearm. at the admission presented loss of substance and hemorrhage in the medial and lateral faces of left leg and foot with signs of ischemia. an arteriography of the member was carried out showing infrapopliteal arterial lesions of the three axes. during surgery, fracture and losses of peroneum substance was observed with macroscopic tibial and peroneal common nerves integrities. he was submitted to tibial interposition grafts with subsequent reversed contralateral internal saphena vein bypass.in the th postoperative day it was carried out surgical debridement and plastia with partial skin graft. he presented good cicatricial evolution, with hospital discharge days after, oriented to external consultations of vascular surgery, plastic surgery, physical/ rehabilitation medicine and pain consult. five months after surgery, pain was controlled with the medication instituted, with improvement of the left lower member limitations with physiotherapy, good cicatricial evolution and posterior tibial and dorsalis pedis pulses palpables. dıscussıon: the incidence of arterial wounds following penetrating injury of the members is %. the vascular trauma occurs more frequently in the lower extremities, being the most common clinical presentation acute isquemia. the most frequent causes are vehicle accidents, falls and firearm wounds. in the united states, injuries by firearm represents the first cause of death in young individuals of male sex. the arterial bellow-knee injuries by firearm remain like a challenge, with an associated rate of amputation of to %. jorge pereira, luis filipe pinheiro surgery department, sã o teotó nio hospital, viseu, portugaltrauma represents one of the most important causes of death and disability of today. the exponential growth of the major cities, the continuous building of roads and the uprising of terrorism, foresee that trauma will keep is importance as a major cause of disease.recently, the management of the trauma patient as been modified, with the introduction of the atls method. this fact has produced great improvement, proven and reproducible, decreasing mortality and morbidity of trauma. the next stage of treatment implies surgery. the dstc course, and other similar ones, allow the teaching of surgical damage control to surgeons. in this courses, the surgeon not only learns the theoretical basis of the surgical techniques but also acquires the skills to perform them. more importantly, he learns trauma pathophysiology, so he can perform the difficult task of surgical decision-making. using the same computer-animated drawing technique as in a previous video (primary survey), the authors continue to present a trauma patient, after the stabilization of the primary survey, at the operating room. the patient has a severe abdominal trauma and needs damage control of his lesions, for he is already suffering from the deadly triad: hypocoagulation, acidosis and hypothermia. a year-old male patient was admitted to our hospital for severe abdominal pain. thoracoabdominopelvic ct scan demonstrated incarcerated bowel loops in the right hemithorax. strangulated transverse colon segment and omentum through the defect at the dome of right diaphragma was found at diagnostic laparoscopy. diaphragmatic hernia was primarily repaired with endostitches, and supported with a polipropylene mesh fixed with endotuckers subsequent to reduction of strangulated organs to the abdomen. resection of necrotic intrabdominal organs and a side-to-side stapled colocolonic anastomosis was performed through a subcostal minilaparotomy. drainage of right hemithorax was provided with a tube thoracostomy. the patient was discharged on the th post-operative day without any major complications. introduction and objectıves: single incision laparoscopic procedures are accepted as a step towards pure natural orifice transluminal endoscopic surgery. however, loss of requirement of any perforation of visceral organ and an endoscopic equipment make this technique more popular and easily performable. here in we report our first appendectomy case who was performed with single incision laparoscopic surgery (sils) technique. methods: years old male patient with the diagnosis of acute appendisitis underwent single incision laparoscopic appendectomy. a key: cord- -c m gq authors: pinilla, inmaculada; martí de gracia, milagros; quintana-díaz, manuel; figueira, juan carlos title: radiological prognostic factors in patients with pandemic h n (ph n ) infection requiring hospital admission date: - - journal: emerg radiol doi: . /s - - - sha: doc_id: cord_uid: c m gq the aim of this study was to determine the radiologic findings associated with admission to the intensive care unit (icu) and the development of acute respiratory distress syndrome (ards) in patients with ph n infection. one hundred and four patients ( – years) with laboratory-confirmed ph n infection seen at the emergency department from july to december who underwent chest radiographs were studied. radiographs were evaluated for consolidation, ground-glass opacities, interstitial patterns, distribution, and extent of findings. eighty-seven ( . %) of the patients were managed in the ward, and ( . %) patients eventually required admission to the icu. all patients admitted to the icu showed abnormalities on the initial radiograph. the presence of consolidation, multifocal, diffuse, and bilateral involvement on the initial radiograph was associated with a statistically higher risk of requiring icu admission (p < . ). there were no significant differences regarding age, sex, and presence of underlying comorbidities. evolution to ards was found in eight cases that necessitated icu care. all of them had on the initial radiograph patchy multifocal consolidations (p < . ) with bilateral lesions in six cases. a higher number of lung zones involved and consolidation on the initial chest radiograph as well as a rapid progression of the radiological abnormalities were identified in patients requiring icu admission and development of ards. initial chest radiographs show acute abnormalities in all patients with severe disease. the findings of a multifocal patchy consolidation pattern with bilateral or diffuse lung involvement on admission should alert of the impending severity of disease and the risk of necessitating icu admission in the spring of , an outbreak of respiratory disease caused by a novel swine-origin influenza a virus was reported in mexico [ ] . this virus, known as pandemic h n (ph n ), shared molecular features with north american and european swine, avian and human influenza viruses. pandemic h n virus is extremely contagious with person-to-person transmission [ , ] . in june , the world health organization (who) raised the pandemic level to lasting until august [ ] . as of august , more than countries have reported to the who laboratory-confirmed cases of pandemic influenza h n with over , deaths [ ] . symptoms of ph n infection include: fever, cough, sore throat, rhinorrhea, dyspnea, headache, myalgia, nausea, vomiting, and diarrhea. afebrile and atypical clinical presentations have been described in some risk groups such as pregnant women and immunosuppressed patients [ ] . most patients have a relatively mild and selflimited disease. however, ph n infection may cause severe disease requiring intensive care unit (icu) admission because of severe hypoxemia, acute respiratory distress syndrome (ards), and shock [ , ] . in contrast to seasonal influenza, children and young adults, frequently with no predisposing chronic illnesses, are more affected and prone to complications [ , [ ] [ ] [ ] . it has been reported that between % and % of hospitalized patients required admission to the icu, where - % died [ ] [ ] [ ] [ ] . among the sickest patients, children seem to be more often complicated by secondary bacterial infections, whereas severe disease in adults is usually caused by primary viral pneumonia and ards [ ] . several reports describe the initial radiographic and ct findings in patients with h n infection of both mild and severe cases including interstitial markings, nodules, ground-glass opacities (ggo), and consolidations with focal, multifocal, or diffuse distribution [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . there are, however, very few reports addressing predictors of illness severity in these patients [ , [ ] [ ] [ ] . the aim of this study was to determine the radiologic findings associated with admission to the icu and development of ards in patients admitted to the emergency department (ed) with pandemic h n influenza. the study was approved by the hospital ethics committee with a waiver of informed consent due to the observational nature of the study. the study group consisted of consecutive adult patients (at our center, any patient older than years is considered an adult) with acute respiratory illness and laboratoryconfirmed ph n infection seen at the ed of our hospital from july to december and who underwent chest radiographs. fifty-three were male and were female. the median age was years (range, - years). we reviewed the medical charts and laboratory and radiologic findings. specimens from nasopharyngeal swabs and/or bronchial aspirate samples were obtained in all cases. respiratory specimens were tested with reverse transcriptase polymerase chain reaction (pcr). a positive result was obtained in all patients. in addition, other potential respiratory pathogens were ruled out in all patients with the use of a multiplex pcr assay for respiratory viral and atypical bacterial panels for the detection of influenza a and b, adenovirus, parainfluenza, respiratory syncytial virus, rhinovirus, mycoplasma pneumoniae, legionella pneumophila, chlamydias, and coxiella burnetti. an initial chest radiograph was obtained in all patients on admission to the emergency department. follow-up chest radiographs were obtained as clinically indicated. posteroanterior and lateral projection radiographs were obtained using a general electric healthcare digital equipment. a technique of kv and mas was used for the posteroanterior view and kv and mas for the lateral projection. bedside anteroposterior projection radiographs were obtained with a mobile unit using kv mas and a -cm film-focus distance. two patients underwent chest ct on a -detector row ct scanner (asteion, toshiba, tokyo, japan) with the following parameters: kv, ma, s after intravenous injection of ml of a nonionic contrast agent (iohexol mg of iodine per milliliter). using the descriptors defined in the fleischner society's glossary of terms [ ] , chest radiographs and ct scans were evaluated for: consolidation (defined as an area of increased opacity obscuring the underlying vessels), ggo (defined as an area of increased attenuation without obscuring the underlying vessels), nodules (focal round opacity less than cm), reticular opacity (defined as linear opacities forming a mesh-like pattern), and peribronchial markings (prominent peribronchial markings defined as coarse linear markings from the hila into the lungs) [ ] . the location of these findings was also recorded (lobar, segmental, and number of lobes affected). the extent of disease was further categorized as unilateral or bilateral, as well as focal (defined as a single focus of abnormality), multifocal (defined as more than one focus), and diffuse (defined as involving the volume of one lung). images were also assessed for the presence of other abnormalities such as pleural effusion and enlarged mediastinal and hilar lymph nodes. the radiological anomalies caused by underlying comorbidities or present in radiographs obtained before the acute respiratory illness were not accounted for. radiographs and ct scans were reviewed independently by two experienced radiologists who reached a consensus decision. all statistical analyses were carried out with the spss for windows software package (release . ). quantitative data were described as the median, minimum, and maximum, while the qualitative data were represented as counts and percentages. qualitative data were compared with chisquare tests and quantitative variables with mann-whitney u test. two-sided tests were used, and a p value less than . was considered statistically significant. eighty-seven ( . %) out of the patients admitted to the ed were managed in the ward. forty patients were female and were male, ranging from to years with a mean age of years. forty-three of these patients had at least one coexisting medical condition that included: heart disease (n= ), asthma (n= ), chronic obstructive pulmonary disease (copd) (n= ), immunosuppression (n= ), neurologic disease (n= ), obesity (n= ), crohn's disease (n= ), and sickle cell disease (n= ). in ( . %) patients, posteroanterior and lateral views were obtained, and in ( . %) patients, anteroposterior projection was performed. the initial chest radiograph showed abnormalities in ( . %) patients including: consolidation in ( . %), ggo in ( %), and prominent peribronchovascular markings in ( . %) cases. lung involvement was focal in ( %), multifocal in ( %), and diffuse in ( %) patient. the right upper lobe was involved in patients, the middle lobe in , the left upper lobe in , the right lower lobe in , and the left lower lobe in patients. seventeen ( . %) out of the patients admitted to the ed eventually required admission to the icu, and ( . %) required advanced mechanical ventilation. eleven were female and three were male, ranging in age from to years with a mean age of years. the clinical features of the patients admitted to the icu are summarized in table . eleven of these patients had at least one coexisting medical condition that included: asthma (n= ), copd (n= ), morbid obesity (n= ), pregnancy (n= ), diabetes (n= ), neoplasia (n= ), seizure disorder (n= ), and heart disease (n= ). anteroposterior chest radiograph was performed in fig. ). distribution was focal in ( . %), multifocal patchy in ( . %), and diffuse in ( . %) cases. the right upper lobe was involved in six, the middle lobe in nine, the left upper lobe in four, the right lower lobe in five, and the left lower lobe in seven patients. pleural effusions were observed on the initial radiograph in six patients. none of the patients showed hilar or mediastinal lymph node enlargement. the clinical course of five ( %) of the patients admitted to the icu was complicated with pulmonary superimposed infections ( table ) : three patients developed respiratory superinfections with acinetobacter, (two of them also developed ards), one with klebsiella, and in one patient, ph n infection was complicated with fatal secondary invasive pulmonary aspergillosis. two patients died from shock and multiorgan systemic failure and one patient from systemic secondary infection with aspergillus. the comparison between the clinical and radiological characteristics of the patients admitted to the icu and those managed without icu care is shown in table . the presence on the initial chest radiograph of lung consolidation, multifocal, diffuse, and bilateral involvement (fig. ) was associated with a statistically higher risk of requiring icu admission (p< . ). there were no significant differences between both groups regarding age, sex, and the presence of underlying comorbidities. evolution to ards was found in eight cases ( . %) that necessitated icu care, all of them requiring advanced mechanical ventilation. the clinical and radiological features as well as the evolution of patients with ards are summarized in table . all of them had on the initial radiograph a patchy multifocal consolidation pattern of involvement (p< . ) with bilateral lesions in six cases. ct scans were available in two of these patients. in both cases, patchy areas of parenchymal consolidation and ggo as well as small pleural effusions were found (fig. ) . no nodules, reticular pattern, or lymphadenopathies were found. in five out of eight patients, a rapid progression of the initial radiological abnormalities in less than h was in the multivariant analysis, a higher number of lung zones were involved, and the patchy consolidation pattern on the initial chest radiograph as well as a rapid progression of the radiological abnormalities within the first h were identified in patients requiring icu admission and development of ards. the pandemic h n influenza a virus has rapidly spread worldwide, resulting in the first influenza pandemic in the twenty-first century [ ] . the clinical spectrum of the ph n infection ranges from acute mild respiratory illness to a severe viral pneumonia that may be associated with profound hypoxemia, ards, and sometimes shock [ , ] . the importance of early administration of antiviral drugs in the treatment of severe cases has been highlighted [ , , ] . therefore, early identification of patients with a high risk for a complicated course may assist in patient management. zimmerman et al. [ ] found that the elevated c-reactive protein level on admission to the ed significantly correlated with impending disease severity in patients infected with ph n [ ] . also, coinfection with streptococcus pneumoniae has been correlated with illness severity [ ] . however, studies assessing radiological findings at presentation that might be used as predictors of the severity of disease are sparse [ , ] . our results show that the initial chest radiograph on admission to the ed is invariably abnormal in patients with ph n infection that eventually require mechanical ventilation and icu admission. in contrast, more than half of patients with mild self-limited disease show a normal initial radiograph. these findings are in concordance with those of other studies carried out in both pediatric [ ] and in adult populations [ , ] , reporting between % and % of normal initial radiographs. however, aviram et al. [ ] reported normal initial radiographs in % of patients requiring mechanical ventilation. in our series, the most frequent radiological abnormality in patients with ph n infection was lung consolidation, similar to the reported data for ph n virus as well as for other influenza virus [ , [ ] [ ] [ ] [ ] . we have found a slightly lower lobe predominance of the abnormalities, an inconstant finding in the literature. as lee et al. [ ] , we found fig. ). chest ct (lung window) reveals widespread ground-glass opacities and small perihilar and peripheral foci of parenchymal consolidation in lower lobes prominent peribronchial marking in a substantial minority in the subgroup of patients that did not precise icu admission. this pattern, which is rare on other series of adult patients with ph n infection, may be explained by the inclusion of very young patients, between and years in our cohort. it has been attributed to age-related differences in immunity [ ] . in our study, the most common radiological pattern on admission to the ed in patients eventually requiring intensive care measures was bilateral multifocal patchy consolidation. diffuse lung involvement was found in % of these patients. these findings are consistent with those inferred from the literature in the subgroups of sickest patients [ ] [ ] [ ] [ ] [ ] [ ] ] . in the largest series, aviram et al. [ ] reported that extensive lung involvement as expressed by multizonal and bilateral peripheral opacities on the initial radiograph was associated with adverse prognosis. one difference is, however, the lower prevalence of ggo in our series compared with other reports in which there were a higher number of patients studied with ct. in addition, the fact that a substantial proportion of bedside anteroposterior radiographs (instead of the two projections) were obtained in the group of patients with eventual admission to icu may have decreased the detection of subtle areas of ggo and underestimated the presence of small consolidations in the retrocardiac area. in our study, most patients developing ards showed progression of the radiological abnormalities (multifocal areas of lung consolidation) within h of admission to the ed. the rapid progression of viral pneumonia caused by ph n leading to intubation within h of diagnosis has been previously reported [ ] . as aviram et al. [ ] , we have not observed a significant association between the presence of comorbidities and a complicated course of the infection with icu admission. this is in high contrast with the findings reported by lee et al. [ ] , although their study was carried out in patients under years of age, and it has been communicated that severe cases among pediatric patients occur predominantly in children with underlying conditions, while adults seem to have severe viral pneumonia and ards often in previously healthy subjects [ ] . our study has several limitations. firstly, it is retrospective in nature, and it includes a limited number of patients necessitating mechanical ventilation and intensive care measures. in addition, it is difficult to draw conclusions about the actual prevalence of abnormal chest radiographs and the evolution to severe viral pneumonia because an undetermined number of patients with a mild form of illness may have not sought attention at the hospital ed or their physicians may have different criteria to perform thoracic imaging. secondly, correlation with ct, which is more accurate, was available only in two patients. this fact may account for the lower prevalence of ggo in our series compared with the literature. however, it must be noted that ct does not play a significant role in the initial diagnosis of ph n infection, and it should not be used in the initial evaluation, especially in children. thirdly, none of our patients underwent lung biopsy for histopathologic correlation. in conclusion, initial chest radiographs show acute abnormalities in all patients with severe disease. the findings of a multifocal patchy consolidation pattern with bilateral or diffuse lung involvement on admission should alert of the impending severity of disease and the risk of necessitating icu admission. pneumonia and respiratory failure from swine-origin influenza a (h n ) in mexico swine influenza a (h n ) infection in two children-southern california virus investigation team et al ( ) emergence of a novel swine-origin influenza a (h n ) virus in humans global alert and response: current who phase of pandemic alert influenza ( ) clinical aspects of pandemic influenza a (h n ) virus infection complications of seasonal and pandemic influenza critically ill patients with influenza a (h n ) in mexico pulmonary imaging of pandemic influenza h n infection: relationship between clinical presentation and disease burden on chest radiography and ct radiological and clinical characteristics of a military outbreak of pandemic h n influenza virus infection swine-origin influenza a (h n ) viral infection in children: initial chest radiographic findings chest radiographic and ct findings in novel swine-origin influenza a (h n ) virus (s-oiv) infection swine-origin influenza a (h n ) viral infection: radiographic and ct findings high-resolution computed tomography findings from adult patients with influenza a (h n ) virus-associated pneumonia radiographic and ct findings in pandemic swine-origin influenza a (h n ) c-reactive protein serum levels as an early predictor of outcome in patients with pandemic h n influenza a virus infection streptococcus pneumoniae coinfection is correlated with the severity of h n pandemic influenza h n influenza: chest radiographic findings in helping predict patient outcome fleischner society: glossary of terms for thoracic imaging chest. in: donnelly lf (ed) diagnostic imaging: pediatrics. amirsys, salt lake city viral pneumonias in adults: radiologic and pathologic findings radiographics and highresolution ct findings of influenza virus pneuomonia in patients with hematologic malignancies the radiologic manifestations of h n avian influenza key: cord- - rvfsx p authors: nan title: ps - date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: rvfsx p nan as a base line, we retrospectively reviewed patient characteristics (time ventilated and icu mortality) of all patients ventilated > days over months. over the following months, we determined the impact of the long term care plans on patients ventilated > days. those who failed > weaning attempts from mechanical ventilation were assessed by the mdt for suitability for long term weaning plans. not all were accepted by the mdt team due to resource limitations. both groups were similar with regard to age, gender and apache ii. in the second group, patients adhered mdt weaning plans; all survived to icu discharge. the introduction of the mdt plan was associated with a significant reduction in mortality for all patients ventilated > days (p< . ), with the most significant difference seen in those patients ventilated > days (p< . ). the duration of mechanical ventilation was greater following the introduction of the long term plans. conclusion. we demonstrated the feasibility of applying a long term mdt weaning approach to patients receiving prolonged mechanical ventilation across different consultant weeks. our preliminary data suggests that this approach did not lead to harm and was in fact associated with a significant reduction in icu mortality. the increase in median time to wean requires further investigation. multidisciplinary team involvement with this difficult patient group was essential to enable a change in practice to occur and led to a culture shift within the unit. conclusion. the inclusion of plasmatic levels of transthyretin as an a additional variable improves the predictive ability of the severity scales and indicators of organ failure. . early administration of aas in the acute coronary syndrome, during the months of the study we diagnosed a total of patients with acs, all of them received aas in the first hours which results in a % compliance for this indicator. . semi-upright positioning of patients with invasive mechanical ventilation (imv), during the period of monitoring we attended patients with imv > hours, which made a total of days of imv, we complied to the indicator of semi-upright position % . prevention of tromboembolic events, in the days of monitoring we attended to a total of patients with a stay over hours and we achieved profylaxis of deep venous thrombosis in , which leads to a compliance of %. . pneumonia associated with mechanical ventilation, during the months of monitoring we recorded a total of days of imv in a total of patients and pneumonias associated with imv, which comes down to a total of per episodes. . profylaxis of gastrointestinal hemorrhage in patients with invasive mechanical ventilation, during the days of the study we attended a total of patients with imv > hours with a compliance to the indicator of %. conclusion. discussion. in our unit the indicators have a high percentage of compliance, the only divergence being the pneumonia associated with mechanical ventilation which is due to the small number of patients with imv. due to the characteristics of our unit, with the private setting and the high number of admissions of post surgical patients ( %), imv > hours constitudes a low percentage of our patients. we also have to stress the fact that there where non-labour days during the time of the study. conclusions. in our unit the indicators of quality of the critical patient have a high compliance rate. the use of imv > hours in our unit has a low occurance rate. grant acknowledgement. work group of quality indicators of the semicyuc. drug-drug interactions can cause adverse drug events (ades) and affect icu patient care. a pharmacist on rounds decreases the number of preventable order-writing ades and positively impacts patient safety, outcome and drug costs. the aim of this study is to describe the frequency of drug-drug interactions and its implications on patient outcome. from august to february our clinical pharmacist, present on daily rounds, conducted an active screening of all icu physician orders searching for drug-drug interactions (epocrates rx ® drug reference). these interactions were classified in seven different groups according to potential adverse effects: neurological, cardiovascular, gastrointestinal, renal / metabolic, pharmacokinetic, hematological and others. once an interaction was identified the icu team was warned to detect and report any possible ade and the pharmacist could make interventions judged necessary like a recommendation of an alternative therapy or dose adjustments. physicians , acceptance rate of these interventions and incidence of ades were recorded. we analyzed orders with prescribed items. there were drug-drug interactions identified ( interaction per prescribed items) and these interactions were present in orders ( %). neurological was the leading group with . % (n= ) followed by cardiovascular . % (n= ), gastrointestinal . % (n= ), renal/metabolic . % (n= ), pharmacokinetic . % (n= ), hematological . % (n= ) and others . % (n= ). a great variety of therapies was involved in these interactions. the clinical pharmacist made interventions in order to change the prescribed drug therapy and acceptance rate was %. the incidence of order-writing ades was . per patient days. there was not ades-associated mortality rate during the study period. conclusion. drug-drug interactions are frequent and involve the majority of routinely prescribed items in icu environment. neurological and cardiovascular are the most common affected systems. these interactions can adversely affect patient outcome and a clinical pharmacist integrating the multiprofessional icu team can help to identify and minimize its effects. patients with severe and persistent bleeding have high mortality rates despite standard therapy. recombinant activated factor vii (rfviia) must be considered as a pharmacological complementary treatment for critical ill patients suffering from acute bleeding (acbl). the aim of this report is to evaluate the role of rfviia in the management of severe bleeding refractory to other treatments following a regular protocol for its administration in our icu. during a one year period (february -february ) a protocol of rfviia was applied to patients who were admitted with acbl diagnosis in our icu. the protocol was developed by a commission of experts according to the recommendations of use of rfviia indicated by martinowitz et al ( ). indication: any salvageable patient suffering from massive uncontrolled bleeding that fails to respond to appropiate surgical measures and blood component therapy. preconditions: fibrinogen > mg/dl, platelets > xmm , ph > , , no hypothermia. results. patients with acbl fulfilled the criteria of the protocol. etiology of the bleeding: surgical and obstetric. the average of age was . mean apacheii was . in all cases only one dose of rfviia of mcgr/kg was given. transfusion requirements: red blood concentrates (rbc), fresh frozen plasma (ffp), cryoprecipitate (cry) and platelets (plt) decreased significantly. in addition, prothrombin time (pt) and activated partial thromboplastin time (aptt) improved. patients survived and were discharged from hospital, one patient died due to nosocomial pneumonia. there were no adverse events. before an after rfviia administration before-after pt (s) case . - . - . - . following an agreed protocol model, the use of rfviia may have an important role in achievement of an adequate hemostasis, reduces blood requirements and the adverse events in patients with acbl. intensive care units (icus) provide intensive observation and treatment for critically ill patients, but the total hospital mortality is high at . %. this is according to statistics from the intensive care national audit and research centre (icnarc) case mix programme database. most of the deaths occur in icu itself ( . %), rather than after discharge from icu ( . %). the purpose of this study was to see if the deaths in the lister hospital icu were related to the initial clinical insult or caused by a complication that developed during the icu stay. methods. this retrospective study included all patients admitted to the lister hospital icu over a -year period from april to march . for all patients who died in icu, an icu consultant classified the cause of death into the following three categories: ( ) initial reason for admission; ( ) co-morbidity -e.g. myocardial infarction that occurred after icu admission on a background of ischaemic heart disease in a patient who was admitted after having had major surgery; or ( ) complication that developed because the patient was in icu -e.g. line sepsis or ventilator-associated pneumonia. results. there were admissions to lister icu over the -year period. some were repeat admissions, leaving individual patients to study. the total hospital mortality was . %. patients ( . %) died in icu, patients ( . %) died after discharge from icu but prior to hospital discharge and patients ( . %) survived to hospital discharge.we were able to obtain medical notes for of the patients who died in icu. of these patients, patients ( . %) died due to initial reason for admission, patients ( . %) died due to co-morbidity, and patients ( . %) died due to a complication that developed because the patient was in icu. of the patients for whom we could not obtain medical notes, patients stayed in icu for day, patients stayed for days and patient stayed for days before dying in icu. the short lengths of stay for these patients suggest that they died due to initial reason for admission. our study reveals that most of the deaths in icu were related to the initial clinical insult for which they were admitted. less than a third of the deaths were related to a complication that developed during their icu stay, whether the complication was related to co-morbidity or being in the icu environment. this is surprising, as icu admissions are for patients who suffer an acute deterioration that is potentially recoverable. therefore, deaths that occur in icu should be related to complications that subsequently develop rather than the initial clinical insult. our finding that the converse is true could imply that we may be too unrealistic in our assessment of whether the acute clinical problem is potentially recoverable or not. the practise of withdrawal of treatment varies from unit to unit. if it is carried out properly it could decrease the amount of suffering the patients and the relatives undergo and it would also save valuable resources, which could be utilised more constructively. there was a relative's complaint on unnecessary prolongation of treatment and this lead to this prospective study. we proposed to study the frequency, reasons, documentation, delays and the process of withdrawal of treatment. the study was carried out at the new cross hospital, wolverhampton uk over a period of months may and june . the critical care unit has itu and hdu beds. a proforma was prepared after obtaining the suggestions from the consultants and the nursing staff working in this critical care unit. i was contacted when a decision to withdraw treatment was made. i went through the notes and the monitoring charts to fill in the details in my proforma. the patients were followed up from this point. . treatment was withdrawn on patients and there were admissions during the audit period. the commonest reason was 'unfavourable response in spite of aggressive treatment' followed by 'poor neurological condition'. out of patients suffered from multi organ failure while patients suffered irreversible neurological damage. the decision to withdraw was made by a single itu consultant in majority of the cases. withdrawal decision to death time ranged from minutes to hours. the commonest mode of withdrawal was by extubation. dnar forms were filled for patients only. quality of documentation varied from short and concise to long notes lacking relevant information. there was no documentation in one case. the documentation by the trainees was found to be sub standard. conclusion. partial withdrawal was associated with delay in death. complete withdrawal was associated with quicker death. documentation was sub optimal. inadequate information was provided when trainees did the documentation. majority of the patients suffered from multi organ failure. identification of variables correlated with predisposition p is an initial step. subsequent studies would then be needed to test the clinical efficacy of piro scoring system in the diagnosis and management of sepsis. grant acknowledgement. we acknowledge elililly for the access to the databases. we declare no financial support. to identify genetic markers of proc and proc c loci that may be associated with the susceptibility to develop sepsis, which may adversely affect the prognosis of patients. in the group of patients with severe sepsis and/or septic shock, there were statistically significant differences (p = . ) for the mean apache ii score in genotype cc of snps of proc c, without significant differences for the remaining variables (sofa h, prothrombin time, partial thromboplastin time). snp type groups or subgroups or % ci-p rs cases vs controls . . - . * . rs presence of shock . . - . . rs presence of mof . . - . . † or: odds ratio, ci: confidence interval, mof: multiple organ failure, *sasieni test, †homozygous test conclusion. genotype aa + ga vs gg of the proc gene (snps ) was found to be involved in a higher susceptibility to develop sepsis, genotype cc (snps ) to present multiple organ failure, and genotype gc to develop shock. genotype cc of proc c was related to a higher apache ii score. none of the snps studied seemed to affect the prognosis of patients. patients with sepsis, particularly those in septic shock often develop atrial fibrillation (af) ( , ). interestingly, incidence and prognostic impact of af in septic shock have scarcly been examined so far. the aim of the present study was to answer the following questions: . what is the incidence of newly diagnosed af on a surgical intensive care unit (icu)? . which percentage of patients suffering a septic shock eventually does develop af? . what is the impact of newly diagnosed af on mortality and length of icu stay in patients with septic shock? we prospectively recorded data of all patients who were newly diagnosed with af and all those with a septic shock on a surgical icu (no cardiac surgery) during a one year period according to the requirements of the local ethical committee. during the observation period patients were admitted to the icu. patients ( , %) newly developed af during their stay on the icu. patients ( , %) had a septic shock. of the patients with septic shock had chronic af. of the remaining septic patients, ( %) were newly diagnosed with af. those patients with septic shock who developed af, had a higher mortality as compared to septic patients without af ( % versus %). moreover the median length of stay in the icu of surviving patients was significantly longer in patients with newly diagnosed af as compared to those without af ( versus days). conclusion. according to our data, more than % of patients with septic shock develop af. those patients who do develop af during septic shock seem to have a considerably poorer prognosis compared to those without af. af is a clinically important complication in septic patients and might be a useful criterion in assessing the prognosis of patients with septic shock. to our knowledge this is the first study to describe the incidence and prognostic relevance of newly diagnosed af in septic shock. a. socias* , a. rodríguez salgado , l. gutiérrez , r. morales , a. villoslada , b. comas , m. borges intensive care unit, surgery department, internal medicine, emergency department, h. son llàtzer, palma de mallorca, spain our objective was to evaluate the utility of seriated lactate measurement as a part of a cpims to predict outcome in patients with sepsis. prospective study, conducted in a teaching hospital in patients with sepsis included in a cpims. it automatically produces an annotation on the medical chart and a serie of analytics forms when activated. plasmatic lactate levels were determined at the moment of activation and after and h. clinical and analitical variables, as well as severity scores were also collected. patients have been included fron january to january . statistical tests: chi-square, mann-whitney, anova, kruskal-wallis, spearman, logistic regression. roc curves were traced for all seriated lactate determinations and for lactate clearance at h [ ] . results. patients were included, ( %) had sepsis, ( , %) severe sepsis and ( , %) septic shock. eighty-five ( , %) patients deceased, of whom ( %) had sepsis, ( , %) severe sepsis and ( , %) septic shock at the moment of activation. mean lactate levels were , ( , ) mmol/l, , ( , ) mmol/l and , ( , ) mmol/l at the activation moment, at and a hour respectively. patients with septic shock had significantly higher lactate levels at every moment (p< , ). moreover those levels correlated with the number of organ failure (nof) for the first d (table ) and the sofa score for the first days (p< , ). using roc curves we established a cutoff of mmol/l for lactate levels and of % for lactate clearance. pacients with initial lactate > (p< , ), at h (p , ) or at h (p < , ) and those with a lactate clearance at h < % (p , ) had higher mortality. recently it was suggested that critically ill patients can tolerate hemoglobin levels as low as g/dl and a more "liberal" red blood cell (rbc) transfusion strategy may in fact lead to worse clinical outcomes. objective: to study the rbc transfusion practice in critically ill patients and to examine the relationship of rbc transfusion to clinical outcomes. prospective observational study of patients admitted in the icu between / / and / / . we excluded patients with active haemorrhage. data on demographics, comorbidities, length of icu stay and icu mortality were collected. . patients were enrolled. ( . %) were transfused. pre-transfusion hemoglobin was . ± . g/dl. related factors to transfusion in multivariate analysis (od (ic)): uci los . ( . - . ). mv . ( . - . ). rr ( . [ ] [ ] [ ] [ ] [ ] [ ] [ ] . chronic anemia ( - ). transfused patients had higher icu mortality ( % vs %, p < . ). however, in a multivariate analysis including saps , mv, rr and transfusion, only saps was significantly related to outcome. conclusion. our transfusional trigger was approximately gr/dl. rbc transfusion was related to chronic anemia (prior to icu admittance), the use of invasive supports and the icu los. in our group of patients, rbc transfusion was not related to icu mortality. w. huber* , m. neudeck , a. umgelter , w. reindl , m. franzen , c. lampart , m. hennig , r. schmid nd medical department, institute for medical statistics and epidemiology, klinikum rechts der isar,technical university of munich, munich, germany introduction. np still has a high mortality and the outcome is hard to predict in the individual patient. while in the last years non-surgical therapy of sterile necroses has become the standard of care, infected necroses are currently treated surgically in most centres. we here present the data of consecutive patients with np treated non-surgically regardless of the infection of the necroses. it was the aim of our study to find prognostic factors relevant for the outcome of patients with conservative therapy of np focussing on the relevance of the infection of pancreatic necrosis. methods. data analysis of consecutive patients with np proven by contrast-enhanced ct-scan admitted to a medical icu. patients were treated with with imipenem as first line antibiosis and ct-guided puncture or drainage if appropriate. surgery was restricted to complications of the puncture or fluid collections not accessible to radiological drainage (n= ). hemodynamic monitoring using picco or pac and monitoring of intra-abdominal pressure if appropriate. statistics: multiple regression analysis (backward selection); chi-square-test (comparison of survival); sas software. patients characteristics: n= ; female; male; age . +/- . years, maximum crp . +/- . mg/dl, max. apache-ii-score . +/- . , max. lipase +/- u/l; max. ldh +/- u/l. / ( %) of the patients required mechanical ventilation and / ( %) dialysis/hemofiltration. .) prognosis: the only independent risk factors at admission to the icu for an unfavourable outcome were the level of serum creatinine (p= . ) and old age (p= . ). the following parameters were not predictive: etiology of pancreatitis, blood/serum levels of lipase, calcium, glucose, leukocytes and hematocrit as well as the presence of a cullen-and/or a grey-turnersign. .) mortality: the overall mortality was / ( %). in patients puncture and drainage of the necroses was performed. the mortality of these patients ( / ; %) was not different compared to the patients without puncture/drainage ( / ; %). in / ( %) of the patients with puncture bacteria and/or fungi were cultured in the aspirates. the mortality of these patients ( / ; %) was not different compared to the patients with sterile necrosis ( / ; %). conclusion. .) the overall mortality of % was low with regard to the severity of np. .) infection of the necroses had no impact on the outcome. therefore, the presence of infected necrosis is no contraindication to conservative management of np. .) the most important predictors for the outcome were serum creatinine levels and old age. x. schmit*, j. vincent intensive care, erasme university hospital, brussels, belgium sepsis remains an increasingly common killer. although there are a lot of studies about sepsis, it is a clinical syndrome and uncertainties will remain in its clinical course. the patient populations are very heterogeneous. some patients will respond well to initial empirical antibiotic therapy while others do not improve and need an adaptation or even a procedure in order to contol the infection. our study addresses for the first time the value of a dynamic evaluation of blood crp concentrations in an icu heterogeneous population of septic patients. clinical an other biological variables were also studied. in critically ill patients with sepsis, enrolled in a prospective observational multicenter study, crp levels and standard clinical and biological variables were measured daily from the day of identification of sepsis until death, transfer to the regular floor, or the th day, whatever came first. patients were divided into three groups according to their clinical course: group -patients with a favourable response to the initial antibiotic therapy; group patients who required a change in antibiotic therapy (shift to or addition of another antibiotic class); group -patients who needed surgery or drainage to control the infection. the studied population, from two large institutions was similar to those found in most of the icu's, with a median age of years, a majority of male patients and the lungs as the most common infectious site, and about % of positive cultures. we found that an increase in crp of at least . mg/dl in the first hours was associated with an inadequate response to therapy with a sensitivity of % and a specificity of %. crp concentrations decreased more rapidly and more significantly in group than in group (p= . ). there is quite a significant variability in baseline crp levels but we show that the time course during therapy is meaningful. in contrast, no correlation was found between crp levels and any of the clinical or other biological studied variables. these variables may also vary in numerous other situations than sepsis. conclusion. changes in crp over the first hours of therapy can help to evaluate the response to therapy in septic patients. the daily dosage of crp is easily accessible, inexpensive to perform, and offers much information, aiding in the clinical course of sepsis and early adequate therapeutic attitudes. is it not our rescuer? in septic patients scoring systems such as acute physiology and chronic health evaluation ii (apache ii) as well as sequential organ failure assessment (sofa) on admission and during treatment quantify the disease severity and therefore stratify the risk of adverse outcome. predictive roles of certain in-hospital parameters such as hypoalbuminemia, increased serum creatinine, c-reactive protein (crp), lactate and serum blood glucose were studied in some prospective clinical studies, however, their independent predictive roles of outcome in septic patients remain uncertain. our aim was to evaluate the predictive role of admission apache ii, admission and total maximum sofa score, hypoalbuminemia, increased serum creatinine, c-reactive protein, lactate, and serum blood glucose for the -day mortality of septic patients admitted to medical icu. included were all consecutive patients admitted to our medical icu in with criteria for sepsis according to sccm/esicm/accp/ats/sis international sepsis definitions conference. the data were collected retrospectively and the predictive roles of variables were tested by univariate and multivariate regressional statistical method. in patients (mean age . +/- . years, . % men) mean admission apache ii was . +/- . , mean admission sofa score . +/- . and total maximum sofa score . +/- . . -day mortality was present in %. we observed significant differences between nonsurvivors and survivors in mean apache ii ( . +/- . versus . +/- . , p = . ), peak blood glucose ( +/- . mmol/l vs . +/- . mmol/l, p = . ) peak serum lactate ( . +/- . mmol/l vs . +/- . mmol/l, p < . ), minimum serum albumin ( . +/- . g/l vs . +/- . g/l, p < . ), peak serum creatinine ( . +/- . micromol/l vs . +/- . micromol/l, p < . ), admission sofa score ( . +/- . vs . +/- . , p < . ) and total maximum sofa score ( . +/- vs . +/- . , p < . ). according to regressional statistical analysis, minimal serum albumin level was the most significant independent predictor of the -day mortality of septic patients in medical icu (or . , hi-square . , p = . , % ci . to . ). serum hypoalbuminemia was the most significant independent predictor of the -day mortality in septic patients. conclusion. the early decrease in mhla-dr expression is related with mortality, but after the severity adjustment, it does not predict outcome globally or in septic subgroups. a flat trend curve of mhla-dr expression is associated with a high risk of ni, which increases the icu length of stay. reference(s). ( )v caille, shock ;( )monneret g icm grant acknowledgement. university paris (ea ), all investigators introduction. intravenous fluid therapy is a cornerstone in the management of severe sepsis and septic shock but the effects of rapid boluses of either crystalloids or colloids on septic-induced microcirculatory alterations are not well defined. we hypothesized that fluid administration may improve the microcirculation in the early phase of severe sepsis and septic shock. we used a sidestream dark-field (sdf) imaging device (microvision medical, amsterdam, the netherlands) to evaluate the sublingual microcirculation in patients with severe sepsis or septic shock during the first hours of resuscitation, in whom fluid challenge was indicated to improve tissue perfusion. hemodynamic and microcirculatory measurements were obtained before and after a fluid challenge with either ml of a % albumin solution or ml of crystalloid over min. at each assessment, sequences of seconds each were recorded and stored under a random number. an investigator blinded to the patient's clinical course and sequence order, analyzed the images semi-quantitatively. the vessels were separated into large and small using a cut-off value of µm in diameter and two microcirculatory variables were evaluated: percentage of perfused vessels and percentage of perfused small vessels. a student t-test was used and data are presented as mean ± sd. a p< . was considered as significant. while arterial pressure and vasopressor use remained unchanged, microcirculatory perfusion increased and lactate levels decreased during fluid challenge (table ) . before after p mean art p, mmhg , ± , , ± , , card outp, l/min (n) , ± , ( ) , ± , ( ) , scvo , % , ± , , ± , , lactate, mmol/l , ± , , ± , , % total perfus vessel , ± , , ± , < , % small perfus vessel , ± , , ± , < , these results suggest that fluid resuscitation can improve the sublingual microcirculation in the early phase of severe sepsis. sdf monitoring may become a new tool to guide fluid therapy in critically ill patients. the study was held in a bed multidisciplinary icu of a tertiary hospital. twenty four norepinephrine dependent (> . γ/kg/min) patients, fulfilling the criteria of septic shock, were enrolled in the study. patients were divided in groups according to the continuous administration of mg hydrocortisone for > days (group a: pts) or conventional treatment (group b: pts). end points of the study were, the within days vasopressors weaning, evolution of mods and -day as well as -day survival. mods was described by sofa score. statistics : statistical analysis was computed by using paired t-test and linear regression analysis. groups were similar regarding demographics ( + vs + y), initial sofa score ( + vs , + ), initial norepinephrine dose ( . + . vs . + . γ/kg/min) and mean elapsed time from the onset of shock ( . + . vs . + . days). an early and significant decrease in norepinephrine dose (p< . ), was observed in all group a pts, while no difference was detected in group b pts. this decrease was associated with hemodynamic stability. on days and mean abp was significantly higher in group a pts (p< . , p< . ). weaning from vasopressors within days was achieved in pts in group a ( . %) and pts in group b ( . %). seven day mortality was . % in group a vs % in group b while -day mortality was % and % respectively. in the treatment group a positive correlation between the within days shock reversal and survival (cor coeff = . , r = . , p= . ) was found. there was no relation between the time elapsed from the onset of shock to the steroid administration and survival (p= . ). oxygenation parameters (fio /po ), sofa score and creatinine did not differ between groups. wbc in group a pts were significantly higher (p< . ) only on day . no significant adverse effects were detected. in late septic shock patients with mods the administration of low doses of hydrocortisone is associated with decreased vasopressors requirements, hemodynamic improvement and beneficial effect on survival. the within days shock reversal was a good predictor of survival. prolonged sepsis is associated with the development of immunoparesis, a down-regulation of the immune system, the degree of which is associated with a poor outcome. little is known about its evolution during the septic process (including the recovery phase), particularly in terms of functionality of the different leukocyte populations. below are preliminary data from an ongoing study. after appropriate consent was obtained, ml blood samples were drawn from previously healthy patients with septic shock (n= ). associated demographic and clinical data (eg sofa score, steroid use etc) were also collected plus icu and hospital outcomes. samples from healthy volunteers acted as controls (n= ). total and differential counts were performed by coulter counter. flow cytometry was used to assess viability (dual staining annexin v/ propidium iodide to determine apoptosis and necrosis), and characterization of populations (surface molecule expression of characterising lymphocytes, monocytes, and neutrophils). functional assays were performed on the phagocyte cell population using phagotest (phagocytic activity assessed as % ingestion of opsonized fitc-labeled bacteria) and phagoburst (measure of oxidative burst activity in response to opsonized e coli, pma and the chemotactic peptide fmlp expressed as % positive cells vs non-stimulated controls, and the increase in median fluorescence intensity [mfi]) (kits from orpegen pharma). compared to controls, septic shock samples taken on icu day showed a wide range of functional responses with some having a reduced number of functionally phagocytic phagocytes while others retained their phagocytic capacity. changes in phagocytic capacity were not related to the respiratory burst. respiratory burst was generally suppressed in septic patients. the viability of the phagocytic population ranged between - % in all septic patients. the proportion of neutrophils of total leukocytes remained constant ( - %) whereas the monocyte population was more variable ( - %) . conclusion. phagocytic populations of septic patients differ from healthy controls. variable effects were seen in phagocytic activity and/or respiratory burst in different septic shock patients on day of admission. this may possibly relate to previous priming or to as yet unexplained immunoparetic mechanisms. further work will assess the evolution of leukocyte number and functionality, and any relationship to outcome. it has been established that raised procalcitonin (pct) levels > ng/ml in critical care patients are associated with an elevation of infection-related mortality risk . we have performed a study to assess the effect of drotrecogin alfa (activated)(daa) on outcome in patients with severe sepsis and very high procalcitonin levels > ng/ml. we examined the outcome data for consecutive patients with severe sepsis and two or more organ failures who had procalcitonin levels greater than ng/ml at the time of critical care admission. pct was measured using the brahms pct-q immunochromatographic test. patients were divided into groups depending on whether or not they received drotrecogin alfa (activated). for all patients we recorded age, sex, apache ii score, and outcome at days. risk of death and standardised mortality ratio (smr) were then calculated. between july and november a total of patients with severe sepsis and multiple organ failure had pct > ng/ml. fourty-seven were not given daa because of or more contraindication or because their prognosis was so poor. the results are shown in the table. the smr was lower in the group not given daa. in patients with very high pct > ng/ml there was no reduction in mortality associated with the administration of daa. it is known that mortality increases with elevated pct > ng/ml and there may be a point at which the physiological derangement is so severe that daa is less effective. given that this drug is expensive and has significant side effects it would be prudent to avoid its use under such circumstances. pct may be useful in selecting patients for this treatment if our results are repeated in a larger study. since adrenergic stress and catecholamine-induced myocardial stunning may contribute to the pathogenesis of septic cardiomyopathy we evaluated the effects of beta blockers in patients with septic cardiomyopathy and shock. twenty patients with septic shock requiring milrinone therapy who were treated with enteral metoprolol after stabilization of cardiovascular function and within hours after onset of shock were included into the retrospective study protocol. hemodynamic, laboratory and clnical data documentation was performed immediately before, , , , , , and hours after the first metoprolol dosage. the incidence of the following adverse events was evaluated during metoprolol therapy: symptomatic or asymptomatic bradycardia, decrease in mean arterial blood pressure, cardiac or stroke volume index, central venous oxygen saturation, and hypoglycemia. descriptive methods and a linear mixed effects model was used for statistical analysis. metoprolol therapy was started after cardiovascular function had been stabilized ( . ± . hrs after onset of shock) and was targeted to reduce heart rate to - bpm. hemodynamic data and laboratory parameters were documented immediately before, , , , , , and hours after the first metoprolol dosage. a linear mixed effects model was used for statistical analysis. heart rate (p< . ), central venous pressure (p= . ), norepinephrine (p< . ) and milrinone dosages (p= . ) significantly decreased during beta blocker therapy. cardiac, stroke volume and cardiac power index remained unchanged. metoprolol was discontinued in two patients because of asymptomatic bradycardia. norepinephrine and milrinone dosages had to be increased in seven and four patients, respectively. in none of the four patients with a decrease in cardiac index a decrease in central venous oxygen saturation occurred. arterial lactate levels (p< . ) and c-reactive protein serum concentrations (p= . ) decreased during the observation period. enteral metoprolol therapy in combination with phosphodiesterase inhibitors seems to be safe and may be beneficial in patients with septic cardiomyopathy and shock. further studies on the use of beta blockers for septic cardiomyopathy are warranted. septic shock represents the leading cause of mortality in critically ill patients worldwide. the cornerstone of therapy continues to be early recognition and prompt initiation of antibiotic plus hemodynamic support measures. continuous renal replacement therapies (crrt) seem to play an important role in the early management of septic patients with acute renal failure, based on classical depuration properties and mediator clearance capacity. different crrt include: -convection techniques as high-volume hemofiltration (hvhf). -adsorption techniques as coupled plasma filtration adsorption (cpfa); introduced in recent years,it's a technique that separates plasma from the blood by means of a plasma filter. the plasma is then passed through a synthetic resin cartridge and returned to the blood. a second blood filter is used to remove excess fluid and small molecular weight toxins. the aim of this prospective and not randomized study was to analyze and compare the hemodynamic effects of both techniques(hvhf and cpfa). we studied twelve patients (n= ) with septic shock and acute renal failure. we initiated either of the two crrt when patients fullfilled renal depuration criteria. we analyzed the clinical effects by measuring main hemodynamic parameters and vasoactive drugs requirements during the first twelve hours. we started cpfa in four patients (mean age was years, % were male, and mean apache ii was ), and hvhf in eight patients (mean age was years, % were male, and mean apache ii was ). in table we represent the variation percentages in main hemodynamic parameters and norepinephrine requirements after the first twelve hours of crrt. no adverse effects due to crrt were registered. (up to %) . the aim of this study was to analyze the clinical presentation and to evaluate mortality associated factors (timing and accurancy of diagnosis, timing of surgery, severity score and organ failure, surgical and medical treatments). this study retrospectively investigated the medical records of patients (pts) diagnosed and treated for nf who were admitted to a -bed general icu from to . the pt characteristics are shown in table . the mean delay from onset of symptoms and hospital admission was . ± days. the provisional clinical diagnosis was incorrect in % pts. eighty % of pts was admitted with clinical signs of septic shock (ss). the mean time from diagnosis until surgery was ± , hrs. all pts underwent a mean of ± , surgical procedures related to necrotic tissue debridement. the wounds were sealed with a vacuum-assisted closure device which was exchanged every days until second intention healing. only pt required above-knee amputation. after surgery % of pts were submitted to hyperbaric oxygen therapy (n= - /pt). all pts received broad-spectrum antibiotics therapy which was changed according to the results of culture and sensitivity. mechanical ventilation was performed in all pts for respiratory failure (mean time= , ± days). two pts required surgical tracheostomy at admission for airways obstruction due to nf. all pts were in ss requiring vasopressor therapy for , ± days. thirty % of pts showed renal dysfunction (rifle class injury) and % were treated with high volume hemofiltration for anuric renal failure. disseminated intravascular coagulation was diagnosed in % of pts. low dose steroids were prescribed in % of pts and pts were treated with apc. the average lenght of icu and hospital stay were respectively of , ± and , ± days. overall mortality in our series was %. two pts died of severe ss and mof. in one case hyperkaliemia of unknown origin (after ss resolution) was fatal. sepsis is a common source of morbidity and mortality among critically ill patients. targeting measures to reduce the incidence and promote early recognition and treatment of sepsis is at the forefront of many critical care initiatives. advances in the management of severe sepsis have evolved over recent years in an attempt to combat the spiraling mortality trends. the "surviving sepsis campaign" (ssc) is a worldwide initiative promoting the evidence-based treatment of sepsis, with the explicit goal of reducing both the morbidity and mortality associated with sepsis. protocol watch (pw) was developed as a tool to assist clinicians at the bedside with the implementation and compliance of the ssc guidelines. participants were critically ill patients in -bed intensive care unit in a large university-affiliated teaching hospital in the northwestern united states. prior to the installation of pw, implementation of the ssc was done using a paper-based system of standing orders. base line data on compliance with the ssc guidelines were collected. protocol watch, which offers an electronic version of the guidelines and is resident on the bedside patient monitor, was then installed in all critical care beds. the post pw installation data collection is currently being completed. preliminary results show a significant improvement in both the early identification of sepsis as well as compliance with the ssc guidelines. in addition, the feedback from the clinical users has been extremely positive. if the final data analysis supports the preliminary findings, pw could emerge as an important method for assisting in the implementation of the ssc guidelines, thus making a valuable contribution in the care of critically ill patients with sepsis. hyperglycemia during acute brain injury such as ischemic stroke, cerebral hemorrhage, or head trauma is frequent and is associated with increased morbidity and mortality [ ] . there is also a profound increase in glucose utilization (hyperglycolysis) that can persist for up to one week after traumatic brain injury (tbi). however, little is known about the optimal glycolytic rate and about the influence of intensive insulin therapy on the tbi-induced changes in glucose metabolism [ ] . this study was designed to estimate the safety of routine versus intensive insulin therapy on the basis of hypoglycemic episodes defined as blood glucose concentration < . mmol/l (< mg/dl), in patients admitted to intensive care unit (icu) after severe tbi. in this prospective, single-blind, randomized clinical trial patients admitted after severe tbi, were enrolled and randomly assigned to one of two groups on the basis of the targeted levels of glycemia. insulin infusion was administered either at conventional rates, to maintain glycemia at . - . mmol/l ( - mg/dl), or intensive rates, to maintain glycemia at . - . mmol/l ( - mg/dl). hypoglycemic episodes, duration of icu stay, infections rate, mortality and neurologic outcome measured using the glasgow outcome scale (gos) at months follow-up, were recorded. in patients receiving intensive insulin therapy, hypoglycemic episodes were significantly higher ( . % vs . %, p< . ), duration of icu stay shorter ( . vs . days; p< . ), and infections rate lower ( . % vs. . %, p< . ) than in patients treated with conventional insulin therapy. mean gos and overall mortality at months were similar in the two groups ( . % vs. . %). intensive insulin therapy significantly increased the risk of hypoglycemic episodes. despite the shorter icu stay and lower infection rates, no differences were observed at months follow-up mortality and neurologic outcome. therefore, in tbi patients receiving intensive insulin infusion, whether to avoid episodes of hypoglycemia either with a stricter blood glucose monitoring or with a wider target blood glucose level needs further investigation. severe head injuries are a frequently encountered problem in intensive care medicine, and a cause of significant mortality and long term morbidity. various clinical features related to the initial trauma and secondary brain injuries are associated with adverse outcomes. [ ] we developed a head injury database, and investigated the management and outcome of head injured patients in our department, with particular emphasis on ventilation and haemodynamics in the pre-hospital and resuscitation phases. in this observational cohort study we collected data on head injured patients admitted to the icu at the royal london hospital (rlh) between march and november . demographic, clinical and outcome data was extracted from the patient notes and the icnarc database and then entered in a data collection proforma and subsequently in a ms excel spreadsheet for analysis. outcome measures were primarily mortality, and for survivors, the length of stay both in intensive care and in hospital were recorded. data was collected on head injured patients. the group of patients that died tended to be older, to have a lower gcs at the scene, a higher systolic blood pressure both at the scene and in the emergency department, and a lower pao in the emergency department although these results were still in the physiological range for the majority of patients. of the patients that had abg results recorded, only % had an initial paco < . in the emergency department. the lowest mortality ( . %) was associated with an initial a&e paco in the range . - . kpa. the mortality rate for patients brought directly to rlh was . % compared with . % for patients transported from other hospitals. ( , ) . we evaluated the association between bnp and the presence of sah, intracranial hypertension, hyponatremia, csws as well as water and salts balance in patients with severe traumatic brain injury (tbi). we examined patients with severe tbi coming from emergency ward. serum bnp was measured five times: t ( ˚- ˚day), t ( ˚- ˚day), t ( ˚- ˚day), t ( ˚- ˚day), t ( ˚- ˚day). daily and cumulative balance of water, sodium and potassium were calculated for all the patients. the presence of hyponatremic events, csws, intracranial hypertension episodes, sah (tc evidence) and the use of cathecolamines were notified, as well. seventeen male patients were included in the study (with a total of days of monitoring in icu and samplings of bnp). no association between bnp and the other observed variables (hyponatremia, csws, sah, the use of cathecolamines and intracranial hypertension) was observed. on the other hand, positive correlations between bnp levels and cumulative sodium balance (r= , ; p< , ) as well as between bnp and water balance (r= , ; p< , ) were observed. bnp level was higher in patients with positive cumulative sodium balance than in patients with negative balance: mean (sd) , ( ) pg/ml vs ( ) pg/ml (p= , ), respectively. bnp levels were also higher in patients with positive cumulative water balance: mean (sd) , ( , ) vs , ( , ) pg/ml (p= , ), respectively. our study does not confirm the role of bnp in the genesis of hyponatremia and csws. moreover, observing higher bnp levels in patients with positive sodium and water balance, we conclude that bnp in patients with severe tbi has a physiological role in the regulation of water and salts balance in order to avoid the excessive expansion of extracellular compartment. brain tissue oxygen monitoring plays important role in prevention of secondary brain injury. values of partial brain oxygen pressure (pbto ) in first hours after severe brain trauma should predict final patient's outcome. aim of this study is to analyze relationship between early values of brain oxygen in severe head trauma and the patient's outcome one year after this traumatic accident. study follows up our previous observation. we analyzed data of consecutive adult patients treated in our icu during time period of month for severe head trauma with glasgow coma scale (gcs) and less and with monitoring of intracranial pressure (icp) and partial brain oxygen pressure (pbto ). we placed sensor for pbto monitoring at the same time as icp sensor. all patients were treated according standard therapeutical protocol used in our department. target of our treatment was to avoid icp hypertension, to maintain cerebral perfussion pressure above mmhg and to reach optimal pbto levels. we compared data of first hours of the treatment in icu with neurological status using glasgow outcome scale (gos) in time intervals , and months after trauma in all patients. all this studied patients were already not at these times treated in our hospital. group with gos at the time of leaving icu had patients and initial values of pbto in first hours of treatment , mmhg (mean). group with gos had patients and initial valus of pbto , mmhg (mean). from this group patients died a one improved to gos . group with gos had patients, initial values of pbto , mmhg. from this group patients improved to gos and patients to gos , both in months. there were no changes in neurological status between and month after injury. group with gos had no patients. group with gos had patients and initial values of pbto , mmhg at a time of leaving icu. conclusion. there were found in our study no clear relationship between initial values of brain tissue oxygen and long term outcome. patients in vegetative state at a time of leaving of icu had in our group bad prognosis. all patient with severe dissability improved. values of brain tissue oxygen were in this group below mmhg. group with gos had values also relative low. we have no database of patients treated without brain tissue oxygen monitoring to make direct comparation and to evaluate real benefit of brain tissue oxygen monitoring. can protein s predict neurological deterioration after moderate or minor traumatic brain injury? p. bouzat* , p. jaffres , p. declety , j. brun , g. francony , j. c. renversez , a. kaddour , c. jacquot , j. f. payen department of anaesthesiology and critical care medicine, department of biochemistry, department of emergency medicine, albert michallon hospital, grenoble, france serum protein s "eta (ps ) is believed to reflect brain damage following traumatic brain injury (tbi). since patients with moderate tbi (glasgow coma scale, gcs, score - ) or minor tbi (gcs - ) may be at risk for subsequent neurological deterioration, we wondered whether the determination of serum ps on admission could be associated with the neurological outcome. methods. patients with moderate or minor tbi were prospectively studied. they had normal or moderate ct scan (trauma coma data bank, tcdb, classification i or ii, respectively) on admission. serum ps dosages were performed on admission within hours post-injury using a commercially available kit (elecsys s roche, detection limit . mathrmµg/l). neurological outcome was assessed up to days after trauma. secondary neurological deterioration was defined as a decrease in gcs score of points or more from the initial gsc score, or any treatment for neurological deterioration. two groups of patients were defined : group (absence of secondary neurological deterioration) and group (presence of neurological deterioration). data are expressed as median and range. univariate analysis (non parametric mann-whitney test, chi test) was used to identify factors related to the neurological outcome. . patients had a secondary neurological deterioration days after trauma (group ). they had significant higher gcs score and more injuries on ct than group . however, serum ps were not different between the groups (table) . ( - ) serum ps (µ µ µg/l) . ( . - . ) . ( . - . ) tcdb classification i/ii (n) / / ** gcs score on admission ( - ) ( - )** **p< . conclusion. serum ps cannot be viewed as a biological marker for detecting patients at risk for neurological deterioration after minor or moderate tbi. the contribution of this blood sampling is not as informative as a ct scan or the gcs. methods. seventy patients with traumatic brain injury (tbi) and stroke with glasgow coma scale (gsc) < were evaluated. thirty-degree head-up position was used during the study. icp was monitored during the following procedures: chest compression, vibration associated to chest compression, unilateral continuous chest compression, tracheal suction with open circuit and closed circuit, passive mobilization of arms and legs, hip rotation, scapular mobilization in lateral decubitus and lateral flexion of the lower trunk. wilcoxon test was used to evaluate changes on icp during the procedures. algorithm of intracranial hypertension (ich) therapy in patients with tbi should be modified on the base of the level of cerebral autoregulation (ca) impairment. the aim of the study was the application of the pressure reactivity index (prx) monitoring in the treatment of tbi patients. tbi patients with gcs< underwent the monitoring of the arterial blood pressure (abp), icp, prx. analog outputs from the monitors abp and icp were connected to the analog-to-digital converter (dt , data translation) installed into a laptop computer. data were sampled, digitized, and stored on the hard disk with the software for the waveform recording. digital signals were processed with software (icm plus, england). the therapeutic strategy modified on the base of results clinical evaluation and prx, abp and icp. all the patients were divided into two groups. patients had preserved ca with prx [- ; , ], gcs , +/- , ; icp , +/- ;cpp , +/- mmhg. in patients gos was favorable ( -with good recovery; -moderate disability) and unfavorable in patients ( -severe disability; -vegetative state). in this group we used iv infusion of colloids and vasopressors for cpp-protocol. in patients were determined "optimal" levels of cpp: in it was - mmhg, in - - mmhg, and in - - mmhg. in patients developed ca failure on the day after brain trauma and uncontrolled intracranial hypertension demanded decompressive craniotomy. second group included patients with impaired ca -prx [ , ;+ ], gcs , icp , +/- , , cpp , +/- mmhg. gos: both patient had unfavorable outcome (one-severe disability, other-vegetative state). conclusion. the monitoring of prx added to routine measuring of the abp and icp in tbi patients is helpful in choice of the best therapeutic strategy. grant acknowledgement. we thank dr. marek czosnyka and peter smielevski for their scientific support. a. raigal*, g. hernandez, l. marina intensive care unit, hospital virgen de la salud, toledo, spain severe traumatic brain injury (tbi) defined with a glasgow coma score (gcs) ≤ with normal or near normal craneal ct at hospital admission (type i-ii traumatic coma data bank classification) represents a common clinical dilemma about the real severity of cerebral lesions and neurological prognosis. the aim of the study was to relate some clinical factors with a higher probability of developing neurological complications (intracraneal hypertension) and bad neurological function on icu discharge defined as the presence of a motor component of gcs≤ . retrospective series of patients consecutively admitted for severe tbi in the general -bed icu of a tertiary trauma center during one year. we study patients with craneal ct admission classified as tcdb i-ii, after excluding those with another non traumatic cause of the coma and encephalic death on admission. after the admission ct the radiologic study was repeated in the first hours posterior to the trauma. icp was monitorised in all patients with tcdb> in the second ct or type i and confirmed gcs ≤ after transitory withdrawal of any sedative agent. the radiologic study was repeated after hours, on the th day and if the clinical evolution or icp required it. epidemiological, clinical and radiologic associated variables were also analysed and the gcs at icu discharge. a multivariant study was done adjusted by age, genre, initial gcs, radiologic lesion, associated trauma lesions and vital signs during the early phase of the traumatic injury (arterial oxygenation, blood pressure, etc). five patients ( %) had a poor gsc on discharge (m≤ ). those five patients showed an early damage of tcdb type at second ct and hypericp during icu admission. a sixth patient showed unfavorable outcome of the second ct with normal icp and gcs= on discharge. of the left over patients with a favorable neurologic evolution, showed hemodynamic and/or respiratory deterioration. the multivariant study displayed a relation between the early progression of lesions in the second craneal ct (or . , % ci: . - . ) with increase of icp or a poor gcs on icu discharge. also, the presence of systemic factors associated to admission was related to a good gcs on discharge (or . , % ci: . - . ). conclusion. . the early progression of type tcdb is related to hypericp and bad neurologic prognosis on icu discharge. . systemic factors in the initial phase of trauma (hypotension, hypoxia, etc) are related in these patients with a good final neurologic outcome, absence of both radiologic deterioration and intracraneal hypertension. the glasgow coma score on hospital admission has been shown to be correlated with outcome in patients with traumatic brain injury( ). however many patients who arrive at a neurosurgical referral centre have been sedated and intubated some time prior to transfer and so their glasgow coma score cannot be accurately recorded. an option in these cases is to use the last recorded score prior to sedation and intubation. this may be the glasgow coma score recorded in the accident and emergency department of the referring hospital, or in some cases that recorded on the ward after deterioration. in some cases the only available score is that recorded at the scene of the injury. in our study we examined the degree of correlation between these various glasgow coma scores and outcome at one year in order to assess the validity of using a surrogate for the admission glasgow coma score when this is not available. data were collected prospectively on all patients admitted to the queens medical centre from to with a recorded glasgow coma score of or less within hours of a traumatic brain injury. three glasgow coma score groups were identified. patients in group (certainty factor ) had a glasgow coma score recorded on admission to the queens medical centre. group (certainty factor ) was made up of patients in whom the last pre sedation and intubation glasgow coma scores was recorded at the referring hospital. in group (certainty factor ) the glasgow coma scores were recorded at the injury scene. for each group we looked at the strength of the association between the glasgow coma score and glasgow outcome score using linear regression analysis. results. data were available on patients. mean age years (range - ), % male and % victims of road traffic accidents. linear regression between the glasgow coma score and glasgow outcome score was highly significant in all three groups (p = < . for all three groups). the strength of the association was similar for groups and and superior to group (r = . for group , r = . for group , r = . for group ). we found a good correlation between the glasgow coma scores and outcome for all three groups. the best predictor of outcome is the glasgow coma score actually recorded on admission to the referral centre, but the pre-intubation glasgow coma score at the referring hospital provides an acceptable alternative. head injury remains a common cause of hospital admission, morbidity and mortality. uk recommendations are that all head injuries are managed either in the emergency department or the regional neurosciences centre. many patients are managed in local hospitals despite evidence that outcomes are improved by specialist care. we reviewed outcome data for all head-injured patients admitted to a regional centre over a -month period (sept -aug ). consecutive adult patients (> years) were studied prospectively. gcs following resuscitation, demographic data and surgical intervention were recorded. glasgow outcome scores were determined at discharge from the regional centre, and at and months following injury. whilst at the regional centre, patients were managed according to locally established protocols. . patients were admitted ( m, f). gcs following resuscitation was - in patients, - in , and < in . patients were aged - years, were - years and > years. patients had evacuation of an extradural haemorrhage, had evacuation of a subdural haemorrhage, had contusionectomies and patients required decompressive craniectomy. gos data were available for all patients at discharge, at months and at months (table ) . for patients with initial gcs < , gos was available for at discharge, at months and at months ( table ). mortality from head injury was % with only / patients with severe head injury dying. patients were discharged in a vegetative state with only remaining so at months. a bolus infusion of . % saline in % hydroxyethyl starch / . (hs) attenuates mean intracranial pressure (icp) in patients suffering from spontaneous subarachnoid hemorrhage (sah) ( ). it has been suggested that intracranial pulse pressure is more useful for prediction of intracranial compliance than mean icp alone ( ) . in this study, the effect of an infusion of hs on the parameter mean icp wave amplitude (i.e. intracranial pulse pressure) is compared with the effect on mean icp. prospectively collected data was retrospectively analyzed. all patients included were sedated and mechanically ventilated patients suffering from spontaneous sah. nine patients received infusions of hs, mean . (range . to . ) ml/kg. mean values of a minute period just prior to the infusion were compared with a -minute period after maximum effect was reached. results. the mean icp wave amplitude decreased . mmhg ( % confidence interval - . to - . ) from a baseline of . (sd . ) mmhg, p = . . mean icp decreased . mmhg ( % confidence interval - . to - . ) from . (sd . ) mmhg, p <. . comparing mean icp and mean icp wave amplitude, there was no statistically significant correlation for baseline values or change (table ). there was a stronger correlation between baseline values and change for mean icp wave amplitude than for mean icp (table ) . this study documents an effect of osmotherapy on intracranial pulsatility; mean icp wave amplitude was attenuated after infusion of hs. this reduction was strongly correlated to baseline mean icp wave amplitude. however, regarding the association between mean icp wave amplitude and mean icp, we found neither any correlation for baseline values nor for change after hs infusion. hence, monitoring of one parameter can not substitute the other. the value of mean icp wave amplitude in clinical practice should be further evaluated. hyponatraemia is an important electrolyte dysbalance in acute brain diseases. there are two known syndromes: the more frequent cerebral salt wasting (csw) syndrome due to natriuresis, and the less common syndrome of inappropriate secretion of antidiuretic hormone (siadh) caused by free water retention. differentiation between them can be made using renal function parameters, and is essential because each syndrome requires different therapy. we retrospectively analysed all patients (pts) with acute brain diseases admitted to our neurologic-neurosurgical care unit (nnicu) over a period of five years who developed hyponatraemia (serum sodium < ). first we divided them according to measured serum osmolality (normal values - mmol/kg) and then we evaluated the group with hypoosmolality (s osm < mmol/kg). the type of hyponatraemia was diagnosed using renal function parameters established in clinical practice in our nnicu. there were pts (mean age +/- yrs, m ) with days of hyponatraemia. the majority of pts had normal serum osmolality ( pts, days), some had hyperosmolality ( pts, days) and only pts ( days) had low plasma osmolality. osmolality was not measured for the remainder. pts in the hypoosmolal group (mean age +/- yrs, m ) were with the following diagnoses: subarachnoid haemorrhage , intracerebral haemorrhage , ischemic stroke , tumour , trauma , infection and others . the mean gcs at the start of hyponatraemia was . (range - ), the mean discharge gos was . (range - ). hyponatraemia lasted from to days (mean . days) and in patients was already present on the day of admisson. the mean value of hyponatraemie was . mmol/l (range - mmol/l, p< . ) and the mean value of serum osmolality was . mmol/kg (range - mmol/kg, p< . ). the mean increase of natraemia over hours was . mmol/l (range - mmol). no patients had central pontine myelinolysis. renal function parameters were examined in patients ( %), of whom patients were diagnosed csw syndrome (diuresis +/- ml/day; fu na+ . +/- . mmol/day, p< . ; c osm . +/- . ml/s, p< . ; c el . +/- . ml/s, p< . ; c na+ . +/- . ml/s, p< . ; ewc - . +/- . ml/s, p< . ; fe na+ . +/- . , p< . ), patients had other causes of hyponatraemia and no one siadh. renal function parameters are very useful to diagnose the type of hyponatraemia and available to put into clinical practice. hyponatraemia with hypoosmolality is not so frequent, and csw syndrome is more prevelant then siadh. microbial colonization of the respiratory and gastrointestinal tract (rt and gt) of a critically ill patient is an early event in the chain leading to invasive infection. systematic colonization surveillance permits monitoring of transmission dynamics, early detection of epidemics in the icu and possibly guidance for adequate empiric antimicrobial treatment in infectious episodes. we retrospectively analyzed the ability of colonization surveillance to predict microbial etiology of subsequent infections and permit adequate empiric therpay in septic episodes. the study was performed in a -bed general icu from november to december . infection control policy included weekly surveillance cultures of bronchial secretion and stool samples. all cases of ventilator-associated pneumonias (vap) and bloodstream infections (bsi) during the study period were recorded and the relationship between infectious etiology and most recent colonization was analyzed, based on species, antimicrobial susceptibility patterns and molecular typing by rep-pcr of selected isolates. in cases of new septic episodes, empiric treatment was determined, among other risk factors, by the antimicrobial susceptibility of most recent colonizers in either the rt or gt. during the three years of the study, we recorded vap and bsi cases ( catheter-related). pathogens isolated from vap cases correlated with bronchial or stool colonizers in %, with prior rt colonization being most important. in bsi cases, gram-negative pathogens were recent colonizers in % associated with both the gt and rt. no relationship was observed between gram-positive colonization and subsequent infection. rep-pcr techniques confirmed pathogen and colonizer concordance in all cases tested. systematic colonization surveillance use to determine empiric antimicrobial treatment in new vap episodes permitted % adequacy, compared to only % if the hellenic society of intensive care vap guidelines were used. empiric treatment for bsi cases was adequate % of the time. conclusion. rt and gt colonization is strongly related to microbial etiology of subsequent infection. systematic weekly colonization surveillance of rt and gt specimens could be helpful in implementing adequate antimicrobial therapy, especially for multidrug resistant gram (-) pathogens, in the icu. s. barbadillo* , m. olsina , a. leon intensive care unit, microbiology, capio hospital general de cataluña, sant cugat del vallés, spain production of extended-spectrum beta-lactamases (esbl) by enterobacteria is an important resistance mechanism against antimicrobial beta-lactamics. klebsiella pneumoniae and escherichia coli (esbls) strains had mostly been described but infection due to enterobacter producing extended-spectrum beta-lactamases (esbls) is a relatively uncommon clinical entity. this study was performed to investigate the risk factors associated with the acquisition of enterobacter-esbls strais infections in an intensive care unit (icu). this case-control study took place at a tertiary spanish hospital with a polyvalent icu beds from january to december . demographic data, underlying diseases, risk factors, length of icu stay and hospitalization and antimicrobial treatment were investigated by comparing infections due to enterobacter esbl-positive to cases due to esbl-negative strains. enterobacter were tested for esbl production by double disc diffusion synergy test (ddst) as well as by the mic reduction test. thirty-six enterobacter infections over a period of years were collected. ventilator associated pneumonia was the most frequent infection ( %). nine cases ( %) of esbl-producing eneterobacter isolates were compared to those infections with enterobacter non-esbl. days of mechanical ventilation, length of icu stay, tracheotomy, peripherical venous catheter and administration of cephalospin were all associated with esbl-enterobacter infections in the univariate analysis. there was not differences for sex, age, prognostic scores and mortaliy between groups. the multivariate analysis revealed the administration of broadspectrum cephalosporin as the unique risk factor for the presence of esbl-producing strains [odds ratio (or) . ; % confidence intervals (ci) . - . ; p= . ]. use of cephalosporines was associated with enterobacter esbl-positive isolates. thus, rational antimicrobial administration and antibiotic protocol regimens appears to be critical for control emergence of esbl production. to evaluate and characterize the ni in two intensive care units (icu) of a central portuguese hospital. a retrospective study of patients with ni, hospitalized in two icu (one medical and other surgical)between / / and / / identified by a computer-based program vigi@ct (biomerieux) and confirmed after. in the surgical icu we found episodes of ni. of this ( . %) were respiratory infections; ( . %) were surgical site infections and ( . %) bacteriemias. in the respiratory infections the most frequent agents were acinetobacter baumannii ( - . %) and pseudomonas aeruginosa ( - . %). enterococcus faecalis ( - . %) was the most frequent in surgical site. staphylococcus epidermidis ( - %) and acinetobacter baumannii ( - . %) the most frequent agents in bacteriemias. among all microrganisms . % of acinetobacter baumannii; . % of pseudomonas aeruginosa and . % of klebsiella pneumoniae were multiresistent bacteria (mrb). in the medical icu we found episodes of ni. half of these were due to respiratory infections ( - %), ( . %) were bacteriemia and ( . %) were urinary infections. pseudomonas aeruginosa was the most frequent microrganism ( - . %) among respiratory infections. in the bacteriemias coagulase negative staphylococcus (cns) (staphylococcus epidermidis and staphylococcus hominis) were the agents most frequently found ( - . %). escherichia coli was the bacteria most isolated in urinary infections ( - %). in medical icu we found mrb, among these were pseudomonas aeruginosa ( . %); were staphylococcus epidermidis ( . %) and ( . %) were acinetobacter baumannii. conclusion. ni is a significant problem in our icu's. we found more ni episodes in the surgical icu than in the medical. respiratory infection were the most common ni in both icu. as expected surgical site infection is also a serious occurence in the surgical icu as well bacteriemia. in the medical icu bacteriemia was also a considerable issue. gram negative bacteria and cns were predominat in this ni. acinetobacter baumannii was the most frequent mrb. we study retrospectively icu pts, men ( %), women ( %) who developed bacteremia. all had been operated at least once under general anaestesia. mean age: . ± . years, length of stay (los): . ± . days. all were mechanically ventilated and were divided in groups according to their age: group a ( . %) < and group b ( . %) ≥ years. in groups a and b we had respectively: mean age: . ± . and . ± . years. los: . ± . and . ± . days. underlying diseases: multiple trauma ( . %) and ( . %), complicated surgery ( . %) and ( . %), other ( . %) and ( . %). in groups a and b respectively: site of infection: pneumonia ( . %) and ( . %), intra-abdominal infection ( %) and ( . %), central venous catheter-related infections (cvc-ri) ( . %) and ( . %), other ( . %) and ( . %). invading microorganisms in single strain bacteremia: ps. aeruginosa ( . %) and ( . %), ac. baumannii ( . %) and ( . %), st. aureus ( . %) and ( . %), kl. pneumoniae ( . %) and ( . %), st. epidermidis ( . %) and ( . %), other and ( . %). mods occurred in ( . %) and ( . %). mortality rates (mr): / ( . %) and / ( . %). global mr: / ( . %). conclusion. ) cvc-ri appeared more frequently in elderly (p< . ), while all other sites of infection did not differ. ) invading organisms were similar in both groups except ac. baumannii which was isolated much more frequently in younger pts and very rarely in the elderly (p< . ). the resistance was similar in both groups. ) los was smaller in elderly (p< . ). ) elderly developed more frequently mods (p< . ) and had higher mr (p< . ), while the outcome of the infection was independent of the type of invading organism and its resistance. j. pavleas , a. skiada* , g. thomopoulos , i. stefanou , n. kouna , b. kaitanidi , a. salvari , p. tassiopoulou , a. papadopoulou , e. christofilou intensive care medicine, laikon general hospital, research laboratory for infectious diseases "g.l. daikos", athens university, microbiology laboratory, laikon general hospital, athens, greece nosocomial catheter-related bloodstream infections (cr-bsi) have been associated with increased morbidity and possibly increased mortality in critically ill patients. the aim of this study was to analyze the epidemiology of cr-bsis in our intensive care unit. prospective epidemiological study, in a mixed icu of a tertiary care hospital, of the incidence of cr-bsis, the responsible bacteria and the outcome of the episodes of bacteremia. the demographic and clinical characteristics of all patients admitted in the icu were recorded. each bacteremia recorded was classified as primary, catheter-related or secondary. the study took place in a tertiary care hospital, mixed icu, during a thirty-two months period. three hundred and thirty patients were admitted. their mean age was years and % of them were male. mean apache score was and the mean duration of stay in the icu was days. the total number of bloodstream infections (recorded in patients) was . of these, % were catheter-related. specifically, sixty-five cr-bsis occurred in catheter days ( . per catheter days). sixteen cr-bsis were due to gram-positive ( methicillin-resistant staphylococcus aureus, coagulase-negative staphylococci and enterococcus spp.) and to gram-negative bacteria ( acinetobacter baumanii, pseudomonas aeruginosa, klebsiella pneumoniae and one each of morganella morganii, enterobacter cloacae and serratia marcescens). of the gram-negative bacteria, % were multi-drug resistant, while % of the enterococci were vancomycin resistant. a positive outcome was noted in % of the catheter-related and in % of the other bacteremias. although cr-bsis have a better prognosis than the other bacteremias, they are still a serious cause of morbidity and mortality in the icu. since these infections are preventable, appropriate measures should be meticulously applied. opportunistic invasive aspergillosis in an immune compromised patient is being increasingly reported. however, this condition is thought to be rather rare in an immune competent host and therefore often unrecognized. we report two cases of invasive aspergillosis in patients without previous medical history of conditions leading to immune compromised status admitted to our intensive care unit. first case concerns a -year old woman who underwent an exploratory laparotomy because of acute abdomen without any significant findings. in the postoperative period, the patient developed sepsis with multiorgan failure necessitating ventilation, vasopressive and inotropic support and hemofiltration. early microbiologic analysis of the sputum showed an aspergillus fumigatus and patient was treated with voriconazol. the further evolution was unfavorable with hemodynamic instability and the patient died after two months of treatment. the autopsy revealed a severe tracheobronchitis and aspergillus endocarditis. the second patient, a -year old man admitted to our intensive care unit due to recurring arterial embolism and fever was diagnosed culture-negative endocarditis of the native mitralis valve on the transoesophageal echocardiography. subsequently, patient underwent a successful valve replacement. the culture of explanted valve revealed an aspergillus fumigatus infection and appropriate antimycotic treatment was started. in the postoperative period, the course was complicated by a sudden neurological condition with altered consciousness and patient eventually died of cerebral aspergillosis. in both patients, an exogenous infection possibly took place. the first patient was admitted to our hospital during the reconstruction work next to the intensive care unit. this may have led to her exposure to increased pathogen load during the early postoperative period. the second patient probably contracted the infection during the reconstruction work he was executing himself at his house before the admission to the hospital. invasive aspergillosis is a severe condition which is not only limited to patients with immune compromised status. alertness of the physicians ensuing in early diagnosis may be crucial for determining the individual patient prognosis. k. clabault* , f. soulis , m. tavolacci , g. beduneau , f. tamion , g. bonmarchand , j. richard medical intensive care unit, epidemiology and public health, rouen university hospital, rouen, france introduction. surgical hand rubbing (sr) has been proved to be an efficient alternative to traditional hand scrubbing. we tested an educational program based on continuous direct observing practice in order to implement this technique in a medical icu. residents and medical students benefit from an educational program included a ten minutes video demonstration of the sr presented by the infection control practionner. results of each observation was immediatly feed back to residents. medical students were encouraged to complete a form for each sr occuring h activity. data collection were due to sr (in emergency or not), duration of sr procedure, quantity of alcohol hand based (ahr) rub used. two successive groups of residents and groups of students participated to the study. two hundred and twenty-five observations were performed during a month period. the mean of the procedure time was s (sd . ). time expected according to the institutionnal protocol was s. . % of sr was inferior to mn , . % between mn and mn , . % superior to mn . time of sr did not differ between emergency or planned procedure ( s vs s, p= . ). cumulative volume of ahr was significantly correlated with duration of the procedure (r= . ,p< - ). our study suggest that implement of a new procedure of surgical hand disinfection in a icu is feasible on result on good adhesion of educated residents. the original method based on a audit performed by medical students may allow both hand hygiene education and adherence to an infection control program of future practionnners. infection surveillance: it is based in the unit not in the patient, using the envin-helics tool. this information from the patients was gathered: age, diagnosis on admission, apache ii, exposure and use to invasive devices (mechanical ventilation, central venous and urinary catheter). a multidisciplinary team from microbiology, preventive and intensive care units composed the team. the criteria for infection diagnosis were those from the cdc. incidence rates were calculated. handwashing surveillance: it was recorded in two periods: january-march (p ) and october-december (p ); each observation period lasted minutes. we observed the opportunity, defined as every time in which an indication for handwashing exists. . patients were enrolled, , % male, mean age ± ; more frequence of patients with medical pathology ( , %) with a media ± standard deviation of , ± , . apache ii . ± , . overall mortality rate was , %. a greater incidence of infections were found in the traumatic group. there is a large number of central venous catheter (use rate , %, , %:coronary patients). infections were detected as acquired in our unit ( , % and , %o patient-day). the respiratory tract infections and bactraemias were the most frequent localizations, with ventilator-associated pneumonia (vap) as the predominant nosocomial infection ( . % over total infections; , % in intubated patients, an incidence rate of , %o). there were two outbreaks of methicillin resistant staphylococcus aureus (mrsa). thus, the most frequent were pseudomona aeruginosa ( , %), escherichia coli ( , %) and staphylococcus aureus ( , %); acinetobacter baumanii and methicillin resistant staphylococcus aureus were quite very infrequent ( , % and , % repectively). opportunities of handwashing were detected (p : , p : ). the compliance increased from , % in p to , % in p . conclusion. )nosocomial infections affected to one out of five of the admitted patients. the vap was the most frequent infection. )we had a large rate of vap but similar to spanish standard ( , / days of use of mechanical ventilation). )the microbiology was similar to other critical care units, with a predominance of pseudomona aeruginosa. there were two outbreaks by mrsa. ) despite an increase in handwashing compliance, the rate of vap did not was lowered. m. karvouniaris* , s. xitsas , p. kasviki , d. lagonidis , m. stougianni , a. tefas icu, microbiology lab, general hospital of giannitsa, giannitsa, greece introduction. icu physicians are nowadays faced with the formidable task of dealing with bacteria that can hardly treat. multidrug resistant gram(-) bacteria are usually isolated from brocheal aspirates and associated with the development of vap , while their presence increases the risk of death. sometimes the only option for treating them is colistin , which was until recently an obsolete antibiotic of questionable efficacy. methods. patients with at least a -day stay in our icu had the following characteristics : men ( . %) , median age years ( interquartile range years) , median icu stay days (interquartile range days) , a mean apache ii score of . ( % confidence interval . - . ) these patients where retrospectively divided in two groups. the first one included patients with at least one brocheal culture positive for panresistant gram ( -) bacteria and the second one consisted of patients carrying bacteria sensitive to colistin only. a comparison was made according to days of stay in the icu , survival in months , age and apache ii score. statistical analysis was made using mann-witney analysis and a kaplan-maier analysis for survival. the patients in the group with the panresistant bacteria spend more days in the icu (p< . ) , while tended to live longer ( mantel-cox pairwise , p< . ). multidrug resistant bacteria are poorly responsive to colistin which failed to make an impact in survival. introduction. aids is a increasing chronic disease , with a great impact in medical costs. objective: to analyze incidence and epidemiological factors and outcome in aids patients (with previous or actual diagnosis) admitted to a general adult icu, comparing them with non-aids patients. retrospective cohort comparative study made in a general adult -bed icu of a university hospital, in a -month period. it were analyzed all patients admitted during this period. it was made descriptive statistics, analysis of variance and t-test. during studied period, there were patients admitted with a previous or actual diagnosis of aids. most common admission cause in these patients was sepsis by community pneumonia ( patients) and neurological diseases ( cases). there were patients with association with pulmonary tuberculosis, and patient with coexistent pulmonary paracoccidioidomycosis. among most frequent complications, ( . %) had acute renal failure (arf), ( . %) plaquetopenia (of these, had associated leucopenia), and ( . %) ards (all secondary to pneumonia). conclusion. in this study, aids patients admitted to icu were younger, mainly male, more severe and with a higher icu and hospital mortality. systemic complications were frequent, and commonest admission cause was community pneumonia with sepsis. it is emphasized the association with tuberculosis and paracoccidioidomycosis. grant acknowledgement. this study was not supported by any companies. th esicm annual congress -berlin, germany - - october a. sencan* , t. adanir , h. er , m. aksun , g. aran , n. karahan anesthesiology and icu, infection deseases, anesthesiology, izmir ataturk training and research hospital, izmir, turkey acinetobacter baumanii is a gram-negative coccobacillus that is normally a commensal pathogen but can be a nosocomial pathogen which is responsible for severe icuacquired infection, mainly pneumonia and bacteraemia. the aim of this study was to determine the risk factors and mortality rate of acinetobacter baumanii infections in icu patients. in this retrospective study, we analyzed acinetobacter baumanii infections developing in all patients who were admitted into our icu between january , and december , . a comparison of data was collected from the patients' record cards. age, gender, mortality ratio, apache ii and sofa values, length of mechanic ventilation (lomv) and length of icu stay (loicus) up to determination of infection, total length of mechanical ventilation (tlomv) and icu stay (tloicus), region of culture from which the infectious agent was obtained, existence of another microorganism together with acinetobacter baumanii (eamo), tracheotomy, intubation tube, central catheter, urinary catheter and nasogastric tube days up to the determination of infection and the feeding route were evaluated. these characteristics were compared between living and dead patients. during that time period, cases of acinetobacter infection were found in our clinic. the mortality ratio was %. the comparison of living and deceased cases is shown in the following table. we observed that this nosocomial infection was seen in the - year-old age group and in the first week of mechanical ventilation. mortality was greater in patients with high sofa scores and the infection prolonged the length of total icu stay. if the infection was located in the lungs, the mortality rate could be higher. there were cases of a baumanii nosocomial pneumonia and of them died. in addition, the rate of female patients dying was greater ( of female patients died). r. e. farah* , a. kondratov , r. michelis , n. makhoul internal medicine, intensive care unit, eliachar research laboratory, nahariya hospital, nahariya, israel community-acquired pneumonia, that requires hospitalization, is a severe illness with high mortality rates, especially, in the cases of delay of appropriate treatment. at times, the correct diagnosis of the disease is difficult due to equivocal clinical picture or chest film, accompanying diseases that could mask or simulate the pneumonia. the aims of our study were: .follow-up levels of scd and oxidized fibrinogen (of) throughout hospitalization in the group of patients admitted to the hospital due to pneumonia and pulmonary edema of non-infectious origin; .an estimation opportunity using them as possible new markers for diagnosis of pneumonia and for following response to treatment. three groups of patients were studied: a group of patients admitted due to pneumonia, a group of patients admitted due to pulmonary edema, and a control group - healthy subjects. the blood samples for white blood cells count, erythrocyte sedimentation rates, levels of fibrinogen, c-reactive protein, albumin, scd , oxidized fibrinogen were taken for each patient on admission, and hours following admission and on discharge day. the received dates were compared using student t-test. the levels of scd were higher, but still in the normal ranges, on admission in the patients with pneumonia and pulmonary edema in comparison with control group (p< . for both groups), with gradual declining throughout hospitalization period (p> . for both groups in discharge day). the comparison of scd levels between groups of patients with pneumonia and pulmonary edema did not reveal statistically significant results (p> . ). the rates of oxidized fibrinogen were in the normal ranges (< . nmol/mg) throughout hospitalization period in both groups of patients, but surprisingly higher in the control group (p< . ). oxidized fibrinogen and scd can't be used as reliable markers neither for primary diagnosing of pneumonia or differential diagnosis from pulmonary edema, nor for patient follow-up throughout hospitalization period. the finding of elevated levels of of in the group of healthy persons demands additional studies for discovering other factors that cause changes in fibrinogen oxidation rates. appearance of myocardial infarction and stroke during the same hospitalization is rare and has great mortality ratio. it was expected these events to take place more often during winter and in connection with infection. we have retrospectively analyzed data of patients with diagnose of acute myocardial infarction and stroke during the same hospitalization, treated in our internal intensive care unit from january to december . none of these patients were subjugated to thrombolytic therapy, percutaneus coronary intervention or coronary artery bypass graft. all included were caucasians (who were maked . % of total number of hospitalised patients during that period), ( %) males,and ( %) females. age of patiens was between and years, mean ± . (ci - ). six patients have survived ( %), and died ( %) ( males and females). the average age of deceased males was ± . years (ci - ), and females was ± . (ci - ). mean apache ii score was ± (ci - ), and mean gcs was ± (ci - ). most of the patients ( patients or %) were admitted during the winter, six in autumn ( %), five in spring ( %) and in summer only one patient ( %). in patients ( %) ( males and females) we found connection between current state with recent infection (within last month) or signs of infection on admission in icu. respiratory infection was found in patients, urinary infection in , and in cases we have found some other source of infection. also we found significant connection between current state (myocardial infarction and stroke during same hospitalization) and infection during winter (p= . ) and positive correlation between infection and mortality of these patients (r= . , p< . ). although exact mechanisms are still unknown. we can expect these events more often during winter period when are respiratory infection are more frequent. introduction. vap is the most frequently occurring nosocomial infection among patients requiring mechanical ventilation in the icu and is associated with increased morbidity and mortality. the major route of acquiring vap is oropharyngeal colonization by the endogenous flora or by pathogens acquired from the icu environment. oral decontamination with hexetidine , % reduces the risk for vap according the results of many reported studies and is the most common oral antiseptic in greek icus. our aim was to determinate the effect of oral decontamination with hexexidine , % on development of oropharyngeal colonization and vap. methods. patients admitted to the icu and received mechanical ventilation for more than days. were males ( , %) and ( , %) females. mean apache ii score on admission was , ± , . we excluded patients with multiple icu admissions. only the first admission was considered for analysis. we excluded also all patients with a diagnosis of pneumonia on or before the first day of mechanical ventilation, so that the sample would include only patients who had hospital-acquired pneumonia develop while receiving mechanical ventilation. all patients were randomized to hexetidine . % applied every hrs into the mouth, beginning hrs after admission. oropharyngeal sample cultures were obtained on admission on the nd and on the th day of hospitalisation and analyzed for gram positive, gram negative microorganisms and fungi. all patients were examined daily for the presence of vap with clinical criteria and chest x-rays. the most common isolates were: pseudomonas aeruginosa , %,klebsiella pneumoniae , %,s.aureus %,enterococcus faecium % ,acinetobacter %,e.coli , %,proteas mirabilis , % and candida species , %. coupled plasma filtration adsorption (cpfa), using a sorbent once the separation between plasma and blood has been obtained with a plasma filter, has been designed to non-selectively remove inflammatory mediators released in sepsis and septic shock. the aim of this study was to test whether cpfa is beneficial in septic shock. fourteen h-fasted, anesthetized, invasively monitored, mechanically ventilated female sheep ( . ± . kg) received . g/kg body weight of feces s lactate (rl)+ hydroxyethyl into the abdominal cavity to induce sepsis. ringer starch (voluven) (volume ratio= : ) was titrated to maintain cardiac filling pressures at baseline levels throughout the experimental period. four hours after feces injection, animals were randomized to two groups: cpfa treatment (n= ) or control (n= ). a four-pump hemofiltration machine (lynda, bellco, mirandola, italy) was used for the study. although mean arterial pressure and cardiac index were significantly lower in the cpfa group compared to the control group (p= . and p= . , respectively) and blood lactate concentrations tended to be higher in the cpfa treated group (p= . ), survival time tended to be longer in the cpfa than in the control group ( . ± . vs . ± . hours, log rank p= . ). in this clinically relevant septic shock model, cpfa treatment tended to prolong survival time. acute severe liver failure (alf) is a clinical syndrome that results from rapid loss of the major liver functions. despite improvements in the treatment of these patients, including liver transplantation, mortality rates remains high. a liver support system capable of removing endogenous toxins may be useful in alf patient's management. the aim of this study was to assess the efficacy of the extracorporeal liver assist device mars ® (molecular adsorbent recirculating system) in patients with alf unresponsive to intensive medical therapy. the study was performed in a medical-surgical intensive care unit of a tertiary referral hospital with multi-organ transplant program. a prospective clinical case-control study was designed. patients with severe alf of any etiology admitted to icu were included if mods was present and an indication for liver transplantation was done. standard treatment measures were applied in all cases according to patient's clinical condition. patients received mars ® treatment after this therapy was introduced in our icu. patients without mars treatment were the control group. outcome parameters were the main variables for comparison between groups. complications related with mars treatment were also analyzed. methods. in a previously-described test set-up, a l jar serving as a dummy lung was ventilated through a heated water-filled reservoir placed on a weighing scales so that gain or loss of water from it could be detected. the ventilator was a viasys sensormedics b using a fisher/paykel mr humidifier the ventilator was set to maximum power at a frequency of hz. three investigations were performed with humidifier temperatures of . ˚c, . ˚c and . ˚c. weight gain or loss over - hours was recorded and calculated in g/h. four measurements were made at . ˚c, four at . ˚c and two at . ˚c. previous spirometry studies suggested - % tracheal stenosis following percutaneous tracheostomy(pt) based on techniques that involved either the original ciaglia serial dilatation or griggs modified forceps blunt dilatation of the trachea. subjective voice changes and hoarseness has been reported at an incidence of % following pt by the blue rhino single dilator technique. aim of this study was to assess upper airway narrowing effects based on spirometry and symptoms following pt by blue rhino technique. invitations were sent to patients(identified from the liver database) who underwent pt during their intensive care stay and were attending liver clinic beyond months after the procedure. all participants underwent formal pulmonary function tests and filled in a standardized questionnaire on symptoms (pain, dysphonia, dyspnoea, cough, throat tightness, dysphagia) and scar appearance. flow volume loops were recorded using a jaegar master-lab . pneumotachograph, and best values for forced vital capacity(fvc),forced expiratory volumes at . and second(fev . ,fev ),peak expiratory flow rate(pefr),forced inspiratory flow at %vital capacity(fif ),forced expiratory flow at %vital capacity(fef )and peak inspiratory flow(pif) recorded. values for fev /pefr,fef /fif and fev /fev . ratios were then calculated. during august to january , patients underwent pt, of whom survived. of the outpatient attendants participated in the study. median age was . years ( - y) and m:f ratio was : . of the current or past smokers had obstructive airway disease based on fev /fvc ratio. median interval between pt and review was months ( - mth,n= ; - mth,n= ; - mth,n= , beyond y,n= ). median apache ii score on day of pt procedure day was . nine patients had failed extubation, and one patient underwent pt procedures during the same hospital stay. median duration of translaryngeal intubation prior to pt and from pt placement to decannulation were days ( - d) and days ( - d) respectively. moderate/severe dyspnoea was reported by patients (mild,n= ) and cough by patients (mild,n= ). patients reported voice changes and patient with hoarseness. assessment of scars at the time of review showed patient with keloid scar and patient with an ugly indurated scar (at and months respectively); all others were good to barely visible. satisfactory flow-volume loops were obtained for patients. patients had evidence of extrathoracic tracheomalacia based on the fef /fif ratio > ( with symptoms), however fev /pefr ratio did not suggest obstruction in any of them. dyspnoea and cough were the most common symptoms, notably in smokers. late complications were uncommon, other than one patient with indurated scar, hoarseness and possible tracheomalacia. leonard rc. chest fikkers bg. anaesthesia j. dellamonica*, a. lyazidi, f. vargas, l. brochard medical icu, henri mondor hospital, creteil, france high frequency percussive ventilation (hfpv) is a technique that delivers small bursts of gas with frequency higher than hz (usually - hz). intrapulmonary percussive ventilation using hfpv has been used during spontaneous breathing, but is also proposed superimposed to conventional ventilation (cv). airway humidification during hfpv has not been studied, however, and is generally provided with an aerosol. a poor airway humidification could lead to secretion thickening and atelectasis. we therefore performed a bench study to assess hygrometry provided by different devices when hfpv is added to cv. methods. circuits have been tested: . a heater humidifier (hh) (fisher & paykel mr ) placed on the inspiratory line of the cv. .& . heat and moisture exchanger (hme) and active hme (ahme) were tested placed at the y piece. for these circuits, hfpv was connected to a branches y piece with inspiratory and expiratory lines of the cv. . hh was connected between hfpv and y piece. all circuits were tested with the aerosol provided by the manufacturer. hygrometry (relative and absolute humidity rh and ah) was measured using psychometric method at y piece. hygrometry provided was compared with non parametric test. p< , was considered significant. conclusion. the minimal level of humidity recommended during prolonged mechanical ventilation is mgh o /l, and the fourth circuit was the only one to provide sufficient ah. temperature drop due to gas acceleration and large admission of gas during hfpv may explain the lack of efficacy of the other devices. coagulation abnormalities are very frequent in critical illness. these, often secondary to sepsis and dic, significantly contribute to mortality in the intensive care unit (icu). thrombelastography (teg ® ), a cell-based whole blood analysis, enables global evaluation of the haemostatic system and the purpose of the present study was to evaluate whether the haemostatic competence on admission to the icu, evaluated by teg ® was associated with mortality in critical ill patients. blood samples were prospectively obtained upon arrival from consecutive patients admitted to a multidisciplinary tertiary icu. teg ® analysis was performed (teg ® haemostasis analyzer, haemoscope corporation, niles il, usa), measuring clot formation,stability and degradation in whole blood. the teg ® parameters r time, angle, and the maximal amplitude ma were evaluated. the r time represents the initiation of the coagulation process (normal reference - min), the ma represents maximal clot strength mainly dependent on the platelet function (normal reference - mm), and angle represents the clot build up, involving fibrinogen function (normal reference - ˚). the primary endpoint of the study was defined as death within days. data are presented as mean (sd). mann-whitney's u-test and fischer's exact test were applied with a p value < . considered statistically significant. the age was . ( ) years in a cohort of . % medical (n= ) and surgical (n= ) patients of whom were male ( . %). length of stay in the icu was . ( . ) days and the apache ii score was . ( . ). thirty-one patients died ( . %). r time ( . ( . ) min vs. . ( . ), respectively; p= . ), ma ( . ( . ) mm vs. . ( . ), respectively; p= . ) and angle was significantly lower in non-survivors than in survivors ( . ( . )v s. . ( . ), respectively; p= . ). patients with a normal teg did receive less cvvhdf ( . % vs. . % (p< . )and had a lower mortality rate ( . % vs. . (p< . ) than patients with not-normal teg. a compromised haemostatic competence on admission to the icu as evaluated by the teg ® r time, angle, and ma are associated with increased -day mortality in un-selected critically ill patients. this finding is consistent with the hypothesis that a dysfunctional haemostatic system could be a central part of developing organ failure and, hence, mortality. this prognostic tool may be useful as a rapid, point-of-care assessment. the possibility of goal-directed haemostatic intervention should be investigated in a randomized controlled trial. n. komitopoulos* , a. kanavou , a. giakoumaki , i. ioannidis , a. komitopoulou , e. varsamis nd internal medicine dpt, biochemistry lab, konstantopoulion general hospital, athens, greece introduction. brain natriuretic peptide (bnp) is a -amino-acid polypeptide mainly secreted by the ventricles of the heart in response to excessive stretching of myocytes. cardiac dysfunction, characterized by reduced ejection fraction, biventricular dilatation and decreased response to resuscitation with fluids, is often present in patients with sepsis. the myocardial depression is probably due to tumour necrosis factor-α and interleukin- β acting in synergy. the aim of the study was to determine whether bnp levels in elderly septic patients are related to the severity of the disease. in patients ( males) with sepsis of various origin, aged ± years, hospitalized in the internal medicine department, bnp serum levels (direct immunochemiluminescence, centaur, bayer) and apache ii score were measured within hours after hospital admission. sepsis was determined according to the criteria of the consensus of the american college of chest physicians and the society of critical care medicine ( ) . patients with acute myocardial infarction were excluded from the study. the mean bnp value (pg/ml) in our subjects was ( - ). the bnp levels in the subgroup of individuals with chronic heart failure (n: ) were higher than those of the rest of the patients [ ( - ) vs ( - ), p= . , mann-whitney test]. a statistical significant difference was also found in bnp levels of the patients with apache ii score ≥ as compared to those of lower score [ ( - ) vs ( - ), p= . , mann-whitney test]. patients who succumbed (n: , %) had extremely high bnp levels [mean: ( - ) ]. a positive correlation was observed between bnp values and apache ii score (linear regression analysis , r= . , p< . ). in conclusion, brain natriuretic peptide was found to be correlated with the severity of sepsis in elderly patients and thus it might be used as a useful prognostic marker in septic process. prometheus ® is a newly developed extracorporeal liver support that combines fractionated plasma separation and adsorption (fpsa) with high-flux hemodialysis. clearance of albumin-bind and water-soluble toxins are achieved in several steps. here we present our results in applications. thirteen patients ( patients with viral hepatitis acute on chronic liver failure, three mushroom intoxication, one liver failure after metastatectomy and one cittrullinemi) have undergone ( . ± . [ - ] ) times fpsa with high flux hemodialysis between june till march in our icu. inclusion criteria were hyperbilirubinemia (total bilirubin > mg/dl), or hepatic encephalopathy (grade ), or inr > . during a six-hours period of application, a variety of clinical and biochemical parameters were assessed; and data before and after the procedure were recorded. seven of the patients survived. one patient has undergone liver transplantation; six survived without liver transplantation. there was a decrease of ± % in total bilirubin per application (from . ± , mg/dl to . ± . mg/dl; p< . ), blood urea nitrogen (bun) was decreased from ± gr /dl, to , ± , gr/dl (p< . ), white blood cell (wbc) increased from , ± , mm to ± , mm (p< . ), albumin decreased from , ± , gr/dl to , ± , gr/dl (p< . ). consequent applications have led to additional decreases in bilirubin. regarding the hemodynamic parameters, there were no significant changes during the procedure. conclusion. fpsa obtained decreases in bilirubin and bun (but also in albumin levels). there can be an increase in white blood cell count. this procedure can be considered a bridge therapy for liver transplantation: it can increase the tolerance time until the liver transplantation or can improve the clinical status achieving a treatment without an organ donation. at present orthotopic liver transplantation is the only treatment modality that provides significant improvement in outcome of hepatic liver failure; but the availability of transplantation is hindered by organ shortage resulting in extended wainting list. extracorporeal liver support devices are effective therapies to overcome periods of descompensation or to bridge until transplantation. although its main therapeutic indication is hepatic failure, the possibility of removing metabolits opens new therapeutics options for other entities. we reports clinical cases where patients were treated with prometheus as a bridge to transplant or to treat refractory pruritus. several analytics results like bilirubin, platelets, creatinine, urea were measured before and after each treatment. extracorporeal liver support devices have recently attracted increasing interest. although its role in liver failure and other conditions with toxin accumulation is yet to be better characterized, we believe that its use may be advantageous and life saving in selected patients. thrombocytopenia is a common problem in the icu and cardiovascular patients. it has been considered to play a role in worsening the prognosis of icu patients. especially patients submitted to cardiac surgery may be exposed to high dose of unfractionated heparin (ufh) infusions, mainly during extra-corporeal circulation. after open-heart surgery, as opposed to other surgical procedures, the platelet count falls, primarily due to platelet damage and destruction in the bypass circuit and hemodilution. heparin is the most common drug to be implicated in thrombocytopenia in icu patients. determining the etiology for the low platelet count is important for the implementation of appropriate management. the use of a direct thrombin inhibitor in treatment should be considered early (< hours) if a diagnosis of heparin-induced thrombocytopenia is possible( ). the aim of the study is to present one case of heparin-induced thrombocytopenia after a mitral valve replacement surgery and to compare the rotational thromboelastometry (rotem) and coagulation tests before and after argatroban administration. an -year-old female patient was hospitalized because of acute mitral regurgitation secondary to chordal rupture and submitted to a mitral valve replacement. past medical history included hypertension, diabetes, chronic atrial fibrillation and mild renal failure. before the surgery, a coronary angiography was performed and revealed normal coronary arteries and a normal left function. after four days using ufh, the platelet count dropped % and the anticoagulation was changed from ufh to low molecular weight heparin. postoperatively, the patient presented in shock, acute renal failure and signs of peripheral hypo perfusion and increased abdominal pressure. seven days after the surgery, the suspicion of hit was confirmed by elisa test for pf -heparin antibodies. heparin was stopped and argatroban was initiated. the patient died from multiple organ failure week later. we evaluate the rotem and coagulation tests (platelets; ptt; tat; pai; ptn-c; fibrinogen; d-dimer and antithrombin-iii) before and after the argatroban use. conclusion. comments: in this case the roteg was as good as a wide coagulation profile test to evaluate the effects of anticoagulation using argatroban in a hit patient. the objective of this study is to evaluate the efficacy and safety of this technique in a multidisciplinary icu environment following a procedures' protocol. it was created a fiberoptic bronchoscopy protocol to implement in a routine basis, and we are testing it in this study. we applied it, in a prospective manner, in every patient undergoing fiberoptic bronchoscopy from january to march , to evaluate the indications, risk factors, the use of drugs (sedatives, analgesics and muscle relaxants) and monitoring (ecg, bp, spo , etco , plateau pressure and blood gas analysis), complications and results of this technique. our sample included patients (medical, surgical and trauma patients), with a median saps ii of ( - ). ten patients had criteria of severe respiratory failure (pao /fio < ). twenty four fbo were done in the study period; for diagnostic reasons ( pulmonary infiltrates, hemoptysis and stridor), for therapeutic reasons (bronchial toilet) and to assist percutaneus tracheostomy. seventeen of our patients had risk factors for this procedure (bronchodilator therapy in patients, pao /fio < in patients, peep > cmh o in patient, platelet count < /mm in patient and altered coagulation screen in another). all exams were successfully concluded. the median procedure time was minutes ( - minutes). beyond sedation, exams were done with topical anaesthesia and with muscle relaxants. concerning safety, the exam was interrupted due to hypoxemia in one patient and due to episodic tachycardia in another patient, both concluded without major problems. two patients showed new pulmonary infiltrates in x-ray evaluation hours after the technique. no significant variation of the pao and paco were noticed during the first hour after the procedure. concerning efficacy, from broncho-alveolar lavage samples, were microbiology positive. one small-cell lung carcinoma was diagnosed by a bronchial biopsy. all these findings have therapeutic relevance. full pulmonary reexpansion was achieved after fbo in cases of lobar atelectasis. conclusion. implementation of a protocol and an individual risk assessment policy may improve safety of bfo in ventilated patients in icu. fbo contributes to valuable diagnostic information and is useful for therapeutic purposes. n. markou* , p. malamos , p. myrianthefs , i. alamanos icu-b, athens university school of nursing icu, kat hospital, athens, greece there is a scarcity of data on the effects on oxygenation of the position of the mixing tube relative to the t-piece and the venturi mask. some data show that while a mixing chamber positioned between the venturi mask and the t-piece is associated with improved oxygenation, positioning of the t-piece between the mixing chamber and the venturi mask has no effect on patients' pao ( ). yet there are no data on an alternative arrangement, with two mixing chambers, one at each end of the t-piece. we relate our experience with this arrangement. we studied critically ill patients who were either intubated or on tracheostomy and who although clinically stable and spontaneously breathing on a t-piece for at least hours could not be extubated. the patients initially (t- ) had one mixing chamber that was positioned between the t-piece and the venturi mask. after sampling of arterial blood gases, a second mixing chamber was inserted at the other limb of the t-piece and arterial blood gases measured again after a further minutes (t- ). patients in whom interruption of these arrangements (for administration of nebulized drugs or for endotracheal suction) was needed at the time period starting at minutes before t- and up to t- , were excluded from the study. during this time period fio for all patients was , . in all patients ( intubated and on tracheostomy) were studied. results are expressed as median and interquartile range. statistical analysis was performed with wilcoxon signed-rank test. there was a significant increase in pao from t- (median mmhg, %- % range - mmhg) to t- (median mmhg, %- % range - mmhg) (p = , ), with no significant change in paco , breathing frequency, arterial blood pressure or heart rate. a second mixing chamber adjusted to the limb of the t-piece opposite to the venturi mask is associated with significant improvements in oxygenation. presumably the second mixing chamber acts as a reservoir with high-content oxygen mixture, and this might be beneficial, especially in patients with higher peak inspiratory flows. percutaneous dilatational tracheotomy (pdt) is one of the procedures more frequently performed at the patient bedside in icu. airway control is usually maintained through an endotracheal tube (ett) but a laryngeal mask airway (lma) can be successfully used as well ( , ). lma ensures a high quality fiberoptic view of laryngotracheal structures; furthermore mechanical ventilation is easier and more uniform with lma than with an ett withheld at vocal folds level. potential disadvantages of lma are the risk of inhalation and a failed ventilation in case of oedematous airway. methods. icu patients were scheduled for pdt in the last three years. all pts were admitted to pdt after a - hours fast time from enteral nutrition. predictive anatomic and anthropometric parameters or history of difficult airway were considered. in case of suspected difficulties in airway management, an evaluation laryngoscopy was made. if tube removal was considered possible, a lma, proportional to body weight, was positioned. the following parameters were registered: • classification of fiberoptic laryngeal view through lma • uniformity of inspired/expired tidal volumes during mechanical ventilation • trends of pco and po during whole procedure by seriated blood gas analysis • need of lma repositioning or its substitution with an ett during the procedure • suspect or clinical evidence of airway inhalation • chest x-ray after pdt results. in patients lma positioning was unsuccessful; in patients lma did not allow an adequate ventilation due to a increasing laryngeal oedema evident at fob endoscopy. in these cases the ett was soon repositioned. in other patients ventilation was maintained thorough lma but an increase in pco higher than % was registered during procedure. in all the other patients we had no problem neither in lma positioning nor in mechanical ventilation. in all our population we did not have any difficulty in airway management. no cases of airway inhalation were registered. conclusion. in our experience lma is an effective and successful ventilatory device during pdt. it improves the quality of endoscopic view, makes easier tracheal puncture and allows a more uniform ventilation. it is important to remember that, before removing ett, we must always evaluate the risks related to full stomach and to the presence of a difficult airway. single dilator technique is increasingly used for percutaneous tracheostomy ( ). although complications have shown a decreasing trend, there remains a concern that the posterior tracheal wall damage can occur during tracheostomy tube placement over a loading dilator. the lip between the loading dilator and the tracheostomy tube tip often causes an obstruction requiring greater force which may be responsible for posterior tracheal wall damage. the percutan tracheostomy set ( tracoe medical, gmbh, frankfurt) claims to overcome this problem by having a tracheostomy tube-loading dilator assembly with a collapsible silicone sleeve covering the tip of the tracheostomy tube. we were interested to evaluate this in practice. a total of patients scheduled for elective pdt were enrolled in this open prospective observational clinical trial. assent was obtained from the immediate relatives. patients were excluded if they had unidentifiable anatomy, severe coagulopathy, a history of difficult tracheal intubation or required significant levels of ventilatory support ( fio > . or peep > cmh o). experienced operators conversant with pdt techniques performed the procedures whilst the airway and bronchoscopy were maintained by an anaesthertist. the trachea was punctured in all cases between the nd and rd tracheal rings and dilated using the percutan single rhino dilator. the tracheostomy tube-loading dilator assembly was then inserted. the ease of tracheostomy tube insertion was graded by the operator on a scale of - , being extremely difficult and extremely easy. all complications were recorded during the procedure. a total male and female patients aged ± years (mean±sd) were enrolled. patients were ventilated for . ± . days (range - days) before tracheostomy. the operating time was . ± . minutes (range - minutes). stoma dilatation and placement of a size tracheostomy tube was successful patients. other two cases required a second dilatation before tracheostomy tube placement. average grade of tracheostomy tube placement was median (range - ). the operators stated that the force required to place the tracheostomy tube was less than that required with other single dilator manufacturers kit. there were no serious perioperative complications and blood loss was estimated for all cases between - ml except in one patient surgical ligation of a venous bleed was required. no significant difference was seen in pre and post tracheostomy arterial blood gases. this study suggests that the percutan tracheostomy set allows a single step dilation of tracheal stoma and relatively easier placement of tracheostomy tube. further randomised controlled trials are warranted to assess its advantages over the other singe dilator techniques. nebulizers designed for use with oxygen or air require high flows of heliox to create aerosol in the respirable range. this aerosol is not well characterized for standard nebulizers and the high flow of heliox is costly. the objective of this study was to characterize the performance of a new breath enhanced nebulizer designed for use with heliox ( / ) gas and compare it to an industry standard breath enhanced nebulizer. using a malvern spraytec laser difractor we measured the aerosol particle size (vmd), total output rate (tor), respiratory fraction (rf) and calculated the respiratory drug delivery rate (rddr = tor x rf). heliox flows of and lpm were used and normal saline was nebulized. we performed trials with each flow. a pari lc plus reusuable breath enhanced nebulizer was used for comparison at lpm source gas flow. table . a novel active humidification system has been developed which can heat and humidify dry therapeutic gases during mechanical ventilation. this study measures the ability of this in-line humidification device (pari hydrate , pari respiratory equipment, midlothian, va, usa) to heat and humidify gas during mechanical ventilation. the new technology (c-force ; pari respiratory equipment) produces water vapor from an in-line, small device placed proximal to the circuit 'wye' in the inspiratory line. a controller allows precise water vaporization and heating directed into the gas flow. this study was performed to determine the performance of this humidification device for mechanical ventilation. we used a puritan bennett mechanical ventilator under various settings to produce minute ventilation volumes of , , , . , and . litres. our test lung (quick lung, ingmar medical, pittsburg, pa, usa) was set to normal lung settings to simulate cp= . l/cm h o and ra= cm h o/l/s. the disposable c-force was inserted into the ventilator circuit inches proximal to the patient wye. gas temp and relative humidity (rh) were recorded at the patient wye using an electronic thermometer and hygrometer. the source gas was dry medical air; measured at % rh and oc. ambient temperature was . oc and relative humidity was . %. although the amount of water and the temperature are adjustable with this device we used a constant temperature setting of oc and the calculated water setting that would saturate the volume of gas using minute ventilation. no attempt was made to optimize the temperature and humidification of the gas beyond these settings. patients were similar in terms of demographics,type of admission and reason for intubation. the overall incidence of severe life-threatening complications was significantly lower in the after group than in the before group ( % vs. , p< . ) (fig ). the implementation of eti management protocol permitted to decrease the incidence of severe life-threatening complications in icu patients. ( , ) . the aim of this study was to review the tracheostomy practice and to determine if either technique was associated with better outcomes in the setting of an inner city general hospital. we identified patients who had had tracheostomies over a / year period (may -dec ) by using our institution's icnarc (intensive care national audit and research centre) database. the case notes of these patients were examined in detail. we divided the patients into two groups (st and pt) depending on method of tracheostomy insertion. patient age, sex, weight and apache score were recorded. we collected figures on icu length of stay (los) and icu & hospital mortality. we also compared the following data: duration from intubation to tracheostomy, time from clinical decision to actual procedure, size of tracheostomy tube inserted and number of tracheostomy days. high flow gas therapy is a new therapy which has been shown to reduce intubations, ventilator days and non-invasive ventilation. the purpose of this study is to determine the efficacy of a novel humidification device (pari hydrate tm g) for high flow gas therapy and compare it to current high flow oxygen humidification devices. we compared aquinox (smiths medical ), mr (fisher & paykel), i (vapotherm) and pari hydrate (pari respiratory equipment). each device was setup as per manufacturer's instructions to heat and humidify medical air at flow of lpm. temperature settings were adjusted to c. we recorded warm-up time from "on" to highest stable temperature when set at c, exiting gas temperature, maximum device surface temperature, and water condensate. water condensate was obtained from a condensation tube connected to outlet side of the devices and measured after minutes. temperature of the condensate tube water was set at c. ( ) suggest that, in patients liberated from mechanical ventilation (mv), the persistence of the tracheostomy tube at discharge from icu to the ward may increase the post-icu mortality rate. our objective was the confirmation of this hypothesis with close attention to selection biases as confounding by indication, patients characteristics and the prognosis at icu-discharge ( ). prospective observational study in the general -bed icu of a tertiary hospital without a step-down unit. inclusion criteria: patients tracheostomized in our icu during a -month period without neurological damage. exclusion criteria: patients tracheostomized before icu-admission, tracheostomies for difficult to control airway, and patients with "do-not-resucitate" orders. data collection: age, gender, comorbidities, severity of illness at icu admission, admission category, indication for tracheostomy, length of icu and hospital stays, length of mv, need for aspiration and characteristics of respiratory secretions, and glasgow coma scale (gcs) at icu-discharge. patients with tracheostomy tube were discharged only to wards with specific "tracheostomy care protocols" with a nurse-to-patient ratio of : - . statistical analysis: multivariate logistic regression analysis adjusted for age, gender, body-mass index (bmi), severity of illness and diagnosis at icu-admission, indication for tracheostomy, duration of mv, glasgow coma scale, need for aspiration and characteristics of respiratory secretions at icu-discharge. lung recruitment (rm) can be considered as an adyuvant for lung protection in the ventilatory support of ards patients. the recruitment pressures needed to achieve full lung recruitment in these patients are generally above cmh o. however little is known about the hemodynamic effects of the brief application of pressures beyond this level in ards patients when using a sequential cycling recruitment maneuver. we , ) that were± mmhg; lis , ±present six ards patients (pao /fio managed with a global lung protective ventilation (lpv) strategy. we used trans-esophageal echocardiography (tee) to assess the effects of a rm using increasing levels of pressure. after confirming hemodynamic stability with predefined criteria, patients were submitted to a cycling sequential rm in pressure controlled ventilation that included three consecutive pip/peep levels of / , / and / cmh o each one of them maintained for min and followed by a min period of pressure reduction to / cmh o before the next pressure level was explored ( ). data were collected during the second minute of each recrutiment step. after rm, lpv was reinstituted: vt - ml/kg and a peep level adjusted to a level immediately above maximum dynamic compliance obtained during a decremental peep trial after recruitment ( ). all patients could be mmhg). no significant decreases in mean±fully recruited (pao + paco systemic arterial pressure (less than % during maximal intrathoracic pressure) and in heart rate were observed. tee measured left (lv) and right (rv) cardiac output (co) and systolic volume (sv) decreased significantly only at rm pressures of and cmh o (around and % respectively). recovery to baseline levels occurred within minutes after reducing the airway pressures (table) . central venous pressure increased progressively to a maximum of % of the baseline value at maximal rm pressures. we hypothesized that patients in acute (arf) on chronic respiratory failure (crf) have complex acid-base disorders and that stewart's quantitative approach may be useful to make the situation clearer. in this approach, plasma ph is dependent on independent variables: strong ion dissociation (sid), total weak acid negative charge (atot) and paco . in a prospective observational study, arterial plasma from consecutive patients with crf, obstructive and restrictive, admitted to our medical icu in arf between november , and april , were studied. they were compared with those from patients with ards admitted to our icu in the same period. in addition, values in patients were compared with those in normal subjects from the literature( ). the plasma values were taken from the samples obtained at icu admission (d ), d and d . arterial blood gas, electrolytes, lactate and albumin were measured and the following variables computed: sid = hco − + albuminate (alb-) + phosphate (pi-)) from reference ( ), strong ion gap (sig) computed from reference ( ), atot= (alb-)+(pi-). the values (mean±sd) were compared using anova (table ) . there was no effect of time on the variables and, therefore, the values in table correspond to icu admission. for statistical similar ph between crf and ards, paco was higher in obstructive crf than ards. sid was not different between crf and normal subjects but greater in crf than in ards, as was sig. atot was lower in ards than in obstructive crf. in crf patients, low ph mostly resulted from hypercapnia without metabolic alkalosis on average. in ards patients, acidemia is mostly metabolic. the positive sig expresses accumulation of unmeasured anions. ( ) open lung approach has been based on a lower inflection point (lip) and an upper inflection point (uip) of the pressure-volume (p-v) curve. but we cannot always find out them, so we examined the method to get maximal compliance point in stead of uip and lip from static compliance curve. in ten patients with ards(ards group) and twelve non-ards patients (control group), we found a maximal compliance point by the static compliance curve induced by differentiation of the pressure volume curve led by polynomial approximation of scattergram of plateau pressure and tidal volume. in the ards group the compliance at the range from to cmh o were smaller than that of the control group (p< . ). but there was no difference between the maximal compliance point of the ards group and that of the control group ( . ml/cmh o at . cmh o vs. . ml/cmh o at . cmh o). we conclude that maximal compliance points were detected in all patients by this method and there was difference of the compliance between the ards group and the control group in low pressure range. p. kopterides* , i. i. siempos , a. armaganidis critical care department, attikon university hospital, department of experimental surgery, "evangelismos" hospital, critical care department, "attikon" university hospital, athens, greece prone positioning is increasingly used to improve oxygenation in patients with hypoxemic respiratory failure, especially those with acute respiratory distress syndromeacute lung injury. however, its benefits in regard to clinical outcomes are uncertain. we performed a systematic review and meta-analysis of the pertinent randomized controlled clinical trials to assess at what extent prone positioning has an effect on mortality and various clinical outcomes in patients with hrf. we conducted a systematic literature search of medline, current contents, and cochrane central register of controlled trials (from inception to january ). we included only rcts(in which prone positioning was the applied intervention and supine positioning the control treatment) that reported clinical outcomes in patients with hrf. there were no language restrictions. four trials met our inclusion criteria, including patients randomized to prone and patients to supine ventilation. data were extracted independently to assess intention to treat intensive care unit (icu) and hospital mortality, days of mechanical ventilation, length of stay, incidence of ventilator-associated pneumonia and pneumothorax, and associated complications of the implemented intervention. data were also collected to assess the quality of the included studies. the pooled odds ratio (or) for the icu mortality in the intention-to-treat analysis was . (confidence interval . - . ), for the comparison between prone and supine ventilated patients. interestingly, the pooled or for the icu mortality in the selected group of the more severely ill patients favored prone positioning (or . ; ci . - . ). the duration of mechanical ventilation and the incidence of pneumothorax were not different between the two groups. the incidence of ventilator-associated pneumonia was lower, but not statistically significant, in patients treated prone compared with patients treated supine (or . ; ci, . - . ). however, prone positioning was associated with a higher risk for development of pressure sores (or . ; ci, . - . ) and a trend for more complications related to the endotracheal tube (or . ; ci, . - . ). despite the limitations of the meta-analysis (ie the included studies were heterogeneous in terms of design, case mix, report of outcomes etc), the available evidence suggests that prone positioning has no discernible effect on mortality in the general population of patients with hypoxemic respiratory failure. it may decrease the incidence of ventilatorassociated pneumonia at the expense of more pressure sores and complications related to the endotracheal tube. however, some data imply that the more severely ill patients may benefit most from the intervention and await confirmation from adequately powered and designed clinical trials. in severe acute respiratory distress syndrome (ards), short-term high frequency oscillation (hfo) and tracheal gas insufflation (tgi) improves oxygenation relative to both standard hfo and ards network conventional mechanical ventilation (cmv)( ). we hypothesized that hfo-tgi may improve pulmonary function indices relative to cmv, if repeatedly employed on a daily basis. thirty adult patients with severe ards {pao /inspired o fraction (fio ) < mm hg at peep > cm h o}were randomized to receive either low tidal volume cmv ( - ml/kg predicted body weight) alone or in combination with daily, - -h-lasting hfo-tgi until resolution of severe ards or death. primary end-points were the time courses of gas exchange, respiratory mechanics, and hemodynamics. survival to days following randomization was also evaluated. data from all patients were analyzed. patient clinical profiles were similar. median hfo-tgi use was h/day for days. within the first eight days following randomization, study (hfo-tgi) group patients vs. controls had higher pao /fio ( . - . ± . - . mm hg vs. . - . ± . - . mm hg; p < . - . ) and quasistatic respiratory system compliance, and lower oxygenation index ( . - . ± . - . vs. . - . ± . - . ; p < . - . ), shunt fraction, and plateau and mean airway pressures. hemodynamics were not significantly affected by hfo-tgi. there was a trend toward improved -day survival in the study group vs. control ( / vs. / , p = . by fisher's exact test). in severe ards, the systematic daily use of hfo-tgi substantially improves gas exchange and respiratory mechanics. pressure-volume (pv) curve could help knowing which patient can benefit from a recruitment manoeuvre (rm). this study has been design to compare the hys of the quasi-static pv curve and the volume recruited by a rm. after ethical approval and relatives informed consent, early onset (< h) ards patients were investigated (igs ii = [ - ], lis = , [ , [ ] [ ] [ ] ] ). patients were sedated and paralyzed throughout the study. a to cmh o pv curve (pv tool, hamilton medical) was realized to measure hys i.e. the surface between the inflation and deflation curve measured between and cmh o. after min of ventilation, a rm consisting of a seconds pause at cmh o was realized using the pv tool. the volume recruited during the seconds/ cmh o rm was obtained by integration of the flow signal necessary to maintain the pressure of cmh o. no correlation was found between the lower/upper inflection points and the point of de-recruitment on the deflation limb of the pv curve. the volume recruited during a pause at the end of the inflation curve was well correlated with hys (r = , ; p = , ) (figure). in the early course of ards, the hys of the pv curve may be an indicator of how much the lung can be recruited by a seconds/ cmh o rm. treating acute respiratory failure (ali/ards) in the icu often requires mechanical ventilation, which carries a risk of vili. it is now commonly accepted that these patients should be ventilated "gently", i.e. reducing transpulmonary pressure fluctuations during ventilation. it is however still much debated as to how peep should be applied. methods to identify "best peep" are based upon descriptions of respiratory mechanics. however, only little is known as to how changes in peep modify pulmonary gas exchange. pulmonary gas exchange is usually described by arterial blood gas analysis or over-simplifying models such as the pao /fio ratio, the alveolar-arterial oxygen difference or the effective shunt. we describe the use of a more complex two-parameter model ( ) describing the effects of a peep-change using routine icu equipment. this method has potential for non-invasive use and may be incorporated in standard respiratory monitoring. eleven adult patients with acute respiratory failure on mechanical ventilation were included in the study. the patients were studied at two different levels of peep, i.e. either increasing or decreasing peep with cmh o. on each occasion the fio was varied in - steps to achieve values of sao ranging from - %. at each fio level measurements were taken of ventilation and arterial acid base and oxygenation status. these data were then used to estimate pulmonary shunt (shunt) and a measure of ventilation/perfusion mismatch, i.e. deltapo . upon increasing peep shunt decreased significantly by % (median) in patients, whereas deltapo improved in patients by kpa (median). as assessed by the p/f ratio oxygenation improved in patients by kpa (median). the increase in p/f ratio was, however, in cases explained by decreased deltapo not shunt. in patients where p/f-ratio was unchanged the value of shunt decreased significantly. the results suggest that by describing gas exchange by shunt and deltapo additional information can be obtained. these information may enable improved assessment of potential for recruitment and/or peep optimization. further studies are warranted. optimal peep avoids ventilator induced lung injury. this study determined the value of the elimination time-constant for co (tau-co ) to assess optimal peep. methods. pigs received lung lavage and hrs of injurious mechanical ventilation. a recruitment maneuver (rm) was performed for ' at / cmh o of peep/plateau pressure. the open lung peep (ol-peep) was defined as the level of peep after rm that kept the lung free from collapse. ol-peep was determined by respiratory dynamic compliance (cdyn), during a peep titration trial using the open lung tool ® (maquet, sweden), which was performed in vcv at a vt of ml/kg while decreasing peep from to cmh o in steps of cmh o every ' ( ). thereafter, we randomly assigned six ' periods at diff. peeps: ol-peep and peep either cmh o above or below it both, in recruited and non-recruited conditions. baseline ventilation was applied between study periods. we recorded dynamic lung mechanics and volumetric capnography data on a breath-by-breath basis (nico, respironics, usa). abg data were collected at the end of each period. paco was added to volumetric capnography to perform a complete dead space analysis using the standard bohr-enghoff formula. tau-co was calculated multiplying the respiratory time constant (cdyn x raw) by the amount of co eliminated per breath (vtco ,br). lung mechanics and gas exchange were best at ol-peep after rm. tau-co was longest at this moment due to an increase in both, cdyn and vtco ,br. the increase in cdyn and the decrement in raw slowed down peak expiratory flow during ol-peep ventilation. a reduction in vdalv/vtalv after rm and ol-peep indicated an increased ventilatory efficiency ( ) . vdalv/vtalv was more sensitive for determining ventilatory efficiency than the classical vd/vt. positive pressure ventilation in patients suffering from acute lung injury (ali) affects both, the distribution of ventilation (v) and perfusion (q) within the lungs. the aim of this work was to study the effect of lung recruitment and peep on v/q as assessed by multiple inert gas elimination technique (miget). a recruitment maneuver (rm) was performed for ' at / cmh o of peep/plateau pressure. the open lung peep (ol-peep) was defined as the level of peep after rm that kept the lung free from collapse. ol-peep was determined by respiratory dynamic compliance (cdyn), during a peep titration trial using the open lung tool ® (maquet, sweden), which was performed in volume control at a vt of ml/kg while decreasing peep from to cmh o in steps of cmh o every ' ( ). thereafter, we randomly assigned six 'periods at diff. peep levels: ol-peep and peep either cmh o above or below it both, in recruited and non-recruited conditions. baseline ventilation was applied between study periods to standardize lung volume history. we recorded dynamic lung mechanics on a breath-by-breath basis. hemodynamic data were recorded continuously and discont. by the picco monitor (pulsion, munich, germany). miget and abg data were collected at the end of each study period. ventilation at ol-peep after a rm resulted in better oxygenation and lung mechanics, lower shunt and lower amounts of areas with a high v/q as compared to the other periods studied (table) . recruited lungs ventilated at ol-peep showed better gas exchange and ventilatory condition than any other condition studied. these findings show that rm in conjunction with ol-peep make ventilation and perfusion more homogeneously distributed within the lungs and lead to an adequate matching of both. the onset mechanism of ali/ards and subsequent tissue injury are considered to be associated with neutrophil elastase, and the main two causes( direct lung injury: group d. and indirect lung injury: group i) of ali/ards are considered to be pneumonia ( bacterial, fungal, viral et al), aspiration pneumonia and sepsis. in japan, sivelestat sodium hydrate, a selective elastase inhibitor, was approved in for ali/ards accompanied by sirs, and this medicine has been evaluated in clinical situation. in this study, we performed a retrospective comparison of the sivelestat sodium hydrate administration between two groups of patients: group d, consisting of patients ( males and females, aged ± years old) , and group i, consisting of patients ( males and females, aged ± years old) with ali/ards accompanied by sirs who were treated with sivelestat sodium hydrate at a dose of . mg/kg/hour for hours or more in the icu. il- , il- , elam- (endothelial leukocyte adhesion melucule- ), pai- (plasminogen activator inhibitor- ) and pct (procalcitonin) were measured every hours. elisa and eia methods were used for the measurement of il- , pai- and elam- , respectively, and icl method was used for pct. the apache ?scores of group d and group i were ± and ± , and the lung injury score(lis) were . ± . and . ± . , respectively, with no significant differences between the groups. sofa scores of group d and group i were ± and ± , which was significantly higher than that of group d (p< . ). the pao /fio ratios under mechanical ventilation management , and hours after the beginning of drug administration were ± , ± , and ± mmhg in group d, and ± , ± , and ± mmhg in group i. furthermore, the survival rate after days was significantly higher in group d than in group i (group d: . %, group i: . %, p< . ). these results suggest that sivelestat sodium hydrate is a good option as a treatment strategy for neutrophil elastase-associated direct lung injuries accompanied by sirs. grant acknowledgement. no disclosure pulmonary edema significantly contributes to ventilation-perfusion mismatching and hypoxemia in ards. while inhaled nitric oxide (ino) has been shown to lower pulmonary pressures and edema accumulation in experimental acute lung injury (ali)( ), its clinical use has been questioned because of a lack of improvement in outcome, rebound phenomena and potential toxicity. we investigated the effects of aerosolized iloprost, a stable prostacyclin analogue, compared to ino on pulmonary pressures and lung edema in oleic acid lung injury. the most effective dose of iloprost in this setting was determined in healthy animals prior to the experiment. the anesthetized and ventilated sheep received a central venous oleic acid infusion ( . ml/kg) and were continuously infused with ringer's lactate to achieve a positive fluid balance ( ml/kg/h). in the ino group (n= ), inhaled nitric oxide ( ppm) was then administered continuously for hours, while animals in the iloprost group (n= ) received aerosolized iloprost ( µg every hours). animals in the control group (n= ) had no further intervention. pulmonary edema was measured by transpulmonary thermodilution (extravascular lung water). oleic acid infusion was associated with impaired oxygenation, pulmonary hypertension, and lung edema in all groups. while ino significantly decreased pulmonary vascular resistance index (pvri), effective pulmonary capillary pressure (pceff), and extravascular lung water index (evlwi), both parameters were unaffected by iloprost. oxygenation index (pao /fio ) increased significantly both during no and iloprost inhalation but also tended to improve in the control group over time. conclusion. this is the first study directly comparing the effects of inhaled nitric oxide and aerosolized iloprost on pulmonary hemodynamics and lung edema in experimental lung injury. in contrast to ino, µg iloprost inhaled every hours was ineffective to reduce pulmonary pressures and extravascular lung water. these findings partly contradict previous investigations, and may be best explained by dissolution of the highly water soluble iloprost in alveolar edema, which is a common finding in oleic acid lung injury. much higher doses of iloprost may thus be required to achieve a reduction of pulmonary pressures and fluid filtration when alveolar edema is present. while inhaled nitric oxide (ino) may be used in the management of ards, data would suggest that its benefits pertain to a short-term improvement in oxygenation with no significant beneficial effect on mortality . we performed a retrospective audit on the use of ino in our mixed medical and surgical intensive care unit. the following data were collected; age, apache ii score, length of icu stay, duration and cost of ino therapy, percentage change in pao /fio ratio, icu mortality. patients were sub-divided into responders/non-responders and survivors/non-survivors. a response to ino was defined as > % increase in pao /fio ratio . results are displayed in the table below. five responders survived to icu discharge ( . %), while non-responders survived ( . %). this difference did not reach statistical significance (p = . , chi-square). the total group costs of ino for responders, non-responders, survivors and non-survivors were £ , , £ , , £ , and £ , respectively. responders only accounted for % of the total ino expenditure in our icu. conclusion. ino is an expensive therapy. in this small retrospective audit we were unable to show any significant benefit of ino on outcome. the use of ino within our icu needs to be reappraised, especially in those ards patients classified as non-responders. the pvm tool of the respirator was easy to use. we observed no clinically evident haemodynamic complication. as a consequence of the pvm peep was increased in patients from ± to ± cm h o and decreased in patients from ± to ± cm h o. peep was not changed in two patients. there was a significant increase in pao /fi o ratio from ± to ± (p= . ) ( figure) while the change in paco was not significant ( ± versus ± ; p= . ). changes in peep did not correlate with changes in paco (r = . ; p= . ). after the implementation of the pvm into commercially available respirators, this manoeuvre can be performed safely and quickly. the setting of peep according to the results of the pvm lead to an improved oxygenation of the patients. we conclude that patients with ali/ards may profit from a routinely performed pvm. introduction. ards is a common syndrome with a high mortality rate in intensive care units. several pharmacological therapies have been proposed but none of them improved survival up to now. pulmonary hypertension occurs already in early stages of the disease and its magnitude has been shown to be associated with poor outcome. the phosphodiesterase type inhibitor sildenafil selectively dilates pulmonary vessels and has been approved for treatment of pulmonary arterial hypertension.. we investigated the effects of oral sildenafil in combination with inhaled prostacyclins in five patients with ards and septic shock. five patients with severe ards were investigated. underlying diseases were: copd (n= ), small airway disease (n= ), idiopathic fibrosing alveolitis (n= ), as well as cardiac insufficiency (n= ). four patients showed severe obesity, mean bmi was , ( ± , ). all patients fulfilled criteria of septic shock, three of them developed acute renal failure requiring continuous venovenous hemofiltration. all patients were monitored by a pulmonary artery catheter. mechanical ventilation was carried out according to recommendations of the ards-network. prone positioning (at intervals of hours) was instituted if possible. inhaled prostacylins (iloprost) were given times daily (max. concentration µg/d). if no persistent improvement of oxygenation could be achieved, sildenafil was added per os ( x mg/d). the combination of oral sildenafil ( x mg/d) and inhaled prostacylins resulted in a significant decrease of the mean pulmonary arterial pressure (pap-m). on the third day of therapy pulmonary arterial pressure was reduced by about % of the initial value (table ) . within a week a % improvement of the horowitz indices could be achieved. administration of sildenafil was continued in four patients until they could successfully be weaned from mechanical ventilation. these four patients left hospital alive. one patient died because of cardiogenic shock. , ± , * * significant difference from day (p < , ) conclusion. sildenafil in combination with inhaled prostacyclins causes significant reduction of pulmonary arterial hypertension as well as significant improvement of oxygenation in patients with ards and septic shock. increasingly the mouse has become the experimental animal of choice in immunological research because of the large set of immunological tools that is available. this is of particular interest in the area of inflammatory and immunological response to mechanical ventilation. most available rodent ventilators only ventilate one mouse at a time. in order to expedite the results of interventions, larger series of mice must be ventilated in a short period of time. therefore, we developed a method to ventilate mice simultaneously using a conventional ventilator. twelve mice were anesthetised, tracheotomised and subsequently connected to a servo ventilator c with a distribution system allowing simultaneous ventilation of six mice. a canula was inserted into the carotid artery for bloodsampling. for consecutive hours the mice were ventilated in a pressure-controlled, time-cycled mode, pip cm h o, peep cm h o, i/e ratio of : , fio . and a frequency of /min. during the hours of ventilation, arterial bloodgasses were collected after various periods of ventilation, with a maximum of bloodsamples per individual mouse. (n= ) not only demonstrated normocapnia (paco . ± . ) but also a normal ph (ph . ± . ) and adequate oxygenation (pao . ± . ). six mice can be ventilated simultaneously using a servo ventilator c with a distribution system, thereby decreasing the number of days spent to the experimental procedure and expediting experimental time. pulmonary vascular permeability increases in response to lung overstretching. phosphoinositide -kinase gamma (pi k gamma) is activated by mechanical stretch. akt, a major downstream signal molecule of pi k gamma, induces nitric oxide (no) production. we investigated the contribution of pi k gamma to acute alveolar edema formation by mechanical stretch. in wild type (wt) and knock-out (ko) pi k gamma mice, lungs were ventilated and perfused with two settings: eip - cmh o and eep cmh o (stress) or eip - cmh o and eep - cmh o (no stress). at the end of each experiment histological alveolar edema, lung elastance, pulmonary expression of erk, akt, enos, nitrate/nitrite (nox) on pulmonary perfusate were measured. see table . data are mean ± sd. during high stress ventilation vascular permeability changes were pi kgamma, akt, enos mediated. the lack of pi k gamma activity protected from alveolar edema increases. recent experimental data suggest that intrapulmonary cxc chemokine release, neutrophil infiltration and myeloperoxidase activity is considerably increased in aged individuals [ ] . years represented the best age threshold value that discriminated survival in mechanically ventilated patients [ ] and, we speculated that inflammatory responses may differ considering this age threshold. in patients bronchoalveolar lavage (bal) was performed with aliquots of ml . % saline on initial hospital presentation within hours after multiple trauma. cytokines were quantified using a sandwich immunoassay and neutrophil secretion products were determined with immunoluminometric assays. bal-phospholipids were determined with electrospray ionization mass spectrometric analysis. we compared older (> years, n= ) with younger patients (< pg/ml) (n= ) using the mann-whitnes-u-test or fisher's exact test and used the spearman rank correlation to assess relations between inflammatory parameters and age. older patients (mean±sd, . ± . years) had similar injury severity scores, thoraxtrauma severity and pao /fio -values as compared to younger patients ( . ± . years) (p> . ). of the older and of the younger patients developed ards (p> . ). only one patient died days after trauma. he was years old and developed ards due to sepsis weeks after trauma. intraalveolar il- release and both pulmonary and systemic neutrophil activation as reflected by myeloperoxidase and lactoferrin concentrations were reduced in older compared to younger patients (p< . ). pulmonary inflammatory parameters decreased significantly with increasing age: bal-neutrophils (rho=- . , p= . ), the inflammatory cell membrane phospholipid phosphatitylinositol : / : (rho=- , , p= . ), bal-lactoferrin (rho=- . , p= . ) and bal-il- (rho=- . , p< . ). in contrast to experimental data proinflammatory responses were reduced in aged individuals. it is tending to speculate that reduced immune competence instead of exacerbated inflammation may contribute to worse prognosis seen in the aged given an inflammatory insult. design: prospective, randomized controlled study. setting: medical and surgical intensive care units in a university tertiary care centerpatients: a total of patients with localized ards ready for recruitment maneuver (rm) were included. intervention: patients were randomized to receive mechanical ventilation (mv) in supine (smv, control group) or in prone position (ppmv, study group). both groups were ventilated with protective lung strategy (tidal volume to ml/kg). an rm was applied using a pressure control mode (pcv) with a cm h o and a cm h o peep for s. peep was subsequently reduced by cm h o increments until a decrease in compliance was observed. a second rm was then performed and peep was set one step above the level at which compliance declined. pcv level was kept at cm h o during the determination of optimal peep. results: bronchoalveolar lavages (bal) and blood samples were collected before randomization and at hours to determine the concentrations of interleukine (il- ), interleukine (il- ), interleukine (il- ) and tumor necrotic factor (tnf-±), pao / fio . pao /fio was improved and paco was lower in ppmv when compared with smv with statistic significance. at hours after rm, il- ( p = . ), il- ( p = . ) and il- ( p = . ) in bal was lower in the ppmv group than smv group. the serum level of il- ( p = . ) and tnf-± ( p = . ) were reduced with statistic significance and il- was reduced also (p = . ) for the ppmv group. conclusion. ppmv may improve oxygenation and reduce pco than in the smv position in patients with the localized ards during rm. the pro-inflammatory cytokines can be reduced during ppmv, which indicates attenuation of vili during pcv with peep recruitment maneuver for these patients. grant acknowledgement. this research is sponsored by the grants of vghnsu - . inflammatory cytokines have been found to be elevated in bronchoalveolar lavage fluids (balf) of ards patients. mediators formed from n- fatty acids (fa) and those developed from n- fa have opposite influences upon inflammatory processes. the aim of this study was to investigate whether n- fa may modulate inflammatory cytokines release in a cell culture of human pneumocytes exposed to balf of ards patients. thirty-one patients ( males, ± yr, sapsii ± ) with ards (as defined by the american-european consensus conference) requiring mechanical ventilation were included in the study. the p. were divided into those with pulmonary ards [ardsp, pneumonia (pn) n= ], and those with extrapulmonary ards (ardsexp, sepsis n= ; other n= ) without pn. all p. were examined by bal for clinical purposes within h after intubation. tnf-alpha, il- beta, il- and il- levels were measured in balf. we exposed a cells, a human pulmonary cell line with type ii pneumocyte properties, to the collected balf. after h, fa were added as docosahexaenoic acid (n- ) and arachidonic acid (n- ) in two different n- /n- ratios ( : and : ). h later, culture supernatants were collected to evaluate cytokine and prostaglandin (pg)e release. the fa percentage content was determined in phospholipids of a cells. level of peroxisome proliferator-activated receptor (ppar)gamma and nf-kb binding activity were determined. cytokine levels in balf were found higher in ardsp than ardsexp (p<. ). the baseline n- /n- fa ratio of : in a cell phospholipids approximately dropped to : and raised to : after : n- /n- ratio and : ratio incubation, respectively. we found that pge levels were significantly lower in a cells treated with the : ratio than those with : (p<. ). the release of cytokines from a cells was reduced by the : ratio (p<. ), but increased by the : (p<. ). nf-kb activity was induced in a cells by balf. addition of : ratio to the cells resulted in an increased expression of ppargamma, whereas nf-kb activity was more inhibited compared to : (p<. ). our results showed that increasing the n- share in n- /n- fa ratio induces a significant reduction of pro-inflammatory mediator (cytokines,pge ) release in stimulated a cells, whereas the administration of an n- fa predominance increases their release. although different cytokine levels in ardsp vs. ardsexp, the cause of ards did not influence the effect of n- addition. fa are ligands for ppargamma. our results suggested that n- fa might exert their anti-inflammatory effects through direct actions on the intracellular signaling pathways which lead to activation of ppargamma and inhibition of nf-kb activity. inflammatory response in a cells exposed to balf can be modulated by n- fa, due to their incorporation into membrane phospholipid pools that modifies lipid-related intracellular signaling events. th esicm annual congress -berlin, germany - - october s type plasminogen activator inhibitor (pai- ) is one of the primary regulators of fibrinolysis in vivo. a - g- g sequence polymorphism in the promoter of the pai- gene has been described as response polymorphism, since its release is regulated by various inflammatory factors. elevation of pai- levels after stressful events is much more pronounced in patients with the g allele. thus, the formation of microthrombi is no longer counteracted by the fibrinolytic system, resulting in impaired microcirculation, multiple organ dysfunction and poor outcome. our aim was to study the impact of the g allele on the survival rate of ali-ards patients. methods. ali-ards ( ali) due to sepsis ( ), pneumonia( ), aspiration ( ), severe trauma ( ), cardiac surgery ( ), pancreatitis ( ) and pulmonary embolism ( ) were studied. the mean apache ii score was ± . identification of the g- g polymorphism was based on polymerase chain reaction and reverse-hybridization. the comparison of the death rates between the two polymorphism groups ( g g versus non- g g group) was done by means of a logistic regression model, with survival as the dependent variable and the polymorphism, as well as the apache score, as the independent variables. . patients died (mortality . %). patients had a genotype g- g, patients were g- g heterozygous, while were g- g homozygous. apache scores were not significantly different between subgroups. the death rate among the g- g patients was %, while in the non- g- g patients was %. the univariate analysis showed that the g- g patients had % higher odds of dying compared to the non- g- g patients (odds ratio = . , % ci: . to . , p-value= . ). in the multivariate analysis the g- g patients had approximately . times higher odds of dying compared to the non- g- g patients (odds ratio = . , % ci: . to . , p-value= . ). however results were not statistically significant. our findings suggest a negative effect of this polymorphism on the survival odds of ali-ards patients. however, the small number of patients limited our power to detect a statistically significant difference regarding its influence on the prognosis of ali-ards patients with disorders triggering the coagulation cascade. our data might support further research on the relation between g- g polymorphism and outcome of ali-ards patients. excessive production of nitric oxide by neuronal nitric oxide synthase (nnos, nos- ) is one major factor in the pathogenesis of acute lung injury and systemic inflammation after burn and smoke inhalation injury. we hypothesized that the use of the selective nnos inhibitor -nitroindazole ( -ni) will block molecular mechanisms in ovine acute lung injury. adult ewes (n= ) were chronically instrumented to determine cardiopulmonary hemodynamics and pulmonary transvascular fluid flux. after seven days of recovery, sheep were randomly allocated to either an injured untreated control group (n= ), or an injury group treated with -ni (n= ). the injury consisted of a % total body surface area flame burn and breaths of cotton smoke. -ni ( mg/kg/h) was continuously infused from h post injury to the end of the -h study period. this double hit injury was associated with oxidative stress, severe pulmonary derangements and systemic inflammation, as evidenced by a . -fold increase in plasma nitrite/nitrate (nox) levels, as well as -fold, -fold, -fold and -fold increases in interleukin- (il- ), myeloperoxidase (mpo), malondialdehyde (mda) and poly-adp-ribose-polymerase (parp) lung tissue concentrations, respectively. compared to untreated controls, -ni significantly reduced nox plasma levels ( . ± vs. ± µmol/l) and decreased il- , mpo ( . ± . vs. . ± . u/g tissue), mda ( . ± . vs. . ± . nmol/mg protein) and parp lung tissue content ( . ± . vs. . ± . ), thereby decreasing pulmonary obstruction ( . ± . vs. . ± . obstruction score) and increasing pao /fio ratio ( ± vs. ± , each p< . ). these data show that nnos-derived no plays a pivotal role in the pathophysiology of combined burn and smoke inhalation injury and suggest selective nnos inhibition as a useful approach to attenuate pulmonary injury. h. qiu*, p. li, y. yang department of critical care medicine, nanjing zhong-da hospital, nanjing, china hpmecs were cultured, and used lps with a gradient concentration ( ng/ml, ng/ml, ng/ml, and ng/ml) to stimulate the cells for h, h, h, and h. subsequently, the experiments below were carried out. total ribonucleic acid was extracted from the cells for reverse transcription polymerase chain reaction (rt-pcr) to identify the expression level of angii receptor mrna. the total protein was extracted from the adhere cells for western blot to identify the protein expression of the at receptor. radioreceptor assay (rra) was used to obverse the affinity (kd) and maximum receptor binding (bmax) of angii with its receptor after lps stimulation. rt-pcr demonstrated that angiotensinii type (at ) receptor mrna level escalated after varying concentrations lps stimulating in h, h, h and h. there was obvious time-dependent increase in ng/ml group. the level of the at receptor mrna in ng/ml and ng/ml groups have not time-dependent increase. irrespective of lps stimulating or not, hpmecs didn't express mrna of angiotensinii type receptor (at ). western bolt presented that the protein level of at receptor had a predominant increase followed the lps treat compared with control group ( ng/ml). after stimulated for h, the level of at receptor protein reached to the peak value in ng/ml group, and no notable difference was defined at every time after that. the significant dose-dependence was showed in every stimulating time, but the time-dependence was defined just in ng/ml and ng/ml groups. rra was confirmed that there was no striking statistics difference between each group for kd. as far as bmax is concerned, bmax of the three groups ( ng/ml, ng/ml, and ng/ml) had a significant increase compared with the control group. the groups of ng/ml and ng/ml had peak value at h and h respectively, and had a significant decrease after respective peak value time. the bmax of the ng/ml group escalated to the peak value and demonstrated a notable time-dependence. lung ischemia and reperfusion in the pulmonary vascular compartment is an unavoidable consequence of transplantation. it is associated with release of inflammatory mediators promoting chemotaxis and adherence of neutrophils, which finally disrupt endothelial cell layer and increase permeability, possibly leading to acute lung injury ( ). rare data exist about similar mechanisms in the upper and lower respiratory compartment with tracheobronchial (tbec) and alveolar epithelial cells (aec). purpose of this study was to evaluate the effect of hypoxia/re-oxygenation (h/r) regarding the inflammatory response in the respiratory compartment. aec and tbec were placed in a hypoxic incubator with % oxygen for hours and re-oxygenated at % oxygen during , , and hours. for each time point, control cells were left at % oxygen. supernatants were analyzed performing a sandwich enzymelinked immunosorbent assay (elisa) for mcp- and cinc- (pharmingen, san diego, ca). caspase- and ldh measurements were performed. statistical significance was assessed by student's t-test. (values: mean ±sem). protein expression of mcp- and cinc- in aec was decreased upon h/r: at h hypoxia with h re-oxygenation mcp- decreased fromm ± pg/ml to ± pg/ml (p< . ), cinc- from ± pg/ml to ± pg/ml (p< . ). at h/ h h/r no difference in mcp- and cinc- expression could be observed in comparison to control cells. interestingly, inflammatory mediators released from tbec did not show any differences upon stimulation compared to control cells. caspase- activity in stimulated and unstimulated aec was similar. in tbec, however, caspase- activity was decreased by % at h/ h h/r, at h/ h by %, and at h/ h by % (p< . ). ldh values did not differ in stimulated and unstimulated aec and tbec, indicating that no process of necrosis is involved. upon h/r the lower respiratory compartment with aec reacts with decreased production of inflammatory mediators, while the upper compartment with tbec shows diminished apoptosis rate. biological significance of this attenuation of epithelial injury upon h/r has to be further investigated. , . : - grant acknowledgement. société suisse d'anesthésiologie et de réanimation schweizerische gesellschaft für anästhesiologie und reanimation: ssar/sgar methods. ards was induced in healthy pigs ( ± kg) by repeated saline lung lavage until pao decreased to less than mmhg. after a stabilisation period, the animals were randomly assigned to two groups: cmv: fio = . , vt = ml/kg, and hfov/av-ecla: fio = . , frequency = - hz. after lung recruitment, the peep in the cmv group and the mean airway pressure (mpaw) in the hfov/av-ecla group was set cmh o above the lower inflection point (lip) of the p/v-curve. gas exchange and hemodynamic data were determined hourly. after h, mrna expression of tnf-alpha, il- -beta, il- , il- and il- in lung tissue was quantified by real time pcr. histopathologic analysis from the lungs was performed using a four point semi-quantitative severity based scoring system. ( ). h s also exerts a variety of cytoprotective effects in vitro and in vivo ( ) . therefore, we tested the potential cytoprotective effect of infusing the h s-donor nahs during porcine thoracic aortic occlusion-induced ischemia/reperfusion(i/r)-injury. methods. after random assignment to either nahs (n= ); mg/kgxh started h before and continued until h after aortic occlusion) or vehicle (n= ) anesthetized, ventilated and instrumented pigs underwent min of aortic occlusion using inflatable balloons placed immediately downstream the a.subclavia and upstream the aortic bifurcation. during aortic occlusion, mean arterial pressure (map) was maintained between - % of the baseline levels using continuous i.v. esmolol, nitroglycerine and atp. during the reperfusion continuous i.v. noradrenaline (na) was titrated to maintain map> % of the baseline level. dna damage in blood samples was evaluated with single cell gel electrophoresis (tail moment in the comet assay). data are median (range), within group effects over time were analyzed using a friedman anova on ranks, intergroup differences with an unpaired rank sum test. results. infusing nahs resulted in significantly lower heart rate and cardiac output, while map and stroke volume remained unchanged. nahs significantly reduced the na requirements needed to achieve the hemodynamic targets, significantly decreased glucose turnover, and completely blunted the i/r-induced dna damage (see septic shock is associated with increased oxidative stress, which in turn depresses mitochondrial activity. the key antioxidant enzyme superoxide dismutase (sod) was reported to restore mitochondrial function ( ). since glucose oxidation represents the most effective energy generating process, we investigated the effect of genetic cuzn-superoxide dismutase overexpression on glucose oxidation in a clinically relevant model of murine septic shock ( ) . h after sepsis induction by cecal ligation and puncture (clp) or sham-operation heterozygous (he), homozygous (ho) sod overexpressing and wildtype (wt) mice were anesthetized, mechanically ventilated and instrumented. in the clp groups normotensive, hyperdynamic hemodynamics were achieved with colloid fluid resuscitation and intravenous noradrenaline (na) titrated to maintain mean arterial pressure (map) > mmhg. glucose oxidation rate was calculated from simultaneous determination of co enrichment and co concentration (gas chromatography/mass spectrometry) in the expired gas during continuous i.v. stable-isotope , , , , , - c -glucose infusion. measurements were recorded , and h after clp. within group effects over time were analyzed using a friedman anova on ranks, intergroup differences with an unpaired rank sum test. all parameters of gut and liver macro-and microcirculatory perfusion and oxygenation were well maintained. na infusion rates did not differ between clp groups. glucose oxidation (percentage of the infused c -glucose) did not differ between groups nor over time. liver sod-activity prior to anesthesia and surgery was . -fold and -fold higher in he and ho mice, respectively. while it decreased by about % in the septic he and ho mice, sod activity was not significantly affected in the wt animals. given the comparable parameters of macro-and microcirculatory perfusion and oxygenation, the lacking na-induced increase in glucose oxidation rate confirms the sepsis-related defect in energy metabolism. the higher tissue sod-activity did not restore the impaired carbohydrate utilisation, possibly due to a sepsis-related loss of tissue sod and/or catalase activity. anemia is frequent in icu and involved both functional and true iron deficiency due to inflammation and blood loss. hepcidin (hepc) is a negative regulator of iron recycling by macrophages. its synthesis is highly inducible by inflammation and repressed by iron deficiency and stimulation of erythropoiesis. we explored iron metabolism and hepc gene expression in this complex situation of icu anemia. we developed a model of inflammation in c bl/ mice, by ip injections of zymosan (z), combined or not with repeated blood withdrawals (w). we followed blood numeration and tissue iron concentrations. using qrt-pcr, we quantified hepc and il- mrna in the liver as well as erythropoietin (epo) mrna in the kidney (normalised to s mrna and expressed as a ratio to controls (c)). hepatic ferroportin protein concentrations were assessed by western-blot. kruskal-wallis or anova were used for comparisons of mean±sd. p< . significant. anemia was found already days after zymosan injection, and was more severe blood withdrawals, either alone (w) or following z (z+w). at day , epo mrna expression was stimulated in both w ( . ± ) and z+w ( ± . ), as compared to c( ± . ) or z ( . ± . )(p< . ). as expected, z injection induced il- mrna expression ( . ± . for z; . ± . for z+w). interestingly, hepc mrna was induced following z injection ( ± . ) but the combination of inflammation and w repressed hepc mrna expression ( . ± . ). to confirm that it was due to erythropoiesis stimulation, we injected epo on consecutive days following z and found that it prevented activation of hepc mrna( . ± . ). in mice undergoing w or epo injections, spleen iron was reduced, as opposed to c and z ( ± , ± , ± , ± vs ± and ± µg/g for z+w, w, z+epo, epo, c and z). ferroportin was reduced in z and increased by w and epo (western-blot). conclusion. in this mouse model of inflammation, induction of hepc gene expression is prevented by repeated w or epo ip. it seems that the signalling pathway which represses hepc expression in response to activation of erythropoiesis dominates over the pro-inflammatory signal. furthermore iron exporter ferroportin is also induced. these results raise the possibility that iron supplementation might be proposed for critical care patients' anemia. studies examining the effect of glutamine supplementation in critical illness have demonstrated significant beneficial effects in animals and man although the mechanisms by which this protection occurs are not understood. we aimed to examine the effect of various glutamine concentrations on the ability of c c myoblasts to differentiate and its effect on heat shock protein expression (hsp). methods. c c myoblasts were raised under standard conditions. differentiation to multinuclear myotubes was induced by replacing fcs with % horse serum. cells were supplemented with glutamine at concentrations between and mm throughout and this was replaced every other day. photographs were taken at day of differentiation. hsp content of cells was determined using western blotting as described previously (maglara et al, ) . at low levels of glutamine ( - mm), cell survival was greatly impaired and differentiation was reduced. however hsp content of cells grown in media of . m and m glutamine showed an increased hsp response compared with cells grown and differentiated in physiological glutamine concentrations. no effect of higher glutamine concentrations (between . - mm) on cell viability or hsc and hsp content was evident. conclusion. glutamine supplementation affects heat shock protein (hsp) expression in various cell types. several authors have suggested that exposure of cells to relatively high concentrations of glutamine results in increased hsp expression and an enhanced cell survival (wischmeyer et al. ) skeletal muscle degeneration occurs following a number of insults and muscle repair is reliant upon activation and differentiation of stem cells or myoblasts to form mature multinucleated muscle. transgenic studies in our laboratory have demonstrated that the ability of skeletal muscle cells to produce hsps during stress and development is crucial to the correct maturation and functioning of these cells (mcardle et al, ) . our data suggests that the glutamine concentration for optimal myoblast proliferation and differentiation is ∼ mm. reduction below this value resulted in reduced cell viability and modified hsp although levels higher than physiological had little effect on cell growth and differentiation. this might suggest that reduced glutamine concentrations in it self acts as a stressful stimulus. further reduction however renders the cell unable to respond at all. in addition g regulation might be linked to other stress hormones, such as cortisol (c) and prolactin, in rats and humans in physiological conditions. our aim is to study the circadian variations of cortisol and ghrelin plasma levels in patients with acute coronary syndrome (acs) admitted to the intensive care unit. eight male ( ± years old) patients with acs were studied. seven showing non-st-elevation and one with st-elevation. within the first hours of admission, blood samples were taken every hours (nine samples) in all acs patients. patients were kept nothing per os during the sample drawing period. eight patients admitted in the department of internal medicine in a stable clinical situation were studied on the day before being discharge, as control group. g and c levels were measured in all samples using specific ria (phoenix pharm. usa). control subjects showed a cortisol circadian rhythm with peak values at : a.m. ( , ± , mcg/dl) and nadir values around : p.m. ( , ± , mcg/dl). in this patients g levels also present circadian variations, with peak values at : a.m. ( , ± , pg/ml) and nadir values at : p.m. ( ± , pg/ml). in contrast, patients with acs showed a very demised c circadian rhythm, and the amplitude of the circadian variations of g levels is markedly reduced, showing a shift of the peak values to : p.m.( , ± , pg/ml ) and nadir values around : a.m. ( , ± , pg/ml). there is a circadian rhythm of ghrelin with a peak ranging from : a.m. to : a.m. in hospitalized subjects. those variations are o shifted in phase respect to cortisol rhythm. opposite, in patients with acs the circadian variations of ghrelin levels are lost. the results of lft of patients admitted to the general intensive care unit of a large teaching hospital in south london, between st december and th february were obtained from the chemical pathology department. mortality statistics were obtained from the hospital electronic patient record. lft of patients who were readmitted were excluded. a total of patients had a first admission to the general icu during the three months studied. the average age was . yrs (sd . ), % were male and the mean length of stay was . days (range - ). mortality rate at days was % ( / ). at the time of admission only ( %) patients had entirely normal lft. patients with cholestatic lft above the normal range on admission were more likely to be female (akp odds ratio: . ( . - . ), gammagt or: . ( . - . )). abnormalities in alt, akp and gammagt on admission, were associated with a higher likelihood of death at days (table). average length of stay was greater in those with abnormal lft but only reached statistical significance with akp above the normal range (table) . conclusion. abnormality of liver function tests is common in the critically ill patient admitted to the general intensive care unit. even relatively minor elevations of lft are associated with an increased risk of death within days. the cause of these abnormalities is likely to be multifactorial and further studies are needed to elucidate the cause. myxedema coma with extreme hypothermia: a case report e. brands* intensive care, academisch ziekenhuis maastricht, maastricht, netherlands a patient is presented with an undiagnosed hypothyroidism which progressed to myxedema coma with extreme hypothermia, bradycardia, anaemia and somnolence. a year old male patient, with a history of hypertension and a cerebral vascular accident, was admitted to the emergency room after a collapse. during several months he showed progressive disability due to fatigue, unstable gait and chilliness. the last weeks his condition worsened leading to muscle weakness, dysarthria, dysphagia, cognitive dysfunction and somnolence. upon physical examination we saw a somnolent patient with a gcs (glasgow coma scale) of - - , with hyporeflexia and pareses of the lower extremities. respiratory rate of per minute. blood pressure was / with a heart rate of beats per minute. the patients temperature was . oc. the patients gcs decreased to - - upon which an endotracheal tube was placed and mechanical ventilation instituted. laboratory tests showed a haemoglobin . normal adrenal function test. one day after thyroid hormone substitution ( µgr t intravenously on day one, followed by µgr t once a day, µgr t orally every hours on day one only), the patients regained consciousness. his heart rate increased to beats per minute after normalisation of body temperature. gastroscopical evaluation showed an ulcus duodeni. despite of a ventilator associated pneumonia the patient recovered well. hypothyroidism may lead to a variety of symptoms ranging from malaise and fatigue to specific organ related complaints. especially in the elderly the symptoms may be mistakenly attributed to the physiological aging process, psychiatric, neurological illnesses or even dementia. numerous precipitating factors can evolve untreated hypothyroidism to myxedema coma. in our patient infection, cold exposure, gastro intestinal bleeding or iron deficiency could have played a role. the elderly patient is already prone to hypothermia due to physiological changes, in myxedema this may lead to an extreme low temperature. myxedema in its classical, full clinical presentation is a rare occurence in present times. especially in the elderly patient it can cause pronounced hypothermia. according with surviving sepsis guidelines we must control blood glucose levels to a less than mg/dl after h of admission to an icu. objectives: to evaluate the results obtain with the use of an intensive insulin treatment (iit) in a polyvalent intensive care unit. we conducted a prospective cohort study in a -bed polyvalent icu in a portuguese university hospital. adult patients who were assumed to require at least days of intensive care were eligible for inclusion. the study was carried out during months. capillary blood glucose (cbg) levels were measured on admission and subsequently every two or four hours in all patients during days. with the iit, insulin infusion was started when the blood glucose level exceeded mg per decilitre. we enrolled patients, age: , ± , ( , ), sapsii: , ± , ( , ), sofa: , ± , ( , ), length of stay in icu: , ± , ( , ), mortality rate: . %. , % of the patients were diabetes. incidence of hypoglycemia - , %. to examine the effect of central venous catheter (cvc)location on the incidence of catheter related blood stream infection (crbsi) in a total parenteral nutrition (tpn) population over a -year period ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . . bed university hospital. tpn population includes all medical and surgical patients hospital-wide referred for tpn. service based in intensive care. tpn committee meets quarterly to examine prospectively collected data. . cvcs were included. we compared incidence in different anatomical locations(figure). femoral cvcs were rarely used for tpn and so were excluded. subclavian cvc insertion was associated with a peak incidence of crbsi of per cvc days in which dropped to in . peak incidence of crbsi in internal jugular cvcs was per cvc days in , per cvc days in . this study prospectively examines the effect of anatomical location on crbsi. crbsi in subclavian cvcs remains almost consistently lower than internal jugular throughout study. this correlates with published data in the literature and cdc recommendations for use of subclavian site in preference for cvc insertion . patients after urgent abdominal surgery require adequate nutritional support. we aimed to assess the effectiveness of parenteral nutrition (pn) by "all-in-one" system with adding of glutamine to eliminate metabolic disturbances in patients after small bowel obstruction surgery. methods. patients after small bowel obstruction surgery (mean age . ± . years) was divided into groups. control group (n= ) received standard basic intensive therapy including pn by "all-in-one" system "oliclinomel" in first hours after an operation. glutamine group patients (n= ) received additional glutamine (dipeptiven - ml/kg/day). plasma whole protein and its fractions, amino acids spectrum, transferrin concentration, glucose and insulin levels, as well as standard laboratory and instrumental data were assessed before, at rd and th day of pn. in all patients metabolic disturbances with protein status shifts was revealed. dynamic analysis of data showed faster compensation of these disturbances in glutamine group. in both groups whole protein and albumin/protein ratio decreased gradually while amino acid sum, essential and nonessential amino acid concentration, glucose and insulin levels remained normal. by th day glutamine group showed faster increasing of transferrin concentration ( . ± . g/l vs. . ± . g/l) and fisher index ( restoration of metabolic activities confirms adequate nutritional support in both groups but glutamine adding provides faster improvement of protein disturbances and helps to avoid glutamine deficiency. y. kang* , h. jiang , x. qiang , x. jin , q. yi icu, general surgery, respiratory, west china hospital of sichuan university, chengdu, china to investigate the effect of supplementation with alanyl-glutamine dipeptide on insulin resistance and outcome in critically ill copd and respiratory failure patients. prospective, randomized and controlled study. patients who were admitted to west china hospital icu between jan and feb were selected and randomized into two groups which were given the similitude nutrition support protocol. two groups' nonprotein calorie were kcal/kgd, % were provided by fat emulsion. the nitrogen supply were . g/kg in each group. in treatment group %- % of nitrogen was given from the parenteral nutrition by the alanyl-glutamine dipeptide, the rest was the equilibrium amino acids. in the rd and th day, blood glucose clamp were performed in both groups, and blood glucose was rigidly controlled between . to . mmol/l. daily blood gas, glucose and insulin dosage and th day mortality , length of stay (los) in hospital and in icu, duration of mechanical ventilation (dmv) and the costs of icu and hospital were measured respectively. . patients completed the research. there was no difference in blood gas between two groups, but pao rose gradually. compared with control group, the five day's blood glucose level have a decreasing trend in treatment group. during the five days, the average insulin dosage have an obviously decreasing in treatment group. there were no difference between two groups in th day mortality, los in hospital and the costs of hospital. but the los in icu and dmv have a decreasing trend in treatment group. alanyl-glutamine dipeptide have not improved pulmonary function in critically ill patients with copd and respiratory failure. however, alanyl-glutamine dipeptide have contained certain function at attenuated insulin resistance and stabilized the level of blood glucose. alanyl-glutamine dipeptide did not reveal the effect of improving outcome in critically ill patients with copd and respiratory failure, the th day mortality, los in hospital and the costs of hospital. but the the los in icu and dmv have a decreasing trend in treatment group. adrenocortical dysfunction is a common finding in severe illness. however, it remains currently unclear whether adrenocortical responses predict outcome in acute critically ill patients. to investigate this, ( men) acute critically ill patients, with a median age of years were studied. admission diagnoses included multiple trauma (n= ), medical (n= ) or surgical (n= ) critical conditions. within hours of icu admission, a morning blood sample was obtained to measure baseline cortisol, corticotropin (acth), and dehydropiandrosterone sulphate (dheas). subsequently, a low-dose ( mcg) acth test was performed to determine stimulated cortisol. the incremental rise in cortisol was defined as stimulated -baseline cortisol. overall, patients survived and patients died. non-survivors were older and in a more severe critical state, as reflected by the higher sofa and apache ii scores. furthermore, non-survivors had a lower incremental rise in cortisol ( . vs. . mcg/dl, p< . ) along with lower dheas than survivors ( vs. ng/ml, p= . ). the two groups had similar baseline and stimulated cortisol. multivariate logistic regression analysis revealed that age (odds ratio= . , % c.i. . - . , p= . ), sofa score (odds ratio= . , % c.i. . - . , p< . ), and the incremental rise in cortisol (odds ratio= . , % c.i. . - . , p= . ) were independent outcome predictors. in mixed critically ill patients a blunted cortisol response to acth within hours of icu admission is an independent predictor for poor outcome. in contrast, baseline cortisol or adrenal androgens are not of prognostic significance. teicoplanin is a gycopeptitide antibiotic for treatment of highly resistant gram-positive bacteria such as methicillin resistant staphylococci and enterococcus faecalis. it is eliminated unchanged by the kidneys. in renal impairment the maintenance dose has to be reduced. data on pharmacokinetics of teicoplanin in patients requiring continuous veno-venous haemofiltration (cvvh) are sparse. therefore teicoplanin pharmacokinetics was assessed in critically ill patients during on cvvh. teicoplanin serum levels were measured in adult critically ill patients requiring cvvh for acute renal failure after the first dose and at approximate steady state conditions (day - of therapy). cvvh was performed using . m polyetersulfone membranes; blood flow was ml/min and the ultrafiltration rate amounted ml/kg body weight. a loading dose of , mg of teicoplanin was administered (infusion time h). subsequently the dosage was guided by serum levels and reduced to an average daily dose of ± mg per day. samples were drawn , , , , and h after start of infusion. teicoplanin was measured by a fluorescence polarisation immunoassay in serum and ultrafiltrate. pharmacokinetics was calculated using a non-compartmental model by kinetica . concentration time profiles of patients were determined after the first dose and of patients during steady state. the teicoplanin peak concentration was . ± . µg/ml (mean sd) after the first dose and . ± . µg/ml at steady state. trough levels amounted . ± . µg/ml and . ± . µg/ml, respectively. the half-life increased from . ± . h after the first dose to . ± . h at steady state, whereas the clearance declined from . ± . l/h to . ± . l/h. the apparent volume of distribution decreased from ± to ± l. the sieving coefficient of teicoplanin amounted . after the first dose and . after repeated administration. a loading dose of , mg of teicoplanin followed by a maintenance dose of about , mg per day appears to result in adequate serum levels in a majority adult critically ill patients on cvvh. however, because of a considerable variability of teicoplanin pharmacokinetics in this group of patients, therapeutic drug monitoring is recommended to warrant safety and efficacy of treatment. although heparin is the most frequently used anticoagulant in cvvh, alternatives to heparin are needed in case of heparin induced thrombocytopenia (hit). argatroban, a direct thrombin inhibitor approved for hit is primarily metabolized by the liver, thus, should not accumulate in renal failure. however, there is only limited data regarding its use in continuous venovenous hemofiltration (cvvh). we report a patient with acute renal failure where anticoagulation by argatroban appears to be influenced by cvvh. a years old woman was admitted to the icu department with septic shock and acute renal failure. bilateral infected crural ulcers could be identified as focus and therefore both calves had to be amputated. after days of cvvh with heparin as anticoagulant a rapid drop in platelet count of more than % occurred, a suspected hit was confirmed by heparin-pf antibodies (elisa). although there was no hepatic failure argatroban was started at mg/h ( , µg/kg/min) because of cholestatic cholecystitis and severe sepsis. results. aptt increased from to seconds after hours of argatroban infusion and further to sec after hours (figure ). at the same time pt fell from % to %. therefore argatroban dose was reduced by % to , mg/h. after h cvvh had to be stopped for h. after discontinuation of argatroban a decrease in aptt from to sec, as well as an increase in pt from to % was observed. h after argatroban was restarted at , mg/h, cvvh was stopped again for , hours without discontinuing argatroban. shortly after cvvh was halted aptt increased from to sec and pt decreased from to % within hours. this trend continued even after stepwise reduction of the dose of argatroban to , mg/h. the trend could not be reversed until the dose was further reduced to , mg/h and argatroban was stopped. after restarting cvvh without argatroban infusion a further decline in aptt as well as an increase in pt was observed. conclusion. this case demonstrates that argatroban may be influenced by cvvh and that dose may have to be substantially reduced in these patients. regional citrate anticoagulation (rca) is the recommended strategy when risk of bleeding is increased in continuous venovenous hemofiltration. we evaluated the feasibility and the safety of this method in high volume hemofiltration (hvhf) in critically ill patients with severe coagulopathy. methods. patients ( ± years, saps ii ± , sofa . ± . , septic shocks and sirs) have been retrospectively studied between january, and december, . continuous renal replacement therapy, daily limited to hours, was performed with a frésénius hdftm generator. blood flow was ml/min. the generated replacement fluid, calcium free, was used in pre-dilution. a citrate solution (acdar-fréséniustm) was infused to target a prefilter ionised calcium level below . mmol/l whereas systemic calcium perfusion maintained normal plasmatic calcium level. hemofiltration characteristics, filters lifetime and metabolic complications were the main collected data. . hfhv days ( filters needed) were analysed. mean hemofiltration volume was ml/kg per hour (about l per hour or l per day). percent of the prescribed hfhv dose could be carried out. mean filters lifetime was . hours. percent of them prematurely clotted. citrate and calcium perfusion flow respectively needed to be modified an average of and , time per day. metabolic alkalosis (ph> . ), hypocalcemia (ca++< . mmol/l), hypercalcemia (ca++> . mmol/l), hypernatremia (na+> mmol/l) and one citrate intoxication (total to ionised calcium ratio> , ) occurred. none of these events lead us to modify the anticoagulation strategy. prefilter ionised calcium level in non clotting filters was , ± , mmol/l versus , ± , mmol/l in clotting filters (p= , ). % of the patients died in hospital whereas predicted mortality was %. conclusion. rca is a reliable and simple method for hvhf with high hemorrhagic risk patients. frequent minor metabolic complications require a narrow biological monitoring. to improve our practices, prefilter ionized calcium levels should be decreased. continuous venovenous hemofiltration(cvvh) or hemodiafiltration (cvvhd) are the commonest renal replacement therapies(rrt) prescribed to the patients with the septic shock having renal failure. each cvvh session for hours costs around e in india as against intermittent hemodialysis(ihd),which costs around e per to hour session. hence ihd is still the commonest form of rrt in indian icus. major concern of ihd in septic shock patients is hemodynamic instability. whether stringent hemodynamic monitoring and maintaining preset goals would reduce these instabilities & deliver optimal rrt is not clear. we undertook a prospective study to evaluate this concept. we attempted to achieve preset goals of keeping mean arterial pressure (map) > mm, cardiac output (co) > lit./min & cardiac index (ci) > . lit./min/m throughout the session by following the protocol in the given sequence-: ) fluid boluses ) increase in vasopressor or inotrope dose ) adjustment in ultra filtration rate between - ml/hr and )adjustment in blood flow rate between - ml/min on hemodialysis machine. dopamine, norepinephrine, vasopressin and dobutamine were used alone or in combination to achieve these goals. hemodynamic monitoring & data collection was done with flotrac-vigileo monitoring systemtm (edwards lifesciences,irvine,ca,usa) and intellivue mp (philips,germany). . ihd sessions of patients with septic shock needing vasopressor were monitored and managed in icu. base line apache ii score was . ± . and all patients had at least organ failure. average duration of ihd was . ± . hrs and net negative fluid balance achieved per ihd session was . ± . ml. table showing hemodynamic parameters before ihd and during ihd preset goals were maintained without any intervention in sessions, with fluids alone in sessions, fluids and escalation of vasopressor in sessions and fluid bolus plus vasopressor escalation plus reduction in ultra filtration & blood flow in sessions. only / sessions were terminated at & min. due to development of new myocardial infarction in one and persistent hypotension in the other. additional cost of c. o. and c.i. monitoring was aboute per session. continuous veno-venous haemofiltration (cvvh) clears solutes and improves acidosis in critically ill patients with renal failure and sepsis. we studied solute clearance and filtration quantity prospectively in the first hours of patients requiring cvvh on two teaching hospital intensive care units. data collected included demographic data, reason for starting cvvh, blood biochemistry prior and after starting cvvh as well as duration of cvvh, including reasons for any interruptions. blood tests were collected once in a -hour period. data was collected for the entire period that patients required cvvh. solute clearance on cvvh within the first hours was expressed as a percentage change of urea and creatinine levels compared with levels prior to cvvh. quantity of haemofiltration was calculated over the interval between the first two blood tests and expressed in relation to bodyweight. data from patients is presented ( patients died before blood samples on cvvh was taken). the main indication for commencing cvvh was sepsis/acidosis in patients and renal failure in patients. the values for urea and creatinine on admission differed considerably between both groups. patients with sepsis/acidosis received a median cvvh-dose of . mls/kg/hr, whereas patients with renal failure were treated with a median cvvh-dose of . mls/kg/hr. table shows the respective median values for urea and creatinine prior to cvvh and from the first sample on cvvh, as well as the median (interquartile range;iqr) cvvh dose delivered in the period between the two samples. ( ) . we therefore studied the effect of anticoagulation on cvvh delivery. over a four month period data from patients across adult intensive care units was recorded. the number and reasons of interruptions and subsequent time lost as well as the type of anticoagulation was documented. infusion of heparin into the circuit was the primary form of anti-coagulation. heparin was started at units/kg/hr and adjusted according to local protocol to achieve a target heparin ratio (aptr) of . - . . aptrs taken from the circuit within the previous hours were defined to represent the degree of heparinisation at the time of a filter clotting off. a total of . patient hours of cvvh was delivered. filter clotting was implicated in of interruptions ( %). table shows the various forms of anticoagulants used, the number of interruptions and total time lost due to filter clotting. in the heparin group, aptrs were recorded. only % of these were therapeutic and % were sub-therapeutic. aptrs were recorded within the hours prior to filter clotting, representing % of all clotting events occurring on heparin. clotting events occurred with a therapeutic aptr, with recorded subtherapeutic ratios (relative risk . ), and event with an aptr > . filter clotting is by far the most common cause for interruptions in cvvh delivery ( %). adequate anticoagulation of cvvh circuits with heparin is problematic and failure to achieve the terget aptr carries a considerable risk of filter clotting. % of ap-trs were subtherapeutic despite use of a written protocol, suggesting that many patients are exposed to an increased risk of filter clotting regardless of other causative factors. whilst we recognise that the aetiology behind filter clotting is multifactorial, reducing these interruptions with adequate anticoagulation is important and may have positive effects on patient outcome. during continuous renal replacement therapy (crrt) anticoagulation of the extracorporeal circuit is generally required to prevent clotting of the circuit, preserve filter performance, optimize circuit survival, and prevent blood loss due to circuit clotting. unfractionated heparin (ufh) and low molecular weight heparin (lmwh) are generally used to perform this strategy. however, this anticoagulation may cause dangerous bleeding especially in acute renal critical patients. in these patients, it's very difficult to predict bleeding or thrombosis correctly during crrt. to asses the safety and efficacy of the use of an enoxiparin dose protocol based on anti-xa activity in crrt. methods. consecutive patients with acs was admitted to a coronary care unit of terciary hospital between [ ] [ ] patients presented heart failure during their hospitalization. clinical, ecg, echocardiographic, features were prospectively investigated. we also took blood samples in the first hours of their admittance to the ccu for a complete hemogram, levels of total cholesterol, hdl cholesterol, ldl cholesterol, triglycerides, creatinine, clearance of creatinine (mdrd equation), glucose, hbac , high sensibility-c reactive protein (hs-crp) and a follow up of levels of troponine, ck and ck-mb. we determined the presence of microalbuminuria (ma) (> mg/dl in a -hour urine sample). all patients were submitted to a coronary angiography in the first hours. we defined rd if the clearance of creatinine < ml/min/ . m . non-st segment elevation myocardial infarct (nstemi) was the most frequent cause of heart failure ( . %). the rd was present % of hf. the patients of this group was oldest, more diabetes mellitus, more previous myocardial infarct more anterior descendent occlusion. moreover, the patients with hf and rd had a lowest hematocrit ( % vs %), troponin i peak concentration ( . ng/ml vs ng/ml) and had higher of creatinine ( . mg/ml vs . mg/ml), ma, admission glycemia ( mg/dl vs mg/dl), nt probnp ( pg/ml vs pg/ml) and cystatin c ( . vs . ). both group present similar reduced ejection fraction ( % vs %). this group presented higher incidence of post infarct angina ( %; p= . ). in-hospital mortality was in patients with hf and rd % vs % in hf without rd (p= . ). in the follow-up (median days) the mortality of patients with hf and rd was % (p= . ). the mortality of the group with rd and treatment with ace-inhibitors was % vs % without ace-inhibitors (p= . ). the multivariate analysis identified the rd was a independent predictor of mortality in the patients with heart failure ( . ; p= . ) and the impact negative of rd was reduced by ace-inhibitors (or= . , ci % . - . ; p= . ). conclusion. the rd is common and a strong predictor of mortality in patients with hf complicating acute coronary syndrome. it is associated with a worse risk profile. ace-inhibitors improve the prognosis this group of patients. acute renal failure is a very frequent problem in the critically ill patients and contributes to their high mortality. the most frequent cause is sepsis,usually in the context of multiple organ dysfunction. the more prevalent admission cause in our arf patient were medical illness and pos-operative urgent surgery. the arf patients presented higher saps ii and initial sofa scores. the most common risk factor was shock;other factors frequently seen were sepsis,mod and rhabdomyolysis. the mortality rate measured was lower than that referred in the literature. following a needs-assesment, realistic acute-care simulations were designed using a modified delphi approach. didactic instruction was given regarding crm strategies including "the three c's of communication": clear instructions, citing names, closing the loop (eliciting feedback following instructions). teams of four: two physicians (a leader and an assistant);a pre-briefed critical-care nurse (rn) and critical-care respiratory therapist(rt), then responded to standardized simulation scenarios, delivered using a laerdal high-fidelity mannequin in a working critical care unit. we found insufficient crm skills on the first simulation (suggesting poor retention from didactic instruction alone) with gradual improvement following the three simulations (suggesting simulation offers a supplementary technique but may still be insufficient). we therefore made the team perform a fourth resuscitation, but with the physician-leader blindfolded. we found immediate/marked improvement in crm skills: physicians elicited help sooner and ensured instructions were completed. other members were quicker to volunteer changes in vital signs. debriefing confirmed that this novel approach was well received and participants reported enhanced understanding of the importance of teamwork. in the early stages of undifferentiated shock we are essentially "blind" to the diagnosis, and hence must rely on others. this strategy is also useful for trainees whose first language is not english: blindfolding forces them to focus on communication, with the result of increasing their confidence and reassuring supervisors. this technique allowed us to emphasize crm principles. we now expectat senior trainees to perform at least one blindfolded simulated-resuscitation. it is no longer an exaggeration to say our teams are "good enough to resuscitate blindfolded"! in current spanish population around % of people are over years of age. in our country, life expectancy is years. it is obvius that this population aging has modified some approachs in organs donation and transplantation process, forcing to include older people in waiting lists. the increase in the organs demand for transplantation has conditionated changes in the donor profile, therefore the evaluation, acceptance and rejection criteria of donors have been changing. the acceptance for older donors with associated comorbidity provide transplantations with acceptable results getting to reduce tranplant waiting lists and mortality. the consequence that arise from it is the concept of expanded criteria donor (ecd). we studied retrospectively donors from a hospital with no neurosurgery service from january to december , comparing donation potential between over and under years of age donors. . four of the donors younger than years (n: ) were not appropriate ( , %) whereas older than years (n: ) were ( , %) (p-ns). donors older than years provided kidneys and livers available for transplantation ( , % and , % of total organs, respectively) whereas younger than years group obtained kidneys and livers available ( , % and , % of total organs, respectively). number of useful organs per donors was , and , for younger and older than years donors, respectively (p: , ). conclusion. in our serie, age was not a predictor variable for hepatic usefulness whereas it was for renal usefulness. nowadays dce are indispensable and age can not be an exclusive factor in this donors evaluation. pct has many indications in icu patients, mainly prolonged mechanical ventilation / weaning difficulties and airway protection in comatose patients. the consensus conference on artificial airways in patients receiving mechanical ventilation recommended translaryngeal intubation for an anticipated need of up to days and a tracheostomy if an artificial airway for more than days is anticipated. however this decision should be individualized. the aim of this study is to analyse the indications and timing pct in our icu patients, and icu and hospital survival. we conducted a retrospective study, analysing patients submitted to pct, in months: since the technique was implemented in our icu in december , until march . we reviewed their age, gender, apache ii score, length of icu stay, ventilation time before and after pct, icu and hospital survival. patients were stratified in groups, based on the indication for the pct: prolonged mechanical ventilation (n= ) and airway protection in comatose patients (n= ). data was treated in spss programme, using the mann whitney test. the results presented are in mean values. conclusion. )the indications for pct in our icu were prolonged mechanical ventilation (n= ) and airway protection in comatose patients (n= ), a reduced sample size to analyse. )there was no significant difference in age ( years), gender, apache ii ( , ) and saps ii ( , ) scores. )comatose patients submitted to pct for airway protection had less ventilation days prior ( , vs , p= , ) and after ( , vs , p= , ) tracheostomy. their length in icu was shorter ( , vs , p= , ) . they had a lower hospital survival rate ( % vs , % p= , ), although there was no significant difference in icu survival. ) , % of patients submitted to pct due to prolonged mechanical ventilation were discharged alive from our icu, but only , % were discharged alive from hospital. recent literature suggests that early pct (in - days) could have had an influence on this high mortality hospital rate. )overall icu survival rate is %, but hospital survival is only % -a high mortality rate is seen after discharge from icu, in hospital wards. t. van galen*, o. p. groenendijk recovery room -high care, vu university medical center, amsterdam, netherlands introduction. the vu university medical centre (vumc) has chosen to integrate competence management (cm) within the human resource structure. functioning as an health care professional is not only about performing medical or nursing interventions. cm explicates not only knowledge and skills, but also attitude. cm contributes in developing abilities to cope with complex medical and nursing situations. cm is about managing professional behavior for reaching personal and organizational objectives. cm also contributes to an organization wide understanding of achieving the mission statement objectives. after introducing cm to the high care (hc) nursing staff, the set of (chosen) competences was integrated within the unit's mission statement (september ) . during team sessions competences were described to fit into the daily organizational and professional practice (october ) . personalizing cm is performed during an (competence based) assessment (december ) . strengths and weaknesses are determined. personal objectives are integrated within a defined educational and development structure guided by the clinical supervisor educator. although cm is relatively new in our organization and the return on investment is hard to determine, some results are clear. with cm observable behaviors were defined and thereby manageable, next to the set of nursing skills definitions (already defined as part of the primary training course and daily practice). increased employee responsibilities led to % more (non mandatory) training course attendance. during the hc nurse attended full training course hours. in the training course attendance increased to full hours for each hc nurse. with cm the relation between organizational and individual performance objectives is more clear. a prismant survey proclaimed decreasing sickness absence when cm is implemented. this result was confirmed on our ward. sickness absence decreased from > % to < %. because most of the personal development targets were easy to combine, the educational/training course budget was not exceeded. cm provides more different development levels, thereby individual talents are easier to discriminate. the employee satisfaction with cm is growing. conclusion. cm was successfully implemented on our hc unit within a month period. starting with a manageable package of competences the rollout strategy was easy to cope with for the hc supervisor and nursing staff. there are a few conditions the organization has to facilitate. cm must be integrated in the organization mission statement and adopted by hospital management. nursing supervising staff, including the clinical supervisor educator, must be capable to apply and practice cm. span of control and educational/training budgets must be fitted for applying cm. cm is a well manageable and applicable tool to increase and improve nursing outcomes. [ ] have shown immune modulatory effects. the alpha agonist dexmedetomidine produces sedation more analogous to nrem sleep compared to traditional agents [ ] . obstructive sleep apnoea and depression are known to alter both sleep architecture and immune function. we postulated that immune modulation could be produced by pharmacologically altered sleep pathways. methods. pvg hooded lister rats (harlan)were randomly allocated to midazolam, dexmedetomidine or sham infusions. all animals were instrumented with implanted telemetry week, and jugular lines day prior to the infusions. infusion rates were targeted to maintain deep sedation, mg/kg/hr for midazolam and . - mcg/kg/min for dexmedetomidine. infusions were commenced at am, and continued for hrs during the sleep phase, and recommenced hours later for a further hrs. animals were then given mg/kg ultrapure e.coli lps at am the following day. blood was taken every mins for facs and cytokine analysis. at mins post lps animals were sacrificed and their brains and lungs harvested. lungs were macerated and the samples were stained for ox and cd b and analysed by facs. there was no statistical significance difference between the groups at any time points for serum tnf,il- ,il- , crp, total blood pmn and monocytes, platelet-leukocyte aggregates. there was a non-significant trend to lower monocyte/neutrophil margination into the lung bed in the dexmedetomidine group. conclusion. in this underpowered study pharmacological manipulation of sleep does not produce immunoparesis in a rat model of icu sedation and sub-lethal endotoxaemia. from these data animals in each group would be required to detect a true difference. gut microbiota is a stable community with high biodiversity index and plays a key role in maintenance of health status. several factors of gut ecology alteration occur during the critical patients(pts) care:luminal hypoxia/hypercarbia, gastric-secretions inhibitors, vasoactive, sedation, nutrient/fiber scarcity, antibiotics, sepsis/injury, digestive surgery. ecological balance disruption of gut microbial community often results in reduced protection against pathogens,including opportunistic ones. we studied faecal microbiota changes in critical pts during icu stay. consecutive pts expected to need mechanical ventilation (mv) for> days were enrolled. exclusion criteria: hospital stay and/or antibiotic treatment before icu admission, opportunistic/autoimmune diseases, cancer/steroid therapy. faeces were collected at icu admission(t ) then weekly(t ,t ,t ). pts were excluded if t or t samples could not be harvested. total bacterial dna pattern analysis was performed by denaturing gradient gel electrophoresis (dgge). the % of similarity between the t -dgge profile and the following ones in each pt was used as index of microbiota modification. a similarity value > median at t versus t was defined as index of microbiota biodiversity preservation. new dominant dna bands were analyzed to identify bacteria species. . pts ( peritonitis, lung infections, cellulitis, meningitis, trauma) were enrolled. pts ( alive) were discharged before t , pts ( alive) before t , and pts ( alive methods. rfviia was used in adult patients aged between - (mean ± ) years average bmi . ± . underwent massive perioperative haemorrhage. all patients were admitted to icu with the diagnosis of sepsis or severe sepsis. all septic patients has been received da therapy within - hrs of icu admission. the following diseases were diagnosed: post abdominal surgery bleeding (severe sepsis after surgery: laparoscopic cholecystecomy, laparotomy due to peritonitis) - pts, gastrointestinal bleeding (severe sepsis in acute pancreatitis ) - pts, postpartum bleeding (septic shock in the course pyelonephritis and right hydronephrosis) - pts, intracranial bleeding (septic shock in pregnancy) - pts. we used the questioners of novo nordisk to asses the indications and effectiveness of treatment. we compared haemoglobin level, haematocrit, number of platelets and laboratory coagulation profile parameters before treatment, hours and hours after treatment. the dosage of rfviia was . ± . µg/kg. continuous iv mg infusion is effective for spasticity due to tetanus. compared to previous reports, our case series contributes meaningful additional data, as mg therapy was applied effectively for up to days without major toxicity, and all pts had good outcome. iv mg therapy has been proposed as first-line treatment for tetanus ( ), but the optimal dose and maximum duration of therapy are unknown. we believe that iv mg is a promising treatment option but, until more data are available, it should be reserved for carefully selected tetanus cases. observational, prospective, multicenter study in which patients admitted to the icu during the periods of the envin study for the years and were included. the following rates as markers of quality were defined: ) rate of amc use, ) rate of directed treatments, ) overall rate of changes in the amc used for therapy, ) rate of amc change due to inappropriate treatment, ) rate of amc change due to adjustment of treatment or deescalating therapy, ) rates of use of selective digestive decontamination (sdd), and ) duration of prophylaxis of cefazolin, amoxicillin-clavulanate, and cefuroxime. data of all variables in and are compared. high rate of use of antimicrobials in the icu. twenty-five percent of antimicrobial agents were used as directed therapies and in % of cases, antimicrobials were changed. changes for inappropriate treatment decreased, whereas changes for adjustment of treatment increased. there was an increase in the use of sdd. duration of prophylaxis with antimicrobials was is longer than the length of days prescribed. [ , ] . our goal was to evaluate this marker in critically ill patients with severe sepsis and sirs. methods. patients with severe sepsis and patients after coronary artery bypass grafting (cabg) have been included in this pilot study. plasma samples have been collected daily in the sepsis group or on day after surgery in the cabg-group. bg was measured with the turbidometric assay (wako pure chemical ind.) with a cut-off of pg/ml. results. bg levels were elevated after uncomplicated cabg and differed to the sepsis group. median concentrations were in the normal range in sepsis patients but fraction of elevated beta-glucan levels tend to increase with length of stay and were higher in nonsurvivors. this first observational study demonstrated consistent results of higher bg levels in different populations of critically ill patients. while bacterial translocation has been suspected as reason for sirs after cabg, this has never been associated with fungemia. this finding and higher bg levels in nonsurvivors with sepsis warrants further research. reference(s a prospective, observational and multicenter study in which an analysis was made of antimicrobials used in patients admitted to the spanish icu during the time periods of the envin study. the present report includes data for the years to . reasons for the use of antimicrobials included community-acquired infection, extra-icu nosocomial infection, and as a prophylactic measure. empirical or directed treatments were also differentiated. the antimicrobial drugs most frequently used for each indication as well as the mode of therapy are described. rate of antimicrobial use is expressed as percentage of patients in which one or more drugs were administered. descriptive statistics are presented. of a total of , patients admitted to the icu during the study period, , ( %) received , antimicrobials. changes in the number of antimicrobials and rates of antibiotic use are shown in table . table shows the distribution of antimicrobials according to reasons of prescription and modes of use antimicrobial agents most frequently used in the -year study period were amoxicillin-clavulanic acid, piperacillin-tazobactam, cefazolin, and vancomycin. data of the drugs most frequently used in each category are available. candidemia is a major cause of morbidity and mortality in modern icus. candidemia rates and patterns in icu appear to be changing over time. non-albicans spp, especially c. tropicalis and c. glabrata may be associated with higher mortality ( ). we describe the epidemiology and outcome of candidemia caused by candida albicans and non-albicans spp. from to , consecutive cases of candidemia in a general medical-surgical icu were identified from the computerized microbiology database. apache ii scores, demographic and clinical data were abstracted from clinical records. antibiotic usage was retrieved from the pharmacy database. . cases of candedemia were identified, giving an incidence of ( %ci - ) per patient-days. candidemia rates (per patient days) increased, with non-albicans making up a greater proportion over time ( fig. ). antibiotic use did not change significantly over time. non-albicans species made up % of isolates -c. tropicalis ( . %), c. glabrata ( . %), c. parapsilosis ( %), c. krusei ( . %), c. guillermondi ( . %). risk factors more commonly present in non-albicans species were: haematological neoplasm (p= . ) and neutropenia (p= . ). c. albicans was associated with diabetes (p= . ) and male sex (p= . ). baseline apache ii scores for non-albicans vs c. albicans (median, iqr , ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) were similar, however patients with non-albicans had a higher icu mortality ( % vs %, p= . ), and a trend towards higher hospital mortality ( % vs %, p= . ). despite stable antibiotic usage, candidemia rates are progressively increasing over time, with non-albicans making up a higher proportion of cases. mortality rates were higher than generally reported, but may be partly related to the high baseline illness severity. the comparatively higher mortality of non-albicans candidemia may be related to the high incidence of c. tropicalis and c. glabrata, which made up > % of non-albicans spp. risk factors associated non-albicans were identified and could help guide early empiric therapy in this group. previous studies have investigated the role of diabetes mellitus(dm) as risk factor for infections. tight glycemic control has recently been proved to reduce morbidity in icu patients. the aim of our study was to assess the association of prior dm history with bsi in icu patients. we prospectively studied medical patients admitted to a -bed general icu, during a -month period. history of dm, age and apache ii at admission were recorded. all patients were under tight glycemic control and were followed up for the development of bsi during icu stay. cox proportional hazards regression models were fitted for each consecutive bsi episode. statistical significance was set at p< . . although myocardial systolic dysfunction is common in sepsis/sirs, its time course over longer periods in severely ill patients is not well investigated. the aim of this project is to investigate the time course of left ventricular (lv) systolic function over a period of days in patients with severe sepsis/sirs using transthoracic echocardiography (tte), and to evaluate the adequacy of different tte methods. methods. patients with severe sepsis/sirs with circulatory failure despite adequate fluid resuscitation were included. tte examinations were performed daily for a total of days. lv systolic function was assessed by eyeballing ejection fraction (eb), simpson's biplane method in the chamber view, atrioventricular plane displacement (avpd) with m-mode in the septal, lateral, anterior and inferior view, tissue velocity imaging (tvi) in the mitral annulus and stroke volume in the left ventricular outflow tract (sv-lvot). data were analysed for differences over time using anova. systolic function was impaired and there were statistically significant changes with time in the measured parameters except tvi. table . avpd, eb, tvi, sv-lvot and simpson's were obtained in %, %, %, % and % respectively of all possible measurements. conclusion. lv systolic function was impaired in this heterogeneous group of patients as expected . all parameters improved significantly throughout the observation period reaching normal values by day . simpson's biplane method was difficult to perform due to poor imaging quality. the eb method was inconclusive in several patients due to hyperdynamic status. the fact that tvi was not significantly improved was unexpected and may be due to small sample size, wall filter settings and variations in sampling volume. the avpd method was easy to obtain and seemed the most consistent marker of systolic function in this group of patients. the small sample size of this study precludes subgroup analysis however it would be relevant to study differences, eg. between survivors and non-survivors. in view of the adverse consequence of af "chronic or paroxysmal" comprising hemodynamic deterioration, risk of thromboembolic complications, and the intolerable fast palpitation, etc., cardioverting af to sinus rhythm seems an ideal goal. there had been some controversy concerning the effects of af on atrial and ventricular dimensions as well as functions. the present work addresses the latter issue through trial of cardioverting patients( females and males) with a mean age of . years (range from to years). underlying cardiac examination revealed rheumatic heart disease in pts, hypertension in , ischemic heart disease in , and lone af in pts. only one pt had cardiomyopathy and one pt had thyrotoxicosis. prior to cardioversion, all pts were subjected to clinical evaluation, and transthoracic echocardiography (tte). transesophageal echocardiography (tee) was done only in cases with heparin or warfarin anticoagulation for at least days. standard m-mode, cross sectional and pulsed doppler echocardiography were obtained using hewlett-packard sonos echocardiograph. echo parameters measured before cardioversion comprised left ventricular end diastolic diameter (lvedd), left ventricular end systolic diameter (lvesd), fractional shortening (fs), and left atrial dimensions (length, diameter and volume by planimetry). left atrial function after cardioversion was expressed as atrial ejection force (aef) and doppler a-wave, with aef defined as the force that the atrium exerts to propel blood into the lv and expressed as aef= . *mitral orifice area*(peak a velocity) . effective mechanical atrial function (emaf) was defined as a-wave more . m/s. the presences of la thrombus or spontaneous echo contrast (sec) were studied by tte or tee. measures were recorded weeks after cardioversion to avoid la stunning. a questionnaire was sent to the lead clinicians of itus in germany inviting them to describe their current practice for the management of new-onset af. the questionnaire sought to establish the type of hospital and unit in which the intensivist practiced, whether there was a protocol in place for the management of af, satisfaction with current management strategies, and opinions about the immediate goals of treatment. in addition, colleagues were asked to identify and rank their choice of medical treatment. there were responses, with describing their units as mixed medical-surgical, as medical, surgical and cardiothoracic. thirty were teaching hospitals, district hospitals, and the remainder specialist or unstated. sixty-seven had no protocol for treatment of af in itu patients, but only expressed dissatisfaction with their current approach. those who did use a guideline cited the european society of cardiology guideline most commonly. for reversion to sinus rhythm was the goal of treatment, whilst for ventricular rate control was satisfactory. for hemodynamically unstable af in the itu, considered electrical cardioversion to sinus rhythm to be optimal treatment, would use medication with the aim of reversion to sinus rhythm, and for ventricular rate control with medication was sufficient. when medication was thought appropriate, the ranked choice of drugs is given in the table (findings for uk practice are given in parentheses, and percentages are used for easier comparison). conclusion. the lack of a uniform approach to the management of new-onset atrial fibrillation in the itu is common to both uk and germany. however, both consider amiodarone to be the first choice drug, while β-blockers and calcium channel blockers feature more prominently in germany. the use of magnesium appears to be far more emphasised in the uk. we suggest a pan-european consensus to manage this prevalent problem. atrial fibrillation is a common problem in the intensive care population, with a reported incidence between % and %. it is associated with an increased mortality, but there is some question whether this represents a true mortality increase, or whether it occurs in a group with a higher risk of dying. few studies have defined the extent of the problem in the mixed medical-surgical intensive care population. all patients admitted to our intensive care unit for more than hours were enrolled into the study over a six month period, with the exclusion of children and those who had an existent or treated tachyarrhythmia. they were then followed up prospectively for days, with various parameters recorded, including the development of atrial fibrillation, the presence of sepsis, apache ii score, treatments and interventions, and outcome at days. the population studied were divided into those who developed new-onset atrial fibrillation (new-onset af) and those that did not (no af). data from the two groups were then compared to determine any significant associations. two hundred and twenty-eight patients were admitted over a six month period, with one hundred and twenty-two meeting the inclusion criteria (excluded were for duration of stay less than hours; who already had af or a pacemaker; and who were children). twenty-eight patients developed new-onset af ( %). of the patients who had sepsis, ( %) developed af, as opposed to out of ( %) in the non-septic group. the af group tended to be older (mean age vs ) and more ill (mean apache vs ), with a higher mortality rate ( % vs %). when the mortality rate was standardised (observed/predicted mortality), the af group still appeared to have a worse outcome (smr . vs . ). this result is in contrast with a recent finding that showed smr to be similar in the two groups . our study found no association with low serum potassium or magnesium levels. findings are summarised in the table. conclusion. the rate of new-onset af in our mixed medical-surgical intensive care unit is %. there is a strong association with sepsis, with over one third of septic patients developing af ( %). our findings of older age and greater degree of illness being independent risk factors for af concur with other studies, but we have also shown an increased standardised mortality rate associated with af, suggesting that the arrhythmia confers a higher risk of death. after myocardial infarction, venous lactate levels as determined in the central laboratory are known to be increased. the relationship between systemic lactate levels and hemodynamic parameters at presentation is largely unknown. we hypothesized that arterial lactate immediately measured in the catheterization laboratory provides optimal information to study this relation. we determined arterial lactate with a point-of-care analyzer (poc) in patients with st-elevation myocardial infarction (stemi) prior to primary percutaneous intervention (pci), and investigated if lactate was related with blood flow in the involved coronary vessel. we prospectively measured arterial lactate levels (reference values , - , mmol/l) in patients with stemi directly before treatment with primary pci. patients on mechanical ventilation were excluded. all blood samples were analyzed within minutes from sampling. thrombolysis in myocardial infarction (timi-)flow in the infarct-related vessel at first angiogram was recorded for all cases and dichotomized as timi - (inadequate) and - (adequate). additional data was taken from the medical chart. lactate levels were analyzed after lognormal transformation. . with multivariate analysis, shock, body mass index, tachycardia, smoking and especially timi-flow were independently related with lactate levels. the relation of timi-flow with lactate was more pronounced than the relation of timi-flow with heart rate and blood pressure. in patients with myocardial infarction, systemic arterial lactate measured before revascularisation with a poc-device allowed detection of a strong relation between poor timi-flow and elevated arterial lactate levels. there are few echocardiographic investigations of myocardial dysfunction in sirs and sepsis. the aim of this project was to investigate left ventricular diastolic function over a period of days in patients with sirs/sepsis and circulatory shock using transthoracic echocardiography (tte). methods. patients with severe sepsis/sirs were included. tte examinations were performed daily for days. diastolic function was assessed by transmitral pulsed doppler with e/a ratio, deceleration time(dt), and tissue velocity imaging (tvi) in the mitral annulus. patients were subdivided into < and > years of age. changes in these parameters over time were analyzed using anova. median values for dt, e/a, e/É andÉ for all patients were calculated. there were no differences with time for all parameters exceptÉ (table ). in patients < y.o., subnormal values for e/É andÉ were seen ( table ) . reliable continuous hemodynamic monitoring of critically ill patients is essential for effective volume management and adequate administration of vasoactive drugs. the picco-system (pulsion, germany) allows continuous measurement of cardiac index (ci) using arterial pulse contour analysis. calibration of this system by transpulmonary thermodilution is recommended every hours. in this study we examined the reliability of the continuous measurement of the cardiac index using the arterial pulse contour analysis (cipc) compared to the cardiac index acquired by the transpulmonary thermodilution (citd) when calibrating the system. our study includes measurements in critically ill patients ( male, female, age - years, mean . ± . ) requiring hemodynamic monitoring with the picco-system. patients had an infection, hepatorenal syndrome, gastrointestinal bleeding, acute pancreatitis and were admitted to the icu for other reasons. first the cipc was recorded immediately before the next calibration and afterwards the citd was measured times what resulted in a simultaneous calibration of the pulse contour algorithm of the picco-system. we performed a mean of . ± . measurements per patient ( - ). the time-lag between the measurements was h min ± h min ( min- h min). the comparison of cipc immediately before calibration and the calibration-derived citd resulted in a correlation coefficient of . with a p-value of < . . in mean the aberration between cipc and citd was . ± . l/min*m . in the bland-altman-analysis the cipc was in mean . l/min/m lower than the mean of citd and cipc. the standard deviation was . l/min/m . there was no correlation of the time-lag between the calibrations and the difference of cipc and citd (r= . ; p= . ). there was an increase of the aberration of cipc and citd in low and high cipc values. reliable cipc values with an aberration from citd less than . l/min*m can be obtained with a cipc in-between and l/min*m . ) the picco-system allows a reliable continuous measurement of the ci using the pulse contour analysis. ) in our study we could not find an increased difference of cipc and citd even with longer time periods in-between the calibrations using transpulmonary thermodilution. ) reliable ci values using the pulse contour analysis can be obtained in-between and l/min*m . ) because calibration is easy to achieve and additional data for the intrathoracic blood volume and the extravascular lung water are obtained a - hours period in-between the calibrations is reasonable. n. zoremba* , g. schälte , j. bickenbach , b. krauss , r. rossaint , r. kuhlen intensive care medicine, anaesthesiology, university hospital rwth aachen, aachen, intensive care medicine, helios klinikum, berlin-buch, germany cardiac function monitoring in patients at risk for cardiac failure is a very useful tool to recognize and treat cardiac dysfunctions. the objective of this study was to compare a new method of non-invasive determination of cardiac output (ev-co) based on electrical velocimetry with invasive cardiac output measurements performed with a pulmonary artery catheter (pa-co). methods. twenty-five patients ( male, female) were included into the study during a three month period. the non-invasive measurements of cardiac output (co) were obtained with a new cardiovascular monitor (aesculon eletrical velocimetry, osypka medical gmbh, berlin, germany). simultaneous invasive measurements of co were made by injection of iced . % saline and the recording of thermodilution curves with a pulmonary artery catheter (baxter swan-ganz catheter, . french, edwards life sciences, irvine, usa). the analysis of the data was performed based on statistical methods recommended by bland and altman for evaluation studies( ). in all patients invasive and non-invasive co values could be obtained. the analysis of co showed a strong linear correlation (r= . ) between ev-co and pa-co (fig. a) . the mean difference between ev-co and pa-co was - . ± . litre*min − (mean±sd). the lower and upper limits of agreement for the comparison of ev-co with pa-co were - . litre*min- and . litre*min − and are defined as the mean difference± sd (fig. b) . the percentage error between ev-co and pa-co was . %. in this present study we found a good correlation between the haemodynamic values measured by electrical velocimetry and those obtained from pulmonary artery catheter measurements. therefore, electrical velocimetry, a new icg algorithm, is a suitable method to evaluate haemodynamic parameters with clinically acceptable accuracy. reference(s). ) bland jm, altman dg: statistical methods for assessing agreement between two methods of clinical measurement. the pulmonary artery catheter (pac) is still used to assess the hemodynamic status in cardiac patients, because it allows the measurement of pulmonary artery occluded pressure (paop), an indirect marker of left ventricular function. we studied the relationship between the cardiac function variables derived from pac and those provided by the transpulmonary thermodilution technique (picco) in patients with acute heart failure (hf) and severe sepsis or septic shock. twenty-one patients with circulatory failure requiring invasive hemodynamic monitoring were included. icu diagnosis was hf in and severe sepsis or septic shock in patients. all patients were monitored with a pac (edwards lifesciences, usa) and a picco catheter (pulsion medical system, germany). the following parameters were simultaneously assessed during the first day in each patient: cardiac index by either method (ci-pac, ci-picco), paop, cardiac function index (cfi), global ejection fraction (gef), and global end-diastolic volume index (gedvi). pearson correlation, bland-altman analysis and nonparametric mann-whitney u test were performed, as appropriate. results are given as median (interquartile range, iqr). a total of simultaneous measurements were performed during the first hours after icu admission ( measurements in each patient). the overall correlation showed a pearson correlation coefficient between ci-picco and ci-pac of . (p< . ). bland-altman analysis showed a mean bias of . l/min/m and limits of agreement (± two standard deviations) - . to + . l/min/m . using the pac the median (iqr) ci in hf and septic patients was . ( . - . ) and . ( . - . ) l/min/m (p< . ), respectively. the paop was ( - ) in hf and ( - ) mmhg in septic patients (p= . ). the gedvi in hf and septic patients was ( - ) and ( - ) ml/m (p= . ), respectively. in hf patients the cfi was . ( . - . ) and in those with sepsis . ( . - . ) min- (p< . ), and the gef was ( - ) versus ( - ) % (p< . ), respectively. in critically ill medical patients, assessment of cardiac function using transpulmonary thermodilution technique is a valuable alternative to the more invasive pulmonary artery catheter. cardiac output and cardiac function index better discriminate between patients with and without impaired cardiac function than pulmonary artery occluded pressure. endotoxin (lipopolysaccharide, lps) tolerance is characterized by a reduced sensitivity to subsequent challenge of lps. in animal models lps tolerance is closely associated with marked, unbalanced production of pro-and anti-inflammatory cytokines as several animal studies have shown a decrease in proinflammatory cytokines and an increase in il- (anti-inflammatory cytokine). the presence and mechanism of lps tolerance in humans is unclear. the aim of this study was to test whether -day administration of endotoxin leads to lps tolerance by an enhanced anti-inflammatory response and a suppressed proinflammatory response. methods. healthy volunteers received iv bolus injections of ng/kg escherichia coli lps on consecutive days. blood samples (tnfα, il- , il- β, ifnγ and il- ) were drawn before (t= ) and after (t= , , min, , , and hrs) administration of lps on day and and on t= hrs on day till . symptom scores were obtained including nausea, vomiting, headache, muscleache, backache and shivering. the volunteers were asked to score above mentioned complaints ranging from 'nihil' (score ) up to 'severe'(score ) every half hour after administration of lps on five consecutive days. both tnfα (proinflammatory cytokine) and il- (anti-inflammatory cytokine) showed a peak level the first day which was almost completely abolished on the fifth day (anova repeated measures between day and : p< . , figure ). all volunteers experienced the expected and transient influenza-like symptoms on the first day, at t= . hrs after the administration of±maximum clinical symptom score . . (p±lps. the symptom score on day was . < . )(figure ). conclusion. endotoxin tolerance developed after consecutive days of lps administration as demonstrated by the attenuated release of proinflammatory cytokines on the fifth day. in contrast to animal studies, the attenuated cytokine response was not limited to the proinflammatory response, but also the anti-inflammatory response was diminished. this human endotoxin tolerance model appears to be useful in exploring the possible beneficial effects of endotoxin tolerance, for example, in ischemia-reperfusion damage. t. eduardo* , f. alvarez , j. gomez-hererras , s. florez , s. soria , c. lajo anaesthesiology and reanimation, university hospital, pharmacology and therapeutics, faculty of medicine, university of valladolid, valladolid, spain systemic inflammatory response occurs frequently after coronary artery bypass surgery, and it is strongly correlated with the risk of postoperative morbidity and mortality. we have analysed the effects of gelatin priming versus ringer's lactate priming on cytokine release and during the inflammatory state following coronary artery bypass surgery with cardiopulmonary bypass. a prospective, randomized study was designed. forty four patients undergoing elective coronary artery bypass grafting were allocated randomly to one of two groups: patients with ringer's lactate prime and patients with gelatine containing prime during coronary artery bypass surgery. the study protocol was approved by the ethics committee of the 'clinico' hospital of valladolid. written informed consent was obtained from each patient. plasma levels of interleukin il- , il- , tnf-alpha, c-reactive protein (crp), complement (c ), and sris score were measured along the surgery and within the first postoperative hours at various time points. cytokine levels were measured by enzyme-linked immunosorbent assay from plasma sample obtained. the spss program (version ) was used for the statistical analysis of the data. differences from baseline and between the groups were evaluated by two-way analysis of variance for repeated measurements (anova, followed by scheffe's test). correlation analysis between variables was calculated using pearson's correlation coefficient. a probability value of p < . was considered significant. there were no significant differences between the groups regarding pre-operative data. patients were similar with regard to type of procedure, bypass time, aortic cross-clamp time and number of grafts. in both groups the serum levels of the proinflamatory cytokines (il- , il- , tnf-alpha), sris score, c , crp, and leukocytes increased significantly over baseline, with no difference between either the colloid or crystalloid group. the operation time, blood loss, need for inotropic support, extubation time, and length of intensive care unit stay did not differ significantly between the two groups. priming with gelatin versus ringer's lactate produces no significant differences in the inflammatory response in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. a prerequisite to evaluate resuscitation from hemorrhagic shock is a reproducible experimental model, which leads to a predictable outcome. in order to evaluate the best predictor of death, blood lactate was compared to mean arterial pressure in hypotensive animals submitted to severe controlled hemorrhage. forty immature pigs were anesthetized with ketamine, atropine and halothane, intubated and maintained breathing spontaneously with atmospheric air and halothane. pulmonary, femoral and jugular vein catheters, were inserted in order to measure cardiac output, mean arterial pressure (map), blood gases and blood lactate. group i (n= ) was hemorrhaged to a map of mmhg breathing room air with halothane . %. group ii (n= ) remained as control of group i, breathing room air with halothane . % and no bleeding. group iii (n= ) was hemorrhaged to a map of mmhg breathing room air with . % halothane. finally, group iv (n= ) remained as control of group iii breathing room air with halothane . % and no bleeding. variables were recorded every ten minutes with no further intervention for minutes, when anesthesia was discontinued in the surviving animals. death of the animals was registered up to twenty four hours after the experiment. all animals in group i died. all animals in group iii survived, despite the fact that both groups had equal degree of hypotension (map = mmhg). however, only group i exhibited high levels of blood lactate. receiver operating characteristic (roc) curve analysis with death of the animals as the variable of interest, demonstrated that only blood lactate exhibited % sensitivity, % specificity and a roc curve area of . . mean arterial pressure was less accurate in predicting the death of the animals. tissue oxygen tension (tpo ) represents the balance between local supply and demand and may be a useful monitoring modality. we previously reported that lipopolysaccharide infusion produced different responses in four organ beds studied ( ). in the present study we sought to compare peripheral tpo measurements (bladder, muscle) against those measured in more vital organs (liver, renal cortex) during acute hypoxaemia. under isoflurane anaesthesia, male wistar rats (approx g weight) underwent left common carotid and right jugular venous cannulation for blood sampling/bp monitoring and fluid administration, respectively. flow in the descending aorta (abf) and left renal artery (rbf) were monitored by ultrasonic flow probes (transonic systems, usa). arterial po was measured using a blood gas analyser (radiometer, copenhagen, denmark). tissue po was determined using oxylite probes (oxford optronix, uk) placed in thigh muscle, between the right and left lobes of the liver, in the left renal cortex and within the bladder lumen. after a -min stabilisation period, fluid-resuscitated rats ( ml/kg/h, n-saline) were subjected to progressive increases in hypoxaemia ( , . and % inspired oxygen). comparisons were made to time-matched controls breathing room air. statistics were performed using two-way rm-anova and post-hoc tukey's test. results. data shown as mean (± se), *p< . between control (c; n= ) & hypoxaemia (h; n= ); $ p< . between timepoint & baseline. ( ) ( ) conclusion. patients with erd have higher severity and more frequently immunodepression and medical pathology. they needed more invasive procedures and antibiotic therapy so infection rates and resistance patterns are superior to the rest of icu patients. conclusion. an improvement of the methods of regulation and of the monitoring of treatments are essential if we take into account the increasing bacterial resistance. if glycopeptides are still the initial standard treatment of serious infections, new therapeutic strategies should be emerging, depending on the confirmation of presented innovations. prospective observational cohort study, performed in a -bed icu. all copd patients with ae who required intubation and mechanical ventilation were eligible. at icu admission, information on endotracheal aspirate purulence, and hyperthermia was collected. in all patients, gram stain and quantitative endotracheal aspirate culture (positive at cfu/ml) were performed. in addition, leucocytes count, c-reactive protein (crp), and procalcitonin (pct) levels were measured. univariate and multivariate analyses were used to determine variables associated with bacterial severe aecopd. positive predictive value and negative predictive value were calculated for variables independently associated with bacterial severe aecopd. . severe aecopd were diagnosed in patients. bacteria were isolated at significant threshold in exacerbations. s. pneumoniae ( %), methicillin-sensitive s. aureus ( %), and h. influenzae ( %) were the most frequently isolated bacteria. age ( ± vs ± ), male gender ( % vs %), saps ii ( ± vs ± ), duration of mechanical ventilation ( ± vs ± d), and mortality ( % vs %) were similar in patients with bacterial severe aecopd and those with nonbacterial severe aecopd. rate of patients who received prior antibiotic treatment was significantly lower in patients with bacterial severe aecopd than in patients with nonbacterial severe aecopd ( % vs %, p = . ). no significant difference was found in rates of patients with hyperthermia ( % vs %), purulent endotracheal aspirate ( % vs %), and leucocytosis ( % vs %) between the two groups. although leucocytes, crp and pct levels were similar in the two groups, rates of patients with pct > . ng/ml ( % vs %, p = . ), and patients with positive gram stain of endotracheal aspirate ( % vs %, p< . ) were higher in patients with bacterial severe aecopd than in patients with nonbactrerial severe aecopd. pct > . ng/ml (or [ % ci] = . [ . - ], p = . ), and positive gram stain of endotracheal aspirate ( [ - ], p < . ) were independently associated with bacterial severe aecopd. conclusion. positive gram stain of endotracheal aspirate, and pct > . ng/ml are independently associated with bacterial severe aecopd. these results could be helpful for future interventional studies aiming at reducing antibiotic use in these patients. systemic inflammatory response (sir) in patients with infection clearly influences outcome. the aims were to study the sir in icu-acquired infection (i-icu) according to the source and etiology and evaluate outcome impact. multicentre prospective study from april to july in ucis of hospitals. the number of patients admitted to icu> h until icu discharge or a -day period. i-icu diagnosed according to the cdc's criteria, source, etiology and sir were analyzed. conclusion. % of the i-icu worsen in sepsis severe/septic shock. vap and bacteriemias had more severe sirs and uti less frequent. septic shock presented a high mortality (> %) without significant differences in infection sites. c albicans, a baumannii and p aeruginosa developed the worst sir. conclusion. this analysis confirms that a small percentage of long stay patients occupy a large proportion of icu patient-days. the mortality is higher in this group than the overall unit, but the survival rate of . % could justify the extra resources required to treat these patients. age does not appear to influence length of stay in this study. the patients who are most likely to have a prolonged length of stay are re-admissions, patients who are peri-transplant or have ventricular assist devices. editorial: safe use of cricoid pressure cricoid pressure: knowledge and performance amongst anaesthetic assistants assessment of the ml syringe as a simple training aid in the application of cricoid pressure reference(s). possum and portsmouth-possum for predicting mortality possum scoring for patients with fractured neck of femur this study would not have been possible without the contribution of all icu team and the following people: wagner fontes, marilia calipo ferreira and ivy dantas gangiredddy ch admission of older patients to intensive care units is a controversial issue. the outcome of elderly patients with critical illness in india has not been previously studied. retrospective chart review of males > years & female > years from may till november . data collected included age, gender, disease category, comorbidities, mechanical ventilation days, length of stay in icu and hospital, apache ii, sofa, premorbid functional state and mortality. in admissions to micu, were critically ill elderly [ ( . %) males, ( . %) females]. premorbid functional state assessment showed: independent ( . %), partially dependent ( . %) and wholly dependent ( . %). at admission, organ involvement was respiratory [ ( . %) ], renal [ ( . %)], neurology ( . %), metabolic ( . %) and cardiac ( . %). mean apache ii and sofa scores were . + . (median ). and . + . (median . ) respectively. mean length of stay (los) in icu was . days + . and . days + . in hospital. mean icu stay was . + . & in hospital was . + . in - year age group, vs . + . and . + . in the over group [ . ] . total mechanical ventilation days were (range - ). died ( %) of which [ / ( %) ] were in - yrs and / ( . %) in > yrs [ns] . decisions to limit life support were taken in / cases ( . %), dnr in ( %) and withholding in ( %). apache score > correlated with mortality ( deaths in score> ; death in score < (chi square test . ). there was no correlation between premorbid functional status and mortality. respiratory involvement was the predominant cause of admission. the hospital mortality for the elderly was only %. apache ii score correlated with mortality. the sample size was too small to detect any significant differences between age groups in terms of los and mv days. % of the deaths were preceded by eol decisions. introduction. the phenomenon of increased intra-abdominal pressure and the resultant physiologic compromise were first described in the late s. acs has been defined as the cardiovascular, pulmonary, renal, splanchic, abdominal wall and intracranial disturbances resulting from elevated iap. korn and associates first used the term acs in . malbrain et al found during one day point prevalence study in icus had . % of patients has acs. intra abdominal pressure (iap) was measured in consecutive patients (age range - ; males: females) who were admitted to the micu with diverse clinical problems. iap was routinely measured using the transurethral measurement of urinary bladder pressure using a foley's catheter. abdominal compartment syndrome (defined as > cm h o) was found in patients (age range - , males; females). of these patients had primary acs, had secondary and had recurrent acs. the mean apache ii score was and sofa score was . in the acs group; the apache ii score was . the sofa score was . the group without acs. ( p value not significant) out of , patient with acs had a surgical intervention to reduce iap (pd catheter in , decompressive celiotomy in ). the indications for intervention were unexplained respiratory deterioration seen as in increase in plateau pressure or fio , fall in urine output despite adequate map and fluid resuscitation and iap> cm of water. / in the intervention group died ( . %). patients in the raised iap group managed conservatively with fluid restriction and diuretics. the mortality in the patients without acs was . %. in addition, increased iap alone gave a clue to the need for surgical intervention in / patients; these would have otherwise been managed conservatively. our study suggests that routine iap measurement of patients in the icu is beneficial because of the presence of unsuspected acs in a significant proportion of patients ( %) irrespective of the primary disease. acs may cause renal, hemodynamic and respiratory compromise that can be improved by judicious and timely intervention. further, raised iap alone may sometimes give a clue to the need for a surgical intervention, which may beneficially affect the clinical course. a. lorx* , b. szabó , m. hercsuth , z. hantos anesthesiology and intensive therapy, semmelweis university, budapest, medical informatics and engineering, university of szeged, szeged, hungary introduction. the low-frequency respiratory impedance (zrs) has been shown to reflect the respective contributions of the airway and tissue mechanical properties accurately in healthy subjects. little information is available, however, on the values of airway and tissue parameters derived from low-frequency zrs data in ali patients before and after bronchodilator therapy. zrs was measured with small-amplitude forced oscillations between . and hz at three peep levels ( , and hpa) before and after nebulised berodual in mechanically ventilated patients including with severe pneumonia and with postoperative respiratory failure, without any previous pulmonary disease. airway resistance (raw) and inertance (iaw), and constant-phase tissue damping (g) and elastance (h) were estimated from zrs spectra by model fitting. raw decreased with peep, and on the administration of berodual in both groups. in the postoperative patients, g decreased with peep, and g and h decreased following berodual inhalation; this indicates that bronchodilation was accompanied by recruitment of previously closed regions of the lungs. there was no change in iaw and hysteresivity (g/h), suggesting that the peripheral airway inhomogeneity was not markedly affected by the intervention. the decreases in raw reflect the presence of reversibly elevated airway resistance in all patients. the decreasing g/h in the pneumonia patients after berodual indicates improved homogeneity in the mechanical properties of the peripheral lung with consequent improvement in ventilation, although the changes did not reach the level of statistical significance. berodual inhalation results in improved tissue properties of the respiratory system, i.e. decreases in elastance and tissue damping, which is associated with the bronchodilator effect. overall, the low-frequency oscillation technique proves to be an informative and accurate method for bedside monitoring of critically ill patients. dialysis disequilibrium syndrome -report of cases n. shaikh* , m. kettern , y. hanssens anesthesia and intensive care, pharmacy, hamad medical corporation, doha, qatar introduction. dialysis disequilibrium syndrome (dds) is a central nervous system disorder occurring in pts (pt), either during or within hours of dialysis. dds is unknown in pt who are on dialysis for some time and no case had been reported in ventilated pts. report of cases of fatal dds in ventilated pts with acute renal failure (arf) on haemodialysis (hd) for more than a week. case : a year old male pt victim of motor vehicle accident, spleenic and bowel injury. ct head normal, gcs / . he underwent spleenectomy, hartman's procedure and abdominal packing. post-op, he was in dic and haemorrhagic shock. he remained hypotensive, adrenaline and noradrenaline were started. pt was oliguric and developed arf on day , daily hd was started over hours, normal bath and heparin free. on day , pt was trying to obey commands. on day , pt developed sepsis and meropenem was started. on day , pt underwent hd, became unresponsive after hour and pupils fixed-dilated. ct brain showed severe oedema and herniation. eeg was flat and brain stem reflexes absent. diagnosed as brain dead on day and expired same evening. case : a year old male pt fell from height, on arrival gcs was / . he had severe chest trauma and liver laceration,underwent laprotomy, haemostasis and packing of abdominal cavity. on day , pt developed arf, started on slow hd ( - hours) , low sodium, potassium and heparin free. ct brain on day was normal. on day pt developed septic shock, started vancomycin and ciprofloxacin. pt required noradrenaline. on day , during hd (increased potassium, heparin free), pt developed hypotension, pupils became dilated and fixed. hd was stopped, mannitol was given and pt was hyperventilated. ct brain showed severe oedema and herniation of brain. brain stem functions were absent. eeg was flat and heart stopped after hours. tioxidant capacity, as well as the detection of oxidized biological markers. the direct, in vivo quantitative measurement of the production of superoxide radical, an important parameter of the oxidative load, is difficult due to its low concentration and a short half life ( ) . in this study, the effect of h/s and resuscitation on the oxidative state in vital organs (gut, liver, lungs, kidneys) was estimated for the first time by measurement of the production of superoxide radical in vivo, using a new superoxide assay.methods. male wistar rats were divided in two groups (n= ): sham and h/s group. h/s was induced by withdrawal of blood targeting to a mean arterial blood pressure of - mmhg, which was maintained for minutes. at the end of the shock period, rats were resuscitated with re-injection of the removed shed blood volume. tissue samples were collected hours after resuscitation and the oxidative load was assessed by a new superoxide assay which directly measures the production of superoxide radical and an established lipid peroxidation assay which measures the production of organic hydroperoxides. statistical analysis was performed using anova. animals that underwent h/s exhibited a statistically significant increase in the production of organic hydroperoxides in the gut (p< . ), liver (p< . ) and lung (p< . ) tissues, whereas no change was observed in the kidneys. the rate of production of superoxide radical increased more in the gut and the liver (p< . respectively) and to a lesser extent in the lungs (p < . ), while kidneys were not affected as well.conclusion. this study demonstrates an increase in oxidative load in the gut, the liver and the lungs after h/s-resuscitation, which was estimated by two different methods. moreover, and for the first time in a model of h/s, the new superoxide assay directly and more precisely estimates oxidative stress in vivo, since the formation of superoxide radical seems to play a pivotal role in the cataract of reactions that lead to the oxidation of biological structures. these results suggest that predominantly the gut and the liver, and to a lesser extent the lungs, but not the kidneys are the organs primarily affected by h/s in this model. reference(s). . biasi f, et al.: free radic. biol. med. ; : - . . georgiou cd, et al.: anal. biochem. ; : - . g. luckner* , s. jochberger , v. d. mayr , v. wenzel , h. ulmer, in this retrospective analysis, we examined if a low-dose avp infusion ( iu/h) can reverse isolated postoperative vasodilatory hypotension and prolonged vasopressor requirements (> hrs) in fifteen patients under chronic ace inhibitor treatment. hemodynamic and laboratory parameters were recorded , , hrs, and immediately before start of avp therapy, , , , and hrs after start of avp, as well as , , and hrs after cessation of avp infusion. the primary endpoint was to evaluate hemodynamic effects and changes in phenylephrine dosages during avp infusion. the secondary endpoint was to evaluate changes in laboratory parameters during avp. . avp infusion did not show any significant effects on hemodynamic variables. only mild, non-significant effects on map (+ . %, p= . ) and phenylephrine (- . %, p= . ) dosages were observed during the first hrs after avp infusion. there were no changes in laboratory parameters during avp infusion. a supplementary, low-dose avp infusion proved to be ineffective to improve hemodynamic function and reverse vasopressor dependency in patients with chronic ace inhibitor therapy and prolonged postoperative hypotension. results. drotaa was administered in patients [ ± years old, simplified acute physiology score (sapsii): ± ]. a community acquired infection was the causal infection in % of cases. patients had > organ failures before the drotaa onset (hemodynamic failure in patients,respiratory in ). all patients received hydrocortisone (started ± hours before the onset of drotaa) and patients received hemofiltration (started ± hours before the onset of drotaa). serious bleeding events occurred in patients. interestingly, the icu mortality was % while mortality predicted from saps ii was %. we observed a significant improvement in the pao /fio ratio and in the blood lactate level after the onset of drotaa (h ) ( table ). in patients treated with norepinephrine (n= ), we also observed a rapid decrease in the vasopressor dose after drotaa onset while the mean arterial pressure was maintained stable in the same period ( figure) . in this observational study, we evidenced significant improvement in the hemodynamic and respiratory failures and a decrease in blood lactate after the onset of drotaa administration. in the past few years new insights in the role of microcirculatory alterations during sepsis have been elucidated by means of orthogonal polarization spectral (ops) imaging. persistent alterations appeared to have prognostic value. several other techniques, such as near infra red spectroscopy, laser doppler and peripheral temperature have been used to asses peripheral circulation. however there is unclarity about relation between peripheral and microcirculation during sepsis. aim of this study was to evaluate the relation between peripheral and microcirculatory alterations during sepsis. we performed a single centre observational study in patients with < h severe sepsis/septic shock. ops imaging of the sublingual region and semi-quantitative analysis were performed as described in detail elsewhere . skin perfusion was measured as central-to-toe temperature difference (deltat). non-parametric rank correlation is expressed as spearman's rho(rs). , ( , - , ) , ( , - , ) , serratia marcescens (n= ) , ( , - , ) , ( , - , ) , acinetobacter baum (n= ) , ( , - , ) , ( , - , ) , klebsiella pneumoniae (n= ) , ( , - , ) , ( , - , ) , all pathogens (n= ) , ( , - , ) , ( , - , ) , msc -meropenem serum concentration, mic -minimum inhibitory concentration conclusion. we conclude that continuous infusion of meropenem in dose g per hours in critically ill patients provides reliable serum meropenem concentrations in relation to mics of meropenem sensitive pathogens. grant acknowledgement. this study is supported by the czech ministry of education (project msm ) s. boyes* , g. l. thomas speech and language therapy, salford primary care trust, intensive care unit, hope hospital, salford, united kingdom although several key documents recommend that slt should be integral to the multidisciplinary care of critically ill patients , , , these services are often not funded. without this input there is increased risk of nosocomial pneumonia, malnutrition and dehydration. antibiotic prescription and length of stay may increase with higher dependency and a slower transition through levels of care. communication difficulties may also impact on the patient experience. as per royal college of speech & language therapists guidelines our project explored unmet need and defined the potential role of slt at hope hospital, a regional neuroscience centre. slt provided daily input to critical care patients for a month period. prospective data were collected detailing referrals and slt management, and were compared with retrospective data from months prior to the project. stakeholder evaluation was carried out using pre and post project staff questionnaires, and by collecting anecdotal evidence from patients and staff.results. referrals to slt increased by % ( pre-project versus during the project). pre project, % referrals( ) were inappropriate and % ( ) transferred before asessment. % referrals ( ) during the project were appropriate and assessed. % of pre-project referrals were seen on the day of referral compared to % during the project. pre-project slt intervention focused on assessment and advice alone. the project promoted earlier identification of needs, early management of clinical risk and contributed to multidisciplinary care. major training and education needs were identified. stakeholder evaluation was overwhelmingly positive, demonstrating slt contribution to multidisciplinary care and the patient experience.conclusion. dedicated slt input in critical care increased referrals to slt. the number of inappropriate referrals and the time to slt assessment decreased. input promoted the identification of clinical risk, facilitating early intervention and rehabilitation. training needs and additional roles for slt (weaning, decannulation and risk management) were identified. stakeholder evaluation demonstrated improved patient experience. these findings form the basis of a business case to expand slt resources in critical care. whereas several studies established cefotaxime, or other rd generation cephalosporins, amoxicillin/clavulanic acid and oral quinolones as effective first-line antibiotic regimens in community-acquired cases, little is known about the spectrum of antimicrobial resistance, impact of an effective initial antibiotic regimen on survival and the spectrum of causative micro-organisms in hospital acquired cases. all cases of sbp diagnosed in a university hospital between january and august were retrospectively analysed. . cases ( m, f) were retrieved. mean (± sd) age was (± ) years. meld-score was . (± . ) at the time of the diagnostic tap. in patients the infection was community acquired, in patients hospital acquired. patients ( . %) died in the hospital. the initial antibiotic regimen was a third generation cephalosporin in , an ampicillin/sulbactam in and a quinolone in cases. cases (all hospital-acquired infections) were initially treated with a carbapenem and vancomycin had been added in cases. in patients the antibiotic regimen had to be changed during the course of treatment. survival was not worse in hospital-acquired cases than in community-acquired cases, but hospital-acquired cases were more often treated with broader antibiotic regimens at the onset of therapy. patients in whom the initial antibiotic treatment had to be modified had a higher mortality than patients in whom the initial treatment was continued ( % vs. %; p= . ). in patients with positive culture results, an effective first-line antibiotic regimen was associated with lower mortality ( % vs. %; p= . ). binary logistic regression analysis found meld-score at diagnosis (p= . , % confidence interval (ci) . - . ), ascitic fluid cell count (tsd) (p= . , % ci . - . ) and an escalation of antibiotic therapy (p= . , % ci . - . ) to be independently associated with mortality. the most commonly cultured micro-organism was e. coli (n= ), followed by enterococcus faecium (n= ). among culture positive cases the causative micro-organism was resistant to ceftriaxone in ( %), to ampicillin/sulbactam in ( %) and to ciprofloxacin in ( %).conclusion. the incidence of resistance to one of the recommended standard regimens is high in hospital-acquired and community-acquired cases of sbp. failure of the initial antibiotic regimen is associated with higher mortality. broader antibiotic regimens should be considered as initial approach. the multidrug-resistance (mdr) of gram (-) strains in the icu is a severely growing problem, so colistin has been recently reintroduced in clinical practice. colistin had fallen out of favour after due to nephrotoxicity, neurotoxicity and poor pharmacokinetics in lung tissue. the aim of this clinical trial is to study the efficacy and safety of colistin in mdr gram (-) nosocomial infections (ni) in the icu during the last months. we enrolled retrospectively icu patients (pts), men ( %) and women ( %), who developed a mdr gram (-) ni. mean age: . ± . years, mean stay: . ± . days. underlying diseases: multiple trauma , complicated surgery , other . the pts were treated ( courses) with intravenous (iv) colistin . . iu x daily (adjusted for creatinine clearance) in combination with carbapenems or b-lactamase inhibitors. in pts aerosolized colistin ( . iu x daily) was added to iv colistin. the ni treated were: pneumonia ( . %), central venous catheter-related infection ( %), peritonitis ( %), central nervous system infection (cnsi) ( . %). pts with cnsi additionally received colistin intrathecally. the responsible bacteria were: ac. baumannii ( . %), ps. aeruginosa ( . %) and kl. pneumoniae ( . %), with double pathogen in episodes of ni. clinical success (important lessening of the signs and symptoms of ni) occurred in ni ( . %); microbiological success (eradication of the pathogen in cultures of blood, peritoneal fluid, bronchial secretions or celebrospinal fluid) was obtained in ( . %). nephrotoxicity was observed in pts ( . %); it was reversible. mortality rates: / = . %.conclusion. ) colistin in combination with other antibiotics is an effective treatment of severe mdr gram (-) ni in the icu. ) the incidence of adverse events is low; a close surveillance of renal function is needed. ) when aerosolized colistin was included in treatment, microbiological success was accelerated (p< . ). ) pneumonia was the ni best corresponded to colistin than other sites of ni, but not statistically significantly (p< . ). ) prognosis was independent of type of invading gram (-) microorganism. introduction. the biggest concern in infection epidemiology in intensive care is the emergence of multidrug-resistant gram-negative (pseudomonas aeruginosa, klebsiella pneumoniae and acinetobacter baumannii) and gram-positive (staphylococcus aureus) organisms. two periods of six months were analyzed for each icu: in the first six months (from mar/ to aug/ ) no infectious disease advice was given in any; in the following six months (sep/ the fev/ ) infectious disease consultation was given in icu when requested, as opposed to icu , where it was continuously provided by an infectious disease consultant with degree in intensive care. the number of multi-resistant organisms grown was then compared. a t-test for two independent samples was used in statistics. the species distribution of the pathogens evaluated in icu is summarized in table . there was reduction in the occurrence of p.aeruginosa % ( - , %), a.baumannii % ( , - %) and s.aureus % ( , - , %), with significant p value for p.aeruginosa, the most common microorganism.* k.pneumoniae percentage of increase = , %. table summarizes the results in icu , where the decrease in growth of the multi-resistant stains was higher: % for p.aeruginosa ( , - , %), , %for k.pneumoniae ( , %- , %) and % for s.aureus ( , - %) also with significant p value for p.aeruginosa. introduction. intravascular catheter related infections are very critical in icu environment, with elevated morbi-mortality and impact on costs. in our unit, according to a quality political, it had established standards on prevention, diagnosis and treatment of nosocomial infections, with a periodic review of the ours rates. we will describe the managerial model chosen when we noticed an increase of the catheter related infections incidence: outcome management. in december it was created a multi-professional work group ( doctors, nurses and respiratory therapists) who performed a weekly meeting with the brainstorm technique. all the infections data were reviewed. the group identified main risk factors related to the problem using a diagram cause-effect. then, it had established corrective measures, deadlines and ways for execution. measures chosen: team for catheter insertion; using full-barrier precautions for insertion of central venous catheters; using of semipermeable and transparent dressings; avoiding the jugular and the femoral sites; routine replacement of the catheters after ten days insertion; removal of the unnecessary catheters. target was return of catheter related infection rate to level of the previous year. in the first three months after the intervention, we noticed a reduction of the median rate of catheter-related bloodstream infection per catheter-days: , infections to , . catheter-related bloodstream infection is the nosocomial infection par excellence: costly, common, and frequently fatal. efforts to improve patient safety must focus on simple and inexpensive interventions and prevention measures. the managerial tool showed us main causes of the problem and caused the adhesion of all staff around the catheter related infections and the correct measures to solve it. limited data suggest that vancomycin when given by intermittent injection may not be as affective as linezolid for the treatment of ventilator acquired pneumonia and this inferiority may be negated by administering vancomycin by continuous infusion ( ). administration in this fashion may improve the drug's tissue penetration and is easier to control but a double blind randomised controlled trial has not been carried out. the way in which vancomycin was administered in our icus was changed in may so that any patient with central venous access was given vancomycin by continuous infusion according to a strict protocol ( ) . data from our electronic prescribing system was correlated with icnarc data for mortality. we conducted a retrospective audit from december to october comparing icu outcome in patients who were treated with one agent only. patients who received both linezolid and vancomycin or were on a bd and infusion regiment were excluded. . patients were treated with vancomycin infusion, of whom . % died. this was not significantly different from the mortality for vancomycin when given by intermittent injection of . %. interestingly the mortality for those treated with linezolid in an unmatched group of patients was . % (p< . ). conclusion. contrary to previous audits, our data suggest that vancomycin is not inferior to linezolid for icu mortality. the mode by which vancomycin is administered does not affect mortality. the increased mortality found in patients treated with linezolid has yet to be explained. further analysis is required. there are recommendations for control and prevention of methicillin-resistant staphylococcus aureus (mrsa) ( ); surveillance reduction in antibiotics use, screening, nasal and skin decolonization, handwashing, isolation, decontamination of clinical areas, adequate staffing. these recommendations however, are frequently based on large series and case reports rather than randomised trials ( ) . of those recommendations, only two (handwashing and adequate staffing) are reliably carried out in our icu. even conventional 'deep cleaning' has been shown to be unreliable ( ). all patients admitted to itu at university hospital birmingham between june and may were retrospectively studied so that any microbiological sample that was positive for mrsa was correlated with the date of icu admission. conclusion. there has been a steady decline in the number of primary mrsa infection occurring in our icu whilst the number of cases admitted has remained constant. colonisation pressure from patients admitted to icu is independent of mrsa acquisition. the reasons for our decline in mrsa infection remain unclear as full recommendations to inhibit mrsa spread can not be implemented. in our tertiary surgical icu, antibiotic policy restricts prescription of meropenem to ) the empirical treatment of suspected bacterial severe sepsis in patients with risk factors for antimicrobial resistance or with documented colonisation with multiresistant gram negative (mrgn) organisms, or ) the directed treatment of infections caused by mrgn organisms. to evaluate compliance with these restrictions, the indications for meropenem use were reviewed, and the feasibility of a de-escalation strategy in case of empirical meropenem prescription was evaluated. we performed a retrospective study of all meropenem prescriptions in the surgical icu from / / to / / . patients who received more than one dose of meropenem were included in the analysis. age, apache ii, prior length of stay, duration of meropenem administration, antibiotic prescription other than meropenem, microbial etiology and site of infection were recorded. the presence of risk factors for antimicrobial resistance, i.e. either previous exposure to broad spectrum antibiotics or a hospital stay for longer than days prior to infection were documented. data are presented as mean (standard deviation). data from hundred and thirteen meropenem prescriptions were available for analysis. mean age of the patients was ( . ), and the mean apache ii score was ( . ). pulmonary ( %) and intraabdominal ( %) infections were the most frequent sites of infection. meropenem was prescribed according to the restricted indications in / patients ( %). in patients it was initiated empirically with both risk factors for antimicrobial resistance present, and in patients it was used because of documented colonisation with mrgn organisms prior to the current infection; in cases it was used after identification of a mrgn organism as the causative organism of the infection. in the other patients (n= ), meropenem was started empirically with no or only risk factor for resistance and without documented colonisation with mrgn organisms. empirical prescription of meropenem was de-escalated in patients ( %). reasons for not de-escalating were the identification of mrgn organisms or uncontrolled polymicrobial infections. compliance with the restricted indications for meropenem in our icu was high. empirical prescription of meropenem was de-escalated upon culture results in half of the cases. d. r. goldhill , a. badasconyi* , a. a. goldhill , c. waldmann anaesthetic department, the royal national orthopaedic hospital, stanmore, anaesthetic department, the whittington hospital, medical school, kings college london, london, anaesthetic department, the royal berkshire hospital, reading, united kingdom patient position in icu is important for preventing complications such as pneumonia [ ] . two hourly turning is a common standard of care [ ] . evidence suggests that patients may not be turned this frequently [ ] . we therefore conducted a prospective observational study of patient position and turning in icu and the factors that may affect the frequency of turns. forty eight of uk icus contacted agreed to participate in this study. the position of each icu patient was recorded every hour over two hour periods, one midweek and one weekend. the patient age, gender, estimated height and weight, diagnosis, whether intubated and ventilated, hourly sedation score, nurse:patient ratio and number of patients on the unit were also recorded. patients could be on their back, front, left or right side. a turn was defined as a change from one of these positions to another. the degree of rotation and whether patients were flat, head down or head up was also noted. analysis of the relationship between the average time between turns and factors that may be associated with this was performed using multiple regression on the log transformed dependent variables. . sets of observations were analysed. patients were prone at some time. other positions are in the table. the average time between turns was . hours, median . (range . - ; interquartile range - . ). there was no significant association between the average time between turns and age, gender, respiratory tract-related diagnosis, intubated and ventilated, sedation score, day of week or nurse:patient ratio. there were significant differences between hospitals in the frequency with which they turned patients on their unit. patients are rarely nursed flat. some patients go for prolonged periods without a change in their position. there was no association between the average frequency of turns and the patient and organisational factors we examined. however there are differences between hospitals in the practice of turning patients. introduction. this study compares the incidence of vap in traumatic patients receiving mechanical ventilation for > hours with a endotrachealtube with a dorsal lumen for intermitent drainage of subglotic secretions with others that received mechanical ventilation with a conventional endotracheal tube. traumatic patients admitted to the reanimation unit of the complexo hospitalario de ourense from march to august that received mechanical ventilation for at least hours were eligible for study. the follow-up period consisted of the patients remaining stay in the reanimation unit. demographic and clinical characteristics of patients were collected on admission. vap was suspectted in patients with a clinical pulmonary infection score or more. the diagnosis was done by tracheal aspiration and protected specimen brush. the bacteriologic examination was done by cuantitative and cualitative methods. patients were included inthe study ( that received intermitent drainage of subglotic secretions and in group control). there were not early-onset pneumonia on patients with intermitent drainage of subglotic secretions. there were not significative stadistycal differencies in incidence, duration of ventilation, reanimation length of stay or mortality.conclusion. this study didn't find statystical differences between the two groups because of the short number of patients; but it is important that inthe group wich received intermitent drainage of subglotic secretions there weren't eppisodies of early-onset pneumonia. f. lambiotte* , t. levent , x. lemaire , m. castro , l. gaybor , w. joos , t. ngheim intensive care, chsa, maubeuge, infectious disease, tourcoing, france to analyze the indications and the quality of the prescription of glycopeptides (gp) in an intensive care unit of beds. a -months retrospective study. the treatment was indicated if it answered the recommendations were selected. it was correct if:correct initial dose,corrects glycopeptides concentrations,serum dose obtained with fixed levels, antibiogram justifying the prescription of a gp in the event of bacteriological documentation. . saps ii , (± , ), age years (± , ),gender (m/f) , . , % of the patients presented a renal insufficiency. treated pathology: pneumoniae( %), septic shock( %), intra-abdominal infections ( %), blood stream infections, hyperthermia of unknown origin ( %), infections of the skin ( %), pyelonephritis ( %). frequency of organism recovery was: coag-neg staphylococci (including oxa-r), staphylococci aureus (including mrsa), entérococcus (including ampi-r),others : . the indications of regulation were largely respected but the methods of use of the gp were failing. even when the regulation was correct (n= ), the fixed serum rate was reached only in % of the cases. there is no difference between this patients in septic shock and other patients. taking into account the profile of the patients of intensive care unit, it seems difficult to predict that a treatment will be effective and that sub-inhibiting serum concentrations will be avoided even if the recommendations were respected. the situation becomes more and more delicate because of the increasing bacterial resistance. nosocomial pneumonia (np) continues to be an important cause of morbidity and mortality in the icu. the type of icu (medical, md or surgical, sg) has been described as an important factor to influence their etiology. prospective, observational study conducted between / and / in specialized icus of a tertiary hospital. all patienst who fulfilled clinical criteria ( of ) of np were included. epidemiological and microbiological features were registered. the patients were grouped according their origin from a md or sg icu. we included patients (md, n= and sg n= ). age ± yrs. icu admisión apache ii . ± . the distribution of infections between icus was for md and sg respectively: ventilator-associated pneumonia (vap) % vs %, ventilator-associated tracheobronchitis (vat) % vs %, and np % vs %. we could not find significant differences in epidemiological characteristics (except age ± vs ± , p= . ), risk factors for nn and blood test between the groups. patients ( %) had microbiological diagnosis (md= vs sg= ). the most frequent microorganism producing pneumonia in these patients were mrsa and mssa (same distribution: , % vs , %, p= . ), followed by p. aeruginosa ( , % vs %, p= . ). the inadequate initial ab therapy was slightly higher in sg patients ( % vs %, p= . ) and the mortality rate was not influenced by this variable. the icu and hospital los were alike and hospital mortality rate was significant higher in md than sg icu patients ( , % vs , %, p= . ). for a predicted mortality of % and %. we find some differences in this small cohort of md and sg icu patients with np. the microbiology profile showed important differences between the groups. the main limitation of this study is the small sample size. renal insufficiency is a frequent complication of septic shock. aminoglycosides are highly potent bactericidal antibiotics that together with beta-lactam antibiotics will result in a broad antibacterial coverage. yet, the use of these antibiotics in the treatment of early gram-negative septic shock has been hampered by the assumption that aminoglycosides may be nephrotoxic even in short term therapy. as this is very difficult to investigate in the clinical setting, an experimental study was set up, the aim of which was to evaluate whether the addition of tobramycin further deteriorates kidney function in pigs with endotoxin-induced renal damage. the animals were anaesthetised, catheterized, mechanically ventilated and randomised to groups. groups i (n= ) and ii (n= ) received endotoxin infusion in a dose of mcg x kg- x h- for h, whereas groups iii (n= ) and iv (n= ) received corresponding amounts of saline. groups i and iii received a -min infusion of tobramycin sulphate in a dose of mg x kg- starting minutes after the initiation of the endotoxin infusion, whereas groups ii and iv received corresponding amounts of saline. in parallel with the tobramycin/saline infusions, a cefuroxime infusion in a dose of mg x kg- was given to all pigs. renal function was evaluated by cefuroxime clearance, creatinine clearance, plasma cystatin c, plasma urea, urine output and urine nag (n-acetyl-beta-d-glucoaminidase) excretion. there was no significant difference in physiological baseline variables between the groups of pigs. the elimination rate of cefuroxime - h decreased in both endotoxemic groups whereas it was constant in the non-endotoxemic groups. at h cefuroxime concentration and cystatin c were higher in endotoxemic vs. non-endotoxemic pigs (p< . and p< . , respectively), whereas urine output and creatinine clearance were lower (p< . for both). however, there were no differences between groups i and ii or iii and iv in cefuroxime elimination, urine production, cystatin c or creatinine clearance. plasma urea and urine nag did not differ between any of the groups. endotoxin in the dose administered caused a significant renal dysfunction in this porcine model. the results indicate that the addition of a high single dose of tobramycin seems not to further aggravate the endotoxin-induced renal injury.grant acknowledgement. this work was financed by grants from the nielsen-olinder foundation. the overall nosocomial infection rate was decreased in the chx-treated patients by % ( / vs / ; p< . ). we also noted a % reduction in the incidence of total respiratory tract infections in the chx-treated group ( / vs / ; p< . ). gram-negative organisms were involved in significantly less (p< . ) of the nosocomial infections and total respiratory tract infections by % and %, respectively. no change in bacterial antibiotic resistance patterns in either group was observed. a reduction in mortality in the chx-treated group was also noted ( / : . % vs / : . %). inexpensive and easily applied oropharyngeal decontamination with chx oral rinse reduces the total nosocomial respiratory infection rate in patients undergoing off pump cabg surgery. this results in significant cost savings for those patients. staphylococcus aureus (mrsa) has sparked development of alternative anti-microbial strategies. one such approach involves the use of light-activated antimicrobial agents (photosensitisers), termed photodynamic therapy (pdt). following excitation of the photosensitiser by light of an appropriate wavelength, singlet oxygen and free radicals are generated locally which directly attack the plasma membrane and lead to bacteriolysis. although pdt is well established as an oncological treatment, its use in the treatment of wound infections, in particular those involving resistant strains of bacteria, has yet to be established. after anaesthesia and depilation, week old female c black mice received either a single excisional wound or a superficial scarified wound that were immediately inoculated with an emrsa- bacterial suspension ( cfu/wound) and treated after hour with pdt using methylene blue (mb) as the photosensitiser and laser light with a wavelength of nm to a dose of j.cm − per wound. at the end of treatment, the wounds were excised and processed to assess the total number of viable bacteria per wound. two further experiments investigated the heating effect of pdt and possible collateral damage caused by pdt. three control groups were used to sequentially test the effect of mb alone, light alone and an untreated group which received neither mb nor light illumination. pdt treatment resulted in at least a log reduction (p< . mann whitney-u test) in the number of viable bacteria isolated from the wounds (figure) . there were no obvious histological differences between pdt-treated and untreated wounds. the temperature of the treated wounds rose by an average of . ˚c (± . ˚c) at the end of the treatment.conclusion. pdt is effective in reducing the total number of viable mrsa in an inoculated wound and this effect is not due to local heat generation. there were no gross histological changes apparent between pdt-treated and untreated inoculated wounds. candida species have become the third most common nosocomial bloodstream isolates worldwide. an early adequate treatment is undoubtedly a major prognostic factor. on the basis of efficacy and cost considerations, the empirical treatment often consists in fluconazole administration. yet, given the ever increasing incidence of potentially azoleresistant species such as candida glabrata (which currently accounts for one fourth of cases), this therapeutic option may be ineffective and result in subsequent poor prognosis. moreover, definite identification of candida glabrata may take up to five days, thus delaying modification of initial antifungal therapy and further impairing prognosis. the purpose of this study was to identify early risk factors for candida glabrata candidemia, likely to guide and improve the efficacy of the empirical treatment. all non neutropenic patients with blood culture-confirmed candidemia were included in this prospective study, performed in five french icus. for each patient, baseline characteristics and potential risk factors for candida glabrata candidemia available at candidemia diagnosis were collected. comparisons between patients with and those without candida glabrata candidemia were based on student's t-tests or chi-square tests, as appropriate.variables with a p value < . were entered into a multiple logistic regression model to determine independent risk factors for candida glabrata candidemia. of the patients included over a -year period, had a candida glabrata candidemia. independent risk factors for candida glabrata candidemia were: age > yrs (odds ratio -or- . , p < . ), recent abdominal surgery (or . , p < . ), recent use of cephalosporins (or . , p < . ), solid tumor (or . , p = . ), and diabetes mellitus (or . , p = . ). the model showed satisfying goodness of fit (hosmer-lemeshow statistic = . ) and discrimination (auc = . ). we found early available and easy-to-identify risk factors for candida glabrata candidemia. when these factors are present, alternatives to fluconazole for the empirical treatment should be considered. ventilator-associated pneumonia (vap) is an airways infection that must have developed more than hours after the patient was intubated. vap is the leading cause of death amongst hospital-acquired infections, exceeding the rate of death due to central line infections, severe sepsis, and respiratory tract infections in the non-intubated patient. hospital mortality of ventilated patients who develop vap is percent compared to percent for ventilated patients who do not develop vap.[ ] reducing mortality due to ventilator-associated pneumonia requires an organized process that guarantees early recognition of pneumonia and consistent application of the best evidence-based practices. the ventilator bundle is a series of interventions related to ventilator care that, when implemented together, will achieve significantly better outcomes than when implemented individually. to evaluate the implementation effect of a vap bundle in a general intensive care unit (icu), with the utilization of a software house made designed for this goal.(http://www.bundles.com.br) in a bed general icu, implementation of the bundle was done over months beginning on january . the key components of vap bundle are: elevation of the head of the bed; daily "sedation vacations"; ventilation tube with subglotic aspiration system; peptic ulcer disease prophylaxis; deep venous thrombosis prophylaxis; oral feeding tube instead of nasal feeding tube and oral hygiene with chlorexidine twice a day. we compared the incidence density rate from april to december to the same period in (software stata . ). the vap incidence rate reduced from , / to , / mechanical ventilation days (p< , ) -incidence rate ratio , (ci: % , - , ). after months, the rate of vap was zero. this period was the lowest incidence of vap ever registered in the icu. the incidence of multi-resistant gram-negative bacteria infections was also the lower than before bundle implementation. after five months of a vap bundle implementation with the aid of software house-made to help clinicians follow the results in daily basis, has demonstrated an important reduction in the incidence of vap in our icu. the impact of this system implementation for longer period should be followed. amphotericin b desoxycholate (ampho b) has been nebulized in transplant patients to prevent aspergillus infections, but also as part of selective digestive decontamination (sdd) to decrease fungal colonization and infection in critically ill patients. severe adverse effects of ampho b after systemic administration, particularly nephrotoxicity, led to its substitution by less toxic antimycotics. however, it is still unknown whether even small amounts of ampho b found systemically after inhalation therapy ( ) may be associated with organ dysfunction and increased mortality in critically ill patients subjected to sdd prophylaxis. topical (polymyxin, tobramycin, ampho b) and systemic (cefotaxime for days) antimicrobial chemotherapeutics were routinely administered to ventilated surgical patients who were expected to remain in the icu for more than hrs. a prospective observational study was conducted to accompany the change in sdd regimen ( months of data collection with nebulization of ampho b ( mg every hrs) and months without). conclusion. the use of nebulised amphotericin b as part of a sdd prophylaxis was associated with an increased incidence of renal failure and increased mortality in this study. in the view of the nephrotoxic properties of ampho b, this finding may be potentially explained by systemic effects after prolonged drug inhalation in predisposed critically ill patients. however, in the ampho b group, there were a slightly higher percentage of patients suffering from pre-existing diabetes and renal insufficiency, and potentially nephrotoxic antibiotic regimens were administered more frequently in the study period. drainage for septic focus is the most important process in the management for severe sepsis and septic shock. however, there is no reliable evidence concerning the drainage technique, because the condition is usually so complexed and various that there can not be managed with the uniform standard technique. we have preferred double luminal drain with continuous high pressure aspiration method (dld-chpa) in patients with these conditions. the aim of this study is to clarify the effectiveness and safetiness of dld-chpa by clinical experience.methods. dld-chpa was performed for septic foci. the effectiveness of drainage was examined before and after dld-chpa. the structure of dld is same as that of aspiration device used during surgery which consists of outer tube with multiple pore and inner tube directly connected with high pressure aspirating central vacuum system. the aim of dld-chpa is rapid and continuous removing of discharge and pus, to maintaining dry condition of the abscess and fistula, and stimulating granulation; which leads (a) to quickening the closure of the abscess and fistula and (b) prevention of worsening of local condition of localized abscess and leaking point of injured intestine until definitive surgery. mean grade of discharge soaking in gauze, a wash recovered in intermittent lavage, local inflammation of skin surrounding drain (dld) improved after dld-chpa. mean volume of discharge from wound and drain other than dld was depressed after dld-chpa. the sum of volume of discharge and aspirated material after dld-chpa is smaller than before dld-chpa. the frequency of dressing change was decreased. in all cases, we could perform definitive surgery without worsening of local inflammation, especially inflammation of skin around drain. there was no complication with dld-chpa.conclusion. dld-chpa is useful and safe procedure for managing septic foci by draining mucinous purulent fluid effectively, which can prevent worsening of local condition of localized abscess, and keeping the local condition good until definitive surgery, if definitive surgery is necessary. to evaluate pre-dialysis full-dose aminoglycoside administration in septic anuric critically ill patients. in a prospective observational study, all septic patients with anuria received fulldose gentamycin (g), tobramycin (t) or amikacin (a) consisting in a mg/kg (g/t) or mg/kg (a) dose, infused hours before daily dialysis. the pharmacokinetic study of serum dosages was compared to that of septic patients with normal renal function. dosages were compared to that of patients with normal renal function who received infusions and served as controls. anuric patients' demographic data were as follow: mean age [iqr - ], mean saps ii [iqr - ], former renal failure %, respiratory tract infection %, nosocomial infection %, icu mortality %. pre-determinated aminoglycoside peak concentration targets for g/t ( - mg/l) and a ( - mg/l) were achieved in respectively % and . % of anuric patients versus and % of controls. compared to target (theoretically non-toxic) trough mg/l for a), trough concentrations in≤ mg/l for g/t and ≤concentrations ( anuric patients were higher (g/t : median . mg/l; a: median . mg/l) than in normorenal patients (g/t : median . mg/l; a: median . mg/l). with aminoglycoside clearance due to intensive dialysis (median kt/v . / session), delay in aminoglycoside infusion was reduced to hours with an observed half-life of . hours.conclusion. this pilot study supports the feasibility of a new aminoglycoside dosing schedule consistent with full-dose administration three hours before dialysis in anuric septic critically ill patients. the prerequisite is that hemodialysis should be performed daily, using high efficacy membranes. further randomised controlled trials are needed to confirm these results. conclusion. mortality in gram negative nosocomial infection remains high but the impact is greatest for nf-gnb due to their intrinsic resistance to many antibioitics, making selection and optimal therapy difficult. in our population, bsi due to nf-gnb was not associated with significantly increased mortality. this could be explained by older age in f-gnb cf nf-gnb. our study highlights the importance of risk stratification to identify patients at risk. empirical combination antimicrobial therapy (ecat) has been recommended for bacteraemia due to gram positive microorganisms during many years, especially for streptococcus pneumoniae, although its use still remains controversial. the aims of this study were to determine the prevalence of ecat in icu patients with gram positive bacteremia (gpb), to describe the main clinical, epidemiological and microbiological features of such patients comparing with monotherapy treatment and to know the impact of this strategy on related mortality to gpb in critically ill patients. during a ten years and a half period, from to , icu-patients with gpb were prospectively evaluated. empirically antibiotic combination or monotherapy regimen was administrated until the agent of infection was identified following the patient's physician criteria. the administration of two or more antibiotic with activity against gram positive microorganism was defined as ecat. clinical and microbiological variables were recorded. logistic regression analysis was performed to deterrmine the impact of this strategy on related mortality to gpb. there is evidence that current practice could be improved. to achieve this, teaching and assessment techniques that are acceptable to both consultants and trainees must be developed. in other specialities video is used to teach communication skills, although its application to intensive care training has not been widely studied. after obtaining ethics approval, specialists in intensive care at general hospitals in the north-east of england were invited to take part in the study. participants were given a written scenario describing the admission to the icu of an elderly woman with pneumonia. data was included which suggested deterioration despite treatment and progression toward multi-organ failure. the consultants were then videoed conducting an initial meeting with the patient's closest relative (played by an actress). questionnaires were used to record previous experience of communication skills training and reaction to the video exercise. . consultants gave written, informed consent to take part. only half of the participants had previous, limited experience of audio or video recording to teach communication skills. none felt 'significantly experienced' in this area or had used the technique with trainees. most had developed their communication skills by sitting-in as an observer when colleagues were talking to relatives. participants stated they had never had any formal teaching in communication skills either through lectures, workshops or role-play. the plausibility of the scenario and actress were rated highly by all the participants. despite individuals choosing to agree with the statement 'i was anxious and uncomfortable throughout the video exercise', none of the respondents disagreed with the statement 'i managed to settle into the normal style i use when speaking to relatives'. only participants did not support the statement 'overall i feel happy with the way the consultation went'. of the participants disagreed or strongly disagreed with the statement 'i feel the video does not represent my normal practice of speaking to relatives.'conclusion. this study shows that video techniques can be used to reproduce realistic intensive care scenarios. the format was well received by a majority of specialists and despite no previous experience of being filmed, participants felt that the simulation closely replicated their normal practice. teaching-training would be required to introduce these techniques as current specialists have received little formal training in communication skills. during a two-month period, consecutive adult icu patients (sapsii score: ± ; ventilated patients) requiring a transthoracic echocardiography were prospectively studied. after a curriculum including a -hour training course and hours of hands-on, one of noncardiologist residents and an intensivist experienced in ultrasound subsequently performed hand-held echocardiography (hhe), independently and in random order. assessable "rule in, rule out" clinical questions were purposely limited to easily identifiable conditions by the sole use of two-dimensional imaging. cricoid pressure should be applied lightly ( n) before induction of anaesthesia and while the patient is still awake. once the patient is unconscious the force should be increased to n (vanner & asai, ) . a simple training aid using an air filled, capped ml syringe has been described (ruth et al., ) , but a lack of knowledge and poor technique amongst anaesthetic assistants has already been highlighted (meek et al., ) . the aim of this study was to investigate knowledge and skills of a group of intensive care unit nurses in performing cricoid pressure, using a structured interview questionnaire and simple practical test. we asked intensive care nurses from queen elizabeth hospital, birmingham uk to participate in a structured interview. volunteers were asked about their own experience, training and knowledge of cricoid pressure in a questionnaire conducted by one of the authors. each subject was then asked to apply the force that they would normally use in clinical practice to the plunger of a plastipak (b-d) ml syringe filled with air. the destination of the plunger was recorded (ml). the subjects were then informed of the recommendations stated above and allowed to practice the application of n on the syringe ( . ml standard destination). they were than asked if they thought a simulator would be useful for training. . % respondents (n= ) were staff nurse with to years experience, and % performed cricoid pressure less than monthly. only % nurses had formal training and % described their training as 'totally inadequate'. . - % nurses applied and released cricoid pressure only on instruction by anaesthetist and . % respondents did not know the optimum force to use. on simulation, the mean force applied was nearer n than n (mean plunger destination . ml, less than . ml standard. s.d = +/- . , variance = . ). of ( . %) respondents thought simulation training would be useful. intensive care nurses perform this procedure infrequently and become deskilled. this study also highlights the inadequacy of training they receive. using a readily available training aid such as a ml syringe is reliable and may improve staff confidence, performance and patient safety. j. m. boles* , g. prat , a. berthouloux , b. seys , a. renault réanimation médicale, hôpital de la cavale blanche -chu, psychothérapie, société civile alternatives, brest, france the policy of our -bed medical icu includes helping members of the staff to cope with the burden of job stress. our university hospital agreed to finance a focus group to help staff relieve their stress. we performed an evaluation months after. a first non-anonymous survey was conducted in / amongst the staff to know who was willing to attend a focus group. an independant family therapy psychologist was selected out of candidates. a focus group was set up in / open to any volunteer; -hour monthly reunions were conducted by the psychologist. an anonymous questionnaire was sent to all staff members in / . initial survey: mds/ , daytime nurses/ ( night nurses/ ), / auxiliary nurses,the secretary and the chief nurses agreed to attend = , % of the daytime staff. the group held reunions, attended respectively by , , and members of the staff. the group was then suspended. anonymous evaluation: / staff members answered = , %. conclusion. ) in a two hour icu oriëntation in the undergraduate curriculum the icu nursing staff was as successful as the medical staff in improving understanding of the icu organization as well as in improving the ability to recognize vital organ functions and principles of the monitoring of critically ill patiënts. this study suggests that icu nursing staff can enhance learning the basic practical monitoring of undergraduates and can be successfully integrated into undergraduate medical education. in meeting the needs of increasing numbers of medical students there is a potential for this role to be to developed. ) interest to qualify as an intensivist increased significantly when the intensivist was the teacher. guidelines for cpr teach us to do chest compression per minute and to ventilate for a minimum time. however, paramedics tended to do chest compression more quickly and to do ventilation more slowly. in japan, prehospital cpr has been performed by emergency life support techniciens (elst), who belongs to the fire department. in this study, we tried to clarify the actual condition concerning prehospital cpr. japanese elsts are licensed after hours of lecture and , hours of experience, and they are trained repeatedly. in yokohama, one supporting medical doctors is working in the central operation center of the fire department. they can detect the frequency of chest compression and ventilation during cpr in the ambulance. we recorded these frequency for and evaluate the quality of cpr by elst.results. in our system, elst performed chest compression times per . sec, that meant times per minute. they perfom ventilations for . sec. we should train elsts more frequently and repeatedly and should use metronome, voice guide or aed with voice guide during cpr in the ambulance. tracheostomy is often required in icu patients to prevent the consequences of long term translaryngeal intubation, indicated in prolonged mechanical ventilation and long term airway maintenance. it has lots of benefits like increasing patient comfort, less need for sedation, improving oral and bronchial hygiene, allowing oral nutrition, and ease the process of weaning from mechanical ventilation. percutaneous tracheostomy (pct) as opposed to surgical tracheostomy (st) has many advantages: it can be made at bedside (and be performed immediately once the decision is made), being safe and easy, with less operative time, and less intra and early postoperative complications (reduced stomal bleeding and infection, due to the tamponade effect of the tightly fitting tracheostomy tube). it is also associated with lower costs and has better cosmetic results than st. the aim of this study is to compare the timing and outcomes of tracheostomies in our icu, and hospital mortality of these patients. we conducted a retrospective comparative study in distinct periods: and , when all patients in our icu were submitted to st (n= ); and and when patients were preferentially submitted to pct (n= ). we reviewed their indications for tracheostomy, age, gender, apache ii and saps ii score, days to tracheostomy, length of icu stay, ventilation time before and after tracheostomy, icu and hospital mortality. the results presented are in mean values. conclusion. )there was no significant difference in indications for tracheostomy (prolonged mechanical ventilation and airway protection in comatose patients), age( ), gender, mean ventilation days prior to( , ) and after ( , ) tracheostomy. )pct was performed sooner ( , vs , day), and these patients had a sooner icu discharge ( , vs days). )patients submitted to st had higher apache ii( , vs , ) and sapsii( , vs , )scores; higher icu( % vs , %) and hospital mortality ( % vs , %). reported here. the study was carried out in finland. the expert panel was formed of intensive and critical care nurses and physicians of five university hospitals and four central hospitals. altogether (=n) experts participated in first round. the experts completed a questionnaire which consisted of demographics and one essee question. text were analysed according to research questions by content analysis. competence requirements in intensive and critical care nursing can be described as five main domains: specific ) knowledge base, ) skill base, ) attitude and value base and ) experience base of intensive and critical care nursing. additionally competence can be described as several ) personal attributes of competent intensive care nurse. competence requirements can be divided into clinical and professional competence requirements. the sub domains of clinical competence requirements are implementation of principles of nursing care, implementation of clinical guidelines and implementation of nursing interventions. the sub domains of professional competence requirements are then ethical activity, decision making, development work and collaboration.conclusion. competent nurse in intensive and critical care nursing has to have specific knowledge base, skill base, attitude and value base and experience base that differs from overall competence in nursing. additionally competent intensive and critical care nurse has to have spesific personal attributes.grant acknowledgement. we would like to thank the experts of university and central hospitals who participated in this study. to define examine catheter related bloodstream infections (crbsi) over a -year period ( - ) , and compare three expressions of incidence.methods. -bed tertiary referral centre. hospital-wide, total parenteral nutrition(tpn) service based at department of intensive care. quarterly meetings of tpn committee analyse prospectively collected data to examine crbsi incidence. effect of introduction of education protocols and appointment of dedicated tpn nurse were assessed. . patients, cvcs were included. a consistent decline in incidence was observed, % of patients in to % in (figure) . incidence may also be expressed as percentage of cvcs infected, decreasing from % of cvcs to % . finally, incidence is expressed per cvc days which peaked at / cvc days dropping to / cvc days .conclusion. crbsi occurs commonly in tpn populations, but published data remains limited. irrespective of means of expression, our data demonstrates a falling incidence in crbsi, which we attribute to the appointment of a tpn nurse, ongoing education protocols regarding cvc insertion and maintenance. this data supports the pronovost paper that an intervention may result in a sustained decline in the incidence of crbsi. dimension and course of cognitive ability change after elective coronary bypass (cabg) or valvular replacement (vr) interventions are discussed controversely. the aim of our study was ( ) to measure the difference of cognitive abilities concerning attention, memory and fluid intelligence before and after cardiosurgery, ( ) to investigate the outcome difference between cabg-and vr-patients and ( ) to investigate the relevance of duration of bypass-and aortic-clamping as well as duration of anesthesia as predictors of cognitive outcome. subjects: consecutive patients; cabg, vr; timepoints of measurement: t : - days before intervention, t : days and t : - days after intervention: cognitive assessment instruments: d -test (selective attention), rbmt (memory), cft- (fluid intelligence). a significant decline of all measured cognitive functions at t compared to t could be demonstrated for the cabg-(d : p< . ; cft : p< . ; rbmt: p< . ) as well as for the vr-sample (d : p< . ; cft and rbmt: p< . ). both groups showed a remission at t concerning memory and intelligence scores, only vr-patients had persistent deficits in selective attention (p< . ). there were no significant differences between cabgand vr-samples at any time of measurement. no parameter of surgery reached significance as predictor for cognitive outcome in regression analysis. in the early postacute phase ( days) after cabg-and vr-surgery we could show deficits in various areas (attention, memory, fluid intelligence) of cognitive performance as well as rapid remission within one week. despite expectations there were no significant differences between cabg-and vr-samples. abdominal complications in postoperative cardiac population are not frequent but may be catastrophic. non-occlusive mesenteric ischemia appears when there is a mismatch between perfusion and metabolic demands. the symptoms and signs are not incontrovertible and the suspicion of this complication may improve prognosis. indocyanine green plasma disappearance rate (icg-pdr) has been proposed as a tool for the assessment of liver perfusion and function ( , ) so that it may help in diagnosis and to optimize treatment. a prospective study was conducted in cardiac surgery patients. icg-pdr values were measured hours and hours after icu admission transcutaneously by a commercially available system (limon; pulsion medical systems, munich, germany). icg-pdr values and other postoperative data were compared between patients suffering and not suffering from abdominal complications. mann-whitney and wilcoxon tests were applied for statistics. significance was considered when p < . . . patients were analysed but we did not find major abdominal complications. minor abdominal complications were suspected in because they suffer abdominal pain, ileus and higher serum amylase values. this group of patients were older ( ± vs ± , p= . ) and suffer from more hypertension (p= , ). their preoperative risk (numeric eu-roscore) was higher(es num ± vs ± , p= . ) and so was the apache ii score ( ± vs ± , p= , ). twelve hours after icu admission icg-pdr values were lower ( . ± vs ± ,p= . ) and normalized at hours. length of stay (los) was longer (icu-los was ± vs ± , p= . and hosp-los was ± vs ± , p= . ). they had associated more complications : cardiovascular (p= . ), renal (p= . ), neurolgical disorders (p= . ) and infectious (p= . ). procalcitonine (pct) values were also higher(p= . ). they suffer from higher preoperative pulmonary hypertension (pap de ± vs ± , p= . ). cardiac index values were lower hours after admission (ic- . ± . vs ± . , p= . ). serum amylase values were higher in first postoperative day (amy- was ± vs ± , p= . and amy- was ± vs ± , p= . ). and so were aspartate amino-transpherasa (ast) values hours after admission (p= . ). the incidence of gastrointestinal hemorrhage was also higher (p= . ).conclusion. . patients suffering from minor abdominal complications had worse icg-pdr values hours after admission. . they were were older and their preoperative risk and apache ii score were higher. . they suffer more complications and their los was longer. . serum amylase, ast, pct, pap and cardiac index values were worse in these patients. deployment of an intraaortic balloon pump is a technique that is used and recommended in high-risk surgical patients. this group includes patients with haemodynamically significant stenosis of the left coronary artery trunk and ejection fraction minor %, preoperative unstable angina, and intraoperative and postoperative cardiogenic shock. we examined the pre-and post-operative use of an intraaortic balloon pump in our surgical series and its association with morbidity and survival. we undertook a prospective, observational, cohort study of patients who underwent cardiac surgery with extracorporeal circulation between january -june who were admitted to the polyvalent intensive care unit of our third-level hospital. the data collected were analysed statistically with spss . . the study included patients, with a mean age of . ± . years and % were men. the incidence of iabp were: preoperative . %, intraoperative . %, postoperative . %, technically imposible . % and no need of iabp . %. % had some degree of surgical morbidity (including atrial fibrillation). the overall mortality was % and the mean stay was . ± . days (range, - days). the indication were: ejection fraction %, unstable angina %, vessel disease %. after an univariate analysis iabp and postoperative complications there was relation with low output or shock (the indication of iabp, p< . ). the others postoperative complications (mechanical ventilation > h, kidney failure, important haemorrhage and perioperative infarction) were no relationed and has the same incidence as the moderate-low risk interventions.conclusion. the intraaortic balloon pump is a commonly used technique in high-risk patients, reducing the incidence of postoperative complications to the limits of those in moderateor low-risk patients. mecc is a new approach to cardio-pulmonary bypass (cpb). the system differs from conventional bypass (cpb) as follows: minimal priming volume (< ml); no venous reservoir (closed system); active venous drainage; no cardiotomy suction; heparin coating (tip-tip). practical advantages of mecc include: minimal haemodilution; no blood-air interface; reduced foreign-body contact; less haemolysis; reduced heparin given. potential improvements in clinical outcome in icu as a result include: reduced requirement for inotropes; fewer blood transfusions; less systemic inflammation; reduced coagulopathy; improved endorgan function. these factors combine [ ] to significantly reduce prbc transfusion (u/patient) requirements with mecc ( . ± . ) compared with cpb ( . ± . ), or opcab surgery ( . ± . ). mecc has recently been introduced in the swcc for routine cabg surgery. intraoperative data were collected for quality control purposes (n= ), compared with historical controls (same surgeon and anaesthetist) but with cpb (n= ). conclusion. an improved haematological profile (seen here with hb, but theoretically reflected in other blood components) with mecc may reduce postoperative coagulopathy, costs and risks associated with blood and other blood product transfusion, and improved oxygen delivery and therefore end-organ function. g. satkurunath*, p. wilton intensive care and anaesthesia, harefield hospital, harefield, united kingdom cardiothoracic units have high usage of intensive care unit (icu) beds and patient flow-through affects their continued productivity and cost-effectiveness. prolonged icu stay patients are a small percentage but consume a disproportionate amount of resources and have a higher mortality. our aim was to determine the type and the outcome of icu patients requiring prolonged stays at our institution to determine if resources were used appropriately on patients with a reasonable chance of survival. our institution is a cardiothoracic hospital specializing in adult cardiothoracic surgery and transplantation. a retrospective analysis of the institution icu database was performed and all admissions with a duration ≥ days from april to march were identified. the medical records of these patients were reviewed to determine individual risk factors for prolonged icu stay. this data was compared to the overall icu outcome audit data for that year. there were a total of icu admissions of which ( . %, patients) were ≥ days. the median icu length of stay in the study group was . days (range - ). the patients had a cumulative total of bed days which was . % of the total icu bed days ( ). icu mortality was . times greater than the overall unit mortality ( . % versus . %). mean and median age was similar to that of the overall unit. the percentage of readmissions in the study group was . times greater than the overall percentage ( . % versus . %). in the prolonged stay group patients ( . %) survived the hospital admission: were discharged home and were transferred to another hospital for further rehabilitation. cardiac surgery necessitating cardiopulmonary bypass involves periods of ischaemia followed by reperfusion. reperfusion of previously ischaemic tissue may itself result in tissue damage through the activation of neutrophils, production of oxygen free radicals and endothelial damage. this phenomenon has been termed ischaemia reperfusion injury (iri). the consequences of iri may be observed locally in the form of reversible cellular dysfunction or more remotely with effects observed in the lung, liver and cardiovascular system. ultimately, a systemic inflammatory response syndrome (sirs) may develop with the potential to progress to multiple organ failure in the most extreme cases. remote ischaemic preconditioning (ripc) is a technique which provides protection against experimental iri in humans. we performed a randomised controlled trial to investigate the effect of ripc on patients with triple vessel coronary artery disease undergoing cabg surgery (n = ). ripc was induced by cycles of minutes of inflation ( mmhg) and deflation of a blood pressure cuff around the upper arm hours prior to surgery. patients were assessed post operatively for the development of sirs. blood samples were collected up to hours post operatively. myeloperoxidase (mpo), interleukin- (il- ), c-reactive protein (crp), and von willebrand factor (vwf) were measured as biochemical markers of neutrophil activation and endothelial damage.results. sirs developed in % of patients who had undergone ripc compared to % in the control group (p = . ). mpo, il- , (table ) crp, and vwf (table ) were elevated post operatively but no protection was observed in patients pre-treated with ripc. of note, the study was not powered to measure these variables as the primary outcome and thus it is possible that a protective effect may be observed in a larger study population. gender differences in the coronary bypass surgery have been the focus of numerous publications in recent years. compared to men, women undergoing coronary artery bypass grafting appear to have a higher morbidity and mortality, particular in the perioperative period. the aim of this study was to analyze which clinical parameter and laboratories data effect on gender differences in postoperative course. . to the end of december .,all patients on whom were performed elective coronary bypass surgery were included in this retrospective study. age,ef,euroscore,numbers of days in jil,total numbers of day in hospital stay, troponin t (t - hours after addmision,t - hours after addmision in jil),lactate (l ,l ),cardiac output,cardiac index were observed. for all variables was made descriptive statistics. we used student-t test and mann-whitney u test. . patients ( m and f)were observed. analyzing age, ef,euroscore,cardiac output and cardiac index we did not find statistical important differences man versus female. analyzing troponin t, level of lactate (particulary l )we found statisticaly important higher levels in women group. women needed longer support with inotropes and are more likely to spend longer time in the hospital. fortunately, the last decade has produced a surge of public interest and scientific research in womens health, including gender issues related to cabg. it is now well accepted that there are major differences in the risk profile of man compared to the profile of woman undergoing cabg procedures. even when both genders share a common risk factors, the relative impact of risk factor is often quite different in man as compared to woman. w. baulig* , v. hinselmann , m. lachat , k. rentsch , e. schmid devision of cardiac anaesthesia, department of cardiac surgery, institute of clinical chemics, university hospital zurich, zurich, switzerland reports regarding the benefit of continuous local analgesia after various surgical procedures are conflicting ( ). the aim of this prospective, randomized, double-blind study was to investigate the efficacy of continuous local anaesthesia using the pain relief system (i-flow corp, usa) in patients after abdominal aortic surgery. after closing the peritoneum, two multi-hole catheters (length cm) were placed in the opposite direction of the skin incision. following skin closure, both catheters were connected to the elastomeric pump filled with ml of an unknown solution (either sodium chloride [nacl] . % or ropivacaine . %) and a continuous infusion of ml.h- was started through each catheter. every hours until h after surgery combined visual analog pain scale (vas) and numeric rating scale (nrs), partial oxygen (pao ) and partial carbon dioxide pressure (paco ), arterial oxygen saturation (sao ), pulse rate, and mean arterial pressure were recorded. the serum concentration of ropivacaine, free ropivacaine and alpha- -acid glucoprotein were measured daily. the total amount of intravenous morphine sulphate and nonsteroidal analgetics, ventilation time, length of stay in the icu, and the condition of the removed catheters were documented. sixteen patients were enrolled, but one patient had to be excluded because of accidental catheter removal at icu arrival. demographic and surgical data were not different between groups. ropivacaine was applied in , nacl . % in patients. vas/nrs was lower in the ropivacaine group during the first postoperative hours ( . ± . ) than in the control group ( . ± . ), but this difference did not reach statistical significance. no significant intergroup differences were found with regard to morphine sulphate, metamizole and paracetamole consumption, pao , paco , sao , ventilation time and length of stay in the icu. serum concentrations of free ropivacaine ( . ± . µmol/l) were well below toxic levels ( . ± . µmol/l). in two thirds of the removed catheters > % of the holes were closed. . ± . . ± . metamizole (g) . ± . . ± . continuous infusion of ropivacaine . % ml.h- using two multi-hole catheters at the surgical site in patients after abdominal aortic surgery did not reduce the consumption of intravenous morphine and nonsteroidal analgetic drugs. introduction. prognostic scores have been developed for assessing patients's risk of complications or death and are useful to identify high risk patients allowing specific interventions. surgical scores have been developed but it is still not clear if they offer any benefit compared to general icu scores. the aim of this study was to compare the accuracy of the scores apache ii, apache iii and p-possum in a brazilian surgical intensive care unit. consecutive surgical patients admitted in the surgical unit were included prospectively from august to march . cardiac and neurosurgery, age < and length of stay in the icu < h were excluded. after exclusion, the scores were applied in patients. we compared actual in-hospital mortality with those predicted by the apache ii, apache iii and p-possum scoring systems applying receiver operating characteristic (roc) curve analysis by integrated methods using r-system . . . the physiological parameters of p-possum score were obtained in the postoperative period. the operative parameters in orthopedic surgery were adapted. the most common surgeries were: abdominal surgery ( . %), orthopedic ( . %), urologic ( . %), vascular ( . %), bariatric ( %) and thoracic ( . %). procedures done before h of hospital admission were and before h of admission were . the average number of days in icu was . (+- . ) and the mean number of postoperative days before discharge was . (+- . ). the rate of icu readmission in days was . %. the median age was years. overall hospital mortality was . %. the mean absolute values of apache ii, apache iii and p-possum were . (+- . ), . (+- . ), . (+- . ) and mean predicted in-hospital mortality were . %, . % and . %. respectively. the area under the curve from receiver operator characteristic curve analysis for apache ii was . , for apache iii was . and for p-possum was . . these data suggest that p-possum may provide a better estimate of the risk of mortality than apache ii and is at least as accurate as apache iii. p-possum requires fewer individual patient parameters to be calculated and is thus easier than apache iii to be generated. preeclampsia is a multisistemic disease that may occur in pregnancy or in the immediate post-partum period. the incidence of pregnancy induced hypertensive disease is observed in . % in spain. we analise the mortality and the clinical profile of this entity in our icu. the study comprise prospectively women admitted in icu with the diagnose of severe gestosis, from january to october . we define preeclampsia, eclampsia and hellp syndrome as used by the american college of obstetric and gynecology. we consider hellp as a different disease as its mortality rises up to a %. cualitative variables are shown as percentage and cuantitative variables as mean ± standard deviation or median and range in asymmetric variables. we used chi square test, t-test and multivariant testing for statistical analysis of the data. we report data from women admitted in icu in the period january . we didn't find significant difference on systolic pressure between preeclampsia, eclampsia or hellp nor in uric acid levels. there were significant differences in aminotransferase enzymes and platelet count between preeclampsia-eclampsia and hellp. gestational age was significantly lower in preeclampsia than in eclampsia or hellp (p< , ) and, additionally, the weight of newborn were significantly lower in preeclampsia versus eclampsia and hellp. fetal death is associated with a birth weight below gr (p< . ), or . , ci % ( . - . )). maternal death is associated with renal failure, heart failure or coagulopathy (p< . ) or . (ci % . - . ). multivariant analysis show that primiparity appears as a protection versus mortality, p< . or . (ci % . - . ) and pulmonary oedema as a risk factor p< . or . (ci % . - . ). fetal mortality is associated in multivariant analysis with gestational age and consequently with low weight (p< . ) and (p< . ) respectively, or . , ci % . - . and or . ci % ci . - . respectively. women admitted to the icu are mostly years old, in the week gestational age of their first pregnancy. in our environment, delivery mostly occurs in the following to days of admission. maternal mortality is low but not so fetal mortality that rises up to , %. maternal mortality is associated with multiparity and complications such as pulmonary oedema, and fetal mortality mostly with gestational age and low birth weight. in order to reduce postoperative morbidity and mortality following liver resection due to hepatic failure it is important to carefully monitor liver function. as lactate is mainly cleared by the liver, it has the potential to be a good indicator of liver performance. many factors may determine liver function, such as the extent of the liver resection, pre-existent liver conditions, the amount of blood loss, and other patient and operation characteristics. we assessed the value of fast and inexpensive point-of-care lactate measurements as an indicator for liver function next to prothrombin time which is the current standard. in a retrospective observational study we included all patients admitted to the surgical icu after liver resection between april and march . lactate levels were frequently measured in arterial blood with a point-of-care device (abl radiometer). maximal lactate during the first hours after icu admission were determined. extent of liver resection, preoperative liver condition and red blood cell transfusions were recorded. . patients were studied ( males, females) with a median age of years (range - ). abnormal liver parenchyma was present in ( %) patients. in patients, more than % of the liver was resected (major resection). red blood cells were administered in patients with a mean of . (± . ) packed cells. lactate measurements were performed during the first postoperative day. multivariate analysis with the parameters volume percentage resected, peri-operative blood loss, age, gender, preexistent liver condition, showed that the extent of liver resection was significantly associated with lactate levels (p= . ). mean lactate levels were respectively . for major resections and . for minor resections. blood lactate levels were significantly correlated to pt (pearson's r= . ; p< . ).conclusion. the extent of liver resection was an independent predictor of lactate levels. age, gender, amount of blood loss and preexistent liver disease were not associated with lactate levels. lactate levels were clearly correlated with prothrombin time. phaeochromocytoma is a rare chromaffin cell tumour predominantly arising in the adrenal medulla. following pharmacological control, elective surgical excision is performed ( ). postoperative admission to itu is standard as cardio-respiratory, renal and metabolic complications (hypertension, hypotension, pulmonary oedema and hypoglycaemia) may occur ( ) . the aim of this study was to identify postoperative complications following adrenalectomy, requiring critical care support. the data collected would allow us to evaluate the statement that, 'not every patient following adrenalectomy for phaeochromocytoma requires itu admission'. over years, adrenalectomy patients with a clinical, laboratory and histological diagnosis of phaeochromocytoma, were studied retrospectively. twenty three patients were identified from clinical databases and data collection followed a review of the perioperative records.results. % of the adrenalectomies were open, the remainder were laparoscopic ( were converted to open). multiple anaesthetic techniques were used by four anaesthetists. % arrived on itu intubated, but extubation followed within to hours. with a map between and mmhg, % received postoperative inotropic support (noradrenaline . to . mg/h) for to hours. one patient ( %) required inotropic support for hours and remained intubated for hours. six developed postoperative respiratory infections ( % were open adrenalectomies); one of which required reintubation, ventilation and inotropic support. all of those that developed respiratory infections had morphine infusions or pca for analgesia. although the difference between the preinduction and peak intraoperative blood pressures (systolic and mean) were smaller in those receiving remifentanil, it was not statistically significant.conclusion. ) following adrenalectomy for phaeochromocytoma, few patients experienced significant perioperative morbidity and the traditional practice of electively admitting all patients to the itu, should be reviewed. ) an experienced team approach ( ) is more likely to limit perioperative complications than using surgical duration, tumour size and urinary catecholamine concentration to predict postoperative complications ( ). ) standardising the anaesthetic technique could increase the 'in theatre' extubation rate. ) the routine use of epidural analgesia may reduce the incidence of postoperative respiratory infections and may influence the incidence of reintubation. ) the role of remifentanil requires further investigation but prior to venous ligation of the tumour, it appears to improve intraoperative haemodynamic stability. thoracoabdominal aortic aneurysm (t(a)aa) repair is associated with major blood loss exceeding the intravascular volume and complex perioperative coagulopathies requiring transfusion of blood products. there have been three reports evaluating bloodproducts needs in t(a)aa repair. the combination of surgery induced tissue damage and massive blood products transfusion may enhance post operative organ dysfunction and infections. mortality in cabg surgery is associated with number of bloodproduct transfusions. in t(a)aa surgery this relation has not been studied. this question might be of clinical importance as elective t(a)aa repair is associated with considerable mortality ( - %) and morbidity (e.g. respiratory failure - %). in this retrospective single centre study we identified all consecutive patients with taa(a) surgery during the period - . patients records in an icu database and transfusion database were combined and evaluated. baseline characteristics, apache ii score, respiratory failure (ventilator support > hours), transfusion and mortality data were collected. association between variables was determined with multivariate regression analysis. in all patients cellsaver was used. results. patients underwent t(a)aa surgery in the study period. patients ( ( . %) male and ( . %) female) were identified in both databases. the mean age was . ± . years. in hospital mortality was . %. mean apache ii score in the first hours was ± . rbc transfusion results in an significantly increased mortality risk (or . ( %ci . - . )). rbc transfusion was significantly associated with respiratory failure (or . ( %ci . - . )). increased post operative apache ii score results in significantly more rbc infusion (p< . ). these findings could not be demonstrated for ffp and platelets infusion. we did not find a significant difference in blood transfusions and extent of aneurysm, as found by others. our quantity of blood transfusion is much less than reported previously (with and without cellsaver use). conclusion. large volume of blood transfusion may be necessary during and after t(a)aa surgery. rbc transfusion is associated with increased mortality rates. as apache ii score is related to rbc transfusions, peri operative optimalisation might contribute to less blood transfusions. blood transfusion in our population is less than reported previously. cardiac surgery is occasionally complicated by refractory postcardiotomy bleeding, leading to increased mortality and morbidity. recombinant activated factor vii is being increasingly used as rescue therapy in such cases. we report our experience with the use of rfviia in our -bed csicu. all patients who received rfviia as rescue therapy for intractable bleeding during or after cardiac surgery over a -year period was analyzed. we assessed and compared the use of blood products (rbc, ffp, plt), coagulation indicators (international normalized patio [inr] , activated partial thromboplastin [aptt], and fibrinogen), and platelet levels before and after rfviia administration. results. patients (mean age, , +/- , years) received a single dose of rfviia ( , +/- , microg/kg). surgical procedures were aortic surgery (n= ), double valve operation (n= ) and left ventricular assist device (n= ). the men time between icu admission and rfviia administration was hours while patient received it intraoperatively. the mean blood product usage prior and after the administration of rfviia was the following: packed rbc, , versus , u; ffp, , versus u; platelets versus , u; bleeding stopped in all cases and no patient needed reoperation. the mean coagulation results were ptt, , +/- . versus , +/- , seconds; p= , ; inr, , +/- , versus , +/- , ; p< , . in all cases, blood loss decreased considerably after rfviia administration almost eliminating the need for additional blood products, and the prolonged prothrombin time normalized. no side effects of rfviia treatment were noted. there were no thrombotic complications, cardiac ischemic events or deaths. our results support the use of rfviia as rescue therapy in severe, uncontrollable, nonsurgical, postoperative hemorrhage after cardiac surgery as efficacious and safe. however the data are still limited, and further studies are necessary to determine the safety and efficacy of this new hemostatic agent. coumarin oral anticoagulants are widely used to prevent thromboembolic complications in patients at risk for such events. rapid reversal of anticoagulant effects may be required in cases of severe bleeding or emergency surgery and the use of prothrombin complex concentrate (pcc) is recommended. as a surrogate marker international normalised ratio (inr) is used to evaluate the effective use of treatment with pcc. however, a clear correlation between correction of inr and improved haemostasis has not yet been established. this study intended to validate the correlation between the correction of inr, shortening of time to haemostasis, and reduction of blood loss in anticoagulated rats. four groups of female wistar rats were used in the study. rats in groups to were anticoagulated with . mg/kg body mass of phenprocoumon on occasions ( and hours), group , the control group, received isotonic saline. approximately hours after the second treatment, ml/kg body mass isotonic saline was administered intravenously (iv) in groups and . groups and received and iu octaplex ® /kg body mass. fifteen minutes after treatment blood samples were taken. the tail tip was cut off and the tail immersed in isotonic saline at + ˚c. bleeding time and haemoglobin concentration in the saline were measured subsequently. mean bleeding time in group was ± s. in groups and , the maximum observation time of minutes was recorded (except of one which died after minutes). in group mean bleeding time was ± s, complete cessation of bleeding was observed in out of animals. one animal died before minutes and in the remaining clotting was noted with markedly reduced bleeding. haemoglobin concentrations in groups and ( , µg/ml and , µg/ml) were significantly higher (p < . ) than in group ( µg/ml). no statistically significant difference was found between group ( µg/ml) and group . pulmonary thromboembolism (pe) is a critical complication after general surgery with an incidence ranging between , % and % and a mortality rate up to %. systemic thombolytic therapy is the core treatment of submassive and massive pe but may be associated with severe bleeding complications after major surgery. we report a case series of four postoperative patients with suspected (n= ) or proven (n= ) massive, life threatening pulmonary thromboembolism. diagnostic and therapeutic measures as well as decision-finding pro and contra thrombolytic therapy are discussed. one female and three male patients (age to years) presented with acute hypoxemia and severe cardiogenic shock (n= ) or cardiac arrest (n= ) on postoperative day to day following major surgery. pe was suspected in all cases and confirmed by a computer tomography pulmonary angiography (ctpa) in two patients. thrombolytic therapy with mg alteplase (actilyse ® ) was indicated in one patient under cardiopulmonary resuscitation and in two patients by severely impaired right ventricular ejection fraction, and was waived in one patient with moderately impaired right ventricular function. immediate thrombolysis lead to successful resuscitation and to a marked improvement in right heart function and gas exchange within min after administration. bleeding complications following alteplase injection occurred in all patients within the following hours requiring transfusion of - units packed red cells as well as minor surgical revision in two patients. three patients survived in good conditions and one patient died from progressive therapy-refractory right heart failure. we carried out a single-centre, prospective, randomized, double-blind trial with the aim of assessing the efficacy of postoperative prophylactic treatment. this prospective study examines the relationship of haemoviscoelastography (hvg) mednord (ukraine co analyser), a viscoelastic test, measures clot formation and includes information on the cellular, as well as the plasmatic coagulation, system and serum anti-xa concentration in patients treated with enoxaparin. patients scheduled for open prostatectomy using epidural anesthesia were enrolled. epidural catheters were removed the morning after surgery before the commencement of subcutaneous enoxaparin mg once daily. venous blood samples were obtained at: ) the induction of anesthesia (baseline), ) immediately before the third dose of enoxaparin operatively; ) h after the third dose postoperatively, and ) immediately before the fifth dose postoperatively. whole blood samples were obtained for haemoviscoelasthgraphy (hvg), activated clotting time, and anti-xa level analyses at each of the four time intervals. at the four sample intervals, the r time (mean ± sem) ( , ± , ; , ± , ; , ± , min) and the κ time ( , ± , ; , ± , ; ± , ± , min) of the hvg were significantly correlated with the expected peak and trough levels of lmwh and serum anti-xa levels (p < . ). after fifth dose immediately, hvg r times exceeded the normal range in of patients ( %). prolongation of r time and κ time on postoperative day may indicate an exaggerated response to lmwh. lowfrequency haemoviscoelastography is a test that could potentially correlate with the degree of anticoagulation produced by low molecular weight heparin enoxaparin. lowfrequency haemoviscoelastography mednord (ukraine co analyser), a viscoelastic test, measures clot formation and includes information on the cellular, as well as the plasmatic coagulation system is a test that could potentially correlate with the degree of anticoagulation produced by lmwh. the r time from the haemoviscogram correlates with serum anti-xa concentration. hvg is a convenient test to measure the degree of anticoagulation from lmwh. despite the evidence of perioperative hypercoagulability in cancer patients, there are no consistent data evaluating the extent, duration, and specific contribution of platelets and procoagulatory proteins by in vitro testing. this study compared efficacy of haemoviscoelastography versus thromboelasthgraphy for monitoring of coagulation imbalance. patients undergoing open surgery for abdominal cancer received mednord (ukraine co analyser) analysis (hvg), a viscoelastic test, measures clot formation and includes information on the cellular, as well as the plasmatic coagulation system. we examined the efficacy of a variety of coagulation tests. a complete coagulation screen, activated clotting time (act), thromboelasthgraphy (teg) and haemoviscoelastography (hvg) were performed before surgery, at the end of surgery, and enoxaparin anticoagulation monitoring on postoperative days , , , and . there were analyzed for the reaction time and the maximal amplitude (ma). we calculated the elastic shear modulus of standard ma (gt) and hvg ma (gh), which reflect total clot strength and procoagulatory protein component, respectively. the difference was an estimate of the platelet component (gp). there was a % perioperative increase of standard ma, corresponding to a % increase of gt (p < . ) and an %- % contribution of the calculated gp to gt. we conclude that serial standard thromboelas-tography and hvg viscoelastic test may reveal the independent contribution of platelets and procoagulatory proteins to clot strength. using multiple linear regression, all coagulation, teg and hvg variabities were used to model postoperative hypercoagulation. results showed that some components of the teg failed to identify hypercoagulation (r < . , p > . ). however, three components of the routine coagulation assay, including bleeding time, prothrombin time, and platelet count could be modeled to show prolonged postoperative hypercoagulability (p < . ). we conclude that all components of the hvg test reflect postoperative coagulopaties, these results suggests that it may be usefull in determining the coagulation status of cancer patients perioperatively. postoperative hypercoagulability, occurring for at least week after major cancer abdominal surgery, may be demonstrated hvg viscoelastotest. hypercoagulability is not reflected completely by standard coagulation monitoring and teg and seems to be predominantly caused by increased platelet reactivity. hvg provides a fast and easy to perform bedside test to quantify in vitro coagulation, may be usefull in determining the coagulation status of cancer patients perioperatively. in the epidural anaesthesia group (n = ), haemoviscoelasthography (hvg) was performed after crystalloid preloading and during the immediate postanaesthesia course. in the general anaesthesia group (n = ) hvg was performed before induction and during the immediate postanaesthesia course. hvg were repeated postoperativly at , and h. [kk] in the preanaesthesia period were similar in both groups. intraoperative blood loss was not significantly different between between the epidural and general anesthesia groups. there was no significant difference in measured coagulation variables between both groups, but there were significant differences in postoperative r, t and f variables (p < , ). in the postanaesthesia period r and t significantly decreased (p < , ), and ar and f increased (p < , ) in general anaesthesia group. the total blood loss after open prostatectomy was correlated (r = , ; p < , ) with the prostatic tissue weight. when the tissue weight resected exceeded g, blood loss was in excess of the linea correlation shown with the weight of resected prostatic tissue. ( , %) patients has significantly increased f (fibrinilytic activity) and h postoperatively. thromboelastography (teg) provides information on patients' coagulation status within minutes. the value of the teg has not been established in general icu patients. we present cases of critically ill patients with bleeding tendency in whom clinical decisions based on conventional laboratory results were modified by teg. we started implementing routine use of teg (haemoscope,usa). we describe patients in whom teg results changed clinical decisions that were taken before information from teg was available. case - y. o parturient admitted with massive pulmonary hemorrhage of unknown etiology. because of concern of a bronchial tear and bronchial arterial source bleeding, angiography with embolization was performed. despite this, bleeding recurred. there were no coagulation abnormalities and the patient was not thrombocytopenic. teg showed significant early thrombolysis and therefore treatment with tranexamic acid begun. within few hours bleeding stopped and did not recur. case - y. o man with autoimmune vasculitis presented with acute on chronic renal failure and epistaxis. after dialysis which was performed without heparin,the patient became hemodynamic unstable,was intubated and ventilated due to massive pulmonary hemorrhage. blood samples showed inr . ,prolonged ptt,normal fibrinogen level,thrombocytopenia and hemoglobin . g/dl. teg showed no primary fibrinolysis. repeated teg with heparinase showed normalization of the teg tracing. it thus evident that the patient did receive heparin during dialysis and the diagnosis of dic was negated. the patient was treated with packed red cells only,and further bleeding was not demonstrated. case - y.o man with status epilepticus due to an a-v malformation and brain edema,developed left arm compartment syndrome secondary to thrombophlebitis. the patient's platelet count was , . he was operated uneventfully without correcting the thrombocytopenia. a few hours later there was bleeding from the operative site. a teg test showed normal parameters. therefore,despite an initial assessment by the surgical team that the reason for bleeding is a coagulopathy,the patient was taken for a re-exploration of the wound. an arterial bleeder was found which was coagulated.conclusion. laboratory abnormalities are critical for making decisions in critically ill patients. occasionally, the clinical setting of bleeding with mild coagulation and platelet count abnormalities, preclude the patient from receiving invasive procedures prior to correction of the abnormality. thromboelastography can identify alteration in platelet number and function and abnormalities in the coagulation system. in our cases teg tracings were performed in addition to other coagulation tests. we found that in some patients as demonstrated here, the information provided by teg is different from that derived from conventional coagulation tests and leads to a change in clinical decisions. candida airway colonization is common in mechanically ventilated icu patients but the implications of this finding are not well appreciated. fluconazole prophylaxis is a reasonable approach to decrease fungal infections in critically ill surgical patients and is routinely administered in all of our cardiac surgery patients that stay in sicu for more than days. the present study was undertaken to evaluate the incidence and clinical significance of positive bronchial secretion cultures (bsc) for candida in mechanically ventilated cardiac surgery patients, who were febrile (t> c) after the first h in sicu. positive bsc for candida developed in . % of our general sicu population ( . % after cabg, . % after vr, . % after cabg+vr and % in others). the average time for candida airway colonization of sputum was . ± d. the vast majority ( %) of patients developed positive bsc prior to initiation of fluconazole prophylaxis ( pts within - d, pts within - d and pts after d of sicu stay). the icu stay ( ± d), hospital stay ( ± d) and mortality ( %) were significantly higher in patients with positive bsc for candida, compared to the general sicu population (icu stay . ± . d, hospital stay . ± d, mortality . %). candida airway colonization of febrile cardiac surgery patients after the first h in sicu is associated with a grave prognosis and could be a marker of compromised immune response. this colonization appears early in the course of icu stay and therefore the initiation of earlier fluconazole prophylaxis may be necessary. the current incidence of ie is estimated as cases per . population per year and continues to increase. the prognosis is significantly influenced by proper diagnosis and adequate therapy. cardiac surgery for active ie is established as a cornerstone therapy as it is required in % of patients but remains a challenging and high-risk procedure. the purpose of this study was to analyze the clinical characteristics of the patients underwent cardiac surgery for active ie in our center for a -month period. to evaluate principal indications for cardiac surgery and assess the major causes of surgical morbidity and mortality in ie patients. retrospective review of ie cases who underwent cardiac surgery from december to november in our -bed csicu. we collected age, gender, site of endocarditis, native or prosthetic, microbiological agent, indication of surgery, postoperative complications, icu stay and mortality. . patients with ie underwent surgical intervention in acute phase of infection. their ages ranged from to years (mean , ) and % were males. the causative agents were: streptococci-enterococci ( %), staphylococci ( %), candida spp ( %), pseudomonas aeruginosa ( %). the principal indications for cardiac surgery were development of heart failure due to severe heart valve defects or prosthetic valve dysfunction and intracardiac abscess. all patients had positive blood culture endocarditis but only two were still positive before operation. cases of aortic valve involvement were the most frequent, followed by cases of mitral valve endocarditis. native valve endocarditis prevailed over the prosthetic ones versus . surgery was performed using a mechanical prosthesis of the infected valve. in patients the procedure was complemented with tricuspid valve annuloplasty. patients underwent bentall procedure. the mean icu stay was , days (range to ). thirty-days mortality of patients undergone surgery for ie was %, patients died in the icu. operation for active ie carries a relatively higher mortality in comparison with elective surgery. an indication of surgery depends on several clinical variables but the main indication remains heart failure due to severe heart valve defect or prosthetic valve dysfunction. a high degree of clinical suspicion, at an early diagnosis, and indication of surgical treatment prior to deterioration of ventricular function and installation of generalized sepsis may improve prognosis. severe sepsis is a major cause of morbidity and mortality following major surgery. factors that are associated with an increased risk of sepsis following surgery include emergency surgery, patient comorbidities and degree of surgical insult. the risk of developing severe sepsis following major surgery for cancer has been shown to relate to the charlson comorbidity score , with a higher score predicting a greater risk of developing severe sepsis .we conducted a prospective observational study in order to investigate whether the charlson score could be correlated to the risk of developing sepsis following elective major general surgery in patients without cancer. we collected data on patients undergoing elective major surgery in a large teaching hospital. the charlson comorbidity index was calculated preoperatively for each patient. the patients were followed up for days postoperatively, and signs of the systemic inflammatory response syndrome (sirs), sepsis and septic shock were documented each day. the source of sepsis was recorded, if present. admission to critical care bed was also documented. . data was complete on patients, ( . %) were male, and ( . %) had cancer. the median age of the patients was years. mean operation time was hours, and mean transfusion requirement intraoperatively was . units. the median charlson score was . ( . %) patients were admitted to a critical care bed for reasons other than routine postoperative care. ( . %) patients developed sirs postoperatively. ( . %) patients developed sepsis postoperatively, and ( . %) of these went on to develop septic shock. there was a progressive, but non-significant difference in charlson score in those patients who developed septic shock or sepsis and those who did not. those patients who developed septic shock had a mean charlson score of . , while those with sepsis had a mean charlson score of . . those patients who did not develop sepsis had a mean charlson score of . . sepsis and septic shock are common after elective major surgery, but the charlson comorbidity index was not a useful predictor of the likelihood of developing sepsis in our population of cancer and non-cancer patients. rate of neurological complications after central nerve blockade is < . % ( ) and spinal epidural abscess vary from : to : ( ) . we audited the complications following epidural analgesia in postoperative patients admitted to our critical care unit with sepsis. we performed a retrospective case note review of all septic patients who had epidural analgesia for postoperative pain relief or for weaning from mechanical ventilation. all patients who had a major laparotomy and sepsis were included. we looked into the complications of epidural during insertion, usage and after removal of epidural catheter. patients were followed up by the critical care outreach and acute pain teams on discharge from the critical care unit. data are presented as mean and standard deviation. in a year period there were septic patients who had epidural analgesia. of these were commenced immediately prior to the laparotomy and were inserted in itu to enable weaning from mechanical ventilation. the male: female ratio was : with an average age of . ( . ). there were patients with or more organ failure. only ( . %) patients had positive blood cultures during the period of epidural analgesia. multiple attempts at epidural insertion were found in patients. mean duration of epidural catheter was . ( . ) there were survivors and non-survivors in this group. of the nonsurvivors died during the period epidural analgesia. the other nonsurvivors were followed up for an average period of . days and a median duration of days after the epidural catheter was removed. none of the patients developed any complications attributable to the epidural. the serious complications of epidural analgesia like epidural abscess and nerve injuries, although rare, are reported in case series( ). we did not note any adverse complications of epidural analgesia in this high risk group of septic patients admitted to the critical care unit. key: cord- -x uxdi authors: daniel, dennis a.; poynter, sue e.; landrigan, christopher p.; czeisler, charles a.; burns, jeffrey p.; wolbrink, traci a. title: pediatric resident engagement with an online critical care curriculum during the intensive care rotation* date: - - journal: pediatr crit care med doi: . /pcc. sha: doc_id: cord_uid: x uxdi residents are often assigned online learning materials as part of blended learning models, superimposed on other patient care and learning demands. data that describe the time patterns of when residents interact with online learning materials during the icu rotation are lacking. we describe resident engagement with assigned online curricula related to time of day and icu clinical schedules, using website activity data. design: prospective cohort study examining curriculum completion data and cross-referencing timestamps for pre- and posttest attempts with resident schedules to determine the hours that they accessed the curriculum and whether or not they were scheduled for clinical duty. residents at each site were cohorted based on two differing clinical schedules—extended duration (> hr) versus shorter (maximum hr) shifts. setting: two large academic children’s hospitals. subjects: pediatric residents rotating in the picu from july to june . interventions: none. measurements and main results: one-hundred and fifty-seven pediatric residents participated in the study. the majority of residents ( / ; %) completed the curriculum, with no statistically significant association between overall curriculum completion and schedule cohort at either site. residents made more test attempts at nighttime between pm and am ( , / , ; %) regardless of whether they were scheduled for clinical duty. approximately two thirds of test attempts ( , / , ; %) occurred when residents were not scheduled to work, regardless of time of day. forty-two percent of all test attempts ( , / , ) occurred between pm and am while off-duty, with % ( / , ) occurring between midnight and am. conclusions: residents rotating in the icu completed online learning materials mainly during nighttime and off-duty hours, including usage between midnight and am while off-duty. increasing nighttime and off-duty workload may have implications for educational design and trainee wellness, particularly during busy, acute clinical rotations, and warrants further examination. i n busy clinical rotations such as the icu, patients, diagnoses, and clinical acuity vary between rotations, and limited time and competing demands are common for both trainees and faculty ( ) . supplementing the icu rotation experience with a blended online educational curriculum may help improve knowledge and ensure consistent exposure to core content ( ) , but these resources are often superimposed on the demands of patient care and other educational experiences ( ) . for our icu residents, we designed curricula that included short videos with pre-and posttests and hypothesized that residents would use these materials most frequently during breaks in patient care while on clinical duty. however, there is a lack of previously published data that describe when and to what extent resident physicians complete online materials during icu rotations. such understanding would help inform decisions about how to best implement educational interventions for residents rotating in the demanding, high-acuity clinical setting of the icu. we conducted a prospective cohort study examining junior (post-graduate year ) resident use of online curricula during their first rotation in medical-surgical picus at two large academic children's hospitals (boston children's hospital and cincinnati children's hospital) that are similar in size, patient population, and resident scope of responsibility. this study was approved by the institutional review boards at both sites. icu resident rotation directors created individualized curricula for each site that covered core concepts in pediatric critical care medicine. both sites also provided in-person educational experiences (bedside teaching, didactic lectures, and manikin-based simulations). site delivered in-person education between : and : every weekday, and site did so between : and : every monday through thursday. we administered the online curricula from july to june at site and june to june at site . neither site provided protected time for curriculum completion. although residents were informed of the expectation to complete curricula by the end of their icu rotation, there were no formal consequences for failing to complete. at both sites, residents were e-mailed weeks before their rotation and instructed to complete the curriculum before the end of their icu rotation, with e-mail reminders provided at rotation weeks , , and . residents were excluded from the time-of-use analysis if their daily schedule data were unavailable. curricula were delivered on openpediatrics (www.openpediatrics.org), which is based at site . each lesson contained a pretest, video, and posttest. the curriculum contained lessons at site and lessons at site . individual lesson videos ranged in length from to minutes (average length min). the total curriculum video duration at site was hours, minutes and at site was hours, minutes. the website required strictly linear progress; a pretest, then video, then posttest for each lesson needed to be completed before a resident could progress to the next lesson. residents were only able to take the pretest once, but posttests could be attempted multiple times until the minimum passing score (≥ %) was achieved. the platform allowed residents to stop and restart within preor posttests, as well as within videos, if they did not complete a given item in one sitting. during the study interval, residents worked within two different clinical schedules as part of a concurrent trial of resident physician work hours randomized order safety trial evaluating resident schedules ( ), where each schedule operated for year of clinical rotations at each site. one schedule cohort involved daytime and nighttime work shifts limited to a maximum of hours of duration, whereas the second involved traditional extended duration (> hr) work shifts, with daytime shifts alternating with extended duration work shifts every fourth night. on average, residents worked about % more hours per week on the extended duration work schedule ( ) . throughout this article, we refer to these differing schedule cohorts as "short call" and "long call". we collected curriculum completion data for each resident and timestamps for every pre-and the first posttest attempt that occurred during the icu rotation and in the days preceding. we did not include test attempts occurring prior to the icu rotation in the time-of-use analysis due to the significant heterogeneity in resident clinical rotations immediately prior to the icu rotation. we only included the first posttest attempt to avoid over-representing a given time of day if a user attempted a posttest multiple times. video viewing activity is captured only in aggregate, deidentified fashion on the platform, so individual video view timestamps were not available for specific residents. for test attempts during the icu rotation, we cross-referenced timestamps with each resident's schedule to determine whether or not they were scheduled for clinical service in the hospital. we calculated frequencies and percentages for resident and site characteristics and compared data between cohorts and between sites using chi-square tests of independence using a significance level of . . data were analyzed using stata/se . (statacorp, college station, tx) and microsoft excel (microsoft corp., washington, dc). during the study, residents rotated through the icu for the first time, and % ( / ) accessed the curriculum. fifty-three percent of residents ( / ) accessed the curriculum during the icu rotation at least once while on duty. seven residents at site accessed the curriculum during the rotation but did not have daily schedule data available for analysis. we included residents ( / ; %) in the time-of-use analysis. there were no statistically significant differences in demographic characteristics (gender or residency track) between the two sites or between the schedule cohorts within each site. sixty-eight percent of residents ( / ) completed the curriculum ( table ) . a greater percentage of residents completed the curriculum at site ( / ; %) compared with site ( / ; %), p value of less than . . there was no statistically significant association between overall curriculum completion and schedule cohort at either site. we included , test attempts by residents from the two sites in the time-of-use analysis. of the test attempts made during clinical duty, % ( / , ) occurred during daytime shifts versus % ( / , ) at night. approximately two thirds of test attempts ( , / , ; %) occurred when residents were not scheduled to work, regardless of time of day. approximately two thirds of all test attempts ( , / , ; %) occurred during nighttime hours (between pm and am), regardless of work status (fig. a) of all test attempts occurring between midnight and am while residents were not scheduled to work. we observed an association between time-of-use patterns and schedule cohort at site but not at site . at site , residents in the long call cohort used the curriculum more during nighttime hours ( / ; %) compared with residents in the short call cohort ( / ; %), p value of less than . . the long call cohort also used the curriculum more during times when they were not scheduled to work ( / ; %) compared with the short call cohort ( / ; %), p value of less than . . figure b displays the distribution of test attempts by day of rotation, ranging from days prior to the start of the rotation to days after the start date. for test attempts within the icu rotation, a greater proportion occurred in the second half of the rotation ( , / , ; %) versus the first half ( , / , ; %). three hundred and forty-eight additional test attempts occurred prior to the start of the rotation, the majority of which ( / ; %) were in the days immediately prior. using years of timestamped online learning data from two large pediatric residency programs, we found that the majority of residents in our study accessed a supplemental online curriculum during the icu rotation. however, despite designing the icu curriculum to include short lessons that could be completed during breaks from clinical work while on duty, only half of the included residents accessed the curriculum during clinical periods, and they frequently chose to use the materials during nighttime hours and when not scheduled to work clinically. notably, % of test attempts occurred between midnight and am while residents were not scheduled to work. test attempts were made immediately prior to, and throughout the rotation, with a majority occurring in the second half of the rotation. the inconsistent association of completion rate or time of use with schedule cohort makes it less likely that the type of schedule is a main contributor to online curriculum engagement. because both sites provided in-person educational experiences during most workdays in addition to the online curriculum, it is possible that residents were biased against completing online materials while on-duty, since other materials were already being presented during on-duty hours. other studies have supported the notion that medical learners often prefer online learning to be supplementary to in-person learning experiences ( , ) . the greater proportion of on-duty use at night compared with during the daytime may be a consequence of the greater volume of clinical care demands requiring resident attention during the day, including but not limited to rounds and scheduled admissions. the greater number of test attempts in the second half of the rotation may reflect residents catching up on incomplete lessons before the end of the rotation or may be related to residents focusing on getting comfortable in the clinical environment before turning their attention to self-directed learning. several studies have highlighted successful implementation and outcomes of online medical learning, noting improvements in knowledge ( ) and perceived utility and satisfaction from clinicians and instructors ( ) . however, although residents have always incorporated self-directed learning at night and during off hours, blended learning models that increase trainees' obligatory nonclinical workload outside of dedicated educational time may have a different impact. despite our intention to provide short lessons that would provide education during breaks from patient care, residents accessed the curriculum more often during nonclinical hours. previous reports have commented on the need to consider the distinct time constraints and serviceeducation task conflicts in graduate medical education ( ) and on the risk of creating information overload when educational content is shifted to the online environment ( ) . increases in workload added to preexisting stressors of the clinical learning environment can contribute to resident physician burnout ( , ) and sleep deprivation. sleep deficiency is known to adversely impact resident clinical performance ( ) and increases risk of physical harm, such as motor vehicle crashes ( ) and needlestick/sharps injuries ( ) . therefore, program and rotation directors of busy, inpatient rotations may need to consider alternative approaches to implementing online learning, such as incorporating protected time to complete curricula; making the curriculum optional or controlling the volume of content shifted to the asynchronous, self-directed setting ( , , ) . our study has several important limitations. as this was a purely an observational study, we did not qualitatively assess resident motivations for why they accessed the curricula at the times they did nor did we formally survey participant satisfaction with the curriculum or any potential impact on their wellness. these are important areas that warrant further investigation. additionally, not all residents completed the online curricula, and rates of curriculum completion differed between the two sites despite having identical procedures to encourage completion. this may reflect differences in willingness to engage with online curricula during clinical rotations between residents and between the two sites, which may have led to a sampling bias. interestingly, despite the fact that openpediatrics (https:// www.openpediatrics.org/) is primarily based at site , curriculum completion rate was lower at that site, suggesting that there was not increased pressure among residents to use the platform due to the shared institutional affiliation. although we have no reason to suspect differences in resident roles or workload between the sites, we did not directly assess this either. curricular length has also been described as a barrier to curriculum completion ( , ) ; however, we observed higher completion rates by residents at the site with the longer curriculum. our data show that residents will engage with online learning materials during and immediately prior to their icu rotation but do so most often at nighttime and when off-duty, with a portion of use occurring during midnight and am while offduty. this may have implications for resident well-being, including sleep, personal life disruptions, and/or burnout, and warrants further examination. program and rotation directors will need further guidance on how best to implement blended learning models in busy clinical rotations, such as the icu. we wish to thank the residents at boston children's hospital and cincinnati children's hospital for their participation in this study, as well as the administrative staff at both hospitals and at openpediatrics who provided coordination and support for this study. drs. poynter's, landrigan's, and czeisler's institutions received funding from the national heart, lung, and blood institute (nhlbi), and they received support for article research from the national institutes of health. dr. landrigan received funding from midwest hospital association/executive speakers bureau and midwest lighting institute; he reports receiving grants from patientcentered outcomes research institute, consulting fees, and equity from the i-pass patient safety institute, and consulting fees from virgin pulse; and he has received monetary awards, honoraria, and travel reimbursement from multiple academic and professional organizations for teaching and consulting on sleep deprivation, physician performance, handoffs, and safety and has served as an expert witness in cases regarding patient safety and sleep deprivation. drs. landrigan and czeisler report being principal investigators of the randomized order safety trial evaluating resident-physician schedules, which is supported by grants (u -hl- and u -hl- ) from the nhlbi. dr. czeisler serves as the incumbent of a harvard medical school professorship that was endowed in by cephalon, inc., which has been since been acquired by teva pharmaceutical industries ltd., and he is supported in part by funding from the national institute of occupational safety and health r -oh- . dr from ganésco and zurich insurance, and fees for serving as a member of an advisory board from the institute of digital media and child development and the klarman family foundation, holding a number of process patents in the field of sleep and circadian rhythms (e.g., photic resetting of the human circadian pacemaker) and an equity interest in vanda pharmaceuticals, being the incumbent of an endowed professorship provided to harvard university by cephalon, receiving fees for serving as an expert on various legal and technical cases related to sleep or circadian rhythms from casper sleep, comair/delta airlines, complete general construction, fedex, greyhound, hg energy, purdue pharma, south carolina central railroad, steel warehouse, stric-lan, texas premier resources, and united parcel service, and receiving royalties from the new england journal of medicine, mcgraw-hill, houghton mifflin harcourt/penguin, and from philips respironics for the actiwatch and actiwatch spectrum devices. dr. czeisler's interests were reviewed and managed by brigham and women's hospital and partners healthcare in accordance with their conflict of interest policies. the remaining authors have disclosed that they do not have any potential conflicts of interest. this study was approved by the institutional review boards at both participating sites prior to data collection and analysis. for information regarding this article, e-mail: dennis.daniel@childrens.harvard.edu balancing service and education in residency training: a logical fallacy flipped classrooms in graduate medical education: a national survey of residency program directors a systematic review of the effectiveness of flipped classrooms in medical education rosters study group: design and recruitment of the randomized order safety trial evaluating resident-physician schedules (rosters) study effects on resident work hours, sleep duration, and work experience in a randomized order safety trial evaluating resident-physician schedules (rosters) blended learning: how can we optimise undergraduate student engagement the effectiveness of online and blended learning: a meta-analysis of the empirical literature internet-based learning in the health professions: a meta-analysis the impact of e-learning in medical education flipping out: does the flipped classroom learning model work for gme? twelve tips for "flipping" the classroom a narrative review on burnout experienced by medical students and residents effect of reducing interns' work hours on serious medical errors in intensive care units extended work shifts and the risk of motor vehicle crashes among interns resident wellness matters: optimizing resident education and wellness through the learning environment effects of health care provider work hours and sleep deprivation on safety and performance advances in medical education and practice: student perceptions of the flipped classroom impact of required versus self-directed use of virtual patient cases on clerkship performance: a mixedmethods study efficacy of an asynchronous electronic curriculum in emergency medicine education in the united states massive open online course completion rates revisited: assessment, length and attrition key: cord- -p s p fd authors: decavèle, maxens; gatulle, nicolas; weiss, nicolas; rivals, isabelle; idbaih, ahmed; demeret, sophie; mayaux, julien; dres, martin; morawiec, elise; hoang-xuan, khe; similowski, thomas; demoule, alexandre title: one-year survival of patients with high-grade glioma discharged alive from the intensive care unit date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: p s p fd introduction: only limited data are available regarding the long-term prognosis of patients with high-grade glioma discharged alive from the intensive care unit. we sought to quantify -year mortality and evaluate the association between mortality and ( ) functional status, and ( ) management of anticancer therapy in patients with high-grade glioma discharged alive from the intensive care unit. patients and methods: retrospective observational cohort study of patients with high-grade glioma admitted to two intensive care units between january and june . functional status was assessed by the karnofsky performance status. anticancer therapy after discharge was classified as ( ) continued (unchanged), ( ) modified (changed or stopped), or ( ) initiated (for newly diagnosed disease). results: ninety-one high-grade glioma patients ( % of whom had glioblastoma) were included and ( %) of these patients were discharged alive from the intensive care unit. anticancer therapy was continued, modified, and initiated in %, %, and % of patients, respectively. corticosteroid therapy at the time of icu admission [odds ratio (or) . ] and cancer progression (or . ) was independently associated with continuation of anticancer therapy. the mortality rate year after icu admission was %. on multivariate analysis, continuation of anticancer therapy (or . ) and karnofsky performance status on admission (or . ) were independently associated with lower -year mortality. conclusion: the presence of high-grade glioma is not sufficient to justify refusal of intensive care unit admission. performance status and continuation of anticancer therapy are associated with higher survival after intensive care unit discharge. previous presentation: preliminary results were presented at the most recent congress of the french intensive care society, paris, . electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. patients with solid tumor or hematologic malignancies account for % of intensive care unit (icu) admissions [ , ] . because the prognosis of cancer patients is similar to that of non-cancer patients [ , ] , a diagnosis of cancer should not preclude icu admission. this general rule also applies to patients with primary malignant brain tumors admitted to the icu [ ] . the outcome of patients with primary malignant brain tumors has been described in terms of short-term and medium-term mortality [ ] [ ] [ ] . however, data on -year mortality in these patients discharged alive from the icu are lacking [ ] [ ] [ ] [ ] [ ] , and previous series included mixed highgrade gliomas (hgg), low-grade gliomas, and primary central nervous system lymphomas which have a heterogeneous prognosis [ ] [ ] [ ] . in addition, the impact of an icu stay on health-related performance status and the opportunity to continue anticancer therapy remains unclear [ ] [ ] [ ] [ ] . these last two points are of utmost importance, as a marked reduction of performance status is commonly observed in patients electronic supplementary material the online version of this article (https ://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. requiring mechanical ventilation or vasopressors [ ] [ ] [ ] [ ] [ ] . in turn, this poor performance status at icu discharge may jeopardize long-term outcome by postponing or canceling anticancer therapy [ , ] . this risk is particularly high in patients with primary malignant brain tumors, as these tumors are known to reduce performance status [ ] [ ] [ ] , especially in patients with hgg. we designed the present study to identify factors associated with -year outcomes in patients with hgg who survived an unplanned medical icu stay. in addition, we examined changes in performance status and changes in the management of anticancer therapy after icu discharge. this study focused on a homogeneous population of hgg, corresponding to majority of primary brain tumors with the most severe prognosis and raising the most challenging decisions concerning icu admission. our hypotheses were that, among hgg patients discharged alive from the icu: ( ) a substantial proportion of patients would still be alive year after icu discharge, with relatively good performance status, ( ) anticancer therapy could be continued in a substantial proportion of patients, and ( ) the performance status at icu admission and maintenance of anticancer therapy were associated with a higher -year survival rate. the study was conducted from january to june in two medical icus: a -bed icu in a pulmonology department and a -bed icu in a neurology department. both icus are located in a university hospital with a strong neurological orientation including a specific neuro-oncology department (about newly diagnosed patients each year) and the national reference center for high-grade oligodendroglial tumor (i.e., pola network). this study was approved by the french intensive care society institutional review board (ce srlf - ) and information was given to the patients or their relatives. data from this cohort have been previously published [ , ] . data were extracted from a prospectively managed database that comprehensively describes all patient stays in the two icus (fusion, varimed, france). the database of the two icus comprised , records, corresponding to % of admissions over the study period. in patients with several readmissions, only the first stay was included in the analysis. this set of , records was retrospectively searched for all consecutives cases of hgg, defined as grade iii (anaplastic astrocytoma and oligodendroglioma) and grade iv (glioblastoma) glioma according to the world health organization (who) classification of tumors of the central nervous system [ ] . patient who underwent recent neurosurgery (< weeks) or any other recent surgery (< weeks) and patients under the age of years were excluded. at the time of admission, gender, age, comorbidities using the charlson comorbidity index (cci) [ ] , physiological variables such as body temperature, respiratory rate, heart rate, systolic blood pressure, and glasgow coma scale and various laboratory variables were recorded. severity on admission was assessed by the simplified acute physiology score (saps) ii [ ] and the sequential organ failure assessment (sofa) [ ] . performance status was assessed during the week before icu admission and , , , , and months after icu admission, using the karnofsky performance status scale [ ] . the tumor type was determined histologically on either the resection specimen or a biopsy. idh / mutation and p/ q codeletion molecular status were also collected when available (systematic testing in our center since ). the reason for admission was determined retrospectively from the conclusions of the medical records. in case of admission for coma, the diagnosis of seizures was adopted when abnormal movements highly suggestive of seizures were observed, with or without electroencephalographic confirmation, or in the absence of suggestive movements, by consciousness alteration associated with electroencephalographic confirmation of seizures. cancer disease status was classified as controlled (partial response, complete response, or stable disease), in progression, or newly diagnosed when the cancer was diagnosed during or after icu admission or when the cancer was diagnosed during the weeks preceding the icu stay and no anticancer therapy had yet been delivered. anticancer therapy after icu discharge was classified as follows: ( ) continued, when the anticancer therapy planned and initiated before icu admission was continued unchanged after icu discharge, ( ) modified, when the anticancer therapy planned and initiated before icu admission was changed or stopped after icu discharge, and ( ) initiated, when, for patients with newly diagnosed cancer, anticancer therapy was initiated during or after the icu stay. anticancer therapy only comprised chemotherapy and radiation therapy. we also recorded whether or not patients were receiving corticosteroid therapy at the time of icu admission. the presence of corticosteroids at admission was not considered to constitute anticancer therapy. finally, advanced life support measures taken during the icu stay and vital status year after icu admission ( -year mortality) were recorded. continuous variables were reported as median and interquartile interval, and categorical variables were reported as frequencies (%). categorical variables were compared using the chi-square test or fisher's exact test, as appropriate. continuous variables were compared using the mann-whitney test or the kruskal-wallis test. all tests were two-sided and p values < . were considered statistically significant. multivariate logistic regression was performed to identify factors associated with one-year mortality after icu admission. in patients receiving anticancer therapy prior to admission, multivariate logistic regression was performed to identify factors associated with continuation of anticancer therapy. factors yielding p values < . or considered to be clinically relevant were entered in the model and missing data (l. %) were imputed by the nearest-neighbor method. odds ratios (ors) and their % confidence intervals (ci) were calculated for significant factors. one-year survival according to continuation of anticancer therapy after icu discharge was evaluated using kaplan-meier survival function estimates. the impact of anticancer therapy on survival was assessed with the log-rank test. the karnofsky performance status was analyzed using a linear mixed model with anticancer therapy and times as fixed-effect factors, and the patient as random-effect factor. the linear mixed model was fitted with the restricted maximum-likelihood method. post hoc tests of significance of the fixed-effect factor between pairs of conditions were performed with a likelihood ratio test. statistical analyses were performed using r version . . . and matlab version . . . (r a). figure displays the study flowchart. of the patients included, ( %) were admitted to the medical icu and ( %) were admitted to the neurological icu. the diagnosis of hgg was confirmed histologically in all patients and was based on examination of the surgical resection specimen for ( %) patients or a biopsy specimen for ( %) patients. the main characteristics of the patients are displayed in table . tumor types were distributed as follows: ( %) glioblastomas (grade iv), ( %) anaplastic astrocytomas (grade iii), and ( %) anaplastic oligodendrogliomas (grade iii). the cancer diagnosis was initiated or established during the icu stay for ( %) patients and was established prior to icu admission for the remaining ( %) patients; median time between cancer diagnosis and icu admission was ( - ) months. icu and hospital lengths of stay were ( - ) and ( - ) days, respectively. seventy-eight patients ( %) were discharged alive from the icu. among the icu survivors, anticancer therapy was continued in ( %) patients, modified in ( %) patients, and initiated in ( %) patients. table shows the factors associated with continuation or modification of anticancer therapy after icu discharge. on multivariate logistic regression, two factors were independently associated with continuation of anticancer therapy after icu discharge: cancer progression at icu admission (or . , % ci . - . , p = . ) and use of corticosteroids (or . , % ci . - . , p = . ) at icu admission. the mortality rate year after icu discharge was % ( / patients). table depicts the factors associated with mortality year after icu admission identified by univariate analysis. on multivariate logistic regression analysis, two factors were independently associated with lower mortality year after icu admission: continuation of anticancer therapy after icu discharge (or . , % ci . - . , p = . ), and karnofsky performance status at icu admission (or . , % ci . - . , p < . ). cumulative survival probability significantly differed between patients in whom anticancer therapy was continued, modified, or initiated (fig. ) , with the greatest survival probability observed among patients in whom anticancer therapy was continued. figure shows changes in karnofsky performance status from icu admission to year after icu discharge in icu survivors, according to management of anticancer therapy. karnofsky performance status was significantly different between the three anticancer therapy strategies and was the lowest in patients with anticancer therapy modified. karnofsky performance status year after icu admission was > % in more than % of patients in whom anticancer therapy was initiated or continued. the main results of the study can be summarized as follows: in hgg patients discharged alive after an unplanned medical icu stay ( ), we observed a substantial proportion of survivors year after icu admission (more than one quarter of patients) and most of these patients exhibited relatively favorable performance status even year after icu admission, ( ) continuation of anticancer therapy was possible in almost % of patients and was strongly associated with cancer progression and use of corticosteroids at admission, and ( ) continuation of anticancer therapy and karnofsky performance status at admission were associated with higher -year survival rates. to the best of our knowledge, this is the first report based on a homogeneous cohort of patients with hgg discharged alive after an icu stay, focusing on -year mortality, health-related functional status, and management of anticancer therapy after icu discharge. first of all, the low icu mortality rate observed in this study ( %) is consistent with recent findings, showing that icu mortality is not higher in patients with primary malignant brain tumor than in patients with other types of solid cancer ( , - ) and patients without cancer [ , ] . the survival rate of hgg patients year after icu admission observed in the present study was non-negligible ( %) and most patients still presented favorable performance status at year (> %). indeed, considering the median time between cancer diagnosis and icu admission [ ( - ) months] and considering the median survival of patients with hgg [ ] , the % survival after icu admission observed in this study appears to be substantial and encouraging. moreover, the survival rate year after icu admission was fairly similar to that observed in patients with other types of solid cancer [ , , [ ] [ ] [ ] [ ] or hematologic malignancies [ ] [ ] [ ] [ ] [ ] . young age, limited comorbidities, and a high proportion of rapidly reversible causes, such as seizures, could explain this relatively high -year survival rate. the performance status observed over the study period is consistent with a previous report of primary malignant brain tumor patients admitted to the icu [ ] . in addition, our study shows that more than one-half of patients achieved a performance status, indicating that they were able to selfcare at home (karnofsky performance status ≥ %) [ ] . this is a valuable observation when assessment of functional outcome is considered to be essential to evaluate the relevance of icu admission or maintenance of intensive therapy. to date, only a few studies have explored the impact of an icu stay on anticancer therapy and the long-term outcome after icu discharge [ ] [ ] [ ] ] . the rate of continuation of anticancer therapy observed in our study was similar to that reported in other studies [ ] [ ] [ ] [ ] . two factors, cancer progression and use of corticosteroids, were independently associated with failure to continue anticancer therapy in icu survivors. while there is an obvious relationship between cancer progression and modification of anticancer therapy, the link between the use of corticosteroids and modification of anticancer therapy is less obvious and could be explained by the fact that corticosteroid prescription is generally driven by the presence of perilesional brain edema or neurological symptoms, which are both surrogates for disease activity [ ] . corticosteroid administration is a marker of poor disease control, often requiring modification of anticancer therapy. this finding is also in line with the fact that the cumulative corticosteroid dose delivered to patients with primary malignant brain tumor is associated with higher mortality [ ] and decreased progression-free survival [ ] . the strong influence of anticancer therapy management after icu discharge on -year survival is also in line with the other reports concerning patients with solid cancer or hematologic malignancies, in whom -month [ , ] and -year [ ] survivals were higher in patients in whom anticancer therapy was continued after icu discharge. interestingly, we did not observe a higher survival rate in patients in whom anticancer therapy was initiated for a newly diagnosed cancer, which is consistent with the previous reports on patients admitted to the icu with a newly diagnosed cancer, supporting the idea that critically ill patients with underlying undiagnosed cancer are likely to present locally advanced or metastatic disease with poor medium- [ ] and long-term prognosis [ ] . in these reports, karnofsky performance status at icu admission was also independently associated with long-term mortality [ , ] . the present study has several limitations. first, it was a retrospective study, which implies a potential bias in patient selection or data collection. however, data were extracted from a prospectively managed database and the rarity of the disease remains a major obstacle to prospective studies, even with a multicenter design. second, the relevance of karnofsky performance status as a health-related functional endpoint in this very specific population could be questioned. it is possible that other decisive aspects of quality of life, psychological states, and cognitive function, all likely to be impaired in hgg [ , ] , were ignored. third, while we report data for patients admitted to the icu, we did not report the proportion of hgg patients for whom icu admission was refused during the study period, or the policies or criteria that motivated these refusals, and it is possible that patients with the poorest prognosis were, therefore, not admitted to the icu and, thus, not included in this analysis. finally, because molecular testing has been systematically performed only since , whereas the study period started in , this study comprises many missing data and consequently failed to demonstrate any association between molecular testing and prognosis [ ] . in conclusion, we report that a high proportion of hgg patients who survived an icu stay may benefit from continuation of anticancer therapy after discharge, with preserved performance status, and can, therefore, expect a non-negligible survival year after icu admission. simple factors, which can be easily identified before icu admission, such as cancer progression, use of corticosteroids, or karnofsky performance status at admission, are strongly associated with outcomes. if decisions concerning life-sustaining interventions are no longer considered to be futile in patients with active cancer, even metastatic cancer, a similar attitude could also be applied to hgg patients, who have probably been unreasonably denied icu admission for many years. these results will certainly contribute to refine icu admission policies which, in every case, should take into account the neuro-oncologists' experience and the patient's willingness. from norgine and alpha-wasserman and consultant fees from med-day pharmaceuticals. ahmed idbaih reports research funding from la fondation arc pour la recherche sur le cancer, carthera, beta-innov, and intselchimos; travel funding from hoffmann-la roche; and personal fees from novartis, la lettre du cancérologue, bms, and cipla unrelated to the submitted work. other authors had no conflict of interest to declare. the study was approved by the french intensive care society institutional review board (ce srlf - ) and information was given to the patients or their relatives. incidence, life expectancy and prognostic factors in cancer patients under prolonged mechanical ventilation: a nationwide analysis of cases during the impact of critical illness on perceived health-related quality of life during icu treatment, icu stay, and after icu discharge long-term survival, quality of life, and quality-adjusted survival in critically ill patients with cancer quality of life after intensive care: a systemic review of the literature long-term health-related quality of life of critically ill patients with haematological malignancies: a prospective observational multicenter study review on quality of life issues in patients with primary brain tumors health-related quality of life in patients with high grade gliomas: a quantitative longitudinal study glioblastoma and other malignant gliomas: a clinical review the world health organization classification of tumors of the central nervous system: a summary a new method of classifying prognostic comorbidity in longitudinal studies: development and validation new simplified acute physiology score (saps ii] based on a european/north american multicenter study the sofa (sepsis-related organ failure assessment] score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine karnofsky performance status revisited: reliability, validity, and guidelines characteristics and outcomes of cancer patients in european icus intensive care unit outcomes among patients with lung cancer in the surveillance, epidemiology, and end results-medicare registry urgent chemotherapy for life-threatening complications related to solid neoplasms in-hospital and -day survival of critically ill solid cancer patients after discharge of intensive care units: results of a retrospective multicenter study-a groupe de recherche respiratoire en reanimation en onco-hématologie (grrr-oh) study lung cancer in critical care (lucca) study investigators characteristics and outcome of patients with newly diagnosed advanced or metastatic lung cancer admitted to intensive care units (icus) determinants of -year survival in critically ill acute leukemia patients: a grrr-oh study outcomes and prognostic factors in patients with haematological malignancy admitted to a specialist cancer intensive care unit: a yr study outcome and early prognostic indicators in patients with a hematologic malignancy admitted to the intensive care unit for a life-threatening complication outcome of critically ill allogeneic hematopoietic stemcell transplantation recipients: a reappraisal of indications for organ failure supports time trend analysis of long-term outcome of patients with malignancies admitted at dutch intensive care units use of dexamethasone in patients with high-grade glioma: a clinical practice guideline impact of overall corticosteroid exposure during chemoradiotherapy on lymphopenia and survival of glioblastoma patients steroids use and survival in patients with glioblastoma multiforme: a pooled analysis idh mutation status and role of who grade and mitotic index in overall survival in grade ii-iii diffuse gliomas affiliations maxens decavèle , · nicolas gatulle · nicolas weiss , · isabelle rivals , · ahmed idbaih · sophie demeret · julien mayaux · martin dres , · elise morawiec · khe hoang-xuan service de pneumologie brain liver pitié-salpêtrière (blips) study group, inserm umr_s acknowledgements we thank anthony saul for his help with english style and grammar. availability of data and material our data are available to ensure transparency. key: cord- -zsoc wec authors: martin-loeches, ignacio; leone, marc; einav, sharon title: antibiotic prophylaxis in the icu: to be or not to be administered for patients undergoing procedures? date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: zsoc wec nan definition: the expression "prophylactic" antimicrobial therapy has multiple uses in the context of intensive care (supplement b) [ ] . there is also significant overlap in the use of "prophylactic" and "pre-emptive" antibiotic administration in the literature [ ] . prophylactic therapy usually entails administration of a single dose or, at most, a day of antibiotic treatment for prevention of infection when there is no evidence or suspicion of infection already being present [ ] . there is also little-to-no literature on the ideal time for antimicrobial prophylaxis; this time frame may eventually vary depending on patient and environmental conditions and the type of procedure to be performed. such time frames should ideally be determined in multicentre studies randomising critically ill patients to different timing of antimicrobial administration. in the interim, extrapolation from populations that are not critically ill and from database analyses suggests that prophylactic antimicrobial therapy is generally best timed to around h before performance of invasive procedures [ , ] . prevalence: several studies suggest that prophylactic administration of antimicrobials is commonly practiced in the icu. a single-centre prospective study conducted in belgium showed that among , antibiotic treatment courses recorded for years, % (n = ) were prescribed for prophylaxis [ ] . a nationwide, single-day survey conducted among icus in japan found that % (n = / ) of the prescriptions for intravenous antibiotics written that day were for prophylaxis [ ] . antimicrobial prophylaxis may be administered to patients undergoing a surgical procedure during their icu stay and as a non-surgical prophylaxis to icu patients who undergo insertion of an external-internal foreign body that remains in situ for a prolonged period of time. these two clinical scenarios differ and are, therefore, discussed separately. surgical procedures: surgical antimicrobial prophylaxis (sap) for prevention of surgical site infections is the most frequent hospital-wide indication for antimicrobial use. however, sap is also commonly practiced in many icus. a single-centre study conducted recently in a belgian icu showed that sap and prophylaxis for immunocompromised patients constituted two-thirds of prophylactic antibiotic treatments prescribed [ ] . in non-icu patients, it is recommended that sap be administered - min before surgical incision to enable achievement of a high serum concentration of antibiotics prior to incision [ , ] . re-injection is recommended during the procedure every two half-lives of the antibiotic [ ] . if surgery is conducted prior to icu admission and/or within the first h of icu admission, the recommendations for sap remain unchanged; they are similar to the recommendations of any department of emergency medicine or ward [ ] . however, in icu, patients undergoing unplanned surgery after staying > days in the icu other considerations come into play. colonization with mdr pathogens increases during the hospital stay [ ] . prior antibiotic treatment and prior environmental exposure also affect the prevalence of colonization by mdr pathogens [ ] . in such cases, the spectrum of antibiotics required constitutes a major challenge because of the potential need to cover and manage mdrs in the operative setting and because in fragile patients, there is an unproven concern not only for surgical site, but also for systemic infection [ ] . a single-centre, observational study which reported on a small number of patients (n = ) has shown great variability of practices in these patients [ ] . to date, there is no evidence to support the universal use of prophylaxis targeted against mdr. this approach should be investigated in future studies, as it can constitute a vicious circle for the development of mdr. some of the multiple factors that should be taken into account when determining the choice of antibiotic in such cases are presented in table . there are no randomised controlled trials on the effects of timing or choice of antibiotic prophylaxis on the outcomes of icu patients requiring unplanned surgical procedures. nor are there recommendations for antibiotic prophylaxis in critically ill patients. non-surgical prophylaxis: many icu patients require insertion of an external-internal foreign body. questions arise regarding prophylaxis before insertion and for tubing remaining in situ for a prolonged period of time. we discuss three of these many dilemmas; endotracheal intubation due to an altered level of consciousness, chest drain insertion and insertion/maintenance of an intracranial ventricular drain. endotracheal intubation: prophylactic antimicrobial treatment following endotracheal intubation of patients with an altered level of consciousness is not recommended in most guidelines for prevention of healthcare-associated pneumonia [ , ] . however, french guidelines for the prevention, diagnosis and treatment of hospital-acquired pneumonia in icu suggest consideration of selective digestive decontamination with both topical and systemic antibiotics (for a maximum of h) to decrease the rate of pneumonia immediately after urgent intubation based on indirect evidence from several studies [ ] . sirvent et al. randomised comatose patients undergoing intubation to doses of cefuroxime versus no treatment. patients receiving cefuroxime had a lower rate of ventilator-associated pneumonia (vap) briefer hospital and icu length of stay [ ] . aquarolo et al. randomised comatose mechanically ventilated patients with brain injury to ampicillin-sulbactam prophylaxis plus standard treatment or standard treatment alone and showed that antibiotic prophylaxis reduced the occurrence of early-onset pneumonia ( % vs %, p = . ). [ ] . similar findings have been reported in other icu settings [ ] . more recently, a systematic table factors that should be taken into account when determining the choice of an antibiotic review and meta-analysis reported that systemic administration of antibiotics for no more than h following intubation did not affect mortality [relative risk (rr) . ; % confidence interval (ci) . - . ], but was associated with a reduction in the incidence of early-onset vap and briefer icu lengths of stay [ ] . the literature does seem to suggest that a short course of prophylactic antibiotic following intubation may confer some benefit. however, this finding is inconsistent and if it does exist, the strength of this effect remains to be determined. at this time, the results of a trial planned to include patients with brain injury randomised to either one dose of ceftriaxone within h of intubation or placebo are expected [ ] . additional multicentre prospective studies are required. chest drains: placement of a chest drain may theoretically be accompanied by bacteraemia, particularly if placed in a source of infection or nearby already infected lung. alternatively, the chest drain is a foreign body which could theoretically become a source of ascending infection (i.e. pneumonia, empyema). there are no recommendations regarding antibiotic prophylaxis in icu patients requiring chest drain insertion. a metaanalysis of studies focused on antibiotic prophylaxis for chest drain insertion in non-icu patients (i.e. thoracic injury), concluded that treatment after chest drain insertion was significantly associated with a reduced risk of empyema (rr . ; % ci . - . ) and pneumonia (rr . ; % ci . - . ) when compared with placebo alone [ ] . this study is often quoted as a reason to provide prophylactic antibiotic treatment to patients who undergo chest drain insertion or who have a chest drain in situ. however, a trauma setting may differ in both urgency and hygiene conditions, and young trauma patients are very different from most surgical patients who are older and comorbid, thus extrapolation may be inappropriate. furthermore, the length of required prophylactic treatment (if any) also remains unclear. this question is particularly pertinent in patients that undergo drain insertion in sterile conditions (e.g. during elective thoracic surgery). most of these patients receive antibiotic prophylaxis before surgery in accordance with perioperative guidelines [ ] . meta-analysis of the data on this topic in the literature suggests that prolonged postoperative antibiotic prophylaxis does not reduce the number of infectious complications related to chest drains compared with preoperative prophylaxis only [ ] . cerebral intra-ventricular drains-current neurocritical care society recommendations suggest that one dose of antimicrobials be administered prior to insertion of an external ventricular drain. this recommendation is based on a weak level of evidence [ ] . in conclusion, antimicrobial prophylaxis constitutes a large part of antibiotic prescriptions in the icu. antimicrobial prophylaxis could theoretically prevent appearance of infectious complications in critically ill icu patients that must undergo an invasive procedure in the icu or the or. on the other hand, redundant antimicrobial prophylaxis could drive emergence of mdr pathogens and increase the rate of adverse drug reactions. there is an urgent need to conduct methodologically sound multicentre randomised clinical trials in the icu environment on this topic; the literature is particularly poor with regards to both surgical and non-surgical procedures in critically ill patients. the online version of this article (https ://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. bloodstream infections caused by antibiotic-resistant gram-negative bacilli: risk factors for mortality and impact of inappropriate initial antimicrobial therapy on outcome the influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the icu setting bacterial contamination of inanimate surfaces and equipment in the intensive care unit general principles of antimicrobial therapy cost-effectiveness analysis of implementing an antimicrobial stewardship program in critical care units clostridium difficile and the microbiota effect of selective decontamination on antimicrobial resistance in intensive care units: a systematic review and meta-analysis antimicrobial use in european acute care hospitals: results from the second point prevalence survey (pps) of healthcare-associated infections and antimicrobial use esicm/esc-mid task force on practical management of invasive candidiasis in critically ill patients timing of surgical antimicrobial prophylaxis: a phase randomised controlled trial antibioprophylaxis in surgery and interventional medicine a complete and multifaceted overview of antibiotic use and infection diagnosis in the intensive care unit: results from a prospective four-year registration a nationwide survey of intravenous antimicrobial use in intensive care units in japan clinical practice guidelines for antimicrobial prophylaxis in surgery colonization pressure as a risk factor of icu-acquired multidrug resistant bacteria: a prospective observational study accuracy of american thoracic society/infectious diseases society of america criteria in predicting infection or colonization with multidrug-resistant bacteria at intensive-care unit admission anesthesia in patients with infectious disease caused by multi-drug resistant bacteria surgical antimicrobial prophylaxis in intensive care unit (icu) patients: a preliminary, observational, retrospective study management of adults with hospital-acquired and ventilator-associated pneumonia: clinical practice guidelines by the infectious diseases society of america and the international ers/esicm/ escmid/alat guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia hospital-acquired pneumonia in icu protective effect of intravenously administered cefuroxime against nosocomial pneumonia in patients with structural coma antibiotic prophylaxis of early onset pneumonia in critically ill comatose patients. a randomized study efficacy of single-dose antibiotic against early-onset pneumonia in comatose patients who are ventilatedpreventing pneumonia in comatose patients systemic antibiotics for preventing ventilator-associated pneumonia in comatose patients: a systematic review and meta-analysis prevention of early ventilation-acquired pneumonia (vap) in comatose brain-injured patients by a single dose of ceftriaxone: prophy-vap study protocol, a multicentre, randomised, double-blind, placebo-controlled trial systematic review and metaanalysis of antibiotic prophylaxis to prevent infections from chest drains in blunt and penetrating thoracic injuries postoperative antibacterial prophylaxis for the prevention of infectious complications associated with tube thoracostomy in patients undergoing elective general thoracic surgery: a double-blind, placebo-controlled, randomized trial the insertion and management of external ventricular drains: an evidence-based consensus statement: a statement for healthcare professionals from the neurocritical care society the work was funded by jpiamr (grant no. - ). springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- - rrhcm authors: luce, judith a. title: use of blood components in the intensive care unit date: - - journal: critical care medicine doi: . /b - - . - sha: doc_id: cord_uid: rrhcm nan most patients admitted to an intensive care unit (icu) require the administration of one or more blood components during their stay. such patients exhibit great diversity in conditions necessitating care in the icu, age, underlying medical problems, and integrity of physiologic compensatory mechanisms. all these patients, however, share the need for optimized oxygen-carrying capacity and tissue perfusion. ongoing blood loss resulting from injuries, surgical wounds, invasive monitoring equipment, and blood sampling requirements, coupled with inadequate marrow function and, in some, red cell destruction, makes red cell transfusion a necessity for many icu patients. additionally, many patients are susceptible to the development of hemostatic disorders requiring the administration of such blood components as plasma, cryoprecipitate, or platelet concentrates. blood components should be considered drugs because they exert potent therapeutic responses yet are also capable of causing signifi cant adverse effects. the food and drug administration (fda) regulates blood component preparation, testing, and administration. unlike pharmaceutical agents, however, blood components have fewer objective indications for use and no therapeutic index relating dose to safety. it is not as simple to monitor the effi cacy and continuing need for a blood component as it is to determine the blood level of a drug. in addition, the risks associated with transfusion cannot be known in advance and may be lethal; such risks include medical errors, as well as infectious and immunologic hazards. unlike pharmaceutical agents, these prescribed products require documentation of patient consent and indication for use. although the american blood supply is now safer than ever before, zero-risk transfusion is not achievable, even if blood components could be sterilized. the process of donor selection and screening has become increasingly stringent, an evolution that began in response to the welldefi ned risks of transfusion-transmitted hepatitis and human immunodefi ciency virus (hiv) infection. although the value of maximizing recipient safety is unarguable, increasing donor selectivity has its price. as more tests are added and more conditions placed on the donor, the number of usable donations has declined. this trend has led to occasional regional and seasonal blood shortages and, rarely, outright inability to provide certain blood components. clinicians who prescribe blood components must be aware of these uncertainties in availability and contribute by using blood products appropriately while the national blood banking system seeks strategies to ensure an adequate, safe blood supply. donor screening strategies to ensure recipient safety take several forms. , american blood donors are voluntary donors; cash payment was eliminated in the s after studies linked professional donors with transmission of hepatitis. confi dential questionnaires were initiated to limit transmission of hiv and hepatitis and to allow voluntary self-exclusion and involuntary exclusion of donors who pose an increased risk of transmitting infectious agents. multiple specifi c serologic and biochemical tests are performed to detect the potential for transmission of hiv and other retroviruses, hepatitis, and syphilis. any donor who indicates high-risk behavior or who tests repeatedly positive is placed on a permanent deferral list. some patients may insist on blood obtained from relatives or friends. this practice is termed directed or designated donation. these selected donors must undergo the same rigorous questioning and testing as volunteer donors. some studies have found an increased frequency of hepatitis markers in the blood of directed donors when compared with blood drawn from unselected volunteers, but others suggest that designated donors may be no different from new volunteers. , there continues to be no consensus about whether directed donors are, as a group, as safe as volunteer donors. , institutional policies about the acceptability and processing of directed donations vary widely. in any case, supporting icu patients who require large-volume transfusion with directed donations is unlikely to be advantageous or practical. the basic principle of blood component therapy is prescription of the specifi c blood product needed to meet the patient's requirement. a single whole blood (wb) donation can be separated into its composite parts, or components, which can be distributed to several recipients with differing physiologic needs. component therapy thus meets the clinical requirements of increased safety, efficacy, and conservation of limited resources. as the variety of blood product components increases, however, the complexity of transfusion medicine also increases. a wb donation is typically separated into red blood cells (rbcs), a platelet concentrate, and fresh frozen plasma (ffp) within hours of its collection. the plasma may be further processed into cryoprecipitate and supernatant (cryopoor) plasma. one unit of wb measures approximately ml, including ml of citrate anticoagulant/preservative solution. each unit of wb supplies about ml of rbcs and ml of plasma for volume replacement. wb is refrigerated for to days, depending on the preservative used. after less than hours of refrigerated storage in this preservative and bag system, platelet and granulocyte function is lost. with further storage, levels of the "labile" coagulation factors v and viii decrease. some blood centers offer modifi ed wb, which is produced by removal of the platelet or cryoprecipitate fraction and return of the supernatant plasma to the red cells. this permits provision of the more labile components to patients with specifi c needs, with the remainder forming a product having a composition essentially the same as cold-stored wb. however, the growing need for specialized blood components has resulted in processing the majority of blood donations into components, thus limiting the availability of wb and modifi ed wb. rbcs, or in common usage, "packed" red cells (prbcs), are the blood component most commonly transfused to increase red cell mass. prbcs are derived from the centrifugation or sedimentation of wb and removal of most of the plasma/anticoagulant solution. if collected into citrate-phosphate-dextrose-adenine solution, the volume is approximately ml, the hematocrit (hct) is % to %, and the storage life is days. extended additive solutions permit storage up to days but increase the volume to ml and decrease the hct to %. these extended storage units are commonly used and easier to transfuse because of lower viscosity, but they may pose a problem because of their larger volume. the transfusion of leukocyte-reduced rbcs may benefi t certain patients. transfusion of blood components containing leukocytes may lead to febrile reactions, a greater propensity for alloimmunization, platelet alloimmunization, and transmission of pathogens carried by leukocytes, such as cytomegalovirus (cmv). leukocyte reduction, as defi ned by the fda, requires fi ltration of the blood component by a special fi lter. filtration may be performed either at the time of blood donation and processing or later at the time of transfusion ("bedside fi ltration"). filtration before storage conveys the benefi t of removing white blood cells (wbcs) before they can deteriorate and elaborate cytokines and other unwanted substances during storage. because of proven and theoretical benefi ts of leukocyte reduction of blood components (discussed later in the section covering the adverse effects of transfusion), many european countries and canada require that all transfusions be leukocyte reduced, a process called universal leukoreduction (ulr). some institutions in the united states have also made that decision, but either method of leukocyte reduction adds signifi cantly to the cost of each transfusion ($ to $ ), and the benefi ts of this measure when applied globally have yet to be quantifi ed. washing prbcs involves recentrifuging to remove the plasma/preservative solution from the unit. however, washing may take an hour or more, limits subsequent storage time, and causes some loss of rbcs. washing is also not an effective method of leukoreduction. there are very few indications for the use of washed rbcs, although some recipients with plasma reactions may benefi t. prbcs can be frozen in cryoprotective solution and stored for extended periods. frozen rbcs are generally limited to units of special value, such as those with a rare rbc antigen profi le or autologous blood donations that need to be stored for future use. a rare-donor registry of frozen prbcs exists to assist in providing blood to patients with complex or multiple alloantibodies to red cell antigens. signifi cant advanced planning is necessary to acquire and thaw frozen prbcs for transfusion, thus limiting their use in acute situations. wb and prbcs suffer some cell loss during storage. the current technology of bag and preservative solutions attempts to optimize cell quality and quantity by using strict criteria to determine the length of allowable storage time. nonetheless, as red cell metabolism decreases progressively, a "storage lesion" results, with accumulation of a variety of undesirable substances and loss of cellular function. over time in storage, a slow rise in the concentration of potassium, lactate, aspartate aminotransferase, lactate dehydrogenase, ammonia, phosphate, and free hemoglobin and a slow decrease in ph and bicarbonate concentration occur. cytokines and infl ammatory mediators such as interleukin- , interleukin- and tumor necrosis factor also accumulate. the ph of freshly stored blood in citrate solution is . , which declines to approximately . at the end of the unit's shelf life. as potassium leaks from red cells during storage, levels as high as meq/l may result. however, each unit transfused supplies at most meq of potassium, which is well tolerated under most circumstances. during the storage period there is also a progressive decrease in rbc-associated , -diphosphoglycerate ( , -dpg) and adenosine triphosphate (atp). a decrease in , -dpg increases the affi nity of hemoglobin for oxygen, which shifts the oxygen dissociation curve to the left and decreases oxygen delivery to tissues. there is little evidence, however, that this transient increase in oxygen affi nity has clinical importance. after infusion, , -dpg gradually increases as the transfused red cells circulate, with % recovery in hours and full replacement by hours. decreased atp during storage diminishes the viability of red cells after transfusion and is one of the chief factors limiting storage time. there is no currently available storage or rejuvenation solution that optimizes these cellular constituents. the majority of blood transfusions are in the form of prbcs, the component indicated for normovolemic patients or those for whom intravascular volume constraints are necessary. the use of wb may be desirable for patients who require both increased oxygen-carrying capacity and volume resuscitation because of a large and ongoing hemorrhage; however, the availability of wb is generally limited. resuscitation is effectively achieved with the use of prbcs and crystalloid solutions. each unit of prbcs or wb is expected to raise the hemoglobin level by g/dl and the hct by % in stable, nonbleeding, average-sized adults. although some studies have demonstrated a slight superiority of fresh wb over components when used during cardiac surgery in selected patients, the benefi ts of fresh blood remain controversial, and current testing and processing requirements limit general availability. despite a long tradition of transfusion of rbcs in critically ill patients, the precise indications for transfusion remain a source of controversy, and specifi c transfusion practices may vary widely among clinicians. before the major randomized studies of rbc transfusion policies, a survey of transfusion practice showed that about half of icu patients were receiving red cell transfusions, and another showed that if the icu stay was longer than a week, the rate of transfusion was %. the total number of transfusions was high, and icu practice was characterized by high rates of transfusion. the reasons for the controversies are clear: rbcs should be transfused only to enhance tissue oxygen delivery, but the underlying physiology of anemia, the complex adaptations to anemia, and the potential advantages and disadvantages to particular groups of patients are not as well understood. compensatory mechanisms for acute and chronic anemia are diverse and complex. , all work in concert to maintain oxygenation within the microcirculation. cardiovascular adjustments leading to increased cardiac output include decreased afterload and increased preload resulting from changes in vascular tone, increased myocardial contractility, and elevated heart rate. lowered blood viscosity permits improved fl ow of erythrocytes within capillaries. blood fl ow is redistributed to favor critical organs with higher oxygen extraction. pulmonary mechanisms, though contributing relatively little to shortterm oxygenation demands, exert potent effects on related metabolic variables. finally, the hemoglobin molecule can undergo biochemical and conformational changes to enhance unloading of oxygen at the capillary level. all these mechanisms contribute to an "oxygen reserve" capacity that exceeds baseline requirements by approximately fourfold. no experimental model exists that encompasses the diversity of physiologic compensations for hypoxia. experiments carried out in animals and case reports in patients refusing transfusion indicate that an extremely low hct is tolerated if tissue perfusion is adequate. [ ] [ ] [ ] certain objective, though indirect, measurements of tissue oxygenation exist and are available to clinicians caring for patients monitored invasively in the icu. mixed venous oxygen content (pv o ) and cardiac output can be measured in patients undergoing pulmonary artery catheterization; arterial oxygen content can also be measured directly. the oxygen extraction ratio (er) can be calculated directly, and in the presence of normal or high cardiac output it is a measure of tissue oxygen extraction and, indirectly, the adequacy of tissue oxygen delivery. the total body er at baseline is about %. a falling pv o and an er increasing to greater than % have been proposed as indicators of the need for red cell transfusion. there have been only randomized trials of transfusion policy in the icu, and only of them was large enough to draw specifi c, statistically signifi cant conclusions. the canadian critical care trials group compared a liberal (target hemoglobin, to g/dl) with a restrictive (target hemoglobin, to g/dl) red cell transfusion policy in patients stratifi ed for disease severity. at days from randomization, the restrictive strategy was at least as good as, if not better than (p = . ) the liberal strategy, and overall hospital mortality was signifi cantly lower in the restrictive strategy group (p = . ). for patients younger than years and for patients with lower (< ) apache (acute physiology, age, and chronic health evaluation) ii scores, the restrictive strategy was clearly superior. in addition, liberal transfusion was not associated with shorter icu stays, less organ failure, or shorter hospital stays; longer mechanical ventilation times and cardiac events were more frequent in the liberal strategy group. a later subgroup analysis of patients with cardiovascular disease, though small enough to have statistical doubt, suggested that a more liberal transfusion strategy was probably appropriate for patients with severe ischemic coronary disease. this observation has some support in experimental studies of the effects of anemia in laboratory animals with coronary occlusion. the canadian study has highlighted the many and complex issues involved in transfusion decision making in the icu. since publication of the canadian study, several large reports have examined the use of red cell transfusions in critical care units. vincent and colleagues surveyed european icus and found that the transfusion rate in patients was % during the icu stay and . % after the stay. the mean pretransfusion hemoglobin level was . g/ dl. corwin and colleagues studied icus in the united states a year later and found great similarity: nearly % of patients received transfusions, and the mean threshold hemoglobin level was . g/dl. a single large scottish teaching hospital reported a more parsimonious practice: the rate of transfusion was still % in its icu patients, but the total volume of blood used was slightly smaller and the mean pretransfusion hemoglobin level was only . g/dl. all these authors have concluded that icu practice has not fully embraced the guidelines of the canadian clinical trial. in contrast, hospitals in australia and new zealand have reported on transfusion in consecutive icu admissions, and although the authors found a median pretransfusion hemoglobin concentration of . g/dl, the rate of transfusion was lower, at only . % of patients, % of whom were bleeding. the "inappropriate" transfusion rate was %. the authors speculate that the practitioners may have been infl uenced by publication of the canadian study and their own regional survey of transfusion practices. nonetheless, they agree that full implementation of the canadian guidelines in their clinical setting might be controversial. the literature on rbc transfusion in the setting of surgery, particularly surgery with the use of blood products, is growing. a mounting body of data illustrate the human tolerance of a low hct during and after surgery. a recent randomized trial of rbc transfusion strategy in orthopedic surgery demonstrated no signifi cant differences in outcome between a restrictive ( g/dl) and a liberal ( g/dl) transfusion threshold and included monitoring for silent myocardial ischemia preoperatively and postoperatively. provided that adequate perfusion of the microcirculation is maintained, purposeful maintenance of a low hct during surgery, a technique called normovolemic hemodilution, can be a powerful tool in minimizing blood loss and the attendant need for red cell transfusion. table - summarizes guidelines proposed by the national institutes of health, the american society of anesthesiologists, and the american college of physicians relative to the transfusion of rbcs. these guidelines have been provided with the intent of establishing parameters, not with the intent of substituting for the individual clinician's judgment. the art of medical decision making in transfusion, as in other areas of medicine, lies in determination of the appropriate treatment for the individual patient. a platelet concentrate (random-donor platelets) is obtained by centrifugation from a unit of donated wb. each unit contains a minimum of × platelets suspended in about ml of plasma. platelets are stored at room temperature to avoid loss of function from refrigeration and are constantly agitated to maximize gas exchange. the length of storage varies with the container used, but most systems permit -day storage. because of this limited storage time and the increasing demand for this component, platelets are often subject to supply shortages. some loss of viability and platelet numbers occurs during storage, but -day-old platelets still effect hemostasis. once the bags are entered for pooling before transfusion, the platelets must be administered within hours. each unit of platelets is expected to increase the platelet count by × /l in a typical -kg adult. the usual dose is units, or u/ kg of body weight. a -hour post-transfusion platelet count should be obtained to determine the adequacy of response. the following equation, which relates platelet number and body size to the post-transfusion increment, can be used to assess the effectiveness of the transfusion: abo-compatible platelets are desirable but not essential. when abo-mismatched platelets are given, removal of some of the incompatible plasma can be carried out at the time of pooling for transfusion. likewise, volume reduction may be necessary for patients at risk for fl uid overload from the to ml of plasma present in to units of platelets. nonetheless, the remaining plasma is a good source of stable coagulation factors and contains diminished but still potentially benefi cial amounts of factors v and viii. there is no contraindication to the use of rh-positive platelets in rh-negative patients; if given to women with future childbearing potential, rh immune globulin (rhig) may be used prophylactically against the small risk of rh alloimmunization from red cells that may be contained in the platelet concentrate. plateletpheresis (common terms: single-donor platelets, apheresis platelets) involves separating and removing platelets from one donor by cytapheresis during a / -to -hour procedure on an automated device and then retransfusing the remainder of the blood back into the donor. each collection contains an equivalent of to units of platelet concentrates. single-donor platelets are suspended in about ml of plasma, so the same abo and volume considerations discussed earlier pertain. single-donor platelets offer the clear benefi t of reducing the risk of multiple-donor exposure to the recipient. single-donor platelets may also be the only available alternative for recipients who have been alloimmunized by previous platelet transfusions because they may be human leukocyte antigen (hla) or platelet antigen matched to the recipient. the use of apheresis platelets now exceeds the use of pooled random-donor platelets; however, use of this product in emergency situations is limited by the availability of volunteer donors. platelet transfusions are indicated for patients bleeding because of thrombocytopenia or functional platelet defects. guidelines for transfusion continue to evolve, and the current guidelines merely provide a desirable range for platelet counts, assuming normal platelet func-tion (table - ). there is ample evidence that bleeding medical or surgical patients with platelet counts of × /l or above will not benefi t from transfusion if thrombocytopenia is the only abnormality. for critical invasive procedures in which even a small amount of bleeding could lead to loss of vital organ function or death, maintaining the platelet count at × /l or greater is typically preferred. the presence of other factors that diminish platelet function, such as certain drugs, foreign intravascular devices (e.g., intra-aortic balloon pump or membrane oxygenator), infection, or uremia, may alter this requirement upward. patients at risk for small but strategically important hemorrhage, such as neurosurgical patients, may need to be maintained at counts of to × /l. patients without hemorrhage who have platelet counts of × /l or lower appear to be at increased risk for signifi cant hemorrhage. indications for transfusion to patients with counts above × /l are less well established; thus, the majority of guidelines propose prophylactic platelet transfusion to prevent hemorrhage at a threshold of × /l. the bleeding time is not a useful procedure in this situation because it is usually prolonged at counts below × /l, may be insuffi ciently reproducible, and correlates poorly with the risk for bleeding. patients undergoing cardiac bypass surgery experience a drop in platelet count and often acquire a transient platelet functional defect from damage associated with the bypass apparatus. most patients do not experience platelet-associated bleeding, however, so prophylactic transfusion in the absence of bleeding is not warranted. in a patient who continues to bleed postoperatively, more likely causes are a localized, surgically correctable lesion or failure to reverse heparinization. if these conditions are excluded, empiric transfusion of platelets may be justifi ed. patients thrombocytopenic by virtue of immunologic destructive processes such as idiopathic thrombocytopenic purpura (itp) receive little benefi t from platelet transfusions because the transfused platelets are rapidly removed from the circulation. in the event of life-threatening hemorrhage or an extensive surgical procedure, transfusion may prove benefi cial for its short-term effect. transfusion may be accomplished effectively by pretreatment with high-dose immunoglobulin or high-dose anti-d antiserum (rhig). , platelet transfusion has been reported to be deleterious in thrombotic thrombocytopenic purpura (ttp), in the related hemolytic-uremic syndrome, and in heparin-induced thrombocytopenia. cautious administration, in cases of life-threatening thrombocytopenic bleeding only, is prudent. prophylactic platelet transfusion for thrombocytopenia secondary to underproduction remains controversial. the common practice of transfusion to maintain the platelet count above × /l derives from data published in , which demonstrated an increase in spontaneous bleeding in leukemic patients at that level. however, critical evaluation of the data reveals that serious hemorrhage was not greatly increased until counts fell to × /l or lower and that these patients received aspirin for fever, which might have compromised platelet function and enhanced the bleeding. a somewhat more recent study quantitating stool blood loss in aplastic anemia patients defi ned a bleeding threshold at platelet counts of to × /l. a prospective study of a more conservative transfusion protocol found that major bleeding episodes occurred on . % of days with counts of less than × /l and on only . % of days with counts of to × /l. the trigger for prophylactic platelet transfusion in the to × /l range, however, applies primarily to stable thrombocytopenic patients. factors such as fever, use of anticoagulant or antiplatelet drugs, and invasive procedures must be considered when generating a treatment plan for individual patients. patients experiencing rapid drops in platelet count may be at greater risk than those at steady state and thus may benefi t from transfusion at higher counts. benefi ts to the patient with more judicious use of platelet transfusion include decreased donor exposure, which lessens the risk of transfusion-transmitted disease; fewer febrile and allergic reactions that may complicate the hospital course; and the potential delay or prevention of alloimmunization to hla and platelet antigens. the development of refractoriness to platelet transfusions is a serious event heralded by a falling cci. poor response to platelet transfusions can be seen in patients with other reasons for platelet consumption, including splenomegaly, fever, trauma and crush injury, burns, disseminated intravascular coagulation (dic), concomitant drugs, or transfusion of platelets of substandard quality. these factors should be sought and corrected if possible. alloimmunization is characterized by the development of anti-hla or platelet-specifi c antibodies, with resultant immune platelet destruction. as many as % of patients receiving multiple red cell or platelet transfusions become immunized. leukocyte depletion of transfused components can prevent or delay this phenomenon, but it is important to use leukoreduced components early in the course of transfusion therapy. , when patients fail to achieve expected increments after platelet transfusion, provision of abo-specifi c platelet concentrates that are less than hours old may improve the response. if no improvement is seen and the aforementioned medical conditions are excluded, the patient should be screened for hla antibodies or be hla typed and provided with hla-compatible single-donor platelets. alternatively, platelet crossmatching with the patient's serum can be carried out. there is no advantage to unmatched singledonor platelets in this situation. standard ffp is prepared by centrifugation of wb and is frozen within hours of blood donation. , ffp may be stored frozen for year. the usual volume is about ml, depending on the donor's hct. the most common method of thawing before transfusion is soaking in a ° c water bath, which requires about to minutes. once thawed, ffp can be stored refrigerated for a maximum of hours. when prepared and stored in this manner, ffp supplies all the constituents in the amounts normally present in circulating plasma, including stable and labile coagulation factors, complement, albumin, and globulins. by convention, the coagulation factors are present in concentrations of u/ml. crossmatching to the recipient is not performed, but ffp must be abo compatible. standard ffp is as likely to transmit hepatitis, hiv, and most other transfusion-related infections as cellular components are. new ffp products have recently been introduced in response to concern about the transmission of infectious diseases. one such product is solventdetergent-treated ffp. solvent-detergent treatment is a means of viral inactivation that removes the infectivity of lipid-enveloped viruses, such as hepatitis b and c and hiv. because the product is derived from pooled plasma, with as many as donors in each lot, it has the potential to actually increase recipient exposure to pathogens not inactivated by the solvent-detergent method, such as hepatitis a and parvovirus b , and be more vulnerable to any newly emerging non-lipid-enveloped agent. a variety of other techniques for reducing pathogen exposure in ffp have been developed, including exposure to low ph or vapor heating and treatment with ultraviolet irradiation, gamma irradiation, or psoralens and light to inactivate pathogens by inducing dna damage. because none of the ffp products is entirely free from the risk of disease transmission or other adverse effects and because infection-reducing modifi cations add significantly to the cost of the components, ffp should be used judiciously. it should be administered only to provide coagulation factors or plasma proteins that cannot be obtained from safer sources. ffp is commonly used to treat bleeding patients with acquired defi ciency of multiple coagulation factors, as in liver disease, dic, or dilutional coagulopathy, or to treat patients with congenital defi ciency of a coagulation factor or other protein for which concentrates or safer sources do not exist. ffp may be indicated for emergency reversal of the coagulopathy induced by warfarin anticoagulants when more concentrated products are not available or for the provision of protein c or s in patients who are defi cient and suffering acute thrombosis. ffp should be administered as boluses as rapidly as feasible so that the resulting factor levels allow hemostasis. the use of ffp infusions without adequate bolus administration is not helpful. ffp should not be used for volume expansion or wound healing or as a nutritional source of protein. ffp does not reverse anticoagulation induced by heparin and in theory might exacerbate bleeding by supplying more antithrombin, heparin's cofactor. prophylactic administration of ffp does not improve patient outcome in the setting of massive transfusion or cardiac surgery unless there is bleeding with an associated documented coagulation abnormality. , patients do not usually bleed as a result of coagulation factor insuffi ciency when the international normalized ratio (inr) is less than about . , and even then the results are not always predictable. the partial thromboplastin time (ptt) is not useful in predicting procedural bleeding risk. ffp is often requested prophylactically before an invasive procedure when the patient exhibits mild prolongation in coagulation studies. most of these procedures may be carried out safely without transfusing ffp. , ffp is probably the most misused blood component, as illustrated by retrospective surveys. coagulation factors are normally present in the blood far in excess of the minimum levels required for hemostasis. as little as % of the normal plasma concentration of several factors will effect hemostasis. conversely, ffp treatment of acquired multiple defi ciencies, as in hepatic failure, is often ineffective because many patients cannot tolerate the infusion volumes required to achieve hemostatic levels of coagulation factors, even transiently. the plasma half-life of transfused factor vii is only to hours. it may be impossible to administer suffi cient ffp every few hours without encountering intravascular volume overload. finally, in some instances, transfusion of seemingly adequate volumes may still fail to correct the coagulopathy. careful documentation of both the need for ffp and the adequacy and outcomes of therapy is essential. cryoprecipitate is manufactured by thawing and centrifuging ffp below º c and resuspending the precipitated proteins in about ml of supernatant plasma. , each bag is a concentrated source of factor viii ( to units), von willebrand factor (vwf) ( % of original plasma content), fi brinogen ( mg), factor xiii ( % of original plasma content), and fi bronectin. cryoprecipitate offers the advantage of transfusing more specifi c protein and less total volume than the equivalent dose of ffp does. it has been used to treat patients with inherited coagulopathies, such as hemophilia a, von willebrand disease, or factor xiii defi ciency. in the critical care setting, it is more commonly used to replenish fi brinogen, especially in bleeding patients with hypofi brinogenemia caused by dilutional or consumptive coagulopathy. cryoprecipitate also reportedly improves hemostasis in uremic patients, presumably by reversing the functional platelet defect, but desmopressin acetate (ddavp) or conjugated estrogens exert similar effects and should be used preferentially to avoid potential transfusion-transmitted disease. the usual dose of cryoprecipitate to treat hypofi brinogenemia is bags/units to start, then to bags/units every hours or as necessary to keep the fi brinogen level above mg/dl. each bag/unit of cryoprecipitate carries a risk of disease transmission equivalent to that of unit of blood. for this reason, commercial factor viii concentrates, recombinant or treated to inactivate viruses, are preferred over cryoprecipitate for treating hemophilia a patients. immune serum globulin (ig), rhig, and hyperimmune globulins for diseases such as hepatitis b and varicella zoster are obtained by fractionation of pooled plasma, followed by chromatography, delipidation, and other steps to remove aggregates and infectious agents. intravenous ig (ivig) is available in solution or lyophilized form, with protein content varying by mode of preparation. the available products vary slightly in the amounts of iga and igm contained in them, which are mostly present in only trace quantities. ig preparations can be used to provide passive antibody prophylaxis or to supply ig in certain immunodeficiency states. hyperimmune globulins may be used to treat active infections in immunosuppressed hosts. recent applications have exploited ig's immunomodulatory effects in treating a wide variety of disorders with an immune basis. the specifi c mechanism of action of ivig in such conditions has not yet been identifi ed, but possibilities include interference with macrophage fc receptor function, neutralization of anti-idiotypic antibodies, and interference with the incorporation of activated complement fragments into immune complexes. a recent review more completely discusses the effects of ivig on the immune system and its potential uses. rhig is prepared from pools of plasma obtained from donors sensitized to the red cell antigen d from the rh group. the standard-dose vial contains primarily igg anti-d, with a protein content of µg in ml. this dose will protect against ml of d + red cells or ml of wb. rhig carries no risk of virus transmission. although rhig is used primarily in obstetrics, it may also be indicated to prevent alloimmunization in rh-negative patients receiving small amounts of rh-positive red cells, as in platelet concentrates. routine prophylaxis against large numbers of red cells, as in a unit of rh-positive wb or prbcs given by accident to an rh-negative recipient, is not reliable and usually involves the administration of large amounts, but instances of its effective use in these circumstances have been reported. higher doses of intravenous rhig have been used in the treatment of itp. plasma-derived colloids include human serum albumin (hsa), available in % and % solutions, and plasma protein fraction (ppf), available in a % solution. both are derived from pooled donor plasma but are essentially pathogen-free. hsa is composed of at least % albumin, whereas ppf is subjected to fewer purifi cation steps and contains at least % albumin, with correspondingly more globulins. the % solutions are iso-oncotic, whereas the % solution of hsa is hyperoncotic and requires infusion with crystalloid solutions. potential clinical indications for colloid solutions include hypovolemic shock, hypotension associated with hypoproteinemia in patients with liver failure or protein-losing conditions, as a replacement solution in plasma exchange or exchange transfusion, and to facilitate diuresis in fl uidoverloaded hypoproteinemic patients. albumin solutions are not indicated as a nutritional source to raise serum albumin. their use in some indications, particularly for resuscitation, has become controversial, and pulmonary edema has been reported in association with their infusion. although albumin solutions are reasonably safe products to administer, expense and limited availability restrict their use. anaphylactic reactions have been reported in less than . % of recipients. the use of ppf has been associated with severe hypotensive episodes, with hageman factor fragments or prekallikrein activator being demonstrated, thus making ppf a less desirable resuscitation fl uid and contraindicated in cardiac surgery. granulocyte concentrates for transfusion are obtained from a single donor by cytapheresis methods, which generally involve the administration of hydroxyethyl starch and corticosteroids to the donor to improve granulocyte yield. granulocyte colony-stimulating factor (g-csf) has been added to some collection regimens and increases both cell counts and granulocyte survival substantially. each collection should contain at least granulocytes , and is suspended in approximately ml of plasma. a signifi cant number of red cells are present, so crossmatching for the recipient is required. because of the potential risk for graft-versus-host disease (gvhd), granulocytes are usually collected from hla-matched donors. granulocytes are stored at room temperature and must be transfused within hours of collection, although sooner is better because of rapid deterioration of the cells. patients who may benefi t from granulocyte transfusions include those who are neutropenic (absolute neutrophil count of less than . × /l) and those who are unresponsive to appropriate antibiotic treatment but in whom bone marrow recovery is expected to occur. a course of therapy generally involves daily infusion for to days. granulocytes have been used for progressive fungal infections in immunosuppressed granulocytopenic patients, in patients with defective leukocytes (e.g., chronic granulomatous disease), and in the neonatal icu for neonatal sepsis. randomized trials had suggested that granulocyte transfusions under these circumstances can reduce mortality, but such trials have not been conducted for more than decades. effective antibiotic regimens and the signifi cant adverse effects associated with the use of granulocyte concentrates, including pulmonary insuffi ciency related to alloimmunization and cmv infection, have limited their use in recent years. the decision to transfuse blood components, like any therapeutic maneuver, must be made with full awareness of the potential risk to the recipient, as well as the expected benefi ts. public expectations of a zero-risk blood supply help raise the acuity of physicians' decisions. for some patients, the benefi t from transfusion is so obvious that the associated risks pale in comparison to the consequences of withholding transfusion. however, the clinician's knowledge of the incidence and management of adverse reactions to transfusion is vital, not only to ensure the best patient care but also to provide appropriate patient education and true informed consent. almost every patient who receives an allogeneic blood transfusion will experience some adverse reaction if such universal effects as immunomodulation and bone marrow suppression are considered. measurable reactions to transfusion occur in about % of patients; more serious adverse responses may be expected in only % to % of transfusions. the nature of these adverse reactions ranges from those that are common but clinically unimportant to those that may cause signifi cant morbidity or death (table - ) . transfusion in the icu is a common and often lightly regarded event. however, because the signs and symptoms of severe, life-threatening reactions are frequently indistinguishable from those of troublesome, but less signifi cant reactions, every transfused patient who experiences a signifi cant change in condition, such as an elevation in temperature, change in pulse or blood pressure, dyspnea, or pain, must be promptly and fully evaluated to identify the cause of the reaction and to institute treatment when necessary. the basic approach to all acute reactions should be to maintain a high index of suspicion for acute hemolytic reactions by stopping the transfusion immediately, maintaining venous access with intravenous fl uids, and informing the blood bank laboratory immediately so that the appropriate transfusion reaction protocol can be in stituted and post-transfusion specimens obtained. early recognition of severe transfusion reactions may be lifesaving. the most feared reaction to blood transfusion is intravascular hemolysis, caused by the recipient's complementfi xing antibodies attaching to donor rbcs with resultant rbc lysis. abo incompatibility is most often implicated in these incidents. intravascular hemolysis is still the single most common acute cause of fatalities associated with the transfusion episode. in addition to hemolysis, complement activation stimulates the release of infl ammatory mediators and cytokines and thereby leads to hypotension and vascular collapse. activation of the coagulation system may result in dic. acute renal failure may also occur, presumably on the basis of immune complex interactions. morbidity and mortality are directly related to the quantity of incompatible blood transfused, which is why prompt recognition and cessation of transfusion cannot be overemphasized. misidentifi cation of the patient, or "clerical error," at any time beginning with the process of specimen acquisition through release of the unit and initiation of infusion is the major cause of acute intravascular hemolysis. , this reaction is more likely to occur in critical care settings, such as the icu, operating room, and emergency department, than anywhere else in the hospital. it is far preferable to transfuse uncrossmatched group o red cells than to chance abo incompatibility caused by improper patient and specimen identifi cation procedures. the most common clinical sign of hemolysis is fever, with or without chills. other common signs and symptoms include back or fl ank pain, anxiety, nausea, lightheadedness, dyspnea, and hemodynamic instability. in a comatose or anesthetized patient, many of these symptoms will not be evident; therefore, signs such as hypotension, hemoglobinuria, and diffuse oozing from puncture sites or incisions may be the only notable features. immediate management of hemolytic transfusion reactions must include cessation of the transfusion; the remainder of care is supportive. rapid verifi cation of patient and unit identifi cation must be made, not only to confi rm the suspected reaction but also to prevent a second patient from receiving a reciprocally incompatible unit if a clerical error has been made. desired end points of supportive care include maintenance of blood pressure, high urine output, and support of coagulopathy or further blood loss. steroids, heparin, or other specifi c pharmacologic interventions have no role in treatment. anaphylactic reactions to blood transfusions are fortunately rare but may be life-threatening. the usual cause is recipient antibody to a component of plasma that the patient lacks, most commonly antibody to iga in igadefi cient individuals. signs and symptoms include severe malaise and anxiety, fl ushing, dizziness, dyspnea, bronchospasm, abdominal pain, vomiting, diarrhea, hypotension, and eventually shock. fever and hemolysis do not occur. management includes immediate cessation of transfusion and standard therapy for anaphylaxis. if anti-iga antibodies are determined to be the cause of this reaction, the patient must receive blood components donated by iga-defi cient individuals or, if unavailable, specially prepared washed rbcs and platelet concentrates. plasmaderived preparations, such as albumin, and ig contain varying amounts of iga and pose a substantial risk in these patients. febrile nonhemolytic reactions (fnhrs) are the most commonly occurring immediate transfusion reaction. these reactions are annoying to the clinician, patient, and transfusion service alike in that they can cause signifi cant discomfort and, because they share certain manifestations with acute hemolytic reactions, must be investigated in every instance. fnhrs occur in approximately . % to . % of transfusion episodes. the etiologic factors are probably complex and multiple, but many reactions are caused by the release of cytokines and pyrogens, either within the transfused unit of blood or as a result of recipient antibodies to donor leukocytes. clinical signs include fever, with or without chills, usually beginning to hours after the start of the transfusion but occasionally delayed up to to hours. multiparous women and patients who are multiply transfused are particularly prone to fnhrs. the transfusion must be stopped and the appropriate transfusion reaction evaluation instituted. antipyretics such as acetaminophen may be administered. though commonly used, antihistamines such as diphenhydramine are neither preventive nor therapeutic. once acute hemolysis is excluded, transfusion of a new unit may be instituted. most patients will not experience a second such reaction. if repeated reactions become problematic, leukocyte-depleted blood components may be supplied. the implementation of ulr results in a reduction in the frequency of all fevers seen after transfusion by only about %. hives and pruritus are relatively common adverse effects of transfusion. they are a hypersensitivity reaction localized to the skin, and their cause is unknown but may include both donor and recipient characteristics. these reactions consist of localized or generalized urticaria beginning shortly after the start of transfusion without other signs or symptoms of anaphylaxis or hemolysis. the transfusion should be temporarily stopped, and antihistamines may be administered. if the hives resolve in a short time, the same unit of blood may be cautiously restarted. if repeated urticarial reactions occur, premedication with antihistamines may be effective, or blood components washed to remove plasma may be required. intravascular volume overexpansion is particularly likely to occur in critical care patients with limited cardiac reserve. aside from the inherent volume of the blood components, the intravenous normal saline concurrently administered adds to the volume load. unfortunately, normal saline solution is the only intravenous fl uid that may be administered with blood components. with careful attention to transfusion requirements and the use of volume reduction maneuvers available to the transfusion service, volume overload can be minimized in most instances. the frequency of this complication of transfusion is not reported. delayed hemolysis is an uncommon but probably underrecognized reaction to transfusion that results from the stimulation of a primary or secondary (anamnestic) recipient antibody response to foreign rbc antigens. these antibodies are undetected at the time of transfusion but increase after transfusion in a manner analogous to the vaccination "booster" effect. these reactions typically occur to days after transfusion but are unrecognized because of the lack of a clear temporal association with transfusion. fever, chills, and an unexplained decline in hct are the usual signs. transient elevation in bilirubin and lactate dehydrogenase may also occur. the diagnosis is established by a positive direct antiglobulin (coombs) test resulting from recipient antibody coating donor rbcs. the antibody may be identifi ed by eluting it from the rbcs or by demonstrating it within the recipient's serum. the specifi city of the antibody is often against such rbc antigens as the rh family, kidd, duffy, or kell systems. hemolysis may not occur, but if it does, it is likely to be extravascular and only rarely causes renal failure or dic. prevention of these reactions is diffi cult. alloimmunization to foreign rbc antigens occurs in approximately % of transfusions. detection of delayed antibodies is the purpose for requiring a new blood bank specimen every hours if the patient has recently been transfused. permanent transfusion records should record the occurrence of delayed antibodies, even though they may not be apparent at a later crossmatch. access to transfusion databases is critical for the care of patients with a past history of transfusion. transfusion-related acute lung injury (trali) is an uncommon ( . %) but serious adverse effect of transfusion that has only recently been gaining recognition. similar reactions have been called pulmonary leukoagglutinin reaction or noncardiogenic pulmonary edema. these reactions consist of acute respiratory distress syndrome (ards), which develops to hours after transfusion. signs and symptoms include bilateral pulmonary infi ltrates, hypoxemia, fever, and occasionally hypotension. monitored patients are found to have normal or low pulmonary wedge pressure and central venous pressure, as contrasted with patients experiencing volume overload. if adequate respiratory support and oxygenation are established promptly, spontaneous resolution generally occurs within to days. deaths have nonetheless occurred, particularly with a delay in diagnosis. , episodes of trali appear to have several possible causative mechanisms. some cases may be caused by donor antibodies reacting with recipient neutrophil or hla antigens. plasma factors related to blood storage have also been implicated, such as lipid substances from deterioration of donor cell membranes that prime recipient neu-trophils, which then damage the pulmonary vasculature and lead to increased capillary permeability and an ardslike syndrome. other clinical factors may contribute to increased risk, such as cardiac bypass surgery or other procedures. in the antibody model at least, the implicated antibody is unique to the donor and the affl icted recipient will probably not experience another such reaction, provided that the recipient is not exposed to the same donor. trali is undoubtedly under-recognized in the critical care setting and may frequently be confused with fl uid overload or cardiogenic pulmonary edema. transfusion-associated gvhd (ta-gvhd) is a welldocumented, but probably under-recognized, highly lethal immunologic complication of blood transfusion. immunocompromised patients infused with blood components containing viable donor lymphocytes are at risk for engraftment of the allogeneic lymphocytes and ensuing rejection of recipient (host) tissues. transfusion recipients who are at highest risk include neonates, especially the very premature, bone marrow and organ transplant recipients, and leukemia and lymphoma patients. ta-gvhd has also been reported in patients after cardiac surgery who received designated donor blood from relatives; presumably, the hla antigenic differences between donor and recipient were insuffi cient to stimulate a recipient immune response but suffi cient to elicit a donor immune response. the onset of ta-gvhd is usually within to days after transfusion, and it is manifested as fever and rash, followed by diarrhea and evidence of liver and bone marrow injury. ta-gvhd differs from that seen in bone marrow transplantation (bmt) by its involvement of the marrow and by far greater mortality. treatment is largely ineffective, and mortality exceeds %. irradiation of blood components at gy prevents ta-gvhd by eliminating the donor lymphocyte mitogenic response. all cellular blood components should be irradiated before transfusion to high-risk patients. the functions of the cellular components of blood are unaffected, although damage to rbc membranes limits postirradiation storage of prbcs. blood donated by a relative for any patient should be irradiated, as should hla-matched or crossmatched platelet products. allogeneic blood transfusion has been shown to modulate and suppress the recipient's immune response, an effect fi rst noted with kidney transplantation. immunosuppression in a critical care setting is generally undesirable, but whether transfusion has a signifi cant impact is debated. ongoing clinical issues center around two areas of controversy: the putative association between blood transfusion and increased numbers of postoperative infections and increased and more rapid rates of tumor recurrence in surgical oncology patients with certain malignancies. there has been no resolution of either issue despite a few prospective trials having been performed. the largest pro-spective trial of colorectal cancer resection, for example, is negative, but a meta-analysis of the extant data suggests that an adverse effect on recurrence does exist. similarly, most of the randomized trials of postoperative or critical care unit infections are too small to indicate an effect of transfusion, but all point in the direction of an adverse effect. , controversy will continue until larger randomized trials are conducted. the precise mechanism of the immunosuppression induced by allogeneic transfusion has not yet been delineated, and several mechanisms may be involved. alterations identifi ed in laboratory and clinical transfusion recipients have included depression of the t-helper/tsuppressor lymphocyte ratio, decreased natural killer cell activity, diminished interleukin- generation, formation of anti-idiotype antibodies, impairment of phagocytic cell function, and chronic persistence of donor lymphocytes (microchimerism), suggestive of low-level gvhd. difficulties in analysis of human data arise because patients requiring blood transfusions have conditions that themselves induce immune changes. there is some evidence, bolstered by the results of two large clinical trials, to suggest that leukocyte reduction of blood components reduces or eliminates this immunosuppressive effect. proponents of this viewpoint argue that for this reason, ulr would benefi t most patients receiving blood transfusions and lead to fewer infections, tumor recurrences, and other related putative risks of transfusion, all potentially resulting in saving lives and cost. prospective trials will be extremely important. public awareness of transfusion-associated acquired immunodefi ciency syndrome (aids) has done more to revolutionize transfusion practice than any other transfusion risk by resulting in more conservative blood use, more stringent donor selection criteria, and improved screening tests. the result is that viral transmission rates are now diffi cult to measure, and the risk of transfusionrelated infectious diseases is lower than ever. the current best estimate is that to units per , will transmit some kind of infection if agents such as cmv or epstein-barr virus are included. bacterial infection has become the most common infectious risk thanks to increasingly sensitive donor screening tests, including nucleic acid testing (nat) to detect viral dna or rna, which has shortened the infectious period and reduced the risk for post-transfusion hepatitis (pth) and other viral infections. several fatalities are reported yearly from the transfusion of blood components contaminated with viable, proliferating bacteria, with or without the accumulation of endotoxin. platelet concentrates, because they must be stored at room temperature, are particularly prone to bacterial growth, with a reported incidence of in , transfusions. organisms isolated from platelets and implicated in fatal transfusion reactions include staphylococcus and streptococcus species and gram-negative bacilli. fatalities resulting from bacterial contamination of refrigerated rbcs have occurred as well and more often involve cryophilic bacteria. rbc transfusions contaminated by yersinia enterocolitica have been consistently reported for a decade. transfusion reactions caused by bacterial or endotoxin contamination are fortunately quite rare, but mortality exceeds %. signs and symptoms of reactions caused by microbial contamination overlap those of hemolytic transfusion reactions and consist primarily of fever and hypotension, along with other signs of endotoxic shock. if recognized promptly, a gram stain of the implicated unit can be prepared immediately and, if positive, appropriate antibiotic and supportive therapy instituted. autologous blood components may also be contaminated at the time of collection; therefore, reactions occurring in patients who are receiving their own blood should not be dismissed but instead should be evaluated as fully as though the patients had received allogeneic blood. the success of viral screening measures is most clearly illustrated by the fall in the risk for pth over the past decades. although pth continues to be a signifi cant cause of morbidity and mortality, the nature of pth has changed through the years with the stepwise institution of various donor screening measures. the elimination of paid donors in and the successive introduction of immunologic tests for hepatitis b have resulted in a steady reduction in the rates of pth caused by hepatitis b virus (hbv) to approximately per million units of transfused blood products. although about % to % of hbv transmissions will result in acute hepatitis, chronic hbv infection develops in less than % of such patients. in contrast, the risk for chronic hepatitis c virus (hcv) infection after transfusion is higher, nearly %, and the long-term risk for cirrhosis-or hepatocellular carcinoma-related mortality is about % over more than years after pth secondary to hcv. , the clinical course of hepatitis a is generally milder, and the lack of a chronic carrier state means that with donor screening for symptoms of the acute illness, the risk of transmission is much lower, estimated at less than one in a million units. the prevalence of hepatitis b surface antigenemia among fi rst-time blood donors is . %, and the prevalence of hepatitis c antibodies in donors is approximately . % to . %. at this time, given the sensitivity of current screening assays, including the latest generation of enzyme immunoassays (eias) and nat, the current risk of pth resulting from hcv is believed to be about in , or less. although hbv is still implicated in pth (attributable to the seronegative "window" period in newly infected donors), the risk of transfusion-associated hepatitis b is about in , units. retroviruses, rna-based viruses characterized by their reverse transcriptase and integration into the host genome, and lentiviruses, a subset of retroviruses, are ubiquitous in animals and were initially identifi ed in humans in the early s. those known to be capable of transmission by transfusion are hiv- , hiv- , and human t-cell leukemia/lymphoma virus (htlv) i and ii. transfusion-associated aids was initially reported in late . the fi rst report of an associated viral agent did not appear until late in , and in march the screening enzyme-linked immunosorbent assay (elisa) to detect antibody to hiv- was licensed and immediately incorporated into the blood-screening process. improved confi dential donor screening appeared to decrease the risk of infectious units appearing in the donor pool. , the discovery that heat treatment reduced transmission resulted in a reduction in transmission by plasma products, especially to persons with hemophilia. clinical aids developed in more than % of recipients of infected blood products, and the vast majority succumbed to the disease. removal of donor units with seropositivity by elisa was insuffi cient to prevent transmission of hiv- ; several hundred cases were reported annually after introduction of the elisa test. subsequent development of an assay for the p antigen and then nat has lowered the risk of transfusion-associated hiv- infection to less than one in a million (see table - ). despite donor screening and sensitive assays, including eia, nat, and p antigen, an extremely small, but fi nite risk of hiv- transmission by screened blood transfusions remains. this risk is largely due to the seronegative "window" period experienced by newly infected donors, which is estimated to be an average of days. a second retrovirus, hiv- , fi rst described in residents of countries in west africa and subsequently detected in migrants to western europe, causes an immunodeficiency syndrome similar to that caused by hiv- . although very few cases of hiv- have been reported in the united states , and there have been no reported transfusion-transmitted cases, experience with other retroviruses suggests that screening may prevent the majority of potential transmission. therefore, donated blood is now screened by an assay for the presence of antibody to hiv- . the retrovirus htlv-i is the causative agent of adult t-cell leukemia (atl) and is strongly implicated in the chronic, progressive neurologic disorder termed tropical spastic paraparesis or htlv-i-associated myelopathy (tsp/ham). htlv-ii has been linked to hairy cell leukemia, but no transfusion-transmitted cases have been reported. the virus exhibits strong serologic crossreactivity with htlv-i such that screening assays fail to distinguish between antibodies to either virus. transfusion-transmitted htlv-i has been demonstrated. tsp/ham has developed in a small percentage of infected transfusion recipients, but no transfusionassociated cases of atl have been seen. approximately . % of donors in the united states are seropositive for htlv-i and htlv-ii ; further testing reveals the majority of them to be htlv-ii. donated blood is currently screened for antibodies to htlv-i and htlv-ii. the estimated risk of htlv transmission by screened negative blood is believed to be in , to million. cmv is a human herpesvirus that establishes latent infection in the host's tissues, particularly leukocytes, and is transmitted by all cellular blood components. seropositivity, or the presence of antibody, denotes previous exposure to the virus but does not confer protective immunity. secondary reinfection or reactivation of latent infection can occur. antibodies to cmv persist for life and serve as a marker indicating the potential for transmission of live virus. immunocompetent recipients of transfused cmvpositive blood experience minimal morbidity and mortality. the majority are asymptomatic, whereas a heterophile-negative mononucleosis syndrome may develop in a few. immunocompromised patients, however, may suffer life-threatening manifestations such as severe interstitial pneumonitis, gastroenteritis, hepatitis, or disseminated disease. several groups of patients are at particular risk (box - ), and these patients should receive blood incapable of transmitting the virus. other patients may benefi t from cmv-negative blood as well, such as seronegative solid organ transplant recipients or autologous bmt patients. screening of donated blood for cmv is not routinely done but can be performed quickly if necessary. because the prevalence of donor seropositivity is quite high in some regions ( % to %), cmvseronegative blood may not be readily available. blood that is leukocyte depleted ("cmv safe") may be as effective as seronegative blood in the prevention of cmv transmission, although a recent meta-analysis of clinical trials comparing the two methods suggests that cmvnegative blood products might have a slight advantage over leukocyte-depleted products. many blood-borne parasites may be transmitted by transfusion, although this is a rare occurrence in the united states because of donor screening questions and the low endemicity of implicated agents. changing immigration patterns and worldwide travel, however, make transfusion-transmitted parasites an increasing concern. on a worldwide basis, malaria is the most important transfusion-transmitted infective organism, although only about three cases occur in the united states each year. such infections are manifested by delayed fever, chills, seronegative pregnant women seronegative premature infants weighing less than g seronegative allogeneic or autologous bone marrow transplant recipients seronegative transplant recipients of seronegative organs diaphoresis, and hemolysis, often masked by underlying medical conditions. fatalities have occurred. babesiosis, a tick-borne disease, is endemic in regions of the united states, especially the northeast, with a seroprevalence of about %. transfusion-transmitted cases have been reported, with asplenic or immunocompromised patients being particularly susceptible. with increases in the number of latin american immigrants to the united states, american trypanosomiasis (chagas' disease), which is endemic in latin american countries, has emerged as a potential pathogen. other parasitic diseases that have been transmitted by transfusion include toxoplasmosis, leishmaniasis, and lyme disease. parvovirus b has now been recognized as a pathogen capable of transmission by transfusion, with typical clinical fi ndings and the potential for severe hematologic complications. cases of epstein-barr virus infection with a typical mononucleosis-like illness have been reported after transfusion. west nile virus has also been transmitted by transfusion. h n infl uenza, severe acute respiratory syndrome (sars), and other new viral infections should be capable of transmission by transfusion, although cases have not been reported and the prevalence of asymptomatic disease is unknown. a rising area of concern is the transmission of prion disease, either jacob-creutzfeldt disease or bovine spongiform encephalopathy (bse). donor referral criteria were implemented in for these diseases, and transmission of bse has been reported in the united kingdom. massive transfusion is defi ned as the administration of blood components in excess of one blood volume within a -hour period. in an average adult ( kg), this represents approximately units of wb or equivalent prbcs, crystalloid solution, and other components. massive transfusion, especially in the range of or more units of blood products, causes complications not generally seen in usual transfusion practice: accumulation of undesirable substances present within banked blood and dilutional depletion of normal blood constituents that are lacking in stored units. trauma victims, surgical patients undergoing extensive procedures, and patients with vascular or coagulation disorders may be massively transfused in the critical care setting. survival of the massive transfusion episode is determined more by the nature and degree of the patient's injuries or medical conditions than by the transfusions themselves, but the presence of adverse effects of massive transfusion can complicate patients' courses in the icu. transfusion of large quantities of stored blood defi cient in functional platelets often results in hemostatic defects or outright thrombocytopenia. circulating platelets consistently decrease in inverse proportion to the amount of blood administered, with the hemostatically signifi cant level of × /l reached after u. , functional defects have also been noted, and the bleeding time is prolonged. despite these laboratory changes, severe diffuse bleeding develops in less than % of massively transfused patients, and no laboratory studies predict those who will. prophylactic platelet transfusion has not been shown to be of benefi t. platelet counts may return to hemostatically effective levels quickly in patients with normal marrow function. currently, resuscitation of massively bleeding patients is most often accomplished with prbcs in combination with crystalloid solution. this should result in hemodilution to about % of normal plasma factor levels after the transfusion of about units; this factor level can effect normal hemostasis. in reality, however, crystalloids may be given in excess of prbcs, so after units is transfused, less plasma protein may remain. bleeding is unlikely until prothrombin time (pt)/inr and ptt prolongations exceed . to . times the midpoint normal range, the equivalent of an inr approaching . . as with platelets, prophylactic administration of ffp has not proved effective in preventing diffuse bleeding. thus, the decision to transfuse should be made on an individual basis, as determined by the presence of bleeding or unacceptable risk in patients with documented abnormalities in coagulation. one new area of controversy in the treatment of patients with massive hemorrhage is the use of recombinant activated factor vii. this new agent was created for the treatment of hemophiliac patients with high titers of antibodies to factor viii, which makes them unable to benefi t from transfusion of recombinant factor viii. activated factor vii bypasses that problem by binding to tissue factor and directly activating thrombin and hence generating fi brin. it is extremely expensive, has a short half-life, and carries a risk of inducing pathologic thrombosis, with potentially grave consequences. nevertheless, in numerous case reports, this new agent appears to potentially be benefi cial if used early in the resuscitation of massively injured patients. unfortunately, its unsupervised use has also resulted in thrombotic complications and relative lack of success, both of which suggest that carefully controlled clinical trials are appropriate. blood preservative solutions contain excess citrate, which anticoagulates stored blood by binding ionized calcium. wb contains approximately . g of citrate/citric acid per unit in the plasma fraction. patients with normal liver function can metabolize the citrate load in unit of wb in minutes, but hepatic impairment may extend removal to minutes or longer. toxicity may result when citrate is administered in excess of the metabolic rate, thereby causing a decrease in ionized calcium levels. although paresthesias, cramps, and myoclonus accompany citrate excess, the chief danger of hypocalcemia is depression of myocardial contractility and potential prolongation of the qt interval. because the effects of citrate are transient and the use of prbcs containing little residual citrated plasma is far more common than massive transfusion with wb, routine administration of calcium is not indicated; clinically signifi cant rebound hypercalcemia may result. calcium infusion should be limited to hypoperfused patients with hepatic or cardiac failure who manifest citrate toxicity, and careful monitoring is essential. as potassium leaks from rbcs during storage, up to meq of extracellular potassium may accumulate in each unit. however, dangerous levels of potassium rarely develop in adults from stored blood; the potassium level is more likely to be determined by the patient's acid-base status. studies of massively transfused patients have demonstrated a wide range of potassium levels, with hypokalemia seen as frequently as hyperkalemia. because of the many physiologic mechanisms altered during resuscitation, including those of the respiratory, renal, cardiac, and hepatic systems, it is impossible to predict the net effect of massive transfusion on serum potassium levels. the ph of banked blood drops during storage, from . at the time of collection to as low as . after several weeks of storage. administration of large quantities of acidic blood, together with the metabolic acidosis common in these patients before resuscitation, would lead one to expect worsening acidosis as the outcome of massive transfusion. however, patients are more likely to exhibit metabolic alkalosis at the end of the transfusion episode, , partly because of improved tissue perfusion and the metabolism of citrate and lactate to bicarbonate. patients in renal failure may be unable to handle the bicarbonate load and require dialysis. acidosis persisting after transfusion suggests inadequate tissue perfusion. empiric administration of bicarbonate to counter the acid load is not warranted and may contribute to the deleterious effects of hypercapnia in patients with impaired ventilation. as discussed previously, the level of rbc-associated , -dpg in banked blood declines during storage, which increases the affi nity of hemoglobin for oxygen and thereby results in decreased oxygen off-loaded to tissues. even in massively transfused patients, it has been diffi cult to document a clinical impact of this shift, and no reliable method for restoring red cell , -dpg has been developed. wb and prbcs are stored at approximately º c and require to minutes to warm to room temperature. elective transfusions at standard fl ow rates are tolerated without the need to warm the blood; however, core body temperature, measured by esophageal probe, can fall to º c or lower with the administration of large volumes of cold blood over a period of to hours. adverse effects of hypothermia include a decreased heart rate and myocardial contractility, cardiac arrhythmias, increased affi nity of hemoglobin for oxygen resulting in decreased tissue oxygen delivery, dic, and impaired ability to metabolize the citrate load of stored blood. both blood warmers and patient warming may be instituted during massive transfusion, and patient core temperature should be monitored during such resuscitative efforts. whether massive transfusion in and of itself is a cause of ards is another source of controversy. there are certainly theoretical reasons why massive transfusion might precipitate ards: all cellular transfusions contain damaged or activated wbcs, cell membranes, aggregated platelets, and microthrombi, all of which are capable of lodging in and damaging pulmonary capillaries. despite this possibility, neither microfi ltration of transfusions nor routine leukocyte depletion has shown a signifi cant impact on the incidence of ards in massively transfused patients. certainly, other causes of ards exist in patients who undergo massive transfusion, and the possibility of volume overload and trali should be considered in the evaluation of patients with hypoxia and diffuse pulmonary infi ltrates after massive transfusion. management of such patients is supportive, consistent with the overall management of massive transfusion. , autoimmune hemolytic anemia patients with autoimmune hemolytic anemia (aiha) have an autoantibody, usually of broad specifi city, that fi xes itself to their rbcs and triggers extravascular immune-mediated destruction. patients with aiha have a positive direct antiglobulin test (dat, commonly known as the coombs test) and varying degrees of he molysis, and their autoantibodies cause agglutination of rbcs from all donors during crossmatching. if the hemolysis is brisk, patients may require red cell transfusion to support oxygen needs before medical management of the aiha is effective. hence, transfusion is diffi cult because agglutination during crossmatching interferes with proper defi nition of compatible units of rbcs and because the transfused rbcs are themselves subject to the same immune hemolysis as the host rbcs. many blood banks have methods for depletion of autoantibodies from the recipient's plasma and elution of antibodies from rbcs to arrive at a proper crossmatch. although such crossmatches are time consuming and not generally available on an emergency basis, they can be lifesaving. criteria for transfusion should remain the same as for other recipients. rbcs are crossmatched for red cell antigens in the abo and rh (d) group and for other red cell antigens when antibodies are present. however, there are several hundred other red cell antigens in the human family, and with repeated transfusion recipients may become alloimmunized to other antigens. generally, alloimmunization occurs in approximately % of transfusions, but the prevalence of alloantibodies is higher in chronically transfused, relatively immunocompetent patients, especially african americans, whose distribution of red cell antigens has signifi cant variation from the white population. alloimmunization rates of % or higher may be found in chronically transfused patients with hemoglobinopathies who have not received rbcs matched to potent minor antigens such as kell, duffy, and lewis. alloimmunization may present diffi culties in crossmatching of blood, to the point that compatible blood must be obtained from raredonor registries, if at all. other patients present unresolved serologic problems in that the alloantibody is never precisely identifi ed yet the majority of blood available for transfusion is incompatible. the delay engendered by working with multiple or unidentifi ed antibodies may be unacceptable in some critical care situations in which the need for oxygen-carrying capacity leaves no choice but to transfuse incompatible blood. the behavior of these antibodies in the laboratory may assist in predicting the clinical outcome of the incompatible transfusion. special procedures such as clearance studies, fl ow cytometry and in vivo crossmatching (cautious administration of a small aliquot of blood, with subsequent observation of serum and urine for evidence of hemolysis) are useful if time permits. emergency transfusion of type o, rh-negative uncrossmatched blood is generally reserved for the resuscitation of trauma patients, for whom the delay in crossmatching may be life-threatening. the risks of alloimmunization are generally accepted as low. even rh-positive type o rbcs may be used because rates of alloimmunization to rh (d) are low under the circumstances of emergency transfusion. , dic can present the clinician with diffi cult therapeutic choices. this common disorder in critically ill patients may be manifested as severe hemorrhage or thrombosis. therapy is primarily directed at alleviating the cause and supporting the patient. supportive therapy includes the transfusion of components needed to correct the bleeding diathesis caused by the consumption of platelets and fi brinogen, in addition to prbcs to restore oxygencarrying capacity. platelets and fi brinogen (as cryoprecipitate) are the most useful components needed to repair the coagulopathy, but their use risks merely "fueling the fi re" and increasing the microthrombosis of dic. heparin anticoagulation is controversial , and may increase the risk of bleeding, especially if depleted factors are not replenished. no defi nitive clinical trials have endorsed the routine use of heparin, and randomized trials of other components and coagulation inhibitors have uniformly been negative. in general, the use of heparin and antifi brinolytic agents has been confi ned to the most severe and protracted cases of dic. cirrhotic patients or those with fulminant hepatic failure have a variety of hemostatic disorders that complicate transfusion management of a bleeding patient. hepatic synthesis of coagulation factors may be markedly diminished, thereby necessitating replacement by ffp or cryoprecipitate. patterns of factor diminution may vary between acute hepatic necrosis and chronic cirrhosis. associated hemodynamic alterations may make it impossible to administer the volumes required for effective hemostasis, however, and any effect is transient. the use of factor concentrates or antifi brinolytic agents may precipitate thrombosis. activation of fi brinolysis and decreased clearance of activated factors may produce or mimic chronic dic, thus further exacerbating the factor defi ciencies and impairing coagulation. abnormal platelet function and thrombocytopenia may contribute to the coagulopathy of liver disease, with concomitant splenomegaly reducing the effectiveness of platelet transfusions. bleeding in uremic patients is exacerbated by an acquired platelet defect, in part secondary to dialyzable circulating molecules soluble in platelet membranes. plateletassociated vwf and plasma high-molecular-weight vwf multimers have also been shown to be decreased, which may explain the benefi t shown by ddavp and cryoprecipitate in shortening the bleeding time and improving hemostasis in some uremic patients. raising the hct by red cell transfusion in anemic patients has also been shown to shorten the bleeding time, presumably as a result of blood vessel wall-laminar blood fl ow interaction. transfusion of platelets in the absence of thrombocytopenia is unlikely to be of benefi t because the transfused platelets rapidly become dysfunctional. more aggressive hemodialysis is the most widely accepted method of reducing platelet dysfunction. bmt patients are vulnerable to the severe infectious and toxic side effects of ablative treatment and hence may be cared for in critical care units. these patients may have intensive red cell and platelet transfusion requirements and need specialized products such as cmv-negative and irradiated blood components. a blood bank problem uniquely encountered in bmt is the need to switch the patient's abo group because of an abo-mismatched transplant, thus necessitating an exchange transfusion of red cells and plasma-containing products (i.e., platelet concentrates) of differing abo type to avoid hemolysis of donor and recipient cells. bmt patients may also manifest an increased rate of delayed hemolytic reactions as donor "passenger" lymphocytes recognize recipient or transfused red cell antigens. patients should be monitored particularly closely between days and after a minormismatched allogeneic transplant, and aggressive transfusion should be undertaken if the hemoglobin level falls and the dat result becomes positive. the safest transfusion is one that is not given. therefore, alternatives to blood component therapy continue to be sought and are valuable adjuncts in some instances. it is possible to limit homologous blood exposure by the appropriate use of pharmacologic agents that promote hemostasis and the administration of recombinant hematopoietic growth factors or biologic growth modifi ers to stimulate marrow hematopoiesis. only one substitute for rbc transfusions has been approved in the united states, a polyfl uorocarbon oxygen carrier with signifi cant limitations as a blood substitute. other preparations that have been explored in clinical trials are cell-free hemoglobin solutions cross-linked or polymerized by chemical manipulation to prevent rapid clearance from the circulation. they are intended to provide short-term oxygen-carrying capacity for acutely ill patients and have the advantage of not requiring crossmatching or infection control. although these proposed products may have a longer shelf-life and are easier to transport, their drawbacks are many. most have a circulatory half-life of only about hours. the oxygen dissociation curve for these substitutes is also frequently not favorable: either a high fio is required to "load" these molecules or they are less likely to deliver oxygen efficiently at lower po levels. because the hemoglobin source is reclaimed bovine or human red cells, it is unlikely that patients who do not accept blood components because of their religious beliefs (jehovah's witnesses) will accept these types of hemoglobin solutions. one product in development uses recombinant technology to generate hemoglobin, and it is hoped that this solution may be acceptable to these patients. the licensed perfl uorocarbon solutions have failed to demonstrate any utility as intravascular oxygen carriers because of their unfavorable p- (oxygen half-saturation pressure) and oxygen off-loading characteristics. they are fi nding limited application in regional oxygenation during angioplasty or stent placement procedures and a more novel use in "liquid ventilation." this involves the ventilation of intubated patients experiencing severe pulmonary compromise with superoxygenated perfl uorocarbon solutions in place of oxygen-enriched air. the synthetic vasopressin analogue ddavp increases plasma factor viii : c and promotes the release of vwf from endothelial stores. ddavp has provided effective hemostasis in bleeding patients with mild hemophilia a and type i von willebrand's disease and has been used as prophylaxis for patients undergoing surgery. ddavp reportedly improves platelet function in some patients with qualitative platelet disorders associated with uremia, cirrhosis, and aspirin ingestion. studies of its effi cacy in cardiopulmonary bypass procedures are confl icting, but a subset of these patients may benefi t. the chief drawback to its use is tachyphylaxis, which develops in essentially all cases after short-term repeated administration. the lysine analogues ε-aminocaproic acid and tranexamic acid inhibit fi brinolysis by blocking the binding of plasminogen and plasmin to fi brin. these antifi brinolytic agents may decrease bleeding and thus the need for homologous blood components in patients with hemophilia, thrombocytopenia, and systemic fi brinolysis. a novel and effective use of tranexamic acid involves administration as a mouthwash in preparation for oral surgery in patients with hemophilia or those receiving oral anticoagulant therapy. the most serious side effect of these agents when systemically administered is thrombosis; thus, it is important to use them appropriately and monitor the patient carefully during their use. aprotinin is a naturally occurring bovine serine protease inhibitor that acts on plasma serine proteases such as plasmin, kallikrein, trypsin, and some coagulation proteins. aprotinin has been shown to reduce blood loss in patients undergoing cardiopulmonary bypass surgery by inhibiting fi brinolysis and preventing platelet damage. however, more recent reports of renal injury and longterm mortality may mean an end to its use. aprotinin has been used extensively in liver transplantation, which involves high blood loss. repeated administration poses the risk of anaphylaxis and renal dysfunction. when time permits, vitamin k is the preferred agent to reverse the coagulopathy induced by oral anticoagulants. normalization of the pt can be seen in as few as to hours. additionally, selected cirrhotic patients may exhibit improvement in the pt when treated with therapeutic doses of vitamin k. many patients in critical care units exhibit a prolonged pt, especially if dietary supplements are limited and broad-spectrum antibiotic therapy is given. vitamin k is a safe and effective agent for reversing this effect. recombinant erythropoietin (epo) has dramatically reduced the red cell transfusion requirements of patients in chronic renal failure. epo also has applications in the adjunctive treatment of the anemia of premature infants and the anemia of chronic disease, especially rheumatoid arthritis, cancer, and aids. studies of its effi cacy in reducing perioperative red cell transfusion requirements by increasing the yield of predeposited autologous blood or stimulating bone marrow synthesis after surgery have shown benefi t in reducing blood transfusion, although preoperative planning and autologous deposits are required. in contrast and probably because the impact of epo is not immediate, the effi cacy of epo in the icu is unproven and awaits the results of large clinical trials. recombinant growth factors such as granulocytemacrophage colony-stimulating factor (gm-csf) and g-csf stimulate marrow production of leukocytes by enhancing several different granulocyte and macrophage functions. these agents are fi nding application in reducing the neutropenic period in bmt and cancer chemotherapy by increasing the leukocyte count in hypoproliferative marrow conditions. these myeloid growth factors are replacing granulocyte transfusions for their few remaining indications. cell salvage equipment has been in clinical use for several decades, and although cell salvage is clearly capable of rescuing otherwise "lost" red cells, its full impact on transfusions has been poorly documented. cell salvage generally consists of collection of shed blood from a clean, uncontaminated operating fi eld, followed by removal of the cellular elements and retransfusion into the patient. cell salvage has been used both intraoperatively and postoperatively, especially in cardiac surgery. although the clinical studies of cell salvage have many fl aws, the overall success of this therapy in reducing transfusion has resulted in its wide application. risks include bacterial contamination, febrile reactions, triggering of dic, and coagulopathy as a result of dilution. when combined with acute intraoperative hemodilution, this technology is also potentially cost saving. the word apheresis is derived from the greek aphairein, "to take away"; thus, therapeutic hemapheresis is performed to remove unwanted plasma constituents (plasmapheresis) or blood cells (cytapheresis). automated cell separators use centrifugation or membrane fi ltration to remove and concentrate the selected blood element. many of the same devices used to prepare apheresis blood components for transfusion are used to perform patient procedures, so therapeutic apheresis is often administered under the auspices of the transfusion medicine service. rapid removal of plasma or cells may fi nd several applications in intensive care practice (box - ). the goal of plasmapheresis, or plasma exchange (pe), is to remove or reduce the levels of an undesirable plasma constituent or, alternatively, by means of plasma replacement, to supply a missing substance. the agent to be removed by pe is thought to be an autoantibody in some of the neurologic, renal, or hematologic conditions treated in this manner. immunomodulation by pe is another explanation for its effect, a theory indirectly supported by the equivalent effi cacy of ivig therapy for several of these disorders. pe for the amelioration of hyperviscosity from either excess igm in waldenström's macroglobulinemia or excess ig in multiple myeloma is an effective temporizing measure in the treatment of these conditions. plasmapheresis with pe is the standard therapy for ttp. unfortunately, few controlled trials of pe exist, although anecdotal reports abound. pe is seldom the defi nitive treatment of most of these conditions and is used most appropriately as a short-term adjunct to other medical modalities. the kinetics of pe predicts that a one-volume exchange removes % of a given plasma constituent if the blood volume does not change or additional synthesis or mobilization of the substance does not occur. two or three volume exchanges remove % and %, respectively. highly protein-bound, intravascularly concentrated substances are most effi ciently removed, whereas substances with a large volume of distribution such as igg, active synthesis, or large extravascular stores are removed at less than predicted rates. the usual short-term intense course of pe schedules fi ve one-volume exchanges (approximately l in normal-sized adults) over a -day period. the appropriate replacement fl uid in most conditions is an albumin-saline mixture, which provides oncotic support without the risk of disease transmission borne by ffp. pe in patients with ttp uses replacement with ffp to supply the plasma protease that is consumed during the disease. side effects of pe are relatively common ( % to % of procedures) but generally minor and are related to vascular access, temporary discomfort, or vasomotor symptoms. patient death is rarely due to the procedure itself but is largely of cardiopulmonary causes. plasma proteins such as coagulation factors, immunoglobulins, and complement will be removed by pe, and laboratory test results of coagulation and electrolytes may be deranged in the hours after pe. clinical bleeding is rarely observed. most coagulation factors do not fall below hemostatic levels and recover within hours, with the exception of fi brinogen, which may require several days for complete replenishment. leukapheresis may be required to urgently reduce the wbc count in patients with acute myeloid or lymphoblastic leukemia or chronic myelogenous leukemia with peripheral counts of × /l or greater. each procedure is expected to drop the count by a third, but the effect is short lived. leukapheresis should be reserved for use only as an adjunct to chemotherapy in patients with pulmonary or cerebral leukostasis or for cytoreduction before chemotherapy in patients at risk for severe tumor lysis syndrome. plateletpheresis may be benefi cial as short-term therapy in patients with symptomatic thrombocythemia manifested as cerebral or myocardial ischemia, pulmonary emboli, or gastrointestinal bleeding. each procedure should effect a % reduction in the platelet count. cytotoxic therapy should be started concomitantly as the defi nitive treatment. litigation related to blood transfusion has become prominent, particularly after the epidemic of transfusionassociated aids. most states regulate blood banking and medical practice, but blood products are regarded as symptomatic hyperviscosity thrombotic thrombocytopenic purpura neurologic diseases: myasthenia gravis, guillain-barré syndrome uncontrolled systemic vasculitis with critical end-organ injury symptomatic leukocytosis symptomatic thrombocythemia sickle cell anemia crisis (pulmonary or central nervous system manifestations) a service, not as a commodity, so standard product liability does not pertain to blood components. however, negligence in the course of preparing, testing, transferring, crossmatching, or administering blood products is still a potential cause for legal action. every clinician who orders transfusions must be aware that blood components, like drugs, are approved for specifi c uses and that the indications should be clearly documented in the medical record. the informed consent of the patient is an important area of potential liability. the joint commission on accreditation of healthcare organizations (jcaho) has required written patient consent for blood transfusions since . what constitutes adequate informed consent and who is responsible for advising the patient are still in contention. elements of informed consent include an understanding of the need for transfusion, its risks and benefi ts, and the alternatives, including the risk of not undergoing transfusion, as well as the opportunity to ask questions. whether the clinician documents informed consent with an individual progress note in the patient record or with a standardized form is generally established as institutional policy. similarly, institutions vary with respect to policies for consenting adults who are temporarily incompetent, such as sedated patients in the icu. a competent adult patient may refuse blood transfusion, and jehovah's witnesses commonly do so for religious reasons. case law is clear in upholding this right of the patient, which extends to care given at such time as the patient may become incompetent (i.e., comatose) after such refusal was expressed before becoming incompetent. courts will usually order a lifesaving transfusion for minors. exceptions have been made in the case of some "emancipated minors" who are at the age of reason. most states have evoked a "special interest" in the welfare of a fetus in ordering transfusions to pregnant women. the advent of sentinel event reviews and other quality management procedures for patient safety has had an impact on transfusion practice as well. procedures for patient identifi cation before surgical procedures, including devices such as bar code readers, have also been applied to transfusion practice. however, annual sentinel event reviews reporting transfusion errors have remained constant according to jcaho records. ■ blood components should be prescribed like drugs. appropriate blood component therapy requires that the specifi c blood product needed for a clear indication be prescribed, with avoidance of a formulaic approach. ■ red blood cells should be transfused only to increase oxygen-carrying capacity. transfusion decisions should be based on individual patient physiology. the majority of patients with hemoglobin levels greater than or g/l will not require transfusion unless they have limited cardiopulmonary reserve or active bleeding. ■ platelet transfusions are indicated for patients who are bleeding because of thrombocytopenia or functional platelet defects. guidelines for platelet transfusion are also conservative. prophylactic platelet transfusion remains controversial and is not warranted in many situations. ■ fresh frozen plasma is indicated for the repletion of coagulation factors in bleeding patients defi cient in those factors or to provide specifi c plasma proteins that cannot be obtained from safer sources. ■ cryoprecipitate is a concentrated source of fi brinogen and selected coagulation factors. cryoprecipitate may be more helpful in correcting the hypofi brinogenemia of dilutional or consumptive coagulopathy than fresh frozen plasma. ■ adverse reactions to blood components occur in % to % of transfusion episodes. adherence to routine protocols for the evaluation of transfusion reactions may save lives. ■ acute hemolytic reactions are the leading cause of immediate transfusion fatalities. prevention of these reactions requires strict adherence to transfusion and patient identifi cation procedures. ■ transmission of infectious agents by transfusion has been markedly reduced, and bacterial infection is now the most common infectious complication of transfusion. ■ adverse effects unique to massive transfusion are likely to occur in the icu and complicate the management of critically ill or severely injured patients. component therapy for such patients should remain conservative. the emerging role of activated factor vii in the treatment of these patients requires further evaluation. ■ informed consent for blood transfusion is a standard of practice. a competent adult has the legal right to refuse blood transfusion. consent in critically ill patients remains subject to individual institution policies. department of health and human services, food and drug administration: the code of federal regulations, cfr parts , , standards for blood banks and transfusion services markers for transfusiontransmitted disease in different groups of blood donors comparative safety of units donated by autologous, designated and allogeneic (homologous) donors directed blood donations: con goldfi nger d: directed blood donations: pro shelf-life of bank blood and stored plasma with special reference to coagulation factors generation of cytokines in red cell concentrates during storage is prevented by prestorage white cell reduction universal wbc reduction: the case for and against chemical and hematological changes in stored cpda- blood restoration in vitro of erythrocyte adenosine triphosphate, , -diphosphoglycerate, potassium ion, and sodium ion concentrations following the transfusion of acid-citrate-dextrose stored human red blood cells comparison of the hemostatic effects of fresh whole blood, stored whole blood, and components after open heart surgery in children a practice guideline and decision aide for blood transfusion rbc transfusion in the icu: is there a reason? descriptive analysis of critical care units in the united states: patient characteristics and intensive care unit utilization oxygen transport in man physiologic aspects of anemia oxygen extraction ratio: a valid indicator of myocardial metabolism in anemia human cardiovascular and metabolic response to acute, severe isovolemic anemia transfusion guidelines for cardiovascular surgery: lessons learned from operations in jehovah's witnesses physiologic effects of acute anemia: implications for a reduced transfusion trigger a multicenter, randomized, controlled clinical trial of transfusion requirements in critical care is a low transfusion threshold safe in critically ill patients with cardiovascular diseases? oxygen extraction ratio: a valid indicator of transfusion need in limited coronary vascular reserve? for the abc investigators: anemia and blood transfusion in critically ill patients the crit study: anemia and blood transfusion in the critically ill-current clinical practice in the united states red cell transfusion practice following the transfusion requirements in critical care (tricc) study: prospective observational cohort study in a large uk intensive care unit appropriateness of red blood cell transfusion in australasian intensive care practice silent myocardial ischaemia and haemoglobin concentration: a randomized controlled trial of transfusion strategy in lower limb arthroplasty mathematical analysis of isovolemic hemodilution indicates that it can decrease the need for allogeneic blood transfusion guidelines for perioperative red blood cell transfusions american society of anesthesiologists task force: practice guidelines for blood component therapy prudent strategies for elective red blood cell transfusion platelet transfusion therapy. onehour posttransfusion increments are valuable in predicting the need for hla-matched preparations volunteer donor apheresis national institutes of health consensus conference: platelet transfusion therapy the bleeding time as a screening test for evaluation of platelet function changes in blood coagulation during and following cardiopulmonary bypass: lack of correlation with clinical bleeding gamma globulin for idiopathic thrombocytopenic purpura intravenous anti-d treatment of immune thrombocytopenic purpura: experience in patients hazard of platelet transfusion in thrombotic thrombocytopenic purpura mantel n: the quantitative relation between platelet count and hemorrhage in patients with acute leukemia controversies in platelet transfusion therapy safety of stringent prophylactic platelet transfusion policy for patients with acute leukemia the natural history of alloimmunization to platelets clinical factors infl uencing the effi cacy of pooled platelet transfusions optimizing platelet transfusion therapy current status of solvent/detergenttreated frozen plasma update on pathogen reduction technology for therapeutic plasma: an overview national institutes of health consensus conference: fresh frozen plasma: indications and risks the role of prophylactic fresh frozen plasma in decreasing blood loss and correcting coagulopathy in cardiac surgery: a systematic review hemostasis testing during massive blood replacement: a study of cases should plasma be transfused prophylactically before invasive procedures? screening for the risk for bleeding or thrombosis lack of increased bleeding after liver biopsy in patients with mild hemostatic abnormalities why is fresh-frozen plasma transfused? effect of plasma transfusions on the prothrombin time and clotting factors in liver disease clotting factor levels and the risk of diffuse microvascular bleeding in the massively transfused patient fresh frozen plasma and platelet transfusion for nonbleeding patients in the intensive care unit: benefi t or harm? treatment of the bleeding tendency in uremia with cryoprecipitate desmopressin: a nontransfusional form of treatment for congenital and acquired bleeding disorders clinical uses of intravenous immunoglobulin american college of obstetricians and gynecologists: prevention of d isoimmunization, technical bulletin no human albumin solution for resuscitation and volume expansion in critically ill patients hypotension associated with prekallikrein activator (hageman-factor fragments) in plasma protein fraction granulocyte transfusions for treating infections in patients with neutropenia or neutrophil dysfunction special report: transfusion risks transfusion errors: scope of the problem, consequences, and solutions transfusion errors in new york state: an analysis of years' experience jcaho: blood transfusion errors: preventing future occurrences: available at hemolytic transfusion reaction transfusion reactions associated with anti-iga antibodies: report of four cases and review of the literature febrile transfusion reaction: what blood component should be given next? clinical outcomes following institution of the canadian universal leukoreduction program for red blood cell transfusions delayed hemolytic transfusion reaction: an immunologic hazard of blood transfusion transfusion-related acute lung injury and pulmonary edema in critically ill patients: a retrospective study for the nhlbi working group on trali: transfusion-related acute lung injury: defi nition and review transfusion-associated acute lung injury (trali): clinical presentation, treatment and prognosis transfusion-related acute lung injury caused by two donors with antihuman leucocyte antigen class ii antibodies: a look-back investigation for the trali consensus panel: proceedings of a consensus conference: towards an understanding of trali graft-versushost disease: new directions for a persistent problem survey of transfusion-associated graft-versus-host disease in immunocompetent recipients the effect of prestorage irradiation on post-transfusion red cell survival improvement of kidney-graft survival with increased numbers of blood transfusion blood transfusion-modulated tumor recurrence: first results of a randomized study of autologous versus allogeneic blood transfusion in colorectal cancer surgery transfusion-associated cancer recurrence and postoperative infection: meta-analysis of randomized, controlled clinical trials transfusion practice and nosocomial infection: assessing the evidence transfusion increases the risk of postoperative infection after cardiovascular surgery immunosuppressive effects of blood transfusion transfusion of leukoreduced red blood cells may decrease postoperative infections: two meta-analyses of randomized controlled trials transfusion immunomodulation or trim: what does it mean clinically? risks of blood transfusion transfusiontransmitted cytomegalovirus and epstein-barr virus diseases current status of microbial contamination of blood components: summary of a conference septic reactions to platelet transfusions: a persistent problem red blood cell transfusions contaminated with yersinia enterocolitica-united states, - , and initiation of a national study to detect bacteria-associated transfusion reactions routes of infection, viremia, and liver disease in blood donors found to have hepatitis c infection clinical outcomes after transfusionassociated hepatitis c adverse consequences of blood transfusion: quantitative risk estimates stramer sl: current prevalence and incidence of infectious disease markers and estimated window-period risk in the american red cross blood donor population possible transfusionassociated acquired immune defi ciency syndrome (aids): california impact of explicit questions about high-risk activities on donor attitudes and donor referral patterns. results in two community blood centers the effectiveness of the confi dential unit exclusion option human immunodefi ciency virus type infection in the united states: epidemiology, diagnosis, and public health implications update: hiv- infection among blood and plasma donors-united states transmission of human tlymphotropic virus types i and ii by blood transfusion a prospective study of transmission by transfusion of htlv-i and risk factors associated with seroconversion post-transfusion cytomegalovirus infections reducing the risk for transfusion-transmitted cytomegalovirus infection is white blood cell reduction equivalent to antibody screening in preventing transmission of cytomegalovirus by transfusion? a review of the literature and meta-analysis transmission of parasitic infections by blood transfusion hemostasis in massively transfused trauma patients laboratory hemostatic abnormalities in massively transfused patients given red blood cells and crystalloid serial changes in primary hemostasis after massive transfusion prophylactic platelet administration during massive transfusion clotting factor levels and the risk of diffuse rnicrovascular bleeding in the massively transfused patient potential role of recombinant factor viia as a hemostatic agent recombinant factor viia: unregulated continuous use in patients with bleeding and coagulopathy dues not alter mortality and outcome massive blood replacement: correlation of ionized calcium, citrate, and hydrogen ion concentration potassium levels, acid-base balance and massive blood replacement acid-base status of seriously wounded combat casualties: resuscitation with stored blood blood temperature: a critical factor in massive transfusion an in vivo evaluation of microaggregate blood fi ltration during total hip replacement massive transfusion as a risk factor for acute lung injury: association or causation? guidelines on the management of massive blood loss autoimmune hemolytic anemia approaches to selecting blood for transfusion to patients with autoimmune hemolytic anemia the clinical implications of platelet transfusions associated with abo or rh(d) incompatibility survival curves of incompatible red cells: an analytical review isotype-specifi c detection of abo blood group antibodies using a novel fl ow cytometric method use of rh positive blood in emergency situations pharmacologic agents in the management of bleeding disorders disseminated intravascular coagulation. approach to treatment the pathogenesis and management of disseminated intravascular coagulation coagulation disorders in liver disease new insights into haemostasis in liver failure plasma and platelet von willebrand factor defects in uremia deamino- -d-arginine vasopressin shortens the bleeding time in uremia donor-derived red blood cell antibodies and immune hemolysis after allogeneic bone marrow transplantation fluosol-da as a red-cell substitute in acute anemia the prospect for red cell substitutes low-dose perfl uorocarbon: a revival for partial liquid ventilation? response of factor viii/von willebrand factor to ddavp in healthy subjects and patients with haemophilia a and von willebrand's disease management of oral bleeding in haemophiliac patients amelioration of the bleeding tendency of preoperative aspirin after aortocoronary bypass grafting for investigators of the multicenter study of perioperative ischemia research group: mortality associated with aprotinin during years following coronary artery bypass graft surgery does the use of erythropoietin reduce the risk of exposure to allogeneic blood transfusion in cardiac surgery? a systematic review and meta-analysis cell salvage for minimizing perioperative allogeneic blood transfusion cost-effectiveness of cell salvage and alternative methods of minimizing perioperative allogeneic blood transfusion: a systematic review and economic model plasmapheresis in nephrology: an update national institutes of health consensus conference: the utility of therapeutic plasmapheresis for neurological disorders correction of hyperviscosity by apheresis improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome therapeutic plasma exchange as a nephrological procedure: a singlecenter experience a review of transfusion-associated aids litigation: through legal, fi nancial, and public health consequences of hiv contamination of blood and blood products in the s and s legal aspects of transfusion of jehovah's witnesses joint commission on accreditation of hospitals and healthcare organizations: sentinel event statistics: available at key: cord- -oswgjaxz authors: nan title: abstracts: (th) european congress of trauma and emergency surgery may – , brussels, belgium date: journal: eur j trauma emerg surg doi: . /s - - -z sha: doc_id: cord_uid: oswgjaxz nan introduction: frequently fractures of modern sport disciplines are fractures of the clavicle. most of them are uncomplicated and still treated without operation. therefore there is a lack of bigger studies about the treatment of clavicle fractures by elastic stable intramedullary nailing (esin). nevertheless this method becomes more and more popular, especially for young and active people. intention of this investigation was to analyze risks and results of this method to check the indication for operative treatment of simple fractures in this group of patients. material and methods: this study is a retrospective analysis of patients whose fractures of the clavicle were treated by intramedullary nailing. crucial for the decision for operation was the individual request of the patient after information of the relative indication. included were patients with fractures of the middle third, fractures of the lateral third and fractures with concomitant shoulder injuries from to . the duration of operation, intraoperative radioactive loading and complications were analyzed from the medical file. the functional outcome was measured by the constant-score. the anatomical reduction was proved by measuring the difference of the length of both clavicles ( - month after operation). results: the average duration for the middle third was min ( - ), for the lateral third ( - ) minutes and for fractures with concomitant injuries min . the mean radioactive surface dose was , cgy/cm . four complications ( %) cause revision operations: one secondary dislocation which leads to pseudarthrosis and two imminent penetrations of the medial end of the nail. one patient had developed a painful pseudobursa due to lateral penetration of the nail. additional there were two prematurely nail extractions because of medial irritation of the soft tissue. altogether we documented complications in % of the operations. overall an open reduction was necessary in %. after healing there has been no significant shortening of the fractured clavicle in comparison of both sides. the constant-score showed good postoperative results (average: , median: , lowest / ). conclusion: esin with titan nails is an alternative method of treatment with good results. nevertheless we documented complications in %. in the literature complication rates from - % has been described. the complication rate of esin seems to be comparable to the conservative treatment. in our opinion the relevant intraoperative radioactive dose is an often underestimated factor. the operation time is often longer than thought before starting and often an open reduction is necessary. because of these reasons the conservative therapy should still be the standard. esin can be an alternative especially for young athletic ambitious patients after a detailed information about the risks. disclosure: no significant relationships. introduction: the optimal management of clavicle fractures is still controversial, although the nonoperative treatment remains the standard in most fractures. recent studies have reported a higher nonunion rate and unsatisfactory functional results after nonoperative treatment. therefore, there is an increasing interest in the primary operative management of displaced midshaft fractures. however, no treatment-consensus exists at this moment. the goal of the present study was to compare plate fixation with nonoperative treatment of displaced midshaft clavicle fractures in adults with a minimum of weeks follow-up. material and methods: in a multi-center prospective clinical trial patients with a fully displaced midshaft clavicle fracture were included within one week after the injury. after a standard information procedure, patients were asked if they wanted to have a operative or a nonoperative treatment. outcome analysis included standard clinical follow-up, the constant shoulder score, the disability of the arm, shoulder and hand (dash) score and complication rate at and weeks after the injury. results: between january and october a total of patients were included: patients were treated operatively ( . % men, mean age . years) and patients were treated nonoperatively ( . % men, mean age . years). constant and dash scores were significantly higher in the operative group compared with the nonoperative group at weeks ( vs and . vs . ). there was no significant difference at weeks ( vs and . vs . ). in both groups two patients developed pseudartrosis, all four required surgery. in the nonoperative group symptomatic malunion was more frequent: twelve patients at weeks ( . %) versus none in the operative group. other complications in the operative group were mostly hardware related: pain and irritation requiring plate removal after consolidation in four patients ( . %), two broken plates due to the earlier mentioned pseudartrosis ( . %), one early outbreak of the plate ( . %) and one woundinfection ( . %). furthermore, patients with heavy professional work activities returned to their jobs at an average of three weeks after injury in the operative group compared with seven weeks in the conservative group. at weeks after the injury, the patients in the operative group were more satisfied compared to those in the nonoperative group ( % vs %). conclusion: operative fixation of a displaced midshaft clavicle fracture results in improved functional outcome at weeks after injury and in a higher satisfaction rate at weeks. this study shows that patients with heavy jobs restarted their professional activities sooner if they were treated operatively. furthermore, higher satisfaction with the appearance of the shoulder may be a reason for surgery. introduction: the unstable shoulder girdle with a fracture of the clavicle (floating shoulder, ipsilateral serial rib fractures) is a classical indication for a plate osteosynthesis of the clavicle. despite a relatively high complication rate ( - %), such as implant failure, non-union and refracture after implant removal, open reduction and internal plate fixation (orif) has been the gold standard for many years. this open procedure with direct reduction maneuvres might be blamed for at least some of the complications due to iatrogenic damage of the blood supply of the fracture fragments. our hypothesis is that a closed method with indirect reduction might reduce some of the complications. the goal of our study was to test the practicability of the mipotechnique in clavicle fractures in unstable shoulder girdles. material and methods: between and we included, out of internally fixed shaft fractures in total ( x plate, x elastic nail), patients with either a floating shoulder (n = ) or a clavicle fracture in combination with ipsilateral serial rib fractures (n = ), in this study. operative technique: a locking compression plate (lcp) . with - holes was anatomically shaped to the anterior (-caudal) contour of the contralateral clavicle and then inserted percutaneously from lateral to medial using a short incision at the anterior border of the lateral end of the clavicle. using mainly indirect maneuvres, the fracture was reduced and then fixed in a pure bridging technique never using interfragmentary lag screws. free unloaded rom was allowed immediately after the operation with full loading - weeks later. follow-up examination was performed to years later with clinical (dash-score, shoulder function, length measurement) and radiological (fracture healing, length measurement) examination. results: / fractures healed without complications. clinical and radiological length measurement showed no significant differences to the contralateral side (range: + mm to - mm). in all patients a very good functional result was achieved with an average dash score of . ( - ). one implant failure occured two years after the initial trauma in a road workman. at reoperation only a partial consolidation of the original fracture was observed. restabilization and bone grafting led to an uneventful healing. conclusion: the mipo technique is feasible even in clavicle fractures and can lead to good functional and cosmetic results. the advantage might be its low invasiveness which better preserves the vascular supply of the fracture fragments. however it is technically demanding mainly due to the small size of the fractured bone. therefore in our opinion it requires a surgeon experienced in the mipo technique of treating fractures of larger bones as tibia and femur. introduction: there are some reports on the difficulties of removing the locking compression plate in clavicle fractures, due to problems of removing the self tapping locking screws. we retrospectively investigated if this was also the case in our institution in removal of lcp plate of the clavicle and if this was incidential or becoming a trend. material and methods: from october till october , we have removed locking compression plates after claviclefracture stabilization. all of the locking screws were inserted by trauma surgeons with the use of the torque limiting srewdriver according to the manufacturer's recommendations. a total of screws where removed. they consisted of fifty-one . mm self tapping cortical screws and hundred and twenty . mm self tapping locking screws. results: from the locking compression plates that where removed after claviclefracture stabilization, in eleven patients ( %) a problem with removal of the plate arised. this was caused by a total of self tapping locking screws. in all cases jamming of the screwheads in the plate was found to be the reason. there was ''cold welding'' between the threaded head of the locking screw and the locking plate. for removal four different strategies were used. in two screws the head was drilled off and the plate removed and subsequent the rest off the screw removed with forceps. five times the plate was bend around the screw and by rotating the plate (helicopter) both were taken out. in eight screws the recess of the head of the screws were enlarged and a conical extraction screwbit . was used to remove the screws. two times a combination of cutting the plate and helicopter tecnique was used succesfull. in comparison the fifty-one . mm selftapping cortical screws were removed without any problem. conclusion: the locking compression plate is a usefull attribute in fracture treatment of the clavicle. however in one-third of the patients removal of locking compression plates and especially the . mm self tapping locking screws from the clavicle, becomes an increasingly challenging procedure. we find this an unacceptably high percentage. number of mri studies it was possible to describe the intraarticular disc. until now there was no in vivo verifying of one of these mri protocols. the introduction of a high resolution mri protocol using a superficial coil ( d wats and t ffe) that has been developped in an ex-vivo model allows the visualisation of the intra-articular structures. the aim of this study is to ascertain the significance of the mentioned mri protocol and the applicability in the clinical practice in a limited patients cohort with instability of the ac-joint. the mri findings are compared to the arthroscopic findings. material and methods: in a one year period patients with chronic acromioclavicular-joint dislocation rockwood type ii and iii were seen in the outpatient clinic the major symptom was pain followed by loss of power. inclusion criteria where a history of more than three month the exclusion of subacromial pathologies, age over and the indication for arthroscopic revision of the ac-joint. the radiological examiner was blinded to the clinical findings. the mri-scan was performed on both sides. at the time of the operation the surgeon was blinded to the mri reading. the surgical procedure was performed by arthroscopy in beach chair position. the surgical findings have been documented by video and also in a descriptive manner. the examination was performed on a . t mri-system . results: throughout the radiological examination, in / patients a rupture of the intra-articular disc was suspected. in / cases degenerative alterations were described. in one case the reading was negative (e.g. ,,no rupture of the intra-articular disc''). during the surgical examination / patients showed ruptures of the intraarticular disc. in one patient no signs of macroscopical disintegration of the disc could be detected. in the case with negative radiologiocal reading, the disc was verified as intact during surgery. in all other cases the disc was disintegrated, including those with the radiological reading ''alterations without clear signs of rupture''. the significance of the described mri protocol was %. introduction: cancer of the colon is a common disease. the choice of treatment after diagnosis is surgery, in an elective setting, to remove the tumor. however, a large number of patients present with colonic obstruction requiring acute surgery before the diagnosis is known, or before the set date for elective surgery. previous studies have shown a worse outcome for patients who undergo surgery in the acute setting compared to patients in scheduled care. the aim was to establish characteristics and prognosis in patients with acute obstructing colon cancer compared to patients who underwent elective colon cancer surgery. material and methods: all patients diagnosed with colon cancer during - in the linkoping area were identified through the swedish colorectal cancer register (n = ). a retrospective analysis of patients with colonic obstruction (n = ) was done using various criteria from the medical records. exclusion criteria were acute surgery due to reason other than obstruction (n = ), non-surgical treatment (n = ), other diagnosis (n = ), or missing medical records (n = conclusion: acute surgery due to colonic obstruction of colon cancer is common. tumor stage seems to be more advanced in patients with obstructing disease than in patients scheduled for elective surgery and consequently the rate of complications is higher and the outcome is worse. however, when stratified for different tnm-stages, the worse outcome in -year survival for patients with acute obstructing colonic cancer still remains. the explanation for this difference is to be elucidated in further studies. disclosure: no significant relationships. introduction: acute colonic obstruction due to malignancies is often a surgical emergency. hartmann's procedures or one stageresection with primarary anastomosis (with or without ileostomy) have been the treatment of choice. however these procedures are associated with a significant morbidity and mortality rate. self expanding metallic stents (sems) have shown their efficiency as palliative treatment in colonic cancer. colonic stenting has been advocated as a''bridge'' towards surgical procedures in potentially resectable diseases. the aim of this study is to evaluate the efficacy of colonic stenting in the emergency treatment of large bowel occlusion either for palliation or to enable to planned surgical procedure. s. tamulis, e. v. gaidamonis surgical, vilnius unuversity emergency care hospital, vilnius, lithuania introduction: to evaluate the results of the treatment of patients with the small bowel obstruction due to intestinal adhesions. material and methods: medical records for the patients treated with small bowel obstruction due to adhesions from to were reviewed. the patient's age, gender, previous abdominal operations, method of the treatment and outcomes were analyzed. results: there were patients admitted to the vilnius university emergency hospital during years period. appendectomy as a previous operation was recorded in % of cases. surgery was required in of the cases ( . %). strangulated small bowel was found in patients ( , %). in cases ( , %) the surgical procedure was limited to adhesiolysis, whereas in cases ( , %) an intestinal resection was performed. enterodecompresion tube was used in cases ( , %). the operative mortality was , % ( cases). mortality after the treatment due to strangulation was , % ( cases). conclusion: there were % of surgicaly treated patients. main reasons of adhesions formation was previous performed apendectomy and midline lower laparotomy. the criteria of uneffective conservative treatment were absent of the positive results of the physical, laboratory, rentgenological and ultrasound examination. mortality after the strangulated small bowel resection was higher. operative enterodekompresios reduces the risc of the postoperative complications and mortality. disclosure: no significant relationships. introduction: hartmann's procedure (hp) still remains the most frequent performed procedure in diffuse peritonitis due to perforated diverticulitis. [ ] [ ] [ ] nevertheless it is associated with high morbidityand mortality . the aim of this study was to assess feasibility, morbidity and mortality of resection with primary anastomosis (pa) with or without diverting loop ileostomy versus hp in case of diverticular peritonitis. , . material and methods: we retrospectively reviewed our prospectively collected database from / to / of patients who were operated in the emergency department of bellvitge university hospital. only patients operated on generalized diverticular peritonitis (hinchey iii-iv) were included. data on patients' demographics, asa classification, hinchey score, peritonitis severity score (pss), surgical procedure, post-operative morbidity, mortality and post-operative hospital stay were studied. results: a total of patients [median age ( - ) years], female . % were included. sixty ( %) had undergone hp and ( %) pa. only in patients ( . %) a diverting ileostomy was performed. overall post-operative morbidity was . %, most frequent complications were wound infection . %, respiratory complications . % and sepsis . %. overall mortality was . % ( pt). these patients had a mean pss of . while the survival group . . there was an overall reintervention rate of . %, after pa . % and after hp . %. significant differences were found in the hp versus pa group in asa score (asa i-ii: % v %, asa iii-iv: % v %) and the median pss ( versus ) . % ( / pt) with pss £ underwent pa, but none ( / ) with pss ‡ . the post-operative morbidity was significantly higher for hp ( . %) compared to pa ( . %). focusing on hospital stay there was a significant difference between pa (mean . days) versus hp (mean . days). in the stratified analysis considering patients with hinchey iii peritonitis we found a mortality of . % ( / pt) in the hp group versus . % ( / pt) of the pa group. the mortality rate stratified for asa and surgical procedure shows no difference in asa i-ii, but in asa iii-iv a lower postoperative mortality for hp ( . %) versus pa ( . %). including only patients with pss less than ( patients) there is a significantly lower morbidity in pa ( . %) versus hp ( . %). conclusion: our data show that pa can be performed safely with lower morbidity and mortality for diverticular peritonitis in patients with asa i-ii, hinchey iii peritonitis grade or pss less than respectively to hp. these findings are supported by a shorter hospital stay in favor to pa. y. arlettaz orthopaedics and trauma, chcvs hô pital du valais, sion, switzerland introduction: one of the most demanding steps of intramedullary nailing is the distal locking. most of young surgeon are ''affraid'' to treat a long bone fracture by a nail because of the distal locking. the aim of this study is to evaluate a new frendly radiation free targeting device on cadavers. material and methods: the study was conducted on fixed cadavers. femurs were available. the method consists of the following steps: determining the zero position of the device; opening the tip of the great trochanter; introducing the nail (sirus nailÒ x (zimmer inc.)); introducing an emitter inside the nail to be positioned in the distal holes; adaptation of the guide on the standard handle with a receptor; moving the receptor to be aligned to the emitter; changing the receptor for the sleeve and performing the drilling and the locking. for the second or even third screw, the targeting device needs a little adjustment. results: on the distal locking procedures ( screws), we observed only one failure due to the breakage of the prototype. this translates as a % success rate for two screws with a mean time of . min. two surgeons conduct this study. not only the inventor but also a inexperimented surgeon tested the new device with the same succes. conclusion: this new device has the advantage to be fully mechanical, to be solidly linked to the patient and to be totally radiation free. it can be used in any hospital, by any surgeon. the procedure is easy to learn and reproducible. it could be adapted to any nail system and does not need external power supply. introduction: anterior knee pain is one of the most frequent complication of tibial nailing. its aetiology remains unclear, potentially being a multifactorial event. the aim of this prospective study was to evaluate if anterior knee pain has any negative influence on: bone healing(the hypothesis is if the patient has anterior knee pain he or she will not put weight on the affected leg and this will not stimulate the bone healing), ability to return to work and quality of live. material and methods: european level trauma center was involved in this study. methods: between januari and december , patients with a tibia fracture was admitted to the trauma departments we used a standard t tibia nail(stryker) with the possibility of proximal and distal fixation with screws the approach was trans or parapatellar. results: at - weeks, months, months follow-up we had , , patients with anterior knee painthe vas decreased from , to , , bone healing was % and for % of patients it was possible to do their previous full time job after months. the quality of life (walking up and down stairs normally without any help, putting on shoes and socks, sitting/standing from a chair, total weight bearing,) was improving. conclusion: we conclude that anterior knee pain in this study is mild, that the two different method of patellar tendon approach(trans or paratendinous approach) have no relevance and it does not have a negative influence on bone healing, ability to return to work and the quality of live. introduction: the aim of this study was to see if there is any difference between manual traction and fracture was applied in one step. twenty-seven femurs and thirthy-three tibias were treated. the mean distraction rate was . mm (range . - . mm) for the femur and . mm (range . - . mm) for the tibia. the necessary pressure to advance the distraction in the tibia was average of bar (range - bar), to distract the femur, bar (range - bar). results: bone healing index for tibia . and femur . months/cm distraction. implant failure five cases; infections three cases. nonunion of the distraction site or docking site four cases. we did not encounter major stiffness of the adjacent joints. conclusion: although the presented technique is a semi-closed distraction procedure, we find this system appealing because of it simplicity in use, low cost and the ability to immediate weight bearing. introduction: bone transport for treatment of segmental bone defects as a salvage procedure is related to a high complication rate. posttraumatic soft tissue problems and callus insufficiency are to be dealed with especially in posttraumatic conditions. the ilizarov ringfixator allows a stable external bone fixation enabling full weight bearing. in bone defect reconstruction bone transport is commonly used. a major problem is the skin cutting wires for bone fixation. a new method of the cable transport with intramedullary cable passing avoids skin cutting thus reducing skin problems. material and methods: patients with a metaphyseal and diaphyseal bone defect of the tibia after open trauma and posttraumatic infection were treated with debridement, bone resection and soft tissue coverage by local and free flaps. after soft tissue healing the monolateral external fixation was replaced in each patient by a four ring ilizarov fixator with a proximal percutaneous tibia osteotomy. for bone transport a flexible cable was placed around the distal part of the segment and passed intramedullarly through the distal segment out of the tibia and onto the ilizarov fixator and the transport clickers. the bone segment was transported after a delay of days anterograd by the intramedullar placed cable one mm per day. results: in all patients the bone defect was closed by the bone transport. in one patient early consolidation of the regenerate occurred and a rupture of the cable. two patients had an insufficiency of the callus. the distal docking site was augmented in all patients after the segment transport with iliac bone graft for consolidation. the one patient with early consolidation was treated by a second osteotomy; the two patients with insufficiency were augmented during the docking operation with iliac bone graft. conclusion: the intramedullar cable transport is a new modification of the bone transport with the ilizarov ringfixator. the main advantage is the soft tissue spearing and protecting transport mechanism enabling bone transports after free flap soft tissue coverage with micro vascular anastomosis. therapeutical course before and after amputation (number of operations before and after amputation) in relationship to co-morbidities and bacteria which caused the infection. results: hospital data from ( female, male) patients were available for septic amputations in the lower extremities on account of non-manageable infections. the average age was . years ( to years). the first age peak lies with , the second with years. in cases infected endoprostheses were found ( total hip arthroplasties, total knee arthroplasties) in cases osteomyelitis was diagnosed. before amputation the patients underwent an average of . interventions (between and ) in oder to control the infection. the average treatment period before the amputation was . days (from to days). post amputationem an average . interventions were necessary (from to ). the average period of treatment was about . days (from to days). the analysis of the co-morbidities showed that hypertension was the most frequent, cases ( . %), followed by diabetes in cases ( . %), coronary desease in cases ( . %), obesity in cases ( . %) and copd in cases ( . %). conclusion: a statistical relevant risk-assesment based on these data (correlation of microbiological findings co-morbidities and risk of amputation) cannot be carried out due to the relatively small number of patients. however, a trend may be estemated: combination of mrsa, diabetes and cardial disease in combination with a great number of operations leads to an increased amputation-risk independent to the individuals age. introduction: maggot debridement therapy (mdt) as an ancient method is succesfully used for the treatment of acute and chronic wound infections in trauma surgery . the underlying mechanisms of action of mdt are unknown, but could provide information for a novel treatment modality against infection, which is important in these times of increasing antibiotic resistance. therefore, in this research the effect of living maggots on planktonic cells was investigated. furthermore, the influence of maggot excretions on planktonic cells and on bacterial biofilms was tested. material and methods: sterile tubes were filled with living maggots in a bacterial suspension and every two hours samples were cultured and compared with controls. a turbidimetric assay was performed to test the susceptibility of six bacterial species to maggot excretions. bacterial biofilms were formed in vitro on polyethylene, stainless steel and titanium and maggot excretions were added to test their influence. results: the results show that living maggots as well as their excretions stimulate the bacterial growth of s. aureus, e. faecalis, cns, s. pyogenes and k. oxytoca (all p-values £ . ). only p. aeruginosa had a decrease of bacterial growth (p = . ). the strongest biofilms in vitro were formed by s. aureus, s. epidermidis and p. aeruginosa in contrast to the weak and inconsistent formed biofilms by e. faecalis, e. cloacae and k. oxytoca. for p. aeruginosa, stainless steel was the best biomaterial with respect to biofilm formation and for s. aureus and s. epidermidis, the best biomaterial was titanium. maggot excretions were added to the strongest biofilms, named above, and reduced these on all biomaterials. the maximal biofilm inhibition by maggot excretions was seen on polyethylene: % for p. aeruginosa (p < . ), % for s. aureus (p < . ) and % for s. epidermidis (p < . ). conclusion: this study shows that nor living maggots, neither maggot excretions have direct antibacterial properties. however, maggot excretions do reduce biofilms formed by different bacterial species on commonly used biomaterials. future research will focuss on the exact mechanism and the substance(s) that cause biofilm reduction. furthermore, possible indirect antibacterial activity will be investigated and the potential role herein of the immune system. introduction: tetanus is an acute disease caused by a neurotoxin produced by the bacterium clostridium tetani, characterised by generalised rigidity, muscle spasm and fatality. open orthopaedic injuries are at particular risk of developing infection from tetanus spores found in the environment. the uk department of health has established guidelines for the prevention of tetanus infection. we assessed the adherence of these guidelines on the initial pre-operative management of tetanus prone open orthopaedic injuries in trauma patients admitted for surgery. material and methods: a retrospective case note review was conducted on patients admitted to the orthopaedic department for intervention with a tetanus prone wound between february and june . tetanus prone injuries included open fractures, soft tissue injury requiring surgical intervention that is delayed for > h, wounds with significant devitalised tissue, wounds in contact with soil and open injuries containing foreign bodies. we assessed to what extent these patients had their immunisation status ascertained, application of wound irrigation and appropriate dressing, correct tetanus prophylactic cover (tetanus toxoid booster versus human tetanus immunoglobulin) and appropriate administration of antibiotics. results: of the patients included in the study, ( %) of patients were considered to have a 'high risk' tetanus prone injury and ( %) patients were deemed as having a 'low risk' clean wound based on the nature and extent of injury. performance within the high risk category showed that % of patients had their tetanus immunisation status ascertained, % correctly received wound irrigation and betadine dressing, % of patients were appropriately given prophylactic antibiotics. only % of patients with a high risk tetanus prone wound received tetanus immunoglobulin and % of patients were given a tetanus toxoid booster as a method for prophylaxis. conclusion: our study showed that a large proportion of patients correctly received supportive wound care and antibiotics. we also demonstrated that patients with open tetanus prone orthopaedic injuries are not adequately receiving correct tetanus immunoglobulin as the indicated prophylaxis. a large number of patients were given tetanus toxoid instead, which does not protect immunity early enough to cover the acute injury period, thus posing a major risk of developing a devastating and largely preventable infection. the orthopaedic and trauma doctor attending these patients must adhere closely to the correct initiation of simple measures in the management of tetanus prone orthopaedic wounds. all patients were irrigated and debrided, before the application of vac system. required debridements were maintained during vac therapy. time elapse between the injury time and vac application time was days on the average (min , max ). when the granulation tissue became sufficient to cover the bone, these wounds have been closed secondarily with several methods. time elapse between the start of vac and wound closure or formation of sufficient granulation tissue for grafting was days on the average (min , max ). results: distribution mean postinjury time for the osteosynthesis was , hours. three of these wounds were closed spontaneously without any need for other wound closure procedures. split thickness grafting is applied in patients, free flap to patients, full thickness grafting to patients, secondary suturing was applied in wound to close it. there was no infection in any extremities that we had osteosynthesed by internal or external methods. conclusion: wound care is as much important as osteosynthesis in open fractures. even if osteosynthesis is successful, failures in wound care may result in loss of extremity. vac alone does not suffice for wound closure. expectation in this therapy is to obtain ideal granulation tissue and to prevent infection development via appropriate wound care. the greatest disadvantage of vac therapy at the time being is its high economic cost. introduction: surgical haemostasis in trauma patients can be difficult and hazardous. commercial products are promoted to accomplish this task at a reasonable cost. in this study we compared the effectiveness of two topical gelatin-based haemostatic agents, flosealÒ and surgifloÒ in a porcine liver trauma model. material and methods: we compared the activity of flosealÒ (with human or bovine thrombin), surgifloÒ and surgifloÒ with added bovine thrombin in two porcine models. one anesthetised piglet mimicked ''normal'' conditions, while the other was kept in a status of hypotension, hypothermia and haemodilution, necessitating inotropic support (''critically ill''). laparotomy was performed, after which we inflicted five identical stab wounds on each liver lobe. each wound was treated with one of the four agents, while one wound was kept as a control. haemostasis was evaluated clinically. after euthanizing the piglets, the pathologist performed a macroscopic, microscopic and electron microscopic evaluation, blinded for which agent was used in which wound. results: clinically, surgifloÒ was able to produce a clot in some of its applications in the healthy piglet (''normal'' conditions), which was not the case in the critically ill animal, not even with the added thrombin. flosealÒ induced clotting in every wound. both microscopic (hematoxylin and eosin and mallory stain) and electron microscopic examination of the stab wounds confirmed that flosealÒ created a stable and dense agglomerate of gelatin and fibrin, firmly attached to the adjacent liver tissue, whereas with surgifloÒ, the gelatin contained more air bubbles, there was a lot less fibrin included in the clot and the clot was not strongly adherent to liver tissue. conclusion: it would seem that flosealÒ is a superior haemostatic agent, creating a dense and stable blood clot, even in a critically ill animal, hence ensuring haemostasis. disclosure: no significant relationships. introduction: bleedings stemming from splenic traumas are still among important causes of morbidity and mortality. aim of this study is comparison of fibrin glue with hemostasis effectiveness of ankaferd blood stopper lower lob resections on spleen of rats. material and methods: the study was performed at the animal laboratory of istanbul university after obtaining an approval from the ethics committee. twenty-four rats were randomly divided into three groups, namely, fibrin glue group (n = ), abs group (n = ) and control group (n = ). a wedge resection was performed on the lower lobe of the spleen. in fibrin glue group, spleen was hemostasis with fibrin glue (tisseel), while abs was administrated on the lower lobe surface in abs group. chronometric measurements were made to determine bleeding times. blood samples from the tail and vena cava were used for whole blood count and blood chemistry. histopathological scores were measured postoperatively on day th. results: in abs group, chronometric bleeding period is , s. whereas in fibrin glue group it takes , secods (p > , ). it was noted that the hemogramme test results, hemoglobin and hematocrit levels on the th days of abs and fibrin glue groups did not show sensible differences from one another ( . vs . ) p = . ( , vs , ) p = , . conclusion: there are no differences between the hemostasis speed and effectiveness of ankaferd blood stopper and fibrin glue as an applied material in bleeding stemming from experimental partial lower lob resections on spleen of rats. of the hemoperitoneum in right iliac fossa was performed and days after trauma, resulting in drainage of and cc of blood. patients were discharged month later and follow up was successful. conclusion: in selected hemodynamically unstable patients and upon availability of appropriate facilities, nom can be safely challenged over the usual limits. the indicators of tissue perfusion such as ph and be seems to be more reliable and sensitive prognostic parameter than hemodynamic instability evaluated by blood pressure and heart rate, in selecting the patients needing surgical control of hemorrhage. a moderate iah in young patients able to tolerate an increased intra-abdominal pressure, can allow a mechanical compression of the injured parenchyma achieving the arrest of hemorrhage, and extend the indications for nom in selected hemodynamically unstable patients, without signs of severe tissue hypoperfusion. material and methods: our case describes a year old male who fell m and landed on the right side of his torso dislocating a rib through the diaphragm, causing a transecting grade liver injury to liver lobes iv and vii, the right hepatic artery and a lesion of the retrohepatic vena cava (vc). the patient presented alert, hemodynamically stable with normal breath sounds. ct scan showed right sided hemothorax and a grade liver injury. a right sided chest tube drained ml of blood. the patient became unstable and was transferred to the or. profuse haemorrhage from the liver was encountered and massive blood transfusion protocol was initiated. the right hepatic artery showed to be injured and was ligated. pringles manoeuvre and packing of the liver were not enough to control the bleeding. an injury to the retrohepatic vc was suspected and manual compression was not sufficient to gain control. endovascular assistance was called for and using a bilateral femoral vein approach two occlusive balloons were placed and inflated under x-ray and open view in the vc to gain proximal and distal control. the patient stabilized and the injury to the vc could be sutured and covered with a topical haemostatic agent. the balloons were deflated but were left in place as a security measure. the liver was then again packed. the pringle manoeuvre had intermittently been used for approximately h in total. two vessel loops were left tension free around the hepatodoudenal ligament and brought out through the midline incision as a security measure. units of rbcs, units of ffps and units of platelets were given. angioembolization of the right hepatic artery was performed after the first surgery. during the second operation, the haemostats, vessel loops and occlusion balloons could safely be removed. days after the injury the patient showed increasing signs of liver failure. the patient was accepted for liver transplantation days after the injury; this procedure was carried out successfully. the combined open and endovascular approach in this case was crucial. the nature of the injury, the pringle manoeuvre, packing of the liver and arterial embolization caused permanent damage to the liver which had to be managed with liver transplantation which was successful. the use of endovascular occlusive balloons might also have had a role in the permanent damage of the liver, but had great benefit in saving the patients life. introduction: the incidence of pulmonary failure in multiple trauma patients is postulated to be influenced by several factors such as thoracic trauma and liver injury. the incidence of pulmonary failure increases in patients with an abbreviated injury scale thorax ‡ (ais) and they are more likely to face poor outcome. thus, the aim of the present study was to test the hypothesis that patients sustaining significant thoracic trauma (ais thorax ‡ ) in combination with a relevant liver injury (ais liver ‡ ) are more likely to develop pulmonary failure when compared to patients which sustained thoracic trauma without additional liver injury. material and methods: records of multiple trauma patients documented in the trauma registry of the german society for trauma surgery were analyzed using uni-and multivariate analyses. patients were subdivided into four groups according to their liver and thoracic injury: group (ais thorax < ; ais liver < ); group (ais thorax ‡ ; ais liver < ), group (ais thorax < ; ais liver ‡ ) and group (ais thorax ‡ ; ais liver ‡ ). potential relevant variables were subjected to univariate analysis between groups using the chi square test to predict the probability for pulmonary failure rate. subsequently, multivariate logistic regression analysis was performed, employing pulmonary failure as the dependent variable. differences at the level of p < . were considered statistically significant. results: , patients with a mean age of . ± . years and a mean iss of . ± . points fulfilled the inclusion criteria and were enrolled in this study. the overall rate of pulmonary failure was ± %. % of the patients in group , % in group and % in group developed pulmonary failure. the largest proportion of patients ( %) who developed pulmonary failure was found in group . those factors which proved to show a significant correlation with the incidence of pulmonary failure were included in a subsequent multivariate analysis. however, the presence of relevant lung injury, male gender, pre-existing medical conditions (pmcs), transfusion of more than packed red blood cells (prbcs) as well as iss and age played a significant role. in contrast to our hypothesis, liver injury did not proof to be associated with the incidence of pulmonary failure. conclusion: pulmonary contusion and significant liver injury seem to have a synergistic effect on the incidence of pulmonary failure. however, multivariate analysis with adjustment of further relevant factors reveal, that liver injury is not a predictive factor for the incidence of pulmonary failure. rather male gender and reported pmcs together with relevant lung injuries are more likely to develop pulmonary failure following multiple trauma. nethertheless, patients with combined pulmonary and liver injury are at higher risk for pulmonary failure with critical outcome. disclosure: no significant relationships. introduction: thoracic trauma is the leading death cause in % of politraumatised patients and contributes to the death of another % of these fatalities. identifying the determining causes, assessing their severity, early and qualified intervention in a multidisciplinary team may improve outcome of these patients. the goal of this paperwork is to assess the effects of thoracic trauma on clinical management, morbidity, mortality and outcome. material and methods: retrospective study of politraumatised patients admitted in the emergency department of st. pantelimon hospital between jan and jun . the followed parameters were most common injuries, severity, mortality, survival rate correlated with iss and rts, using data from emergency charts, hospital charts and anatomopathologic exams. results: out of patients, associated thoracic trauma, with a survival rate of , %. patients had blunt trauma. injuries that claimed early surgical intervention and had the highest death rate were: massive haemothorax patients ( % mortality rate), aortic and great vessels injuries patients ( % mortality rate), open pneumothorax patient ( % mortality rate), tension pneumothorax patients ( % mortality rate), flail chest patients ( % mortality rate). conclusion: thoracic trauma is often associated to politrauma and may increase significantly the mortality rate of these patients. lifesaving surgical procedures must be immediately performed, on patient arrival. it is important to adopt intervention protocols for multiple trauma, with a leading role of the emergency department medical staff. disclosure: no significant relationships. introduction: to evaluate treatment modalities of penetrating and/or contusive hemothorax, we reviewed our experience with patients admitted for traumatic hemothorax to our center for thoracic surgery. material and methods: from january to we treated consecutive patients (mean age, + sd years; m/f, / ) presenting traumatic hemothorax: patients had contusive hemothorax (cont) following car accident ( %), fall ( %), motorbike accident ( %), crushing trauma ( %), bike accident ( %); patients had penetrating trauma (pen) following stab wound ( . %), gunshot ( %) and impalement ( . %). we recorded demographic data, injury severity score (iss) at admission, endo-and extrathoracic injuries, method of treatment and outcome. results: there were no statistically significative differences between cont group and pen group regarding mean age ( vs years), gender (m/f = / vs / ), mean iss ( vs ) and icu admission rate ( % vs %). the cont group however presented a higher rate of extrathoracic lesions (bone, visceral, cns) than the pen group ( . % vs %: p < . ). in all patients a chest tube was immediately inserted, as the definitive treatment in % of cont pts and in % of pen pts (p < . ). surgical introduction: evaluation of penetrating injuries to the chest presented at a level traumacenter. the main study question was to see whether there was an increase in incidence in time. material and methods: in this retrospective study fifty-nine consecutive patients were included with penetrating injuries of the chest during the period of june until june . the penetrating injury had to be caused by gunshot or stab incident. statistical analyses of the data was performed using spss . . results: the study group consisted of fifty-nine patients. ninety percent were male with a mean age of years (range - ). the mechanism of injury were stab ( , %) and gunshot wounds ( , %). sixteen patients required a thoracotomy. in four other cases a laparotomy was performed. twenty-two ( , %) patients were admitted to the icu. the number of patients treated in the first year of the study period ( of the patients with a shotwound % died of their injuries and mortality rate of the patients with a stabwound was . %. in the last year of the study period the mortality of gunschot wounds was . %. conclusion: there is an increase in incidence of penetrating injury of the thorax for both stabwounds and gunshot wounds. the increase of gunshot wounds was especially large in the period july -june . the risk of suffering a gunshot or stabwound to the chest in our traumaregion is gender related. with the increase in the number of gunshot wounds, and thus experience, the mortality seems to decrease. introduction: rib fractures and more specific the flail chest are currently treated conservative. in our level one trauma centre we have on average patients with rib fractures and flail chests/yr. until recently we mainly treated the patients conservative. according to the literature the morbidity and mortality increases twofold with or more ipsilateral rib fractures and an age > yrs old. , some studies have also shown that operative fixation of rib fractures may reduce the morbididity significantly with this data and the recent development of specific dedicated osteosynthesis material for rib fractures we devised a pilot study in order to analyse the efficacy of this new matrixÒ rib fixation system (synthesÒ) and the effect on the morbidity/mortality of the patient. material and methods: during a month period we included all patients with the before mentioned criteria( rib fractures, > yr) or with a flail chest. we analysed operation details, lenght of icu stay, hospital stay and recorded complications. the results were compaired with a matched control group from . results: patients were included with an average age of yrs and a m:f distribution of : . patients had a flail chest and patients had or more rib fractures. on average all patients were operated within days ( - ). on average ( - ) rib were stabilized with an operating time of min ( - ). no implant failures were seen. patients had an average icu stay of days ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . total hospital stay for the whole group was days ( - ), specific for flail chest it was days and for the ipsilateral rib fractures it was days. one patient sustained an extra rib fracture due to the procedure and one patient sustained an iatrogenic pneumothorax. one patient died due to neurologic complications. one patient had a superficial wound infection. no deep infections, pneumonia or chest related mortality occurred. compared to a matched control group of , the overall length of stay was not significant different. vs days. the length of stay for the ipsilateral fractures was not significantly shorter, vs . however the length of stay for the flail chest was significantly shorter in the study group vs (p < . ) the control group had significant more pneumonia, vs (p < , ). conclusion: the new matrixÒ system is easy and safe to work with. the system has good stabilizing capabilities. operative treatment reduces pneumonia and length of stay with flail chest. these results warrant a randomised study, comparing operative treatment vs conservative treatment. introduction: severe thoracic wall injuries can result in long time icu stay with ventilatory support substantial morbidity and even death. if the patient recovers persistent thoracic wall pain, restricted respiratory capacity and/or non union of the rib fractures can be the consequence. in a systematic review of literature we demonstrated that there is some evidence that early internal fixation can shorten the on-ventilator time, the icu stay and lower the short time morbidity. long term pulmonary function is not altered by internam fixation, however the rate of rib nonunion and chest wall pain is decreased. however high quality evidence is lacking. in order to evaluate the feasability of rib osteosynthesis with a new plating system: the synthes matrix system a preliminary study is performed and its results presented. this study preceeds a randomised controled trial comparing plate ad screw osteosynthesis and conservative treatment. material and methods: consecutive patients with flail chest and or serial rib fractures involving at least five ribs necessitating measures other than analgetics to maintain pulmonary function are included and prospectively documented. exlusion criteria: *hemodynamic instability necessitating a damage controle approach *intrathoracic injuries necessitating surgery *normal pulmonary function *patient refusing surgical treatment *patient not available for follow-up all patients are operated upon with use of the matrixrib system. postoperative icu stay, on-respirator time, pain at defined moments of follow-up, healing of the rib fractures and complications are recorded prospectively. patients grade their rate of satisfaction (functional and esthetical) on a scae of to . the results in these patients concerning on-ventilator time, icu stay and morbidity are compared to a historical series of patients with comparable iss. prospective case series with historical control group.(level iii) results: preliminary data indicate: *a shorter time on ventilator than anticipated (based on comparisson to historical data) * a shorter time on icu * less pneumoniae * no intra-operative complications * good healing results of the rib fractures * no implant failures * acceptable pain scores * good overal satisfaction * acceptable cosmetic results conclusion: internal fixation of rib fractures (flair chest or multiple sequential fractures with pulmonary function compromise) results in a earlier recuperation of pulmonary function with shortened icu stay. the overal satisfaction of the patient after operative treatment is good, with acceptable cosmetic results. there were no implant related complications. these results form the basis for a randomised control trial comparing operative fixation with the matrix rib system to conservative treatment. disclosure: no significant relationships. a. e. elsherif , m. fawzy , n. badr , m. marashda surgery, tawam hospital/johns hopkins international, abu dhabi, uae, surgery, tawam hospital, abu dhabi, uae, surgery, tawam hospital/johns hopkins international, abu dhabi, uae introduction: acute airway emergencies result from a wide variety of malignant and benign diseases. for both the patient and the clinician, the presentation can be frightening, and advanced interventional pulmonary/endobronchial techniques are required to achieve prompt relief of symptoms. general anesthesia is sometimes prohibited in these situations with complete loss of airway. we report our initial experience with these patients in a tertiary referral center. material and methods: three patients (two males) with acute proximal airway emergencies were included. two patients presented with acute stridor. the third presented with massive bronchial air leak and purulent drainage after an acute traumatic event. all patients were treated emergently with bronchoscopy and placement of an ultraflex bronchial stent under local anesthesia. all patients were followed up after discharge. results: there was no perioperative mortality or morbidity. the median age was . one patient had anaplastic thyroid cancer obstructing the trachea and was denied treatment elsewhere. the second patient had a malignant tracheoesophageal fistula. the third patient had an acute bronchopleural fistula following pneumonectomy for a gunshot wound. complete symptom relief was obtained after stenting under local anesthesia in all patients. median length of stay was days for the patients with malignancy. on a median follow up of months; two patients were symptom free, one patient died from malignant disease progression. conclusion: stenting under local anesthesia is feasible with acute airway emergency. obstruction of the central airways by malignant tumor is associated with poor prognosis.the alleviation of central airway obstruction by tumor is most often palliative, with improvement of quality of life the primary goal rather than cure. introduction: on april th an earthquake measuring . on the richter scale stuck a large area of the abruzzo region in central italy. the first notice suggested a lot of injured people and destroyed structures, incuded the main hospital of the area, the san salvatore hospital. material and methods: the national civil protection immediately send the field hospital (fh) of the marche regional government, the neighbouring region, together with a large amount of medical staff and personnel by the non governmental organization ares (regional association sanitary emergencies). this association, already involved during other national and international disaster situations and relief efforts, sent professionals volunteers (md and nurses) whit disaster knowledge and specific medical specializations. the international literature demonstrated that a fh is a complex structure and often the time required to be completely functionally is very long, indeed longer than the affected people needs. results: from april th , june th when the mission ended, the fh provided medical treated to almost patients, and the ares personnel ( ) where backed by the sanitary personnel of the san salvatore hospital. conclusion: a well planned medical response is very important to provide health assistance during a disaster, yet it is very hard to substitute a damaged hospital in the hearth of the disaster area. a modular sanitary structure, very light at the beginning, with specific and restricted medical supplies, with a little number of specialists in disaster medicine and disaster logistics, could improve the already good results obtained in the l'aquila abruzzo mission. disclosure: no significant relationships. around , people died, twice as many were injured, and almost million people were made homeless. in any situation of disaster, both natural and complex, may be produced a large number of victims that defeat the ability of local health resources to provide adequate health care. on one hand, the system may be overwhelmed with a high number of casualties. on the other hand, hospitals and other health care facilities generally may be compromised heavily: buildings may be destroyed or damaged and the supply of water, electricity, medical gasses, etc. may be limited. the transportation infrastructures may be severely damaged, creating problems for both people and equipment arriving at the hospital. damage to the health care infrastructure will further compromise the delivery of health services. material and methods: italian government responded immediately to this emergency after the official request for international relief efforts from the president of pakistan. two days after the impact, the first italian evaluation emergency team was already arrived in pakistan and the initial field structure was already fully operative, offering medical care, especially advanced trauma care and life support intervention, provided by specialists. later, when the structure had been completed and became larger provided also hospitalization, and surgical abilities, appropriate treatments and essential drugs. all the medical activities of the responding italian mission team field hospital in manshera were recorded and evaluated. results: a total of , patient contacts occurred at the field hospital during the days it operated, patients were admitted in the field hospital with a total number of nursing days with a average length of stay per admission of , days and with the occupancy rate of , %. a total number of major operations were performed. introduction: mass casualty incident's (mci) management is a present problem which is now more frequent because of iraki, afghan wars and terrorists actions. numerous new plans are evolved in each emergency association or military organization. nato as built a ''masscal'' plan to help teams in role ii in afghanistan to take care mci. through two experiences of mci in french role ii in afghanistan (kaboul) and through the litterature, we discuss the different ways of taking in charge mci. material and methods: the french role ii is located in kaboul near helicopter area. there are surgical teams ( pax, nationalities), emergencies boxes, icu beds and operating theatres. we have a pool of blood units, an echograph, a first generation ct-scan and all materials for traumatologic surgery. for mci, we use nato triage classification. each trauma undergoes ressucitation room, has needing x-ray exams, fast echography and intensive care if necessary. patient who needs urgent surgery runs immediately to operating theatre. iss score is calculated. the first mci concerns patients involved in a suicid bomber's explosion near the role ii. all were taken in charge min later. the second concerns an attack against a french coy occured km in the east of kaboul. there were casualties and soldiers died. they were taken in charge belatedly between to h later. results: fisrt mci : surgical interventions, one %burned, and a blast injury. second mci : surgical interventions, injuries with no surgery, blast injuries. we organize for these second mci a stratevac in france for casualties in less than h. mean iss score is for alive injuries and for the died soldiers. through these mci, we analyse the litterature and discuss about presents concepts in mci management. conclusion: the contemporary history of war, especially in iraqi and afghanistan constrains military surgical teams to improve their way of management of mci. training is necessary. first of all we have to define clearly each place of each actor, the conditions of triage, wich priority for which surgery and the possibility of modern communications and fast and efficient transports. the lower extremity ( %). % suffered multiple severe injuries, % upper extremity injury, % upper extremity and head/neck injury, % back injury, % head/neck injury, % upper and lower extremity injury, % abdominal injury and % miscellaneous. patients ( %) underwent an primary amputation of one or more extremities. ( %) patients underwent secondary amputation. all primary amputated limbs were shortened later. patient ( %)died one day after arrival in the cmh because of multiple severe injuries. conclusion: this single-center, and therefore complete dataset of the repatriated military personnel demonstrates the impact of participating in a nato mission for a small european country. it puts a high and challenging burden on the shoulders of the medical personnel in our hospital. further it shows, in contrast to studies from owens and dougherty, a higher prevalence of lower extremity injuries than upper extremity injuries. data regarding admission time, infection rate, disposition and quality of life will be presented. a lot of medical-ethical decisions had to be made about continuation of medical threatment or to decide whith patient will be treated and with patient will not be treated. as war surgeon you have to do operation for which you were not educated. because there is no other surgeon you have to the operation or the patient will die. it gives the opportunity to learn and gives a lot of surgical experience. this can be useful in civilian circumstances also. conclusion: the period as war surgeon in afghanistan has been of a forse impact. i had to take a lot of medical-ethical decisions and to do operations in which i was not trained. but i have learned a lot about war surgery and on human aspects also. introduction: there are a lot of unique challenges for the medical personnel which are assigned to the combat environment in afghanistan. especially the medical groups are in contact with patients from different nationalities and with different characteristics under special and difficult war circumstances. this article evaluates the effectiveness of the co-operation between a german and a greek surgical team during a -month period in a role ii hospital in north afghanistan. material and methods: from st july through th september , patients were admitted. there were male ( %) and female ( %). we reviewed the type of diseases, mechanism and location of injuries, management, type of surgical procedures performed, blood supply and outcome. results: . % of the patients were international security assistance force (isaf) personnel. most of the patients were men in a percentage of %. four children were included among the local patients. . % of the patients had surgical diseases while the rest . % were of orthopaedic interest patients. ( . %) patients underwent a surgical operation; ( . %) of them were operated immediately. gunshots were the main mechanism of injury for local patients whereas isaf personnel were usually presented with burns after improvised explosive devices (ieds) and rocket attacks. conclusion: the co-operation between medical teams from different countries, when appropriately trained, staffed, and equipped, can be highly effective in order to manage war casualties. introduction: in the emergency caused by natural and social disasters there are evident deficits between the health needs of affected population and the local health system capacity. the causes of disasters are various and not predictable, usually the health structures can not face up to the population needs. knowing that disaster medicine has different protocols and materials from ordinary medicine structures and that improvisation during the disaster's acute phases is not a good practice, it has been created an emergency operating health group, the non-profit ares association. (regional association sanitary emergencies) material and methods: the ares, whose members are about , all over the nation, is configured as an extraordinary health resource, activated by the national civil defence operations centre, in according with the regional centre of marche, in disater situations results: the main objectives of ares are training and organization of medical staff and structures and its growth crosses several missions including: ae earthquake in molise, introduction: cephalomedullary nails rely on a large lag screw that provides fixation into the femoral head. there is an option to statically lock the lag screw (static mode) or to allow the lag screw to move within the nail to compress the intertrochanteric fracture (dynamic mode). the purpose of this study was to compare the biomechanical stiffness of static and dynamic modes for a cephalomedullary nail used to fix an unstable peritrochanteric fracture. material and methods: thirty intact synthetic femur specimens (model # , pacific research laboratories, vashon, wa) were potted into cement blocks distally for testing on an instron (instron, canton, ma). a long cephalomedullary nail (long gamma nail, stryker, mahwah, nj) was then inserted into each of the femurs. an unstable four-part fracture was created, anatomically reduced, and the cephalomedullary nail was reinserted. mechanical tests were conducted for axial, lateral, and torsional stiffness with the lag screws in: ) static and ) dynamic modes. a paired student's t-test was used to compare the two modes. results: the axial stiffness of the cephalomedullary nail was significantly greater (p < . ) in the static mode ( . ± . n/mm) than in the dynamic mode ( . ± . n/mm) (fig a) . similarly, the lateral bending stiffness of the nail was significantly greater (p < . ) in the static mode ( . ± . n/mm) than the dynamic mode ( . ± . n/mm). the torsional stiffness of the nail was significantly greater (p = . ) in the dynamic mode ( . ± . n/mm) than in the static mode ( . ± . n/mm). a post hoc power analysis with a = . and ß = . revealed that the paired t-test on samples was sufficiently powered to determine a difference in mean axial stiffness of . n/mm ( . % of static stiffness), a difference in mean lateral bending stiffness of . n/mm ( . % of static stiffness) and a difference in mean torsional stiffness of . n/mm ( . % of static stiffness). conclusion: our results show that there is a n/mm reduction in axial stiffness of the cephalomedullary nail when the lag screw is changed from static to dynamic mode. this represents a . % reduction in axial stiffness with a change from axial to dynamic modes which may be clinically significant. the differences in lateral ( . n/mm, . %) and torsional ( . n/mm, . %) are small enough that they are likely not clinically significant. we felt that a difference of greater than % in axial stiffness and a difference of greater than % in lateral or torsional stiffness would be clinically significant. our study was adequately powered to detect these differences. given the significant reduction in axial stiffness with dynamization of the cephalomedullary nail construct, we recommend use of the static mode when treating unstable peritrochanteric fractures with a cephalomedullary nail. disclosure: no significant relationships. introduction: minimizing tip-apex distance has been shown to reduce clinical failure of sliding hip screws used to fix peritrochanteric fractures. the purpose of this study was to determine if such a relationship exists for the position of the lag screw in the femoral head using a cephalomedullary device. material and methods: thirty intact synthetic femur specimens (model # , pacific research laboratories, vashon, wa) were potted into cement blocks distally for testing on an instron (instron, canton, ma). a long cephalomedullary nail (long gamma nail, stryker, mahwah, nj) was inserted into each of the femurs. an unstable four-part fracture was created, anatomically reduced, and repaired using one of lag screw placements in the femoral head: ) superior (n = ), ) inferior (n = ), ) anterior (n = ), ) posterior (n = ), ) central (n = ). mechanical tests were repeated for axial, lateral and torsional stiffness. all specimens were radiographed in the anterioposterior and lateral planes and tip-apex (tad) distance was calculated. a calcar referenced tip-apex distance (caltad) was also calculated. anova was used to compare means of the five treatment groups. linear regression analysis was used to compare axial, lateral and torsional stiffness (dependent variables) to both tad and caltad (independent variables). results: anova testing proved that the mean axial (p < . ) and torsional stiffness (p < . ) between the five groups was significantly different, but lateral stiffness was not statistically different (p = . ). post hoc analysis showed that the inferior lag screw position provided significantly higher mean axial stiffness ( . ± . n/mm) than superior ( . ± . n/mm; p < . ), anterior ( . ± . n/mm; p = . ) and posterior ( . ± . n/mm; p = . ) lag screw positions. there as no significant difference in mean axial stiffness between inferior ( . ± . n/mm) and central ( . ± . n/ mm) lag screw positions (p = . ). post hoc analysis revealed significantly less mean torsional stiffness for the superior lag screw position compared to other lag screw positions (p < . all pairings). there were no significant correlations between tad and axial (r = - . , p = . ), lateral (r = - . ,p = . ) or torsional (r = . , p = . ) stiffness. there were significant correlations between caltad and axial (r = - . , p < . ), lateral (r = - . , p = . ) and torsional (r = - . , p = . ) stiffness. conclusion: our results suggest that placement of the lag screw inferiorly in the femoral head when using a cephalomedullary nail to treat an unstable peritrochanteric fracture results in the stiffnest construct in axial and torsional biomechanical testing. a simple radiographic measurement, caltad, provides an intraoperative method of determining optimal cephalomedullary nail lag screw position to achieve greatest construct stiffness. introduction: a potential of polymethylmethacrylate (pmma) augmentation to increase the purchase of cephalic implants in the treatment of intertrochanteric hip fractures has been proven in sev-eral biomechanical studies [ ] [ ] [ ] [ ] . the aim of this study is to compare the cut-out ratio of pmma augmented helical blades to not augmented ones in human cadaveric femoral heads. material and methods: six pairs of osteoporotic cadaveric femoral heads were instrumented with a proximal femoral nail antirotational (pfna) blade in a standardized manner. within each pair, one blade was augmented using ml of pmma cement. cyclic loading was performed at hz. starting at n, the load was monotonically increasing by . n/cycle until failure of the construct. x-rays were taken at cycle increments to monitor the movement of the blade with respect to the head. paired nonparametric test statistics were used to identify differences between groups. results: a significant higher number of cycles to cut-out was found for the augmented group (p = . ). a significant correlation was observed between bone mineral density and cycles to cut-out for the non-augmented specimens (p < . , r = . ), whereas no correlation was found for the augmented group (p = . introduction: when treating distal tibial deformities or fractures with the ilizarov external fixator the ankle joint and foot is often transfixed within the ring construction. for some patients full weight bearing can only be achieved in assembling a walking device on the distal ring. the biomechanical effect of the indirect loading on the fixator stiffness, the osteotomy and the wire tension is still unkown. material and methods: on the basis of a standarized ilizarov external fixator ( rings, mm diameter) with two , mm wires per ring applied in anatomical position on composite tibiae ( rd generation sawbones) direct and indirect loading was analyzed using a universal testing machine (model , uts germany). a middiaphyseal osteotomy of , mm was performed. the following parameters were recorded: micromotion at the osteotomy, relative movement between bone and rings, compressive forces at the osteotomy and strain of the wires. each experimental setup was tested ten times with kg maximal axial loading. results: the osteotomy gap closure occurred at n at direct loading and at an average of n at indirect loading. the compressive forces at the osteotomy were almost double as high at direct loading. regarding the relative motions between rings and bone the amplitude of motion was higher at indirect loading. the stress on the wires was up to four times higher when the walking device was applied on the distal ring for indirect loading. conclusion: the indirect loading using a walking device has a substantial influence on the mechanical characteristics of the ilizarov fixator which determine the biomechanical environment of the osteotomy/fracture. the results showed a higher mechanical load while achieving less compressive forces at the osteotomy. in the need of the walking device we suggest to apply additional half-pins at least in the distal fragment. ) . three randomized groups of pairs were formed. after the osteosynthesis with the implants was done the fracture (a . ) was made with a jigsaw. for further destabilsation the troch. minor was removed. the femura were fixed in the testing machine and tested under dynamic condition with a physiologic load for normal walking ( . x bodyweight) under cycles. we measured the load on the implant, the migration and rotation of the bone around the implant. the data was dokumented with lab view, results: the intramedulare implants showed significant lower migration rates (mean . mm) of the head compared to the extramedular implants (mean . mm). the rotation of the head around the lag screw startet earlier within the dhs an showed higher rates (mean °) followed by the gamma (mean °) until the end of the cycle. the best stabilisation against rotation was documented for the pfn a (mean °). the post x-rays showed a significant migration and sintering process of the femoral head with lateralisation and fracture of the lateral wall. this was even higher in probes with a low bmd. introduction: excising part of an implant through the femoral head is a rare but severe complication of osteosynthesis of proximal femoral fractures. there is little evidence in the literature about incidence and management of this complication. according to opinion leaders in an recent international user meeting most cases end up in total hip arthroplasty (tha). the value of re-osteosynthesis remains unclear. most patients that suffer an excision are geriatric and multimorbid patients, rather suitable to less invasive revision surgery. to assess the incidence and management of cutting out of the pfna blade (proximal femoral nail antirotation by synthes gmbh international) was the aim of this multicenter study. material and methods: the incidence and management of excision of the pfna blade in trochanteric femoral fractures was assessed retrospectively in cases in participating hospitals all over europe in a time period between and . all implantations were screened for this complication. the preoperative, follow up x-rays and patients' medical records including the surgical reports were collected and analysed with a special focus on revision surgery until union or tha. results: the incidence of excision of the implant was . % ( / ). the mean age of patients was years. % of mostly female ( %) patients sustained an unstable a fracture according to the ao classification. final revision surgery was performed with tha in cases ( %). in cases re-osteosynthesis led to union ( %). reosteosynthesis was either exchange of blade with or without cement augmentation alone or re-nailing. in % of tha revisions additional revision was necessary. in % of revisions with exchange of blade additional revision was required (all tha). % ( / )of revision cases with cement augmented blades healed. in % of revision with re-nailing, additional surgery was inevitable. on average . operative procedures were performed after excision of the pfna blade. conclusion: cutting out of the blade of the pfna is a rare complication. nevertheless the management after removal is challenging as indicated by the high number of surgical revisions. revision with total hip arthroplasty showed a lower rate of reoperations compared to re-osteosynthesis. nevertheless % of all revision cases were managed successfully with a minimally invasive osteosynthesis. this gives a rationale for osteosynthesis in managing this complication in geriatric multimorbid patients with a high risk for operation. references: . simmermacher, r. k., j. ljungqvist, et al. ( ) . ''the new proximal femoral nail antirotation (pfna) in daily practice: results of a multicentre clinical study.'' injury ( ) in a prospective series of subtrochanteric fractures with or without involvement of the pertrochanteric region and in revision procedures of this area the pf lcp was applied. in out of patients a fixation failure was observed. this paper reports on these fixation failures. material and methods: all patients with a multifragmented subtrochanteric fracture with or without involving the trochanteric or the femoral neck region which where judged to present a compromised nail entry point from may until may were stabilized using the pf lcp. the plates were applied in a minimally invasive manner through soft tissue windows (mipo). intrinsic stability of the fixation was increased by excentric drilling or applying the tensioning device. all patients were followed up to fracture healing. intraoperative and postoperative complications were noticed. intraoperative and postoperative x-rays were analysed using the ccd angle and the gardens alignment index. results: we report out of patients who sustained a fixation failure with secondary varus collapse requiring revision surgeries until healing. revision consisted in a reosteosynthesis in one, a plate exchange to a o blade plate in the second and a dhs in the third patient. in all our reported cases of implant failure the posteromedial buttress was missing [two ao a and two seinsheimer type v], and all patients were not able to restrict wheight bearing due to different reasons like, noncompliance (alcohol abuse, limited force, advanced age) leading to increased axial bending forces and finally to breakage of the femoral neck screws with varus collapse of the fracture. conclusion: in conclusion the pf lcp proximal femoral plate . / . due to its guide wire technique allows for straightforward plate application and reduction also in very complex fractures of the trochanteric region, including fractures with extension into the greater trochanter or reverse oblique intertrochanteric fractures. however in fracture patterns with missing posteromedial support and limited ability to restricted weight bearing (e.g.: advanced age, additional handicap or mal-compliance) an alternative fixation device should be considered, e.g. the hook plate extension of the lcp proximal femoral plate to apply higher intrinsic stability of the fixation when using the tensioning device. further clinical and biomechanical studies are needed to evaluate the potentiality and limitation of this device for the treatment of these challenging fractures of the trochanteric region. the majority of the the former fixation was replaced by a blade plate. in % we performed a total hip prosthesis. in these cases we saw an overproportional tend to prosthesis-luxations. conclusion: we conclude that mechanical complications like cut out are a little more frequent after dhs-implantation and should be treated by change to a blade-plate-osteosynthesis. this allows a fracture consolidation in that the minor trochanter becomes that stable, that a regular total hip replacement becomes possible. this seems to be the best prevention of mechanical complications after posttraumatic hip replacement like luxations. disclosure: no significant relationships. introduction: hip fractures often concern elderly patients with a high degree of co-morbidity and therefore susceptible for the associated postoperative morbidity and mortality. according to the literature, several factors have an influence on the amount and severity of postoperative complications after hip fractures. low preoperative haemoglobin levels (hb) in elderly patients seem to be associated with increased short-term morbidity and even mortality after surgery. the aim of this study was therefore to establish the impact of anaemia and blood transfusion on postoperative recovery of hip fracture patients. results: there were women and men with medium age of , years ( - years) and with medium follow-up of years ( - years). the lesions occur in sports, % of the fractures occur while practicing soccer. the fractures were bimalleolar (n = ), medial malleolus (n = ), lateral malleolus (n = ), with sindesmotic lesion (n = ) and trimalleolar (n = ). months after surgery % of the patients returned to sports activity ant at months %. at months the younger patients (p = , ) and men (p = , ) returned earlier to sports activity. at one year % of the amateur and % of the professional athletes, had returned to sports practice. fractures of the lateral malleolus returned earlier in , weeks than medial malleolus fracture in , weeks. the smfa and aofas scores were high in all types of fracture. conclusion: correct treatment of instable ankle fractures in athletes, with anatomic reduction and preservation of the integrity of the articular surface, is crucial to the return to sports practice. the fractures that influence an earlier return were younger age, male sex and less severe fracture, and negative predictors were older age and female sex. athletes submitted to open reduction and internal fixation with adequate and precocious programme of physical rehabilitation, can return to the same level of sports practice, despite the seriousness of the fracture without pain and functional limitation( ). results: in all cases anatomic reduction could be achieved. no secondary dislocation was observed and all fractures healed uneventfully. conclusion: indirect reduction of the volkmann triangle from anterior makes an image intensifier mandatory and has potential of not achieving anatomic reduction due intercalated tissue. in larger fragments the fixation with a lag crew from anterior, the buttressing effect might not be sufficient to avoid secondary displacement. with the use a postero-lateral approach and dorsal plate for fixation of the volkmann triangle, it is possible to reliably obtain an anatomical reduction of the dorsal articular surface of the tibia, thus potentially minimizing the risk of posttraumatic osteoarthtitis. introduction: after ankle-and hindfoot fractures, edema often delays surgery and postoperative mobilisation. therefore effective treatment of edema is of great importance. the aim of this study was to evaluate the efficacy of the continuous lymphological multi-layer compression therapy and of the av-intermittent impulse compression (avi) in reducing ankle-and hindfoot edema. material and methods: randomized, controlled, single-blinded, clinical trial. patients ( ± years, m, f) with unilateral fractures of the ankle or hindfoot pre-or postoperatively were randomized into a) the control group (elevation and cold packs), b) the continuous multi-layer compression therapy group (cct) or c) the av-impulse compression group (avi). primary outcome was the pre-respectively postoperative reduction of edema as measured with the figure-of-eight methode . results: pre-and postoperatively the continuous lymphological multi-layer compression therapy (cct) showed a significant better edema reduction when compared to the control group. after three days of intervention the mean preoperative edema reduction in the control group was - . ± . mm ( . %) figure-of-eight methode vs. - . ± . mm ( . %) in the cct group (p < . ) and vs. - . ± . mm ( . %) in the avi group. three days postoperatively the mean edema reduction was - . ± . mm ( . %) in the control group vs. - . ± . mm ( . %) in the cct group (p < . ) and - . mm ± . ( . %) in the avi group. pre-and postoperatively the cct group shows moderate effect sizes after two days of intervention and large effect sizes after three days. avi is more effective when combined with elevation during off-session periods. conclusion: continuous lymphological multi-layer compression therapy leads to a clinical relevant and significant better reduction of ankle-and hindfoot edema as compared to the standard treatment with elevation and cold packs. av-intermittent impulse compression shows a tendency towards a better edema reduction compared to the standard treatment. continuous lymphological multi-layer compression therapy reasonably can be applied when edema delays operation or postoperative mobilisation. considering the avi application we strongly recommend to elevate the leg during off-session periods. introduction: the objective of the study is to define the global hospital costs of a group of patients that suffered from severe trauma. additionally we identify the distribution of the expenses between the different services and the different procedures fulfilled to the patient. ( ), season ( ), moon phases ( ), times on duty ( ) and weather condition ( ) . the observed mortality was adjusted with the risc based prognosis and the smr calculated. results: the selected collective had an average age of . years and % of the patients were males. the mean iss was . and the mean hospital mortality was of . %. for the time of day the highest rate of admission was between : and : p.m., with the highest numbers on saturdays. in the times of on-call duty (weekend, public holiday, weekday between : p.m. and : a.m.) twice as much trauma patients were delivered to trauma centers as within the regularly working hours. in summer, the admission rate was highest ( . %) and lowest in winter ( . %), with more victims of car accidents in autumn and winter as in the warm season and more victims of motor-and bicycle accidents in spring and summer as in the cold season. but none of the mentioned factors showed an effect on survival (smr between . and . ). the moon phases had no influence either on frequency of accidents nor on outcome. the effects of temperature was similar to this of the seasons: with warm temperatures/month less car accidents and more bike accidents occurred (and the opposite for cold temperatures). in the subgroup with temperatures under zero degree the mortality was % higher ( . %) than in the subgroups with temperatures above zero ( , to , , even though a similar iss ( , vs. , to , ) . in a second step a multivariat analysis was done in order to improve the predictive power, but none of the external factors could improve the prognosis. conclusion: there are large variations in the incidence of severe accidents due to time of day, day of week and time of year. but there is no effect of patient's outcome in regard to medical care in german trauma centers. the quality of medical trauma care is consistent around the day, the week and throughout the year. additionally, we observed an increasing difference between mortality rate and risc prediction rate from - , % to - , %, means less deceased polytraumatized patients than predicted. within the late secondary transferring patients with spinal cord injuries were leading ( %), followed by patients with pelvic injuries ( %), infections ( %) and complex extremity injuries ( %). conclusion: with this investigation, we tried to characterize the influence of the new mapping of germany on patient data using the example of the regional trauma network ''saar-(lor)-lux-west-rhineland-palatinate''. although, knowing a lot of interferences, we noticed an abrupt rise of primary admittances of trauma patients in our level- hospital since starting networking. among the load rejection for smaller hospitals this fact leads to a distinct concentration of the treatment of polytraumatized patients in specialized trauma centers. the improved routine by increased quantity could be responsible for the improvement of process and outcome quality in the treatment of severely injured patients. but, the enormous quantity of emergency patients also reflects a future challenge in dealing with emergency operations besides routine operations as well as seldom icu-beds in these trauma hospitals. the role of the nlfc is to work in parallel to doctor led clinics, assessing and treating uncomplicated musculoskeletal injuries with a favourable natural history. since its inception, throughput in this clinic has increased and with greater clinical exposure and training, the spectrum of referred injuries has also broadened. the aim of the present study was to determine patient satisfaction with the nlfc using a validated questionnaire with a specific emphasis on how patients viewed being seen by a nurse rather than a doctor material and methods: consecutive patients were prospectively recruited in the nlfc in january . patients were referred by their resepective consultants after reviewing the presenting history, examination findings and radiographs. after their consultation with the nurse, each patient was asked to fill in a item questionnaire consisting of different domains related to patient satisfaction based on a validated patient satisafction questionnaire adapted for use in the fracture clinic setting. results: there were respondents, men and women, with a mean age of years (range - years). questionnaires were completed by parents, by carers and the remainder by the patients themselves. the most common treated injuries were distal radial, metatarsal and metacarpal fractures. % of patients felt they received the best care from the staff working in the clinic with greater than eighty percent of patients registering satisfaction with the nurse's assessment of their injury, their bedside manner and the treatment and information given. only % of patients felt that they would rather be seen by a doctor for their injury. the highest rates of dissatisfaction related to the building and seating comfort. conclusion: generally, over % of patients were satisfied with their clinic visit with the vast majority of patients not having any objection to seeing a nurse rather than a doctor. patient satisfaction with treatment remains the ultimate outcome measure by which healthcare interventions should be assessed. the results of this study demonstrate the nlfc to be an effective method of managing selected patients in a clinic setting thus reducing the workload of patients which would traditionally be reviewed by the doctor. this has significant implications for improving opportunities for doctors training as well as reducing clinic waiting times. [ ] [ ] [ ] [ ] . the aim of this study is to evaluate the anatomical correlation between the lateral end of the clavicle and the attachment area of the supraspinatus tendon. material and methods: using a mathematical model based upon ct-scan data performed on healthy individuals, the dimensional correlation between the lateral and of the clavicle and the rotator cuff is analyzed. each individual is examined in supine position, using different positions of the arm (maximum external rotation, maximum internal rotation and maximum abduction and external rotation (''aber position''), respectively). for every position the contact area of the lateral end of the clavicle and the spupraspinatus tendon is calculated. results: six healthy individuals ( shoulders) could be included into the study. the average contact area between the lateral end of the clavicle and the supraspinatus tendon (%) is . % for maximum external rotation, . % for maximum internal rotation, respectively. in the aber position only / shoulders showed a contact area > % (av. . %). conclusion: according to these morphological findings the contact area between the lateral clavicle and the supraspinatus tendon is less than %. this contact zone is located in the dorsal aspect of the clavicle. therefore the additional resection of an osteophyte, especially at the anterior part of the lateral clavicle should not have a significant influence on the outcome after subacromial decompression. and good to moderate outcome in the cs (mean ), one patient had a moderate dash score of with a poor cs of . irrespective of treatment strategy the majority of the patients regained normal range of motion and grip strength in the affected shoulder. the most common complication was impingement of the shoulder, which occurred three times in the conservatively and four times in operatively treated patients. all but one conservatively treated patient with a non-union healed without complications. conclusion: minor ( £ mm) and moderate ( - mm) displaced greater tuberosity fractures can successfully be treated conservatively with good to excellent long-term rehabilitation of function with a low risk of complications. whereas there is no doubt that major displaced fractures (> mm) should be treated operatively, special attention must be paid to moderate ( - mm) displaced fractures, as the degree of displacement may be misinterpreted on plain standard radiographs. disclosure: no significant relationships. introduction: a recent study found that after median term follow-up disability correlated with pain rather than the limited residual impairments in motion and strength. we studied impairment and disability an average of twenty-one years after injury in a cohort of dutch patient, with the hypotheses that ) objective measurements of impairment correlate with disability, ) depression and misinterpretation of nociception correlate with disability; and ) patients injured when skeletally mature and immature have comparable impairment and disability. material and methods: seventy-one patients were evaluated an average of years after injury. the majority of the skeletally immature patients were treated conservatively with closed reduction and cast immobilization and the majority of the skeletally mature patients were treated with plate and screw fixation. objective evaluation included radiographs and measurements of range of motion and grip strength. questionnaires were used to measure arm-specific disability (disabilities of the arm, shoulder and hand: dash), misinterpretation or over interpretation of pain (pain catastrophizing scale-pcs-), and depression (ces-d). multivariable analysis of variance and multiple linear regression were used to analyse the ability of the independent variables to account for variation in the dash-score. (spss . , spss inc., chicago). results: there were men and women with a an average age of forty-one at time of follow-up (range, to ). fractures were classified as ao/ota-type a in patients (simple), b in (including wedge fragment) and c fractures in patients (comminuted). the average dash score was points ( to ) and % reported no pain. both rotation and wrist flexion/extension were % of the uninjured side; grip strength was %. there were small, but significant differences in rotation ( versus degrees, p = . ) and wrist flexion/extension ( versus degrees, p = . ), but not disability between skeletally mature and immature patients. the best predictors of dash score were pain catastrophizing, pain, ipsilateral injury and grip strength, explaining % of the variation in dash scores. pain alone accounted for % of variation in dash scores. conclusion: twenty-one years after initial fracture, both skeletally immature and mature patients have limited impairment (averaging over % motion and grip strength) and disability after non operative and operative treatment respectively. patients that were skeletally immature at the time of injury had better motion, but comparable disability. disability correlated with pain and pain catastrophizing rather than motion. results: the mesenteric injuries vizualized on initial ct-scan were mesenteric vascular beading or extravasation in cases, and mesenteric infiltration or hematoma in cases. associated abnormalities of the gastrointestinal tract (thickening, abnormal enhancement, perforation) were present in / cases ( %). nine patients underwent surgery ( %), patients in the early hours, and others after a delay of more than h. indication for surgery was hemodynamic instability in cases and suspicion of bowel perforation in cases. in total, intestinal perforations were found in patients. three patients ( . %) died of associated injuries. no false positive scan has led to unnecessary surgery. however, the negative predictive value of initial ct was % for intestinal associated lesions. conclusion: the mesenteric injuries in blunt polytrauma patients are uncommon but serious. the whole body scanner is a powerful tool for the diagnosis of these mesenteric lesions. conservative treatment is feasible but a clinical and paraclinical reassessment is essential for early detection of intestinal lesions initially undiagnosed, or aggravation of initial lesions. disclosure: no significant relationships. introduction: drug smuggling by gastrointestinal concealment, body-packers, is an increasing problem in developed countries. although conservative treatment is usually successful in most cases, some of these patients suffer complications such as obstruction, gastrointestinal perforation or massive drug intoxication due to a leaking package. despite an urgent surgery and a careful management in the icu, morbidity and mortality remain high. our aim was to assess the outcomes of conservative and surgical management of these patients in our hospital, the referral centre for this entity in madrid. ( ) ( ) pre-hospital fatalities were more frequent (although not statistically significant), which may reflect improvement of trauma organization in recent years ( ) ( ) ( ) ( ) . domestic (may related to delay due to victim's solitude) and urban environment (inexperienced personnel, delay due to referral to another hospital) incidents lead more frequently in pre-hospital death. age and iss as indicators of physiologic reserve and severity of injury were independent predictors of fatality before the victim reaches hospital. introduction: the triad of the elbow is a complex traumatic injury. these injuries have traditionally been considered a poor prognosis for the consequences that arise as a secondary instability, stiffness and loss of functional ability. the objective of this free paper is to review from a clinical and radiological perspective our experience with cases. material and methods: we retrospectively reviewed patients with this type of injury. in patients was not carried out a comprehensive treatment of all existing lesions. the coronoid process was not addressed specifically and fractured radial head was removed or and an osteosynthesis was performed. in the remaining were treated by a treatment protocol trying to repair all the damaged structures (coronoid synthesis, radial head arthroplasty/orif and ligament repair, at least in the external lateral ligament complex). the median followup was months ( - ).the results were evaluated by the scale of may elbow performance score (meps), range of mobility, radiographic parameters and complications during follow up. results: patients treated according to protocol in a systematic manner trying to repair all damaged structures had better outcomes in both the radiological point of view as functional, as well as a lower rate of complications. meps in these patients the average was points (vs. the other group), the arc of º flexoextensió n (vs. º) and the arc pronosupinació n º (vs º). conclusion: despite being an injury traditionally associated with poor results, which have been established treatment protocols that try to treat all manner of injured structures involved in the injury outcomes have improved significantly. we think it must be performed a radial head artroplasty/orif (not resection), anchorage/ osteosynthesis coronoid process and a ligament repair at least of the external lateral ligament complex. if residual instabilty results it may be repaired the medial colateral ligament complex and a temporal external fixator may be used. disclosure: no significant relationships. tion. patients received a secondary implantation including chronic luxations, nonunions, failed osteosynthesis and reimplantation after deep prosthetic infection. the mean follow up was ± months. the functional outcome was measured by using the mayo elbow performance score. results: we had female and male patients with a mean age of ± years. all patients achieved very good results based on the ,,mayo elbow performance score'' with a postoperative mean of points (range between and points) with a maximum performance of points. the mean range of motion concerning extension and flexion was degrees ( to degrees), concerning pronation and supination degrees ( to degrees). the mean flexion deformity was degrees ( to degrees), the mean maximum flexion was degrees ( to degrees). we had two partial ruptures of the triceps tendon, one treated by operative refixation and one conservative, one temporary lesion of the ulnar nerve with complete recovery and one postoperative hematoma which needed surgical treatment. one patient needed revision surgery and resection arthroplasty due to a deep infection, but received a new prosthesis after two months. we recorded no radiographic loosening or other mechanical problems so far. conclusion: according to the used ''mayo elbow performace score'' all patients achieved a very good functional outcome. eventhough they all had severe injuries of the elbow. with modern types of elbow prosthesis the rate of complications and revision surgery is quite low. Ô ur findings indicate that total elbow arthroplasty should be considered as an additional treatment alternative. patients with a lower functional demand and of higher age benefit most from a prosthesis. for younger patients preservation of the joint should be achieved as far as possible. introduction: it is not always possible to reconstruct complex radial head fractures. as non-anatomical reconstruction and healing disturbances result is loss of motion and severe post-traumatic arthritis of the elbow joint, radial head resection as been proposed for these cases. however secondary overload of the lateral facet of the humero-ulnar joint (with consequent arthritis), instability (especially in the presence of medial collateral ligament injury), painfull anteroposterior instability of the radial stump, and radial shortening (in essex-lopresti lesions) with wrist pain can be the result. radial head arthroplasty widely is proposed as prevention of these complication. however as we demonstrated in a systematic review of the litterature, radial head arthroplasty has equally high secondary arthritis rates as radial head resection. the complex anatomy of the radial head, articulating both with the capitellum and the proximal ulna is not reproduced by most contemporary radial head prostheses. material and methods: we describe the complex radial head anatomy based upon an analysis of mriâ e tm s of the elbow performed in healthy volunteers under standardised situations. we describe the next variables: â e¢radial head shape and diameter at the most proximal part of the pruj (proximal radio-ulnar joint) â e¢radial head shape and diameter at the midpoint of the pruj â e¢radial head height medial and lateral â e¢depth of the radial head through â e¢offset of the radial headâ e tm s through relative to the center of the radial head â e¢offset of the radial headâ e tm s through relative to the axis of the radius â e¢offset of the radial head relative to the axis of the radius â e¢angulation of the radial neck to the axis of the radius we compare these parameters to the available radial head prostheses. results: there is a high variability of the different parameters and no relation between all of the parameters could be determined. the existing radial head prostheses do only reproduce the anatomy to a limited extend. conclusion: the high rates of post arthroplasty arthritis can be related to the non-anatomical shape of the existing designs. as the proximal radius articulates both with the capitellum and the proximal ulna, a precise reconstruction of both joints is a necessity to avoid maltracking and/or edge contact in both joints. given the high variability this only can be realised using a theoretic modular prosthesis that allows for reconstruction of the synchronisation between both joints. we found no significant differences (p > . ) in the deficit of the range of motion. flexion: screws ± °, prosthesis ± °, plate ± °e xtension: screws ± °, prosthesis ± °, plates ± °p ronation: screws ± °, prosthesis ± °, plates ± °s uppination: screws ± °, prosthesis ± °, plates ± °a ccording to elbow functional evaluation criteria by broberg and morrey, we found excellent and good results in % of all patients treated with screws, in % of all patients treated with prosthesis and in % of all patients treated with plates (p > . ) the average dash score of patients treated with screws was ± points, of patients treated with prosthesis ± points and of patients treated with plates was ± points (no significant differences, p > . ). the physical and mental component of the sf- score was at the time of follow-up within the normal range at all patients (physical component: screws ± . , prosthesis ± . , plate ± . ; mental component: screws ± . , prosthesis ± . , plate ± . ). in the subcategory of physical functioning, screws performed better than prosthesis (p < . ). no other items of sf- were significantly different (p > . ). conclusion: according to our results osteosynthesis with only screws seem to be the best of the three studied methods. radial head prosthesis replacement yields better functional results than treatment with plates. it must be considered that prosthesis replacement of the radial head has the long-term risk of loosening, especially in young and active patients. plates showed worse clinical results especially in rotation of the forearm even after removing the plate in patients. disclosure: no significant relationships. s is angular stable osteosynthesis of the olecranon more economical than traditional treatment? n. spaepen , k. govaerts , s. nijs , p. broos trauma surgery, uz leuven, leuven, belgium, department of traumatology, university hospitals leuven, leuven, belgium, traumatology, university hospitals leuven, leuven, belgium introduction: although tension band wiring is considered as the gold standard in the treatment of simple olecranon fractures and olecranon osteotomies, the complication rate is high (delayed healing in up to % of cases, hardware migration %). in an historical series using anatomical preshaped lcp plates, we could lower the rate of healing disturbances, but the volume of the implant did make hardware removal necessary in the majority of patients. the lcp , mm hook plate is a low volume angular stable compression plate, designed for the treatment of simple fractures and osteotomies of the olecranon. in this study we want to evaluate the early results of using this new device for the treatment of acute fractures and osteotomies at a level trauma centre. material and methods: we prospectively include all patients treated by lcp , mm hook plate between and. months results considering range of motion (as measued by), meps (mayo elbow performance score), complications and radiographic results are presented. we perform a cost analysis of primary operation using the different implants available, length of stay and time off work. we also perform a cost analysis for reoperation because of delay in union results: we included patients. average age is , years (range - ). there were female and male patients. at months average extension deficit was °, the average flexion °. there was no substantial loss of pro-supination. all factures but one united anatomical (early loss of reduction, but patient refused reoperation). there were complications: early loss of reduction (treated conservatively), crps (complex regional pain syndrome) and arthrofibrosis necessitating implant removal). because of symptomatic hardware two additional hardware removals have been performed. according to the mayo elbow performance score all but patient scored good to based upon the cost analysis the predicted average cost per patient is significantly lower in the hook plate group as compared to the tension band and anatomical preshaped plate group. conclusion: although still a limited series, the early results of this implant are very promising. we document ranges of motion witch are comparable to those described previously in tension band wiring or anatomical plating, but at lower complication and reoperation rates. based upon an analysis of the cost of treatment and of reoperation we advocate the routine use of the olecranon hook plate in the treatment of simple olecranon fractures and osteotomies. disclosure: no significant relationships. material and methods: dutch surgeons (n = ) were asked to draw two incisions for an olac on embalmed human specimen (n = ). they also filled out a questionnaire of their experience. all incisions were photographed and digital measurements were taken. each incision was compared to the gold standard on criteria. incisions should not be closer than two-thirds of the distance between: ) distal tip of the lateral malleolus and the achilles tendon. there was no correlation between number of mistakes and number of procedures per year or years of experience (spearman correlation: . and - . respectively) the median of the mistakes for l-shaped incisions was (iqr = ) and (iqr = ) for j-shaped incisions (p = . , mann-whitney). the spearman correlation between the mistakes for the two incisions drawn by each surgeon was . . conclusion: conclusions: inter-surgeon variation of incision lines was high and since the number of mistakes per incision was not correlated to the surgeon's experience, casam can be useful in two ways: ) pre-operative planning using casam, might assist the surgeon in determining a 'tailor made' safe zone in each patient. ) for educational purposes casam is able to compare a student's incision with the gold standard or the computed location of the sural nerve, thus providing personal feedback. introduction: a precise sustentaculum tali screw placement is crucial for the fixation strength of operatively treated calcaneus fractures, as shown in biomechanical studies. due to the complex anatomic shape of the calcaneus and the limited visualization of the sustentaculum tali fragment via the common lateral approach, the exact screw positioning is demanding and a bright knowledge of the surgeon is mandatory. with the introduction of navigation procedures an increased precision of implant positioning could be achieved for different applications, as reported for pedicle-and iliosacral screw placement. the aim of this study was the evaluation of different navigation procedures compared to the conventional technique for the placement of the sustentaculum tali screw. material and methods: sustentaculum tali screws were placed via a standard lateral approach in artificial calcanei with a prefabricated soft tissue envelope. we used different navigation techniques: group i: d-based fluoroscopic navigation group ii: d-based fluoroscopic navigation group iii: fluoro-free navigation compared to the standard procedure without navigation (group iv). for each screw the time of procedure and time of fluoroscopy was measured. the precision was evaluated in postoperative ct scans. results: no x-ray exposure was necessary for the standard procedure and the fluoro free navigation, whereas ± . and . ± . s of fluoroscopy time were needed for the d-and d-based fluoroscopic navigation. significant differences were observed for the mean procedure time: . ± . (group iv), . ± . (group iii), . ± . (group i) and . ± . min (group ii). no significant differences were seen for the precision with one mal-placed screw in each group. whereas for the image based navigation procedures wide experience in computer assisted surgery was necessary, the fluoro free navigation procedure could easly used without that experience, due to a simplified and self-explanatory workflow. conclusion: all three navigation procedures increase the intraoperative orientation for the placement of the sustentaculum-tali screw, but significant differences of precision compared to the standard technique could not be observed in our experimental set up. potential reasons are a visual and tactile memory effect, despite a randomized order of drillings and a better visualization of the osseous structures in the used artificial model. in clinical situations a lack of surgical routine for this rare injuries and a limited display of anatomic landmarks exist, making all of the evaluated navigation procedures to a helpful tool. if the fracture reduction is controlled intraoperatively by an d fluoroscopic scan, we recommend the d navigation, otherwise we use the fluoro free navigation. disclosure: no significant relationships. overall satisfaction of functional status was measured using a visual analogue scale (vas; range zero to ten). results: four-hundred metatarsal fractures were identified in patients. the distribution of fractured metatarsals was: first metatarsal %, second %, third %, fourth %, and fifth %. multiple metatarsal fractures were seen in . %. most fractures were caused by an inversion injury or fall from height ( %). more than eighty percent of fractures were undisplaced or minimally displaced, and most fracture patterns were transverse or oblique/spiral. a total of patients ( . %) returned the questionnaire with a median follow-up of months. responders were female in % and had a median age of years (p -p - ). in . % of cases the left side was affected. the median aofas-score was points (p -p - ), the median vas was points (p -p - ). in the univariate analysis the aofas and vas score were inversely dependent of the body mass index (r s = - . and - . ; p < . ). patients with known diabetes reported lower vas (p = . ) and aofas scores (p = . ). female patients reported a lower aofas (p = . ). an increase in dislocation (> mm) resulted in a decrease in vas (p = . ). no correlations were identified with outcome and which metatarsal was affected, number of fractured metatarsals, fracture type and location, articular involvement, and smoking habits. in the multivariate analysis the bmi correlated with the aofas (p < . ) and vas (p = . ) and the dislocation with the vas (p = . ). conclusion: this is the first investigation using two validated outcome scoring systems to determine functional outcome in metatarsal fractures. overall outcome in metatarsal fractures is high, as almost all fractures healed without complaints at months. outcome is dependent of bmi, diabetes, gender, and dislocation at the fracturesite. disclosure: no significant relationships. introduction: incidence of fracture non-union is increased after severe trauma. the systemic inflammatory response syndrome (sirs) resulting from major trauma appears to play a role in this healing impairment. especially the cellular reaction associated with sirs influences the inflammatory response, which is of vital importance in fracture healing. we hypothesize that systemic inflammation may impair healing through an altered interaction between neutrophils and stem-or osteoprogenitor cells within the fracture hematoma. we therefore investigated the effect of neutrophils on differentiation of mesenchymal stem cells (mscs). material and methods: osteogenic differentiation of mscs was assessed using an alkaline phosphatase colorimetric assay on the adhered cell lysate after culturing mscs for days in the presence of different quantities of neutrophils. chondrogenic differentiation of mscs was assessed within the same samples using a glycosaminoglycan colorimetric assay in the cell medium. proliferation was measured within the same samples using a picogreen(r) dsdna fluorescent assay. to assess whether any effect was mediated through release of soluble factors or through direct cell-cell contact, supernatants of stimulated neutrophils were used. stimulation of neutrophils was achieved during h with tnf-alfa. tnf-alfa in the supernatant was subsequently blocked with humira prior to interaction with mscs. results: low neutrophil concentrations resulted in increased alkaline phosphatase concentrations compared to control levels. high concentrations of neutrophils resulted in increased glycosaminoglycan concentrations and decreased alkaline phosphatase concentrations. introduction: angiogenesis is a cue element in the early wound healing and is considered most important for tissue regeneration. in addition to aiding research in understanding the regulatory mechanisms of angiogenesis and vasculogenesis, the concept of co-cultures has helped to better understand the mechanisms of interactions between osteoblasts and endothelial cells focusing on new therapeutic approaches for critical size bone defects. here, we describe in detail the cellular and molecular interaction between human osteoblasts (hob) and human endothelial progenitor cells (epc) in a complex d-environment. material and methods: we investigated endothelial differentiation and morphological organization of human epc in cocultures with hob using methylcellulose sphaeroids as well as collagen biomatrices. cocultures of human umbilical vein endothelial cells (huvec)/ hob were used as controls. epc were tracked with cell tracker red, whereas hob were transduced using a lentiviral egfp-vector to allow direct cell visualization using confocal laser microscopy and analysis of cell-specific gene expression. we studied the survival of both cell types and formation of vessel-like sprouts as a criterion of endothelial activity of epc. expression of several relevant angiogenic and osteogenic markers, as well as different extracellular matrix proteins was investigated using quantitative rt-pcr. results: using the hybrid coculture technology we could clearly show that hob regulate the survival, proliferation, and spouting of epcs. concordantly, expression of endothelial cell markers cd and vwf was significantly up-regulated by cocultivation with hob. by contrast, epcs did neither proliferate nor did they form any apparent vessel-like structures when cultured in a monoculture. using the lentiviral egfp-reporter transduction method the expression of osteoblast marker genes was also estimated accurately. we could clearly show that epcs inhibit the terminal differentiation of hob by interfering with expression of specific transcription factors runx and sp . in contrast, cell proliferation and expression of the early osteoblastic differentiation marker alp were induced in cocultures. conclusion: in the present study we demonstrate that human endothelial progenitor cells interact with human osteoblasts on the cellular level. we have identified a complex regulatory mechanism which accounts for endothelial cell survival and cell differentiation of both cell types. this study provides new insight into regulatory mechanisms of bone regeneration and may unveil potential applications in bone tissue engineering and fracture healing. introduction: failure of fixation is more common in osteoporotic than in other fractures. early treatment of osteoporosis as well as early stimulation of the fracture healing may improve the later clinical outcome. bisphosphonates are effective in osteoporosis treatment, and bone morphogenetic proteins (bmps) stimulate fracture healing, although several studies show less effect in estrogen deficient models. in order to determine the effect on early fracture healing of bisphosphonates and bmps in osteoporotic fractures, these treatment modalities were applied in estrogen deficient rats. material and methods: fourty rats underwent an ovariectomy (ovx), followed by low calcium diet during six weeks. ten rats underwent a sham operation, followed by normal diet. after six weeks, a closed femoral fracture was induced in all animals. the ovx animals were then assigned to four different groups: ovx alone, injection of bisphophonate, injection of bmp- in the fracture gap, or the combination of these. all animals received a normal diet after the fracture. after sacrifice at two weeks, fracture healing was evaluated using radiographs and four-point bending stiffness andstrength. results: radiographs showed a higher score in the bmp- treated animals, with or without the bisphosphonates (p = . , kruskal-wallis test). no delay in healing was seen in estrogen deficiency as compared to the sham group. bending stiffness was higher in the bmp- treated groups compared to the others (p = . , kruskal-wallis), as was the strength (p = . , kruskal-wallis). no significant improvement was found by the injection of bisphosphonates conclusion: early fracture healing is significantly stimulated by injection of bmp- in the fracture gap in estrogen deficient rats. early treatment with bisphosphonates showed no effect on fracture healing. introduction: traumatic brain injury (tbi) is associated with an increased rate of heterotopic ossification within skeletal muscle, possibly due to humoral factors. however, the pathophysiological mechanism of heterotopic ossification after tbi is still not fully understood. this study investigated whether cells from skeletal muscle adopt an osteoblastic phenotype in response to serum from patients with tbi. material and methods: blood was collected from patients with severe tbi as well as ten control subjects. primary skeletal muscle cell cultures were isolated from orthopedic surgery patients and characterized using immunohistochemical techniques. proliferation and osteoblastic differentiation were assessed using commercial cell assays, western blotting (for osterix protein) and the villanueva bone stain. results: all serum-treated cell populations expressed osterix after one week. cells treated with serum from both study groups in mineralization medium had increased alp activity and mineralized nodules within the mesenchymal cell subpopulation after three weeks. serum from patients with tbi induced a significant increase in the rate of proliferation of these cells compared to the controls (p < . ). introduction: the current gold standard to establish the diagnosis of osteoporosis and to follow the pharmacological treatment is the measurement of the bone mineral density (bmd). with a growing number of predicted fractures due to osteoporosis the expenses for bmd-measurement will increase. it was therefore the objective of this study to determine parameters that possibly allow a laboratory follow-up of these patients. material and methods: since we operated patients (Ø . y, % female) with an osteoporotic fracture (group ). all of them were more than years old and underwent a laboratory screening including the serum levels of vit-d -oh, vit-d . -oh, calcium (s-ca), phosphate (s-pho), p np, b-cross-laps, intact pth, osteocalcin, tsh and sex hormones as far as the urine concentration of calcium (u-ca) and phosphate (u-pho). in vit d -oh insufficient patients without treatment a therapy with alandronat lg once a week and daily calcium and vitamin d substitution was started. patients (Ø . y, % female) of the orthopedic department underwent the same screening and served as a control (group ). these patients did not sustain a fracture or relevant surgery within at least months. in a second part we checked the evolution of group -patients laboratory screening at a , and -months postoperative interval. results: group and displayed significant differences with regard to s-ca, u-ca, u-pho (p < . ), osteocalcin (p < . ) and vit-d -oh level (p < . ). after separating male and female patients significant serum concentration differences of testosteron (p < . ) in the male patients and of fsh (p < . ) and oestradiol (p < . ) in the female patients could be observed. during the follow up at , and months we could demonstrate a significant elevation of s-ca (p < . ), s-pho (p < . ), osteocalcin (p < . ) and vit-d -oh (p < . ) concentration. further we found a significant elevation of fsh-(p < . ), lh-(p < . ) and testosteron (p < . ) concentration as well as a significant decrease of the oestradiol (p < . ) concentration. as former studies showed we confirmed by comparing group and a deficiency of vit-d -oh, s-ca and an elevation of u-ca in patients with osteoporotic fractures. we could also show a significant difference of the concentration of osteocalcin. by following these blood parameters during treatment we found an improvement or normalization of these differences as a result of the treatment. therefore we believe that vit-d -oh, s-ca, u-ca and osteocalcin could serve as follow-up parameters in the treatment of osteoporosis. further our preliminary results suggest that under the treatment there is a decrease of the testosterone level in male patients and a decrease of the fh-and increase of the oestradiol-concentration in female patients which has not been reported in the literature yet. in consecutive cycli an alternating traction of newton was exerted on the subscapularis and infraspinatus, while a continuous force was applied for the supraspinatus. the motion of the tuberosities and the shaft were recorded by high-speed cameras. the following parameters were investigated: failure of osteosynthesis, intertuberosity motion, motion lesser tuberosity-shaft, motion greater tuberosity-shaft, motion metaphysis-shaft. results: group : cable fixation was significantly more stable for intertuberosity motion and tuberosity-shaft motion. furthermore we found failures for the lesser tuberosity in the suture group. we found no significat difference for the metaphysis-shaft motion. group : the greater tuberosity-shaft motion was significantly lower using two cables. all other parameters showed no significant difference. we found no failures. group : since the tuberosity-shaft motion and the intertuberosity motion were significant higher using fibre-wire, this series was abandoned after / pairs. conclusion: cable fixation is significantly more stable than suture fixation for tuberosities in shoulder arthroplasty. double-cable fixation does not improve intertuberosity stability. we found tendencies for an enlarged tuberosity-shaft stability. introduction: the results following prosthetic treatment of primary humeral head fractures present great variability. dissolving of tuberosities leading to dysfunction of the rotator cuff with limited motion, pain and instability are often reported. the short term results on inverse prosthesis on the one hand are promising, whereas scapular notching turns out to be a major problem leading to a high failure rate in the long run. high complication rates are also reported. material and methods: in an ongoing prospective and consecutive multicentre study until today, cases with an inverse shoulder prosthesis system are documented. in this series we analyse the results of the cases treated for primary fracture as indication. in all cases the affinis Ò fracture inverse prosthesis has been used. this implant was specially designed as a reversed treatment option for selected fracture cases. mechanical and biological notching should be reduced due to the special design features of the prosthesis. patients were asked to describe pain and satisfaction for the injured shoulder one week before the trauma and also to fill in the ases score. the constant score for the healthy shoulder was measured whenever possible. postoperatively constant and the ases score were assessed. the x-rays were evaluated for notching and the healing of the tuberosities. results: from february until today a total of n = cases ( females and males) were treated for primary fracture with the fracture prosthesis. mean age at operation was . years (range . - . ). according to the neer classification we treated patients with a -part fracture, with a -part fracture and cases with a head split fracture. after a mean of months (range - ) the cs reached . points. active forward elevation was . °and passive . °. the active lateral elevation (abduction) was . °for the active movement and . °passive. the ases score was . points at the latest follow-up and the value for pain and satisfaction were . and . respectively. we found no notching in this series and the tuberosities were judged as anatomically healed in % of the cases. we found no difference in the clinical outcome between patients with healed tuberosities compared to the group with non visible tuberosities. postoperatively two complications occurred one fracture of the clavicula and one fracture of the acromion. so far we did not have any luxations or implant disconnections. introduction: the purpose of this study is to evaluate the survival and function of splenic autotransplants using spleen imaging with tc m labeled heat-damaged erythrocytes. material and methods: patients with splenic rupture underwent spleen imaging with tc m labeled heat-damaged erythrocytes at to months after splenic autotransplantation (early scans); also, of them underwent the same imaging technique at to months after operation (follow-up scans). results: on early scans, splenic autotransplants were faintly and the intensity of radioactivity in autotransplants was lower than in liver. the increase of intensity of tracer accumulation in autotransplants was significant higher on follow-up scans. one week after operation the levels of cd , cd and cd /cd ratio were significantly lower than those of controls and returned to normal months later. conclusion: the spleen imaging with tc m labeled heat-damaged erythrocytes is a valuable and effective method for evaluation of the survival and function of splenic autotransplants. , respectively / in the group ''skiers''( %) and / in the group ''snowboarders''( %). the aast grade of injury was: aast case; aast cases; aast cases; aast cases; aast case. of the ''skiers''( %) and of the ''snowboarders''( %) showed a high grade (aast > ) splenic injury. patients has an injury severity score > ( / skiers and / snowboarders): cases of severe brain injury, case of associated liver injuries, cases of associated left renal injuries. patient had associated colonic and pancreatic injury. four patients were not stables at admission and had immediate laparotomy with splenectomies. patients were elected for nonoperative management. results: splenectomies was performed with a splenic salvage rate of. %. there was no mortality and morbidity was %. for thr three patients who had immediate splenectomy the recovery was uneventfull. in te group nonoperative management three patients had angioembolization and four had delayed laparotomy ( for delayed splenic rupture at post injury , and resectively; for sirs). in the patients with availables data, mean hospital stay was days ( - ), . days ( - ) for the group skiers and - days ( - ) for the group snowboarders. patients( %) were recovered less than days. patients were admitted initially in icu ward(from h to days). conclusion: ski accidents are in cause for more the one-third of all splenic injuries admitted to grenoble university hospital. the mean age is lower and male incidence is higher than splenic injuries admitted for others causes (road traffic accident, falls, other mountain accidents). an high number of snowboarder's' accidents was observed and pattern of injury is poor in these patients. the incident of polytrauma cases was the same in two groups and this observation confirm that snowboard practice is at higher risk than skiing for severe splenic injuries. in france, if number of raod traffic accidents is decreasing, the number of sport accidents is imcreasing in the last years. a better comprehension of mechanism, epidemiology and hystological findings of splenic injuries resulting from skiing and snowboarding is necessary to improve trauma preventiin programs. introduction: management of splenic injuries has evolved over the past three decades. prior to that time, a diagnostic peritoneal lavage positive for blood was an indication for exploratory laparotomy because of the concern about ongoing hemorrhage and/or missed intraabdominal injuries. in children the nonoperative management (nom) of splenic injuries rapidly gained interest because of the significant incidence of post-splenectomy sepsis as well as the complications associated with non-therapeutic laparotomies. the last decade has witnessed a proliferation of reports of nom in adults with injuries to the spleen. inclusion criteria for nom in adults, which have been a source of controversy, continue to evolve. moreover we noted that most publications focused on isolated splenic injury and not on patients with multiple injuries. this study was conducted to summarize the indications for the nom of blunt splenic injury with special attention to the multiply injured patient. material and methods: we conducted a medline search. the search was designed to identify english language citations between and : using the keywords: blunt splenic injury, conservative management, multiply injured patients and blunt abdominal trauma. the bibliographies of the selected references were examined to identify relevant articles not identified by computerised search. one hundred articles were identified. a cohort of three trauma surgeons selected articles for review and analysis. we used the methodology developed by the agency for health care policy and research of the united states department of health and human services to group the references into three classes. reviewing all data showed that the nom of blunt splenic injury is a save treatment modality in isolated cases but also the multiply injured patient. conclusion: currently the non-operative management of blunt injury to the spleen is the treatment modality of choice. important is a haemodynamically stable patient, with no signs of peritonitis on physical examination. patients who only maintain their blood pressure by the constant infusion of crystalloid or blood products are not haemodynamically stable and need surgical intervention. ct scan findings and grade of injury are not, in themselves, criteria for laparotomy. these criteria are applied to isolated injuries to the spleen but can also be applied to the multiply injured patient. age itself is not a contraindication. the general condition of an individual patient needs to be decisive. and finally hospitals with a low trauma incidence can safely use these guidelines in their management protocol. introduction: the treatment of trauma patients with solid organ injury has changed over the last years towards a less invasive treatment. still our algorithms especially in dealing with trauma patients with ongoing internal abdominal haemorrhages is still based on fast control en stopping of the bleeding by any means. the use of ct-abdomen and subsequent performing angiography and embolization takes time. we analyzed the time path involved in angiographic control of the bleeding spleen. material and methods: a retrospective study. the study group consisted of ten patients presenting at our institution with a traumatic spleen injury in the period november till november . all patients were managed according to the principles of atls. data were analyzed using spssÒ . . results: the study group consisted of seven men and three women. average age was years (range till ). the iss was on average (range - ). all patients in the study group received an angiography after ct-abdomen which showed an active bleeding focus in the spleen. organ injury score were eight grade and two grade spleen injuries. average time from admission to angiography was min. time to control of bleeding by embolization took average min. time loss between ct and angiography was on average min. conclusion: the time paths involved in managing this group of trauma patients with spleen injuries by embolization are much longer than expected. the time involved after diagnoses to actual control of the bleeding spleen injury is much longer than anticipated. logistic changes to limit the time loss in interpretation of data from the ct-a, transfer of the patient, preparation of the angio-suite and less time consuming technique to actual embolization are needed. articles were eligible if they reported the failure rate of nom with or without angio-embolization (ae) in pediatric patients with splenic and/or liver injuries with a contrast blush on ct and included two or more trauma patients. two reviewers independently assessed the eligibility and the quality of the articles and performed the data extraction. interrater differences were resolved by discussion. results: nine studies were included describing pediatric patients. the median sample size was five (range - ). seven studies (including patients) reported a total of patients with failure after nom without ae. failure rates across these studies ranged from . to %; the pooled percentage was . % ( % ci: . %- . %). the failure percentages after nom with or without ae ranged from to %; the pooled percentage was % ( % ci: . %- . %. two studies (including patients) reported a total of patients with failure after nom with primary ae: a percentage of . %. conclusion: despite the current low level of evidence on failure rate of nom when a contrast blush is present on ct we emphasize that there is a significant amount of patients in whom nom fails. we therefore recommend that the management of splenic and hepatic injury in children should not only be based on the physiological response but also when a contrast blush is present on ct. results: primary blast injury: this form of injury results from the deleterious effects of the blast wave passing through the body. these waves have little or no effect on solid organs but have their major destructive potential in air containing organs, especially lungs. secondary blast injury refers to the impact on a patient's body of projectiles usually inert. the addiction of destructive metal fragment, nails and other such objects to bombs increase the severity of injury and lethality. tertiary blast injury refers to the deceleration and impact with the ground, wall or other inanimate object of the patient whose body is displaced by the blast. quaternary blast injury refers to the miscellaneous forms of injury by-products of explosions, burns, inhalation of dust, contamination in case of ''dirty bombs'' or penetration of allogenic body parts shrapnel. this last one asks the question of contamination by hepatitis or hiv and modalities of surveillance and treatment. conclusion: blast injuries are complex and require the expertise of surgeons for their evaluation, treatment and longterm recovery. the victims of this form of terrorism sustain unusually severe and complex multidimensional forms of trauma not typically encountered in routine surgical practice. surgeons must be leaders and active participants in disaster planning and management; they are uniquely qualified to manage the physical trauma that results from most forms of mass casualty events, including blasts. disclosure: no significant relationships. a. s. dogjani general surgery, military university central hospital, tirana, albania introduction: as the risk of terrorist attacks increases in the world, disaster response personnel must understand the unique pathophysiology of injuries associated with explosions and must be prepared to assess and treat the people injured by them. the explosions at the army depot in gerdec village, some km north of tirana, were heard more than km ( miles) away. introduction: during the last decades there is a debate concerning the fact if the facial fracture can cause further damage or somehow to protect the brain parenchyma from a more severe injury. the aim of our study is to analyze the effects of facial trauma exerted upon brain parenchyma. material and methods: a series of patients with craniofacial fractures was studied. the injuries were separated into five grades of severity based on neurological examination including cranial ct. the injuries was also grouped into three categories based of facial regional involvement ct -facial reconstruction results: the control group included patients with head trauma but without any facial fracture or brain injury. in group a included ( , %) patients with both facial fracture and brain damage.among them diagnosed with temporal-mandibular fractures accounting for , %, patients( , %) had lower mandibular fracture, patients ( , %) diagnosed with nasal fractures and patients ( , %) had orbital fractures. in group b were categorized patients with only brain damage accounting for %. conclusion: the data demonstrated that patients with upper facial fractures were at greatest risk for serious closed head injury (chi).injuries to both the mandibular and the midfacial regions with no upper facial involvement more frequently resulted in mild chi with a modest likelihood of no neurological deficits. trauma to only the mandibular region or to only the midfacial region was least likely to involve chi disclosure: no significant relationships. introduction: post-traumatic stress disorder (ptsd) is a psychiatric disorder that results from exposure to a traumatic event. the individual may develop symptoms of three distinctive types: intrusive and unwanted recollections, avoidance followed by emotional withdrawal, and heightened physiological arousal. people who are exposed to traumatic events may also have somatic symptoms and physical illnesses, particularly hypertension, asthma and chronic pain syndromes. hospitalized victims of suicide terror attacks are unique due to the circumstances and severity of their injuries which could have possibly affected the occurrence of ptsd and delayed the recognition of ptsd development. our objectives were to evaluate the prevalence and severity of ptsd among hospitalized victims of suicide bombing attacks and to assess variables of physical injury as risk factors for the development of ptsd. material and methods: forty-six hospitalized victims of suicide bombing attacks were evaluated for ptsd using the pss-sr questionnaire by phone. demographic and medical data considering the severity of injury, type of injury and medical treatment were collected from the medical files. injury severity scale (iss) was used to assess severity of physical injury. results: the prevalence of ptsd among hospitalized victims of suicide bombing attacks was . %. presence of blast lung injury was significantly higher in the ptsd group compared with the non-ptsd group ( . % vs. . % respectively, p < . ). there was no significant difference in iss values between ptsd and non-ptsd groups. blast lung injury and intracranial injury were found to be predictors of ptsd (odds ratio and , respectively). no correlation was found between length of hospital stay, length of icu stay or severity of physical injuries to the severity of ptsd. conclusion: hospitalized victims of suicide bombing attacks are considerably vulnerable to develop ptsd. they should be evaluated with a high level of suspicion in order to identify ptsd symptoms and treated as soon as possible in conjunction with physical treatment. blast lung injury and intra cranial injury are predictors of ptsd. victims suffering from these conditions should be monitored closely and treated in conjunction with their physical treatment. conclusion: from the use of the smart adopted for the evaluation of the code of entrance in emergency department, we have deduced and confirmed the facility and the speed of use of this new model of triage. the triage smart typically holds not only besides in consideration the traumatic pathologies but also internists that, it is an usable advanced triage both on the territory and in the hospital. we can classify the model smart triage as a valid system in case of a disaster as is reliability and sensibility of assessment of patients result to be more appropriates in comparison to the other models of triage taken in examination. conclusion: we showed that alcohol, massive bleeding needed blood transfusion and age were risk factor of trauma and japanese emergency medical technician attendance was effective for trauma care. we suggested the reason of detachment by the injury form was that japanese penetrating wound include many stub wound not gun shot wound. introduction: rapid aging of japanese population is causing numbers of emerging problems in trauma patients care which consists of trauma in elderly people and increased pre-existing co-morbidities such as cardiovascular diseases, neoplasms and organ failures. nevertheless, little is known about the relationship between co-morbidities and trauma. the aim of the study was to clarify the influences of co-morbidities on the trauma mortality, using data from the japan trauma data bank (jtdb), a multicenter, nationwide and prospectively recruited trauma registry in japan. material and methods: we selected the records from jtdb which fulfilled the requirements to estimate trauma injury severity score (triss) system. logistic regression analysis after adjustment for baseline trauma severity based on triss system assessed the risk of in-hospital trauma death for following co-morbidities: hypertension (ht), diabetes (dm), psychotic disorders (pd), dementia (de), stroke (st), chronic obstructive lung diseases (cold), bronchial asthma (ba), coronary diseases (chd), congestive heart failure (chf), liver cirrhosis (lc), chronic hepatitis (ch), chronic renal failure on dialysis (crf) and active cancer (acn). we conducted a couple of analysis which were adjusted or unadjusted by age in consideration for confounding between co-morbidities and elderly in age. introduction: monitoring the quality of trauma care is frequently done by analyzing the preventability of trauma deaths and errors during trauma care. in the academic medical center traumatic deaths are discussed during a monthly morbidity and mortality meeting. in this study an external multidisciplinary panel assessed the trauma deaths and errors in management of a dutch level- trauma center for (potential) preventability. material and methods: all patients who died during or after presentation in the trauma resuscitation room in a two year period were eligible for review. all information on trauma evaluation and management was summarized by an independent physician. an external multidisciplinary panel individually evaluated the cases for preventability of death. disagreements in classification were resolved during two consensus meetings. potential errors or mismanagements during the admission were classified for type, phase and domain. overall agreement on (potential) preventability was compared between the panel and the amc consensus. results: of the evaluated trauma deaths one was judged preventable and were judged as potentially preventable by the review panel. overall agreement on preventability between the review panel and the amc consensus was moderate (kappa . ). the classification of the panel was more favourable than the amc consensus. the interobserver agreement between the review panel members was also moderate (kappa . ). the panel judged errors to have occurred in the (potential) preventable death group and errors in the non-preventable death group. most frequently mentioned errors were related to choice or order of diagnostics, rewarming of hypothermic patients, and correction of coagulopathies. conclusion: the preventable death rate in the present study was comparable to the available literature. external review does not seem necessary to improve our current internal reviewing system. however, multidisciplinary reviewing of our trauma deaths provided us potential insights to optimize trauma care. disclosure: no significant relationships. arab emirates (uae). the aim of this paper is to report on the long term effects of our early analysis of this registry. material and methods: data in the early stages of this trauma registry were collected for patients during a period of months in . data was collected on a paper form and then entered into the trauma registry using a self-developed access database. descriptive analysis was performed. results: most were males ( %), the mean age (sd) was . ( . ). uae citizens formed . %. road traffic collisions caused an overwhelming . % of injuries with . % of those involving uae citizens while work-related injuries were . %. the early analysis of this registry had two major impacts. firstly, the alarmingly high rate of uae nationals in road traffic collisions standardized to the population led to major concerns and to the development of a specialized road traffic collision registry three years later. second, the equally alarming high rate of work-related injuries led to collaboration with a preventive medicine team who helped with refining data elements of the trauma registry to include data important for research in trauma prevention. conclusion: analysis of a trauma registry as early as six months can lead to useful information which has long term effects on the progress of trauma research and prevention. disclosure: no significant relationships. as a result of injuries related to skating on natural ice. we analysed epidemiological aspects, diagnostically examinations, prevalence of injuries per anatomical location as well as the necessary therapeutic interventions and costs for national health services. results: injuries related to skating on natural ice accounted for % of all attendances. the mean age for man and women did not significantly differ ( , and , years resp.; p < . ), but adults aged - years are more prone to injuries. women were affected in %. radiological examinations were requested in % ( % xrays; % ct-scans). the upper extremity was affected in %, with the wrist accounting for % of those injuries. fractures accounted for % of all ice-skating related attendances. an operative therapy was indicated in %. the mean costs for national health services were e per patient. conclusion: fractures, especially those of the upper extremity, were the predominate type of injury as a consequence of collectively performed skating on natural ice. this incidence is > times higher compared to fractures occured during skating on artificial ice-rinks [ ] . wearing wrist guards is an effective tool in protecting skaters against injuries. we recommend wearing wrist guards during skating on natural ice [ , ] . especially (employed) adults aged - years are very prone to injuries resulting in a high loss of work days [ ] . in contrast to children, adults might be more accessible for wearing protectors [ ] . in future it seems reasonable for national health services to provide steps to increase public awareness on the benefits of prophylactic safety measures. this might result in a substantial reduction of costs for health care and society. introduction: liver cirrhosis has been shown to be associated with impaired outcome in patients who underwent elective surgery. we therefore investigated the impact of alcohol abuse and subsequent liver cirrhosis on outcome in multiple trauma patients. material and methods: using the multi-center population-based trauma registry of the german society for trauma surgery, we retrospectively compared outcome in patients (iss > = , > = ) with pre-existing alcohol abuse and liver cirrhosis with healthy trauma victims in univariate and matched-pair analysis means were compared using student's t-test and analysis of variance (anova) and categorical variables using chi (p < . = significant). results: overall , patients met the inclusion criteria and were, thus, analyzed. ( . %) patients had a documented alcohol abuse and ( . %) suffered from liver cirrhosis. patients abusing alcohol and suffering from cirrhosis differed from controls regarding injury pattern, age and outcome. more specific, liver cirrhotic patients showed significantly higher in-hospital mortality than predicted ( % vs. predicted %) and increased single-and multi organ failure rates. while alcohol abuse increased organ failure rates as well this did not affect in-hospital mortality. of note, alcohol abuse significantly decreased -hour mortality. conclusion: patients suffering from liver cirrhosis are at maximised risk for impaired outcome after multiple injuries. pre-existing condition such as cirrhosis should be implemented in trauma scores to assess the individual mortality risk profile. introduction: early in-hospital treatment of severely injured patients has been internationally standardized by the implementation of algorithms such as the atls Ò -concept. however, due to lack of time, the instability of the patients and the complexity of injuries, there is a risk that some lesions will be missed at this stage. the purpose of our study was to evaluate the incidence and significance of these missed injuries. material and methods: retrospective chart analysis (in-hospital and follow-up as outpatient) of data prospectively collected via an accessÒ-based documentation system was performed. missed injuries were determined as injuries not found during primary and secondary survey. introduction: complication registration is important for monitoring the quality of health care. aim of this article was to describe the incidence, type and impact of complications occurring within months after the initial trauma in multitrauma patients. second, we assessed potential risk factors for the occurrence of complications. material and methods: during a -year period all trauma patients presented to the academic medical center and having an injury severity score of ‡ were included. patients who were directly transferred to other hospitals were excluded. we used the prospective dutch national surgical complication registry of the amc, a level- trauma center, to assess complications within months after the initial trauma. for verification we additionally performed a chart review and searched the decubitus specialists-and icu registration. complications were graded (no real health loss) to (lethal). identification of risk factors associated with an increased risk of complications was performed by univariate analysis. we also analyzed an autopsy findings of these patients and found that of ( . %) had a difference between clinical and autopsy iss. the most frequent missed injury were rib fractures. six of these patients were hospitalized in a period when we did not use msct routinely in multiple injured patients. conclusion: triss is not a clinical prognostic tool but is used retrospectively for clinical and epidemiological research, performance evaluation, and resource allocation. it is required as a basis for quality assessment and improvement. in combination with autopsy findings, triss methodology can be an valuable tool for recognition of unexpected trauma deaths and further analyze of possible treatment errors. patients had to be operated , times and were treated days in the icu and stayed days in hospital. mortality rate was % and rate of multi-organ failure %. % demonstrated severe senso-motoric dysfunction as well as residues of severe head injury. % recovered well or at least moderately. out of survivors answered the polochart. a personal interview was performed with patients. the state of health was at least moderate in % of patients. in % interpersonal problems and in % severe pain was observed. in % problems in working ability concerning duration, as well as quantitative and qualitative performance were observed. symptoms of post-traumatic stress disorder were found in %. the more distal the lesions were located (foot/ankle) the more functional disability affected daily life. in only %, working ability was not impaired. out of interviewed patients demonstrated complete work disability. conclusion: even severely injured patients after polytraumatization have a good prognosis. the iss is an established tool to assess severity and prognosis of trauma, whereas prediction of clinical outcome cannot be deducted from this score. introduction: one of the most common cause of preventable deaths in severe trauma is represented by delay in diagnosis and treatment of injuries, therefore a good teamwork aimed to reduce time consumption and errors is essential. there is in fact good evidence that the outcome of trauma care depends on effective trauma team performance (ttp). critical points during trauma management are represented by lack of leadership, information sharing, difficult communication and decision making. to improve ttp, advanced simulators with full scale realistic patients ( ) and trauma crew resource management (crm) educational programmes are increasingly being used. material and methods: we made a survey among health care professionals (hcp) from different level i and level ii trauma centers in the milan area that confirmed that difficulties in communication and conflictual behavior during trauma action is perceived as a barrier to ideal management. after a focus group interview to establish the need to improve performance we tested in our hospital a tailored trauma teamwork course using an advanced human patient simulator. the peculiarity of this course is the recreation of the same location of the trauma bay using same trauma team components and teamwork laboratory conducted by a professional coach as facilitator for the teamwork. this role is particular important since with this facilitation hcp can reach the awareness of wrong attitudes that lead to errors and bad performance. in particular, the tasks of the facilitator were the following: to help people understand their common goals to assists the trauma team to plan to achieve common goals to assist the group in achieving a consensus of any disagreements that preexist or emerge in the meeting so that it has a strong basis for future action a second survey few months after the course was made among hcp of our institute to evaluate the possible improvement of the ttp. results: the second survey confirmed a perceived benefit among hcp who started to work in a proactive manner. in particular % of hcp reported the feeling of a better ttp and % suggested regular practice with advanced simulation. conclusion: integration of a tailored advanced simulation and a facilitator assisted teamwork could be a powerful method to improve quality of treatment in trauma patients. a score index to evaluate the improvement of the ttp during the course and in reality is although needed and is under evaluation. introduction: our university hospital is one of the only two national university hospitals in tokyo and our emergency medial center is one of the busiest emergency center in japan that receives to ambulances per day. japan has a quite unique emergency medical system in the world. in japan, emergency patients are stratified into tiers, minor-primary, moderate-secondary, severe-tertiary. japanese emergency doctor, that is not same as the emergency physician in the usa, take care only for the most severe emergency cases, tertiary level emergency patients. and if they find out the patient who needed an emergency operation, then they do the surgery by themselves. if the patients need to admit to icu, they take care the patient in icu by themselves. this unique system was installed in mid- s. japanese emergency doctors do not only trauma cases, but also nontrauma severe emergency cases. for talking about trauma, they do not only the initial management of trauma patients but also do emergency surgery and trauma critical care. the mou came into effect with the signatures of the appropriate representatives, acknowledging that four courses had been run in portugal prior to its signature and that all future courses would be conducted in accordance with the essential requirements established by iatsic. in practical terms, the first two courses run after signing the mou must be of the form and nature as laid down by iatsic. thereafter, variations as determined by the nsc may be allowed. the slide material will be provided ''locked''. after the two initial courses, the ''unlock'' code will be provided. details of all modifications must be lodged with the iatsic. nsc will be responsible for ensuring the maintenance of high standards in the conduct of all courses and the selection of participants, ensuring that they meet the minimum standards as laid down by iatsic. nsc is entitled to appoint two representatives at international subcommittee meetings. introduction: clinical skills must be to the fore of medical occupation, especially in surgery, where the mastery of basic skills is of great importance for the young learner. the acquisition of basic clinical skills during surgery clerkships has been shown to be inadequate. this work presents an analysis of different teaching methods in a standardized training program for basic clinical skills in surgery. material and methods: the program is part of a four week surgical rotation for th year medical students, consisting of the one-week training program in basic surgical skills and a three-week clerkship on surgical ward. during the skills training, a maximum of students per group rotate through modules. in a randomized study, the effects of different teaching modalities as skills lab, simulation and role play, as well as different teaching methods as four-step-approach, short-lecture, video were tested on their effect on theoretical and practical skills acquisition. results: a total of students participated on a voluntary basis. the theoretical and practical examinations revealed significant differences in the acquired skills comparing the different teaching modalities and methods. the use of video as part of the -step approach was effective for training the basic skills such us suturing and wound care. least effective for all skills were short-lectures. conclusion: the choice of teaching modality and method has a significant impact on students' skills acquisition and its long term retention. disclosure: no significant relationships. training in trauma center: where to pay attention to? l. handolin traumatology, helsinki university hospital, helsinki, finland introduction: systematic trauma team simulation training was started in helsinki university hospital in . in terms of getting the optimal advantage of training and maintaining the justification of resource allocation, an advantageous balance in various team training principles has to be applied. the aim of the present study was to analyze the standardized written feedback given by trainees after training sessions. material and methods: the study period was three years ( ) ( ) ( ) . the collected data consisted of a subjective self-assessment on the level of knowledge, skills, and team work in traumaresuscitation. also a selfassessment on the effect of training on decision making, communication, skills, team work, and leadership, as well as a general rating of training session were collected. self-assessment was done using five step scoring system from one to five. results are presented as means. conclusion: the actual evaluated interspinous devices led to a significant reduction of rom during flexion-extension, but to a significant increase of rom for the whole specimen (l -l ) during lateral bending and rotation, which increases the risk of adjacent level degeneration. therefore the decision for the optimal individual treatment should be made on the knowledge of the biomechanical effect of each device and the underlying disease of the patient's symptoms. introduction: gait analysis is a powerful tool to monitor the degree of convalescence in fracture care after fracture fixation and during bone healing. because of the availability of a large array of monoclonal antibodies and gene-targeted animals, the mouse has become the preferred species for molecular studies on fracture healing. of interest, gait analysis after fracture fixation and during the bone healing process has not been performed in mice yet. we present a novel technique for dynamic gait analysis in mice and report the change of motion pattern after femur fracture and fixation. materials and methods: all animal procedures were performed according to the national institute of health guidelines for the use of experimental animals and were approved by the german legislation on the protection of animals. ten cd- mice were divided into two groups: fracture group (n = ) and control group (n = ). all mice were anesthetized by an i.p. injection of xylazine ( mg/bw) and ketamine ( mg/bw). a standardized closed midshaft fracture according to ao-classification a -a was stabilized by a common pin. the non-fractured tibia was additionally marked with a pin, allowing a measurement of the tibio-femoral angle by a digital videoradiography system recording images/s. for the control group, one pin was inserted into the femur and one into the tibia without producing a femoral fracture. dynamic gait analysis was performed at day fourteen after surgery in a x-ray compatible running wheel and the following gait parameters were determined: the minimum and maximum tibio-femoral angle, the stride frequency, the stride time, the stride length and the stride velocity. eighteen representative strides per mouse were analyzed. all measurements were done using osirix imaging software and the open source program imagej. all data are given as means ± standard error of the mean (sem introduction: single distal locking screw insertion had been accepted as an option in clinical practice of femoral nailing. however, effect of number and location of the screw on rotational stability of the construct was still doubtful. therefore, this experimental study was conducted to compare rotational stability of the femoral nail construct among three different conditions (two distal screws, single distal screw in different locations). materials and methods: eight right femoral sawbones were selected for this study. each of which was implanted with gk femoral interlocking nail ( · mm) and a static proximal locking screw follow by single distal screw insertion in the most distal screw hole. then, transverse osteotomy was performed at the mid-shaft to simulate simple fracture. after the femur was stabilized on the custom holding jig, rotational force was applied to the femoral condyle by using a torque wrench connecting to the distal part of the jig starting from to nm in nm increment. total rotational angle in each situation was measured by modification of navigation system. thereafter, testing protocol was repeated to the same specimen but two distal locking screws and single distal locking screw in the most proximal screw hole, sequentially. different angle in each testing condition was compared among the different constructs by using paired t-test. results: rotational stability was significantly better in the group of two distal locking screws in every testing condition (p < . ). single distal screw in the most proximal screw hole provided more rotational stability than that in the distal screw hole at nm (p = . ). conclusion: this study demonstrated that two distal locking screws provide more rotational stability than single screw in the case of simple mid-shaft femoral fracture stabilized with interlocking nail. if single distal screw was considered, insertion in the most proximal hole would be a better option in term of rotational stability than that in the most distal hole. introduction: the exothermal reaction of pmma leads to an extensive interaction between the bone cement and the plastics of the application system. this chemical reaction changes the structure of the bone cement and especially makes air pockets. it is necessary to develop application systems with a special composition of the plastics so that there is no interaction between the cement and the application system. in this study a new application system is presented for the first time which does not interact with the bone cement. materials and methods: two different application systems for bone cement were tested in this study. one popular and frequently used system made of polyethylene and a new system made of polypropylene. a special testing unit, in which the application systems were mounted, was used. the testing unit worked with a certain pressure so that a defined amount of bone cement was injected. the resistence data and the time were digitally collected and statistically evaluated. in all procedures were carried out. after the injection all application systems and the injected bone cement were microscopically analyzed. results: two groups, old versus new application systems, were divided. both groups showed significant differences. when using the old application systems made of polyethylene the time frame for injection of the cement was min while the time frame with new system made of polypropylene was min. microscopically there is a significant interaction between the plastics and the cement in the old systems with massive air pockets. in contrast there is no interaction, no air pockets and a homogeneous pattern of the cement when using the new systems. conclusion: the new application system made of polypropylene showed a significant longer time frame for application of the cement as well as no interaction with the plastics. it is possible to treat more than one localization with one application system which makes it financially rewarding. additionally there are no air pockets reducing the danger of infection und increasing the structural stability of the bone cement. introduction: femoral neck fractures are common fractures. despite the frequency of this fracture and the consequences associated with it, little is known about the functional changes that can be expected during and after rehabilitation. the aim of this study was to identify prognostic factors for functional outcome, using a modified harris hip score, after a femoral neck fracture treated with an arthroplasty. materials and methods: we included patients who sustained a displaced femoral neck fracture treated with an arthroplasty. functional outcome after surgery was assessed using a modified harris hip score, and was evaluated after (hhs ) and (hhs ) years. we analyzed the following prognostic factors for functional outcome of patients after treatment of femoral neck fractures with an arthroplasty: age, pre-operative co-morbidity, asa-score, type of arthroplasty (hemi-or total hip replacement), surgeon experience (resident or attending surgeon), interval between trauma and operation, blood loss, direct (associated with the arthroplasty) peri-and post operative in-hospital complications related to the arthroplasty and general post operative in-hospital complications. to challenge the outcome of the analyses we used the cronbach's alpha coefficients for testing the internal consistency. results: after one year the existence of co-morbidities ( ‡ ) was a significant predictor for a poor functional outcome. with and without co-morbidities the mean hhs was . and . , respectively. after years all potential prognostic factors did not have significant influence on the functional outcome. to further analyse this outcome, internal consistency of the hhs was assessed. when pain and function of the hhs were analysed together the internal consistency was poor (hhs : . and hhs : . ). the internal consistency of the harris hip score solely in function (without pain) improved to . (hhs ) and . (hhs ). when the potential prognostic factors were analysed with only the functional aspect, age and the existence of co-morbidities could be defined as a predictors for the functional outcome of femoral neck fractures after and years (r and % resp). conclusion: pain has such a dominant position in the harris hip score that even immobile patients without pain can obtain a reasonable hhs score. the hhs, with the omittance of pain, is therefore a more reliable score to estimate the functional outcome. after using the hhs in this modification, age and the existence of preoperative co-morbidities appeared to be predictors of the functional outcome after and years. many studies have shown that delay to theatre beyond h has an associated increased risk of morbidity and mortality in this cohort. our data revealed that there is certainly room for improvement regarding treated more patients within the h guideline however, there will always be a group of patients whom medical input is required prior to surgical management. lack of theatre time appears to be a significant administrative reason for delay. this is an area of potential improvement however it must be noted that any system of this nature will carry an intrinsic delay in processing. . x-rays and post-op data were analyzed on displacement, postoperative reduction, loss of reduction, and avascular necrosis (avn) and revision rates. high volume surgeons were defined as surgeons who performed > fixation procedures for proximal femoral fractures annually. results: mean age ( vs. years) and percentage of fracture displacement ( vs. %) were equal in both groups. re-operations following loss of reduction or infection was seen in ( %) patients. less frequent complications were avn ( %), coxarthrosis ( %) and pain due to screws bulging out ( %) led to a total conversion rate to arthroplasty in %. displaced fractures show a higher rate in loss of reduction ( %, p < . ) and revision ( %, p = . ) than non-displaced fractures ( . %; . %). patients > years showed % loss of reduction, % avn and taking the reoperations due to coxarthrosis and pain into account, a total revision rate of % was seen compaired to , , and % in younger patients. radiological analyses revealed that the lack of medial support lead to revisions in % of the cases, dorsal angulation in %. low volume surgeons did not perform worse than high volume surgeons. the latter group showed % loss of reduction, % avn and total revision rate %, compared to , and % in the low volume group. we found no differences in the outcome of treating displaced fractures. conclusion: the outcome of fixation of femoral neck fractures is poor. especially displaced fractures, inadequate fracture reduction and high age were associated with poor outcome. therefore, arthroplasty should be considered in patients older than years with displaced fractures that cannot be reduced anatomically. we could not demonstrate that high volume surgeons performed better in this group but we are convinced that further specialization of care is mandatory to improve results of this unsolved fracture. ( ) ( ) ( ) ( ) . internal fixation has shown to provide minor results. the majority of these patients are therefore treated by a hemiarthroplasty of the hip. since the primary goal is to regain the pretraumatic level of mobility as soon as possible( ; ), we sought to investigate, if a minimal invasive anterior approach would be beneficial in regard of perioperative blood loss ( ), postoperative pain( ; ) and thus postoperative mobility ( ) . material and methods: in a randomised controlled trial, patients were treated by a hemiarthroplasty of the hip via an anterior or lateral approach in supine position within hours after trauma( ). apart from parameters like age, asa-score or body-mass-index, the main focus was set on perioperative blood loss, pain and postoperative mobilisation. all data collected were compared between groups to detect statistical significant differences. additionally the same parameters were checked for significant differences comparing patients with or without complications within their group. results: a significant difference between groups was found for postoperative pain within the first hours and for operation time, both to the disadvantage of the minimal invasive approach group. within groups, time of operation and patient's age were significantly higher in patients with complications in the minimal invasive group such as pain at hours was rated higher in patients with complications in the lateral approach group. these results though did not seem to influence postoperative mobility since no significant differences were found between groups at follow-up. conclusion: despite some differences in the postoperative course, postoperative mobility does not seem to be greatly influenced by the choice of the approach for hemiarthroplasty of the hip in femoral neck fractures. still, the operation time was significantly linked to postoperative complications. in this respect, it can be concluded, that the approach an individual surgeon is most familiar with is likely to lead to best results. of the patients, ( . %) received a formal assessment for antiresorptive therapy. the outcomes of this assessment is as follows: . % did not require any antiresorptive therapy, . % awaiting bone clinic assessment on discharge, . % awaiting a dexa scan, . % of patients were started on antiresorptive therapy and % were continued on antiresorptive therapy from pre-admission. conclusion: our study highlighted that in our trust only . % received this assessment formally. we can conclude that when this assessment occurs the guidelines and hence subsequent fragility fracture secondary prevention is addressed. we have then presented this data locally and amended our integrated neck of femur documentation pathway to include a section on antiresorptive therapy assessement. to follow this up we plan to re-audit from st january to st january . in the upper thoracic spine / ( %) could be placed with navigation, / ( %) were controlled intraoperatively. occasionally, scan-setup was problematic, in addition, we experienced technical problems. correct placement was seen for each screw, thus correlating well with theintraoperative findings. conclusion: the application of the combination of intraoperative d-imaging and navigation for posterior instrumentation of the cervical and the upper thoracic spine is technically feasible and reliable in clinical use. user-and software-dependant sources of error could be solved during the first course of the series. image-quality at the cervical spine is depending on individual bone density, and possible metal artifacts. with undisturbed visibility of the vertebral body, the reliability of d-based navigation at the cervical spine is comparable to that of ct-based procedures. additionally, it has the advantage of skipping preoperative acquisition of data as well as thematching-process. furthermore, exposure to radiation is reduced due to the possibility of sparing pre-and postoperative ct. disclosure: no significant relationships. the average lka measurements in order were: . °, . °, . °( p < . ), and for aca: . °, . °, . °(p < . ). while a significant difference between the averages of lka, e/f of group and group (p < . ), no statistical difference was found comparing the average aca angle (p = , ). while there was no significant change in e for all groups (p > . ), the increase in f after surgery was considered significant (p < . ), and no difference was observed between the averages of group and group (p > . ). vas was . ( - ). conclusion: at the end of an average year follow up period of posterior tl fractures no difference was found between the early and late period measurements of aca and anterior height although lka showed a statistical loss in height the correction degree achieved in the late period was found to be significantly higher than preop. ( cases), crushing without skeletal injuries ( cases) in all these cases, pulse was present at the first evaluation, and the onset of acute post-traumatic ischaemia was at - hrs after trauma . tha diagnosis, based on clinical suspicion, became definite after doppler evaluation and arteriography. the anatomical base of ischaemia was late thrombosis ( cases) and compressive hematoma ( cases). thrombosis was due to obstruction of the big arteries ( cases) and microcirculation, due to overrun compartment syndrome- cases.vascular restoration and fasciotomy was performed whenever muscles were viable, but amputation was necessary in cases results: the patients were analysed from the point of view of the corelation between the moment of onset of the ischaemia, the type of injury, the status of the muscular structures, the algorithm of diagnosis, the type of the treatment, and the clinical outcome. the study revealed that the clinical outcome was better when the time between trauma and ischamia onset was less, since the muscular ischaemic had less time to develop. in the same time, there were cases in which clinical symptomes were not corresponding to the imagistic evaluation. conclusion: high energy trauma affect all the structures of the limbs. clinical suspicion has particular importance especially when trauma affects one of the regions which is known as establishing a dangerous environment between the arteries and the bones / joints. in all the cases that authors analyse, complete and early diagnosis and treatment of acute post-traumatic ischaemia, based on the close monitoring of the patient and '' clinical alarm signs '' seemd to be the conditions for the favourable outcome of the patients. introduction: the aim of presentation is to demonstrate the surgical treatment and postoperative period of a patient who was caught on a fence-pole and suffered severe injuries of perineal region and lower extremity. material and methods: after a long time of technical rescue the patient arrived to our department with a one meter long portion of fence in his perineal region. after the urgent extraction of metal fence we performed an intraoperative rectoscopy. during the debridement and exploration of deep perineal injuries we realised a heavy swelling around the punctated wound of the left leg. we made a femoral incision and exploration and recognised the several injury of the femoral vein and artery. we provided the cm long injuries with stitches. results: in the postoperative period we made a second-look and debridement because of lymhphatic retention and small skin necrosis around the incision. no real vascular or circular lesions were recognised during the control period of the patient. injuries were totally improved. conclusion: the edification of this case is that it's never sure that the major wound makes the biger trouble to the patient or to the surgeon. in our presentation we plan to demonstrate the intra -and postoperative pictures and the results of controll period. results: the incidence of various types of trauma were blunt in patients ( %), gunshot wounds in patients ( %), and stab wounds in patients ( %). only ( %) patients were hemodynamicaly stable. isolated abdominal vascular trauma was detected in patients ( %). vessels injured included aorta ( , %), inferior vena cava ( , %), named visceral arteries ( %), named visceral veins ( %), iliac arteries ( , %), and iliac veins ( , %), epigastric, hypogastric, intercostal arteries ( , %), epigastric, hypogastric, intercostal veins ( %), gonadal vessels ( %), renal veins ( %), non-named mesenteric vessels with segmental bowels necrosis ( , %). two or more vascular injuries were found in ( , %) patients. according to organ injury scaling, st grade injuries were found in ( %), nd -in ( %), rd -in ( %), th -in ( %), and th -in ( , %) patients. the most frequent associated injuries were small bowel - , liver - , colon - , stomach , duodenum - , diaphragm - , pancreas - , spleen - , with an incidence of %, %, %, , %, , %, %, % and , % respectively. all injuries were managed according to injury score. infrarenal v. cava ligation was performed in all cases of hemodynamic instability. minor named abdominal vessels were ligated in all cases. segmental intestinal resection was performed in all patents with th grade of intestinal injuries due to devascularisation. overall mortality rate was %. the vessels with the highest mortality rates were inferior vena cava ( % - / ). there were no mortalities in isolated abdominal vascular trauma patients and in cases of st grade of injury. mortality rate in accordance to ois was: nd - patients ( %), rd - patients ( , %), th - patients ( %), th - patient ( %). no differences in mortality rate were found according to type of trauma (blunt or penetrating). the associated injuries with the highest mortality rates were pancreas ( / - %), diaphragm ( / - , %), liver ( ( ), a rupture of the heart ( ) or a aneurysma dissecans with a rupture of the aorta ( ). in addidtion to the detailed forensic examination and autopsy, we took the anthropometrical measurement of all corpses in dimensions, so that we were able to create a biomechanical simulation of the accidents with ''finite element models''. there the shear forces affecting the aorta can be calculated. as three forces (frontal impact, side impact and deceleration) are the most important, we will present three comprehensible example accidents. the reason of death is always the ''aortic rupture'', but every time the biomechanical way of application of the force was completely different. in detail they are a car accident (frontal collision of a small car with a wall); a downfall from the height of meters in suicidal purpose and a compression of the thorax of a eight year old boy with a shovel of an excavator. results: although all three accidents have completely different course of crash, we were able to see the same reason for death: a rupture of the aorta at the onset of the ligamentum arteriosum botalli. by using the numerical simulation, it can be shown that three main directions of force are important in an accident: the frontal impact, the side impact and the deceleration. in all these examples, it was able to simulate the reaction of the aorta in relation to the development of the force. the simulation will be presented as well as all clinical treatement made by the medical stuff. conclusion: although the rupture of the thoracic aorta is a frequent cause of death, the injury mechanism has not been comletely known. a database with several victims of aortic ruture was created and special accident types will be presented and simulated. introduction: overlooked compartment syndrome represents a catastrophic complication for patients and orthopedic surgeons. invasive compartment pressure measurement continues to be the gold standard. however, repeated measurements in uncertain cases can be difficult to achieve. we, therefore, developed a model for a noninvasive technique to assess tissue pressure by ultrasound based elastography. material and methods: a perforated plastic tube filled with saline was surrounded by a silicone sealed plastic cover, mimicking the shape of the tibial compartment. a pressure transducer inside the compartment was installed. a second pressure transducer was installed on the ultrasound probe to allow simultaneous monitoring of the pressure inside the compartment and the tissue deformity. for calibration, ultrasound images were generated at and mmhg. the plastic cover to tube distance was measured before and after compression (delta d). subsequently, increments of mmhg pressure increases were used to generate a standard curve ( - mmhg), thus mimicking rising compartment pressures. the intra-observer reliability was tested by using subsequent measurements. a correlation was determined between the skin to bone distance (delta d) and the pressure measurement (p). the pearson correlation coefficient was calculated, and a regression analysis was performed. ( ), better antibiotics and computed tomography-guided percutaneous drainage ( ). however, when everything else has failed, the burder of decision making the choice of a 'last resort' operation will be shifted again to the surgeon. we here described our recent experience with such cases treated by abbreviated laparotomy using the bogota bag technique ( ). results: for the seven first patients, we performed colon resection with colostomy. after extensive debridement, lavage and drainage, the peritoneal cavity was closed with a sterile gastric bag sutured on the rectus aponeurosis according to the so-called bogota-bag procedure ( ). the mean operative time was minutes. a second look laparotomy was planned after hours: one patient required one reexploration, four patients required two and two required three. the decision of re-exploration was based on the visual aspect of the peritoneal content, the clinical evolution and the bacteriologic results. for the last three cases, we elected perform colon resection without colostomy followed by anastomosis in two patients in the second look laparotomy and colostomy in one because of two relaparotomies. none of the ten patients required further percutaneous drainage. two patients died in multiple organs failure (one with perforated diverticulitis and one with ischemic colon after aneurysm repair). conclusion: abbreviated laparotomy with temporary closure of the abdominal wall associated with planned re-exploration of the peritoneal cavity is a simple and effective way to treat patients with severe abdominal sepsis. introduction: pelvic fractures usually are the result of high energy trauma and such patients often have many associated injuries. long term outcome data of pelvic injury patients is sparse, we present our information with special emphasis on poly-trauma patients, with consideration for the combined involvement of associated injuries on functional outcome. material and methods: general functional outcome and clinical outcome were determined with an examination by a physician and patient assessment at a minimum of years after the injury. pelvic fracture patients that had suffered poly-trauma were categorized by fracture location: acetabular, pelvic ring, or a combination. results: the long term outcome in the patients with pelvic ring fractures (exclusive of acetabular fracture) was the worst clinically, as evidenced by evaluation of pain( . %), increased use of special medical aids( . %), a poor merle d'aubigne score( . %), and worse sf- and haspoc scores. patients with acetabular fracture had poorer general functional outcomes than those with combined pelvic acetabular fractures and were noted to have higher incidence of associated injuries such as type iv pipkin fractures. further subcategorization of pelvic ring fractures into anterior, posterior or combination showed specifically those patients with combined anterior posterior pelvic ring fractures had the worst long term outcome. conclusion: a combined anterior posterior pelvic ring injury accounts for the worst long term outcome of pelvic injury poly-trauma patients. we found that bilateral pelvic injury and particular associated injuries greatly influence long term functional outcome. disclosure: no significant relationships. material and methods: canulated screws were placed in human semi-cadaver models and plastic pelvis models in d navigated, d navigated and conventional matta technique. aim of this study was to evaluate intraoperative time, intraoperative radiation dose (fluoroscopy time, area dose product and images per screw) and accuracy (amount of exactly placed screws, mean deviation of tip placement and misplaced screws per group). results: the accuracy of d navigated procedures is significantly higher (p < , ) than in the conventional technique. there is a significant lower radiation dose in the navigated procedures (p < , ) for the operation team. the intraoperative radiation dose is increasing significantly from conventional method to d navigated to d navigated procedures for the patient (p < , ). there is a significant higher time per screw necessary for navigated procedures (p < , ). conclusion: the usage of flatpannel technology seems promising in d navigation. our data shows a benefit from using navigated procedures in transilliosacral screw placement. the higher precision and lower radiation exposure for the operation team show that d navigation is superior to d navigated procedures. the higher accuracy of the d navigated procedures renders a postoperative routine ct scan obsolete thus lessening the total radiation exposition of the patient. introduction: the purpose of this biomechanical study was to determine whether locking screws or smooth locking pegs optimize fixation of ao a distal radius fractures. material and methods: pairs of fresh-frozen human distal radii were used. ao a extra-articular distal radius fractures were created by removal of a -cm-wide dorsal wedge of corticocancellous bone centered cm from the articular margin of the distal radius and were fixed using palmar locking plates. the radii were divided into matched-paired groups for comparison. the side order, the fixation order and the testing order were randomized. the distal fragment in group i was stabilized with angular stable screws. the distal fragment in group ii was fixed with locking pegs. the proximal fragment in both groups was fixed with screws. the probes were tested with . nm for torsion and with n axial load for cycles each. stiffness was measured from the first cycles regarding torsion and axial load. then the differences of the stiffness were recorded during the remaining cycles. the wilcoxon test was performed, a value of p £ . was considered statistically significant. results: there were no statistically significant differences in the first load cycles within the eight matched pairs. after cycles the constructs with locking screws (group i) showed statistically higher stiffness values (p = . ) compared to the constructs with smooth locking pegs (group ii introduction: plate fixation of the odontoid process without c -c arthrodesis appears to a practicable option for the management of odontoid fractures that are not suitable for conventional screw fixation. although previous biomechanical works have evaluated the effectiveness of different odontoid screw fixation techniques, no study has quantified the mechanical stability of odontoid fixation by a plate device. the purpose of this study was to measure the mechanical stability of odontoid plate fixation using a specially designed plate construct, and to compare the results to those after odontoid single-and double screw fixation. material and methods: the second cervical vertebra was removed from fifteen fresh human spinal columns. the specimens were fixed to the experimental apparatus, with the load cell at the articular surface of the odontoid process. in a first test series, stiffness and failure load of the intact odontoid were measured. type ii odontoid fractures were created by °oblique extension loading at the articular surface of the odontoid process. afterwards, the specimens were randomly assigned to one of the following three groups: in group i (n = ) the fractures were stabilized using a specially designed plate construct, in group ii the fractures were fixed using two . mm cortical screws, and in group iii we used one regular . mm cortical screw. in a second test series, stiffness and failure load of the stabilized odontoid fractures were assessed for comparison and statistical analysis. results: group i (plate device) showed a significantly higher mean failure load than group ii and group iii. the mean failure load of group i after fixation of the odontoid fracture was % of the mean failure load that was necessary to create a type ii odontoid fracture, initially. comparing group ii (double screw technique) and group iii (single screw technique), there was no significant difference regarding the mean failure load. in both groups the mean failure load after odontoid fixation was approximately % of the mean failure load of the intact odontoid. statistical analysis also revealed a significantly higher stiffness of the stabilized odontoid after plate fixation, than after single or double screw fixation. conclusion: plate fixation of the odontoid process as an alternative procedure in certain fracture patterns provided a significantly higher biomechanical stability than the technique of odontoid screw fixation. using a specially designed plate construct fixed with two cancellous screws into the body of c and an additional cortical screw inserted in the odontoid process, % of the original stability of the intact odontoid was restored. single or double screw fixation of the odontoid only restored approximately % of the original strength. results: extension and flexion were not influenced of all implants significantly. all dynamic implants and also the rigid implant led to a significant increase of the mobility during side bending and rotation in the area of the adjacent segments. conurrently the cephaled adjacent segment (l /l ) showed a significantly higher mobility than the caudal adjacent segment (l /l ). conclusion: dynamic implants such as the interspinous spacer enlarge the mobility of the adjacent segments during side bending and rotation in a comparable size as the rigid implant. to this extent is to be assumed that reinforced adjacent degeneration cannot be prevented by the use of the interspinous spacer substantially. introduction: osteoporosis is a systemic skeletal disease characterized by reduced bone mineral density and disrupted microarchitecture of bone tissue. the most severe consequence of osteoporosis are osteoporotic fractures. these are mainly low-energy fractures, which anamnestically, clinically and radiologically differ from fractures in healthy bone. we tried to find the answer to a queston, whether it is possible, that osteoporotic compression fractures are single events, or if they represent a gradual, progressive vertebral collapse in patients with osteoporosis. we evaluated the forces, necessary for vertebral fractures, regarding the bone mineral density. material and methods: cadaver vertebrae were isolated with the approval of ethics committee. we mesured their bone mineral density and then subjected them to the stress-test. we used the computer-controlled hydraulic press and stress vertebrae to the fracture point and beyond, monitoring the deformation and the load. a sigma-epsilon diagram was constructed from the data. results: with the loading of vertebrae the pressure grew exponentially as a function of deformation to the breakage point. then we observe a plateau of saw-like shape, which corresponded to the progressive vertebral collapse. further deformation led to gradual compacting of vertebrae and we observed once again an exponential increase in pressure. this bone compaction is therefore the first mechanisms of fracture repair. the saw-like plateau form suggests progressive collapse of vertical trabeculae and their jaming into the horizontal, which then with the increasing deformation and load also fail. a similar phenomenon can be observed in the collapse of buildings during the demolition. (the - phenomenon). conclusion: unlike a high energy vertebral fractures, the osteoporotic fractures are presented as a gradual vertebral collapse. they take place parallel with the processes of bone reparation and remodelation. from this standpoint, osteoporotic fracture is unique. vertebral collapse increases the bone mineral density in the broken vertebrae, what is observed radiologically and densitometrically. repair of medium to large, but reparable, rotator cuff defects, augmented with a restore patch or not. patients have been randomly assigned to receive standard repair augmented with the restore implant or to receive non-augmented standard repair as the repair procedure is exactly the same in both patient groups, and the implantation of the restore implant does not necessitate any additional incision or measures, neither the patient nor the assessors are aware of the fact an implant has been used. the ethical committee of the university hospitals leuven has approved the study. all patients get full information and are enrolled in the screening program after written consent only. clinical evaluation, both pre-operatively and at months post-operative is performed by the same, independent physiotherapist trained in shoulder evaluation using the constant score structural evaluation is performed by ultrasonography, performed by a radiologist specialised in musculoskeletal radiology and sonography. unpaired two-tailed t tests, performed with prism software for mac osx, were used to compare the results of the scores in the control group with those in the xenograft group. fisher exact tests were used to evaluate the significance of differences in the proportions of retears in the patients for whom a sonography was obtained. results are expressed as the mean and standard error and significance was set at p < . . results: we included patients. there were female and male patients. in the non-augmented group there were females and males. in the restore group there were female and male patients. the average age of patients was years of age. in the non-augmented group the average age is , y (+/- , ) years of age, in the restore group , y (+/- , ). the mean pre-operative constant score of the non-augmented group was , +/- , points whereas it was +/- , points for the restore augmented group. post-operative the functional outcome months after surgery again was scored using the constant score. the mean score in the non-augmented group was +/- , points; in the restore group it was , +/- , points in the non-augmented group we documented a retear in / patients, in the restore group we had a retear in / patients ( small tears, massive tear). introduction: it has been estimated that up to % of adults suffer from rotator cuff tears [ ] , which can impair their ability to work or perform household tasks [ ] . management of rotator cuff tears is difficult as a large proportion of technically correct surgical repairs re-rupture, estimated between - % [ ] . it has been estimated that thousands of extracellular matrix repair grafts are used annually [ ] to augment surgical repair of rotator cuff tears and act as temporary scaffolds to support tendon healing. the only mechanical assessment of the suitability of these grafts for rotator cuff repair has been made using tensile testing only, and compared grafts to canine infraspinatus [ ] . as the shoulder is subject to shearing as well as uniaxial loading, we compared the response of repair grafts and human rotator cuff tendons to shearing mechanical stress. we used dynamic shear analysis (dsa), which is a form of rheology and allows the study of flow and material deformation. material and methods: the shear properties of four different commercially available rotator cuff repair grafts were measured (restore, graftjacket, zimmer collagen repair and sportsmesh). mm punch biopsies were taken from the grafts and subjected to oscillatory deformation under compression. the bulk storage modulus (g') was calculated [ ] and used as an indicator of mechanical integrity. to assess how well the repair grafts were matched to torn and normal rotator cuff tendons, the storage modulus was calculated for human rotator cuff specimens obtained from the edge of rotator cuff tears during surgery, from patients aged between and years. age and sex matched normal controls were also obtained during shoulder hemiarthoplasties and stabilisations. results: we report a significant difference in the shear moduli of all four rotator cuff repair grafts (p < . , way anova). of the repair grafts (restore and graftjacket) had a significantly lower storage modulus when compared to human rotator cuff tendons (p < . , dunn's multiple comparison test). only the zimmer collagen repair and sportmesh had a storage modulus which was comparable to that of normal rotator cuff tendons (p > . ), and thus were most closely matched. conclusion: with increasing numbers of repairs of rotator cuff tears, and augmentation of these repairs, there is a need to understand the mechanical and biological properties of the both repair grafts and the tendons they are designed to augment. there is no clear definition of the ideal mechanobiological properties. current rotator cuff repair grafts display a wide variation in their shear mechanical properties, and how closely they are matched to the mechanical properties of human rotator cuff tendons. it is hoped that this study, in conjunction with others, will help to guide surgeons in deciding on the most appropriate repair graft. three-dimensional computed tomography reconstructions also improved the average intraobserver reliability for all fracture characteristics, from j d = . (substantial agreement) to j d = . (substantial agreement). the addition of three-dimensional images had limited influence on the average interobserver reliability for the recognition of specific fracture characteristics (j d = . versus j d = . , both moderate agreement). three-dimensional computed tomography images improved interobserver reliability for the recognition of coronal plane fractures from fair (j d = . ) to moderate (j d = . ) but this difference was not statistically significant. conclusion: three-dimensional computed tomography is helpful for; ) individual orthopaedic surgeons for preoperative planning (improves intraobserver reliability for the recognition of fracture characteristics), and for ) comparison of clinical outcomes in the orthopaedic literature (improves interobserver reliability of classification systems). disclosure: no significant relationships. introduction: in recent years, d fluoroscope has used increasingly in orthopaedic surgery because it offers some advantages such as generation d data without anatomic registration requirement. previous studies have focused on the clinical use of d fluoroscope in surgical procedures such as calcaneus or acetabular fracture reduction, or placement of screws in spinal surgery. there are no reported data on radiation exposure of d flu to orthopaedic theater staff. we want to correlate radiation exposure and distance concerning the patients and members of surgical team during using three-dimensional fluoroscope and study how far is enough until radiation exposure can not be measured. material and methods: an isocentric c-arm fluoroscope (siremobile isoc d) was used for the study. human cadaveric extremity was used for target. digital dosimeters (mydose mini pdm- , aloka) were used to measure radiation exposure at specific distances. dosimeters were systematically exposed by the following protocol. represented positions were direct contact and every -cm. radius from the center of the beam. the distances were increasing until the dosimeters could not detect the radiation. each radius distances were designed to record different positions; top, bottom, left and right side. dosimeters were exposed and removed ( dosimeter positions at a time from each radius). first we used low resolution scan technique to obtain the images. after all radiation exposure records were collected, we changed to use high resolution scan technique and repeated the protocol. each technique was repeated in times to obtain the mode of data. results: radiation dose at ground zero is lsv in high resolution and lsv in low resolution. radiation in high resolution technique can not be measured beyond meter from the center of the beam at the top, bottom, and right direction and . meters at the left direction. in low resolution, radiation cannot be detected farther than cm. in the top, bottom and right direction and . meters at left direction. conclusion: radiation dose measurements in each direction are decreased during increasing distance and dose in left direction is higher and farther than others. beyond . meters is safe from radiation in knee application. high resolution gives higher radiation and farther than low resolution. introduction: tibial plateau fractures with impression are often associated with poor outcomes and a high rate of complications. the current guidelines advocate anatomic reduction, re-establishment of tibial alignment, stable fixation, and filling of the sub-articular defect. we hypothesized that fixed-angle liss-plates provide adequate stabilization with less need for void filling, minimal complications and good radiological outcome. material and methods: retrospective evaluation study. in the period - , we operated patients with an intra-articular tibial plateau fracture. forty were treated with a liss-plate. mean age was years, were male. all fractures were classified as ao type b or c; were schatzer type ii, type iv, type v, and type vi. five patients were initially treated with external fixation. mean time until definitive surgery was days (range, - days). in fractures, the subchondral void was filled with either hydroxy or bone graft, in the other cases no graft was used. demographic data and fracture classification were equal in both groups. articular impression was measured by independent evaluators pre-operatively, post-operatively and months after surgery on plain x-rays. results: mean pre-operative impression was . mm (with void filling . mm, without . mm, ns). thirty-four fractures were additionally stabilized with k-wires or screws. the post-operative impression was on average . mm. evaluation criteria included the lysholm and tegner activity score. all fractures were stabilized post primarily. the surgical main approach was strictly medial. exposure of the entire medial condyle fracture was first performed anteromedial following the fracture line to the articular border. the posterolateral impaction was addressed directly through the main fracture gap. small fragments were removed, larger reduced and preliminarily fixed with separate kwire(s). the posteromedial part of the condyle was then prepared for main reduction and application of a buttress t-plate in a posteromedial position, preserving the pes anserinus and medial collateral ligament. in addition a parapatellar medial mini-arthrotomy through the same main approach was performed for reduction and pds-suture-fixation of the anterior eminence (acl and anterior horn of lateral meniscus). results: we treated patients with fractures. median age was years ( - ). we could evaluate patients ( %), patients were lost to follow-up due to foreign residency. the fractures were treated post primarily at an average of days, of them in a twostaged procedure with initial knee-spanning external fixator. all fractures healed without secondary displacement or infection. patients showed none to moderate osteoarthritis after a median of years. one patient showed a severe osteoarthritis after years. all patients judge the result as good to excellent. the lysholm score reached ( - ) and the tegner activity score ( - ). all patients have achieved a minimum flexion of °. conclusion: in our view it is crucial to recognize this increasingly observed type of knee injury in winter sport areas. with our strategy we achieved good results in nearly all patients. the described larger medial approach allows addressing most of the injured parts of the tibial head (medial condyle with posteromedial buttressing, tibial spine, posterolateral impaction). material and methods: it is presented one new minimally invasive method for closed fracture reduction and one extramedullary selfdynamisable internal fixator (sif). there is no contact between bone and internal fixator in fracture area. it has been widely investigated biomechanicaly. in clinical use it has been applied to metaphyseal fractures of distal femur and proximal and distal tibia. the age of patients was from to years. this internal fixator is applied by two small incisions. reduction is achieved using standard traction table or using special reduction device. for opened fracture it has been used high mobile external fixation system as temporarily ( fractures) or definitive ( fracture) method. results: received clinical results are promising, as it has been shown early callus formation and radiological union within the . - months. it has been allowed to patients early full weight bearing, if fractures not intraarticular. during the treatment it has been confirmed working of self-dynamisation concept, which probably all together with d configuration resulted in unexpectedly quick fracture healing. follow up was months ( - ). when used external fixation system, axial dynamisation has been regularly activated. conclusion: according to results obtained, it can bee concluded that new biological internal fixator is suitable for minimally invasive technique, without opening of fracture site if no intraarticular dislocation. it can be used as primary method or soon after external fixation if damaging control concept used. introduction: disaster, is the disproportion between the need for medical care and the means available in the community. this discrepancy of needs /means is the major problem in every step of the rescue chain, when a disaster situation is present. this is more obvious at the end of the chain, which is the hospital and especially, the bottleneck of the entire disaster's management system, the emergency department. material and methods: in greece, the most common and frequent disaster situation is the earthquake. and so, the most expected pathology of the victims is trauma. because of the lack of . special organization of emergency medicine and . independent modern emergency departments in greek hospitals, their directors did not give the appropriate attention to organize a disaster plan (internal or external introduction: accurate response to major incidents requires accurate decisions on all levels, from command level to the care of the individual patient. development, evaluation and training of the process of decision-making requires standardized models providing complete and accurate information as a base for the decisions; a decision based on incomplete or incorrect data can not be properly evaluated. the aim of the present project was to design a simulation model that could be used both for evaluation of different methods in the response to major incidents and for training and evaluation of skills in making correct decisions. material and methods: a system was created providing the information required for this process in the whole chain of management and performance: scene, transport, hospital response, co-ordination and command. input data were based on real scenarios and real resources. for evaluation of methodology, all parameters except the one studied, in this study triage, were standardized. the results from (a) physiological and (b) anatomical triage, performed by staff on different levels of competence and experience, serving as their own controls, were compared. for training, the system was used in courses in medical response to major incidents with training of the whole chain of management and performance, from prehospital patient management to over all co-ordination and command. results: the methodological evaluation showed differences in priority and outcome between anatomical and physiological triage related to the level of experience and to the position in the chain of response, providing a base for choice of method related to those factors. the results from training with the use of the system, so far only evaluated by the participants own ranking, showed high percepted improvement of relevant skills. conclusion: a methodology for simulation of major incident response designed for scientific evaluation of methodology also provides a very good educational tool, since correct and complete data as a base for decision making also gives an effective and realistic training. disclosure: one of the authors, sl, has the copyright to the mac-sim system, a non-commercial system intended mainly for scientific use. equipment for training can be produced by users, but also purchased for production costs. introduction: interhospital referral of traumapatients for reasons of special (most neuro-)surgical competencies to a specific level traumacenter, is common practice in the netherlands. these traumapatients are sometimes admitted directly through specialized intensive care units and therefore do not enter the emergency department (ed). therewith the standard assessment according to the atls guidelines is bypassed in these cases. this withholds the risk of an incomplete assessment. we therefore consistently coordinate the assessment of all transferred traumapatients. in this study we analysed the number of newly found injuries in referred polytraumatized patients and the clinical consequences in terms of extra treatment, permanent damage or death to the patient. we also analysed possible risk factors for missing injuries. introduction: synchronous admission of large numbers of patients into the hospital requires a perfect coordination of activities of designated teams in the process of reclassification at the entry to the hospital and subsequent continuous provision of medical care for the patient in the course of examination and treatment, up to his hospitalisation at the target department, in accordance with the characteristics of the injury and seriousness of his medical condition. this process cannot be accomplished through improvisation but only with creating a uniform organisational scheme, defining the recommended structure of medical teams and their activities during a multiple admission of casualties into the hospital. in this article, we present a proposal of such consensual organisational scheme, partially verified in practice. the organisational scheme is defined in the following areas: -space arrangements -places of admission and organisation of work -creation of mini trauma teams (anaesthesiologist, traumatologist and surgeon or another traumatologist take over the most serious patients, the teams are accompanied by consulting specialists of relevant specialities (neurologist, neurosurgeon, radiologist), the whole teams or at least parts of them, accompany the patients for the whole period up to the definite treatment at operating theatre, or his placement at a destination department -the continuity of care is secured in this way, without the need to pass on any findings and information -placement of patients into individual hospital departments (follows certain rules, it is necessary to direct all the admitted patients into as few departments as possible (one or two), and thus keep the best possible view over the priorities during their treatment -entry corridors -,,green corridor'' -patients are immediately transported through this area by transport teams into the ''green'' designated area, the ''red'' and ''yellow'' entry area does not have to be extremely large, however it requires an adequate equipment from the material and technical point of view results: multiple admission of patients must be well-organised and managed, most often by a head-physician of the ua department, or another authorised specialist (in hospitals without the ua department). the idea of the traumanetwork d dgu is to built up regional networks of various trauma centers with the objective to standardise and optimise the treatment of severely injured patients -with the additional involvement of rescue services, physicians and competent facilities and centres for the treatment of specific injuries as severe burn or spinal cord injuries etc. to assure that all participating hospitals meet the criteria needed for the treatment of trauma patients, a certification firm (diocert) was assigned to accomplish the audits and to control the process of certification. thus, every hospital has to pay a sum of nearly eur for audit, certification, benchmarking, yearly quality reports and the use of special it-tools which were designed for the traumanetwork d dgu. material and methods: coordination of traumanetwork implementation coordination of audit and certification process results: since the beginning in the year actually hospitals are participating the traumanetwork d dgu. these hospitals are organized in regional traumanetworks. % of the hospitals are preliminary categorized as local trauma centers, % as regional trauma centers and % as over-regional traumacenters (the highest category). % still aren¢t categorized. hospitals have already signed the contract with the german trauma society and paid the participation fee. hospitals meet the criteria for audit and hospitals are already audited by the firm. in october the first regional trauma network (trauma network east bavaria / tno) was certificated with a total of participating hospitals. conclusion: in the past years the number of participating hospitals increased year by year. the nationwide acceptance and the high level of participation in the traumanetwork d dgu in germany show that the treatment of severely injured patients is one of the main topics and exercises for trauma surgeons in germany. if the expected improvement in treatment quality and the decline in trauma mortality is only wish and fiction or reality and fact has to be proven by studies in the next years. therefore a working group with focus on quality improvement, changes in mortality, improvement in rehablitation results etc. was founded. introduction: one of the challenges in trauma care is diagnosing all injuries. any delay in treatment can lead to increased morbidity, prolonged length of hospital stay, costs, and even mortality. despite the use of standardized guidelines for initial evaluation such as atls, the incidence of missed injuries in the literature is considerable. the aim of this study was to assess the rate of missed injuries in trauma patients evaluated in two dutch level- trauma centers and to determine potential factors that contribute to injuries being missed. we assessed all radiological reports during initial admission and operation records of the patients included in the prospective randomized react trial. this study was part of a randomized trial conducted in two dutch level- trauma centers investigating the role of ct scanning in the trauma room. missed injuries were defined as not diagnosed during initial radiological evaluation in the trauma room. we assessed all missed injuries and the phase in which these injuries were diagnosed. second, we assessed potential contributing factors by univariate analysis. results: there were a total of total calls performed with real patients and test calls. of the actual calls, ( %) were performed while moving and ( %) were done from a stationary position. initial video quality in was rated good in cases ( %) and initial audio quality was rated good in ( %) cases with actual patients. of the actual calls ( %) experienced some sort of temporary video drop during the entirety of the call and calls ( %) experience some sort of temporary audio drop. these drops were a result of the setup of mesh wifi and the need to jump from router to router. users in the hospital found the program to be a very useful trauma and emergency medicine tool, but adjustments need to be made to improve the network. conclusion: the use of telemedicine in a pre-hospital setting may play a significant role in the management and treatment of trauma and critically ill patients as hospital medical staff can intervene in real time during transport. patients can be evaluated in real time which allows the necessary staff and resources to be available on arrival. initial user feedback has been encouraging with users acknowledging its usefulness as a pre-hospital tool. ( ) in the elective setting it is logical that a lower egfr reflects poor renal function and low overall physiological reserve. the same is not obviously true for emergency patients who may have an ''artificially'' low egfr merely as a reflection of acutely altered fluid balance. change in egfr from admission to hospital to itu admission was also significantly different between survivors and nonsurvivors. this would suggest that egfr reflects a response to treatment as well as renal function. this study supports the use of egfr in the decision making process when trying to predict outcome in emergency general surgery patients. introduction: the surgical medium care (smc) in our hospital is a bed ward with monitoring facilities, and is used critical ill patients from the trauma and other surgical wards. over the last years there has been an increase in the number and severity of trauma patients admitted to out hospital, as well as there has been an increase in patients undergoing major elective surgery. the aim of this study was to verify if these trends are reflected in an increase in patient-and workload on our smc. in this study we describe the patient-and workload on the smc between and using the tiss- . the modified therapeutic intervention scoring system (tiss- ) is a validated score of therapeutic activities and an alternative approach to evaluate outcome of critically ill patients ( ) ( ) ( ) . material and methods: a prospective cohort study of all consecutive patients admitted to the smc between / / and / / was performed, using the tiss- database. of all admitted patients a daily tiss-score was performed. besides the tiss data, patients demographics, referring ward, discharge destination, length of stay, and hospital mortality were retrieved from the database. results: there were a total of admissions of patients in the study period. % of patients were male, % were female. the median length of stay was days ( - ). the overall hospital mortality rate was , %, with no significant differences over the years. % of the patients admitted to the smc came from the icu, % came from the emergency department, , % came from home, , % came from the recovery ward, and % came from the trauma and surgical ward. these percentages did not change over time. the average tiss score during the study period was and did not significantly differ during the study period. there was, as expected, no significant difference in tiss score between patients who survived and the non survivors. introduction: the demands placed on systems and organisations that protect the general population are constantly growing. the reasons for this include, among other things, circumstances altered by the threat of inter-national terrorism and the increasing frequency and magnitude of mass public events and natural catastrophes. crisis situations such as these present unique, often completely unprecedented chal-lenges to those affected and to all actors with responsibility for crisis management and the protec-tion and rescue of people.with regard to effective interdisciplinary crisis management, both germany's security and rescue forces and its general population suffer from widely acknowledged and scientifically proven deficits. impact on people and the society. in this context, all natural and man-made threats will be considered (''all hazards approach''). elearning and virtual reality modules based on these scenarios will be offered to target groups via the internet on an individualised basis. results: the aim of this project is to develop a platform to prepare security and rescue forces, doctors, caregiv-ers and the general population for terrorist attacks, crises and disasters. an online platform with a modular structure (employing teaching methods such as e learning, blended learning etc) will offer innovative and specialised instruction and advanced training to all users. conclusion: experts agree that the modern teaching methods and computer-based simulations mentioned here (such as virtual reality methods) are excellent tools to help train people efficiently to respond to events that cannot be planned, such as terrorist attacks and other catastrophes. the use of these innovative methods and com-pletely novel, userfriendly, web-based instruction and information modules is designed to address -to a heretofore unprecedented degree -all security and rescue forces concerned as well as the general population in particular. ultimately this will signifi-cantly improve security and rescue operations in the event of terrorist attacks, crises and disasters. conclusion: in a proper setting, laparoscopic emergency is feasible, effective, safe and beneficial for patients to be a part of a common surgical practice, as long as adequate training is obtained and proper preparation observed when more advanced procedures are attempted in critically patients. the diagnostic and therapeutic versatility afforded by the laparoscopic approach avoids extensive preoperative studies, averts delay in operative intervention and minimize morbidity and shorten the postoperative hospitalization. we do think that laparoscopy should be incorporated into general surgeon's armamentarium for the management of patients with acute abdomen as just as another tool to be used selectively when indicated. laparoscopy, however, must not be used as an alternative to good clinical judgment. about our algorithm in patients with acute abdomen: if there aren't any contraindications to laparoscopy, obtained an informed consensus, in presence of a well trained surgical team in minimally-invasive surgery, excluded any major gynaecological diseases (about which we and our gynaecological colleagues haven't a skilled experience with a laparoscopic approach), we always approach laparoscopically. introduction: stable patients with thoracoabdominal penetrating or blunt injuries resulting in diaphragmatic injuries represent a difficult and challenging management dilemma. although laparoscopy and thoracoscopy have now emerged as the most reliable and efficient diagnostic and treatment modality of these injuries, a conversion to laparotomy for mere evidence of peritoneal penetration and or diaphragmatic injuries is common for most trauma surgeons. we hypothesized that laparoscopically-assisted mini-thoracotomy for repair of diaphragmatic injuries will be as effective as open laparotomy or thoracotomy and will prevent the morbidity associated with open technique and should be used in hemodynamically stable trauma patients. we designed a minimally invasive technique that combines laparoscopic exploration of the intraperitoneal cavity and existing injury site as an entrance to the injured site or organ. open hassan technique, using vertical midline incision is used to create the pneumoperitoneum. additional two to three or mm ports are placed to enable thorough examination of the peritoneum, running the small bowel and examining other abdominal viscera. diaphragmatic lacerations are repaired by extending ( - cm) the existing thoracic stab or gunshot wound. the diaphragm is grasped with two graspers and brought to the operative field. continuous or interrupted suture are used for repair. we applied this technique to hemodynamically stable trauma patients (la group) treated over a year period at the university level i trauma center and compared to trauma patients requiring laparotomy (og) for isolated diaphragmatic injury repair . all laparoscopically assisted procedures were performed by the senior author (rl). length of stay, morbidities and complications were studied in both groups. both groups were matched for iss, age, and gender and mechanism of injuries. results: there were patients (five with stab, two with gunshot wound and one with blunt trauma and chronic diaphragmatic injury) in the la group. introduction: acute small bowel obstruction is mostly due to adhesions ( %), while internal hernia can cause acute small bowel obstruction in % of cases. this clinical condition has been considered for many years a relative contraindication for laparoscopic surgical treatment. with the introduction of ct-scan in the diagnosis of this clinical situation and the experience in laparoscopic techniques, more surgeons are now attempting laparoscopic management for this indication. the advantages of laparoscopy in abdominal surgery are now well defined, such as a shorter intestinal function recovery, a shorter hospital stay and less post-operative pain complained by the patients. in our presentation we want to analyse the importance of laparoscopy in the diagnosis and the treatment of acute small bowel obstruction, in order to underline advantages and limits of this technique. material and methods: in san raffaele hospital milan (italy) a total of patients underwent a surgical intervention for small bowel obstruction from january to december . % of the obstructions was due to adhesions, % to internial hernias. all the patiens underwent preoperative abdominal x-ray and ct-scan. results: of the total of patients, have been operated on with a laparoscopic approach, with a conversion rate of . %. postoperative morbidity was % in the laparoscopic group and . % in the traditional surgical approach, with a shorter hospital staying in the first group. conclusion: the analysis of our data suggests us that the selection of patients that can benefit from a laparoscopic approach to acute small bowel obstruction has to be made accurately, better with the use of ct-scan, in order to limit the percentage or useless laparoscopy and to diminish the conversion rate and to give the patient the better curative option. introduction: intestinal obstruction has remained one of the most common surgical emergencies. the aim of our study is to evaluate the feasibility, safety and palliative role of laparoscopic bowel surgery in the management of large bowel obstruction. material and methods: in a period of years, patients were subjected to loop sigmoidostomy. in patients the diagnosis was bowel obstruction due to rectal cancer. in patients the obstruction was attributed to ovarian cancer. from those patients with rectal cancer, patients had contominant liver and lung metastases and had an unresectable liver lession. in that period lapassisted ileo-transverse anastomosis were performed due to obstruction from cecum carcinoma together with mlitple liver and lung metastases. single surgeon-performed pocus in the evaluation of acute appendicitis led to a correct diagnosis in , % ( / ). surgeons trained in us ordered a ct scan in , % of cases and ratio of negative appendectomy was , %. surgeons not trained in us ordered a ct scan in , % and their ratio of negative appendectomy was , % (including pts that underwentent surgery on clinical investigation basis only). conclusion: surgeon-performed pocus has a high sensitivity in the assessment of acute appendicitis and it is a powerful tool that minimize the use of ct scan and ratio of negative appendectomy with reduction of hospital and social costs; furthermore an advantage for the patients in terms of radiation exposure can be achieved. moreover, to reduce additional costs, laparoscopic approach should be indicated only when the appendix cannot be perfectly visualized and localized. introduction: severe bleeding is, besides head injury, the most important predictive factor in severe trauma. therapy of hemorrhagic shock starts already at the scene of accident. however, the best strategy regarding preclinical volume therapy is controversially discussed. the traumaregister of the german society for trauma surgery (tr-dgu) observes the routine management of severely injured patients since many years. this registry will be used to describe the behaviour of preclinical volume administration as well as the consequences in early hospital care and its changes during the last ten years. material and methods: the tr-sdgu is a voluntary anonymous documentation of severely injured patients for the purpose of quality management. data collection started in . about parameters are collected per patient. for the present investigation only adult patients (age >= ) admitted directly from the scene to one of the participating hospitals during the past ten years ( - ) were considered. a minimum injury severity of iss > = and available data for volume administration and blood transfusion were required. means and prevalence rates were analyzed on a yearly basis. results: a total of , patients injured between and were analyzed. mean age was . years, and % of patients were males. in % of cases there was a blunt trauma mechanism, and % of cases were unconscious at the scene (gcs £ years that required presentation in one of the two level- trauma centers (amc or vumc) were eligible. in the amc the ct scanner was located in the trauma room (intervention group) and in the vumc the scanner was located in the radiology department (control group). randomization was performed prehospitally at the time of dispatch from the scene. primary outcome measure was the number of non-institutionalized days within the first year following trauma. secondary outcomes were mortality, length of initial admission and transfusion requirements. preplanned subgroup analyses consisted of multitrauma patients and severe traumatic brain injury (tbi) patients. results: in total, patients were included for analysis of which were multitrauma patients and had severe traumatic brain injury (tbi). demographic data were comparable between both groups except that there were more multitrauma patients evaluated in the amc. introduction: the effective initial treatment in the emergency room of polytraumatized children requires a sound knowledge of common injury patterns, incidence, mortality, and consequences. the needed inital radiological imaging remains controversial and should be adapted to the expected injury pattern. material and methods: in this retrospective study, the injury patterns of polytraumatized paediatric patients (age £ years) in the period from december to may were evaluated. all children were initially diagnosed with a whole body ct scan. the cause of accident, the localization including the detailed diagnose, the lethality and the severity of the injuries were analyzed. the ais (abbreviated injury scale) and iss (injury severity score) were used to classify the severity of injuries in different body regions. moreover the number and the kind of operation as a consequence of the initial made diagnoses were investigated. results: the mean score of the iss was ± in boys and girls with a mean age of ten years. the lethality was % and only % in the first hours. the most severe and most frequent injury was craniocerebral trauma in % with an ais ‡ in %. surgical intervention of the head was done in %. thorax injuries were found in % with % with an ais ‡ and in % a thoracic drainage was needed. abdomial trauma was found in % (surgery %) with an ais ‡ in %. fractures of the spine occured in % (surgery %) with an ais ‡ in % and pelvic injuries were diagnosed in % (surgery %) with an ais ‡ in %. injuries of the upper extremity were found in % (surgery %) with an ais ‡ in % and of the lower extremity in % (surgery %) with an ais ‡ in %. conclusion: especially because of the detected high percentage of head and thorax injuries in polytraumatized children and the needed head surgery the authors recommend a whole body ct scan in children who are potentially polytraumatized. not only in adults but especially in children the authors suggest the initial use the quickest imaging with a high sensitivity-the whole body ct scan. introduction: patients who suffer physical injuries following a traumatic event are at risk for developing posttraumatic distress. care workers in hospitals treating polytrauma patients are in an optimal position to screen and identify patients developing posttraumatic stress disorder (ptsd). to start early intervention procedures and possibly lower the prevalence, a screening instrument to identify patients at a higher risk is needed. aims of this study were to determine if the severity of injury is related to the prevalence of ptsd and to review the personality traits of patients with ptsd. with these results a screening instrument might be developed. to simulate an unstable extraarticular distal radius fracture, an osteotomy with a mm gap was made. axial loads of - to - n and torque loads of - , to , nm were applied by a testing machine to the intact radii and to the radii after each device was fixed as recommended by the manufacturer. after that, cycles of dynamic torque load alterations of , to , nm (or - , to - , nm convenient to side) at , hz with a preload of - n were performed. in the specimens that were still intact after cycles, loading in torque was continued until failure occurred. axial and torque stiffnesses of the osteosynthesis system were calculated. results: with a median of , n/mm axial stiffness of xscrewÒfixed specimens was higher than of dnpÒ-fixed specimens with a median of , n/mm but did not reach statistical significance. with a median of , nm/°torque stiffness of xscrewÒ-fixed specimens was significant higher than of dnpÒ-fixed specimens with a median of , nm/°. the xscrewÒ-group reached % of the axial stiffness and % of the torque stiffness and the dnpÒ-group reached % of the axial stiffness and % of the torque stiffness of the intact radii. conclusion: fixation of unstable extraarticular distal radius fractures with a xscrewÒ provide biomechanically more stability than a fixation with a dnpÒ. disclosure: no significant relationships. after distal radius fractures occur in % to % of fracture cases. the resulting deformity resembles madelungs deformity and is also called pseudo-madelungs deformity. this deformity leads to ulnocarpal impaction and dorsal dislocation of the distal radioulnar joint (druj). several treatment options such as lengthening of the radius and shortening of the ulna or epiphysiodesis of the distal ulna have been described. the taylor spatial frame (tsf) is a hexapod based external ring fixator, which is widely used to perform six-axis deformity corrections of the lower limb. tsf-planning is web based (www.spatialframe.com) but its use is only available for lower extremities. the purpose of this study was to apply the tsf to the upper extremities to correct pseudo-madelung deformities. material and methods: defining the nomenclature to correct bony deformities with the tsf, one must determine the deformity parameters, the frame parameters, and mounting parameters for the web based planning program. the six deformity parameters and the four mounting parameters use the anatomic nomenclature for the lower extremities. to use the tsf on the forearm, one must transfer the nomenclature of the deformity parameters and the mounting parameters to the nomenclature of the forearm with the transferred nomenclature, one can correct forearm deformities with the correction mode long bone of the planning program for the lower limb. patients two boys (patient , years, patient , years old) and two girls (patient , years, patient , years) were seen in our clinic with progressive pseudo-madelung deformities after an epiphysial fracture of the distal radius at age in the boys and in the girls. skeletal maturity (rus, tw method) was equivalent to the patientâ e tm s age. results: in the four patients, the multiplanar deformitiy of the distal radius could be corrected anatomically with the tsf. there were no frame changes or frame modifications necessary for deformity correction. patient was slightly overcorrected because of some growth in the distal ulnar growth plate. during the distraction, each patient had two low-dose ct scans for better visualization of the radiocarpal and radioulnar joint. the web-based planning program was adjusted twice until total deformity correction was achieved. no further immobilization after frame removal was required. the one-year follow-up showed an anatomic aligned forearm/hand relation with increased pronation and supination compared to the preoperative range of motion in all patients. the wrist and especially the druj were stable and reduced at the one-year follow-up examination. the patients did not complain about any pain or functional deficits in the hand. conclusion: in conclusion, the power of the tsf with the ability to move two fragments precisely can be transferred to the forearm. this allows for the correction of multiplanar radial deformities simultaneously without the need for frame modifications of rotational and translational deformities, as is necessary with the standard ilizarov system. material and methods: thirty-four consecutive patients with a suspected scaphoid fracture (post-injury tenderness of the scaphoid and normal radiographs) underwent ct and mri within ten days after trauma. ct-reconstructions were made in planes defined by the long axis of the scaphoid. the reference standard for a true fracture of the scaphoid was -week follow-up radiographs in four views, based on current available evidence in the literature. a panel including surgeons and radiologists came to a consensus diagnosis for each type of imaging considered in a randomized and blinded fashion, independent of the other types of imaging. we calculated sensitivity, specificity and accuracy as well as positive (ppv) and negative predictive values (npv) for both imaging modalities. results: according to the reference standard there were six true fractures of the scaphoid (prevalence % both mri and ct are better at ruling fractures out than in ruling them in and both were subject to false positive and false negative interpretations. the best reference standard for a true fracture is debatable, but for now it is not clear when bone edema on mri and small unicortical lines on ct represent a true fracture. we advice ct because costs are lower and overall availability is higher. introduction: the scaphoid bone is the carpal bone most commonly fractured in wrist trauma. traditionally, non-displaced scaphoid fractures are considered by most as stable with predictable rates of healing with conservative treatment. conversely, displaced fractures are recognised as unstable, with a significant risk of non-union if not treated surgically. there is a current trend in orthopaedic practice, however, to treat non-or minimal displaced fractures also with early open reduction and internal fixation. this trend is not evidence based. in this systematic review and meta-analysis, we pool data from trials comparing surgical and conservative treatment for acute scaphoid fractures, thus aiming to summarise the best available evidence. material and methods: fourty fresh frozen cadaver scaphoid bones have been sampled at our disposal for testing of screws. the bone density measurement of all specimens has been performed using a qct scan. a transverse osteotomy will be performed at the waist of each scaphoid simulating a b fracture according to the herbert classification. a load cell will be interposed, in an already established method, between the proximal and distal pole of the bone to measure compression force while introducing the screw. the screws will be applied as recommended by the manufacturer using original instruments. the intrascaphoid compression will be recorded at the peak during insertion of the screw, and after and seconds, , , and minutes. results: preliminary results determined that a greater compression can be sustained over a time by headless compression screws with significant differences between those screws. the tests will be finished at the end of january and we will present the final results. conclusion: in more than % of our cases a fracture was missed with the initial radiograph. bone scintigraphy is still a good choice to detect an occult fracture around the wrist. introduction: operations in trauma patients represent a second insult and the extent of the surgical procedures influences the extent of the inflammatory response. the aim of this study was to evaluate the operative burden related to femoral intramedullary nailing. our hypothesis was that a reamer-irrigator-aspirator (ria) system would cause lesser inflammatory response than traditional reaming (tr) due to a lesser intramedullary pressure increase and thereby reduced intravasation of bone marrow content. material and methods: coagulation, fibrinolysis and cytokine responses were studied in norwegian landrace pigs during and after intramedullary reaming and nailing with the two different reaming system; the tr (n = ) and the ria (n = ) reaming system, and compared to a control group (n = ). the animals were followed for hours. simultaneously arterial, mixed venous and femoral vein blood were withdrawn peroperatively and until two hours after the nail was inserted for demonstration of pulmonary, systemic and local activation. results: significantly procedure-related increased levels were found for tat, t-pa and il- in the tr group and tat in the ria group. the local and the pulmonary activation of coagulation, fibrinolysis and cytokine response was more pronounced in the tr than in the ria group, but the difference did only reach significance for il- (femoral vein) and pai- (arterial). the arterial levels of il- and tat exceeded the mixed venous levels indicating an additional pulmonary activation. these differences, however, did not reach significance. two animals in the tr group, who died prior to planned study end point, demonstrated higher inflammatory response compared to rest of the tr group. conclusion: the inflammatory response to the reaming and nailing procedure was modest, and the response was lesser in the ria group than in the tr group. introduction: approximately . million joint arthroplastic operations are performed annually worldwide. implant failure due to massive bone loss and aseptic prosthesis loosening, however, is a major complication of joint replacement. it is generally accepted that small particles (''wear debris'') and activated macrophages play a key role in aseptic loosening. but also the prosthesis loosening fibroblast (plf) plays an important role. material and methods: between and abg- -hip arthroplasties were implantated. after a year analysis % had to be removed because of massive wear of polyethylene (pe) and consecutive acetabular osteolysis. we analysed the influence of patient and surgeon, the implantdesign incl. pe-thickness, anchorage coupler, material roughness i.e. and the material i. medtronic) the application of the cements was done according to the specifications of the manufacturer. after extrapedicular kyphoplasty on cadaveric lower thoracic spine vertebrae (th - ), the intervertebral distribution pattern was investigated by microtomography ( lct). besides creating high resolution d and d reconstructions, the mathematic calculation of the porosity of the vertebra, the bone substitute material and the relative part within the different compartments was performed. of special interest were the characterization of the bone substitute material -spongiosa -interface and the penetration of the calcium phosphate cement into the adjacent spongiosa. the following parameters were investigated: . trabecular structure, porosity and hydroxylapatite concentration of the native vertebrae . structure (homogeneity, distribution of pores) of the bony substitute material . characterization of the bone-bone substitute-interface a. central located, filled kyphoplasty defect b. transition zone with spongiosa and bone substitute material c. solitary spongious bone results: the investigation of the native spongiosa yielded a comparable trabecular structure, porosity and hydroxylapatite concentration in the intra-individual comparison of the vertebrae of the lower thoracic spine. between the cements differences in the solitary structure as well as distribution pattern during kyphoplasty were observed. especially the analysis of the ability to penetrate into the spongiosa adjacent to the centrally located kyphoplasty defect yielded significant differences. the main influencing factor of the ability to penetrate into the spongiosa is the different viscosity of the -according to manufacturer specification -used calcium phosphate cements. the cements differ in their native structure as well as in their distribution pattern during kyphoplasty. the differences in micro-morphology of the calcium phophate cements have a high probability to influence the degradation of the sedimentation products and later osseointegration. disclosure: this research was funded by a grant of ao germany. introduction: it is difficult to predict the long-term clinical outcome in the early period following an acetabular fracture. introduction: the tremendous increase of acetabular fractures in the elderly provides new challenges for the surgical treatment of acetabular fractures. surgical reduction of the acetabular joint represents the most reliable possibility to prevent the development of premature arthrosis even in the elderly. biomechanical studies showed, that plates with periarticular long screws result in an increased stability of the osteosynthesis, it has to be considered that the insertion of these screws always bears the risk of penetrating the joint the aim of this study was to evaluate the biomechanical properties of these standard plates and newly developed minimal invasive osteosynthesis techniques for stabilization of an anterior column combined with posterior hemitransverse fracture type (acphtf), which represents a typical acetabular fracture in the elderly. material and methods: using a single-leg stance model we analyzed different implant systems for the stabilization of acphtfs in synthetic pelvises (standard reconstruction plate, new developed prototype and definitive repofix Ò (adi -ao foundation, switzerland). applying an increasing axial load in a biomechanical testing machine, fracture dislocation was analyzed with a multidirectional ultrasonic measuring system (zebris, germany). differences in change of center of gravity are statistical analysed by man-whitney-u -test. results: analog to a long bow, the repofix Ò supports the quadrilateral surface sufficiently and reconstructs the surface of the pelvic brim from the inner side of the pelvis. in synthetic pelvises, the new repofix Ò is associated with a significantly less pronounced dislocation (center of gravity) of the fractured quadrilateral surface when compared to prototype and the standard reconstruction plate. the biomechanical results could be seen at a measuring point at the quadrilateral surface and in the rotation around the x -axis (angle y results: we collected data on acetabular fractures. a conventional image intensifier was used in cases (group a), d-navigation was used in cases (group b). in group a the kocher-langenbeck-approach was used in most of the cases ( %), followed by the maryland-approach ( %). in group b, the kocher-langenbeck-approach and the ilio-inguional-approach were used in an almost equal number of patients ( % / %), but extended approaches were only used twice. in % of the cases in group b fractures were stabilised by navigated placement of percutaneous lag screws. when we excluded the percutaneous operations in group b (n = ), the difference in or-time between navigated (n = , ± min) and conventional treatment (n = , ± minutes) was significant (p < , ). in group a we detected relevant postoperative complications in % of patients. the complication rate was significantly lower in group b ( %, p < , ). the postoperative radiological analysis revealed a better qualitiy of reduction in group b (n = ) with an average post-op fracture gap of , mm vs , mm in group a (p < , ). conclusion: by using a navigation system and a d image intensifier we found a significant increase in the or-time in the navigated group. however, in the postoperative radiological analysis, we detected a better quality of fracture reduction in the navigated group. navigation in combination with the -dimentional pictures of the iso-c d led to a better visualisation of the acetabulum, therefore the need for extended approaches was reduced. to our opinion, this explains the significant reduction of postoperative complications in group b. we conclude that navigation and a d image intensifier should always be used for orif of acetabular fractures. disclosure: no significant relationships. introduction: the traumatism is the first cause of the mortality in patients under . it means a serious incapacity in of trauma patients. the initial management in trauma patients is essential to improve these results material and methods: this is a prospective and multicentric study with the participation of hospitals in catalunya (spain). the objectives are to improve the evaluation and the initial management of trauma patients, and to improve the knowledge of the frequency, the magnitude and the approach of these trauma patients. we defined points to improve which are: to intubate patients with glasgow < ( ); to not remove the cervical collar without clinical or radiologic cervical exploration ( ); to move trauma patients monitorized ( ); to not move haemodinamically instable trauma patients ( ); to use two thick intravenous cannulations ( ); to take thorax and pelvic simple radiographies in the trauma box ( ); to fix pelvis fracture with a grassland before moving the patient ( ) we took more thorax and pelvic radiographies in the trauma box (from . % and % in the first period to . % and . % in the second period, p < . ). and we also fixed more pelvis fracture with a grassland before moving the patient, from % in the first period to . % in the second period. conclusion: the registration of the information about trauma patients allows the identification of the points to improve. we improved the evaluation and the initial management of the trauma patients, especially in the monitorization of trauma patients and in the management of the thoracic and pelvic traumatism introduction: there is wide evidence about the importance of having good protocols for assisting trauma patients and a teaching system for the personnel involved in this assistance is needed. it is also well known that the formation for assisting trauma patients in spain is not very much spread in general. material and methods: we describe how we have arranged the care for this type of patients in a level ii center and a teaching system for our staff and we prospectively analyze the impact of this specific formation by means of a questionnaire and analyzing how correctly the trauma team is activated. results: from november through october ( months), editions of our course have taken place and people have participated ( , % of the staff for whom the course is aimed to). we found a clear improvement on the results of the test (prior and after the course: % of improvement for physicians and % for nurses, p < . ) and the qualification of the final exam was superior. the incidence of rightly activated trauma team improved as the staff was completing the course. conclusion: we conclude by enhancing the importance of having adequate protocols for treating these patients and the correct means for teaching the personnel because they can improve the care of these patients. (tonk) score. this system is specialty specific and tries to eradicate the weaknesses in a previously published scoring system, which was generic. material and methods: a total score of is assigned to each firm from the beginning and marks are deducted for missed documentation. sets of notes are randomly selected from discharged patients for each firm, one from trauma and one from elective surgery, each having at least entries. each case note is given marks and the total deduction for both case notes are then subtracted from the total score of to give the resultant score. the tonk score has four major parts comprising initial clerking, subsequent entries, discharge letter and legibility. an objective system of scoring the legibility of medical notes is part of the tonk score. this scoring system is easily reproducible and it's been validated using the kappa statistic. introduction: despite the increasing mechanization in medicine, clinical skills must be to the fore of medical occupation and consequently must have a main focus in medical training. especially in surgery, the mastery of basic clinical skills is of great importance for the young learner as it besides the knowledge of elementary principles substantially contributes to the understanding of the subject, the development on the wards, the operation theatre and the ambulance. in order to assure a standardized training using reliable, effective modern teaching methods, a ''train-the-teacher''-course was developed. material and methods: in an -hour training, the important teaching modalities and methods for surgical skills as skills lab, simulation, role play, -step approach are presented and trained in small groups with a maximum of participants per group. furthermore, the training focuses on ,,giving adequate feedback'' and examining practical skills. the training is evaluated using a standardised evaluation form. furthermore, the teachers are evaluated by their students after each of their teaching sessions before and after the training. results: a total of surgeons participated in the training program ( chief physicians, senior physicians). overall, the training was rated to be very good ( %) or good ( %). in students' evaluation, there was a significant increase in positive ratings for teachers' didactical compentencies as well as for their overall training after the participation in the training program. introduction: sports injury risk management and prevention is a very complex challenge that must be addressed . one of the basic tasks is to perform epidemiological studies to estimate the risk in different types of sport. up to now many studies were conducted on injury rates in specific organised sports . just a few taking into account any physical activity (pa) . therefore only for specific sports data about the influence of higher sport skills on injury risk can be found . the goal of our study was to investigate the relevance of motor skills and sport education on injury risk, including the total pa and the occurrence of any injury in any type of sport. material and methods: in two austrian secondary schools (gymnasien) fifty-five of classes were asked to fill out a two sided questionnaire regarding pa and sports injuries within the last year. demographic data and information about the types of sport, the intensity and the occurrence of injuries was collected. pupils, from a ''normal'' school (ng) and from a ''sports-school'' (sg) filled out the questionnaire. in the sg every child has to pass an entrance exam containing basic coordinative and motor tasks as well as complex motion sequences in different types of ballgames. in the educational program of this school a strong emphasis is placed on sports. in the ng just the basic sport lectures are held. results: the total physical activity (pa) containing organised, unorganised sports and leisure time activities was significant higher in the sports-school (sg), . hours per week vs. . h/w (p < . ). the most performed types of sport were similar: in the sg soccer (n = , %), riding bike (n = , %) and running (n = , %); in the normal school (ng) riding bike (n = , %), soccer (n = , %), snowboarding (n = , %) and running (n = , %). proportionally there were more boys than girls in both schools: % boys, % girls vs % boys, % girls. boys ( . h/w, . h/w) were more active than girls ( . h/w, . h/w) in both schools. the rate of injury was statistically significant higher in boys ( . ) than in girls ( . ) (p < . ). the mean age was higher in the normal school . vs . years. the proportion on injured children was at the same highest level ( %) in and , and , and in and year-olds. the ratio of injury per pupil is statistically significant higher in the sg ( . ) than in the ng ( . ) (p < . ). but including the extension of activity the injury risk is a little bit lower in the sg: . injuries in hours of pa vs . . conclusion: it seems that better motor skills and intense sport education have no effect on the population risk . the individual risk has to be investigated more extensively in future studies. references: fuller, spinks, spinks, schwebel disclosure: no significant relationships. introduction: pain is one of the main complaints of trauma patients in emergency medical care ( ). in the netherlands, a third of all prehospital emergency medical systems (ems) rides concern trauma patients and yearly . patients are treated in the accident & emergency department (ed) due to an injury. significant deficiencies in pain management in emergency medicine have been identified ( ) . as a consequence, patients unnecessarily suffer from pain, and also recovery and healing are delayed. furthermore, chronic pain is reported one year after trauma ( ). there is no appropriate systematic approach to acute pain management in the chain of care for trauma patients in prehospital ems and the ed. aim: the aim of the research project is the development of a national evidence-based guideline for the management of acute pain in adult trauma patients in prehospital ems and the ed. during the open reduction we applied a incision allowing to remove soft tissues and to set fragments of fractured bone correctly. in patients we performed close reduction of the fracture without the fixation because of a patient's age. results: xr month after surgical procedure was done and in all cases we achieved consolidation of the ulnar fracture and good of radial head reduction. complication after the treatment was the paresis of the median nerve, neurosurgical procedure needed. the nails were remove , month after procedure ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . after obtaining the union of the fracture and rehabilitation of the limb we removed the nails ( - month after procedure). conclusion: featured way of the operative treatment doesn't claim wide opening region of the fracture and reduces possibility of complications. dislocated radial head after close reduction and immobilization period shows full stability. years. data and x-rays were retrospectively gathered and analyzed. all fractures were scored according to the ao-pediatric classification. patients were treated with solely closed reduction and cast immobilisation and patients were additionally treated with k-wire fixation. spss version . was used for all statistical analysis. results: incidence of recurrent dislocation was significantly higher in patients treated solely with closed reduction ( %) compared to patients treated with additional k-wire fixation ( %) (p . ). the proportion of patients requiring a second surgical intervention was also higher in patients treated with closed reduction: % versus % of patients treated with additional k-wire fixation (p . ). additional k-wire fixation results in a relative risk reduction of % and % for recurrent dislocation and secondary surgical interventions respectively. complications of k-wire fixation comprised local infection (n = ) and k-wire migration (n = ). conclusion: additional k-wire fixation might reduce the incidence of recurrent dislocation and secondary surgical interventions after closed reduction of displaced distal forearm fractures in children. larger and randomized studies will have to be obtained to confirm the results from our data. radiographic controls were planned after one and six month and until the removal of the intramedullary nailing. we documented all peri-and postoperative morbidity, further operative procedures, the radiographic findings as classified by capanna and the time till removal of the nails. results: a cohort of children (four girls, six boys) was recruited. mean patient age was , years ( - y). the bone defects included eight juvenile and two aneurysmatic bone cysts. four patient suffered earlier unsuccessful treatment after pathologic fracture. the other six presented with acute pathologic fractures (five humeral, one femoral). no postoperative complications occurred after the treatment combination of elastic intramedullary nailing, curettage, artificial bone substitute and autologous platelet rich plasma (gps Ò-system). the radiographic findings showed at six month a total resolution of the cysts in eight cases (capanna typ i), in two cases a tiny residual cyst remained (capanna typ ii). the removal of the nails was possible after six to nine month. one fourteen year old boy (typ ii capanna) wished a further gps application to reach a total resolution. all patients showed very good functional results and no refracture occurred. conclusion: the gpsÒ-system enhances the treatment of bone cysts in children. it is a save method without additional perioperative complications. by this, total treatment time can be shortened and secondary procedures as difficult changes of the elastic nails will be lessened. technically the decisive factor is the debridement of the . albumin values were significantly lower in patients with two or three complications than those with zero complications (zero and two complications p = . , zero and three complications p = . ). no significant difference in levels was found between one and zero complication (p = . ). admission albumin was not significantly lower in patients with wound infection than those without ( . ± . g/l versus . ± . g/l, p = . ). patients with a dry and intact wound had a higher mean albumin value than those with wound healing complications (mean albumin ± . g/l versus ± . g/l, p = . ). conclusion: our study findings support the hypothesis that lower preoperative albumin levels are associated with a more adverse inpatient post-operative recovery. these patients can be identified and optimised early in preparation for adverse events likely to occur in the post-operative period. material and methods: the targon fn is a new kind of side plate with six locking screw ports. the two distal holes are used to fix the plate to the lateral cortex of the femur with angle stable . mm cortical screws. the proximal holes allow the implementation of up to four ''telescrews'' which cross the fracture site. these . mm screws are dynamic and allow therewith the collapse of the fracture at the femoral neck. we present a prospective study on patients with a comparative patients case control with a total hip cementless arthroplasty for the same indication at the same period. results: this new device show a lower incidence of complications on the first weeks than with the total hip group. wereas the month control show no difference between the two groups. there are an x rays neck collapse one year folow up in osté oporotic patients with singh an stade with no significant consequences on the functional score. conclusion: targon fn is a good alternative for older and multimorbid patients with less surgical burden and reduced early access morbidity in comparison to the prosthesis group. conclusion: the number of re-interventions and the mortality within one year after hip fracture surgery is sizable. nonetheless, our numbers are not unfavourable in comparison with international literature. the percentage of re-interventions in the cannulated hip screw group is significantly higher than in the other subgroups. on the contrary, the mortality in this group is low. this is undoubtedly an expression of our attempts to preserve the femoral head in vital, active patients. possibly, the combination of the two standardsnamely the re-intervention and mortality-is a new accurate performance indicator. informed. the operative treatment with lcp and tension bandages shows small morbidity regardless the comorbidities and the geriatric cohort. it remains standard procedure for periprosthetic fractures of the femur at our institution. we are expecting the number of periprosthetic fractures to be increasing rapidly. introduction: periprosthetic femoral fractures are rare but severe complications following total hip-or knee-arthroplasty. the incidence for of these fractures are increasing, caused by a raising frequency of total arthroplasty for both younger and elderly patients as well as by a higher life expectation. so far there are very little long-term results regarding this issue. material and methods: patients ( female, male) with a mean age of years ( - ) were clinically and radiologically examined on average months after surgery. we investigated the prosthesis (total hip arthroplasty vs. total knee arthroplasty) and compared the treatment (revision arthroplasty vs. osteosynthesis) in this study. for the clinical examination we used the harris-hip-score (hhs), oxford-hip-score (ohs), the oxford-knee-score (oks), the sf- and the funktionsfragebogen hannover (ffh) which measured the functionality of patients in his daily routine in his environment. results: tha + osteosynthesis (n = ) % of the patients had fair or better results with an average hhs of . % of this group had a good or excellent result with an average ohs of and % had a ffh score of ‡ %. % of the patients had a possible hip flexion of ‡ °and ( % ‡ °). the average sf- score for this group was . tha + revision arthroplasty (n = ) % of the patients had fair or better results an average hhs of . % of this group had a good or excellent result with an average ohs of and % a mean ffh score of ‡ %. % had a possible hip flexion of ‡ °( % ‡ ° the results of the scores are mainly caused by the high age, the common multimorbidity and the low overall functionality of the patients and confirm the severity and importance of these kinds of fractures. most authors suggest a treatment of these fractures according to the classification by using osteosynthesis to treat stable fractures and revision for unstable fractures. however we see a slightly better outcome of the revision arthroplasty compared to the patients that were treated with osteosynthesis. we suggest more studies with a higher number of patients regarding this issue. introduction: fracture dislocation of the proximal humerus is a rare but challenging situation for the orthopaedic surgeon. if a closed attempt to reduce the dislocation fails, a demanding surgical procedure is required and the emergency setting is not always the best situation to face difficult cases. as a matter of fact a proper approach to this fractures involve an experienced surgeon, more than one assistant and a variety of instrumentation that often lack in emergency. fracture dislocation of the humeral head is related with a significant increase of the risk of the humeral head necrosis and it is widely accepted that these lesions are best treated in emergency, but there are no reports on the influence of the dislocation time on the results of the surgical procedure. with this study we wanted to determine if a delayed procedure could affect the outcome of these lesions and if there is a rationale in postponing the procedure to allow a better organisation of the surgical time. material and methods: we retrospectively analysed the clinical and radiological records of patients admitted at out institute for fdhh between jan and jan . ten out of them were operated in emergency while with a minimum delay of hours. all the patients underwent open reduction and fracture fixation with locking plates. results: the results of the two groups were similar and influenced mainly by the bone quality and age of the patient. it seems that a delay in the procedure do not alter the result in terms of rate of necrosis of the humeral head or influence a worse clinical outcome conclusion: on the basis of these results we do not consider these fractures as emergencies anymore: our preference is still an immediate operation provided the presence of an experienced surgeon, assistant and nurse and the availability of the proper instrumentation, conversely we believe that the risks of an immediate procedure overwhelm its benefits. introduction: minimal invasive plate osteosynthesis (mipo) should belong nowadays to the armentarium of each trauma surgeon. applied correctly, mipo not only meets the criteria of a ''biological'' osteosynthesis by minimizing invasivity as well as iatrogenic soft tissue damage caused by the operation, but can also provide adequate reduction and stability for fracture healing and early functional aftertreatment. up to date, only few publications report on mipo of humeral shaft fractures mainly using the antero-lateral deltopectoral approach for plate insertion - . material and methods: in this present study, we evaluated patients (mean age years, range - ) with displaced metadiaphyseal fractures of the proximal humerus treated in mipo technique using an angular stable long philos Ò -plate. a lateral deltoid-split approach was used proximally and a brachialis/ brachioradialis intermuscular approach with exposure of the radial nerve was used distally. there were acute fractures including two periprosthetic as well as one pathological fracture. three patients were operated after failed conservative treatment, one for delayed-union and two cases were revision surgeries. results: there were no infections and no iatrogenic injuries to the axillary and radial nerve, respectively. all the patients were immediately allowed active shoulder and elbow movement. one patient had to be reoperated ten weeks postoperatively for redislocation of the distal fragment with screw breakage, which was most likely due to incorrect screw placement. this patient was successfully operated using the same method and implant. whereas one patient refused follow-up, patients showed entirely healed fractures and satisfactory shoulder and elbow function after a mean follow-up of months (range - months). conclusion: minimal invasive long philos Ò -plate osteosynthesis using a combined lateral deltoid-split and brachialis/brachioradialis intermuscular approach proved to be a safe and viable procedure for the treatment of metadiayphyseal fractures of the proximal humerus with low morbidity and good functional outcome. introduction: plating for reduction and stabilization of proximal humerus fractures is a common orthopaedic procedure. however, angular and rotational malalignment is not an infrequent result, and extensive use of fluoroscopy is commonly involved. we checked the accuracy of a computerized navigation system(vector vision trauma navigation system, brain lab) to enhance multiplanar fracture reduction and to decrease the requirement for fluoroscopy. material and methods: men and women aged to (mean, ) years underwent philos plate fixation for proximal humeral fractures. all fractures were closed with no associated injuries and classified as -a (n = ), -b (n = ), and -b (n = ), according to the ao classification. the cases were assessed operation time, radiation time. and accuracy measurements were taken. results: patients were followed up for to (mean, ) months. all the fractures united and occured no avascular necrosis. the mean operation time and radiation time were minutes (range, - ) and . minutes (range, - ). the mean distance between fluoroscopy and navigation of reduction accuracy at the fracture site were . mm (range, - ). conclusion: the fluoroscopic operation using pilos plate was troublesome, but navigated operation was easy to reduce the fracture because of the direction visualization at the same time. and computerized navigation has the potential for increasing precision in fracture reduction while minimizing fluoroscopic requirements at proximal humerus fractures. introduction: the proximal humerus fracture is a frequent fracture in the elderly people. the lower density of the bone with increasing age is one of the main reasons for implant failure after osteosynthesis with a range of - %. the options of therapy are including the screw-, platelet-or nail-osteosynthesis or the endoprosthesis.belonging to failure rates and the demand for early activity there is a tendency to be seen for early and strong stabilisation. material and methods: since august proximal humerus fractures were operated with the retron-humerus-shortnail. the average of age was , +- , ( - ) years. the demographic data, bone quality and fracture classification were documented including procedure of reposition, details of the implants, complications and postoperative course. results: there were , % a fractures, , % c , , % c and , % c fractures (ao-classification). the reposition was done in a closed mannor with a direct percutaneous assistance respectively. intraoperatively secondary dislocations and corticalis brake was to be seen. there have been insufficient nailing procedures. screws had to be exchanged. the gymnastic began immediately after operation or with a delay of - weeks depending on the fracture classification. the evaluation of the constant score is on the way. the results show a good stability of the nail especially in osteoporosis. comparing with platelets or antegrade nailing it is a minimal invasive procedure. the exraarticular access avoids any damage to the shoulder structures, especially to the rotator muscles. therefore early gymnystic of the shoulder is possible. shoulder impingement, screw dislocation and problems with the shoulder are avoided principally. the learning curve is short. shoulder score was used to evaluate functional outcomes. anova was used for statistical analysis, with significance set at p < . . results: files were available on patients. failure rate was . % at mean follow-up of . years and a mean ases-score of . . there was a reoperation rate of . %. mean age at operation was . years. mean operative delay was days (range - ). delay did not influence outcome. young age at operation was associated with better results. when evaluating fracture characteristics significant better outcomes were evaluated with ao type aand b-fractures, valgus or neutral fracture type, the presence of impaction and less displaced fractures. quality of reduction and fixation of the fracture was evaluated with significant better results with anatomic reduction of the medial cortical border, less residual displacement and a ccd-angle that was corrected or in residual valgus. osteosynthesis failed significantly more in c-type fractures, in fractures with an avascular head fragment, in varus displaced fractures and in fractures where an anatomical reposition was not obtained. introduction: fractures of the proximal humerus are responsible for - % of all fractures.the most extensive used operative treatments are the plate osteosynthesis and the intra-medullarry nail fixation with proximal locking nailsscrews. especially the latter technique can give iatrogenic injury of the axillary nerve. in this study, we define a safe-zone by using radiological parameters material and methods: the following procedure was performed in ten shoulders of embalmed specimen. first, the deltoid muscle was dissected from the clavicle. then the axillary nerve was identified together with its branches and was marked with clips and radioopaque wires. the muscle was then re-attached to its anatomical position.standard ap radiographs were made with the forearm in neutral (anatomical) position and exorotation. on these radiographs, the distance between the cranial side of the humeral head and the axillary nerve and its branches was measured. results: the median distance from the head of the humerus to the axillary nerve is mm (sd = . mm, range - mm) measured on the ap radiograph in degrees exorotation. the mean number of branches to the deltoid muscle is three. the distances vary from to mm. the median distance from the first proximal branch measured from to the humeral head is mm (n = , range - mm), to the second branch mm (n = , range - mm), to the third branch mm (n = , range - mm) and to the fourth branch mm (n = , range - mm). conclusion: there is a great variation in the course of the axillary nerve and its branches. with the insertion of an intra-medullar nail from the proximal side or by placing locking-screws nails the surgeon has to reckon with the course of this clinically important nerve. it is unsafe to place the locking-screws nail in the zone between mm and mm from the humeral head with the arm in exorotation. the greatest risk to damage the main branch of the axillary nerve is in the zone between and mm. this study provides distances to avoid damage to the axillary nerve. in contrast to the existing literature these distances are measured from the humeral head. there are several reasons to use the humeral head instead of the acromion are: first, the distance between the humerus and the acromion can vary due to the preceding trauma, relaxation of the deltoid muscle or by manipulation of the arm. second, from an anatomical perspective, the position of the axillary nerve is determined by the position of the humerus due to the connection to the deltoid muscle. results: emg/eng records were without pathologic variances of the axillary nerve. of them pre-operatively showed pathologic variances. of these continued to show variances months after the operation, which indicates a chronic lesion. just one patient showed a pathologic eng after surgery which was not seen before. the constant score was as expected. introduction: patella recurrent dislocation and patellofemoral pain syndrome is a common cause of instability in young patients and especially athletes. in the present study we present the results of the extension mechanism realigment throughout the fulkerson oblique osteotomy of the tibial tubercle and soft tissue balancing. material and methods: during the last two years patients ( men, women, mean age . / range - ) were treated operatively for recurrent dislocation of the patella using the fulkerson procedure. all our patients had as onset a traumatic dislocation of the patella that developed to recurrent. all patients were underwent knee arthroscopy for the treatment of potential chondral trauma or loose bodies removal and lateral retinaculum release. after that, we performed oblique osteotomy of the tibial tubercle, medialization and internal fixation with two cortical screws. this oblique osteotomy provides additionally to the medialization, anteriorization of the tibial tuberosity as we move it medially. moreover we perform medial plication. all patiens used functional brace locked in  º immediately after the operation and gradual rom increase untill the th p.o. week. results: the patients had no initial or long term complication. during their last follow up examination had a painless knee with full rom and marked improvement of the patella tracking. the mean lysholm score was improved from . to . . no patella dislocation was referred. conclusion: our findings show that fulkerson procedure of the tibial tubercle osteotomy and anteriomedialization, with additional intervention on the lateral and medial patella retinaculum is an excellent option for the treatment of recurrent patella instability and relief of patellofemoral pain. disclosure: no significant relationships. introduction: injuries to the knee involving the anterior cruciate ligament (acl) are very common related to sports especially in soccer and skiing. more than % of those with acl injury will develop radiographic osteoarthritis (roa) within years of injury although it is not known if return to sports is a risk factor for longitudinal roa development. in this retrospective study, we evaluated the long term radiographic and clinical results of acl reconstruction by comparing the injured knee with the contralateral knee in athletes returning to pre-injury sports. material and methods: twenty-eight patients ( men and women, mean age years at the time of acl surgery, bmi . ± . kg/ m ) were studied. patients returning to previous sports and without meniscal injury at baseline were selected. acl reconstruction was performed using patella tendon or hamstrings tendon graft. radiological assessments using x-ray and a -t mri of both legs were obtained at a mean follow up of years after acl reconstruction. roa was determined according to the classification of bohndorf. the ikdc score and tegner activity index were used for clinical evaluation and the knee injury and osteoarthritis outcome score (koos) for evaluating self-reported knee function. results: the -t mri revealed positive signs of roa on the operated knee in % and on the non-operated knee in %. these changes were however limited to small localized areas of the knees. the statistical difference of morphological and clinical outcome of acl reconstructed patients weeks after injury vs. replacement after this period showed no significance (p = , - . ). the total ikdc score was . ± . points and the total koos was . ± . . the median pre-injury tegner score was (range - ) corresponding to (range - ) at follow up. in % of the patients the tegner score was unchanged from pre-injury to follow up. according to the ikdc score % had type a symptoms, % type b, % type c, and none type d. conclusion: eight years after acl reconstruction in athletes returning to pre-injury sports, the risk of developing knee roa in the injured knee was not higher than the risk of developing roa in the contra lateral knee. disclosure: no significant relationships. radiographs and a mri of the knee were available for all patients. all patients were followed prospectively and lysholm, tegner and ikdc score were surveyed before treatment and after at least months. after diagnosis, a brace immobilization with tibial supporter with full extension of the knee was applied for weeks followed by another to weeks of pcl brace with tibial supporter and posterior elastic rubber band to prevent posterior sagging of the proximal tibia. all patients received concomitant physiotherapy. after at least weeks, stress radiographs were taken for evaluation of the pcl. the further treatment depended on the harner classification based on the stress radiographs. in cases of grade a or asymptomatic grade b injuries, conservative treatment was continued. in cases of symptomatic grade b, grade c or d injuries, operative treatment with arthroscopic transtibial pcl reconstruction using single bundle hamstring tendons was performed. results: patients were treated conservatively (group i), patients had an arthroscopic pcl reconstruction (group ii). mean patient age was . years (range - years). the mean tegner score in group i raised from . before treatment to at follow up, in the operative group from . to . . the mean lysholm score ascended in the conservative group from to , in group ii from . introduction: the virtual reality (vr) d arthroscopy surgical simulator provides arthroscopy training on knees in a controlled, stressfree, and virtual-reality environment. it is unknown whether better visomotoric three-dimensional ( d) condition will facilitate arthroscopic training. therefore, our objective was to evaluate the visomotoric condition to novice individuals and assess whether visomotoric abilities ameliorates arthroscopic performance within a d surgical environment. material and methods: medical students without any knee arthroscopic experience were investigated. both groups received a fixed protocol of simulator based arthroscopic skills training and a visomotoric skills test. this consisted of an arthroscopy of a longitudinal meniscus tear on a vr knee arthroscopy simulator. . their learning curve was assessed objectively using motion analysis. time taken, path length and roughness for probe and camera were recorded. results: motion analysis demonstrated objective improvement in performance during simulator training, if visomotoric skills performed better. conclusion: better condition of visomotoric skills lead to subsequent improvement at an arthroscopic vr skills training simulator. this may assume that visomotoric skills training before arthroscopic vr skills training is a useful tool. however further studies are necessary to find preliminary practice exercises to get a better performance at an arthroscopic vr skills training simulator. -ii and c-iii after tscherne § open fractures o-ii and o-iii after gustilo o urgent operative treatment § first stabilisation with miniosteosynthesis and external fixation § soft tissue debridement and their temporary closure o second look after - hours, next looks after the soft tissue condition o delate treatmentdefinitive stabilisation -osteosynthesis conversion in - days after injury. o type of osteosynthesis § orif with lcp distal tibia platesmedial or anterolateral § imterlocked intrtamedullary nail § external fixation -in cases of serious soft tissue defects we prefer fracture stabilisation ae serious soft tissue defects closing with rotation or microsurgery stem lobs. introduction: fractures of the distal tibial metaphysis account for . % of fractures over the distal end of the tibia. many of them are high-energy injuries causing extensive articular damage and compromise the soft tissues. managing these fractures continues to challenge most orthopaedic surgeons, as soft tissue injury could be further compromised by unjudicious surgical technique. aim of the treatment is to restore physiological alignment of the distal tibia and stabilize the fracture with minimal damage to soft tissues. material and methods: we designed an implant for the stabilization of distal tibial metaphyseal fractures, and gave the name ''angle stable''. the features of the implant are: precontoured plate with holes above the distal metaphysis providing positioning of screws with angular stable characteristics. the screws are self tapping and self cutting at the threaded part (far end) and have a cylindrical shape with a rim at the near end, that tightly fits into the holes at a special angle, guided by a targeting device. the distal screws penetrate the opposite cortex, and when they are tightened, compression is achieved. the plate is introduced through a small incision and guided onto the surface of distal tibia. screws can be inserted distally, proximal screws are inserted through stab wounds. biomechanical tests of this system were performed on cadaver bones. since the ''angle stable'' system has been used in patients in cases as a primary stabilization, and in cases as conversion of external fixation. follow-up time was months. outcome was assessed with regard to function, pain and alignment. introduction: the fracture of the distal lower limb with or without participation of the ankle joint remains a challenge to the surgeon. due to the high energy released at the time of fracture, these injuries are usually accompanied by a severe soft-tissue damage. the success of the surgical therapy of tibial pilon fractures depends largely on the extent of the soft tissue damage as well as the quality of reconstruction of the tibial joint surface. a problem of the minute anatomical reconstruction is an increase in soft tissue problems and bone infection. aim of this study was to investigate the results gained by a primary stabilization by external fixator followed by a multidirectional locked plate osteosynthesis after soft tissue consolidation. material and methods: setting is a level trauma centre, the design a consecutive series with a retrospective data evaluation. between and , patients with high-energy fractures of the tibial plafond were treated using a two-staged treatment plan: . the fracture was stabilized with an external fixator immobilizing the ankle joint. . after stabilization of the soft tissue situation (mean . days) internal fixation with a locked-screw plate was performed. the implant used was a multi-directional locking internal plate fixator (tifix, litos, hamburg/germany), made of pure titanium with locking holes for titanium screws which can be fixed in different angles and is available in seven different lengths ( - holes in the diaphyseal area). the mean follow-up time was . months. all follow-up examinations were supervised by a specialized orthopedic trauma surgeon. the examination consisted of a set of standardized questions, clinical evaluation, the aofas score and radiographs. results: superficial wound-necrosis was noted times, conservative treatment led to complete wound healing. dvt of the injured leg occurred in cases. in cases autologous bone graft was necessary after and months. deep wound infection or postoperative osteomyelitis was not observed. the definitive treatment was performed after an average of . days. in cases an autologous bone graft was used. in a further cases a later autologous bone graft was performed for delayed union at and weeks after orif. full weight bearing was reached after an average of . weeks. bony union was achieved in all cases after an average of . months as determined by conventional radiographs. in cases range of motion (rom) of the ankle did not show any restriction compared to the opposite side. in cases the range of motion was reduced by less than / compared to the opposite side, of up to / in patients and restriction of > / was not noted in cases. the mean aofas score was . . conclusion: a twostage treatment plan in fractures of the distal lower limb with external fixation followed by locked-plate osteosynthesis reduces local complications with a good functional result. disclosure: no significant relationships. introduction: the internal fixation for complex distal tibial fractures is sometimes challenging. nowadays, successful outcome were reported about osteosynthesis through medial and anterior approaches including minimally invasive plate osteosynthesis (mipo). however, there are cases in which such methods are not indicated because of their soft tissue problems or their fracture pattern. in this presentation, the new posterior plating procedure using the mipo technique is reported. material and methods: this procedure was indicated only when no other internal fixation methods were present, which includes intramedullary nailing or medial/anterior plating, were found. so the indication for this procedure was extremely rare. from to , cases of ao classification -a and c type fractures were treated operatively in our institution. cases met the criteria. both of them were female and aged and . the follow up period was and months. the procedure was as follows; before the operation, the spanning external fixator was applied and the alignment was reduced as properly as possible. the patient was in the supine position and the knee was flexed at about degrees. the distal window for mipo was positioned between the distal fibula and achilles tendon, which is called a ''posterolateral approach.'' blunt dissection was performed, and exposed the edge of the flexor hallucis longs muscle (fhl). the tunnel over the periosteum at the posterior surface of the distal tibia was made and the plate was inserted. then an incision was made at the posteromedial border of the tibial shaft and exposed the proximal part of the plate (proximal window). the plate was placed properly under the image intensifier and fixed with screws. the wounds were irrigated and sutured in layers. postoperative rehabilitation included a range of motion exercise and non-weight bearing gait and use of crutches immediately begun. full weight bear was permitted around twelve weeks post operatively. time to union, complication and final ambulatory ability were evaluated. results: bony union was uneventfully completed within three months in both cases. there were no complications such as infection, skin problems, or plate irritation/impingement. free gait was achieved within four months in both cases. conclusion: posterior plating using the mipo procedure for complex distal tibial fractures can be a good option, although our experience is very limited. however, this procedure should be indicated only when no other osteosynthetic methods are found because irritation/ impingement of the fhl or the achilles tendon or some other complications may arise, which has already been reported in open reduction and internal fixation through posterolateral approach. references: hayes ag, nadkarni jb. extensile posterior approach to the ankle. j bone joint surg ; b: - . disclosure: no significant relationships. introduction: even the most modern technology has failed to induce satisfactory functional regeneration of traumatically severed peripheral nerves. delayed neural regeneration and in consequence slower neural conduction seriously limit muscle function in the area supplied by the injured nerve. this inferiority study aimed to compare a new nerve coaptation system involving an innovative prosthesis with the classical clinical method of sutured nerve coaptation. besides the time and degree of nerve regeneration, the influence of electrostimulation was also tested. material and methods: the ischiatic nerve was severed in female gö ttinger minipigs with an average weight of approx. - kg. the animals were randomized electronically to four groups: group i: nerve prosthesis without stimulation; group ii: nerve prosthesis with stimulation; group iii: microsurgical coaptation without stimulation; group iv: microsurgical coaptation with stimulation. in groups iii and iv, the nerve was sutured microsurgically, while the animals in groups i and ii received the new nerve prosthesis. postoperative monitoring and the stimulation schedule covered a period of months, during which axonal budding was evaluated monthly. results: preliminary data indicate that results with the nerve prosthesis are comparable to those with conventional coaptation. the results of this pilot study indicate that implantation of the nerve prosthesis allows good and effective neural regeneration. this new and simple treatment option for peripheral nerve injuries can be performed in any hospital with surgical facilities as it does not involve the demanding microsurgical suture technique that can only be performed in specialized centers. disclosure: no significant relationships. in mean there were , previous operations. in cases a change of osteosynthesis was neccessary. in cases bmp was used alone. in cases bmp was expanded by autologeous bone grafting. in cases the bmp was extended by autografts or ceramic scaffolds. results: divided in a healing group and a not healing group we found in the healing group a excellent clinical result by . points (able for sports) for the atrophic non unions and a good result of . points (walking long distances) for the post infected non unions. the radiological score is as high . / . ( cortices healed and bridging callus). in the non healing group the clinical rate was . / . (walking with splint) and the radiological rate was . / . (two cortices healed) the overall healing rate was %. divided in several groups the healing rate increases from % (infected non unions not tibia) to % (atrophic aseptic non union tibia). overal the secondary intervention rate was %. the healing time is . months in the middle. we see only mild side effects in %, like swelling. the most serious complication was the bony reinfection in %. there were amputations. conclusion: compared to the literature the healing rate of non unions could be increased using a strong concept in the treatment. as a part of the treatment the bmp treatened group increases the healing rate from % (friedlä nder) to %. the results are similar to the papers from kanakaris or zimmermann. there were no significant side effects noticed. material and methods: methods: at our level i trauma institute, from july, to september, each patient who presented with a clavicle fracture that was deemed operative received plate fixation alone or supplemented with bioresorbable calcium phosphate cement or autogenous bone grafting. patient records and radiographs were retrospectively reviewed. follow-up included standard radiographs to evaluate union at a minimum of months. all complications were also reviewed. results: results: two different clavicle plating systems, smith and nephew (smith and nephew, memphis, usa) ( clavicles) and implant technology systems (i.t.s., lassnitzhohe, austria) ( clavicles), were used with orif alone ( ), autogenous bone graft ( patients), or bioabsorbable calcium phosphate ( clavicles). of patients treated with open reduction internal fixation, complications have occurred at a minimum of month follow-up. three prominent hardware occurrences necessitated plate removal. one nonunion, one distal screw cut-out and one hardware breakage have been treated successfully with revision plating. using fisherâ e tm s exact test, no statistical significance was seen between the orif alone, autogenous bone grafting ( ) and bioabsorbable calcium phosphate ( ) in regard to overall failure incidence (p = . ). complications necessitating revision orif with bioabsorbable calcium phosphate ( ) and bone graft ( ) were not statistically significant either (p = . ). conclusion: there appears to be no statistically significant difference between union and complication rates between orif alone, or orif augmented with bioresorbable calcium phosphate cement or autogenous bone graft in this retrospective study. introduction: the purpose of the present study was to determine the effect of two anti-osteoporotic treatments on fracture healing in osteoporotic ovx rats, days after fracture occurrence. pth which has been proven to influence fracture healing in ovx rats, was taken as a control treatment. strontium ranelate is acting on both resorption and formation. we combined the rat model of a closed, standardised diaphyseal fracture of the femur with the model of a post-ovariectomy osteopenic rat, mimicking post-menopausal bone loss. material and methods: forty-five animals were ovariectomised at the age of weeks and a further were sham operated. at the age of weeks, osteopenia in the ovx rats was diagnosed. then, in all animals, a standardised mid-diaphyseal fracture was induced. at the time of fracture, the animals were divided into four groups. group was the sham control group, groups , and were the ovx treatment groups. groups and were treated with nacl . % s.c. daily, group was treated with mg/kg/d strontium ranelate p.o. daily and group received lg pth - x/ week s.c. the animals were killed after days and the fractured femur removed. the samples were scanned using microct by scanco medical, zurich, switzerland. the evaluation of the data focused on outer callus contour, cortical contour and marrow contour as well as cortical thickness. torsion testing on the bones was carried out using the axial-torsional system by instron (darmstadt, germany). results: treatment with strontium ranelate significantly improved the mechanical properties of the callus when compared to the ovx control group, while the improvement induced by the treatment with pth - did not reach significance. pth - and strontium ranelate both showed a significant increase in bone volume of the callus when compared to ovx control rats with no significant difference between the two treatments. as for the callus tissue volume, the increase induced by strontium ranelate was significant compared to ovx whereas pth induced no change and the difference between both drugs was significant . in both the pth - -and strontium ranelate-administered animals bv/tv was significantly increased compared to the ovx control rats . the bv/tv of the pth-treated rats was even higher than in the sham rats. conclusion: this is the first report on the enhancement of fracture healing with strontium ranelate. the callus in strontium ranelatetreated animals is even more resistant to torsion in comparison to ovx and sham-untreated animals and even to those treated with pth - . pth did not significantly enhance the resistance of the callus versus ovx, despite a significant increase in bv/tv within the callus. the superior results obtained with strontium ranelate compared to pth could be the consequence of a better quality of the new bone formed within the callus. introduction: recent clinical and animal studies suggest an elevated homocysteine serum concentration to be a risk factor for osteoporosis and fragility fractures ( ) . in vitro studies showed that increasing homocysteine concentrations stimulate the activity of human osteoclasts ( ). however, there is no data demonstrating that circulating homocysteine is related to structural and biomechanical properties of human bones. this study aimed to investigate the relation between morphological as well as biomechanical bone properties and homocysteine serum concentrations in humans. material and methods: fasting blood samples and femoral heads were obtained from males and females who underwent hip arthroplasty. bones were assessed by dual energy x-ray absorptiometry (dxa), biomechanical testing (indentation method), and histomorphometry. blood was sampled to measure homocysteine, folate, vitamin b , and vitamin b . according to their homocysteine serum concentration, subjects were classified as hyperhomocysteinemic (> lmol/l, n = ) and normohomocysteinemic (< lmol/l, n = ). results: folate and vitamin b , but not vitamin b , were significantly lower in hyperhomocysteinemic subjects when compared to controls. however, dxa, biomechanical testing, and histomorphometry did not reveal significant differences in bone quality between hyperhomocysteinemic subjects and controls. the results of the present study do not indicate a significant relation between circulating homocysteine and morphological as wells as biomechanical bone properties. introduction: sometimes fractured bones heal poorly with standard treatment and sometimes a bone defect is a major problem. although the bone grafting technique is considered a standard, there is a need for enhancement of this procedure. healing of the cancellous bone is a complex process in which many inflammatory and signaling molecules take part. to improve the outcome of the healing process, one can influence it by applying platelet rich plasma gel locally, thereby releasing cytokines and growth factors ( ). cancellous bone is rich with mesenchymal stem cells that produce new bone when stimulated. material and methods: we enlisted patients with hard to heal fractures and fractures that demonstrated poor healing in the study. five of the patients had osteomyelitis in the fracture and all fractures resulted in a bony defect as a serious complication after treatment. we designed a protocol for the preparation of allogeneic platelet rich plasma gel with suspended autologous cancellous bone, based on laboratory experiments in vitro ( ) . cancellous bone was harvested from iliac bone crest. we used standard ab and rhd identical, leukocyte depleted and irradiated platelets from a blood bank. activation of the platelet gel was achieved by using a cacl and thrombin mixture. we accepted patients after fulfilling the inclusion criteria and they were operated on in a standardized manner by their elected surgeons under technical supervision. in their follow-up, the ingrowths of bone grafts were measured by using x-ray analysis ( ). results: in patients the transplant was sufficiently incorporated in the fracture to give a limb full function. there were no major complications related to the platelet rich plasma additives. in one patient a nerve paresis was observed, which resolved spontaneously. in patients bone graft was not sufficiently incorporated, once because of poor compliance and the other time because of complex nature of distal tibia fracture. the clinical outcome of the operated patients ( %) is satisfactory and encouraging. conclusion: the preliminary clinical results show that using platelet rich plasma and cancellous bone in the treatment of large bone defects has a promising therapeutic potential. ( ) marx re. platelet-rich plasma: evidence to support its use. time from injury to reduction and to surgical intervention was noted. apoptosis was verified by microscopy with tunel, hematoxilin and eosine stained specimens after decalcification of the samples, a time consuming process. the number of live, apoptotic and necrotic chondrocytes were counted. the patients are followed with harris hip score, merle de aubigne score and radiographs for two years. results: patients were admitted directly to our hospital, the rest transferred from other hospitals. patients had their hip reduced after a mean time of minutes. had femoral traction applied and patients were not reduced. mean time from trauma to operation was ± . days. three patients received total hip arthroplasty. the results of will be presented at the congress. conclusion: the conclusions will be given at the presentation. introduction: distal inter-locking using free-hand technique in intramedullary nailing is always a time consuming procedure. the use of xray amplifier is mandatory and the exposure to radiation is rarely modest. if we use navigation devices we rarely trust the device completely and that is why we check the position with x-ray amplifier more than we need to. that is why we did laboratory testing of the new system using the electromagnetic navigation with the use of micro sensors for free-hand interlocking technique in laboratory without the use of x-ray amplifier to ensure the use of system in the operating theatre. material and methods: three residents with little experience in distal interlocking and no experience with this device were testing the electromagnetic navigation system with the use of micro sensors for free-hand interlocking technique. interlocking holes were drilled by the use of guiding star platform in lidis module, ekliptik, slovenia. the system producer had minutes of introduction time, afterwards drilling was done. distal locking was done on utn synhes nail and instead of bone, cannulated hard wood rods were used. we measured time needed for calibration and time needed for reaming and weather we were successful or not. introduction: percutaneous catheter drainage (pcd) is a useful method to manage pericardial effusion. however, pcd is not always effective in a case of hemopericardium due to clot. to perform subxiphoid pericardiotomy within a minute for emergency cases, we have done this procedure in a blind method following finger dissection by subxiphoid approach, which was preliminary reported in . we present the final data to report the usefulness of blind subxiphoid pericardiotomy (bsp) for emergency cases with acute hemopericardium. material and methods: we designed a study to determine a favorable management for cardiac tamponade due to hemopericardium. emergency patients with acute hemopericardium secondary to trauma (n= ), acute aortic disease (n= ) and cardiac rupture following acute myocardial infarction (n= ), were the subjects. board certified surgeons performed bsp (n= ) and other emergency physicians performed pcd (n= ) for patients with cardiopulmonary arrest (cpa) or near cpa due to cardiac tamponade from to . since , bsp (n= ) or pcd (n= ) has been performed at the physicians' discretion. results: bsp was effective to relieve cardiac tamponade in all cases but pcd was ineffective in cases ( . %, p=. ) because of clot in pericardium (n= ) or right ventricular puncture (n= ). in addition to ineffective drainage, acute occlusion of percutaneous drainage tube (n= ) were observed and resulted in deaths in the pcd group. procedure-related complication rates of bsp and pcd and survival rates of bsp and pcd were % and . % (p=. ), . % and . %, respectively (p=. ). sixteen patients (bsp, ; pcd, ) could discharge following emergency surgery (n= ) or conservative treatment (n= ). conclusion: blind subxiphoid pericardiotomy was safe and could be performed quickly in an emergency situation. percutaneous catheter drainage for hemopericardium could not avoid critical complications because of clot in pericardium in some cases. disclosure: no significant relationships. introduction and objectives: heart trauma, mostly penetrating, is not common in our community, but carries a significant morbidity. its clinical presentation can be variable. our objective was to asses the incidence, clinical presentation, associated injuries and mortality of our patient population with trauma to the heart. material and methods: observational, descriptive, retrospective analysis of patient with heart trauma included in our trauma registry between and . we reviewed demographic characteristics, mechanism of injury, associated injuries, injury severity score (iss) and new injury severity score (niss), mortality, triss probability of survival (ps), and hospital length of stay. results: we found ( . %) patients with cardiac traumatism out of . patients included in our registry, ( %) with associated injuries and ( %) isolated; ( . %) were from penetrating trauma, and only ( . %) were from blunt trauma. mean iss and niss were of (+/- ) and (+/- ), respectively. three patients presented ''in extremis'' (agonal status), nine presented with hemodynamic ''stability'' (sbp> mmhg) ( % of them with a hr> bpm), and five patients presented with hemodynamic instability. only % of the patients presented with cardiac tamponade, without hemothorax. two pericardiocentesis ( %), pericardial windows ( %), and emergency room thoracotomies were done ( . %). the most frequent location was in the left ventricle, followed by right atrium and right ventricle. the most frequent associated injuries were in the lungs ( %), followed by the abdomen and vascular injuries ( . %). fifty-nine percent required icu admission, with a median length of stay of days. ten patients died ( %), and three of them ( . %) were dead on arrival. two patients ( . %) died with a ps > . . conclusion: heart trauma is not frequent in our community, and displays great variability in its clinical presentation, with a high mortality. over half of the patients presented with hemodynamic ''stability''. disclosure: no significant relationships. approach of two cases of secondary aortoesophageal fistula results: the st patient was a -y-old man in which fistula was secondary to a fish-bone ingestion, days before the admission. in the nd cause, a -y-old man, fistula was secondary to rupture in oesophagus of a known thoracic aortic aneurysm. diagnosis was made by a contrast-enhanced ct scan; a gastrografin x-ray in the st and an endoscopy in the nd case completed the examination. in both cases the lesion consisted of a few-mm-diameter defect of the oesophageal wall. in the i case an emergent endovascular repair of thoracic aorta by bolton relay · mm stent graft was per-formed; in the ii case, endovascular repair of thoracic aorta (by bolton relay x mm) was associated to an endoprosthesis placement for primary treatment of a preexisting infrarenal abdominal aortic aneurysm. postoperatively tpn was administered. definitive treatment of fistula was performed in both cases by an explorative right thoracotomy (in v and vii post-operative day respectively): oesopagus was primarily repaired and reinforced by a pedicled intercostal muscle flap and a nutritional jejunostomy was associated. subsequent post-operative course consisted in ne administration, prolonged nasogastric suction, resuscitation with fluids, antibiotics. hemorrhagic complications or infections were excluded by repeated ct scan. oral feeding was in th and th postoperative day, after exclusion of a persistent fistula at a gastrografin x-ray of oesophagus. hospital stay was of days in both cases. no late complications were registered at follow-up. conclusion: when an aortoesophageal fistula occurs (if consists of a small oesophageal lesion), emergent treatment of endovascular aortic repair can be successfully associated to a second-step primary repair using a pedicled intercostal muscle flap via a right thoracotomy. results: case : a -year-old male is taken to our hospital after a car crash. on ct scan there was a periaortic hematoma from isthmus to diaphragm, multiple rib (flail chest) fractures, and a pelvic fracture. the aorta was repaired with an endograft with good immediate results. case : a -year-old male, injured in a frontal car crash. on ct scan a mediastinal periaortic hematoma was seen, with a pseudoaneurysm at the origin of the descendent thoracic aorta, distal to the sublavian artery. the aorta was repaired with an endograft, which was replaced at day th because of a leak. on follow-up he is doing very well. case : a -year-old male, injured in a car crash. ct scan findings were as follows: a left diaphragamatic herniation, bilateral lung contusion, traumatic laceration of the descending aorta, pelvic fracture and spleen laceration. he underwent an emergency laparotomy with splenectomy and diaphragmatic repair. on the nd postop. day an endograft was placed at the descending thoracic aorta, without complications. case : a -year-old male, injured in a frontal car crash. on ct scan there was a thoracic aortic laceration, distal to the isthmus, and an aortic endovascular repair was undertaken at day th , after complete hemodynamic normalization. the patient died at day th from multiple organ failure. conclusion: traumatic thoracic aortic injuries are frequently associated to severe thoracic, abdominal and orthopaedic injuries. traditional early surgical aortic repair through thoracotomy, with single lung ventilation and, occasionally, extracorporeal circulation carries a high morbidity and mortality. that is the reason why aortic repair has classically been delayed, but this carries an additional mortality rate of between % and %. endovascular treatment allows for an early management in severely traumatized patients who otherwise wouldn't stand such a risky surgery. it has also revealed lower rates of paraplegia after years of follow-up. introduction: injuries in zone i of the neck are rare and difficult to manage particularly in environment of war. this area gathers aerodigestive, vascular, lymphatic and nervous elements. all the difficulties lie in diagnosis of the lesions, in the decision of a surgical exploration and in the way of repair if necessary. in that situation, fistula between carotid artery and jugular vein is very uncommon, accounting for % of all arterial injuries. through one case, which has occurred in afghanistan, we discuss the various possible solutions to repair such a lesion. material and methods: we report one case of a french soldier, yo, who was wounded by a rocket splinter on left side of the area i of the neck. he was transported immediately in french role ii in kaboul. respiratory tracks are not injured, there's no neurologic lesions. he had a huge haematoma of the area with a tracheal back pushing (xray exam). during an effort of cough, a haemorrhage through the wound occurred requiring an oro-tracheal intubation and a surgical exploration by a cervicotomy. no obvious vascular lesions were found but just a thrill at the base of the neck. the patient was hemodynamically stable. he was transferred by medevac to france in the night. an angioscanner showed a fistula between carotid and jugular vein ( photos). results: he was re-operated h after. the fistula was just behind the first rib requiring an enlarging by sternotomy to control the origine of left carotid. there was a section of left pneumogastric nerve. after exclusion of the fistula and the vein, we interposed an allograft on carotid artery ( photos). the patient discharged from the hospital one week later without lateral damage except a bitonal voice with no need of re-education. conclusion: arterio-veinous fistula is an uncommon consequence of carotid injury. the taking in charge of this patient and the decision of the kinds of repair are difficult. stenting has also been used to repair distal internal carotid injuries that are not easily approached surgically. the favorable outcome of this case illustrates that surgery is a reasonable alternative when an endovascular approach is not feasible in patients with trauma-acquired arteriovenous fistulae. allograft or vein graft, if possible, is also a good solution for this kind of injuries. introduction: we report cases of subclavian artery injury caused by traffic accidents. in all cases, surgical vascular reconstruction was undertaken. in of the cases, the subclavian artery was obstructed by intimal dissection caused by falling down from a motorcycle. in the remaining case, subclavian artery aneurysm caused by seat belt injury occurred. material and methods: case : -year-old male while driving a large motorcycle, the patient collided with a car and the left side of his body was trapped in the car. this resulted in traumatic pneumothorax and severe ischemia of his left upper limb, and he was transported to our level trauma center for surgical treatment. bypass surgery using a mm diameter ptfe was performed. postoperative arteriography showed good patency of the graft and the patient was discharged. recovery from the motor dysfunction caused by brachial plexus injury took months. case : -year-old male for this case, the patient ran into a wall while driving a cc motorcycle. bypass surgery and clavicular orif were undertaken simultaneously for right clavicular fracture and ischemia of the right upper limb. postoperative arteriography showed good patency of the graft and the ischemia improved. however, rehabilitation was needed for the motor dysfunction caused by brachial plexus injury. case : -yearold female the patient ran into a tree while driving a car resulting in hemorrhagic shock caused by bilateral femoral and humeral fractures. she was transported to our center by helicopter. a scar from seat belt injury was found in the right cervical area. she presented with an expanding mass around the subclavian artery with accompanying pulsating pain. arteriography detected a cm-diameter pseudoaneurysm and aneurysmectomy was undertaken. postoperative computed tomography confirmed the disappearance of aneurysm and she was discharged. results: these cases showed favorable outcomes with surgical vascular reconstruction. conclusion: traumatic subclavian artery stenosis is caused by crushinduced local dissection and is frequently complicated with brachial plexus injury. subclavian artery aneurysm caused by seat belt injury occurred. disclosure: no significant relationships. results: case description: years old male patient who was brought in after receiving a large stab wound below the mid-portion of the left clavicle. severe external bleeding was prevented by manual compression in transit to the hospital. three foley catheters introduced through the wound at the ed failed to temporarily control the bleeding due to its large size, and he was rushed to the or. an emergency left antero-lateral thoracotomy allowed for the blind manual compression of the bleeding vessel from within the thoracic cavity, and was very successful in stopping the external bleeding. a long supra-and infra-clavicular incision was done, and the clavicle was divided. this failed to expose the bleeding vessel, due to the large muscle mass of the patient. a decision was taken to split the sternum in a ''trap-door'' approach, which nicely exposed a large laceration of the subclavian vein. this was suture-ligated, and the incision closed, in a surgical field with profused oozing from coagulopathy. he was taken to the icu, and then back to the or two hours later because of persistent bleeding through the chest drains. the ''trap-door'' incision was reopened and careful haemostasis was performed. the patient had a protracted course in the icu but eventually recovered. as a striking and very uncommon sequel he developed severe blindness from bilateral ischemic optic neuropathy attributed to hypotension and use of vasopressors. he is free of pain at the incision and with good cosmetic results conclusion: ''trap-door'' incisions are very infrequently used nowadays, but should be kept in mind in the armamentarium of trauma surgeons. disclosure: no significant relationships. conclusion: mortality in patients with ivc injuries can be well predicted by hemodynamic parameters on arrival and intra-operative findings .hemodynamic instability and intraoperarive findings of expanding hematomas and active intra-peritoneal bleeding are associated with high mortality. introduction: vascular complications due to intravenous drug abuse pose significant challenges to vascular surgeons and no standardized surgical management of the resultant infected pseudoaneurysm was established. material and methods: we present our successful management of a case of an expanding retroperitoneal haemathoma due to external iliac artery pseudoaneurysm caused by self inflicted trauma (heroin administration). mri showed an external iliac artery pseudoaneurysm surrounding by an infected old haemathoma, venous thrombosis (external illiac and femoural) and multiple muscular abscesses of the left thigh. a self-expandable stent-graft was deployed across the pseudoaneurysm after crossing the lession with an exchange glide wire through the left brachial artery route. post-stenting angiography showed complete exclusion of the pseudoaneurysm with no residual stenosis. we decided local surgical debridement; after haemathoma evacuation we identified external illiac artery presenting a stent graft and reinforced it by double layer of tissue sealing surgical patch. results: postoperative course was favorable under complex general and local therapy. conclusion: endovascular treatment of arterial pseudoaneurysms has become feasible as natural extension of the endovascular techniques. ct, mri, sonography and angiography may all be valuable in the imaging working of pseudoaneurysms. prompt diagnosis and treatment are necessary to avoid the morbidity and mortality secondary to hemorrhage and rupture. although endovascular stent-grafting is not considered a standard therapy for infected aneurysms, our case suggest that stent-graft deployment, secondary surgical debridement and major antimicrobial therapy may be the most favorable treatment option for patients unfit for major surgery. introduction: the incidence of traumatic vascular injuries (tvi) has increased significantly in the last decades, with penetrating trauma as the most frequent mechanism. our aim was to estimate the incidence, management by interventional radiology, and the preventable death rate in our patient population. material and methods: a retrospective observational study based on our trauma registry covering a -year period (july to july ) . we have assessed the demographics, severity, diagnostic and therapeutic approaches, outcome, and triss probability of survival (ps). results: patients ( % males, with a mean age of years) suffered a tvi located at the head ( ), neck ( ), thorax ( ), abdomen ( ), upper extremities ( ) and lower extremities ( ), respectively. ( . %) were caused by a blunt mechanism, and ( . %) by an open one. the average time spent before being taken to hospital was minutes. upon arrival to hospital, were in shock, required orotracheal intubation, and a cardiac massage. the diagnostic methods used were a ct scans in , dpl in , fast in , angiography in , echocardiogram in and duplex-doppler in . ( . %) patients underwent emergency surgery and ( . %) were treated with interventional radiology ( of them associated with surgery). only ( . %) were treated conservatively. overall mortality was of patients ( . %) ( of them died upon their arrival to hospital or in the operating room, all of them with an aortic injury), out of which ( . %) had a triss ps > . . the incidence of tvi increased from cases in the - period to in - , remaining stable in - ( ) . however, the mortality rate has shown a steady decline over the years (from % in - , to % in - ) . conclusion: the incidence of traumatic vascular injuries has increased considerably during the last years in our hospital. these injuries are most commonly located in the lower extremities, followed by the thorax. % of patients could be managed by interventional radiology techniques. introduction: the tip apex distance (tad) is a simple measurement that predicts screw cut out in the femoral head in peritrochanteric fractures treated with a fixed angle sliding hip screw device. we wanted to assess whether the tad measurements in our centre were comparable to previously published results, how reproducible these measurements were between observers and how accurate we were at reducing the fractures. material and methods: a retrospective review was conducted of consecutively treated peritrochanteric fractures over a month period. patients were excluded because they did not sustain a peritrochanteric fracture, had treatment of a pathological fracture or because of incomplete radiographic data. three observers used a standardised method to measure the tad (from orthogonal projections with a correction for magnification). the stability of the fracture patterns and the accuracy of reduction were measured according to criteria from the original baumgaertner paper introduction: distal locking screw insertion of the short gamma nail is normally performed by using a targeting device attached firmly to the proximal part of the nail. generally, the accuracy of targeting device should be promising. however, missing the target in the process of drilling might be a potential risk. we report cases of such condition in term of early radiographic finding, method of solving and the result of treatment. material and methods: the patient records, operative notes and intraoperative c-arm images of the patients underwent short gamma nailing for unstable pertrochanteric fractures during october to october have been reviewed in order to identify an error of distal locking screw insertion via a targeting device. the intraoperative radiographic finding, solving procedure and the outcome has been analyzed. results: there were cases of short gamma nailing over the past one year in our institute. five of which had an error during distal screw insertion even using the targeting device. an error occurred in the drilling process in all cases. intraoperative images showed that the drillbit missed its target posteriorly after perforating the near cortex of the femur. all has been corrected by using a free-hand technique under c-arm guidance. no any serious complication afterword and all fractures healed in an appropriated time. conclusion: distal screw insertion during gamma nailing can be missed even though using the targeting device. therefore, radiographic confirmation on the lateral view after perforation the near cortex is recommend in all cases in order to obtain early detection prior to bicortical perforation. freehand technique can be carried out in order to correct the error. . systemic antibiotics were used in patients ( %). ten different types of antibiotics were used after wound exploration for a period between and weeks. in-hospital mortality was %. sixty-nine percent (n= ) was finally discharged from follow-up. conclusion: we conclude that our infection rate was higher than reported in literature and the infections classified initially as superficial required a prolonged treatment as well. moreover, the treatment of this disastrous complication showed no uniformity whatsoever and should be the topic of further research, resulting in a clear protocol to increase survival and decrease morbidity. introduction: allograft meniscal transplantation is known as a possible procedure to solve pain and loss of function in the knee of patients with a history of subtotal or total meniscectomy. medium-term and long-term results after meniscal allograft transplantation in the knee are scarce. in this study patients who received an arthroscopically assisted meniscal allograft transplantation with a follow-up between and years were evaluated using subjective questionnaires, a clinical and a radiographical evaluation. material and methods: demographic data of all patients were collected and pre-operative results, using the koos (knee injury and osteoarthritis outcome score), the lysholm score, the tegner score, the sf and the vas (visual analogue scale) for pain were compared with actual results of those questionnaires to evaluate the therapeutic effects of allograft meniscal transplantation in the knee during medium-term follow-up. patients were evaluated with a standardized clinical examination of the knee to objectivate knee related symptoms. standard weight bearing radiographs and a full leg standing radiograph were performed to evaluate the evolution of osteoarthritis and malalignment. results: for all questionnaires (vas, koos, lysholm, sf ) there is a significant (p< , ) and clinically relevant increase in postoperative score. this improvement stays consistent during the followup period. the more severe the osteoarthritis, the lower the improvement. despite the meniscal transplantation, there is still a significant (p= , ) increase in osteoarthritis. an increase in osteoarthritis grade was seen in % of the patients, as scored following the kellgren-lawrence classification. when strictly respecting the indications, there is no significant correlation between preoperative cartilage damage, pre-operative osteoarthritis, alignment deviation, gender and body mass index on the one hand and outcome scores or improvement on the other hand. conclusion: meniscal allograft transplantation results in important pain relief and functional improvement in patients with a history of (sub)total meniscectomy and pain localized in the affected compartment. strictly following the indications, meniscal transplantation can give good and predictable results. introduction: intramedullary nailing of the tibia has become the conventional therapy for tibial shaft fractures. one of the most common complaints associated with this procedure is chronic knee pain. incidence rates between % and % have been reported and a significant number of patients have problems in kneeling, affecting professional and recreational activities. surgical damage to the infrapatellar nerve is one possible causative factor for post-nailing knee pain. the infrapatellar nerve is exclusively sensory and runs subcutaneously almost perpendicular to the patellar tendon just below the patella. the purpose of this study was to determine the prevalence of chronic knee pain in our institute and its relation with sensory disturbances in the knee area. material and methods: a chart review was conducted. all patients between and years with healed traumatic tibial shaft fractures treated with an intramedullary nail between and were included. exclusion criteria were: fracture lines extending into the knee or ankle joint, any other fracture in the affected leg, lacerations in the knee area, pre-operatively existing knee pain and loss of follow-up. chronic knee pain was defined as persisting pain in the knee area months after tibial nailing. sensory disturbances were defined as hyperesthesia or anesthesia at the nail entry site. introduction: femoral nailing causes an influx of fat in the circulation. in the multiply injured patient, especially in the patient with concomitant lung or brain contusion, this can lead to ards, fat embolism syndrome and multiple organ failure. the timing and kind of fixation of femoral fractures in patients with multiple injuries is controversially. the advantage of damage control orthopaedics (external fixation) would be less fat embolisation but some authors report more problems of infection and delayed healing. the aim of our study was to investigate the effect of external fixation on healing and infection rates of femoral shaft fractures in the multiply injured patient. material and methods: between january and januari , we treated femoral shaft fractures. in this group there where polytrauma patients with a total of fractures. we compared the rate of infection and delayed union in the group treated by damage control external fixation to the group primarily treated by intramedullary nailing. results: no significant difference in infection or union rates could be demonstrated between the damage control external fixation and the primary nailing group. we also noted that there's a correlation between the complexity of the fracture and the percentage of prolonged healing. and although not statistical significant there seems a tendency of less healing problems with the reamed femoral nail in comparison with the unreamed femoral nail. introduction: the diagnostic information power of a level one emergency room has risen excessively within the last years. the need for quality control, judicial regulations, insurance claims and forensic reasons still lead to a high number of autopsies being performed in patients not surviving the first h after admission to the er. however, the number of autopsy clarification featured in a level one trauma centre after trauma related deaths considerably vary and also the rate of deathly diagnoses missed within er assessment of early stage deceased patients differ in the literature. the aim of this study was to assess the value and necessity of autopsy after modern er assessment with a multi-slice ct-scan as an integrated part of the diagnostic algorithm. material and methods: prospectively reviewing our emergency database, case histories, laboratory values and radiological findings compared to findings in autopsy between jan and sep , we charged for missed deathly diagnoses in early stage deceased trauma patients (< h). patients were classified into two groups: group : patients with limited diagnostic assessment (conventional xray, sonography). group : patients with full er assessment (msct). all patients in group could not be sufficiently stabilised in terms of circulation patterns and therefore did not receive full assessment. non-trauma patients and patients reaching the er under cpr were excluded. results: the autopsy rate of all included patients was %. the overall incidence of missed deathly diagnoses was . %. in terms of missed deathly diagnoses, groups varied significantly (group : . %;group : . %).the iss after autopsy increased significantly in group from to . . in group there was no difference of iss between status emergency room and after autopsy. the most concerned region of missed deathly injuries was thorax with . % of all patients with autopsies followed by pelvic ( %) and spine injuries ( . %). conclusion: in spite of complete and nearly ideal conditions within a modern emergency room assessment nowadays, detecting all diag-noses is still challenging. overall, our findings show that almost every tenth early stage deceased patient showed at least one missed potential deathly diagnose in a level one trauma centre. regarding the insufficient assessment performance in group , the relative high rate of missed diagnoses seem explicable. nevertheless, even having acquired full assessment power (group ), still . % deathly diagnoses were missed. for this reason, autopsy is still the most powerful and indispensable tool in finding the ''whole'' diagnosis. completeness of autopsies after trauma related death therefore is essential referring a continuous gain of quality. introduction: in a physiological environment metallic biomaterials undergo corrosion through a variety of mechanisms. this study investigated whether, beside the well recognized electrochemical aspect of corrosion, human osteoclasts are able to directly corrode titanium alloys, uptake and finally release corresponding metal ions into their environment. the released ions are believed to cause inflammatory reactions and activate osteoclastic differentiation and activity, which most likely play a role in the pathophysiological mechanisms of aseptic loosening [ ] . material and methods: human monocytes and in vitro generated osteoclasts were seeded onto titanium and aluminum (positive control) foils. after days scanning electron microscopy analysis was performed in order to assess whether monocytes were able to grow and differentiate on the metals. in order to visualize uptake and distribution of intracellular metal ions, a novel protocol using confocal microscopy analyses with newport greentm dcf diacetate ester staining was developed [ ] . additionally, the concentrations of metal ions released into the culture supernatant were measured using atomic emission spectrometry. ). nine bre-gfp mice were used. mice were allowed unrestricted activity. a mini-external fixator fixed to the proximal and distal tibia was applied under general anesthesia on day . the animals were permitted full weight baring and unrestricted activity after awakening from anaesthesia. the gfp signal of tibia and fibula in bilateral limbs was measured on days , , , and after application of the external fixator. results: baseline measurements of the gfp-signal ranged from . x e photons to . x e photons between individual mice. after application of the external fixator, the gfp signal of the unloaded tibia and fibula decreased in all mice to on average % of baseline on day (sd ± %, p = . ), % on day (sd ± %, p < . ), % on day (sd ± %, p < . ), % on day (sd ± %, p = . ) and % on day (sd ± %, p < . ). in the contra-lateral non-operated limb, the gpf signal increased to an average % on day (sd ± %, p = . ), % on day (sd ± % p < . ), % on day (sd ± %, p = . ), % on day (sd ± %, p < . ) and % on day (sd ± %, p < . ). introduction: the aim of the present study was to assess the effect of antibiotic loaded fresh-frozen allografts and compare it with antibiotic loaded acrylic bone cement in staphylococcal tibia osteomyelitis and to combine the effects of bone repair and eradication of infection in one stage surgery. material and methods: a unicortical . -mm-diameter defect was created in the proximal tibial metaphysis of thirty-six new zeland albino rabbits. after contamining the wounds with x colony forming units of staphylococcus aureus, we divided the animals into four groups. the negative control group received no treatment, the positive control group received teicoplanin-impregnated polymethylmethacrylate beads, the allograft group received fresh-frozen allografts and the experimental group received teicoplanin-impregnated fresh-frozen allografts. histopathological evaluation with light microscope were made and intraosseous tissue cultures were performed on postoperative day . clinical evaluation in a daily-routine were made. results: the cultures showed no evidence of intramedullary infection in the experimental or the positive control group in eight of the nine rabbits, but they were positive for staphylococcus aureus in one of the nine rabbits in the experimental group, one of the nine rabbits in the positive control group and all of the rabbits in the negative control and allograft groups. the experimental group and the positive control group has similar effects in eradication of the infection. conclusion: teicoplanin-impregnated allografts was effective in preventing intramedullary staphylococcus aureus infection in a staphylococcal tibia osteomyelitis model. this combination therapy could potentially eliminate the need for surgical removal of cement beads. using an antibiotic-graft compound, eradication of pathogens and grafting of bony defects may be carried out in a one stage procedure. introduction: we first report a case of an infection in humans by streptococcus pluranimalium, a new streptococcal species that has been isolated in the genital tract and tonsils of cattle, tonsils of a goat and a cat, and from the crop and the respiratory tract of canaries. according our knowledge there are a few reports in the literature reporting infections by this strain of streptococcus in animals, but never since now in humans. a year old farmer, fit and well, nonimmunocompromised has been treated in our department, for a close tibial plateau fracture (schatzker vi), with a circular external fixator. postoperatively, i.v antibiotics -cefuroxime mg every h was administrated for hours. radiological and clinical healing of the fracture achieved successfully within weeks of the fracture. the frame removed and the patient was followed up as an outpatient. six days after the removal of the frame, the patient turned up to the a&e department, systematically unwell, complaining for a swollen painful knee, and a discharging abscess in one of the proximal pin sites near by the joint line.fluid samples from the abscess and the knee aspiration, obtained and revealed streptococcus pluranimalium in all samples. debridement of the abscess and an arthroscopic wash out was performed twice, followed by i.v antibiotics according to the sensitivity test (levofloxacin ( mgx ) ceftriaxone ( grx )) for six weeks, and p.o antibiotics (clarithromycin mg every h and levofloxacin mg every ) for another two weeks. results: symptoms were settled and the patient is free of infection for the last months. conclusion: we hypothesized that the bacterium was settled on the wires of the circular fixator and was inoculated in the patient during the removal of the frame. according our knowledge, it is the first case of infection in a human individual by this specific strain of streptococcus. disclosure: no significant relationships. introduction: post traumatic knee joint contracture is the most difficult complication of the lower limbs traumas, considerably limits the functional abilities and make the patients invalids. besides, the frequent consequence of knee joint injure is gonarthrosis, and kinesitherapy is one of the element of the complex treatment. the basis of the procedure is the joint relief, leading to adjoining muscles tonus lessening, and paraarticular tissues general tense lessening and infrajoint hydrostatic pressure, joint tissues nourishing improvement. the introduction: ilizarov frames are still removed in the operating theatre in a lot of centers. this is due to a variety of reasons, the main one being that it is a painful procedure. we decided to evaluate patient satisfaction and pain experienced on removal of ilizarov frames in an outpatient setting, using oral analgesia and entonox. material and methods: seventy consecutive patients, who had their frames removed in the out patients department, had their level of pain scored using a visual analogue score (vas) and a simple questionnaire. results: the mean score for frame removal was . on the vas. there was no difference between male and female scores. the age of the patient does make a difference in the pain score, the pain score decreases with the age of the patient. pain increases when there are or more olive wires to be removed conclusion: removal of ilizarov frames in the outpatient department is a moderately painful but well tolerated procedure. introduction: the proximal metaphyseal tibial fractures are difficult to treat due to their frequent association with tibial plateau fracture and due to their aspect, which is often comminuted and has a significant impact on the function of the knee. surgery has to restore local anatomy and to allow early rehabilitation, meaning proper evaluation and stabilization of the fracture. material and methods: cases, operated between . . - . . (mean age - yrs) with proximal metaphyseal tibial fractures, were analysed. pre-operative planning using ct scan was used. the fractures were complicated with compartment syndrome ( cases) which needed additional fasciotomy.the fractures were stabilized with : plates and screws ( cases) or external fixation ( cases) depending on the soft tissue status. bone graft was used in cases. the patients were monitorised at , , , and months postoperative, concerning: bone healing, restoring of the axis of the knee, joint mobility, septic complications. results: the axis of the knee were completely restored in all the cases. bone healing appeared in all the patients (starting from months- cases, at months in the rest of the fracture) depending on the initial aspect of the fracture. flexion of the knee was limited in cases ( % of the pactients) and extension was affected in patients, depending, also, on the initial characteristics of the fracture. the frequency of the complications depended on the initial aspect of the fracture, initial stabilization, time from intial stabilization to final fixation. conclusion: results after surgery for tibial plateau fractures depend on the initial aspect of the fracture, but also on the results of surgery . the method proposed by the authors, which allows the suspension of the articular surphace, is valuable especially when the fracture is cominuted and has small fragments. the double plate fixation (medial and lateral) with single anterior incision is the best, effective and simple procedure in treatment of complex proximal tibial fractures (type v and vi of schautzker classification). introduction: compartment syndrome is one of the most frequent complications after proximal metaphyseal tibial fractures, due to the anatomical characteristics of this area. the importance of the problem is that the compartment syndrome radically changes the local and general and especially the type of fixation of the fracture. the purpose of this study is to evaluate the impact of the compartment syndrome on the outcome of the patients with this type of fracture, when recognized and treated early and complete. material and methods: the authors analyse cases of proximal metaphyseal tibial fractures treated in the emergency hospital, bucharest, between . . - . . . from these, in cases, compartment syndrome was diagnosed. in all these cases, the patients were operated and the fracture stabilized (with plates and screws in cases and external fixation in cases). decompressive fasciotomy was performed in all the cases with installed compartment syndrome and intra-compartimental pressure was monitored post-operative in all the other cases. frome these, in cases secondary compartment syndrome developed and fascitomy was necessary - hours after surgery the patients are analysed concerning: the moment of surgical treatment, and the characteristics of the patient in that moment, post-operative treatment, the postoperative local and general outcome, local and general complications. results: the incidence of the complications was influenced by the time between trauma and complete surgery. there were cases of superficial infection and case of deep infection, without needing implant removal. all the fractures healed, the interval proved to be longer when external fixation was first used. there were no systemic definitive complications after these trauma. conclusion: compartment syndrome is frequent after proximal metaphyseal tibial fractures and the incidence of this complication was significant in the group of patients we studied, and the outcome was good when the treatment was early and complete . the compartment syndrome influenced the local and general prognosis, due to the importance of microcirculation in healing after trauma. results: a ct pulmonary angiogram illustrated a metallic density, which appeared to lie in the lumen of the main pulmonary artery just proximal to the pulmonary valve. conclusion: in this case, the respiratory symptoms and signs were due to a metallic pulmonary embolus rather than fat or thrombus. formal anticoagulation was initiated and the patient's clinical condition consistently improved without the need for cardiothoracic surgery, although this is described in the literature with retained catheter fragments. eight months after the injury, the fracture has consolidated with the patient returning to work. toid is often necessary to obtain adequate exposure. as an alternative to this we promote the minimal invasive transdeltoid approach. material and methods: the operative technique of the minimal invasive transdeltoid approach is explained in a first section. this approach has the advantage of direct access to the fracture site with more opportunities for adequate reduction and good plate placement without extensive distraction of the muscles. an important step in the procedure is the palpation of the axillary nerve. in a second section the results of a prospective cohort of the first patients treated with this technique will be presented. the neer criteria were used as guidelines for operative treatment. fractures were classified according to the ao-classification. the ases shoulder score was used to evaluate functional outcomes. preoperative xrays were used to evaluate displacement, vascularity of the humeral head (according to the hertel criteria) and ao fracture type. postoperative x-rays were analyzed for quality of reduction of the ccd angle, reconstruction of the medial hinge and reposition of the tuberosities. follow-up x-rays were evaluated for healing, avascular necrosis, loss of reduction and implant related failures of osteosynthesis. the -year-old male patient was taken to hospital after a traffic accident. he was a pedestrian hit by a car. he suffered comminuted proximal humeral fracture on the dominant right side. the fracture was closed. the glenoid cavity was damaged and acromion was broken. the fractures of the v-vi th ribs were found without complication. otherwise the patient's condition was good. he had only a controlled hypertension. for preoperative planning ct scan was performed. as pieces of the humeral metaphysis wedged into the glenoid cavity insertion of glenoid component seemed uncertain. an early shoulder replacement was done on the th day. the denudated fragments were removed. the tubercles with the muscle attachments were preserved. as a long bone defect remained in the metaphyseal zone normal stem would have been insufficient. a cm long stem used in tumor cases was implanted. the length of the arm and size of the humeral head were compared to the intact side. the tubercles were attached to the prosthesis by non absorbable sutures. after the operation long bone defect remained which was filled up by heterotopic bone visible on x-ray. the postoperative period was complication free. fever, severe pain, hematoma did not occur. the arm was in rest for weeks, only controlled pendulum exercises were done from the second week. active physiotherapy was started on the th week. after months the patient finished the follow up treatment. he was pain free and self-sufficient. conclusion: for three-or four-part displaced fractures in which replacement is indicated, hemiarthroplasty with tuberosity reattachment remains the reference treatment/ , /. in trauma cases short prosthesis stem is usually sufficient but in comminuted fractures involving the metaphyseal zone long stem has to be used for certain bone-prosthesis contact. introduction: there is a trend to apply plate and screw fixation directly medial and lateral (so-called parallel plating), and many implants designed specifically for the distal humerus extend more laterally to improve fixation. this may risk injury to the origins of the common extensor and flexion musculature and the collateral ligaments either via operative dissection or by damage to the blood supply. internal plate and screw fixation is often accomplished with subperiosteal elevation of muscle attachments and tight apposition of the plate to the bone, but this should not be done over the epicondyles. plates applied to the medial and lateral aspects of the lateral and medial epicondyles should be placed directly over the soft tissues without elevating or disturbing them. damage to the collateral ligaments could cause elbow instability. material and methods: in order to emphasize these important technical aspects, we report three patients in whom detachment of the origins of the lateral collateral ligament and common extensor muscle origins from the lateral epicondyle led to post-operative instability after open reduction and internal fixation of a fracture of the distal humerus. results: while the cases are very complex and the exact cause of elbow instability by necessity somewhat speculative, our concern is that the operative dissection performed to apply implants to the lateral side of the elbow contributed to the ulnohumeral instability. injury to the lcl is the most common cause of recurrent elbow dislocation. attempts to place a direct lateral implant directly on the bone by elevating soft tissues will put the origin of the lcl at risk. it is preferable to place implants directly over the soft tissues, although there is a risk of interfering with blood supply leading to soft tissue insufficiency. it seems safe to assume that the operative treatment contributed in some way to the instability in each patient. patient one in particular had osteoporotic bone noted intraoperatively, so that one would expect failure to occur through bone with any subsequent trauma. the failure through the ligamentous structures seems to implicate the operative technique. conclusion: in any case, these three patients establish that instability of the ulnohumeral joint is an uncommon complication or sequel of the operative treatment of a bicolumnar fracture of the distal humerus. our intention in reporting these cases is to increase awareness of these potential complications and we encourage others to report any similar cases so that we can learn enough to limit the risk of this complication. introduction: orif of comminuted distal humerus fractures carries a high risk of complications such as secondray loss of reduction, pseudarthrosis and heterotopic ossifications. especially elderly patients with osteoporotic bone quality are struck by these complications. therefore total elbow arthroplasty (tea) is gaining more and more in importance as it has proven to achieve good results in elderly patients with poor bone quality. the latitude total elbow system (tornier inc., stafford, usa) is a modular, convertible implant that allows not only linked and unlinked tea with or without radial head replacement but also hemiarthroplasty. the aim of this system is to reproduce the patient's anatomy to reconstitue the elbow's physiologic kinematics. therefore the latitude prosthesis is offered in four different sizes, respecting the flexion-extension axis and three different humeral offsets based on anatomical findings. the purpose of our study was to evaluate the short-term results after elbow arthroplasty with the latitude system. introduction: it is not always possible to reconstruct complex radial head fractures. as non-anatomical reconstruction and healing disturbances result is loss of motion and severe post-traumatic arthritis of the elbow joint, radial head resection as been proposed for these cases. other authors propose radial head arthroplasty as an alternative to radial head resection to avoid the complications of radial head resection. different concepts of radial head prostheses are available: silicon prosthesis, monopolar prosthesis (loose fit and cemented/thight fit) and bipolar prostheses. evidence is lacking on the exact place for arthroplasty as opposed to radial head resection. to answer this question we performed a systematic review of litterature. material and methods: inclusion criteria are clinical studies reporting on radial head resection or radial head arthroplasty, published between and today in english, french, german or dutch language. a search has been performed using the pubmed and embase databank. a secondary search has been performed based upon the reference list of the included publications. exclusion criteria are: â e¢cadaver or animal studies â e¢biomechanic studies â e¢clinical studies with a follow up of less than years â e¢clinical studies with less than patients data extraction â e¢elbow function â e¢complication rate â e¢arthritis rate data are reported according to the moose guidelines. results: only low evidence studies are available. we did not find any randomised controlled trial comparing resection to radial head arthroplasty. there is evidence that radial head resection results in high complication rates (including arthritis) and poor function in case of elbow instability and/or essex-lopresti lesions. the rate of complications in these indications is higher than for radial head arthroplasty. in cases without instability or essex-lopresti lesion there is a trend to better function in radial head resection. complication rate is higher in the prosthesis patients. the rate of post-traumatic arthritis is not significantly differing between the resection and the arthroplasty group, and remains very high (+/_ %). conclusion: complex radial head fractures remain difficult to treat. based upon the findings of this systematic review we suggest: â e¢that adequate level of evidence studies are a necessity â e¢that in case of fracture without evident instability or essex lopresti lesion resection results in better function and less complications than arthroplasty â e¢that in case of fracture with evident instability or essex lopresti lesion resection results in worse function and higher complication rates than arthroplasty â e¢as secondary arthritis rate remains %, further therapeutic optimisation is a must. often, mortality. a new pelvic stabilizer (t-pod Ò ) provides secure and effective simultaneous circumferential compression of the pelvis. material and methods: in this study we have managed fifteen patients with a prehospital untreated unstable pelvic fracture with signs of hypovolaemic shock with the t-pod Ò . before and minutes after applying the t-pod Ò , heart rate and blood pressure were measured. an x-ray before and after applying the t-podÒ was made to measure the effect on reduction in symphyseal diastasis. results: application of the t-pod Ò reduced the symphyseal diastasis with % (n= ; p= . ). the mean arterial pressure (map) increased significant from . to . mmhg (n= ; p= . ) and the heart rate declined from beats per minute to (n= ; p= . ). in ten patients of whom circulatory response before and after the t-pod Ò was recorded, there were seven good responders, one transient and two poor responders. conclusion: in the acute setting, the t-pod Ò device has a clear compressive effect on the pelvic volume in unstable pelvic fractures. the t-pod Ò is therefore an easy to use and effective way of (temporarily) stabilizing the pelvic ring in an acute setting. introduction: thoracolumbar and lumbar fractures treated with surgical methods aim to decompress the spinal cord and correct the deformity. we aimed to compare the effects of anterior, posterior and anterior-posterior surgery on the local kyphosis angle in thoracolumbar and lumbar vertebral fractures. material and methods: thoracolumbar and lumbar, burst or compression fractured and surgically treated patients were evaluated retrospectively. preoperative, postoperative and follow-up local kyphosis angles were measured on the x-rays and changes in these angles were compared according to the applied surgical treatment methods. results: early application of surgical treatment following trauma decreases the correction loss suffered after surgery. the increase in correction loss continues after removal of the hardware. it is observed that laminectomy applied in the course of posterior surgical interventions has no effect on the correction loss. the length of the implantation, fusion and the addition of a hook to the lamina of the vertebra which is located one segment lower than the transpedicular screw applied vertebra do not affect the loss of correction. conclusion: in the surgical treatment of thoracolumbar and lumbar vertebral fractures, different degrees of correction loss are observed after each surgical treatment modality. considering the corrective effect of combined anterior-posterior surgery on the correction of kyphotic derformity due to trauma and the preoperative local kyphosis angle, follow-up correction achievement is higher when compared with anterior and posterior surgical approaches. domain questionnaire (eq- d), the point self-rated back pain (vas) and device and/or procedure related adverse events. the ethic committee of the hospital did not accept a randomized study because of the results in this proof of concept, they accepted the study with a minimum of patients (based on the results of a previous proof of concept). the incidence of missed injuries without the application of the tertiary survey was % and this incidence has been reduced to % with the application of the tertiary survey (it means a reduction of the . % in the incidence of missed injuries). the incidence of clinically significant missed injuries without the application of the tertiary survey was % and it has been reduced to % with the application of the tertiary survey (it means a reduction of the % in the incidence of missed injuries). the tertiary survey is an essential task in the management of the trauma patients to reduce the incidence of missed injuries and clinically significant missed injuries. introduction: knee-arthroscopy is a complex surgical ability. it is a combination of factors like anatomical knowledge, hand-eye coordination, three-dimensional mental activity and operating experience. surgeons as well as students were not able to train knee arthroscopy before. parts of these abilities were trained by playing video games. former studies indicated a correlation between a better performance in virtual reality (vr) laparoscopy simulation and video game experience. the aim of this study is to show that experienced video gamer perform better in a virtual arthroscopy simulation. material and methods: medical students did an arthroscopy of a longitudinal meniscus tear on a vr knee arthroscopy simulator (the insight arthro vr Ò gmv, madrid, spain). the students completed a questionnaire asking for their game experience: none (n = ), monthly (n = ) weekly (n = ) daily (n = ) before they did the arthroscopy. the simulator assessed different parameters: time, distance moved and roughness both for probe and camera and a global score (combination of all metrics). results: students with game experience (n = ) performed significantly (p <= , ) better than not experienced students (n = ). there is a tendency that the performances get better with more game experience. conclusion: gamer performed better in a vr knee arthroscopy than not gamer. these result correlates to the laparoscopic simulator training. there is a tendency of achieving a better performance in vr arthroscopy simulation due to a higher frequency of playing games. extensive training on the simulator improves the abilities of nongamers with respect to their arthroscopy skills. we will evaluate these dates in the future. ) and mostly injuries of tendons (n = ) and/or vessels / nerves (n = ). buzzsaws of different manufacturers and different price ranges were used. the work conditions were well in all cases, the saws were placed firmly on the ground and the lighting was sufficient. most injuries appeared on the week-end (friday n = , saturday n = ). a break or a meal, taken shortly before the accident, had no influence on the injury risk. all patients had a several years lasting experience in dealing with buzzsaws, half of the patients even for at least years. the safety device of the saw was folded back in most cases (n = ), only few patients (n = ) had correctly put on the saw safety device at the accident time, patients provided moreover no information. the accident had entered in cases shortly before working end, mostly with the last cut. in cases a wooden piece had become stuck in the saw and the patient had tried to solve it. conclusion: a many years' routine in dealing with buzzsaws can lead to the fact that necessary safeguarding measures are not followed any more and so cause an increased injury risk. in particular shortly before working end the attention decreases and the injury risk rises. an especially injury-laden situation is becoming stuck of wooden parts in the saw. the attempt to solve these parts without switching off the saw before bears a high injury risk. the patients showed predominantly heavy injuries. this might be the result of our clinic as a university clinic. patients with less severe injuries are concerned to be treated in smaller clinics next to their residence . ethibond was then used to anatomically oppose the ends of the sleeve fracture. the construct was reinforced with a circlage wire with the wire twisted so that it could be retrieved later through a small lateral incision post operatively the legs were immobilised in lightweight casting material for a period of weeks followed by an unlicked hinged knee brace for weeks. the circlage wires were removed at months. the child now has full, pain free range of motion. the knee is stable and he has no functional problems. conclusion: we report a rare case and emphasize the timing of diagnosis as being crucial in outcome. early operative intervention with accurate open reduction will yield good results. this publication serves to educate and refresh those who deal with general and paediatric lower limb trauma. introduction: the purpose of this study was to evaluate the effect of electromagnetic fields in healing progression of delayed union of long bones in the lower extremities. we defined delayed union, as failure of expected healing progression and nonunion when a minimum of nine months has elapsed since injury and failure or halting of healing progression was observed in three successive monthly radiographs (infection ruled out results: an average of . x-rays were performed on each patient from the time of diagnosis to discharge from clinic. none of these fractures displaced on follow up x-rays. conclusion: stable undisplaced ankle fractures treated conservatively with a below knee non weight bearing cast do not displace. hence these patients do not require to be followed up frequently with serial x-rays as they may be exposed to unnecessary harmful radiation and follow up appointments thereby saving time, money and resources. ( ). we aim to describe the rate of postoperative complications after calcaneal plate osteosynthesis in relation to the hospital fracture load as a means to increase insight into the clinical audit data. material and methods: a search was performed using the disease code for intra-articular calcaneal fractures and operative code for orif for the period - . the medical records of all included patients were obtained. as postoperative complications we included superficial and deep wound infection, mobilisation problems with need for orthopaedic shoes or walking aid and secondary arthrodesis. current complication rate of deep infection and arthrodesis rate from the clinical audit were compared with the mean logarithmic correlation coefficient relating complication rates with the institutional fracture load data, reported earlier in the literature ( ) . results: over a period of months a total of intra-articular calcaneal fractures were reconstructed with a calcaneal plate using orif (mean institutional fracture load = . fractures per month). eight patients had a wound infection, six of them were treated with antibiotics and two of them needed surgical debridement. thirteen patients have mobilisation problems, patients suffered from pain when walking, patients used orthopaedic shoes and one patient mobilised using a wheelchair. two patients had an secondary arthrodesis (n = , . %). in seven patients the osteosynthesis was removed due to pain. both deep infection rate and arthrodesis rates related to the institutional fracture load were below the % ci reported in the literature. the outcome of open reduction and internal fixation of intra-articular calcaneal fractures is known to be determined not only by factors related to patient and the fracture, but also to the institutional fracture load ( ) . the complication rate regarding deep wound infection and arthrodesis is below the data reported in the literature, related to the institutional fracture load. clinical audits studying the complication rate should take the institutional fracture load into account. introduction: toe fractures are the most common fracture of the foot. there is little data on demographics and no studies on functional outcome of toe fractures. material and methods: the initial radiographs of all consecutive patients with toe fractures treated between january and september at the reinier de graaf groep in delft, the netherlands were re-evaluated; patient and fracture characteristics were collected. all patients in aged to ( patients) were sent a questionnaire concerning pain, activity and functional limitations, footwear, walking distance, and gait (aofas midfoot score). overall satisfaction was measured using a visual analogue scale (range zero to ten). results: a total of patients with digital and phalangeal fractures of the foot were identified. the distribution of fractured toes was: first %, second %, third %, fourth %, and fifth %. multiple digital fractures were seen in . %. most fractures were caused by stubbing the toe or a crush injury ( . %). more than % of the fractures were undisplaced or minimally displaced and most fracture patterns were transverse or oblique/spiral. a total of patients ( %) returned the questionnaire with a median follow-up of months. responders were female in . % and had a median age of years (p -p - ). in . % of cases the left side was affected. the median aofas-score was points (p -p - ), the median vas was points (p -p - ). no correlations were identified with outcome and which toe or phalangeal bone was affected, number of fractured toes, fracture type and location, articular involvement, gender, age, body mass index, smoking habits, and diabetes. in the univariate analysis a trend was found for dislocation and aofas score (p = . ). in the multivariate analysis the vas was dependent of age (p = . ) and gender (p = . ). the aofas midfoot score was not influenced by any of the parameters. conclusion: this is the first investigation using two validated outcome scoring systems to determine functional outcome. almost all toe fractures were healed without complaints at months. patient satisfaction is slightly less in younger female patients. the appendix has been one of the most common site of carsinoid tumors( ). carsinoid tm is seen incidental in appendectomised cases( , - , ) and frequently in female( , ). mean diagnosis age is between - in literature, whereas in our serise it is ( ). postoperative living prognosis is good in incidental carsinoid tumors of appendix ( ) .in our cases, additional surgical procedure was not applied because tumor is less than cm, mesoappendix is healthy, and vascular invasion was not seen in hystopathologic examination. introduction: for clinical importance, two cases are presented who were operated with diagnosis of acute apppendicitis. intraoperatively,appendixes were normal, for this reason meckel's diverticulas were explored and diverticulitis were seen. material and methods: two cases are explored retrospectively results: case :the case is years old male patient.he admitted to emergency department with abdominal pain for days.there were defans and rebaund on the right inferior quadrant of the abdomen. leucocytosis( , x /mm ), aperistaltic intestinal ans in ultrasonografic examination were seen. in the operation appendix was normal,so meckel's diverticula researched and diverticulitis was seen at th cm from ileocecal valve.wedge resection for diverticulitis and appendectomy for appendix were performed.in microscopic pathologic examination appendix was normal, and meckel's diverticulitis was seen case :the case is years old male. he admitted to emergency departmant with abdominal pain for days because his pain increased last days. he has nausia, vomiting, fever( , °c), leucocytosis( , x /mm ), defans and rebaund on the right inferior abdomen. in the operation appendix was normal,so meckel's diverticula researched and diverticulitis was seen at th cm from ileocecal valve.wedge resection for diverticulitis and appendectomy for appendix were performed.in microscopic pathologic examination appendix was normal, and meckel's diverticulitis was seen. conclusion: meckel's diverticula is the most congenital anomalies of the gastrointestinal anomalies and it was found % in autopsy ser-ies. ( ) .it is asymptomatic generally. risk of complication is - %( ). preoperative diagnosis may not be done frequently, so to delay of operation may be serious complication.( )in our clinic, we explore meckel's diverticula, over(in female) and duodenum, if we do not see pü rü lant material on the appendix. results: patients with abdominal tb were diagnosed by laparoscopy and peritoneal biopsy in cases and by laparotomy in cases. from these patients we observed peritoneal tb in cases, intestinal tb in cases, mesenteric lymph nodes tb in case. at admission patients presented complications: cases with perforations and peritonitis, case with intestinal obstruction and cases presented as ileo-cecal ''tumors'' (solved by right colectomy); other surgical procedure performed was enterectomy with either entero-entero-anastomosis, either ileo-colic anastomosis. in abdominal tuberculosis ascites was present in cases. other common findings were weight loss ( cases), weakness ( cases), abdominal pain ( cases), anorexia ( cases) and night sweat ( cases). only patients had chest radiography suggestive of a new tb lesion. in those patients with peritoneal tuberculosis subjected to operation, the findings were multiple diffuse involvements of the visceral and parietal peritoneum, white ''miliary nodules'' or plaques, enlarged lymph nodes, ascites, ''violin string'' fibrinous strands, and omental thickening. biopsy specimens revealed granulomas, while ascitic fluid showed numerous lymphocytes. postoperative management was applied by the tb medical system. all patients were treated for months by specific drug therapy, with favorable evolution. pcr of ascitic fluid was positive for mycobacterium tuberculosis (m. tuberculosis) in all cases. introduction: abdominal trauma represents an important cause of morbidity and mortality in children. conservative management is preferred in blunt trauma with hemodynamic stability although there is a risk of intestinal damage when free fluid without solid organ injury is found in image studies. early laparotomy may be unnecessary in most cases but a delay in diagnosis of bowel perforation could lead to increased rate of complications. on the other hand the presence of a penetrating abdominal trauma is considered an absolute indication of laparotomy. we present five cases of abdominal trauma treated in our department in which laparoscopy proved to be an optimal diagnostic and therapeutic tool. material and methods: chart review of our cases and literature review results: three cases of blunt abdominal trauma underwent laparoscopy. we found a small bowel perforation in one case that was repaired by externalization of the jejuna loop by one of the ports. in the other two cases we found intestinal and mesenteric contusions that were treated by peritoneal drainage. two cases of penetrating trauma underwent laparoscopy. one of them presented omentum evisceration with no other injuries and the second presented a gastric perforation that needed reconversion to laparotomy. conclusion: in our experience and according to literature, laparoscopy should be taken into account as a diagnostic procedure in blunt abdominal trauma in stable children with abnormal abdominal examination and moderate free fluid and no solid organ injury in image studies, and it could be a first and sometimes definitive approach to minimal penetrating abdominal trauma. %) patients, biliary tract injury in ( . %) patients, multiple stones in the abdomen due to perforation in ( . %) patients, inadequate technical equipment in ( . %) patients, liver injury in ( . %) patient, intraoperatively detected umbilical hernia in ( . %) patient, uncontrollable bleeding in trocar entry site in ( . %) patient, insufficient insufflation in ( . %) patient, and unstoppable bleeding of arteria cystica in ( . %) patient, respectively. conclusion: although laparoscopic cholecystectomy is the golden standard of treatment in cholecystectomy, it involves the risk of conversion to open surgery. the rate of conversion to open surgery has been reported to be between - % in many series and is considered to be % on average. in our study, we found it as . %, a rate which is close to the rate reported in the literature. chief reasons for conversion from laparoscopic to open cholecystectomy include the difficult dissection of callot's triangle due to obscured anatomy and adhesions, gallbladder perforation, bleeding, the failure to produce pneumoperitoneum, gallbladder cancer, and injury in main biliary tracts and neighboring organs. the presence of pericholecystic adhesion and liquid in acute cholecytitis cases and the presence of edema in the tissue affect regional anatomy and complicate dissection, which increases the risk of gallbladder perforation. in our study, changes due to acute cholecytitis and difficulties in the preparation of callot's triangle ranked first among the indications for open cholecystectomy with a rate of . % ( / introduction: the most difficult decision in the management of the patients with severe necrotizing pancreatitis is whether surgery is required and which of the complementary approaches to necrosectomy and drainage is appropriate. recently a great deal of data has emerged suggesting that a pulsating irrigation stream delivered at high pressure and with a high flow effectively decreases bacteria, foreign bodies, and necrotic crushed tissue in wounds and decreases the incidence of resultant wound infection. this study evaluates the effect of inter pulse jet irrigation, used for the first time in open abdominal surgery. material and methods: twelve patients presenting proven infected/ non-infected pancreatic necrosis during course of acute pancreatitis and not responding to radiological or laparoscopic drainage were prospectively offered necrosectomy using itner pulse jet irrigation. open necrosectomy and subsequent jet irrigation were performed using a midline laparotomy. in all patients, to tube drainages were placed during necrosectomy for continuous closed lavage. temporary abdominal closure using modified mesh-foil laparostomy was applied for relief of abdominal compartment syndrome. results: no intraoperative complications were recorded with a median operative time of +/- minutes. in cases two sessions of necrosectomy were sufficient to completely clear the necrotic tissues. another patients with extended retroperitoneal necrosis required irrigation procedures. necrosectomy using inter pulse jet irrigation was successful in all patients, and none required complementary surgical or radiological treatment. introduction: intra-abdominal hypertension (iah) and abdominal compartment syndrome (acs), have been described often in patients with abdominal trauma or after emergency abdominal surgical operations. we present patients with vomiting, meteorism, acute abdomen and acute respiratory insufficiency provoked by phytobezoars. aetiopathogenesis, symptoms and differential diagnosis are analyzed and a brief report of the literature is discussed. material and methods: three patients, were admitted to the emergency department of our hospital during the last year. all patients were presented with acute respiratory failure, abdominal pain, discomfort, meteorism and vomiting. the first patient, a years old man, alcoholic was admitted with meteorism, acute abdominal pain and discomfort. a fr nasogastric tube was introduced and the symptoms were remitted after gastric evacuation. the second patient suffered from bowel obstruction after closure of colostomy as a result of traumatic injury of sigmoid colon. a laparotomy was performed and a phytobezoar was revealed at the level of anastomosis. the last patient was presented with meteorism, vomiting and dyspepsia, as a result of enlarged gastric mass, revealed after endoscopy. results: gastric evacuation in the first patient revealed lt of fluid mixed with a smelly gas under pressure (iap = cmh o after evacuation) followed by washouts. laparotomy was performed in the second patient revealing a large phytobezoar at the level of anastomosis. mini laparotomy and gastrotomy in the third patient (after two unsuccessful gastroscopies) revealed large phytobezoars. introduction: the objective was the substantiation of using dcs tactics in wounded with ctmi. material and methods: in case of cranial injuries dcs tactics implied treating superficial wounds of skin, arrest of exterior bleeding and subsequent evacuation of the wounded within the first hours after getting trauma. in case of extremity injuries, dcs tactics implied first of all the operations on the occasion of gunshot injuries, including the arrest of bleeding, application of the external fixation apparatuses, application of temporary shunts for injured vessels. the burn wounds treating were carried out after helping the patient out of shock. in case of the wounded with chest injury in the presence of hemo-and pneumothorax, drainage of pleural cavity of silicone tubes with active air aspiration was fulfilled. in case of abdomen injuries after laparotomy abdominal cavity was cleaned and inspected including examination of the most probable sources of bleeding: liver, spleen, magistral vessels. on the background of unstable hemodynamics the abdominal cavity tamponage along the right and left side canals, supraliver and underliver space and small pelvis. results: thus, in accordance with dcs principles in case of ctmi, operations regarding gunshot injuries were made in the first turn, and operations connected with burns -in the second turn. the first were urgent operations. then, intensive therapy in the conditions of resuscitation unit. conclusion: the repeated operation of the second stage -final removal of lesions -was carried out after the condition of the wounded had been stabilized. introduction: the aa highlight the importance of the damage control philosophy in difficult emergency surgery situations like the perforation of an oesophagojejunal anastomosis by an oesophagojejunal tube. material and methods: man, age , rd pod after total gastrectomy with precolic reconstruction for gastric cancer (t n mxr ) in another institution. no significant past diseases. mechanically ventilated, in septic shock, with purulent drainage from right hemithorax and blue drainage from right abdominal upper quadrant, after ''methilene blue'' swallow. distended abdomen. relaparotomy with median frenotomy (pinotti) and damage control procedures for oesophagojejunal and cardiophrenic pleural sinus perforation by an esophagojejunal tube, with right pleural empyema, mediastinitis and peritonitis: primary closure of the perforation, washing and drainage of the pleura, mediastinum and peritoneum, delayed abdominal closure (dac, rotondo and schwab) and intensive care unit (icu). on th pod, revision of the mediastinum and peritoneum, no evidence of fistula: internal pleural drain retired, fibrin glue and collagen placed to protect the anastomosis, dac and icu. on th pod, anastomotic leak: a ttube (kehr) has been placed as a minimal drainage procedure; dac and icu. on th pod, descendent feeding jejunostomy and abdominal closure. on th pod, subfrenic abscess on ct scan: surgical drainage through the upper third of the previous closed laparotomy. on nd pod, intestinal suboclusion: drainage jejunostomy above the feeding one. on st pod, right pleural drainage: oesophagoscopy, t-tube removed and expansible silicon covered oesophageal prosthesis inserted, covering the anastomotic fistula. on nd pod, patient left the icu. results: on th pod, patient sent back to the institution where he has been operated first. on th pod, endoscopical removal of the prosthesis with baritated swallow control, with patient sent back home. conclusion: this case highlights the importance of the damage control philosophy in difficult emergency surgery situations like the perforation of an oesophagojejunal anastomosis by an oesophagojejunal tube. disclosure: no significant relationships. y. el-ashaal , a. hefny , y. saadeldinn , f. m. abu-zidan al-ain hospital, department of surgery, al-ain, united arab emirates, al-ain hospital, department of radiology, al-ain, united arab emirates, surgery, department of surgery, uae university, al-ain, united arab emirates introduction: acute gastric dilatation due to superior mesenteric artery syndrome in healthy subjects is extremely rare. herein we report its sonographic findings and highlight the value of point of care bedside ultrasound in such a case. material and methods: a -year old female was admitted to al-ain hospital complaining of epigastric pain of two days duration following excessive eating. she was nauseated but could not vomit. succussion splash was positive. bedside ultrasound has shown a hyperactive duodenum, a distended stomach compressing on the ivc, and a narrowed angle between the superior mesenteric artery and the aorta. these findings were confirmed by abdominal ct scan. the angle between the aorta and superior mesenteric artery was only â -p p . gastrographin follow through has shown complete obstruction of the third part of the duodenum. nasogastric tube immediately drained ml of yellowish fluid. results: five days later gastrographin follow through has shown free passage of the dye to the small intestine with significant reduction in the stomach size. the patient was discharged home in a good condition. conclusion: bedside ultrasound has proven extremely useful for both the diagnosis and management of this rare case. introduction: a rare and potentially lethal complication during right hemicolectomy material and methods: a year-old male, underwent a right hemicolectomy due to malignancy in the cecal region. during the operation the relatively constant venous anastomosis between the middle colic vein and the inferior pancreaticoduodenal vein close to the lower border of the pancreas was injured, resulting in excessive haemorrhage. in the effort to manage the bleeding, the superior mesenteric vein (smv) was torn, and after multiple unsuccessful efforts to repair the vein, we finally had to ligate the smv. the operation was completed by typical right hemicolectomy and the abdomen was closed. five hours later the patient showed acute distention of the abdomen together with respiratory distress. due to increased abdominal pressure (> cm h o), the patient was taken back to the or. the small bowel was edematous, bluish but viable. the abdomen left open and was closed by using the vac. the patient was taken to the icu. six days later the small bowel returned to normal colour and thickness, but the generalized edema made the closure of the abdomen impossible. by day ten the patient was on full enteral feeding, and was taken to the or, where free partial thickness skin grafts were used to close the abdomen. results: the patient was extubated by day sixteen and was taken to the rehabilitation center. conclusion: accidental injury of the venous anastomosis between the middle colic vein and the inferior pancreaticoduodenal vein close to the lower border of the pancreas, may prove a potentially life threatening condition. we present this case in order to point out this rare complication of right hemicolectomy. aimed to explore the influence of different surgical diagnosis groups on long term health status and to make comparisons with general population norms. material and methods: qol was measured in all surviving surgical icu patients admitted to a dutch teaching hospital between and . patient-reported data on qol were collected with the euroqol- d + after a mean follow up of (range - ) years. patient characteristics, surgical diagnosis group, length of icu stay and survival were prospectively registered. eq-utility scores (eq-us), eq visual analoge scales (vas) and prevalences of domain-specific health problems were calculated. the effect of surgical diagnosis group on eq-us/eq-vas was assessed by multivariable generalized linear regression analysis. logistic regression was used to explore the influence of surgical diagnosis group on domain specific health problems. long term quality of life of surgical icu patients was compared to an age-and sex-matched general dutch population using the t-test analysis. results: patients survived the icu and were available for follow up. in ( %) patients the health-related qol was measured. for all surgical groups combined, after - years nearly half of all patients still suffered from problems in the dimensions mobility ( %), usual activity ( %), pain ( %) and cognition ( %). compared to the age-and sex matched general dutch population hrqol was worse with a difference of . on the eq utilities score (range - ). oncological surgery patient had the best (eq-us . ) and vascular patients had the worst (eq-us . ) hrqol. trauma (odds ratio between . - . ) and vascular surgery ( . - . ) showed significantly increased prevalences of problems in mobility, self-care, usual activities and cognition. conclusion: more than years after a surgical icu admission, quality of life of this patient population is largely reduced. many patients still suffer from a variety of health problems, including decreased cognitive functioning. treatment advances should be made to reduce the current health deficit of surgical icu survivors compared to the general population. disclosure: no significant relationships. u. sekmen , g. altaca , s. aktas kalayci , g. moray general surgery, baskent university, ankara, turkey, general surgery, baskent university, ankara, turkey, internal medicine and division of gastroenterology, baskent university, ankara, turkey introduction: predicting the prognosis in severe acute pancreatitis is cruciate in order to constitute effective treatment strategies. material and methods: thirteen consecutive patients admitted with the diagnosis of severe acute pancreatitis according to glasgow or ranson criteria were evaulated. we searched the prognostic values of age, gender, etiology of pancreatitis, comorbidity and labarotory values and their affects on complications and length of hospital stay. results: mean age was , years (range: - yrs). etiology was biliary in patients ( after ercp). acute cholecystitis was also present in patients. patients had diabetes mellitus. two patients had percutaneous cholecystestostomy. five patients had ercp at a mean of , days after admission. cholecystectomy was performed in patients, either at the first admission (n: ) or after - weeks. mean wbc, alt, ast, and ldh values on admission and mean highest hscrp levels and mean lowest serum calcium (ca) levels in the first hours were /mm , u/l, u/l, u/l, and mg/l and mg/dl, respectively. pancreatic necrosis ( , %) was diagnosed by computerised tomography in patients ( / in diabetics, / in nondiabetics); a total of patients ( %) had systemic complications. mean ldh ( u/l vs u/l) and lipase levels ( u/l vs u/l) were higher in patients who developed necrosis, though not statistically significant. other parameters were similar in patients with or without necrosis. two patients who had pancreatitis due to ercp underwent pancreatic necrosectomy. median hospital stay was days (range: - days). all patients survived. mean highest hscrp and lowest ca levels in the first hours correlated significantly with the hospital stay (r: . p: . for hscrp, and r: - . p: . for ca). conclusion: although we have a limited number of patients, we may conclude that high levels of ldh, lipase, hscrp and low levels of ca can be used as predictive factors for severe pancreatitis. pancreatitis seen after ercp and in diabetic patients tend to be more severe. abdomen. abdominal imaging reveals persistent bleeding and multiple bone lesions compatible with bone hemangioma with low blood platelets count -kasabach-meritt syndrome. patient is transferred to a central hospital for arterial embolization of the right hepatic artery that is not effective. the authors describe surgical control of the bleeding without liver resection. second look surgery was undertaken with removal of hepatic packing and pringle's manoeuvre with temporary control of the haemorrhage with haemostasis and ligation of the right hepatic artery. it was needed several surgery's more with additional packing, haemostatic mesh and haemostatic products in order to control the bleeding. the patient was proposed for liver transplant during the process but was not accepted. introduction: management of splenic injury has evolved over the past years. nonoperative management has gained currency, first in children and after in adults. material and methods: we present a case of a years-old man who falled for m, haemodinamically stable, presenting pain on the left part of thorax and upper abdomen. results: the patient fall for m hours before the arrive in our er; he was haemodinamically stable (bp= / mmhg, av= bpm) and presented pain on the left thorax and left hypocondrium. laboratory showed , g/dl haemoglobin. radiologic test: laterally th left rib fracture. ct scan revealed iv grade spleen injury and perisplenic hemoperitoneum. we choosed non-operative managementafter days ct scan showed reduced dimensions of dilacerated spleen injury and no hemoperitoneum. the patient status was stable during the days hospitalisation. imagistic control after month: homogenous spleen structure. conclusion: the haemodinamic status of the patient is the most reliable criteria for non-operative management, not ct aspect of the injury. years old) submitted to upper partial splenectomy for blunt trauma. residual spleen after surgery was / and / respectively. ceus was preceded by standard b-mode us with color flow mapping in all cases; videoclips of each exam were stored for forensic medicine issue too. mean time for ceus exam was - minutes. results: ceus allowed to recognize regular perfusion of the residual spleen in both patients. conspicuity of ceus imaging was high and impressive. homogeneous complete distribution of the contrast medium in the parenchyma was observed on day in both pts. ceus follow-up on day and did not add any supplementary information. pts were discharged on day and day respectively, without indications for vaccinations or antibiotic prophylaxis. conclusion: ceus is an effective method for assessing perfusion of the residual spleen after partial splenectomy. ceus can be performed bedside by the surgeon in the early po period or on an outpatient basis. imaging interpretation is immediate and distribution of the contrast medium assure about viability of the splenic tissue. ceus imaging allowed us to omit prophylactic vaccinations. it is the first description of the use of ceus in this particular setting. introduction: injuries to the abdominal visceral vessels are uncommon but devastating entities that incur extremely high rates of mortality.the rarity of these injuries prevents many trauma centers and trauma surgeons from developing a significant knowledgement learning curve. the authors describe a case with abdominal visceral vascular abdominal blunt trauma, presented with laceration in the confluence of inferior mesenteric vein and splenic vein, laceration of the hepatic artery associated with hepatic hematoma, periduodenal and peripancreatic hematoma. the routine principles of vascular surgery were applied to the management of these visceral blood vessels injuries :adequate exposure, proximal and distal control, dé bridement of the vessel wall,meticulous arteriorraphy and venorraphy with fine monofilament vascular sutures and early instituition of damage control resulting a successfull repair. material and methods: the authors made a review of several large series in the literature wich are also consistent with a low incidence of visceral vessel injuries. vascular trauma is complex and ideally is carried out by experts in a multidisciplinary environment a broad spectrum of surgical specialities are involved in the ressuscitative phase of trauma care including general, trauma, thoracic and vascular surgery . despite a relatively low incidence of vascular trauma in portugal, the results are satisfactory because of active and early management by surgeons on call, weather with vascular training or not, treating all kinds of vascular surgical emergencies. a trauma and emergency surgical speciality is a challenge. results: little information describing the first repair or ligation of any visceral vessel injuries can be found in the literature. visceral vascular injuries carry a significant mortality rate. vascular injury poses a small but significant challenge in portugal trauma care. opportunities such as better practise guidelines and minimum standars will allow surgeons to improve delivery of quality care to the next generation of vascular trauma victims. training in the management of vascular trauma surgery with integration of vascular and general surgeryin trauma care should optimize outcomes. conclusion: from reviews of large series dealing with the management of abdominal vascular injuries, the incidence can be estimated to be between . % to . %of all vascular injuries. few data are available describing the mortality rate for patients with portal veins injuries. te author's vision is that all vascular and general surgery trainees would eventually undertake the definitive surgical trauma care course and improve outcomes and reduce mortality. introduction: high rates of intra-abdominal pressure, has been proved to increased mortality, especially in multi-trauma patients followed laparotomy. multiple organ failure syndrome (mofs), derived by intra-abdominal hypertension, has been called abdominal compartment syndrome (acs), the epidemiology and the characteristics of which, have not been thoroughly determined. introduction: intercostal pulmonary hernias are rare and mostly resulting from complications related to the chest trauma.the authors report a case of traumatic intercostal pulmonary hernia in a -yearold man. he was admitted to the hospital as a traumatic patient after a motor-cycle accident . material and methods: beside multiple polytraumatic injuries the patient had a blunt injury to the left chest.physical examination revealed a bulge on palpation of the left chest wall.computed tomography (ct) scan of the chest revealed the protrusion of lung tissue outside the intercostal space.size of hernia, incarceration and respiratory insufficiency mandate immediate surgical intervention.postoperative course was uneventful, and there has been no sign of recurrence of hernia. results: post -traumatic lung herniation through a defect in chest wall is an uncommon injury .various methods of tratement and repair have been described, including both purely thoracoscopic to full open techniques.the authors repaired a case using a minithoracotomy. conclusion: lung hernia is an uncommon entity defined as the protrusion of pulmonary tissue and pleural membranes through defects of the thoracic wall.chest trauma is the most common cause.timely surgical intervention is critical to favorable patient outcomes.effective management, surgical approaches and repair of thoracic injuries are discussed and the available literature. of the hernia from the outside, dé bridement and closure layer-bylayer with maxon- was performed. the postoperative course was uneventful. conclusion: a tawh after blunt trauma is a rare entity. the reported incidence of acute hernia ranges from ,%- , % . in our case the tawh was already diagnosed in the trauma room. mahajna et al. reported the case of herniation of the right colon with vessel strangulation, which wasn't seen in the primary survey. a right hemicolectomy had to be performed on the nd posttraumatic day. in our case we decided intraoperatively to perform a primary reconstruction of the abdominal wall without mesh repair. the potential advantage of a mesh implantation lies in the augmentation of the abdominal wall, thereby potentially lowering the risk of incisional hernia. however, the benefits of such augmentation should be cautiously weighed against the risk of foreign body contamination when resecting bowel during the same operation. introduction: impalement is an uncommon and spectacular injury, which combines aspects of both blunt and penetrating trauma. impalement injuries from falls are rarely seen, because most of the patients die at the scene of injury. we present an unusual case in which a patient survived a perineal impalement after a fall.with reference to our latest case and discuss the initial management and the operative treatment of this rare injury according to a literature review. material and methods: a young man was working on a construction site when he suddenly lost his footing and fell m off a scaffold. he orientated such that he landed in a sitting position on a vertical aluminium u-tube, which penetrated his perineal region and stucked. upon arrival at the emergency room he was in stable condition, intubated. after the initial treatment and diagnosis according to atls a ct of the abdomen was performed; it showed a penetrating tube perianal left, from caudal into the cavity of the pelvis, the point of the tube stucked in the sacrum -in the hole of neuroforamina s . there was no intraabdominal or laceration. the patient was taken to the operating room in stable condition. the laparotomy was performed. there was no laceration detected, explorating the praesacral cavity brought out a profuse bleeding of the main pelvic vein. after the active bleeding was stopped the tube was removed from the outside. after lavage and positioning of drains, a protective loopileostoma was placed to avoid further contamination. the perineal wound was carefully debrided, drains were inserted and the wound was not completely closed by adapting stitches. a wash-out of the colon was performed, he received antibiotics and the perineal wound was rinsed daily. he was dismissed days post-trauma. results: impalement injuries result when a solid object pierces a body cavity or extremity. the object often remains fixed within the body. this case report showed a positive outcome. impalement injuries are impressive but also rare, so it is important to show an algorithm in management of such injuries. the object should be in situ during transport. in large or immoveable objects, the impaling device should be cut just above the skin. the management of the injuries depend on the particular body region of penetrating. perineal impalement often appear quite complex. these injuries may need the assistance of gynecology and urology surgery praesacral drainage and distal rectal washout is recommended. wound care is essential in the care of impalement injuries. the skin should generally left open. even uncomplicated wounds have to be treated with antibiotics. conclusion: impalement injuries are rare and treating is a challenge for the surgeon. the degree of the injury determines the functional result. strict adherence to the transportation and management principles outlined in this paper are necessary to decrease morbidity and mortility disclosure: no significant relationships. introduction: the insertion of foreign objects into the anus and rectum is a well-known phenomenon. rectal foreign bodies can present a difficult diagnostic and management dilemma. . a foreign body may be inserted by a doctor for diagnosis or treatment like rectal thermometer, enema tubes or anal packs, by the patient for self eroticism or by a third party as a result of assault or sexual activity, but the most common cause for insertion of a foreign body is sexual stimulation. , , . anorectal foreign bodies are more common in men than in women . they can be caused by a wide variety of objects, lead to variable degrees of local trauma to the surrounding tissues, rectal bleeding and can be associated with perforation or delayed injury. material and methods: in this study, in the ten years from to , we used the medical records of patients with foreign bodies in the rectum have been diagnosed and treated,at izmir teaching and research hospital,izmir. results: all patients were men.they ranged in age from to (mean age ).two of these patients had impulse body spray, two patients had bottle, one patient had eggplant,one patient had brush and one patient had wishbone (after oral ingestion) in the rectum. five objects were removal transanally extracted by anal dilatation under general anesthesia.two patients required laparotomy.one patient of these the object was high lying in the rectosigmoid and performed laparotomy.the object was removal transanally extracted by abdominal manuplation.one patient had a intraperitoneal rectosigmoidal perforation.the perforation was treated by primer suture, proximal colostomy and appropriate antibiotic therapy. routine rectosigmoidoscopic examination is performed after removal.one patient had perforation of the rectosigmoid and had lacerations of the mucosa. no patient had a mortality. conclusion: foreign bodies in rectum should be managed in a wellorganized manner. the diagnosis is confirmed by means of plain abdominal radiographs and rectal examination. manual extraction without anaesthesia is usually only possible for very low lying objects. patients with high lying foreign bodies generally require general anaesthesia to achieve complete relaxation of the anal sphincters to facilitate extraction.open surgery should be reserved only for those patients with perforation, peritonitis and impaction of the foreign body. results: definitive pathological examination confirmed the diagnosis of pancreatic pseudocyst. the patient postoperative outcome was unremarkable and was discharged from the hospital at the seventh postoperative day. conclusion: retroperitoneal and ''well protected'' location implies that a high energy traumatism is needed to injury the pancreas. the fact that in this case a non-classical injury mechanism has occurred, makes the diagnosis more difficult to reach. pancreatic pseudocyst is the most frequent complications in this type of traumatisms. effective treatment of fracture-dislocations of the olecranon requires a stable trochlear notch uncomplicated mason type-ii and iii fractures of the radial head and neck in adults. a long-term follow-up study surgical treatment of intra-articular fractures of the distal part of the humerus. functional outcome after twelve to thirty years disclosure: one or more of the authors received funding from the small bone innovations (dr) fractures of the neck of the talus. long-term evaluation of seventy-one cases tuberosity malposition and migration: reasons for poor outcome after hemiarthroplasty for displaced fractures of the proximal humerus tuberosity osteosynthesis and hemiarthroplasty for four part fractures of the proximal humerus abdominal -mdct for suspected appendicitis: the use of oral and iv contrast material versus iv contrast material only socioeconomic factors, medicolegal issues, and trauma patient transfer trends: is there a connection? are patients being transferred to level-i trauma centers for reasons other than medical necessity? the delaware trauma system: impact of level iii trauma centers improving outcomes in a regional trauma system: impact of a level iii trauma center jupiter -metaanalysis: nondisplaced scaphoid fractures. operative vs. nonoperative management(update to nov dodds -minimally invasive management of scaphoid nonunions chess -a biomechanical analysis of intrascaphoid compression using the herbert scaphoid screw system. an vitro cadaveric study is the mortality rate for septic shock really decreasing? systemic inflammation after trauma in vivo effects of a synthetic -kilodalton macrophage-activating lipopeptide of mycoplasma fermentans after pulmonary application alveolar macrophages from septic mice promote polymorphonuclear leukocyte transendothelial migration via an endothelial cell src kinase/nadph oxidase pathway macrophage inflammatory protein- alpha mediates lung leukocyte recruitment, lung capillary leak, and early mortality in murine endotoxemia fracture-dislocation of the hip joint. the nature of the traumatic lesion, treatment, late complications, and end results cervical spine trauma in the pediatric patient spinal injuries in children and adolescents long-term clinical and radiographic outcomes after open reduction for missed monteggia fracture-dislocations in children elastic stable intramedullary nailing as alternative therapy for pediatric monteggia fractures unstable diaphyseal fractures of both bones of the forearm in children: plate fixation versus intramedullary nailing delayed radial paralysis after monteggia fracture-a case report, unfallchirurg a simple modified arthroscopic procedure for fixation of displaced tibial eminence fractures a fracture of the intercondylar eminence of the tibia treated by arthroscopic fixation an analysis of different types of surgical fixation for avulsion fractures of the anterior tibial spine modified arthroscopic suture fixation of a displaced tibial eminence fracture tibial spine fractures in children fractures of the tibial spine in children seventeen-year follow-up of a reattachment of a nonunited anterior tibial spine avulsion fracture arthroscopic fixation of displaced tibial eminence fractures: a new growth plate-sparing method the mechanism of clavicular fracture: a clinical and biomechanical analysis functional outcome following clavicle fractures in polytrauma patients evidence-based orthopaedic trauma working group. treatment of midshaft clavicle farctures: systemic review of fracturese: on behalf of the evidence-based orthopaedic working group harnroongroj t, vanadurongwan v. biomechanical aspects of plating osteosynthesis of transverse clavicular fracture with and without inferior cortical defect autologous bone versus calcium-phosphate ceramics in treatment of experimental bone defects iliac crest autogenous bone grafting: donor site complications clinical results of harvesting autogenous cancellous graft from the ipsilateral proximal tibia for use in foot and ankle surgery healing and graft-site morbidity rates for midshaft clavicle nonunions treated with open reduction and internal fixation augmented with iliac crest aspiration literature review of current techniques for the insertion of distal screws into intramedullary locking nails a new fluoroscopy-free navigation device for distal interlocking screw placement disclosure: we all are surgeons at gregorio marañ ó n hospital, madrid. dr. turegano is the chief of the emergency surgery department. references: -nandapalan and al factors related to mortality in inferior vena cava injuries: a year experience disclosure: we certify that all our affiliations with or financial involvement (employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending) with any organization or entity with a financial interest. references: . blaisdell, f.w. the pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review. references: robinson cm evaluation of consecutive patients with the extended data set of the standardised audit for hip fractures in meniscus allograft transplantation: a current concepts review homologous meniscus transplantation: experimental and clinical results cell survival after transplantation of fresch meniscal allografts: dna probe analysis in a goat model freezing causes changes in the meniscus collagen net: a new ultrastructural meniscus disarray scale meniscus replacement with bone anchors: a surgical technique meniscal allograft transplantation: long-term clinical results with radiological and magnetic resonance imaging correlations clinical evaluation of arthroscopic-assisted allograft meniscal transplantation knee joint biomechanics following arthroscopic partial meniscectomy an evaluation of a shockroom located ct scanner: a randomized study of early assessment by ct scanning in trauma patients in the bi-located trauma center north-west netherlands (react trial) overlooked spine injuries associated with lumbar transverse process fractures frequency and importance of transverse process fractures in the lumbar vertebrae at helical abdominal ct in patients with trauma traumatic lumbosacral dislocation: report of two cases references: prevalence of suicide ideation and suicide attempts in nine countries uptake and intracellular distribution of various metal ions in human monocyte-derived dendritic cells detected by newport green dcf diacetate ester biomechanical analysis of bicondylar tibial plateau fixation:how does lateral locking plate fixation compare to dual plate fixation? operative treatment of tibial plateau fractures.:five to years follow-up results treatment of high energy tibial plateau fractures with half ring external fixation combined with minimal internal fixation. nan fang yi ke da xue xue bao disclosure: no significant relationships de smet l, debeer p, degreef i. fixation of a periprosthetic humeral fracture with ccg-cable system results of non-operative and operative treatment of humeral shaft fractures. a series of cases complex distal humeral fractures: internal fixation with a principle-based parallel-plate technique. surgical technique the anteromedial facet of the coronoid process of the ulna ring d, doornberg jn. fracture of the anteromedial facet of the coronoid process. surgical technique broberg ma, morrey bf. results of treatment of fracture-dislocations of the elbow disclosure: one or more of the authors received funding from the small bone innovations (dr perilunate and axial carpal dislocations and fracture dislocations evaluation of the spanish versió n of the dash and carpal tú nel síndrome health-related quality-of-life instruments: cross-cultural adaptation process and reliability philadelphia: w. b. saunders company; . p. - . . meyer pr. complications of treatment of fractures and dislocations of the dorsolumbar spine no significant relationships. references: . general medical council. consent: patients and doctors making decisions together is informed consent effective in trauma patients is informed consent in trauma a lost cause? a prospective evaluation of acutely injured patients' ability to give consent factors affecting the quality of informed consent the impact of objective assessment and constructive feedback on improvement of labrascopic performance in the operating room united arab emirates, medical education at the main trauma hospital. results: patients were studied ( . % males) having a mean age of . years. % of patients were from the indian subcontinent and % were uae nationals. % of patients presented immediately following injury. ambulances brought only % of the patients. % of trauma took place in the street or highway, % in work places and % at home. the mechanisms of injury were road traffic collision in % and falls in %. % of injuries were to extremities, % to head, face and neck, and % to chest. the mean iss was . . the mean (range) hospital stay was . ( - ) days; ( %) patients needed icu admission of whom ( . %) died. the mean icu stay was . days (range - ). overall mortality was ( . %). conclusion: road traffic collisions and falls are the main cause of trauma admissions in al ain city. extremities, head, neck, face and chest are the main body regions sustaining injuries. disclosure: no significant relationships hip fractures in the elderly: a world-wide projection disclosure: no significant relationships. references: d. ring et al.: predictors of acute carpal tunnel syndrome associated with fracture of the distal radius pm non-surgical treatment of the distal radial fracture. is there an advantage in immobilization in degrees dorsiflexion compared to immobilization in a neutral position? janzing , l. horta emergency department, viecuir medical centre the netherlands introduction: according to the literature immobilization of collespoints where radiological (dorsal dislocation, radial inclination), functional, the necessity for surgical intervention a comparison of methods of plastic cast fixation in treatment of loco classico radius fracture. a prospective, randomized study, unfallchirurg pm buzzsaw injuries: mechanisms of damages and predisposing factors r. ziegler , w. knopp woodworking injuries: an epidemiologic survey of injuries sustained using woodworking machinery and hand tools references: beasley ls, vidal af. traumatic patellar dislocation in children and adolescents: treatment update and literature review long-term functional outcome after lateral patellar retinacular release in adolescents: an observational cohort study with minimum -year follow-up mri of traumatic patellar dislocation in children reconstruction of the medial patellofemoral ligament for the treatment of habitual or recurrent dislocation of the patella in children injuries to the inferior pole of the patella in children disclosure: no significant relationships pm results of electromagnetic fields in healing progression of delayed union in the lower extremities the effect of low-frequency electrical fields on osteogenesis references: complex trauma of the limbs with vascular injuries-olivera lupescu, mihail nagea carcinoid tumour of the appendix:an analysis of consecutive emergency appendectomies tuberculous peritonitis of the wet ascitic type: clinical features and diagnostic value of image-guided peritoneal biopsy. dig. liver dis at perforated ulcer treatment, suture of the place of prefotation was used at ( , %) people, billroth ii stomach resection at six ( , %), suture of the place of prefotation with psv at three ( , %), and billroth i stomach resection at one ( , %) patient. postoperative complications were noticed at ( , %) people. we had postoperative mortality at four ( , %) patients. recidive ulcer was registred at ( , %) patients who were surgically treated for perfored ulcer before. conclusion: ulcer perforation is an acute complication of the ulcer disease that appears most frequently after bleeding and which usually requires surgical treatment. references: . behçet disease complicated by a perforated ileal ulcer presenting as an acute abdominal emergency gastro-duodenal ulcers with perforation caused by short-term acetylsalicylic acid ingestion: case report culafiÄ à d, matejiÄ à o perforated gastroduodenal stress ulcer melinte c, dragomir c pubmed -indexed for medline] spontaneous rupture of the spleen as immediate complication in autologous transplantation for primary systemic amyloidosis delayed splenic rupture as a cause of haemoperitoneum in a capd patient with amyloidosis boluda garcà a f, calvo català ¡ j, campos fernà ¡ndez c, parra rà denas jv, gonzà ¡lez cruz mi laparoscopic cholecystectomy for acute cholecystitis disclosure: no significant relationships. references: . pokorný j. et al. urgentní medicína, . st edition: praha, galé n . stetina et al. medicína katastrof a hromadný ch neštÄ >stí pt perforation of oesophagojejunal anastomosis by venous anatomy of the right colon: precise structure of the major veins and gastrocolic trunk in cadavers pt validation of fournier's gangrene severity index score (fgsis) general surgery dobrzanska l, newell r. readmissions: a primary care examination of reasons for readmissions of older people and possible readmission risk factors pt spontaneous rupture of giant cavernous hemangioma of the liver in a patient with systemic hemangiomatosys and kasabach-meritt syndrome. an interactive and multidiscipline case b general surgery general surgery portugal introduction: hemangiomas are frequent benign tumors of the liver nonoperative management of blunt splenic and liver injury is ct grading of splenic injury useful in the nonsurgical management of blunt trauma? management of blunt splenic trauma: ct contrast blush predicts failure of nonoperative management references: . ochsner mg. factors of failure for nonoperative management of splenic injuries associated injuries in blunt solid organ trauma: implications for missed injury in nonoperative management introduction: aim. to establish the diagnostics and management trauma, ( , %) -head trauma, ( . %) -limbs injuries, and ( %) -severe shock. in cases the splenic injury was initially manifested - ( . %), and in ( , %) cases the clinical signs developed later (p < . ) practice management guidelines for the evaluation of blunt abdominal trauma: the east practice management guidelines work group diagnostic accuracy of surgeonperformed focused abdominal sonography (fast) in blunt paediatric trauma surgeon-performed bedside organ assessment with sonography after trauma (boast): a pilot study from the wta multicenter group disclosure: no significant relationships. pt incidence of abdominal compartment syndrome in patients with multiple injuries. a single institution experience koulas , o. mousafiri hatzikosta general hospital, ioannina, greece, intensive care unit, g. hatzikosta general hospital intensive care unit, g hatzikosta general hospital delayed presentation of traumatic parasternal lung hernia management of retained colorectal foreign bodies:predictors of operative intervention disclosure: no significant relationships. treatment. disclosure: no significant relationships. references: .demetriades d, velmahos g. technology-driven triage of abdominal trauma: the emerging era of nonoperative management management of high grade renal trauma: -year experience at a pediatric level i trauma center pt blunt abdominal trauma. year experience in our department greece ( , %), without spinal fractures. resection/anastomosis was permorbidity. in first group, there were deaths ( , %), cases due to intestinal injuries. the second group (without seatbelt sign) had deaths ( , %), none due to intestinal injuries but related with multiple thoracic and cranial lesions. conclusion: in this study we found a consistent evidence that ''seatbelt sign small-bowel and mesentery injuries in blunt trauma mortality reduction with air bag and seat belt use in head-on passenger car collisions disclosure: no significant relationships. references: management strategies in isolated pancreatic trauma disclosure: no significant relationships. references: enterocutaneous fistula complicating trauma laparotomy: a major resource burden the american surgeon staged management of giant abdominal wall defects injured patients -documentation of black spots j. heinzmann , u. culemann , t. pohlemann universitä tsklinik des saarlandes, klinik fü r unfall-, hand-und wiederherstellungschirurgie, homburg, saar, germany, trauma-, hand and reconstructive surgery, university of saarland, homburg, saar, germany, klinik fü r unfall-, hand-und wiederherstellungschirurgie, universitä tsklinikum des saarlandes, homburg, saar, germanyintroduction: nonunions of the tibia represent a complex problem, particularly if they occur at the distal third of the tibia. the aim of the study was to evaluate a standardized treatment concept to manage different types of nonunions of the tibia with regard to their location within the tibia. material and methods: prospective, non randomised study ( / - / ); nonunions of the diaphyseal and metaphyseal tibia (ao type / ); standardized treatment concept: diaphysis: reamed intramedullary nailing; dia-metaphyseal junction and pilon: lcp with a minimal invasive approach or an open approach plus bone grafting from the iliac crest; infected nonunions: external fixator. analysis parameters: demographic data, fracture type (ao classification), primary surgery, healing process, time to union (radiographic), complications. results: forty-eight patients ( m, f; mean age , y) with hypertrophic (primary surgery: x nail, x external fixator) and atrophic nonunions of the tibia (primary surgery: x nail, x plate, x screws and x external fixator) were included in the study. fifteen tibial nonunions had been primary treated in our department, patients had been admitted from other hospitals. seventy-three% of all nonunions were located at the distal third of the tibia ( % at the diaphyseal-metaphyseal junction, ao-classification type ; % at the pilon, ao-classification type ). seventy-five% of the dia-metaphyseal fractures and % of the pilon fractures were primary treated with an intramedullary nail. the mean time between injury and nonunion-surgery was , ( - ) months. follow up: / patients ( %) for an average time period of , months; union-rate: / (hypertrophic nonunions / ; atrophic nonunions / : re-nonunions each). complications: death by lung embolism, re-nonunion (united after second surgery), implant (plate) loosening with the need of reosteosynthesis, x varus malalignment, x valgus malalignment, x peroneal nerve lesion. conclusion: especially the distal third of the tibia still represents a high risk area for nonunions. impaired perfusion, thin soft tissue coverage, as well as the rising number of nailing even of distal tibial fractures are some of the causes. we think that the herein introduced treatment concept is effective to manage tibial nonunions. thus, the union-rate in this study population was % , . an adequate primary osteosynthesis as well as the prevention of extensive soft tissue damage during surgery are mandatory to improve the outcome of tibial fractures. besides, new therapy options as e.g. the application of growth factors and ultrasound have to be considered also for the treatment of tibial nonunions. g. heinrichs , a. p. schulz , e. wilde , r. oheim , c. jü rgens trauma&orthopedics, university lü beck, lü beck, germany, trauma&orthopaedics, university lü beck, lü beck, germany, trauma + orthopaedics, university lü beck, lü beck, germany, trauma&orthopedics, university lü beck, hamburg, germanyintroduction: high energy tibial head fractures with bicondylar involvement have a much poorer outcome compared to the other forms of tibial head fracture. soft tissues are almost allways compromised. bilateral plating carries the risk of soft tissue and bone infections. due to loss of reduction, steps or gaps might remain in the joint surfaces. aim of this study was to evaluate the clinical and radiological outcome of schatzker , and six type fractures treated with locked osteosynthesis plating. material and methods: between january und january we treated patients suffering from a tibial head fracture. in cases osteosynthesis was performed with the use of an angular stable implant, this group forms the study population. indication for locked screw plates were bicondylar fractures treated unilateral to avoid bilateral approach with double-plate osteosynthesis and tibial head fractures with a shaft involvement (schatzker ). follow-up was performed after an average of . months after surgery. we treated male and female patients with an average of . years of age ( to years). there were no patients with open fractures or primary nerve injury included in this study. operative treatment was performed after an average of . days after trauma. we used an angular stable plate fixator made from pure titanium (tifixÒ, litos, hamburg/ germany). the plate is consisting of the softer titanium grade ; the screws are made from harder titanium grade .results: there was one case of a postoperative peroneal nerve lesion with spontaneous regression after two weeks. no postoperative wound necrosis or infection occured. all patients showed bony consolidation after a mean of . weeks as judged by radiographs. additional autologous bone transplantation was not necessary. we did not observe any secondary loss of reduction or loosening of the internal plate fixator when comparing direct postoperative radiographs to those at follow up. rom of the knee did not show any restriction compared to the opposite side in patients. cases showed mild and cases a remarkable restriction of rom compared to the not injured side.applying the rasmussen score, cases achieved a good and very good result. patients had to be judged as moderate and as poor conclusion: unilateral plate fixation for the treatment of bicondylar tibial head fractures seems to offer advantages in particular concerning infection rate and implant failure in the treatment of tibial head fractures. results: the adjacent level th-l fracture was found in . % ( / patients) in kyphoplasty group and in % ( / patients) in vertebroplasty group. we did not found any serious complication but established postoperative bmd loss. we did not found any intradiscal cement leakage in cases with adjacent level fractures. intraoperative correction of kyphosis was better achieved in kyphoplasty group; pain relief was similar in both groups.conclusion: natural process of further bone loss seems to be the most influent factor for future compression fractures in elderly patients. trauma patients represent a challenge in terms of obtaining informed consent as they are often in significant pain and maybe under the influence of strong medication at the time of the consent process. we designed a prospective, randomised un-blinded control study to test the hypothesis that there would be no difference in the ability of trauma patients to recall details of the consent process whether the patients were given verbal compared with verbal and written information.material and methods: a consecutive cohort of trauma patients presenting to a major teaching hospital were recruited and randomised into two groups. group a received structured verbal information only. group b received structured verbal information and written information about the proposed procedure. all patients were interviewed within the first post operative week (mean . days) and scored on their ability to recall key facts given in the original consent interview. results were analysed using the mann-whitney u test.results: patients have been recruited. information recall was significantly improved in the group receiving written information (mean questionnaire score % vs % for verbal information alone, p= . ). patient satisfaction with the consent process was also significantly improved in the group receiving written and verbal information, with . % of patients reporting they understood the risks of surgery when they signed the consent form, compared to . % who received verbal information alone (p= . ).conclusion: written information improves patient recall of the consent process. it is a simple, cost-effective intervention with high patient acceptability. introduction: survivorship of second hip fracture patients is worse than initial hip fracture patients. however, previous studies included in-hospital mortality. the actual survivorship of initial hip fracture patients with subsequent second hip or major long bone of extremity or vertebral body fracture by exclusion of in-hospital mortality patients have not been studied. we aim to compare the actual survival of initial hip fracture patients with and without second hip or subsequent major fracture. in addition, risk factors, mortality causes, and hazards ratio of each fracture groups were studied. material and methods: in - , after exclusion of in-hospital mortality patients, initial hip fracture patients were reviewed and divided into four groups. group i, ii, iii, and iv were initial hip fracture patients with second hip, subsequent major long bone of extremity, vertebral body fracture, and without any subsequent fractures, respectively. we set group i, ii, and iii as study groups comparing the data with group iv (control group). age, gender, mobility-status, co-morbidity, causes of death, and survival years after hospitalization of last fracture treatment of each group were recorded. actual survival rate and risk factors difference between initial hip fracture with and without subsequent fracture were analyzed by chi-square test. hazards ratio differences among the groups were analyzed by cox regression models.results: there were ( . %), ( . %), ( . %), and ( . %) subjects in group i, ii, iii, and iv respectively. at one-year and one-to-five year mortality of group i were . % and . %, group ii were . % and . %, group iii were . % and . %, and group iv were . % and . % respectively. statistical analysis by using chi square test of one-year mortality and one-to-five year mortality rate showed no significant difference among four groups (p > . ). but from cox regression analysis, second hip fracture produced significant hazards ratio as . (p = . ). the actual survivorship of initial hip fracture patients with second hip or other subsequent fracture were not different from patients who have only one hip fracture. however, special care should be focused in patients with second hip fracture which produced significantly highest hazards ratio for mortality.reduction or redislocation after one week of treatment. due to the lack of sufficient patient data a statistical analysis was not carried out. it was obvious that the dorsal dislocation after reduction was worse in the dorsiflexion group. there was no obvious difference in radial inclination or functional outcome between the two groups. conclusion: mainly the dorsal inclination was worse in the degrees dorsiflexion group. a possible explanation for these results is the technique used when modeling the plaster cast. in our hands immobilization in dorsiflexion yielded poorer results then immobilization in a neutral position. due to the poor results the study was terminated prematurely. the traumatic patellar luxation in adult patients is operatively treated with medial reefing and lateral release. the value for the treatment of adolescents is still discussed controversially in literature. the aim of the present study was to evaluate the efficacy of the minimal-invasive treatment of traumatic patellar luxation in adolescents. , that was treated with acute angular shortening using a monolateral ao fixator followed by gradual correction using the taylor spatial frame (tsf). the conversion in the tsf was achieved in exchanging only two half-pins. results: the deformity was anatomically corrected without any soft tissue complications. the fixator was worn for weeks under full weight bearing while the actual correction took only days. we did not see any typical external fixator complications like pin trac infection. conclusion: acute angular shortening can lead to direct soft tissue closure without any additional plastic surgery. the accuracy the the fixator allows the gradual anatomical reduction of the fracture and simplifies the correction of the mostly multiplanar deformities. when the surgeon is familiar with the tsf even a primary treatment of such fractures could be recommended. the image control (plain x-rays, ct) revealed and definitively determined whether a two-part or three part triplane fracture in the distal tibial physis were present, the amount of the displacement, and the co-existed fracture of the fibula. the principal goal must be the anatomical reduction of the fracture initially closed and in failure opened. an open reduction and fixation with steinmann via anterior approach followed. a long-leg cast worn for initial weeks, followed by a short-leg cast for weeks. results: at a minimum of fourteen months of clinical follow -up all patients lacked complaints and had full range of motion in ankle.conclusion: these injuries occur in the adolescent age group generally slightly younger than the child with a tillaux fracture, needed good image control (ct) and must reduced anatomically and fixed. disclosure: no significant relationships. it is necessary in - % of patients. to provide dynamisation using conventional methods, it is necessary to perform one additional surgery. in this presentation it is shown one new method of selfdynamisation. material and methods: it is presented one new minimally invasive method for closed fracture reduction and one extramedullary selfdynamisable internal fixator. there is no contact between bone and internal fixator in fracture area. it has been widely investigated biomechanicaly. in clinical use it has been applied to , patients in treatment of femoral fractures. the age of patients was from to years. this internal fixator is applied by two small incisions. reduction is achieved using standard traction table or using special reduction device. this reduction device provides possibility of reduction with minimal using of fluoroscopy or even, after more experience without using of any imaging technique as fluoroscopy, ultrasound or computer navigation. results: received clinical results are promising, as it has been shown early callus formation and radiological union within the - months. it has been allowed to patients early full weight bearing. during the treatment it has been confirmed working of self-dynamisation concept (in % of patients), which probably all together with d configuration resulted in unexpectedly quick fracture healing. follow up was months ( - the severity of injury was measured by the injury severity score (iss). the outcomes for categorical variables were tested using v test and a significance level at p < . was maintained. delayed complications were defined as any complication directly attributable to the splenic injury that occurred more than hours after injury. the following data was retained: age, sex, mechanism of injury, iss, number of icu days, overall length of stay, number of blood units transfused, day of operation and discharge status. results: our study found , % incidence of delayed complications after nom. these complications include delayed hemorrhage ( cases), splenic artery pseudoaneurysm ( ) and splenic abscess ( case). the need for operation due to ongoing bleeding was retained in following situations: more than u of blood to maintain a hb higher than g/dl, systolic pressure to less than mm hg despite resuscitation and evidence of peritoneal signs. of the patients failing nom, % failed between days and and % in the first week. in all cases a splenectomy is performed with no mortality rate. the results of this study indicate independent risk factors of failure of nom: a high ct grade of splenic injury (grade iii and above) and a transfusion with more than u of blood. results: results : out of the patients suffering of liver injuries patients had grade , and grade liver injuries and were treated conservatively. patients had grade and liver injuries and were operated. patient who was initially managed conservatively was operated due to inability to control the blood loss. out of the patients suffering injuries of the spleen, were grade and grade and were successfully operated and were grade and and were treated conservatively. all patients suffering of injuries of the retroperitoneal space, unilateral kidney injuries and injuries of the hypogastrium were managed conservatively. conclusion: blunt abdominal injuries can be managed successfully and safely by conservative treatment whenever it is allowed by the circumstances. the ct scan is a very sensitive diagnostic scanning, capable of diagnosing intrabdominal haemorrhages retroperitoneal lesions as well as the extent of the organ injury and is a necessary tool for the physician in order to diagnose accurately any abdominal injury. disclosure: no significant relationships. introduction: more and more hepatic injuries are treated non operatively if the hemodinamic's and lesion's stability is confirmed. the count and the scaling of lesions doesn't directly influence surgical indications. we report about cases of blunt trauma with serious hepatic and renal lesions treated successfully with a non operative management material and methods: we treated liver and renal injury associated in a period from to . patients were admitted to tor vergata -roma and hospital universitario clínico san carlos-madrid. data collected were: age, sex, comorbidities, sequence of events, type and number of associated lesions, management, morbidity and mortality. all liver and renal organ's injuries were evaluated by abdominal ct scan with contrast and classified according to ct-based scale results: middle age was ± sd years. patient were male in ( , %) of cases. ct scale of liver lesion was °for ( , %) patient and °for two ( . %) patients. renal lesions were i°category in cases ( , %) and ii°category in patient. no ureteral or major vessels rupture were founded. all patients have been treated non operatively. a ct based follow up of lesions was planned (at admittance, after hours, after a week and after a month). the mean length of hospitalization was ± sd days. during hospitalization, patients were monitored by clinic and labs daily. all patients were dismissed in good conditions and are in in health on a months follow up. at ct follow up, one patient presented an intra-hepatic biloma, that was successfully treated with ct-guided drainage conclusion: this work support the hypothesis that the association of liver and renal lesions in a blunt abdominal trauma, doesn't necessarily influences indications for an explorative laparotomy. if an ureteral rupture is suspected, a more aggressive treatment is necessary, in order to prevent peritonitisintroduction: the aim of this study is to analyze the most frequent mechanisms of injury, the evaluation in the emergency department and the period of increase of the blunt abdominal trauma incidence. material and methods: during the last years ( - ) patients were admitted to our department for blunt abdominal trauma.the most frequent mechanisms of injury were: traffic accidents (automobile crashes and motor vehicle collisions) ( , %) work accidents ( , %) . others (fall from high altitude, beating) ( , %) we analyzed the most frequent injuries observed, the final treatment for these patients and the period of increase of blunt abdominal trauma.results: the peak incidence occurs in persons aged - years. the male/female ratio was : . the most frequent abdominal injuries regarded: spleen ( , %), liver ( , %), large bowel ( , %), small bowel ( %), pancreas ( , %). patients underwent surgical treatment ( , %). the incidence of missed injuries is quite low, one case with pancreatic injury and one with small bowel injury. during summer period a significant increase in blunt abdominal trauma incidence occurs because of the increase of population due to tourism. the initial physical examination, after appropriate primary survey and initial resuscitation with the help of diagnostic studies such as ultrasonography, abdominal ct scan, is essential for the final treatment for these patients, operative or not operative. abdomino-throcal injuries were found in ( %) patients.abdominal organ injuries were found in decreasing frequencies in small bowel( %),liver ( %),large bowel ( %), spleen ( %), major vasculer, stomach and others. thoracal injuries were found in lung and heart in and cases.one organ injury was found in ( %) patients,mostly small bowel,and these group had a good haemodynamic status.thirty-two( %) patients had two organ injuries which of them associated with lung injury.three, and < organ injuries were found in , and patients. haemodynamic unstability at presentation,and shock was found in five patients( , and organ injury in , and cases). the overall mortality was found in ( %) patients.mortality from gun injury was % from major vascular injury ,lung,pancreas and large bowel ,lung and large bowel one.mortality from penetrating trauma was % from lung and multipl abdominal organ injury ,heart ,lung,spleen and stomach injury and major vasculer injury from blunt trauma in one ( %) patient. five patients who remain haemodynamically unstable after resuscitation died intraopreoperative period.these group was not received some resuscitation, and they referred to our hospital later than hours of injury. introduction: retroperitoneal location of the pancreas makes the diagnostic of any traumatism to be difficult, especially when this is not suspected. we report on a case of blunt pancreatic trauma with months delayed diagnosis, after injury due to maneuvers in a difficult birth. material and methods: we report on a case of a twenty-nine year-old female who consulted at the emergency department for constant right upper quadrant pain that didn't ease with any analgesic prescribed by the general practitioner. these symptoms started after a birth six months before and loss of kg of weight was associated. after reviewing the previous history of the patient, the birth had been difficult and forceps, suction pad and repeated abdominal pressure maneuvers were needed. abdominal examination showed a painful non-pulsatile mass located at epigastrium and both right and left upper quadrants. abdominal ultrasonography and enhanced ctscan were performed and demonstrated the presence of multicystic x x cm mass located between the stomach, spleen and left kidney. the high density content seemed to be blood. the mass was pushing the stomach anteriorly and no communication between both of them was shown. the splenic vein was pushed superiorly and thinned and plenty collateral circulation was evidenced. the tail and the body of the pancreas were not identified in any of the studies. the first choice diagnosis was posttraumatic complicated (with bleeding) pancreatic pseudocyst. the patient underwent emergency operation and a big cystic pancreatic mass was encountered, with plenty of collateral circulation. intraoperative biopsy confirmed that it was a pseudocyst and therefore, the majority of the cyst was removed and roux-en-y pancreatojejunostomy was performed. cholecistectomy was also done. introduction: unnoticed traumatic injuries produce avoidable morbidity, mortality and a higher medical cost. we present a special case of the reconstruction of a catastrophic abdomen with several intestinal fistulae and giant abdominal wall defect. material and methods: we present the case of a year old woman with blunt thoraco-abdominal trauma secondary to a road traffic accident. several lower left rib fractures, a fast echo with free fluid without solid organ injury and fractures of l and l were seen in the initial assessment. on the third day surgery was required due to septic shock with diffuse peritonitis due to a jejunal laceration and section of the body-tail of the pancreas. simple suture of the jejunal laceration, distal pancreatectomy, and abdominal packing without closure of the abdomen was performed. she developed several intestinal and colonic fistulae. over surgical procedures were performed on her and she was discharged months later with night parenteral nutrition, a closed abdomen by secondary intention and intestinal fistulae. she was readmitted a year later for reconstruction. we performed monoblock resection of the abdominal wall and the fistulized loops, subtotal colectomy and bowel transit reconstruction with three enteroenteric and an ileosigmoid anastomosis, leaving , m of small bowel. abdominal plastia with permacol mesh was also performed. results: surgical time was of minutes and oral tolerance was initiated on the th postoperative day. she was discharged on the th day postop. the only complication was a fever secondary to infection a central venous catheter on the rd day. key: cord- -nycbjqn authors: nan title: op - date: - - journal: intensive care med doi: . /s - - -z sha: doc_id: cord_uid: nycbjqn nan the global results for the cohort were % (ic= - %) for mortality, tracheostomy % (ic= - %), vap incidence of . cases/ days of ventilation and duration of ventilation days ± (ic= - ). in the groups e and y, the measured variables were respectively: apache ii ± (ic= - ) versus ± (ic= - , p= . ); sofa ± (ic= - ) in both groups (p= . ); mortality % (ic= - %) versus % (ic= - %, p= . ); duration of ventilation ± days (ic= - ) versus ± days (ic= - , p= . ); incidence of vap . versus . cases/ days of ventilation (p= . ) and the incidence of tracheostomy % (ic= - %) versus % (ic= - %, p= . ). % of the patients in group e and % of group y had non-surgical cause of admission (p= . ). in the multiple regression model there was no statistically significant impact on mortality of apache ii, diagnosis category (clinical versus surgical) or age, only a tendency for direct relation of vap with this endpoint (p= . ). conclusion. in our otherwise homogeneous population, advanced age was not an independent predictor of mortality or longer duration of ventilation. neither the incidence of vap nor tracheostomy pointed out any statistically significant difference in the patients over years of age comparing to those younger. impact on successful treatment of septic patients - renieris p , gerovasili v , poriazi m , loukas t , markaki v , routsi c , roussos c , nanas s first critical care department, medical school, national and kapodistrian university, evangelismos hospital, athens, greece introduction. microcirculatory impairement in septic patients has long been implicated as a major causative factor of post-rescucitation multiple organ failure. the aim of the study was to investigate the microcirculatory alterations in septic patients with different severity of disease with the non invasive method of near infrared spectroscopy. we studied ( males/ females, age ± ) patients of a general icu devided in severity groups: sirs (n= ), severe sepsis (n= ) and septic shock (n= ). we also studied healthy volunteers. we used the inspectra near infrared spectroscopy device to continuously measure tissue oxygen saturation (sto ) at the thenar muscle before, during, and after a -minute occlusion of the brachial artery via pneumatic cuff. the decrease rate of the sto signal during the occlusion period was used as an index of tissue o consumption rate, and the increase rate of the sto signal after the cuff was released was used as an index of reperfusion to assess endothelial reactivity. tissue oxygen saturation (sto , %) was significantly lower in patients with sirs or severe sepsis when compared to healthy volunteers ( ± vs. ± p= . and ± vs. ± p= . respectively). oxygen consumption rate (sto decrease rate, %/min) was significantly lower in patients with severe sepsis when compared to healthy volunteers or patients with sirs ( . ± . vs. . ± . p< . and . ± . vs. . ± . p= . respectively). patients with septic shock also had a significantly lower oxygen consumption rate when compared to healthy volunteers or patients with sirs (p< . and p= . respectively. reperfusion rate (sto increase rate, %/min) was significantly lower in patients with sirs or severe sepsis when compared to healthy volunteers ( ± vs. ± p< . and ± vs. ± p< . respectively). patients with septic shock had significantly lower reperfusion rate when compared to healthy volunteers (p< . ). conclusion. the microcirculation of septic patients is severely impaired, and this seems to depend upon severity of disease. further studies should evaluate the potential role of near infrared spectroscopy in guiding therapy and in providing prognostic information in this patient population. in the "prevalence of severe sepsis and septic shock in intensive care units in germany" study, a prospective observational cross-sectional study, data from icus in randomly selected hospitals in germany were collected by local one-day visits of trained physicians from sepnet's regional study centers. data was evaluated concerning nutrition modalities. logistic regression analysis was used to identify predictors for death. . in a total of patients with severe sepsis/septic shock, enteral nutrition was applied to . % of patients whereas . % received only parenteral nutrition. both parenteral and enteral nutrition was administered to . %, . % were not fed at all. valid mortality information was available for patients. in-hospital mortality was similar in the patients receiving only parenteral nutrition ( . %) or mixed nutrition ( . %). in the group enteral nutrition only mortality was . %. by multivariate analysis, the apache ii score (or= . , % ci= . - . ), renal dysfunction and parenteral nutrition (or= . , % ci= . - . ) were significant independent predictors for mortality. parenteral nutrition is still the most common way of nutrition in patients with severe sepsis in germany. in contrast, the literature recommends the preferential use of enteral nutrition which is associated with reduced morbidity. however, an impact on mortality could not be identified so far. in this study the risk of death was increased in patients receiving only parenteral or mixed nutrition. despite the higher apache ii score in both groups (median score or . , respectively compared with . in the enteral group, p< . ) our results indicate that parenteral nutrition has an important attributable effect on mortality in septic patients. in total, adult intensive care units (icus) in england, wales and northern ireland participate in the audit. data are collected on every patient in whom an infusion of drotrecogin alfa (activated) is commenced, in three sections: infusion -timing, interruptions and incomplete infusions; infection -site, organisms cultured, and primary pathogen; and adverse events. these data are linked to the case mix programme, the national comparative audit of patient outcome, for case mix and outcomes. at the time of analysis, data were available on patients receiving drotrecogin alfa (activated) in icus. table shows a comparison of the patients in this study with those in prowess and enhance. the median (quartiles) time from icu admission to the start of the infusion was ( - ) hours. twenty-four percent of infusions were interrupted, the most common reasons being insertion, change or removal of lines, cannulas, drains etc ( %), transfer to theatre ( %), and possible bleeding ( %). the median (quartiles) duration of interruption was ( - ) hours. thirty percent of infusions were not completed, the most common reasons being patient deteriorated/died ( %), possible bleeding ( %), and patient improved/left the unit ( %). table shows the adverse events compared with prowess and enhance. the xpress study was a large phase b study designed to assess whether there was a true negative interaction with coadministration of drotrecogin alfa activated (daa) and lowdose heparin. we prospectively planned subgroup analyses to examine mortality and serious adverse events in patients with or without baseline heparin due to recent reports of rebound thrombosis after heparin cessation. from december to july , adult patients with severe sepsis at high risk of death were enrolled in a randomized, double-blind, parallel, placebo-controlled study conducted at centers in countries. daa (xigris ® , eli lilly and company, indianapolis, in) at mcg/kilogram/hour for a planned hour infusion was administered to each patient. the study drug was either unfractionated heparin ( units subcutaneously twice a day), enoxaparin ( mg subcutaneously per day) or placebo in a : : randomization scheme. to enhance patient safety, all patients who were receiving commercial heparin at baseline for any indication were required to stop heparin during the daa infusion. -day mortality and serious adverse events were analyzed. a total of patients received daa, but only patients received study drug and make up the intention to treat (itt) population. a total of patients were randomized to placebo and to heparin ( to low molecular weight heparin and to unfractionated heparin). an important treatment-by-subgroup interaction was noted in the subgroup defined by exposure to commercial heparin at baseline, breslow day p = . . among patients who were exposed to commercial heparin at baseline, higher mortality and serious adverse events were observed in placebo patients compared with heparin patients, . % versus . % and . % versus . %, respectively. however, heparin and placebo patients who were not exposed to heparin at baseline had similar mortality and serious adverse events. patients who were exposed to commercial heparin at baseline had higher mortality and serious adverse events in the placebo versus the heparin group. these data suggest that, in patients with severe sepsis, prophylactic heparin should not be abruptly discontinued unless risk outweighs benefit. grant acknowledgement. the xpress study was funded by eli lilly and company. guidet b , jasso-mosqueda g , priol g , aergerter p intensive care, hôpital saint antoine, paris, economic, aremis consultant, neuilly sur seine, economic, aremis consultant, neuilly-sur -seine, medical data processing, hôpital ambroise paré, paris, france the use of albumin for the treatment of severe sepsis remains controversial. the safe study (nejm (nejm , : reported a mortality rate of . % in the group resuscitated with saline compared to . % in the group that received albumin (relative risk . , p = . ). this potential beneficial effect could be explained by several properties of albumin. despite existing recommendations, albumin remains largely underused in this indication. given its higher cost compared with other volume expansion products, modelling of its cost/efficacy ratio would be justified in the light of the product's potential advantages. routine medical practice was compared with the systematic use of albumin. the study population was defined as all adult patients having been treating for severe sepsis in one of the units in the cub-rea database between january and december , excluding burn patients, patients with mediastinis, organ transplant recipients and those having received extracorporeal circulation. only hospital stays longer than hours and including at least circulatory, kidney or respiratory failure were considered. two efficacy indicators were used: the number of lives saved and the number of years of life gained, using the . % reduction in mortality as the baseline case in the albumin arm of the safe study: albumin costs were estimated according to the quantities administered in this same study i.e. . l. life expectancy was determined using the deale method, with the following factors into account: age, sex, saps ii score and mac-cabe score. there were intensive care deaths according to the cub-rea database. the use of albumin induced a . % reduction in the number of deaths ( lives saved amongst the patients included in the study). the mean survival of the patients discharged alive from the hospital was estimated at . years [ %ci: . - . ]. the average cost of albumin administration per patient was evaluated at . e. the cost per life saved was e and per year of life saved was e. our results provide strong evidence for a very favourable cost effectiveness ratio of albumin in severe sepsis. long-term outcomes - bral e , ingels c m m , milants i , wouters p j , van den berghe g intensive care medicine, university hospital gasthuisberg, catholic university of leuven, leuven, belgium in this follow up study, we document the impact of intensive insulin therapy on long term mortality and objective and subjective well-being of high risk cardiac surgical patients. methods. years after icu-admission, we assessed long term outcome of the subgroup of cardiac surgical patients (n= ) included in the original insulin trial ( ) . patients or next of kin, or if unavailable the referring physician, were contacted by phone call. some data were collected from the hospital database or the civil registration services. we studied the perceived health-related quality of life (qol) using the validated dutch version of the nottingham health profile (nhp) ( ), and the functional capacity with the karnofsky index. results. years after icu, the number of post-hospital-discharge deaths was similar in the conventional treatment group (ris) and in the intensive insuline treatment group (iis), reflecting maintenance of the acute survival benefit with insulin. for the long-stay patients (> d icu), y-mortality was reduced from . % (ris) to . % (iis) (p= . ). karnofsky scores were available for % (n= ) of the patients ( / ). more than % of the patients reached a karnofsky index of > %, indicating functional autonomy. ( / ) patients provided answers to part of the nhp, ( / ) answered part of the questionnaire. for part , there was no difference between both groups. the dimensions mostly affected by critical illness were "sleep" and "physical mobility". for the second part, "long stay" patients in the iis had worse scores in the dimensions concerning household activities (p= . ), social (p= . ) and family (p= . ) life. the short-term survival benefit of intensive insulin therapy ( ) was maintained after years. the increased survival of sicker, "long stay" patients, was accompanied with a more compromised subjective qol. the objective, functional capacity, however was similar in both groups. when evaluating the long-term outcome of icu patients, the timing of ql assessment is essential. this study has shown that preadmission ql in our medical-surgical pts was substantially reduced after icu discharge. eighteen months after admission to the general icu most survivors had regained most of their preadmission ql status. their pao /fio ratio was significantly higher than in the non-survivors. ledoux d , piret s , canivet j , damas p intensive care, liège university hospital, liège, belgium there is a growing number of heart surgery procedures performed in octogenarians. however, the benefit for the patient of such procedures may be questionable. in this work, we analysed -year survival and quality of life in octogenarian patients operated for heart surgery. from april to january , all consecutive patients were prospectively included in the protocol. we collected data on preoperative comorbidities, surgical procedures characteristics, postoperative complications and hospital outcome. one-year after surgery, survival was obtained via patients' general practitioner. patients were then interviewed and asked to complete the euroqol questionnaire ( ) . data were analysed using chi-square test and mann whitney test. a cox model was used for survival analysis. a p-value < . was considered as significant. over a -month period, patients were included in the protocol. among them, ( . %) patients were octogenarian. during the -year follow-up, ( . %) patients died. there were ( . %) death in octogenarian patients and ( . %) in younger patients (p= ). the euroqol questionnaire was completed for ( % of survivors) patients. in developed countries, the st century will see an exponential increase in the elderly population. octagenarians are already increasingly referred for critical care when our medical and surgical colleagues perceive the need. differentiation between those who will benefit from critical care, and those in whom we will only delay death, is difficult. death after icu stay is rarely studied, but, particularly in the elderly, should also contribute to the decision to submit them to intensive therapy. we prospectively collected demographic and survival data on patients > y admitted to our intensive care in , and followed up for months. survival to icu discharge, hospital discharge, and months post icu discharge, was determined. age, sex, apache ii scores, and length of icu stay (los) were compared for survivors and non-survivors. apache ii scores were compared by student t-test for survivors and non-survivors. equal variance was assumed for apache ii scores. logistic regression analysis was performed for icu and hospital discharge and for survival at year. intensive care unit (icu) admission for bone marrow transplant recipients during the early post-transplantation period is associated with poor outcome. survival of these patients with icu admissions during subsequent hospitalizations is unknown. we sought to determine the long-term outcome of bone marrow transplant recipients who were admitted to icu during subsequent hospitalizations. we conducted a population-based retrospective cohort study in ontario, canada from january , to march , . all ontario bone marrow transplantation recipients who received subsequent icu care during the study interval were included. the primary outcome was mortality at one year. we also examined the association of specific icu procedures on mortality. a total of patients received bone marrow transplantation; of which received icu care during subsequent hospitalizations. patients receiving any icu procedure had higher one-year mortality ( % vs %, p< . ). death rates were highest for those receiving mechanical ventilation ( %), right heart catheterization ( %), or dialysis ( %). in combination, the strongest independent predictors of death were mechanical ventilation (hr . ; % confidence interval . to . ) and dialysis (hr . ; % confidence interval . to . ). regardless, no combination of procedures uniformly predicted % mortality. conclusion. the prognosis of bone marrow transplant recipients receiving icu care is very poor, but should not be considered futile. health-related quality of life (hrqol) is an indicator of outcome for intensive care patients. therefore, a prospectively designed substudy on hrqol days after icu admission was proposed as an additional option to icus participating in the saps project [ , ] . the euroqol questionnaire (eq- d) [ ], in the appropriate language version, was administered to the patients who spent > h in icu and survived for days. a question to compare present health status with that months before icu admission (better/same/worse) was added. nineteen icus ( located in italy, in belgium, and in each of the following countries: argentina, austria, greece, hungary, and slovakia) participated in the present substudy. all data on hrqol were recorded by using the saps stand-alone database system provided by the coordination and communication centre of the saps project. we studied patients out of admitted. functional status at hospital discharge was reduced in two-thirds of the patients (p < . ), and partially recovered along follow-up (p < . ). patients from to years (n = ) and those older than years (n = ) had similar apache ii, sofa and omega scores as well as comparable functional status at admittance and hospital discharge (bi: vs , respectively). however, patients > years were significantly more dependent at -month follow-up whereas functional status in younger had returned to baseline values after -month hospital discharge (bi: vs , respectively, p = . ). perceived quality of life was also significantly lower at hospital discharge than baseline (p < . ), remained low at three months of follow-up. however, the perception of quality of life returned to a level comparable to baseline, after months of hospital discharge. functional recovery and perceived quality of life of elderly patients after non-elective icu admission is slowly achieved in the following six months after hospital discharge, especially in those from to years old. methods. an observational, prospective, international multi-center study was conducted in european icus. patients that required invasive mechanical ventilation (mv) for > hours were included in the database. a comparison was made regarding the days on mv and the length of stay (los) in icu between patients with and without nosocomial pneumonia. statistic analysis was performed using spss . . during the first months of the study consecutive patients were included; . % (n= ) were men, and the mortality rate was . % (n= ). the % (n= ) had nosocomial pneumonia (hap n= and vap n= ). the mv patients with nosocomial pneumonia (n= ) were compared with mv patients without pneumonia (n= although attributable mortality rate for ventilator-acquired pneumonia (vap) is still controversial, any delay in adequate antibiotic treatment compromises its outcome. moreover, vap diagnosis and its optimal treatment remains a challenge for the intensivists. we therefore performed routine weekly endotracheal aspiration (ea) to guide the initial antibiotic treatment before the results of broncho-alveolar lavage (bal) for vap. we prospectively studiedy vap. we evaluated the concordance between the latest ea and the bal and separated patients into three groups: group i: concordant ea-bal, group ii discordant ea and bal, group iii: no ea. we then compared the ad equation of the initially antibiotic initially prescribed, the morbidity and the mortality between the three groups. . assessable samples ea-bal could be were evaluated. the early antibiotic strategy guided by the ea was adequate in % of the situations and was significantly superior to the treatment recommended by the ats guidelines ( ) ( %) and better than the treatment recommended by the trouillet ( ) guidelines ( %) but did not reached the significativity. when clinicians could not have a pre-vap ea to guide their treatment (group iii) only % of the treatments were adequate. there was not any no statistical difference between the three groups for length of mechanical ventilation, length of icu stay in icu, extra-pulmonary nosocomial infections or mortality. systematic oncee weekly systematic pre-vap ea allowspermits an adequate early adequate antibiotic therapy. however, the impact of our strategy, "early and guided by the ea" on outcome needs to be evaluated prospectively by a randomised clinical trial. ( ) de wolf a , blot s , vandevelde s , depuydt p , poelaert j intensive care, anesthaesia, university hospital ghent, ghent, belgium cardiac surgery patients are at risk for post-operative pneumonia, with perioperative micro-aspiration as a possible cause. we hypothesised that the use of poly-urethane cuffed endotracheal tubes (puc tube)(seal guard ® , tyco healthcare, usa) could be protective due to enhanced sealing of the pharyngo-tracheal barrier, in comparison with conventional poly-vinyl cuffed tubes (pvc tube). all patients planned for cardiac surgery during a days period were randomised between a pvc tube or a puc tube after informed consent. patients with preoperative antibiotic therapy, prior pneumonia or endocarditis were excluded. diagnosis of early post-operative pneumonia was based on an infiltrate on chest x-ray, purulent tracheal secretions, fever and leucocytosis or increase in c-reactive protein serum levels, within days after surgery. statistical analysis was performed by means of chi-square test and mann witney u test for categorical and continuous variables respectively. we included patients with patients in each group. occurrence rate of co-morbidities such as diabetes mellitus, copd, tabagism and chronic kidney failure was equal between the two groups. there was no difference in type of surgery and peri-operative transfusion need. patients characteristics are in the table. ) was associated with a -fold decrease in vap rate.( ) however, according to a recent study, this measure seems difficult to implement. ( ) the aim of the study was to assess adherence to this measure in routine practice and its influence on vap rates. all intubated and mechanically ventilated patients admitted in french icus (one medical, and surgical) were prospectively followed-up during a month-period. demographic and clinical characteristics of patients were collected on admission. bed positioning and trunk flexion were measured twice daily until extubation, first episode of vap or death. in clinically suspected patients, vap was ascertained by a positive (≥ cfu/ml) plugged telescopic catheter culture. a total of patients ventilated ≥ h were enrolled. median bed angle was • (interquartile (iqr), - ) but actual median patients' trunk flexion was only • (iqr, - ). median bed angle was significantly higher in the medical icu than in surgical icus ( • vs • , respectively, p>. ). vap incidence was % overall, % in the medical icu and % in surgical icus (p= . ). vap were classified as early-onset pneumonia in cases ( %) and late-onset pneumonia in cases ( %). potential risk factors for vap identified in univariate analysis were: icu admission for surgical emergency, trauma, high saps ii score. a bed angle < • was found in % of patients with vap and in % of patients without vap (p= . ). by logistic regression analysis, only a surgical emergency reason for admission was independently associated with vap occurrence (adjusted or, . ; %ci, . no association could be found with bed angle whatever the value considered. conclusion. in our setting, elevating the head of the bed at an angle > • was not achieved on a routine basis during mechanical ventilation. despite half of the patients being kept at less than • , this was not associated with an increased risk of vap. the presence of tracheostomy is considered a major risk factor to develop ventilator-associated pneumonia (vap), but there are not enough studies that have been designed to address the incidence and density of incidence for this infection, following the nnis protocol. the present study was conducted with this end-point. this cohort study has been conducted in a -bed adults university multidisciplinary icu during the last years, in a prospective way. vap was defined following the cdc criteria with positive microbiological confirmation. all refered patients received percutaneous dilational tracheostomy like ciaglia technique (pdt). the moment to perform the tracheostomy was chosen by consensus, once the patient was hemodinamically and respiratory stable and without intracraneal hypertension crisis. the patients were under general anaesthesia and mechanical ventilation (mv). the variables are expressed as mean and standard deviation. we recluted patients, % male, ± years old, with apache ii at admission of ± and ± at the date of the pdt. this series included % neurocritical patients. patients were ± days in icu [previous (pr) and posterior (po) to pdt during ± and ± days respectively] and mv in all of its modes was administrated during ± days ( ± pr and ± po). there were episodes of vap microbiologically addressed ( pr and po). eight patients had two episodes of vap. the incidence of vap-po in pdt-patients, as it has been defined in this study, is similar to vap-pr but the infection density incidence is clearly superior. the crude incidence of vap during all their stay in the icu is very high compared with nnis or envin-uci reports. however, the incidence of vap corrected by the adjusted density of infection is online or even slightly inferior overall, considering the frequency of neurocritical patients in this series. koulenti d methods. an observational, prospective, international multi-center study was conducted in european icus. during the first months of the study consecutive patients that required invasive mechanical ventilation (mv) for > hours were included in the database. statistic analysis was performed using spss . . results. the patients' mean age was . ± . , . % (n= ) were men, mean admission' sapsii was . ± . , mean days on mv was . ± . , mean los in icu was . ± . , and the mortality rate was . % (n= ). the % (n= ) of the patients included in the study were admitted with or developed pneumonia: % (n= ) cap, . % (n= ) hap, and . % (n= ) vap. the diagnostic techniques used are shown in the table: our objective is to evaluate the clinical resolution pattern in ventilator associated pneumonia (vap) due to pseudomonas aeruginosa (pa) and establish the influence of inadecuacy of empirical antibiotic therapy in the evolution. prospective observational multicenter study on intubated patients with clinical suspicion of vap. incluison criteria included episodes of vap due to pa. clinical variables of resolutions were collected daily as reported elsewhere . "failure to resolve pneumonia" was defined as the lack of resolution of at least two clinical variables during the first hours after vap onset. appropriate antibiotic therapy was defined by the presence of at least one active agent against pa. one hundred and seventy-two episodes of vap were admitted during the study period. fourty-two of them were due to pa and were included in the study. twelve ( %) patients received adequate initial antibiotic therapy. patients with adequate therapy were older than patients with initial inadequate antibiotic therapy ( . ± . vs . ± . ; p< . ) but the apache ii at admission was the same in both groups ( vs ' ; p=ns). mean stay in the icu and the time of mechanical ventilation was also the same in both groups. after hours of antibiotic therapy, defervescence was observed in % of patients with adequate compared to % of patients with inadequate empirical antibiotic therapy (p= . ). clinical resolution of hypoxemia was also different in the patients with adequate and inadequate antibiotic therapy ( % vs %; p< . ). the rate of failure to improve was higher in patients with inadequate empirical antibiotic therapy ( . % vs . %; p< . ). length of antibiotic therapy was also longer in the group of patients with inadequate therapy ( . ± . vs . ± . ; p< . ). pseudomonas aeruginosa vap resolves during the first hours of adequate therapy. inadequacy of initial antibiotic therapy is the only modifiable factor which influence clinical resolution of vap due to pseudomonas aeruginosa. weaning-induced pulmonary edema is a classical cause of failure of weaning from mechanical ventilation in high risk patients (copd and chronic left heart disease). the diagnosis may require pulmonary artery catheterization, showing increased pulmonary artery occlusion pressure (paop) during the weaning trial. among the numerous transthoracic echocardiography parameters in mechanically ventilated patients, the best estimate of paop is e/ea, which is the ratio of the protodiastolic mitral velocity (e) to the early diastolic velocity of the mitral annulus (ea), obtained by using tissue doppler imaging. the aim of our study was to test the hypothesis that the e/ea ratio could be used to detect weaninginduced pulmonary edema defined by intolerance to spontaneous breathing (sb) and increase in paop above mmhg during the weaning trial. sixteen patients who failed two consecutive weaning trials and in whom insertion of a pulmonary artery catheter was decided by the attending physician entered the study. in all patients, a weaning trial was performed over a maximum -h period of sb using a t-piece. at baseline and during the weaning trial, end-expiratory paop and e/ea were measured. overall ( simultaneous measurements) e/ea correlated with paop (r = . , p= . ). from baseline to the end of the weaning period, paop increased from ± mmhg to ± mmhg (p< . ) and e/ea increased from ± to ± (p< . ). during the weaning trial, the increase in paop and the increase in e/ea strongly correlated (r = . , p< . ). in patients (n= ) who experienced weaning-induced pulmonary edema, paop increased significantly from ± mmhg to ± mmhg (p< . ) and e/ea from ± to ± , (p< . ). in patients (n= ) without weaning-induced pulmonary edema paop did not significantly increase (from ± mmhg to ± mmhg, p= . ) whereas e/ea significantly increased from ± to ± (p= . ). the best threshold value of e/ea allowing to detect an increase in paop > mmhg, was with a sensitivity of % and a specificity of %. the weaning-induced changes in e/ea measured using tissue doppler imaging, correlated with the weaning-induced changes in paop. however, e/ea did not appear to be reliable enough for diagnosing weaning induced pulmonary edema. lambert p , kjaersgaard hansen l , sloth e , smith b w , koefoed nielsen j , larsson a l s it is well known that positive end-expiratory pressure (peep) depresses circulation at hypovolemia and that fluid loading could counteract this circulatory impairment. therefore, in an animal model of mild hypovolemia, we investigated whether a peep challenge might predict fluid responsiveness. the hypothesis was if peep reduces cardiac output (co), this would indicate fluid responsiveness at cmh o peep, while on the other hand if peep does not reduce co, this would indicate that further fluid administration will not improve circulation. introduction. beta and beta adrenergic receptors (ars) mediate the primary effects of catecholamines in the mammalian heart. although structurally similar, these receptor subtypes differ in some important ways. for example, continuous beta ar stimulation protects the heart. continuous beta ar activation causes myocardial injury. previously, the beta ar was thought to play only a minor role in the enhancement of cardiac inotropic performance. our data suggest that this theory may be incorrect. we found that in the absence of beta ars, cardiac contractility was significantly impaired. wild type (wt) and beta ar knockout (beta ko) mice underwent analyses of left ventricle function and structure. electrocardiogram and respiratory-gated magnetic resonance imaging as well as conductance pressure-volume (pv) catheter studies were performed. . mri analyses revealed that left ventricle stroke volume (sv) and end diastolic volume (lvedv) were significantly greater in wt compared beta ko mice (p= . and p= . , unpaired t-tests). pv loop studies demonstrated significantly reduced cardiac contractility (slope of the end systolic pressure-volume relationship) in beta ko mice relative to wt animals (p= . , unpaired t-test). our mri sv data suggested that left ventricle performance of wt mice might be more robust than that of beta ko mice. our pv loop data were consistent with the mri findings and demonstrated that differences in the cardiac performance were not simply a result of differences in preload. cardiac contractility was impaired in beta ko mice. absence of beta ars during development might cause structural changes that lead to reduced cardiac inotropic performance of beta ko mice. we are currently testing this hypothesis using conditional beta ko mice in which beta ar expression is suppressed only in adult animals. we favor the hypothesis that beta ars facilitate the primary role of the beta ars in stimulating cardiac contractility. according to this hypothesis, direct interaction between beta ars and beta ars (e.g., heterodimer formation) or interaction at the intracellular signaling level might occur. in the absence of these interactions, attenuation of b ar-mediated stimulation of inotropic performance would be expected. introduction. icu patients with multiple organ failure (mof) benefit from iv glutamine supplementation in terms of mortality and morbidity. also neurosurgical patients in the icu may be candidates for exogenous glutamine support, but in head trauma patients there are concerns regarding the close connection between glutamine and glutamate. elevated intracerebral levels of glutamate are seen in patients with high icp and an unfavourable outcome. we have recently reported that cerebral glutamate concentration is not influenced during an intravenous glutamine infusion in head trauma patients. here the utilization of exogenous glutamine was studied. patients (n= ) with severe head trauma (gcs< ) in the icu were studied. study protocol had a cross over design where patients were randomised to receive glutamine (dose . g/b.w/ h) before placebo or placebo before glutamine on two consecutive h periods. the decay of plasma concentration after the end of the glutamine infusion was used to calculate rate of appearance (ra) for glutamine. student's t-test for paired samples was used. during glutamine infusion plasma glutamine concentration increased by %, ( ± , v. ± µmol/l; p= . ) while glutamate concentration was unaltered. av-difference across the brain (a-v-jugular) indicates a glutamine efflux. (- ± , v. - ± µmol/l; p= . ), while glutamate balance was not different from zero. glutamine flux across the leg was not significant different between glutamine infusion and control periods (treatment day - ± , control day - ± nmol/ ml/min; p= . ). glutamine ra was ± µmol/kg/h. exogenous glutamine was not utilized in the brain or in muscle. in addition the endogenous production of glutamine was within the normal range. hypothetically the exogenously supplied glutamine was mainly utilized in the splancnic area, where more glutamine was used than is normally produced endogenously. tight glycaemic control improves outcome in critically ill patients but requires frequent blood glucose monitoring. subcutaneous adipose tissue (sat) has been characterised as a promising site for glucose monitoring in diabetic patients. however, tissue perfusion might be altered in critically ill patients and therefore it remains unclear whether glucose in sat can be used as alternative for blood glucose monitoring. the present study was performed to evaluate the relation of glucose in sat compared to arterial blood using a well accepted insulin titration guideline in patients under severe septic conditions. critically ill patients with severe sepsis were investigated. arterial blood and sat microdialysis samples were taken in hourly intervals for a period of h. glucose concentrations from sat were calibrated to arterial blood glucose (bg) by one point calibration using the first bg reading (bgsat h), or using the bg reading after hours (bgsat h) to allow stabilisation of the tissue after insertion of the microdialysis probe. the relation between blood (bg) and calibrated sat glucose readings was clinically evaluated applying a newly established insulin titration error grid analysis. conclusion. under conditions of severe sepsis, paired glucose readings indicate a close relation between arterial blood and sat. introduction of a -hour stabilisation period for the trauma as caused by the microdialysis probe results in a substantial improvement of this relation. overall, the majority of the data suggests sat as a possible alternative measurement site for glucose to establish tight glycaemic control in patients who developed severe sepsis. hermans g , wilmer a , meersseman w , bruyninckx f , milants i , wouters p , bobbaers h , van den berghe g university hospitals, ku leuven, leuven, belgium critical illness polyneuro-and/or myopathy (cipnmp) is a major problem in critically ill patients causing limb weakness, prolonged mechanical ventilation (mv), extended hospital stay and increased mortality. recently, the incidence of cipnmp in a surgical icu was reduced in patients receiving intensive insulin therapy (iit). we investigated whether iit could similarly reduce cipnmp and prolonged mv in a high-risk population in a medical icu. this study is a subanalysis of a large rct ( patients) comparing outcome in a medical icu using iit or conventional it (cit). we analyzed cipnmp and prolonged mv in a subgroup with an icu stay of at least days with weekly emgs of all limbs. diagnosis of cipnmp was based on abundant spontaneous activity (sharp waves/fibrillation potentials), only if present in multiple distal and proximal muscles in all extremities. baseline and outcome variables were compared using student's t, chi-square or mann-whitney test when appropriate. the effect of treatment allocation was assessed using multivariate logistic regression, correcting for baseline and icu risk factors. the latter were also evaluated using cumulative hazard estimates and proportional hazards regression analysis, censoring for early deaths. . patients were evaluated. cit and iit groups were comparable on admission. inhospital mortality in the iit group was . % vs. . % in the cit group (p= . ). cipnmp was more frequent in the cit group ( . % vs. . %) (p = . ). prolonged positive emg findings (at least positive emgs) were also reduced in the iit group ( . %, vs . %, p= . ). multivariate logistic regression demonstrated iit as an independent protective factor for cipnmp (p= . ) after correction for baseline severity of illness and known risk factors. mean daily glucose levels and insulin dose could not independently explain the benefit of the iit group. after correction for these however, corticosteroids had a protective effect on the occurrence of cipnmp (p= . ). iit also reduced prolonged mv from . % (cit group) to . % (iit group) (p= . ). iit remained an independent protective factor for prolonged mv (p= . ) in a multivariate logistic regression model correcting for preadmission risk, diagnostic categories and organ failure. conclusion. iit reduces cipnmp and thereby prolonged mv in a medical icu population with a high incidence of other known risk factors for this disease. ) minnick a. f et al prevalence and patterns of physical restraint use in the acute care setting this study was endorsed by eccrn/esicm. stress factors in nursing staff in an intensive care unit clinic and psichobiology dpt, icu deparment, basic, clinic and psychobiology dpt, basic jansen t c , mulder p g , bakker j intensive care, epidemiology and biostatistics, erasmus mc university medical center, rotterdam, netherlands introduction. hyperlactatemia has been associated with high mortality. however, pathophysiology of hyperlactatemia varies according to the underlying disease and this has not been related to prognosis. the aim of this study was to analyze the prognostic characteristics of lactate in different types of critical illness. in this prospective observational study we evaluated icu patients of university affiliated hospitals from may to april . lactate levels were collected at admission (t= ), t= and t= hrs and in-hospital mortality was recorded. we enrolled patients of which re-admissions were excluded. patients were classified as sepsis (sepsis, severe sepsis or septic shock, n= ), low flow (hemorrhagic or cardiogenic shock, n= ) or others (n= ) by admission diagnosis of the dutch national intensive care evaluation (nice) registry. after withdrawal of patients with incomplete lactate measurements sepsis patients remained for comparison with low flow patients. . analysis was performed in patients with mean age ± yrs. mean apache ii was . ± . and in-hospital mortality was . %. in the sepsis group mean lactate levels (mmol/l) of survivors and non-survivors at t= were . ± . vs . ± . (p= . ), at t= : . ± . vs . ± . (p= . ) and at t= : . ± . vs . ± . (p= . ). in the low flow group mean lactate levels of survivors and non-survivors at t= were . ± . vs . ± . (p< . ), at t= : . ± . vs . ± . (p< . ) and at t= : . ± . vs . ± . (p= . ). the effects of the lactate evolutions during the first hours on mortality were significantly different between the two groups (p= . ). in the sepsis group each % decrease in the to hrs lactate ratio resulted in a . % lower mortality rate ( %ci: . %- . %; p= . ). for to hrs this was . % ( %ci: . %- . %; p= . ). in the low flow group no significant effects of lactate changes during the first hours were seen (p= . and . for to hrs and to hrs lactate ratio). in septic patients the course of lactate levels over time seems to be a major determinant of outcome. in contrast, in patients with a low-flow state (hemorrhagic or cardiogenic shock) a strong reduction of lactate within hours does not rule out a detrimental outcome. here, the initial lactate level, rather than the ability to decrease lactate over time, predicts outcome. pirat a , finch c , nates j l anesthesiology, baskent university faculty of medicine, ankara, turkey, critical care, university of texas, md anderson cancer center, houston, united states introduction. accurate determination of caloric requirements, one of the first and essential components of nutritional support in intensive care unit (icu) patients, can be particularly challenging in critically ill cancer patients. this study was designed to determine the daily caloric requirements and the incidence of inappropriate feeding in critically ill cancer patients in our icu. after obtaining institutional approval, all adult patients who were admitted to the icu between march and july and had an indirect calorimetry (ic) measurement were included in this study. cases with missing or incomplete data were excluded. specially trained critical care respiratory therapists performed all ic measurements according to the policies and guidelines in our icu. a dietitian performed a complete nutritional assessment for all icu patients within hours of admission and calculated the resting energy expenditure (ree) based on a kcal per kilogram equation. ic was performed in all patients to measure ree (mree). underfeeding, appropriate feeding, and overfeeding were described as calculated ree < % of mree, calculated ree > % and < % of mree, and calculated ree > % of mree, respectively. forty two patients ( males and females) with a mean age of . ± . years were studied. patients' mean body weight and body mass index were . ± . kg and . ± . kg/m , respectively. mean apache ii score was . ± . for this group. respective estimated ree and mree were ± kcal ( . ± . kcal/kg) and ± kcal ( . ± . kcal/kg). a significant correlation was detected between the mree and estimated ree (p= . and r= . ), however the mean values for these two parameters were significantly different (p= . ). ten patients were being underfed ( %), patients were in the appropriate feeding group ( %), and patients received overfeeding (% ). this study showed that our group of mechanically ventilated critically ill cancer patients had a lower daily caloric requirement than the generally used kcal/kg/day. our results also indicate that estimation of caloric requirements with a kcal per kilogram equation was associated with a high incidence of both over-and underfeeding in this subgroup of icu patients. ic remains the best method of determining patients' energy needs in the icu. creative solutions for nursing and ahps - benbenishty j s , adam s intensive care, hadassah medical organization, jerusalem, israel, critical care, uclh, london, united kingdom patients in intensive care are monitored and treated using a range of invasive devices and equipment. in order to support ongoing acceptance of these measures, the patient must either be cooperative and competent, sedated, or physically unable to disturb the devices. in order to facilitate this, many patients are either chemically sedated or physically restrained to allow effective patient management to occur. anecdotally, the practice of using physical restraints in intensive care varies widely across europe. little data is available on the extent and criteria for its use. most published data to date is based on practices in the united states. in a study of icus in the us, minnick et al. [ ] found that % of patients were restrained, although practice did vary across different types of icu the purpose of the present study was to gather exploratory data on the incidence of and the reasons for physical restraints in adult icus in europe. a prospective descriptive study of incidence of physical and chemical restraint use involving icus across europe was carried out. recruitment of icus occurred through esicm membership. icus taking part collected data on all adult (> yrs) icu patients hospitalized on data collection days (one week day and one weekend day). data collectors were asked to collect the following data. baseline -country, number of beds, nurse:patient ratio. restraint policy restraint datanumber of patients restrained, reason for restraint, motivation for restraints, alternative measures used in addition to physical restraints, effectiveness of restraint, physical effect on the patient, length of time patient is restrained, type of sedation used. . units contributed data from countries in europe. mean size of icu was beds (range - ) with a mean admissions /month (range - ). patient episodes were recorded. % of these patients were physically restrained and % of patients received sedation. nurse: patient ratios ranged from : to : . there did not seem to be a relationship between restraint use and this ratio. however, there was an association between use of sedation and use of physical restraint. in most countries, the more patients were physically restrained, the less were sedated. there is an negative association between number of patients restrained and presence of a physical restraint policy.conclusion. levels of physical restraint use vary across europe but its use would appear to be cultural rather than as a result of reduced levels of nurse staffing or a deliberate decision to avoid sedation. psychological stress is frequently argued as a burning-out factor in nursing staff in icus. our aim has been to identify the main job factors able to cause such stress in a multidisciplinary icu nursing staff. the study was ruled in a multidisciplinary icu during . sample size was nurses and psychological investigation instruments were: the sanitary staff stressing factors scale, created by our group. it is a likert like scale composed by items through whose answers (ranked in levels from "not at all - " to "very much - ") the individual gives information about factors related with his/her job and causing distress. staff participation was voluntary, anonymous and confidential and it was performed on a single fellow basis at each time. thirty five ( ) percent of nurses express "some" distress related to their job, and they consider their position as "very stressing" in % and "very much stressing" in %. the more stressing factors are: too much workload ( . +/- . ); lack of human manpower ( . +/- . ); daily work time pressure ( . +/- . ); under professional consideration ( . +/- . ); lack of ruled resting periods during job ( . +/- . ); consequences of too much rapid decisions ( . +/- . ); elevated requirements ( . +/- . ); uncertainty situations with lacking of information ( . +/- . ); emotional overload ( . +/- . ) and too much responsibility ( . +/- . ) conclusion. icu nursing staff is under a high level of stress associated to their job position. main factors causing it are too much workload, professional underestimation, and too much responsibility. it seem of the greatest importance to offer to this staff some kind of programs for establishing psychological and organizational strategies to help them to cope with their job. continuous positive airway pressure (cpap) is frequently used in critical care to improve oxygenation. however, some patients cannot tolerate cpap therapy via a mask because of physical discomfort or anxiety and we sought an alternative method. the cpap hood has proven efficacy and is well tolerated with minimal adverse effects ( , ). castar cpap hoods were procured from vital signs ltd. clinical guidelines were drawn up by the critical care outreach team. patient suitability was assessed by the outreach nurses and prescribed by critical care doctors. treatment was initiated with cpap mask but if poorly tolerated, a cpap hood was used. some patients' therapy was initiated with the hood, if for example they had previous facial surgery or claustrophobia. extensive training of nursing, medical staff and physiotherapists was undertaken by the outreach nurse educator in areas of the hospital currently able to care for patients requiring facial cpap. training packs including guidelines, photographs and nursing care protocols were provided to each area. the cpap hood was used on patients in months. data collected on the first patients showed the average length of time the hood was worn, was . hours, with / patients ( %) wearing the hood for long periods, and / ( %) wearing it for intermittent treatments of less than hours at a time. only patient did not tolerate the hood at all and it was removed after minutes. in / patients ( %) the hood was used as a weaning treatment after extubation. / patients ( . %) progressed to intubation and ventilation despite using the hood, though one of these patients was intubated for transfer to ct scan. / patients ( . %) never required intubation and ventilation after having hood therapy. all ( %) patients showed improvement in oxygenation. work of breathing was reduced and overall patient comfort was improved. patient comments were generally positive. nursing staff found caring patients with hood therapy easier than a cpap mask. though it is recognized a formal trial to compare tolerance, length of treatment, and progression to ventilation with the two methods of cpap delivery is necessary, our evaluation has shown the cpap hood to be an easy, efficient, well tolerated and safe alternative to cpap mask therapy. lortat-jacob b , mateo j , kéréver s , payen d , cholley b anesthesiology and intensive care medicine, ap-hp, lariboisière hospital, paris, france introduction. esophageal doppler (ed) is a minimally invasive monitor, that estimates stroke volume (sv) from descending aortic flow velocity. this technique is considered easy to learn, however, the reliability of sv measurement by icu nurses has never been evaluated in comparison to measurements obtained by "expert" physicians. after irb approval, icu nurses received a -hour theoretical training to learn how to place ed probe in order to measure flow velocity from the descending aorta. they were asked to obtain the best possible flow velocity signal in stable, sedated, mechanically ventilated patients monitored by ed (cardioq, deltex) . the numeric values for sv and parameters derived from the velocity envelope remained hidden, and the signal was considered optimal when spectral brightness and peak flow velocity were maximum. gain was adjusted to optimize signal/noise ratio. the monitor was set to average sv values over cardiac cycles to minimize respiratory variability. the operators (nurses and experts) were asked to freeze the scrolling when they thought they had obtained the best signal, and an independent observer recorded the sv values. after sv acquisition, the probe was retrieved by a few centimeters to loose the signal and the operator was asked to replace it two more times. experts completed their sv acquisitions immediately before or after nurses. sv values obtained by nurses (svnurs) and experts (svexp) were calculated as the average of the consecutive measurements. correlation and agreement between svnurs and svexp have been studied, as well as intra-observer reproducibility for each category. a mann-whitney test was used to check if bias was statistically different from .results. nurses and experts have made triplets of sv measures in patients. mean sv measured by the experts was +/- ml, and by the nurses was +/- ml. intra-observer reproducibility was %, for both, nurses and experts. the correlation between svnurs and svexp was very tight (r = . ), and the agreement was characterized by a systematic bias of + ml (svexp > svnurs; p< - ) and limits of agreement of +/- ml. after a minimal training, icu nurses acquired an intra-observer reproducibility similar to that of expert operators for sv measurement. correlation and agreement for sv values obtained by each category were satisfactory. however, experts did achieve greater sv values consistently, indicating a better probe placement. bakker k m m , spanjersberg r , ligtenberg j j m , meertens j h j , tulleken j e , zijlstra j g intensive and respiratory care unit, university medical centre groningen, groningen, netherlands when an acute life threatening event occurs within the medical department, a cardiopulmonary resuscitation team of the medical intensive care unit is immediately alerted. this cpr team is specifically designated resuscitation team, available hours a day. in an dnr protocol was introduced at the medical department in our hospital for all admitted patients. the physician on the ward decides the dnr status in consultation with the patient or relatives on admission with adjustment of the decision whenever necessary. the dnr code is recorded in the patient's medical file. the aim of this study is to determined whether the introduction of the dnr protocol, in the medical department, influences the total number of outreaches, the icu-admissions and the overall survival the first hours after cpr. between and all events where the cpr-team was involved were recorded in a logbook and described according to characteristics and outcome. false alarms were omitted. we compared the results before ( - ) and after ( - ) in the period - the cpr team was alerted times. in comparison, in the period - the cpr team was alerted times. this is a significant decline (p = . ). when comparing the - with the - period one can also see a significant decline in the number of icu admissions after cpr; versus (p < . ). in the period before the introduction of the dnr protocol the percentage of patients who were alive after hours was % for cardiac arrest patients, % for respiratory arrest and % for other serious events. in the period after the introduction the percentage of patients who were alive after hours was % for cardiac arrest patients, % for respiratory arrest and % for other serious events.conclusion. the introduction of a dnr protocol has led to a significant reduction in emergency calls and also a significant reduction in icu admissions after cpr. there is no shift in type of event. the hour survival percentage for cardiac arrest, respiratory arrest and other serious events is roughly the same before and after the introduction of a dnr protocol. critically ill patients often have a prolonged icu and hospital stay, associated with deconditioning and muscle weakness. this prospective trial examined whether an early daily cycling session program while still bed-bound could reduce the level of deconditioning and thus reduce hospital stay. stable patients, ventilatory supported for at least days, were randomized into an experimental and a control group. both groups received identical medical treatment and daily sessions of chest physiotherapy, standardized mobilizations and functional rehabilitation. in addition, the exercise group was treated with active or passive cycling sessions for minutes per day using a bedside ergometer. functional status was assessed using item of the berg balance scale (bbs), functional ambulation categories (fac) and the physical functioning item of the sf health questionnaire. six-minute walking distance ( mwd) at hospital discharge and length of hospital stay (los) were registered. results are reported in table . we included patients (mean age ± ; % male). there was no difference in apache ii score ( . ± . ) between groups. the experimental group had a statistically significant better functional outcome at hospital discharge as measured with pf sf . at icu discharge there was no significant difference. ( ). we hypothesized that the physical training component of such a programme would improve exercise tolerance and qol in former intensive care unit (icu) patients without copd. former (non-copd) icu patients were screened for study inclusion, using previously published criteria ( ) and, after hospital discharge, commenced a week exercise programme. this involved hospital-based treatment sessions in the physiotherapy dept. and one home exercise session per week. exercise tolerance and qol were measured using the incremental shuttle walking test (iswt), a treadmill exercise test (trdex), pulmonary function tests (pfts) and the functional limitations profile questionaire (flp). all assessments were performed before and after the week programme. five consecutive subjects fulfilling the entry criteria entered the pilot study. mean (sd) values were; age . ( . ) yrs, length of stay in icu . ( . ) days, duration of mechanical ventilation . ( . ) days, admission apache ii score . ( . ). each subject completed the programme and had improved pfts, iswt, trdex and flp scores. group data ( table ) showed significant improvement between assessments performed prior to the programme (baseline) and after weeks. a six week course of physical training was associated with improved exercise tolerance, pulmonary function and qol in a small group of former (non-copd) icu patients. we intend to conduct a larger controlled study. key: cord- -c ytamge authors: da fonseca pestana ribeiro, jose mauro; park, marcelo title: less empiric broad-spectrum antibiotics is more in the icu date: - - journal: intensive care med doi: . /s - - -z sha: doc_id: cord_uid: c ytamge nan antibiotics are administered in approximately % of patients who are admitted to the intensive care unit (icu) and have helped to save millions of lives [ ] . however, up to half of all antibiotic prescriptions may be unnecessary [ ] . antibiotic overuse has contributed to alarmingly high levels of global antibiotic resistance, which is increasing at a rate faster than that at which novel antibiotics are produced. therefore, finding a fine balance between the appropriate use and avoidance of unnecessary administration is crucial to prevent the renaissance of a new world without antibiotics [ ] . antibiotics largely reduce mortality associated with moderate and severe infections, with a historical numberneeded-to-treat estimated in . for severe pneumonia patients [ ] . infection progressing to sepsis is the leading cause of death in icu patients and can be potentially treated using antibiotics, along with organ dysfunction support, and infection source control [ ] . from the cognitive dimension, the fear of patient deterioration due to sepsis favours the empirical use of antibiotics in icu patients. once a severe infection is diagnosed, the early administration of broad-spectrum antibiotics is recommended to decrease the risk of death [ ] . this intuitive recommendation is also based on observational studies that have been carried out in the emergency department [ , ] . in contrast, a randomized study, showed that the pre-hospital administration of antibiotics in septic patients did not reduce the mortality [ ] . furthermore, in a prospective cohort of icu patients with bacteremia, early initiation and appropriateness of antibiotic intervention were not found to impact mortality when adequately adjusted for confounders [ ] . additionally, a pooled analysis of the current literature failed to demonstrate a survival benefit related to antibiotic administration within the first hour or within the first h following a diagnosis of sepsis [ ] . in surgical and trauma patients, a quasi-experimental before and after study demonstrated that more aggressive antibiotic use had similar outcomes and higher antibiotic exposure compared to conservative use [ ] . interestingly, when antibiotics were administered following the diagnosis of shock (mean arterial pressure < mmhg), the mortality of the aggressively-treated group was higher than that of the conservatively-treated group ( % vs. %, p < . ). the authors presented several plausible factors to explain these findings. the adequacy of initial antibiotic treatment was lower in the aggressivelytreated group, which therefore extended the antibiotics exposure. moreover, the waiting time for blood cultures and observation of the clinical course may also disclose alternative diagnosis to infections. at last, up to % of patients initially diagnosed as septic shock did not have an identified infection h after their initial diagnosis [ ] . from the physiological point of view, there is no plausibility that minor time differences in antibiotic administration reduce the intensity of the inflammatory response, and may even be associated with a transient worsening after administration. lastly, it is difficult to differentiate the effect of early antibiotic use per se from the awareness of critical illness and the timely institution of high quality-of-care [ ] . several adverse effects related to antibiotic use are described in the literature; with acquired multidrug resistance (mdr) being the most concerning effect. since *correspondence: marcelo.park@hc.fm.usp.br intensive care unit, emergency department, hospital das clínicas, university of são paulo medical school, são paulo, brazil , antibiotic resistance has been a major fear of sir alexander fleming. currently, mdr bacteria are largely spread across the world [ ] . the real impact of mdrs on the outcomes of icu patients is debatable, but despite this controversy, the incidence of mdrs is related to poor quality-of-care, as an expression of reduced compliance to hand hygiene [ ] , and a high burden of antibiotic exposure [ ] . de-escalation approach, in which the antibiotic spectrum is narrowed or even withdrawn after re-evaluation, has been implemented to reduce exposure to antibiotics. de-escalation has proved to be safe in terms of survival; however, it is associated with an increased icu lengthof-stay, without reducing the incidence of mdrs [ ] . de-escalation decreases the time of antibiotic use, but a short exposure still exists; in this way, a single antibiotic dose may be enough to treat severe infections such as fig. two different mindsets in the decision making process to initiate antibiotics to critically ill patients who are getting worse. a aggressive mindset, in which the antibiotics are initiated as soon as possible to avoid further clinical deterioration; and b conservative mindset, in which antibiotics are only initiated with the infection diagnosis, or in shock patients without non-infectious alternative suspicion. mdr denotes multidrug resistant bacteria. atms denote antimicrobials. kpc denotes klebsiella pneumonia carbapenemase. cre denotes carbapenem resistant enterobacteriaceae. *in the intensive care unit, patients have h of close clinical observation. # the gram-positive cocci absence in the tracheal aspirate has a high negative predictive value to staphylococcus aureus growing in patients with high clinical probability of ventilator associated pneumonia and clinical worsening-new fever, hypothermia, unexplained tachycardia and hyperventilation. laboratorial worsening-leukocytosis, leukopenia, increased c-reactive protein and increased procalcitonin. red boxes⇒no evidence-no randomized study or cohort evaluation on favor the practice, or randomized study against the practice. yellow boxes⇒some evidence-at least one cohort evaluation on favor the practice. green boxes⇒clinical evidence-at least one randomized study on favor the practice meningococcal meningitis [ ] , and to promote profound and sustained microbiome unbalances, therefore facilitating opportunistic infections and damping the potential benefit of the de-escalation approach [ ] . the main step toward the reduction of antibiotic use is the adequacy of hand hygiene in healthcare professionals [ ] . an antibiotic stewardship focusing on feedback, monitoring, persuasion, and audit after each drug prescription is associated with a long term reduction in healthcare associated infections, antibiotic prescriptions, and health care costs, without the deleterious effects on length-of-stay, readmissions, and in-hospital mortality [ ] . furthermore, the decrease in the use of carbapenems, has been associated with an overall reduction in the incidence of mdrs [ ] to ensure patient safety, the early aggressive administration of broad-spectrum antibiotics in the icu setting is common practice [ ] . however, maintaining a conservative mindset with respect to antibiotic use and safety is fundamental to both the patient and environment. mindset modification accomplishes many dimensions; for instance, the reset model which has been applied to dairy cattle farms resulted in a reduction in antibiotic use in this area [ ] . reset dimensions are ( ) (r)ulesan external motivation to reduce antibiotic prescription; ( ) (e)ducation-showing that antibiotic prescriptions are unnecessarily excessive, expensive, and paradoxically unsafe; ( ) (s)ocial pressure-ensuring societal awareness that unnecessary use of antibiotics is dangerously growing; ( ) (e)conomics-the awareness of economic consequences of reduced use of antibiotics to save costs; and ( ) (t)ools-ways to spread knowledge regarding the conscious use of antibiotics. a schematic, aggressive, and conservative mindset to commence antibiotics is presented in fig. . there are several reasons why aggressive early use of broad-spectrum antibiotics should be avoided in icu patients. presence of shock without an alternative diagnosis other than infection, and a diagnosis of infection based on cultures, bacterioscopic examinations, and imaging results for the initiation of antibiotics is currently considered safe practice. furthermore, clinicians can consider investigating feasible alternative diagnosis for shock in unstable icu patients before antibiotics initiation. consideration of antibiotic use in our icus is essential, and if necessary; there is great plausibility in changing our mindset to restrict antibiotic use. the authors declare that they have no conflicts of interest. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. international study of the prevalence and outcomes of infection in intensive care units ready for a world without antibiotics? the pensières antibiotic resistance call to action treatment of pneumonia with -(p-aminobenzenesulphonamido) pyridine surviving sepsis campaign: international guidelines for management of sepsis and septic shock the timing of early antibiotics and hospital mortality in sepsis empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program prehospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomised trial antibiotic use and impact on outcome from bacteraemic critical illness: the bacteraemia study in intensive care (basic) the impact of timing of antibiotics on outcomes in severe sepsis and septic shock: a systematic review and meta-analysis aggressive versus conservative initiation of antimicrobial treatment in critically ill surgical patients with suspected intensivecare-unit-acquired infection: a quasi-experimental, before and after observational cohort study septic shock with no diagnosis at hours: a pragmatic multicenter prospective cohort study association between state-mandated protocolized sepsis care and in-hospital mortality among adults with sepsis clinical epidemiology of the global expansion of klebsiella pneumoniae carbapenemases interventions to reduce colonisation and transmission of antimicrobial-resistant bacteria in intensive care units: an interrupted time series study and cluster randomised trial effect of short-term carbapenem restriction on the incidence of nonpseudomonal multi-drug resistant gram-negative bacilli in an intensive care unit de-escalation versus continuation of empirical antimicrobial treatment in severe sepsis: a multicenter non-blinded randomized noninferiority trial ceftriaxone as effective as long-acting chloramphenicol in short-course treatment of meningococcal meningitis during epidemics: a randomised non-inferiority study profound alterations of intestinal microbiota following a single dose of clindamycin results in sustained susceptibility to clostridium difficile-induced colitis long-term effects of phased implementation of antimicrobial stewardship in academic icus the reset mindset model applied on decreasing antibiotic usage in dairy cattle in the netherlands key: cord- -lcgeingz authors: nan title: th international symposium on intensive care and emergency medicine: brussels, belgium, - march date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: lcgeingz nan introduction: increasing evidence supports a central role for "immunosuppression" in sepsis. it is necessary to develop biomarkers of immune dysfunction that could help to identify patients at risk of poor outcomes [ ] . the decreased expression of human leucocyte antigen (hla)-dra is proposed as a major feature of immunodepression and its persistent decrease is associated with mortality in sepsis [ ] . in a previous study, we evidenced that fcer a (fc fragment of ige receptor ia) is the gene showing the lowest expression levels of the entire transcriptome in sepsis [ ] . here we studied the association between fcer a expression and mortality in infected surgical patients. methods: fcer a and hla-dra expression levels were quantified by droplet digital pcr in blood of infected surgical patients. patients died within days ( . %). spearman test was used to evaluate the association between gene expression and the sequential organ failure assessment (sofa) score. areas under receiver operating curves (auroc) were used to determine the gene expression cut-off values predicting mortality. kaplan-meier survival curves were obtained and differences in survival between groups were evaluated using the log rank test. cox regression was employed to assess mortality risk at days. results: gene expression levels of fcer a and hla-dra correlated inversely with patients' severity (r: - . p< . ; r: - . , p< . respectively). both genes showed significant aurocs to predict survival, but fcer a showed the best accuracy (fig. ) . patients with introduction: severe pulmonary and renal conditions such as acute respiratory distress syndrome (ards), respiratory failure, and deterioration in kidney function often occur in patients with nosocomial pneumonia (np). the emergence and course of infection is genetically determined, hence host genetic landscape may influence an ability to resist infection. methods: variants for genotyping were selected using the phewas catalog which presents genotypic data for caucasian patients, phenotypes and single nucleotide polymorphisms (snps) with p < . [ ] . snps with the lowest p-values for phenotypes with both, respiratory and renal manifestations were selected: intergenic variants rs and rs , rs (edil ) and rs (cyp a ). cyp a gene was associated with pneumonia and ards in our previous investigations, so we included in our analysis three sites of cyp a gene (rs , rs and rs ) studied on a smaller sample. genotyping was performed on sites for a sample results: allele rs -g of the cyp a gene was protective against ards and an increase in creatinine level (fig. ) . the rs -g allele was associated with lung complications and with the development of severe respiratory insufficiency (fig. ) . conclusions: the snps rs and rs can influence the aggravation of pulmonary and renal symptoms through genetically mediated response to infection. introduction: an uncontrolled inflammatory response plays a major role in the sepsis related organ dysfunction. mesenchymal stem cells(mscs) can improve survival of sepsis experimental models by modulating the inflammatory response. macrophages have been considered as important immune effector cells and their polarization imbalance aggravates the disordered inflammation reaction. the project aims to identify the effects of mscs on macrophages polarization against dysregulated inflammatory response. methods: raw . cells were plated in the lower chambers of transwell system in the presence or absence of lipopolysaccharide (lps). then, mscs were seeded in the upper chambers and incubation for different time. finally, transforming growth factor beta (tgfβ) receptor (tgf-βr) inhibitor was added in transwell system. the phenotype of raw . cells were analyzed by flow cytometry, the levels of inflammatory cytokines were detected by enzyme-linked immunosorbent assay (elisa). results: our data showed that lps increased the level of interleukin (il)- in raw . cells (p< . ) (fig. ). in line with il- expression, lps induced the expression of m macrophage (p< . ). moreover, lps stimulated raw . cells co-culture with mscs in transwell system, mscs inhibited the expression of il- and m macrophages, while increased m macrophages (p< . ). compared with lps group, the concentration of tgf-Β was obviously increased in mscs treatment groups (p< . ), furthermore, there were no significantly difference between mscs directed and indicted groups. more significantly, tgf-βr inhibitor abolished the impact of mscs on lps stimulated raw . cells (p< . ) (fig. ) . conclusions: mscs polarized m macrophages into m macrophages and decreased pro-inflammatory cytokine levels by paracrining tgf-β. introduction: sepsis is dysregulated response to an infection, which can lead to progressive microcirculatory dysfunction, release of reactive oxygen intermediates (roi) and life-threatening organ dysfunction. our aim was to investigate the relationship between organ damage -characterized by the sequential organ failure assessment (sofa) scores, microcirculatory failure and roi production, in a large animal model of experimental sepsis. methods: fecal peritonitis was induced in anesthetized minipigs (n= ; . g/kg autfeces containing - x cfu bacteria i.p.), control animals (n= ) received sterile saline i.p. invasive hemodynamic monitoring and blood gas analyses were performed between - hrs, the signs for failure of circulatory, respiratory and urinary systems were evaluated in accordance with the sofa score. the microcirculatory perfusion rate in the sublingual region was measured by orthogonal polarization spectral imaging technique (cytoscan a/r). the leukocyte-origin roi production was determined by lucigenine (mostly o -. ) and luminol-based (h o ) chemiluminescence methods. results: between - hrs after induction the sofa score indicated moderate organ failure in animals (m: . ; p: . , p: . ) and the change was statistically significantly higher in pigs, suggesting severe organ dysfunction (m: . ; p: . , p: . ). the microcirculation was significantly deteriorated in all cases, independently of sofa score data. the h o production was significantly lower in septic animals as compared to controls, while the lucigenine enhanced roi production correlated with the sofa score-indicated moderate and severe organ dysfunction. conclusions: sublingual microcirculatory parameters are not correlating with the severity of sofa score-indicated organ dysfunction in abdominal sepsis. the measurement of roi production of the whole blood seems to be better biomarker for the detection of the progression of events from moderate to severe organ damages. introduction: the purpose of this study was to characterize differences in sepsis management in patients with and without left ventricular (lv) dysfunction. septic patients with lv dysfunction have higher mortality, and limited guidance exists for sepsis management of patients with lv dysfunction. the possibility exists that the cornerstones of sepsis management may contribute to these poor outcomes. methods: a retrospective chart review was conducted from may -january at two centers. adult patients who had a diagnosis of sepsis, were treated with vasopressors for > hours, and had an echocardiogram within months were included. patients were divided into two groups: reduced ejection fraction (ef) of < % and preserved ef defined as ef ≥ %. information about patient outcomes and sepsis management were collected. the primary outcome was the need for mechanical ventilation (mv). categorical and continuous data were analyzed using the chi-squared and mann-whitney u tests, respectively. the irb has approved this project. results: a total of patients with ef < % and patients with ef ≥ % were included. no significant differences in fluid management, vasoactive agent maximum rate or duration, or steroid use were observed. net fluid balance between low and preserved ef was positive . liters vs. . liters (p = . ), respectively. the number of patients that needed mv was higher in the low ef cohort ( % vs. %, p = . ), and this cohort had fewer mv-free days ( , iqr - vs. (iqr - ), p= . . conclusions: no significant differences were observed with regard to sepsis management, reflecting current guidelines. the significantly increased need for mv is a provocative result. a potential mechanism is the inability of a patient with reduced lv dysfunction to maintain appropriate cardiac and respiratory function in the face of fluid overload. prospective analysis of the role of fluid balance in septic patients with lv dysfunction is warranted. introduction: the relationship between myocardial injury and systemic inflammation in sepsis response is not well understood [ ] . it´s proposed to evaluate the association between myocardial injury biomarkers, high-sensitive troponin t (hs-ctnt) and n-terminal pro-brain natriuretic peptide (nt-probnp), with inflammatory mediators (il- , il- Β , il- , il- , il- / il- p , il a, il- and tnf-α ) and biomarkers, c protein reactive (cpr) and procalcitonin (pct), in septic patients methods: this was a prospective cohort study performed in three intensive care units, from september to september enrolling patients with sepsis (infection associated with organ dysfunction), and septic shock (hypotension refractory by fluids infusion requiring vasopressor). blood samples were collected up to h after the development of first organ dysfunction (d ) and on the th day after inclusion in the study (d ) results: ninety-five patients were enrolled, with median age years (interquatile? - ), apache ii: median ( - ), sofa: median ( - ); . % were admitted in icu with sepsis and . % with septic shock. hospital mortality was . %. in d , nt-probnp correlated with il- (r = . , p < . ) and il- (r = . , p < . ). in d , hs-ctnt and nt-probnp correlated with pct (r = . , p < . and r = . , p < . ; respectively). nt-probnp d was higher in nonsurvivors than in survivors on mortality in seventh day (p = . ) and in-hospital mortality (p = . ). hs-ctnt d (p = . ) and nt-probnp d (p < . ) were significantly higher in non-survivors on in-hospital mortality. nt-probnp d (or . ; ic % . - . , p= , ) and hs-ctnt d (or , ; ic % . - . , p= , ) were independently associated with in-hospital mortality conclusions: nt-probnp plasma levels at d correlated with il- and il- , and both nt-probnp and hs-ctnt at d correlated with pct. in addition, nt-probnp has been shown to be an important predictor of mortality introduction: heparin-binding protein (hbp) acts proinflammatory on immune cells and induces vascular leakage through cytoskeletal rearrangement and cell contraction in the endothelium and is a promising novel prognostic biomarker in sepsis and septic shock. however, studies on repeated measures of hbp are lacking. our objective was to describe the kinetics of plasma hbp during septic shock and correlate it to hemodynamic parameters. methods: we included patients with septic shock (sepsis- ) on admission to helsingborg hospital's intensive care unit (icu) during september to february . patients were sampled from icu admission and every hours for hours or until death or icu discharge. the plasma samples were analyzed for hbp and converted using the natural log (lnhbp) for normality. lnhbp was then evaluated against mean arterial pressure (map) as primary analysis and against systemic vascular resistance index (svri) as a secondary analysis, using mixed-effects linear regression models, treating patient id as a random intercept and adjusting for hemodynamic parameters. results: a total of patients were included with median age years, females ( %), surgical admissions ( %), median sofa-score points on day one and deaths from all causes within days ( %). plasma hbp ranged from to ng/ml with a median of ng/ml (lnhbp range . to . , median: . ). an increase lnhbp was significantly associated with a decrease in map (coef. - . mmhg, % ci: - . to - . , p= . , n= ), when adjusting for heart rate (hr), noradrenaline (na), vasopressin (vp), dobutamine (dbt) and levosimendan (ls). in a secondary subgroup analysis, an increase in lnhbp was also significantly associated with a decrease in svri (coef. - . dyne*s*cm- *m- , % ci: - . to - . , p= . , n= ), when adjusting for map, hr, na, vp, dbt, ls and cardiac index. conclusions: repeated measures of plasma hbp during septic shock were correlated with important hemodynamic parameters in this small pilot study. introduction: mid-regional pro-adrenomedullin (mr-proadm) comes from the synthesis of the hormone adrenomedullin (adm), which is overexpressed during inflammation and progression from sepsis to septic shock. thus, mr-proadm can be a useful biomarker for the clinical management of septic patients [ ] . the aim of our study was to understand the ability of mr-proadm to predict -day ( -d) mortality and to find a correlation between mr-proadm and sequential organ failure assessment (sofa) score in the first hours from intensive care unit (icu) admission. methods: we evaluated consecutive septic shock patients according to sepsis iii definitions. clinical data from the medical records included demographics, comorbidities, laboratories, microbiology and biomarker levels. whole blood samples for biomarker profiling were collected at , and hours from icu admission. mr-proadm measurement was detected in edta plasma using a sandwich immunoassay by trace® (time resolved amplified cryptate emission) technology (kryptor thermo fischer scientific brahms). results: overall -d mortality rate was . %. mr-proadm [odds ratio (or) = . ], sofa score (or = . ) and lactate (lac) levels (or = . ) in the first hours were associated with -d mortality in univariate logistic analysis (p value < . , table ). -d mortality rate was not associated with procalcitonin (pct) levels (or = . ). further linear regression analysis showed significant correlation between mr-proadm and sofa score at hours from icu admission (p value< . , fig. , table ). conclusions: mr-proadm demonstrated superior accuracy to predict -d mortality compared to pct levels and is directly linked to sofa score at hours from admission. mr-proadm may aid early identification of poor prognosis septic patients who could benefit a more intensive management. introduction: study of the expression of cell free dna (cfdna) in the search for new biomarkers for infection, sepsis and septic shock. methods: the population studied was all patients included in the sepsis protocol from march to january , hospitalized patients of a federal public hospital. plasma samples were collected for quantification of cfdna, which after centrifugation were stored at - °c and then thawed and analyzed by fluorescence using a varioskan flash fluorometer). cfdna values were expressed as ng/ml. the patients were divided into groups: infection and sepsis/septic shock. we analyzed mortality, sequential organ failure assessment score (sofa score), qsofa (quick sofa), comorbidities, cfdna and laboratory parameters of patients. results: among the patients, % were classified as infection and % sepsis/septic shock. overall lethality was %, infection . %, and sepsis/septic shock . % (p< . ). the mean of cfdna, sofa and lactate was higher according to the classification of infection and sepsis/septic shock: cfdna ( . ± . and . ± . , p= . ), sofa ( . ± . and . ± . , p< . ), qsofa (positive in % and %, lactate ( . ± . and . ± . , p< . ). we analyzed leukocytes, creatinine, crp (c reactive protein), inr (international normalized ratio), as predictors of severity and only crp showed no association with disease severity (p= . ). levels of cfdna and qsofa showed worse prognostic utility as a predictor of sepsis / septic shock when compared to lactate and sofa: or . ( % ci . - . ), p= . for cfdna, or . ( % ci . - . ), p= . for sofa and or . ( % ci . - . ), p= . for lactate. negelkerke r square was , for cfdna. in addition, area under the curve for cfdna mortality was . ( % ci . - . ) and sofa . ci % . - . ). conclusions: our study suggests that cfdna and qsofa have worse prognostic accuracy when compared to lactate and sofa, variables already used in clinical practice and easily measured. introduction: the aim of this study is to develop a "molecular equivalent" to sequential organ failure assessment (sofa) score, which could identify organ failure in an easier, faster and more objective manner, based on the evaluation of lipocalin- (lcn /ngal) expression levels by using droplet digital pcr (ddpcr). sepsis has been classically defined as the exuberant, harmful, pro-inflammatory response to infection. this concept is changing [ ] and the presence of a life-threatening organ dysfunction caused by a dysregulated host response to infection is now considered a central event in the pathogenesis of sepsis [ ] . methods: lcn expression levels were quantified by ddpcr in blood of a total of surgical patients with a diagnosis of infection. spearman analysis was used to evaluate if lcn correlated in a significant manner with sofa score. area under the receiver operating curve (auroc) analysis and multivariate regression analysis were employed to test the ability of lcn to identify organ failure and mortality risk. results: spearman analysis showed that there was a positive, significant correlation between lcn expression levels and sofa score (fig. ) . aurocs analysis showed that lcn presents a good diagnostic accuracy to detect organ failure and mortality risk (fig ) . in the multivariate regression analysis, patients showing lcn expression levels over the optimal operating points (oops) identified in the aurocs showed a higher risk of developing organ failure (table ) and a higher mortality risk (table ) . conclusions: quantifying lcn expression levels by ddpcr is a promising approach to improve organ failure detection and mortality risk in surgical patients with infection. introduction: sepsis is an inflammatory state due to an exacerbated immune response against infection. in cancer patients, sepsis presents a -fold higher mortality than in general population and leads to longer intensive care unit (icu) and hospital lengths of stay. it has been shown that reduced levels of circulating immunoglobulins (ig) might be a surrogate marker of unfavorable outcome in sepsis [ ] . the aim of this study was to evaluate the association between ig levels in plasma and -day mortality rate in cancer patients with septic shock. methods: from december to november , we conducted a prospective study in the intensive care unit (icu) of cancer institute of state of sao paulo, an -bed icu linked to university of sao paulo. patients ≥ years old with cancer and septic shock were enrolled. descriptive statistics were computed for demographic and outcome variables. laboratory data and ig levels were collected at icu admission and at days , and . a multivariate analysis was performed to evaluate predictors of -day mortality. results: a total of patients were included in the study. the -day and -day mortality were . % and . %, respectively. no significant differences in igm and igg levels were observed between survivors and non-survivors. in both groups, the median igm levels were low and the median igg levels were normal. in the multivariate analysis for -day mortality, a favorable status performance measured by the eastern cooperative oncology group (ecog) was associated with better survival; metastatic disease, higher sequential organ failure assessment (sofa) score at admission and higher levels of initial lactate were associated with increased mortality. conclusions: low levels of serum endogenous immunoglobulins are not predictors of -day mortality in cancer patients with septic shock. introduction: cytovale has developed a rapid biophysical assay of the host immune response which can serve as a rapid and reliable indicator of sepsis. neutrophils and monocytes undergo characteristic structural and morphologic changes in response to infection. one type of response is the generation of neutrophil extracellular traps (nets), these have been proposed as potential mediators for widespread tissue damage. during netosis there is a fundamental reorganization of a cell's chromatin structurea signal that we have shown is sensitively measured by the cytovale cytometer. we hypothesized that quantification of plasticity (deformability) of leukocytes in the peripheral blood provides an early indicator of sepsis. the cytovale assay uses microfluidic cytometry to measure the plasticity of up to , white blood cells from edta-anticoagulated, peripherally-collected whole blood and provides a result in minutes. methods: in two prospective studies conducted in two academic medical centers in baton rouge, la, the cytovale test was performed on peripheral blood samples obtained from patients who presented to the emergency department with signs or symptoms suggestive of infection. the two studies included high acuity patients ( patient study) and low acuity patients ( patient study). an adjudicated reference diagnosis of sepsis or no sepsis was established for each subject, using consensus definitions, by review of the complete medical records. results: the receiver operator curve (roc) performance of the cytovale assay for both studies demonstrated an area under the curve (auc) greater than . (fig. ) . conclusions: measurement of neutrophil and monocyte plasticity by a novel assay provides an accurate and rapid indication of sepsis in patients who present to an emergency room with signs or symptoms of infection. plasma hepatocyte growth factor in sepsis and its association with mortality: a prospective observational study introduction: sepsis and septic shock are commonly associated with endothelial cell injury. hepatocyte growth factor (hgf) is a multifunctional protein involved in endothelial cell injury and plays a pivotal role in sepsis. this study assesses its correlation with relevant endothelial cell injury parameters and prognostic value in patients with sepsis. methods: a prospective, observational cohort study was conducted in patients with sepsis admitted to the department of critical care medicine at the zhongda hospital from november to march . the plasma hgf level was collected on the first h after admission (day ) and day , then was measured by enzyme-linked immunosorbent assay. the primary endpoint was defined as all-cause -day mortality. furthermore, we analyzed the correlation of hgf with relevant endothelial cell injury markers. results: eighty-six patients admitted with sepsis were included. hgf levels of non-survivors were elevated upon day ( . ± . pg/ml vs. . ± . pg/ml; p = . ) and day ( . ± . pg/ml vs. . ± . pg/ml; p = . ) compared with that in survivors, and showed a strong correlation with von willebrand factor (r = . , p < . ), lactate (r = . , p = . ), pulmonary vascular permeability index (r = . , p = . ), first h fluid administration (r = . , p < . ) and sequential organ failure assessment score (r = . , p = . ) (fig. ) . plasma levels were able to discriminate prognostic significantly on day (auc: . , %ci: . - . ) and day (auc: . , %ci: . - . ) (fig. ) . conclusions: hgf levels are associated with sepsis and are correlated with established markers of endothelial cell injury. elevated hgf level in sepsis patients is a predictor of mortality. methods: adult patients with septic shock by the sepsis- classification due to lung infection or primary bacteremia or acute cholangitis are screened using two consecutive measurements of ferritin and of hla-dr/cd co-expression for mals (ferritin above , ng/ml) or immunosuppression (hla-dr/cd less than %) and randomized into immunotherapy with either anakinra (targeting mals) or recombinant ifnγ (targeting immunosuppression) and into placebo treatment. main exclusion criteria are primary and secondary immunodeficiencies and solid and hematologic malignancies. results: patients have been screened so far. most common infections are community-acquired pneumonia ( . %), hospitalacquired pneumonia ( . %) and primary bacteremia ( . %). mean +/-sd sofa score is . +/- . and charlson's comorbidity index . +/- . ; patients have mals ( . %); two immunosuppression ( %); the majority remain unclassified for immune state. conclusions: current screening suggests greater frequency of mals than recognized so far in a setting of septic shock due to lung infection or primary bacteremia or acute cholangitis. development of an algorithm to predict mortality in patients with sepsis and coagulopathy d hoppensteadt , a walborn , m rondina , j fareed study was to develop an equation incorporating biomarker levels at icu admission to predict mortality in patients with sepsis, to test the hypothesis that using a combination of biomarkers of multiple systems would improve predictive value. methods: plasma samples were collected from patients with sepsis at the time of icu admission. biomarker levels were measured using commercially available, elisa methods. clinical data, including the isth dic score, sofa score, and apache ii score were also collected. -day mortality was used as the primary endpoint. stepwise linear regression modeling was performed to generate a predictive equation for mortality. results: differences in biomarker levels between survivors were quantified and using the mann-whitney test and the area under the receiver operating curve (auc) was used to describe predictive ability. significant differences (p< . ) were observed between survivors and non-survivors for pai- (auc= . ), procalcitonin (auc= . ), hmgb- (auc= . ), il- (auc= . ), il- (auc= . ), protein c (auc= . ), angiopoietin- (auc= . ), endocan (auc= . ), and platelet factor (auc= . ). a predictive equation for mortality was generated using stepwise linear regression modeling. this model incorporated procalcitonin, vegf, the il- :il- ratio, endocan, and pf , and demonstrated a better predictive value for patient outcome than any individual biomarker (auc= . ). conclusions: the use of a mathematical modeling approach resulted in the development of a predictive equation for sepsis-associated mortality with performance than any individual biomarker or clinical scoring system. furthermore, this equation incorporated biomarkers representative of multiple physiological systems that are involved in the pathogenesis of sepsis. the effects of biomarker clearances as markers of improvement of severity in abdominal septic shock during blood purification t taniguchi , k sato , m okajima introduction: sepsis associated coagulopathy (sac) is commonly seen in patients which leads to dysfunctional hemostasis. the purpose of this study is to determine the thrombin generation potential of baseline blood samples obtained from sac patients and demonstrate their relevance to thrombin generation markers. methods: baseline citrated blood samples were prospectively collected from patients with sac at the university of utah clinic. citrated normal controls (n= ) were obtained from george king biomedical (overland park, ks). thrombin generation studies were carried out using a flourogenic substrate method. tat and f . were measured using elisa methods (seimens, indianapolis, in). functional antithrombin levels were measured using a chromogenic substrate method. results: the peak thrombin levels were lower ( ± nm) in the dic patients in comparison to higher levels observed in the normal plasma ( ± nm). the auc was lower ( ± ) in the dic group in comparison to the normals ( ± ). the dic group showed much longer lag time ( . ± . ) in comparison to the normal group ( . ± . ). wide variations in the results were observed in these parameters in the dic group. the f . levels in the dic group were much higher ( ± pmol) in comparison to the normal ( ± pmol). the tat levels also increased in the dic group ( . ± . ng/ml) in comparison to the normal ( . ± . ng/ml). the functional antithrombin levels were decreased in the dic group ( ± %). conclusions: these results validate that thrombin generation such as f . and tat are elevated in patients with dic. however thrombin generation parameters are significantly decreased in this group in comparison to normals. this may be due to the consumption of prothrombin due to the activation of the coagulation system. the decreased functional at levels observed in the dic group are due to the formation of the complex between generated thrombin and antithrombin. introduction: sepsis-associated disseminated intravascular coagulation (dic) is a complex clinical scenario involving derangement of many processes, including hemostasis. assessment of markers including inflammation, endothelial function, and endogenous anticoagulants may provide insight into dic pathophysiology and lead to improved methods for assessment of patient condition and response to treatment. methods: citrated plasma samples were collected from patients with sepsis and suspected dic at icu admission and on days and . dic score was determined using the isth scoring algorithm (e.g. platelet count, pt/inr, fibrinogen and d-dimer). cd ligand (cd l), plasminogen inhibitor (pai- ), nucleosomes, procalcitonin (pct), microparticle tissue factor (mp-tf) and prothrombin . (f . ) were measured using commercially available elisa kits. protein c activity was measured using a clot-based assay. interleukin (il- ), interleukin (il- ), interleukin (il- ), tumor necrosis factor alpha (tnfα), and monocyte chemoattractant protein (mcp- ) were measured using biochip technology. results: significant differences in levels of protein c (p= . ), pct (p= . ), il- (p= . ), il- (p= . ), pai- (p= . ), were observed between survivors and non-survivors. significant variation of protein c (p= . ), nucleosomes (p= . ), pct (p< . ), il- (p= . ), il- (p= . ), il- (p= . ), tnfα (p= . ) and mcp- (p= . ) were observed based on severity of dic score. conclusions: markers from multiple systems perturbed in dic were associated with mortality, suggesting that while these systems may not be routinely evaluated in the normal course of patient care, dysfunction of these systems contributes significantly to mortality. in addition, numerous inflammatory cytokines showed an association with dic score. this suggests that the measurement of additional markers in sepsis-associated dic may be of value in the prediction of mortality and may be helpful in guiding treatment for these patients. introduction: the endotoxin activity assay (eaa) is a rapid immunodiagnostic test based on chemiluminescence. it was approved by the fda in as a diagnostic reagent for risk assessment of severe sepsis in the icu. ascertaining endotoxin levels in the bloodstream is important in targeting patients and determining the appropriate timing for initiation of treatment. it has high sensitivity and specificity for endotoxin, and is considered to be useful in predicting clinical symptoms and determining prognosis. the usefulness of the eaa has yet to be fully clarified. methods: a total of patients admitted to the icu between january and june with suspected sepsis or sepsis were enrolled. the eaa was conducted within hr after admission. patient characteristics were determined, together with levels of il- , procalcitonin, presepsin, and pao /fio . thereafter, the patients were classified into groups depending on their eaa value: ) < . ; ) from ≤ . to < . ; ) from ≤ . to < . ; ) from ≤ . to < . ; and ) ≤ . ). the transition of various markers was also examined. the spearman rank correlation, wilcoxon rank sum test, and a nonrepeated anova were used for the statistical analysis. a p-value of < . was considered statistically significant. the eaa values showed a positive correlation with both the apache ii (r= . ) and sofa scores (r= . )(p< . ), although that with the latter was stronger. a significant correlation was also observed with levels of procalcitonin (r= . ) and presepsin (r= . early diagnosis is important to allow early intervention. the current clinical methods are insufficient for early detection. we hypothesized that intraperitoneal microdialysis allows detection of peritonitis prior to changes in standard clinical parameters in a pig model. methods: bacterial peritonitis was induced in pigs by bowel perforation and intraperitoneal fecal instillation, one pig underwent sham surgery. intraperitoneal microdialysis catheters were placed in each abdominal quadrant. the observation time was hours. results: in peritonitis pigs the intraperitoneal lactate increased during the first two hours and remained elevated throughout the observation time (table ) , whereas the arterial lactate remained within reference range (< . mm). intraperitoneal glucose decreased significantly. hemodynamics were hardly influenced during the first two hours, and decreased thereafter. sham surgery did not influence in any of the parameters. conclusions: a rapid and pronounced increase in intraperitoneal lactate and decrease in intraperitoneal glucose was observed after instillation of intraabdominal feces. systemic lactate increase was absent, and the hemodynamic response was delayed. postoperative intraperitoneal microdialysis is applicable in detecting peritonitis earlier than standard clinical monitoring and should be evaluated in a clinical study in order to explore if early intervention based on md data will reduce icu length of stay, morbidity and mortality. introduction: procalcitonin (pct) is a serum biomarker suggested by the surviving sepsis campaign to aid in determination of the appropriate duration of therapy in septic patients. trauma patients have a high prevalence of septic complications, often difficult to distinguish from inflammatory response. pct values typically declined after h from trauma and increased only during secondary systemic bacterial infections. the aims of the study are to evaluate reliability and usefulness of pct serum concentration in trauma. methods: we retrospectively analyzed data from trauma patients admitted to icu at bufalini hospital -cesena, from july to august . we collected data about antimicrobial therapy, injury severity score (iss), first arterial lactate in emergency room, sofa score and sepsis severity. plasma pct concentration was measured using an automate analyzer (modular e-brahms) on st day of antimicrobial therapy and every h hours. antimicrobial therapy was stopped according to a local protocol; however medical judgment was considered the overriding point for therapeutic decision. results: median iss of patients was . , inter quartile range (iqr) . . pct mean concentration at the starting of antimicrobial treatment was . μg/l (d.s . ), median . (iqr . ). no significative correlation (spearman´s rho test) was found between pct at day of antimicrobial therapy and iss (rho - . ), between first arterial lactate in er and pct (rho . ). daily course of pct was not related to distance from trauma (rho - . ). in of patients ( . %) pct measurement led physician to save days of antimicrobial therapy compared with standard clinical practice. we couldn´t find any cut off value. conclusions: our experience suggests that pct could help physician to optimize duration of antimicrobial therapy in trauma patients. no standard approach can be recommended at present. introduction: long duration of antimicrobial treatment may predispose to colonization and subsequent infections by multidrugresistant organisms (mdro) and clostridium difficile. progress (clinicaltrials.gov registration nct ) is an on-going trial aiming to use pct for the restraining of this calamity. methods: adult patients with sepsis by the sepsis- classification and any of five infections (pneumonia community-acquired; hospital-acquired or ventilator-associated; acute pyelonephritis; primary bacteremia) are randomized to pct-guided treatment or standard of care (soc) treatment. in the pct arm antibiotics are discontinued when pct on or after day is decreased by more than % of the baseline or remains below . ng/ml; in the soc arm antibiotics are discontinued at the discretion of the attending physician. patients are followed for six months. primary endpoint is the rate of infections by mdro and/or c.difficile or death. serial stool samples are cultured for mdro and screened for glutamate dehydrogenase antigen and toxins of c.difficile. results: patients have been enrolled so far. mean ± sd sofa score is . ± . . most common diagnoses are community-acquired the progress trial is the first trial assessing the probable benefit from pct guidance to reduce ecological sequelae from long-term antibiotic exposure. analysis of baseline patient characteristics indicates that progress is a real-world trial so that results can have major clinical impact. prospective multi-site validation of -gene host response signature for influenza diagnosis s thair , s schaffert , m shojaei , t sweeney there are no blood-based diagnostics able to identify influenza infection and distinguish it from other infections. we have previously described a blood-based -gene influenza meta-signature (ims) score to differentiate influenza from bacterial and other viral respiratory infections. methods: we prospectively validated the ims in a multi-site validation study by recruiting individuals ( patients with suspected influenza, healthy controls) in community or hospital clinics across australia. we assayed the ims and genes from viral genome of influenza strains to generate the blood flu score (bfs) as a measure of viremia using nanostring from whole blood rna. results: using clinically determined phenotypes, the ims score distinguished patients with influenza from healthy (auc= . ), non-infected (auc= . ), bacterial (auc= . ), other viruses (auc= . ) ( figure a) . interestingly, probes of bfs were found in all phenotypic groups (non-infected, bacterial, and other viral infections) to varying degrees, and positively correlate with the ims score (r= . ). ims aurocs improve when the bfs is used to inform the phenotypic groups: healthy (auc= . ), non-infected (auc= . ), bacterial (auc= . ), other viruses (auc= . ) ( figure b ). patients who were clinically influenza negative but had a high ims and bfs were admitted less often, yet had~ -fold higher mortality than those who were clinically influenza negative with low ims and no bfs (table ) . conclusions: collectively, our prospective multi-center validation of the ims demonstrates its potential in diagnosis of influenza infections. introduction: previous findings of our group suggest that patients with gram-negative hospital-acquired severe sepsis have better prognosis when sepsis is developing after recent multiple trauma through stimulation of favorable interleukin (il)- responses [ ] . under a similar rationale, we investigated if preceding osteomyelitis may affect experimental osteomyelitis. methods: sham or experimental osteomyelitis was induced in male new zealand white rabbits after drilling a hole at the upper metaphysis of the left tibia and implementing diluent or log of staphylococcus aureus using foreign body. after three weeks, the foreign body was removed and experimental pyelonephritis or sham surgery was induced after ligation of the right pelvo-ureteral junction and instillation of log of escherichia coli in the renal pelvis. survival was recorded and circulating mononuclear cells were isolated and stimulated for the production of tumour necrosis factor-alpha (tnfa) and il- . at death or sacrifice, tissue outgrowth and myeloperoxidase (mpo) were measured. results: four sham-operated rabbits (s), rabbits subject to sham surgery and then pyelonephritis (sp) and rabbits subject to osteomyelitis and then pyelonephritis (op) were studied. survival after days of group sp was . % and of group op % (log-rank . ; p: . ). lab findings are shown in figure . il- production was blunted. negative correlation between e. coli outgrowth and tissue mpo was found at the right kidney of the op group (rs: - . , p: . ) but not of the sp group (rs: - . , p: . ). conclusions: preceding staphylococcal osteomyelitis provides survival benefit to subsequent experimental osteomyelitis through downregulation of innate immune responses leading to efficient phagocytosis. introduction: activation of neutrophils is a mandatory step and a sensitive marker of a systemic inflammatory response syndrome (sirs) which is closely related to development of multiple organ failure. the search for drugs that can prevent sirs and reduce mortality in critically ill patients remains significant. the aim of this study was to study the anti-inflammatory effect of the synthetic analogue of leu-enkephalin (dalargin) on human neutrophils. methods: the study was conducted on isolated from the blood of healthy donors neutrophils. their activation was assessed by fluorescent antibodies to markers of degranulation cd b and cd b (sd b-fitc and cd b-alexafluor (bd biosciences, usa). as inductors of inflammation lipopolysaccharide (lps) and the peptide formyl met-leu-pro (fmlp) were used. mkm fmlp and dalargin in concentrations of and μ g / ml were added to neutrophils at a concentration of ppm / ml and incubated for min at °c; then antibodies were added and incubated for min on ice; then fluorescence was assessed by flow cyto flow meter beckman-coulter fc . non-parametric criteria were used; data were presented as a median and %- % interquartile intervals. the statistical significance was estimated using mann-whitney test. the difference was considered statistically significant at p< . results: synthetic analogue of leu-enkephalin in various concentrations has an anti-inflammatory effect on both intact and preactivated with bacterial components neutrophils, reducing their activation and degranulation in a dose-dependent manner (figs. , ) . conclusions: synthetic analogue of leu-enkephalin prevents neutrophil activation by bacterial compounds. this has a potential of translation into clinical practice for sepsis treatment. introduction: the endothelin system plays important roles in circulatory regulation through vasoconstrictor et-a and et-b receptors and vasodilator et-b receptors (etar; etbr, respectively). tissue hypoxia during the progression of sepsis is associated with microcirculatory and mitochondrial disturbances. our aim was to investigate the possible influence of etar antagonist, etbr agonist or combined treatments on oxygen dynamics, microcirculatory and mitochondrial respiration parameters in experimental sepsis. methods: male sprague-dawley rats (n= /group) were subjected to faecal peritonitis ( . g/kg faeces ip) or sham-operation. septic animals were treated with sterile saline solution, or received the etar antagonist etr-p /fl peptide ( nmol/kg iv), etbr agonist irl- ( . nmol/kg iv) or same doses as combination therapy, hr after sepsis induction. invasive hemodynamic monitoring and blood gas analyses were performed during a -min observational window. introduction: sepsis often induces immunosuppression, which is associated with high mortality rates. nivolumab is a human igg- antibody directed against the programmed cell death (pd- ) immunecheckpoint inhibitor, which disrupts pd- -mediated signaling and restores antitumor immunity. nivolumab is an approved anti-cancer drug that may have the potential to improve sepsis-induced immunosuppression. methods: this multicenter, open-label study investigated the safety, pharmacokinetics and pharmacodynamics of a single intravenous infusion of or mg nivolumab in japanese patients with immunosuppressive sepsis (lymphocytes ≤ /μl). the dosing of nivolumab was set using the predicted steady state concentration of nivolumab at mg/kg every weeks (q w), which was the approved dosage for cancer patients at the time of planning. results: five and eight patients were assigned to the and mg groups, respectively. the mean (standard deviation) peak serum drug concentration in the mg group was comparable to the predicted median concentration ( % pi [prediction (figures and ). adverse events (aes) were observed in four patients in each group. drug related-aes were observed in only one patient in the mg group (table ) . no deaths related to nivolumab occurred. conclusions: a single dose of mg nivolumab appeared to be well tolerated and sufficient to maintain nivolumab blood concentration in patients with sepsis. results suggest both and mg nivolumab therapy could improve relevant immune indices. introduction: the systemic inflammatory response syndrome (sirs) accompanies tissue trauma and infection and, when severe or dysregulated, contributes to multiple organ failure and critical illness. observational studies in man and animal have shown that low-dose acetyl-salicylic acid promotes resolution of inflammation and might attenuate excessive inflammation by increasing the synthesis of specialised pro-resolving lipid mediators (spms). methods: we randomly assigned patients with sirs who were expected to stay in icu for more than hours to receive enteral aspirin ( mg per day) or placebo for days or until death or discharge from the icu, whichever came first. the primary outcome was il- serum concentration at h after randomisation. the secondary outcomes included safety and feasibility outcomes. in one center, additional blood samples were taken during the first three days for exploratory analysis of spms using reversed-phase highperformance liquid chromatography -tandem mass spectrometry (rp-hplc-ms/ms). results: from march through december a total of patients across four general icus in australia underwent randomization (table ) . compared to placebo patients, il- serum concentration after h in aspirin-treated patients was not significantly lower ( [ - ] pg/ml vs [ . - ] pg/ml; p= . ). there were no significant differences for control vs. aspirin-treated patients in the change of pro-resolving/anti-inflammatory lipids between the time points (figure , ). there were no between-group differences with respect to icu or hospital mortality, number of bleeding episodes or requirements for red cell transfusions (table ) . conclusions: in patients admitted to the icu with sirs, low-dose aspirin did not result in a decreased concentration of inflammatory biomarkers compared with placebo. introduction: sepsis is associated with excessive ros production, nf-kb, inos and inflammatory mediators overexpression. vitamin c is a cellular antioxidant, it increases enos and decreases nf-kb; it has several immune-enhancing effects and is crucial for endogenous vasopressors synthesis. vitamin c reserves in sepsis are often as poor as in scurvy [ ] . in recent studies, intravenous high vitamin c dose seems to reduce organ failure and improve outcome in septic shock. methods: we treated all septic shock patients admitted to our icu in months (from / to / ) with intravenous vitamin c . g/ h and thiamine mg/ h (for its synergistic effects) [ ] as adjunctive therapy for consecutive days and we compared data to septic shock patients admitted in the previous months period. we enrolled patients: received vitamins supplementation, standard of care. we analysed -days mortality, sofa at and hours, pct variation from baseline in first days, vasoactive therapy length and daf (days alive and free from vasopressors, mechanical ventilation and rrt in days follow up). patients with end stage kidney disease were ruled out. we analysed data with mann-whitney and wilcoxon tests. results: vit c group showed lower -days mortality ( % vs . %: ns); sofa improvement at (- . ± . vs - . ± . : p= . ) and hours (- . ± vs - . ± : p< . ) was higher in vit c group; vit c patients had faster pct reduction without statistical significance. mean vasoactive therapy length was quite similar. daf was . (± . ) days in vit c group and . (± . ) in controls (p= . ). control patients needed rrt, none in vit c group. conclusions: despite small study size, we found that vit c has positive effects on survival and improves sofa score (fig. ) and daf (fig. ) in septic shock. no vit c patient developed oxalate nephropathy nor worsened renal function. introduction: toxin-producing gram-positive organisms cause some of the most severe forms of septic shock [ , ] . adjunctive therapies such as intravenous immunoglobulins (ivig) have been proposed for these patients [ , ] . however, at patient presentation, the presence of a toxin-producing organism is most often unknown. methods: we reviewed the use of ivig in our patients requiring extracorporeal membrane oxygenation (ecmo) in a -year period between february and march . results: in % ( / ) of the patients that received ivig for presumed toxin-mediated shock, group a streptococcus or panton-valentine leukocidin producing s. aureus was isolated, but the clinical characteristics of these patients were not significantly different from the ones with other final diagnoses, except for a predisposing influenza infection and the presence of an often very high procalcitonin level. these patients were extremely unwell at presentation with a sofa score of ± , high lactate levels ( . ± . mmol/l) and need for vasopressors (equivalent norepinephrine dose of . ± . μ g/kg/min). they had very high inflammatory parameters with a procalcitonin ≥ ng/ml in more than half of patients ( / ). ivig use in these patients was generally safe, with only possible transfusion reaction. the mortality of % ( / ) was lower than predicted based on the sofa scores. conclusions: ivig administration can be considered in a selected group of patients presenting with acute and very severe septic shock, as part of a multimodal approach [ ] . introduction: extra corporeal treatments are used in septic patients to decrease the inflammatory mediators, but definitive conclusions are lacking . more over in many studies the effect of aki isn't evaluated and this may be an important bias. . the aim of this study is to evaluate in septic patients with aki: the effect of the adsorbing membrane oxiris on the immunological response -the different response in survivors and non survivors methods: from our local data base we analyzed retrospectively septic shock patients with aki (kdigo classification) submitted to crrt with the adsorbing membrane oxiris (baxter, usa ) . at basal time ( t ) and at the end of the treatment ( t ) we evaluated the following variables: il il procalcitonin endotoxin (eaa). all data are expressed as mean ±sd or median and iqr. student t test or mann-whitney was used to compare values changes. p < . was considered statistically significant. results: thirty patients with sepsis /septic shock and aki were enrolled in this study. patients had aki , patients aki , patients aki . the duration of treatment was ± hours. patients had citrate as anticoagulation and heparine continous ev. at table are shown the main results of this study in all the patients. survivors vs non survivors had a significant decrease of il , procalcitonin and eaa. conclusions: data of this study confirm on clinical ground previous study "in vitro" [ ] that the adsorbing membrane oxiris has important immunological effect during septic shock with aki. this must be confirmed in a rct. introduction: sepsis is common and often fatal, representing a major public health problem. hemoadsorption (cytosorb) therapy aims to reduce cytokines and stabilise the overall immune response in septic shock patients. methods: a prospective, multi-centre, investigator initiated study to evaluate hemoadsorption (cytosorb) therapy in septic shock patients admitted to a tertiary icu's in india during to . all centres followed a common protocol and received ethics committee approval. results: a total of patients were administered cytosorb in addition to standard of care. a total of patients ( %) survived out of patients. among survival group, patients ( %) were administered cytosorb within hours of icu admission resulting in significant reduction in sepsis scores, apache ii ( . vs . ) and sofa ( . vs . ) post cytosorb therapy. also there was reduction in inflammatory markers like cytokines il in most of the patients. all patients in survivor group showed a significant improvement in map ( . vs . ) and reduction in vasopressors (epinephrine . to . mcg/kg/min, nor-epinephrine . to . mcg/kg/min) after cytosorb therapy. no device related adverse effect was observed in any of the patients. among the non-survivor group, ( patients, %) we observed that cytosorb was administered after hours of icu admission. although a few patients showed improvement in sofa score, majority did not show a significant improvement with map ( . vs . mm of hg) and required increased demand in vasopressors. conclusions: in this multi-centered prospective iis study, we could observe clinical benefits of hemoadsorption (cytosorb) therapy in septic shock patients if the therapy was initiated early. larger randomised study are required to establish the above clinical benefits in larger patient population. a single centre experience with hemoadsorption (cytosorb) in varied causes of sepsis and mods y mehta , c mehta , a kumar , j george , a gupta , s nanda , g kochar , a raizada introduction: sepsis and the multiorgan failure is a leading cause of mortality in the intensive care unit. promising new therapies continue to be investigated for the management of septic shock. we tried to evaluate a novel hemoadsorption therapy (cytosorb) through a retrospective evaluation of patient's data in our centre. we used it as an adjuvant therapy in our patients with sepsis due to varied causes. methods: we retrospectively analysed data of introduction: septic shock is a life-threatening multiple organ dysfunction that has high morbidity and mortality in critically ill patients, due to a dysregulated host response to infection. the aim of this study was to evaluate the efficacy of therapeutic cytokine removal (cytosorb®) in the management of patients with septic shock. methods: we retrospectively analyzed patients admitted to icu with septic shock between june and november . patients included in the study were diagnosed according to the third international consensus definitions for sepsis and septic shock (sepsis- ), received maximal supportive care including continuous veno-venous hemodiafiltration (cvvhdf) for acute kidney injury and cytosorb® haemoadsorption column was added to return limb of the cvvhdf circuit. demographic data, procalcitonin and leukocyte levels before and after therapeutic cytokine removal and duration of cytosorb® haemoadsorption column application and apache ii scores were recorded. results: the mean age of patients included in the study was ± . years ( % male) and the mean body mass index was . ± . . the mean apache ii score was . with an expected and actual mortality rates of % and %, respectively. % of the patients were admitted with sepsis and % of them with septic shock. . % (n= ) of the cases were solid organ transplant recipients. cvvhdf was applied in all patients during therapeutic cytokine removal. treatment was combined with ecmo in patients. while the mean duration of cvvhdf was . hours, the duration of cytosorb® haemoadsorption column application was . ± . hours. procalcitonin ( . ± ng/ml vs ± ng/ml) and leucocyte levels ( ± / mm vs ± mm ) after therapeutic cytokine removal were found significantly lower than the pretreatment values (respectively p= . , p= . ). conclusions: therapeutic cytokine removal applied with cvvhdf in septic shock patients have positive contributions to biochemical parameters and provide survival advantage. introduction: recent studies have focused on demonstrating the potential benefits of immunomodulation in the management of septic patients. the aim of our study was to assess the effects of a hemoadsorption column (cytosorb®) in critical ill septic patients. methods: after ethical approval was obtained, we prospectively included patients admitted to the general icu of fundeni clinical institute. three consecutive sessions of renal replacement therapy (continuous venovenous hemodiafiltration) in combination with cytosorb® were applied after icu admission. clinical (heart rate, arterial pressure, temperature, glasgow coma scale) and paraclinical data (pao , serum bilirubin and creatinine, platelet count, white blood cell count, ph, c-reactive protein and procalcitonine), vasopressor support and need for mechanical ventilation were recorded before and after the three sessions. results: the mean age in the study group was ± years. median number of organ dysfunction at the time of icu admission was [ ] [ ] [ ] [ ] [ ] and the mean sofa score was . ± . . the use of cytosorb® was associated with a non-significant increase in pao /fio ratio from ± to ± (p= , ) and creatinine levels from . ± . to . ± . mg/dl (p= . ). although we observed a non-significant increase in c-reactive protein levels from ± mg/l to ± mg/ l (p= . ), we noted a significant decrease in procalcitonine levels from a median of . [ . , . ] ng/dl to a median of . [ . , . ] ng/dl (p= . ). a significant decrease in platelet count was also noted from ± /mm to ± /mm (p= . ). mean sofa score decreased non-significantly from . ± . to . ± . (p= . ). conclusions: the use of cytosorb was associated with a slight nonsignificant improvement in organ function and a decrease of procalcitonine levels. thrombocytopenia remains one of the most important complications of renal replacement therapy. introduction: circulating cell-free neutrophil extracellular traps (nets) would induce a microcirculatory disturbance of sepsis. the removal of nets remnants from the circulation could reduce nets-dependent tissue injury. to address this issue, we evaluated the effect of hemoperfusion with a polymyxin b cartridge (pmx-dhp; toray, japan), which was originally developed for the treatment in patients with gram-negative bacterial infection, on circulating cell-free nets in patients with septic shock and in phorbol myristate acetate (pma)-stimulated neutrophils obtained from healthy volunteer. methods: ex vivo closed loop hemoperfusion was performed through a circuit formed by connecting the small pmx module to a tube and a peristalsis pump. whole blood from healthy volunteers incubated with or without pma or from septic shock patients were applied to circuit and perfused. blood was collected at , and hr after perfusion. circulating cell-free nets were assessed by myeloperoxidase (mpo)-, neutrophil elastase (ne)-, and cell free (cf)-dna. results: plasma mpo-dna, ne-dna and cf-dna levels were significantly increased at hr after pma stimulation when compared with plasma levels without pma. when either blood from septic shock patients or pma-stimulated neutrophils obtained from volunteers were applied to circuit, circulating mpo-dna, ne-dna and cf-dna were significantly reduced in perfusion with pmx filter than in perfusion without pmx filter at times and hr. conclusions: in the ex vivo experiments, mpo-dna, ne-dna and cf-dna were found to decrease after ex vivo perfusion through pmx filters. selective removal of circulating components of nets may improve the remote organ damage in patients with septic shock. a retrospective study of septic shock patients who were treated with direct hemoperfusion with polymyxin b-immobilized fibers based on the levels of endotoxin activity assay s sekine, h imaizumi, i saiki, a okita, h uchino tokyo medical university, anesthesiology/icu, tokyo, japan critical care , (suppl ):p introduction: the purpose of this study was to evaluate the outcomes for septic shock patients with direct hemoperfusion with polymyxin b-immobilized fibers (pmx-dhp) and endotoxin activity assay (eaa). methods: according to the levels of eaa, patients were classified for three groups (low group (gl); eaa < . , intermediate group (gm); eaa > . or eaa < . , high group (gh); eaa > . ). in order to evaluate the severity of illness, acute physiology and chronic health eva-luationii (apache ii) score, the sequential organ failure assessment (sofa) score, catecholamine index (cai) were recorded. and the presence of pmx-dhp treatments were also recorded. blood samples were obtained to measure eaa levels, inflammatory markers (procalcitonin (pct), c-reactive protein (crp), and white blood cell count (wbc)), serum lactate level as an indicator of tissue hypoxia, and for blood culture. apache ii score, sofa score, cai, inflammatory markers, serum lactate levels (lac) and blood culture results were examined for diagnosis of septic shock and prognosis of -days mortality. each values were also compared to eaa levels. results: septic shock patients were included (gl/ gm/ gh: / / ). in gh, apache ii and sofa score was significantly higher than that in gl (p< . ). eaa levels were significantly increased in gramnegative bacteremia patients compared to the patients with grampositive bacteremia or fungemia. there was no relationship between eaa levels and other inflammation markers, cai, and lac. in gm, days mortality in patient with pmx-dhp treatments was lower than that of without pmx-dhp treatments ( . ( / ) vs . ( / ), p= . ). in gh, -days mortality in patient with pmx-dhp treatments was same as that of without pmx-dhp treatments ( . ( / ) vs . ( / ), p= . ). conclusions: these results of this study suggest pmx-dhp treatment may improve the outcome of septic shock patients with intermediate eaa levels. introduction: numerous inconclusive randomized clinical trials (rcts) in sepsis in the past years suggest a need to re-think trial design to improve resource allocation and facilitate policy adoption decisions. the inclass study (clinicaltrials.gov nct: ) is an ongoing rct evaluating clarithromycin as an immune modulator in high-risk septic patients with clinical and cost-effectiveness outcomes. we aim to compare the original one-shot trial with an alternative sequential design that balances trial costs and value of information. methods: adult patients with sepsis, respiratory failure and total sofa score of at least , are randomized to receive intravenous clarithromycin or placebo adjunctive to standard-of-care therapy. for the cost-effectiveness study, efficacy is measured in quality-adjusted life years (qalys) by eq- d- l questionnaire at days. the endpoint is the incremental net monetary benefit (inmb) of clarithromycin compared to placebo, defined as wtp x (increment in qaly) -(increment in costs), where wtp is willingness to pay per qaly gained. fixed and variable costs of trial execution (including administrative, insurance, supplies, tests) are calculated; hospitalization cost is extracted from patient records; medical care beyond day is recorded; cost of adoption in the general population is estimated. previous data from rcts using clarithromycin are used to form a prior belief about the inmb. known incidence of sepsis with respiratory failure allows estimation of the population to benefit from trial decision. a bayesian model is used to determine the sequential design that maximizes trial value. results: we will compare the performance of the sequential trial design with the one-shot design of inclass trial in terms of sample size, cost, social-welfare, and probability of correctly identifying the best treatment. conclusions: in this protocol we validate a bayesian model for sequential clinical trials and assess the benefits for the patient population and health care system. the effect on the outcome of critically ill patients with catecholamine resistant septic shock and acute renal failure through implementation of adsorption therapy g schittek introduction: cytosorb-adsorption has been described as an effective way for hemodynamic stabilisation in septic shock [ ] . aim of this study was to examine whether the adsorption-therapy could influence patient-outcome with catecholamine resistant septic shock (crss) and acute renal failure(arv). furhtermore we tried to identify clinical constellations that would predict an effective use of adsorbers [ , ] . initial il- in patients with catecholamine-reduction through adsorption was non-significantly different to those with no reduction ( ng/l [ , ] vs. ng/l [ , ]). mortality did not differ significantly between the groups ( % vs %). length of intensive care unit stay (los) did differ significantly ( days [ , ] vs days [ , ] ). conclusions: il- can be reduced with adsorption. patients with catecholamine-reduction did not differ in regard to their initial il- . los was shorter for patients treated with adsorption. according to our experience adsorption can be taken into consideration when crss is beginning. introduction: in our intensive care unit (icu), we have already started expanded application to the contact precautions. applied patients are; ) emergency admission, ) patients who had already had bacteria* that are required to contact precautions, ) scheduled surgical patients with prolonged icu stay, although we have not yet decided the started period of expanded application exactly. *detected bacteria(db);mrsa, cd, mdrp, esbl, pseudomonas a, pisp, prsp, vrsa. the aim of this study was to determine the adequate starting period of expanded application to the contact precautions in the scheduled surgical patients in the mixed icu. methods: we performed retrospective observational study on patients who were admitted to our icu after planed surgery from may to dec. . we detected the patients who acquired bd newly and investigated the relation to the length of icu stay. the relationship between detection rate and categorized date was also analyzed using logistic regression adjusted for age, gender, apache , and sofa score. using youden´s index and roc curve, we also calculated cutoff point of the duration of icu stay related to detection rate. finally, we made the logistic regression model of each cutoff day(day to ) and compared odds ratio(or) and auc of each models using stata. results: category day or more, especially day or more had significantly higher detection rate of db compared to day ( results: pao /fio was lower than mmhg in ( %) patients. compared to patients in group , patients in group were less severely ill at admission but presented a higher sofa and cpis score and a greater incidence of ards and shock at pneumonia onset (fig ) . ( %) patients in group had a microbiological diagnosis of pneumonia, compared to patients ( %) in group (p= . ). pao /fio ≤ mmhg was associated with less probability of having microbiological diagnosis of pneumonia (or . , % ci . to . , p= . ). when adjusted for other variables significantly associated with positive microbiology, pao /fio ≤ mmhg remained significantly associated with less probability of a microbiological diagnosis (adjusted or . , % ci . to . , p= . ). hospital mortality was significantly higher in patients in group compared to group ( % vs %, p= . ). however, no difference was found in non-response to treatment, icu and hospital stay, icu mortality (table ) and -days survival (fig ) . conclusions: a significant higher number of patients with vap didn't have a definitive etiological diagnosis when using the proposed threshold criteria of pao /fio ≤ mmhg. pao /fio ratio does not seem a good predictor of etiology in patients with vap. introduction: immunological dysfunction is common in critically ill patients but the optimal method to measure it and its clinical significance are unknown. levels of tumor necrosis factor alpha (tnf-α) after ex-vivo whole blood stimulation with lipopolysaccharide has been proposed as a possible method to quantitate immunological function. we hypothesized that patients with a lower post-stimulation tnf-α level would have increased rates of nosocomial infections (nis) and worse clinical outcomes. methods: a secondary analysis of a phase randomized, multicentre, double-blinded placebo controlled trial [ ] . there were no differences in allocation groups; all the patients were analyzed as one cohort. on enrolment, whole blood was incubated with lps ex-vivo and tnf-α level was measured. patients were grouped in tertiles according to delta and peak tnf-α level. the primary outcome was the development of nis; secondary outcomes included -day mortality. results: data was available for patients. baseline characteristics and outcomes are reported in tables and . patients in the highest tertile for post lps stimulation delta tnf-α compared to the lowest tertile were younger, had a lower acuity of illness and had lower baseline tnf-α. when grouped according to peak post-stimulation tnf-α levels, patients in the highest tertile had higher serum tnf-α at baseline. both comparisons showed no difference between nis and clinical outcomes between tertiles. in multi-variate analysis peak or delta tnf-α were not associated with the occurrence of nis. conclusions: admission ex-vivo stimulated tnf-a level is not associated with the occurrence of nis or clinical outcomes. further study is required to evaluate the ability of this assay to quantify immune function over the course of critical illness. results: sanitary and epidemiological examination revealed the connection between infection and intravenous infusion of dexamethasone performed concurrently with chemotherapy. in patients fever with chills and hypertension developed within hours after infusion of the infected drug; empirical intravenous antibiotic therapy started immediately after collecting blood culture. in patients fever appeared after - days outpatiently, so they received antibiotics per os. all these patients had permanent vascular access, and bsi was detected either the next chemotherapy course when fever reappeared ( pts) while using vascular access, or as a result of a specific examination ( pts). in all cases empirical antibiotic therapy started on the first day of fever, drug correction was performed in patients according to results of bacteriological research. septic shock developed in patient, pneumonia in patients. permanent vascular access was preserved only in case. all patients were cured and continued to receive antitumor treatment. conclusions: detection of more than case of b. cenocepacia bsi should be the reason for sanitary and epidemiological examination. a favorable outcome of bsi treatment is associated with the early start of antibiotic therapy and its correction after microbiological examination. emerging conclusions: implementation of asp in hospital allows to decrease incidence of eskape-bacteremia and candidemia, which may lead to improved clinical outcomes in icu's patients (fig ) . association of multi-drug resistant (mdr), extended-drug resistant (xdr) and pan-drug resistant (pdr) gram negative bacteria and mortality in an intensive care unit(icu) s chatterjee , s sinha , a bhakta , t bera , t chatterjee , s introduction: colistin-resistant klebsiella pneumoniae (cr-kp) is increasingly reported around the world. it is worrying to note emergence of resistance to last line of defence against mdr gram negative infections in regions endemic to carbapenem resistance. we report the first outbreak of cr-kp co-producing carbapenemases in an adult intensive care unit (icu) from south india. methods: retrospective analysis of all patients with carbapenem resistant klebsiella pneumoniae blood stream infection (bsi) was done between january and december . microbiological and clinical variables along with outcomes were analysed. results: seven patients had cr-kp with no prior exposure to colistin. all seven were modified hodge test (mht) negative making probability of blakpc unlikely. in resource limited setting, analysis beyond mht could only be performed for cr-kp samples. / samples belonging to cr-kp isolates produced the blandm- whilst / cr-kp isolates did not produce either blakpc or blandm carbapenemases prompting hypothesis of blaoxa- or blavim as the causative factor. compared to carbapenem resistance only group, cr-kp group had higher apache ii, icu length of stay and mechanical ventilation duration. day mortality was noted to be . % for carbapenem resistant and % for cr-kp groups. aggressive infection control measures were undertaken with successful containment of cr-kp strains along with reduction in overall bsi. conclusions: infection control measures form the backbone of patient care in centres showing endemicity for carbapenem resistant klebsiella to prevent colistin resistance and also to reduce occurrence of overall blood stream infections. rapid diagnosis of carbapenem resistance: experience of a tertiary care cancer center with multiplex pcr s mukherjee tata medical center, critical care medicine, kolkata, india critical care , (suppl ):p introduction: sepsis due to carbapenem resistant organisms has high mortality; inappropriate empirical antibiotic is one of the main causes of this poor outcome. on the contrary, "too much" broad spectrum empiric antibiotics will increase drug resistance, even in community, because of selection pressure. so, early diagnosis of resistance pattern (carbapenemase genes) is crucial. aim of this study is to compare rapid diagnostic test like polymerase chain reaction (pcr) with conventional culture sensitivity (c/s) to identify carbapenem resistance. methods: this is a prospective observational study done in tata medical center, kolkata, india. real time multiplex pcr technique has been developed "in house" in our microbiology lab and can identify ndm, ndm , kpc, oxa - , oxa - , oxa - & vim carbapenemase genes. blood cultures were sent as per clinical & laboratory diagnosis of sepsis in icu patients. culture positive samples had been used for conventional c/s by vitek system along with pcr study to identify carbapenemase genes. result of pcr technique was been compared with conventional c/s method. results: multiplex pcr results were available within - hours of positive blood culture compared to conventional c/s method that takes - days. among positive blood cultures, samples were positive for carbapenemase genes. most common gene identified was oxa - ( %), followed by ndm ( %). our pcr technique has very high sensitivity, specificity, positive & negative predictive value ( . %, . %, . % & . % respectively) while comparing with final c/s report by vitek system (table ) . there was only one false negative diagnosis for carbapenem resistance. conclusions: real time multiplex pcr for carbapenemase gene can be helpful for early diagnosis of carbapenem resistance and can help us to choose / modify antibiotics or to use 'targeted therapy'. it is more practical to "rule -in" infection rather than "rule -out" by this technique. carbapenemase producing enterobacteriaceae colonization in an icu: risk factors and clinical outcomes m miranda, jp baptista, j janeiro, p martins centro hospitalar e universitário de coimbra, intensive care unit, coimbra, portugal critical care , (suppl ):p introduction: carbapenemase-producing enterobacteriaceae (cpe) colonization has been increasingly reported in intensive care units (icus) since their first identification more than years ago. colonization with cpe seems to constitute a risk factor for mortality. the aim of our study was to identify associated risk factors and clinical outcomes among patients with fecal colonization by cpe admitted to a portuguese tertiary hospital icu. methods: a -year retrospective study was performed in patients with previous unknown cpe status (colonization or infection), admitted to our icu. rectal swabs were performed and analyzed using real-time polymerase chain reaction testing. clinical records were reviewed to obtain demographic and clinical data. results: of patients admitted, ( . %) harbored cpe, ( . %) were colonized at admission and ( . %) acquired cpe colonization during icu stay. the most frequent carbapenemase genes detected were kpc ( . %) and vim ( . %). cpe carriers had high rates of hospitalization (previous or ongoing), invasive procedures (mainly intraabdominal surgery), malignancy (hematopoietic or solid tumor), introduction: gram-negative pathogens-particularly pseudomonas aeruginosa and enterobacteriaceae-predominate in nosocomial pneumonia (np) and ciai both. these infections are becoming difficult to treat with available treatment options due to growing antimicrobial resistance in india. ceftazidimeavibactam has in-vitro activity against gram-negative organisms producing class a, class c and some class d beta-lactamases. we carried out a qualitative analysis to assess the safety and efficacy outcomes of the indian population cohorts involved in the re-prove and reclaim trials. methods: in line with the global reprove protocol, indian patients enrolled in the study with np, were randomly assigned ( : ) to mg ceftazidime and mg avibactam or mg meropenem. in the reclaim study, indian patients with a diagnosis of ciai were enrolled in the study and were randomly assigned ( : ) to receive either ceftazidime-avibactam ( mg of ceftazidime and mg of avibactam) followed by metronidazole ( mg); or meropenem ( mg). the primary efficacy outcome measure in the reprove and reclaim studies was clinical cure rate of caz-avi compared with that of meropenem at toc (test-of-cure) visit in pre-defined analysis sets. in both studies, non-inferiority was concluded if the lower limit of the twosided % ci for the treatment difference was greater than - · % in the primary analysis sets. as the indian subset study was not statistically powered to detect a difference in the subgroup, we descriptively analysed the efficacy results in the indian population and compared them with the overall results in the global trial. in addition, the study also analysed the safety of caz-avi in the indian patients by monitoring the number and severity of adverse events. introduction: early administration of effective intravenous antimicrobials is recommended for the management of the patients with sepsis. although meropenem (mepm) is one of the first-line drugs in patients with sepsis because of its broad spectrum, the optimal dose in the critical care settings especially during continuous renal replacement therapy (crrt) has not been established since therapeutic drug monitoring of mepm has not been popular. methods: eighteen critically ill patients who received crrt were enrolled in this study. one gram of mepm was administered over hour, every hours, and blood samples at , , , and hours after administration were collected on day , and . all samples were stored at - °c until analysis. the measurement of the blood concentration of mepm was performed using high performance liquid chromatography with ultraviolet detection (hplc-uv introduction: meningitis is one of the complications of severe traumatic brain injury, and it is often associated with encephalitis (incidence from . - . % to - %). the aim of the investigation was to study the dynamics of the concentration of meropenem in serum and cerebrospinal fluid (csf) with intravenous and intrathecal administration of meropenem. methods: in eight patients with bacterial meningoencephalitis blood serum and csf were studied prior to the administration of meropenem and - min, , . and hrs after it. antibiotic regimen: mg of vancomycin ( mg bid) and meropenem ( mg tid diluted in ml of saline iv + mg bid diluted in ml of saline bolus slowly intrathecally). meropenem infusion was carried out for minutes, mins after it ml of blood and ml of csf were sampled. prior to antibiotics administration blood and csf were taken for microbiological examination. to determine the concentration of antibiotics iquid chromatography/mass spectrometry was used. the samples were analyzed on an agilent infinity liquid chromatograph coupled to a sciex qtrap mass detector (sciex, us introduction: the prophylactic use of probiotics has emerged as a promising alternative to current strategies viewing to control nosocomial infections in a critically-ill setting. however, their beneficial role in vap prevention remains inconclusive. our aim was to delineate the efficacy of probiotics for both vap prophylaxis and restriction of icu-acquired infections in multi-trauma patients. methods: randomized, placebo-controlled study enrolling multitrauma patients, requiring mechanical ventilation for > days. participants were randomly assigned to receive either probiotic (n= ) or placebo (n= ) treatment. a four-probiotic formula was applied and each patient received two capsules per day from day to day post icu admission. the content of one capsule was given as an aqueous suspension by nasogastric tube, while the other one was spread to the oropharynx after being mixed up with water-based lubricant. the follow-up period was days, while icu stay and mortality were also assessed. ], while no difference in -day mortality rate was identified between groups ( . % probiotics vs . % placebo). conclusions: the prophylactic administration of probiotics exerted a positive effect on the incidence of vap or other icu-acquired infections and icu stay in a critically-ill subpopulation being notorious for its high susceptibility to infections, namely multi-trauma patients. use of a c-reactive protein-based protocol to guide the duration of antibiotic therapy in critically ill patients: a randomized controlled trial i borges introduction: the rational use of antibiotics is one of the main strategies to limit the development of bacterial resistance. in this study we aimed to evaluate the effectiveness of a c reactive protein (crp) based protocol in reducing antibiotic treatment time in critically ill patients. methods: an open randomized clinical trial was conducted in two adult intensive care units of a university hospital in brazil (clini-caltrials.gov: nct ). patients were randomly allocated to: i) intervention -duration of antibiotic therapy guided by crp levels, and ii) control -duration of therapy based on best in the intention to treat analysis, the median (q -q ) duration of antibiotic therapy for the index infection episode was . ( . - . ) days in the crp group and . ( . - . ) days in the control group (p= . ). in the cumulative suspension curve of antibiotics, a significant difference in the exposure time between the two groups was identified, with less exposure in the crp group (p= . ). in the pre-specified per protocol analysis, with patients allocated in each group, the median duration of antibiotics was . ( . - . ) days in the crp group and . ( . - . ) days in the control group (p= . ). mortality and relapse rates were similar between groups. conclusions: daily levels of crp may aid in reducing the time of antibiotic therapy in critically ill patients, even in a scenario of judicious use of these drugs. introduction: the macrophage activation syndrome (mas) or hemophagocytic lymphohistiocytosis(hlh) is a life threatening complication characterized by pancytopenia, liver failure, coagulopathy and neurologic symptoms and is thought to be caused by the activation and uncontrolled proliferation of t lymphocytes and well differentiated macrophages, leading to widespread hemophagocytosis and cytokine overproduction [ , ] .the etiology is unknown, but is considered to have an infectious trigger.the aim of our study is to evaluate the impact of hlh in our beds infectious diseases icu, during months period ( - ). methods: a retrospective study based on electronic databases, including all patients admitted in our icu, that have matched at least out of criteria for hlh diagnosis ( ):fever; hepatosplenomegaly; > cytopenia (hb < g/dl, plt</dl, pmn -n< /mmc); hypertriglyceridemia> mg/dl, fibrinogen< mg/dl; hemophagocytosis-bone marrow, spleen, and/or lymphnodes; nk activity reduced/ absent; ferritin level> ui/l; cd > . we have evaluated the etiology established with cultures, serology, and molecular methods, treatment with corticosteroids, iv immunoglobuline, cyclosporine, etoposide and outcome ( ) . results: patients were admitted to icu, patients( . %) met the criteria for hlh. the average length of stay in icu was days; patients died ( %) without relation with the followed treatment. conclusions: hlh is not a rare condition in infectious diseases icu. the etiology is more frequent established compared with literature data. treatment (corticosteroids, immunoglobuline, cyclosporine, etoposide) is not associated with increased survival forecasting hemorrhagic shock using patterns of physiologic response to routine pre-operative blood draws introduction: irreversible hemorrhagic shock (ihs), a critical condition associated with significant blood loss and poor response to fluid resuscitation, can induce multiple organ failures and rapid death [ ] . determining the patients who are likely to develop ihs in surgeries could greatly help preoperative assessment of patient outcomes and allocation of clinical resources. methods: machine learning model of ihs is developed and validated via porcine induced bleed experiment. healthy sedated yorkshire pigs first had one ml rapid blood draw during a stable period, and then were bled at ml/min to mean arterial pressure (map) of mmhg. subjects had ihs defined as map< mmhg. arterial, central venous and airway pressures collected at hz during the blood draw [ fig ] were used to extract characteristic sequential patterns using graphs of temporal constraints (gtc) methodology [ ] , and a decision forest (df) model was trained on these patterns to determine subjects at high risk of impending ihs. results: in a leave-one-subject-out cross-validation, our method confidently identifies % ( % ci [ . %, . %]) of the subjects who are likely to experience ihs when subject to substantial bleeding, while only giving on average false alarm in , such predictions. this method outperforms logistic regression and random forest models trained on statistically featurized data [tab , fig ] . conclusions: our results suggest that by leveraging sequential patterns in hemodynamic waveform data observed in preoperative blood draws, it is possible to predict who are prone to develop ihs resulting from blood loss in the course of surgery. future work includes validating the proposed method on data collected from human subjects, and developing a clinically useful screening tool with our investigations. work partially funded by nih gm . introduction: the h s and oxytocin(oxy) systems are reported to interact with one another [ ] . h s plays a major role in the hypothalamic control of oxy release during hemorrhage [ ] . there is scarce information about oxy receptor(oxyr) expression in the brain in general and what is there is ambivalent. oxyr has been immunohistochemically(ihc) detected in the human hypothalamus but not in the hippocampus, in contrast to rodents [ ] , which underscores the need for additional characterization in relevant animal models. thus the aim of this study is to map the expression of the oxy and h s systems in the porcine brain in a clinically relevant model of hemorrhagic shock (hs). methods: anesthesized atherosclerotic pigs (n= ) underwent h of hs (map +/- mmhg) [ ] , followed by h resuscitation. ihc detection of oxy, oxyr, the h s producing enzymes cystathionine-γ -lyase (cse) and cystathionine-β -synthase(cbs) was performed on formalin fixed brain paraffin sections. results: oxy, oxyr, cse and cbs were localized in the porcine brain. proteins were differentially expressed in the hypothalamus (fig ) , parietal cortex and cerebellum (fig ) . cell types positively identified were: magnocellular neurons of the hypothalamus, cerebellar purkinje cells and granular neurons, and hippocampal pyramidal and granular neurons of the dentate fascia. arteries and microvasculature were also positive for oxyr and cse. conclusions: our results confirm the presence of oxy and oxyr in the hypothalamus similarly to the human brain. novel findings were: oxyr in the cerebellum and cse expression in the hypothalamus and cerebellum. the coexpression of oxyr and cse may link and help better understand neurochemical systems and physiological coping in hemorrhagic shock. funding: crc introduction: septic shock is one of the main causes of intensive care unit (icu) admission, leading to mortality up to % of patients. acute kidney injury (aki) frequently occurs and is associated to great morbidity and mortality. hemodynamic optimization may reduce the incidence of aki, but the use of vasopressors to increase mean arterial pressure (map) could have deleterious effect on renal perfusion. we aimed at investigating the effect of map and norepinephrine (ne) on the incidence of aki in septic shock patients methods: retrospective study based on prospectively collected data on digital medical records (digistat) at our icu. introduction: in patients with distributive shock, increasing mean arterial pressure (map) to a target of > mmhg can improve tissue perfusion. patients unable to achieve the target map of > mmhg despite adequate fluid resuscitation as well as catecholamines and vasopressin standard care (sc), may benefit from the noncatecholamine vasopressor angiotensin ii to increase map. this posthoc analysis examined whether patients from the athos- study with a baseline (bl) map < mmhg and treated with sc plus either angiotensin ii (ang ii) or placebo achieved a map of > mmhg for consecutive hours, without increasing the dose of sc therapy. methods: patients were assigned in a : ratio to receive ang ii or placebo, plus sc. randomization was stratified according to map (< or > mmhg) at screening. in patients with bl map < mmhg, we evaluated whether patients achieved a map of > mmhg for the first hours after initiation (map measurements taken at hours , , and ), without an increase in the dose of sc. results: among treated patients, had bl map < mmhg (ang ii, ; placebo, ). median bl map (iqr) was ( - ) and ( - ) mmhg for placebo and ang ii groups, respectively. patients with bl map < mmhg who were treated with ang ii were more likely to achieve map ≥ mmhg for consecutive hours after initiation without an increase in sc dose ( %, %ci - ), compared with placebo-treated patients ( %, %ci - , or= . , p< . ). conclusions: in this post-hoc analysis of patients with bl map < mmhg, patients receiving ang ii plus sc were significantly more likely to achieve a map > mmhg for the first consecutive hours after initiation than patients receiving sc only. this suggests that administering ang ii may help patients with catecholamine-resistant distributive shock to achieve the consensus standard target map. norepinephrine synergistically increases the efficacy of volume expansion on venous return in septic shock i adda, c lai, jl teboul, l guerin, f gavelli, c richard, x monnet hôpitaux universitaires paris-sud, hôpital de bicêtre, aphp, service de médecine intensive-réanimation, le kremlin-bicêtre, france critical care , (suppl ):p introduction: through reduction in venous capacitance, norepinephrine (ne) increases the mean systemic pressure (psm) and increases cardiac preload. this effect may be added to the ones of fluids when both are administered in septic shock. nevertheless, it could be imagined that ne potentiates in a synergetic way the efficacy of volume expansion on venous return by reducing venous capacitance, reducing the distribution volume of fluids and enhancing the induced increase in stressed blood volume. the purpose of this study was to test if the increase in psm induced by a preload challenge were enhanced by ne. methods: this prospective study had included septic shock adults. to reversibly reproduce a volume expansion and preload increase at different doses of ne, we mimicked fluid infusion through a passive leg raising (plr). in patients in which the decrease of ne was planned, we estimated psm (using respiratory occlusions) at baseline and during a plr test (plr high ). the dose of ne was then decreased and psm was estimated again before and during a second plr (plr low ). . the increase in cardiac index induced by plr low was significantly greater than that induced by plr high (p< . ). Δ psmhigh -Δ psmlow was moderately correlated with the diastolic arterial pressure at baseline-high (p= . , r= . ) and with the ne-induced change in mean arterial pressure (p= . , r= . ). conclusions: ne enhances the increase in psm induced by a plr, which mimics a fluid infusion. this suggests that it may potentiate the effects of fluid in a synergetic way in septic shock patients. this may decrease the amount of administered fluids and contribute to decrease the cumulative fluid balance. introduction: arginine vasopressin (avp) can be used in addition to norepinephrine (ne) for ne-resistant septic shock. however, a subgroup who will response to avp is unknown. the purpose of this study was to determine factors which could predict the response to avp in patients with ne-resistant hypotension. methods: this was a single-center, retrospective analysis of patients who administered avp for ne-resistant hypotension in our intensive care units (icus). eligible patients were adult patients who administered avp in addition to ne due to hypotension (mean arterial pressure (map) < ) in our icus between august and december . we divided all patients into two groups by response to avp; responders and non-responders. the responders were defined as an increase of map ≥ mmhg at h after avp initiation. we conducted univariate and multivariate logistic regression analysis to evaluate the effect of variables on avp response. results: a total of patients were included; responders ( %), non-responders ( %). there was no significant difference for map at the time of avp initiation ( vs mmhg; p = . ), initiation dose of avp ( . vs . u/min; p = . ), and dose of ne at the time of avp initiation ( . vs . μ g/kg/min; p = . ). map at h after avp initiation was significantly higher in responders than non-responders ( vs mmhg; p < . ). responders were older ( vs ; p = . ) and had lower heart rate (hr) ( vs. ; p = . ) and lactate ( . vs. . mmol/l; p = . ) at the time of avp initiation. the multivariate logistic analysis revealed that hr ≤ (or . , % ci . - . , p < . ), lactate ≤ (or . , % ci . - . , p < . ) and age ≥ (or . , % ci . - . , p = . ) were significantly associated with the response to avp. conclusions: hr, lactate levels and age before avp initiation can predict the response to avp in icu patients with ne-resistant hypotension. the maximum norepinephrine dosage of initial hours predicts early death in septic shock d kasugai , a hirakawa , n jinguji , k uenishi nagoya university gtaduate school of medicine, department of emergency and critical care, nagoya, aichi, japan; fujita health university, department of disaster and traumatology, fujita health university, toyoake, japan; fujita health university hospital, department of emergency and general internal medicine, fujita health university hospital, toyoake, japan critical care , (suppl ):p introduction: the mortality of septic shock refractory to norepinephrine remains high. to improve the management of this subgroup, the knowledge of early indicator is needed. we hypothesize that maximum norepinephrine dosage on the initial day of treatment is useful to predict early death in septic shock. methods: in this retrospective single-center observational study, septic shock patients admitted to the emergency intensive care unit (icu) of an academic medical center between april and march were included. cardiac arrest before icu admission and those with do-not-resuscitate orders before admission were excluded. the maximum dosage of norepinephrine initial hours of icu admission (md ) was used to assess -day mortality. results: one-hundred-fifty-two patients were included in this study. median sofa score was ( - ), and median md was . ( . - . ) mcg/kg/min. vasopressin and steroid were administered in ( %) and ( %) cases. nineteen patients ( %) died within a week. non-survivors had higher md , higher sofa score, and higher rate of vasopressin use. the higher md predicted -day mortality (area under curve . , threshold . mcg/kg/min, sensitivity %, specificity %). after adjustment of inverse probability of treatment weighing method using propensity scoring, md higher than . mcg/kg/min was independently associated with -day mortality (or: . , %ci: . - . , p < . ). conclusions: the maximum dosage of norepinephrine higher than . mcg/kg/min initial hours was significantly associated with day mortality in septic shock, and may be useful in the selection of higher severity subgroup. the impact of norepinephrine on right ventricular function and pulmonary haemodynamics in patients with septic shock -a strain echocardiography study k dalla sahlgrenska university hospital mölndal, göteborg, sweden critical care , (suppl ):p introduction: septic shock is characterized by myocardial depression and severe vasoplegia. right ventricle performance could be impaired in sepsis. the effects of norepinephrine on rv performance and afterload in septic shock are not immediately evident. the aim of the present study was to investigate the effects of norepinephrine on rv systolic function, rv afterload and pulmonary haemodynamics. methods: eleven, volume-resuscitated and mechanically ventilated patients with norepinephrine-dependent septic shock were included. infusion of norepinephrine was randomly and sequentially titrated to target mean arterial pressures (map) of , and mmhg. at each target map, strain-and conventional echocardiographic were performed. the pulmonary haemodynamic variables were measured by using a pulmonary artery thermodilution catheter. the rv afterload was assessed by calculating the effective pulmonary arterial elastance (epa) and pulmonary vascular resistance index (pvri). results: the norepinephrine-induced elevation of map increased central venous pressure ( %, p< . ), stroke volume index ( %, p< ), mean pulmonary artery pressure ( %, p< . ) and rv stroke work ( %, p= . ), while neither pulmonary vascular resistance index nor epa was affected. increasing doses of norepinephrine improved rv free wall strain from - % to - % ( %, p= . ), tricuspid annular plane systolic excursion ( %, p= . ) and tricuspid annular systolic velocity ( %, p= . ). there was a trend for an increase in cardiac index assessed by both thermodilution (p= . ) and echocardiography (p= . ). conclusions: the rv function was improved by increasing doses of norepinephrine, as assessed both by strain-and conventional echocardiography. this is explained by an increase of rv preload. pulmonary vascular resistance is not affected by increased doses of norepinephrine. peripheral perfusion versus lactate-targeted fluid resuscitation in septic shock: the andromeda shock physiology study. preliminary report g hernandez , r castro , l alegría , s bravo , d soto , e valenzuela , m vera , v oviedo , c santis , g ferri , m cid , b astudillo , p riquelme , r pairumani , g ospina- tascón table . conclusions: this preliminary results suggest that using crt as a target for fr in septic shock appears to be feasible, and not associated with impairment of tissue perfusion-related parameters as compared to lactate-targeted fr. grant fondecyt chile introduction: shock patients often become resistant to catecholamines which often require the addition of a non-catecholamine vasopressor. preclinical studies suggest that in the presence of aadrenoceptor antagonism, the renin-angiotensin aldosterone system exerts the major vasopressor influence. we sought to determine the effects of angii or lypressin (lyp [porcine vasopressin]) on blood pressure in a norepinephrine (ne)-resistant hypotension pig model. methods: phentolamine (phn), a reversible α-blocker that antagonizes the vasoconstriction by ne, was continuously infused to induce hypotension. after ne-resistant hypotension was established, lyp or angii was then co-infused with phn. mean arterial pressure (map) and heart rate were continuously recorded (fig. ) . results: as shown in fig. conclusions: in a background of α-adrenoceptor blockade, at clinically comparable doses, the vasopressor effect of ang ii was maintained while those of ne and lyp were attenuated. these data suggest that the blood pressure effect of vasopressin-like peptides may require a functioning α-adrenoceptor. patients with shock who are resistant to increasing doses of catecholamines may also have vasopressin resistance potentially making angiotensin ii a preferred vasopressor for these patients. introduction: resuscitative endovascular balloon occlusion of the aorta (reboa) has been increasingly used for the management of both traumatic and non-traumatic hemorrhagic shock. however, there is limited evidence for its use in gastrointestinal bleeding (gib), especially in the icu setting. we successfully treated a patient with massive gib using reboa in the icu. we will discuss the difficulty performing the procedure and its countermeasure. methods: a case report. results: an -year-old woman was transferred to our hospital with shock. coffee grounds material was found in a nasogastric aspirate after intubation and upper gastrointestinal endoscopy identified a pulsating large duodenum ulcer without active bleeding, for which an elective procedure was planned. she was admitted to our icu, responded to initial resuscitation, and thereafter extubated. her systolic blood pressure (sbp) suddenly dropped to mmhg with massive hematochezia at that night, and did not increase despite resuscitation with blood products, crystalloid and norepinephrine. to buy time until measures for stop bleeding, we planned to place reboa in the icu. following the placement of a sheath in the left femoral artery, we tried to place a fr intra-aortic balloon occlusion catheter, which unintentionally and repeatedly went into the right common iliac artery because her left femoral artery was tortuous. after compressing the right lower abdomen, we managed to introduce reboa in zone . it took approximately minutes to successfully place the catheter. the patient's sbp increased immediately after the balloon inflation and bleeding was endoscopically controlled. introduction: the natural components of the pomegranate fruit may provide additional benefits for endothelial function and microcirculation. we hypothesized that chronic supplementation with pomegranate extract might improve glycocalyx properties and microcirculation during anaerobic condition. methods: eighteen healthy and physically active male volunteers aged - years were recruited randomly to the pomegranate and control groups ( in each group). the pomegranate group was supplemented with pomegranate extract for two weeks. at the beginning and end of the experiment, the participants completed a high intensity sprint interval cycling-exercise (anaerobic exercise) protocol. the systemic hemodynamics, microcirculation flow and density parameters, glycocalyx markers, and lactate and glucose levels were evaluated before and after the two exercise bouts. results: no significant differences in the microcirculation or glycocalyx were found over the course of the study. the lactate levels were significantly higher in both groups after the first and repeated exercise bouts, and were significantly higher in the pomegranate group relative to the control group after the repeated bout: . ( . - . ) vs. . ( . - . ) mmol/l, p = . . conclusions: chronic supplementation with pomegranate extract has no impact on changes to the microcirculation and glycocalyx during anaerobic exercise, although an unexplained increase in blood lactate concentration was observed. introduction: extracorporeal membrane oxygenation in adults in accompanied by high mortality. our ability to predict who will benefit from ecmo based on currently available clinical and laboratory measures is limited. the advent of single cell sequencing approaches has created the opportunity to identify cell populations and pathophysiological pathways that are associated with mortality without bias from a priori cell type classifications. identification of such cell populations would provide both an important prognostic markers and key insight into immune response mechanisms and therefore a possibility for advanced drug matching that may impact clinical response to ecmo in these patients. methods: whole genome transcriptomic profiles were generated from a total of , peripheral blood monocytes obtained from patients at the time of cannulation for ecmo (fig ) . differential gene expression analysis was performed with the monocle package for the r statistical analysis framework. time-to-event data were analyzed in a survival analysis with a log-rank test for differences. results: genes encoding several members of the heat shock family of proteins were up-regulated in cells from non-survivors. notably, these genes were expressed by a small fraction of cells ( . % on average). nevertheless, the proportion of cells expressing these genes was a significant predictor of survival to days (p = . by log rank test), with a particularly pronounced effect in the first days after initiation of ecmo support (fig ) . conclusions: the proportion of cells expressing genes encoding members of the heat shock proteins is predictive of survival on ecmo. majority of pt ( %) had no known predisposing conditions, followed by immobility ( %) and cancer ( %). in ecg analysis tachycardia and v -v t wave inversion were the most common findings whereas hypoxemia± hypocapnia were the most prominent features in abg analysis. pt ( %) had bleeding complications (none intracranial), ( . %) during rtpa, ( . %) in the first h and only pt required transfusion. mortality rate was %: % directly due to pe (all during cpr) and % due to late complications (newly diagnosed cancer and infections). conclusions: in our experience, fibrinolytic therapy is safe and effective but in submassive pe should be applied after thorough assessment of risks and benefits on individual basis aiming to patient tailored precision medicine. [ ] trials evaluated the role of levosimendan in preventing low cardiac output syndrome in patients undergoing cardiac surgery. the studies were similar in their design and recruited patients with preoperatively low lvef undergoing either isolated cabg or valve surgery combined with cabg (table ). in both, a -hour levosimendan infusion was started at induction of anesthesia. neither study met the primary efficacy composite enpoints, but both showed a clear tendency for better outcome in patients undergoing a cabg compared to a valve procedure. we are currently evaluating the solidity of a co-analysis based on shared end-points. we are planning a shared analysed of the data related to the cabg settings and analyze the aggregated mortality data for both studies at and months by cochran-mantel-haenszel odds ratio. data from individual studies would be analysed as fixed effect and breslow-day test was used to evaluate homogeneity of the odds ratios results: in the placebo groups of the two studies, the mortality is similar; . % ( / ) in levo-cts and . % ( / ) in licorn, corroborating the working hypothesis that the two studies can be coanalysed. in a preliminary combined analysis (fig ) , -day mortality was . % ( / ) in the placebo group and . % ( / ) in the levosimendan group. odds ratio was significantly in favor of levosimendan ( . ; % confidence interval . - . ; p= . , fig. ) conclusions: the levo-cts and licorn trials can be co-analysed in their sub-setting of patients requiring isolated cabg surgery for mortality at and months. a preliminary analysis on mortality reinforce the hypothesis that, in isolated cabg surgery, levosimendan lowers post-operative mortality significantly both at and months, when started at the induction of anesthesia introduction: emergency medical system (ems) -based st elevation myocardial infarction (stemi) networks allows not only stemi diagnosis in the pre-hospital phase but also reduces treatment delays; treat your fatal complications and the immediate activation of the catheterization laboratory. the aim of study was to investigate the effect of out-of-hospital by mobile intensive care (micu) versus hospital beginning treatment in hospitalization length and survival of patients with stemi diagnosis introduction: contrast induced nephropathy (cin) is a complex acute renal failure syndrome, which can occur after primary percutaneous coronary intervention (pci) and is an important cause of morbidity and mortality in this subgroup of patients. the aim of our study was to establish the incidence and predictors of cin after primary pci. we performed a retrospective analysis of stemi patients treated with primary pci in the period from january until september of . cin was defined as an absolute increase in baseline serum creatinine of ≥ . mg/dl ( μmol/l) or > % relative rise within hours after primary pci. we analyzed demographic characteristics, risk factors, clinical status at hospital admission, laboratory parameters, left ventricle ejection fraction and data regarding pci procedure. results: the study included patients, with an average age of . ± . years, . % of the patients were males. an average of . ± . ml of contrast medium per patient was utilized. cin developed in ( . %) patients and overall intra-hospital mortality was . %. in multivariate analysis, the independent predictors of cin were age> years ( introduction: left main coronary artery (lmca) disease is a disease of the main coronary branch that gives more than % of blood supply to the left ventricle, it carries high mortality without surgical intervention; [ ] however the influence of lmca surgery on morbidity icu measures needs to be explored. we aim to determine whether lmca is definitive risk factor for prolonged icu stay as a primary outcome and whether lmca is definitive risk factor for early morbidity methods: retrospective descriptive study with purposive sampling analyzing patients underwent isolated coronary artery bypass surgeries (cabg). patients were divided into groups those with lmca disease as group ( patients) and those with coronary arty disease requiring surgery but without lmca disease as group ( patients) then we will correlate with icu outcome parameters including icu stay length, postoperative atrial fibrillation, acute kidney injury, re-exploration, perioperative myocardial infarction, post operative bleeding and early mortality. results: patients with lms had significantly higher diabetes prevalence ( . % vs %, p= . ). however, we did not find a statistical significant difference regarding icu stay, or other morbidity and mortality outcome measures conclusions: diabetes was more prevalent in patients with lms. the latter group showed similar outcome as those without lms in this study these findings may help in guiding decision making for future practice and stratifying the patients care. introduction: multimorbidity in patients admitted for acute myocardial infarction [ami] is associated with higher risk for in-hospital mortality and adverse clinical outcomes. we investigated to what extent an increasing number of comorbidities affects the age-stratified excess risk of death and other clinical outcomes among patients with myocardial infarction. methods: we analyzed nationwide administrative data of ` admissions for an acute myocardial infarction between and . we calculated multivariate regression models to study the association of four comorbidities (chronic kidney disease [ckd], diabetes mellitus, heart failure [hf], and atrial fibrillation) and excess risk of in-hospital mortality, length of hospital stay [los] , and -day readmission and stratified the analysis for different age categories. results: the incidence of admissions for ami increased continuously during the observed decade without an increase in in-hospital mortality, los, and -day readmission. among admitted patients with ami, there was a stepwise increase in risk for adverse outcomes for each comorbidity. compared to patients with no comorbidity, patients with comorbidities had -fold increased risk for mortality (adjusted odds ratio [or] . , % confidence interval [ci] . to . ) and a similar risk for readmission (or . , ci . to . ). the los was . days (ci . to . ) in patients with no comorbidity and increased by . days (ci . to . ) with each additional comorbidity. these associations were stronger in younger compared to older patients. ckd was the strongest predictor of in-hospital mortality and los, while hf was the strongest predictor of -day readmission. conclusions: this study of nationwide admitted patients with ami found a stepwise increase in the risk for adverse outcome with increasing number of comorbidities, particularly in the younger patient population. younger, multimorbid patients may thus have the largest benefits from multidisciplinary treatments. introduction: certified cardiac arrest centers, sophisticated post cardiac arrest care and prehospital ecls teams aim to increase survivor rates with a preferable neurological outcome after cardiac arrest. centers also provide emergency ecls and ecls pick ups for cardiogenic shock patients before arresting. few data answer the question of the long-term quality of life after ecls therapy. methods: in a retrospective single center register we included patients after emergency ecls (ecpr and cardiogenic shock) between / and / discharged alive and performed a follow-up after years on average at / . in our center criteria to initiate ecls therapy in cardiogenic shock or under cardiac arrest are an observed collaps, shockable rhythm, absence of frailty and severe comorbidities. all patients were requested to take part in a telephone interview. thus, we analyzed survival, cpc scores and sf scores. results: patients with hospital survival after ecls were screened. % (n= ) had survived until / ; patients were not accessible; had ceased. survivors (mean±sd; min-max; ± ; - years, women) answered sf questionaires ± ; - months after ecls ( % cardiogenic shock, % ecpr with shockable rhythm in %). the participantsĆ pc scores were in median . the results of the sf were physical functioning ± , physical role functioning ± , bodily pain ± , general health ± , vitality ± , social role functioning ± , emotional role functioning ± and mental health ± . survivors who did not take part at the sf had a cpc score of in median (n= , personally signed refusals, language barriers, vegetative states). conclusions: after emergency ecls therapy and hospital survival % of our patients survived the following years up to over years with a preferable neurological outcome and a general mentally and physically satisfactory quality of life. a vague outcome in % limits the results of our study. introduction: successful weaning from va-ecmo requires the restoration of a sufficient cardiac function to ensure an adequate tissue perfusion. skin blood flow (sbf) is among the first to deteriorate during circulatory shock and the last to be restored after resuscitation. sbf would be a good predictor of successful weaning from va-ecmo. methods: patients with va-ecmo, who required a first weaning attempt, were included. weaning procedure (wp) was performed by a reduction of va-ecmo blood flow to l/min for minutes. the weaning criterion was an aortic velocity-time integral (vti) > cm. successful weaning from va-ecmo was defined as hemodynamic stabilization and without the need to increase the vasopressor dose during the next hours. sbf, assessed by skin laser doppler (peri-flux , perimed, right index finger); perfusion unit: pu), together with global hemodynamic parameters were obtained before and after min of weaning. receiver operating characteristic curves (roc) were generated to assess the ability and reliability of baseline parameters to predict a successful weaning. results: we studied wps in patients with va-ecmo for pulmonary embolism (n = ), post cardiotomy (n = ), acute coronary syndrome (n = ), myocarditis (n = ). these were successful (sw) in and unsuccessful (nsw) in . at baseline, hemodynamic variables, lactate, ecmo blood flow were similar in both groups (table ). sbf was greater in sw than nsw patients (table ). during wp, ci rose from baseline and was similar in sw and nsw (p= . ) ( table ). vtis were higher in sw than nsw ( ( - ) vs ( - ), respectively, p= . ). sbf decreased in sw and remained low in nsw (table ) . from the roc curves analyses, baseline sbf had the highest area under the roc curve with a cut off ≥ pu (sensitivity %, specificity %) (figure ). conclusions: sbf is a good predictor of successful weaning from va-ecmo introduction: postoperative cognitive dysfunction (pocd) is defined as a temporarily decline in cognition associated with surgery. long-term pocd ( months after surgery) occurs in - % of cardiac patients and is associated with a higher morbidity and mortality. endo-cabg is a new minimally invasive endoscopic coronary artery bypass grafting (cabg) technique that requires retrograde arterial perfusion which may be associated with a higher incidence of neurological complications. the aim of this study is to assess the incidence of pocd after endo-cabg. methods: sixty consecutive patients undergoing an endo-cabg were enrolled. pocd was assessed following the recommendations of the " statement of consensus on assessment of neurobehavioral outcomes after cardiac surgery". a comparative group of patients undergoing percutaneous coronary intervention (pci) and a control group of healthy volunteers were also enrolled. additional tests included the digit span test and digit symbol-coding test. patients were tested at baseline and at month follow-up. pocd is defined as a reliable change index (rci) ≤ - . (significance level %), or z-score ≤ - . in at least two different tests. results: after enrolling patients in each group, respectively in the endo-cabg-group, in the pci-group and healthy controls were analysed. patients suffering from a cva within three months after their procedure were automatically classified as having pocd (pci: n= ; endo-cabg: n= ). the total incidence of pocd was not different between groups (pci: n= ; endo-cabg: n= , p= . ). conclusions: our results suggest that the risk of pocd after endo-cabg is low and comparable with the risk of pocd after pci. introduction: rhabdomyolysis ( rml) post aortic surgery probably affects the renal outcome adversely [ , ] . there is no robust data regarding the same in literature. methods: retrospective single center data review; prior approval from institutional review board. patients were divided to two groups group -with rml ( ck above cut off levels u/litre) and group without rml. the determinants of rml and the impact of the same on outcome; predominantly renal function was evaluated. chi-square tests are performed for categorical variables whereas, student t tests (un-paired ) are performed with continuous variables. correlation is performed between creatine kinase and creatinine rise. p value . (two tailed) is considered for statistical significant level. results: out of patients, patients ( . %) developed rhabdomyolysis ( group rml) and did not( group non rml). demographic and intraoperative factors had no significant impact on the incidence of rml. there was a significantly higher incidence of renal complications including new postoperative dialysis in the rml group. other morbidity parameters were also higher in the rml group. conclusions: there is high prevalence of rml after aortic dissection surgery -identification of risk factor and early intervention might help to mitigate the severity of renal failure introduction: we investigate whether central venous pressure (cvp) pressure waveform signal can be informative in detection of slow bleeding in post-surgical patients. we apply a novel machine learning method to analyze cvp datasets to characterize bleeding in a porcine model of fixed rate blood loss. methods: thirty-eight pigs were anesthetized, instrumented with catheters, kept stable for minutes, and bled at a constant rate of ml/min to mean arterial pressure of mmhg. cvp waveforms were extracted from inspiration and expiration phases of respiration and statistically featurized. the proposed machine learning method, canonical least squares (cls) clustering, identifies correlation structures that differ between subsets of observations. we extend it to supervised classification. both clustering and classification methods yield human-interpretable models that reflect distinctive patterns of correlations within cvp waveforms. results: we conducted three experiments to discover structure in the physiological response to bleeding. first, we clustered respiration cycles with full knowledge of blood loss. the color-coded cluster assignments are shown in the figure . they are consistent with escalation of bleeding. second, we deployed clustering on only cvp features without blood loss. temporal structure was complemented with some subject-specific clusters (fig ) . third, we ran cls classification to decide whether an observation came from before or after the onset of bleeding (performance shown in the results: over the last decade, the number of patients with hlhs who underwent norwood has increased. interstage mortality has decreased, and is currently - %. significant morbidity was not seen at a rate higher than in the international literature. discharge planning, and community access to allied health professional services remained a concern. conclusions: the paediatric congenital cardiac surgical service in the united arab emirates is relatively new (compared to some services around the world). interstage mortality in hlhs is improving as a result of programme development, surgical progress and postoperative care. in the interstage period, there is currently no home monitoring programme in place. some patients were found to have had very extended hospital admissions. improved community support may reduce interstage mortality further, as well as improve the social situation of many of these patients. postoperative complications were observed in ( . %) patients. we lined out the prevalence of cardiac complications, such as heart failure and rhythm disturbances, observed in ( . %) and ( . %) patients respectively. hospital mortality rate was . % ( / ). the cause of mortality in all cases was acute heart failure, due to the initial severity of the disease, and in ( . %) cases an acute myocardial infarction was diagnosed. duration of postoperative period was . ± . days. conclusions: off-pump coronary artery bypass grafting can be safely performed with relatively low incidence of mortality and postoperative morbidity. prognostic value of mid-regional pro-adrenomedullin and midregional pro-atrial natriuretic peptide as predictors of multiple organ dysfunction development and icu length of stay after cardiac surgery with cardiopulmonary bypass in adults introduction: one of the most harmful complications after cardiac surgery with cardiopulmonary bypass is a syndrome of multiple organ dysfunction (mods). we consider that mid-regional proadrenomedullin (mr-proadm) and mid-regional pro-atrial natriuretic peptide (mr-proanp) plasma concentrations can be used as predictors of mods development and los in icu. methods: thirty six adult patients (mean age years, male) with cardiovascular diseases undervent cardiac surgery with cardiopulmonary bypass (heart valve(s) replacement - ( . %) patients, aorta and it`s branch surgery - ( . %) patients, valvular surgery and coronary artery grafting - ( . %) patients). nyha heart failure class ii was in ( . %) patients, iiiin ( %) patients, ivin ( . %) patients. in the dynamics levels of mr-proadm and mr-proanp were measured in the venous blood with the kryptor compact plus analyzer (thermo fisher scientific, germany) before day and on the st and th days after surgery. all patients were divided into subgroups according to the lengths of stay in the icu and the development of mod in the postoperative period. the data are shown as median and th and th percentiles. the data were compared by mann-whitney u-test, pvalue of < . was considered statistically significant. results: levels of mr-proanp did not significantly change at the study stages and did not have a significant difference between subgroups. the levels of mr-proadm increased in the first postoperative day and remained elevated for days. this increase was significantly higher in subgroups of increased los in icu and with mods. the data are shown in the table . conclusions: mr-proadm can be used as predictor of mods and los in the icu for adult patients underwent cardiac surgery with cardiopulmonary bypass. introduction: prolonged intensive care unit (icu) stay after cardiac surgery is associated with increased mortality and cost .the aim of this study was to investigate factors influencing prolonged icu stay. methods: consecutive patients who underwent cardiac surgery from june to october in our cardiothoracic department, were retrospectively investigated. group a consisted of pts with prolonged stay defined as more than days and group b the rest of the cohort. the following characteristics and perioperative factors were compared between the groups: smoking, diabetes, copd, redo(re-operation), ejection fraction (ef)< %, emergent procedure, cardiopulmonary bypass time (cpb)> min, low cardiac output syndrome (lcos), acute kidney injury(kdigo) and mortalitychi square test was used for the statistical analysis. introduction: hemorrhagic complications of extracorporeal membrane oxygenation (ecmo) pose a major morbidity and mortality. optimal anticoagulation strategies balancing risks of bleeding and thrombosis in children are poorly understood. we aimed to identify factors associated with non-surgical bleeding in the first ecmo hours. methods: we evaluated all pediatric (< yrs) post-cardiotomy patients requiring ecmo between dec -july stratifying them by presence/absence of surgical bleeding. non-surgical bleeding was defined as chest tube output > cc/kg/hr during the first -hours not requiring reoperation. patient characteristics and coagulation parameters at various time points after ecmo initiation were compared between groups, and receiver operator characteristic (roc) curves were constructed to identify models and thresholds with optimal predictive performance. figure . conclusions: deranged coagulation parameters, particularly kaolin rtime may predict non-operative bleeding in pediatric ecmo patients. these findings may guide therapeutic anticoagulation while avoiding hemorrhagic sequelae in at risk patients. introduction: elevated cardiac troponin (ctn) level in patients (pts) admitted in the intensive care unit (icu) is multifactorial and has been associated with a worse prognosis. the aim of the study was to review the frequency and the main cause of ctn elevation and to calculate a discriminating index. methods: we retrospectively assessed all pts admitted in our eightbed general icu during a -month period with at least one measurement of ctn during their icu stay. we recorded clinical characteristics, the level of ctn on admission, the maximum ctn during icu stay and the possible causes of elevation. variables are expressed as mean ± sd or as median and interquartile ratio (ir), according to the normality of their distribution. student´s Ô test or the mann whitney u tests were used to compare the group of elevated ctn with the group of normal ctn. the prognostic performance of elevated ctn was evaluated by the receiver operating characteristics (roc) curve. statistical analysis was performed using spss version . (spss, inc., chicago, illinois). results: in out of pts that ctn was measured at least once, abnormal levels (> . pg/ml) were found in ( %) of them, and the maximum ctn value was ( . ) pg/ml. the clinical characteristics of the pts are depicted in table . sepsis was the main cause of troponin elevation, which complicated by acute kidney injury (aki) in pts ( %). maximum ctn, aki and the difference of maximum -admission ctn (Äctn) differed significantly between pts who survived and pts who died (p= . and . , respectively). the area under the curve (auc) was . and the optimal prognostic cut-off value of Äctn was pg/ml with a sensitivity of . and a specificity of . conclusions: raised cardiac troponin values is a frequent finding in icu pts and sepsis is the driving cause. aki and the difference between maximum and admission ctn measurements differ significantly between pts who survive and pts who die. an elevation of ctn during icu hospitalization > pg/ml seems to be a threshold indicating poor prognosis regarding both mortality and aki. the prognostic role of nt-pro-bnp in septic patients with elevated troponin t level introduction: sepsis is frequently accompanied with release of cardiac troponin t (tnt) and nt-pro-bnp, but the clinical significance of this myocardial injury and cardiac dysfunction remains unclear [ ] . tnt is known to be an independent predictor of mortality, whereas the prognostic role of nt-pro-bnp is uncertain. methods: here, we report data of va-ecmo-patients, treated with dobutamine, levosimendan, suprarenin or no inotropic agens, in respect of -day survival. all data were collected retrospectively ( / to / ) at a single center, all patients with a survival below hours were excluded. while treatment of va-ecmo patients is strongly guided by standard operation procedures at our institution, no recommendation on positive inotropic therapy could be made. results: a total of va-ecmo patients were evaluated, of which patients were treated with levosimendan within hours after cannulation. day survival in the whole cohort was . %. a total of patients did not receive any positive inotropic therapy at hours after implantation (survival . %). survival was best in the levosimendan plus dobutamine group %, followed by dobutamine mono-therapy . % and levosimendan mono . %. survival with suprarenin mono was . %, suprarenin plus levosimendan . % and suprarenin plus dobutamine , %. pooling data, we found no evidence that levosimendan and/or dobutamine (survival . %, n= , p= . ) improves survival over no inotropic therapy (fig ) . therapy with any combination including suprarenin however resulted in poor survival ( . %, n= , p= . ). adjustment for lactate levels or ecpr did not change the results. conclusions: this retrospective analysis of va-ecmo patients shows no evidence that early inotropic therapy improves outcomes in va-ecmo patients. this conclusion is obviously biased by retrospective design. until randomized data are available, suprarenin however should be avoided. survey of non-resuscitation fluids in septic shock a linden-sonderso introduction: positive fluid balance is associated with poor outcome in septic shock. the objective of the present study was to characterize non-resuscitation fluids in early septic shock. methods: consecutive patients > years of age were screened for inclusion criteria during a -month period in icus in sweden and in canada. inclusion criteria were septic shock per sepsis- definition within hrs of icu admission. a maximum of patients per center were included. type, indication and volume of non-resuscitation fluids were recorded during the first days of admission. fluids other than colloids, blood products and crystalloids given at rate > ml/kg/h were considered to be non-resuscitation fluids. the study was registered on clini-caltrials.gov (nct ). data are presented as median (interquartile range). results: a total of patients were included between march st and june th (see table for demographics). patients received ( - ) milliliters (ml) of non-resuscitation fluids introduction: we aimed to ascertain the extent and make-up of fluid overload in critically ill patients and to identify whether delivery of more concentrated medications could reduce this. positive fluid balance is associated with increased mortality [ ] . a recent study has shown that the predominant component of fluid overload was from iv medications and maintenance fluid [ ] . methods: we reviewed sequential patients admitted to our icu with an apache ii score of greater than and a length of stay (los) greater than hours. the patients' electronic admission summary was interrogated to establish: length of stay (los) fluid balance at hours, total volume administered as iv medications, total volume administered as maintenance fluid and total fluid administered introduction: in children less than kilograms, maintenance fluids are routinely added to the resuscitation requirements calculated using parkland's or other formulae. the contribution of this component for fluid resuscitation in children can add a significant quantity to total estimated fluid requirements. for example, in a child who is kilograms with a % burn, the maintenance fluid requirement is mls per hours and the resuscitation component per parkland's will be x x %= mls. hence, the maintenance requirement can exceed the resuscitation requirement in this child if the burn surface area is less than a % burn. the contribution of maintenance fluids to the total fluid requirements in small children with thermal injuries is under-recognised and not frequently studied. methods: to understand the contribution of maintenance fluids to the total fluid requirements in children less than kilograms who need resuscitation for thermal injuries of different sizes, we numerically simulated . children who had similar weights but different burn sizes and . children with similar burn size but different weights. the results are as shown in fig introduction: accurate quantification of fluid in resuscitation of thermal injuries is important for benchmarking, comparing and improving outcomes. in adults, it is usually expressed as mls/kg/%tbsa. in children, maintenance fluids are added to the resuscitation requirements. this is kept constant and the resuscitation component is titrated to meet pre-defined end points-usually urine output. maintenance fluids are not uniformly stratified across the weight ranges. we propose that quantification of fluids in mls/ kg/%tbsa in children does not accurately capture fluid needs for resuscitation due to the maintenance component of the fluid requirement. methods: we conducted this retrospective study in children admitted to a single-center burns intensive care unit (bicu) between january and december . children ≤ kilograms with tbsa ≥ % admitted within hours of their injury were included. oe (observed to expected ratio) and fluid in mls/kg/% tbsa were calculated as shown in figure . results: there were children in the cohort with half requiring invasive mechanical ventilation in the bitu and nearly a quarter requiring inotropic support. the demographic details are as shown in table . the oe ratio at the end of hours in the cohort was . ( . - . ). the total fluid given was . ( . , ) mls/kg/ % tbsa. the titrated resuscitation component was . ( . , . ) mls/kg/tbsa. total fluid (which included the maintenance fluid) had a poor correlation with oe ratio r = . (fig ) . exclusion of the maintenance fluid had a better correlation with the oe ratio r = . conclusions: to capture differences in the titratable resuscitation component rather than differences in the maintenance requirements, fluid should be quantified in children by excluding the maintenance component when expressed as mls/kg/%tbsa. dynamic arterial elastance for predicting mean arterial pressure responsiveness after fluid challenges in acute respiratory distress syndrome patients p luetrakool , s morakul , v tangsujaritvijit introduction: dynamic arterial elastance (eadyn; pulse pressure variation/stroke volume variation; ppv/svv) is a dynamic parameter of arterial load that can be continuously monitored. previous study proposed that eadyn was able to predict mean arterial pressure (map) responsiveness after fluid challenge [ ] [ ] [ ] [ ] [ ] . the objective of this study was to assess whether the eadyn was able to predict map responsiveness in acute respiratory distress syndrome (ards) patients ventilated with low tidal volume. methods: we performed a prospective study of diagnostic test accuracy in adult ards patients with acute circulatory failure and fluid responsiveness. all patients are continuously monitored blood pressure via arterial line connected with flotrac® transducer and vigileo® monitor. once the attending physicians decided to load intravenous fluid, we recorded ppv/svv and also other hemodynamic parameters before and after fluid bolus. map responsiveness was defined as an increase in map ≥ % from baseline after fluid challenge. results: twenty-three events were included. nine events ( . %) were map-responsive. cardiac output, heart rate and stroke volume were similar in both map-responder and map-nonresponder group. baseline map, diastolic blood pressure (dbp) and pulse pressure (pp) were significantly different after fluid challenge in map-responder group. eadyn of preinfusion phase was failed to predict map conclusions: one of the arterial load parameters such as eadyn derived from non-calibrated pulse contour analysis method was unable to predict map responsiveness in ards patients with low tidal volume ventilation. the our aim is to test the hypothesis that in fr septic shock patients, fluid load will determine a significant increase in pmsf but not in cvp. we prospectively included all mechanically ventilated patients with diagnosis of septic shock with invasive hemodynamic monitoring (transpulmonary thermodilution volumeview-ev ed-wards©). we collected hemodynamic and metabolic data and pmsf with the inspiratory holds technique, before and after a fluid challenge (fc) of ml of ringer lactate in minutes). fr was defined as an increase in cardiac output (co)> %. results: measures were obtained in patients. in case we observed fr. we found a significant increase in pmsf after a fc (mean difference(md) . ± . mmhg, p=. ). cvp increased significantly (md . ± . mmhg, p=. ). pmsf increased significantly in non-fr (md ± mmhg, p=. ) but not in fr while cvp was higher after fc only in fr (md . ± . mmhg, p=. ). venous return gradient (pmsf-cvp) globally increased after fc (md ± mmhg, p=. ), but only in non-fr such increase was significant (md ± mmhg, p=. ). no correlation was found between the variation co and venous return gradient. we did not find any improvement in metabolic parameters after the fluid challenge. conclusions: pmsf and combined cvp variations do not correlate with fr in our cohort of septic shock patients. inspiratory holds may not be adequate to infer pmsf in such context. further studies are warranted to investigate the effect of fc on pmsf in this field. evaluation of pre-load dependence over time in patients with septic shock i douglas , p alapat , k corl , m exline , l forni , a holder , d kaufman , a khan , m levy , g martin , j sahatjian , w self , e seeley , j weingarten , m williams , c winterbottom , d hansell is an effective method to predict fluid responsiveness (fr) or cardiac response to preload expansion. we have previously shown that fluid responsiveness is a dynamic state, changing frequently over a hour monitoring period. methods: fresh is a currently enrolling prospective randomized controlled study, evaluating the incidence of fr and patient centered outcomes in critically ill patients with sepsis or septic shock (nct ). patients randomized to plr guided resuscitation were evaluated every - hours over the first hours of care and classified as fr if the sv increased > % when measured with non-invasive bioreactance (starling sv, cheetah medical). the time of first fr was noted. results: a total of plr assessments were performed in patients over a hour monitoring period. % were female, and the average age was years. plrs were evaluated over time, with time representing initial fluid resuscitation ( figure ). when individual subjects were evaluated over time, % of subjects who became fr only after hours showed evidence of lv/rv dysfunction ( figure ). conclusions: fluid responsiveness or preload dependence frequently changes for septic shock patients over the first hours of care. evidence suggests it is beneficial to periodically perform an assessment of preload responsiveness to guide fluid administration, as preload dependence is a dynamic and changing state. preload dependence provides additional information beyond fluid responsiveness. those patients who remain primarily fluid non-responsive (preload independent) are more likely to demonstrate echo confirmed lv/rv dysfunction, as the delay in return to cardiac function may be related to underlying cardiac deficits. further evaluation may be indicated in preload independent patients. introduction: hydroxyethyl starch (hes), a synthetic colloid, has been used as a volume expander, and is associated with renal impairment in patients with sepsis. however, a small dose of hes ( %, / . ) has sometimes been used in acute ischemic stroke. therefore, we investigated whether a small dose of hes was linked with renal deterioration in patients with acute ischemic stroke. methods: a consecutive patients with acute ischemic stroke within days from onset were included between january and may (fig ) . we collected admission serum creatinine (scr), estimated glomerular filtration rate (egfr), and renal function was assessed using kdigo definition of acute kidney injury on hospital days to as to patient's hospitalization period. is crucial for venous return and volaemic status, and as such it is a useful parameter in physiology and clinical settings alike. we tested whether: near infra-red spectroscopy (nirs) could be effective at measuring msfp both in healthy individuals and in conditions with a rise in interstitial pressures; after an occlusion pressure is relieved, the decrease in venular blood volume could allow calculation of τ (time constant) and thus venous resistances (rv). in order to verify these hypotheses we used a forearm nirs probe on healthy individuals at rest and during different degrees of maximal voluntary contraction (mvc). methods: healthy subjects volunteered in the study that took place at sant'andrea hospital in rome (italy). all subjects had venular pressures and volumes assessed via a nirs probe positioned on the forearm using a pressure-cuff in steps of mmhg from to mmhg, at rest and at % and % mvc. for each patient msfp, unstressed volume (vu) and stressed volume (vs) were measured. a temporary mmhg occlusion was obtained and volume time course was calculated upon release, to derive τ . results: p-v relationship was found to have a -slopes shape reflecting venular network changes. we measured vu, vs, and obtained msfp values of . ± . mmhg, p< . ; during exercise no changes in vu and vs were noted but msfp values rose; value was found to be . ± . sec at rest and . ± . sec after exercise, reflecting a reduction in rv. conclusions: nirs measurements on healthy subject may have implications in the clinical assessment of critical care patients where changes in interstitial pressure are possible. introduction: in the pathogenesis of multiple organ dysfunction syndrome (mods) important role plays the development of hepatic dysfunction. a known method for assessing hepatic blood flow is reohepatography (rhg). however, it requires the analysis of a large number of parameters of the rheogram curve. the aim of this study was to develop a method for assessing arterial hepatic blood flow based on the rhg in patients with mods after abdominal surgery. methods: patients in the department of anesthesiology and intensive care unit were included in a prospective study ( men and women, age . ± . years, weight . ± . kg.). all patients were divided into two groups: group -patients after orthopedic and trauma surgery (n = ), group -patients after abdominal surgery with mods (n = ). patients in the groups did not have statistical differences by sex, age, body weight, height. rhg was carried out using the "reo-spectr" (russian federation). we have compared the rhg indicators between the groups ( table ) . we have developed a method for assessing hepatic arterial blood flow, which consists in determining the area under the arterial part of rhg curve using the simpson's rule. its normal values range from . mΩ *s to . mΩ *s. the method is non-invasive, can be applied at the patient´s bed. its advantage is simplicity, it can be used for rapid diagnosis and monitoring the effectiveness of treatment. area under the rhg curve in the group were . ± . mΩ *s and . ± . mΩ *s in the group (p < . ). conclusions: patients after abdominal surgery with mods have impaired hepatic blood flow, which may be associated with liver pathology caused by main surgical disease (obstructive jaundice) and hemodynamic disorders caused by acute cardiovascular failure. the method we developed allows us to determine disorders of hepatic arterial blood flow in the early stages before signs of liver dysfunction appear. comparison of pulse oximetry hemoglobin with laboratory measurement of arterial and central- results: patients: % male, median years ( - ); p:f ratio ( - ); peep ( - ); apache iii . ( ); median ventilation time days ( - ). fair agreement was seen in subjective assessment vs objective measures with binary assessment of rv size and function. ordinal data analysis showed poor agreement with rvfws ( figure ) and rv dimensions. if onestep disagreement was allowed the agreement was good ( table , ). significant overestimation of severity of abnormalities was seen comparing subjective assessment with rv eda and tapse, s' and fac. there was no difference in agreement values when accounting for clinician echo experience, perceived expertise (at level of cardiologist) or type of qualifications. conclusions: relatively low levels of agreement were seen with subjective assessment vs objective measures of rv size and function assessed by echo. it seems prudent to avoid subjective rv assessment in isolation and a combination of objective and subjective measures should be used. introduction: even short periods of hypotension are associated with increased morbidity and mortality. using high-density numerical physiologic data, we developed a machine learning (ml) model to predict hypotension episodes, and further characterized risk trajectories leading to hypotension. methods: a subset of subjects with / hz physiological data was extracted from mimic , a richly annotated multigranular database. hypotension was defined as > measurements of systolic blood pressure ≤ mmhg and mean arterial pressure ≤ mmhg, within a -minute window. derived features using raw measurements of heart rate, respiratory rate, oxygen saturation, and blood pressure were computed. random forest (rf), k-nearest neighbors (knn), and logistic regression models were trained with -fold cross validation to predict instantaneous risk of hypotension using features extracted from the data leading to the first episode of hypotension (cases) or icu discharge in subjects never experiencing hypotension (controls). for a given subject, risk trajectory was computed from the collation of instantaneous risks. results: from a source population of subjects, subjects met our definition of hypotension, and subjects without hypotension comprised the control group. features were generated from the four vital signs. the area under the curve (auc) for random forest classifier was . , out-performing logistic regression (auc . ) or k-nearest neighbors (auc . ) (fig ) . risk trajectories analysis showed average controls risk scores < . (< % risk of future hypotension), while the hypotension group had a rising risk score ( . to . ) in the hours leading to the first hypotension episode, and significantly higher scores leading into subsequent episodes (fig ) . conclusions: hypotension episodes can be predicted from vital sign time series using supervised ml. subjects developed hypotension have an increased risk compared to controls at least hours prior to the episode. introduction: in critically ill patients or in patients undergoing major surgery, monitoring of co is recommended [ ] [ ] [ ] . less-invasive advanced hemodynamic monitoring with pwa is increasingly used in perioperative and critical care medicine. in this study, we evaluate the measurement performance of an uncalibrated pulse wave analysis (pwa) device (mostcareup, vygon, ecouen, france) compared with cardiac output (co) assessment by pulmonary artery thermodilution (patd) in patients after cardiac surgery. methods: in patients after cardiac surgery, we performed seven sets of patd measurements to assess patd-co. simultaneously, we recorded the pwa-co and compared it to the corresponding patd-co. to describe the agreement between pwa-co and patd-co we used bland-altman analysis showing the mean of the differences and %-limits of agreement and calculated the percentage error. results: we included patients in the analysis. the bias between pwa-co and patd-co was . l*min- . upper and lower % limits of agreement were + . l*min- and - . l*min- . the percentage error was . %. conclusions: pwa-co estimated with using the mostcareup device shows good agreement with pulmonary artery thermodilutionderived co in patients after cardiac surgery. introduction: non-invasive continuous blood pressure monitoring devices have been investigated, however, these devices did not have sufficient accuracy and precision. we developed a continuous monitor using the photoplethysmographic technique and tested the accuracy and precision of this system to ensure it was comparable to conventional continuous monitoring methods used for critically ill patients. methods: the study device was developed to measure blood pressure, pulse rate, respiratory rate, and oxygen saturation, continuously with a single sensor using the photoplethysmographic technique. patients who were monitored with arterial pressure lines in the icu were enrolled. the physiological parameters were measured continuously for minutes at -minute intervals using the study device and the conventional methods. the primary outcome variable was blood pressure. results: pearson fs correlation coefficient between the conventional method and photoplethysmography device were . for systolic blood pressure, . for diastolic blood pressure, . for mean blood pressure, . for pulse rate, . for respiratory rate, and . for oxygen saturation. percent errors for systolic, diastolic and mean blood pressures were . % and . % and . %, respectively. percent errors for pulse rate, respiratory rate and oxygen saturation were . %, . % and . %, respectively. conclusions: the non-invasive, continuous, multi-parameter monitoring device presented high level of agreement with the invasive arterial blood pressure monitoring, along with sufficient accuracy and precision in the measurements of pulse rate, respiratory rate, and oxygen saturation. conclusions: stroke volume measurement using bioreactance technique had strong correlation with odm while pwtt had moderate correlation. both devices had small bias with wide limits of agreement and percentage error compared with odm. therefore, these devices are not interchangeable with odm. however, using trends in stroke volume to guide treatment might still be acceptable. introduction: hemorrhage is the most common cause of trauma deaths and the most frequent complication of major surgery. it is difficult to identify until profound blood loss has already occurred. we aim at detecting hemorrhage early and reliably using waveform vital sign data routinely collected before, during, and after surgery. methods: we use waveform vital sign data collected at hz during a controlled transition from a stable (non-bleeding) to a fixed bleeding state of pigs. these vital signs include airway, arterial, central venous and pulmonary arterial pressures, venous oxygen saturation (svo ), pulse oximetry pleth and ecg heartrate, continuous co, and stroke volume variation (lidco). we used gated recurrent units (gru), long short-term memory (lstm) and dilated, causal, one-dimensional convolutional neural (table ) . however, outside of the very low fpr range (cf. rocs in fig. and ), our models appear inferior to a referenced random forest (rf) classifier. conclusions: our work demonstrates the applicability of deep learning models to diagnose hemorrhage based on raw, waveform vital signs. future work will address why the rf classifier can address the greater homogeneity of subjects when they bleed compared to an apparently wide dispersion of their statuses when being stable. this work is partially supported by nih gm . can myocardial perfusion imaging with echo contrast help recognise type acute myocardial infarction in the critically ill? introduction: many instances of significant bleeding may not occur in highly monitored environment, contribution in the delay in recognition and intervention. we therefore proposed a noninvasive monitoring for early bleeding detection using photoplethysmography (ppg). methods: fifty-two yorkshire pigs were anesthetized, stabilized and bled to hemorrhagic shock, and their invasive arterial blood pressure (abp), and ppg data were collected [ ] . time series of vital signs were divided into data frames of minute updated every seconds and beat to beat features were computed. the final feature matrix contained abp features and ppg features. a supervised machine-learning framework using least absolute shrinkage and selection operator regularized logistic regression model was constructed to score the probabilities for hemorrhage of each data frame. data in stabilization was set as negative and data in bleeding was set as positive. model performance was evaluated by receiver operating characteristic (roc) area under the curve (auc) with leave-one-out cross validation, and its precision was assessed with activity monitoring operative characteristic (amoc). results: two different models were proposed using abp and ppg features separately. figure showed the ppg model could classify the hemorrhage with auc = . , where the auc of abp model was . . figure showed the ppg model could detect the hemorrhage on average . minutes (equals to ml blood loss) if the false alarm rate of / was tolerated, whereas the average detection time of abp model were . minutes at same threshold of false alarm rate. conclusions: we proposed a novel non-invasive bleeding detection approach using ppg signals only. this method potentially can improve the identification of hemorrhage with in patients and environments where invasive monitoring is unavailable. table , catheter and procedure characteristics are shown in table . the median angle of bed position was °. no patients were positioned in neutral or tp. all procedures were successful with a mean of . punctures per patient, and a maximum of . the median procedure time was . minutes. no major complications occurred in any of our patients. conclusions: central venous catheterisation in moderate upright position is feasible and can be done safely when using realtime ultrasound by well-trained physicians. we recommend performing clinical assessment and pre-procedural ultrasound to choose the optimal puncture site and position in order to attain an optimal ultrasound visualisation of the vessel and patient comfort. methods: a retrospective analysis of patients presenting to tertiary-care emergency department who required cvc for vasopressor administration was carried out. all central venous cannulation into the right brachiocephalic vein was performed with ultrasound guidance using the high frequency linear probe. right brachiocephalic vein was visualised in its long axis. the needle was positioned just beside the centre of ultrasound probe degrees below the coronal plane and degrees angle to the ultrasound probe and advanced just behind the clavicle. results: the mean puncture time taken to perform this procedure, calculated from the needle piercing the skin until to the aspiration of blood from the brachiocephalic vein through the needle, was ± . s. no procedure-related complications were detected. conclusions: the oblique needle trajectory of right brachiocephalic vein cvc in adult is feasible and able to visualised well the anatomical structure, hence avoid complications. introduction: central venous cannulation, a routine procedure on intensive care units, is associated with a low complication rate. as a consequence, the routine use of chest x-ray (cxr) or ultrasound (us) to assess these complications is under discussion. our aim was to identify risk factors for central venous catheter (cvc) placement associated complications that can help decide whether or not follow-up using cxr and/or us is indicated. methods: multicenter prospective, observational study. consecutive critically ill adult patients who underwent cvc placement. either the internal jugular vein or subclavian vein was cannulated. complication rates were determined. predicting factors were obtained through a questionnaire filled in by physicians after placing a cvc. if the questionnaire was incomplete or data was missing, analyses were performed using the available data. patient characteristics were duplicated if a patient recieved more than one cvc. outcomes were iatrogenic pneumothorax and malposition. pneumothorax was detected using us, whereas cxr was used to determine cvc malposition. table . usguidance, insertion site, and setting were predictive for complications. the overall cvc placement associated complication rate is low and multiple risk factors associated with the occurrence complications were identified. a complication rate this low, strongly suggests that routine post-procedural diagnostics is superfluous. therefore, we suggest, provided that uneventful execution of the procedure is assured, post-procedural diagnostics are only necessary in selected cases with (multiple) risk factors. introduction: the use of ultrasound for subclavian vein cannulation (scv) has developed poorly due to the difficulty of visualizing this vein via the classical infraclavicular approach. we explored the feasibility of ultrasound-guided subclavian vein catheterization via a supraclavicular approach methods: prospective study conducted over six-month period in intensive care unit. after approval of the ethics committee, we included patients over years of age and requiring central venous access. exclusion criteria were: hemostasis disorders, puncture area infections and cervico-thoracic vascular malformations the procedure consisted of catheterization of the vsc with a supraclavicular approach under ultrasound guidance using an ultrasound in plane approach (fig and ). data collection included clinical and ultrasound data: scv depth, diameter and length, catheterization time, number of needle redirection, cannulation success and complications. results: thirty four patients were included. age: ± (mean ± sd), % of whom were male. the success rate of scv catheterization was % (one failure). the depth of the scv was ± . mm and its diameter was ± . mm. the puncturable length of the scv was ± mm and the puncture angle was ± °. the time required to obtain an adequate ultrasound image was ± seconds. the interval between the beginning of the puncture and the insertion of the guidewire into the vein was ± sec. the total catheterization time was ± seconds. the number of needle redirection . +/- . redirects. the quality of the ultrasound image was excellent or good in . % of cases. an arterial puncture was observed in two patients conclusions: this preliminary study demonstrated the feasibility of the subclavian vein cannulation via the supraclavicular approach. more study are required to confirm its safety and to compare this approach to the infraclavicular acces using ultrasound. introduction: lung ultrasound b-lines, a comet-like reverberation artefacts arising from water-thickened interlobular septa, indicate extravascular lung water which is a key variable in heart failure management and prognosis. aim of this study is to measure the correlation between lung ultrasound b-lines and nyha functional classification. methods: this is a months prospective study on congestive heart failure patients conducted in urban emergency departments in malaysia. following enrolment, patients had their functional capacity categorised based on nyha classification, followed by point of care ultrasound (pocus) lung scan using a mhz linear probe. the scanning was performed by trained emergency physicians. the longitudinal scan done at the recommended zones of both left and right lungs and the total number of b-lines identified were summed up as the comet score. comet score of , , and were categorised based on amount of blines of less than , - , - and more than b-lines respectively. results: hundred and twenty-two patients were analysed ( males( . %) and females( . %)) ranging from to years old. comet score of , and were found to be statistically significant with presence of paroxysmal nocturnal dyspnoea, elevated jugular venous pressure, lung crackles, bilateral pitting oedema and chest radiographic findings. a moderate correlation between nyha classes with comet score , and (rs= . (p< . )) was documented. conclusions: our study demonstrated a moderate correlation between nyha classes and lung ultrasound b-lines. lung ultrasound may be a potential tool to objectively determine the functional capacity in patients with congestive heart failure and monitor its changes in response to treatment and disease progression. the introduction: point of care ultrasound (pocus) is a tool of increasing utility in the management of the critically ill patient. guidelines exist for training and accreditation in pocus [ , ] however the widespread use of pocus has been hampered by a lack of mentors. online communication with end-to-end security, such as whatsapp ™ are increasingly used in medicine as a communication aid [ ] . some individuals are using such communications to share pocus images for review-the overall sentiment around these tools is unknown. methods: an online survey of pocus users was conducted via twitter ™. the question was "in situations where an expert opinion on an ultrasound is not immediately available, is it acceptable to get an expert review via an online medium such as whatsapp, and would you be happy to be that expert?" results: votes were received. voters were a mix of pocus users from the usa, europe, and australia. % said the medium was acceptable, and that they would be happy to provide expertise. % voted "no", with % voting "other" (fig ) . conclusions: in this international survey of pocus users, % were happy to provide and receive mentorship using remote software such as whatsapp. distance mentorship for pocus training should be explored. [ ] . a description of the development and refinement of insight -a feasibility and clinical effectiveness randomized controlled trial. methods: a modified delphi exercise was used to select the most beneficial ultrasound windows and imaging questions to ask for each window in scheduled inter-professional ultrasound. nurses, doctors and physiotherapists from critical care were given the same information regarding potential utility of each window. the windows and associated questions were individually ranked; each window and question tested against three further criteria; and filtered by ease of training to level standard; clinical usefulness; time of practical delivery and applicability across an inter-professional group. results: the modified delphi exercises and prioritization exercise ranked ease of adoption by training; feasibility within the time frame and clinical usefulness to develop a core insight scan of domains, each with set binary questions (tables and ) conclusions: we have developed a research intervention that will allow us to test the effectiveness of inter-professional scheduled whole body assessment of critically ill patients by ultrasound. we now plan to conduct a clinical effectiveness trial with an internal pilot to confirm feasibility. to search for optimal pressing time, the plots from the color sensor during nail bed compression were analyzed. we found two phases in the color sensor plots. in the initial part of compression, the plots changes rapidly (rapid phase) and then the slope of plots reduces (slow phase). the pressure release during the rapid phase could destabilize the measurement. the longest period of the rapid phase was . s among all the study subjects. thus, a pressing time of s seems to be needed to obtain stable crt measurements. conclusions: on our study for the investigation of standard pressing time and strength for crt measurements, pressing the nail bed with - n and s appears to be optimal. detection of pancreas ischemia with microdialysis and co sensors in a porcine model introduction: pancreas transplantation is associated with a high rate of early graft thrombosis. current postoperative monitoring lack tools for early detection of ischemia, which could precipitate a graft-saving intervention. we are currently exploring the possibility of ischemia detection with microdialysis and co -sensors in the organ tissue or on the surface in a porcine model. methods: in anesthetized pigs, co -sensors and microdialysis catheters are inserted into the parenchyma or attached to the surface of the pancreas. pco is measured continuously and lactate is sampled with microdialysis every min. ischemia is induced by sequential arterial and venous occlusions for minutes, with minutes of reperfusion in between. results: pco increased and decreased in response to ischemia and reperfusion within minutes. lactate increased and decreased with the same pattern, but with a considerable delay as compared to pco . an example is depicted in figure . the values are presented in introduction: reliable automated handheld vital microscopy (hvm) image sequence analysis is a prerequisite for use of sublingual microcirculation measurements at the point-of care according to the current consensus statement. we aim to validate a recently developed advanced computer vision algorithm [ ] versus manual analysis in a wide spectrum of populations and contexts. methods: our collaborators were invited to contribute raw data of published or ongoing institutional review board approved work. inclusion criteria were use of the cytocam hvm device, manual analysis with the ava software, and image quality as independently assessed by massey score of < in > % of recordings in a random subset of each study. subjects from studies were included, covering clinical and experimental populations, major shock forms and interventions to recruit the microcirculation (table ) . results: , , red blood cells were tracked by the algorithm across , frames in measurements in real time. a good to excellent correlation was found between algorithm-determined and manual capillary density (p< . , r . - . , figure ). capillary perfusion was classified using space-time diagram derived red blood cell velocity (rbcv), yielding good correlation with manual analysis for functional capillary density und proportion of perfused vessels. microcirculatory alterations during disease and interventions were equally detected by the algorithm and manual analysis. change in flow short of severe abnormality was reflected in absolute rbcv but not microcirculatory flow index. conclusions: we demonstrate the validity of automated software for hvm image sequence analysis across broad populations, disease conditions and interventions. thus, microcirculatory assessment at the bedside may finally complement point-of-care evaluation of disease severity and treatment response in critically ill patients and during surgery. introduction: in , naumann et al introduced the poem score as a real-time, point-of-care score to assess sublingual microcirculation [ ] . our study aimed to determine the reproducibility of the poem score. methods: two expert operators used a sidestream darkfield (sdf) videomicroscope (cytocam, braedius, netherlands) to separately acquire four high-quality video clips and assign a poem score to each image in adult mechanically ventilated patients. each operator was blinded to the other's images and analysis. video clip scores and acquisition times were recorded. results: of the patients enrolled in this study, % (n= ) required vasopressors. we categorized poem scores - as "normal" and poem scores - as "impaired." (fig ) . with only one instance of interrater disagreement (i.e., a single image scored as versus ), cohen's kappa ( . ) confirmed a strong correlation between interpreters. the mean time to complete a study session was minutes. conclusions: the present inability to quickly characterize the quality of sublingual microcirculation as either normal or impaired at the point of care limits real-world clinical application of this resuscitative endpoint. the rapidly obtained poem score appears to be reproducible between bedside interpreters. future studies should assess the effect of poem score-guided resuscitation. . sublingual microcirculatory images were obtained using a cytocam-idf device (braedius medical, huizen, the netherlands) and analyzed using standardized published recommendations. results: the median age of participants was years. we found no significant difference in proportions of hemodynamic responders before and after marathon ( % vs %, p= . ). also we did not find differences between plr induced changes of total vessel density (tvd) and proportion of perfused vessels (ppv) of small vessels before and after marathon. correlations between changes of sroke volume and changes of tvd or ppv of small vessels during plr were not significant. conclusions: marathon running did not change microcirculatory responsiveness. introduction: clinical measurement of mitochondrial oxygen tension (mitopo ) has become available with the comet system [ ] . a question with any novel technique is whether it is feasible to use in clinical practice and provides additional information. in elective cardiac surgery patients we measured cutaneous mitopo and tissue oxygenation (sto ). methods: institutional research board approved observational study in patients undergoing cardiopulmonary bypass (cpb). mitopo measurements were performed on the left upper arm (comet, photonics healthcare b.v.) by oxygen-dependent delayed fluorescence of aminolevulinic acid (ala)-induced protoporphyrin ix [ ] . priming of the skin was done with ala (alacare, photonamic gmbh) applied the evening before surgery. sto measurements (invos, medtronic) were done in close proximity to the comet sensor. results: at the time of writing of patients were enrolled and mitopo measurements were feasible in this clinical setting. mitopo appeared sensitive with a high dynamic range. for example, highdose vasopressor therapy decreased mitopo and blood transfusion increased a low mitopo but not a high mitopo . in the example in figure , mitopo is clearly dependent on cpb flow and the restored cardiac circulation is able to maintain good cutaneous oxygenation after cpb even before returning of cellsaver blood. sto had the tendency to provide relatively stable values within a small bandwidth and little response to even major hemodynamic changes. conclusions: mitopo shows the effect of interventions on mitochondrial oxygenation and provides additional information compared to standard monitoring and sto . introduction: traumatic asphyxia is a rare condition in which breathing and venous return is impaired due to a strong compression to the upper abdomen or chest region, and induces swelling, purplish red appearance, and petechiae around the face and neck. to our knowledge, there are no reports describing details of traumatic asphyxia including the clinical course and the therapeutic reactivity from cardiac arrest. we focused on cardiac arrest among all traumatic asphyxia patients treated at our hospital, and investigated their clinical features and therapeutic reactivity. methods: sixteen cases of traumatic asphyxia involved with our hospital between april and march were reviewed by using the pre-hospital activity record, medical record, and hyogo prefectural inspection record. these patients were divided into three groups. the first group had already cardiac arrest at the time of rescue from the trapped place (group a; cases). the second group became cardiac arrest after the rescue (group b; cases). the third group did not experience cardiac arrest (group c; cases). results: all cases had abnormal findings in skin or conjunctiva (table ) . total mortality rate reached %, but among cases of group a and b who resulted in cardiac arrest, there were cases with injury severity score or more and abbreviated injury scale in the chest or more. they had pneumothorax, flail chest, pericardial hematoma. seven of them restored spontaneous circulation, and two cases achieved neurologically full recovery. conclusions: there are some cases of traumatic asphyxia whose therapeutic reactivity is very good even after cardiac arrest, so it is important not to spare efforts for life support in such cases. rhythm and % witnessed arrest, five hundred ten ( %) patients had a good functional outcome at -months. physiological derangements were each negatively associated with outcome in bivariate analysis at the p < . level. a summary score of physiological derangements was included with potential confounders in the final regression model, and was independently associated with outcome with the chance of a good outcome decreasing by % for each increase of one physiologic derangement ( % ci . - . ). conclusions: uncorrected physiological derangements are independently and cumulatively associated with worse outcome after cardiac arrest. although causality cannot be established, it is reasonable to consider that the correction of physiological parameters may be an important step in the chain of survival after resuscitation. characteristics introduction: glan clwyd hospital (gch) was recently designated one of three cardiac arrest centres for wales. it has offered a / percutaneous coronary angiography (pci) service to a geographically dispersed north wales population of approximately , since june . prior to this, urgent coronary angiography was available on a more limited basis to patients requiring pci. the aim of this study was to investigate factors associated with hospital mortality after critical care admission following cardiac arrest. methods: retrospective review of the ward watcher critical care database at gch to identify patients who had undergone cpr in the hours prior to critical care admission in - . patients likely to have sustained ooha of cardiac aetiology (ooha-c) were identified from primary and secondary diagnoses and free text entry. data were subsequently analysed using excel and spss. the project was registered as a service evaluation with gch audit department. results: there were cardiac arrest admissions over this period, increasing from in - to in - . of these were ooha, of which were considered ooha-c. although ooha-c hospital mortality appeared to decrease over the time period ( %% to %), this was not statistically significant (p= . ). factors associated with survival to hospital discharge are presented in the tables below. on logistic regression, only pci and low ph within the first hours of critical care remained statistically significant (p= . and p< . respectively). conclusions: although we have been unable to make a distinction between patients presenting following stemi and nstemi, and appreciating a potential influence of selection bias, the significant association between pci and survival to hospital discharge supports the introduction of clinical pathways enabling pci access following ooha-c [ ] . chest radiography. [ ] here, we aimed to derive and validate rules to estimate p_max.lv using anteroposterior chest radiography (ches-t_ap), which is performed for critically-ill patients urgently needing determination of personalised p_max.lv. methods: a retrospective, cross-sectional study was performed with non-cardiac arrest adults who underwent chest_ap and computed tomography (ct) within h (derivation:validation= : ). on chest_ap, we defined cd (cardiac diameter), rb (distance from right cardiac border to midline) and ch (cardiac height, from carina to uppermost point of left hemi-diaphragm) (fig , ) . [ ] setting p_zero ( , ) at the midpoint of xiphisternal joint and designating leftward and upward directions as positive on x and y axes, we located p_max.lv (x_max.lv, y_max.lv). the coefficients of the following mathematically-inferred rules were sought: x_max.lv=a *cd-rb; y_max.lv=ß *ch+γ . (a : mean of (x_max.lv+rb)/cd; ß , γ : representative coefficient and constant of linear regression model, respectively ) . conclusions: evaluable echocardiographic records were reached in most of the patients. etco positively correlated with all parameters under consideration, while the strongest correlation was found between cimax and etco . therefore, cimax is a candidate parameter for real-time monitoring of haemodynamic efficacy of chest compressions during cpr. introduction: the uk resuscitation council has set out guidelines for management of patients post cardiac arrest [ ] . this is in line with european resuscitation council guideline. we set out to find if we are following the guideline. methods: we did a retrospective audit over the course of years looking at the data of patients who had in hospital and/or out of hospital cardiac arrest and after the return of spontaneous circulation were admitted to the intensive care unit (icu). we focused on whether the care they received was as per the standards set by the uk resuscitation council. results: we had in the hospital and out of hospital cardiac arrests; patients had less than minutes of cpr, had more than minutes cpr and patients the data was not recorded; patients needed more than minutes to reach from the site of arrest to the icu. the partial pressure of carbon dioxide was > . kpa in patients at two or more occasions. target map was not documented in patients; blood sugar target was not documented in patients and was not maintained within limits in patients. target temperature was not documented in patients. the withdrawal of treatment was not delayed for hours in patient out of . in patients neurological tests were not documented. multimodal assessment tools were not used in patient. electroencephalography and serum neuron specific enolase were not used to diagnose brain deaths as they were not available at our trust. patients were discharged, died in the icu and died in hospital after discharge from icu. conclusions: the audit reflected our local practice and showed that our mortality was in line with the acceptable limits; poor documentation of plan of care which posed problems in analyzing the care that these patients received; some of the parameters were not being maintained as set by uk resuscitation guideline. introduction: high-quality chest compressions (cc) with minimized interruptions are one of the most essential prerequisites for an optimal outcome of resuscitation. therapy of reversible causes of cardiac arrest often requires intra-hospital transportation (iht) during ongoing cpr. the present study investigated cc quality during transportation depending on the position of the provider. methods: paramedics were enrolled into a manikin study with four groups: a reference group with the provider kneeling beside manikin on the floor (group ), and groups performing cc during a simulated iht of meters: walking next to the bed (group ), kneeling beside the patient in bed (group , fig. ) or squatting above the patient in bed (group , figure ). indicators of cc quality were measured as defined in the erc guidelines (pressure point and depth, compression frequency, complete relief, sufficient pressure depth) [ ] . all paramedics performed cc during each scenario (group - ). results: there were no statistical differences in quality of cc between groups , and . notably, group performed significantly worse in respect to the proportion of cc with correct pressure point (p = . vs group ), correct cc depth (p= . vs. group , p= . vs. group , p= . vs. group ). the results are shown in table . conclusions: carrying out guideline-compliant cc [ ] during iht is feasible with multiple provider positions. based on the present results, kneeling or squatting position next to the patient ( figure and ) is recommended, whereas "walking next to the bed" while performing cc should be avoided. methods: a retrospective review of clinical notes was undertaken for patients admitted to icu following return of spontaneous circulation but whom remained comatose. this audit encompassed three-month periods before and after introduction of the care bundle in october . audit standards were assigned from target parameters documented in the bundle and reflected guidance from the cheshire and merseyside critical care network. results: patients were included in our audit; admitted prior to and admitted following implementation of the care bundle. in patients whom targeted temperature management was indicated, improved adherence to thermoregulation between - °c was observed ( vs %). significant improvements were since in the observance to target values for oxygen saturation ( vs . %, p= . ) and mean arterial pressure ( vs . %, p< . ) following the introduction of the care bundle. improved observance of ventilation targets was also seen; maintenance of p a co > . kpa ( vs %, p= . ) and tidal volumes < ml/kg ideal body weight ( to . %, p= . ). conclusions: the introduction of a post-cardiac arrest care bundle in our icu has improved care by providing discrete physiological targets to guide nursing staff and standardising management between clinicians. variations in care are associated with poorer patient outcomes [ ] and introduction of this bundle has reduced disparities in practice. array of cardiac diseases and reported survival rate is low in spite of advances in resuscitation and ems services. methods: single-centre retrospective study analyzed outcomes of ohca patients admitted to cardiac icu between .- . we studied demographic data, initial rhythm, type of cpr, comorbidities and various post admission diagnostic findings in order to identify their impact on survival. results: ohca comprised , % of all admissions. mean los was . days ( - ). mean age was , y ( - ), m: f ratio : and bystander cpr was performed in only % ohca patients. the most common initial rhythm was vf ( . %), followed by vt ( . %), pea was found in , % and asystole in . % of pt more than half of pt received adrenalin ( %) and defibrillation ( %) and only % required a temporary pacemaker. % of pt had an ecg consistent with mi after rosc, % underwent coronary angiography resulting in pci in % of cases. in pt ( %) therapeutic hypothermia protocol was performed. most ohca pt had hypertension ( %) and hyperlipidaemia ( %) as the most common risk factors followed by cardiomyopathy ( %), diabetes ( %) and cad ( %). only % had a preexisting significant valvular disease and the rest were extracardial comorbidities: chronic renal disease ( %), copd ( %) and cerebrovascular disease ( %). patients survived ( %) and gcs on admission was the only significant impact factor on survival along with comorbidities (mean gsc was in survivors vs. in deceased). interestingly, age, initial rhythm, troponin i level, ph and therapeutic hypothermia had no impact on survival. conclusions: our data demonstrate the importance of early onsite resuscitation as the most important factor of neuroprotection and outcome and puts an emphasis on the importance of cpr education for layman population. prediction of acute coronary ischaemia and angiographic findings in patients with out-of-hospital cardiac arrest j higny , a guédès , c hanet , v dangoisse , l gabriel , j jamart introduction: coronary artery disease (cad) is the leading cause of out-of-hospital cardiac arrest (ohca). however, diagnosis of acute coronary ischaemia (aci) remains challenging, particularly in patients without st-segment elevation on the post-resuscitation ecg. in this regard, a consensus statement recommends the implementation of a work-up strategy in the emergency room (er) to exclude noncoronary causes of collapse within hours. methods: retrospective single-centre study performed on consecutive patients with resuscitated ohca who underwent a diagnostic coronary angiography (ca). we present data on coronary angiograms for patients who underwent cardiac catheterization after resuscitation. afterwards, we sought to identify parameters associated with aci. results: st-segment elevation was noted in patients ( %). stsegment depression or t-wave abnormalities were noted in patients ( %). invasive coronary strategy allowed to identify an acute culprit lesion in cases ( %). patients with st-segment elevation underwent an immediate angioplasty for an acute coronary occlusion. patients without st-segment elevation underwent an ad hoc percutaneous coronary intervention for a critical lesion. stable cad was found in cases ( %) and a normal angiogram was found in only cases ( %) (figure ). conclusions: aci was the leading precipitant of collapse. stsegment elevation was highly predictive of coronary occlusion. in addition, a culprit coronary lesion was identified in nearly % of patients undergoing ca despite the lack of stsegment elevation. finally, our findings suggest that the identification of risk criteria may help to improve the recognition of aci after ohca. the prediction of outcome for in-hospital cardiac arrest (pihca) score e piscator , k göransson , s forsberg , m bottai , m ebell , j herlitz , t djärv figure. predictive value for classification into < % likelihood of favorable neurologic survival was . %. false classification into < % likelihood of favorable neurologic survival was . %. the phica score has potential to be used as an aid for objective prearrest assessment of the chance of favorable neurologic survival after ihca, as part of decision making for a dnar order. introduction: prognosis of survival in patients with cardiac arrest remains poor. during and after cardiopulmonary resuscitation, pathophysiological disturbances in relation with a cytokine storm, are described as "post-resuscitation" disease like a combination of cardiogenic and vasodilatory shocks. veno-arterial extracorporeal membrane oxygenation (va ecmo) allows to restore adequate perfusion but little is known about its effect on left ventricular (lv) function and about the role of cytokines. methods: this study was performed in an experimental model of cardiac arrest performed in groups of anesthetized and mechanically ventilated pigs. cardiac arrest was obtained by application of electrical current to epicardium inducing ventricular fibrillation. after a no-flow period of minutes, medical resuscitation with catecholamines and vasopressors was performed in "control" group while va ecmo was started in "ecmo" group and va ecmo in combination with cytosorb (extracorporeal blood purification therapy designed to reduce excessive levels of inflammatory mediators such as cytokines) was started in "ecmo-cyto" group. lv function was assessed with transthoracic echocardiography and arterial pressure with aortic pressure catheter. results: hemodynamic stability was obtained after ± and ± minutes in ecmo and ecmo-cyto groups, respectively. no return of spontaneous circulation was observed in control group. at minutes following cardiac arrest, lv area fractional change on short axis was normalized in ecmo and ecmo-cyto groups ( ± and ± %, respectively). vasopressor requirements were significantly lower in ecmo-cyto group than in ecmo group. conclusions: after cardiac arrest (no-flow) of minutes duration, va ecmo allowed complete lv recovery and hemodynamic stability within minutes of "post-resuscitation" disease. cytosorb added to va ecmo could contribute to reduce post-resuscitation vasodilatation. impact of rapid response car system on ecmo in out-of-hospital cardiac arrest: a retrospective cohort study m nasu , r sato , k takahashi introduction: extracorporeal life support (ecls) has been reported to be more effective than conventional cardio-pulmonary resuscitation (cpr). in ecls, a shorter time from arrival to implantation of extracorporeal membrane oxygenation (ecmo; door-to-ecmo) time has been reported to be associated with better survival rates. this study aimed to examine the impact of the physician-based emergency medical services (p-ems) using a rapid response car (rrc) on door-to-ecmo time in patients with out-of-hospital cardiac arrest (ohca to study the interest and the educational contribution in the short and medium term of medical simulation compared to a classical training. methods: cohort, prospective, observational, single-center, randomized study with control group including residents ( in anesthesia resuscitation and in emergency medicine). all benefited from a theoretical training with a reminder of the latest recommendations on the management of cardiac arrest and anaphylactic shock. they were randomized into groups and received practical training on a high-fidelity simulator for the management of either cardiac arrest (acc group) or anaphylactic shock (ca group). each group was evaluated at weeks (t ) and at months on two scenarios: refractory ventricular fibrillation (fv) scored on points and grade anaphylactic reaction (ra ) scored on points. each group served as the control group for the pathology in which they did not receive specific simulator training. the results are expressed on average with their standard deviations with "p" < . . introduction: simulation is a tool for improving the quality and safety of care, and its recognized as an essential method of evidence-based education. emergency medicine is a discipline in which there is a constant concern for the safety of patients. the emergency physician is often called upon to take charge of critical situations that use knowledge, know-how and knowledge as skills that must be mastered and whose theoretical learning alone is insufficient. methods: it´s a prospective study including residents in emergency medicine performing their specialty courses in emergency services and emergency medical assistance in the region of sousse from january to june . they were randomized into two groups: the one benefiting from a traditional education and the other from an education based on simulation sessions. the chosen scenario was the management of a cardiac arrest. a pre-test and a post-test were performed in both groups. results: we included emergency residents who did not receive specialized training in the management of cardiac arrest, there was a female predominance with an average age of , there was no significant difference regarding the pretest between the two groups with . there was no significant difference with respect to the pre-test score between the two groups . ± . / for the control group versus . ± . / for the simulation group. there was a significant progression after the course with an average posttest score of . ± . in the simulation group while this score was . ± . in the control group with a statistically significant difference (p < . ). conclusions: simulation learning has led to a better acquisition of cognitive knowledge by learners. the simulation is not intended to replace bed-based teaching, nor theoretical or faculty teaching, but it is an essential complement . in tunisia, the simulation must continue its current integration in the initial and continuous training of doctors. introduction: recent studies have shown that obesity and its related metabolic dysfunction exacerbates outcomes of ischemic brain injuries in some brain areas, such as the hippocampus and cerebral cortex when subjected to transient global cerebral ischemia (tgci). however, the impact of obesity in the striatum after tgci has not yet been addressed. the objective of this study was to investigate the effects of obesity on tgci-induced neuronal damage and inflammation in the striatum and to examine the role of mtor which is involved in the pathogenesis of metabolic and neurological diseases. methods: gerbils were fed with a normal diet (nd) or high-fat diet (hfd) for weeks and then subjected to min of tgci. hfd-fed gerbils showed the significant increase in body weight, blood glucose level, serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol without affecting food intake. results: in hfd-fed gerbils, neuronal loss occurred in the dorsolateral striatum days after tgci and increased neuronal loss were observed cholesterol days after tgci; however, no neuronal loss was the in ndfed gerbils after tgci, as assessed by neuronal nuclear antigen immunohistochemistry and fluoro-jade b histofluorescence staining. the hfd-fed gerbils also showed severe activated microglia and further increased immunoreactivities and protein levels of tumor necrosis factor-alpha, interukin- beta, mammalian target of rapamycin (mtor) and phosphorylated-mtor in the striatum during pre-and postischemic conditions compared with the nd-fed gerbils. in addition, we found that treatment with rapamycin, a mtor inhibitor, in the hfd-fed gerbils significantly attenuated hfd-induced striatal neuronal death without changing physiological parameters. conclusions: these findings reveal that chronic hfd-induced obesity results in severe neuroinflammation and significant increase of mtor activation, which could contribute to neuronal death in the stratum following tgci. abnormal mtor activation might play a key role. associations between partial pressure of oxygen and neurological outcome in out-of-hospital cardiac arrest patients introduction: exposure to hyperoxemia and hypoxemia is common in out-of-hospital cardiac arrest (ohca) patients following return of spontaneous circulation (rosc) but its effects on neurological outcome are uncertain and study results are inconsistent. methods: exploratory post-hoc substudy of the target temperature management (ttm) trial [ ] , including patients after ohca with rosc. the association between serial arterial partial pressures of oxygen (pao ) during hours following rosc and neurological outcome at months, evaluated by cerebral performance category (cpc), dichotomized to good (cpc - ) and poor (cpc - ), was investigated. in our analyses, we tested the association of hyperoxemia pao > kpa and hypoxemia pao < kpa, time weighted mean pao , (twm-pao ) (fig ) , maximum pao difference (Δ pao ) and gradually increasing pao levels ( . - . kpa) with poor neurological outcome. a subsequent analysis investigated the association between pao and a biomarker of brain injury, peak serum tau levels. results: patients were eligible for analysis. patients ( %) were exposed to hyperoxemia or hypoxemia after rosc (table ) . our analyses did not reveal a significant association between hyperoxemia, hypoxemia, twm-pao exposure or Δ pao and poor neurological outcome at -month follow-up after correction for co-variates (all analyses p= . - . ) (fig ) . we were not able to define a pao level associated with the onset of poor neurological outcome. peak serum tau levels at either or hours after rosc were not associated with pao . conclusions: hyperoxemia or hypoxemia exposure occurred in one third of the patients during the first hours of hospitalization and was not significantly associated with poor neurological outcome after months or with the peak s-tau levels at either or hours after rosc. introduction: cerebral hypoperfusion may aggravate the developing neurological damage after cardiac arrest. near-infrared spectroscopy (nirs) provides information on cerebral oxygenation but its clinical relevance during post-resuscitation care is undefined. we wanted to assess the possible association between cerebral oxygenation and clinical outcome after out-of-hospital cardiac arrest (ohca). methods: we performed a post hoc analysis of a randomised clinical trial (comacare) where both moderate hyperoxia and high-normal arterial carbon dioxide tension (paco ) increased regional cerebral oxygen saturation (rso ) as compared with normoxia and low-normal paco , respectively. rso was measured from ohca patients with nirs during the first h of intensive care and neurological outcome was assessed using the cerebral performance category (cpc) scale at months after cardiac arrest. we calculated the median rso for patients with good (cpc - ) and poor (cpc - ) outcome and compared the results using the mann-whitney u test. we compared the rso over time with outcome using a generalised mixed model. finally, we added median rso to a binary logistic regression model to control for the effects of possible confounding factors. results: the median (interquartile range [iqr]) rso during the first h of intensive care was . % ( . - . %) in patients with good outcome compared to . % ( . - . %) in patients with poor outcome, p = . . we did not find significant association between rso over time and neurological outcome ( figure ). in the binary logistic regression model rso was not a statistically significant predictor of good outcome (or . , % ci . - . , p = . ). conclusions: we did not find any association between cerebral oxygenation during the first h of post-resuscitation intensive care and neurological outcome at months after cardiac arrest. fig. introduction: near-infrared spectroscopy (nirs) provides a noninvasive means to assess cerebral oxygenation during postresuscitation care but its clinical value is unclear. we determined the possible association between cerebral oxygenation and the magnitude of brain injury assessed with neuron-specific enolase (nse) serum concentration at h after out-of-hospital cardiac arrest (ohca). methods: we performed a post hoc analysis of a randomised clinical trial (comacare) comparing two different levels of carbon dioxide, oxygen and arterial pressure after ohca and successful resuscitation. we measured rso continuously with nirs from patients during the first h of intensive care. we determined the nse concentrations at h after cardiac arrest from serum samples using an electrochemiluminescent immunoassay kit. the samples were tested for haemolysis and all samples with a haemolysis index > mg of free haemoglobin per litre (n = ) were excluded from the analyses. we calculated the median rso for all patients and used a scatterplot and spearman's rank-order correlation to assess the possible relationship between median rso and nse at h. in addition, we compared the nse concentrations at h after cardiac arrest in patients with good (cerebral performance category scale [cpc] - ) and poor (cpc - ) neurological outcome at months using the mann-whitney u test. results: we did not find significant correlation between median rso and serum nse concentration at h after cardiac arrest, rs = - . , p = . (figure ). the median (iqr) nse concentration at h was . ( . - . ) μg/l and . ( . - . ) μg/l in patients with good and poor outcome, respectively, p < . . conclusions: we did not find any association between cerebral oxygenation during the first h of post-resuscitation intensive care and nse serum concentrations at h after cardiac arrest. the association between lactate, cerebral oxygenation and brain damage in post-cardiac arrest patients introduction: patients admitted to the intensive care unit (icu) after being successfully resuscitated from a cardiac arrest (ca) have a large cerebral penumbra at risk for secondary ischemic damage in case of suboptimal brain oxygenation. therefore, resuscitation during icu stay should be guided by parameters that adequately predict cerebral hypoxia. the value of lactate as resuscitation parameter may be questioned in post-ca patients since the brain critically depends on aerobic metabolism. we aimed to investigate the relationship between arterial lactate, cerebral cortex tissue oxygenation (scto ) by near infrared spectroscopy (foresight) and unfavorable neurological outcome at days (cpc score - ) methods: subanalysis from the neuroprotect post-ca trial. lactate values and scto were recorded hourly in post-ca patients during hours ttm and subsequent rewarming. results: in total paired lactate/ scto measurements were analysed. we found no correlation between paired lactate and scto² (fig. ) . moreover, temporary trends in lactate did not correlate with corresponding trends in scto during the same one-hour time interval (r²= . ) (fig ) . if lactate values above . mmol/l are considered to be abnormal, lactate could not adequately detect clinical important brain ischemia (scto < %): sensitivity % and specificity % (table , ). nevertheless, time weighted lactate at h (or . ; p . ), h (or . , p . ), h (or . ; p . ) and h (or . ; p . ) were inversely correlated with unfavorable neurological outcome at days (fig , ) . conclusions: although lactate was a marker of prognosis in post-ca patients, it should not be used to guide resuscitation since lactate values were not correlated with scto and changes in lactate do not correspond with changes in scto during the same time interval. simplified introduction: the aim of the study was to investigate whether simplified continuous eeg monitoring (ceeg) [ ] post-cardiac arrest can be reliably interpreted by icu physicians after a short structured training, and whether acceptable interrater agreement compared to an eeg-expert can be achieved. methods: five icu physicians received training in interpretation of simplified ceeg (fig ) consisting of lectures, hands-on ceeginterpretation, and a video tutorial -total training duration day. the icu physicians then interpreted simplified ceeg recordings. basic eeg background patterns and presence of epileptiform discharges or seizure activity were assessed on -grade rank-ordered scales based on a standardized eeg terminology [ ] . an experienced eeg-expert was used as reference. results: there was substantial agreement (κ . ) for eeg background patterns and moderate agreement (κ . ) for epileptiform discharges between icu physicians and the eeg-expert. sensitivity for detecting seizure activity by the icu physicians was limited ( %), but with high specificity ( %). among icu physicians interrater agreement was substantial (κ . ) for eeg background pattern and moderate (κ . ) for epileptiform discharges. conclusions: after a one-day educational effort clinically relevant agreement was achieved for basic eeg background patterns after cardiac arrest. assessment of epileptiform patterns was less reliable, but bedside screening by the icu physician may still be clinically useful for early detection of seizures. interpretation of simplified ceeg requires awareness of its limitations and support from an eeg-expert when clinically indicated. introduction: hypoxic-ischemic injury on head computed tomography (ct), which manifests with varying degrees of cerebral edema and loss of gray-white matter differentiation, is a poor prognostic sign after resuscitated out-of-hospital cardiac arrest that may influence early clinical decision-making. agreement among physicians on the presence of hypoxic-ischemic injury on early head ct is unknown. methods: we recruited faculty physician participants ( emergency medicine, critical care, neurocritical care, and general radiology; average . years of practice) across academic medical centers each with > admissions for resuscitated out-of-hospital cardiac arrest each year. participants, blinded to clinical context, reviewed unique head cts obtained within hours of cardiac arrest that were randomly selected from a local registry. a blinded neuroradiologist also reviewed all scans (gold standard). participants determined if hypoxic-ischemic injury was present on each ct, and agreement was determined using multi-and dual-rater kappa statistics with % confidence intervals. results: overall agreement among physicians regarding the presence of hypoxic-ischemic injury on head ct was fair (kappa . ; % ci, . - . ) with agreement consistent across most specialties (table ) . when compared to the neuroradiologist, individual physician agreement ranged widely, from poor (kappa . ) to substantial (kappa . ), with of physicians having fair or worse agreement compared to the gold standard interpretation. conclusions: the finding of hypoxic-ischemic injury on early head ct after cardiac arrest had high interobserver variability as interpreted by acute care physicians and general radiologists. pending the development of objective diagnostic criteria, clinicians should bear in mind the subjectivity and subtlety of cerebral edema or loss of graywhite matter differentiation soon after return of spontaneous circulation in these patients. figure ). baseline characteristics and differences between the wlst and no-wlst groups are shown in table . utilization of neuro-prognostication tests is shown in table . while ct and eeg were commonly employed, ssep and mri were used less frequently. basic multimodal neuroprognostication (arbitrarily defined as at least one ct or mri, plus eeg, plus ssep) was performed only in . % of all patients undergoing wlst but the rate increased significantly over six years (p< . ) and was higher in the time period after , compared to the one prior to ( figure ). this association remained significant after adjustment for confounders such as age, arrest rhythm, downtime, targeted temperature management, apache ii score and organ failure in a logistic regression model (p= . ). in an institution with access to a wide range of imaging and neurophysiology tests, mri and ssep remained underutilized but the rate of basic multimodal neuro-prognostication increased significantly over the study period, especially in the period after . introduction: although multiple reports using animal models have confirmed that melatonin appears to promote neuroprotective effects following ischemia/reperfusion-induced brain injury, the relationship between its protective effects and the activation of autophagy in cerebellar purkinje cells following the asphyxial cardiac arrest and cardiopulmonary resuscitation (ca/cpr) remains unclear. methods: rats used in this study were randomly assigned to groups as follows; vehicle-treated sham-operated group, vehicletreated asphyxial ca/cpr-operated group, melatonin-treated shamoperated group, melatonin-treated asphyxial ca/cpr-operated group, melatonin plus (+) p-pdot (the mt melatonin receptor antagonist)-treated sham-operated group and melatonin+ p-pdot-treated asphyxial ca/cpr-operated group. results: our results demonstrate that melatonin ( mg/kg, ip, time before ca and times after ca) significantly improved the survival rates and neurological deficits compared with the vehicle-treated asphyxial ca/cpr rats (survival rates ≥ % vs %). we also demonstrate that melatonin exhibited the protective effect against asphyxial ca/cpr-induced purkinje cell death. the protective effect of melatonin in the purkinje cell death following asphyxial ca/cpr paralleled a dramatic reduction in superoxide anion radical (o ·-), intense enhancements of cuzn superoxide dismutase (sod ) and mnsod (sod ) expressions, as well as a remarkable attenuation of autophagic activation (lc and beclin- ), which is mt melatonin receptor-associated. furthermore, the protective effect of melatonin was notably reversed by treatment with p-pdot. conclusions: this study shows that melatonin conferred neuroprotection against asphyxial ca/cpr-induced cerebellar purkinje cell death by inhibiting autophagic activation by reducing expressions of ros, while increasing of antioxidative enzymes, and suggests that mt is involved in the neuroprotective effect of melatonin in cerebellar purkinje cell death induced by asphyxial ca/cpr. introduction: fucoidan is a sulfated polysaccharide derived from brown algae and possesses various beneficial activities, such as antiinflammatory and antioxidant properties. previous studies have shown that fucoidan displays protective effect against ischemiareperfusion injury in some organs. however, few studies have been reported regarding the protective effect of fucoidan against cerebral ischemic injury and its related mechanisms. methods: therefore, in this study, we examined the neuroprotective effect of fucoidan against cerebral ischemic injury, as well as underlying mechanisms using a gerbil model of transient global cerebral ischemia (tgci) which shows loss of pyramidal neurons in the hippocampal cornu ammonis (ca ) area. fucoidan ( and mg/kg) was intraperitoneally administered once daily for days before tgci. results: pretreatment with mg/kg of fucoidan, not mg/kg fucoidan, attenuated tgci-induced hyperactivity and protected ca pyramidal neurons from ischemic injury following tgci. in addition, pretreatment with mg/kg of fucoidan inhibited activations of resident astrocytes and microglia in the ischemic ca area. furthermore, pretreatment with mg/kg of fucoidan significantly reduced the increased -hydroxy- -noneal and superoxide anion radical production in the ischemic ca area after tgci and significantly increased expressions of superoxide dismutase (sod ) and sod in the ca pyramidal neurons compared with the vehicle-treated-group. we found that treatment with diethyldithiocarbamate (an inhibitor of sods) to the fucoidan-treated-group notably abolished the fucoidanmediated neuroprotection in the ischemic ca area following tgci. conclusions: these results indicate that fucoidan can effectively protect neurons from tgci-induced ischemic injury through attenuation of activated resident glial cells and reduction of oxidative stress following increasing sods. thus, we strongly suggest that fucoidan can be used as a useful preventive agent in cerebral ischemia. the effects of cold fluids for induction of therapeutic hypothermia on reaching target temperature and complications-a sub-study of the tth study a holm , m skrifvars , fs taccone ). there was no difference in early bleeding incidences (fig ) . during late observation, ttm patients had fewer minor bleeding ( . % vs. %) and more intracranial bleeding ( . % vs. %; fig ) . adjusted calculated risk ratio for major bleeding (including intracranial) for ttm was . ( %ci . - . ) at baseline and . ( %ci . - . ) over time. conclusions: bleeding complications were common. although the risk ratio for major bleeding increased over time in ttm patients, residual and unmeasured confounding in addition to selection and detection bias may limit the clinical relevance of this finding. methods: patients with neurological deficit > by nhiss were included. the t°of the brain was recorded non-invasively using radiothermometer rtm- -res (russia). we measured t°in symmetric regions of left & right hemispheres, calculated the average t°of brain, fig. (abstract p ) . temperature of patients given and not given pre-icu fluids (table ) . conclusions: observed moderate brain t°heterogenecity in hp, marked increase brain t°heterogenecity in is & sharp decline of t°h eterogenecity in cci. supposedly, correcting the impairment of cerebral tb (increase or decrease t°) through physical (selective cerebral hypothermia, magnetic stimulation etc.) or pharmacological (sedation) can contribute to positive therapeutic results in is & cci. nonivasive radiothermometry of the brain can be an objective method of patients' condition evaluation & their rehabilitation potential. introduction: basilar artery stroke has a multitude of different presentations and may not be captured on plain computed tomography (ct). it can progress to severe disability, locked in syndrome and death [ ] . with the advent of thrombolytic and endovascular therapies, prompt diagnosis can change the outcome. we present a case of basilar artery stroke, which was heralded by tongue spasticity and dysarthria, indicative of pseudobulbar palsy. methods: case reviewed with consent. a literature search was conducted using pubmed and medline. results: a -year-old presented with pulmonary oedema and hypertension. he was transferred to our intensive care unit for treatment of a suspected anaphylaxis. his marked lingual swelling was associated with dysarthria. glyceryl-trinitrate and labetalol infusions were started for hypertension. he developed left sided weakness and deteriorated over several days to the point that he could only move his right foot (table ) . magnetic resonance imaging (mri) showed midbrain ischaemia and angiogram showed no flow in the basilar artery (fig , ) . conclusions: common presenting features of basilar artery occlusion include dysarthria, vertigo, vomiting, headache and motor defects; these may evolve gradually or be intermittent [ , ] . presentation with pseudobulbar palsy is described in early literature [ ] . delayed recognition of the stroke led to aggressive treatment of hypertension, potentially compromising perfusion to the penumbral area [ , ] . this case highlights the need for a wide index of suspicion with posterior strokes. consent: informed consent to publish has been obtained from the patient prognosis is related to gcs < or = on admission (p = . ) and to malignant cerebral edema (p = . ). conclusions: our study has shown some predictive factors closely related to mortality and morbidity in patients with acute ischemic stroke. gcs at admittance < or = and onset of malignant cerebral edema lead to a worst prognosis at discharge from nicu. coherence analysis of cerebral oxygenation using multichannel functional near-infrared spectroscopy evaluates cerebral perfusion in hemodynamic stroke tj kim table ). in addition, severe stroke patients were more likely to have higher phase coherence in interval iii (p = . ). conclusions: our results demonstrated that the higher phase coherence of oxyhb in myogenic signal, which was originated locally from smooth muscle cells in brain was related to impaired cerebral perfusion. this suggests that monitoring cerebral oxygenation using fnirs could be a useful noninvasive measuring tool for evaluating impaired cerebral autoregulation in stroke patients. is esmolol associated with worse outcome at the acute phase of ischemic stroke that receives thrombolysis? introduction: ischemic stroke patients experienced frequent early neurological deterioration (end) events. since ischemic stroke has also been shown as inflammatory disease, the neutrophil-tolymphocyte ratio (nlr) may associated with end events. however, the direct study regarding this association has not been addressed. poor grade sah, use of vasopressors, mechanical ventilation, intracranial pressure monitoring, external ventricular drainage, blood transfusions and renal replacement therapy were all more frequent among nonsurvivors (all p< . ). mortality was also higher with initial lactate above mmol/l, in those admitted to public hospitals and when admission to icu was delayed more than hours after ictus. after adjusting for common predictors (age, gender and wfns) saps non-neuro, sofa non-neuro, early vasopressor use and admission to a public hospital were independently associated with hospital mortality. moreover, the area under the curve for prediction of mortality with saps , sofa and wfns was . ( figure ). hospital, austria. the association of intensity and duration of intracranial hypertension episodes with -month glasgow outcome score (gos) was visualized using the methodology introduced by güiza et al. [ ] . results: in both cohorts, it could be demonstrated that the combination of duration and intensity defined the tolerance to intracranial hypertension, and that a semi-exponential curve separated episodes associated with better outcomes from those associated with worse outcomes. the association with worse outcomes occurred at a lower pressure-time burden than what has been previously observed in patients with tbi. nevertheless, the percentage of monitoring time spent by every patient in the zone associated with poor gos was independently associated with worse -month neurological outcome, even after correcting for age and fisher score ( introduction: apnea test is an essential component in the clinical determination of brain death, but it may incur a significant risk of complications such as hypotension, hypoxia and even cardiac arrest [ ] . we analyzed the risk factors associated with failed apnea test during brain death assessment in order to predict and avoid these adverse events. methods: medical records of apnea tests performed for brain-dead donor between january and january in our institution, were reviewed retrospectively. age, gender, etiology of brain death, use of catecholamine and results of arterial bleed gas analysis (abga), systolic/diastolic blood pressure (sbp/dbp), mean arterial pressure (map) and central venous pressure (cvp) prior to apnea test initiation were collected as variables. a-a gradient and pao /fio were calculated for more precise assessment of the respiratory system. in total, cases were divided into a group which was completed apnea test and the other which was failed the test. introduction: tunisia has already suffered recurrent outbreaks since . outbreak started relatively earlier this year. we were interpellated by the frequency of neuroinvasive presentation of the disease. methods: we report a case series of patients presented to icu with niwnd. results: we report cases of niwnd with different severe presentations overlapping neurological manifestation including encephalitis (n= / ), meningitis (n= / ) and flaccid paralysis (n= / ). almost all patients live in the locality of sousse. six patients presented a long course of isolated fever before developing neurological signs. cerebrospinal fluid was consistent with encephalitis within the patients. cerebromedullar mri identified brain lesions (n= / ), myelitis (n= / ) and polyradiculoneuritis (n= / ).three patients had electromyography for flaccid paralysis showed diffuse axonal polyneuropathy with motoneuron involvement. ten cases had a positive wnv igm antibody and nine had a positive wnv igg antibody in serum. urine polymerase chain reaction was positive for wnv in / patients. ten patients were mechanically ventilated. all patients were managed symptomatically. two received high doses of methylprednisolone for days, one patient received polyclonal immunoglobulin intravenous and one patient had plasmapheresis. two patients died consecutive to brainstem lesions. two patients recovered significantly and discharged with no complications. five other patients evolved to persistent flaccid paralysis with a minimal consciousness state and weaning difficulties requiring tracheostomy. the last remaining patient is still evolving. conclusions: modification of the regional climatic conditions accounted probably for the early outbreak of niwnd. this initial case series displays the severity and the poor outcomes of niwnd with higher incidence compared to past epidemics. noninvasive estimation of intracranial pressure with transcranial doppler: a prospective multicenter validation study c robba , c fig. ], mean bias was - . mmhg (limits of agreement are ± sd . mmhg). . % measures were outside the limit of agreement in the overall population. however, when icp was high, % of measures were out of the limit of agreement. the auc [ fig. introduction: surgical treatment of aortic aneurysm needs extracorporeal circulation (ecc), aorta clamp and hypothermia, and it is often related to poor systemic perfusion and blood flow velocity. one of the main concerns of intensive care team is to prevent secondary neurological injury after long time without blood flow pulsatility, such as brain edema and seizure. the most common parameters for neuromonitoring would be intracranial pressure and eeg, however, for non-neurological patients this information is unusual and prevents optimal management. methods: we aimed to assess brain compliance and neurological condition of icu patients on immediate post-operative recovery of bentall-de bono procedure and/or other aortic aneurysm surgical treatment using a novel non-invasive intracranial pressure (icp) device. this device uses mechanical displacement sensor capturing extracranial continuous volumetric variation of the skull and this information proportionally reflects intracranial dynamic [ ] . results: twenty patients were included in this study. ecc mean time was minutes for patients and only one did not need it. eleven presented altered icp curves with poor brain compliance (p /p ratio > . ) assessed by icp curve morphology analysis. volemic optimization and neuroprotective measures were taken based on this icp information for acute case management. among these patients with altered icp curves, eight were discharged from icu with good clinical condition and glasgow coma scale of . overall mortality rate was six out of twenty ( %) and three of these had altered icp curves. conclusions: brain monitoring of cardiovascular post-operative patients is important to prevent secondary neurological complications and can be a helpful tool for neuroprotective acute management on icu. the technique supplies electrical current to muscle, combined with passive cycling. prior to a clinical trial, we first investigated the effects of one session of fes in healthy volunteers. methods: healthy male volunteers (n= ) were recruited. the participants had their postural sway assessed on a pressure sensitive board, and measurement of maximal inspiratory pressure (mip). ultrasounds were taken assessing thickness of the quadriceps and rectus abdominis. they performed minutes of supine passive cycling, with fes supplying the lower limbs and abdomen. after a minute rest, the tests were repeated. a further participants performed just the initial baseline tests, to help assess muscular factors affecting balance and sway. results: the current needed for palpable contraction was significantly correlated to weight in the abdomen (r= . , p< . ) and quadriceps (r= . , p< . ). current required to stimulate the abdominal muscles was also correlated to depth of the subcutaneous fat layer (r= . , p< . ) and echogenicity of the muscle (r= . , p= . ). pre-cycling, left and right vastus lateralis thickness inversely correlated to postural sway in the antero-posterior (r=- . , p< . ) plane. compared to pre-cycling, postural sway in the antero-posterior and lateral planes increased significantly after cycling. there was a significant decrease in mip after cycling and greater reductions in mip were found in participants who had thinner rectus abdomni. conclusions: sway at baseline is related to quadriceps thickness, which atrophies during critical illness, and could worsen balance. mip is reduced during fes and the severity of reduction is related to the thickness of the abdominal wall muscles at baseline, suggesting that fes can fatigue the diaphragm and abdominal muscles. in awake healthy volunteers, fes is a safe, comfortable technique. introduction: in most cases postoperative cognitive dysfunction (pocd) is transient, but still some patients suffer from persistent cognitive impairment which is associated with increased length of hospital stay, early withdrawal from labor market and higher mortality. available data on the prevalence of pocd after cardiac surgery is very diverse from % to % upon discharge and up % months after surgery. we aimed to investigate the prevalence of short-term and long-term pocd after off-pump coronary artery bypass grafting (cabg) surgery. methods: psychometric testing was performed in (mean age . ± . ) patients before, days and months after the surgery. we used following tests to assess cognitive capacity: auditory verbal learning test (avlt), digit span test (dst), digit-letter substitution test (dlst), stroop's test and trail making test (tmt). a decline in comparison to preoperative test results for % or more in two or more tests was declared as pocd. results: the prevalence of pocd after days was . % ( patients) and . % ( patients) after months. when comparing patients who developed pocd with those who did not we found the former were older ( . ± . vs . ± . years; p< . ), had lower education level ( . ± . vs . ± . years; p< . ) and had longer surgery duration ( . ± . vs . ± . minutes; p< . ). the most affected cognitive domains were long term memory (avlt) and executive function (tmt) and least affectedworking memory (dst) and selective attention (stroop's test). conclusions: in our prospective study the prevalence of long-term pocd after cardiac surgery was slightly less ( . %) in comparison to available data (from % to %). it might be due differences in psychometric testing and interpretation of its results among authors. advanced age, low cognitive reserve and long duration surgeries are linked with higher incidences of pocd. introduction: postoperative cognitive dysfunction (pocd) is a common and widely described phenomenon in surgical patients. advanced age, major surgery, certain general anesthetics, genetic factors, sleep deprivation and other factors were described as contributing factors to pocd. the hospital stay itself is a major 'social' trauma for patients; social isolation, sleep deprivation and changes in daily regimen may effect neurocognitive behavior of patients. in this trial we tried to assess the link between pocd and the length of hospital stay in cardiac surgery patients. methods: patients who underwent 'off-pump' coronary artery bypass grafting (cabg) surgery selected for this trial. neuropsychological testing was performed prior to the operation and upon discharge. we used auditory verbal learning test (avlt), digit span test (dst), digit-letter substitution test (dlst), stroop test and trail making test (tmt). a % or more decline in two or more tests in comparison to preoperative test results was declared as pocd. patients were allocated into two groups according to the length of hospital stay: the short-stay group (group ) included patients (n= ) who were discharged on the th day after surgery or earlier and the long-stay (group ) group consisted of patients (n= ) who were discharged on the th day after surgery or later. patients received similar anesthesia, postoperative care and were operated by the same surgical team. reasons for prolonged duration of hospital stay were mainly surgical. results: patients ( . %) in group and patients ( . %) in group had pocd upon discharge (p< . ). mean length of hospital stay were ± . and ± . days in group and group patients respectively (p< . ). conclusions: prolonged length of hospital stay increased the prevalence of pocd in our trial. studies with various types of surgical procedures and larger patient populations needed to further understand the effect of length of hospital stay to pocd. the influence of multiple trauma with head trauma on posttraumatic meningitis: a nation-wide study with hospital-based trauma registry in japan introduction: posttraumatic meningitis is one of severe complications and results in increased mortality and longer hospital stay among head trauma patients. however, it remains unclear whether there is a difference in the incidence of post-traumatic meningitis due to single traumatic brain injury (tbi) and multiple trauma including head injury. methods: this study was a retrospective observational study during years we included trauma patients registered in japanese trauma data bank whose head ais score was > in this study. multivariable logistic regression analysis was used to assess potential factors associated with posttraumatic meningitis such as csf fistula, skull base fracture, type of injury that divided into single tbi and multiple trauma. introduction: the aim of this study was to determine if regional cerebral oxygenation (rsco ) can be used as an indicator of tissue perfusion in icu patients with tbi [ , ] , and to determine the prognostic value of cerebral oxygenation rsco in survival prediction. methods: patients were enrolled retrospectively from january through july in the icu of derince kocaeli training hospital. patients with trauma patients and traumatic braine injury patients who were admitted to the icu from the emergency room were included in the study. the sedation levels of the patients were followed up with bis. the rsco , bis was taken as well as blood lactate level, mean arterial blood pressure and cardiac output at baseline time, , , , and hours. results: no significant difference was also detected between the value of rsco in all patients . it was average sco (right) . ± . and average rsco (left) . ± . . conclusions: cerebral regional oxygen saturation might be helpful as one of the perfusion parameters in patients with tbi but it could have no prognostic value in mortality prediction. however, further studies with larger sample size are still needed to validate these results. introduction: tbi in elderly is an increasingly cause of admission in icu. data regarding management and prognosis of these patients are lacking. validated prognostic models refer to younger patients and do not adequately consider the influence of pre-injury functional status, which often compromises with aging. frailty has been defined as a state age-related of increased vulnerability and decline in autonomy of daily life activity. aim of the study is to evaluate the impact of frailty on outcome in tbi elderly patients. methods: moderate and severe tbi patients > years, admitted in neuroicu from january to may , were prospectively enrolled. data of age, comorbidity, glasgow coma scale (gcs), pupils' reactivity, ct scan characteristics, neurosurgical intervention and gose (extended glasgow outcome scale) at -months were collected. frailty status was measured by clinical frailty scale (cfs) [ ] and patients were divided as frail (cfs> ) and not frail (cfs< ). bad outcome was defined as gose< . results: ( %) of the studied patients were frail. frailty was not related to age. frail patients had more comorbidities and worse pupils' reactivity at admission (table ) . other variables did not differ between groups. in univariate analysis neurological diseases, gcs, tsah (traumatic subarachnoid haemorrhage), compressed/absent basal cisterns, non-reactive pupils and cfs were significantly associated to bad outcome. in multivariate analysis only gcs and cfs remained associated to bad outcome ( table ) . conclusions: pre-injury frailty is strongly associated to outcome in tbi elderly patients. the age of the patients was . ± . years. patients were operated on for intracranial traumatic ( cases) and non-traumatic hematomas ( ), brain tumors ( ) and the need for plastic of postoperative skull defects ( ). general endotracheal total intravenous anesthesia with fentanyl, propofol, rocuronium, or tracrium was used. after tracheal intubation, - nerves were blocked (e.g., supraorbital, supratrochlear, zygomaticotemporal, auriculotemporal, great auricular, greater and lesser occipital nerves), depending on the surgical site. . - . % ropivacaine was used. for blockade of one nerve used . - . ml of local anesthetic. fentanyl was applied on section of a periosteum, dura matter and at inefficiency of blockade of nerves. anesthesiology monitoring included hr, ecg, spo , nib, respiratory parameters, eeg (csi), body temperature, blood glucose and lactate levels. in and - hours post-surgery, the intensity of pain was ranked by alert patients using vas. results: the volume of local anesthetic for blockade in one patient was . ± . ml. in ( . %) from patients, an additional fentanyl injection was required to skin incision due to an increase in blood pressure and heart rate by % of the baseline values, and an increase in csi until un. patients available to productive contact in hours post-surgery ranked the pain by vas at ( ; ) point, and in - hours post-surgery ranked it at ( ; ) p. conclusions: at patients with craniotomies scalpe-block with lowvolumes of a ropivacaine showed high efficiency ( . %). were transferred to hospital ward or ( . %) to the center of intensive nursing care; ( . %) went to the surgical recovery room. acute renal failure, hypernatremia and hyperphosphatemia were independent predictors of mortality as described in table . conclusions: hypernatremia and hyperphosphatemia were independent predictors of mortality in critically ill patients. introduction: the strong ion difference (sid) is essential for the assessment of acid-base equilibrium, thus requiring an accurate measurement of plasma electrolytes. currently there is no gold standard for electrolyte measurements and sid computation. differences in electrolyte values obtained with point-of-care (poc) and central laboratory (lab) analyzers have been reported [ , ] . in previous studies [ , ] we have shown that changes in pco induce electrolyte shifts from red blood cells to plasma (and vice versa), yielding variations in sid. aim of the present in-vitro study was to induce sid changes through acute changes in pco and compare values of electrolytes and sid obtained with poc and lab techniques. methods: blood samples from healthy volunteers were tonometered (equilibrator, rna medical) with gas mixtures at fractions of co (fco ) of , , and %. electrolytes were measured quasisimultaneously with a poc analyzer (abl flex, radiometer) and a routine lab method (cobas ise, roche). for both techniques a simplified sid was computed as sodium + potassiumchloride. results: bland-altman analysis of sid calculated with poc and lab showed a proportional bias (slope = . , r = . , p < . ), indicating a variable agreement between methods according to the average sid value (fig. ) . sid values measured with poc and lab at different fco differed significantly (p< . , fig. ) . a similar discrepancy was observed for chloride (p < . , fig. ), while sodium (p= . ) and potassium (p= . ) were similar. conclusions: sid measured with poc and lab differed significantly, mainly due to a variable discrepancy in chloride. our findings suggest that our poc analyzer is superior to the lab in measuring electrolytes and thus compute sid. introduction: this study evaluated the safety of half dose insulin (hdi) versus standard dose insulin (sdi) for the treatment of hyperkalemia in a medical intensive care unit (micu) population with renal insufficiency. recent emergency medicine data demonstrated a lower incidence of hypoglycemia in patients with renal insufficiency when hdi was used for the treatment of hyperkalemia [ ] . there is limited data describing the safety of hdi in a micu population with renal insufficiency. methods: this was a retrospective, chart review of patients admitted to the micu with a diagnosis of aki and/or ckd stage - with a serum potassium ≥ . meq/l from january to september . sdi is defined as units of regular iv insulin and hdi as units. the primary outcome was the incidence of hypoglycemia within hours of insulin administration. secondary outcomes included severe hypoglycemia and change of serum potassium after insulin administration. results: a total of patients were screened and were included for analysis. the incidence of hypoglycemia occurred in / patients ( . %) and / patients ( . %) who received sdi and hdi, respectively. one patient in the sdi group and two patients in the hdi group developed severe hypoglycemia. the mean decrease in serum potassium after insulin administration was . meq/l in both groups. patients in the hdi group who were re-dosed with units of regular insulin did not have any hypoglycemic events. conclusions: in a micu population with renal insufficiency, sdi and hdi regimens appear safe and effective for the treatment of hyperkalemia. introduction: sepsis and septic shock are common causes of admission in the intensive care unit with a high mortality rate [ , ] . hence, electrolyte disturbances are common in this group of patients. acute hypernatremia is one of the multiple features of homeostasis disturbances and available data in the literature suggest that its incidence can reach % [ , ] . (fig , ) . the main source of sepsis was pneumonia with affected patients ( . %). conclusions: hypernatremia is significantly associated with higher mortality in septic patients. (abstract p ) . the outcome versus the sodium levels higher in the group - % vs . % (p= . ). there were no significant differences between the groups in length of stay in the icu. in group , there was an increase of serum phosphorus level and in the group the tendency to decrease. however, statistically significant differences were obtained only on the nd day after surgery . ± . mmol/l (group ) vs . ± . mmol/l (group ) (p= . ). the roc curve was constructed to assess the predictive significance of serum phosphorus levels (fig. ) . auc was . ; % ci . - . ; p= . ; sensitivity . %, specificity . %. the kaplan-meier survival analysis (fig. ) introduction: the rate of extubation failure might be higher in obese patients than in non-obese patients. effect of obesity on mortality is controversial [ , ] (obesity paradox). several pathophysiological changes contribute to an increase of respiratory complications [ ] . we sought to identify incidence of extubation failure in obese and non-obese patients. methods: the primary endpoint of this post-hoc analysis of a prospective, observational, multicenter study [ ] performed in intensive care units was extubation failure, defined as the need for reintubation within hours following extubation. only patients with body mass index (bmi) recorded were included. results: between december , and may , , among the patients with bmi available undergoing extubation, obese patients ( %) and non-obese patients ( %) were enrolled. extubation-failure rate was . % ( / ) in obese patients, and . % ( / ) in non-obese patients (p= . ). delay of reintubation did not differ between obese and nonobese patients (figure ). length of intubation > days was significantly more frequent in obese patients ( / , %) than in non-obese patients ( / , %, p< . ). precautions to anticipate extubation failure were more often taken in obese patients ( / , %) than in non-obese patients ( / , %, p< . ). spontaneous breathing trial (sbt) characteristics differed between obese and non-obese patients (table ) . physiotherapy was more often used in obese patients ( / , %) than in non-obese patients ( / , %, p= . ). conclusions: incidence of extubation failure did not differ between obese and non-obese patients. in obese patients, clinicians anticipate more a possible extubation failure, delaying the moment of extubation, performing more physiotherapy and providing an optimal sbt. introduction: in the acute phase of critical illness, growth hormone (gh) resistance develops, reflected by increased gh and decreased insulin-like growth factor-i (igf-i), mimicking fasting in health. the epanic rct observed fewer complications such as muscle weakness and faster recovery with accepting a macronutrient deficit in the first icu week, as compared with early full feeding [ , ] . we characterized its impact on the gh axis in relation to the risk of acquiring muscle weakness. methods: in this epanic rct sub-analysis, for matched patients per group, and all patients assessed for muscle weakness (n= ), serum gh, igf-i, igf binding protein (igfbp ) and igfbp were measured upon icu admission and at day or the last icu day for patients with shorter icu stay (d /ld). for matched patients per group, gh was quantified every min between pm and am, and deconvolved to estimate gh secretion. groups were compared with wilcoxon test or repeated-measures anova. associations between changes from baseline to d /ld and muscle weakness were assessed with logistic regression analysis, adjusted for baseline risk factors, baseline hormone concentrations and randomization. results: in the fully fed group gh, igf-i and igfbp increased, whereas igfbp decreased from admission to d /ld (all p< . ). accepting an early macronutrient deficit prevented the rise in gh and igf-i and the decrease in igfbp (all p< . ) but did not affect igfbp , whereas basal, but not pulsatile, gh secretion was lowered (p= . ). a stronger rise in gh and igf-i was independently associated with a lower risk of acquiring muscle weakness (or ( %ci) per ng/ml change . ( . - . ) for gh; . ( . - . ) for igf-i). conclusions: accepting an early macronutrient deficit suppressed basal gh secretion and reduced igf-i bioavailability during critical illness, which may counteract its protection against muscle weakness. introduction: aim of the study was to relate hypokalemia (hypok) and hypoglycemia as diabetic ketoacidosis (dka) treatment complications and precocious insulin interruption also use of sodium bicarbonate with length of stay (los) in intensive care unit (icu). methods: analysis of retrospective cohort study data of patient (pt) treated for dka at icu of hospital kaunas clinics of lithuanian university of health sciences during - has been carried out. serum kalemia, glycaemia; rate of episodes of hypok, hypoglycaemia and precocious insulin interruption; use of sodium bicarbonate, in relation with los in icu were analysed. spss . was used for statistic calculations. traits evaluated as significant at p< . . results: at the beginning of dka treatment hypok ( . ± . mmol/l) was recorded in / ( %) pt. due to disregarding of blood ph ( . - . ( . ± . ) kalemia was falsely misinterpreted as "normo-" or "hyperkalemia" . - . ( . ± . mmol/l) in of ( %) pt, as normo-and hyperkalemia thus not treated and complicated by hypok additionally in / ( %) pt. in hypok los in icu was . ± . vs . ± . h, p< . . insulin use has caused hypoglycaemia ( . - . ( . ± . mmol/l)) in / ( %) pt, los in icu . ± . vs . ± . h, p< . . insulin use was interrupted in case of normo -and hypoglycaemia with still persisting ketoacidosis in / ( %) pt, los in icu was found to be . ± . vs . ± . h, p< . . sodium bicarbonate was given for symptomatic treatment of acidosis during the first h of dka in / ( %) pt with stable hemodynamic: hco buffer has increased ( . ± . - . ± . mmol/l), p< . , but ketoacidosis has still persisted, los in icu was . ± . vs . ± . h, p< . . conclusions: hypok ( %), hypoglycemia ( %), precocious interruption of insulin use ( %) have prolonged los in icu almost twice. symptomatic treatment of ketoacidosis with sodium bicarbonate ( / pt) didn't control it and has prolonged los in icu. introduction: cystathionine-γ -lyase (cse), a regulator of glucocorticoid (gc)-induced gluconeogenesis [ ] , correlates with endogenous glucose production in septic shock [ ] . the hyperglycemic stress response to noradrenaline (noa) is mediated by the kidney [ ] and less pronounced with low cse [ ] . gc receptor (gr)-mediated gene expression is differentially regulated: the gr monomer is considered to repress inflammation, and gc side effects are attributed to the gr dimer; recent reports challenge this view [ ] . gc-induced gluconeogenic gene expression is reduced in gr dimerization deficient (grdim) mice [ ] . the aim of this study is to investigate renal cse expression and systemic metabolism in grdim and grwt mice in a resuscitated model of lps-induced endotoxic shock. methods: anesthetized grdim (n= ) and grwt (n= ) mice were surgically instrumented, monitored, resuscitated and challenged with lps. noa was administered to maintain map and c glucose was continuously infused. h after lps, cse expression was determined via immunohistochemistry of formalin-fixed paraffin sections (n= p.gr.). results: grdim required . -fold more noa than grwt and had . fold higher glucose and . -fold higher lactate h after lps. this was concomitant with elevated endogenous glucose production ( -fold), % lower glucose oxidation and . -fold higher renal cse expression in grdim. conclusions: increased cse expression together with higher glucose production (confirming [ , ] ) and glucose levels in grdim mice suggest an association that may link cse to gc signaling. the higher noa administration in grdim mice could contribute to these effects. introduction: to achieve safe glycemic control in critically ill patients frequent blood glucose (bg) measurements and according titration of insulin infusion rates are required. automated systems can help to reduce increased workload associated with diabetes management. this bi-centric pilot study combined for the first time an intraarterial glucose sensor with a decision support system for insulin dosing (sgcplus system) in critically ill patients with hyperglycemia. methods: twenty-two patients ( females, males, with preexisting diabetes mellitus, age . ± . years, bmi . ± . kg/ m , creatinine level . ± . mg/dl, saps (simplified acute physiology score) . ± . , tiss- (therapeutic intervention scoring system) . ± . who were equipped with an arterial line and required iv insulin therapy were managed by the sgcplus system during their medical treatment at the intensive care unit. results: sgcplus-based bg determinations were performed and . ± . sensor calibrations per day were required. sensor glucose readings correlated well with reference bg (figure ). mean treatment duration was . ± . days. time to target was ± min ( - mg/dl) and ± min ( - mg/dl). mean blood glucose was ± mg/dl with seven blood glucose values < mg/dl. mean daily insulin dose was ± u and mean daily carbohydrate intake ± g /day (enteral nutrition) and ± g/day (parenteral nutrition). acceptance of sgcplus suggestions was high (> %). the novel intraarterial glucose sensor demonstrated to be highly accurate. the sgcplus system can be safely applied in critically ill patients with hyperglycemia and enables good glycemic control. introduction: we aimed to assess the effect of frailty as assessed by clinical frailty scale (cfs) and karnofsky performance score (kps) on critical care (cc) and hospital mortality in this group at a nonspecialist tertiary critical care unit. methods: patients admitted to critical care were identified from our electronic database by screening for liver disease or cirrhosis in the admission diagnoses. those with an aetiology of liver disease other than alcoholic liver disease (ald) were excluded. data was collected on patient demographics, length of stay, status at discharge from critical care and hospital and cfs. kps was also calculated where sufficient in-formation was available in the medical record. data was analysed using logistic regression multivariate analysis with stata software. [ ] . results: tg diagnosis criteria and severity grading criteria for acute cholangitis and acute cholecystitis were judged from numerous validation studies as useful indicators in clinical practice and adopted as tg diagnostic criteria and severity grading without any modification. provide initial treatment, such as sufficient fluid replacement, electrolyte compensation, and intravenous administration of analgesics and full-dose antimicrobial agents, as soon as a diagnosis has been made. in new flowchart for the treatment of acute cholecystitis (ac) in the tg , grade iii ac was indicated for gallbladder drainage, but some grade iii ac can be treated by laparoscopic cholecystectomy (lap-c) at advanced centers with specialized surgeons experienced in this procedure and for patients that satisfy certain strict criteria. we also redefine the management bundles for acute cholangitis and cholecystitis. introduction: c-acetate breath tests provide a non-invasive assessment of gastric emptying [ ] and could, hence, be used to judge tolerance to enteral nutrition. result values like t (time for % absorption) correlate with scintigraphic measurements. the data evaluation is based on model equations like the β -exponential function (bex) [ ] . it considers a mono-phasic breath gas response. this may not be the case during critical illness, which could reduce precision too low for a reliable personalized assessment [ ] . methods: we recently developed an evaluation of irregular gastric emptying patterns, which separates absorption from post-absorptive distribution and retention of tracer and from the terminal respiratory release of the oxidized tracer [ ] . using breath test data of icu patients (mean saps +/- ) the precision of this approach was compared with a bex analysis to explore how often an extended analysis is warranted and whether it improves the reliability of estimates. results: patients had a release profile consisting of series of peaks with a periodicity of - min. a first dominant peak carries about % of the released moiety, as reported [ ] for controls. for these patients the precision in t for the bex approach was +/- % of that observed for the new approach. for the other patients, the secondary peaks had a similar periodicity but were more pronounced, indicating persisting peristaltis, which has been linked to tolerance to enteral nutrition [ ] . the bex approach achieved a precision of +/- % relative to the new one, challenging its applicability for these patients. introduction: clinical scoring systems used to prognosticate the severity of acute pancreatitis (ap), such as apache ii, are cumbersome and usually require hours or more after presentation to become accurate, at which time the window for early therapeutic intervention has likely passed. sirs at presentation is sensitive but poorly specific for severe ap. we postulated that sirs and accompanying hypoxemia would specify at presentation patients with ap who have severe inflammation and are at risk for clinically severe disease. methods: patients with ap who had sirs and hypoxemia at presentation were enrolled in an open-label study evaluating the safety and efficacy of cm -ie, a calcium release-activated calcium (crac) channel inhibitor (nct ). hypoxemia was defined as an estimated pao < mm hg calculated using a log-linear equation and the spo on room air at the time of presentation. a contrastenhanced computed tomography (cect) was performed at presentation and a cbc with differential, d-dimer and crp were analyzed daily. the cect was read by a blinded central reader who assessed the degree of inflammation using the balthazar scoring system (table ) . results: patients, seven men and six women, have been randomized in the study. the mean estimated pao at presentation was mm hg. patients had sirs criteria present and the other patients had sirs criteria present. the median value for age was . (iqr - ), initial neutrophil-lymphocyte ratio (nlr) . ( . introduction: to investigate whether circulating immune profiles were able to serve as early biomarkers in predicting persistent organ failure (pof methods: thirty-nine patients with predicted severe acute pancreatitis (psap) and healthy control subjects were prospectively enrolled in our study. we measured the expression of monocytic human leukocyte antigen-dr (mhla-dr), the proportions of dendritic cells (dc) and its subtypes (including myeloid dendritic cell (mdc) and plasmacytoid dendritic cell (pdc)), the different cytokineproducing cd + t helper (th) cells and regular t (treg) cells. plasma crp and several inflammatory mediators levels were measured by elisa. results: compared with healthy controls, there is a significant decrease in the expression of mhla-dr, the frequencies of total circulating dcs and its subsets, and percentage of th cells in patients with psap. however, we found significantly higher frequencies of th cells, higher proportion of treg cells than healthy subjects. of interest, we observed that there was a significant decrease in the positive percentage and mean fluorescence intensity (mfi) of mhla-dr, the proportions of total dcs and pdc, and th cells in patients with pof compared with transient organ failure (tof). besides, there is a significantly higher frequency of th cells in pof than those in tof. area under the receiver-operating characteristic curve analysis showed that disease severity scores had a moderate discriminative power for predicting pof in patients with psap. more importantly, the expression of mhla-dr and the percentage of dcs and pdc had a significantly higher auroc and thus, better predictive ability than disease severity in patients with psap. conclusions: circulating immune profile show multiple aberrations in patients with psap who have developed pof. both the expression of mhla-dr and the percentage of total dc and pdc may be early good biomarkers for predicting risk of pof in patients with psap. introduction: pancreatic fistula (popf) due to anastomosis insufficiency is a common ( - %) complication after pancreaticoduodenectomy and often discovered with delay, causing severe morbidity, icu stay and deaths. microdialysis (md) catheters have been shown to detect inflammation and ischemia in several postoperative conditions and organs. the aim was to investigate if md catheter monitoring could facilitate earlier detection of popf than current standard of care. methods: in a prospective, observational study patients ( to years) were investigated. a md catheter was fixed to the pancreaticojejunal anastomosis. samples for analysis of glucose, lactate, pyruvate and glycerol were acquired hourly during the first hours, then every - hours to discharge. popf was defined according to the international study group of pancreatic fistula update definition. results: patients who developed popf (n= ) had significantly higher glycerol levels (p< . ) in microdialysate than did patients without popf (n= ) during the first h. thereafter, the difference diminished. a glycerol concentration > μmol/l during the first h detected patients who later developed popf with a sensitivity of % and a specificity of %. lactate and lactate to pyruvate ratio were significantly higher (p< . ) and glucose was significantly lower (p< . ) in patients with popf from about h. fig. shows microdialysis measurements in patients with (red lines) and without (blue lines) popf. conclusions: a high level of glycerol in microdialysate is an early (first hours) indicator of popf. glucose, lactate and lactate to pyruvate ratio are indicators of peritonitis caused by the leakage. thus, md monitoring detects popf several days earlier than current methods and may play an important clinical tool in the future. we are currently conducting a rct to explore if md monitoring will improve prognosis in these patients the phenomenon of total impaired of metabolic activity of gut microbiota in critically ill septic patients introduction: during a critical condition, dramatic disturbances occur not only in the change of species diversity, but in gut microbiota metabolism as well, that might lead to nonreversible breakdowns of host homeostasis and death [ ] . metabolic activity of microbes can be assessed by the measurement of the levels of aromatic microbial metabolite (amm) in blood serum, which are associated with the severity and mortality of icu patients. critically ill patients are characterized by the totally different sfs profile than in healthy people, particularly by the absence of phpa; but dominated by p-hphaa and p-hphla [ ] . the purpose of our study is to assess the gut metabolic activity via amm in sepsis. methods: in this study simultaneously serum and fecal samples (sfs) were taken from icu patients: -with sepsis, -chronic critical ill (cci) patients and control - sfs from healthy people. after liquid-liquid extraction from serum and fecal samples, phenylcarboxylic acids (amm) were measured using gc/ms (thermo scientific). results: the sum of the level of most relevant amm in serum samples were higher in patients with sepsis (median - . μm) than in cci patients ( . μm) and healthy people ( . μm). at the same time the opposite pattern was observed in the fecal samples - . , . and . μm, respectively. the ratios of sums amm gut/serum were higher in healthy people than icu patients (fig. ) introduction: the aim of this study is to describe the characteristic of bioelectric impedance vector analysis (biva) and muscular ultrasound during the first week after admission in the icu, and their correlation with indices of metabolic support. biva is a commonly used approach for body composition measurements [ ] . muscular ultrasound represents a valid tool to provide qualitative and quantitative details about muscle disease [ ] . methods: consecutive patients admitted to icu and expected to require mechanical ventilation for at least hours were enrolled in the study. within the first hours of icu admission (t ), patients were evaluated with muscular ultrasonography comprehensive of diaphragm thickness (dth) and rectus femoris cross-sectional area (csa). at the same time, biva and biochemical analysis. all the same measures were repeated at day (t ) and (t ) (figure (table ) . dividing the patients in two groups based on prealbumine changes (t vs t : increase, anabolic vs decrease, catabolic), those in which prealbumine increased had a higher reduction in muscle mass ( figure ). conclusions: this study showed how the pa tends to be reduced in the first week of icu stay. it is correlated with a concomitant introduction: the modified nutrition risk in critically ill (mnutric) has been developed in order to identify critically ill patients who may receive benefit from nutrition support [ ] . several evidences showed the association between the mnutric score and clinical outcomes [ , ] , however there are no data in thai critically ill patients. the purpose of this study was to find the association between mnu-tric score and -day mortality in medical intensive care unit (icu) patients, ramathibodi hospital. methods: we retrospectively reviewed the medical patient records from june to january . a mnutric score of each patient was calculated to evaluate the risk of malnutrition. statistical analysis of the association between mnutric score and -day mortality, length of stay in icu and hospital were performed. results: a total of critically ill patients were included in the study. the -day mortality was . % in patients with high mnutric score ( - ) and . % in patients with low mnutric score ( - ). modified nutric score was significantly correlated with day mortality (r = . , p< . ), length of stay in icu (r = . , p< . ) and length of stay in hospital(r = . , p< . ). in the receiver operating characteristic (roc) curve analysis, the auc of mnutric score and -day mortality was . ( % confidence interval (ci), . - . ) (fig ) . optimal cut-off value of showed sensitivity of . % and specificity of . % in mortality prediction (youden's index, . ). additionally, patients who received adequate nutrition supplement within days was . % for calorie and . % for protein. there was no association between nutrition support and -day mortality. conclusions: in thai medical intensive care population, the mnutric score was associated with -day mortality in critically ill patients. fig. (abstract p ) . within the first hours of icu admission (t ), patients will be evaluated with muscular ultrasonography comprehensive of diaphragm thickness and rectus femoris (medial vastus) cross-sectional area. at the same time, anthropometric measure will be collected (such as body height, ideal body weight, real body weight declared, right arm circumference) as well as biva measure (xc, r, pa, lean body weight and % of extracellular body weight) and biochemical analysis (inclusive albumin, pre-albumin, blood count, lymphocyte count, magnesium, phosphorus, reticulocytes, renal and hepatic function test). the day after, the fluid balance will be calculated as well as the nitrogen balance. all the same measures will be repeated at day (t ) and days (t ) introduction: ultrasonography is an essential imaging modality in critical care to diagnose and guide for therapeutic management of shock, multiple organ failure, etc. enteral tube feed intolerance occurs frequently in hospitalized patients and more so in critically ill patients. in present study, we consider that nursing staff may be able to use bedside ultrasound as an alternative to standard aspiration protocol or radiographic studies to assess gastric volume and nasogastric (ng) tube in patients with enteral feed intolerance. methods: in present prospective, single-center study, we performed ultrasound residual stomach volume and ng tube placement assessments of adult critically ill patients (figure ) compared to standard protocol of stomach volume assessment (routine daily shift -ml syringe aspirations) and ng (nasogastric) tube placement verified by abdominal x ray. we used an abdominal (linear ultrasound transducer) probe ( - mhz). the residual volume was calculated according to formula: gv (ml) = + . x right-lateral csa- . x age). results: hundred simultaneous double (ten critically ill patients) ultrasound measurements sessions were performed by nursing staff of our intensive care (icu) (fig ) . double simultaneous measurements of the ultrasound assessments were compared to standard nurse icu protocol for assessment of residual volume of stomach. the new ultrasound assessment method demonstrated excellent intra-class reliability (icc- . ( . - . , p< . ) and strong correlation with standard residual volume assessment method (icc- . ( . - . , p< . ). ng tube placement was successfully verified by ultrasound measurements in all ten critically ill patients and, thereafter, confirmed by abdominal x-rays. conclusions: preliminary results of our study demonstrated good correlations between both methods of ng tube placement and residual stomach volume: standard icu nurse protocol and ultrasound assessment. evaluating the documentation of nasogastric tube insertion and adherence to safety checking l roberts introduction: enteral feeding into a misplaced nasogastric (ng) tube is recognised by the national patient safety agency as a never event. ng tubes are commonly indicated in level / patients, thus we set out to evaluate current practice in critical care. the aim was to evaluate: documentation of insertion, adherence to safety guidance pertaining to checking safe use, chest x-ray interpretation. methods: this prospective cohort study was based on inpatients in critical care who had insertion of ng tubes over four weeks; there were insertions. data was analysed from patients' medical notes and the hospital's imaging system. results: % of insertions were documented using proformas. . % of proforma documentations included or more details: type of tube, tube length at the nostril, nex measurement, aspirate adequacy, chest x-ray adequacy, whether it was safe to feed. only . % of hand-written documentations included or more details. % of initial aspirates were obtained on insertion, of these, % had an appropriate ph between and . . this led to % of patients having chest x-rays to confirm initial placement of the ng tube. only % of chest x-rays adequately satisfied the four criteria. written documentation in medical notes stating if it was safe to feed was completed in % of cases. conclusions: we found that proformas ensure a higher level of detail and uniformity in the documentation of ng tube insertions. there was a high incidence of chest x-rays performed to confirm correct placement of tubes due to difficulties in obtaining aspirates and failure to follow guidelines. a need for a uniform, ward-specific proforma on ng tube insertion has been identified, as well as a teaching session on chest x-ray interpretation and on techniques to aid obtaining aspirates. we have established critical care's shortcomings in ng tube insertion documentation and tube safety checking. introduction: pressure ulcers(pu) are considered as important types of public health problems, due to high mortality and cost. we aimed to investigate the efficiency of curcumin and fish oil on prevention and treatment of pu using a feasible mice model. methods: mice were randomly divided into control(group ), curcumin(group ), fish oil(group ), curcumin and fish oil(group ) groups. mm skin bridge between two gauss magnets was formed on the back of mice, followed by ischemia reperfusion cycles as hours of rest after hours of magnet placement [ ] . a single dose of curcumin and fish oil was injected intraperitoneally. tissue samples had taken th day of first compression, rates of pu, inflammation, reepithelisation, neovascularisation and granulation were examined histopathologically. the data analyzed by pearson chi-square test. results: third degree pu were observed in all groups.there was no significant difference between groups in terms of inflammation.the formation of reepithelisation showed a significant difference between groups.partial reepithelisation ratios in group and group was elevated.there was significant difference between groups in terms of neovascularisation, the highest rate as % was observed in group .formation of granulation was observed at maximum rate as . % at group . conclusions: depending on positive results of curcumin, fish oil, cur-cumin+fish oil on wound healing it may be advised to use them in treatment of acute pu.after similar rate of pu with control group we consider that it should be beneficial to evaluate the effect of these therapies with more studies by changing the mode of administration, time of initiation and duration of therapy. introduction: inflammation is a key driver of malnutrition during acute illness and has different metabolic effects including insulin resistance and reduction of appetite. whether inflammation influences the response to nutritional therapy in patients with disease-related malnutrition remains undefined. we examined whether the effect of nutritional support on the risk of mortality differs based on the inflammatory status of patients. methods: this is a secondary analysis of a multicentre trial in eight swiss hospitals, where patients with a nutritional risk score (nrs) of ≥ upon hospital admission were randomly assigned to receive protocol-guided individualized nutritional support according to nutrition guidelines (intervention group) or a control group. the inflammatory status was defined based on admission crp levels as low inflammation (cpr < mg/dl), moderate inflammation (crp - mg/dl) and high inflammation (crp > mg/dl). results: we included a total of , patients of which . %, . % and . % had low, moderate and high inflammation levels on admission. while overall there was a significant reduction in day mortality associated with nutritional support (adjusted or in the overall cohort . , %ci . - . ), the subgroup of patients with high inflammation did not show reduced mortality (adjusted or . , %ci . - . , p for interaction = . ). there was no difference in other secondary endpoints when stratified based on inflammation. nutritional support did not affect crp levels over time (kinetics). conclusions: this secondary analysis of a multicentre randomized trial provides evidence, that the inflammatory status of patients influences their response to nutritional support. these findings may help to better individualize nutritional therapy based on patients initial presentation. introduction: low plasma glutamine levels have been associated with unfavourable outcomes in critically ill patients. this study aimed to measure plasma glutamine levels in critically ill patients and to correlate glutamine levels with biomarkers and severity of illness. methods: we enrolled critically ill patients admitted to three icus in south africa, excluding those receiving glutamine supplementation prior to admission. we collected clinical, biochemical and dietary data. plasma glutamine levels were determined within hours of admission, using liquid chromatography mass spectrometry and categorized as low (< μmol/l), normal ( - μmol/l) and high (> μmol/l). results: of the patients (average age . ± . years, % male), % were mechanically ventilated, with a mean apache ii score of . ± . and a mean sofa score of . ± . . plasma glutamine levels were low in . % (median plasma glutamine of . μmol/l). baseline plasma glutamine correlated inversely with crp (r=- . , p< . ) and serum urea (r=- . , p< . ), and positively with serum bilirubin (r= . , p< . ) and serum alt (r= . , p= . ). significantly more patients with low admission glutamine levels required mechanical ventilation (chi = . , p< . ) and had higher apache scores (p= . ), higher sofa scores (p= . ), higher crp values (p< . ), higher serum urea (p= . ), higher serum creatinine (p= . ), lower serum albumin (p< . ) and lower bilirubin levels (p= . ). using multiple logistic regression analysis, apache score (odds ratio, [or] . , p= . ), sofa score (or . , p= . ) and crp (or . , p< . ) were significant predictors of low plasma glutamine levels. roc curve analysis revealed a crp threshold value of . mg/l to be indicative of low plasma glutamine levels (auc . , p< . ). conclusions: . % of critically ill patients had low plasma glutamine levels on admission to icu. this was associated with increased disease severity and higher crp. introduction: the east of england deanery operational delivery network in the united kingdom came together as a group of intensive care units to comply an evidence-based care bundle. one of the branches of this care bundle is on parenteral nutrition and states: 'parenteral nutrition should not be given to adequately nourished, critically ill patients in the first seven days of an icu stay.' this is based on evidence [ ] [ ] [ ] that showed that 'in patients who are adequately nourished prior to icu admission, parental nutrition initiated within the first seven days has been associated with harm, or at best no benefit, in terms of survival and length of stay in icu.´the objective of this second cycle was to assess whether or not we are adhering to the guidelines, last year we were failing to hit targets and after some action i reassessed how we performed in the year compared to . methods: a retrospective audit of the whole year of for all patients admitted to icu who had parenteral nutrition started at any point during their stay. results: there is a significant improvement in the percentage of patients who are being started incorrectly on tpn before days ( % compared to %) (fig , ) . i also found a total reduction in the number of patients prescribed tpn, a reduction in the number of bags being used and a reduction in length of hospital stays. conclusions: as we have recently switched over to an electronic icu programme for all documentation and prescriptions, as part of our plan and act in the pdsa cycle we are organising for several things to be put in place on the new system on prescription: pharmacy authorisation, links to guidelines and alert/justification boxes. i will do a further cycle in another year. jg and mpc contributed equally. introduction: recent rcts revealed clinical benefit of early macronutrient restriction in critical illness, which may be explained by enhanced autophagy, an evolutionary conserved process for intracellular damage elimination [ ] . however, in the absence of specific and safe autophagy-activating drugs, enhancing autophagy through prolonged starvation may produce harmful side effects. a fasting-mimicking diet (fmd) may activate autophagy while avoiding harm of prolonged starvation, which also improved biomarkers of age-related diseases in an experimental study [ ] . we evaluated if short-term interruption of continuous feeding can induce a metabolic fasting response in prolonged critically ill patients. methods: in a randomized cross-over design, prolonged critically ill patients receiving artificial feeding were randomized to be fasted for hours, followed by hours full enteral and/or parenteral feeding, or vice versa. patients were included at day in icu and blood glucose was maintained in the normal range. at the start and after and hours, we quantified total bilirubin, urea, insulin-like growth factor-i (igf-i) and beta-hydroxybutyrate (boh) in arterial blood. insulin requirements were extracted from patient files. changes over time were analyzed by repeated-measures anova after square root transformation. results: as compared to hours of full feeding, hours of fasting decreased bilirubin (- . ± . mg/dl; p= . ) and igf-i (- . ± . ng/ml; p< . ), and increased boh (+ . ± . mmol/l; p< . ), without affecting urea concentrations (fig ) . fasting reduced insulin requirements (- . ± . iu/hour; p< . ). conclusions: short-term fasting induces a metabolic fasting response in prolonged critically ill patients, which provides perspectives for the design of a fmd, aimed at activating autophagy and ultimately at improving outcome of critically ill patients. introduction: recent evidence has led to changed feeding guidelines for critically ill patients, with a shift towards lower feeding targets during the acute phase [ ] . when micronutrients are not provided separately, prolonged hypocaloric feeding could induce micronutrient deficiencies and increase risk of refeeding syndrome once full feeding is restarted, which are both potentially lethal complications [ ] . since there is limited evidence how to optimize micronutrient provision in order to avoid deficiencies, we hypothesized that there is a great variation in current practice. methods: within the men section of the european society of intensive care medicine (esicm), we designed a questionnaire to gain insight in the current practice of micronutrient administration. in email blasts, invitations were sent to all esicm members, with currently more than respondents. the survey will be closed at december , . results: first, we will describe demographic characteristics of the respondents, including geographical location, icu and hospital type, and function. second, we will describe some aspects of the current practice of micronutrient administration. we will identify the proportion of respondents having a protocol, on which evidence such protocol is based and whether it takes into account the stability and daylight sensitivity of micronutrients. next, bearing refeeding syndrome in mind, we will identify whether there are respondents who never measure and/or separately administer micronutrients and phosphate. finally, we will make a top of the most measured and most supplemented micronutrients. conclusions: this survey will deliver more insight in the current practice of micronutrient provision across different types of icus and may identify areas for future research. furthermore, we will evaluate whether there is need to increase awareness for refeeding syndrome. introduction: large gastric residual volumes (grvs) have been used as surrogate markers of delayed gastric motility to define enteral feeding intolerance (efi). recent studies have challenged the definition of efi. study objectives: ) investigate the potential relationship between grvs and clinically outcomes, ) develop an algorithm for early identification of patients at increased risk of mortality due to efi. methods: a retrospective study of inpatient encounters from electronic health record charts within the dascena clinical database. , patients were included in the study; patients had efi. eight vital signs (diastolic/systolic bp, heart rate, temperature, respiratory rate, grv, glasgow coma scale, and feeding rate) and their trends were input to the classifier. machine learning classifiers were created using the xgboost gradient boosted tree method with -fold cross validation. results: rate of change in grv (Δ grv) was measured over a -day period, beginning at the time of efi onset (figure a) . figure b shows a high likelihood of mortality for patients with none or modest grv reduction. patients with an increase in grv over the five-day period after efi onset had the highest mortality likelihood. a stratification algorithm was developed to identify efi patients who died inhospital despite grv reduction at , , and hours in advance of efi onset. area under the receiver operating characteristic (auroc) curves demonstrated high sensitivity and specificity of algorithm predictions of in-hospital death up to hours in advance of efi onset (table ) . conclusions: the analysis suggests an association between grv and mortality, especially in patients with persistent grv increase over the -day period after efi onset and the potential of algorithmic models to predict efi development. prospective validation of these fig. (abstract p ) . changes in metabolic markers of fasting over time for both randomization groups algorithms may assist in clinical trial design to develop treatments for patients at highest risk of experiencing serious outcomes due to efi. a quality improvement project to improve the daily calorific target delivery via the enteral route in critically ill patients in a mixed surgical and medical intensive care unit (icu) b johnston, d long, r wenstone royal liverpool and broadgreen university hospital trust, critical care, liverpool, united kingdom critical care , (suppl ):p introduction: 'iatrogenic underfeeding' is widespread with the calo-ries study reporting only %- % of prescribed daily kcal was actually delivered to patients [ ] . in the present project, quality improvement methodology was utilised with the aim of delivering greater calories by implementing -hour volume-based feeding and allowing increased feeding rates for, 'catch up' of missed daily feed volume. methods: baseline data assessing the percentage of daily kcal delivered to ventilated patients was collected in september . data was presented and new intervention guidelines agreed based upon the pepup protocol [ ] . nurse champions were identified and were responsible for cascade training of the pepup protocol. educational tools to help determine daily calorific requirement and volume of feed required were provided. repeat data was collected at months (cycle ) after pepup implementation. results: ten patients were included in cycle . during cycle the percentage of kcal achieved via enteral feeding was %. following intervention this increased to % (p< . ) during cycle . this increased further to . % of daily kcal when calories obtained from propofol were included. conclusions: a -hour volume-based feeding regimen is a simple and cost-effective method of improving enteral feeding targets. through the use of quality improvement methodology, we demonstrated that this approach is achievable. the success of this project has led to the adoption of the protocol in other icu units in a regional critical care network. effect of non-nutritional calories on the calory/protein ratio in icu patients s jakob, j takala university hospital bern, dept of intensive care medicine, bern, switzerland critical care , (suppl ):p introduction: nutritional diets are composed to match the needs of critically ill patients. while effective calory needs can be measured or calculated, the needs of proteins are more controversial. we aimed to calculate non-nutritional calories and assess how they influence the ratio of calories to protein delivered to the patients. methods: in this retrospective analysis, nutritional and nonnutritional calories and protein delivery were calculated in consecutive icu patients receiving enteral nutrition in . introduction: marked protein catabolism is common in neurocritical patients. optimal nutritional monitoring and protein nutritional adequacy could be associated with outcome in neurointensive care unit (ncu) patients. we aimed to evaluate the impact of monitoring and optimal support of protein using nitrogen balance on outcome in neurocritical patients. methods: a consecutive patients who were admitted to ncu were included between july and february . nitrogen balance was calculated using excreted urine urea nitrogen during icu admission. follow-up nitrogen balance monitoring was performed in patients. we divided patients into two groups based on the results of nitrogen balance (positive balance and negative balance). moreover, we evaluated improvement of nitrogen balance in patients. we assessed the outcome as length of stay in hospital, length of stay in ncu, and in-hospital mortality. we compared the clinical characteristics and outcome according to nitrogen balance. results: among the included patients (age, . ; and male. . %), ( . %) patients had negative nitrogen balance. the negative balance group was more likely to have lower glasgow coma scale (gcs), longer length of stay in hospital, and longer length of stay in ncu. in patients with follow-up nitrogen balance monitoring, improvement of nitrogen balance group had lower in-hospital mortality ( . % vs. . %, p = . ), and received adequate protein intake ( . g/kg/day vs. . g/kg/day, p = . ) compared to no change group (table ) . there was no significant difference in baseline nitrogen balance, baseline body mass index, and gcs between two groups. conclusions: this study demonstrated that critical illness patients in ncu are underfeeding using nitrogen balance, however, adequate provision of protein was associated improvement of nitrogen balance and outcome. this suggests that adequate nutrition monitoring and support could be an important factor for prognosis in neurocritical patients. increased protein delivery within a hypocaloric protocol may be associated with lower -day mortality in critically ill patients introduction: to test the hypothesis, using real world evidence that increasing protein delivery and decreasing carbohydrates (cho) may improve clinical outcomes. methods: retrospective analysis of existing electronic medical records (emr) of patients admitted to the intensive care units (icu) at the geisinger health system. logistic regression analysis was used to determine correlation between protein delivered (which was proportional to the concentration of protein in the formula utilized) and clinical outcomes. results: medical encounters for a total number of , icu days were collected and analyzed. average age was . years ( . % male) and . % were obese and overweight. primary diagnoses included sepsis or septic shock, acute and/or chronic respiratory failure (or illness), cardiovascular diseases, stroke and cerebrovascular diseases among others. median hospital los was . days, . days in the icu, median days of invasive mechanical ventilation of . -day readmission rate among patients discharged alive was . %. patients in the high protein group received lower amounts of chos (data not shown). unadjusted -day post-discharge mortality was inversely proportional to the amount of protein delivered (table ) . conclusions: a significant improvement in mortality is observed with increased protein delivery while decreasing carbohydrate loads. prospective randomized trials are warranted to establish causality. introduction: acute kidney injury (aki) is associated with high mortality. the risk increases with severity of aki. our aim was to identify risk factors for development and subsequent progression of aki in critically ill patients. methods: we analysed patients without end-stage renal disease who were admitted to the icu in a tertiary care centre between january to december and did not have aki on admission. we identified risk factors for development and non-recovery of aki as defined by the kdigo criteria. results: the incidence of new aki in days was % (aki i %, aki ii %, aki iii %). multivariate analysis revealed bmi, sofa score, chronic kidney disease (ckd) and cumulative fluid balance as independent risk factors for development of aki. among patients who developed aki in icu, % had full renal recovery, % partial recovery and % had no recovery of renal function by day . aki patients without renal recovery in days had significantly higher hospital mortality ( %) compared to the other groups. independent risk factors for non-recovery of renal function were ckd, mechanical ventilation, diuretic use and extreme fluid balance before and after first day of aki. (table ) the association between cumulative fluid balance before aki and hours after aki with risk of aki non-recovery are shown in figure and . conclusions: aki is common and mortality is highest in those who do not recover renal function. cumulative fluid accumulation impacts chances of aki development and progression. (table ). all were in r . / ( %) of those with an admission ck> had aki or . all ( %) patients who required crrt for aki associated with rm were at risk for aki regardless of initial ck: vascular surgery ( / ), multi-organ dysfunction ( / ), and/or pre-existing renal disease ( / ). conclusions: raised ck is common in icu but its cause is multi factorial thus an isolated measure > does not require immediate high output treatment for rm aki. aki is more common in patients who have more than ck> on sequential days or those whose first ck was > as rm may be contributing. a single ck> in patients with a clear reason to develop rm should also start treatment. surgical outcomes of end-stage kidney disease patients who underwent major surgery p petchmak , y wongmahisorn , k trongtrakul introduction: acute kidney injury (aki) occurs in more than % of successfully resuscitated out-of-hospital cardiac arrest patients treated with targeted temperature management (ttm) [ ] . the effect of the duration of cooling on aki has not been well studied. in this post-hoc analysis of the tth randomized controlled trial that compared vs -hours of ttm ( °c) after cardiac arrest [ ] , we studied the impact of ttm length on the development of aki. fig. . duration of ttm had a significant impact on the development of creatinine values during the first days in the icu, p< . . this was primarily driven by an increase in creatinine during rewarming on day for the hour and day for the -hour group (fig ) . conclusions: in a trial of vs hours of ttm after out-of-hospital cardiac arrest, the length of ttm did not affect the incidence of aki. fig. (abstract p ) . creatinine over time patients [ ] , but there are no published data on longer-term renal outcomes in adult patients. the purpose of this study was to assess longer-term trends in serum creatinine in this cohort. methods: a retrospective study was conducted of all patients admitted to an adult regional referral centre for ecmo at a uk university hospital between and . those who survived for > months were included. demographics, baseline serum creatinine, presence of aki during icu admission, and serum creatinine at hospital discharge were determined. serum creatinine and dependence on renal replacement therapy (rrt) were assessed at and months post ecmo. results: patients had a complete (or near-complete) data-set available. the mean age was . years, % of whom were male. / had aki during their critical care admission. none were dependent on rrt at or months post ecmo. most patients had lower serum creatinine results at hospital discharge compared to their pre-hospitalisation baseline, but creatinine concentrations at and months post ecmo tended to be higher than at hospital discharge ( figure ) . conclusions: in this cohort of ecmo patients who were discharged from hospital alive, serum creatinine tended to be lower at hospital discharge compared to baseline and rose again in the following months. decreased creatinine production due to deconditioning and muscle wasting may offer a biological rationale for the lower creatinine results at hospital discharge [ ] . therefore, caution should be exercised in the use of serum creatinine at hospital discharge to assess renal dysfunction -further research is warranted. introduction: aki complicates more than half of icu admissions [ , ] and is associated with development of chronic kidney disease (ckd), need for renal replacement therapy (rrt) and increased mortality [ ] . we prospectively evaluated all icu admissions during a one-year period in order to determine incidence, etiology and timing of aki as well relevant clinical outcomes. methods: prospective observational study of all patients admitted from jan to dec to a multidisciplinary icu in greece. patients with end-stage renal disease and anticipated icu stay less than hrs were excluded. aki diagnosis and classification was based on kdigo criteria [ ] . lowest creatinine level within months before admission or first creatinine after icu admission served as reference. (fig ) . conclusions: although aki alert does not include urine output criterion or aki risk factors, it remains a helpful tool to point out patients with aki. education and diagnostic algorithms are still needed to early diagnose and treat aki patients. influence of severity of illness on urinary neutrophil gelatinaseassociated lipocalin in critically ill patients: a prospective observational study c mitaka, c ishibashi, i kawagoe, d satoh, e inada untendo university, anesthesiology and pain medicine, tokyo, japan critical care , (suppl ):p introduction: neutrophil gelatinase-associated lipocalin (ngal) is a diagnostic marker for acute kidney injury (aki). ngal expression is highly induced not only in kidney injury, but also in epithelial inflammation of intestine, bacterial infection, and cancer. however, the relationship between ungal and severity of critically ill patients has not been well understood. the purpose of this study was to elucidate whether ungal is associated with severity of illness and organ failure in critically ill patients. methods: we prospectively enrolled patients with sepsis (n= ) and patients who underwent esophagectomy with gastric reconstruction for esophageal cancer (n= ). sepsis was defined according to sepsis- . ungal levels were measured on icu day , , , and . ungal levels and aki rate in patients with sepsis were compared with those in patients who underwent esophagectomy. aki was defined according to kdigo. acute physiology and chronic health evaluation (apache) ii score and sequential organ failure assessment (sofa) score were calculated. results: median ungal level ( ng/mg creatinine) was significantly higher in patients with sepsis than that ( ng/mg creatinine) in patients who underwent esophagectomy on day . median apache ii score and median sofa score in patients with sepsis were significantly higher than those in patients who underwent esophagectomy. four patients with sepsis developed aki, and out of them underwent continuous renal replacement therapy, whereas no patients who underwent esophagectomy developed aki. ungal levels were positively correlated with apache ii score and sofa score in patients with sepsis. ungal levels were remarkably elevated (> ng/mg creatinine) in urinary tract infection (n= ), loops enteritis (n= ), and obstructive jaundice due to cholangiocarcinoma (n= ). conclusions: these findings suggest that ungal level is associated with severity of illness and organ failure in patients with sepsis. ungal levels might be influenced by severity of illness and inflammation. to assess the quality of the course us renal images had to be evaluated in "post-renal obstruction" (p-ro) or "no p-ro". the rate of correctness (roc farius ) was determined. in we, once again, contacted the students to attend a web-based online "follow-up". this online survey was created with "google formular". new and unknown us images were presented and rated in "p-ro" or "no p-ro" (roc fup introduction: septic-induced kidney injury worsen the patient's prognosis [ ] . renal resistance index (rri) is correlated with an increased mortality in septic patients [ ] . the aim of this study was to describe the evolution of rri in a rat sepsis model. methods: the local ethics committee approved the study (apa-fis# - ). sepsis was induced in -month-old male rats by caecal ligation and puncture (clp) [ ] . the rri was assessed before and h after clp by pulse doppler on the left renal artery (rri=(peak systolic velocityend diastolic peak)/ peak systolic values expressed as % per column. abbreviations in alphabetical order: aki acute kidney injury; akin acute kidney injury network definition; ckd chronic kidney disease. there were statistical differences between subgroups with and without aki for the subgroups of patients with previous ckd (p = . *), sepsis at admission (p = . **), hypotension (p= . ***) fig. (abstract p b) . target comparing accuracy and precision of aki alert and actual aki diagnoses velocity) (fig ) . rri were compared by a paired wilcoxon test (r software v. . . ). a p value < . was considered significant. results: rats were included. hours after sepsis induction, all rats were in septic shock with cardiac dysfunction. the rri increased after sepsis induction compared to baseline ( . ± . vs . ± . , p< . ) and mean renal artery velocity decreased ( . ± . vs . ± . , p< . ) (fig ) . systolic and diastolic peaks velocity of the renal artery were unchanged. conclusions: sepsis induced changes in rri and mean velocity on the left renal artery whereas no changes in systolic or diastolic velocities were seen. these results are consistent with available clinical datas. the rri could be an additional tool to assess renal failure in septic rats. further studies are needed to confirm the validity of this marker during sepsis. kidney failure is one of the most common organ dysfunction during sepsis. the rri could be an additional tool in small animals to assess the effects of potential therapeutic targets on renal function induced by sepsis. (fig ) . the egfr improved more with the heparin group ( % vs %; p= . ) (fig ) . interruptions of the filter circuit were as expected less with the citrate group ( mins vs mins; p= . ). finally, inotropic requirements increased following therapy interruptions, more so with patients receiving citrate ( . % vs . %; p= . ). conclusions: our analysis suggests that using citrate anticoagulation for rrt results in a monitoring cost saving of approximately £ per hours, alongside the other conferred savings previously reported. furthermore, results demonstrate the efficacies of both systems are similar in the initial hours, although there is a suggestion that heparin systems improves renal parameters more quickly. finally, interruptions and 'filter downtime' caused an increase in the patient's inotropic requirements, however results suggestive that this is greater in the citrate group. mmol/l respectively. demographic characteristics of the study group and the main parameters of the procedure were presented in fig . conclusions: regional citrate is a safe and effective anticoagulation method for crrt in children, when it is applied following a protocol. it significantly prolongs circuit survival time and thereby should increase crrt efficiency. we did not find any serious adverse effects of regional citrate anticoagulation. - ) , deceased at year n= ( %). the mdrd trend is more indicative than creatinine of decline of renal function in the post operative period (fig ) . crrt was used in . % ( pts) and was associated to a greater los and mortality (fig ) . preoperative bilirubin, bun and creatinine are among the greatest risk factors for its use ( table . at year follow up n= pts ( . %) were on hemodialysis. conclusions: aki requiring crrt in after lt is associated with higher mortality and los. identify patients at risk and adopt preventive strategies in the perioperative period is mandatory. introduction: we developed a new co removal system, which has a high efficiency of co removal at a low blood flow. to evaluate this system, we conducted in vivo studies using experimental swine model. methods: six anesthetized and mechanically ventilated healthy swine were connected to the new system which is comprised of acid infusion, membrane lung, continuous hemodiafiltration and alkaline infusion. in vivo experiments consist of four protocols of one hour; baseline= hemodiafiltration only (no o gas flow of membrane lung); membrane lung = "baseline" plus o gas flow of membrane lung; "acid infusion" = "membrane lung" plus continuous acid infusion; "final protocol" = "acid infusion" plus continuous alkaline infusion. we provided an interval period of one hour between each protocol. we changed the respiratory rate of the mechanical ventilation to maintain pco at - mmhg during the experiment. results: the amount of co eliminated by the membrane lung (vco ml) significantly increased by . times in the acid infusion protocol and our final protocol compared to the conventional membrane lung protocol, while there was statistically no significant difference observed in the levels of ph, hco -, and base excess between each study protocol. minute ventilation in the "final protocol" significantly decreased by . times compared with the hemodiafiltration only protocol (p < . ), the membrane lung (p= . ) and acid infusion protocol (p= . ). we developed a novel ecco r system which efficiently removed co and is easy-to-setup to permit clinical application. this new system significantly reduced minute ventilation, while maintaining acid-base balance within the normal range. further studies are needed for the clinical application of this easy setup system comprising of the materials typically used in a clinical setting. , and psychomotor agitation ( %) while the most common symptoms of hypertensive emergency were chest pain ( . %), dyspnea ( . %) and neurological deficit ( %). clinical manifestations of hypertensive emergency were cerebral infarction ( . %), acute pulmonary edema ( . %), hypertensive encephalopathy ( . %), acute coronary syndromes ( . %), cerebral hemorrhage ( ,. %), congestive heart failure ( %), aortic dissection ( . %), preeclampsia and eclampsia ( . %). conclusions: hypertensive urgencies were significantly more common than emergencies ( . % vs. . %, p< . ). there was no statistically significant difference in the number of patients with hypertensive urgency and emergency in relation to age, gender, duration of hypertension, except for the - age group, where urgency was statistically significantly higher (p= . ). introduction: emergency department (ed) crowding is a major public health concern. it delays treatment and possible icu admission, which can negatively affect patient outcomes. the aim of this study was to investigate whether ed to icu time (ed-icu time) is associated with icu and hospital mortality. methods: we conducted an observational cohort study using data from the dutch nice registry. adult patients admitted to the icu directly from the ed in academic centers, between and , were eligible for inclusion. for these patients nice data were retrospectively extended with ed admission date and time. ed-icu time was divided in quintiles. the data were analyzed using a logistic regression model. we estimated crude and adjusted (for disease severity; apache iv probability) odds ratios of mortality for ed-icu time. in addition, we assessed whether the apache iv probability (divided into quartiles) modified the effect of ed-icu time on mortality. results: a total of , patients were included. baseline characteristics are shown in table . the median ed-icu time was . [iqr . - . ] hours. icu and hospital mortality were . and . %, respectively. the crude data showed that an increased ed-icu time was associated with a decreased icu and hospital mortality (both p< . , figure a ). however, after adjustment for disease severity, an increased ed-icu time was independently associated with increased hospital mortality (p< . , figure b ). figure shows that only in the sickest patients (apache iv probability > . %), the association between increased ed-icu time and hospital mortality was significant (p= . , figure d ). we found similar results with respect to icu mortality. conclusions: this study shows that a prolonged ed-icu time is associated with increased icu and hospital mortality in patients with higher apache iv probabilities. strategies aiming at rapid identification and transfer of the sickest patients to the icu might reduce inhospital mortality. reliability and validity of the salomon algorithm: -year experience of nurse telephone triage for out-of-hours primary care calls e brasseur, a gilbert, a ghuysen, v d´orio chu liege, emergency departement, liège, belgium critical care , (suppl ):p introduction: due to the persistent primary care physicians (pcp) shortage and their substantial increased workload, the organization of pcp calls during out-of-hours periods has been under debate. the salomon (système algorithmique liégeois d'orientation pour la médecine omnipraticienne nocturne) algorithm is an original nursing telephone triage tool allowing to dispatch patients to the best level of care according to their conditions [ ] . we aimed to test its reliability and validity under real life conditions. methods: this was a -year retrospective study. out-of-hours pc calls were triaged into categories according to the level of care needed: emergency medical services (amu), emergency department visit (maph), urgent pcp visit (upcp), delayed pcp visit (dpcp). data recorded included patients' triage category, resources and potential redirections. more precisely, patients included into the upcp + dpcp cohort were classified under-triaged if they had to be redirected to an emergency department. patients from the amu+maph cohort were considered over-triaged if they did not spend at least resources, emergency specific treatment or any hospitalization. results: calls were actually triaged using the salomon tool, of which . % were classified as amu, . % as maph, . % as upcp and . % as dpcp (fig ) . as concerns the amu+maph cohort, the triage was appropriate in . % of the calls, with an over-triage rate of . %. as concerns the upcp + dpcp cohort, . % of the calls were accurately triaged and only . % were under-triaged. sal-omon sensitivity reached . % and its specificity . %. these results indicate that salomon algorithm is a reliable and valid nurse telephone triage tool that has the potential to improve the organization of pcp out-of-hours work. introduction: inappropriate visits to the emergency department (ed), such as patients manageable by a primary care physician (pcp), have been reported to play some role in the ed crowding [ ] . indeed, non-urgent patients directly managed by pcps could reduce ed workload [ ] . triage and diversion to alternative care facilities, eventually co-located within the ed, could offer a solution [ ] provided fig. (abstract p ) . distribution of different calls, their triage using the salomon algorithm and the inappropriate triages (over and undertriages) based on the preselected criteria the availability of a reliable triage tool for their early identification. we created a new triage algorithm, persee (protocoles d'evaluation pour la réorientation vers un service efficient extrahospitalier) and tested its feasibility, performance and safety. methods: after initial evaluation with a -level ed triage scale [ ] , ambulatory self-referred patients classified as level or below benefited from a simulated triage with persee identifying categories of patients: ed ambulatory patients and primary care (pc) treatable patients. we collected patients data and resources. patients requiring less than resources, no specific emergency treatment and no hospitalization were considered as manageable in a pc facility. results: patients were included in the study of whom . % were self-referred (fig ) . among those self-referrals, . % were triaged as level or below. . % patients were triaged as ambulatory patients of whom % were as pc treatable. we noted a redirection rate of % of the global visits or % of the self-referrals, an error rate of %, a sensitivity of . % and specificity of . %. conclusions: using advanced ed triage algorithm in addition to classical ed triage might offer interesting perspectives to safely divert self-referrals to pc facilities and, potentially, reduce ed workload. introduction: generally, prehospital medical provider should minimize staying prehospital scene to reach the patient to definitive care as soon as possible in prehospital medical activity. in addition, some textbook and report saids that medical provider minimize the number of procedure or limit minimum requirement procedure because unnecessary procedure may extend the staying time in prehospital scene. however, there are few studies evaluating this hypothesis and that this "extension is significant or not. therefore, we perform this study. methods: we evaluated the operated air ambulance(doctor-heli) case from st april to st march , in gifu university hospital using our mission record. we evaluated about time from landing to ready for taking off(activity time), operation doctor, mission category (i.e. trauma), number of procedure in the each activity and work load. we only focused on prehospital care and exclude transportation from hospital to hospital . in addition, we exclude the case which are not suitable for analysis. results: cases were operated in these period. cases were suitable for analysis. average activity time in prehospital scene was . ± . . there was weak correlation between the number of procedure and activity time. (r= . ) the length of the activity time did not depend on mission category. if the doctor perform and over procedures, staying time was minutes longer, this was significantly longer than that of under and under procedures. conclusions: we confirmed that we have to minimize the number of procedure or limit minimum requirement procedure in prehospital scene. and our result suggest we may have to limit appropriate number of procedures. introduction: organ failure is a critical condition, but the prevalence is largely unknown among unselected emergency department (ed) patients. knowledge of demographics and risk factors could improve identification, quality of treatment, and thereby improve the prognosis. the aim was to describe prevalence and all-cause mortality of organ failure upon arrival to the ed. methods: this was a cohort-study at the ed at odense university hospital, denmark, from april , to march , . we included all adult patients, except minor trauma. organ failure was defined as a modified sofa-score > within six possible organ systems: cerebral, circulatory, renal, respiratory, hepatic, and coagulation. the first recorded vital, and laboratory values were extracted from the electronic patient files. primary outcome was prevalence of organ failure; secondary outcomes were - -day and - -day mortality. results: of , contacts . % were female and median age (iqr - ) years. the prevalence of new organ failure was . %, individual organ failures; respiratory . %, circulatory . %, cerebral . %, renal . %, hepatic . %, and coagulation . %. the - -day and - -day all-cause mortality was . % ( % ci: . - . ) and . % ( % ci: . - . ), respectively, if the patient had new organ failures at first contact in the observation period, compared to . % ( % ci: . - . ) and . % ( % ci: . - . ) for patients without. seven-day mortality ranged from hepatic failure, . % ( % ci: . - . ) to cerebral failure, . % ( % ci: . - . ), and the - -day mortality from cerebral failure, . % ( % ci: . - . to renal failure, . % ( % ci: . - . ). conclusions: new organ failure is frequent and serious, with a prevalence of . % and a one-year mortality of % with wide variation according to type of organ failure. results: we proceeded to a descriptive study that showed that % of patients were male and % of them were female with a sex ratio of . .the average age of patients was years old and ranged between and years old.we found that patients of our population had medical background, dominated by diabetes in cases, high blood pressure in cases and asthma in cases.the results also showed that . % of patients had a history of abdominal surgery while % of them had history of other types of surgery.the patients were oriented according to their severity level as following: % care unit of emergency department, . % close monitoring room .the vaspi score was ranged between and with an average of ± . it was higher than in . % of cases.the results of physical examination found an isolated pain in , % of cases, a reactionnal pain syndrom in % of cases, a peritoneal syndrome in % of cases and an occlusive syndrome in % of cases.the final diagnosis was mostly represented by the following causes: . % of gastroenteritis . % of constipation and % of ulcer disease.the final orientation of patients according to the diagnosis led to hospitalization in % of cases and to outpatient clinic in % of cases while % of them did not need any more care. conclusions: appropriate diagnostic evaluation and decision for or against hospitalization is a challenge in the patient who comes to the emergency department with acute abdominal pain it need an adequate evaluation and management. introduction: we assessed patients' impressions of a selfadministrated automated history-taking device (tablet) to gather information concerning emergency department (ed) patients prior to physicians' contact. the quality of communication was compared with the traditional history-taking. methods: the algorithm content was developed by two emergency physicians and two emergency nurses through an iterative process. item-content validity index (i-cvi) was measured by five experts rating the relevance of each item (from : not relevant to : highly relevant) [ ] . next, quality control was realized by research team. to assess the feasibility, we used a computerized randomization. low acuity, ambulatory adult patients presenting to the ed were assigned either to a control group (cg, n= ) beneficiating form a traditional history-taking process or to the experimental group (eg, n= ) assigned to use the tablet with further history-taking by the ed physician. communication was analyzed by the health communication assessment tool [ ] and satisfaction assessed by questionnaires. results: after two rounds, validity was excellent for each item (i-cvi > . ). the universal agreement method was of . . refusals (n= ) to participate were analyzed: they fear using an electronic device or the experimentation. content satisfaction revealed that % of patients understood the questions. % of patients indicated that the device was easy to hold and use. medical communication was not affected by the device (p= . ). we noticed that, among the subsections, physicians significantly introduced themselves better in the eg (p= . ). conclusions: in this feasibility study, patients were highly satisfied. the use of a self-administrated automated history-taking device does not generate miscommunications and allow physicians better introduce themselves. . a positive point we have established is the possibility for the detorsion of a twisted retention ovarian cyst after its transvaginal aspiration. we used this method only in cases when the onset of torsion did not exceed hours. . % of all emergency conditions associated with retention cysts were recurred by conservative therapy, and . % of patients with the retention cysts rupture were successfully treated in this way. conservative management is possible in the case of a small loss of blood (up to . - . ml), hemodynamic stability and the absence of signs of continuing bleeding. the detorsion and resection of the cyst when torsion is not more than °and even longer than hours, in most cases did not reveal necrosis in the appendages. conclusions: improvement of organs of preservation and reproduction in women. criteria for admission to an intensive care unit of a tertiary hospital: analysis of the decisions of the outreach intensivist and day in-hospital mortality introduction: the aim of this study was the analysis of icu admission criteria and evaluation of in-hospital mortality of patients assessed by our critical care outreach team. criteria for admission to the icu should be defined to identify the patients most likely to benefit from icu admission. this triage process is complex, associated with several factors, including clinical characteristics of the patients, but also subjective factors because it depends on the judgment of the intensivist who decides whether to admit or not the patient and is obviously conditioned to the structure and size of the icu. methods: the outreach intensivist records the patient observation in a form with questions (reversibility of acute illness, objective of admission in icu, comorbidities, functional reserve and intuitive prognosis of the doctor). analysis of months (january through june , ) of admission decisions in icu, mean delay, icu mortality, and day in-hospital mortality ( hm). results: the intervention of the intensivist in "outreach" was requested on occasions. the main places of observation were the emergency room ( . %) and the wards ( . %). the hm increased with the degree of comorbidity decompensation. functional reserve also influenced hm, reaching . % in partially dependent patients and . % in totally dependent patients. there was agreement between the mortality and the physician´s intuitive prognosis in % of the cases. conclusions: a larger sample is needed to draw sustainable conclusions, however, the evaluation algorithm correlated well with hospital mortality. decompensated comorbidities and low functional reserve have a negative impact on prognosis, regardless of acute disease. there was agreement between mortality and the physician´s intuitive prognosis. electrochemical methods for diagnosing the severity of patients with multiple trauma introduction: multiple trauma is one of the leading causes of death worldwide [ ] . timely diagnosis and treatment is crucial in this state. one of the promising areas is the use of new electrochemical methods they are simple, flexible, efficient and of low cost. among these methods, attention is paid to the measurement of open circuit potential (ocp) of the platinum electrode and cyclic voltammetry (cva). the ocp is a reflection of the balance of pro-and antioxidants in the body, and the amount of electricity (q) determined by cva is proportional to the antioxidant activity of the biological environment. methods: a total of patients with severe multiple trauma ( . ± . y.o., men and women) were enrolled; apacheii . ± . ; iss . ± . ; blood loss ± ml. blood plasma was collected from patients. measurement of the ocp was carried out according to [ ] , cva analysis -according to the original method on a platinum working electrode. results: a shift in the ocp towards more positive potential values (fig. ) , while the antioxidant activity of blood plasma decreased (fig. ) . a more significant change of ocp, as compared to the q values, may indicate not only a deficiency in the components of the antioxidant defense system of the body, but also an increase in the concentration of prooxidants (e.g., reactive oxygen species), which are involved in oxidative stress. who underwent surgical fixation). information was collected from tarn, icnarc and surgical team databases. our primary outcome was itu resource utilisation (itu los and mechanical ventilation days). our secondary outcomes were morbidity and mortality (hospital los, infection burden, inotrope use and death before discharge). data was collected and analysed in microsoft excel and r. results: patients were included (group = , group = , group = ). mortality was significantly higher when comparing the post groups undergoing conservative ( %, / ) vs. surgical fixation ( %, / ), p-value = . . regarding potential temporal changes, there was no significant difference in mortality between the non surgical groups; pre- (group : / ) and post (group ), p-value . . group patients did spend more time mechanically ventilated (p-value . ) and used more antimicrobials (p-value . ) ( table ) . conclusions: patients undergoing surgical rib fixation at the rlh had significantly improved mortality with more days spent mechanically ventilated. pilot study on ultrasound evaluation of epiglottis thickness in normal adult a osman introduction: as the prevalence of epiglottitis is decreasing due to immunization, the difficulty in early detection remained. the aim of this study is to determine the thickness of epiglottis in normal adult with the utilization of bedside ultrasound. methods: this was a prospective observational study of convenience selection among healthy staff in emergency department, university malaya medical centre. the identification and measurement of epiglottis were performed using a mhz linear transducer by trained emergency physicians and registrars in em. subjects were scanned in either standing or upright seated position with the neck neutral or mildly extended. the epiglottis, thyroid cartilage and vocal cord were visualized and the epiglottis anteroposterior(ap) diameter was measured. difference in categorical parameters were analyzed by independent-sample t-test. the relationship between height, weight and epiglottic size was analyzed using pearson's correlation. results: fifty-six subjects were analyzed with males and females age ranging from to years old. the epiglottis ap diameter ranged from . cm to . cm, with average of . cm. there was significant difference in epiglottic ap diameter between male (m= . cm, sd= . ) and female (m= . cm, sd= . ; t( )= . , p=< . , twotailed). moderate positive correlation between height and epiglottic ap diameter (r= . ) and weight (r= . ) was documented. conclusions: our study demonstrated the identification and visualization of epiglottis was feasible and easy with the use of bedside upper airway ultrasonography. there was a little variation in the ap diameter of epiglottis in adults. indoor vs. outdoor occurrence in mortality of accidental hypothermia in japan y fujimoto , t matsuyama , k takashina introduction: the impact of location of accidental hypothermia (ah) occurrence has not been sufficiently investigated so far. thus we aimed to evaluate the differences between indoor and outdoor occurrence about baselines, occurrence place, mortality, and length of icu stay and hospital stay. methods: this was a multicenter retrospective study of patients with a body temperature ≤ °c taken to the emergency department of hospitals in japan between april and march . we divided the included patients into the following two group according to the location of occurrence of ah (indoor versus outdoor). the primary outcome of this study was in-hospital death. secondary outcomes were the length of icu stay, and hospital stay. results: a total of patients were enrolled in our hypothermia database. there were and patients with the outdoor and indoor occurrence. the indoor group was older ( versus . years-old, p< . ) and worse in adl than the outdoor group. the proportion of in-hospital death was higher in the indoor group than the outdoor group ( . % [ / ] versus . % [ / ], p< . ). the multivariable logistic regression analysis demonstrated that adjusted odds ratio of the indoor group over the outdoor group was . ( %ci; . to . ) ( table ) . as for secondary outcomes, both of the length of icu stay and hospital stay in survivors were longer in the indoor group than the outdoor group. conclusions: our multicenter study indicated that indoor occurrence hypothermia accounts for about % of the total in this study, and the proportion of in-hospital death was higher in the indoor group. we have to raise an alert over the indoor onset accidental hypothermia and need to take countermeasures for prevention and early recognition of ah in indoor location. conclusions: during acute asthmatic attack, arterial hyperlactatemia is frequently present at ed arrival. nevertheless, the plasma lactate level was no significant difference between ed admission and hr after treatment. the introduction: this is a case series of traumatic aortic injury (tai) which was diagnosed by transesophageal echocardiography (tee) in the emergency department. the number of patients with blunt thoracic aorta injury arriving at emergency department is on the rise and survival rate is time-dependent on early diagnosis. tee offers several advantages over transthorasic echocardiography (tte) including reliability, continuous image acquisition and superior image quality. methods: all trauma patients who presented to emergency department from st january until th november at hospital raja permaisuri bainun, perak, malaysia with suspected tai were evaluated with transesophageal echocardiography. over the years period, tee was performed in patients. patients had positive findings suggestive of tai. results: the first case was an old lady who presented after a deceleration injury in a car accident. tee was performed due to hemodynamic instability and found an intimal flap along the ascending aorta. the second case, a stanford type a (figure ) , was complicated with pericardial tamponade. the intimal flap was visualised from the aortic arch extending to the descending aorta by tee. the third case was a case of intramural haematoma involving distal aortic arch extending to the descending aorta which survived until corrective surgery. in the fourth case, tee revealed a motion artefact which mimicked an intimal flap in the ascending aorta. in the fifth case, tee showed intimal flap at aortic isthmus which was not detected by tte. in the last case, a traumatic aortic dissection was complicated by aortic regurgitation (figure ) . conclusions: tee can be a useful point of care tool use by emergency and critical care physicians for early diagnosis of blunt traumatic aorta injury. introduction: reboa is an endovascular intervention intended to preserve central perfusion in the context of shock due to noncompressible torso haemorrhage. more so, it is less invasive than the traditional approach of resuscitative thoracotomy (rt) and aortic crossclamping. though its use dates back to the korean war, it has not been widely adopted in trauma management, as evidence demonstrating clear benefit compared with conventional rt is lacking [ ] . we aimed to evaluate feasibility, outcomes and complications after reboa for haemorrhagic shock and traumatic cardiac arrest. methods: we performed a systematic literature review, searching scopus and pubmed databases using relevant terms (july ). we included studies enrolling patients with haemorrhagic shock or cardiac arrest after civilian trauma who had undergone reboa and reported hospital mortality (our primary outcome). abstract-only studies and single-patient case reports were excluded. we collated and analysed data using review manager v . . the newcastle-ottawa scale was used to assess risk of bias. results: sixteen in-hospital studies met inclusion criteria (n= ). ten were case series and six were cohort studies comparing reboa outcomes with those of rt. there were wide differences between studies' inclusion criteria, case-mix (including cardiac arrest), injury severity, insertion details, and reported outcomes. overall hospital mortality post-reboa was . %. meta-analysis of cohort studies indicated notably lower mortality in patients undergoing reboa (or . , . - . ) than rt with low statistical heterogeneity between studies (i = %), shown in fig . conclusions: whilst our findings are limited by methodological differences and biases in the included studies, almost % of patients undergoing reboa for haemorrhagic shock and/or cardiac arrest survived to discharge. furthermore, reboa appeared to offer a consistent mortality benefit compared with rt. introduction: trauma related coagulopathy remains a primary contributor to mortality on battlefields and in civilian trauma centres. fibrinogen is considered to be the first to drop below critical level and correspondingly compromised coagulation process. however, it is unclear if fibrinogen concentrate at a very early stage is feasible and effective to prevent from coagulopathy. methods: a total of acutely injured patients in austria, germany and czech republic were screened and enrolled in this controlled, prospective randomized placebo controlled double blinded multicentre and multinational trial. upon the completion of randomization, fibrinogen concentrate ( mg/kg, fgtw©, lfb france) or placebo was reconstituted and given to the patients at the scene or during helicopter transportation from the scene to nearby hospitals. blood samples were taken at baseline (scene of accident before study drug administration), at the emergency room, three hours, nine hours and twentyfour hours after admission to the hospital as well as after three and seven days after admission, for measurements of blood gases and coagulation, together with clinical data and outcome records. results: the demographic and injury characteristics and the estimated blood loss, iss, and gcs at the scene were similar in both groups. in the placebo group, fibrinogen concentration dropped from mg/dl at injury site to mg/dl () at er admission and clot stability reduced from . mm ( , mm) to mm (p= . ) (fig ) . fibrinogen concentrate administration prevented the drop of fibrinogen level (baseline of mg/dl to mg/dl and improved clot stability from mm at baseline to mm at er. conclusions: pre-hospital administration of fibrinogen concentrate in traumatic bleeding patients is feasible and effective in preventing the development of coagulopathy. data from this study support the use of fibrinogen to prevent trauma related coagulopathy. fibrinogen concentrate vs cryoprecipitate in pseudomyxoma peritonei surgery: results from a prospective, randomised, controlled phase study results: the per-protocol set included pts (hfc, n= ; cryo, n= ). the mean total intraoperative dose of hfc was . g vs . pools of cryo (containing approx . g of fibrinogen). median duration of surgery was . h. overall haemostatic efficacy of hfc was non-inferior to cryo and was rated excellent or good for % of pts receiving hfc and cryo, with similar blood loss. intraoperatively, only red blood cells were transfused (median: unit). intraoperative efficacy is shown in table . infusions were initiated . h earlier with hfc than cryo due to faster product availability. preemptive hfc led to a greater mean increase vs cryo in fibtem a ( figure ) and plasma fibrinogen (figure ). there were serious adverse events (saes) in the hfc group and in the cryo group, including thromboembolic events (tees; deep vein thromboses, pulmonary embolisms). no aes or saes were deemed related to the study drug. conclusions: hfc was efficacious for treatment of bleeding in pts undergoing surgery for pmp. no related aes and no tees occurred in pts treated with hfc. fig. (abstract p ) . fib mcf t to t with % ci fig. (abstract p ) . fibtem a prior to and following the preemptive dose of hfc/cryoprecipitate introduction: patients in the intensive care unit often suffer from thrombocytopenia. in dealing with this problem, we need to figure out not only the cause of thrombocytopenia but also the risk of bleeding. however, there is no reliable method for evaluating bleeding risk. methods: in this preliminary study, four thrombocytopenic patients who required platelet transfusion before undergoing invasive procedure were enrolled. written informed consent was obtained from all patients for participation in the study. bleeding was graded using the who bleeding scale. thrombogenic activity was evaluated using total thrombus-formation analysis system (t-tas), rotational thromboelastometry (rotem), and multiplate impedance aggregometry. for t-tas analysis, we prepared a novel microchip, named hd chip, which is suited for analyzing low platelet samples rather than those with normal platelet counts. , key patient groups in which it was wasted and the use of standard laboratory tests (slts) to guide its use. the purpose was to assess the potential benefit a point of care viscoelastic haemostatic assay (vha) could have on ffp transfusion and waste. the national blood transfusion committee and nhs blood and transplant committee have published data showing that up to % of ffp is transfused inappropriately [ ] . methods: blood bank data was obtained evaluating haemorrhaging patients in whom ffp was requested across a nine-month period in . patient bleeds were categorised by speciality. the mean time ffp dispensed and wasted was recorded, as were timings of slt requests. where available, the inr result was recorded. results: patients were identified. transfusions were requested. table shows that the highest transfusion requirements are for acute medical emergencies and major trauma. % of transfusion were surgical specialities, it would be expected that these patients would have anaesthetic or critical care input. units were wasted. acute medical emergencies wasted the highest amount of ffp ( units). table demonstrates that . % of transfusions had an inr available one hour prior to ffp being dispensed. conclusions: we conclude that use of slts to guide ffp transfusion is low. this suggests transfusion decisions are being made clinically. a point of care vha could give treating physicians better access to timely haemostatic data. introduction: we developed the process for the out-of-hospital packed red blood cells (prbc) transfusion in the hems of castilla-la mancha clm according to criteria of medical indications, security, monitoring and tracking. haemorrhage is a preventable cause of death among population suffering accidents or bleeding injuries in regions with low population density where health services should reach people in remote areas. hems of clm is the first out-ofhospital emergency service in spain that provides prbc transfusion there where the accident takes place. this program has been developed jointly between hematologists of the center for transfusions ct and the hems team. methods: observational retrospective study with data collected from june to august . the medical helicopter was provided with two prbc o rh(d) negative (fig ) . shock index was selected as indication for transfusion. to achieve feasibility and preservation of the prbc it was established a prospective monitoring and microbiological culture for both groups: case group for the prbc kept in the hems and control group in the hospital (fig ) . controls and comparison of hematologic analysis were performed immediately and days after collection. statistics used spss . (signification p< . ). results: prbc were evaluated, case - control. analyses were tested days and after collection. hemolysis was not observed. all cultures were negative. results obtained of the prbc after days transported in the hems related to monitoring parameters were not different than those observed on prbc conserved in the ct. prbc were transfused to patients in out-of-hospital assistance. neither post-transfusional reactions or undesirable events have been registered. prbc units are changed every days. conclusions: the process designed (collection, conservation, tracking and tests) to make prbc available in the medical helicopter has demonstrated to keep the standard conditions and properties to be transfused in critically ill patients out-of-hospital. outcomes in patients with a haematological malignancy admitted to a general intensive care unit a corner east sussex healthcare nhs trust, intensive care, eastbourne, united kingdom critical care , (suppl ):p introduction: recent published data have challenged the view that critically ill patients with a haematological malignancy have a poor prognosis [ ] . reports have largely originated from tertiary centres. the aim of this audit was to evaluate the intensive care unit (icu), in hospital and one year mortality for a cohort of patients admitted to a mixed medical and surgical icu in a district general hospital. methods: details were obtained for all patients with a haematological malignancy admitted to eastbourne and hastings icu between march and august . patient characteristics, type of malignancy, reason for admission, degree of organ support and survival rates at icu discharge, hospital discharge and year postadmission were collected. results: patients, % male, were identified. median (interquartile range, iqr) age was ( - ) years. % had neutropenia. the commonest malignancies were acute leukaemia %, lymphoma % and myeloma %. reasons for admission were respiratory %, cardiac % and renal %. organ supports used were noradrenaline %, intubation and mechanical ventilation %, renal replacement therapy (rrt) % and dobutamine %. overall survival rates are shown in figure . patients were discharged from hospital following a period of mechanical ventilation. for these patients, median (range) age was ( - ) years. all were male. median (iqr) time in hospital prior to admission was ( - ) days, / patients required vasoactive support, / required rrt, median icu length of stay was ( - ) days. / were admitted following surgery for an unrelated condition. to date, only / patient has survived years post icu admission. conclusions: although survival rates were disappointing, particularly in those patients requiring mechanical ventilation, selected patients have the potential for a good outcome. these results outcomes have been presented to our haematology department to aid patient counselling. analyses. cox regression was used for the survival analysis. organ failure was defined as the occurrence of renal failure based on acute kidney injury network (akin)-creatinine or need for; vasopressors, invasive ventilation or continuous renal replacement therapy (crrt) the first days after admission. length of stay was only analysed in survivors. results: the study included unique patients. prolonged aptt was associated with mortality with a % confidence interval (ci) of hazard ratio . - . . prolonged aptt correlated also with the occurrence of renal failure and the need for vasopressor and crrt with % ci of odds ratio (or) . - . , . - . and . - . (fig ) . increased pt-inr was associated with the need for vasopressors and invasive ventilation with % ci of or . - . and . - . . both aptt and pt-inr correlated with length of stay with % ci of or . - . and . - . . conclusions: activated partial thromboplastin time on admission to the icu is independently associated with mortality. both aptt and pt-inr are independently associated with length of stay and the need of organ support. all regression models were adjusted for saps score which means that aptt prolongation and pt-inr increase on admission represent morbidity that is not accounted for in saps . introduction: the goal was to assess if daily venous thromboembolism (vte) assessment was being done in our critical care (cc) unit, and if not, what changes could be made. a mortality review showed the need for a dynamic vte assessment in cc patients, who are subject to daily changes influencing vte risk. a daily risk assessment was introduced, and a 'tab' on our clinical information system, metavision(r)(mv) was created. recently published national institute for health and care excellence guidelines on vte risk assessment in cc provided us cause to assess our compliance [ ] . methods: data was collected from mv. review of daily vte assessment was made and a percentage completion of daily vteassessments was calculated per patient.interventions were done using standard improvement methods through pdsa cycles. results: baseline data, of patients, was collected in july, .compliance with daily vte assessment was %. the results were presented at the clinical governance forum(cgf), and posters were displayed in cc. the second cycle, of patients, was collected in october. compliance had increased to %.following discussion from presenting results at the cgf, the vte tool was appropriately modified.the responsibility of vte assessment was also shifted to becoming more shared, including all clinical staff, rather than mainly consultants. the third cycle, of patients, was collected in november. compliance had increased to %.introducing a nursing care bundle with vte is in progress. conclusions: despite the identification of a risk in our clinical practice and the development of an appropriate it tool to facilitate improved practice, the advent of new national guidance revealed poor compliance with agreed standards. this shows the difficulties with achieving practice change in complex multiprofessional clinical environments. a sustained effort is required focusing on dissemination and engagement across the whole team. introduction: we describe the changes in anti factor xa (afxa) activity, thrombin generation and thromboelastography (teg) in critically ill patients with and without acute kidney injury (aki) following routine administration of tinzaparin as part of venous thromboembolism (vte) prophylaxis. methods: pilot prospective observational study. patients divided into those with and without aki were administered tinzaparin by subcutaneous injection as per established local guidelines. patients who did not receive tinzaparin were recruited as a 'control'. plasma afxa activity and thrombin generation were measured at intervals over a hour period. teg parameters were collected at t and t . results: afxa activity: results are shown in figure . / patients failed to achieve a prophylactic afxa level of > . at any point. / patients achieved a level of > . however in all cases this was at the lower end of the prophylactic range and was achieved for only a short time (median . hours). / achieved a level of > . for the whole h period. there was no difference between the aki and no aki groups. endogenous thrombin generation: there is no significant difference in thrombin generation between the aki and no aki groups. there is a significant decrease in thrombin generation between h and h (p< . ) and a significant increase between h and h (p< . ) (figure ). there is no significant difference between h and h (p= . ). teg: all teg parameters for all patients were within normal range conclusions: standard vte prophylactic dose tinzaparin rarely achieves an afxa range that has been suggested for vte prophylaxis. however, as assessed by thrombin generation, a hypo-coagulable state is generated in response to lmwh. there is no difference between critically ill patients with or without aki that would suggest the need for dose reduction in this context. (abstract p ) . thrombin generation at h, h and h. t = time of tinzaparin administration, with the sample taken just prior to administration. patients from aki group shown with dotted line and from no aki shown with solid line % which takes the third place between cpb-associated complications . current data demonstrates the importance of researching of changes in haemostatic system in paediatric patiens after cpb. provided below data is an intermediate result of our research. methods: patients in age up to mohth days (median age - , months, youngest age - days after birth, oldest - months days), who underwent cardiac surgery with cpb to treat congenital heart diseases, were enrolled in this study. all patients were divided into two groups: stwithout tc, ndwith tc. protein c (pc) and fibrin-monomer (fm) plasma levels were assessed in there points: before surgery, -hours and hours after surgery. thrombotic cases were provided by doppler ultrasound or mri. results: thrombotic complications were diagnosed in chidren ( %). between all tc ischemic strokes were diagnosed in % ( cases), arterial thrombosis in % ( cases), intracardiac thrombus in % ( cases). in group with tc fm-mean values in points , and respectively were . ; and mcg/ml, meamwhile in group without thrombosis - . ; . and . mcg/ml .pc-mean value in st groupwere ; and %, in the nd group - ; and % respectively in the points , and . statistically significant differences between groups in rd point (p< . ) and correlation between pc and fm (r=- . ; p< . ) were detected. conclusions: cpb causes hypercoagulation with increasing of pc consumtion and fm level. moreover, cp associated with a high risk of tc on the rd day after cardiac surgery. further studies to investigate prognostic values of fm and pc in thrombosis are required. these studies would help to asses fm and pc as markers of tc and possibility of pc-prescribing for prevention and treatment of these complications. introduction: thrombocytopenia is a common condition in critically ill patients and an independent predictor of mortality. the relevance of a supranormal platelet count remains unclear. septic patients with disseminated intravascular coagulation (dic) are also known to have a high mortality, but the influence of sepsis on mortality rates in coagulopathic patients is less well characterised. our objectives were to: ) evaluate mortality amongst patients with sepsis and nonsepsis associated dic. ) assess incidence of dic during the first days of admission. ) assess the relationship between platelet count and mortality. methods: records of adult critical care patients admitted to the royal liverpool university hospital between - were retrospectively reviewed. the presence of sepsis (using the definition of sirs with infection), coagulopathy, degree of thrombocytopenia and day mortality were noted. modified isth dic score was used to define dic. results: the overall mortality rate was %. patients were identified as having sepsis ( %) and non septic patients ( %). mortality rates of patients with sepsis were significantly higher than without sepsis ( % vs % respectively, p< . ). in patients with dic, their dic scores tended to be 'positive' for the first days of admission. fibrin-related markers were often not available for dic scoring. mortality rates amongst patients with sepsis-associated dic were greater than patients with non-sepsis related dic. thrombocytopenia severity was associated with mortality, and patients with platelets above the upper limit of normal had lower mortality rates ( % when platelets > x ^ /l, % when platelets < x ^ /l). conclusions: sepsis-associated coagulopathy is associated with a higher mortality rate than non-sepsis associated coagulopathy. supranormal platelet counts may be associated with a mortality benefit. introduction: deep vein thrombosis (dvt) is a major problem in icu and affects overall lethality. dvt is widespread complication in icu, especially in elderly patients, when early activisation may not be achieved. aim of this study is comparison of haemostatic potential and analgesia methods of elderly patients who underwent major urological surgery during their stay in icu. methods: a cross-sectional study was employed. participants were ≥ y.o., underwent major urological surgery, have had normal initial hemocoagulation data (thromboelastography was performed to all of them), had received analgesia with epidural catheter or iv by opioids use and were treated in icu > days due to non-coagulopathy states, were included. data were collected from october till october . the patients were examined with thromboelastograph "mednord" for thromboelastogramm (teg) and with esaote usg for thrombi occurrence in lower limb deep veins. the anticoagulants were prescribed under the esa guidelines . results: participants (n= ) were divided in two groups -non-opioid analgesia with epidural catheter (n= ) and opioid analgesia (n= ). we received moderate decrease in anticoagulants dosage to the patients with epidural analgesia with the same teg goals compared to the patients with opioid analgesia. other factors as comorbidities may provoke dvt events, but was not evaluated in this study. the dvt events were monitored by expert with the use of usg to locate thrombi in the vein. conclusions: use of epidural catheter analgesia provides moderate decrease of anticoagulants dosage compared to opioid analgesia patients; however strict control of teg data must be presented. comorbidity need to be monitored for early detection and prevention of dvt events. introduction: patients with morbid obesity (mo) have a high risk of thromboembolic events. in patients with a bmi > , the hypercoagulable state is due to impairment of all parts of the blood coagulation as well as anticoagulation mechanisms by obesity. methods: the hemostasis system was studied in patients with a bmi> kg/m with various pathologies that were admitted to icu. all patients were divided into groups depending on the type of therapy: group (n= ) received monotherapy with enoxaparin sodium . % . ml sc times a day every h; group (n= ) received combination therapy with enoxaparin sodium . % . ml sc times a day every h and pentoxifylline mg times a day every h. to study the hemostasis system, we used lpteg immediately after hospitalization, on , , days. results: in both groups, prior to treatment: contact coagulation intensity (icc) was increased by . %, intensity of coagulation drive (icd) -by more than . %, clot maximum density (ma) -by . %, index of retraction and clot lysis (ircl) - . % above normal. patients of the st group: icc increased by . %, icd was close to normal values, ma increased by . %, ircl was increased by . %. patients of the nd group on the th day: icc decreased by . % compared with the norm; the coagulation and fibrinolysis parameters were close to normal values and the decrease in fibrinolysis activity reaches to normal. conclusions: combined therapy of thromboembolic complications in patients with obesity sodium enoxaparin sodium and pentoxifylline is more effective than enoxaparin sodium monotherapy because it affects all parts of the hemostatic system. introduction: a laryngeal injury secondary to blunt neck trauma can lead to life-threatening upper airway obstruction [ , ] . ultrasound enables us to identify important sonoanatomy of the upper airway [ ] . the purpose of this report is to discuss role of pocus airway in blunt neck trauma and to determine airway management based on standard schaefer subgroups classification. methods: three cases of blunt neck trauma presented to our centre with either subtle or significant clinical signs and symptoms. standard airway management was performed prior to pocus airway using mhz linear transducer and it findings were later compared to flexible fibreoptic laryngoscopy and computed tomography (ct). results: pocus airway had identified one out of cases to have schaefer and the remaining as schaefer . all pocus airway findings were confirmed with flexible fibreoptic laryngoscopy and ct scan (figs , ) . based on schaefer, supportive care and early steroid administration are advisable for group and . for groups to , immediate open surgical repair is deemed necessary due to extension of injuries.all cases were intubated using glidescope.all including those presented with schaefer were managed conservatively and discharge well with proper follow-up. conclusions: upper airway ultrasound is a valuable, non-invasive and portable for evaluation of airway management even in anatomy distorted by pathology or trauma. an organised approach using pocus airway as an adjunct can expedite care and prevent early and long term complications in facilities without flexible laryngoscope and ct. introduction: high-flow nasal oxygen (hfno) and helmet noninvasive ventilation (hniv) are increasingly used for the early management of acute hypoxemic respiratory failure (ahrf). we compared the physiological effects of hfno and hniv during ahrf. methods: in this randomized cross-over study, we enrolled patients with acute-onset (< days), non-cardiogenic respiratory distress (respiratory rate> /min), pulmonary infiltrates at the chest-x-ray and hypoxemia (spo < % while breathing on room air). all patients received hniv (peep cmh o, pressure support adjusted to achieve a peak inspiratory flow of l/min) and hfno (flow l/min) for one hour each, in a randomized cross-over manner. at the end of each period, arterial blood gases, inspiratory effort (esophageal pressure) and respiratory rate were recorded. self-assessment of dyspnea and device-related discomfort ( [ ] [ ] [ ] [ ] [ ] ). conclusions: as compared to hfno among critically ill patients with ahrf, hniv ameliorates oxygenation, limits inspiratory effort and relieves dyspnea, without affecting paco , respiratory rate and comfort. introduction: pre-intubation hypoxemia is a predictor of negative patient outcomes including in-hospital mortality. while successful first intubation attempt is also an important factor of patient outcomes, little is known about whether physicians achieve successful first intubation attempt for the hypoxemic patients in the emergency department (ed). the aim of this study is to investigate the first-pass success for patients with pre-intubation hypoxemia in the ed. methods: this is an analysis of the data from the second japanese emergency airway network study (jean- study)a multicenter, prospective, observational study of eds in japan. we included all patients who underwent intubation in the ed from through . we excluded patients ) aged < years and ) patients who underwent intubation for cardiac arrest. we grouped pre-intubation hypoxemia as follows: non-hypoxemia (oxygen saturation [spo ], ≥ %), moderate-hypoxemia (spo , %- %), and severehypoxemia (spo , < %). primary outcome was the first-pass success rate. to demonstrate the association between pre-intubation hypoxemia and the first-pass success in the real-world setting, we fit two unadjusted logistic regression models ) using grouped preintubation hypoxemia as a categorical variable and ) using the preintubation spo as a continuous variable. results: among , patients who underwent intubation in the ed (capture rate, %), , patients were eligible for the analysis. compared to the non-hypoxemia, the first-pass success rate was low in moderate-hypoxemia ( % vs %; or= . [ %ci, . - . ]) and severe-hypoxemia ( % vs %, or= . [ %ci, . - . ]). additionally, there was a linear association between pre-spo and lower first-pass success rate (or for the success, per one pre-spo decrease, . [ %ci, . - . ]). conclusions: based on the large, multicenter data, the first-pass success rate was low in hypoxemic patients compared to nonhypoxemic patients in the ed. introduction of rapid-sequence induction guideline to reduce drug-associated hypotension in critically unwell patients introduction: the aim of this project was to assess whether the introduction of a rapid sequence induction (rsi) agent guideline changed drug choice and the incidence of peri-intubation vasopressor use at st john's hospital, livingston. it is well documented that emergency airway management in the critically ill can be a source of significant morbidity and mortality [ , ] and the choice of induction agent matters [ ] . methods: an rsi agent guideline was instituted for all critically ill patients being intubated in icu and the ed [ figure ]. following this, we set up an intubation registry to collect data from all intubation events. this data was then compared to a previous audit of intubations completed in . results: the choice of agent used pre-and post-intervention are summarized in figure . forty-five intubation events were included in the initial audit in , of which, ( %) required vasopressor support immediately following intubation. of the intubation events following the guideline's introduction, ( %) required vasopressors. ketamine use changed from % to %, propofol use from % to % and midazolam from % to %. thirty-eight of these intubation events ( %) were compliant with the guideline. conclusions: the introduction of the rsi guideline dramatically affected the choice of induction agent and reduced the incidence of significant hypotension requiring vasopressors ( % versus %). overall compliance with the guideline was excellent ( %). introduction: the purpose is to test the feasibility of using the i-gel® device for airway maintenance during bronchoscopic-guided percutaneous dilatational tracheostomy (pdt). usually pdt is accomplished via the tracheal tube. failure to position the endotracheal tube correctly can result in further complications during the procedure. the alternative implies extubation and reinsertion of an i-gel® airway device. methods: the pdt was performed using the blue dolphin method in patients in intensive care unit. before undertaking bronchoscopicguided percutaneous dilatational tracheostomy (pdt), the patient's tracheal tube (et) was exchanged for i-gel®, as a ventilatory device for airway maintenance. the insertion of the i-gel®, the quality of ventilation, the blood gas values, the view of the tracheal puncture site, and the view of the balloon dilatation were rated as follows: very good ( ), good ( ), barely acceptable ( ), poor ( ), and very poor ( ) [ ] . results: the i-gel® successfully maintained the airway and allowed adequate ventilation during percutaneous tracheostomy in all patients. the ratings were or in % of cases with regards to ventilation and to blood gas analysis, for identification of relevant structures and tracheal puncture site, and for the view inside the trachea during pdt. conclusions: the i-gel® successfully maintained the airway and allowed adequate ventilation during percutaneous tracheostomy in all patients. the ratings were or in % of cases with regards to ventilation and to blood gas analysis, for identification of relevant structures and tracheal puncture site, and for the view inside the trachea during pdt. no damages to the bronchoscope, reports of gastric aspiration or technical problems were detected. the bronchoscopic view obtained via an i-gel® seems to be better than that obtained through an endotracheal tube (et) or through traditional laryngeal mask [ ] . introduction: the purpose of this study was to investigate the efficiency of nasal airway inserted in the oral airway (on airway) in securing the airway patency during mask ventilation [ ] (fig ) . methods: fifty eight patients undergoing general anesthesia were randomly assigned to either oral airway group (group o) or on airway group (group n). in both group, mg/kg of propofol was infused intravenously and mask ventilation was performed in the sniffing position without head extension or jaw thrust. the patients were ventilated with a volume-controlled ventilator with o flow of l/min, tidal volume of ml/kg (ibw), and respiratory rate of /min. before the start of mask ventilation, airway was placed in the oral cavity. oral airway was used in group o and on airway was used in group n. peak inspiratory pressure (pip), tidal volume and etco were compared between the two groups. the location of airway tip was graded by fiberoptic bronchoscope as; : airway obstructed by tongue, : epiglottis visible, : airway touches epiglottis tip, : airway passes beyond epiglottis tip [ ] . methods: a prospective uncontrolled observational study in - in ukrainian hospitals. sma-pts from - mo were involved. all pts. ready for extubation: afebrile, no infiltrations on chest x-ray, normal wbc. however, each sma-pts. failed sbt (t-tube or psv). we evaluated: extubation success (no reintubation in hours), icu los, one year survival. three pts. were excluded: two pts. by staff decision, family have choosen tracheostomy. sma-pts. included. a cuff leakage test performed -with a negative, dexamethazone mg iv was administered. after extubation niv was started by ventilogik ls in st mode via nasal mask giraffe. the epap and ipap settings were titrated to reach the chest excursion and target levels of spo ( - %) and etco ( - mmhg). a sputum was draining by mechanical insufflation-excuflation (mie) and aspirator results: all pts, were extubated successful. the mean icu los was . days ( - days), one year survival rate was %, respiratory failure fully compensated by niv, there was no icu admission. every sma-pts. are in good condition, gaining weight introduction: aerosol delivery has previously been assessed during simulated adult hfnt, delivered by various stand-alone humidification systems [ ] . the objective of this study was to evaluate aerosol delivery during simulated hfnt delivered by a mechanical ventilator, across three clinically relevant gas flow rates. methods: ml of mg/ml salbutamol was nebulised using an aerogen solo nebuliser (aerogen, ireland). an adult head model was connected to a breathing simulator (asl , ingmar, us), vt ml, bpm and i: e, : (fig ) . hfnt was supplied via the servo-u ventilator (maquet, getinge, sweden), using the integrated nebulisation option. tracheal dose was recorded at two nebuliser positions; a (after the humidification chamber) or b (before of the cannula), at three gas flow rates ( lpm, lpm and lpm) (n= ). the mass of drug captured on a filter placed distal to the trachea (tracheal dose) was quantified using uv spectroscopy at nm. results: presented in table . conclusions: to our knowledge, this is the first study to successfully demonstrate aerosol delivery during simulated hfnt, delivered by a mechanical ventilator. increasing gas flow rate was associated with a reduced tracheal dose (p= < . ). at lpm, a significantly greater tracheal dose was observed when the nebuliser was positioned before the nasal cannula (p= < . ). at lpm, a greater tracheal dose was yielded when the nebuliser was positioned after the humidifier (p= < . ). introduction: tracheotomies are often performed in critically ill patients who are in need of prolonged mechanical ventilation and respiratory care. our aim was to evaluate the possible effect of percutaneous and surgical tracheotomies on thyroid hormone levels. methods: eighty seven adult patients were included in our study from january to september . patients were in need of prolonged mechanical ventilation and tracheotomies were performed after consent was taken. we have excluded patients with preexisting thyroid diseases. forty five patients were undergone percutaneous tracheotomies and forty two patients were undergone for surgical. thirty eight female patients and forty nine male, age range - . we studied tsh, t and ft serum levels using chemiluminescence immunoassay method before either procedure and hours post each procedure.: statistical analysis was performed using spss . significance was estimated at the level of p< . results: tsh levels were increased in surgical group compared to percutaneous group at hours post procedure but the difference was not found statistically significant (p> . ). the rise in post operative levels of t compared to preoperative was found statistically significant for surgical tracheotomy group (p< . ).elevated ft levels for both groups have shown statistically significant difference between preoperative and postoperative period for the surgical tracheotomy group (p< . ) conclusions: we analyzed the effect of surgical versus percutaneous tracheotomy on thyroid hormones and it was found that both introduction: insertion of a tracheostomy for weaning purposes is associated with prolonged critical length of stay (los) and several adverse patient outcomes [ ] . previous work has suggested that protocolised weaning may reduce weaning times [ ] . we aimed to assess the impact of protocolised weaning on los following introduction of a standardised weaning protocol in . conclusions: introduction of a standardised weaning protocol for patients with a tracheostomy in our unit has had a beneficial effect on several patient outcomes, notably duration of weaning and length of critical care admission. introduction: delirium is a relatively frequent neurologic complication in liver transplantation (lt) recipients, which is an important cause of increased morbidity, mortality, extended icu stay, and increased cost of medical care. extubation of the endotracheal tube at an appropriate timing is an essential part of intensive care after lt, suggested to improve graft perfusion and systemic oxygenation, and thus decrease intensive care unit (icu) stay and positively affect prognosis. the aim of this study was to compare the incidence of delirium between early and late extubation groups after lt. methods: medical records from patients who received lt from january to july in a single university hospital were retrospectively reviewed. patients were divided into groups: those who underwent early extubation after lt (group e, n = ) and those who underwent extubation within few hours of icu admission after surgery (group c, n = ). the data of patients´demographics, perioperative management, and postoperative complications were collected. early extubation was defined as performing extubation in the operating room after lt. a propensity score matching analysis was performed to minimize the effects of selection bias. results: postoperative delirium occurred in / ( . %) in group e and / ( . %) in group c, respectively (p = . ). after propensity score matching, there was no difference in icu stay (p = . ), time to discharge after surgery (p = . ), and incidence of delirium between groups (p = . ). conclusions: although this study is retrospective in nature, limited by small sample size, early extubation did not affect the incidence of delirium after lt. further prospective studies on this area are required. weight estimation and its impact on mechanical ventilation settings in queen elizabeth hospital intensive care unit a nasr, a iasniuk, a roshdy queen elizabeth hospital, icu, london, united kingdom critical care , (suppl ):p introduction: documented weight in the intensive care unit (icu) can be the total, ideal, adjusted or predicted body weight (pbw). lung protective ventilation depends on tidal volume (vt) delivery which is based on accurate calculation of patients´weight [ ] . the weight is most probably documented on admission to the icu using estimation or one of many available equations. the aim of this study is to assess the documented versus the pbw and its impact on tidal volume delivery for mechanically ventilated patients in queen elizabeth hospital icu. methods: data was collected prospectively from all ventilated patients over a period of weeks in june . vt delivered in the first hour was calculated for each patient. documented body weight and height of each patient was obtained from the nursing chart. pbw was calculated and compared with the documented weight. the difference in vt attributable to the difference in weight has been subsequently calculated. results: ventilated patients were included ( males). the mean tidal volume delivered according to the documented body weight was . ml/kg versus . ml/kg based on pbw. vt more than ml/ kg was delivered in % of patients based on documented weight versus % when correcting the weight according to the pbw equation. conclusions: inaccuracy in documenting weight on patients´admission to the icu is a potential cause of delivering unsafe tidal volume [ ] . the harm can extend to drug dosage, nutrition provision and renal replacement therapy. introduction: ventilator-associated pneumonia (vap) is the leading cause of death among mechanically ventilated critically ill patients [ ] . chest radiography (cxr) is essential in the diagnosis of vap. in the past decade lung ultrasonography has proven to be a valuable tool in the diagnosis and monitoring of lung diseases. the aim of the study is to assess sensitivity and correlation between cxr, lung ultrasound and clinical pulmonary infection score (cpis). methods: in this retrospective, non-randomized study seven patients with proved vap were enrolled. in all patients cpis and lung ultrasound score (lus) [ ] were assessed. comparison of patients that had lus≥ and cpis≥ points was performed. the correlation between lus and cxr was done using the pearson model. results: we found significant difference between positive cxr patients with lus≥ and cpis≥ ( % vs %, p< . ). there is a very high correlation between cxr and lus. these results render lung ultrasound as a highly sensitive tool in the diagnosis of vap. conclusions: our study shows that lung ultrasonography could be used as a reliable supplementary method in the diagnosis of vap. the benefits of lung ultrasound include the ability to perform it at the patient´s bed without need for transportation, no radiation exposure and repeatability. the high correlation between cxr and lung ultrasound makes echography a valuable adjunct in the diagnosis of vap. color introduction: it is difficult to differentiate between pneumonia and atelectasis as cause of lung consolidation in intensive care unit patients. tools like the clinical pulmonary infection score are of little help (sensitivity % and specificity % for detecting pneumonia) [ ] . the objective of this study was to determine the accuracy of ultrasound assessed vascular flow within the consolidation to distinguish these causes. methods: adult patients with pulmonary symptoms and lung consolidation on lung ultrasound that were scheduled for chest-ct were included. vascular flow was analyzed with color doppler imaging (flow velocity scale was chosen at . m/sec.). the final diagnosis made by the treating physician was regarded as the gold standard. results: patients were included of which nine ( %) were diagnosed with pneumonia. vascular flow in the consolidation was present in seven ( %) out of nine patients with pneumonia, compared to three out of ( %) patients with atelectasis (p = . ). the diagnostic accuracy in differentiating between pneumonia and atelectasis was %. the sensitivity and specificity were % and % respectively. the positive predictive value was % while the negative predictive value was %. conclusions: vascular flow in lung consolidations assessed by lung ultrasound in icu patients aids in differentiating between pneumonia and atelectasis. it outperforms the frequently used clinical pulmonary infection score. methods: three intubated patients for various causes of respiratory distress undergoing mechanical ventilation were subjected to tee. at the level of mid-esophagus, the descending aorta short-axis view ( °) the imaging plane is directed through the transverse axis of the descending aorta. sector depth was increased to image the left pleural space beneath the aorta. for the right lung, the tee is rotated to the right at the level of atria until lung is seen or until the image of the liver is seen and the probe was withdrawn until the right lung is seen. recruitment manoeuvres were performed after identifying pbl atelectasis. atelectatic lungs were visually observed to open up during and after the recruitment manoeuvres. results: the time to acquire the image of pbl atelectasis from the time of insertion by tee is short. the images of posterior lung and the effect of lung recruitments is successfully viewed (fig ) . no immediate complication seen. conclusions: tee provides an excellent view of pbl atelectasis and able to directly monitor the success and failures of recruitment manoeuvres. introduction: high respiratory driving pressure (Δ prs) is strongly associated with increased risk of lung injury and increased mortality during mechanical ventilation. Δ prs consists of the pressure required to distend the lung the transpulmonary driving pressure (Δ pl) and the pressure required to distend the chest wall. Δ pl is the pressure that increases the risk of lung injury. data on Δ pl is limited because its measurement requires an esophageal catheter. we aimed to assess changes in Δ prs and Δ pl during proportional assist ventilation (pav+) at different experimental conditions. methods: we retrospectively analyzed patients ventilated with pav+ who had esophageal pressure measurements before and after dead space or chest load addition. we calculated end-inspiratory plateau pressure (pplateau), Δ prs, respiratory system compliance (crs) and Δ pl during occluded breaths in pav+ (figure ). data were compared with wilcoxon signed rank test and p value< . was considered significant. results: patients were analyzed. dead space increase ( patients) did not affect the studied parameters. chest load ( patients) significantly increased pplateau (p= . ) and Δ prs (p= . ) and decreased crs (p= . ) but Δ pl remained the same (p= . ). median (iqr) changes were . ml/cmh o ( . - . ) for crs, . cmh o ( . - . ) introduction: particle flow in exhaled air from mechanically ventilated patient's mirrors the opening and closing of small airways and can be detect by optical particle counter [ ] . we hypothesized that this particle flow is affected by cardiac function. methods: exhaled air from mechanically ventilated patients was analyzed using a customized optical particle counter pexa, figure . introduction: we assessed the diagnostic accuracy of mechanical power (mp) and driving pressure (dp) alone and combined with stress index (si) to identify ventilator settings likely to produce ventilator induced lung injury caused by tidal hyperinflation [ ] [ ] [ ] . methods: secondary analysis of a previous database of ards patients [ ] . computerized tomography markers of tidal hyperinflation (were used as a "reference standard". analysis of the area under the receiver-operating characteristics curve (auc) was used using a two-fold cross-validation. results: in a cluster of patients, a "training set" of not hyperinflated patients was compared with a "validation set" of hyperinflated patients. (figure - ) . conclusions: si seems to be more accurate than mp and dp in identifying tidal hyperinflation in patients with ards. specificity and sensibility were not improved combining si with mp or dp. the introduction: the pao /fio (p/f) ratio is widely used to assess the severity of lung injury. conceptually, the p/f ratio should be independent of the fio and solely depend on the pulmonary condition. however, effect of fio modulation on the p/f ratio has not been well characterized in ventilated intensive care (icu) patients. the purpose of the present study was to investigate the relationship between fio and the p/f ratio in icu patients on mechanical ventilation. methods: in a prospective, interventional study patients with a swan ganz catheter in situ were included. the p/f ratio was calculated at fio levels ranging from . to . with minute intervals. during the study other ventilator settings were not modulated. to understand the physiological effects of fio modulation on gas exchange and hemodynamics, mixed venous oxygen saturation and cardiac output were assessed. shunt fraction was calculated as described by west [ ] . results: patient characteristics and ventilator settings are reported in table . all patients were admitted to the icu after elective cardiac surgery. modulation of fio did have a significant effect on the p/f ratio, following a u-shaped pattern (p < . ) (figure ). the shunt fraction varied with altering fio levels, also exhibiting a u-shaped pattern (p < . ) (figure ). cardiac output was not affected by fio . conclusions: in contrast to current thinking, the p/f ratio varied substantially with altering fio levels in mechanically ventilated icu patients. this is an important novel physiological observation. in addition, it demonstrates that the assessment of the severity of respiratory failure by using the p/f ratio should be standardized to a fixed fio level. conclusions: in patients undergoing prolonged mechanical ventilation, we must take into account all the factors that may affect our patients. the assessment of diaphragmatic dysfunction is key to preventing weaning failure. an optimal level of consciousness as well as a good management of secretions are key to a successful weaning. prognostic value of the minute ventilation to co production ratio as a marker of ventilatory inefficiency in the icu r lopez , r pérez , Á salazar , i caviedes , j graf introduction: ventilatory inefficiency for co clearance may provide better severity stratification in acute respiratory failure than oxygenation [ ] . ventilatory inefficiency (vi) is best assessed by the bohr-enghoff physiological dead space [ ] . we recently reported that the minute ventilation to co production ratio (ve/vco ), a simplified vi index from exercise testing that obviates the paco measurement, correlates better than other vi indices to physiological dead space in mechanically ventilated patients [ ] . here we report the prognostic performance of this index using a survival analysis. mean±sem ve/vco was higher in patients who died than those who survived ( ± vs ± , p< . , figure ). we found a ve/ vco cutoff value of . mortality was higher in patients with high-ve/vco (≥ ) as compared to those with low-ve/vco ( % vs %, p= . ) with an odds ratio of . [ %-ci . - . ]. cumulative mortality was higher in the high-ve/vco than in the low-ve/vco group (log-rank p= . , figure ). conclusions: in this unselected cohort of mechanically ventilated patients an early high ve/vco ratio was associated to -days mortality. the ve/vco ratio may be a simple and non-invasive vi index with prognostic value in this population. introduction: sodium thiosulfate (sts) is a clinically relevant and safe hydrogen sulfide donor that improved acute lung injury (ali) and brain ischemia/reperfusion injury in previous studies [ , ] . methods: in a prospective, controlled, randomized, and doubleblinded trial, twenty adult, anesthetized, mechanically ventilated and surgically instrumented swine with preexisting coronary artery disease [ ] underwent h of hemorrhagic shock (hs; removal of % of the calculated blood volume and subsequent titration of mean arterial pressure to mmhg). post-shock resuscitation ( h) comprised re-transfusion of shed blood, crystalloids, and norepinephrine. animals were randomly assigned to "placebo" or "sts" ( . g·kg - ·h - for h). before, at the end of and every h after shock, hemodynamics, blood gases, and lung function were recorded. results: survival rates did not differ between groups. sts-infusion attenuated the hs-induced impairment of lung mechanics and pulmonary gas exchange (table , ), resulting in a significantly higher horovitz/peep-ratio ( figure ). conclusions: sts during acute resuscitation from hs may protect comorbid swine against hs-induced ali. introduction: alveolar epithelial cell (aec) death is a main mechanism of severe respiratory failure in acute respiratory distress syndrome (ards). classically, cell death is classified into necrosis or apoptosis. recent studies have reported that not only apoptosis but also certain types of necrosis are molecularly regulated and that these regulated necrosis can be therapeutic targets for various diseases. however, the relative contribution of necrosis and apoptosis to aec death in ards has not been elucidated. our study aimed to elucidate which type of cell death is dominant in aec death and to evaluate whether the regulated necrosis is involved in lps-induced experimental ards. methods: we established ards model by instilling μ g of lps intratracheally to mice. to estimate the relative proportion of apoptosis and necrosis in aec death, we measured cytokeratin m level (total cell death marker) and m level (apoptosis maker) in bronchoalveolar lavage fluid (balf) by elisa, and quantified propidium iodide-positive necrotic cells and tunel-positive apoptotic cells in the lung sections. moreover, we performed pathway enrichment analysis of gene expression data from pcr array to evaluate whether regulated necrosis pathway is associated with the ards model. results: both m and m levels were increased in the ards mice. the m /m ratio (an indicator of the proportion of apoptosis to total cell death) in the ards mice was significantly lower than that of healthy controls. moreover, the number of propidium iodidepositive necrotic cells was significantly higher than that of tunelpositive apoptotic cells in ards mice. in the pathway enrichment analysis, the necroptosis pathway, a regulated necrosis pathway, was associated with lps-induced experimental ards. conclusions: aec necrosis is more dominant than apoptosis in lpsinduced ards model. moreover, necroptosis may contribute to ards pathogenesis. aec necrosis including necroptosis is a potential therapeutic target for ards. clinical ards diagnosis is not associated with a unique circulating neutrophil cell surface phenotype t craven , s duncan , s johnston , c haslett , k dhaliwal , t introduction: acute respiratory distress syndrome (ards) is a form of non-cardiogenic oedema due to alveolar injury secondary to an inflammatory process. the clinical diagnosis is defined by the berlin criteria but this may not reflect the underlying biological process. the activated neutrophil is central to the pathogenesis of ards, characterised by altered cell surface markers. methods: three cohorts of seven participants were recruited. the first cohort suffered from mild, moderate or severe ards as defined by the berlin criteria [ ] . the second cohort was composed of ventilated patients on the intensive care unit with acute inflammatory lung disease (diagnosis of clinical suspicion) but did not meet the berlin criteria for ards. a third cohort was composed of age and sex matched healthy volunteers. procurement of human tissue was approved by a regional ethics committee ( /ss/ or /s / or amrec: -hv- ) and with the informed consent of the participant or their personal legal representative. patients were excluded if aged under or over years of age, were expected to survive for less than hours, if the attending physician refused, due to the absence of suitable indwelling vascular catheter, if the haemoglobin concentration was below . g/dl, or if the patient was enrolled in a trial of novel anti-inflammatory agent. whole blood (lysed erytocytes) underwent flow cytometry to determine cd b, , b, , l and . results: a description of the enrolled cohorts can be found in table . there were no significant differences between the mechanically ventilated, critically ill cohorts for any cell surface molecule in the multiplicity adjusted p values (fig ) . the results support the conjecture that clinical diagnostic criteria should not be used as a surrogate to stratify patients according to biological changes, with implications for the testing of biological therapies. introduction: aim of the present study was to compare the global and regional diagnostic accuracy of lung ultrasound (lus) compared to lung computed tomography (ct) scan in patients with the acute respiratory distress syndrome (ards). ards is characterized by a diffuse, inhomogeneous, inflammatory pulmonary edema. lung ct scan is the reference imaging technique, but requires transportation outside the intensive care and exposes patients to x-rays. lung ultrasound (lus) is a promising, inexpensive, radiation-free, tool for bedside imaging. methods: lung ct scan and lus were performed at peep cmh o. lus was performed using a standardized assessment of regions per hemithorax: superior and inferior; anterior, lateral and posterior. each region was classified for the presence of normally aerated, alveolar-interstitial syndrome, consolidation regions and pleural effusion. agreement between the two techniques was calculated, and diagnostic parameters were assessed for lus using lung ct as a reference. both a global and a regional analysis were performed. results: thirty-two sedated and paralyzed ards patients (age ± years, bmi . ± . kg/m and pao /fio ± ) were enrolled. global agreement between lus and ct was . ± . . the overall sensitivity and specificity of lus are shown in table . similar results were found with regional analysis (anterior/lateral/posterior lung regions is a common practice in our icu. during the interruption eit belt was positioned. when the presence of spontaneous breathing activity was evident by clinical assessment and ventilator traces analysis, nmba were administered to reach full paralysis, in accordance with the treating physician. eit tracing were analyzed offline and the change in eeli after nmba bolus, as compared to before nmba administration, was measured. respiratory mechanics and arterial blood gas (abg) data were collected results: we enrolled ards patients, undergoing controlled mechanical ventilation with muscle paralysis. baseline respiratory mechanics and abg data are shown in table . in out of patient the bolus of nmba led to an increase of eeli. in case, the nmb administration led to no changes in eeli. the mean change in eeli was ± ml conclusions: in our small population of ards patients, the administration of a bolus of nmba after the regain of spontaneous breathing activity led to an increase in eeli in out of patients. further study are needed to ) correlate this increase to global and regional respiratory system compliance and ) correlate this increase to the time needed to wean the patient from nmba introduction: to analyze the use of the orthostatic board as an auxiliary device for the treatment of severe ards by assessing its risks and benefits. methods: we selected patients, females and males, hospitalized in a neurological icu, between june and july , in a physiotherapeutic follow-up with diagnosis of severe ards. the patients were submitted to orthotics assisted for to minutes and monitored hr, pam, fr, sato at °and °of inclination and the pao / fio ratio after the procedure. the mean number of sessions per patient was . . all patients were undergoing anticoagulation in rass - , in the treatment of the cause of ards. the mean time of mechanical ventilation was . days. results: among the patients selected, . % presented tachycardia above bpm, requiring intervention in . % and interruption of the procedure in . %. pam arterial hypotension < mmhg was observed in . %, requiring intervention (increase of vasopressor dose and / or change of plank angulation) in % and interruption of the procedure in . %. hypoxemia sato < % was observed in . %, without interruption, but an improvement in pao / fio was observed in only . % of the patients. conclusions: assisted orthostatism as an auxiliary device for the treatment of severe ards was shown to be an alternative, with improvement of pao / fio in . % of the patients, safe and without significant hemodynamic repercussions that could lead to interruption of the procedure. introduction: the eolia trial found that vvecmo compared to conventional mechanical ventilation (cmv) did not improve mortality in patients with severe ards [ ] . the cmv strategy consisted of airway pressures below cmh o. in patients with severe ards higher airway pressures are required to maintain lung aeration. grasso et al. measured the transpulmonary pressure (p l ) in patients with severe ards and increased peep until p l was cmh o, accepting airway pressures above cmh o. fifty percent of patients responded to an increase in airway pressure and did not require vvecmo [ ] . we hypothesized that a p l guided open lung concept (olc) improves oxygenation and prevents conversion to vvecmo in patients with severe ards. methods: a retrospective study was conducted in a tertiary referral icu. the records of patients referred to our icu for advanced medical care were reviewed. inclusion criteria were severe ards according to the berlin definition and the eolia trial inclusion criteria for vvecmo. results: mechanical ventilation was limited to a p l of < cmh o instead of plateau pressures below cmh o. the p l guided olc resulted in an increase in p/f ratio and none of the patients required vvecmo. during the first hours peak airway pressure was increased, but was reduced within hours while peep was maintained ( fig. ). at hours both peak airway pressures and peep were reduced to baseline values while p/f ratio remained stable. only one patient ( . %) died of disseminated invasive aspergillosis. conclusions: the p l guided olc improved oxygenation and none of the patients required vvecmo. these findings support a ventilation strategy guided by transpulmonary pressures instead of plateau pressures in patients with severe ards. introduction: the mortality benefit conferred by early prone positioning in the treatment of acute respiratory distress syndrome (ards) has been well established. we also know that aprv improves oxygenation, and more recently has been shown to reduce ventilator dependent days and icu length of stay [ , ] . however, controlled ventilation remains the mainstay mode of ventilation used during prone position. literature looking at combined aprv and prone positioning is scarce. we aim to explore and report our institutional experience with respect to feasibility and outcomes in combining aprv and prone positioning, and perform a literature review in this area. methods: we undertook a single-centre retrospective cohort study within a surgical icu of a tertiary hospital in singapore between jan -oct . patients with ards who received combined prone positioning and aprv were reviewed retrospectively. a literature review of patients with ards who received combined intervention was also performed. results: adult patients aged - years old diagnosed with ards received a combination of aprv and prone positioning for a duration of - h ( table ). all the patients tolerated aprv with prone positioning well. our patients saw an improvement of p:f ratio ranging from - upon completion of combination therapy. out of patients were extubated within hours of turning supine, was weaned to tracheostomy mask after days and died while on the ventilator. only case report and randomized clinical trial were found on this topic upon literature review, which corroborated our findings. conclusions: in our experience, aprv is a practical and feasible alternative mode of ventilation that can be employed in the prone position, yielding significant p:f ratio improvements. the synergistic effects on improving oxygenation herald potential, especially in the subset of severe ards patients with refractory hypoxemia, where extracorporeal membrane oxygenation is unsuitable or unavailable. introduction: the recirculation during veno-venous extracorporeal membrane oxygenation (vv ecmo) had been a drawback, which could limit sufficient oxygenation. purpose of this study is to compare the short-term oxygenation in acute respiratory distress syndrome (ards) patients under vv ecmo according to their cannula configurations, especially in the national environment of the absence of newly developed double-lumen, single cannula. introduction: vv-ecmo is most commonly used in severe potentially reversible respiratory failure. this report looks at two patients in whom vv-ecmo was used to facilitate surgical airway stenting. methods: case -a -year-old with recurrent respiratory arrests, on a background of neurofibromatosis type and kyphoscoliosis. he had complex airway pathology, including, airway neurofibromas and granulation tissue, tracheobronchomalacia, severe kyphoscoliosis and a permanent tracheostomy tube. rigid bronchoscopy was performed and following debridement of granulation tissue, a trouser-leg stent was deployed. case -a -year-old with progressive stridor due to recurrence of a malignant melanoma, which was causing mid-lower tracheal compression. three tracheal stents were deployed via a rigid bronchoscope. in both cases, percutaneous bi-femoral vv-ecmo was established prior to general anaesthesia and decannulation took place the following day. results: in these cases, vv-ecmo provided stable extracorporeal gas exchange without conventional tracheal intubation. cardiopulmonary bypass and veno-arterial ecmo have been described in patients at risk of compression of the heart and distal airway [ ] . however, if the major threat is airway collapse, vv-ecmo can provide cardio-respiratory support without the problems associated with arterial cannulation and with lower anticoagulation requirements. introduction: ecco r facilitates the use of low tidal volumes during protective or ultraprotective mechanical ventilation when managing patients with acute respiratory distress syndrome (ards); however, the rate of ecco r required to avoid hypercapnia remains unclear. methods: we determined ecco r requirements to maintain arterial partial pressure of carbon dioxide or co (paco ) at clinically desirable levels in ventilated ards patients using a six-compartment mathematical model of co and oxygen (o ) biochemistry [ ] and whole-body transport [ ] with the addition of an ecco r device for extracorporeal veno-venous removal of co . the model assumes steady state conditions and is comprehensive from both biochemical and physiological perspectives. o consumption and co production rates were assumed proportional to predicted body weight (pbw) and adjusted to achieve pao and paco levels at a tidal volume of . ml/(kg of pbw) as reported in lung safe [ ] . clinically desirable paco levels during mechanical ventilation were targeted at mm hg for a ventilation frequency of . /min as previously reported [ ] . results: model simulated paco levels without and with an ecco r device at various tidal volumes are tabulated in tables and , respectively. table shows a substantial increase in paco at a tidal volume of ml/(kg of pbw) that is more pronounced when further reducing the tidal volume. additional simulations showed that predicted ecco r rates were significantly influenced by ventilation frequency. conclusions: the current mathematical model predicts that ecco r rates that achieve clinically acceptable paco levels at tidal volumes of - ml/(kg of pbw) can likely be achieved with current technologies; achieving such paco levels with ultraprotective tidal volumes of - ml/(kg of pbw) may be challenging. figure a ). pulmonary infections for each subtype of immunosuppression are shown in figure b . conclusions: ards vv-ecmo patients with underlying immunosuppression have higher mortality rates and higher rates of ecmo weaning failure. immunosuppressed patients suffer from a different spectrum of pulmonary infections in comparison to not immunosuppressed patients. introduction: acute asthma attack in children is a life-threatening emergency that requires urgent medical intervention. in the present study, we aim to clarify the effect of non-invasive ventilation (niv) on the heart rate (hr), respiratory rate (rr), and fraction of inspired oxygen (fio ) in children with acute severe asthma (asa) who failed to respond to standard medical treatment; and to evaluate the associated complications and length of stay (los) at the pediatric intensive care unit (picu). methods: this is a retrospective descriptive study of prospectively collected data. it was carried at the picu of a tertiary university hospital, saudi arabia. the study included children ≤ years old with asa admitted to the picu from november to november and required niv. outcome measures include the effect of niv on the hr, rr, fio , and los. the study included children with asa and ( %) of them required niv. of those patients, ( %) were excluded due to incomplete data, and ( %) patients were included in the final analysis. they were ( %) male and ( %) female with a mean age of months and a median pediatric index of mortality (pim ) score of . %. of them, ( %) had moderate asthma scores (≥ - ) and ( %) had severe asthma scores (≥ ). the median duration of niv was hours and the median los in the picu was three days. at hours, only rr showed a significant decrease compared to initiation of niv (p-value < . ) (fig ) ; while hr, rr, and fio were significantly improved at hours from initiation of niv (p-value < . ) (fig ) . conclusions: non-invasive ventilation, in association with standard medical treatment, was associated with clinical improvement in children with asa not responding to standard medical treatment alone. niv was not associated with significant complications or side effects. neurally adjusted ventilatory assist (nava) is a partial support ventilatory mode which triggers and tailors the level of assistance delivered by the ventilator to the electrical activity of the diaphragm. the objective of this study was to compare nava and pressure support ventilation (psv) in patients who were difficult to wean. methods: a total of difficult-to-wean patients who were able to sustained psv in the critical care medicine unit (icu) of the zhongda hospital, southeast university were enrolled in the study (fig ) . patients were classified according to the reason for weaning failure and were randomly assigned to receive nava or psv during weaning ( table ). the primary outcome was the duration of weaning. secondary outcomes included the proportion of successful weaning and patient-ventilator asynchrony. results: there were % ( / ) and % ( / ) patients in the psv and in the nava group never weaned from mechanical ventilation (p = . ). the duration of weaning was significantly shorter in the nava group [ . ( . - . ) days], than in that in the psv group [ . ( . - . ) days] (p = . ). the proportion of patients with successful weaning was % (n= / ) in nava group which was much higher than that in psv group ( %, n= / ) ( table ) . compared with psv, nava improved the rate of successful weaning in patients with single reason ( % vs. %, p = . ) but not in patients with multiple reasons for difficult weaning ( % vs. %, p = . ). nava decreased ineffective efforts and improved the trigger and cycling-off delays when compared with psv. mortality was similar in the two groups (fig ) . in patients who were difficult to wean, nava decreased duration of weaning and increased the probability of successful weaning. nava which improved patient-ventilator asynchrony, is safe, feasible and effective over a prolonged period of time during weaning. conclusions: only mrc score is independently associated with sbt failure and difficult or prolonged weaning. hgs is also associated with these two outcomes related to mv weaning and may serve as a simple tool to identify icuamw. introduction: there is evidence to support that in patients with hypoxemic respiratory failure (ahrf) under non invasive ventilation (niv), high tidal volume (tv) and high respiratory rate (rr) are associated with niv failure and possibly poor prognosis. we postulated that high minute ventilation (mv); or tv x rr; is associated with mortality in ahrf, when niv is initiated. methods: single-center, prospective and observational study. we included consecutives ahrf adults requiring niv. ahrf was defined as acute dyspnea with new pulmonary infiltrates on chest radiography and paco below or equal to mmhg. we registered demographic and clinical parameters (including rr, mv, arterial blood gases, heart rate and blood pressure) at baseline and after hours of first session of niv, apache ii score, diagnosis, need for intubation and icu mortality. we performed a multivariate analysis to assess independent factors associated with mortality and roc . ) and (auc = . ; p = . ), respectively for mortality, future exacerbations and readmissions. the optimal cut-off point for the mwt ratio to predict mortality was . and to predict future exacerbations and readmissions was . . the mwt ratio performed at icu discharge reveals interesting discriminative properties to predict early mortality, future exacerbations and readmissions in ae/copd patients. diffuse alveolar haemorrhage in an intensive care unit -search and you will find m matias , e ribeiro , j baptista , p martins introduction: the incidence of diaphragmatic ruptures after thoracoabdominal traumas is . - % [ ] and up to % diaphragmatic hernias present late [ ] when there is a complication. we report two cases of delayed traumatic diaphragm rupture to highlight the diagnostic difficulties. methods: case (image ) presented left diaphragmatic hernia containing the stomach, spleen, bowel and pancreas. the patient reported a motor vehicle accident dating months. he had thoracoabdominal trauma with several broken ribs on the left side. he then reported occasional pain in his left shoulder and occasional dyspnoea. case (image ) showed right diaphragmatic hernia containing right hemicolon, right hepatic lobe and gallbladder, he reported occasional dyspnoea and recent right chest pain. he had a years car accident in which three ribs broke on the right side. results: almost % of the patients with delayed diaphragmatic rupture presented with complications between and months after trauma, singh [ ] reported a diaphragmatic rupture presenting years after the traumatic event. the physical examination is often not helpful. conclusions: those cases emphasizes on the delayed presentation, patients may be asymptomatic or produce only mild, nonspecific symptoms, such as vague abdominal pain, chest pain or recurrent dyspnoea for months or years. the best tool to guide the clinician toward the appropriate diagnosis is a high index of suspicion whenever there is a history of high velocity trauma, regardless of how remote. factors associated with asynchronies in pressure support ventilation (psv), a bench study introduction: critically ill patients frequently have increased risk of ocular surface disorders (osds) due to poor eyelid closure and reduced tear production due to sedation during mechanical ventilation. we conducted a study to look at the incidence of osds in our icu with the current eye care practices and the impact of a protocolised eye care on the incidence and outcome and to determine the correlation of risk factors with the incidence of osds methods: this study was done in our mixed medical surgical icu. it had a prospective cohort design and was done as before and after study in two phases (phase i and phase ii). in phase i existing eye care practices were continued. in phase ii protocolised eye care was implemented and incidence of osds was noted in both phases. introduction: both fentanyl and morphine are known as opioid analgesics, which blocks the brain from receiving pain signals, the route of administration and the adverse effects affect their use. we compare the efficacy of intranasal fentanyl versus intravenous morphine adults population presenting to an emergency department (ed) with acute post traumatic severe pain. methods: we conducted a prospective, randomized, double-blind, placebo-controlled, clinical trial in a tertiary emergency department between october and june . adults with severe post traumatic was included to receive either active intravenous morphine ( mg immediately and then mg every min if persistence of severe pain maximum mg) and intranasal placebo or active intranasal concentrated fentanyl ( μ g /kg maximum μ g) and intravenous placebo. exclusion criteria: significant head injury, allergy to opiates, nasal blockage, or inability to perform pain scoring, pain scores were rated by using a digital scale at , , , and minutes. routine clinical observations and adverse events were recorded. conclusions: iscs were related to k over-use in our bicu. burnt patients are at risk of hepatic injury [ ] , but k related hepatic injury likely occurred. its not clearly understood mechanisms may involve a cumulative dose effect. although involvement of concomitant medications is being investigated, k restriction policy seemed to contain hepatic disorders. introduction: in november , our institution switched from using alfentanil to fentanyl for analgesia and sedation in adult patients receiving ecmo. there is no published evidence comparing the clinical use of alfentanil vs fentanyl for sedation in ecmo patients, although some reported increased fentanyl sequestration into the circuit [ ] . for these reasons, we conducted a retrospective observational study to explore whether there were any significant differences in patient outcome or adjunctive sedation before and after the switch. methods: outcome data and total daily doses of alfentanil or fentanyl as well as adjunctive sedation/analgesia for each patient where obtained from our clinical information system (philips icca®). data was included from ecmo patients who were sedated with alfentanil or fentanyl from / / to / / until ecmo decannulation. patients not requiring either opiate or who were switched between the two during ecmo therapy were excluded. all medicines prescribed for the management of sedation or agitation were included. for each patient an average total daily dose of each drug, was calculated. data was analysed using stata®. results: both groups were found to be statistically equivalent for mode of ecmo, age, apache score and charlson score (p= . ) except for bmi (p= . ). no difference in patient outcomes were found between groups (table ) . patients in the alfentanil group were found to have received significantly higher median average total daily dose of quetiapine and midazolam (table ) . conclusions: no differences in patient outcomes were found between patients sedated with alfentanil compared to fentanyl. we introduction: the european society of intensive care medicine consensus statement recommends that for comatose survivors of cardiac arrest hours without sedation is the minimum acceptable before neurological assessment. they highlighted the need to investigate the pharmacokinetics of opioid drugs in post-cardiac arrest patients, especially those treated with controlled temperature [ ] . methods: following approval by research ethics committee, we measured the blood concentration of fentanyl in post-cardiac arrest patients treated with ttm following cessation of continuous infusion. the fentanyl was discontinued when the patients were rewarmed to a temperature of . degrees celsius and a blood sample taken hours later. the blood was analysed using a commercial elisa kit (neogen corporation). using the total dose of fentanyl administered, the half-life of fentanyl was calculated for each patient. patient physiological data, cyp a and abcb polymorphism and drug history were compared with half-life. results: the median fentanyl concentration at hours was . mcg/l with a very wide range ( . - . mcg/l). the results for calculated half lives are shown in figure . there was no correlation between fentanyl level and bmi, illness severity (saps ll), creatinine clearance, transaminase or lactate level. there was no correlation between co-administration of drugs of metabolised by the cyp a and abcb enzyme systems or genotype. conclusions: there is marked variation in the concentration of fentanyl at hours in patients managed with ttm following cessation of fentanyl infusion. the calculated clearance of fentanyl in some patients is greater than hours and a hour cut off is not safe. introduction: objective of this study was to compare the effects of three analgesic regimens, one opioid and two multimodal ones, on cardiovascular stability and pain intensity in patients undergoing elective surgery under general endotracheal anesthesia during the h postoperative period. methods: sixty elderly patients, asa ii, undergoing elective knee sugary were assigned to receive ) morphine or mg iv q h, depending on body weight, and paracetamol g iv q h (mp group), or multimodal nerve block: ) femoral nerve block, single shot (fnb group) or ) fascia iliaca compartment nerve block single shot (ficnb group). measurement of pain intensity was performed with numerical introduction: opioids are frequently used in the intensive care unit (icu) to relieve pain and facilitate tolerance of life-support technologies. when discontinued abruptly, patients may develop a cluster of symptoms known as opioid-associated iatrogenic withdrawal syndrome (oiws). this phenomenon is poorly described in critically ill adults although it is associated with unfavourable outcomes, such as prolonged icu stay. the objective of this study was to describe the signs and symptoms of oiws in adult icu patients. methods: a prospective observational study was conducted in two tertiary care centres in patients requiring mechanical ventilation and regular opioids for more than hours. after an opioid dose reduction of at least %, patients were assessed daily for signs and symptoms of withdrawal using a standardized form. concomitantly, the presence of oiws was assessed daily by a physician using modified dsm- criteria. all physician evaluations were blinded and performed independently. inter-rater reliability for dsm- evaluations was assessed with the kappa coefficient. results: a total of patients were screened and twenty-nine enrolled. the majority were male ( . %) with a median age of . the median apache ii score was . withdrawal occurred in . % of patient within a median of three days (iqr to days) from opioid weaning. according to investigator assessment, restlessness, agitation, anxiety, hallucinations, insomnia/sleep disturbance, mydriasis and elevated blood pressure were more prevalent in oiws-positive patients. dsm- evaluations identified dysphoric mood, muscle aches, lacrimation/rhinorrhea, pupillary dilation/piloerection/sweating, diarrhea and yawning more frequently in oiws-positive patients. the kappa coefficient showed good agreement ( . ). conclusions: oiws in critically ill adults presents with a large spectrum of signs and symptoms that occur within a median of three days from onset of opioid weaning. further studies are needed to confirm these preliminary findings. withdrawal reactions after discontinuation or rate reduction of fentanyl infusion in ventilated critically ill adults s taesotikul introduction: propofol is a well-known sedative, commonly used in intensive care units (icu s), that on rare occasions has been reported to cause green urine and has also been associated with pink or transient white urine discoloration. it can cause several adverse effects, such as low blood pressure, pain on injection, apnea, hypertriglyceridemia and when administered in high doses it may lead to the "propofol infusion syndrome". methods: we present two examples of interesting urine discolorations observed unexpectedly in our icu in patients under propofol sedation requiring mechanical ventilation. results: dark green urine discoloration as presented in fig. is the result of a phenolic metabolite of propofol that is produced in the liver and is subsequently excreted in the urine, thus changing its color. it is considered a reversible phenomenon that resolves after propofol discontinuation.respectively, pink urine discoloration as presented in fig. can also be the result of propofol infusion. the increase in urine excretion of uric acid caused by propofol, in combination with a low urinary ph can lead to the formation of uric acid crystals and turn the urine pink. discontinuation of propofol and urine alkalization can reverse the phenomenon. conclusions: green or pink urine discoloration due to propofol is generally a benign, reversible condition. its presence should not compel the physician in charge to perform unnecessary testing, although other causes of discoloration should be considered. as far as green urine discoloration is concerned, other factors such as drugs, dyes, certain nutritional supplements or even a pseudomonas urinary tract infection may be at fault. on the other hand, pink urine syndrome due to propofol infusion seems to be even rarer. although its presentation is not alarming, it may well increase the risk of uric acid lithiasis, a fact that the physician in charge should always keep in mind. conclusions: hepatic changes related to propofol are frequently observed and should be systematically monitored to ensure patient safety. fig. (abstract p ) . dark green urine discoloration introduction: clevidipine (clev) and propofol (prop) are lipid-based medications used in the intensive care unit (icu) for hypertension and sedation, respectively. no data exists regarding potential adverse effects of concurrent therapy with this combination. this study aims to evaluate the incidence of hypertriglyceridemia (htg) and pancreatitis in icu patients using concurrent clev and prop. methods: this was a single-center, retrospective chart review in patients utilizing clev and prop concurrently from february to november . patients were included if they were years and older, on clev and prop concurrently for at least hours with no more than hours of interruption at a time, had at least one triglyceride (tg) level during concurrent therapy, and admitted to the medical or surgical icu. the incidence of htg (defined as tg equal to or greater than mg/dl) and pancreatitis (provider assessment based on american college of gastroenterology guidelines) was evaluated. patients with and without htg were compared to identify risk factors for the development of htg. results: of patients screened, patients were included which comprised observations. the incidence of htg was . % with no patients developing pancreatitis. patients with htg had a higher median age compared to without htg ( . vs. ), p= . . in patients with htg the median dose of clev and prop were mg/h and . mcg/kg/min, respectively, which was higher but not statistically significant when compared to patients without htg. cumulative lipid load (g/kg/d) was non-significantly higher in patients with htg ( . vs. . ), p= . . conclusions: the incidence of htg was comparable to what is cited in literature for prop alone. patients with htg were older, had higher median clev and prop doses, and a larger cumulative lipid load compared to patients without htg. introduction: the society of critical care medicine guidelines for pain, agitation and delirium suggested use of nonbenzodiazepine sedatives like dexmedetomidine which is associated with a reduced duration of mechanical ventilation, shorter length of hospital stay and a lower incidence of delirium [ ] . enteral clonidine represents a potentially less costly alternative for agitated patients with prolonged dexmedetomidine infusion. limited literature exists examining this transition for management of agitation [ ] . methods: the critical care management initiated an action plan on the transition of patients with prolonged dexmedetomidine infusion to oral clonidine. a protocol was prepared with clinical pharmacist's assistance. risk factors were assessed and inclusion criteria were applied as per protocol. dexmedetomidine infusion rate was reduced gradually with oral clonidine administration in selected patients. other rescue managements were implemented as per protocol. oral clonidine was then tapered down by reducing frequency of administration over few days. results: post intervention data in showed significant decrease of dispensed doses and cost of the injections compared to . the annual cost saving was % equating to , usd (table , figure ). conclusions: transitioning to clonidine may be safe and less costly method of managing agitated critically ill patients on prolonged dexmedetomidine infusion. more studies are needed to evaluate the efficacy and safety of this practice. incidence of dexmedetomidine associated fever at a level trauma center na beaupre, jt jancik hennepin county medical center, pharmacy department, minneapolis, united states critical care , (suppl ):p introduction: we evaluated the incidence of dexmedetomidine associated fever (daf) in a level trauma center's medical intensive care unit (micu). hypotension and bradycardia are the most commonly reported adverse effects associated with dexmedetomidine (dex) infusion. case reports suggest dex can cause fevers and the clinical trials that led to the approval of dex demonstrated fever rate to be - % [ ] . methods: this was a single-center, retrospective chart review of patients admitted to the micu at hennepin county medical center between march and july of that were started on a dex infusion. patients were included if they were years and older, on a dex infusion for at least hours, and had temperature data available. fever was defined as > . c and other causes of fever including infections, medications, withdrawal, recent surgery, thromboembolic disease, thyroid disorders and seizures were excluded from analysis. results: of the patients screened, were included. the mean age was years and . % were males. of all the patients included, the mean change in temperature after initiation of dex infusion was + . c from baseline. the mean initial dose was . mcg/kg/hr. four of patients ( . %) had a daf. of those that had a daf, the median initial dose was . mcg/kg/hr; the median time of infusion was . hours; and the median cumulative dose was . mcg/kg/hr. the median time to fever after initiation of dex was hours, with a range of to hours. the median time to fever cessation after discontinuation of dex was hours. conclusions: in our population, the incidence of dexmedetomidine associated fever was relatively rare at . % and similar to current literature rates. the results obtained showed a statistically significant fact that fewer points on the test, from to points, received older patients who underwent an urgent surgical procedure, over years of age, of which % . also statistically significant data were obtained that patients who used a higher amount of sedatives during emergency surgery, % had a worse test result than under points due to increased preoperative anxiety. the older population is more susceptible to postoperative delirium, especially in emergency surgery situations, which they carry, unpreparedness for surgery, increased use of medication for fig. (abstract p ) . flowchart of enrolled patients calm, unpredictability of the duration of surgery, and therefore anesthesia as well the use of anticholinergics, which is sometimes impossible to avoid in operative procedures such as gall bladder surgery. the results of the study suggest that in cases of emergency surgery, the use of protocols for postoperative delirium should be planned regularly to prevent or at least mitigate the clinical picture of delirium that can lead to complications postoperatively. introduction: delirium is a serious and often underestimated condition with implications for morbidity, mortality and healthcare costs. as it presents in a wide range of settings from admission to discharge, early prediction and risk assessment are essential. e-pre-deliric is a delirium prediction score which has been validated in itu patients but not in other populations, and we conducted a quality improvement project using this score to assess its utility in other settings. methods: data was gathered from three patient categories: those undergoing elective surgery (es), admissions to the emergency observation unit (eou) in the a&e, and patients with fractured neck of femur (nof). clinical notes were reviewed to collect data to calculate e-pre-deliric score at admission, along with a number of other clinical variables including incidence of delirium, and statistical analysis performed. results: a total of patients were included, with in the es group, in the eou group, and in the nof group respectively, with an overall average e-pre-deliric score of . %. es had a . % average e-pre-deliric score, a mean age of and no cases of delirium. the eou group had an average age of , a . % average e-pre-deliric score and no incidence of delirium. the nof group had a mean age of and an average e-pre-deliric score calculated on admission of . %. this was the only group in which patients developed delirium. a % cut off was demonstrated to be the most accurate to predict delirium in this population with a sensitivity of . and a specificity of . . conclusions: despite the limitation of a small sample size, this project has shown that e-pre-deliric score could be a useful tool to predict patients at high risk of delirium in a non-itu setting, with a % cut off in hip fracture patients. further investigation should be conducted into the potential use of e-pre-deliric in non-itu patients. comparison of long-term mortality between patients with and without delirium during admission in medical intensive care units in a university hospital n kongpolprom king chulalongkorn memorial hospital, pulmonary unit, bangkok, thailand critical care , (suppl ):p that delirium is linked with preoperatory comorbidities. the complexity of surgery has a big influence on the development of delirium, especially in the cases of aortic dissection. delirium was associated with intraoperatory blood transfusions. finally, our data point to a bridge between postoperatory electrolytic disturbances, as well as inflammation as factors potentially triggering delirium onset. introduction: we did a retrospective case note study of mortality due to sepsis of our unit over three months as observational study in which we noted the causes of deaths, origin of sepsis, organism, patient characteristics and icnarc physiology scores and icnarc h model predicted risk of acute hospital mortality percentage. methods: icnarc data base was used to gather the data and coding was used to identify the patients with sepsis for three months. patients mortality attributed to sepsis were identified from mortality list.causes of death were noted from patients notes and death certificates.cyber lab was used to access the data and case note were ordered for review.patients characteristics were noted including dnacpr orders and treatment withdrawal orders. scores (apache scores, icnarc physiology scores, icnarc h predicted risk models of acute hospital mortality percentage) were noted. results: mortality percentage was found to be % as per codig which was reduced to % as % deaths were attributed to other causes. % patient had dnacpr in first hrs. average length of stay was . days with median of . days.median age was yrs in surviving age group and years in other. icnarc physiology score with predicted risk of . %. commonest cause was found pneumonia % followed by urine tract infection. % patients were with no source identification. conclusions: conclusion was made that we do need to improve the coding as significant percentage was mentioned as sepsis as cause of death where clinicians differed. pneumonia was found to be the commonest killer in critical care followed by urine tract infection. it was pointed to be useful to carry out further audit targeting pneumonia .review of icnarc case mix program, development of icnarc physiology score, which provides excellent local use with downside of lacking international comparison was done also. introduction: hospitals vary widely in the quality of care they provide for septic patients. since many septic patients present to their nearest hospital, local variations in care quality may lead to geographic disparities in access to optimal sepsis care. we sought to better understand geographic access to high quality sepsis care, taking advantage of publicly reported data on sepsis management and outcomes in a large us state. methods: we performed a cross-sectional analysis of geographic access to high quality sepsis care, taking advantage of a new york state initiative that mandates public reporting of sepsis quality data to the state government. we linked these data to the locations of hospitals in new york state from the us centers for medicare and medicaid services and population data from the us census bureau for . we defined hospital sepsis performance using self-reported risk-adjusted mortality rates (ramr) and defined high-performing hospitals as those with a ramr < %, which represents the lower end of short-term mortality typically observed in sepsis. we used arcgis to generate drive-time estimates and assess population access to high performing acute care hospitals for sepsis care. results: hospitals publicly reported treating , cases of sepsis from a population of , , persons. overall access to an acute care hospital was excellent at the -minute drive threshold ( . %), good at the -minute threshold ( . %), and marginal at the -minute threshold ( . %). we classified hospitals ( . %) as high-performing based on a ramr < %. high-performing hospitals reported , ( . %) of the total sepsis cases. high-performing hospitals were geographically dispersed across the state, although population access diminished substantially with increasing drive times ( . % at -minutes, . % at -minutes, and . % at minutes; figure ). conclusions: one in six people do not have timely access to a high performing hospital for sepsis care using a -minute threshold. [ ] . this poses a significant safety risk. a previous study found that the implementation of a multidisciplinary medication safety group in intensive care increased reporting of errors and near misses [ ] . the purpose of our work was to set up a multidisciplinary group to provide a forum to review and improve medication safety at all stages of the process. here we discuss some of the initiatives and outcomes implemented in the last months. methods: ccmsg was formed in , under the leadership of the critical care pharmacy team, with representation from medical and nursing disciplines. the group meet fortnightly to analyse trends in medication errors, implement changes to local practice and review outcomes to improve patient safety. the cohesive, multidisciplinary nature of the group allows medication safety initiatives to be delivered in the most effective way. results: on average, ccmsg reviewed medication errors per month. the most common high risk drug classes involved are seen in table . medication safety initiatives implemented were based on these trends and included writing guidelines and policies, bedside education, teaching and training, informatics optimisation and operational changes. examples are seen in table . conclusions: initiation of a ccmsg provides a cohesive approach to facilitate the implementation of targeted safety initiatives, which are proven to reduce some of the most common medication errors in critical care. in addition, these often result in optimisation of operational and financial inefficiencies. introduction: cis/hospital electronic medical records downtime can cause major disruptions to workflow, patient care, key communication and information continuity [ ] . here we describe the consequences of deploying a business continuity plan (bcp) designed to support a critical care clinical informatics system (cis) failure, during an -hour unplanned downtime in a large central london icu. the institutional bcp was developed through an iterative process based on cis provider recommendations and internal workflow knowledge. it consisted of a web offline chart (woc) that is accessible at every computer connected to the network (in the event of a cis server fault), and via hard copy from designated back up computers connected to a printer (in the event of whole network loss). operational and clinical consequences were recorded during informal and formal debrief of the informatics team. the decision making around´drop-to-paper´was reviewed. -the bcp permitted´drop-to-paper´, service continuity and controlled uptime -patchy network loss and lack of a general institutional bcp delayed initial system failure diagnosis (network vs primary server); reduced reliability of´read-only´data and delayedd rop-to-paper-day-to-night handover during downtime led to loss ofḿ emory´of key patient data/events, and should have accelerated decision to´drop-to-paper-transfer of prescriptions was time consuming, distracting (occupied cis team) and prone to error conclusions: previous end-to-end testing of the bcp had not identified many of the observations and recommendations that came from the analysis of an actual period of unplanned downtime. we recommend sharing of similar experiences and scheduled high-fidelity simulated downtime in other institutions to replicate real world conditions, particularly in a critical care setting. . ) were predictors of icu transfer. we developed a simple score to predicting icu transfer from previous variables and performed analysis of auc of roc, which was compared to that of apa-che ii. the result showed the auc of roc of a new score was slightly higher than the apache ii, namely . vs. . respectively. conclusions: the immunocompromised patients take two times higher risk than the immunocompetent ones regarding icu transfer. the other risk factors are lower gcs, lower sbp, and higher rr. a newly developed score may be a promising tool for predicting and triaging site of care in patients who require imcu admission. introduction: this research aims to explore the role of situation awareness in the decision-making of patient discharge from the intensive care unit (icu). the discharge of these patients is a complex and, moreover, a challenging transition of care. readmissions are undesirable given the association with a more extended hospital stay and a possible chance of higher mortality. little is known on how the decision-making process takes place and accordingly, the role of situation awareness of patient discharge from the icu. in order to improve the quality of care of patient discharge from the icu, further research is necessary. methods: this research concerns a qualitative study in which various health care providers, working in an icu adults of a large teaching hospital, were interviewed. through purposive sampling, six nurses, two physician assistants, two intensivists and a physiotherapist were included. on the obtained data a thematic analysis was applied, based on the principles of the grounded theory. results: the discharge decision of icu patients seems mainly based on the team´s situation awareness, with the initiating role of the intensivist and the guiding role of the nurse. furthermore, there is an additional role for the physician-assistant and a consultative role for physiotherapy in the process of the decisionmaking. worries of patients and family seem not to affect the decision-making directly. in the decision-making process, the well-being of the patients and the possibility to provide the most suitable and best possible care were central. organizational factors, such as an urgent demand for icu beds do count but seem not to push the decision to transfer patients from the icu to the regular hospital ward. conclusions: the decision to dismiss icu patients is a complex process with different disciplines and a variety of factors involved. obtained knowledge and insights into the role of situation awareness provide starting points for improving the quality of the discharge process of icu patients. conclusions: despite the fact that older people was more severe illnes, and similar frequency of respiratory failure, the use of mechanical ventilation, the use of central venous catheter and arterial catheter was less frequent. the addition of a simulation fellow within the intensive care team and introduction of in situ simulation n bhalla, d hepburn, g phillips royal gwent hospital, intensive care unit, newport, united kingdom critical care , (suppl ):p introduction: traditionally, simulation based medical education has been carried out in off site simulation centres, however, we trialled the addition of a simulation fellow, within our intensive care team, to run an in situ simulation (iss) program on our intensive care unit over a month period. methods: our multi-disciplinary iss program, led by a simulation fellow, incorporated participants, observers and facilitators including doctors (junior trainees up to consultants of varying medical specialties), nursing staff, healthcare support workers, operating department practitioners, physiotherapists and medical students. we ran simulated emergency scenarios and technical skills sessions. with every scenario, we collected data on participant and observer feedback using the world health organisation participant feedback form and conducted a satisfaction survey at the end of our trial period. results: our results, highlighted in table , show participants found iss led by a simulation fellow realistic, well structured and organised. it was useful for testing and understanding our response systems, fig. (abstract p ) . patient journey of group : those patients discharged home days after step down from critical care identifying strengths and gaps and establishing individual roles/functions within emergencies; overall leaving us feeling better prepared for critical care emergencies. from our satisfaction survey, % of participants found the simulation fellow a useful addition to the intensive care team and expressed the need for more in situ simulation. conclusions: the addition of a simulation fellow allowed for numerous disciplines within the critical care team to be involved in challenging emergency scenarios (fig , ) , with the additional realism of being on the intensive care unit playing the role they would in real life; as well as having opportunity for spontaneous discussion and learning. from this they reported great benefit and satisfaction. following our initial success with this program, we plan to have a simulation fellow as an ongoing role within our critical care team. impact of multidisciplinary team in readmission in a brazilian cardiac intensive care unit c bosso , p introduction: the aim of this study is to determine the importance of the multidisciplinary team at readmission rates in a cardiac intensive care unit (cicu). methods: retrospective study with analysis of patients in a cicu of a medium size brazilian hospital. the years of and represent the reduced team (physician, nurse and physiotherapist) and and the complete multidisciplinary team (additional presence of phonoaudiologist, psychologist, pharmacist, dentist and nutritional professional). the risk of mortality was determined by saps score. in order to compare the teams, it was utilized odd ratio of a logistical sample to the discrete data, and t-student test to the continuous data. the data analysis was executed from the software rstudio ( . . ), and the significance level adopted was %. results: the number of patients was of n= ( from the reduced team and from the multidisciplinary team). the age, sex and bmi didn`t present significant difference between groups. the average age of the sample was ± years old (p= . ). the male sex represented % (p= . ), and the bmi was around . ± . (p= . ). the main diagnoses were similar in both groups -coronary angiography with stent ( %), unstable angina and non st elevation myocardial infarction ( %). table shows the average, standard deviation, p-value to t-student test to saps score and lengh of stay (days), according to both reduced and multidisciplinary teams. table exposes the mortality rate and readmission for both teams. the figure shows the odds ratio and its ic % to the comparison of the mortality, readmission, hours readmission and hours readmission rates between the teams. conclusions: the multidisciplinary team performance reduced the number of hospital readmissions in and hours in a cicu. methods: during the initial audit hours' worth of waste from one itu bed was manually divided into the categories above. results: based on these figures it was estimated that a saving of £ per year would be made (£ . per bed space) over the course of a year should domestic waste bins be placed across the bed icu/hdu. a business case was made, and every bay had a domestic waste bin installed with poster signs for explanation.the reaudit in which all domestic waste across the unit was weighed produced an even greater figure of a saving of £ per bed space (£ ) per year. conclusions: introducing a domestic waste bin may save approximately £ per year per bed. in a typical itu such as lewisham ( itu beds/ hdu beds) that may mean a saving of £ per year (with % capacity). there are also environmental benefits, burning of plastics releases harmful dioxins. the authors wish to make intensive care units and indeed all areas of the hospital aware of the cost and environmental impact associated with disposing of waste in incorrect categories. we hope that our quality improvement project demonstrates how easily money may be saved and environmental footprint reduced. association between resilience and level of experience in intensive care doctors in india j gopaldas, a siyal manipal hospital, bangalore, critical care medicine, bangalore, india critical care , (suppl ):p introduction: attrition of doctors in intensive care unit (icu) is one of the highest amongst all medical specialities globally, and is strongly associated with stress and burn out syndrome (bos). factors that contribute to bos are low pre-morbid resilience and low level of icu experience. studies from india have shown high levels of stress in intensive care doctors (> %), but there are no published studies measuring pre-morbid resilience and risk of burnout in relation to years of experience amongst icu doctors. our main aim was to measure cross sectional resilience levels in icu doctors compared between those with less than years of experience to those with years or more. a secondary aim was to assess the impact of other factors that may contribute to low scores. methods: an anonymised survey was conducted involving doctors in icus across different states in india, using the connor-davidson resilience scale (cd-risc ), which is validated in indian population. results: a statistically significant correlation was found between low levels of resilience in icu doctors with under years of experience . ) , and the significance level adopted was %. a logistic regression model was used to test the difference between the mortality and readmission rates in < and ≥ groups, which enabled the calculation of odds ratios. chi-square test was used to evaluate categorical variables and t-student test to some quantitative variables. the roc curve was constructed to verify the sensitivity of prediction of mortality through different saps scores. results: among the < and ≥ groups, respectively % and % was male (p = . ). mean weight of the> years was ± kg and < years was ± (p < . ). odds values indicated a significant difference only for the mortality rate, which was more than double among ≥ . readmissions in any time, h and h as well the mortality is shown in table and odds in figure . there was a significant difference in saps points between groups ( table ). the ≥ group presented an average of points higher on the severity scale when compared with those in the < group. there was no significant difference in lengh of stay. the highest amount provided by saps scores was % and a specificity of % for hospital mortality not group < years. in ≥ group the highest sensitivity was % and the specificity was %. roc curve for saps is shown in figure . conclusions: the extremely elderly patients of a cicu is more severe, with higher mortality and have the same lengh of stay and readmission rates. introduction: the purpose was to assess the prevalence and impact of non-urgent interruptions (nui) within critical care (cc).a root cause analysis of a never event in our cc discussed nui as a contributory factor, paralleled by learning from serious incidents.the negative impact of nui is well evidenced, resulting in delayed task completion, increased stress, and affecting patient safety. methods: any nui during a consultant ward round (cwr) or invasive procedure (ip), not relating directly to the current clinical episode, was included. qualitative data was collected by a survey, assessing the cc multidisciplinary teams(mdt) perception of nui. results: one third of reviews during the cwr, and %of ips, had a nui. adverse effects included prescription omissions, delayed cwr, near-miss with a cvc, and failed picc insertion. overall, % of staff considered nui a problem; % had experienced nui that led to distraction in train of thought. % felt that nui had led to an error: % of doctors, versus % of nurses. % overall felt nui contributed to stress at work. reasons for interruptions included: feeling overloaded, needing to resolve concerns before forgetting/being distracted, unable to prioritise, and to shift responsibility.lack of leadership or clinical supervision providing a point of contact for problems during shifts was mentioned as contributory. senior staff raised that whilst attempts have been made to level hierarchy, allowing a voice for all to express concerns contributes to interruptions. potential solutions included awareness on impact of nui, jobs book,´sterile cockpitd uring ips, and increased clinical supervision during shifts. conclusions: we have demonstrated the prevalence and consequences of nui within cc is significant.the impact on staff is significant, both for contribution to errors and also the negative impact on stress in the workplace. identified potential solution will be implemented. the impact of an education package on the knowledge, skills and self-rated confidence of medical and nursing staff managing airway & tracheostomy/laryngectomy emergencies in critical care l o´connor , k rimmer , c welsh methods: the factors affecting the delivery of intensive care was elucidated by a comprehensive review of the intensive care literature. a further understanding of intensive care delivery in south africa was obtained by "making sense of the mess" with eight workshops and interviews using a systems approach. systemic intervention served as the meta-methodology and methods and techniques from interactive planning, critical systems heuristics, soft systems methodology and the viable system model were employed. results: making sense of the mess emphasised the complexity of intensive care delivery, on both a situational and a cognitive level. it became clear that a single methodology would not suffice, but that a pluralist methodology was required to guide improvement in intensive care delivery. based on this understanding, nine principles were formulated to guide the development of a framework. systemic intervention was again used as the meta-methodology. interactive planning was identified as the key methodology, incorporating methods and techniques used in the making sense of the mess phase to build a systemic framework for the improvement of intensive care delivery. embedded in the proposed framework are matters relating to systemicity, complexity, flexibility, empowerment, and transformation of intensive care delivery. the proposed framework allows for multiple-perspectives, including that of marginalised stakeholders, the mitigation of multivested interests and power relationships (fig ) . it is both flexible and adaptable to promote learning about the complex problems of intensive care delivery and it accommodates the strengths of various relevant approaches to complex problem solving. conclusions: the proposed framework aims to facilitate sustainable improvement of intensive care delivery and to ensure the "just-use" of resources to foster distributive justice. the perioperative management of adult renal transplantation across the united kingdom: a survey of practice c morkane , j fabes , n banga , p berry , c kirwan introduction: there is a limited evidence base to guide perioperative management of patients undergoing renal transplantation and no national consensus in the uk. we developed an electronic survey to provide an overview of uk-wide renal transplant perioperative practice and determine the need for future guidelines on patient management. methods: a -question survey was developed to encompass the entire renal transplant perioperative pathway with input from clinicians with expertise from renal transplant surgery, anaesthesia, nephrology and intensive care. the survey was sent to lead renal anaesthetists at each of the transplant centres across the uk. results: twenty-two centres ( %) returned complete responses. there was limited evidence of guideline-based approaches to preoperative work-up, with marked variety in modality of preoperative cardiorespiratory function testing performed. questions regarding intraoperative fluid management (fig ) , blood pressure targets and vasopressor administration (fig ) identified a broad range of practice. of note, the routine use of goal-directed fluid therapy based on cardiac-output estimation was reported in six ( %) centres whilst nine centres ( %) continue to target a specific central venous pressure (cvp) intra-operatively. a dedicated renal ward was the most common postoperative destination for renal transplant recipients ( % of centres), whilst a renal or transplant-specific hdu provided postoperative care in ( %) centres. the need for care in an icu setting was decided on a case-by-case basis. conclusions: this questionnaire highlighted a high degree of heterogeneity in current uk practice as regards the perioperative management of renal transplant recipients. development of evidence-based national consensus guidelines to standardise the perioperative care of these patients is recommended. fig. (abstract p ) . framework for the improvement of intensive care delivery introduction: postoperative care of high risk patients in the icu used to be considered the gold standard of care in terms of reducing perioperative mortality [ ] . new evidence comes to question this practice [ ] . the primary objective of our study was to detect any benefit of postoperative icu care after elective surgery in terms of patient's outcome, length of hospital stay, complications and cost. methods: a -month retrospective analysis of high perioperative risk patients who were about to be subjected into an elective operation were included into the study. subsequently they were allocated into two groups. group i patients were those admitted into the icu for postoperative care while those admitted into the standard ward consisted group ii. demographic data, length of hospital stay, outcome, need of mechanical ventilation, complications and total cost were recorded. results: a total of patients were recorded, in each group. there was no statistical difference regarding the demographic data between the two study groups. seven patients died before hospital discharge ( in group i and in group ii, p> . ). there was no impact of icu admission on length of hospital stay (p= . ) which is primarily affected by the need of mechanical ventilation (p= . ) and reoperation (p< . ). the total cost and the postoperative cost of hospital care did not statistically differ among study groups. conclusions: according to our study the need of postoperative care of high risk patients in the icu is rather questionable in terms of perioperative mortality, length of hospital stay and cost of care. introduction: tivap is a preferred vascular access device for patients with solid tumors and radiological-guided insertion is a standard of care. however, many hospitals have no access to interventional radiology service. our study aimed to determine whether it is safe to place tivaps in icu for immediate administration of chemotherapy. methods: we analysed prospectively maintained database of our department and collected data for adult pts with tivaps implanted between / and / . the median age was (range - ) years, % were women. all procedures were performed by trained physicians with experience in ultrasound (us). puncture technique was used and tip location was controlled with electrocardiographic (ecg) and us with subsequent chest x-ray confirmation. pts were followed up for at least days after the procedure for complications, functioning of tivap and surgical wound healing. results: all tivaps were successfully implanted in pts. infraclavicular route was used in cases ( . %). difficulties with indwelling guide wire were observed in ( . %) pts but did not precluded implantation. placement complications included pneumothorax (n = ), catheter malposition (n = ) and artery bleeding (n = ). these complications required additional therapy but were managed successfully and resolved without consequences. in the rest cases internal jugular vein (jv) was used. complications were not observed. ecg and us navigation provided optimal tip location control in these situations. surgical wound healed after - days and chemotherapy initiation did not affect healing. all tivaps had adequate functioning days after placement. conclusions: it is feasible to implant tivaps in icu. these devices can be used on the implantation day without jeopardizing patient safety. jv catheterization seems to be optimal approach and us navigation and ecg are sufficient methods for placement control. introduction: there is increasing use of clinical information systems to improve patient safety and quality of care in critical care. with all these systems, a rigorous business continuity access (bca) plan needs to be in place so patient safety is not compromised [ ] and ensure continuity of care. here we evaluate the types of medication errors that occurred during a period of unscheduled downtime; potential contributory factors [ ] and the number of errors involving critical medicines [ ] were analysed. methods: during the unscheduled downtime, all prescribing and administration of medicines were transferred to a paper based system using the patients' web offline chart (woc -philips healthcare). pharmacists at the time double checked the paper charts that were transcribed, to mitigate errors but this was not consistent due to the timing of the event. we retrospectively compared the paper drug charts against the electronic prescriptions and noted all errors for patients. results: in total medication errors were identified & allergy omission ( table ) . pharmacists double checked % of the paper charts. conclusions: our data highlights the risks associated with unscheduled electronic patient management system downtime and the heterogeneity of the types of errors & potential contributory factors. it underscores the need for robust local bca plan implementation, critical review of the woc document and regular staff training around potential unscheduled system downtime. introduction: the transfer of patient care (toc) between the intensive care unit (icu) and hospital ward is associated with a high risk of medical errors [ ] .according to uk national data between - % of patients have an error or unintentional medication change made when moving between care settings [ ] . currently different prescribing systems without interoperability are used between icu areas & ward settings in our institution, resulting in medications needing to be re-prescribed on transfer. we aimed to evaluate the time delay in medication re-prescribing, number of unintentional omissions of drug doses and reasons, as well as percentage of critical medicines [ ] omitted in the first h following discharge. methods: over a month period, discharged patients ( % of all discharges) from two icu units were included. the icu discharge letter which contained the medication list on transfer was compared against the ward based electronic drug chart to identify all unintentional omitted medication doses during the first hours. the starting time point was when the patient physically left icu. results: / ( %) of patients had their medication prescribed more than hours post discharge. there were a total of / , ( %) unintentional omitted doses (table ) . of these / ( %) were considered critical medicines ( table ) . conclusions: this data confirms the risk associated with toc especially around medicines. the need of interoperable electronic prescribing systems is one solution and could improve patient safety by streamlining the process. introduction: staff perceptions of safety may contribute to workforce stress and be organisationally important [ ] . this study explored the feasibility of capturing perceptions of safety with a bedside professional reported (bpr) shift safety score, and explored relationships between bpr and measures of staffing and workload. methods: uk health research authority approval was obtained (id ). data were collected for consecutive days at imperial college healthcare trust ( general critical care beds on sites).the bpr asked all icu staff to rate each shift as "safe, unsafe, or very unsafe". responses were described and correlated with data on organisational staffing (care hours per patient day chppd) and nursing intensity (total number of organs in failure/ total number of nurses). results: a total of bpr scores were recorded (response rate %). we noted heterogenous responses between sites and days, and within shifts, only % of shifts were unanimously rated. whilst % of shifts were rated by staff as "unsafe" or "very unsafe", organisational metrics recorded only % as 'unsafe'. we did not find a correlation between measures of staffing (chppd) and perceptions of safety ( figure ). preliminary analyses suggest that staff perceptions of safety are not well correlated with nursing intensity (figure ), although these numbers commonly inform staffing metrics. conclusions: completing the bpr tool was feasible and acceptable to staff. responses showed variations in perceptions of safety and a gap between organisational metrics and individual perceptions. introduction: delivery of intensive care (icu) is complex because of multiple stakeholders with varied perspectives and conflicting goals that interact and are interdependent. to inform the development of a framework for the improvement of icu delivery in south africa, it was essential to first understand icu delivery or "make sense of the mess". a systemic approach such as systems thinking is required to holistically explore and understand the complexity of icu. no methodology is perfect and methodological pluralism as proposed by systemic intervention, a systems thinking approach, was used for a more flexible and responsive intervention. the methods used was the making sense of the mess phase of interactive planning, stakeholder analysis as describe by critical systems heuristics, rich pictures from soft systems thinking and viable systems model diagnosis. making sense of the mess was done in phases: first the mess was formulated with rich pictures generated in workshops and interviews. the discussions of the rich pictures by the respective stakeholders were transcribed and analysed using braun and clark's thematic analysis. secondly, based on the data generated from phase a diagnosis of the viability of the icu system was made. results: the data from the phases were very rich and complex and themes emerged (figure ). these themes were interdependent and resulted in disorganised icu delivery with limited opportunities for learning to improve icu delivery with dichotomies that existed at various levels of icu. it was a problem to present the complex data in the traditional linear manner due to the interdependence of the themes. the analysis is presented as stories, a known approach in the complexity discipline, where the themes of the analyses are portrayed. the making-sense-of-the-mess phase confirmed the complexity of icu delivery, at both a situational and a cognitive level and with this understanding a framework for the improvement of icu delivery could be developed. introduction: improving prescribing practice involves changing prescriber behaviour. education is assumed to change behaviour but other approaches may be more effective (figure ) [ ] . changes to the presentation of information and the configuration of choices have potential to rectify common prescribing errors through subtle 'nudges' [ ] . the implementation of clinical information systems (cis), including electronic prescribing, provides an opportunity to deploy strategies such as standard orders, dose limits, and product level prescribing. with an infinite number of configuration options available, clinical leaders need to know which interventions are most effective. we evaluated several of these strategies in a before and after observation study methods: interventions, utilising cis nudges, were chosen to improve four areas of prescribing practice in a tertiary critical care unit using methods matched to the top levels of the hierarchy. data were collected for months before and after interventions to map changes in compliance with a pre-defined standard except for the standardisation intervention where months' data were collected due to low prescription numbers. no education on changes was given during the baseline data collection so any change in performance after the go-live date is entirely attributable to the intervention. results: the change in performance for each level ranks the intervention levels in the order (highest first) forced function, automation and standardisation ( table ). the use of point of prescribing reminders was not associated with a significant difference in performance. conclusions: the effectiveness of intervention levels seen in practice is consistent with that of the model. further studies could be undertaken to strengthen these conclusions but in the meantime the approach to changing practice using cis nudges should focus on standardisation or above. introduction: intensive care unit (icu) sound pressure levels (spl) are persistently above world health organisation recommendations for clinical areas [ ] . this may impact patient recovery. standard spl monitoring records single values for each h period (laeq ). we hypothesise this reporting rate is unsuitable for icu. methods: we measured spl october -may , logging frequency (hz), spl (db), and loudness (perception of sound) every second [ ] . the resulting dataset was of a size that conventional statistics programs would require computational resources not easily obtainable on standard university commodity hardware. we processed the full dataset without sampling by using distributed task dispatching, parallelism and scheduling of a cluster computing framework (apache spark). we created a system consisting of a single workstation ( cores; gb ram) running ubuntu . lts, oracle java . , apache spark . , scala . , r core . , r studio . and sparklyr . . . we utilised the sparklyr library in r studio to run arbitrary r code using the dplyr library. we analysed aggregate data in r core & used ggplot (v ) to create visuals. results: we achieved more complex analysis than standard spl reporting with relatively modest computing resources. specifically we identified lower spl peaks in the early hours & loudness levels considerably higher than parallel spl. conclusions: simple laeq do not facilitate reflection on practice thus impetus for change is limited. loudness data highlight the patient experience of spl in the icu is more intrusive than laeq indicates due to high sensitivity to sounds~ - khz, a common frequency range for alarms. higher fidelity increases understanding of spl which can lead to targeted interventions to reduce patient disturbance. introduction: survivors of critical illness face significant long term impairments in mental and physical function. early mobilisation (em) in the intensive care unit has been suggested to improve functional outcomes and reduce delirium in the icu. we hypothesized that implementing a protocol for em in the icu would improve mobilisation rates while remaining safe. methods: design: prospective non-blinded observational cohort study, based on a quality improvement project. data was collected conclusions: only of variables in boyd criteria were significant associated with morbidity or mortality. the physiologic score and operative score were significant higher in the patient on mortality and morbidity after sicu admission. effects of structural hospital characteristics on risk-adjusted hospital mortality in patients with severe sepsisanalysis of german national administrative data d schwarzkopf introduction: the quick sequential organ failure assessment (qsofa) score is a simple tool used to identify severe patients with infection. as this score is calculated from three variables that can be measured at the scene of trauma-systolic blood pressure, respiratory rate and consciousness-the prehospital qsofa score may also be a good predictor of mortality in trauma patients. so we evaluated the discriminative ability of the prehospital qsofa score in patients with trauma for in-hospital mortality. methods: this is a retrospective multicenter study using the data from nationwide trauma registry in japan. we included patients with trauma aged ≥ years old transferred to hospitals from scene. primary outcome is in-hospital mortality. results: the mean age was . ± . years old and patients ( %) were male. in-hospital mortality occurred in patients ( %). in-hospital mortality in each qsofa score was / ( . %), / ( %), / ( %) and / ( %) in qsofa score , , and , respectively (p< . for trend). area under receiver operating characteristics curve (auroc) of the aqsofa score for inhospital mortality was . ( % confidence interval . - . ). if we use the cutoff ≥ , sensitivity and specificity of the qsofa score were . and . . conclusions: in patients with trauma, the prehospital qsofa score was strongly associated with in-hospital mortality. we can identify patients with very low risk of death by using the cutoff ≥ of the prehospital qsofa score. introduction: only one prospective study is available of the validation of the diagnostic and prognostic role of qsofa (quick sofa score) in the emergency department (ed). a prospective study was conducted in greek eds. methods: the prompt study (clinicaltrials.gov nct ) run in the ed of six hospitals in greece among patients with suspected infection and presence of at least one of fever, hypothermia, tachycardia, tachypnea and chills. clinical data were collected and the -day outcome was recorded. sepsis was defined by the sepsis- criteria. results: the sensitivity and the specificity of at least signs of qsofa for the diagnosis of sepsis was . % and . % respectively and for the prognosis of -day mortality . % and . % respectively. the odds ratio for -day mortality when qsofa was equal to or more than was . among patients with charlson's comorbidity index (cci) equal to or less than ; this was . among patients with cci more than (p: . between the two ors by the breslow-day's test; p: . by the tarone's test). conclusions: data validated the sensitivity of qsofa for the diagnosis of sepsis. cci was an independent predictor of severity. qsofa could better predict unfavorable outcome among patients with low cci. comparative accuracy between two sepsis severity scores in predicting hospital mortality among sepsis patients admitted to intensive care unit n sathaporn, b khwannimit prince of songkla university, internal medicine, hat yai, thailand critical care , (suppl ):p introduction: recently, the new york sepsis severity score (nysss) was developed to predict hospital mortality in sepsis patients. the aim of this study was to compare the accuracy of nysss with the sepsis severity score (sss) and other standard severity scores for predicting hospital mortality in sepsis patients. methods: a retrospective analysis was conducted in a medical intensive care unit of a tertiary university hospital. the performance of severity scores was evaluated by discrimination, calibration, and overall performance. the primary outcome was in-hospital mortality. results: overall , sepsis patients were enrolled, patients ( . %) were classified to septic shock by sepsis- definition. hospital mortality rate was . %. the nysss predicted hospital mortality . +/- . %, which underestimated prediction with smr . ( %ci . - . ) . however, the sss predicted hospital mortality +/- . %, which slightly overestimated mortality prediction with smr . ( %ci . - . ). the nysss had the moderate discrimination with an auc of . ( % ci . - . ), in contrast to the sss presented good discrimination with an auc of . ( %ci . - . ). the auc of sss was statistically higher than that of nysss (p< . ). nevertheless the apache iv and saps ii showed the best discrimination with auc of . . the auc of the nysss and sss was significant lower than that of apache ii, iii, iv, saps ii and saps ( figure ). the calibration of all severity scores was poor with the hosmer-lemeshow goodness-of-fit h test < . . the nysss was the lowest overall performance with brier score . . the apache iv present the best overall performance with brier scores . . conclusions: the sss indicated better discrimination and overall performance than the nysss. however the calibration of both sepsis severity scores and another severity score were poor. furthermore, specific severity score for sepsis mortality prediction needs to be modified or customized to improve the performance. introduction: metabolic markers, especially lactate, have been shown to predict mortality in acutely unwell patients. we hypothesised that early changes in metabolic markers over time would better predict mortality and length of stay, with patients who correct their metabolic derangement having lower risk of death and reduced length of stay (los). methods: single centre, retrospective cohort study in a bed icu. we included all patients who had an arterial measurement of lactate, paco , base excess (be) and ph on admission and at hours after admission to icu between / / and / / . the 'clearance' of these markers was calculated using the equation ((value at admissionvalue at hours)/value at admission). clearance calculations only included those patients with deranged results on admission (lactate> mmol/l, be<- mmol/l, ph< . , paco > . kpa). roc analysis was used to predict in-hospital mortality and length of stay, using both the initial admission values, and using the clearance value, as well as icnarc and apache ii scores for comparison. if a patient was admitted twice in the time period, only the first admission was included. results: patients were included (sex ratio . , mean age . ). table ). none of the values tested had a auc greater than . for predicting length of stay. conclusions: the clearances of metabolic markers over the initial hours after icu admission does not provide better prognostic information than the value at admission. initial lactate level was the best predictor of mortality, but compared poorly to icnarc score. metabolic markers do not accurately predict length of stay. . - . ) vs . (iiq . - . ), p= . ]. the other hemogram parameters did not differ between groups (table ) . when adjusted for severity score, in patients submitted to emergent surgery, the mpv value was still independently associated with mortality (or . ci . - . , p= . ), and its roc curve (auc) was . to mortality (figure ). conclusions: mpv is a cheap and easily accessible marker which can add prognostic value in this specific population. in the future, we will validate it in a larger cohort of cancer pts admitted to intensive care. haematological malignancy in critical care: outcomes and risk factors c denny introduction: about % of patients admitted to hospital with a haematological malignancy will become critically ill [ ] . life expectancy in these patients is poor with a month mortality of % or more in specialist units [ ] . in contrast, patients without critical illness can expect a year survival rate exceeding % for many cancers. this disparity results in differences of opinion on the best strategy for such patients among haematologists and critical care physicians. we conducted a local quality improvement project to quantify mortality and risk factors in critically ill patients with a haematological malignancy in our hospital. methods: patients admitted to the critical care unit of broomfield hospital, a district general hospital with tertiary specialist services, from january to december with haematological malignancy were included in the analysis. patients in remission for more than years and patients admitted following elective surgery were excluded from analysis. death in critical care or in hospital after critical care discharge were the primary outcomes. mortality was correlated with demographic data using simple statistical measures and regression analysis. results: patients were included in the analysis. overall mortality was %(n= ). survivors tended to be younger ( vs years) but had similar clinical frailty scores. early critical care admission (within hours) was associated with better survival ( . vs . %). nonsurvivors had a greater incidence of sepsis and respiratory failure, and required more ventilatory and vasopressor support. mortality was higher in patients requiring more than one organ support. conclusions: the overall mortality in our data is lesser than previously published data but supports the conclusion that mortality is determined primarily by the number of organs supported with the effects of malignancy playing a secondary role. (figure ). increasing levels of frailty were associated with increasing risks of death at year (p< . ) (figure ). frailty significantly increased -year mortality hazards in unadjusted analyses (hr . ; %ci; . - . ; p< . ) and covariate-adjusted analyses (hr . ; %ci . - . ; p= . ) ( table ) . conclusions: frailty was common and associated with greater age, more severe illness and female gender. frailty was significantly associated with heightened mortality risks in both unadjusted and covariateadjusted analyses. frailty scoring may encapsulate variables affecting mortality which are omitted in current predictive systems, making it a promising risk stratification and decision-making tool in icu. fig. (abstract p ) . unadjusted survival curves stratified by frailty status. frail patients were statistically significantly less likely to survive to year plateau at day = , delta peak= and hpr= . . were assigned respectively a point value of , , and to these predictors based on their beta coefficient in the predictive model. the score yielded a roc-auc: (auc= . ; %ci, [ . - . ]; p= . ). using the validation data set (n= ), the score had an roc-auc= . and similar estimated probabilities for mortality. conclusions: the paw-mps seems to demonstrate interesting discriminative properties to predict mortality. what is the role of the pulmonary embolism severity index (pesi) and rv/lv ratio as clinical risk assessment tools for patients undergoing ultrasound-assisted catheter-directed thrombolysis (uacdt)? introduction: to evaluate if the pulmonary embolism severity index (pesi) score correlates with rv/lv ratio, biomarkers of cardiac injury, fibrinogen and length of stay(los). also to evaluate the correlation between rv/lv ratio with biomarkers of cardiac injury, fibrinogen and los for patients who underwent uacdt. methods: a retrospective review of patients with sub-massive pulmonary embolism (pe) who underwent ultrasound-assisted catheterdirected thrombolysis (uacdt) was performed. pesi score, rv/lv ratio, length of stay(los), fibrinogen levels, troponin levesl, and brain natriuretic peptide(bnp) levels, were calculated and collected prior to uacdt. spearman's rank correlation coefficient was calculated for all non-parametric variables. results: patients, males and females, were included in the study. the mean (±sd) age was ± years. the mean pesi score was ± . mean rv/lv ratio was . ± . . a significant correlation between the rv/lv ratio and both fibrinogen and troponin level (p= . , p= . ) was noted. no significant correlation existed between pesi score and rv/lv (p= . ). no significant correlation existed between both rv/lv ratio and pesi score with length of stay (p= . ) after uacdt. there were no noted mortality or complications. conclusions: pesi score is used as a prognostic factor for the patients with pe, however, our study shows that pesi score does not correlate with rv/lv ratio or length of stay after the uacdt. there was inverse correlation between rv/lv ratio and fibrinogen. there was also positive correlation between rv/lv ratio and troponin for patients with and without heart failure. according to our data, there may be limited use of pesi score and rv/lv ratio for risk stratification of pe patients undergoing uacdt. introduction: conventional scores for prediction of risk and outcome, such as sapsii and sofa, have not been validated for patients admitted to level ii critical care units (intermediate level or imcus). we compared the performance of sapsii and sofa scores with the intermediate care unit severity score (imcuss) in a general population admitted to imcu. methods: we conducted a prospective observational cohort study in a -bed level ii-iii icu from a university-affiliated hospital, during a three-month period. we applied sapsii, sofa day one and imcuss to all patients admitted during that period. primary outcome was a composite of hospital mortality and need to increase level of care. additionally, we tested the relevance of each variable within each score to predict the outcome. results: we included patients with a mean age of . ± . years. patients were considered "step-down" (transferred from our level iii beds), and the remaining originated from the emergency conclusions: months after completion, the primary care management intervention had no effect on mental health-related quality of life and physical function among survivors of sepsis. increase in ptsd symptoms in the control group may suggest a possible protective effect of the intervention. introduction: critically ill patients and their families are often confronted with an overwhelming amount of clinical information shortly after hospital admission. their reliance on internet resources for additional information is increasing, particularly for unfamiliar medical terminology. yet, little is known about whether these online resources meet the recommended reading level and complexity appropriate for the average reader. methods: an online search of websites containing four common critical care diagnoses in the icu (respiratory failure, renal failure, sepsis and delirium) was performed. a total of readability formulas were used. the flesch-kincaid grade reading level (grl) and flesch reading ease (fre) were used in the final analysis. document complexity was evaluated using the pmose/ikirsch formula. results: websites on respiratory failure were written at the th grl with fre of . . renal failure resources had a th grl with fre of . . sepsis websites had an th grl with fre of . . delirium websites had a th grl with fre of . . when comparing website types (government, non-profit and private), anova showed a difference in fre across all groups and government websites had a conclusions: online resources used by intensive care unit patients and families tend to be written at higher than the recommended th grl, with government sites better meeting this target than nonprofit and private organizations. online resources should be improved to lower this unfortunate barrier to patient education. introduction: the recent enactment of the data protection act , the general data protection regulations, and a series of data breaches in the healthcare sector, have renewed interest in how our patients' information is collected, used and shared. the complex framework of laws and regulations governing the use and disclosure of personal data may lead to professional and financial consequences if information is disclosed inappropriately. disclosures to the police when they concern incapacitous patients are particularly challenging, as the disclosure may have no direct benefit to the patient and may cause the patient considerable harm. methods: we have reviewed the relevant laws and regulations to identify the circumstances in which doctors must release information regarding incapacitous patients to the police. the laws and regulations are examined to identify the extent of the disclosure required, and any requirements for the disclosure to be lawful. we have also identified laws which confer a power to disclose information about incapacitous patients, and the circumstances in which these powers can be used. results: in conjunction with a local police constabulary we have developed an information request form which makes it easier for those requesting and disclosing information to understand the legal basis of the disclosure. we have also developed guidelines to allow practitioners to understand where a disclosure is obligatory or discretionary. conclusions: the next stage of the project is to audit disclosures of information in the intensive care unit, and identify whether information is being released lawfully and following the correct procedure. introduction: family members are affected both physically and psychologically when their relative is admitted to icu. there is limited knowledge describing their experiences and structured interventions that might support them during their relative's critical illness. the aim of this review is to describe published literature on the needs and experiences of relatives of adult critically ill patients and interventions to improve family satisfaction and psychological well-being. methods: design: scoping review. standardised processes of study identification, data extraction on study design, sample size, sample characteristics and outcomes measured (figure ) . results: from references, studies were identified for inclusion four key themes were identified: ) different perspectives on meeting family needs ) family satisfaction with icu care ) factors impacting on family health and well-being and capacity to cope ) psychosocial interventions conclusions: family members of patients in icu experience unmet information and assurance needs which impacts on their physical and mental health. structured written as well as oral information show some effect in improving satisfaction and reducing psychological burden. icu's who are able to support interventions based on meeting family information needs, in addition to reducing psychological burden and increasing satisfaction will enable each family to provide more support to their relative within the icu. introduction: unmet informational needs lead to dissatisfaction with care and psychological distress. identifying interventions to help meet specific needs is a crucial and necessary step in providing family centred care in icu. we aimed to implement and evaluate the impact of delivering a structured communication strategy on levels of anxiety, uncertainty and satisfaction with care and decision making in families of critically ill adults. methods: a quasi experimental study with pre and post test design. a convenience sample of family members were recruited from july to february . the intervention group (n= ) received both oral and printed information to guide them in preparing for a structured family meeting. the control group (n= ) received usual fig. (abstract p ) . article selection process for scoping review routine care and existing family informational support. anxiety, uncertainty and family satisfaction were measured in the two groups on icu admission and icu discharge. results: mean anxiety, uncertainty and satisfaction with care and decision making scores pre and post intervention were compared. there were no significant differences in mean anxiety, uncertainty or satisfaction scores between the two groups before the intervention (p> . ). mean scores on anxiety ( . vs . ), and uncertainty ( . vs . ) were lower post intervention, but not significantly so ( figure & ). total satisfaction, satisfaction with care and satisfaction with decision making mean scores were similar in both groups before and after the intervention (p. . ). conclusions: providing relatives with a combination of targeted written and oral information delivered by nursing and medical staff reduced anxiety and uncertainty with this reduction being evident through to discharge from icu. although not statistically significant, there was what may be seen as a suggestion of a clinically significant drop in anxiety and uncertainty following the intervention introduction: clinical studies in intensive care unit (icu) patients are warranted in order to improve healthcare. the aim of this study was to analyse barriers and challenges in the process of achieving informed consent from icu patients. methods: we analysed patients considered for inclusion in a prospective observational study of venous thromboembolism in the icu, i.e. the norwegian intensive care unit dalteparin effect (norides) study. data were collected from the screening log, consent forms and associated research notes of the norides study. results: we observed that of ( %) eligible patients according to inclusion and exclusion criteria were omitted from the nor-ides study due to barriers and challenges in the process of receiving informed consent. were categorized as psychiatric diseases consisting of known psychosis or recent suicide attempt, likely or actual treatment withdrawals and due to language barriers among non-norwegians. among the patients included in the norides study, ( %) consents were from patients and ( %) obtained from their next of kind. from the patient consents, ( %) consents were oral and ( %) were written. patients were physically unable to sign, and patients did not recognize their own signature. the study further pointed at some specific challenges in the process of consent, herein questionable competence to give consent, failure to remember being asked/included, inability to separate research from treatment etc. there were also difficulties in evaluating who was next of kin and how to reach them. conclusions: barriers and challenges in obtaining informed consent from icu patients led to exclusion of one fifth of the eligible patients in our study. informed consent directly from patients was obtained from less than half of the included patients. obstacles in the process of achieving informed consent were practical, medical, ethical and/or legal. determinants of end-of-life decision-making in the intensive care unit p eiben, c brathwaite-shirley, s canestrini king´s college hospital nhs foundation trust, london, united kingdom critical care , (suppl ):p introduction: although the majority of intensive care unit (icu) deaths follow the decision to forgo life sustaining treatment (lst), variability in patterns is commonly observed [ , ] . we reviewed end of life (eol) practice at our institution in order to explore: (i) patient characteristics affecting eol decision-making, (ii) communication among surrogate decision-makers, and (iii) eol management. methods: we retrospectively analyzed data from consecutive patients who died in our ten-bed icu over months (study period). patient demographics, apache ii, functional status, diagnosis on admission, icu length of stay (los) were collected; family/next-of-kin (nok) involvement and rationale for lst limitation were recorded ( conclusions: our analysis shows that in our institution eol deliberations follow a shared decision-making process. lack of family/nok involvement and incomplete documentation was exceptional. the significant difference in los between w-group and nw-group, in the face of similar apache ii, warrants further investigation. vae calculator rheumatology review . van der jagt m. crit care consensus on circulatory shock and hemodynamic monitoring. task force of the european society of intensive care medicine cardiac output monitoring: how to choose the optimal method for the individual patient perioperative cardiovascular monitoring of highrisk patients: a consensus of guidelines for nutrition support therapy in the adult critically ill patient references . nice guideline for aki: prevention, detection and management serial creatinine results pre-and post ecmo references . polit et al. research in nursing & health reference . sherliker et al national blood transfusion committee, nhs blood and transplant arch otolaryngol head neck surg fig. (abstract p ). rsi agent guideline references . nuckton tj nejm icm baseline characteristics reference elso guidelines for cardiopulmonary extracorporeal life support s -leitlinie invasive beatmung und einsatz extrakorporaler verfahren bei akuter respiratorischer insuffizienz .auflage p handgrip strength does not predict spontaneous breathing trial failure or difficult or prolonged weaning of critically ill patients g friedman total burn care introduction: we aimed to evaluate safety and efficacy of light sedation with dexmedetomidine (dex-ls) in acute brain injury (abi) patients. methods: retrospective analysis on icu patients with traumatic/medical abi, out of the neuroprotection window and undergoing dex-ls. data of pre-infusion and infusion periods were compared. results: patients (age ± , males . %) were included. traurespectively. conclusions: dex-ls among icu patients affected by abi turned out to be feasible and safe. it enabled discontinuation from mv and maintenance of spontaneous breathing in the majority of cases %) delirious patients and of ( . %) non-delirious patients could be discharged from the hospital. we evaluated the -year mortality in the hospital survivors. results: totally, patients participated in our study. the majority of them ( . %) were male with the median age of [ , . ] years and the median apache ii score on the first day of icu admission of risk of delirium was associated with preoperatory euroscore ii (p= . ) and history of previous cardiac surgery (p= . ). moreover, in the intraoperatory period the risk of delirium was associated with red blood cell transfusion, intervention for aortic dissection (p= . ), hypothermic circulatory arrest (hca) with anterograde cerebral perfusion (acp) (p= . ) (table ). in the postoperatory period risk of delirium was associated with levels of creatinine clearance (p= . ) and c-reactive protein (crp) (p= . ). conclusions: delirium is relatively frequent in the cardiac surgical icu patient journey of group : those patients discharged directly home from critical care unit poor compliance with co-signing in icca ( %, n= ) compared to paper ( %, n= ) (figure ) and the reported difficulty in co-signing ( %, n= ) reveals significant usability concerns and potential safety issues. % (n= ) found icca intuitive, though % (n= ) found navigating the interface difficult and reported concerns with losing saved work ( %, n= ). conclusions: this study highlights important usability issues that may impact staff satisfaction th national audit project of the royal college of anaesthetists and the difficult airway society. major complications of airway management references . guidelines for provision for intensive care services (gpics), version medicines optimisation: the safe and effective use of medicines reducing harm from omitted and delayed medicines. a tool to support local implementation p understanding the delivery of intensive care in south p mobilising ventilated patients early with interdisciplinary teams (move it) singapore general hospital, department of respiratory and critical care p validation of boyd criteria and possum-score on mortality and morbidity in general surgical intensive care unit k chittawatanarat, y chatsrisuwan faculty of medicine pts with central nervous system neoplasms or submitted to elective surgeries were excluded. descriptive analysis and χ test, pearson´s, wilcoxon rank-sum, uni and multivariate logistic regressions were used when appropriate. results: from a total of pts identified, . % (n= ) were admitted after emergent surgery and . % (n= ) for medical reasons. global icu mortality was . % (n= ). in comparison to survivors, the patients that died had a similar age were recorded data regarding demographics, clinical variables, paw (at admission and at day ), high pressure ratio (hpr = number of days with high pressures: peak ≥ and/or plateau ≥ ; and/or driving pressure ≥ ; and/or auto-peep ≥ ; divided by los), trends of paw (paw at day -paw at admission) and outcomes. the patients were divided into two groups: a construction group (n= ) and a validation group(n= ). the paw-mps was developed and validated by analyzing in a multivariate regression model the different paw ± . ; pco , ± mmhg paw were respectively for peak, plateau, driving, and auto-peep at admission: ± , . ± , . ± and three independent mortality risk factors were identified centro hospitalar do porto p five-year mortality and morbidity impact of prolonged icu stay n van aerde , g hermans laboratory of cellular and molecular medicine we investigated differences in mortality and morbidity after short (< days) and prolonged (≥ days) icu-stay. methods: prospective, -year follow-up study of former epanicpatients (clinicaltrials.gov:nct , n= ). mortality was assessed in all. for morbidity analyses, all long-stay and a random sample ( %) of short-stay survivors were contacted. primary outcomes were total and post- -day -year mortality in multivariable cox regression analysis, icu-risk factors comprised hypoglycaemia, corticosteroids, nmba, benzodiazepines, mechanical ventilation, new dialysis, new infection, liver dysfunction, whereas clonidine may be protective. among long-and short-stay -year survivors hgf, mwd and pf sf- were lower in long-stayers mwd: % ( %ci: %- %) vs % ( %ci: %- %) multivariable regression identified associations with benzodiazepines (hgf and pf-sf ), vasopressors (pf-sf ) and opioids ( mwd) ptsd related symptoms were accessed with the post traumatic stress syndrome questions inventory (ptss- ) at the post icu follow up clinic, six months after the acute stress event. the post icu consultation was carry out by an icu doctor and an icu nurse. exclusion criteria: previous severe psiquiatric disorders, not able to respond the questionnaire medical %, surgical % and trauma %. patients ( %) were on imv and the median ventilation days was . ptsd scores ranged from to . delusional memories were conclusions: in this study the rate of ptsd was lower . % and related with a lower saps ii and the presence of memories of the icu stay. no relation was found with delusional memories, imv or superior icu length of stay. patients with lower illness severity and without imv, should be elective to the follow up-clinics. p long-term effects of a sepsis aftercare intervention k schmidt united states; jena university hospital patras general university hospital, intensive care unit, patras, greece; patras general university hospital, division of infectious diseases results: ( . %) patients were readmitted within hours and ( . %) in to days. the two groups didn't differ in age, gender, charlson comorbidity index and length of stay on both admissions. elective surgery was the most common type of admission ( . %) followed by medical ( . %), emergency surgery ( %) and trauma ( . %). the mean time to readmission in the late group was . (± . ) days. patients in the late group had higher apache ii score on their first and second admission, ( . ± . vs . ± . ; p= . ) and ( . ± . vs . ± . ; p= . ) respectively. respiratory insufficiency was the most common cause of readmission in both groups followed by sepsis and cardiac arrest. finally in the early group p introduction: in intensive care units, perceived inappropriate treatments (pit) have been associated with negative impact on caregivers univariate analysis revealed that burn-out, pit and intention to leave were greater in units where nurses´teams included no activity in the icu, compared to "shared" work in icu and idtcu. in multivariate analysis, perception of non beneficial treatment of patients with life support witholding was associated with: bad collaboration with other units p profile of intensive care unit (icu) patients on whom life-sustaining medical treatment were withdrawn or withheld s chatterjee variables collected-age, sex, apa-che iv score, diagnostic-category and co-morbidities. primary outcomes were icu and hospital mortality. secondary outcomes included icu and hospital length of stay(los) female sex, n (%) ( . %) diagnosis on admission: medical, n (%) rrt at time of wlst, n (%) ( . %) dnr order, n (%) ( . %) organ donation services involved, n (%) ( . %) introduction: high flow nasal cannula(hfnc) is a new modality in respiratory failure management [ ] . this study objectively held to compare the physiological outcomes in the non-invasive ventilation(niv) treatment of cardiogenic acute pulmonary oedema(apo) patient in the emergency department(ed) delivered by helmet cpap(hcpap) and hfnc. methods: single-centre randomized controlled trial on patients presenting with cardiogenic apo. primary endpoint was a heart rate reduction.secondary endpoints included: improvement in subjective dyspnoea scales, respiratory rate, blood oxygenation, intubation rate and days mortality rate. results: patients were enrolled and randomized ( patients to hcpap; to hfnc) ( to . ± . ). intubation rate was lower in hcpap ( . % for hcpap versus . % for hfnc) and days mortality rate is lower in hcpap ( . % for hcpap versus . % for hfnc). conclusions: both hcpap and hfnc significantly improved patient condition in patient presenting to the ed with cardiogenic apo. however, hcpap was better than hfnc in improving physiology outcomes, lower intubation rate and mortality rate in patient introduction: the aim of the study was to compare the confusing assessment method of the intensive care unit (cam-icu) and the nursing delirium scoring scale (nu-desc) for assessment of delirium in the icu. furthermore we wanted to test the interpersonal variation of the nu-desc. delirium is proved to be associated with increased mortality [ ] . nu-desc is an observational five-item scale that does not require patient participation and is adapted to the fluctuating nature of delirium. each item can be scored from to . delirium is defined with a score > . the nu-desc has recently been translated into danish (nu-desc dk) but has not been validated.methods: icu patients, who met the inclusion-criteria for the cam-icu were scored with both cam-icu and nu-desc dk. patients were scored of two independent nurses at approximately the same time every day.results: a total of patients were enrolled, and comparisons between cam-icu and nu-desc dk were registered ( figure ).there was agreement between nu-desc and cam-icu in of registrations (hereof registrations were delirium negative). in interpersonal variation, registrations were made. the conclusion was identical in % of registrations, but only % agreed in all scoring-scale items (all negative).conclusions: a high agreement between nu-desc and cam-icu was found however the comparison was based on predominately patients with negative delirium score. the interpersonal variation of nu-desc scoring was substantial. a future validation of the nu-desc dk as a screening tool in the icu requires thorough training and instructions to minimize interpersonal variation. introduction: an increasing number of patients are being discharged directly home from critical care units and this is currently viewed as a negative quality indicator [ ] . the purpose of this audit was to characterise a cohort of patients who can be safely discharged directly home from adult critical care at st thomas´hospital (sth). methods: retrospective observational study of two groups of patients; ) those discharged directly home from critical care, ) those discharged within two days of step down to a ward from critical care (admissions st june- st october ). the clinical notes of these patients were reviewed via online systems. results: baseline demographics of the patients in group and patients in group were similar (mean age of years, versus years, p= . ); average length of stay in critical care was also similar ( . days versus . days respectively p= . ). in group , of icu days were after considered fit for step down versus of days in group , p= . (fig , ) . in group , drug related presentations were more common ( % versus % p= . ), fewer patients had specialist follow up post discharge ( % versus %, p< . ). in group , patients ( %) were readmitted within days, to critical care. in group , patients ( %) were readmitted, to critical care (p= . and . respectively); none of these readmissions were felt to have been preventable.conclusions: there is a cohort of patients suitable for discharge directly home from critical care who did not spend significantly longer in icu awaiting discharge than those who were stepped down to the ward. identifying these patients early, potentially by their diagnosis, and creating a pathway including access to specialist follow up clinic could allow prompt discharge directly from critical care, thus improving patient satisfaction and reducing hospital-acquired morbidity healthcare costs [ ] . the evaluation of the usability of a critical care information system ( introduction: critical care information systems (ccis) support clinical processes by storing and managing data, but poor usability can lead to staff dissatisfaction and increased workload, promoting workarounds that may compromise patient safety [ ] . the purpose of the study was to evaluate the usability of a philips intellispace critical care and anaesthesia (icca) ccis, recently implemented in beds across three critical care units of a large uk teaching hospital. methods: a prospective, mixed method observational study conducted in may , comprising of ( ) an audit assessing the ease of linking bedside devices to icca, ( ) an audit assessing the usability of co-signing medications in icca compared with a non-icca paper factors that commonly drive workforce metrics may not correlate with staff perceptions of safety. the bpr is a pragmatic, staff driven, tool to augment other measures of safety and is applicable to various icu settings. further research is needed to explore staff perceptions in order to understand the importance of this organisationally, and for staff stress. ventilator-free duration in icu, central venous catheter duration, urinary catheter duration, rates of deep vein thrombosis (dvt) and stress ulcer prophylaxis, rates of de-escalation antibiotic therapy, dvt prophylaxis duration, stress ulcer prophylaxis duration, icu and hospital mortality, -day mortality, rate of central venous catheter infection, length of stay in icu and hospital between two groups were analyzed. results: rate and duration of dvt prophylaxis in the intervention group were . % and ( , ) days respectively, in the control group were . % and ( , ) days, the differences between two groups were statistically significant(p< . ) ( table ). there were no differences in ventilator-free duration in icu, central venous catheter duration, urinary catheter duration, rate of stress ulcer prophylaxis, rates of de-escalation antibiotic therapy, stress ulcer prophylaxis duration, icu and hospital mortality, -day mortality, rate of central venous catheter(cvc) infection, length of stay in icu and hospital between two groups ( table ) . conclusions: electronic checklist in ward rounds can increase the rate of dvt prophylaxis and reduce the duration, but it cannot improve the prognosis of critically ill patients. introduction: the goal of the project "i see you" is family-centeredcare based on family meetings that improve the experience of the patient´s family members during hospitalization in the icu. the meetings focus on relaying information, raising knowledge and addressing the social and emotional needs of families. providing support along with information was found to be the strongest predictor of family satisfaction and could lead to improve cooperation between family and staff [ ] .methods: meetings and questionnaire: family meetings consist of a multidisciplinary team, a group facilitator and combined with a multimedia presentation about the unit and equipment. in addition, they focus on social and emotional needs: managing daily routine, sharing problems, fears and anxieties and more. at the end of the session a questionnaire was given to assess the impact of the intervention. sharing data: at the end of the first quarter, the data from meeting was summarized and sent to the staff alongside tools for effective communication.results: the project began in february . to date, family members of patients have attended the sessions. the topics discussed by the participants include: contact with the patient, prevention of infections, procedures, visits, conversations with doctors, medical confidentiality; guardianship; tracheotomy and social issues (fig ) . a sample of questionnaires was transferred to participants report satisfaction at a very high level.conclusions: the meeting received a very positive feedback from the participants. the project has achieved its goals and therefore it has been decided to be continued.introduction: possum score and boyd criteria are used to predict the outcome for high risk surgical patients. the aim of this study was to validation of these two measurement tools on mortality and morbidity in a university-based surgical intensive care unit (sicu) in thailand.methods: nine hundred and fifty two patients were enrolled onto this prospective review. all patients who had been admitted to sicu in a university-based hospital were included. all patients were collected for boyd criteria and possum score and outcomes and morbidity during sicu admission and discharge. introduction: aromatic microbial metabolites (amm), such as phenyllactic (phla), p-hydroxyphenylacetic (p-hphaa), and phydroxyphenyllactic (p-hphla) are involved in the pathogenesis of septic shock and are associated with mortality [ ] . according to previous studies, amm have a high prognostic value in patients with abdominal infection [ , ] . we hypothesize that amm have the prognostic value in patients with pneumonia in icu. methods: data of patients with community-acquired pneumonia was obtained on admission to icu. the levels of amm (phla, p-hphla and p-hphaa) were measured in blood serum using gas chromatography with flame ionization detector and compared in groups of patients: with favorable and with lethal outcome (mann-whitney utest). spearman's correlations between amm and clinical and laboratory data were calculated. using method of logistic regression and roc analysis, we measured the prognostic value of amm. (table ) . it was revealed, that some amm have similar prognostic characteristics in comparison with sofa and curb- scales; high level of amm is associated with high risk of death (roc-analysis - fig. ) .conclusions: serum concentrations of amm can be used as independent and practical criteria for the assessing of prognosis in patients with infection in icu. introduction: frailty in the critically ill is associated with increased morbidity and mortality but the optimal timing of frailty assessment, how to best measure frailty, reasons for adverse outcomes and how critical illness impacts frailty are unknown [ ] . in preparation for a multi-center study designed to address these knowledge gaps, we conducted a pilot study whose aim was to assess feasibility as determined by recruitment rates, ability to assess frailty at icu admission and hospital discharge, ability to measure icu and hospital processes of care and ability to conduct -month assessments. conclusions: a multi-center study is feasible but follow-up losses due to mortality and inability to return for assessment will require sample size adjustment. frailty characterization is method dependent, can be done on hospital discharge but varies with time of assessment. these findings will need to be confirmed in our larger study currently in progress. introduction: given the ageing of the world´s population, the demands of critical care resources for elderly patients has increased during the past decade. however, little is known about quality of life and outcomes of elderly icu survivors. the aim of the study is to assess outcomes of elderly icu survivors at least months after discharge: quality of life and mortality. methods: it is a retrospective study performed in a medical adult icu between january to december . the study included all elderly survivors ( ≥ years) after icu admission. outcomes were assessed by telephone interviews at least months after icu discharge. the primary outcome was assessing the quality of life after icu stay, measured by euro qol d questionnaire. the eq- d descriptive system contains five dimensions (mobility, self-care, usual activities, pain and discomfort, and anxiety and depression). for each dimension, there are five levels (no problems, slight problems, moderate problems, severe problems and unable to/extreme problems figure . conclusions: most elderly survivors patients showed a good health related quality of life using the euroqol d- l after icu discharge. fig. (abstract p ) . quality of life (euroqol d) scores after icu discharge introduction: sepsis survivors face mental and physical sequelae even years after discharge from the intensive care unit (icu). effects of a primary care management intervention in sepsis aftercare were tested. exploratory analyses suggest better functional outcomes within the intervention group compared to the control group at six and months after icu discharge. longer term effects of the intervention have not been reported. methods: a randomized controlled trial was conducted, enrolling patients who survived sepsis (including septic shock), recruited from nine german icus. participants were randomized to usual care (n= ) or to a -months intervention (n= ). the intervention included training of patients and their primary care physicians (pcp) in evidence-based post-sepsis care, case management provided by trained nurses and clinical decision support for pcps by consulting physicians. usual care was provided by pcps in the control group. the primary outcome of the trial was the change in mental healthrelated quality at -months after icu discharge. secondary outcomes included measures of mental and physical health. data were collected by telephone interviews using validated questionnaires at the -months follow-up ( months after the -year intervention).results: [ . %, intervention, control] of patients completed the -months follow-up. unlike the intervention group, the control group showed a significant increase of posttraumatic symptoms (diff. ptss- to baseline, mean (sd) . ( . ) control vs.- . ( . ) intervention; p= . ). there were no significant differences in the mcs and all other secondary outcomes between intervention and control group.introduction: survivors of sepsis often show symptoms of posttraumatic stress disorder (ptsd). only few studies report on courses of more than month after discharge from the icu. the aim of this study was to identify predictors for changes in ptsd symptoms over time up to month. methods: follow-up data of the smooth triala rct to evaluate a primary care management intervention on sepsis survivorswere analyzed. included patients were surveyed by phone for ptsdsymptoms at one, , and months after discharge from icu using the post-traumatic-stress-scale (ptss- ). scores changes between follow-up periods were analyzed using latent-change scores in structural equation models. predictors were clinical and sociodemographic baseline characteristics as well as physical, cognitive and functional sepsis sequelae assessed by validated questionnaires.results: patients were included of which participated in the month follow-up. a decrease of ptsd symptoms between and months was predicted by higher education (b=- . , p= . ), while higher pain intensity at one month predicted an increase (b= . , p= . ). increasing ptsd symptoms between and months were predicted by reporting more than two traumatic memories at one month (b= . , p= . ), more sleep problems (b= . , p= . ) and worse cognitive performance at months (b=- . , p= . ) as well as more neuropathic symptoms at months (b= . , p= . ).conclusions: sepsis patients that suffer from physical, cognitive and functional impairments after icu discharge may be at increased risk for developing late-onset ptsd. these predictors need to be replicated by future studies. early versus late readmission to the intensive care unit: a ten-year retrospective study v karamouzos , n ntoulias , d aretha , a solomou , c sklavou , d logothetis , t vrettos , m papadimitriou-olivgieris , d velissaris , f fligou conclusions: icu patients whose life-sustaining treatment was withdrawn or withheld had higher illness-severity scores, were older, had longer icu los and higher mortality than those in active-treatment group. healthcare introduction: caring for the critically ill patient is a complex task and becomes tougher when a death process takes place. a number of needs and coping strategies emerge from the healthcare providers before these issues but are mostly displayed out of individual skills and intuition. if those approaches are unappropriate and the needs are not met, patients' death process may be burdensome for caregivers. this could affect the quality of care for patients and families during the whole end-of-life care process. the aim of our study was to explore the different needs and coping strategies used by icu healthcare providers when facing patients in the dying process. methods: qualitative and collective case study. ten semi-structured interviews were conducted in icu personnel ( physicians and nursing professionals). a thematic analysis was done using nvivo software. local ethics committee approved the study. results: respondents were % women, had . ± . years-old and . ± . years of icu experience. main needs identified in icu healthcare providers refer to a lack of tools for doing emotional containment when delivering bad news to families, handling personal mourning, the need to perceive consistency regarding end-of-life care management across the icu team, and a wish of having regular training from a psychologist. main identified coping strategies included closing rituals, finding quiet spaces to spend time, and asking for counselling with more expert colleagues. a need for systematic, although basic training on these issues from qualified professionals is demanded. conclusions: usually, basic needs from patients and families in the process of dying are well addressed, but healthcare providers' needs are underrecognized and coping strategies mostly unknown. visibilization of those needs and basic but formal training in emotional containment, self-care and coping strategies are greatly desired. introduction: in the intensive care unit (icu), patients often exhibit cognitive impairments that prevent them from participating in decisions related to therapeutic options at the end of life. consequently, their families are often asked to speak for them when difficult decisions must be made. the main of this study was to determine the frequence in wich family want to share in end of life decisions and factors associated with this desire.methods: a prospective study was conducted in one mixed icu in montevideo. relatives of patients were invited to participate in this study after hours in the icu and completed a survey that included the hospital anxiety and depression scale. results: we analized relatives from patients hospitalized in the intensive care unit. the relationship with the patient was as follows: % spouses, % siblings, % grown children, % parents, and % other family members and friends. of them, . % reported a desire to share in end of life decisions. anxiety and depression symtoms were present in % and % respectively. factors asociated with the desire of involvment in end of life decisions by bivariate analysis were: female sex ( % vs %, p= . ), presence of anxiety ( % vs %, p= . ) and patient ecog - ( % vs %, p= . ). multivariate analysis shows that the presence of anxiety is the only independent factor associated with the desire to participate in end of life decisions (or . , ic % . - . ; p= . ). conclusions: have a loved one in icu is often associated with anxiety and depression after hours of admission. only % of the relatives want to participate in end of life decisions. the presence of anxiety is independently associated with the want to share in decisions making process. introduction: intensive care aims to treat failure of vital organ systems. sometimes, a patient's condition is of such a degree that intensive care is no longer beneficial, and decisions to withdraw or withhold intensive care are made. this means that life-sustaining treatments are terminated or not initiated. we aimed to identify variables that are independent factors for the decision to withdraw or withhold intensive care. methods: registry study using extracted data from a national quality registry the swedish intensive care registry (sir) - . data are delivered to the registry by nurses and doctors daily, during each patients' stay in the intensive care unit (icu). a total of , intensive care cases reported to the sir from - . results: data regarding each patient´s age, sex, diagnoses, condition at admission (expressed as simplified acute physiology score version , saps ), comorbidities and registered decisions to withdraw or withhold intensive care were analyzed. of the , cases reported, . % were women and . % men, and . % were - years old. a total of . % received a decision to withdraw or withhold intensive care, accounting for . % of all women and . % of all men, p< . . independent variables associated with increased odds of receiving a decision to withdraw or withhold intensive care were older age, worse condition at admission, and female sex. female sex was associated with an increased odds of receiving a decision to withdraw or withhold intensive care by % (ci . - . %) after adjustments for condition at admission and age. conclusions: older age, worse condition at admission and female sex was found to be independent variables associated with an increased odds to receive a decision to withdraw or withhold intensive care.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -zc ve le authors: leclerc, angela m.; riker, richard r.; brown, caitlin s.; may, teresa; nocella, kristina; cote, jennifer; eldridge, ashley; seder, david b.; gagnon, david j. title: amantadine and modafinil as neurostimulants following acute stroke: a retrospective study of intensive care unit patients date: - - journal: neurocrit care doi: . /s - - - sha: doc_id: cord_uid: zc ve le background/objective: neurostimulants may improve or accelerate cognitive and functional recovery after intracerebral hemorrhage (ich), ischemic stroke (is), or subarachnoid hemorrhage (sah), but few studies have described their safety and effectiveness in the intensive care unit (icu). the objective of this study was to describe amantadine and modafinil administration practices during acute stroke care starting in the icu and to evaluate safety and effectiveness. methods: consecutive adult icu patients treated with amantadine and/or modafinil following acute non-traumatic is, ich, or sah were evaluated. neurostimulant administration data were extracted from the electronic medication administration record, including medication (amantadine, modafinil, or both), starting dose, time from stroke to initiation, and whether the neurostimulant was continued at hospital discharge. patients were considered responders if they met two of three criteria within days of neurostimulant initiation: increase in glasgow coma scale (gcs) score ≥ points from pre-treatment baseline, improved wakefulness or participation documented in caregiver notes, or clinical improvement documented in physical or occupational therapy notes. potential confounders of the effectiveness assessment and adverse drug effects were also recorded. results: a total of patients were evaluable during the . -year study period, including ( %) with ich, ( %) with is, and ( %) with sah. the initial neurostimulant administered was amantadine in ( %) patients, modafinil in ( %), or both in ( %) patients. neurostimulants were initiated a median of ( . , . ) days post-stroke (range – days) for somnolence ( %), not following commands ( %), lack of eye opening ( %), or low gcs ( %). the most common starting dose was mg twice daily for both amantadine ( %) and modafinil ( %). of the patients included in the effectiveness evaluation, ( %) were considered responders, including / ( %) receiving amantadine monotherapy and / ( %) receiving both amantadine and modafinil at the time they met the definition of a responder. no patient receiving modafinil monotherapy was considered a responder. the median time from initiation to response was ( , ) days. responders were more frequently discharged home or to acute rehabilitation compared to non-responders ( % vs %, p = . ). among survivors, / ( %) were prescribed a neurostimulant at hospital discharge. the most common potential adverse drug effect was sleep disruption ( %). conclusions: neurostimulant administration during acute stroke care may improve wakefulness. future controlled studies with a neurostimulant administration protocol, prospective evaluation, and discretely defined response and safety criteria are needed to confirm these encouraging findings. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. approximately , americans suffer a new or recurrent stroke each year, including % that are ischemic (is), % that are intracerebral hemorrhages (ich), and % that are subarachnoid hemorrhages (sah) [ ] . stroke is a leading cause of disability, with . % of noninstitutionalized adults reporting stroke-related disability, including - % reporting ≥ long-term comorbid medical conditions [ , ] . the national institute of neurological disorders and stroke recently identified early recovery after stroke as a research priority, highlighting specific interventions (including pharmacologic agents), for future investigation [ ] . early rehabilitation is a central component of poststroke care, with clinical practice guidelines recommending early mobilization and rehabilitation within - h [ ] and inpatient rehabilitation rather than skilled nursing care whenever possible [ ] . efforts to provide early rehabilitation following acute stroke can be compromised by a variety of conditions, including apathy and hypersomnia, which may occur in up to % and % of stroke survivors, respectively [ , ] . disordered consciousness after ischemic or hemorrhagic stroke can result from damage to many different structures, including bilateral cerebral cortical injury, pontine tegmentum, midbrain, basal forebrain, hypothalamus and central thalamus, putamen, caudate, and pallidum [ ] . strategies to circumvent these impairments and increase participation in early rehabilitation are needed. neurostimulants such as amantadine and modafinil promote wakefulness and may increase patient participation in early rehabilitation, with data largely extrapolated from patients with traumatic brain injury (tbi). although amantadine is commonly administered to patients with disorders of consciousness, its mechanism of action remains unclear. it may modulate dopamine activity by increasing its release, blocking its reuptake, and increasing postsynaptic dopamine receptors or altering their conformation and may also antagonize n-methyl-d-aspartate (nmda) receptors [ , ] . the mechanism of action of modafinil has been attributed to stimulation of alpha b noradrenergic receptors, reduced gamma-aminobutyric acid (gaba) release, increased glutamate or histamine release, or altered hypocretin activity [ ] . modafinil's effects appear independent of serotonin, dopamine, gaba, adenosine, histamine- , melatonin, and benzodiazepine receptors. compared to conventional neurostimulants, modafinil appears to be devoid of dopaminergic effects, which may be of significance as post-stroke dopaminergic system dysfunction has been recently described [ , ] . among the many neurostimulants available, amantadine has the strongest evidence supporting its administration. when started weeks post-tbi during acute rehabilitation, amantadine accelerates functional recovery [ ] . smaller controlled studies treating tbi patients with amantadine during their acute hospitalization have shown improved glasgow coma scale (gcs) and mini mental status examination (mmse) scores [ , ] , but whether similar benefits would occur during acute hospitalization after stroke is unknown. amantadine and modafinil are administered to patients following acute stroke in our intensive care unit (icu) on an ad hoc basis, but data supporting this practice are largely limited to delayed treatment in rehabilitation or outpatient facilities with very few reports during the acute care hospitalization [ ] [ ] [ ] . the primary purpose of this study was to describe amantadine and modafinil administration practices during acute stroke care in patients initially treated in an icu. we also sought to evaluate the safety and effectiveness of this practice. consecutive acute stroke patients treated in the -bed medical, surgical, and neurological icu and the -bed cardiac icu at maine medical center between december and july were evaluated in this retrospective cohort study. patients were included if they were ≥ years of age, admitted with an acute nontraumatic ich, is, or sah, and were treated with amantadine, modafinil, or both for at least h starting in an icu. the -h window was chosen based on our anecdotal observation that patients generally respond within acute rehabilitation compared to non-responders ( % vs %, p = . ). among survivors, / ( %) were prescribed a neurostimulant at hospital discharge. the most common potential adverse drug effect was sleep disruption ( %). conclusions: neurostimulant administration during acute stroke care may improve wakefulness. future controlled studies with a neurostimulant administration protocol, prospective evaluation, and discretely defined response and safety criteria are needed to confirm these encouraging findings. this time frame and shorter treatment intervals may be inadequate to assess response. patients were excluded if they were receiving amantadine or modafinil prior to hospitalization, were admitted with tbi, encephalopathy (including hypoxic ischemic encephalopathy after cardiac arrest), brain tumor, encephalitis, or had a history of seizures. patients were identified using a pharmacy-generated report. the institutional review board at maine medical center reviewed this study design and determined it was exempt from regulatory review. demographic information (age, gender, ethnicity), clinical characteristics including type of stroke (ich, is, or sah), stroke-specific severity grading (ich score for ich, hunt and hess scale for sah, and national institutes of health stroke scale [nihss] for is), laterality for ich and is, and presence or absence of an aneurysm for sah were recorded. descriptive clinical outcomes included icu and hospital length of stay, icu and hospital mortality, and discharge disposition (home, acute rehabilitation, skilled nursing facility, hospice, or death). all information was obtained from the electronic medical record, including notes entered by physicians, nurse practitioners, physician assistants, nurses, pharmacists, and occupational, speech, and physical therapists. a single pharmacist investigator (csb) extracted amantadine and modafinil administration data from the electronic medication administration record (mar), including specific neurostimulant(s) initiated (amantadine, modafinil, or both), starting dose, time from stroke to initiation, changes in dosing, and whether or not the neurostimulant was continued at hospital discharge. discharge prescriptions were assessed for dose taper instructions, no taper instructions, or no mention of the neurostimulant. no protocol for neurostimulant administration following acute stroke existed during the study. no single clinical effectiveness measure following neurostimulant administration after an acute stroke has been defined. accordingly, we adapted the approach used by studies evaluating acute administration of amantadine to tbi patients [ , ] . acute stroke patients were characterized as responders if they met two of the following three criteria on any one calendar day within days after neurostimulant initiation: increase in gcs score ≥ points from pre-treatment baseline, clinical improvement in wakefulness or responsiveness documented in caregiver notes, or clinical improvement in wakefulness or responsiveness documented in physical or occupational therapy notes. caregiver notes and gcs scores were assessed by a neurocritical care physician assistant (aml), and physical and occupational therapy notes were assessed by a doctor of physical therapy (kn) and a registered, licensed occupational therapist (jc). supplement describes the approach used by these chart reviewers. patients who did not meet the definition for responsiveness were classified as non-responders. if patients had an additional neurostimulant added or substituted, the timing of this change was considered when interpreting which drug the patient responded to or did not respond to. since there was no published literature to establish an expected duration of treatment prior to a response, if a patient responded after at least h of a new combination, we considered them a responder to the new regimen. potential confounders of the clinical effectiveness assessment were identified a priori, including hydrocephalus, intracranial pressure (icp) crisis, seizure, cerebral vasospasm or ischemia, craniotomy for hematoma evacuation, and receipt of a concomitant psychoactive medication (including sedation for mechanical ventilation). hydrocephalus was defined as placement of a cerebrospinal fluid (csf) shunting device with radiographic evidence of ventriculomegaly. intracranial pressure crisis was defined as an icp > mmhg and/or dilated pupils requiring decompressive surgery or hyperosmolar therapy. new seizures were defined as treatment (not prophylaxis) with an antiepileptic drug and/or electroencephalographic seizures beginning after neurostimulant initiation. radiographic cerebral vasospasm was present if diagnosed by transcranial doppler ultrasound, computed tomography angiography, or digital subtraction angiography. delayed cerebral ischemia was present if focal neurological deterioration requiring fluid bolus, vasopressors, or intraarterial vasodilators occurred. craniotomy for hematoma evacuation was identified by reviewing neurosurgical procedure notes. mechanical ventilation was identified by reviewing respiratory flow sheets and required an endotracheal tube or tracheostomy with use of a ventilator. administration of psychoactive medications (sedatives, opioids, antiepileptics, antipsychotics, or sleep aids) was identified by reviewing the electronic mar. supplement includes a list of the potential confounders encountered in this study and suggested approaches to account for them in future studies. potential adverse drug effects were selected based on published studies [ , ] , the prescribing information for amantadine and modafinil [ , ] , and our anecdotal experience. these included spasticity, confusion, sleep disruption, seizures, qtc prolongation (amantadine), agitation, and delirium. spasticity and confusion were identified by reviewing caregiver notes. sleep disruption was present if the patient received a new sleep medication after starting a neurostimulant, and for the other adverse events, the medical record was reviewed for the h prior to initiating neurostimulant therapy, and if the adverse event was not described prior to initiation but was identified afterward, we considered it possibly drug related. measurements of qtc were obtained from -lead electrocardiograms (ecg) and were considered prolonged if > ms after an initial ecg with a normal qtc. agitation and delirium were assessed using a previously published algorithm [ ] . the probability that an adverse reaction was related to neurostimulant administration was not assessed using grading scales (e.g., naranjo scale or bradford hill criteria) because of the numerous confounders present in icu patients, and the lack of demonstrated validity and reliability in critically ill patients. instead, as is standard with good clinical practice for research, we reported all potential adverse drug effects [ ] . continuous data are reported as median (interquartile range - %), and categorical or dichotomous variables as number and percentage. discharge status was grouped into two outcomes, either "home or acute rehabilitation, " or "skilled nursing facility, hospice or death. " response rates according to neurostimulant administered and discharge locations were compared using chi-square analysis or fisher's exact testing and p < . was statistically significant. if a patient transitioned to another neurostimulant for non-response or adverse event, they were counted in both medication categories. adverse events and responsiveness were assigned to the medication they were receiving at the time these were first detected. two hundred five patients received amantadine and/ or modafinil during the . year study period and patients were initially excluded: neurostimulant administered for an indication other than acute stroke (tbi [n = ], cardiac arrest [n = ], brain tumor [n = ], encephalitis [n = ], or encephalopathy [n = ]); neurostimulant prescribed prior to hospital admission (n = ) or administered for < h (n = ); or history of seizures (n = ). after our initial chart review of patients, inconsistent data prompted a second review in which patients were confirmed to have received drug for < h; these were excluded from the effectiveness analysis but maintained in the safety analysis. the final evaluable cohort for effectiveness included acute stroke patients. the median age was ( , ) years, and most patients were male (n = ; %) and caucasian (n = ; %) ( table ). the cohort included patients ( %) with an ich, ( %) with an is, and ( %) with a sah (all aneurysmal). at the time of neurostimulant initiation, ( %) patients were receiving mechanical ventilatory support. the hospital mortality rate was / ( %); no death was associated with neurostimulant administration, and most patients ( / ; %) were discharged to acute rehabilitation (table ) . the initial neurostimulant administered was amantadine in ( %) patients, modafinil in ( %), or both amantadine and modafinil simultaneously in ( %). neurostimulants were initiated a median of ( . , . ) days post-stroke (range - days). indications for neurostimulant administration in caregiver notes included somnolence ( %), not following commands ( %), lack of eye opening ( %), or low gcs ( %); more than one indication could be documented for each patient. time of day for neurostimulant administration was variable, but most twice daily doses were administered at : and : , and most daily doses were administered at : . the most common initial dose of amantadine in patients with an estimated creatinine clearance (crcl) > ml/min was mg twice daily (n = ; %), followed by mg once daily (n = ; %) or mg once daily (n = ; %). among three patients with impaired kidney function, the initial dose was mg once every other day (n = ; %, crcl = ml/min), or once weekly doses of mg or mg (one patient each) for two patients receiving hemodialysis. the amantadine dose was increased in ( %) patients a median of ( , ) days after initiation for persistent somnolence (n = ; %), not following commands (n = ; %), lack of eye opening (n = ; %), low gcs (n = ; %), aphasia (n = ; %), or an undocumented reason (n = ; %); more than one reason could be documented for each patient. the amantadine dose was decreased in ( %) patients a median of . ( , ) days after initiation due to delirium (n = ; %), agitation (n = ; %), or an unknown reason (n = ; %). modafinil was added to patients who initially received amantadine monotherapy a median of ( , ) days following amantadine initiation, with an initial modafinil dose of mg once daily in ( %), mg twice daily in ( %), and mg daily in ( %) patients. the most common initial dose of modafinil was mg twice daily (n = ; %), less frequently mg twice daily (n = ; %), mg once daily (n = ; %), or mg three times daily (n = ; %). the modafinil dose was increased in ( %) patients and days after modafinil initiation for somnolence or not following commands (n = each). the modafinil dose was decreased in ( %) patients and days after modafinil initiation for agitation (n = ) or an unknown reason (n = ). amantadine was added to ( %) patients who initially received modafinil monotherapy a median of ( , . ) days following modafinil initiation, with an initial amantadine dose of mg twice daily (n = ; %), mg once daily (n = ; %), or mg every h (n = ; %). in patients starting both amantadine and modafinil simultaneously, the initial dose of amantadine was mg twice daily (n = ; %) or mg twice daily (n = ; %) and for modafinil it was mg twice daily (n = ; %) or mg twice daily (n = ; %). the amantadine dose was increased from mg twice daily to mg twice daily days after initiation in ( %) patient because they were not following commands. with transitions to different medication groups, and including patients in every medication group they received, a total of patients received amantadine monotherapy, continuous variables are reported as median (iqr) and frequencies as number (%). responder denominators sum to more than patients because patients were included in multiple groups if they transitioned to different medications ich, intracerebral hemorrhage; icu, intensive care unit; sah, subarachnoid hemorrhage; snf, skilled nursing facility a from the enrolled subjects, were excluded from effectiveness analysis, including who died and who were transferred to rehabilitation or skilled nursing facilities b this single patient was discharged to hospice, expired h after transfer, and was counted as a death in fig. icu length of stay, days ( received combined amantadine/modafinil therapy, and received modafinil monotherapy at some time during their hospitalization. of the ( %) patients who survived to hospital discharge, ( %) patients had their neurostimulant stopped prior to discharge, and ( %) were provided neurostimulant prescriptions. amantadine prescriptions were provided to ( %) patients, ( %) received a modafinil prescription, and ( %) received a prescription for both neurostimulants. among the discharge neurostimulant prescriptions, ( %) included dosing without taper instructions, ( %) had taper instructions, and ( %) included no information about continuing or tapering the neurostimulant. among the patients included in the clinical effectiveness analysis, ( %) were considered responders, including / ( %) receiving amantadine monotherapy and / ( %) receiving both amantadine and modafinil at the time they first met the definition of a responder; no patient receiving modafinil monotherapy was a responder (p < . ; fig. , table ). the median time from neurostimulant initiation to responder status was ( , ) days (range - days). responders were more frequently discharged to home or acute rehabilitation compared to non-responders ( % vs %, p = . ; fig. ). many factors potentially confounded the effectiveness assessment. the most common was hydrocephalus (n = ; %), including / ( %) patients with ich, / ( %) with sah, and / ( %) with is. most of these patients (n = ; %) required csf diversion. supplement includes a complete list of confounders, their estimated impact on our assessments, and a recommended approach for future studies. among the patients included in the safety analysis, the most common potential adverse drug effect was sleep disruption requiring administration of a new sleep medication (n = ; %) (fig. ) . other potential adverse drug effects occurring after neurostimulant initiation included agitation (n = ; %), spasticity (n = ; %), and qtc prolongation (n = ; %) with amantadine. new onset seizures requiring antiepileptic drug administration occurred in ( %) patients (n = with ich and n = with is). amantadine was discontinued due to seizure in one is patient and continued in the other four. amantadine was discontinued in patients a median of ( , ) days after initiation. the decision to stop was made by clinical teams, and included sustained wakefulness after and days of treatment (n = ; %), or adverse drug effects including agitation (n = ; %), anxiety (n = ; %), delirium (n = ; %), seizures (n = ; %), qt prolongation without arrhythmia (n = ; %), and decision to transition to comfort measures only (cmo) (n = ; %). modafinil was discontinued in one patient days after initiation due to insomnia and agitation. participation in rehabilitation activities during acute stroke care and eventually in specialized rehabilitation settings is an important component of stroke recovery and is prioritized in stroke guidelines [ , ] . neurostimulants have proven beneficial for tbi patients when administered in rehabilitation units and, with weaker evidence, earlier in their recovery during acute care [ ] [ ] [ ] . this study represents the largest cohort of stroke patients treated with neurostimulants during their acute hospitalization, and suggests amantadine started in the first week after stroke may be associated with improved wakefulness or responsiveness in approximately half of treated patients. responders showed a promising trend with more frequent discharge to home or acute rehabilitation compared to non-responders, but these findings must be considered hypothesis-generating. early rehabilitation after stroke is recommended by the american heart association and american stroke association [ ] , and efforts to increase rehabilitation participation during acute stroke care with neurostimulants may be beneficial in somnolent or non-participatory patients. in our study, patients were started on neurostimulants a median of days after stroke, with a single patient starting in the first h. the best time to start neurostimulants is not known, and caution has been advised to avoid very early, high-intensity mobilization in the first h after acute stroke, since this has been associated with a reduction in favorable outcome at months [ , ] . several patients had neurostimulants started late in their hospital course and were either transferred or had support withdrawn prior to h of treatment. it is not clear if a longer duration of monitored dosing would have resulted in a response or not, but because of the short administration time, we excluded them from our effectiveness analysis. among our responders, the median time to response was days, providing some justification for this a priori threshold for minimal duration. no valid and reliable clinical effectiveness measure exists to assess response to neurostimulants in the acute adverse effects by neurosƟmulant administered amantadine modafinil both fig. potential adverse drug effects during neurostimulant administration. potential adverse drug effects were identified by reviewing provider progress notes, the medication administration record, electrocardiograms, and nursing flow sheets. causality assessments were not conducted due to the presence of confounding variables in this patient population. *qtc prolongation was only assessed in patients receiving amantadine care setting after stroke. studies describing amantadine administration to one rehabilitation and five acutely hospitalized stroke patients utilized the coma recovery scale-revised (crs-r) and disability rating scale (drs) [ , ] . a randomized study comparing modafinil and placebo administration within days of stroke reported the multidimensional fatigue inventory at , , and days post-stroke [ ] . the lack of consensus supporting a specific clinical effectiveness measure in the acute stroke setting and the retrospective nature of our study necessitated the development of a novel method. glasgow coma scale was shown to increase during acute administration of amantadine to and tbi patients [ , ] ; we utilized a similar approach. assessing the effectiveness of neurostimulant administration during acute stroke care is complicated by patient care needs, which often persist into the rehabilitation phase (e.g., mechanical ventilation or medications for sedation, analgesia, or seizures). even in the rehabilitation setting, medications confounded assessment of responsiveness in prior studies for up to a third of patients [ ] . the common sequelae of stroke (e.g., pain, seizures, vasospasm, hydrocephalus, and intracranial hypertension) also complicated our neurostimulant response assessments. for example, hydrocephalus (which required csf diversion % of the time) may have induced somnolence, while csf diversion or unclamping external drains may have induced wakening. similarly, intubated patients who are liberated from mechanical ventilation may become more interactive as their communication improves and sedation is reduced. a recent study of tbi patients treated acutely with neurostimulants in the icu encountered many of the same confounders [ ] . supplement includes a list of the potential confounders we encountered in this study and suggested approaches to them in future studies. the most common potential adverse drug effect was need for a new sleep medication, suggesting sleep disruption may have been occurring. our most common administration schedule of amantadine at : and : may alleviate this, but this remains unproven. two subjects were initially prescribed twice daily doses at : and : ; both had insomnia noted and the timing of doses was adjusted to : and : . the ideal dose and whether a predictable dose-response relationship exists for amantadine during acute stroke care is unclear. amantadine may increase the number of postsynaptic dopamine receptors or alter their conformation over several weeks, suggesting time of daily administration may not influence sleep [ ] . the most concerning potential adverse drug effect during amantadine therapy was seizures, though it was impossible to assess causality since seizures are not rare after the types of stroke we studied. amantadine has been safely administered to patients with epilepsy since the mid- 's [ ] , but caution is still required. many patients had multiple other reasons for potential adverse effects (i.e., confusion potentially caused by amantadine or modafinil, urinary tract infection, steroids, vasospasm, hydrocephalus, or hypernatremia). prior studies examining the accuracy of delirium screening following acute stroke using the cam-icu have suggested decreased accuracy results [ ] [ ] [ ] . the number of patients with delirium in our study was low but use of accurate screening tests after stroke in future studies may increase recognition. all adverse events identified have been previously reported, though it is possible other adverse drug effects occurred and were not identified in our retrospective study. several limitations of this study warrant comment. due to the paucity of published data for stroke patients treated with neurostimulants in the acute setting, no protocols or robust data were available to guide us or allow for a power calculation. we performed this retrospective evaluation to obtain baseline data and response estimates to help design future studies. reliance on caregiver notes was an additional limitation but prompted us to incorporate more consistent documentation regarding neurostimulant administration and response. it was not possible to control for changes in the quality of caregiver and pt/ot documentation over time as neurostimulants were more frequently administered. physical and occupational therapists used a semi-structured template including initial and subsequent evaluations, which differ in frequency and domains evaluated from patient-topatient. future studies in the acute care setting should utilize a clinical effectiveness measure that evaluates the indication for neurostimulant use and regularly assesses response. whether adding a second neurostimulant (if no improvement is observed from the initial neurostimulant) adds benefit, risk, neither, or both is unclear. herrold and colleagues retrospectively evaluated tbi patients treated with neurostimulants in a rehabilitation center, finding that those treated with multiple agents had no better outcome than those treated with a single medication [ ] . given the lack of an untreated control group in this retrospective study, we cannot be certain that any improvements resulted from the medications and it is possible they reflect the natural phase of recovery over time after stroke. not all patients were monitored for the full -day period after starting or changing a neurostimulant, due to transfers to rehabilitation or skilled nursing facilities or decisions to withdraw lifesustaining therapy. ideally, a consistent follow-up period would have been maintained for all patients. similarly, after a change in neurostimulant, a response within the first few days could be from the new regimen or a delayed response from the initial treatment. it is possible our approach to assign credit for a response to the new regimen if > h of drug had been given was incorrect. our results suggest modafinil may not be effective as monotherapy in the acute care setting, but larger, prospective studies are needed. in a non-randomized study, potential bias related to gender, comorbidities, severity of illness, or other factors must be considered. lack of response to modafinil in our study may have been the result of a mechanism of action separate from dopamine neurotransmission. pre-clinical and clinical data suggest dopamine activity is disturbed following acute stroke, and dopamine supplementation or augmentation may be of benefit, but this requires confirmation [ , ] . analysis by stroke type and location was not possible due to the small sample size. such an analysis may be important as previous studies have suggested stroke location may play a role in neurostimulant responsiveness [ ] . due to small numbers, we did not include patients who received other neurostimulants, such as dextroamphetamine or methylphenidate. prior data have been published for these agents [ , ] , and amantadine and modafinil were the two most prescribed stimulants in a recent acute tbi study [ ] . continuing medications started in the icu at the time of hospital discharge may be inappropriate in some settings [ ] , but in the case of neurostimulants, declines were seen when medication was stopped after weeks in tbi patients [ ] , suggesting continuation may be appropriate. initiation of neurostimulants during the acute care of patients admitted with is, ich, or sah is potentially associated with improved wakefulness. those who responded were more frequently discharged home or to acute rehabilitation, but we can neither confirm these improvements were medication related, nor that these outcomes are generalizable to other settings. these results are encouraging but must be considered hypothesis-generating given the uncontrolled nature of the study, and the many potential biases and confounders. further study using standard dosing and escalation strategies, prospective assessment of response and drug safety, and appropriate controls is needed. the online version of this article (https ://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. author contributions aml, rrr, and djg contributed to study design, data collection and manuscript development. tm and dbs contributed to study design and manuscript development. csb, kn, and jc contributed to data collection. ae contributed to study design. all authors approved the final manuscript prior to submission. this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. heart disease and stroke statistics- update: a report from the prevalence and most common causes of disability among adults-united states multimorbidity in stroke stroke research priorities meeting steering committee and the national advisory neurological disorders and stroke council, national institute of neurological disorders and stroke. research priority setting: a summary of the early mobilization after stroke: early adoption but limited evidence american heart association stroke council, council on cardiovascular and stroke nursing, council on clinical cardiology, council on quality of care and outcomes research, et al. guidelines for adult stroke rehabilitation and recovery: a guideline for healthcare professionals from the post-stroke apathy and hypersomnia lead to worse outcomes from acute rehabilitation deep structural brain lesions associated with consciousness impairment early after hemorrhagic stroke amantadine: a new clinical profile for traumatic brain injury amantadine as n-methyl-d-aspartic acid receptor antagonist: new possibilities for therapeutic applications? a systematic review of modafinil: potential clinical uses and mechanisms of action the intersection of central dopamine system and stroke: potential avenues aiming at enhancement of motor recovery placebo-controlled trial of amantadine for severe traumatic brain injury the effects of amantadine on traumatic brain injury outcome: a double-blind, randomized, controlled, clinical trial amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: a pilot double-blind randomized trial modafinil may alleviate poststroke fatigue: a randomized, placebo-controlled, double-blinded trial can amantadine ameliorate neurocognitive functions after subarachnoid haemorrhage? a preliminary study attention level and event-related evoked potentials in patients with cerebrovascular disease treated with amantadine sulfate: a pilot study the outcome of patients with severe head injuries treated with amantadine sulphate stimulant therapy in acute traumatic brain injury: prescribing patterns and adverse event rates at level trauma centers north wales: teva pharmaceuticals valproate for agitation in critically ill patients: a retrospective study guideline for good clinical practice e (r ) very early versus delayed mobilisation after stroke efficacy and safety of very early mobilisation within h of stroke onset (avert): a randomised controlled trial awakening with amantadine from a persistent vegetative state after subarachnoid haemorrhage pharmacological changes in dopaminergic systems induced by long-term administration of amantadine outside the box: medications worth considering when traditional antiepileptic drugs have failed routine use of the confusion assessment method for the intensive care unit: a multicenter study deconstructing poststroke delirium in a prospective cohort of patients with intracerebral hemorrhage in the middle of difficulty lies opportunity-albert einstein prescribing multiple neurostimulants during rehabilitation for severe brain injury dopamine for motor recovery after stroke: where to from here? effect of modafinil on subjective fatigue in multiple sclerosis and stroke patients effect of dextroamphetamine on poststroke motor recovery: a randomized clinical trial effect of methylphenidate and/or levodopa combined with physiotherapy on mood and cognition after stroke: a randomized, double-blind, placebo-controlled trial an analysis of psychoactive medications initiated in the icu but continued beyond discharge: a pilot study of stewardship the authors report no conflicts of interest. we adhered to ethical guidelines. the institutional review board at maine medical center reviewed this study design and determined it to represent exempt research. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -dzl afq authors: stoclin, a.; rotolo, f.; hicheri, y.; mons, m.; chachaty, e.; gachot, b.; pignon, j.-p.; wartelle, m.; blot, f. title: ventilator-associated pneumonia and bloodstream infections in intensive care unit cancer patients: a retrospective -year study on prospectively monitored patients date: - - journal: support care cancer doi: . /s - - - sha: doc_id: cord_uid: dzl afq purpose: some publications suggest high rates of healthcare-associated infections (hais) and of nosocomial pneumonia portending a poor prognosis in icu cancer patients. a better understanding of the epidemiology of hais in these patients is needed. methods: a retrospective analysis of all the patients hospitalized for ≥ h during a -year period in the -bed icu of the gustave roussy hospital, monitored prospectively for ventilator-associated pneumonia (vap) and bloodstream infection (bsi) and for use of medical devices. results: during first stays in the icu, cases of vap and primary, secondary, and catheter-related bsis were recorded. the vap rate was . / ventilator days ( % confidence interval [ci] . – . ); the catheter-related bsi rate was . / catheter days ( % ci . – . ). the cumulative incidence during the first days of exposure was . % ( % ci . – . %) for vap, . % ( % ci, . – . %) for primary, . % ( % ci . – . %) for secondary and . % ( % ci . – . %) for catheter-related bsis. vap or bsis were not associated with a higher risk of icu mortality. conclusions: this is the first study to report hai rates in a large cohort of critically ill cancer patients. although both the incidence of vap and the rate of bsi are higher than in general icu populations, this does not impact patient outcomes. the occurrence of device-associated infections is essentially due to severe medical conditions in patients and to the characteristics of malignancy. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. intensive care unit (icu) patients develop life-threatening healthcare-associated infections (hais) more frequently than other patients due to their acute illness and invasive procedures. infection surveillance networks provide comparative hai data that can be adjusted, at least partially, for intrinsic and extrinsic risk factors in patients [ ] . the hai rates differ electronic supplementary material the online version of this article (https://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. according to the icu type and patient mix [ ] . among the hais, ventilator-associated pneumonia (vap), clinical sepsis and bloodstream infections (bsis) are associated with a poorer prognosis [ ] . a growing number of cancer patients are admitted to icus and regular improvement of their prognosis has been observed [ ] . the rare publications available show high hai rates [ ] and the poor prognosis of nosocomial pneumonia in critically ill cancer patients [ ] . there is a need for a better understanding of the epidemiology, risk factors, and outcomes concerning hais in this population. our main objective was to report the incidence of vaps and bsis in critically ill cancer patients based on a -year prospective cohort in our oncology icu. our secondary objectives were to describe pathogen distribution and assess the risk factors for hais and their potential influence on icu mortality. the gustave roussy cancer centre is a tertiary care hospital treating exclusively patients with solid or hematological malignancies. the average annual admission volume in the -bed medical surgical icu is to patients. a dedicated infection control team is in place since . we collected data from the hospital activity and associated expenditure database (programme de médicalisation des systèmes d'information, pmsi) and from the icu case report forms for stays ≥ h. the pmsi national database contains information on admission categories, patient demographics, disease characteristics, eastern cooperative oncology group performance status (ecog-ps [ ] ), and simplified acute physiology score (saps ii [ ] ). the icu registry is based on a questionnaire, filled out by the same two physicians since . the case report forms include information on the following: invasive devices (mechanical ventilation [mv] and central venous catheters [cvcs]), hais (vap, primary bsis, catheter-related bsis, and secondary bsis), neutropenia (white blood cell [wbc] count < /mm or acute leukemia) before admission (duration and nadir), and outcomes at discharge from icu (infections [date of diagnosis, pathogen] and death. mv by intubation or tracheotomy and cvcs (including totally implanted ports and hemodialysis lines) were studied. as the majority of long-term cvcs were used throughout the icu stay, we did not differentiate between long-term and temporary central lines. all patients were prospectively monitored for infections from admission to h after discharge. all the icu stays between january , , and december , , were considered. during this period, the main change in routine practice was the use of a sedation scale for mechanically ventilated patients since . the data are strictly confidential and available only to authorized clinicians and staff. (medical procedures are described in the supplementary material) diagnostic techniques and infection criteria remained unchanged during the study period. all cases of pneumonia and bsis were audited by two authors (as, fb) in - , using the microbiology data and medical records. all clinically suspected vap were confirmed using a quantitative culture of distal respiratory tract secretions, bblindly,^or via a fiberoptic bronchoscope (or sometimes a semi-quantitative culture of sputum after extubation). for details, see web supplements. bacteremia or fungemia were defined as at least one positive blood culture (except for skin commensals). bsis were classified as primary, secondary, or catheter-related bsi (cr-bsi) (see supplementary material). we retrospectively described the use of invasive devices in terms of the number of devices, median placement time, and inter-quartile ranges (iqrs). device usage rates (ratio of the duration of device use to the duration of the stays) were calculated separately for the first (per patient) icu stays and for the remaining stays. we computed the rates of hais as times the ratio of the total number of infections to the total number of icu days. hai rates were calculated as ( ×) the ratio of the total number of infections (vap and cr-bsis) to the total duration of the device. for patients with several stays exceeding h, only the first stay was included in the prognostic analyses. analogously, only the first hai was considered. to verify whether the infection risk was constant over time, we compared the exponential estimation of the cumulative incidence to the % confidence bands of the kaplan-meier estimate. we identified factors associated with infection using logistic models adjusted for the exposure time. we computed univariate models, then multivariate models via stepwise selection based on likelihood ratio tests (α in = . , α out = . ). the methods used for sensitivity analyses and factors associated with mortality are shown in the supplementary material. all analyses were performed using sas . and r . . the number of icu stays was , of which lasted < h (flowchart: figure s ). the number of first stays ≥ h was to per year until , then it increased. the median length of the icu stay was constantly about - days ( figure s ). table describes patient characteristics. among the stays ≥ h, were first stays (median duration days). most of the patients ( ; %) were admitted for medical reasons; ( %) had solid tumors, and ( %) had metastatic disease. at icu admission, patients ( %) had experienced leukopenia, for more than days in ( %) cases. the icu mortality rate was constantly %. among the first stays (n = ), patients ( %) experienced one or more episodes of mv (median duration days) and patients ( %) underwent at least one cvc placement (median dwell time days; le s ). the total cvc dwell time ( , days) exceeded the total duration of stays ( , days) because most patients had several catheters, including cvcs (preexisting and implanted in the icu). the icu device usage rate was . % for mv and . % for cvcs. figure shows the yearly number of stays ≥ h with devices and median device duration. during the first stays (table ) the most common secondary bsis were of abdominal origin ( . %, / ). thirty-four bsis were due to vap and to urinary tract infections. figure shows the number of stays with at least one hai of each type. among the patients with infections, % ( ) experienced only one type of infection, two types, three, and all four types. the most common pathogens (table s ) were gram-negative aerobes bacilli ( isolates, . %) and gram-positive cocci ( isolates, . %). candida species and other fungi accounted for isolates ( . %). polymicrobial infections were recorded in / ( . %) vaps (first episodes) and / ( . %) bsis: / ( . %) primary bsis, / ( . %) secondary bsis, and / ( . %) cr-bsis. almost . % of bloodstream isolates (n = ) were candida species, % (n = ) of which were candida albicans. figure shows the cumulative incidence rates of vap and primary and secondary bsis and cr-bsis. the results of multivariate prognostic analyses are summarized in table , and details are provided in the supplementary material (tables s -s ) . among the patients with mv, were excluded from the prognostic analyses ( had vap) due to missing values among risk factors. vaps were recorded for ( %) of the fig. ). the duration of mv, older age, scheduled surgery, and solid tumors were vap-specific risk factors (table s ) . among the first stays, were excluded from the prognostic analyses for the risk of bsi ( had primary and secondary bsis) because of missing values among risk factors. primary bsis were recorded for ( %) of the remaining stays. the cumulative risk of primary bsi after a -day icu stay was . % ( % ci . - . %; fig. ). the length of stay, a high saps ii score, scheduled surgery, ecog-ps > , absence of metastases, and recent leukopenia were significant risk factors (table s ) . secondary bsis were recorded for / stays ( %). the cumulative risk of secondary bsis after a -day icu stay was . % ( % ci . - . %; fig. ). the length of stay, surgery, and leukopenia were significant risk factors for secondary bsi (table s ) . among the patients with a cvc, were excluded ( had cr-bsi) because of missing risk factors. cr-bsis were recorded for ( %) of the remaining stays. the cumulative risk of cr-bsis after a -day cvc dwell time was . % ( % ci . - . %; fig. ). no significant risk factors were associated with the risk of cr-bsi, probably due to a lack of power (the low number of cr-bsis; table s ). sensitivity analyses (tables s -s ) confirmed the robustness of these results. the occurrence of a vap episode or bsi was not associated with a higher risk of icu mortality in the univariate or multivariate analyses (table s ) . a significantly higher risk of death was observed for high saps ii and ecog-ps values, medical admission, and the presence of metastases. we presented the results of a retrospective study on prospectively collected data, with drastic quality control measures which eliminated some inconsistencies. the stability of the admission categories, severity scores, and length of stay suggest that the case mix has not changed over time. to our knowledge, this study is the largest prospective series ( ; years) on hais in cancer patients (see supplementary material). the study began after the introduction of alcoholbased hand gels. the main change in routine practice was the use of a sedation scale for mechanically ventilated patients since . specific comments on device usage rates, slightly different from those reported previously, are given in the online supplementary material. briefly, the rate of catheter use is higher (almost all of our patients have a long-term intravascular device) and the mv rate is lower [ ] but has been increasing over time. as we focused on avoidable device-associated infections only, the overall incidence cannot be compared with other non-cancer populations. we observed a higher vap rate ( . / ventilator days) than in other studies ( / at the end of the s to < / during the past decade [ , ] ), but lower than the vap rate in the only study in cancer patients ( / [ ] ). the incidence of vap may have been underestimated given that microbiological samples were postponed when palliative care was decided, and some patients may have died with untreated pneumonia (or, similarly, with undiagnosed bsi…). immunodeficiency due to malignancies and anticancer therapies can explain the high rate of vap in cancer patients. however, neutropenia did not appear to be a risk factor for vap, which is consistent with other studies [ , ] . we observed a higher bsi rate ( . / icu days) than that reported in a mixed population of french icu patients ( . / ) [ ] and by the french national surveillance network [ ] ( . / ). our cr-bsi rate ( . / catheter days) is higher than those reported in the usa [ ] . mixing long-term and short-term cvcs in our study makes interpretation difficult: the reacat study excluded long-term and pre-inserted cvcs. interestingly, when cr-bsi secondary to long-term and short-term cvcs were examined in a post hoc analysis, a very similar infection rate was observed for catheters previously inserted when in the operating room (including totally implanted ports) and those inserted during the icu stay. unlike the steadily declining device-associated infection rates often reported [ , ] , our incidence of cr-bsi increased between and and then decreased to below / cvc days ( figure s , right) . we focused on cr-bsis because they are more sensitive to preventive interventions than central line-associated bsis and more relevant for comparisons between icus [ ] . the distribution of germs is relatively close to that of general icu populations, except for yeasts and anaerobic organisms. candida species represented . % (n = , including cases of candidemia during leukopenia) of the isolated blood culture organisms, a rate that is similar to [ ] or higher than [ ] that of previous reports. indeed, our population exhibited many recognized risk factors for candidemia [ ] . our high rate of anaerobic germs ( %) is mainly due to the numerous heavy abdominal surgery cases admitted in our center. scheduled surgery and a solid tumor were vapspecific risk factors, mainly due to hyperthermic intraoperative peritoneal chemotherapy (hipec) surgeries and esophagectomies, with regular complications requiring mv. surgery (scheduled or not) and leukopenia were risk factors for secondary bsi, which could be due to hipec, often complicated by leukopenia and peritonitis. nevertheless, after excluding scheduled surgery patients (table s ) , unscheduled surgery and leukopenia remained significant risk factors. mucosal barrier injury (bsi), due to neutropenic enterocolitis, is not preventable and is classified as a secondary bsi in our study: in this case, leukopenia is not only a risk factor but also the fig. number of first stays in the intensive care unit (total = ) with at least one of each type of infection. vap ventilator-associated pneumonia, pbsi primary bloodstream infections, sbsi secondary bloodstream infections, cr-bsi catheter-related bloodstream infections cause of the bsi. the fact that icu mortality was not influenced by the occurrence of vaps or bsis means that nosocomial infections mainly reflect the severity of the underlying disease or of the patient's condition. nevertheless, we had no information on the adequacy of initial antimicrobial treatment, a key point in mortality attributable to vap [ ] . finally, the design of our study does not allow a detailed analysis of the real prognostic burden of each hai on mortality; aggregation of data into broad categories, such as vaps and bsis, lessens the actual impact of some types of hai on the prognosis. thus, the occurrence of a deep fungal infection in a neutropenic patient obviously has a greater impact on the prognosis than a catheter-related fungemia, for example. identifying the mortality indeed attributable to each hai (rather to underlying conditions) would require further analysis and studies. the occurrence of device-associated infections is essentially due to severe medical conditions in patients and to the characteristics of the malignancy, but these infections do not influence the outcome of icu cancer patients. given the data were obtained in an oncology icu in a specialized cancer center, extrapolation from these findings should be made very cautiously. however, these data may be useful for comparative studies with other oncology icus and for developing quality improvement activities. they could be also useful for comparison with hai rates in the era of innovative treatments such as immunotherapy. estimated probabilities (pr) with their % confidence interval ( % ci) from univariate and multivariate analyses, adjusted for the icu length of stay. for each category, the probability is computed for a mean profile of the other factors vap ventilator associated pneumonia, pbsi primary bloodstream infection, sbsi secondary bloodstream infection, saps simplified acute physiology score, ecog ps eastern cooperative oncology group performance status and fr had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. author contributions as and fb contributed to conception and design. as, mw, and mm were involved in the data acquisition. fr and jpp planned and performed the statistical analyses. all the authors were involved in the interpretation of the results, read, and approved the final manuscript. conflict of interest the authors declare that they have no conflict of interest. national nosocomial infections surveillance system ( ) nosocomial infection rates in adult and pediatric intensive care units in the united states. national nosocomial infections surveillance system the prevalence of nosocomial infection in intensive care units in europe. results of the european prevalence of infection in intensive care (epic) study. epic international advisory committee intensive care of the cancer patient: recent achievements and remaining challenges nosocomial infections in an oncology intensive care unit nosocomial pneumonia in haematological malignancies in the medical intensive care unit toxicity and response criteria of the eastern cooperative oncology group a new simplified acute physiology score (saps ii) based on a european/north american multicenter study a report from the nnis system effect of an education program aimed at reducing the occurrence of ventilator-associated pneumonia consider saying yes prognosis of neutropenic patients admitted to the intensive care unit outcomes of primary and catheter-related bacteremia. a cohort and case-control study in critically ill patients saint-maurice : institut de veille sanitaire sustaining reductions in catheter related bloodstream infections in michigan intensive care units: observational study national healthcare safety network (nhsn) report, data summary for , deviceassociated module catheter-related vs. catheter-associated blood stream infections in the intensive care unit: incidence, microbiology, and implications bacteremia and severe sepsis in adults: a multicenter prospective survey in icus and wards of hospitals. french bacteremia-sepsis study group epidemiology of candidemia: a oneyear prospective observational study in the west of france attributable mortality of ventilator-associated pneumonia: a metaanalysis publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgments we thank monique monhonval for data entry, pascale jan for technical support, and lorna saint ange for editing. as key: cord- -e g lns authors: nan title: poster sessions - date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: e g lns nan the improvement in p/f ratio in the hfov group compared to cmv was statistically significant [at hours (p= . ) and hours (p= . )] and this trend continued through the study period. though the fio was higher in the hfov group at baseline, by , and hours this was significantly lower as compared to cmv group(p< . and p< . and p< . respectively)and again this trend continued over the study period. we studied patients with heatstroke admitted in icu during the august heat wave in france. plasma samples were available at the admission for all patients and during the course of the disease in patients. to assess the extent of the inflammatory response in the patients, plasma concentration of cytokines was studied by elisa. leucocyte activation was evaluated by the expression of eta integrins and l-selectin by flow cytometry using specific moabs; reactive oxygen production (ros) by chemoluminescence and metalloproteases mmp and mmp by gelatin zymography. as markers of cell activation and/or apoptosis, microparticles (mp) isolated from plasma were double-stained with annexinv (av) and cell specific moabs against platelets (cd ) or granulocytes (cd ) and analyzed by flow cytometry. microparticles procoagulant phospholipids were measured by prothrombinase assay. whole blood and microparticles tf was determined by a specific clotting assay. increased levels of il , il and il -ra were observed whereas il , il -eta and tnflpha were normal or undetectable (table) . blood leucocyte activation was demonstrated by:-an up-regulation of eta -integrin expression, -a down-regulation of l-selectin expression, -an increased ros production. moreover, pro-mmp and , possibly released by activated granulocytes were increased in the tested patients with presence of active mmp in three. markers of dic (thrombocytopenia, decreased fvii and fv levels, presence of soluble fibrin and increased levels of tat) were observed in / patients. whole blood tf was increased in all patients ( ± pg/ml, mean ±sd) vs controls (< pg/ml). compared to healthy controls, the number of av positive mps was not increased, but the cellular origin was different, with a significant decrease in platelet mps (p< . ) and a significant increase in granulocyte mps (p< . ). furthermore, mps tf was increased and contributed for a large part to the high procoagulant state. high levels of inflammatory cytokines play a crucial role in leucocyte activation leading to down regulation of l-selectin, ros production and active mmp . our results suggest a major role of mps of granulocyte origin in the tf-dependent procoagulant state that correlates with the severity of the disease. kalenka a , münch e , fiedler f departement of anesthesiology and critical care medicine, faculty of clinical medicine mannheim, university of heidelberg, mannheim, germany introduction: recombinant factor viia (rfviia; novoseven, novo nordisk, agsvaerd, denmark) has been approved for prevention and treatment of bleeding in patients suffering from hemophilia with inhibitors. numerous case reports and retrospective studies submitted to a webbased drug surveillance have been published, that record the sucessfull use of rfviia to treat lifethreatening haemorrhage in patients without pre-existing coagulation disorders. however, it is unknown whether rfviia induces hemostasis in septic patients with disseminated intravascular coagulation. therefore, the objective of this study was to investigate clinical efficacy of rfviia in septic and non-septic patients with bleeding complications methods: between / and / , adult patients with life-threatening haemorrhage without pre-existing coagulopathy were entered into the study retrospectively. out of patients with severe sepsis and dic (known infection and at least organ dysfunction) and non-septic patients with severe bleeding complications due to different reasons, we reviewed coagulation parameters and the amount of transfused blood products prior to and hours after application of rfviia. the patients´s underlying diseases and dosages of administered rfviia are illustrated in table . relevant thromboembolic complications were recorded results: prior to administration of rfviia, . ± . (mean ± standard error of the mean) units of red blood cells (rbc), . ± . units of fresh frozen plasma (ffp) and . ± . units pooled platelets (plt) were substituted to the non-septic patients. after administration of rfviia, significantly less rbc . ± . (p< . ), ffp . ± . (p< . ) and plt . ± . (p< . ) were transfused. coagulation analysis demonstrated normalisation of international normal ratio ( . ± . versus . ± . ; p< . ) and partial thromboplastin time ( ± . s vs. ± . s; p< . ) after administration of rfviia. no differences were detected concerning the platelet count. in the septic-group administration of rfviia neither resulted in a reduction of transfused blood products nor in a reversed coagulopathy. three thromboembolic complications were observed in the non-septic patients. mortality rate was % in the non-septic group vs. % in the septic group (p= . ) marsilia p f , imperatore f , munciello f , scarpelli m , teodori r , de cristofaro m , occhiochiuso l unit of anaesthesia and intensive care, department of emergency, a. cardarelli hospital, naples, italy introduction: acute septic descending mediastinitis (asdm) has been defined as the mediastinum infection which results from the spreading of oropharyngeal infections, or deep neck structures ( ). drotrecogin-alpha (activated) or recombinant human activated protein c (rhapc) is the only biological agent approved for use in severe sepsis syndrome that has demonstrated efficacy in reducing -day all-cause mortality and new data suggests a trend towards longer term survival( ). very few data in literature report the use of rhapc in the treatment of asdm. aim of this study is to report our experience of cases of asdm complicated by a severe sepsis-induced multiple organ failure syndrome (mofs) and successfully treated with the infusion of rhapc. four male and three female patients were admitted to our intensive care unit for asdm due to oropharyngeal infection and complicated by a severe sepsis-induced mofs. all patients were undertaken to combined cervicotomy and thoracotomy surgical operation with toilette and drainage of infection. moreover the infusion of rhapc at gamma/kg/min for hours was given together with all other certain established procedure. respiratory failure was managed with sedation, orotracheal intubation and invasive mechanical ventilation. cardiac failure was managed with invasive arterial and central venous pressure monitoring together with the infusion of catecholamines up to standard doses; while renal failure was managed with continuos venous-venous haemodiafiltration. antibiotics were given first empirically and then according to lab test results. in cardiac surgery, more than in any other type of surgery, in early postoperative period can occur low cardiac output syndromes due to hypovolemia or to myocardial failure. our objective is to evaluate the accuracy of the systolic pressure variations (spv) and of its negative component ∆ down under mechanical ventilation in predicting the response to volume loading and to diagnose hypovolemia. in a group of patients who underwent cabg surgery, in the early postoperative period we monitored: co/ci, cvp, pcwp, bp (s/d/m), vps and ∆ down. the including criteria were: sinus rhythm, ci ≤ . l x min- x m-?, pcp < mm hg. all the patients underwent a fluid challenge ( ml of colloids in min). according to the ci variation the patients were then divided in two groups: group a ( pts) with a raise of ci > %, and group b ( pts) with a ci variation < %. we analyzed the variations of the parameters mentioned above due to fluid loading and the differences between the two groups. in the following table are the data obtained. all parameters are measured in mm hg and are expressed as the average value ± standard deviation (*p< . ).statistical analysis shows significant differences between the two groups regarding only the initial value of spv ( . ± . mm hg in group a, . ± . mm hg in group b, p< . ) and ∆ down ( . ± . mm hg in group a, . ± , mm hg in group b, p< . ). there also significant differences of the values before and after the fluid challenge only in group a and for the same parameters: spv (from . ± . mm hg to . ± . , p < . ) and ∆ down (from . ± . mm hg to . ± . mm hg, p< . ). in predicting a significant raise of ci after volume loading a spv > mm hg the new parameters of preload dependency tend to replace the classic pressure parameters in hemodynamic assessment, being more accurate as predictor of ci response to volume loading and as detector of hypovolemia ( ). the low costs and accuracy of the spv method advocate for using it in critical care settings, even in cardiac surgery. marangoni e , volta c a , alvisi v , bertacchini s , ragazzi r , orlando a , alvisi r anesthesia and intensive care, university of ferrara, ferrara, italy several studies provide compelling evidence on the clinical role played by fluid optimization. till now, the assessment of the intravascular volume has been based on data derived by pulmonary-artery catheter. however, some studies suggest that the use pulmonaryartery catheter is associated with an increased mortality and hence the central venous pressure (cvp) remains the only parameter to be used. nine patients undergoing mechanical ventilation were enrolled. cvp was determined while patients were breathing spontaneously (sb) and during assisted control ventilation (acv) at different peepe levels ( - - - cmh o). patients clinical characteristics are (mean±sd): age (yr) ± ; weight (kg): ± ; tidal volume (ml, acv): ± ; respiratory rate (b.min- , acv): ± ; static compliance of the respiratory system (ml.cmh o- , acv): ± . the following parameters were determined: mean airway pressure (acv), mean systemic blood pressure (map), cvp. the most dramatic increase of cvp was registered when the patients were ventilated in acv compared to spontaneous ventilation ( fig. ) . surprisingly, cvp values were much less influenced by progressive rise of mean airway pressure obtained by different peepe level. moreover, map variations were closely linked to those of cvp. our data shows that cvp monitoring is useful for assessing the intravascular volume in patients requiring high peepe level. however, the cvp values obtained during acv are very different from those calculated during sb and hence, when possible, it is advisable to determine cvp during sb. pottecher j , bouyges s , caron s , moreau x , beydon l dept of anesthesia, hôpital larrey, angers, france routine use of pulmonary artery catheters (pac) measuring continuous cardiac output but not svo is controversial in cardiac surgery. oxygenation derived variables like arteriovenous oxygen difference (avdo ) could better reflect supply-demand balance than cardiac index (ci). moreover, bedside, respiratory changes in arterial pulse pressure (deltapp) are a more reliable indicator of fluid responsiveness than pressures obtained from pac (cvp and pcwp). the goal of our study was to compare two hemodynamic assessment methods: one based on pac derived variables, the other taking avdo and dpp into account. fifty consecutive mechanically ventilated patients emerging from cardiac surgery in a university hospital icu were included without informed consent since pac insertion is systematic in our institution.an independent observer simltaneously recorded pac variables (cvp, pcpw, ci) (first set, s ), avdo and deltadpp (second set, s ). initially, the caring physiscian could get the first set of value, was asked about volemia, inotropism and vasomotor tone and gave a therapeutic option. then he had access to the second set of value, answered the same questions and was able to maintain or to change his opinion. patients were divided in four categories, according to deltapp (< or >= ) and avdo (< or >= ) and discrepancies between the two sets of answers were analysed. based on s data, new drugs or therapeutic were introduced ( % of patients): inotropic drug, fluid loading, diuretic, vasodilatator, vasopressor. after knowing s , in patients ( %) we challenged the initial decision. deltapp did not correlate with cvp nor with pcpw. similarly, ci did not correlate with avdo . according to table: case : therapies decided knowing s challenged by s : all should not have been fluid loaded; case : therapies decided knowing s challenged by s : they should have received a fluid load; case : therapies decided knowing s challenged by s : should not have been fluid loaded and should have received inotropes; case : therapies decided knowing s challenged by s : should have been fluid loaded and should not have received inotropes. deltapp >= (n) deltapp >= (n) avdo < ( ) case ( ) case avdo >= ( ) case ( ) case conclusion: conventional pac measurements do not allow optimal therapeutic guidance, postoperatively in cardiac surgery. indeed, ci does not reflect metabolic requirements at best measured by avdo . also, cvp and pcpw do not reflect hypovolemia contrarily to deltapp. the association all data provided by s albers j , heggemann f , kayhan n , bahner m , vahl c f abt. herzchirurgie, icu, abt. radiodiagnostik, chirurg. universit, heidelberg, germany noninvasive imaging of coronary artery disease (cad) using multidetector computer tomography (mdct) provides theoretically additional information to the classical d coronary angiography. the objective was to determine: ( ) how accurate is the d imaging compared to the d method? ( ) is it feasible to profit from the additional d information in the clinical setting? methods: study population consisted of consecutive patients with diagnosis of -vessel-cad (n = ).every patient underwent both, d coronary angiography and mdct scanning (siemens somatom plus vz, slice thickness . or . mm, pitch . , contrast medium ml). retrospective gating was used. d visualization was performed using raytracing. comparison of d and d imaging was performed in a blinded manner, blinded investigators scored applicability of the coronary segments (cs) for aortocoronary bypass grafting (acb) (necessary/not necessary) and stenosis (stenosis < %/ - %/ - %/ - %). ( ) agreement in applicability for acb was (cs number/% agreement) / . , / . , / . , / . , / . , / . , / . , / . , / . , / . . cs rarely being object to acb, showed poor agreement: / . , / . , / . , / . , / . . agreement in quantification of stenosis was: . % for the right coronary artery, . % for the left anterior descendent and . % for the circumflex coronary artery. ( ) d volume data were acquired in a single breathhold. temporal resolution was ms (reconstruction time min/image) enabling calculation of stroke volume. d visualization showed distribution of coronary calcifications together with non-calcified lesions. severe cad was identified noninvasively in all cases studied. ( ) accuracy of the d method was sufficient for bypass planning purposes. however, quantification of stenosis was not acceptable. ( ) data acquisition was quick, safe and provided additional data superior to conventional d (calcification, soft plaques, d quantification of stroke volume). in conclusion, patients with severe cad can be diagnosed with high accuracy using noninvasive imaging. boulo m , fleyfel m , robin e , lebuffe g , lecoutre h , onimus j , tavernier b , vallet b anesthesiology and intensive care medicine, university hospital, lille, france aortic surgery can be taken as a model of fluid and blood losses leading to volume status variation and hemodynamic impairment. these variations together with aortic clamping may compromise tissue perfusion. in intubated and ventilated operated patients, respiratory pulse pressure variation (∆pp) reflects ventricular preload dependency ( ). ∆pp is a good predicting marker of increase in stroke volume index (svi) after a fluid challenge (fc) ( ). the aim of this study was to evaluate whether preload dependency as assessed by ∆pp measurement was associated with impaired tissue perfusion. after approval from the local ethics committee, patients undergoing aortic surgery were prospectively enrolled. intraoperative hypovolemia was suspected when heart rate increased and/or systolic blood pressure dropped more than % from baseline. a ml colloidal fc was then systematically performed. automated gastric tonometry (tonocap, datex-ohmeda, finland) was used to assess pgco -petco before and after fc (co gap- ,co gap- ) . an increased co gap larger than mmhg can be taken as a threshold value of decreased tissue perfusion. an increased svi larger than % was identified as responder (r) and fc was repeated until svi did not increase more than % again. an increase in svi of less than % was identified as non-responder (nr conclusion: increased production of gut wall lactate was previously shown to be associated with increased leakage of macromolecules across the gut wall due to gut barrier dysfunction ( ). in this study we were able to show that even short and uncomplicated cpb leads to increased gut wall lactate detected by gut luminal microdialysis, indicating gut barrier dysfunction. simultaneous tonometry proved to be insensitive to these changes. we propose that gut luminal microdialysis in the rectum may be a good method to estimate markers of metabolism and gut barrier dysfunction during surgery and in the critically ill patient. matamis d , tsagourias m , vakalos a , synefaki e , kareklas m icu, papageorgiou general hospital, thessaloniki, greece introduction: copd patients are often aged, smokers and may suffer from right ventricular (rv) failure. moreover, they may have smoking and age -related diseases of the left heart, as ischemic heart disease or valvulopathies. left ventricular (lv) failure may induce hypercapnic respiratory failure (hrf) and mimic the clinical picture of copd, especially in patients with heavy smoking history. the aim of our study was to identify, in patients with hrf leading to mechanical ventilation (mv), the prevalence of rv, lv, or biventricular failure, the presence of severe valvulopathies and the impact of the targeted cardiac treatment (according to echo findings) on the mv days and mortality. over a period of seven years patients ( m and f) with a mean age of ± years and a mean apache score of ± included in the study. heart function was assessed with echo within the first hours from intubation. patients were divided in three groups (rv failure, lv failure and normal heart group) according to echo criteria. cardiac treatment was given according to echo findings. respiratory treatment and weaning process was identical in all patients. anova and chi square test were used for statistical analysis. the objective of this study was to measure the cost-effectiveness of an igm enriched immunoglobulin preparation in adult patients treated for severe sepsis and septic shock. we performed a meta-analysis followed by an economic analysis conducted from the hospital perspective in germany. effectiveness data from a meta-analysis of eight randomised trials (n= ) was used to assign probabilities in a decision model to estimate cost-effectiveness of igm enriched immunoglobulin preparation and its comparator standard therapy. analysis of effectiveness data used all cause hospital mortality as the primary outcome and intensive care (icu) length of stay (los) as a secondary outcome. benefit was expressed as lives saved (ls). published icu treatment cost data was applied to assess differences in treatment costs. cost-effectiveness was calculated as the incremental cost per ls. we develop a systematic data collection of all the admitted patients in our icu through a home-made software and database leading to a broad description of the population and activities of the icu during the last five years; this was correlated with the classical scoring systems of icu patients. the system was utilisator friendly made by automatically generating hospitalisation icu reports which guaranteed the use of the database and its completion. at the end of each year and after a data validation period standard reports were generated with classical parameters: mean age of the population, mean length of stay, mortality rate, readmission rate, daily repartition of all the icu admissions ... and correlated with the severity of the icu population. the following observations were noted during this five years period: non significant elevation of the mean age and of the mean icu length of stay, but significant reduction of the global mortality while the mean icu scores remain stable. in the same period the number of icu technical procedures (right catheterisation days, artificial ventilatory days, cvvhdf days...) was also significantly higher but without significant influence on nosocomial infection rate. interesting management data were also available: more than thirty procent of the icu patients were admitted during the night shifts (between pm and am) which can be an important data to discuss the staffing problems (during the night shifts for example). the use of antibiotics was also significantly reduced during the same period. a five years data collection period of standard icu indicators correlated with the use of severity scores can be an interesting icu management tool to promote quality of care (and communication procedures inside and outside the icu) and to reduce mortality and morbidity in icu populations. further studies are necessary to confirm these interesting observations. the national intensive care evaluation (nice) registry (www.stichtingnice.nl) aims to analyse and improve the quality of dutch intensive care. the nice registry contains data items for each patient admitted to one of the participating icus. to support the individual icus in comparing their population and performance to several standards nice has introduced an internet application, nice online. users of nice online compose their own data analyses by selecting a)functions, b)split-elements, c)comparisons, d)subpopulations. figure (left side) shows an example of a request for a graph which presents the mean length of stay (function) for survivors and nonsurvivors (split-element) of the user's own icu and of all participating icus together (comparison). readmissions to the icu are excluded (subpopulation). results of analyses, presented in graphs or tables, can easily be copied, e.g. to management reports. privacy of patients and of icus is ensured by )login and password, )encryption of transferred data, )using a copy of the original nice database without patient-or icu-identifying information, )disabling combinations of functions and comparisons which may lead to identifiable information. in figure transport of the critically ill patient between hospitals or intrahospital remains an hazardous road trip where the patient is exposed to less controlled circumstances outside the icu. to gain more insight in the incidence of complications, circulatory-and respiratory instability (ci/ri) related to intrahospital transport, we investigated transports from our surgical icu. all data concerning transports from the surgical icu to the department of radiology from - were retrospectively reviewed. clinical relevant circulatory instability (ci) was defined as the necessity to start vasoactive medication(vam)or to change the existing dosage of vam during or directly after transport to maintain a map ≥ . clinically relevant respiratory instability (ri) was defined as the need to change the settings of the mechanical ventilator (fio , peep, minute volume) during or directly after transport. we also evaluated the administration additional opiates and sedatives (aos) prior to or during transport and the possible impact of i.v. administration of contrast fluid jopromide (ultravist ®) on renal function. sedation and analgesia are essential components of patient care in the intensive care unit (icu). "bottom up" costing of intensive care is more accurate but more labour intensive and difficult to perform compared to "top down" costing ( ). "bottom up" cost of sedative, analgesic and neuromuscular blockade drugs have not been reported. we therefore performed an audit of the cost of these drugs in our icu using the "bottom up" costing approach. over a month period, we prospectively recorded the daily amount of sedative, analgesic and neuromuscular blockade drugs administered to patients in a -bedded icu and multiplied the amounts by the cost of drug per milligram using pharmacy costing figures. patients were divided into groups that corresponded, roughly, to the length of stay quartile marks. out of patients admitted during the study period, data were collected for ( %). we also collected data for % ( days) of icu patient days. table shows cost of sedation per group, patient and icu day. around % of the cost was on drugs administered to the % of patients who stayed in icu for more than hours. propofol and alfentanil were the commonest drugs used (administered to % and % of patients respectively) and the most expensive ( , and , respectively). total cost was , which was % of the pharmacy ("top down") cost. cost of sedation per group. several medical specialities have conducted surveys among their residents during their training, in order obtain a feed back and assess possible improvement issues. at our knowledge, not such a survey has been conducted in europe. in france, icu specialisation can be obtained by two separate trainings: either specifically in medical icus or jointly to the anaesthesia training which is followed by the majority of future icu practitioners. a shortage in icu doctors is expected, urging raised efforts to make this training as attractive as possible. this inquiry was intended as a first step in this purpose. a question questionnaire was mailed to the first year residents (y ) whereas a question one was sent to the forth year residents (y ) registered to the joint icu-anaesthesia training program (lasting years) in france. anonymity of answers was insured. a total of questionnaires were received ( %) for y and ( %) for y . main y answers were: age: ± year, ( % female). they chose icu for good job opportunities ( %), a clinical ( %) and dynamic ( %) speciality. they had discovered icu-anesthesia during medical studies ( %). night shifts were: not disturbing ( %), are shared by many other specialities ( %), and are more interesting that non-specialised night wards ( %). a % of them hesitated before starting this specialisation. half of them changed geographical region for specialisation. medical english was spoken and red: %. a computer was owned personally: %. main y answers were: ± year, ( % female), their -year training was judged for theory: excellent ( %), good ( %), fair ( %); for practical teaching: excellent ( %), good ( %), fair ( %). medical english was spoken and red: %. only % had a position at the end of their training. they wished to join public institutions: %, private: %. research was a professional issue for %. future practice restricted to icu was aimed by %, whereas % preferred anaesthesia and % emergency medicine and pain clinics. they had published in french at least once during training: %, in english: %. additional degrees (mainly in infectiology and as sub-specialisation in some icu techniques) were obtained by % during specialisation. periods spent in non-academic hospitals (one year) were rated as excellent: %, good: %, fair: %; and medical supervision was judged excellent-good in %. they spent an average euros/year for medical furniture (books, computer). a computer was owned personally: %. finally, % did not regret choosing icu (and anaesthesia) as a speciality. training in icu (and anaesthesia) was judged as good especially for practical aspects by most of residents. about a third aimed at working exclusively in icu. more efforts should be performed to improve formal job offer at the end of the training. conclusion: diagnostic and imaging testing represents a significant amount of hospitalization costs in our icu due to the high number of tests performed per patient per day and especially for abg analysis. thus, a better control of lab tests ordering will result in costs reduction and a cost containment policy is becoming mandatory. kanevetci b n a c i , dosemeci l , y?lmaz m , cengiz m , ramazanoglu a anesthesiology and reanimation, akdeniz university, antalya, turkey the common problem arising in the icu's is the use of the beds for the patients who are expected not to benefit from icu treatment. in this prospective study, we aimed to determine the proportion, costs, length of icu stay and prognosis of those patients who were expected to die according to our clinical experiences. one hundred and forty five patients over year of age admitted to our -bed icu between march and february and expected not to benefit from icu treatment according to the experiences of the physicians working in icu. the apache ii, saps ii and gcs scores were noted and according to those scores, the estimated mortality rates were determined by the formulas. also icu stay, icu beds occupied by those patients, icu and hospital discharge mortality and morbidity and costs were determined. we didn't change the treatment strategies of those patients. the patients who had high risk of mortality but could possibly recover completely after given therapy were not included in the study. the mean age was . ± . . the most common underlying diseases were nontravmatic intracerebral hemorrhage ( % . ), cerebrovascular accident ( % . ), head injury ( % . ), metastatic tumors and vascular diseases of gastro-intestinal tract ( % . ), cardiac arrest ( % . ), lung cancer and end-stage lung diseases ( % . ) and the others ( % . ). the mean gcs, apache ii, saps ii scores were . ± . , . ± . , . this represents a % increase in activity with no change in the number of beds available or alteration to admission criteria. in both time periods bed occupancy was > %.length of icu stay decreased from a mean of . days to . days (p< . )and the length of ventilation decreased from . days to . days (p< . ). this reduction was observed across all specialites excluding neurosurgery. the use of information technology to provide iterative feed back has reinforced the adoption of the ventilator and euglycaemia carebundles making the desired elements of the care bundle the default mode within the intensive care unit. the culture of the icu has changed enabling more reflective practice ready for the adoption of the sepsis care bundle and other packages of evidence based treatment. papadopoulos a c , karakoulas k k , vassilakos d , filippidou m , skourtis c t h , giala m m anaesthesiology and intensive care, ahepa university hospital, aristotle university of thessaloniki, thessaloniki, greece proper heparinization is perhaps the most important aspect of sampling technique for arterial blood gas and ph analysis. ( ) the aim of our study was to evaluate two sampling techniques for arterial blood gases and ph measurements and their possible cost implications. we obtained paired samples from postoperative spontaneously breathing patients in icu having an indwelling arterial line. body temperature and blood hb of patients were within normal ranges. commercially available preheparinized (quik a.b.g.tm, marquest medical products, co, usa) and self-prepared with liquid sodium heparin syringes were used. ( ) the pao , paco and ph values were obtained from the same analyzer within minutes of sampling. the cost of each sampling technique was also estimated. data were analyzed by bland and altman analysis. the mean differences (+/-sd) between the results of the sampling techniques were - . (+/- . ) mmhg for pao , . (+/- . ) mmhg for paco , and - . (+/- . ) for ph. the % confidence interval was . - . for pao , . - . for paco , and . - . for ph. the correlation coeffiecient (r) between measurements from the two syringes was r= . for pao , r= . for paco , and r= . for ph. the cost of each sampling technique was . euros for preheparinized and . euros for self-prepared syringes, per sample. our data demonstrated a relationship between the results of the two sampling techniques, close enough, to justify the use of self-prepared heparinized syringes for arterial blood gas and ph measurements. a significant -fold cost reduction would result by the routine use of this latter technique. we checked the performance degree of the following measures in two stages, pre and post intervention: prophylaxis of pulmonary embolism (pe), elevation of the head of the bed to > degrees, intensive insulin therapy, lower tidal volumes in acute lung injury, daily trial of spontaneous breathing, daily withdrawal of sedation, stress ulcer prophylaxis and use of nimodipine in subarachnoid hemorrhage.the intervention consisted in the handing over of written information and talk on the therapeutics measures to the medical staff and to the nursing. conclusion: with only one diagnose, the system is unable to identifie the complex cases. the stay and most of the icu procedures, do not interfere nor modify the weight of the drg. dias f s , nagel f , wawrzeniak i , fonseca c , guerreiro m , froemming j , canabarro m general icu, hospital são lucas da pucrs, porto alegre, brazil there is no information regarding the impact of the resident in critical care medicine on the outcome of critically ill patients in our environment. we performed a comparative study between two periods in an icu, the first without ccmsp (pi) and the second with ccmsp (pii). we collected prospectively the following data: gender, age, apache ii and mods in days (d ), (d ) and (d ), prevalence of sepsis/septic shock, duration of mechanical ventilation (mv), use or renal replacement therapy and icu survival. between january and june , there were icu admissions, of which in the pi period ( ) ( ) and in the pii ( ) ( ) ( ) ( ) . after the implementation of a ccmsp, despite an increase in organ dysfunction in d and in prevalence of sepsis/septic shock, there was a significant reduction in the utilization of renal replacement therapy and mortality. these findings suggest that, the participation of a ccmsp medical resident was an important factor in the support of septic patients, reduction in renal replacement therapy and mortality. pachl j , haninec p , tencer t , tomas r , mizner p anaesthesiology and ccm, dept. of neurosurgery, charles university, rd school of medicine, prague, czech republic introduction: delayed cerebral ischemia due to vasospasm is a major cause of death and disability in patients after subarachnoidal hemorrhage (sah). the outcomes of several experimental studies designed to investigate an effect of nitric oxide donors on the treatment and prevention of this life-threatening condition appear controversial [ , ] . the purpose of our study was: ) to specify the influence of prophylactic subarachnoidal administration of sodium nitropruside (snp) on the incidence of vasospasm ) to determine the role of brain tissue monitoring-pbtio , pbtico and phbti, measured in the area of high risk of vasospasm, for management of snp administration. prospective observational study on patients with non-traumatic sah (hunt-hess grade i-iv) with secured ruptured aneurysma. in postoperative period all patients underwent triple-h protocol with calcium channel blocker. subarachnoidal preventive snp was administred in initial dose of mg by catheter which was inserted to basal cisterns during neurosurgical procedure. the timing of following dosage (period of or hrs) was directed by the changes of pbtio , pbtico and phbti after snp administration. snp administration did not exceed a period of postoperative days. the brain tissue respiratory values were estimated by codman neurotrend multiparameter sensor®. the blood flow velocity was simultaneously measured on circuit of willis by transcranial doppler sonography (tcd). in case of detected signs of vasospasm the dosage of snp was increased and maintained by monitoring modalities (tcd and values of pbtio , pbtico , phbti). : patients were enrolled. no brain infarction was developed in the studied group. all patients survived. the vasospasm was identified in two patients by tcd and simultaneously by changes of tissue respiratory values.these patients arrived at hospital with delay of several days from the beginning of symptoms. the overall outcome was good in out of patients including patients with vasospasm. preventive subarachnoidal administration of snp controled by tcd and brain tissue multiparameter sensor might increase the effect of triple-h protocol with calcium channel blocker. multimodal brain tissue monitoring could be the way to maintain titratable prophylactic snp administration. the therapeutical intervention requires considerable raise in doses frequency and its effect cannot be evaluated until now. basílio c , rio e , barbosa s , paiva j , mota a department of anesthesiology and critical care, department of neurology, hospital s. joão, porto, portugal the search for drugs to minimize neuronal lesions after prolonged seizures has been the goal of treatment of patients with status epilepticus. topiramate is a new anticonvulsant with multiple mechanisms of action: potenciation of gaba, blockade of glutamate receptors (ampa), inhibition of sodium and calcium channels. recent studies state that topiramate is effective in treating refractory status epilepticus and may reduce post-status epilepticus neuronal lesions. description of two clinical cases of patients, admitted in the icu, with status epilepticus refractory to conventional therapy were treated with topiramate. case : woman, years old, with a history of alcohol abuse and psychiatric disease was admitted with encephalitis and tonic-clonic seizures. the patient was treated during days with hidantin, valproate sodium and thiopental. despite this, the eeg showed a periodic epileptiform activity. topiramate ( mg daily) was added to valproate with clinical improvement and an absence of ictal discharges on eeg after days. case : male, years old, admitted with hematemesis, shock and eventual cardiopulmonary arrest. admitted in the icu for postoperative care of duodenal ulcer surgery. two days later, the patient developed partial status epilepticus. he was treated with midazolam, clonazepam and phenytoin. the eeg showed bilateral periodic epileptiform discharges with no recent cerebral lesions in the cerebral ct scan. pentobarbital coma was induced for seven days. status epilepticus persisted despite appropriate measures and on the th day topiramate ( mg daily) was added to clonazepam. after days, there was clinical improvement and eeg showed periodic generalized slow wave activity with motor response to painful stimulus wich was a prediction for a better outcome. in both cases, topiramate was able to induce clinical improvement and disappearance of ictal discharges in the eeg in case . however, in case the pattern of eeg persisted with signs of better prognostic. it needs further investigation with larger prospective series to better confirm the results. van tulder l , chioléro r , regli l , revelly j , berger m surgical intensive care unit, neurosurgical, university -chuv, lausanne, switzerland hypovolemia is deleterious in patients developing a vasospasm after subarachnoid haemorrhage (sah). fluid resuscitation to induce hypervolemia is considered by many as the cornerstone of management. the efficacy of this approach is however not established.the aim was to assess the effect of fluid resuscitation on blood volume and fluid balance during the initial phase of icu management for cerebral vasospasm after sah retrospective analysis of the database of a clinical information system (metavision, imd soft). patients with the diagnosis of vasospasm after sah (angiography) were studied. cardiac index (ci) and intra-thoracic blood volume (itbv) measured with transthoracic thermodilution (picco, pulsion) were determined as part of the clinical management. fluid supply consisted of isotonic saline. the value of mean arterial pressure (map), ci, itbv, as well as fluid supply and fluid balance at time , , , and hours were analysed (presented as mean±sd). comparisons between these time-points were performed with one-way analysis of variance for repeated measurements. p< . was considered significant. results: ten patients were studied. fluid supply amounted to . ± . l at h, . ± . at h, and . ± . at h (p< . ). initial map was ± mmhg, ci . ± . l/min/m^ , and itbv ± ml/m^ . there was no significant change over time for these variables, although itbv increased to ± at h, and decreased to ± ml/m^ at h. cumulative fluid balance amounted to . ± . l at h, . ± . at h, and minus . ± . at h (not significant), due to a diuresis. despite aggressive volume loading with normal saline, the fluid balance of patients with vasospasm was not significantly altered over the first hours of icu admission. these preliminary data suggest that, these patients may become rapidly resistant to fluid loading due to induced natriuresis. this escape phenomenon, may contribute to the absence of documented benefit of fluid expansion in vasospasm this was a prospective study design. all cases of sah(n= )of ages between to years which were admitted over a period of thirteen monthswere included in this study. aneurysm detection criterion was digital substraction angiography or ct angiography. mean hunt-hess grading in coiling group was , whereas in clipping group it was . .fisher grade was > in all patients clipped and between - in patients coiled. exclusion criteria included cases witha-v malformation, preexisting neurological deficit or where no intervention was done. outcome analysis was done using modified rankins scale (mrs) and world federation of neurologicalsurgeons gradingwfns).stastisticallyanalysed using chi-square and standard error of difference between two means-tests results: % aneurysms (n= ) were coiled and %(n= ) were clipped. there were no significant differences in age race, gender, but there was a significant difference in the hunt-hess grading ( ajderian s stepan , petrov n department of anesthesiology and icu, military medical academy, sofia, bulgaria background: the modulation of the intracranial pressure in patients with head injuries is important precondition in the optimizing of the therapeutic management. the goal of the authors is to study the influence of the hypocapnea over intracranial pressure as a part of complex treatment of the head injuries methods: : there are encompassed patients with head injury ct-scan data for brain contusion and perifocal edema who assessed according glasgow comma scale under pct. all patients had ventricle drainage placed in one of the lateral brain ventricles in order to measure intracranial pressure and received standard therapy. the patients divided in two groups: i -in patients we applied controlled hypocapnea with ???? value between - mm hg and ii group - patients with ???? values between - mm hg. statistical program was used -sd, tcriteria and p-value. we received significantly dropping of the intracranial pressure in patients set at artificial ventilation with moderate hypocapnea. in first group the mean value of intracranial pressure was . mm hg. in this group ( %) patients died. botsis p , litis d , nikolopoulou i , chatzivasiliadis h , ioannidou h icu, kat hospital athens greece, athens, greece acute pancreatitis and acute acalculus cholecystitis are frequent and serious complications in severely head traumatized patients. the aim of this study is to find if the early administration of somatostatin plays a role in the prevention of these complications. methods: brain injured icu patients ( men and women), with no abdominal or thoracic trauma, were entered the study. age +/- , apache ii score ≤ , gc +/- on admission, with no signs of preexisting gallstones in the u/s of the upper abdomen. surgical on conservative therapy for the brain injury, with drugs known not to interfere with the pancreatic and biliary system and early e.n. via nasogastric tube, was performed. after the admission in icu they were divided into two groups: a) at group a ( patients) somatostatin ( ?g/h) was added in the standard therapy for the next days. b) at group b ( patients), the standard therapy was continued, as planned. daily laboratory tests for: temperature, blood type, bilirubin, blood sugar, ca, alkaline phosphatase, serum-urine amylase, serum-lipase and daily clinical examination as well for: pain and tenderness of the abdomen, vomiting, distention, decreased bowel sounds. every second day an u/s of the upper abdomen was performed. at patients of group b ( %) and at patient of group a ( %) acute pancreatitis was developed the th day-of-stay in icu. at patients of group b ( %) and at patients of group a ( %) acute acalculus cholecystitis was developed as well at the same day. diagnosis of both complications was based on clinical and laboratory findings. early administration of somatostatin in brain injured icu patients diminishes the possibility of development of acute pancreatitis, but does not influence the development of acute acalculus cholecystitis in these patients. rijnsburger e r , girbes a r , spijkstra j j , peerdeman s m , polderman k h department of intensive care, department of neurosurgery, vu university medical center, amsterdam, netherlands hypothermia is widely used to improve neurological outcome in various types of neurological injury; however, this has not yet been well studied in patients with subarachnoid haemorrhage (sah), where cooling has been used mainly to prevent or treat vasospasms [ ] . hypothermia has been used to treat refractory intracranial hypertension in patients with tbi and severe stroke; however, its potential to treat cerebral oedema in patients with sah has not been well studied [ ] . only one small feasibility study dealing with this issue has been published, but here various interventions (such as induction of barbiturate coma and mild hypothermia) were applied simultaneously [ ] . thus it remains to be determined whether induction of hypothermia per se can decrease icp in patients with sah. methods: patients admitted with sah and refractory intracranial hypertension (icp> mmhg lasting longer than minutes despite prevention of hypovolemia or induction of hypervolemia, induction of hypertension, and treatment with nimodipine, mannitol and hypertonic saline, and following coiling or clipping of the cerebral aneurysm) were treated with induced hypothermia ( - oc) according to a protocol guided by icp. hypothermia was induced using cooling blankets and infusion of refrigerated fluids. target temperatures were achieved within (range - ) minutes. icp decreased from . ± . to . ± . (normal value: < mmhg). icp< mmhg was achieved in / patients; in / patients icp decreased but remained at levels between - . hypothermia was maintained until normal icp had been observed for hours, after which patients were slowly rewarmed (again guided by icp). hypothermia was maintained for an average of ± hours. no patients died during treatment with hypothermia. two patients ( . %) died in the icu after hypothermia was discontinued; ( . %) died in the subsequent months. good functional outcome at months (glasgow outcome score - ) was achieved in patients ( . %). previous studies had reported a high incidence of side effects such as pneumonia in patients treated with hypothermia. we observed no increase in infectious problems, perhaps because our patients were treated with sdd. conclusion: induced hypothermia can be safely and effectively used to treat refractory intracranial hypertension in patients with sah. vasospasms and intracranial hypertension are thought to be the two key factors in the development of additional brain injury in sah; however, it remains to be determined whether this treatment also improves neurological outcome and survival in these patients. to evaluate the usefulness of magnetic resonance images (mri) in patients suffering from severe brain injury, unfavourable clinical progress and marshall brain scans types i and ii. fifteen patients with severe brain injury were retrospectively studied, considering their age, gender, initial gcs initial head scans and mri upon admission to intensive cares unit (icu), their outcome (gos) at discharge form icu. mri level i was defined as being when the subcortical white matter was affected, mri level ii being level i plus affectation of the corpus callosum, and mri level iii was defined as being mri-ii as well as damage to the brain stem and spinal cord. gos was also evaluated, defining gos i-ii as positive and gos iii, iv and v as negative. the average age of the patients studied was . years old. nine ( %) were males and six ( %) were females. the average gcs on admission was . . five patients ( %) had and initial marshall scan type i and ten ( %) had marshall scan type ii. two patients ( . %) showed mri-i, five ( %) mri-ii and eight ( . %) mri-iii. in the two patients with mri-i their initial gcs was . and both progressed favourably and were discharged from intensive care unit. the five patients with mri-ii had an initial gcs of . three of these ( %) did not progress well. in the eight patients with mri-iii, the initial gcs was . . seven of these ( . %) progressed unfavourably when discharged from intensive care. magnetic resonance images are related to the severity of head damage and have a high diagnostical and prognostical value for use with patients suffering from diffuse axonal lesions. pakulski c , badowicz b , bak p , kwiecieñ k , mikulski k , surudo t department of emergency medicine, pomeranian medical university, szczecin, poland, intensive care unit, regional hospital, pasewalk, germany, traumacentre, pomeranian medical university, szczecin, poland the management of patients with severe head injury should include monitoring of mean arterial pressure (map) and intracranial pressure (icp), cerebral perfusion pressure (cpp) and levels of jugular bulb oxygen saturation (sjo ). the aim of the study is to present the outcome in patients with severe central nervous system injuries treated in the traumacentre, pomeranian medical university. this retrospective study evaluates the methods of treatment in patients with severe brain injury treated between july st, and december st, in the our traumacentre. these patients were admitted to our institution directly from the accident sites or from the referring hospitals during the first post-injury day. glasgow coma score of or less was the inclusion criterion. in all patients map and icp values were monitored, cpp values were calculated, and additionally in patients sjo values were measured. the initial treatment protocol was always the same: analgosedation (fentanyl, midazolam), normoventilation, osmotic diuretics (mannitol , - , g/kg/day in doses and furosemide , - , mg/kg/dose in doses), supine position. the protocol was modified with regard to map, icp and sjo values (brain ischemia or brain hyperemia). the patients with increased icp values resistant to osmotic diuresis were scheduled for unilateral or bilateral decompressive craniectomy. the results of treatment were evaluated with glasgow outcome classification after months following the injury. the mortality in our ample was , % - deaths out of treated patients. isolated brain injury was the cause of death in patients, and in patients-multi-organ injury. sixty seven ( , %) patients were transferred from the trauma icu for further treatment to other wards. out of the patients discharged from the trauma icu patients died -goc ( , %), none of the patients were in the neurovegetative state -goc ( %), patients with persistent aphasia or hemiparesis were classified as goc ( , %), patients with mild neurological deficits that didn't impair their social life were classified as goc ( , %), and finally patients without any neurological sequelae were classified as goc ( , %). out of patients with treatment modified according to sjo values patients survived. brain hyperemia was found in non-survivors and severe brain ischemia was found in non-survivors. the outcomes in our patients treated with the protocol based on monitoring of cpp and sjo are encouraging. monitoring of sjo is a significant element of the modern treatment protocol for patients with brain injury and the best method of diagnosing both hyperemic and ischemic episodes. anastasiou e , tsaousi g , giannakou m , efthimiou k , geka e , albanèse j , boyadjiev i , chaabane w , antonini f , leone m , martin c intensive care and trauma center, hopital nord, marseille, france in severely head-injured patients, it is often needed to add vasopressive amines to maintain adequate cerebral perfusion pressure (cpp). norepinephrine (n) and dopamine ((d) are proposed, but their vasoconstrictive effects may be deleterious for regional circulations.objective is to compare the effects of d and n on cerebral, splanchnic, and renal circulations when used to raise cpp after severe head injury. prospective, randomized, cross-over study including patients with head trauma, requiring intracranial pressure (icp) monitoring and vasopressor therapy. after and min of administration of d or n, were studied : systemic hemodynamics (mean arterial pressure (map), cardiac index (ci), central venous oxygen saturation (svo ), cerebral circulation (icp, cpp, transcranial doppler : mean velocity in the middle cerebral arterey (vmca)), splanchnic circulation (gastric intramucosal ph (phi)), renal circulation (urin flow (uf), creatinine clearance (clcreat) and metabolic data (energy expenditure) (es), oxygen consumption (vo ), and lactate (lac)). the wilcoxon signe test was used with p< . considered significant. they are presented in table . no significant differences were observed in systemic hemodynamics when the two drugs were compared. none of the studied local circulation were altered with any of the studied drugs. vakalos a , doukelis p , kareklas m , setzis d , matamis d i.c.u, papageorgiou general hospital, thessaloniki, greece in patients with severe head injury the main complication is cerebral edema and intracranial hypertension that may cause cerebral ischemia, disability and in certain cases brain death. transcranial doppler (tcd) is a non-invasive, bedside technique which detects the blood flow velocities in the great intracranial arteries. the aim of our study was to investigate if there is a relationship between tcd findings and the outcome of patients with severe head injury. methods: patients with severe head injury (gcs< ) were included in our study. from these patients were males and females. their mean age was . years, with a range from to years. among these patients died in the icu ( . %). in each tcd examination we measured the maximum, mean and the end diastolic velocity (vmax, vmean and vmin respectively), and we calculated the pulsatility index (pi). the patient's outcome was recorded at the disharge from the icu according the glasgow outcome scale as following: good recovery (gr), moderate disability (md), severe disability (sd), persistent vegetative state (pvs) and death. the patient's outcome was compared with the cerebral flow velocities and the pi index. there was a statistically significant difference in the mean values of all velocities between the outcome categories of the patients. we found the stronger difference in the mean values of vmax and vmin between the death and the categories pvs and sd, and in the mean values of vmean between the death and the categories pvs, sd and md. inter-hospital transfers of the critically ill patient raises important medical and ethical dilemmas . in a transfer questionnaire assessed the views of intensivists in scotland, regarding the problem, that when no intensive care bed is available, is it ever acceptable to transfer an existing patient to another facility to create a bed for a new referral . % of scottish consultants would not transfer a stable patients to create space for a new patient under any circumstances. reasons given included no intrinsic benefit to the current patient and that there was a designated transfer team who were experienced in transferring critically ill patients and providing critical care without walls. this time the questionnaire was repeated among intensivists in south thames to determine any regional variation. the questionnaire was sent to consultants in intensive care units (icus). consultants were asked if they would ever consider transfer of an existing patient to another hospital in order to admit a new referral and if so what would they consider the most compelling reasons for doing so.we also asked whether or not formal consent was sought prior to undertaking a transfer and what risks, if any, were explained to the patient and their family. prior knowledge of their wishes regarding this form of therapy is essential in order to preserve their autonomy. objective: to examine the knowledge of copd patients related to the illness, about mechanical ventilation as a potential treatment and their wish to participate in the health care decision-making process and advanced care planning. methods: a qualitative research of an intentional sampling of homogeneous subgroups with copd outpatients (ii and iii by gold score) was performed between november and march in an ambulatory setting by means of semistructurated interviews and later content analysis with a sample size defined by saturation criteria. : male outpatients with copd were interviewed (age range from to years). they feel to be correctly informed and trust their respiratory physician or family doctor, but in most cases there have not been prior discussions with the health care team concerning mv as a potential treatment of their disease. they consider themselves to have a good quality of life although their health is not good. they are interested in participating in the health care decisionmaking process. in case of treatments and cares as mv or admittance to an intensive care unit they accept any option that keeps their usual quality of life at the same level. this sample of copd patients are in favour of advanced care planning and show the aim to shape their own specific advanced directives. conclusion: patients with copd do not have enough information to take autonomous decisions. although mv is a potential treatment for copd patients with acute exacerbations, most of them were unaware of mv as a possible treatment option for them because discussions about this topic occur infrequently between physicians and patients. they are in favour of participating in health care decision-making with physicians and accepting any therapy that makes them able to keep their quality of life. the patients consider advanced directives as an opportunity to express their preferences in order to be considered when they are not able to communicate with the health care team. conclusion: wh/wd in ireland is common ( %) and similar to european practice( %). there was no sdp although the prevalence was % in europe. the increased use of sedation ( %) in association with wd suggests an awareness of patient comfort. despite only one advance directive, patient wishes were known in %. icu physicians were the primary initiators of eol discussion ( %) suggesting their important role in icm practice. the majority ( % v %) of eol decisions were taken during 'office hours'. this is finding warrants further study; it may represent the inexperience of on call personnel or may reflect the complexity of the decision. despite popular opinion extubation is infrequent and comfort measures tend to be continued. an anonymous questionnaire including questions was sent out to all staff mebers including medical staff, nurses and physiotherapists. questions included potential benefits to staff and patients and concerns regarding the use of restraint. of the questionnaires sent out, were returned completed. most respondents ( , %) felt that sedative drugs are used as a form of restraint in care of the patients. most ( , %) thought there is a place for physical restraint in critical care and that it might benefit patients, ( %) believed it might benefit staff but ( %) of responders had concerns regarding the use of physical restraint. a majority ( %) stated that concerns would be answered if undertaken as part of a clear unit policy. responders ( %) would be happy to use physical restraint with sedation to ensure patient's safety, but only ( %) would agree to its use if they were a patient. the majority of responders ( %) felt that some form of physical restraint may be appropriate. practice should be re-examined and consideration given to the use of some physical restraint in addition to sedative drugs. in some patients shock is so severe that extremely high doses are needed to elevate their blood pressures. studies show that % of icu physicians withhold or withdraw vasopressor administration because patients did not respond to "maximal" therapy. however the "maximal" dosage of vasopressors is not defined so each physician has his/her own limit as to the highest dose of adrenaline or noradrenalin that he/she will administer to a patient. many icus physicians order doses of up to mg of adrenaline or noreadrenalin per hour ( mg/kg/hour) we hypothesize that this dose is futile. following helsinki approval, all intensive care charts from were reviewed ( patient charts patient days) patients were found to have received a vasopressor. demographic data as well as apache ii scores, icu days and total hospital days, biochemistry, liver functions, blood gases, diagnoses and secondary complications were recorded. vasopressors, adrenaline and noradrenalin, maximal doses , initial dose, number of days/hours patient received all subsequent doses, and mortality were recorded. the data showed that all patients who received more than microgram per kilogram per minute of adrenaline or noradrenalin died. (p value < . ). the length of time that the patients received vasopressors had no influence on survival. these data showed a direct correlation between the number of days a patient received vasopressors and the length of hospitalization. the length of time a patient received low dose of vasopressors had no significance on mortality, but the vasopressor dose had an indirect association with survival. there was no significance difference in age between survivors and non-survivors. the elderly (over years of age) and the young had the same of survival rates when receiving vasopressors. patients who received more than microgram per kilogram per minute of noreadrenaline or adrenaline died. it thus appears that therapy with such high doses is futile. th annual congress -berlin, germany - - october s ehrmann s , mercier e , bertrand p , dequin p medical intensive care unit, department of biostatistics, bretonneau university hospital, tours, france to carry on indefinite invasive treatments in the intensive care unit for patients with a high probability of death in the short term, is ethically objectionable. on the individual level it extends the agony and suffering of the patient and on the community level it consumes precious limited resources. as there is no tool that can objectively and reliably help the physician to make ethical decisions of therapeutic limitations, we examined whether the absolute change of the lod score between the day of admission to the icu and the third day of unlimited treatment could be predictive of death in the icu. methods: consecutive patients admitted to the icu were prospectively included during a three-month period. for all of these patients the simplified acute physiologic score ii (saps ii) and the lod score (lod ) were calculated on the day of admission. the lod score was calculated again between the nd and the th hour in the icu (lod ) for the remaining patients ( patients left the icu before the nd hour, of whom died) without exclusion criterions ( therapeutic limitations before the nd hour). the endpoint was death in the icu. the performance of the deltalod = lod -lod index to predict death was examined through univariated and multivariated analysis and through calculation of the positive predictive value of death (ppv) for different cut-offs. after hours of unlimited treatment in the icu, deltalod appears to be a good predictor of death in the icu, independent of the initial severity of disease. the ppv is not high enough even for high cut-offs to assist with making individual therapeutic limitation decisions. accordingly to the bayes theorem, the performance of deltalod deserves to be evaluated in a population of patients exhibiting greater severity of disease. developed as an answer to the stressful everyday practice. indeed, in icu, the caregivers are under a great pressure induced by several factors: the explicit urgency to act, the implicit burden to face patients and families in critical situations and the requirement of a high level of technicity. such a creative workshop was set up for physicians and nurses in our unit, in order to give the opportunity to express the "unspoken", to share the experiences, explore the patient's perspectives. methods: sessions of hours were planned. at the first session, the participants were proposed to imagine a situation starting from one of pictures of icu patient. they were invited to write as "i" or "you" in order to take the patient's or the relative's place through their imagination. the written texts were distributed to all participants and discussed at the second session. the workshop was organized and moderated by a senior specialist in intensive care medicine and the person in charge of the medical humanities teaching program. the participation to the workshop was optional. : physicians ( m, f) and nurses (all f) and ( f, m) medical students participated to workshops. one month later, they answered a questionnaire. all participants gave a positive global appreciation and underlined the importance of the discussion which allowed the sharing of their experiences. felt encouraged to adopt the patient's perspective, were reassured about their feelings of their practice. the relevant themes of the texts were the behaviour of the caregivers, the abrupt change of worlds, a strange perception of time, the importance of noises in the icu environment. despite the similarity of the themes, the way the narrators shaped the story was very different. the author's selection of words, details, and literary devices confers the personal touch of his/her experience. none of them considered the writing as an obstacle to their expression, even if they first felt difficult to step in the writing process. all of them were satisfied with the workshop and with the sharing of their experiences. the most important point reported was the awareness that the others, either physician or nurses, had the same preoccupations and feelings. the fact that this workshop did not give any concrete recipe for the resolution of problems induced some frustration among icu caregivers. there have been few studies to investigate how well the results obtained by co rebreeding to assay cardiac output (co) ( - ). a reliable non-invasive co monitor could enhance patient safety and reduce risk. this study evaluates a nico measurement and calculated derived parameters from co. co was based on differential from of the co fick equation. twenty three co measurements with derived parameters were obtained from male patients admitted to a medical intensive care unit, st vincent hospital, medellín, colombia, . the nico monitor (novametrix medical systems inc) was connected between the ventilator circuit and tracheotomy tube. previously, multilumen swan-ganz thermodilution catheters, edwards labs were placed into the external jugular vein via an introducer sheath. co was calculated from pulmonary blood flow by correcting for shunt. the difference between consecutive thermodilution and nico measurements was calculated. also, calculated derived parameters from s-g catheter such as ci, svri, lvswi, rvswi, and svi were compared to measurements derived from nico. on nico measurements, central venous pressure replaces the value of pcwp. correlation between the two methods was determined by pearson´s correlation. a bland-altman analysis was used to compare the bias and precision of the two methods, and a difference > % was considered as a limit of accuracy. significance was assessed at the % confidence interval. twenty-three matched pairs of consecutive changes in co and calculated derived parameters measurements were recorded in three critically ill patients. with a mean (±sd) age of , y. relationship between changes in thermodilution and nico co measurements was significant (r = . , p = . ). none of calculated derived parameters (ci, svri, lvswi, rvswi, and svi) were considered significant. only co and rvswi showed difference between means to compare the degree of agreement measurements (co . % and rvswi . %% respectively). the results of the current study agree with those from previous studies where is suggested that nico monitor would provide a good alternative to invasive co measurements on critically ill patients. however, nico cannot be a substitute to get calculated derived parameters when pulmonary artery occlusion pressure is a necessary value. (std) has been demonstrated to be sufficiently accurate for estimation of intrathoracic blood volume (itbv) and evlw when compared with the clinical standard, i.e., transpulmonary thermo-dye dilution (tdd) [ ] . in this study, we examined the reliability of std for estimation of itbv and evlw with respect to several influencing factors. we retrospectively analyzed data of critically ill patients patients ( male, female; age - , mean ± years) who underwent extended hemodynamic monitoring by the transpulmonary thermo-dye dilution technique. the agreement between itbvstd/ itbvtdd and evlwstd / evlwtdd was determined as mean bias and standard deviation (sd) within different categories (level of peep, pao /fio ratio and evlw). linear regression analysis was applied to compare overall bias between evlwstd and evlwtdd with the different factors. : mean bias ± sd within the different categories are shown in the clinical judgement of an adequate volume status in critically ill patients remains a challenge. current clinical parameters to assess the adequacy of resuscitation often do not adequately reflect the volume status of the patient. therefore additional information about the adequacy of circulating blood volume in critically ill patients could be of great value. on occasions in critically ill patients on a surgical intensive care unit the adequacy of circulating blood volume (bv) was clinically judged by the parameters central venous pressure, mean arterial blood pressure, heart rate, and urine production. clinically estimated blood volume was compared with measured blood volumes using pulse dye densitometry with indocyanine green (ddg- a/k, nihon kohden, japan). obtained bv measurements were categorized in low blood volume (lbv), normal blood volume (nbv), and high blood volume (hbv) using reference values for men and women - ml/kg and - ml/kg respectively( ). clinical judgements led to hypovolemic (hv) versus not hypovolemic (nhv) cases. there was no statically significant relation between the clinical judgement of volume status and measured bv. in hv patients no lbv was measured and in clinically nhv patients lbv as well as hbv were measured. no significant correlation between measured bv and calculated fluid balances was found. conclusion: there seems to be a discrepancy between the clinical judgement of circulating blood volume and the measured circulating blood volume in critically ill icu patients. these results emphasize the difficulty of judging the volume status by current clinical parameters in critically ill patients. schütz n , romand j a , stotz m , gerard i , bendjelid k apsic, geneva university hospitals, geneva- , switzerland we recently demonstrated the accuracy of a new miniaturized transcutaneous sensor (tosca monitor, switzerland) to monitor non invasively paco (tcpco ) in white skinned patients [ ] . the objective of the present study is to analyse the same accuracy in a subgroup of dark skinned patients. eight post operative patients (mean ± ) were included. tcpco sensor was applied at the ear lobe. the simultaneously obtained tcpco and paco values (measured using a blood gas analyser) were compared by linear regression analysis. the difference between paco and tcpco values were compared using the method of bland and altman. : paired measurements were correlated. tcpco correlated with paco (r = . , p< . ) in the paco range . to . kpa. the mean bias between the two methods was . ± . %. our results demonstrate that skin pigmentation affects slightly the accuracy of the sensor. ( ). in critically ill patients it is difficult to gain knowledge of the intravascular volume using the conventional clinical parameters such as mean arterial blood pressure, central venous pressure (cvp), heart rate and urine production. new insights in the assessment of hemodynamics such as central venous saturation (svo ) and blood volume (bv) monitoring may give additional information of a patient's intravascular volume status. methods: blood volume measurements were performed in critically ill icu patients on occasions using pulse dye densitometry with indocyanine green (icg)(ddg- a/k, nihon kohden, japan). blood volume measurements were compared with the parameters svo and cvp in assessing the patient's intravascular volume status. also the relation between bv and albumine and colloid oncotic pressure (cop) was investigated. th annual congress -berlin, germany - - october s hofmann d , sakka s g anesthesiology and intensive care medicine, friedrich schiller university, jena, germany introduction: patient management guided by extravascular lung water (evlw) is associated with reduced mortality of patients with pulmonary edema [ ] . recently, single transpulmonary thermodilution (std) has been demonstrated to be sufficiently accurate for estimation of intrathoracic blood volume (itbv) and evlw when compared with the clinical standard, i.e., transpulmonary thermo-dye dilution (tdd) [ ] . in this study, we examined the reliability of std for estimation of itbv and evlw with respect to several factors of pulmonary function. we retrospectively analyzed data of critically ill patients patients ( male, female; age - , mean ± years) who underwent extended hemodynamic monitoring by the transpulmonary thermo-dye dilution technique. the agreement between itbv std / itbv tdd and evlw std / evlw tdd was determined as mean bias and standard deviation (sd) within different categories (level of peep, pao /fio ratio and evlw). linear regression analysis was applied to compare overall bias between evlw std and evlw tdd with the different factors. mean bias ± sd within the different categories are shown in acute-on-chronic (aoc) liver failure but data on the use of this procedure is yet scarce. we communicate our experience after centralizing all the procedures of our centre in the icu data of all treatments performed in our centre (liver transplant program; icu with continuous renal replacement therapies -crrt-experience; a unique protocol for surgery, hepatology and icu patients and a prospective registry). alf patients stay in the icu but aoc patients are admitted every other day for the procedure. mars is performed with a prisma monitor and sessions are aimed for a length of al least hours if feasible (in alf continuously with h changes). we analysed clearance, metabolic control, tolerability and technical and clinical complications. we used pearson correlation coefficient and linear regression analyses to detect relation between hours of treatment and clearance capabilities electrical impedance tomography (eit) is a promising technique to assess continuously respiratory function with high temporal resolution . changes in thoracic gas volume lead to corresponding changes in thoracic impedance. the aim of this study was to evaluate air distribution during volume controlled mechanical ventilation. five adult patients undergoing elective thoracic surgery with single lung ventilation were included. eit data were collected during ventilation of both lungs (tidal volume (tv): ml), left lung (tv: ml), and right lung (tv: ml), respectively. eit was performed using electrodes placed around the thorax. data are presented as percent of impedance change of both lungs (normalized electrical impedance (nei)). during one lung ventilation nei was reduced to . ± . in right lung and . ± . in left lung compared with both lungs with a clear separation between ventilated and nonventilated lung. in addition we found an imbalance of distribution of ventilation along the vertical axis in favor of the ventral part of the lungs (fig. ) . conclusion: eit seems to be a sensitive non-invasive method for monitoring distribution of ventilation. the use of pet in adults with tma has dramatically improved outcome. resistance to pet, which is observed in / of such patients and may affect mortality, remains however incompletely understood. we retrospectively studied adults with tma treated by pet in our unit to evaluate the short and long term outcome and to identify predictive factors of mortality and of resistance to pet. all records of adults with tma treated by pet between and were reviewed. tma associated with bone marrow transplantation were excluded from the study. age, sex, cause of tma were collected. glasgow and sofa scores were estimated at the admission. clinical data including: neuroligical or pulmonary disorders with mechanical ventilation (mv), renal failure, and therapeutic delay (td) to pet; biological data including: hemoglobinemia, platelet count, and ldh; plasmatic volume exchange per procedure and number of plasmapheresis sessions were also collected. mortality was assessed at one month and at one year follow-up. all data were analyzed and compared between survived/deceaded and between responders/nonresponders (r/nr) patients. : females and males were included. mean age: . ± . yo, mean glasgow coma score: ± , mean sofa score: . ± . . etiologies of tma: post-immunologic , post-infectious , post-neoplastic , drugs associated , idiopathic . two patients were in mv, underwent hemodialysis and had at least two organ dysfunction. the mean td for pet was . ± . days and the mean plasmatic volume exchange per procedure was . ± . ml/kg. patients ( %) partially or fully responded to pet. patients ( %) survived after one month and ( %) after one year follw-up. the comparison between survived and deceaded patients showed that response to pet ( / vs / responders respectively) was the only significant determinant parameter. the comparison between r and nr showed that a longest td ( . ± . vs . ± . ) and neoplastic cause of tma ( / vs / ) were significantly discriminant for a non-response to pet. almost all of the r patients ( %) exhibited a positive response to pet before the tenth plasmapheresis session. in a median follow-up period of , ( - ) months, relapses episodes occured in patients ( %). adults with tma, characterized by a mild to important severity, treated by pet have a relatively good outcome since survival reached % at month and was maintained at % after year follow-up. among the parameters studied, lack of response to pet was the only predictive factor of mortality. two factors were predictive of resistance to pet: neoplastic etiology of tma and a longer td to pet. adult with tma non-responding to pet after the tenth plasmapheresis session could be considered as totally non-responder and should benefit shortly from another therapy. ) . additional in-formation can be gained by visual conditioning of large data sets. we report a novel approach on data inter-pretation by visualizing the gastric tonometry values in a case of necrotizing pancreatitis and septic shock and the correlating clinical events ( ( y., male, apache ii score , measurements, days running). pgco was measured every min. with a gastric tube (trip, ngs catheter) and an automatic gas analyzer (tonocap, finland). we recorded these values continuously and calculated the frequency distribution in an h interval and in an area between and mmhg (increment ). this histogram was displayed as a contour-plot. in that kind of visualization the frequency is displayed as colour in the area and not as third axis in a graph. our form of data processing provides additional information on pathological patterns at an early stage. in context with other parameters, this can be helpful in guiding treatment, e.g. volume substitution, catecholamines or blood transfusion. in this case we can see episodes of normal tonometric values as well as periods of pathological patterns like periods of septic shock (t , t ), daily abdominal lavage in a period of severe sepsis (t ), major abdominal surgery (t ), unsuccessful trials of enteral feeding (t ), successful enteral feeding (t ), weaning period and extubation (t ). the graphical presentation of the frequency distribution of a large number of data easily allows to conceive the information of the data. the aim of future activities has to be the development of a real-time bedside display of the progress of changes in the measurement of pgco -values. our study population consisted of patients undergoing elective cardiac surgery (n= ). blood samples for tnf alpha mrna were taken preoperatively (baseline), hr and hrs postoperatively. total rna was extracted from purified peripheral blood mononuclear cells (rneasy, qiagen). we utilised real time rt-pcr to quantify tnf alpha gene expression after cardiac surgery using abi prism sequence detection system and normalised against an endogenous reference gapdh. the patients were divided into two groups: group a: eighteen patients who developed complications post surgery as defined by i) hypotension requiring inotropes (n= ) ± intra-aortic balloon pump counterpulsation (n= ) and /or ii) lactate > mmol/l (n= ). group b: control group of patients with an uneventful postoperative course (n= ). statistical analysis was performed using the kruskal-wallis test. ischaemia of the colon is a recognised but infrequent complication following cardiac surgery. colonic ischaemia is thought to lead to a disruption in the intestinal barrier and this has been implicated in the progression to the systemic inflammatory response syndrome (sirs) with some patients going on to develop multi-organ dysfunction syndrome (mods). little is known of the early pathophysiological processes occurring in the colon during cardiac surgery. thus, the aim of this study was to investigate the early histological changes within colonic mucosa and cytokine release during cabg surgery. methods: patients undergoing coronary artery bypass surgery ( on-pump, off-pump) were prospectively recruited. mucosal biopsies of the sigmoid colon were obtained after induction of anaesthesia and immediately at the end of the procedure. microscopic examination was performed using haematoxylin and eosin staining. peripheral blood was assayed intraoperatively for cytokines il- and il- and for up to hours post-operatively. on-pump surgery produced a . -fold increase in columnar epithelium apoptosis. no other histological changes occurred. there was a -fold rise in il- in both two groups intraoperatively. post-operatively, il- continued to rise to -times baseline levels in contrast with the off-pump group which remained at intra-operative levels. il- did not change significantly in the off-pump group. in the on-pump group there was a fold increase in il- associated with initiation of cardiopulmonary bypass (p< . student's t-test). post-operatively, il- levels returned to baseline levels. apoptosis of colonic mucosa occurs during on-pump cabg but not in offpump cabg. this precedes the inflammatory process. thus, we identify apoptosis, rather than necrosis, as the principal mode of cell death following on pump cabg surgery. further elucidation of this process may identify targets for pharmaceutical prevention colonic mucosal apoptosis. cabello b , rubio o , delgado m , vera p , mancebo j intensive care, hospital sant pau, barcelona, spain liberation from mechanical ventilation can be interfered by the development of congestive heart failure (chf). this issue has been poorly studied as a cause of weaning failure. we designed a clinical-physiologic study to analize the mangnitude of the problem and its physiological characteristics. during a two months period we daily screened all the intubated mechanically ventilated patients in our -bed icu looking for those who meet usual weaning criteria. these patients went on a t-piece trial (sb) during minutes. patients who presented respiratory distress were studied with esophageal-gastric balloon and a swan-ganz catheter. hemodynamic and respiratory measurements were collected in assist control ventilation (acv), pressure support (ps) of cm h with peep of and again sb. we defined chf when the pulmonary wedge pressure (pcwp)was normal during acv and above mm hg during sb. unsuccessful extubation in copd patients is associated with increased morbidity and hospital mortality, and accurate prediction of post-extubation acute respiratory failure (arf) is potentially important. our hypothesis was that two parameters i.e., the airway occlusion pressure at . s (p . ) and the expiratory flow limitation (efl) determined by applying a negative expiratory pressure (nep) during tidal breathing, both recorded repeatedly after extubation, could be good indicators of postextubation arf in copd patients. copd patients were included prospectively after extubation. a specially devised system (micro ; medisoft , dinan, belgium) was used to measure efl and p . . each patient was placed in half sitting position and breathed spontaneously. after stabilization of the patient, a nep of - cm h o was applied at the beginning of expiration and maintained throughout the ensuing expiration. the test breath was the breath during which the nep was applied, and the preceding expiration served as control. five test breath separated by periods of quiet breathing were recorded. the expiratory flow-volume loops generated with nep were compared by superimposition with those obtained during the immediately preceding breaths. the portion of the tidal expiration over which there was no appreciable change in flow with nep was considered as flow-limited and was expressed as a percentage of the expired control tidal volume (%vt). the module of nep was replaced by that allowing to measure the p . . five measurements of p . were made, spaced by at least seconds. gas exchange, p . and efl under nep were measured at the st , th, th and th hour following extubation. if a limitation of flow was evidenced at a given time, the subsequent measurements were not carried out. post-extubation arf was defined by a respiratory rate of more than per min, a respiratory acidosis with a paco > . mmhg and a ph lower than . without metabolic acidosis. to date, patients have been included. heighteen of them ( %) presented a elf at ± hours following extubation. nine patients presented an arf at ± hours in post extubation. these patients had a elf and a p . significantly higher than those without postextubation arf (respectively . ± . % vs. . ± . %; and . ± . cm h o vs. . ± . cm h o; p < , ). seven patients ( %) did not have elf and did not present arf in post extubation. conclusion: elf by nep and p . are easily measured in the period following extubation in copd patients. this preliminary report seems to demonstrate that p . and efl, measured precociously then repeatedly after extubation, could be good indicators of postextubation arf in copd patients. serebriysky i i , galstian g m , gorodetsky v m . intensive care unit, national centre of hematology, moscow, russian federation acute respiratory failure (arf) is the most frequent and serious complication in patients (pts) with hematological malignancies. respiratory insufficiency in this group of patients can be caused by a combination of increased vascular permeability, heart failure and liquid overload. the aim of this study was to analyze the effects of colloid replacement therapy in pts with hematological malignancies and arf. we examined pts with acute leukemia, complicated by sepsis and arf (bilateral radiographic infiltrates, pao /fio = ± ). three of them had pawp> mmhg, respectively , and mmhg. all the patients received infusions of % albumin (a.). the first infusion of ml was carried out during minutes, later the speed was ml/ min. we measured extravascular lung water index (elwi), pulmonary vascular permeability index (pvpi) by picco-plus (pulsion, germany), central hemodynamics parameters by swan-ganz catheter. in the first group that received a. in doses of . ml/kg ( pts) there were no significant changes in ci, pawp, elwi, pvpi, apart from pt ( st pt, see should critical illness polyneuropathy (cip) itself prolongs mechanical ventilation or whether this prolongation is the effect of concurrent risk factors for weaning failure is a matter of debate. our primary objective was to evaluate the impact of cip on the length of mechanical ventilation after controlling for coexisting risk factors for weaning failure. we also set out to assess the impact of cip on the length of the stay as well as to determine the costs associated with this neurological complication. a prospective cohort study. setting: icu of a tertiary hospital. patients: all patients with severe sepsis or septic shock that required mechanical ventilation for at least days who were considered ready to discontinue mechanical ventilation. patients underwent a neurophysiologic evaluation at onset of weaning from mechanical ventilation. gianesello l , pavoni v , paparella l , gritti g dept. of critical-medical surgical area, section of anaesthesia and intensive care, florence, italy extubation failure (ef) has an important effect on length of icu and hospital stay,icu and hospital mortality( ).ef can occur secondary to upper airway obstruction or to an inability to manage respiratory secretions a cause of laryngeal dysfunction (ld) and ineffective cough.ld can result from depressed mental status or local trauma after intubation.pre-admission functional status can also delay post-estubation swallowing impairment in critically ill elderly patients( ). over a -month period patients who needed reintubation after successful trial of weaning and planned extubation, in a polyvalent intensive care unit (icu) were identified.data including clinical features (age, sex, saps ii on admission, glasgow coma score (gcs) on day of extubation, type of patient, length of intubation and mechanical ventilation (mv) before extubation, length of icu stay (los), icu and hospital mortality) were collected.moreover we considered two parameters that asses airway patency and protection like predictors of ef:cough strength and suctioning frequency after extubation.cough strength on command was measured with a semiobjective scale of to ( = weak cough, = strong cough). ( / )( . %), pulmonary embolism( / )( . %)and severe sepsis( / )( . %).seven of patients who received reintubation a cause of defective airway manage needed at least one suctioning every two hours; moreover the same patients and other three with alteration in neurological function had weak cough (grade to ).the los of ef patients was ± . days, their icu and hospital mortality were . % and . %, respectively, both higher when compared with not reintubated patients.results of logistic regression showed that saps ii is the only independent risk-factor of reintubation (odds ratio . , sig. . ),while age, type of admission,length of intubation and gcs seem to do not influence ef.data were analysed using the spss . for windows. conclusion: ef can depend from defective airway protective mechanisms due to alteration in consciousness or glottic incompetence.this event influences negatively los and outcome.severity of illness is the only independent risk-factor. over a year-period, patients with dild ( males; age: ± years; saps ii: ± ) were retrospectively studied. among them, patients were immunocompromised and patients sustained complications attributable to the procedure: airleak (n= ), pneumothorax (n= ). the median duration of the chest tube drainage was ± days (range: to days). both the pao /fio ratio and mean level of peep were comparable before and hours after the olb (table ) . no patient died in the perioperative period. olb allowed to establish a diagnosis in patients ( %). in patients ( %), the dild was idiopathic (table ) . in patients, histologic diagnoses obtained from olb were not suspected clinically or by radiological investigations: invasive pulmonary aspergillosis, diffuse amyloidosis, methotrexate lung toxicity. ± ± peep level (cm h o) ± ± idiopathic interstitial pneumonia diagnosis uip aip* boop n. of patients *: acute interstitial pneumonia (ards) conclusion: in ventilated patients, olb can be performed with acceptable morbidity at bedside in the icu. in this study, olb established a definite diagnosis in % of patients and corrected the clinical and radiological diagnosis in % of the cases. fonsato v , mariano f , triolo g , camussi g , nederlof b , tetta c laboratory of renal immunopathology, university of turin, unit of nephrology and dialysis, cto hospital, turin, italy, department of research, fresenius medical care, bad homburg, germany introduction: high porosity membranes may enhance cytokine elimination by convection and also diffusion. however, there is need to balance the high permeability between cytokine removal and a clinically acceptable loss of plasma proteins. here,we studied the sieving coefficients (sc)and clearances of different cytokines (tnfa; il- b;, il- , il- , il- ra) and protein permeability profile (albumin, cystatin c, igg)in an ex vivo hemofiltration (hf), hemodiafiltration (hdf)and hemodialysis (hd)circuit of nanostructured high porosity polysulfone membranes with different albumin permeabilities of %(type a)and %(type b). three hundred ml of fresh normal human blood was incubated with endotoxin ( mg, e. coli, sigma, °c, hr and overnight at room temperature). we set up the three circuits under the following conditions: i) post dilutional hf, at three different blood flow rates ( , or ml/min) and with a fixed ( %) ultrafiltration rate (ufr: . , . and . l/hour, respectively). the circuit operated at zero balance. samples for scs and clearances were obtained conventionally at , , , , , and min; ii) hd, at a dialysate flow rate of l/h and l/h; iii) hdf, dialysate flow rate of l/h and l/h included . l/h of ultrafiltrate. both hd and hdf were conducted always at blood flow rate of ml/min. cytokines were determined by commercially available kits, albumin, cystacin c and igg by nephelometry (beckman). median sc was nearly up to for il- b and il- ra, at about . for il- , . for il- and . for tnfa (type a vs b, p > . ). despite similar high cytokine clearance ( and mil/min), permeability profile showed a higher sc for albumin, cystacin c and igg for type b than for type a (p< . ). sc for all cytokines was significantly reduced in hd (at both l/hr and l/hr) as compared with hf and hdf. it was of interest that in hdf sc of il- and il- at l/h were overlapping those obtained in hf. however, sc of il- b, il -ra and tnfa in hdf were about half of those obtained with hf. in addition, increasing dialysate flow (from l/h up to l/h) in hd and hdf at a constant blood flow of ml/min led to decrease sc of il- , il- , tnfa and albumin. albumin clearance was . ± . and . ± . ml/min in hdf and hd, respectively. our data show that high cut-off polysulfone membrane are associated with high clearances of cytokines independently from blood flow rate and ufr. tailoring membrane porosity on the basis not only of cytokine clearances but also on ex vivo plasma protein permeability was instructive to formulate their clinical application in mixed convective-diffusive treatments rather than in pure convective or diffusive modes. nunomiya s , momose k , ohtake k division of intensive care, dept of anesthesiology and intensive care med, jichi medical school, minamikawachi, japan introduction: several clinical and experimental studies have reported recently that direct hemoperfusion using a polymyxin b immobilized fiber column (pmx-dph) is effective for septic ards and improves pulmonary oxygenation. unfortunately, however, little is known about the exact mechanism in such effects. therefore, we studied the role of circulating leukocytes activities in endotoxemic pigs undergoing pmx-dph. eleven anesthetized pigs were received endotoxin infusion (etx) to develop ards state and submitted to either pmx-dph group or ctrl group. ards state was defined when pao /fio ratio decreased to the level less than % compared to the point before etx. extracorporeal circulations (ecc) were done for hours in both groups. blood samples were obtained at points; the time before etx (t- ), ards state (t ), hour (t ) and hours (t ) after the start of ecc. leukocyte activities were measured as the abilities of oxygen radical productions from leukocytes using chemiluminescence assay. one was dead within hour and another was dead within hours after the start of ecc in ctrl group, whereas no animals were dead in pmx-dph group during the study period. time courses of pao /fio ratio and leukocyte activities in both groups are shown in tables. changes in p/f ratio compared to t- cotogni p , muzio g , trombetta a , canuto r , trompeo a , viale a , ranieri m anestesia e rianimazione, patologia generale, university of turin, turin, italy in the early phase of ards, intense inflammatory reactions occur in the alveolar space. in this setting, the balance between pro-and anti-inflammatory cytokines may be a critical component for prognosis. evidence is accumulating that n- /n- polyunsaturated fatty acids (pufa) ratio may influence inflammation, since the eicosanoids formed from n- pufa and those developed from n- pufa have opposite effects upon inflammatory mediators production. in standard artificial nutrition -both in parenteral and in enteral formulas -n- /n- pufa ratio is quite low (between : and : ), since most nutrients are richer in n- than in n- pufa. though, the most favourable n- /n- pufa ratio is not yet defined. our study tested the hypothesis that n- /n- pufa ratio may modulate inflammatory cytokines production in a cell culture of human pneumocytes exposed to lipopolysaccharide (lps). a cells, a human pulmonary cell line with type ii pneumocyte properties, were cultured ( /cm ) in ham f- k medium. in all cultures but in controls, lps was added hours after seeding, to obtain a final concentration of mug/ml. three hours after lps, pufa were added as docosahexaenoic acid (dha) (n- ) and arachidonic acid (aa) (n- ) in different n- /n- ratios. four hours later, all culture supernatants were collected to determine the release of tnfalpha, il- , il- , and il- (elisa). pro-inflammatory cytokines production was significantly reduced by a : ratio of n- /n- pufa, but increased by a : ratio. a higher ratio ( : ) was not associated with further cytokines reduction (table ) . *n- /n- conclusion: in a human pulmonary cell culture stimulated with lps, inflammation can be modulated by pufa, through appropriate changes of n- /n- ratio. high doses of selenium could be a promising way for septic shock treatment. however, selenium (se) toxicity is supposed to be related to oxidative stress through a reaction with thiols. in the situation of an oxidative stress such as severe sepsis, it is to be feared that selenium toxicity could be increase, despite the fact that preliminary results are in favor of two different pathways for lipopolysaccharide (lps) and se toxicity. after approval by the crssa ethical committee, wistar male rats were studied. rats were quarantined for days. then, lipopolysaccharide (lps) followed one hour later by selenium, as sodium selenite (lps-se group) or se alone, as sodium selenite, (se group) were administered intraperitoneally. in ten rat lps-se groups, lps were administered at the dose of mg/kg followed by se at increasing doses from . to mg/kg. in ten rat se groups, se was administered with increasing doses from . to . mg/kg. mortality rate was observed at hours. surviving animals were sacrificed under anesthesia by halothane. blood samples were taken on two surviving rats of each group. plasma selenium concentration was measured using electrothermal atomic absorption. mortality related to se appears for lower doses in lps-se groups than in rats receiving se alone. mortality rate of rats receiving mg/kg lps alone was % ( / ). for doses of more than . , septic rats died in respiratory distress in less than one day. for lps alone or followed by se at the dose of . mg/kg, rats were rapidly sick. they rolled up into a ball. their fur was dull, and stood on end. they were asthenic and had diarrhea. se rats developed an encephalopathy the first day and later recovered, except rats with extremely high doses of se, according to the literature on selenium acute toxicity. mortality related to se (mg/kg) mg/kg . . . . lps-se / / / / / not do se / / / / / / conclusion: in a % mortality non reanimated lps rat model, mortality related to selenium administration appears at lower doses those administred in healthy rats. mortality was related to respiratory distress in lps followed by se rats. doses of . mg/kg, presently considered as the maximum selenium level administration, seems not to modify the spontaneous evolution of sepsis in this model. zimmermann t department of visceral-, thoracic-and vascular surgery, technical university dresden, dresden, germany selenium plays a dual role in the regulation of the inflammatory response in mononuclear blood cells. first, selenium enzymes (gpx , trr) are essentiel for the physiological regulation of the redoxsensitive transcription factor nf-kb (key role in inflammation). second, selenium is capable to inhibit the activity of nf kb. another transcription factor (ap- ) is being specific activated via the subunits (c-jun,c-fos) by means of selenium. the authors investigated patients with severe sepsis within the sic-study (selenium in intensive care). mononuclear blood cells: nf-kb-and ap- binding activity, p /p (nf-kb)-protein concentration in the nucleus and cytoplasm. mrna-expression of ikb, tnf, tissue factor, mif, gpx- and trr (selenoenzymes), intracellular synthesis of mif and ikb. ros in whole blood. blood was taken on the ., ., ., ., ., . day of sepsis. septic patients with supplementation of selenium showed a increase of the nf-kband a strong increase of the ap- binding activity during the course of the sepsis. in the same time a rigorous reduction of the mrna-expression of ikb (inactivator of nf-kb) and mif could be observed. the mrna-expression of the tissue factor and tnf was not influenced. supplementation of selenium lead to a amplified translocation of p /p (nf-kb) within the nucleus, whereas in the placebo group this effect was not shown. in contrary to septic patients, only the nf-kb bindung activity was strongly suppressed in healthy controls. selenium seems to possess a regulatory role in der inflammatory response of mononuclear blood cells. the positive effect of selenium in septic patients could be dependent on the time point of the supplementation, within the inflammatory (anti-or hyperinflammatory) response. this could be one explanation of "non-responders" of selenium supplementation. high dose of selenium (se) could be a promising way for septic shock treatment. however, selenium toxicity is supposed to be related to oxidative stress through a reaction with thiols. in the situation of an oxidative stress such as severe sepsis, it is to be feared that selenium toxicity could be increased. presently human administration of sodium selenite of more than µg per dose must be avoided, outside carefully conducted study. however preliminary results are in favor of two different pathways for lipopolysaccharide (lps) and se toxicity, which leads to think that selenium, especially as sodium selenite, could be a new way of treatment. after approval by the crssa ethical committee, wistar rats were studied. rats were quarantined for days. sixty four rats received mg/kg of lps intraperitoneally, followed one hour later by milliliters of saline water (placebo) (n = ), or . mg/kg selenium as sodium selenite (n= ) corresponding to around mg for a kg man, or . mg/kg selenium as sodium selenite (n= ). mortality rate was observed at hours. videos were performed during the -hour course. surviving animals were sacrificed under anesthesia by halothane. blood samples were taken on two surviving rats of each group. there is a tendency of the mortality decrease in this post-treatment septic rat model. moreover, rats receiving lps alone or supplemented by . mg/kg sodium selenite were rapidly sick. they rolled up into a ball. their fur was dull, and stood on end. they were asthenic and had diarrhea. lps non-surviving rats died in an asthenic syndrome, and surviving lps alone rats remain very asthenic at hours. on opposite, surviving lps followed by se rats were much more dynamic, even quite normal. th annual congress -berlin, germany - - october s kepa l , oczko-grzesik b department of infectious diseases, silesian university medical school, bytom, poland cytokines and neutrophiles play an important role in pathogenesis of bacterial sepsis with purulent meningoencephalitis (bs-pme). experimental studies in animals revealed that pentoxyfiline (pf) exerted inhibitory influence of cytokines on these cells with beneficial outcome of the disease. the aim of the presented study was the estimation of pf influence on clinical course and outcome of bs-pme in adults. between - bs-pme was recognized in patients treated in our centre. neisseria meningitidis and streptococcus pneumoniae were etiological agents in subsequently % and % of cases. in the remaining % of subjects the etiology was not elucidated. all patients were divided at random way into two groups: i - patients (mean age yrs.) treated with antibiotics, symptomatic drugs and pf ( mg/kg/day) beginning from the first day of treatment, ii - patients (mean age yrs.) treated only with antibiotics and symptomatic drugs. cerebrospinal fluid (csf) samples were taken on the st, th and th day of therapy with estimation of pleocytosis and protein, glucose, lactic acid, tnf-alpha, il- beta and crp concentrations. mean periods of consciousness impairment, fever persisting as well as hospitalization were comparable in both groups of patients. faster normalization of csf protein, glucose, lactic acid and crp concentrations were recorded in patients of group i, who survived, compared to subjects of group ii, but the differences were not statistically significant. csf parameters remained abnormal in fatal cases. most frequent sequeles of bs-pme were: partial deafness, deafness, paresis and paralysis. side efects of pf were not observed. death sequels group i ( %) ( %) ( %) group ii ( %) ( %) ( %) conclusion: pentoxyfiline used as adjunctive therapy in adult patients with bacterial sepsis and purulent meningoencephalitis did not reveal evident beneficial influence on clinical course and outcome of the disease. zahorec r , setvak d , cintula d , blaskova a , belovicova c of anesthesia and icu, st. elizabeths cancer institute, bratislava, slovakia sepsis is a common cause of acute renal failure (arf). arf in early phase of severe sepsis occurred in - % septic patients and is associated with significant influence on sepsis mortality. the aim of this observational study was to measure the incidence of arf syndrome and to evaluate the efficacy of noradrenaline and furosemide infusion (martin et al. (martin et al. , for the treatment arf in early phase of severe sepsis. an observational study of consecutive critically ill cancer patients with severe sepsis ( ) and septic shock( ). acute renal injury/arf syndrome was detected according bellomo et al ( ) criteria. the surrogate markers of renal dysfunction involve serum urea, serum creatinine and urine output (diuresis per hour). we measured creatinine clearance and excretion fraction of sodium from collected urine.the severity of severe sepsis was measured by apache ii and sofa score during the first - hrs of icu stay. we monitored in all pts invasive sap,map,cvp,temperature, pulse oximetry, urine flow per hour and per day.blood sampling were done every hrs for wbc counts, platelets count, procalcitonin, crp, urea, creatinine and lactate. : severe septic patients with mods (initial sofa score were , and , p., and apache ii score , and , )received full intensive therapy. severe sepsis was documented by proven infection and high serum levels of procalcitonin (mean , ng/ml) and crp(mean mg/l). acute renal injury ( pts) and arf( pts) syndrome was detected in patients ( %) out of septic cancer pts. we used the combination of noradrenaline infusion ( , - , mcg/kg/min) and furosemide infusion( - mg/hr) for hemodynamic and renal support. we induced polyuria and reverse ari/arf to nonoliguric arf in pts ( %) from severe septic pts. we used no renal replacement therapy.we recorded % hospital mortality. acute renal injury and acute renal failure syndrome occurred in % of severe septic patients. criteria for ari/arf syndrome diagnosis are very simple and useful in early detection of renal dysfunction. renal rescue protocol (combination of noradrenaline and furosemide infusion) seems to be very effective modality in the treatment for ari/arf syndrome in early phase of severe sepsis, when it is instituted very early with low/moderate dosage of noradrenaline and furosemide. the purpose of the present study was to evaluate the effects of intravenous lornoxicam on hemodynamic and biochemical parameters, serum cytokine levels, patients' outcome in humans suffering from severe sepsis methods: patients were included to the study. after applying, lornoxicam mg was administered intravenously every hrs for six doses vs placebo. hemodynamic parameters (heart rate,mean arterial pressure), nasopharyngeal body temperature, arterial blood gas changes (ph, po , pco ), plasma cytokin levels (interleukin -b, interleukin -r, interleukin , interleukin , tumor necrosis factor-a), biochemical parameters (lactat, leucocyt, trombocyt, creatinin, total billirubin, serum glutamat oxalat transaminase), staying time in the intensive care unit, time of mechanical ventilation support, mortality, with the control group were recorded. all measurements were obtained at baseline (before start of the study) and were repeated immediately at th , th and th h. after lornoxicam. no differences were found differences in major cytokines, duration of ventilation and icu stay, and fi / pa intravenous lornoxicam vs placebo (p> . ). we found that the effect of intravenously lornoxicam did not effect hemodynamic and biochemical parameters, or cytokine levels or in patients' outcome in severe sepsis in humans. because of the limited number of patients in our study and the short period of observation, our findings need to be confirmed by larger clinical trials of intravenously lornoxicam in a dose-titrated manner bernard gr, wheeler ap, russell ja, et al: n engl j med , : - . bubenek-turconi s s t , sefu f , stelian e , boros c , miclea i , timofiev l , moldovan h , iliescu v st cardiovascular anaesthesia and intensive care dept., st cardiac surgery dept., institute of cardiovascular diseases c. c. iliescu, bucharest, romania severe systemic inflammation with a vasodilatory syndrome occurs in about one third of all patients after cardiac surgery with cardio-pulmonary bypass (cpb). we studied the effects of early continuous veno-venous hemofiltration (cvvh) on the course and outcome of the patients with severe systemic inflammatory response syndrome (sirs) after cardiac surgery. a group of patients with severe sirs [fulfilling the criteria of accp/sccm consensus committee ( )] in early postoperative period after cardiac surgery with cpb was divided in two subgroups: a - patients receiving conventional therapy and b - patients who received cvvh for a period of h. criteria for receiving cvvh was a severe cardiovascular dysfunction (catcholamine support required in large amounts, norepinephfrine or epinephrine > . ?g x kg- x min- , for maintaining a map > mm hg or a svr > dyne x sec x cm- ). of those patients had also a severe respiratory dysfunction with pao /fio < . there were no significant diferences regarding demographic data and type of surgery between the two groups. the patients from group b had a dramatic improvment of the cardiovascular function, the catecholamine support being tapered off faster than in group a even the initial dose was very much higher in group b. also the patients with respiratory dysfunction from group b were extubated earlier than those from group a, with the same amendament regarding the severity of the dysfunction. the result are sumarized in the following ricci z , salvatori g , bordoni v , bonello m , ratanarat r , d'intini v , ronco c nephrology dialysis and transplantation, ospedale civile s.bortolo, vicenza, italy sepsis and mods are associated with a disruption of normal homeostasis and alteration of biological systems. the accumulation of pro-apoptotic factors in plasma may contribute to organ dysfunction. removal of such factors by extracorporeal blood purification techniques may help to re-establish homeostasis and cell function. we investigated the effect of treatment dose comparing standard and high volume hemofiltration. in a prospective, randomised, cross over study two hemofiltration regimes in two consecutive days were administered to anuric septic patients: we studied hours high volume hemofiltration (hvhf: l/h) followed by hours standard hemofiltration (cvvh: l/h) and viceversa. replacement solution was administered pre filter and performed by m polysulfone membranes. blood flow rate was ml/min. routine laboratory and clinical data were collected including illness severity scores. prefilter plasma and ultrafiltrate were collected at treatment start, at hour, at hour, for each hemofiltration regimen. plasma samples and ultrafiltrate were frozen at - °c. samples were close labelled. samples from normal human blood were used as control. samples were studied for apoptosis using a u monocyte cell line. a quantitative analysis of the apoptotic u cells in culture was carried out by fluorescence microscopy at hours. u cells were also assayed for caspase , activation. during the sequence hvhf/cvvh cell apoptosis significantly decreased after hour of l/h treatment start (p< , ); after hours of l/h treatment apoptosis rate continued to decrease significantly (p< , ). after passing to l/h regime the percentage of apoptosis remained constant. the fold-increase of caspase- measured at hr correlated with the above findings (r= , ). similarly when the inverse sequence (cvvh/hvhf) was studied cell apoptosis did not show a decrement in the first hours, while after switching hemofiltration dose to l/h apoptosis was significantly decreased either at the first and at the fifth hour (p< , ; correlation between apoptosis and caspase- fold increase: r= , ). the results where independent from the administration sequence. conclusion: high hemofiltration rates seem to correlate with a decrease in plasma apoptotic pattern during crrt in anuric septic patients. the clinical relevance of such findings may contribute to explore new therapeutic options in septic patients. epinephrine (e). we conducted a casenote review of patients with septic shock. the unit icnarc/midas database was searched for all patients admitted over a two year period with septic shock. the icu notes and charts were then retrieved and data found on physiology, choice and dose of catecholamine given. : patients were identified, of whom were treated with ne and with e. there were notable differences in outcome between the two vasopressors commonly used. patients receiving either drug were seen to have an increased mortality in association with higher doses used. no patient survived to hospital discharge who was treated with a dose of e above . micrograms/ kg/ min or ne above . micrograms / kg/ min. conclusion: there is an increased mortality seen in patients with septic shock receiving e. whilst they may be older, with worse apache scores and calculated risk of death; this doesn't explain the degree of the problem. some of the answer may lie in their worse glucose metabolism. there was also an increasing mortality seen with increasing dose of vasopressor given. this was independant of apache score and as such may repesent a drug effect rather than a marker of illness severity. (vili) .but positive end expiratory pressure with or without low tidal volume is protective against lung injury. in this study we investigated the effect of different inspiratory times on vili. methods: sprague dawley rats were used. all were started to ventilate on pressure controlled ventilation mode, after anesthetized and tracheostomized, with the parameters of cmh o peak inspiratory pressure (pip), cmh o peep, fio : . , breaths/min and i/e: / . after minutes stabilization period baseline blood samples were taken for blood gas and cytokine analysis, then the rats were randomized into groups due to their peak inspiratory pressure, peep and inspiratory/expiratory ratios as follows: other ventilator settings were kept as baseline values. the rats were ventilated with these parameters for two hours. at the end of experiment before sacrification of rats, blood samples were obtained for blood gas and cytokine analysis. then the lungs were taken out and the left lung was used for measurement of wet weight/dry weight ratio (ww/dw). there were no differences in baseline ph, pao , paco , map values among groups. as compared to baseline values pao decreased in lp / , hp / , / , / groups and hpp / , / groups but significant differences was found only in hp / group(p= . ). at the end of experiment map decreased in all hp groups and hpp / group. ww/dw ratio was found lower in hpp groups when compared to hp groups (p< . ). il- level was found higher in hp groups than lp and hpp groups at end of experiment. high pip caused lung injury with deterioration of oxygenation and increase in ww/dw ratio. while application of peep was protecting lungs from vili changing inspiration expiration ratio did not. dragazis i , mariatou v , kopteridis p , kapetanakis t h , karidis n , balanika m , michalia m , armaganidis a nd critical care department, athens university medical school, athens, greece our purpose was to investigate whether temperature modulates ventilatorinduced lung injury (vili). we perfused (constant flow ml/min) isolated sets of normal rabbit lungs and ventilated them using different perfusate temperatures and two different ventilatory settings ( groups). after initial stabilization all preparations were ventilated for min using pressure controlled ventilation [pcv] with peep cm h o and pcv cm h o above peep. following the results of randomisation the necessary adjustments were made during this period to obtain in the perfusate: ) a ph . with a partial pressure of co mm hg and ) a perfusate temperature of oc, oc or , oc. two groups of preparations were tested at each temperature level: a control or low pressure (lp) group ventilated with peep cm h o and pcv cm h o above peep for min and a high pressure (hp) group, in which a pcv = cm h o above peep (= cm h o) was applied for min. the weight gain (deltawg in g/min) observed in each group during this period, as well as changes in ultrafiltration coefficient (kf in gr/min/ cm h o/ g) were used to assess vili (indexes of pulmonary edema and of vascular permeability respectively). our results are summarized in table . deltawg in hyperthermic isolated, perfused lungs was significantly higher than deltawg in any other group. significant kf changes were observed only in hp groups, with a significantly higher deltakf in the hp_ . group (p= . ). there were no important differences between normothermic and hypothermic preparations. methods: sprague-dawley rats were anaesthetized, paralyzed and mechanically ventilated. rats were ventilated similarly (vt= ml/kg, rr= bpm, fio . ), but were randomized to peep , or cmh o (n= per group). the abdomen was then inflated stepwise with helium up to mmhg of abdominal pressure (iap, intra-peritoneal direct measurement). airway pressure (paw), esophageal (pes) and gastric (pga) pressure were also measured, together with invasive blood pressure. data were simultaneously recorded and digitally stored for subsequent analysis. this allowed to consider end-expiratory (pes exp), mean (pes m) values of pes and the difference between pes at end-inspiration and end-expiration (dpes). data are presented as mean±sd. we conclude that in our study study the closed tracheal suctioning system did not decrease the incidence of ventilator-associated pneumonia, not even the exogenous pneumonias. we believe that the respiratory secretions suction may be done with guarantee with an open tracheal suctioning system if it is performed with suitable asepsis measures. and we think also that it is not necessary the high cost that the routine use of a closed tracheal suctioning system represents. however the closed tracheal suctioning system may be recommended in patients with severe impairment of gaseous exchange. in order to avoid decrease in bacterial count due to empiric ab before sampling, we evaluated the feasability of delaying the cultures of broncho-alveolar lavage (bal) frozen at - °c et - °c for hours. the results from these delayed processing were compared with those from immediate ones. a total of bals were performed on icu patients suspected of nosocomial or community-acquired bacterial pneumonia. each sample was divided in three, one for immediate culture (h ), the nd and rd for a delayed processing after storage at - °c and - °c for hours (h ) respectively. all negative h samples (n= ) were also negative at h except for one sample that yielded and cfu/ml of streptococcus sp on - °and - °h culturing respectively. seventy seven bals yielded one or more microorganisms, with a total of microorganisms in one or both samples. h and h (- °& - °) hájek r , nìmec p , zezula r , fluger i , rù?ièková j cardiac surgery, university hospital, olomouc, czech republic introduction: thrombelastography (teg)is a method frequently used in perioperative assessment of haemostasis in cardiac surgery. this bedside examination can reveal some specific disorders of haemostasis especially hypercoagulation and fibrinolysis. one hundred fourteen consecutive patients with acquired heart desease were assessed. all the patients were operated electively and the cardiopulmonary bypass was used. standard laboratory perioperative assessment of coagulation was performed. these results were compared with teg performed afer indtroduction of anaesthesia, after minutes of cpb and immediately after admission on icu after operation. preoperative anticoagulation therapy, blood loss and the necessity of transfusion were evaluated. only patients nad no anticoagulation medication preoperatively. in laboratory assessment all the patients had normal results preoperatively, patients had coagulation disorder and patients thrombocytopenia postoperatively. teg examination revealed hypercoagulation status in patients and hypocoagulation in patients preoperatively. during operation increased fibrinolysis was found out in , % patients ( , % during operation, , % after operation and , % both during and after operation), only in % of them aprotinin was used because of increased bleeding. thrombocytopatia was revealed in , % patient and only in of them thrombocyte infusion was required. in patients the residual high level of heparin was confirmed. the average blood loss during operation was ml and during first hours was ml. no patient was reoperated because of bleeding. correction of hypocoagulation was made with ffp in average dose tu ( case with normal postoperative teg tracings versus cases with pathological teg). conclusion: teg revealed hypercoagulation status in many patient preoperatively, which was not confirmed by standard laboratory tests. during operation mainly fibrinolysis and thrombocytes dysfunction was present but any specific therapy was usually not necessary. the use of blood products depends more on clinical status of the patient than on the teg results. clinicians are facing the challenge to differentiate between postoperative inflammation a condition considered to be benign and early signs of infection. the aim of our study was to define the timecourse of sirs and severe sirs after cardiac and thoracic surgery. we utilised a structured data mining process to the prospectively collected data within the patient-data-management-system (picis caresuite v. . ) from the cardiothoracic icu of a university hospital between january and may . data from all monitoring device are collected in intervals of minutes, laboratory data and blood gas analysis was done according to institutional standards. in this data mining process we determined in a first step the fulfillment of each individual item of the sirs criteria (accp/sccm consensus conference) during a minimum of one hour. in the second step we identified the first occurrence of simultaneous fullfillmment of at least criteria as the starting point for sirs. severe sirs was defined as sirs with at least two criteria for organ dysfunction as defined in the sofa score. we used three categories sirs, sirs with low blood pressure (sirs low bp) and severe sirs with additinal organ dysfunction (sirs severe). a total of patients were admitted during the observation period. sirs was present in ( . %), sirs with hypotension in ( . %) and sirs with additional signs of organ dysfunction in ( %). the timepoints of first fullfillment are given in the table. the timeprofile with very early fullfillemtn was not changed by censoring the first hours after admission since the identified state persistent for a prolonged period. timepoint of first sirs fullfillment: in this large cohort of patients after cardaic and thoracic surgery we found dystinct profiles for sirs with additional signs of organ dysfunction. in the majority of the patients the three different sirs categories occurred within the first hours. further research is necessary to determine whether any of these categories are indicative of a changed outcome depending on the starting point. th annual congress -berlin, germany - - october s samalavicius r , misiurine i , norkiene i , juozaitis m , urbonas k , bubulis r , baublys a anaesthesiology and intensive care, vilnius university hospital santariskiu clinics, vilnius, lithuania introduction: preoperative risk stratification for predicting mortality and morbidity is widely used in cardiac surgery. the goal of this study was to assess the value of serum lactate level in predicting mortality and morbidity following coronary artery bypass grafting (cabg) procedures. methods: consecutive cabg patients, operated on from . . to . . , were included in this prospective observational study. all patients were operated using cardiopulmonary bypass. serume lactate levels were measured before cardiopulmonary bypass, before declamping of the aorta, after heparin neutralisation and at the icu admission. : lactate level greater than mmol/l was found in . % of patients during cardiopulmonary bypass, in . % of patients shortly after weaning from cpb and in . % of patients at icu admission. mortality rate of patients, with hyperlactemia at icu admission was . % and morbidity . %. mortality rate of patients without hyperlactemia was . % and mobidity - . %. lactate levels on icu admission were raised in non survivors (median . +/- . , range . - . mmol/l)compared with survivors (median . +/- . , range . - . ). conclusion: increased serum lactate levels following coronary artery bypass grafting allows to identify a group of patients with increased risk of postoperative mortality and morbidity. since the year , we have been studying prognosis in cardiac surgery (cs) and noticed the lack of models with similar populations in the literature. the objective this study is create a predictive score (rio score-pre) of in-hospital mortality in patients (pts) undergoing cs based on preoperative variables. classical cohort with data of pts, of whom undergoing valvular surgery (vs) and admitted to intensive care units (icu), public and private, consecutively selected between june and february . all variables were previously defined. the data underwent univariate analysis with the chi-square, student t, mann-whitney, and pearson tests, followed by logistic regression, and stepwise (likelihood ratio), with the chi-square linear tendency test and a classification table. the score created (appendix) allows the following prediction: from to -low risk; from to -medium risk; and from to -high risk. pérez-vela j , renes e , escribá a , alonso m , corres m , garcía a , perales n intensive care unit, hospital de octubre, spain, spain vital parameters monitorization is an usual practice in the management of critically ill patients. cardiac index (ci) is one of more important perfusion parameters used. picco system is a device that offer the quantification of intermittent ci by transpulmonary thermodilution (citp) and in a continuous manner by arterial pulse contour analysis. objective: to compare the agreement between the standard thermodilution monitorization system (citd) with the transpulmonary system. also, we analysed the complications secondary to the picco system. prospective study, in patients in the immediate postoperative period after cardiac surgery with cardiopulmonary bypass. ci by standard themodilution was measured with pulmonary artery catheter abott optiq svo /ccoâ. we made a transpulmonary thermodilution with ml physiologic fluid injection with a temperature less than celsius degrees, through a central venous line, and we analysed the thermodilution in the femoral artery catheter thermistor (a -fr gauge, cm long arterial with a thermistor embedded in its wall: pulsiocath pv l) using the picco system from pulsion medical system (munich; germany). we calculated ci (both methods) after inserting the picco system, one hour later and then, every two hours. also we measured parameters when staff considered appropriate to value the results of a therapeutic attitude. results between techniques were compared by lineal regression analysis and the bland-altman method. we analysed a total of pair of data obtained in patients, male and female, in the immediate postoperative period of valvular replacements ( mitral, aortic and one both), aortic grafts, myocardial revascularizations, mixoma and pericardiectomy. mean age: ± . years, mean citd . ± . and citp . ± . l/m. the range of measured ci: . a . l/m/m . in comparison we obtained a r= . and a bias of - . ± . . in tables we have the realised statistic analysis. we did not have complications attributed to the system. both ci measurement methods are comparable, showing a good agreement between systems, indicating that citp is as reliable and precise as standard thermodilution. this suggests that picco is a monitorization system applicable to clinical routine in critically ill patients. we did not observe complications attributed to the system. gomes r v , rouge a , nogueira p m m , fernandes m a o , olival s a , campos l a a , dohmann h f r , santos m surgical intensive care unit, hospital pró-cardíaco -procep, surgical intensive care unit, instituto nacional cardiologia laranjeiras, rio de janeiro, brazil the left ventricular ejection fraction (lvef) has been extensively studied as a prognostic marker in cardiac surgery (cs); our group, however, has found a correlation between left atrial diameter (lad) and several outcomes in cs. the objectives this study is show the importance of lad as a prognostic marker by assessing the following outcomes: in-hospital mortality (hm), surgical intensive care unit length of stay (siculos), pneumonia (pn), and need for hemodialysis (nhd). compilation of data collected in the databank of several cohorts with patients (pts) of sicu from june/ to february/ . the variables studied underwent uni-and multivariate statistical analysis. the few reports exist about lad on echocardiography as a risk marker for cs; in our studies, however, lad has reached greater significance than the subjective analysis of lv function. the great prevalence of valvular surgery (vs - %) might be another possibility. these findings should be validated in a cohort with other centers. conclusion: amylase level > un/ml and bilirubin concentration of mg/dl in duodenal aspirated fluid has a high positive predictive value. position of the feeding tube within the gastrointestinal tract can be determined objectively by using simple ph and bilirubin reagent strips. webb i , gibbs t , beale r , jones a . department of intensive care medicine, guy's and st thomas' hospital, london, united kingdom septic shock may be accompanied by dysfunction of the hypothalamic-pituitaryadrenal axis (hpa). in a recent multi-center randomized controlled clinical trial, treatment with hydrocortisone and fludrocortisone significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency (as determined by acth stimulation) but not in patients with an adequate adrenal response ( ). subsequently it has become accepted practice to start corticosteroid replacement in patients with septic shock following an acth stimulation test to determine the presence (non-responder-nr) or absence (responder-r) of "adrenal insufficiency". in those patients with "adequate" adrenal function, corticosteroids are withheld or withdrawn. it is known that in patients who recover, this "adrenal insufficiency" is temporary. however, less is known about the temporal changes in hpa function within the period of critical illness. methods: our clinical information system (carevue, philips medical systems, uk) was interrogated to find all patients with septic shock who underwent repeated acth stimulation ( \mug) testing in an month period. baseline cortisol, nr/r status (\deltacortisol < \mug/dl), vasopressor requirements and use of hydrocortisone were identified. we identified patients who underwent repeated acth stimulation testing within a single episode of septic shock, who received no or limited steroid replacement therapy. in subjects ( , , the recognition that hpa abnormalities exist in sepsis and that exogenous steroids are beneficial in some individuals has changed practice over recent years. however, the best indicator of which patients would benefit from corticosteroid replacement remains unclear. in addition, this preliminary data suggests that an individual patient's response to acth stimulation may change during an episode of septic shock. of particular concern are patients who are initially "responders" who would not recieve beneficial therapy if only single estimates of adrenal dysfunction are used. twenty four neonates with tof were divided into two groups after getting parents consent and local ethical commitee approval into two groups ( each); group i : after general anaesthesia they had continous thoracic paravertebral block with a catheter placed at right fifth space with continous infusion of . ml/kg of . % ropivacaine every minutes to be maintained post operatively in nicu this. group ii :had balanced general anesthesia. measurements: -number of neonates required post operative ventillatory support in both groups. -mean total dose of opioids required for analgesia in both groups. -days of stay in nicu in both groups. -mortality in both groups results: -there was statistically significant less need for ventilatory support in group i ( %) in comparison to group ii ( %). -mean total dose of opioid analgesia was higher in group ii -more days of stay in group ii. -three cases of mortality in group ii ,while one case of mortality in group i. conclusion: picu mortality was relative high, partly due to high prism scores and the high proportion of mv pts. mortality continues to increase up to y and stayed the same thereafter. the majority of our pts reached their preadmission cognitive status (pcpc) at two y. on the other hand they didn't reach their overall functional status (popc) even after two y mainly due to the high proportion of pts with mild disability, popc , which is however compatible with near normal and independent life. s -s . .jalan r, williams r. blood pruif predictors of transfusion requirements for cardiac surgical procedures at a blood conservation center references: maillet jm grant acknowledgement: chris stoutenbeek foundation references: .debra henry fiser ( , ) ( , ) ( , ) ( ) e coli ( , ) ( , ) ( , ) ( , ) s pneum+ ( , ) ( , ) ( , ) ( . ) others**+ ( , ) ( , ) ( , ) ( , ) *p= . g / g ; **p< . g /g ,+all groups conclusion: in our country, late-onset vap showed important variations in aetiology considering th and th days and that should influence antimicrobial prescribing practices. nosocomial pneumonia represents a significant cause of morbidity and mortality in intensive care units (icu). the high incidence of nosocomial pneumonia among icu patients can be attributable to dysregulation of lung immune responses elicited by systemic inflammation. in a previous study with endotoxin-challenged mice, defects of lung adaptive immunity were heralded by reduced numbers of lung-resident cd + t-lymphocytes. the depletion of cd + t-lymphocytes was associated with a higher susceptibility to lung infection caused by staphylococcus aureus in some clinical and experimental studies. the aim of our study was to evaluate the mechanism by which endotoxemia reduces the number of lung-resident cd + t-lymphocytes and increases susceptibility to s. aureus in the lungs. experimental systemic inflammation was initiated in balb/c mice (n= ) with \mug of endotoxin (lps) given intraperitoneally; hrs after this challenge, the animals were anesthetized and x cfu of s. aureus (s.a.) were administered into the trachea. for the control group, mice were challenged only with s. aureus (n= ). mice were sacrificed hrs after the challenge with s. aureus. lung-resident lymphocyte subsets were obtained by enzymatic digestion of lung tissue. lung-derived and circulating total t-(cd +) and b-(cd +) lymphocytes, cd + and cd + t-lymphocytes as well as nk cells were enumerated with monoclonal antibodies, single platform method and cytometric analysis. colony forming units (cfu) of s. aureus were obtained from lung tissue homogenates using a plate dilution method. the differences between groups of animals were evaluated by one-way anova with a level of significance p< . . data are presented as mean standard ± error. results are shown in the table (number of cells is expressed as cellsx /ml for the blood and cellsx lobe for the lung). conclusion: our results demonstrate that mice challenged with endotoxin and s. aureus have reduced recruitment of cd + t-lymphocytes to the lungs when compared to animals infected only with s. aureus. despite this finding, the susceptibility to secondary lung infection due to s. aureus was significantly decreased after endotoxin challenge indicating its protective effect against staphylococcal infection. aranha f g , rouge a , gomes r v , dessen m , nogueira p m m , fernandes m a o , campos l a a , dohmann h f r surgical intensive care unit, hospital pró-cardíaco -procep, rio de janeiro, brazil the need for dialytic support (hd) in the po period of cs relates to a significant increase in costs and length of hospitalization, in addition to high rates of morbidity and mortality.the objective this study is assess the incidence of hd and its association with mortality in adult patients (pts) undergoing cs. historical cohort with data of pts undergoing cs collected from june/ to january/ . the pts were divided into groups as follows: ) group i, pts who did not undergo hd; and group ii, pts who required hd, accounting for . % of the sample. their mean age was . years, . % were males, . % were diabetic, and % of the cs were elective. the mean aha mortality score was . ± . , and the mean euroscore was . ± . . analysis of frequency and the chi-square test were used for comparing mortality. fifty-six ( . %) pts died in the hospital, ( . %) in group i, and ( %) in group ii. thirty-nine ( . %) pts died within days, of whom ( . %) were in group ii. an important statistical significance (p< . ) was observed between both groups. the po intensive care unit length of stay was significantly longer in group ii, in which % of the pts remained hospitalized for more than days (p< . ). the po intensive care unit length of stay and mortality were significantly greater in the group of pts undergoing hd in the po period of cs. a high percentage of patients underwent hd ( . % of the sample), which may be explained by the profile of the population studied. in group ii, in-hospital mortality was %, and mortality in days was . %. in the entire sample, these indices were . % and . %, respectively, and the euroscore predicted a mortality rate greater than . %. the conventional choice for type-b aortic dissection has been medical treatment. surgical repair has been kept for cases presenting complications. both treatments are associated with high mortality rates. endovascular stent-graft placement opens up new perspectives in the controversial treatment of thoracic aorta dissections. the objective of this paper is to describe our experience in the post-operative handling of type b aortic dissections treated with endovascular stent grafting. twelve patients admitted to an all-purpose icu from january to march treated with endovascular stent grafting. ten patients with acute type b dissection and one patient with traumatic rupture of thoracic aorta. the pre-operative study included transesophagic ecography and ct to evaluate the extent of the dissection, the relation with the left subclavian exit, true and false lumen size, and vascular complications. placement of the endovascular stent-graft (talent type) was successful in all cases. three patients died within the first days, two of them in the icu, with a mortality rate of %. complications: one patient had retroperitoneal hematoma, and another presented perioperative ami. two cases were observed of paraplegia, and one case of perioperative acute cerebellar ischemia in relation with type a retrograde dissection of the thoracic aorta. the mean stay in the icu was . days. mean mechanical ventilation time was . days. five patients ( %) presented nosocomial infection: four infections by catheter ( %), one episode of urine infection ( %) and one episode of pneumonia associated with mechanical ventilation ( %). four patients presented acute kidney collapse ( %), without the need for hemodialisis in any case.conclusion: endovascular stent-graft placement can be an alternative to open surgery in the treatment of type b aortic dissection. preliminary results on post-operative morbimortality are promising. randomized and controlled studies are needed to assess the therapeutic potential. durand m , gardelin m , bertet m , tessier gonthier-maurin y , bouzat p , girardet p anaesthesia, chu de grenoble, grenoble, france global tissue hypoxia is associated with a poor outcome after cardiac surgery [ ] . the best predictor of anaerobic metabolism in septic patient seemed to be the ratio of venoarterial co difference (dpco )/arteriovenous o (ca-vo ) content [ ] . the aim of the present study was to verify if this ratio had the same predictive value after cardiac surgery. we performed a retrospective analysis of patients with simultaneous measurements of arterial and venous blood gases and arterial lactate levels during the first hours after surgery. we tested the predictive value of heart rate (hr), cardiac index (ic), mixed venous oxygen saturation (svo ), dpco , ca-vo , dpco /ca-vo and oxygen consumption (vo ) to predict anaerobic metabolism (lactate > mmol/l). the area under roc curves was calculated for the main parameters. results are expressed as mean +/-sd. : results of lactate were below mmo/l (gr ), were above (gr ). dpco (kpa) was significantly higher in gr than in gr ( numerous prospective, randomized studies in critically ill patients indicated that enteral feeding is superior to parenteral feeding and that early enteral feeding, compared with delayed enteral feeding, improves patient outcome as measured by length of stay or complication rates. ideally, tube insertion would be inexpensive and would require minimal time and technical expertise. we inspected a simple bedside technique for positioning the feeding tube. all included patients received a polyurethane feeding tube with a flexible wire stylet ( - silk enteral feeding tube, corpack, wheeling, il).one size cm - fr of feeding tubes was used in this study. feeding tube position was confirmed by an abdominal radiograph. each radiograph was reviewed by a radiologist. equipment to measure ph and bilirubin consisted of color -coded paper (multistic sc bauer corp.usa), amylase and bilirubin (second test) were measured in the central clinical laboratory. successful aspiration of duodenal fluid was performed in ( %) patients. median time for perform bilirubin and ph by color -coded paper (multistic sc bauer corp.usa) -up to seconds. median time for perform bilirubin and amylase analysis in duodenal fluid in central laboratory was . ( + . ) hours. koulenti d , mis m , myrianthefs p , tsigou e , ioannidis c , gavala a , grigoriou p , baltopoulos g icu, kat hospital, athens, greece introduction: liver dysfunction is very common in critically ill patients due to a variety of reasons including trauma, sepsis, congestive heart failure, gall stones, hemorrhagic shock, transfusions, and drug hepatotoxicity. the purpose of the study was to investigate the characteristics of liver dysfunction in icu patients. we prospectively collected data concerning demographic characteristics and liver biochemistry in critically ill patients for a total period of months. liver dysfunction was defined as an increase in liver enzymes by twofold times including sgot, sgpt, alkaline phosphatase, gamma-gt, and bilirubin. during the study period, patients were admitted in our icu. mean age was . ± . , saps ii was . ± . , apache ii was . ± . and mods was . ± . . icu los was . ± . . forty-five patients ( . %) developed liver dysfunction. five of them ( . %) had more than one episodes of liver dysfunction. mean peak values of liver enzymes in patients developing liver dysfunction were sgot . ± . , sgpt . ± . , alp . ± . , gamma-gt . ± . , total bilirubin . ± . , and direct bilirubin . ± . . mean duration of liver dysfunction was . ± . days. mean day of liver dysfunction developed was on . ± . day. confirmed aetiology of liver dysfunction included sepsis ( pts), trauma-rhabdomyolysis ( pts), cholestasis ( pts) and drugs ( pts). we found statistically significant differences (p< . ) between the patients developing liver dysfunction and those who did not concerning los ( . ± . vs. . ± . days), saps ii score ( . ± . vs. . ± . ), apache ii . ± . vs. . ± . and mods score . ± . vs. . ± . . mortality was also significantly higher in patients developing liver dysfunction ( . vs. . %). half of the critically ill patients may develop liver dysfunction during icu hospitalization due to a variety of reasons which may be related to increased los, increased illness severity and other organs dysfunction and worst outcomes. hoeksema m , wester jp , bosman rj , oudemans-van straten hm , van der spoel ji , haak eaf , leyte a , zandstra df intensive care unit, clinical pharmacy, clinical chemistry, olvg, amsterdam, netherlands in critically ill patients with multiple organ dysfunction (mods), thrombocytopenia is frequently observed. heparin-induced thrombocytopenia (hit) accounts for - % of all causes of thrombocytopenia. as hit may be complicated by arterial and venous thrombosis (hitt), alternative anticoagulation is indicated. fondaparinux sodium (arixtra®) is a newly developed synthetic pentasaccharide and acts by selective antithrombin-mediated indirect factor xa inhibition resulting in subsequent thrombin inhibition. fondaparinux sodium has no cross-reactivity to heparin and has not induced an immune-mediated thrombocytopenia in non-icu patients. the elimination is almost exclusively renal. its major drawback is the increased risk of bleeding, to which patients with mods are prone. data on treatment schedules in critically ill patients are non-existent. we describe our experience with fondaparinux anticoagulation in the treatment of hit. we have treated patients with mods and laboratory-proven hit with fondaparinux sodium between december and february . treatment with unfractionated heparin or nadroparin calcium was stopped and laboratory tests for hit were performed with the hit-antibody elisa test. awaiting the test results, fondaparinux sodium (arixtra®, sanofi-synthelabo, the netherlands) was administered as a once daily subcutaneously injection or a continuous infusion of . - . mg/day without loading dose. study endpoints were increase of platelet counts, thrombo-embolic and bleeding complications, and need of transfusion. one female and two male patients, aged between and years, with apache ii scores between and , were diagnosed of hit due to concomitant nadroparin calcium anticoagulation. minimum platelet counts varied from to g/l. hit-antibodies were present in all patients. all patients suffered acute renal failure and were treated with continuous venovenous hemofiltration. treatment with fondaparinux sodium varied from to days. platelet counts improved during fondaparinux sodium. one patient died and autopsy revealed a new myocardial infarction. in another patient recurrent major bleeding resulting in acute tamponade and hematothorax occurred under treatment of both unfractionated heparin and nadroparin as well as under fondaparinux. the third patient suffered a minor bleeding complication. totally, units of erythrocyte concentrates, units of plasma, and units of platelet concentrates were transfused during treatment days.conclusion: treatment with low-dose fondaparinux sodium in patients with mods and hit may be an alternative to treatment with direct thrombin inhibitors. the efficacy and safety need to be determined. caballero zirena a , cortés díaz s , Álvarez terrero a intensive care unit, hospital virgen de la concha, intensive care unit, "virgen de la concha" hospital., zamora, spain introduction: acute pancreatitis is an "acute inflamatory process of the pancreas with variable involvement of other regional tissues or remote organ systems". the definitions of severe pancreatitis accepted generally are: acute physiology and chronic health evaluation (apache ii) score greater than , three or more ranson´s criteria and ct grading system of balthazar. predicting severity of pancreatitis early in the course of disease is very important to prevent and minimize organ dysfunction and complications. from to a total of patients were hospitalized with the diagnosis of acute pancreatitis. of these, patients ( %) were admitted to the intensive care unit. the aim of this study was to compare apache ii score, ranson´s criteria and ct grading system of balthazar for predicting severity and fatal outcome in severe pancreatitis. : patients were identified. there were men and women. the mean age was years (range - ). the most common cause of severe acute pancreatitis were gallstones ( %) and alcoholism ( %). the mean of apache ii score at the admission was , (range - ). most of the patients had higher ct score. all of them had more than three ranson´s criteria. the overall mortality was % ( patients). the intensive care unit length of stay ranged from to days ( mean days). high apache ii or ranson´score at admission significantly determined survival. ranson criterium has the disadvantage of delay. apache ii score is useful in organ failure prediction. balthazar score is superior in predicting pancreatitic necrosis. none of the parameters tested achieved sufficient predictability when used alone. claessens y e , marque s , chiche j d , mira j p , dhainaut j f , cariou a emergency medicine, icu, icu and emergency medicine, cochin hospital, paris, france introduction: saving red pack cell (rpc) transfusion is an important goal in critical care management. the need for rpc transfusion after icu discharge has never been evaluated. prospective monocentric study in critically ill patients admitted between july and december in the medical icu of a teaching hospital. data collected: demographics; saps and lod (d & discharge) ; comorbidity; diagnosis, treatments, icu and hospital lenght of stay ; hb level at icu admission and discharge ; rpc transfusion in icu and during the days following icu discharge with hb threshold and active haemorrhage. information letter was given to patients and families results: population: consecutive pts ( ( ) yrs, saps ( ), (med(sd)). icu mortality %. hb at admission . ( . ) g/dl. . % needed rpc transfusion, threshold . ( . ) g/dl) ; % mortality among rpc transfused pts. , however, with unknown impact on the pituitary-glucocorticoid axis (key mediators: acth / cortisol, affected key metabolite: serum glucose). both, the acth / cortisol system [ ] and blood glucose levels [ ] are increasingly regarded important in intensive care medicine. since the effects of levo on this system may depend on the state of consciousness, we studied respective endocrine effect of levo both in the awake and anesthetized state. we compared respective effects of levo with those of established inotropes, milrinone and dobutamine. awake and anesthetized ( . mac sevoflurane, ventilated) dogs (total: experiments) randomly received levo ( µg/kg plus steps: . - . µg/kg/min), mil ( . µg/kg plus . - µg/kg/min) or dob ( . - µg/kg/min). under steady state conditions (each dose: min) we measured arterial acth-, cortisol-and glucose-levels. statistics: data presented as mean±sem, wilcoxon test, p< . , alpha-adjusted for multiple testing. : levo preserved the levels of acth both in the awake state ( . ± . vs. . ± . pg/ml, baseline and highest drug dose) and during anesthesia ( . ± . to . ± . pg/ml). levo dose-dependently -but insignificantly-increased cortisol under both conditions (awake state: ± , ± , ± and ± ng/ml; anesthesia: ± , ± , ± and ± ng/ml). levo preserved (as did mil and dob) arterial glucose at ~ - mg/dl under all conditions. mil maintained acth in the awake state ( . ± . to . ± . pg/ml) and during anesthesia ( . ± . to . ± . pg/ml), also cortisol ( ± to ± ; ± to ± ng/ml). dob maintained acth in the awake ( . ± to . ± pg/ml) and anesthetized state ( . ± . to . ± . pg/ml), and caused insignificant increases in cortisol ( ± to ± ; ± to ± ng/ml). hfov is an ideal method of ventilation to minimize vili. however, there is limited data regarding outcome in children treated with hfov. we therefore report our experience with hfov at our picu. we retrospectively analysed the chartrecords of all children treated with hfov after failure on cmv between - . the following were recorded: demografic variables, admission diagnosis, pim ii scores, and oi and aado at several timepoints before and after transition to hfov. end points included survival at days post-admission to picu and total number of ventilation days (cmv and hfov). twenty-four children aged day to . years were treated with hfo. seven died and seventeen children survived. non-survivors had a significant higher pim score ( . vs . ), shorter duration of pre-cmv ( vs h). the oi and aado between non-survivors and survivors were . vs . and vs , respectively. both oi and aado did not decrease over time in the non-survivors. total ventilation days were lower in the non-survivors ( vs h).conclusion: hfov was associated with a high survival percentage ( %)in a selected group of children were cmv failed. olsen p , rasmussen m , tønnesen e , zhu w , stefano g deptartment of anaesthesia, Århus university hospital, Århus, denmark, neuroscience research institute, state university of new york, new york, united states exogenously administered morphine has immune modulating effects. the discovery of endogenously synthesised morphine and increased synthesis in response to surgical stress ( , ) and endotoxin infusion imparts a role to endogenous morphine in the immune response. morphine may also affect cancer progression. however, in vitro and xenograft experimental studies illuminating morphine's role in carcinogenesis show conflicting results. the aim of the present study was to analyse human gliomas for the content of endogenous morphine. the study was approved by the regional ethical committee on human research.twelve gliomas were extracted during craniotomy and frozen instantaneously in liquid hydrogen. patients did not receive morphine intra-or postoperatively. pathological analyses confirmed the diagnoses glioma. upon preparation samples were analysed for morphine content with radioimmunoassay (ria) and specificity was confirmed with mass spectrometry. all tumours contained endogenous morphine with concentrations ranging from , ng/g - , ng/g. the identity of morphine was subsequently confirmed by mass spectrometry. the demonstration of endogenous morphine in gliomas suggests its potentially role in carcinogenesis either as an inherent protective measure or as a result of neoplastic transformation. however, it remains to be clarified where the endogenous morphine production takes place. it is also unknown whether the presence of morphine is a pan-cerebral phenomenon or specific to cancerous tissue. the present study revealed a high content of endogenous morphine in human gliomas, providing further support to the idea of potential influence of endogenous morphine in cancer growth. . the majority of infections were exogenous, i.e., the bacterium was introduced into a normally sterile organ, directly from the picu environment. one quarter of the infections were primary endogenous, i.e., the child developed an infection due to a micro-organism present in the admission flora. the death of one child was unrelated to infection. this study shows an infection and mortality rate of % and %, respectively. low level pathogens caused practically all infections which were mainly exogenous following breaches of hygiene. sdd was effective as endogenous infection due to agnb was controlled. scale (gcs),hypotension (systolic blood pressure < mmhg) and hypoxia (cyanosis or pulse oximetry < %)on admission, other traumatisms, head computed tomography (ct) based on marshall's classification (tcdb), intracranial pressure (icp) monitoring,jugular bulb oxygen saturation (sjo ), transcranial doppler (tcd), intracranial hypertension (htic) defined as icp> mmhg.brain edema treatment,length of stay in critical care unit (icu) and hospital,gcs at icu and hospital discharge, and mortality. we also studied hemodinamic and respiratory (pao /fio < ) complications, fever (axilar temperature > , ºc) and electrolytic disorders (sodium < mmol/l or > mmol/l). lewejohann j c , hansen m , zimmermann c , muhl e , bruch h p surgery-icu, universitätsklinikum schleswig-holstein-campus lübeck, lübeck, germany propofol infusion syndrome (pris) is a very rare and often fatal syndrome in critically ill patients undergoing long-term propofol infusion at high doses. until today cases of pris in adults have been described in the literature and of them died. the aim of our representation is to demonstrate the clinical course of a patient with severe rhabdomyolysis subsequent to a multiple trauma and sedation with propofol and to make obvious the importance of this life-threatening syndrome. a year old multiple trauma patient of about kg bodyweight was admitted to our surgical-icu at a university hospital. he had a severe head trauma, a fracture of the cervical vertebra, an ards, multiple rip fractures, severe lower leg fractures with severe vascular damage and the nead of amputation h after admission, fractures of the femora, pericardial effusion and hematoma of the spleen. he received from the beginning on high doses of catecholamnies (norepinephrine, epinephrine), hemofiltration because of renal failure. after resection of his right lower leg one day after admission he received propofol % in a dose range between to ml/h over a time period of days. an initial myoglobin level of µg/l as a result of the multiple trauma on admission decreased to µg/l when the propofol infusion was started with ml/h at first. myoglobin level decreased to µg/l after h. propofol infusion then was increased to ml/h and after h to ml/h. in the following h we saw a dramatic increase of the myoglobin level to a peak level of µg/l. the propofol infusion was stopped then because of the severe rhabdomyolysis and because we thougt about the recently publihed review about the propofol infusion syndrome. soon after removal of propofol myoglobin level decreased rapidly and the patient survived later on. the propofol infusion syndrome is a very rare complication subsequent to propofol use. our patient was severe head injured and received high doses of catecholamines as triggering factors like the patients described in literature. rhabdomyolysis decreased rapidly after stopping the propofol infusion.conclusion: think about the propofol infusion syndrome in patients with severe rhabdomyolysis receiving high dose propofol long-term sedation and consider alternative sedative agents. in northern ireland the process of co-ordinating appropriate and timely therapeutic intervention for severe traumatic brain injury (stbi) is somewhat fragmented. the objectives of the audit were to obtain baseline epidemiological data for stbi in northern ireland and to review current regional critical care management. this was a month prospective audit. stbi patients were identified for inclusion through referrals made to the regional neurosurgical unit (rnsu). during the audit period adult patients were referred to the rnsu. patients were admitted to the regional icu (ricu). % of these patients were male and mostly in the - year age group. % of the injuries were due to falls, . % road traffic accidents and . % assaults. alcohol was detected in % of the patients. icp monitoring was utilised in % of cases, and on day of admission intracranial hypertension (icp > mmhg) was diagnosed in %. this figure fell to % by day . muscle relaxants were used for icp control in % of patients on day and in % on day . over % of individuals developed a ventilator-associated pneumonia (vap) during their ricu stay. this significantly increased the length of stay, but did not increase individual mortality. % of patients required a tracheostomy prior to discharge. there was a high incidence of vap in stbi patients in northern ireland. this may be related to the increased frequency of alcohol intoxication in these patients. heavy reliance on muscle relaxants for icp control may be a further contributing factor. in light of these findings new critical care management guidelines for stbi are being considered.pradl r , chytra i , kasal e , bosman r , ?idková a , ?tepán m dept. of anaesthesia and intensive care medicine, charles university hospital, plzen, czech republic transesophageal doppler was confirmed as useful non-invasive tool for hemodynamic optimisation in group of elective surgery patients. the aim of prospective randomized study was to evaluate the efficacy of early hemodynamic optimisation in multiple trauma patients using transesophageal doppler in comparison with traditionally used basic hemodynamic monitoring (arterial blood pressure, heart rate, central venous pressure). patients with multiple trauma and expected blood loss more than ml admitted and mechanically ventilated on interdisciplinary icu of university hospital in were randomized in protocol group (doppler) and control group (control). hemodynamics of doppler group patients were immediately after admission to icu managed according to the protocol based on data obtained by transesophageal doppler. hemodynamics of control group patients was aimed at generally used resuscitation endpoints -mean arterial pressure (map), central venous pressure, heart rate (hr), urine output and skin perfusion. the age, the apache ii score and injury severity score (iss) were assessed. map, hr and blood lactate level (lact) were evaluated at the time of icu admission (map- , hr- , lact- ) and after hours of icu stay (map- , hr- , lact- ). mann-whitney, wilcoxon, unpaired and paired t-test were used accordingly; p< , was considered statistically significant. a total of patients ( men and women) were enrolled and randomized in doppler (n= ) and control (n= ) group. no differences between doppler and control group in age ( , ± , vs , ± , ), apache ii score ( , ± , vs , ± , ) and iss ( , ± , vs , ± , ) were found. no differences between both groups in map- , map- , hr- , hr- , lact- and lact- were detected, however significant differences between map and blood lactate level at the admission to icu and after hours of icu stay were observed in doppler group (see table) .map- mm hg map- mm hg p lact- mmol/l lact- mmol/l p doppler , ± , , ± , * , ± , , ± , * control , ± , , ± , n.s. , ± , , ± , n.s. n.s. -non-significant, * -p < , conclusion: we conclude that early hemodynamic optimisation by transesophageal doppler in multiple trauma patients can contribute to better tissue perfusion and elimination of oxygen debt. the study is supported by a research grant iga mz cr nd/ - fotouhi ghiam a , abootalebi s , tavana r neurology unit, internal medicine department, al-zahra hospital, bushehr university of medical sciences, bushehr, shiraz university of medical sciences, shiraz ,iran introduction: awareness of the relative prevalence of diseases causing loss of consciousness (loc) in a particular geographic locality could greatly facilitate the approach to patient management. so this study has established to determine the etiologies responsible for nontraumatic loc and hospital outcome in an emergency ward (ew).methods: patients older than twelve years old who present with loc were enrolled in this cross sectional study during the -month period in the ew of the al-zahra teaching hospital. loc was defined as a clinical state manifested by any decrease in level of consciousness ranging from confusion to deep coma. these numbers of patients (accounting for % of the ew patient volume) were identified with a mean age of . years ( . % men). etiology was metabolic in . % , structural in . % and infective in % of patients. it remained unknown in % despite extensive investigation. the most prevalent causes in subgroups were cerebrovascular accidents ( . %) , drug intoxication ( . %), and hypoxic-anoxic conditions ( . %) respectively. the history taking and physical examination were most useful in diagnosis. computed tomography (ct) scan plays an important role in diagnosis of structural causes. lateralizing signs ( %) and nausea/vomiting ( . %) were particularly evident in the presenting symptoms. prognosis is highly dependent on etiology. the admission glasgow coma scale significantly correlated with outcome (p < . ). overall series hospital mortality was . %. most of the patients have been referred to center in less than hours after loc onset. metabolic causes were the commonest overall etiology. the number of undiagnosed cases are significantly higher than other similar domestic and foreign (usa , europe , asia , africa) studies, so emphasis on educating the medical staff to approach to loc and establish cpr committee in ew should be considered. poor outcome was associated with low gcs score. endobronchial blockade represents an alternative to a double-lumen tube (dlt)( ). the wire-guided arndt endobronchial blocker (web, cook inc) can be coupled to a fiberscope and directed as a unit through an endotracheal tube into the area to be blocked. this is of particular interest in patients with a difficult airway in whom intubation with a dlt is contraindicated( ). in contrast to a dlt, that results in complete blockade of either the left or right lung, the web can be positioned in almost any portion of the airway, thereby allowing to isolate a single lobe. we report on the use of the web in a patient with bronchopleural fistula and pulmonary hemorrhage. a yr-old male was admitted after being hit by a truck. orotracheal intubation had been performed at the scene. ct scan revealed fractured ribs, severe bilateral lung contusion, bilateral pneumothorax, pneumomediastinum and -percardium. chest tubes placed in the right thoracic cavity were suggestive of bronchopleural fistula. bronchoscopy revealed a tear in the right lower lobe bronchus and significant bleeding into the airway. due to massive leakage, selective ventilation of the left lung was decided. because of severe mediastinal emphysema, the risk of airway loss during tube exchange seemed high. we decided to perform selective blockade using the web. the web was inserted through the endotracheal tube together with the fiberscope and endoscopically directed into the right lower lobe bronchus with its cuff proximal to the bronchial tear. once the cuff was inflated, the bronchopleural fistula closed, and ventilation improved to normal within minutes. the web was left in place for hrs, and the fistula did not reccur thereafter. the patient's trachea was extubated on day , and he was transferred to a peripheral ward on day in good condition. the web for use in single-lung ventilation with single-lumen intubation proved to be an appropriate tool in an emergency situation caused by severe bronchopleural fistula. intubation with a dlt was considered a high-risk maneuver because of severe mediastinal emphysema and difficult airway. with the web inserted through the endotracheal tube it was possible to isolate the injured right lower lobe from ventilation, to prevent spread of hemorrhage, and to avoid the risk of airway loss during tube exchange. because the web is fixed to the fiberscope with a wire loop, both fiberscope and blocker can be navigated through the tracheobronchial tree as one unit, the web released as soon as in place. our expercience with the web prompts us to recommend this device as a highly practicable alternative to a dlt whenever one-lung ventilation or lobe isolation is required. ( ) campos jh, kernstine kh. anesth analg ; : - .( ) arndt ga, et al., acta anaesthesiol scand ; : - . chaparro m , prieto m , aragonés r , muñoz j , curiel e , arias d , delgado m , ruíz m . intensive care unit, hospital materno-infantil, málaga, spain postpartum haemorrhage is one of the most common causes of maternal morbidity and the primary cause of maternal mortality. only a few case reports have shown that recombinant activated fvii (rfviia) successfully controlled intractable obstetric bleeding ( ). three obstetric patients with massive bleeding and clinical and analytical repercussion, without previous coagulopathy are presented. the use of rfviia in three consecutive obstetric patients with unresponsive lifethreatening haemorrhage admitted to our intensive care unit within the last six months is reported. demographic data, rfviia doses, timing of treatment and diagnosis, among other variables are presented in the floros j , maratheftis n , kolliass , vletsas c , roussos c icu, neurosurgery, evangelismos, athens, greece cerebral microdialysis is a relatively new technique for measuring the levels of brain extracellular chemicals, which to date has predominantly been used as a research tool. there are many reports which emphasize the importance microdialysis to monitor patients with head injury. we describe a significant relation lactate/pyruvate ratio and icp in ten severely head injured patients admitted in the icu in the perioperative period. microdialysis catheters inserted via a bolt fixation device together with the icp catheter. the catheters implanted into the brain to reflect changes in the penumbra of a lesion under computed tomographic control. we used the standardized equipment (cma microdialysis oma ). the lactate/pyruvate ratio is a better marker of ischemia in these patients. there is a strong difference between the values (repeated measured anova) l/p (p< . ) and icp (p< . ) in tracking secondary ischaemic and edema events. the lactate/pyruvate ratio was increased in all ten patients - hours before any change in the ct scan. the lactate/pyruvate ratio is also a better marker of ischemia (p< . ) than lactate alone (p< . ).conclusion: .microdialysis is an effective tool for studying extracellular chemistry and, thus, has great potential for exploring the pathophysiology of secondary brain damage. . the sensitivity and specificity of microdialysis for ischemia and secondary damage are better than icp. . there are data to confirm that microdialysis can be used to direct therapy and influence outcome. moriwaki y , sugiyama m , toyoda h , fujita s , yamagishi s , kanaya k , hasegawa s , kosuge t critical care and emergency center, yokohama city university medical center, yokohama, japan recently, most of trauma patients can be non-operatively treated. one of the most important issues is a few chances of experience of surgery for trauma patients (on-jobtraining). many training courses (off-job-training) for initial trauma care are held frequently, which training course obtain good results in many country. however, it is obvious that on-jobtraining is more effective training method. the objective of this study is to clarify the hourly incidence of trauma patients and surgery for them in one typical urban emergency center and how surgeons are effectively trained for initial care of trauma patients in this center in the education of surgical specialty. our city yokohama is one of the biggest city in japan and has of third level emergency center, including our center, for , people. we examined , of trauma patients treated mainly by surgeons (neck-chest-abdominal trauma cases and polytrauma cases) in our emergency department (ed) including cardiopulmonary arrest (cpa) patients, and of them including cpa who underwent emergency operation. the planning of training in the education of surgical specialty was discussed from a viewpoint of an hourly incidence of trauma patients and surgery for them. trauma patients were mainly transferred during the night shift: . of non-cpa trauma patients ( . %) were transferred during the day shift and . during the night shift per months. surgeries for them were also performed mainly during the night shift: . of non-cpa patients ( . %) and . of all trauma patients (including cpa) underwent surgery during the day shift and . and . patients, respectively, during the night shift per months. we conclude that trainee for surgeon in japan can have adequate opportunity of the initial care and surgery for trauma patients if they belong to the emergency center as an exclusive staff and are on frequent night duty. key: cord- -sbds sda authors: portran, philippe; jacquet-lagreze, matthias; schweizer, remi; fornier, william; chardonnal, laurent; pozzi, matteo; fischer, marc-olivier; fellahi, jean-luc title: improving the prognostic value of ∆pco( ) following cardiac surgery: a prospective pilot study date: - - journal: j clin monit comput doi: . /s - - - sha: doc_id: cord_uid: sbds sda conflicting results have been published on prognostic significance of central venous to arterial pco( ) difference (∆pco( )) after cardiac surgery. we compared the prognostic value of ∆pco( ) on intensive care unit (icu) admission to an original algorithm combining ∆pco( ), ero( ) and lactate to identify different risk profiles. additionally, we described the evolution of ∆pco( ) and its correlations with ero( ) and lactate during the first postoperative day (pod ). in this monocentre, prospective, and pilot study, patients undergoing conventional cardiac surgery were included. central venous and arterial blood gases were collected on icu admission and at , and h postoperatively. high ∆pco( ) (≥ mmhg) on icu admission was found to be very frequent ( % of patients). correlations between ∆pco( ) and ero( ) or lactate for pod values and variations were weak or non-existent. on icu admission, a high ∆pco( ) did not predict a prolonged icu length of stay (los). conversely, a significant increase in both icu and hospital los was observed in high-risk patients identified by the algorithm: . ( . – . ) days versus . ( . – . ) days (p = . ) and . ( . – . ) versus . ( . – . ) days (p < . ), respectively. an algorithm incorporating icu admission values of ∆pco( ), ero( ) and lactate defined a high-risk profile that predicted prolonged icu and hospital stays better than ∆pco( ) alone. tissue perfusion after cardiac surgery may become impaired due to multiple factors and in turn induce organ dysfunction, organ failure, prolonged stay in intensive care unit (icu) and in hospital and increased mortality [ ] . unfortunately, the adequacy of tissue perfusion remains difficult to assess. surrogate markers like central venous to arterial pco difference (Δpco ), oxygen extraction ratio (ero ) and lactate are used to evaluate this adequacy [ , ] . elevated arterial lactate is a commonly used marker of global anaerobic metabolism and even mild hyperlactatemia has recently found to be correlated both with microcirculatory flow abnormalities and a worse outcome [ ] [ ] [ ] . however, lactate is not a pure marker of anaerobic metabolism and non-hypoxic causes of hyperlactatemia are common in septic shock or after cardiopulmonary bypass [ ] [ ] [ ] . accordingly, additional markers of tissue perfusion have been explored. ero can be calculated on basis of oxygen arterial saturation (s a o ) and central venous saturation (s cv o ) using the following formula: ero = (s a o −s cv o )/s a o . hemodynamic monitoring guidelines recommend to monitor this ratio after cardiac surgery and a s cv o ≥ % is often considered a target for optimal hemodynamic resuscitation [ , ] . however, because of the potential extraction defect some patient might have microcirculatory impairment with a normal or supranormal s cv o . in this context Δpco has been proposed as a global marker of tissue perfusion adequacy [ ] [ ] [ ] . Δpco is a marker of the venous blood flow ability to remove the excess co produced in tissue. an impaired tissue perfusion, due to low cardiac output or microcirculatory alteration, is therefore the main determinant of an elevated Δpco [ ] . yet, the prognostic significance of Δpco after cardiac surgery remains unclear and conflicting results have been published [ , ] . moreover, limited prospectively reported data on Δpco after cardiopulmonary bypass (cpb) are available. finally, in clinical practice Δpco and lactate or ero values frequently appear contradictive, which makes the interpretation of an elevated Δpco difficult. several authors already suggested that interpreting Δpco with s cv o improve the prognostic significance of these markers [ , , ] . de backer in a recent review on hemodynamic in shock suggests an algorithm combining Δpco , s cv o and lactate [ ] . this multiparametric approach could better discriminate different cardiovascular profiles and improve our understanding of apparently contradictive patterns. still, no clinical study has yet evaluated algorithms combining these three markers following cardiac surgery. in this pilot study, we evaluate the prognostic value of Δpco at the time of icu admission and compare it to an original algorithm combining Δpco , ero and lactate to identify different risk profiles after elective conventional cardiac surgery. additionally, we describe the evolution of Δpco and its correlations with ero and lactate on the first post-operative day (pod ). all adult patients scheduled for elective cardiac surgery with cpb were eligible for this monocentric, prospective, observational study, which was approved by the local ethics committee (comité de protection des personnes, reference cpp: a -d -vol. ). according to french law and because data were collected during routine care, authorization was granted to waive written informed consent. however, verbal consent was obtained from all study participants before surgery. all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the helsinki declaration and its later amendments or comparable ethical standards. from april to june , patients who were scheduled for cardiac surgery at caen university hospital, caen, france, were eligible for participation in the study. inclusion criteria were as follows: patients > years old who were admitted to the surgical icu following elective conventional cardiac surgery (coronary artery bypass graft (cabg) and/or aortic or mitral valvular surgery) with cpb. exclusion criteria were age < years or patient under tutorship, off pump surgery, cardiac transplantation, ventricular assist device implantation and any emergency situations. the anesthesia was standardized (target-controlled infusion of propofol and remifentanil) and adjusted to obtain a bispectral index value between and . immediately after the induction of general anesthesia and tracheal intubation in the operating room, a radial artery catheter and a right jugular central venous catheter were inserted. more advanced hemodynamic monitoring was left at the anesthetist's discretion. patients were ventilated at - ml kg − of ideal body weight, positive end expiratory pressure was set to - cm h o. the ventilator was switched off during cpb. anticoagulation was obtained during cpb with an initial bolus of heparin ( ui kg − ) to maintain activated coagulation time more than s. reversion was systematically per-formed with protamine at the end of cpb. cpb was performed under normothermia and myocardial protection was achieved by intermittent cold blood cardioplegia. boluses of ephedrine and/or phenylephrine were given intraoperatively to maintain mean arterial pressure between and mm hg. the heart was defibrillated after aortic unclamping, if sinus rhythm did not resume spontaneously. after the termination of cpb, norepinephrine was used to maintain the mean arterial pressure greater than mm hg, and the trigger for transfusion of packed erythrocytes was set to a hematocrit of % in all patients and complied with routine practice at the study institution. on arrival in the icu, all pressure monitors were zeroed at the mid-axillary line upon arrival and the position of the tip of the central venous catheter in the upper part of the right atrium was verified by chest radiography. discontinuation of invasive ventilation, administration of blood products, management of hemodynamics and fluid balance, icu and hospital discharge followed institutional standards. data elements included demographic variables: age, gender, body mass index (kg/m ), euroscore (%), baseline serum creatinine value (μmol/l); intra operative data: type of surgery, cpb time, cross clamp time, use of epinephrine, norepinephrine or dobutamine, preoperative. the first blood sample was collected on admission to the icu (t ) and h (t ), h (t ) and h (t ) after. venous and arterial blood gas were drawn simultaneously from radial arterial catheter and central venous catheter. central venous and arterial lactate serum level, co partial pressure, oxygen saturation and content were obtained from the blood gases. Δpco was calculated as p cv co minus p a co . the patient's heart rate, mean arterial pressure (map), central temperature and oxygen saturation were measured simultaneously to the blood samples. the primary outcome was icu length of stay. at the icu discharge, we also collected duration of mechanical ventilation, the need for epinephrine, norepinephrine or dobutamine on pod and total postoperative chest tube drainage. secondary outcomes included sequential organ failure assessment (sofa) score on pod , acute kidney injury (aki) on first and second postoperative day (pod and pod ) and hospital length of stay [ ] . aki was defined according to the acute kidney injury network criteria as stage or higher (increase in peak postoperative serum creatinine level to > % or ≥ . μmol/l from baseline value) [ ] . hyperlactatemia was defined as an arterial lactate level above . mmol/l [ , ] . we choose a Δpco > mmhg to define an elevated Δpco and a normal ero as a level of % or lower. these cutoff values were chosen according to previous studies [ , ] . we constructed an algorithm combining Δpco , ero and lactate. this algorithm helped us identifying a low-risk profile and a high-risk profile (fig. ). in the algorithm, lactate elevation was considered a marker of global anaerobic metabolism in the presence of altered values of Δpco or ero . if Δpco and ero were both normal, lactate elevation was considered to be non-hypoxic hyperlactatemia. Δpco elevation was considered to reflect low cardiac overall, ( %) patients had high-risk profile whereas ( %) patients experienced a low-risk profile output (co) in case of high ero or microcirculatory dysfunction with impaired oxygen extraction if ero was normal. an elevated ero in presence of a normal Δpco was considered to reflect a decrease in do non-related to a low co (anemia, hypoxemia). patients with global anaerobic metabolism, non-hypoxic hyperlactatemia or microcirculatory dysfunction with impaired oxygen extraction as determined by the algorithm were considered to have a high-risk profile. the icu length of stay (los) of high-risk profile patients was then compared to the rest of the population. the number of patients included in that pilot study was fixed empirically to . all data were tested for normal distribution with the kolmogorov-smirnov test. normally distributed data were displayed as mean ± standard deviation and not normally distributed data were displayed as median with th percentile and th percentile. comparisons were performed using fisher's exact test or chi squared test for categorical data according to the distribution. independentsamples t test was used to test the differences in normally distributed variables and mann-whithney u test for not normally distributed variables. trends in the parameters over time in two groups were compared with repeated-measures anova. pairwise comparisons were corrected for multiple testing with the bonferroni procedure. pearson or spearman correlation coefficients for data normally distributed and not normally distributed, respectively, were used to evaluate the relation between two variables. we analyzed correlation between values of the whole dataset and markers pod variations. to calculate markers pod variations we identified, among the whole dataset, the successive samples of lactate, Δpco and ero measured within to h intervals in a given patient and calculated the markers variations as following: marker variation = % × (second marker value−initial marker value)/initial marker value. we used the log-rank test to compare the length of stay in icu according to the patient risk group on admission. for all tests, a two-tailed p value less than . was considered significant. statistical analyses were performed using r software (r foundation for statistical computing ). twenty-five consecutive adult patients were included in the study ( % cabg, % valvular surgery and % combined surgery). baseline characteristics and surgery-related parameters in the whole cohort of patients and in both lowand high-risk groups are shown in table . no significant difference was found between groups with the exception of the icu los. at the time of admission, % of the patients had elevated Δpco (fig. ) . on pod a Δpco ≥ mmhg was reported at least once in all patients. Δpco did not significantly decrease on pod and patients with high Δpco on admission did not have significantly different Δpco at t , t and t compared with patients with normal Δpco (fig. ) . correlations between Δpco and lactate or ero for pod values and variations are shown in table . a weak correlation was found between Δpco and ero both for pod absolute values (r = . , p < . ) and variations (r = . , p < . ). correlation between s cv o and ero was excellent (r = − . , p < . ). other correlations between markers were weak or non-significant ( table ). s cv o was not significantly different in patients with normal or elevated Δpco ( ( - ) % versus ( - ) %, respectively, p = . ). at the time of icu admission an elevated Δpco did not predict prolonged icu and hospital stays ( fig. a and b) . the algorithm combining Δpco with ero and lactate identified patients with a low-risk profile and patients with a high-risk profile at the time of admission. out of the patients with elevated Δpco upon admission, ( %) were classified as low-risk profile while ( %) were identified as high-risk profile. conversely, out of the patients with low Δpco upon admission, ( %) were identified as high-risk profile and ( %) as low-risk profile. the precise incidence of the different hemodynamic patterns is further described in fig. . temperature on icu admission was not different in patients with normal and elevated Δpco ( . ± . °c vs. . ± . °c respectively, p = . ) and between high and low risk groups ( . ± . °c vs. . ± . °c respectively, p = . ). the high-risk patient group at the time of admission had icu los twice as long as those in the low-risk patient group. (table and fig. c ) hospital length of stay was also significantly longer for patient in the high-risk group compared to the low risk group ( . ( . - . ) versus . ( . - . ) days respectively, p < . ). (figure d ) we found significantly more aki in patients of the high-risk group compared to the low risk group (( ( %) vs. ( %), respectively, p = . ) and serum creatinine on pod and pod were significantly higher ( table ). all aki were stage according to the acute kidney injury network. need for prolonged mechanical ventilation, inotropic support and sofa on pod were not significantly different between groups ( table ). the icu los was not significantly different across patients with low or elevated lactate ( . ( . - . ) days versus . ( . - . ) days, respectively, p = . ) and/or low or elevated ero ( . ( . - . ) days versus . ( . - . ) days, respectively, p = . ) at the time of admission. the main results of this prospective pilot study are as: -high Δpco (≥ mmhg) on admission and on pod of conventional cardiac surgery was found to be very frequent and did not predict an elevated Δpco at t , t or t . correlations between pod values and pod variations for Δpco and ero or lactate were weak or non-existent. -at the time of admission an elevated Δpco alone did not predict a prolonged icu stay. conversely, icu los increased by -fold in the high-risk patient group identified with the algorithm. high-risk patients also had significantly more postoperative aki and longer hospital los. limited prospectively reported data on Δpco after cpb are available. as previously reported in retrospective studies, our prospective study demonstrates that a widening in Δpco on pod after conventional elective cardiac surgery is quite frequent [ , ] . the reason why Δpco remains elevated on icu admission and on pod is unclear. an adequate venous blood flow is the main contributor of Δpco and depends on both cardiac output and tissue perfusion [ , ] . it has been demonstrated that Δpco after cardiac surgery is only poorly correlated to cardiac output or regional blood flow [ ] . it has been suggested that impaired microcirculation could be responsible for the widening in Δpco especially when it is associated with normal s cv o [ , ] . in these studies the pattern of a high Δpco with a normal s cv o was associated to further post-operative complications, impaired splanchnic function or elevated lactate. yet, it is still uncertain whether a high Δpco after cardiac surgery is related to microcirculatory hypoperfusion and further studies are needed. we found no strong correlations between Δpco and ero or lactate, which is concordant with previous studies in the settings of cardiac surgery and septic shock [ , , [ ] [ ] [ ] . this particular lack of strong correlation is not surprising, since Δpco , ero and lactate provide information on different hemodynamic mechanisms. for example, high lactate is a marker of global anaerobic metabolism whereas high Δpco indicates decreased blood flow that can occur without anaerobic metabolism [ ] . conversely, tissue hypoxia from non-ischemic cause will not be detected by Δpco . but will induce a rise in lactate value [ ] . concerning ero , its elevation is a normal adaptation mechanism that can also occur without tissue hypoxia [ ] . we did not find any significant prognostic value of an elevated Δpco at the time of admission. similarly, ero and lactate level taken alone at the time of admission did not predicted a prolonged icu stay. it is important to not misinterpret these results. we underline that the prognostic value of hyperlactatemia or abnormal ero after cardiac surgery has been demonstrated in several studies [ , , , ] . concerning Δpco , an elevation ≥ mmhg at admission has also been shown to be associated with poor prognosis in high surgical risk patients but the results are conflicting in cardiac surgery [ , , ] . in a recent retrospective study, high Δpco after cardiac surgery was not associated with a worst outcome but the authors analyzed Δpco alone [ ] . conversely, habicher et al. found that in presence of normal s cv o ≥ %, a high Δpco (Δpco ≥ mmhg) was associated to further post-operative complications [ ] . the combination of these two markers seem to better predict complications. similarly, our study suggests that an algorithm combining Δpco with ero and lactate improved prognostic signification of these markers at admission. indeed, in our study, % of patients with high Δpco at the time of admission were classified as low-risk group and % patients with low Δpco were eventually categorized in the high-risk group. consequently, we think that Δpco , ero and lactate should not be interpreted separately but together using an algorithm. our study population was at low risk according to the euroscore evaluation. however, when associating to this preoperative scoring system the Δpco , ero and lactate measures immediately at the icu admission almost half of our population was eventually classified as highrisk group. interestingly, although our study was lacking of power for prognosis evaluation, icu and hospital stays were significantly longer and patients had more acute renal failure in the high-risk group compared to the low-risk group while their euroscore did not differ significantly. we think that our algorithm-based evaluation at the time of icu admission may have led to the identification of clinically significant intraoperative complications. the design of our interpretation algorithm is quite similar to the algorithm which was recently published by de backer in a review on hemodynamic in shock [ ] . yet, some differences should be discussed. for example, de backer considers hyperlactatemia with normal ero and Δpco as a profile of high cardiac output with dysoxia (i.e. sepsis). in our algorithm we consider this pattern as non-hypoxic hyperlactatemia. indeed, in the setting of cardiac surgery, the occurrence of hyperlactatemia without evidence of inadequate oxygen delivery (do ) has been reported [ ] . although, the pathogenesis of this disorder remains unclear, according to the authors it should be considered as reflecting a type b lactic acidosis instead of an anaerobic metabolism. these patients with non-hypoxic hyperlactatemia were still considered as high risk. indeed, an increased lactate level with a normal tension difference/arteriovenous o content difference ratio (Δpco /Δconto ; another anaerobic metabolism marker) was shown to be correlated to poor prognosis in a medical icu [ ] . another difference of interpretation relates to the pattern of an increased ero with normal lactatemia and Δpco . both our algorithm and de backer's findings agree on a decrease in do but de backer associates it with dysoxia while we consider a rise in ero to be a normal adaptation mechanism [ ] . nevertheless, we regard both algorithms as useful tools for clinicians to improve comprehension of the patterns drawn by these routine markers of systemic perfusion. this study is the first to describe the incidence of the different hemodynamic profiles defined by these algorithms. there are several limitations to our study. first, the circulatory profiles defined by the algorithm were not externally validated by, for example, a measurement of cardiac output and an evaluation of microcirculation by video microscopy. further studies are needed to assess both macro and microcirculation in the suggested hemodynamic profiles. another important limitation was the small size of the study population and the moderate severity of disease within it. we used central instead of mixed-venous blood to assess ero and co derived variables; our results may have differed if a pulmonary artery catheter (pac) had been used [ ] . fig. length of stay in icu stay according to Δpco alone (a) or according to risk group (Δpco in combination with ero and lactate) (b) at the time of admission. Δpco central venous to arterial pco difference, icu intensive care unit. patients with global anaerobic metabolism, non-hypoxic hyperlactatemia or microcircula-tory dysfunction with impaired oxygen extraction as determined by the algorithm were considered to have a high-risk profile (fig. ) . patients with normal tissue perfusion or decreased oxygen delivery without anaerobic metabolism were considered to have low-risk profile however, pac is no longer used in conventional cardiac surgery. hypothermia is also a potential confounder for Δpco measurement. it may decrease cellular respiration and co generation, especially for very low temperature [ ] . nevertheless none of our patients had profound hypothermia on icu admission and normothermia was rapidly achieved for all of our patients. finally, lactate, Δpco or ero surely have different physiological kinetics, with the clearance of lactate probably slower than that of ero and co derived variables. this makes it difficult to interpret a snapshot of those markers. that being said, taking the kinetics variations of the markers into account would also be very difficult. we designed our algorithm to provide clinicians with an everyday tool for the interpretation of arterial and central venous blood gases, and it appears to correlate with a clinical reality as it predicts occurrence of post-operative aki and longer icu and hospital stays. in this original pilot study on patients who underwent standard cardiac surgery high Δpco (≥ mmhg) on admission and on pod of conventional cardiac surgery was found to be very frequent and high Δpco on admission did not predict an elevated Δpco at t , t or t . correlations between pod values and pod variations for Δpco and ero or lactate were weak or non-existent. an algorithm incorporating the icu admission values of Δpco , ero and lactate defined a high-risk profile that predicted prolonged icu and hospital stays better than Δpco alone. relation between oxygen consumption and oxygen delivery in patients after cardiac surgery blood lactate and mixed venous-arterial pco gradient as indices of poor peripheral perfusion following cardiopulmonary bypass surgery frequency, risk factors, and outcome of hyperlactatemia after cardiac surgery mildly elevated lactate levels are associated with microcirculatory flow abnormalities and increased mortality: a microsoap post hoc analysis even mild hyperlactatemia is associated with increased mortality in critically ill patients lactate/pyruvate ratio as a marker of tissue hypoxia in circulatory and septic shock type b lactic acidosis following cardiopulmonary bypass lactate is an unreliable indicator of tissue hypoxia in injury or sepsis mixed venous oxygen saturation predicts short-and long-term outcome after coronary artery bypass grafting surgery: a retrospective cohort analysis s guidelines for intensive care in cardiac surgery patients: hemodynamic monitoring and cardiocirculary system central venous-arterial pco difference identifies microcirculatory hypoperfusion in cardiac surgical patients with normal central venous oxygen saturation: a retrospective analysis central venous o saturation and venous-to-arterial co difference as complementary tools for goal-directed therapy during high-risk surgery central venous-to-arterial carbon dioxide difference as a prognostic tool in high-risk surgical patients ) difference during regional ischemic or hypoxic hypoxia high veno-arterial carbon dioxide gradient is not predictive of worst outcome after an elective cardiac surgery: a retrospective cohort study a prospective, randomized study of goal-oriented hemodynamic therapy in cardiac surgical patients detailing the cardiovascular profile in shock patients the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury central venous-arterial carbon dioxide difference as an indicator of cardiac index venoarterial co gradient after cardiac surgery: relation to systemic and regional perfusion and oxygen transport high central venous saturation after cardiac surgery is associated with increased organ failure and long-term mortality: an observational cross-sectional study low and "supranormal" central venous oxygen saturation and markers of tissue hypoxia in cardiac surgery patients: a prospective observational study central venous-to-arterial carbon dioxide difference: an additional target for goal-directed therapy in septic shock? combination of arterial lactate levels and venous-arterial co to arterial-venous o content difference ratio as markers of resuscitation in patients with septic shock no agreement of mixed venous and central venous saturation in sepsis, independent of sepsis origin acknowledgements the proofreading of this article was supported by the bibliothèque scientifique de l'internat de lyon and the hospices civils de lyon. conflict of interest the authors declare that they have no conflict of interest.ethical approval all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the helsinki declaration and its later amendments or comparable ethical standards.informed consent according to the french law and because data were collected during routine care, authorization was granted to waive written informed consent. however, verbal consent was obtained from all study participants before surgery. key: cord- -pl ag zz authors: nan title: editor’s picks, – : fifteen articles in open access in intensive care medicine date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: pl ag zz nan dear icm readers, it is our pleasure to present you a small compendium of articles published in our journal in and . in order to make the data more accessible, these articles are now open access and available in the ''editor's picks'' section of the springer icm page (http://www.springer. com/medicine/critical?care?and?emergency?medicine/ journal/ ?detailspage=press). we hope that you will be as thrilled as we are to (re)discover the following papers. . highly virulent e. coli strains involved in vap: new therapies on the horizon? [ ] we invite you to read a very interesting study that establishes antibioresistance and genotypic characteristics of e. coli isolates isolated from vap in adult icu patients. these isolates are highly virulent, suggesting potential targets for new therapies. . how early should we think about invasive pulmonary aspergillosis (ipa) in critically ill h n patients? [ ] in a retrospective study, ipa was diagnosed in as many as % of critically ill patients with severe h n virus infection at a median of days after icu admission! the data suggest that use of cephalosporins days before icu admission is an independent risk factor for fungal superinfection. these findings point out the need for increased awareness of ipa, especially in those critically ill h n patients already receiving cs. )-b-d-glucan as a tool discriminating between colonization and invasive candida infection. [ ] in neutropenic critically ill patients with severe abdominal condition at icu admission, b-d-glucan [ pg/ml with a positive candida albicans germ tube antibody accurately differentiated candida colonization from deep-seated candidiasis. . ultrasound-guided vascular access: a ''third eye'' for icu clinicians. [ ] there is a clear advantage of d vascular screening prior to cannulation, and a real-time ultrasound needle guidance with an in-plane/long-axis technique optimizes the probability of correct needle placement. ultrasound guidance can be used not only for central venous cannulation but also in peripheral and arterial cannulation. ultrasound can also be used in order to check for immediate and life-threatening complications as well as for the catheter's tip position. . how objective are we in end-of-life decision making process? [ ] patients who spend their birthday in the icu receive a higher intensity of life-sustaining therapies and have a longer icu stay. however, this increased therapeutic intensity does not translate into survival benefits compared to matched controls. staff members caring for patients whose birthdays fall during their icu stay should be aware that this feature can bias end-of-life decisions, leading to inappropriate goals of care. communication may improve quality of care and adherence to guidelines. especially the use of mechanical prophylaxis combined with anticoagulants and appropriate drug monitoring should be encouraged. in severe pediatric pneumonia: an evaluation. [ ] survival in children with pneumonia supported with ecmo can reach up to % and is almost comparable to that in patients only requiring invasive mechanical ventilation. venoarterial ecmo may be associated with more serious complications and should be reserved for children with profound hemodynamic instability and severe ventricular dysfunction. risk factors for poor outcome include the need to change the ecmo circuit and the need for renal replacement therapy. group on abdominal problems: back to the roots… and definitions! [ ] the esicm working group on abdominal problems suggests definitions of gastrointestinal dysfunction, as well as experts' opinions about patient management. this group also encourages further research to better define the characteristics of gi function in critically ill patients. more recently, the world society of the abdominal compartment syndrome (wsacs) updated their consensus definitions and suggested guidelines on intra-abdominal hypertension and the abdominal compartment syndrome [ ] . contrast-associated acute kidney injury occurs in one out of six icu patients who undergo a contrast-enhanced noncoronary radiography examination and is associated with worse short-and long-term outcomes (i.e., renal replacement therapy, kidney function at discharge, increased length of icu and hospital stays, and mortality). preventive measures are used in only two-thirds of at-risk patients and do not translate into lower incidence of aki. . the alien study: incidence and outcome of acute respiratory distress syndrome in the era of lungprotective ventilation. [ ] this is the first study to prospectively estimate ards incidence during routine application of lung-protective ventilation. the findings support previous estimates in europe and are an order of magnitude lower than those reported in the usa and australia. despite the use of lung-protective ventilation, overall icu and hospital mortality of ards patients remains as high as %. . eurobact: characteristics and determinants of outcome in hospital-acquired bloodstream infections (bsi). [ ] this study provides contemporary information on outcomes associated with hospital-acquired bsi within the context of increasing rates of antimicrobial resistance, particularly among gram-negative pathogens. both mdr pathogens and failure to administer adequate antimicrobials were associated with day- mortality. furthermore, the results of eurobact confirm the importance of source control in critically ill patients with severe infections. . cost-effectiveness of the surviving sepsis campaign protocol for severe sepsis? [ ] the ssc protocol is a cost-effective option for treating severe sepsis in spanish icus. future research, guided by value of information methods, should be conducted to determine whether this is also true in other countries. more recently, the surviving sepsis campaign guidelines committee including the pediatric subgroup have updated their guidelines for management of severe sepsis and septic shock [ ] . . sepsis after aki: incidence, outcomes, interactions and quality improvement. [ ] more than half of patients with aki who are free of sepsis at the time of aki diagnosis develop sepsis during hospitalization, half of them within days after aki diagnosis. mortality from sepsis following aki is similar to that for sepsis occurring before aki diagnosis. it is likely that sepsis complicating aki can contribute to the overall poor outcomes in this patient population. new preventive strategies in aki patients might help to reduce the exceptionally high rate of mortality and morbidity associated with aki in the critically ill. . analgesia in icu: do old drugs still do a good job? [ ] critically ill patients require analgesia for pain associated with their underlying medical conditions and to facilitate life-support technology. the focus of this study was to investigate a possible difference between fentanyl and remifentanil in achieving an analgesia target. the use of remifentanil-based analgesia in critically ill patients was not superior to fentanyl-based analgesia with regard to the achievement and maintenance of sufficient analgesia. . the variability of critical care bed numbers in europe: an important confounder when assessing outcomes in different settings… [ ] this study collected prospective data on the number of critical care beds for each country in europe (july -july ). strikingly, a marked heterogeneity in the number of critical care beds across european countries was found, even after correction for population size and age distribution, gross domestic product, expenditure on healthcare, and number of total acute care beds. pathophysiology of escherichia coli ventilator-associated pneumonia: implication of highly virulent extraintestinal pathogenic strains invasive pulmonary aspergillosis is a frequent complication of critically ill h n patients: a retrospective study value of b-dglucan and candida albicans germ tube antibody for discriminating between candida colonization and invasive candidiasis in patients with severe abdominal conditions international evidence-based recommendations on ultrasound-guided vascular access increased nonbeneficial care in patients spending their birthday in the icu coagulation day : an austrian survey on the routine of thromboprophylaxis in intensive care outcomes in children with refractory pneumonia supported with extracorporeal membrane oxygenation gastrointestinal function in intensive care patients: terminology, definitions and management. recommendations of the esicm working group on abdominal problems epidemiology of contrast-associated acute kidney injury in icu patients: a retrospective cohort analysis the alien study: incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation characteristics and determinants of outcome of hospital-acquired bloodstream infections in intensive care units: the eurobact international cohort study cost-effectiveness of the surviving sepsis campaign protocol for severe sepsis: a prospective nation-wide study in spain sepsis as a cause and consequence of acute kidney injury: program to improve care in acute renal disease a prospective, randomized, double-blind, multicenter study comparing remifentanil with fentanyl in mechanically ventilated patients the variability of critical care bed numbers in europe pediatric guidelines sub-committee for the world society of the abdominal compartment syndrome. intraabdominal hypertension and the abdominal compartment syndrome: updated consensus definitions and clinical practice guidelines from the world society of the abdominal compartment syndrome surviving sepsis campaign guidelines committee including the pediatric subgroup. surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock key: cord- -n f xupw authors: nan title: ps - date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: n f xupw nan bronchoscopy bronchoalveolar lavage (bal) may be followed by a systemic inflammatory response which clinical effects in critical patients are unknown. we designed this study to examine the effects of fiberoptic bronchoscopy (fob) with and without bal on body temperature, systemic arterial pressure, heart rate and supportive therapies requirements in mechanically ventilated patients. methods. consecutive mechanically ventilated patients were prospectively enrolled. fob with bal ( ml of isotonic saline instilled by aliquots of ml) was performed in patients and without bal in . heart rate and mean arterial pressure were recorded hrs before (time ), at the beginning (time ), and (time ) and hrs after the procedure (time ). body temperature, vasopressors, urine output and fluid balance were registered during hrs before and after fob. there were not changes in hemodynamic parameters, body temperature nor supportive therapies (p: n.s.) in fob patients without bal. on the contrary, in patients with bal, there was a significant decrease in mean arterial pressure hrs after the procedure (table). fluid balance and urine output remained unchanged (p: n.s.), but number of patients on vasopressor therapy and mean vasopressors dosage increased after bal (from . ± . µg/kg/min to . ± . µg/kg/min; p < . ); body temperature did not change (p: n.s.). conclusion. global tests may better reflect physiological haemostasis than standard screens or individual factor assays in critically ill patients with sepsis. studies that involve clinically relevant endpoints of bleeding are required. abizanda r , reig-valero r , bisbal-andres e , mas-font s , sánchez-morán f , madero-peréz j , iranzo-velasco j intensive care department, hospital universitario asociado general de castello, castello, spain to limit therapeutic effort (let) is a reasonable acceptable medical and ethical attitude that must be offered to those cases where the evolution of patients is no good in spite appropiate treatment. our aim has been to look into the let decisions and in the participation of patients and surrogates in them. retrospective analysis of decision making processes about let attitudes in a multidisciplinary beds icu during and , as compared to practices registered during and . since , a consensus attitudes form has been fulfilled between the attending medical team and the surrogates of patients to whom let was proposed (by any part). the agreement offered differentiated possibilities of let (no cpr, no increases in fio , no use of vasoactive drugs, no use of extracorporeal renal depurative techniques, and so on). existing agreement for each individual patient was reviewed every time that the attending team or the surrogates ask for that. during the analyzed years, let attitudes were performed ( in and in ) over a whole in icu mortality of patients ( and ). in patients in whom let was decided, age, severity of illness, risk of death, nursing workload and icu length of stay, were significantly higher than in patients not subjected to let. agreement on let attitudes, between the attending medical team and the patient's representatives was present in % of cases, and in the % the let was decided only on professional-technical reasons. in those cases, medical decision was also informed to relatives. the number of patients being discharged from the icu in whom let was established was ( %). withholding approaches were more than three times higher than withdrawing indications. shorten of death process, was performed in patients ( % of let). these observational data agree with the theoretical approaches established by our group in . no claim was presented by relatives or patients against medical attitudes. conclusion. an increasing transparency in decision making about let does not meet refusal from the patient's representatives, and, by the contrary, it favours that the decision becomes a collegiate one and makes more easy the implementation of non futile attitudes. rubulotta f m , gullo a , levy m m , ramsay g intensive care, gasthuisberg uz, leuven, belgium, intensive care, cattinara, trieste, italy, intensive care, brown, providence, united states, hospital director, atrium, heerlen, netherlands the objective of this study is to assess the end-of-life decision-making process in different countries. questionnaire administered by the same interviewer to north american physicians after an end-of-life discussion with proxies of patients admitted to a medical intensive care unit (micu). questionnaire administered by the same interviewer to italian icu physicians during a regional meeting. physicians in both countries were asked, using a five point linkert scale, to indicate their percentage of responsibility in the decision making process. . usa physicians reported a % of responsibility in the end-of life decision-making process in the micu. italian physicians claimed % of responsibility in the end of life decision making process. physicians have different percentage of responsibility in the end-of-life decision making process according to their culture and working environment ( ) . decision to withhold or withdraw of life-sustaining treatment for an incapacitated brain-damaged patient raises complex issues regarding legal or medical concerns. it is the main question how a "clear and convincing" evidence based decision can be constituted or who has the right to make decision in end of life for a patient living in persistent vegetative state. here we present the care of a woman who was left in a persistent vegetative state after having a cardiac arrest. in , the case of n.u. had a cardiac arrest triggered by a delivery with severe abruption placentae. hypoxic-ischemic encephalopathy developed after a poor response to resuscitation. after one-year stay in icu, she was discharged from hospital without a ventilatory support but still required tracheotomy cannula, gastrostomy tube and urinary catheter. nursing homes caring for incapable patients are not under the cover of health insurance policy in turkey. so the sole solution for caring ms. u was being nourished at own home. to both improve and supply a constant care for ms. u, her sister and her husband agreed on to 'err on the side of life': the final decision was a marriage between mr. u and sister-in-low. it perhaps seems like a moral disturbing solution at first sight, but we do not have to forget that the families commonly disagree over how best to care for a loved one. those unfortunate circumstances need stronger bond shared by each family member, rather than a familial dispute. participation of sibling into the care of ms. u, of course, did not improve the neurological outcome or any cognitive function, but resulted in nearly uninterrupted care, which could be so hard to ensure in a different manner. furthermore since , artificial nutrition and hydration delivered by family without a nurse support, surprisingly maintain normal levels of hematological and biochemical parameters, measured periodically. we believe that the acceptance of diagnosis by all family members that her condition was irreversible, and then they had submitted to her unfortunate destiny. nevertheless, it is difficult to analyze underlying factors, which cause perhaps a compulsive marriage. this profound decision, whether reflects what the patient would want for herself or what the family would want for their incapacitated loved one, is rather debatable. in order to help relieve conscious patients and family members from the burden of an icu stay, we introduced in our icu non-professional hospice volunteers (hv), trained to intervene in palliative care settings. we performed an evaluation after one year. after an agreement was signed with the hv association, hv's role and hours of presence were defined and adapted between the hv women and the icu staff. an hv was on duty one afternoon every weeks from / to / and every week from to / . hv met patients and family members either upon request or suggestion by the staff. a special logbook could be consulted to transmit information. evaluation was performed using questionnaires for staff and hv. these results clearly indicate that introducing hv in an icu is considered by a large majority of the medical and nursing staff as useful and appropriate, though some expressed reluctance to share informations with the hv. satisfaction of patients and family members is being evaluated. a working group has proposed improvements. italy has icus. these include adult and pediatric units. we contacted icus selected at random all over the country. local icu regulations allow family members one visit a day in % of cases. only one family member can enter inside the icu after wearing gloves, mask and gown in % of cases, two family members wearing the same protection in % of cases, and more than two people in % of icus. icu physicians meet the family members at admission and once a day in % of cases. reasons given for adopting these rules include-in % of cases a lack of physical space to receive relatives longer than minutes, in % of cases a lack of icu staff, in % of cases concern about an increased risk of infection, and in % of cases other reasons. all units have special rules for caring for families of terminal patients. the communication between physicians and families in italy could be improved first of all by more space inside the unit, second by dedicating more staff time. families seem to be adequately supported by the icu staff in terminal or difficult situations. masnou n , pont t , gracia r , salamero p transplant coordination, hospital vall d'hebron, bcn, spain the aim of the study is to compare tissue donation refusal between organ donors and potential tissue donors. methods. prospective and descriptive study of all family interviews from to , through specifically designed protocol. this included epidemiological data, the manner of comunication to transplant coordinator (tc), interview features and perceived family attitude. there were deaths in this period. we evaluated as potential tissue donnors patients. a tc carried out the interviews with these families, % ( ) refused donation. over % were actual tissue donors.we followed patients in brain death in this period. only could be organ donors, % of these families didn't consent to tissue donation; so only % of patients could give tissue. we did interviews ; % of families were familiar with spanish law about transplant and presumed consent, and only % of people carry donor cards or have made a living will. regarding the family ties to the deceased, in the case of organ donation the parents refused in % of cases, the partner in % ,the children in %, siblings in % and % in the case of more distant relatives.in the case of tissue donors the refusal was from the parents in % of cases,the partner in %, the children in %, siblings in % and other relatives in % of cases.these differences were due, in part, to the advanced age of the tissue donors. if we relate the cultural level of the interviewed people with the refusals we find the following results: mo low cultural level %, average % and high % while in the tissue group , low %, average % and high % (ns). the reasons for family refusal were as follows (mo-mt %): deceased had expressed negative attitude / , family opposition / , resentment of the health system / , difficulties with image of the corpse / , deceased's will unknown / , contrary religious beliefs / ,flat refusals / , others / .regarding reversed refusals in mo, consent was obtained in % of cases and in % of mt. tissue donation is still the war horse for tc.this is due to a general lack of awareness of every aspect of this subject.there remains to carry out the lengthy task of social education in this area. methods. this is a descriptive study on the level of satisfaction of students who received these classes.it was carried out with th year students( y)and th( y).we used a post-course questionnaire, which included:level of interest,clarity and usefulness of explanation, students'environtment.it was agreed by the professionals working on this project not to use audiovisuals.the lesson was structured in six parts: introduction,donation rate, difference between organs and tissues,characteristics of the waiting list,conditions to become an organ donnor(brain death),discussion on transplant law and personal experiences.sometimes,kidney receptors participated and explained their experiences. we considered the experience useful and satisfying.both the institutions and the students supported the presentation in over % of cases.the teachers considered the course enjoyable and accessible.we feel that we need to evaluate the level of comprehension and therefore we have designed a new study with two questionnaires, one prior and one a week after the course so as to evaluate the changes in the students' sensivity and perceptions. organ transplantation activities are dependent on legislation, attitudes of the general public and health care professionals, and the organization of transplantation. reports from countries throughout the world have emphasized the importance of positive attitudes in health workers on organ donation and transplantation, yet there is a lack of studies on this subject. even in spain, the leading country in organ donation rates, there is also an existing shortage of these studies. however, donation rates have not kept pace with demand, resulting in a critical deficit of available healthy organs. it has been suggested that the attitudes of medical personnel regarding organ retrieval is a key success factor to improve organ donation. the aim of this study is to examine attitudes towards organ donation in health care workers. we analysed a long survey, which evaluates attitudes, knowledge, roles and experience towards organ, and tissue donation and transplantation. this survey was administered to all participants before and after the post graduate courses ( and ) in organ donation. we studied this changes in term of prognosis (glasgow outcome scale). we prospectly studied patients the first hours after sah. patients with chronic cardiac disease or brain death were excluded. clinical characteristics (glasgow scale, heart rate, systolic blood pressure), cardiac enzymes (troponin i, total serum creatine kinase and myocardial isoenzyme, myoglobin), ecg changes (st-t changes, prolonged qt and corrected qt intervals), echocardiographic assessment of cardiac function (left ventricular ejection fraction, hypokinesia) were studied on the day of the admission. data are shown in the table. only systolic blood pressure bpm were found to be independent factors of poor outcome. measurements of myocardial specific enzymes and echocardiographic assessment of cardiac function have no prognosis impact in this study. )the more the patient sleeps during the day, the more likely to have poor quality sleep at night. )sleep disruption in icu is related to the degree of illness-severity and length of stay in the unit. )actigraphy is a simple method of assessing sleep that is well tolerated by patients and doesn't interfere with nursing activities. it is well-known that the ischemia-reperfusion injury in patients resuscitated from cardiopulmonary arrest (cpa) severely damages the brain. some recent studies have been reported that neuron-specific enolase (nse) is an useful marker for outcome prediction. the aim of this study was to compare the prognosis of patients resuscitated from cpa with levels of s protein and nse in serum and cerebrospinal fluid (csf). twenty four patients resuscitated from cpa were eligible in this study. patients were divided into two groups according to the glasgow outcome scale (gos) at three months after the initiation of therapy. group g had the favorable neurological outcome and group p had the poor outcome, evaluated by gos. the blood and csf samples were taken within hours after resuscitation and the levels of s protein and nse were compared between the two groups. jugular bulb oxygen saturation levels were measured when hemodynamics were stabilized. mann-whitney's u test was used for continuous variables. correlations were tested using spearman's rank correlation test. a p-value less than . was considered statistically significant. six patients in group g had favorable neurological outcome and eighteen patients in group p had poor outcome. the levels of s protein in serum and csf (median, . and . ng/ml, respectively) in group p were significantly higher than those (median, . and . pg/ml, respectively) in group g. the levels of nse in serum and csf (median, . and . ng/ml, respectively) in group p were significantly higher than those (median, . and . ng/ml, respectively) in group g. jugular bulb oxygen saturation levels in group p were significantly higher than those in group g. the levels of s protein in serum correlated well with those of nse in serum (σ= . , p< . ). the outcome and jugular bulb oxygen saturation levels correlated with the levels of s protein in serum (σ= . , p< . , and σ= . , p< . , respectively). the levels of s protein in serum and csf correlated well with nse and their neurological outcome, so that s protein would be an excellent biological predictor in patients resuscitated from cpa. grant acknowledgement. this work was supported by the grant from the japan society for the promotion of science, japan. wright k , munasinge a critical care and emergency medicine, royal surrey county hospital, guildford, united kingdom injury to the cervical spine occurs in - % of blunt multisystem trauma. spinal immobilisation consists of a hard collar, headblocks and tape immobisation.this immobilisation is maintained until the cervical spine can be cleared of injury. often this relies on the patient being able to co-operate with a neurological examination. following head trauma some patients may never regain sufficient neurological ability to co-operate with an examination. others may remain obtunded for some time. until the spine is cleared the patient needs to be log-rolled and turned in accordance with spinal care bundles. complications such as pressure sores can ensue if this is not followed. evidence has also shown that removal of the cervical spine collar in head injured patients improves venous drainage from the head and so is beneficial in managing intracranial pressure .we therefore need an approach to clearing the spine in obtunded multisystem trauma patients. literature review study leading to institutional protocol. a safe clearence protocol is suggested. a protocol guided approach will allow the rapid removal of cervical spine precautions in multisystem injured patients. patients who have a spinal injury demonstrated are excluded from this approach and are managed in accordance with the spinal service guidance. hypothalamic-pituitary-adrenal (hpa) function has been recently studied in patients with traumatic brain injury (tbi), but few studies have shown its relationship with outcome. the aim of this study was to analyze hpa response and its relationship to intensive care unit (icu) survival in patients with isolated tbi. we studied consecutive patients ( male) with isolated tbi. norepinephrine (ne) was used to maintain cerebral pressure perfusion over mmhg when necessary. at - hours following tbi, we recorded values for plasma acth, baseline serum cortisol and stimulated cortisol at and minutes after performing high-dose corticotropin stimulation test (hdcst). mean and sd are reported. chi-square and logistic regression analysis were done. age was . ± . years. iss . ± . ; apache ii . ± . ; gcs score after resuscitation . ± . . plasma acth was . ± . ng/ml (normal values - ng/ml). baseline cortisol was . ± . ug/dl, stimulated cortisol at minutes . ± . ug/dl and at minutes . ± . ug/dl. all patients increased at least ug/dl after hdcst or had a stimulated value greater than ug/dl. overall survival was . % ( patients). univariate analysis of variables related to icu survival showed: age < years (p= . ),apache ii < (p= . ),acth < ng/ml (p= . ),baseline cortisol < ug/dl (p= . ),use of ne (p= . ),second-tier measures to control icp (p= . ), gcs > (p= . ). logistic regression analysis revealed that no need of second-tier measures to control icp (or . ci % . to . ) and plasma acth lower than ng/ml (or . ci % . to . ) were significant independent predictors of icu survival. conclusion. )adrenal gland function, assessed by hdcst, is not impaired at early stage of tbi. ) tbi patients with low levels of plasma acth had a high icu survival. paramythiotou e , katsarelis n , papakonstantinou k , stathopoulos g , varveri m , fousfoukis s , roussos a , karabinis a icu, george gennimatas general hospital, athens, greece aspiration of foreign bodies during trauma is a known com-plication. it usually concerns teeth, pieces of food etc and for their removal several procedures, invasive or not -like bronchoscopy or thoracotomy -must be underta-ken. we describe three patients with foreign body aspira-tion in our icu. a year -old male was admitted in our icu with face trauma, a broken mandible and a broken femoral bone. a foreign body was observed in the left lower bronchus on the chest x -ray. an attempt to retrieve it with the flexi-ble bronchoscope failed and the foreign body moved to the right lower bronchus. a rigid bronchoscope was then used with success and the foreign body was removed. it was a part of the broken mandible. the patient was discharged after two weeks. case . a year -old male was admit-ted after a road accident suffering from a severe cerebral injury, a pneumothorax and a broken lower mandible. a fo-reign body (piece of a broken tooth) was aspirated in the right upper bronchus. it was retrieved with a flexible bronchoscope. he remained in a "vegetative" situation for a long time and finally died because of a septic shock. case . a yearold patient was admitted with cerebral injury and a low glascow coma scale, a pneumothorax and acute respiratory failure. a foreign body was present in his right upper bronchus. the flexible bronchoscope and a basket were used in order to retrieve it. it was a large tooth. his neurological situation never ameliorated and the patient developed a septic shock and a multiorgan fai-lure and died. severe cerebral injury may result in foreign body aspira-tion especially when it is accompanied by facial trauma. for comatose patients, x -ray of the chest and thorax c/t scan are the main diagnostic tools for this situation. retrieval of the foreign bodies is necessary to avoid further complications such as atelectasis, pneumoniae etc. flexible bronchoscope used through the endotracheal tube is very effective in their removal. medical personnel dealing with trauma patients must have a high index of suspicion for the presence of foreign bodies in the tracheobronchial tree. flexible bronchoscopy or use of the rigid bronchoscope in case of failure, are very use-ful and safe techniques for the removal of these foreign bodies. mandila c , koukoulitsios g , stathopoulos g , paramythiotou e , theodoropoulos g , karabinis a icu, general hospital of athens ''g gennimatas'', athens, greece we report angiographic detection of vertebral artery dissection (vad) in two sedated patients in the intensive care unit (icu). in both cases vad was suspected solely by the presence of ischemic lesions evident on cervical spine and brain magnetic resonance imaging (mri). two patients were intubated, sedated, and admitted to the icu with glascow coma scores < after having suffered blunt head and neck injuries due to motor vehicle accidents. in the first patient computed tomography (ct) of the brain and cervical spine revealed traumatic subarachnoid haemorrhage, anterior atlas arc fracture, axis fracture, and a c body fracture. in addition, brain and cervical spine mri depicted a medullar contusion at the c level, an increased interarticular space c -c , and a left cerebellar hemisphere infarct. based on these findings carotid and vertebral angiography was performed, which showed complete left vertebral artery occlusion at the c level with incomplete distal filling due to a hypoplastic right vertebral artery. in the second patient brain ct was normal, while cervical spine ct revealed c -c dislocation with accompanying posterior sliding of c , and a subdural haematoma at the c -c level on the right. cervical mri showed dislocation with spinal cord dissection at the c -c level, and a large ischemic right occipital brain lobe lesion that was ascribed to putative right vertebral artery thrombosis/dissection. carotid and vertebral angiography revealed bilateral vad at the c -c level with distal reopacification by collateral perfusion. anticoagulant therapy was not administered due to coexisting contraindications (subarachnoid haemorrhage, hemorrhagic contusions, subdural hematoma). the level of consciousness increased step-wise in both patients. while the second patient suffered bilateral vad, his recovery was more complete than that of the first patient. in patients with brain and cervical trauma, the coexistence of cerebral lesions due to accompanying vad is probable. mri can prompt further investigation by depicting ischemia of vertebral artery-dependent areas. the impact of vad largely depends on the efficiency of collateral flow to the affected parenchyma. maintaining of normal cerebral oxygenation is the main goal of intensive care of patients with severe head injury. it can be achieved by different methods. one of them is hyperoxya. in this study we investigated the influence of different fractions of inspired oxygen (fio ) on cerebral oxygenation and intracranial pressure (icp). two patients with traumatic brain injury (tbi) with glasgow coma scale on admission enrolled in the study. patients had one-side lesions and underwent decompressive craniotomy. we compared fio with icp (n= ), cerebral oxymetry in non-lesioned hemisphere rso (nl) (n= ), oxygen partial pressure in cerebral tissue (ptio ) in lesioned (les) (n= ) and nonlesioned (nl) hemisphere (n= ), pao (n= ), jugular bulb saturation (sjo ) (n= ), o extraction ratio (o er) (n= ), arterio-venous o difference (avdo ) (n= ) and lactate concentration in jugular bulb (lac(v)) (n= ). plasma osmolality, cardiac output, invasive mean arterial blood pressure, paco and blood temperature were stable during investigation. fio changing from to , leaded to decrease in pao (m±sd) ( , ± , vs , ± , torr ((p< , )), sjo ( , ± % vs , ± , % (p< , )), rso (nl) ( , ± % vs ± , % (p< , )), ptio (les) ( , ± , vs , ± , torr (p< , )) and non-significant changes in ptio (nl) ( , ± , vs , ± , torr), lac(v) ( , ± , mmol/l vs , ± , mmol/l), icp ( , ± , vs , ± , torr), o er ( , ± , vs , ± , ) and avdo ( , ± , vol% vs , ± , vol%).we found good correlation between fio and pao (r= , (p< , )), sjo (r= , (p< , )), rso (nl) (r= , (p< , )), ptio (nl) (r= , (p< , )) and ptio (les) (r= , (p< , )).during comparing of different methods of cerebral oxygenation assessment we found good correlation between sjo and ptio (nl) (r= , (p< , )) and no correlation between sjo and ptio (les) (r= , (p= , )), rso (nl) and ptio (nl) (r= , (p= , )), rso (nl) and ptio (les) (r= , (p= , )). fio increasing is effective and quick method of cerebral oxygenation improving.icp is not influenced by fio changes.fio must be noticed during interpretation of high levels of sjo and rso . jugular oxymetry reflects the oxygenation mostly of the non-lesioned brain hemisphere. cerebral oxygenation monitoring can be improved by combination of sjo and ptio methods. nijboer j m m , van der horst i c c , hendriks h g d , ten duis h j , nijsten m w n surgery, cardiology, anesthesiology, university medical center groningen, groningen, netherlands there is a longstanding belief that in trauma patients hematocrit(ht) is more sensitive than hemoglobin(hb) in detecting blood loss. this association of ht with trauma is reflected by numerous references in medline. we studied the relation between hb and ht in trauma patients. trauma patients with an iss> from to were included. all blood samples taken during the first week in which hb and ht were both measured, were analysed. in patients (mean age ± yrs; % male) paired hb and ht values were available. the mean hb was . ± . mmol/l with a range from . to . mmol/l. the mean ht was . ± . , ranging from . to . . hb and ht had a pearson r of . (figure) . in a large series of trauma patients hb and ht behaved as identical parameters. the idea that ht is different from or superior to hb is a misconception and there is no reason for determining both hb and ht in trauma patients. paramythiotou e , papakonstantinou k , tsirantonaki m , kalogeromitros a , noulas n , pedonomos m , apostolakou h , karabinis a icu, george gennimatas general hospital, athens, greece introduction. propofol is often used as a sedative in icu patients. unfortunately large doses may be needed sometimes causing propofol infusion syndrome (pris). we are presenting a patient with this syndrome followed by manifestations compatible with a catastrophic antiphospholipid syndrome (caps). a year old female was admitted to our icu with a multiple trauma. she had many skull fractures, a subarachnoid hemorrhage and a small acute subdural hematoma. she was put to sedation with propofol. large propofol doses were used to keep her sedated ( - ml/h of propofol infusion %) along with noradrenaline and corticosteroids to maintain a normal arter. pressure. three days later she developed high fever, cpk rose to . µg/l and a multiple organ failure followed including renal and right heart failure. a cvvhd was immediately started. she was also put on broad spectrum antibiotics and the propofol infusion was interrupted. a week later her situation had become stable, she was free from vasoactive agents and her renal and cardiac functions were reestablished. the blood cultures taken did not prove the presence of bacteremia, though the simultaneous presence of an infection could not be excluded. thirty -two days after her admission she presented a status epilepticus. a brain c/t and mri were performed, revealing the presence of multiple hypodense areas not following a vessel distribution. an anticardiolipinantibody titer igg ( st u, nd > u ) gave us the hint for a probable caps. after a combined therapy with plasma exchange and immunoglobulins she recovered and survived later on. propofol infusion is very popular in icus hospitalizing patients with cerebral injuries permitting physicians to perform regularly a neurological examination. large propo-fol doses and concomitant use of corticosteroids and catecholamines with or without sepsis could precipitate pris as in our case. our patient's condition was complicated by the neurological manifestations attributed to probable catastrophic antiphospholipid syndrome. the question aroused is if pris could have triggered such an autoimmune disorder. conclusion. attention must be paid to propofol doses used for sedation of patients with craniocerebral injuries especially adolescents. alternative sedation or combination with other sedative and/or analgesics must be considered. tsarenko s v , petrikov s s , huseynova k t , krylov v v neurosurgical icu, neurosurgery, sklifosovsky scientific research institute of emergency medicine, moscow, russian federation invasive measurement of the intracranial pressure (icp) is known as the best method of intracranial hypertension evaluation. unfortunately it is associated with high equipment costs and risk of infection complications. we compared non-invasive methods of intracranial hypertension assessment with invasive icp measurement. methods. patients enrolled in the study (severe head injury (n= ), arterial aneurism rupture (n= ), hemorrhagic stroke (n= ), arterio-venous malformation (n= ). average age (m±sd) ± . m/f ratio was / . all patients were operated ( underwent decompressive craniotomy, boneplastic craniotomy and -insertion of icp sensor only). all patients received invasive icp monitoring (average time , ± days). we used codman intracranial pressure microsensors or ventricular icp monitoring systems (hanni-set, smith medical). average preoperative glasgo coma scale (gcs) was , ± , . all patients had head ct scan and neurological examination on admission, and dynamically in postoperative period. we compared icp values with ct scan data (volume of zones with high and low density, signs of lateral and axial dislocation), gcs and neurological signs of brain stem dislocation. analyses of all data showed correlation between icp and gcs (r= - , ; p< , ; n= ), neurological signs of brain stem dislocation (r= , ; p< , ; n= ), volume of zones with high and low density (r= , ; p= , ; n= ) and lateral dislocation on head ct scan (r= , ; p= , ; n= ). then icp values obtained before the mass lesion evacuation were compared with preoperative head ct scan and neurological signs of brain stem dislocation. we found good correlation between icp and signs of axial (r= , ; p< , ; n= ) and lateral dislocation (r= , ; p= , ; n= ) on head ct scan. we did not find correlation between icp values and gcs (r=- , ; p= , ; n= ), neurological signs of brain stem dislocation (r= , ; p= , ; n= ) and volume of zones with high and low density on ct scan (r= , ; p= , ; n= ). we found that invasive icp monitoring is the best method of intracranial hypertension assessment. neurological examination or ct scan data can not reflect all cases of icp changes but they can be used as screening methods of intracranial hypertension estimation. markogiannakis h , sanidas e , messaris e , tsiftsis d st department of propaedeutic surgery, hippocration hospital, athens medical school, university of athens, athens, department of surgical oncology, herakleion university hospital, herkleion medical school, university of crete, herakleion, greece nonoperative management (nom) is considered to be the treatment of choice for carefully selected blunt hepatic trauma patients. the objective of this study is to identify and evaluate the factors that can safely predict nom of these patients. our study is a retrospective analysis of trauma registry data of all consecutive adult blunt hepatic trauma patients admitted in a greek level i trauma center over a -year period. factors that were included in the analysis were: sex, age, mechanism of injury, initial vital signs, grade of liver injury, concomitant injuries, and injury scoring systems used for total injury severity estimation. nineteen patients ( %) were immediately operated, whereas ( %) were initially selected for nom. concomitant abdominal, pelvic and spinal cord trauma, high injury severity score (iss), low international classification of diseases - th revision injury severity score (iciss), and low probability of survival (ps) were predictive factors for operative management of these patients. immediately operated patients suffered statistically significantly more frequently concomitant abdominal ( . % vs . %, p= . ), pelvic ( . % vs . %, p= . ), and spinal cord injuries ( . % vs . %, p= . ) than conservatively treated patients. additionally, immediately operated patients with blunt liver injury were significantly more severely totally injured than those treated with nom as expressed by higher iss ( . ± . vs ± . , p= . ), lower iciss ( . ± . vs . ± . , p= . ), and lower ps ( . ± . vs . ± . , p= . ). moreover, the percentage of patients that were admitted in the icu and mortality rate were significantly lower in patients treated with nom than those treated with immediate operation ( . % vs . %, p= . and . % vs %, p= . , respectively). thirty-three patients that were initially selected for nom were successfully treated conservatively; thus, the rate of success of nom was %. conclusion. nom of blunt hepatic trauma patients is safe and efficient resulting in significant reduction of icu admission and mortality. concomitant abdominal, pelvic and spinal cord trauma, iss, iciss, and ps are predictive factors for operative or nonoperative management of these patients. ruler van o , lamme b , reitsma j b , gouma d j , boermeester m a surgery, epidemiology and biostatistics, academic medical center, amsterdam, netherlands the decision when to perform a relaparotomy for secondary peritonitis is largely subjective and experience-based. to date there is no reliable scoring system that aids the decisional process by predicting relaparotomy outcome. our aim was to identify variables predictive of a positive outcome of relaparotomy in the acute phase of the disease. the study population was derived from a retrospective cohort of secondary peritonitis patients(n= ). patients with a positive relaparotomy (n= ) were compared to patients undergoing a negative relaparotomy (n= ) and patients undergoing an index laparotomy only (n= ). a prediction model was build from a logistic regression model by the addition of patient, peritonitis, operative and postoperative variables. a stepwise build-up of predictive models incorporating the chronology in which information is achieved in clinical practice was used. variables entered were assessed on clinical judgment and statistical analysis. accounting for chronology of information, postoperative variables are most predictive for positive relaparotomy. this implicates that information on the clinical course after the index laparotomy is required to predict who will need a relaparotomy. further adjustment and external validation of this model and development of a prediction rule is needed in a prospective, cross-sectional series of patients with secondary peritonitis. schöniger-hekele a , klingbacher e , hiesmayr m department of cardiac thoracic vascular anaesthesia and intensive care, department of cardiothoracic anaesthesia and intensive care medicine, medical university of vienna, vienna, austria in general icu-patients nasal carriage of staphylococcus aureus was associated with a higher risk of developing staphylococcal infections and death. the aim of this study was to determine the impact of mssa-colonisation on postoperative infections and los in elective cardiac surgery patients. we prospectively collected all data for the analysis. the cohort consisted of patients, that underwent routine preoperative nasal swab one week before surgery. only patients with mrsa were treated topically with mupirocin. before surgery patients ( , %) were identified as staphylococcal aureus nasal carriers, while , % were free of nasal colonization. compared to the non-carriers the mssa-carriers did not have a significant difference of the total and staphylococcus aureus infection rate. other indicators of infection and inflammation parameters(crp, leukocytes)did not show significant differences. data-mining searched publications from common languages for randomised clinical trials that supplemented with impact® before and/or after major elective surgery. infectious complications, mortality, and hospital stay were primary outcomes. seventeen studies (n= ) were analyzed, and (n= ) described patients undergoing elective gi surgery. studies were conducted in countries, however, the clinical effects of impact® treatment were homogenous across the set of trials. impact® use significantly reduced postoperative infections overall (p < . ), and anastomotic leaks in gi surgical patients (p = . ). furthermore, impact® use shortened the average hospital stay by . d (p < . ), and a trend was observed towards reduced risk of mortality. considerable differences in country-specific operation modalities were noted. in a chinese trial, nosocomial infection prevalence was unusually low, % when supplemented with a control formula vs. % with impact®. in all other trials, nosocomial rates were - % with control feeds vs. - % with impact®. in germany and switzerland, hospital stays were extended for gi surgical patients. there, average stays were d for the impact® group and d for the control group vs. d and d, respectively, in all other countries. conclusion. impact® specialized nutrition support, as a component of infection control during surgery, is valuable for all methods practiced worldwide. to determine the incidence of nosocomial infection in critically ill patients with brain trauma. it is a prospective study performed during months of the patients with brain trauma admitted in a -beds medical-surgical icu of a -beds university hospital. infections were diagnosed according to cdc criteria. infections were classified bassed on the onset moment as early onset and late onset: early onset (eo) were those developed during the first days of icu-stay; and late onset (lo) were those developed days after icu-admission. the statistical analysis was performed using spss . program. continuous variables are reported as means and standard deviation, and categoric variables as percentages. turkmen a , turgut n , altan a , medetoglu a , gökkaya s department of anaesthesiology and reanimation, okmeydani training hospital, istanbul, turkey airway suctioning is classically performed with disconnection of the patient from the ventilator and the introduction of suction catheter into endotracheal tube. several authors suggest that application of closed suction catheters (csc)in intubated patients for more than h is safe and can reduce the costs associated with mechanical ventilation. therefore, we evaluated the possible role of prolonged application of csc in causing enhanced colonization of the lower respiratory tract. the prospective, randomized study included mechanically ventilated patients. the csc tips, tracheobronchial aspirates of each patient were examined for microbial growth. we analyzed the data with the student's t test for paired samples and fisher exact test. application for h significantly enhanced the microbial growth on the csc tips (table) . to decrease vap incidence in the icu is necessary to implement infection control policies. nevertheless that implementation is not always simple and requires effort by the icu workers. new infection control policies were applied in our icu in . those recommendations were adapted from the published guidelines concerning the prevention of vap and adapted to our icu. particular concern was made on the handwashing and contact isolation precautions. to analysed the impact of these measures the incidence of vap was analysed before and after that implementation. prospective study of all patients admitted in the icu for more than hours, between and . patients data collected included the number of ventilation days, the date of the vap diagnosis with or without microbiological confirmation. the vap diagnosis was made by new radiographic infiltrate for at least h and at least two of the following criteria: fever > . °c or < . °c; leukocytes > , /µl or < , /µl, purulent sputum, or isolation of pathogenic bacteria from lower respiratory tract. the microbiological samples were collected by proximal or distal bronchial aspirated. the vap diagnosis was made on the patients receiving mechanical ventilation, , and patients during the study period. theodorakopoulou m , lignos m , diamantakis a , zoupa p , stelliou a , karabekiou i , armaganidis a icu, nursing icu, attiko university hospital, athens, greece hand hygiene is the most important action to control spread of nosocomial infections.hand washing compliance among health care workers remains low.the objective of this study was to assess compliance of hygiene in our icu. a month prospective study on a bed icu of a university hospital.antiseptic solution were placed at the bottom side of each bed and one hand washing facility exists within the unit. well instructed observers recorded opportunities of hand washing, and actual performance of hand washing or hand disinfection. observation time was set at hrs. it was performed on morning and afternoon shifts all days of the week.every observer monitored beds.the staff was not informed of the study.staff was classified according to their work status (doctors, nurses etc.). . hrs of observations were recorded in sessions. a total of opportunities for hand hygiene were observed. see table for hand washing opportunities and actual hand washing compliance among the staff. the average hand washing opportunities were . opp/pt/hr and the average actual hand washing was . act.wash/pt/hr.hand washing compliance was similar for doctors,nurses and nursing assistants.medics, physiotherap, and visiting doctors showed significant difference in actual hand washing compliance.the overall compliance rate was / ( . %). it is a prospective study during months of the patients admitted in icu during hours o more. were taken throat swab, tracheal aspirate and urine on admission and twice weekly. were registered the colonization and infection by pseudomonas. the infections were diagnosed according to cdc criteria. the infections were classified bassed on thorat flora as: primary endogenous (pe) when they were caused by germs that were already colonizing the throat on the icu admission; secondary endogenous (se) when they were caused by germs that were not colonizing the throat on the icu admission but were acquired during the stay in icu; exogenous (ex) when they were caused by germs which were not colonizing the throat. the infections were classified bassed on the onset moment as: early onset (eo) were those developed during the first days of icu-stay; late onset (lo) were those developed days after icu-admission. conclusion. in our serie, the most of infections caused by pseudomonas were pneumonias, had a late onset and were secundary endogenous. prolonged critical illness is characterized by feeding-resistant wasting of lean body mass. this catabolic state is due to an impaired activity of the thyroid and gh axes, since restoration of physiological levels of igf- and thyroid hormones by continuous infusion of trh+ghrp- is capable to induce anabolism [ ] . whereas the cause of hyposomatropism during prolonged critical illness is mainly located within the hypothalamus, concomitant changes in peripheral thyroid hormone metabolism are involved in the low t syndrome. the aim of this study was to examine these peripheral changes into more detail in an animal model of prolonged critical [ ] . burn-injured, parenterally fed, new zealand white rabbits ( x n= ) were randomized to receive -d treatment with saline, trh ( \mug/kg/h) ,ghrp- ( \mug/kg/h), or trh+ghrp- . blood glucose was maintained below mg/dl by continuous insulin infusion. endocrine and biochemical organ system markers were studied. animals were sacrificed for assay of deiodinase activity in snap frozen samples. infusion of trh+ghrp- and trh increased hepatic activity of type deiodinase (d ) versus the saline group (p= . and . resp.), restoring tt levels within physiological range. only combined infusion of trh+ghrp- induced a significant increase in igf- levels into the range observed in healthy rabbits. administration of trh alone resulted in a further decline of serum igf- levels. ( ) infusion of ghrp- +trh is able to restore peripheral thyroid hormone and serum igf- levels within the physiological range, mainly due to re-activation of d . ( ) d activity during critical illness is regulated via alterations in the thyroid axis. ( ) reactivation of the thyroid axis in prolonged critical illness, without concomitant reactivation of the gh-axis, might worsen catabolism. and strong ion difference (sid) approach, to our knowledge is still not available a systematic comparison. the approach to sid may be more or less rigorous: we can calculate the apparent sid (the difference between strong ions, sidapp) or the effective sid (the sum of weak anions, sideff); moreover, when computing the sid variation (Äsid) the reference value of sid can be considered fixed ( meq/l) or variable (the expected sid) as a function of total non volatile weak acids concentration. the aim of this study was to suggest how the computation of Äsid should be sophisticated in order to obtain a good correspondence with be in icu patients. conclusion. the rigorous computation of the corrected Äsid seems to be necessary in the icu population, because of non-neglectable concentration of unmeasured anions and of diffuse and serious hypoalbuminemia in these patients. moreover, Äsid is a measure of plasma buffer base variation, so it should be compared with an equivalent be formulation, that is plasma be. leditschke i a , southcott e , gissane j , enslin a , hickman p e , potter j m intensive care unit, act pathology, australian national university medical school, the canberra hospital, canberra, australia recently it has been shown that total plasma cortisol measured by immunoassay may not detect elevations in plasma free cortisol in hypoproteinaemic critically ill patients( ). we investigated the relationship between urinary free cortisol and total serum cortisol in a group of critically ill patients. methods. patients were studied within hours of icu admission. patients with neurotrauma or oliguria were excluded. hourly total plasma cortisol and -hourly urinary cortisol were measured for hours using routine immunoassay for the plasma samples and high performance liquid chromatography for the urine samples. statistical analysis was performed using graphpad instat software. summary results for total plasma cortisol at the mid point of the urine collection and urinary free cortisol are shown in table . using a non parametric (spearman r) test of correlation, urinary free cortisol was found to correlate moderately well with total plasma cortisol; spearman r = . , % confidence intervals . to . , p to further investigate this topic, we conducted a prospective study of patients admitted to a general adult icu. morning blood samples were taken within hours of icu admission to measure plasma cortisol, corticotropin (acth), dehydroepiandrosterone sulphate (dheas), free thyroxine (ft ), tri-iodothyronine (t ), thyroid-stimulating hormone (tsh) and prolactin (prl). . critically ill patients ( males) with diverse underlying diagnoses, having a median age of years (range - years) were enrolled. their median apache ii and sofa scores were and respectively. there were no differences between survivors and non-survivors in plasma cortisol, acth, ft , and t . in contrast, survivors had higher median values for tsh ( . mciu/l vs. . mciu/l, p= . ), dheas ( ng/dl vs. ng/dl, p= . ) and prl ( ng/ml vs. ng/ml, p= . ) compared to non-survivors. our data indicate that hormone concentrations differ between survivors and nonsurvivors acutely ill patients. further studies are required to investigate whether endocrine measurements are helpful in predicting clinical outcome. mekontso-dessap a , lellouche n , brochard l , brun-buisson c , dubois-randé j medical intensive care unit, coronary care unit, henri mondor hospital, créteil, france relative adrenal insufficiency has been demonstrated to be associated with increased mortality in septic shock patients. cardiogenic shock (cs) induces a stress response involving the adrenal cortex, but functional hypoadrenalism has never been investigated in this setting. the aim of the present study was to prospectively evaluate adrenal function in patients admitted to intensive and coronary care unit for cardiogenic shock. methods. consecutive patients ( men) admitted for cs, with a mean age of ± years were included. patients submitted to any steroid therapy or etomidate were excluded. patients needed mechanical ventilation and patients were equipped with an intraaortic balloon pump. causes of cs included acute myocardial infarction (n= ), cardiomyopathy (n= ), arrrythmia (n= ), and others (n= ). patients underwent a high dose short corticotrophin test (sct) and relative adrenocortical insufficiency (nonresponders) was defined by a rise in cortisol less than microg/l after stimulation. . ( . %) patients were classified as nonresponders and ( . %) as responders. no significant difference was evidenced between responders and nonresponders concerning clinical characteristics and outcome (table ) . in contrast to international guidelines, it is common practice in some icu's in the netherlands to treat septic critically ill patients with high dose dexamethason on admission. increase in mortality might be associated with the induction of adrenal failure. we compared adrenal function in patients with high, single dose ( mg) dexamethason (dexa) with patients receiving no steroids during the study period. we studied ventilated patients with mods admitted for emergency reasons. excluded were patients after elective surgery, with an expected short stay or steroid use. cortisol (co) was measured day and at . am. at day the co response and minutes after mcgr synthetic acth was determined. the patients did not receive corticosteroids, other than dexa on admission if they were included in the dexa+ group. all / patients ( %) with dexa had baseline co levels on day below . mmol/l, compared to / ( %) in the control group (ns). however, adequate co response (rise in co of more than . mmol/l, min after mcg synthetic acth iv) was % in patients with dexa and % ( / ) for patients without dexa. in a case control analysis apache score was not a determinant. neutrophils are believed to occupy a prominent position in the pathogenesis of organ failure that arises from the systemic inflammatory response syndrome (sirs). the epidermal growth factor-like -transmembrane (egf-tm ) family of molecules are a group of glycoproteins whose structure suggests a dual role in cell adhesion and intracellular signaling. two members of this family, hcd and the egf molecule-containing mucin-like hormone receptor (emr ) are expressed on human monocytes and macrophages. the aim of this study was to examine the expression of hcd and emr on neutrophils from patients with sirs and ascertain if they were associated with sepsis or the clinical course of disease. we analysed erythropoietin, interleukin- (il- ), interleukin- (il- ), and interleukin- p (il- p ) in the blood of patients (controls n= ) with circulating nrbcs. in-hospital mortality of nrbc-negative and nrbc-positive patients was . % ( / ) and . % ( / ; p< . ), respectively. in-hospital mortality increased with the nrbc concentration ( figure ). . % ( / ) of patients with more than nrbcs/µl in the peripheral blood died. multiple logistic regression revealed a significant association between the appearance of nrbcs in the blood and age (odds ratio . ; . - . ; p< . ), erythropoietin (odds ratio . ; . - . ; p< . ), il- (odds ratio . ; . - . ; p< . ), and il- (odds ratio . ; . - . ; p< . ), respectively. gender and il- p were not significantly associated with the appearance of nrbcs in the blood to estimate the red blood cell production in the bone marrow the increase in the reticulocyte concentration in blood was measured. the reticulocyte concentration in nrbc-positive patients was ± /nl, being significantly higher than in nrbc-negative patients ( ± /nl; p< . ). furthermore, in the course of hospitalization the increase in the reticulocyte concentration in nrbc-positive patients was significantly higher ( ± /nl; n= ) than in nrbc-negative patients ( ± /nl; n= ; p< . ). conclusion. an association of the appearance of nrbcs were found with increased levels of erythropoietin, il- , and il- , respectively. therefore, nrbcs in the circulation could be an indicator which summarises hypoxic and inflammatory injuries. thus, generally the appearance of nrbcs in blood is a valid parameter to identify patients at high mortal risk. moreover, the increased number of reticulocytes in the blood of nrbc-positive patients may indicate that the appearance of nrbcs is not associated with disturbed bone marrow function as far as the erythropoiesis is concerned. grant acknowledgement. sysmex europe corp. macrophage migration inhibitory factor (mif) was originally described as a tlymphocyte derived cytokine that inhibits the migration of the macrophages at the site of inflammation( ).subsequently it was also identified as a stress induced hormone released from the anterior lobe of the pituitary in response to some pro-inflammatory stimuli ( ) .the glucocorticoid counterbalancing proinflammatory actions of mif have been thoroughly documented. our study compared postoperative changes in serum mif levels of patients undergoing bowel and liver resections. patients were recruited in our descriptive study.patients in the first group (a) underwent only hepatic resection without surgically opening the bowel. the other group (b) comprised of patients who have had bowel resection with surgical bowel opening. mif, il- β, il- , prealbumin, albumin, α fibrinogen and c-reactive protein levels were measured before and immediately after the operations and also for three consecutive days. to evaluate organ functions the mods-test was used. statistical analysis was carried out by means of spss for windows, applying the mann-whitney test. a higher level of mif ( pg/ml / - /) was found in group a as compared to that of group b immediately after the operations, that proved to be significant. other parameters monitored in this study were not statistically different between the two sets of patients. higher elevations in mif levels with liver resections compared to bowel resections might be attributable to mif release from damaged liver cells. the presumably minimal endotoxin exposure during the bowel surgery was either insufficient or inefficient to induce relevant mif elevations in our patients. chromogranins are prohormones, precursors of numerous peptides displaying various biological activities. some even have antifungal and antibacterial properties. as catecholamines, they result from secretory granules of the chromaffin cells in adrenal medulla. aims of the study: to analyze the physiological secretion of cgb and its derivatives in healthy subjects; and to compare its characteristics with those of patients undergoing the stress of septic shock. methods. healthy voluntaries and patients with septic shock were included. samples of serums were taken at several times to establish a kinetic of secretion. serum proteins were studied by mono and two-dimensional electrophoresis with anti-cgb specific immunodetection, using polyclonal antibodies; and by chromatography (rp-hplc) with specific immuno-detection of each eluted sample, and then by mass spectrometry (maldi tof) and antimicrobial tests. the healthy subjects' electrophoretic profiles are identical. we did not find fragments of molecular weights (mw) lower than kda. but patients' profiles show a great number of short fragments. there were no qualitative modifications of monodimensional electrophoresis profile over time in healthy subjects, whereas for patients, we observed the disappearance of a kda band and of short fragments of weak mw. this modification occurs hours after the end of the infusion of norepinephrine. rp-hplc chromatograms show strong similarities between controls and patients. however the peaks of albumin (hsa) and transferrin are higher in healthy controls. for the whole population, we observe at the end of the chromatogram, immonreactive peaks: the peak of hsa (immunoreactive zone which corresponds to an association of cgb and hsa); and an isolated peak after hsa peak. conclusion. this is the first study of cgb secretion in human serum. we show noticeable differences between healthy controls and patients with septic shock. the clinical improvement of a patient corresponds to the modifications of the electrophoretic profile (backwards to the profile of a healthy control). for the first time, an association is also shown between the hsa and the cgb. in septic shock, the free cgb seems to be more abundant. patients with septic shock or non infectious sirs within hours of admission were included and allocated to the following groups according to usual criteria : group (surgical patients with septic shock), group (surgical patients with sirs), group (medical patients with septic shock) and group (medical patients with sirs). pct at study entry was compared between groups and and between groups and to determine the diagnostic cutoff value for septic shock in surgical and in medical patients respectively. identifying sepsis in intensive care unit (icu) can be difficult. we assessed the utility of the biphasic aptt waveform (bpw) and procalcitonin (pct) determinations, alone or combined, for the diagnosis of sepsis in icu patients. this prospective observational study included adult patients admitted to a -bed university hospital medical-surgical icu during a -month period. the presence of sepsis, severe sepsis or septic shock was determined on the day of admission by standard clinical and laboratory criteria, without knowledge of aptt or pct. aptt transmittance waveforms (biomérieux mda system) and pct levels (brahms pct lumitest) were determined on the day of admission. threshold values for the prediction of any form of sepsis were assessed by receiver operating characteristic (roc) curves. the bpw was detected when the slope of the pre-coagulation phase (slope_ ) exceeded the threshold value (i.e., became more negative). the combined assessment of aptt transmittance waveforms and pct levels provides a rapid means of identifying septic patients on icu admission. van nuffelen m , abraham a , zakariah a , vincent j l intensive care medecine, erasme university hospital, brussels, belgium both c-reactive protein (crp) and procalcitonin (pct) concentrations have been proposed to monitor sepsis in acutely ill patients. the aim of this study was to study their time course in septic icu patients. the study included infectious episodes (mean age: years, ratio m/f: / ), as defined by standard cdc criteria. patients were divided into two groups, depending on their evolution: favorable (clinical and white blood cell count) or unfavorable (need for additional procedure and/or change in antibiotic regimen). crp was measured daily by direct immunoturbimetry and pct by immuno luminometric assay. and pct were as follows(median values): where day represents the day where antibiotics were started. conclusion. crp and pct kinetics in septic patients show no significant trend in patients who respond favorably to therapy. however, an increase in these variables indicates a poor response. percutaneous tracheotomy (pt) is frequent in the icu to help wean patients from mv. we compared the effectiveness and airway management of laryngeal mask-airway (lma) vs endotracheal intubation (ei) we included consecutive intubated adult patients in the icu who required pt, randomized into two groups of . one group had a proseal lma and the other underwent laryngoscope-assisted partial withdrawal of the endotracheal tube. ventilator settings in both groups were: volume-control ventilation, fio , minute volume . l, peep . arterial blood gas pressure was measured before the start of each pt and before insertion of the tracheotomy tube. data were recorded concerning the duration of the procedure from commencing airway manipulation to insertion of tracheotomy tube and airway complications results. % of patients were men (median age years). reasons for tracheotomy were a low level of consciousness( %), lung disease ( %), neuromuscular disease ( %) and airway obstruction ( %). no significant changes were seen in duration, ph, p or pc . complications included six accidental extubation, four tube cuff tears, four guidewire bends and four difficulty to insert the tracheotomy tube. three patients planned for lma required ei because of impossibility to place correctly the pro-seal laryngeal mask-airway. no other complications arose in this group the differential diagnosis between sepsis and sirs is of considerable importance in burn patients. delay in the initial adequate treatment increases the mortality rate. the aim of this study was to assess whether plasma procalcitonin (pct) level was related to sepsis, burn size and organ failure in severely burned patients over the entire clinical course. methods. forty one patients, mean age ± (sd), (range - year), mean burn size . ± (sd) % of body surface area (bsa), (range % - % bsa) were included in our study. all patients were classified daily in one of the following three categories: negative, sirs, sepsis according to the definitions of the accp/sccm. a total of patient days were evaluated: negative (n: ), sirs (n: ), sepsis (n: ). measurement of pct levels and evaluation of organ function by sofa score were performed daily until discharge from icu. admission pct levels were significantly higher in patients with burn size > % of bsa than in those with burn of less than % of bsa ( . ng/ml vs . ng/ml, p= . ). pct plasma concentrations differed among the three diagnostic classes and were higher in sepsis than in sirs ( table ) . a statistically significant correlation was observed between pct levels and sofa score (r= . , p< . (pearson' bivariate correlation)). the optimal timing of tracheotomy in critically ill patients requiring prolonged mechanical ventilation (mv) is debated. recent studies suggest that early tracheotomy could substantially reduce both infectious morbidity and mortality. in a prospective, randomized, study we compared early tracheotomy with prolonged endotracheal intubation in icu patients needing prolonged ventilatory support. patients projected to need ventilatory support for > days were prospectively randomized to either early (open or percutaneous) tracheotomy within days (et) or prolonged intubation (pi) with or without delayed tracheostomy. the primary end-points were: days mortality and cumulated incidence of nosocomial pneumonia, and number of ventilatory free days between day and . time in the icu and on mv, days mortality, number of septic episodes, accidental extubation and amount of sedation were recorded as secondary end-points. a sample size of patients was determined for a reduction of the days mortality from % to %¨(two-sided, power= . ). the study was prematurely closed because of poor accrual, after patients (et= , pi= )have been included. no difference was found between the groups for any of the primary (table ) or secondary end-points. in addition, laryngeal or tracheal damage and time for resuming oral nutrition did not differ between the groups. early pdt has several advantages when long-term mechanical ventilation is adamant. however, in patients suffering from tbi, one major concern are increased intracranial pressures (icp´s). during pdt, decrease of venous return and hypercapnia might seriously comprise icp. therefore, changes in icp´s during videobronchoscopic guided pdt were measured. methods. patient with tbi,treated at our neurosurgical intensive care unit, required long-term (> days) mechanical ventilation due to intracranial lesions. indication and feasibility to perform pdt were evaluated in patients treated with severe tbi from the day after admission on a daily routine. icp levels below mmhg (over at least hours) without extended icp treatment and no icp increase > mmhg during neck extension was considered to be a safe timepoint for pdt. videobronchoscopic guided, single-step pdt with modified ciaglia technique (blue rhino, cook, germany) was performed in patients, in two patients pdt had do be aborted for anatomic reasons. as operation time we defined begin of videobronchoscopy until the intra-tracheal position of the tracheostoma was confirmed. icp´s were recorded either through intraparenchymal catheters (n= ) or by external ventricular catheters (n= ). methods. an anonymous questionnaire was distributed among croatian anaesthesiologists at three universities (zagreb, split, rieka) and during two anaesthesia meetings (split, dubrovnik) between sept. and may . . completed forms were returned which was % of the anaesthesiologists in croatia. male and female respondents were % and %, respectively, with a mean age of . years. they had been practicing anesthesia from to years with % practicing in an academic center, and % in a community hospital. % completed a difficult airway course, receiving training at their hospital or at a meeting such as the european society of anaesthesiology. per respondent per year, an average of anesthetics were performed, with patients having endotracheal intubation. the most frequently preferred laryngoscope blade was macintosh ( %) followed by miller ( %) and mccoy ( %). % indicated they rarely failed an intubation using a conventional laryngoscope. in difficult airway situations, following laryngoscopy, the technique of choice was the laryngeal mask airway followed by the gum elastic bougie. for anticipated difficult intubations, % performed sedated awake intubation, and % used the flexible bronchoscope. while the asa difficult airway algorithm was used by % of respondents, % stated that they used an internally developed difficult airway protocol. croatia. laryngoscopy and sedated awake intubation are used more frequently than fiberoptic bronchoscopy. the asa difficult airway algorithm was used by % of the anaesthesiologists surveyed. in a randomized crossover trial, special forces (sf)-medics of the royal netherlands army and residents in anesthesiology performed cricothyrotomies using two different emergency airway devices on larynges from freshly slaughtered pigs ( ) . we compared the quicktrach with the portex emergency cricothyroidotomy kit. all data were analyzed using spps version . (wilcoxon test for non-normal distributed -paired comparison and mcnemar test for nominal values). the quicktrach-technique was done significant faster than the portex-technique in both groups. intratracheal placement of the cannula was achieved by ( %) sf-medics and ( %) residents using the portex-technique and using the quicktrach-technique by ( %) sf-medics and ( %) residents. despite the fact that it was a procedure performed in very critically ill patients, tracheostomy was associated with very few minor complications in this sample. we hipothetized that this low rate of complications is due in part to the very high expertise of the operators involved in the realization of conventional tracheostomies in the two centers. grant acknowledgement. the authors are indebted with dr. ederlon a. c. rezende for his support and suggestions. kiessling a h , isgro f , skuras j , lehmann a , pieper s , saggau w klinikum ludwigshafen, cardiac surgery, klinikum ludwigshafen, anaesthesiology, ludwigshafen, germany tracheotomies are routinely performed for severely ill patients with respiratory failure. the procedure facilitates the weaning procedures by reducing dead space and decreasing airway resistance, by improving secretion clearance and by decreasing the risk of aspiration. this intervention is correlated with a poor survival rate. the aim of the investigation was the evaluation of the quality of life scores (qof) and outcome after cardiac surgical procedures. the retrospective, non-randomized follow up study was performed in a single surgical intensive care unit in patients after cardiac procedures and surgical tracheotomy. preoperative data and items were collected and outcomes analyzed after a mean follow up period of . years. a written questionnaire for the documentation of the sf score and beck depression scale were used. in addition to the test battery, healing outcome and vocal function were components of the questioning. overinflation of the endotracheal tube cuff (> mmhg) may cause tracheal damage and complications such as tracheal stenosis and tracheo-oesophageal fistula. we have surveyed the practice of tracheal cuff pressure measurement in our medical-surgical intensive care unit (icu) and evaluate the impact of a regular cuff pressure monitoring program (cpmp) on reducing cuff overinflation. cuff pressure have been evaluated over three periods (p = before cpmp, p = months after cpmp and p = years after cpmp) obtained in measurements in - patients each period. the cpmp consists of regular cuff pressure monitoring twice a day. comparing to the first period, mean cuff-pressure decreased in the second period from ± mmhg to ± mmhg (p< . ) and the rate of overinflated cuffs from % to % (p< . ). in the third period, mean pressure was in the normal range ( ± mmhg) but there was a significant increase in underinflated cuffs. however, in these patients, the operator hasn't noticed any leakage around the tube cuffs. a regular cuff pressure monitoring program can reduce significantly the overinflation of tracheal cuffs in icu and this may lead to prevent subsequent complications. icu medical stuff may also maintain this protocol by a regular education of the nurse team in order to always keep endotracheal tube cuff pressures in the normal range preventing over (tracheal damage) and underinflation side effects (nosocomial pneumonia). further studies are needed to evaluate this educational procedure on the outcome of the icu patients. forty-three patients ( men, women) with a mean age of . and a mean simplified acute physiologic score (saps) ii of . were studied. three patients were excluded because of insufficient data. ts was done because of traumatic brain injury with persistent glasgow coma score < (nineteen patients), unsuccessful weaning -failure of spontaneous breathing trial in or more occasions ( patients), hypoxic encephalopathy ( patients) and prolonged invasive ventilation ( patients). in the subgroup of patients with unsuccessful weaning, spontaneous breathing could be achieved in seven patients by day to day (mean of . days) after ts. in patients, ts has been considered an adjunctive intervention for the weaning process, and in these patients, spontaneous breathing was achieved in patients and bipap ventilation in patients. thirty nine patients could be discharged from icu (mean of . days after ts) in spontaneous breathing ( patients) or bipap ventilation ( patients). mortality analysis revealed a total of deaths (four in the icu, during hospital stay and after hospital discharge at six months). in patients with hypoxic encephalopathy ( ), five deaths were observed during hospital stay. complication rate was low, with local haemorrhage in seven patients. our study revealed that ts was useful as an adjunctive therapy in the weaning process in the majority of patients and could reduce icu stay; however, the subgroup of patients with hypoxic encephalopathy did not benefit from ts and should be considered for alternative strategies of airway protection. zgoda we report a prospective case series of successful percutaneous tracheostomy procedures in the critically ill without complication. the balloon-tracheostomy tube apparatus (image ) was placed overwire then inflated to form the stoma, then deflated. the tracheostomy tube followed the deflated balloon into the airway. almost no anterior tracheal compression took place. the average procedure time from puncture to tube placement was - minutes. ten icu patients underwent bfpt. six of the patients had a successful tube placement after only balloon dilation. the rest had successful tracheostomy placement after a second dilation. one of these patients had a previous tracheostomy and the procedure was successful with balloon dilation attempts at the site of the previous tracheostomy. two were coagulopathic with inr> and/or platelet count(s) of less than k. the average estimated blood loss was less than ml. one patient had an obvious tracheal ring fracture without immediate clinical significance. there was no posterior tracheal wall damage, no pneumothorax, and no obvious damage to the anterior neck. thus far, there have been consecutive tracheostomy tubes placed without bleeding complications, or damage to the posterior tracheal wall but more study is needed. bfpt is an easy and effective means of placing an elective tracheostomy tube at the bedside in the icu. despite surgical percutaneous emphysema is a recognised complication following percutaneous tracheostomy [ ] ,it is not usually reported with a fenestrated trachesotomy tube as the direct cause [ ] .the rationale to use a fenestrated tube when performing percutaneous tracheostomy is to eliminate the need to change the tube when the patient is weaned from mechanical ventilation. report of a cluster of complications associated with fenestrated tracheostomy tubes placed percutaneously. in our trust ( hospitals) within a week period patients developed subcutaneous emphysema (one with an associated pneumothorax). the cases were performed by experienced doctors. all using portex blue rhino kits, with the insertion of tracoe-twist fenestrated tracheostomy tubes (using the non-fenestrated inner cannula); bronchoscopic guidance was used in all of the cases.we also have performed a bench top study on the fenestrated tubes to find the source of leak. eight patients developed subcutaneous emphysema (one with an associated pneumothorax).the emphysema was immediate in some, but only becoming apparent several hours after insertion in the majority.in at least two,the emphysema was so extensive that it compromised the patients' airway making exchanging the tracheostomy impossible and oral endotracheal intubation very difficult. fortunately there were no directly attributable deaths or hypoxic injuries. the bench top study revealed air can track between the inner and outer cannulae at quite low pressures. surgical percutaneous emphysema is a complication following percutaneous tracheostomy using fenesterated tubes which can lead to pneumothorax and airway compromise.it seems that the fenestrations can remain in the pre-tracheal fascia with air tracking between the inner and outer cannula leading to the development of subcutaneous emphysema.we have now changed our practice to insert only non-fenestrated tubes for percutaneous tracheostomies. therapeutic hypothermia (th) improves outcome after cardiac arrest (ca) due to ventricular fibrillation (vf). however, due to lack of protocols and to technical difficulties inherent to its practical application, this treatment has not been widely implemented in daily practice. we evaluated whether th could be effectively introduced in icu practice and assessed its impact on patient outcome. we retrospectively analyzed comatose patients resuscitated from out-of-hospital ca due to vf and non-vf rhythms (asystole or pulseless electrical activity in patients with circulatory shock before initiating the treatment, th was also beneficial ( / patients had good outcome vs / patients treated with sr, p= . ). in contrast, th had no impact on the outcome of survivors of ca due non-vf rhythms ( / patients in the th group survived with good neurological outcome vs / in the sr group). conclusion. therapeutic hypothermia can be safely and effeciently introduced in icu practice for the treatment of all comatose patients resuscitated from cardiac arrest with a major impact on the outcome of patients resuscitated from ca due to vf, independently from their hemodynamic status. in contrast, our data do not support the use of therapeutic hypothermia after cardiac arrest due to asystole or pulseless electrical activity. lavery g g , hickland b , caddell p , dillon m , northern, ireland intensive care society audit group regional intensive care unit, royal hospitals trust, belfast, united kingdom since october , a centralized service has facilitated the interhospital transfer (iht) of over critically-ill adult patients using a standard ambulance and mobile icu equipment. quality of escort is an important factor in the transport of all potentially unstable patients ( , ) and so all ihts are performed by an experienced icu team ( doctor and nurse) . the aim of this project was to assess the use and the quality of this service. information regarding the indications for, and conduct of, iht was recorded prospectively for all patients transferred by the service over yr ( / - / ). icus prospectively collected data including admission apache ii score and icu (and hospital) outcomes. all data were entered on a central database (ms access). molnar t , köszegi t , bogar l , szakmany t anesthesiology and intensive therapy, institute of laboratory medicine, university of pecs, pecs, hungary it has been proposed, that procalcitonin (pct) might be used as a prognostic factor for outcome after cardiac arrest ( ) . to date no studies addressed the question whether pct levels are different after vf and pea induced in-hospital cardiac arrest. methods. consecutive patients were studied following cardiac arrest. pct levels were measured on icu admission (t ), then on the first (t ) and third day (t ) post-arrest. for statistical analysis mann-whitney u test and chi-square test were used with spss . . data are presented as median and interquartile range. out of the patients suffered pea and vf arrest. there was no significant difference between the groups regarding age, male/female ratio and anoxic time and time to rosc. mortality was % vs. . % in the pea and vf groups, respectively, p< . . serum pct levels were significantly higher in the pea group (table ) . s b levels did not differ significantly between the two groups. serum pct: . ( . - . ) vs. . ( . - . ) and s b: . ( . - . ) vs. . ( . - . ) were significantly higher at t among non-survivors in the pea group, p< . respectively, whereas in the vf group no such difference was observed. conclusion. significantly lower inflammatory response was detected in patients initially in vf arrest, with significantly better survival compared to pea arrest, although anoxic time and time to rosc was similar in the two groups as reflected by nearly identical s b levels. however, patients with pea arrest often have long, undetected hypoxic period, which may trigger the release of inflammatory markers such as pct. the significantly higher pct and s b values in the nonsurvivor group of pea patients may indicate the potential prognostic value of such measurements. horn j , zandbergen e j g , vos p e , verlooy p , van dijk g w , vroom m b , hijdra a ic, amc, amsterdam, neurology, rijnstate, arnhem, neurology, umc, nijmegen, neurology, olvg, amsterdam, neurology, umcu, utrecht, neurology, amc, amsterdam, netherlands after cardiopulmonary resuscitation (cpr) many patients develop post-anoxic encephalopathy (pae) often accompanied by myoclonic seizures or epilepsy.( , )treatment is often difficult, several strategies have been advocated. ( , ) in this study we investigated the medication used in these patients. from the database of the propac study, a prospective cohort study in pae patients, we selected patients with myoclonic or epileptic seizures. medication used to treat these conditions was extracted from the records. in patients, showed myoclonic seizures or epilepsy. records of patients could be retrieved. differentiation between myoclonus and epilepsy was difficult, we used the description as found in the records. eleven patients received no medication. treatment was started in patients ( %): in ( %)a benzodiazepine, in ( %) another antiepileptic drug, in a combination of both. clonazepam was used most often ( patients, %). valprioc acid was used in patients ( %), phenytoin in . seventeen patients (out of ) received propofol and in patients a second benzodiazepine was administered. outcome after month: had died ( %), were in coma, vegetative state or severely handicapped ( %) and were moderately handicapped or completely recovered. conclusion. dutch neurologists prefer benzodiazepines in patients with seizures in post-anoxic encephalopathy, often combined with an antiepileptic drug. myoclonic status reacts poorly to medication, however, treatment is often started because of problems in daily care or mechanical ventilation. in this study we found that the different types of seizures were often not specified in the records, despite the consequences on prognosis. we suggest to use the definition proposed by wijdicks et al for myoclonus status. in this study epileptic or myoclonic seizures in patients with post-anoxic encephalopathy seemed to be related to poor outcome, as % had a poor outcome. we conducted an etiologic study among parturients presenting a cerebrovascular stroke. the aim was to determine the frequency of the various types of vascular accident and their moment of arisen,to underline the factors of risk and to estimate the prognosis of vascular accidents in this population(p-values < , were considered to be statiscally signifiant). among our patients, had an ischemic accident, of which had venous origin, an arterial origin and had an hemorragic accident .the majority of damage occurs in the rd quarter of pregancy or in the post-partum. five of our patients had no risk factor and had several risk factors.as for the arterial accident , the etiologic inquiry was not decisive for four patients.they had however several risk factors of thrombosis vascular. five patient with an ischemia died and three of the patients having a bleeding died. uni-varieted logistic regression did not find statiscally-significant result concerning mortality in relation with the age,the term gestationnel or the type of accident . conclusion. cerebrovascular strokes complicating the evolution of a pregnancy remain an unknown entity. they can cause sequela and have fatal issues.studies including a larger number of patients are requested in order to decrease the incidence and the important morbi-mortality. they are also meant to find out all risk factors,take them in to consideration and therefore work on their mechanism. bubnova i d , dobrinin i n , astakhov a a anaesthesiology and reanimatology, ural postgraduate medical academy, chelyabinsk, russian federation one of the ways for the cerebral perfusion support in severe brain trauma (sbt) patients is the cardiac output optimization. but we must know whether the decreasing of hypovolemia range be better for brain protection or not in each case. this study we tried to reveal if the the topic level of central haemodynamic regulation disturbances (chrd) can determine the response on the volume load (vl). in the previous works we showed that the patients with sbt may have different types of the haemodynamic regulation due to interfere of the humoral and the autonomic nervous stimulus. this study we examined patients with main regulatory types. all patients were under artificial ventilation and had and less gcs. for the estimation of the type and topic level of chrd we compared the absolute data and the variability (spectral power (sp) in - . hz band) of blood pressure (bp), heart rate (hr), peripheral vessels pulse (pvp), and stroke volume (sv), determined by the bioimpedans method. also we determined the variability of eeg amplitude in the alone biparietal channel. all comparisons were made before and after infusion of , ml of % stabisol. especial attention were paid to the p ( . - . hz) and p ( . - . hz) bands of sv, which reflect the hormonal, more often adh activity (p ) and predominantly connect with patients breathing (p ). last findings showed it may be used as a marker of hypovolemia. the patients with the worst type of regulation (a result of brain stem dysfunction) responded on the vl by the sv increasing in , % cases. but they showed a decreasing sp of p only in , %, and sp of p increased in , %. in cases of hypothalamic dysfunction (type ) the sv grew in % patients, sp of p decreased in , % and p increased in %. the patients with the best adaptive type of regulation (type ) responded on the volume load only in , %, but had sp of p decreasing in , % and low growth of p ( , %). surprisingly, in some cases we revealed the great decreasing of variability of hr, bp, pvp and eeg amplitude as a transformation from type or to after infusion. in sbt the vl partly compensates hypovolemia, but creates an exertion in regulatory system, especially in case of significant chrd. so we need to find out the predictive marker of response on the vl in different level of brain damage. engström m , schött u , reinstrup p anaesthesia and intensive care, lund university hospital, lund, sweden acidosis has been found to be a predictor of worse outcome in trauma patients suffering from exsanguination. it has, however, not been studied if acidosis may be a causal factor in the development of coagulopathy. rotational thromboelastography (roteg) is a coagulation monitoring tool that is gaining increasing popularity as it seems to be more sensitive and specific than routine coagulation tests in detecting defects of the coagulation system. clot formation time (cft) and alpha angle are roteg parameters primarily dependent on the rate of fibrin formation and the platelet activity. methods. blood samples of ml each were obtained from healthy volunteers. one sample was studied without any additions. three samples were adjusted to ph . , . and . by the addition of , and µl of m hydrochloric acid (hcl). the last sample was first adjusted to a ph of . by the addition of µl of hcl and then reversed to a ph of . by addition of µl of tromethamol (tham) . mmol/ml. after adaptation of the ph to the desired level roteg was performed to study the coagulation system. we found a strong correlation between decreasing ph levels and an impairment of the coagulation (p< . ) (figure ). the impairment of the coagulation caused by the acidosis was reversible after addition of the buffer tham. in subarachnoid haemorrhage (sah), old age and high clinical grade at presentation are poor prognostic factors. treatment for these patients has been largely conservative. with endovascular coil embolisation a less invasive treatment option has become available( ). this study focuses on elderly and high grade patients admitted to the nicu. retrospective analysis of patients with aneurysmal sah. demographic features, wfns grade at presentation (low grade: & ), fisher grade, data for aneurysm site and mode of intervention were recorded. outcome at three months coded according to the modified rankin score (good outcome: rankin - ). conclusion. our data suggest that favourable outcomes (rankin score - ) can be achieved in elderly patients with high grade (wfns - ) sah. % of high grade patients > years made a good recovery. this may be due to the less invasive nature of coil embolisation and careful patient selection. gama r x , oller a m , bortoletto t c , almeida c r m , gurgel a p a , henrique l m p , zanini a a , faintuch j central pharmacy, hospital alemao oswaldo cruz, sao paulo, brazil lipid-based parenteral nutrition (tpn) mixtures are deemed safer than glucosebased preparations as regards possibility of hyperglycemia, but few comparative studies are available. aiming to determine glucose concentrations during such therapy, a clinical study was done. stable septic patients submitted to tpn (n= ) during a -month period were investigated on the st and the th day of therapy. both glucose-based (group i, n= , . ± . % of total calories as fat) and lipid-based (group ii, n= , . ± . % of calories as fat) programs were employed. groups were comparable regarding age ( . ± . vs . ± . years , ns), gender ( . % females in both groups) and features of septic problems . energy intake was slightly higher in the lipid-based preparations, but without statistical difference ( ± vs ± kcal/day ). conclusion. ) glucose-based tpn was associated with moderate hyperglycemia when compared to a lipid-containing prescription in this septic population; ) no clinically significant hyper or hypoglycemia was registered. guidelines for blood transfusion (bt) are based on plasmatic haemoglobin value (hb) and on clinical state. apart cardiac and septic patients, the threshold value of hb for bt is g/dl. the aim of the study was to evaluate the central venous oxygen saturation (scvo ) as a guide for bt decision. methods. patients of general and urologic surgery for whose a bt was discussed were included. scvo (%) and hb (g/dl) were measured before and after bt. the following parameters were registered: age, history of cardiovascular disease (cv), presence of sepsis, number of blood units. patients were retrospectively divided into groups according to scvo before bt < or > %. overall, demographic characteristics were similar. bt provided a significant increase of hb for each patient while scvo value rose significantly only in patients with scvo before bt < % (table ) . results are given in median (range). * wilcoxon test for values before vs after bt; # mann-whitney test or chi- for scvo < vs > %; significance for p< . . . ( . - . ) hb after bt . * ( . - . ) . * ( . - . ) . * ( . - . ) conclusion. among the patients studied, only those with a low scvo before bt had a better tissue oxygenation by hb increase. scvo might be an interesting parameter to help the clinician in his decision of postoperative bt. szakmany t , dodd m , dempsey g , lowe d , rogers s n department of anaesthesia, regional maxillofacial unit, university hospital aintree, liverpool, united kingdom perioperative blood transfusion is reported to be related to cancer recurrence and reduced survival . to date, little is know about the effects of blood transfusion on outcome in oropharyngeal cancer. we undertook this study to test the hypothesis that perioperative blood transfusion has an adverse effect on survival of patients with oropharyngeal cancer. methods. patients undergoing oropharyngeal cancer resection were evaluated from jan to december . transfusion rate, units of blood transfused and tumour stage were recorded. the primary outcome measure was oropharyngeal cancer death within two years. cox logistic regression was used to assess the association between cancer death and blood transfusion. data are presented as median (interquartile range). overall transfusion rate was % ( / ), units of blood transfused ( ) ( ) ( ) ( ) ( ) . mortality was . % ( / ). mortality was significantly higher in the transfused group (table .) however, in the cox regression analysis only tumour size, stage and clear resection margins were predictive of survival. after stratification of patients for these predictors, transfusion did not affect disease specific survival. in patients who are supported by mechanical ventilation with tracheostomy and who undergo neck surgery because of the neck trauma or neck infection, there is some risk of dislocation of the tracheostomy tube, contamination of the fixation device during daily surgical wound management and daily nursing care. the object of this study is to clarify the usefulness and safety of our technique of easily detachable fixation of tracheostomy tube with small clip in these patients. methods. patients who underwent this technique were examined. we detach the clip fixing the tracheostomy tube during daily surgical wound management and attached it as soon as finishing wound management. we did not experienced dislocation of the tube during daily surgical management and daily nursing care in all cases. we easily protected contamination of fixation device of the tracheotomy tube during surgical wound management. our technique of fixing the tracheostomy tube using detachable small clip is useful and safe in patients who are supported by mechanical ventilation with tracheostomy and who undergo neck surgery because of the neck trauma or neck infection. schachtrupp a , toens c , afify m , lawong g , schumpelick v surgery, rwth aachen, aachen, surgery, marien hospital, dusseldorf, germany in the presence of abdominal compartment syndrome (acs) the increased intraabdominal pressure (iap) leads to organ damage and reduced cardiac output (co). decompression is of utmost importance but occasionally circulatory collapse occurred. moreover, it is unknown whether reperfusion will increase organ damage. aim of the underlying study was to determine the influence of decompression on circulation and organ damage in a porcine model of the acs. we investigated pigs (dl, kg). in two groups (each n= ), iap was increased to mmhg for h using co . in one group a period of decompression lasting for a period of h followed. in the control group, iap remained unchanged for h. all animals received a basic volume substitution of ml/kg. additionally, ml of kristalloids were given whenever the continuously monitored co was lower than the control reading of ml/min x kg. heart rate (hr), mean arterial pressure (map), central venous pressure (cvp) and urine output (uo) were recorded. at the end of the experiment, specimen from the lung, liver, kidney and bowel were taken for histological examination. moreover, liver tissue was examined for the expression of icam- displaying leukocyte sticking. statistical analysis was done using analysis of variance as well as paired and unpaired ttesting. a p< . was considered significant. in case of repeated pairwise testing, level of significance was adjusted. results. co did not differ between groups but additional volume was needed in study groups. hr, map and uo did not differ. cvp was significantly increased. after decompression, hemodynamic parameters remained stable, uo increased significantly. medium grade histological was found after h of increased iap. reperfusion did not increase organ damage. the highest expression of icam- was found after h of increased iap without reperfusion. conclusion. in this model, administration of additional volume was sufficient to preserve co despite the presence of an iap of mmhg. decompression did not lead to circulatory collapse. nonetheless, organ damage was present which was not increased by decompression. these results imply, that in the presence of critically increased iap, adequate volume substitution is needed together with an immediate decompression in order to avoid organ damage. there were episodes of ventilator associated pneumonia in patients of total admitted patients ( . %) and patients who required mechanical ventilation support ( . %). the mean ventilator associated pneumonia rate was . / ventilator days. leading causative agents detected in our picu patients were pseudomonas aeruginosa ( . %),enterococcus ( . %) and staphilococcus aureus ( / %). all patients with ventilatory associated pneumonia survived. ventilator associated pneumonia occurs at significant rates among mechanically ventilated picu patients. ultrasonic guided pleural aspiration is a safe ed accurate method of obtaining fluid in pleural effusion, caused by several mechanisms (pneumonia, cancer, congestive heart failure etc). drainage could improve pulmonary ventilation and allow the laboratory examination of the fluid, useful for the differential diagnosis. pneumothorax (pnx)is the principal complication of thoracentesis. for this reason, five years ago, the emergency department of this hospital, adopted the plastic catheter (pc)in use for iv infusion in order to perform a pleural drainage. the aim of this study was to evaluate the effectivness of this method compared with the more common metallic needle (mn)contents in the set for thoracentesis. where insert the needle. after a local injection of anesthetic lidocaine, one of the two needles was chosen. in particular, for the pc, after the inserction, the metallic core was removed and only the plastic tube was left in place and connected to the drainage system. pleural aspiration was removed when the patient had thoracic pain, cough or fluid flow ceased. by ultrasonography, at the point of drainage, was measured the space between the two pleural layers and this was considered a parameter of drainage entity: the lower the space, the greater the drainage. results were analised on a statistical manner by t test of student for impaired data. patients who underwent thoracentesis by pc had more complete thoracic drainage (pleuric space , +/- , cm vs , +/- , cm; p < , )without case of pnx ( vs ). ultrasound is more accurate than plain chest radiography for estimating pleural fluid volume and aids thoracentesis. chest drainage by plastic catheter increases efficacy and safety. prospective randomized study included enterally fed patients with an expected mechanical ventilation period of at least days. the diagnosis of vap was based on clinical, radiological and bacteriological criteria. qualitative and quantitative bacteriological study of microorganisms isolated from gastric content as well as from upper and lower respiratory tract was carried out on the st, th and th day of the therapy. material from lower respiratory tract was taken by protected specimen brush (psb) using bronchoscope. introduction. vap is a frequent nosocomial infection. since delayed appropiate antimicrobial therapy worsens prognosis, broad-spectrum antibiotics are frequently administered. early clues on potential microorganisms involved could help select a more focused antimicrobial therapy. the known relation between vap and upper airways colonization prompted us to determine if uas at the time of icu admission (day ) could accurately identify microbial agents involved in early vap (within the first days following tracheal intubation). consecutive icu patients who had a clinical pulmonary infection score (cpis) consistent with the diagnosis of vap between and were retrospectively analyzed. uas (nose and throat) were obtained at day for all patients, and specific pathogens (other than normal oropharyngeal flora) were cultured. pulmonary plugged specimen (pps) were obtained whenever vap was suspected and were considered positive beyond cfu/ml. the concordance between uas at day and the first pps was analyzed. in level i(unit-based), . %( % ci . - . )of patients stayin > d, acquired at least one episode of iapn. the percentage varied strongly according to the country ( . to . %),type of icu ( . % in mixed, . % in medical and . % in surgical icus) and percentage of intubation. incidence density (id)per patient-days was . ( . - . )in icus with < % of intubation, . ( . - . ) in icu with - % intubation and . ( . - . ) in > % of intubation, p< . ). the median n of days from admission to iapn were . ( . - . ). the most frequently isolated were p aeruginosa ( . %) and s aureus ( . %), with large variations between countries.gp cocci were isolated in . %, gnb-enterobacteriaceae in . %,gnb non-enterobacteriaceae . % and fungi/parasites . %. table shows the distribution of micro-organism according to the time of onset of iapn. in level ii surveillance (patient-based) intubation utilisation ratio was . ( . - . ) and deviceadjusted indicator: . iapn* / intubation days ( . - . ). % of all general critical care patients were transferred for their care. these patients accounted for % of all bed days in the network. transferred patients had a mean icu stay of days, days longer than non-transferred patients (p= . ) together with a slightly longer hospital stay. there was also a small ( . %) increase in hospital mortality associated with transfer which was not statistically significant. there is a large number of level patients who are at risk of deterioration or have stepped down from higher levels of care.these patients can be looked after on an acute ward with additional support from the critical care/outreach team the critical care network has level beds and the audit identified level patients. ( . %)of these patients(at the time of the audit) could not access a level /hdu bed despite their condition warranting care in an hdu area. the care delivered to this group of patients is therefore by staff trained for a level / area.with level beds, capacity for level patients was appropriate on this day with beds available. the networks patient transfer activity for was non clinical transfers and clinical transfers. sepsis is one of the leading causes of death in intensive care medicine (icm). the rapid diagnosis and management of sepsis is critical to successful treatment. since we have integrated diagnostic and treatment feature of severe sepsis into our berlin simulation training in order to optimize team functions. lectures and interactive simulation scenarios are combined and discussed. participants are postgraduates with differing professional experience in icm (pe). to evaluate the structure, content and impact of those courses participants of four simulation courses in were given anonymised questionnaires both in advance and immediately after the course. pairs of items were defined to measure the acquirement of knowledge in sepsis and the impact of several teaching methods. participants were also asked whether the course content should have been given earlier or later during their postgraduate training. answers were given on a five point scale (likert-like) and results are given as median and interquartile range (iqr). participants' pe in icm varied from two months to years. all participants expressed benefits from the course. both lectures and scenarios were evaluated helpful to identify sepsis patients earlier. most of the participants thought that the course was at a right point of time during their postgraduate training (pt) (n= , median of icm/pe . a, iqr - a) and participants thought that this course would have been even more helpful if had been given earlier during their pt [n= , pe . a ( . - . a)]. "the course was being helpful concerning future identification of sepsis patients" - ( - ). "the lectures were being helpful concerning future identification of sepsis patients" - ( . - ) "the scenarios were being helpful concerning future identification of sepsis patients" - ( . - ) "the scenarios were realistic" - ( - ) and "i enjoyed the course" - ( - ) conclusion. simulation courses to train early identification and timely treatment of septic patients are very helpful and appreciated at every stage of pe in icm. simulation courses should be integrated as early as possible. jermin s p , kapila i , dyson m critical care, south manchester university hospital, manchester, united kingdom there is a recognised shortage of icu beds in the uk.critical care outreach services help reduce pressures on critical care by providing clinical support, increasing staff skills and by providing educational support( ). early identification of sick patients may lead to a reduction in number of admissions to icu, length of in hospital and icu stay ( ) . this study aims to compare the level of care of all inpatients on a normal 'in hours'working day(tuesday) with those of all in patients on an average winter 'out of hours' day(sunday) data was collected from every inpatient in the hospital(excluding psychiatric,paediatric and long term rehabilitation patients) on an average tuesday in april between the hours of - and then on a sunday in january between the hours - . data consisted of levels of care(using uk intensive care society definitions)( ) during both periods but also included demographic details for the second period.presence of respiratory rate(used as an index of deterioration) recording was also noted for the second period. conclusion. the current complement of level and beds in the hospital is and (dependant on staffing levels)respectively.despite some flexibilty in using level beds for level patients and assuming an % bed occupancy, there is a considerable need for more level capacity particularly during the winter period.extension of the current theatre recovery area into a bedded post-operative hdu could provide additional beds .outreach services would also need to be vastly extended. abizanda r , nicolás-picó j , mateu-campos l , carregui-tusón r , sánchez-morán f , mas-font s , ferrándiz-sellés a intensive care department, hospital universitario asociado general de castelló, castellÓ, spain when no icu specific analytical accounting is available, the only indicators of direct costs are the number of icu stays per patient, and pharmacy costs. it is usually accepted that these pharmacy costs represent between and % of total costs, and that they are very much influenced by therapeutic attitudes of the attending teams and the introduction of new pharmacological options or the change in the already existing ones. our aim is to analyze the changes in pharmacy costs occurred during the interval between and . methods. this is a retrospective analysis performed on a multidisciplinary beds icu activity, in a teaching referral hospital. the analysis has been performed through data coming from the managerial departments and the pharmacy service, and costs have been classify as related to therapeutic group (pharmacy instructions from the spanish national health system) and to individual active drugs. the analysis collects information raised from the icu daily patients chart. pharmacy costs amount ranged between , % in and , % in . since then a slight increment in pharmacy costs has been detected up to , %. the reasons for cost decrements are linked to the progressive control on albumin use and antibiotic policies. by the contrary, increasing percentages are associated to the introduction of new sepsis therapeutic approaches (drotecogin) and the routine introduction of antiplatelet agents in non elevated st coronary syndromes. the "top twenty" drugs cost evolution is presented, and in a constant fashion the two firs places represent the use of sedatives (propofol) and fibrinolytic agents in ami (tecneplase). factors that allow or avoid to keep the stability of what pharmacy costs represent are strictly linked to changes in physician attitudes (abandon of non demonstrable efficacy of certain agents -albumin -, the incorporation of new options -drotrecogin, antiplatelets -and the maintenance of consolidated practices -fibrinolytic agents, sedatives, nutritional strategies. physician teams are obliged to keep this information "alive" in order to avoid unnecessary raises in direct costs. cotogni p , bini r , forno g , porta c , aliffi s , ranieri v m , pittiruti m anestesia e rianimazione, chirurgia d'urgenza, school of nursing, university of turin, turin, chirurgia generale, catholic university, rome, italy enteral nutrition (en) is the preferred method for nutrient delivery in icu critically ill patients. nonetheless, there is always a significant gap between prescribed and delivered feed. this is partly due to 'patient-related' problems, e.g. gastrointestinal (gi) intolerance to en, but also by logistic 'management-related' events which imply transient nutrient delivery interruptions, which are often mandatory but sometimes avoidable. the aims of this study (prospective, descriptive study of en delivery in teaching hospital icus) were (a) to analyze the causes for en transient interruptions; (b) to assess whether a specific nurse training might be associated with better nutrient delivery. in two icus (group a), all nurses had been previously trained in en through a h education module, while nurses of other icus (group b) had not. over a period of months, we studied all icu pts receiving en (either alone or combined to parenteral nutrition). pts receiving en for < days were excluded. en was administered as a continuous ( / h) intragastric infusion of a standard polymeric diet. we recorded any transient interruption of nutrient delivery lasting more than min, noting the duration and the cause. we examined pts fed by en accounting for en days ( . + . days/pt). in the groups, patient populations were similar in saps, diagnosis on admission to icu, complications, days of mechanical ventilation and mortality. the main causes of transient en delivery discontinuation were mechanical ( %), or secondary to diagnostic and therapeutic procedures ( %), or related to true gi intolerance to en ( %). comparing groups, we found that group a was characterized by a lower incidence of discontinuations for mechanical causes (p<. ), as well as by a shorter duration of interruption due to mechanical causes (p<. ), to procedures (p<. ), or to intolerance (p<. ). also, the difference between prescribed and delivered feed was significantly lower in group a (p<. ). our study shows that (a) the majority of discontinuations of en delivery is secondary to 'management-related' causes and not to patient's intolerance; (b) a specific training in artificial nutrition of the icu nurses may be effective in increasing nutrient delivery by reducing incidence and duration of those en discontinuations which are not 'patient-related'. saura p , ortiz d , prat r , fernández r , artigas a critical care center, hospital de sabadell, sabadell, spain, critical care center, hospital de sabadell, sabadell, the role of icu staff on cost containment is a matter of debate being drugs consumption, diagnostic test and fungible the main able to be improved. we hypothesised that these items could have the major impact in cost variability per patient in the icu. our objective was to prospectively evaluate the relative role of these variables compared with other classical items as length of stay, quality of life, age, severity of illness. design: prospective cohort study setting: -bed intensive care unit patients: consecutive patients with a length of stay longer than hours. measurements: we prospectively recorded: demographic data, spas ii score and diagnostic related group on admission, length of icu stay, health-related quality of life (euroqol d), and consumption of fungible, pharmaceutical and diagnostic procedures. the costs of the fungible, pharmaceutical and diagnostic tests were recorded from the hospital administrative database as cost per unit. we elaborated a multivariate linear predictive model in order to analyse the variables causing the variability of the cost per patient. patient transfer between hospitals is associated with increased mortality ( ), and patients transferred from intensive care unit (icu) to icu have also been shown to have increased mortality ( ) . the aim of our analysis was to compare our mortality figures with those of published data. . a retrospective analysis of , patients admitted to a -bedded unit in a university teaching hospital over a -year period. we compared those patients admitted from our own hospital (internal) with patients transferred from other icus (external icu) and those transferred from other hospitals from an area outside icu (external other). we compared icu mortality with apache ii predicted mortality and calculated the standardized mortality ratio (smr). results. over the year period, , patients were admitted into the icu. forty-nine( %)were transferred from another icu, ( %)were transferred from areas outside the icu in other hospitals and ( %) were admitted from our own hospital. mortality figures are shown in the table. conclusion. lipid solutions enriched with w- fatty acids are safe, well tolerated in patients with ards, and without changes in the hemodynamic or gas exchange of these patients. cdc defintions for nosocomial infections nosocomial infections in pediatric intensive care units in united states nosocomial respiratory infections picu ventilator-associated pneumonia nosocomial pneumonia in the picu (abstract k- ) pediatric ventlator-associated pneumonia last's anatomy the impact of malnutrition on morbidity, mortality, length of hospital stay and costs evaluated through a multivariate model analysis incidence of nutritional risk and causes of inadequate nutritional care in hospitals nutritional risk screening (nrs ): a new method based on an analysis of controlled clinical trials r:an update on perioperative management of diabetes intensive insulin therapy in critically ill patients introduction. the objective of this study was to evaluate the use of human resources in icu comparing the planned level with the operative level. prospective study involving all the patients admitted in the icu between and . simplified therapeutic intervention scoring system (tiss ) was used to assess nurse workload in the icu. provision of resources was measured as the number of nurses per icu bed (patient nurse ratio -p/n). the operative level of care was calculated dividing the measured tiss points equivalent to the nursing activities of one nurse per shift. the efficiency in the use of nursing manpower was based on the number of available nurses, the amount of work that one nurse can perform per shift and the level of tiss during the study. the work utilization ratio was calculated. severity of illness was evaluated by the apache ii score. conclusion. the apache ii score remained elevated through the study period. the measured tiss was higher than planned and as a result the work utilization ration was above %. nevertheless the number of patients admitted increased every year and the mortality remained lower that the expected by the apache ii score. adverse drug reactions (adr) are common in hospitalised patients, but few empirical data are avalaible regarding patients with serious adr requiring intensive medical care. as morbidity linked to adr remain underappreciated, delay for diagnosis may contribute to organ failure requiring artificial life support. the aim of this study was to determined the proportion of admissions related to serious adr and potential avoidability. we have prospectively included all adults patients coming from university hospital admitted in a -bed medical intensive care unit (icu) in a french university hospital in bordeaux, france, during a -month period. for each patient, we have determined if serious adr have contributed to organ(s) failure(s) requiring admission by follow-up and with independant clinical pharmacologists. clinical pharmacologists have estimated the strenght of relationship between drug(s) prescribed in hospital and potential avoidable adr as the cause of organ failure.results. of patients admitted from medical icu between may and october , ( , %) were hospitalised because of almost one organ failure related to adr, % of cases adr were potentially avoidable. coma, seizures with acute respiratory failure and metabolic life-threatening disorders were the most frequently avoidable adr and linked to drugs prescribed in a short delay before admission. artificial life support was required in % of cases.vasopressives drugs were prescribed in cases , hemodialysis in , non invasive ventilation in , and mechanical ventilation was needed in cases.the mean of simplified acute physiologic score ii of work load omega score, of length of stay and the rate of mortality were not significantly different between patients with or without adr. serious adr were a frequent reason of admission ( , %) and were often potentially avoidable if cautions of prescriptions would have been taken into account. measures are needed to improve adr detection and reduce drug-induced morbidity. performing every interventional procedure strictly lege artis is of significant importance not only to the patient, but also to the medical personnel. ensuring the maximum alertness to stay strict to the rules and performing by book leads to minimal complications, more wise decisions and reduction of the cost as it minimizes the single use material waste. : in our polyvalent six bed icu we installed cameras providing full surveillance of each bed. all of the cameras were in use for two weeks registering every interventional procedure on hour basis. medical and nursing stuff were aware of the registration process. the whole medical team reviewed the collected videos every five days. we totally registered central vein catheterizations, oro-tracheal intubations, three tracheostomy operations, radial artery catheterizations, rhinogastric tube insertions, urinary bladder catheterizations, pulmonary artery catheterizations bronchoscopies, and six chest drainage procedures. all procedures were graded on to scale, in respect with asepsia,, antisepsia ,speed of performance, material waste and complications. procedure days - days - days - central veins access radial artery access pulmonary artery access tracheal intubations bladder catheteriasations levin tube insertion bronchoscopy tracheostomy bulau insertion conclusion. increased stress among the medical personnel was noted due to the presence of the cameras, although procedures were more exact as the time advanced in spite of the fact that the duration in time of each procedure seemed to be longer. complication rates were constant. [ ] , thereby increasing providers' financial risk considerably [ ] . in future, reimbursement in germany will be based on a special procedure (ops ) which may be quantified through a specific, patientdependent cost predictor score. the aim of this study was to develop and validate such a score capable of predicting the total direct costs of intensive care services in large teaching hospitals. individualized clinical as well as economic information was collected for all consecutive patients across mostly surgical icus in university hospitals across germany during a month period. resource consumption covered hotel and personnel costs, medication, laboratory tests, diagnostic and invasive procedures. resources were valued with local costs through bottom up costing. an "icu cost predictor score" (icu-cps) was devised by combining a routine measure of severity of illness (daily saps ii score without gcs) with a daily measure of selected medical interventions ( highly rated parameters of tiss- : mechanical ventilation, multiple catecholamines, > l daily fluid replacement, peripheral artery catheter, pulmonary artery catheter, haemofiltration, intracranial pressure measurement, alkalosis/acidosis treatment, special interventions, actions outside icu) during the entire icu stay. based on a preliminary analysis of patients from icus, the icu-cps demonstrated a strong positive correlation of . (p < . , -tailed) with total icu costs. this coefficient varied from . to . between icus. the correlation of the icu-cps score with costs was better than that of saps ii (without gcs) ( . ; p< . , -tailed). the mean icu-cps per day was ± (mean ± sd). average costs per day were € , ± , . on average, each score point of the icu-cps thus corresponded to a cost of . the preliminary results of this study indicate that intensive care services may be adequately reimbursed on the basis of the icu-cps predictor score, taking into account patients' acute severity of illness as well as required medical interventions. the aim of our study was to analyse variable cost determinants of severe sepsis treated in intensive care units in hungary. we selected a non-random sample of intensive care units. each unit identified patient retrospectively, who were treated with severe sepsis. the resource use of variable costs were collected on a daily basis (for day - ) from medical and nursing documents. these costs were divided into disposables, radiology, biochemistry, blood products and drugs&fluids. personnel costs were calculated from annual salary report and the indirect costs were calculated by the financial directors. the mortality of severe sepsis in our sample (n= ) was found to be . %, with average lenght of stay . (sd . ). mean icu cost per day of severe sepsis was euro. there were no differences found between day - cost of radiology, biochemistry and blood products, however, disposables had much higher cost on day (p= . ). drugs&fluids costs were higher on day only for those patients who did not survive. analysing drugs&fluids by grouping them into categories, we found that colloid use was significantly higher on day in those, who died later ( ml vs. ml, p= . ). there was no correlation found between apache ii scores and any cost components. egdt has shown significant reduction in mortality and health care resource consumption and is recommended by the surviving sepsis campaign . this study assessed data from severe sepsis and septic shock patients prior to implementation of an egdt program and projected the potential impact on resource utilization at our hospital. we queried the clinical data repository and found emergency department(ed)patients admitted from jan -dec meeting search criteria including: patients > years, hospital admission from the ed with documented infection, antibiotic treatment and requiring vasopressors (day , ), ventilator assistance (day , ), new dialysis (day - ) or a serum lactate > mmol/l. exclusion criteria were admission gi bleed or traumatic injury. based on resource utilization data from the henry ford health systems corporate data stores, percent differences between egdt and non-egdt groups were calculated and applied. assuming constant mortality, the projected impact on hospital resource consumption and costs was assessed. cost savings was assoicated with survivors. increased costs were noted in non-survivors. cost benefit favored egdt. . four consecutive tptd measurements were performed with ice-cold saline. the volume of the injectate varied between and ml depending on bodyweight. the mean of consecutive measurements with a normal td curve and injectate temperature lower than °celsius was considered as the gold standard. a total of quadruple measurements fulfilled the quality control criteria. mean cardiac index (ci) was , l/min/m (sd , ). the mean coefficient of variation (percentage of the sd of the mean) for quadruple tptd measurements of ci was , % (sd , ). the table shows the differences between measurement, the mean of and the mean of measurements in comparison with the mean of measurements. measurements were performed at our catheterisation laboratory in seven children with a bodyweight of - , kg. evlw was measured with the cold system (cold, pulsion medical systems) incorporating both tptd and tpdd techniques. ice-cold indocyanine green was injected close to the right atrium. changes in temperature and dye concentration were measured using a special catheter located in the distal aorta. mean cardiac index (ci) was , l/min/m (sd , ) and mean evlw-tpdd was , ml/kg ( , - , ). repeatability ( . x sd of the difference between repeated measurements) for ci, evlwi-tptd and evlwi-tpdd were , l/min/m , , ml/kg and , ml/kg respectively. the bias between the two methods is - , ml/kg with a precision of , .conclusion. transpulmonary thermodilution appears to be an adequate method to measure evlw in children. children may have higher normal values of evlw compared to adults. loh t f children intensive care unit, kk hospital, sin, singapore a common approach for insertion of central venous catheter is to access the subclavian vein via subclavian approach. this approach is associated with arterial puncture and air leak , . local pressure is difficult to apply as the vein runs under the clavicle. we describe an axillary approach to access the subclavian vein in paediatric patients. patients were selected for this approach when conventional approaches for central venous access were exhausted or contraindicated. the patient's arm is kept abducted with slight external rotation perpendicular to the thorax with the dorsum of the palm flat to the bed. head is turned to the contralateral side. the axillary artery is palpated and followed as it inserts into the apex of the axilla lateral to the teres minor when it becomes the subclavian artery. the axilla vein runs medial to the artery becoming anterior to the artery as it enters the axilla apex to become the subclavian vein . a puncture is made medial to the artery at the base of axilla and directed towards the axilla apex. the needle is punctured - degrees to the skin and limited to the apex of the axilla. confirmation of venous access is made by free flow of blood. the catheter is inserted using the seldinger technique and secured. chest xr done to confirm placement. . paediatric patients were selected for this approach. arterial puncture was made in one patient and hemostasis secured with direct local pressure and subsequent insertion was successful. access required a mean of . attempts. one patient hand was swollen days after the line inserted but doppler study did not reveal any venous thrombosis and the line left in situ. routine limb neuromuscular and vascular assessments were made. no malposition or air leak was seen on cxr.no local or line related infections were documented. catheters were removed after . days. follow up (mean of weeks) after the catheter was removed showed normal hand power and movement in all patients. axillary approach maybe a novel alternative to central venous catheter insertion in paediatric patients when conventional approaches are not possible. change was recorded on capnography in all tests performed. radiographs confirmed correct placement of ngt throughout study period. in the subgroup of children(n= )who had an endotracheal placement the time to complete capnograph colour change was ≤ seconds, (median ( - )) in all cases. in critically ill children sufficient gastric aspirate can be obtained for ph testing and capnography rapidly discriminates between ngt placed correctly from those passed in to the trachea. a one year prospective & observational study included all admissions (n= ) until h after discharge. cultures for bacteria and fungi and antibiotic sensitivity tests ( antibiotic using bauer-kirby disc diffusion method) were obtained on admission [ blood, stool, urine & cerebrospinal fluid (if needed)] and repeated on suspicion of nis .all cannulae, endotracheal tube (et) aspirates & tips, nasogastric tubes & different catheters were cultured. all picu health care workers (hcws) were subjected to throat & under-finger nails culture as well as inanimate objects , both on bimonthly basis. the referral place (ward or emergency), prism iii score, length of stay (los) & fate, were recorded. reports of the dutch society of pediatrics concerning transport and stabilizing critically ill children, resulted in a reorganization of the transport of critically ill children in the netherlands. as of february , all children in the northwestern region of the netherlands requiring mechanical ventilation were transported by pediatric intensive care teams of the vu and amc university medical centers. these teams consist of a pediatric intensivist or anesthesiologist (in training) and pediatric intensive care unit (picu) nurse and were on call hours, days per week. the objective is to report the first year results and to compare an experienced (amc) and a novice (vumc) center. demographic data, diagnosis at admission and severity of illness score (prism) and duration of transport (preparation, travel time, intervention in other hospital and complications during transport) were prospectively collected. all data were analyzed per center and in total in order to identify any difference between both picu-teams. transport frequency was divided according to picu-capacity ( % vumc and % amc). statistic analysis included student t-test for continuous variables and chi test for dichotomous variables. in total patients were transported by either picu-team. half of the transports took place during the evening or night. demographics, prism-score and admission diagnosis were comparable. mean transport time was hours and minutes. there was a significant difference in preparation time . results concerning other transportation variables are similar for both clinics. neither picu-team reported complications during transport. a continuous picu transport system carried out by two specialized centers is feasible and efficient. apart from a difference in preparation time, which may be influenced by a multitude of factors, there were no differences concerning other transport variables between an experienced and inexperienced team. after cardiac surgery it is not uncommon that a solitary collapse of a lobe, e.g., the left lower lobe develops. it has been difficult to experimentally study therapeutic interventions for lobar atelectasis due to lack of suitable animal models. the aim of this study was therefore to develop a reproducible model in pigs.methods. anesthetized pigs were tracheotomized and ventilated vcv, fio . , peep cmh o, vt ml/kg. this ventilation was maintained under the experiment except during the lung recruitment maneuver (lrm). a bronchial blocker (cook c-aebs- . ) was inserted in the right lower lobe (about cm from the et-tube opening) by the use of a fiberoptic bronchoscope. to ensure a correct position, the balloon of the blocker was inflated shortly and thereafter deflated under inspection via the bronchoscope. thereafter, a lrm (pcv with peak pressure of cmh o, peep cmh o, i:e : and rr of /min during min) was performed to optimize the lung volume history after which end-expiratory lung volume (eelv), quasistatic compliance of the respiratory system (crs) were measured and blood gases (mixed venous and arterial) were obtained. the balloon of the bronchial blocker was inflated, the air of the isolated lobe exsufflated and measured ("lobe volume"). thereafter the lobe was selectively lavaged (with a "lobe volume" of °c . % nacl) using a syringe times or until no frothing of the lavaged fluid was seen. eelv, crs and blood gases were obtained. in one pig ct thorax was done and another pig was thoracotomized and the lungs were inspected. statistics:wilcoxon. the "lobe volume" was ± ml (mean±sd). after the selective lobe lavage, eelv decreased from ± to ± (p< . ), pao from ± to ± (p< . )and crs decreased from ± to ± (p< . ).both ct and the inspection of the lung showed atelectasis of the right lower lobe. a reproducible experimental lobe atelectasis can be obtained by selective lobe lavage in pigs. this method may be used experimentally for studying methods treating atelectasis. garcia-hernandez r , perez-vela j l , corres m a , hernandez-sanchez e , renes e , gutierrez j , arribas p , perales n postoperativecardiac unit, hospital doce de octubre, madrid, spain in the literature donor´s norepinephrine (ne) usage was considered high vasoactive support and leads to refuse heart graft implantation.the sortage of available donor hearts limits cardiac transplantation and nowadays some authors point that vasoactive drugs (vad) could be useful to improve donors hemodynamics and so graft function in the recipient. objetive: to assess graft function and icu evolution in patients who underwent cardiac transplantation depending on donor´s ne dose. retrospective study from until of intrahospital donors and theirs recipients two groups were set: low ne dose: donors who received < . mcg/kg/min or no ne; high ne dose: donors who received >/= . mcg/kg/min. we assessed in the donors: number, type, length and dosage of vad; volume intake and clamp time; in the recipients: presurgical left ventricular eyection fraction (lvef); extracorporeal circulation (ecc) time; incidende of ventricular disfunction, cardiogenic shock, primary graft failure (pgf); mortality and others icu evolution parameters (incidence of acute renal failure-arf-, acute lung injury/respiratory distress -ali/ards-, sepsis, length of dva usage, mechanical ventilation and icu admission, etc...). statistical analysis was done with t-student´s test and chi( ) (using yates´ or fisher´s modification when indicated). conclusion. in our serie, the donor´s ne dose did not have an influence on the heart graft disfunction or in the others items assessed. the ne use for hemodynamic management on heart donors could not worsen the recipients evolution, but new studies with high number of patiemts should be developed in order to set a clear limit in the dosage used. jacquet l , rubay j , vancaenegem o , laarbaui f , lovat r , noirhomme p cardio-vascular intensive care, cardio-vascular surgery, saint-luc university hospital, brussels, belgium many patients with complex congenital heart disease,the majority having been operated on during their first years of live, are now adults and pose unusual problems for cardiologists, surgeons and intensivists caring for adult patients. we have reviewed the charts of patients > years old who were admitted in our cardiovascular icu after operation for guch from january to december in order to describe their specific outcome. during this years period, data from pts ( males, females and xxyy karyotype) were collected. the mean age was y (rang - ).among these, had tetralogy of fallot and had been already operated before, having had previous surgical procedures. the main indication for surgery was pulmonary insufficiency and pts received a pulmonary homograft. retrospective review of all echo examinations in this setting over a one-year period (jan -jan ) we performed echo in patients ( % of ). echos were carried out during the first hours in % and on the next day in %. sixty-eight percent were performed during the first postop days. echo was performed as urgent in %, semi-urgent (> hours) in % and for control in % of cases ( % tte, % tee). % were carried out by cardiologists and % by anesthesiologists. however, % of the urgent echos were performed by anesthesiologists. indications were: hemodynamic instability ( %), cardiac transplantation follow-up ( %), cardiac ischemia ( %), cardiac function follow-up ( %), and suspected cardiac tamponade ( %). findings were left ventricular dysfunction ( %), hyperdynamic left ventricle ( %), right ventricle dysfunction ( %), new segmental wall motion abnormalities ( %) and hypovolemia/vasodilation ( %). % were normal or similar to previous echos. new myocardial infarction was diagnosed in %. echo induced changes in patient management in %: resternotomy ( %), medical therapy ( %) and others ( %)(iabp insertion/removal, anti-rejection therapy). main changes in therapy were: inotropic agents ( % increase, % decrease) and iv fluid administration ( %). in % echo findings were unexpected/unrelated to the symptoms. % of patients were also managed with a pulmonary artery catheter(pac). in % of these there was no agreement between two techniques. number of echo carried out by the anesthesiologists increased from % in the first four months of the study to % in the second four months and to % during the last four months. in this study, echo provided important diagnostic and therapeutic data on postoperative cardiac surgical patients. findings led to management changes in % of patients. echo should be included in training of physicians working in csicu. is . %. the mean age is ± years. the mean bmi is ± . kg/m . patients with normal bmi ( - kg/m ) and patients with more than normal weight(above bmi) had a similar outcome. (fig. ) we ruled out that younger age compensates for a possible higher mortality in heavier patients.however, the age turned out to be similar in the different bmi groups and cannot be held accountable for lack of increased mortality in patients with more than normal weight. (fig. ) .conclusion. bmi does not show to increase mortality in cardiac surgical patients, despite of possible increased comorbidities. samalavicius r , misiuriene i , norkiene i , juozaitis m , baublys a department of cardiac anaesthesia, vilnius university hospital, vilnius, lithuania obesity is one of the risk factors for adverse outcomes of major surgery. we assesed the influence of obesity on outcomes of cabg in our institution. the data of consecutive patients, who underwent coronary artery bypass grafting at vilnius university heart surgery clinic between january , and december , were analysed. obesity was defined as body mass index > . kg/m . obese patients (n= ) were compared to remaining group of patients. preoperative risk factors, postoperative outcomes, mortality rates were analysed. associations between obesity and postoperative outcomes were analysed. in a prospective observational study we assesed nutritional status of consecutive cardiac surgery patients with a nutritional risk screening form, which contained bmi, food intake, weight lost and stress factor. we evaluated mortality, icu stay and frequency of impaired healing in the groups in nutritional risk and with normal nutrition. we identified from ( , %) patients as in nutritional risk. both groups did not significantly differ in age, bmi, left ventricle function, preoperative serum albumin level, prevalence of chronic renal failure or perifery vascular disease. there were significantly more diabetics ( , % vs. , %, p< , ) and patients with copd ( , % vs. , %, p< , ) in risk group. we found out the rate of complicated wound healing , % (all sites and grades). there was significantly higher rate of complicated wound healing ( , % vs. % p< , ) and longer icu stay ( , vs. , hrs., p< , ) in group in risk compared to group without risk. there was trend to higher mortality in risk group, statisticaly nonsignificant( , % vs. , %). we identified diabetes, copd and nutritional risk as to be preoperative independent risk factors of impaired healing in elective cardiac surgery by multivariate analysis.conclusion. cardiac surgery patients have a similar prevalence of nutritional risk as general population of patients. simple screening form is able to identify group of patients in increased risk of impaired healing. maximum sofa during first three days (maxsofa d) and deltasofa between first and third postoperative days (deltasofa ) revealed to have strongest correlation to mortality (p= . , roc area . and p= . , roc area . respectively). the maxsofa d of points corresponded to mortality with sensitivity of . and specificity of . . maxsofa d correlated to the icu stay (p= . ).conclusion. the sequential assessment of organ dysfunction during the first three days postoperatively is an independent predictor of mortality and morbidity in cardiac surgery patients. hájek r , rùžièková j , zezula r , fluger i , nìmec p , jarkovský j , nemethová d cardiac surgery, university hospital olomouc, olomouc, center of biostatistics, masaryk university, brno, czech republic introduction. thromboleastography (teg) is reliable and extensively used method of haemostasis monitoring. using teg as a bed-side method, we are able to detect a coagulation disorders, especially hypercoagulation and fibrinolysis methods. in prospective randomized study two groups of elective cardiac surgery patients were compared. patients of group a (n= ) were monitored both conventional lab tests and simultaneously with teg. the following teg measurements were performed: st -baseline after the anesthesia induction, th-at rewarming on cpb (with heparinase) and th-immediately after icu admission (both nativ and heparinase). patients of group b (n= ) were monitored only using lab tests. pre and postoperative coagulation status, incidence of thrombocytopenia, fibrinolysis,blood loss , transfusion therapy, surgical reexploration were evaluated. changes of hemostatic profile using teg diagnostic algorithm and also changes of pre-and postop.lab tests were evaluated results. both groups were comparable by age ( , / , ) , male gender ( %, / , %) and surgery type. the lab coagulation tests including platelet count were within normal range in both groups before surgery. no diference between both groups were recorded in : average blood loss during and postoperative, incidence of surgical reexploration because of bleednig , red blood cell, fresh frozen plasma and platelet transfusion and using of aprotinin. in both groups lab values of quick test, platelet count and fibrinogen were lower and aptt and tt were higher after surgery. the changes of teg parameters characterised by coagulation index : ci >ci , ci <ci . frequency of coagulagulation patterns: teg : enzymatic hypercoaguability , %, platelet hypercoag. , %, sec.fibrinolysis , %. teg : low platelet function , %, primary fibrinolysis , %, low clotting factors , %. teg (heparinase): enzymatic hypercoag.. , %, platelet hypercoag. , %, low platelet function , %. only one parameter-quick test value(%) correlated with ecc duration (r- , , p< , )in both groups. this study shows no diference of therapy between groups monitored with teg compared with conventional lab tests. most of patients in teg group showed the signs of hypercoagulation on teg before and after elective surgery. . to achieve a better glucose control in diabetic cardiac surgery patients a three to five-fold increase of basal insuline dose has been suggested. ( ) .our objective was to determine wether three or five-fold increase in basal insulin-dose during hypothermic cpb makes a better glycemic control without risks.methods. type ii diabetes patients were included in this prospective study. two hours before surgery a continuous endovenous insulin infusion was started to achieve the target glucose level results. (median+/-sd) pts were excluded due to off-pump surgery. one due to continuous hypoglycemia .itg showed lower blood glucose levels( +/ mgdl- )than cg( +/- mgdl- ) during intraoperative period (p< . ). % of itg and % of cg patients presented at least one blood glucose level.mean time with blood glucose levels conclusion. -in type ii diabetic patients sheduled to cardiac surgery a five-fold increase in insulin dose at the begining of cpb achived intraoperatively safe and better glycemic control than three-fold increase;. -patients with better glycemic control had less infections and shorter hospital stay as it was also demonstrated by others ( ) .this results give support to stablish insulin protocols that allow a tight glycemic control in the perioperative setting. giuliano k k patient monitoring, philips medical systems, andover, united states introduction. the purpose of this research was to develop a predictive model for the early identification of sepsis using the currently recommended physiologic parameters that are continuously or frequently monitored in the critical care setting. data from the project impact ® international dataset were used to assess whether a combination of the physiologic parameters of heart rate, mean arterial blood pressure, body temperature and respiratory rate could distinguish between critically ill adult patients with a diagnosis of sepsis and those without a diagnosis of sepsis in the first hours of intensive care unit admission. all four predictor variables used in the analyses (respiratory rate, heart rate, mean arterial blood pressure, and temperature) differed significantly between the septic and nonseptic patient groups. however, using logistic regression, only two out of the four predictor variables (mean arterial blood pressure and temperature) were independently associated with being septic. according to hosmer and lemeshow goodness-of-fit tests, the logistic regression model was a good fit and explained between . % and . % of the variance. using the significant predictors of temperature and mean arterial blood pressure, the odds ratio for having sepsis was . for patients with a temperature of oc or higher and . for patients with a mean arterial blood pressure of less than mmhg. in addition, the odds of having sepsis were . times greater if the patient had both of these physiologic conditions present. the results of this research provide support for the use of some of the currently recommended clinical monitoring guidelines for patients with sepsis. however, the results also underscore the limitations of using these variables for sepsis monitoring, since this group of variables alone was not sufficient for discriminating between critically ill patients with and without sepsis. more work needs to be done to see if these variables would perform better if different cut-off values were used. zubani f , de peri e , rasulo f , candiani a , latronico n intensive care unit, spedali civili, university hospital of brescia, brescia, italy introduction. more than percent of patients with sepsis syndrome or septic shock present altered mental status manifested by decreasing attention, disorientation, agitation, obtundation and in worst cases profound stupor and coma (septic encephalopathy). we don't know the exact physiopathological mechanism which cause se, but many clinical studies have shown that cerebral blood flow (cbf) is reduced in these patients. the current study was performed to evaluate the behaviour of cerebrovascular autoregulation during systemic inflammatory response syndrome (sirs), sepsis syndrome, septic shock and multiple organ failure (mof). we have studied all patients with se admitted into the intensive care unit of the spedali civili university hospital of brescia from january to september . cerebral autoregulation has been evaluated bilaterally in the mca territory with thetransient hyperemic response test (thrt). twelve patients were included in this study and thrt have been totally performed. cerebral autoregulation was impaired in % of thrt: the two conditions most associated with worst cerebrovascular response are sepsis ( , %) and mof ( %); patients with septic shock have shown unexpectedly the best autoregulatory response. in patients with infections caused by gramnegative organisms cerebral autoregulation was impaired in % of measurements: there are many evidences in literature about endotoxin's ability to influence cerebral blood flow. another important factor able to influence the behaviour of cerebral blood-vessels is paco : the effect of hypercapnia is more evident in patients with septic shock and with mof, particularly, the share of patients with septic shock with cerebral autoregulation completely impaired, was hypercapnic in % of measurements. cerebral autoregulation was impaired in the most part of measurements. gramnegative organisms and hypercapnia play a fundamentally roll in the loss of this mechanism. conclusion. platelet transfusion is associated with longer icu stay and % increased risk of death. rudiger a , fischler m , harpes p , gasser s , hornemann t , von eckardstein a , maggiorini m wolfson institute of biomedical research, university college london, london, united kingdom, medical icu, university hospital, department of biostatistics, university, zurich, medicine, regional hospital, zofingen, clinical chemistry, university hospital, zurich, switzerland introduction. b-type natriuretic peptide (bnp) and its n-terminal portion (nt-probnp) may be useful in the assessment of cardiac preload in patients with chronic heart failure. however, it remains controversial whether or not this option is still valid in critically ill patients. to resolve this question we sought to establish the relationship between natriuretic peptide levels and surrogates of cardiac preload and inflammation in this kind of population.methods. this retrospective study included critically ill patients with heart failure and/or refractory shock, all monitored with a pulmonary artery catheter (pac). linear correlations between hemodynamic and laboratory parameters were performed using relative differences and described by the pearson correlation coefficient (r). a mixed linear model for repeated measurement was used to control for repeated effects. the analysis included measurements from patients with heart failure (n= ) and septic shock (n= ). mean (sd) age was ( ) years, and % were men. icu-and hospital mortalities of the population were % and %. bnp and nt-probnp correlated (p< . ) well with c-reactive protein (r= . and r= . ), to a lesser extent with leukocyte count (r= . and r= . ) and central venous pressure (r= . and r= . ), but not (p> . ) with the pulmonary artery occlusion pressure (r= . and r= . ). these relationships were confirmed in mixed linear model analyses for repeated measurements. supported by other clinical observations and evidence from laboratory studies, our results suggest that inflammation is a important stimulus for bnp and nt-probnp elevations in humans. natriuretic peptide levels may therefore not be used as surrogates of cardiac preload in critically ill patients with heart failure or shock. animal studies suggest that melatonin plays an adjunctive role in defence mechanisms to overcome severe illness and, accordingly, melatonin seem to affect morbidity and mortality.we report on correlations between nocturnal melatonin serum levels and measures of illness severity in patients consecutively admitted to a medical intensive care unit. on the day of admittance at : h am blood for the determination of serum melatonin levels was obtained and illness severity was assessed according to the acute physiology and chronic health evaluation score (apache) and the therapeutic intervention scoring system (tiss). for the entire study group there was a weak negative correlation between tiss and nocturnal melatonin concentration (r = - . , p< . ) while such correlation was not observed for melatonin and apache. subgroup analysis revealed that in patients with sepsis both apache and tiss scores correlated negatively with nocturnal melatonin concentrations (n = , apache: r = - . , p< . ; tiss: r = - . , p< . ). such correlation did not occur in other disease entities like coronary syndromes or intoxications. our study indicates that melatonin is specifically affected by serious infectious disease and low melatonin levels may contribute to the adverse outcome of sepsis. baykara n , aydemir e , solak m , toker k anesthesiology and reanimation, university of kocaeli, school of medicine, kocaeli, turkey the purpose of the present study to assess changes in antidiuretic hormone (adh), growth hormone(gh) levels and hemodynamic response during a standart weaning protocol in patients with copd. this study was carried out in patients undergoing ventilatory treatment with synchronized intermittent mandatory ventilation (simv)+peep for respiratory failure due to copd. their durations of mechanical ventilation (mv) were between - days. exclusion criteria were:abnormal left or right ventricular function,abnormal liver or renal function,diabetes mellitus,cns disease or mv exceeding one week. weaning was carried out in stages of min each, from / of the initial rate of simv (simv / ) +peep, to continuous positive airway pressure (cpap), to spontaneous breathing. systolic blood pressure, diastolic blood pressure,heart rate,central venous pressure,pulmonary capillary wedge pressure,cardiac output,hourly urine output,plasma osmolality and adh, gh were measured during at each ventilatory condition. hemodynamic parameters did not change significantly among the ventilatory conditions. adh concentrations during simv+ peep and simv i / +peep were similar and were significantly higher than during spontaneous breathing. adh concentration during cpap was not significantly different from spontaneous breathing. even though statisticallyinsignificant,hourly urine output was higher during cpap and spontaneus breathing than during simv+peep and simv / +peep modes. gh level did not change significantly among ventilatory conditions. accordingly, weaning appears to be well tolerated from a hemodynamic standpoint in copd patients with normal cardiac function after short term mv. cpap is the ventilator mode causing the least adh secretion in patients with copd. jukes a l , saayman a g critical care directorate, university hospital of wales, cardiff, united kingdom enteral feeding is the preferred method of nutritional support in the critically ill patient (jolliett et.al., ) . the enteral feeding protocol within our unit advocates prompt replacement of wide-bore tubes with fine-bore feeding tubes once enteral tube feeding is established to maximise patient comfort and safety. the aim of this review was to compare the current fine-bore feeding tube used within the critical care directorate (ccd), medicina (entrafeed, fg or eng) with that manufactured by merck, (corflo, fg or cng). it was hypothesised that as a result of the specific features of the cng tube, it would be easier to aspirate; reduce the incidence of occlusions; and have increased radio opacity when compared with the eng.methods. an audit proforma was completed for patients who had a fine-bore feeding tube placed within the ccd: (eng); (cng) placed. the patients were followed until feeding was stopped due to a complication, or no longer required. chest x-rays were reviewed by a consultant at the end of the study, unaware of ng type. all nasogastric feeding tubes were placed by medical staff. very few measured the tube length required to insert prior to placement. auscultation, was used in % of tubes placed. aspiration of gastric contents was attempted in % of tubes but only obtained in ( %)tubes ( eng, cng). only of these had a ph of or less, confirming gastric placement. all patients received a chest x-ray, visibility comparable ( eng and cng clearly visible on x-ray). there were occlusions ( eng, cng). many tubes were accidentally displaced or pulled out by patients ( eng, cng). the majority of tubes ( %) remained insitu for days or less ( eng, cng). the results of the review did not warrant a change in the type of nasogastric feeding tube used within the ccd. it has highlighted that education and training of doctors is required within the ccd regarding the placement, and appropriate methods used to confirm correct ng position. radiological confirmation of ng tube position is advised on initial placement in critically ill patients. however, attempts should be made to aspiration and ph test to assist subsequent confirmation, avoiding unnecessary x-rays. administration of lipid solutions to critically ill patients may be associated with changes in laboratory and gas exchange parameters. lipid solution composure may impact in these changes. methods. investigate gas exchange and hemodynamic changes in patients with ards treated with a lipid solution enriched with w- fat acids. prospective, randomise, double blind study of parallel groups. sixteen patients with ards within hours of diagnosis were randomised in two groups. group a (n= ) received lipid solution lipoplus® % b.braun medical ( % mct, % lct, % w- ) and group b (n= ) intralipid® % ( % lct). lipid solution was given over hour at . mg/kg/h. hemodymanic and gas exchange parameters were analysed before treatment and at and h of lipid solution infusion. statistics: bmdp, wilcoxon and sign tests. the following table shows the percentage of change after lipid solution infusions compared with baseline levels. no side effects were observed with both lipid solutions in the patients studied. immunonutrition is a balanced nutritional support containing immune enhancing substances like arginine and omega- -fatty acids. the aim of this study is to find out if immunonutrition can reduce the number of blood transfusions and blood loss in cardiac patients. in this prospective and double-blind study we randomised patients who either received immunonutrition or an isocaloric placebo. comparison of the group was done with repeatedmeasures anova. we could not find a difference concerning postoperative blood loss and blood transfusions. ± ± (mean ± sd) number of blood transfusions , ± , ± , per patient (mean ± sd) infection rate (%) length of stay (hospital) ± ± (median ± sd) conclusion. we could not prove a significant advantage of immunonutrition as reported in the literature. ( ) . the objective was to apply rifle in the postoperative cardiac population and to analyze outcome, length of icu stay (los) and mortality for each subgroup. we stratified patients according to their preoperative plasmatic creatinine (ppc in mg/dl). theoretic plasmatic creatinine is obtained according to simplified formula mdrd (modification of diet in renal disease) ( ) . the expected mortality was calculated using logistic euroscore (european system for cardiac operative risk evaluation) ( ). we evaluated patients: with ppc < ; with ppc < ' ; and patients were classified according to "r" (ppc ' - ), "i" (ppc - ), "f" (> without renal replacement therapy (rrt)), "fo" (oliguria treated by rrt). "fo" subgroup suffered major complications than non-oliguria subgroups (p< ' ). conclusion. . mortality was equal in "i" and "f" patients, but higher than "r" group (p < ' ) and lower than "fo" (p < ' ). . los was similar in "rif". . "fo" los was longer than "rif" los. . "fo" group suffered more severe complications and developed acute renal failure as a part of multi-organ dysfunction syndrome (mods), which needed multiple organ support therapy (most). standard hemofiltration is reported to improve hemodynamics and survival in animal models of septic or endotoxic shock. in humans, despite the lack of convincing data, hemofiltration is thought to be the gold standard to treat acute renal failure (arf) in case of septic shock. we compared survival of septic arf treated with ihd or continuous veno-venous hemodiafiltration (cvvhdf) in the prospective randomised hemodiafe study. we performed post-hoc analysis of data from a prospective, multicenter ( centers) randomised study. patients with arf (urea > mmol/l or serum creatinine > micromol/l or oliguria) associated with mods (lod > ) and needing renal replacement therapy were enrolled. they were randomised to receive ihd or cvvhdf performed with the same membrane (polyacrylonitrile, an ) and a bicarbonate based buffer. guidelines to improve hemodynamic tolerance and efficiency were provided. primary endpoint was -day survival evaluated in an intention-to-treat analysis. septic arf was defined if any sepsis was diagnosed before the occurrence of arf. data are presented as mean±sem among the patients enrolled in hemodiafe, the overall septic population consisted of pts ( ± y.o., m /f , saps ii ± , lod score . ± . ) randomised in the ihd (n= ) or in the cvvhdf group (n= ). eighty-nine percent of patients had septic shock and % were under mechanical ventilation. mean serum urea and mean serum creatinine were respectively . ± mmol/l and ± micromol/l just before the first session. the -day survival in the whole population of the study was % with no significant difference between the two groups (respectively , % and , % in cvvhdf and ihd). survival was significantly lower in septic patients compared to non septic ( , % versus , % p = , ). in septic patients, we found no significant difference in survival between the two treatment groups (respectively , % versus , % in cvvhdf and ihd p = , ). standard cvvhdf does not offer any survival benefit compared to ihd to treat septic arf associated with mods. methods for evaluation of glomerular filtration rate -gfr-( -hours creatinine clearance - hcrcl-or cockcroft-gault formula -cg-) are not well suited for critically ill patients: hcrcl requires a steady state and cg has not been completely validated. shorter time crcl can be used but this method has not been evaluated in unstable patients. we intend to demonstrate that hours crcl ( hcrcl) is similar to hcrcl even in unstable patients prospective study on adult icu patients. we calculate hcrcl, hcrcl and cg estimate. hcrcl was measured at the beginning of the hcrcl interval. age, sex, weight and diagnosis were recorded and for the hours period registered sofa, nutrition, diuretics, nephrotoxics, hypotension or hypoxemia, use of vasopressors and regularity of urine flow. we defined groups: patients recently admitted (less than hours) and in stable condition and expected stable renal function. statistical analysis: paired t-test, pearson correlation coefficient and partial correlation coefficients results. patients, ( . %) on admission and ( . %) in stable condition. in cases ( . %) hcrcl was lost and in ( . %) hcrcl because methodological problems. patients completed the protocol ( stable and on admission) and were included for analysis. no differences were detected in both groups. mean hcrcl was . ± . and hcrcl . ± . ml/min with a mean difference of . ± . (p . ). hcrcl correlated well with hcrcl (coefficient . , p< . ) and less well with cg formula (coefficient . , p< . ). these coefficients were not affected by group of patient, antecedents, sex, age, sofa score, and use of diuretics, nutrition or nephrotoxic drugs, hypotensive episodes, hypoxemia, use of vasopressors and irregular urine flow. we observed less aggregation for values in the high range of clearance; analysing only patients with crcl below (n= ) the correlation was even higher ( . , p< . )conclusion. hclcr correlates well with hcrcl, is easier to obtain, is most reproducible and eliminates unnecessary delays and methodological problems complicating hcrcl. hcrcl can be a good estimate of gfr in icu, even in unstable patients key: cord- -l n is authors: nan title: poster sessions - date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: l n is nan total protein concentration in bal increased significantly and led to peak at ± mg/ml hour after intubations . mucin concentration was highest at hour after ventilation ( . ± . mg/ml). bal sp-a concentration ratio increased about times after hour ventilation. compare to mg/ml total protein, the ratio was . ± . in hour later, and . ± . in hours after ventilation.the change of bal wbc level led to peak in after hour ventilation, but blood wbc level led to peak in hours later. for elastase level both peak were hours later in bal and blood.in the caller components of bal, the neutrophyl cells were dominant in hour after intubation, but hours after ventilation, mast cells with phagocyted mucine and dusts were dominant. just introduction. coronary disease is prevalent in diabetic patients resulting in a frequency of invasive cardiac procedures four times that of non-diabetics. after cardiac surgery diabetics have twice the mortality and morbidity in early and late phases after operation. the reasons for this increased risk are poorly understood. diabetics exhibit complex abnormalities of lung structure and of the control of the cardiorespiratory system. these include pulmonary micro-vascular disease, autonomic neuropathy associated with an increased cardiovascular instability, an increased incidence of central and obstructive sleep apnoea and a reduced response to hypercapnia. this study was undertaken to determine whether at risk diabetic patients could be identified pre-operatively. methods. patients awaiting urgent cardiac surgical re-vascularisation were studied with measurement of: spirometry; percentage increase in transfer factor from sitting to lying position (tf) as an indicator of micro-vascular lung disease; overnight oximetry on air; and hour holter monitoring at present arf is one of the most spread and serious complication of postoperation period. practically the experience of carring nimv on patients with arf on early stadies of mosf is absent. until now, the criteria of uneffectiveness of nimv and indications for cessation of mask ventilation and moving of patients to mechanical ventilation are not determined. methods. there were included patients with ali in the examination. the cause of this condition was the mosf, developed in postoperative period. diagnosis of ali/ards was stated on the criteria adopted the american european consensus conference on ards ( ). presence of organs failure was determined on multiple organ dysfunction score (table ) . nimv was carried out by seances from to hours. average duration of nimv consisted . ± . hours. results. improvement of gases change was determined on patients ( %) out of . though patients with mosf were reintubated, out of which patients ( %) died lately as the result of mosf progressing. the condition of gases changing functions before intubation is one of the determining factors of prognosis. the patients reintubated under satisfactory indices of gase blood composition and early symptoms of mosf survived. patients, who were reintubated on decreased indices of arterial oxygenation under mosf progressing died in % cases ( nimv is effective method in complex therapy of arf, developing in postoperative period after cardiac surgery, that leads to significant improvement of lungs biomechanics and gases change function. progressing of mosf and storage disturbance of lung oxygenation is absolute indication for intubation and applications of special regimes of mechanical ventilation. references. . bernard gr, artigas a, brigham kl. am j respir crit care med - : : introduction. several bioimpedance cardiac output systems have been developed in the past in order to measure cardiac output in a wide variety of clinical situations. however, open thorax surgery negatively influences the accuracy of the measurement of thoracic electrical bioimpedance cardiac output (teb-co) ( ). the purpose of the present study was to evaluate the performance of a new bioimpedance cardiograph hl- (vrije universiteit medical centre amsterdam and hemologic amersfoort, the netherlands), using a new algorithm and a new electrode configuration, during open and closed chest in cabg patients, comparing teb-co with transcardiopulmonary thermodilution (tcpco). methods. after hospital ethics committee approval and written informed consent, fourteen patients with preserved lv-function at cineangiography or echocardiography, scheduled for coronary artery bypass grafting were included. for the teb system two current injecting electrodes were placed on the forehead and the left thigh respectively and two voltage sensing electrodes were used: one above the left clavicle at the base of the neck and the other at the level of the xyphoid in the left midaxillary line. for tcpco, the picco-system (pulsion, munich, germany) was used. hemodynamic measurements were recorded at three time points: t before the operation, t after weaning from bypass before sternal closure and t after sternal closure. teb-co and tcpco data were compared with pearson's r correlation coeficient. p< . was considered significant. bland-altman analysis ( ) with bias and precision was carried out at each of the three time points. results. ten males and females with age ± yr, body weight ± kg and height ± cm were included. a total of matched data pairs were available for analysis. table shows the results of correlation, bias and precision of the measurements at the three different time points. teb consistently underestimated tcpco. at all time points, there was a good correlation between both techniques. introduction. isoflurane sedation of icu patients has previously been shown to be useful but has not come into wide clinical use for a number of reasons.a new device(the anesthetic conserving device,"acd") enables easy and safe administration of isoflurane in the icu setting.we conducted a randomised, controlled study to evaluate efficacy of sedation and environmental safety during administration of isoflurane with the acd. the acd is a modified heat and moisture exchanger connected to the breathing circuit at the endotracheal tube.isoflurane is administered via a syringe pump to a vaporiser rod in the acd.due to the physical properties of the acd most of the exhaled isoflurane is returned to the patient. mechanically ventilated patients were randomised to receive isoflurane via the acd. control patients received midazolam intravenously. all patients received morphine analgesia. quality of sedation was assessed hourly in all patients."adequate sedation" was pre-defined as a set interval on the bloomsbury sedation scale. additionally, the patient's nurse determined if sedation over the previous hour in general had been adequate or not. time from discontinuation of the sedative drug until the patient followed verbal command and to extubation was compared between groups. in the isoflurane group a gas evacuation system was used during isoflurane administration. athmospheric concentration of isoflurane was measured at . m from the acd. results. in the isoflurane group patients were adequately sedated by the bloomsbury scale for ± % of the study period, compared to ± % in the control group.nurse satisfaction in the isoflurane group was % of time and % of time in the control group.mean time to extubation after cessation of sedative administration was min in the isoflurane group and min in the control group, mean time to patient cooperation was min in the isoflurane group, and min in the control group. no significant hemodynamic changes were noted at initiation of the sedation in either of the groups. no serious complications related to sedation were noted in either group.opioid requirements in the isoflurane group were lower, with a mean rate of . . mg/hr, compared with a mean rate of . . mg/hr in the control group.mean isoflurane infusion rate was . ml/hr, with mean end-tidal isoflurane concentrations of . % ( . - . %).environmental levels of isoflurane were generally low,with a mean of . ± . ppm, well below the recommended long-term exposure limit of ppm. brief peaks (< min) between and ppm were noted during endotracheal suctioning, etc on an average of . times/hour of exposure. conclusion. isoflurane administered via the acd for sedation of icu patients is environmentally safe, requires small volumes of isoflurane and may provide better quality of sedation than midazolam. it appears to be more titratable with a shorter time from adequate sedation to extubation and ability to cooperate. references. millane ta, bennett ed,grounds rm,anaesthesia ; : - .spencer em,willatts sm,intensive care brudney c. s. , gosling p. , manji m. anaesthesia, biochemistry, anaesthesia, university of birmingham, birmingham, united kingdom increased capillary permeability has been implicated in the pathogenesis of ards and organ failures. surgery and ischaemia-reperfusion injury are both associated with stimulation of the acute inflammatory response, an early feature of which is an increase in systemic capillary permeability. the kidneys amplify small changes in systemic capillary permeability ( ).the aim of this study was to explore any association between acr during and after cardiopulmonary bypass (cpb) and subsequent pulmonary and renal function. methods. forty patients ( female) mean (range) age . ( - ) yrs undergoing coronary artery bypass grafting were enrolled. patients with severely impaired left ventricular function (< % ef) were excluded. ten ml of urine was collected at intervals from the start of surgery until hours post cpb. microalbuminuria was measured by automated immunoturbidimetry and expressed as the albumin creatinine ratio (acr: ref. range < . mg/mmol). acr was compared with po /fio ratio, hours on ippv, renal function and duration of inotropic support, using spearman's rank correlation procedure. results. two patients were excluded (death at hours and acute renal failure post cpb). the median (range) duration of ippv was ( - ) hours. patients required inotropic support for median (range) ( - ) hours. median (range) acr increased during surgery and was maximal minutes post cpb. (table) two hour acr was inversely correlated with the mean po /fio ratio up to hours (rs = - . p = . ). two and hour acrs were both positively associated with duration of ippv (rs = . p = . and . p < . respectively). acr at and hours were associated with serum creatinine hours post cpb, (rs = . p = . , rs = . p = . respectively). acr at , and hours post cpb were associated with serum creatinine hours post cpb (rs = . p = . , rs = . p = . and rs = . p = . respectively). there was no significant association between duration of inotropic support and acr at any time point up to hours. conclusion. cpb leads to a perioperative microvascular insult, causing increased capillary permeability which influences later pulmonary and renal function. these rapid changes in microvascular permeability can be monitored as the acr, and in the patient group studied, the magnitude of the acr as early as hrs post cpb is associated with later organ function. acr may provide a tool allowing early identification of patients at risk of developing organ dysfunction, who may benefit from early intervention aimed at modifying the inflammatory response. acute lung injury (ali) is a major complication of gram-negative bacterial sepsis. to date, bacterial lipopolysaccharide has been held responsible for triggering ali ( ). whether additional bacterial toxins play a role in the development of acute pulmonary inflammation during gram-negative sepsis remains an unresolved issue. flagellin, a principal component of bacterial flagella, has been recently shown to elicit immune responses via activation of the toll-like receptor ( ). we have newly found that flagellin induces an expression of icam- and a massive production of il- by human lung epithelial cells. in mice, flagellin produces a severe acute lung inflammation with local release of pro-inflammatory cytokines, accumulation of inflammatory cells and increased pulmonary permeability that was more pronounced than following endotoxin ( ). the purpose of the present investigation was to evaluate the influence of flagellin on lung fluid filtration in rats. wistar rats ( - g) were exposed either to intravenous injection of flagellin . - mg/kg or corresponding volume of normal saline (controls). after - h, the rats were anesthetized and the lungs were isolated. the isolated lungs were ventilated under a normoxic condition and perfused with homologous blood ( ºc) at a constant flow for h or until development of irreversible edema. airway pressure, pulmonary arterial pressure, pulmonary vascular resistance, and changes in the lung weight were assessed. the increments in outflow pressure of . kpa for min were used to determine the fluid filtration rate and filtration coefficient in the lungs every min ( ). flagellin induced a dose-and time-dependent increment in the lung fluid filtration rate. in parallel, flagellin markedly increased airway pressure, pulmonary arterial pressure, pulmonary vascular resistance, and filtration coefficient. in contrast to the control lungs, all the lung preparations from flagellin-treated animals developed irreversible edema within the first two hours of perfusion. in isolated blood-perfused rat lungs, flagellin enhances fluid filtration, most likely, through elevation both of pulmonary microvascular permeability and hydrostatic pressure. the present study provides further evidence that flagellin may contribute to the development of sepsis-associated ali. . whether protein c conversely affects eosinophil function has not yet been reported. we investigated the effects of protein c and activated protein c on chemotaxis of eosinophils. possible involvement of endothelial protein c receptor (epcr) in the regulation was studied by using specific epcr antibodies. for preparation of eosinophils we used macs cd+ microbeads according to the manufactor's protocol. chemotaxis assays were performed using a -well boyden microchemotaxis chamber in which a -micrometer pore sized cellulose nitrate filter separates the upper and the lower chamber. eosinophils were pretreated by various protein c preparations with or without epcr antibodies, followed by washing and assessment of their migratory responses toward eotaxin. protein c and activated protein c exerted no significant chemotactic effect on eosinophils. however, eosinophils pretreated with protein c or activated protein c showed a sigificantly reduced response to the specific chemoattractant, eotaxin. moreover, this effects of protein c and activated protein c were inhibited using an antibody against epcr. conclusion. protein c as well as activated protein c inhibit the chemotactic effect of eotaxin on eosinophils via mechanisms involving epcr. this result indicates that protein c as well as activated protein c may decrease the number of eosinophils in tissue and thereby inhibiting inflammation and coagulation. deleterious effect of severe sepsis may be related to an oxidative stress, particularly related to peroxynitrite. selenium (se) toxicity is supposed to be related to oxidative stress through reaction with thiols. we perform a study to compare these toxicities. methods. wistar rats were studied. after day quarantine lipopolysaccharide (lps) or se was administered intraperitoneally in ml saline water. lps and se were administered in groups of rats with increasing doses from to mg/kg for lps, and from . to . mg/kg for se. mortality was observed at hours. animals were sacrificed under halothane. blood samples were taken in surviving rats of each group. nitric oxide (no) and nitrotyrosine (nit), a marker of oxidative stress especially related to peroxynitrite, were measured by elisa techniques, and plasma se concentration using atomic flame absorption. results. septic rats were rapidly sick. they rolled up into a ball. their fur was dull, and stood on end. they were asthenic and had diarrhea. at autopsy, intestinal abnormalities, and in some rats echymotics dots and hemolytic plasma were observed. rats were dehydrated. se rats developed an encephalopathy the first day and later recovered. se rats were lively, and seemed to required higher level of halothane for induction. ( )however the mechanisms responsible for this alteration remains under investigation. depressed micochondial respiration has also been found in different tissues during sepsis. ( ) the objective of this work was to study diaphragmatic function in rats after peritoneal sepsis and to correlate these findings with diaphragmatic mitocondrial respiration. cecal ligation and perforation was done under general anesthesia in wistar rats (septic group, n= ) . after hours the animals were monitored for arterial blood gases, systemic hemodynamia and body temperature. then, they were sacrified and the diaphragm force-frequency curves were obtained in vitro before and after fatigue. contraction time and relaxation time were also measured. mitochondrias were isolated from the diaphragm and oxygen consumption and other respiratory indexes were studied in septic animals. the results were compared to sham operated animals (control group, n= ). the septic group showed significantly lower values of aortic blood flow, arterial oxygen partial pressure, body temperature and arterial bicarbonate (p< . ) when compared to the control group. the forces measured at the different frequencies of stimulation were lower in the septic diaphragms both before and after fatigue when compared to controls (p< . ). mitochondrial respiration evaluated by oxygen consumption and rcr indexes was found decreased in the septic animals (p< . ). diaphragmatic contractile failure along with hemodynamic, respiratory and metabolic dysfunctions was found in peritoneal sepsis in rats. diaphragmatic dysfunction could be explained by mitochondrial damage during sepsis. we speculate that mitochondrial injury and dysfunction could be related to oxidative stress in this animal model. introduction. protein c is activated by thrombin bound to thrombomodulin and this effect is enhanced in the presence of the endothelial protein c receptor (epcr). in vivo and in vitro studies have revealed that components of this pathway may also inhibit inflammatory responses. protein c was able to inhibit leukocyte adhesion to vascular endothelial cells and to reduce neutrophil accumulation in rat lungs [ ] . protein c inhibits proinflammatory cytokine release in monocytes [ ] that were shown to express epcr [ ] . soluble epcr binds to proteinase- and cd b/cd of activated neutrophils [ ] , which were previously shown to synthesize thrombomodulin but not to promote thrombin-dependent protein c activation [ ] . if protein c directly affects neutrophil functions has not jet been sufficiently demonstrated. we investigated the in vitro effects of protein c and activated protein c on chemotaxis of isolated human neutrophils and explored wether epcr may be involved. neutrophils were obtained from forearm venous blood by standard methods. leukocyte migration toward gradients of soluble attractants into cellulose nitrate micropore filters was measured using a -well microchemotaxis chamber. cells were either directly exposed to gradients of protein c or were pretreated with protein c followed by washing; then chemotaxis toward typical attractants was tested. neither protein c nor activated protein c induce chemotaxis of neutrophils. both inhibit neutrophil chemotaxis toward interleukin- , fmlp and c a and there is no significant difference in the effects of these two substances. a blocking antibody against the epcr is able to diminish the effects of protein c and activated protein c. conclusion. protein c as well as activated protein c is able to inhibit neutrophil chemotaxis. this indicates that an activation of protein c is not necessary for effects on neutrophils to occur or that neutrophils are able to activate protein c followed by migration. the reduction of the protein c effects by an antibody against the endothelial protein c receptor suggests that neutrophils express epcr capable to signal anti-migratory stimuli. during sepsis increased vascular permeability results in fluid extravasation and edema. lymphatics contribute in draining interstitial fluid from the abdomen to central circulation, but several factors (outflow venous pressure, pattern of mechanical ventilation) can act upon flow in the thoracic duct ( , ). we have tested if lymph flow is affected by endotoxin infusion under different ventilatory conditions. methods. anesthetized pigs ( . ± kg) were studied. septic damage was induced by continuous infusion of endotoxin (lipopolysaccharide e.coli, lps). abdominal lymph flow was continuously recorded by an ultrasound flow probe positioned on the thoracic duct at the diaphragm level; hemodynamics, respiratory system data, bga and intra-abdominal pressure (iap) were registered. during the first . hours of lps infusion animals were ventilated in volume controlled mode tv - ml/kg, rr bpm, peep , fio . ; during the next hours animals were divided in group (control, peep ), (peep ) and (spontaneous breathing, cpap peep ). during lps infusion lymph flow significantly increased from . to . ml/min (p< . ), cardiac output and compliance decreased from . to . l/min * and to ml/cmh o * respectively, while mean pulmonary artery pressure and iap increased from to mmhg * and to cmh o * (* p< . ). in all the pigs a positive correlation was found between iap and lymph flow (mean pearson´s coefficient . ). no correlation was found between lymph flow and central venous pressure and airway pressure (mean pearson´s coefficient . and . ). in group and lymph flow changes averaged - % and + % (versus value before randomization). cpap increased lymph flow by %. lymph flow from the abdomen increases during lps infusion: role of lymphatics in draining abdominal fluid could thus be significant during sepsis (~ ml/h are drained). these preliminary results suggest that spontaneous breathing could improve lymphatic flow from the abdomen. despite the following rise in intra-thoracic pressure, increase of peep is not associated with lymph flow reduction. animals in peep group have however shown different patterns of response, and more data are needed to clarify this aspect. introduction. : ischemia/reperfusion or sepsis is initially responsible of an acute activation of pro-inflammatory cytokines (e.g. tumour necrosis factor (tnf-)). it is followed by a rise of anti-inflammatory cytokines (e.g. interleukin- (il- )). in human umbilical vein endothelial cell (huvec) tnf-induces a mitochondrial release of reactive oxygen species (ros) in a dosedependent manner. the signalisation pathway which links tnf-at mitochondria involves ceramide pathway ( ).the goal of our study is to evaluate the action of il- on the oxidative stress induced by tnf-in huvec and to define the mechanism of this interaction. huvec were grown on plastic cover slides. at confluence they were placed in a perfusion chamber under a microscope equipped with a digital camera connected to acquisition software. cells were perfused with krebs solution containing two fluorescent probes: dichlorodihydrofluorescein diacetate (dcfh) to study the release of reactive oxygen species (ros) and propidium iodide (pi) to study cell mortality. three cell groups were studied: a reference group, a tnf-group where, after one hour stabilisation, tnf-was added ( ng/ml) in perfusion medium during one hour, · a group tnf-+ il- where il- was added to perfusion medium minutes before tnf-. variations in fluorescence were recorded each minutes for dcfh and each one hour for pi. for a non lethal concentration (pi remaining unchanged), il- reduces significantly the ros production induced by tnf-(anova for repeated measures). interleukin- has an inhibitory effect on the release of ros induced by tnfin huvec. this effect could be the result of an interaction with acid sphingomyelinase. ( ) am. j. cell. molecular biol. : - , . the immunosuppresive drug cyclosporine a (csa) is an inhibitor of mitochondrial permeability transition (mpt) which could afford protection against cell death [ ] .to test whether csa protects against endotoxin-induced myocardial apoptosis [ ], we produced i-annexin v [ ], a marker of apoptotic cells, and measured its myocardial uptake during endotoxaemia in csa-treated rats. the specificity of the signal has been previously verified with caspase inhibitors and i-human serum albumin. methods. ) i-annexin v was produced with a radiochemical purity higher than % as confirmed by hplc. ) young male sprague-dawley rats were either given iv : saline ( . ml) : control group, n= , or lipopolysaccharide (lps) from e coli ( mg/kg) ± csa ( mg/kg): lps group, n= and lps+csa group, n= . h later, all animals were given i-annexin v ( mbq, mg protein). after h, hearts were harvested and divided into apex, septum, right and left ventricle (rv, lv) for determination of i-annexin v myocardial uptake with a lkb gamma counter. results were expressed as a mean percentage ± sd of the injected dose per gram of tissue (%id/g). statistical analysis was performed by mann-withney test; a p value < . was considered as significant (*). i-annexin v myocardial uptake is significantly increased in the lps group compared to control group; there is no significant difference between the septic groups . control lps lps+csa mean + -sd . + - . . + - . * . + - . ns mortality % % % i-annexin v myocardial uptake conclusion. our results confirm that endotoxaemia is associated with significant myocardial apoptosis but fail to demonstrate that csa can reduce the cell death signal detected by i-annexin v . in spite of its action on mpt and its myocardial dysfunction reducing effect in septic rats [ ] , csa provides no myocardial protection in this model . a reducing effect of csa on endotoxin-induced mortality is not excluded but remains to be demonstrated. further investigations are needed to clarify the effect of csa on the inflammatory responses due to endotoxaemia. sepsis induced alterations in hemostasis with dysbalances in fibrinolysis may lead to capillary obstruction due to fibrin deposition. the aim was therefore to investigate regional net fluxes of the fibrinolytic enzyme tissue-type plasminogen activator, tpa, and its main inhibitor plasminogen activator inhibitor type- , pai- , in response to endotoxemia. methods. anesthetized pigs (n= ) were instrumented for registration of cardiac output (co, thermodilution) and portal (qpv), hepatic (qha) and renal (qra) blood flows (ultrasound flowmetry, transonic). blood samples were collected from the aorta and pulmonary artery as well as the portal, hepatic and renal veins. after baseline registrations, all animals were subjected to an e. coli endotoxin infusion for min, followed by a volume/norepinephrine resuscitation for min targeting baseline co levels. plasma concentrations of both total and active tpa and pai- were determined as described [ , ] and net organ fluxes (ng/min) were calculated based on in-/outflowing plasma concentrations and local plasma flow [ ]. results. endotoxemia induced a low co state and a decrease in qpv. total liver blood flow was preserved due to a concomitant increase in qha. during resuscitation co and qpv were restored to baseline values. systemic plasma levels of total tpa increased over time during endotoxemia, peaking at min, whereupon a decline occurred. however, plasma levels of total tpa had not returned to baseline values at the end of the registration period ( min). changes in systemic levels of active tpa mirrored changes in total tpa. a marked ( -fold) increase in mesenteric net release of total tpa was observed. this response was paralleled by a pronounced increase in hepatic uptake of tpa. pai- described a different response to endotoxemia. by the end of the experiment plasma levels of both active and total pai- increased. in contrast, no significant net fluxes of pai- were observed across any of the investigated vascular beds except for the hepatic vascular bed, where a net release of both total and active pai- occurred at approximately min. hepatic pai- release rates then increased progressively. conclusion. endotoxemia induced a marked increase in mesenteric release of tpa which however was not entirely responsible for the increase in systemic plasma level of tpa. the results indicate that this profribrinolytic response at later stages are counteracted by increased plasma levels of pai- and this increase is mainly derived from the hepatic vascular bed. thus, patients with altered regional endothelial functions or liver capacity prior to a septic challenge can be expected to demonstrate varying susceptibility to thrombotic events. antithrombin has been shown to reduce mesenteric venular leukocyte interactions and intestine injury in a leukocyte-dependent model of endotoxemia ( ). however, endothelial damage during early endotoxemia has been shown to be leukocyte-independent ( ). the role of antithrombin in this setting is still unknown. therefore, it was the aim of the study to investigate the effects of antithrombin on leukocyte-independent endothelial damage. in male wistar rats, microvascular permeability (mp) and leukocyte-endothelialinteraction (leukocyte rolling, lr) were determined in mesenteric postcapillary venules using intravital microscopy at baseline, and min after start of a continuous infusion of endotoxin (etx; mg/kg/hr, e.coli o :b ) (group a, n= ). therefore animals were laparotomized and the mesentery was exposed beneath an in-vivo videomicroscope. mp was measured using fluorescein isothiocyanate (fitc) labelled albumin. leukocyte-endothelial interaction was blocked in all groups by fucoidin ( mg/kg b.w.), a l-selectin-binding carbohydrate, min before laparotomy. animals in group b (n= ) received antithrombin (kybernin®, aventis-behring, germany; ie/kg b.w.) prior to baseline measurement and additionally to the procedure described above. animals in group c (n= ) received equivalent volumes of nacl . % instead of antithrombin and endotoxin. statistical analysis was performed using two-way repeated measures anova followed by the scheffé test. a p-value < . was considered significant. in groups a-c, fucoidin prevented lr during the entire experiment. however, in all groups mp increased significantly, starting at min. animals in group a were characterized by a stronger increase in mp and showed significantly higher values in mp in comparison to groups b and c at min. there were no significant differences in mp between groups b and c. leukocyte-independent endothelial damage during early endotoxemia is attenuated by antithrombin. endothelial damage during early endotoxemia has been shown to be leukocyte-independent ( ). paf (platelet-activating factor)-and serotonin-receptor antagonism has been shown to reduce leukocyte-independent macromolecular leakage significantly ( , ). nevertheless, the exact mechanisms involved in leukocyte-independent endothelial dysfunction are unknown. therefore, it was the aim of the study to investigate the effects of nitric oxide (no) on leukocyte-independent endothelial damage during endotoxemia methods. in male wistar rats, microvascular permeability (mp) and leukocyte rolling (lr) were determined in mesenteric postcapillary venules using intravital microscopy at baseline, and min after start of the experiment. in all groups, leukocyte-endothelial interaction was blocked by fucoidin. rats were randomized into groups, animals each. the experiments were divided into two parts. part i (no-inhibitor): in group a, the mesentery was superfused with a l-name superfusion ( mmol/l) combined with a continuous infusion of endotoxin (etx; mg/kg/hr) after baseline measurement. group b received a l-name superfusion of the mesentery combined with a continuous infusion of saline . %. groups c and d were treated like groups a and b but without l-name. part ii (no-donator): group x received sin- (initial bolus of mg/kg b.w. followed by . mg/kg b.w. after min-measurement) followed by a continuous infusion of endotoxin (etx; mg/kg/hr). group y was treated similar to group c and group z was treated similar to group d. statistical analysis was performed using two-way repeated measures anova followed by the scheffé test. a p-value < . was considered significant. fucoidin prevented leukocyte-endothelial-interaction in all groups. part i: pe increased in all groups, being significant in group d at min (p< . vs. baseline) and being significant in groups a-c starting at min. animals in group d were characterized by a slighter increase in mp and showed significantly lower values in mp in comparison to groups a and b at min, and to groups a-c at min. there were no significant differences in mp between groups a-c at min. part ii: pe increased in all groups being significant in group z at min (p< . vs. baseline) and being significant in groups x and y starting at min. animals in group y were characterized by a stronger increase in mp and showed significantly higher values in mp in comparison to groups x and z at min. there were no significant differences in mp between groups x and z. leukocyte-independent endothelial damage during early endotoxemia is a nitricoxide mediated event. overproduction of nitric oxide (no) is thought to be a principal cause of the hypotension of septic shock. two nitric oxide synthase (nos) enzymes have been described in blood vessels: endothelial nos (enos) and inducible nos (inos). constitutive activity of enos in the endothelium is a major determinant of blood vessel tone in health; however, in experimental sepsis it appears endothelial enos expression is reduced while smooth muscle inos expression is increased ( ). in contrast, another model of human sepsis found an increase in enos but not inos in the vessel wall ( ). to resolve this discrepancy, we studied enos and inos protein concentrations in arterial smooth muscle (asm) from patients with clinical sepsis. asm was isolated from mesenteric vessels from patients undergoing bowel resection for perforated viscus (who in the perioperative period met the accp/sccm criteria for septic shock), and from controls with bowel cancer. after mechanical removal of endothelium and adventitia, the tissue was homogenised in protease inhibitor and frozen until sufficient samples had been accumulated. western blotting was performed under reducing conditions, with membranes incubated in : (inos) or : (enos) primary antibody followed by : peroxidase labelled secondary antibody. protein bands were quantified by computer analysis of the chemiluminescence detection film, then normalised to the protein concentration of the sample prior to dilution. . enos protein was increased in arterial smooth muscle from patients with septic shock (control . . units/mg, septic . . units/mg; n= controls and septics; p = . , student's t test). in contrast, there was no increase in concentration of inos; indeed inos protein was only detectable in asm from control and septic patients. we suggest that overexpression of enos, rather than inos, in the arterial smooth muscle of patients with septic shock may be responsible for the hypotension observed in these patients. introduction. data published in the literature concerning the effect of sepsis on intestinal motility found a reduction as well as a stimulation of intestinal motility . the settings used are mostly in vivo settings, and therefore not usable to investigate intestinal motility independent from circulatory changes. the aim of our study was to evaluate the direct effect of endotoxinemia on guinea-pig small bowel motility in vitro, independent from circulatory changes, and in a second step to evaluate the effect of vasoactive drugs on motility of these septic animals. two groups of guinea-pigs received mg/kg e. coli lps intraperitoneally or hours before the experiments started. in the following hours the animals developed severe symptoms of sepsis. a control group did not receive lps before the experiments started. the small bowel of sacrificed guinea-pigs was excised, cleaned and kept in tyrode's solution. after a resting period segments of cm length were set up in parallel organ bathes containing oxygenated tyrode's solution. peristaltic contractions were elicited by perfusion of the segments with tyrode's solution at a rate of . ml/min, against an aboral resistance of pascal. the intraluminal pressure increased gradually until it reached a pressure threshold (pt) which triggered peristaltic contractions. these contractions were recorded via a pressure transducer at the aboral end of the segments. increasing concentrations of epinephrine, norepinephrine, dopamine, dobutamine, clonidine and dexmedetomidine were cumulatively added to the organ bath at min intervals. each drug was tested on different segments. statistics was performed using ncss for windows, one-way and two-way anova for repeated measures were used, p values < . were considered statistically significant. in the control group all tested vasoactive drugs had a dose-and substance-dependent inhibitory effect on peristalsis. higher concentrations of all tested substances led to a complete block of peristalsis. hours after lps application a pronounced reduction of the inhibitory effects of clonidine, epinephrine, norepinephrine and dopamine were found. the reduced inhibitory effect of dexmedetomidine was not significant. hours after lps application the inhibitory effect was reduced again, but for most substances this reduction was not statistically significant. dobutamine was the only tested substance with a more pronounced effect after hours than after hours. endotoxinemia per se did not affect small bowel motility in vitro. a possible explanation for the controversy to in vivo data demonstrating an inhibitory effect on peristalsis might be that intestinal ischemia is a common event during sepsis, and ischemia in turn might cause paralysis. a described reduced sensitivity of alpha-adrenoceptors during sepsis, or a central effect of lps additionally inhibiting peristalsis ( ), might also be responsible for our findings. high cytokine levels in patients admitted to the emergency department are associated with an increased incidence of sepsis/septic shock. patients with cardiogenic shock (cs) who often develop sepsis during icu-stay,have not been particularly studied. we studied whether plasma levels of cytokines are better predictors of sepsis/septic shock than routinely determined laboratory parameters. il- ,il- and il- plasma levels were determined in pts with cs(cardiac index < . l/min/m²,pcwp > , mean arterial pressure < mmhg or need for vasopressor therapy and signs of organ hypoperfusion) on admission to the icu (median hrs after shock onset). patients who were not surgically treated during icu stay were eligible for the study and evaluated for development of sepsis or septic shock within week after onset of cs. c-reactive protein (crp) levels and white blood cell (wbc)-counts were routinely evaluated once daily in all patients until discharge. data are given as median and interquartile range. all pts with cs were free of demonstrable infection at time of blood sampling. nevertheless % had a crp-level > mg/dl at time of enrollment. pts ( %) developed septic shock within week after onset of cs. pneumonia ( %, n= ) and catheter related infections ( %, n= ) were the leading causes of sepsis. sepsis after cs was not associated with a higher mortality rate ( % vs. %, p=ns) and sirs that was encountered in % of cs pts at the time of blood sampling did not predispose for development of sepsis ( vs. %, p=ns).crp levels,and wbc-counts as well as il- , il- and il- plasma levels on admission to the icu did not differ significantly between cs-pts who developed sepsis and cs-patients without sepsis ( in pts who survived for more than hrs (n= ) the absolute crp levels hrs after admission (crp hrs) and the increase in crp levels over hrs following icu admission (dcrp) were significantly higher in pts who developed sepsis as compared to pts without sepsis. (crp hrs: . mg/dl [ - . ] vs. . [ . - . ], p= . ; dcrp: . mg/dl [ . - . ] vs. . [ . - . ], p= . ). a dcrp > . mg/dl in hrs was more sensitive than an absolute crp level > mg/dl hrs after icu-admission for predicting sepsis ( vs. %), but both parameters had equal specificity ( %). conclusion. although many pts with cs exhibit elevated crp levels the increase in crp over hrs (dcrp hrs)is a valuable parameter to identify pts at risk for sepsis. single-point determination of cytokines on admission to the icu is not superior to follow-up determinations of crp for predicting sepsis. mitochondrial dysfunction may be implicated in sepsis-induced multi-organ failure. glycolytically-generated atp may thus be an important alternative energy source if aerobic respiration is compromised. little is known about glycolysis during sepsis, though both up-and down-regulation are reported , . we therefore examined changes in glycolytic activity in a longterm sepsis model. an instrumented, fluid-resuscitated, faecal peritonitis rat model was used. this has a -hour mortality rate of approx. %. septic (n= ) and sham (n= ) rats were sacrificed at various time points ( , , , h) and liver samples harvested and assayed for maximal activity of the rate-limiting glycolytic enzymes, hexokinase (hk), phosphofructokinase (pfk) pyruvate kinase (pk). we demonstrate an initial rise (albeit non-significant) then significant downregulation in two rate-limiting glycolytic enzymes during sepsis. the lack of difference at h may reflect prior demise of the severely ill animals. whether the degree of glycolytic down-regulation is related to subsequent death requires further study. we presume the interesting finding of upregulation seen in the sham animals to be a response to surgery and/or fluid loading. recent studies have shown that low-dose vasopressin infusion or terlipressin bolus (tp, its long acting analogue; o'brien, ) restores blood pressure and reduces norepinephrine (ne) requirements in septic shock. however they have no effect upon blood pressure in non-septic patients. exact mechanisms underlying this hyperreactive effect in sepsis patients remain unknown. we chose to investigate this using our established in vivo and in vitro models of endotoxic shock in rats. in vivo -spontaneously breathing anaesthetised male wistar rats was given either saline (sham) or endotoxin (lps) (klebsiella mg kg - ) over mins and then fluid resuscitated with colloid mls kg - hr - for mins. at mins either a bolus of tp ( . mg kg - ) or a bolus and infusion of ne ( . mg kg- and mg kg hr - ) was administered. measurement of flow and pressure (mean arterial pressure -map) were made from appropriately sited probes and transducers. in vitro -rings of rat mesenteric artery (rma) were harvested, cleaned and incubated for h with or without mg ml - lps (s. typhosa). they were then mounted in organ baths for measurement of isometric tension. cumulative concentration-response curves to phenylephrine (pe: - to - m) or vasopressin (vp: - to - m) were then constructed. statistical analysis was by anova. results. in vivo -while ne had a significantly greater effect upon map in shams compared with lps rats (p= . ), tp caused a greater increase in lps animals than shams. a bolus of tp lasted approximately mins. in vitro -lps significantly depressed contractile responses to pe compared to control tissues (max contraction controls - . ± . g, lps - . ± . g, p< . , anova). however there was virtually no contractile response to vp even in control tissues after h incubation. the cytokine cascade activated in response to injury consists of a complex biochemical network with diverse effects on the injured host. leukocyte activation after trauma is essential for inflammation. it is a multistep process in which chemokine -interleukin (il)- has pivotal role. in two-hit hypothesis, sepsis represent a second insult to a previously injured and primed host, converting a low-grade or regulated host response into an accelerated or dysregulated host response, triggering new or progressive organ dysfunction ( ). aim of this study was to assess pro-inflammatory response to trauma with or without sepsis as a second insult. twenty five patients with severe trauma (explosive and sclopetarious) who developed sepsis and patients with same kind of severe trauma without sepsis were enrolled in this study. in the trauma+sepsis group patients developed multiple organ dysfunction syndrome (mods) and died. in trauma group developed mods and died. blood was drown on the first, third and fifth day of trauma. concentrations of il- , il- , tumor necrosis factor (tnf)alpha and interferon (ifn)-gamma were determined in plasma using elisa assays. when compared trauma+sepsis group with trauma group we found statistically highly significant difference (p< . ) in il- and ifn-gamma and statistically significant difference (p< . ) in tnf-alpha concentrations; mean values of il- were -fold higher, ifn-gamma -fold higher and tnf-alpha -fold higher in patients with trauma with sepsis. il- was not statistically different (p> . ) between two groups. when compared mods group with group without mods, we found statistically highly significant difference (p< . ) in il- and tnfalpha concentrations; mean values of il- were -fold higher and tnf-alpha . -fold higher in patients with mods; il- and ifn-gamma were not statistically different (p> . ) between two groups. when compared non-survivors with survivors, we found statistically highly significant difference (p< . ) in il- and tnf-alpha and statistically significant difference (p< . ) in il- concentrations; mean values of il- were . -fold higher in non-survivors, mean values of tnfalpha were . -fold higher in survivors, il- was also higher in survivors. ifn-gamma was not statistically different (p> . ) between two groups. there is augmented pro-inflammatory response after trauma with secondary sepsis. high concentrations of il- and tnf-alpha indicated higher severity (mods). but, fatal outcome was predicted with high concentrations of il- only; survivors had higher concentrations of tnf-alpha and il- . therefore, pro-inflammatory response was partly beneficial and partly detrimental to the host. in patients with shock hypoxia is considered to be the most important cause of organ failure and death. the goal of treatment therefore is to restore tissue oxygen delivery (tdo ). due to impaired oxygen extraction in distributive (septic shock) the relation between tdo and tissue oxygenation is less conclusive. direct measurement of tissue oxygen pressure (pto ) could be of great importance in gaining a better insight in tissue oxygenation in these patients. previously published data concerning pto in patients with sepsis/septic shock are contradictory ( , ). furthermore the techniques used were not easily applicable at the bedside. in a prospective observational study we performed bedside pto measurements in patients with sepsis/septic shock to gain insight in pto values and their dynamic changes related to the course of the illness, as well as investigating the practical applicability of tissue oxygen measurement in the icu setting. pto was measured continuously during the course of the illness using polarographic clark-type o electrodes (licox catheter measurement system, gms), which were placed subcutaneous in the upper arm. disease progression over time was expressed as the daily calculated sequential organ failure assessment (sofa) score. results. five men and women with septic shock n= or sepsis n= were included. the median (range) age was years ( - ), median apache-score on the day of admission was ( - ), median duration of pto measurement per patient was , days ( - ). in none of the patients technical problems were encountered during the pto measurements. the first day of measurement the median pto of the eight patients was ( - ) mmhg. in the six surviving patients the sofa score decreased over time and this was associated with a concomitant decrease in pto to a median of ( - ) mm hg. in the nonsurvivors an increasing sofa score was associated with an increase in the mean pto to mmhg on the day of death. in seven patients linear regression analysis showed a positive correlation between the daily sofa scores and the daily mean pto : r= . , . , . , . , . , . , . . in one patient no correlation was found. conclusion. bedside pto measurements in the icu using the licox measurement system are easily performed. pto in septic patients is variable but changes with the clinical course reflected by the sofa score: clinical improvement was associated with a decrease in pto while deterioration was associated with an increase of pto . these findings suggest that in patients with septic shock decreased oxygen utilisation may play a more important role than tissue hypoxia as such. to precise the diagnostic value of macrophage migration inhibitory factor (mif) as a marker of severity in patients with sepsis and to determine relations between mif and interleukin (il- ), we conduced a prospective, observational, cohort study, in two general intensive care units. we analyzed patients with septic shock, patients with sepsis, and healthy volunteers. the median mif serum level was significantly higher in septic shock patients ( . ng/ml, range . - . ) than in sepsis patients ( . ng/ml, range . - . ) or in healthy volunteers ( . ng/ml, range . - . ). there was a direct correlation between mif and il- concentrations (r= . , p< . ). the area under the curve (auc) of the receiver-operating characteristic (roc) for prediction of septic shock was . (p< . ) for mif and . (p< . ) for il- . the auc under the roc curve for prediction mortality was . (p< . ) for mif and . (p< . ) for il- . in this trial we found significant elevated serum levels of mif in patients with septic shock and sepsis. moreover, mif levels were discriminative for septic shock and mortality, and had a direct correlation with levels of il- with a similar diagnostic accuracy. in conclusion, mif appear to be a promissory marker of severity in sepsis. high density lipoprotein (hdl) modulates the inflammatory response to injury and infection via several pathways. hdl also directly binds and neutralises lps. administration of reconstituted hdl reduces cytokine release and attenuates shock in experimental endotoxaemia ( ). the hdl associated enzymes paraoxonase (pon) and lecithin cholesterol acyl transferase (lcat), destroy oxidised lipids that induce inflammatory changes in vascular endothelium ( ). incorporation of serum amyloid a (saa), an acute phase protein, into the hdl particle during the inflammatory response, may displace these protective enzymes producing a particle with proinflammatory properties ( ). alterations in hdl composition may, therefore, be implicated in dysregulation of the inflammatory response and could influence outcome from septic shock. methods. patients with septic shock, not given tpn or propofol, were recruited. apache ii scores and icu mortality were recorded. plasma and serum samples were taken within hours of the onset of shock. hdl cholesterol was measured by microenzymatic colorimetric assay. apolipoprotein ai (apo ai) was quantified by liquid phase radioimmunoassay. pon activity was determined by measuring the rate of paraoxon hydrolysis and described as percent of a control serum pool. lcat activity was quantified by measuring the esterification rate of c labelled cholesterol. saa was measured by elisa. results were compared with those of a pool of healthy volunteers and between survivors and nonsurvivors. (mann whitney u test). results. patients were recruited. there were survivors (s) and nonsurvivors (ns). pon activity was significantly higher in s than ns: . ( . - . ) vs. . ( . - . ), p< . . saa concentration was significantly higher in s than ns: ( . - ) severe trauma and sepsis are the major sources of morbidity and mortality despite the rapid development of intensive therapy. studies have indicated that there are marked alterations in immune response in patients exposed to major trauma or prolonged surgical procedures, including altered pro-and anti-inflammatory mediator/cytokine release ( ). traumatic injury results in profound immunosuppression which predisposes the patients to sepsis and/or multiple organ dysfunction syndrome (mods). aim of this study was to assess the prognostic value of anti-inflammatory cytokines: interleukin (il)- receptor antagonist (il- ra) , il- , il- and transforming growth factor (tgf)-beta regarding severity and outcome in patients with trauma and sepsis, trauma only and sepsis only. twenty five patients with severe trauma (explosive and sclopetarious) who developed sepsis, patients with same kind of severe trauma without sepsis and patients with severe sepsis were enrolled in this study. twenty nine patients developed mods (of all patients), died. blood was drown on the first, third and fifth day of trauma or sepsis. concentrations of il- ra, il- , il- and tgf-beta were determined in plasma using elisa assays. when compared mods group (regardless of initiating insult -trauma or sepsis) with group without mods, we found statistically highly significant difference (p< . ) in il- ra and il- concentrations; mean values of il- ra were -fold higher and il- -fold higher in patients with mods; il- and tgf-beta were not statistically different (p> . ) between two groups. when compared non-survivors with survivors, we found statistically highly significant difference (p< . ) in il- ra and il- concentrations; mean values of il- ra were . -fold higher and il- . -fold higher in non-survivors; il- and tgf-beta were not statistically different (p> . ) between two groups. when compared trauma+sepsis group with trauma group, we found statistically highly significant difference (p< . ) in il- ra and il- concentrations, they were higher in trauma+sepsis group (il- ra . -fold, il- -fold). il- and tgf-beta were not statistically different (p> . ) between two groups. when compared trauma+sepsis group with sepsis group and trauma group with sepsis group, we found no statistically significant difference in either one of anti-inflammatory cytokines. our study shows that il- ra and il- are excellent predictors of severity and outcome of critical illness; higher concentrations were found in group with more severe clinical status (mods) and in non-survivors. il- and tgf-beta had no significance as predictors of severity and outcome what so ever. fifty-eight patients admitted to two medical intensive care units for reasons other than acute coronary syndrome were consecutively included and analyzed according to their troponin status. thirty-day mortality, left ventricular ejection fraction, the presence or absence of underlying coronary artery disease, and a panel of inflammatory cytokines were compared between troponin-positive and troponin-negative patients. thirty-two of critically ill patients ( %) without evidence for an acute coronary syndrome were troponin-positive. positive troponin levels were associated with higher mortality ( . % vs. . %, p < . ) and lower left ventricular ejection fraction (p = . ). troponinpositive patients had significantly higher median levels of tumor necrosis factor a, its soluble receptor and interleukin- . a subgroup of ten aplastic patients was troponin-negative at study entrance. three became troponin-positive during leukocyte recovery and subsequently died, whereas all the others stayed troponin-negative and survived. conclusion. elevated troponin is a mortality risk factor for medical intensive care patients admitted for reasons other than acute coronary syndromes. it is associated with decreased left ventricular function, and this may be mediated by tumor necrosis factor a and mediators produced by neutrophilic granulocytes. it is very interesting to notice the high correlation among protein c and atiii activity levels and sofa scores (p< . ) and the dramatic decrease of the protein c system is already firmly present hours before negative outcome (not survivors). we also register the significant alterations of c inhibitor specially in the group (ns) patients with severe candidemia and this marker assumes a significant role with an interesting clinical future . tumour necrosis factor-a (tnf) is an important pro-inflammatory mediator and high levels of this cytokine have been associated with a poor outcome from sepsis. recently, genetic polymorphisms of the tnf locus and its promoter region have been associated with the incidence and outcome of severe sepsis ; , although the results have been conflicting . we chose to investigate the association between a known functional single nucleotide polymorphism (snp) in the tnf gene promoter (- g/a, guanine to adenine substitution) and outcome in severe sepsis and septic shock. caucasian adult patients with a diagnosis of severe sepsis or septic shock on icus in the uk and from an icu in sydney, australia were recruited. whole blood was collected in edta, dna extracted and amplified by pcr using specific primers and digested with the restriction endonuclease nco . this enzyme cuts the wild type (allele g) but this cutting site is abolished by the polymorphism (allele a). the restriction fragments were then size separated, visualised and scored on agarose gels. fisher's exact test was used for statistical analysis. shedding of membrane bound tumour necrosis factor receptors to produce soluble molecules (stnfrsf a and b) is an important inflammatory control mechanism . we and others have previously demonstrated that increased levels of stnfrsf a and stnfrsf b are associated with decreased survival from sepsis. furthermore, there appears to be an association between polymorphisms of the tnfrsf b locus and plasma levels of stnfrsf b . we have therefore investigated whether polymorphisms of the tnfrsf b gene and its promoter region might influence outcome from severe sepsis and septic shock. caucasian adult patients with a diagnosis of severe sepsis or septic shock from icus in the uk and from an icu in sydney, australia were recruited. we analysed polymorphisms of the tnfrsf b gene. a single nucleotide polymorphism in exon (snp t/g) was studied by pcr-rflp, a microsatellite in intron (ms ) using an abi a sequencer and a base pair insertion/deletion in the promoter region (indel) by polyacrylamide gel electrophoresis. analyses of associations between genotype and allele frequencies and outcome were by fisher's exact test. . icu mortality was %. overall genotype and allele frequencies for each of the polymorphisms were similar to published population frequencies. there were no statistically significant differences in allele frequencies in any of the three polymorphisms between survivors and non-survivors (snp p= . , ms p= . , indel, p= . ). the mortality was lower in patients homozygous for the base pair repeat in the microsatellite polymorphism in intron (the genotype associated with high levels of stnfrsf b) (mortality % v . %) and was higher in those with the snp (t/g or g/g) (mortality . % v . %). these differences, however, did not reach conventional levels of significance (p= . and . respectively). larger studies will be required to confirm or refute associations between tnfrsf b gene polymorphisms, particularly ms homozygosity, and outcome from sepsis. when associated with end organ dysfunction, sirs is a major cause of morbidity and mortality in the intensive care unit (icu) population ( ). lps concentrations in the gastro-intestinal tracts of these patients are elevated as a consequence of bacterial overgrowth. lps processing in the mesenteric circulation may influence the systemic inflammatory response ( ). tlr is an integral part of the lps receptor complex. a tlr polymorphism (asp gly) is associated with hypo-responsiveness to lps in human bronchial epithelial cells. we examined the association of this polymorphism with clinical outcome in icu patients with severe sirs. methods. adult icu patients with evidence of severe sirs were studied. patient demographics, apache ii data, length of stay and outcome data were collected. genotype was determined using pcr amplification. statistical analysis was performed using spss . . results. patients have been genotyped of whom are still in icu. of the remaining patients, / ( %) died in icu and died in hospital after discharge from icu, giving an overall hospital mortality rate of / ( %). mean (sd) apache ii score was ( ).the tlr genotype frequencies were asp/asp . % ( / ), asp/gly . % ( / ) and gly/gly . % ( / ). the allele frequencies were asp % and gly %, similar to previously reported frequencies in caucasians. preliminary analysis revealed no significant differences between apache ii scores in patients with the asp/asp genotype (mean . , sd . ) and those with asp/gly or gly/gly genotypes (mean . , sd . ) (p= . , student's t-test). / ( %) of patients who died during the hospital episode carried the gly polymorphism, compared to / ( %) of those who survived the hospital episode (p= . , fisher's exact test, or . , % ci . - . ). conclusion. no associations with severity of illness on admission to icu, icu length of stay or hospital outcome were detected with the present sample size. recruitment is ongoing, to attain sufficient power. we aim to study genes coding for components of the lps receptor complex, which are biologically relevant to innate immunity and the development of sirs. detailed, prospective study of the role of polymorphisms in innate immunity has the potential to improve our understanding of the pathogenesis of sirs, and to influence risk stratification and management of this severe complication of life-threatening infection. the present study was designed to evaluate the effect of low dose albumin infusion vs. control on the local inflammatory response following abdominal surgery. albumin loss during surgery is a well described phenomenon. in previous experiments a loss of plasma proteins, resp. albumin was observed during abdominal surgery. intravital microscopy for five hours was used to evaluate the effect of low dose albumin on the mesenteric microcirculation. urethan-anesthetized sprague-dawley rats underwent median laparatomy and placement of a doppler flow probe around the abdominal aorta. an ileal loop was prepared for eventration onto a microscopic stage using a plastic foil technique and the mesentery was immersed with krebs-henseleit buffer( %co in n ). low dose albumin ( . g/(kg bw*h)) was given vs. control (nacl . %) during the experiment. heart rate, map, aortic blood flow were registered on a beat-to-beat basis. abg's were drawn hourly for analysis of metabolic(be), respiratory (po , pco ) and hct values. rolling and adherent leukocytes significantly increased in the control group until the end of the experiment, whereas they constantly remained on a low level in the albumin group. velocity and shear rate in the mesenteric microcirculation were significantly higher in the albumin group which was supported by increased abdominal flow and stroke volume vs. control. low dose albumin infusion significantly reduces the inflammatory response on the mesenteric microcirculation following abdominal surgery. beneficial effects on systemic hemodynamics, mesenteric microcirculation and attenuation of leukocyte rolling and adhesion in mesenteric venules could only be observed in the albumin group, whereas the inflammation progressed in the control group. iasonidou c. , pertsas e. , koletsos k. , kapravelos n. , tsagalof s. , riggos d. icu, g.papanikolaou, thessaloniki, greece optimizing patient's hemodynamics in the icu can be challenging.the pa catheter has been used to determine preload, afterload and myocardial performance. however,insertion of a catheter is not a risk-free procedure and the values obtained can in some circumstances be misleading.the use of tee in icu has been increasing.previous studies have examined the correlation between the pulmonary vein (pv) velocities and mitral valve (mv) velocities and pcwp. the purpose of our study was to evaluate the relationship between these variables during different loading conditions as assessed by tee in icu patients. ( ) patients,with a mean age of ± years, requiring mechanical ventilation were prospectively studied. in all patients a pa catheter was inserted and baseline measurements were obtained.the pv velocities and mv velocities were evaluated during three different loading conditions: ) in a control situation ) in a state of decreased preload by intravenous administration of nitroglycerin )in a state of increased preload by administration of fluids.in all patients we used the following indices from the pv velocity : s (systolic),d (diastolic), decelaration time(dt) of d wave, apv (atrial reversal) and from mv velocity: e,a wave and deceleration time of e wave. the decrease in preload resulted in a trend toward a lower amplidute of d wave peak velocity as compared with the control state and a significant prolongation of the deceleration time (p< , ).there was a decrease in height of the systolic (s) wave (p< , )and the apv (p< , ). the mv curve demonstrated a significant decrease in e velocity (p< , ) and prolongation of deceleration time (p< , ).the increase in preload resulted in a significant increase in systolic and diastolic wave in pv (p< . ) with a shortening of the dt of d wave.the apv became significantly higher (p< , ).the mv curves demonstrated a significant increase in e wave (p< , ) with a decrease in dt.there was a good correlation between d wave and pcwp (r: , ),apv wave and pcwp (r: , ) and e wave and pcwp (r: , ).a direct correlation was present between changes in e and d waves (r: , ) and changes in dt of e and dt of d velocities (r: . ). this study provides evidence that tee gives information additive to the pa catheter in the assessment of preload in an icu population. examination of pv velocities and mv velocities and their changes during different loading conditions provide additional information regarding diastolic function. this may prove useful in minimizing the use of invasive methods for hemodynamic monitoring in icu patients. further investigation is required to correlate these doppler measures with the invasive hemodynamic measurements. methods. patients with spe ( women and men), with a mean age of years (sd of ; range: to years), were studied prospectively. coloured doppler-echocardiography was performed in all cases at admission, confirming that diagnosis by perfusion gammagraphy and / or helycoidal ct scan. emboli were observed in six patients ( %): in right atrial chamber, in pulmonary artery and in output tract of right ventricle. in patients ( %) right ventricular dilatation with a mean value of . mm (sd ), and tricuspid insufficiency in ( %) with mean estimated systolic pulmonary arterial pressure of mmhg (sd ). pulmonary acceleration time was measured in patients and found shortened in all of them: milliseconds (sd ), and septal abnormal movement was detected in patients ( %). out of patients had more than one sign of severe pulmonary embolism (spe), had two sign and the other had three or more signs. echocardiography is a simple technique, which allows the diagnosis of spe by the detection of emboli in the right heart cavity and / or the objectivation of indirect signs of functional alteration of right ventricle. coagulopathy and systemic inflammatory response have been previously reported in patients after cpr ( ). the coagulopathy includes activation of coagulation and inhibition of fibrinolysis, alterations similar to those reported in sepsis where profound depletion of anticoagulation proteins have been evidenced, and had significant therapeutic consequences ( ). however, anticoagulation proteins: protein c and s (pc -ps), as well as antithrombin (at) levels were not reported after cpr. consequently, serial measurements of markers of coagulation (thrombin-at [tat], d-dimers), fibrinolysis (plasminogen-activator inhibitor : pai- ), inflammation (il- ) and endothelial injury (soluble thrombomodulin: stm) were performed in patients (age: ± years; saps: ± ) after successful cpr.analyses on biomarker levels by anova were performed. the aim was to evaluate the effect of thrombolytic therapy in massive and submassive pulmonary embolism methods. patients ( women and men), with a mean age of years (sd ), range: to , studied prospectively. diagnosis at admission was confirmed with spiral ct scan and/or ventilation-perfusion (v/p) gammagraphy. a study protocol was performed in all patients consisting of: complete analysis, electrocardiography, thorax radiography and echocardiography.one hundred milligrams of rt-pa was infused in hours due to severity of the clinical presentation: haemodynamic instability ( cases) and/or severe hypoxemia or echocardiographic abnormalities ( patients). clinical improvement was seen in the entire group. studied variables pre and postthrombolysis are shown in the table. mean arterial pressure (map); right ventricular diameter (rvd), systolic pulmonary arterial pressure (spap), acceleration pulmonary time (apt), oxygen saturation (os), fibrinogen, hematocrit and heart rate (hr). postthrombolytic changes in electrocardiogram were objectivated, showing that some abnormalities had disappeared, such as: right bundle heart block in out of patients ( %), s q t pattern in out of ( %), t wave alterations in out of ( %), and the pulmonary p in out of ( %). minor hemorrhagic complications were observed in cases; only one needed transfusion. one patient had hematuria, one other hemarthrosis, and another one suffered pericardial blood effusion (after coronary by-pass graft). we have previously shown that the measurement of gut intraluminal redox potential (eh) during progressive bleeding and reperfusion is useful to monitor changes in oxygen transport . eh could provide with a different type of information from other parameters of tissue oxygenation, such as lactate and intramucosal ph. our goal was to show the rate of decrease of eh after the occlusion of superior mesenteric artery blood flow (qintestinal). eight anesthetized and mechanically ventilated sheep were studied. eh was measured as a voltage difference using a milivoltmeter with a platinum electrode, against a reference electrode. qintestinal was measured with an electromagnetic flowmeter. after basal measurements, superior mesenteric artery was occluded and eh was continuously registered during minutes. data (mean ± sd) were analyzed with repeated measures of anova followed by dunnett's test. response time was defined as a decline greater than three sd from basal values. assessment of heart rate variability (hrv) has been used in risk stratification after acute myocardial infarction, in congestive heart failure, and in the early diagnosis of diabetic neuropathy. patients with end-stage renal disease (esrd) constitute a population of increased cardiovascular morbidity and mortality. hemodialysis patients often show signs of autonomic neuropathy. data on hrv are usually derived from -hour holter recordings. however, short term rr interval variation as measured on standard -lead ecg holds important prognostic implications in subjects with dilated cardiomyopathy. the purpose of this study was to look at short term rr variation in esrd patients, and its modification after dialysis. methods. ( male, female) patients were included in the study.all of them were in three times a week hospital hemodialysis. twenty control subjects, of similar age and gender distribution, with normal renal function and blood pressure, were recruited among ward stuff. the rr intervals were measured from a continuous -min recording of lead ii. rr variation was calculated as the standard deviation of the rr intervals (rrsd), and the coefficient of variance of the rr (rrcv), i.e. standard deviation divided by the mean rr and expressed as percentage. ecgs were also analysed for left ventricular hypertrophy (lvh). . rrsd and rrcv were significantly decreased in dialysis patients compared to controls. rrsd was . ± . vs . . p= . , and rrcv was . ± . vs . ± . , p= . . rrsd and rrcv were not affected by dialysis, but were significantly decreased in those with ecg evidence of lvh, compared to those without. rrsd was . ± . vs . ± . (p= . ), and rrcv was . ± . vs . ± . , (p= . ). rrcv was associated with mg and k postdialysis. rrsd and rrcv were inversely correlated with cornell voltage, an ecg index of lvh. hemodialysis patients present with low short term rr variation in comparison with control subjects. electrocardiographically detected lvh among esrd patients is also associated with depressed rr variability. increased intracranial pressure,as that was seen in patients with large cerebral tumors, reduces frequency of the pulse.prolapsus of the brain masses in tentorial incissura of foramen magnum and consequently bradycardia,respiratory arrest,coma and death might occur in these patients. the aim of this study is to examine the ecg changes in patients with brain tumors in regard to the kind of tumors and localisation . the study group was consisted of patients ( male and female) of average age , years (range to ). there were patients with temporal lobe tumor ( left and right), patients with frontal lobe tumor ( left and right), with parietal lobe tumor ( left and right) and with occipital lobe tumor ( left and right). ecg changes were evaluated during the first hours from receiving in the icu. large cerebral tumors confirmed with ct, and definitive diagnosis was made pathohystologicaly. the most common ecg abnormalities associated with central lesions that we found were: prolongation of the q-t interval in . % patients with right and % with left cerebral hemisphere tumor; elevated, peaked, or notched t waves in . % patients with right and . % with left cerebral hemisphere tumor; and increased p-wave amplitude in . % with right and . % patients with left cerebral hemisphere tumor. the most frequent ecg changes that we registered among rhythm and conduction disturbances were: narrow-qrs tachycardia with regular rhythm; sinus tachycardia in % with right and % patients with left cerebral hemisphere tumor, sinus bradycardia in . % with right and % with left cerebral hemisphere tumor, and incomplete/complete right bundle branch block (bbb) in % patients with left cerebral hemisphere tumor. we did not find any specific differences according to the pathohystologicaly type of the tumors. conclusion. ecg abnormalities associated with central lesions in the patients with brain tumors are not depend from the kind of tumors and side of the brain where tumor is located. in the patients with brain tumors on left side of the brain prevails incomplete and complete right bundle branch block (bbb). prolonged mechanical ventilation support (mv) is associated with increased morbidity and less cost -effective admissions in the postoperative period (po) of heart surgery (hs). study conducted to identify variables associated with prolonged mv in patients that underwent hs. methods. cohort study; consecutive patients enrolled from / to / of . inclusion criteria: patients submitted to hs and admitted to intensive care unit (icu) in use of mv. exclusion criteria: non-cardiac surgery, admission to icu in spontaneous ventilation or death during the first hours of the po. variables that could be associated with prolonged mv were pre-selected for analysis and grouped according to the period it represented. preoperative period: in-hospital stay duration, age, body mass index, gender, severity of left ventricular dysfunction (lvd), pulmonary hypertension, chronic obstructive pulmonary disease, redo, urgency for the procedure. peroperative period: surgery, extracorporeal circulation (ecc) and aortic clamping duration, fluid and blood input/output differences, type of surgical procedure, combined procedures, need for post-ecc intraaortic balloon counterpulsation (iab). admission to the icu: oxygen alveolar/arterial difference, blood oxygen partial pressure/oxygen inspired fraction ratio (p/f). first hours of po: dobutamine or norepinephrine (nor) use, blood drainage volume, lowest blood lactate measurement and prognostic scores sofa, tiss and mods. for dichotomyc variables, mann-whitney test was applied; for continuous variables we used kendall's tau non-parametric correlation test; cuzick tendency test was used to evaluate association with lvd. results. median mv duration: hours; mean duration time . hours ( to ). increased mv duration was associated with emergency surgery (p= . ), coronary artery bypass graft surgery (p= . ), need of iab counterpulsation after ecc (p= . ), use of nor (p< . ). increases in mv duration were associated with increasing values of some variables (positive correlation): age (p< . ), surgery duration (p= . ), blood input/output difference (p< . ) and sofa, tiss and mods scores (p< . ). negative correlation was presented for fluids input/output difference (p= . ) and p/f (p< . ). increased linear tendency for mv duration correlates with worsening of lvd (p= . ). conclusion. more sophisticated statistical analysis should be applied in order to determine the cause-effect correlation for these variables. interventional studies will be conducted in the following months. cerebral vasospasm is a, potentially, life threatening phenomenon after aneurysmal subarachnoid hemorrhage (sah). as part of "triple h" therapy, fenylephrine and norepinephrine in combination with dobutamine and dopamine, are used most frequently to elevate systemic arterial blood pressure (abp) in order to preserve optimal cerebral blood flow. in obtaining increased arterial blood pressure during episodes of vasospasm we altered medical therapy from fenylephrine to norepinephrine but experienced an increasing incidence of paralytic ileus. in a retrospective cohort study we evaluated clinical outcome and the incidence of paralytic ileus. methods. in - , a consecutive series of patients had surgery (aneurysmal clip ligation) within hours after sah. patients with clinical vasospasm, were subdivided into two groups with respect to medication used. group a (n= ) was treated with a combination of dobutamine, dopamine and fenylephrine (mean increase syst. abp . ± . mm hg). in group b (n= ) norepinephrine was used instead of fenylephrine (mean increase in syst. abp . ± . mm hg). we compared basic variables of the two treatment groups, and investigated the clinical outcome using the glasgow outcome scale (gos), one year after initial sah. complications were registered and compared between these treatment groups. results. the two treatment groups were evenly matched concerning age (p= . ), wfnsscore at admission (p= . ), amount of subarachnoid blood on ct-scan (fisher) (p= . ), and observed prognostic variables as hypertension (p= . ) and smoking (p= . ). the clinical outcome, was not influenced by the kind of medication used (p= . ). the incidence of paralytic ileus differed between the two groups (group a: / vs group b: / , p< , ). paralytic ileus occurred mainly in patients treated with norepinephrine ( / = . %, odds ratio= . ). no relationship was found in height of systolic abp or dosage of norepinephrine administered to these patients. we observed a significant difference in duration of administration of norepinephrine in patients, who did develop a paralytic ileus (see - . / - . p= . table: norepinephrine use in cerebral vasospasm; patients with or without paralyticileus. conclusion. -the use of norepinephrine in patients with cerebral vasospasm after sah did not influence clinical outcome, although higher blood pressure levels were reached. -norepinephrine administered during longer periods than days, increases the risk of paralytic ileus.-fenylephrine is recommended in the treatment of cerebral vasospasm after sah. amigues l. , klouche k. , massanet p. , canaud b. , béraud j. j. intensive care unit, lapeyronie university hospital, montpellier, france introduction. slow discontinuous ultrafiltration (sduf) is nown recognized as an effective complementary treatment for congestive refractory end stage cardiac failure(escf). however, an organic kidney disease is often associated with heart failure and may worsen the prognosis. this study was undertaken to compare the effects of sduf in escf patients with and without previous kidney disease. methods. patients fullfilling escf criteria with fluid overload and oliguria (grade iv nyha) were treated by sduf. sduf was performed with a double head pump monitor (bsm , hospal), blood flow rate: - ml/mn, ultrafltration rate: . to l/h. vascular access was provided by femoral silicone twin catheters. a renal replacement therapy was institued when indicated. age, sex, cardiopathy, and nephropathy were collected in each patient. patient follow up before and after sduf: systolic arterial pressure, heart rate, diuresis, total fluid volume removed, cardiothoracic index, creatinemia, blood urea nitrogen, natremia, natriuresis, mortality and average survival. datas were compared between two groups: group without and group with nephropathy. mean age was ± yo and sex ratio was / , . myocardiopathy origin was: ischemia ( ), hypertension ( ), valvulopathy ( ), primary non-obstructive cardiopathy ( ), multifactorial ( ). oliguric renal failure: fonctional in patients (group ) and associated with mild chronic nephropathy in patients prior to heart attack (group ). no significant differences in clinical and biological datas were observed between the two groups except for blood urea nitrogen: , ± in group vs , ± , mmol/l in group . during scud, hemodynamic stability was observed in both groups; diuresis and natriuresis significantly increased and remained stable at the end of the treatment despite significant decreased diuretic doses. mean sessions of sduf was , ± , in group and , ± , in group (ns). renal replacement therapy was institued in both groups but the number of sessions was significantly higher in group : , ± , vs , ± , . mortality during hospitalisation was % in group and %in group . from the surviving patients, / patients in group and / patients in group underwent a chronic hemodialysis treatment. average survival was higher but not significant in group ( , ± vs , ± months). our study sugests that sduf remains a long term beneficent treatment for patients with both escf and renal failure. paradoxically, prognosis is slightly better than in patients with isolated refractory congestive heart failure. organic renal failure could artificially worsens cardiac function by increasing diuretic resistance which may be improved by sduf. ( ). this study aims to evaluate the influence of factors affecting renal blood flow including map, cvp, pulmonary artery wedge pressure (pawp), cardiac index (ci), systemic vascular resistance (svr) and pulmonary vascular resistance (pvr) on immediate graft function. methods. consecutive patients undergoing live-related kidney transplant were included. prior to anaesthesia, a . f continuous cardiac output pulmonary artery catheter was placed via the right internal jugular vein. a continuous cardiac output monitor (baxter edwards px ) was used for haemodynamic monitoring. baseline values of the map, cvp, pawp, ci, svr and pvr were computed. data was collected at -minute intervals thereafter and immediately before and after release of the vascular clamps. the ischemia time, intravenous fluids, dopamine use and blood transfusion were noted. if warranted by low preoperative haemoglobin or increased surgical blood loss, blood was administered as ml packed cell units using leukocyte filters. the outcomes chosen for graft function were the urine output on table (uo-ot), -hour urine output (uo- ), fall of serum creatinine from the preoperative value on day (creat- ) and day (creat- ). using spss statistical software, multiple linear regression analysis was done to find the variables significantly affecting the outcome. results. the only variable found to have a statistically significant influence on uo-ot was the map. no variable had any effect on the uo- . blood transfusion had a negative influence on the fall of creatinine on day and day ( since clinically adopted during cardiac surgery, cardiopulmonary bypass (cpb) has been implicated in complement activation and postoperative acute phase reaction. corticosteroids are usually employed as an attempt to dampen these phenomena and related postoperative morbidity. methods. after informed consent previously approved by the local ethical committee, we included adult patients submitted to cardiac surgery under cpb at a non-emergency setting. preoperative risk stratification employed euroscore (es) and cleveland clinic score (ccs). methylprednisolone (mp) - mg/kg, was added to cpb priming solution for group (n= ) but not for group (n= ). blood samples were collected from all patients at anaesthesia induction (t ), (t ), (t ) and -hour postoperative (t ) for measurement of total c and c-reactive protein (crp) levels, by nephelometric technique. postoperative multiple organ score (mods) were daily registered. results. the groups were considered comparable concerning to preoperative risk stratification, length of cpb and postoperative organ dysfunction at h postoperative (mod , as well. starting from similar levels of c and crp, we did not observe significant differences between groups and concerning to postoperative levels of c . nevertheless, patients treated with mp (group ) exhibited higher crp levels at h postoperative, as shown bellow: . ± . . ± . . perioperative administration of mp failed to show evidences of beneficial effect over postoperative organ failure and complement activation. the acute phase response, expressed as crp systemic levels, instead of softened, was significantly enhanced among patients to whose cpb priming solutions was added mp. these results support a larger randomised trial to reassess routine use of corticosteroids during cpb. objective: to evaluate the influence of enteral application of an immunoglobulin enriched bovine milk preparation on endotoxin plasma levels, endotoxin neutralizing capacity of plasma (enc) and the acute phase response (il- , crp) during and after cardiac surgery in a pilot study. design, patients and methods. patients who were treated by coronary bypass operation were enrolled in a controlled randomized study. the patients were treated by enteral application of g of a bovine colostrum milk preparation per day for days preoperatively. endotoxin and enc were sequentially determined intra-and postoperatively by a chromogenic modification of the limulus amebocyte lysate test. interleukin- , crp, transferrin, alpha- macroglobulin, albumin, apo-a, apo-b, igg, iga, igm were determined by "elisa" and nephelometrically. the clinical course was followed up by daily evaluation of the apache-ii-score. main results: demographic data were comparable in both groups. no differences of the apache-ii-score ( . . verum group, and . , control group, on admission) were observed. endotoxin plasma levels and enc showed high levels at the end of the procedure and seemed to have a trigger function for the acute phase response but were not significantly reduced throughout the observation period in patients receiving the milk preparation as calculated by comparing the area under the curve. plasma levels of endotoxin binding proteins did not differ significantly. plasma levels of il- increased to maximal median values of pg/ml in the verum and pg/ml in the control group and h after surgery. a tendency to lowered il- levels was observed throughout the whole observation period for the verum group. crp-levels showed their maximum values h after the procedure and were significantly reduced in patients of the verum group (p = . ). conclusion. this study revealed that endotoxemia occurs early during an elective surgical intervention, which is followed by a subsequent increase in mediators of the acute phase reaction. the prophylactic enteral application of a bovine milk preparation for two days in cardiac patients did reduce postoperative crp-plasma levels but contrary to a former prospective double blind study in abdominal surgery did not reduce perioperative endotoxemia. one reason could be the too low application of the bovine colostrum milk preparation. to compare a possible effect of improved therapeutical approaches in head trauma, epidemiological data should be compared at certain time points. due to the legal obligation to document all in-patient treatments in germany and to forward these data in an anonymous form to the office for statistical affairs (statistisches bundesamt) it is possible to provide a nationwide epidemiological analysis of head trauma and to compare the yearly obtained data. the incidence, the mortality, and the duration of hospital stay for the treatment of all hospitalized patients suffering from head trauma were calculated and compared to the data from while considering the data obtained from the office for statistical affairs in bonn and wiesbaden. the data were investigated while separating them according to the international classification of diseases (icd- ; no. - and - ). to further elucidate the causes of altered mortality and duration of hospital stay the number of cts and mris in german hospitals in and were compared. in addition, data indicating the number of patients admitted to neurological rehabilitation centers were analyzed. the incidence of head trauma did not change between and and was calculated to be at / . . the mortality, however, decreased from . / . in to . / . in ( vs. patients). in addition, the duration of hospital stay declined in all icd- encoded subgroups including mild brain trauma. this could be due to the increased number of ct devices and mris in german hospitals (ct: vs / mri: vs ) while comparing and . the number of patients transferred from hospitals to neurological rehabilitation centers increased from in to in (+ %). it could be speculated that both improved knowledge on the field of brain trauma therapy and a higher number of technical devices allowing rapid diagnosis of brain injury or potential intracranial complications following head trauma accounted for the reduction in mortality due to brain trauma in germany from through . the decline of the duration of hospital stay especially in patients with more severe head injury could also be due to a more rapid transfer of patients with head trauma from hospitals to rehabilitation centers. therapeutic hypothermia may improve outcome in patients with severe head injury, but clinical studies have produced conflicting results. we hypothesised that severe side effects of artificial cooling might have masked positive effects in earlier studies, and treated a large group of patients with severe head injury with hypothermia, using a strict protocol to prevent the occurrence of cooling-induced side effects. methods. consecutive patients admitted to our hospital with severe head injury (glasgow coma scale (gcs) < ) in whom icp remained above mmhg in spite of therapy according to a step-up protocol described previously [ ] were included in our study. those who responded to the last step of our protocol (barbiturate coma) constituted the control group (n= ). those who did not respond to barbiturate coma (n= ) were treated with moderate hypothermia ( oc- oc). average apache ii scores were higher, and average gcs at admission slightly lower in the hypothermia group, indicating greater severity of illness and more severe neurologic injury. predicted mortality was % for the hypothermia group vs. % in controls. actual mortality rates were significantly lower: % vs. %, p< . . the difference in overall mortality between hypothermic patients and controls was statistically significant (p< . ). the number of patients with good neurologic outcome was also higher in the hypothermia group: . % vs. . % for hypothermic patients vs. controls, respectively (p< . ). these differences were explained almost entirely by the subgroup of patients with gcs of or at admission (mortality % vs. %, p< . ; good neurologic outcome % vs. %, p< . ). artificial cooling can significantly improve survival and neurologic outcome in patients with severe head injury, when used in a protocol with great attention for the prevention of side effects. these effects are especially clear in patients with gcs of or at admission. because there is likely to have been bias against the hypothermia group in this study, the positive effects of hypothermia might even have been underestimated. introduction. s b, a glial calcium-binding protein, is a serum marker of cerebral damage. posttraumatically, however, s b in increased in all patients suffereing from hemorrhagic-traumatic shock, regardless of whether trauma is cerebral or extra-cerebral. the aim of this experimental study was to determine whether the posttraumatic s b increase is caused by extra-cerebral trauma or by hemorrhagic shock and whether it is influenced by the severity of shock. hemorrhagic shock was achieved by bleeding anesthesized rats to a mean arterial pressure (map) of - mm hg through a femoral catheter and maintaining this map until incipient decompensation. subsequently, map was either increased immediately to - mm hg (moderate shock) or maintained at - mm hg until % of shed blood had been returned (severe shock), and then increased to - mm hg. resuscitation was provided after - mm hg map had been maintained for min. trauma was achieved by midline laparotomy. hemorrhagic-traumatic shock caused an early s b increase at the onset of decompensation. s b in serum was highest at the end of the min. period during which map was maintained at - mm hg and was significantly higher at all time points after severe shock than after moderate shock. in contrast, trauma (laparotomy)without hemorrhagic shock did not cause any increase of s b in serum. the posttraumatic s b increase in serum appears to be caused by hemorrhagic shock rather than by extra-cerebral trauma. regardless of whether the source of s b is cerebral, indicating cerebral damage linked to shock, or extra-cerebral, the main determinant in the clinical setting remains the severity of shock. romera m. a. , chamorro c. , silva j. a. , pardo c. , marquez j. , ortega a. intensive care unit, clínica puerta de hierro, madrid, spain in patients with non-traumatic subarachnoid hemorrhage (sah), the development of myocardial abnormalities has been widely described. however, the true incidence of myocardial injury in this group of patients is unknown yet. we analyze the incidence of myocardial injury, in this population, using cardiac troponin i (tn i) assay and also we assess if the increase in tn i concentration has prognostic value. prospective study, including all patients with non-traumatic sah admitted to our intensive care unit (icu), from december to december . serum tn i concentration was measured, at least once, within the first hours after onset of symptoms. inmunoassay based on the "sandwich" principle was employed. the chi-squared test and fisher exact test were used for statistical analysis. of the patients admitted, were excluded ( admission later than hours, absence of tni determination, previous cardiopathy or renal failure ). eighty-two patients were included in the study ( women ). mean age ± years. the tni concentration was increased in / patients ( % ). sixteen ( . % ) patients died in icu. twelve of the ( % ) with a high tni concentration and / ( % ) with a normal tni concentration died [ relative risk (rr) . ( . to . ; % confidence interval (ci); p< . ]. thirty-seven ( % ) patients had a hunt-hess (hh ) grade greater or equal to iii. poor grades of sah ( hh>or = iii ) were associated with a higher incidence of raised tni concentration ; ci %); p< . ]. among this group of poor grade patients, elevated tn i levels were associated with a higher mortality [ / ( %) with a raised tni compared with / ( % ) with a normal tni concentration; rr ( . - ; ci % ); p< . ]. however, mortality in every case was related to neurological problems. seven patients ( . %) suffered from pulmonary edema and all had elevated tni levels. echocardiography was performed in all patients, being abnormal in of them. conclusion. in our series, the incidence of myocardial injury in sah was %. this cardiac injury was more frequent among patients with severe grades of sah. elevations in tn i levels had prognostic value, being associated with a higher mortality. therefore, we should closely monitor those patients with sah who develop an increase in the tni levels. renaud e. , matéo . j. , benlolo . s. , payen . d. dept of anesthesiology and critical care, lariboisiere hospital, department anesthesiology intensive care, lariboisiere, paris, france respiratory failure is one of the major complication of acute stroke ( ). we have investigated the impact of the location stroke on respiratory failure incidence, cause of intubation and outcome. we reviewed consecutive patients with acute stroke admitted to icu from to . following data were collected, glasgow coma score (gcs), cause of icu admission, presence of acute respiratory failure (arf), reason for intubation, presence of aspiration, length of mechanical ventilation (lomv), severity of hypoxia, length of stay in icu (los) and mortality. continuous data were compared by paired t-test and nominal data by chi-test. explicative variables for arf were assessed by univariate analysis. . patients had a middle cerebral artery (mca) stroke and had brainstem stroke (bs). age (mca ± sd yrs vs bs ± sd for), gsg score (mca ± sd vs bs ± sd for), length of stay in icu ( ± sd days for mca vs ± sd) were not significantly different. % bs and % mca patients were admitted in icu for respiratory failure (p= . ). admission to icu with loss of consciousness was significantly higher in mca ( / , %) than in bs ( / ) (p= . ). indication for intubation was always for aspiration pneumonia that was the leading cause of arf ( . ) associated with swallowing paralysis in bs (p= . ) and to unconsciousness in mca (p= . ). there was no difference for the lomv, the severity of hypoxia between the groups. arf, intubation or reason for intubation were not associated with mortality in the groups (p= . ). the major cause of death was the presence of cerebral herniation in the groups (p= . ). pulmonary complication due to aspiration more predominant in bs than mca stroke, represents the major cause of intubation and arf for bs patients. in the contrary, loss of consciousness in mca stroke group predominates for icu admission. outcome in all patients (mca and bs) was not influenced by presence of respiratory failure or reason for intubation. the major cause of death for stroke's patients is the neurologic state, and especially the presence of herniation. stroke code (sc) is a guidelines of united actuatio between out of hospital enmergency services from barcelone and the most four important hospitals of the city; which aim is to optimize the sequence time for stroke treatment; this allows to increase the number of candidates for reperfusion therapy. the present study aim is to evalute differents times sequences in the acute strokes in which trombolysis has been practised according to the acute stroke code first priority; and secundary to describe findings in the ct scan of these patients pro-inflammatory cytokines, such as tnf and il- are released in the brain within hours after closed head injury (chi). they were shown to have deleterious effects, mainly when active in the early post-injury period. a variety of anti-inflammatory and anti-apoptotic modalities have been shown to ameliorate the outcome of chi. erythropoietin (epo) is a kidneyderived cytokine regulating haematopoiesis both by acting as a growth factor and by inhibiting apoptotic cell death. recently it has been shown to be produced in cultured neurons, brain astrocytes and neurons under hypoxic/ischemic conditions and in response to oxidative stress. other studies have shown that the erythropoietin receptor (epor) is present under normal conditions on neuronal and brain capillary endothelial cells. epo has been found to have newly discovered neuroprotective properties in different models. these models include neuronal cultures against glutamate toxicity, global glutamate toxicity and rodent models of cerebral ischemia. in addition it induces brain endothelial cell proliferation and stimulates neovascularization in vivo. the present study was designed to test the protective effects of epo in rats udergoing controlled chi. methods. chi in rats was induced using a weight-drop device. clinical status was evaluated by the neurological severity score (nss), which tests tasks including reflexes, behavior and motor activity. a point is awarded for failing to perform a task so a higher score corresponds to a more severe trauma. study animals were treated with doses of i.p. units/dose ( ml) of rhu-epo, h and h after chi (treatment group) or with ml of vehicle injected i.p. at the same time points (control group). nss was evaluated by an observer blinded to the different groups at , and days post chi. nss scores were compared using a two tailed student t-test. control and study rats were subjected to chi of similar severity, ( h nss . + . and . + . respectively, p= . ) and followed at d, d and d following chi. clinical recovery was facilitated in the treatment group starting at h after chi and reached statistical significance at days post chi. the treatment group's d nss was . (n= ) vs. . in control animals (n= ) p= . . the present findings point to a neuroprotective role of epo in traumatic brain injury. brain tissue of treated and control animals is currently being analyzed for parenchymal cytokine levels. we have examined the role of post trauma treatment with epo of rats undergoing chi. as has been shown in other models of brain injury (stroke, ischemia, glutamate toxicity) epo seems to have a neuroprotective effect in head trauma. the exact mechanism of this protection has yet to be elucidated. this is the first time, to our knowledge, that epo has been studied in an animal model of traumatic head injury. ( ) ( ) ( ) is . %. it is difficult to know how to apply these figures to individual patients. we have used the anaerobic threshold in a prospective observational study to try and identify patients with an increased risk of mortality. forty-five patients scheduled for elective aaa repair had their anaerobic thresholds measured pre-operatively. the anaerobic threshold is the patient's oxygen consumption in ml/kg/min when anaerobic metabolism occurs(reference ). it is calculated by using a bicycle ergometer and a metabolic cart. clinical presentation and evolution of valvular heart disease (vhd) patients have great significance in determining the best moment for surgical correction but lacks correlation with surgical outcome in most cases. this study tries to determine the preoperative variables associated with mortality in the course of surgical treatment of vhd. cohort study conducted from january to february . inclusion criteria: patients submitted to vhd surgery during the period of study. exclusion criteria: vhd surgery combined with non -vhd procedures. data were analyzed with chi -squared, fisher and mann -whitney tests. one hundred five patients met the inclusion criteria. the preoperative variables associated with surgical mortality were: systemic arterial hypertension (p= . ), peripheral vascular disease (p= . ), redo (p= . ), age (p= . ), blood creatinine level (p= . ), left ventricular dysfunction (p= . ). conclusion. based on these data, efforts will be held in order to develop a prognostic score index for mortality in vhd surgical patients. in our setting, the diffusion of institutional education in basic cardiopulmonary resuscitation (bcpr) is low. the number of patients admitted to our units after resuscitation following cardiac arrest is rising due to the population demand on the out-of-hospital emergency services, . the patients with neurological sequelae secondary to incorrect bcpr in the first minutes are common. through the association of ex-patients of the intensive care medicine department, and with the psycho-social support of voluntary helpers on patient discharge, relatives are offered bcpr as part of the quality care programme. every three months, professionals from the department organise this course for relatives in the form of a hour module. the concepts of the prevention of ischaemic heart disease are presented together with the content of the national plan for bcpr. practical sessions are undertaken in small groups of to persons, using dummies. a total of relatives in courses have received this training over the past years. the mean age of the students was . (sd ) years ( - ), % women, % with middle and higher education, % housewives, and % manual labourers. the evaluation of the scores obtained in the item test before and after the course is shown in the tables below. multiorgan system failure (mosf) is an infrequent but very serious complications after cardiac surgery, with high rates of mortality. this study was undertaken to determine the frequency, prognosis and risk factors for mosf this study was performed in a twelve-bed cardiac surgery intensive care unit over a -month period. all adult consecutive patients undergoing coronary, valvular and combined (valvular and coronary) surgery were prospectively studied (n = ). all patients were assessed by the "modified" parsonnet score results. mosf developed in ( . %) patients, of whom ( . %) died. this was the main cause of overall hospital mortality ( / , . %). in a logistic-regression anlysis, the development of sepsis, postoperative low cardiac output syndrome, mechanical ventilation more than hours, a "modified" parsonnet score more than and and preoperative ventilatory support were independantly associated with the development of mosf. an organ system failure index (osfi) of or more was most significantly associated with icu mortality (p< . ). conclusion. in our series mosf was a leading cause of mortality after open-heart surgery. the development of mosf with an osfi of or more was the main predictor of postoperative mortality. we studied patients who underwent cabg surgery. fifteen patients ( male and female) were younger than years and patients ( male and female) were older than years. perioperative death occured in one patient from the < years group and in patients from the > years group (p=ns). categorical data were compared using the chi-square test and numerical data were analysed using the student t-test. differences were considered significant at p< . . in a n investigation conducted in ours icu, % of patients hospitalised after elective cardiac surgery presented a pain score > ( min score ; max ) . these results were considered inadequate. a quality improvement initiative was undertake. the aim of the present study was to test if pain evaluation and treatement improved following pain guidelines implementation in a surgical icu. the design consisted in observing de pain evaluation both before and month after implementation of guidelines. these guideline are divided in two item : first introduction of a regular pain evaluation using a visual analogue scale (vas) and second in a proportional vasderived analgesic prescription protocol. recommendation were given during repetitive meetings, feedback sessions and regular poster information on the icu walls. pocket guideline and vas tool was distributed. pain intensity evaluation of the nursing team was checked by an independent observer and compared with the nurses-charted vas. improvement of pain control was tested based on the following criteria: utilisation of the algorithm at least twice per working shift; corresponding analgesic drug to observed vas; and follow up check of vas after analgesic administration. the independent observer measure vas at a.m. and at p.m. postoperative day and . proportion of algorithm adherence before and after introduction of the recommendation were tested using fisher's exact test. variance of median vas was tested using mann-whitney test. these preliminary results indicate that the implementation of an algorithm on pain intensity evaluation and treatment increases the number of pain evaluation and re-evaluation after drugs administration. although the administration of analgesic drugs increased, the number of patients with insufficient pain treatment stays still high. the prognosis of liver transplant has improved the last few years due to advance in surgical techniques and immunosuppressive regimes, but early complications show a high prevalence affecting morbi-mortality in these patients a beds icu in a teaching rd level hospital. prospective observational study on all patients with the mentioned condition treated in our centre from october to october . follow up during icu stay. we have collected data from patients ( grafts) with a mean age of . ± . years, . % women, mean apache ii on admission ± . , median child score , ( - ) and mean sofa score . ± . . surgical data were as follows: fluids balance ± , hours of graft ischemia . ± . , reperfusion syndrome in % and fibrinolysis in . %. at admission mean core temperature was . ± ºc. median icu stay . ( - , max. ) days and median hours under mechanical ventilation ( . - , max ). the prescribed immunosuppression was cyclosporine in % and tacrolimus in % of patients results. icu mortality was . % ( patients). complications were present in % ( . % of them more than two episodes). patients had to be reoperated, one because early graft dysfunction treated with mars and retransplantation (death because a new graft dysfunction), and the other because abdominal haemorrhage. one patient developed an early rejection. metabolic complic . % (high insulin requirements . %) -renal failure . % (renal replacement , %)-cardiac complic . % (chf . %, hbp . %) -respiratory complic . % ( . % sdra) -bleeding % -neurological complic . % (myelinolysis patient) -infection . %. patients who died had higher apache ii, child and sofa scores, lower serum albumin levels, longer graft ischemia, higher percentage of fibrinolysis and reperfusion syndrome during surgery and higher percentage of acute renal failure an need for renal replacement (not statistical analysis due to the low mortality rate we report the effects of substitution with a virus-inactivated protein c (pc) concentrate in disseminated intravascular coagulation (dic) in preterm infants and children with sepsis (meningococcal in the children and aldolecent; staphylococcal and enterobacter in the preterms) associated with purpura fulminans. this was a prospective open-label study. a total of patients, paediatric and adolescent patients age . to . years with dic associated with severe acquired pc deficiency (range . to . iu/ml; median, . iu/ml) in meningococcal septic shock and purpura fulminans; and preterm infants with severe acquired pc deficiency (range . to . iu/ml; median, . iu/ml) due to staphylococcal and enterobacter sepsis were studied. replacement therapy was initiated with a virus-inactivated pc concentrate with an initial intravenous bolus of to iu/kg followed by iu/kg up to six times per day as an adjunctive therapeutic regimen to otherwise optimal intensive care treatment. after initial pc administration, plasma pc levels rose to normal ranges and were maintained under pc replacement therapy. improving or even normalising global hemostatic parameters were assessed in all patients. markedly elevated plasminogen activator inhibitor type (pai- ) levels prior to treatment, reflecting a reduced fibrinolytic potential, decreased rapidly under pc substitution. concomitantly improving signs of purpura fulminans reflected by decreasing size of skin lesions, demonstrated a restoring microcirculation. seven of the nine paediatric and all of the neonatal patients survived. one patient (paediatric) required limb amputation; two patients died because of multiorgan failure. both presented with a severely low plasma pc activity of . iu/ml on admission to the hospital. no adverse effects were observed with the pc concentrate administration. ait can be concluded that the administration of pc concentrate had a marked benefit on the deranged coagulation status of patients with purpura fulminans and septicaemia. normalisation or even partial correction of haemostasis as well as improvement of microcirculation accompanied by improving signs of purpura fulminans were demonstrated in all patients the main purpose of this study is to report medical and surgical complications of spine surgery in a third level universitary pediatric hospital with a reference spine surgical program. methods. study design is a retrospective clinical series of pediatric spinal surgeries.all spine surgeries performed on children under years of age between january and january were included. patient were grouped in four diagnostic categories (idiopathic, neuromuscular, congenital scoliosis and miscellaneous) and procedure performed (posterior (p) fusion, anterior/posterior (ap) fusion, anterior (a) fusion, (iw) instrumental withdrawal). next data were recorded from clinical chart:age, gender, needs of transfusion products, volume demands during first postoperative day,days on mechanical ventilation,medical and surgical complications. results. study sample included patients, female and male. age ranged between and years with average of . years. characteristics were: idiopathic , neuromuscular ,congenital scoliosis ,miscellaneous . procedures performed were:p fusion ,ap fusion ,a fusion ,iw . .average lenght of stay in pediatric intensive care unit were . days (range - ).average days on ventilatory support . ( range - . ). no patient required intubation after weaning.major complications were: deep wound infection( ), respiratory distress( ), large intraoperative blood loss ( ),and paraplegia ( ).no deaths were observed.minor complications were: atelectasis( ), pleural effusion( ), pneumonia( ), pneumotorax( ), superficial wound infection( ), urinary tract infection( ) and electrolitical disturbances( ). postoperative transfusion needs were . ml/kg ( % confidence interval (ci) . - . ) for ap fusion, . ml/kg ( % ci . - . )for p fusion; a fusion and iw doesn't need postoperative blood replacement. total blood transfusion was . ml/kg ( % ci . - . )for ap fusion, . ml/kg ( % ci . - . )for p fusion; . ml/kg for a fusion and . ml/kg for iw.volume demands(no blood products)during first postoperative day were . ml/kg ( % ci . - . )for ap fusion, . ml/kg ( % ci - . ) for p fusion; ml/kg for a fusion and . ml/kg for iw. conclusion. spine surgery has few major complications rate in a reference spine surgery pediatric hospital. minor respiratory complications affect % of our patients without repercussion in outcome. total blood loss is greater in ap fusion than in other procedures, but postoperative blood replacement in picu didn't differ between procedures. background elevated intra-abdominal pressure (iap) adversely affects pulmonary, cardiovascular, renal, splanchnic and central nervous system physiology, and it determines the common clinical picture called "the abdominal compartment syndrome". nevertheless the direct monitoring of iap is not always practicable, because it requires an abdominal drainage. a lot of authors demonstrated in the adults that the bladder pressure is a reliable index of iap, but there are not studies on pediatric population. the aim of this study is to evaluate the level of significance of this index in a pediatric population. population: we enlisted a group of pediatric patients, sedated and paralysed ( oltx, abdominal surgery, cardiac surgery), age . ± , (range - ) months. methods. the bladder pressure was measured with the patient in supine position, with a trasduction circuit connected to the bladder catheter and to the abdominal drainage ( jpratt, pig tail, catheter for peritoneal dialysis). to obtain a good transduction of pressure, a volume of saline was pushed into the bladder. the volume of saline was variable according to the weigth and age: we obtained a scheme (table ) from our empirical evaluation of the pediatric bladder compliance and urodinamic data. table , there aren't significative differences between the level of pressure measured in the bladder and in the peritoneal cavity ( p= . ). mean: , ds: , from to , pediatric patients (age range . to years, mean . years) were treated using nppv during distinct episodes of acute respiratory failure (arf) of neuromuscular origin. in all patients immediate intubation for an acute, life-threatening presentation was avoided and respiratory status improvement was achieved. few data are available up to now about nppv application and indications in the acute setting in infants affected by neuromuscular disorders (nmd). a prospective observational study was carried out on non-consecutive neuromuscular patients admitted to picu because of arf and managed with nppv in the acute phase;remarkably, out of were < months aged. all the patients were treated by a flowtriggered intensive care mechanical ventilator (siemens servo ventilator, siemens-elema, sweden) through a tight fitting face mask. nppv was administered for at least hours postadmission. a pressure-control mode was adopted for better compensation of leaks around the mask. flow-sensitive trigger permitted a better synchronization of patient's spontaneous breathing, limiting the need for deeper patient sedation (low-dose midazolam drip). initially, a relatively low ventilator frequency delivery was set ( - b/min). peak inspiratory pressure was tritrated upward to obtain an exhaled tidal volume of - ml/kg maintaining a paco value < mmhg and a ph > . ; peep value was adjusted to maintain an oxygen saturation > - % with a required fio < . . results. all patients were referred to picu on spontaneous breathing: those admitted with et tube already positioned were not considered eligible for this study. an oxygenation improvement was obtained in all patients within hours from the onset of nppv . the pao /fio increased from . ± . to . ± . (p< . ) and . ± . (p< . ) on selected time points ( and hours after nppv introduction, respectively); conformly, alveolar-to-arterial oxygenation difference (a-ado ) decreased from a . ± . to . ± . (p< . ) and . ± . (p< . ) respectively. conclusion. nppv resulted a safe and effective therapeutic approach in both hypoxemic and hypercapneic arf episodes in this children group affected by nmd. even in cases of emergency presentation or when resuscitation is needed, it is of importance to identify nmd children with residual ventilator-free breathing ability thus performing a nppv trial. life-threatening respiratory distress and young age should not preclude nppv application in a picu setting. pulse oximeters are widely used in paediatric intensive care but they have some severe limitations. the technique relies on the presence of adequate peripheral arterial pulsations, which are detected as photoplethysmographic signals (ppg). when peripheral perfusion is poor as in states of hypovolaemia, hypothermia and vasoconstriction oxygenation readings become extremely unreliable. hence, pulse oximetry becomes unreliable in a significant group of children just at the time when accurate readings are most needed. to overcome this limitation, the oesophagus has been investigated as a potential measurement site on the hypothesis that perfusion may well be better preserved at this central site. studies on adult patients have shown that measurable ppg signals at red and infrared wavelengths can be detected within the whole depth of the oesophagus. a new system to investigate the quality of oesophageal ppg signals is being constructed with the aim of developing a neonatal and paediatric oesophageal pulse oximeter. a reflectance optical sensor has been constructed comprising miniature infrared and red emitters and a photodetector. the sensor was design to fit into a conventional disposable transparent stomach tube, french gauge. the oesophageal ppg sensor within the stomach tube was inserted through the nose into the oesophagus of a kg, day old neonate. the stomach tube was advanced into the oesophagus under direct vision until the probe was cm from the nose. ppg traces from the oesophagus were recorded for approximately minutes at this depth on a laptop computer. measurements were repeated at and cm from the nose. measurable ppg traces of good quality were obtained in the oesophagus at all three depths. the ppg signals in the mid to lower region of the oesophagus on average had larger amplitudes at both red and infrared wavelengths than the ppgs recorded in the upper oesophagus. artefacts on both wavelengths due to oscillations as a result of high frequency ventilation. filtering successfully eliminates the artefact. the new oesophageal reflectance optical sensor has allowed ppg measurements to be made within the whole length of the neonatal oesophagus. the red and infrared wavelengths used are suitable for pulse oximetry. these results are the first to demonstrate that pulse oximetry may be feasible in the neonatal or paediatric oesophagus. further studies are required to develop a neonatal/paediatric pulse oximeter. we used protein c (ceprotein; baxter -immuno) in two patients with moderate or severe, therapy-resistant vod. . patient (e.g, swiss, , y) suffered from an acute myelogenous leukemia (m with t( ; ) of early infancy after complete first remission by conventional chemotherapy an allogeneic stem cell transplantation with a matched unrelated donor was performed. conditioning comprised busulfan, vp and cyclophosphamide. patient (m.k, iranian, y) suffered from beta-thalassemia major with secondary moderate hemosiderosis, as well as chronic persisting hepatitis c infection with liver fibrosis. he received a matched related bone marrow transplantation, using i.v. busulfan , reduced cyclophosphamide dose and fludarabine. both patients received low dose heparin ( iu/kg) and antithrombin iii substitution. in addition, pat. got prophylactical defibrotide ( mg/kg) and n-acetylcystein. two weeks after transplant both patients developed vod (severe (pat ); moderate to severe (pat ))with weight gain, hepatomegaly, massive ascites and severe thrombocytopenia. maximal bilirubin was mg/dl (pat ) and mg/dl)(pat ). therapy with defibrotide ( mg/kg) was started immediately. in pat. the pulmonary situation deteriorated rapidly with massive aszites and oxygen need and a reversed portal venous flow. defibrotide was stopped after days. thrombolytic therapy using rtpa and a continuous pc substitution (pc level %; bolus iu/kg, followed by iu/kg every h)) were started. lysis therapy had to be abandoned due to respiratory tract bleeding global coagulation (pt %, aptt sec) and pc level normalized within hours after pc substitution. a normal centripetal portal flow could be achieved by high dose defibrotide ( mg/kg) and continued pc substitution after several weeks. pat. showed only a temporary improvement under defibrotide treatment. due to clinical deterioration (hepatic pain, increased ascites) and low pc level ( %) a continuous pc substitution ( iu/kg every h) was initiated. there was a prompt recovery after adding pc with a dramatic reduction of ascites, weight and abdominal pain within - days after start of pc infusion. elevated bilirubin levels returned to normal in both patients. in our patients neither prophylactic administration of at iii nor of defibrotide were able to prevent moderate to severe vod.our data indicate that pc substitution may be a useful adjunctive treatment in severe vod. until controlled studied will be initiated we recommend a stratified treatment in vod, starting with defibrotide, and adding pc in unresponsive cases. ( ) showed recently that restrictive strategy of red-cell transfusion could be at least as effective as and possibly superior to a liberal transfusion strategy in critically ill patients. the aim of this study was to assess the impact of local transfusion guidelines emphasizing restrictive strategy on patients undergoing heart surgery and the prognostic value of transfusion following those restrictive criteria. methods. two groups of heart surgery patients were compared before and after the introduction of local transfusion guidelines. these guidelines involved general information on blood transfusion risks and obligation for the physician to respect predetermined transfusion criteria (hb < g/dl or > g/dl associated to systolic arterial pressure < mmhg or age over yrs or hr > /min or ci < . l/mim/m² or other associated disease . . . * . . . . * < . mortality (%) * * < . conclusion. introduction of local restrictive transfusion guidelines was associated to a significant reduction in red cell transfusion during the postoperative period of heart surgery. the global morbidity and mortality rates in the whole group of patients were not affected. however patients who required blood transfusion following the restrictive strategy had a worse outcome. transfusion was probably more the consequence than the cause of this worse prognosis. if transfusion was the cause of the worse prognosis, then morbidity and mortality rates would have been higher among patients requiring transfusion during liberal period than in the whole group of patient. ( ) hebert pc and col. a multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. n engl j med ; : - . risk factors and outcome in european cardiac surgery higgins tl. quantifying risk and assessing outcome in cardiac surgery intensive care medicine, hospital del mar, servicio de microbiología to analyze if morbid obesity (mo) is associated with critical pathology in relation to patients undergoing vertical banded gastroplasty (vbg). all critical patients (cp) suffering mo, with a mean body mass index = , , receiving programmed surgical treatment, and admitted in the icu during the next period: st oct. to th feb. , were prospectively included. · surgery procedures. *restrictive: vbg according to masson's technic. *derivative: vbg + gip according to salmon's technic. vbg + gip according to capella's technic. ·type of study: descriptive. -vbg in association to other surgical procedures: cp ( cholecystectomies, right inguinal herniorhaphy, and other procedures). · mortality: cp: -septic shock -multiorganic disfunction · readmission: cp (subphrenic abcess and ards). complications . hypoxemia: cp ( % of the total) . . . . not secondary to hypoventilation: cp ( . %). . . . . associated to hypoventilation: cp ( . %) . need for noninvasive mechanical ventilation: cp ( %) . high blood pressure: cp ( . %). . disturbances of cardiac rythm and conduction: cp ( %). . metabolic acidosis: cp ( %). . other complications: cp ( %). conclusion. -the mo patient undergoing vbg, with or without gip, rather than a patient bound to the reanimation or recovery room, is indeed a patient who requires admission in the icu for, at least, - hours. -hypertension of difficult management and hypoxemia not due to hypoventilation nor shunt are the most frequent complications. -an important percentage of cp requires also mechanical ventilation. -complications related to surgery are exceptional. karlicek a. , haveman j. w. , verhoeven e. , van den dungen j. j. a. m. , tielliu . i. f. n. , hulsebos r. g. , nijsten m. w. n. surgery, groningen university hospital, groningen, netherlands introduction. the mortality in acute abdominal aortic aneurysms remains high. recent series still report a hospital mortality rate of more than % ( , ). despite the large number of published studies on hospital outcome, long-term outcome after icu admission has hardly been studied. here we present hospital survival and long-term outcome in patients with an acute abdominal aortic aneurysm. the records of all patients operated for aneurysm surgery between and were retrospectively reviewed. in patients surgery was performed for an acute abdominal aortic aneurysm. all operation reports were analysed. for complete follow-up the general practitioner was contacted if necessary. after arrival in the emergency department and confirmation of the diagnosis by physical examination and/or ultrasound all patients were immediately brought to the operation room. in our hospital even patients with cardiac arrest on arrival in the operation room are treated without delay, and were thus included in our study. all surviving patients were admitted at the intensive care. in case of postoperative haemodynamic instability, multiple organ failure, sepsis or diarrhea a sigmoidoscopy was performed to assess the presence of ischemia or infarction. three hundred and eight patients were operated for an acute abdominal aortic aneurysm, men and women. operative mortality was % ( / ). calculated from the moment of icu admission, day survival was %. cumulative survival rates calculated with the kaplan meier method at , , and years were %, %, % and % respectively. in patients in whom sigmoid resection was performed, day survival was % compared to % in the other patients. mortality in ruptured abdominal aortic aneurysm remains high, day survival was % in our group. sigmoid resection was associated with lower survival but sigmoidoscopy should be augmented to exclude sigmoid necrosis. outcome in these patients is not invariably poor. long term follow-up shows that also after discharge from the hospital these patients have a high mortality. carvalho a. g. r. , gomes r. v. , santos jr. b. , barbosa o. n. , weksler a. , pontes a. p. , camara a. c. surgical intensive care unit, instituto nacional de cardiologia laranjeiras, rio de janeiro, brazil introduction. prognostic markers developed in europe and north america cannot be applied in latin america where life expectancy is % lower according to world health organization. the objective of this study is to analyze patients profile submitted to heart surgery (hs), type of surgery distribution and the impact of variables, previously reported in medical literature, in the mortality and duration of intensive care unit (icu) stay in a public tertiary hospital. cohort study of patients submitted to hs from january to april . patients profile, type of surgery distribution and many variables were analyzed. variables that were studied: age, gender, body mass index (bmi), body area (ba), preoperative in-hospital stay (preop), extracorporeal circulation (ecc) duration, ventricular function (vf), surgical indication, combined procedures (comb), urgency for the surgery, presence of diabetes mellitus (dm), systemic arterial hypertension (ah) and cigarette smoke (cs). the profile and patients variables were analyzed and compared in two different groups. group a (ga): patients discharged from icu or in-icu stay lower than or equal to days (median in-icu stay in this study). group b (gb): death during icu admission or in-icu stay longer than days. t-student, mann-whitney, chi-squared and fisher tests were used in the statistical analysis. conclusion. there is a rather singular distribution of surgeries in this group. many of the previously described variables showed correlation with mortality or longer admission in the icu. prospective studies will be held in order to adjust these variables and determine new ones more relevant to underdeveloped countries. pierce c. m. , fortune p. , petros a. j. picu, great ormond street hospital, london, united kingdom, picu, royal children's hospital, melbourne, australia there are anecdotal reports of sildenafil, a type phospodiesterase inhibitor, being used to reduce pulmonary artery pressure in children with mainly cardiac induced pulmonary hypertension (pht). we have given oral sildenafil to children on our paediatric intensive care units with pht from various causes. diaphragmatic hernia ( ), avsd ( ) vsd ( ) pda ( ), pphn ( ) pulmonary hypoplasia ( ). the median age of the group was m (iqr - m). were receiving inhaled nitric oxide during sildenafil. median dose was . mg/kg (iqr . - . mg/kg hrly) and duration was days (iqr - ). pulmonary artery pressures were directly measured in of the cardiac children and deduced from doppler echocardiographic measurements of the tr jet in children.results. pap decreased significantly (p< . ) following oral doses of sildenafil (n= ). mean pulmonary/system (p/s) ratios decreased from . to . (n= ) within hours of the oral dose. systemic pressure was unaltered in all children. in one child with pulmonary hypoplasia the p/s ratio was unaffected. oral sildenafil can significantly reduce raised pap in children when there is a reversible etiology. this may be particularly useful in children and neonate with pphn. central venous catheters (cvc) are an important means of securing intravascular access in pediatric intensive care unit patients. one of the major morbidity's in use of cvc is catheter-related infection (cri). the incidence of bacteremia with cvc use is approximately . / catheter days and mortality as high as %. one approach to reduce the incidence of cri has been to decrease catheter bacterial colonization (cbc). reduction in cbc is achieved by coating or impregnating antimicrobial substances into the catheter material. use of minocycline/rifampin treated catheters has been shown to reduce the rate of cri in critically ill patients. the concern in pediatric population is the use of minocycline. tetracycline and its derivatives (minocycline), when used in young children, carry the risk of dental and sceletal abnormalities. the problem of potential eluting of minocycline from minocycline-impregnated catheters may pose a risk for young children. our study examined whether detectable levels of minocycline and rifampin were present in the serum of the pediatric intensive care unit patients with indwelling minocycline/rifampin impregnated cvc. methods. patients admitted to pccu age - years and in need of cvc were eligible for study. six patients were enrolled. each patient had two samples of blood and . ml withdrawn for rifampin and minocycline assays respectively. collection times were at the time of catheter insertion and h thereafter for seven days or until catheter removal, whichever came first. rifampin serum samples were processed prospectively soon after colection by standard hplc. minocycline serum samples were stored frozen in - centigrade and assayed in one batch using reverse phase hplc. results. demographic data are in table. ranges with mean values in ( ). none of the minocycline samples had detectable level of antibiotic. the limit of sensitivity for minocycline was . mg/l. therapeutic levels are . - . mcg/ml. one patient had consecutive samples to with low therapeutic levels of rifampin ( - mcg/ml). therapeutic levels of rifampin are - mcg/ml. rifampin sensitivity was mcg/ml. rifampin has distinct peak time and no interfering substances were identified.sex ( ), the emergence of this consequences required fast and corrective treatment. an inotropic agents commonly used in vlbw infants such as dopamine and norepinephrine in some cases do not produce elevation in blood pressure despite using of very high dose. in this study i would like to exam the influence of hydrocortisone administration in vlbw infants with hypotension unresponsive to stndard catecholamine treatment. i have reviewed the cardiovascular response to hydrocortisone therapy in preterm infants. mean gestation age was . ( - ) weeks, postnatal age . ( - )days, mean birth weight g ( - ). eight of them suffered from respiratory distress syndrome and eight from sepsis. the first line of hypotension therapy was always volume administration (normal saline or albumine) and catecholamine infusion. hydrocortisone at the dose mg/kg was administered when dopamine at the dose mcg/kg/min ( patients or norepinephrine . mcg/kg/min ( patients)failed to normalized arterial blood pressure. pneumococcal meningitis is an important cause of morbility and mortality in children. we describe the epidemiological characteristics and clinical features of pneumococcal meinigitis in children admitted to a children's hospital in barcelona. medical records of children with a diagnosis of pneumococcal meningitis based on identification of s. pneumoniae in the blood or cerebrospinal fluid between january, , to april, , were retrospectively reviewed. results. cases of pneumococcal meningitis were diagnosed in patients. median age was months (range . m- . y). children were younger than years old ( %). male-female ratio was . : . none of the children had a previous immunological deficit. thirteen patients ( %) were pre-treated with antibiotics. the most frequent signs on admission were fever ( %), vomiting ( %), headache and irritability ( %), othalgia ( %) and shock ( %). neurological findings were lowered level of consciousness in patients ( %), signs of meningismus in patients ( %) and arreactive mydriasis in patients ( %). the mean leukocyte counts in blood were /mm and the mean c-reactive protein was mg/l. cerebral spine fluid indices on admission were: white blood cell= ( - ) /mm ; protein= ( - ) mg/dl; and glucose= ( - ) mg/dl. main serogroups were: ( %), ( %), ( %), ( %), ( %), ( %), ( %) and ( %). overall, % of the pneumococcal isolates were penicilin-nonsusceptible, % cefotaxim-nonsusceptible and % were vancomycinnonsusceptible. an initial abnormal cranial computed tomography was found in patients. the median duration of parenteral antibiotic therapy was days. all patients were empirically treated initially with cefotaxime (associated to vancomycin in of them). twenty-six patients ( %) received dexamethasone. the administration of mannitol was necessary in patients ( %) and anticonvulsants were administrated in patients ( %). only patients ( %) needed inotropic support (no longer than hours). mechanical ventilation was required in patients ( %) during a mean of . days (range - ). acute complications were: metabolic acidosis ( / ), disseminated intravascular coagulopathy ( / ), seizures ( / ), siadh ( / ) and diabetes insipidus ( / ). twelve patients ( %) suffered deafness, three patients ( %) hemiparesia and four ( %) were exitus. the mean hospital stay was . days and mean intensive care stay was . days. there is an increased prevalence of pneumococco with decreased susceptibility to penicillin and to cefotaxime. deafness is one of the most common and serious sequelae of pneumococcal meningitis. corticotherapy has reduced the incidence of hearing loss. the new, antipneumococcal conjugated vaccine will confer effective prevention from the age of two months and will reduce the incidence of this meningitis. aims : to analize sedation/anesthesy methods used in our hospital for painfull or unconfortable procedures in children in relation to : )patient confort, )sedation complications, )and efficacy of the procedure a prospective study was conducted from january to march in disconfortable procedures in children. mean age was m ; their asa score was in %, in %, in %, and in %. more frequent procedures were : lumbar punctures (lp), thoracentesis or drainages, central catheters insertion, endoscopys . we identified different groups in relation to methods of sedation/analgesy : -procedures done in the emergency department with local anesthesia; -procedures done with administration of intravenous midazolan+ketamine; -procedures done with anesthesic support. we used the ramsay scale to classify the degree of anesthesia and the serna behavioral scale to classify the reaction to the procedure.results. group (n= ): %patients fighted against the procedure (serna scale ) and in % of the patients, complications of the procedure were found to be related to inadequate sedation. group (n= ): in %, sedation was considered inadequate -serna level (n= ) and (n= )-and in case there were complications of the procedure related to unsufficient sedation; there were ( %)cases of minor complications sedation-related; group (n= ): patient confort and adequacy of the sedation were found in %, with ( %) complications of the anesthesic method.conclusion. sedation/anesthesia were needed for the confort of the patients; only minor complications of sedation/anesthesy were found ; efficacy of the procedure was best achieved with the anesthesic method. introduction. the goals of emergency airway management are to antecipate and recognize respiratory problems and support therapy. the endotracheal intubation ( et) is not a routine procedure and it requests planning and personnel qualified to reduce the complications associated to this technique . the purpose of this study is to evaluate early complications associated with endotracheal intubation methods. data were collected prospectively from february to january in tertiary teaching hospital. the variables were obtained in four age groups: group (> month); group (between month to months); group (between months to months)and group (> months). the data were collected as demographic data, reason for endotracheal (et) intubation, sedation administered, local of et, physician responsible for et, complications associated with airway management. the major complications were defined as technical problems that resulted increased morbidity. minor complications were incidents that should be avoided. the complications were compared between emergency or elective et intubation. statistical analysis by chi-square, fisher exact test . we evaluated ( % female and % male) no consecutive patients. indication for intubation were: respiratory failure ( %), coma or depressed sensorium ( . %), post-operative ( %) and shock ( %). sedation and/or analgesic were used in % of patients and . % did not receive a sedative or analgesic for et intubation. a total et emergency intubation ( we report an outbreak due to rsv in a bedded picu with an annual admission rate of approximately patients, cardiac and medical patients accounting each for % of the population and % surgical.methods. an outbreak is defined as an event in which minimally patients develop bronchiolitis due to rsv following transmission via hands of carers within a limited period of week.nasopharyngeal aspirates were obtained from children with symptoms of lower airway infection, all samples were tested for rsv using the enzyme immuno assay, followed by tissue culture when the assay was negative. rsv positive children were isolated in cubicles and strict standards of hygiene were implemented. introduction.the objective of the study was to investigate the validity of outcome prediction after severe head injury using serum levels of protein s- b and of neuron specific enolase nse. methods.fifteen patients with severe head injury were included in this prospective study ( men and women) mean age yrs ( - ). none of the above patients had spinal cord injury or any other neurological disease. venous blood samples were taken on admission and consecutively the , , , , and day. immunoluminometric assay was used for the specimens. we tried to correlate the s- b and nse serum concentrations with the ct scan intacerebral pathology as well with the age, gender and outcome. results. all patients had elevated s- b and nse serum concentrations, with a gradual reduction towards the th day of icu stay. the mean values of day , for s- b were . ìg/l and for nse were . ìg/l. of day , they were for s- b . ìg/l and for nse . ìg/l. patients who died had the first day mean values of s- b . ìg/l and nse . ìg/l, whereas the survivors had mean values of s- b . ìg/l and of nse . ìg/l (p < . ). there was no strong correlation between the ct scan findings, the initial serum s- b and nse values and the gcs, on admission. conclusion. the protein s- b and nse are biochemical markers that seems to be elevated during the first days of injury, in patients with severe head trauma and could be used as markers of he severity of the injury. if protein s- b and nse could be used as a prognostic factor of the patient outcome, needs more investigation. our study is continued. estimates such as -day survival may be grossly misleading for assessment of intensive care utility. late mortality and morbidity may severely affect overall outcome. we studied -day survival rate in addition to survivors´ general health evaluation and prevalence of signs indicating post-traumatic stress disorder (ptsd). the setting is a university general intensive care unit. during the study period all adult patients who had been intubated and mechanically ventilated for at least hours were included (patients who died before hours are excluded). three to six months after their critical illness, survival data were retrieved from hospital and national registers. all patients surviving at this time were sent a health survey questionnaire (sf- ) and the post-traumatic stress syndrome -questions inventory (ptss- ). results. patients fulfilled the inclusion criteria. the mean age was years, % were women. health questionnaires were returned by ( %) of the survivors at follow-up time. -day survival rate was %, at days survival rate had fallen to %. among the responding survivors the frequency of a response pattern compatible with ptsd was %. survivors without signs of ptsd had sf- mean scores more than standard deviation (sd) below the swedish norm in the domains of physical functioning, role-physical and social functioning. survivors with signs of ptsd scored below non-ptsd survivors in every domain, and were more than sd below the swedish norm in the domains of social functioning, roleemotional and mental health. in total, there were only five persons ( % of respondents) who scored at or above the swedish norm for both the physical and the mental health summary scales. assuming the same outcome in non-respondents this figure would correspond to about % of all the included patients. conclusion. in this cohort of severely ill patients -day mortality was in the expected range but much mortality (another %) occurs in the following weeks, indicating a number of patients who have been subjected to long-lasting care with very meagre benefits. at - months following onset of their disease, survivors show considerably reduced subjective rating of their general health and life quality. as much as % of the survivors show signs compatible with ptsd. it could be estimated that about % of all patients included will both survive and within - months reach a level of general health comparable to that of the general population. the aim of this study is to probe that critically ill patients gender is not associated with differences in severity of illness and related mortality. we had tested the premise in front of a controversial evidence offered by several years of our icu activity. observational study. retrospective analysis using data prospectively collected in a medical-surgical icu of beds, in a teaching reference hospital, from november to july . we analyzed consecutive admissions considering reason for admission, age, icu length of stay, severity of illness (mpm , mpm , saps ii and spanish version of apache iii) and related risk of death. cases were analyzed according to gender and age decades. therapeutic effort was analyzed according nems system. standarized mortality ratio (smr) and its % ci was determined. one thousand and twelve cases out of were women. mean age (sd) was ( ) years. significative differences were founded in mpm prognostic values ( . ± . for men and . ± . for women, p . ). the rest of epidemiological data do not offer significant differences. smr for men was . , and for women . , but % ci overlapped . - . vs. . - . , p ns. the same differences were found when different age intervals were analyzed. only admission diagnostic (ischemic cardiopathy, post cardiopulmonar arrest and multiple trauma with no head trauma) showed greater mortality rates in women, but these differences disappeared when age intervals were considered. in spite of certain confusing data about greater mortality ratios in women admitted to our icu, accurate analysis does not show significant differences in severity of illness, associated prognosis and mortality, and therapeutic effort between male and female. bacterial infection is one of the most frequent and most feared complications in patients with a hematologic malignancy (phm). in a retrospective study, we found that bacteremia precipitating icu admission in phm was associated with a better outcome [ ]. however, it remained unclear whether this finding could be extrapolated to all bacterial infections. the aim of this prospective study was to evaluate whether bacterial pneumonia (bp) and bacterial sepsis or other bacterial infections (bs) had a better outcome compared to non-bacterial or noninfectious complications (nbc) in critically ill phm.methods. consecutive phm admitted to the icu over a year period were categorized into bp (n= ), bs (n= ) or nbc (n= ) according to strict diagnostic criteria by an independent panel of physicians who were blinded for the outcome. the impact of bp and bs on the inhospital mortality was assessed by logistic regression after adjustment for severity of critical and underlying hematologic illness, duration of hospitalization before icu admission and other potentially important prognostic factors. two models were tested, the first using a classical severity of illness score (apache iii) and the second using a score system especially designed for cancer patients (groeger score) [ ] . bacterial infection is one of the more favourable complications precipitating icu admission in phm and is associated with comparable mortality rates as in general icu patients. therefore, reluctance to admit phm to the icu for advance support is unjustified, especially when a bacterial infection is suspected to be the cause of deterioration. ( , ) the cleveland clinic score is the only one, to compile intraoperative data until the timepoint of icu admission.( , ) we wanted to find out, whether the combination of pre and postoperative score, in alliance with additional parameters, improves the predictability of outcome. from from until adult cardiothoracic patients were examined. logistic regression was used for analyzing those variables, dealing with mortality. the selection of significant factors is based on a stepwise forward procedure(p< , ). the accuracy of multivariate analysis is shown as roc(receiver-operator characteristic) curve. . variables, pre as well as intraoperative parameters proved to be statistically significant in the analysis, in the multivariate analysis: both scores, operation and aox time, preop at iii, assessment of intraop course, hb at icu admission, blood loss h< ml and rethoracotomy for bleeding. the pre and the postoperative cleveland clinic risk score were both statistically significant in the uni and multivariate analysis, but their combination improved roc. additional parameters had only little further impact. pre and postoperative cleveland clinic score are reliable in predicting the risk of cardiothoracic patients. adding further intra and postoperative data, risk stratification becomes more precise. the appearance of unexpected intraoperative difficulties was highly significant for adverse outcome. the collection of data should be continued on the icu and therapy should be reevaluated and modified any time. objective: to describe the frequency, etiologies, forms of presentation, and foci of bacteremia identified in patients admitted to the icu. prospective epidemiological surveillance study carried out from april to march . bacteremia was defined as the isolation of a pathogenic microorganism in one or more blood samples. bacteremias were classified into contaminating or true according to clinical manifestations. a descriptive analysis of variables including mean values, ranges, and standard deviations is presented. a total of episodes of bacteremia were identified, of which were true bacteremias ( . episodes per patients). the characteristics of patients with true bacteremia were as follows: mean (sd) age ( . ) years; male sex . %; mean apache ii score on admission . ( . ); and mean length of previous hospitalization ( ) days. in ( . %) cases, bacteremias were acquired in the icu and in ( . %) episodes were polymicrobial. a total of pathogens were cultured. these included gram-positive cocci in ( . %) cases, gram-negative bacteria in ( . %), and fungi in ( . %). initial presentation included severe sepsis in ( . %) cases and septic shock in ( . %). the most frequent origin of intra-icu true bacteremias was unknown in . % of cases (primary bacteremia) followed by catheterrelated bacteremia. crude mortality was . % and bacteremia-related mortality . %. primary bacteremia and catheter-related bacteremia were the most common. a total of . % bacteremias were polymicrobial. gram-positive cocci were the predominant causative pathogens. gyurov e. g. , milanov m. s. , milanov s. g. , neichev p. g. general icu, emergency medicine hospital "pirogov", sofia, bulgaria intensive care units are unique because they house seriously ill patients in confined environments where antibiotic use is extremely common. since our last publication ( ) there is a substantial rise in emergence of nosocomial infection namely gram-positive as well as changes of pattern of emergence. to study the frequency of emergence of nosocomial infection (nci) in intensive care unit (icu) we studied retrospectively data from case records and flow sheets of postoperative patients in our icu during - and compared data with last period. results. of patients in our icu during two years, we include those ( . %) who stayed for more than hours. according to results from cultures we divided them to three groups. group one included ( . %) patients without bacterial growth. group included patients with proved nosocomial infections /nci/. we obtained samples: from urinary catheters ( positive- . %), from tracheal tube ( positive- . %), from blood ( positive- . %), intradermal segments from central venous lines ( positive- . %), and from sputum ( positive- . %). the most common place for emergence of nci in our icu is respiratory tract. on -th icu day the tract became infected in almost % of the patients. the major role among pathogens played acinetobacter spp. ( . %), citrobacter spp. ( . %), p.aeruginosa ( % and serratia spp. ( %). the second place for emergence of nci is "reserved" for blood-stream infections. almost the half of the cultures ( . %) showed bacterial growth. the isolated pathogens were the same: acinetobacter spp ( %), serratia spp. ( %), but there was substantial rise in frequency of emergence of s. epidermidis during the last years (see figure) . its frequency almost equalized that of acinetobacter spp. the other two main sources for nci were urine catheters and cv catheters. they remained on -rd and -th place. group included patients with endogenous surgical wound infections. in this group we obtained samples from surgical wounds and drainages. in . % of cultures showed bacterial growth. during next this figure rose nearly twice ( . %). the leading role played the same acinetobacter spp., citrobacter spp., p. aeruginosa, enterococcus spp. and e. coli. the role of s. epidermidis increased greatly during this period de waele j. j. h. c. , hoste e. , blot s. , colardyn f. icu, ghent university hospital, gent, belgium introduction. intra abdominal infections frequently complicate the postoperative course of patients with acute necrotizing pancreatitis. the objective of this study was to analyze the incidence of pancreatic surinfection after surgery for acute necrotizing pancreatitis, describe its characteristics and identify associated risk factors. we retrospectively ( ) ( ) ( ) ( ) ( ) ( ) ( ) analyzed patients treated surgically for acute pancreatitis. surgical treatment consisted of debridement and postoperative continuous lavage. we recorded demographic characteristics, incidence of organ failure, data on surgical and infectious complications, data on surgical and medical treatment and disease severity by ranson and apache ii score. surinfection of the pancreatic necrosis was present in out of patients ( %). the surinfection was polymicrobial in patients. most of the organisms were gram-negative ( %), the others were gram-positives ( %) or fungi ( %). patients with surinfected necrosis were younger ( y vs. , p< . ), had surgical complications more often ( % vs. . %, p= . ), needed retroperitoneal lavage for a longer time ( days vs. , p< . ), and had a longer hospital stay ( days vs. , p< . ) than patients without surinfection. multivariate analysis demonstrated that age (or . ; % ci: . - . , p< . ) and the occurrence of a surgical complication or ; % ci . - . , p< . ) were independently associated with pancreatic surinfection. the mortality in patients with infected necrosis was higher ( % vs. %, p= . ), although in multivariate analysis no association was found. pancreatic surinfection is high after debridement and retroperitoneal lavage, with mainly gram negative bacteria involved. surgical complications and younger age are significant risk factors for surinfection. the aim of this report is to describe the current status of sap in spanish icu's methods. sap cases are identified in accordance with generally accepted criteria in each icu, such as ranson, imrie, pcr and ct-dynamic criteria. sap was selected from the data base of the national study of spanish nosocomial infection monitoring (envin). this study covered the period from to . envin is an observational, prospective and multicentre study. sap patients hospitalized during more than hours in all the participating icu's have been included in the study. these patients were monitored until their discharge from the icu or up to a maximum of - days. secondary infections have also been monitored. severity is measured by means of apache ii. infections, mortality, epidemiological data and antibiotics used as a means of prevention are described. the statistical analysis used the chi x test for the association of qualitative variables, the student t for the comparison of averages and the % statistical significance level results. patients ( . %) of the , patients monitored by envin were found to have sap. the average apache ii was . and the average stay was . days. the base illness was medical ( . %) and surgical ( %). . % of the patients underwent emergency surgery. ni accumulated incidence was . % and density incidence was / hospitalization days. crude mortality was % and ni-related mortality was %. infections were detected: of abdominal origin ( . %), ventilator-associated pneumonias ( . %), secondary bacteremias related to abdominal infection ( . %), catheter-associated urinary tract infections . %; primary bacteremias ( . %); central venous catheter-associated bacteremia ( . %). a total of pathogens were isolated. bgn . %, cgp . % (mrsa . %), fungii % (principally candidas), enterococci % and anaerobes . %. . % of the sap patients received antibiotic treatment. the antibiotic most frequently used in prophylaxis was imipenem-cilastatine ( %) and piperaciline-tazobactam ( %). the antibiotics most frequently used in absolute indication were imipenem %, piperaciline/tazobactam . %, metronidazol %, vancomicina . %, ciprofloxacino %, amikacina in % and fluconazol . % conclusion. sap cases in spanish icu's account for little more than % of all hospital cases, but they result in high levels of severity, morbidity and mortality. crude mortality and sap septic complication-related mortality in spanish icu's are much higher than the average indicated in the literature ( . % and . %). imipenem is the antibiotic most frequently used in prophlaxis. the irruption of candidas has been detected. fluid /blood warmers help to prevent hypothermia by raising the temperature of intravenously administered fluids & blood. the hl- hotline fluid warmer is the model used in our hospital. it consists of disposable tubing set with a central channel through which the fluid is infused and outer tubing through which heated water circulates. the water is contained in a reservoir, which is heated by an electric element. the manufacturer's instructions recommend changing the water in the reservoir every days. this water is a potential source of infection and we therefore sampled the water in the reservoir for microbiological contamination. this study was conducted at royal london hospital during the month of december .there are fluid warmers, all hotline in our operating theatres. samples of water were taken from each of the reservoirs at the end of the working day. using aseptic techniques ml of water were added to a labeled blood culture bottle. each sample was cultured for hours. after one week we repeated procedure results. after hours of incubation, pseudomonas sp. grown in out of culture bottles. the results from the second sets also grew pseudomonas sp. in the same out of water reservoirs.conclusion. the water in the reservoir is heated to - degree celsius. this temperature does not inhibit the growth of pseudomonas. each time the disposable tube is disconnected from the reservoir approximately ml of water is spilled potentially spreading microorganisms. in addition there are case reports of cracks/splits in the inner tubing of the disposable tubing potentially exposing infused fluid or blood to heated water from the reservoir ( ). methods. ( . %) of consecutive cardiac surgery patients operated at onassis cardiac surgery center, from january st to june th , developed t> . c and leucocytosis, without evidence of specific site of infection. those patients were examined for possible catheter related infection, by removing central and arterial catheters and sending them along with blood specimens for culture. infections within the first postoperative h were defined as early, whereas those developed after the first h were defined as late. we examined the relation between the incidence of catheter related infection and the type of microorganism isolated, the type of operation performed, the icu stay and the hospital mortality. . coronary artery bypass grafting(cabg), valve or ascending aorta replacement(vr), combined(cabg+vr), acute dissecting aneurysm(ada) and other operations were carried out. positive blood or catheter cultures were found in patients ( . %). staphylococcus epidermidis was cultured from all patients with early(n= ) and % of those with late(n= ) infection, while candida was found in % of those with late infection. icu stay and hospital mortality was ten times higher in patients with positive blood or catheter cultures compared to the general icu population ( . vs . days and . % vs . %, respectively). finally, mortality was higher in patients with late compared to those with early infection( % vs %). (pts) who had suffered traumatic brain injury (tbi) as well as the immune response of these pts. pts with moderate to severe tbi (gcs =< ) and age > were enrolled under the presupposition they remained on mechanical ventilation (mv) > days. a total of tbi pts were followed-up; infected pts were identified and associated factors were studied. in addition, serum immunoglobulin (sig) levels and soluble interleukin- receptors (sil- r) were measured in infected pts. c. albicans species. candidemia in icu patients is associated with a high mortality rate. c. albicans was the most common yeast isolated from blood. non-c. albicans species have a frequent occurence among candidemic icu patients. the moderate susceptibility of azoles against non-c. albicans species indicates the usefulness of susceptibility testing for antifungal treatment. prospective, cohort, observational, and multicenter study. urine cultures were performed once a week to all patients admitted to the icu. samples were processed at the different clinical microbiology laboratories of the participating hospital using specific culture medium (sabouraud) and the bactec technique and the a c (biomerieux) system for the identification of species. candiduria was defined as < cfu of candida spp. in the urine. frequencies are expressed as cumulative incidence (%) and incidence density (episodes per days of urinary catheter). . results. a total of patients admitted > days to the participating icus between may to january were included in the study. of these patients, ( %) had a urinary catheter inserted, with , urinary catheter days. one or more candida spp. in the urine were detected in patients. the rate of candiduria was per patients/icu and the incidence density . per days of urinary catheter. in cases, candida spp. in association with different bacteria ( . %) were found, mostly gram-negative pathogens ( cases), in particular p. aeruginosa (n= ) and e. coli (n= ), and gram-positive pathogens ( cases) especially enterococcos (n= ). in respect to candida spp., c. albicans predominated ( . %) followed by c. glabrata ( . %), c. tropicalis ( . %), c. parapsilosis ( . %), and c. krusei ( . %), independently of the week in which isolation of pathogens was made. conclusions: candiduria was diagnosed in % of critically ill patients admitted for more than days in the icu. candida albicans was the pathogen most frequently recovered ( . %), although c. non-albicans was isolated in one out of each three cases. a retrospective study was done over the last year that included neonatal patients admitted at the intensive care unit. all patients had congenital anomalies ( patients with gastroschisis ( . %), patients with esophageal atresia ( . %), and others with intestinal obstruction, duodenal atresia and malrotation). . % of the patients were on total parenteral nutrition and mechanical ventilation. the average stay in the icu was . days. candida albicans was checked for in swabs of wound, in blood-culture, stool-culture, urine-culture, tracheal aspirate, gastric asp results candida albicans was identified in patients ( . %). it usually appeared - days after the introduction of the antibiotic therapy. it was most commonly found in gastric aspirate ( . %), stool-culture ( . %) etc. it would first appear in gastrointestinal tract (stool-culture and gastric aspirate after days). in respiratory and urinary tract candida was identified after days, and in blood-culture after days. . % of the patients received cephtriaxon or ampicillin, and . % amikacin or gentamycin and metronidazol. morbidity in patients with yeast infection is very high. the most common causative agent is candida, and the predilection organ is digestive tract. risk factors are: prematurity, mechanical ventilation, total parenteral nutrition, longer hospital stay and widespectrum antibiotics. due to unspecific clinical picture early diagnosis is usually made according to the results of taken cultures. there are still many dilemmas regarding systemic antimycotic profilaxys. key: cord- -zdwmxaz authors: tong, c. y. w.; schelenz, s. title: clinical virology in nicu, picu and aicu date: - - journal: infection control in the intensive care unit doi: . / - - - - _ sha: doc_id: cord_uid: zdwmxaz viruses are significant causes of nosocomial infections, particularly in intensive care unit (icu) where seriously ill and vulnerable patients are being cared for. four major routes of nosocomial virus transmission in the icu are identified, viz. respiratory, faecal–oral, exposure to blood and body fluid and direct contact with infected patients or through fomites. different infection control measures are available according to the natural history, biology, pathogenesis, epidemiology and mode of transmission of each virus. in this chapter, we discuss some of the important viruses that could be associated with nosocomial infections in the icu. intensivists should work closely with microbiologists, virologists and the laboratory to diagnose such infection early, work proactively to prevent outbreaks and manage viral infections using appropriate strategies. influenza viruses (family orthomyxoviridae) are classified into types a, b and c. annual seasonal outbreaks of influenza are caused by minor antigenic changes (antigenic drift) seen in influenza a and b viruses. major changes in antigenic subtypes (antigenic shift) are only found in influenza a virus and typically involve the emergence of novel hemagglutinin (h) and/or neuraminidase (n) proteins on the viral envelope. pandemic influenza occurs when a new influenza a strain emerges, to which the majority of the world's population has little or no immunity. there were three influenza pandemics in the last century, of which the pandemic in due to the h n virus was the most severe. the first pandemic of this century occurred in [ ] and was due to another h n variant that emerged through a quadruple reassortment of viral rnas derived from human, avian, eurasian and north american swine influenza sources [ ] . the presence of animal influenza subtypes, particularly avian influenza viruses such as h n , is of continuous concern, as these could be the source of future pandemics. though with relatively high case-fatality rate, h n avian influenza virus has so far only caused a limited number of human infections in restricted geographical locations with little evidence of human to human spread. however, the pandemic h n virus proved to be a major burden for icu staff [ ] . clinically, influenza infection is characterised by abrupt onset of fever, sore throat, myalgia, cough, headache and malaise. young children may develop croup, pneumonia or middle ear infection. with seasonal influenza, complications are often seen in the elderly, the immunocompromised and those with pre-existing chronic heart or lung disease or diabetes. during the h n pandemic, children and young adults were more susceptible [ ] . overall fatality rate was . %, but as many as - % of hospitalised patients needed icu admission [ ] . severe disease and high mortality rates were seen in pregnant women, patients with underlying medical pulmonary, cardiac, metabolic, neuromuscular illness and severe obesity, and those in whom the diagnosis and admission was delayed [ ] [ ] [ ] . respiratory failures could be caused by viral pneumonia and acute respiratory distress syndrome (ards). in addition, secondary bacterial infection with streptococcus pneumoniae or staphylococcus aureus (often methicillin resistant) were found in - % of icu patients and - % of patients who died [ , , ] . fatal cases were often complicated by multiorgan failure. influenza has a short incubation time of - days. the virus is transmitted via droplets, and patients are infectious during the prodromal phase and up to days after symptom onset. rapid antigen detection from respiratory secretions is available, but this was found to be insensitive for the h n pandemic virus [ ] . more sensitive and specific real-time polymerase chain reaction (pcr) methods had to be used [ ] . due to the infection-control hazards of taking nasopharyngeal aspirates or bronchoalveolar lavage, the use of throat and nasal swabs were advocated. a complete respiratory diagnostic workup needed to be performed to exclude other viral, bacterial and noninfectious causes. a single negative influenza pcr result on an upper respiratory sample did not definitively exclude the diagnosis [ ] . in addition, other concurrent or secondary infections had to be considered. protocols needed to be in place to ensure satisfactory triage of patients according to severity [ ] . early administration of specific neuraminidase inhibitors, such as oral doses of oseltamivir or inhalation zanamivir, seemed to be beneficial [ ] . in more refractory cases, the off-license use of intravenously administered zanamivir or peramivir was tried. extracorporeal membrane oxygenation (ecmo) was found to be useful in very severe cases [ ] . the risk of nosocomial transmission to other hospitalised patients and staff is well documented. infected patients should ideally be cared for in a single room or cohorted together. health care workers should be protected through the proper use of personal protective equipments, including respirators or masks, eye protection, gowns/aprons and gloves [ , ] . high-filtration respirator to ffp (europe) or n /n (usa) standard should be used for staff carrying out aerosol-generating procedures after fit testing and training. surgical masks should be adequate for nonaerosol contacts [ ] . environmental contamination is an important source of transmission. good hand hygiene can prevent transmission through this route. vaccination is the most specific preventative measure. annual seasonal influenza vaccination to vulnerable individuals and health care workers has been advocated. a specific vaccine against the h n pandemic strain was developed within months of the onset of the outbreak. however, vaccine uptake rates amongst health care workers are usually poor, and more needs to be done to educate both patients and staff. respiratory syncytial virus (rsv) (family paramyxoviridae) is a major cause of lower respiratory tract infections in young children and infants. there are two subtypes, a and b, with varying dominance in different years [ ] . the incidence of rsv is seasonal in temperate climates, and hospital admissions usually peak during winter months. prematurity, bronchopulmonary dysplasia and congenital heart disease are associated with a significant risk for admission to high-dependency units or picu. in switzerland, it was estimated that approximately - % of each annual birth cohort required such admission. rsv can also cause significant disease in adults, particularly in immunocompromised individuals such as patients undergoing therapy for haematological malignancies, the elderly and those with chronic pulmonary disease [ ] . the most rapid diagnosis of rsv is by direct antigen detection methods such as chromatographic immunoassays. a typical rapid test method is completed within min and can be used as a point of care testing method in emergency rooms and icus. however, these rapid tests lack sensitivity [ ] . more recently, many laboratories have begun using multiplex real-time nucleic acid amplification techniques (naat) to diagnose respiratory tract infections, including rsv [ ] . although naat is highly sensitive, it is not a rapid testing method. hence, it is desirable to have a mixed strategy of diagnostic approaches, such as an initial rapid direct antigen test followed by retesting of negative samples by naat. nosocomial transmission of rsv in the icu and haemoncology units has frequently been reported. it is important to identify infected patients and to apply prompt and effective infection control measures (table . ). it is recognised that a combination of cohorting patients using dedicated health care staff, contact isolation of patients, strict adherence to hand hygiene; and screening visitors, family members and health care staff for upper respiratory tract infection symptoms significantly reduce the cross-infection rate of rsv. in haemoncology units, the practice of enhanced seasonal infection control programs for rsv has been shown to be effective [ ] . the usefulness of wearing masks and goggles is less clear. there is no safe and effective vaccine to prevent rsv infection. however, immunoprophylaxis in the form of rsv immunoglobulin (rsv-ig) or humanised monoclonal antibodies (palivizumab) is available as prophylaxis for some highrisk patients to prevent serious rsv disease or to limit further nosocomial spread. both palivizumab and rsv-ig have been shown to decrease the incidence of rsv hospitalisation and icu admission, although there was no significant reduction in the risk of mechanical ventilation or mortality rate. when given prophylaxis, infants born\ weeks gestational age and those with chronic lung and congenital heart disease all had a significant reduction in the risk of rsv hospitalisation [ ] . treating rsv infection is mainly supportive, including oxygen, ventilation and bronchodilatative drugs. aerosolised ribavirin has often been used in severe cases, with or without gamma globulin i.v. [ ] . however, evidence for the clinical efficacy of ribavirin in rsv infection remains inconclusive [ ] . the use of aerosolised ribavirin needs to be carefully controlled, as there are potential teratogenic effects on pregnant staff and visitors. others have tried a combination of palivizumab i.v. with or without ribavirin [ ] . another paramyxovirus, known as human metapneumovirus (hmpv), shares a similar spectrum of clinical illness as rsv. it is likely that general infection control measures against rsv would also be effective against hmpv. there are four types of human parainfluenza virus (piv) types: piv - (family paramyxoviridae). infections with piv and are seasonal, with a peak in autumn affecting mainly children between months and years of age. clinically, patients often present with croup or a febrile upper respiratory tract infection. in contrast, piv is endemic throughout the year and infects mostly young infants in the first month of life and up to years of age. clinically, there is no specific presentation in piv , but bronchiolitis and pneumonia are not uncommon. in immunocompromised adults, such as stem cell transplant recipients, piv is associated with a high mortality rate. such patients often present with severe pneumonia and many require admission to the icu. the diagnosis of piv infection can be confirmed by immunofluorescence antigen detection or naat [ ] . nosocomial transmission is often due to piv and has been documented in neonatal care and adult haematology units [ ] . infection control precautions are the same as for rsv. despite several uncontrolled case series of apparent successful use of intravenously, orally or aerosolised administration of ribavirin to treat piv infections, there is no clear evidence that ribavirin with or without immunoglobulin alters mortality rates from piv pneumonia or decreases the duration of viral shedding from the nasopharynx [ ] . nevertheless, there may be a role for pre-emptive early therapy with ribavirin to prevent progression of upper airway infection to pneumonia. adenovirus (family adenoviridae) multiplies in the pharynx, conjunctiva or small intestine. clinically, the infection is localised and typically presents with pharyngitis, conjunctivitis or gastroenteritis depending on serotype. however, in young infants and immunocompromised patients such as organ transplant recipients or aids patients, adenovirus can cause severe pneumonia, disseminated infection or haemorrhagic cystitis. the diagnosis can be confirmed by specific antigen detection tests on respiratory or stool samples. viremia and viruria can be confirmed and quantified using real-time pcr. in respiratory infections, the virus spreads via droplets or through contaminated hands or fomites. nosocomial adenovirus infections have been reported and can be a particular problem in neonatal units. it is important to adhere to strict infection control procedures to prevent nosocomial spread (table . ). in vitro, adenovirus is susceptible to antivirals such as cidofovir and ribavirin [ ] . use of cidofovir in selected patients may be successful [ ] . a respiratory virus that caused a severe acute respiratory syndrome (sars) emerged from southern china in . the virus was subsequently identified as a novel virus from the coronaviridae family and was named sars coronavirus (sars cov) [ ] . sars was associated with a high mortality rate, and of the most concern to the international community was the potential in causing nosocomial infections. from a single index case in a hong kong hotel, a series of chains of outbreaks occurred in vietnam, singapore and canada [ ] . subsequently, infections were reported in major cities in asia, europe and usa, transmitted through international travel. in total, , individuals were infected, with deaths around the world. the emergence of sars was the first wake-up call to the medical community regarding the need for comprehensive infection control policies in hospitals and icu. this also led to the general provision of personal protective equipment (ppe) with training and fitting programmes for health care workers in many countries. sars is infectious from the onset of illness and infectiousness correlates with the degree of viral shedding. incidences of superspreaders or superspreading events may have accounted for most of the large-scale transmissions. older age and underlying comorbidity are major risk factors for fatality [ ] . viral loads in various anatomical sites also correlate with the severity of symptoms and mortality. shedding of sars cov peaks at day after the onset of symptoms. the disease pathology is characterized by uncontrolled viral replication, with a major proinflammatory response. the optimal therapy for sars is still not clear, as there were no randomized controlled trials conducted. treatment with interferon (ifn)-a, steroid, protease inhibitors (such as lopinavir) together with ribavirin, or convalescent plasma containing neutralising antibody, could all be useful. prophylaxis with ifn or hyperimmunoglobulin may also be considered as postexposure prophylaxis [ ] . sars cov is identified as a zoonosis with a natural reservoir in chinese horseshoe bats [ ] . its emergence is associated with local culinary practice in southern china, leading to captured palm civets acting as the amplifying host and passing on infection to human. as long as the reservoirs and amplifying hosts coexist, there is a potential for sars to re-emerge. intensivists should always be on the lookout for patients with unexplained severe respiratory infections and consider sars as a possible differential diagnosis. primary varicella zoster virus (vzv) (family herpesviridae) infection causes chickenpox. this is a common self-limiting childhood infection characterised by a mild fever and a generalised vesicular rash. risk factors for severe disease include immunosuppression, smoking and pregnancy. complications include bacterial sepsis, pneumonia, encephalitis, ataxia, toxic shock, necrotising fasciitis and haemorrhagic chickenpox with disseminated coagulopathy and fatality [ ] . chickenpox is highly infectious and can be transmitted via inhalation of respiratory secretions or by direct contact. patients are likely to be infective h before the appearance of the rash until the last lesion has crusted over. outbreaks in the icu have frequently been reported [ , ] . infected patients should be promptly isolated, preferably in negative-pressure rooms. a rapid diagnosis of chickenpox can be made by electron microscopy or immunofluorescence of scrapings from the vesicle base. a person who has had chickenpox does not develop chickenpox again, but the virus may reactivate as zoster/shingles. susceptibility to chickenpox can be determined by testing for the presence of vzv immunoglobulin (ig)g. infected patients need to be isolated immediately, and exposed patients and staff investigated. exposed staff who are susceptible to vzv should be excluded from contact with high-risk patients for - days postexposure. susceptible individuals at risk of severe disease should receive varicella-zoster immunoglobulin (vzig) prophylaxis, which could be given up to days after exposure. neonates born to mothers who developed chickenpox days before to days after delivery are highly susceptible due to a lack of protective maternal antibodies. in such cases, vzig prophylaxis to the neonate is recommended. the baby should also be isolated. intravenously administered acyclovir should be started promptly at the first sign of illness. most childhood chickenpox does not require treatment. however, in severe cases (e.g. pneumonitis, disseminated disease with visceral involvement and patients requiring hospitalisation), intravenously administered acyclovir ( mg/kg hourly) is the treatment of choice. treatment of neonates will require a higher dose ( mg/kg hourly). a live attenuated vaccine against vzv is available. susceptible health care workers should be immunised. rotavirus (family reoviridae) is highly infectious and a significant cause of nosocomial gastroenteritis, particularly in children \ years of age. patients present with sudden onset of fever, vomiting, abdominal pain and watery diarrhoea. due to the high viral shedding in the faeces, a diagnosis can be easily obtained using antigen-detection enzyme-linked immunosorbent assay (elisa) or electron microscopy. in temperate climates the infection is seasonal with peaks in winter, and hospital outbreaks often coincide with outbreaks in the community. in europe, it was found that - % of paediatric nosocomial gastroenteritis was positive for rotavirus, with an incidence of - . per , hospital days, leading to prolonged hospitalisation between . and . days [ ] . very sick infants with gastroenteritis may require intensive care and could, in turn, be the source of nosocomial infection in icu. premature and very low birth weight infants (\ , g) are particularly at risk, as severe complications such as necrotising enterocolitis and intestinal perforation are commonly reported. a dutch study found that amongst all nosocomially acquired viral infections in nicus, % were due to rotavirus, which demonstrates the importance of this infection in the icu setting [ ] . nosocomial rotavirus infections in adults have also been reported and occasionally cause serious complications in the elderly and immunosuppressed patients. nosocomial transmission has been previously associated with ungloved nasogastric feeding, contaminated toys, shortage of nurses, overcrowding and high patient turnover. adherence to effective infection control measures (hand hygiene, enteric precautions; table . ), as well as adequate staffing and patient cohorting/ isolation can therefore help prevent or manage an outbreak [ ] . the recently developed rotavirus vaccine could substantially reduce the incidence of nosocomial infections [ ] . norovirus (family caliciviridae) is the most common cause of nosocomial outbreaks of gastroenteritis. symptoms typically comprise profuse diarrhoea and projectile vomiting. the diagnosis can be confirmed by elisa, rt-pcr or electron microscopy of stool samples. noroviruses are highly infectious and are usually transmitted by direct contact via the faecal-oral route or via oropharyngeal exposure to aerosolised vomit. a number of outbreaks have recently been described in nicus involving mainly premature neonates, some of whom developed necrotising enterocolitis. neonates and immunocompromised patients can shed the virus for a prolonged time over months, which emphasises the need for rigorous adherence to effective infection control measures (table . ). additional measures such as increased hand hygiene and wiping of floors and incubators with agents active against caliciviruses have been proven to be particularly useful in controlling outbreaks in nicu wards [ ] . both enteroviruses and parechoviruses (family picornaviridae) have numerous subtypes. enteroviruses include polioviruses, coxsackieviruses, echoviruses and other numbered enteroviruses. there are as many as types of human parechoviruses [ ] . parechovirus type , in particular, can cause severe infection in young infants [ ] . both viruses are significant causes of nosocomial infections, particularly in the nicu. enterovirus outbreaks involving up to neonates have been reported [ ] , and an attack rate of % was reported. enterovirus infections can present as neonatal sepsis, meningoencephalitis, myocarditis, hepatitis or gastroenteritis. necrotising enterocolitis with pneumatosis intestinalis is a known complication in neonates. some enteroviruses, such as enterovirus , can cause severe and fatal illness in older children. parechoviruses can cause meningoencephalitis [ ] and a sepsis syndrome in young infants [ ] . enteroviruses and parechoviruses are genetically distinct from each other and require a different rt-pcr for diagnosis. sequencing of the gene encoding the vp region of the virus has been used to identify outbreak strains. with the global polio eradication programme, poliomyelitis is no longer a common nosocomial infection, although health care workers in the icu who may [ ] • hand washing (liquid soap) or decontamination (aqueous antiseptic/alcohol based-hand rub) (a). however, alcohol-based products are known to be less effective against nonenveloped viruses, for which hand washing with soap and water is preferred (b) • wear disposable gloves and aprons when contact with stool or vomitus is likely (b) • isolate symptomatic individuals (particularly with uncontrolled diarrhoea, incontinence, and children) (b) • avoid unnecessary movement of patients to unaffected areas (b) • staff working in affected areas must not work in unaffected areas within h (b) • exclude symptomatic staff members from duty until symptom free for h (b) • if a large number of patients is involved and no further isolation facilities are available, close the unit to new admissions or transfers until h after the last new case (b) • terminal cleaning of the environment, using freshly prepared hypochlorite ( , ppm) on hard surfaces (b) • caution visitors and emphasise hand hygiene (b) categorisation of recommendations: a strongly recommended for all hospitals and strongly supported by well-designed experimental or epidemiological studies; b strongly recommended for all hospitals and viewed as effective by experts in the field be in contact with live vaccine poliovirus shedding infants should ensure that they are immunised. rigorous hand washing (table . ) is the most important measure during an outbreak. cohort nursing, source isolation and screening are other measures frequently used (table . ). clearance of the virus by the host is antibody-mediated and many have advocated the use of normal human immunoglobulin (nhig). hepatitis a virus (family picornaviridae) belongs to the same family as enteroviruses and is usually transmitted via the faecal-oral route. nosocomial transmission of hepatitis a virus is well documented. an outbreak in an adult icu (aicu) occurred as a result of inadequate precautions taken while handling bile of a patient not suspected of incubating hepatitis a [ ] . most other outbreaks occurred in picus or nicus, with attack rates varying between and %. risk factors for outbreaks have been attributed to handling soiled bed pads, nappies or gowns of an index patient, failure to wash hands, and eating in the icu. in the nicu, vertical transmission and blood transfusion have been implicated as the cause of infection in the index case. the effect of nosocomial hepatitis a infection varies from asymptomatic to classic presentation with acute hepatitis. diagnosis is by serological detection of hepatitis-a-specific igm. the use of molecular techniques such as rt-pcr can help identify early infection or in difficult cases, such as those with immunodeficiency. sequencing of pcr products is useful in establishing epidemiological linkage during outbreaks. nhig has been successfully used for postexposure prophylaxis to control outbreaks. there is now increasing evidence that hepatitis a vaccine can be used for prophylaxis if the contact occurs within days from onset of illness in the index case [ ] . the most commonly encountered nosocomial blood-borne viruses are hepatitis b virus (hbv), hepatitis c virus (hcv) and human immunodeficiency virus (hiv). the main risks are transmission from patients to health care workers. however, transmissions between patients and from health care workers to patients have been reported. the best way to prevent occupational exposure of blood-borne viruses is to practice universal precautions. blood and body fluids (table . ) from any patient, whether or not there are identifiable risk factors, should be considered as a potential risk. this encourages good and safe practice and helps prevent unnecessary accidents. physical isolation of patients with blood-borne virus infection is generally not necessary unless there is profuse uncontrolled bleeding. infection-control teams and occupational health departments should adopt a proactive approach to educate and prevent sharps injury (table . ). there should also be specific instructions on how to deal with blood and body fluid exposure (table . ). hbv is the most infectious of the three common blood-borne viruses. the risk of transmission depends on the viral load of the source patient. an hbv-infected individual with hepatitis b ''e'' antigen (hbeag) tends to have a high viral load and is therefore more infectious than carriers without hbeag. estimate of infectivity ranges from % (hbeag absent) to % (hbeag present). all health care workers should be immunised against hbv. exposed health care workers who are susceptible (not immunised or vaccine nonresponders) should receive hepatitis b immunoglobulin for postexposure prophylaxis. a booster dose of vaccine should be given to those exposed individual who had previously been successfully immunised. hcv is probably the commonest blood-borne virus encountered in western countries. in the uk over a -year period, incidences of occupational exposure to hcv were reported in comparison with of hiv and of hbv [ ] . follow-up studies of health care workers who sustained a percutaneous exposure to blood from a patient known to have hcv infection have reported an average incidence of seroconversion of . % (range - %). no vaccine or postexposure prophylaxis was available to prevent hcv transmission. early diagnosis is essential, as early interferon treatment after seroconversion has a high success rate for eradication [ ] . exposed health care workers should be followed up at and the average risk of hiv transmission after percutaneous exposure to hiv-infected blood is about . %. after mucocutaneous exposure, the risk is estimated to be . %. a case-control study [ ] identified four factors with increased risk of transmission: • deep injury; • visible blood on the device that caused the injury; • injury with a needle that has been placed in a source patient's artery or vein; • terminal hiv-related illness in the source patient. this study also showed that the use of zidovudine prophylaxis reduce the risk of transmission by %. postexposure prophylaxis (pep) should therefore be offered to all health care workers who have significant exposure to blood or body fluid from a patient known to be at high risk of or to have hiv infection. various pep options are available depending on national recommendations. this should be started as soon as possible after exposure and continued for weeks. viral haemorrhagic fevers (vhfs) are severe and life-threatening diseases caused by a range of viruses. they are either zoonotic or arthropod-borne infections and are often endemic in certain parts of the world. they are often highly infectious through close contact with infected blood and body fluid and therefore pose a significant risk of hospital-acquired infection. as many patients with vhf present with shock and require vigorous supportive treatment, it is a potential problem in the icu. the major viruses of nosocomial concern in this setting are marburg, ebola, rift valley fever, lassa and crimean congo haemorrhagic fever (table . ). the incubation period for these vhfs ranges from - days. initial symptoms are often nonspecific but may eventually lead to haemorrhage and shock. any febrile patient who has returned from an endemic area of one of the vhf agents or has a history of contact with cases suspected to have vhf within weeks should be considered as at risk. however, malaria should always be excluded. a risk assessment needs to be performed, and any patient known or strongly suspected to be suffering from vhf should be admitted to a high-security infectious disease unit that is designed to manage these patients. while awaiting transfer to a secure unit, such patients should be placed in a negative-pressure room with strict source isolation. specimens for patient management should be processed in a high-security laboratory designated for category pathogens, and the aetiological agent established using pcr, serology and virus culture. all areas and materials in contact with infected patients should be autoclaved, incinerated or treated with hypochlorite ( , ppm of available chlorine). if the patient dies, the body should be placed in a sealable body bag sprayed or wiped with hypochlorite. individuals who have been in contact with a case of vhf should be put under surveillance for weeks. the successful i.v. use of ribavirin has been reported in some cases of vhfs (lassa, crimean congo haemorrhagic fever and hantaan). apart from yellow fever, no vaccines are available. shingles or zoster is the result of the reactivation of latent vzv (family herpesviridae) in the dorsal root or cranial nerve ganglia. the clinical presentation is a painful vesicular eruption covering the affected dermatome. the clinical diagnosis can be confirmed rapidly by immunofluorescence, electron microscopy or pcr of the cellular material obtained from a vesicular scraping. the infection is usually self-limiting but can be more severe in immunocompromised patients, in whom it may present over multiple dermatomes or as a disseminated infection. the latter cases should be managed as if they were chickenpox, and respiratory precautions for infection control have to be enforced. patients or health care staff members with classic shingles are contagious from the day the rash appears until the lesions are crusted over. there is some risk of nosocomial transmission if the lesions are on exposed areas of the body or in immunocompromised infected patients. nonimmune (vzv-igg negative) patients or health care staff members with no history of chickenpox are susceptible if they have close contact with shingles and should be managed as described for chickenpox contact. the herpes simplex virus (hsv) (family herpesviridae) consist of two types: hsv- and hsv- . clinically, they most commonly manifest with oral (mainly hsv- ) or genital (mainly hsv- ) ulcerations/vesicles, and reactivation is common, particularly in the icu. other presentations include keratitis, encephalitis, meningitis, herpetic whitlow or neonatal infection. the diagnosis can be confirmed rapidly by immunofluorescence, electron microscopy or pcr of vesicle/ulcer scrapings. in the immunocompromised patient, hsv can cause life-threatening disseminated infection and, early treatment with acyclovir i.v. is recommended. it has also been suggested that occult herpes virus reactivation may increase the mortality risk of icu patients [ ] . as the infected lesions contain virus, there is an increased risk of nosocomial transmission until the lesions have crusted over. standard isolation precautions should be in place to reduce transmission (table . ). patients with active lesions should be nursed away from high-risk patients (i.e. immunocompromised, severe eczema, burns, or neonates). as patients can be asymptomatic secretors, health care workers should wear gloves when dealing with mucosal secretions (i.e. saliva) to avoid infections such as herpetic whitlow. infected staff should cover lesions if possible and should not attend those at risk. neonatal herpes is usually transmitted from mother to the child at the time of delivery and may not be noticed until the infant develops the disease. universal precautions, in particularly, hand washing, should always be in place to reduce transmission of infection. to contain or prevent an outbreak, infected cases should be cohorted and nursed by dedicated staff who will not attend noninfected infants. rabies virus (family rhabdoviridae) is usually transmitted to humans following exposure to saliva of a rabid animal (e.g. dog, fox, bat) via a bite or scratch, but only % of exposed people develop disease. the virus spreads from the wound to the central nervous system causing fatal encephalitis, and the virus may be present in the patient's saliva, skin, eye, and brain tissue. the diagnosis can be confirmed by demonstrating the virus directly in brain tissue or saliva by rt-pcr or by immunofluorescence detection of antigen in skin biopsies from the nape of the neck. due to the severe and paralysing effect, patients may be admitted to the icu. to date, no case of nosocomial transmission has been reported apart from two patients who received corneal transplants from infected donors. suspected or proven cases should be placed in standard isolation and appropriate precautions taken when dealing with potential infectious secretions (e.g. wearing of mask if dealing with oral secretions). any health care worker with a significant exposure (e.g. splash of secretion onto mucosa or broken skin) should receive rabies vaccine and specific immunoglobulin. viral infection can cause significant morbidity and mortality and has the potential to result in cross infection, involving patients as well as health care workers. good infection-control practice is essential to prevent nosocomial infection. intensivists should be on the alert for important viruses causing infections according to age group of patients and mode of transmission and should never be complacent. good liaison with the laboratory is essential for determining correct diagnostic tests and timely report of results to help in patient management. human swine influenza a geographic dependence, surveillance, and origins of the influenza a (h n ) virus critical care services and h n influenza in australia and new zealand in vitro and in vivo characterization of new swineorigin h n influenza viruses writing committee of the who consultation on clinical aspects of pandemic (h n ) clinical aspects of pandemic influenza a (h n ) virus infection pandemic influenza a(h n ) virus illness among pregnant women in the united states risk of severe outcomes among patients admitted to hospital with pandemic (h n ) influenza preliminary estimation of risk factors for admission to intensive care units and for death in patients infected with a(h n ) influenza virus bacterial coinfections in lung tissue specimens from fatal cases of pandemic influenza a (h n )-united states evaluation of rapid influenza diagnostic tests for detection of novel influenza a (h n ) virus-united states evaluation of four real-time pcr assays for detection of influenza a (h n ) viruses novel h n influenza virus infection requiring extracorporeal membrane oxygenation in a pediatric heart transplant recipient critical care triage. recommendations and standard operating procedures for intensive care unit and hospital preparations for an influenza epidemic or mass disaster hospitalized patients with h n influenza in the united states protection of patients and staff during a pandemic. recommendations and standard operating procedures for intensive care unit and hospital preparations for an influenza epidemic or mass disaster prevention of nosocomial transmission of swineorigin pandemic influenza virus a/h n by infection control bundle genetic variability of group a human respiratory syncytial virus strains circulating in germany from to prospective population-based study of rsv-related intermediate care and intensive care unit admissions in switzerland over a -year period respiratory syncytial virus outbreak in a longterm care facility detected using reverse transcriptase polymerase chain reaction: an argument for real-time detection methods comparison of the luminex rvp fast assay with in-house real-time pcr for respiratory viral diagnosis successful prevention of respiratory syncytial virus nosocomial transmission following an enhanced seasonal infection control program a meta-analysis of the effect of antibody therapy for the prevention of severe respiratory syncytial virus infection respiratory syncytial virus infection in adults randomized controlled multicenter trial of aerosolized ribavirin for respiratory syncytial virus upper respiratory tract infection in hematopoietic cell transplant recipients intravenous palivizumab and ribavirin combination for respiratory syncytial virus disease in high-risk pediatric patients quantitative rt real time pcr and indirect immunofluorescence for the detection of human parainfluenza virus , , control of an outbreak of human parainfluenza virus in hematopoietic stem cell transplant recipients parainfluenza virus infections after hematopoietic stem cell transplantation: risk factors, response to antiviral therapy, and effect on transplant outcome clinical features and treatment of adenovirus infections a clinical algorithm identifies high risk pediatric oncology and bone marrow transplant patients likely to benefit from treatment of adenoviral infection a novel coronavirus associated with severe acute respiratory syndrome identification of severe acute respiratory syndrome in canada a comparative epidemiologic analysis of sars in hong kong, beijing and taiwan the management of coronavirus infections with particular reference to sars severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection severe complications of chickenpox in hospitalised children in the uk and ireland occupationally related outbreak of chickenpox in an intensive care unit outbreak of varicella-zoster virus infection among thai healthcare workers international variation in disease burden of rotavirus gastroenteritis in children with community-and nosocomially acquired infection clinical and epidemiologic characteristics of viral infections in a neonatal intensive care unit during a -year period guideline for hand hygiene in health-care settings. recommendations of the healthcare infection control practices advisory committee and the hipac/shea/apic/idsa hand hygiene task force healthcare-associated viral gastroenteritis among children in a large pediatric hospital norovirus infections in preterm infants: wide variety of clinical courses parechovirus typing in clinical specimens by nested or semi-nested pcr coupled with sequencing specific association of human parechovirus type with sepsis and fever in young infants, as identified by direct typing of cerebrospinal fluid samples diagnosis of horizontal enterovirus infections in neonates by nested pcr and direct sequence analysis extensive white matter abnormalities associated with neonatal parechovirus (hpev) infection human parechovirus infections in dutch children and the association between serotype and disease severity an outbreak of hepatitis a in an intensive care unit hepatitis a vaccine versus immune globulin for postexposure prophylaxis exposure of healthcare workers in england, wales, and northern ireland to bloodborne viruses between management of acute hepatitis c a case-control study of hiv seroconversion in health care workers after percutaneous exposure. centers for disease control and prevention needlestick surveillance group occult herpes family viral infections are endemic in critically ill surgical patients key: cord- -w ysjf authors: nan title: th international symposium on intensive care & emergency medicine: brussels, belgium. - march date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: w ysjf nan ventriculostomy-related infection (vri) is a serious complication in patients with hemorrhagic stroke. in such patients, diagnosis of vris is complicated by blood contamination of csf following ventricular hemorrhage. we aimed to evaluate the diagnostic potential of white blood cells count (wbc), c-reactive protein (crp), and procalcitonin (pct) to identify vris in patients with hemorrhagic stroke during the time of external ventricular drain (edv) in situ. this retrospective study was conducted at the neurosurgical-icu, university hospital of zurich. a total of patients with hemorrhagic stroke and an external ventricular drain (evd) were admitted over a years period at the icu. of those, patients with vris ("vri"), defined by positive csf bacterial culture and increased wbc in csf (> /ul), and patients without vris and with serial csf sampling ("no-vri") were analyzed. patients with csfcontamination or suspected vri (negative csf cultures but antibiotic treatments) were excluded. wbc, crp, and pct were measured daily. csf was sampled routinely twice a week or by t> °c. for the analysis, mean peak values of wbc, crp, pct during the time of evd in situ were compared between groups (t test). data are expressed as mean with ci %. results: between groups, wbc and crp were similar (wbc: . g/l and . g/ l, p= . and crp: . mg/l and . mg/l, p= . in the group vri and no-vri, respectively) ( figure , panel a and b ). in the group vri, pct was low and significantly lower than in the group no-vri ( . ug/l and . ug/l, p= . in the group vri and no-vri, respectively) (panel c). wbc in csf were similar between groups ( . /ul and . /ul p= . in the group vri and no-vri, respectively). in this study, serum-inflammatory markers were not able to screen patients with vris. their routine measurement should be carefully evaluated. introduction: central nervous system (cns) infections constitute a potentially lifethreatening neurological emergency. patients admitted to the intensive care unit (icu) usually present with a severe disease and organ failure, leading to high mortality and morbidity. we have performed a retrospective analysis during a -year period of patients admitted to a polyvalent icu. clinical, demographic and outcome data were collected to evaluate its clinical impact on the outcome of patients with cns infections. we identified patients with the diagnosis of meningitis, meningoencephalitis and ventriculitis, where the median age was , years (range - ). upon clinical presentation, their most frequent signs were fever ( %), meningeal signs ( %), seizures ( %), and a glasgow coma scale score < ( %). all needed ventilation support and % needed cardiovascular support. a definitive microbiological diagnosis was achieved on patients and antibiotic therapy was adjusted on of them. most common microorganisms were streptococcus pneumoniae (n= ), listeria (n= ) and pseudomonas aeruginosa (n= ) (figure ). other gram negative microorganisms were detected and lead to more adverse outcomes. meningitis was the cause of admission on patients and on a minority (n= ) meningitis was considered to be a secondary diagnosis on patients admitted for other causes (traumatic brain injury, subarachnoid or intraparenchymal hemorrhage, postoperatively of neurosurgical tumor). patients that eventually died had at least one risk factor (age> , immunocompromised due to diabetes, corticotherapy, hiv or heart transplantation). patients admitted to the icu were not so aged, but had some comorbidities and risk factors leading to more uncommon microorganisms, increasing the risk of adverse outcomes. this lead to an increase of mortality: % in the icu and an overall of %. study of selenium levels in unresponsive wakefullness (uws) patients with systemic inflammatory response syndrome (sirs) e kondratyeva , s kondratyev , n dryagina the objective of this study was to evaluate the pharmacokinetics (pk) of levetiracetam (lev) in critically ill patients with normal and augmented renal clearance (arc), and determine if the recommended dosage regimen provides concentrations in the therapeutic range ( - mg/l) [ ] . a prospective observational study was conducted in a tertiary hospital. six blood samples were taken during a dose interval at steady state and lev was quantified by hplc. a population pk study was carried out. statistical analysis was conducted to evaluate the differences in pk between patients with and without arc. the suitability of drug concentrations was also assessed. results: seventeen patients were included, with normal creatinine clearance (crcl) ( - ml/min) and with crcl≥ ml/min (arc). ten patients received mg q h, one mg q h and two mg q h. the data were best fitted to a two-compartment model. figure shows lev concentrations during the dosing interval. mean clearance (cl) was l/h and mean volume of distribution of central compartment (v) was l. interindividual variability was and % for cl and v, respectively. no differences were identified between both groups (p> . ) in pk parameters. no correlation was found between lev cl and crcl. trough levels were below the minimum concentration (c min ) mg/l of the therapeutic range in all patients except . furthermore, between - h % of samples were below the c min . conclusions: administered doses were not able to maintain lev concentrations in the recommended therapeutic range. other dosage strategies, such the extension of infusion time with higher doses, could be evaluated in order to obtain a more favourable profile. no correlation between lev cl and crcl was found. the mechanical properties of muscles such as tone, elasticity, and stiffness are often affected in chronic critical ill (cci) patients. a hand-held device known as the myotonpro demonstrated acceptable relative and absolute reliability in a ward setting for patients with acute stroke [ ] . the technology works on the principle of applying multiple short impulses over the muscle bulk via the testing probe. the aim of our study is to assess the feasibility of objective measurement of muscle tone in cci patients with neurological dynamics and serum biomarkers. the study included cci patients with neurological disorders (stroke, traumatic brain injury, neurosurgical intervention for brain tumors) with more than a -weeks stay in icu. dynamic measurements of the muscle properties were taken on the deltoideus, brachioradialis, quadriceps femoris, gastrocnemius using the myo-tonpro. to identify the leading factor in impaired muscle tone also were measured neurological (s , nse), inflammatory (il- ), bacterial load (pct) biomarkers using elecsys immunoassay and the serum level of microbial metabolites using gc-ms (thermo scientific). results: all patients were divided into groups depending on positive and negative clinical dynamics. significant differences were obtained in parameters characterizing changes in muscle tone of lower limbs -f gastrocnemius (tone) - . vs . hz, r quadriceps femoris (the mechanical stress relaxation time) - . vs . ms (p < . , respectively). some significant correlations between five parameters of muscle tone biomarkers and microbial metabolites were revealed. the results of a quantitative measurement of muscle tone objectively reflect the dynamics of neurological status, which in the future may be promising technique for the personalized approach cci in patients. introduction: changes in hormonal status in patients with unresponsive wakefulness syndrome (uws) remains poorly understood. methods: patients in uws were examined at the period from to . patients ( men) with tbi and patients ( men) after hypoxia. acth, cortisol, tsh, free t and t , sth, prolactin and natriuretic peptide were studied in the period from to months uws. in men, the level of total testosterone, lh and fsh was additionally studied. the obtained data was compared with the uws outcome in - months (crs-r scale assessment). none of the studied hormones of the hypothalamic-pituitary-adrenal axis were a reliable criterion for predicting the outcome of uws. most often and consistently was revealed a tendency of disrupt the rhythm of cortisol secretion, with higher rates in the evening hours. the average value of sth was higher in men with the consequences of head injury who had recovered consciousness than in those who remained in uws. significant decrease in testosterone levels, regardless of age, was found in patients with a consequence of tbi. mean levels of lh were higher in patients with tbi and hypoxia who remained unconscious than in patients who later restored consciousness. the average level of fsh was higher in patients who had recovered consciousness . the increase of natriuretic peptide level was observed both in patients who remained in chronic uws and in those who restored consciousness. no certain endocrine background, characterising this category of patients was found. violations of some hormones secretion rhythms, in particular, cortisol can be considered usual for uws patients, especially in patients with tbi. therapeutic hypothermia has not been used before our research in chronically critically ill (cci) patients. temperature decrease in neuronal cells is a strong signal that triggers endogenic cytoprotection programs using early response genes expression. our goal is to determine influences of craniocerebral hypothermia (cch) on level of consciousness in cci patients. we examined patients with different types of brain injuries. males and females, mean age . ± . . patients were divided into groups: main group - patients (vegetative state (vs) - , minimally conscious state (mcs) - ), comparison group - patient (vs - , mcs - ), groups were equal on main parameters (severity, functional state, comorbidity). patients from main group received courses of cch, duration - minutes, scalp temperature - °С, cerebral cortex cooling up to - o c, session end was without slow reheating period, and session's amount was set -until signs of consciousness recovery. cortex temperature check done noninvasively by using detection of brain tissue emi in shf-range. consciousness recovery in vs and mcs patients controlled using crs-r scale. results: cch sessions significantly increased level of consciousness in vs and mcs patient groups. in vs patients vegetative state increased until minimally conscious state and mcs +, and in mcs group until lucid consciousness (p < . ) (figure ). craniocerebral hypothermia is used in chronically critically ill patients for the first time. our research results demonstrated effectiveness of cch as an additive treatment tool in such patients. this let us optimistically determine the perspective of inclusion of cch method in chronically critically ill patient's rehabilitation to increase level of consciousness. despite the clinical benefit of endovascular treatment (evt) for large vessel occlusion (lvo) in ischemic stroke, space-occupying brain edema (be) represents a common complication during the course of disease. routinely, ct imaging is used for monitoring of these patients, notably in the critical care setting, yet novel and easy bed-side techniques with the potential to reliably predict be without repetitive imaging would be valuable for a time and cost effective patient care. we assessed the significance of automated pupillometry for the identification of be patients after lvo-evt. we enrolled patients admitted to our neurocritical-care unit who received evt after anterior circulation large vessel occlusion. we monitored parameters of pupillary reactivity [light-reflex latency (lat; s), constriction and re-dilation velocities (cv, dv; mm/s), and percentage change of apertures (per-change; %)] using a portable pupilometer (neuroptics®) up to every minutes during the first hours of icu stay. be was defined as midline-shift ≥ mm on followup imaging within - days after evt. we assessed differences in pupillary reactivity between patients with and without be (u-test) and evaluated prognostic performance of pupillometry for development of be (roc analysis). in patients ( women, . ± . years) without be, , assessments were compared to assessments in patients ( women, . ± . years) with be. on day , day , and day after evt, patients with be had significantly lower cvs and dvs, and smaller perchanges than patients without be, whereas lat did not differ between both groups. roc-analyses revealed a significant negative association of cv, dv, and per-change with development of be. conclusions: automated pupillometry seems to identify patients at risk for be after evt. a prospective study should validate whether automated pupillometry harbors the potential to reduce unnecessary follow-up ct imaging. the aim of this preliminary analysis is to detect differences between the qualitative and quantitative evaluation of the pupillary function carried out by doctors and nurses of an intensive care unit (icu) of a tertiary level hospital. secondary purpose is to investigate new indications for the use of pupillometry in a population admitted in icu methods: the study has been conducted (currently in progress) at the intensive care unit and ecmo referral center at careggi teaching hospital (florence; italy). the enrolled patients are adult subjects (> years) with alteration of consciousness defined by a glasgow coma scale (gcs) < , following a primary brain injury and/or the use of sedative drugs. the studied parameters, obtained with neurolight pupillometer ® (id-med, marseille, france) are analyzed, integrated and visual/qualitative evaluation of the pupil function shows a lower reliability if compared to automated pupillometry. the estimated error in the proper determination of photomotor reflex is . % (p< . ). no significant difference is reported between quantitative and qualitative pupillometry in the detection of anisocoria. our preliminary results are compatible with previously reported data [ ] [ ] [ ] , even if there was no difference in anisocoria determination. interestingly, a longer latency period among patients treated with opioids has been observed. other results are still in progress. introduction: due to the dynamic of critical care disease, a rapid bedside, noninvasive and highly sensitive and specific method is required for diagnosis. in this study we set out our experience with trancranial color-coded duplex ultrasound (dxt) [ ] . the dxt study identifies cerebral arteries as well as hemorrhagic phenomenon, hydrocephalus, mass-occupying lesions and midline shift. this is the main difference between dxt and conventional transcranial doppler (dtc) which is a blind study and do not provide any image. descriptive, cross-sectional and observational study from december to june . patients were included. inclusion criteria: neurocritical patients. exclusion criteria: no acoustic window, presence of ultrasound artifacts. data collection was performed. it was used a lowfrequency transducer from . - . mhz with trancranial duplex preset ( figure) . the patterns were defined as normal, vasospasm, high resistance, hypermedia and cerebral circulatory arrest, depending on the cerebral flow velocity, lindegaard ratio (lr) and pulsatility index (ip). results: men ( . %) and women ( . %). average age . ( - ). patients diseases: subarachnoid hemorrhage , traumatic brain injury , av malformation , stroke , hemorrhagic cerebrovascular accident and mass occupying lesions . normal pattern: patients (rel. freq . ). vasospasm: patients (rel. freq . ). high resistance: patients (rel. freq . ). hyperemia: patient (real. freq . ). cerebral circulatory arrest: patient (rel. freq . ) conclusions: dxt should be part of the routine of neuromonitoring, it allows real time images especially useful in unstable conditions. although it will be needed a large amount of patients to be statistical significant, dxt is useful considering a non invasive study, bedside and it allows early identification of different clinic conditions. introduction: embolization of the draining vein during endovascular treatment of arteriovenous malformation (avm) may result in venous outflow obstruction and hemorrhage. anaesthesiologist can use deliberate hypotension to reduce blood flow through avm which may be somehow helpful to prevent this scenario. adenosine-induced cardiac arrest may facilitate the embolization too. the goal of our study was to improve the results of endovascular treatment of avm using adenosine-induced cardiac arrest. methods: after obtaining informed consent patients ( male, female) were selected for adenosine-induced cardiac arrest during endovascular avm embolization. main age was , ± years old. of them were evaluated as iii class asa, as iv. endovascular treatment in all cases was performed under general anaesthesia. propofol, fentanyl, rocuronium were used to induce anaesthesia, then all the patients were intubated and ventilated with parameters to keep etco - mm hg. sevoflurane , - , vol% ( cases) or desflurane vol% ( case) were used to maintain anaesthesia. hemodynamic monitoring consisted of ecg, pulsoximetry, non-invasive blood pressure measurement. onyx or/and squid were used as embolic agents. ct was performed to every patient just after procedure as well as neurological examination. results: adenosine dosage was . - . mg/kg. time of consequent cardiac arrest was - sec. there were cases we administered adenosine for time, in one case we had to administer it twice, in one fig. (abstract p ) . circle of willis and pulsed-wave doppler mode of middle cerebral artery - times and times in one more case as well. hemodynamic parameters recovered without any particular treatment in all the patients. embolization has been performed in all the cases uneventfully. postoperative ct showed no hemorrhage. nobody from investigated group had neurological deterioration in postoperative period. our study shows that adenosine-indused cardiac arrest is not very difficult to perform method and it can be useful during avm embolization. a major risk factor for stroke is atrial fibrillation (af). to treat af anticoagulation is needed. there are now several anticoagulants available. however, a lack of head to head data as well as the absence of accurate techniques makes it difficult to compare them and measure determine there efficacy. stroke is known to produce an abnormal clot microstructure which is a common factor in many thrombotic diseases. this pilot study aims to use a functional biomarker of clot microstructure (d f ) and clotting time (tgp) to investigate the therapeutic effects of different anticoagulants in stroke and af. we recruited patients ( af and stroke & af). two samples of blood were taken: before anticoagulation (baseline) and post anticoagulation ( - weeks) . patients were either given warfarin ( %) or axipaban ( %). d f and tgp were measured and compared before and after anticoagulation. results: warfarin increased t gp ( ± secs to ± secs (p< . )), and decreased d f ( . ± . to . ± . (p< . )). apixaban increased tgp ( ± sec to ± sec (p< . )) but did not change df ( . ± . & . ± . ). interestingly we found that in the apixaban group tgp significantly correlated (p= . ) with blood drug concentration levels. in this study we show that d f and tgp can quantify and differentiate between the therapeutic effects of two different oral anticoagulants. showing that warfarin prolongs clotting and weakens the ability of the blood to form stable clots. conversely apixaban prolongs clotting time but does not affect the bloods ability to form stable clots. this shows the utility of the d f and tgp biomarkers in comparing two different treatment options, something no other current marker has proven able to do. where d f and tgp may prove useful tools in a personalized approach to anticoagulation treatment and monitoring in an acute setting. hospital mortality compared to the model with the original hairscore. patients with poor-grade aneurysm subarachnoid hemorrhage (asah) world federation of neurological surgeons (wfns) grades iv and v, have commonly been considered to have a poor prognosis ( - % mortality). though early intervention and aggressive treatment in neuroicu has improved outcome in the past years, it is controversial because most of the patients left hospital severely disabled. the objective of this study was to investigate the clinical and social outcomes in intracranial aneurysm patients with poor-grade asah underwent different intervention therapies. a single center observational registry of poor-grade asah consecutive patients, defined as wfns grades iv and v, treated at tertiary chilean referral center from december to march were enrolled in this study. the clinical data including patient characteristics on admission and during treatment course, treatment modality, aneurysm size and location, radiologic features, signs of cerebral herniation (dilated pupils), and functional neurologic outcome were collected. clinical outcomes were assessed via gose and and sociooccupational outcome, both at discharge and at months. figure ). % mortality is less than previously reported, and survivors had a favorable recovery, confirmed with neuro psychological test. poor-grade asah patients in our study shows a more positive outcome than previously considered. prognosis of subarachnoid hemorrhage (sah) is scarce, indeed almost half patients die or become severely disable after sah. outcome is related to the severity of the initial bleeding and delayed cerebral infarction (dci). infection and more precisely pneumonia have been associated with poor outcome in sah. however, the interaction between the two pathologic events remains unclear. therefore, we hypothesized that dci may be associated to pneumonia in sah patients. thus the aim of our study was to analyze the association between delayed cerebral infarction and pneumonia in patients with sah. in this retrospective, observational, monocentric cohort study, patients included in the analysis were admitted in neurosurgical intensive care unit or surgical intensive care unit in the university hospital of brest (france) for non-traumatic sah. primary outcome was diagnosis of dci on ct scan or mri months after sah. multivariate analysis was used to identify factors independently associated with dci. a total of patients were included in the analysis (female male ratio / , median age [ - ] years). multivariate analysis was adjusted on sedation, intracranial surgery, fisher classification of sah severity, pneumonia occurrence and non-pneumonia infectious event occurrence ( figure ). pneumonia occurred in patients ( . %) and other causes of infections in patients ( . %). dci was found in patients ( . %). factors independently associated with dci were pneumonia (or . [ . - . ]; p= . ) and non-pneumonia infectious events (or . [ . - . ]; p= . ). interestingly severity table (abstract p ). correlation of safety and efficacy markers of thrombolysis and thrombolysis time with distance from stroke centre results expressed as odds ratio with % confidence interval of initial bleeding evaluated by fisher scale was not independently associated with dci. dci is independently associated with the occurrence of pneumonia or other cause of sepsis. those results may highlight the need for rigorous approach for prevention protocol, early diagnosis and treatment of hospital acquired infectious diseases in sah patients. introduction: traumatic brain injury (tbi) can have devastating neurological, psychological and social sequelae. increased psychiatric morbidity after tbi has been shown in both adult and the pediatric population. also, critical illness as such is a risk factor for psychiatric problems in youth. our aim was to assess risk factors for later being prescribed psychiatric medication in survivors of intensive care unit (icu)-treated pediatric tbi. we used the finnish intensive care consortium (ficc) database to identify patients - years of age, treated for tbi in four icu in finland during the years - . we examined electronic health records and ct scans and collected data on drug prescription after discharge. we used multivariable logistic regression models to find statistically significant risk factors for psychiatric drug reimbursement. we identified patients of which patients received psychiatric drug prescription ( %) during follow up. the median time to prescription was months after tbi (interquartile range [iqr] - months). patients received antidepressants, received stimulants and received antipsychotics. increasing age showed a positive association with all drug prescriptions except for stimulants, where an inverse relationship was observed (table ) . using multivariable analyses, we could not find any admission or treatment related factors that significantly associated with being prescribed psychiatric medications. teenage survivors with moderate disability (glasgow outcome scale [gos] ) showed high numbers of psychotropic drug utilization ( % received any medication, % received antidepressants, % received antipsychotics). our data suggests, that the risk of psychotropic drug prescription after tbi depends on factors other than those related to injury severity or treatment measures. the incidence of drug prescription is especially high in patients with moderate disability. the effects of -adamantylethyloxy- -morpholino- -propanol hydrochloride on the formation of steroid neurotoxicity in rats with brain injury a. semenenko , s. semenenko , a. solomonchuk , n. semenenko depending on the nature of the brain injury and the severity of the victims, mortality in traumatic brain injury (tbi) ranges from to % [ ] . one of the targets for pathogenetic influence on the course of tbi is the use of pharmacological agents that are able to counteract the negative effects of excess concentrations of glucocorticoids on brain. the therapeutic effect of new pharmacological derivative adamantylethyloxy- -morpholino- -propanol hydrochloride (ademol) in rats with tbi was evaluated for days. the pseudoperated animals and control group received . % nacl solution and the comparison group received amantadine sulfate. cortisol levels were used to determine the efficacy of the test drugs in tbi. in rats treated with ademol, the level of cortisol in the blood ranged from to ng/ml (p -p ) and was . -fold lower (p< . ) compared to control pathology group on the day of therapy. instead, the effect of amantadine sulfate on the level of cortisol in the blood was significantly less than that of ademol. the concentration of cortisol in rats with amantadine sulfate in the blood ranged from - ng/ml (p -p ), was . times lower (p< . ), compared with the control pathology group, and by . % (p< . ) exceeded the corresponding value in animals treated with ademol. therapeutic treatment of rats with severe tbi with a solution of ademol, preferably better than rats in the group with . % nacl and amantadine sulfate protect the brain from the formation of steroid neurotoxicity by cortisol (p< . ). although cerebrovascular pressure reactivity (prx) well correlate to patient's outcome [ ] , it requires continuous monitoring and mobile average calculation for its determination. we therefore hypothesized that a simplified model of variation between mean arterial pressure (map) and intracranial pressure icp over the first three days of admission would have been able to predict patient outcome: we call this new parameter cerebrovascular pressure correlation index (cpc). we performed a retrospective observational study of all adult patients with severe tbi admitted to icu from january to april inclusive. all consecutive patients with a clinical need for icp monitoring were included for analysis. both for icp and map data were mean value over -hours registration, for a total of observations/day, cpc was therefore calculated as the pearson correlation coefficient between icp values (x axis) and map values (y axis), obtaining one single value every hours. variables included in the model (i.e. cpc, cpp, icp, systemic glucose, arterial lactate, paco , icp, and internal body temperature) were collected for the first days since trauma. for the main outcome only the minimum value of cpc fit the regression analysis (p = . ). the correspondent roc curve showed an auc of . . the associated youden criterion was ≤ . (sensitivity = . ; specificity = . ). of all the variables considered for the secondary outcome only cpcmin fit the regression model (p = . ). table reports the median and iqr range for sg and nsg of all the variables considered in the model. this observational study suggests that cpc could be a simplified model of variation between map and intracranial pressure icp over the first three days of admission predicting patient outcome. introduction: impaired cerebrovascular reactivity (car) after traumatic brain injury (tbi) is a marker for disease severity and poor outcome. it is unclear how dynamic changes in body temperature and fever impact car and outcome. we calculated the pressure reactivity index (prx) using the center-tbi high-resolution intensive care unit cohort, as a moving correlation coefficient between intracranial pressure (icp) and mean arterial pressure (map). minute and hourly values of prx and temperature were averaged in patients with simultaneous recording of icp and abp. demographic data was based the core registry (v . ). linear mixed models were calculated based on minute-by-minute data using r with lme v . - and ggeffects v . . . generalized estimating equation models were used to analyze changes during effervescence (increase of temperature of > °c within hours). we assessed high frequency physiological data during days of patients admitted to the icu with predominantly a closed injury type (n= / ). median age was years (iqr - ), baseline gcs was (iqr - ), and % had at least one unreactive pupil. the main measurement site for temperature was the urinary bladder / ( %). half of the patients ( / ) developed fever(> h with mean t ≥ . °c) with a total of h fever and a median of h fever(iqr - ) per patient. of effervescence episodes ( %) reached the febrile threshold of . °c which was associated with an increase in prx from . (±sd . ) at baseline ( h before) to . (±sd . ) during the febrile peak (p= . ) (figure -a) . linear mixed models showed a quadratic relationship between prx and temperature (p< . ) with an increase in predicted prx with febrile and hypothermic temperatures ( figure b ). the association of increasing body temperature with worsening of car supports prevention of fever in severe tbi. prospective studies are needed to further differentiate between mechanisms involved (i.e. inflammation) and central autonomic dysregulation. fig. (abstract p ) . the patients with a good -month outcome (gose> ) after severe traumatic brain injury showed an increase in root mean square of successive differences between normal heartbeats (rmssd) (compared to baseline -minutes before tracheal succtioning) acute kidney injury (aki) is relatively common in patients with severe traumatic brain injury (stbi) and it can contribute to morbidity and mortality [ ] . nephrocheck is a point-of-care urine test that flags two biomarkers that indicate if a critically ill patient is at risk for aki. we investigated the incidence of subclinical aki in patients with stbi. we performed a prospective observational study of all adult patients with severe tbi admitted to icu from january to april inclusive. all consecutive patients with a clinical need for icp monitoring were included for analysis. urine samples of severe tbi patients was collected at icu admission from patients to measure nephrocheck (nc) test [igfbp ] x was performed using the nephrocheck® astute ™ meter. serum creatinine was collected at admission, during the first three days, at icu dismission and -days follow up to assess renal recovery. the diagnosis of aki was based on kdigo criteria. hemodynamics, electrolytes, peep, p/f, kind of fluid administered, fluid balance, % fluid overload, length of stay, the sequential organ failure assessment score, injury severity scores and mortality were collected. a total of patients ( %) presented a median nc higher values at icu admission. one patient with positive nc value experienced aki at hrs. the positive nc group had more plasma transfusion (p-value . ) and a lower median hematocrit at hrs (p-value . ), but similar hospital length of stay (p= . ) and mortality rate (p= . ) conclusions: nc at icu admission identifies subclinical aki in tbi patients and it maight be used to predictclinical aki. hemodilution (but not fluid overload) seems to be associated with development of subclinical aki. higher nc at icu admission is not associated with worst longterm outcome in tbi patients. severe traumatic brain injury (tbi) is considered a serious public health problem in europe. partly because of the heterogeneity of tbi, considerable uncertainty may exist in the expected outcome of patients. the international mission for prognosis and analysis of clinical trials in tbi (impact) and the corticosteroid randomization after significant head injury (crash) prediction models are considered the most widely validated prognostic models [ , ] . however, studies using these prediction models for benchmarking of outcomes have been scarce. we aimed to compare actual outcomes in a tbi cohort of critically ill tbi patients with predicted outcomes in a quality of care initiative in an academic hospital. in this retrospective cohort study, we included consecutively admitted tbi patients to the icu adults of erasmus mc, university medical center, rotterdam, the netherlands between january and february . we included patients with tbi. -day mortality was %, sixmonth mortality was % and six-month unfavourable outcome was %. the impact core+ct+lab model predicted % -month mortality (vs % actual, p= . ) and % unfavourable outcome (vs % actual, p= . ). the -day mortality prediction by crash prognosis calculator was % versus actual -day mortality of only % (p= . ), whereas -month unfavourable outcome prediction by crash was % (vs. % actual, p= . ) ( figure ). the impact model, although developed more than a decade ago, seemed appropriate for benchmarking purposes in this single center cohort in the netherlands, while crash predictions were less applicable to our setting. introduction: out of hospital cardiac arrest (ohca) continues to be associated with significant mortality and morbidity. centralisation of care has considerably improved patient survival but has resulted in increased morbidity in the form of neurological deficit. accurate neurological prognostication remains challenging incorporating repeated clinical examination and ancillary investigations [ , ] . data was collected retrospectively and analysed for patients admitted post ohca from october to october . patient arrest demographics were collected in conjunction with extensive inpatient investigation findings including ct, traditional pupil assessment, pupillometry and eeg. results: % of patients survived to hospital discharge. patients presenting in a shockable rhythm continue to have higher survival rates ( table ) . % of patients who received immediate cpr survived to hospital discharge in comparison to % of patients who did not receive immediate cpr. % of patients underwent non-contrast ct head. % of patients had traditional pupillary examination performed on arrival. pupillometry was introduced in december ; out of a possible patients had pupillometry during their inpatient stay. eeg was undertaken in % of cases. our data shows receiving immediate cpr and presenting with a shockable rhythm remain positive prognostic factors. ct head as a stand-alone prognostic modality is unreliable with % of patients who survived to discharge, with intact neurology, had an admission ct head reported as hypoxic brain injury. a new neuroprognostic strategy is required in our unit that adds further certainty to likely clinical outcome. this includes increased use of tests such as eeg and pupillometry and the introduction of biomarkers such as neuron specific enolase, somatosensory evoked potential testing and magnetic resonance imaging. introduction: post-resuscitation care of patients following an out-of-hospital cardiac arrest (oohca) is set out by the uk resuscitation council [ ] . this is in line with the european resuscitation council guideline [ ] . the aim of this audit was to review compliancy to this guideline at the intensive care unit at the bristol royal infirmary . a retrospective audit was performed over a six-month period in adults who were admitted to the intensive care unit at the bri following an oohca whom later died during that admission ( patients). the focus was on whether the neuroprognostication and end-of-life (eol) care received was as per the standards set by the uk resuscitation council. the main neuroloical examinations documented were pupillary reflex ( %), corneal reflex ( %) and motor response to pain ( %). . % of patients received an ssep analysis > hours post-rosc, . % underwent an eeg and . % had > serum neuron-specific enolase measurements recorded. all patients ( %) underwent a ct head during their admission. . % of patients were referred to palliative care during their admission. % of patients were prescribed all eol medications. most common prescriptions included alfentanil ( . %) and midazolam ( . %). finally, % of appropriate patients were referred to be potential organ donors. the audit reflected our local practice and that some parameters were not being maintained as set by uk resuscitation guideline. multiple introduction: the prognostication of neurological outcome in comatose out-ofhospital cardiac arrest (ohca) patients is an integral part of post cardiac arrest care. biochemical biomarkers released from cerebral cells after hypoxic-ischemic injury represent potential tools to increase accuracy in predicting outcome after ohca. currently, only neuronspecific enolase (nse) is recommended in european prognostication guidelines. in this study, we present the release dynamics of gfap and uch-l after ohca and evaluate their prognostic performance for long-term neurological outcome in ohca patients. serum gfap and uch-l were collected at , and h after ohca. the primary outcome was neurological function at -month follow-up assessed by cerebral performance category scale (cpc), dichotomized into good (cpc - ) and poor (cpc [ ] [ ] [ ] . outcome prognostic performance was investigated with receiver operating characteristics (roc) by calculating the area under the receiver operating curve (auroc) and compared to nse. results: of included patients had at least one serum gfap or uch-l value at , or h after ohca. gfap and uch-l levels were significantly elevated in patients with poor outcome. gfap and uch-l discriminated excellently between good and poor neurological outcome at all time-points (auroc gfap . - . ; uch-l . - . ) and overall predictive performance measured by auroc of gfap and uch-l was superior to nse (auroc . - . ) ( figure ). however, the roc at the highest specificities of uch-l and gfap overlap those of nse and comparing the sensitivities for uch-l and gfap with those of nse for the highest specificities (> %) revealed higher sensitivities for nse than for uch-l and gfap at and h. gfap and uch-l predict poor neurological outcome in patients after ohca excellently and with a higher overall accuracy than nse, but both biomarkers perform inferior to nse at specificities over % at and h limiting their clinical use to guide decisions on prognosis. blood pressure after cardiac arrest and severity of hypoxicischemic encephalopathy c endisch , s preuß , c storm introduction: blood pressure management in post cardiac arrest (ca) patients ensures sufficient cerebral perfusion to avoid secondary brain injury. in local chain-of-survival improvements affect p-ohca survival [ ] [ ] [ ] [ ] [ ] . also initial rhythm in p-ohca is an important predictor of survival [ , ] . little is known about the relationship between initial rhythm in p-ohca and long-term outcome [ ] [ ] [ ] . our aim was to establish the relation between shockable rhythm and favorable long-term outcome in pohca. all children aged day- years who experienced non-traumatic ohca between - and were admitted to the sophia children's hospital in rotterdam were included. long-term outcome was determined using a pediatric cerebral performance category score at the longest available follow-up interval. the primary outcome measure was survival with favorable neurologic outcome, defined as pcpc - or no difference between pre-and postarrest pcpc. the association between shockable rhythm and the primary outcome measure was calculated in a multivariable regression model, adjusted for the pre-defined variables. from the patients included in the year study period ( %) patients survived to hospital discharge of which patients ( %) had favorable neurologic outcome (median follow-up duration of months). the rate of favorable neurologic outcome rose from % in to % in (p < . for trend) (fig. ) the odds of favorable neurologic outcome at the longest follow-up duration were significantly higher after a shockable initial and unknown rhythm. secondly, trend analysis showed an increase in aed defibrillation and shorter cpr duration. this was followed, finally, by a rise in rosc, survival to hospital discharge and favorable neurologic outcome rate. low socioeconomic status is associated with worse outcome after cardiac arrest. this study aims to investigate if patients´socioeconomic status impacts the chance to receive early coronary angiography after cardiac arrest. in this nationwide retrospective cohort study, patients admitted alive after out-of-hospital cardiac arrest (ohca) and registered in the swedish registry for cardiopulmonary resuscitation were included. individual data on income and educational level, prehospital parameters, coronary angiography results and comorbidity were linked from other national registers. in the unadjusted model there was a strong correlation between income level and rate of early coronary angiography where % of patients in the highest income quartile received early angiography compared to % in the lowest income quartile. when adjusting for confounders (educational level, sex, age, comorbidity and hospital type) there were still higher chance of receiving early coronary angiography with increasing income, or . (ci . - . ) and . (ci . - . ) for the two highest income quartiles respectively compared to the lowest income quartile. when adding potential mediators to the model (initial rhythm, location, response time, bystander cardiopulmonary resuscitation and if the arrest was witnessed) no difference in early angiography related to income level where found. the main mediator was initial rhythm (figure ). higher income is strongly related to the rate of early coronary angiography after ohca. this finding is consistent when adjusting for known confounders. however, the association between income and early angiography seems to be mediated by initial rhythm. patients with low income more often presents with non-shockable rhythms which lowers the likelihood to undergo early coronary angiography. a. the total amount of mortality as a stacked bar: in light-red the number of patients who deceased at scene, in green the number of patients deceased during admission, in red patients who died after discharge. the grey line is the total number of inclusions. b. the rate of bystander aed use, rate of initial shockable rhythm, rate of less than minutes of cpr and rate of favorable neurologic outcome over time. p for trend significant for bystander aed use, less than minutes of cpr and favorable neurologic outcome. trend analysis performed using binary logistic regression for dichotomous data (and a kruskal-wallis test for non-normally distributed continuous data) effect of simulation teaching of cardiopulmonary resuscitation for nursing v spatenkova introduction: simulation teaching is a modern type of critical care (cc) education. the aim of this study was to assess the effect of simulation teaching of cc on a comparison of final examination in different model levels of cardiopulmonary resuscitation (cpr) after the first (cc ) and third, final cc . the success rate of cpr was tested in prospective study ( ) ( ) on two groups with a total of students in cc and cc at the faculty of health studies. three semester of undergraduate nursing simulation education (lectures and training) used the laerdal simman g. quality of cpr was evaluated according to parameters: compression depth, compression rate, chest release and time of correct frequency. we tested if cpr quality differed between the two groups. for the compression depth and compression rate parameters, first the conformity of variance was verified and then two-sample t-test. as the chest release and time of correct frequency are recorded as percentages, the wilcoxon rank-sum test was conducted for these parameters. to ensure good resuscitation, all recorded parameters must be properly performed during resuscitation. thus, pivot tables were used to generate statistics and test if the number of correctly performed resuscitation parameters for cc and cc differ. the compression depth parameter was statistically significantly higher for the cc than for the cc (p= . ). there were no differences in compression rate (p= . ), chest release (p= . ) and time of correct frequency (p= . ). it was also tested how many of the parameters were performed correctly by students at cpr. the chi-square test shows the relative frequency of cpr success is higher for the cc group than for the cc group. at least out of parameters were correctly performed by % of cc students compared to % of cc students. the study showed a significant improvement of cpr in the final cc and supported the three semester simulation education. changes in blood gases during intraoperative cardiac arrest jj wang, r borgstedt, s rehberg, g jansen protestant hospital of the bethel foundation, anaesthesiology, intensive care and emergency medicine, transfusion medicine and pain therapy, bielefeld, germany critical care , (suppl ):p introduction: blood gas analysis (bga) is a common approach for monitoring the homeostasis during surgery. while it is well known that cardiac arrest (ca) leads to circulatory collapse and disturbances in homeostasis, little is known about changes of blood gas during peri-operative ca. we retrospectively analysed patients ≥ years who suffered from peri-operative ca during non-cardiac surgery from / to / . peri-operative ca was defined as need for cardiac compression during anaesthesia care. collected data included ph, paco , pao , return of spontaneous circulation (rosc) and -day mortality after ca. within the study period, we observed peri-operative ca (m= , f= ; age ± ) during anaesthesia procedures (rosc occurred in patients ( %). days after ca, the mortality was % (n= ), % (n= ) were discharged, and % (n= ) still in hospital. % (n= ) of ca patients had an invasive blood pressure monitoring, % (n= ) had bga before and % (n= ) during peri-operative ca. prior to ca, the average values were: ph . ± . , paco ± and pao ± . during ca, the average values were ph . ± . , paco ± and pao ± . table shows the distributions of blood gas before and during ca. there were no statistical differences between the groups (ph: p= . ; paco : p= . ; pao : p= . ). hypercapnia and respiratory acidosis is common in peri-operative ca. these data suggests inadequate ventilation during peri-operative resuscitation. further studies should focus on its impact on the outcome. ]. comparing cases with and without rosc, there were significant more diagnostics done in the group without rosc but more therapeutic consequences seen in the rosc-group (table ) . icu-ca is frequent. diagnostics to detect reversible causes of ca were used rarely in icu-ca ( %), even in patients without rosc. notably, diagnostics often had therapeutic consequences particularly in rosc. further studies are required to define standardized diagnostic algorithms during icu-ca. continuous monitoring of cardiac patients on general ward were improved short term survival of in-hospital cardiac arrest uj go introduction: the importance of early detection in the in-hospital cardiac arrest (ihca) is emphasized. previous studies have reported that clinical outcomes are improved if ihca is witnessed, or if a patient admitted to a monitored location [ , ] . this study aimed to evaluate the association between continuous monitoring and survival of ihca on general ward. a retrospective cohort study of ihca in patients admitted to ward at an academic tertiary care hospital between january and december was performed. the primary outcome was return of spontaneous circulation (rosc). the secondary outcomes were hour survival and survival to hospital discharge. (table ) . cardiac patients with continuous monitoring on general ward showed improving rosc and -hour survival but not survival to hospital discharge in ihca. in-hospital cardiac arrest is associated with poor outcomes. although steroids are frequently used in patients with septic shock, it is unclear whether they are beneficial during cardiac arrest and after return of spontaneous circulation (rosc). of cardiac arrest patients evaluated, were enrolled. advanced life support was conducted according to the resuscitation guidelines. forty-six patients were randomly assigned to receive methylprednisolone mg during resuscitation, and to receive saline (placebo). after resuscitation, steroid-treated patients received hydrocortisone mg daily for up to days, followed by tapering . there was no significant difference between the two groups in scvo andall the secondary outcomes (p> . for all comparisons). the present study found no significant physiologic benefit of corticosteroid administration during and after resuscitation in hospitalized patients with cardiac arrest. the experiences of ems providers taking part in a large randomized trial of airway management during out of hospital cardiac arrest, and the impact on their views and practice. results of a survey and telephone interviews m thomas introduction: the aim is to explore ems experiences of participating in a large trial of airway management during out-of-hospital cardiac arrest (air-ways- ), specifically to explore: . any changes in views and practice as a result of trial participation. . experiences of trial training. . experiences of enrolling critically unwell patients without consent. . barriers and facilitators for out-of-hospital trial participation. an online questionnaire was distributed to ems providers who participated in the trial. in-depth telephone interviews explored the responses to the online questionnaire. quantitative data were collated and presented using simple descriptive statistics. qualitative data collected during the online survey were analysed using content analysis. an interpretive phenomenological analysis approach was used for analysis of qualitative interview data results: responses to the online questionnaire were received from % of airways- study paramedics and study paramedics were interviewed. paramedics described barriers and facilitators to trial participation and changes in their views and practice. the results are presented in five distinct themes: research process; changes in views and practice regardingairway management; engagement with research; professional identity; professional competence. conclusions: participation in the airways- trial was enjoyable and ems providers valued the training and study support. there was enhanced confidence in airway management as a result of taking part in the trial. study paramedics expressed preference for the method of airway management to which they had been randomized. there was support for the stepwise approach to airway management, but also concern regarding the potential to lose tracheal intubation from 'standard' paramedic practice. causes of medical care-associated cardiac arrest on the intensive care unit s entz introduction: cardiac arrest on intensive care unit (icuca) following therapeutic interventions is of imminent importance, because the interventions are comparatively predictable and precautions can potentially be taken. this study investigates medical care associated complications that led to icuca. intensive care database was screened for patients ≥ years who experienced icuca in a tertiary hospital with five icu (two medical, two surgical, one interdisciplinary, with a sum of icu beds) in germany from - . icuca was defined as receiving chest compression and/or defibrillation after admission on icu and classified as "medical care associated" if it was preceded by a therapeutic intervention (i.e. induced by medication, bedding procedures, iatrogenic injuries, procedure associated). subgroups included patients with recurrence of spontaneous circulation (rosc) vs. no-rosc and patients with vs. without vasopressor therapy before intervention. there were icuca in patients of totally , icu patients. medical care associated complications leading to icuca were detected in cases ( %) [incidence . / , (ci . - . )]. icuca following therapeutic interventions occurred because of circulatory insufficiency [n= ( %)], respiratory failure [n= ( %)] and airway associated problems [n= ( %)]. nine of the patients ( %) with care-associated icuca died. table demonstrates therapeutic interventions followed by icuca. care-associated complications were common reasons for icuca. most of events were induced by circulatory insufficiency due to induction of anaesthesia and bedding procedures. further investigations should focus on preventive strategies, such as vasopressor infusion before therapeutic interventions. in-hospital cardiac arrest (ihca) is a lethal event. however, ihca has received less attention than out-of-hospital cardiac arrest (ohca). there have been some studies on ihca; however, there is a lack of information on the evidence and clinical features of ihca compared with information for ohca. we therefore conducted this study to clarify important aspects of the epidemiology and prognosis of ihca in patients with code blue activation. we carried out a retrospective observational study of patients with code blue events in our hospital during the period from january to october . we obtained information on the characteristics of patients including age and gender, ihca characteristics including the time of cardiac arrest, event being witnessed, presence of bystander cardiopulmonary resuscitation (cpr), initial shockable rhythm, vital signs h or h before cardiac arrest, survival to hospital discharge (shd), and the cardiac arrest survival postresuscitation in-hospital (caspri) score. the primary endpoint was shd. we performed univariate and multivariate logistic regression analyses. a total of code blue events were activated during the study period. finally, patients were included in this study. overall, the shd rate was . %. the median time of cpr was min (interquartile range, - min). the rate of initial shockable rhythm was . %. there were significant differences in cpr duration, shockable rhythm, and caspri score between the shd group and non-shd group by univariate-logistic regression analysis. caspri score was found to be the most effective predictive factor for shd (or= . , p= . ) by multivariate-logistic regression analysis. our results demonstrated that caspri score is associated with shd in cpa patients with in-hospital code blue events. caspri score in ihca patients would be a simple and useful adjunctive tool for management of post-cardiac arrest syndrome (pcas). peri-operative cardiac arrest in prematurityincidence and causes at a tertiary care hospital between - g jansen, j popp, e lang, r borgstedt, b schmidt, s rehberg protestand hospital of the bethel foundation, anaesthesiology, intensive care and emergency medicine, bielefeld, germany critical care , (suppl ):p the peri-operative care of premature pediatric patients requires special expertise and is therefore reserved for specialized centers. although premature birth is described as a risk factor for peri-operative complications and cardiac arrest (poca) there are no data on its incidence and causality in this particular population [ ] . the present study investigates the incidence and causality of pediatric poca at a tertiary care hospital and level i perinatal center in germany. in the anesthesia database of the study center, all anaesthesiological procedures in patients < years of age were examined for poca in preterm infants (gestational age < th week of gestational age) between and . the peri-operative period was defined between the beginning of anesthesiological care up to minutes after anesthesia and/or sedation. we defined cardiac arrest as the necessity of chest compressions. the perioperative phase and the cause of the poca, gestational age and birth weight were recorded. between and , ( . %) of the , pediatric anesthesiological procedures were performed on premature infants. in total, poca occurred in of these patients (f= , m= ; average gestional age ± days; average birth weight ± g (incidence . %, ci . - . %). the time of occurrence and the causes of poca are shown in table . poca in premature babies is rare and has an incidence of . %, which is significantly higher than the non-premature babies. the main causes are problems or complications associated with the respiratory tract and its management, as well as massive hemorrhage. introduction: peri-operative cardiac arrest (poca) in children's anesthesia care is a dreaded event. depending on the country and population, studies describe incidences between . - . per , children's anesthetics. there are no data on the current incidence of pediatric poca in germany. the present study investigates the incidence of poca at a tertiary hospital and level i perinatal center in germany. in the anesthesia database of the study center, all anaesthesiological procedures in patients < years were examined for poca. the peri-operative period was defined between the beginning of anesthesia care up to minutes after anesthesia or sedation. cardiac arrest was defined as the necessity of chest compressions. age, weight, asa status, cause of death and survival after days were recorded. results: poca (median weight was g [q ;q ( )]) were observed in , anaesthesiological procedures (incidence . ± . per , [ci . - . ]). table shows the distribution of the individual age groups, incidences and mortalities of poca. peri-operative -day mortality was per , [ci [ ] [ ] [ ] [ ] [ ] . three children died intraoperatively as a result of hemorrhagic shock, one on the picu as a result of malignant hyperthermia. days after poca, more children had died on the icu due to their underlying disease. poca is a rare event. risk factors are an age < days and an asa status ≥ iii. the main cause of peri-operative death in patients < years of age is massive hemorrhage, the -day mortality is determined by the underlying disease. in-hospital cardiac arrest -predicting adverse outcomes t partington, j borkowski, j gross northwick park hospital, anaesthesia/critical care, london, united kingdom critical care , (suppl ):p introduction: cardiac arrest occurs in . per hospital admissions in the uk. return of spontaneous circulation (rosc) is achieved in approximately half of resuscitation attempts, but rate of survival to hospital discharge is substantially lower [ ] . in our centre, post-arrest care accounts for . % of icu admissions. premorbid social function is purported to affect outcomes, but comorbidity scores are more often used for risk stratification. using a novel social function score alongside an existing comorbidity scale, we aimed to identify trends to inform management of patients at risk of deterioration. a six-month prospective observational study was conducted in a major uk hospital from october to april . for all adult inpatient cardiac arrests, medical notes were reviewed and data collected on the following domains: patient demographics comorbidities and functional status admission details post-arrest events statistical analysis was performed using student's unpaired t-test. results: cardiac arrests occurred. % were in medical patients, with the majority male ( %) and aged over ( %). % were emergency admissions, with mean duration of hospital stay pre-arrest days. in cases ( %) sustained rosc was achieved. however, seven of these ( %) were not subsequently admitted to the icu. only six patients ( %) survived to hospital discharge. pre-admission function and comorbidity were worse in patients who did not survive to discharge ( fig. ), but these were not statistically significant in view of small survivor group size. in an increasingly frail inpatient population, a substantial proportion of patients in whom circulation is restored after cardiac arrest are subsequently considered unsuitable for icu admission. given our understanding of inferior outcomes in patients with poor physiological reserve, we encourage early discussion regarding the appropriateness of cpr in selected patients, guided by social function and comorbidity. references: . national cardiac arrest audit / introduction: there are studies that determine events related to poor outcome in cardiac arrest [ ] . in our study, following parametres were determined ohca patients; age median years, asian/europe/syrian, bystander cpr, bystander aed, ems defibrillation, initial cardiac rhythm, prehospital rosc, corneal and pupillary light reflex and day survival. we determineted poor prognostic sign with post-cardiac arrest patients. in this study, we identified the causes of poor outcome in patients with ohca. this was a single-centre, retrospective study. we determined incidence and epidemiological factors including: demographics, initial cardiac rhythm. our study population were non-traumatic ohca. our icu, all ohca patient were evaluated wtih echo, and fluid, inotrope and vazopressor were added according to cardiac performance. results: during our study, patients who were admitted to intensive care unit between - were screened. of these patients were out-of-hospital arrest and of them were in-hospital arrest. development of cerebral oedema during treatment in hospital remains a poor prognostic sign. the evaluation of initial cardiac ritm is useful to predict neurological outcome in post-cardiac arrest patients. survival after ohca remains low. the evaluation of initial cardiac ritm is useful to predict mortality and neurological outcome in postcardiac arrest patients. basic life support (bls) education and training for school children is active in japan. however, the bls action by schoolchildren may be limited by school rules. this study aimed to analyse the time factors for basic life support performance and outcome in classmatewitnessed out-of-hospital cardiac arrest (ohca) and to investigate how schoolchildren act when they detect ohca. methods: nation-wide database for , school children cases with ohca and local extended database for , ems-unwitnessed ohca, both of which were prospectively collected during the period of - , were retrospectively analysed. proportion of schoolchildren-detected ohca was low in classmate cases ( . %, / ) in nationwide database and extremely low in all ems-unwitnessed ohcas ( . %, / , ) in local database. nationwide database analyses revealed that both emergency call and bystander cpr were delayed when a classmate witnessed the ohca case: median, vs. min and vs. min, respectively. classmate-witnessed cases were associated with higher incidences of shockable initial rhythm, aed use and traumatic causes. the rate of neurologically favourable outcome was . % and . %, respectively in classmate-witnessed and other cases: adjusted or; % ci, . ; . - . . of cases detected by schoolchildren in our prefecture, ( %) cases had presumed cardiac aertiology and ( . %) cases were caused by suicide attempts (hanging and fall). school children placed emergency calls as the first action only in ( . %) cases. emergency calls were largely delayed when school children dialled other numbers or left the scene to seek adult help. school children were rarely involved in bystander cpr ( %) and aed placement ( %). school children are rarely involved in entire bls. emergency calls and bystander cpr are delayed when schoolchildren act to seek help. because schoolchildren detect suicide-related ohcas, psychological care to schoolchildren involved in bls may be necessary. prognostic value of neutrophil/lymphocyte and platelet/ lymphocyte predicting cardiopulmonary resuscitation with spontaneous circulation recovery c li the affiliated suzhou hospital of nanjing medical university, suzhou, china critical care , (suppl ):p to investigate the predictive value of peripheral blood neutrophil-tolymphocyte ratio (nlr) and platelet-to-lymphocyte ratio (plr) on inhospital mortality in patients with spontaneous circulation recovery after cardiac arrest. a retrospective analysis was made of patients who recovered from cardiac arrest in our hospital from april to november and were admitted to the intensive care unit for more than hours. they were divided into survival group and death group according to the outcome of discharge.the dynamic changes and differences of nlr and plr in hours and - hours after admission to icu between the two groups were analyzed and compared. multivariate analysis and roc curve were used to explore the predictive value of nlr and plr for in-patient mortality. compared with the survival group, plr in the dead group was significantly lower within hours of admission to the intensive care department (p < . ), while nlr in - hours was significantly higher (p < . ). the nlr of surviving group was significantly lower than that of hours (p < . ), while the nlr and plr of death group were not significantly different (p < . ) from that of hours (p < . ). multivariate logistic regression analysis and roc curve showed that nlr of - h in icu was an independent risk factor for predicting in-patient mortality, and had high sensitivity and specificity in predicting death outcomes. neutrophil to lymphocyte ratio, platelet to lymphocyte ratio can help to judge the outcome of patients with cardiac arrest and recovery of autonomic circulation after cardiopulmonary resuscitation. [ , ] patients with sofa score > (vs sofa score ≤ ) had a higher free iron level ( . μmol/l vs μmol/l, p = . ) ( figure ). we found a positive correlation between free iron level at h and changes of sofa score between h and h (r= . ic [ . ; . ]). out-of-hospital cardiac arrest is associated with a significant change of plasma free iron level. free iron level at admission is associated with short term outcome. further research is warranted to better determine the significance of such changes. the optimal level of arterial oxygen in the post-resuscitation period is unknown. recent studies show conflicting results in regard to hyperoxia and its association with survival after out-of-hospital cardiac arrest (ohca) [ ] . the aim of this trial is to study the association between early hyperoxia after ohca with return of spontaneous circulation (rosc) and -day survival. observational study using data from three swedish national registers (i.e. intensive care, cardiac arrest and national patient registries after a successful resuscitation, a systemic inflammatory response occurs, and the c-reactive protein (crp) level represents the degree of inflammation [ ] [ ] [ ] . this study examined the association between increased inflammation and early-onset pneumonia (eop) in patients treated with extracorporeal cardiopulmonary resuscitation (ecpr) after out-of-hospital cardiac arrest (ohca). this retrospective study included data of patients with ohca treated with ecpr admitted to st. luke's international hospital between april and april . the exclusion criteria were as follows: age < years, therapeutic hypothermia withdrawal due to death or circulatory failure, or sepsis as a suspected cause of cardiac arrest. patients were diagnosed with eop according to clinical signs and symptoms acquired after a hospitalization period of > h and within days of admission. the crp levels were measured daily from admission to day . we studied patients with a median age of years (interquartile range: - years). furthermore, ( %) patients were males, and the median time interval from collapse to adequate flow was ( - ) min. all patients received prophylactic antibiotics, and ( %) of them had favorable neurological outcomes (cpc, - ). eop occurred in ( %) patients, with a significantly higher crp level on day than that in those without eop ( . categorizing reasons for death after ecpr is important for comparing outcomes to other studies, assessing benefits of interventions, and better define this heterogeneous patient collective. a categorizing for death after cardiac arrest in both in-hospital (ihca) and outof-hospital (ohca) arrests has been proposed in non-ecpr patients by witten et al. here, we adopt this categorization to ecpr patients. single-center, retrospective, cohort study of patients without rosc after ihca or ohca and ecpr between and . patients with survival below hours were excluded. patients were allocated to one of five predefined reasons for death. results: va-ecmo patients were included (age . ± . , . % female, % ecpr, day survival . %). reasons for death for patients with va-ecmo for shock (survival %) and ecpr ( %) were: neurological withdrawal of care ( % vs %), comorbid withdrawal of care ( % vs %), refractory hemodynamic shock ( % vs %), respiratory failure ( % vs %), and withdrawal due to presumed patient will ( % vs %) ( figure ). the differences in reasons for death among the two groups were significant (p < . ), driven by withdrawal due to neuroprognostication, comorbidity and hemodynamic instability. categorizing death after va-ecmo into five categories is feasible. there are significant difference between patients with va-ecmo for shock and ecpr. interestingly, only a quarter of patients after ecpr died due to brain damage. introduction: scarcity of potential dead brain donors and the persistent mismatch between supply and demand of organs for transplantation has led the transplant community to reconsider donation after circulatory death (dcd) as a strategy to increase the donor pool. normothermic regional perfusion (nrp) by extracorporeal membrane oxygenation (ecmo) may be the most effective method for preserving abdominal organs in dcd, especially in liver transplantation [ , ] . a pitfall of this method is its complexity and the unavailability of this resource in some hospitals, especially in regional hospitals, where potential dcd donors may exist. aim of this study is to report the use of mobile ecmo team in controlled dcd. from june to november our group has worked as a mobile ecmo team for cdcd outside our center. portable equipment included cannulation material and the ecmo device. the transplant team consisted of transplant coordinator (anesthesiologist-intensivist, ecmo operator and organ extraction supervisor), cardiac surgeon (cannulation), interventional radiologist (cannulation) and one cardiovascular perfusionist (ecmo operator). twenty-five cdcd donations were performed. characteristics of donors and organs retrieved are summarized in figure . from cdcd, livers, lungs, kidneys were obtained. the evolution of grafts and receptors was favorable at day post-transplant. mobile ecmo teams may enable cdcd in hospitals without these resources, thereby increasing the pool of donors and optimizing graft outcomes. what is the useful coagulation and fibrinolysis marker for predicting extracorporeal membrane oxygenation circuit exchange due to intra-circuit thrombus? y izutani, k hoshino, s morimoto, k muranishi, j maruyama, y irie, y kawano, h ishikura fukuoka university hospital, emergency and critical care center, fukuoka-shi, japan critical care , (suppl ):p a thrombus formation is one of the most frequent and adverse complications during extracorporeal membrane oxygenation (ecmo) support. previous studies have reported that increased d-dimer is a useful predictor of thrombus formation within the ecmo circuit. the purpose of this study was to identify coagulation/fibrinolysis markers for predicting the replacement of ecmo circuit due to intra-circuit thrombus during ecmo support. fourteen patients who underwent veno-venous ecmo for acute respiratory failure between january and december were enrolled. these patients received a total of days of ecmo support. of these, days (times) on which the ecmo circuits were replaced was regarded as the replacement group, while the remaining days were considered as the non-replacement group. the several coagulation/fibrinolysis markers were routinely measured every day during ecmo support. we compared with the levels of these markers between two group to identify the most relevant marker for ecmo circuit replacement due to thrombus. the mean duration of ecmo support was ± days, and the mean number of ecmo circuit replacement was . ± . times per patient. ddimer, thrombin-antithrombin complex (tat), plasmin-α plasmin inhibitor complex (pic), and soluble fibrin (sf) were significantly higher in the replacement group rather than in the non-replacement group (p < . , respectively). according to a multivariate analysis, sf was the only independent predictor of ecmo circuit replacement due to thrombus. the odds ratio ( % confidence intervals) for sf ( μg/ml) was . ( . - . ). the area under the curve and optimal cut-off value were . and ng/ml for sf, respectively (sensitivity, %; specificity, %). from these results, we concluded that sf may be the useful marker rather than d-dimer for predicting the replacement of ecmo circuit due to intra-circuit thrombosis. inhomogeneity of lung elastance in patients who underwent venovenous extra corporeal membrane oxygenation (v-v ecmo)-a computed tomography scan study rd di mussi , ri iannuzziello , fm murgolo , fd de carlo , e caricola , na barrett , lc camporota , sg grasso università degli studi di bari "aldo moro", department of emergencies and organ transplant, bari, italy; università degli studi di bari "aldo moro", bari, italy; department of adult critical care, guy´s and st thomas´nhs foundation trust, king´s health partners, london, uk critical care , (suppl ):p in patients with acute respiratory distress syndrome (ards), nonaerated, poorly aerated, and normally aerated regions coexist to variable degrees in lung parenchyma. the recruitment maneuvers aim to reopen collapsed lung tissue. in a theoretical point view, this strategy may also prevent the normal aerated lung tissue hyperinflation [ ] . the objective of our study was to evaluate lung characteristics in terms of hounsfield units (hu), volume and elastance before and after a recruitment maneuver. in patients with severe ards who underwent v-v ecmo, computed tomography scans (ct-scans) at cmh o of continuous positive airway pressure (cpap) and cmh o were performed. the same ct image was selected at the two different levels of pressure. the distribution of lung opacities, in terms of hu, was classified using the "ucla" colour coding table (osirix image processing software, geneva, switzerland). correspondent lung regions of about voxels were selected. the quantitative analysis, in terms of volume air (vair) was performed with maluna software (version . ; maluna, goettingen, germany). elastance was calculated as the pressure(cmh o)/ vair (ml) ratio. results: see figure . lung inhomogeneity occurs also after recruiting maneuvers. our data confirm that the elastance of recruited lung regions is higher than the elastance of the normal aerated lung regions at low positive end-expiratory pressure (peep) (baby lung). on the contrary the "baby lung" frequently develops hyperinflation. the unpredictable pattern of distribution of volume after recruitment maneuverers may explain the controversial role of peep during the ards treatment. . formal recommendations on target, timing, and rate of at supplementation are lacking. we conceived this study to evaluate the effect of prolonged at supplementation in adult patients requiring veno-venous ecmo for respiratory failure on heparin dose, adequacy of anticoagulation and safety methods: before ecmo start patients were randomized to either receive at supplementation to maintain a functional at level between and % (at supplementation group) or not (control group) for the entire ecmo course. anticoagulation was provided with unfractionated heparin following a standardized protocol [ ] . the primary outcome was the dose of heparin required to maintain the ratio of activated partial thromboplastin time between . and . secondary outcomes were the adequacy of anticoagulation measured with anti-factor xa and the incidence of hemorrhagic and thrombotic complications and amount of blood products fig. b) . conclusions: this retrospective analysis was not able to show a survival benefit for additive pp to ecmo support in general. early initiation of pp could be an important factor for improving survival in this setting and should be considered in a randomized controlled trial for further evaluation. cause-specific mortality during extracorporeal membrane oxygenation, a single center review of medical records m panigada, d tubiolo, p properzi, g grasselli, a pesenti fondazione irccs ca´granda ospedale maggiore policlinico, intensive care unit, milano, italy critical care , (suppl ):p introduction: mortality during extracorporeal membrane oxygenation (ecmo) settles around % and the occurrence of bleeding during ecmo is associated with a high mortality rate. however, cause-specific mortality is rarely reported, probably due to the difficulty of its classification. the purpose of the study was to evaluate the agreement between two expert icu physician in the classification of the cause of death of patients supported with ecmo for either respiratory or cardiac support. methods: two intensive care unit (icu) expert staff physicians independently reviewed the entire medical records of all ecmo patients who died before icu discharge from january to september at fondazione irccs ca' granda, milan. they were asked to choose the cause of patient's death among six categories. in case of disagreement, a third expert adjudicated the case. the two reviewers were also asked whether, in their opinion, bleeding during the last hours contributed to death. elso definition of major bleeding [ ] during the last hours was also recorded for each patient. results: two-hundred and two patients were supported with ecmo of whom ( . %) died. most of these patients (n= , . %) died during ecmo. interrater agreement for cause-specific mortality between the two expert physicians was substantial (k . , se . , p< . ) of the discordant cases were categorized as refractory respiratory failure and as multiorgan failure and septic shock respectively. the distribution of cause-specific mortality is shown in figure . major bleeding (elso) was present in ( . %) patients, only in ( . %) of them bleeding contributed to death according to the reviewers. patients treated with early pp while ecmo showed a superior survival to patients treated with late pp or without pp while ecmo. optimal cut off value for duration of ecmo initiation to first pp was calculated using roc-analysis (auc = . ) and the youden-index. highest sensitivity and specificity for beneficial survival were achieved for a beginning of pp in < . days. (log rank= . ). pp: prone positioning p non-invasive mechanical ventilation in veno-venous extracorporeal membrane oxygenation j rilinger, v zotzmann, x bemtgen, pm biever, d duerschmied, c bode, dl staudacher, t wengenmayer heart center freiburg university, department of cardiology and angiology i, freiburg, germany critical care , (suppl ):p introduction: veno-venous extracorporeal membrane oxygenation (ecmo) support can be combined with a variety of different non-invasive ways to deliver oxygen to the patient's lung. several positive effects might be linked to this so called "awake ecmo". so far there is little evidence about indications and outcome of this approach. we report retrospective registry data on all ards patients treated with ecmo support at a university hospital between / and / . in a systematic review of medical records, we distinguished between patients with invasive mechanical ventilation (imv) from the initiation of ecmo therapy (imv group) and patients that received any kind of non-invasive oxygen supply (non-imv group). a total of patients could be analysed. ( . %) patients received non-imv ecmo support. patients receiving non-imv ecmo therapy showed severe underlying pulmonary disease and immunosuppression (fig. ) . these patients had higher rates of lung fibrosis, long-term oxygen therapy, pulmonary hypertension, renal insufficiency and immunosuppression (p< . ). of patients ( %) required imv during the hospital stay in average . ± . [ . - . ] days after ecmo initiation. reasons were hypoxia despite of ecmo, insufficient ecmo-flow, insufficient protective reflexes or patient agitation. patients with initially non-imv ecmo support showed a numerical but not significant lower icu and hospital survival ( . % vs. . %, p= . ). non-imv ecmo support was applied in patients with severe underlying pulmonary disease and/or immunosuppression. in a high proportion of patients the ventilation regime had to be switched from non-invasive to invasive. survival in this very selected cohort was low. in this retrospective analysis no evident benefit for a noninvasive ventilation strategy could be found. the high proportion of patients who switched from non-imv to imv therapy underlines the need for rigorous patient selection. intra-hospital transportation on extracorporeal membrane oxygenation (ecmo) -a single centre experience in ireland. z siddique, s o´brien, e carton, i conrick-martin mater misericordiae university hospital, department of critical care medicine, dublin, ireland critical care , (suppl ):p the objective of this study is to evaluate intra-hospital transportation of patients on extracorporeal membrane oxygenation (ecmo). it is a retrospective analysis of prospectively collected database, performed as part of ongoing quality improvement initiatives. the setting of this study is an -bed, combined surgical and medical adult intensive care unit (icu) located in a -bed hospital that serves as the national referral centre for cardiothoracic surgery, heart & lung transplantation and ecmo in ireland. we reviewed months of data (from to ) regarding patients admitted to our critical care unit who required intra-hospital transfer for diagnostic and/or therapeutic interventions. we also compared the data to available local guidelines. results: patients were transported on ecmo on a total of occasions; the most common indication being ct brain (table ) . ecmo cannulation sites were peripheral in patients, patients were centrally cannulated. median time from start of the transfer until the patient was returned to icu was minutes (range: - ). the ecmo console was placed on a dedicated ecmo trolley apart from two occasions where it was placed on the patient's bed. number of staff required for transport was between to ; with an icu consultant as team leader. ecmo specialist nurses were always present on the transport team. transfers were during normal working hours with happening on a weekend. a total of complications occurred during the transports, of underlying pulmonary disease or status of immunosuppression in ecmo patients without invasive mechanical ventilation which was significant and were not. the significant complication encountered was ventricular tachycardia in a v-a ecmo patient which required electrical defibrillation. no adverse events related to transport were seen following return to icu. in this single-centre study, we have demonstrated safe intra-hospital transport of ecmo patients. the use of local guidelines, appropriate personnel and performance during normal working hours is recommended. a novel approach for flow simulation in ecmo rotary blood pumps a supady , c benk , j cornelis , c bode , d duerschmied heart center freiburg university, cardiology and angiogiology i, freiburg, germany; heart center freiburg university, department of cardiovascular surgery, freiburg, germany; fifty technology gmbh, freiburg, germany critical care , (suppl ):p introduction: extracorporeal membrane oxygenation (ecmo) is used increasingly in critically ill patients suffering from acute respiratory failure, cardiogenic shock or cardiac arrest. however, this therapy can have deleterious side effects such as bleeding or clotting complications and hemolysis. these complications are particularly caused by physical stress acting upon the blood components while passing through the ecmo system, especially within the rotary pump. we here present a novel approach to simulate blood flows through rotary blood pumps used in current ecmo systems in order to better understand the genesis of these complications. geometries of the xenios dp (xenios ag, heilbronn, germany) rotary pump were reconstructed by ct-scans and manual measurements using computer-aided design (cad). the computational fluid dynamics (cfd) simulation was performed using the software preon-lab (fifty technology gmbh, freiburg, germany), which implements a mesh-free lagrangian method requiring minimal preprocessing of the cad data. the geometries are introduced to the simulation model as tessellated surfaces. five operating points have been specified by the rotation of the centrifugal fan and the corresponding inflow and outflow of blood. the blood is approximatively modelled as a newtonian fluid with a density of kg/m . preonlab allows detailed assessment of the blood flow while passing through the rotary pump including analysis of local flow rates, pressure gradients and shear stress acting upon the blood. dead zones in the fluid flow can be detected which gives reference points for optimizations of the pump design. for the first time, we demonstrate a novel approach for flow simulation in an ecmo rotary pump ( figure ). this approach may help better understand hemodynamics within the extracorporeal system to define optimal operating points or re-design components aiming to limit hemolysis, coagulation disorders and bleeding in seriously ill patients. one-year experience of bedside percutaneous va-ecmo decannulation in a territory ecmo center in hong kong km fong, sy au, pw leung, kc shek, hj yuen, sk yung, hl wu, so so, wy ng, kh leung queen elizabeth hospital, intensive care unit, hong kong critical care , (suppl ):p when veno-arterial extra-corporeal membrane oxygenation (va-ecmo) support can be terminated, arteriotomy wounds of the patients of are traditionally closed by open repair in the operation theaters. lots of manpower are involved and timeslots in operating theaters are scarce. transport of the critically-ill is risky. successful va-ecmo decannulation using percutaneous device called proglide has been reported and our group had adopted and modified this approach [ ] . methods: this is a retrospective study analyzing the one-year experience of bedside va-ecmo decannulation. our institution is a -bed tertiary ecmo referral center in hong kong. our first bedside decannulation was performed in november , and since then, this practice had replaced the traditional open repair, unless contraindicated. data from november to october were analyzed. in the study period, patients received va-ecmo. survived to decannulation and received bedside percutaneous decannulation. their median age was ( - ). the default arterial catheter size was fr, with fr in cases and fr in one. five ( %) failed percutaneous closure and they were subsequently surgically repaired without extra corporeal life support (ecls) continues to be associated with high mortality rates. our ability to predict outcome prior to initiation ecls remains limited. here we take a single cell rnaseq approach in an effort to identify novel immune cell types that are associated with-and may contribute to-survival on ecls. whole genome transcriptomic profiles were generated from~ , peripheral blood monocytes obtained from patients at the time of cannulation for veno-arterial ecls (va-ecls). within each subpopulation, differential gene expression analysis was performed to identify new markers associated with survival. findings were validated in a additional cohorts by flow cytometry. surviving patients had significantly higher proportions of cd + nkt cells (cd + /cd + /cd -/cd + ) that were cd + (p = . , fdr < . ) ( figure ). to validate this observation, we performed fc analysis of a second cohort of patients. for each patient, we quantified the proportion of cd + nkt cells that were cd + . using the median proportion as the cutoff, we again found that a high proportion of cd + cells among cd + nkt cells was predictive of hour survival (p= . ). we noted that while high levels of cd + cells among the cd + nkt cells was protective in this cohort of va-ecls patients, this relationship did not hold for patients with sepsis. as only a few the va-ecls patients were septic, we analyzed a third cohort of septic ecls patients. we observed that high levels of cd + cells among the cd + nkt populations was not protective in this population. the proportion of cd + nkt cells that are positive for cd is predictive of survival among patients undergoing va-ecls for noninfection related indications. introduction: the use of calcium sensitizers has grown enormously in the last decade, probably due to their interesting pharmacodynamic properties. levosimendan (ls) is frequently administered in patients under mechanical circulatory support. we performed a retrospective evaluation of patients treated with ls prior to weaning from mechanical support. this evaluation was combined with a review of the literature. a query of our icu patient data management system revealed patients receiving ls prior to or during vad/ecls support. outcome data were obtained from the patients medical records. of our patients, % was successfully weaned off ecls. fourteen patients ( %) died before being discharged of whom while on ecls support. of the weaned patients, died afterwards. of the converted patients needed subsequent veno-venous ecls support for right ventricular support after the implantation. survival to discharge ratio for the whole group was %. more detailed demographic results can be found in table . a pubmed search using the terms "(ecmo or ecls) and ls and weaning" resulted in publications which dealt specifically with weaning of ecls support. several weaning approaches are available, however poor outcome has remains a problem. some recent studies show a possible beneficial effect of ls infusion prior to weaning from ecls. however most of these studies are retrospective or observational at best. because ls is primarily reserved for the most severe cases, outcome interpretation is difficult. overall weaning success ranges from %- % and variation is very dependant of inclusion criteria. the calcium sensitizer ls can be used when weaning off patients from ecls, certainly given its low incidence of complications. future, large randomized trials are however needed in order to confirm this strategy. cardiogenic shock is well described in newly diagnosed pheochromocytoma, and crisis may be precipitated by hemorrhage into tumour. v-a ecmo represents a rescue therapy in a subset of these patients refractory to medical management, facilitating cardiac recovery and subsequent definitive surgery. consent to publish: written informed consent for publication was obtained from the patients. during a spontaneous breathing trial respiratory mechanics can worsen, and respiratory muscle effort can increase, leading to respiratory muscle fatigue, pump failure, hypercapnia and an unsuccessful weaning from mechanical ventilation. this case report discusses the possibility of applying extracorporeal co removal (ecco r) to reduce respiratory muscle effort in a liver transplant recipient who already failed three weaning attempts from mechanical ventilation. the ecco r membrane lung was integrated into a conventional renal replacement therapy circuit and blood flow was increased from to ml/min. measurements of respiratory mechanics (including esophageal pressure, as shown in fig. ) were used to assess the reduction of respiratory effort before and during the application of ecco r. was delivered through a fr-double-lumen-cannula; ml/min blood-flow with lt oxygen sweep-gas-flow and aptt . - baseline were maintained (iv-heparin). in all cases respiratory and metabolic parameters improved without complications ( figure ). ecco r-crrt facilitated extubation ( out imv pts). in out of pts at risk of niv failure, it avoided imv. treatment mean duration was ± hours, mean lenght of icu stay was ± days. all patients survived to the treatment, nevertheless patients died due to irreversible multiple mof. in our aecopd series prismalung®-prismaflex® facilitated weaning from imv and avoided intubation in patients at risk of niv failure without complications. these positive results may be related to minimal invasiveness of the low-flow device used and may constitute the rationale for a larger randomized controlled trial. consent: written informed consent for data publication has been obtained. extracorporeal the primary outcome findings from the supernova trial [ ] demonstrated that the use of extracorporeal carbon dioxide reamoval (ecco r) allows a reduction in tidal volume (tv) to ultraprotective levels (≈ ml/kg predicted body weight or pbw) during mechanical ventilation in ards patients without significant increases in the arterial partial pressure of carbon dioxide (paco ). unfortunately, it was not feasible to directly measure ecco r rates during the trial. we used a mathematical model of whole-body oxygen (o ) and carbon dioxide (co ) transport and biochemistry [ ] to calculate ecco r rates that permit a fit to the data reported for hemolung (alung technologies) and ila (novalung)/cardiohelp (getinge) devices in the supernova trial [ ] . the mathematical model was calibrated under baseline conditions where patients were mechanically ventilated at a tv of ml/kg pbw in the absence of an ecco r device; the o consumption rate, co production rate and pulmonary shunt fraction were adjusted to match the measured baseline arterial partial pressure of o and paco . assuming all baseline parameters were fixed, tv was then reduced to . ml/kg pbw and the mathematical model predicted the ecco r rate to the change in the paco level. model predictions for the devices are shown in table . these predictions suggest that ecco r rates for ila/cardiohelp devices were approximately twice those for hemolung devices during the supernova trial. these results may be useful to evaluate the expected performance of novel ecco r devices. efficiency and safety of a system crrt plus ecco r to allow ultraprotective ventilation protocol in patients with acute renal failure f maldarelli despite renal function replacement techniques (crrt), a patient who develops acute renal failure(aki) in intensive care unit (icu) has a mortality rate of - %. this risk is partly due to the adverse effect of aki on other organs than the kidney. respiratory complications are frequently associated with the development of aki. new machines combining crrt with a carbon dioxide removal membrane (ecco r) allows the setting up of an ultra-protective ventilation ( ml/kg of predicted boby weight (pbw)) to reduce any lung damage from mechanical ventilation (mv). the reduction in tidal volume (vt) is associated with a decrease in lung damage partly triggered by aki. we evaluated the efficacy of a combined system crrt+ecco r to reduce the vt to ultraprotective values in patients with acute respiratory failure and aki. ards is a syndrome with high morbidity and mortality. an emerging treatment option is ecco r, but the benefit its remains unclear. we assess different degrees of ecco r and varying dead space (ds) on ventilator settings in order to minimize mechanical power. we calculated mechanical power as ( ) power=rr*{Δ〖vt〗^ *[ / *el+rr*( +i:e)/( *i:e)*r]+ Δvt*peep} (el: system elastance, r: airway resistance, peep: positive end expiratory pressure, i:e: inspiratory to expiratory ratio). we calculated the combination of respiratory rate (rr) and tidal volume (vt) ("optimal rr" and *optimal vt*) leading to minimal applied power for a stable carbon dioxide elimination of ml/min (vco ) for two scenarios: ) variation of physiological ds from to % of vt at a fixed rate of eccor . ) variation of ecco r of either , , or ml/min at a fixed physiological ds of %. the alveolar ventilation (va) necessary to eliminate the vco was calculated as ( ) va= (-vco *σ_co *r*t*( +k_c ))/(vco /q-p_vco *σ_co *r*t*(( +k_c ))/ ) σco : co solubility in blood, r: gas constant, t: temperature. pvco : venous partial pressure, kc: function of ph ( . for a ph of . ), q: blood flow [ l/min]). increasing ds from to % increases the minimal mechanical power from . to . j/min, primarily caused by an increase of optimal vt ( - ml). optimal rr was only slightly increased ( . - . /min, figure panel a). for varying ecco r removal, necessary ventilation ranges from . to . l/min. this predicts a minimal power between . and . j/min with an unchanged optimal vt ( - ml) and an increasing optimal rr ( . to . /min ( figure panel b)). in order to minimize mechanical power, increasing shunt or co production should be met with increases in rr while increases in ds should be met with increases in vt. our results indicate that during ecco r, mechanical power and thus risk for lung injury can be minimized with higher vt compared to conservative ventilation strategies. validity of empirical estimates of physiological dead space in acute respiratory distress syndrome jd dianti, eg goligher, as slutsky university of toronto, interdepartmental division of critical care medicine, toronto, canada critical care , (suppl ):p increased physiological dead space fraction (v d /v t ) is a hallmark of the acute respiratory distress syndrome (ards) and has been shown to predict ards mortality. v d /v t is also important in estimating the reduction in tidal volume (v t ) and driving pressure (Δp) with extracorporeal co removal (ecco r). v d /v t can be measured with volumetric capnography but empirical formulae using the patient's age, weight, height, gender and paco have been proposed to estimate v d /v t based on estimates of co production (v co ). the accuracy of this approach in critically ill patients, however, is not clear. secondary analysis of a previously published trial [ ] in which v d /v t and v co were measured in ards patients. estimated dead space fraction (v d,est /v t ) was calculated using standard formulae. agreement between methods was evaluated by bland-altman analysis. the predicted change in Δp with ecco r was evaluated using both measured and estimated alveolar dead space fraction (v dalv /v t ). results: vd,est/vt was higher than measured vd/vt, with a low correlation between the (r = . ). vco was underestimated by the predicted approach (table ) , accounting for % of the error in estimating vd/vt. the expected reduction in Δp with ecco r using vdalv/ vt was in reasonable agreement with the expected reduction using introduction: acute respiratory distress syndrome (ards) is a common condition in critically ill patient. however neuromuscular blockers (nmb) result controvertial in early treatment of ards [ ] . we ought to search systematically and realize a meta-analysis on the matter. an electronic search of randomized clinical trials in adult patient treated with early neuromuscular blockers compared without neuromuscular blockers in ards. the primary objective of the analysis was the mortality at to days. secondary endpoints included mechanical ventilation free days, icu acquired weakness and barotrauma. the search obtained studies for the analysis [ ] [ ] [ ] [ ] [ ] [ ] (figure ). the early use of neuromuscular blockers in ards showed no increase in mortality, but the results should be taken with caution. there was no differences in mechanical ventilation free days. barotrauma is less with the use of nmb. ultrasound is fairly sensitive in the detection of lung infiltrates in patients with hematologic malignancies. in patients with pneumonia requiring intensive care (icu) admission, we hypothesise that abnormal right ventricular (rv) function is associated with an increased -day mortality. rv dysfunction in critically ill patients has a well-known association with adverse outcomes [ ] . however, its impact on mortality in patients with pneumonia has not been directly studied. patients admitted to the queen elizabeth hospital birmingham icu between april and july with a diagnosis of pneumonia who had a formal cardiologist tte were included. abnormal rv function was defined by either depressed function, dilated size or moderate to severe risk of pulmonary hypertension (phtn). abnormal lv function was defined by an lv ejection fraction £ % or grade ii or more diastolic dysfunction. patients with a clinical suspicion of pulmonary embolism were excluded. the primary outcome was -day mortality. continuous data is presented as median (iqr). categorical data is presented as % and analysed using a chi-squared test. results: patients were admitted to icu with pneumonia, of which ( %) had a tte. patients were % male, had a median age of ( - ) and -day mortality of %. abnormal rv function was present in % (n= ), with % depressed, % dilated and % with moderate to severe risk of phtn. rv dysfunction was associated with an increased -day mortality compared to normal rv patients ( % vs. %, p< . ). lv function was abnormal in % (n= ) and was not associated with a higher -day mortality compared to normal lv patients ( % vs %, p = . ). rv dysfunction was associated with a higher -day mortality than lv dysfunction ( % vs %, p = . ). conclusions: this is one of the first studies to demonstrate that abnormal rv function is associated with an increased mortality in icu patients with pneumonia. interestingly, abnormal lv function was not associated with an increased mortality. rakuno gakuen university, anesthesiology, hokkaido, japan critical care , (suppl ):p we previously reported a simple correction method of estimating pleural pressure (ppl) by using central venous pressure (cvp) and that it can be used to estimate ppl and transpulmonary pressure in pediatric patients with respiratory failure. however, it remains unknown that this method can be applied to patients with various levels of chest wall elastance and/or intravascular volume. the objective of this study is to investigate whether our method is accurate in various conditions of chest wall elastance and intravascular volume. the study was approved by the animal care and use committee of rakuno gakuen university. ten anesthetized and paralyzed pigs ( . ± . kg) were mechanically ventilated and subjected to lung injury by saline lung lavage. each pig was subjected to different intravascular volume and different intraabdominal pressures; in each condition, the accuracy of our method was tested. specifically, airway flow, airway pressure (paw), esophageal pressure (pes), and cvp were recorded in each condition, then changes in pes (Δpes) and Δppl calculated using a corrected Δcvp (cΔcvp-derived Δppl) were compared. cΔcvp-derived Δppl was calculated as κ × Δcvp, where κ was the ratio of the Δpaw to Δcvp during the occlusion test. means and standard deviations of the two variables that reflect Δppl (Δpes and cΔcvp-derived Δppl) in all pigs with all conditions were . ± . and . ± . cmh o. the bland-altman analysis for the agreement between Δpes and Δcvp showed a bias of - . the activity and functionality of the diaphragm are difficult to measure in patients ventilated in intensive care. ultrasound can be a useful tool for monitoring diaphragm muscle activity during different ventilation modes. few data currently exist on diaphragm muscle activity in critically ventilated patients [ ] . our goal is to evaluate the respiratory muscular work of the diaphragm with different settings of the respirator by means of an ultrasound scan. the ultrasound assessments of the diaphragm were performed with a mhz linear probe at the apposition zone. we measured the thickening of the diaphragm with the respiratory acts, through the thickening fraction (thickening fraction, tf), defined as:tf = (tdimax -tdimin / tdi min)% tdimax: diaphragm thickness at the end of inspiration (maximum thickness) tdimin: diaphragm thickness at the end of expiration (minimum thickness). ventilatory support was divided into classes: -spontaneous breathing (sb) or continous positive airway pressure (cpap); -pressure support ventilation (psv) with low pressure support ( - cmh o); -psv with high pressure support (> cmh o); -controlled mechanical ventilation (cmv). a total of assessments were performed in patients. the evaluations were all possible at the right hemidiaphragm, while on the left they were not possible in % of the cases. the median tf (iq range) of the ventilation classes was respectively: % ( - %) in sb / cpap; % ( - %) in low-psv; % ( - %) in high psv; and % ( - %) in cmv. the kruskal-wallis test confirms a significant difference between the groups (p < . ). the ultrasound of the diaphragm can be a valid tool for monitoring respiratory muscle activity during mechanical ventilation. introduction: extubation failure is defined as reintubation after hours of extubation in mechanically ventilated critically ill patients. it is associated with morbidity and mortality. the aim of our study was to assess reintubation rates in a busy district general hospital and evaluate the impact of high flow nasal oxygen therapy (hfno) on reintubation rates. we performed a retrospective observational study looking at patients admitted to our bedded level critical care unit ( patients a year) for a period of years between st november and st october . we included patients over years of age who were mechanically ventilated and length of stay was greater than hours. exclusions were age < years, tracheostomy and patients requiring ventilation for < hours. data was collected from ward watcher, a sicsag database and electronic patient records. our study failed to show any impact of hfno on reducing extubation failure. further work is needed to develop a standardized approach to weaning and to consider routine application of noninvasive ventilation to reduce reintubation rates [ ] . fig. (abstract p ) . the bland-altman analysis for the agreement between Δpes and cΔcvp-derived Δppl in various conditions. low: low intravascular volume, normal: normal intravascular volume, high: high intravascular volume, abd-: without an abdominal compression band, abd+: with an abdominal compression band oral endotracheal intubation is common to critically ill patients in intensive care unit. oral care for an intubated patient is important to maintain the moisture of oral mucosa. also, the securement method of oral endotracheal tube developed from cloth tape to commercial tube holder. training powerpoint and video for microteaching was prepared to train up icu nurses to perform the new practice. demonstration and re-demonstration was arranged to assess skills of every nurse. afterwards, each nurse answered a quiz to evaluate the understanding of oetth and its special techniques in application. questionnaire was designed to collect the feedback from all nurses too. the result showed there was nurses ( %) out of nurses achieved full marks in the post-quiz which demonstrated their full understanding of the use of oral ett holder and its nursing care. about the feedback from nurse, % of nurses claimed that they were confident in using the new oetth in clinical setting after training. % of nurses agreed in time-saving of nursing care routine with the use of an oetth. however, only % of nurses agreed that the oetth is effective in prevention of oral mucosa injuries and another % of nursing staff disagreed on its function in improving the patient's oral care. in conclusion, some of the nurses did not agree the prevention of oral mucosa injuries by the new securement method with oetth while some nurses welcomed the new oetth as more easy and effective in oral care to intubated patients. execution of percutaneous dilatational tracheostomy using the standard laryngeal mask airway for ventilation: a prospective survey study g gagliardi , v gagliardi , c chiani , g laccania , f michielan aulss -veneto, anesthesia and intensive care, adria, italy; aulss -veneto, university of padua, adria, italy; aulss -veneto, anaesthesia and intensive care, adria, italy; aulss -veneto, anaesthesia and intensive care, padua, italy critical care , (suppl ):p we fulfilled a survey study dealing with bronchoscope-guided percutaneous dilatational tracheostomies (pdt), using the classic laryngeal mask airway (lma) for the airway management [ ] . the aim was to verify the safety and the effectiveness of the aforementioned procedure methods: we performed an observational prospective survey study enrolling patients hospitalized in the intensive care unit. before performing the tracheostomy, the endotracheal tube has been replaced by the laryngeal mask airway. arterial blood gases, ventilation pressures and tidal volumes have been monitored, registered and compared. the median peak inspiratory pressure has been detected stable in all patients. furthermore, during the ventilation with the laryngeal mask, the tidal inspiratory and expiratory volume difference observed between before and after the bronchoscope positioning, has shown a statistically significant variation. finally, in all cases etco , spo . , pao , and blood ph values persisted within the normal range. the standard lma provides for a reliable airway management and allows an effective ventilation while performing the pdt. once positioned in the supraglottic zone, the lma does not need to be moved throughout all the pdt performance, avoiding risks of displacement, glottic harm and airway device damage, and permitting an easy handling of the bronchoscope, which gives an appropriated visualization of the trachea and a more efficient aspiration. in consequence to the large internal diameter of the lma tube, ppeak has continued to be stable in all patients, providing for minor resistance and inspiratory work. eventually, no late complications, such as tracheal stenosis and infections, have occurred. tracheostomies are the most common surgical procedure performed on critically ill patients. randomized control trials comparing tracheostomy timing in intensive care patients have been equivocal. in order to perform non-urgent tracheostomy in our icu, consent is required from the patient or a formal guardian appointed ad hoc by the courts. since tracheostomies are practically the only elective surgery performed in the critically ill, icu requested guardianship almost always indicates a clinical decision to perform tracheostomy. as appointing a guardian and arranging a tracheostomy takes about a week, the decision to appoint a guardian offers a unique "intention to treat" opportunity to evaluate outcomes in patients for whom tracheostomy is planned. we performed a retrospective analysis over years on patients for whom guardianship was sought excluding those requiring urgent tracheostomy and those with a do-not-resuscitate order. patients were divided according to outcome (tracheostomy, extubation or death prior to tracheostomy) and compared. guardianship was sought for ventilated patients. a decision to withhold tracheostomy was made for patients, who were excluded, leaving patients for analysis. tracheostomy was performed for / ( %) patients, / ( %) were extubated and / ( %) died while waiting for tracheostomy (from nonairway related reasons). tracheostomy was performed on mean ventilation day ± . comparing extubated patients to those who had tracheostomy (table) shows similar demographics, but significantly lower mortality and hospital length of stay. a significant proportion of patients initially planned for tracheostomy were successfully extubated. despite demographic similarities, mortality in this group was significantly lower than for patients undergoing tracheostomy. for a selected subgroup of possibly difficult to characterize patients, delaying tracheostomy may be beneficial. figure ). ptis were analysed by speciality and by outcome. complications occurred in cases (incidence . %). there were cases of subcutaenous emphysema, pneumothorax (occuring d post procedure) and case each of stoma and suture site infection. there was unplanned cannula change within days of insertion. % of cases had cuff inflated on discharge from icu. handover of care was suboptimal; follow up care plans were documented in % of cases. a supervising consultant was present for all ptis. there was a trend of increased insertion by consultant and increased reliance on theatre, with corresponding decrease in the number inserted by trainees. pti in our training icu appears safe with low incidence of complications and good senior support for tracheostomy insertion. emphasis must continue on training junior intensivists in pti. transition of care beyond icu requires further work where currently there is suboptimal handover of care and safety netting for non-icu colleagues. supplemental oxygen administration is ubiquitous in the critical care environment, yet evidence is mounting for the deleterious effects of hyperoxia [ ] . concerns over the adverse effects from hypoxaemia often exceed those of hyperoxaemia in developing world settings, and inconsistent availability of blood gas monitoring may limit judicious oxygen titration. the aim of this project was to audit oxygen delivery practice and introduce qi measures to avoid excess oxygen delivery in a tertiary icu in lusaka, zambia. a prospective snapshot of ventilatory parameters were recorded for critically ill patients over a -week period, including positive end expiratory pressure (peep), fio , and time-course spo . systematic education was provided through group and one to one tutorials to empower nursing and medical staff to titrate oxygen safely and appropriately. repeat data collection was then performed over weeks. initially / patients ( %) were over-oxygenated, as defined by fio > . and spo consistently > %. / patients with an fio of > . had peep ≤ cm ( %). no patient had a pao recorded in the past hours. education was provided as well as implementation of unit protocols above all patient beds documenting a stepwise approach to titration peep and fio . post intervention fewer patients were over-oxygenated: / ( %) had fio > . and spo consistently > %, and / with an fio > . ( %) had a peep ≤ cm. in addition, / ( . %) had a pao recorded within hours. this qi project has shown that nurse engagement and systematic education to titrate fio and peep can be achieved in a resource poor setting and may decrease the incidence of hyperoxia in critically ill patients. availability of blood gas monitoring and knowledge of interpretation was a major barrier to oxygen titration tracheal intubation (ti) in adult burn patients might be unnecessary in to % of cases [ , ] . in pediatric burn patients, there is little data on both the rate of ti and the rate of early extubation [ ] . it has been common practice for a child with a facial burn and/or a suspected airway injury to be intubated early due to the risk of losing airway patency. however this risk should be mitigated against the potential risks of ti and mechanical ventilation in children. therefore the aim of this study was to describe the airway status of child burn victims taken in charge of in our pediatric burn intensive care unit. focused on patients arriving with ti, we investigated the rate of early extubation. in addition we compared non intubated patients with those with prolonged ti. this retrospective study described a cohort of patients hospitalized between and . data was retrospectively recorded from the patient's paper clinical chart. the mean age of our patients was . ± . years [mean±sd] with an average burn area of ± %. % had scald burns and % had facial burns. % of the children were admitted in the burn icu with ti. for % of them, tracheal tube was removed within the first hours after admission. the probability of prolonged ti increased independently with the burned skin area (bsa) (p < . ), the presence of facial burns (p = . ), and in case of flame burns (p = . ) ( figure ). among patients with more than % bsa, % were intubated more than h. among patients with less than % bsa, . % were intubated more than h. according to our retrospective data, it seems appropriate to intubate children with % and more bsa, while for patient with less than % bsa, it might be relevant to seek guidance from physician of the nearest burn center. under % bsa, ti seems rarely required. an analysis of the predictive applicability of initial blood gas parameters for the need for intubation and the presence of inhalation injury in patients with suspected inhalation injury c pirrone , m chotalia , t mangham , r mullhi , k england , t introduction: we hypothesise that initial blood gas parameters have a good predictive applicability in detecting the need for intubation and the presence of inhalation injury in patients with suspected inhalation injury. to the best of our knowledge, this has not been directly studied in the literature. patients with suspected inhalation injury admitted to the icu at queen elizabeth hospital, birmingham between april and may were included. the initial blood gas parameters analysed were pao (kpa), paco (kpa), ph, carbon monoxide level (cohb; %) and pao /fio (pf) ratio. receiver operator characteristics (roc) for these parameters were plotted against the need for intubation for more than hours and the presence of inhalation injury as detected by bronchoscopy and laryngoscopy. area under the curve (auc) for each parameter was calculated. results: patients were admitted with suspected inhalation injury to the icu. % were intubated for more than hours. of patients who were intubated, % had inhalation injury as indicated by bronchoscopy or laryngoscopy. table outlines the auc for initial blood gas parameters in detecting the need for intubation for more than hours and the presence of inhalation injury. ph was the parameter with the most prominent auc, with reverse correlation indicating fair accuracy. no clear inflection point was identified, although all patients with ph < . required intubation and had inhalation injury. paco had a fair predictive applicability in detecting the need for intubation. pf ratio, pao and cohb had poor accuracy. conclusions: initial blood gas parameters had a broadly poor predictive applicability for the need for intubation and the presence of inhalation injury in patients with suspected inhalation injury. severe acidosis (ph < . ) was the most useful blood gas parameter. clinicians should be cautious in using blood gas parameters alone to inform intubation decisions. lung cancer surgery is associated with a high rate of pulmonary complications including ards and mandates lung protective ventilation strategies [ , ] . such strategies include non-intubated video assisted thoracic surgery (nivats) with spontaneous breathing [ ] . currently neither data on respirator settings nor on gas exchange have been reported for applying the latter. this data constitutes a prerequisite for meaningful evaluating the respiratory consequences of non-intubated spontaneous breathing during lung cancer surgery. the aim of this case series was for the first time providing such data from lung cancer surgery including pneumonectomy. during a month period patients without contraindications [ ] scheduled for video assisted thoracic surgery (vats) for non-anatomical and anatomical lung resection including one pneumonectomy (px) were offered non-intubated spontaneous breathing. all patients gave informed written consent to the procedure as well as for analysis and publication of data. anaesthetic management included target controlled infusion of propofol and remifentanil, laryngeal mask airway, and pressure support ventilation. we present early data that early trials of cuff deflation within hours of tracheostomy insertion can be achieved using a standardized protocol. its impact on length of stay, duration of ventilation and patient-centered outcomes needs to be investigated in larger multi-centre trials. preventing underinflation of the endotracheal tube cuff with a portable elastomeric device. a randomized controlled study je dauvergne , al geffray , k asehnoune , b rozec , k lakhal hopital laënnec -chu de nantes, service d´anesthésie-réanimation, nantes, france; hotel-dieu -chu de nantes, service d´anesthésieréanimation, nantes, france critical care , (suppl ):p the management of the endotracheal tube cuff pressure (p cuff ) is routine practice for critical care nursing staff. underinflation could lead to ventilator-associated pneumonia [ ] whereas overinflation exposes to tracheal damage [ ] . multi-daily check and adjustment is recommended to ensure that p cuff lies between and cmh o [ ] . to automate this task some devices exist but may be inconvenient, bulky and/or ineffective. their use is not supported by guidelines. a portable elastomeric device could be appealing for p cuff automated regulation. this prospective randomized controlled study tested whether the tracoe smart cuff manager tm reduced the rate of patients undergoing ≥ episode of underinflation (p cuff < cmh o), as compared with routine manual p cuff adjustment. monocentric, randomized controlled study. patients with acute brain injury and receiving mechanical ventilation were prospectively allocated to one of the two arms: manual reading and adjustment of p cuff at least every h (routine care) or adjunction of the smart cuff manager tm (intervention). this study was approuved by an institutional review board. among randomized patients (routine care in , smart cuff manager tm in ), measurements were performed in h. with routine care, a higher rate of patients experienced at least one episode of underinflation ( . vs. . %;p< . ). episodes of underinflation episodes ( % vs. %;p< . ) and manual adjustments ( % vs. %;p< . ) were more frequent with routine care. for overinflation, there was no between-arms difference (p> . ). the adjunction of continuous p cuff control with the tracoe smart cuff manager tm reduced the incidence of p cuff underinflation as compared with manual intermittent adjustments. overinflation was not promoted by this device. direct laryngoscopy as a technique for tracheal intubation is a potentially lifesaving procedure that healthcare professionals in a variety of fields are taught. however, this skill is challenging to acquire and difficult to maintain. poorly performed intubation technique can lead to potentially serious complications [ ] . the intersurgical iview video laryngoscope is a new intubation tool which may have advantages over direct laryngoscopes, such as the macintosh, in the hands of novice personnel. a prospective randomized counterbalanced trial of medical students, who did not have previous airway management experience, was conducted. each student received brief didactic teaching,following this, participants were directly supervised performing laryngoscopy and intubation using the macintosh and iview devices in an alternating pattern. students were permitted up to three attempts to successfully intubate under four conditions, three laryngoscopy conditions using alaerdal intubation trainer and one using a laerdal simman manikin. there was no significant difference in the success rate of intubation or time to intubation between the two devices. the iview outperformed the macintosh in time to intubation in the normal airway in the final scenario, once students gained experience with both devices. no significant difference was found in the number of optimisation manoeuvres, or intubation attempts between groups. areas where the iview outperformed the macintosh included severity of dental trauma and participants' perception regarding ease of use ofthe device. the iview may prove to be a useful teaching tool for novice personnel who are acquiring the skills of tracheal intubation. patients with a primary pulmonary pathology were more likely to respond to aprv. this association has not been described before and warrants further multi-centre exploration in a larger patient group. introduction: airway suctioning is common during mechanical ventilation, using either an open endotraqueal suctioning or closed endotracheal suctioning (ces). closed circuits were developed to prevent arterial desaturation and atelectasis associated to ventilator disconnection. however, ces may cause substantial loss of lung volume. the purpose of this study was to investigate the effects of a compensation method to prevent the loss in aeration during ces. the suctioning technique was performed for seconds, negative pressures limited at mmhg. closed suction catheters with fr (halyard health, georgia, eua) were used. electrical impedance tomography (eit) monitoring and arterial blood gas were collected. a nihonkoden mechanical ventilator (nkv , california, eua) was applied, having a newly developed algorithm for suctioning which overcomes any pressure loss during suctioning (inlinesuction-app). when activated, the app delivers pcv ventilation, adding cmh o of end-expiratory pressure above peep, and delivering driving pressures of cmh o. results: pigs ( ± . kg) with injured lungs and mechanically ventilated. we tested the aspiration procedures using low peep= cmh o, or high peep=± . cmh o with v t o), whereas maintenance of compliance was observed when the app was on (from . ± . ml/cmh o to . ± . ml/cmh o. blood gas in a representative animal showed a drop in pao when app was off (from , to mmhg after min, and to mmhg after min) ( figure ). with app on the pao changed from (pre-suction), to ( min), to mmhg ( min). the new nksoftware, delivering pcv ventilation during suctioning, could prevent atelectasis and functional loss associated to the procedure. tyrosine kinase inhibitor: an effective tool against lung cancer involvement responsible for acute respiratory failure in icu y tandjaoui-lambiotte patients with advanced-stage non-small-cell lung cancer have high mortality rates in the intensive care unit (icu). in the last two decades, targeted therapies have changed the prognostic of patients with lung cancer outside the icu. the fast efficacy of targeted therapies led some intensivists to use them as rescue therapy for icu patients. we performed a national multicentric retrospective study with the participation of the grrroh (groupe de recherche en réanimation respiratoire en onco-hématologie). all patients with non-small-cell lung cancer admitted to the icu for acute respiratory failure between and were included in the study if a tyrosine kinase inhibitor was initiated during icu stay. cases were identified using hospital-pharmacies records. the primary outcome was overall survival days after icu admission. results: thirty patients (age: +/- years old) admitted to a total of icus throughout france were included. seventeen patients ( %) were nonsmoker. adenocarcinoma was the most frequent histological type (n= , %). most patients had metastatic cancer (n= , %). epithelial growth factor receptor mutation was the most common oncologic driver identified (n= , %). during the icu stay, ( %) patients required invasive mechanical ventilation, ( %) catecholamine infusion, ( %) renal replacement therapy and one ( %) extracorporeal membrane oxygenation. eighteen patients ( %) were discharged alive from icu and ( %) were still alive after days (see figure) . moreover, patients ( %) were alive one year after icu discharge. despite a small sample size this study showed that, in the context of lung cancer involvement responsible for acute respiratory failure, the use of tyrosine kinase inhibitor should not be refrained in patients with severe condition in icu. the burned patient is one of the most complex patients whith a very high mortality. those patients with inhalation injury have a worst prognosis, typically associated with respiratory complications. the aim of our study is to evaluate the mortality of burn patientes with inalation injury in a critical burn unit. a prospective, observational and descriptive study was conducted over a period of years. inhalation injury was defined with these criteria (≥ ): history of injury in an enclosed space, facial burns with singed nasal hair, carbonaceus sputum and stridor. if they were intubated it was diagnosed by bronchoscopy. demographic data, tbsa, absi, baux score, apache ii, sofa, mechanical ventilation (mv), complications, length of stay, hospital course and mortality data were collected. results: burns patients were admitted. % ( patients) had inhalation injury. mortality among patients with inhalation injury was , % ( patients). most patients were men and those who died were older and with higher severity scores (fig. ) . we found no significant differences between groups in the need for mv ( % vs. %) or in the percentage of tracheostomy performed ( . vs. . ). however, patients who died had more respiratory complications like ards, and also shock, renal failure and need of renal replancement therapies although infectious complications were similar in both groups. there was no statistically significant difference in volume used during initial resuscitation in the different groups. patients with inhalation injury who died had higher severity scores at the begining. although there were no differences in the need for mv patients who died had more respiratory complications as well as shock, renal failure and need of rrt, but no infectious complications.the volume used during inicial resuscitation, that was always related to the prognosis, was similar in both groups. further studies are needed to see if this greater initial severity corresponds to the degree of inhalation. aerogen, medical affairs, galway, ireland; aerogen, science, galway, ireland critical care , (suppl ):p patients with acute exacerbations such as asthma are prescribed aerosol therapy from presentation in the emergency department to progression through to the intensive care unit. however, the variability in dose delivery to the lung across the possible patient interventions is not well characterized. here, we assess the predicted lung dose of a bronchodilator in a simulated spontaneously breathing adult patient via both facemask and nasal cannula, and via tracheostomy during mechanical ventilation. a standard dose of . mg in . ml salbutamol was aerosolized using the aerogen solo nebulizer (aerogen, ireland). for facemask testing, the nebulizer was used in combination with the aerogen ultra with lpm supplemental oxygen flow. for nasal cannula testing, the nebulizer was used in combination with the airvo system (fisher and paykel, nz) system at both and lpm gas flow rate. tracheostomy-mediated ventilation was assessed in combination with a hme, with the nebulizer placed between the hme and the tracheostomy tube. international standard iso adult breath settings (vt ml, bpm , i:e : ) were used across all tests, and generated using a breathing simulator (asl , ingmar medical, usa) or mechanical ventilator (servo-u, maquet, sweden). the dose delivered to the lung was assessed using a capture filter at the level of the trachea, with drug mass determined using uv spectrophotometry at nm and interpolation on a standard curve. the results of testing are illustrated in figure . the bronchodilator dose delivered to the simulated patient was seen to be relatively consistent between progressive interventions, except during high flow therapy, with the more clinically relevant lpm gas flow rate having a profound effect on the dose. these results may go some way towards explaining how different patient interventions can affect aerosol dose. the the mechanical ventilation (mv) have been identified as an independent factor indicating a worse prognosis for lung cancer patients [ ] . this study was conducted in order to assess the results of noninvasive mechanical ventilation (niv) and/or invasive mechanical ventilation (imv) modalities in lung cancer patients admitted to the icu with acute respiratory failure (arf). in this study, lung cancer patients with respiratory failure who were admitted to the icu between january and december were evaluated retrospectively. results: patients were included in the study. the mortality rate was . %. patients had niv. imv was applied to patients. in the first hours, of the patients who were initially treated with niv were administered imv. the duration of hospital stay, diagnosis of pneumonia and mortality rate were found to be significantly lower in patients treated with niv alone (p≤ . , p= . , p= . ), but glaskow coma score (gcs) was significantly higher in this group (p≤ . ). the mortality rate was similar between the patients who were initially treated with imv and those who were treated with imv in the first hours. charlson comorbidity index (cci) and mv duration were significantly higher in patients who died (p= . , p= . ), but gcs was significantly lower in this group (p= . ). in the linear regression model for the likelihood of mortality, ccl≥ and unsuccessful niv increased the mortality rate by . ( . - . ) and . times ( - . ) respectively (p= . , p= . ). niv has been an effective modality for respiratory support in most lung cancer patients presenting with arf. however, failed niv seems to be a factor for increased mortality. therefore, the choice of respiratory support modality to be applied in this patient group should be decided by considering the gcs, cci and etiology of arf. the interaction between ventilator settings and the occurrence of acute kidney injury is not fully elucidated. this study aimed at investigating the effect of stepwise increase in peep level on the risk of acute kidney injury as evaluated with the renal resistivity index (rri).the primary outcome is to investigate whether increased levels of peep could lead to increase rri and whether rri could predict the occurrence of aki. methods: patients mechanically ventilated for at least hours and without aki at admission were included in the study. rri was calculated at icu admission. posterolateral approach was used for kidney ultrasound. the peak systolic velocity (v max ) and the minimal diastolic velocity (v min ) were determined by pulse wave doppler, and the rri was calculated as (v max -v min )/v max . the exam was performed modifying the peep levels: , and cm h o in random order for minutes. occurrence of aki was defined within days according to kdigo criteria. sixty-four patients were enrolled in the study and incidence of aki was / ( %). demographical and clinical characteristics are reported in table . increase in peep showed a significant increase in rri from peep to peep (p< . ) and from peep to peep (p= . ) ( figure ). the area under the roc curve of rri to predict aki was . at peep , . at peep and . at peep (all p< . ). the youden index analysis showed an rri> . as the best cut off for aki with a sensibility of % and a specificity of %. patients with rri> . were / ( %), / ( %) and / ( %) at peep ,peep and peep respectively. patients ventilated with a peep value associated with rri> . had higher incidence of aki ( / vs / , p< . ). the application of peep can increase intrarenal vascular resistance,which is associated occurrence of aki; peep level should therefore be balanced taking into account the rri. the rri seems able to predict occurrence of aki in mechanically ventilated patients. alveolar and respiratory mechanics modifications produced by different concentrations of oxygen in healthy rats subjected to mechanical ventilation with protective ventilatory strategy d dominguez garcia , r hernandez bisshopp , jl martin barrasa , d viera camacho , a rodriguez gil , j arias marzan , s garcia hernandez high oxygen can damage tissues [ ] . in this study, we analyze the histological and pulmonary mechanics modifications that can occur when identifying different inspiratory oxygen fractions (fio ) in lungs of healthy rats during protective mechanical ventilation. we use sprague-dawley rat. groups were designed, each with animals, the tidal volume ( ml/kg), peep ( cmh o) and respiratory rate ( rpm) were kept constant, changing the fio between the groups. four groups were established: fio . , . , . and . after hours, the lungs were removed for histological study and obtaining the wet/dry index. the histological modifications studied were: alveolar septa (as), alveolar hemorrhages (ah), intraalvelolar fibrin (if) and inflammatory infiltrates (ii). each parameter was rated from to [ ] . peak pressure (pp) and pulmonary compliance were monitored every minutes. different statistical tests will be used to analyze the data. results: references to the damage produced in the as, ah, if, ii and the global histological pattern were identified in the groups with the highest fio and there was more damage (p < . ) ( figure ). the wet/dry index rose significantly as the oxygen concentration increased (p = . ). in the groups to which a fio of . and was administered, the pp selected specific values with respect to the baseline intake from the first minutes, an aspect that was not appreciated in the other groups (p < . ). regarding pulmonary compliance, it will be seen that, in the fio . and groups, it decreased from the first minutes, finding differences with respect to the other groups (p < . ). conclusions: mechanical ventilation applied for hours in healthy animals produces disorders that are more pronounced as oxygen concentration increase. fio greater than or equal to . should be avoided without clinical justification. introduction: patients requiring prolonged acute mechanical ventilation (pamv, defined as + days on mv) are sicker and incur disproportionate morbidity and costs relative to patients on short-term mv (stmv, < days of mv). we quantified specific clinical outcomes among patients requiring pamv vs. stmv in a contemporary database. we conducted a multicenter retrospective cohort study within~ hospitals in the premier database, - . using icd- -cm and icd- codes we identified pamv and stmv patients, and compared their baseline characteristics and hospital events. because of the large sample size, we omitted hypothesis testing. a total of , patients met the enrollment criteria, of whom , ( . %) received pamv. at baseline, patients on pamv were similar to stmv with regard to age (years: . ± . pamv vs. . ± . stmv), gender (males: . % pamv vs. . % stmv), and race (white: . % pamv vs. . % stmv). pamv group had a higher comorbidity burden than stmv (mean charlson score . + . vs. . + . ). the prevalence of each of the indicators of acute illness severityvasopressors ( . % vs. . %), dialysis ( . % vs. . %), severe sepsis ( . % vs. . %), and septic shock ( . % vs. . %)was higher in pamv than stmv, as were hospital mortality and combined mortality or discharge to hospice (figure ), extubation failure ( . % vs. . %), tracheostomy ( . % vs. . %), development of c. difficile ( . % vs. . %), and incidence density of ventilator-associated pneumonia ( . / , patient-days vs. . / , patient-days). conclusions: over / of all hospitalized patients on mv require it for days or longer. pamv patients exhibit a higher burden of both chronic and acute illness than those on stmv. commensurately, all clinical outcomes examined are substantially worse in association with pamv than stmv. identifying the readiness of patients recovering from critical illness for liberation from invasive mechanical ventilation (imv) is not always straightforward [ ] . the scottish intensive care society (sics) trainee audit conducted a scotland-wide study to understand current practices relating to liberation from imv. data were prospectively collected on patient demographics, indication for intubation, spontaneous breathing trial (sbt) practices, physiological markers, icu outcome and icu los. all patients > years ventilated with imv for > hrs from the st nov. - th nov. were eligible for inclusion. exclusion criteria included extubation for end-of-life, death whilst intubated and presence of tracheostomy. logistic regression was performed to detect factors associated with extubation failure (ef). results were analysed via excel and stata v. . . patient benefit and privacy panel approval was granted. total population of patients were included: ( %) male and median apache score (iqr - ). ef at first attempt occurred on occasions ( . %), median icu los of days (iqr - ), mortality rate . %. the cohort successfully extubated first time had a median icu length of stay of days (iqr - ) and mortality rate of . %. methods of sbt and extubation outcomes detailed in table . no sbt prior to extubation had higher odds of ef (or . , ci . - . , p= . ); patient ventilation for < days had a three times higher odds of ef (or . , ci . - . , p= . ). these were independently associated with ef on multivariate analysis conclusions: we found a reintubation rate of . % in scottish icus. type of sbt most commonly used is divergent from the methods advocated in the literature. the lack of sbt and early extubation attempt was associated with failure, which in turn was associated with longer icu los and higher mortality. in patients undergoing prolonged invasive ventilation we hypothesise that abnormal right ventricular (rv) and left ventricular (lv) function are associated with increased -day mortality. whether changes in lv or rv function could aid in the prognostication of these patients has not been directly studied. patients admitted to the queen elizabeth hospital birmingham icu between april and july who were intubated and ventilated for more than days and had a formal transthoracic echocardiogram (tte) whilst in icu were included. abnormal rv function was defined by the presence of depressed function, dilated size or moderate to severe risk of pulmonary hypertension. abnormal lv function was defined by the presence of lv depression (lv ejection fraction £ % or grade ii or more diastolic dysfunction) or a hyperdynamic lv (formally mentioned in tte report). patients who had a neurological cause for prolonged ventilation were excluded. the primary outcome was -day mortality. categorical data is presented as % and analysed using a chi-squared test. continuous data is presented as median (iqr). results: patients required prolonged ventilation, of which ( %) had a tte. patients were aged ( - ), were % male and had a % -day mortality. the median ventilator days were ( - ) and % required a tracheostomy. abnormal rv function was present in % (n= ) and was associated with an increased -day mortality compared to normal rv function ( % vs. %, rr . [ . - . ], p< . ). lv function was abnormal in % (n= ) and was associated with an increased -day mortality compared to normal lv function ( % vs %, rr . [ . - . ], p < . ). abnormal rv function had a trend towards an increased mortality compared to abnormal lv function ( % vs %, rr . [ . - . ], p = . ). in this study, abnormal rv and lv function were present in a quarter of patients undergoing prolonged ventilation and were associated with an increased mortality. introduction: tidal volume delivered by mechanical ventilation (mv) in sedated patients is distributed preferentially to ventral alveoli, causing overdistention and associated collapse in dorsal alveoli, driving volutrauma, atelectrauma and ventilator-induced lung injury [ ] . temporary transvenous diaphragm neurostimulation (ttdn) stimulates diaphragm contraction [ ] . when used in synchrony with mv, ttdn encourages increased dorsal ventilation due to the change in pressure gradients with diaphragm contraction, mimicking a more normal physiological pattern. this may improve gas exchange and reduce injury. a pilot study was conducted using kg pigs undergoing mv in a mock icu. deeply sedated subjects were provided lung-protective volume-control ventilation at ml/kg. ttdn diaphragm contractions were delivered in synchrony with inspiration on every second breath, reducing the ventilator pressure-time-product by - % during mv+ttdn breaths. tidal volume distribution was recorded in each condition using electrical impedance tomography, and compared to never-ventilated, spontaneously breathing subjects (nv). results: dorsal ventilation changed from % during mv breaths to % during mv+ttdn breaths, compared to % in the nv group (p= . ). ventral ventilation changed from % during mv breaths to % during mv+ttdn breaths, compared to % in the nv group (p= . , figure ). conclusions: ttdn diaphragm contraction used as an adjunct to mv yields a more physiological pattern of volume distribution. this translates into less overdistension in the ventral areas and less atelectrauma in the dorsal areas and reduces ventilator-induced lung injury. this technology introduction: by measuring the pes and its derivatives, we can measure the relationship that exist between the diaphragmatic excursion and the oscillation of the esophageal pressure curve: pswing (ps) so we infer that, just as with the pes, the variations of it might be related to a weaning failure [ , ] . however, no nominal value exists in the bibliography to predict the test result. patients who meet with the inclusion criteria start the weaning process through a test of minutes of spontaneous ventilation, t-tube (tt). and also the respiratory rate (rr) and the tidal volume (tv). from this analysis, an average ps (aps) is determined for each moment of the test (aps , initial and aps , final.).a quotient was obtained in relation to these variables using the value previously obtained (quotient dtv/dps x . a total of patients were included (n= ).regarding the evolution during tt, (n= ) ( %) were successful, while (n= ) ( . %) failed when analyzing a rate that relates the variables tv and ps, a quotient was obtained in relation to these variables using the value previously obtained (quotient dtv/dps) for patients who were successful and who failed, (dtv/dps)/ successful patients presented a value of . while those of the failure group presented a value of . , (or , - p= . ) ( table ) . when presenting the relationship between tv and ps through the quotient (dvt/dps)/ , it is observed a tendency to have a higher quotient among patients who failed versus those who did not fail. the process of weaning from mechanical ventilation imposes an additional workload on the cardiovascular system, which may result in impaired myocardial function, increase in left ventricular filling pressure and respiratory distress. among surgical patients, those undergoing heart surgery are particularly susceptible to cardiac dysfunction induced by weaning because of inadequate cardiovascular reserve. the aim of our study was to depict the pathophysiological changes assessed by echocardiography during the steps of weaning and to identify possible predictors of weaning failure (wf). we enrolled consecutive patients undergoing isolated coronary artery bypass grafting in our institution. data were obtained by intraoperative transesophageal echocardiography before sternotomy (t ) and by transthoracic echocardiography at the beginning of weaning (t ) and at the time of extubation (t ). wf was defined as deferral of planned extubation or respiratory failure needing reintubation or non-invasive mechanical ventilation within hours. results: wf occurred in patients ( . %) and involved manifestations of respiratory distress in ( . %). we found a significant association between left ventricle outflow tract-velocity time integral (lvot-vti) and ventricular-arterial coupling measured at t and wf, with lvot-vti emerging as the best predictor of wf with an area under roc curve of . ( figure ); an optimal cutoff value of cm provided % sensitivity and % specificity. significant increase in e/e' measured at t ( . vs . , p . ) suggested a cardiac etiology of respiratory distress in patients who failed the weaning trial. our study showed that serial assessment of hemodynamic parameters by means of echocardiography is feasible in cardiac surgical patients and can provide insight into pathophysiological changes during weaning. although these preliminary data need to be confirmed in a larger population sample, lvot-vti emerged as a promising predictor of subsequent wf. compliance with guidelines for respiratory therapy in preclinical emergency medicine g jansen, n kappelhoff, s rehberg protestand hospital of the bethel foundation, anaesthesiology, intensive care and emergency medicine, bielefeld, germany critical care , (suppl ):p introduction: current guidelines on pre-hospital emergency ventilation are based on the guidelines for lung protective ventilation in the intensive care unit. the present survey was designed to determine the accordance of actual pre-hospital emergency ventilation by german emergency physicians (gep) with these recommendations. recommendations include a respiratory rate (rr) between - /min, a tidal volume (vt) between - ml/kg, a maximum pressure (pmax) < mbar and a positive end-expiratory pressure (peep) of mbar. an anonymous web-based questionnaire encompassing questions was sent to gep from september to december of . gep were asked to specify their level of education, their preferred ventilation settings and the usually chosen parameters employed to guide mechanical ventilation. statistical analysis was performed using the ch²-test with a significance level ≤ . . % of the questionnaires were completed ( / ). % of the participants were trainees (tr), % consultants (co). as target parameters for guidance of ventilation, % of the tr and % of the co use capnometry. the vt controlled % of the tr and % of the co on the basis of body weight. % of the tr and % of the co reported to control oxygenation using spo . table shows our analysis of the given answers. there were no statistically significant differences between the groups. deviations from the guidelines of pre-hospital emergency ventilation settings are common and mainly concern the use of a guidelinecompliant peep. in addition, recommended target parameters for guidance of ventilation were not applied in a significant proportion of gep. prospective observational study including ltx recipients admitted to our icu from february to january , who underwent a spontaneous breathing trial (sbt) using a t-piece for minutes. clinical variables and arterial blood gas samples were recorded before starting sbt and after minutes on the t-piece. diaphragmatic excursion (de) and thickening fraction (dtf) were also assessed using ultrasound(us) after minutes on the tpiece. us-dd was defined as de< mm or dtf< . of at least one hemidiaphragm. patients who successfully completed a sbt, defined according to clinical criteria,were extubated. extubation failure was defined as the need for reintubation within h. results are expressed as medians (iqr) or frequencies (%). ltx recipients were admitted to the icu, of whom underwent an sbt. were male, and the median age was y. main indications for ltx were interstitial lung disease ( . %), copd and cystic fibrosis. were bilateral ltx, and and were left and right unilateral ltx respectively. patients were extubated after sbt and required reintubation within h. presented us-dd, though there were no differences between patients who succeeded and those needing reintubation. in contrast, patients who succeeded showed higher pao /fio after minutes on the t-piece (table ) . similarly, higher reductions in deltapao /fio after minutes on the t-piece were observed in patients who failed. oxygenation after sbt performed using a t-piece may predict extubation failure in ltx recipients with successful sbt. us-dd was not associated with the need of reintubation. descriptive study about the relationship between self-extubation episodes and patient-ventilator interaction s nogales , introduction: to evaluate the relationship between self-extubation and patientventilator interaction, among other physiological variables, in order to predict and to prevent these events. self-extubation (se) are quality indicators in patients under invasive mechanical ventilations (imv) and are related with mortality [ ] . planned secondary analysis of a prospective data base of clinical and physiologic signals of patients receiving imv. we included se episodes ( - ) with continuous record of ventilator and monitor signals (bclink bettercare®). we analysed demographic data, physiological parameters (peripheral oxygen saturation spo , heart rate hr, respiratory rate rr and media arterial pressure map) and patientventilator interaction (asynchrony index ai, ineffective efforts during expiration iee and double cycling dc). we studied a period of hours prior to the se episode. we used the wilcoxon non-parametric test and for a proper analysis a linear mixed effects model. we included episodes of se, mean age ± years, %men, apache ii at admission ± , , ± , days under imv until the episode, reintubation rate . %, icu stay , ± , days, icu mortality %. at the time of the se, % were under sedation, % with physical restraint. the % were in weaning. we observed a trend to increase in spo , rr, hr, map and asynchronies in the -hour period prior to se episode. we compared these variables from this period with a -hour period before and we observed a statistically the data presented in this study show that our results are in accordance with the literature with favorable mortality and early postoperative complication rates and support that this procedure is an excellent alternative for surgery in the elderly patients. it is reported that patients with pulmonary hypertension (ph; systolic pulmonary arterial pressure (spap)≥ mmhg)) have frequent cardiac complications after transcatheter aortic valve implantation (tavi). ph often gets worse in some patients despite the normal cardiac function after tavi. no studies have ever examined prognosis after tavi in patients with or without worsening of ph. therefore, we retrospectively examined the frequency of mid-to long-term heart failure and cardiac death in patients with and without deterioration of ph after tavi. among patients who underwent tavi at our hospital between february and march , we analysed patients with ph (spap≥ mmhg) before surgery. spap was measured in transthoracic echocardiography before and within week after tavi. patients were divided into two groups according to whether spap worsened/ did not change or improved after tavi. we examined the frequency of admission due to heart failure or cardiac death (death caused by heart failure, angina, or myocardial infarction) during the period of years after tavi. ph worsened or did not change after tavi in patients, while it improved in patients. the left ventricular ejection fraction measured within week after tavi showed no difference between the two groups ( . ± . % vs . ± . %, p= . ). the worsened/ no change group was higher in frequency of admission due to heart failure (logrank; p< . ) and cardiac death (logrank; p< . ). despite successful treatment for as by tavi, the frequency of heart failure and cardiac death was higher in patients who did not show improvement of ph after tavi, even in the absence of cardiac function decrease. vigorous intervention for ph worsening after tavi may be helpful to improve prognosis. the there are several different anti platelet drugs that can be used to treat acute cardiac events. currently there are no effective markers that can assess how these drugs modify coagulation profile and quality. a new functional biomarker that measures fractal dimension (df ) and clot formation time (tgp) has been developed [ ] . df quantifies clot microstructure whereas tgp is a real-time measure of clotting time. we aimed to validate df and tgp in st elevation myocardial infarction (stemi) and assess the effect of two p y inhibitors which have different pharmacological mechanisms: clopidogrel and ticagrelor. we prospectively recruited stemi patients in the emergency setting. venous blood samples were collected hours after admission, following treatment with either ticagrelor or clopidogrel, in accordance with the local guidelines at the time. the blood samples were tested using the df and tgp biomarker, platelet aggregometry, clot contraction and standard markers of coagulation. results: patients received clopidogrel and received ticagrelor. the df for clopidogrel was higher than ticagrelor ( . ± . vs . ± . , p= . which corresponds to a decrease in clot mass of % figure ) and the tgp was reduced ( ± sec vs ± sec, p= . a % reduction in time). the results of the study suggest that clopidogrel is less powerful in its effects on clotting characteristics compared to ticagrelor. blood from patients receiving clopidogrel formed quicker and denser clots. this would suggest the risk of secondary events or stent occlusion is lower in those patients on ticagrelor, highlighting that df and tgp may be important in identifying patients at risk of future thrombotic events, the study is ongoing and will investigate the long term outcome in these patients. introduction: new onset atrial fibrillation (noaf) during critical illness frequently resolves prior to discharge. however long-term risks of noaf (i.e. heart failure, ischemic stroke and death)remains high [ ] . previous studies noted that nearly half of noaf cases did not have diagnosis recorded [ ] . addressing this may reduce post critical illness mortality by increasing af surveillance post intensive care (icu) discharge. retrospective data was collected from an electronic health record for icu admissions over a month period from a biomarker is defined as a measurable indicator of some biological state or condition. combined with a good clinical evaluation, they can enable an early and safe diagnostic, thus a faster management for the patient. cardiac biomarker testing is not indicated in routine in the emergency department (ed) because of low utility and high possibility of false-positive results. however, current rates of testing are unknown. the aim of our study was to evaluate the importance of measuring cardiac biomarkers especially troponins, d-dimer, and btype natriuretic peptide in our daily practice, and to identify the latest recommendations for a better use of these biomarkers in the diagnostic and therapeutic approaches. we conducted a prospective observational study, over a months periods performed in the ed of the university hospital center ibn rochd, casablanca, morocco, including all patients admitted during our study period and having a blood test for at least one biological marker. the dataset was analyzed by spss statistics . . a total of patients was enrolled. troponins were tested in . % patients (high sensitive in . % and troponin i tni in . %), ddimer in . %, bnp % and nt pro bnp in . % of cases. the diagnostic impact was significant in . % of cases for troponins, . % of cases for d-dimer and . % for bnp. the therapeutic impact was considered important in . % cases for troponins, . % for ddimer and . % for bnp. cardiac biomarkers have an important role in the ed, not only do they confirm the diagnosis (including the role of troponins in acs) but also eliminate others (with a strong negative predictive value of d-dimer for thromboembolic disease) and prove the cardiopulmonary origin of acute dyspnea (the significant place of bnp in confirming the diagnosis of acute heart failure). a multicenter study on the comparison of inter-rater reliability of a new and the original heart score among emergency physicians from three italian emergency departments the heart (based on history,ecg,age,risk factors,troponin) score is a valid tool to stratify the acs in chest pain. but some reports suggest that its reliability could be low for heterogeneity in the assignment due to the subjective interpretation of the history. we used the chest pain score for the "history". in this study we compare the reliability of the new heartcps and original heart. this is a multicenter retrospective study conducted in italian ed between july and october using clinical scenarios. ten physicians were included after a course on heart and heartcps score. we used scenarios which included clinical and demographic data. each participant independently assigned scores to the scenarios using the heart and heartcps. we tested the interrater agreement using the kappa-statistic (k), the confidence intervals are bias corrected ; we used stata/se . statistical software . a p-value of < . defines statistical significance. the overall inter-rater reliability was good for heart and heartcps: kappa = . (ci %; . - . )and , (ci %; . - . ); with good agreement among all the class of risk for heartcps but moderate in the medium class for heart . we found significant differences of inter-rater reliability among the senior and junior physicians who used the heartcps:k= . (ci %; . - . )and . (ci %; . - . ). heartcps score increased its history inter-rater reliability specially among the junior physicians from k= . (ci %; . - . ) to k= . (ci %; . - . ).the junior physicians seem to be more reliable than senior with the heartcps:k= . ( . - . ) vs k= . (ci %; . - . ). the heartcps showed inter-rater reliability better than original heart among the medium class of risk and the junior group. it could be proposed to young doctors to stratify the acs risk of chest pain. limit: we used scenarios rather than real patients. a hybrid approach as treatment for coronary artery disease: endo-cabg or pci first, does it matter? introduction: the aim of this study is to discuss the short-term results of a hybrid approach combining minimally invasive endoscopic cabg (endo-cabg) with a percutaneous coronary intervention (pci). to bypass the disadvantages and potential complications of conventional cabg via median sternotomy, we developed the endocabg technique to treat patients with single-and multi-vessel coronary artery disease (cad). this procedure is performed with three -mm thoracic ports and a mini-thoracotomy utility port ( cm) through the intercostal space. this technique can be combined with pci: the hybrid approach. the sequence of the procedures (endocabg followed by pci or vice versa) may result in different outcomes. from / to / data from consecutive patients scheduled for a hybrid technique at jessa, belgium, were prospectively entered into a customized database. this database was retrospectively reviewed. subgroup analysis was performed to compare outcomes of patients who first received endocabg with patients who first received pci. a p-value < . is considered significant, a p-value < . is considered as a trend toward significance. four patients underwent revision surgery and patients died within the first days. in patients the left anterior descendens artery (lad) was grafted with the left internal mammary artery (lima), the right coronary artery (rca) was the most stented vessel using pci. patients first treated with pci received more units of fresh frozen plasma after endocabg compared to those who were first treated with endocabg (p= . ). there was also a trend toward significant more transfusion of packed cells in this small subgroup (p= . ). the hybrid approach is a feasible technique as a treatment option for patients with multi-vessel cad. if cabg follows the pci, patients are more likely to receive transfusion. a possible explanation could be the need for dual antiplatelet therapy prior to surgery in this group, but this needs further investigation. prognostic difference between troponin elevation meeting the mi criteria and troponin elevation due to myocardial injury in septic troponin t (ctnt) elevation in critically ill patients is common and is associated with poor outcome. using common assays, - % of patients in the icu will have elevated troponin level. our aim was to determine whether there is any prognostic difference between troponin elevation meeting the mi criteria (rise and fall more than % together with echo and ecg new abnormalities) and troponin elevation due to myocardial injury in septic patients. we enrolled patients with sepsis and mean sofa score , respectively in which ctnt level was measured more than once and analyzed there ecg and echo findings. patients were classified into three groups:definite mi (rise and fall ctnt ≥ % and contemporaneous changes on ecg and/or echo),possible mi (rise and fall ctnt ≥ % and no other findings),myocardial injury (ctnt rise less than %) results: data from patients were analyzed ( % female; mean age . (sd . )). a total of patients had at least one elevated ctnt more than . mkg/l. in ( %) of patients ctnt level rised more than % from the first elevated measurement. ( %) of patients met mi criteria considering new ecg and echo findings. the overall mortality rate in all patients was . %.the mortality rate didn't differ significantly in three groups: in the definite mi group . %, in the suspected mi group %, in the non mi ctnt elevation group , %, p= , . coronary angiography was performed in ( %) of patients from the definite mi group,pci was performed in ( %) of patients. the mortality rate in the invasive group was not significantly lower comparing to the nonivasive group % vs , %, p= , . bleeding complications were significantly more frequent in the definite mi group % vs % and % respectively conclusions: ctnt level elevation is associated with poor outcome regardless coronary or non coronary injury. myocardial revascularization may be beneficial in patients with sepsis and definite mi, but it is also associated with increased bleeding risk. diagnostic interest of "marburg heart score" in patient consulting the emergencies department for acute chest pain chest pain is a common reason for emergency department visits, although this primarily refers to acute coronary syndrome (acs), this symptom may be frequently related to other non-ischemic etiologies. the aim was to validate the marburg heart score as a tool to exclude coronary artery disease in emergency department patients with nontraumatic acute chest pain. methods: a prospective, observational, descriptive and analytic cohort study conducted in the emergency department, from february st to march st, , collecting patients consulting for nontraumatic acute chest pain, the "marburg heart" score was calculated for all these patients. telephone contact was made after weeks to look for an ischemic cardiovascular event. we included patients. the mean age was +/- years, the sex ratio was . . the majority of the patients ( . %) consulted directly to the emergency department, . % were referred by a primary care physician. the median time to consultation after the onset of chest pain was hours. high blood pressure was the most common risk factor ( . %), followed by smoking ( %), diabetes ( . %) and dyslipidemia ( . %). thirty-five patients ( . %) had already coronary heart disease, ecg was pathological in . % of patients, patients had an acs with st segment elevation. at six weeks, . % of the patients had an acute coronary event. according to the patients' answers on the questions of the marburg heart score. the area under the roc curve of this score was . with a negative predictive value of . %; the "marburg heart score" is a simple, valid and reproducible clinical score with a discriminatory power to rule out the diagnosis of coronary artery disease from the first contact with the patient presenting for chest pain in emergencies. the abdominal aortic aneurysm (aaa) surgery is a complex procedure in elderly patients with high cardiovascular risk. anesthesiological techniques should play special attention to the volume status during cross-clamping as well as to the blood loss. goal directed fluid therapies (gdt) in aaa surgery in elderly patients decrease the perioperative morbidity and mortality [ ] . aim of this study is to investigate administration of fluid-based on either a gdt approach or a control method (fluid administered based on static preload parameters and traditional hemodynamic) in all phases of aaa surgery and especially in the phase of clamping and de-clamping. a total of patients asa iii, randomly scheduled for elective, open aaa surgery were included in this clinical trial. they were randomly assigned to two groups i -gdt with targeting stroke volume variation (svv) and ii -control group where fluids were administered at the discretion of the attending anaesthesiologist. in both these groups hemodynamic parameters, central venous pressure (cvp), temperature, blood loss and diuresis were registered during the operation and hours postoperatively. each group was assessed for postoperative complications. gdt group received less fluids and had a higher cardiac index (ci) ( . ± . vs. . ± . l/minute per m , p < . ) and stroke volume index ( . ± . vs. . ± . ml/m , p < . ) than the control group. there were significantly fewer complications in the intervention than control group ( vs. , p = . ). gdt fluid administration enables less use of fluids, improved hemodynamic and fewer postoperative complications in elderly patients undergoing aaa surgery. ultrasonography is a valid diagnostic tool, used to measure changes of muscle mass. the aim of this study was to investigate the clinical value of ultrasound-assessed muscle mass, in patients undergoing cardiothoracic surgery that present muscle weakness postoperatively. for this study, consecutive patients were enrolled, following their admission in the cardiac surgery intensive care unit (icu) within hours of cardiac surgery. ultrasound scans, for the assessment of quadriceps muscle thickness, were performed every hours for days. muscle strength was also evaluated in parallel, using the medical research council (mrc) scale. of the patients enrolled, ultrasound scans and muscle strength assessment were performed in patients. the muscle thickness of rectus femoris (rf), was slightly decreased by . % ([ %ci: - . ; . ], n= ; p= . ) and the combined muscle thickness of the vastus intermedius (vi) and rf decreased by . % ([ % ci: - . ; . ], n= ; p= . ). patients whose combined vi and rf muscle thickness was below the recorded median values ( . cm) on day (n= ), stayed longer in the icu ( ± vs ± hours, p = . ). patients with mrc score ≤ on day (n= ), required prolonged mechanical ventilation support compared to patients with mrc score ≥ (n= ), ( ± vs ± hours, p = . ). the use of muscle ultrasound seems to be a valuable tool in assessing skeletal muscle mass in critically ill patients after cardiothoracic surgery. moreover, the results of this pilot study showed that muscle wasting of patients after cardiothoracic surgery is of clinical importance, affecting their stay in icu. prediction of cardiac risk after major abdominal surgery s musaeva, i tarovatov, a vorona, i zabolotskikh, n doinov kuban state medical university, anesthesiology and intensive care, krasnodar, russia critical care , (suppl ):p the aim is to assess the incidence of cardiovascular incidents in major abdominal surgery [ ] using the revised lee index. a study was conducted of elderly patients who underwent major abdominal surgery in the krasnodar regional clinical hospital no. under combined anesthesia. in the preoperative period, the risk of cardiovascular incidents was assessed using the revised lee index and the functional status was assessed by met. depending on the lee index, groups were identified: group (n = ) -low risk (index value - ), group (n = ) -intermediate risk (index value - ); group (n = ) -high risk (index value> ). we estimated the incidence of critical incidents in groups: hypo-, hypertension, arrhythmias, and bradycardia. in the general population, cardiac risk was . ± . points; functional status - . ± met. the greatest number of critical incidents was recorded in patients with high risk ( . %), the smallest -in patients with low risk ( . %), in patients with intermediate risk - . % (n < , between groups according to chi-square criterion). in the structure of critical incidents, hypotension was most often encounteredin ( %) patients, while some patients revealed several incidents from the circulatory system (n = ). overall, the lee scale showed good prognostic ability (auroc = . ) in predicting hemodynamic incidents. the revised lee index is a useful tool to help assess the risk of cardiovascular incidents and determine patient management tactics in the perioperative period. postoperative cognitive dysfunction (pocd) remains an unresolved problem due to lack of consensus on its etiology and pathogenesis. some believe that pocd is the result of the direct toxic effect of general anesthetics on the nervous system. others claim that surgical trauma activates proinflammatory factors that induce neuroinflammation. wistar rats were allocated into groups: -minor surgery (n= ), major surgery group (n= ). after days of handling and habituation rats undergone surgery under isoflurane general anesthesia ( vol.%). group rats underwent laparotomy with gentle gut massage followed by wound closure. rats in group undergone left side nephrectomy. starting from the th postoperative day spatial memory in rats was studied in morris water maze which is a cylinder metal pool with a diameter of . and a height of . m filled with water (temp. ± o c) up to half. it has a platform with a diameter of cm and a height of cm below the water level. testing was preceded by a training stage, which included sessions daily for days. thus, rats developed spatial memory to the location of the platform. on the th day of the study test stage was conducted to assess spatial memory: rats were launched from points into maze without platform and data were recorded for seconds at each session. time spent on the target quadrant (ttq) and the number of target area crossings (tac) were registered. a second test was conducted days after the first test to evaluate long-term spatial memory. the duration of surgery and anesthesia did not differ significantly between groups. there was a significant difference between groups in average ttq and tac in test (table ). in test minor surgery group showed better results but they were less significant. major surgery is associated with a more pronounced deterioration of spatial memory in rats in early postoperative period compared to minor surgery. cardiac inflammatory markers in icu patients with myocardiac ischemia after non cardiac surgery (a pilot study) p manthou , g lioliousis , p vasileiou , g fildissis national kapodistrian university of athens, athens, greece; national kapodistrian university of athens, general thoracic hospital´´sotiria´´, athens, greece; national kapodistrian university of athens, university of athens, athens, greece critical care , (suppl ):p patients with known coronary artery disease have higher perioperative risk for myocardial ischemia [ , ] . mortality is frequent following cardiac ischemia in the intensive care unit (icu) after non-cardiac surgery. the first group includes patients admitted to the intensive care unit for post-operative follow-up without myocardiac ischemia in the first hours. the second group includes patients with myocardiac ischemia postoperatively and needs intensive care monitoring. cardiac risk assessment was made with the lee index,hemorrhagic risk assessment with the has-bled bleeding score and thrombotic risk assessment with cha ds -vasc score. postoperatively, pathological test values such as bnp, troponin, crp, calcitonin were estimated. the sequential organ failure assessment (sofa) systeme was used to assess sepsis. the nursing activity score (nas) scale was used to measure the workload of various nursing activities in the icu. according to the pilot study, the sample consists of patients. . % had myocardial ischemia. the lee index was significantly higher in patients with myocardial ischemia. the duration of hospitalization, the high dose of vasoconstrictive drugs, the length of stay in the icu, the duration of mechanical stay and the nursing workload were higher in patients with myocardial ischemia. ck-mb and troponin levels differed significantly between the two groups. creatinine, bilirubin and bnp during the hours were significantly higher. patients with myocardial ischemia had significantly higher mortality. cardiac risk assessment, has-bled score and cha ds -vasc score in combination with cardiac enzymes such as troponin could predict myocardiac ischemia in severely ill icu patients. introduction: according to the literature an airway complication followed thyroid gland surgery are: difficult trachea intubation, tracheomalacia, postextubation stridor and bleeding [ , ] . most common cause of death was problem with respiration and airway obstruction [ ] . subsequent hypoxia could require emergency airway and even tracheostomy [ ] . aim of our study was to determine the most common of airway complications and their association with type of surgery in our region. the retrospective cohort study included pts., ( women, men) was performed in odessa regional hospital, oncology centre odessa. there were three types of patients: with euthyroid goiter - ( %), polynodos goiter - ( %) and thyroid cancer - ( %) ( table ) . airway complications were diagnosed after trachea extubation based on indirect laryngoscope, presence of stridor, desaturation. the pearson's criteria was calculated. the ratio of airway complications after thyroid surgery was . % ( pts). the main reasons of airway complications in thyroid surgery included: laryngeal edema - pts ( . %); recurrent laryngeal nerve injury - pts ( . %) and postoperative bleeding pts ( . %). thyroid gland cancer and polynodosal goiter associated with laryngeal edema and recurrent laryngeal nerve injury (pearsen criteria were . -moderate and . consequentially). it's may require more attention from the anesthetists after extubation and readiness for an urgent airway. serum iron level and development of multiple organ dysfunction syndrome in patients in the perioperative period s tachyla mogilev regional hospital, department of anesthesiology and intensive care, mogilev, belarus critical care , (suppl ):p recently there has been attention of researchers to the problem of perioperative anemia. it was found that it increases the risk of death and postoperative complications. threatening complication is multiple organ dysfunction syndrome (mods). the objective was to determine the level of serum iron in the perioperative period in patients with endoprosthetics of large joints, and with the presence of mods in abdominal surgery. a prospective cohort study was conducted in patients, including men and women, age . ± . years. two groups were identified: st (control) -patients after endoprosthetics of large joints (n = ), nd (main) -patients in abdominal surgery with the presence of mods (n = ). the presence of mods was established based on the criteria for the sccm / accp conference. serum iron was monitored using an au analyzer (usa). the study identified several stages: st -before surgery, nd - st day after surgery, rd - rd day, th - th day, th - th day. when studying the indicators of serum iron, its significant decrease (p < . ) in the postoperative period was established. in the st group: st stage - . ( - . ) mmol / l, nd stage - . ( . - . ) mmol / l, rd stage - . ( - . ) μmol / l, stage - . ( . - . ) μmol / l, stage - . ( . - ) μmol / l. in the nd group: st stage - . ( - ) mmol / l, nd stage - . ( . - . ) mmol / l, rd stage - , ( . - . ) μmol / l, stage - . ( . - . ) μmol / l, stage - . ( . - ) μmol / l. moreover, in both groups, iron increased at the th stage against the nd stage (p < . ). when comparing the level of iron between the groups, significant differences were found (p < . ) at the nd, rd and th stages. in patients in the postoperative period, a decrease in serum iron is observed, the level of which rises by the th day, but does not reach the initial values. this decrease is more pronounced in patients with the presence of mods after abdominal surgery. kidney and pancreatic graft thrombosis happened in . % and . %, respectively, and bleeding in . %. forty-one ( . %) developed at least one infection during hospital stay. infection during icu was found in . % and main pathogens were gram negative bacilli sensible to beta-lactam. after icu, the incidence of multi-drug resistant pathogen was . %, predominantly gram negative bacilli. fungal infection was lower %. all-cause hospital mortality rate was . %. infectious complications are the main cause of morbidity and mortality following spk transplantation. the administration of broadspectrum prophylactic antibiotics are leading to the appearance of multi-drug resistant pathogens. knowing local microbiological flora may be helpful, allowing more adequate antibiotic prophylaxis. introduction: cardiopulmonary bypass (cpb) is associated with thrombotic complications. occurrence of thrombosis after cpb is % which takes the third place between cpb-associated complications. our study determined preoperative predictors of thrombosis in children with congenital heart defects. patients with congenital heart diseases in age up to months days (median age - , months, youngest age - days after birth, oldest - months days), underwent cardiac surgery with cpb, were enrolled in this study. all patients were divided into two groups: st -without thrombosis, nd -with thrombosis. protein c, ddimer, von willebrand factor and plasminogen plasma levels were assessed directly before surgery. thrombotic cases were proven by performing doppler ultrasound or mri. thrombotic complications were diagnosed in children ( %). between all thrombotic complications ischemic strokes were diagnosed in % ( cases), arterial thrombosis in % ( cases), intracardiac thrombus in % ( cases) and mechanical mitral prosthetic valve thrombosis %( ). receiver operating characteristic (roc) curves are created for the listed indicators. area under the curve (auc) for protein c , (sensitivity(sn)- %, specificity(sp) - %), d-dimer is , (sn - %, sp %), for plasminogen activity - , (sn %, sp %) and for von willebrand factor level - , (sn %, sp %). an roc curve was created for all three indicators, the auc was . (sn - %, sp - %). these parameters can be recommended as predictors of thrombosis in children after cardiac surgery. cpb is related with a large number of life-threatening complications. in our work, preoperative predictors of thrombosis were identified. based on this data, it is possible to create thrombosis risk scale change the tactics of the anaesthetic approach, the prevention of thrombosis in the postoperative period. further studies are needed to identify other possible predictors of thrombosis. introduction: abdominal ischemia occurs in % of patients submitted to aortic aneurysm repair. its early diagnosis requires an elevated index of suspiction, particularly in more severe patients. we hypothesized that earlier increase and higher levels of c-reactive protein (crp) may help to predict intra-abdominal ischemia. we performed a retrospective study of patients admitted to the intensive care department (icd) after abdominal aorta aneurism surgery. we included all patients admitted during a two-year period, that survived for more than hours. primary outcome was splanchnic ischemia assessed by abdominal ct-scan. we also evaluated the presence of bacteremia, abdominal compartment syndrome and icd mortality. association between inflammatory parameters and ischemia was evaluated by multivariate logistic regression. introduction: crp (c-reactive protein) has been shown to be a useful biomarker in identifying complications after major abdominal surgery. gastrectomy is a high-risk surgical procedure that requires post-operative critical care support to monitor for complications which are predominantly infective in nature. the aims of this study were to determine whether there is a relationship between post-operative crp levels and patients who developed post-operative infective complications. a retrospective analysis was performed on patients undergoing elective gastrectomy for gastric cancer at a single centre between september and july . post-operative crp levels for each day following resection were analysed for all patients. roc curve analysis was used to determine which post-operative day (pod) gave the optimal cut-off. of patients included, the majority were male ( . %), mean age was . years and . % had node-negative disease. a total of patients ( . %) had an infective complication, which includes those who experienced an anastomotic leak. crp levels on post-operative day gave the greatest auc for the gastrectomy group ( . ). crp cut-off of mg/l was significantly associated with infective complications (or . , % ci . - . , p= < . ) and gave a sensitivity of % and specificity % (ppv %, npv %). more patients with a crp > on post-operative day experienced an infective complication ( % vs %, p = < . ) or a leak in particular ( % vs %, p = . ). a crp level of less than mg/l on pod may be useful to predict the development or exclude the likelihood of such infective complications in this group of patients prior to clinical signs (ppv %, npv %). this may prompt and facilitate decision-making regarding early investigation and intervention or prevent inappropriate early discharge from critical care, whilst providing more assurance in identifying those who could be stepped down to ward level care. vasoplegia is commonly observed after cardiopulmonary bypass surgery (cpb) and associated with high mortality. chronic use of reninangiotensin aldosterone system inhibitors (raasi) is associated with its incidence and ensuing need for vasopressor support after cpb. renin serves as marker of tissue perfusion [ ] . we examined the role of renin in the setting of raasi exposure and vasopressor needs in the peri-cpb period. prospective observational study of adult patients undergoing cpb, aged . ± . years ( men, women). blood was collected ) post induction, pre-cpb; ) min post cardioplegia, and ) immediately post bypass. vital signs and perioperative medications were recorded. as control, blood was collected from men and women aged . ± . , not diagnosed with lung disease and not prescribed any raasi. baseline plasma renin in cpb patients tended to be higher than in control subjects (mean= . pg/ml± . vs. . pg/ml ± . , respectively, p= . ). minutes into cpb, mean renin was increased from baseline ( . pg/ml± . , p= . ), and remained elevated immediately post cpb ( . pg/ml± . ). patients using raasi prior to cpb tended to have a larger increase in renin post cpb (delta= . pg/ ml± . ) vs. those not previously on raasi ( . pg/ml± . , p= . ). renin was elevated in patients requiring vasopressor support in the hours post cpb vs. those not requiring pressors ( . pg/ ml± . vs. . pg/ml± . p= . ). in those prescribed raasi and requiring pressors post cpb, there was a tendency toward greater renin increase than those not requiring pressors postoperatively ( . pg/ml± . vs. . pg/ml± . , p= . ). this study suggests a trend toward higher renin levels, particularly during cpb, in patients prescribed raasi, and a positive association between renin and postoperative vasopressor needs. we speculate that increased renin levels may predict postoperative vasoplegia. cardiac surgery is associated with perioperative blood loss and a high risk of allogenic blood transfusion. it has been recognized that high blood product transfusion requirement is associated with adverse clinical outcomes. guidelines on patient blood management therefor aim at reducing blood loss and blood transfusion requirements in cardiac surgery. as there remains controversy about the advantage of minimal invasive techniques on blood loss an transfusion requirements, we wanted to investigate if the average blood loss and transfusion requirement in minimal invasive endoscopic coronary artery bypass graft surgery (endo-cabg) differ from conventional technique. we assessed the influence of pre-operative anticoagulant medication for blood loss. estimated average blood loss after conventional cabg is ml (+/- ) and transfusion requirement , units packed red blood cells . we performed a retrospective cohort study of our cardiac surgical database. from / / to / / , we collected data from patients undergoing endo-cabg. we analyzed blood loss, transfusion as well as pre-operative use of anti-coagulants as a risk factor for blood loss. we found that mean total blood loss in endo-cabg does not differ from conventional cabg, nonetheless mean transfusion requirement was lower in our cohort. use of direct oral anticoagulant is aossciated with increased blood loss and transfusion requirements (table ) . total blood loss is not influenced by minimal invasive technique for cabg (endo-cabg). an explanation for the lower transfusion requirements is the use of a minimal extracorporeal circulation, which is known to reduce the risk of transfusion. another important factor is the implementation of a standardized transfusion-protocol based on available evidence. reducing transfusion requirements is an important component in improving patient outcome after cardiac surgery and is related to multiple factors in perioperative care of our patients. retinal microvascular damage associated with mean arterial pressure during cardiopulmonary bypass surgery v shipulin retinal perfusion corresponds to cerebral perfusion and it is very sensitive to hemodynamic disturbances [ , ] . we investigated the association between retinal microvascular damage and hemodynamic characteristics in patients undergoing coronary artery bypass grafting surgery (cabg) with cardiopulmonary bypass (cpb). methods: patients with coronary artery disease and systemic hypertension were examined. ophthalmoscopy and optical coherence tomography were performed before and - days after cabg. the hemodynamic parameters during cpb were analyzed. results: ( %) patients had changes in the retinal vessels and in the ganglionic fiber structure on - day after surgery: in % of patients the foci of ischemic retinal oedema appeared, in % the decrease of the thickness of ganglionic fiber were observed. these changes may be associated with intraoperative ischemia of the central retinal artery. in ( %) patients the mean arterial pressure (map) during cpb was increased up to mmhg. in ( %) of them the association between map and foci of ischemic retinal oedema were revealed. the ischemic retinal changes were observed significantly more often if the delta of map during cpb was over then mm hg compared with the patients where the delta of map was less than mm hg (p= . ). this is probably due to an intraoperative disorders of the myogenic mechanism of blood flow autoregulation in the retinal microvasculature in patients with coronary artery disease [ ] . the level of map up to mm hg during cpb is associated with retinal blood flow impairment and the foci of ischemic retinal oedema. delta of map more than mmhg was associated with the foci of ischemic retinal oedema and decreased ganglionic fiber thickness in % of cases. atrial fibrillation after cardiac surgery: implementation of a prevention care bundle on intensive care unit improves adherence to current perioperative guidelines and reduces incidence introduction: atrial fibrillation after cardiac surgery (afacs) is a very frequent complication affecting - % of all patients. it is associated with an increase in morbidity, mortality and hospital and intensive care unit (icu) length of stay. we aimed to implement an afacs prevention care bundle based on a recently published practice advisory [ ] , focusing on early postoperative (re)introduction of β-blockers. baseline afacs incidence and β-blocker administration practices in our centre were audited for all patients undergoing valve surgery or coronary artery bypass graft (cabg) during a weeks period. the afacs prevention care bundlean easy to follow graphical toolwas subsequently introduced to the cardiac icu by a multidisciplinary team and audited following a model of improvement approach. after exclusion of patients with preoperative af, differences between pre-and post-implementation groups were compared with chisquare and fisher's exact tests for categorical, and one-way anova for continuous variables, using spss. a total of patients were analysed. patient and surgery characteristics did not differ between groups. significantly more patients received postoperative β-blockers after bundle implementation ( . % pre-vs . % post-bundle, p= . ) with a higher proportion on day ( . % pre-vs % post-bundle, p< . , figure ). the incidence of afacs was significantly reduced from . % to . % (p= . ), with a particularly marked reduction in the age group - years and for isolated aortic valve and cabg surgery. there was no significant reduction in hospital length of stay for this cohort. introduction of an afacs prevention care bundle using a graphical tool improved adherence to current guidelines with regards to early β-blocker administration and significantly reduced afacs incidence. future care bundles should include preoperative interventions and might reduce hospital length of stay. in neonates with univentricular physiology, there is a delicate balance between pulmonary and systemic circulations, with a tendency towards generous pulmonary blood flow, and a risk of systemic underperfusion. preoperatively, the use of hypoxic gas mixture (hm) has been advocated as a therapy to increase pvr, with the aim of improving systemic oxygen delivery. it is a therapy which has been routinely initiated in our institution in the setting of signs of pulmonary overcirculation. we performed a retrospective analysis of all patients in our institution who underwent a norwood procedure and who received hm preoperatively. we compared peripheral saturations, arterial blood gas analysis, serum lactate, regional cerebral and renal saturations and invasive blood pressure, prior to, and then , and hours after hm was commenced. between and (inclusive), patients underwent the norwood procedure. patients received preoperative hm. average fio was % during administration of hm. average peripheral saturations were . % prior to hm, and dropped to . % at hours, and % at and hours after initiation (p < . ). there was no change in any of the measured markers of systemic oxygen delivery, including regional cerebral and renal saturations, lactate, urine output or blood pressure. there was an association between an extended period of hm (> hours) and the need for pulmonary vasodilator therapy post norwood procedure. hypoxic gas mixture in patients with parallel systemic and pulmonary cicrculations causes desaturation and hypoxia. it does not lead to an increase in systemic perfusion and thus an improvement in systemic oxygen delivery. its ongoing use in this fragile population should be considered. introduction: analgesia in the critical patient, and especially in the neurocritical patient, is a basic goal in all therapeutic practices. patients in the icu are frequently administered prolonged and/or high doses of opioids. multiple serious complications due to the use of infusion of opioids at large doses has been described. to reduce high doses of intravenous opioids, multimodal forms of analgesia can be used. prospective observational study of the use of tapentadol enteral and buprenorphine in transdermal patches, at low doses, for the control of pain and its effect on reducing the use of fentanyl infusion in high doses on patients admitted to neuro icu of indisa clinic during consecutive years ( - ). enteral tapentadol (through ng tube) mg/ hours, was considered in patients who required intravenous fentanyl in continuous administration. buprenorphine was also added at low doses ( ug/hr) in a weekly transdermal patch, in cases of neurosurgical spine patients, fractures and long-term neuropathic pain. pain was controlled on behavioral pain scale (bps) and visual analogical scale (vas) scores, according to the conditions of each patient. their hemodynamic, gastrointestinal complications and the appearance of delirium episodes according to cam-icu scale were recorded. results: patients received tapentadol. of them also received transdermal buprenorphine. all managed to maintain adequate level of analgesia, not requiring fentanyl at doses greater than . ug / kg / hr. distribution by diagnoses: neurotrauma patients, guillain barre , spine surgery , hsa , hice , malignant ischemic acv . complications: gastric retention patients ( %), hypotension ( %), acute hypoactive delirium ( . %), acute hyperactive delirium ( %). no drug interactions were found. the introduction of enteral tapentadol and buprenorphine patches in neurocritical patients was safe and resulted in a decrease in the use of endovenous opioids and its adverse effects. we hypothesized that changing the pain management for our post cardiac surgical patients to an assessment-driven, protocol-based approach using fast acting and easily titratable agents will significantly improve patient satisfaction by reducing pain intensity in the first h after surgery as suggested by society of critical care [ ] guideline. we prospectively assessed and ( . vs . ) consecutive patients before and after introducing our pain management protocol. the nursing and medical team received rigorous training on the guideline as well as the correct assessment using appropriate pain scores measured at least hourly (numeric pain score, ≥ is timing of beta-blocker (re)initiation versus incidence of afacs before and after prevention care bundle implementation, per post-operative day and for postoperative days - (insets) moderate to severe or critical care observation tool, > is moderate to severe). we introduced a multimodal approach with a combination of fast acting iv, long acting oral opiates, regular paracetamol and rescue iv boluses for difficult to control situations and we created a prescription bundle on our electronic prescribing record. among other variables we assessed hours spent in moderate to severe pain in the first h after surgery and compared to the data collected before the guideline was introduced. we analysed patients from and from . baseline characteristics were similar between the two groups. in only . % of the patients spent less than hours and . % spend more than hours in moderate to severe pain. the data showed significant improvement in that . % of patients spent less than hours and only % patients who spent more than hours in moderate or severe pain. (p < . , chi square) ( figure ). only % of the patient needed rescue medications. % of time was the protocol inadequate necessitating other approach. introducing an assessment driven, stepwise, protocolized pain management significantly improved patient satisfaction by reducing pain intensity in the first h on our cardiothoracic intensive care unit. introduction: proximal femur fractures are most common fractures in the elderly and associated with significant mortality and morbidity, with high economic and social impact. perioperative pain management influence outcomes and mortality after surgery with early mobilization being possible [ , ] . the goal of the study was to compare the efficacy and safety of the compartment psoas block for perioperative analgesia in elderly patients with proximal femur fractures. the randomized controlled study was held in medical center "into-sana" (odesa, ukraine) from january till july . patients with proximal femur fractures and older than years were included in the study. they were randomly allocated to groupscompartment psoas block group (bupivacaine analgesia was started as soon as possible before surgery and prolonged during and after surgery with additional ischiadicus block before surgery) and general (inhalational) anesthesia with systemic analgesia perioperatively. results: patients were included in this study. perioperative compartment psoas block was associated better pain control, decreased opioid consumption, better sleep quality, earlier mobilization after surgery, decreased incidence of opioid-associated vomiting/nausea and myocardial injury. there were no difference in the incidence of hospital acquired pneumonia and delirium. perioperative compartment psoas block is effective and safe for perioperative analgesia in elderly patients with proximal femur fractures, and is associated with better pain control and decreased complications incidence. parenteral olanzapine is frequently used in combination with parenteral benzodiazepines for hospitalized patients with severe agitation. the fda issued a warning for increased risk of excessive sedation and cardiorespiratory depression with this combination based on post-marketing case reports with overall limited quality of evidence [ ] . the purpose of this study is to evaluate the safety and efficacy of concomitant parenteral olanzapine and benzodiazepine for agitation. this retrospective chart review evaluated agitated patients who received concomitant parenteral olanzapine and benzodiazepine within minutes from / / to / / . the primary end points were rate of respiratory depression requiring mechanical ventilation and hypotension requiring vasopressors. the secondary end points were percentage of patients requiring additional sedatives for agitation during the same time frame, cumulative dose of olanzapine and benzodiazepine (midazolam equivalent) received, and rate of cardiac arrest and death. a total of patients were included with notable baseline characteristics: median age of years old, % with a history of substance abuse, and % with a history of psychiatric illness. for the primary outcomes, . % of patients required mechanical ventilation and % required vasopressors. additionally, . % patients received additional sedating agents to control agitation. refer to table for more details. no cardiac arrests or deaths were observed. concomitant use of parenteral olanzapine and benzodiazepine within minutes for the treatment of agitation appears to have a small risk of respiratory depression without significant hypotension. hip fracture is very common in the elderly,it causes moderate to severe pain often undertreated. ficb is a simple safe method, easy to learn and use. the aim of our study is to assess the efficacy and safety of preoperative ficb compared with intravenous analgesia for elderly patients with femoral fracture and hip surgery in terms of opioid consumption and perioperative morbidity methods: after informed consent obtained, patients - yo asa i-iii with hip fracture were randomized to receive either an us guided ficb( ml of ropivacaine , %) or a sham injection with normal saline ' before surgery. both groups were operated under general anesthesia. postoperative analgesia was done according to vas: vas - mm, paracetamol g iv at h, vas - mm, ketoprofen mg iv at h, vas> , morphine , mg/ kgbw iv. the primary outcome was the comparison of vas score at rest over the first 'following the procedure, at the end of the surgery and at h intervals for h. the secondary outcome were the incidence of the cardiovascular events, of the ponv and of the confusion episodes, the amount of morphine consumption for h results: at baseline, ficb group (a) had a lower mean pain score than the sham injection group (b). the same difference was observed over h of follow-up (p< . ). there was a significant difference between the two groups in total cumulative iv morphine consumption at h and in the incidence of ponv and confusion episodes ( figure ). ficb provides effective analgesia for elderly patients suffering from hip fractures, with lower morbidity and lower opioid consumption compared with intravenous analgesia. pain assessment in chronic disorders of consciousness patients with ani monitoring e kondratyeva, m aybazova, n dryagina almazov national medical reseach centre, minimally conscious research group, st petersburg, russia critical care , (suppl ):p pain and suffering controversies in doc to be debated by the scientific, legal and medical ethics communities. methods: ani (anti nociception index) monitor was used to assess pain in patients with chronic disordersof consciousness (doc) age range to years - in vegetative state/ unresponsive wakefulness syndrome (vs/uws) and minimal consciousness state (mcs). average age: in mcs group , ± , and , ± , in vs/uws group. neurological status was assessed using crs-r scale. the average score on the crs-r scale was ± . in vs/uws and . ± . in mcs. pressure on the nail phalanx was used as a pain impulse. ani and nociception coma scale was evaluated before the application of pain stimulus, immediately after and past minutes. prolactin level was measured before the pain stimulus application and minutes after. ani less than indicates pain, - hypoalgesia, severe pain. the mean value of the ani in mcs patients: before the pain stimulus . ± . , after the pain stimulus application ± . and minutes later . ± . . prolactin level in mcs patients before pain . ± . ng/ml; after pain . ± . ng/ml (p> . ). prolactin in vs/uws patients before pain . ± . ng /ml, after pain . ± . ng / ml (p> . ). conclusions: ani monitor revealed that vs/uws and mcs patients react equally to the pain impulse. prolactin dynamics showed poor statistical mean and can not be consider as a marker of nociception in this group of patients. it is possible that the level of pain impulse was insufficient neuroendocrine response activation or the increase of prolactin level occurs in the long term (more than minutes). in all patients the total hip arthroplasty tha is one of the most common major surgical procedures associated with significant postoperative pain that can adversely affect patient recovery and could increase morbidity. effective perioperative pain management allows an accelerated rehabilitation and improve the functional status of these patients. multimodal analgesia mma combines analgesics with different mechanism of action which by synergistic and additive effects enhance postoperative pain management and reduce complications. the aim of our study is to assess if perioperative association of very low dose of ketamine, a potent nmda antagonist and dexamethasone, by antiemetic and antiinflammatory properties could decrease opioid consumption and postoperative morbidity of patients with tha. after informed consent, patients scheduled for primary hip joint replacement surgery aged - yo asa i-iii were prospective randomized in two groups. both groups were operated under general anesthesia fentanyl/sevoflurane. supplementary, patients in group a received mg iv dexamethasone and mg at h and ketamine mg iv bolus at induction and mg/h iv during surgery. postoperative analgesia was done according to vas, - mm paracetamol g iv at h, - mm ketoprofen mg iv at h, vas> mm morhine , mg/kgbw iv. we recorded perioperative opioid consumption, the number of intraoperative cardiac events, vas score at the end of surgery and at h, the incidence of ponv and persistance of chronic pain at months. we obtain a significant less pain score at the end of surgery p< . in group a, no significant difference at h, a significant less chronic pain at months, a fewer npvo and cardiovascular events in group a, p< . ( figure ). a multimodal approach with very low doses of ketamine and dexamethasone could be efficent in the treatment of pain for elderly patients with hip arthroplasty, decreasing postoperative side-effects and reducing chronic pain persistance. introduction: treatment in an intensive care unit (icu) often necessitates uncomfortable and painful procedures for patients. chronic pain is becoming increasingly recognized as a long term problem for patients following an icu admission [ ] . throughout their admission patients are often exposed to high levels of opioids, however there is limited information available regarding analgesic prescribing in the post-icu period. this study sought to examine the analgesic usage of icu survivors pre and post icu admission. methods: patients enrolled in a post-intensive care programme between september and june . intensive care syndrome: promoting independence and return to employment (ins:pire), is a -week multicentre, multidisciplinary rehabilitation programme for icu survivors and their caregivers. patients' level of analgesia was recorded pre-admission and upon attending ins:pire, their level of prescribed analgesia was categorized using the word health organisation (who) analgesic ladder [ ] . results: . % of patients (n= ) were prescribed regular analgesia preadmission; this increased to . % (n= ) post-admission, representing a significant absolute increase of . % ( % ci: . % - . %, p< . ) in the proportion of patients who were prescribed regular analgesia pre and post icu. in addition, pre-admission, . % (n= ) of patients were prescribed a regular opioid (step and of the who ladder) compared to . % (n= ) post-admission, representing an absolute increase of . % ( % ci: . % - . %, p< . ). this study found a significant increase in analgesic usage including opioids in icu survivors. follow-up of this patient group is essential to review analgesic prescribing and to ensure a long term plan for pain management is in place. introduction: pain, agitation, and delirium (pad) are commonly encountered b patients in the intensive care unit (icu). delirium is associated with adverse outcomes, including increased mortality and morbidity. clinical guidelines suggest that routine assessment, treatment and prevention of pad is essential to improving patient outcomes. despite the well-established improvements on patient outcomes, adherence to clinical guidelines is poor in community hospitals. the aim of this quality improvement project is to evaluate the impact of a multifaceted and multidisciplinary intervention on pad management in a canadian community icu. a pad advisory committee was formed and involved in the development and implementation of the intervention. the -week intervention targeted nurses (educational modules, visual reminders), family members (interviews, educational pamphlet, educational video), physicians (multidisciplinary round script), and the multidisciplinary team (poster). an uncontrolled, before-and-after study methodology was used. adherence to pad guidelines in the assessment of pad by nurses was measured weeks pre-intervention and weeks post-intervention. data on patient-days (pd) and pd were available for analysis during the pre-and post-intervention, respectively. the intervention significantly improved the proportion of pd with assessment of pain and agitation at least times per -hour shift from . % to . % and from . % to . %, respectively ( figure ). proportion of pd with delirium assessment at least once per -hour shift did not significantly improve. a multifaceted and multidisciplinary pad intervention is feasible and can improve adherence to pad assessment guidelines in community icus. quality improvement methods that involve front-line staff can be an effective way to engage staff with pad. oversedation introduction: sedation is a significant part of medical treatment in icu patients. a too deep sedation is associated with a longer time of mechanical ventilation, lung injury, infections, neuromuscular disease and delirium, which can lead to a longer duration of icu hospitalization, as well as an increase of morbility and mortality. many patients spend a considerable amount of time in a non-optimal sedation level. a continuous monitoring system of the sedation level is therefore necessary to improve clinical evaluation. our goal was to evaluate the incidence of non-optimal sedation (under and over sedation) comparing the parameters expressed from ngsedline with clinical evaluations and to correlate oversedation and the incidence of delirium. we have studied a cohort of patients admitted to the icu of spedali civili of brescia university hospital requiring continuous sedation for more than hours. in addition to standard monitoring, the patients have been studied using next generation sedline (masimo). sedation depth was evaluated through rass scale and the presence of delirium was evaluated with cam-icu scale. we collected data from adult patients. our data showed high incidence of oversedation. of our patients had a sr> and had a psi level< . a logistic regression analysis was performed and it showed statistically significant association between incidence of delirium and the age of the patients (p . ). the association between delirium incidence and suppression rate time was at the limits of statistics significance (p . ) and was statistically significant for non neurocritical patients (p . ). our study didn't show an association between delirium and the total time of sedation. non-optimal sedation is an unsolved problem in icu, affecting lot of patients, with a major incidence of over-sedation compared to under-sedation. our study shows an association between sr levels and the incidence of delirium. predictors of delirium after myocardial infarction, insights from a retrospective registry m jäckel, v zotzmann, t wengenmayer, d dürschmied, c von zur mühlen, p stachon, c bode, dl staudacher heart center freiburg university, department of cardiology and angiology i, freiburg, germany critical care , (suppl ):p delirium is a common complication on intensive care units. data on incidence and especially on predictors of delirium in patients after acute myocardial infarction (mi) are rare. by analyzing all patients after acute mi, we aim to identify incidence and potential risk factors for delirium. in this retrospective study, all patients hospitalized for acute mi treated with coronary angiography in an university hospital in were included and analyzed. incidence of delirium within the first days of care attributed to the mi and was defined by a nudesc score ≥ , which is taken as part of daily care three times a day by especially trained nurses. this research is authorized by ethics committee file number / . results: patients with acute mi (age . ± . years, stemi, mortality . %) were analyzed. delirium occurred in ( . %) patients and was associated with a longer hospital stay ( ± . d vs . ± . d, p< . ). patients with delirium were significantly older than patients without ( . ± . vs. . ± . years, p< . ) and had more often preexisting neurological diseases ( . % vs. . %, p< . ) and dementia ( . % vs. . %, p< , ). multivariate logistic regression analysis suggested that odds ratio for delirium was higher in patients after resuscitation or . ( % ci . - . ), preexisting dementia or . (ci . - ) and in patients with alcohol abuse or (ci . - ). while maximum lactate was also connected to delirium or . (ci . - . ), infarct size or type had no effect on the incidence of delirium. in patients with mi, delirium is frequent. incidence is associated with clinical instability and preexisting neurological diseases rather than infarct size. incidence and risk factors of delirium in surgical intensive care unit ma ali, b saleem aga khan university, anaesthesia, karachi, pakistan critical care , (suppl ):p introduction: delirium in the critically ill patients is common and distressing. the incidence of delirium in the icu ranges from % to %. although delirium is highly common among intensive care patients, it is mostly underreported. to date, there have been limited data available related to prevalence of delirium in surgical patients. in a study published in , the risk was observed % in surgical and trauma patients [ ] . the purpose of this study was to find out the incidence and associated risk factors of delirium in surgical icu (sicu) of a tertiary care hospital. we conducted prospective observational study in patients with age more than years and who were admitted to the surgical icu for more than hours in aga khan university hospital from january to december . patients who had preexisting cognitive dysfunction or admitted to icu for less than hours were excluded. delirium was assessed by intensive care delirium screening checklist icdsc. incidence of delirium was computed and univariate and multivariable analyses were performed to observe the relationship between outcome and associated factors. delirium was observed in of patients with an incidence rate of . %. multivariable analysis showed that copd, pain > and . ] were also the strongest independent predictors of delirium while analgesics exposures was not statistically significant to predict delirium in multivariable analysis. delirium is significant risk factor of poor outcome in surgical intensive care unit. . there was an independent association between pain, sedation, copd, hypernatremia and fever in developing delirium delirium is an acute mental syndrome which may cause negative consequences if it is misdiagnosed [ , ] . the aim of this study was to determine the incidence of delirium in different intensive care units and reveal the risk factors. the study was performed with patients hospitalized in intensive care units of anesthesia, neurology and general surgery departments. written informed consent was obstained from patients or relatives. delirium screening test was performed twice daily with camicu (confusion assessment method for the icu). patients who met the study criterias, were evaluated for the possible risk factors of delirium and the data was recorded daily. patients were reevaluated after the treatment. the incidence of delirium was . %. delirium was found to increase with the length of stay (p < . ). the mean age of the patients with delirium was . . this was higher than the patients without delirium ( . ) (p< . ). visual impairment (p< . ), hearing impairment (p= . ), educational status (p= . ), hypertension (p= . ), mechanical ventilation (p = . ), oxygen demand (p= . ), midazolam infusion (p= . ), propofol infusion (p= . ), infection (p < . ), sofa (p = . ), apache ii (p < . ), nasogastric catheter (p= . ), aspiration (p < . ), number of aspirations (p< . ), enteral nutrition (p< . ), albumin (p= . ), steroid (p= . ), hypercarbia (p= . ) hypoxia (p= . ), sleep disturbance (p< . ) were found risk factors for delirium. oral nutrition (p< . ) and mobilization (p= . ) were found to prevent delirium development. various factors are important in the development of delirium. these risk factors should be considered in reducing the incidence of delirium in intensive care units. ). an unplanned and brutal stop of alcohol consumption, as it can occur during icu admission, may lead to an alcohol withdrawal syndrome (aws). the most severe clinical manifestation of aws is described as delirium tremens (dt). there are no current guidelines available for aws treatment in icu. the study's aim was to describe the clinician's practices for dt treatment and the outcome of dt in icu patients. observational retrospective cohort study in two icus of a universityaffiliated, community hospital in france. patient diagnosed for dt during their icu stay, as defined by dsm-v classification, were enrolled in the study. results: patients with dt were included between and . benzodiazepines was administered to % of the patients in order to prevent an aws. as associated measures, vitamin therapy was administered to % of the patients and % had an increased fluid intake (mean . l+/- . ). concerning the curative approach of aws, the treatment's heterogeneity was notable. there was a high frequency of treatment's association ( % of the patients), every patient had benzodiazepines and the use of second line treatments such as neuroleptic, alpha- agonist, propofol was variable ( figure ). complications of dt were the following: need for mechanical ventilation due to unmanageable agitation or acute respiratory distress ( % of the patients) self inflicted injuries such as pulling out of central lines, tubes, surgical drain ( %) falls ( %). seizures ( %). delirium tremens is a severe complication of an untreated aws, which can lead to serious adverse events in icu. the current lack of evidence concerning the management of aws in icu probably explains the heterogeneity of treatments. given the potential severity of aws in icu, further evidences are required to optimize care of aws in icu patients. the incidence and related risk factor of delirium in surgical stepdown unit s yoon , s yang , g cho , h park , k park , j ok , y jung asan medical center, nursing department, seoul, south korea; asan medical center, seoul, south korea critical care , (suppl ):p step down units (sdus) provide an intermediate level of care between the icu and the general medical-surgical wards. the critically ill patients who are in recovery after long-term intensive care or who require monitoring after acute abdominal surgery are admitted to sdus. delirium in critically ill patient is common and leads to poor clinical outcomes. it is, however, preventable if its risk factors are identified and modified accordingly. to determine risk factors associated with delirium in critically ill patients to admitted surgical sdu at asan medical center. this is retrospective study conducted on critically ill patients who were admitted to the sdu from september to april and able to express themselves verbally. delirium status was determined using the short-cam tool. data were analyzed by spss . software, using t-test, fisher's exact test and logistic regression. the incidence of delirium was . %( of patients) and hypoactive delirium( case, . %) was the most commonly assessed, followed by hyperactive delirium( case, . %), mixed type( case, . %). risk factors associated with developing delirium identified from univariate analysis were age(p= . ), admission via icu (p= . ), tracheostomy (p= . ), chronic heart failure (chf) (p= . ), invasive hemodynamic monitoring (p= . ), heart rate (p= . ). after adjusted in multivariate analysis; factors those remained statistically significant were old age (rr we identified risk factors consistently associated with incidence of delirium following admitted to surgical sdu. these factors help to focus on patients at risk of developing delirium, and to develop preventive interventions that are suitable for those patients. patients with sepsis frequently develop delirium during their intensive care unit (icu) stay, which is associated with increased morbidity and mortality. the prediction model for delirium in icu patients (pre-deliric model) was developed to facilitate the effective preventive strategy of delirium [ ] . however, the pre-deliric model has not yet been validated enough outside europe and australia. the aim of this study is to examine the external validity of the pre-deliric model to predict delirium using japanese cohort. this study is a post hoc subanalysis using the dataset from previous study in nine japanese icus, which have evaluated the sedative strategy with and without dexmedetomidine in adult mechanically ventilated patients with sepsis [ ] . these patients were assessed daily throughout icu stay using confusion assessment method-icu. we excluded patients who were delirious at the first day of icu, were under sustained coma throughout icu stay and stayed icu less than h. we evaluated the predictive ability of the pre-deliric model to measure the area under the operating characteristic curve. calibration was assessed graphically. of the patients enrolled in the original study, we analyzed patients in this study. the mean age was . ± . years and patients ( %) were male. delirium occurred at least once during their icu stay in patients ( %). to predict delirium, the area under the receiver operating characteristics curve of the pre-deliric model was . ( . to . ). graphically, the prediction model was not well-calibrated ( figure ). to predict delirium in japanese icus, we could not show the well discrimination and calibration of the pre-deliric model in mechanically ventilated patients with sepsis. introduction: delirium is a serious and common complication and in some cases it treatment is difficult. aim of the study was an evaluation of the prevalence, structure of delirium and efficacy of dexmedetomidine and haloperidol sedation in geriatric patients after femur fracture. after local ethic committee approval case-records of geriatric patients with femur fracture in the period from to in the institute of traumatology and orthopedics in astana were analyzed. patients was divided for groups: in dpatients with delirium treated by i/v dexmedetomidine ( . - . mkg/kg per hour), in g group patients with delirium treated by i/v galoperidol ( . - . mkg/kg). delirium was assessed by rass at day of permission and every day at a.m. the prevalence, structure of delirium and efficacy of sedation were analysed. results: by anthropometric and gender characteristics of the group did not differ. the average age in the d-group with delirium was . ± . years old, which was comparable to the g-group - . ± . years old (p = . ). all study participants had similar comorbidities. delirium in all patients debuted at . ± . days, with an average duration of . ± . days. the effect of dexmedetomidine was better and expressed in % decrease in the duration of delirium in compare to haloperidol (p < . ). dexmedetomidine provided a more controlled and safe sedation compared with haloperidol. the average consumption of narcotic analgesics in the subgroup with dexmedetomidine was two times less than in the subgroup with haloperidol. thus, the average consumption of trimeperidine hydrochloride in patients of group d was . mg versus . mg in group g (p = . ). in gerontological patients with femur fracture treatment delirium by dexmedetomidine was more effective in compare with haloperidol. when using dexmedetomidine, the consumption of narcotic analgesics in postoperative period was % less than with haloperidol. live music therapy in intensive care unit mc soccorsi , c tiberi , g melegari , j maccieri , f pellegrini , e guerra intensive care units (icu) are not comfortable for patients, relatives or next of kin. in the last years many news approaches were described to implement the humanization of medical treatments. the positive effect of music therapy in icu is well described, especially reducing delirium risk [ ] . the aim of this paper is describing the effect in patients and their family of a music live performance in icu. after ethical committee approval (procedure aou / , italy) for three months (november -january ) patients in icu were treated twice a week with live music therapy performed by coral vecchi-tonelli of modena, italy (fig. ). data were collected all awake and conscious patients. vitals parameters, gcs, raas and cam icu were collected before, during and after the treatment, at every performance. after the treatment a feedback questionnaire were given to patients and to next of kin. results: subjects were enrolled in the research with mean age of . years old, delirium rate before the treatment was . % later . %, raas does not show any difference. over % of patients were satisfied, and relatives felt less anxiety. we recorded also a satisfaction also in relatives not enrolled. the study does not demonstrate a delirium risk reduction for the small sample and the length treatment, anyway it was recorded a low delirium rate. the safety and the potential effect of music therapy are well known, surely the research underlines the feeling of patients and their next of kin: icu is the most stressful setting for admitted patients and its humanization is a current topic for medical literature. live performances could be an entertainment moment and probably create a moment of an interaction among patients, their family and medical and nurse: icu become more human. the high level of satisfaction push us to continue this experience. introduction: patients undergoing medical procedures benefit from distraction techniques to reduce the need for drugs alleviating pain and anxiety. this study investigates if medical hypnosis or virtual reality glasses (vrglasses) as adjuvant method reduces the need for additional drugs. in a prospective, randomized, interventional trial, patients undergoing procedures were stratified in four age groups, and randomly assigned into three arms by means of a closed envelope system. all patients received standard care for pain before the procedure; the control group received further drugs for pain and stress as indicated by the visual analog scale (vas; threshold / ) and comfortscore (threshold / ), two index groups received either medical hypnosis or vr glasses as a plus before and during the procedure. vas and comfort were scored continuously and analysed with the kruskal-wallis test. patients, parents and healthcare providers scored their satisfaction at the end. of included patients to years old, % were female. regardless of age, pain and comfort scores were similar before and at the start of the procedure (vas . - . ; comfort - . ), but as of one minute after starting the procedure, both vas and comfort reduced significantly more in both index groups compared to the control (p< . ), remaining far below the threshold for both pain and stress ( figure ). there was no advantage of one index group over the other (p= . ). there were no adverse effects. patients in the vr group were more satisfied than in the standard group (p= . ) or in the hypnosis group (p= . ). there was no significant difference in satisfaction of parents or healthcare providers. from the very start of the intervention, the application of either medical hypnosis or vr glasses significantly reduces pain and anxiety in patients undergoing medical procedures. more studies are needed but both are promising safe adjuvant tools to standard pharmacological treatment. music to reduce pain and distress due to emergency care: a randomized clinical trial ne nouira, i boussaid, d chtourou, s sfaxi, w bahria, d hamdi, m boussen, m ben cheikh mongi slim academic hospital, emergency department, tunis, tunisia critical care , (suppl ):p recent clinical studies have confirmed the benefits of music therapy in managing pain and improving quality of care in the emergency department. the aim wasto evaluate the impact of receptive music therapy on pain and anxiety induced by emergency care methods: a randomized controlled study in patients consulting the emergency department. two groups: the music therapy group; patients needed venous sampling, peripheral venous catheter or arterial catheter. will bless ten minutes music therapy by headphones and a second control group of patients with the same care without music therapy. consent was requested from all participants. the level of pain caused by the act of care was assessed by visual analogic scale. heart rate, blood pressure and the mood of the patient were assessed before and after emergency care. we assessed patient satisfaction, adverse events. patients admitted to the emergency room, patients with communication difficulties and non-consenting patients were not included results: two hundred and forty patients were included randomized in both groups, with music therapy and without music therapy, the results showed comparable characteristics between the two groups: demographic data, pathological history, and initial clinical presentation. after the session of music therapy a difference was noted in the evaluation of the mean vas who was in the group with music of . ± . versus . ± . in the control group p< . ci % [- . ; - . ], and the mean of diastolic blood pressure which was , mmhg in the first group against . mmhg for the control group p = . ci % [- . ; - . ]. as for the mood, the patients were more smiling after the act of care in the group music therapy. all patients were satisfied with their experience and % recommend this therapy to their relatives . music therapy may reduce pain and anxiety in patients during emergency care. the music therapy is the intervention of music and/or its elements to achieve individual goals within a therapeutic.the music has proved to have positive physiological and psychological effects on patients [ ] . patients admitted to the intensive care unit (icu) experience anxiety and stress even when sedated, negatively influencing recovery [ ] . methods: two groups are established, a music therapy group (mg) and a control group (cg). the first one undergoes music therapy interventions, it consists of -minutes sessions of live music. patients of the gc will receive the usual treatment established by the service protocol for weaning management and the data are collected during the same time interval. data collection includes mean arterial pressure (map), heart rate (hr), respiratory rate (rr), oxygen saturation (sao ) and temperature (t). a total of patients were recruited, of which patients had to be excluded for meeting any of the exclusion criteria (n= ). of which (n= ) were randomized in the gm and the rest to the gc (n= ) ic %. regarding delirium in gm ( . %) presented a positive cam-icu, while in the cg were ( . %) (p= . ). when analyzing the variables in the cg and gm, it was observed that there were no differences with respect to hr, rr and map variable ( figure ). according to the results, we can say that music therapy as a nonpharmacological strategy for management of anxiety and delirium in patients of critical care units, might be an useful tool for the management of patients in weaning of mechanical ventilation introduction: coagulopathy and basopenia are common features of anaphylaxis, but the role of coagulopathy in anaphylaxis remains uncertain. the aim of this study is to evaluate the association between coagulopathy and clinical severity or basopenia in patients with anaphylaxis. we conducted a single-center, retrospective study of patients with anaphylaxis about their coagulopathy. levels of fibrin degradation products (fdp) and d-dimer were analyzed with the cause of anaphylaxis, clinical symptoms, medications and outcomes. we also studied the levels of intracellular histamine as a biomarker of basophil degranulation in the peripheral blood in relation to fdp and ddimer. in total, sixty-nine patients were enrolled to the study, and the levels of intracellular histamine were analyzed in patients. the symptoms included respiratory failure (n= ), shock (n= ), abdominal impairment (n= ), and consciousness disturbance (n= ). thirty-two patients needed continuous intravenous vasopressors for refractory shock. the increase of fdp was significantly associated with consciousness disturbance (p= . ) and refractory shock (p< . ). the increase of d-dimer was also significantly associated with refractory shock (p= . ). there was no correlation between the levels of intracellular histamine and either of fdp or d-dimer (p= . and p= . , respectively). the increase of fdp and d-dimer were associated with severe symptoms of anaphylaxis, while they were not correlated with intracellular histamine. these results suggest that anaphylaxis is closely associated with coagulopathy in a mechanism which is different from basophile degranulation in anaphylaxis. cardiac manifestations of h n infection in a greek icu population e nanou , p vasiliou , e tsigou , v psallida , e boutzouka , v zidianakis , g fildissis agioi anargiroi hospital, attiki, greece; agioi anargiroi hospital, icu, attiki, greece critical care , (suppl ):p introduction: cardiovascular involvement in influenza infection occurs through direct effects on the myocardium or through exacerbation of pre-existing cardiovascular disease [ ] . the aim was to study cardiac manifestations in all pts admitted to the icu with severe influenza's attack. clinical, laboratory, electrocardiographic, echocardiographic and hemodynamic data were retrospectively recorded in all pts admitted to the icu due to influenza infection (winter -spring ). diagnosis was established by pcr on bronchial aspirates the next days after admission. myocardial injury was defined by troponin levels > pg/ml ( fold uln). left ventricular systolic dysfunction was defined as ef < % and was characterized as either global or regional. hemodynamic monitoring by fig. (abstract p ) . comparison between mg and cg transpulmonary thermodilution method (picco) was recorded in pts with shock (norepinephrine > . μg/kg/min). values are expressed as mean±sd or as median (ir). results: nine pts ( males) with a mean age . ± . years, apache ii ± . and sofa score . ± . were assessed. icu admission was due to ards ( ) and copd exacerbation ( ) . icu los was . ± . days and mortality rate was %. no history of vaccination or coronary heart disease was referred. results are shown in table . levosimendan was administered in pts with severe cardiogenic shock. in all survivors, shock and indices of myocardial dysfunction subsided till discharge. coronary angiography was performed in pt showing no abnormalities. mortality was attributed to septic shock and multi-organ failure. myocardial involvement, though common in influenza pts admitted to the icu, didn't contribute to a dismal prognosis. the cardioprotective effects of levosimendan could be related to the modulation of oxidative balance. we aimed to examine the effects of levosimendan in patients with cardiogenic shock or with ejection fraction (ef) lower than % on cardiac systo-diastolic function and plasma oxidants/antioxidants (glutathione, gsh; thiobarbituric acid reactive substances, tbars). in patients undergone coronary artery bypass grafting or angioplasty, cardiovascular parameters were measured at t (before the beginning of levosimendan, . mcg/kg/min), t ( h after the achievement of the therapeutic dosage of levosimendan), t (at the end of levosimendan infusion), t (at h after the end of levosimendan infusion), t (at the end of cardiogenic shock). the same time-course was followed for plasma gsh and tbars measurements. we found an improvement in cardiac output, cardiac index and systolic arterial blood pressure. ef increased from mean % to %. a reduction of central venous pressure and wedge pressure was also observed. moreover, indices of diastolic function were improved by levosimendan administration (e/e' from to ; e/a from > to < ) at early t . it is to note that an improvement of gsh and tbars was observed early after levosimendan administration (t ), as well ( figure ). the results obtained have shown that levosimendan administration can regulate oxidant/antioxidant balance as an early effect in low cardiac output patients. the modulation of oxidative condition could be speculated to play a role in exerting the cardio-protection exerted by levosimendan in those patients. table . early administration of vasopressors and their use in the emergency department was associated with survival in septic shock. this seemed to be independent of median map recorded in the ed. we excluded all the traumatic or post-myocardial infarction forms. out of patients, the tuberculous etiology was identified in cases ( , %), mean age was years, , % were men. patients reported a tb contact in their environment, had a medical history of pulmonary tb. after pericardiocentesis, the liquid was citrine yellow in cases and hematic in patients, no patient underwent surgical drainage in our serie. mycobacterium tuberculosis was found in the expectorations in cases and ada was positive in patients. hiv serology was negative in all our patients. a months anti bacillary therapy with isoniazid, rifampin, pyrazinamide, and ethambutol was initiated in all our patients with a good evolution in cases, deaths, chronic constrictive pericarditis, small pericardial effusion and lost to follow-up. althought cardiac tamponade is rarely caused by tuberculosis, this condition remains common in endemic countries such as morocco and affect younger population, hence the importance of a better knowledge of its prevalence and and multidisciplinary management and more importantly the treatment of the underlying cause using combined antibacillary medication that has shown satisfying results. . the main perceived limiting factor is the absence of a standardized didactic program, followed by mentor's availability in residents' perception and by mentor's experience in consultants' one. pocus teaching is present although not optimal and not homogenous in italian acc residency schools. standardisation of residents' ultrasound curriculum is suggested to improve ultrasound teaching. the study included a convenience sample of critically ill patients with supradiaphragmatic cvcs and a cxr for confirmation. us is used for direct confirmation of the guidewire in the internal jugular (ijv) or subclavian (scv) vein and visualizing the guidewire in the right atrium. to evaluate for pneumothorax, "sliding sign" of the pleura was noted on us of the anterior chest. results: patients have been included, % of the catheters have been placed in the scv and % in the ijv. it was possible to confirm the position of the cvc tip for . % ( correct, incorrect cxr) of (figure ). overall, it was not possible to identify the guide in the right atrium cases ( false negatives, of them due to the presence of defibrillator leads). regarding the case where an incorrect position was seen on cxr it was also detected on ultrasound: us of the inserted vein and a negative tte confirmation. in all cases it was possible to exclude a pneumothorax by us. these results show that bedside ultrasound might be a feasible technique to confirm the cvc positioning. it is important to note that the level of the operator's expertise is significant when assessing the feasibility of this method. we only had a limited sample size and the occurrence of only one misplaced catheter. these preliminary results need to be confirmed on a larger scale. central venous catheter (cvc) misplacement occurs more frequently after cannulation of the right subclavian vein compared to the other sites for central venous access. misplacement can be avoided with ultrasound guidance by using the right supraclavicular fossa view to confirm correct guidewire j-tip position in the lower part of the superior vena cava. however, retraction of the guidewire prior to the cvc insertion may dislocate the j-tip from its desired position, thereby increasing the risk of cvc misplacement. the aim of this study was to determine the minimal guidewire length needed to maintain correct guidewire j-tip position throughout an us-guided infraclavicular cvc placement in the right subclavian vein. methods: adult intensive care patients with a computed tomography scan of the chest were retrospectively and consecutively included in the study. the distance from the most plausible distal puncture site of the right subclavian/axillary vein to the junction of the right and left brachiocephalic veins (= vessel length) was measured using multiplanar reconstructions. in addition, measurements of the equipment provided in commonly used - cm cvc kits were performed. the minimal guidewire length was calculated for each cvc kit. the guidewires were up to mm too short to maintain correct j-tip position throughout the cvc insertion procedure in seven of nine commercial cvc kits. four of these are shown in table . when us guidance is used to confirm a correct guidewire j-tip position, retraction of the guidewire prior to the cvc insertion must be avoided to ensure correct cvc-tip positioning. this study shows that most of the commonly used - cm cvc kits contain guidewires that are too short for cvc placement in the right subclavian vein. the reliability of lung b-lines to assess fluid status in patients with long period of supine introduction: ultrasound-guided cannulation is usually done using either longitudinal or transverse approach. the oblique approach utilizes advantages of both these approaches allowing visualization of the entire course of needle including tip and lateral discrimination of artery from vein [ ] . the reported incidence of the complete overlap of femoral vein by the femoral artery is - percent [ , ] . we describe the use of the oblique approach for successful cannulation of such a femoral vein which is not possible by usual approaches (figure ). endothelial cells play a pivotal role in the atherogenic process. endothelial cell dysfunction (ed) is the main risk factor for cardiovascular diseases such as hypertension, coronary heart disease (chd) and peripheral occlusive disease (pod). these diseases significantly increase the risk for perioperative complications. therefore, identifying patients with ed is important and should influence our prospective perioperative strategy. however, sensitive tools to diagnose ed are still missing and do not belong to our standard of care. aim of this study was the validation of a new non-invasive method to detect ed and a correlation with a set of established an new endothelial biomarkers. the cohort includes preoperative patients without anamnestic relevant cardiovascular disease and patients with known peripheral occlusive disease (pod). we used non-invasive endopat® technology from itamar-medical to measure ed by changes in vascular tone before and after occlusion of the brachial artery and calculate a reactive hyperemia index (rhi). in addition, we measured established markers and alternative biomarkers potentially indicate vascular diseases such as substrates and products from the no-metabolism l-arginin, asymmetric/symmetric dimethylarginine (adma/sdma), von-willebrand factor (vwf) and sphingosine- -phosphate (s p). rhi was able to identify patients with pod. rhi was significant lower in patients with clinical signs and symptoms of pod (p< . ). among other markers adma was significant higher in pod patients compared to controls and correlates with rhi. the pad technology is a helpful non-invasive functional test to measure ed and seems able in identify patients with vascular disease. in future, a combination of anamnesis, new diagnostic tools and biomarkers may further increase our sensitivity in identifying risk-patients. single-lumen fr and triple-lumen fr peripherally inserted central catheters (piccs) for cardiac output assessment by transpulmonary thermodilution s d´arrigo achieving effective critical care in low-and middle-income countries is a global health goal [ ] , which includes the provision of effective point of care ultrasound [ ] . we sought to establish zambia's first focused critical care echocardiography training programme in a bedded icu at university teaching hospital, lusaka. the programme was accredited by the uk intensive care society fice programme, with teaching adapted for local disease patterns such as tuberculous pericardial effusions. parasternal, apical and subcostal windows were used to assess ventricular dysfunction, hypovolaemia, pleural effusion, alveolar interstitial syndrome and pneumothorax. zambian doctors working with critically ill patients received an intensive one-day course, followed by mentored scanning at the bedside. teaching was delivered by visiting fellows from the uk who are accredited in echocardiography and experienced ultrasound educators. patients with abnormal mean ci or hr suffer from increased hospital mortality. abnormality of mean svi was not associated with mortality. these data support accurate measurement of ci as a hemodynamic target and the normal range defined for ci. since ci also carries the hr information, ci seems to be the more important target than svi. our data cannot necessarily be interpolated to less invasive and less precise measurements of ci. an evaluative study of the novelty device with the function of auto-aspirating and pressure indicator for safety central venous catheterization ly lin, wf luo, cy tsao national taiwan university hospital, taipei, taiwan critical care , (suppl ):p previous studies have shown that . % of cvc attempts resulted in arterial punctures that were not recognized by blood color. to overcome the problem, our team has developed a concept of pressure detecting syringe that can indicate the artery puncture [ ] . based on previous research, different springs, the actuator of the design, have been evaluated to optimize the proposed device and reduce the risk of cvc procedure. tested devices -the inner-spring is set between the pressure indicator and plunger (fig. a ). three springs are tested. test condition -blood samples were simulated by glucose solution with absolute viscosities of and mpa-s. different blood pressures were applied to simulate the artery and vein (fig. b) . the response time (rt) is defined as the time required to show the indicating signal (is) which is the movement of the piston from the position in fig. b : a - to a - . the rt is strongly influenced by spring (fig. b) but every design can show the is when pressure is higher than mmhg, the assumed minimum artery pressure. the rt of s , the strongest spring design, is about s in the mmhg-pressure and high viscosity condition. during our tests we found the user can realize the is before the position be fully changed from fig. ib : a - to a - . thus, we believe the s rt, the worst case, is still acceptable. we also found the weak spring force may lead to difficulty to empty the syringe because the spring must to overcome the blood pressure and the friction between the piston and barrel. as a result, it was difficult for s to absolutely empty the syringe even if the blood pressure is only mmhg. the spring will be compressed as fig. b : a - and fail to push the piston when pushing the plunger forwardly, which is not acceptable in clinical use. the results indicate the feasibility of using the device to facilitate cvc and we believe the s or s are more suitable for the future application. introduction: models using standard statistical features of hemodynamic vital sign waveforms (vs) enable rapid detection of covert hemorrhage at a predetermined bleed rate [ ] . by featurizing interactions between vs we can train powerful hemorrhage detectors robust to unknown bleed rates. waveforms (arterial, central venous, pulmonary arterial pressures; peripheral and mixed venous oxygen saturation; photoplethysmograph; ecg) of healthy pigs were monitored min prior and during a controlled hemorrhage at ml/min (n= ) and ml/min (n= ). two sets of vs features were extracted: statistical features [ ] and maximal pairwise cross correlations between pairs of vs within a s lag over various time window sizes ( s, s, s, s); and normalized with pre-bleed data of each given animal. for each feature set, a tree-based (ert) model [ ] was trained and tested in a one-animal-out setting to mitigate overfitting on the ml/min cohort, and another trained on the ml/min and tested on the ml/min cohort. we evaluated models with activity monitoring operating characteristics curves [ ] that measure false alert rate as a function of time to detect bleeding. models using cross-correlations show no significant deterioration of performance when applied to detect bleeding at different rates than trained for, while standard models require s longer on average to detect hemorrhage at % false alert rate in the previously unknown setting ( figure ). correlations between vs data encode physiologic responses to hemorrhage in a way independent of the actual bleed rates. this enables training effective hemorrhage detectors using only limited experimental data, and using them in practice to detect bleeding that occurs at rates other than used in training. we validated a dataset of data lines containing hemodynamic variables and treatment options. we selected nine hemodynamic variables as inputs. furthermore, data were collected regarding underlying conditions: heart failure, septic shock, renal failure or respiratory failure or a combination. we applied datastories regression on the dataset (turnhout, belgium, www.datastories.com). six different interventions were analyzed as kpi: administration or removal of fluids, increasing or decreasing inotropes and increasing or decreasing vasopressors. finally, we elaborated and challenged predictive models to generate a decision algorithm to predict each kpi. we first looked at how each hemodynamic parameter impacts the prediction of each kpi individually and performed a standard correlation analysis as well as a more involved analysis of the mutual information content between each kpi and all other hemodynamic parameters individually. confusion matrix and variable importance was obtained for each kpi. the baseline hemodynamic parameters were: gedvi ± ml/m , evwli . ± . ml/kg pbw, svv . ± %, mbp . ± . mmhg, hr . ± . bpm, ci . ± . l/min.m . the results of the regression analysis identified the different variables of importance for each of the different interventions ( fig a) . based on these results the hemodynamic variables (hr, mbp, gedvi, elwi, ci, svv) were used to develop the final hemoguide prediction model ( fig b) . the hemoguide app can be used to advise physicians with respect to basic therapeutic decisions at the bedside or as an educational tool for students. with the collection of new data, the accuracy of the system may grow over time. the next step of the project is to develop a more-sophisticated suite: the icu cockpit. feedback function contributes to accurate measurement of capillary refill time r kawaguchi , ta nakada , m shinozaki , t nakaguchi , h haneishi , s oda chiba university, department of emergency and critical care medicine, chiba, japan; chiba university, chiba, japan critical care , (suppl ):p capillary refill time (crt) is well known as an indicator of peripheral perfusion. however, it has been reported to have an intra-observer variance, partly because of manual compression and naked-eye measurement of the nailbed color change. we hypothesized that a we developed a novel portable crt measurement device with an oled display that feedbacks weather the strength of the nailbed compression is enough and counts the time. we settled the target strength and time as n and seconds according to the study we reported before [ ] . examiners measured crt with and without the feedback function. the pressing strength and time during the measurement were evaluated. there was a significant difference among the pressing strength and time between the crt measurement using the device with and without the feedback function (strength: p< . ; time: p< . ). furthermore, intra-examiner variance was significantly reduced with the feedback function (strength: p< . ; time: p< . ). in all measurements without the feedback function, % was outside the optimal strength while the measurements with the feedback function % achieved the targeted range. without the feedback function, % could not reach the optimal time, while % with the feedback function did. in total, % of the measurements could not achieve the optimal pressing strength and time. the feedback function for crt measurements, guiding examiners to an optimal pressing strength and time, fulfilled the required measurement conditions and reduced intra-examiner variance. our novel portable device would assist an accurate crt measurement regardless of personal work experience. introduction: the aim of the study was to detect the difference of conjunctival microcirculation between septic patients and healthy subjects and evaluate the course of conjunctival microcirculatory changes in survivors and non-survivors over a hours period of time. this single-centre prospective observational study was performed in mixed icu in a tertiary teaching hospital. we included patients with sepsis or septic shock within the first hours after icu admission. conjunctival imaging using idf videomicroscope as well as systemic hemodynamic measurements were performed at three time points: at baseline, hours and hours later. baseline conjunctival microcirculatory parameters were compared with healthy control. a total of patients were included in the final assessment and analysis. median apache ii and sofa scores were ( - ) and ( - ) respectively. ( %) were in septic shock, ( %) required mechanical ventilation. patients were discharged alive from the intensive care unit. we found significant reductions in all microcirculatory parameters in the conjunctiva when comparing septic and healthy subjects. we found a significant lower proportion of perfused vessels and microvascular flow index (mfi) of small vessels during all three time points in non-survivors compared with survivors. in nonsurvivors we observed no significant changes in conjunctival microcirculatory parameters over time. however, survivors had significantly improved mfi of small vessels at second and third time points compared to first time point. microcirculatory perfusion in conjunctiva was altered in septic patients. over hours evaluation survivors in comparison with nonsurvivors had better microcirculatory flow with incremental improvement of microvascular flow index. healthy pigs were centrally cannulated for veno-arterial ecmo and precision flow probes were placed on the pulmonary artery main trunk for reference. ml boluses of iced . % saline chloride solution were injected into the ecmo circuit and right atrium at different ecmo flow settings ( , , , l/min). rapid response thermistors of standard pa-catheters in the ecmo circuit and pulmonary artery recorded the temperature change. after calibration of the catheter constants for different injection volumes in the ecmo circuit, the distribution of injection volumes passing each circuit was assessed and enabled calculation of pulmonary blood flow. analysis of the exponential decay of the signals allowed assessment of right ventricular function. calculated blood flow correlated well with true blood flow (r = . , p < . , figure panel a, individual measurements organ congestion is susceptible to be a mediator of adverse outcomes in critically ill patients. point-of-care ultrasound (pocus) is widely available and could enable clinicians to detect signs of venous congestion at the bedside. the aim of this study was to develop prototypes of congestion scores and to determine their respective ability to predict acute kidney injury (aki) after cardiac surgery. this is a post-hoc analysis of a prospective study in patients for which repeated daily measurements of hepatic, portal, intra-renal vein doppler and inferior vena cava (ivc) ultrasound were performed before surgery and during the first hours after cardiac surgery [ ] . five prototypes of venous excess ultrasound (vexus) scores combining multiple ultrasound markers were developed (figure ). the association between each score and aki was assessed using timedependant cox models as well as conventional performance measures of diagnostic testing. a total of ultrasound assessments were analyzed. we found that defining severe congestion as the presence of severe flow abnormalities in multiple doppler patterns with a dilated ivc (> cm), corresponding to grade of the vexus c score, showed the strongest association with the development of subsequent aki compared with other combinations of ultrasonographic features (hr: . there is an increasing awareness on the consequences of fluid administration in patients leading to the development of methods that evaluate the effects of fluids loading on the cardiocirculatory system. however, most of methods used in the clinical practice investigate the effects of fluids on the cardiac function, instead of investigating those on the determinants of venous return. besides volume of fluids, the determinants of fluid loading are the blood volume distribution and the availability of vascular bed. in this study we aimed to test non-invasively the effects of fluids administration on the venular compartment in the skeletal muscle. in addition to the mean systemic filling pressure (msfp), we calculated changes in the stressed and unstressed volumes (vs, vu) and the venular bed availability. we enrolled critically ill patients in our intensive care unit. we assessed volumes and pressures by the near infra-red spectroscopy on the forearm using graded venous occlusions in steps of mmhg from to mmhg. the msfp, vu and vs were measured as previously reported (microcirculation ; : - ). the vascular bed availability was measured by changes in the volume recruited from the occlusion maneuvers. all the measures were done at baseline and after a fluid load ranging from to ml. values were expressed as median and interquartile range. wilcoxon test was used to compare data and a p< . was considered as significant. introduction: hypotension is a common side effect of general anesthesia (ga) and is associated with organ hypoperfusion and poor perioperative outcome [ ] . post-induction hypotension (pih) is caused by the depressant cardiovascular effect of anesthetic drugs and could be amplified by hypovolemia. the aim of this study was to assess the ability of two echocardiographic fluid responsiveness markers to predict pih: the inferior vena cava collapsibility index (ivc-ci) and the velocity time integral change (Δvti) after passive leg raising. sixty patients > years of age and scheduled for elective surgery were included. ivc-ci and Δvti were measured before ga induction. anesthesia protocol, fluid infusion and vasopressor administration were standardized in all patients. pih was defined as a mean arterial pressure (map) < mmhg or a relative decline from pre-induction value of at least % within minutes of ga induction. receiver operating characteristic (roc) curve analysis was used. the optimal cutoff was selected to maximize the youden index (sensitivity + specificity − ). the measurement of ivc-ci and/or Δvti were unsuccessful in seven patients ( . %). pih occurred in patients (incidence %). the areas under the roc curves ( figure ) preload responsiveness might be detected by the changes of cardiac index (Δcimini) induced by a "mini-fluid challenge" (mini-fc) of ml or even by the changes (Δcimicro) in response to a "micro-fluid challenge" (micro-fc) of ml. however, the smaller the fluid challenge, the larger the "grey zone" of diagnostic uncertainty. we tested whether ( ) micro-and mini-fc monitored by calibrated pulse contour analysis detect preload responsiveness and ( ) adding ml when the result of a micro-fc is within the grey zone improves diagnostic accuracy. in patients with circulatory failure, we infused ml saline over s followed by ml over s. we measured Δcimicro and Δcimini by the pulse contour analysis (picco ). preload responsiveness was defined by an increase in ci (Δciplr) during a passive leg raising test ≥ %. diagnostic uncertainty was described by calculating the grey zone after bootstrapping. Δcimicro were larger in responders than in non-responders ( . for the micro-fc, the area under the receiver operating characteristic curve was . ± . (threshold %), while it was . ± . for the mini-fc (threshold %). for the micro-fc, the grey zone ranged from . % to . % and included ( %) patients. for the mini-fc, it ranged from . % to . % and included ( )% patients, among which were already in the grey zone of the micro-fc. when evaluated by pulse contour analysis, micro-and mini-fc reliably detect preload responsiveness but with a large diagnostic uncertainty. it seems that adding ml more fluid to a micro-fc when its result is within the grey zone does not improve the diagnostic accuracy. the study is ongoing. the starling-sv bioreactance device (cheetah medical) reliably detects passive leg raising (plr)-induced changes in cardiac index (Δci). we tested whether it can also track the small and short-time Δci induced by the end-expiratory occlusion (eexpo) test, and whether shortening the time over which it averages cardiac output ( s in the commercial version) improves the detection. in mechanically ventilated patients, during a -sec eexpo, we measured Δci (in absolute value and in percentage) through calibrated pulse contour analysis (ci pulse , picco device) and starling-sv. for the latter, we considered both ci starling- provided by the commercial version and ci starling- obtained by averaging the raw data over s. we calculated the correlation between Δci pulse and both Δci starling- and Δci starling- , and the area under the receiver operating characteristic curve (auroc) to detect preload responsiveness, defined by a plr test. when considering absolute values, the correlation coefficient r between Δci pulse and Δci starling- was . (p= . ), which was lower than the one between Δci pulse and Δci starling- (rr comparison). when considering percentage changes, no correlation was observed between Δci pulse and Δci starling- . conversely, the correlation coefficient between Δci pulse and Δci starling- was . (p= . ), but it was lower than the one obtained for absolute values (p= . for r comparison). eexpo-induced Δci starling- , both in absolute values and in percentage, detected preload responsiveness with aurocs of . (sensitivity %, specificity %) and . (sensitivity %, specificity %), respectively. shortening the averaging time of the bioreactance signal increases the reliability of the starling-sv device to detect eexpo-induced Δci. moreover, the accuracy of the method is increased when absolute rather than percentage changes of ci are considered. fluids are among the most prescribed drug in intensive care, particularly among patient with circulatory failure. yet, very little is known about their pharmacodynamic properties and this topic has been left largely unexplored. there is a lack of strong scientific evidence in current guidelines for fluid administration in shock. several factors may impact the hemodynamic efficacy of fluids among which the infusion rate. the aim of this study was to study the influence of fluids administration rate on their pharmacodynamics in particular by studying mean systemic pressure (p ms ). we conducted a prospective observational study in patients with circulatory failure to compare two volume expansion strategies. when a patient required a fluid bolus, ml of normal saline were administered and several hemodynamic parameters were recorded continuously: cardiac output (co), arterial pressure (ap), mean systemic pressure (p ms ). infusion rate was let to the discretion of the attending physician and a "slow" and a "fast" group were determined based on the median of the infusion time. fluids effect was measured by the area under the curve (auc), maximal effect (e max ) and time to maximal effect (t max ) for each hemodynamic variable. results: p ms auc was higher in the "fast" group compared to the "slow" group (p= . ). we observed a shorter t max and a higher e max for p ms in the "fast" group compared to the "slow" group (p= . and . respectively). regarding co, t max was also shorter in the "fast" group (p= . ). auc and e max were similar between the two groups. fluid effect dissipated within minutes following the end of fluid infusion for every patient in both groups. the decreasing slope from maximal effect was comparable in the groups, for p ms and co alike. the effect of a ml fluid bolus in septic shock patients vanished within one hour. a faster infusion rate increased maximal effect and shortened the delay to reach it. study is ongoing. fluid management in the control arm of sepsis trials aa anparasan, ac gordon, mk komorowski imperial college london, department of surgery and cancer, london, united kingdom critical care , (suppl ):p in the past, high-volume intravenous fluid resuscitation in severe sepsis and septic shock was common. more recently, concerns over the harmful effects of this practice have led some clinicians to adopt less liberal fluid strategies. we sought to analyse temporal trends in fluid administration in the control arms of recent adult sepsis trials and assess any correlation with patient severity and mortality. a literature search was conducted to identify relevant randomized controlled trials that reported fluid administration published post . we recorded outcomes: total amount of iv fluid administered in the control arms of these trials between hospital admission and hour and hour following trial enrolment, mortality rates at the latest reported time point and apache-ii score at admission. we computed the pearson correlation coefficient and linear regression between study dates and the outcomes. we identified relevant trials [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , which recruited a total of , patients in their control arms, from to . the temporal analysis revealed no obvious trend in the in the total volume of iv fluid given by hour following trial enrolment (correlation p= . ) ( figure ). however, the total volume of fluid given by hour decreased significantly over the period of interest (r=- . , p= . ). in parallel, we observed a decrease in mortality (r=- . , p= . ) but there was no evidence of decrease in illness severity over time (p= . ). we found that in published rcts over the last two decades, the amount of intravenous fluid given to patients with sepsis in the initial hours did not appear to change, however less intravenous fluid was given over the first three days. upcoming large rcts will test the safety and efficacy of restrictive fluid administration approaches in sepsis. clinical practice guidelines recommend prompt intravenous (iv) fluid resuscitation for pediatric sepsis, including an initial fluid bolus of ml/kg [ ] . however, recent evidence is conflicting as to the effectiveness, volume, and consequences of aggressive fluid resuscitation in septic children. therefore, we sought to determine the epidemiology of early iv fluid resuscitation in an integrated health system, specifically at community hospital emergency departments (ed). we studied a retrospective cohort of pediatric patients (ages > month to < years) with sepsis identified in electronic health record data at community eds in southwestern pennsylvania from to . sepsis was defined as ) suspected infection (combination of fluid culture collection and administration of antibiotics and ) organ dysfunction (pediatric sofa score ≥ ) within hours of suspected infection. fluid bolus therapy was defined as electronic documentation of administration of . % normal saline iv bolus within hour of the time of sepsis onset. results: among , patients with pediatric sepsis, ( %) received iv fluid bolus therapy within hour of time of sepsis onset. the volume of fluid administered ranged from ml/kg to ml/kg (figure , panel a), corresponding to a median volume of ml/kg (iqr - ml/kg). patients who received ≥ ml/kg of fluids (n = , %) were younger (mean age years, sd vs. years, sd ; p< . ), more often had blood cultures collected during evaluation ( % vs. %, p= . ), and were more often transferred to another facility ( % vs. %, p< . ) when compared to patients who received < ml/kg of fluids (n = , %). mean fluid bolus volume within hour of time of sepsis onset by hospital ranged from ml/kg to ml/kg (figure , panel b) . in a cohort of community emergency departments, % of septic children received intravenous fluid boluses within one hour, and of those, only one half received volumes concordant with guidelines. (figure ). a wide range of fluid balance exists in septic shock patients cared for in icu. trends of serum albumin in septic and non-septic critically ill introduction: the link between hypoalbuminaemia and poor outcomes in critical care is well established [ ] . limited data are available on serum albumin trends during critical illness [ ] . in this study we assessed trends in serum albumin for up to days in both septic and non-septic critically ill patients. we retrospectively examined the records of adult patients admitted to critical care at the royal liverpool university hospital between and . we then excluded patients who did not have albumin data available for the first days, leaving us with patients. patients ( . %) had sepsis, and of these patients had died by day . of the non-septic patients ( . %), patients had died by day . albumin levels were collected for days from admission to critical care, in addition to other demographic and biochemical data. statistical analysis was performed using repeated measures analysis. septic patients had lower serum albumin than non-septic patients throughout the day period (p< . ). we observed a decrease in albumin by day in all groups, with levels increasing over the subsequent days. there was no difference in daily serum albumin between non-septic patients who survived or died. this is the first study, to our knowledge, to compare albumin trends in septic and non-septic critically ill patients over days. further research is needed to elucidate the optimal recipients and timing of albumin therapy. introduction: burn injury is characterized by marked inflammation, capillary leakage, and profound hemodynamic alterations. early albumin resuscitation is avoided fearing a paradoxical fluid escape into the interstitium. on the other hand, administration of crystalloids in massive amounts causes tissue edema and fluid extravasation, which deteriorates tissue perfusion by increasing oxygen diffusion distance. albumin administration could reduce the amount required to maintain hemodynamic stability in this population. we investigated whether albumin improves tissue perfusion and microcirculation by reducing tissue edema. this is an observational study conducted in the burn unit of maasstad hospital, rotterdam. patients with burns higher than % of total body surface area (tbsa) were included in the study. sublingual microcirculation was measured at admission (t ), (t ), and (t ) hours after burn injury. total vessel density (tvd) and functional capillary density (fcd) were analyzed. fluid management was calculated according to the modified parkland formula. albumin ( %) infusion was started hours after the burn insult. a total of nine patients were recruited between january and december . patients were included in the study after . ± . hours of the insult with a mean tbsa of ± %. the amount of crystalloid infusion was ± ml and ± ml at t and t ,respectively. within the first h (t ) ± ml albumin was given. tvd decreased from . ± . at t to ± . at t (p< . ) (figure ) introduction: spontaneous bacterial peritonitis (sbp) accounts for ≥ % of the bacterial infections that occur in patients with cirrhosis, and sbp has a high mortality rate ( % to %). albumin infusion has been shown to improve the outcome of sbp. the aim of this study is to examine the impact of albumin infusion on hospital length of stay (los) for cirrhotic patients with sbp. we utilized a nationwide electronic health record data set (cerner health facts®) to extract real-world data on adult patients (≥ years old) with cirrhosis and sbp who received antibiotics and admitted between january , , and april , . international classification of diseases (icd- / ) codes were used to identify cirrhosis and sbp. we used laboratory data for calculation of the model for endstage liver disease sodium (meld-na) score and vital signs data for calculation of the quick sepsis related organ failure assessment (qsofa) score at baseline for each encounter. a generalized linear model was used to assess the relationship between albumin infusion and hospital los. results: there were , encounters that identified patients with sbp and cirrhosis, of which , survived hospitalization. albumin was infused within hours of admission ('early albumin') in % (n= ), after hours in % ('late albumin', n= ), and not administered in % ('no albumin', n= ). meld-na was higher at presentation in early albumin cases versus late-or no-albumin cases (mean . and . ). unadjusted los was lower in patients receiving early albumin ( . days versus . days). risk-adjusted analysis demonstrated that early albumin led to a . % reduction in los ( % ci . %- . %, p = < . ). in these real-world data, albumin infusion within hours of admission in patients with cirrhosis and sbp was associated with a shorter hospital stay despite more severe illness. early albumin may not only improve clinical outcomes but may also reduce the costs of hospitalization in cirrhotic patients with sbp. early albumin use in patients with septic shock is associated with a shorter hospital stay: real-world evidence in the united states introduction: septic shock is among the most common critical care illnesses and incidence is rising, with mortality in excess of %. septic shock predisposes patients to multiple organ failure. while albumin is effective in management of circulatory dysfunction in septic shock, its utilization in this population is understudied in the us. we evaluated the impact of albumin utilization on hospital length of stay (los) among septic shock patients. we used a nationwide electronic health record data set (cerner health facts®) to extract real-world data on adult patients (≥ years old) with severe sepsis or septic shock, admitted between january , , and april , , identified by international classification of disease (icd- / ) codes, and receipt of antibiotics and vasopressors. we calculated the charlson comorbidity index (cci) and the acute physiology score (aps) at baseline. a generalized linear model was used to examine the association between albumin and hospital los, especially accounting for the timing of albumin infusion. we identified , unique visits for septic shock patients that survived to discharge. albumin was infused within hours of admission ('early albumin') in %, after hours ('late albumin') in %, and not administered in %. both cci and aps were higher, at presentation, in early albumin cases than late-or no-albumin cases (mean: . and . , and . and . , respectively). unadjusted los was slightly lower in patients receiving early albumin ( . days versus . days). a risk-adjusted analysis demonstrated that early albumin was associated with . % shorter los ( % ci . %- . %, p = . ). albumin infusion within hours of admission was associated with a shorter length of hospital stay. early albumin infusion may lead to better outcomes and reduced costs in patients with septic shock. further research is being conducted to assess other potential benefits of early albumin administration in this patient population. every new septic event follows by hemodynamic instability may lead sequentially to decreased organ perfusion, multiple organ failure. acute renal failure is recognized clinical feature during sepsis (up to - % in all cases). furthermore, urine output close monitoring is a cornerstone diagnostic clinical tool in each septic critically ill patient. in present study, we analyzed the dynamic minute-to-minute changes in the urine flow rate (ufr) and also the changes in its minute-to-minute variability (ufrv) during new septic event in critically ill patients. demographic and clinical data were extracted from the of critically ill patients who were admitted to the icu and developed new septic event (followed by fever and leukocytosis) and analyzed. a foley catheter was inserted into the urinary bladder of each study patient. the catheter was then connected to electronic urinometer, a collecting and measurement system which employs an optical drop detector to measure urine flow. the urine flow rate variability (ufrv) is defined and calculated as the change in ufr from minute to minute. results: ufr and ufrv both decreased significantly immediate after new septic episode until beginning fluid resuscitation (ppvalues < . ) (figure ) . statistical analysis by the pearson method demonstrated a strong direct correlation between the decrease in ufr, ufrv and the decrease in the map (r= . , p= . ; r= . , p= . ) ( figure ), and heart rate (r= . ,p=< . ) since systemic pressure starts to drop. ufrv and ufr demonstrated good clinical response to fluid administration despite the fact that systemic blood pressure did not improve (figure ) . we consider that dynamic changes in ufrv and ufr could potentially serve as a more sensitive signals ofclinicaldeterioration during the new septic event in critically ill patients.we also suggest that those parameters mightbeable to identify the optimal end-point of fluid resuscitative measures in septic critically ill patients. diminished urinary output (uo) is largely used as marker of acute kidney injury (aki) in critically ill patients. we aimed to explore the role of urinary output on incidence and mortality of aki developed during icu admission. the study population consists of all patients admitted between and to one of the dutch icus included in the nice database with an icu length of stay of at least hours, having daily measurement of creatinine and uo. only patients without renal replacement therapy that have a serum creatinine lower than . mg/dl ( . μmol/l) or a uo above . ml/kg/h on the day of the index icu admission were considered at risk for aki. patients were followed during their icu stay and classified according to the highest kdigo criteria reached based on creatinine alone (model ) and creatinine plus uo (model ) using icu admission serum creatinine as baseline. in both models, patients were classified as: no aki, renal impairment at the first day of icu admission, aki stage , aki stage , and aki stage . we identified , patients ( % male, mean age years, median icu-los days). of those, . % of patients had renal impairment at the first day of icu admission. among the remaining patients, . % in model and . % in model were classified as having no aki, . % and . % as aki stage , . % and . % as aki stage , and . % and . % as aki stage , respectively. survival at -day markedly differed according to the aki classification model used (figure) . similarly, adjusted hrs for -day mortality differed among patients with and without aki compared to patients with renal impairment at the first day of icu admission ( figure ) . among patients admitted to the icu % had renal impairment at the first day of icu admission. our findings suggested that uo plays an important role both on aki incidence and mortality and should be carefully interpret in the clinical setting especially in aki stage classification. introduction: acute kidney injury (aki) mostly attributed to renal tubular damage, has a high morbidity and mortality outcome [ ] , so a sensitive tool to assess the degree of tubular affection is needed for early detection and management of this condition. we investigated the ability of furosemide stress test (fst) (one-time bolus dose of mg/kg or . mg/kg if on prior furosemide-intake) to predict progression to akin stage-iii in critically ill subjects with early aki. we studied subjects; consecutive patients in group i receiving fst and consecutive patients in group ii receiving standard medical management for aki; patients ( . %) and patients ( %) met the primary endpoint of progression to akin-iii in groups i and ii respectively. patients with progressive aki had significantly lower urine output following fst in the first hours (p< . ). the area under the roc curves for the total urine output over the first hours following fst to predict progression to akin-iii was . (p = . ). the ideal-cutoff for predicting aki progression during the first fig. (abstract p ) . thirty-day survival according to aki classification model and model . hazard ratios (hrs) for -day mortality adjusted by sex, age, type of admission, apache iv score, sofa score at day of admission (excluded renal sofa score) for patients with aki classified with model and model fig. (abstract p ) . clinical correlation between urine flow rate variability (ufrv) and ufr and mean arterial blood pressure over new septic event (black arrows) and and after initial fluid resuscitation (red arrows). note: the ufrv and ufr decreased progressively in parallel with the falling mean arterial blood pressure and, than, rose again after the administration of fluids hours was a urine volume of less than milliliters with a sensitivity of . % and specificity . % group receiving fst. on the other hand, statistically significant hypotension, hypo-(kalemia, phosphatemia and magnesemia) occurred in group i. the fst in patients with early aki could predict liability for progression of aki, however it should be performed under adequate monitoring. introduction: ischemia-reperfusion (ir) causes renal dysfunction and damage. ir induces renal tubular injury triggered by hypoxia and hyperoxia, mediated by oxidative stress and inflammation. furosemide inhibits na + -k + - clcotransporter in the thick ascending limb of the renal medulla to decrease na + reabsorption, reducing oxygen consumption. we investigated if furosemide could improve renal oxygenation, function and damage by reducing o consumption and oxidative stress after ir. methods: wistar albino rats were divided into groups, with in each group; sham-operated control (c), control + furosemide (c+f), ir and ir+f. after anaesthesia (bl), min supra-aortic occlusion was applied to ir and ir+f groups followed by min (t ) and hours of reperfusion (t ). furosemide μg/kg/h infusion was simultaneously administered to c+f and ir+f after ischemia. systemic hemodynamic, renal blood flow (rbf), renal vascular resistance (rvr), renal oxygen delivery (do ren ), renal oxygen consumption (vo ren ), creatinine clearance (ccr), sodium handling, urine output (uo), cortical (cμo ) and medullar (mμo ) microvascular oxygenation were measured. results: rbf was reduced in ir ( . ± ) and ir+f ( . ± ) at t (p< . ) but it was further reduced in ir+f ( . ± ) (p< . ) at t compared to c and c+f. rvr was increased in ir ( ± ) and ir+f ( ± ) at t compared to c. rvr was normalized in ir ( ± ) but not in ir+f ( ± ) at t compared to c (p< . ). cμo and mμo did not differ between groups after ir insults (figure ). tissue o was reduced at the medulla, but not at the cortex in ir+f group compared to ir. do ren and vo ren were reduced in ir ( ± and ± ml/ min) and ir+f ( ± and ± ) at t (p< . ). pc was higher in ir+f ( . ± . ) compared to ir . ± . (p< . ). vo / tna + was increased in ir+f compared to ir. no change in ccr and uo was observed. furosemide after ir causes further impairment of renal perfusion, energy utilization and renal oxygenation resulting in renal damage. acute renal failure induced by hypoxemia: incidence and correlation study a trifi , h fazzeni , a mehdi , c abdennebi , f daly , y touil , s abdellatif , s ben lakhal la rabta hopital, medical intensive care unit., tunis, tunisia; la rabta hopital, tunis, tunisia critical care , (suppl ):p introduction: acute renal failure (arr) is a common complication in icus and usually caused by hypoperfusion. arf induced by hypoxemia is a concept rarely reported in icu. its incidence and pathogenesis are not well understood. we aimed to study the relationship between hypoxemia and the occurrence of arf. retrospective cohort study including patients with hypoxemia whatever its etiology between january and august . patients with chronic renal failure were excluded. arf was defined and ranked according to the kdigo criteria . arterial blood gas, urea, creatinine and clearance were reordered on the first, third and seventh days of evolution. results: patients were included and groups were obtained: group of hypoxemic patients with arf (arf+, n= ): versus group of hypoxemic patients without arf (arf-, n= ). the incidence of hypoxemie-induced arf was therefore %. clinical characteristics were comparable in both groups with a mean age of ± and a sex ratio of . . the comparative study showed in arf+ group: a lower ph ( . . ], p = . ). the most significant correlation was showed with mdrd clearance at day and p/f ratio at day (rho = . , p = . ). multivariate analysis found that septic shock and non invasive ventilation in hypoxemic patients were the factors related to arf with respectively or= . , % ci= . - . , p= . and or= . , % ci= . - . , p= . . overall mortality was % (n= ) and arf was an independent factor of mortality: or= , and % ci= . - . , p = . . hypoxemia-induced arf is a common complication associated with excess mortality. our study suggests that renal function is correlated with the degree of hypoxemia and that this correlation is rather distinct hours from hypoxemia. in preclinical models of sepsis, we have previously demonstrated that activation of amp activated protein kinase (ampk) using metformin, improves survival and organ function. thus, ampk activation is a potential therapeutic target in sepsis, and we hypothesize that exposure to metformin during sepsis is associated with decreased aki and mortality methods: retrospective analysis of a -hospital cohort of adult icu patients with type diabetes mellitus (t dm) who presented sepsis. we investigated if exposure to metformin during the hospitalization was associated with reduced -day mortality and aki. we used : propensity score matching (psm), propensity score stratification (pss) and propensity score weighting (psw) based on the probability to be exposed to metformin using covariates. for psm an exact match for insulin, amputation, cardiovascular diseases, retinopathy, charlson index, egfr, hba c, and apache iii, were used. sepsis was defined using sepsis criteria, and aki as kdigo stage or . from , patients, we found diabetic adults exposed to metformin during hospitalization and , who were not. metformin exposure during hospitalization is associated with decreased -day mortality and aki in septic adult patients with t dm. these findings suggest that metformin may constitute a potential therapeutic strategy in sepsis, and the potential role of ampk activation as a protective mechanism. however, studies are needed to confirm this association and the specific mechanisms of action. introduction: acute kidney injury (aki) may occur up to % in the intensive care unit (icu). predicting aki recovery may allow for risk stratification of patients, patient and family counseling, and early post-discharge renal care planning. however, predicting aki recovery at an early stage remains a challenge. methods: this is a retrospective study of the epanic multicenter randomized controlled trial database [ ] , which was split into development (n= ) and validation (n= ) cohorts, and patients experiencing aki stage and/or renal replacement therapy (rrt) in the icu were included [ ] . aki recovery was defined as being alive, without any stage of aki, and without need of rrt at hospital discharge. a logistic regression model with backward feature elimination was developed. the model performance was assessed by discrimination, calibration, and net benefit analysis, and internally validated with ten-fold cross validation. only the results in the development cohort are reported. of the patients who developed aki , patients ( . %) recovered from aki. the multivariable model selected age, bilirubin, heart rate, mean arterial blood pressure, surgical diagnostic group on icu admission, mechanical hemodynamic support on icu admission, suspected sepsis on icu admission as aki recovery predictors. the model had a mean area under the receiver operating characteristic curve (auroc) of . (standard deviation (sd) . ), mean calibration slope of . (sd . ), and mean calibration-inthe-large of < . (sd . ) (figure ). at the classification threshold that maximized sensitivity and specificity, mean net benefit with respect to treat-none was . (sd . ) and mean net benefit with respect to treat-all was . (sd . ). by using the routinely collected clinical data, the developed prediction model can fairly identify patients with a higher chance of aki recovery at hospital discharge. introduction: acute kidney injury (aki) is a frequent complication in critically ill patients and is associated with increased morbidity and mortality. sepsis is one of the most common cause of aki. a prospective study was conducted over months (january -june , ).we included patients with septic shock at admission or at any time during hospitalization.the aki staging was based on kdigo criteria.patients were divided into two groups, a group with aki (aki+) and a group without aki (aki-).then we compared the baseline characteristics, laboratory and physiologic data. patients with aki (aki+) were subdivided according to their prognosis. were enrolled patients. the mean (sd) age was . (± ) years.sex ratio was . . fifty-two ( %) patients developed aki.sapsii and sofa score in admission were higher in patients with kidney injury [ vs points (p= . ), . vs points ;(p= . )] respectively.the serum lactate level was significantly higher in (aki +) group patients during the first day of septic shock [ . ± . mmol/l (aki+)vs . ± . mmol/l(aki-);(p= . ) ] and its clearance was lower [( ± . % (aki +)vs ± %(aki-);(p= . )]. a significant difference was observed in c reactive protein level [ ± mg/l (aki +) vs ± mg/l (aki-) ; (p= . )].among (aki+) patients, kadigo iii was observed in . % of cases.nineteen ( . %) patients received hemodialysis.a normal kidney function was recovered in . % of cases.aki+ patients had a higher occurrence in disseminated intravascular coagulation ( vs patients, p= . ),acute respiratory distress syndrome ( vs patients; p= . ) and cardiac dysfunction ( vs patient, p= . ).mortality was higher in aki group ( % vs %; p= . ). the development of septic aki was associated with poor outcomes and prognosis.a better understanding of sepsis induced aki pathway will enable us to develop targeted therapeutic protocols.newer tools,permitting aki early detection, may make these therapies more fruitful. this study aims to show that contrast procedures do not significantly increase the risk of renal injury and should not be deferred. traditionally ciaki is the most important cause of in-hospital renal failure after nephrotoxic drugs and shock. problem is also the non-uniform definition of ciaki proposed by three different initiatives (akin, esur and kdigo). akin, being the most rigorous, defines ciaki as an increase in serum creatinine > . mg/dl or > % of baseline within hours. a retrospective observational single-centre cohort study analyzed patients who underwent a contrast procedure with iomeron . the first group underwent a ct pulmonary angiography (ctpa), and the fig. (abstract p ). internally validated model performance: (top row) roc curve; (middle row) calibration curve; (bottom row) decision curve second a coronary angiography with pci. no patient was previously prepared (raas blockade removal, crystalloid administration etc). we studied demographics, history of ckd and comorbidities and their impact on the ciaki by the akin criteria. a total of patients were divided into two groups (ctpa and pci). ctpa group ( m, f) all had acute pe and the pci group ( m, f) were treated for acs. the mean age was and years respectively. ckd was more prevalent in the pci group ( pt vs. pt) possibly explained by the more advanced atherosclerotic disease. advanced chd (nyha iii/iv) was found in pt (pci) vs. pt (ctpa) while diabetes and shock were equally distributed ( pt and pt) in both groups. the mean amount of contrast was significantly higher in the pci group ( . ml vs. ml). the mean creatinine/egfr measured before and after contrast in the ctpa group was . the goal of this study was to determine whether changing the body mass (bm) with fat-free mass (ffm) in cockcroft-gault (cg) formula could provide a more accurate prediction of aki in obese patients undergoing cardiac surgery. in this retrospective study, we reviewed institutional data of patients who underwent elective cardiac surgery in a tertiary referral university hospital. baseline patient creatinine value was collected and gfr was estimated using the mdrd, ckd-epi and cg formulas. cg formula was further modified by replacing the bm with ffm derived from the bioelectrical impedance analysis. postoperative aki was defined by kdigo creatinine change definitions. accuracy of the egfr values to predict the aki was calculated with roc-auc analysis. all the calculations were performed in different categories of bmi. figure ). the egfr is a poor predictor of aki in obese patients undergoing cardiac surgery. the ffm modified cauckraft-gault formula yield more accuracy in this specific group. retroaki: a ten-year retrospective study of acute kidney injury in intensive and progressive care units introduction: acute kidney injury (aki) is a frequent condition in intensive care units (icu) and progressive care units (pcu), affecting % to % of the patients, depending on the studied population and aki definition. aki has been identified as an independent risk factor of icu mortality and development of chronic kidney desease. the objective of this study was to describe the incidence of each aki stages as defined by kdigo definition (with evaluation of urine output, serum creatinine and initiation of renal replacement therapy (rrt)), in a mixed medical and surgical population of patients hospitalized in icu and pcu over a -year period ( - ). we included all patients who stayed more than hours in icu or pcu of edouard herriot hospital from may to january . data used to classify the patients were the urine output over a sixhour period, serum creatinine and the need for rrt, according to kdigo classification results: , hospital stays were analyzed. median icu/pcu length of stay was days [iqr: . - . ]. among icu patients, % had at least one aki episode graded , or and % had at least one severe episode (stage or ). among pcu patients, % had at least one episode of aki and % a severe episode of aki. patients had an average of . episodes of aki per stay. table represents the incidence of maximal aki stage during one stay. we found that urine output was the more frequent criteria to make diagnosis of aki stage or whereas rrt was more frequent for aki stage . this retrospective study reports a more important aki incidence in our icu/pcu than in previous studies. the difference could be fig. (abstract p ) . when comparing auc in different categories of bmi, the mcg appeared to be the only statistically accurate formula in patients with bmi - . explained by the difficulty to collect urine output from conventional database. serum creatinine and the use of rrt are often the only two criteria used to define and classify aki. these results confirm the high incidence of aki in icu and pcu and the importance to make an early aki screening of patients for whom preventive nephroprotective actions are needed. introduction: icu-patients with acute kidney injury (aki) requiring renal replacement therapy (rrt) are at risk for infections [ , ] . in this study we evaluated the incidence of infection in icu patients with and without less severe aki. finally, impact on outcomes was explored. this is a retrospective study on the pdms (protection data management system) of the adult icus of a university hospital. aki was assessed on kdigo criteria (creatinine (scr) and urine output), during the first -d of icu stay. infection was validated in the pdms by a team of icu specialists. results: during a -year period, a total of subjects were enrolled. aki was diagnosed in . % of patients during icu stay. aki patients were older ( vs. y, p= . ), had higher saps ( vs. , p< . ), and had more urgent icu admission ( % vs. %, p< . ). more aki patients had mechanical ventilation ( % vs. %, p< . ) and vasopressors on d- ( % vs. %, p< . ). aki stage , , and was present in . %, . % and . % of patients. more aki patients had infection ( % vs. %, p< . ) and increasing aki stages were associated with higher infection rates (aki- : %; aki- : %, aki- : %, aki- : %, p< . ) (figure ). we observed - times higher mortality in aki patients with infection, and a stepwise increase of mortality with increasing aki stages. after correction for infection and other confounders we found that all aki stages were associated with in-hospital mortality (ors aki- : . , aki- : . , aki- : . , all p< . ). over half of aki patients experienced an episode of infection and increasing aki severity was associated with higher infection rate. aki patients with infection had marked higher mortality, suggesting that infection was an important driver of outcome. however, after adjustment, aki stages had strong association with hospital mortality. several new biomarkers have been introduced to improve early diagnosis of acute kidney injury (aki). "nephrocheck" (nc; astute medical, usa) is a bedside test calculating "akirisk" (product of urinary concentration of the cell cycle arrest-markers timp- and igfbp ). several studies suggest the usefulness of nc in selected populations. however, the value of early routine measurement of nc is unclear. methods: therefore, we compared the prediction of a combined endpoint (cep: death < days and/or requirement of renal replacement therapy rrt) by nc within h of icu admission (nc ) and h later (nc ) with admission values of serum-creatinine, bun, cystatin c, urinary ngal, apache ii and sofa (roc-analysis). as a secondary endpoint we investigated the additional value of pathological measurements of nc ≥ . critically ill patients showed increased relative uce in the first days of icu admission, which may be attributed to higher protein catabolism. increased relative uce was associated with arc and both had no effect on -day mortality. introduction: this study compared epidemiology, short-and long-term outcomes for patients with community-acquired (ca) and hospital-acquired (ha) acute kidney injury (aki). we retrospectively analyzed all episodes of aki over a period of . years ( - ) on the basis of routinely obtained serum creatinine measurements in , patients whose creatinine had been measured at least twice and who had been in the hospital for at least two days. we used the "kidney disease: improving global outcomes" (kdigo) criteria for aki and analyzed the first hospital admission. a total of were admitted in hospital and fulfilled the inclusion criteria. average observation period per patient was days. the incidence of ca-aki among included hospital admissions was . % compared with an incidence of . % of ha-aki, giving an overall aki incidence of . %. patients with ca-aki were younger than patients with ha-aki ( vs . y) and had significantly less comorbidities, including preexisting cardiac failure, ischemic heart disease, hypertension, diabetes. patients with ca-aki were more likely to have stage aki ( , vs , %, p< . ) and had significantly shorter lengths of hospital stay than patients with ha-aki ( vs d, p< . ). those with ca-aki had better survival than patients with ha-aki (figure ; p< the evidence base for management of fluid removal during renal replacement therapy (rrt) is limited. a recent international survey revealed the extent of practice variation worldwide [ ] . our aim was to summarise the responses from europe-based healthcare professionals who participated in the survey. the international self-administered, cross-sectional, internet-assisted, open survey was disseminated between january and january via website links and emails to members of different critical care societies. results: participants from european countries completed the survey of whom ( %) were intensivists and ( %) worked in university-based hospitals. persistent oliguria / anuria was the most common indication for fluid removal ( % responders). the parameters which guided fluid removal included hemodynamic status ( % responders), cumulative fluid balance since admission ( % responders), and -hour fluid balance ( % responders). % of participants reported using crrt with a median net ultrafiltration rate ml/hr (iqr - ml/hr) for hemodynamically unstable and a rate of ml/hr (iqr, - ml/hr) for hemodynamically stable patients. only % of practitioners checked net fluid balance hourly ( % nurses, % physicians). new hemodynamic instability, defined as new onset or worsening tachycardia, hypotension, or need to start or increase the dose of vasopressors was reported to occur in % fig. (abstract p ). long-term survival patients (iqr . - . ). different strategies to re-gain hemodynamic stability were used. (figure ) main barriers to fluid removal were patient intolerance ( % physicians, % nurses) and interruptions in fluid removal ( % physicians, % nurses). the majority of participants agreed that guidelines and protocols would be beneficial. the practice of fluid removal during rrt is very variable across european countries. nurses and doctors identified a need for evidencebased protocols and clear guidelines. introduction: kidney disease improving global outcomes (kdigo) guidelines suggest the use of anticoagulation in continuous renal replacement therapy (crrt) [ ] . the effectiveness of the anticoagulation is important because replacing the hemofilter and tube interrupts crrt and increases total therapy time. regional citrate anticoagulation (rca) and unfractionated heparin (ufh) are most commonly using methods for crrt anticoagulation [ ] . the aim of this study was to investigate the efficacy, safety and metabolic differences of the patients in icu who underwent crrt and anticoagulation method changed from ufh to rca for different reasons. after ethics committee approval ( - / ) patients who underwent crrt between - at bursa uludag university hospital icu have been investigated and patients who underwent crrt by both rca and ufh included in the study. we divided patients in two groups (rca, ufh), demographic data (sex, age), sofa score, creatinine, urea, mean filter life time (flt) and ultrafiltration flow (uf), platelets, electrolytes (na, k, ca, mg), lactate, nahco and ph of groups at beginning and ending of first rca and ufh hemodialysis collected. we used t-test and bootstraps statistic tests. in agreement with other studies [ , ] , flt and uf was statistically significant lower in ufh group (table ) . there was no statistically significant difference in efficiency (urea and creatinine decrease), ph, lactate, nahco level, platelets count and electrolytes between two groups. to our knowledge, there are no studies comparing these two anticoagulation methods in the same patients. small number of patients and retrospective evaluation are limitations of the study. our results suggest that the implementation of rca method is safe and effective as ufh method with longer flt and uf. regional citrate anticoagulation during crrt in liver failure mj jain, pk kumar g, dg govil, jk kn, sp patel, ms shafi, rh harne, dp pal, sm monanga medanta the medicity, critical care, gurugram, india critical care , (suppl ):p continuous renal replacement therapy (crrt) with regional citrate anti-coagulation (rca) is increasingly being used as a treatment modality in critically ill patients. there is limited experience of use of citrate anticoagulation patients with acute liver failure and acute on chronic liver failure who pose a tough challenge of being at a higher risk for bleeding. an institutional protocol was formulated for use of commercially available citrate solutions and the same was studied to assess filter life and safety of citrate in liver disease. the primary objective was to assess safety of citrate anticoagulation in liver disease. this study was a single centre, prospective, non-randomized, single arm, observational study. all adult patients, with acute liver failure and acute on chronic liver failure requiring crrt were included. blood ionized calcium levels of . to . mmol/l was targeted throughout the therapy and total to ionized calcium ratio of less than . was maintained. rca was stopped if the ratio was more than . for consecutive assessments. incidence of citrate accumulation and toxicity were assessed. average filter life was also assessed. metabolic parameters, electrolytes and strong ion gap were followed till hours after completion on crrt. a total of patients were included in the study. nineteen patients of acute on chronic liver failure and patients of acute liver failure underwent crrt with rca. baseline average serum bilirubin, lactate and inr were . mg/dl, . mmol/l and . respectively. the average filter life was hours minutes. citrate accumulation took place in (n= ) patients and rca had to be stopped for ( n= ) patients due to the same. none of the patients had evidence of citrate toxicity. citrate anticoagulation was well tolerated in patients with acute liver failure in patients with or without pre-existing chronic liver disease on crrt. introduction: the intention of this study is to highlight the levels of citrate load for the general population that increases the risk of citrate complications (insufficient trisodium citrate delivery; net citrate overload and citrate accumulation) [ ] . this was a prospective data collection between february and march in a fourteen bedded critical care unit. eleven consecutive episodes of crrt were collected (a new episode characterized if crrt was discontinued for hours and above). one episode was excluded due to short duration (less than hours). patients undergoing rca-crrt received either a fixed or ml/kg/h effluent dose protocol. median patient age was , male %. average time on crrt was . days ( - ). % of the patients had complications, although % were minor ( figure ). all of the patients with net citrate overload had citrate loads of . mmol/h or above. the main risk factors were found to be shock and liver impairment which occurred in % of cases of which % developed complications. a fixed dose effluent protocol to standardise practice can potentially lead to a higher risk of minor complications. in our experience this is likely due to a lack of appropriate monitoring for rca-crrt complications. despite this, our complication rate of citrate accumulation is in line with that reported in literature. citrate loads in our ml/kg/ hr protocol were . % higher than our ml/kg/hr protocol and strongly related to higher complication rate that worsened in patients with risk factors for poor citrate metabolism. introduction: there is no optimal timing of continuous renal replacement therapy (crrt) in acute kidney injury (aki); however, it is based on volume overload, azotemia, hyperkalemia and severe metabolic acidosis [ ] . an important reason for metabolic acidosis in aki is increased unmeasured anions (ua) [ ] . delta-ph-ua (Δph ua ) detects the degree of metabolic acidosis caused by ua and is calculated by using 'the partitioned ph model' [ ] . in this study, we investigated whether Δph ua was a predictor to start crrt in patients with aki. the study was designed as a multicentric, prospective, observational study in . patients who were ≥ years old and diagnosed with aki [ ] were included. the moment aki was diagnosed, arterial blood gas, albumin, magnesium, inorganic phosphorus, urea, creatinine and Δph ua values were recorded. all patients were divided into two groups as crrt(-) and crrt(+) which consists of patients performed crrt due to traditional criteria. fig. (abstract p ) . incidence of complications introduction: continuous renal replacement therapy (crrt) is labor intensive and requires advanced nursing knowledge and skills. however, % of registered nurses (rn) are less than -year post-registration experiences in our unit. also there is an increasing demand of crrt from crrt days in to crrt days in . the obstacles for crrt in our department, includes variation of regimen, complicated workflow and insufficient training of nurses. a continuous quality improvement project is carried out to standardize the regimen, enhance workflow and provide structured training to nurses in the intensive care unit, to enhance nursing competence. methods: introduction: sepsis and septic shock is a leading cause of mortality in the intensive care unit. we tried to evaluate a novel hemoperfusion cartridge through a retrospective evaluation of patient's data in our centre. we used it as an adjuvant therapy in our patients with sepsis and septic shock due to varied causes. the aim of this study was to evaluate the efficacy of therapeutic hemoperfusion cartridge (hc-foshan biosun medical ® ) in the management of patients with sepsis. we retrospectively analysed data of group (n= sepsis) and group (n= sepsis+hemoperfusison; sepsis treated with hemoperfusion cartridge) admitted between to . group had received hemoperfusion cartridge as adjuvant therapy along with standard of care. demographic data, procalcitonin [ ] and leukocyte levels before and after therapeutic cytokine removal and duration of hc were recorded. while the mean duration of cvvhdf was . hours, the duration of hemoperfusion cartridge (application was . ± . hours). among patients who survived patients were administered hemoperfusion cartridge within hours of icu admission. there was a significant reduction in scores like apache and sofa score post hemoperfusion cartridge therapy procalcitonin and leucocyte levels after therapeutic hemoperfusion cartridge were found significantly lower than the pretreatment values (respectively p= . , p= . ). retrospective analysis showed significant reduction of vasopressors, and improvement in map in group . therapeutic hemoperfusion cartridge with cytokine removal applied with cvvhdf in septic patients have positive contributions to provide survival advantage. removal of activated leukocytes and endotoxin from the blood is a complex therapeutic effect of the device for removing endotoxin. in the main group ( patients with abdominal septic shock) after surgery, the traditional treatment was supplemented with two sessions of endotoxin removal ( hours each with an interval of hours) using "alteco lps adsorber" (sweden). the control group consisted of patients with a similar diagnosis and only traditional treatment. results: % of white blood cells were adsorbed in lps adsorber. among them, granulocytes ( %) were maximally extracted, then cd + monocytes (cd + mo) ( %), hla-dr + mononuclear cells ( %), monocytes ( %). il- , il- , procalcitonin (pct) were not adsorbed. the -day mortality rate in the main group was % and was lower compared to the control group - %. during monitoring, in the main group hours after the first removal of endotoxin, a decrease in the initially increased amount of activated cd + mo by . times, as well as functionally mature defensin + granulocytes (def + gran) by . times was observed. il- , il- , and pct decreased by . ; . ; and . times, respectively. during this period, the control group showed an increase in cd + mo and def + gran, while il- , il- did not change, and pct increased . times. a day after the second removal of endotoxin and then days later, the main group of il- , il- , and pct continued to decline. in the control group, only il- decreased after days, the rest continued to grow. the cellular adsorption of endotoxin-bound cd + mo and mature def + gran is an important part of the mechanism of action of the endotoxin removal device. does the endotoxin adsorption of pmx column saturate in hours? preliminary study c yamashita in the euphrates trial, the polymyxin b-immobilized fiber column (pmx) hemoperfusion (hp) had no significant effect on -day mortality. endotoxin (lps) burden by endotoxin activity assay > . may exceed μg [ ] , so the dose and duration of pmx-hp could be insufficient to lower the lps burden. to confirm this issue, we experimented in a closed-circuit with h continuous lps addition, and pmx can adsorb > μg [ ] . further, lps concentration became constant within h in the single lps spike test for determining pmx-hp duration [ ] . to prove our hypothesis that the single lps spike test reflects the adsorption equilibrium, and not saturation, we added lps intermittently to reaction. methods: lps ( ng/ml) was mixed with ml deactivated fetal calf serum as a reflux solution, as previously described [ ] ; this concentration is much higher than that observed in septic patients. we created a closed circuit that incorporates pmx- r at / th the amount of an adult pmx and performed pmx-hp at ml/min for h. lps was added in two shots (post h: ng, ng/ml; post h: ng, ng/ml). lps was measured using the limulus amebocyte lysate test at , . , , , , and hr. after an initial decrease between and h, lps concentration did not decrease between and h after pmx-hp initiation. post lps pulse addition at h, it increased and then decreased till h. futher, it did not decrease between and h, but it increased and then decreased again after lps pulse addition post h (figure ). lps adsorption rates were . , . , and . % at , , and h, respectively. conclusions: lps adsorption capacity of pmx- r was maintained even after two additional shots of lps, suggesting that the constant lps concentration in the previously reported lps spike test might be indicative of adsorption equilibrium rather than saturation. a coohort study included patients admitted to three intensive care with sepsis / septic shock ( sepsis criteria ) and aki ( akin score). all patients were submitted to cvvhdf with the oxiris filter (baxter, usa) . the main clinical data, il , procalcitonin, endotoxin ( eaa ) and sofa score were evaluated at basal time ( t ) and at the end of the treatment ( t ). all data are expressed as mean ± sd or median and iqr . anova test was used to compare the changes in the time. results: patients were submitted to rrt with the oxiris filter for ± hours . patients had aki stage , patients aki stage and patients had aki stage. at t all groups had an high vasopressor fig. (abstract ) . lps concentration in lps pulse addition test support to maintain map ≥ mmhg. il , procalcitonin eaa and sofa total were also elevated with no difference between the groups. at t creatinine improved better in aki ( p< . vs. t ) and in aki ( p< . vs t ) then in aki group. map increased in aki ( p< . vs t ) and aki ( p < . vs t ) , but not in aki group. il , procalcitonin decreased more in aki ( p < . vs t ) then aki . at t sofa total was higher in aki then aki ( p< . ) and aki ( p< . ). conclusions: aki and aki stage patients submitted to bp with the filter oxiris respond better then aki stage patients . -this transalte in a better clinical course. -crrt with oxiris filter is useful in septic patients with aki, but aki stage septic patients represent an high risk group. a non-interventional, multicenter, non-randomized patient registry for multiple organ dialysis with the advos system multiple organ failure is a challenging problem in the icu. as an advanced dialysis system, the advos procedure can eliminate watersoluble and protein-bound substances, regulate the acid-base balance as well as fluid and temperature. in , a national registry was established to collect data under "real-life" conditions of patients treated with advos without any trial-specific interventions (drks id: drks ). methods: data from / to / from german hospitals (university hospitals in hamburg-eppendorf, mainz, essen, and klinikum weiden) were analyzed. clinical parameters, treatment settings and adverse events were documented. the -and -day mortality rates were compared with extrapolated rates based on the sofa score. results: patients with a median age of years (iqr - ), of whom ( %) were male, were evaluated. patients had a median sofa score of (iqr: - ) before the st advos treatment, which is associated with an expected mortality of %. the number of failing organs was (iqr - ): cardiovascular ( %), lungs ( %), liver ( %), kidneys ( %), coagulation ( %) and cns ( %). treatments with a median duration of (iqr: - ) hours were evaluated. were discontinued, of which ( %) were due to a device error. adverse events were documented, were related to the device (all due to clotting and recovered without sequelae). significant removal of protein-bound (bilirubin: . vs . mg/dl) and water-soluble toxins (bun vs and creatinine . vs . mg/dl). in addition, improvement in acid-base balance was observed: ph ( . vs. . ), bicarbonate ( . vs. . mmol/l) and base excess (- . vs. . mmol/l) ( table ) . -and -day mortality rates were % and %, respectively. in a cohort of patients with multiple organ failure, we observed an improvement in the expected mortality rate, especially if the advos procedure was applied early. adverse events are comparable to other dialysis therapies in intensive care patients. introduction: acute kidney injury (aki) due to ischemia-reperfusion affects onethird of the patients in cardiac surgery. we investigated the potential role of cyclosporine (csa) to prevent postoperative aki and mitigate inflammatory response to extracorporeal circulation (ecc). methods: double-blind, randomized, placebo-controlled single-center study. patients (n= ) scheduled for elective cardiac surgery were randomized to , mg/kg csa or placebo before the surgery. the primary objective was to assess the role of csa to reduce the incidence of postoperative aki. the secondary objective was to study csa induced changes in the inflammatory response to ecc. results: all enrolled patients were analyzed. postoperative aki was more pronounced in the cyclosporine group compared to placebo. or= . ( . - . ), % ci. the cytokine production in response to ecc was not affected by cyclosporine (figure ) . in patients undergoing cardiac surgery, a single preoperative dose of csa does not prevent the postoperative decrease in renal function. csa does not alter cytokine release in response to extracorporeal circulation. elevated post-ecc levels of pro-inflammatory cytokine il- are associated with kidney dysfunction and may be predictive. new generation adsorbent such as oxiris r was introduced as novel technique in renal support for critically ill patients [ ] . septic shock patients require decatecholaminization strategies emphasizing blood purification to remove catecholamine-producing mediators and evacuate overload fluid in interstitials. our -year-old female patient, admitted to icu after surgery with history of ovarium cancer. her septic shock was worsened with ards, hypercoagulable state and aki. vasopressors were set. patient was controlled with mode simv ,ps ,tv ml,peep ,fio %. renal support was implemented by diuretic and cvvh started on the second day. at first,regular adsorbent was used, post-filter mode was set, and periodic fluid removal target was ml/h. but after hours, no significant changes observed. oxiris r added and after hours passed, requirements of vasopressors reduced, tidal volume increased, hemodynamic parameters stabilized, urine production increased. it was continued for days and patient was recovered. our patient had fallen into inadequate cars stage in which not able to counter septic effects on vital organs (figure ). renal would be primary target for filtration and monitoring tool. adsorbent consisted of an and polyethyleneimine was useful to purify blood from endotoxins conjoined with slower filtration. continuous yet cautious process in cvvh evacuate fluid and mediators while maintain steady hemodynamics. biomarkers could not be evaluated due to limited resources, but improving parameters could be signs that showed recovery process had already took place. advanced hemofiltration is a privilege. implementing and enhancing it with new generation adsorbent would increase survivors by extracting unnecessary fluids and eliminating catastrophic endotoxins and mediators. consent to publish: written informed consent for publication was obtained from the patient. analysis of retrospective cohort study data of patients (pt) treated for dka at icu of kaunas clinics during - has been carried out. serum kalemia, glycemia; hypokalemia, hypoglycemia episodes; rate of insulin interruption for hypo-and normoglycemia during ketoacidosis; use of nah co for ketoacidosis, and los in icu were analysed. spss . was used for statistic calculations. traits evaluated as significant at p < . . at the beginning of dka treatment in totally hypokalemia ( . ± . mmol/l) was recorded in / pt ( . %). due to ignoring of blood ph ( . - . ( . ± . ) kalemia was falsely misinterpreted as "normo-" or "hyper-" . - . ( . ± . mmol/l) in / pt ( . %), thus disregarded so complicated by obvious hypokalemia additionally in / pt ( . %). in hypokalemia los in icu was . ± . vs . ± . h, p < . . insulin use has caused hypoglycemia ( . - . ( . ± . mmol/l)) in / pt ( . %), los in icu . ± . vs . ± . h, p < . .insulin use was interrupted in case of normoand hypoglycemia with still persisting ketoacidosis in / pt ( . %), los in icu was found to be . ± . vs . ± . hr, p < . . nah co was given for symptomatic treatment of ketoacidosis during first h of dka in / pt ( . %) with stable hemodynamic: hco - buffer has increased ( . ± . - . ± . mmol/l), p < . , but it didn't control ketoacidosis, and los in icu was . ± . . vs . ± . h, p < . . hypokalemia, hypoglycemia, precocious interruption of insulin use were recorded as complications of dka treatment. all of them have prolonged los in icu. symptomatic treatment of ketoacidosis with nah co had no effect on it, and prolonged los in icu as well. a growing interest exists about co derived parameters in shock management. central venous-arterial pco difference (p cv-a co ) is strictly related to cardiac output; central venous-arterial pco difference to arterial-central venous o content difference ratio, p cv-a co / c a-cv o , has been proposed as anaerobic metabolism when it's > . mmhg/ml [ ] . to evaluate p cv-a co /c a-cv o reliability in detecting anaerobic metabolism, we analyzed it in consecutive patients affected by mala admitted to our icu, considering these patients as a prevalent anaerobic metabolism model. we calculated, by douglas formula, central venous-arterial co content difference to arterial-central venous o content difference ratio, c cv-ca co /c a-ccv o , as a respiratory quotient surrogate. we performed arterial and central venous blood gas analysis simultaneously at admission, we calculated p cv-a co , p cv-a co /c a-cv o and c cv-a co /c a-cv o and we recorded scvo . we verified relationship between p cv-a co /c a-cv o and scvo and arterial ph, arterial lactates, sofa score at admission and c cv-a co /c a-cv o by linear regression analysis. pcv-aco /ca-cvo greatly increases in mala ( . ± . ). pcv-aco / ca-cvo (fig. ) shows significant co-variation with ph (r = . ; p= . ) and sofa score at admission (r = . ; p= . ). pcv-aco / ca-cvo has poor agreement with ccv-aco /ca-cvo (r = . ) and disagrees with it in identifying anaerobic metabolism, in our series, in fact, ccv-aco /ca-cvo is, in patients, < like an aerobic rq value. pcv-aco /ca-cvo shows better agreement with ph, sofa score and lactate level than scvo . in our series, p cv-a co /c a-cv o is good illness and acidosis severity marker, but it seems to be affected by ph value in accord with haldane effect [ ] . p cv-a co /c a-cv o , in our study, doesn't seem to be a reliable anaerobic metabolism marker nor a rq surrogate. it is thought that early administration of basal insulin to patients with diabetic ketoacidosis (dka) may improve outcomes. small studies have shown trends towards decreases in time to closure of anion gap (tcag), rates of rebound hyperglycemia following discontinuation of intravenous (iv) insulin, rates of hypoglycemia, intensive care unit (icu) length of stay (los), and hospital los [ ] [ ] [ ] [ ] . this was a single-center, retrospective chart review of our institution's dka protocol between january and august . patients that received early basal insulin within hours of initiation of iv insulin and before closure of the anion gap (ag) were compared to those that did not receive early basal insulin. the primary outcome was median tcag. secondary efficacy outcomes include: time on iv insulin infusion, time to de-escalation of level of care, hospital los, and re-elevation of ag. secondary safety outcomes included incidences of hyperglycemia, hypoglycemia, and hypokalemia. a total of patients were identified meeting inclusion and exclusion criteria. median tcag was longer in the experimental group ( vs. hours, p < . ). incidence of re-elevation of ag and incidence of hyperglycemia were lower in the experimental group. other outcomes were similar (figure ). early administration of basal insulin to patients with dka resulted in a longer tcag with a lower incidence of re-elevation of ag and hyperglycemia. early administration of basal insulin appears to be safe with respect to hypoglycemia and hypokalemia. glycaemic control continues to be a challenge in critically ill patients. stress induced hyperglycaemia has been associated with increased morbidity and mortality [ ] . conversely, patients receiving intensive glucose control have a higher risk of death [ ] . a quality improvement project was designed to develop a comprehensive insulin protocol that recognized pre-existing diabetes and reduced hypoglycaemia. data was collected prospectively in all adult patients admitted to the rah intensive care unit (icu) between october and august from the national icu audit database and electronic patient records. daily figures were collected for numbers of hypoglycaemic episodes (< mmol/l), "in range" ( - mmol/l) blood sugar measurements and patients with a pre-existing diagnosis of diabetes. data was collected and analysed using microsoft excel. results: patients were identified; patients ( . %) had pre-existing diabetes. a total of blood sugar measurements were reviewed; ( . %) were "in range" and hypoglycaemic episodes ( . %) occurred. there was no significant correlation between number of diabetic patients and measurements within range. of note, there was an increase in number of measurements per patient in the second half of the time period ( vs ). the development of this protocol has improved glycaemic control in our icu. there are considerably fewer episodes of hypoglycaemia and a large proportion of blood sugar measurements are in range. we hope to continue data collection and interrogate the prevalence of pre-existing diabetes further to reduce glycaemic variability. the optimal management of blood glucose levels for critically ill patients remains unclear. hypoglycemia, hyperglycemia and glycemic variability are associated with mortality. the time in targeted blood glucose range (tir) has been suggested to correlate with mortality depending on the status of antecedent glycemic control, but it has not been verified optimal tir and whether there is an optimal disease-specific tir. a retrospective observational study was performed at a single center. in the present study, we enrolled all critically ill patients admitted in intensive care unit from january to october. patients with diabetic ketoacidosis or hyperosmolar hyperglycemic syndrome and patients who had < blood glucose readings were excluded. gathered information included, in part, demographics, comorbidities, severity of illness scores, diagnosis at admission, length of icu stay and hospital discharge status. the primary outcome was -day mortality. we analyzed to find the optimal tir for critically ill patients. several tirs were each tested for correlation with mortality. a total of , patients, . % of whom had diabetes, were studied. tir to mg/dl (or, . ; %ci, . - . ), tir to mg/ dl (or, . ; %ci, . - . ) and tir to mg/dl (or, . ; %ci, . - . ) > % was independently associated with mortality in critically ill patients respectively. the optimal tir did not differ depending on diagnosis at admission. in this retrospective evaluation, tir to mg/dl > % was independently associated with mortality in critically ill patients, especially those with good antecedent glucose control. these findings have implications for the design of future trials of intensive insulin therapy. the prevalence of chronic dysglycemia (diabetes and prediabetes) in patients admitted to swedish intensive care units (icus) is unknown. we aimed to determine the prevalence of such chronic dysglycemia and asses its impact on blood glucose control and patient-centred outcomes in critically ill patients. in this retrospective, observational study, we obtained routine glycated hemoglobin a c (hba c) measured in patients admitted to four tertiary icus in sweden between march and august . based on previous diabetes history and hba c we determined the prevalence of chronic dysglycemia (prediabetes, undiagnosed diabetes and known diabetes). we compared indices of acute glycemic control in the icu and explored the association between chronic dysglycemia and icu-associated infections, mechanical ventilation, renal replacement therapy, vasopressor therapy, and mortality within days. of patients, ( %) had chronic dysglycemia. of these patients, ( %) had prediabetes or undiagnosed diabetes and fig. (abstract p ) . results ( %) had a known diabetes diagnosis. during icu stay, patients with chronic dysglycemia had higher average blood glucose, spent less time in target glucose range, had greater glucose variability, and were more likely to develop hypoglycemia than patients without chronic dysglycemia. chronic dysglycemia was associated with greater need for renal replacement therapy (odds ratio . , % ci . - . ) and increased -day mortality (hazard ratio . , % ci . - . ) after adjustment for simplified acute physiology score . in contrast, chronic dysglycemia was not associated with mechanical ventilation, vasopressor therapy, or icu-associated infections. in four tertiary swedish icus, measurement of hba c showed that / of patients had chronic dysglycemia (prediabetes or diabetes). chronic dysglycemia was associated with marked derangements in glycemic control during icu stay, greater need for renal replacement therapy and with increased mortality at days. case report: modern antidiabetic therapie causes ketoacidosis am heiden, m emmerich krankenhaus bad oeynhausen, institut für anästhesie, bad oeynhausen, germany critical care , (suppl ):p the modern antidiabetic class of sglt -inhibitors, that are known to reduce the risk for cardiac events [ ] , are increasingly used in the last few years. a -year old male patient with diabetes mellitus suffered days after colectomy surgery from abdominal pain and nausea. the patient had an antidiabetic therapy with empaglifozin that was paused until day after surgery (nutrition start on day , weaning on day ). methods: this is a case report of one male patient seen in the icu setting. daily blood values including arterial blood gases, vital parameters and clinical status of the patient were observed and evaluated. the blood gases showed this metabolic acidosis: ph . ; pco . mmhg, bicarbonate mmol/l, be - . mmol/l, lactate . mmol/l, glucose mmol/l. a ketonuria despite normal blood glucose values was noticed, so that the diagnosis of ketoacidosis was clear. after analyzing the possible causes we found out, that empaglifozin in times of catabolism and fasting can cause this severe symptomatic. we terminated the therapie with empaglifozin and under the treatment with insulin the symptoms disappeared within days and the patient could be discharged from the icu on day after surgery. after one episode of ketoacidosis the therapy with sglt -inhibitors should lifelong never be started again. we recommend that intensivists should be aware of the modern sglt -inhibitors because of the shown severe complications and the increased use of this medication. consent to publish: written informed consent for publication was obtained from the patient. while obesity confers an increased risk of death in the general population, numerous studies have reported an association between obesity and improved survival among critically ill patients. this contrary finding has been referred to as the obesity paradox. this retrospective study uses two causal inference approaches to address whether the survival of non-obese critically ill patients would have been improved if they had been obese. the study cohort comprises , adult critically ill patients hospitalized at the intensive care unit of the ghent university hospital between and . obesity is defined as a body mass index of ≥ kg/m . two causal inference approaches are used to estimate the average treatment effect in the untreated (atu): a naive approach that uses traditional regression adjustment for confounding and that assumes missingness completely at random, and a robust approach that uses super learning within the targeted maximum likelihood estimation framework and that uses multivariate imputation of missing values under the assumption of missingness at random. obesity is present in . % of patients. the in-hospital mortality is . % in non-obese patients and . % in obese patients. the marginal associational risk difference for in-hospital mortality between obese and non-obese patients is - . % ( % confidence interval (ci) - . % to . %, p= . ). the naive approach results in an atu of - . % ( % ci - . % to - . %, p= . ), whereas the robust approach yields an atu of - . % ( % ci - . % to . %, p= . ). a robust causal inference approach that may handle confounding bias due to model misspecification and selection bias due to missing data mitigates the obesity paradox, whereas a naive approach results in even more paradoxical findings. the robust approach does not provide evidence that the survival of non-obese critically ill patients would have been improved if they had been obese. bowel management within an icu environment is often difficult. recent data collection from an intensive care unit at the rvi identified either loose stool or constipation on > % of patient days. it was postulated this could be improved with a more tightly controlled bowel management regimen. to test this hypothesis a step-wise bowel protocol was created and introduced. data was collected in the month period following its implementation with the following aims: ) assess effectiveness of the protocol ) further observe the reasons for loose or constipated stool on an diarrhea is an important problem in each critically ill pateints [ ] . we aimed to investigate the frequency and management of diarrhea in our icu. in this study patient retrospectively reviewed, in our icu between . . - . . . patients were divided into two group as diarrhea "positive" and "negative". patients with diarrhea had fluid or loose stools or more times a day. each diarrhea period of the patients with diarrhea was examined separately and compared with the group without diarrhea. nutritional status, enteral product formulation, leukocyte, neutrophil, albumin values, gastric sparing, antibacterial and antimycotic use, los in hospital and in icu were compared. in diarrhea positive group, on the day of hospitalization, laxative and/or enema administration, toxin a in stool, nitrogen balance before and after diarrhea, enteral product change in diarrhea, probiotic, metronidazole or oral vancomycin use were examined. the incidence of diarrhea was . %. the most common diagnosis of icu admision was respiratory failure ( - %) in both groups. diarrhea occurred in two days after laxative and/or enema treatment. enteral nutrition was higher in both groups (≥ %). nasogastric tube feeding was significantly higher in the diarrhea group (p= . ). there was no difference between nutritional product formulation and diarrhea development (p> , ). antibacterial use was high in both groups ( %); however, teicoplanin use was significantly higher in the group diarrhea negative group (p= . ). the los in icu, and hospital was higher in diarrhea group (p< . ). no difference in mortality rates (p> . ). many factors may cause diarrhea in icu, and diarrhea may adversely affect patient treatment and increase morbidity. we think that preventive methods are as important as the treatment of diarrhea. the use of parenteral glutamine is studied in number of rcts and systemic reviews (heyland d , wischmeyer p ), while there is a lack of data about the use of enteral glutamine. the aim of our study was to determine the effect of enteral glutamine supplementation on the incidence of hospital infections and death. design: retrospective cohort study. inclusion criteria: males and females > years of age, tbsa burned %- %, nasogastric intubation.patients were divided in two groups: glutamine group (n= ) and control group (n= ). in the study group enteral glutamine was administered to the patients for days after admission to the icu. baseline characteristics were well balanced between groups. no significant difference was found between groups on patients' age, sex, tbsa, need for mechanical ventilation and rate of inhalation injury. primary outcome was all-cause mortality. secondary outcome was rate of nosocomial infections (skin and skin structure infections (sssi), lower respiratory tract infections, urinary tract infections, bacteremia, sepsis). mortality rate was ( %) and ( %) in the glutamine group and the control group, respectively, p= . . rate of nosocomial infections was ( %) in the glutamine group and ( %) in the control group, respectively, р= . . rates of sssi, lower respiratory tract infections, urinary tract infections and sepsis did not differ significantly between the groups: ( %) and ( %), p= . ; ( %) and ( %), р= . ; ( %) and ( %), р= . ; ( %) and ( %), р= . , respectively. rate of bacteremia was significantly different between the groups: ( %) in the glutamine group and ( %) in the control group, p= . . retrospective design is a significant limitation of our study. enteral glutamine supplementation may reduce the incidence of bacteremia in burn patients, but has no influence on the incidence of other nosocomial infections and mortality. further large clinical trials are needed. with outcomes were assessed with multivariable logistic regression and cox proportional hazard analyses, adjusted for baseline risk factors and randomization. in sensitivity analyses, models were further adjusted for key regulators of ketogenesis to assess whether any effect was direct or indirect. late pn increased plasma hb as compared with early pn, with maximal effect on day (p< . for day to and for the "maximal effect" day in the patients). adjusted for baseline risk and randomization, plasma hb associated with a higher likelihood of earlier live weaning from mechanical ventilation (p= . ) and of earlier live picu discharge (p= . ). as plasma hb replaced the effect of the randomization, the hb effect statistically explained these benefits of the randomization. further adjustment for key regulators of ketogenesis did not alter these findings. plasma hb did not independently associate with the risk of infections and mortality. withholding early pn increased ketogenesis in critically ill children, an effect that statistically mediated part of its clinical benefits. critical care patients are prone to frequent feeding interruptions for various reasons including feeding intolerance. these interruptions can lead to adverse outcomes. the aim of the study was to determine the reasons for and the duration of interruptions of enteral nutrition (en). single-center observational, cross-sectional study in a -bed mixed icu of a tertiary hospital. duration: months. patients, aged . years old (± . ), that stayed in the icu > hrs and were fed with en were included. anthropometric data, bmi, time of initiation of prescribed en, type of en formula, daily calories delivered were recorded. energy intake was calculated according to espen guidelines ( kcal/ kg bw/day). the causes for and duration of interruption were reviewed from the patient's chart. apache ii and mnutric score was calculated for all patients. mnutric score ≤ was used to diagnose malnutrition. all patients included in the study were endotracheally intubated. apache ii was . ± . . % of patients had increased risk of malnutrition. icu stay was . ( . ± . ) days, and the in-hospital mortality was %. there were episodes of en interruptions over a median icu stay of . days. median . interruptions/patient. the most common reason for en interruption was gastric residual volume monitoring followed by diagnostic and therapeutic procedures (figure ). other reasons include surgery, intolerance and/or delayed feeding and extubation. the median lost feeding time was . hours/ day ( . - . ) for all causes, while the mean loss of total energy intake was kcal/day (± )/day. average body weight of the patients was kg (± ). caloric deficit was calculated at kcal/day or % of the prescribed caloric goal. the results of this study showed that interruptions can lead to substantial caloric deficit, malnutrition and adverse events. an interruptionminimizing protocol could be useful in order to reduce the missing hours and to improve the clinical outcomes. relationship of goal-directed nutritional adequacy with clinical outcomes in critically ill patients pc tah there are controversies surrounding the effects of optimal nutritional intake on clinical outcomes in critically ill patients. this study aimed at investigating the relationship of goal-directed energy and protein adequacy on clinical outcomes which includes mortality, intensive care unit(icu) and hospital length of stay (los), and length of mechanical ventilation (lomv). this was a single centre prospective observational study. nutritional requirements were guided by indirect calorimetry and -h urinary urea.nutritional intake was recorded daily until death, discharge, or until day of icu stay. clinical outcomes were collected from patient's hospital record. the relationship between the two groups (< % and ≥ % of overall nutritional requirement) with mortality outcomes was examined by using logistic regression with adjustment for potential confounders. terlipressin, despite being one of the main treatments for acute variceal bleeding, may lead to severe hyponatremia due to its antidiuretic activity.we aimed to identify risk factors for development of hyponatremia during terlipressin treatment. retrospective study of patients admitted to acute intermediate care unit for hypertensive upper gastrointestinal bleeding due to chronic liver disease who received terlipressin(december -decem-ber ).hyponatremia was defined as a decrease in na serum levels ≥ meq and severe hyponatremia as > meq within days of treatment. we studied patients, . % male, mean age of . years (sd . ). alcohol-related liver disease was the most frequent etiology. hyponatremia occurred in patients ( . %). serum na Δbetween - and - meq and serum na Δ>- meq occurred in . and . %, respectively (table ) . severe hyponatremia occurred in patients ( . %) and symptoms were reported in two cases (status epilepticus and altered mental status). patients with higher baseline levels of na were more susceptible to terlipressin-induced hyponatremia and a longer length of stay was observed in patients with serum naΔ>- meq ( . vs . days, p< . ). the prevalence of hyponatremia in our study was lower than previously reported.higher serum na at admission and aih as etiology of cirrhosis were predictors of terlipressin-induced hyponatremia. neither the cumulative dose of terlipressin nor the duration of treatment appear to be related to the development of hyponatremia a Δ h-[na] > mmol/l was associated with larger hazards of mortality ( figure ). an increase in serum sodium in the first hours of icu admission is independently associated with a higher mortality in patients admitted with mild hyponatremia, normonatremia, and hypernatremia. based on our findings, it is possible that mild hyponatremia may be a protective mechanism in critical illness, which questions common practice of routinely correcting serum sodium when it is too low. introduction: acute liver failure (alf) represents a life-threatening organ dysfunction associated with increased mortality and liver transplantation represents the only definitive treatment. the aim of this study was to assess the effects of renal replacement therapy in combination with hemoadsorption in alf patients. twenty-nine patients with alf admitted to the intensive care unit (icu) of fundeni clinical institute were included in the study. after icu admission, consecutive session of hemoadsorption in combination with continuous veno-venous hemodiafiltration were applied. number of organ dysfunctions and sirs criteria were recorded at icu admission. the following data were recorded before and after the hemoadsorption therapies: glasgow coma scale, pao /fio , creatinine, -hours urine output, bilirubin, leucocyte and platelet count, heart rate, mean arterial pressure and vasopressor support, c-reactive protein and procalcitonine. clif-sofa score was calculated before and after the therapy. icu length of stay and -days outcome were noted. the mean age in the study group was ± years. the median number of sirs criteria was [ , ] and the median number of organ dysfunctions was [ , ] . the use of hemoadsorption was associated with a decrease in creatinine (from . ± . to . ± . mg/dl, p= . ), bilirubin (from . ± . to . ± . mg/dl, p= . ) and platelet count ( ± / ul to ± /ul, p= . ). we also observed a decrease in clif-sofa score from . ± . to . ± . (p= . ). overall mortality was . % (n= ). six patients ( . %) underwent liver transplantation with % -days survival. the use of hemoadsorption in patients with alf is associated with improvement in liver and kidney functional tests and may represent a new therapy in bridging these patients to liver transplantation. introduction: impairment of intestinal mucosal barrier function is the initiating factor of sepsis. in order to explore the effect of lactic acid bacteria on intestinal barrier function impaired by sepsis, it is necessary to establish sepsis and lactic acid bacteria ecological models. however, how to construct these models is still unclear. co-cultures with a gradient of lactic acid bacteria and caco- cells were constructed. the symbiotic state was observed under an inverted microscope and lactate dehydrogenase (ldh) toxicity tests, transepithelial electrical resistance(teer) tests and western blots were used to determine effective concentrations of lactic acid bacteria in monolayer cell models. lipopolysaccharide (lps) was used to treat cells, and cell counting kit- , quantitative reverse transcription pcr(rt-qpcr) and enzyme linked immunosorbent assays (elisa) were used to determine the appropriate concentration for sepsis models. the number of living cells decreased significantly when the moi(number of lactic acid bacteria/cell number) reached ( figure , panels a, b). the release of ldh indicated that damage to cells began to increase when the moi exceeded (panels a, b). at an moi of . , resistance values began to increase over time, whereas resistance values began to decrease when the moi reached (panel ). as the number of lactobacilli increased, the expression of tight junction protein increased and then decreased (panel a, b, c). in sepsis model experiments, the cell survival rate began to decrease once the concentration of lps exceeded ^ ng/ml (panel ). rt-qpcr results showed that ng/ml lps significantly increased inflammatory cytokines (panel ), and elisa results consistently showed that tnf-α and il- increased significantly when lps concentrations reached ng/ml (panel a, b). it is feasible to construct a cell monolayer model of lactic acid bacteria and lps. the appropriate moi of lactic acid bacteria is . and the optimal concentration of lps is ng/ml. introduction: sepsis is associated with high mortality and morbidity. as the severity increases, physiological parameters such as ph changes are one of the most notable features in metabolic acidosis secondary to high lactate. currently there is no point of care test other than blood gas measurement that could detect these ph changes. this is challenging especially in prehospital environment. the aim of this study is to develop a novel rapid point of care testing using a sensor to detect ph change in blood. sensors were produced by screen printing graphene and silver electrodes and functionalizing the graphene working electrode with an active layer of melanin. a preclinical sensor model was produced by adding lactic acid to a citrated plasma sample thus altering its ph over a clinically relevant range. the ph sensors were exposed to modified plasma, recording any changes in the voltage. the relationship between the voltage potential and plasma ph was established using weighted least squares regression. a ph dependent change in the measured voltage, with respect to the ph of the solution, was observed with a sensitivity of - . mv/ph +/- . over a physiologically relevant ph range between ph . and ph . . in this first phase proof of concept study a low cost, ph sensor was fabricated and demonstrated to be effective in measuring the ph of the plasma. this is the first time that such a sensor has been demonstrated and validated to work in this preclinical model of acidosis. the technology demonstrated here is a promising candidate for a point of care test whereby abnormal blood ph levels can be detected and monitored outside of a laboratory environment in a rapid manner. further studies are now underway to detect this change in whole blood. (figure ) . over one year only a small proportion of patients (n= , %) were classified as 'intermediate high' risk and potential candidates for reperfusion therapies. the revised national early warning score (news) with modified glasgow prognostic score (mgps) is superior to the news for predicting in-hospital mortality in elderly emergency patients t mitsunaga jikei university school of medicine, emergency medicine, tokyo, japan critical care , (suppl ):p the national early warning score (news) was developed in the ukto identify the risk of death. the previous study showed that the modified glasgow prognostic score (mgps) correlate with frailty in elderly patients [ ] . the aim of this study is to evaluate the predict value of the revised news with mgps for in-hospital mortality (in days) in elderly emergency patients. this study is secondary analysis and was carried out in jikei university kashiwa hospital, in japan, from april to march . the acute medical patients aged and older were included. the news was derived from seven physiological vital signs. the mgps was derived from c-reactive protein (crp) and albumin. discrimination was assessed by plotting the receiver operating characteristics (roc) curve and calculating the area under the roc curve (auc). the aucs for predicting in days in-hospital mortality were . for revised news with mgps and . for the original news. the auc of the revised news with mgps was significantly higher than that of the original news for predicting in-hospital mortality (p < . ) (figure ) . our single-centred study has demonstrated the utility of the revised news with mgps as a high predictor of acute phase in-hospital mortality in elderly emergency patients. the diagnostic performance of the five main emergency department (ed) triage systems has been shown to be poor in distinguishing acute coronary syndromes (acs) from mild severity diseases in chest pain patients. these ed triage systems are either clinically-based, being more sensitive or ecg-based, more specific [ ] . the goal of the study was to evaluate if incorporation of cardiovascular risk factors (cvrf) into ecgbased triage could increase his diagnostic performance. cecidoc is a prospective, observational, single-center study in an academic hospital. all consecutive adult patients admitted for acute chest pain were included. we compared the ecg-based french triage system [ ] to a modified system upgrading patients with a normal ecg but significant cardiovascular risk from a low acuity triage score (waiting period before medical assessment of max. min.) to a high acuity triage score (waiting period before medical assessment of max. min.). the final diagnosis was determined after a -day follow-up. we predefined as being adequate a high-acuity triage score (level or ) for acs and a low-acuity score (level , or ) for mild severity diseases. a total of patients was enrolled over a -month period (age . ± . ; m/f ratio . ). triage scores of patients ( . %) with acs were compared to patients ( . %) with mild severity diseases. taking into account cvrf, the sensitivity of the triage system increased from to % whereas the specificity decreased from to %. area under the roc curve (auc) went from . to . (fig. ) . for chest pain triage at ed, addition of cardiovascular risk factors into ecg-based triage increases his diagnostic performance. approximately % of patients presenting to hospital with an intentional overdose require admission to an intensive care unit (icu) [ ] . there are currently no uk guidelines regarding the optimal use of ct head scans (cth) in this patient cohort [ , ] . this study aims to determine whether we should be performing ct head scans in obtunded patients with suspected overdose requiring admission to intensive care. we performed a retrospective search of the icnarc database for plymouth university hospital trust, looking for patients admitted to the icu with overdose or self-poisoning as a primary diagnosis. patients were identified and of these patients required intubation due to obtundation(gcs< ). there were males and females with an average age of years old. the median length of stay on the unit was day. of the patients has a past medical history of mental illness, and overdosed on prescribed medications. the average gcs recorded on admission was . of the ( %) patients had a cth on admission, of which were part of a trauma scan. were known overdoses and were suspected overdose as per the cth request form. the main rationale behind those requests were to exclude additional intracranial injury. none of those cth showed any signs of acute pathology (figure ) . in this retrospective study, obtunded patients with suspected or known overdose with no history of apparent trauma or injury do not benefit from cth. in the absence of a history of trauma or focal neurological signs our conclusions are that cth provides limited value in the management of these patients. the audit was carried out to objectively investigate the problems associated with technique of folley catheterization in emergency department and indoor units of internal medicine wards [ ] . introduction: cellular and molecular mechanisms, epigenetic aspects of acute clozapine poisoning are studied insufficiently. the aim of this study was to identify morphological and epigenetic alteratons in brain neurons during acute exposure to clozapine combined wit ethanol. the experiments were carried out on male wistar rats weighting - g (n= ). group i (control) received . % nacl solution enterally; group iiclozapine mg/kg in . % nacl solution; group iiiclozapine mg/kg in % ethyl alcohol. after hours euthanasia was performed. autopsy included withdrawal of brain samples for histological examination (n = ) and for determination of global dna methylation level (n = ). the global dna methylation level ( -mc%) was determinated by fluorimetric method. inter-group comparisons were made by kruskal-wallis test. histological examination of paraffin sections of brains stained with hematoxylin and eosin was performed by light microscopy. in acute сlozapine poisoning and its combination with ethanol morphological changes in neurons of the cerebral cortex were detected. in acute сlozapine with alcohol poisoning an increase of global dna methylation level was observed. probably the identified changes have a common pathogenesis which will be clarified in our further studies. there is limited information available regarding the prevalence of adder bites and the complications of envenomation. nhs data suggests there are adder bites annually in the uk with the last fatality in [ ] . we performed an audit into adder bites in south west wales to identify the number attending our emergency departments, their management and clinical course as well as any environmental factors that predict increased likelihood of being bitten or the severity of the bite. a retrospective study of adder bites attending emergency departments in south west wales was undertaken (jan to aug ). measurements included were patient demographics, clinical presentation, type of treatment (conservative vs anti-venom) and outcome. results: patients were included, age range - years ( figure ). the majority of bites occurred in sand dunes ( . %) and all bites were on extremities. anti-venom was administered to . % ( / ) of patients. there was a significant positive association between the use of anti-venom and the length of hospital stay (r = . ; p= . ) and a significant negative correlation between the anti-venom use and both diastolic and systolic blood pressure (p= . and . respectively p= . ). all patients fully recovered. in this study, we demonstrated that with a full clinical assessment on presentation it is safe to decide whether anti-venom is required. the current guidelines are safe and effective in the treatment of adder bites. μmol/l, for pao < . kpa and > . kpa, platelets < * ^ /l and > * ^ /l, and bilirubin > μmol/l. in our population of adult ed patients, the thresholds of vital values associated with increased -day mortality were very close to routinely used values, and most of the thresholds were included in the lowest urgency level in triage and risk-stratification scoring systems. the workload in the emergency room: direct assessment by the therapeutic intervention scoring system- and indirect assessment by the nasa task introduction: the number of emergency room admissions continues to increase each year, which increases the care workload of the emergency department staff, who should to use its theoretical and practical knowledge in order to provide quality care in difficult working conditions. the aim of our study was to assess the emergency room staff workload its impact on health workers and patients and to suggest an improvement strategy to decrease this workload. a prospective, monocentric cohort study with descriptive and analytic approach over one month (december ) conducted at the emergency department of an academic hospital. the workload endured by the emergency room staff was evaluated by the nasa task load index and on patients by the therapeutic intervention scoring system- . there were cumulative days of hospitalization in consecutive patients admitted to the emergency room. the average age was ± years. the average length of stay at the emergency room was about ± h. the average tiss- score was . ± . . factors associated with important care workload were: age ≥ years, diabetes, more than comorbidities, the use of intravenous antibiotics; the use of vasoactive drugs and the use of mechanical ventilation; a high tiss score was predictive of emergency room mortality. in the indirect assessment of the care workload, medical and paramedical staff were interviewed, % of them were under years old with a sex ratio of . . a high level of mental and physical workload was expressed by ed staff with considerable level of frustration; the ed staff suggested mainly to improve the working conditions, communication and to redefine tasks "who does what". our study had shown a significant workload in the emergency room, a process to reduce this workload is being implemented medical simulation is a modern teaching tool increasingly used in specialties such as anesthesia, emergency medicine and obstetrics. however, it's not widely used in specialties like cardiology, althought cardiovascular emergencies are very frequent. the purpose of our study was to assess the effectiveness of simulation-based medical education in the management of cardiovascular emergencies among moroccan graduate students. we conducted a prospective, observational, multi-centrer study including the students of three moroccan universities from the th to the th year of medicine who underwent phases: first a pre-test, then a theoretical and practical training on cardiovascular emergencies after which the students were separated in two groups, one undergoing the medical simulation training (group ) and one who didn't (group ), followed by a theoretical then a practical post-test on resusci anne and simman®. at last, the students were asked to answer a satisfaction survey. the reform procedure in the tunisian army consists in repairing the physical damage and deciding on the applicant's ability to continue working. terrorism increases the impact of the co-morbidity generated and the socio-economic consequences that result from it. the purpose of this work was to study the epidemiological, clinical and evolutionary profile of terrorist injuries, to specify the rates of consequent partial permanent disability (ppi) and the possibilities of returning to work. descriptive retrospective cross-sectional study of reform files on military personnel injured during anti-terrorist operations from fig. (abstract ) . changes in total bcpr rate in family-and friends-witnessed ohca cases with dispatcher-assisted instruction during -week period after the day of disaster during three years january to september . the data collection was carried out on the basis of a collection form. our wounded were male, % of whom belonged to the army. the average age was years and months ± . . half of our wounded were troopers. infantry and special forces were the most exposed military units. half of the accidents were recorded in the kasserine region ( cases). chronic post-traumatic stress disorder (cptss) was found in injured, followed by amputations in injured. the after-effects were psychological in %, physical in % and mixed in % of our injured. the ppi rate ranged from % to % in . % of injuries.. more than half of the injured had returned to their professional activity, % were put on reform for health reasons. our results showed that the esptc was the most recorded sequel, and that the ppi rate was significant in a quarter of our injuries. in our series, a third of our wounded were put on reform for health reasons. to state the importance of initial care and adequate and rigorous follow-up to recover a greater number of war wounded. introduction: the rapid response system (rrs) has been shown to decrease hospital mortality [ ] . the japanese coalition for patient safety has set a major goal for hospitals to more widely implement the rrs. however, prevalence and actual circumstances of use in acute care hospitals (including small scale hospitals) in japan are as yet not well-known. web-based questionnaires were sent to acute care hospitals (of scale beds-or-larger) of prefectures in western japan. each participant hospital selected a certain department which answered the questionnaire. the rrs included the medical emergency team (met), the rapid response team (rrt), and the critical care outreach team (ccot). we investigated the presence and circumstances of in-hospital emergency calls, rrs and other systems, and then illuminated issues to be solved. our study suggests that delays in patient transfer to the icu after rrt activation in the wards were associated with slower physiological improvement.these findings support further and larger studies. blood and blood products use in intensive care unit m akcivan, s bozbay, o demirkiran istanbul university cerrahpasa, anesthesiology and intensive care, istanbul, turkey critical care , (suppl ):p blood and blood product (bp) transfusions are frequently used in intensive care units (icu) [ ] . it is important to know transfusion epidemiology and the effect of adverse transfusion reactions and their effect on mortality and morbidity.we aimed to investigate the blood and bp transfusions in the icu. blood and bp transfusions in icu, between - were reviewed retrospectively. we evaluated each transfusion as a data and examined the pre-and post-transfusion laboratory values, demographic data, cause of icu admission and comorbidities. results: patients who underwent transfusion in the icu, and transfusion data from these patients were included. the most frequent cause of hospitalizations were respiratory failure and sepsis. the rate of patients transfused in the five-year period decreased from . % to . %. the hemoglobin threshold before transfusion decreased from . g / dl to . g / dl. a total of transfusion reactions were observed and the most common transfusion reaction was febrile non-hemolytic reaction. the most commonly transfused product was red blood cell suspension. transfusion reactions were found to be slightly higher in men than women in young age group(< y) (p = . and p= . , respectively). transfusion reactions were found to be more frequent in emergency transfusions (p < . ). the number of transfusions was significantly lower in patients with apache ii score < (p < . ). the need for transfusion was found to be higher in patients with hematological malignancy (p < . ). it was observed that as the mean number of transfusions increased the mortality is also increased (p < . ). transfusion therapies are the treatments that are vital but have a serious mortality and morbidity risk. in particular, intensive care patients should be considered in detail because of their specific features. restrictive transfusion practices have positive results. association between anemia or red blood cell transfusion and outcome in oncologic surgical patients. figure a) . the association between rbc transfusion and adverse events also remained after adjustment (or . [ . - . ] ; p < . ) ( figure b) . in oncologic surgical critically ill patients, there was an independent association between anemia (even moderate anemia) or rbc transfusion and patient outcomes. our findings highlight the need for further research to determine the optimal transfusion strategy in surgical oncologic patients. transfusion impaired skin blood flow when initially high e cavalcante dos santos, w mongkolpun, p bakos, al alves da cunha, c woitexen campos, jl vincent, j creteur, fs taccone erasme hospital, intensive care department, brussels, belgium critical care , (suppl ):p red blood cell transfusion (rbct) increases global oxygen delivery (do ) and may improve microcirculation. however, the effects on blood flow have been found to be conflicting. we studied icu patients with stable hemodynamic status (mean arterial pressure (map) ≥ mmhg for at least hours) and without active bleeding, who received a rbct. skin blood flow (sbf) was determined (periflux system , perimed, index finger; perfusion unit, pu) together with map, heart rate (hr), hemoglobin (hb), lactate levels and scvo before and after rbct. sbf was measured before rbct (t ) and after (t ) for each min. according to previous data indicating the lowest sbf value found in noninfected icu patients was pu, all patients were analyzed according to the baseline sbf (i.e. < pu -low sbf vs. ≥ puhigh sbf). the relative change of sbf (Δsbf) was calculated after rbct and the responders were defined by the function of > %. results: icu patients were studied. rbct was associated with increases in map and scvo but no change in sbf. at baseline, scvo was lower in the responders than in the non-responders (p= . ) and lower in patients with low sbf than in the high sbf (p= . ). there was no difference in hb, map, and lactate, between the patients with low and high sbf. after rbct, map rose in the responders (p< . ) and in the non-responders (p= . ), sbf (p< . ) rose in patients with low sbf, and sbf (p= . ) decreased in patients with high sbf. there was a negative correlation between baseline scvo (r= - . , p< . ) or baseline sbf (r= - . , p< . ) and the relative increase in sbf after rbct. rbct increases skin blood flow only when it is impaired at baseline. severe immune dysregulation is associated with adverse outcomes and is common in intensive care unit (icu) patients [ ] . erythropoietin-stimulating agents (esas) have both anti-apoptotic and immune-modulating properties [ ] . despite potential benefit, both the safety and efficacy of these agents remains unclear [ ] . here we evaluate the impact of esas on morality at hospital discharge in critically unwell adult patients admitted to the icu. we conducted our search strategy in accordance with a predetermined protocol. the use of ffp is associated with an increased incidence of complications such as acute respiratory distress and infections, and the rate of complications increased with the quantities of ffp transfused [ ] . pcc contain several important coagulation factors and it has been suggested that they could replace ffp. this has been shown mainly in case reports or series in which coagulation factor deficit was detected by using poc viscoelastic tests in trauma [ ] or traditional hemostatic tests in obstetric patients [ ] . multicenter observational study of the safety and efficacy of the prothrombin complex concentrate. a survey of anesthetists was conducted in maternity hospitals at various levels of care in the russian federation. data has been collected and processed. as a result, patients were analyzed. pph was determined as a volume of blood loss more than ml during vaginal delivery or cs. the most significant risk factors for pph were: preeclampsia or arterial hypertension and a history of postpartum hemorrhage. . % had no risk factors for pph. it was determined that the use of prothromplex iu decreased the number of patients with transfusion ffp - ml/kg by . % and increased the number of patients without transfusion by . %, compared with patients without use of prothromplex iu (figure ). no complications were detected. the use of pcc safety and efficacy reduce use of ffp during pph. the full analysis included patients on either hfc (n= ) or cryoprecipitate (n= ). the intraoperative and postoperative changes in etp and fibrinogen concentration are shown in table . for fibtem a (intraoperatively) and fibrinogen concentration (intraoperatively and postoperatively), the mean numerical values appeared higher with hfc than cryoprecipitate. fxiii (hfc: . %, . %; cryoprecipitate: . %, . %, at baseline and hr after surgery start), fviii and vwf were maintained throughout surgery in both treatment groups. this was also the case for laboratory tests activated partial thromboplastin time, prothrombin time and platelet count. the forma- coagulation parameters analyses showed broad overlaps between hfc and cryoprecipitate, with satisfactory maintenance of the clot quality parameters, fxiii concentrations and thrombin generation parameters. the study group includes men and women with a mean age of , vs. . years (p= . ) admitted with the diagnosis of multiple trauma. we found a directly proportional and highly significant statistical correlation between base excess and fibrinogen level diagnosed using the mcf/fibtem parameter(r= . , p< . )and an inverse proportional correlation between lactate level and fibrinogen level (r= - . , p= . ). in the roc analysis that uses as a variable the level of base excess and as a criterion of classification the fibrinogen deficit (mcf/fibtem< mm) it can be observed that at a value of be<- mmol/l, we can diagnose a fibrinogen deficit with a sensitivity of . % and a specificity of . % (auc= . ,p< . ). lactate appears to be inferior to the excess base (figure ) , but still has a good diagnostic power, a value of . mmol/l has a sensitivity of . % and a specificity of % (auc= . ,p< . ). the difference between the two roc curves ( . ) is statistically significant (p = . ). both base excess and serum lactate can be used to diagnose fibrinogen deficiency with the mention that base excess appears to have a higher sensibility and specificity ability. based goal-directed algorithm. this approach requires further clinical validation. we conducted a retrospective study comparing transfusion strategies in patients with major trauma between and . we retrieved demographic data and blood products administered from patients with at least one red-blood cell (rbc) transfusion. primary outcome was a reduction of rbc administration. secondary outcomes were mortality, icu length of stay and acute kidney injury. we included patients admitted in the icu due to severe trauma (sapsii: . ± . ), and mainly after emergent surgery ( . %). they featured a mean age of . ± . y, were predominantly male ( . %) and % were in shock. in the first hours of hospital admission a mean of . ± . rbc units were administered. most patients received a fibrinogen-based protocol (fbp) ( %), with an average of ± g of fibrinogen and ± fresh-frozen plasma (ffp) units, versus ± g of fibrinogen and ± ffp units in the ffp group. the fbp was associated with a decrease administration of rbcs in the first hours (r = - . ; p < . ), even after adjustment for severity (p= . ) and for tranexamic acid use (p = . ). it was associated also with a decrease of platelet transfusion (p= . ). fibrinogen-based protocol was not associated with a decrease in mortality, acute kidney injury or noradrenaline dose. treatment of tic in past years has progressively changed to a goaldirected fibrinogen-based approach. in our population, the use of fbp lead to a reduction of rbc administration in severe trauma patients. prospective, multicenter, randomized study comparing administration of clotting factor concentrates with a standard massive hemorrhage protocol in severely bleeding trauma patients the objective of this study was to assess the ability of the quantra® qstat® system (hemosonics) to detect coagulopathies in trauma patients. many level trauma centers have adopted whole blood viscoelastic testing, such as rotational thromboelastometry (rotem®, fig. (abstract ) . study treatment plan instrumentation lab) for directing transfusion therapy in bleeding patients. the quantra qstat system is a cartridge-based point-of-care (poc) device that uses ultrasound to measure viscoelastic properties of whole blood. and provides measures of clot time, clot stiffness and a test of fibrinolytic function. methods: adult subjects were enrolled at two level trauma centers which use a rotem based protocol to guide transfusion decisions. study protocols were approved by the site's ethics committee. for each subject, whole blood samples were drawn upon arrival to the emergency department and again, in some cases, after administration of blood products or antifibrinolytics. samples were analyzed on the quantra (at poc) in parallel to rotem delta (in lab). a total of patients were analyzed. approximately % of samples had a low clot stiffness (cs) values suggestive of an hypocoagulable state. the low stiffness values could be attributed to either low platelet contribution (pcs), low fibrinogen contribution (fcs), or a combination ( figure ) . additionally, % of samples showed evidence of hyperfibrinolysis based on the quantra clot stability to lysis parameter. samples analyzed on standard rotem assays showed a lower prevalence of low clot stiffness and fibrinolysis based on extem, fib-tem results. the correlation of cs and fcs vs equivalent rotem parameters was strong with r-values of . and . , respectively. this first clinical experience with the quantra in trauma patients showed that the qstat cartridge detected coagulopathies associated with critical bleeding and may be useful for directing blood product transfusions in these patients. ability to perform testing at poc may provide additional clinical advantage. the objective of the study was to describe the conditions of use of fibryga® g, a new, highly purified, human fibrinogen (hf) recently granted a temporary import authorization for use in congenital and acquired fibrinogen deficiencies in france. observational, non-interventional, non-comparative, retrospective study conducted in french hospital centres using fibryga®. data from patients with fibrinogen deficiency having received fibryga® from december to july were retrieved from their medical files. indications, modalities, efficacy and safety outcomes were recorded. indications encompassed non-surgical bleeding (nsb) either spontaneous or traumatic, including post-partum hemorrhage (pph), bleeding during surgery (sb) or administration to prevent bleeding during planned surgery. treatment success was defined as control of the bleeding or hemoglobin loss < % for bleeding treatment and as absence of major perioperative hemorrhage for pre-surgical prevention. this analysis included patients aged , ± . years and % were male. all presented an acquired fibrinogen deficiency requiring administration of hf. indications were nsb (n= , . %) including ( . %) pph, sb (n= , . %), and prevention of sb (n= ; , %). cardiac surgeries were the main procedures associated with treatment and prevention of sb. mean total doses of fc were . ± . g, . ± . g and . ± . g for nsb, sb and prevention of sb. success rates were . % ( %ci . - . %), . % ( %ci . - %) and . % ( %ci . - %) respectively. for pph, mean dose of hf was . ± . g with a success rate of . % ( %ci . - %). overall, tolerance was good. fibrinogen concentrate fibryga® is mostly used for bleeding control. in one third of patients, hf was administered preventively to avoid bleeding during surgery. use of fibryga® was associated with favourable efficacy outcomes. functional testing for tranexamic acid effect duration using modified viscoelastometry t kammerer , p groene , s sappel , p scheiermann , st schaefer ruhr-university bochum, institute of anaesthesiology, heart and diabetes center nrw, bad oeynhausen, germany; ludwig-maximilans university, department of anaesthesiology, munich, germany critical care , (suppl ):p tranexamic acid (txa) is the gold standard to prevent or treat hyperfibrinolysis [ ] . effective plasma concentrations are still under discussion [ ] . in this prospective, observational trial using modified viscoelastometry we evaluated the time-course of the antifibrinolytic activity of txa in patients undergoing cardiac surgery. methods: patients were included. modified viscoelastometry (tpa-test) was performed and txa-plasma-concentration, plasminogen-activatorinhibitor- (pai- ) and pai-antigen-plasma-concentrations were measured over h. additionally, in vitro dose-effect-curves from blood of healthy volunteers were performed. data presented as median with interquartile range (q /q ). results: txa plasma-concentration was increased compared to baseline (t : μg ml - ) at every time-point with a peak concentration min (t ) after application (p< . ; see fig. a ). lysis was inhibited from min (lysistime tpa-test : p< . ; lysisonsettime tpa-test :p< . ). maximumlysis tpa-test was decreased at t (t : % ( / ) vs. t : % ( / ); p< . ). of note, after h some patients (n= ) had normalized lysis whereas others (n= ) had strong lysis inhibition (ml< %;p< . ) up to h. high and low lysis groups differed regarding kidney function (cystatin c: . mg l - ( . / . ) vs. . mg l - ( . / . );p= . ) and active pai- ( . ng ml - ( . / . ) vs. . ng ml - ( . / . );p= . ). in-vitro, txa concentrations > μg ml - were effective to inhibit fibrinolysis. in our trial, after h there was still completely blocked lysis in patients with moderate renal impairment. this could be critical with respect to postoperative thromboembolic events [ ] . here modified viscoelastometry could be helpful to detect the individual fibrinolytic capacity. introduction: peri-operative coagulopathy correction based on viscoelastic hemostatic assays (vhas) and single-factor coagulation products has changed the paradigm of bleeding management in cardiac surgery [ ] . in a retrospective study, we analysed patients with emergency surgery for thoracic acute aortic dissection (taad), before and after the introduction of fibrinogen concentrate in clinical practice. data were collected from paper and electronic records. the study was approved by the institutional ethical committee. patients were included in the analysis, operated in , before fibrinogen concentrate was approved for human use, and in - . therapy was guided by a rotational thrombo-elastometry (rotem) algorithm. exclusion criteria were non-compliance with the institutional protocol and intra-operative death. we investigated allogeneic blood transfusion (abt), fibrinogen use, peri-operative bleeding (pob), surgical reexploration and post-operative complications (poc). the groups were similar in gender, age, body weight, additive euro-score and aortic cross-clamp time. fresh frozen plasma, cryoprecipitate and red blood cell transfusion were lower in the fibrinogen group, but not platelet transfusion (table). , % of patients in the study group received fibrinogen concentrate and median dose was g (iqr - ). day postoperative chest tube drainage and surgical reexploration were significantly lower. there were no differences in stroke, renal replacement therapy, mechanical ventilation time and icu stay. in patients with taad surgery, rotem-guided algorithms which include fibrinogen concentrate are associated with less (pob), surgical re-exploration and abt. further research is needed to document the role of vhas and concentrated factors in reducing (poc). andexanet alfa (aa, portola pharmaceuticals, san francisco, ca) represents a modified factor xa agent which is approved antidote for apixaban and rivaroxaban. andexanet alfa may also neutralize the anti-xa effects of betrixaban and edoxaban. this study aims to compare the relative neutralization of these four anti-xa agents by andexanet alfa in different matrices. andexanet alfa was diluted at mg/ml. apixaban (a), betrixaban (b), edoxaban (e) and rivaroxaban (r) were diluted in ph . , . m tris buffer (tb), blood bank plasma (bbp) and in % albuminated buffer (ab) at . - . ug/ml. anti-xa activities of all four agents were measured in three systems and the reversibility indices of aa were profiled. the reversibility index (ri ) of anti-xa effects by aa was determined at - ug/ml. each of the four agents produced varying degrees of inhibition of anti-xa at . - . ug/ml, the ic ranged . - . ug/ml in bbp, . - . ug/ml in ab and . - . ug/ml in tb. andexanet alfa produced a concentration dependent reversal of all four anti-xa agents. in the bbp, the ri values for a ( ug/ml), b ( ug/ml), e ( ug/ml) and r ( ug/ml). in the ab, the ri values for a ( ug/ml), b ( ug/ml), e ( ug/ml) and r ( ug/ml). in the tb, the ri values for a ( ug/ml), b ( ug/ml), e (> ug/ml) and r ( ug/ml). each of the four anti-xa agents exhibit varying degrees of matrix independent anti-xa potencies in different systems, the collective order follows edoxaban > apixaban > betrixaban > rivaroxaban. andexanet alfa produced matrix dependent differential neutralization of the anti-xa effects of these agents. individualized dosing of andexanet alfa may be required to obtain desirable clinical results. the diagnostic and prognostic value of thromboelastogram (teg) in sepsis has not been determined. this study aimed to assess whether teg is an early predictor of coagulopathy [ , ] and is associated with mortality in patients with sepsis. in total, patients with sepsis on intensive care unit admission were prospectively evaluated. we measured teg and conventional coagulation tests(ccts)on preadmission and observed for development of , days and , , days respectively. multivariable logistic regression was utilized to determine odds of icu/hospital mortality. the parameter of teg (maximum amplitude, reaction time; ma/r ratio) was calculated to evaluate sepsis-induced coagulopathy. the admission patients were divided into three groupsma/r group(ma/r= - mm/min); ma/r group(ma/r> mm/min)and ma/r group(ma/r< mm/min). in our cohort of patients with severe sepsis, coagulopathy defined by ma/r ratio was associated with increased risk of icu/hospital mortality. introduction: blood sampling for coagulation assessment is often carried out in either arterial or venous samples in the intensive care unit (icu). there is controversy as to the accuracy of this method due to the inherent differences in physicochemical properties as well as the underlying effects of individual diseases in arterial and venous blood. clot microstructure has shown to be a new biomarker (fractal dimension-d f ) which encompasses the effects of diseases in all aspects of the coagulation system [ , ] . in this study, we compared the effect of all these factors in venous and arterial blood to see if there is a difference in the clot microstructure and quality. patients admitted to a tertiary intensive care unit and busy teaching hospital were recruited. arterial and venous blood was sampled from an arterial line and central venous catheter in situ from the same patient. standard markers of coagulation (pt, aptt, fibrinogen, full blood count), rotational thromboelastometry (rotem), whole blood impedance aggregometry and measured clot microstructure (d f ) were measured on both arterial and venous samples. no significant difference was observed in standard laboratory markers, rotem and platelet aggregation between arterial and venous blood. there were no differences in the fractal dimension (d f ) between the arterial and venous blood samples (d f . ± . vs . ± . respectively, p= . ). samples from patients with critical illness give comparable results from either arterial or venous blood despite their underlying pathophysiological process or treatment. this confirms blood for coagulation testing can be taken from arterial or venous blood. clinicians in the emergency setting use a wide range of hemostatic markers to diagnose and monitor disease and treatment. current methods rely on the anticoagulant effect of citrate on whole blood prior to laboratory analysis. despite the well-recognized modulatory effects of citrate on hemostasis, the use of anticoagulated blood has clear analytical advantages, including repeat sampling and storage. however by altering the physiological state of the blood reproducibility and accuracy of the test is affected. recent studies have shown the potential of a novel functional biomarker of clot formation: fractal dimension (d f ), that may give an improved diagnostic accuracy. in this study we assessed the potential of this new biomarker in scientifically measuring the effects of recalcification of citrated samples. methods: healthy volunteers were included. unadulterated and sodium citrate samples of blood were taken from each volunteer. citrated samples were recalcified using ( m cacl ). in the study we compared unadulterated whole blood d f results to citrated d f results and repeated the citrated d f experiments times for each sample over a hour period to ascertain reproducibility. the d f of citrated blood was significantly lower than that of unadulterated blood ( . ± . vs . ± . , p< . ). the results of the citrate samples when tested times over hrs gave a coefficient of variation of . %. for the first time we show that a functional biomarker of clot microstructure, d f , can precisely quantify and measure accurately the direct effect that the addition of the anticoagulant sodium citrate has on whole blood clot microstructure. the study also shows that the test is reproducible and has potential utility as a biomarker of acute disease in the emergency setting in citrated blood. this procedure now needs to be evaluated in a group of acute disease states. in this study, we analyzed the hematological abnormalities of dengue patients by thromboelastography (teg) at initial and -hour of fluid resuscitation. methods: this is a cross-sectional study evaluating teg readings of dengue patients with different severities presenting to the emergency department. laboratory confirmed dengue patient (positive ns antigen or igg/igm) was consecutively sampled. teg readings were taken at presentation and after -hour of fluid resuscitation. twenty dengue patients with varying severity had a median reaction time (r), α -angle, k time, maximum amplitude (ma) and lysis % (ly ) of . min, . ο , . min, . mm and . % respectively. mean fibrinogen was normal before and after fluid infusion. there is a non-significant reduction in ma with prolongation of other teg parameters between different dengue severities. there is a statistically significant reduction of α-angle and ma between pre and post -hour fluid resuscitation (p= . and p= . ). normal fibrinogen with low ma, which signifies a weak clot strength, may indicate either a platelet reduction, platelet dysfunction or both. reduction in ma and α-angle post fluid resuscitation is an alarming finding. this is in contrast with previous teg studies although none of it used normal saline exclusively, studied initial fluid resuscitation in emergency department settings or studied a subject with dengue. a bigger study, especially in severe dengue is needed to validate our findings. agreement between the thromboelastography reaction time parameter using fresh and citrated whole blood during extracorporeal membrane oxygenation with teg® and teg® s m panigada, s de falco, n bottino, p properzi, g grasselli, a pesenti fondazione irccs ca´granda ospedale maggiore policlinico, intensive care unit, milano, italy critical care , (suppl ):p the r (reaction time) parameter of kaolin-activated thromboelastography (teg) may be used to assess the degree of heparinization of blood during ecmo. a teg analysis is usually performed on two types of samples: fresh (f) or citrated-recalcified (c) whole blood. teg® can perform the analysis on c and f whole blood, the new teg® s (haemonetics corp., ma, usa) only on c whole blood. aim of the study was to compare the response of r to heparin using the two types of samples and two teg devices methods: during a three months period at fondazione irccs ca' granda -policlinico of milan, teg was performed (using teg ® and teg s® with and without heparinase, an enzyme that degrades heparin) on consecutive ecmo patients (as part of the gatra study, nct ) and in consecutive non-ecmo patients in whom a teg was requested for clinical purposes. bland altman analysis and lin's concordance correlation coefficient were used to assess agreement results: a total of paired samples were taken ( in-ecmo and off-ecmo). ecmo patients received . ( . - . ) iu/kg/h of heparin. among non-ecmo patients, of them did not receive any dose of heparin, two of them a very low prophylactic dose ( . and . iu/ kg/h, respectively), and one of them . iu/kg/h of heparin. using teg® , r was - . (- . ; . ) min shorter on c compared to f blood in patients receiving heparin (this difference disappeared using heparinase) and only - . (- . ; . ) min shorter in patients notreceiving heparin. r was - . (- . ; . ) min shorter using teg® s (which performs the analysis only on c blood) than teg® on f blood (figure ) . when evaluating the effect of heparin using teg, clinicians should be aware that results obtained using citrated-recalcified or fresh whole blood are not interchangeable. using citrated-recalcified blood to perform teg might lead to underestimation of the effect of heparin trauma patients are at high risk for venous thromboembolism (vte). the east guidelines recommend low molecular weight heparin (lmwh) for vte prevention and antixa monitoring after initiation of the medication or after adjusting doses in certain populations [ ] . studies have shown standard enoxaparin dosing of mg every hours may result in low antixa levels [ ] . this study aims to evaluate the efficacy of a pharmacist-lead protocol for adjusting enoxaparin dosing based on antixa levels in trauma patients. this single center retrospective chart review included adult trauma patients admitted from / / to / / . per protocol, patients with body mass index (bmi) ≤ kg/m were initiated on enoxaparin mg twice daily, and patients with bmi > kg/m were initiated on enoxaparin mg twice daily. peak antixa levels were drawn to hours after at least the third dose of enoxaparin with a goal therapeutic range of . - . iu/ml. the primary objective was time in days to goal peak antixa level. secondary objectives include vte occurrence, bleeding attributed to lmwh, and dosing regimens utilized. subgroups were analyzed based on body mass index (bmi). of patients identified, patients met inclusion criteria. median time to therapeutic antixa level was days (iqr - ). of patients fig. (abstract ) . agreement between teg® s and r teg® on citrated recalcified and fresh whole blood with bmi ≤ kg/m , patients ( . %) were dosed initially per protocol and / patients ( . %) met goal antixa level at first check (table ) . of patients with bmi > kg/m , patients ( . %) were dosed initially per protocol and / patients ( . %) met goal antixa level at first check. our results indicate the protocol is safe due to lack of bleeding attributed to enoxaparin, but less than % of patients achieved goal antixa level at first check. however, despite low rates of achieving goal antixa level, vte rates also remained low. introduction: most patients in the icu are given prophylactic anticoagulation with a fixed dose of mg once daily of enoxaparin (clexane) if cct is normal and mg if cct is low. studies on non icu patients have shown that afxa is below desired range for venous thromboembolism (vte) prevention. in the icu, many factors might influence afxa levels including weight, creatinine clearance (cct), shock and other medication. atxa activity was not yet reported in a big mixed icu population with variable morbidity. our study hypothesis is that enoxaparin is underdosed in most cases and routine afxa activity should be monitored in all icu patients. preventive enoxaparin ( mg qd) was given to all patients unless therapeutic dose was needed or contraindication existed. levels of afxa activity were taken hours after the rd dose. therapeutic vte preventive effect was defined as afxa activity of . - . . patient data was collected from medical files. the study is still ongoing, preliminary results were analyzed for patients. of patients ( %) had afxa activity below normal (subtherapeutic). weight and cct were negatively correlated with afxa activity (figure ). mean weight in the subtherapeutic afxa was significantly higher than the therapeutic group ( . vs. . respectively, p= . ). cct in the subtherapeutic afxa was significantly higher than the therapeutic group ( . vs. . respectively, p= . ). the normal cct group (> ) had significantly more patients with subtherapeutic afxa ( vs , p= . ). in our icu, % of the patients receive insufficient vte prophylaxis. overweight patients and patients with normal cct should probably receive higher enoxaprin dose. afxa activity should be routinely monitored in icu patients. in this study we use a new bedside biomarker to test its ability to measure anticoagulation effects on patients who present with acute first time deep vein thrombosis (dvt). dvt requires oral anticoagulants to prevent progression to potentially fatal pulmonary embolism and recurrence. therapeutic efficacy monitoring of direct oral anticoagulants (doac) including rivaroxaban is problematic as no reliable test is currently available. advances in hemorheological techniques have created a functional coagulation biomarker at the gel point (gp) which allows quantitative assessment of: time to the gel point (t gp ), fractal dimension (d f ) and elasticity (g') [ , ] . the prospective observational cohort study measured t gp , d f , g', standard coagulation and cellular markers in first time dvt patients at three sample points: pre-treatment and approximately and days following mg bd and mg od rivaroxaban respectively. strict inclusion and exclusion criteria applied. results: dvt patients (mean age years [sd± . ]; male, female) and non-dvt patients were well matched for age, gender and co-morbidities. mean t gp on admission was s (sd± . s) and . s (sd± . s) for dvt and non-dvt respectively. doac therapy significantly increased t gp to . s (sd± . s) after days, and subsequently increased to . s (sd± . s) at days as shown in table . d f , g' and standard hemostatic markers all remain within the normal range. conclusions: t gp demonstrates its utility in determining the anticoagulant effect of rivaroxaban. the significant difference in t gp between males and females needs further exploration. localized stasis as a result of transient provoking factors appears not to generate a systemic strength fig. (abstract p ) . correlation of anti factor xa activity with patient cct and weight. anti fxa activity value below . (red line), was considered "non-effective prevention" introduction: trauma remains the leading cause of death all over the world. to better exploit the trauma care system, precise diagnosis of the injury site and prompt control of bleeding are essential. here, we created a nursing protocol for initial medical care for trauma. the aim of this study was to evaluate the impact of protocoled nursing care for trauma on measures of quality performance. this was a retrospective historical control study, consisted of consecutive severe trauma patients (injury severity score > ). people were divided into two groups: protocoled group (from april to march ) and control group (from april to march ). we set the primary endpoint as mortality for bleeding. the secondary endpoints included time allotted from arrival to start of ct scan and surgery, administration rate of several drugs (sedations, painkillers, preoperative antibiotics, and tranexamic acid). for the statistical analysis, continuous variables were expressed as median (interquartile range) and were compared by wilcoxon rank sum tests given a nonnormal distribution of the data. we included patients in the study: in the control group before the introduction of the protocol, in the protocoled group. as a primary endpoint, the mortality for bleeding was similar between two groups ( % in the control group and % in the protocoled group). as a secondary endpoint, the time to ct initiation [group a ( - ) min vs group b ( - ) min; p < . ], and emergency procedure [group a ( - ) min vs group b ( - ); p < . ] were shortened by the protocol introduction. furthermore, the administration rates of sedations, painkillers, preoperative antibiotics, and tranexamic acid were increased in the protocoled group compared with the control group. although the mortality as a patient-oriented outcome was not affected, improved quality of medical care by nursing protocol introduction may be suggested in this analysis. this single-institutional prospective study included patients with uprf who were admitted to the trauma surgical intensive care unit (tsicu) and survived until discharge to home between and . we evaluated the activities of daily living after the discharge using physical and mental component scores of sf- ® and defined physical dysfunction (pd) as physical function (pf-n) score of or less. we divided the patients in the pd (n= ) and control (without pd, n= ) groups and compared the groups. the patients had experienced blunt injuries, including falls ( %) and pedestrian injuries ( %). the mean age was . years (men: . %); the median injury severity score was (interquartile range: - ); and the mean length of tsicu stay was . days. the average period from the injury until the survey was . months. there was no difference between the pd group and the control group in the patient characteristics, fracture type, pelvic fixation, and complications. at the time of the survey, the pd group had significantly more painful complaints than the control group (pd: . %, c: . %, p < . ), and had more physical and mental problems. the sf- ®subscale score showed a significant positive correlation between physical function and body pain, mental health respectively. the percentage of those who were able to return to work was not different in both groups (pd: . %, c: . %). in the multivariate analysis of pd, only age (odds ratio: . , % ci: . - . , p = . ) was relevant. long-term pd was observed in % of patients with uprf. the elderly were particularly prominent, and there was an association between pain and mental health. cells (rbc) this can lead to inhibition of oxygen transport function and development of hypoxia. currently used methods for analyzing the state of rbc either do not have sufficient accuracy or require lengthy analysis and expensive equipment. the use of a simpler and more informative electrochemical approach to assessing the state of rbc is very promising. electrochemical measurements in rbc suspensions (~ • cells / l) were carried out in a special electrochemical cell [ ] in the potentiodynamic mode in the potential range from - . to + . v using the ipc pro mf potentiostat (kronas, russia); optical measurements were performed using an eclipse ts inverted microscope (nikon, japan), a cfi s plan fluor elwd x / . lens (nikon, japan); rbc morphology was recorded in real time using a ds-fi digital camera (nikon, japan). when examining rbc of patients with severe multiple trauma a decrease in the ability of rbc to change their shape during electrochemical exposure was observed, indicating a decrease in deformability, which can lead to a disruption in the oxygen supply to tissues. at the same time, with the stabilization of the patient's condition a restoration of the ability of rbc to change morphology was detected which in turn could have a positive effect on the rheological characteristics of the blood (fig. ) . the results of the analysis of red blood cells using electrochemical changes in their morphology can be used as an additional method for the diagnosis of critical conditions. severe trauma should be treated immediately. whole-body ct (wbct) is widely accepted to improve the accuracy of detecting injuries. however, it remains the problem of time-consuming. therefore, we focused on the scout image taken in advance of wbct. detecting major traumatic injuries from a single scout image would reduce the time to start treatment. a previous study suggested that even specialists could not easily find chest and pelvic injuries using wbct scout image alone. in this study, we aimed to develop and validate deep neural network (dnn) models detecting pneumo/hemothorax and pelvic fracture from wbct scouts. we retrospectively collected anonymous wbct scouts together with their clinical reports at the osaka general medical center between january , , and december , . we excluded incomplete, younger than years old, postoperative, and poorly depicted images. the part of this dataset from january , , until december , , was used for validation and the rest for training dnn models. pneumo/hemothorax detection model and pelvic fracture detection model were trained respectively. accuracy, and areas under the receiver operating characteristic curves (aucs) were used to assess the models. the training dataset for pneumo/hemothorax contained images (mean age years; % female patients), and for pelvic fracture consisted of images ( years; %). the validation dataset for the former contained images ( years; %), and for the latter consisted of images ( years; %). the models achieved % accuracy and an auc of . for detecting pneumo/hemothorax, % and . for pelvic fracture. our results show that dnn models can potentially identify pneumo/ hemothorax and pelvic fracture from wbct scouts. increasing the number of samples, dnn model could accurately detect severe trauma injuries using wbct scout image. clinical information system (cis) is a computer system used in collecting, processing, and presenting data for patient care. it can reduce staff workload and errors; help in monitoring quality of care; track staff's compliance to care bundles; and provide data for research purpose. however, the transition from paper record format to electronic record involves changes in all kind of workflow in icu. therefore, an effective, efficient and evaluative rollout plan was required to minimize the risk that might arise from the new practice. methods: . small groups training were provided. a working station with different case scenarios were set up for practices. . individual tutorials were conducted to clarify questions. emphasis on patient care was always top priority. . contingency plans were available in case of server breakdown and power failure. downtime drills were conducted to prepare the staff in emergency situations. . step-by-step transition from paper record to electronic format was gradually carried out. a plan was discussed among cis team with clear dates and goals. . new items in cis were first reviewed and amended in team meeting until consensus was made; then were promulgated to all staffs during handover before implementation. fig. (abstract p ) . the effect of therapy on the electrochemically induced change in the morphology of red blood cells in patients with combined trauma . staff compliance and outcomes were then monitored; further review and amendment would be possible if necessary. cis roll-out plan was smooth. all staffs were able to integrate cis into the daily routine. the contingency plans were well acknowledged. new items were followed as planned. ongoing enhancement in cis was put forward on nursing orders, handover summary, and integration with inpatient medication order entry (ipmoe) system. with emerging benefits cis brings along, our staff has more time to devote to direct patient care. human input in data interpretation and clinical judgment on top of cis play an irreplaceable role in patient care. the daily request for laboratory tests in intensive care units is a common practice. although common, this strategy is not supported, since more than % of the exams requested with this rationale may be within the normal range [ ] . misconduct based on misleading results, anemia, delirium and unnecessary increase in costs may happen [ ] . we have developed a strategy to reduce laboratory tests without clinical rationale. observational retrospective study, from july to june . the number and type of laboratory orders requested, the epidemiological profile of hospitalized patients, the use of advanced supports, the average length of icu stay and the impact in outcomes such as mortality and hospital discharge at a private tertiary general hospital in the city of rio de janeiro / rj -brazil were analyzed. a strategy was implemented to reduce the request for exams considered unnecessary. approximately , patients underwent icu during this period. the epidemiological profile and severity of patients admitted to the unit were similar to those observed historically. there was a significant reduction (> %) in the request for laboratory tests and there was no negative impact on outcomes such as mortality, mean length of stay and no greater use of invasive resources. over the period evaluated, the estimated savings from reducing the need for unnecessary exams were approximately $ , per year. the rational use of resources in the icu should be increasingly prioritized and the request for routine laboratory tests reviewed. a strategy that avoids such waste, when properly implemented, enables proper care, reducing costs and ensuring quality without compromising safety. evaluating the medication reconciliation errors in icus after implementing a hospital-wide integrated electronic health record system a rosillette, r shulman, y jani university college hospital, centre for medicines optimisation research and education, london, united kingdom critical care , (suppl ):p introduction: medication errors in intensive care unit (icu) are frequent [ ] and can arise from a number of causes including transition of care. our aim was to investigate the impact of an integrated electronic health record system (ehrs) on medication reconciliation (mr) errors occurring at critical steps: during the transition from an icu to the hospital ward and from the ward to hospital discharge. the objective was to examine the influence of icu admission on long-term medication. we performed a monocentric study in icus of a university-affiliated hospital using drug chart and medical notes review to identify mr errors before, during and after icu admission. data were collected retrospectively from ehrs for consecutive patients discharged from the icu between june- july , and who were newly initiated on specific drugs of interest. results: drugs of interest were initiated in icu. many of these were continued after hospital discharge as shown in table . there was appropriate discontinuation of all the antipsychotics newly initiated in icu. other than anticoagulants, there was no reason documented for continuation of the initiated drugs. the planned durations were documented more often after hospital discharge than icu discharge for the following drug classes (% of patients with a plan after icu discharge to the ward; % after home discharge): antibiotics ( . %; . %), and steroids ( . %; . %), but less so for analgesics ( . %; . %), insomnia ( . %; . %), and gastroprotective drugs ( . %; . %). our study has shown that medications initiated in the icu can be inadvertently continued at icu and hospital discharge due to failure in documenting indication or duration. systems are required to deprescribe icu only drugs at discharge or communicate a plan for ongoing treatment. introduction: the surviving sepsis campaign advocates the use of care bundles to guide the management of sepsis and septic shock [ ] . our study aim was to assess compliance with a locally introduced sepsis pathway and to review intensive care unit admission outcomes. we carried out a prospective audit of patients admitted to the icu at royal surrey county hospital with a diagnosis of sepsis between / / and / / , assessing compliance with local sepsis bundle delivery, outcome of icu admission and degree of associated organ dysfunction. results: patients were identified, male ( . %), with a mean age of . ( - ). mean st hour sofa score on icu was . ( - ). % of patients required vasopressors, with % requiring noradrenaline > . mcg/kg/min, and % requiring an additional vasopressor/ inotrope. % required niv, % invasive ventilation and % rrt. icu mortality was %, in-hospital mortality %, mean icu stay days ( - ), and mean length of hospital stay days . in the presence of septic shock mortality was % with post-resuscitation lactate > , versus % in patients with no vasopressor requirement or lactate < (p< . ). the sepsis bundle was delivered in one hour to patients ( %). where the bundle wasn't completed, antibiotics were delayed in % of cases and blood cultures weren't taken in %. where the bundle was fully delivered, unit mortality was % vs. % where it was not (p< . ), but there was no significant difference in hospital mortality ( % vs. %, p> . ) or rates of vasopressor requirement, niv, ippv or rrt. there is room for improvement in timely delivery of the sepsis bundle in our hospital and various measures are being instituted. though there was no significant difference in hospital mortality, icu mortality was significantly lower in patients when the bundle was fully delivered. surviving sepsis campaign recommends h and h sepsis resuscitation bundle for sepsis. the study was done to assess the feasibility of the guideline and the compliance to sepsis- recommendations at an emergency department. prospective interventional study was conducted during one year. were involved in the study all sepsis cases with a qsofa ≥ . were assessed a composite of six components (measurement of serum lactate, obtaining blood culture before antibiotic administration and provision of broad-spectrum antibiotic before the end of h and provision of fluid bolus in hypotension, attainment of target central venous pressure assessed by cardiac ultrasonography, target lactate to normal level before the end of h ). time base line was the first medical contact at triage zone. secondary outcomes of study were the mortality rate and length of stay at intensive care unit (icu). were involved in the study, patients (mean age ± years, sex ration , ). pulmonary infections were the main cause of sepsis ( %) and urinary tracts infections ( %). at h components were achieved in % of cases [lactates ( %), blood culture ( %) and provision of antibiotics ( %)]. at h components were executed in % of cases (fluid provision achievement in %, ultrasonography assessment in % and normal lactate target achieved in %) (figure ). the reliability-adjusted rate for completion of the hours and hours bundle was at %. patients compliant to composite bundle got the mortality benefit (odds ratios = . , % [confidence interval, . - . ]). the study, however, did not show any benefits of mean intensive care unit (icu) length of stay. faisability of - h bundle ratio was at %. it has shown a significant improvement in adaptation and mortality benefit without reducing mean hospital/icu length of stay. more adapted procedures are needed to improve results targeting full compliance of patients to the - h bundle sepsis management. patterns and outcome of critical care admissions with sepsis in a resource limited setting m edirisooriya maddumage , y gunasekara , d priyankara national hospital of sri lanka, medical intensive care unit, colombo , sri lanka; sri jayawardenepura general hospital, department of critical care, nugegoda, sri lanka critical care , (suppl ):p introduction: paucity of epidemiological data is a major barrier in expansion of critical care services, especially in resource limited settings. we evaluated the patterns and the outcome of critically ill patients with sepsis admitted to a level medical intensive care unit in sri lanka. a retrospective cohort study was performed to describe the characteristics and outcome of patients with sepsis, admitted to a medical intensive care unit. sepsis is defined according to sepsis definition. we examined critically ill patients admitted over a period of months. sepsis was the commonest presentation, accounted for . % of all admissions. mean age was . ± . years. septic shock was present in . % on admission. pneumonia ( . %) was the commonest cause, while leptospirosis ( . %) and meningoencephalitis ( . %) accounted for fig. (abstract p ) . sepsis - h bundle components (% of goals achievment) second and third commonest causes of sepsis respectively. the sofa score on admission ( . ± . vs . ± . , p< . ), occurrence of aki ( % vs . %, p< . ) and the length of icu stay ( . days vs . days, p < . ), were significantly higher in sepsis than in patients without sepsis. icu mortality in sepsis (n= ) did not show a significant difference to nortality (n= ) in those without sepsis ( % vs %, p= . ). patients with leptospirosis had a mean sofa score of . , however the mortality ( . % vs %, p = . ) was similar to others with sepsis. in contrast, mortality related to sepsis was significantly high ( %, p< . ) in the packground of immunosuppression (n= ). respiratory failure secondary to pneumonia was the commonest cause of critical care admission with sepsis. sepsis related icu mortality was high in the background of immunosuppression. introduction: training in placement, and the subsequent safe confirmation of position, of a nasogastric (ng) tube, relies on clinicians completing an e-learning module at our trust. feeding through an incorrectly placed ng tube is a 'never event,' associated with significant morbidity and mortality [ ] . analysis of these incidents reveal that the misinterpretation of chest radiographs, by medical staff, who had not received competency-based training, is the most frequent cause [ ] . e-learning has revolutionized the delivery of medical education [ ] , however, there are barriers to its use [ ] . we hypothesized that, by taking e-learning content, and delivering it face-to-face, we would improve training rates, and thus patient safety. a questionnaire was completed by critical care doctors, concerning their knowledge of the existence of the e-learning module, whether they had completed formal training in ng tube placement, and how confident they were, on confirming correct positioning, using a point likert scale. all clinicians underwent training in the interpretation of ng placement, using chest radiographs. after the session they were asked to re-appraise how confident they felt. results were compared using paired t tests. confidence improved in all, rising from a pre-test average score of . (sd= . ), to post-session . (sd= . ), p=< . . prior to the intervention, % of the doctors were aware of the trust guidelines, but only % had completed the training. after the session, % were aware of the guidelines, and % had completed the training (figure ) . conclusions: e-learning is a useful tool, but has its limitations. by using course content, delivered with more traditional learning methods, we im-proved the number of appropriately trained clinicians, and thus the safe use of ng tubes in our unit. a systematic review of anticoagulation strategies for patients with atrial fibrillation in critical care a nelson, b johnston, a waite, i welters, g lemma university of liverpool, liverpool, united kingdom critical care , (suppl ):p there is a paucity of data assessing the impact on clinical outcomes of anticoagulation strategies for atrial fibrillation (af) in the critical care population. this review aims to assess the existing literature to evaluate the effectiveness of anticoagulation strategies used in critical care for atrial fibrillation. only studies contained analysable data. anticoagulated patients had a lower mortality at days and days post admission to critical care, however there was an increased incidence of major bleeding events compared to the non-anticoagulated population. thromboembolic events were comparable in both cohorts. data from current literature is scarce and inferences regarding the effectiveness of anticoagulation in patients in critical care with af requires further investigation and research. every new admission to the icu prompts a handover from the referring department to the icu staff. this step in the patient pathway provides an opportunity for information to be lost and for patient care to be compromised. mortality rates in intensive care have fallen over the last twenty years, however, % of patients admitted to an icu will die during their admission [ ] . communication errors contribute to approximately two-thirds of notable clinical incidents; over half of these are related to a handover [ ] . nice have concluded that structured handovers can result in reduced mortality, reduced length of hospital stay and improvements in senior clinical staff and nurse satisfaction [ ] . a checklist was created to review the information shared and to score the handover. this checklist was created with doctors and nurses and is relevant for handovers between all staff members. information was gathered prospectively by directly observing handovers on the icu. there is a notable discrepancy in the quality of handovers of new patients ( figure ). this is true of handovers between doctors, nurses and a combination of the two. it is also true of all staff grades. whilst a doctor may have reviewed the patient prior to their arrival, % (n= ) of patients weren't handed over to a doctor. the most commonly missed pieces of information were details of the patient's weight ( %, n= ), their height ( %, n= ), whether the patient has previously been admitted to an icu ( %, n= ) and whether the patient has any allergies ( %, n= ). the handover of new patients to the icu is often unstructured and important information is missed. this can be said for all staff members and grades, and for handovers from all hospital departments. post intensive care syndrome-family (pics-f) describes new or worsening psychological distress in family and caregivers after critical illness but remains poorly studied within specialist groups [ ] . we aim to define the degree of pics-f within our tertiary referral cardiothoracic centre and map change over the course of months. caregivers attended a -week multi-professional clinic alongside patients. peer support was facilitated through a café area and a caregiver group psychology session was offered with individual appointments if required. caregiver surveys were completed including: caregiver strain index; hospital anxiety and depression scale (hads); and insomnia severity index. patients also completed hads questionnaires. repeat surveys were completed at and months. results: over cohorts, caregivers attended, of which were spouses ( %), children ( %), and others ( %), with caregivers completing surveys at months. patients' median apache score was (iqr - . ) and median icu length of stay was days (iqr - . ). most admissions were from scheduled operations ( %). severe caregiver strain was present in / ( %) with changes to personal plans ( %) the most common sub category. hads demonstrated caregivers ( %) with anxiety and ( %) with depression. caregiver anxiety exceded that of patients', only reaching fig. (abstract p ) . each handover was scored according to the information accurately given to icu staff similar levels at months, while depression remained static ( figure ). median number of nights with 'bothered' sleep was (iqr - . ) and % of caregivers expressed problems with sleep. conclusions: significant psychological morbidity in caregivers from our tertiary cardiothoracic centre is in keeping with the general icu population [ ] . caregiver strain was reduced suggesting higher levels of resilience. future work should address mental wellbeing, particularly anxiety, to minimise the effects of pics-f. burnout syndrome is an illness that has increasingly affected health professionals. it is characterized by great emotional stress, physical and mental exhaustion and depersonalization of the individual. more serious cases can lead to job loss or even suicide. the described work identifies the burnout level of the multidisciplinary team through a specific questionnaireburnout syndrome is an illness that has increasingly affected health professionals. it is characterized by great emotional stress, physical and mental exhaustion and depersonalization of the individual. more serious cases can lead to job loss or even suicide. the described work identifies the burnout level of the multidisciplinary team through a specific questionnaire methods: application of a questionnaire suitable for the multidisciplinary group in november . the same was answered by professionals among physicians and nursing team. there was no identification of employees. after analysis of the results it is observed that % of the group presents initial burnout, % with the syndrome installed and about % with characteristics of greater severity. main factors found were: mental and physical exhaustion during the work day, the level of responsibility existing in the activity and the perception of disproportionate remuneration by work performed. all interviewees presented some degree of burnout or high risk to develop it. the most severe cases should be traced through occupational medicine and anti-stress measures with reorganization of work performance should be discussed in order to reduce the prevalence of this syndrome. introduction: burnout affecting the psychological and physical state of healthcare workers is recognized in the last years. burnout has been shown to affect the quality of care. whilst some risk factors have been identified, there are gaps within the literature related to mental health and burnout. the aim of this study is to measure levels of burnout across icu units in the metropolitan setting. to determine the level of burnout we used surveys, the maslach burnout inventory human services survey (mbi-hss) and the centre for epidemiologic studies depression scale (ces-d). with the mbi-hss we analysed different variables of burnout; exhaustion, cynicism and emotional exhaustion. basic demographic data and information regarding workout schedules were collected. we studied prevalence and contributing risk factors using and analysing the outcomes of the self-scoring questionnaires. analysis was performed using descriptive statistical analysis. there were respondents, % scored the threshold for depressive symptoms on the ces-d depression scale. interestingly, % (ci . - . %) of those meeting the score for depressive symptoms identified as having frequent restless sleep compared with % ( . - . %) from those not meeting. gender did not affect depressive symptoms % of females and % of males met the threshold. with the mbi-hss for exhaustion the mean was . (sd . ) which is a high level of exhaustion, the second variable cynicism the mean score was . (sd . ), which was considered high. the final variable was emotional exhaustion the mean was . (sd . ), this is considered moderate levels of emotional exhaustion. fig. (abstract p ) . hospital anxiety and depression scale (hads) scores for patients and caregivers at baseline, months, and months there was high prevalence of burnout in icu in all different categories as well as depressive symptoms. age and gender had no affect on burnout. interestingly, we identified that sleep and shift variables were linked to increased burnout. following the implementation of a fully integrated ehrs on march at our university-affiliated hospital we conducted a prospective study in icus by analysing pharmacists' contributions during data collection periods of days at , , and weeks post implementation. a pharmacists' contribution was defined as contacting the physician to make a recommendation in a change of therapy/ monitoring [ ] . the types of contribution were: a medication errorrectification of an error in the medication process; an optimizationproactive contribution that sought to enhance patient care, and a consult -reactive intervention in response to a request. a panel of experts composed of a senior pharmacist, a consultant, a nurse, and a pharmacy student assessed the impact of each contribution, scoring low impact, moderate impact or high impact. there were pharmacist contributions recorded in the periods. of these, ( . %) were medication errors, ( . %) were optimizations, and ( . %) was a consult ( table ) . % of the contributions were assessed as having medium impact, % as high impact and % as low impact. in general, the consultant assessed fewer contributions as having high impact compared to other members of the panel, with contributions assessed as high impact by the consultant versus by the senior pharmacist. implementing an ehrs in combination with contributions of clinical pharmacists can prevent medication related issues. interestingly the types of incident did not change over time. introduction: most icu's are noisy and may adversely affect patients outcomes and staff performance [ ] . who reports that the noise level in hospitals should not exceed db at daylight and db at night. the aim of this study is to evaluate the noise levels in intensive care unit, to apply awareness training to intensive care staff in terms of noise and to compare the noise levels before and after education. noise measurement areas are separated into points including patient bedsides, nurse desk, staff desk, wareroom, corridor and entrance of intensive care unite. measurements were performed times per day. after day, awareness training were given to staff in terms of harmful effects of noise. after the training, noise measurements were repeated during days. after total days the measurements were terminated. noise was measured with incubator analyzer (fluke model: bio-tek serial no: ). the mean noise values before and after the training were not statistically different from the mean average noise values (p> . ). when the time of measurement were compared, the noise levels were higher between - hours to other measurements before and after the training statistically (p= . ). seventeen different noise measurement areas were compared in terms of noise level, there was no statistically significant difference (p> . ). the differences were examined at the same hours between before and after training. contrary to expectations, noise levels were found to be higher after training statistically (p< . ). all of noise measurements were higher than the threshold values that who recommended. increased noise levels in critical care units may lead to harmful health effects for both patients and staff. our results suggest that much noise in the icu is largely attributable to environmental factors and behavior modifications due to education have not a meaningful effect. critical care medicine has focused on continuous, multidisciplinary care for patients with organ insufficiency in the face of lifethreatening illness. despite significant resource limitation low income countries carry a huge burden of critical illness. available data is insufficient to clearly show the burden and outcomes of intensive care units in these developing countries [ ] . the objective of our study is to evaluate the morbidity and outcomes of patients admitted to the intensive care unit of a tertiary university hospital in hawassa, ethiopia. this was a prospective observational study. data was registered and analysed starting from patient admission to discharge during a month period beginning september . data regarding demographics, sources of admission, diagnosis, length-of-stay and outcomes were analysed. the total number of patients admitted to the icu was , with patients dying over a one year period. the highest admission was from emergency medical unit, % and the lowest source was from pediatrics department, %. out of these, . % were males. the mean age was years ( - ). the most frequent aetiologies of morbidity in the admitted patients were traumatic brain injury ( . %), acute respiratory distress syndrome ( . %) and seizure disorder ( %). average median length of stay was . days (interquartile range: . - . ). the overall mortality rate was . %. the top four causes of death in the icu were respiratory illness at % followed by sepsis with multiorgan failure at %, trauma ( %) and central nervous system infection ( %). infection morbidity and mortality remains very high and needs institution of aggressive preventive strategies. the increase in frequency of trauma patients need to receive due attention. sepsis causes a high number of deaths, though overtaken by respiratory illnesses. improving the overall system of icu may achieve better outcomes in resource limited countries. introduction: icu mortality has been widely studied in the literature in relation to outcome index that primarily value organic failure [ ] . however, early mortality, in the first hours of admission has been little documented in the literature. the aim of this study is to analyze factors related to early mortality in icu. retrospective study at a second-level hospital. time of study was months. patients who died in icu were included, patients were classified according timing of dead, including those who died within the first hours of icu admission. the variables analyzed were age, sex, comorbidity, charlson index, apache ii, need for supportive treatments, more frequent admission diagnosis, origin and support treatment limitation decisions. the statistical study was carried out using the spss statistical program. patients were included during the study period, ( . %) died within the first hours of admission. no differences in the needs of support treatments were observed, more than % of patients received mechanical ventilation and vasoactive therapies. table shows characteristics of patients. half of icu deaths occur within the first hours of admission. severity at icu admisison was the main factor related with early mortality. severe stroke and coronary disease were the most frequent causes of early deaths in icu. in august the royal college of anaesthetists published guidelines on care of the critically ill woman in childbirth and enhanced maternal care [ ] . approximately babies are born across the area covered by leicester university hospitals that includes two large maternity units and is part of the uk ecmo network. this audit sets out to assess current practice and form a basis for future planning, which will likely be representative to most major obstetric centres. a retrospective audit of all patients admitted to 'intensive care units' in leicester over a month period following publication of the guidelines. the focus was on patients admitted to general adult intensive care and excludes all patients cared for in 'enhanced obstetric care' units. simple standards were proposed relating to accessibility, resuscitation, follow up and multi-disciplinary learning. in total women were identified with a broad range of diagnosis. the intensive care services are split across hospitals and we found this led to a number of problems. the presence of trained staff to resuscitate a newborn were easily accessible, no steps to provide necessary equipment pre-emptively were present in any centre. none of our critical care units had a plan for perimortem section. on-going reviews by the obstetric and midwifery teams were very variable. contact with the infant and breastfeeding support was also poor. despite the large number of deliveries significant work needs to be done in order to come in line with the new national guidelines for critically ill woman in childbirth. clearly defined pathways around escalation of care, resuscitation of both the mother and baby, integrating care of the mother and the infant in the first few days of life, and multidisciplinary learning events are being produced de novo in response to these guidelines, some of which will be illustrated in the associated poster. interprofessional collaboration scale [ ] . data were analyzed with ibm spss . results: it was found that cooperative attitudes with an average score of to are considered to be of average significance. interprofessional cooperation at an average score of , states that the level of cooperation is high and the quality of working life averages to , suggesting that it is very good. as far as professional satisfaction is concerned, nurses are happy, content and satisfied with their work, despite workload and burnout conclusions: interprofessional cooperation at the icu of the general hospital of larissa is high, but satisfaction from wages, resources, working environment and conditions is low. in addition, the results showed that improvements in hospital communication between staff, has a positive impact on the quality of professional life (table ) . contrasting with previous reports, decreased admissions per unit population in older and oldest age groups, and those with high comorbidity, suggest resource constraints may have influenced admission discussion and decision-making over the -year study period in wales. further investigation is warranted. icu discharge into weekends and public holidays: an observational study of mortality n mawhood, t campbell, s hollis-smith, k rooney bristol royal infirmary, general intensive care unit, bristol, united kingdom critical care , (suppl ):p introduction: up to a third of in-hospital deaths in icu patients occurs following ward stepdown [ ] . discharge time seems to be associated with in-hospital prognosis, but meta-analyses have not shown a difference in weekday compared to weekend discharge [ , ] . however, papers that examined discharge 'into' out-of-hours days, particularly on fridays, have found differences [ ] . our aim was to assess whether discharge from icu 'into' out-of-hours (ooh -weekends and public holidays) is associated with in-hospital mortality or re-admission to icu, and whether these patients were seen on the wards ooh by medical staff. all adults discharged from the general icu to a ward at the bristol royal infirmary in december - were included. in-hospital mortality rates were assessed for each day, with 'into weekdays' defined as sunday to thursday and 'into ooh' friday, saturday and the day before a public holiday. a subset of patients with data on readmission rate to icu was also examined. all available notes from patients discharged into ooh in were reviewed. the study included patients with a subset of with readmission data. sets of notes were reviewed from patients discharged into ooh (figure ). the in-hospital mortality was significantly higher in patients discharged into ooh ( . % vs . %, p= . ). within the subset, ooh was associated with in-hospital mortality or readmission to icu ( . % vs . %, p= . ), though readmission rate alone was not ( . % vs %, p= . ). of patients discharged into ooh, once on a ward % were reviewed by a specialty doctor but . % were not seen. this is the first study to examine icu discharge 'into' ooh days including public holidays. we found increased hospital mortality in ooh, similar to other studies [ ] . up to a fifth of high-risk icu stepdown patients were not reviewed by a doctor on ooh days. exploring the experiences of potential donors' family members (fm) in a follow up clinic is crucial to analyze the effects of organ procurement (op) on the bereavement process, to gain insight on the reasons of family refusals (fr), and to improve family care during op. a mixed-method study involving fm at and months after patients' death was developed and approved by local ethics committee. fm of potential donors after brain (dbd) and cardiac death (dcd) treated in careggi teaching hospital, florence (italy) were eligible if adult and consenting. invitation letters were sent to the entitled months after death and those who actively responded were involved in an encounter with a multidisciplinary group including a clinical psychologist, two nurses and two cultural anthropologists with expertise in op. organ replacement procedures such as ecmo (extracorporeal membrane oxygenation), lvad (left ventricular assist device) and dialysis are routinely used to treat multi-organ failure (mov). globally transplantation programs struggle with increasing organ shortage. patients (pts) with mov are a potential source for procurement. however, outcome data after kidney transplantation (ktx) from such donors are sparse. we retrospectively studied the cadaveric ktx at the charité berlin in and identified donors with ongoing organ replacement procedures. donor and recipient risk factors were assessed. overall patient and graft outcomes were analyzed at months post-transplant. a total of kidneys were transplanted. we identified ktx from donors with mov ( following cardio-pulmonary resuscitation, with acute renal failure - on dialysis) (figure ). in donors, a venoarterial ecmo was implanted during ecls-resuscitation. one donor needed a veno-venous ecmo due to ards, and donor had a lvad implanted due to cardiac failure. the donor age was ± . years (yrs). in addition, donors had at least one cardiac risk factor. the kidney donor risk index averaged . (sd ± . ) and s-creatinine prior to ktx was . (sd ± . one way to expand the potential donor pool is donation after circulatory death (dcd), and a strategy to reduce the complications related to the ischemic time is the use of normothermic regional perfusion (nrp) with extracorporeal membranous oxygenation (ecmo) [ , ] . we compare the use of standard nrp with an effective adsorption system inflammatory mediators (cytosorb®) in the regional normothermic reperfusion phase via regional ecmo, that involves a reduction in cellular oxidative damage, assessed as a reduction in levels of proinflammatory substances. we report a case series of dcd-maastricht iiia category donors, treated in ecmo with nrp, to maintain circulation before organ retrieval, in association with cytosorb® in patients. during perfusion, from starting nrp (t ), blood samples are collected times, every minutes (t , t , t ). during treatment with cytosorb®, lactate levels progressively decrease, ast and alt increase less than without cytosorb®, as sign of improvement in organs perfusion ( figure ). nrp with cytosorb® might help to successfully limit irreversible organ damages and improve transplantation outcome [ ] . development and implementation of uniform guidelines will be necessary to guarantee the clinical use of these donor pools. introduction: shock is a common complication of critical illness in patients in intensive care units (icus), who are undergoing major surgery. this condition is the most common cause of death in postsurgical icus. nowadays, there are different icu scoring systems for predicting the likelihood of mortality, such as apache or sofa. nevertheless, they are used rarely because they also depend on the reliability and predictions of physicians. in these sense, gene expression signatures can be used to evaluate the survival of patients with postsurgical shock. methods: mrna levels in the discovery cohort were evaluated by microarray to select the most differentially expressed genes (degs) between groups of those that survived and did not survive days after their operation. selected degs were evaluated by quantitative real time polymerase chain reactions (qpcr) for the validation cohort to determine the reliability of the expression data and compare their predictive capacity to that of established risk scales. introduction: this study evaluates the prognostic ability of frailty and comorbidity scores in patients with septic shock. the -day mortality rate of individual medical conditions are also compared. the burden of comorbid illness and frailty is increasing in the critical care patient population [ ] . outcomes from septic shock in patients with chronic ill-health is poorly understood. interstitial lung disease is a group of diseases associated with poor prognosis in the intensive care unit despite major improvement in respiratory care in the last decade. the aim of our study is to assess factors associated with hospital mortality in interstitial lung disease patients admitted in the intensive care unit and to investigate the long-term outcome of these patients. we performed a retrospective study in an intensive care unit of teaching hospital highly specialized in interstitial lung disease management between and . a total of interstitial lung disease patients were admitted in the intensive care unit during the study period. overall hospital mortality was %. two years after intensive care unit admission, / patients were still alive ( %). one hundred eight patients ( %) required invasive mechanical ventilation of whom % died in the hospital (figure ). acute exacerbation of interstitial lung disease was associated with hospital mortality (or= . [ . - . ] ), especially in case of acute exacerbation of idiopathic pulmonary fibrosis. multiorgan failure (invasive mechanical ventilation with vasopressor infusion and/or renal replacement therapy) was associated with very high hospital mortality ( / ; %). survival after intensive care unit stay of patients with interstitial lung disease is good enough for not denying them from invasive mechanical ventilation, except in case of acute exacerbation for idiopathic pulmonary fibrosis patients. if urgent lung transplantation or extracorporeal membrane oxygenation are ruled out, multiorgan failure should lead to consider withholding or withdrawal life support therapies. Αgi is a malfunctioning of the gi tract in icu patients associated with prolonged mechanical ventilation, enteral feeding failure and high mortality risk. the wgap of esicm proposed a grading system for agi. four grades of severity were identified: agi grade i, a selflimiting condition; agi grade ii (gi dysfunction), interventions are required to restore gi function; agi grade iii (gi failure); agi grade iv, gi failure that is immediately life threatening. the aim was to evaluate the feasibility of using agi grades i and ii as predictors of malnutrition and -year mortality in critically ill patients methods: single-center retrospective cohort study in a tertiary university hospital ( - ). agi grade iii and iv patients were excluded. Αnthropometric data, gi symptoms (vomiting,diarrhea), feeding intolerance, gastric residual volumes and abdominal hypertension were recorded. daily prescribed caloric intake was calculated using a standard protocol and daily achievement of caloric intake was recorded. mnutric score was calculated for all patients. a score ≤ was used to diagnose malnutrition. patients ( % men, mean age years) that stayed in the icu for > hours were included in the study. % were at high nutritional risk. -year mortality was %. the prevalence of agi ii was %. age, gender, bmi, mortality and energy intake did not differ significantly between patients with agi ii and those with agi i (table ) . logistic the study aimed to assess the effects of icu admission on frailty and activities of daily living in the ≥ 's population at -months. a prospective observational study with data used as a subset of the vip- trial [ ] . research ethics committee approval from the mater misercordiae university hospital (mmuh). inclusion criteria -≥ years of age and acute admission to icu from may to july . data collected on consecutive patients. frailty and activities of daily living (adl) were assessed using the clinical frailty score (cfs) and the katz index of independence in activities of daily living (katz). results: csf pre-admission frailty was present in % of patients, increasing to % at months ( figure ). % of survivors at -months had a cfs score increase by ≥ point. pre-frail and frail cfs patients suffered an average -point deterioration in their instrumental activities of daily living (iadl). % of katz patients were fully functional preadmission, deteriorating to % at months. % of patients declined by adl at months. % of the deceased were deemed fully functional initially. we demonstrate an association between an icu admission event and enduring functional decline at months. icu admission resulted in patients acquiring on average . new iadl limitations despite their initial cfs. this is echoed in a study by iwasyna et al. who also showed similar deteriorations in iadl and cognitive impairment [ ] . katz benefits may be best used in describing functional decline. % of patients developed at least one new limitation. however, the cfs takes into account iadl's and thus may be more sensitive in predicting the functional outcomes of an icu event at months. frailty: an independent factor in predicting length of stay for critically ill t chandler, r sarkar, a bowman, p hayden medway maritime hospital, critical care, gillingham, united kingdom critical care , (suppl ):p frailty has attracted attention in the healthcare community in recent years, as it is associated with worse outcomes and increased healthcare costs [ ] . our objective was to study the impact of frailty as recorded by clinical frailty scale(cfs) to prospectively evaluate the effect of frailty on hospital length of stay (los). a retrospective analysis of consecutively admitted critical care (cc) patients' data (jan' -oct' ) was performed. electronic health records were used to collect demographics, cfs and clinical outcomes. statistical analysis was performed using stata. students t-test, simple and multiple (adjusted for age, disease severity/icnarc score) linear regression were used for comparison between groups and to see group effect. we excluded extreme outliers (los> days; n= ). frailty was defined as cfs> . out of the patients (male %), ( %) were emergency admissions, the rest elective (table ) . ( %) were non-frail. the mean los were days (d) ± and d± (p< . ) in the frail and non-frail patients respectively. for emergency patients, los were d(± ) and d(± ) for the groups, (p< . ). for elective patients; los were d(± ) and los d(± ), (p= . ) for frail and nonfrail respectively. after adjusting, los was significantly higher in frail patients by days ( %ci , ; p< . ), by days ( %ci , ; p= . ) and by days ( %ci , ; p< . ) for total cohort, elective and emergency admissions respectively. the los was days higher in frail than non-frail (p< . ) for cc survivors. frailty was associated with significantly increased los in this cohort, independent of age and illness severity. hospital capacity planning should take this into consideration when modelling bed allocation fig. (abstract p ) . clinical frailty score -month trend robust clinical governance requires analysis of patient outcomes during an icu admission [ ] . on one adult icu weekly mortality meetings are used for this purpose and aid multidisciplinary reflections on individual patient deaths. however, such reviews run the risk of being subjective and fail to acknowledge themes which may relate to preceding or subsequent deaths. this paper describes a new mortality review process in which: a) reviews are structured using the structured judgement review (sjr) framework [ ] ; and b) themes are generated over an extended period of time to create longitudinal learning from death. the sjr framework has been developed by nhs improvement for the new medical examiner role, looking at inpatient deaths. we adapted this to better suit the icu creating a novel review structure. this involves explicit judgement comments being recorded, and the use of a scoring system to analyse the quality of care during the patient's stay with a focus on elements of care delivered on the icu. tabulation of this information allows analysis over time, identifying trends across all patients, and in specific subgroups. this framework has been rolled out at the st george's cardiothoracic icu weekly mortality meetings. themes that have emerged include parent team ownership, delayed palliative care referrals and inadequate documentation of mental capacity. this will continue as part of a three-month trial and following review of this trial may be extended to other critical care units in the trust. this system allows greater insight into patient deaths in a longitudinal fashion and facilitates local identification of problems at an early stage in a way that is not possible within the traditional mortality review format. the nature of the process means that key areas for change can be identified as a routine part of the clinical week. [ ] . in this study, we evaluated three distinct machine-learning methods for predicting possible patient deterioration after surgery. the data was collected retrospectively from the catharina hospital in eindhoven. this dataset contained all the surgeries conducted in the hospital from up to . the variables in this dataset were tested on their ability to differentiate between patients with a normal recovery versus patients with an unplanned icu admission after being admitted to the ward. the dataset contained variables related to either the preoperative screening, surgery or recovery room. all variables were tested for statistical significance using a univariate logistic regression (lr), from which a subset of statistically significant (p< . ) variables was created. these variables were used to train three different types of models, namely, the lr, support vector machine (svm) and bayesian network (bn). the network structure of the bn was designed using expert knowledge and the probabilities were inferred using the data. the three models were validated using five-fold cross-validation, resulting in the following areas under the receiver operating characteristic curve: . ( . - . ) for lr, . ( . - . ) for svm and . ( . - . ) for bn (fig. ) . the results indicate that machine learning is a promising tool for early prediction of patient deterioration. the bn was included because it permits incorporating clinical domain knowledge into the learning process. however, its performance resulted inferior to the lr and svm. in future work, we will investigate alternative domainaware methods, and compare the performance with that of the clinical experts. intensive care unit (icu) admission decisions of patients with a malignancy can be difficult as clinicians have concerns about unfavourable outcomes, such as mortality [ ] . a diagnosis of a malignancy is associated with an almost -fold increased likelihood of refusal of icu admission [ ] . recent large long-term mortality studies of patients with a malignancy admitted to the icu are scarce. therefore, our aim was to compare mortality of patients with either a hematological or a solid malignancy to the general icu population, all with an unplanned icu admission. all adult patients registered in a national intensive care evaluation registry with an unplanned icu admission from to were included. subsequently, we divided these patients into cohorts: cohort (all patients with a hematological malignancy), cohort (all patients with a solid malignancy), and cohort (a general icu population without malignancy). as primary outcome, we used -year mortality, and as secondary outcome, icu and hospital mortality. we included , ( . %) patients in cohort , , ( . %) patients in cohort and , ( . %) in cohort ( table ). the year mortality of patients of cohort , , and was . %, . % and . %, respectively (p< . ). age, comorbidities, organ failure, and type of admission (i.e. surgical or medical) were positively associated with -year mortality in all cohorts (p < . ). one-year mortality is higher in both patients with a hematological malignancy and patients with a solid malignancy compared to the general icu population. in addition, several factors were positively associated with -year mortality, i.e., age, comorbidities, medical icu admission, and organ failure. future research should focus on predictive modelling in order to identify patients with a malignancy that may benefit from icu admission. introduction: drug abuse is associated with immunosuppression in multiple mechanisms. despite that, the only study retrospectively reviewing drug abusers in the icu demonstrated less infections and better outcomes. we compared matched patient populations in order to fully understand whether drug abuse is a risk factor for infection and a predictor of poorer prognosis as is perceived by most physicians. we hypothesized that the drug abusers admitted to the icu will fare as good as or better than non-abuser icu patient populations. methods: this is a prospective study done between the years - on the entire patient population of the detroit medical center. after the drug abuse population was identified, controls were matched according to age and admission icu units. patients charts were reviewed and data regarding baseline demographics, infectious complication and outcome was extracted. data was retrospectively collected for drug abusers and matched controls. comorbidities and hospital admission diagnosis were significantly different between the two groups. disease severity scores were significantly higher in the drug abuser's patient group (dapg) on admission and during the icu stay. dapg had significantly more organ failure: more need for ventilation ( . % vs . % in the dapg (p< . )), more ards ( % vs . %, p= . ), more renal failure ( % vs . %, p= . ) and more need for renal replacement therapy ( . % vs . %, p< . ) .they had longer hospital length of stay (los). there was no difference in icu or hospital mortality. multivariable modeling did not find drug abuse to be an independent risk factor for hospital mortality, icu mortality (hosp: or = . , p = . ; icu: or= . , pp = . ), but was a risk factor for a longer hospital los (me= . , p < . ). drug abuse is not an independent risk factor for mortality or icu los. drug abusers should be evaluated like other patients based on baseline comorbidities and disease severity. this is a small audit which although it did not include general icu still reflects the need for encouraging clinicians and patients to speak freely regarding escalation plans. medical decsions is clinician led however this audit was carried by nursing staff as we have a duty to be advocate for our patients involvement in medical care [ ] . a retrospective analysis of independent risk factors of late death in septic shock survivors c sivakorn , c permpikul , s tongyoo (fig. ) . the pap and katz scales seem to be adequate for predicting mortality of critically ill patients admitted to a medical icu. this finding may help in the elaboration of future icu mortality scoring systems, as well as in more rational use of resources. however, further multicenter studies are needed to better elucidate these results. adherence this last group was chosen because of its experience and specific training in the field of bioethics as a control group or reference. a total of respondents participated in the study. . % were emergency physicians, . % intensivists, . % emergency nursing, . % icu nursing, . % resident doctors, . % medical students and . % other professions. we observed variability in the responses observed not only between different groups of professionals but even within the same group reflecting the difficulty in decision making. variability was observed regarding decisions in end of life ethics conflicts. a high degree of similarity with the group of master in bioethics was observed in the responses issued by medicine students. the barriers and facilitators to framing goals of patient care (gopc) and factors motivating decision making is relatively unexplored [ , , ] . a three part survey of physicians at an australian hospital in a culturally and linguistically diverse suburb ( table ) . identification of levels of confidence and barriers and facilitators to gopc discussion and decision making was the main outcome measure. factors influencing decision-making was analysed through scenarios. results: out of eligible participants responded; female, male, clinical experience - years. level of confidence was ranked between "somewhat confident and very confident." all but one respondent had six months of icu experience. no differences in the level of confidence among physician groups. barriers and facilitators were identified; poor prognosis and patient or family request were most common facilitators; conflict between treating teams and the patient/surrogate and language barriers were most common barriers. factors driving gopc decision-making included clinical, value judgement, communication, prognostication, justice and avoidance. numerous barriers and facilitators were identified. factors driving decision making did not just consider clinical factors; conflict and we aimed to investigate physician-related factors contributing to individual variability in end-of-life (eol) decision-making in the intensive care unit (icu). qualitative study with semi-structured interviews with specialists in critical care, (experience - years) from swedish icus. data was analyzed in accordance to principles of thematic analyses. most of the respondents felt that the intensivist's personality played a major role in eol decisions (table ) . individual variability was considered inevitable. views on acceptable outcome: respondents experienced that the possible outcome for patients was interpreted very differently and subjectively among colleagues, and what seemed an acceptable patient-outcome for one doctor, was not acceptable for another. values: most of the respondents were well aware that they might be affected by their own values and attitudes in the decision-making process. interestingly, several respondents mentioned that they thought that patients that were marginalized by society, especially drug-abusers could be at risk for receiving decisions to limit life sustaining treatments (lst) more often than others. none of the respondents thought that their own religious beliefs played any part in decision making. fear of criticism: among the less experienced respondents there was a clear sense of fear of making a questionable assessment of the patient's medical prognosis. there was a fear for criticism from colleagues that were not directly involved in the decision-making, and may have made another decision. this created a wish among younger respondents to defer or avoid participating in decision-making. physician-related, individual variability in eol decisions primarily consisted of differing views on acceptable outcome, values and fear of criticism. can (figure ). within each quartile of sofa score, mortality was highest in patients with pneumonia and peritonitis and lowest in patients with cellulitis (see figure ). the sepsis- consensus definition identified organ dysfunction as the hallmark feature of sepsis [ ] . in developing sepsis- , the sequential organ failure assessment (sofa) score was chosen for its prognostic value and relative ease of implementation clinically [ ] . we propose an update based on epidemiologic data from two intensive care databases that more effectively captures organ dysfunction in the context of sepsis- . using the mimic-iii (exploration) and e-icu (validation) databases, we extracted patients with suspicion of infection to form the study cohort. the predictive power of each sofa component was assessed using the area under the curve (auc) for in-hospital mortality. a logistic model with the lasso penalty was used to find an alternative statistically optimal score. results: by utilising alternate markers of organ dysfunction (e.g. lactate, ph, urea nitrogen) we demonstrated a significant improvement in auc for several versions of the new score, sofa . ( figure ). the sofa score can be updated to reflect current advances in clinical practice. using epidemiologic data, we have shown that substitution of existing components with more powerful measures of organ dysfunction may provide an improved score with greater predictive power. moreover, sofa . exhibits equivalent ease of implementation, but better reflects organ dysfunction in the context of sepsis- . introduction: risk of acute organ failure (aof) in cancer patients(pts) on systemic cancer treatment isunknown. however, % of non-hematologic and % of hematologic cancer pts will need admission to intensive care unit (icu). ipop-sci- / is a prospective cohort study designed to ascertain the cumulative incidence of aof in adult cancer pts. single centre prospective cohort study with consecutive sampling of adult cancer pts admitted for unscheduled inpatient care while on, or up to weeks after, systemic cancer treatment. primary endpoint was aof as defined by quick sofa. six months accrual expected an accrual of pts to infera population risk aof with a standard error of %. between / and / pts were on systemic anticancer treatment, had unscheduled inpatient care and were eligible for inclusion and were included. median age was years, % were male, % had adjusted charlson comorbidity index (cci) &gt; and hematologic cancers accounted for % of pts. the cumulative risk of aof on hospital admission was % ( %ci: - ); and of aof during hospital stay was % ( %ci: - ). aof was associated with older age, cci &gt; ,hematologic malignancy, shorter median time from diagnosis and &gt; prior line of therapy. on admission, % of pts were considered not eligible for artificial organ replacement therapy (noaort) and % of pts who developed aof while inhospital were judged noaort. overall, ( %) of aof pts wereadmitted to icu, . % for aort. median follow up . months (min ; max ). inpatient mortalitywas %, with icu mortality rate of %, with median cohort survival . months ( %ci: . - . ). on multivariate analysis, aof was an independent poor prognostic factor (hr . ; %ci . - . ). risk of aof in cancer pts admitted for unscheduled inpatient care while on systemictreatment is %, and risk of icu is %. aof in cancer pts was an independent poor prognostic factor. a severity-of-illness score in patients with tuberculosis requiring intensive care u lalla, e irusen, b allwood, j taljaard, c koegelenberg tygerberg academic hospital, internal medicine, division of pulmonology and icu, cape town, south africa critical care , (suppl ):p we previously retrospectively validated a -point severity-of-illness score aimed at identifying patients at risk of dying of tuberculosis (tb) in the intensive care unit (icu). parameters included septic shock, human immunodeficiency virus with cd < /mm , renal dysfunction, ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (pao :fio ) < mmhg, diffuse parenchymal infiltrates and no tb treatment on admission. the aim of this study was to validate and refine the severity-of-illness score in patients with tuberculosis requiring intensive care. we performed a prospective observational study with a planned post-hoc retrospective analysis, enrolling all adult patients with confirmed tb admitted to the medical intensive care unit from february to july . descriptive statistics and chi-square or fisher's exact tests were performed on dichotomous categorical variables, and t-tests on continuous data. patients were categorized as hospital survivors or non-survivors. the -point score and the refined -point score were calculated from data obtained on icu admission. results: forty-one of patients ( . %) died. the -point scores of nonsurvivors were higher ( . +/- . vs . +/- . ; p= . ). a score ≥ vs. < was associated with increased mortality ( . % vs. . %; or . ; %ci, . - . ; p= . )( table ) . post-hoc, a pao :fio < mmhg and no tb treatment on admission failed to predict mortality whereas any immunosuppression did. a revised -point score (septic shock, any immunosuppression, acute kidney injury and lack of lobar consolidation) demonstrated higher scores in non-survivors ( . +/- . vs. . +/- . ; p< . ). a score ≥ vs. ≤ was associated with a higher mortality ( . % vs. . %; or . ; %ci, . - . ; p< . ) ( table ) . the -point severity-of-illness score identified patients at higher risk of death. we were able to derive and retrospectively validate a simplified -point score with a superior predictive power. chronic critical illness remains a scientific challenge, from its conceptualization to its impact on patient prognosis [ ] . we evaluated the long-term evolution of icu survivors by identifying the real burden of prolonged critical illness on survival, quality of life and hospital readmissions. we conducted a prospective cohort in brazilian hospitals including icu survivors with an icu stay > h. we compared the patients diagnosed with chronic critical illness with the other patients. telephone follow-up at and months. quality of life was measured by the sf- questionnaire. it was observed that % of patients had some definition of chronic critical illness. chronic critically ill patients had higher mortality at months (p= . ). this difference is mainly due to higher intrahospital mortality (p= . ). mortality after hospital discharge was similar between groups. there was no difference in hospital readmission rate at months. various scores are developed to predict pulmonary complications such as ariscat for patients at-risk of postoperative pulmonary complication [ ] and lips for patients at-risk of lung injury [ ] . the aim of this study was to compare these scores with ours for predicting pulmonary complications in mechanically ventilated patients in sicu. this prospective observational study was conducted in sicu at a university hospital. adult patients admitted to sicu and required mechanical ventilation > hours were included. primary endpoint was the composite of pulmonary complications including pneumonia, ards, atelectasis, reintubation, and tracheostomy. multivariate analysis was performed to identify risk factors of pulmonary complications and the predictive score was developed. the roc analysis was performed to compare power of ariscat, lips and our newly developed score for predicting pulmonary complications. outcomes in intensive care units have been reported to be better in higher-volume units [ , ] . we compared outcomes for high-risk patients between low and higher volume units. audit data from irish icus is analysed and reported by the intensive care national audit & research centre (icnarc) in london. icnarc report risk-adjusted mortality rates in all patients and in low-risk patients(predicted mortality rate < %) for each unit, using the icnarch- model to predict the risk of death. we used this data to calculate the proportion of high-risk patients(predicted mortality > %) in each unit, the mortality rate for high-risk patients, the riskadjusted mortality rate and we compared the overall risk-adjusted mortality between low and high volume units. the median number of annual new-patient admissions among participating units was ; units below this were defined as lowvolume and those above as high-volume units. the proportion of all admissions to each unit who were high-risk ranged from % to %(mean %). unit mortality rates for high-risk patients ranged from % to %. the ratio of observed to expected mortality(standardized mortality ratio -smr) for high risk admissions in each unit ranged from . to . (mean . ). in fig. introduction: adl weakening is often seen after intensive care and called postintensive-care syndrome (pics). this is also seen in even outside icu and proposed to be called post-acute-care syndrome (pacs), especially in elderly patients. in patients with infection, sofa score is famous for predicting in-hospital mortality, but there are no tools for predicting adl weakening during admission. to search for risk factors for adl weakening during admission other than the age, we conducted a retrospective observational study. the subjects were surviving patients with infection, aged from to who were admitted to our department from april , to may , . information of basic characteristics, laboratory data on admission and adjunctive therapies were extracted from our database. we use barthel index (bi) as adl evaluation, and the bi at discharge were evaluated by nurses. we stratified patients by bi at discharge of over or not, and investigated factors that predicted it. we compared each factor between groups, and perform a logistic regression analysis with those that had a significant effect clinically or statistically. despite improved outcomes of intensive care unit (icu) patients, sleep deprivation remains a major concern after icu discharge. multifaceted causes make it difficult to treat and understand [ ] . not many studies have explored sleep deprivation beyond icu. this is evidenced by findings from a recent systematic review [ ] which included studies with only one study [ ] reporting sleep deprivation beyond icu. the aim of this paper is to present findings of sleep deprivation beyond icu from a larger study that examined the experience of critical illness in icu and beyond in the context of daily sedation interruption. hermeneutic phenomenology was used to conduct the study. participants aged years and above who fulfilled the enrolment criteria were enrolled into the study. the cohort comprised male and female participants. in-depth face to face interviews at two weeks after discharge were conducted and repeated at six to eleven months. interviews were audio taped, transcribed and thematically analysed. significant statements were highlighted and categorized for emergent themes. six participants continued to experience sleep deprivation up to eleven months after icu. two cited dreams about icu, three could not explain why they continued to fail to sleep and one stated that he continued hearing icu alarms in the silence of the night. sleep deprivation continues beyond icu due to nightmares, delusional memories and unexplained reasons. further research is needed to establish causes of sleep deprivation and explore ways to promote sleep in critical illness survivors after icu discharge. frailty is being increasingly seen as an independent syndrome. frail patients now account for an increasing proportion of hospital and critical care admissions [ ] . we aimed to compare frailty and mortality in our intensive care unit. clinical frailty score (cfs) was incorporated within the electronic health record (ehr) . we performed this retrospective analysis on the data collected between jan' and oct' . the predictor and outcome for this study were frailty and hospital mortality respectively. all demographic data, acute physiology score, critical care and hospital outcome data were automatically collected in the ehr and recorded. we used a cut off of cfs> and above to define non-frail and frail respectively. chi-squared test, simple and multiple logistic regression were used. adjustment was done for icnarc score and age. total number of patients was , of which ( . %) died in hospital. within the patients< years (n= ), ( %) were recorded as frail or vulnerable. the number of elective and emergency admission were ( %) and ( %) respectively. in the frail and nonfrail, mortality rates were % and . % (p< . ) respectively, with odds ratio of . ( % ci . , ; p< . ) ( age is a well-known risk factor for critical care (cc) outcome and is incorporated into many prognostic tools; however, this has been criticized for assumption of normal physiology for young at baseline. in recent years, frailty in cc prognostication has been of interest, with meta-analysis correlating worsening outcomes with increasing frailty [ ] . in this study, we compared the effect of frailty versus age for determining hospital survival for critically ill patients. we conducted a prospective cohort in brazilian hospitals including survivors of an icu stay > h. we compared chronic critically ill patients (icu stay> days) and the other patients. we performed psychological and functional presential assessment in patients within hours of icu discharge and by telephone at and months. the prevalence of chronic critically ill patients was %. regarding outcomes, chronic critically ill patients had a higher incidence of depressive symptoms than other patients in the immediate post-icu discharge (p = . ), as well as a higher incidence of muscle weakness (p < . ). however, in subsequent evaluations, we found no difference between groups regarding psychological symptoms -depression, anxiety and post-traumatic stress. higher functional dependence was observed in critically ill patients, but without difference in the quality of life score, both in the physical (p = . ) and mental (p = . ) domains. chronic critically ill patients, when compared to patients with stay> h, have a higher incidence of depressive symptoms at icu discharge. this difference disappears in the follow up. chronic critically ill patients present higher levels of functional dependence but without repercussions on quality of life scores. introduction: activation of the inflammatory response after cardiac arrest (ca) is a welldocumented phenomenon that may lead to multi-organ failure and death. we hypothesized that white blood cell count (wbc), one marker of inflammation, is associated with one-year mortality in icu treated ca patients. we used a nationwide registry with data from five academic icus to identify adult ca patients treated between january st and december st . we evaluated the association between the most abnormal wbc within hours of hospital admission and one-year mortality. we accounted for baseline risk of death using multivariable logistic regression (adjusted for age, gender and h sequential organ failure assessment [sofa] score). a total of , patients were included in the analysis. of those patients , ( %) were alive one year after ca. we plotted wbc against baseline risk of death and through graphic examination of a locally weighted scatterplot smoothing (lowess) curve found the lowest risk of death to be associated with a wbc of (e /l) ( figure mrps were identified by a specialist icu pharmacist during this programme and classified by their significance on a scale of one to four. logistic regression was used to determine if demographic factors were associated with the occurrence of a clinically significant mrp -a significance score of two or above (figure ) . the adjusted model included age, icu los, hospital los, apache ii, number of days of renal replacement therapy, number of days of ventilation, the number of medications prescribed at icu discharge, and the who analgesia classification at ins:pire. there were increased odds of having a clinically significant mrp for hospital los (or results: · % (n= ) of patients required at least one pharmacy intervention. the median number of interventions required per patient was one (iqr - ); the maximum number was six. mrps were recorded in this cohort. the most common intervention was clarifying duration of treatment (n= ), followed by education (n= ), and correcting drug omissions (n= ). the bnf drug class most frequently associated with mrps was neurological (n= ), which comprises analgesics (n= ) and psychiatric medications (n= ) ( figure ). this was followed by cardiovascular medications (n= ), gastrointestinal medications (n= ), nutritional medications (n= ), and others (n= ). many icu survivors experience mrps. the most common class of mrp was neurological, reflecting the high incidence of chronic pain and psychiatric illness in this population following discussion with icu staff, ward staff and fy doctors, a formal standardized handover system was introduced. this involved a verbal handover to the appropriate fy by an icu doctor and the patient drug chart to be rewritten in icu at the time of handover. the next change was to display posters on the wards to alert staff that the medical team are to be contacted when a patient comes to the ward from icu and to ensure the drug chart is completed. the baseline data showed a median time delay of hours, with one patient waiting hours for a drug chart. following the interventions the median time delay has decreased to hours within months as demonstrated in figure . the changes have received positive feedback from icu staff, ward staff and fy doctors. the aim of reducing the time delay by % has been achieved with the median time delay now hours. this has improved patient safety by significantly reduced delays in medications and through the introduction of a standardized handover. this has also provided an opportunity for junior doctors on the wards to seek clarification regarding medications and the clinical management plan for the patient. this has established a communication channel between icu and the wards making patient care safer and more effective. telemonitoring outside the icu is scarce. but with innovative wearables measuring respiratory and heart rate wirelessly, culture on intrahospital telemonitoring should definitely change. however, culture has been known to be one of the most crucial success factors in innovation, especially in health care. human design thinking is a promising tool in health care innovation but rarely used in a multidisciplinary team to initiate an innovation culture and stimulate sustainable collaboration. the aim of this study was to initiate a pilot project with a multidisciplinary team to start using wearables for early warning score (ews) on a clinical ward. human design thinking was used to write a value proposition on wearables in clinically admitted neutropenic hematologic patients in an academic center. a multidisciplinary team was performed to cover all disciplines involved in the technical, clinical and administrative parts of the project. a vendor was chosen based on its product specifications in relation to the present hospital monitoring infrastructure. in design thinking sessions, critical appraisal of multiple telemonitoring factors was performed by sub teams and a canvas projectplan was constructed. the project team was formed of registered nurses, physicians, itspecialists, electronic health record consultants; a critical care physician was appointed as project leader. the main critical factors were: unseamlessly transmitting of both heart and respiratory rates including appropriate movements filtering to the nurse's smartphones direct uploading into electronic health record with automated ews calculation nurse driven protocol on ews follow up. philips healthcare with their intellivue guardian wearable biosensor was the chosen vendor ( figure ). design thinking in a multidisciplinary health care team could positively influence the innovation culture. scientific evaluation of this wearable will focus on both nurse's acceptance and data storage and is expected in the summer of . severity, readmission and lengh of stay were lower in patients receiving discharges directly to home. it seems like a safe way to discharge low-risk short stay patients. it seems to save resources and reduce costs, as well as the need for hospital beds. however, futher estudies are needed to actualy evaluate this safety. forty-four cultures were analyzed with eplex ( figure ). complete agreement with conventional diagnostics was observed in / cases. no false-positive results were observed, yielding a sensitivity and specificity of % and % respectively for target pathogens. time to result was, on average, . h faster with eplex compared to conventional diagnostics. antimicrobial therapy could have been optimized in patients based on the eplex result, but treatment was only changed in one case (e.coli ctx-m+) receiving meropenem . h before the antibiogram was available. the eplex blood culture panels provide high accuracy and significantly faster results. the current implementation offers substantial potential value at a minimal cost, and is a feasible approach to -h/ days blood culture diagnostics in many hospital settings. however, efforts to increase adherence are needed. the rapid increase of extended spectrum β-lactamases (esbl)-producing pathogens worldwide makes it difficult to choose appropriate antibiotics in patients with gram-negative bacterial infection. cica-beta reagent (kanto chemical, tokyo, japan) is a chromogenic test to detect beta-lactamases such as esbl from bacterial colonies. the purpose of the study was to reveal whether cica-beta reagent could detect esbl-producing pathogens directly from urine rather than bacterial colonies to make a rapid bedside diagnosis of the antibiotic susceptibility of gramnegative pathogens. we conducted a prospective observational study from july to october . patients were eligible if they were performed urinary culture tests and gram negative pathogens were detected at least + from their urine samples. the urine sample was centrifugated at x g for min. the supernatant of sample was re-centrifugated at x g for min and the pellet was mixed with cica-beta reagent. the test was considered positive when the enzymatic reaction turned from yellow to red or orange. (fig. ) . the bundle approach could be an effective strategy to prevent hospital-acquisition of drug-resistant pathogens in icus. fig. in the aspect-np trial, c/t was noninferior to mem for the treatment of habp/vabp. we evaluated outcomes from that study in the subgroup of pts failing current antibacterial therapy for habp/vabp at enrollment. methods: aspect-np was a randomized, controlled, double-blind, phase trial in which mechanically ventilated pts with habp/vabp received g c/t or g mem every h for - days. pts with > h of active gram-negative antibacterial therapy within h prior to first dose of study therapy were excluded, except those pts failing current treatment (i.e. signs/symptoms of the current habp/vabp were persisting/worsening despite ≥ h of antibiotic treatment). primary and key secondary endpoints, respectively, were -day all-cause mortality (acm) and clinical response at test of cure (toc; - days after end of therapy) in the intent to treat (itt) population. pts failing current antibacterial therapy for habp/vabp were prospectively categorized as a clinically relevant subgroup. at baseline, failing current therapy for habp/vabp was reported in / ( %) c/t and / ( %) mem itt pts, mostly piperacillin/ tazobactam ( %), rd/ th-generation cephalosporins ( %), fluoroquinolones ( %), and aminoglycosides ( %). baseline demographic and clinical characteristics in this subgroup, including prior therapy regimen, were generally similar between treatment arms. there were greater proportions of patients with esbl+ enterobacterales ( %) and pseudomonas aeruginosa ( %) in the c/t arm than the mem arm ( % and %, respectively). lower -day acm was seen with c/t than mem, as evidenced by % confidence intervals for treatment differences that excluded zero ( figure ); statistical significance cannot be assumed because subgroup analyses in this study were not corrected for multiplicity. conclusions: c/t was an effective treatment for habp/vabp pts who had failed initial therapy. catheter-related blood stream infection (crbsi) is common serious infections and associated with increased mortality in intensive care units (icu). one of the most important strategy to prevent crbsi is to minimize the duration of central venous catheterization. we built a medical team consisting of doctors, nurses and pharmacists in icu to discuss whether patients needed central venous catheter (cvc) in terms of monitoring hemodynamics and administering drugs, and recommend catheter removal to attending physicians every day in april . the purpose of this study is to evaluate whether our team-based approach could shorten the total duration of catheterization and reduce crbsi. this was a retrospective historical control study conducted from april to october in the icu of a tertiary care hospital in japan. every patient admitted to the icu during the study period was eligible if they were inserted cvc. patients were divided into groups: conventional (from april to march ) or intervention (from april to october ). we set the primary endpoint as onset of crbsi. the secondary endpoints included the duration of central venous catheterization, the length of icu stay and hospital mortality. crbsi was defined as bloodstream infection in patients with cvc, not related to another site. we included patients: in the conventional group and in the intervention group. the reduced, though nonsignificant, tendency of crbsi was observed in the intervention group [hazard ratio, . ( % confidence interval, . - . ; p = . )]. the intervention group was significantly associated with reduced duration of central venous catheterization ( days vs days; p < . ). no difference was observed in the length of icu stay and in-hospital mortality between groups. the team-based approach to assess cvc necessity could shorten the duration of central venous catheterization and might reduce crbsi. introduction: empiric antibiotic therapy decisions are based upon a combined prediction of infecting pathogen and local antibiotic susceptibility, adapted to patients' characteristics. the objective of this study was to describe the pathogen predominance and to evaluate the probability of covering the most common gram-negative pathogens in icu patients with respiratory infections. methods: data were collected from multiple us and european hospitals as part of the smart surveillance program ( ). mic (mg/l) testing was performed by broth microdilution, with susceptibility defined as follows for p. aeruginosa & enterobacterales: ceftolozane/tazobactam results: hospitals from countries provided gram-negative respiratory isolates from patients located in an icu in the us ( %), eastern europe ( %) and western europe ( %) in . the most common pathogens isolated were p. aeruginosa ( %), k. pneumoniae ( %), e. coli ( %), and a. baumannii ( %). among enterobacterales, % ( / ) were esbl positive. figure provides the probability of covering the most common respiratory gram-negative pathogens from icu patients. co-resistance between commonly prescribed first line β-lactam antibiotics is common: when nonsusceptibility (ns) of one agent was present, susceptibility to other βlactams was generally < %. ceftolozane/tazobactam provided the most reliable in vitro activity in both empiric and adjustment prescribing scenarios compared to other β-lactam antibiotics. ceftolozane/tazobactam ensured a wide coverage of the most common gram-negative respiratory pathogens demonstrating high susceptibility levels and provided the most reliable in vitro activity in both empiric and adjustment antibiotic prescribing scenarios. further studies are needed to define the clinical benefits that may translate from these findings. evaluation of compliance of icu staff for vap prevention strategies on the outcome of patients a kaur fortis hospital, critical care, mohali, india critical care , (suppl ):p ventilator-associated pneumonia is the most common nosocomial infection diagnosed in adult critical care units. it is associated with prolonged duration of mechanical ventilation, increased icu stay and increased mortality. it continues to be a major challenge to the critical care physicians despite advances in diagnostic and treatment modalities. the primary objective of the study was to determine the compliance of icu staff towards vap prevention bundle and secondary objective was to determine the incidence, risk factors and outcome of vap patients. single center, prospective, observational study carried out from february to july . patients mechanically ventilated for more than hours and satisfying the inclusion and exclusion criteria were enrolled in the study. vap was diagnosed using the cdc criteria and clinical pulmonary infection score. vap preventive strategies were employed and compliance of icu staff was assessed. a total of patients were admitted to icu over the set time period and out of them patients were ventilated for more than hours. among them only patients fulfilled the inclusion and exclusion criteria and were enrolled in the present study. excellent compliance was observed in head end elevation, sedation vacation, stress ulcer prophylaxis, and heat moist exchanger filter use, good compliance in oral care and hand hygiene and moderate to poor compliance in subglottic suctioning. the incidence of vap was . % with a vap rate of . / ventilator days. there was a significant correlation between primary diagnosis, hemodialysis, massive blood transfusion and development of vap (p< . )). mean duration of ventilation (p< . ) and mortality (p< . ) were highly significant in vap patients. conclusions: improvement in compliance towards vap bundle and reduction of risk factors can help decrease incidence of vap and related morbidity and mortality. preventive strategies are effective in reducing ventilation-associated pneumonia (vap) in adults [ , ] . in paediatric population there are no data about vap prevention, so we introduced a new bundle (vap-p) based on the available evidence for adults. this was designed as a before-after study. we enrolled all patients admitted to -bed medical-surgical paediatric icu at gemelli hospital in rome, requiring mechanical ventilation for at least hours. patients with pre-existing tracheostomy were excluded. vap-p has been introduced since in order to improve quality of assistance. our bundle consisted in twice a day oral hygiene with chlorhexidine swab, daily check of oral bacterial colonization and aspiration prevention. comparison was made with an historical group including patients admitted before vap-p introduction (since to ). all data about demographics, antimicrobial therapy, icu stay and treatments, were collected. results: patients were included ( after and before vap-p introduction). ( %) events of vap were recorded in vap-p group compared to ( %, p= . ) vap-p group had less vap per days of mechanical ventilation ( / compared to . / p= . ). multivariate analysis yielded an or of . ( %ci . - . ) for vap incidence after bundle introduction. mortality rate was slightly reduced in vap-p group ( . %vs . % p=ns). patients who developed vap required more days on mechanical ventilation and had higher mortality rate ( vs days p< . and %vs % p= . , respectively). our vap-p seems effective in reducing vap incidence in critically ill paediatric population. introduction: ceftolozane/tazobactam (c/t) is a new antibiotic against mdr gramnegative bacteria infections, whose target population are the critically ill patients. even though / g dose safety administered as a hour-infusion has been already assessed, these patients can be under renal replacement therapy (rrt) and suffer changes in their volume of distribution (vd) that may affect antibiotic concentrations. the objective was to determine concentration reached by g c/t ( hour infusion) in septic patients on rrt (cvvhdf) and interdose behavior. we have used rrt machine prismaflex with oxyris filter and m . hplc-uv method was used for simultaneous quantification of c/t. study population consisted of three obese critically ill patients with sepsis, on cvvhdf while receiving g c/t every hours. samples were taken of prefilter, post filter blood and effluent, min before infusion and , and hours after the end of it. we found great interpatient variability with the lowest cconcentration values in the patient with more hemodynamic instability using oxyris filter. even though cmax was less than reported in healthy subjects, we found similar values of auc and t ½ in comparison with healthy population studies. cmax of t was also compromised in comparison with values reported in healthy subjects, but with higher auc and t ½. cvvhdf contributes to c/t clearance. m filter showed the least clearance and higher values of auc and t ½. extraction rate was similar in all patients and filters (figure ) . cmax achieved may be impaired because of the varying vd caused by obesity and rrt, but not affecting the antibiotic characteristics and behaviour. we conclude that because of the variety of clinical conditions, c-concentration is compromised particularly in hemodynamically unstable patients. however, the small sample doesn´t let us extrapolate these results. the extended infusion seems to be adequate to achieve the interdose antibiotic concentration. the use of biomarkers in sepsis is useful for early diagnosis and prognosis. the desired marker should be sensitive, specific, fast and accurate. procalcitonin (pct) measurement is approved by the fda even its efficacy is still under question. the determination of alfatorquetenovirus (ttv) could be a useful marker [ ] . we analyzed samples from patients admitted to icu with clinical suspicion of sepsis. analytical data of c-reactive protein (crp), neutrophils and procalcitonin were collected. the sofa and apache ii scales were calculated and patients stratified according to these values in good and poor prognosis. ttv quantitative determination was carried by using a quantitative crp . we calculated area under the curve (auc) of ttv plasma levels as a function of time. the statistical analysis involved u-mann-whitney and spearman test, using chi for qualitative variables. results showed a not significant (ns) inverse relationship between the ttv auc and the patient proinflammatory level. a tendency (ns) was found between poor prognosis and the pct median values and crp being higher in the poor prognosis.group. a trend showed lower ttv dna count related to worse prognosis. an inverse relationship was found between pct and crp values and the ttv copies /ml plasma, ns correlation in the case of pct. there was a clear trend between the neutrophils´expansion and the regression line slope, obtained between ttv loads in the first two study steps. fig. (abstract p ) . patient pk/pd measurements value> . ), suggesting that the adsorptive mechanism wasn't primarily mediated by plasma protein. ha was saturated after adsorption of a total of . ± . mg of van. the adsorptive kinetics showed an exponential reduction of van mass that reached a plateau after minutes of circulation. in our study, simulating in vivo conditions of hp using ha during sepsis, a rapid and clinically relevant removal of van has been shown. after hours of hp, we suggest to assess van plasma concentration and a loading dose of van should be considered. however, not knowing the potential interactions with other drugs, further in vivo studies are warranted to confirm these findings. assessing the volume of blood taken for blood culture and culture positivitydo we need to take less blood? it is commonly accepted that larger blood culture (bc) volumes (bcv) increase the yield of true positive cultures, and optimally cc of blood should be obtained per set ( bottles). only scarce data exists on the matter of optimal bcv. it is unknown what is the minimal volume that is acceptable for bc. the objective of this study was to determine the association between bcv and the rate of positive bc. blood taken for cultures in bd bactec plus aerobic/f negative bottles was collected from icus and acute care floors at hospitals at the dmc over months. blood volume was estimated automatically from blood background signal data in the bd bactec fx instrument. cultures were analyzed for each bottle. data was summarized for every month as the average volume and number of cultures taken and rate of positive bc for every unit. units were classified according to unit type (icu, medicine, surgery, mixed, emergency department (ed), organ/bmt or "other" which did not fit the previous categories) and analyzed as a group. a total of cultures were taken in units. there is a positive association between bv and positive bc rate for ed and "other" units (irr= . , p= . for the ed, irr= . , p< . for "other" unit). all other units had no association between bv and positive bc rate (figure ). secondary analysis, excluding pediatric units, gave very similar results. when comparing bv between unit types, the ed and "other" unit had significantly lower bv ( . ml in the ed and . ml in "other" unit compared to . ml in the icu, . ml in surgery, . ml in mixed and . ml in bmt). the correlation between bv and positive bc rate is probably limited to units taking very low bv for cultures. units taking volumes above ml show no improvement in positive bc rate when higher volumes are taken. better prospective studies should be done to further establish the minimal bcv needed and spare unnecessary blood loss to hospitalized patients without compromising bc yield. de-escalating antibiotics in sepsis with the use of t mr in a bed greek university icu c vrettou, e douka, i papachatzakis, k sarri, e gavrielatou, e mizi, s zakynthinos st icu department, university of athens, evangelismos general hospital, icu, athens, greece critical care , (suppl ):p in septic patients, the early use of appropriate empiric antibiotic therapy reduces morbidity and mortality. de-escalation refers to narrowing the broad-spectrum antibiotics once the pathogen and sensitivities are known. t magnetic resonance (t mr) is a novel method of detecting eskape pathogens. we aim at investigating if using t mr technology can expedite de-escalation of broad spectrum antibiotics. this is a prospective observational study conducted in our -bed university icu. inclusion criteria were critically ill patients age> y.o., with newly diagnosed sepsis and clinical suspicion of eskape bloodstream infection. a sample for t mr and a blood culture (bc) sample were collected simultaneously from the patients enrolled. the t mr bacteria panel test was run according to the manufacturer's guidelines and the bcs were processed according to the hospital standard procedures. we recorded clinical data and administered antibiotics. results: patients were included in the study. mean time to culture positivity was hours while mean time to t mr result was . hours. in patients the results of t mr were in concordance with the bcs. in the remaining cases, the bcs were negative while the t mr detected one or more eskape pathogens. there were no false negative results. de-escalation in at least one drug was applied to patients ( . %). no escalation was applied to patients ( . %) and antibiotic escalation in ( . %). conclusions: t mr provides a quicker detection time that could shorten the time to targeted therapy. in our population this corresponded to early (within - h) antibiotic de-escalation in approximately / of the included patients. antibiotic stewardship in icu. a single experience l forcelledo , e garcía-prieto , l lópez-amor , e salgado , j fernández dominguez , m alaguero , e garcía-carús the increasing antibiotic resistance in microorganisms urged interventions such as the antibiotic stewardship programs in icu focused on reducing the inappropriate use of antibiotics by improving the antibiotic selection, the dosage, administration route and length as well as improving clinical outcomes and reducing antibiotic resistance. retrospective study where antibiotic consumption was analysed and measured in days of therapy (dots) between and in a medical-surgical icu of a university hospital where a multimodal educational program was established. specific training in infectious diseases in critically ill patients, periodic clinical and formative sessions fig. (abstract p ) . correlation of blood culture positivity rate with blood culture volume by unit type were performed for icu staff and specific leaders within the icu staff designated. results: patients were admitted to icu. there was a reduction of , % in dots (figure ), reduction in antimicrobial resistance rates ( , in , , in [days of resistant microorganism/ patientdays]) without an impact in icu global mortality ( , % in , , % in ). the resistant bacteria registered were acinetobacter baumannii, s. aureus mr, blee and carbapenemase-producing enterobacteriaceae, pseudomonas aeruginosa mr and clostridium difficile. the safe in antimicrobial consumption was € ( % reduction). the icu stay decreased from , days ( ) to , ( ) , with no variation in mean apache ii ( , ) . the bigger decrease in antibiotic consumption was in colistin related to the reduction in resistance bacteria, in special acinetobacter baumannii, in linezolid and in piperacilin/tazobactam, even more remarkable in due to shortage of supplies which meant an increase in meropenem. the application of an antibiotic stewardship program in icu succeeded in reducing antibiotic consumption, antibiotic resistance and costs without an impact in clinical outcomes like mortality or icu stay. clinical outcomes of isavuconazole versus voriconazole for the primary treatment of invasive aspergillosis: subset analysis of indian data from secure trial p kundu, s kamat, a mane pfizer limited, medical affairs, mumbai, india critical care , (suppl ):p the secure trial was designed to compare the safety and efficacy of isavuconazole (a) versus voriconazole (v) for primary treatment of invasive mould disease caused by aspergillus and other filamentous fungi. the present analysis is aimed at comparing the indian subset of patients with that of the overall trial population and to ascertain any similarity or difference in the primary efficacy endpoint and safety/tolerability in these two groups. in secure trial, patients in one group received (i) & another patients received (v). the indian subset had patients. we have done a qualitative analysis as the sample size of the indian subset was small. non-inferiority of (i) to (v) in terms of all cause mortality from first dose to day was assessed in overall patients. the treatment difference between (i) and (v) group in the indian subset of patients was analyzed. proportion of patients who had to discontinue treatment due to teaes was analyzed. the all-cause mortality in the overall trial population met noninferiority margin (table ). in the indian subset, it was higher for (i) than (v). there was a lower incidence of ocular, hepatobiliary, skin & subcutaneous tissue disorders in the (i) treated patients (see table ). in indian subset, the above adverse events were less in the (i) group, but statistical inference could not be done due to small sample size. however, similar trend of less number of patients discontinuing therapy due to teaes in the (i) treated patients was seen in the overall patients & the indian subset. the all-cause mortality in the indian subset was higher in the (i) patients. a trend similar to the overall population regarding safety parameters favoring (i) was seen in the indian patients. considering the significantly higher prevalence of ia in india, suitably powered study design is necessary to draw definitive conclusions on the non-inferior efficacy & better safety & tolerability of (i) over (v) in patients of ia. introduction: ventilator-associated pneumonia (vap) is one of the most frequent healthcare-associated infections, correlated with increased mortality,extended hospital stay and prolonged mechanical ventilation. considering the latest outbreak of multiresistant a. baumannii infections in the critically ill patients with vap, there is a growing concern regarding challenges of the antibiotherapy in these patients. although ceftazidim-avibactam is considered to have limited effects on a. baumannii, it is reported to have a synergic activity in combination with other antibiotics. we performed a retrospective, observational study which included icu patients diagnosed with vap(cpis > ). oxa a. baumannii was isolated from the tracheal secretions using a rapid molecular diagnostic platform(unyvero a system). patients were divided in two groups according to the antibiotherapy:group a meropenem + colistin and group b meropenem + colistin + ceftazidim-avibactam.statistical analysis was performed using graphpad applying t-test and kaplan-meier curves, having the in-hospital mortality as primary outcome and days of mechanical ventilation and hospital stay as secondary outcomes. mean age(y.o) in group a was and in group b and in both groups mean charlson comorbidity index was points. survival percent was higher in the group treated with ceftazidim-avibactam ( % vs %, p = . )- (fig. ) . length of stay was significantly decreased in group b ( . days vs days in group a, p = . ). number of days under mechanical ventilation was also decreased in the ceftazidim-avibactam group ( vs ) but the data was not statistically significant. in light of the important thread of multiresistant a. baumannii and the lack of therapeutic measures, the synergistic activity of ceftazidim-avibactam use in combination with other antibiotics may be a promising approach to lower the mortality and hospitalization in critically ill patients diagnosed with vap. impact of patient colonization on admission to intensive care on and days mortality g dabar , c harmouch , e nasser ayoub , y habli , g sleilaty , j infections caused by multi resistant bacteria are a major health problem, especially in icus, and it may be associated with high mortality rates. colonization precedes infection in most instances; therefore it may be a marker of a poor outcome. we tried to determine the impact of colonization on mortality at and days in a population of patients admitted to one medical and one surgical icu in the same institution. medical records review over three years - of all patients admitted to one surgical et one medical icu at hotel dieu de france hospital staying more than h. colonization to resistant bacteria was defined as mrsa, esbl, mdr, and vre. all patient received a nasal and rectal screen on icu admission, in intubated patients tracheal aspirate was considered as colonization in the absence of clinical respiratory tract infection. demographics, apache, sofa, immunosupression, charleston comorbidity index, length of stay, mechanical ventilation, hospitalization and antibiotic use in the previous month were collected. mortality at and days was assessed through medical records or phone call. pearson chi-square was calculated for the association of colonization and mortality at and days, and subsequently odd ratio was estimated. introduction: critically unwell patients have been observed to respond unpredictably to traditional intermittent dosing (id) schedules of vancomycin, likely due to the complex physiological derangements caused by critical illness. continuous infusion (ci) of vancomycin has been suggested to overcome such problems by allowing more regular therapeutic drug monitoring and subsequent effective dose titration [ ] . this study conducted at a tertiary intensive care unit, reports our experience following implementation of a continuous vancomycin infusion protocol. prospective data was collected over two consecuative periods of three months, initially capturing plasma levels for id (target level of - mg/l) followed by reviewing plasma concentration levels in a ci protocol (target level of - mg/l). patients recieving renal replacement therapy were excluded. a total of intermittent vancomycin prescriptions were administered and dosing levels observed. in the three month ci period, patients received ci vancomycin and levels subsequently checked. the ci protocol resulted in increased blood sampling ( samples in ci group vs. samples in id cohort). two non serious incidents were reported in the ci cohort relating to preparation of vancomycin. both groups had a comparable median time to therapeutic range ( hours). however, ci vancomycin group had a greater proportion of first samples outside the desired therapeutic range ( %vs %) (figure ). as the therapy continued, ci vancomycin demonstrated a greater propensity towards consistent therapeutic levels than that observed with id. % of patients on a ci regime achieve the desired target levels compared to % in the id cohort (fig. ) . it was positive for single or multiple microbes in ( . %) and ( . %) samples respectively. single or multiple resistance genes were detected in ( %) and ( %) samples respectively. bfpcr was positive only for bacteria in ( . %), virus in ( . %) and for both in ( . %) cases. influenza a was found in ( . %) cases. the most common organisms in community and hospital acquired pneumonia were streptococcus pneumoniae ( / ) and a. baumannii ( / ) respectively. bacterial cultures were concordant with bfpcr in / ( %) of positive cases. decisions to change antibiotics could be taken earlier based on bfpcr (p< . ) than if were based solely on culturesboth in culture positive ( . ± . vs . ± . hrs) and negative cases ( . ± . vs . + . hrs) where antibiotics would have remained unchanged. based on bfpcr antibiotics were escalated in ( %) patients and teicoplanin ( / ) was most often stopped. bal bfpcr were obtained significantly earlier, identified more organisms and bacterial resistance than culture reports and lead to more frequent and earlier antibiotic changes. severe community-acquired pneumonia (scap) is a frequent cause of hospitalization and mortality. ceftaroline is efficacious for treatment of cap (port risk class iii or iv). most severe patients were excluded from the clinical trials, so the efficacy of ceftaroline in these kind of patients is unknown methods: this is a health record-based retrospective before-after study in a tertiary care hospital. all scap patients admitted in icu between november and february receiving ceftaroline were included. control group included patients with same inclusion criteria but receiving ceftriaxone. propensity scores to adjust for potential baseline differences between groups were performed. levofloxacin or azythromicin were administered in both groups. primary outcome was the change in sofa score over the first h and secondary were days of mechanical ventilation, respiratory failure at h, need of rescue antibiotics, length of stay and mortality results: there were patients in ceftaroline group and in ceftriaxone group. baseline characteristics were similar except from more intubated patients in ceftaroline group (figure ). there were less respiratory failure at h in patients with ceftaroline treatment (- . % vs. - . %; p , ), but no differences in other organ failures, mortality, days of mechanical ventilation or los. there were more need of rescue antibiotics in ceftriaxone group ( . % vs . . %; p , ). we found more streptococcus pneumoniae isolation in ceftaroline group ( ( . %) vs ( . %); p = . ); more empiric use of oseltamir ( ( . %) vs ( . %); p = . ), but no more influenzae infections ( ( . %) vs ( . %); p = . ). s. aureus was detected in patient in ceftaroline group and in in ceftriaxone group. introduction: acute respiratory failure (arf) due to pulmonary infections is a usual cause of intensive care unit (icu) admission. immigration patterns and iatrogenic immune-suppression have made tuberculosis (tb) a common disease in western europe. severe tb requiring icu care is rare. nevertheless, mortality associated with active tb and arf is poor [ ] . adult patients with tb admitted to icu from - were identified retrospectively. diagnosis was based on: positive cultures of sputum, bronchial aspirates or bronchioalveolar lavage fluid. demographic characteristics, reasons for admission, hiv status, anti-tb treatment and mortality were recorded. total of patients with tb were admitted to icu. mean apache ii score was , ± , . sixteen were male. mean age , ± , years. eight ( %) were hiv-positive, ( %) diabetes mellitus type , ( %) chronic liver disease. six ( %) had other causes of immunesuppression. main causes for icu admission were arf due to non- mycobacterium tuberculosis pathogens in %, acute liver failure in %, septic shock due to non-respiratory cause in %. overall, % were on anti-tb treatment at time of admission. tb involved the lung parenchyma in all patients. pleural involvement was present in % and lymph node in %. extrapulmonary sites were present in %: urogenital, gastrointestinal, bone marrow. pathogens identified in over-infections: % gram positive coccus, % gram negative bacilli, % fungal, % mdr-pathogen. one patient hiv-positive suffered arf due to pneumocystis jiroveci. overall, % died during icu stay. besides its latent evolution, mortality of tb patients admitted to icu is extremely high. arf due to over-infection seems to be the main cause for icu admission and mortality. better preventive approach of these patients may improve their outcome. introduction: human african trypanosomiasis (hat) is rarely encountered by critical care clinicians, but is an important differential for fever in the returning tropical traveler. late disease is characterized by seizures, fever and multi-organ failure [ , ] . we present an anonymized case presenting from an endemic area in zambia referred for tertiary critical care management. the patient was too obtunded to give informed consent and his relatives could not be contacted despite extensive efforts. a middle-aged man with no past medical history from rural zambia presented to a local clinical officer post with fever and arthralgia. he was treated twice with anti-malarial medication without resolution of symptoms. two months later he was admitted febrile and obtunded to a local hospital with worsening confusion. he was transferred hours by ambulance to our facility in lusaka, which is the only public tertiary critical care unit in zambia results: gcs on arrival was e m v without localizing neurology. microbiology investigations were negative, including for toxoplasma, cryptococcus, hiv or malaria. the patient suffered a generalized seizure followed by a sustained gcs of and was admitted to the icu for invasive ventilation and seizure control. peripheral blood smears demonstrated trypanosomes consistent with hat secondary to trypanosoma brucei rhodesiense. he was commenced on melarsoprol but rapidly deteriorated, with signs of melarsoprol-induced arsenic encephalopathy and subsequent tonsillar herniation. his death was confirmed by neurological criteria. conclusions: icu management of fulminant hat involves supportive neurocritical care plus melarsoprol, a toxic arsenic compound with common side effects of hepatotoxicity and dysrhythmia. arsenic encephalopathy occurs in % of late hat, with a fatality rate of % [ ] . early diagnosis is associated with a % survival rate in developed world travelers repatriated from endemic areas [ ] . lithium chloride to prevent endothelial damage by serum from septic shock patients (in vitro study) a kuzovlev the aim of the study was to investigate into effectiveness of lithium chloride (licl) as agent that prevents damage to the monolayer of endothelial cells under the action of serum from multiple trauma patients with septic shock. methods: serum from pts with septic shock (sepsis- ) and healthy donors was withdrawn. monolayer of ea.hy endothelial cells were incubated for hrs at °c with healthy person's serum and with septic patient's serum without licl and with it at concentrations of . mmol, . mmol, mmol, mmol. licl was added hour before the change of serum. after incubation cells were washed and fixed with % paraform solution and permeabilized with % triton x- solution. fixed cells were stained with primary antibodies to vecadherin and then incubated with secondary antibodies conjugated with oregon green fluorescent dye as well as with phalloid red and hoechst dye . images were processed by fluorescence microscope and imagej . p and metavue . programs. western blotting was used to detect antibodies to ve-cadherin, claudin and gsk- beta. statistics included mann-whitney test and chi-square test. incubation of a monolayer of endothelial cells with % serum of septic shock patients led to loss of ve-cadherin contacts and decrease of claudine. preincubation with licl . mmol did not prevent dismantling of claudine, actin, ve-cadherins; . mmol licl prevented it (p> . ), but at higher concentrations ( mmol, mmol) almost completely protected endothelial monolayer from destruction of intercellular contacts (p< . ). serum had almost no effect on the phospho-gsk- β level after min, min, min and hr, but caused a significant ( %) decrease in its level after and hrs. licl ( mmol) caused a significant increase in phospho-gsk- β already mins and up to hrs after exposure. licl prevents septic damage to the monolayer of endothelial cells in vitro in a gsk- beta mediated way. introduction: the autonomic nervous system (ans) controls both heart rate and vascular tone, which are known to be impaired during septic shock (ss) . acute inflammation is presumed to increase arterial stiffness of large arteries in experimental studies [ ] . the objectives of this work are to verify if standard ss resuscitation modulate mechanical vascular properties and to verify if alterations in these vascular properties and ans activity are correlated. a protocol of fecal peritonitis septic shock and standard resuscitation (fluids and noradrenaline) was applied on pigs. the arterial blood pressure waveform was recorded in the central aorta and in the femoral and radial arteries. the characteristic arterial time constant tau was computed at the three arterial sites, based on the twoelement windkessel model [ ] . the total arterial compliance (ac) and the total peripheral resistance (tpr) were also estimated. baroreflex sensitivity (brs), low frequency (lf, . - . hz) spectral power of diastolic blood pressure, and indices of heart rate variability (hrv) were computed to assess ans functionality. results: septic shock induced a severe vascular disarray, decoupling the usual pressure wave propagation from central to peripheral sites, as shown by the inversion of pulse pressure (pp) amplification, with a higher pp in the central aorta than in the peripheral arteries during shock. the time constant tau together with ac and tpr were independently decreased. a decrease in brs, lf power, and hrv describe an ans dysfunction. after the administration of fluids and noradrenaline, both vascular and autonomic dysfunction persisted and these were found to be significantly correlated. measures of mechanical vascular function and ans activity could represent an useful end-point to guide further clinical investigations and refine our understanding of ss mechanisms, especially under medical treatment. introduction: lipopolysaccharide (lps), is a component of gram-negative bacteria known for its activation of the host immune system. the phospholipid transfer protein (pltp) has previously been shown to promote the binding of lps to lipoproteins, to limit inflammation and to lower mortality following injections of lps or bacterial infection. the aim of the present study was to investigate the role of pltp and lipoproteins in the detoxification of lps from the peritoneal cavity. injection of lps intra-peritoneally (ip) ( mg/kg) to wild type (wt) and pltp knocked-out mice (pltp-ko) (n = per group). mass concentration and activity of lps were quantitated by lcmsms analysis of -hydroxymyristate and lal bioassay, respectively. lipoprotein fractions in plasma were separated by ultracentrifugation (n= vs n = ). following intra-peritoneal injection, clearance of intra-abdominal lps was faster and plasma neutralization was more efficient in wt than in pltp-ko mice ( figure ) . indeed, lps found in plasma of wt mice was proportionally less active, sustaining a higher capacity for wt mice to neutralize lps (figure b) . quantitative dosage of lps in portal blood, minutes after ip injection, revealed that plasma lps associates rapidly with the lipoprotein fraction (hdl plus ldl), and in higher proportions as compared to pltp-ko mice ( [ - ] % vs [ - ] %, respectively; p < . ). in line with previous studies, these observations now indicate that, lps readily associates with lipoproteins in a neutralizing process pltp mediated. finally, even with a heavy lps load ( mg/kg), the bulk of lps was still found in the lipoprotein fraction ( [ - ] %), suggesting that lipoproteins plus pltp in wt mice have a high capacity to detoxify intraperitoneal lps. in a model of peritonitis, lipoproteins and pltp were found to constitute key playors for peritoneal clearance and neutralization of lps. it emerges as a key pathway for the resolution of the inflammatory response in peritonitis. introduction: autotaxin (atx, enpp ) is a secreted enzyme present in biological fluids that catalyses the production of lysophosphatidic acid (lpa). lpa is a bioactive phospholipid evoking various cellular responses in most cell types. upregulated atx levels have been reported in various chronic inflammatory diseases. given the established role of lpa in the inflammatory response, we investigated a possible role for the atx/lpa axis in lps-induced endotoxemia. methods: lps was injected intraperitoneally ( mg/kg) in mice producing % atx levels (atx df/+ , heterozygous null mutant mice), in mice producing - % reduced atx levels upon inducible inactivation (r creer t /enpp n/n mice) and in mice expressing - % increased atx levels (enpp -tg mice). kaplan-meier survival analysis was performed. atx activity was measured using the toos activity assay. results: atx df/+ mice that produce almost % reduced serum atx levels show increased survival compared to their littermate controls. for the inducible inactivation of atx, enpp n/n targeted mice were crossed with the r cre-er t mice and tamoxifen induction enabled temporal control of floxed gene expression. r creer t /enpp n/n mice were more protected against lps-induced endotoxemia compared to control mice. enpp -tg mice overexpressing autotaxin and showing a -fold increase in plasma levels do not display improved survival rates compared to control group. conclusions: atx participates in systemic inflammation, as reduced atx levels in circulation decrease lethality of mice from caused by lps. the excess amount of circulating atx does not exacerbate the systemic inflammatory response to lps. introduction: pneumonia (pn) is a prevalent and severe infectious lung disease. host genetics plays an essential role in the pathogenesis of infectious diseases including pn [ ] . the aim of the study was to analyze the variability of genes associated with neutrophil activation in pneumonia. to identify differential expressed genes (degs) in communityacquired (cap) and hospital-acquired pneumonia (hap) dataset «genome-wide blood transcriptional profiling in critically ill patients -mars consortium» (gse ) from gene expression omnibus was analyzed (logfc≥ . , fdr-corrected p-value< . ). degs associated with neutrophil activation were selected according to gene ontology go: («neutrophil activation»). with the use of gtex portal and blood eqtl browser, we searched for esnps (expression single nucleotide polymorphisms) in whole blood for neutrophil activation genes differentially expressed in cap/hap. these esnps were further analyzed for their association with pn via the global biobank engine (gbe). a total of degs from gse correspond to go: genes ( up-and down-regulated) of which genes were common to cap and hap. functional enrichment of degs based on disgenet detected top- diseases associated with these genes (fdr-corrected p-value< . ): myeloid leukemia, chronic; sepsis; asthma; lung diseases; allergic asthma. for these genes esnps common to gtex portal and blood eqtl browser were identified. more than half of all variants were located on the second chromosome and influenced the expression of tnfaip and il rap genes. among all esnps we identified variants associated with pn in the gbe (table ) . we identified genes related to neutrophil activation, genetic variability of which was associated with pneumonia. sepsis was induced in wild-type c bl mice (n= ) and cse knockout mice (n= ) by i.p. injection of cfu/mice mdr p. aeruginosa. similar experiments were repeated after cyclophosphamide induced neutropenia. survival was recorded for days. mice were sacrificed for determination of bacterial load and myeloperoxidase (mpo) activity as a surrogate marker of myeloid cell recruitment. cytokines were measured in serum by legendplex inflammatory panel. total leukocytes from mice spleens, with or without pretreatment with the h s donor gyy , were incubated with x cfu/ml mdr p. aeruginosa. bacterial clearance was recorded. we observed a significant decrease in survival of cse -/mice as compared to cse +/+ mice ( % vs. %; p: . ). this survival advantage was eliminated in neutropenic mice ( % for both groups, p: . ). cse -/mice had increased pathogen load in the liver ( . ± . vs . ± . , p: . ) and lung ( . ± . vs . ± . , p: . ). mpo activity was lower in cse -/mice in the liver ( ± vs ± , p: . ) and lung ( ± vs ± , p: . ). cse +/+ mice had increased serum levels of il- ( . ± . vs . ± . of cse -/-, p: . ); mcp- ( . ± . vs . ± . , p: . ) and gm-csf ( . ± . vs . ± . , p: . ). phagocytic activity of leukocytes from cse -/mice was reduced compared to cse +/+ mice. this deficit was eliminated after gyy pretreatment (fig. ) . deficiency of host-derived h s leads to increased susceptibility to mdr p. aeruginosa infection due to an inefficient neutrophil chemotaxis and neutrophil mediated phagocytosis. acknowledgement funded by the itn horizon marie-curie european sepsis academy introduction: neuroinflammation often develops in sepsis along with increasing permeability of the blood-brain barrier (bbb), which leads to septic encephalopathy [ ] . the barrier is formed by tight junction structures between the cerebral endothelial cells [ ] . we investigated the expression of tight junction proteins related to endothelial permeability in brain autopsy specimens in critically ill patients deceased with sepsis, and analyzed the relationship of bbb damage and measures systemic inflammation and systemic organ dysfunction. case series included all adult patients deceased with sepsis in the years - with brain specimens taken at autopsy available. specimens were categorized according to anatomical location (cerebrum, hippocampus, cerebellum). the immunohistochemical stainings were performed for occludin, zo- and claudin. patients were categorized as having bbb damage if there was no expression of occludin in the endothelium of cerebral microvessels. results: % ( / ) developed multiple organ failure before death. . % ( / ) had septic shock. the deceased with bbb damage had higher sofa maximum scores ( vs. , p= . ), and had more often procalcitonin levels above ( % vs. %, p= . ). bbb damage in cerebellum was more common in cases with c reactive protein above mg/l as compared with crp less than ( % vs. %, p= . ). absence of zo- expression in cerebral meningeal samples associated with bbb damage ( % vs. %, p= . ). positive blood cultures (n = ) were associated to absence of zo- expression in cerebellar glial cells ( % vs. %, p= . ). in fatal sepsis, damaged bbb defined as loss of cerebral endothelial expression of occludin ( figure ) is related with severe organ dysfunction and systemic inflammation. loss of zo- in endothelial cells associates with bbb damage, and sepsis contributes to zo- loss in cerebellar glial cells. oxylipins are oxidative breakdown products of cell membrane fatty acids. animal models have demonstrated that various vasoactive oxylipin pathways may be implicated in septic shock pathophysiology but these have been poorly studied in humans. oxylipin profiling was performed on serum samples collected on enrolment to the vanish (vasopressin vs. norepinephrine as initial therapy in septic shock) trial. samples were analysed with liquid chromatography-mass spectrometry. patients were followed up until days. results: samples were collected from of ( . %) patients on inclusion to the trial and ( . %) had died by days. non-survivors were found to have higher levels of a number of oxylipins including: , -dihydroxyeicosatrienoic acid (dhet) (p< . ), , -dhet (p= . ), (s)-hydroxyeicosatetraenoic acid (p= . ), -hydroxyoctadeca-pentaenoic acid (p= . ) but lower levels of the precursor eicosapentaenoic acid (p= . ). when corrected for multiple comparisons with the benjamini-hochberg test, only , -dhet remained significant (p= . ). although there was a difference in median , -dhet levels between survivors and non-survivors, many values were below the level of detection (n= / ( . %)). as such, we also analysed - -dhet as a binary variable (figure ). patients with detectable , -dhet were more likely to die (hr . [ % ci . - . ], p< . ) and have a higher median lactate (p = . ) and total sofa score (p< . ) than those patients where baseline , -dhet was undetectable. our study suggests the oxylipin , -dhet may be associated with septic shock severity and -day mortality. these results are consistent with the known vasodilatory actions of this class of oxylipin. more work is needed to confirm its exact role in septic shock and whether this pathway is amenable to therapeutic intervention. introduction: activation of neutrophils is a mandatory stage and a sensitive marker of systemic inflammatory conditions that can lead to the development of multiorgan failure. the aim of the study was to investigate into the antiinflammatory effects of lithium chloride on human neutrophils in vitro. study was carried out on neutrophils isolated from the blood of healthy donors. % of neutrophils were activated by mkm fmlp, % -by ng/ml lipopolysaccharide (lps); then their activity was evaluated by fluorescent antibodies to cd b and cd b degranulation markers. intact and activated neutrophils were treated with a solution of lithium chloride ( mmol). immunoblotting was used to assess gsk b activity in neutrophils. mann-whitney criterion and p< . were used for statistics. results: lithium chloride mmol decreased the level of expression of cd b on intact neutrophils by % (p= . ), cd b by % (p= . ). fmlp increased cd b expression on neutrophils by . times (p= . ), cd b by . times (p= , ). addition of lithium chloride solution to fmlp activated neutrophils reduced the expression of cd b (p= . ) and cd b (p= . ). lps increased cd b and cd b expression by . times (p= . , p= . , respectively); addition of lithium chloride reduced the expression of cd b (p= , ) and cd b (p= . ) on neutrophils. fmlp led to a dephosphorylation of gsk- b by % (p< . ), lithium chloride increased its phosphorylation by % (p < . ). adding lithium chloride to activated fmlp neutrophils restored the level of gsk- b phosphorylation by % compared to controls (p< . ). lithium chloride modulates the inflammatory activation of neutrophils by bacterial components through the phosphorylation of gsk b in neutrophils. human host immune responses to lipopolysaccharide: a comparison study between in vivo endotoxemia model and ex vivo lipopolysaccharide stimulations using an immune profiling panel dm tawfik introduction: sepsis, a leading cause of mortality among critically-ill patients in the icu, recently recognized by the who as a global health burden. patients that suffer from sepsis exhibit an early hyper-inflammatory immune response which can lead to organ failure and death. in our study, we assessed the immune modulations in the human in vivo endotoxemia model and compared it to ex vivo lipopolysaccharides (lps) stimulation using transcriptomic markers. methods: eight healthy volunteers were challenged with intravenous lps in vivo. in parallel, blood from another volunteers was challenged with lps ex vivo. blood was collected before and after hours of lps challenge and tested with the immune profiling panel (ipp) prototype using the filmarray® system. the use of ipp showed that markers from the innate immunity dominated the response to lps in vivo, mainly markers related to monocytes and neutrophils. comparing the two models, in vivo and ex vivo, revealed that most of the markers were modulated in a similar pattern ( %). some cytokine markers such as tnf, ifn-γ and il- β were under-expressed ex vivo compared to in vivo. t-cell markers were either unchanged or up-modulated ex vivo, compared to a down-modulation in vivo. interestingly, markers related to neutrophils were expressed in opposite directions, which might be due to the presence of cell recruitment and feedback loops in vivo. the majority of ipp markers showed similar patterns of expression post-lps challenge in both models, except for several markers related to neutrophils and t-cells. the ipp tool was able to capture the early immune response in the human in vivo endotoxemia model, which is a translational model mimicking immune host response in septic patients. introduction: serum levels of tyrosine kinase receptor mer and its ligand gas predict mortality in septic patients in the intensive care unit. however, whether their early measurement at emergency department (ed) presentation also predicts mortality and organ failure still needs to be clarified. in this multicentre observational study, septic patients admitted to italian eds were included [ ] . at ed presentation blood samples were taken for routine biochemical analyses and serum mer and gas measurement. urinalyses, blood gas analyses and chest x-ray were routinely performed. mortality at and days, as well as the presence of organ damage such as acute kidney injury (aki), thrombocytopenia, pt-inr derangement and sepsis-induced coagulopathy (sic) were evaluated according to baseline levels of mer and gas . in conclusion, neither mer nor gas are early predictors of mortality in septic patients at ed presentation. however, mer independently predicted the development of sic, thrombocytopenia and pt-inr derangement in this population. glycocalyx shedding correlates with positive fluid balance and respiratory failure in patients with septic shock n takeyama, y kajita, t terajima, h mori, t irahara, m tsuda, h kano aichi medical university, department of emergency and critical care medicine, aichi, japan critical care , (suppl ):p endothelial hyperpermeability would play a major role in septic shock related organ failure. the aim of this study is to clarify the relationship between glycocalyx shedding and respiratory failure, sofa score, plasma angiopoietin (ang)- level and patient survival. methods: plasma samples were collected from septic shock patients from admission to icu discharge and healthy volunteers. plasma syndecan (syn)- and ang- were measured and clinical data was also collected. septic shock patients were classified into groups according to the time-course change of syn- levels. excess syn- (> ng/ml) during to days and remaining high following to days were assigned to group i. excess ang- during to days and decreased following to days were assigned to group ii. moderate increase (< ng/ml) during to days were assigned to group iii. results: plasma syn- levels are positively associated with increased ang- levels (r = . , p= . ), suggesting that ang- is involved in endothelial hyperpermeability. fluid balance and ventilator-free days (vfd) are significantly increased in group i as compared with group iii. sofa score, apache ii and patient outcome does not show any differences between groups i, ii, and iii. the positive correlation between glycocalyx shedding and fluid balance indicates plasma syn- may be a valuable marker for endothelial hyperpermeability. the negative correlation between glycocalyx shedding and vfd indicates plasma syn- may be a valuable marker for respiratory failure. the plasma level of syn- for prognosis and organ failure excluding ards in patients with septic shock requires further investigation. serial procalcitonin measurements in the intensive care unit at hiroshima university hospital k hosokawa, s yamaga, m fujino, k ota, n shime hiroshima university hospital, department of emergency and critical care medicine, hiroshima, japan critical care , (suppl ):p introduction: serum procalcitonin (pct) is a promising biomarker for differentiating bacterial infections from other inflammatory states. moreover, including serial pct measurements in the management of acute respiratory infection reduces the duration of antibiotic therapy without increasing the mortality. however, limited real-world information is available regarding the use of pct in intensive care units (icus). we extracted and analysed data from january to december , from all the orders and results of pct measurements in the icu ( beds) at hiroshima university hospital. a total of , pct measurements from icu patients were included. in patients, pct was tested ≥ times during a single icu stay. serial pct measurements showed a fade-out pattern ( [ %] patients), a second day-peaked decrease pattern ( [ %] patients), and a series of negative patterns ( [ %] patients). compared to patients who demonstrated the fade-out pattern, those who demonstrated the second day-peaked decrease pattern had higher mortality rates ( % vs. %, p < . ). approximately one-third patients in the icu who had decreasing serial pct values demonstrated the second day-peaked decrease pattern. since this group of patients had poorer survival, further studies are needed to clarify the association between a late rise in pct levels and delayed therapeutic intervention. the research was performed on full-term newborns; no clinical signs of bacterial infection were diagnosed. on the , , days the plasmà concentration of il- ß, il- , il- , tnf-α, g-csf, sfas, fgf, no was determined by capture elisa; cd cd , cd cd , cd cd , cd , cd , cd , hla-dr, cd , cd , cd cd , lymphocytes in apoptosis -immunophenotype analysis. by applying the statistical cluster population analysis of the immunological criteria under study we have evaluated the feasibility of sepsis diagnostics at the admission to the intensive therapy unit. the diagnostic rule for sepsis has been formulated by applying the "decision tree" approach to the "r" statistic medium. the cluster analysis confirms the presence of two clusters (presence of absence of sepsis: these two components explain the . % of the point variability). the diagnostic rule for the early diagnostics of sepsis is as follows: disease develops providing during the first hours cd ≥ . %, no≤ . mkmol/l or cd ≤ . %, cd ≤ . %, cd ≥ . % or cd ≤ . %, cd ≤ . %, cd ≤ . % and lymphocytes annexinv-fitc+pi-≥ . %. newborns featured the confirmed sepsis development. the accuracy of this diagnostics amounts to . %; sensitivity to . %; specificity to . %; diagnostic false positive share to . %; diagnostic false positive share to . %; positive result accuracy to . %; negative result accuracy to . %. the aggregate determination of cd , cd , annexinv-fitc+ pi-, cd and the plasma concentration of no enables the pre-clinical diagnostics of sepsis development. efficacy of pancreatic stone protein in diagnosis of infection in adults: a systemic review and metaanalysis of raw patient data j prazak , p egimann , i irincheva , mj llewelyn , d stolz , lg de guadiana-romualdo , r graf , t reding , hj klein , ya que fig. (abstract p ) . impact of h lactate and bio-adm values in patients with elevated lactate level at admission. the green curve in the left km-plot illustrates data from patients with events; the red curve patients with events. the green curve in the right km-plot illustrates data from patients with events; the red curve patients with events. of note, differences in numbers between admission (n= ) and h (n= ) is related to initial mortality introduction: adrenomedullin (am) is a peptide synthesized in vascular endothelial cells and cleared by the lungs. the use of am as an inflammatory biomarker and his predictive value has been studied in critically ill patients, but not yet in veno-venous extracorporeal membrane oxygenation (ecmo). the purpose of this study was to describe the plasmatic levels of am in patients supported with ecmo for acute respiratory failure methods: am (normal values < . nmol/l) was measured at time points: immediately before (t ), -h (t ) and -h after (t ) ecmo initiation and immediately before (t ) and -h (t ) after ecmo removal, in consecutive patients with severe respiratory failure supported with ecmo enrolled in the gatra study (nct ) at fondazione irccs ca' granda -policlinico of milan. data are reported as median ( th - th percentile). statistical analysis was performed using logistic and random effects regression models (to account for repeated measurements within individuals) results: a total of measurements were taken in consecutive patients. am (nmol/l) decreased along the course of ecmo: t = . ( . - . ), t = . ( . - . ), t = . ( . - . ), t = . ( . - . ), t = . ( . - . ) (mean diff.= - . , %: ci - . , - . ). am was lower in patients with viral compared to bacterial ards (mean diff.= - . , %ci - . , - . ) (figure ). am was higher in more severe patients (sofa>= , n= ) compared to less severe patients (sofa< , n= ): . ± . vs . ± . nmol/l, respectively p< . . basal values of am could not predict mortality at days (or= . , %ci: . - . ) after conditioning for sofa score and respiratory failure etiology conclusions: am plasmatic values seem to be higher in more severe patients and in patients with bacterial ards. am decreased along the ecmo course but could not predict mortality in our group of patients fig. (abstract p ) . plasmatic adrenomedullin during ecmo heparin binding protein (hbp) is released from activated neutrophils upon stimulation of b integrins. this pro-inflammatory effect generates the hypothesis that it can be a sepsis biomarker for patients admitted at the emergency department (ed) methods: the prompt study (clinicaltrials.gov nct ) took place at the ed of six greek hospitals. participants were admitted with suspected acute infection and at least one vital sign change. hbp was measured by an enzyme immunosorbent assay in plasma. sepsis was diagnosed by the sepsis- criteria. the primary study endpoint was the sensitivity for the diagnosis of sepsis. outcome prediction was the secondary endpoint. a total of patients were enrolled; had sepsis. the most common infections among patients without and with sepsis were upper respiratory tract infections in . % and . %; community-acquired pneumonia in . % and . %; and acute pyelonephritis in . % and . %. median hbp was . and . ng/ml respectively (p: . ). following analysis of the area under the curve (auc) it was found that the best discriminatory cut-off for sepsis was . ng/ml. the comparative diagnostic performance of hbp versus qsofa score is shown in figure . the odds ratio for sepsis with hbp above . ng/ml was . (p: . ). at the same cut-off point the sensitivity, specificity, positive predictive value (ppv) and negative predictive value (npv) for the prediction of early death after hours was %, . %, . % and % respectively. hbp is more sensitive but less specific than qsofa for the diagnosis of sepsis in the ed. the rule-out prediction of early death seems the great merit. chronobiological and recurrence quantification analysis of temperature rhythmicity in critically ill patients introduction: rhythmicity and complexity of several circadian biomarkers, such as melatonin, cortisol and temperature have been found to be modified by critical illness. we examined the potential alterations of core body temperature (cbt) fluctuations and complexity in three groups (n= ): patients with septic shock upon icu admission (group a, n= ), patients who developed septic shock at icu hospitalization (group b, n= ) and controls (group c, n= ). the hourly, average cbt was computed for h upon icu admission and discharge in groups a and c, as well as during septic shock onset in group b. cosinor analysis of cbt curves was performed leading to the estimation of mesor (mean value), amplitude (the difference between peak and mean values) and acrophase (phase shift of maximum values in hours). complexity of cbt signals was evaluated with recurrence quantification analysis (rqa). no significant alterations in any circadian feature within groups were found, except for amplitude. controls exhibited increased entry cbt amplitude ( . ± . ) compared to groups a ( . ± . , p < . ) and b ( . ± . , p < . ). higher entry cbt amplitude in groups b and c was related with lower saps ii (r = - . and - . , p < . ) and apache ii scores (r = - . and - . , p < . ) respectively, reduced icu and hospital stay in group b (r = - . and - . , p < . ) and entry sofa score in group c (r = - . , p < . ). recovery cbt time series appeared more periodic in relation with icu entry, for all groups. a more random cbt signals pattern upon results: among . . individuals, . received inpatient treatment for sepsis. % had severe sepsis. % of sepsis and % of severe sepsis patients had an explicitly coded hai. the proportion of hai was higher in patients that received icu-treatment than in patients without icu-treatment ( % in icu/ % in non-icu sepsis, % in icu/ % in non-icu severe sepsis patients). tab. shows the foci of explicitly coded hai. nosocomial pneumonia was the most common hai in all patient groups. clabsi occurred more frequently in icutreated patients; % were affected. cauti and c. diff infections were more common among non-icu-treated sepsis patients. more than one quarter of non-icu-treated sepsis patients had a c. diff infection. hai are common causes of sepsis and pose a significant healthcare burden. the proportion of patients affected and the distribution of foci differ between non-icu-and icu-treated sepsis patients with important implications for sepsis management within hospitals. impact of sepsis protocol triggered by ramathibodi early warning score (rews) in ipd sepsis on clinical outcomes s matupumanon , y sutherasan , d junhasawasdikul , p theerawit sepsis is now early identified and managed during triage in the emergency department. however, there is less focus on the effect of patients' management at the ward level. we aim to evaluate the impact of the implementation of the sepsis protocol on clinical outcomes in in-patients with new-onset sepsis. we conducted a prospective observational cohort study among adult medical patients admitted to the general wards in a university hospital. a -month pre-protocol period (august to august ) was assigned to a control group, and a -month protocol period (september to october ) was allocated to a protocol group. an in-patient sepsis protocol comprised nurse-initiated sepsis protocol by ramathibodi early warning score (rews)≥ plus suspected infection, prompt antibiotic, lactate measurement, and fluid resuscitation was implemented. (table ) . the implementation of in-hospital sepsis protocol was associated with significant improvement in patients' outcomes, namely lactate measurement, starting antibiotic within hr, fluid management, and the shorter length of icu stay. icu routine nursing procedures interfere with cerebral hemodynamics in a prolonged porcine fecal peritonitis model sl liu , dc casoni , w z'graggen , d bervini , d berger , sj jakob routine nursing procedures (np) can interfere with blood pressure and cardiac output and may therefore alter cerebral hemodynamics in critical illness. this may be risk factor of sepsis-associated encephalopathy. methods: sedated and mechanically ventilated pigs were randomized to fecal peritonitis or controls (n= , each). after hours of untreated peritonitis, the animals were resuscitated for hours (resuscitation period). np [assessment of sedation (as), tracheal suctioning (ts), change in body position (cp), lung recruitment maneuver (rm)] were performed at baseline and h, h, h and h after start of rp. systemic and cerebral hemodynamics and o saturations were recorded continuously. shock is the most common cause of death in the postsurgical icu, including septic shock and hypovolemic shock, reaching the - % mortality in septic shock. the inadequate response of the immune system to the infection triggers a potent inflammatory cascade, where the c-reactive protein (crp) is an essential key in the amplification and maintenance of this cascade. the gene encoding to crp is located on the proximal long arm of human chromosome ( q ). the gt polymorphism in the promoter sequence of crp gene (rs ) has been associated with invasive pneumococcal disease. thus, we analyze the relationship between rs polymorphism and the risk of developing septic shock in postsurgical patients. an observational, retrospective and single-center study was conducted on a sample of caucasian patients undergoing major abdominal surgery, of which one part developed septic shock and another part developed systemic inflammatory response syndrome, who were used as control. the rs polymorphism was analyzed by vasoactive medications are commonly used in sepsis treatment but may correlate with peripheral ischemia and the well-publicized complication of limb and digit loss. yet, the association between limb and digit threat and the intensity, duration, and pattern of vasopressor exposure are unknown. we studied adults ( - ) at hospitals in an integrated health system who met criteria for sepsis- . we identified the time to clinically apparent limb or digit threat using clinical adjudication among those with vasopressor-dependent sepsis (i.e. > hour of vasopressors at sepsis onset) who had a surgical evaluation within -days of sepsis onset. we defined daily vasopressor intensity as to vasopressors administered. then, we created a time-dependent model for threat with mortality as a competing risk with a weight function to estimates the varying contribution of vasopressors over time. we determined the subdistribution hazard (sh) ratio of threat for various patterns of vasopressor exposure and intensity, adjusted for age, baseline risk factors, and sequential organ failure assessment (sofa) score at sepsis onset. of , adults with sepsis, , ( %) were vasopressordependent (age, [iqr, - ]; , [ %] males; max sofa score, [sd ] ). of these, , ( %) died and ( . %) had evaluations for limb or digit threat [iqr, - ] days after sepsis onset. the model-based weight function showed the contribution of vasopressors to threat was stable over time ( fig a) . overall, a unit increase in cumulative vasopressor exposure was associated with risk of threat (sh ratio, . [ %ci, . - . ], p<. ). for various patterns of vasopressor exposure, greater intensity associated with increased risk of threat ( fig b) . compared to constant exposure, an increasing and peak pattern associated with the greatest sh (fig c) . cumulative vasopressor exposure was associated with an increased risk-adjusted hazard of limb or digit threat following sepsis. fig. (abstract p ) . relationship between vasopressor exposure and limb or digit threat following vasopressor-dependent sepsis. panel a demonstrates the estimated contribution of daily vasopressor intensity prior to surgical evaluation for limb or digit threat, with mortality as a competing risk. panel b and c explore the relationship between threat and both cumulative vasopressor exposure and the pattern of exposure following sepsis onset. (b) the maximum cumulative vasopressor exposure was associated with the highest risk of limb or digit threat (shr . ) when compared to reference exposure pattern (shr . , reference). (c) increasing (shr . ) and peak (shr . ) patterns of cumulative exposure were associate with an increased sh of limb threat, while a decreasing pattern was associated with a lower risk (shr . ) when compared to constant intensity (shr . , reference). abbreviations: shr: subdistribution hazard ratio proportion of encounters transitioning from phenotype at presentation within hrs, by arrival phenotype assignment and probability of membership. (c) tsne plots for α-type, ß-type, y-type, and ∂-type, with core (dark), marginal (light), and non-members (grey) in plots on the left and core, marginal, non members, and transitioning members (black) on the right fig. (abstract p ). isolated microorganisms critical care references: . wertz et al. critical care explorations : e the process investigators choosing wisely guidelines for the provision of intensive care services, version . ics structured patient handovers references: . care of the critically ill woman in childbirth the proqol manual: the professional quality of life scale:compassion satisfaction, burnout & compassion fatigue/secondary trauma scales references: . shimabukuro-vornhagen a et al. ca the code: professional standards of practice and behaviour for nurses, midwives and nursing associates p introduction: the aim of this study was to compare factors associated with the icu mortality for vap due to multidrug-resistant (mdr) klebsiella spp. in case of monobacterial (mo) vs polibacterial (po) origin. methods: retrospective data analysis of patients treated in icu with mdr klebsiella spp. strains as pathogens of vap during three year period was carried out. results: data of patients were evaluated. mo vs po of mdr klebsiella spp. vap cases was found to be ( . %) vs ( . %), p = . . the icu mortality was / ( . %) in mo, and / ( . %) in po one, p = . . statistical significant differences of survivors vs non-survivors in mo and po vap due to mdr klebsiella spp. were found in medians of neutrophilosis p introduction: we study the population structure and resistome of mdr enterobacterales and pseudomonas aeruginosa isolates, c/t-susceptible or -resistant, recovered from low respiratory, intraabdominal and urinary tract infections of icu patients of portuguese hospitals (step study results: in e. coli, two vim- producers were found (st -b -h -o :h -ctx-m- and st -c-h -o :h ) (c/t-mic= . / - / mg/l). a kpc- -st -cladev-h -o :h ( / mg/l) was also detected. the most frequent esbl-e. coli clone was st cpr klebsiella pneumoniae ( patients), candida spp. ( patients). the comparison subgroup consisted of patients with bacteremia caused by non-escape pathogens. we evaluated the days of mechanical ventilation, duration of antibiotic therapy (amt), icu length of stay (los), hospital los and mortality (table ). results: mortality in patients with bacteremia caused by non-eskape pathogens was . %, candida spp vancomycin mass removal over minutes of hemoperfusion using ha . bars refer to vancomycin mass (mg): blue (experiment ) and red (experiment ) bars using blood while green (experiment ) bar using balanced solution. yellow dashes are mean mass values of the three experiments (with standard deviations) and yellow line represents the reduction curve over time table (abstract p ). results. * p-value versus non-eskape subgroup mechanical ventilation p translational value of the microbial profile in experimental sepsis studies sp tallósy , a rutai , l juhász , mz poles , k burián , d Érces , a szabó , m boros invasive hemodynamic monitoring and blood gas analyses were performed on anesthetized animals between - h of sepsis. the respiratory, cardiovascular, renal, hepatic and metabolic dysfunctions were evaluated with the species-specific sequential organ failure assessment (sssofa) score, the microbial profile was determined with selective media and maldi-tof ms in the initial inoculum and in the abdominal fluid taken h after sepsis induction. results: strong correlation was found between the initial dose of the inoculum (cfu) and the sssofa scores for organ dysfunction (rats: r = . , p= . ; pigs: r= . , p = . ) p introduction: pancreatic stone protein (psp) has shown promise as a biomarker of infection however, its diagnostic potential has not been systematically evaluated. we performed a systematic review and meta-analysis of available data on psp to evaluate its value for detecting infection in adults and determining a plasma or serum threshold value. methods: the pubmed and cochrane library database were searched for studies on psp in adult patients and their raw data were analyzed to estimate the best psp cut-off value that could detect infected patients using the youden's index. the cut-off sensitivity, specificity, positive predictive value (ppv) and negative predictive value (npv) were computed and compared to those for procalcitonin (pct) and c-reactive protein (crp). finally, we explored the potential value of a model combining all three biomarkers to detect infection. results: from a total of potentially eligible published studies, containing patients were included in quantitative analysis. among them, patients suffered from a clinically confirmed infection. the median appropriate statistical tests were used using spss . cd was expressed as % age of neutrophils expressing positivity. results: sixty patients were analyzed. all parameters were compared between survivors and non survivors. demographics were comparable. most common source of sepsis was lungs and majority were admitted due to medical reason. non-survivors had significantly increased number of days with septic shock. at day median values of all the biomarkers and the sofa score were significantly higher in the nonsurvivor group (p< . ). there was a decreasing trend of all biomarkers and sofa score amongst survivors. on multivariate logistic regression analysis, increased cd and crp levels between baseline and day , increased days with septic shock and increased sofa references: introduction: we characterized the association of c-reactive protein (crp) with extracellular vesicles (evs) in plasma from sepsis patients and assessed a commercial crp adsorbent (pentrasorb, pentracor, hennigsdorf, germany) to deplete free and ev-associated crp. in addition, we characterized the potential pro-inflammatory effects of ev-bound crp on monocytes and endothelial cells monocytes and human umbilical vein endothelial cells (huvecs) were stimulated with isolated evs ( , g, min) monocyte il- secretion was quantified by elisa; the activation of huvecs was assessed by their expression of icam- and e-selectin using confocal microscopy. results: septic plasma (n= ) contained . ± . mg/l crp vs. . ± . mg/ l for healthy controls (n= ). both, total evs and crp + evs were significantly elevated in septic plasma as incubation of septic plasma with pentrasorb resulted in depletion of free crp ( . ± . mg/l before vs. . ± . mg/l after adsorption) as well as in a significant reduction in crp evs from crp-depleted septic plasma induced significantly lower il- levels. huvec icam- or e-selectin expression, however, did not increase upon stimulation with septic evs. conclusions: treatment of septic plasma with pentrasorb efficiently removes free crp and detaches crp from the ev surface, resulting in reduced proinflammatory effects flow cytometry confirmed the association of monocytes with platelets and platelet-derived evs as well as the uptake of evs by monocytes. conclusions: storage of isolated monocytes induces a shift towards cd expressing proinflammatory monocytes, which seems to be mediated by residual platelets and platelet-derived evs. it remains to be clarified whether evs released from activated platelets can also trigger a shift towards proinflammatory, intermediate monocytes in vivo ethical approval was provided by ucl research ethics committee ( / ). paired parametric analyses were performed and data displayed as mean +/- % ci. results: plasma calprotectin concentration began to increase . hours after endotoxin administration, was significantly higher than baseline by hours ( . ng/ml vs. ng/ml, p < . ), peaked at hours (mean ng/ml, figure ) and normalized by hrs. calprotectin peaked earlier than comparator soluble mediators (procalcitonin hrs, crp, hrs) and exhibited % sensitivity; all participants demonstrating a minimum -fold increase from baseline (mean . x). calprotectin displayed greater baseline variability (sd . ng/ml) than either crp or procalcitonin. conclusions: our results indicate the potential of plasma calprotectin as a biomarker for bacterial infection. it increases earlier and peaks more rapidly than standard biomarkers. whilst higher baseline variability was observed p a multicenter randomized controlled study on landiolol for the treatment of sepsis-related tachyarrhythmia: subanalysis of the j-land s study o nishida kagoshima university graduate school of medical and dental sciences, department of emergency and intensive care medicine methods: we analyzed a retrospective cohort of electronic health records from adult sepsis patients at upmc hospitals from to . we defined sepsis- by i.) suspected infection (e.g., administration of antibiotics or body fluid culture) & ii.) organ dysfunction (e.g., or more sofa points) in the first hours of care. data were organized by hour and included vital signs, lab values, and treatments (e.g., total hourly iv fluids (ml) and norepinephrine equivalent dose). for each hour we describe, i.) available data elements, ii.) presence of sepsis- , and iii by hour , most patients had vital signs ( %; n= , ), basic labs ( %; n= , ), fluid cultures ( %, n= , ), while serum lactate was completed in % (n= , ) conclusions: early sepsis care patterns are variable. iv fluids were given during early hours, when uncertainty about sepsis was greatest, while vasopressors were administered after sepsis- elements were present. p effects of abdominal negative pressure treatment on splanchnic hemodynamics and liver and kidney function in a porcine fecal peritonitis model sl liu department of intensive care medicine splanchnic hemodynamics and laboratory parameters were measured at baseline (bl, start of rp), and h, h and h after start of rp. two/three-way rm-anova or mixed-effects analysis, and student t tests were performed. results: npt in controls had no effect. after sepsis induction, mean arterial pressure (map) decreased by ( - ) mmhg, cardiac output (co) by . ( . - . ) l/min, and arterial lactate increased by . ( . - . ) mmol/l. sepsis and resuscitation was associated with increasing hepatic and renal arterial flows (p≤ . , both), and increasing prothrombin time npt in sepsis resulted in numerically less noradrenaline administration ( . ± . ug/ min/kg in sepsis with npt vs. . ± . ug/min/kg without npt, p= . ) and positive fluid balance ( . ± . ml/h/kg with npt vs. . ± . ml/h/kg without, p= . ). conclusions: in our experimental fecal peritonitis model, npt did neither impair splanchnic hemodynamics nor abdominal organ function. whether npt helps to reduce noradrenaline and volume administration in abdominal sepsis should be evaluated in further studies. p association between a c-reactive protein gene polymorphism (rs ) with the risk of develop septic shock in postsurgical patients of major abdominal surgery p martínez-paz valladolid, spain; hospital of medina del campo notably, the three groups received a comparable pro kg dose of acetaminophen. no difference was found between groups in term of toxic effects. patients carrying the cyp a p showed a more pronounced effect on body temperature in respect of wt and ugt a p °c respectively, but it does not reach statistical significance (fig. b). only % of the patients reach a temperature < °c at t and only % < . °c. conclusions: polymorphisms in enzymes involved in the metabolism of acetaminophen are relatively common. cyp a p seems to lead to higher peak plasmatic concentration and a slightly increased efficacy in fever control panel a: variations of acetaminophen plasmatic levels after minutes (t ) and hours (t ) after administration of an iv dose of g of paracetamol in wt patients and patients carrying mutation; panel b: body temperature variations in wt patients and patients carrying mutations clinical research, investigation, and systems modeling of acute illness (crisma) center, department of biostatistics we determined phenotype cohesiveness using probability of assignment at presentation, defining core members as ≥ % and marginal as < % probability. we determined how members transitioned to other phenotypes over hrs using t-distributed stochastic neighbor embedding (tsne) plots and determined the odds ( %ci) of transition. results: we studied , adult sepsis encounters (median age c) the odds of ever transitioning from presenting phenotype increased significantly for marginal members vs publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank the department of education of the basque government (piba - ) and the university of the basque country upv/ehu (ppg / , giu / ) for their financial support. a great disaster affects the family-and friend-performance of bcpr by diminishing the willingness of family and friend bystanders to follow the instruction provided by dispatchers. the experimental method ifitem could be an alternative of fibtem in cases when internal coagulation pathways assessment is prioritized (i.e. heparinized patients on extracorporeal supports). patients undergoing limitation of life-sustaining therapy had lower karnofsky scale scores. therefore, this scale may be useful to guide end-of-life decisions in the future, but further studies with larger number of patients are needed. readmission after discharge home from critical care: a qualitative study c robinson , f nicolson , p mactavish , t quasim , jm mcpeake nhs greater glasgow and clyde, nhs greater glasgow and clyde, glasgow, united kingdom; university of glasgow, nhs greater glasgow and clyde, glasgow, united kingdom critical care , (suppl ):p readmissions to acute care occur in a high number of critically ill patients within days of hospital discharge [ ] . biomedical drivers such as frailty and pre-existing co-morbidities have been identified as drivers for readmission. however at present there is limited data on the influence of social problems on readmission. this study, using a grounded theory approach, sought to understand from a patient/caregiver perspective what the drivers for readmission to acute care were. ethical approval was granted from the west of scotland research ethics service ( /ws/ ). a grounded theory approach was used to explore from a patient and caregiver perspective what the drivers for readmission are [ ] . using a clinical database, we identified those patients who had an icu admission ≥ days who were readmitted to acute care within days of hospital discharge. the researcher attended the ward and after discussion with the direct care team conducted a semi-structured interview with patient and/or caregiver. the interview was recorded and transcribed verbatim. the transcripts were analysed to generate initial codes, followed by the development categories and sub-categories. theoretical sampling was undertaken. results: participants were interviewed. ( . %) were patients and ( . %) were caregivers. the themes that have emerged from the data were: pain and polypharmacy; lack of social support and/or isolation; strained relationships with primary care providers and information provision across the patient journey. subsequent theory development is underway to understand how this learning could help reduce readmissions in future. in conclusion, both social and biomedical drivers are likely to contribute to acute care readmission in this group. future interventional work is required in order to identify modifiable factors to reduce this burden for patients and the healthcare service. frailty has shown to have prognostic relevance for patients with critical illness. since a wide range of tools has been described to screen for frailty, we aimed to describe the association of two frailty screening tools, the clinical frailty scale (cfs) score and the modified frailty index (mfi) in critically ill patients. we performed a post-hoc analysis of a multicenter cohort of patients admitted to six canadian intensive care units (icu) between february and july . frailty was identified using the clinical frailty scale (cfs) and the modified frailty index (mfi). concordance of the frailty screening tools was evaluated with partial spearman rank correlation and intraclass correlation (icc). discrimination and predictive ability of the tools for hospital mortality, -year mortality, hospital readmission and adverse events were compared using concordance statistic (c-statistic) and calibration plot adjusting for age, sex, sequential organ failure assessment (sofa) score and icu admission source, respectively. the cohort included patients. prevalence of frailty was . % ( % confidence interval [ci] . %- . %) with the cfs and . % ( % ci . %- . %) with the mfi. concordance between the two tools was low [(icc of . ; % ci . - . ) and partial correlation coefficient of . ( % ci . - . )], even after adjustment. hospital and -year mortality were greater for frail compared to non-frail patients using of both tools. similarly, both tools found frail patients were less likely to be living independently after hospital discharge, and more likely to be rehospitalized when compared to non-frail patients. while the cfs and mfi show low concordance, both showed good discrimination and predictive validity for hospital mortality. both tools identify a subgroup of patients more likely to have worse clinical outcomes. the post-intensive care syndrome (pics) is a myriad of physical, psychiatric and cognitive disorders secondary to critical illness, leading to a decreased quality of life and an important socioeconomic burden. this study aimed to identify if the conformity to a pics prevention bundle was able to reduce the incidence of the syndrome at icu discharge. all patients admitted to the icu from january st to december st were included. the conformity to each of the ten components of the pics prevention bundle was assessed daily, and the patients were evaluated for anxiety, depression, cognitive dysfunction, muscular weakness, mobility impairment and nutritional risk at icu discharge and at a -to- -months follow-up consultation. the patient cohort was divided in terciles according to bundle conformity for the analysis. results: from the enrolled patients, ( %) were evaluated at icu discharge, and ( %) attended to the follow-up consultation. there was no difference in baseline characteristics between the cohorts. there was no correlation between the prevalence of pics at discharge and bundle conformity during icu stay ( % vs. % vs %, p . ), though there was a decrease in nutritional risk and days in mechanical ventilation (table ) . after to months there was a reduction on the prevalence of any kind of pics, mobility impairment, muscular weakness and nutritional risk. the patients that developed pics were older and had a higher simplified acute physiology score iii at icu admission. a higher adhesion to a pics prevention bundle was not able to prevent the occurrence of the syndrome. post intensive care syndrome (pics) is well recognized following general icu care [ ] . intensive care syndrome:promoting independence and return to employment (ins:pire) is a multidisciplinary complex intervention designed to address pics [ ] . with a paucity of evidence on pics after cardiothoracic intensive care, we aim to evaluate pics and the feasibility of the ins:pire intervention in this population. those attending the clinic received weeks of intervention including individual appointments with icm nurse, physician, pharmacist, and physiotherapist. a café area facilitated peer support alongside psychology group sessions. primary outcome was quality of life measured by eq- d- l. further surveys included: pain, mental health, and selfefficacy. questionnaires were taken at baseline, and months. results: over cohorts, patients attended, % male, median age years (iqr - ), median apache score of (iqr - . ), and median icu length of stay was days (iqr - ). a total of ( %) patients completed surveys at one year. scheduled admissions represented % of those attending. mean euroqol eq-vas score was / (sd +/- ) at baseline increasing to / (sd +/- ) by year (table ) . those with problems in at least one domain of eq- d- l fell from % at baseline to % at -year with the breakdown shown in table . severe problems were seen in % falling to % at year. hads demonstrated an anxiety or depression rate of %. brief pain inventory identified patients ( %) with ongoing chronic pain. mean self-efficacy was / (sd +/- ) at baseline and / (sd +/- ) at year. cardiothoracic intensive care patients have ongoing and persistent features of pics with significant effects on health-related quality of life. further, the ins:pire multi-professional complex intervention is feasible within this specialist group. screening approach might be implemented whenever screening of the total icu population is not deemed feasible. influenza is an acute viral illness with a significant financial burden. point of care testing for influenza is available and has demonstrated accuracy [ , ] , the current gap in knowledge is the question around the opportunity cost of influenza testing. if poct is financially a less costly test this could free up scarce resource. the study adopts a cost minimisation approach. the point of care test is the roche cobas® liat® machine which can detect flu a/b and is compared with the west of scotland specialist virology centre's established in house multiplex real time pcr assay.the model was developed using microsoft excel and has arms comparing analysis of the above mentioned tests. the model estimates that the total cost of poct per patient tested is £ . compared with £ . for lab testing ( figure ). this is a saving of £ . per patient when poct is used. the result swings in favour of the lab test when poct specificity falls to . %. if the lab could provide the result of influenza testing within hours the result would swing in favour of lab testing. zanamivir which will potentially be used increasingly in the intensive care setting can more than double the difference between the tests in favour of poct. this research suggests that poct offers potential cost savings in the icu setting. this is the case as long as poct specificity is higher than a threshold of . % and the lab take longer that hours to return the result. the sensitivity analysis should allow for external validity given the usual variations in icu practice. the aim of the present study is to describe the demographic, clinical, microbiological aspects and the outcome of patients with intensive care unit-related (icu-related) bacteremia. moreover, we aimed to study the patient outcome in association with colistin susceptibility. retrospective, single-center study in a -bed icu for months, from / / to / / . icu-related bacteremia was defined as bacteremia in patients with icu stay > hours or icu readmission (first admission ≥ month before). only the first episode of bacteremia was considered. the primary outcome was -day mortality. data regarding clinical, demographic and outcome characteristics were retrieved from the patient files. the hospital's ethics committee approved the present protocol. moreover, the patients with bacteremia due to colistin-resistant pathogens were compared with the patients affected by colistin sensitive microbes. forty episodes of gram-negative icu bacteremia were collected during the aforementioned period in patients ( . % male) with a mean age and apache ii of . ± . years and ± . , respectively. the event had taken place at an average of . days. the responsible isolates were resistant to carbapenems in . % of the episodes. the majority of the events were due to a single isolate ( %). acinetobacter baumannii and klebsiella pneumoniae presented the majority of the implicated microbes ( % and . %, respectively). the crude -day mortality was %. finally, we could not detect any difference in mortality between the colistin sensitive and the colistin-resistant pathogens ( figure ). the present study denotes that, in a setting of extremely drugresistant pathogens with limited treatment options, gram-negative bacteremia in the icu is associated with increased mortality. image : characterization of resistance mechanisms affecting ceftolozane/ tazobactam in enterobacterales and pseudomonas aeruginosa icu isolates using whole genome sequencing (step study) m hernández-garcia , cc chaves , jm melo-cristino , ds silva , ar vieira , mp f. pinto , jd diogo , eg gonçalves , jr romano , rc cantón hospital ramón y cajal-irycis, microbiology department, madrid, spain; introduction: clostridium difficile infection (cdi) is the main cause of hospital acquired diarrhoea [ ] . the aim of this study was to compare characteristics of cdi during yr and . a retrospective observational study was carried out in lithuanian university of health sciences hospital -the largest teaching facility of tertiary care in country. according to department of infection control records, patients (pt) with (w.) diarrhoea and the first positive stool test for c.difficile toxin a/b were included. age, charlson comorbidity index (cci) score, profile of hospital department (medical (md), surgical or icu) where cdi was diagnosed, type of cdi (healthcare-associated (ha), hospital or community-acquired) and rate of risk factors (rf) have been estimated in both and . ibm spss . ; pearson's chi-square, fisher's exact tests were used for statistics. p < . was statistically significant. results: in total pt from , from were enrolled. in n= ( %) pt were ≥ yr old, in -n= ( %), (p= . ). in cci> was estimated in n= ( %) pt in comparison of n= ( %) in , (p= . ). in n= ( %) of cdi cases were ha, in -n= ( %), (p= . ). in n= ( %) of cdi were diagnosed in md in comparison of n= ( %) in , (p= . ). in weeks prior to cdi n= ( %) pt have been admitted to hospitals, n= ( %) have been treated w. antibiotics, n= ( %) -w. ppis, n= ( %) -w. h antagonists, n= ( %) -w. immunosupressants in comparison of n= ( %), n= ( %), n= ( %), n= ( %) and n= ( %) in , respectively, (p> . ). overall rate of cdi cases among in-hospital patients increased tenfold by yr and . in , more elderly patients had cdi and severe comorbidities were less frequent in comparison with . in , more cases of cdi were hospital-acquired and have occured in medical departments. rate of risk factors of cdi remained unchanged.these results indicate a possible relationship between ttv dna count and immunological alteration. the ttv quantitative determination could be useful as a proinflammatory marker in sepsis, with some benefits: low cost, easy determination and good correlation with immune system functionalit. it will be necessary to perform a larger study to check our hypothesis and to establish a ttv level threshold that may allow to anticípate the disease prognosis. introduction: acute kidney injury (aki) is a serious complication in sepsis and associated with high morbidity and mortality. the combination antimicrobial regimens with vancomycin (vcm) and broad-spectrum betalactams (bsbl), such as piperacillin tazobactam and cefepime, have been identified as potentially nephrotoxic combinations, but existing studies have not provided sufficient evidence. the aim of this study was to evaluate detailed association between the combination antimicrobial therapy and the risk of aki in septic patients. this investigation was a post hoc analysis of prospective nationwide cohorts enrolling consecutive adult patients with sepsis in intensive care units in japan. in this study, progression of aki was defined as one or more elevation of renal sub-score in sequential organ failure assessment score from day to day . we regarded anti-pseudomonal penicillins, fourth generation cephalosporines, and carbapenems as bsbl. multivariable logistic regression analysis including a two-way interaction term (vcm x bsbl) was performed to assess the add-on effects of each antimicrobial agent on the progression of aki. the final study cohort comprised patients with sepsis. among them, received vcm without bsbl, received bsbl without vcm, received both vcm and bsbl, and received other type of antimicrobials. the administration of vcm was associated with an increased risk of aki in patients with bsbl [odds ratio (or), . ( . - . ); p= . ]. however, the tendency was not evident in patients without bsbl [or, . ( . - . ); p= . ]. the interaction effect on the progression of aki between vcm and bsbl were statistically significant (p for interaction= . ). the regression model including two-way interaction term suggested that the combination of vcm and bsbl might synergistically increase the risk of aki in patients with sepsis. increasing resistance to carbapenems due to carbapenemase productionone of main actual problems of antibacterial resistance in burn icu. production of several types of carbapenemases (kpc, ndm and oxa- ) is common in k. pneumoniae strains. carbapemenase production is a marker of extreme antibacterial resistance. the aim of our study was to investigate the epidemiology of nosocomial infections caused by producing kpc, ndm and oxa- k. pneumonia strains in burn icu. total of patients with nosocomial infections caused by carbapenem resistance strains of k. pneumoniae were included in the study, from whom had lower respiratory tract infection, had skin and skin structure infection. initial identification of isolates was performed in laboratory by automatic microbiological analyzer. for all of k. pneumoniae isolates presence of bla ndm , bla oxa- and bla kpcgenes were examined by pcr method. baseline characteristics of patients: me (iqr) of age - ( ; ) years, me (iqr) of tbsa - ( ; ) percent, me (iqr) of icu los - ( ; ) days. inhalation injury was diagnosed in ( . %) patients. total of patients died, mortality rate was . %. all patients were diagnosed with nosocomial infection caused by k. pneumoniae. from k. pneumonia strains ( . %) were found to be producing kpc, ( . %)producing ndm and ( . %) -producing oxa . only ( . %) carbapenem resistance k. pneumoniae isolates were not producing carbapenemases. from patients infected by oxa producing k. pneumoniae patients died, mortality rate was %. from patients infected by oxa or ndm producing k. pneumoniae patients died, mortality rate was . %. from patients infected by non-carbapenemase producing k. pneumonia no one died. carbapenemase producing strains are widely spread among carbapenem resistance strains of k. pneumoniae in burn icu. mortality of patients infected by producing oxa or ndm k. pneumoniae strains reaches . %. the rationale for blood purification as adjunctive therapy during sepsis involved the capacity in removing endogenous and exogenous toxins, but currently no recommendations exists [ ] . a critical point may be the potential interaction with antimicrobial therapy, which remains the mainstay of sepsis treatment. the aim of our study was to investigate the vancomycin (van) removal during blood purification using an in vitro model of hemoperfusion (hp) with ha cartridge (jafron, zhuhai city, china), most widely used in china and actually available in europe. this is an experimental study. three independent experiments were performed: we injected mg of van in ml of whole blood from healthy donors (experiment and ) or in ml of balanced solution (experiment ) in order to assess membrane saturation. a closed-circuit (blood flow of ml/min) simulating hp ran using ha . samples were collected from arterial line at , , , , , , , , minutes; van plasma concentrations were measured and removal was evaluated using mass balance analysis. differences in mass removal was assessed using kruskal-wallis test. results: figure shows van mass at each timepoints. we observed no difference between in blood and in balanced solution experiments (p- the aim of this study is to determine if routine bbv testing in the icu contributes to the discovery of undiagnosed bbv infections. icu patients may require renal replacement therapy (rrt). sharing rrt equipment carries a risk of bbv transmission, which mainly relates to hepatitis b (hbv), hepatitis c (hcv) and hiv. since , all glasgow royal infirmary icu patients undergo routine bbv screening, with rrt machines allocated for patients with specific bbv statuses. routine bbv testing is beneficial to both the individual and society. hcv is a pertinent health issue in scotland. the scottish government aims to eliminate hcv by and is researching innovative and costeffective methods to identify undiagnosed infections. this single-centre retrospective observational study examined prospectively collected clinical data from icu admissions. proportions were compared using a two-proportion z-test and a logistic regression model was carried out to determine if deprivation quintile was independently associated with the seroprevalence of bbvs. the bbv seroprevalence in the cohort studied: . % (hbv), . % (hcv), . % (hiv). the seroprevalence of hbv in the cohort studied was similar to that of scotland (p= . ), but the seroprevalence of hcv (p< . ) and hiv (p= . ) were statistically significantly higher than that of scotland. due to the small number of reactive test results for hbv and hiv, the relationship between deprivation and bbv seroprevalence was explored for hcv only. the only independent variable associated with a reactive anti-hcv test result was "current or previous illicit drug use" (adjusted odds ratio of . ; % confidence interval of . - . ; p< . ). this study shows that routine bbv testing in the icu is useful in discovering new bbv infections. this is the first observational study focusing on the value of routine bbv testing in an icu setting to our knowledge. continuous infusion vancomycin protocol is a safe, acceptable and effective alternative to intermittent dosing of vancomycin in critical care. ceftaroline is an efficacious treatment in patients with severe cap, admitted in icu. it relates to earlier resolution of respiratory failure and less rescue antibiotics. we need an adequately pragmatic trial to confirm our findings organ dysfunction in scrub typhus, incidence and risk factor a sarkar , a guha , r dey [ , , , , ] . its preads by bite of larval stageof thromboculid mites or chigger [ ] . clinical features may include fever, headache, myalgia, lymphadenopathy, eschar, skinrash. it may also cause pneumonia, renal failure, shock, meningoencephalitis, multiple organ failure [ , ] . our study aims to discuss the incidence of organ dysfunction in a comprehensive way taking the overall population of patients with identified scrub typhus infection. there is lack of data in eastern india regarding the incidence and risk factors of developing multiorgan dysfunction syndrome (mods) in scrub typhus. in this retrospective study we studied the incidence of various organ involvement and the risk factors associated with the development of mods in scrub typhus. we collected data from december to november in tertiary care hospital at kolkata. we have included all patients who are having fever, scrub typhus igm antibody positive, age more than years. sofa score was used in evaluating patients with mods. exclusion criteria involves patient who are having coinfectional ong with scrub typhus. in a cohort (n= ), patients with multiorgan dysfunction syndrome was seen in patients ( . %), the mean age in group of patients with mods was . +/- . years (mean+/-sd). in group of patients with mods, fever duration in days was of +/- . days (mean+/-sd), interval from treatment to defervescenc in days was . +/- . days (mean +/-sd). among patients with mods, hematologic involvement was seen in patients ( . %), hepatic involvement was seen in patients ( . %), renal involvement was seen in patients ( . %), neurologic involvement was seen in patients ( %), respiratory involvement was seen in patients ( . %), cardiovascular was seen in patients ( . %), icu shifting was necessary in patients ( . %), mechanical intubation was needed in patients ( . %) in multiorgan dysfunction syndrome patients. hospital mortality in patients with mods was patients ( . %). no mortality was seen in patients without mods. other parameters were evaluated among patients with mods. they include eschar in patient ( . %), seizure in patients ( . %), hepatoslenomegaly in patients ( . %), leucopenia in patients ( . %), leucocytosis in patients ( . %), thromnbocytopenia in patients ( . %),decreased hemoglobin in patients ( . %), transaminitis in patients ( . %). the risk factors associated with the development of mods are platelet counts, bilirubin, transaminitis, glasgow coma scale, time interval from treatment to defervescence, hemoglobin, total leucocyte count and fever duration. scrub typhus is an important cause of acute febrile illness in this part of the country and is frequently associated with organ dysfunction. however, the overall mortality is low which is similar to other studies done before [ ] . score at baseline were significant (p< . ) predictors of mortality.highest area under the roc curve was obtained for number of days with septic shock ( . ) followed by increased cd between baseline and day ( . ). though serial pct levels significantly increased amongst non-survivors, it did not predict mortality. serial level of biomarkers in icu patients may predict mortality. larger trials are needed to confirm the results. plasma strem- levels were retrospectively measured at day - , - and - in septic shock patients from the immunosepsis cohort (nct ), included between / and / , using a validated elisa method. the associations between strem- , mhla-dr, -day survival status, and occurrence of icu-acquired nosocomial infection (ni) were assessed. neither strem- nor mhla-dr levels at d / were associated with the occurrence of icu-acquired ni. however, -day mortality was significantly higher in patients with d - strem- value superior to the median ( . % vs . %, p= . ; median= pg/ml). a significant inverse correlation was found between mhla-dr at d - and strem- at d - (sp - . , p< . ) and at d - (sp - . , p< . ). at d - , when stratifying patients based on strem- ( pg/ml) and mhla-dr ( ab/c), patients combining elevated strem- and low mhla-dr presented with significantly higher day mortality ( . % vs . %, p = . , chi-squared test) and ni incidence ( . vs %, p= . ) compared with patients with low strem- / high mhla-dr. this study shows for the first time that trem- pathway activation is associated with septic shock-induced immunosuppression, as shown by an inverse correlation between strem- at baseline and mhla-dr expression at d - . persisting high strem- values and low mhla-dr expression in septic shock patients are significantly associated with higher rate of icu-acquired infection and mortality. introduction: sepsis mortality remains high [ ] . the surviving sepsis campaign (ssc) recommends to guide resuscitation on normalization of lactate levels [ ] , however this is debated [ ] . we have shown that plasma levels of bio-adrenomedullin (bio-adm) were associated with patient outcome during sepsis [ ] . we therefore aimed to evaluate the added value of bio-adm to lactate measurement in the adrenoss cohort. this is a post-hoc analysis of the adrenomedullin and outcome in severe sepsis and septic shock (adrenoss) cohort study. the adre-noss study is a prospective observational study conducted in twenty-four centers and included septic patients [ ] . we studied the relationship between the association of initial evolution of lactate plasma levels and bio-adm level at h and outcome in patients for whom both markers were available at admission and one day later (" h"). bio-adm levels below pg/ml were considered as low, and high if greater than pg/ml [ ] . in patients with high lactate levels (> mmol/l) at admission (n= ), lactate normalization (< mmol/l) at h was associated with better outcome than in patients with persistently high lactate at h ( day mortality . % vs . % respectively, hr . [ . - . ], p< . ) ( figure ). among patients with decreasing lactate, high and low bio-adm levels at h identified patients with different outcomes ( day mortality % vs % for low vs high bio-adm respectively, hr . [ . - . ], p< . ). high and low bio-adm levels at h also differentiated outcome of patients with persistently elevated lactate (hr . [ . - . ], p< . ). in patients with low initial lactate, neither lactate or bio-adm had no added prognostic. our data suggest that measurement of bio-adm in addition to lactate may help physicians to refine risk stratification and therefore to guide resuscitation during sepsis. the effect of fluid replacement in sepsis, severe sepsis and septic shock in first hrs in clot quality and microstructure s pillai , g davies the inflammatory response in sepsis can lead to a spectrum of coagulation system defects [ ] . sepsis and severe sepsis is associated with a hypercoagulable state where the clot microstructure is known to be a tight and highly elastic clot, which is potentially resistant to fibrinolysis ( figure ). conversely, septic shock is associated with a hypocoagulable state where the clot microstructure is loose and structurally weak. the study aim to investigate the effect of fluid resuscitation and replacement in clot microstructure over hours. methods: patients ( sepsis, severe sepsis and septic shock) were included in the study. all these patients received standard fluid replacement therapy with crystalloids. blood samples were collected at hours, hours and hours. clot microstructure, standard markers of coagulation and inflammatory markers were measured. in sepsis group following fluid administration, the d f reduced initially and then remained stable ( . - hours, . - hours, . - hours, normal d f range . ± . ). in severe sepsis group, the d f reduced initially, then increased ( . - hours, . - hours, . - hours) and in septic shock, the df was very low to start with and there were only slight increase with fluid administration ( . - hours, . - hours, . - hours). the hypercoagulable state and clot quality in both sepsis and severe sepsis group improved with fluid resuscitation, however despite an early improvement in clot quality, ongoing fluid resuscitation resulted in markedly reduced functional clot with very low clot strength and functionality. this study demonstrates that d f as a marker of clot quality and function may have potential in fluid and component replacement in critical illness and injury. this study analyses the prognostic ability of white blood cell count (wbc), neutrophil:lymphocyte ratio (nlr) and c-reactive protein (crp). hypo-and hyperimmune responses have been associated with increased mortality from septic shock [ ] . patients with septic shock (sepsis . ) admitted to queen elizabeth hospital birmingham, between december and july were included. the primary outcome was -day mortality. data was tested for normality and presented as median (iqr) and analysed using a mann whitney u test. categorical data was presented as % and analysed using a chi-squared test. a p value of < . was used to determine significance. a multivariate binary logistic regression analysis was conducted using age, apache ii, charlson comorbidity index, performance status, and initial lactate as covariates. a hosmer lemeshow test of > . indicated good fit. results: patients were admitted with septic shock. the majority ( %) were male, with a median age of ( - ) and a -day mortality of %. on day , wbc was lower in patients who died compared to patients who survived ( [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] patients who died of septic shock had a lower wbc, nlr and crp response early on compared to survivors. this may represent early immunoparesis that allows infection to propagate unchecked. however, this was not independently associated with mortality when confounding factors were accounted for. a specific metabolite of mitochondriaitaconic acid is formed upon proinflammatory activation. the attempts of various researches to find the itaconic acid in peripherical blood of patients with sepsis were unsuccessful [ ] . some phenylcarboxylic acids (phcas) are known to be microbial metabolites and sepsis biomarkers; they also affect the mitochondrial functions [ ] . concentrations of phcas (phenyllactic, p-hydroxyphenylacetic, phydroxyphenyllactic acids) and mitochondrial metabolites (succinic, itaconic acids) in serum samples from patients on the st day of diagnosis of sepsis and serum samples from patients with late stages of sepsis (sepsis- ) were measured by gas chromatographymass spectrometry; control group - donors. results: itaconic acid was found in low concentrations ( . - . μm) only at early stage of sepsis. the multiple increase in levels of phcas and mitochondrial metabolites were detected in patients with late stage of sepsis in comparison with early stage and donors, p< . . increased succinic acid (up to - μm) concentration is the result of succinate dehydrogenase inhibition by microbial metabolism intermediates (phcas), which was confirmed by in vitro experiments in isolated mitochondria (fig. ) . itaconic acid may be a promising marker in early stage of sepsis, which needs to be proved. prediction of severe events in clinical sepsis is challenging. for such prediction we aimed to compare the novel biomarker calprotectin in plasma, with routine biomarkers. in a prospective study, blood samples were collected from consecutive patients who triggered the sepsis alert in the emergency department in our hospital. c-reactive protein (crp), procalcitonin, neutrophils, and lymphocytes were analysed according to routine practice. p-calprotectin was analysed using a specific particle enhanced turbidimetric assay (gentian diagnostics as). the composite endpoint, which was termed severe event, was defined as death or admission to the intensive care unit (icu)/high dependency unit (hdu) within hours from arrival. the study included patients with written informed consent, of whom were considered to have infection (defined as obtained blood culture and subsequent antibiotic therapy for at least days or until discharge or death), and had no infection. seventy-four patients ( %) with infection developed a severe event. mean pcalprotectin was . mg/l (standard deviation (sd) . ) among patients with infection and . mg/l (sd . ) among patients without infection (p= . ). in patients with infection mean p-calprotectin was . mg/l (sd . ) among those with and . mg/l (sd . ) among those without a severe event (p= . ). analysis of area under the receiver-operating characteristic (roc) curve for prediction of severe events showed superiority for p-calprotectin compared with procalcitonin and neutrophil-lymphocyte-ratio, both regarding all sepsis alert cases and regarding the patients with infection (p< . for all comparisons), fig . in addition, there was a trend toward superior performance compared to crp (p= . and . ). in sepsis alert patients, p-calprotectin was elevated in those who subsequently developed severe events. p-calprotectin was superior to traditional biomarkers for prediction of severe events. introduction: rapid diagnosis of acute infections and sepsis is critical in emergency departments (eds). current tests have slow turnaround times, low sensitivities, and/or signals from contaminant or commensal organisms. empirical antimicrobial treatment may result in severe adverse events and contributes to antimicrobial resistance. diagnostics to distinguish bacterial from viral infections and noninfectious etiologies support clinicians in efforts toward antimicrobial stewardship. in a prospective, non-interventional study in the eds of sites in greece (prompt study nct ), we evaluated hostdx sepsis, a host response test for suspected acute infections and suspected sepsis. hostdx sepsis measures human mrna targets and employs advanced machine learning to differentiate patients with bacterial and viral infections, and noninfectious etiologies. adult patients presenting with suspected acute infection and at least one vital sign change were enrolled. whole blood rna was quantified using nano-string ncounter. predicted probabilities of bacterial and viral infection were calculated (bvn- algorithm). patients were adjudicated in a retrospective chart review by independent infectious disease specialists blinded to hostdx sepsis results. among patients adjudicated as bacterial ( ), viral ( ), noninfected ( ), or indeterminate ( ) the area under the receiver operating characteristics (auroc) of hostdx sepsis for predicting bacterial vs. viral/non-infected patients was . , and auroc for viral vs. bacterial/non-infected patients was . (fig. ) . our results indicate that hostdx sepsis distinguishes bacterial from viral infections and other etiologies with high accuracy. hostdx sepsis is currently developed as a rapid point-of-care device with a turnaround-time of less than minutes. hostdx sepsis may therefore assist ed doctors in making appropriate treatment decisions earlier, towards the ultimate goal of antimicrobial stewardship. we studied the diagnostic value of a leukocyte deformability assay that rapidly quantifies the immune activation signatures of sepsis in an undifferentiated population of adults presenting to the ed. ed clinicians must balance the benefits of early intervention against the risks of indiscriminate use of resource-intensive interventions. there are no currently available rapid diagnostics with acceptable performance to achieve this balance. we prospectively enrolled adult patients within hours of presentation with signs of suspicion of infection in two eds in the usa. edta-anticoagulated blood was drawn and analyzed using deformability cytometry [ ] . procalcitonin (pct) levels were also measured. patients were retrospectively adjudicated for sepsis- by physician committee using the entire medical record. diagnostic performance characteristics and receiver operating curves were used to examine the diagnostic performance of the assay as well as pct. of the patients enrolled, . % were adjudicated as septic. the leukocyte deformability assay demonstrated % sensitivity, % specificity, and % negative predictive value for a single cutoff. the auc was . ( figure ). pct with a cutoff of . ng/ml had % sensitivity, % specificity, and % negative predictive value. the auc for pct (as continuous variable) was . . the leukocyte deformability assay of immune activation signatures demonstrated superior diagnostic performance for sepsis when compared to pct. the assay's diagnostic performance and rapid turnaround time of minutes may positively impact patient outcomes while minimizing indiscriminate use of valuable resources in the ed. it is already known in literature that high levels of midregional proadrenomedullin (mrproadm) are related with organ disfunction in infections despite of source and pathogens [ ] . similarly, microcirculatory impairment has been reported in sepsis. we examine the correlation between microcirculatory disfunction and mrproadm as a sign of early organ failure. we included consecutive adult patients with suspected infection, sepsis or septic shock admitted to our intensive care unit (icu) as first hospital admission with an expected icu stay of > hours. mrproadm was measured daily during the first five consecutive days and sublingual microcirculation was assessed with incident dark field (idf) technology at t , t , and t . we collected information on saps ii, apache scores, and sofa score for each timepoint. results: ten patients had septic shock, sepsis and infection. three patients died during icu stay. a mrproadm clearance of % or more between t and t was found associated with the improvement of mfi (mann-whitney u test, median increase . % versus . %, p= . ) (figure ) . a mrproadm > . nmol/l at the icu admission was associated with a worse sofa score at all the timepoint. moreover, mrproadm levels at admission was found significantly related with icu mortality (auc . [ . - ]; p= . ). mrproadm shown no relation with absolute value of mfi. the study shows a good correlation between the clearance of the biomarker and the improvement in mfi. moreover, our results support previous findings on the prognostic value of mrproadm in terms of sofa and icu-mortality. clinical performance of a rapid sepsis test on a near-patient molecular testing platform r brandon , j kirk , t yager , s cermelli , r davis , d sampson , p sillekens , i keuleers , t vanhoey immunexpress, seattle, united states; immunexpress, immunexpress, seattle, united states; biocartis nv, biocartis, mechelen, belgium critical care , (suppl ):p the purpose of this study was to clinically validate a new, rapid version of the septicyte™ assay on a near-patient testing platform (biocartis idylla™). septicyte™ lab is the first-in-class sepsis diagnostic to gain fda-clearance but has a complex workflow and a turnaround time (tat) of~ hours. the assay in idylla™ cartridge format is called septicyte™ rapid. septicyte™ lab was translated to the biocartis idylla™ near-patient testing platform and analytically validated. for this study, . ml of peripheral blood paxgene tm solution from previously collected patient samples was pipetted directly into the cartridge and inserted into the idylla™ reader. patients were part of an independent cohort (n= ) from intensive care units located in the usa and europe. septicyte™ rapid results were reported as a septiscore™ between and with higher scores representing higher probability of sepsis. assay performance determined included technician hands-on-time (hot), assay tat, failure rates, and area under roc curve based on comparison to retrospective physician diagnosis. average hot was minutes, and average tat was minutes. clinical samples could be processed immediately with septicyte™ rapid and did not require hour pre-incubation of paxgene blood, greatly improving tat. correlation of septiscore™ values between lab and rapid, based upon a subset of samples run on both platforms, was very high (r > . ). estimated roc auc performance for discriminating sepsis from non-infectious systemic inflammation (nisi/sirs) was similar to that previously reported for septicyte™ lab. this is the first demonstration of a validated, fully-integrated, rapid, reproducible, near-patient, immune-response sepsis diagnostic, providing actionable results~ hr, to differentiate sepsis from non-infectious systemic inflammation / sirs. accuracy of septicyte™ for diagnosis of sepsis across a broad range of patients r brandon , k navalkar , d sampson , r davis , t yager immunexpress, seattle, united states; immunexpress, immunexpress, seattle, united states critical care , (suppl ):p the purpose of the study was to demonstrate sepsis diagnostic performance of the biomarkers of septicyte™ in subjects other than critically ill adults, and in hospital locations other than icu. septicyte™ lab was the first immune-response sepsis diagnostic assay to gain fda-clearance (k ) and, as part of gaining this clearance, clinical validation was performed on adult patients admitted to intensive care (icu) only [ ] . we therefore performed an in silico analysis across a broad range of patients using the septicyte™ host immune response biomarkers and algorithm. peripheral blood gene expression data, including public and private datasets, were chosen based on quality, annotation, and clinical context for the intended use of septicyte™. multiple comparisons were performed within datasets to better understand the diagnostic performance in certain cohorts including healthy subjects. diagnostic performance was determined using area under curve (auc). results: table shows some characteristics of the selected datasets and patients, including number of datasets (n= ) and comparisons (n= ), number of cases (n= ) and controls (n= ) used in comparisons, patient category and hospital location. septicyte™ aucs for the three groups of adults, adult / pediatric and pediatric / neonates were . , . , and . respectively, which is similar to that previously reported ( . - . ) [ ] . these results suggest that the septicyte™ signature has diagnostic utility beyond adults suspected of sepsis and admitted to icu. this signature has now been translated to the near-patient testing platform biocartis idylla™ (as septicyte™ rapid) which promises rapid (~ hour) diagnosis of sepsis in a broad patient population following further validation. introduction: especially extracorporeal cardio pulmonary bypass (cpb) is known to induce severe inflammation. postoperative inflammation is associated with a sepsis like syndrome including endothelial barrier disruption, volume depletion and hypotension. sphingosine- -phosphate (s p) is a signaling lipid regulating permeability and vascular tone. in septic humans decreased serum-s p levels could be identified as marker for sepsis severity. we addressed three main issues: ( ) are serum-s p levels affected by cardiac surgery? ( ) are potential alterations of serum-s p levels related to changes of acute-phase proteins, s p sources or carrier? ( ) is the invasiveness of the surgery a factor that may influence serum-s p levels? methods: elective major cardiac surgery patients were prospectively enrolled in this study. serum samples were drawn pre-, post-procedure and on day and day after surgery. we analyzed s pand its potential sources: red blood cells (rbc) and platelets. we further quantified levels of other inflammatory markers and documented other clinical parameters. median serum-s p levels in all patients before the procedure were . (iqr . - . ) nmol/ml. serum-s p levels decrease after surgery, whereas all other inflammatory markers increase. serum-s p levels dropped by % in the on-pump and % in the off-pump group. changes of serum-s p levels are associated with s p sources and carriers: albumin, hdl and vwf:ag activity. patients with a full recovery of their serum-s p levels after surgery compared to their individual baseline presented with a lower sofa score (p> . ) and shorter icu stay (p< . ). serum-s p levels are disrupted by open heart surgery and levels might be negatively affected by endothelial injury or loss of s p sources. low serum-s p levels may contribute to prolonged icu stay and worse clinical status. future studies may investigate the beneficial effects of s p administration during cardiac surgery. the aim of study is to measure and correlate the expression of ncd , mhla-dr, pct (procalcitonin) and qcrp (quantitative creactive protein) to predict development of sepsis and its outcome. in this tertiary centre based longitudinal cohort study, a total patients were enrolled in whom sepsis was suspected on the basis of clinical diagnosis and supported by lab investigations. they were divided into two groups sepsis/case and non-sepsis/control. disease severity in icu was assessed by sequential organ failure score (sofa). blood samples for routine lab investigations and biomarkers were taken at the time of admission in icu before administration of first dose of antibiotics at time d /d . assessment of biomarkers was done simultaneously with tlc at d /d , d and during follow up of patients till their final outcome. there was no significant (p> . ) mean change in pct, qcrp, sofa, ncd , mhla-dr from day to day , however, mean change was higher among cases than controls.on comparison of mhla-dr between the groups across time periods, mhla-dr was significantly (p= . ) lower among septic patients than controls at both day and day . all biomarker correctly predicted cases among different percentage of patients with different sensitivity and specificity. there was no significant (p> . ) association of mortality with the study biomarkers except for pct. in our study, diagnostic value of pct in differentiating sepsis from non-sepsis was similar to ncd among all biomarkers studied. no advantage of ncd or mhla-dr was found over pct in diagnosis and correlation with disease progression and mortality. introduction: aqp is a water channel protein contributing to astrocyte and immune cells migration, blood-brain barrier maintenance and cell survival [ ] [ ] . aqp genetic variants represent biomarkers associating with outcome after traumatic brain injury and intracerebral hemorrhage [ ] [ ] . linking aqp genetic polymorphism to the course of sepsis has not been studied. methods: study cohort included icu patients diagnosed according to sepsis- consensus. aqp rs polymorphism was studied by analyzing pcr products in a % agarose gel using an aqp specific polynucleotide tetraprimer set. data were analyzed by log rank test (medcalc . . ), and odds ratios/hazard ratios were computed. statistical significance was determined by fisher test (ft) or mann-whitney test. results: of sepsis patients had the minor mutation a for snp rs located within the regulatory ' region of the aqp gene. septic shock occurred more frequently in homozygotic carriers of aqp c allele vs. patients with aa or ca genotype: or= . ( %ci: . - . ), p= . (ft). lethality in septic shock patients, n= , significantly increased compared to sepsis patients with no shock, n= ( % vs. %, p= . , ft). maximum sofa values were significantly lower in patients with minor allele a compared to cc carriers of ( . vs. . , respectively, p= . ). in post-surgery group of patients, carriers of ac or aa genotypes had significantly increased survival compared to patients with cc genotypes: chi-square= . ; hr= . ( %ci: . - . ) for lethality; p= . (figure ) . association of minor allele a of aqp snp rs with survival in sepsis patients seems secondary to linking the snp to decreased development of multiorgan failure and septic shock that contribute to mortality. validation of presepsin as a biomarker of sepsis in comparison to procalcitonin, il- and il- v chantziara , f kaminari , c sklavou , s fortis , p kogionou , s perez , a efthymiou saint savvas hospital, icu, athens, greece; saint savvas hospital, cancer immunology and immunotherapy center, athens, greece critical care , (suppl ):p sepsis is an everyday challenge for the intensivist and biomarkers are useful tools for identification and treatment of this syndrome. we sought to validate presepsin as a biomarker of sepsis in comparison to pct(procalcitonin) and interleukins (il- ,il- ). we enrolled patients, men and women average age ( . - ) years old, apache ii ( . - . ), saps ii ( . - . ), sofa ( . - ). patients were septic on admission (according to surviving sepsis campaign: international guidelines for management of sepsis and septic shock: ), had a septic episode during their hospitalization in the icu while patients never endured sepsis. we measured presepsin, procalcitonin, il- , il- during sepsis and on remission. results: all septic patients had increased values of presepsin, pct, il- and il- during sepsis with a cutoff value for presepsin pg/ml, while the values of these biomarkers were significantly decreased during remission or in comparison to non-septic patients(presepsin p = . , pct p≤ . , il- p≤ . , il- p= . . all patients who were not septic survived while among septic patients died ( % mortality). presepsin correlated significantly with pct, il- and il- (p< . ). presepsin is a valid biomarker of sepsis and correlates significantly with all the other values of pct, il- and il- . clinical sepsis phenotypes are proposed at hospital presentation. these phenotypes, biomarker profiles, and outcomes are not yet reproduced in prospective data. even less is known about the biologic mechanism the drives these distinct groups. thus, we sought to validate clinical phenotypes and to determine markers of innate immunity, coagulation, tolerance and tissue damage in a prospective cohort. we prospectively studied patients with sepsis- criteria within hours of presentation at hospitals in pennsylvania ( - ) using automated electronic alerts. using clinical variables, we predicted phenotypes (α, β, γ, δ) for each patient using euclidean distance anchored to published seneca phenotype centroids. discarded blood was analyzed in a subset (n= ) for markers of innate immunity (e.g. il- , il- ), coagulation (e.g antithrombin iii, eselectin), tolerance (e.g. ho- , igfbp ), and tissue damage (e.g. serum lactate, bicarbonate) results: among patients, α-type was present in ( %), β-type in ( %), γ-type in ( %) and δ-type in ( %, figure a ). on average, β-type was older and more comorbid (mean , sd yrs; mean elixhauser . , sd . ) with renal dysfunction (median creatinine . [iqr . - . ] mg/dl, p< . all). the δ-type had more acidosis (mean hco - . , sd . meq/l), higher serum lactate (median . [iqr . - . ] mmol/l, p < . both) and inpatient mortality ( %, figure b) . the γand δ-type had greater markers of innate immunity and abnormal coagulation (e.g il- , icam p< . both), while markers of increased tissue damage (lactate) and poor tolerance (ho- ) were present in δ-type, compared to α-type (figure c) . the distribution and characteristics of clinical sepsis phenotypes were reproduced in a prospective validation cohort. similar to the seneca study, distinct biomarker profiles of tissue damage, innate immunity and poor tolerance were present for the δ-type. the effect that neoadjuvant chemotherapy and hyperthermic intraperitoneal chemotherapy (hipec) may have in the postoperative kinetics of biomarkers remains unknow. some studies demonstrate that neoadjuvant chemotherapy and hipec do not invalidate the use of inflammatory markers in postoperative patient monitoring, but none have compared biomarkers kinetics between patients who underwent hipec or only cytoreduction surgery. our main purpose was to identify a difference pattern in c-reactive protein (crp). we conducted a single-center observational study from january to november , including all patients who underwent cytoreductive surgery with or without hipec. crp was measured daily until seven post-operative day. we compared patients with and without hipec. a total of patients were included, were female. mean age was yrs ( - ). no clinical and demographical differences were observed between groups. no documented infection was found. after surgery crp increased markedly in both groups. crp time-course from the day of surgery onwards was significantly different in hipec patients ( . ± . mg/dl vs . ± . mg/dl; p= . ). multiple comparisons between hipec and non hipec patients were performed and crp concentration was significantly different on the th and th pod (figure ). no differences were found in other biomarkers (leucocytes and platelets) neither in body temperature. after a major elective surgical insult crp levels markedly increase independently of hipec. serum crp time-course showed a higher pattern in hipec patients despite no infection detected. decreased thrombin generation potential is associated with increased thrombin generation markers in sepsis associated coagulopathy d hoppensteadt , f siddiqui , e bontekoe , r laddu , r matthew , e brailovsky , j fareed. introduction: sepsis associated coagulopathy (sac) is commonly seen in patients which leads to dysfunctional hemostasis in which uncontrolled protease generation results in the consumption of clotting factors. the purpose of this study is to determine the thrombin generation potential of baseline blood samples obtained from sac patients and demonstrate their relevance to thrombin generation markers. baseline citrated blood samples were prospectively collected from patients with sac at the university of utah clinic. citrated normal controls (n= ) were obtained from george king biomedical (overland park, ks). thrombin generation studies were carried out using a flourogenic substrate method. tat and f . were measured using elisa methods (seimens, indianapolis, in) . functional antithrombin levels were measured using a chromogenic substrate method. the peak thrombin levels and auc levels were lower in the sac patients in comparison to higher levels observed in the normal plasma ( table ). the sac group showed much longer lag time in comparison to the normal group. wide variations in the results were observed in these parameters in the sac group. the f . and tat levels in the sac group were much higher in comparison to the normal. the functional antithrombin levels were decreased in the sac group. these results validate that thrombin generation markers such as f . and tat are elevated in patients with sac. however, thrombin generation parameters are significantly decreased in this group in comparison to normal. this may be due to the consumption of prothrombin due to the activation of the coagulation system. thus, persistent thrombin generation with simultaneous consumption of clotting factors such as prothrombin contributes to the consumption coagulopathy observed in sepsis patients. introduction: procalcitonin (pct) is used in the icu as an inflammatory marker to monitor bacterial infections and guide antibiotic therapy. whether pct can predict bacteremia and therefore could prevent expenses attached to bloodcultures is unknown . we investigated whether pct can predict the outcome of blood cultures in the icu and reduce expences. a single centre observational cohort study was performed in a dutch community teaching hospital . adult patients who were staying in the icu and were suspected of bacteremia were included. simultaneously with drawing of blood cultures, samples for pct measurement were obtained. expenses for pct measurement and bloodcultures were calculated. in the study period of one year, a total of patients were included. three patients were excluded because of incomplete data. out of the included patients, ten patients had positive blood cultures. there was a significant difference in pct levels between patients who had positive bloodcultures versus patients with negative bloodcultures ( . ng/ml vs . ng/ml) ( figure ). the negative predictive value for negative blood cultures is % when pct is below ng/ml, there was no difference in crp levels between the two groups ( mg/l vs mg/l, p= . ).a set of negative blood cultures in our centre costs euros. positive blood cultures however costs significantly more depending on the micro-organisms found. pct only costs . euros per measurement. so when blood cultures are omitted when the pct level is below ng/ml, a cost reduction of % can be achieved. a pct value below ng/ml is a good predictor of a negative blood cultures in icu patients suspected of bacteremia. pct guided bloodculture management in these patients could lead to a significant cost reduction introduction: level of cfdna in plasma is a promising prognostic candidate biomarker in critical illness [ ] . oxidized cfdna (ocfdna) have not been studied as a biomarker although its functional role in cellular stress have attracted attention of researches [ ] . the goal of our study was to assess the early prognostic value of plasma cfdna/ocfdna for sepsis in a nicu setting. the cohort included nicu patients diagnosed with stroke, intracerebral hemorrhage (ich), anoxia, encephalopathy. cfdna was isolated from day plasma and stained with picogreen. oxidized dna was determined using dna immunoblotting with anti- -oxo-desoxiguanosine antibodies. genotyping of allelic variants of the tlr rs gene was performed using a pcr and designed allele-specific tetraprimers followed by electrophoretic separation of the products statistics was performed by the fisher test and mann-whitney test. results: sepsis was diagnosed by sepsis- criteria in patients ( . %). average nisu staying was , ± , days. circulating dna plasma levels on day predicted the future sepsis development (figure ): or for cfdna was . ( %ci: . - . ), p< . ; or for ocfdna was . ( %ci: . - . ), p= . . power of both performed tests with alpha= . : . . log rank test demonstrated better predictive value of cfdna vs. ocfdna (figure) . concentrations of cfdna, but not ocfdna, on day significantly positively correlated with maximum sofa values during hospitalization, day and pre-outcome leukocyte count and neutrophil-to-lymphocyte ratios in a limited cohort of nisu patients with tlr rs cc genotype and not in other patients with genotype tlr ct+tt. increased level of plasma cfdna better then ocfdna predicts sepsis development in nisu. further studies are warranted to clarify the fig. (abstract p ) . pct values in patients with positive blood cultures and patients with negative blood cultures possible utility of tlr rs polymorphism determining for sepsis risk stratification early on nisu admittance. admission was related with higher severity of illness and extension of icu stay for all groups. reduced cbt fluctuations upon icu admission was found to more severely ill patients with worse clinical outcomes, while the more periodic cbt patterns were correlated with high cbt rhythmicity and better outcome. the impact of sex on sepsis incidence and mortality have been elucidated in previous studies, and sex is increasingly recognized as one key factor in sepsis [ ] . some studies indicate that women have better immunologic responses to infections [ ] . later investigations assume this advantage is linked to immune modulating genes located on the x-chromosome [ ] . the purpose of this study is to reveal sex differences in incidence of and mortality of sepsis in a large population-based cohort. methods: adult participants in the hunt study ( - ) were followed from inclusion through end of . incident bloodstream infections (bsi) from all local and regional hospitals in nord-trøndelag county were identified through linkage with the mid-norway sepsis register, which includes prospectively registered information on bsi used as a specific indicator of sepsis. we estimated age-adjusted cumulative incidence of first-time bsi and compared the risk of a first-time bsi and bsi mortality in men and women using age-adjusted cox proportional hazard regression. during a median follow-up of . years individuals experienced at least one episode of bsi, and died within days after a bsi. cumulative incidence and cumulative mortality curves are shown in fig. a introduction:the proportion of hospital-acquired infections (hai) among sepsis patients is unknown in germany. systematic differences in hai foci between sepsis patients with and without icu treatment are insufficiently described. retrospective cohort study based on nationwide health claims data of the german statutory health insurance aok. incident inpatient sepsis cases were identified in / among insured persons > y without preceding sepsis in months prior to index hospitalization. sepsis was defined according to explicit sepsis icd- -codes (incl. severe sepsis/septic shock). hai were defined based on specific icd- -codes for surgical site infection, catheter- introduction: elevated renin is associated with an increased risk of death in patients with vasodilatory shock (vs). recent data show that patients with vs and elevated renin levels have improved survival when treated with angiotensin ii (ang ii) + standard care (sc) vs placebo + sc. patients with acute respiratory distress syndrome (ards) can develop angiotensin-converting enzyme (ace) defects that can lead to elevated renin levels and insufficient endogenous ang ii production. we hypothesized that patients with severe ards and elevated renin shock would have improved survival when treated with ang ii + sc vs placebo + sc. in the randomized, placebo-controlled, double-blind athos- study, patients with severe vs receiving > . μg/kg/min of norepinephrine or the equivalent were randomized to intravenous ang ii (n= ) or placebo (n= ). in a post hoc analysis, we assessed the subset of patients with elevated renin (defined as a renin level greater than the median value of the overall athos- population) and ards (defined by a pao /fio ratio < ) at the time of randomization. survival to days was compared between the ang ii group (n= ) and the placebo group (n= ). in patients with elevated renin and ards, baseline age, acute physiology and chronic health evaluation ii score, and blood pressure were similar in the ang ii and placebo groups. the median serum renin level was . pg/ml (iqr: . - . ) compared to the normal range for serum renin: - pg/ml. a significantly higher proportion of patients receiving ang ii survived to day compared to those in the placebo group ( % vs %; p= . ). elevated renin identified patients with vs and ards who were most likely to gain a survival benefit from ang ii. elevated renin is likely caused by an ace defect and may describe an important subset of patients with a biotype that responds well to ang ii therapy. introduction: elevated renin levels have been shown to be associated with an increased risk of death and more severe acute kidney injury (aki) in patients with vasodilatory shock (vs). recent data show that patients with vs and elevated renin levels have improved survival when treated with angiotensin ii (ang ii) + standard care (sc) vs placebo (pbo) + sc. we hypothesized that vs patients with severe aki and elevated renin levels would have improved survival and enhanced renal recovery with ang ii treatment. in the randomized, pbo-controlled, double-blind athos- study, patients with severe vs received > . μg/kg/min of norepinephrine or the equivalent and were randomized to intravenous ang ii + sc (n= ) or pbo + sc (n= ). in a post hoc analysis, we assessed the subset of patients with elevated renin (defined as a renin level greater than the median value of the overall athos- population) and severe aki (defined as those with aki requiring renal replacement therapy [rrt] at baseline). survival and renal recovery were assessed in patients treated with ang ii + sc (n= ) and pbo + sc (n= ). in patients with elevated renin and severe aki, baseline age, acute physiology and chronic health evaluation ii score, and blood pressure were similar between ang ii + sc vs pbo + sc. the median baseline serum renin level in the whole group was . pg/ml (iqr: . - . ; normal range for serum renin: - pg/ml). a significantly higher proportion of patients receiving ang ii + sc vs pbo + sc survived to day ( % vs %, respectively; p= . ). ang ii recipients also had a higher rate of discontinuation from rrt by day ( % vs %; p= . ). in this study, elevated-renin shock patients with aki treated with ang ii + sc gained a survival benefit and earlier discontinuation from rrt compared to those receiving pbo + sc. elevated renin is likely caused by an angiotensin-converting enzyme defect and may identify those patients with a biotype that responds well to ang ii therapy. most clinical trials conclude the ineffective use of anticoagulation for sepsis-induced coagulopathy [ ] . however, post hoc analyses of randomized control trials report positive results [ ] , suggesting anticoagulation is effective in specific populations exhibiting coagulopathy. further, anticoagulants should be administered in the early phase [ ] ; however, methods for precisely predicting the progression of sepsis-induced coagulopathy are not established. this study aimed to create and evaluate a prediction model of coagulopathy progression using machine-learning techniques. we performed a subgroup analysis of data from a retrospective cohort study involving adult septic patients in japanese institutions from january to december and used the japanese association for acute medicine disseminated intravascular coagulation (dic) score as a dic severity index test. the predictive ability of Δdic ([dic score on day ] -[dic score on day ]) was evaluated using various statistical methods. using variables available at the outset, we compared the predictive ability of random forest (rf) and support vector machine (svm) with that of multiple linear regression analysis. a total of adults with sepsis were included in the analysis. the root mean square error in Δdic score for the multiple linear regression analysis model was . compared with values of . and . for rf and svm, respectively. thus, the rf method predicted the progression of sepsis-induced coagulopathy more accurately than multiple linear regression analysis. conclusions: rf, a machine-learning technique, was superior to multiple linear regression analysis in predicting the progression of sepsis-induced coagulopathy. this prediction model might enable us to use anticoagulation in an early phase. this study examined the efficacy and safety of landiolol, an ultrashort-acting β -blocker, for treating sepsis-related tachyarrhythmia, according to patient background characteristics. the j-land s study (japiccti- ) was conducted in patients with sepsis, diagnosed according to the sepsis- criteria, and tachyarrhythmia (atrial fibrillation, atrial flutter, or sinus tachyarrhythmia). the patients had a mean heart rate of ≥ beats/min and required catecholamine administration to maintain a mean blood pressure of ≥ mmhg. the efficacy endpoint was the percentage of patients whose heart rate could be controlled within - beats/min at h of registration. the safety endpoint was the incidence of adverse events within h of registration. subgroup analyses of efficacy and safety were performed after stratifying the patients according to various patient background characteristics. a total of patients were randomized, to landiolol and to the control group. the efficacy endpoint, percentage of patients with a heart rate of - beats/min at h of registration, was significantly higher in the landiolol group ( . % vs . %; mantel-haenszel test: p = . ). the incidence of adverse events was . % and . % in the landiolol and control groups, respectively, and there was no difference between the two groups. most adverse events were related to sepsis or septic shock. the subgroup analyses showed that no patient background characteristic clearly affected the efficacy and safety of landiolol. landiolol is a well tolerated and effective therapeutic agent for controlling heart rate in patients with sepsis-related tachyarrhythmias; its safety and efficacy were not affected by the patient background characteristics investigated. tissue oxygenation monitoring in sepsis r marinova, at temelkov umhat alexandrovska, anesthesiology and intensive care, sofia, bulgaria critical care , (suppl ):p near-infrared spectroscopy (nirs) was proposed as a concept in the end of th century. this method offers noninvasive monitoring of oxy-and deoxyhemoglobin in tissues.nirs could be measured on the thenar or forehead within few santimeters of the skin. it was first applied as a monitoring in cardiovascular surgery. patients with sepsis have changes in the microcirculation which are important target for therapy. invasive monitoring of oxygen delivery and consumption has been used in patients with sepsis but as every invasive technique such a monitoring hides risks. nirs offers a noninvasive method for tissue oxygenation monitoring (sto ) and could be useful in patients with sepsis and septic shock. the aim of the study is to compare noninvasive tissue oxygenation monitoring with hemodinamic monitoring and lactate values in patients with sepsis methods:the study includes critically ill patients in icu of umhat alexandrovska, sofia. of the patients fullfil the criteria for septic state. the other patients do not have sepsis. in both group of patients are measured tissue oxygenation with invios monitor, mean arterial pressure, oxygen saturation in mixed venous blood and lactate values during h after icu admission. patients with sepsis are reported with significantly lower values of tissue oxygenation, compared to patients without sepsis. the values of tissue oxygenation correlate well with the mixed venous blood oxygenation, mean arterial pressure and lactate values but not significantly with apache scores. conclusions: nirs when used for tissue oxygenation monitoring correlates well with the hemodinamic monitoring and lacate values in patients with sepsis and could be used as an noninvasive monitoring for guiding teurapeutic strategies. tissue oxygenation monitoring has no linear correlation with the severity of illness in patients with sepsis and could not be reccomended as a guidance in the early ressuscitating stage of sepsis. further investiganions in these field are needed.the sequenom´s massarray platform and a recessive inheritance model was selected (cc vs tt/ct). the possible association between the cc recessive form of the rs polymorphism and the septic shock risk was analyzed, demonstrating a statistically significant relationship (p= . ) between both conditions. among patients who developed septic shock, . % presented a recessive inheritance pattern while . % showed the ct/tt genotype. on the other hand, those patients with the recessive form of the rs polymorphism were selected and a statistical analysis was performed comparing those patients who developed septic shock from those who did not develop it, obtaining a statistically significant relationship (p= . ) between the presence of the recessive form of polymorphism and the likelihood of developing septic shock. the recessive form of rs polymorphism is a risk factor for septic shock in post-operative patients of major abdominal surgery. introduction: sepsis remains one of the major causes of morbidity with mortality rates as high as % worldwide, representing significant clinical challenge to confront highly intangible therapeutic needs. rnabased structures are emerging as versatile tools encompassing a variety of functions capable to bypass the current protein-and cellbased therapies. rna aptamers act as disease-associated protein antagonists. here, the effects of an aptamer, apta- , were evaluated in animal models that mimic systemic inflammation in humans. high dose of lps endotoxin was used to induce systemic inflammation in mice and in non-human primate animal models. apta- was administered intravenously in two doses post lps infection. animals were monitored and blood samples collected up to hours after apta- administration. healthy-and lps-only treated animals served as control groups. complex analyses of clinical parameters, hematology, serum biochemistry, inflammation and tissue damage markers were performed. results: apta- increased survival of endotoxin challenged animals up to % in a dose-dependent manner and exerted profound effects on wellbeing and recovery of healthy eating habits. administration of apta- led to delayed coagulation and enhanced fibrinolysis; maintained the complement cascade activated while preventing it from further amplification. expression of pro-inflammatory cytokines was reduced while anti-inflammatory increased. endogenous pro-inflammatory molecules (damps), secreted from injured cells, were preserved at healthy level in animals treated with apta- . systemic inflammation and sepsis lead to severe dysregulation of several arms/axis of innate immune response. our studies showed that apta- affects various components of this system and restores the organism's control over its dysregulated immune response. thus, apta- might be a promising potential therapeutic candidate to treat life-threatening conditions such sepsis. several preclinical studies demonstrated beneficial effects for methane (ch ) administration in various inflammatory conditions. our aim was to investigate the consequences of post-treatment with inhaled ch in a clinically relevant intra-abdominal sepsis model. anesthetized minipigs were subjected to fecal peritonitis ( . g/kg, - x cfu i.p.; n= ) or sham-operation (sterile saline i.p; n= ). invasive hemodynamic monitoring with blood gas analyses was started between - hours, organ dysfunction parameters (pao /fio ratio; mean arterial pressure; lactate, bilirubin, creatinine; urine output and platelet counts) were determined according to a modified porcinespecific sequential organ failure assessment (ps-sofa) score system, the perfusion rate (pr) of sublingual microcirculation was measured by incident dark field illumination imaging. the animals were divided into non-treated septic or septic shock groups (n= - ) and ch treated septic or septic shock (n= - ) subgroups, ch inhalation started from the th hr ( . % ch in normoxic air; ml/min). despite the standardized induction, heterogeneous severity of organ damage was evolved. in septic and septic shock groups the median values of ps-sofa score reached ( . - . ) and ( . - ), respectively. septic shock was characterized by significant elevations of creatinine and bilirubin levels, while the platelet count decreased (from to * /l). inhalation of ch increased the sublingual pr by % in the septic group, the creatinine and bilirubin levels were decreased by % and %, respectively. ch post-treatment significantly decreased the ps-sofa score (to ; . - . ) and resulted in lower values in septic shock group (to ; . - . ). methane post-treatment effectively influences sepsis-related end organ dysfunction. up to a severity threshold it may be a promising additional organ protective tool. evaluation of sepsis awareness among various groups in turkey: a survey study s erel, o ermis, Ö nadastepe, l karabıyık gazi university school of medicine, anesthesiology and intensive care, ankara, turkey critical care , (suppl ):p introduction: sepsis is a common life-threatening condition in critically ill patients [ ] . public awareness is important for early recognition of sepsis and improvement of outcomes [ ] . we aimed to evaluate sepsis awareness among different groups of people. methods: prospective paper-based surveys were issued between st july and st august to patients, the relatives of the patiens, hospital staff and general public who gave consent to participate in the study. the questionnaire included ten questions about demographic informations, occupational informations of hospital stuff and sepsis awareness. a total of participated in the survey. of these participants, ( . %) were patients, ( . %) were relatives of patients, ( . %) were physicians, ( . %) were medical students, ( . %) were nurses, ( . %) were other hospital stuff and (% . ) were other people. of these participants, ( . %) had heard of the word "sepsis". ( . %) responded correctly regarding the definition of sepsis. ( . %) of the participants heard the word "sepsis" during their education, but only ( %) heard it through the media. in the groups of high school graduates, university graduates and postgraduates, the rate of hearing the word sepsis and correctly identifying sepsis is significantly higher than the primary school graduates or illiterate groups. (p< . ). physicians, nurses and medical students were heard of the word "sepsis" significantly more than other groups (p< . ). physicians and medical students responded more accurately to the definition of sepsis than other groups (p< . ). public awareness of sepsis is limited compared to healthcare workers. increasing public knowledge of sepsis through education and through media may contribute to raising public awareness and improving outcomes. the association between clinical phenotype cohesiveness and sepsis transitions after presentation jn kennedy , eb brant , km demerle , ch chang , s wang , dc angus , cw seymour key: cord- - a pviol authors: kamilia, chtara; regaieg, kais; baccouch, najeh; chelly, hedi; bahloul, mabrouk; bouaziz, mounir; jendoubi, ali; abbes, ahmed; belhaouane, houda; nasri, oussama; jenzri, layla; ghedira, salma; houissa, mohamed; belkadi, kamal; harti, youness; nsiri, afak; khaleq, khalid; hamoudi, driss; harrar, rachid; thieffry, camille; wallet, frédéric; parmentier-decrucq, erika; favory, raphaël; mathieu, daniel; poissy, julien; lafon, thomas; vignon, philippe; begot, emmanuelle; appert, alexandra; hadj, mathilde; claverie, paul; matt, morgan; barraud, olivier; françois, bruno; jamoussi, amira; jazia, amira ben; marhbène, takoua; lakhdhar, dhouha; khelil, jalila ben; besbes, mohamed; goutay, julien; blazejewski, caroline; joly-durand, isabelle; pirlet, isabelle; weillaert, marie pierre; beague, sebastien; aziz, soufi; hafiane, reda; hattabi, khalid; bouhouri, mohamed aziz; hammoudi, driss; fadil, abdelaziz; harrar, rachid al; zerouali, khalid; medhioub, fatma kaaniche; allela, rania; algia, najla ben; cherif, samar; slaoui, mohamed taoufik; boubia, souhail; hafiani, y.; khaoudi, a.; cherkab, r.; elallam, w.; elkettani, c.; barrou, l.; ridaii, m.; mehdi, rihi el; schimpf, caroline; mizrahi, assaf; pilmis, benoît; le monnier, alban; tiercelet, kelly; cherin, mélanie; bruel, cédric; philippart, francois; bailly, sébastien; lucet, jc; lepape, alain; l’hériteau, françois; aupée, martine; bervas, caroline; boussat, sandrine; berger-carbonne, anne; machut, anaïs; savey, anne; timsit, jean-françois; razazi, keyvan; rosman, jérémy; de prost, nicolas; carteaux, guillaume; jansen, chloe; decousser, jean winoc; brun-buisson, christian; dessap, armand mekontso; m’rad, aymen; ouali, zouhour; barghouth, manel; kouatchet, achille; mahieu, rafael; weiss, emmanuel; schnell, david; zahar, jean-ralph; artiguenave, margaux; sophie, paktoris-papine; espinasse, florence; sayed, faten el; dinh, aurélien; charron, cyril; geri, guillaume; vieillard-baron, antoine; repessé, xavier; kallel, hatem; mayence, claire; houcke, stéphanie; guegueniat, pascal; hommel, didier; dhifaoui, kaouther; hajjej, zied; fatnassi, amira; sellami, walid; labbene, iheb; ferjani, mustapha; dachraoui, fahmi; nakkaa, sabrine; m’ghirbi, abdelwaheb; adhieb, ali; braiek, dhouha ben; hraiech, kmar; ousji, ali; ouanes, islem; zaineb, hammouda; abdallah, saousen ben; ouanes-besbes, lamia; abroug, fekri; klein, simon; miquet, mattéo; thouret, jean-marc; peigne, vincent; daban, jean-louis; boutonnet, mathieu; lenoir, bernard; merhbene, takoua; derreumaux, celine; seguin, thierry; conil, jean-marie; kelway, charlotte; blasco, valery; nafati, cyril; harti, karim; reydellet, laurent; albanese, jacques; aicha, narjess ben; meddeb, khaoula; khedher, ahmed; ayachi, jihene; fraj, nesrine; sma, nesrine; chouchene, imed; boussarsar, mohamed; yedder, soumaya ben; samoud, walid; radhouene, bousselmi; mariem, bousselmi; ammar, asma; cheikh, asma ben; lakhal, hend ben; khelfa, messaouda; hamdaoui, yamina; bouafia, nabiha; trampont, timothée; daix, thomas; legarçon, vincent; karam, henri hani; pichon, nicolas; essafi, fatma; foudhaili, nasreddine; thabet, hafedh; blel, youssef; brahmi, nozha; ezzouine, hanane; kerrous, mahmoud; haoui, saad el; ahdil, soufiane; benslama, abdellatif; abidi, khalid; dendane, tarek; oussama, ssouni; belayachi, jihane; madani, naoufal; abouqal, redouane; zeggwagh, amine ali; ghadhoune, hatem; chaari, anis; jihene, guissouma; allouche, hend; trabelsi, insaf; brahmi, habib; samet, mohamed; ghord, hatem el; habiba, ben sik ali; hajer, nouira; tilouch, najla; yaakoubi, sondes; jaoued, oussama; gharbi, rim; hassen, mohamed fekih; elatrous, souheil; arcizet, julien; leroy, bertrand; abdulmalack, caroline; renzullo, catherine; hamet, maël; doise, jean-marc; coutet, jérôme; cheikh, chaigar mohammed; quechar, zakaria; joris, magalie; beauport, dimitri titeca; kontar, loay; lebon, delphine; gruson, bérengère; slama, michel; marolleau, jean-pierre; maizel, julien; gorham, julie; ameye, lieveke; berghmans, thierry; paesmans, marianne; sculier, jean-paul; meert, anne-pascale; guillot, max; ledoux, marie-pierre; braun, thierry; maestraggi, quentin; michard, baptiste; castelain, vincent; herbrecht, raoul; schneider, francis; couffin, severine; lobo, david; mongardon, nicolas; dhonneur, gilles; mounier, roman; le borgne, pierrick; couraud, sophie; herbrecht, jean-etienne; boivin, alexandra; lefebvre, françois; bilbault, pascal; zelmat, setti-aouicha; batouche, djamila-djahida; mazour, fatima; chaffi, belkacem; benatta, nadia; sik, ali habiba; talik, i.; perrier, maxime; gouteix, eliane; koubi, claude; escavy, annabelle; guilbaut, victoria; fosse, jean-philippe; jazia, rahma ben; abdelghani, ahmed; cungi, pierre-julien; bordes, julien; nguyen, cédric; pierrou, candice; cruc, maximilien; benois, alain; duprez, frédéric; bonus, thierry; cuvelier, grégory; ollieuz, sandra; machayekhi, sharam; paciorkowski, frédéric; reychler, gregory; coudroy, remi; thille, arnaud w.; drouot, xavier; diaz, véronique; meurice, jean-claude; robert, rené; turki, olfa; ben, hmida chokri; assefi, mona; deransy, romain; brisson, hélène; monsel, antoine; conti, filomena; scatton, olivier; langeron, olivier; ghezala, hassen ben; snouda, salah; ben, chiekh imen; kaddour, moez; armel, anwar; youness, lafrikh; abdelhak, bensaid; youssef, miloudi; najib, al harrar; mustapha, amouzoun; noufel, mtioui; mohamed, zamd; salma, el khayat; ghizlane, medkouri; mohamed, benghanam; benyounes, ramdani; montini, florent; moschietto, sébastien; gregoire, emilien; claisse, guillaume; guiot, julien; morimont, philippe; krzesinski, jean-marie; mariat, christophe; lambermont, bernard; cavalier, etienne; delanaye, pierre; benbernou, soumia; ilies, sofiane; azza, abdelkader; bouyacoub, khalida; louail, meriem; mokhtari-djebli, houria; arrestier, romain; daviaud, fabrice; francois, xavier laborne; brocas, elsa; choukroun, gérald; peñuelas, oscar; lorente, josé-angel; cardinal-fernandez, pablo; rodriguez, josé-maria; aramburu, josé-antonio; esteban, andres; frutos-vivar, fernando; bitker, laurent; costes, nicolas; le bars, didier; lavenne, franck; devouassoux, mojgan; richard, jean-christophe; mechati, malika; gainnier, marc; papazian, laurent; guervilly, christophe; garnero, aude; arnal, jean michel; roze, hadrien; richard, jean christophe; repusseau, benjamin; dewitte, antoine; joannes-boyau, olivier; ouattara, alexandre; harbouze, nadia; amine, a. m.; olandzobo, a. g.; herbland, alexandre; richard, marie; girard, nicolas; lambron, lucile; lesieur, olivier; wainschtein, sarah; hubert, sidonie; hugues, albane; tran, marc; bouillard, philippe; loteanu, vlad; leloup, maxime; laurent, alexandra; lheureux, florent; prestifilippo, alessia; cruz, martin delgado maria; romain, rigal; antonelli, massimo; blanch, torra lluis; bonnetain, franck; grazzia-bocci, maria; mancebo, jordi; samain, emmanuel; paul, hebert; capellier, gilles; zavgorodniaia, taissa; soichot, marion; malissin, isabelle; voicu, sebastian; garçon, pierre; goury, antoine; kerdjana, lamia; deye, nicolas; bourgogne, emmanuel; megarbane, bruno; mejri, olfa; hmida, marwa ben; tannous, salma; chevillard, lucie; labat, laurence; risede, patricia; fredj, hana; léger, maxime; brunet, marion; le roux, gaël; boels, david; lerolle, nicolas; farah, souaad; amiel-niemann, hélène; kubis, nathalie; declèves, xavier; peyraux, nicoals; baud, frederic; serafini, micaela; alvarez, jean-claude; heinzelman, annette; jozwiak, mathieu; millasseau, sandrine; teboul, jean-louis; alphonsine, jean-emmanuel; depret, françois; richard, nathalie; attal, pierre; richard, christian; monnet, xavier; chemla, denis; jerbi, salma; khedhiri, wafa; necib, hatem; scarfo, paolo; chevalier, charles; piagnerelli, michael; lafont, alexandre; galy, antoine; mancia, claire; zerhouni, amel; tabeliouna, kheira; gaja, ali; hamrouni, bassem; malouch, abir; fourati, sami; messaoud, rihab; zarrouki, youssef; ziadi, amra; rhezali, manal; zouizra, zahira; boumzebra, drissi; samkaoui, mohamed abdennasser; brunet, jennifer; canoville, bertrand; verrier, pierre; ivascau, calin; seguin, amélie; valette, xavier; du cheyron, damien; daubin, cedric; bougouin, wulfran; aissaoui, nadia; lamhaut, lionel; jost, daniel; maupain, carole; beganton, frankie; bouglé, adrien; dumas, florence; marijon, eloi; jouven, xavier; cariou, alain; poirson, florent; chaput, ulriikka; beeken, thomas; maxime, leclerc; haikel, oueslati; vodovar, dominique; chelly, jonathan; marteau, philippe; chocron, richard; juvin, philippe; loeb, thomas; adnet, frederic; lecarpentier, eric; riviere, antoine; de cagny, bertand; soupison, thierry; privat, elodie; escutnaire, joséphine; dumont, cyrielle; baert, valentine; vilhelm, christian; hubert, hervé; leteurtre, stéphane; fresco, marion; bubenheim, michael; beduneau, gaetan; carpentier, dorothée; grange, steven; artaud-macari, elise; misset, benoit; tamion, fabienne; girault, christophe; dumas, guillaume; chevret, sylvie; lemiale, virginie; mokart, djamel; mayaux, julien; pène, frédéric; nyunga, martine; perez, pierre; moreau, anne-sophie; bruneel, fabrice; vincent, françois; klouche, kada; reignier, jean; rabbat, antoine; azoulay, elie; frat, jean-pierre; ragot, stéphanie; constantin, jean-michel; prat, gwenael; mercat, alain; boulain, thierry; demoule, alexandre; devaquet, jérôme; nseir, saad; charpentier, julien; argaud, laurent; beuret, pascal; ricard, jean-damien; teiten, christelle; marjanovic, nicolas; palamin, nicola; l’her, erwan; bailly, arthur; boisramé-helms, julie; champigneulle, benoit; kamel, toufik; mercier, emmanuelle; le thuaut, aurélie; lascarrou, jean-baptiste; rolle, amélie; de jong, audrey; chanques, gérald; jaber, samir; hariri, geoffroy; baudel, jean-luc; dubée, vincent; preda, gabriel; bourcier, simon; joffre, jeremie; bigé, naïke; ait-oufella, hafid; maury, eric; mater, houda; merdji, hamid; grimaldi, david; rousseau, christophe; mira, jean-paul; chiche, jean-daniel; sedghiani, ines; benabderrahim, a.; hamdi, dhekra; jendoubi, asma; cherif, mohamed ali; hechmi, youssef zied el; zouheir, jerbi; bagate, françois; bousselmi, radhwen; schortgen, frédérique; asfar, pierre; guérot, emmanuel; fabien, grelon; anguel, nadia; sigismond, lasocki; matthieu, henry-lagarrigue; gonzalez, frédéric; françois, legay; guitton, christophe; schenck, maleka; jean-marc, doise; dreyfuss, didier; radermacher, peter; frère, antoine; martin-lefèvre, laurent; colin, gwenhaël; fiancette, maud; henry-laguarrigue, matthieu; lacherade, jean-claude; lebert, christine; vinatier, isabelle; yehia, aihem; joret, aurélie; menunier-beillard, nicolas; benzekri-lefevre, dalila; desachy, arnaud; bellec, fréderic; plantefève, gaëtan; quenot, jean-pierre; meziani, ferhat; tavernier, elsa; ehrmann, stephan; chudeau, nicolas; raveau, tommy; moal, valérie; houillier, pascal; rouve, emmanuelle; lakhal, karim; gandonnière, charlotte salmon; jouan, youenn; bodet-contentin, laetitia; balmier, adrien; messika, jonathan; de montmollin, etienne; pouyet, victorine; sztrymf, benjamin; thiagarajah, abirami; roux, damien; de chambrun, marc pineton; luyt, charles-edouard; beloncle, françois; zapella, nathalie; ledochowsky, stanislas; terzi, nicolas; mazou, jean-marc; sonneville, romain; paulus, sylvie; fedun, yannick; landais, mickael; raphalen, jean-herlé; combes, alain; amoura, zahir; jacquemin, aemilia; guerrero, felipe; marcheix, bertrand; hernandez, nicolas; fourcade, olivier; georges, bernard; delmas, clément; makoudi, sarah; genton, audrey; bernard, rémy; lebreton, guillaume; amour, julien; mazet, charlotte; bounes, fanny; murat, gurbuz; cronier, laure; robin, guillaume; biendel, caroline; silva, stein; boubeche, samia; abriou, caroline; wurtz, véronique; scherrer, vincent; rey, nathalie; gastaldi, gioia; veber, benoit; doguet, fabien; gay, arnaud; dureuil, bertrand; besnier, emmanuel; rouget, antoine; gantois, guillaume; magalhaes, eric; wanono, ruben; smonig, roland; lermuzeaux, mathilde; lebut, jordane; olivier, andremont; dupuis, claire; radjou, aguila; mourvillier, bruno; neuville, mathilde; d’ortho, marie pia; bouadma, lila; rouvel-tallec, anny; rudler, marika; weiss, nicolas; perlbarg, vincent; galanaud, damien; thabut, dominique; rachdi, emna; mhamdi, ghada; trifi, ahlem; abdelmalek, rim; abdellatif, sami; daly, foued; nasri, rochdi; tiouiri, hanene; lakhal, salah ben; rousseau, geoffroy; asmolov, romain; grammatico-guillon, leslie; auvet, adrien; laribi, said; garot, denis; dequin, pierre françois; guillon, antoine; fergé, jean-louis; abgrall, gwénolé; hinault, ronan; vally, shazima; roze, benoit; chaplain, agathe; chabartier, cyrille; savidan, anne-charlotte; marie, sabia; cabie, andre; resiere, dabor; valentino, ruddy; mehdaoui, hossein; benarous, lucas; soda-diop, marième; bouzana, fouad; perrin, gilles; bourenne, jeremy; eon, béatrice; lambert, dominique; trebuchon, agnes; poncelet, géraldine; le bourgeois, fleur; michael, levy; camille, guillot; naudin, jérôme; deho, anna; dauger, stéphane; sauthier, michaël; bergeron-gallant, krystale; emeriaud, guillaume; jouvet, philippe; tiebergien, nicolas; jacquet-lagrèze, matthias; fellahi, jean-luc; baudin, florent; essouri, sandrine; javouhey, etienne; guérin, claude; lampin, marie; mamouri, ouardia; devos, patrick; karaca-altintas, yasemin; vinchon, matthieu; brossier, david; eltaani, redha; teyssedre, sonia; sabine, meyet; bouchut, jean-christophe; peguet, olivier; petitdemange, lucie; guilbert, anne sophie; aoul, nabil tabet; addou, zakaria; aouffen, nabil; anas, benqqa; kalouch, samira; yaqini, khalid; chlilek, aziz; abdou, rchi; gravellier, perrine; chantreuil, julie; travers, nadine; listrat, antoine; le reun, claire; favrais, geraldine; coppere, zoe; blanot, stéphane; montmayeur, juliette; bronchard, régis; rolando, stephane; orliaguet, gilles; leger, pierre-louis; rambaud, jérôme; thueux, emilie; de larrard, alexandra; berthelot, véronique; denot, julien; reymond, marie; amblard, alain; morin-zorman, sarah; lengliné, etienne; pichereau, claire; mariotte, eric; emmanuel, canet; poujade, julien; trumpff, guillaume; janssen-langenstein, ralf; harlay, marie-line; zaid, noorah; ait-ammar, nawel; bonnal, christine; merle, jean-claude; botterel, francoise; levesque, eric; riad, zakaria; mezidi, mehdi; yonis, hodane; aublanc, mylène; perinel-ragey, sophie; lissonde, floriane; louf-durier, aurore; tapponnier, romain; louis, bruno; forel, jean-marie; bisbal, magali; lehingue, samuel; rambaud, romain; adda, mélanie; hraiech, sami; marchi, elisa; roch, antoine; guerin, vincent; rozencwajg, sacha; schmidt, matthieu; hekimian, guillaume; bréchot, nicolas; trouillet, jean louis; besset, sébastien; franchineau, guillaume; nieszkowska, ania; pascal, leprince; loiselle, maud; sarah, chemam; laurence, dangers; guillemette, thomas; jacquens, alice; kerever, sebastien; guidet, bertrand; aegerter, philippe; das, vincent; fartoukh, muriel; hayon, jan; desmard, mathieu; fulgencio, jean-pierre; zuber, benjamin; soufi, a.; khaleq, k.; hamoudi, d.; garret, charlotte; peron, matthieu; coron, emmanuel; bretonnière, cédric; audureau, etienne; audrey, winters; christophe, duvoux; christian, jacquelinet; daniel, azoulay; cyrille, feray; aissaoui, wissal; rghioui, kawtar; haddad, wafae; barrou, houcine; carteaux-taeib, anna; lupinacci, renato; manceau, gilles; jeune, florence; tresallet, christophe; habacha, sahar; fathallah, ines; zoubli, aymen; aloui, rafaa; kouraichi, nadia; jouet, emilie; badin, julie; fermier, brice; feller, marc; serie, mathieu; pillot, jérôme; marie, william; gisbert-mora, chloé; vinclair, camille; lesbordes, pierre; mathieu, pascal; de brabant, fabienne; muller, emmanuel; robaux, marie-aline; giabicani, mikhael; marchalot, antoine; gelinotte, stéphanie; declercq, pierre louis; eraldi, jean-pierre; bougerol, françois; meunier-beillard, nicolas; devilliers, hervé; rigaud, jean-philippe; verrière, camille; ardisson, fanny; kentish-barnes, nancy; jacq, gwenaëlle; chermak, akli; lautrette, alexandre; legrand, matthieu; soummer, alexis; thiery, guillaume; cottereau, alice; canet, emmanuel; caujolle, marie; allyn, jérôme; valance, dorothée; brulliard, caroline; martinet, olivier; jabot, julien; gallas, thomas; vandroux, david; allou, nicolas; durand, arthur; nevière, rémi; delguste, florian; boulanger, eric; preau, sebastien; martin, ruste; cochet, hélène; ponthus, jean pierre; amilien, virginie; tchir, martial; barsam, elise; ayoub, mohsen; georger, jean francois; guillame, izaute; assaraf, julie; tripon, simona; mallet, maxime; barbara, guilaume; louis, guillaume; gaudry, stéphane; barbarot, nicolas; jamet, angéline; outin, hervé; gibot, sébastien; bollaert, pierre-edouard; holleville, mathilde; legriel, stéphane; chateauneuf, anne laure; cavelot, sébastien; moyer, jean-denis; bedos, jean pierre; merle, philippe; laine, aurelie; natalie, de sa; cornuault, mathieu; libot, jérome; asehnoune, karim; rozec, bertrand; dantal, jacques; videcoq, michel; degroote, thècle; jaillette, emmanuelle; zerimech, farid; malika, balduyck; llitjos, jean-françois; amara, marlène; lacave, guillaume; pangon, béatrice; mavinga, josé; makunza, joseph nsiala; mafuta, m. e.; yanga, yves; eric, amisi; ilunga, jp; kilembe, ma; alby-laurent, fanny; toubiana, julie; mokline, amel; laajili, achraf; amri, helmi; rahmani, imene; mensi, nidhal; gharsallah, lazheri; tlaili, sofiene; gasri, bahija; hammouda, rym; messadi, amen allah; allain, pierre-antoine; gault, nathallie; paugam-burtz, catherine; foucrier, arnaud; chatbri, bassem; bourbiaa, yousra; thabet, lamia; neuschwander, arthur; vincent, looten; beck, jennifer; vibol, chhor; amelie, yavchitz; resche-rigon, matthieu; pirracchio, jean mantzromain; bureau, côme; decavèle, maxens; campion, sébastien; ainsouya, roukia; niérat, marie-cécile; prodanovic, hélène; raux, mathieu; similowski, thomas; dubé, bruno-pierre; demiri, suela; dres, martin; may, faten; quintard, hervé; kounis, ilias; saliba, faouzi; andré, stephane; boudon, marc; ichai, philippe; younes, aline; nakad, lionel; coilly, audrey; antonini, teresa; sobesky, rodolphe; de martin, eleonora; samuel, didier; hubert, noemie; nay, mai-anh; auchabie, johann; giraudeau, bruno; jean, reignier; darmon, michaël; ruckly, stephane; garrouste-orgeas, maïté; gratia, elisabeth; goldgran-toledano, dany; jamali, samir; dumenil, anne sylvie; schwebel, carole; brisard, laurent; bizouarn, philippe; lepoivre, thierry; nicolet, johanna; rigal, jean christophe; roussel, jean christian; cheurfa, cherifa; abily, julien; lescot, thomas; page, isaline; warnier, stéphanie; nys, monique; rousseau, anne-françoise; damas, pierre; uhel, fabrice; lesouhaitier, mathieu; grégoire, murielle; gaudriot, baptiste; gacouin, arnaud; le tulzo, yves; flecher, erwan; tarte, karin; tadié, jean-marc; georges, quentin; soares, m.; jeon, kyeongman; oeyen, sandra; rhee, chin kook; gruber, pascale; ostermann, marlies; hill, quentin; depuydt, peter; ferra, christelle; muller, alice; aurelie, bourmaud; niles, christopher; herbert, fabien; pied, sylviane; loridant, séverine; françois, nadine; bignon, anne; sendid, boualem; lemaitre, caroline; dupre, celine; zayene, aymen; portier, lucie; de freitas caires, nathalie; lassalle, philippe; le neindre, aymeric; selot, pascal; ferreiro, daniel; bonarek, maria; henriot, stépahen; rodriguez, julie; taddei, mara; di bari, mauro; hickmann, cheryl; castanares-zapatero, diego; deldicque, louise; van den bergh, peter; caty, gilles; roeseler, jean; francaux, marc; laterre, pierre-françois; dupuis, bastien; machayeckhi, sharam; sarfati, celine; moore, alex; mendialdua, paula; rodet, emilie; pilorge, catherine; stephan, francois; rezaiguia-delclaux, saida; dugernier, jonathan; hesse, michel; jumetz, thibaud; bialais, emilie; depoortere, virginie; michotte, jean bernard; wittebole, xavier; jamar, françois title: proceedings of réanimation , the french intensive care society international congress date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: a pviol nan introduction the study of the bacterial cartography in thoracic surgery is extremely important for the treatment of post-operative infections due to the severity of the underlying pathology, the fragility of patients after surgery in addition to the choice of the empiric antibiotic therapy. we led a prospective study following all the patients who underwent a pulmonary resection surgery for a period of months from january to july , jointly with the microbiology department, chu ibn rochd, casablanca. the bronchial secretions were collected by a protected distal bronchial sample using a (combicath) after the intubation. results during the period of the study, patients underwent a pulmonary resection, % for a neoplastic pathology. the medium age was years ± and % of our sample were male. % of our patients had smoking habits and of them had pulmonary tuberculosis, had repeated respiratory infections. the antibiotics used in pre-operative: % of beta-lactams; % of fluoroquinolones; % of macrolides. moreover, % of our patients were classified asa . of the obtained samples, were positive ( . %). the most frequently observed germs were the acinetobacter baumannii ( . %), pseudomonas aeruginosa ( . %), klebsiella pneumoniae ( . %), staphylococcus aureus ( . %). the acinetobacter baumannii was the most resistant germ ( % sensibility to carbapenem). these patients were followed until their d after surgery, of them developed a post-operative pneumonitis with cases of multi-resistant acinetobacter baumanii, of which deceased. conclusion pneumonitis after pulmonary resection are common and severe that's why it is necessary to establish a global prevention strategy mainly based on general patricians and pneumologists' awareness concerning the choice of the prescribed antibiotics, in order to avoid the spread of multi-resistant germs. introduction carbapenemase-producing enterobacteriaceae (cpec) are increasingly reported worldwide and constitutes a real challenge antibiotic for clinicians to preserve the bacterial ecology. its incidence has remarkably increased in our intensive care unit during the last years. the esbl spread has a major consequence in term of antibiotic choices. carbapenem antibiotic are regarded as the most effective treatment. however numbers of authors suggest that alternatives antibiotics (i.e. noncarbapenems) could be used in esbl-pe infections. there are some conflicting data regarding the use of alternatives in case of esbl-pe infections. moreover as far as we know, there are no data in icu. objectives the aim of this study was to describe esbl-pe infections in icu and therapeutic options chosen in these specific situations. patients and methods prospective multicentric observational cohort study conducted in volunteers icu. all consecutive patients hospitalized in icu with esbl-pe infection according to cdc definitions were included. severity of illness was defines according to bone criteria, saps ii and sofa. demographic datas, empirical and definitive antibiotic therapy (et and dt), clinical evolution, and outcome were recorded. in vitro antimicrobial susceptibility testing was performed by the disk diffusion method or the vitek system according to the guidelines of the antibiogram committee of the french microbiologic society. results during the study period patients with esbl-pe infection met eligibility criteria with respectively a median age and saps ii score of ( - ) and ( - ). the median sofa score at first day of antibiotic therapy and icu admission were ( - ) and ( ) ( ) ( ) ( ) ( ) ( ) ( ) respectively. the most frequent site of infection were respiratory tract ( %), urinary tract ( %) and abdominal ( %). the most frequent isolated species were: escherichia coli ( %), klebsiella sp ( %) and enterobacter sp ( %). respectively , and % patients had septic shock, severe sepsis and sepsis according to bone criteria. among esbl-pe, . % were carbapenem and . were blbi sensitive. among the whole population, ( %) patients received a carbapenems as et. ( %) received a dt with carbapenems and ( %) patients received an alternative dt. the most frequent reasons for maintaining carbapenems as dt were: antibiotic susceptibility tests ( % of cases), severity level ( % of cases) immunosuppression ( % of cases). the median length of icu stay after infection was respectively ( - ) and ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) days for carbapenems and alternatives dt (p = . ). the d mortality was % for patients with carbapenems dt and % for patients with alternatives dt (p = . ). surprisingly, there were no differences between the groups (carbapenems vs alternatives) in term of severity. conclusion alternatives are frequently used for esbl-pe infections in icu. in our cohort ( %) patients received antibiotics other than carbapenems regardless of the severity. introduction bacterial resistance to antibiotics is a common problem worldwide. in south america, this prevalence is reported to be the highest in the world. however, in french guyana, there is no data on the epidemiology of colonization and infection caused by extended spectrum b-lactamase producing enterobacteriaceae (esbl-pe). we conducted this study to investigate the prevalence of colonization with esbl-pe and subsequent icu acquired infection in french guiana. introduction the implementation of hemofiltration (hf) as a renal replacement therapy in septic shock patients requires the supply of large quantities of replacement solutions. these solutions are either industrially prepared in autoclaved expensive plastic bags (conventional hemofiltration, chf) or continuously provided in unlimited amounts at the dialysis machine directly from the water treatment plant to form the replacing solutions (on-line hemofiltration, olhf).the aim of our study was to evaluate the safety and effectiveness of on-line hemofiltration compared to conventional hemofiltration in septic shock patients. the investigative protocol was approved by the institutional ethics authorities and all patients or their legally authorized representatives provided written informed consent. it was a prospective, randomized, clinical study, including septic shock patients with acute renal failure. patients were randomized to receive either on-line hemofiltration (n = ) or conventional hemofiltration (n = ) for renal replacement therapy during days. hemodynamic monitoring was conducted by conventional devises, including: electrocardiogram and a radial arterial catheter for invasive arterial pressure every h during period study. we collected serum samples also every h (urea, potassium and sodium levels, troponin, hemoglobin, platelets, c-reactive protein and lactates). results the evolution of heart rate (hr), mean arterial pressure (map), biological markers were comparable between the two groups over time except a significant decrease in map in the olhf group compared to chf group only at h (p = . ) and h (p = . ) and a significant decrease in c-reactive protein level in the olhf group at h (p = . ). conclusion on-line hemofiltration seems to be a safe and reliable method of renal replacement therapy in septic shock patients. it may be associated with attenuated pro-inflammatory cytokine profile (c-reactive protein). none. introduction therapeutic plasma exchange (tpe) is crucial for the management of auto-immune diseases like thrombotic thrombocytopenic purpura or myasthenia gravis. tpe is performed either by centrifugation, with specific machines which are not routinely available in icus, or by using specific plasma separation membranes with widely spread in icus hemofiltration machines. regional citrate anticoagulation for tpe is well established with centrifugation but has been seldom described for membrane tpe. we are reporting the experience of our icu in this field. patients and methods retrospective study including all patients who received tpe with citrate regional anticoagulation between and in an -bed icu. tpe is performed solely in the icu in our institution. results patients were included. tpe was required for thrombotic microangiopathy ( patients), vasculitis ( patients), hyperviscosity syndrome ( patients), guillain-barré syndrome ( cases) and others ( patients) . mean saps score was [standard deviation (sd) . ] . tpe were performed, with a mean number of . (sd . ; range - ) tpe per patients. coagulation of the circuit of tpe occurred in ( %) patients. coagulation of the circuit occurred in . % ( / ) of the tpe. minor adverse events have been reported in two patients: one had a rash during the first tpe (no recurrence during the next tpes) and the other had paresthesia during the first two tpes (the calcium infusion was increased and there had been no recurrence during the next tpes). no serious adverse events related to citrate were observed. conclusion regional anticoagulation with citrate allowed us to perform tpe in patients, without significant adverse events. the rate of circuit coagulation was . % per tpe. none. introduction a reduced incidence of membrane thrombosis after injection of anti-thrombin (at) has been reported in septic patients with acquired deficit in at undergoing continuous hemofiltration. as this strategy was routinely performed in our unit until , we investigated its cost-effectiveness. patients and methods data about the use of hemofiltration, the consumption of at and hemofiltration devices during (period with routine use of at) and (period with use of at only if a membrane thrombosis occurred) were extracted from the administrative database of the institution. a decisional tree was built to modelize the impact of at on the consumption of hemofiltration devices and blood products. the decisional tree took into account the probability of membrane thrombosis with and without at and the probability of transfusion after membrane thrombosis. costs were obtained from the pharmacy of the institution (at, hemofiltration devices) and from the literature (blood products). results during , days of hemofiltration were performed, with the use of doses of at ( , €) and hemofiltration devices ( , €) . during , (− %) days of hemofiltration were performed, with the use of (− %) doses of at ( €) and (+ %) hemofiltration devices ( , €) . the mean cost of day of hemofiltration decreased from € to € with the diminution of the use of at. according to the decisional tree, at was almost never cost-effective. the only circumstances associated with a benefit for the use of at was the association of a probability of thrombosis with at inferior to . , of a probability of thrombosis without at equal , of a probability of transfusion after thrombosis equal and a cost of transfusion of €. in these extremely favorable circumstances, at could decrease the daily cost of hemofiltration of . - . €. discussion the model has several limits: the losses of utility related to transfusion and to interruption of hemofiltration due to thrombosis were not taken into account; the cost of at measurement was not estimated; the work load of changing a membrane and of transfusion after membrane thrombosis was not analyzed. conclusion our results suggest that anti-thrombin is not costeffective to reduce the costs of hemofiltration related to membrane thrombosis. none. introduction in intensive care unit (icu), some patients suffering from acute kidney injury need renal replacement therapy (rrt). it requires the circuit anticoagulation, this could be done by a regional citrate method. today, this is a recommended approach for the everyday care, even if the technique isn't widespread yet [ ] . the ionized calcemia dosing through the filter ("post-filter" ionized-calcemia) is used to monitor the technique efficacy, with a target of . - . mmol/l showing a good filter anticoagulation. the objective of our study was the assessment of efficacy and safety of our regional citrate anticoagulation protocol, with a less restrictive post-filter ionized calcemia target ( . - . mmol/l). the main goal was the analysis of the circuit lifespan, considering a lifespan above h, as well as the search of some clinical and biological factors affecting the technique efficacy. moreover, we analyzed the side effects incidence of the protocol (hypernatremia, metabolic alcalosis), and their consequences. the study received the scientific ethical agreement of university hospital of toulouse, and is registered with number - . patients and methods patients, admitted to one of the two university hospital icus of toulouse, needing a continuous rrt method, without any need for systemic heparin anticoagulation, and without severe hepatocellular failure, were included in the study. filters included over a -year period were analyzed. results results show a mean filter lifespan of h, with a lifespan above h for . % of all filters. coagulation was the cessation reason for . % of filters, most of them before h of the filter use. a value of post-filter ionized calcemia at day below . mmol/l was the main factor influencing a filter lifespan above h. an age older than and a saps ii severity score below were other factors conditioning a filter lifespan of more than h. side effects of citrate were rare and didn't have any clinical impact among our patients. discussion these results suggest that citrate used for anticoagulation in rrt could have an additional anti inflammatory effect through the induced hypocalcemia, as well as an energetic gain which could lead to a renal protection against ischemia-reperfusion mechanism [ ] . moreover, these results call into question the need of post-filter ionized calcemia dosing for the monitoring of citrate anticoagulation efficacy, since the method safety is monitored by the total-to-ionized calcium ratio. conclusion during continuous rrt in icu, a regional citrate anticoagulation protocol with a non-restrictive post-filter ionized calcemia target seems to be efficient and could reduce side effects. these results need to be confirmed with a randomised control study. introduction continuous veno-venous haemofiltration (cvvh) is used to treat acute kidney injury in critically ill patients. to optimize its efficiency, cvvh requires effective anticoagulation. systemic anticoagulation with standard heparin, the most used, can lead to major bleeding complications. hemofilters that are able to adsorb heparin molecules on their surface such as an st and oxiris membranes represent an alternative. the objective of this study was to compare these two types of filters in terms of duration, efficiency, dysfunctions and cost. materials and methods from october to may , we conducted a retrospective, observational, and non-interventional study. all patients admitted in the intensive care unit needing cvvh were included. the primary endpoint was the filter lifespan: an st versus oxiris. the secondary endpoint was the filter efficiency (urea reduction ratio: urr). the main analysis did not consider the anticoagulation type. we conducted a subgroup analysis taking into account the use or not of an anticoagulation. results sessions in patients were carried out using filters representing , h of treatment. the mean an st filter lifespan was ± h and ± h for oxiris filters (p > . ). there is no significant difference in terms of duration between the two filters. the subgroup analysis taking into consideration the use or not of anticoagulation did not show any difference either. the mean urr was ± % in the an st group and ± % in the oxiris group (p > . ). concerning the dysfunctions, there were no significant difference between the two filters. one hundred and seventy-six an st filters were used for a total cost of , euros. two hundred and ten oxiris filters were used for a total cost of , euros. conclusion the an st and oxiris lifespans are not significantly different. they were as efficient in terms of blood epuration and had as many dysfunctions. the use of an oxiris filter rather than an an st to extend the circuit's lifespan in the same clinical conditions is not justified considering the extra cost generated. introduction because oliguria is a poor prognostic sign in patients with acute renal failure (arf), diuretics are often used to increase urine output in patients with or at risk of arf. from a pathophysiological point of view there are several reasons to expect that loop diuretics could have a beneficial effect on renal function. however, a review of literature shows that the use of loop diuretics in patients with arf has been associated with inconclusive results despite the theoretical benefits [ ] . to assess the adjunctive effect of diuretics, to alter the progression to kidney injury or failure, in patients at risk for acute renal failure. patients and methods this is a retrospective chart review of consecutive patients who developed arf with oliguria in the intensive care unit. chart abstractors were well trained residents. two chart reviewers (senior intensivists) studied all the charts. an explicit protocol was used to precise all needed definitions. uniform handling of data was ensured especially for conflicting, missing or unknown data. oliguria was defined as urine output lower than . ml/kg/h for at least h. rifle score was assessed before and after urinary output normalisation. therapeutic intervention to optimize pre-renal perfusion was described. mean arterial blood pressure (mbp) before and after therapeutic initiation, oliguria duration, delay from oliguria onset to diuretic administration, delay from diuretic administration to urinary output normalisation were measured. results patients were studied over a years period. ] h. the delay from diuretic administration to urinary output normalization was [ . , ] h. after resumption of diuresis, rifle score was assessed as (patients without risk, %; r, %; i, %; f, % l, zero; e, zero) (fig. ) . increased serum creatinine level, above . fold normal range, was observed only in ( %) patients. conclusion rapid optimization of pre-renal hemodynamic disturbances associated with short delay administration of diuretics could significantly alter the progression to kidney injury or failure in at risk acute renal failure icu patients. the ventilator associated pneumonia (vap) is a common and severe complication of assisted ventilation. it's the leading cause of nosocomial infections in intensive care unit and remain responsible for a high morbidity and mortality because of the emergence of multidrug resistant (mdr) bacterial agent such us acinetobacter baumannii (ab). the aim of this study was to determine the incidence, risk factors and prognosis of ab vap. patients and methods retrospective study extending over a year period (january -january ) that included all patients over patients were divided into two groups: one consisting of patients who developed vap to ab and the second developed vap to another bacterial pathogen. results one hundred and forty patients developed vap. the incidence rate of ab vap was . % with a density of incidence of . per ventilator days. age, male gender, the time between hospitalization and mechanical ventilation and the medical pathology were risk factors for developing ab vap. ab was resistant to ceftazidime in %, to imipenem in %, tobramycin in % and netilmycin in . %, rifampin in % with a sensitivity to colistin in % of cases. the resistance of this germ to imipenem increased from % in to . % in . the evolution of patients with ab vap developed frequently septic shock compared to other patients ( vs . %; p = . ). the ab vap mortality was higher ( vs %; p = . ). conclusion the increasing incidence of multi-drug resistant ab vap is responsible for a high morbidity and mortality. so we need to identify risk factors and to strengthen the means of prevention of hand contamination and cross transmission during invasive procedures. introduction central line associated bloodstream infections (clabsi) are among the serious hospital-acquired infections. the aim of this study is to determine the incidence of clabsi, the pathogens and the risk factors that play a role in the development of bsi among patients followed in a tunisian medical intensive care unit. patients and methods all patients admitted for more than h were included in the study over a -year period in an -bed medical icu. the enrollment was based on clinical and laboratory diagnosis of bsi. blood samples were collected from catheter hub of all patients for culture, followed by identification and antibiotic sensitivity testing of the isolates. was higher compared with the mean rate of clabsi in icu reported by the nnis system surveillance for , which is . / catheter.days [ ] . duration of catheterization, frequent manipulation of catheter, catheter location, catheter type, underlying diseases, suppression of immune system, and types of fluids administered through the catheter are significant risk factors in development of bsis [ ] . in our study both duration of catheterization and number of attempts are independent factors for clabsi. conclusion in a monocenter cohort, clabsi had a moderate density rate but are associated with poor outcome. identifying the risk factors is necessary to find solutions for this major health problem. introduction according to some studies, field-intubated patients have . - times greater risk of ventilator associated pneumonia (vap). endobronchial intubation (ei) can be unrecognized by the physicians and may result in complications such as atelectasis which in turn could increase the risk of vap. the aim of our study was to confirm this hypothesis. patients and methods this monocentric retrospective study included all consecutive patients > years who underwent an out-of-hospital tracheal intubation before their admission to the intensive care unit (icu) between january and december . exclusion criteria were suspected aspiration or pneumonia on admission, patients who died within the first days of icu stay, extubation in less than h and underlying disease making radiological interpretation difficult for vap diagnosis. vap were divided into early onset (< days) and late onset (≥ days) events and were independently diagnosed by two experienced intensivists who had no access to the initial chest x-ray performed to check the position of the tracheal tube, based on the clinical pulmonary infection score. onset of ventilator associated tracheobronchitis (vat) was also noted. inadvertent endobronchial intubation was determined by another independent physician based on the interpretation of admission chest x-ray. results patients were intubated out-of-hospital. of the patients excluded, had an extubation in less than h, were died within the first days, had a suspicion of pneumonia, a suspicion of aspiration and an underlying disease making radiological interpretation difficult. of the patients included, ( . %) had an ei upon admission. no significant difference was observed between the ei and non-ei group for gender, age, saps , comorbidities and diagnostic category (cardiorespiratory arrest, trauma, coma and cardiorespiratory failure). early-onset vap were diagnosed in % in the ei group and in % of non-ei patients (p = . ). adding early onset vat, the respiratory infection rate was % in the ei group and % in the non-ei group (p = . ) (fig. ). late-onset vap were observed in . % in the non-ei group and . % in the ei group, without difference between groups (p = . ). there was no inter-group difference in the duration of ventilation, duration of icu stay and icu mortality. staphyloccocus aureus was the most prevalent pathogen in patients with early-onset vap ( . %, only one strain was methicillin-resistant). conclusion this study found a high rate of inadvertent prehospital endobronchial intubation with a higher incidence of early-onset vap. these results support the implementation of specific procedures to decrease the incidence of ei. introduction ventilator-associated pneumonia (vap) is associated with increased hospital stay and high morbidity and mortality in critically ill patients. the classic dichotomy between early and late onset vap is no longer helpful available. the aims of this study were to determine the incidence of multidrug-resistant pathogens in the first episodes of vap and to assess potential differences in bacterial profiles of subjects with early-onset versus late-onset vap. patients and methods retrospective cohort study over a period of months including all patients who had a first episode of vap confirmed by positive culture. subjects were distributed into groups according to the number of intubation days: early-onset vap (< days) or late-onset vap (≥ days).the primary endpoint was the nature of causative pathogens and their resistance profiles. results sixty patients were included, men and women. the average age was ± years. the igs at admission was . [ ; ] apache [ ; ] . monomicrobial infections were diagnosed in of patients ( %).two different bacteria were isolated in cases ( %). a. baumannii was the most frequently isolated in % (n = ) of patients; followed by p. aeruginosa in % (n = ), enterobacteriaceae in % (n = ) and s. aureus in % (n = ). the isolated bacteria were multidrug-resistant in most cases ( / ). the vap group comprised episodes ( %) of early-onset vap and episodes ( %) of late-onset vap. a. baumannii was isolated in % of early vap (n = ) versus % of late vap (n = ) (p = ns), p. aeruginosa in % of early vap (n = ) versus % of late vap (n = ) (p = ns) and enterobacteriaceae in % of early vap (n = ) versus % of late vap (n = ) (p = ns). for the resistance profile of the different pathogens isolated, there was no difference between early and late onset vap. conclusion according to new data from the literature, there were no microbiological differences in the prevalence of potential multidrugresistant pathogens or in their resistance profiles associated with early-onset versus late-onset vap. the bacterial nosocomial infection is a major cause of morbidity and mortality in burned. the bacterial ecology in an icu has a major impact in terms of morbidity and mortality, particularly in the center of burned or length of stay of patients is increased compared to a general intensive care. we conducted an observational study spread over months in icu for severe burned burnt including any who have spent more than h with nosocomial infection (modified cdc criteria), and in which all biological and bacteriological samples were taken. the different types of infections studied were: skin, urinary, lung and bloodstream infections. they excluded all patients belatedly supported or having stayed in other healthcare facilities. results one hundred twenty ( ) patients showed nosocomial infection during this period. the sex ratio (m/f) was . and the mean age was ± years. bacteremia was present in . % of cases, followed by the urinary tract infection that was present in . % of cases, followed by the cutaneous infection in . % of cases, and last pulmonary infection in % of cases. infection was polymicrobial in . % of cases. the main bacteria identified were: acinetobacter baumanii ( . %) of which % is resistant to imipenem, enterobacteriaceae ( . %), pseudomonas aeruginosa ( %) of which . % is resistant to ceftazidime and . % is resistant to imipenem, enterococcus ( %) and staphylococcus aureus ( . %). conclusion the incidence of nosocomial infection is very high compared to literature. the rate of resistance to common antibiotics is very high. a drastic management of antibiotics in our context, the selection of patients and the frequent use in the operating room for skincare allow a better management of these patients. introduction acinetobacter baumannii (ab) ventilator-associated pneumonia (vap) is common in critically ill patients. the aims of this study were to describing the epidemiological characteristics of ab-vap, to identify risk factors for acquisition and factors predictive of a poor outcome. materials and methods a retrospective-prospective study was conducted at the medical intensive care unit of the university hospital ibn sina, rabat-morocco from january to december . they were included in the study that all patients developed vap with identified germ. for identification of risk factors of acquisition of ab vap, two groups of patients were compared: patients with ab vap versus patients with vap caused by other germs. to identify factors associated with mortality, two other groups were compared: survivors versus died. results patients presented vap among which were caused by acinetobacter baumannii. among isolates of ab, . % were drug susceptible, and . % were multidrug-resistant while % were extensively drug-resistant. they were independent risk factors for acquisition of ab vap in multivariate analysis: the presence of a central venous catheter before the occurrence of vap, duration of prior hospitalization ≥ days and icu duration of stay ≥ days. the mortality rate of ab vap was %. the independent risk factors for poor outcome in multivariate analysis were: duration of antibiotic treatment > days, the reintubation and the presence of a previous hospitalization. discussion our data were similar to those of the literature with a high incidence of vap due to the ab ( %) and a high rate of resistance to this bacterium particularly to carbapenems. however, and compared to the literature, the vap ab were responsible for a death rate much higher ( %). conclusion our data were similar to those of the literature with a high incidence of vap due to the ab ( %) and a high rate of resistance to this bacterium particularly to carbapenems. however, and compared to the literature, the vap ab were responsible for a death rate much higher ( %). introduction ventilator-associated pneumonia (vap) is common in critically-ill patients. in fact, - % of patients requiring invasive mechanical ventilation develop this complication. the onset of vap has been reported to be associated with increased mortality. however, data related to critically-ill elderly patients are scarce. the aim of this study is to assess the prognostic impact of vap in critically-ill elderly patients. patients and methods mono-center, retrospective study conducted from / to / / . all old patients (age ≥ years) requiring mechanical ventilation were included. two groups were compared: patients who developed vap (vap (+) group) and those who did not develop vap (vap (−) group). results during the study period, patients were included. the causes of admission in the intensive care unit (icu) were shock (n = ), acute respiratory failure (n = ) and disturbed level of consciousness (n = ). diabetes mellitus, hypertension and chronic obstructive pulmonary disease were the most common comorbidities ( . , . and . % respectively). mean age was . ± . years. sex-ratio (m/f) was . . mean apache(ii) score was ± . the mean duration of mechanical ventilation was ± days. thirty patients ( . %) developed vap. icu-mortality was significantly higher in the vap (+) group ( vs . %; p = . ). multivariate analysis identified two independent factors predicting icu mortality: shock on admission (or = . , ci % [ . - . ], p < . ) and vap (or = . , ci % [ . - . ], p = . ). conclusion vap is common in critically-ill elderly patients and is associated with worse outcome. therefore, preventing its onset is of paramount importance. increased health-care costs. among pathogens responsible of vap, acinetobacter baumannii which is characterized by its ability to spread in the hospital environment and to acquire resistance leading sometimes to therapeutic impasses is associated with a particularly high mortality reaching - %. objective to describe the epidemiological characteristics of a. baumannii vap, to determine their prognosis and identify factors associated with mortality. patients and methods it is a monocentric observational study conducted over a period of years in a tunisian intensive care unit (icu) including mechanical ventilated patients for more than h with confirmed a. baumannii vap. results one hundred and twenty-three patients were included in the study. a. baumannii was responsible for % of vap in our icu. the vap were late in % of cases. more than % of isolates pathogens were resistant to ticarcillin, piperacillin, piperacillintazobactam, ceftazidime and ciprofloxacin. sixty percent of germs were sensitive to imipenem. resistance to imipenem has increased consistently from % at the beginning of the study to % in . all pathogens were susceptible to colistin. a. baumannii vap was complicated by septic shock in % of cases. the median duration of mechanical ventilation and of icu stay were (iqr: [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and days (iqr: - ) respectively. the use of parenteral nutrition was the only factor associated with the occurrence of a. baumannii vap resistant to imipenem (odds ratio . , % ci [ . - . ], p = . ). icu mortality was %. it was higher in patients with a. baumannii vap resistant to imipenem ( vs %, p > . ). in the multivariate analysis, the age, the use of renal replacement therapy and the occurrence of vap relapse have been identified as factors associated with mortality. conclusion a. baumannii resistance to imipenem became threatening. the use of parenteral nutrition was the only factor associated with the occurrence of a. baumannii vap resistant to imipenem. the choice of empiric antimicrobial for vap caused by this pathogen must take in consideration the epidemiologic data of each country and each icu. a. baumannii vap was associated with high mortality. the age, the use of renal replacement therapy and the occurrence of vap relapse have been identified as predictive of poor outcome. none. admission in intensive care unit for severe adverse drug event: what finding? julien arcizet , bertrand leroy , caroline abdulmalack , catherine renzullo , maël hamet , jean-marc doise , jérôme coutet introduction adverse drug events (ade) remain a serious public health problem. they represent between . and . % of hospital admissions and between . and . % of intensive care unit (icu) admissions. they are defined as any injury related to a drug, and include both adverse drug reactions, expected or not, but also underuse, overuse and misuse, unintended or undesired, preventable or not. indeed, mortality from iatrogenic event would rise between . and . %, whereas these ade that resulted in icu hospitalization could be prevented in . - . % of cases. these unplanned admissions overload icu, limit access to health care for other patients and have serious economic consequences for the health system. it is therefore necessary to study these ade to know their main causes and attempt to find a solution to avoid them. the main objectives of our study were to clinically and pharmaceutically analyze and stratify the different ade leading to hospitalization in our icu. this is a monocentric prospective study, between june to january , in medico-surgery icu. from all admissions, we had included patients admitted in our hospital for involuntary ade (plausible, likely and very likely causal). we had collected clinical aspects (failure mode, igsii score, mortality in icu) and pharmaceutical aspect (number of drug, offending drugs) at daily medical staff meeting. conclusion hospitalizations in icu for ade are still too common despite their preventability for most cases. many patients with known cognitive disorder manage their treatment themselves and this is probably one of the reasons of iatrogenic events. anticoagulants and antiplatelet agents, by side effects, misuse, underuse or overuse are very often involved. the onset of kidney failure from dehydration and the continuation of nephrotoxic and antidiabetic treatment also remain one of the most common causes. consequently, it is necessary to continue and develop primary, secondary and tertiary prevention strategies to prevent their appearance, to limit their consequences and to reduce recidivism. introduction intensive care unit (icu) is usually identified as a place of acute care, concentrated over a short period. for many reasons, a prolonged stay in the icu has a pejorative connotation for the intensivist physician. the aim of our study is to describe the epidemiological, clinical, paraclinical profile of patients hospitalized for a long time in icu (over days) and to identify the main prognostic factors and those that can predict the duration of stay in icu. we conducted a retrospective study, over a period of years and months (january to june ), enrolling patients whose length of stay was greater than or equal to introduction despite an improvement in prognosis of patients with hematologic malignancies for the last decade, mortality of such patients admitted to the intensive care unit (icu) remains high. yet, it seems that a first icu stay does not modify prognosis of the malignancy. until now, there is no data on readmission in the icu of such patients and its effect on short and long term prognosis impact. patients and methods this retrospective, single-center study conducted on a years period in the medical icu from our university hospital included patients with hematological malignancies admitted for a first stay. objectives were to evaluate the icu, day and months mortality, to identify prognostic factors associated with mortality within uni-and multivariate analysis, to evaluate readmission rate within the days after discharge, to indentify the admission risk factors associated with icu readmission and the prognosis factors associated with mortality during the second icu stay. multivariate analysis poor performance status, igs ii, hlh, mv and anti-fungal administration were associated with increased icu mortality, infections with pseudomonas were associated with higher day mortality. catheter related infections were associated with better icu survival and cr was associated with lower day mortality. of ( . %) candidate patients for icu readmission after a first stay were readmitted within the days following discharge. median overall survival was lower in readmitted versus non readmitted patients. months mortality was . % for readmitted versus . % for no readmitted patients (p < . ). the second icu stay mortality was . % and month mortality was . %. by multivariate analysis, only mv was associated with prognosis. the months mortality rate of patients who survived to the second icu stay was significantly higher than the patients who survived to the first admission but were not readmitted ( . vs . %, p = . ). conclusion main features, short and long term mortality and prognostic factors associated with icu admission are in lines with previous studies. early readmission rate was high with a negative impact on survival. despite admission in the icu of patients with hematologic malignancies seems not to affect long term prognosis, early readmission seems to have a pejorative impact on the course of the malignancy. introduction lung cancer is among all types of cancer, the most common solid tumour admitted in intensive care [ ] . recent studies showed that the prognosis of patients with lung cancer during intensive care unit (icu) stay has improved [ ] . the aim of our study was to determine the causes of icu admission of lung cancer patients, their prognosis and to identify factors predicting hospital mortality and survival after hospital discharge. in fact, temporary full-code icu management in patients with relapsed aml seems to be appropriate. none of the life-sustaining interventions at admission and on day were able to predict survival. an icu trial of days might not be enough to appraise precisely the outcome. bone marrow transplant was associated with a high mortality in our study. in case of relapsed aml with bmt, icu management is still challenging. the growing population of chronically critically-ill patients has a poor prognosis despite all the resources mobilised [ ] . our primary objective was to analyse the prognostic value of different definitions used to describe them. our secondary objective was to look for early clinical and biological factors that could be associated with the in-hospital mortality. we conducted an epidemiological prospective study in intensive care units (neurosurgical, cardiosurgical and medical) of a large french teaching hospital (henri mondor, créteil). we included all the patients hospitalized for at least days. we tested definitions: the prolonged mechanical ventilation, the definition taken up by kahn et al. [ ] , the prolonged length of stay, the persistent critical illness and the persistent inflammation-immunosuppression and catabolism syndrome. two biological examinations were performed: upon entering the study and week later. the study endpoint was the in-hospital mortality. results thirty patients were included between april and july . among them, only % matched the definition of prolonged mechanical ventilation, which is still the most used in the literature. further, it was not associated with the mortality, but the prolonged length of stay was, with % of these patients, that did not survive to their hospital stay. other parameters that were significantly different between the patients who died and those who survived were an advanced age, an elevated igs ii score at hospital admission, an elevated sofa score at study entry, a late healthcare-associated infection and several biological variables: a high c reactive protein, low albumin and prealbumin and a poor percent of monocytes expressing hla-dr, all measured at day . conclusion the in-hospital mortality of chronically critically-ill is still high. a prolonged length of stay is the only definition who may be helpful to identify the patients with the poorest outcome. among the early factors associated with mortality, we found a late healthcareassociated infection and a low percent of monocytes expressing hla-dr, pointing to the value of studying the immune system of these patients. introduction as a result of demographic transition, the proportion of «very elderly» (≥ years) patients is increasing worldwide and more of these patients are nowadays admitted to intensive care units (icu). among physicians the discussion about appropriateness of these icu admissions still remains controversial mostly due to questionable outcome, limited resources and costs. the aim of the study was to determine and evaluate the clinical characteristics and outcome in a very old population admitted to a medical icu in an urban teaching hospital. we present here a monocentric, retrospective and observational study. we reviewed the charts of all patients (≥ years) admitted to a medical icu between and ( years). we collected epidemiological, clinical and biological parameters and all therapeutic measures during the icu stay. a longterm survival follow-up was also performed. two hundred eighty-four patients were included for statistical analysis. multivariate cox regression was also performed to identify risk factors for -day outcome. results a total of patients were included, which represented . % of admissions to the icu during the period of the study. the mean age was . ± . years, the sex ratio was . . most of patients ( %) were admitted from the emergency department. % of these admitted patients suffered of previous dementia. the mean charlson comorbidity score was . ± . and the mean mccabe score was . ± . . the admission diagnosis in the icu was mainly respiratory distress ( %), septic shock ( %), cardiac arrest ( %) and coma ( %). the mean saps-ii score within h of icu admission was . ± . . half of these patients required support by mechanical ventilation (mean duration . days) and vasoactive drugs and % of patients received renal replacement. icu and in-hospital mortality rates were and % respectively. overall survival at months after hospital discharge was %. multivariate regression revealed necessity of catecholamines and mechanical ventilation as independent risk factors and urinary sepsis as protective factor for -day outcome. in fine, for % of these patients, a limitation of active treatment was decided (on average after days of stay). for all others there was no justification for limiting care because of a well-established treatment plan (with family, gp, icu team). conclusion the proportion of elderly patients remains low, but they are increasingly being treated in intensive care units. nevertheless, the in-hospital mortality is high compared to the average mortality in our icu over the same period ( %). the prognosis is often not as poor as initially perceived by physicians. the indication for icu treatment in our study was mostly justified; in the setting of consistent patient care and good clinical practice. it remains therefore appropriate to discuss every single icu admission of elderly patients without any restriction related to age. thus, the ongoing cluster-randomized trial of icu admissions for the elderly patients (ice-cub study) is deeply awaited to confirm or not these results [ ] . keywords intensive care; prognosis; outcome; elderly patients; over -years old. introduction regardless of the route of delivery, the postpartum hemorrhage (pph) is defined as blood loss ≥ ml after childbirth, and severe pph as blood loss ≥ ml. pph is the leading cause of maternal mortality in africa. the aim of this prospective study was to assess the quality of the initial management of pph in algeria in oran ehu and to determine the factors of care with the severity of this complication. we conducted a prospective cohort study between april and september at the ehu oran. all women who delivered vaginally and showed hpp including the suspected cause was uterine atony were included. the severe pph was defined as bleeding that required invasive surgical treatment (hysterectomy, arterial ligation), a transfusion, a transfer to an intensive care unit or death of the patient. the quality of care was evaluated using objective criteria defined by a delay of diagnosis and care and mortality. results among the women who delivered vaginally during the study period, had a pph, link with uterine atony alleged at diagnosis, of which presented signs of severity. in % of cases, the delay in diagnosis of pph was less than min; % of women received oxytocin within min after diagnosis. the tranexanique acid was used in case. the examination of the cervix, uterine exploration and uterine massage was performed in , and %, respectively. the failure of first line treatment involved % of patients. among them, the time between the diagnosis of pph and administration of blood derivatives was greater than h in a third of cases. the administration of oxytocin delay exceeds min multiplied by . the risk of severe pph. however we had deaths in our series. discussion in our study the optimal period of care was not adequate, obtaining blood derivatives in our institution remains among the factors aggravating among the main risk factors for pph, uterine atony was the main source of complication. bleeding postpartum aggravated in our two patients has led to the deaths from late diagnosis and care that was not optimal. these hemorrhages pp is the leading cause of mortality: % of obstetric deaths ( % in the confidential survey - ) [ ] . a hysterectomy was indicated after failure to conservative treatment. the death rate is estimated at % following a disorder complicated hemostasis of disseminated intravascular coagulation (dic). in some series, the mortality rate is estimated between and % [ ] . conclusion the management of pph in obstetrics gynecology service the ehu oran was not optimal. the issue of timing of diagnosis and initial treatment is crucial. solutions must be sought locally to ensure the administration of essential medicines in time, especially the injection of oxytocin within min after diagnosis. introduction chronic obstructive pulmonary disease (copd) is a common pathology that would represent the third cause of death worldwide by . its evolution is interspersed with episodes of acute exacerbations (aecopd) that may indicate an admission in intensive care unit in the most. objective to study the evolution of management modalities of patients admitted in our intensive care unit for aecopd, to determine their prognosis and to identify factors associated with mortality. patients and methods it is a retrospective, monocentric study, performed in a tunisian intensive care unit (icu) over a period of years. we including all patients admitted in icu for aecopd. parameters collected were demographic features, comorbidities, regular treatment, dyspnea assessed by the mrc scale, initial clinical severity reflected by saps ii and apache ii scores, modalities and icu admission deadlines, initial arterial blood gas analysis, management of patients in the icu (ventilation modalities, prescription of antibiotics, use of vasoactive drugs) and their outcomes (incidence of nosocomial infections and their sites, length of stay and icu mortality). results a total of patients, which represents . % of all hospitalizations, with mean age of years (iqr: - ) were admitted for aecopd during the study period. the mean saps ii and apache ii were respectively (iqr: - ) and (iqr: - ). of these, % were ventilated with niv whose overall failure rate was % with a significant decrease between the beginning and the end of the study ( vs % p = . ). sixty-four percent of patients received antibiotics at admission. the prescription rate of antibiotics has decreased significantly over the years from to %. the incidence of nosocomial infections was %. it remained steady between and %. their sites were pulmonary in % of cases. icu mortality was %. in multivariate analysis, icu admission deadlines, niv failure and the use of vasoactive drugs were identified as factors associated with mortality. conclusion our study showed the importance of aecopd in the activity of our icu. the management of these patients has evolved over the years, which was reflected by the significant decrease in the prescription of antibiotics and the enhancement of niv success rate. this result could be attributed to the combination of several factors: precocious management of patients, experience of the healthcare team and the use of efficient ventilators. icu admission deadlines, niv failure and the use of vasoactive drugs were identified as factors associated with mortality. introduction aim. investigate the effect of music therapy on the tolerance of non-invasive ventilation (niv) during its introduction. currently, % of the trauma are intubated. thirty-three percent of the patient admitted in intensive care suffers from acute respiratory distress syndrome (ards). the fmhs chose oxygen concentrator as oxygen source in addition to oxygen pressurized bottles. their supply can be uncertain in conflict areas. insufficient data are available concerning the use of oxygen concentrator in intensive care unit. the primary endpoint was to determine over the total duration of oxygen therapy, the number of days on which the use of pressurized oxygen was needed for patients oxygenated by oxygen concentrator. the secondary endpoints were to identify when pressurized oxygen was needed, describe the characteristics of the population with oxygen therapy and estimate the oxygen quantity economised thanks to the use of oxygen concentrator. the study took place in the forward surgical unit of bouffard. it's a french role located in djibouti republic in africa. all patients over admitted in the intensive care and needing oxygen therapy were included. all the patients were oxygenated with an oxygen concentrator. the oxygen concentrators used were sequaltm integra om, that could deliver up to l/min of normobaric oxygen. the ventilator used were pulmonetictm ltv and . results thirty-six patients were included over the months' study period. sixty percent of the patients were men with an average age of two hundred and fifty-one days represents the total number of days of oxygen therapy divided into days of invasive ventilation, days of noninvasive ventilation and days of oxygen mask. the use of pressurized oxygen was necessary times over the days of oxygen therapy which represents . % of the total time. the causes of its use were in ten cases ( . %) criteria of severe ards, in six cases an emergency intubation and in three cases a transfer. one dysfunction of an oxygen concentrator happened during our study. the oxygen concentrator produced m of oxygen over the study period, which represents oxygen pressurized bottles of litres. this enabled an economy of , euros. conclusion it is safe to use oxygen concentrator to take care of critically ill patients in limited resources environment. the use of pressurized oxygen is still compulsory in two situations: in case of electricity failure and in case of high fio (above %). oxygen concentrators are sufficient in . % of the time. they enable to deliver oxygen any time which is essential when supply is uncertain in conflict areas. none. table ). for the same mv and level of ofr, fdo was in our experiment, with an ofr of l/min, when ifr = l/min (mv = l/min and ti/ttot = . ), the fdo is equal to % (± %) (see table ). to this value of ifr, the fdo is in accordance with the formula of ats, but when ifr increase beyond l/min, the fdo decrease and the formula is not in accordance with ats. this can be explain because during inspiratory phase, air room (fractional oxygen = . ) entry in airway mixes with ofr (fo = ), which modifies the fdo . in this case, when ifr increase then fdo decrease and vice versa. medical and paramedical staff must be aware that with patients who receive ofr by nasal cannula, any change of ofr and/or inspiratory flow changes the fdo . in this case, for maintain the same fdo , it is necessary that modify the value of ofr. the actual fio delivered under oxygen mask in patients with acute respiratory failure and the factors that may influence the fio are poorly known. in clinical practice, different methods including formula or conversion tables based on oxygen flow can be used to estimate delivered fio . we aimed to assess first the factors influencing measured values of fio , and second the best method to estimate fio in patients breathing under oxygen mask. we included icu patients admitted for acute hypoxemic respiratory failure from a previous prospective trial [ ] in whom fio was measured under oxygen mask using a portable oxygen analyzer. we collected demographic variables and respiratory parameters that may influence measured fio . low fio was defined according to the median measured fio . for each patient, measured fio was compared to "calc + %" formula (fio = oxygen flow in liters per minute × . + . ) to "calc + %" formula (fio = oxygen flow in liters per minute × . + . ), and to a conversion table [ ] . a ± % limit of agreement for each estimation method was arbitrarily considered acceptable. results among the patients included, median measured fio was % [ - ]. after adjustment on oxygen flow, the three variables independently associated with low measured fio using multivariate analysis were patient's height, a low paco , and a respiratory rate greater than breaths/min. using paired analysis, each estimation methods differed significantly from measured fio (p < . for each). values outside the limits introduction acute hyperglycemia is common in intensive care. it was associated with poor prognosis and increased mortality. the purpose of our study is to investigate the frequency of hyperglycemia in our icu, to determine the main causes of high blood sugar and to analyze the impact of this hyperglycemia. our study is prospective during months. it was conducted in the intensive care unit of the university hospital habib bourguiba sfax-tunisia. were included in our study all patients admitted to the service during the period of the study. for each patient included were collected from the icu admission, clinical and biological data. results during the study period, patients were hospitalized in our icu and the diagnosis of hyperglycemia (> mmol/l) was admitted in patients ( %). the comparison between patients who developed hyperglycemia and those free hyperglycemia group showed that, the patients of the first group were significantly older (p < . ). additionally, hyperglycemic patients had more medical history including history of diabetes (p < . ), a higher saps ii (p < . ), a more significant frequency of active infections (p < . ). moreover, the presence of hyperglycemia was associated with shock (p < . ) and respiratory distress (p < . ). their evolution was marked by the significantly higher frequency of infectious complications (p < . ), thromboembolic complications (p < . ) and acute renal failure (p < . ). the average duration of mechanical ventilation and the length of stay were also significantly prolonged in hyperglycemia group patients (p < . for both). finally, the presence of hyperglycemia was significantly associated with a higher mortality rate. conclusion we concluded that hyperglycemia is correlated with poor prognosis of morbidity and mortality. but strict glycemic control remain controversial. thus, further studies on this subject will be recommended to define the exact place of glycemic control in intensive care. none. the rrt was prophylactic in four cases started when phophatemia was more than mmol/l, and therapeutic for renal failure and established tls in three cases. the median duration stay in icu was [ ] [ ] [ ] [ ] j. thirteen patients left the icu without major metabolic dysfunction. two patients deceased due to infectious complications. discussion monitoring of electrolytes was done on average, three times a day which is hard to do in onco-hematology unit. the early use of rasburicase and the aggressive iv hydration helped to prevent tls for seven patients. the aggressive iv hydration was made according to echocardiography data and close monitoring of vital signs and urine output which has allowed to avoid volume overload and acute pulmonary edema. the early prophylactic rrt prevented renal failure and metabolic complications. conclusion early management of tls in icu can prevent tls and most of its serious complications and should be considered in tls prophylaxis recommendations. none. the both urinary (expressed as the ratio of ngal on urinary creatinine) and plasma ngal were predictive of aki stage . predictive value of plasmatic measurements was higher than the urinary one (auc of . and . , respectively, p = . between auc), but not higher than either baseline serum creatinine (auc = . ) or h diuresis (auc = . ). backward multivariate regression showed that plasma ngal concentration was associated with serum creatinine, crp and albumin, whereas urinary ngal was associated with leucocyturia and baseline creatinine. discussion previous positive studies with ngal did not compare the performance of this costly biomarker with simple usual clinical parameters to predict aki. moreover, several parameters were associated with ngal concentrations with a high risk of collinearity (crp) and/or false positive results (leucocyturia). our data do not support any added value of ngal concentration over baseline serum creatinine or urine output to predict aki. introduction acute renal failure (arf) is a common entity in intensive care, concern that the heavy morbidity and mortality it is associated [ ] . early diagnosis of this entity remains difficult, neither diuresis and creatinine are early parameters in the diagnosis of arf. the kidney is an organ that suffers long to become faulty, the priority is to recognize renal aggression and to achieve a therapeutic allowing reversibility of the infringement. a number of markers have been developed for the diagnosis of the ira but costs remain high not allowing their routine use. the measurement of resistance index with the renal doppler could be a solution for the diagnosis of aggression and also of the etiology. the elevation of creatinine was seen later within h after the ir > . discussion in our series the resistance index has a value of early diagnosis of renal prognosis aggression in the occurrence and development of renal failure. renal doppler associated with a strictly applied standardized protocol achieves the two goals of monitoring who aid in the diagnosis and guide treatment. although the recommendations of experts to this tool provides that it should probably not use the resistance index measured by renal doppler to diagnose or treat an ira (grade ) [ ] . identifying the cause of kidney aggression is a prerequisite before any therapeutic action. hypovolemia and soda hydro overload are the causes principales. excess filling hyper intra thoracic pressure and hypoxia are the main causes of kidney congestion. conclusion doppler is an early renal medium in the diagnosis of renal aggression. a larger series could assert this observation. none. ), had significantly more pre-eclampsia, / ( %) versus / ( %) p = . . pe were started at an average of . days after foetal extraction, and with an average of sessions. patients of the pe group had significantly lower nadir of hemoglobin but also lower hemoglobin level at day and day . nadir of platelets count was also lower and level remain lower at days , , and . acute kidney injury (using kdigo classification) was more frequent with a higher rate of dialysis in icu, in the pe group ( / ( %) vs / ( %) p = . ) with a more frequent need for dialysis at the exit of icu. proteinuria was significantly higher in the pe group ( . mg/mmol vs . mg/mmol, p = . ). adamts dosage was done only in patients with pe. we find a diminution of adamts activity (before pe) with an average of % [ - ] in this group. there was no death, and adverse effects were not significantly different. discussion this study shows that pe was used when diagnosis was uncertain in the most severe form of pp-tma. low hemoglobin, low platelets, acute kidney injury and high level of proteinuria are the main factors associated with the decision to begin pe. this technique was safe and not associated with major adverse events. several studies show that there are physiopathological crossovers between diseases associated with pp-tma, for example low adamts activity in hellp or mutation in alternative complement pathway which induced hellp. moreover, studies and case reports show a benefit of pe in hellp syndrome. our study did not find significant difference in adverse events (maybe due to a lack of power), but this is another argument to discuss pe in the management of pp-tma in severe patients. the main limits of our study are that none of the patients who had a plasmatic exchange had a diagnosis of ptt and that diagnosis tests were not performed in all patients with pp-tma (complements level, adamts …). conclusion pp-tma treated with pe has lower hemoglobin, lower platelets, higher rate of kidney injury and proteinuria than those treated without pe. no difference were found for adverse events. begining of pe should be discussed for management of a pp-tma without amelioration after foetal extraction. none. introduction diffuse alveolar damage (dad) is the typical histological feature of acute respiratory distress syndrome (ards). however, in a previous study including patients with criteria for ards, we found that only % of them had dad at autopsy exanimation [ ] . it has been shown that patients with ards and dad on open lung biopsy had higher mortality than those without dad [ ] . thus, we aimed to identify markers associated with dad in patients with ards. we included the patients who met criteria for ards at time of death in our large database of clinical autopsies [ ] . we assessed the proportion of dad according to the severity of ards including the degree of hypoxemia and the ancillary variables from the berlin definition: use of high levels of positive endexpiratory pressure (peep at least cmh o), radiographic severity ( or quadrants on chest radiograph), altered respiratory system compliance (≤ ml/cmh o), and large dead space defined as a corrected expired volume per minute (≥ l/min). results dad was associated with all the severity markers abovementioned using univariate analysis. after multivariable logistic regression, the three markers independently associated with presence of dad were the gender with an odds ratio ( conclusion dad was significantly more frequent in females. in addition to the severity of hypoxemia, diffuse infiltrates involving the quadrants was a significant marker of dad. introduction ventilation induced lung injury (vili) is responsible for an increased mortality in ards [ ] . mechanical ventilation may trigger an inflammatory response, comprising alveolar macrophage activation and recruitment, which may be specifically, repeatedly and spatially assessed by functional imaging techniques such as positron emission tomography combined with computerized tomography (pet/ct) [ ] . c-pk is a pet radiotracer with potential to quantify macrophage inflammation. we aim to assess its performance to detect lung macrophage recruitment in an experimental highvolume vili model. materials and methods vili was performed in anesthetized pigs under neuromuscular blockade by rapidly increasing the tidal volume (vt) to obtain a transpulmonary pressure (tpp) between and cmh o under zero end-expiratory pressure. pet/ct acquisitions were performed before (t ) and after h of high-volume ventilation (t ), and image-derived measurements were realized on the whole lungs, and regionally on distinct lung regions (divided along the anteroposterior and the cephalocaudal axes). c-pk lung uptake was estimated using the standardized uptake value (suv), normalized to the ct-derived tissue fraction in the region of interest (roi). mechanical lung aggression was estimated by ct-derived dynamic and static strains, and tidal alveolar hyperinflation (expressed as a fraction of the tidal variation in the roi volume). after euthanasia, alveolar damage and macrophage recruitment were assessed in the lung regions, using semi-quantitative scores. results between t and t , vt and tpp significantly increased from . ± . to . ± . ml/kg and . ± . to . ± . cmh o, respectively. suv on the whole lung significantly increased from . ± . to . ± . between t and t and dynamic strain from . ± to . ± . , whereas static strain did not significantly vary. tidal alveolar hyperinflation significantly increased from ± to ± % on the whole lung between t and t . regionally, dynamic strain, and tidal alveolar hyperinflation significantly differed between regions, as well as between t and t . regional suv differed between t and t but not between regions. regional static strain did not differ between regions, nor between t and t . in multivariate analysis, regional suv was independently and significantly associated with dynamic strain and tidal alveolar hyperinflation. histologic analysis showed significant regional differences in alveolar damage but not in macrophage recruitment. suv was positively associated with macrophage recruitment but not with alveolar damage. discussion in this experimental vili model, c-pk suv was significantly increased after h of injurious ventilation, and was significantly and positively associated with high-volume ct-derived mechanical parameters, such as dynamic strain and tidal alveolar hyperinflation. the radiotracer's specificity for macrophages is confirmed by the suv significant association with macrophage recruitment and the lack of association with alveolar inflammatory edema. conclusion c-pk is a macrophage-specific pet radiotracer, with potential to dynamically and specifically assess alveolar macrophage inflammation induced by high-volume ventilation. research founded by the french society of intensive care medicine (srlf) and la fondation pour la recherche médicale (dea ). the reverse triggering (rt) is the term used to name the contractions reflexes of the muscle diaphragmatic provoked ("triggered") by the periodic insufflations, delivered by the ventilator, at sedated patients under mechanical ventilation [ ] . the rt constitutes a new form of patient-ventilator interaction clinically difficult to detect and little known. the rt could have potential implications during the management of acute respiratory distress syndrome (ards). at present, the management of severe ards consists among others, on the use of an early and systematic perfusion of neuromuscular blockade agents (nmba) during a h' period, continuation to the acurasys essay which showed a reduction of the mortality in the group of the severe ards patient receiving nmba. the reason of the beneficial effect of curare is not perfectly known. it is possible that the phenomenon of rt is a mechanism implied in the deleterious role of the mechanical ventilation during ards. the abolition of this phenomenon by nmba could explain the beneficial effect of nmba in ards [ ] . the objective was to look for the phenomenon of rt in two groups of ards patients: a group receiving nmba and a group not receiving nmba. patients and methods physiological observational and comparative study in intensive care units. we record continuous signals of airflow, airway pressure, and esophageal pressure during h of consecutives patients with ards criteria and pao /fio ratio ≤ at a positive end-expiratory pressure (peep) of cmh o evolving for less than h under mechanical ventilation. recording of esophageal pressure of consecutives moderate to severe ards patients were blinded analyzed (group nmba n = ; group unless nmba n = ). any phenomenon of rt was observed in the group of mild ards patients receiving nmba (fig. a) . we confirmed the existence of rt on patients of in the group of mild ards who not receiving nmba (p = . ) (fig b) . discussion one of the main limits was the quality of the collection of the signal of esophageal pressure. the monitoring of esophageal pressure is technically difficult, and can d influence the quality of the signal and the reliability of the results. conclusion this study confirms the existence of the phenomenon of reverse triggering among deeply sedated patients not receiving nmba with a % incidence. more research is needed to determine if the reverse triggering is a risk factor independent from vili, associated with the bad prognosis of severe sdra patients and, if a strategy of early treatment based on nmba, could improve the prognosis of reached patients. after ecmo removal had a significant median reduction of days in the bipap-aprv group, p = . (fig. ). we reported the feasibility of a protocol based on bipap-aprv aiming at resuming sv as soon as possible in ards patients under ecmo. the occurrence of spontaneous inspiratory efforts in ards patients can major variability of transpulmonary pressure and as result jeopardise vt and driving pressure control. this might be an issue if protective ventilation is not guaranteed anymore. vt with bipap-aprv remains within safe range when the ratio fig. circles are pac group, rhombus are aprv group. mv mechanical ventilation, psv pressure support ventilation. data are presented as median (iqr), comparison between the groups at each time mann-whithney test, *p < . of spontaneous minute ventilation to total minute ventilation is between and % [ ] . bipap-aprv is more efficient than psv to increase lung aeration in patients with ards [ ] . recruitment of dependent region is more likely to achieve if sv is not supported by synchronized positive airway pressure as during bipap-aprv [ ] . our strategy targeting a percentage of sv between and % with high peep could be viewed as a compromise in order to promote sv and protective ventilation at the same time. conclusion protective ventilation combined with sv under ecmo by using a specific protocol based on bipap-aprv is feasible and safe. it may facilitate weaning and thus reduce the time under mv after ecmo. to what extend this beneficial effect is directly due to the presence of sv deserve further investigations. introduction since the first transplant from a patient in a state of brain death conducted in at the university teaching hospital ibn rushd of casablanca, the number of transplants has increased. however, it is still inadequate meet the growing needs of organs. the refusal of families remains the main obstacle to the developpement of organ transplantation in morocco. the aim of our study is to monitor and analyse the evolution of family refusal to organ donation in a brain dead patient. patients and methods this is a retrospective and comparative study from august until december .the data were collected from records of brain dead patients candidates for organ donation at the intensive care units on ibn rushed hospital. the coordination registers were also studied. a questionnaire was distributed to families who refused organ donation to investigate the causes of the refusal. results during this period, patients with brain death have been identified and families had been approached. families ( %) refused organ donation. the main causes of refusal were: fear of body mutilation ( %), lack of will ( %) and religious causes in % of cases. the refusal rate for families decreased from % in to % in . only patients experienced cardiac arrest before transplantation. during this period, cornea transplants from braindead patient were conducted with kidney transplants and two liver transplants. discussion the evolution of the refusal of families saw a decline through awareness and communication campaigns for organ donation. conclusion improvements to our health care system must be proposed including strengthening detection of potential donors and relationships with the donor's family and effective communication policy. in the icu, three major actors are involved in the caring relationship: patient, relatives and caregivers. acting as spontaneous testimonials of the lived experience, thank-you letters from relatives may be considered by icu teams as a source of original information which could help in improving care for critically ill patients and families. this study aimed to investigate the qualitative content of thank-you letters from relatives of patients who stayed in the icu. specifically, our research questions were, with regards to the letters' content, ( ) how is the caring relationship tackled and characterized by relatives? ( ) to what extent does this relationship impact their experience of icu? materials and methods the study took place in a -beds icu during a -month period. the research team consisted in a care assistant, a nurse (also clinical research associate), a psychologist (not working in the icu) and an intensivist. the corpus consisted in twenty thankyou letters received in the icu. we conducted a qualitative study according to the thematic inductive approach. the process of coding was intended to create established meaningful patterns. results two main themes emerged as specific determinants of the caring relationship: ( ) the temporality, comprising the time dedicated to the patients and their family, the time spent with the icu team, the striking time corresponding to significant events for relatives needed to be shared with the staff, the extension of the link with caregivers by evocating a new life after icu stay, the writing time as a countergift to the caregivers; ( ) the caregivers behaviour, including human skills detailed in many core values (kindness, availability, devotion, attention, goodwill, sensitivity) psychological support, emotional sharing, capabilities to give informations. relatives feel to be "at the center of all attention" in the same way as their loved ones. through the narration of icu experience, the caring relationship is characterized as follows: ( ) the caregiver becomes a close person with an equal relationship (feelings of friendship, emotional closeness); ( ) the icu team becomes a new family (contrasting with the poor living environment of icus); ( ) the relative becomes a caregiver (with appropriation of medical terms or speaking of his loved one as a patient); ( ) the caregiver is seen as a "super-hero" through an asymmetrical relationship with an overstatement of personal dedication and investment of the staff members (abnegation, vocation, involvement). the caring relationship impacts relatives' experience of intensive care in several ways: ( ) relatives are deeply touched by caregivers' human behavior, emotional support being a source of solace and resilience in particular for bereaved families; ( ) relatives express the idea that taking care of humans is not a valued and rewarded task and the emerging awareness of hospital realities and difficulties of work in the icu; ( ) the most striking transformational change in relatives is the perception of their own vulnerability and humanity, leading them to exhibit an outward-looking attitude (for example filling out their organ-donation card), and encouraging the icu caregivers to continue their missions for the others. conclusion thank-you letters provide both encouraging and informative messages for icu teams about relational care for patients and families notably the indivisibility of the families and their critically ill loved ones. the relatives' experience of the icu appears strongly influenced by the caring relationship in the way they express an authentic revelation of their own humanity and altruistic thoughts. the thematic content of thank-you letters questions determinants and fundamental values at stake in the patient-relatives-caregivers relationship. introduction far from medical paternalism, the doctor-patient relationship has now evolved to respect "the autonomy and patients' rights". changing behavior has been gradual, while the law offered the patient the freedom to consent to care and then of expressing their wishes regarding the therapeutic intensity they would benefit, in critical situations where consent would not be possible, through advance directives (ad) [ ] . their use is of paramount interest for intensivist in many critical situations. unfortunately, the use of ad remains marginal because of the unfamiliarity of patients with their use and an appropriation default by clinicians [ ] . the aim of our study was to investigate the perspective of the coming family physician generation on advances directives. patients and methods population of interest was general practitioner fellow (gpf) from class of to . we built an online questionnaire survey about knowledge and the place they want to give to ad in their forthcoming daily clinical activity. this questionnaire was sent to gpf emails obtained by universities, unions and via the official mailing lists of different regionals classes provided by the first contacted. descriptive analysis of quantitative data was expressed as mean and standard deviation, qualitative data in number and percentage. the comparison of continuous variables was performed by the student t-test and the comparison of categorical variables by a chi test. analyzes were conducted on biostatgv website and microsoft excel ® . results gpf answered the survey, mainly from ile de france (n = ), toulouse (n = ) and lille (n = ). for gpf the majority of patients do not know the ad ( . %) and % think that those who know do not know how to use it. . % of gpf think writing ad by patients requires better information. according to them, the information should concern the support offered in the icu ( . %), the use of mechanical ventilation ( . %), dialysis ( . %) and the evolution of patients after hospitalization in icu ( . %). nevertheless information on the prognosis of chronic diseases or organ failure seems interesting for only and . % of them respectively. . % of gpf wish to propose the drafting of ad to their patients. however, only . % of them are willing to suggest ad to patients with cancer or hematologic malignancies, . % to patients with neurological and/or degenerative disorders, . % to elderly patients. discussion despite the low proportion of the population we think these observations to be of interest because we probably selected the gpf the most interested in ad as the participation was not mandatory. conclusion a large majority of young of future general practitioner is willing to be involved in the implementation of ad with their patients, however the target population remains very limited, considering that half of them do not want to discuss ad with patients suffering from diseases potentially associated with icu admission or therapeutic intensity discussion. this study was conducted in adult intensive care units in public or private hospitals in four countries: canada, france, italy, spain. in each country, health care professionals were solicited for an exploratory interview about the sources of stress in the work environment: senior physicians, residents, experienced nurses (with more than years of experience in the service) and inexperienced nurses (with less than years of experience in the service). all the interview transcripts were analysed using an inductive coding approach. results one hundred and sixty professionals ( physicians and nurses) were included in the study. eight themes emerged from the analysis, and they concerned the stress linked to ( ) patient ( ) care, ( ) team, ( ) family, ( ) institutional context, ( ) environment, ( ) organizational context, ( ) individual dimensions. in each theme, sub-themes have been identified and determine more precisely the difficulties at work. discussion our findings emphasize the complexity of work in icus and show the specifics factors not taken into account in the generic stress scales such as stress in relation with family relationships, the end of life decisions and inequity of health care. conclusion the specific stress scale should allow to better identified stress in icu and to develop measures of prevention and support and training programs. introduction intensive care units (icu) is a place where caregivers face many constraints that can affect their physical and mental health due to the use of specific care and strong emotional charge related to patient death and pain of the families. the aim of the present study is to detect anxiety disorders and/or depression among staff working in icus. on september , a questionnaire was distributed to staff (medical and paramedical) operating in icus in the university hospital fattouma bourguiba monastir, tunisia ( medical icu, surgical icu, cardiologic ccus and nephrologic intermediate care unit). this questionnaire included demographic data of participants (age, sex, marital status, length of service, psychiatric history, consumption of anxiolytic and/or antidepressant) and the hospital anxiety and depression scale (had: scale composed by items to screen the anxiety (a) and/or depression (d) among hospital staff ). results during the study period, participants completed the questionnaire ( %), % of them were women, the median age was years ± . . forty-nine participants were doctors (the majority of them residents: / ). . % of participants (all paramedics) worked on night shift, seniority of more than a year in the icu was found in % of participants. . % of staff interviewed were married and only . % of them reported consumption of anxiolytics and/or antidepressants. . and . % of the participants had respectively symptoms suggesting anxiety and depression. the median had score was (iqr = ); the medical function seems to be significantly associated with the occurrence of symptoms of anxiety and depression compared to paramedics, however the type of icu (medical/surgical icus vs cordiologic/nephrologic icus) does not appear to be related to the occurrence of symptoms of anxiety or depression (table ) . conclusion anxiety and depression are common symptoms among caregivers in icus. improved conditions of work in these units should be a target to avoid burn out syndrome. none. anxiety, n (%) depression, n (%) introduction carbon monoxide (co) poisoning is one of the common causes of poisoning specially in the cold season, which leads to a significant morbidity and mortality. we retrospectively reviewed the medical data of patients who presented to the toxicology emergency department with co poisoning during january to march . we analyzed patients' characteristics, management, and outcomes. results a total of six hundred and sixty-six patients ( female and male), aged of ± years, were included; poisoning occurred between december and february in % of cases, secondary to an indoor heating system exposure in the majority of cases ( %). the estimated duration of exposure was . ± h [ . - h], with a mean carboxyhaemoglobin (cohb) level on arrival at . ± %. neurological changes were the most presenting symptoms including headache (n = , %), dizziness (n = , %), seizure (n = , . %) and loss of consciousness (n = , . %). digestive disorders involving vomiting and nausea were observed in . % (n = ). one woman without cardiovascular risk factors developed non stsegment elevation myocardial infarction complicated by lung edema. the majority of patients (n = , %) received normobaric oxygen during h (n = ) and h (n = ). hyperbaric oxygen therapy was administered at . ata during h to patients for neurological changes (n = ), pregnancy (n = ) and elevated cohb ≥ % (n = ). mechanical ventilation was required for patients, and admission into intensive care unit in patients ( %). death occurred in cases ( . %). conclusion the carbon monoxide poisoning is a common reason for emergency department visits in winter. the physician should be aware of the serious neurological and cardiovascular complications, if symptomatic treatment and oxygen therapy regimens were not respected. none. neuro-respiratory toxicity of baclofen in the rat: study of the concentrations/effects relationships and role of gabaergic introduction baclofen, a gaba-b receptor agonist is used as muscle relaxant agent and recently for the treatment of alcohol dependence. the number of poisonings has significantly increased since this new indication. clinical presentation of poisoning mainly includes sedation, hypotonia, respiratory depression and seizures. to characterize the neurorespiratory toxicity of this molecule at high doses, we aimed at investigating alterations in sprague-dawley rat ventilation and brain electrical activity after baclofen administration and studied their reversal by gaba-receptor antagonists. materials and methods rat ventilation was investigated using plethysmography and arterial blood gas analysis while brain electrical activity was studied using eeg with one implanted frontal electrode. three baclofen doses were used including . mg/kg ( % lethal dose- %), . mg/kg ( %) and mg/kg ( %). baclofen concentrations were obtained using hplc-msms assay. we modeled baclofen pharmacokinetics and analyzed the doses/effects and effects/concentrations relationships. results baclofen induced early-onset and prolonged dosedependent sedation (p = . ), hypothermia (p = . ), eeg and respiratory depression ( . ) characterized by significant increase in the inspiratory (p = . ) and expiratory times (p = . ). significant increase in paco and decrease in arterial ph and pao were observed at mg/kg (p = . ), peaking at min. eeg showed signal slowing, burst-suppression aspects and spikes peaking at - h post-injection without normalization at the end of the experiment at h. we did reverse baclofen-induced decrease in tidal volume with saclofen (a gaba-b receptor antagonist) and interestingly no alteration of baclofen-induced respiratory depression was observed with flumazenil (a gaba-a receptor antagonist). pharmacokinetic parameters of baclofen were obtained at the three doses and were dose-dependent. significant but non-linear relationships were observed between baclofen-induced effects and concentrations. conclusion baclofen causes dose-dependent neurorespiratory toxicity in rats. however, due to increased poisonings, its safety profile at high doses remains to be established in humans. none. poisoning was deliberate in % of cases. mean ingested dose was . ± mg. the majority of patients presented to the emergency room at . ± h after ingestion. digestive decontamination was performed in . % (n = ) of patients. clinical presentation was dominated by neurological symptoms; including coma (n = ), hypotonia (n = ), hyporeflexia (n = ), agitation (n = ), seizures (n = ) and delirium in case. hemodynamic manifestations included bradycardia in patients, three of them required atropine infusion. one patient presented with hypotension responding to vascular resuscitation. sixteen cases required mechanical ventilation. aspiration pneumonia was noted in cases. mean duration of ventilation was . h ± . mean hospital length of stay was h ± . complications included ventilation associated pneumonia in one case and moderate rhabdomyolysis in cases. all patients evolved favorably. there is no correlation between coma and assumed ingested dose. conclusion baclofen overdose causes mainly neurological effects and except for bradycardia cardiovascular effects were uncommon. prognosis is good if full supportive care is administered properly. none. introduction the lack of an effective treatment for the maintenance of abstinence from alcohol has led physicians to take an interest in baclofen. beyond efficacy, safety of baclofen, prescribed in high doses, is a concern, especially in case of drug overdose. indeed, patients with chronic alcohol abuse frequently develop psychiatric disorders, and are at risk of voluntary drug intoxications. thus, we set up a retrospective study to describe morbidity and mortality associated with baclofen overdose. conclusion baclofen, prescribed in high doses, may lead to severe intoxications: self-poisonings frequently require endotracheal intubation and are associated with an increased risk of death. dialysis decreases baclofen elimination half-time but clinical relevance of this difference could not be determined. none. introduction baclofen, a gaba-b receptor-agonist with muscle relaxant properties established since , has been recently used at elevated doses to treat dependence to ethanol. the number of prescriptions has exponentially increased without an exact evaluation of its toxicity. we aimed to describe acute baclofen poisoning requiring intensive care unit (icu) admission and study the relationships between the toxic encephalopathy and the plasma baclofen concentration. we conducted a single-centre retrospective study including all baclofen-poisoned patients admitted to the icu in - . when requested by the clinical situation, repeated electroencephalograms and measurements of the plasma baclofen concentrations were performed. toxic eeg encephalopathy on a scale of zero to five was graded according to the international rating system (markand, ). plasma baclofen concentration was determined using liquid chromatography coupled to mass spectrometry in tandem developed with a quantum ultra apparatus (thermo fisher scientific) and electrospray source ionization in positive mode (limit of quantification: ng/ml). linear regression and chi- or mann-whitney tests were used as requested for subgroup comparisons. baclofen pharmacokinetics and the relationships between the toxic encephalopathy and the plasma baclofen concentration were modeled using winnonlin software v. ) were closed to the observed values reported at therapeutic doses. the relationship between baclofeninduced encephalopathy as a function of the baclofen concentrations was described using a sigmoidal emax model. conclusion baclofen poisoning may be life-threatening. toxic encephalopathy is well-described with eeg and its grade correlated to the baclofen concentration. prescribers should be aware of the dangers of baclofen which benefits to treat dependence to alcohol are still lacking. none. results initial examination suggested that an illness other than bacterial meningitis was the cause of patients' complaints. first hypothesis was meningitis receiving uncomplete dosage regimen of antibiotics. thereafter owing to apparent loss of consciousness with abnormal eyes movements, non-tonico-clonic seizures were considered meanwhile. the ratio of individuals less y-o to those equal to and greater was / %. the male to female ratio was / %. the mean duration of hospitalisation was . ± . days (extremes - days). extrapyramidal syndrome predominant on the upper part of the body was noted by paediatrician neurologists who suggested considering a genetic disease. however, signs and symptoms were present in people from different families in different areas at the same time. the definitive diagnosis made on pictures and videos of children and adults and was facio-troncular dystonia resulting from drug-induced adverse effect. four urine samples were collected in children and sent to a toxicological laboratory in france. all urine samples were positive for haloperidol meanwhile the other causes of facio-troncular dystonia were excluded, including other neuroleptics, metoclopramide, antidepressants, amodiaquine, anti-histaminic drugs, anti-epileptics, and cocaine. from january to august , hospitalisations were recorded in patients. looking for the source of haloperidol showed that tablets sold as 'diazepam' and consumed by symptomatic patients contained haloperidol as the sole active pharmaceutical ingredient, suggesting that this large outbreak was due to haloperidol toxicity from falsified diazepam. initial treatment was diazepam to relieve severe facio-troncular dystonia which was efficient but resulted in long-lasting sedation more especially in children. a dosage regimen using bipéridène administered by intravenous and oral route was refined to prevent adverse effects related to this anticholinergic agent used in children. the complete reversal of the facio-troncular dystonia was the antidotal evidence supporting the toxicological diagnostic. the mortality rate was less than % meanwhile the direct causal relationship with adr is questionable. an epidemiological study, including toxicological analysis in controls in ongoing. indeed, facio-troncular dystonia induced by haloperidol does not result from a drug overdose but is an adr occurring in about % of patients treated with haloperidol. who is involved in the inquiry related to this counterfeature involving different countries. the cause of the error is presently under investigation. discussion this outbreak emphasizes the need to consider toxicity resulting from counterfeatured medicines when facing collective atypical signs and symptoms in countries with unrestricted access to medication with limited control of qualities of the medicinal drugs. conclusion counterfeatured medicinal drug may result not only in poor efficacy but also in onset of unexpected outbreak of unknown diseases that should suggest a toxic origin. in late -early , médecins sans frontières (msf) had to face an outbreak of severe facio-troncular dystonic syndrome (ftds) in north-east congo. this outbreak resulted from counterfeature of pills sold as diazepam. toxicological analysis revealed one pill contained about mg of haloperidol. ftds induced by haloperidol does not result from a drug overdose but is an adverse drug reaction (adr) occurring in about % of patients treated with haloperidol. nine-hundred and twenty-five individuals were admitted in msf structures for ftds. the ratio of individuals less than y-o and equal to or greater of age was / %, including ( . %) of children less than y-o. initial treatment was based on diazepam which relieved ftds but resulted in long-lasting sedation, preventing given any drug by the oral route. owing to the definitive diagnosis, a shift to the use of a more specific antidote was chosen. biperiden was selected as existing in the intravenous and oral form in the swiss pharmacopea. the study was approved by the ethical committee of the ministery of health of the republic democratic du congo. patients and methods as a whole, biperiden was used in cases ( % of the total). treated children presented with severe dystonia as evidenced by inability to cooperate and to swallow. verbal informed consent was obtained from relatives. the dosage regimen to treat drug-induced dystonic syndrome in the swiss pharmacopea is as follows: for parenteral use in children, intravenously or intramuscularly: . mg/kg or . mg/m bsa every , according to response and tolerance; a maximum of four doses per day should be used. the internal msf recommendations for biperiden use in children were . - . mg/kg of body weight that might be repeated four times a day. initially, biperiden administration was administered under medical supervision by the msf referent at the scene. results there was no pediatric preparation of biperiden. accordingly, the adult preparation was used in children. the preparation contained mg of biperiden in one milliter of solvent. the initial planned dose for children of y-o and less and those up to y-o were and mg, respectively. the mg ( ml) of biperiden was diluted in ml of saline resulting in a final dilution of mg/ml. six children were treated according this dosage regimen. however, the one mg dose was either of limited efficacy while being associated in others of signs suggestive of adr, including agitation, heart rate greater than b/ min, the upper limit for children aged of y-o and less. two children greater than y-o presented severe abnormal behavior resulting in an attempt at escape. owing to question about safety, the dosage regimen was changed, as follows: mg ( ml) of biperiden was diluted with ml of saline resulting in a final dilution of . mg/ml. an initial dose of . mg was administered intravenously as a bolus dose. the effects were looked for over min. in the absence of improvement in facial dystonia, a second bolus dose of . mg was administered, a third dose could be considered min later if the ftds did not resume. the cumulative initial dose should not be greater than mg. in addition to the reversal of facial dystonia, the therapeutic effect of biperiden included the return of swallowing to normal allowing to give further doses of biperiden by the oral route for three days. the first oral dose was administered no less than h after the last initial dose at a dose equal to the efficient initial cumulative dose. the following doses were halved every h. no adr related to biperiden were reported using this dosage regimen. the mean duration of hospitalisation was . ± . days. discussion the bioavailability of biperiden by the oral route is equal to %. accordingly, the corresponding intravenous dose should be divided by a factor three. dosage regimen of anticholinergic drugs in children are poorly documented. the dosage regimen recommended by the pharmacopea resulted in frequent and severe adr. titration of biperiden resulted in efficient and safe dosage. conclusion when biperiden administration is required by intravenous route in children of y-o and less, biperiden should be administered intravenously and titred using bolus dose of . mg till the therapeutic effect is obtained. introduction severe poisoning by rodenticides is frequent. it represents nearly % of patients admitted to the new intensive care unit (icu) of the region. that is why we decided to perform this study. the aim of this work was to describe the epidemiology, clinical features and management of all patients admitted to our unit for acute poisoning with rodenticides. patients and methods it was a retrospective study performed in the year from january to december. the study included all patients admitted in the icu for rodenticide poisoning. results patients were enrolled in the study. our patients were young with a mean age of ± years. poisoning was more common in females (n = ; %). the mean delay between rodenticide poisoning and first medical contact was about ± h in the cases where this information. most of our patients ( %) attended the emergency department of zaghouan with a non-medical transportation. it was a suicide attempt in most cases ( %) and an accidental poisoning in % of patients. the most frequent cause of poisoning in our study was organophosphorus pesticide (n = ; %). the second cause was alpha-chloralose poisoning with seven cases ( %). one patient ingested accidentally an anticoagulant rodenticide. most of patients had ingested (oral route) the rat poison (n = ; %). clinical examination found normal vital signs in ten cases ( %). nine patients ( %) had a shock, eight patients ( %) had an acute metabolic disorder and five patients ( %) had acute respiratory failure or were comatose. all patients enrolled in the study were admitted in the icu for a period of clinical observation of h. stomach pumping (gastric lavage) was performed in patients ( %). an antidote which was atropine was needed in twelve patients. three patients ( %) who ingested alpha-chloralose needed intubation and mechanical ventilation. all patients had a good outcome and were discharged from icu and from hospital. the mean icu length of stay was ± days. conclusion this is the first study of acute poisoning with rodenticides admitted in the new icu. the results of our study were similar to those published in recent literature. cases of acute poisoning with rodenticides reported in this work were not severe. none. introduction the systemic arterial load imposed to the left ventricle (lv) is a major determinant of normal/abnormal cardiovascular function. the lv mean ejection pressure (lvmep) is the best estimate of load faced by the lv throughout ejection. the contribution of the steady and pulsatile blood pressure (bp) component of arterial load to lvmep is debated. we studied the hemodynamic correlates of lvmep using carotid tonometry. intensive care unit patients equipped with an indwelling catheter were studied, thus allowing precise calibration of the tonometer. patients and methods carotid tonometry (complior analyse ® alam medical, france) was prospectively performed on hemodynamically stable, spontaneously breathing patients ( f, mean age ± sd = ± years). carotid waveforms were calibrated from diastolic bp and time-averaged mean bp invasively obtained at the radial (n = ) and femoral (n = ) artery. all patients were free of aortic stenosis. lvmep was the area under the systolic part of the carotid pressure waveform divided by ejection time. results lvmep ( ± mmhg) was strongly related to central systolic bp ( ± mmhg; r = . ) and was also related to mean bp (r = . ), peripheral systolic bp (r = . ), peripheral (r = . ) and central (r = . ) pulse pressure (each p < . ). the lvemp was not related to age, heart rate and stroke volume. systolic pulse wave amplification ratio from carotid to periphery was . ± . . conclusion lvmep was most strongly related to central systolic bp, which combines the influences of the steady and pulsatile components of central arterial load (r = . ). lvmep was less strongly related to peripheral systolic bp, which may be less informative given variable systolic pulse wave amplification across patients. introduction myocardial dysfunction is one of the main predictors of poor outcome in septic patients, with mortality rates next to %. many pathological findings were found in the sepsis induced cardiomyopathy including myocardial ischemia, alterations in microcirculation and proinflammatory cytokines. the aim of this study was to assess the prognostic value of a recently developed highly sensitive cardiac troponin i (hstni) assay in patients with septic shock. we performed a prospective observational study in septic shock icu patients within h of admission. exclusion criteria were age > years; pregnancy; post-cardiac arrest and braindead. hstni was measured soon after admission and , , and h after. patients were subjected to transthoracic echocardiography (tte) at study inclusion and regular biochemical and hemodynamic assessments were performed. pearson's chi square and fisher's exact tests were used. p < . was considered significant. conclusion circulating hs-ctni is present in patients with septic shock. a rise of hstni may be an indicator of poor outcome. also, right heart functional abnormalities exist in patients with septic shock. none. evolution of the right distribution width as a pronostic marker during the differents state of shock introduction right distribution width (rdw) has been recently proposed as a pronostic factor in different pathologic situations and especially to the septic patients who stay in icu. some works substantiate the relationship between an alteration of the red blood cell rheology during the septic shock and a severe state of the disease. no one has studied the rdw between the differents shocks yet. we are going to determinate the relationship between rdw and apache ii score, mortality rate in the intensive care unit (icu), at the hospital, at the day and . we investigated those parameters near patients who were admitted at the icu and needed norepinephrine between the first of march and the st of december. they were stratified in différent groups: septic shock n = , cardiogenic shock n = , hemorragic shock n = and obstructive shock n = . results we did not observe any correlation between the rdw and the icu mortality, hospital mortality and at the day and . only a poor significant correlation has been found between the cardiogenic shock and the mortality rate: at the hospital (p = . ), at day (p = . ) and at the day (p = . ) but not in the icu (p = . ). the receiver operating characteristics (roc) curves do not show significant differences between rdw, apache ii score and icu mortality rate or intra hospital. the sample of the hemorrhagic shock and obstructive shock was not usable for this calculation. compared to other studies which were focused on the septic shock where the mortality was approximately %, we determinated a mortality rate near %. conclusion the delta of the rdw d /d did not present any correlation with the mortality rate. in our study, the rdw in the different kind of shocks do not look like to be a good predictive marker of the mortality, except for the patients included in the cardiogenic shock where a poor significant correlation could be highlighted. conclusion cardiogenic shock was the most frequent complication of ami who led to icu admission, whereas mechanical complications are rare at the era of early coronary reperfusion strategies. in addition to severity score, serum creatinine and cardiogenic shock appeared as independent factors of hospital death. none. introduction pulmonary embolism (pe) in high-risk is a partial or total obliteration of the pulmonary arterial network by a fibrin-clot cruoric more than %, the management requires a rapid reduction of pulmonary arterial resistance and right ventricular post load through rapid revascularization by thrombolysis. our aim is to determine the value of thrombolysis in pulmonary embolism and describe the clinical, paraclinical and outcome pulmonary embolism at high risk. patients and methods this is a descriptive study of cases of pulmonary embolism at high risk admitted to the cardiology department to chu oran between and . signs of gravity of (pe) comprising: syncope, circulatory collapse, cardiogenic shock or acute pulmonary sonographic sign of heart. it was confirmed in chest ct. all patients received thrombolysis using the protocol accelerated by two types of molecules: streptokinase or actilyse. the sex ratio was . ; mean age years, ranging from to years; risk factors were dominated by contraception was % and the postoperative % the clinical picture was dominated by cardiogenic shock in % of cases. % cardiovascular collapse and syncope in %; doppler echo all patients had signs of dysfunction of the right ventricle represented by the dilatation of the right cavities and pulmonary hypertension. the cta found a (pe) bilateral in % right in %. thrombolysis using actilyse in patients and streptokinase in cases. the outcome was favorable in patients; with two cases that are complicated by chronic pulmonary heart and the death of patients with cancer. discussion the female predominance is explained by the increase of risk factors hormonal contraception, whose first generation combination hormonal. our patient had a high probability with clinical signs of severity based on the score wells [ ] . this diagnosis was confirmed by chest ct; which shows the vascular bed obstruction degree with a very good sensitivity and specificity. the suspect patients with severe pe and that presented signs of acute pulmonary heart ultrasound have effectively (pe). the indication of thrombolysis was chosen on hemodynamic criteria; success is found in % of patients with improved hemodynamics dice the early hours. this success is explained by the role of thrombolytic in lysis clot to obtain pulmonary arterial revascularization; and reduce pulmonary arterial resistance and the right ventricular afterload which accelerates the healing of right heart failure and improvement of pulmonary capillary volume. the cases who developed a chronic pulmonary heart; it was done immediately a right ventricular dysfunction with pulmonary arterial outset of very high pressures suggestive that the embolism occurred on an already pathological right heart. no cases of massive bleeding were noted in our series. conclusion severe pulmonary embolism is burdened with high mortality; diagnosis is based on the stratification of risk score, was facilitated by the non-invasive strategies that articlent around the doppler echocardiography and ct angiography; thrombolysis can reduce the high mortality related to severe pulmonary embolism. introduction hypertension is a frequent motif for admission to emergencies. the diabetic is increasingly exposed to this risk [ ] . the objective of this study is to evaluate the proportion of diabetic patients presenting to the emergency department with high blood pressure (bp) and to identify their epidemiological and clinical characteristics. introduction sepsis associated liver dysfunction (sld) is usually attributed to systemic and/or microcirculatory disturbance. hypoxic hepatitis, also known as shock liver or ischemic hepatitis, is a life threatening event associated with high morbidity and mortality. doppler ultrasonography is a non invasive method to measure doppler hepatic hemodynamic parameters. the primary objective of this study was to assess the accuracy of the hepatic hemodynamic parameters (portal venous blood flow pvbf and resistance index of the hepatic artery hari) in predicting sld in septic shock patients. the secondary aims were to identify factors associated with sld, investigate the effects of volume expansion (ve) on systemic and intrahepatic hemodynamics and to assess the intra-and interoperator reproducibility. we also analyzed -day mortality. in a prospective design, we included consecutive patients with septic shock ( males; median age: . years) admitted to the icu with septic shock in charles nicolle hospital of tunis from february to july . all patients were resuscitated following the surviving sepsis campaign guidelines. we measured systemic hemodynamic variables (mean arterial pressure (map), and cardiac index (ci)) and performed hepatic doppler before and after volume expansion. we measured pvbf and computed the hari. we recorded the liver function tests (alt, ast and bilirubin) for h. sld was defined as an increase in serum bilirubin ≥ µmol/l (hepatic sofa ≥ ). accuracy of the hepatic hemodynamic parameters to predict sld was measured by the area under the roc curve. p < . was taken to indicate statistical significance. the median sofa score at t was points and the median igs score was points. the sources of infection were as follows: the lungs (n = ), the abdomen (n = ) and the urinary tract (n = ). the incidence of sld in our cohort was . % (n = ). there was no significant difference between "sld group" and "no-sld group" in all hepatic hemodynamic parameters especially the pvbf and the hari. lactate levels were significantly higher in patients with sld (median . vs. . mmol/l). similarly, the platelet count was significantly lower in the "sld group" [mean (± sd) . ± . ( /l) vs. . ± . ( /l); p = . ]. there was no difference in duration of mechanical ventilation, icu length of stay and -day mortality between the groups. the pvbf was significantly lower in patients who died before d (median: vs. l/min in the survivors; p = . ). volume expansion caused a significant increase in ci, mean hepatic artery velocity and the pvbf. the intra-and interoperator reproducibility was good to excellent for the systolic and mean velocities of the hepatic artery, portal vein diameter and the pvbf. conclusion our results don't support the hypothesis that the hepatic sonography is predictive of sld in septic shock. our pilot study showed higher lactate levels and hematologic sofa in sld group. the pvbf was significantly lower in patients who died before d . more experience will be necessary to define the ultimate role of doppler ultrasonography in the evaluation of hepatic perfusion in patients with septic shock. introduction early surgery is the current trend for management of patients with valvular disease. that said many of them, particularly from developing countries, are still operated at a very advanced stage of disease. despite improvements in myocardial protection and surgical techniques, postoperative care after multiple valve surgery (mvs) for advanced rheumatic heart disease (rhd) remains to be a clinical challenge. we conducted a study to determine postoperative complications and morbidity-mortality risk factors in this subgroup of patients. results sixty-two patients were included: with out-of-hospital refractory cardiac arrest and with in-hospital refractory arrest. the initial rhythms was shockable rhythm in ( %) cases. at ecls initiation, the mean no flow was . ± . min and mean low flow (time between the time of refractory cardiac arrest and time at which an ecls flow was provided) was ± min. the mean ecls flow rate was . ± . l/min. initial blood test results were: arterial ph = . ± . and plasma lactate = . ± . mmol/l. eleven ( %) patients survived ( / ( %) acute coronary syndrome, / ( %) severe poisoning due to drug intoxication, / ( %) dilated cardiomyopathy, and / ( %) others). survival was lower for patients with out-of-hospital refractory cardiac arrest, of ( %), than for patients with in-hospital refractory cardiac arrest, of ( %), respectively, p = . . as expected, out-of-hospital refractory cardiac arrest was associated with a more prolonged low flow ( ± min vs ± min, p < . ) and a more profound acidosis (ph . ± . vs . ± . , p = . and arterial lactate . ± . vs ± , p = . ). in univariate analysis, survival was lower for patient with refractory cardiac arrest unrelated to drug intoxication, vs %, respectively, p = . . in addition, mortality was associated with arterial ph ( . ± . vs . ± . , p = . ) and low flow ( ± vs ± min, p = . conclusion in a highly selected group of critically ill patients with refractory cardiac arrest, the potential beneficial effect of ecls could be due only to its clinical impact on reversible causes of circulatory failure (i.e. severe drug intoxication in our cohort). further studies are needed to clarify whether the use of ecls could be considered as a disproportionate tool, specifically in patients with out-of-hospital refractory cardiac arrest due to acute coronary syndrome or associated with prolonged low flow or a profound acidosis. none. post-cardiac arrest shock treated with veno-arterial extracorporeal membrane oxygenation: an observational study and propensity-score analysis wulfran bougouin , nadia aissaoui , alain combes average time between introduction and removed of the ecd was h ( - ). among the esogastroduodenoscopy performed, ( %) were strictly normal. endoscopy showed minor gastric injuries in patients ( %). within these patients, ( %) also presented minor esophageal injuries. esogastric injuries characteristics were mostly similar to usual orogastric probe injuries. one patient ( %) experienced a serious ulcerous esophagitis mimicking a peptic esophagitis, not firmly related to the ecd. no patients necessitated hemostatic local procedure and no significant gastrointestinal bleeding was observed. eight patients ( %) were alive at d , including patients ( %) with a cerebral performance category score of . this compares favorably to outcomes from previous studies. conclusion ecd seems an interesting and safe semi-invasive method of cooling in ohca patients treated with °c-ttm. although it seems slower than more invasive devices to reach °c, ecd was able to strictly maintained the tt within the maintenance phase of ttm. further studies will be necessary to define the exact place of this new device within the cooling strategy in patients necessitating a precise ttm-strategy. none. fig. see text for description introduction since post-cardiac arrest care might influence the outcome, characteristics of receiving hospitals should be integrated in survival evaluation of patients transported in hospital. we aimed at assessing the influence of care level center on survival at discharge in a regional registry of out-of-hospital cardiac arrest (ohca). we prospectively collected utstein and in-hospital data for all non-traumatic ohca patients, in whom a successful return of spontaneous circulation (rosc) had been obtained, from a large metropolitan area (great paris). receiving hospitals were categorized in groups (a, b, c) depending on their respective characteristics (annual volumes, / catheterization availability and temperature management use). we compared patients' characteristics in the groups and performed a multivariable logistic regression using discharge survival at endpoint. results during the study period (may -dec ), patients were admitted in hospitals ( in group a, in group b and in group c). overall survival rate at discharge was / ( %). patients' baseline characteristics significantly differed, as hospitals from group a treated younger patients and more frequent shockable rhythms (p < . ). unadjusted survival rate differed significantly among the groups of hospitals (respectively , and . % for a, b, c, p < . ). however in multivariable analysis, the category of hospital was no longer associated with survival. conclusion in this population-based study, characteristics of receiving hospitals are not associated with survival rate at discharge. this could result from the strategy used for triage, which aims in matching patients' characteristics and resources. introduction acute kidney injury (aki) commonly occurs after cardiac arrest and is associated with an increased mortality and a delayed awaking. early recognition of aki remains challenging, given that serum creatinine increases belatedly after aggression. introduction out-of-hospital cardiac arrests (ohca) are an absolute urgency and have a very poor prognosis. pediatric guidelines differ from adult guidelines for cardiac arrest management. since , adult guidelines apply from the onset of puberty. the main objective was to describe the epidemiological characteristics and outcome of ohca victims while taking puberty into account. the secondary objective was to determine the prognostic factors for survival at d . materials and methods all patients less than years of age, victims of ohca between july , and september , care by a mobile emergency and resuscitation service (smur) participating in french national cardiac arrest registry (réac) were included. patients were split into groups: prepubescent patients (named "children": girls - years, boys - years), pubescent patients (named "adolescents": girls from to years and boys from to years) and "adults" (men and women - years). the "adolescents" group was consecutively compared to the "children" group and to the "adults" group. results children, adolescents and , adults under the age of have been included. ohca in adolescents occurred more often on public roads ( %) or in public places ( %) and were more often traumatic ( %) than those in children and adults. respiratory causes were more frequent in children ( %) than in adolescents ( %) and adults patients ( %). the proportion of shockable rhythm increased with age ( , and % for children, adolescents and adults respectively). survival at d was greater in adolescents ( %) than in children ( %) and adults ( %) (p = . and p = . respectively). in the studied groups, initial shockable rhythm was a survival factor at d (respectively or [ . - . ] for children, adolescents and adults). other risk factors are described in table . conclusion adolescents had better survival at d than the others groups. adolescents and adults had shockable rhythm more often than children. moreover, respiratory failure was less frequent in adolescent and adults patients compared to children. puberty seems to be a good limit to differentiate pediatric patients with ohca. none. introduction non-invasive ventilation (niv) is an effective alternative to endotracheal mechanical ventilation (mv) in the management of acute respiratory failure (arf) patients. nevertheless, it can be still difficult to assess its real feasibility, application and outcome in daily clinical practice. therefore, we report our clinical experience with routine use of niv since the last national recommendations ( ). our aims were to evaluate the clinical efficacy and outcome of niv, and to identify predictive factors for niv failure based on a daily use. patients and methods we conducted an observational retrospective single-center cohort study by reviewing all medical records from january to december in our -bed medical intensive care unit (icu). eligible patients were those having received niv during their icu stay. two groups were defined according to the indication of niv: niv for hypoxemic or hypercapnic arf (arf-niv), and niv used in the post-extubation period for weaning, prevention or treatment of post-extubation arf (post-extubation niv).the main evaluation criteria were the incidence of niv use, success/failure rate of niv and risk factors for niv failure in each group. niv failure was defined as the need for stopping niv whatever the reason (intubation, intolerance, death) within days after its initiation. ( ; ), and was longer in the post-extubation niv group ( days ( ; ) ) than in the arf-niv ( days ( ; ) for hypoxemic arf, ( ; ) for hypercapnic) (p < . ). the overall icu mortality was . % ( . % in hypoxemic group, . % in hypercapnic group, and . % in post-extubation niv group) (p = . ). in multivariate analysis, the main risk factors for arf-niv failure were: saps ii on admission (p < . ), absence of cardiologic history (p = . ) and the cause of arf (p = . ) with a higher failure rate for pulmonary infections than acute cardiogenic pulmonary edema (or . , p = . ). for post-extubation niv, the only independent risk factor for failure was normocapnia before niv initiation (p = . ). conclusion our large longitudinal study demonstrates the feasibility and efficacy of niv applied in daily clinical practice. provided it is performed in a suitable environment by an experienced team, niv should be considered as a first-line ventilatory treatment in various etiologies of arf and a very useful ventilatory support in the postextubation period. nevertheless, risk factors for niv failure should be known by icu clinicians, hypoxemic arf remaining the more difficult indication to manage with niv. réanimation médicale, hôpital saint-louis, paris, france; service de biostatistique et information médicale, hôpital saint-louis, paris, france; réanimation, institut paoli-calmettes, marseille, france; réanimation introduction acute respiratory failure (arf) is the leading cause for icu admission in immunocompromised patients. in these patients, oxygenation strategy is of major interest to avoid the need for mechanical ventilation (mv), which is associated with high mortality rates. in that setting, use of non-invasive ventilation (niv) and oxygen therapy with high flow nasal cannula (hfnc) could be interesting alone or in association, but data about initial ventilation strategy in immunocompromised patients are controversial. to assess how initial oxygenation strategy actually influences the risk of mv on the coming day within the three first days of icu stay. the study end-point was the need for mv on the coming day. we restricted analyses to these first three icu days given, based on our own experience, most of mv was expected to occur by then. we performed a post hoc analysis combining three prospective studies of critically ill immunocompromised patients (two randomized control trials, the ivnictus and the minimax studies and one prospective cohort, the trial-oh study). we only considered patients with arf and a delay between icu admission and study inclusion less than h. we excluded patients who required invasive mv within the first day, those with an icu stay less than day and those with acute pulmonary edema diagnosis at icu admission. in order to estimate and compare the causal effect of daily respiratory management strategy on the probability of intubation in the coming day, we computed inverse probability of treatment weights (iptw) using propensity-score, defined as the probability of actual treatment selection conditionally on observed covariates. to handle confounding in such dynamic regimens, we considered marginal structural models (msm), which have been proposed to estimate the causal effect of a time-dependent exposure when time-dependent covariates that can be affected by the previous treatment are present. two treatment exposure models were considered: niv versus oxygen therapy regardless the device (model ) and hfnc alone, niv alone versus niv + hfnc versus standard oxygen therapy alone (model ). results patients were included in the study. in model , there was no difference between niv and oxygen groups on mv whatever the landmark time. in model , while the unweighted or for intubation at day was significantly higher in the niv group (or . , %ci . - . ) and hfnc group (or . , %ci . - . ) than those in the standard oxygen alone group, these differences disappeared in the weighted samples. using msm, no effect of the oxygenation strategy on mv was found, regardless of the oxygenation devices but the landmark time was associated with a reduced occurrence of mv. conclusion we found no evidence of any significant difference from several oxygenation strategies on mechanical ventilation probability during the first days of icu in a large cohort of immunocompromised patients with arf. none. introduction the role of noninvasive ventilation (niv) is debated in the management of patients with acute hypoxemic respiratory failure. a recent study showed that patients treated with high-flow nasal cannulae oxygen therapy (hfnc) had lower intubation and mortality rates than those treated by the association of hfnc with niv ( ). high tidal volumes (vt) delivewred with niv may be associated with an increased risk of intubation ( ) . we aimed to identify risk factors associated to intubation, in hypoxemic patients with acute respiratory failure and especially the role of vt under niv. patients and methods this is an ancillary study from a multicenter, randomized, controlled trial including patients with acute hypoxemic respiratory failure (florali-study). we focused on only patients with moderate or severe hypoxemia (pao :fio ratio ≤ mmhg) and we excluded those with mild hypoxemia. the criteria for intubation were predetermined including worsened or persisted respiratory failure, impairment of neurologic status and hemodynamic instability. results after adjustment on the oxygenation strategy, the two factors independently associated with intubation were the presence of bilateral pulmonary infiltrates at admission (or . simulation conditions enables to reproduce its occurence, using different types of tools, from physiological parameters to heart rate variability and psychocognitive tests. future research is required to evaluate the impact of these parameters on teaching. none. with stratification by centre and operator experience. an only inclusion criterion was: "patients must be admitted to an icu and require mechanical ventilation through an endotracheal tube". patients were excluded if: contraindication to orotracheal intubation (e.g., unstable spinal lesion); insufficient time to include and randomize the patient (e.g., because of cardiac arrest); age < years; pregnant or breastfeeding woman; correctional facility inmate; patient under guardianship; patient without health insurance; refusal of the patient or next of kin to participate in the study; previous enrolment in a clinical randomized trial with intubation as the primary end point (including previous inclusion in the present trial). post-hoc analysis was performed to assess occurrence of spo < % during intubation procedure between groups of preoxygenation: bvm (at a minimum flow of l/min, niv ( % fio ), hfnc (at a minimum flow of l/min, with % fio ), and nrm (at a minimum flow of l/min). between-groups difference in desaturation occurrence was adjusted for baseline covariates significantly associated with the group membership (p < . ). multivariate analysis of the occurrence of a desaturation (< %) was performed using logistic regression. bag-valve mask was considered reference. results baseline characteristics were showed in table . groups were similar at baseline except for pao /fio ratio. in univariate analysis, age (p = . ), saps (p = . ), pao /fio ratio (p = . ),spo (p = . ) and method of preoxygenation (p = . ) were associated with occurrence of desaturation below %. in multivariate analysis, spo at randomization and method of preoxygenation were only predictors of desaturation below %. bvm and hrm were associated with similar risk of desaturation occurrence whereas niv (or . introduction intubation procedure is a challenging issue in intensive care unit (icu) [ ] . cardiac arrest related to intubation in critically ill adult patients has been poorly studied. the studies were not powered to conclude on this rare outcome [ ] . the main objective of our study was to establish the incidence of cardiac arrest and to assess the risk factors of cardiac arrest in a large prospective database of intubation procedures performed in icu. five prospective studies were included, with similar data collected before, during and after intubation procedures using the same methodology. the primary outcome was the incidence of cardiac arrest related to intubation. the secondary outcomes were the death (cardiac arrest without return of spontaneous circulation (rosc)), the cardiac arrests with rosc, the complications related to intubation, the length of icu stay and the -day mortality. the factors associated with cardiac arrest related to intubation procedures were assessed by univariate and multivariate analysis based on patient, provider and practice characteristics. results among the intubation procedures included, cardiac arrests ( . %) occurred, including with rosc ( . %) and without rosc ( . %). main patient, provider, procedure characteristics and outcomes according to cardiac arrest related to intubation are presented in table . in multivariate analysis, the independent predictors of cardiac arrest related to intubation were low systolic blood pressure prior to intubation, hypoxemia prior to intubation, no preoxygenation, overweight or obesity and age > years. mortality rate at day was significantly lower in patients intubated without cardiac arrest ( . %, of ) than with cardiac arrests overall ( . %, patients of , p < . ) and cardiac arrest with rosc ( %, patients of , p < . ). conclusion cardiac arrest related to intubation in adult icu is not a rare event occurring in . % of cases with high immediate mortality of . % and at day of . %. we identified five independent risk factors to cardiac arrest which of them could be modifiable. optimal preparation to intubation procedure could help to prevent those cardiac arrests. introduction naasotracheal intubation (nti) has been progressively given up in favour of the orotracheal intubation (oti) in intensive care unit (icu). this could be explained by more frequent infectious (sinusitis and ventilator associated pneumonia) and non-infectious (epistaxis, turbinates bones injury) complications the former being thought to be more frequent with nti. however, whereas infectious sinusitis is a risk factor for vap, no study has yet demonstrated that oti decreases the infectious sinusitis rate compared with nti. furthermore, nasal route could improve patient comfort and decrease auto-extubation. finally nti can be performed without laryngoscopy with less risk of lips and dental injury. in this prospective study, we aimed to compare the complication of nti and oti and to assess the comfort of the patient. we performed a prospective observational study in a -bed medical icu including patients requiring endotracheal intubation. the intubation route was let at the discretion of the physician in care of the patient, however oti was compulsory in case of cardiac arrest, severe hypoxemia (p/f < when available) and clotting perturbation. for each patient, age, sex, sapsii, mechanical ventilation duration. intubation route were recorded as well as complications during the placement of endotracheal tube. infectious and non infectious complications during invasive ventilation period were also recorded. in patients who were successfully extubated, pain, burning feeling, dryness and the wish of tube removal were assessed using visual analogic scales (vas conclusion despite its small size, and the absence of randomization, the present study suggests that nasotracheal intubation improves the comfort and the tolerance of tracheal intubation and is not associated to higher rates of vap. none. effect of mode of hydrocortisone administration in patients with septic shock: a prospective randomized trial oussama jaoued , rim gharbi , najla the baseline characteristics of patients were similar between the two groups. sepsis was secondary to community-acquired infection in % of cases. there was no difference in mortality between groups ( % in continuous groups and % in discontinuous group). sofa score was significantly higher at days , and in discontinuous group. length of stay, duration of mechanical ventilation, number of day without vasopressors, and the occurrence of adverse events were similar in the two groups. conclusion the mode of hydrocortisone administration in patients with septic shock has no influence on morbidity or mortality. the occurrence of adverse events was similar. introduction widespread activation of coagulation with platelet consumption is a pathophysiological feature of severe sepsis and septic shock. thrombocytopenia, either defined by platelet count below g/l or by a significant relative - -percent decrease in platelet count is a potent poor prognostic factor in sepsis. besides their role in hemostasis, platelets also carry various immune and inflammatory functions that are likely to impact on host defense against infections. we aimed to assess whether changes in the platelet count induced by sepsis is associated with the development of subsequent nosocomial infections. patients and methods patients were obtained from two prospective studies about immuno monitoring of dendritic cells and innate-like lymphocytes in critically ill septic patients ( , ) . adult patients with severe sepsis and septic shock were included. exclusion criteria were any immunosuppressive condition (hematological malignancy, hiv infection at any stage, bone marrow or solid organ transplantation, daily corticosteroid therapy > . mg/kg prednisone-equivalent, chemotherapy or any other immunosuppressive treatments), pregnancy, do-not-resuscitate orders on admission. in addition patients who died or who received platelet transfusion during the first week after icu admission were also excluded. platelet counts were collected on the day of sepsis diagnosis (d ) and then on d , d and d . the relative variation in platelet count at day n compared to day was calculated as follows: (count at day n − count at day ) × / (count at day between between d and d , between d and d and between d and d were also similar between patients with and without icuacquired infections (fig. ). discussion in this preliminary study from selected cohorts of nonimmunocompromised patients, sepsis resulted in mild alterations in platelet counts, making it unlikely to become associated with the development of nosocomial infections. it would be relevant to address this question in larger cohorts of non-selected patients, as well as the impact of platelet transfusions in this setting. conclusion changes in platelet counts were not associated with an increased susceptibility towards icu-acquired infections in non-immunocompromised patients with severe sepsis and septic shock. introduction sepsis is the leading cause of mortality in the intensive care unit (icu) patients despite the progress regarding their care. the immunodeficiency due to sepsis with the consequent profound lymphocyte alterations is now well proven. the objective of this work was to determine the prognostic impact of lymphocytopenia in septic patients in icu. retrospective study including all patients hospitalized for sepsis or septic shock between / / and / / . the sepsis and septic shock definitions were adjusted with the third international consensus definitions for sepsis and septic shock. were excluded from the study patients of onco-hematology. lymphocytopenia was defined as an absolute lymphocyte count less than level of /mm during the first h of hospitalization. the prognostic factors analyzed for the lymphopenic and non lymphopenic patients were in hospital mortality, the occurrence of nosocomial infections and hospital length of stay. results among the patients, aged ± years, patients were with septic shock and patients with sepsis. igsii score and sofa score were respectively ± and ± . four patients were immunocompromised due to hiv infection in one case and an immunosuppressive therapy in cases. lymphocytopenia was observed in patients ( %). twenty-eight patients ( %) died within an average of ± days. it was noted the occurrence of nosocomial infections. the median length of stay was days with extremes of one and days. the lymphopenic patients were comparable to non lymphopenic patients in terms of medical history and severity scores. mortality was comparable between the groups with a rate of % (n = ) in lymphopenic patients and % (n = ) in non-lymphopenic patients (p = . ). the earliness of death was correlated with the duration of lymphopenia (r = . , p = . ). the occurrence of nosocomial infections was not different between the two groups: % (n = ) for lymphopenic and % (n = ) for non lymphopenic patients. the hospital length of stay was not different between the two groups but was correlated with the duration of lymphocytopenia (r = . , p = . ). conclusion lymphocytopenia is frequently found in sepsis. lymphocytopenia was not associated with excess of mortality nor with the subsequent occurrence of infectious complications during the icu stay. his persistence was associated with an earlier death and a more prolonged hospitalization. none. introduction relative adrenal insufficiency (rai) is common in icu patients, particularly during septic shock ( ). it has been shown that the rai also occurs during cardiogenic shock ( ) . septic cardiomyopathy occurs in a significant proportion of septic shock patients. the aim of this study was to evaluate the role of rai on septic cardiomyopathy. patients and methods prospective observational study conducted in the intensive care in one university hospital in france. patients meeting the criteria for septic shock without prior corticosteroid therapy and without chronic heart disease were included. total blood cortisol levels were assessed immediately before (t ) a short corticotropin stimulation test ( . mg iv of tetracosactrin) and and min afterward. Δmax was defined as the difference between the maximal value after the test and t . rai was defined as an inappropriate adrenal response with Δmax < µg/dl and septic cardiomyopathy as the appearance of cardiac systolic dysfunction (left ventricle ejection fraction < %) within the first days of septic shock. we performed a multivariable analysis using backward stepwise logistic regression to identify independent predictors of septic cardiomyopathy. discussion although the definition of rai is not consensual, a threshold of Δmax at µg/dl has been widely used in septic shock, with or without the use of t ( ). the usefulness of substitutive doses of steroids in septic shock is controversial, but many authors assume this treatment has a potential in reversing overt vasoplegia. our data suggest an implication of rai in septic cardiomyopathy. conclusion we found rai to be an independent predictor of septic cardiomyopathy. these findings may suggest a new role for substitutive doses of steroids in the hemodynamic management of septic shock. introduction regional perfusion parameters, like lactate, pyruvate and glycerol, may predict outcome in septic shock patients. continuous venovenous haemofiltration (cvvh) has been considered beneficial in septic shock patients. the aim of our study was to investigate whether cvvh, in comparison to intermittent haemodialysis (ihd), is able to improve regional perfusion in septic shock patients studied by muscle microdialysis. patients and methods it was a prospective, randomized, clinical study, including septic shock patients with acute renal failure, aged over years. patients were randomized to receive either cvvh (n = ) or ihd (n = ) for renal replacement therapy. intermittent haemodialysis was carried out during the first h of the h study period. systemic haemodynamics and interstitial tissue concentrations of lactate, pyruvate, glucose and glycerol were obtained at baseline, , , and h after initiation of renal replacement by using muscle microdialysis. results regarding systemic haemodynamics parameters, cvvh caused a decrease in heart rate in contrast to ihd after h (− ± vs + ± /mn). there were no changes in vasopressor support throughout the -h study period and so systolic blood pressure remained stable in both groups. during the h of all renal replacement therapies there was no significant change in muscle pyruvate and glucose levels. during cvvh muscle lactate decreased constantly, as did muscle glycerol levels. this decrease reaches a significant levels at h for muscle lactate and at h for muscle glycerol (fig. ) . conclusion our results suggest that among septic shok patients, cvvh may improves regional perfusion in comparison with ihd. none. introduction acquired hypernatremia (h-na) is an independent risk of death among icu patients ( ). in the rct "hyper s" study, we compared normal to % hypertonic saline during the first h in patients with septic shock with normal serum na concentration (sna) at baseline. the study was prematurely stopped for potential harmful effect associated with more frequent h-na. we assessed the role of h-na on mortality. patients and methods data are a post hoc analysis of the "hyper s" study database including patients. sna was measured at h , every h for days and then daily until d . study fluids were stopped if sna > or > mmol/l increase over h. mild, moderate, and severe h-na were defined as sna > mmol/l, > mmol/l and > mmol/l, respectively. sna profiles were compared between d survivors and non-survivors. acute kidney injury (aki) was defined by doubling serum creatinine and/or need for dialysis. results patients with available data were analysed. ( %) developed h-na (mild: %, moderate: %, severe: %). no matter the absence or presence and its severity, h-na did not affect mortality ( , , , and %, respectively without, with mild, moderate, and severe h-na, p = . ). sna profiles were similar between survivors and non-survivors (table ) . a sensitivity analysis performed among survivors at d did not change the results. compared to patients without h-na, aki occurred in % of patients with h-n vs % (p = . ), atelectasis in versus % (p = . ) and icu acquired weakness in versus % (p = . ). conclusion hypernatremia occurrence is not associated with an increased risk of morbidity and mortality during hypertonic fluid resuscitation in septic shock. none. introduction guidelines about the moderate hypokalemia treatment (between . mmol/l and . mmol/l) are based on experts estimations, and non-specific ones for patients in the intensive care units (icu). the aim of this study was to evaluate the correction of the hypokalemia in an icu and the compliance of recommendations. materials and methods an observational epidemiological, retrospective and monocentric trial has been realized during a period of months (from january to february ). the study population included hospitalized patients in the icu who have shown a first moderate hypokalemia episode, all cause considered. patients who have presented an acute renal failure with a kdigo (kidney disease: improving global outcomes) score of three the day of their inclusion were excluded. the main primary study endpoint was percent correction of the serum potassium after h. the secondary study endpoints were the incidence rate of moderate hypokalemia and the efficacy about the hypokalemia correction in accordance with the achieved treatment consistent or not with recommendations. results patients had at least one episode of hypokalemia. the incidence rate of the hypokalemia first episode was . %. the study population included patients. igs score was . (± ). patients required mechanical ventilation at the inclusion. the serum potassium was greater than or equal to . mmol/l after h about patients ( . %) (corrected group). at h one patient had a serum potassium higher than mmol/l. the average total potassium was respectively . infusion of potassium and ( . %) patients have been a management compatible with the most common recommendations (input potassium chloride of mmol, use of the enteral administration and lack of continuous intravenous infusion). the percent correction of the hypokalemia after h was respectively of / ( . %) in the group in which recommendations had been respected and of / ( . %) in the other one (p = . ). discussion in our knowledge there are no previous studies that have specifically focused on the correction of the moderate hypokalemia in critically ill patients. in our study the incidence rate of the moderate hypokalemia was lower than data from the literature because we have only considered the first episode of the hypokalemia [ ] . among patients without contraindication to the enteral administration, this one was used in less than half of the cases. % of these patients received potassium with a continuous intravenous infusion and only patients received medical care conform to the guidelines. the medium potassium quantity provided was very lower to the guidelines. only % of the patients have been corrected after h without any difference in the medium potassium quantity which has been provided in relation to the uncorrected group. conclusion only . % of moderate hypokalemia in icu are corrected after h. the intravenous way is considerably used (in % of cases) with a poor return. a wide-ranging study is necessary to determine the best correction modes. none. results patients were included. mean ± sd age was ± years, % were male, mean ± sd saps ii was ± . icu length of stay was ± days and icu mortality rate was %. during the first days in the icu, % of patients received at least one nephrotoxic drug. % of patients received one, % received two, % received three and % received more than three nephrotoxic medications. diuretics, antibiotics and iodinated contrast media were the nephrotoxic drugs most frequently administered to, respectively, , and % of patients. aki (kdigo stage or higher) occurred in % of patients during the first days in icu. the proportion of patients with aki increased with the number of nephrotoxic drugs received: / ( %) of the patients not exposed to nephrotoxic drugs developed aki whereas, respectively, / ( %), / ( %), / ( %) and / ( %) of the patients receiving one, two, three, and more than three nephrotoxic drugs developed aki. the univariate association between the number of nephrotoxic medication and aki persisted in the multivariate analysis adjusted on baseline saps ii score (p < . ). conclusion the significant proportion of patients exposed to nephrotoxic drugs and the observed association with aki warrants further investigation. statistical adjustments for multiple potential confounders is needed in order to assess a potential causal relationship which would lay foundations for interventional studies. none. ( ) the minimal kidney aggression by current monomeric nonionic low-osmolar contrast media, late serum creatinine increase being explained by the occurrence of later (between the th and the nd hour) kidney injury due to critical illness or its therapy or ( ) insufficient sensitivity of early ( h) measurements of this biomarker to detect contrast-associated aki. competing interests partial financial support, no implication in data analysis and interpretation. introduction diabetic ketoacidosis, generally resulting from an absolute deficiency of insulin, is a frequent cause of hospitalization in intensive care unit. recommendations for diagnosis of diabetic ketoacidosis, care and site of admission have been published by the english society of diabetology. icu admission are recommended if one of the following criteria is present: gcs < , systolic arterial pressure (sap) < mmhg, spo < %, ketosis > mmol/l, hco < mmol/l, ph < . , potassium level < . mmol/l or anion gap > mmol/l. however, it is suspected that adhesion to recommendations remains low. in this study, we aimed at describing patients admitted for diabetic ketoacidosis in icu. we looked at adhesion to published recommendations regarding admission and care. we also described metabolic complications and looked for an association between complications and dose of initial insulin therapy. complications hypoglycemia (< . mmol/l) was observed in % of patients within the first h in which % were < . mmol/l. this was and % of patients between and h of icu stay. hypokalemia below . mmol/l happened in % of patients within the first h and in % between and h. neither hypoglycemia nor hypokalemia were correlated with initial insulin bolus or initial dosage of continuous intravenous insulin. hypophosphatemia < . mmol/l was observed in % of patients. discussion in this study, admission to icu was consistent with british recommendations since most patients presented at least one clinical or biological criterion indicating icu admission. arterial blood gas were sampled in the large majority of patients despite consistent data showing that venous blood gas might be sufficient in non-hypoxemic patients. also, initial insulin bolus and sodium bicarbonate perfusion were performed in a significant subset of patients despite absence of convincing data or recommendations supporting their use. finally, significant hypokalemia and hypoglycemia were frequent in these patients. these complications are in theory favored by insulin therapy but we did not observe a correlation between administration of an insulin bolus or the dose of continuous intravenous insulin perfusion. conclusion in this retrospective multicentre study, patients admitted in icu for diabetic ketoacidosis were correctly oriented regarding the british recommendations. metabolic complications (hypoglycemia and hypokalemia) were frequent but not correlated with initial dose of insulin. the appropriate rate for hypernatremia (h-na) correction is unknown. under-correction could be associated with worse outcome. experts recommend a rapid correction of acute (< days) and sever (> mmol/l) h-na with a rate of − mmol/l/h until na < mmol/l ( ). correction should be, therefore, obtained within h. in patients with septic shock resuscitated with iso-or hypertonic saline and who acquired acute severe h-na, we assessed if the correction rate was associated with mortality. patients and methods data are a post hoc analysis of the rct "hyper s" database comparing normal to % saline for h in septic shock. serum na (sna) was measured at h , every h for days and ) . h-na correction rate was more rapid in non-survivors, p = . (table ). over-correction occurred similarly in survivors ( %) and non-survivors ( %). the time to reach sna normalization was shorter in nonsurvivors (p = . ). after adjustment for sapsii and maccabe scores, more rapid correction rate remained significantly associated with mortality: or . ; % ci ( . - . ), p = . . conclusion in the context of acute severe h-na induced by fluid resuscitation, a rapid correction rate might be associated with even aggravated rather than improved mortality. introduction systemic capillary leak syndrome (slcs) is a rare disease characterized by recurrent life-threatening attacks of capillary hyper permeability in the presence of a monoclonal gammopathy (mg). during acute episodes, the leak of fluid and proteins from the intravascular compartment to the interstitium results in clinical signs of both acute hypovolemia and interstitial edema. biological profile is pathognomonic with marked hemoconcentration and paradoxal hypoproteinemia. hypovolemic shock is the classical feature of severe scls attacks. however, beside this typical hemodynamic profile, several case report described myocardial dysfunction during scls attacks. the objectives of this study were to assess frequency, characteristics and outcome of myocardial involvement during severe scls attacks. ( %) mechanical ventilation, ( %) renal replacement therapy, ( %) veno-arterial extracorporeal membrane oxygenation, ( %) intra-aortic balloon pump and ( %) an impella. compartment syndrome occurred in ( %) patients and ( %) died in icu. we then compared the patients with myocardial involvement to the without clinical and biological manifestations were similar in between groups. however, chest pain ( vs %, p = . ), dyspnea ( vs %, p = . ) and respiratory failure ( vs %, p = . ) were more frequent in patients with myocardial involvement than in others. there was no difference between groups regarding treatment received in icu, complication and outcome except for the use of va-ecmo ( . vs %, p = . ). conclusion myocardial involvement seems frequent in patients with severe scls attack, occurring in % of the cases. such patients exhibited classical features of scls attacks. myocardial involvement was responsible for altered lvef or transient ventricular hypertrophy. myocardial dysfunction could be severe, even requiring mechanical circulatory support. scls attacks should be known as a cause of severe reversible myocardial dysfunction and hypertrophy. none. introduction in refractory cardiorespiratory emergencies, ecmo appears a good alternative to conventional treatment. its extracorporeal circuit justifies curative anticoagulation explaining haemorrhagic and thrombotic complications. activated clotting time (act) is empirically and commonly used to assess anticoagulation but with large inter and intraindividual variabilities. in practice, antixa activity dosage is available to approach anticoagulant effect of heparin and is less expensive, but data during ecmo are missing. we sought to demonstrate the lack of correlation between antixa and act in patients under ecmo support. we prospectively include patients supported by ecmo in chu toulouse, france, between / and / for circulatory/respiratory support. anticoagulation was achieved by unfractionated heparin: initial bolus then continuous intravenous infusion ( - iu/h), for antixa target of . - . . concomitant dosing of antixa (laboratory) and act (hemocron ® ) was conducted two times a day on the same sample throughout the ecmo period. relationship between act and antixa was analyzed by spearman correlation (rho). after transformation into categorical variables (obtained target = ; outside the target = ), analyzes were completed by a concordance study (kappa). as recognized on literature act's targets were between and . results patients were included: men ( %), median age yo ( - ). indications were veno-arterial (n = ) and veno-venous ecmo (n = ). ecmo median duration was days (hours to days). spearman correlation test found low and inconsistent correlation between antixa and act (rho spearman < . ). this correlation lack present from the day one, worsens over time. analyzed kappa showed no discrepancy between the areas "targets" of act and antixa confirming the results (table ) . conclusion use of act for ecmo anticoagulation monitoring doesn't seem appropriate and high price probably justifies preferential use of antixa in clinical practice. analyzes of relationships between antixa and bleeding/thrombotic events are needed to confirm the antixa place and its target in these indications. introduction postcardiotomy cardiogenic shock (cs) has an incidence of % to % after routine adult cardiac surgery. in . - . % of cases, an venoarterial extracorporeal life support (va-ecls) is requested. the -month survival rate is . % ( ). survivors may suffer of physical and psychological impairments as well as an alteration of quality of life. this study was designed to assess the outcomes, long-term health- since icu discharge, % of patients reported physical sequelae., ecls-related limb pain occurs in % of patients while paresthesia occurs in % and chronic-tiredness in %. mean karnofsky score was % (table ) . conclusion after va-ecls for postcardiotomy cardiogenic shock longterm physical and psychological sequelae are frequent in survivor discussion interest for fluid management is growing in critical patients. nevertheless, no study has yet investigated its impact in selected patients with cardiogenic shock treated with va ecmo. our study suggested a possible association between fluid overload and mortality but lack the power to confirm these results with multivariate analysis. conclusion fluid management is a key therapy during va ecmo but fluid overload could be associated with worsen outcomes. further studies with larger population are warranted before considering fluid restriction trials. introduction extracorporeal life support (ecls) has taken an important place in the treatment of cardiogenic shock (cs) or refractory cardiac arrest (ca). however, ecls deplore a high mortality rate in the first days raising important ethic and economic consequences. in this context, continuation of support should be reassessed precociously. the aim of this study was the research of prognostic factors of -days mortality, h after ecls implantation for cs or ca. materials and methods all patients undergoing ecls in our tertiary center during a -year period were prospectively included. the ecls were managed with a multidisciplinary protocol based on consensus. clinico-biological data were collected just before and h after ecls implantation. these data were compared between survivors and deceased at month. , cpc score was respectively for patients, for , for . at months, cpc score changed only for the patients with a cpc score at (one died after another suicide attempt, one changed his cpc score to ). in the group without ca (n = ), had normal neurological status at months and at months (one patient died because of a cancer). among these patients, % returned at home and % returned to work. ( %) patients re-attempted suicide in the year. the major risk factor of mortality is the presence of a cardiac arrest on hanging site. all the other factors found to be related to mortality are well known risk factors in cardiac arrest of other origin. in univariate analysis, risk factors of neurological sequelae at months were a cardiac arrest on hanging site (p = . ) an elevated diastolic blood pressure ( vs mmhg; p = . ), a lower initial glasgow score ( vs ; p = . ), and an elevated blood glucose ( . vs . g/l p < . ) at admission in icu. discussion our cohort of self-hanging patients can be divided in two parts: a) patients with ca in the pre-hospital period with a high mortality and a good neurological recovery in / surviving patient, but with a small group; b) patients without ca with a very low mortality and a very good neurological recovery. these results seem to be better than in the most important cohort [ ] published until now in self-hanging patients without ca and not treated by hbot (mortality at . % and . % of poor neurological recovery). conclusion patients surviving a self-attempted hanging who have not presented ca and treated by hbot have mainly a good neurological outcome. randomized control study should be undertaken to confirm hbot effectiveness in that indication. introduction venoarterial extracorporeal membrane oxygenation (va-ecmo) is increasingly used to treat refractory cardiogenic shock or cardiac arrest. acute brain injury (i.e. ischemic stroke, haemorrhage and/or failure to awaken because of diffuse brain injury) may occur in up to % of patients on va-ecmo and is associated with increased mortality and poor functional outcome in survivors. however, early indicators of neurological outcome are lacking in this population. we aimed to assess the prognostic value of early electroencephalography (eeg) alterations during va-ecmo. we conducted a prospective single-center study in the medical icu of a university hospital on consecutive patients cannulated to va-ecmo. a standardized clinical neurological evaluation including the rass score, the gcs score, the full outline of unresponsiveness (four) score and brainstem reflexes was coupled to an intermittent eeg. eeg was recorded as soon as possible within the first h after va-ecmo cannulation. eeg characteristics were analyzed by a neurophysiologist who was blinded to the patient's condition. a severely altered eeg pattern was defined as a predominant delta frequency, discontinuous, unreactive and/or an isoelectric background. the primary endpoint was poor neurological outcome, defined as the composite of death or acute brain injury on neuroimaging within days. data are presented as median (interquartile range) or number (percentage). false-positive rates (fprs, corresponding to -specificity) of poor neurological outcome were calculated for each significant predictor, using an exact binomial % confidence interval (ci). results sixty-nine (age ( - ) years) patients with a sofa score of ( - ) were included. main indications for ecmo were: post cardiac surgery (n = , %), terminal dilated cardiomyopathy (n = , %), and acute myocardial infarction (n = , %). cardiac arrest before ecmo cannulation was noted in ( %) patients. eeg was recorded ( - ) days after va-ecmo cannulation and ( %) patients were sedated at time of eeg. at day , ( %) had a poor outcome (n = deaths and n = patients alive with acute brain injury). in univariate analysis, a lower rass score (p = . ), a lower four score (p = . ), a lower score on the motor component of the glasgow coma scale (p = . ), and a lack of cough reflex (p = . ) at the time of eeg were significantly associated with a poor outcome. a severely impaired eeg pattern or presence of a discontinuous background activity were also associated with a poor outcome (p = . and p = . , respectively). indicators of poor neurologic outcome are presented in the table . among all parameters, a discontinuous background activity was the only variable that constantly predicted poor outcome (false-positive poor outcome prediction rate of %, % ci - %). conclusion early intermittent eeg has a strong prognostic value for sedated patients on va-ecmo. presence of a discontinuous eeg background activity seems to be more accurate than clinical alterations to predict a bad neurologic outcome at days. none. table ). it was not found a significant association of ctp to mortality ( % in the case group and % in control group, p = . ). other factors that increased mortality were coma, seizures, shock, oedema, cellularity in csf > units/mm . otherwise, the ventilation length was prolonged with ctp group ( . vs . days, p = . ) and neurological sequels namely the epilepsy was more frequent with the group ctp: ( vs %, p = . ). conclusion the occurrence of ctp on bacterial meningitis was significantly associated with ct scan lesions which seems to be an association be in both directions. also, the positive culture predisposed more to the ctp. mortality was higher with the presence of ctp but without real significance. the ctp was a factor that extends the ventilation time and exposed to the post infectious epilepsy. introduction acute bacterial meningitis requires rapid triage and therapeutic decision-making. the aim of this study was to assess the overall ability of a point-of-care glucometer to determine bacterial infection in cerebrospinal fluid (csf). we performed a prospective, observational study. we included patients for whom an analysis of csf was indicated by the physician in charge with blood sampling performed for glucose concentration measurement within h. we simultaneously measured the glucose concentrations in csf and blood using a central laboratory and point-of-care glucometer. the diagnosis of bacterial meningitis was determined by two physicians after reviewing the complete medical chart. we compared csf and blood glucose concentrations and csf/blood glucose ratios obtained at the bed-side with a glucometer versus those obtained by the central laboratory. we determined the performance characteristics of the csf/blood glucose ratio provided by a glucometer to detect bacterial infection in the csf immediately after csf sampling. conclusion we demonstrated that the csf/blood glucose ratio measured by a glucometer can serve as a clinical decision support tool for the early detection of csf with a high probability of bacterial infection. this costless point-of-care method has the potential to expedite medical decision-making for the triage of adult patients with suspected meningitis in the emergency department immediately after lumbar puncture. none. introduction cardiac arrest remains a frequent cause of admission in intensive care unit. a majority of patients will die during their hospital stay mainly from consequences of hypoxic-ischemic brain injury after a decision of withdrawal of life sustaining therapy support by a prediction of poor outcome. the reliability of prognostication is crucial, but is still a difficult and uncertain exercise. eeg is the most widely used prognostic tool to support a clinical examination and is accessible in most hospitals. it is recommended for both prognostication and ruling out subclinical seizures. there is no high-level evidence for predicting poor prognosis using eeg because of the wide variety of classification systems used and the interrater variability. our objective is to assess the prognostic value of simple eeg features based on the recent american clinical neurophysiology society (acns) standardized classification and to study the interrater variability. we conducted a retrospective monocentric observational study in a bed medical intensive care unit of the university hospital la timone, marseille, france. all patients aged of more than year-old admitted for a resuscitated cardiac arrest between november and july who underwent therapeutic hypothermia and a full multimodal prognostic evaluation including a eeg were included in the study. outcome was classified according to the cerebral performance category score measured at day . unfavorable outcome was defined as death (cpc ), persistent vegetative state (cpc ), or severe neurological disability (cpc ). favorable outcome was defined as moderate neurological disability (cpc ), or no disability (cpc ). eeg was performed in all patients still comatose after rewarming between and h after admission and after discontinuation of sedation. eeg interpretation was made by independent senior neurophysiologists, blind to the outcome. eeg features are based on the latest acns classification. for each eeg feature, sensitivity, specificity, positive predictive value (ppv), negative predictive value (npv) for predicting an unfavorable outcome were calculated. results during the study period, cardiac arrest were admitted of which patients went through a full neurologic evaluation and were finally included in the study. according to neurological outcome, % had a favorable evolution, and % had an unfavorable outcome. the presence of burst suppression, and epileptiform activity was constantly associated with an unfavorable prognostic with a % specificity and % false positive. a non-reactive eeg is strongly associated with an unfavorable evolution with a % specificity and % false positive. other features including periodic or rhythmic patterns and low voltage were inconstantly associated with unfavorable outcome. kappa score for all eeg feature was slight or fair and always under . . discussion this study allowed us to identify a homogenous cohort of comatose patient after cardiac arrest who underwent therapeutic hypothermia. we identified simple eeg features based on the new classification of the acns constantly associated with unfavorable outcome. these features must be known by intensivists to better integrate eeg in the multimodal evaluation of neurological prognostic. there is important interrater variability that must lead to caution and to always use multimodal approach to prognostic an unfavorable outcome. conclusion bedside eeg is an excellent tool for predicting outcome of post-anoxic coma through simple eeg features. burst suppression, epileptiform activity and non-reactive eeg are strongly associated to neurological outcome after cardiac arrest. however, the interrater variability emphasize the need of being well trained for the standardized methods of evaluating eeg parameters. introduction emergent reintubation is a well-known risk of laryngotracheal trauma and of ventilatory acquired pneumonia. to precisely define its risk before extubation for each patient is a part of quality of care in intensive care units. none of these consecutive children representative of picu activity has been reintubated. the coming prospective muticentric study which aims to validate alt in childhood must precisely define this criteria of evaluation. conclusion the different methods of alt are feasible in real clinical conditions in picu. because of the increasing use of cuffed etts in a wide variation of patients with different body weight, the best alt to use at the bedside must be definitively validated in this population. introduction prolonged mechanical ventilation (pmv) and chronic mechanical ventilation (cmv) in neonates is associated with a high morbidity and mortality. the objective of the study is to identify, among the patients with pmv, those that evolved to cmv, as well as the adverse respiratory, neurological and feeding sequelae. we conducted a retrospective study of the last years at the chu sainte-justine (montreal, canada). chart review included patients with pmv (≥ days) using the paediatric definition adapted from the namdrc consensus conference ( ) . demographic and clinical data, including follow-up at and months corrected age, was collected for each included patient. the evolution of pmv neonates with cmv (≥ days) and without ( - days) was compared. we identified neonates that met criteria for pmv. patients born between and (n = , % of the cohort) were analyzed. around half of the patients ( - patients a year) are transferred from the neonatal unit to the paediatric intensive care unit. in our center, they represent around % of total admissions, but their length of stay is among the longest. among these newborns, % were preterm (n = ) with % (n = ) born before weeks gestation. of all patients with a malformation ( %, n = ), had a thoracoabdominal anomaly and had congenital heart disease. thirty-six patients had cmv with mean ventilation time of days (range - days). survival at months corrected age was % ( / ) in the pmv group and % ( / ) in the cmv group. at months corrected age, % of patients were dependent on artificial enteral feeding (nasogastric tube or gastrostomy), with % in the pmv group and % in the cmv group. nine percent of patients had oxygen supplementation ( patients in the pmv group and in the cmv group), and % were mechanically ventilated. ten percent of patients had a tracheostomy ( patients in the pmv group and in the cmv group). discussion neonates with cmv have more sequelae. their rapid identification (at days of ventilation) is essential to implement multidisciplinary development care in order to minimize neurodevelopment impairment. conclusion most newborns in our pmv cohort have a congenital malformation. survival at months corrected age appears equivalent in both pmv and cmv group. artificial enteral feeding is more frequent in the cmv group and most patients have no respiratory support at months corrected age. none. the value of pressures and volumes in assessing the fluid responsiveness depend on the systolic cardiac function in adult ( ). we have studied the relative value of static filling volume and pressure to predict the fluid responsiveness, according to systolic cardiac function in children during acute circulatory failure. patients and methods patients under years old with an acute circulatory failure of two intensive care units during a year period of inclusion were analyzed. an exhaustive cardiac echography was performed initially (indexed end-diastolic volume (edvi) and e/e' from transmitral and tissue doppler were recorded), and the stroke volume index (svi) was measured before and after a fluid challenge (a ml/ kg of crystalloid over min results twenty-five children with acute circulatory failure were included. fluid responsiveness occurred in of the fluid loading events with low lvef, and in of the fluid loading events with normal lvef. pressure approach: for low and normal lvef, the auc-roc for fluid responsiveness was respectively . (ci . - )/ . ( . - ) for a e/e' .the best thresholds of e/e' in low lvef was . with a sensitivity of (ci - ) % and a specificity of (ci - ) %. for low and normal lvef auc roc was respectively . (ci . - . )/ . (ci . - . ) for the pvc. volume approach: for low and normal lvef, the auc-roc for fluid responsiveness was respectively . (ci - ) and . ( . - ). the best thresholds in normal lvef was an edvi below ml/m wit a specificity of (ci - ) and a sensitivity of (ci - ) %. discussion our study shows a variation of the diagnostic value of e/e' and edvi according to the left ventricular systolic function. therefore, the systolic function should be taken into account to analysed the e/e' and edvi value. few preload dependency markers are validated in children and none for children in spontaneous ventilation ( ) . our study suffers from a lack of power that calls into question the validity of our results. another limitation is that both approaches with volume and pressure are not very discriminant as it is known for static value in adults. our study illustrates that, on a pressure-volume curve, when the cardiac inotropism is reduced, the filling of the left ventricle is moved to the up and right of the curvilinear diastolic function curve. therefore, pressure variations are larger than volume variations. these values should be monitored on a larger scale to define their exact diagnostic value. conclusion static pvc value is a low preload-dependency surrogate. when lvef is low a pressure evaluation based approach seems more accurate. when lvef is normal a volume evaluation based approach seems informative as predicted by the slope of the end diastolic pressure volume curve. those both static approaches remain of poor diagnosis accuracy. introduction acute viral bronchiolitis is a primary cause of respiratory distress in paediatric intensive care unit (icu). prone position (pp) is commonly used in neonates to improve respiratory mechanics and has been found beneficial to adult patients with acute respiratory distress syndrome. we aimed to evaluate the effect of pp on work of breathing as compared to supine position (sp) in children with severe bronchiolitis requiring non-invasive ventilation. the protocol was approved by our irb ( -a - ). fourteen infants ( boys) with median age days [firstthird quartiles - ] with severe bronchiolitis requiring cpap were included after written informed consent. children were investigated in pp and sp each applied for h in a random order with a washout period of min between them. level of cpap was set at cmh o in both conditions. oesophageal pressure probe was inserted orally (cto- pressure transducer, gaeltec, scotland) to measure oesophageal pressure. flow and airway pressure (pmo in fig. ) were simultanuously recorded using a neurovent data acquisition system (neurovent inc, toronto, canada). one hundred breaths were analyzed in each condition, in which work of breathing was estimated from oesophageal pressure-time product (ptpes) and oesophageal swings (fig. ). data were expressed as median (first-third quartiles) and compared by using the wilcoxon two-sample paired sign test. a p-value below . was considered significant. . the edtb contains data from ventilated patients (invasively and non-invasively) and details concerning ionotropic and sedative treatment during picu courses. discussion as far as we know, this edtb is currently the only one as exhaustive available in picu worldwide. after almost years of multidisciplinary collaboration, we are able to collect many useful physiological, therapeutic and medical data in an ongoing edtb. although many concerns remain concerning data validation, organisation and exploitation, this edtb already contribute to the development of clinical decision support systems and virtual patient validation and we create international collaborations to further develop these tools. three research protocols using the database are ongoing including: validation of a neuromonitoring clinical decision support system, validation of a cardio-respiratory simulator, developement and validation of the automatic diagnosis of pediatric acute respiratory distress syndrome and development of spo forecast using artificial neuronal network. conclusion thanks to informatics and electronic devices improvement, data gathering in intensive care units has empowered. we hope that our work in picu will encourage other teams on the way of data gathering, in order to build an international picu edtb in a close future. none. introduction severe trauma is rare in the pediatric setting ( % of all trauma in france). however, its morbidity and mortality remain high, in relation to brain injury. pediatric traumatic brain injury (tbi) prehospital care is challenging for non-pediatric retrieval teams. though, we disseminated pediatric tbi pre-hospital care regional guidelines and thereafter intended to assess severe pediatric trauma pre-hospital care and secondary cerebral insults control. we conducted a retrospective study in a single pediatric trauma center. children admitted in emergency room with severe trauma and moderate to severe tbi (glasgow coma scale ≤ ) from june to march were included. pre-hospital and hospital data regarding primary care, equipment, medications and secondary cerebral insults control (i.e. blood pressure, oxygenation, co level, temperature, glycemia) were collected from medical files. two pediatric transport team experts assessed the quality of pre-hospital care, based on two major endpoints. results twenty-nine files were analyzed. median iss was . all the children had been referred directly from the trauma scene to the pediatric trauma center. they were all intubated in the prehospital setting, ( . %) presented with spo < % before or at emergency room admission, and ( . %) presented with a pco > mmhg at admission. at least one peripheral catheter was inserted in all the children. mean total fluid bolus was . ml/kg (± ). nor-epinephrine was administered in ( %) children. mean blood pressure was below age threshold in ( %) children during transport or at admission. an intracranial hypertension treatment (apart from sedation) was delivered in ( %) children before admission. body temperature was monitored in patients and were hypothermic at emergency room admission. experts concluded on sub-optimal care in children: major endpoint was "respiratory care", "hemodynamic care" and "neurologic care" in , and patients respectively. discussion on this small series, we showed pre-hospital sub-optimal care regarding secondary cerebral insults control, especially regarding co level, blood pressure and body temperature. our results will help to design new care improvement strategies (e.g. sedation, fluid bolus and ventilation optimization, early use of vasoactive drugs, systematic body temperature monitoring…). conclusion data on pre-hospital secondary cerebral insults care are rare in the pediatric setting. based on our results, we aim to improve quality of care of children presenting with traumatic brain injury, and to reduce its morbidity and mortality. introduction unsuccessful extubation from mechanical ventilation increases mortality and morbidity. to reduce the extubation failures in our intensive care unit we used a mechanical ventilator weaning protocol, based on published data. during the first part of the study, risk factors and incidence of extubation failure were first described. afterwards in the second part, our mechanical ventilator weaning protocol was tested to determined its efficiency regarding the extubation failure. patients and methods a monocentric and observational study, was first conducted. we included children aged from birth to old, during a period of months and collected for each patient their medical history, intubation and extubation parameters, and existing events of extubation failure or extubation complication. the second part of the study was prospective, we include patients extubated by applying our mechanical ventilator weaning protocol. results average duration of mechanical ventilation was . h in the first part of the study. using a univariate analysis, duration of mechanical ventilation was a risk factor of extubation failure with an average duration of . discussion our study confirms published data about extubation failure risk factor like duration of intubation, chronic respiratory affection, history of previous intubation, and the administration of benzodiazepine. it is the first pediatric study that shows a reduction of extubation failure by using a specific mechanical ventilator weaning protocol. the mean bias of our its retrospective and prospective character. conclusion our study shows the interest of a mechanical ventilator weaning protocol to reduce the incidence of extubation failure. we currently continue the apply our protocol to include more patients in order to confirm our results. stroke of the child is formidable though it is ten times rarer than in adults, but this scarcity can have adverse consequences on the speed and quality of the management and the consequences on later psychomotor development. our goal is to describe the clinical and therapeutic aspects of these pediatric stroke while bringing our experience. patients and methods retrospective study of cases of children hospitalized in general intensive care unit to the pediatric hospital canastel oran for stroke during the period from january to january . the clinical, etiological, para clinical, and scalable were studied and transcribed on a standard electronic form.all patients had a brain ct. magnetic resonance imaging(mri) was possible in patients for lack of availability of the technical facilities during the study. results ten cases were selected. the mean age was months ( month to years), % are male, patients had a history of chd like tetralogy of fallot and complicated bronchiolitis myocarditis, one patient had a history of petechial purpura, other was a factor deficiency, headache history was noted in patients, and patients with no particular antecedent was found. all patients arrived comatose / score on the scale of glasgow, isochores reactive pupils with a motor deficit of hémicorps, patients have degraded their neurological score with onset of clinical signs of hypertension intra cranial namely anisocoria and hypertension requiring osmotherapy, sedation and mechanical ventilation with an average duration of - day. o child arrived brain dead, patients had generalized tonic-clonic seizures which yielded after taking a benzodiazepine (diazepam) and phenobarbital (like gardenal). cerebral ct was performed in all cases and could we revealed the nature of the stroke hemorrhagic in cases and ischemic stroke in cases. two patients have benefited from an mri that found a thrombosis of the artery internal carotid right sylvian. besides symptomatic treatment, treatment was initiated based on the type of stroke, patients received low molecular weight heparin (lmwh) at . ml/kg in addition to symptomatic treatment, patients received vitamin k. four patients died in an array of autonomic disorders and evolved favorably and six patients were transferred to a pediatric unit. the average length of stay in icu was . days ( - days). discussion the mortality rate is important since no specialized center for children, and difficulty especially in the diagnostic imaging field while suspected stroke should be confirmed by imaging and the diagnostic delay. which is due to a poor assessment of the initial situation in half of the cases by the parents, the other half by the swiss magazine consulté.une doctor showed that in a study in % of children with stroke, this diagnosis was not primarily discussed and that in % of cases the cause of the stroke was poorly evaluated [ ] . heart disease certainly represent the second most important risk factor. a collaboration of a team must be multidisciplinary, death has affected mostly older children whose age is between and years, who have a hemorrhagic stroke against by infants who have an ischemic stroke have evolved and oriented they exceed the acute phase to pediatric services for further investigation and monitoring. conclusion the child may also be having a stroke, which usually reaches the elderly. this justifies a good knowledge of this disease, and multiply the initial management efforts to reduce mortality and improve prognosis. anwar armel , benqqa anas , samira kalouch , khalid yaqini , aziz chlilek introduction nosocomial infections are a main problem for public health for their cost as well as for the morbidity and mortality they generate. they are particularly common in intensive care units due to patient's lower defenses and of invasive procedures proliferation. work's purpose: • determine the epidemiology of bacterial noso-comiales infections (ibn) in the medico-surgical pediatric intensive care department of children's university hospital of casablanca. • to identify factors associated with these infections. we led a retrospective study of hospitalized patients, spending more than h in medical-surgical pediatric intensive care department, at the university hospital ibn rochd of casablanca, over a period of months from january to december . results during the studied period, patients were admitted at intensive care with a stay of more than h. thirty episodes of inb were recorded. the incidence rate was . % and the incidence density was . % per hospitalization's days. the admission average age was . ± -month starting from month to years with a male predominance ( %). most of admissions ( %) was related to medical background, . % received from other hospital department. furthermore, % of the patients received prior antibiotics, usually prescribed before icu admission. invasive procedures (intubation, central catheterization) were used in . % of patients, vvp only in . %, tracheotomy in . and . % had received surgery. gram-negative bacilli (bgn) were isolated for a lot of patients, dominated by acinetobacter baumannii. these bacteria were isolated throughout the study year. risk factors analysis underlined that the presence of invasive procedures enhances in risk, that is central venous catheter and the need for mechanical ventilation. conclusion nosocomial bacterial infections are dominated by pneumonia and central catheter infections, and are mainly due to bgn. the factors associated with these infections were identified. the guillain-barré syndrome (gbs) is the most common cause of acute flaccid paralysis in children since the acute anterior poliomyelitis eradication. few studies have been held on the topic and knowledge of gbs in children, although it is recognized that the etiologic mechanisms, and clinicobiological background, are the same as in adults, prognosis remains different. our work's aim is to study this disease's mortality factors of children hospitalized in pediatric intensive care. patients and methods it is a retrospective, descriptive, mono centric study to review patients with gbs between january and december and hospitalized at pediatric intensive care department of abderrahimharouchi hospital of casablanca. the used software is spss . to compare the bivariate variables, we used the khi test, and to compare quantitative variables, the anova to factor test was used. the level of significance was fixed at % with % confidence interval. the disease was predominant in male with a sex ratio of . men/women. after a prodromal event, usually infectious ( . %) and a free interval of days on average to start motor disorders. these are of two types: either a hypo or areflectic flaccid paralysis of the lower limbs ( . %) of ascending evolution in . % of the cases. either flaccid tetraplegia or hypo areflectic, ( . %). ventilation was required in . % of the cases, and specific treatments based on immunoglobulins were administered in . % of the cases. death's rate is still high ( . %) and mainly due to hospitalization complications. in our study respiratory disease was noted in . % of the cases, also other signs of serious illness such as swallowing disorders ( . %) and autonomic disorders ( . %) also noted what led to management in intensive care for all our patients. these patients study allowed to identify some mortality prognosis factors of the disease in intensive care units (such as male gender, ig administration duration, the occurrence of autonomic disorders like blood pressure instability), the most discriminating remains the occurrence of nosocomial infections. conclusion it must be underlined, that in view of our strict inclusion criteria, focusing only on patients admitted at intensive care and of the relatively small sample size ( cases), our results must be qualified and must be enhanced by additional and more varied studies to better understand this disease in children. introduction early surgical treatment is recommended for refractory intracranial hypertension (htic) in children to improve vital and functional prognoses, whether traumatic or vascular cause. the main objective of this study was to compare the mortality and morbidity of children with severe intracranial hypertension after severe head trauma (tc) or due to vascular cause after decompressive craniectomy (dc) or medical therapy alone. the secondary objective was to identify the initial severity factors associated with higher mortality. patients and methods a retrospective study was performed with data collected from patients aged under years-old admitted to our pediatric intensive care unit for severe intracranial hypertension of traumatic or vascular cause, between january and january . they were divided into groups: patients who received medical therapy alone and those treated with decompressive craniectomy after optimal medical management. results a total of children were included. among them, were treated with dc ( htic of vascular cause and htic of traumatic cause), and were supported by medical means only ( htic of vascular cause and htic of traumatic cause). in the population "traumatic intracranial hypertension", we note that children in the "dc" subgroup are more often in mydriasis upon arrival (p = . ) than in the subgroup treated medically. in this same population, children in the "dc" subgroup received higher doses of mida-zolam (p = . ), of mannitol (p = . ) and hypertonic saline (p = . ) than in the other subgroup. in the population "vascular intracranial hypertension" the two subgroups were comparable. in the case of traumatic intracranial hypertension, mortality rate in the "dc" subgroup was . % against . % for children treated medically (p = . ); "dc" children had more metabolic complications such as hypernatremia than "not dc" children, p = . . mortality rate in the «vascular intracranial hypertension» group was % for children treated with decompressive craniectomy, and . % for children treated medically alone (p = . ). patients treated surgically in the «vascular intracranial hypertension» group had longer overall stays (p = . ) and longer icu stays (p = . ). popc score (pediatric overall performance category) upon discharge for children with intracranial hypertension of traumatic cause treated with decompressive craniectomy was . ± . against . ± . among children treated medically, p = . . in "dc" children with intracranial hypertension of vascular cause, popc upon hospital discharge was . ± . against . ± . among non-operated children, p = . . the schooling rate was higher among children treated medically for intracranial hypertension of traumatic cause, p = . . the severity factors related with higher mortality identified in the population "traumatic intracranial hypertension" were mydriasis upon admission, a pim score higher and a lower temperature (< . °); the latter being the only factor identified for htic of vascular cause. in the case of traumatic intracranial hypertension, icp monitoring in survivors was . % against . % in children died, with no significant difference. in the population "vascular intracranial hypertension", all the patients who died had not been monitoring pic. discussion the severity factors related with higher mortality identified in the population "traumatic intracranial hypertension" were mydriasis upon admission, a pim score higher and a lower temperature (< . °); the latter being the only factor identified for htic of vascular cause. other studies have related other severity factors as initial glasgow scale, tardive decompressive craniectomy. conclusion decompressive craniectomy doesn't seem to improve the mortality rate or the outcome in patients with hypertension of traumatic cause in our study but the dc traumatic subgroup was more serious than the subgroup treated medically. in children with refractory intracranial hypertension of vascular cause dc significantly improves survival and outcome. further studies are needed to clarify the role of decompressive craniectomy and its timing in the therapeutic management of refractory intracranial hypertension. introduction shortage of heart grafts is a major problem, leading to a significant mortality rate in the national waiting list, essentially for young children with low weight. the potential paediatric brain-dead donors often have myocardial dysfunction (md), which seems to be reversible. the aim of this study is to assess prevalence, causes and consequences of md when the potential paediatric donors are taken over, up to multi-organ retrieval, and the evolution after cardiac transplantation. materials and methods this observational, monocentric, retrospective study included all brain-dead children aged - years old, who had their myocardial function assessed through a cardiac ultrasound performed by a cardiologist and identified from to . all adult patients and those who didn't undergo a cardiac ultrasound were excluded. md was defined as an lvef ≤ % with or without abnormal segmented cinetic parameters. the main evaluation criteria was the prevalence of md in potential identified donors. the secondary evaluation criteria were the causes and consequences of md on heart retrieval and the origin of this md. results out of included patients, had md. prevalence of md was of %. there was no significant difference between groups regarding aetiology of brain death nor administration of catecholamines. having a cardiopulmonary arrest during intensive care unit stay was associated with a significant risk of presenting a md (p = . ). having a md had no consequences on organ retrieval in general (p = . ), but was significantly associated with a decrease in heart retrieval opportunities (p = . ). the cause of heart grafts refusal was a poor ventricular function in % of cases ( cases out of ). the cause for non-retrieval was parental refusal in one-third of cases. evolution of the cardiac grafts was favorable in cases on , one transplanted patient died (from a non-cardiac cause) and patient was lost to follow up. conclusion md in paediatric brain-dead patients has direct consequences on heart retrieval and transplantation, and otherwise, organ shortage is a major ongoing problem. a better transplant management regarding hemodynamics (with the use of a protocol) could increase the number of heart transplants, especially in small children, and reduce mortality rate in national waiting list. the prone positioning (pp) is a strategy widely used in the treatment of severe forms of acute respiratory distress syndrome (ards) in adults. its early use significantly reduces mortality ( ). however, the studies do not strongly demonstrate its prognostic impact in pediatric ards. the aim of this study was to describe the prone positioning practices in the french-speaking pediatric intensive care units (picu). patients and methods this survey was conducted by email questionnaire to pediatric intensivists belonging to the french society of intensive care medicine and the french-speaking group of pediatric intensive care and emergency medicine. it was conducted from february to may . the survey was addressed to doctors, nurses, physiotherapists practicing in picu. it included questions about indications, contraindications, techniques and medical devices used, and complications. results one hundred and three persons answered ( doctors and nurses) which work in french hospitals and canadian hospital. sixty-eight percent of interviewed persons have more than years experience and % of them treat each year more than children ards. only % of the picu have a pp medical protocol. fifty percent of interviewed persons frequently use pp for the medical care of ards and % systematically use it. thirty-six percent begin pp at the early phase of ards during conventional ventilation, while % before the introduction of unconventional ventilatory strategies (ohf); only % use it after the respiratory failure unless unconventional ventilatory strategies. seventy-three percent report that pp is used with prolonged periods (> h/day), % with short periods (< h/day) and % with very long periods (> h/day). regarding the weaning criteria, most of interviewed persons seem to use multiple and combinated criteria: % use hypoxemia severity parameters (pao /fio , pao , sao ), % use the oxygen level (fio ) and % use the mechanical ventilation parameters (peep, p max, p plate). finally, despite a low level of scientific evidence in children, % of the persons gave a strong recommendation for pp as standard care in severe pediatric ards. see fig. . the survey confirmed the widely use of pp in pediatric ards. however, no specific protocol is avalaible in most of the picu. the timing of the pp beginning can be different according to children, early and prior to use of the conventional ventilation strategy in most cases. the duration of pp seems more consensual. most of the centers use extended periods longer than h/day. these results are close to guérin et al. advocating a duration > h/day. finally, the weaning is a great issue and depends on multiple criteria. in guerin et al. ( ) pp was interrupted if one of the following criteria were present: pao / fio ≥ mmhg, with peep of ≤ cm of water and a fio of ≤ . ; decreased pao /fio than %, compared to compared to the supine position, or the occurrence of complications. no study has validated pp weaning criteria during pediatric ards. conclusion the prone positioning is a strategy commonly used in pediatric intensive care units for the severe pediatric ards. the criterias of implementation and timing are variable, as well as the weaning criterias. more pediatric multicenter randomized studies will be necessary to confirm the benefits of pp in pediatric ards and to define clear weaning criteria. introduction allogeneic hematopoietic stem cell transplantation (hsct) recipients have profound defects in every immunity compartments that can lead to severe opportunistic infections (oi). % of hsct patients require admission to the icu because of diverse infectious or non-infectious complications with dismal outcomes. oi specific course in this population has not been described previously and the management of these infections may be a concern. the aim of this study was to investigate risk factors, management and outcomes of io in hsct recipients admitted to the icu. patients and methods this was a retrospective ( - ) single center study of patients admitted to icu after an allogeneic hsct. patients provided written informed consent according to helsinki declaration. data regarding the transplant, infections and life sustaining therapy use were analyzed. oi were considered if present at the time or during icu admission. results hundred and ninety-four patients (pt) were included. median age was [ ; ] years, . % were males. reason for transplantation was acute leukemia in ( %) pt and the hematological condition was still in complete remission at icu admission in % of patients. ( %) and ( %) had received a myeloablative conditioning regimen and anti-thymoglobulin serum respectively. % had acute graft versus host disease over grade at icu admission. oi was documented in patients ( %). an invasive fungal infection (ifi) was found in pt owing to mucormucosis, trichosporon septicemia and invasive aspergillosis ( possible, probable and proven according to eortc criteria). serum galactomannane antigen was positive in ( %). median time from transplantation and icu admission to ifi diagnosis was respectively [ ; ] and − [− ; ] days. lung was involved in % and patients with aspergillosis were admitted to the icu for acute respiratory failure in % (vs. % for others p = . ). they did not required invasive ventilation more frequently ( vs. % p = . ). and % required vasopressors and renal replacement therapy with no difference as compared to others. median icu length was [ ; ] days. demographic, stem cell source, and donor type were not associated with ifi occurrence in this population. however / had received a total body irradiation ( vs. % p = . ). ifi occurrence was not associated with icu or day mortality ( vs. % p = . and vs. % p = . respectively). a viral infection was found in pt owing to cmv, adenovirus, hsv and vrs infections. analyses were focused on cmv reactivation. median time from transplantation and icu admission to cmv reactivation was respectively [ ; ] and − [− ; − ] days. reactivation was mainly positive blood pcr but pt had cmv colitis. a preemptive treatment was started on the same day in median and lasts [ ; ] days. patients with cmv reactivation had more frequently multiple organ failure ( vs. % p = . ) and higher icu admission sofa score ( [ ; ] vs. [ ] [ ] [ ] [ ] [ ] [ ] p = . ). they trend to have higher admission creatinine serum level ( [ ; ] vs. [ ; ] umol/l, p = . ) and more frequently required emergency renal replacement therapy ( vs. % p = . ) mechanical ventilation ( vs. % p = . ) and vasopressors ( vs. % p = . ). median icu length was [ ; ] days and comparable to others. demographic, stem cell source, conditioning regimen and donor type were not associated with cmv occurrence. cmv reactivation was not significantly associated with icu or day mortality ( vs. % p = . and vs. % p = . respectively). conclusion oi was found in % of allogeneic hsct recipients admitted to the icu. ifi were mainly responsible for respiratory distress and cmv associated to multiple organ failure. non-invasive diagnostic tests were positives in a majority of these patients. in this cohort, io treatment was started quickly after the diagnostic and we did not find an association with mortality. intensivists should always consider oi in their diagnostic panel in this specific population. introduction over the last two decades, targeted therapies in patients with solid tumors have both increased their length of survival and significantly altered their immune functions. however, data on opportunistic infections in this setting remain scarce. in this systematic review, we sought to identify published cases of opportunistic infections in patients with solid tumors, with a special interest on clinical findings, trends over time and outcomes. materials and methods we performed a search of medical subject headings (mesh) on pubmed using the words pneumonia pneumocystis (pcp), invasive aspergillosis (ia), histoplasma, mucor, geotrichum, cryptococcus, coccidioidomycosis combined with the mesh term neoplasms (breast, lung, ovarian, urologic gastrointestinal, digestive system, abdominal, brain, carcinoid tumor, sarcoma, testicular, seminoma). we identify published cases of opportunistic infections in non hiv patients with solid tumors between / / and / / included. results regarding pneumocystis jirovecii pneumonia, cases could be identified. there were men and women, aged of . ( - ) years. underlying tumors were chiefly brain neoplasms (n = , %), lung neoplasms (n = , %) and breast neoplasms (n = , %). at the time of pneumocystis pneumonia onset, patients ( %) had a history of chemotherapy, ( %) had received long term or high dose steroids, and ( %) had an history of biotherapy targeting the malignancy. of note, patients ( %) had received only chemotherapy, ( %) had received steroids alone, ( %) everolimus therapy alone and ( %) received none of these treatments. regarding invasive aspergillosis cases could be identified. mean age was . ( - ) and ( %) were men. solid tumors associated with invasive aspergillosis were primarily lung neoplasms (n = , %) and brain neoplasms (n = , %). at aspergillosis onset, ( %) patients had a history of chemotherapy, ( %) were receiving long term or high dose steroids and ( %) had received targeted therapy. fourteen ( %) patients had received only chemotherapy, ( %) only steroids, and ( . %) had received targeted therapy alone. for both infection, there was a trend for a higher number of reported cases throughout the studied period. conclusion this systematic review provides objective data showing that an increased proportion of patients with solid tumors present with opportunistic infections. we are convinced that it is a clinically relevant but still neglected problem. selected oncologic population may be becoming eligible for antimicrobial prophylaxis against pneumocystis or aspergillus. care unit of strasbourg in france. patients were included only if they are non-immunocompromised according to the european organisation for research and treatment of cancer (eortc). invasive aspergillosis was defined as an association of microbiological evidence, a radiological imaging and a clinical context. results eighteen patients ( males) were identified during the study period. the median of igs ii was . (interquartile range (irq), . - . ). ninety-four percent was under mechanical ventilation. fourteen ( %) patients were suffering from liver failure. among liver failure, twelve ( %) were beforehand suffering from cirrhosis. the median meld score was (interquartile range (irq), - ). sixty-four percent of aspergillosis were due to aspergillosis fumigatus. hundred percent were pulmonary aspergillosis. fifty-six percent of aspergillosis were associated with bacterial pneumonia. the mortality rate at the date of the latest news (an average of years) was seventytwo percent. discussion invasive aspergillosis is not exceptional in the non-immunocompromised patient especially in patient developing liver failure. an active research of colonization/infection with aspergillus in these patients remain to be discussed. conclusion invasive aspergillosis in icu has a poor prognosis. the liver failure seems to be the most important risk factor in non-immunocompromised patients according eorct criteria. introduction chest wall elastance (ecw) has been found to increase in prone (pp) as compared to supine position (sp) in ards patients [ ] . this makes respiratory system elastance (ers) not reflecting lung elastance (el). little is known about the changes of ecw, el and lung resistance (rl) when moving the patient from the sp to the pp via the lateral position (lp). the goal of present study was to measure ecw, el and rl in ards patients in sp, lp and pp during the proning procedure. patients and methods it was a prospective, single-center, controlled study. ards patients intubated, sedated and paralyzed with pao /fio ratio < mmhg, peep ≥ cmh and an indication of pp were included. mechanical ventilation was delivered in volume controlled mode with constant flow inflation and end-inspiratory pause . s included into the inspiratory time. ventilator settings were unaltered during the procedure. an esophageal balloon catheter (nutrivent device) was used for esophageal pressure (pes) measurement. pressure at the airway opening (pao) and airflow were measured by fleish pneumotachograph proximal to endotracheal tube and upstream heat and moisture exchanger. pao, pes and airflow were continuously measured during min in sp, then during min in lp and min in pp. the side for the lateralization was that selected by routine practice (in the opposite side from central venous line). ers and resistance of the respiratory system (rrs) were obtained by fitting flow and pao signals breath by breath to the first order equation. ecw and resistance of the chest wall (rcw) were similarly obtained by fitting flow and pes signals breath by breath to the first order equation pertaining to the chest wall. el and lung resistance (rl) were obtained by subtracting ers and rrs from ecw and rcw, respectively. our ethical committee approved the protocol. data are shown as median (first and third quartiles). comparisons between positions were made by using paired-t-test. results twenty-nine patients, males, of ( - ) years, saps ( - ) and sofa score ( - ) were included ( - ) days after ards criteria were met. the ards severity was moderate in cases ( %) and severe in ( %). tidal volume averaged . ( . - ) ml/kg predicted body weight, peep ( - ) cmh o, fio ( - ) %, pao /fio ( - ) mmhg. the cause of ards was pulmonary in cases ( %), extra pulmonary in ( %) and undetermined in ( %). lateral positioning was on the right side in ( . %) and on the left side in patients ( . %). the results are shown in the table . conclusion during prone positioning in ards patients, as compared to sp we observed a higher rl in lp and an increased ecw in pp. introduction neuromuscular blocking agents (nmba) could exert beneficial effects in acute respiratory distress syndrome (ards) through properties on respiratory mechanics and particularly in modifying transpulmonary pressures (pl). patients and methods prospective randomized control study in moderate to severe ards patients within the first h of the onset of ards. all patients were monitored by an esophageal catheter and followed during h. moderate ards patients were randomized in two groups according to the systematic administration of a h continuous infusion of cisatracurium besylate or not (control group). the severe ards patients group received a h continuous infusion of cisatracurium besylate. the evolution during the h of the study of the oxygenation and the respiratory mechanics including inspiratory and expiratory transpulmonary pressures and driving pressure were assessed and compared. delta transpulmonary pressure (∆pl) was defined as inspiratory pl minus expiratory pl. results thirty patients were included, in the moderate ards group and in the severe ards group. nmba infusion was associated with an improvement in oxygenation both the moderate and the severe ards patients group accompanied by a decrease in both the plateau pressure and the total positive end expiratory pressure. the mean inspiratory and expiratory pl were higher in the moderate ards patients group receiving nmba as compared with the control group (fig. ) . in contrast, there was no modification of both the driving pressure and the ∆pl related to nmba administration. conclusion nmba could exert beneficial effects in moderate ards patients through higher observed inspiratory and expiratory transpulmonary pressures. none. introduction prone position (pp) is a major treatment in management of acute respiratory distress syndrome (ards). the use of pp in patients with severe ards associated with brain injury is at high risk of intracranial hypertension. the aim of this study is to analyze the effect of pp on intracranial pressure (icp) and cerebral perfusion pressure (cpp) in patients with ards and acute neurological condition requiring monitoring of icp. patients and methods it is a retrospective descriptive study including sixteen patients with acute brain injury (subarachnoid hemorrhage, severe head trauma, and hemorrhagic stroke) and continuous monitoring of icp who developed a severe ards during icu stay from january to december and for which pp was performed. pp sessions were analyzed. hemodynamic and respiratory parameters, blood oxygenation, pic and ppc were studied in supine, before pp and after pp. the study was approved by fics ethic comity. results a significant increase in pao /fio ratio was observed in pp, from ± to ± (p < . ). in pp, the icp was increased ± . - ± . mmhg (p < . ) while the cpp was stable ± versus ± mmhg (ns). median duration of pp session was h ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . increasing of icp during pp required medical treatment in sessions ( %). pp session was interrupted in sessions ( %). in subgroup of patients who respond to pp in terms of oxygenation, the increase of icp was lower than in non-responders ( vs %) (p < . ). cpp was not modified whatever the nature of the response to pp ( ± - ± in non-responders and from ± to ± in responders (ns)) (fig. ). discussion our study shows an improvement of oxygenation during pp in severe ards patient with acute brain injury. we observe a constant increment of pic during pp sessions. the increment of icp is less in responders to pp. significant increased icp requiring an enhancement in the medical treatment was observed in % of the cases, and lead in most cases to a discontinuation of the session. our data underlined the absolute necessity to monitor icp during pp session in patients with acute brain injury and ards, even if icp is controlled previously in supine. only prospective ( , ) and one retrospective studies evaluate the effects of pp on icp in patients with acute brain injury and acute respiratory failure (arf). they results are similar to ours. in all these studies, the severity of arf was often not well specified. roth and al. ( ) had included only % of ards in a population of patient with icp not controlled. in others studies, monitoring of icp during pp was not systematic. despite the retrospective nature of the study and the small number of patients, it is the only work studying the effects of pp on intracranial pressure in patients with acute brain injury at risk for intracranial hypertension and severe ards according to the berlin's definition. conclusion our work suggest that pp is a quite secure technique for use for the treatment of severe ards even patients at risk of intracranial hypertension with a benefit in terms of oxygenation without major increase of icp particularly in pp responders. introduction influenza-associated acute respiratory distress syndrome (ards) requiring extracorporeal membrane oxygenation (ecmo) support is known to have a good prognosis ( ). however, the incidence and impact of co-infection in this setting remain unknown. we conducted a retrospective, observational analysis of data prospectively collected from all patients admitted to our medical icu who received ecmo support for influenza-associated ards between and . co-infection was defined as isolation of a pathogen in the lower respiratory tract at a significant level or in the blood during the h following hospital admission. when no pathogen was identified in a patient receiving antibiotics prior to bacteriological sampling, an independent adjudication committee reviewed all charts to assess if the patient had a "high probability" or "low probability" for bacterial co-infection, based on clinical, radiological and biological results available. results are presented as median [iqr] . results among the patients hospitalized for an influenzaassociated infection in our icu, had an ards requiring support by either veno-venous-(vv, n = ), venoarterial (va, n = ) or venoarterio-venous-(vav; n = ) ecmo. - . ), pre-ecmo sofa score > (or . ; % ci . - . ) as independent predictors of hospital mortality, but not co-infection (or . , % ci . - . ). in a second analysis, patients with proven co-infection and high probability of co-infection were grouped and compared to patients with no co-infection and low probability of co-infection; and results were similar. as compared to others co-infected patients, those co-infected with a pvl-positive s. aureus had same characteristics and similar mortality rate, but all received a treatment active against pvl production. conclusion co-infection is frequent in patients with influenzaassociated ards supported by ecmo, occurring in roughly % of the cases. mortality of patients with co-infection is higher than those without, but seems mainly due to the severity of the disease. s. aureus was the most frequently identified pathogen, with a high prevalence of pvl-positive s. aureus, infection with a pvl-positive strain was not associated with a poorer outcome as compared to other co-infections. whether a treatment active against pvl production should be given in those patients remains to be determined. none. the pancreaticoduodenectomy (pd) is major surgery in visceral surgery. this technique performed for the first time in by whipple has seen much progress and development over the years that have enabled a significant reduction in mortality, while the morbidity remains high. the aim of this study was to analyze postoperative morbidity pancreaticoduodenectomies. we retrospectively studied cases of cephalic duodenopancreatectomy at the department of surgical emergencies resuscitation (wing ) spanning years, between january and december . the average age of patients was . years with % of females and % of males, the frequence of pancreatic resections was years. the indications of cephalic duodenopancreatectomy were: tumors of pancreatic head ( %), ampulla vater ( %), duodenum tumors ( %). the restoration of continuity after cephalic duodenopancreatectomy was realized with a rate of % for pancreaticogastrostomy and % for pancreaticojejunostomy. the average hospital stay was , days, with extreme lengths of - days. the postoperative course was marked by the occurrence of deaths ( %), the morbidity rate was , % after pj and % after pg; the most frequent complications were the pancreatic fistula ( %), the postoperative peritonitis ( %), the digestive bleeding ( %), the gastroparesis ( %). conclusion advances in the overall care of patients by surgical teams, anesthesiologists and intensivists, the dpc mortality is currently low in experienced centers. the multidisciplinary, involving surgeons, radiologists and especially intensive care, to manage more effectively the complications of this surgery remains burdened with high morbidity. introduction severe acute pancreatitis (sap) is a common but potentially lethal pathology due to the multiplicity and severity of complications that can occur at all stages of evolution. in the last decade, mini-invasive interventional treatments of infected pancreatic necrosis (ipn) have been developed. the aim of the present study was to assess the management and outcomes of sap patients, as well as to identify the role of ipn. this was a retrospective study of prospectively collected data from all consecutive patients admitted in intensive care unit (icu) in a single french center (hospital of nantes) from to . using logistic regression, we evaluated the association between ipn and patients characteristics at baseline and the outcomes. (fig. ) , highlighting the prognostic importance of respiratory failure and acute renal failure at the time of lt, as well as complex interactions between donor and recipient features. conclusion ventilator support and/or acute renal failure at the time of lt are major predictors of mortality but complex recipients/donors relationships may moderate these associations, as demonstrated by our cart analysis. none. subtotal gastrectomy ( / ). enlarged gastrectomy was performed in patients ( %). the mean operative time was . ± min. per-operative transfusion was required in patients ( . %). the average length of stay in icu was . ± days. postoperative mortality was . %. in our series, patients ( . %) had at least one postoperative complication: an anastomotic fistula diagnosed in patients ( . %), patients ( . %) had postoperative peritonitis and patients had ventilator associated pneumonia. reoperation was necessary for patients ( . %), it was performed after . days ( - days). in univariate analysis, risk factors for postoperative morbidity after gastrectomy was hypoalbuminemia (p = . ), anemia (p = . ), bmi (p = . ) and malnutrition (p = . ). age, sex, neoadjuvant chemotherapy, extended lymphadenectomy, splenectomy or pancreatosplenectomy, total gastrectomy and operative time were not significantly associated with higher postoperative morbidity. in multivariate analysis, malnutrition (p = . ) and bmi (p = . ) were significantly associated with the occurrence of postoperative complications. conclusion the results of our study are similar to those reported in medical literature. preoperative evaluation and nutritional rehabilitation are crucial to improve patient's outcome and reduce morbidity and mortality after gastrectomy for cancer. the mesenteric ischemia is a condition relatively rarely. it is marked by high mortality. mortality is primarily related to the land on which ischemia occurs and especially the time taken to diagnose. this delay is due to the low specificity of clinical signs and the absence of diagnostic laboratory test. the mesenteric ischemia remains a diagnostic and therapeutic challenge. patients and methods twenty cases of acute mesenteric ischemia have been collected at the surgical resuscitation (resuscitation ) at the hospital center ibn rochd of casablanca from january to december . results the mean age of our patients is year old. it is about a disease that the incidence increases these last years, particularly because of the waxing number of old patients and/or suffers from advanced cardiovascular diseases. the cardiovascular risk factor has been present in % of our patients. the abdominal pain has been present in all the patients. it is a sudden, intensive pain localized the most often at the level of the epigastria, becomes diffuse in few hours or even few days. other clinical signs have been described as the bilious vomiting that becomes fecaloid after few days. the digestive hemorrhages as the moelena and the hematemeses. a stop of the matter and the gazes was noticed in % of our patients. the absence of specificity of the clinical signs forced the realization of complementary examinations. the scanner becomes the reference imaging. it permits a differential diagnosis, the search of direct signs of vascular obstruction and the emphasis of intestinal pain. four etiologies are noticed: the arterial occlusion by emboli ( %), the arterial thrombosis ( %), the venous thrombosis ( %) and the "non occlusive" form ( %). the strategy of management of the acute mesenteric ischemia is multidisciplinary, based on the equips of radiology, vascular surgery and/ or visceral surgery and resuscitation. the treatment consists in measures of general resuscitation, the techniques of endoluminal vascular disobstruction and techniques of surgical revascularization. in spite of the improvements in the diagnosis and the therapeutic procedure of the ima, the disease still know a rate of mortality between and % according the studies. in our study, we noticed cases of death ( %), cases of good recovery ( %), cases are unknown evolution ( %). conclusion it is a vital emergency that the evolution still knows great mortality. it is very important to remind the acute mesenteric ischemia in the case of any acute abdominal symptom in order to anticipate about the natural evolution and to act in a reversible stage of the ischemia. none. introduction emergency departments staff are frequently exposed to many complex stressful situations and consequently burnout syndrome. our study aimed to describe epidemiological particularities and determine the risk factors of burnout syndrome in different categories of emergency. patients and methods we studied five academics and four regional hospitals. the level of burnout was assessed using the "maslach burn out inventory" score and the degree of depression with major depression inventory (mdi) test. results one hundred and forty-three correctly completed questionnaires were collected. the mean age of study population was ± years. sex-ratio was at . . fifty-one per cent of the care staff were married. physicians represented % and paramedical %. the general frequency of burnout syndrome was % (n = ). low level burnout was present in %, moderate level in % and high level in %. the depression frequency was %. a statistically significant correlation was found between burnout and depression firstly (p = . ) and between burnout and lack of equipment (p = . ). their relative risk was . [ . , ] and . [ . , . ] respectively). main risk factors associated with high level burnout are detailed in table . conclusion burnout syndrome frequency in our emergency departments is alarming. helping to resolve social and psychological problems and improving work conditions may help to decrease it. the healthcare activity is recognized as a major polluting activity. in france, it generates , tons of waste cremated each year, and represents % of the tertiary energy consumptions. in the united states, it generates tons of waste per day and % of total co emissions in were attributed to him. ultimately, such waste production is associated with adverse environmental and health effects. nevertheless, near half of the hospital waste would be recyclable, particularly in our intensive care units (icu) [ ] . furthermore, sustainable development solutions generate profits. the aim of this study is to make an overview of waste produced in a icu and offer solutions to conserve natural resources and reduce the carbon footprint bound to the healthcare activity. materials and methods experimental study, single-center, concerning a period of months in an icu-high surveillance unit compound of beds. we have identified all waste generated. our packaging were given to the recycling company in connection with the hospital. then we have studied the impact of the implementation of sustainable development solutions. results firstly, we have studied the non-recycled waste and the quantity produced over a period of month. approximately kg of waste is produced per patient per day with % of infectious waste and % of general waste. these results were linked with a bad distribution of garbage bags in the rooms ( l of infectious waste versus l of general waste). secondly, we have improved our way to sort and consume and we have created recycling dies without compromising patient safety. all these measures have not increased workload. changing bags in the rooms ( l of infectious waste and bags of l of general waste) allowed to reach the normal goals of sectors with a net benefit estimated at euros per year. the medical broken glass containing drugs was thrown into plastic containers of l for infectious waste to prevent the risk of cuts. by creating a specific die intended to the general waste, we could quantify the production of this glass to kg per week and to spare the use and the incineration of containers of l per year (global economy of euros). plastic packaging represented an important proportion of the cremated waste. we have created sectors of recycling including the polypropylene ( - kg per month), the polyethylene colorless and colored polyethylene. this plastic is sold to be recycled without additional cost for the hospital. the linerboards was cremated. we have created a recycling die ( kg per month). this sector was subsequently extended to the entire hospital structure, particularly the pharmacy that produces containers of l per month. they are now sold without additional cost. many unnecessary plastic waste is generated daily. we have removed using mild soap plastic bottles of ml by using the same mild soap in pump of ml (economy of euros). the use of l plastic bags for the transitional deposit of linen has been deleted (economy of euros). concerning the paper: % of the impressions were made in simplex. printers were parametrized on both sides by default allowing the economy of reams per year ( , sheets), several thousand liters of water and the reduction of co emissions. discussion recycling is only one component of the sustainable development in health. other avenues that could be considered to improve icu sustainability would include examining water use (for linen), electricity use (reducing non-essential use at night…). beyond these actions, we need to encourage our suppliers to turn to sustainable and recyclable packages to reduce the use of polluting and depletable fossil fuels such as oil. but also to develop with them circular economies where waste is returned to them to be reused. conclusion we must ask the question also resuscitate our tons of waste. our icu produce large quantities of waste (over tons per year per bed). however, a significant proportion, especially plastic, is recyclable with a significant environmental and financial benefit. waste management also requires an optimal and rational use of supplies because "the best waste is that which is not produced" and that excess is not a guarantee of quality. as already said st exupéry in : "we do not inherit the earth from our parents, we borrow it from our children. " so do not expect tomorrow to reduce major adverse ecological impact paradoxically generated by a great profession whose ultimate goal is to cure people. moreover, an external consultant is rarely applied and palliative cares are insufficiently developed after «non-readmission» decisions. for providing corrective measures, this study lead to propose a «nonreadmission» process by integrating the discussion for a real «patient's care project» at the end of the icu hospitalization. this process would lead to collect patient's opinion through advance directives, to ensure a collegial discussion including an external consultant and to allow reevaluation of global patient's clinical status and one or more organ failure(s). then, «non-readmission» decisions would be integrated in a therapeutic project which would promote the initiation of a palliative care program if necessary. the purpose of this process is well to respect patient's autonomy and dignity as required by french law and medical ethics. the proportion of elderly patients is steadily increasing. due to the growth of this part of the population who suffer from multiple pathologies, the need for hospitalization in intensive care increases. according to the simulations, the proportion of octogenarian patients in icu will increase reaching the third of icu patients. while chronological age is not a significant factor of poor prognosis in the icu ( ), many factors should be taken into account to evaluate the relevance of icu admission in the senior population and withholding such intensification should be consensually discussed between clinicians and obviously as often as possible with the patient himself ( ) . the aim of the study was to assess the role of stakeholders (ward physicians, intensivists, family doctor and patient himself ) in the decision of withholding icu admission for elderly patients in our internal medicine department. we made a prospective observational monocentric study, including all the elderly patients (defined as older than ) admitted in the internal medicine department from january to june . the only non-inclusion criterion was patient's refusal to participate to the survey. collected data involve physiological (cognitive, autonomy, nutritional status), morbidities (acute and chronic diseases) and social parameters (marital status, relatives). and evaluation of quality of life by the patient himself using an analog visual scale was also obtained. internal medicine physicians were asked to report any icu withholds decision for their patients. in absence of notification, every physician was questioned again the day of the concerned patient's discharge. results one hundred ninety-one patients were included between january and june . factors associated with a significant reduction of in hospital mortality were higher age (p = . ), higher lactate level (p = . ), chronic obstructive pulmonary disease (p = . ), diabetes mellitus (p = . ), immunodepression (p = . ) and respiratory failure (p = . ). conclusion in patients hospitalized for vs high body mass index, low left ventricular systolic function, high white blood cell count, low creatinine clearance, high lactate level and st-segment depression are the variables correlating significantly with high-sensitivity troponin-t concentrations. peak of hstnt was not significantly associated with in-hospital mortality in this setting. introduction mitochondria are evolutionary endosymbionts that are derived from ancestral aerobic bacteria and so might bear and release bacterial molecular motifs supporting the role of mitochondria in danger signal regulations. free circulating mitochondrial dna (mtdna) is elevated in a wild range of critical illness observed in intensive care units, and is associated with bad outcomes and mortality. the mtdna is a molecular pattern that belongs to mitochondrial damage associated molecular patterns (mtdamps), and can interact with pattern recognition receptors (prr) to induce self defense reaction. free mtdna activates inflammatory signaling pathways through toll-like endosomal receptor (tlr ) interactions. nevertheless, new evidence advocates a role of the receptor for advanced glycation end-products (rage) in mtdna signaling. experimental data suggest a role of mtdna-prr interaction in systemic inflammation and organ dysfunctions as septic acute kidney injury or pulmonary inflammation. impact of free circulating mtdna on endothelial cell is not known. the main purpose of this study was to test whether mtdamps and mtdna can induce endothelial dysfunction. we also evaluated the role of mtdna-rage axis in mtdamps induced endothelial dysfunction. mitochondria were isolated from livers of wild type c b mice. isolated mitochondria were sonicated on ice to obtain mtdamp preparations. semi quantitative evaluation of mtdamp content was tested by qpcr, with specific markers of mtdna (cytochrome b (cytb), nadph oxidase (nd )). intraperitoneal injection of mg of mtdamps was used as experimental model in wild type and rage ko mice, as previously described [ ] . the mtdamps were also administrated after ex vivo dnase preparation. endothelial function was assessed with a mulvany-halpern style myograph, h after mtdamp administrations on aorta (conductive vessel) and on d division of mesenteric artery (resistive vessel). endothelial-dependent relaxation was studied by cumulative expositions of the vessels to acetylcholine ( . - - . - m). endothelial-independent relaxation was studied by sodium nitroprussiate exposition. results the mtdamps preparation contains a high quantity of mtdna with a /cycle threshold (ct) ratio of . for cytb expression. intraperitoneal administrations of mtdamps induced a decrease of endothelial-dependent relaxation mainly on conductive vessel (p = . , n = per group) and to a lesser extent on resistive vessel (p = . , n = per group). rage-ko mice were protected from mtdamps-induced aorta dysfunction (p = . , n = per group). the ex vivo exposition of mtdamps to a dnase preparation decreased mtdna content in mtdamps solution with a /ct ratio of . for cytb expression. eventually, the pretreatment of mtdamps with a dnase preparation prevented the mtdamps-induced aorta dysfunction (p = . , n = ). discussion more than prognostic markers, mtdamps particularly mtdna seems implicated in endothelial dysfunction in critically ill patient. new evidence suggest rage interaction in endosomal tlr pro-inflammatory and pro-oxidant response to mtdna [ ] . also in sepsis, physiological clearance of circulating dna might be impaired, this results comfort the possibility of therapeutic regulation of free circulating mtdna to prevent septic organ dysfunction related to mtdamps accumulations. conclusion exogenous mtdamps can induce endothelial dysfunction in mice. the mtdna-rage axis is a key component of the signaling pathway involved in this dysfunction. the use of dynamic parameters to assess fluid responsiveness was supported by cyclic changes in stroke volume induced by mechanical ventilation. however, these parameters have several limits. venous to arterial carbon dioxide difference inversely related to cardiac index. consequently, fluid administration would be beneficial if carbon dioxide gap increases. objective to investigate whether carbon dioxide gap predicts fluid responsiveness in patients with acute circulatory failure. patients and methods we conducted a prospective study in the medical intensive care unit of hospital taher sfar at mahdia, between march and april . patients with circulatory failure and who required mechanical ventilation were included. we measured the variation of cardiac index between baseline and after volume expansion of ml of saline fluid. the picco was used to measure cardiac index. response to fluid challenge was defined as a % increase in cardiac index. before and after fluid administration, we recorded carbon dioxide difference and hemodynamic parameters. results among included patients, ( %) were responders. the causes of acute circulatory failure were septic shock (n = ), cardiogenic shock (n = ), and hypovolemia (n = ). carbone dioxide gap was significantly higher in responders group ( ± vs ± mmhg, p = . ). the area under the roc curve for carbon dioxide gap was . ( % ci . - . ). the best cutoff value was mmhg (sensibility = %, specificity = %, positive predictive value = % and negative predictive value = %). the area under the roc curve for delta carbon dioxide was . ( % ci . - . ). conclusion in this study, baseline carbon dioxide gap was not universal indicator to predict the fluid responsiveness in patient with circulatory failure. introduction supraventricular arrhythmia (sva) is commun in intensive care unit (icu). its incidence seems to be higher in patients with sepstic shock. sepsis-associated myocardial dysfunction promote the occurrence of sva by constituting an arrythmogenic substrate or under the effect of inotropic drugs. the aim of this study is to assess the incidence and prognostic impact of sva in patients with septic shock. patients and methods we retrospectively studied all patients with new onset sva suffering from septic shock in non cardiac surgical icu. myocardial dysfunction was evaluated by transthoracic echography (tte) after an adequate cardiac resuscitation using intravenous fluids expansion and adjunctive vasoactive agents. sva was detected by the electrocardiogram scope. during the study period clinical and biologic characteristics, hemodynamic tolerance (vasopressors doses, arterial pressure changes), current treatment (such as corticoid), duration of mechanical ventilation, duration of vasopressor requirement and hospital mortality were collected. results sixty patients were included in the study. the sva occurred in patients, with an incidence of %. the median time to onset was days. cardioversion was performed for patients with an effectiveness of %. clinical and biological characteristics were similar between the groups with and without sva: saps and sofa score at the beginning of septic shock, the existence of ards and cardiac biomarkers (nt-probnp, troponin). however, renal failure and the use of corticoid in septic shock were more frequent in the group with sva. the maximum doses of vasopressor agent were not significantly different between the groups with or without sva. myocardial dysfunction in sepsis defined by the left ventricle ejection fraction (lvef) less than % (or the need for inotropic drug for lvef > %) was not associated with the occurrence of sva (+sva group: n = ; −sva group: n = ; p: . ). sva was poorly-tolerated, observed by a significant decrease in mean arterial pressure and a significant increase in norepinephrine doses within h of the start of sva. the occurrence of sva was associated with longer duration of use of vasopressor agent and a longer duration stay in icu (+sva group: days, −sva group: days; p = . ). there was no difference in duration of mechanical ventilation and hospital mortality between the two groups. conclusion the occurrence of sva is common in septic shock, poorly tolerated hemodynamically and associated with longer duration stay in the icu and vasopressor need. sepsis myocardial dysfunction isn't necessarily associated to the occurrence of sva. introduction a short term beneficial effect of prone position on cardiac index has been shown in % of ards patients, and was related to an increase in cardiac preload in preload responsive patients ( ) . the aim of this study was to evaluate the long term hemodynamic response to prone position in a larger series of ards patients. patients and methods single center retrospective observational study performed on ards patients hospitalized in a medical icu between july and march . patients included were adults fulfilling the berlin definition for ards, undergoing at least one prone position session, under hemodynamic monitoring by the picco ® device, with availability of hemodynamic measurements performed before (t ), at the end (t ), and after the prone position session (t ). prone position sessions were excluded if they were performed > days after ards onset. the following variables were recorded: demographic, sapsii, ards severity and risk factor, sofa score and cumulative fluid balance at pp onset, delay between ards session and pp session, hemodynamic, arterial blood gas, ventilatory settings, plateau pressure, catecholamine dose and additional treatments. statistical analyses were performed using prone position session as statistical unit and mixed models taking into account both multiple prone position sessions by patient and multiple measurements during a prone position session. p < . was chosen for statistical significance. data are expressed as mean ± standard deviation. results patients fulfilled the inclusion criteria over the study period, totalizing prone position sessions ( ± sessions per patient). patients' age was ± y, % were male, % fulfilled the criteria for severe ards, and sapsii at icu admission was ± . ards risk factors were pneumonia in ( %), aspiration pneumonia in ( %), and sepsis in ( %) patients. duration of prone position sessions was ± h. hemodynamic measurements were performed in pp ± h after pp session onset. at session onset, sofa score was ± , and cumulated fluid balance was . ± . l. vasopressor were used in %, inhaled nitric oxide in %, and neuromuscular blocking agents in % of the sessions. hemodynamic and respiratory parameters before, during and after the prone position sessions are reported in table . cardiac index increased by at least %, decreased by at least % or remained stable in ( %), ( %), and ( %) of the sessions, respectively. as compared to both other groups, pp sessions with significant increase in cardiac index had the following significant differences at t by univariate analysis: lower cardiac index, lower global end-diastolic volume, lower cardiac function index, and lower vasopressor dose. multivariate analysis is under investigation. conclusion prone position is associated with an increase in global end-diastolic volume, reversible after return in supine position that may explain the positive effect of pp on cardiac index observed in ¼ of the pp sessions. introduction make sure that our patient have a good circulatory condition is a daily challenge for the intensivist. one of the therapeutics is fluid and one of his purpose is to increase venous return and then cardiac output. in order to examine that, there are several tools as the transthoracic echocardiogram wich allows the visualisation and the study of the respiratory variability from the inferior vena cava (ivc). unfortunately there are some situations where the ivc visualisation is difficult (obesity, gut surgery, emphysema). the ivc is easily seen by a transhepatic ultrasound in her retrohepatic section. we make the hypothesis that the shape of the ivc could be predictive of fluid responsiveness. we have performed fluid challenge in patients under mechanical ventilation. the need for fluid therapy is the intensivist in charge decision. we performed a echocardiogram and we take two measures of the icv: major axis and minor axis, the icv is measured avec the sus hepatic vena. a elastometry index (ei) is determined which is the ratio of minor axis to minor axis. the fluid challenge is ml of isotonic saline then we perform a new echocardiogram. a tag is written on the patient to take the same ultrasound slice. we retain one increase of % of the cardiac index (ic) as a success of the filling. we exclude the presenting patients a right cardiac insufficiency, an arrhythmia and/or a htap. the statistical analysis is realized with the software r. results between august, and january, we included patients. the average age is of years ( - ), igs of ( - ), ejectionnal fraction of % - ) and the s wave tricuspid is ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . the causes of the filling were an oliguria ( %), a low blood pressure ( %), a low cardiac output ( %), a hyperlactatémia ( %) and an other cause in % of the cases. we find a positive correlation between the ei and the increase of the ic, also for the area of the vci and the respiratory variations of the vci (p . ) the other variables are not predictive (bp, e/e' , e/a). the data are summarized in the picture . roc curves has been established ( only % of the journals studied required authors to use stard. a high impact factor and the year of the study were the items associated with a better sqs the presence of a conflict of interest was associated with a lower sqs in univariate analysis. a higher impact factor (> ), was the only independent factors statistically significantly (p = . ) associated with higher sqs in a multivariate regression model. discussion our study showed that the sqs were very low. assessment of a study depends on quality of reporting. blindness and participant sampling are the cornerstone to evaluate such bias as spectrum, verification, review and selection bias of a study, and were unfortunately scarcely reported compared to existing data in diagnosis accuracy reporting. one of the limitation is the years sample of the study. we have planned to continue the analysis for a -year review starting just after the stard publication. conclusion our study showed that several items remain poorly reported. we recommend systematic use of stard criteria in the elaboration and reporting of future studies that evaluates the preload dependence. introduction neurological impairment, i.e. encephalopathy, is commonly observed in patients with decompensated cirrhosis and/or portosystemic shunts admitted in icu. often ascribed to high plasmatic levels of ammonia, encephalopathy could also be induced by drugs or infection, due to altered blood-brain barrier (bbb) permeability. this latter setting is often underdiagnosed and encephalopathy related to hyperammonemia (so called hepatic encephalopathy-he) being pointed out as the culpit of all neurological symptoms in cirrhotic patients. quinolones and betalactamins were recently found in the cerebrospinal fluid of he patients and it has been shown that the expression of efflux pumps, responsible for drugs passing through the bbb, was altered in animal models of he. the purpose of this study was to assess the incidence of neurological impairment, i.e. encephalopathy, in cirrhotic patients hospitalized in discussion overall, we reported a higher rate of lumbar puncture than those reporting in others studies concerning status epilepticus. furthermore the rate of % of pleocytosis directly linked to status epilepticus is slightly higher than in most studies. unfortunately we didn't realize a second lumbar puncture to assess the pleocytosis normalization during the days following the first lumbar puncture. the pathophysiological hypothesis of this phenomenon may be that prolonged/repeated seizures during status epilepticus would induce a blood-brain barrier dysfunction thereby favoring a cerebrospinal pleocytosis. conclusion in our study, % of status epilepticus without infectious or neoplastic origin had a cerebrospinal pleocytosis directly linked to status epilepticus. this pleocytosis was significantly associated with myoclonic seizures and blood leukocytosis. these data may help to interpretation of cerebrospinal fluid pleocytosis during status epilepticus. introduction neurological prognostication from cardiac arrest survivor is a current concern. eeg patterns and nse dosage are two important prognostic factors. nse threshold for prediction of poor outcome appear controversial, in part, because of variability in dosage timing and measurement techniques. synek score is routinely used in our center to classify comatose patients in post cardiac arrest. the aim of this study was to assess the prognostic value of nse and synek classification to predict poor neurological outcome. introduction traumatic brain injury (tbi) is a major public health problem. it is the leading cause of death and disability in young subjects. one of the principles of the tbi management is prevention of secondary cerebral insults including maintaining perfusion and cerebral oxygenation, control of intracranial pressure (icp). an increase in icp above mmhg is associated with poor outcome. cerebral hypoxia can occur with normal level of icp and cerebral perfusion pressure (cpp).monitoring of regional partial pressure of brain tissue oxygen (pbto ) is a safe and reliable method for measuring cerebral oxygenation. a retrospective single-center observational study was conducted between january and december , aimed to study the influence of pbto with severe tbi patients outcome at months through glasgow outcome scale (gos). the hourly values of icp, pbto and cpp were recovered on daily monitoring sheets. we compared two groups according to their gos. during the study period, patients underwent a monitoring icp and pbto . results the mean age was . ± . years. . % were men. the initial glasgow score was . ± . . the mean simplified acute physiology score (saps ii) was . ± . and injury severity score (iss) . ± . . at months, patients had died (gos ). forty patients had a good outcome: gos - (group ). sixteen patients had poor outcome: gos - (group ). in group , there are significantly more pbto hourly values below mmhg at day ( . ± . vs . ± , in group , p = . ); and more pbto hourly values greater than mmhg at day ( . ± . vs . ± . , p = . ). conclusion pbto less than mmhg or greater than mmhg at day is associated with poor outcome at months in the severe tbi. the pbto allows a more individual approach of monitored tbi. none. introduction organ donation in patients after a decision to withdraw life-supportive therapies (wlst) (maastricht condition: m ) have been performed in our hospital since may . we report here main characteristics of donors, data on m procedure and results on renal transplant recipients. patients and methods all potential donors were included in a survey from may to june , according to the french national m protocol defined by the french organ procurement agency (agence de la biomédecine:abm) [ ] .the demographical, clinical and biological characteristics of the donors, the different deadlines and times of the protocol and data of renal transplantation were collected and analyzed. results patients had inclusion criteria. patients were admitted in intensive care unit for cardiac arrest ( %), strokes ( %), traumatic brain injury ( %), ards ( %). of them, procedures ( %) were stopped ( refusals of organ donation, medical contra-indications discovered with additional exams, failure of vessel cannulation, deaths more than h after extubation). kidneys were harvested and transplantations performed ( renal cancer discovered during procurement surgery).the characteristics of the donors, deadlines of the protocol and transplant recipients are reported in the table . conclusion the french programm maastricht offered a new possibility of organ donation in our hospital. thanks to these donors, the number of renal grafts increases and the preliminary results on transplant recipients are encouraging in line with the preliminary report of the abm. nevertheless, it is necessary to follow the transplant recipients and extend the procedure to new centres. in this study, we found some relevant risk factors for microaspiration (age, low score at gcs) consistent with literature on the subject. patients with paralytic agents had less gam which may be due to higher peep, higher cuff pressure and less enteral nutrition because of the severity of the underlying diseases. conclusion this study did not show any increased risk of microaspiration in intubated copd patients, whatever stage of copd. introduction protected specimen brush (psb) is considered to be one of the standard methods for the diagnosis of ventilator-associated pneumonia (vap). to our knowledge, there is no study assessing effect of prior antibiotherapy on direct examination, bacteriological culture and concordance of direct microscopy and culture. patients and methods all consecutive episodes of suspected vap were retrospectively evaluated between january and december in a -bed intensive care unit. patient's characteristics and preexisting conditions were abstracted from the medical charts. after assessment of vap probability using the clinical pulmonary infection score (cpis), psb were performed in patients with a cpis of or more. based on antibiotic treatment in patients when bacteriological specimens were obtained, two groups were defined: no antibiotic group and antibiotic treatment started before psb group. two independent bacteriologists retrospectively reviewed direct examination and culture of psb to assess bacteriological concordance, defined as non-concordant when direct examination and culture were different, concordant when direct examination and culture were similar and partially concordant when either direct examination or culture were comparable but with other microorganisms lacking in one or the other method. results during this -months period, among mechanically ventilated patients, episodes of suspected vap with psb were evaluated. we found % of psb (n = ) performed without antibiotic treatment and % of psb (n = ) performed under antibiotherapy. we found no significant differences in patient's demographics, characteristics, and severity between both groups. patients received antibiotics for the following reasons: aspiration pneumonia (n = ), peritonitis (n = ), vap (n = ), community-acquired pneumonia (n = ), septic shock of unknown origin (n = ), pyelonephritis (n = ), meningitis (n = ), acute pancreatitis (n = ) and others (n = ). the median duration of mechanical ventilation in the antibiotic receiving group and in the group without antibiotics was . days (iqr; - days) and days (iqr: - ), respectively. when psb was performed under antibiotic treatment, direct examination was positive in % (n = ), culture was positive in % (n = ) and those methods were concordant, non concordant and partially concordant in % (n = ), % (n = ) and % (n = ), respectively. on the other hand, when psb was performed without antibiotics, direct examination was positive in % (n = ), culture was positive in % (n = ) and those methods were concordant, non concordant and partially concordant in % (n = ), % (n = ) and % (n = ), respectively. in univariate analysis, we found a significantly higher proportion of negative direct examination and negative culture in the antibiotic group (p > . ). moreover, these methods were significantly more frequently concordant (p = . ), with a higher rate of both negative microscopic exam and culture when compared to the no antibiotic group ( %, n = vs %, n = ). surprisingly, among the patients previously treated with antibiotics with positive culture, % (n = ) of the microorganisms showed antibiotics sensitivity. discussion whether prior antibiotic treatment may induce false negative of false positive treatment is a well-recognized phenomenon, the precise effect of antibiotics on direct examination and quantitative culture is not well assessed in vap. moreover, despite recent development of clinico-radiological score, diagnosis of vap remains difficult, with no gold-standard. therefore, bacteriological guided therapy is of particular importance. we found psb realization under antibiotic treatment is associated with a lower rate of positive direct examination and culture and suggest performing these bacteriological samples without antibiotherapy. some authors have suggested lowering the diagnostic threshold point of this bacteriological technique in order to preserve its accuracy. however, we can postulate that microorganisms responsible of superinfection in mechanically ventilated patients treated with antibiotics may be resistant and therefore the psb could be positive. conclusion in patients with a high pre-test probability of ventilatoracquired pneumonia, recent introduction of antibiotics significantly reduced the diagnostic accuracy of protected brush specimen by reducing rates of positive direct examination and culture. further studies should evaluate if antibiotic discontinuation may revert this effect. ann. intensive care , (suppl ): we have had non conflict of interest in this study. results we included patients in the phase and patients in the phase . baseline characteristics of patients were similar in both groups. compliance with all the measures has been improved between the two period from to . %. the incidence density decreased from . to . vap per ventilator days between observational and interventional period, but the all-cause mortality was almost equal in the groups ( . vs. %). discussion with the implementation of our bundle, observance of the team were improved in the second group, compared to the first and the incidence density decreased from . to . vap per ventilator days between both period. this result is consistent with the littérature. sure enough, many studies show the same effect of vap prevention with a decrease of nearly % of the incidence density of vap, after implementation of a «ventilator -bundle [ ] . conclusion the implementation of a "ventilator bundle, " has significantly reduced the incidence of vap in our service. in the contrary, our study failed to demonstrate a reduction in mortality. introduction with an increasing incidence and high mortality rates, sepsis is a public health issue. there is growing evidence that sepsis induces long lasting alterations of transcriptional programs through epigenetic mechanisms that may lead to protracted inflammation, organ failure, sepsis-induced immune suppression (siis), secondary infections and death. we hypothesized that epigenetic changes contribute to the pathophysiology of siis. to test this hypothesis, we studied the effects of histone deacetylases (hdac) inhibition with trichostatin a (tsa) in a double-hit murine model of siis and secondary pneumonia. materials and methods c bl/ mice were treated with tsa ( mg/ kg ip) or saline serum (ctl) min before induction of sepsis by cecal ligation and puncture (clp). surviving mice underwent intratracheal instillation of . × cfu of pseudomonas aeruginosa days after clp. we evaluated the effect of tsa on survival and cellular responses to the primary and secondary infections. cellular responses in the blood, spleen and bal were assessed by flow cytometry after clp (days , & ) and after pneumonia ( & h). we also studied lymphocyte apoptosis and dendritic cells (dc) expression of cd , cd , and mhcii. bacterial clearance was assessed in the bal and in the blood and h after pneumonia. continuous variables represented as mean ± sd were compared using student t test. kaplan-meier curves were compared by the log rank test. p < . indicated statistically significant differences. results whereas treatment with tsa did not change survival after clp, tsa improved survival after tracheal instillation of p. aeruginosa (p = . , fig. ). tsa-treated mice had significantly higher absolute dc, t and b-lymphocytes counts with reduced lymphocyte apoptosis after clp. four hours after secondary pneumonia, tsa-treated mice had significantly higher dc counts and improved bacterial clearance in the bal, with reduced systemic dissemination of p. aeruginosa. conclusion hdac inhibition with tsa improves survival in our murine model of secondary pneumonia, improves bacterial clearance and attenuate cellular features of siis. these results suggest that sepsisinduced epigenetic changes contribute to the advent of siis. comprehensive characterization of epigenetic changes associated with siis might allow us to identify new therapeutic targets to reprogram immune cells in sepsis and avoid siis. length of icu stay was ± days. patients acquired nis ( . % bsi, . % pneumonia, . % cri and . % uti. there was no bacteriological documentation of ni in . % of cases. nis occured days post burns. the most three isolated pathogens were: acinetobacter spp. ( %), p. aeruginosa ( . %) and extended spectrum betalactamase-producing enterobacteriaceae ( %). the most frequently administered antibiotics were polymyxin/carbapenem/teicoplanin combination ( %), polymyxin/carbapenem combination ( %) and carbapenem/tigecycline combination ( %). in our study, mortality rate was %. conclusion nosocomial infection occured in . % of cases in burn patients, caused by acinetobacter spp, p. aeruginosa and enterobacteriaceae blse. so, eradication of infection in burn patients require effective surveillance and infection control in order to reduce mortality rates, length of hospitalization and associated costs. introduction infection of the lower respiratory tract is the most common cause of infection in intensive care unit (icu) ( ) . although the attributable mortality of ventilator associated pneumonia remains debated, the recurrence of these infections is always associated with a significant morbidity ( ) . staphylococcus aureus methicillin-sensitive (sams) is one of the most frequently germs involved in icu pneumonia especially in trauma patients. the aim of the study was to establish the risk factors associated with microbiological treatment failure of pneumonia, caused by sams. materials and methods we retrospectively identified patients who developed a first episode of ventilator associated pneumonia caused by sams during a years-period ( - ). the primary end point was the microbiological treatment failure defined as a second episode of pneumonia caused by sams corresponding to either a persistent or a recurrence of the pneumonia (fig. ) . the primary aim of the study was to identify factors associated with a treatment failure, the secondary objective was to identify factors associated with the occurrence of second episode (i.e. persistent, recurrence, superinfection and/or relapse of pneumonia caused by any bacteria) during or after treatment of the first episode caused by sams. definition of outcomes was based after analysis of current concepts available in the literature. factors associated with primary and secondary objectives in univariate analysis (p-value < . ), or clinically relevant ones, were entered in a multivariate logistic regression. the final selection was performed using the stepwise selection based on the akaike criterion. results fifty-nine patients ( . %) developed a second episode of pneumonia and among them, ( . %) were considered as a microbiological failure. in a multivariate analysis, the association of oropharyngeal flora (fop) with the sams (or, . ; % ci, . - . ; p = . ) and the need of emergency surgery (or, . ; % ci, . - . ; p = . ) were predictive of a microbiological failure. empirical antibiotic therapy with amoxicillin-clavulanic acid (or, . ; % ci, . - . ; p = . ) and performing emergency surgery (or, . ; % ci, . - . ; p = . ) were predictors of a second episode of pneumonia caused by any bacteria. conclusion in this retrospective, monocentric study, the co presence of orophryngeal flora and the need of emergency surgery were associated with microbiological failure of pneumonia caused by sams in icu. introduction ventilator-associated pneumonia is a major iatrogenic problem since it is a cause of hospital morbidity, mortality and increase of health care costs. it has been studied many times, but data's revision is always necessary. our study aimed to describe epidemiology of ventilator-associated pneumonia and identify local causative pathogens. we carried out a prospective study in an intensive care unit. were included patients intubated for more than h, from april to may , and presenting signs of ventilator-associated pneumonia (fever, abundant and purulent secretion, increase of fio greater than . , signs on chest-x ray) with positive culture of endotracheal aspirate. were excluded patients with germ colonization. results a total of patients were ventilated for more than h. among them thirty-four patients aged of ± . years presented episodes of ventilator-associated pneumonia (that is . ± . episodes per patient). the mean sofa score was . ± . . the main reasons of mechanical ventilation were loss of consciousness secondary to poisoning ( %), respiratory distress ( %) and status epilepticus ( %). the mean duration of stay was . days with extremes at and days. the average time between hospitalization and suspicion of ventilator-associated pneumonia was . ± . days. the average value of the clinical pulmonary infection score at suspicion was ± . . the average time between recurrences was . days with extremes at and days. the culture of endotracheal aspirate identified two pathogens in %. it reveled acinetobacter baumanii in % in which % were imipenem resistant, pseudomonas aeroginosa in %, klebsielle pneumoniae in %, staphylococcus fig. see text for description aureus methicillin resistant in %. extended spectrum β-lactamases bacteria were found in % and carbapenemases producers in %. empirical antibiotherapy was always association of imipenem and colistin. it was necessary to adapt it to antibiograms in / . ventilator-associated pneumonia was complicated by septic shock in % and acute respiratory distress syndrome in %. patients evolved to healing in % of episodes (n = ), to superinfection in % (n = ) and to death in % (n = ). pseudomonas aeruginosa was the most frequent germ in superinfection ( / ) , acinétobacter baumanii was the most pathogen associated to death ( / ). conclusion ventilator-associated pneumonia is an iatrogenic disease that threatens lives. it's in part avoidable. preventive measures have to be implemented to reduce its frequency, consequences and costs. introduction during mechanical ventilation, mismatch between respiratory muscles activity and the assistance delivered by the ventilator results in dyspnea and asynchrony and is commonly observed in intensive care unit (icu) patients. proportional assisted ventilation (pav) is a ventilatory mode that adjusts the level of ventilator assistance to the activity of respiratory muscles estimated by an algorithm. to date, pav has been mostly studied in patients without severe dyspnea or asynchrony. we hypothesized that, compared to pressure support ventilation (psv), pav will prevent severe dyspnea or asynchrony. patients and methods were included icu mechanically ventilated patient exhibiting severe dyspnea or asynchrony with psv. three conditions were successively studied: ) psv on inclusion (baseline), ) psv after optimisation of ventilator settings in order to minimize dyspnoea and asynchrony (optimisation), and ) pav. ten-minutes recording were performed with each condition. the intensity of dyspnea was assessed by the visual analogic state (vas, only in patients able to communicate) and by the intensive care respiratory distress operating scale (ic-rdos) for all the patients. the electrical activity (emg) of extradiaphragmatic inspiratory muscles was measured. the fig. bayesian nma with random effect prevalence of asynchrony was quantified by the visual inspection of the airway flow and pressure traces. results patients were included, % male, aged [ - ] years, saps [ - ], mechanically ventilated for [ ] [ ] [ ] [ ] [ ] [ ] days. the tidal volume (tv) was higher in the optimisation and pav than in the basal condition (table ). the respiratory rate(rr) was lower with pav than in the other conditions. the dyspnea-vas was lower with optimisation and pav than with the basal conditions. the ic-rdos was lower with pav than with the two other conditions. the asynchrony index was lower with pav than with the two other conditions. parasternal emg activity was lower with pav and optimisation (fig. ) . conclusion in icu patients receiving mechanical ventilation with psv and exhibiting severe dyspnea or asynchrony, the optimisation of ventilator settings with psv and the pav mode decrease in the simiar way the severity of dyspnea and the prevalence of patient-ventilator asynchrony. introduction in spite of recent research and progress in weaning protocols, extubation failure still occurs in - % of patients and is associated with poor outcomes, with a mortality rate of - %. many risk factors for planned extubation failure have been suggested, including hypercapnia at end of spontaneous breathing trial (sbt). however, performing arterial blood gases at the end of sbt is not routinely recommended whereas etco may be routinely monitored during a low pressure support sbt. the aim of this prospective observational study was to determine the clinical usefulness of etco to predict extubation failure. patients and methods we recorded clinical data and etco during a successful h low level pressure support sbt (at the beginning, after min and at the end of the trial). patients ventilated through tracheostomy and unplanned extubations were excluded. extubation failure was defined as death or the need for reintubation within h ( ) after extubation; this delay was prolonged to days ( ) in case of noninvasive ventilation after extubation, which was systematic in older patients or those with cardiorespiratory disease, as per our weaning protocol. multivariable logistic regression analysis was performed to identify independent variables associated with extubation failure. results one hundred and fifteen ventilated patients were enrolled in our study from july to june . the median age of these patients was [ - ] years, their median simplified acute physiology score (saps) ii was [ - ] points and . % (n = ) were female. seventeen ( %) patients had chronic obstructive pulmonary disease. reintubation rate was % (n = ). etco at other time points as well as its changes during the sbt were also similar between groups. the three variables predicting extubation failure in the multivariable logistic regression model were a past medical history of cirrhosis, acute respiratory distress syndrome before weaning and lower minute ventilation at the end of sbt. conclusion etco during a successful sbt seems useless to predict outcome of extubation. introduction airway management in intensive care unit (icu) patients is challenging [ ] . "airway failure", defined as the inability to breathe without endotracheal tube, differs from "weaning failure", defined as the inability to breathe without an invasive mechanical ventilation. however, most of the studies assessing predictive factors of extubation failure did not separate airway from weaning failure. we aimed to describe incidence of extubation failure in critically ill patients, separating for the first time airway from weaning failure, in a prospective multicenter observational study. patients and methods a prospective, observational, multicenter study was conducted in french icus. all adult patients consecutively extubated in icu were included. an ethics committee approved the study design (code uf: , register: -a - ). the study was registered on clinicaltrials.gov (identifier no.nct ). clinical parameters were prospectively assessed before, during and after extubation procedure. extubation failure was defined as the need to reintubate less than h after extubation. extubation failure could be due to airway failure, weaning failure or mixed airway and weaning failure. results from december to may , intubation-procedures were studied in patients from centers. patients ( . %) were intubated twice. the median number of intubation-procedures included by center was . the flow chart of the study is shown in fig. . incidence of extubation failure was . % ( of intubation-procedures). incidence of airway failure, weaning failure and mixed failure were respectively . % ( of ), . % ( of ) and . % ( of ). conclusion extubation failure at h occurred in . % of the extubation procedures recorded, % due to airway failure, % to weaning failure and % to mixed airway and weaning failure. specific risk factors will be determined using this multicenter database. introduction acute on chronic liver failure (aclf) have been recently defined by an acute decompensation of a chronic liver disease associated to organ failure and a high mortality rate. few authors reported on the use of total plasma exchange (tpe) in patients with the current definition of aclf. the aim of this pilot study was to evaluate the efficiency and safety of tpe in critically ill cirrhotic patients admitted with aclf in the icu. patients and methods a prospective cohort of cirrhotic patients admitted to the icu between february and february . tpe was performed using a plasma filter (tpe , hospal ® ) on a cvvhdf machine (prismaflex ® , baxter ® ) connected to the patient with a femoral double lumen f catheter. the plasma volume exchanged per session was . - . of the total plasma volume. ratio and type of fluid replacement were % with % albumin solution followed by % with fresh frozen plasma. clinical and biological parameters, and the following scores meld, sofa, clif-sofa, clif-of and child pugh were evaluated prior, after tpe session and days distant of treatment. results seven male patients with a mean age of . ± . years comprised the study and had a total of tpe sessions. the etiology of cirrhosis was alcoholic (n = ) or post-hcv (n = ). the reasons of aclf were acute alcoholic hepatitis (n = ), variceal bleeding (n = ) and sepsis (n = ). prior to tpe, the mean scores of sofa, clif-sofa, clif-of, meld and child-pugh were respectively . , , . , . and c . . mean total bilirubin prior and after tpe sessions was reduced from . ± . µmol/l to . ± . µmol/l (reduction of . %; p = . e− ); at day , mean total bilirubin was still lower at ± µmol/l (p = . ). mean inr prior and after tpe improved from . ± . to . ± . (reduction of inr of . %, p = . e− ) and at day of treatment at ± . (reduction of %, p = . ). mean ggt levels reduced by . % (p = . ). mean platelet counts ( . ± . g/l) reduced by . % (p = ns). the probability of survival at , and days was . , . and . %. one patient was transplanted and still alive. tolerance during sessions was good similar to cvvhdf. two side effects related to the femoral catheter were observed (bacteremia and hemorrhagic shock post catheter ablation). conclusion this preliminary study of tpe in aclf showed a marked reduction of liver enzymes and improvement in coagulation parameters with a relative good safety. a specific caution should be undertaken regarding catheter related complications. tpe worth to be fig. flow chart of the free-rea study introduction extubation is a key moment for the patient on his way to recovery. extubation failure concerns - % of icu patients and is closely linked to nosocomial pneumonia. the practice concerning enteral feeding interruption at time of extubation has not been investigated. fasting before extubation may prevent aspiration and development of nosocomial pneumonia. thus, fasting and gastric content suctioning before extubation may be reasonably considered as a mean to reduce this burden. fasting before extubation may prevent aspiration and development of nosocomial pneumonia. thus, fasting and gastric content suctioning before extubation may be reasonably considered as a mean to reduce this burden. however, fasting, as recommended before elective general anesthesia is likely to be ineffective in the setting of extubation in the icu, due to patients' gastroparesis and prolonged gastric stasis. beyond the potentially unnecessary burden in terms of paramedical workload, fasting may have some side effects such as caloric deficit, hypoglycemia, or delayed extubation. given the current lack of objective data concerning the clinical practice of feeding/fasting and gastric tube suctioning before extubation in the icu, we undertook this descriptive study to assess current practice. materials and methods we conducted a retrospective, multicenter study in eleven intensive care units in the west of france over a month timespan. all patients extubated were included and data about enteral feeding during the peri-extubation period as well as extubation failure and nosocomial that pneumonia occured within days were recorded. data observed in the eleven participating centers were completed with a short email survey concerning declarative practice performed among intensive care units. results during the study period, patients were included. overall, patients ( %) failed extubation and needed reintubation within the days following planned extubation. pneumonia was significantly more frequent reintubated patients than the other ( vs. %, p < . ). hundred patients ( %) received enteral feeding at the time of extubation. compared to patients who did not receive enteral feeding, those patients had a higher disease severity (sapsii score , [ ; ] vs. [ ; ], p < . ; longer duration of mechanical ventilation [ ; ] vs. . [ ; ] days, p < . ). accordingly, those patients had a higher rate of extubation failure ( vs. %, p = . ) and pneumonia ( vs. %, p = . ). among the patients receiving enteral feeding, fasting was implemented before extubation for patients ( %). similarly, the incidence of pneumonia was not different between groups (n = ( %) vs. n = ( %), p = . ). after extubation, the fasting patients experienced a longer delay until feeding resumption as compared to non-fasting patients ( h [ ; ] vs. [ ; ] ), but this difference did not reach statistical significance. overall gastric content suctioning before extubation was not commonly performed; before extubation: % of the fasting patients and % of the non fasting patients. among the participating centers, while some centers imposed a fasting period before extubation to all their patients, some did it infrequently. however, no center never imposed fasting, illustrating between and within center heterogeneity. this heterogeneity was confirmed on the larger scale declarative email survey ( % response rate amont units) which showed that only % of the units had a written standardized operational procedure for extubation. survey respondents reported to practice fasting before extubation "always", "frequently" and "never or rarely" in respectively , and % of cases. conclusion both practices, fasting as well as pursued nutrition until extubation are commonly performed in icus, with little standardization of practice. safety seems equivalent, as no clinically significant difference in terms of reintubation rate and pneumonia were observed. thus, the equipoise condition appears met to undertake a trial evaluating feeding strategies in the peri-extubation period. introduction noninvasive ventilation (niv) has become a cornerstone for the supportive therapy of acute respiratory failure (arf). survival benefits in chronic obstructive pulmonary disease (copd) and cardiac patients have been demonstrated. although arf and copd patients are at risk of malnutrition that adversely affects patient outcomes, few data are available regarding the management of nutritional support in non-invasively ventilated patients. we sought to describe nutritional management in patients receiving niv as the first line therapy for arf. secondary objectives were to assess the impact of early nutrition use on the need for invasive mechanical ventilation, occurrence of icuacquired pneumonia, length of stay, and death. patients and methods we conducted an observational study from the multicenter french database fed by french icus. our institutional review board approved this study. adult medical patients admitted to the icu and receiving niv for more than days were included. exclusion criteria were patients admitted after surgery, readmitted in icu, patients with neuromuscular disease and treatment-limitation decisions on admission. four groups of patients were defined according to nutrition received during the first days of niv: ( ) no nutrition; ( ) enteral nutrition: patients who received enteral nutrition with or without parenteral nutrition; ( ) parenteral nutrition only ( ) oral nutrition only. the impact of nutrition on day- mortality was assessed through the use of a cox model adjusted on clinically relevant covariates. the impact of nutrition on other secondary end-point i.e. icu-acquired pneumonia occurrence, need for invasive mechanical ventilation were assessed using a fine & gray models. patients were censored after days of follow-up. choice among collinear variables was performed considering clinical relevance, rate of missing variables and reproducibility of definitions. results were given as hazard ratio (hr) for cox models and subdistribution hazard ratios (shr) and % confidence intervals (ci). the impact on duration of stay was estimated by a multivariate poisson regression. p values less than . were considered as significant. statistical analysis was performed using sas . (cary, nc). results during the study period, , patients were included in the database and met inclusion criteria. among them, received no nutrition; received enteral nutrition, received parenteral nutrition only, and received oral nutrition only. overall, patients developed icu-acquired pneumonia ( %), required invasive mechanical ventilation ( . %) and died before day- ( %). median length of stay was days [ ; ]. after adjustment for confounders, type of nutrition support was associated with an increase day- mortality (p = . ). compared to oral nutrition, enteral nutrition was associated with an increase day- mortality [shr . , % ci . - . ; p = . ] whereas parenteral nutrition and no nutrition did not influence this outcome. the type of nutrition was not associated with the occurrence of icu-acquired pneumonia (p = . ). however, patients who received enteral nutrition experienced more frequently icu-acquired pneumonia [shr = . , % ci . - . ; p = . ] as compared to oral nutrition patients. ventilator free days within the days were negatively associated with the type of nutrition (p < . ). compared to oral nutrition, parenteral and enteral nutrition were negatively associated with ventilator free days within the days [rr per day = . , % ci . - . ; p < . and rr per day = . , % ci . - . ; p < . ]. delta paco measured between the first days was not associated with any type of nutrition. conclusion more than half the patients receiving niv were fasting within the first two niv days. oral nutrition was prescribed for onethird of them and was well tolerated. lack of feeding or underfeeding had no impact on mortality and ventilator free days within the days. however, enteral nutrition was associated with an increased occurrence of icu-aquired pneumonia and a higher mortality rate. was high, caloric debt during temporary ecls was low in comparison with previous results [ ] . overnutrition was frequent in the nec group and would justify implementation of nutrition protocol. incidence of gi intolerance remains frequent and could justify systematic used of motility agents with introduction of en. conclusion enteral nutrition in patients treated with temporary extracorporeal life support is feasible and may be improve with systematic motility agents and implementation of nutritional protocol. introduction cardiac surgery with cardiopulmonary bypass (cpb) is associated with a generalized inflammatory response with concomitant immune paresis which predisposes to the development of postoperative infections and sepsis ( ) . lymphocytes are essential agents of innate and adaptive immune responses during infections or inflammation processes. lymphopenia has been associated with immune dysfunction during septic shock, and it has been shown that low absolute lymphocyte count was predictive of postoperative sepsis ( ) . furthermore, impaired lymphocyte function probably occurs after cpb. thus, we investigated mechanisms involved in postoperative lymphopenia and impaired lymphocyte function after cpb. the aims of this study were: ) to describe a potential relationship between lymphopenia and occurrence of postoperative infections. ) to demonstrate that cpb induces lymphocytes apoptosis. ) to demonstrate that cpb impaired lymphocyte function (ability to proliferate). ) to demonstrate that il- , pd-l (programmed cell death ligand ) and indoleamine , -dioxygenase (ido) could be interesting targets to restore lymphocyte ability to proliferate after cpb. patients and methods blood cell counts with differentials obtained within the first postoperative week were analyzed in patients undergoing cardiac surgery in . postoperative lymphopenia was defined as a lymphocyte count < . × cells l − . postoperative infections were defined following cdc criteria. study procedures: the following analysis were performed before (t ) and h after (t ) cardiac surgery with cpb: lymphocyte apoptosis; t-cell proliferation ability following polyclonal stimulation; hla-dr and pd-l expression on monocytes; plasma ido activity and il- levels; and the ability of lymphocytes to undergo a clonal proliferation when stimulated using specific inhibitors of il- and ido. the study was approved by our local ethics committee. patients were informed of the observational nature of the study and gave their consent. . early lymphopenia after cpb was associated with the occurrence of postoperative infection: postoperative infections occured with a median delay of days. patients who developed postoperative infections had a significantly lower lymphocyte count at day , day and day than patients without postoperative infections. . cpb induced lymphocyte apoptosis and decreased t-cell proliferation ability. . cpb during cardiac surgery decreased mhla-dr expression. . cpb increased ido activity, pd-l expression and il- plasma levels. . il- or pd-l inhibition of inhibition could restore ability of lymphocytes to proliferate, although ido inhibitors did not show any effect. we provided new evidences that cpb induces immunosuppression. we also demonstrated that il- and pd-l could be interesting targets to restore ability of lymphocytes to proliferate. as maintaining mv during cpb decreased plasmatic levels of il- , our study brings new evidences that ventilator strategies could be of interest to decrease postoperative infections. respectively . % (n = ), . % (n = ) and . % (n = ) of the included patients. mortality was of . % in the overall population (n = ) and was higher in neutropenic patients ( . vs. . % in non-neutropenic patients; p < . ). neutropenia was independently associated with poor outcome when adjusted for underlying malignancy, allogeneic stem cell transplantation and severity as assessed by organ support (or . ; % ci . - . ). mortality decreased progressively over time in both non-neutropenic (from to %; p < . ) and in neutropenic patients (from to %; p < . ). when adjusted for confounders, admission during a more recent period was independently associated with favourable outcome and did not change the final model. conclusion this preliminary analysis suggests a meaningful survival in neutropenic critically ill cancer patients despite an independent association between neutropenia and mortality. additional analyses are on-going in order to adjust for study weight, heterogeneity across studies, assess the influence of neutropenia duration or g-csf use, and confirm the influence of neutropenia in a predefined subgroup of patients. introduction candida bloodstream infections (cbi) are frequent and increasing in hospitalized patients, especially in intensive care units. considering the results of some experimental in vitro and animal studies, it seems that yeasts belonging to candida genus are able, so as to survive, to modulate the immune response of the host by guiding t cells polarization to th profile. th and th cytokines are known to be involved in host defense against cbi. however, these data are mainly experimental or collected after candidemia. the aim of this study is to precise kinetic of cytokines network during human cbi. this was an ancillary study of an institutional project dedicated to pathophysiology of candidiasis. we have included patients with candidemia and controls ( matched hospitalized controls and healthy subjects). the sera of cases were gathered before (almost days before), during and after the isolation of yeasts from blood culture, defined as day (d ). quantitative analysis of cytokines by luminex ® technology and of ( , )-β-d-glucans by fungitell ® test were performed on samples. the amplitude of th profile response was expressed by summing the amount of the most relevant cytokines for th , th and th profiles, in pg/ ml. for each patient, the highest level of response was considered as %. results are expressed for the population by means of the results. we then performed univariate analysis (fischer exact test for qualitative variables, mann-whitney and wilcoxon test for quantitative variables, spearman for correlation; graphpad prism v software) and a multidimensional analysis by principal component analysis (pca; igorpro software). results patients with candidemia exhibited an increase in proinflammatory cytokines (ifnγ, tnfα and il- ), in comparison with the anti-inflammatory cytokines (il- and il- ) before d (p = . ) in univariate analysis. the ratio between mean values reverses at d and d (p = . ) and the increase of th response level from d to d is correlated to the decrease of th response (r = − . ; p = . ) in univariate analysis and pca. a pro-inflammatory response (th ) is associated with a reduced mortality (rr = . [ . ; . ]) and with a lower β-d-glucans levels (p < . ). discussion we describe here a dynamic cytokine profiles in response to candidemia. pro-inflammatory response predominates before d and reverses after. this is contradictory to the postulate that an antiinflammatory background could predispose to invasive candidiasis in icu patients and exhibiting a "post-infectious immune suppression conditions". but the relative deficiency in th response compared to simultaneous anti-inflammatory cytokines secretion observed after cbi is in accordance with experimental data, suggesting the modulation of the immune response by candida. the link between cytokinic profile and mortality can also raise the hypothesis of an influence by genetic factors on the regulation and direction of the immune response and so, the existence of a high-risk population. conclusion these data suggest a relation between candida and the orientation of the immune response towards a pattern deleterious for the infected host. this could allow to determine the most relevant cytokines varying during cbi. they could be used as biomarkers to identify the patients who could benefit from an early treatment in a preemptive targeted therapeutic strategy. these data will be paralleled to genetic background and to circulating candida derived molecules to precise the relative part of the host and the pathogen in this complex interaction. introduction lung ultrasound is widely used in intensive care, ermergency and pneumology medicine, for assessing acute respiratory pathologies. it is noninvasive, radiation free and rapidly available at the patient's bedside and provides an excellent accuracy. so, lung ultrasound may be an interesting tool for the physiotherapist as it allows to assess with more accuracy the patient improving the chest physiotherapy indication and monitoring ( ) . as far as we are aware, no study has evaluated the impact of lung ultrasound on clinical-decision making by physiotherapists in the use of chest physiotherapy. this case report highlights the lung ultrasound interest in chest physiotherapy in patient with lung consolidation. patients and methods this was a case report written following the recommendations of the care guideline ( ). the case was a -years-old female patient, non intubated, hospitalized in a respiratory icu. she was hypoxemic (pao = mmhg and sao = %), with dyspnoea at rest and an increasing radiological opacity at the right lung base. hypoxemia was the indication for physiotherapist referral. at the clinical examination, the physiotherapist's findings were: decreased mobility, dullness and abolished vesicular sound at the base of right hemithorax. this clinical examination and chest x-rays analysis allowed the physiotherapist to propose several clinical hypotheses: pleural effusion, obstructive atelectasis or pneumonia. the chest physiotherapy treatment differs according to the type of lung deficiencies. for example, the physiotherapist must to refer the patient to the medical staff in case of pleural effusion or may implement hyperinflation technique in case of obstructive atelectasis. determining the nature of lung deficiencies is essential to provide the more suitable therapeutic strategy. so, the physiotherapist decided to perform a lung ultrasound examination to retain the more likely hypothesis. results ultrasound examination performed by the physiotherapist highlighted the presence of a lung consolidation at the infero-lateral and posterior parts of the right lung with a pneumonia pattern: presence of tissue-like sign, shred sign, dynamic air bronchogram and fluid bronchogram. the medical staff implemented antibiotic treatment. the ultrasound findings guided the physiotherapist to choose chest physiotherapy technique improving the alveolar recruitment: nearly prone position (left side down) and continuous positive airway pressure during min. the patient response to the treatment was monitored by ultrasound and showed a decrease of the lung consolidation size and apparition of b lines, meaning a gain of lung aeration. these findings were associated with spo improvement but without decrease of dyspnoea. discussion lung ultrasound allowed the physiotherapist to precise the nature of the radiological lung opacity. as it is more accurate than clinical examination or chest x-ray, this suggests a more suitable choice of chest physiotherapy techniques than conventional clinical decision-making process. ultrasound findings suggested a positive response to the chest physiotherapy treatment. the apparition of re-aeration signs (b lines, decreased consolidation size) showed a short-term efficacy of the chest physiotherapy treatment. this allowed the physiotherapist to continue the treatment during week and obtain a substantial clinical improvement. conclusion the use of lung ultrasound in the clinical decision-making process may help the physiotherapist to choose with more accuracy the therapeutic strategy. moreover, it allows to monitor the treatment in real-time and assess the patient's response. the use of this tool may allow the physiotherapist to determine the optimal indications for chest physiotherapy and thus avoid unnecessary or inappropriate treatments. introduction critical illness together with immobilization have deleterious effects on patients outcome, especially in the presence of sepsis. increased muscle catabolism and membrane inexcitability reduce muscular mass and impair function within the first days after sepsis onset ( ). early mobilization could potentially limit muscle wasting and functional impairment in this population. the purpose of this study was to test whether exercise during the early phase of sepsis is safe and beneficial and to which extent it can limit skeletal muscle protein catabolism and preserve function. patients and methods adult patients admitted with the diagnosis of severe sepsis were included and randomly allocated to two groups; ) control group (ctrl-g): manual passive/active manual mobilization twice a day or ) experimental group (exp-g): additional two times min of passive/active cycling exercise. both groups benefited from a reduced sedation, adjusted nutritional intake and bed to chair transfer as soon as possible. skeletal muscle biopsy and electrophysiological testing were realized at day- and day- . muscle histology, biochemical and molecular analyses of anabolic/catabolic and inflammatory signalling pathways were performed. a group of four healthy subjects was used to obtain non pathological values. hemodynamic parameters and patients perception were collected during each session. results twenty-one patients were included, however died before the second muscle biopsy. ten patients in ctrl-g and nine in exp-g were finally analysed. muscle fibre cross sectional area (µm ) was significantly preserved by exercise (relative changes were ctrl-g: − ± % vs exp-g: ± %, p = . ). markers of catabolic systems were highly increased during sepsis compared to healthy subjects and reduced in both groups days after admission. however the reduction in mrna (relative change) tended to be more important in exp-g: murf- (ctrl-g: − ± % vs exp-g: − ± %, p = . ), mafbx (ctrl-g: − ± % vs exp-g: − ± %, p = . ), lc b (ctrl-g: ± % vs exp-g: − ± %, p = . ) and bnip (ctrl-g: ± % vs exp-g: − ± %, p = . ). anabolic and inflammatory markers were not affected by exercise. electrophysiological testing, including direct muscular stimulation, was abnormal on day- in of evaluated patients. since only a limited number of patients could be reassessed a second time, comparison between groups was not possible. in general, all activities were well tolerated by patients with no adverse events. the pulmonary auscultation is used by respiratory therapist (rt) to evaluate the efficiency of a treatment. listen to the noises coming from the primary bronchi (pb) is important because it is the place where secretions can be accumulated. therefore, it is crucial to know exactly where to place the stethoscope's chestpiece on the chest. few studies have analyzed the chest area where the pb were located. our hypothesis is that pb are localized on a line that joins axillary fossa (bi-axillary line: bal). the aim of our study is to evaluate the probability to find the primary bronchi by analysis of chest radiography. patients and methods a retrospective study was performed by analysis of chest x-ray using the software: tm reception ® , which allows precise measures to the tenth of millimeter. all the x-rays were made on confined to bed patients hospitalized within intensive care unit, internal medicine and abdominal surgery rooms. the following measures (in mm) were made between: the exclusion criteria were: bmi < . kg/m and bmi > kg/m , scoliosis, minor patient, lack of visibility of one of the axillary fossa, lack of visibility of pb, clavicular asymmetry, kyphosis, lack of symmetry in the shot, atelectasis and pneumothorax. statistics: normality test: ks. mean values are expressed with their sd and % ci. discussion in this study, we performed analysis of chest x-rays of bedridden patients and we demonstrated that it is possible to localize easily, on either side of the bs, the right and left pb at ± mm distance (lp) above a line joining axillary fossa. this study constitutes a new tool for the rt who, by using stethoscope with a chestpiece of cm surface area, will be able to listen to noise coming from pb. conclusion the data presented herein (fig. ) show that right and left pb are located at a mean distance of (± ) mm and (± ) mm above the bal, on both sides of the bs. the bal represents thus an easy and precise mode to detect right and left pb by bedridden. finally, the distance between the hyoid bone and the sc is about cm. as the pb are located after the bifurcation, this information constitutes another useful way for the localization the right and left pb by bedridden patient. introduction critically ill patients frequently develop muscle weakness, which is associated with prolonged intensive care unit and hospital stay ( ). this randomized controlled trial (clinical trials nct ) was designed to investigate whether a daily training session using a tilt table, started early in stable critically ill patients with an expected prolonged icu stay, could improve strength at icu and hospital discharge compared to a standard physiotherapy program. the study protocol was approved by an ethics committee and informed consent was obtained from all patients. patients admitted in adult icu of marie lannelongue hospital, france, who were mechanically ventilated for at least days were included. exclusion criteria were cerebral or spinal injury, pelvic or lower limb fracture. patients were assessed each day for temporary contraindications for mobilization out of bed (rass score <− or > ; hemodynamic instability; a continuous intravenous dose of epinephrine/ . no significant difference was observed in terms of mrc score or in terms of pts with or without weakness (mrc > ) at icu or hospital discharge. however, the number of pts with weakness was significantly higher in the group before tilt mobilization, suggesting a more rapid improvement in the tilt group. the icu and hospital lengths of stay were not different between groups. discussion the prevalence of muscle weakness in our population is high before mobilization ( . %, % ci . - . ), is still . % at icu discharge but represents only ~ % at hospital discharge. this low hospital discharge prevalence is probably related to the early and intense physiotherapy in both groups, which may explain our inability to demonstrate superiority of the addition of tilt table positioning, although a faster recovery is suggested. conclusion training sessions using a tilt table, in addition to early and intense physiotherapy did not improve muscle strength evaluated using mrc score in surgical icu patients with muscle weakness. proposed modifications to the duke criteria for the diagnosis of infective endocarditis quantifying the relationship between staphylococcus aureus bacteremia and s. aureus bacteriuria: a retrospective analysis in a tertiary care hospital recommandations formalisées d'experts «prise en charge des infections intra-abdominales strategies to reduce curative antibiotic therapy in intensive care units (adult and paediatric) risk factors for developing esbl e. coli: can clinicians predict infection in patients with prior colonization? kdigo clinical practice guideline for acute kidney injury citrate anticoagulation for continuous venovenous hemofiltration benefits and risks of furosemide in acute kidney injury national nosocomial infections surveillance (nnis) system report, data summary from prospective evaluation of the risk factors, etiology and the antimicrobial susceptibilities of the isolates in nosocomial bacteriemic patients unrecognized endobronchial intubation of emergency patients endobronchial intubation detected by insertion depth of endotracheal tube, bilateral auscultation, or observation of chest movements: randomised trial nosocomial infections in a burn intensive care unit outcomes of critically ill cancer patients in a university hospital setting outcome and prognostic factors of lung cancer patients admitted to the medical intensive care unit intensive care of the cancer patient: recent achievements and remaining challenges chronic critical illness the epidemiology of chronic critical illness in the united states designing and conducting a cluster-randomized trial of icu admission for the elderly patients: the ice-cub study estimation de la mortalité maternelle en france: une nouvelle méthode emergency postpartum hys-terectomy for uncontrolled postpartum bleeding music interventions for mechanically ventilated patients effets de la musicothérapie en réanimation hors sédation chez des patients en cours de sevrage ventilatoire versus des patients non ventilés. annales françaises d' anesthésie et de réanimation evaluation of a low-flow oxygen-conserving nasal cannula performance of six types of oxygen delivery devices at varying respiratory rates high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure international study of the prevalence and outcomes of infection in intensive care units medical intensive care urinary and serum biomarkers for the diagnosis of acute kidney injury: an in-depth review of the literature diagnostic strategies for renal impairment in the intensive care unit recommendations formalized expert acute renal failure in the perioperative and intensive care (excluding extrarenal purification techniques) frutos-vivar f. comparison of the berlin definition for acute respiratory distress syndrome with autopsy the presence of diffuse alveolar damage on open lung biopsy is associated with mortality in patients with acute respiratory distress syndrome: a systematic review and meta-analysis ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome alveolar macrophages contribute to alveolar barrier dysfunction in ventilator-induced lung injury references . akoumianaki e. mechanical ventilation-induced reverse-triggered breaths: a frequently unrecognized form of neuromechanical coupling neuromuscular blockers in early acute respiratory distress syndrome driving pressure and survival in the acute respiratory distress syndrome mortality and pulmonary mechanics in relation to respiratory system and transpulmonary driving pressures in ards organ donation, reasons for family refusal: a retrospective study in a french organ harvesting center - du avril relative aux droits des malades et à la fin de vie comité consultatif national d'ethique c. fin de vie, autonomie de la personne, volonté de mourir reliability, validity, and health issues arising from questionnaires used to measure psychosocial and organizational work factors (powfs) among hospital nurses: a critical review aging and death signalling in mature red cells: from basic science to transfusion practice most reliable indices in differentiation between thalassemia trait and iron deficiency anemia stratification du risque dans l'embolie pulmonaire aiguë.realites cardiologiques • n° -cahier • septembre european resuscitation council guidelines for resuscitation : section . executive summary breakthrough in cardiac arrest: reports from the th paris international conference changing use of noninvasive ventilation in critically ill patients: trends over years in francophone countries noninvasive mechanical ventilation in acute respiratory failure: trends in use and outcomes high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure failure of noninvasive ventilation for de novo acute hypoxemic respiratory failure: role of tidal volume réanimation médicale polyvalente, hôpital de la source early identification of patients at risk for difficult intubation in the intensive care unit: development and validation of the macocha score in a multicenter cohort study clinical practice and risk factors for immediate complications of endotracheal intubation in the intensive care unit: a prospective, multiple-center study profound and persistent decrease of circulating dendritic cells is associated with icu-acquired infection in patients with septic shock intensive care med specific mait cell behaviour among innate-like t lymphocytes in critically ill patients with severe infections a -level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin prognostic value of relative adrenal insufficiency during cardiogenic shock: a prospective cohort study with long-term follow-up. shock calcium supplementation during sepsis exacerbates organ failure and mortality via calcium/calmodulin-dependent protein kinase signaling hypocalcemia in critically ill patients diabetic ketoacidosis traps joint british diabetes societies guideline for the management of diabetic ketoacidosis peter radermacher , for the hyper s investigators and reva research network réanimation médicale, hôpital henri mondor réanimation medico-chirurgicale, hopital avicenne institut für anästhesiologische pathophysiologie und verfahrensentwicklung département de réanimation médicale et de médecine hyperbare, c.h.u. d' angers, angers, france; service de réanimation médico-chirurgicale réanimation médico-chirurgicale, assistance publique -hôpitaux de paris, hôpital ambroise paré, boulogne-billancourt, france; service de réanimation adulte quantitative measurement of heparin in comparison with conventional anticoagulation monitoring and the risk of thrombotic events in adults on extracorporeal membrane oxygenation elso guidelines for cardiopulmonary extracorporeal life support, version . . ann arbor: extracorporeal life support organization early and late outcomes of consecutive adult patients treated with extracorporeal membrane oxygenation for refractory postcardiotomy cardiogenic shock the french sf- health survey: translation, cultural adaptation and preliminary psychometric evaluation weaning of extracorporeal membrane oxygenation using continuous hemodynamic transesophageal echocardiography predictors of successful extracorporeal membrane oxygenation weaning after assistance for refractory cardiogenic shock extracorporeal membrane oxygenation in the adult: a review of anticoagulation monitoring and transfusion back from irreversibility: extracorporeal life support for prolonged cardiac arrest microcirculatory perfusion is preserved during off-pump but not on-pump cardiac surgery extracorporeal membrane oxygenation causes loss of intestinal epithelial barrier in the newborn piglet the pulsatile perfusion debate in cardiac surgery: answers from the microcirculation? a meta-analysis of complications and mortality of extracorporeal membrane oxygenation impact of fluid balance on outcome of adult patients treated with extracorporeal membrane oxygenation cumulative fluid balance and mortality in septic patients with or without acute kidney injury and chronic kidney disease comparison of two fluid-management strategies in acute lung injury renal function and survival in patients undergoing ecmo therapy extracorporeal membrane oxygenation and the kidney plasma concentrations of inflammatory cytokines rise rapidly during ecmo-related sirs due to the release of preformed stores in the intestine in-hospital mortality and successful weaning from venoarterial extracorporeal membrane oxygenation: analysis of patients using a national inpatient database in japan is the . % rate of in-hospital mortality in patients receiving venoarterial extracorporeal membrane oxygenation really that high? predicting survival after ecmo for refractory cardiogenic shock: the survival after veno-arterial-ecmo (save)-score outcomes and long-term quality-of-life of patients supported by extracorporeal membrane oxygenation for refractory cardiogenic shock usefulness of cardiac biomarkers to predict cardiac recovery in patients on extracorporeal membrane oxygenation support for refractory cardiogenic shock etiology of troponin elevation in critically ill patients esc guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the european society of cardiology (esc) accf/aha guideline for the management of heart failure: a report of the american college of cardiology foundation/american heart association task force on practice guidelines nearhanging injuries: a -year experience unité de réanimation neurologique s rapid diagnosis of bacterial meningitis using a point-of-care glucometer geoffroy rousseau service d'information médicale, epidémiologie et economie de la santé guillain-barré syndrome outbreak associated with zika virus infection in french polynesia: a case-control study early predictors of mechanical ventilation in guillain-barré syndrome paediatric prolonged mechanical ventilation: considerations for definitional criteria cardiac filling volumes versus pressures for predicting fluid responsiveness after cardiovascular surgery: the role of systolic cardiac function respiratory variation in aortic blood flow peak velocity to predict fluid responsiveness in mechanically ventilated children: a systematic review and meta-analysis. pediatr anesth effect of prone and supine positions on functional residual capacity, oxygenation, and respiratory mechanics in ventilated infants and children positioning effects on lung function and breathing pattern in premature newborns l'accident vasculaire ischémique en pédiatrie. quand y penser -quoi faire outcomes of early decompressive craniectomy versus conventional medical management after severe traumatic brain injury: a systematic review and meta-analysis myocardial dysfunction evaluation in pediatric brain death donor service de régulation et d'appui, agence biomedecine prone position for acute respiratory failure in adults prone positioning in severe acute respiratory distress syndrome effects of the prone position on respiratory mechanics and gas exchange during acute lung injury does prone positioning increase intracranial pressure? a retrospective analysis of patients with acute brain injury and acute respiratory failure prone position in mechanically ventilated patients with reduced intracranial compliance maud loiselle -maud.loiselle@outlook.fr annals of intensive care boulogne-billancourt, france; réanimation polyvalente adulte, centre hospitalier intercommunal andré grégoire, montreuil, france; réanimation médicale an audit of intensive care unit recyclable waste s point of care ultrasonography: is there a place for pocket size ultrasonography devices? gabriel preda , vincent dubée , naïke bigé eric maury -ejhmaury@gmail.com annals of intensive care outcome, functional autonomy, and quality of life of elderly patients with a long-term intensive care unit stay berlin: springler; . s icu nurses' perception of end-of-life decision making: a french multicenter survey akli chermak , alexandre lautrette ap-hp) anesthésie réanimation et traitement chirurgical des grands brûlés réanimation médicale hôpital d'instruction des armées percy correspondence: fanny.ardisson@gmail.com (fanny ardisson) annals of intensive care circulating mitochondrial damps cause inflammatory responses to injury rage is a nucleic acid receptor that promotes inflammatory responses to dna beneficial hemodynamic effects of prone positioning in patients with acute respiratory distress syndrome stard : an updated list of essential items for reporting diagnostic accuracy studies towards complete and accurate reporting of studies of diagnostic accuracy: the stard initiative s neurological impairment in cirrhotic patients admitted to icu: hepatic versus drug-induced encephalopathy unité de soins intensifs d'hépatogastroentérologie réanimation polyvalente, hôpital de mercy, ars laquenexy, france; réanimation médicale, centre hospitalier universitaire d' angers, angers, france; réanimation médicale cerebrospinal fluid findings after epileptic seizures effect of epileptic seizures on the cerebrospinal fluid-a systematic retrospective analysis s synek score and nse to predict poor neurological outcome after cerebral anoxia and therapeutic hypothermia réanimation médicale correspondence: dimitri titeca beauport -titeca.dimitri@chu-amiens.fr annals of intensive care guidelines for the management of severe traumatic brain injury. vi. indications for intracranial pressure monitoring reduced mortality rate in patients with severe traumatic brain injury treated with brain tissue oxygen monitoring s organ procurement and kidney transplantation under maastricht condition (m ): update on year of activity coordination prélèvements organes s reference . conditions à respecter pour réaliser des prélèvements d'organes sur les donneurs décédés après arrêt circulatoire de la catégorie iii de maastricht dans un établissement de santé. agence de la biomédecine. version n° mai crcl by cockroft-gault, mean (ml/mn delayed graft function, n (%) ( . %) réanimation médico-chirurgicale infectious diseases society of america. guidelines for the management of adults with hospital acquired, ventilator-associated, and healthcare-associated pneumonia reducing ventilator-associated pneumonia in intensive care: impact of implementing a care bundle chiche@aphp.fr annals of intensive care national nosocomial infections surveillance system. national nosocomial infections surveillance (nnis) system report, data summary from critères d'infection chez les brulés unité d'épidémiologie et recherche clinique international study of the prevalence and outcomes of infection in intensive care units risk and prognostic factors of ventilator-associated pneumonia in trauma patients ventilator-associated pneumonia: never enough, never give up! sahar habacha , bassem chatbri , aymen m'rad , youssef blel , nozha brahmi sahar habacha -sahar.habacha@gmail.com annals of intensive care weaning patients from the ventilator automated versus non-automated weaning for reducing the duration of mechanical ventilation for critically ill adults and children: a cochrane systematic review and meta-analysis unité de réanimation et de surveillance continue, service de pneumologie et réanimation médicale noninvasive ventilation and weaning in patients with chronic hypercapnic respiratory failure: a randomized multicenter trial risk factors for extubation failure in patients following a successful spontaneous breathing trial s a multicenter prospective observational study of extubation procedures in intensive care units: the free-rea study audrey de jong -audreydejong@hotmail.fr annals of intensive care early identification of patients at risk for difficult intubation in the intensive care unit: development and validation of the macocha score in a multicenter cohort study faouzi saliba -faouzi.saliba@pbr.aphp.fr annals of intensive care réanimation médicale polyvalente, hôpital de la source mickael landais -mickaelandais@gmail.com annals of intensive care perioperative fasting in adults and children: guidelines from the european society of anaesthesiology the decision to extubate in the intensive care unit service de réanimation médicale s refeeding hypophosphoremia in a medical critical care unit: -month observational study gioia gastaldi -gioia.gastaldi@chu-rouen.fr annals of intensive care refeeding hypophosphatemia in critically ill patients in an intensive care unit. a prospective study refeeding syndrome: problems with definition and management biosit and inserm u , faculte de medecine, université rennes immune dysfunction after cardiac surgery with cardiopulmonary bypass: beneficial effects of maintaining mechanical ventilation s influence of neutropenia on mortality of critically ill cancer patients: results of a systematic review on individual data quentin georges brazil; department of critical care medicine and division of pulmonary and critical care medicine united kingdom; department of intensive care centre d'infection et d'immunité de lille equipe -basic and clinical immunity of parasitic di delta nlr") were calculated. statistical analysis used appropriate non parametric tests and cox regression for survival analysis. the ability of the variables to discriminate survivors from non-survivors was determined using roc curves results during the study period, cirrhotic patients were admitted in icu. the etiologies of liver cirrhosis were alcoholic in % of cases with severe score: median child-pugh score = %) deaths after icu discharge during the same hospitalization. nlr decreased for survivors between d and d univariate analysis, for predicting survival, higher values of nlrd , delta nlr, meld score at admission, sofa score at admission and at day and delta sofad -d were significant factors. predictors of death in multivariate analysis are shown in fig. . area under delta nlr roc conclusion the blood nlr is a novel inflammation index that has been shown to independently predict poor clinical outcomes. we have demonstrated that delta nlr is an independent predictor of mortality in critically ill cirrhotic patients the association between the neutrophil-to-lymphocyte ratio and mortality in critical illness: an observational cohort study gene-and exon-expression profiling reveals an extensive lps-induced response in immune cells in patients with cirrhosis celine dupre -duprecece@gmail.com annals of intensive care diagnostic accuracy of procalcitonin in critically ill immunocompromised patients the role of pattern-recognition receptors in innate immunity: update on toll-like receptors esm- is a novel human endothelial cell specific molecule expressed in lung and regulated by cytokines thoracic ultrasound: potential new tool for physiotherapists in respiratory management. a narrative review the care guidelines: consensus-based clinical case reporting guideline development department of physical medicine and rehabilitation icu-acquired weakness and recovery from critical illness o where should we place the stethoscope's chestpiece to hear the noise of the primary bronchi? frédéric duprez , bastien dupuis , grégory cuvelier , thierry bonus frédéric duprez -dtamedical@hotmail.com annals of intensive care o aerosol delivery using two nebulizers through high flow nasal cannula: a randomized cross-over spect-ct study correspondence: jonathan dugernier -jonathan.dugernier@uclouvain.be annals of intensive care introduction in , an international consensus conference took stock of the various measures to be implemented for the prevention of ventilator acquired pneumonia (vap) [ ]. these measures are often gathered in groups of or under the term of "ventilator-bundle. " the effectiveness of these "bundles" was poorly evaluated in african environment. objective to establish a vap prevention program and assess its impact on morbidity and mortality of patients under mechanical ventilation in our service. patients and methods prospective, mono centric, quasi-experimental before-after study. it took place in the intensive care unit of the university clinics of kinshasa in the democratic republic of congo (drc). this service is equipped with beds and a respirator for two beds. the observational period (phase ) was carried out from february st to december st, and the intervention period (phase ) from february st, to february st, . all consecutive patients intubated and mechanically ventilated for more than h were included. five preventive measures were held: hand hygiene, the elevation of the head of the bed at °- °, the daily lifting of sedation, oral decontamination with chlorhexidine and control cuff pressure of the endotracheal tube. compliance with this bundle was assessed by direct observation without the knowledge of caregivers. the diagnosis of "vap" was held before a clinically modified sore (m cpis) > . the main outcomes were the incidence of vap and mortality. the protocol for this study was approved by the ethics committee of the school of public health of the university of kinshasa, under the approval number: esp/ec/ / .introduction nosocomial infections (ni) are common in burn patients due to the loss of the first line of defense against microbial invasion, immunocompromising effects of burn injury, and invasive diagnostic and therapeutic procedures. the objective of this study was to identify the incidence of nosocomial infection (ni), the pathogens and their antibacterial patterns, and prognosis of these burn patients. patients and methods a retrospective study was conducted in a bed intensive burn care unit during months. patients were eligible for the study, if they met the following criteria: total burn surface area (tbsa) > %, length of icu stay ≥ h, and infected in accordance with the criteria of the national nosocomial infections surveillance (nnis) and the criteria of the sfetb [ ][ ]. in this study, nis were classified into four main groups: pneumonias, bloodstream infections (bsi), catheter related infections (cri), and urinary tract infections (uti). for included patients, skin levy, blood cultures, urine and sputum cultures were drawn during fever or clinical features of sepsis. results during the -month study period, patients were admitted to the icu, patients were included ( . %). were male and female. the mean age was ± yr. the mean tbsa was ± %. % were admitted from another hospital. burn injuries were due to domestic accidents in % and self immolation in %. the mean none. none. none. none. none. none. none. none. none. none. ann. intensive care , (suppl ): none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. consulting activities with fisher & paykel. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. failure extubation in intensive care unit: risk factors, incidence and evaluation of a mechanical ventilator weaning protocol lucie petitdemange , anne sophie guilbert none. none. none. none. none. none. opportunistic infections in patients with solid tumors: a systematic review julien poujade , elie azoulay none. invasive aspergillosis in non-immunocompromised patients hospitalized intensive care unit guillaume trumpff , max guillot , thierry braun , ralf janssen-langenstein , marie-line harlay , jean-etienne herbrecht introduction characteristics and outcomes of adult patients with invasive aspergillosis in intensive care unit have rarely been described. we performed a retrospective study on consecutive adult patients with invasive aspergillosis who were admitted form january through january to the intensive none. noorah zaid , nawel ait-ammar , christine bonnal , jean-claude merle , francoise botterel , eric levesque anesthesia and intensive care medicine, chu henri mondor, créteil, france; unité de parasitologie-mycologie, département de virologie, bactériologie-hygiène, parasitologie, hopital henri mondor, créteil, france correspondence: eric levesque -eric.levesque@aphp.fr annals of intensive care , (suppl ):s introduction liver transplant recipients have high rate of invasive fungal disease (ifd) with high morbidity and mortality, in part due to its delayed diagnosis. the fungal cell wall component ( , )-betad-glucan (bg) is a biomarker for fungal infection but its utility remains uncertain. this prospective study was designed to review our experience in ifd and to evaluate the impact of bg in the diagnosis of ifd. patients and methods from january to may , liver transplantation were performed in our institution. serum samples were tested for bg (fungitell; cape cod inc., usa) least weekly between liver transplantation and their discharge from hospital. ifd was defined as proposed by the european organization for research and treatment of cancer/mycoses study group. results nineteen patients ( %) were diagnosed with ifd including cases of candidiasis infection (ci) in eleven out of patients, invasive pulmonary aspergillosis (including one who had previously ci) and one case of septic arthritis of the hip caused by scedosporium spp. ifd was associated with significantly high mortality (log-rank p = . ). the area under the roc curves, for bg to predict ifd, was . ( % ci . - . ). using a cutoff of pg/ml, the most discriminative cut-off point from the roc curve, the sensitivity, specificity, positive predictive value (ppv) and negative predictive value (npv) values of bg for overall ifd was % ( % ci, - ), % ( % ci, - ), % ( % ci, - ) and % ( % ci, - ). conclusion based on its high npv, bg value appears to be a good biomarker to rule out the diagnosis of ifd when the value is below pg/ml. a single point bg may guide the investigation and the decision to start antifungal therapy in patients at risk for ifd. none. monitoring of changes in lung and chest wall mechanics in the supine, lateral and prone positions during the prone positioning maneuver in ards patients zakaria riad , mehdi mezidi , hodane yonis , mylène aublanc, , sophie perinel-ragey, , floriane lissonde , aurore louf-durier, , romain tapponnier , jean-christophe richard , bruno louis, , claude guérin , plug working group réanimation médicale, hôpital de la croix-rousse, lyon, france; inserm, u , equipe , équipe biomécanique cellulaire et respiratoire, université paris-est créteil -faculté de médecine, créteil, france correspondence: zakaria riad -zakaria.riad@icloud.com annals of intensive care , (suppl ):s none. introduction systemic rheumatic diseases (srd) are autoimmune diseases that are rare but cause substantial morbidity and mortality. srds chiefly affect the lungs, however, data on critically ill patients with srd admitted for arf are scarce. patients and methods retrospective cohort conducted in french icus ( . the major comorbidities were cardiovascular ( %), tobacco exposure ( %), chronic kidney disease ( %) and neoplasia ( %). two-thirds of patients were on systemic corticosteroids at admission, the median dose of (iqr) mg per day. srd diagnosis was made in the icu in . % of patients. clinically or microbiologically documented bacterial pneumonia was the leading arf etiology ( . %). in % of cases, arf was related to an opportunistic infection (mainly aspergillus (n = ) and pneumocystis (n = )). others arf etiologies included specific lung involvement ( . %) and cardiac pulmonary edema ( . %). sofa on day one was [ ] [ ] [ ] [ ] [ ] [ ] [ ] . associated organ dysfunctions were mainly hemodynamic ( %) and renal ( %). mechanical ventilation was needed in % of patients (non invasive only in . % or invasive in . %), % needed vasopressors, and % renal replacement therapy. systemic corticosteroids were started in % of patients and % of patients received pulse steroids. cyclophosphamide and plasma exchange were required in and % of patients, respectively. length of icu stay was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days. icu-acquired infection occurs in % of cases. in total, patients ( . %) died throughout the icu stay. arf etiology was not associated with mortality. by multivariate analysis, shock on admission (or . [ . - . ], p < . ) and the use of invasive mechanical ventilation (or . [ . - . ], p = . ) were independently associated with mortality, whereas non-invasive ventilation was associated with decreased mortality (or . [ . - . ], p = . ). by considering among the connective tissue diseases, the groups of myositis and scleroderma (n = ), these diseases were associated with a trend for a higher mortality (or . [ . - . ], p = . ). conclusion in patients with srd, arf is associated with a high case fatality, primarily when mechanical ventilation is needed. particular attention must be given to specific srd-sub groups for which pulmonary flare may require intensive immunosuppression. none. none. none. severe acute pancreatitis in icu: management and outcomes of infected pancreatic necrosis charlotte garret , matthieu peron , emmanuel coron , cédric bretonnière , jean reignier , christophe guitton réanimation médicale, chu hôtel-dieu nantes, nantes, france; the acute pancreatitis appears as a pathology that we can define with difficulty because of its clinical presentation or prognosis. patients and methods in our study, we analysed cases of acute necrotic and hemorrhagic acute pancreatitis, hospitalized at the department of resuscitation of the surgical emergencies (p ) of the uhc ibn rochd casablanca during the period ( ) ( ) ( ) ( ) ( ) ( ) ( ) . the purpose of this study is to do a descriptive analysis of the epidemiologic, clinic, radiological, therapeutic and evolutive data of the acute necrotic pancreatitits, we included in our study patients with epidemiologic, clinic, radiologic, biologic criteria of acute necrotic pancreatitits diagnosis whatever is the biliary or alcoholic etiology. the valuation gravity of the pancreatitis has been based on:• ranson bioclinical score > /apache ii > ; • visceral failure.• spreading of the necrosis. the analysis of the results shows that: about the epidemiologic aspect: mean age ( year old), the biliary etiology predominates ( %). about the clinical aspect: pain ( %) vomiting ( %), stop of the transit ( %), the visceral distresses are: the shock ( %), respiratory distress ( %), and neurological distress ( %). about the radiological aspect: pleural effusion ( %), abdominal echography: vesicular lithiasis ( %), dilated principal biliary duct ( %), abdominal computerized tomography: stage e ( %). about the biological aspect: hyperglycemia ( %), hyper-amylasemia ( %). the indexes of gravity that have been appreciated in this study are: ranson score > ( %), imrie score > ( %), igs score ≥ ( %), osf score ≥ ( %). the treatment of the anhp has been symptomatic in particular and the evolution has been characterized by mortality about %, the cause was particularly infectious. the prognostic factors predetermined in this study are:• female type (p = . ).• hemodynamic distress (p = . ).• respiratory distress (p = . ).• scores of gravity:• ranson > (p = . ).• imrie > (p = . ).• osf ≥ (p = ).• infection (p = . ).• duration of the hospitalization (p = . ).• rate of c-reagent protein (p = . ). in conclusion, the mortality is still high in the anhp, considerable effort of search is necessary to prevent the infectious complications of mortality. none. predicting -day mortality following liver transplantation in patients with acute-on-chronic liver failure: a decision-tree model from the french national liver transplantation system, the optimatch study, - none. none. none. none. none. none. the french law and recent expert opinions have emphasized the need for a multidisciplinary approach in decisions to forgo life sustaining therapies for the critically ill. we sought to assess how icu nurses actually rank their involvement and perceive this process. materials and methods we conducted a cross sectional survey using a web-based questionnaire between june and september . results of the icus invited to participate, ( %) agreed. a total of icu participants completed the survey of whom % were nurses and % assistant nurses. median age was (inter quartile range - ) years and % were female. median work experience was ( - ) years and time in the icu was ( - ) years. eighty-five percent of the participants have been involved at least once in a multidisciplinary end-of-life discussion. less than half of the participants reported a good ( %) or partial ( %) knowledge of the current end-of-life legal framework. the decision to start a discussion about withdraw life-sustaining therapy (wlst) was initiated by a senior intensivist in % of the cases, by a nurse in % and an assistant nurse in . %. this decision was approved by % of the participants. the decision-making process was considered to be initiated at the right time for % of the participants, too late for %, and too early for %. the discussion occurred mostly in the afternoon ( %) or during the medical staff ( %), in a dedicated place in % of the cases. a median of ( - ) health-care professionals attended the wlst discussion. half the respondents reported being reluctant to talk during the discussions and % never expressed their own opinion. indeed, although the length of the discussion was ( - ) minutes, participants estimated to talk during only ( - ) minutes. the following reasons were mentioned by the participants to explain these facts: having cared for the patient for too short time ( %), lack of medical knowledge ( %), decision of wlst already taken by the medical staff ( %), their opinion not really taken into account ( %), reluctant to talk during meetings in general ( %), consider that the discussion is limited to a medical expertise ( %), limited professional experience ( %), and fear to express a different opinion ( %). nevertheless, % of the participants were partially ( %) or totally ( %) satisfied by the way the decision making process was conducted, % considered that collegiality was applied, and % agreed with the final decisions.conclusion icu nurses rank favorably multidisciplinary wlst discussions. nevertheless their involvement in the discussion remains limited. beyond factors related to work organization and professional experience, efforts should be made to recognize their role and value, and to encourage them to share their own opinions with the other members of the icu team. none. determinants and prognosis of elevation of high-sensitivity cardiac troponin t in patients hospitalized with vasodilatatory shock marie caujolle , jérôme allyn , dorothée valance , caroline brulliard , none. free plasmatic mitochondrial dna-receptor for advanced glycation end-products: a new signaling pathway of critical illness-induced endothelial dysfunction arthur durand , rémi nevière , florian delguste , eric boulanger, none. quality of reporting of fluid responsiveness evaluation studies: a five year systematic review izaute guillame , matthias jacquet-lagrèze , jean-luc fellahi none. none. none. none. none. introduction microaspiration of gastric and oropharyngeal contaminated secretions occurs frequently in intubated critically-ill patients, and plays a major role in the pathogenesis of ventilator-associated pneumonia (vap). at basic state, patients with chronic obstructive pulmonary disease (copd) have an increased risk of microaspiration (due to gastro-esophageal reflux disease, pharyngo-laryngeal dys-function…), this risk may even be more important under mechanical ventilation. the main purpose of this study is to determine if copd is a risk factor for global abundant microaspiration (gam) in intubated critically-ill patients. we gathered data about two prospective multicentric randomized trials focused on microaspiration in intubated patients. data about copd were retrospectively collected in order to complete previous data. microaspiration of gastric and oropharyngeal secretions was respectively determined by quantitative measurements of pepsin and salivary amylase in all tracheal aspirates during the first h after intubation. gam was defined as the presence at significant level of pepsin (> ng/ml) and/or salivary amylase (> ui/l) in at least % of the tracheal aspirates. in order to find gam independent risk factors, we realized an univariate and multivariate analysis of the variables collected. results out of patients included in the studies, were analyzed among which patients with copd. patients ( %) had gam. neither copd diagnosis, nor spirometric severity nor specific therapeutics were associated with gam. risk factors for gam in univariate analysis were the age, diabetes, low score in glasgow coma scale (gcs), and no recourse to paralytic agents or vasopressors. after none. none. implementation and impact assessment of a "ventilator-bundle" at the university clinics of kinshasa: before and after study josé mavinga , joseph nsiala makunza , m e mafuta , yves yanga , amisi eric , jp ilunga , ma kilembe none. none. amel mokline , achraf laajili , helmi amri , imene rahmani , nidhal mensi , lazheri gharsallah , sofiene tlaili , bahija gasri , rym hammouda , amen allah messadi burn care department, trauma and burn center, tunis, tunisia correspondence: amel mokline -dr.amelmokline@gmail.com annals of intensive care , (suppl ):s none. none. none. introduction mechanical ventilation (mv) weaning is a crucial step in critically ill patients. mv duration is associated with an increased risk of ventilator associated events, even though its specific impact on mortality has never been clearly demonstrated ( ). automated closed loop systems might help the weaning process. a recently published meta-analysis has reported a reduction in mv duration when using an automated weaning mode as compared to non-automated mode ( ) . however, the different automated modes have not been compared to each other. the objective of this network meta-analysis was to compare the performance of the three major automated weaning modes, i.e. the automode°, the smartcare° and the adaptative support ventilation (asv°) for mv weaning in critically ill and postoperative adult patients. we included all randomised control trials that compared automated closed loop weaning applications either to another automated application or standard care, including weaning according to a written weaning protocol or nurse driven protocols. the three modes of automated modes included in the study were asv°, smartcare° and automode°. the primary outcome was the duration of mv weaning, defined as the time between randomization and a successful extubation. we also planned subgroup analyses in the icu and the post-operative populations. the quality of the studies was assessed independently by two blinded investigators, using the evaluation recommended by the cochrane collaboration. a network bayesian meta-analysis using random effect models and based on aggregate data from the included studies was performed using the gemtc package (r project, vienna). this trial was declared in pros-pero in august (crd ). results search of databased identified articles; were screened for eligibility after removal of duplicates. abstract analysis led to the exclusion of articles with a final full text analysis of randomised control trials. ultimately, trials were included in the analysis, representing ventilated patients. nine studies included patients in the post-operative period while six were conducted in icu. the automated mode was asv° (a) in studies, smartcare° (c) in studies and auto-mode° (b) in studies. all studies reported the duration of mv weaning as defined in our protocol. in all studies, the control group was standard care with a weaning process driven either by nurses or physicians. in studies ( %) a written weaning protocol was used in the control group. all icu studies used sedation protocols based on sedation scores, none of them including systematic daily sedation interruption. each one of the automated application was associated with a significant reduction in the duration of mv as compared to the control. when comparing all different modes using the network meta-analysis framework, asv° appeared to be the best automated mode when it pertains to reducing the duration of mechanical ventilation weaning (fig. ) . subgroup analysis showed similar results in the post-operative and the icu populations. conclusion compared to standard weaning practice, the major automated weaning modes significantly reduced the duration of mv weaning in critically ill and post-operative adult patients. asv° was associated with the most significant effect when compared to the two other automated modes (smartcare°, automode°). further physiological respiratory studies would help to understand the underlying mechanisms accounting for the superiority of asv. none. none. introduction in intensive care unit (icu) patients, diaphragm dysfunction is associated with adverse clinical outcomes. ultrasound measurements of diaphragm thickness (tdi), excursion (exdi) and thickening fraction (tfdi) have been proposed as estimators of diaphragm function, but have never been compared to phrenic nerve stimulation. our aim was to describe the relationship between tdi, exdi, tfdi and diaphragm function evaluated using the change in endotracheal pressure after phrenic nerve stimulation (ptr,stim), and to compare their prognostic value. patients and methods ptr,stim and ultrasound variables were measured in mechanically ventilated (mv) patients < h after intubation ("initiation of mv", under assist-control ventilation, acv) and at the time of switch to pressure-support ventilation ("switch to psv"). diaphragm dysfunction was defined as ptr,stim < cmh o. results patients were included. at initiation of mv, ptr,stim was not correlated to tdi (rho = − · , p = · ), exdi (rho = · , p = · ) or tfdi (rho = − · , p = · ). at switch to psv, tfdi and exdi were correlated to ptr,stim, (rho = · , p < . and · , p = · , respectively), but tdi was not (rho = − · , p = · ). at switch to psv, a tfdi < % could reliably identify diaphragm dysfunction (sensitivity and specificity of and %, respectively), but tdi and exdi could not. this value was associated with increased duration of icu stay and mv, and mortality. conclusion under acv, neither tdi, exdi nor tfdi were related to ptr,stim. under psv, tfdi was strongly correlated to diaphragm strength and, when decreased, was associated with poorer outcome. alexandre demoule has signed research contracts with covidien, maquet and philips; he has also received personal fees from covidien and msd. none. none. none. management of enteral feeding during extubation in the intensive care unit: a multi-center retrospective study in french intensive care units mickael landais , noemie hubert , mai-anh nay , johann auchabie , bruno giraudeau , reignier jean , arnaud w thille , stephan ehrmann none. none. nutritional support in patients receiving temporary extracorporeal life support: a retrospective cohort study arthur bailly , laurent brisard , philippe bizouarn , thierry lepoivre , johanna nicolet , jean christophe rigal , jean christian roussel , bertrand rozec réanimation ctcv transplantation thoracique, chu de nantes -hôpital nord laennec, saint-herblain, france; chirurgie ctcv transplantation thoracique, chu de nantes -hôpital nord laennec, saint-herblain, france correspondence: laurent brisard -laurent.brisard@chu-nantes.fr annals of intensive care , (suppl ):s introduction the optimal nutritional intake in patients receiving temporary extracorporeal life support (ecls), including extracorporeal membrane oxygenation (ecmo) venovenous (vv) or venoarterial (va), remains controversial. enteral nutrition (en) is suspect to increase risk of gastrointestinal (gi) intolerance and intestinal ischemia. so, total parenteral nutrition (tpn) is often preferred. the purpose of this study is to describe the nutrition practices for critically ill patients receiving ecls and identify opportunities for improving nutrition therapy in this population. patients and methods retrospective analysis of patients requiring ecmo-va or ecmo-vv between and in the cardiac surgery intensive care unit of the university hospital of nantes. nutritional support was daily monitored with parenteral intake (glucose, lipid and propofol, protein and albumin, parenteral nutrition) and enteral nutrition until ecls weaning. two groups were compared during ecls period: no enteral nutrition delivered (none or tpn) (anec, n = ) and at least once enteral nutrition delivered (nec, n = ) including en alone and supplemental parenteral nutrition (spn). primary outcome was incidence of gi intolerance and risk factors. secondary outcomes were nutritional adequacy (calculated as overall of calories and protein delivered divided by the theoretical amount requirements: kcal/kg/d and . g/kg/d) and clinical outcome. data are reported as median ( th and th percentiles) or number (%), and analyzed with student's t test for continuous variables and χ test for categorical variables. p < . was considered as significant. none.introduction refeeding syndrome (rs) is a potentially lethal condition that remains underdiagnosed. it is characterized by severe electrolyte and fluid shifts associated with metabolic abnormalities in malnourished patients undergoing refeeding orally, enterally, or parenterally. clinical criteria have been proposed for determination of its risk and reported in the national institute for clinical excellence (nice) clinical guidelines. hypophosphoremia (hp) is a prominent feature of the rs and seems to be the earliest abnormality. phosphorus is a vital component of nucleic acids, enzyme systems, and various metabolic pathways. objective to determine the incidence of refeeding hypophosphoremia (rh) < . mmol/l, and severe rh < . mmol/l in a medical critical care unit. patients and methods monocentric, retrospective and observational study with patients from french-speaking icu nutritional survey study frans. critically ill adults (more than yo) were enrolled if they were hospitalized for more than days during a -month period and had an artificial nutritional support. refeeding hypophosphoremia is defined by the occurrence of hypophosphoremia after refeeding. we studied the incidence of hr, risk factors, and prognosis. results patients were enrolled between / / and / / . rh appears in . % and severe rh < . mmol/l in . % (fig. ) . there is no correlation between rs risk factors and rh in our study. logistic regression did not permit to identify neither risk factor nor prognostic modification. there is a lack in phosphoremia measuring ( . %), and overfeeding during the first days occurs in . %. discussion we define that an hypophosphoremia appearing after refeeding is a refeeding hypophosphoremia, and we do not consider others etiologies, such as mechanical ventilation, alkalosis, sepsis, alcoholism, malabsorptive states, poor intake, some medication. our cohort is too small to find some possible correlations with risk factors or prognosis. conclusion refeeding hypophosphoremia is common in our population. hypophosphoremia is not an independent predictor of icu or in-hospital mortality in critically ill patients. the knowledge of the sri requires the follow-up of the phosphoremia during nutrition after critical illness in particular in the undernourished patients. none. introduction to determine the possible relationship between days cumulated proteins ( days cpd) and energy deficits ( days ced) observed in ventilated patients and icu length of stay, duration of ventilator support, incidence of infections and days mortality. patients and methods mixed medical or surgical ventilated for at least days adult patients from icus from chu liège belgium were enrolled into the study. they were fed by enteral route with a target of kcal and . g of proteins by corrected kg of bodyweight and by day. if % of the target was not reached on day seven, parenteral nutrition was added with the same target. ced and cpd were calculated for days, taking into account all the sources of nutrition, and was defined as the difference between the amount of energy or protein intake and the target. results from / / till / / , patients were followed. data from patients could be cumulated on the first days. there were males, mean bmi was . ± . ; saps ii score on day was . ± . , sofa score at day was . ± . . they were ventilated for a median of days (iqr - ), median icu length of stay was days (iqr - ). mean sofa max calculated for the first days was . ± . and the day mortality was . %. on day , only % reached the target of kcal/kg and % the target of . g of protein/kg. mean days ced was − . ± . kcal and mean days cpd was − . ± . g. there was a significant negative relationship between both deficits and the sofa max (p = . for ced and p = . for cpd). however, there were no correlations between any of the deficits and icu length of stay, duration of mechanical ventilation, occurrence of infections and days mortality. discussion saps ii level, sofa max level, icu length of stay, all these parameters emphasize the high severity of this cohort of patients. it could indeed been thought that it is in this group of critically ill patients that the impact of nutrition could be easily demonstrated. clear relationships between sofamax on day and the days ced and cpd could be seen. however, both the deficit and the level of organ dysfunctions could be cause or consequence. unlike previous studies, usually performed in less severely ill patients, we did not find any relationship between ced or cpd and patient's outcome. conclusion contrary to some recent studies, we found no relationship between ced and cpe and outcome of patients. future studies are needed. none. cardiopulmonary bypass induces lymphopenia and decreases lymphocyte proliferation ability: il- and pd-l as potential therapeutic targets to reduce postoperative infection fabrice uhel , mathieu lesouhaitier , murielle grégoire , baptiste gaudriot , arnaud gacouin , yves le tulzo , erwan flecher , karin tarte , jean-marc tadié fig. incidence of hypophosphoremia at admission, the first day, and refeeding hypophosphoremia none. the prognostic impact of neutropenia in criticallyill cancer patients remains controversial. hence, several studies in critically ill cancer patients failed to demonstrate the impact of neutropenia on outcome [ ] . this lack of statistical association might however, reflect a lack of statistical power. a previous meta-analysis of aggregated data suggested % ( % ci - %) raw increase in mortality in neutropenic patients. the available data were, however insufficient to allow adjustment with confounders [ ] . the aim of this study was to assess the influence of neutropenia on mortality of critically ill cancer patients using individual data obtained from studies identified by our systematic review. secondary objectives were to assess the influence of neutropenia on mortality of critically ill patients while taking into account underlying malignancy, use of g-csf or changes related to period of admission. patients and methods this systematic review and meta-analysis was performed according to the prisma statements. public-domain databases including pubmed and the cochrane database were searched by using predefined keywords. the research was restricted to articles published in english and studies focusing on critically ill adult patients from may to may . the methods and objectives of this systematic review were reported in the prospero database (crd ). selected manuscripts' authors were then contacted to obtained part of their dataset. mortality was defined as either hospital or day- mortality. this preliminary analysis reports results from the whole dataset before and after adjustment using logistic regression. period of admission and use of g-csf were then assessed and were a pre-planned analysis. results our initial search yielded citations and studies were retained for further analysis. overall, studies were excluded for redundancy with other included studies, as containing only neutropenic patients, and two as containing only palliative patients. finally datasets ( %) containing sufficient data to allow comparison were obtained from authors. overall, patients were included in this study, including patients with neutropenia at icu admission. median age was of years (iqr - ). median sapsii score at icu admission was (iqr - ). respectively and patients had underlying haematological malignancy and solid tumours, and patients underwent allogeneic stem cell transplantation. mechanical ventilation, vasopressors, and renal replacement therapy were required in none. none. ( ) . in icus, cirrhotic patients are widely admitted and revalued after receiving optimal treatments for days. however, little is known about how manage these patients after day according to their prognosis. the blood neutrophil-to-lymphocyte ratio (nlr) as a novel inflammation index biomarker has been reported to be a predictor of clinical outcomes in various malignancies and in unselected critically ill patients ( ) . nlr has also been identified as a predictor of mortality in patients with stable liver cirrhosis. to our knowledge, the ability of nlr to predict outcome in critically ill cirrhotic patients has never been studied. the aim of this study was to evaluate the usefulness of inflammatory marker such as nlr for diagnosis of infection and predicting the outcome in hospitalized critically ill cirrhotic patients. we performed a retrospective monocentric study including consecutively cirrhotic patients hospitalized in a medical icu from to . for each patient, clinical and biological data at admission and day were collected. nlr at admission ("nlrd "), at day ("nlrd ") and the variation of nlr between admission and d none.introduction diagnosis of infection in immunocompromised patients can be difficult. however, diagnosing infection is very important, particularly in critically ill. this study aims to evaluate the benefit of procalcitonin (pct) blood level as a diagnostic marker for bacterial infection in patients with hematological malignancies admitted to the intensive care unit (icu). this retrospective single-center study included all consecutive patients with acute myeloid leukemia or high grade lymphoid malignancy admitted to the icu. patients were sorted into three subgroups, according to clinical and microbiological data: «infectious disease», «no infectious disease» and «unknown». initial serum pct and when available at day and day were recorded. receiver operating characteristic (roc) curve, sensitivity and specificity were calculated. serum pct was considered as decreasing when the decrease was ≥ % at day and/or ≥ % at day . mortality rates in the icu and at day- were also studied. results fifty-four patients were included in the study. at diagnosis, pct levels were significantly different between the "infection disease" group and the "no infection disease" group (p = . ). there was no difference between the "infection disease" group and the "unknown" group (p = . ). for the diagnosis of bacterial infection, best initial serum pct threshold was . ng per milliliter. for that threshold, sensitivity was . % and specificity was . %. pct area under the roc curve was . [ci % = . - ]. youden's j statistic was . . pct levels weren't different between groups according to the presence of neutropenia or in case of inaugural disease. there was a significant difference in pct values between groups according to the sofa score (p = . ), but not the saps score. mortality rate in the icu and at day- were significantly lower for the patients with decreasing pct (p < . and p < . , respectively). when comparing serum pct and crp predictive values, pct was significantly a better marker of bacterial infection (fig. ). discussion we found that serum pct, with a threshold of . ng/ ml, is a reliable marker of bacterial infection disease in patients with aggressive hematological malignancy admitted to the icu. our study confirms the results of a previous study in unselected immunocompromised patients admitted to the icu, showing a % sensitivity, a % specificity and an area under roc curve of . [ . - . ] for a threshold of . ng/ml ( ). the main limitations of our study are its retrospective design and the small number of included patients. conclusion pct is a reliable marker of bacterial infection in patients with hematological malignancies admitted to the icu. pct kinetic seems to be an interesting prognostic marker in this population. none. in this study, we have found that kinetics of secretion and expression of endocan is faster with huvecs stimlated by tlr agonist than tlr agonist. this results could suggest that endocan may be not only a marker of septic shock but could be also a specific marker to recognize the nature of pathogenic microorganisms in septic shock. furthermore, other studies with more tlr agonists could be useful to confirm these results. conclusion studying the effects of diverse tlrs agonists could make the plasmatic dosage of endocan more specific and helpful to recognize the nature of pathogenic microorganisms in septic shock. none. lung ultrasound: help to the diagnostic and the monitoring of response to physiotherapy. a case report of pneumonia aymeric le neindre introduction chronic critical illness (cci) syndrome is a new condition affecting an increasing number of patients, who survived an acute critical illness but have persistent severe organ dysfunction, requiring prolonged specialized care. cci is a iatrogenic process, reflecting the efficacy of modern life support technologies( ), and encompasses multiple organ failure, need for prolonged mechanical ventilation (mv), organ support, and palsy due to polineuromyopathy. the transition from acute to cci is gradual: definitions are based on duration of mv, with cut-offs of , or consecutive days of mv for ≥ h/day. cci patients may come from either medical or surgical icu; their health status fluctuates between improvements and deteriorations implying recurrent transitions between different levels of care ( ) .the risk of death is reported to be as high as %. despite a relatively young age ( years on average), functional status of cci patients discharged is seriously impaired, thus cci patients require long-term rehabilitation. aim: to estimate the frequency of cci syndrome in careggi, a large academic, tertiary care hospital; to describe the clinical course of cci patients through discharge, and their functional status at discharge. patients and methods administrative data on admission, transfer, death and discharge of all cci patients, consecutively admitted in one of the icu beds at careggi hospital from january to december , , were collected. cci was defined with the cut off of ≥ days of icu stay, representing the index event (ie) without contribution of previous or subsequent hospitalization in other hospitals. reasons for admission were grouped into the broad categories of medical causes, surgery, major trauma and cardio-respiratory arrest. patients discharged were evaluated in daily living, cognitive status, and mobility using barthel index. results we identified subjects who developed cci ( males; age . ± . years, mean ± sem); of them came from an external icu, began their cci course within careggi hospital ( from the emergency room, from a regular ward). average duration of the ie was . ± . days. these sample developed accumulative length of icu stay of days, corresponding to a % icu bed occupation over the theoretical total of , . when days of subintensive care and regular ward were separately added, days of highly specialized care and days of total acute hospital stay were reached. surgical patients had longer hospitalizations (p = . ).cci patients confirmed to be highly erratic: a total of transitions across different services were recorded in the patients, with a maximum of in of them. mean age was comparable between the patients who died ( %) and the remaining who were discharged alive ( . ± . vs. . ± . years; p = . ).fourteen subjects continued their icu stay out of hospital. only , whose age was lower ( . ± . years), were discharged home; half of the participants (n = , . %) were admitted to a residential rehabilitation facility. younger subjects scored better in the domains of self care (p = . ) and cognitive status (p = . ) but not in the domain of mobility, including walking ability: patients required maximal assistance in performing activities of daily living and transfers, other required medium/maximal assistance, with no statistical difference between dg group. conclusion cci is a relevant clinical condition that need to be assessed and possibly prevented, as it causes severe morbidity, long-term functional impairment and exceeding healthcare costs. none.conclusion early mobilization during the first week of the sepsis onset was safe and preserved muscle fibre cross sectional area. none. none. study of efficacy on icu acquired weakness of early standing with the assistance of a tilt table in critically ill patients none.introduction patients with high flow nasal cannula may benefit from combined aerosol therapy. clinical efficacy depends on pulmonary deposition which is related to the type of nebulizer. all new nebulizers or delivery methods require rigorous evaluation. the aim of this study was to compare lung deposition between two nebulizers (jet nebulizer vs vibrating-mesh nebulizer) through high flow nasal cannula in healthy subjects. patients and methods aerosol delivery of diethylenetriaminepentaacetic acid labelled with technetium- m ( mtc-dtpa, mci/ ml) to the lungs using a vibrating-mesh nebulizer (aerogen solo ® , aerogen ltd., galway, ireland) and a constant-output jet nebulizer (opti-mist plus nebulizer ® , convatec, bridgewater, nj) through high flow nasal cannula (optiflow ® , fisher & paykel, new zealand) was compared in healthy subjects. flow rate was set at l/min through the heated humidified circuit. pulmonary and extrapulmonary deposition were measured by single photon emission computed tomography combined with a low dose ct-scan (spect-ct) and by planar scintigraphy. results lung deposition was only . ± . and . ± . % of the nominal dose with the vibrating-mesh nebulizer and the jet nebulizer, respectively (p < . ). dose lost in the high flow circuit, humidification chamber and nasal cannula was higher with the vibrating-mesh nebulizer as compared to the jet nebulizer ( . ± . vs . ± . % of the nominal dose, p = . ). expressed as percentage of emitted dose, lung deposition was similar with both nebulizers. conclusion this study demonstrated that aerosol delivery through hfnc is poor in the specific conditions of the study despite the higher efficiency of the vibrating-mesh nebulizer as compared to the jet nebulizer. placing the nebulizer on the hfnc circuit at l/min induces high aerosol loss on the circuit and the oropharynx. key: cord- - dgmdtj authors: nan title: neurocritical care society th annual meeting: october - , sheraton denver downtown hotel denver, colorado date: - - journal: neurocrit care doi: . /s - - - sha: doc_id: cord_uid: dgmdtj nan ahrq guidelines for venous thromboembolism (vte) prophylaxis recommend risk stratification of patients and tailoring prophylaxis to that risk. while anticoagulation is a mainstay of optimal vte prophylaxis after trauma, little data exists to determine when tbi patients warranting neurosurgical intervention become candidates for such treatment. our group sought to determine the natural evolution of intracranial hemorrhage in these high risk patients and identify factors contributing to early radiographic stabilization. all tbi patients undergoing craniotomy and/or intracranial monitoring and surviving at least hours were followed prospectively from feb to nov . radiographic stabilization was defined as the time between injury and the final ct scan that showed no worsening during the hospital stay. kaplan meier (km) curves were used to compare time to stabilization by type of intervention. binary logistic regression was used to identify covariates contributing to stabilization within hours of injury. for the overall cohort (n= ), km curves showed no difference in time to radiographic stabilization by type of neurosurgical intervention. significant associations were found between stabilization at hours and higher presenting gcs (or: . , %ci . - . ), younger age (or: . , %ci . - . ), and male gender (or: . , %ci . - . ). subjects with a presenting gcs of > (n= ) had an % ppv for radiographic stabilization by hours after injury. the auc for the logistic regression model was . . sentinel headache refers to discrete thunderclap headache in the weeks preceding hospital admission for sah. a large proportion of these events are thought to represent aneurysmal bleeding events. repeat hemorrhages have been found to increase the extent of vasospasm in experimental models, and are often assumed to increase the risk of delayed cerebral ischemia (dci) in humans (the "double bleed effect"). cerebral performance category (cpc) is a standard outcome measure after cardiac arrest, but has limited ability to discriminate between mild and moderate brain injury. we hypothesized that many cardiac arrest survivors with good cpc scores would have significant deficits on blinded neurocognitive testing. patients initially comatose after cardiac arrest treated who awoke after therapeutic hypothermia (th) were evaluated by a neuropsychologist prior to hospital discharge with the repeatable battery for the assessment of neuropsychological status (rbans), a well-validated tool that assesses function in multiple domains compared to standardized normal values. patients admitted between nov and may awoke after th, completed the rbans evaluation after leaving the icu and ready for discharge. median age was yrs (range - ), % male, had initial rhythm vt/vf, median time to rosc was minutes (range - ). seven patients had a cpc of , patient had a cpc of , and patient had a cpc of . seven patients were discharged home and to acute rehab. attention and delayed memory were severely abnormal half of the patients (below th percentile), language and visuospatial domains were affected less often in % of the patients (below th percentile). on cumulative scores of all domains, all patients scored below the th percentile compared to age and education adjusted scores, regardless of cpc score. cardiac arrest survivors with cpc scores considered 'good' frequently had severely abnormal neurocognitive function just prior to hospital discharge. the cognitive domains most frequently affected were attention and delayed memory. more sophisticated testing with tools such as rbans may better identify components of cognitive dysfunction after cardiac arrest which may be targets for additional therapeutic intervention and be a more meaningful tool for long-term follow-up studies. introduction quantitative brain diffusion-weighted imaging (dwi) mri may help predicting the degree of functional recovery in patients ain volume with an apparent diffusion coefficient (adc) < x - mm /sec differentiated between cardiac arrest survivors who regained an independent lifestyle and those with impaired functional outcome. we aimed to validate this threshold in an external dataset. dwi mris of comatose post-cardiac arrest patients were obtained between - hours post-arrest. survivors who regained consciousness by day were assigned to one of two recovery groups: good recovery (discharged to home) and impaired recovery (discharged to a skilled nursing facility, rehabilitation facility or another hospital). the quantitative dwi data were obtained blinded to patient outcomes. the brain masks were semi-automatically created on the b images using medical image processing, analysis and visualization program (mipav). the adc values of each voxel within the brain were determined. data of patients from five us centers (columbia, mgh, mayo clinic jacksonville, northwestern, and stanford) with adequate mris were analyzed. of these, ( %) patients regained consciousness and survived to discharge: mean age ± years, % female, arrest duration ± minutes, % of patients received therapeutic hypothermia, mri obtained at ± hours post-arrest. the median (iqr) percentage of brain volume with adc< x - mm /sec was . % ( . - . ) in patients with good recovery (n= ) and . % ( . - . ) in patients with impaired recovery (p= . ). an adc< x - mm - ) sensitive and % ( %ci - ) specific for good recovery. the results of this validation study support earlier findings that quantitative dwi mri in comatose post-cardiac arrest patients is a sensitive prognostic test to predict the degree of functional recovery in post-cardiac arrest survivors. according to the universal determination of death act, death in the united states is determined in accordance with accepted medical standards, which can be national, regional, or local. as a result, significant variability in brain death (bd) determination has been reported among the best hospitals across the country. we tested the hypothesis that similar variability exists in individual states, such as michigan. michigan health and hospital association and gift of life of michigan (the local organ procurement organization) databases were reviewed for hospital bd policies. only hospitals with > beds and an intensive care unit were included. several bd determination process variables were extracted and analyzed with descriptive statistics. results / hospitals had bd policies, did not and in it was unclear. ten different combinations of physicians allowed to perform the exam were included. in . % there were no prerequisites to initiate bd and in . % no established cause mentioned. ten different temperatures to initiate bd exam were required. five different arterial blood carbon dioxide levels to establish positive apnea test were cited. a single bd exam was requested in . % of policies, a dual in . % and a single or dual in . %. confirmatory tests were optional ( %), recommended ( . %) or mandatory ( %). electroencephalogram was the most common confirmatory test ( %) and ct angiogram the least common ( %). we report significant variability in the bd hospital policies in michigan despite published guidelines from the american academy of neurology. if one accounts for additional variability in the strict implementation of these policies at the bedside level, the urgency for a uniform state-wide bd policy becomes even more obvious. intrathoracic pressure regulation (ipr) therapy is a novel therapy that non-invasively modulates pleural pressures to take advantage of the physiological benefits that occur by creating pressure differentials in the thorax. after each positive pressure breath ipr lowers intrathoracic pressure to subatmospheric levels relative to the rest of the body. this intervention enhances cardiac preload and output and decreases intracranial pressure (icp). we hypothesized that ipr therapy which has been previously shown to increase calculated cerebral perfusion pressures would also increase cerebral blood flow (cbf) in a porcine model of elevated icp. in this pilot study, four isofluorane anesthetized pigs ( . ± . kg) were subjected to a focal brain injury by epidural insertion of an french foley catheter into the left hemisphere which was slowly filled with saline to simulate a traumatic brain injury with elevated icp. in the right hemisphere, a thermal diffusion probe was used to measure cbf (hemedex, inc., cambridge, massachusetts) while a millar catheter was used to measure icp. once a stable elevated icp was confirmed, ipr therapy was applied at a level of - cmh o for minutes. end tidal co was held constant at mmhg by adjusting the respiratory rate during ipr use. tbi is a major risk factor for the development of alzheimer's disease (ad). in previous animal and human studies, an increase in the expression of amyloid precursor protein (app) after tbi was found to correlate with the disruption of neuronal activity, beta-amyloid plaque formation, cognitive decline, and even death.to date, no interventions used at decreasing amyloid plaque load after tbi have been identified. in this study, using the controlled cortical impact device we produced a severe head injury in month old xfad mice. at minutes and hours after injury, the xfad mice were treated intraperitoneally with either placebo or resveratrol (anti-oxidant; mg/kg). at month after injury, the animals were intracardially perfused with . % saline followed by % phosphate-buffered formalin. the whole brain was removed, sliced, and stained for beta-amyloid levels using immunohistochemistry. in addition, tunel+ cells were measured at the indicated time-points to determine the level of neural injury. in this study we found that treatment with resveratrol at minutes and hours post-injury resulted in a significant reduction in beta-amyloid plaque load near the injury zone (parietal cortex) (p< . ) and hippocampus (p< . ). also, the mice treated with resveratrol had reduced (p< . ) tunel+ staining. while a multitude of etiologies may lead to coma, treatments for coma remain elusive. the hypothalamic orexin pathway, critical in sleep/wake cycles, can stimulate multiple areas of the brain and provides a potential pharmacologic target towards improving arousal after coma. we used a post-cardiac arrest (ca) rodent coma model to assess whether postresuscitative orexin-a intracerebroventricular (icv) infusion after bolus injection would provide immediate and long term arousal after ca. seventeen adult wistar rats (male, - gms) were implanted with a icv cannula attached to an osmotic pump. one week later, rats underwent baseline eeg followed by -minute asphyxial ca. forty-five minutes after resuscitation, rats were randomized to either orexin-a (n= ) or saline (n= ) icv bolus and infusion. eeg was monitored continuously for hours after ca, and for minutes at hrs, hrs, hrs, and days post-ca. behavioral testing (neurologic deficit scale; nds) was also conducted at these times. eeg was quantitatively analyzed using information quantity (iq), an entropy based nonlinear previously established by us. rats receiving orexin-a almost immediately exhibited higher iq when compared to saline ( . ± . vs. . ± . ; p< . ). this acute improvement in iq appeared with slowest sub-bands (e.g.ð) improving first followed progressively by faster sub--ca. moreover, orexin--band at hrs ( . ± . -band at hrs ( . ± . vs . ± . ; p< . ). behaviorally, orexin-a allowed rats to perform significantly better on the nds at hrs ( . ± . vs. . ± . ; p< . ); hrs ( . ± . vs. . ± . ; p< . ); hrs ( . ± . vs. . ± . ; p< . ), and hrs ( . ± . vs. . ± . ; p< . ). heart rate variability (hrv) characteristics have been associated with outcome after traumatic brain injury. we sought to determine if hrv characteristics in the first hours after subarachnoid hemorrhage (sah) are associated with hospital morbidity and mortality. continuous ekgs recorded ( hz sampling) during the first hours post-sah was analyzed in of consecutively admitted patients between and . admission clinical scores, radiographic, surgical, ventilation and the pan-tompkins algorithm was applied to identify the qrs complex. fft calculations were generated for the following - . hz), low frequency (lf: . - . hz), very low frequency (vlf: . -nerated sample entropy and /f --minute (fft< . hz), or -minute individual multivariable logistic regression analyses of hospital morbidity and mortality controlling for admission hunt and hess grade, apache ii physiological sub-score, age, and mechanical ventilation status were conducted. dialysis disequilibrium syndrome (dds) is characterized by varying central nervous system manifestations secondary to cerebral edema that most often occurs after the first round of hemodialysis (hd). literature suggests that underlying brain injury may predispose patients to the development of dds. however, the pathophysiology has yet to be elucidated. herniation from hd is thought to be exceedingly rare with current dialysis methods and has not been reported in the era of modern neurointensive care. we present a case series of three patients with acute neurological injury undergoing hd in the intensive care unit that rapidly developed fatal brain edema, secondary to dds, even after several previous uneventful rounds of hd. three patients, ages , and years, with traumatic brain injury, hypertensive intracerebral hemorrhage, and ischemic stroke underwent hd in the intensive care unit. the number of dialysis sessions prior to the development of dds was , and . all three patients developed clinical signs of herniation within minutes to hours of hd. ct scans showed global cerebral edema with both transtentorial and tonsillar herniation. aggressive osmotherapy with mannitol and supersalt were ineffective in reversing the massive edema and all three patients died. two of the patients had a significant reduction of the bun ( % and %) while the third had only a modest reduction. our case series illustrates the potential dangers of hd in patients with acute neurological injury who have a high potential for worsening cerebral edema. it also reaffirms that dds with fatal cerebral edema can occur even after several rounds of hd and with current hd techniques. utilization of continuous veno-venous hemofiltration instead of hd may prevent the rapid shifts of osmoles and prove safer in neurologically injured patients. traumatic coma is believed to be caused by disruption of the ascending reticular activating system (aras), a complex network of arousal pathways projecting from the brainstem to the hypothalamus, thalamus, and basal forebrain. there is a critical lack of diagnostic tools for detecting which components of the aras network are disrupted in traumatic coma. we aimed to determine whether an advanced mri technique, high angular resolution diffusion imaging (hardi), can detect disruptions in the brainstem arousal network that are implicated in the pathogenesis of traumatic coma. we used hardi tractography to analyze neural network connectivity in two postmortem brains: one from a -year-old woman who died three days after traumatic coma, and one from a -year-old woman who died of non-neurological causes. both specimens were scanned as dissected blocks of the brainstem, hypothalamus, thalamus, and basal forebrain on a small-bore, high field ( . tesla) mri scanner. hardi tractography analyses were performed to compare the structural integrity of each component pathway of the aras network in the traumatic coma and control specimens. upon completion of imaging, both specimens were sectioned and stained for correlative histopathological analysis. hardi tractography revealed that specific components of the aras network, including known cholinergic, glutamatergic and noradrenergic projections connecting the brainstem to the thalamus and basal forebrain, were severely disrupted in the traumatic coma specimen, as compared to the normal specimen. these disruptions were consistent with histopathological tissue tears and axonal swellings. by contrast, connectivity between the brainstem and hypothalamus, and within the thalamus itself, was partially preserved in the traumatic coma specimen. hardi tractography can detect disruptions in specific components of the aras network that are implicated in the pathogenesis of traumatic coma. this advanced imaging technique may be used to elucidate the neuroanatomic basis of coma in individual patients. refractory intracranial hypertension (rich) is associated with high mortality rates and is the final pathway of many neurocritical entities, such as severe traumatic brain injury (stbi). objective: to determine modifications in intracranial pressure (icp) and cerebral perfusion pressure (cpp) following indomethacin (indo) infusion after rich secondary to stbi. indo was administered in a loading dose ( . mg/kg/ minutes), followed by continuous infusion ( . mg/kg/h) in patients with icp> mmhg for more than minutes who did not respond to first line therapies. changes in icp and cpp were observed. clinical outcome was assessed at -day according to glasgow outcome scale (gos). analysis of indo safety profile was also conducted. differences in icp and cpp values were assessed using repeated-measures anova with an a-level of p< . twenty-nine consecutive stbi patients ( men and women) with a mean age ±sd ± years wereincluded. median posresucitation gcs score at admission was (iqr: - ) with a predominance of grade iv in marshall ct classification. our findings support the effective and feasibility of indo in reducing icp and improving ccp in rich patients. future studies to evaluate different doses, lengths of infusion and longer-term effects together with effects on outcome are needed. hematoma expansion after acute intracerebral hemorrhage (ich) occurs most frequently in patients presenting within hours of symptom onset. therefore, most investigational therapies have been tested only in patients presenting ultra-early in their disease course. however, the majority of ich patients present outside this time window or with an unknown time of onset. we investigated the prevalence of hematoma expansion in these patients with delayed presentation and assessed the accuracy of the ct angiography (cta) spot sign for identifying risk of hematoma expansion. we performed a prospective cohort study. consecutive ich patients undergoing cta and follow-up head ct were enrolled over ten years. cta spot sign readings were performed by two experienced readers and hematoma expansion was assessed using semi-automated software. expansion was defined as an increase in volume of > ml or an increase of > % from baseline ich volume. hematoma expansion occurred in % of patients. when stratified by time from symptom onset to initial ct, hematoma expansion rates were: % within hours; % between - hours, % beyond hours (but with known onset), and % in patients with an unknown symptom onset time. of patients who developed hematoma expansion, only % presented within hours. the accuracy of the spot sign in predicting hematoma expansion was . for patients presenting within hours, . between to hours, . after hours and . for patients presenting with an unknown onset time. a substantial number of patients destined to suffer from hematoma expansion present either late or with an unknown time of symptom onset. the cta spot sign accurately identifies patients destined to expand regardless of time from symptom onset, and may therefore open a path to offer clinical trials and novel therapies to the many patients who do not present acutely. intraventricular fibrinolysis has been shown effective in clearing intraventricular hemorrhage (ivh) in small series of patients. we present our experience with using fibrinolytics over years. retrospective analysis of prospectively collected data of patients with ivh admitted to two neuro-icus and treated with rt-pa instillation (one patient with tenecteplase) via intraventricular catheter (ivc) until the rd and th ventricles were cleared of blood. all patients were treated by the same neurointensivist with the same instillation protocol but different doses of drug based on individual patient characteristics. the graeb and leroux semi-quantitative scales were used to measure the amount of ivh before and after the last dose. patients (mean age . years, . % male) were admitted with a median gcs . thirty-one had intracerebral and aneurysmal subarachnoid hemorrhage, brain tumors, head trauma, arteriovenous malformation.and primary ivh. t-pa was administered at a total dose of . ± . mg (individual doses ranging between . to mg), with st dose . ± . hours from admission and for a duration of . ± days. the pre-fibrinolysis graeb and leroux scores were . ± . and . ± . and decreased post fibrinolysis to . ± . and . ± . (p< . ). a significant correlation between total fibrinolytic dose and difference in pre-post amount of ivh was found for the leroux scale (pearson . , p < . ). three patients had small tract bleeds (< cc, with one bleeding profusely at the incision site requiring transfusion) and one had extension of ich in the upper midbrain. no patient developed ventriculitis. the total dose of t-pa was lower in patients who received shunt, compared to who did not ( . ± . vs . ± , p< . ). eighteen ( . %) patients had -up of . ± . days. in our large series of patients, intraventricular fibrinolysis significantly decreased ivh with minimal complications. distinguished poster ___________________________________________________________________________________ white matter lesions significantly impact on outcome after aneurysmal subarachnoid hemorrhage (asah). brain extracellular tau is indicative for axonal injury, associated with poor neurological outcome after severe traumatic brain injury, however has not been elucidated so far in patients with asah. twenty-five consecutive asah patients monitored with cerebral microdialysis (cmd) and brain tissue oxygen tension (p b to ) were included. cmd total tau, phospho-tau- and beta-amyloid -- ) levels were analyzed at a hours interval until d and -hours interval until d using an elisa-technique (innogenetics). statistical analysis was performed with non-parametric tests and a mixed effects model as appropriate. median age was y ( - y) and admission hunt&hess grade ranged from to . cmd-tau, phospho-tau-- were detectable in all patients. probe location in perilesional tissue revealed a higher overall cmd-tau level (p< . ) - and phospho-tau. cmd-tau positively correlated with cmd-lactate (r= . , p< . ). brain hypoxic (p b to were associated with increased cmd-tau levels (p< . ). no correlation was found between other variables besides a higher phospho-tau level and cmd samples categorized as brain hypoxic hyperlactatemia. patients with poor outcome -tau level during hospital-course (p< . ) but no difference in phospho-tau-- (adjusted for disease severity). cerebral tau is elevated after asah and associated with perilesional probe location and poor -months functional outcome. association with brain-morphological abnormalities and neuropsychological deficits need further investigations. neurocrit care ( ) :s -s to date only two studies have evaluated anemia status in acute intracerebral hemorrhage [ich] . on admission anemia [oaa] was associated with larger hematoma volume and lower hemoglobin levels during hospital stay were related to poorer outcome. it remains unknown whether anemia impacts outcome primarily through its effects on ich volume or itself has independent effects. this retrospective analysis included consecutive patients with spontaneous supratentorial intracerebral hemorrhage. clinical data including the pre-admission-status, neuroradiological, initial presentation, treatment, and outcome were evaluated through institutional databases, patient's medical charts and by mailed questionnaires. multivariate logistic and graphical regression analyses were calculated to evaluate associations of oaa with functional outcome and to determine independent effects of oaa. oaa was associated with larger ich volume ( . cm³ versus . cm³, p= . ), greater extent of intraventricular hemorrhage [ivh] (p= . ) and poorer neurological status on admission (p< . ). further, oaa showed a true positive and accurate association with larger hemorrhage volumes (roc: p= . ,auc> . ). multivariately, for all patients despite age, only oaa could be elucidated as independent predictor of unfavorable functional outcome (mrs > ) at days (or= . ;p= . ). comparison of separate multivariate models revealed: for oaa-patients no independent predictor could be identified, whereas in non-oaa patients ich volume demonstrated known independent effects on functional outcome (or . ;p= . ). within this study oaa was shown to be a significant predictor of an unfavorable functional outcome and has independent effects beyond its accurate association with larger hemorrhage volumes. oaa appears to be a very relevant and previously unrecognised predictor of functional outcome at days. the recognition of anemia and its treatment could possibly open up new therapeutic avenues to decrease the rate of functionally dependent patients after ich. this strongly supports the need of prospective interventional studies to evaluate the influence of anemia in patients with intracerebral hemorrhage. in patients with suspected subarachnoid hemorrhage and negative brain imaging, lumbar puncture is recommended. this test is frequently complicated by false-positive results due to a traumatic tap. we hypothesized that blood precipitating in the thecal sac following non-traumatic subarachnoid hemorrhage would be visible on mri. a prospective database for subarachnoid hemorrhage was searched for patients who received mr lumbosacral spine imaging during admission for subarachnoid hemorrhage. electronic chart review was completed. all mr studies were read and interpreted by a neuroradiologist. patients (n= ) with subarachnoid hemorrhage underwent delayed mri imaging of the lumbosacral spine an average of days (range - days) after the onset of symptoms. the median hunt-hess grade for this cohort was (range - ). the median fisher grade was . blood precipitating in the thecal sac was visible in out of patients ( %). the density of blood compared to csf was hyper-intense on t (bright) and hypo-intense on t (dark). the blood was most evident at l and s levels and layered in a dependent fashion. delayed ct head non-contrast obtained at the time of the mri ls spine demonstrated resolution of subarachnoid hemorrhage in / patients and a small amount of isodense intraventricular hemorrhage layering in the occipital horns was detected in / patients. delayed neuroimaging with ct head after subarachnoid hemorrhage has a high false negative rate. mr imaging of the lumbosacral spine detected persistent blood products settling in the thecal sac despite clearance of subarachnoid blood on ct head imaging. mr lumbosacral spine imaging could serve as a 'virtual lumbar puncture' in patients with suspected subarachnoid hemorrhage. stroke patients receiving iv tpa can be admitted to an icu or a stroke unit (su) but su admission may be more costefficient. we compared icu admission vs su admission in tpa-treated patients. during the initial years of this retrospective study, patients were admitted to the icu as we lacked a su. in the following years, patients were admitted to a new su. demographics, medical history, nihss, treatment interventions, neurologic and medical complications, and mortality were collected to determine if icu admission resulted in better outcome and less complications. categorical variables were analyzed with fishers exact test and continuous ones with proportion of the means test (t-test). we compared icu admissions and su admissions. icu admission included % males and su admission included % males (ns). median age for icu and su admission was and respectively (ns). admission nihss was for icu patients and for su patients (ns). the median length of stay in the icu was day (as per protocol) and the median su length of stay was days. intravenous anti-hypertensives (bolus) were used in % of icu patients and in % of su patients (p= . ) and continuous infusions in % of icu patients and % of su patients (p= . ). initial nihss scale of > predicted need for mechanical ventilation (p= . ). intracranial hemorrhage occurred in % of icu and % of su patients (ns). complications (pneumonia, venous thromboembolism, sepsis, or death ) did not differ. there was no difference in the proportion of patients with mrs of or less in the two groups ( % vs %). admission to the su resulted in savings of $ , per patients/day. patients receiving tpa can be safely admitted to a su resulting in significant cost savings. patients with nihss > are likely to need icu admission for mechanical ventilation. stroke patients with dysphagia have a high incidence of aspiration, which may lead to pneumonia. evidence suggests that ace inhibitor use may decrease the risk of pneumonia via their inhibitory effects on substance p degradation. the objective of this study was to investigate the association between ace inhibitor use and the development of pneumonia in hospitalized stroke patients. a retrospective case-control analysis was performed. eligible patients (n= ) were individuals admitted to saint louis university hospital with a diagnosis of acute ischemic stroke, spontaneous intracerebral hemorrhage, or non-traumatic subarachnoid hemorrhage between march st , and november th , . patients greater than years of age, who died or were discharged to hospice within days of admission, or who had a baseli excluded. cases were patients with an icd- code for pneumonia or antibiotic treatment course for at least days with a positive respiratory culture. controls were patients without pneumonia matched using primary diagnosis, baseline demographics, history of prior stroke, diabetes, hypertension, heart failure, and initial nihss scores. ace inhibitor use, length of stay, discharge disposition, and other pertinent data were collected and analyzed using descriptive statistics, chisquare, and logistic regression. there is growing evidence supporting the role of inflammation in aneurysmal subarachnoid hemorrhage (asah) pathophysiology and it is of great interest to elucidate which immune mechanisms are involved. methods asah patients (sahp) and healthy control subjects (cs) were enrolled prospectively. the protocol was authorized by the ethics committee of our hospital and all subjects (or patient next of kin) signed an informed consent. the median age of sah patients was years ( - ) and of control subject was years ( - ). we assessed leukocytes subpopulations and their activation status by multiparametric flow cytometry in cerebrospinal fluid (csf) and peripheral blood (pb) of sahp at the same time and in pb of cs. we found an increase in cd +-monocytes percentage (p= . ) in csf compared with pb in sahp and a decrease in pb of sahp compared with cs (p= . ). sahp also showed a marked increase in the expression of cd (activation antigen) in pb cd +t cells compared with cs (p= . ). additionally, csf cd +t cells showed a decreased expression of cd (p= . ) and cd (p= . ) (activation markers) compared to pb cd +t cells in sahp. similarly, pb cd +t cells in sahp showed an increased expression of cd compared with cd +t cells of cs (p= . ). csf cd +t cells showed a decreased expression of cd (p= . ) and an increased expression of cd compared with pb cd +t cells (p= . ). b and nk cells were decreased in sahp compared with cs (p= . and p= . respectively). as far as we know this is the first report that analyzes leukocytes subsets in csf and pb in patients with asah. our data suggests not only csf leukocytes recruitment (from the blood) but also an increase status of activation at this level. overall, these results indicate that asah probably stimulates both the innate and adaptive immune responses. subdural hematoma (sdh) is a common diagnosis in neurosurgical and neurocritical practice. comprehensive outcome data and management guidelines are lacking for non-traumatic sdh. thus, we aimed to determine factors associated with in-hospital mortality in a large sample of patients with non-traumatic sdh. using the nationwide inpatient sample, we included adults with a primary diagnosis of acute non-traumatic sdh (icd- code, . ) hospitalized in the united states between and . demographics, comorbidities, craniotomy treatment and discharge outcomes were identified. univariable and multivariable analyses were performed to identify predictors of in-hospital mortality. of patients with non-traumatic sdh, the mean age was . (sd . ) with % male, and . % admitted during the weekend. surgical evacuation was performed in . % of patients; . % ( . % of patients requiring surgical evacuation) required a second craniotomy. death during hospitalization occurred in . % of patients. factors significantly associated with higher in-hospital mortality included increasing age, female sex, comorbidities (congestive heart failure [chf] , coagulopathy, renal failure, liver disease), mechanical ventilation during the first days (mv), premorbid warfarin use, repeated sdh evacuation, and admission during the weekend. craniotomy was associated with decreased in-hospital mortality. in multivariable analysis, age (or . , % ci . - . ), female sex (or . , % ci . - . ), chf (or . , % ci . - . ), warfarin use (or . , % ci . - . ), mechanical ventilation (or . , ) and weekend admission (or . , % ci . - . ) were independent predictors of inhospital mortality. surgical sdh evacuation was a strong independent predictor for decreased mortality (or . , % ci . - . ). one in nine patients with non-traumatic sdh dies during hospitalization. of several predictors of mortality, the weekend effect and the decision for or against surgical evacuation are potentially modifiable factors. further investigation may lead to improvement of management practice and better outcomes. to determine the burden of structural damage of the central nervous system (cns) in patients who died in the setting of non-neurological critical illness. critically ill patients who died in the medical, surgical or cardiac icus over a year period and underwent autopsy were included. patients with known cns lesions, cardiac arrest, and those from neurological icus were excluded. brain specimens were reviewed by a neuropathologist and classified according to location and lesion type (infarct, hemorrhage, inflammation). acute brainlesions were found in of patients studied. mean gcs at admission was lower in patients with neuropathological findings ( . vs. . ; p= . ). the most common sites of injury were cortex ( . %) and hippocampus ( . %). infarcts ( . %), hemorrhages ( . %), and signs of inflammation ( . %) were the most frequent findings. patients with septic shock and ali/ards had more lesions than patients without these critical illnesses, albeit these differences were not statistically significant. ischemic brain injury is prevalent in patients dying from non-neurological critical illness and may occur secondary to cns hypoperfusion. efforts to optimize brain oxygen delivery during critical illness may be neuroprotective. after ca, microcirculatory reperfusion disorders develop despite adequate cerebral perfusion pressure. increased blood viscosity strongly hampers the microcirculation resulting in plugging of the capillary bed, arteriovenous shunting and diminished tissue perfusion. the rheologic properties of blood depend on hematocrit and plasma constituents, mainly acute phase proteins. the aim of the present study was to assess blood viscosity in relation to cerebral blood flow in patients after a cardiac arrest. we performed an observational study in comatose patients after cardiac arrest. patients were treated with mild therapeutic hypothermia for hours and passively rewarmed to normothermia. blood viscosity was measured ex-vivo at , , , , , and hours after admission using a contraves ls viscometer. mean flow velocity in the middle cerebral artery (mfv mca ) was measured by transcranial doppler (tcd) at the same time points. the median viscosity on admission was . ( . - . )mpa.s, remained stable at . ( . - . )mpa s and . ( . - . )mpa s at and hrs respectively (p= . ). from hrs after admission viscosity decreased significantly to . ( . - . )mpa s (p< . ). median mfv mca was low ( . ( . - . )cm/s) on admission, and significantly increased to . ( . - . ) cm/s at hrs (p < . ). there was a significant association between the viscosity and the mfv mca (p= . ). median hematocrite was . ( . - . )l/l on admission and subsequently significantly decreased to . ( . - . ) l/l at hrs (p < . ) in contrast, acute phase proteins such as crp and fibrinogen increased during admission (from . ( . - . )mg/l to ( - . )mg/l and ( - )mg/l to ( - )mg/l respectively (p < . ). viscosity decreases in the first days after cardiac arrest and is strongly associated (correlated) with an increase in cerebral blood flow. since viscosity is a major determinant of cerebral blood flow, repeated measurements may guide therapy to restore cerebral oxygenation after cardiac arrest. initial hemorrhage burden is an independent predictor for delayed cerebral ischemia (dci) in patients with aneurysmal subarachnoid hemorrhage (sah). among the different definitions of blood burden, cisternal plus intraventricular hemorrhage volume (cihv) has been regarded as the most sensitive blood volume definition in predicting dci. however, it is not clear whether clot clearance is associated with dci. quantitative analysis of hemorrhage volume and clot clearance was made in consecutive patients who were scanned within hours from onset. cistenal plus intraventricular hemorrhage volume (cihv) was calculated for clot burden analysis. serial cihv was measured up to days after sah onset. clot clearance was calculated up to days as a percentage of residual clots compared to the initial scan. initial clot burden and clot clearance were compared in patients with and without dci. included patients were . ± . years old with female preponderance ( . %, ( / )). dci was developed in patients ( . %). conventional risk factors were not different between patients with and without dci including age, sex, ht, dm, smoking, admission h&h scale and apache score. patients with dci had higher cihv ( . ml, ) compared with those without dci ( . ml, iqr ( . had higher odds for dci (or . , % ci ( . - . , p = . ). however, clot clearance rate was not different between patients with and without dci (day : . % vs. . %, p = . , day : . % vs. . %, p = . , day : . % vs. . %, p= . ). quantitative clot clearance rate using cihv is not associated with the development of dci while initial cihv is an independent predictor for dci. the majority of patients who die from subarachnoid hemorrhage have withdrawal or limitation of care and a focus on comfort at the end of life. ethnic disparities at the end of life has been examined in general critical care settings but not specifically in brain injured patients. patients with aneurysmal subarachnoid hemorrhage were prospectively followed in an observational database from august to january . demographic information including ethnicity was collected from medical records and self reported by patients or their family. significant in-hospital events including care withheld or withdrawn (comfort measures only, cmo) and mortality was recorded prospectively. included were patients of white, black or hispanic race. patients were included in our analysis: whites, blacks and hispanics. age was the only baseline characteristic that was different between groups. whites ( ± years) were older than blacks ( ± years) and hispanics ( ± years). no difference in morality was seen: % in whites, % in blacks, % in hispanics. cmo was more commonly ordered for whites ( %) than blacks ( %) and hispanics ( %) (p= . ). in multivariate analysis controlling for age and initially hunt-hess grade hispanics were less likely to have cmo orders than whites (or, . ; %ci, . - . ; p= . ). of the patients who died % of whites had cmo orders compared to % of blacks and % of hispanics (p< . ). in multivariable analysis controlling for age and hunt-hess, blacks (or, . ; %ci, . - . ; p< . ) and hispanics (or, . ; %ci, . - . ; p< . ) were less likely to die with cmo orders than whites. multiple assessment measures are used to evaluate post-aneurysmal subarachnoid hemorrhage (asah) outcomes / complications. the use of a common measure has not been established, thus choosing which measure to control for becomes difficult when conducting multivariable analysis in clinical research. we compared odds ratio (or) and positive predictive value (ppv) to determine measures with strongest associations with post-asah complications / outcomes. subjects (n= ) with asah were recruited from an ongoing study with measures were assessed on admission: hunt and hess (hh), fisher, claassen, glasgow coma scale (gcs), world federation of neurological surgeons (wfns), and nih stroke scale (nihss). dependent variables were measured as follows: delayed cerebral ischemia (dci) was defined as clinical deterioration due to cerebral ischemia, moderate/severe vasospasm was diagnosed using sonography/angiogram, infarction was diagnosed via head ct scan. three and month outcomes were assessed by barthel index and modified rankin scale (mrs). logistic regression and spearman correlation were used. when predicting vasospasm and dci (controlling for age, gender, clipping/coiling), fisher scale had the largest ors ( . and . ), with a ppv of . % and . % (p<. ), respectively. when predicting infarction, hh had the largest or ( . ) with a ppv of ( . %); p=. . all scales were significantly associated with poor mrs ( - ); p<. . for and -month poor mrs, fisher scale had the largest or ( . and . ) with a ppv of . % and . %, respectively. admission nihss had the largest correlation coefficient (-. ) with -month barthel index while wfns had the largest correlation coefficient (-. ) with -month barthel index (p<. ). fisher scale has the strongest association with vasospasm, dci and mrs, while hh has the strongest association with infarction. we recommend clinical studies control for fisher when investigating vasospasm, dci, and mrs and for hh when investigating infarction to determine independent risk factors. to date, there has been a shortage of evidence-based quality improvement initiatives that have shown positive outcomes in the neurosurgical patient population. a single-institution prospective intervention trial with continuous feedback was conducted to investigate the implementation of a urinary tract infection (uti) prevention bundle to decrease the catheterassociated uti rate. all patients admitted to the adult neurological intensive care unit (neuro icu) during a -month period were included. the study consisted of two -month pre-intervention observation periods (approximately catheter days) followed by a month intervention phase ( , catheter days). a comprehensive evidence-based uti bundle encompassing avoidance of catheter insertion, maintenance of sterility, product standardization, and early catheter removal was enacted. the urinary catheter utilization rate dropped from % to . % during the intervention phase (p < . ) without any increase in the rate of sacral decubitus ulcers or other skin breakdown. the rate of catheter-associated uti was also significantly reduced from . to . infections per catheter days (p < . ). there was a linear relationship between the decreased quarterly catheter utilization rate and the decreased catheter-associated uti rate (r = . , p < . ). this single-center prospective study demonstrated that a comprehensive uti prevention bundle along with a continuous quality improvement program can significantly reduce the duration of urinary catheterization and rate of catheterassociated uti in a neuro icu. continued efforts to reduce ca-uti beyond the study resulted in sustained reductions when all components of the bundle were in place and daily foley rounds were maintained as a nursing intervention. matrix metalloproteinases (mmps) are extracellular proteolyic enzymes that may modulate the neuroinflammatory response to brain injury. we sought to determine the effect of mmps on pro-inflammatory cytokine production following severe traumatic brain injury (stbi). as part of a prospective cohort study, adults with stbi underwent multimodal monitoring with high cutoff, cerebral microdialysis and arterial and jugular venous bulb catheters. the concentration of mmps and pro-inflammatory cytokines were measured in microdialysate and blood over -days. interleukin- -alpha (il- ), il- -beta, il- , il- , and tumor necrosis factor-alpha (tnf-alpha) concentrations were initially high in microdialysate and then declined to low levels. the microdialysate concentration of il- also declined after first being high, but then increased between -and -hours. with the exception of il- , il- , and tnf-alpha, the cytokine blood concentration was low to undetectable. using generalized estimating equations, we observed a positive change in the microdialysate concentration of il- [( . pg/ml)/(pg/ml); % ci, . to . ] with an increase in the mmp- microdialysate concentration. in contrast, a significant increase in the microdialysate concentration of mmp- was seen with an increase in il- -alpha [( . pg/ml)/(pg/ml); % ci, . to . ] and il- -beta [( . pg/ml)/(pg/ml); % ci, . to . ]. in blood, a significant change in mmp- occurred during an increase in the levels of il- -beta [( . pg/ml)/(pg/ml); % ci, . to . ] and il- [( . pg/ml)/(pg/ml); % ci, . to . ]. although il- levels were higher in cerebrospinal fluid (csf), no major difference in mmp or cytokine concentration was observed between arterial and jugular venous blood or, for the three patients who were also fitted with csf drainage catheters, between cerebral microdialysate and csf. stbi is associated with a substantial central cytokine or neuroinflammatory response, which may influence or be influenced by production of mmps. severity classification of traumatic brain injury (tbi) has traditionally been based on the glasgow coma scale (gcs), with mild tbi being defined as - . however, there is often a subset of "mild" tbi that requires surgical intervention. the current study examines this subgroup to decipher any symptomatology that may be helpful in identifying who these patients may be. this observational cohort study included consecutive adult patients presenting with a tbi. independent variables included vomiting, seizure, loss of consciousness (loc), alteration of consciousness (aoc), and post-traumatic amnesia (pta); these were tested for correlation with surgical intervention, the dependent variable. data were entered into redcap, a clinical data capture system housed in our center for translational science institute. the z-test for proportions was used to determine significance of symptomatology. statistical analyses were performed in jmp . for the mac. of the total mild tbi cohort (n= , ), % were male. the median age was (iqr: - , r: - ). thirty seven patients required surgical intervention. symptoms significantly associated with surgical intervention on univariate regression included vomiting (p= . ), and aoc (p . ). multiple regression analysis revealed that time (length of) loc (p= . ) and pta (p< . ) were also significantly correlated with surgical intervention. age was also a statistically significant predictor of surgical intervention (p< . ). these pilot data suggest that older patients, as well as patients who present with vomiting, loc, or pta, have a significant likelihood of requiring surgical intervention. this calls attention to proactively seeking these data and ensuring adequate neuroimaging for all patients with tbi, regardless of gcs score at presentation. the prevalence of chronic subdural hematoma (sdh) is expected to increase with an aging population and increased use of anticoagulants. we aimed to develop a tool to predict mortality after sdh. a prospective study was conducted between - of patients with chronic subdural hematoma (n= ) admitted to a tertiary neuro-icu. three-month mortality data was collected. after testing admission demographic, radiographic and - , - , ; p= . ) and herniation (p= . ) were found to be independent predictors of death in multivariate logistic regression analysis. a score was composed ( - ) with each variable weighted based on its independent strength of association with mortality (b value) as - = , gcs - = , herniation= point. overall, % of patients died and -month mortality increased with each point of the sdh score ( = %, = %, = %, = %, = %). the sdh score predicted death (or . , % ci . - . , p< . ) with an area under the curve of . , sensitivity . %, specificity . %, ppv % and npv %. the hosmer and lemeshow and nagelkercke r for this model were . and . , respectively, indicating a strong model. sdh evacuation reduced the odds of death by % when added to a multivariate model including age, gcs and herniation (adjusted or . , % ci . - . , p= . ). the sdh score allows for a reliable prediction of mortality for patients with chronic sdh. this score may help risk stratify patients for surgical treatment. we developed a novel method capable of determining the degree of conformance of observed morphological changes of intracranial pulses with their expected patterns associated with global vasodilatation and vasoconstriction, respectively. these patterns were formed as a template consisting of pulse morphological changes during co tests that were consistent for multiple subjects. we used this novel pulse morphological template matching (pmtm) algorithm to study ) the incidence of cerebral vasoconstriction/vasodilatation associated with lpr increase episodes; ) how likely cerebral vasoconstriction/vasodilatation could lead to or lag behind lpr increase. we studied microdialysis data samples collected in an average interval of . hours from severe tbi patients. the lpr increase episodes were automatically identified using a moving time-window of hours. the pmtm algorithm was applied to the continuous intracranial pressure (icp) signal time-synched to the identified lpr episodes. across all subjects, more than half of the lpr increase episodes are not associated with any detectable cerebral vasoconstriction or vasodilatation (p = e- ). comparing lpr episodes with either vasoconstriction or vasodilatation, it was more likely that vasoconstriction rather than vasodilatation occurred during an lpr increase episode (p = . ). also for out of subjects with dominant number of vasoconstrictive lpr episodes, a causality relationship between vasoconstriction and lpr increase were observed, i.e., vasoconstriction occurred in one hour before lpr increase started. across the tbi subjects studied, the incidence of either vasoconstriction or vasodilatation associated with lpr increase was low. however, about percent of subjects had a dominant number of lpr increase episodes associated with cerebral vasoconstriction. furthermore, cerebral vasoconstriction occurred within one hour preceding lpr increase. placement of an intracranial pressure (icp) monitorto guide the management of severe traumatic brain injury (tbi) patients has been historically performedby neurosurgeons. trials have suggested decreased morbidity and mortality with timely resuscitationand rigorous treatment of intracranial hypertension. we hypothesize that icp monitors can be placed by non-surgeon neurointensivists, with placement success and complication rates comparable to neurosurgeons. we retrospectively reviewed the medical records of tbi patients who required insertion of parenchymal icp monitors from may to december in a large level i trauma center. monitor placement was performed by neurointensivists (board certified by the abim in critical care medicine and by the ucns in neurocritical care). patient data recorded are age, gender, ct findings, icp monitor placement location and length of placement, complications related to the icp monitor, and patient outcomes. twenty seven ( ) these findings were comparable to published outcomes from neurosurgeon placements. we believe that insertion of parenchymal icp monitors should be considered a core skill for neurointensivists and should be included in neurocritical care fellowship training. insertion of icp monitors by neurointensivists is safe and may aid in providing prompt monitoring of patients with severe tbi. use of computers at the bedside for trending primary signals like icp or cpp brings obvious advantages in neuro-critical care unit. software can be extended to calculate secondary indices reflecting underlying pathophysiological phenomena, like disturbance of cerebral compensatory reserve and vascular reactivity. during - more than severe tbi patients were monitored using icm+ software. various modalities were used, including icp, abp, pbtio , nirs, tcd blood flow velocity, brain temperature, etc. from icp and abp waveforms secondary indices were extracted. compensatory reserve was assessed using moving correlation index between slow changes in pulse amplitude and mean icp (rap). pressure reactivity index (prx) was calculated as moving correlation between mean icp and abp. 'optimal cpp' (cppopt) was estimated as cpp corresponding to the best cerebrovascular reactivity within the period of past hours. trending compensatory reserve showed that usually it is good (rap around ) in the first few hours after admission (rap around ), with gradual deterioration triggered by aggravating brain edema. in most cases rap stayed close to + (impaired reserve). it decreased to negative values (exhausted reserve) on top of plateau waves and in refractory intracranial hypertension, indicating critical icp. prx proved to be highly variable, responding to changes in abp, icp and ventilation. it deteriorated on top of plateau waves, and at extreme values of cpp. in cases of refractory intracranial hypertension, deterioration of reactivity seemed to preceed the elevation of icp above mmhg. cppopt fluctuated during the monitoring period. absolute distance between current cpp and cppopt was strongly associated with outcome. too low cpp (below cppopt) correlated with greater mortality rate (p< . ) and too high cpp -with greater rate of severe disability (p< . ). individual observations of secondary indices calculated by icm+ software help in better interpretation of primary signals in intensive care of tbi patients. financial support: the software for brain monitoring icm+ is licensed by the university of cambridge (cambridge enterprise). authors ps and mc have a financial interest in a part of the licensing fee. to determine the differences in hospital outcomes among adult mild traumatic brain injury (tbi) patients where the severity of tbi is defined by glasgow coma scale (gcs) score. this is a retrospective chart review of consecutive adult who came to the ed department of a tertiary care hospital in north central florida. the tbi severity was classified according to gcs score, with patients with gcs score of - categorized as having mild tbi. outcome variables such as admission status, icu admission status, in-hospital death and -month death among patients with different mild gcs scores of , , and . we had a total of mild tbi patients in the specified period of time. the majority of this cohort had a gcs of ( or . %). this was followed by a gcs of ( or . %) and gcs score of ( or . %). there was a statistically significant difference between mild tbi with gcs , , (p< . , anova) with the outcomes of hospital admission ( % vs. % vs. %), icu admission ( % vs. %, vs. %), in hospital death ( % vs. % vs. . %), and month death rate ( % vs. %, vs %). there is a % increase in hospital admission rates for each point decrease in gcs score. the -month death rate nearly doubles with each incremental decrease in gcs score. there is a significant difference in outcome within "mild" head trauma across the continuum. to characterize the patterns of presentation of children with head trauma to the pediatric emergency department. this is an observational cohort study that sought to collect injury and outcome variables with the goal of characterizing the very early natural history of pediatric traumatic brain injury in children over the age of years. statistical analyses were performed using jmp. cohort (n= ) . similar multivariate model showed that as children grew older, they were more likely to be admitted in hospital because of a tbi as a result of recreational activities (p= . ) and traffic accidents (p< . ), and less likely due to sport tbis (p= . ) with adjr = %. % of the children who were admitted ended up in icu with mean icu-los of day with an iqr of - . one percent had an in hospital death. kids with amnesia were significantly more likely to be admitted to the icu (p= . , r = %). children who got admitted to icu (p= . ) and were older ( . ), were significantly more likely to be readmitted to the hospital within days. these preliminary data suggest that pediatric brain injury is not without significant morbidity. the objective of this study was to identify pre-hospital markers of in-hospital mortality in traumatic brain injury (tbi) patients due to fall. this study was an observational cohort study performed at a level- trauma center. study subjects included all adult arriving in emergency department with history of tbi due to fall over a period of months. study variables were symptoms such as vomiting, seizure, loss of consciousness (loc), alteration of consciousness (aoc) & post-traumatic amnesia (pta), glasgow coma scale (gcs) scores, vitals, pre-hospital glucose. jmp for windows & z-test of proportions were used to perform statistical analysis. the study cohort comprised of adult (median age of yrs and iqr of - ). in-hospital death (ihd) was observed in % (n= ) of the total cohort, with male ihd= ( %) greater than female ihd= ( %). pta ( %,p< . ),loc ( %, p< . ) & aoc ( %, p< . ), higher pre-hospital glucose (p= . ) were individually found to be much more significantly associated with ihds versus the whole cohort. multivariate regression analysis showed significant correlation with ihds with: ) higher age (p< . ) when adjusted for severe gcs. ) vomiting (p= . ) and longer duration of loc (p= . ), when adjusted for rest of the symptoms. % of patients presenting to ed with vomiting (p= . ) had gcs score= , and % of that sub-group suffered ihd patients presenting to emergency department with higher blood glucose and symptoms such as pta, aoc, longer duration of loc & vomiting, were more likely to have worse outcome of in-hospital deaths compared to rest of the patients. hence identifying these symptoms in fields might help to make key decisions for providing intensive care and improving the overall patient outcomes. to determine which symptoms affect severity in pediatric traumatic brain injuries (tbi). study design-this observational cohort study was performed at a level one trauma center that has a dedicated pediatric emergency department. consecutive patients age - were included. the age cutoff of years was used because it was decided that younger children may not be ale to report their symptoms, particularly to endorse aoc (alteration of consciousness) or pta(post-traumatic amnesia). the dependent variables were vomiting, seizures(sz), loc (loss of consciousness), aoc, and pta at the time of the head injury. the independent variable was ed tbi severity based of the glasgow coma score, with mild being defined as - , moderate as - , and severe as less than . the median age of the cohort was with an interquartile range of to . % were boys. in the univariate model, all symptoms except vomiting were statistically significant: seizures (p= . ); loc (p= . ); aoc (p< . ), pta (p< . ). multiple regression analysis of these factors revealed all of variables to retain statistical significance. the r coefficient of determination was %, which means that almost one-third of the variance can be explained by just these five factors (symptoms), suggesting that our multivariate model is a robust one. symptoms at time of head injury in children including seizure, loc, aoc and pta were statistically significant predictors of the severity of tbi. this data allows clinicians to judge the severity of the tbi depending on the symptoms at presentation. these pilot data may be useful in designing clinical care algorithms. icp dynamic system of an injured brain is susceptible to various acute changes disturbing the system homeostasis that should be detected by icp monitoring. such a capability is particularly useful for comatose patients. our aim was to demonstrate a novel approach to detect acute deviation from steady state of an icp dynamic system without involving significant mean icp changes. steady state of icp dynamic systems is reflected as icp pulses of similar mean icp resembling each other. therefore, a steady state indicator can be calculated by quantifying inter-pulse distances after matching their mean icp. besides euclidean distance and pearson correlation, geodesic distance was introduced as a novel metric. these different metrics were evaluated on three types of continuous icp: ) those between two consecutive imaging studies showing new acute ventricular enlargement for slit ventricle syndrome patients undergoing a trial of shunt externalization and clamping (svs+); ) those between consecutive brain imaging studies from patients under the same trial without ventricular enlargement (svs-); ) overnight recordings from patients with suspected normal pressure hydrocephalus (nph). it was expected that both svs-and nph recordings represent steady state. we observed that only geodesic distance correctly differentiated between svs+ and svs-and between svs+ and nph while avoiding discriminating between svs-and nph. it was also found that % svs+ cases, none of svs-, and . % of nph cases had a multimodal geodesic distance histogram. pulses with a large number of distant pulses at similar mean icp for the five multimodal-histogram svs+ cases fell in short time windows indicating that acute ventricular changes may have occurred in these confined time windows during which no significant changes of mean icp occurred. geodesic inter-pulse distance is a promising metric to quantify distance intrinsic to the underneath geometric structure of icp signals. patients with severe traumatic brain injury have multiple causes for acute respiratory decompensation. computed tomography pulmonary angiography (ctpa) is being used extensively to evaluate acute cardiorespiratory changes. we reviewed the use of ctpa in critically ill patients with traumatic brain injury to evaluate the results and their impact on patient care. all adult trauma patients with traumatic brain injury who were admitted to our level trauma center intensive care units for greater than hours, were identified (january -december ). those who underwent ctpa for acute respiratory decompensation were reviewed to determine the findings of these studies and the resulting interventions. we identified patients that met these criteria [ admitted to neurosurgery/neurocritical care(ncc) , admitted to trauma service(ts)]; of these patients underwent ctpa studies for acute physiologic changes (ncc- , ts- , p= . ). ts patients were significantly younger with higher severity of injury and longer length of stay. pertinent clinical finding were identified in of the ( %) studies; and included atelectasis/collapse ( %), pleural effusion ( %), pneumonia ( %) and pulmonary embolus ( %). these results prompted targeted interventions, most frequently consisting of modifications of ventilator therapy ( , %), a change or initiation of antibiotic therapy ( , %), mini-bal ( , %) bronchoscopy ( , %), vena cava filter ( , %), and anticoagulation ( , %). no change in patient management occurred after studies. agreement, for different findings, between chest x-ray and ctpa ranged from - %. patients admitted to a ts are more likely to undergo a ctpa evaluation. ctpa is a useful tool in the evaluation of critically ill patients with acute physiologic decompensation beyond the diagnosis of pe. the results of these studies provide significant insight into the underlying pathology in this patient population and offer an opportunity to direct subsequent patient care. somatosensory evoked potentials (ssep) provide valuable information of the neurophysiological state of the patient throughout a surgery and the errors in the surgical procedure are easily noticed. it is hence important to analyze and monitor the ssep during scoliosis surgery in a minimum amount of time. the study uses pca-walsh algorithm to analyze posterior tibial nerve ssep and compare with the conventional signal averaging method in twelve surgical procedures. the tibial ssep from twelve different subjects were recorded and assessed throughout the respective surgeries using a unique pca-walsh algorithm by using only trials at a time and compared the extracted ssep information with conventional method. the ssep were recorded in two bipolar channels c -c and c z -f z throughout the surgery and analyzed remotely using an automated software pca-walsh algorithm. the results are compared with the actual clinical information and presented with the merits. in all the twelve cases, the algorithm results presented consistency throughout the surgery with an average accuracy of . % when compared to the conventional method, which takes several hundred trials. the average variation in time latency was . % and in amplitude was . %, well within the limit of % following the clinical criteria. the pca-walsh algorithm is capable of automated extraction of the tibial ssep during a surgery using a minimum number of trials. the analysis using the algorithm was successful and proved conclusive to the clinical information through the different surgical procedures. the faster recording and analysis of ssep signals provides a much better perspective for neurophysiological monitoring through the surgical procedure. the authors appreciate the support provided by the national science foundation under grants cns- , hrd- , cns- , and cns- . the authors are also thankful for the clinical suppo certain admission characteristics are known predictors of adverse outcomes in moderate-severe traumatic brain injury (mstbi) patients, but explain only / of outcome variability. retrospective studies suggest that non-neurologic organ failure may contribute to / of all deaths after mstbi, but actual incidence rates of intensive care unit (icu) complications and their impact on outcome are not known. we examined the incidence rates of pre-specified medical and neurological icu complications, and their impact on in-hospital mortality and functional outcome at hospital discharge. in a prospective observational study, consecutive mstbi patients from a single level i trauma center between / - / were analyzed. poor outcome was defined as glasgow outcome scale - .multivariable logistic regression was utilized to adjust for admission characteristics and icu length-of-stay. the mean age was years, % were men, and the median glasgow coma scale and injury severity scores were and , respectively. the five most common medical icu complications were: hyperglycemia ( %), fever ( %), hypotension requiring vasopressors ( %), systemic inflammatory response syndrome ( %), anemia requiring transfusion ( %). neurological icu complications were: intracranial pressure crisis (icp; [ % of n= with icp monitor in place]), brain edema ( %), herniation ( %), intracranial rebleed ( %), clinical seizure ( %). among medical complications, hyperglycemia was associated with poor outcome (or . ; % ci - . ]) while cardiac complications (e.g. cardiac arrest, arrhythmia, acute myocardial infarction) were associated with death (or . ; % ci . - . ). when combining medical with neurological icu complications, brain edema (or . ; % ci . - ) was associated with poor outcome, while cardiac complications and brain edema were associated with death (or . ; % ci . - . and or . ; % ci - , respectively). icu complications are very common after mstbi. we identified specific potentially modifiable predictors of adverse outcomes after mstbi. confirmation of our findings in a larger cohort is warranted. too much oxygen may increase oxygen free radical production, possibly triggering cellular injury and apoptosis. although laboratory investigations support the potentially detrimental effects of hyperoxia exposure after tbi, clinical data are lacking. we retrospectively identified tbi patients admitted to our neuro-icu between july and february . we identified a total of patients with complete data including gcs, apache ii, age, gender, abg within hours of injury, and outcome (glascow outcome scale-gos at discharge from the hospital). patients were divided into groups defined a priori based on pao on the first abg values obtained after injury. hyperoxia was defined as pao of mm hg or greater, and normoxia as pao between and . poor outcome is defined as gos of - . the patients in the normoxia group (n = ) and the hyperoxia goup (n = ) were matched on baseline characteristics, age ( among a small number of patients admitted to the neuro-icu following traumatic brain injury, patients with arterial hyperoxia had a trend towards worse outcome compared with patients with normoxia. this provides scientific rationale for large prospective clinical trials of controlled oxygenation in tbi patients. elevated intracranial pressure (eicp) contributes to secondary injury in stbi, therefore its control is paramount. boluses of hypertonic solutions are usually used to reduce icp but the impact of early continuous infusions has not been widely explored. we conducted this study to compare the effect and security of hypertonic saline % (hs %) infusion vs normal saline. all stbi patients arriving to the emergency room within hours of trauma were enrolled to receive an isovolumetric infusion of hs % or normal saline (placebo) during hours. icu physicians and investigators were blinded to the sodium levels during the trial. main endpoint: number of eicp episodes (> mmhg). secondary endpoints: neurologic outcome (gos, mrankin), electrolyte and osmolality levels, and adverse events (ae). twenty non-penetrating shbi patients were included. median age was . years (iq - : . - . ). median iss was (iq - : - ). we didn´t find significant differences for the total number of episodes of eicp at h between groups ( , iq - : - vs. , iq - : - , p= . ); however, when we analyzed patients with at least one episode of eicp we found a significant low number of eicp episodes in hs % group ( , iq - : - vs. , iq - : , - , ; p= . ). we found a sodium plateau at h of infusion (hs %: . ± . vs. control: . ± . meq/l, p= . ) which lasted until the beginning of weaning from hs %. the most frequent ae was hypokalemia and no patient had renal failure. the sixmonth gos and mrankin scores had a non-significant tendency towards better outcomes in hs % group. an early infusion of hs is feasible and seems to be safe in stbi patients. serum sodium kinetics showed a plateau after h of hs % infusion with no consequences in renal function and no rebound effects after tapering. hs % continuous infusion could reduce eicp episodes and it could conduct to better neurologic outcomes at six months. traumatic brain injury causes diffuse shearing of long fiber tracts. this can be detected by quantitative dti imaging even in patients who have primarily localized contusions. in our population the cingulum, cotricospinal tracts and external sagittal striatum were preferentially affected compared to age and gender matched controls. these findings support the use of advanced mri to assess the degree of injury and inform prognosis and goals for rehabilitation. neurocrit care ( ) :s -s most deaths following severe traumatic brain injury (tbi) are associated with a decision to withdraw life-sustaining therapies (wlst)( ). however, the incidence and the impact of wlst in clinical trials is unknown. this systematic review was performed to assess if and how wlst are dealt with in clinical trials involving patients with severe tbi. we searched medline, embase, cochrane central, biosis and cinahl databases and references of included studies. all randomized controlled trials (rcts) published over a -year period (january (january - , in one of selected journals in general medicine, critical care medicine and neurology/neurosurgery were considered for eligibility if ) and reporting data on mortality. our primary outcome was the assessment of wlst. secondary outcomes were the timing of evaluation, justification for wlst, proportion of wlst among deaths, factors that may have influenced the wlst and risk of bias of rcts. two reviewers selected rcts and collected data independently using a standardized case report form. from citations retrieved, rcts were included (n= , , ranging from to patients). were single center rcts and were multicenter. the incidence of wlst was reported in studies ( . %). three studies reported crude numbers of patients, studies reported the timing of wlst and studies reported the justification for the decision to wlst. studies were considered at high risk of bias, study at low risk of bias and studies did not give enough information to conclude on the risk of bias. wlst was rarely reported in rcts involving patients with severe tbi over the last decade. considering the variation of wlst in clinical practice, we suggest that wlst should be systematically reported in rcts performed in tbi. reference : . turgeon et al. cmaj . previous pediatric brain injury studies have considered fevers as discrete events instead of as a "temperature dose." we sought to evaluate the population size difference captured at various fever thresholds in severely brain-injured pediatric patients, considering fever burden in terms of degree-hours; and to compare fever burden in pediatric traumatic brain injury (tbi) vs. cardiac arrest (ca). charts from brain- y, admitted in - within hrs of admission were included. no temperature modulation protocols existed in the pediatric icu during this period. -day core temperatures were used to generate areas-under-the-curve (auc) above fever thresholds of . , , . , and o c. these were normalized for different lengths of stay. charts met inclusion criteria, with mean patient age . y (range d - y). diagnoses distributed (non-exclusively) as ca, accidental tbi, non-subarachnoid hemorrhage (sah) intracranial bleeds, sah, strokes, non-accidental tbi, ca after tbi, and other cns pathologies. cohort mortality was %, with % suffering brain death. fever burdens were measurable in % of patients over . o c, in % over o c, and in % over o c. normalized fever burdens at these thresholds were statistically different by -way anova (p< . ), with all fever burdens being statistically less than at . o c. remarkably, a shift in threshold from . to o c resulted in a % reduction in measured fever burden. fever burdens fell from a peak of . ± . o c-h on day to . ± . o c-h on day after admission. accidental tbi (n= ) and ca (n= ) patients did not experience different fever burdens above . o c. measured fever burden is markedly affected by shifting the threshold from to . o c. tbi and ca appear to induce similar fever burdens. pediatric fever burden reference values will allow more quantitative comparisons in severely braininjured children. little is known about the natural history of function after traumatic brain injury. our objective was to track the stability of drs scores over time and to identify factors associated with worsening drs scores. we collected disability rating scale (drs) scores, which capture the cognitive ability to perform activities of daily living such as communication, motor response, feeding, toileting, overall functioning and employability, longitudinally on severely brain injured patients in neurosurgery clinic. multivariable logistic regression was used to identify patient factors that were independently associated with changes in drs score over time. patients with severe brain injury had more than one drs score collected. of these patients, had worsening scores over time. changes in scores ranged from - to (mean - . , standard deviation . ). this represented a change from partial/no disability to moderate disability for patients and from moderate to severe disability for patients. patients improved from moderate to partial/no disability while only one patient improved from severe to moderate disability. using multivariable logistic regression, there were no patient factors that were associated with worsening drs scores including gender, age, comorbidities, race, insurance status, mechanism, injury severity score, gcs or final disposition. while half of worsening drs scores were seen within the first days after discharge, were seen months or more after the hospital stay, with one seen over a year after hospital discharge. for the most part, drs scores were stable over time. a group of patients were identified who experienced significant decline in function as far out from discharge as a year. this preliminary study highlights the need to identify those at risk for decline and to set up mechanisms for long-term follow-up for those patients in need. the identification of traumatic axonal injury (tai) lesions that undergo neuronal recovery could improve prognostication in patients with traumatic brain injury (tbi) and facilitate the development of novel therapies for preventing secondary axotomy. we aimed to determine whether diffusion tensor imaging (dti) detects neuronal recovery after tai. we retrospectively identified tbi patients ( severe, moderate, mild) who underwent at least acute-to-subacute dti scans and who had at least tai lesion in the corpus callosum (cc), as defined by hyperintensity on dwi or t flair. the median number of days from tbi to image acquisition was (range - ) for the first dti scan and (range - ) for the second scan. tai lesions were manually outlined on the acute dwi datasets and then coregistered to the subacute datasets to measure longitudinal changes in lesional fractional anisotropy (fa) and apparent diffusion coefficient (adc). "neuronal recovery" within a tai lesion was defined on the final scan by mean lesional fa within standard deviations of published normal fa values for the cc. initial fa and adc values in lesions with and without neuronal recovery were compared (unpaired t-test). eleven cc tai lesions ( splenium, body, genu) were identified. fa recovered in splenium lesions ( . +/- . [mean+/-sd]) and genu lesion ( . ) on the final scan. three of these lesions were flair hyperintense, were associated with gre microbleeds, and were initially adc hypointense. splenium lesions with neuronal recovery did not differ significantly from lesions without recovery for fa ( . +/- . vs. . +/- . , p= . ) or adc ( +/- vs. +/- x ^- mm^ /s, p= . ) on the initial scan. dti may detect neuronal recovery within tai lesions, as indicated by subacute normalization of fa. acute dti biomarkers of tai reversibility were not identified in this preliminary analysis. increased intracranial pressure (icp) in patients with traumatic brain injury (tbi) is associated with higher mortality and poor outcome. mannitol and hypertonic saline (hts) have both been used to treat high icp, but it is unclear which one is more effective. we compared the effect of mannitol and hts on lowering cumulative icp burden after severe tbi. the brain trauma foundation tbi-trac® new york state database was used for this retrospective study. a total of patients with severe tbi who received only hts were identified. patients who received only mannitol were matched for age, pupillary reactivity, occurrence of hypotension on day . univariate analysis was performed to compare icp burden, cumulative hyperosmotic doses, number of icu days (wilcoxon signed rank test), and two-week mortality (mcnemar test). icp burden was defined as the total number of days with icp spikes (icp> mmhg) expressed as a percentage of total number of days of icp monitoring. cumulative hts and mannitol doses were converted to osmolar doses for comparison. the mean age and gcs were similar in the two groups ( . vs. . years; . vs. . ; hts vs. mannitol, respectively) . patients received % hts and received . % hts. all patients in the mannitol group received % mannitol. there was no difference in number of days of icp monitoring (p= . ) or number of icu days (p= . ) in the two groups. icp burden was significantly lower in hts group vs. mannitol group ( . % vs. . %. p= . ). there was no significant difference in the cumulative dose of hts and mannitol (p= . ), and two-week mortality in the two groups was similar (p= . ). hts is more effective in lowering cumulative icp burden after severe tbi compared to mannitol. this did not translate into reduction in two-week mortality, possibly due to the small sample size. spreading depressions (sds) have been consistently associated with hypoglycemia in animal studies. the frequency of these depolarization events, while influencing infarct size, also appears to be influenced by the plasma glucose concentration during experimental ischemia. low cerebral dialysate glucose have also been correlated with sd events in humans. we hypothesized that low serum glucose should be associated with an increase in the frequency of sd events in human acute brain injury. to determine the relationship between serum glucose and cortical spreading depolarizations (sds) after traumatic brain injury (tbi), subdural electrode strips were placed on peri-contusional cortex in patients from centers who underwent craniotomy following tbi. prospective electrocorticography was performed during neurointensive care with retrospective analysis of hourly serum glucose data. patients were divided into those with sds and those without and the distribution of glucose values among these two groups were compared using the -way kolmogorov-smirnov method. in patients ( %), sds (spreading depressions and peri-infarct depolarizations) were observed. the probability of a depolarization occurring increased significantly as a function of rising serum glucose (p< . ). median glucose values in patients with and without sds was . and . mmol/l, respectively. among patients with sds, glucose values recorded within minutes of the onset of an sd were higher than those occurring < minutes before an sd (p< . e- ) ( figure ). serum glucose does not appear to affect the generation of sds as it does in animals but paradoxically may be elevated. this may reflect a stress response to the initial acute brain injury and critical illness or a physiologic mechanism to increase glucose supply during sd events in which cerebral glucose utilization is increased. overall, the data suggest that plasma glucose is being managed within appropriate levels in this study group. to determine difference in tbi severity and abnormal radiologic findings in different age groups. this was an observational cohort study on all adult patients (> yrs) arriving to the emergency department, with a history of traumatic brain injury as a result of "fall" at a level trauma center in the southeastern united states. data collected included ed gcs score and head ct results. abnormal ct scans have the presence of either an intra-cranial bleed and/or cranial fracture. there were patients in the cohort with history of fall with median age of yrs (iqr of - ). we divided them into two age groups: group a: - yrs( %) & group-b: > yrs( %). group a comprised mostly of males ( %) compared to females, meanwhile group b was equivocal in gender composition ( % male). out of the whole cohort of patients, % patients had head ct performed. out of these, . % (n= ) showed an abnormal head ct. age group b ( %) had a significantly greater percentage of abnormal ct scans compared to group a ( %) (p< . ). among abnormal ct scans, group a ( %) had a significantly greater percentage of skull fractures than group b ( %) (p= . ). among patients with mild and moderate tbi (gcs> ), group b ( %) was more likely to have an abnormal ct scan than group a ( %) (p< . ), however, there is no significant difference between likelihood of abnormal head ct between group a and b for severe tbi. younger adults are at a higher risk of cranial fractures after a fall related tbi, probably due to severe mechanisms of injury. on the other hand elderly population with mild tbi mostly due to ground level falls had worse outcomes on ct scans. accumulating pre-clinical data suggests that matrix metalloproteinase (mmp) expression following cerebral trauma contributes to brain injury. we sought to characterize the temporal mmp response to severe traumatic brain injury (stbi) in humans and its relationship with outcomes. we conducted a prospective cohort study that included adults with stbi. high-cutoff, cerebral microdialysis and arterial and jugular venous bulb catheters were used to measure the concentration of mmps and other markers over -days. the concentration of mmp- was initially low in microdialysate and blood, but increased between -and -hours. mmp- blood levels were high and stable throughout the study while blood levels of mmp- were initially low and then gradually rose. in microdialysate, mmp- and - increased and then peaked between -and -hours. mmp- also increased in microdialysate following stbi while its levels were low and stable in blood. mmp- and - were initially high in microdialysate and then slowly decreased over time. while the concentration of mmp- was also initially high in blood and then progressively declined, the mmp- blood level increased with time. among the patients that also had cerebrospinal fluid (csf) drains, marked and sometimes opposite concentration trends were observed for mmp- in microdialysate versus csf. generalized estimating equations suggested that significant changes in mean microdialysate concentrations of mmp- , - , - , and - and mmp- , - , - , and - occurred with increases in microdialysate glucose and the lactate pyruvate ratio, respectively. moreover, the mean microdialysate level of mmp- increased with intracranial pressure (icp) [( . pg/ml)/mmhg; % confidence interval, . to . ] while that of mmp- decreased with cerebral perfusion pressure (cpp) [(- . pg/ml)/mmhg; % confidence interval, - . to - . ]. monitoring of mmps following stbi is feasible, and their expression may be associated with cerebral metabolism, icp, and cpp. to determine significance of laboratory markers for in-hospital death after fall related adult traumatic brain injury. this was a consecutive cohort observational study done at a level- trauma center serving surrounding counties. cohort consisted of all adult patients (> yrs) arriving to the ed with a history of fall. study variables were lab values of the following parameters on ed admission: sodium, potassium, bicarbonate, lactate, blood glucose, inr, aptt, wbc, rbc, platelets; along with pre-hospital glucose values in the field. study cohort comprised of adult subjects arriving at ed with history of fall with median age of yrs (iqr of - ). in-hospital death (ihd) was observed in % (n= ) of the total cohort, with male ihd= ( %), and female ihd= ( %). older age groups [> yr] ( %, n= ) had higher incidence of in-hospital deaths compared to younger age group - yr ( %, n= ) with p= . (ci= . - . ). in a univariate regression model higher levels of: pre-hospital glucose (p= . ), ed blood glucose (p< . ), lactate (p= . ), inr (p= . ), aptt (p< . ) and wbc (p< . ) were significant individual predictors of in-hospital death. while lower levels of bicarbonate (p< . ) and rbc (p< . ) were significant individual predictors of in-hospital death. the following multivariate regression models showed statistical significance with higher probability of in-hospital death: ) higher: ed blood glucose (p= . ), aptt value (p= . ) | lower: bicarbonate (p= . ), rbc (p= . ) with adj.r = % ) higher: aptt value (p= . ) and wbc count (p= . ) ) higher: aptt value (p= . ), older age (p= . ) | lower rbc (p= . ) and gcs scores (p< . ) with adj.r = % lab parameters such as ed blood glucose, rbc count, wbc count, bicarbonate level & aptt level are individually or simultaneously important predictors of in-hospital death in adult tbi patients with history of fall. traumatic brain injury (tbi) is an epidemic with severe consequences. brain tissue oxygen tension (pbto ) monitors detect secondary injury and direct clinical therapies to mitigate damage. blood transfusion is one therapy often used, however its effect in tbi patients is not well defined. we studied pbto data in patients who received transfusion after tbi. sixty-nine severe tbi patients were consecutively admitted to a neurocritical care unit and received pbto monitoring as part of standard clinical care for this unit. data were collected from electronic medical records as entered by the bedside nurse. patients were managed according to the brain trauma foundation guidelines. transfusions were identified through nursing comments. hourly pbto values were analyzed for up to six hours after starting transfusion. other factors were also analyzed for their potential influence on pbto readings. of patients, received a total of transfusions in the setting of pbto monitoring. two groups were identified: transfusions that led to an increase in pbto and those that did not. six transfusions resulted in increased pbto , with an average increase of . mm hg. twenty-two transfusions did not: of these were unchanged and decreased. the groups did not differ in age (mean . and . , respectively), maximum temperature (mean . and . ), minimum cerebral perfusion pressure (mean . and . ), or initial glasgow coma scale (gcs) (mean . and . ). blood transfusion is often used in the critical care setting. the effect of transfusion on brain tissue oxygen tension is variable. age, temperature, cerebral perfusion pressure, and initial gcs were not useful in distinguishing patients who benefited from transfusion. pbto only rises in a minority of patients; therefore additional prospective studies are needed to evaluate which patients are likely to benefit from transfusion. mannitol use in patients with traumatic brain injury can lead to acute renal failure and may worsen outcome. the purpose of this study is to determine the rate of acute renal failure (arf) among patients treated with mannitol and its impact on outcome in a multicenter review. we analyzed a one-year data ( ) ( ) from the premier database, a nationally representative hospital discharge database in the united states. we compared baseline and clinical characteristics of patients with traumatic brain injury (tbi) treated with mannitol in the first days of admission who developed arf to those who didn't. length of stay, cost of hospitalization and discharge status were ascertained. from a total of admissions with a diagnosis of traumatic brain injury requiring mannitol within the first days of admission, % (n= ) of patients had arf. arf is a common complication of tbi treated with mannitol. it is associated with longer length of hospital stay and increased rates of in-hospital mortality. the result highlights the importance of using alternative therapy to hyperosmotic agents such as hypertonic saline in treatment of tbi patients at risk for acute renal failure. cervical spine immobilization (csi) is a relative contraindication for percutaneous dilatational tracheostomy (pdt) because of the inability to extend the neck, making tracheal puncture at the correct level more challenging. patients with csi routinely undergo pdt at our institution, however, with both traditional bronchoscopic as well as with real-time ultrasound (rtu) guidance. our objective was to review the incidence of complications related to pdt in patients with csi versus patients without csi. we reviewed the records of consecutive patients who underwent pdt performed by a single operator at our neurocritical care unit between / - / . all patients requiring tracheostomy are screened for eligibility for pdt by the attending neurointensivist on service. we recorded the percentage of patients who successfully underwent pdt vs requiring conversion to surgical tracheostomy, the specific guidance used (bronchoscopy, rtu) and all short-and long-term complications including placement of the tube above the first tracheal ring. a total of patients underwent pdt performed by a single neurointensivist. all patients screened by the operator underwent an attempt at pdt, and all patients successfully completed the procedure without conversion to surgical tracheostomy. ninety-eight of ( %) did not require csi and ( %) required csi. in the csi group, bronchoscopy alone was used in / ( %) and bronchoscopy plus rtu in / ( %). no complications occurred in the csi group. in the no-csi group, there were ( %) complications (one tracheal granuloma and two tube dislodgments within days). no other short or long term complications were recorded. all tubes were placed below the first tracheal ring. it is feasible to safely perform pdt in patients with cervical spine immobilization using bronchoscopic and real-time ultrasound guidance. following traumatic brain injury (tbi), increased serum biochemical marker levels reflect the extent of neurological damage, prognosis and clinical outcomes. effective tbi management strategies are lacking. despite the neuroprotective effects of therapeutic hypothermia after cardiac arrest, its tbi use remains controversial. delays in achieving target temperatures in human trials taking - hours (nabish-i; nabish-ii) may have contributed to the lack of benefit. we hypothesized prompt, rapid induction of hypothermia, immediately following tbi would lower predictive serum biomarkers of brain injured swine. sixteen domestic cross-bred pigs ( - kg) were subjected to a atm ( ms) fluid percussion tbi. eight injured animals were cooled to °c within minutes of injury and maintained for hours using transpulmonary hypothermia. eight control animals were maintained at °c using similar doses of inhalational and intravenous general anesthesia. brain temperature was monitored with camino.® serum markers of tbi: s- calcium binding protein b (s- b), neuron-specific enolase (nse), glial fibrillary acidic protein (gfap) and phosphorylated axonal form of the neurofilament subunit nf-h (pnf-h) were measured prior to injury and seven times over hours. surviving animals were euthanized and necropsied five days post-injury. at , , and hours, s- b, nse and pnf-h, were lower in the hypothermia group vs. controls. gfap levels were decreased at hours. after injury, peaks and troughs of the biomarkers occurred at various intervals. s- b levels were reduced in both groups during the initial hours post-injury, with control levels increasing at hours. early initiation and rapid cooling of brain temperature to - °c for hours was associated with attenuated s- b, nse, gfap and pnf-h levels in swine. general anesthesia was associated with early mitigated s b levels. prompt therapeutic hypothermia and prolonged anesthesia may offer neuroprotection after tbi. mild traumatic brain injury (mtbi) from blast exposure represents a significant threat to military personnel. until now there has been no way of knowing what the individual service member experienced during an exposure. we report the first individual measurements recorded during combat operations and how those readings were used to assist evaluation of the injured service member. the nato role- hospital, kandahar afghanistan received the index case of a service member (sm) exposed to an improvised explosive devise (ied) blast while wearing a blast dosimetry system composed of blast gauges placed on the back of the helmet, chest, and shoulder. the gauges include status lights that allow immediate feedback for injury risk via colored lights: green = negligible (< psi peak), yellow = moderate (between and psi), and red = severe ( psi and above). in addition, time traces of the overpressure and -axis acceleration are recorded and available for download through a micro-usb port. the sm's gauges were initially checked hour minutes after the blast, demonstrating a yellow status light. the blast data downloaded from the gauges demonstrated a consistent exposure of . msec composed of a primary flow immediately followed by a secondary wave. the head gauge recorded a peak overpressure of . psi and impulse pressure of . psi-sec. there was msec of sustained pressure above psi from the primary flow. all gauges demonstrated similar blast profiles, including a secondary reflective wave. these measurements are firsts in both the recording of an individual's exposure during a blast related attack and the use of that data for patient triage and medical evaluation. blast gauges measure environmental exposure and do not diagnose mtbi, however; they do provide clinicians with important information in the evaluation of patients subjected to blast. to consider the definition of initial signs and symptoms to compare outcomes after "severe" traumatic brain injury regard to mechanism of injury. design-this study included all adult patients who presented to ed at a level- trauma center with severe (gcs score< ) traumatic brain injury. from the total cohort(n= ), % suffered tbi because of "fall" and % due to traffic accident(mvc). significant proportion of each sub-group was comprised of males ( % in-mvc with median-age= ; % in-falls with median-age= ) · for all the patients arriving to ed after a traffic accident with severe gcs: % had loc, % had aoc, % had pta, % got admitted to hospital, % had an abnormal head ct (bleed/fracture), % got admitted to icu, % had some neuro-surgical intervention and % patients died in hospital. · for all the patients arriving to ed after a history of fall with severe gcs: % had loc, % had aoc, % had pta, % got admitted to hospital, % had an abnormal head ct (bleed/fracture), % got admitted to icu, % had some neuro-surgical intervention and % patients died in hospital. · decrease in systolic blood pressure (p= . ) and increase in diastolic blood pressure (p= . ) are more likely to have a fracture after a traffic accident in severe tbi. increasing of blood pressure p= . ) and decreasing of pulse (p= . ) is significantly associated with icu admission after a fall. comparing data for two most common mechanism of injury in severe tbi suggest that some vital signs and symptoms have significant impact with outcomes depends on mechanism of injury. these observations should be studied in larger cohort to find more significant association between mechanism and outcomes. cerebral edema is the one of the most significant predictors of poor outcome after traumatic brain injury. it is still unclear what the pathophysiological and cellular mechanisms and predictors of post-traumatic edema are. the exponential growth in genetic information has opened an avenue for investigation in traumatic brain injury and implicated specific genes in the pathophysiology of post-traumatic injury edema. two examples are the aquaporin- and cacna genes, which respectively encode water and calcium channels. the aquaporin- gene on chromosome q . - . encodes the aquaporin- protein (aqp ) water channel. aqp is one of the bidirectional high capacity water channels that is primarily expressed in astrocytic foot processes in the central nervous system at the blood-brain barrier and is thought to be critical for brain water homeostasis. experimental studies showed that aqp deficient mice had significantly reduced cerebral edema and better survival in a water intoxication model. the cacna gene on chromosome p encodes the a a subunit of a neuronal calcium channel. patients with familial hemiplegic migraine and delayed fatal cerebral edema and seizures from minor trauma have been found to have mutations in cacna , which are hypothesized to enhance development of cytotoxic edema. a missense mutation is reported to enhance risk of delayed fatal cerebral edema. hypothesis: the cacna gene missense mutation s l and aqp polymorphisms will be over-represented in patients with post-traumatic cerebral edema. to perform full exon sequence analysis of these two genes in well-defined cases of excessive cerebral edema. our long term goal is to systematically investigate genetic variants as determinants of risk of excessive cerebral edema. patient recruitment is currently ongoing. it is hoped that this will further elucidate secondary mechanisms of injury specifically in the formation of post-traumatic edema and lead to targeted therapies in the future. microwave occurs when improvised explosive devices was exploded. however, the effect for brain by microwave has not been clarified. under general anesthesia, s-d rats were irradiated by head-focused microwave by microwave fixation system (model mmw- / muromachi kikai co., ltd.), which were classified in three groups ( . kw/ . sec (i), . kw/ . sec (ii), . kw/ . sec (iii), and sham group) by intensity (n= in each group). vital signs were evaluated, arterial blood gas was examined, and we checked pathologic findings by hematoxylin-eosin (he) stain immediately after microwave irradiation, post hours, hours, hours, hours, weeks, and weeks in each group. blood pressure was elevated transiently immediately after irradiation, and recovered in short period. pao was unchanged in post-irradiation phase, except in group i. in he stain, neuron was degenerated and left out especially in cerebral cortex and hippocampus, microglia cells were accumulated in these regions. these pathological changes were observed frequently and earlier, when irradiation was intense. the result was firstly reported that head-focused microwave irradiation induced brain injury in s-d rats, and this brain injury was related with intensity of microwave. pathological change was impressive because it was occurred gradually and progressive. further study will be required, whether this type of brain injury is similar with traumatic brain injury, or cerebral ischemia or not, and the study of behavioral effects of microwave irradiation is necessary, especially when the intensity of irradiation was not severe. the efficacy of decompressive craniectomy (dc) in the treatment of moderate-severe traumatic brain injury (mstbi) is a topic of debate in neurocritical care. despite the recently published randomized dc in diffuse tbi (decra) trial, it is still unclear when and for which tbi patients this procedure should be considered. in order to assess the utility of dc in evidence-based clinical practice, we present a matched case-control study that compares surgical and non-surgical outcomes among patients with mstbi. we conducted a retrospective analysis of mstbi injuries treated at a single level i trauma center from to . twenty mstbi patients aged between and years, who underwent dc, were enrolled. paired controls that underwent medical therapy only were selected according to glasgow coma scale (gcs) score and age. primary lesion type, pupil reactivity, hypotension, hypoxia and icp crisis were secondarily considered in matching cases with controls. we focused on mortality, glasgow outcome score (gos) score upon hospital discharge and gos score at months as the primary measures of outcome. in the dc group, we found that % of patients died; % had a favorable outcome at discharge ( or higher on gos); and % had favorable outcome at months. in the control standard-care group, we found that % of patients died; % had favorable outcome at discharge; and % had favorable outcome at months. pupil reactivity and gcs score on admission were the variables highly correlated with mortality. statistical analysis will be available at the meeting and presented for the first time. in this cohort, undergoing dc did not seem to confer a mortality benefit to patients with mstbi. good recovery after mstbi was observed in a larger percentage of the non-surgical group, which is consistent with the findings of the decra trial. each year in the united states, over . million patients present to emergency departments as a result of traumatic brain injury (tbi). severity classification of tbi is based on the glasgow coma score (gcs), with severe tbi being a gcs score between and . there is always a subset of "severe" tbi that requires surgical intervention. the current study examines this subgroup to decipher any symptomatology that may be helpful in identifying who these patients are. the objective is to determine which if any factors predict the need for surgical intervention in patients with severe traumatic brain injury (tbi). this study is a subgroup analysis of the larger cohort of consecutive adult tbi patients that presented to the ed. our sample included only severe tbi patients (gcs< ). besides descriptive analysis, logistic regression analysis was done to determine the significant predictors of surgical intervention in this subset of patients. lab values (sodium, potassium, bicarbonate, lactate, blood glucose, wbc, rbc, platelets, inr, aptt) and symptoms (such as-seizures, vomiting, loss of consciousness, alteration of consciousness, post-traumatic amnesia) were the dependent variables compared with surgical intervention (independent variable). of the total severe tbi cohort (n= ), % required surgical intervention. presence of abnormal head ct (bleed in % of the total cohort) is significantly associated with surgical intervention (p= . ). vomiting (p= . ), lactate (p= . ), higher wbc (p= . ) and lower platelet count (p= . ) individually showed significant association with surgical intervention on a univariate regression model. these data suggest that abnormal head cts, particularly those that result from bleeding, as well as lactate, platelet count, wbc count and vomiting are significantly associated with surgical intervention. the association of lab values with likelihood of undergoing surgical intervention is an interesting future research point. to study the potential usefulness of initial vital parameters and laboratory evaluations to predict short term prognostic this is an observational cohort study of all adult patients who came to the emergency department(ed) of a tertiary care hospital, in a month period during - . for the purpose of analysis, we considered initial vitals and lab values available for all patients. we individually compared vitals (pulse and mean arterial pressure-map) and laboratory values [sodium(na + ), potassium(k + ), bicarbonate(hco -), glucose, wbc, rbc, platelets, inr) for the following prognostic variables: abnormal head ct finding(yes/no), hospital admission (yes/no), icu admission, in-hospital death, hospital length of stay(hlos), and -month mortality using t-tests and correlations. the significant variables were then entered into a logistic regression model (for categorical variables) and a multiple regression model (for continuous variables) simultaneously to determine significant predictors of prognostic outcomes. significance level was set at p= . . increase in glucose(p= . ) and wbc(p< . ) lead to a higher likelihood of having an abnormal head ct, when controlling for map and hco -; increase in glucose (p= . ) and wbc (p= . ), and decrease in hco -(p= . ) and platelets(p= . ) increases the likelihood of getting admitted, when controlling for map, k + , and rbc; increased glucose(p< . ), decreased hco -(p= . ) and decreased platelets(p= . ) increases chances of in-hospital death, when controlling for wbc and inr; increased glucose(p= . ), increased wbc(p< . ), and decrease in rbc(p= . ) increases hlos, while controlling for pulse, k + , and hco -. the study indicates that some initial vitals and lab values can help to determine the prognostic outcomes in adult traumatic brain injury. though our study is limited by a single-site patient population, the interesting findings warrant further research efforts in this specific area. ultrasonic assessment of optic nerve sheath diameter (onsd) as a non-invasive measure of intracranial pressure (icp) has been evaluated in the literature as a potential valid technique for rapid icp estimation in the absence of invasive intracranial monitoring. the technique can be challenging to perform and little literature exists surrounding intra-operator variability. in this study we propose an examination of onsd utilizing a variety of novel ocular models, to both define the ability of the ultrasound linear array probe to capture different known onsd, and to assess intra-operator variability with the technique. here we present the model and data. we designed ocular models composed of gelatin spheres and variable three dimensional printed cylinders, which simulate the globe of the eye and variable onsd's respectively. these models will then be suspended in a gelatin background. operators will then utilize the linear array ultrasound probe on these models in order to determine onsd of sizes, with measurements each in order to assess intra-operator variability with the technique. our optic nerve sheath model offers ultrasound images comparable to in vivo, and is quick to manufacture. analyzing the data, we removed the first two measurements from the series of ten. we defined those as "practice attempts" with the technique. for the onsd models, the means were: . mm with sd of . mm ( % ci of . ), . mm with sd of . mm ( % ci of . ), . mm with sd of . mm ( % ci of . ). utilizing the standard linear array ultrasound probe for onsd measurements in our model provided reliable results with minimal intra-operator variability across variable sheath sizes. knowing this, we can further apply this novel model of onsd to us teaching and training courses with confidence in its ability and the techniques ability to produce consistent results. the objective of this study was to identify factors (signs and symptoms after injury, vital parameters, and glucose) that can be used as predictors of an intracranial bleed. this will improve identification and treatment of patients who present to the emergency department (ed) with tbis. this is an irb approved observational cohort study done at a level trauma center, and included all adult patients presenting to the ed following a tbi. data for patients presented during study variables included age, loss of consciousness (loc), seizure (sz), vomiting, alteration of consciousness (aoc), post-traumatic amnesia (pta), glucose level, pulse, and blood pressure (bp). all variables were tested for association with intracranial bleeding using chi-square tests of independence, t-tests, and then significant variables were included in a regression model. limitation of study were chart review and a single ed. the cohort consisted of , patients, of which % (n= ) had a ct scan of head. % of total patients had an abnormal head ct, and % of those had an intracranial bleed. statistical analysis indicated that loc (p= . ), aoc (p= . ), pta (p< . ) and advanced age (p= . ) were significantly correlated with having a bleed. vomiting and sz were not statistically significant. among patients who had head cts, both pulse and systolic blood pressure decreased between the first and second measurements; both pulse(p= . ) and bp(p= . ) decreased significantly less in patients with bleeds compared to those without bleeds. additionally, higher ed glucose level was associated with having a bleed (p< . ) on head ct. these data indicate that older age, loc, aoc, pta, and elevated glucose levels can be used as predictors of intracranial bleeds. sustained elevation of pulse and systolic blood pressure may also be indicative of a bleed in tbi patients. patients with moderate-severe traumatic brain injury (mstbi) commonly die from withdrawal of support, likely as a consequence of an unfavorable outcome prognosis provided to the family by the treating physician. it is unknown whether prognostication may lead to self-fulfilling prophecies, and whether the presence of intensive care unit (icu) complications may accentuate possible provider bias. in this study, we surveyed clinicians caring for patients with mstbi to examine the variability of outcome prognostication and the influence of icu complications on these predictions. we conducted an anonymous electronic survey of clinicians, including faculty members (neurology, neurosurgery, trauma, anesthesia/critical care), neurology house staff, icu affiliate practitioners and neuroicu nurses at a single level i trauma center. the survey included three tbi case vignettes and their respective icu courses. questions were designed to assess the utilization of known tbi prognostic models, relative importance of icu complications for outcome prognostication and aggressiveness of care recommended by the survey participant. a total of surveys were distributed by email or paper, and have been returned. so far, we have found that % of participants consider medical icu complications as very important in tbi prognostication. age, icu course and head ct findings are the prognostic variables considered most important to outcomes. % of non-critical care neurologists are uncomfortable providing tbi prognostication. case responses suggest that clinicians tend to recommend aggressive care (surgery), but predict unfavorable outcomes. the survey is ongoing, but complete results will be available at the meeting and presented for the first time. we have discovered great variability in outcome predictions made by clinicians with different levels of experience in treating mstbi. self-fulfilling prophecies may exist among mstbi outcomes. outcome studies should focus not only on admission variables, but also on icu complications in order to guide clinicians in providing prognostication. the objective of this study was to identify pre-hospital factors that are associated with worse severity of head injury in order to help physicians identify when tbi treatment may be necessary. this is an observational cohort study that included adult patients presenting to the(ed) following a motor vehicle collision. study variables included age, gender, seatbelt use, loss of consciousness (loc), seizure, vomiting, alteration in consciousness (aoc), and post-traumatic amnesia (pta). severity of tbi was classified according to the glasgow coma scale, with mild defined as - , moderate being - , and severe being anything less than . the gcs was obtained both in the pre-hospital and ed settings. the cohort of was % male. the median age was (iqr: - , r: - ). the breakdown of severity in the prehospital setting (n= ) was % mild, % moderate, and % severe. in the ed (n= ), the breakdown was % mild, % moderate, and % severe. pre-hospital factors significant for the z-test included seatbelt (sb) use, loc, aoc, pta, and gender. males, patients who did not wear seatbelts, and patients who had a positive loc, aoc, or pta were more likely to sustain a moderate or severe tbi. having a seizure was also significantly associated with increased tbi severity (p= . ). (see table ) additionally, the data show that the likelihood of having an abnormal head ct increases with age (p< . ). although vomiting was associated with greater tbi severity, the results were not statistically significant. early symptoms such as loc, aoc, seizures, and pta are early predictors of worse severity in patients who sustain a head injury during their motor vehicle collision. age, male gender, and lack of seatbelt use also correlate with greater tbi severity. identifying crucial symptomatic predictors of icu admissions, icu length of stay and mortality rates in traumatic brain injury (tbi) patients with history of fall. retrospective chart analysis was performed on all adult patients arriving to emergency department with history of fall at a level one trauma center for parameters like vomiting, alteration of consciousness (aoc) & loss of consciousness (loc) after tbi; post-traumatic amnesia (pta) and history of seizures before or after injury, along with outcomes such as icu admission & icu length of stay. from the total cohort (n= ), % (n= ) of patients were admitted to icu, most of them were males( %,p= . ). aoc was found to be strongly associated with icu admission ( %, p< . )[including the patients who had brief loss of consciousness of < mins( %)], and month mortality rates(p= . ) when adjusted for mild gcs scores. · icu length of stay was higher in patients admitted to icu with aoc (p= . ) and pta ( . ). icu admissions had higher day readmission (p= . ), in-hospital death (p< . ) and month mortality rate ( %, p< . ). · % of patients were found to have intra-cranial bleed when presented to ed with aoc(p= . ), and % of these patients were admitted to icu. on a multivariate regression model analysis, patients who had abnormal head ct with mild gcs on ed presentation had higher month mortality rates (p= . ) when adjusted for age. patients with symptoms such as alteration of consciousness and post-traumatic amnesia after traumatic brain injury as a result of fall are more likely to be admitted to icu with significantly longer icu length of stay. mild traumatic brain injuries in fall patients should not be overlooked in daily practices because of significant mortality rates. cardiovascular disturbances remain a leading cause of morbidity and mortality in patients with acute spinal cord injury (asci). asci patients often develop symptomatic and potentially life-threatening bradycardia. our practice has been to use albuterol elixir prophylaxis in asci patients, taking advantage of its side effect profile associated with a typical dose of mg tid or qid, to prevent further symptomatic bradycardia. evidence of efficacy with this regimen is, however, lacking. we set out to determine whether treatment with oral albuterol would decrease the frequency of bradycardic episodes in patients with asci. we retrospectively identified adult patients admitted to university of new mexico hospital between - who sustained an asci and received oral albuterol therapy. the frequency of bradycardic events (hr < bpm) before and after initiation of albuterol was collected. we compared the number of bradycardic events before and after albuterol within each subject using the wilcoxon signed rank test. bootstrap methods were used to further validate our findings. we identified asci patients who had evidence of symptomatic bradycardia before the initiation of the albuterol therapy, including hypotension and in cases bradycardic cardiac arrest. the median number of bradycardic events was ( . , iqr) before albuterol and was ( , iqr) after albuterol. we found that patient's had a significantly lower number of bradycardic events after the initiation of albuterol (p = . ). ten patients experienced less bradycardic events. the median difference was less bradycardic episodes. bootstrap estimates of the median difference were consistent with our initial analysis. albuterol appears to be an effective means of treating bradycardia in patients with acute spinal cord injury. severe traumatic brain injury (tbi) is frequently associated with eeg changes like epileptiform discharges, seizures; periodic lateralized epileptiform discharges pleds or paroxysmal delta activity. we report a case of tbi with generalized hz spike and wave pattern that did not represent seizures a y old girl without epilepsy history presented after being involved in a motor accident. initial gcs was and remained the same over the next days. ct showed contusions with small left subarachnoid hemorrhage. phenytoin was started for seizure prophylaxis. on day , she improved clinically, however, on day she had fluctuating consciousness and continuous eeg monitoring was initiated. various antiepileptic medications were tried over the next several days including lacosamide, valproate, topiramate, levetiracetam and ethosuximide (eth) without significant change clinically or on eeg. she started improving clinically on day but became extremely drowsy on day , all meds except eth were weaned. she showed improvement and was discharged to rehab on day . a prolonged eeg after months was normal and eth was weaned off. she continues to do well almost one year after and is maintaining her school grades at pre-injury level. the patient's initial eeg (day post injury) showed generalized hz spike and wave pattern occurring every - seconds which continued for days despite treatment with various anti epileptics as described. on day eeg pattern changed to generalized rhythmic delta activity( - hz) especially during arousal. mri during the stay showed micro hemorrhages in both frontal lobes and right temporal lobe reflective of diffuse axonal injury. a hz spike and wave pattern mimicking absence seizures can be seen on eeg transiently after tbi, however its clinical significance is unclear. whether it needs to be aggressively treated or not cannot be conclusively established but the longterm prognosis appears to be benign. free radical-induced lipid peroxidation (lp) has been demonstrated to lead to the formation of isoprostanes from arachidonic acid and neuroprostanes from docosahexaenoic acid. lp is common after traumatic brain injury (tbi) and constitutes one of the key mechanisms of pathology related to secondary injury after tbi. one of the consequences of lp is the compromise of neuronal calcium (ca ++ ) homeostasis, leading to ca ++ overload and activation of the proteolytic -spectrin. the purpose of this project is to characterize the concentration--spectrin degradation after tbi. this study is a prospective, single-center study of adult moderate to severe tbi patients. inclusion criteria are age > yo, closed head injury, within hours of tbi, and glasgow coma score (gcs) < . serial samples from urine, blood, and cerebrospinal fluid (csf, when available) are obtained for up to weeks after injury. demographic data and pertinent clinical information are also collected. the biomarkers ( & f t -isoprostanes, f -isofurans and f -neuroprostanes) are measured via -spectrin breakdown products (sbp) by western blot analysis. we have enrolled fifteen patients to date. preliminary results suggest that the study population is typical of tbi (mean age . years, % male, median admission gcs ). serum and csf & f t -isoprostane values are above published values for normal individuals, with csf values peaking at hours after tbi. sbp are also measured in elevated amounts in csf compared to non-tbi controls (in whom they are not measurable). preliminary data suggests that serum and csf isoprostane values are elevated after tbi. continued patient accrual, further sample analysis, and comparison to control groups is needed to more precisely define the effect of tbi on the time course of lp biomarkers. traumatic intraventricular hemorrhage (tivh) is generally considered to be associated with moderate to severe traumatic brain injury and a significant mortality rate. there exists, however, a rare subset of individuals who manifest with isolated traumatic intraventricular hemorrhage and have a good prognosis and outcome. we present a case of an -year old female who suffered polytrauma and an isolated ventricular hemorrhage following a traumatic fall while mountain climbing. her history indicated mild transient confusion and amnesia occurring around the time of the fall. her glasgow coma score was , her neurologic exam was normal and she had no neurologic complaints other than positional lightheadedness and nausea. a comprehensive exam was notable for a right hip dislocation, nasal fracture, l vertebral body fracture, right apical pneumothroax and pulmonary contusion. computed tomography of the head showed an acute hemorrhage in the left lateral ventricle prompting concerns for traumatic brain injury. no additional pathology was noted on a follow-up magnetic resonance imaging. repeat ct scan showed mild interval decreases in the size of her ventricular hematoma. the patient was discharged one week after admission and had developed no neurologic complications. she was diagnosed with concussion and isolated intraventricular hemorrhage. isolated intraventricular hemorrhage is a rare complication of traumatic head injury that can have a good prognosis and outcome. the case shows the difficulty in categorizing this particular condition within the current spectrum of traumatic brain injury and specifically highlights shortcomings with classification systems that utilize neuro-imaging abnormalities to determine severity of injury. traumatic intracranial aneurysms (tias) are distinctly uncommon, comprising fewer than % of all cerebral aneurysms. tias that develop following blunt head injuries present the clinician with both diagnostic challenges and clinical difficulties. the natural histories of giant intracranial aneurysms are generally grave owing to mass effects, severe hemorrhage, and distal thromboembolism. case report. we present the case of a -year-old male was involved in an accident in which he suffered severe head injury from a falling heavy iron hammer. the immediately unenhanced head computerized tomography showed hemorrhagic contusions, subarachnoid hemorrhage, skull fracture and basal fracture. he had been in a deep coma ever since. the computed tomographic angiography (cta) revealed a giant aneurysm of right internal carotid artery about one month after the blunt head injury. the aneurysm was measured . cm at its maximal diameter on image. of note, the patient failed to improve the following day and died on the fiftieth hospital day. giant tias are very rare but fatal complications of blunt head injury probably related to effects of vessel wall trauma and possibly a combination of neurological deterioration. in our case, the involved mechanism was suspected to be related to skull base fractures or resulted from stretching of the artery across the process during the impact. cta has a high sensitivity of about . % and a high specificity of about . % for diagnosing cerebral aneurysms (including traumatic aneurysms). apart from this, cta permits -dimensional visualization of aneurysms and assesses surrounding intracranial structures that are not visible on dsa. therefore, although -dimensional digital subtraction arteriography is currently the diagnostic gold standard in cerebral aneurysmal disease, fast and noninvasive cta may be preferred in the acute setting of tias. julio cabrera , corina puppo major burnt patients require large volumes of fluid replacement due to a generalized increase in permeability and edema caused by cytokines. fifty percent of the administered fluids produce edema in "preserved" tissues. multiple organ edema follows fluid replacement. escharotomy is frequently performed to decompress limbs and thorax, but not neck. our objective was to describe and diagnose neck-head compartment syndrome in patients with neck circumferential burns and/or neck edema by ) suspectng it and ) confirming diagnosis with the help of transcranial doppler (tcd) ultrasonography, searching for a high resistance pattern in cerebral blood flow velocity at basal cerebral arteries. tcd examination was performed before and after escharectomy in two both patients presented a neck-head compartment syndrome, evidenced by the cerebral hemodynamic repercussion of neck compression: hypoperfusion with an increased resistance pattern in dtc. p : secondary compartment syndrome due to massive fluid replacement; without circumferential burn. p : compartment syndrome in circumferential neck burn. tcd confirmed the clinical suspicion of cerebral hypoperfusion, guiding the decision to perform surgical decompression to treat it, and helped to assess the results of the decompressive surgery. introduction . % hypertonic saline is used for the treatment of increased intracranial pressure (icp) and in the prevention and reversal of brain herniation syndromes. the use of hypertonic saline in the management of combat related penetrating and severe traumatic brain injury is described. . % hypertonic saline effectively managed icp with decreased risk of hypovolemia and secondary hypotension compared with mannitol. . % hypertonic saline also preserved cerebral blood flow, decreasing the risk for secondary cerebral ischemia in acute neurotrauma patients, where hyperventilation is contraindicated. the nato hospital, kandahar afghanistan treated eleven ( ) patients with twenty-seven ( ) doses of . % saline from -march to -april . hypertonic saline was used to treat acute elevation in icp, as well as to maintain an elevated serum sodium concentration during periods of cerebral edema. all patients were treated with initial conservative icp management. external ventricular drains were placed and drainage of - cc of csf was performed in an attempt to maintain icp before using hypertonic saline. patients with life-threatening clinical signs of elevated icp secondary to brain edema or acute neurologic deterioration were potential candidates for . % hypertonic saline therapy. - ml of . % sodium chloride was administered via a central line infusion. . % hypertonic saline was successful in acutely reducing icp. a ml bolus of . % saline predictably increased the serum sodium levels allowing reliable titration and maintenance of serum sodium levels and efficient management of the patient's volume status ( cc of . % = cc of %). penetrating and severe closed head injuries have the potential to lead to neurologic emergency as a result of brain edema associated with primary tbi or following neurosurgical intervention. in a combat tbi population, . % hypertonic saline demonstrates a clinical benefit over alternative treatments by decreasing the risk of secondary cerebral injury during the management of elevated icp and was well tolerated. unintentional death was the ninth leading cause of death among elderly patients. given their comorbidity profile, many of them are also on antiplatelets or anticaogulants. we sought to characterize the burden of "pro-bleeding" medications such as antiplatelets and anticoagulants in the population aged over who sustain a head injury. this observational cohort study was conducted at a level one trauma center that has a county catchment area serving over million. the trauma acuity is high, with over % of our patients haveing iss scores over . the age cutoff of for "elderly" is based on our trauma alert activation criteria. thirty-nine percent of the cohort was on at least one type of anticoagulant or antiplatelet, as follows: warfarin %, aspirin %, clopidogrel %, asa+dipyridamole %, heparin/lmwh %.a third of the cohort required icu admission. icu length of stay ranged from - days. patient in particular, on warfarin had a significantly longer icu length of stay (p= . ) when adjusted for inr level. the median inr for the whole cohort was . with an iqr of . to . . the median inr amongst those on warfarin was . with an iqr of . to . . patients on an antiplatelet or anticoagulant agent were significantly more likely to have an abnormal head ct (p= . ). % of the patients who were on warfarin needed some sort of anti-coagulant reversal to minimize bleed. patients on warfarin were more likely to undergo neurosurgical intervention (p< . ) when compared to cohort not on warfarin. antiplatelet and anticoagulant drugs can confer additional morbidity to persons who sustain a tbi. it may be important to recognize this early, and prepare for higher level care needs. introduction therapeutic hypothermia (th) is know to cause immune suppression. determining the degree of immune suppression at the bedside is often difficult or impossible. immune cell function (icf) measures the concentration of atp from circulating cd cells following in vitro stimulation with phytohemagglutinin (pha) as an indicator of immune cell function. icf is often used in solid organ transplant programs to modulate the immunosuppressive treatment. we propose the use of ifc to determine the degree of immune depression in the patient treated with th. immune cell function, cylex inc, columbia, md was obtained in three populations of patients: group : patients treated with th, ifc obtained while at target temperate, degrees c group : patiients that were admitted to the care of the neurocritical care team, requiring icu care. group : patient from sanford renal transplant program with stable immunosuppressive therapy. the average icf of group were , of group , and of group , . patient being treated with th have a profoundly depressed icf. the level of immunosuppression is equal to if not greater that those with solid organ transplants. according to the cylex data a level of less than represents an immune suppressed state. this does not appear to be a phenomenon of the critically brain injured patient since those without th had a normal icf while further studies are in process, this data has effected out practice. we now treat patients on th as immunosuppressed patients. very early prediction of neurological outcome after cardiac arrest (ca) remains challenging. several single center studies have suggested that bispectral index (bis) can predict outcome for patients treated with therapeutic hypothermia (th). we evaluated the ability of bis to predict outcome in a multicenter study. medical centers prospectively enrolled comatose ca patients treated with th. outcome was defined as good (go) if cerebral performance category (cpc) score was - , and poor (po) if cpc - at hospital discharge (hd) and at months ( m). bis data was assessed blind to outcome for initial value after first dose of neuromuscular blockade (nmb -bisi) and at hours post-rosc (bis ). patients were enrolled with a mean age of (sd ) years, % were male, % witnessed, initial rhythm was vt/vf in %, pea in %, asystole in %, and time to rosc was . ( ) minutes. at hd, ( %) had go with similar age as po but shorter median time to rosc at (iqr - ) mins vs ( - , p= . ). go patients also had more vt/vf as initial rhythm and witnessed ca (p< . ), and more males (p= . ). on roc curve comparisons, both bisi (auc . ) and bis (auc . ) performed better than time to rosc (auc . ) or age (auc . ) -p< . for all comparisons. among ca-th treated patients, this is the first multicenter trial to confirm that bispectral index values after first dose of nmb and at hours post-rosc predicted outcome better than time to rosc, rhythm, or age. bis appears promising as a tool to predict outcome very early after ca, and may be helpful during clinical trials to stratify the severity of brain injury sustained during ca. hypotension negates the cerebral protective effect of therapeutic hypothermia (th). myocardial depression, "cold-induced diuresis," and hypokalemia can lead to refractory hypotension during the maintenance phase of th. intravascular volume replenishment and inotropic infusion are effective but cause wide swings in heart rate, blood pressure, cardiac output and acid-base status. we propose the use of vasopressin as a physiologically appropriate agent to correct hypothermiainduced hypotension. hypothesis: in swine, the investigators tested the hypothesis that an infusion of vasopressin would restore blood pressure to normal levels during th. six domestic cross-bred pigs ( - kg) were subjected to a atm fluid percussion injury to the brain followed by systemic hypothermia ( °c) for hours. the animals were turned side to side and to sternal recumbency every six hours. during phase i (first hours), the blood pressures were maintained in the normal range with intermittent doses of epinephrine and fluid boluses. during phase ii (second hours), continuous vasopressin infusion ( . ug/min) was added to maintain blood pressure. the number of episodes of hypotension (map < mm hg), the volume of fluids (liters), and the total dose of epinephrine (mg) used during both phases were compared using student's paired t-test (p> . ). in all animals, the infusion of vasopressin effectively mitigated the occurrence of hypothermia-induced hypotension. the episodes of hypotension ( . ± . v . ± . ), the total volume of fluids ( . ± . v . ± . ), and the total dose of epinephrine ( . ± . v . ± . ) administered were significantly reduced during phase ii. in order to maximize the benefits of th, hypotension must be avoided. animal studies show that despite hypothermia, hypotension causes cerebral cortical tissue depletion of atp and phosphocreatine and an increase of lactate and nadh levels. the infusion of a low dose of vasopressin reverses these anomalies and effectively mitigates hypotension. hypotension, hyperoxia, and hypoxia early after the return of spontaneous circulation (rosc) are each associated with increased mortality, while early hypertension is associated with good outcome. we assessed these variables and their relationship to outcome in cardiac arrest (ca) survivors treated with therapeutic hypothermia (th). with irb approval, we reviewed prospective and retrospectively collected data in a single-center database of patients undergoing th after ca. demographics and clinical factors were compared among patients with cpc - (good outcome) and cpc - (poor outcome) in a bivariate model. various definitions of hypotension, hypertension, hypoxia, and hyperoxia were evaluated. we constructed logistic regression models including potential confounders and the variables of interest. among patients, age, vt/vf rhythm, shorter time to rosc, witnessed arrest, bystander cpr, and stemi on initial ecg were each strongly associated with good neurological outcome, as were a lower peak neuron-specific enolase level and higher bispectral index (bis) score after neuromuscular blockade. hyperoxia (pao > mmhg) was common (present in . with good and . with poor outcomes, respectively) as were hypoxia (pao < mmhg) and hypotension. none of these factors was a predictor of outcome. logistic regression models intended to adjust for the potential confounding influences of age, time to rosc, heart rhythm, witnessed arrest, and bystander cpr, also did not identify a relationship between the variables of interest and outcome. our data did not confirm the previously described relationship between post-resuscitation factors and outcome. this may reflect an inadequate sample size, but it is also possible that post-resuscitation hemodynamic and biochemical factors are minimally important to outcome, compared to the duration and type of the arrest. further investigation in larger data sets is warranted. determining the presence of an infectious process during therapeutic hypothermia (th) can be difficult. in addition, differentiating central vs systemic fever is difficult in the brain injured patient. procalcitonin (pct) was been used to guide the use of antibiotics in sepsis and pneumonia in patients that are critically ill. we propose the use of pct to predict the presence of a systemic infection in patients during th. all patients treated with th had pct measured at the start of th. all patients were cooled with the medivance arctic sun . when the water temperature was < degree c, pct and two sets of blood cultures (bc) were drawn. sputum cultures (sc) were obtained if there was a change in sputum or during bronchoscopy. antibiotic use was determined by the neuro-intensivist results patients were evaluated; ich, tbi, cva and cardiac arrest (ca). a total of pcts were obtained. one patient ( %) had positive bc, pct of . ; patients ( %) had positive sc. remaining patients had negative bc and sc. all ca patients had increased pct > . (normal < . ) of which ( %) had positive sc and none had positive bc. of the remaining without positive bc ( %), ( %) had positive sc, all had pct < . . of the ( %) patients without positive sc, all had pct < . pct is a reliable method to exclude an infectious process in patients being treated with th that have not had a ca. while further studies are warranted, a pct < . appear to exclude both pulmonary and blood infections, while a pct < . appears to exclude a blood stream infection. from this data, pct is not a good marker for infection in the ca patient. therapeutic hypothermia (th) has become widely accepted practice for neuroprotection and improved mortality in comatose survivors of out of hospital v-fib cardiac arrest. evaluation for appropriateness of th is now part of acls algorithm. its use in non-shockable rhythms such as pea and asystolic arrest is less well established. we present our center's experience with th after cardiac arrest and review the clinical and electrophysiological parameters that may impact prognosis. this is retrospective review of medical charts including patients undergoing th after cardiac arrest at a single center from through the first quarter of . demographic and clinical data were collected. continuous eeg results were reviewed by two independent epileptologists who were blinded to the outcome of the patients. eegs were graded based on the synek scale for grading severity of eegs. patient's neurologic outcome will be assessed by grading cerebral performance category (cpc) score at the time of discharge. multivariate regression analysis will be performed on the data to identify parameters that would affect prognosis in cardiac arrest after cooling. fifty-eight patients were identified from our database. the overall rate of survival to discharge was %. the survival rate for v-fib arrest was % whereas the survival rates for asystolic arrest and pea arrest were % and %, respectively. results from the multivariate analysis will be forthcoming. our results affirm the predominant view that th indeed improves outcomes after cardiac arrest. in particular with ventricular fibrillation and pulseless ventricular tachycardia arrest, we have seen very encouraging results. patients with pea/asystolic arrest fared worse but outcomes are still improved compared to historical control. since , mild therapeutic hypothermia (mth) has been the standard of care when spontaneous circulation returns after a witnessed, out-of-hospital ventricular fibrillation arrest[ ]. at our institution, we have initiated mth for approximately fifty patients since february . a knowledge, attitude, and practices survey was conducted querying neurology residents and attendings, emergency medicine (em) residents and attendings, and internal medicine (im) residents. our aim was to identify areas of weakness so that we could strengthen the overall awareness of the utility and benefit of mth. the survey consisted of nineteen multiple choice questions, ranging from asking how many times the participant had initiated mth; to parameters for the protocol; to how it impacts survival. the surveys were completed by: ten neurology residents and five neurology attendings; twelve em residents and two em attendings; and twenty im residents. all of the neurology residents and em physicians surveyed had been the primary provider for a post-arrest patient who underwent mth. the neurology residents unanimously agreed that mth after resuscitation from a shockable rhythm is standard of care, however only % of em physicians and % of im residents agreed. % of em physicians and % of im physicians answered that mth may be initiated in cases presenting after either a shockable or a non-shockable rhythm. % of the participants acknowledged that ventricular fibrillation portends the most favorable outcome. nearly % of participants agreed that ideal rosc is less than thirty minutes. three-quarters of physicians indicated the goal temperature as - °c; however, half of the neurology residents and % of neurology attendings answered this incorrectly. in conclusion, this survey has revealed a general understanding of mth, however, each specialty has its deficiencies. we can now educate each subset of physicians in a problem-focused manner. early quantitative assessment of non-contrast brain computed tomography (ct) using specialized software correlates with outcomes of cardiac arrest survivors. the proposed algorithm compared hounsfield units (hu) in the putamen (pu) to the posterior limb of the internal capsule (plic), but the work has not been validated in patients treated with therapeutic hypothermia (th) or using standard software and equipment. we included ca survivors treated with th who underwent ct in the first h after resuscitation (rosc). hu were averaged bilaterally at two levels in the pu and plic, and the pu/plic ratio calculated by a board-certified radiologist using a ge lightspeed vct slice scanner and agfa pacs system. receiver-operator characteristic (roc) curves were constructed, evaluating pu or pu/plic to predict poor outcome (cpc - ) at hospital discharge (hd) and months ( m). patients had median age years, % male, % out-of-hospital ca, % witnessed, % vt/vf, % pea, and % asystole. median (iqr) time to rosc was ( - ) minutes. / ( %) patients had po. when stratified by outcome, ct performed . ( . - ) hrs after rosc showed similar hu measurements for plic ( . po vs . go, p= . ) but lower hu in pu ( . vs . , p= . ) and pu/plic ( . vs . , p= . ). hu values for pu and pu/plic both predicted outcome: roc area under the curve (auc) for pu = . ( %ci . - . ) and pu/plic = . ( . - . ). among patients with m outcome data, pu predicted outcome ( . po vs . go, p= . ) with auc = . ( . - . ), but pu/plic did not. early after ca, hounsfield unit measurements in the putamen, and the pu/plic ratio were lower among patients with poor outcome, but the magnitude of the differences was small, and clinical utility uncertain. additional study is warranted. global cerebral edema following aneurysmal subarachnoid hemorrhage (asah) is associated with % in-hospital mortality. therapeutic hypothermia (th) is recommended for reduction of intracranial pressure (icp) based on class i evidence; however safety in prolonged states remains poorly studied. we retrospectively reviewed all cases of refractory icp elevation at the mayo clinic florida neurointensive care unit (nicu) from - who received adjunct th for more than hours. primary safety endpoints were qtc prolongation, development of bacteremia, and coagulopathy. additional outcomes included in-hospital mortality, hospital/nicu length of stay, and functional status at months. patients with asah and/or intracerebral hemorrhage underwent adjunct th. median age was ; were male. on admission, median apache was , and wfns was higher than in , all being modified fisher - . required barbiturates in addition to sedation, paralysis and hyperosmolar therapy. th was initiated on a median of hospital day and continued for a median of days (minimum= , maximum= ). mean icp over hours prior to th was . mmhg(sd= . ; range . - . ), decreasing to . mmhg(sd= . , range . - . ) over the first hours of th. patients had external ventricular drains placed and required decompressive craniectomy on average day hospital stay (range - ). safety data showed torsades-de-pointes in , mean qtc prolongation of with mean lengthening of aptt by . . patients had bacteremia on admission with new infections (urine, sputum, blood) documented in during th. overall, ( %) survived to discharge. median nicu/hospital length of stay was / . average modified rankin score at follow up was . . hypothermia greater than hours as an adjunct to standard icp reducing therapies appears feasible in patients with refractory intracranial hypertension. however, definitive safety of prolonged th would require direct comparison with similar cohort. refractory raised intracranial pressure (ricp) secondary to intracerebral hemorrhage (ich) and severe subarachnoid hemorrhage (sah) is a life threatening condition. treatment for ricp typically induces hypothermia (th) and decompressive hemicraniectomy (hct). however, direct comparison of the efficacy of these two therapies is lacking. data from this study may help determine the sequence of therapies that might improve outcomes in this patient population. in the present study using retrospective design, we tested the hypothesis that for patients with ricp, th is as effective in reducing icp as hct, using functional outcome at discharge as defined by modified rankin scale (mrs) as the primary outcome. we retrospectively reviewed all adult patients admitted to the neurointensive care unit from to with sah and ich with resultant elevated icp, who survived the first hours after admission. exclusion criteria included: pupillary anisocoria, limitation of care within hours of admission; or hemicraniectomy or craniotomy with clot evacuation prior to icp monitoring were excluded. initial review included patients (th= and hct= ). based on univariate analysis, admitting gcs score was higher with hct ( vs , p= . ), but other baseline demographic and clinical characteristics were similar. th group had longer icu los ( vs ), los ventilation ( vs ), and higher cost. however, discharge mrs ( vs ,p= . ) was similar. our initial analysis indicates longer icu care and overall cost with th, but similar functional outcomes at discharge. subsequent analysis will include inclusion of additional patients, icp comparison and adjustment for baseline characteristics. malignant middle cerebral artery(mca) infarction is devastating ischemic stroke, which the mortality rate is up to %. therapeutic hypothermia is one of the most promising neuro-protective therapies. successful result of hypothermia for cardiac arrest renewed interest in therapeutic hypothermia for stroke. the purpose of this study was to assess whether therapeutic hypothermia can reduce the cerebral edema and can improve the functional outcome in patients with malignant mca infarction. we reviewed retrospectively patients with malignant mca infarction presented within hours of symptom onset in a single center hypothermia registry. after informed consent, patients who had refused decompressive hemicraniectomy were treated with therapeutic hypothermia and monitored in the neurocritical care unit for complications. a modified rankin scale(mrs) and national institutes of health stroke scale(nihss) were obtained at months after symptom onset. eleven patients with a mean age of ± years and an nihss score of . ± . were treated with therapeutic hypothermia( ± ). seven of eleven patients were mca infarction, and four was ica t-occlusion. the mean time from symptom onset to initiation of hypothermia was . ± . hours and the total duration of hypothermia was . ± . hours. noncritical complications included shivering(n= ), bradycardia(n= ), hypertension(n= ), pneumonia(n= ), and arrhythmia(n= ). electrolyte imbalances were common during the hypothermia (hypernatremia;n= , hypokalemia;n= , hypophosphatemia;n= ). mortality rates was %(n= ) and the mean nihss at discharge was . ± . . the mean mrs at months was . ± . in all patients and . ± . in survivals. this result shows that therapeutic hypothermia can prevent the progression of cerebral edema and improve functional outcome in acute malignant mca infarctions and ica t-occlusion. long duration hypothermia more than days appears feasible and safe in these patients. therapeutic hypothermia may be a good alternative therapeutic option to early decompressive hemicraniectomy. large clinical trials are needed whether hypothermia will be a best treatment to improve functional outcome. therapeutic hypothermia (th) is know to cause immune suppression. determining the degree of immune suppression at the bedside is often difficult or impossible. immune cell function (icf) measures the concentration of atp from circulating cd cells following in vitro stimulation with phytohemagglutinin (pha) as an indicator of immune cell function. icf is often used in solid organ transplant programs to modulate the immunosuppressive treatment. we propose the use of ifc to determine the degree of immune depression in the patient treated with th. immune cell function, cylex inc, columbia, md was obtained in three populations of patients: group : patients treated with th, ifc obtained while at target temperate, degrees c group : patiients that were admitted to the care of the neurocritical care team, requiring icu care. group : patient from sanford renal transplant program with stable immunosuppressive therapy. group , patients, average icf: group : patients, average icf: group : patients, average icf, . patient being treated with th have a profoundly depressed icf. the level of immunosuppression is equal to if not greater that those with solid organ transplants. according to the cylex data a level of less than represents an immune suppressed state. this does not appear to be a phenomenon of the critically brain injured patient since those without th had a normal icf while further studies are in process, this data has effected out practice. we now treat patients on th as immunosuppressed patients. therapeutic hypothermia (th) has become a first-line therapeutic modality in patients suffering from traumatic brain injury and cardiac arrest. shivering induced by th reduces the ability of the cooling device to achieve target temperature. this can lead to increased intracranial pressure (icp) and increased metabolic demand. the bedside shiver assessment score (bsas) has been validated in identifying and grading shivering. however, the bsas cannot identify microshivering which is visually undetectable shivering that is thought to have the same detrimental physiologic consequences as shivering. continuous channel eeg (ceeg) can detect microshivering but is labor intensive, requires specialized training to interpret results and is expensive. we propose that the philips eeg with compression spectral array lead (philips ) can be utilized to detect microshivering as effectively as ceeg but is more cost effective. the philips was placed by the bedside nurse. the lead placement varied depending on underlying injuries. patients were assessed utilizing the bsas and the philips . if high frequency activity increased on the philips , the patients were assessed using the bsas. if the bsas was then - mg of vecuronium was given to intubated, sedated patients. both patient temperature and water temperature were recorded. two patients with tbi were evaluated. the water temperature decreased and the patient's temperature increased during the periods of high frequency activity on the philips . after vecuronium, the high frequency activity ceased, water temperature increased and core temperature returned to the previously set level. the philips is a relatively low cost device when compared to ceeg that can be applied and monitored by the nursing staff to detect microshivering. additionally, we were able to validate that control of microshivering improved the th device's ability to achieve and maintain the patient's temperature goal. therapeutic hypothermia is widely accepted as a standard of practice for out of hospital cardiac arrest (ohhca). however, its implementation is still highly variable in different hospital settings. most of the current data comes from centers of excellence. we wanted to evaluate performance of implementation of "hypothermia protocol" (hp) including its complications and outcomes in our large referral community based hospital. we conducted retrospective chart review of patients who underwent hp from - . data collected included demographics, time of cardiac arrest, time of arrival to er and time to induction of hp, methods used for induction, complications and outcomes. out of the patients, patients ( %) had pulse less electrical activity (pea), ( . %) patients had ventricular tachycardia/fibrillation, and ( . %) had complete heart block as the initial rhythm. average time to arrive to er was minutes. almost % of patients had ht induction in ed, % (%) in icu and . % outside of the hospital. average time to initiate ht from the initial event was hour and minutes. average time to achieve the target temperature from the initial event was hours. inner cool was the most common modality used in . (%). lactic acidosis ( . %) was the most common complication encountered, followed by hypotension ( %), coagulopathy ( %) and seizure ( %) trend of improved outcomes with less renal failure, coagulopathy, seizure was observed with shorter induction times. time to achieve target temperature had no effect. initial rhythm, age and gender also had no impact on the outcome. shorter induction time appears to decrease complications and improve outcomes. using multiple cooling modalities also appeared to have better outcomes. however larger studies are needed to confirm this observation. earlier induction of mild therapeutic hypothermia improves survival and neurological outcome and decreases incidence of some of the complications. introduction secondary brain injury after aneurysmal subarachnoid hemorrhage (asah) is a major cause of mortality. mild hypothermia ( - c) may protect against cerebral ischemia and edema in asah patients. the aim of this study is to describe the use of ct perfusion (ctp) characteristics to initiate re-warming in patients with secondary brain injury after asah. we performed a retrospective review of all patients admitted to a large comprehensive stroke center between and with asah who were treated with hypothermia and received ctp imaging. mild hypothermia ( - c) was started because of severe vasospasm, increased intracranial pressure or cerebral edema. baseline characteristics, including clinical severity grading by hunt hess (hh) and fisher scales, were collected. clinical outcomes were measured by discharge modified rankin score (mrs) and disposition. ctp was performed with a -slice scanner. twenty patients fulfilled inclusion criteria. in / ( %) patients, re-warming was based on favorable ctp characteristics and in / ( %) based on favorable tcd findings. the mean duration of hypothermia was . days. five patients were re-warmed due to normal ctp, despite tcd findings suggesting moderate to severe vasospasm. patients, re-warming was initiated given improving tcd findings and despite less favorable ctp data (most showing "matched" abnormalities of decreased cbv, cbf and increased mtt). clinical outcomes were worse in this group; mrs better outcome was seen in all patients in whom re-warming was initiated based on normal ctp. in these patients, there was a discrepancy between ctp and tcd data. poor outcome was associated with abnormal ctp regardless of tcd findings. ctp may be a useful tool to guide treatment of asah patients receiving hypothermia. diagnosis of pediatric brain death (pbd) continues to be a significant challenge. new guidelines for pbd diagnosis were published in pediatrics in . we recently conducted a mailed survey to assess current understanding of these new guidelines and general perspectives about pbd among a convenience sample of midwest usa physicians. we developed a item survey. items included demographic questions, question about familiarity with the guidelines, and questions concerning perceived discrepancies and other attitudes toward the guidelines. we mailed our survey to physicians at university hospitals: pediatric intensivists, neonatologists, adult neurointensivists, and pediatric neurologists, three weeks after the initial mailing, we followed up with a reminder by mail and/or phone. we performed fisher's exact test to assess statistical significance of responses among different specialties. after weeks, we had a % response rate. respondents included pediatric neurologists, neurointensivists, pediatric intensivists, and neonatologists. twenty percent of respondents were unfamiliar with the new pbd guidelines (neonatologists were least familiar). twenty-three percent stated they were 'not comfortable' making a pbd diagnosis and % deemed it was either preferable or essential to obtain a neurointensivist or pediatric neurology consultation for pbd assessment. there was general agreement that the current intervals for the required exams were appropriate in children (delineated by age). interestingly, % allowed patients to remain ventilated for a significant period of time after pbd declaration. we found that a significant number of pediatric physicians are not familiar of the new pbd guidelines and there remains some variability in the assessment of these patients. pediatric neurologists or neurointensivists are still considered an important part of the process of pbd determination. the mid-position fixed pupil (mpfp) is an imperfect reference to the mid-size pupil that occurs with the complete loss of neural influence from devastating midbrain injury (primary or secondary) and death (brain and cardiopulmonary). for this reason, proper recognition and interpretation of the mpfp is critical to the neurological localization/diagnostic process and a vital element to the clinical verification of brain death. while the description of the size range of the mpfp has been dogmatically passed down from numerous classical texts ( - mm) for decades, it has not been accurately quantified. modern pupillometry offers accurate quantification of pupil size. using a portable infrared pupillometer (forsite, neurooptics inc., irvine, ca), within hours after death, we evaluated the pupil size of dead patients who did not have any previous eye surgery, known eye disease, or use of eye medications. pupils were evaluated in dead patients (mean age ) an average of hours after death. the pupil size range was . - . mm, with a median size of . mm (sd of . mm). / pupils ( %) were < mm and none were > . mm. / patients ( %) had a side-to-side difference of at least . mm. thankfully none were reactive! the mpfp is generally smaller than classically described and % fall between . and mm. % of mpfp's are less than mm. we never found any mpfp's more than . mm. subtle but frequent side-to-side asymmetry (> . mm) existed in approximately % of the dead patients. with our continued work we can finally achieve a more quantitative description of the important finding of the mpfp so that it can be incorporated into our definitive texts, enveloped into our understanding, and applied to our clinical practice. brain death diagnosis is clinical in uruguay. it is defined as the irreversible loss of brain stem functions. ancillary tests are needed as confirmatory tests in selected cases: ) impossibility or contraindication to perform clinical testing (barbiturates, facial trauma, etc.); ) non demonstrable structural lesion; ) unknown coma etiology; ) difficulties to wait for a second clinical test. the most used confirmatory test is transcranial doppler (tcd) ultrasonography. objectives: to study ) the clinical characteristics of patients in whom brain death could not be diagnosed clinically; ) tcd ultrasonographic patterns; ) number of cases in which tcd aided in management. epidemiologic and observational study. patients included: those in who brain death was suspected but the clinical examination of brain stem reflexes and/or apnea test could not be performed for different reasons. period: from to . the variables studied were demographic and clinical characteristics, tcd sonographic patterns. cerebral circulatory arrest was diagnosed when the patterns found were systolic spikes, reverberating flow, and no-flow (if a previous study had demonstrated ultrasound permeability of skull windows) in bilateral anterior sectors and posterior sector. continuous flow or systolic peaks were negative for the diagnosis of cca. patients in who the clinical diagnosis of brain death was not possible or needed to be confirmed. % adults. % were men, with an average of y.o. in adults, and y.o.in children; structural etiology %. etiology: traumatic %; vascular %; anoxic-ischemic %, infectious %, toxic-metabolic %, other %. cca was confirmed in %, systolic spikes in %. cca was discarded in %. in this group the study was repeated in %, confirming cca in %. it was not concluding in %. dtc helped in the decision to how to continue the management of the patient in % of the cases, diagnosing cca in %. there is an awkward physician and cross-institutional variability in the approach to brain death (bd) diagnosis and all of its ramifications; physiological, logistical, and psychosocial. physician variability is related, in part, to a basic knowledge deficit and inexperience. however, public confidence in the reality of bd relies on consistent and accurate diagnosis and the physician's facility with the management of its implications. our full-day ( hour) brain death simulation workshop (bdsw) was designed to enhance confidence with bd diagnosis and management. it included a didactic lecture and seven learning stations: case study analysis (recognizing brain death mimics), a high fidelity mannequin simulation (bd examination including cold water calorics and apnea testing, hemodynamic management, and diabetes insipidus management), family discussions with professional actors trained to provide feedback, and four relevant content stations. each participant was observed by a neurocritical care expert, each receiving one-on-one and group feedback. physicians participants from continents participated in the bdsw with expert faculty. all participants felt much more confident with brain death diagnosis and management. at least % were humbled by the station on "discussion of brain death with families", recognizing their need to practice communicating about brain death effectively. % felt better equipped to contemporize their local policies and advocate for enhanced uniformity of practice. our bdsw provides a model comprehensive training experience that had a favorable impact on trainee confidence and their interest and capacity to advocate for better uniformity and training of peers. . the bdsw can be part of a future tiered approach to credentialing experts in this important clinical area. . we are conducting the nd bdsw on november , with improvements based on the st workshop. neurocritical care experts must embrace the primary responsibility for preserving the integrity of bd diagnosis and educating our colleagues. the use of carbogen in apnea testing to declare brain death may facilitate achieving the prerequisite pco needed to confirm apnea testing by establishing a target end point that is typically reached faster and has been shown to limit adverse effects. as the use of extracorporeal membrane oxygenation (ecmo) in adults increases, so does the need to perform apnea testing while on ecmo. however, traditional apnea testing on critically ill patients is compounded by lung derecruitment and hemodynamic instability rendering an aborted apnea test or worse, cardiac arrest and death. the literature on apnea testing of patients on venous-arterial (va)-ecmo is minimal. per hospital protocol, a carbogen mixture ( % oxygen and % carbon dioxide) was delivered through the ventilator for an apnea test on a year old female on va-ecmo. the ventilator's mandatory rate was set at breaths/minute to adequately deliver the carbogen mixture through the artificial airway. a carbogen formula was used to calculate a target end-point of an etco of mmhg for a positive apnea test. an abg was drawn prior to the apnea test and again once the target etco was achieved. pre-apnea abg: . / / / %. the etco goal was reached within minutes and the post-apnea abg was drawn: . / / / %. the patient remained hemodynamically stable throughout the apnea test which was confirmed as a positive apnea test. the use of carbogen in apnea testing on a patient receiving va-ecmo demonstrates the possibility of performing a successful apnea test for declaration of brain death. although more investigation is needed, this case demonstrates the ability to perform apnea testing on critically ill and unstable patients while maintaining hemodynamic stability which preserves the option for organ donation. drowning victims have historically been eliminated from consideration for lung donation as aspiration may cause direct pulmonary toxicity, often confounded by significant neurogenic pulmonary edema. a significant minority of these patients ( - %), aspirate only minimal amounts of water into their lungs, protected by severe-persisting laryngospasm (dry drowning), but progress to brain death due to significant anoxic injury. historically, even with limited evidence of aspiration,transplant centers do not consider evaluating drowning victims as lung donors. however, as the division between the number of eligible recipients and available donor organs continues to grow, criteria for acceptable donor organs are expanding. once an absolute contraindication for lung donation, this practice has persisted on a per case basis but is reported infrequently with somewhat mixed results. we analyzed the unos registry of donors for lung and heart-lung transplant from january , to december , (n= ), and then examined survival outcomes from lung transplant recipients from donors who suffered drowning between to recipients (n = ) to outcomes previously reported from lung transplant recipients during that period. for recipients of lungs from donors with drowning as cause of death, unadjusted survival at one drowning victims, even when initially resuscitated, often suffer significant anoxic injury and death by neurologic criteria. while the management of drowning victims as organ donors may present additional challenges, with proper donor selection, the use of lungs recovered from carefully screened donors after drowning appears to be a safe option for the expansion of the donor pool. racial disparity in health care utilization and outcomes is an area of substantial concern. a study performed in the 's in our neuro-icu found that nonwhites were half as likely to withdraw life-sustaining therapy (wlst). this may be explained by differences in socioeconomic status (ses), cultural preference, lack of end-of-life planning, or trust in the health-care system. to better understand the basis and evolution of this disparity, we analyzed it over two more recent epochs (determining whether it has improved over time), while specifically accounting for ses. we extracted data from a prospective neuro-icu database on all ventilated patients with gcs of or less between and . we analyzed how the rate of wlst was affected by age, race, gender, insurance and socioeconomic status (quintiles based on median household income of residence zip code), marital status, receipt of surgical/icu interventions, gcs and apache ii. we then compared ses-adjusted disparity for wlst (non-whites vs. whites) in - with - . non-whites accounted for of patients ( %) and were younger, less likely to be married ( % vs. %), insured ( % vs. %), and reside in upper-income zip codes (all p< . ). rate of wlst was lower in non-whites ( % vs. %, p< . ), despite comparable overall hospital mortality. after controlling for ses and other confounders, non-white race was still associated with lower odds of wlst (aor . , % ci . - . ). this disparity was prominent in the earlier epoch (aor . , . - . ) while race was no longer a statistically significant marker in the more recent cohort (aor . , . - . ). race appears to influence the likelihood of wlst in severely brain-injured patients independent of ses. this disparity, which has been attenuated over the past decade in our icu, may be related to cultural differences or barriers relating to end-of-life planning or trust. multiple parameters have been associated with outcome in comatose post-cardiac arrest patients. anecdotal observations suggest that patients who are cooler upon ed arrival tend to have poorer outcomes; if arrival temperature correlates with outcome, it may serve as an additional tool for patient prognostication. we performed a retrospective analysis of a prospectively collected data set from comatose post-cardiac arrest patients to determine if a relationship exists between arrival temperature and outcome. of the patients, patients ( %) with out-of-hospital cardiac arrests and with arrival temperatures recorded prior to initiation of hypothermia treatment were included and divided into those with good outcomes ( subjects; mrs => ) or poor outcomes ( subjects; mrs =< or death) at months; subjects ( poor outcome survivors and who progressed to brain death) remained when patients whose poor outcome (death) was due to withdrawal of care were removed from the poor outcome group. analysis using a two-tailed unpaired t-test on subjects with good versus with poor outcomes demonstrated a significant difference in temperature on ed arrival: mean temperature of patients with good outcomes was . o c (sd= . o c), while that of patients with poor outcome was . o c (sd= . ), p= . . when patients who died due to withdrawal of care were included in the analysis, a strong trend in difference between the two groups remained, but was not statistically significant (p= . ). low body temperature upon ed arrival correlates with poor outcome in post-cardiac arrest patients and may serve as an additional prognostic variable. cooler temperatures may merely reflect longer lapsed time before return to normal circulation; alternatively, they may be a result of poor temperature regulation in more severely brain injured patients. further investigation of this issue with a larger patient pool is warranted. diencephalon injury (di) has been described in neurocritical care. consciousness alterations (ca), dysnatremia, hemodynamic instability, fever, muscle dystonia are signs of di. these symptoms are non-specific. the goal of the study was to describe structure of acute diencephalon dysfunction syndrome (adds) on the model of isolated acute di. this retrospective study evaluated all patients operated in - . inclusion criteria: adult patients in stable preoperative condition; sellar region tumors (srt); complicated postoperative period. exclusion criteria: intra-cranial complications, not related with direct di (epi-, subdural hematomas, brain ischemia). organ dysfunctions and dysnatremia were registered. patients were included, excluded. all had ca and dysnatremia. hemodynamic dysfunction developed in patients, respiratory dysfunction in patients, ileus in patients, thrombocytopenia in patients, renal dysfunction in patients, hepatic dysfunction in patient. there were groups. first (n= ) had ca, dysnatremia. icu los was . days. glasgow outcome scale (gos) had patients; gos : patient. second group (n= ) had ca, dysnatremia, one somatic organ dysfunction (sod). icu los was days. gos had patients, gos : patients. third group (n= ) had ca, dysnatremia, two sod. icu los was . days. gos , had patients; gos : patients; gos : patients. fourth group (n= ) had ca, dysnatremia, sod. icu los was days. gos , had patients; gos : patients; gos : patients. fifth group (n= ) had ca, dysnatremia, sod. icu los was . days. gos had patients; gos : patient; gos : patients. sixth group (n= ) had ca, dysnatremia, sod. icu los was . days. all died. adds consists of ca, dysnatremia, and at least one sod. severity of adds depends on number of sod. intracranial pressure (icp) monitoring is widely used in the management of patients with traumatic brain injury. icp monitoring may also be useful in other situations characterized by high icp, including cardiac arrest survivors (cas) after return of spontaneous circulation (rosc). however, no prospective study has examined the incidence of raised icp among cas. this pilot study will examine the feasibility of screening for elevated icp in cas admitted to the toronto western hospital (twh) in -using the non-invasive technique of optic nerve ultrasonography (onus) --to identify patients with elevated icp, who might benefit from invasive icp monitoring to optimize their management after they survive cardiac arrest. evidence of elevated icp will be examined by blinded ultrasonographers(usf) who will measure the optic nerve sheath diameter (onsd) in both eyes of all cas every hours from rosc. all findings will be defined in a dichotomous method (elevated/not elevated). primary outcome: incidence of major protocol violations, defined as the inability to attain of onus recordings during first hours at the specified time point (every hours) by each usf. for every major protocol violation, an audit will be done to understand the reason for the violation and tailor the protocol to improve compliance in future studies. advances in resuscitation medicine have demonstrated an improvement in patient outcomes in cas by the implementation of th. the exact mechanism of action of th is not well understood and has been postulated to partially involve a decrease in icp. no prospective data currently exists linking th with icp. using onus as a non-invasive modality, we have designed a single centre feasibility study to assess the ability of onus to measure icp in cas, as well as to aid in sample size calculations for a larger multicentre prospective cohort study. a preliminary study demonstrated that > % of whole brain volume with an apparent diffusion coefficient (adc) < x - mm /sec identified poor outcome (death/vegetative state) with % specificity and % sensitivity. we aimed to validate this threshold in an external dataset. a multicenter retrospective observational study of dwi mris of comatose post-cardiac arrest patients obtained between and hours post-arrest was performed. poor outcome was defined as death or persistent coma at day . imaging was processed in a blinded fashion using medical image processing, analysis and visualization program (mipav). the brain was semi-automatically outlined on the b images using a levelset algorithm. the adc values of each voxel within the brain were determined. outcomes were assessed blinded to quantitative dwi information. treating physicians were not blinded to the mri scans, but they were unaware of the quantitative dwi analysis. data from patients from five us centers were included: mean age was ± years, % female, arrest time ± minutes, % of patients received hypothermia, and mris were obtained at ± hours post-arrest. thirty-two percent had a good outcome. the median (iqr) percentage of brain tissue with adc< x - mm /sec was . % ( . - . ) in good and . % ( . - . ) in poor outcome patients (p< . ). an adc< x - mm /sec > % was % ( % ci - ) specific and % ( % ci - ) sensitive for poor outcome with a positive predictive value of % ( - ) and a negative predictive value of % ( - ). the odds ratio of having a poor outcome if > % of brain had an adc< x - mm /sec was ( %ci - ). quantitative dwi mri in comatose post-cardiac arrest patients holds great promise as a prognostic adjunct between and days after arrest. predicting outcome for comatose post-cardiac arrest patients is challenging and compounded by the use of therapeutic hypothermia and sedative agents. brain mri is a potential attractive prognostic adjunct not affected by drugs or metabolic derangements; however, most proposed methods require image post-processing. we assessed the prognostic value of color apparent diffusion coefficient (cadc) maps. consecutive post-cardiac arrest patients remaining comatose after resuscitation were prospectively enrolled. cadc maps were created by assigning adc values to colors ranging from red to blue. the treating teams did not see these maps. two raters independently and blinded reviewed the cadc maps and predicted month outcome as poor (glasgow outcome scale (gos) - ), or good (gos of - ). both raters were "trained" by viewing examples. the agreement between raters and the predictive performance of the cadc maps were assessed. cadc maps of patients ( % with poor, % with good outcome) were reviewed: age ± years, % females, % underwent therapeutic hypothermia, median (iqr) arrest duration min ( - ), and time between the arrest and mri hours ( - ). kappa for agreement on predicting favorable vs. unfavorable outcome was . . for the two reviewers, the sensitivity for predicting poor outcome was . ( % ci . - . ) and . ( . - . ), the specificity . ( . - . ) and . ( . - . ), and the true positive predictive rate % ( - %) and % ( - %), respectively. for mri scans acquired between - hours after the arrest (i.e. the time-interval when adc changes are most apparent), the specificity improved to . ( . - . ) and . ( . - . ), respectively. mri color adc maps are easy to interpret and may be useful for predicting outcome of comatose post-cardiac arrest patients in the first days after the arrest. color adc maps do not require post-processing and can be created in realtime. there are few reports of outcome in patients with fat embolism syndrome with diffuse mri abnormities. we report the outcome of patients with fat embolism syndrome. case a -year-old previously healthy gentleman had a right femur fracture from a motor vehicle accident. he had acute respiratory failure hours later requiring intubation. chest x ray showed bilateral lung infiltrates. neurological examination showed patient comatose with intact brainstem reflexes and extensor posturing. on day , he had fever, tachycardia, profuse sweating, and diffuse petechial rash. mri brain showed diffuse restricted diffusion lesions. he started to open his eyes in weeks and underwent tracheostomy and feeding tube placement. at month follow up he only had mild memory problems. case a -year-old previously healthy gentleman had a gun shot in the left foot. over the next hours he became stuporous. x ray showed multiple fractures including calcaneus, soft tissue swelling and subcutaneous emphysema. over the next hours he worsened and displayed extensor posturing. mri brain showed diffuse innumerable tiny infarcts. patient was noted to have episodic fever, profuse sweating, and severe tachycardia. patient had spontaneous eye opening next day and underwent tracheostomy and gastrostomy. he was transferred to a long term facility. patient improved substantially and at months follow up he was independently living at home with minor neurologic deficits. substantial improvement may occur in comatose patients with fat embolism syndrome despite paroxysmal sympathetic hyperactivity syndrome and significant mri abnormities. malignant pertussis is a rare life-threatening illness characterized by severe respiratory failure, extreme leukocytosis, and pulmonary hypertension. during , an outburst of whooping cough was experienced at montevideo, uruguay. we present the cases of two infants, and months old, suffering malignant pertussis, admitted to a university pediatric intensive care unit (picu) for severe acute respiratory failure associated with severe leukocytosis. both children showed signs of profound coma and bilateral arreactive dilated pupils while being aggressively treated. both of them showed a transcranial pattern of cerebral circulatory arrest (cca) on transcranial doppler (tcd).to our knowledge, a pattern of cca has not been previously reported like mode of death secondary to neurologic injury in this disease. both cases were very similar: a -month-old boy, incomplete vaccinatinon, malnourished. a month-old girl, vaccinated. both had suffered at one and months-old, severe bronchiolitis caused by respiratory syncytial virus, both needed days of mechanical ventilation. both were admitted to icu with cough, fever, increased work of breathing, hypoxemia and were mechanically ventilated. they presented respiratory acidosis, hipoxemia, extreme leukocytosis greater than , bilateral hyperinsuflation in chest x-ray. echocardiography: pulmonary hypertension, - mmhg spap, circulatory failure, anuric renal failure. bordetella pertussis was diagnosed with pcr of airway secretions treatment: blood exchange transfusions, milrinone, maximum dose inotropic drugs, peritoneal dialisis. after one week arreactive dilated pupils and profound coma were evident. brain death was suspected, sedation and muscle blockers were interrupted. neurologic exam confirmed brain death. tcd showed sysytolic spykes in bilateral middle cerebral arteries, basilar artery, confirming cca. necropsy performed in case showed bilateral pneumonia, small pulmonary artery branches thrombosis, neuronal necrosis, with brain edema, and renal tubular necrosis. the mode of death in these two cases was brain death, with cca. the probable pathophysiologic mechanisms were related to hyperviscosity and cardiac failure. davf's can be associated with benign or aggressive symptoms based on location and venous drainage. cerebral venous ischemia is a reversible process emphasizing the importance of early recognition and treatment of davf's. in a geographically isolated region with limited neuroscience intensive care unit (nsicu) capacity, neurointensivists are often challenged to allocate resources and triage intracerebral hemorrhage (ich) patients. we sought to assess the factors impacting the neurointensivists' triage decision for nsicu admission after ich. consecutive patients hospitalized for ich between and at a tertiary center that has the only -bed nsicu for the state, geographically isolated from the nearest nsicu (> , miles away), were studied. multivariable logistic regression models were used to test for predictors of nsicu admission, adjusted for each component of the ich score, transfer from another hospital, initial systolic blood pressure (sbp) > mmhg, and early do-not-resuscitate (dnr) order. among a total of consecutive patients hospitalized for ich, patients ( %) were admitted to the nsicu while patients ( %) were admitted to a non-nsicu unit. the ich patients were more likely to be admitted to the nsicu if they had hematoma volume > cm (or . , % ci . - . ), intraventricular hemorrhage (or . , % ci . - . ), glasgow coma scale (gcs) score of - (or . , % ci . - . ), gcs score of - (or . , % ci . - . ), infratentorial hemorrhage (or . , % ci . - . ), transfer from another hospital (or . , % ci . - . ), and sbp > mmhg (or . , % ci . - . , % ci . - . ) and early dnr order (or . , % ci . - . ). the triage decisions for nsicu admission after ich were based on clinical severity, age and early dnr status. a prospective study is needed to help establish a safe triage algorithm for ich patients in a region with limited neurocritical care capacity. using a semi-automatic threshold based volumetry algorithm. neurological status (nihss) was recorded daily and outcome was assessed at discharge using the modified rankin scale (mrs). the difference of phe volumes between day and day - , representing the edema growth (phe delta ), correlated significantly with the mrs at discharge (p= . ; f= ). this correlation was still significant, when ich volume on admission was controlled. other factors that showed a significant association with outcome at discharge were nihss (anova: p> . , f= . ) and ich volume (anova: p> . , f= . ) on admission. in a multivariate regression model only the initial nihss remained a significant predictor of functional outcome. phe growth showed a weak trend towards significance (p= . ). phe growth at the first days after symptom onset may influence early functional outcome after spontaneous ich. treatment strategies aimed at reduction of phe burden after ich may take advantage of this finding. assess the use of a -factor prothrombin complex concentrate (pcc, profilnine®), compared to fresh frozen plasma (ffp) in establishing hemostasis in warfarin associated intracranial hemorrhage (ich). dmitted to unc health-systems between / / and / / that received pcc, ffp, or both in conjunction with phytonadione for the treatment of warfarin associated ich. patients who received a factor product other than profilnine®were excluded. data collection included hematoma expansion, achievement of inr reversal (inr < . ), -day mortality and endpoints related to safety (thromboembolic events, infection, and transfusion related acute lung injury). of the patients included, patients received pcc alone, patients received pcc plus ffp and patients received ffp alone. hemorrhage expansion occurred in of patients ( %) in the pcc group, of patients ( %) in the pcc plus ffp group and of patients ( %) in the ffp group (pcc versus ffp, p= . ; pcc plus ffp versus ffp, p= . ). inr reversal occurred in % of patients in the pcc alone group, % of patients in the ffp alone group and of patients ( %) in the combination group. this study assessed the impact of profilnine®, ffp, or the combination, on achieving hemostasis based on hematoma expansion. profilnine® achieved inr reversal but appeared to be less effective than ffp in preventing hemorrhage expansion. fever after ich is common and associated with poor outcome. however, the impact of therapeutic temperature modulation (ttm) to treat fever after ich is unclear. we performed a case-control study of ttm in ich patients with fever. patients undergoing ttm with advanced temperature modulating devices were prospectively enrolled in our ttm database from - (ttm group). target temperature was c in all cases. controls were matched in severity by ich score and retrospectively obtained from a period ( ) ( ) ( ) ( ) before our routine use of ttm for ich. primary outcome was discharge modified rankin score. we enrolled patients in each group. median ich score was (range - therapeutic normothermia is associated with increased length of mechanical ventilation and nicu stays, but is not associated with improved discharge outcome. spontaneous intracerebral hemorrhage (sich) is a dynamic process with significant growth in over one-third during the first hours. catheter-based evacuation of sich plus recombinant tissue plasminogen activator (rtpa) is a novel surgical approach for which optimal timing of stereotactic catheter placement and clot aspiration are not known. we investigated factors associated with significant ich expansion (> % or . cc volume increase) on prerandomization ct scans of patients meeting criteria for the mistie trial, a multi-center phase ii clinical trial, evaluating safety and efficacy of minimally invasive surgery plus thrombolytic to treat ich. subjects randomized to surgery underwent stereotactic clot aspiration followed by injections of rtpa through the hematoma catheter every hours, up to doses, or until a clot reduction endpoint. median diagnostic ich volume was . cc (iqr . ). overall, . % of patients exhibited significant hematoma expansion at a median of . (iqr . ) hours from symptom onset. predictors of hematoma growth were smaller diagnostic ich volume (or . ; p= . ), longer interval from symptom onset to pre-randomization ct (or . ; p= . ), non-lobar location (or . , p= . ), lower initial platelet count (or . ; p= . ), and lower initial hematocrit (or . ; p= . ). age, gender, admission blood pressure, initial coagulation parameters, hematoma shape and density scores did not predict hematoma expansion. end of treatment hematoma expansion occurred in / ( . %) patients of whom had early ich expansion and underwent surgical intervention. stabilization of hematoma growth can be anticipated within hours of symptom onset in patients considered for minimally invasive surgery using the mistie protocol. smaller initial ich size, deep location and lower hematocrit and platelet counts were independent determinants of significant ich expansion before surgery. patients with early expansion may represent a group at higher risk for re-expansion with clot aspiration and thrombolytic therapy. financial support: daniel f. hanley received funding from nih grant r ns . thin-section noncontrast ct (ncct) provides a measure of thrombus composition based on hounsfield units (hu) and may predict resistance to thombolytics in acute ischemic stroke. hematoma composition may affect thrombolytic efficacy of tissue plasminogen activator (tpa) in acute intraventricular hemorrhage (ivh). we assessed the value of hematoma hu quantification as a predictive marker of ivh clearance after intraventricular tpa administration. serial ncct was performed on patients who received intraventricular tpa as part of the clear ivh trial (clot lysis: evaluating accelerated resolution of ivh) and controls with ivh treated with external ventricular drainage (evd) alone. a blinded investigator calculated hu values for ivh volumes on admission, day - and day - ncct for each patient. median ivh volume on admission for tpa-treated patients was . (iqr . )cc, and decreased to . ( . )cc at day - . mean(sd) hu for ivh was . ( . ) on presentation and decreased significantly to . ( . ) on day - , and to . ( . ) on day - . ivh hu count was significantly correlated with ivh volume at all ct timepoints: admission:p= . ; day - :p< . ; day - :p< . . there was no correlation between admission serum platelet count, fibrinogen level or hemoglobin and clot hus. only csf protein was positively correlated with ivh hu (p= . ). total ivh hus were significantly lower in tpa-treated (vs. control) patients at day - (p= . ), but not at day - . change in ivh volume from admission to day - was positively correlated with higher initial hu in tpa-treated patients (p= . ), but hu was not significant after adjustment for ivh volume and tpa treatment. hounsfield unit counts of ivh decrease significantly over the first week on ncct and the decrease is greater in tpatreated patients. unlike thrombus hus in large intracranial vessels, ivh hus are not associated with erythrocyte or platelet concentrations. higher hu is not an independent predictor of success of intraventricular thrombolysis. although neurocardiogenic myocardial injury is well described among patients with spontaneous intracerebral hemorrhage (sich), it has not been investigated systematically in patients with acute subdural hemorrhage (asdh). we sought to investigate the prevalence and characteristics of myocardial injury in patients with asdh. consecutive adult patients with a diagnosis of asdh admitted to the rush university neurosciences intensive care unit were analyzed. myocardial injury, defined as troponin i elevation (> . ng/ml) on admission or during hospital course, was identified. electrocardiograms (ecg) and echocardiograms, obtained within the first hours and read by a cardiologist blinded to the patient's history, were retrospectively reviewed. a total of patients were admitted with asdh between / and / . the mean age was years (sd years), and % were male. comorbidities included hypertension ( %), diabetes mellitus ( %), coronary artery disease or prior myocardial infarction ( %), congestive heart failure ( %), coronary artery stent or bypass procedure ( %). ecgs were normal in %. non-specific st-t morphologic changes, qrs changes or sinus arrhythmias were seen in %. st-elevations suggestive of myocardial infarction were not seen. of patients with elevated troponin, had known severe cardiac disease, and had severe medical complications (sepsis, renal failure, hepatic failure and acute lymphoma crisis). diffuse ecg changes ("cerebral t waves") and echocardiographic findings suggestive of neurogenic stunned myocardium (reversible wall motion abnormalities, apical ballooning) were not seen. although we found ecg changes to be common after asdh, myocardial injury was only observed in the context of concomitant cardiac or medical disease. classic neurogenic cardiac findings (cerebral t waves, neurogenic cardiomyopathy) were not observed. while myocardial injury in sich often is attributed to neurocardiogenic causes, these are unlikely prominent mechanisms in patients with asdh. other cardiac or medical causes are common and should be excluded. prognostication in intracerebral hemorrhage is complex and mortality remains high. while tools such as the ich score have been developed to assist with prognostication, physicians clearly use additional parameters in clinical practice. though do-not-resuscitate orders do not indicate the withholding of any treatment other than cpr, they are associated with increase risk of death in patients after ich. we sought to understand early dnr (< hours) designation in patients with hope of moving toward more precise tools for prognostication. patients admitted to the neurological intensive care unit from july to december with a diagnosis of supartentorial ich were identified. data for all patients were collected retrospectively. patients without a dnr order throughout their admission were compared to patients who received a new dnr order in the first hours of admission. patients with pre-existing dnr orders were not included. subjects were included in the study with . % made dnr within hours of admission to our nicu. factors showing a significant correlation with a new dnr order included advanced age, caucasian race, or residence in a skilled nursing facility. history of malignancy, atrial fibrillation, current use of antihypertensives or warfarin, or alcohol abuse predicted a dnr order. ich resulting in a low admission glasgow coma score, high ich score, intraventricular extension and blood volumes greater than ml correlated with a new dnr order. while individual elements of the ich score correlate with a new dnr order in this population, other characteristics were also associated with an early dnr order. early dnr orders may create a self-fulfilling prophecy if limitations of support are instituted without a clear understanding of who may benefit from aggressive care. thus, identification of factors that providers believe to be life-limiting may serve as a starting point to avoid early limitations in aggressiveness of care. intracranial hypotension is caused by low cerebrospinal fluid (csf) pressure, clinically distinguished by orthostatic headaches and neurologic signs. subdural effusions and even hemorrhage can be a secondary effect. known causes include dural punctures as well as spontaneous csf leaks. treatments are guided towards repairing the cause of the hypotension. a year-old man on coumadin for a mechanical aortic valve was transferred to our institution for evaluation of bilateral sdh. he presented twenty-four hours earlier with sudden-onset severe headache and normal neurological exam. upon transfer, he was noted to be drowsy, with a left third cranial nerve palsy. he endorsed a postural headache that worsened upon standing. mri of the brain showed small subdural effusions with subacute hemorrhage and minimal mass effect, as well as severe distortion of the midbrain with narrowing of the ventricular system, crowding of the basal cisterns and extensive pachymeningeal enhancement. mri of the spine did not demonstrate a csf leak but showed a small perineural cyst at t . the patient's headache and exam findings initially improved with lying flat. a trial of elevating his head of bed failed, with the patient further developing decreased level of arousal, frontal release signs, and recurrent left third nerve palsy. two attempts at lumbar epidural blood patch (ebp) did not lead to sustained improvement, but a thoracic-directed ebp led to durable and complete resolution of the headache and neurologic deficits. intracranial hypotension should be considered as a cause for subdural hemorrhages in the absence of trauma. clues include postural headaches and clinical evidence of brainstem dysfunction and radiographic evidence of brainstem distortion out of proportion to the size of the sdhs. ebps directed at suspected csf leaks can be effective when nondirected lumbar ebps fail. multiple guidelines recommend the reversal of oral anticoagulation when a patient experiences an intracranial hemorrhage (ich). both activated prothrombin complex (apcc) and recombinant factor vii activated (rfviia) have been utilized to reverse warfarin-associated coagulopathy. however, there have been no direct comparisons of these agents. this was an irb approved, retrospective cohort analysis of patients with ich. patients were included if they received either apcc (at least units) or rfviia (at least mg), if they had a discharge diagnosis of intracranial hemorrhage, and if they received warfarin prior to admission. patients were excluded if they were less than , or did not have documented pre-treatment and post-treatment inrs. the primary endpoint for this study was the change from pretreatment inr and post-treatment inr in the apcc group and rfviia group. secondary endpoints included change in ct measured hemorrhage volumes, icu length of stay (los), hospital los, mortality, icu discharge gcs, and thromboembolic adverse events. a total of patients were included in the analysis. of those, received apcc and received rfviia. baseline demographics were comparable; however, patients in the apcc group had a higher rate of atrial fibrillation ( % vs. %; p= . ). when compared over time, both apcc and rfviia significantly reduced the inr (p< . ); however, there was no difference in the amount of change observed between the two groups (p= . ). in addition, we saw no significant differences with regard to icu los, hospital los, mortality, icu discharge gcs, or thromboembolic adverse events. over time, an increase in ich volume was observed in both groups. in patients with intracranial hemorrhage, apcc and rfviia are associated with rapid reversal of warfarin-associated coagulopathy; however, these agents may not slow ich growth. accurate prognostication of patients with intracerebral hemorrhage (ich) is critical because it may affect aggressiveness of care and patient outcome. ich prediction models help stratify patients according to their chance of a good or poor outcome. we compared the accuracy of neurointensivists' prediction of functional outcome to outcome prediction by the ich score. adult spontaneous ich patients with an admission gcs > were prospectively enrolled. the treating neurointensivist predicted the -month modified rankin scale score (mrs) within days of hospital admission. none of the neurointensivists used the ich score routinely to help predict outcome. patient outcomes were dichotomized to good (mrs - ) and poor (mrs - ). neurointensivists' predictions were compared to the ich score using the actual -month mrs as the reference. of prospectively enrolled patients, were included: withdrew consent and were lost to follow-up. neurointensivists' overall accuracy was %, which was higher than the accuracy of the ich score at a cut-off of > ( %; p= . ) or > ( %; p= . ). at a cut-off > , the sensitivity for poor outcome prediction did not differ, but the neurointensivists' specificity for poor outcome was greater ( % vs. %; p< . ). conversely, at an ich score cut-off > the specificity for poor outcome prediction did not differ, but the neurointensivists' sensitivity for poor outcome was greater ( % vs. %; p< . ). the results were similar if, instead of the original ich score, a modified ich score was used as the comparison that had been developed on the same patient cohort. neurointensivists at our institution predict ich outcome overall with % accuracy. generally, predictions for poor outcome are more accurate than those for good outcome. outcome predictions for the individual patient by the treating neurointensivist are more accurate than those based on ich prediction models. there is continued controversy regarding glycemic control and its effect on outcomes for patients with ich as well as other icu patient populations. the relationship between ichsize and glycemic control has not been clearly defined. a retrospective review of patients with supratentorial ich and no history of diabetes between and was performed. admission blood glucose (bg) as well as bg at , and hours was measured while all patients were maintained on the same sliding scale insulin regimen. statistical analysis was performed to compare admission ich size to admission bg and subsequent bg control. bg> mg/dl (mean ± ) and mean ich size . ± . . average bg levels over average bg levels over hours were ± mg/dl. elevated admission bg was significantly correlated with admission ich size (p= . ). average bg levels over hours trended towards, but were not significantly correlated with admission ich size (r = . , p= . ). in nondiabetic patients, elevated admission glucose is significantly associated with ich size. poor outcomes associated with elevated glucose may be associated more with extent of cerebral insult than with glycemic control. the benefits of marriage on health have been known for over years. more recently, married couples have been found to have a lower risk of cancer, dementia, and heart disease. we aimed to explore the effects of marital status on outcome after intracranial hemorrhage. a prospective study was conducted between - of patients with subarachnoid hemorrhage (sah, n= ), intracerebral hemorrhage (ich, n= ) and subdural hemorrhage (sdh, n= ), admitted to the neuro-icu at a tertiarycare academic hospital. marital status was coded as married versus single, widowed, divorced or separated. modified rankin score and barthel index were compared between the two groups at -months using multiple logistic regression analysis. of patients, ( %) were married, ( %) were single and ( %) were widowed, divorced or separated. women were less likely to be married, and smoking was less common among the married (both p< . ). there was no difference in age, insurance or employment status, race, education, days to diagnosis, or history of heart disease, diabetes, hypertension, trauma or coagulopathy. after adjusting for age, admission gcs, apache physiologicalsubscore, gender, tobacco and bleed type, marriage was significantly protective against death or severe disability (mrs - ; adjusted or . , %ci . - . , p= . ) and predicted better activities of daily living (barthel index), (aor . , %ci . - . , p= . ). there was no difference in discharge disposition, length of stay or hospitalization costs. marriage is protective against death or severe disability and predicts better activities of daily living among patients with intracranial hemorrhage. warfarin associated intracranial hemorrhage leads to poor outcomes. we studied the influence of a standardized emergent warfarin reversal protocol incorporating prothrombin complex concentrates (profilnine sd®) on time to achieve the protocol was implemented in . sixty three patients ( pre and post protocol) from - with intracranial -protocol patients received recombinant factor a (rfviia); post protocol patients with inr . - and > received and - units/kg of profilnine sd® respectively. hemorrhage volumes were measured on consecutive ct scans using mipav semi-automated software. groups were similar for baseline median inr ( . vs . ), nihss ( vs ), follow-up ct time ( . vs . hours) and hemorrhage volumes ( . vs . cc) but differed in hemorrhage type: ich ( % vs %) and sdh ( % vs %), p= . . treatments also differed: vitamin k ( % vs %, p= . ), profilnine sd® ( % vs % p=< . ), rfviia ( % vs % p= . ) and number of plasma units ( vs , p= . ).time to target inr was similar ( . vs . hours) driven by pre-protocol rfviia use (rfviia used vs not, . vs . , p= . ) and this led to inr rebound in < hours. excluding rfviia, the post protocol group normalized inr faster ( . vs . hours, p= . ). the post protocol group had less absolute ( . vs cc p= . ) and relative hemorrhage growth ( % vs % p= . ) without any thrombotic events. despite comparable mortality ( vs %), post-protocol survivors more frequently achieved mrs - ( vs % p=ns). a standardized emergent warfarin reversal protocol is not only safe but leads to faster inr normalization, less hemorrhage growth, plasma conservation and possibly better neurological outcomes. perihemorrhagic edema (phe) after intracerebral hemorrhage(ich) may exceed the initial hematoma volume by to % respectively and thereby lead to increased intracranial pressure (icp), clinical detoriation or even herniation. intravenous hypertonic saline (hts) has been shown to reduce phe formation after ich. clinical data suggest that hts may be superior to mannitol in lowering icp. eusi and asa guidelines recommend the use of intravenous mannitol up to a serum osmolality (so) of mosmol/kg or hst in order to reduce elevated icp. we aimed to investigate the effect of mannitol and so on the evolution of phe after ich. nineteen patients with supratentorial spontaneous ich treated with % intravenous mannitol solution ( - ml every h) for - days and controls who did not receive mannitol or any other osmotic agents during the course of treatment were identified retrospectively from our institutional ich database. patients treated with mannitol and controls were matched for ich-volume (± ml). phe volume was calculated on ct scans using a semiautomatic threshold based volumetric algorithm. diagnostic ct scans and follow-up scans performed on days , - , - , - and - were analyzed. so, concentration of sodium and glucose were obtained from patient records. the matching resulted in similar ich-volumes in both groups (mannitol: . ± . ml, controls: . ± . ml). mean age was ( - ) years in the mannitol group and ( - )years in controls (p= . ). initial relative phe did not differ significantly in both groups (mannitol: . ± . , controls: . ± . , p= . ). there was no effect of mannitol treatment on the course of phe (f= . ,p= . ). there was no significant correlation between so and relative phe at any timepoint of follow-up. we found no effect of mannitol use and so on the evolution of phe. other underlying mechanisms may explain the shortterm effect of mannitol boluses on icp in patients with spontaneous supratentorial ich. when operating at maximum intensive care unit (icu) bed capacity where allocation of critical care resources is required, physicians may be pressured to initiate do-not-resuscitate (dnr) orders in patients with intracerebral hemorrhage (ich). we sought to assess the relationship between early (< hours from admission) dnr orders and neuroscience intensive care unit (nsicu) bed capacity in patients admitted with acute ich. we retrospectively studied consecutive patients hospitalized for ich between and at a tertiary center that has the only -bed nsicu for the state, geographically isolated from the nearest nsicu (> , miles away). multivariable logistic regression models were used to test for predictors of early dnr orders, adjusted for each component of the ich score and nsicu bed census on admission. nsicu bed census was dichotomized to full (all beds occupied) vs. not full (at least available bed). among maximum icu bed capacity on admission is not associated with the decisions to initiate early dnr orders in ich patients. this suggests that physicians were not preferentially initiating early care limitation when critical care resources were becoming scarce. dural arteriovenous fistulas (davf) are rare, acquired cerebrovascular lesions consisting of abnormal vascular connections between arteries that normally supply the dura and veins that drain the brain parenchyma -that is to say, arteries not associated with the brain parenchyma manage to drain via the dural venous sinus system. the clinical consequences of these lesions are typically hemorrhage, seizure, or venous congestion. venous congestion may present acutely with hemorrhage or subacutely with signs and symptoms such as progressive cognitive decline, seizures, or encephalopathy. parkinsonism, tinnitus, and intracranial hypertension have also been described. case report with review of literature. we describe a -year-old man with no past medical history who developed subacute onset dementia with bithalamic t hyperintensity on mri without restricted diffusion. subsequent intraventricular hemorrhage resulted in emergent transfer to our institution's neurocritical care unit for an emergent diagnostic cerebral angiogram of a borden ii/cognard iib davf with immediate angiographic embolization and obliteration. davfs are lesions with significant risk of aggressive neurologic devastation related to venous congestion and subsequent hemorrhage. the severity of davfs requires clinicians to be aware of these lesions and of their common and uncommon presentations. little is known about the ability of prognostic scores to predict outcome in patients with secondary intraparenchymatous intracranial hemorrhage (iph). our objective was to describe the clinical characteristics, ich scores at presentation and prognosis in patients with secondary iph. we performed a post-hoc analysis of prospectively collected data of consecutive patients admitted to a tertiary hospital with iph. the characteristics of patients with secondary iph were compared to those of patients with spontaneous iph. patients with secondary iph had either a positive underlying vascular lesion identified as the iph etiology or impaired coagulation at presentation (a platelet count < , per cubic mm, an inr > . , or an aptt > than seconds). a total of patients with iph were admitted to our hospital from january- to january- . of those, patients ( %) had a secondary iph ( cavernomas, arteriovenous malformations, dural fistula, reversible vasoconstriction syndrome and sacular aneurysm patients with secondary iph had lower ich scores at presentation and lower in-hospital mortality than patients with spontaneous iph. despite lower ich scores at admission, patients with secondary iph had similar functional outcomes when compared to patients with spontaneous iph. larger studies should focus on specifically developing better prognostic tools in such patients. a large number of studies in traumatic brain injury patients have shown efficacy of hypothermia for control of icp and if used for prolonged duration, has shown to improve mortality and functional outcome. for other neurologic catastrophes, due to a risk of rebound edema during re-warming, medical complications and other factors, it has either not been commonly used or been used when most of other options are exhausted. this is a retrospective analysis of patients with massive ich (blood volume of > ml), of non traumatic etiology, dominantly in brain parenchyma. all patients had intracranial pressure monitoring via external ventriculostomy catheter. hypothermia was induced and maintained at target temperature via non-invasive, surface cooling pads. modified rankling score (mrs) was recorded at months after the ictus in all survivors. patient ages ranged from to years. cause of ich was hypertension in patients and ruptured aneurysm in one patient. duration of treatment ranges from - days. target temperature required to adequately control icp ranged from - c. two patients ( %) survived with good recovery (mrs of ), one ( . %) with moderate disability (mrs of ), two ( %) with moderately severe disability and three ( . %) died. most common side effect of hypothermia was hypotension requiring pressors in five ( %), electrolyte imbalance in ( %), pneumonia in ( %), thrombocytopenia in ( %) patients. all complications were successfully treated and major complications of treatment (bleeding diathesis, septic shock syndrome, death) were not observed. controlled hypothermia for up to days is safe and feasible for the treatment of cerebral edema and intracranial hypertension in young patients with massive (> ml of blood volume) non traumatic ich. however, prolonged duration of treatment may be required for definitive control of icp. this study serves as a template for future efficacy trials. intracerebral hemorrhage (ich) accounts for % to % of strokes and is associated with substantial morbidity and mortality. it remains controversial whether surgical intervention or a conservative approach is the best option for treating ich. we assessed the hypothesis that early surgical intervention in patients with primary supratentorial ich may serve to improve -day outcome. a total of patients with primary supratentorial ich, in whom surgical intervention was indicated for hematoma removal according to the guidelines, were admitted to our hospital during a continuous -month observation period. patients with the consent to the surgical intervention (n= ) underwent surgery within hours of symptom onset and the others (n= ) were given the conservative treatment. the outcome was the proportion of patients who had an unfavorable outcome (persistent vegetative state or death), as assessed on the basis of the glasgow outcome scale (gos) at days. the -day mortality rate was . % (standard error, . %). there was no significant difference in outcome between the two treatment groups. after adjustment for other significant covariates, although a lower unfavorable outcome was found in surgical group but the difference was not significant (odds ratio = . ). among the confounding factors, presence of intraventricular hemorrhage (ivh) and low glasgow coma scale (gcs) score on admission were independently associated with poor outcome days after ich (both p < . ). we found no benefit for early surgical intervention over conservative treatment in patients with primary supratentorial ich. presence of ivh and low gcs score were strong predictors of poor outcome in these patients. given the high morbidity and mortality associated with intracerebral hemorrhage (ich), family members and healthcare providers base early supportive management decisions, at least partly, on expected prognosis. in the comatose patient with ich, this short term prognosis is most overtly characterized by regaining of consciousness. a retrospective consecutive cohort of patients, between and , with ich and admission glasgow coma scale that were associated with regaining of consciousness after coma in ich. variables associated with awakening in univariate analysis were tested in multivariable logistic regression. the group that awakened had higher initial gcs scores, smaller ich volumes, and less ivh, but was similar in other baseline characteristics. early dnr orders, in the first hours, tended to be used more frequently in patients who ultimately remained comatose, but the difference was not statistically significant. admission gcs, volume of ich, and presence of ivh identified in univariate analysis were tested along with age and gender as potential confounders of outcome in multivariable analysis. higher admission gcs score was associated with an increased likelihood of awakening from coma (or . [ %ci . - ] per category, p= . ). % of patients with initial gcs of - , % with initial gcs of - , and % with initial gcs of - regained consciousness. awakening from coma, in the cohort of patients who regained consciousness, occurred in % of patients by day , % by day , and % by day . gcs score is the single most important predictor of early awakening in patients who present in coma after ich. patients who regained consciousness typically did so within the first days of hospital admission. intracerebral hemorrhage (ich) is an infrequent but severe complication in pregnant women with hypertension, it accounts for % of all deaths related to cerebral complications in this group. a- -year-old female, g p at weeks of gestational age, with prenatal care, no relevant past medical history, presented for a follow-up visit. she was admitted with bp / mmhg, and treated with iv labetalol; the preeclampsia work-up was negative, bp range between / and / mmhg. approximately h after admission, she complained of diffuse headache, nausea, vomiting, and epigastric pain. headache symptoms increased follow by focal seizure and progression to generalized tonic-clonic seizures. magnesium sulphate and phenytoin were administered to control the seizure, immediate blood analysis revealed dic. the diagnosis of eclampsia was made, and emergency csection followed. the airway was secured with rapid sequence technique; a healthy infant was delivered under general anesthesia. the patient remained comatose hour after surgery with gcs , minutes later she demonstrated a decerebrate posture with non-reactive pupils. a non-contrast ct-scan revealed an intracerebral hematoma. dic was treated, and neurosurgeon performed a right frontotemporal craniotomy. a postoperative ct scan confirmed the resolution of the ich. the patient opened her eyes and started responding to commands by the third day, on day she was extubated and the gcs was . by the rd week, the patient was transferred to rehabilitation, where she remained for weeks. at years, she regained a full cognitive recovery. this case emphasizes that even short time hypertension should be treated aggressively to prevent ich. the prompt intervention of a multidisciplinary team (obstetric, neurosurgery, and anesthesiology) is required to ameliorate the devastating effects of eclampsia and ich. although hypertension is the commonest cause of non-traumatic intracerebral hemorrhage (ich), it is important to rule out other causes. most patients with ich have an elevated bp on presentation but many are unaware if they have longstanding hypertension. echocardiographic abnormalities may be revealing in such circumstances. we studied the incidence of echocardiographic abnormalities and their usefulness in determining the etiology of ich in these patients. we conducted a retrospective study of echocardiographic abnormalities in ich patients admitted to a tertiary university hospital between jan to oct who also had a cerebral angiogram. subjects with and without underlying vascular location (categorized as typical hypertensive location or not), history of hypertension and the presence of the following echocardiographic abnormalities: left ventricular hypertrophy (lvh), diastolic dysfunction (dd), systolic dysfunction (sd), hyperdynamic ventricular function (hvf), wall motion abnormalities, atrial enlargement (ae) and valvular abnormalities using chi-square test and fisher exact test. we then conducted a multivariate logistic regression analysis including variables with a p< . in the univariate analysis. a total of subjects were admitted with an ich. subjects had an echocardiogram and of these, also had an angiogram (conventional angiogram: , ct angiogram: , mr angiogram: ). the echocardiogram was abnormal in . % ( . % with a history of hypertension p= . ). common abnormalities were: lvh ( . %), dd ( . %), hvf( . %), sd ( . %) and ae ( . %). of these, only dd (p= . ) was significantly associated with absence of underlying vascular abnormalities on a univariate analysis. on multivariate analysis, none of the echocardiographic abnormalities showed a significant association. echocardiographic abnormalities, mainly lvh and dd are commonly seen in ich patients, however none of these abnormalities are independently associated with an absence of underlying vascular anomalies. stroke in the hiv+ population is a growing problem, though it is unclear whether hiv is an independent risk factor. we describe a series of hiv+ patients with intracerebral hemorrhage (ich). we reviewed records of all patients with diagnoses of ich and hiv/aids admitted to an academic, inner-city hospital between and . patients with traumatic hemorrhage, ischemic stroke with hemorrhagic conversion, hemorrhagic neoplasms, toxoplasmosis with hemorrhage, subarachnoid hemorrhage, and extra-axial hemorrhages were excluded. we reviewed demographics, risk factors, laboratory tests, and neuroimaging. outcomes at days were determined by modified rankin scale (mrs). six hiv+ patients ( % male, mean age ) met inclusion criteria, with patient having recurrent hemorrhages; % were black, % hispanic, and % of other racial groups. all patients met criteria for aids. risk factors included: prior stroke ( %), diabetes ( %), hypertension ( %), smoking ( %), and illicit drug use ( %). only patient was taking antithrombotic medication. the co-prevalence of hcv was %. admission blood pressure was > / in / patients. laboratory evaluation demonstrated patient with a prolonged inr (> . ) and patients with thrombocytopenia (< ). the hemorrhages were lobar in / and deep in / . only patients had vessel imaging; one had an avm and none demonstrated aneurysm or vasculitis. at days, four patients were deceased and the two survivors had mrs of and . in this cohort, hiv-associated ich occurred only in aids patients. outcomes were uniformly poor, with % of patients having a htn and unexpected predominance of lobar hemorrhages in younger patients, suggesting a distinct mechanism of ich. in gregory call and marie fleming reported four patients with what appeared to be a reversible form of cerebral vasoconstriction. since then a number of authors have reported reversible cerebral vasoconstriction syndromes (rcvs), often in association with potential etiological precipitants. the major complication of rcvs is ischemic stroke, but hemorrhagic strokes can also occur, eventually leading to permanent sequelae and even death. recent reports and case series have suggested that intracranial hemorrhages may be frequent in rcvsand its presentations may range from cortical subarachnoid hemorrhages to intracerebral hemorrhages and subdural hemorrhages. we report two cases of rcvs in middle age women, with hemorrhagic strokes caused after the prescription of dipirone, isometheptene and anhydrous caffeine, with putaminal hemorrhage, and lobar frontal hemorrhage. both cases showed complete reversion of arterial vasoconstriction weeks later by the transcranial doppler. despite the reversibility of the vascular constrictions that characterize rcvs, brain lesions are observed in up to % of the patients.most of these lesions are of ischemic nature; however hemorrhagic phenomena are not uncommon and have only been reported in %- % of the cases. isometheptene has been described as a trigger for rcvs in only a handful of patients, all of whom were women in the postpartum period. even though rcvs diagnosis demands evidence of complete reversibility of the vasospasms, differential diagnosis with sah can be made by the identification of classic rcvs triggers and assessment of the vascular patterns brain arteries. magnesium (mg) has been hypothesized to have a neurprotective effect against cerebral ischemia. several ongoing studies are examining the effect of exogenous magnesium in reducing disability and maintaining normal cerebral function. we examined initial endogenous mg levels in patients with spontaneous intraparenchymal hemorrhage (iph), in order to determine if higher mg blood serum levels would confer neuroprotective benefit. this is a retrospective study on patients admitted to a university affiliated community hospital. demographic data were obtained from a prospectively collected registry database. initial magnesium levels were gathered retrospectively from the registry database. we included all patients with iph in our analysis. for evaluating the severity and outcome of the patients with iph we used the university of california san francisco intracerebral hemorrhage (ucsf ich) score on admission / hours to quantify stroke severity and mrs on discharge to measure outcome. we employed correlation coefficients (spearman's rho) and the mann whitney test for analysis of the data. spss version was used for data processing. our review identified patients with a diagnosis of iph. the serum mg levels in patients with iph negatively correlated to ucsf ich score on admission (p= . , r= - . ) and at hours (p= . , r= - . ). there was a trend towards better outcomes at discharge in patients with higher mg levels (p= . , r= - . ). higher levels of endogenous serum mg were found to confer reduction in iph severity and progression. initial serum mg levels could serve as an early predictor of iph severity. a larger prospective study is warranted to study the effect of endogenous mg on outcomes in patients with iph. spinal dural arteriovenous fistulas (davfs) account for % of all vascular spinal malformations. the incidence is - /million/year in the general population although it is generally under-diagnosed. men are affected five times more often than women and the mean age at the time of diagnosis is - years. spinal davfs generally do not present acutely and are very rarely located in the cervical region. we present a case of atypical acute spinal cord infarct secondary to a cervical davf. case report and extensive literature search carried out to understand spinal davfs. this year old gentleman presented to our neurocritical care unit with bilateral upper extremity weakness and right lower extremity weakness proceeded by upper back and neck pain. the patient rapidly deteriorated to near quadriplegia and respiratory failure requiring prolonged artificial ventilation. initial studies included normal mri of the brain and ct angiogram of the head and neck. mri of the spine revealed abnormal signal intensity within the anterior cervical cord from c -c levels in the distribution of the anterior spinal artery. there were no flow voids to suggest dilated perimedullary vessels. however, given the clinical picture, a spinal angiogram was obtained and demonstrated a cervical davf supplied by a dural branch vessel originating from the left vertebral artery. understanding spinal vascular anatomy is important for diagnosis of spinal davfs. our case is unusual because ) acute evolution of quadriplegia and respiratory failure, ) lack of any abnormal vessels seen on mri, and ) ischemic changes restricted to the anterior spinal artery distribution. the case emphasizes the importance of proceeding with spinal angiography if the clinical suspicion of davf is high. early detection and management can lead to improved functional outcome. although coma is a syndrome commonly associated to catastrophic brain injury, this patient population remains poorly characterized. the chief goal of therapy is aimed at reversal of coma. despite this urgency, there is paucity of data regarding the factors that predict emergence. we characterize a population of patients with new onset of coma in the neuro-icu and describe clinical and structural factors that predict emergence. prospective longitudinal consecutive cohort of patients, enrolled in an intensive care setting. three hundred patients met investigation enrollment criteria between may and july . a brain lesion was identified at the onset of coma in most patients ( %). frequent etiologic factors were cerebrovascular ( %), seizures ( %), trauma ( %), cns infection ( %), or other ( %). the most frequent cerebrovascular factors were any ich ( %), ivh ( %) and sah ( %), either alone or in combination. emergence from coma was predicted by a higher initial gcs (emergence= [ - ] vs. no emergence= . [ - ] p< . ), seizures as presenting disorder (emergence= % vs. no emergence= % p= . ), and a trend to lesser frequency of ich component (emergence= % vs. no emergence= %, p= . ). the importance of mass effect as measured by midline shift reversal and cisternal compression resolution is presented in a separate poster. mortality in this cohort is %. the population of patients with acute coma is highly heterogeneous. however clinical and structural factors predict emergence. a higher initial gcs predicted recovery of coma. structural cerebrovascular lesions with less ich component had a tendency toward higher rates of recovery. non-structural treatable causes of coma such as seizures were associated with higher rates of recovery. mortality and disability remain dismal in this population. optimal blood pressure (bp) control in intracerebral hemorrhage (ich) patients remains controversial. aggressive bp reduction may limit hematoma expansion, but may also cause hypoperfusion and ischemia. we investigated the relationship bp lowering in the first hours and the presence of diffusion weighted imaging (dwi) lesions on mri. we prospectively enrolled consecutive patients presenting with an acute spontaneous ich. brain mris were reviewed for the presence of lesions with reduced diffusion attributable to tissue compression, vessel compression, or hypoperfusion ipsilateral to the hematoma. bps were recorded on hospital presentation, and at , , , and hours. of eligible patients, met inclusion criteria: age: ± years; hematoma volume: ml (iqr - ); admission nihss: (iqr - ); ich onset to maximal bp reduction hours (iqr - ); and ich onset to mri: hours (iqr - ). dwi lesions were detected in % of patients: % of patients had lesions attributed to tissue compression, % to vessel compression, and % to hypoperfusion (some patients had multiple lesion types). dwi lesions were associated with larger hematoma volumes ( vs. ml, p < . ); higher admission mean arterial pressures (map) ( vs. mmhg, p= . ); and greater average map reductions ( vs. %, p= . ). after controlling for ich volume using logistic regression: for every % of map reduction, the risk of dwi lesions increased (or . , % ci: . - . ); for each % reduction in map the risk of dwi lesions more than doubled (or . , % ci . - . ). the proportion of patients with dwi lesions increased as the maximum percent map reduction increased in a dose dependent fashion. ischemic brain lesions in patients with spontaneous ich are common and associated with hematoma volume and bp lowering. aggressive bp lowering may contribute to ich associated ischemic lesions. financial support: sources of funding: this research was supported by the nih (r ns ) to cacw, and the stanford school of medicine medical scholars program to jtk. coma is a major cause of death, disability and economic burden to the health care system. acutely comatose patients with primarily neurologic injury are at risk to develop neurologic and systemic complications. in this study, we seek to identify the timing of medical complications and their impact on mortality in acutely comatose patients admitted to neurocritical care unit. one hundred patients with acute coma for at least hours or longer were enrolled prospectively in the study from may to jan . major neurologic and systemic complications were identified prospectively and the frequency and timing of each major complication was established. of the patients studied, mean age was ± . years and % were females. a mean of . ± complications occurred. in this cohort of patients with coma, there were more non-neurological ( %) versus neurological ( %) complications. most complications ( %) were noted in the - day interval. further characterization of these complications is essential to the care of comatose patients in the nccu. pathophysiology of brain dysfunction associated with sepsis is still poorly understood. our purpose was to study the metabolic alterations and mithocondrial dysfunction in a clinically relevant model of septic shock. twelve anesthetized, invasively monitored, and mechanically ventilated pigs were allocated to a sham procedure (n = ) or sepsis (n = ), in which peritonitis was induced by intra-abdominal injection of autologous faeces. animals were studied until spontaneous death or for a maximum of hours. in addition to global hemodynamic and laboratory assessment, intracranial pressure and cerebral microdyalisis were assessed , , and hours after sepsis induction. after death, brain were removed and brain homogenates were studied to assess mithocondrial dysfunction. all septic animals developed a hyperdynamic state associated with organ dysfunction. in the septic animals, there was a progressive increase in l/p ratio and glycerol, as well as a progressive decrease in brain glucose concentration during the study period. the comparison between control and septic animals and the analysis of brain homogenates are undergoing. in this model of peritonitis, cerebral metabolism was derranged, with increasing levels of l/p ratio and decreasing levels of brain glucose during study period. these alterations may play a role in the pathogenesis of sepsis-associated encephalopathy. at sanford usd medical center, neuro critical care (ncc) patients are frequently treated with continuous infusions of % sodium chloride. it has been observed that this patient population often develops iatrogenic hyperchloremic metabolic acidosis, frequently managed with intravenous sodium bicarbonate. upon notification of a nationwide intravenous sodium bicarbonate shortage (march th , ), our ncc providers were forced to explore other potential options for managing this acidosis. it was decided that our ncc patients would be initiated on enteral sodium bicarbonate at the time continuous % sodium chloride was started. a retrospective chart review of ncc patients years and older, initiated on continuous % sodium chloride with enteral sodium bicarbonate tablets from march th , to june th , were evaluated. data collected included demographics and the following while in the intensive care unit (icu): baseline serum sodium, chloride, and bicarbonate; type of injury; acidosis defined as serum bicarbonate level < , or lower than baseline; and volume of % sodium chloride and bicarbonate administered. of the patients identified, . % developed iatrogenic metabolic acidosis during icu stay. average duration of continuous % sodium chloride infusion was days (range - days) with an average volume of % sodium chloride dispensed of , mls (range - , mls). three patients evaluated developed an acidosis during icu stay, of which were hyperchloremic at the time of acidosis. only patient required intravenous sodium bicarbonate, however the patient had been off hypertonic saline for more than day. enteral sodium bicarbonate appears to be an effective method at preventing iatrogenic hyperchloremic metabolic acidosis when initiated along with continuous infusions of hypertonic saline in ncc patients. this may be a method to conserve intravenous sodium bicarbonate during drug shortages. further studies are needed. fever is common in neurocritically ill patients. it can be from central causes, inflammatory, infectious, and other conditions. a method to differentiate infectious from non-infectious fever would allow for appropriate initiation of empirical antimicrobial therapy. apart from avoiding unnecessary antimicrobial usage, this approach can save health-care costs and limit the development of antimicrobial resistance. procalcitonin is a peptide precursor of the hormone calcitonin. procalcitonin levels rise as a proinflammatory response to bacterial infections. numerous studies have evaluated procalcitonin levels utility in the initiation and discontinuation of antibiotics in the inpatient setting; however, there is a paucity of studies regarding the use of procalcitonin levels in neurologically ill patients. this study examines the effectiveness of a procalcitonin-guided algorithm in a neurocritical care unit. a modified prorata trial procalcitonin algorithm was developed and utilized prospectively. patients that met criteria of ) admission into the neurocritical care unit ) age > years ) temperature > f in the last hrs ) no obvious source of infection were enrolled. depending on the procalcitonin level and the presence of new sirs criteria antibiotics were initiated per our algorithm. radiographical, microbiological, laboratory, and clinical outcomes were recorded to determine the accuracy of the procalcitonin algorithm in the decision to initiate or modify patient's antibiotic therapy. results from the first enrolled patients found the procalcitonin algorithm had % sensitivity and % specificity in predicting bacterial infections as the etiology of fever with a positive predictive value of %. the study population included intracranial hemorrhage ( %), ischemic stroke ( %), and others ( %). % of the study population had infectious fever while % had non-infectious fever. interim results suggest a procalcitonin-guided algorithm may be a valuable tool in differentiating infectious from noninfectious fever in the neuro-icu. further research is needed; data collection is ongoing. posterior reversible encephalopathy syndrome (pres) is defined by acute neurologic symptoms caused by vasogenic cerebral edema. recurrence of pres is thought to be rare and has not been well described. patients prospectively diagnosed with pres from - were pooled with retrospectively identified patients diagnosed with pres from - at an academic referral center. detailed clinical information and radiologic imaging results were collected. patients without clinical or radiographic resolution between episodes and patients without brain imaging available for review were excluded. of a total of patients with pres, ( %) had recurrence. one patient had four episodes, one patient had three, and ten patients had two episodes each, resulting in total pres episodes. seven patients ( %) had an autoimmune disorder. the average time between episodes was months. acute hypertension was present in of episodes. of these, mean blood pressure was / mmhg. etiologies of pres included hypertension (n= ), cytotoxic medications (n= ), sepsis (n= ), and multifactorial (n= ). renal failure was present in / episodes, and was acute in . clinical symptoms included headache (n= ), seizure (n= ), visual disturbances (n= ), encephalopathy (n= ) and focal deficits (n= ). only one patient ( %) had the exact same clinical symptoms with recurrence. ten patients had mri at each episode of pres. vasogenic edema affected the same brain areas at each episode in patients. in the rest, some affected regions were similar, but additional regions were different between pres episodes. none had entirely new areas of involvement. pres recurred in approximately % of our patients. in the majority, clinical symptoms differed at recurrence compared to the initial episode. in all patients, radiologic patterns of vasogenic edema in the repeat episode were similar to those in the initial pres episode, but also affected other brain regions in approximately %. ventilator-associated pneumonia (vap) is a common complication in comatose patients. diagnosis in this population is unreliable despite physician training and validated criteria leading to potential misdiagnosis and inappropriate antimicrobial use. we investigated clinical features associated with misdiagnosis of vap and excess antibiotic days (ead). ventilated comatose patients (glasgow coma scale motor score < ) suspected of having vap were prospectively identified in a neurocritical care unit in . vap was retrospectively diagnosed using centers for disease control (cdc) criteria by two neurointensivists and an infection control practitioner. appropriateness of the nccu team's vap diagnosis and therapy was performed using clinical, microbiologic and radiographic data. of comatose patients, cases were treated as possible vap by the nccu team. of these, patients had vap by cdc criteria. vap and non-vap groups did not differ in age, admission gcs, total ventilator days or mean total antibiotic days ( . ± . (vap) vs. . ± . (non-vap); p= . ). clinical features significantly associated with vap (vs. non-vap) were change in sputum character, tachypnea, oxygen desaturation, persistent infiltrate on chest xray and positive sputum microbiology. two-thirds ( . %) of non-vap patients received pneumonia targeted antibiotics for > days vs. . % of vap patients (p= . ), contributing eads, including vancomycin days, piperacillin-tazobactam days and cephalosporin days. median days from intubation to starting antibiotics was (non-vap) vs. (vap) days (p = . ). no pre-specified factors were associated with inappropriate continued vap treatment. inappropriate diagnosis and treatment of vap resulted in a cumulative eads in one year in the nccu. clinical differences between patients without vap who had antibiotics continued or discontinued were minimal, suggesting that clinician behaviors contribute to unnecessary prescribing. strategies to improve the diagnosis of and antibiotic use for vap in comatose patients is needed. management of hyponatremia in patients with acute brain injury can be challenging. the oral vasopressin receptor antagonist has been studied extensively in other disease process but not in acute brain injury. we report our experience regarding the efficacy and safety of tolvaptan, an oral vasopression v -receptor antagonist, for the correction of hyponatremia in acutely brain-injured patients. tolvaptan for the correction of euvolemic or hypervolemic hyponatremia. baseline serum sodium concentration was . ± . meq/l. seven patients received mg of tolvaptan once (singledose-users), and patients received another mg on the next days (double-dose-users). hours after tolvaptan administration, serum sodium concentration increased by . ± . meq/l in single-dose-users (p = . ) and . ± . meq/l in double-dose-users (p = . ). hours after administration of first dose of tolvaptan, serum sodium increased by . ± . meq/l in single-dose-users (p = . ) and . ± . meq/l in double-dose-users (p = . ). during four days of observation, the increases in the average area under the curve of the serum sodium concentration was . ± . meq/l in single-dose-users (p = . ) and . ± . in double-dose-users (p = . ). urine output increased by . ± . l during the first hr in single-dose-users (p = . ). no significant changes in fluid balance, serum creatinine and glasgow coma scale were observed. of four patients who underwent neuro-monitoring, intracranial pressures, cerebral perfusion pressures and mean arterial pressure did not change significantly compared with their baseline values. tolvaptan was effective and well-tolerated for the correction of hyponatremia in patients with acute brain injuries. validation can be done with further studies. patients with acute brain injury but normal lung function often undergo intubation and subsequent tracheostomy for the concern of airway protection. we previously described patients with primary brain injury and encephalopathy who fail extubation demonstrated signs of disrupted ventilation usually with periods of prolonged hypoventilation. we examined the clinical characteristics of patients with a tracheostomy who are readmitted to the icu with respiratory decompensation. retrospective review of patients admitted to the neurocritical care unit (nccu) of a tertiary care hospital who underwent tracheostomy from september to june . of patients who received tracheostomies during their admission to the nccu, ( %) were successfully transferred to the floor, ( %) were readmitted to the icu, and ( %) had other dispositions such as discharge to rehabilitation and withdrawal of care. there were a total of readmissions, due to respiratory decompensation and due to cardiopulmonary arrest. hypoventilation is commonly seen in neurological patients who receive a tracheostomy. potential predictors of respiratory decompensation and readmission of these patients include their brainstem reflexes and respiratory patterns as assessed by the four score as well as their duration of mechanical ventilation. twenty-two percent of neurocritically ill patients may become hypernatremic. moderate-severe traumatic brain injury (mstbi) patients may develop hypernatremia possibly from diabetes insipidus (di) or osmotherapy for brain edema treatment. retrospective studies suggest that hypernatremia (serum sodium [sna] > mmol/l) may be associated with an increased risk of death. however, these studies failed to adjust for di and the use of osmotherapy. we examined the impact of mean and peak sna on in-hospital mortality and functional outcome at hospital discharge, adjusted for these important variables. in a prospective observational study, consecutive mstbi patients from a single level i trauma center between / - / were analyzed. poor outcome was defined as glasgow outcome scale (gos) - . multivariable logistic and ordinal regression was utilized to adjust for admission characteristics, injury severity, icu length-of-stay, brain edema, osmotherapy (mannitol/hypertonic saline), and di. firth's method was used in logistic regression models to accommodate small sample sizes. the mean age was years, % were men, and the median glasglow coma scale and injury severity scores were and , respectively. higher mean and higher peak sna were significantly associated with worse outcomes, both when using the dichotomized (or . ; % ci . - . for mean and or . ; % ci - . for peak sna) and ordinal gos (or . ; % ci . - . for mean and or . ; % ci . - . for peak sna). for every mmol/l increase in mean sna and every mmol/l increase in peak sna, patients worsened by one gos category. our results suggest that higher sna values are associated with worse neurological outcome, independent of osmotherapy, brain edema and di. it will be important to determine which sna might be "too high". while autonomic instability occurs as part of anti-n-methyl d-aspartate (anti-nmda) receptor encephalitis, anti-nmda receptor encephalitis is not a recognized cause of the clinical syndrome of paroxysmal sympathetic hyperactivity (psh). we present a case of anti-nmda receptor encephalitis in which psh was a cardinal feature. a -year-old woman had a generalized tonic-clonic seizure, and then developed progressively worsening neuropsychiatric symptoms, including mania, hallucinations, echolalia, and suicidal ideation. diagnostic work-up revealed anti-nmda receptor antibodies detected in the serum and in the cerebrospinal fluid (csf). one week after symptom onset, the patient experienced intermittent episodes of sinus tachycardia, hypertension, tachypnea, diaphoresis and extensor posturing. the episodes were both spontaneous and stimulus responsive (for example, during endotracheal suctioning). the episodes, consistent with psh, were initially treated with dexmedetomidine, which was titrated to effect. gabapentin and propranolol were added later for symptom control, but eventually weaned off as her symptoms abated approximately six weeks into the illness. we believe that the autonomic instability associated with anti-nmda receptor encephalitis may often be psh. psh often goes unrecognized in patients outside of the setting of tbi, thus specific psh management strategies may be overlooked in other contexts. anti-nmda receptor encephalitis may represent the functional companion to the structural lesion encountered in tbi. recognition of psh in this setting is important to guide the management of the autonomic instability, but may also have mechanistic implications. a -year old male with history of motor vehicle accident s/p frontal sinus surgery was admitted with streptococcus pneumoniae meningitis and altered mental status. upon admission, he was febrile with leukocytosis. head ct showed left sinus opacification and csf studies were consistent with bacterial meningitis. despite broad-spectrum antibiotics and interval improvement in his head ct and csf studies, his mental status continued to decline. shortly after icu admission, he became lethargic with a new right-sided hemiparesis. cta revealed diffusely narrowed intracranial arteries most compatible with vasospasm and mri was consistent with multiple areas of infarction. his neurological exam continued to deteriorate necessitating intubation for airway protection. tcds showed bilateral mca vasospasm. initially, vasospasm was managed with nimodipine, hypertension, and euvolemia. systolic blood pressure was artificially elevated with vasopressors, inotropes, and ultimately with methylene blue. despite aggressive medical management, there was little improvement clinically. therefore, he received four sessions of angiography with intra-arterial verapamil. after the final intra-arterial verapamil treatment, he demonstrated angiographic and clinical improvement. we conclude that patient's cerebral vasospasm was a direct complication of streptococcus pneumonia meningitis. intra-arterial verapamil appears to be effective in treating pneumococcal meningitis induced symptomatic cerebral vasospasm. however, there is limited data to predict its vasodilatory sustainability and optimal treatment intervals. pneumococcal meningitis is the leading cause of bacterial meningitis beyond the neonatal period. clinical and experimental research had demonstrated that vascular alterations are common in bacterial meningitis and are associated with stroke. despite the introduction of the pneumococcal vaccine, availability of effective antibiotics, and advances in adjunctive strategies, mortality and morbidity rates associated with arterial complications secondary to pneumococcal meningitis remain high. this case is noteworthy because to our knowledge this is the first reported case of pneumococcal bacterial meningitis induced vasospasm that has been successfully treated with intra-arterial verapamil. xuemei cai , osmotic myelinolysis is a life threatening problem associated with rapid correction of chronic hyponatremia. the brain cannot readily restore organic osmolytes; thus rapid correction of serum osmolality leads to cellular shrinkage causing axonal dissociation from myelin sheaths. current guidelines state that serum sodium (sna) should be corrected at a rate not exceeding - meq/l/day but when extracellular volume depletion is the cause, vasopressin suppression after saline treatment increases risk of rapid overcorrection. there is no standard of care that directs treatment once osmotic myelinolysis occurs. we report a case of a patient who developed clinical symptoms of osmotic myelinolysis syndrome who was successfully treated with re-induction of hyponatremia which led to complete neurological recovery. a -year-old woman on thiazide treatment for hypertension developed protracted vomiting and diarrhea for several days followed by confusion and lethargy. in the emergency department, sna was meq/l. she received isotonic saline and over the next hours, sna rose meq/l. on hospital day two, her neurological condition deteriorated rapidly with development of mutism, increased tone in all extremities, hyperreflexia. osmotic myelinolysis syndrome was diagnosed on clinical grounds. she was given desmopressin with % dextrose in water (d w) to rapidly lower her lower her sna. her neurological status improved at a sna of meq/l. thereafter, sna was slowly uptitrated with desmopressin and % normal saline. she made a complete neurological recovery. mri performed at discharge and one month later showed no abnormalities. overcorrection of sna in chronic hyponatremia is a common iatrogenic problem which can lead to osmotic myelinolysis syndrome, a highly morbid and oftentimes fatal neurological condition. our case supports immediate re-induction of hyponatremia in patients with symptoms suggestive of osmotic myelinolysis at a time when imaging may be unremarkable and complete neurological recovery is achievable. posterior reversible encephalopathy syndrome (pres) is manifested by acute neurological findings with evidence of vasogenic edema on brain imaging possibly due to cerebral vascular endothelial dysfunction. the epidemiology of pres in pediatric critical care has not been well described and it may be under recognized and thus prompt treatment delayed. we performed a retrospective review of all patients with diagnosis of pres over month period (january to june ) in a pediatric critical care unit (pccu) at a tertiary care university hospital. data from hospitalization and month follow up were reviewed. there were admissions to pccu and neurology service consultations during the study. six patients were diagnosed with pres (incidence - in pccu admissions) with median age years (mean±sd; . ± . years). all patients presented at onset with generalized tonic-clonic or clonic type seizures that lasted up to hrs and returned to baseline mental status in - days. other clinical features were headache and visual impairment. risk factors preceding the onset of pres included anemia [hemoglobin . ± . g/dl], azotemia, hypertension, hypernatremia, hypocalcemia, hypomagnesemia, and recent use of chemotherapy (azathioprine, cyclophosphamide, tacrolimus and mycophenolate mofetil). brain mri demonstrated increased t /flair signal within the parieto-occipital white matter in all patients, frontal lobe changes in patients and vertebro-basilar system changes in patients. no regions of restricted diffusion were seen on diffusion weighted imaging. at month follow up, no patients had residual neurological deficits from pres and neuroimaging revealed significant resolution of white matter signal changes. pres is associated with multiple disease states including systemic lupus erythematosus, sickle cell disease, sepsis, recent use of cytotoxic medications and renal failure. knowledge of the risk factors associated with pres, its clinical presentation, and characteristic mri findings may lead to more rapid recognition and treatment. adults with neurological injury are at increased risk for tracheobronchial foreign body aspiration. this report will present a case of silent foreign body aspiration in a patient who presented to the emergency department with status epilepticus. case report and review of the literature. an year-old african american man presented to the emergency department with status epilepticus. seizures were controlled with intravenous lorazepam and fosphenytoin, and the patient was intubated for airway protection. on day four following admission to the neurosciences critical care unit, a routine magnetic resonance imaging (mri) scan demonstrated susceptibility artifact from a metallic focus which completely obscured the spine structures at c -c . upon review of the patient's previous imaging, numerous abnormalities were reported on daily chest x-rays and a foreign body was identified within the trachea on a thoracic ct from admission. a bronchoscopy was performed which revealed a watchband within the trachea and right mainstem bronchus. tracheobronchial foreign body aspiration should be considered in patients with unexplained respiratory symptoms, and a high degree of clinical suspicion should be maintained in patients with neurologic impairment. abnormalities on chest xray and computed tomography should prompt an early pursuit of the diagnosis in high-risk patients. mri, although generally considered to be a safe imaging modality, could be potentially harmful to patients with unidentified foreign bodies. hypokalemic periodic paralysis (hypopp) is a disease characterized by muscle weakness or paralysis secondary to low serum potassium levels. neurogenic diabetes insipidius (di) is a condition where patient excretes large volume of diluted urine due to low level of anti-diuretic hormone (adh). here, we report a case of hypopp in a patient with neurogenic di. a year-old right-handed hispanic male was admitted for seizures after developing a dental abscess. this patient had a history of pituitary adenoma resection at the age of with subsequent pan-hypopituitarism for which he was on hormonal supplementation. on hospital day three, he developed sudden onset of quadriparesis with motor strength in upper extremities / bilaterally and / in both lower extremities and absent deep tendon reflexes throughout. his routine laboratory studies showed severe hypokalemia of . meq/dl. nerve conduction study (ncs) revealed absent compound motor action potentials with normal sensory potentials. electromyography (emg) revealed no abnormal insertional activity or spontaneous activity. some muscles demonstrated no volitional motor units and a few others had decreased recruitment in distal small motor units. following aggressive correction of the hypokalemia he regained his full strength and repeat emg showed normal motor units, normal recruitment, but no myotonic discharges. ncs showed return of compound motor action potentials in all nerves tested. hypopp remains an important differential in an acute case of paralysis and acute management is important. we report a case of a -year-old caucasian male who presented to a community hospital with complaints of flu-like symptoms. he underwent pulmonary-vein isolation for chronic atrial fibrillation thirty days prior to admission. his history includes left frontal and right parietal ischemic infarcts, mitral valve repair, coronary artery bypass grafting, patent foramen ovale closure, and coronary artery disease. approximately hours prior to arrival, he developed nausea, vomiting, fatigue and confusion. he was febrile and appeared encephalopathic. a telemedicine stroke consultation recommended transfer to a tertiary care facility. while the initial concern was for acute cerebral ischemia, he did not meet exclusion criteria for thrombolytic therapy. the patient received aggressive initial hydration and broad spectrum intravenous antibiotics for coverage of meningitis. blood cultures, complete blood count, comprehensive metabolic panel, urinalysis, stool culture and a lumbar puncture were performed. interestingly, his blood cultures remained persistently positive for gram positive cocci in chains and clusters. occult stool was positive and his oral gastric tube demonstrated bloody drainage. the remainder of his laboratory work was unremarkable. ct scan of his head revealed old ischemic infarcts without hemorrhage or hypodensity. the patient continued to decompensate in the neurointensive care unit where he eventually required intubation. a ct scan of the chest was highly suspicious of a left atrial-esophogeal fistula. cardiothoracic surgery was notified of the atrio-esphogeal fistula and he was taken to the operating room for a right thoracotomy with repair of the fistula and intercostal muscle flap. post-operative mri brain demonstrated innumerable air emboli and diffuse areas of ischemic infarction. atrio-esophageal fistula is a very rare complication following pulmonary vein isolation, and because prognosis is dependent upon prompt surgical correction, neurointensivists should be aware of this entity financial support: none propofol infusion syndrome (pris) is a rare but devastating complication of high dose administration of diprivan in children and young adults which presents with metabolic acidosis, rhabdomyolysis and fatal cardiac dysrhythmias. we report a case of pris in a -year old, previously healthy, postpartum female who received a high dose diprivan infusion for hours at an outside institution for the treatment of presumed refractory convulsive status epilepticus. patient received diprivan mcg/kg/min for the first hours. diprivan was increased to mcg/kg/min to achieve burst suppression on the electroencephalogram. diprivan was stopped after hours due to lactic acidosis. subsequently patient developed renal failure and elevation of ck up to , .she was transferred to our institution for continuous hemofiltration and possible extracorporeal membrane oxygenation (ecmo).after transfer she developed atrial fibrillation, ventricular tachycardia and fibrillation. an ecmo catheter was placed when she was in ventricular fibrillation for minutes. after starting ecmo the patient developed asystole for hours, requiring a transvenous pacemaker. her cardiac dysfunction improved rapidly and ecmo was discontinued after days. the patient started to follow commands consistently at days after the onset of fulminant pris. mri of the brain showed a subacute right posterior cerebral artery infarct attributed to cardiac embolism. the patient left intensive care unit after weeks. close metabolic and cardiac monitoring should be applied when a patient is on high-dose of diprivan(> mcg/kg/min). diprivan should be stopped as soon as unexplained metabolic acidosis, rhabdomyolysis and cardiac dysrhythmias are noticed, and transfer the patient to a center with continuous hemofiltration and ecmo capabilities should be considered. ecmo can be a lifesaving intervention in patients with fulminant pris. postpartum cerebral angiopathy (pca) is a rare pregnancy complication. pca is often a benign condition that resolves spontaneously, but can lead to stroke or death. the purpose of this case study is to describe events that transpired in the care of a patient with severe persistent pca, for whom unconventional treatment was initiated because conventional treatment failed. retrospective and current chart reviews were conducted, including relevant medical history. objective data related to the patient's condition were reviewed. we examined the evolution of medical and nursing care as the patient's condition deteriorated despite aggressive conventional therapy, and reviewed ensuing events: multidisciplinary collaboration to search for other viable treatment options, consultation with colleagues from another major medical center regarding their experience with nicardipine and recommendations on off-label use for pca, and decision-making including the family about whether or not to administer intraventriuclar nicardipine. multiple disciplines (i.e., doctors, nurses, and pharmacists) and family members contributed to the complex decision to initiate unconventional treatment. we administered mg intraventricular nicardipine every eight hours for seven days. using transcranial dopplers, cerebral arteriograms, and clinical assessment data, we evaluated the effectiveness of this unconventional treatment. after seven days, we discontinued the nicardipine, while continuing standard treatment to maintain hypertension and hypervolemia. currently, the patient is expected to make a full recovery with few residual stroke deficits. a multidisciplinary approach, including the family in the decision-making process, enabled creative problem-solving for a challenging clinical situation. when conventional methods failed, our team collaborated to think outside the box and take a calculated risk, altering the course of our patient's condition from critical toward survival and recovery. the objective was to determine the diagnostic yield and safety of brain mri in critically ill patients with icu-acquired acute brain dysfunction. patients in the medical and surgical icus who developed acute brain dysfunction and underwent brain mri were included. patients with preexisting brain disorders and those from neurological icus were excluded. mri scans were analyzed by three specialists trained in neuroimaging. outcome variables included glasgow outcome scale at discharge ( - categorized as unfavorable and > as favorable) and death. patients underwent brain mri for evaluation of encephalopathy, seizures, focal deficit. signs of parenchymal brain abnormalities were detected in patients ( %) including white matter hyperintensities in . % and acute cerebral infarcts in . %. results from brain mri led to modification of diagnosis and treatment in % of cases. patients with mri defined lesions were more likely to have an unfavorable outcome. there were no adverse events from transportation to the radiology site or from mri performance. in icu patients with acute brain dysfunction, mri is a safe noninvasive diagnostic tool that often leads to substantial modification of diagnosis and treatment. structural brain injury contributes significantly to the pathogenesis of cerebral dysfunction during critical illness and should be taken into account even if other reasons for encephalopathy are presumed. central nervous system (cns) and intraventricular infections are a devastating complication for patient admitted to an intensive care unit. the use of intrathecal (it) antibiotics for the treatment of cns infections has been reported in small case studies. our purpose was to report patients who have received it antibiotics for intraventricular infections in our facility and discuss our findings. retrospective case series of patients who received intrathecal antibiotics in combination with systemic antibiotics for treatment of intraventricular cns infection over the past years. basic demographic and clinical measures were collected from the hospital data base. seven patients received it antibiotic therapy for cns infection. admitting diagnoses were head trauma ( ), intracranial hemorrhage ( ), and subarachnoid hemorrhage ( ). one patient had an infected ventriculoperitoneal shunt. all of the patients received an external ventricular drainage device during admission prior to developing cns infection. time from hardware placement to first positive csf culture for patient was days; patients were positive with first csf; were within days; and had his vp shunt in place for days prior to positive cultures. pathogens cultured from csf included klebsiella pneumoniae, acinetobacter baumannii and vancomycin-resistant enterococcus faecalis in patients each, and methicillin-resistant staphylococcus aureus in patient. the intrathecally instilled antibiotics were colistin, streptomycin, tobramycin and vancomycin. two of the patients cleared csf cultures in day, patient cleared in days, patients cleared in days and took days to clear csf. based on this small case series we found it antibiotic adjunct therapy as a viable option for treating cns infections as most of our patients cleared csf within days of treatment initiation. further studies are warranted to support our findings. we report a case of an esthesioneuroblastoma or olfactory neuroblastoma (onb) presenting with frontal lobe dysfunction and hence depression with rapidly declining mental status resulting from hydrocephalus and stroke meningitis. this is a year old man who presented with fever, headache and ams. he had months history of progressive headache, face pain, rhinorrhea, nasal congestion and depression. ct head showed destruction of the cribriform plate by a mass arising from the right nasal cavity with extension into the right inferior frontal cranial fossa. an evd was placed emergently for elevated icp. he was also found to have multiple strokes in the right basal ganglia and corpus callosum. an incidental mycotic aneurysm was seen at the right posterior cerebral artery. labs showed wbc of , sodium of , potassium of , bicarbonate is . a lumbar puncture was performed which showed evidence of bacterial meningitis. a diagnosis of onb was established by histopathology and confirmed by immunohistochemistry. on staging, the mass was classified as a kadish stage c tumor. he underwent coiling of the pseudo aneurysm of right pca and maxillary embolization, followed by bifrontal craniotomy and endovascular resection of tumor onb is a rare malignant tumor of neuroectodermal origin and is thought to arise from the olfactory epithelium. symptoms are related to nasal obstruction, orbital extension, invasion of thecribriform plate, paraneoplastic syndromes with hypercalcemia and hyponatremia and can cause frontal lobe dysfunction. physical examination generally reveals a vascular, polypoid mass located in the nasal cavity. mri helps to differentiate tumor from other causes of nasal obstruction. they typically stain for neuron-specific enolase (nse). there has been no standardized rct done due to rarity of the tumor but traditionally the mainstay of treatment in such locally advanced patients is combinedotolaryngologic and neurosurgical craniofacial resection followed by adjuvant radiotherapy. we describe a case of delayed ptld in a year old diabetic patient with esrd several years after multiple solid organ transplants; a successful pancreatic transplant and a rejected renal transplant. she initially presented with mild left hemiparesis and was found to have enhancing and non-enhancing both supra and infra tentorial lesions, without evidence of disease in the graft, skin or bone marrow. the histological diagnosis of ptld was made after a right frontal brain biopsy. she had intercurrent worsening of left hemiparesis post biopsy due to hemorrhagic transformation of one of the lesions. the patient initially responded to a decrease in immunosuppressive medications which included tacrolimus and cellcept however, she eventually also required rituximab and whole brain radiation to maintain remission. in this case report we highlight the manifestations of cns ptld, dilemmas in diagnosis and various strategies for management. this can be a fatal complication of solid organ transplants if not recognized and treated early. dysautonomia has been well associated with guillain barre syndrome (gbs). the dysautonomic effects of gbs may cause a variety of reversible clinical syndromes associated with sympathetic dysfunction including pres and takotsubo cardiomyopathy. pres can be a presenting feature following gbs treatment with intravenous (iv) immunoglobulins or may present later in recovery. dysautonomia resulting from gbs is the most likely explanation for this assocication while another possible mechanism can be the influence of cytokines, produced in the context of gbs, on the permeability of blood brain barrier. in this abstract we highlight a self limited case of pres presenting as an early complication of gbs. case: our patient was a year old female with hypertension who presented to an outside hospital with alteration in mental status. she had developed bilateral lower extremity weakness and difficulty ambulating for - days prior to admission. she reportedly had an upper respiratory infection about weeks prior to presentation. at the time of transfer to our hospital the patient had a generalized tonic clonic seizure and was started on keppra. she had a fluctuating mental status from being awake to stuporous. bilateral lower extremity power was / in all muscle groups. initially, deep tendon reflexes were + in lower extremities but after a few hours she became areflexic in lower extremities with + reflexes in upper extremities and downgoing plantars. mri brain t /flair images showed lesions consistent with pres. csf showed cyto-albuminologic dissociation and diagnosis of gbs was made. she was started on a day course of iv ig. she was discharged to a rehab facility with some improvement in her paraparesis and no recurrent seziures. this case report illustrates that patients can develop pres as a complication of gbs perhaps due to dysautonomia but pres may be self limited in this setting. data exists describing the outcomes of critically ill patients with specific conditions in specialty intensive care units (icu) versus general icus. severe sepsis and septic shock(ss/sh) outcomes have not been robustly evaluated in community hospitals between specialty icus. we chose to evaluate whether patients admitted to icus with ss/sh would have higher mortalities in neuroscience (ns) and cardiac (cards) icus versus general medical surgical icus (msicu). intensivists. the variables collected include age, time to antibiotics, intravenous fluids given, central line placements, code status, vasopressor requirements at hours and mortality. chi-square analysis was used to compare mortality rates. icus who were directly admitted from the ed were ns % (n = ), cards %(n= ), msicu % (n= ) p=. . the mortality rate for patients admitted with ss/sh was similar independent of the type of the icu the patients received care in. a multivariate analysis needs to be done to confirm these outcomes neurocrit care ( ) :s -s s thromboembolism is a known and feared complication of administering prothrombin complex concentrates (pcc) but the true incidence is unknown. most data is in regards to mi, dvt, pe and dic with little reported on ischemic stroke. this is the first known report in the literature of acute basilar thrombosis after reversal of anticoagulation with pcc. we present a year old women with acute basilar thrombosis after reversal of anticoagulation using pcc (profilinine sd). she was admitted with a hemodynamically stable lower gi bleed with a supratherapeutic inr of . she was taking coumadin for a recent pulmonary embolus. anticoagulation was reversed using profilnine sd units ( u/kg) and vitamin k mg intravenously. hours later she developed left facial weakness, quadraparesis and anarthria. ct brain showed no early ischemic changes. ct angiogram showed occlusion from the mid-basilar to the basilar apex with normal vertebral arteries from the origin to the site of occlusion. factor ii activity was elevated with normal activity of factor vii, ix and x. tte showed normal wall motion and ejection fraction without evidence of thrombus or shunt. pcc protocols for reversal of anticoagulation are used with increasing frequency, even in non-emergent situations. thromboembolism is a known complication of administration, even with modern formulations of pcc which include anticoagulants. risk of thromboembolism increases with doses above u/kg and with repeated dosing. the cause of thrombogenicity remains uncertain. accumulating data indicates the importance of factor ii (prothrombin) which has a linear relationship with thrombin generation. our case suggests that given potentially fatal thromboembolic complications, pcc administration should be weighed against the need for rapid correction of coagulopathy. more discussion is needed regarding complications of pcc administration, optimal dosing and uniform production of pcc products on the market. endovascular reperfusion reduces infarct volume to improve clinical outcome; however treatment effect may be diluted by subsequent care. an exploratory analysis was done to determine if discharge disposition impacted day mrs after definitive reperfusion therapy. in our study, patients discharged to snf & ar after thrombectomy have similar medical & neurological severity at admission and similar final infarct volumes at discharge. despite these similarities, patients discharged to snf had a significantly lower probability of achieving a good neurological outcome. further study is required to determine if ar should be considered in more patients to improve clinical outcomes. patients with acute ischemic stroke develop respiratory failure due to airway compromise from loss of protective reflexes or cerebral swelling. in such patients, traditional weaning parameters poorly predict successful extubation. failure of extubation increases complications, prolongs hospitalization and increase cost of care. we hypothesize that predictive factors can be identified in determining ischemic stroke patients with respiratory failure who can be successfully extubated. between january to december , consecutive patients admitted to a metropolitan academic stroke center with acute ischemic stroke and were mechanically ventilated within hours of admission were reviewed after irb approval. patients who were intubated for procedures only, extubated within hours, or placed on comfort measures were excluded, leaving patients for analysis. statistical analysis was done using sas . and univariate or multivariate logistic regression was performed when appropriate. of the included patients, the average age was . ± . years, and ( . %) were male. the median admission nihss was . and majority of patients had cardioembolic ( ) or large vessel atherosclerotic ( ) strokes. patients had posterior circulation stroke ( . %). eleven patients failed extubation ( . %). acute basilar occlusion was found to be a strong predictor of extubation failure (or= . %ci: . - p= . ) when adjusted for age, stroke severity and duration of mechanical ventilation. increasing age and higher nihss showed trend toward increased risk for extubation failure but did not reach statistical significance. hospital length of stay doubled, icu length of stay tripled, and total hospital cost doubled in patients who failed extubation. patients with respiratory failure due to acute stroke from basilar occlusion were more likely to fail extubation. patients who fail extubation had longer icu and hospital stay doubling the cost of care. further studies are needed to determine whether preemptive tracheostomy may be beneficial in this group of patients. early detection of patients likely to develop malignant middle cerebral artery (mca) infarction (mmcai) is essential to enable timely decision for promising interventions (e.g., decompressive hemicraniectomy). this study was designed to evaluate whether quantitative eeg (qeeg) could predict mmcai within hours of stroke onset. this prospective, observational cohort study enrolled patients with a mca infarct. all of them underwent eeg monitoring within hours after symptom onset. subsequently, their raw eeg data were quantitatively analyzed and the qeeg parameters including (delta+theta) / (alpha+beta) ratio (dtabr) and brain symmetry index (bsi) were computed based on the power spectral density. patients were classified in the mmcai group if they had decline of consciousness with radiological signs of space-occupying brain edema, whereas the others were allocated into the non-mmcai group. for the groups, we compared the above qeeg parameters, and clinical and imaging variables. univariate and multivariate discriminant analysis was used to determine the most accurate predictors of mmcai. of the patients included, developed mmcai. univariate analysis showed that the values of dtabr and bsi, the nihss scores on admission and a hypoattenuation on admission cerebral computed tomography (cct) scans > % mca territory were significant predictors of mmcai. the further logistic regression analysis identified bsi > . (odds ratio [or] . , % confidence interval [ci] . to . ; p = . ) and the infarct size > % mca territory on cct scan at admission (or . , % ci . to . ; p = . ) as independent predictors, and bsi > . was the better predictor, which achieves a positive likelihood ratio (lr) of . ( % ci . to . ) and a negative lr of . ( % ci . to . ). quantitative eeg allows the early prediction of mmcai, and can help in the selection of patients for decompressive hemicraniectomy. financial support: none the modified rankin scale (mrs) is a -level outcome scale used to assess level of function in neurological disease. its utility is underscored by widespread use in stroke outcomes assessment, but the basic levels of function encoded by the mrs are not specific to stroke. still, poor interobserver reliability and the requirement for expert and face-to-face interviews are problems in determining an mrs score. we have developed a question "yes/no" questionnaire, the mrs- q, and an online mrs calculator to quickly and accurately determine the mrs. we hypothesize that ( ) the mrs- q has acceptable interobserver reliability, ( ) the mrs- q can be administered equally well in person or over the telephone, ( ) the mrs- q can be administered accurately by personnel without clinical expertise, and ( ) the mrs- q allows application of the mrs to a broad range of neurological conditions. the mrs- q was administered by form or telephone. a web-based tool calculated the mrs and performed error checking. part compared the mrs- q to an mrs structured interview (n= ). part compared mrs- q administration by telephone and by paper form (n= ). part compared administration by an expert interviewer with administration by a non-expert (n= ). part examined reproducibility over weeks (n= ). agreement was very good in all study parts. in part (mrs- q vs. mrs-si), k was . and k w was . . in part (telephone vs. paper), k was . and k w was . . in part (expert vs non-expert), k was . and k w was . . in part (reproducibility), k was . and k w was . . the mrs- q can reliably determine the mrs by paper survey or over the telephone. importantly, the mrs- q survey does not require the participation of trained experts-excellent results are obtained when non-medical study personnel administer the survey. potentially inappropriate medications (pims) are medications that may increase cognitive burden and impact clinical outcomes in elderly icu patients. this study evaluates the use of pims and outcomes in elderly stroke patients. this is a retrospective study of p july . number of pims, length of stay (los), and changes in gcs and rass scores were evaluated. fisher's exact test was used to compare groups. of a significantly longer nsicu los and worse outcomes. introduction ais patients often have acutely elevated bp requiring iv antihypertensives (ivah). previous work shows aha/asa recommended antihypertensives used to reduce bp in ais commonly results in polypharmacy and its consequences: overshoot hypotension and increased mortality. this study evaluates the association between ivah polypharmacy and both clinical and economic outcomes in ais. premier, a us hospital administrative database. patients with ms-drgs to and a primary ais icd- code ( .x or .x ) were included. patients were matched in a : fashion utilizing propensity score methodology controlling icu admission, baseline characteristics, and pre-existing conditions. from january to december , study patients received at least one ivah on day one or two of hospitalization and . % of those received more than one ivah. after matching, patients remained in each group. patients in gp had a lower mortality rate than gp ( . % vs . %, p= . ), lower vasopressor use ( . % vs . %, p= . ), shorter los (median days vs days, p< . ), and lower total hospital costs (median $ , vs $ , , p< . ). t-pa use was similar between groups ( . % vs . %, p= . ). polypharmacy to treat acute hypertension is associated with worse clinical and economic outcomes in ais regardless of tpa administration. recent evidence suggests precise and reliable bp control is critical during the entire stroke pathway of care. currently recommended ivah do not reliably manage bp as single agents. in order to avoid polypharmacy and improve outcomes and costs, the ideal ivah drug needs to reliably manage and maintain precise bp control as monotherapy. financial support: authors are employees of the medicines company which markets an iv antihypertensive agent. mean corpuscular hemoglobin concentration (mchc) is a red blood cell indicie that is obtained as part of a complete blood count (cbc). mchc values reflect individual red blood cell (rbc) hemoglobin (hgb) content, and are directly affected by changes in hgb production and dna synthesis. recently another hematologic indicie: the red cell distribution width (rdw), has been shown to be an independent predictor of outcome in patients with stroke. we sought to determine if mchc on admission could be predictive of clinical outcome. this is a retrospective study on patients admitted to a university affiliated community hospital. initial mchc data were gathered retrospectively from the registry database. we included both ischemic and intraparenchymal hemorrhage (iph) stroke patients in our analysis. for evaluating the severity and outcome of the patients with ischemic strokes we used nihss on admission and mrs on discharge respectively. in iph patients, we utilized the university of california san francisco intracerebral hemorrhage (ich) score on admission / hours to quantify the severity of the stroke and mrs on discharge to measure the outcome. we used correlation coefficients (spearman's rho) and the mann whitney test for analysis of the data. spss version was used for data processing. our review identified patients with a diagnosis of iph and with a diagnosis of ischemic stroke. the mchc values in the iph group positively correlated to ucsf ich score on admission (p= . , r= . ) and at hours(p= . , r= . ), as well as to mrs at discharge (p= . , r- . ). the mchc levels for ischemic stroke patients correlated weakly and negatively to nihss on admission (p= . , r= - . ) and d-mrs (p= < . , r= - . ). mchc levels on admission correlate significantly with clinical measures of stroke severity and disability. mchc could serve as an early predictor for outcome in different stroke subtypes. in the absence of specific guidelines, there is considerable variance in pre-procedural intubation practices for endovascular treatment of acute ischemic stroke. the purpose of this study is to understand and characterize the variance in pre-procedural intubation practices and identify the reasons that influence the choice of pre-procedural intubation practices among treating physicians. we selected random cases from a prospective database of patients undergoing endovascular treatment for acute ischemic stroke and prepared a case summary providing pertinent demographic, clinical, and imaging data. twenty clinicians independently reviewed the case summaries and responded to whether they would intubate any of the patients and identified the reasons for their choices. clinicians were also asked to identify their training background (neurology, neurosurgery or radiology trained endovascular specialist, vascular neurologist or neuro-intensivist). reasons for intubation and agreement between clinicians for each case were ascertained. the decision to intubate the patient was made in of total clinical scenarios. the major reasons identified by the physicians for pre-procedural intubation were high national institute of health (nih) stroke scale scores on admission . % (n= ), labored breathing or desaturation . % (n= ), less than optimal respiratory status of patients combined with drowsiness or reduced level of consciousness . % (n= ), inability to follow command such as due to aphasia . % (n= ), seizures . % (n= ), and no reason . % (n= ). overall agreement between clinicians regarding decision of pre-procedural intubation among the case scenarios was . the decision of pre-procedural intubation varies widely among clinicians. due to recent data that suggests that decision of pre-procedural intubation may impact on patients' outcomes, better standardization of such practices is required. hyperglycemia has been shown to be associated with worse outcomes, increased hemorrhage rates, and increased mortality in patients with acute ischemic stroke (ais). we evaluated the effect of admission hyperglycemia on -day functional outcome, mortality, and hemorrhage rates in patients undergoing multimodal endovascular therapy (met) for ais. retrospective review of glucose on admission was performed in patients undergoing met between and in a tertiary care academic medical center. demographic data, diabetic status, nihss score, radiologic studies, and recanalization timi grade were analyzed, amongst other known predictors of hemorrhage and poor outcome. mean age was . + . and mean nihss . + . . hyperglycemia was present in ( admission hyperglycemia in patients undergoing met is associated with poor -day functional outcome and higher rates of in-hospital death and hi. in non-diabetic patients, hyperglycemia was only associated with increased mortality and hi. despite equivocal results for induced normoglycemia, this data justifies a prospective trial for moderate glycemic control in this patient population. previous studies suggest that low cholesterol levels are associated with higher rates of hemorrhage after acute ischemic stroke (ais). we studied the effect of serum lipoproteins and premorbid statin use on the rate of hemorrhage in ais patients treated with multimodal endovascular therapy (met). retrospective review of statin use and lipoprotein levels on admission including ldl, hdl and total cholesterol (tc) was perfomed in patients undergoing met between and in a tertiary care academic medical center. demographic data, nihss score, radiologic studies, and recanalization timi grade were analyzed, amongst other known ldl < mg/dl was associated with a higher incidence of ht (or . , % ci . - . , p= . ). hdl > was associated with higher rates of ph (or . , % ci . - . , p= . ). tc levels and premorbid statin use were not associated with higher rates of hemorrhage. statin use, ldl, hdl and tc were not independently associated with functional outcome at months. patients with hemorrhage and tc < had significantly higher rates of good functional outcome compared to those with tc > (or . , % ci . - . , p= . ). there was no significant association between statin use and rates of hemorrhage or functional outcome in patients presenting with ldl < . low ldl and high hdl levels are associated with increased rates of hemorrhage after met for ais. statin use had no effect on post-intervention hemorrhage or functional outcome regardless of admission lipid levels. despite the association between low ldl and hemorrhage, statin use in patients with a low ldl was not associated with poor outcomes. this data justifies further study of the effect of continuation and early initiation of statin therapy in this patient population. mexican americans (mas) have shown lower post-stroke mortality compared to non-hispanic whites (nhws). limited evidence suggests race/ethnic differences exist in intensive care unit (icu) admissions following stroke. our objective was to investigate the association of ethnicity with admission to the icu following stroke. cases of intracerebral hemorrhage and acute ischemic stroke were prospectively ascertained as part of the brain attack surveillance in corpus christi (basic) project for the period january, through december, . logistic regression models fitted within the generalized additive model framework were used to test associations between ethnicity and icu admission and potential confounders. an interaction term between age and ethnicity was investigated in the final model. a total , cases were included in analysis. mas were younger, more likely to have diabetes, and less likely to have atrial fibrillation, health insurance, or high school diploma than nhws. on unadjusted analysis, there was a trend toward mas being more likely to be admitted to icu than nhws ( . % versus . %; or= . ; % ci . - . ; p= . ). however, on adjusted analysis, no overall association between ma ethnicity and icu admission (or= . ; % ci . - . ) was found. when an interaction term for age and ethnicity was added to this model, there was only borderline evidence for effect modification by age of the ethnicity/icu relationship (p= . ). no overall association between ethnicity and icu admission was observed in this community. icu utilization alone does not likely explain ethnic differences in survival following stroke between mas and nhws. the medicines company, parsippany, nj, usa the relationship between blood pressure variability and inpatient outcomes and costs following ais is not well understood. using data from > us hospitals (cerner health facts®), we identified all admissions between / / and / / of - -cm diagnosis codes .x , .x ). in patients with principal diagnoses of ais, time of initial clinical presentation was designated "index time"; for those with secondary diagnoses of ais, index time was in-hospital onset of stroke symptoms. we calculated blood pressure variability (bpv) as maximum difference (md) (i.e., highest -lowest recorded bp) in the -hour period following index time. patients were igh"] vs <median value ["low"]). we examined rates of hemorrhagic transformation, in-hospital mortality, and total in-hospital charges in the two groups. a total of admissions satisfied all selection criteria (high bpv: ; low bpv: ); patients were comparable with respect to age (mean age, years), gender, and comorbidities. patients with high bpv were nominally more likely to experience hemorrhagic transformation ( . % vs . %; p= . ) and to die in hospital ( . % vs . %; p= . ), respectively. they also had significantly higher total in-hospital charges ($ , vs $ , ; p< . ). highly variable blood pressure during the hours following ais is associated with increased total in-hospital charges. further research is needed to better understand the degree to which better early hypertensive management may improve patient outcomes. financial support: our research was funded by the medicines company. mr. berger, mr. moynahan, and dr. oster are employed by policy analysis inc., an independent contract-research organization with previous and ongoing previous work from our group revealed an association between lower end-tidal carbon dioxide (co ) values with worse outcomes in intubated, mechanically ventilated patients undergoing intra-arterial procedures for acute ischemic stroke. based on that observation, we hypothesized there might also be an association between lower arterial co and outcomes in this patient group. we retrospectively reviewed the charts of participants in a national, multi-center mechanical thrombectomy trial. all patients were intubated and mechanically ventilated at the time of their intra-arterial intervention per protocol at our institution. arterial blood gasses (abg) were typically obtained post-procedurally at admission to the icu as part of admission laboratory panel. demographics, hospital course data, arterial blood gasses and outcomes ( -day modified rankin score) were collected. descriptive statistics (median and intraquartile range for continuous variables; counts and percentages for categorical variables) were used to describe clinical data. categorical variables were compared using fisher's exact tests, and ordinal comparisons were made with the wilcoxon-mann-whitneytest. significance was set at : mrs - ; vs. unfavorable: mrs - . seventy-five patients were identified as part of the registry, though were excluded from this analysis ( had no recorded abgs, lost to follow up). patients with an unfavorable outcome were older ( [ - ] v. [ - ] , p= . ). in the unfavorable group, median pco levels were statistically significantly lower than those with a good outcome ( [ - ] v. [ - ] , p= . ). our results suggest that there may be an association between lower pco values and outcome in intubated, mechanically ventilated ischemic stroke patients. one possible explanation is that hypocapnea facilitates cerebral vasoconstriction, worsening ischemia and possibly enlarging the ischemic penumbra. this association should be further interrogated in a prospective, controlled trial. although ischemic brain tissue should appear particularly dependent on the main oxygen carrier hemoglobin (hb), optimum hb and hematocrit (hct) levels in neurointensive care unit (nicu) patients with severe ischemic stroke (is) are still unknown. research thereof and of the best red blood cell (rbc) transfusion regimen is neglected. here, we aimed to investigate associations of hb/hct dynamics and transfusion activity with nicu variables and outcome in nicu patients with ischemic stroke. patients with is were retrospectively assessed if admitted to the nicu for at least days and mechanically ventilated. assessment involved clinical characteristics, rbc transfusion events, and laboratory parameters such as hb, hct, creactive protein, blood count, creatinine. mortality and functional outcome (by mrs) were assessed prospectively by telephone interview at , and months after discharge. statistics were descriptive and explorative, i.e. involved correlation / variance tests for associations between hb, hct levels, transfusion events and outcome (linear regression analysis, t-test). patients were analyzed. % had anterior circulation, % posterior circulation ischemic stroke with a median nihss of and a median apacheii of . median nicu stay was days, median ventilation time hours. baseline hb and hct were g/dl and . , mean decrease over nicu stay was % leading to minimum hb and hct of g/dl and . , respectively. mrs at day was ( %), ( %), ( %) and (=dead, %). a first preliminary analysis did not reveal any consistent associations between severity of anemia or transfusion activity and outcome. anemia is frequent in nicu patients with ischemic stroke. at present, this retrospective analysis does not support a more aggressive rbc transfusion practice. more detailed subgroup analysis results will be presented at the time of the meeting. although not clinically validated, physicians frequently use imaging to help predict neurologic and cognitive outcome after hypoxic-ischemic injury to the brain following cardiac arrest. we systematically reviewed the current literature investigating the accuracy of imaging in predicting outcome in adult patients who are comatose after cardiac arrest. the electronic databases of medline via pubmed, embase via ovid, and the cochrane database of systematic reviews were searched using combinations of the search terms "cardiac arrest," "cardiopulmonary resuscitation," "brain hypoxia," and "neuroimaging." eligible studies were reviewed in detail and classified by level of evidence (loe) and methodological quality as defined by the international liaison committee on resuscitation (ilcor). articles were identified, of which met inclusion criteria and were reviewed in detail. articles found imaging to be helpful in accurately predicting outcome: were categorized as loe p ( good, fair, poor quality), loe p ( good, fair, poor quality), and loe p ( good, fair, poor quality). articles found imaging to not be helpful in accurately predicting outcome: were categorized as loe p ( good, fair quality), loe p (all poor quality), loe p ( good, fair, poor quality). article was found to be equivocal, categorized as loe p (fair quality). no loe p trials have been performed and although two loe p studies exist, they do not compare different modalities and have limited generalizability in the clinical setting. there is insufficient evidence to recommend routine use of imaging to predict outcome in comatose cardiac arrest patients. further studies are needed to determine the utility of imaging in this setting, and should include comparison with already validated methods of prognostication such as the clinical exam and electrophysiology. in acute ischemic stroke, factors affecting blood pressure (bp) levels in the first few hours after onset are not well known. the rise in bp levels can be a mechanism to compensate for vessel occlusion and to ensure the viability of penumbral brain tissue (pbt). between january and december , data of consecutive acute ischemic stroke patients admitted to florence nightingale stroke unit within the first hours and evaluated with stroke mri were analyzed. potential early correlates of bp levels were analyzed with multivariate logistic regression technique. age, gender, hypertension (ht) history, treatment for ht, onset to door time, nihss, level of consciousness, stroke type and stroke etiology, pwi/dwi mismatch, index proximal vessel occlusion (ipvo), were included in the analyses. a pwi/dwi mismatch, a potential indicator of pbt, was considered as present if estimated at least to be approximately % by eyeballing the lesion. index pvo was defined as symptomatic occlusion or - % stenosis of carotid or vertebrobasilar artery system vessels. high bp level was defined as sys> mmhg or dys> mmhg at admission. two hundred-six patients ( male; mean age ; range - years) were evaluated. hundred and four patients ( , %) had high bp at admission. in univariate logistic regression analysis, women (p: , ), age (p: , ), tacs (p: , ), hypertension history (p: , ), ipvo (p: , ) were associated with high bp values. only tacs (or: , ; % ci: , - , ) was independently associated with high bp readings at admissions in multivariate analysis. we did not find any argument to state that high admission blood pressure is a compensatory response following brain tissue ischemia. intravenous recombinant tissue plasminogen activator (iv r-tpa) has revolutionized the management of acute ischemic stroke. however, symptomatic intracranial ( %) and severe systemic ( . %) hemorrhagic complications after thrombolysis remain a concern. we present a rare complication of r-tpa and underscore the importance of close monitoring after thrombolysis. the clinical history, laboratory, and imaging studies were reviewed. a year old man with psoriasis and morbid obesity presented with acute aphasia and right hemiplegia. he had fallen as a result, striking his right eye. his examination demonstrated right periorbital ecchymosis without ptosis, expressive aphasia, leftward gaze deviation and corresponding hemianopsia, and right facial weakness and hemiplegia. his summated nih stroke scale (nihss) was . initial cranial imaging demonstrated no blood, though did show an abnormal hyperdensity within the proximal left middle cerebral artery territory. he received iv-tpa hours from symptom onset with significant neurological improvement within minutes of thrombolysis. minutes after initiation of iv r-tpa, he rapidly developed periorbital edema with ecchymosis leading to complete ptosis of the right eye. repeat cranial imaging showed an enlarging retro-orbital hematoma. an emergent lateral canthotomy was performed of the right eye to rapidly decompress the optic nerve. within days of thrombolysis and successful orbital decompression, as visualized on repeat cranial imaging, he made near full neurologic and visual recovery. to our knowledge, this is the first reported case of a near catastrophic hemorrhagic ocular complication after iv r-tpa therapy for acute ischemic stroke. despite the suspected trivial nature of injury, thrombolytic treatment should proceed with caution in the setting of any trauma. this report highlights the importance of careful inspection and maintaining a high index of suspicion and vigilance for unanticipated complications after thrombolytic therapy. in the setting of acute or evolving stroke, outcome may be dependant on the urgent re-establishment of cerebral perfusion.options for restoring cerebral blood flow include the intra-venous or intra-arterial administration of thrombolytic agents, mechanical thrombolysis, and urgent carotid endarterectomy. there is very limited experience with emergency extracrannial-intracranial (ec-ic) bypass in this setting. we reviewed the medical records and neuroimaging studies of consecutive patients who underwent urgent ec-ic bypass in the face of acute cerebral ischemia. none were considered appropriate candidates for endovascular therapy. ages ranged from to years, average . years. average follow-up was . years. preoperative angiographic evaluation identified critical narrowing of the supraclinoid ica in , the m segment of the middle cerebral artery in , and the cervical/petrous ica in . all had progressive, refractory symptoms associated with enlarging areas of ischemic changes on diffusion-weighted mri despite maximal medical therapy including anticoagulation and antiplatelet agents, blood pressure elevation, and fluid resuscitation. all patients underwent urgent sta-mca anastomosis. in every case, bypass resulted in stabilization of the progressive ischemic symptoms; in cases, revascularization was followed by rapid, dramatic improvement of preoperative deficit. five patients awoke with transient worsening of their preoperative neurological deficit which improved over - hours. no patient demonstrated a significant new area of ischemia on mr imaging. emergency ec -ic bypass for acute ischemic injury was both safe and effective in our experience. this population was characterized by relatively young patients with severely limited collateral circulation. in this series of carefully selected patients, bypass was successful in arresting ongoing ischemic symptoms, and in some cases, resulted in rapid neurological improvement. the ability for clinicians to predict outcome is of paramount importance when treating and counseling stroke patients and families. the dragon score is used to predict outcome in patients with anterior circulation strokes that have received intravenous tpa. we sought to determine if the dragon score could be applied to patients undergoing endovascular stroke therapy. charts for patients with interventions performed by a single operator (mfs) from january to march were reviewed. presenting symptoms were used to derive the dragon score. outcome predictability was compared to the findings in the original dragon score paper. twenty-four patients underwent endovascular stroke treatment; fourteen patients presented with anterior circulation ischemic strokes. five patients had only endovascular treatment, and patients had both ivtpa and endovascular treatment. the total average time from onset to termination of the endovascular procedure was minutes. in the endovascular alone patients, patients survived with a mean dragon score of . and mean discharge mrs of . . of the patients who received both intravenous and endovascular therapy, survived with a mean dragon score of . and mean discharge mrs of . . four of the surviving patients had greater than % specificity for poor outcome (mrs - ) based on the original paper. these patients however demonstrated a good recovery with an average mrs of . . despite the extended window for treatment and recanalization, patients who receive acute endovascular stroke therapy appear to have similar outcomes to the predicted outcome using the dragon score. furthermore, our study showed that patients who were expected to have poor outcome had the potential to improve clinically. this study reinforces the benefit of endovascular stroke therapy. intracranial arterial stenosis are relatively common findings of stroke patients in asia area. we reviewed stroke database to investigate clinical risk factors related to intracranial arterial stenosis, including carotid disease, and peripheral arterial disease which reflects advanced atherosclerosis. acute stroke patients at the national health insurance corporation ilsan hospital from january to december with available transcranial doppler(tcd) examination, carotid ultrasound and ankle-brachial indexes(abi) formed the analysis cohorts. retrospective review was performed. a total of patients were included during that period, patients with incomplete tcd study due to poor insonation windows were excluded( %). according to tcd criteria, groups of intracranial arterial stenosis are defined: vessel stenosis is in patients( %), - vessels in patients( %), more than vessels in patients( %). as the arterial number of intracranial stenosis increased, abi is decreased(p= . ) and the size of carotid artery plaque is increased(p= . ). among the risk factors, diabetes, age, past stroke history are increased(p= . , p= . , p= . ) and hdl cholesterol showed tendency of decrease(p= . ). however hypertension, smoking, total cholesterol, ldl cholesterol, triglyceride and sex are not correlated with intracranial arterial stenosis. among the acute stroke patients, about a half of them have intracranial arterial stenosis and these patients tend to have higher burden of advanced atherosclerosis as evidenced by a higher prevalence of diabetes, large sized plaques of carotid artery and peripheral arterial occlusive disease. dedicated neurocritical care service in an acute-icu setting with specialized neuro nurses and physicians improves the quality of care and patient outcomes. we aimed to find out the impact of specialized focused neurocritical service as compared to a general surgical/medical icu setting in a community hospital. we retrospectively reviewed data from - , on patients who received endovascular treatment (iatpa, thrombolysis, mechanical thrombectomy, with or without intra and extra cranial stenting) in order to achieve recanalization. patients were divided into two groups: group a (n= ) general med/surg icu care in - and, group b (n= ) focused neurocritical care - . functional outcome data (mrs days) between the groups was compared through patient records. group a patients were cared for with general surgical/medical icu care nurses while group b patients were cared for by a specialized core group of - nurses specifically trained in neurocritical care. both groups were comparable in terms of age, sex, admission nihss and co-morbidities (hypertension, hyperlipidemia, diabetes, ccf, a.fib, other). group a mrs - (n= ) %, group b mrs - (n= ) %. group a mrs - (n= ) %, group b mrs - (n= ) %. group a mrs (n= ) %, group b mrs (n= ) %. mortality for both groups was comparable at % (group a n= ; group b n= ). functional outcomes of fully independent patients (mrs - ) improved from % to % when a focused neurocritical care nursing service was implemented as compared to standard medical icu nursing care. strict adherence to neurocritical care protocols and proper attention to co-morbidities is the key to improved outcomes in critically sick acute stroke patient populations. in-hospital strokes remain a significant source of morbidity for patients. paradoxical embolism has been implicated as a potential source for these strokes. to date, there is only minimal literature regarding paradoxical embolus as a cause for stroke in the hospitalized patient. over a one-year period we studied in-patient stroke alerts and their etiologies at our institution. the hypothesis of this study is that strokes in hospitalized patients are caused by paradoxical emboli. this is a retrospective analysis of prospectively collected in-hospital stroke team calls (n= ) over a one-year period. we excluded patients on the stroke service or on neurologic floors including the neurological intensive care unit. we further excluded patients that were found to have stroke-mimics by consensus. from these patients, we collected demographic information and results of transthoracic echocardiograms (tte) and lower extremity (le) duplex. the categorical data was analyzed using chi-square on jmp . . a confirmed acute ischemic stroke was found in ( %) of the in-hospital stroke alerts. the majority of stroke alerts in our institution were from the cardiology and cardiothoracic services ( . %). a tte and le duplex were available in . % and . %, respectively. two patients were identified with a patent foramen ovale (pfo) and nine with a deep venous thrombosis (dvt). one patient was found to have both a dvt and pfo which was presumed as the source of embolus. overall, there was no significant association of in-hospital stroke and presumed paradoxical embolus. the present study shows no association of in-hospital strokes and paradoxical emboli. this study is limited by the infrequent ordering of le duplexes in this at risk population but is strengthened by the available tte results. posterior circulation stroke (pcs) is associated with high mortality and poor outcome. this single centre, retrospective analysis evaluates long-term mortality and functional outcome in pcs patients treated with/without revascularization therapy (rt). between january and december , dataof consecutive pcs patients admitted to florence nightingale stroke unit within the first hours were analyzed. after evaluation with mri, eligible patients with pwi/dwi mismatch selected with eye-balling technique were treated with rt. ninety days modified rankin score (mrs) and mortality were the main outcome. eighty-two patients ( male; mean age ; range - years) were evaluated. the mean onset to door time was minutes (sd: ). seventy-eight patients were examined with mri while patients were examined with ct. twenty-one patients received rt; intravenous thrombolysis in , endovascular multimodal revascularization in and bridging therapy in patients. mean nihss score was (range: - ) [treated group (tg): ( - ); untreated group (utg): ( - ) p: , ]. arterial occlusion was present in ( %)(tg: , %;utg: , %; p: , ). mean door to treatment time was minutes (sd: ).mean onset to treatment time was minutes (sd: ).mean discharge nihss score was (range: - ) [tg: ( - ); utg: ( - ) p: , ]. discharge mrs - ratio was , % (tg: , %; utg: , %; p: , ). the inhospital mortality rate was , % (tg: , %; utg: , %; p: , ). first month (tg: , %; utg: , %) and rd month (tg: , %; utg: %). mrs - ratio (p: , vs. , respectively) also th month (tg: , %; utg: , %) and rd month (tg: , %; utg: , %) mortality (p: , vs. , , respectively) were similar between groups. in posterior circulation stroke, despite severe clinical manifestations at admission and hospital discharge, after long term follow up, the outcome in patients treated with revascularization therapy is similar to those patients with benign outcome and not necessitating any revascularization therapy from the outset. we present a case series that highlights the feasibility of decompressive hemicraniectomy (dhc) in pediatric patients with ischemic stroke. a retrospective chart review identified cases of ischemic stroke at texas children's hospital between - where dhc was performed for high intracranial pressure (icp) after standard medical therapy failed to lower icp. information was obtained about patient characteristics on admission, radiological features of the stroke, surgical procedures, complications of the dhc and cranioplasty, and clinical outcomes. we also surveyed published literature on dhc for pediatric patients with ischemic stroke. there was no mortality in this case series. case had a modified rankin score (mrs) of at a follow up visit after months. case had mrs of at a follow up visit after months. cranioplasty was complicated by epidural abscess in his case. case had mrs of at a months follow up. review of literature identified other published case series consisting of cases of dhc in pediatric patients with ischemic stroke. detailed analysis of these cases is presented in the tabular form. this case series highlights the fact that dhc can be performed safely and effectively in pediatric patients with ischemic stroke with potential lifesaving and improved functional outcome. decompressive hemicraniectomy should be considered as a therapeutic option for refractory elevated icp following large hemispheric strokes in the pediatric population. basilar artery occlusion (bao) is a devastating neurological disease that can be difficult to diagnose due to its protean manifestations, and the initial ct will often not reveal an acute infarction. we present a patient with bao who was initially diagnosed with lyme disease. a y/o female presented with neck pain, an unsteady gait, partial facial paralysis, and mild dysarthria. she was noted to have an erythematous area on her neck that contained a tick. the initial head ct was negative. lyme disease was diagnosed and ceftriaxone and doxycycline were initiated. within hours, her symptoms progressed to hemiparesis and aphasia. a stat mri demonstrated the absence of flow in the basilar and left vertebral arteries with restricted diffusion in the pontine and mid-right parietal regions. the patient was transferred to a primary stroke center, but she was outside the window for stroke rescue. acute lyme disease is characterized by lymphocytic meningitis, cranial neuropathy (particularly facial palsy) and radiculoneuritis. though these symptoms usually take weeks to occur, the initial tick bite may not be recognized thus precluding an accurate evaluation of the time course. bao may present with a similar constellation of symptoms including headache, facial paralysis, and transient paresis called the "herald hemiparesis" of bao. the fluctuating course of early bao may be confusing and a high index of suspicion is required. intra-arterial lytic therapy, mechanical thrombolysis, or a combination is recommended up to hours of symptom onset. recanalization is paramount to preserving neurologic function. unfortunately, she arrived at our institution outside the window for invasive therapy. her symptoms continued to progress to a locked-in state and she was transferred to a ltac facility. the neurological manifestations of bao may be confused with other diagnosis and a high index of suspicion is required. metabolic abnormalities negatively influence outcome in patients with traumatic brain injury, subarachnoid hemorrhage, hemorrhagic stroke and ischemic stroke with or without thrombolytic therapy. the prognostic value of many potentially correctable physiologic markers in stroke patients receiving thrombolysis is unknown. twenty-one consecutive acute ischemic stroke patients treated with tissue plasminogen activator (tpa) were retrospectively studied. multiple metabolic and physiological variables including blood urea nitrogen, creatinine, sodium, potassium, chloride, calcium, phosphorous, magnesium and body temperature were analyzed. independent t test was used to compare mean scores of these variables and determine their effect on outcome. functional status at discharge was the primary outcome measure, being fully or partially independent determined as good outcome and fully dependent or dead as poor outcome. secondary outcome was the presence of hemorrhagic conversion. seventeen patients had good outcome, mean age , while patients had poor outcome, mean age . hyperthermia and admission acute physiology and chronic health evaluation (apache) ii score were associated with poor outcome (p< . ). hemorrhagic conversion occurred in patients and was associated with hyperthermia, higher simplified acute physiology score (saps) ii score and hyponatremia (p< . for all). this single-center, retrospective study suggests that mild hyperthermia, hyponatremia and higher apache ii and saps ii scores are associated with poor functional outcome and hemorrhagic conversion in patients with acute ischemic stroke treated with tpa. further study is required to determine if correcting these variables influences outcome. alterations in electrolyte balance and other basic physiologic indicies such as glucose have been implicated in the pathophysiology of coronary heart disease. however, the relationship between the electrolyte levels and other physiologic indicies measured immediately after an acute ischemic stroke has not been clearly delineated. objective: the aim of the present study was to test whether changes in a patient's basic metabolic panel modify the severity or outcomes of acute ischemic stroke. the study is a retrospective study on ischemic stroke patients admitted to a university affiliated community hospital. demographic data were collected from the data registry. values were obtained within one hour of presentation for serum sodium (na), potassium (k), glucose (gluc), chloride (cl), magnesium (mg), bicarbonate (hco ), bun, and creatinine (cr). as well glomerular filtration rate (gfr) and temperature values were also recorded. severity and outcome were measured using the nihss on admission and the mrs on discharge respectively. correlation coefficients (spearsman's rho) and the mann whitney test were employed in the analysis of the data. spss version was utilized for data processing. results consecutive acute ischemic stroke patients met the study criteria. serum ca (p= . , r= - . ) and gluc levels (p= . , r= . ) were significantly correlated with the mrs. serum cl, ca, bicarbonate, temperature and bun were significantly correlated with nihss on admission measurements (p= . , . , . , . ; r= . , - . , ; . ; . respectively). mg showed a negative trend of correlation with the nihss on admission as well (p= . ; r=- . ), suggesting a protective effect of higher mg levels. the study shows that initial metabolic parameters, such as serum mg, ca, hco , bun, and temperature may potentially allow for early prediction of the severity and outcome in patients with ischemic stroke. hypersomnolence is not typically appreciated as a focal neurologic finding, though bilateral thalamic infarcts may present with hypersomnolence as the only neurologic manifestation. a year old man presented with acute onset confusion, somnolence and slurred speech. his neurological examination was notable for somnolence, bilateral ptosis and dysarthria. routine laboratory investigations and csf analysis were unremarkable, aside from a urine toxicology screen which was positive for opiates. initial head computed tomography (ct) with ct angiography of the head and neck were unrevealing. magnetic resonance imaging was contraindicated as the patient had an automatic internal cardiac defibrillator (aicd). a working diagnosis of opiate intoxication was made in light of the urine toxicology results. because the patient failed to improve over the ensuing hours, a repeat head ct was obtained which revealed bilateral medial thalamic infarctions. while hypersomnolence is often associated with toxic-metabolic disorders, it may rarely be the result of acute arterial stroke. in the context of stroke, hypersomnolence can be accompanied by other symptoms including weakness, paresthesias, memory impairment, sectoranopsia, and personality changes. the feature of hypersomnolence is usually the result of an infarct of perforators arising from the posterior cerebral artery, specifically the paramedian,and tuberothalamic arterial branches, which are involved in irrigation of the reticular, and intralaminar nuclei of the thalamus that are involved in arousal. concomitant neurologic signs may not be present or may be difficult to elicit in this setting as patients are often unable to participate in the neurologic exam. acute stroke should therefore be considered in the differential diagnosis of hypersomnolence. failure to consider stroke as a potential eitiology may lead to delay in acute or secondary stroke prevention. metals play key roles in epigenetic events in living organisms. zinc, cadmium, lead, selenium, calcium, magnesium, sodium, and potassium have been found to be associated with stroke risk in nhanes and other studies. the central hypothesis of this pilot study is that metals and metalloproteins may determine and distinguish stroke phenotype (ischemic vs. hemorrhagic). stroke patients at the university hospital emergency department (ed) were enrolled in a plasma banking project. after irb approval and informed consent, blood draws were performed in the ed, and demographic and clinical information recorded. we analyzed plasma samples collected within hours of symptom onset. we used the proteomic techniques of affinity chromatography (to remove the abundant proteins albumin and igg), followed by size exclusion chromatography (sec -to eliminate low molecular weight compounds and fractionate the proteins), inductively coupled plasma mass spectrometry (icpms -to identify differentially expressed metalloproteins in plasma) and electrospray mass spectrometry (to identify the tryptic peptides known to represent specific proteins in the plasma). the areas and standard deviations of the chromatograms for the metalloproteins for stroke mimics (n= ), ischemic (n= ) and hemorrhagic (n= ) stroke patients were calculated using origin software. differences between sec-icpms peak areas of the metalloproteins for the ischemic, hemorrhagic and mimic samples were examined using two-sample t-test and box chart statistics. mg, al, mn, cu, zn, se, mo and pb were studied. significantly different metals were mg, al, mn, cu and se. box chart statistics performed for the sec-icpms metalloprotein peak area data revealed significant differences in all metalloproteins except al. tryptic peptide mapping identified significant differences in metalloproteins. sec-icpms detected differences in fractions of specific metal containing proteins in the plasma of stroke patients and patients who presented with a stroke mimic. ongoing efforts are aimed at identifying potential biologically relevant stroke biomarkers from the current list of differentially expressed proteins. retrospective chart review of patients admitted to the neurocritical care unit from august to august who developed icp crises (> mm hg for > minutes) and were treated with . % hts. only data for the first ever treatment with hts were collected. patient demographics, onset and duration of action, lowest icp achieved and use of adjunctive therapies were recorded. descriptive statistics and correlation analysis were performed. complete data were available for patients. ten subjects ( %) were female, the mean age was + years. glasgow coma scale (gcs) was + and ( %) patients concomitantly received therapeutic hypothermia and pentobarbital coma. a + . % reduction in icp following administration of . % hts was observed (absolute change: + . mmhg). the mean time to icp < mmhg was + minutes and time to rebound icp > mmhg post-hts administration was minutes in % of our cohort. following treatment the mean improvement in gcs was + . a dose-response curve was generated. . % hts was associated with a % reduction in icp values in critically ill neurology/neurosurgery patients. time to clinical endpoint of icp < mmhg was minutes and in % of patients the duration of action was minutes. an improvement of points in gcs was also observed. the first description of a dose-response curve for . % hts in humans is reported. over a ten year period, we accumulated a prospective dataset of severely brain injured patients with multimodality monitoring (brain tissue oxygen monitoring and outcomes project). patients' data existed within individual excel files with heterogeneous fields. as different research subprojects arose, additional excel files were created to support new data extraction from clinical records. several issues were apparent: ( ) merging and querying data was time-consuming and rate-limiting in research productivity; ( ) users were unable to make uniform changes to all files; ( ) different users could not simultaneously enter data, ( ) auditing data entry was difficult. our goal was to convert the dataset into a relational database, to enhance clinical research efficiency. microsoft access was used to build a database with a relational backend structure and a graphical user interface (gui) frontend. a reporting tool was built for analysis, preview, printing, and customized queries. extract-transfer-load functions were programmed to create seamless data integration between the access database and the enterprise-wide clinical data warehouse (e.g. laboratory values, radiology results). it took approximately man-hours to audit existing excel data, and to load distilled data from excel files into structured database tables. it took approximately man-hours for application implementation and testing. the gui supported multiple simultaneous users' during data auditing, enforced validation rules that corrected data entry in realtime, and centralized user account management. we have provided research queries to date. excel has limitations as a tool for clinical research informatics. a relational database that is built with pre-defined rules, fields, and tables dispenses with the time-consuming step of merging and cleaning data and makes large dataset queries and analyses more efficient. it allows straightforward integration with other relational databases such as enterprise-wide clinical data warehouses, enabling expansion of queries into other clinical information systems. financial support: elsa lin is a data analyst whose salary was partially supported within the past twelve months by a grant from integra (brain tissue oxygen monitoring) for the specific purpose of creating a relational objective of this case study is to report a case of central nervous system (cns) histoplasmosis presenting as an ischemic pontine vasculitis and chronic basilar meningitis. histoplasmosis, a disease caused by fungus histoplasma capsulatum, primarily affects immune-suppressed patients and commonly involves the lung but occasionally can have variable cns presentations. a thirty-five year old caucasian immune-competent male came with worsening of aphasia and confusion after having presented four weeks prior with dysarthria, gait ataxia and bilateral upper extremity weakness. he was diagnosed with bilateral pontine ischemic strokes secondary to small vessel vasculitis and but had limited response to high dose steroids. cerebral spinal fluid (csf) examination showed elevated protein, low glucose and elevated cells suggestive of meningitis and he was started on empiric antibiotics and trials of repeat intravenous (iv) steroids. follow-up imaging revealed obstructive hydrocephalous and he underwent successful ventriculo-peritoneal (vp) shunt placement. his csf culture came back positive for h. capsulatum. csf histoplasma antigen and urine antigen were also positive. he was initially treated with ambisome but changed to voriconzaole secondary to renal insufficiency and was eventually continued on itraconazole. at one year, the patient good clinical improvement and follow-up cultures were negative. while pulmonary involvement of histoplasmosis in immune-suppressed patients is common, systemic presentation of this fungal infection in immune-competent patients is exceeding rare. clinicians should consider cns histoplasmosis on the differential diagnosis in atypical stroke cases, particularly those with chronic basilar meningitis. there is increasing incidence of dengue fever in our country and encephalopathy is the most common neurological manifestation of severe infection. however, recent studies have shown that there is increasing evidence for dengue viral neurotropism. dengue encephalitis, a distinct clinical entity have been found to be associated with the neurovirulence involving serotypes den- and den- . the objective of this study is to report the clinical course, laboratory, and radiographic findings of dengue encephalitis that did not go through the usual state of dengue fever. management of this specific viral infection will likewise be discussed. case presentation and report with literature review. a -year old filipino male, methamphetamine and marijuana user was admitted to our hospital because of seizures preceded by headache and fever. he was managed as a case of viral meningitis supported by cranial mri findings and csf studies. after nearly days, he clinically deteriorated initially from a very agitated, restless and combative state progressing to frank stupor. body temperature was uncontrollably high. repeat csf studies revealed elevated pressure, lymphocytosis, normal protein and sugar, and positive igm dengue virus. serum study for dengue virus igm capture elisa was also positive. other significant tests ruled out malaria, hiv and nmda antibody as source of encephalitis. after intravenous steroids were started, on top of antipsychotics, clinical symptoms were noted to eventually resolve. we theorize that dengue encephalitis should be considered in the differential diagnosis of acute viral meningoencephalitis though the classical manifestations of dengue may not exist. while dengue infection may be endemic in asian countries, this should be considered in other parts of the world especially when patients rapidly deteriorate in the course of the disease. immunecompetence definitely play a vital role in the recovery. steroid therapy may be life saving in very severe cases. intracranial monitors can help guide the care of patients with severe brain injury. the devices are invasive and so may be associated with complications. furthermore, accurate interpretation of the monitors' data is needed to be of potential benefit. in this study we asked whether experience influences "device failure" or interpretation. retrospective analysis was performed on a prospective database that included patients (median age ; range - ) with severe brain injury and who received intraparenchymal multimodality monitoring through a triple lumen bolt (licox imp#). a total of triple lumen bolts were placed during an -year period. device failure was defined as: ) broken or bent (n= ; . %); ) improper placement (n= , . %); and ) ineffective (no response to o challenge n= , . %). there were ( . %) devices thought to provide "incorrect" data but subsequently were found to be accurate, i.e. improper data interpretation. there was a decline in device failure over the entire study period. each calendar year was divided into quartiles. device failure incidence was %, %, % and % per quarter, i.e. was greatest during the third quarter during the time of academic and staff changeover (or . ; p = . ). in addition, improper data interpretation was greatest during the rd quarter. our data suggest that experience with multi-modality monitors is associated with a reduced incidence of device failure or improper data interpretation. educational efforts may reduce the need for device replacement. financial support: peter leroux funding from integra for research. while efforts to "go green" and promote sustainability are well-established in many sectors, there has not been an adequate push toward such practice in the healthcare and medical fields. healthcare accounts for % of all commercial energy use, bil pds of waste, and % of greenhouse gas emissions in the us. these figures requires significant for efforts to be implemented; we each subscribe to, "first, do no harm" demands that these negative environmental impacts be addressed and mitigated immediately. the intent of this report is to investigate and analyze the opportunities the healthcare industry has to embark on sustainable practices. we analyzed green architecture for new healthcare campuses and renovation of outdated facilities, submit efficiency and cost analyses of disposable versus reusable textiles, and offer observations on innovative technologies being developed to promote sustainability. this study was conducted after an extensive review of published literature, verified statistical reports presenting the cost-effectiveness and improved efficiency of pursuing an sustainable model of healthcare delivery. in cluded is a cradle-to-grave analysis of multiple facets of the healthcare/sustainability field, and addresses a number of specialist-specific avenues, including critical care and anesthesiology. energy-efficient building options -including rooftop gardens and alternative power sources -can cut energy consumption by %. healthcare providers in all fields are making efforts toward lowering the carbon footprint of hospitals by reducing greenhouse gas emissions and utilizing resourcing, second use and extensive recycling techniques and efforts. extensive life cycle assessments (lcas) prove that reusable medical textiles and tools are dramatically less expensive environmentally and financially than their disposable counterparts. while efforts are being made to promote sustainability in healthcare, more must be done. the evidence is clear: environmentally-conscious endeavors save money and help lessen the stress placed on the environment. for such a heavy-hitting culprit of consumption, the healthcare industry simply must begin implementing "green" practices based on already-present data. standard metabolic prediction equations have been validated in general critical care populations, but have not been well studied in the neurologically critically ill. we sought to determine whether: ) standard prediction equations accurately predict caloric requirements in neurocritical care patients; ) variation in resting energy expenditure (ree) exists among different subpopulations of neurocritical care patients; and whether the same factors influence ree among different neurocritical care subpopulations. indirect calorimetry measurements were retrospectively reviewed for mechanically-ventilated patients admitted to the neuro icu from january to june . the measured ree data were compared to the predicted basal energy expenditure (bee) calculated with the modified penn state university (psu-m) equation. patients were classified into neurological subtypes, stroke (n= ), status epilepticus (n= ), and other (n= ). traumatic brain injury (tbi) patients were not included. of the entire cohort, median measured ree was (iqr - ) kcal/d and median predicted bee was (iqr - ) kcal/d. the predicted bee correlated well with the measured ree (coefficient . ; p< . ) in the overall cohort. there was no significant difference in the predicted calorie requirement for stroke or status epilepticus. however, there was a suggestion that patients with status epilepticus were relatively hypometabolic (defined as ree < % of the predicted bee) compared to other subgroup populations [or= . ; % ci ( . - . ); p= . ]. factors significantly associated with ree include: maximum hour temperature, administration of intravenous sedation, body mass index (bmi) and sex. age and hospital day of ree were not predictive of energy expenditure. the psu-m predictive equation accurately estimates caloric needs for patients with non-tbi neurological injury. patients with status epilepticus may be hypometabolic relative to other neurologically injured patients, which may be due to use of multiple sedatives in this subpopulation. further research is needed to confirm these findings. the american society of anesthesiology provides guidelines for preoperative fasting for healthy patients undergoing elective procedures. these guidelines are often extrapolated to the critically ill population for procedures and extubation. we tested the hypothesis that npo practice differs between subspecialty, institution and practitioner-type. after irb approval, we conducted surveys of the memberships of the society of critical care medicine (sccm), neurocritical care society (ncs), and american burn association (aba) regarding their npo practice in critically ill patients. survey questions included frequency of use of nasogastric (ng) vs. nasoduodenal (nd) tubes, npo time prior to procedures, and npo time prior to extubation. responses were analyzed with stata . , using a one-way analysis of variance by ranks. we received a total of responses ( % response rate) encompassing practitioners from medical, surgical, neurosurgical ( responses), pediatric, cardiac, burn, trauma, and multidisciplinary icus. respondents ( . %) report % use of ng tubes, whereas ( . %) report % use of nd tubes. excluding responses from pediatric icu practitioners, the npo practice in nicus for intubated and non-intubated patients with nd tubes undergoing procedures is similar to respondents from other icus except the burn icu (p< . ). there is no difference in npo practice of patients with ng tubes undergoing procedures across all icus. nicu respondents report the most commonly used npo time prior to procedures is hours for intubated patients with nd tubes ( . %) and hours for those with ng tubes ( . %). for burn icu respondents, the most commonly reported npo time for intubated patients with nd tubes prior to procedures is hours ( . %), while hours is reported for those with ng tubes ( . %). npo practice in critically ill patients varies across the subspecialty units. further research is necessary to develop evidence-based guidelines for npo practices in the critically ill patients. patients intubated for primary neurological reasons represent a unique critically-ill population. extubation failure rates in primary brain injury (pbi) patients are - % compared to - % in the general critical care population. these populations have never been directly compared. we hypothesized that intubated pbi patients would have higher rates of extubation failure compared to non-pbi patients. retrospective cohort of intubated patients admitted to the medical intensive care unit or the neurocritical care unit in a tertiary-care university hospital between october , and september , . extubation failure was defined as requiring endotracheal intubation at hours, hours and one week. of the . failing extubation at hours did not put patients at increased risk for vap. total ventilator days were similar between pbi and non-pbi patients. pbi patients who failed at hours did not have a significant increase in ventilator days, intensive care unit days or mortality. our data indicates pbi patients are at increased risk for extubation failure compared to non-pbi patients. future prospective study is warranted to determine predictors of extubation failure at hours in pbi patients. peripherally inserted central catheters (picc) is been routinely used instead of central venous catheter (cvc) in our intensive care unit (icu) patients, that includes critical neurologic/neurosurgical patients. there are a number of studies has been done to evaluate risks of picc placement in general medical and surgical icus. a retrospective analysis to determine risk of large vein thrombosis due to picc in neurologic sub-population of patients in a general medical/surgical icu. charts and venous ultrasound studies of patients admitted to icu primarily for neurologic condition were reviewed. out of consecutive patients, underwent picc insertion. ( . %) had clinical and ultrasound evidence of large venous thrombosis attributed to picc. the presence of a picc line conferred a relative risk of . for the development of a dvt. patients with picc lines had a longer duration of stay in the icu (mean days = . +/- . ) when compared to patients without picc lines (mean days= . +/- . ) t( ) = . , p <. . routine placement of picc instead of cvc is associated with increased risk of thrombotic events in large veins in neuro critical sub population of a general icu, which may be associated with longer icu stay. more caution should be exercised before routinely using picc instead of cvc. there are many potential obstacles to guideline adoption and compliance in clinical practice. the purpose of this research was to develop a computer-readable format for clinical pathways, guidelines, and research protocols such that they could be rapidly distributed, displayed at the bedside, and driven by patient context. the goal is to increase guideline compliance and reduce errors made at the bedside. we collected institutional clinical practice guidelines from the abstract authors, guidelines from professional societies (including the neurocritical care society), and one multi-center research protocol (boost-ii). we analyzed each to look for common constructs that would form the basis of a computer-readable care path "language". we also reviewed previous attempts at computer-readable guidelines to discover what might be applicable to our system. the analysis showed considerable variation in the way guidelines are put to practice at the bedside. despite this, we found a set of generalized patterns that were used to develop a care path representation (language) that could encapsulate the content of the guidelines. structured goal-oriented steps, alarm and time couplers, and a "monitoring cycle" were designed and represented in an xml-based language. a scripting method for decision logic also was developed. software was written to read the xml script, display the care path "flow-chart", provide interaction with the health care provider, and links to related instructional content. integration with real-time multimodal monitoring data allows the care path to be driven by the context of the patient. this abstract outlines the first part of a larger project to develop an open-standard guideline format and display software that will decrease the time to adoption of neurocritical care guidelines and increase compliance in clinical practice. financial support: funding received by moberg research from nih/ninds and us army/tatrc to carry out this work. one of the authors (r moberg) is president and owner of moberg research. the objective of this study was to develop empiric treatment guidelines for patients admitted to the neurosciences intensive care unit based on unit specific antimicrobial surveillance. a prospective chart review was performed from october to april of all adult patients admitted to the neurosciences intensive care unit with positive cultures from any site. in addition to culture data and antimicrobial sensitivities, time of admission, diagnosis, placement of an external ventriculostomy device (evd), duration of cefazolin prophylaxis and risk factors for healthcare-associated infections (hai) were collected. hospitalization within days, residency in an extended care facility or hemodialysis at the time of admission were considered hai risk factors. cultures were analyzed as those occurring before or after day of nicu stay. patients residing in the unit as a result of overflow were excluded. a total of patients and positive culture results were included and analyzed by duration of icu stay < days (n= ) or > days (n= ). evd placement and cefazolin prophylaxis were present in % of patients for a mean of . days. at < days, methicillin-resistant staphyloccous aureus (mrsa) was the most common pathogen in patients with risk factors for hai. at < days without risk factors, the most common pathogens were methicillin-sensitive staphylococcus aureus (mssa) (n= ) and enterobacter (n= ) in the sputum and enterococcus (n= ) in the urine. a further analysis revealed theseisolates emerged after day of admission in patients receiving cefazolin prophylaxis. beyond days, sputum isolates predominated and consisted of gram negative pathogens (n= ), mssa (n= ) and mrsa (n= ). selective pressure from cefazolin prophylaxis was apparent in unit surveillance and emerged at or after days. based on these results, institutional empiric antibiotic treatment regimens were adjusted to cover these pathogens after day of nicu stay. the direct thrombin inhibitor dabigatran etexilate is approved for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. despite the clinical benefits of dabigatran, hemorrhage remains a feared complication due to the lack of reversal agent and limited experience with interventions to reverse dabigatran's anticoagulant effect. in addition, reliable laboratory tests to measure the degree of anticoagulation associated with dabigatran are not widely available. an interprofessional team developed institutional protocols for the management of dabigatran and dabigatran-associated hemorrhages. clinical and neuroimaging data was collected from four patients with dabigatran-related subdural hematoma, subarachnoid hemorrhage and/or intracerebral hemorrhage who were treated between november and april . data collected includes age, gender, past medical history, renal function, coagulation and hematology parameters, computed tomography findings, blood products or clotting factors administered, and hemodialysis parameters, if applicable. the patients ranged in age from - years. all patients were inappropriately prescribed dabigatran due to age over years, renal insufficiency, increased bleeding risk, and/or an unlabeled indication. serial evaluation of each patient's coagulation assays was conducted in order to quantify the degree of anticoagulation. three of the four patients received emergent hemodialysis and one patient received recombinant activated factor vii. two patients received blood products, including ffp and platelets, with no observed clinical change. all patients survived to hospital discharge. though this case series is small, it demonstrates the importance of thoroughly evaluating a patient's renal function, bleeding risk, and concomitant medications to determine the appropriateness of dabigatran therapy. it is imperative for clinicians to understand dabigatran's pharmacokinetics and recognize the major factors that increase dabigatran exposure. increased age and renal insufficiency seemed to play a significant role in the hemorrhagic cases we encountered. post-surgical cerebral venous sinus thrombosis is extremely rare. the management of this complication is challenging for neurointensivists; since anticoagulation may increase the risk of bleeding after craniotomy. a previously healthy, year-old male was found to have a right cerebellopontine angle mass on brain magnetic resonance imaging (mri) during headache evaluation. he underwent a prolonged surgery with retrosigmoid craniotomy and resection of an acoustic schwannoma in left lateral decubitus position. immediately post-operatively, the patient had a seizure. brain ct-scan showed hyperdensity in the right transverse sinus suggestive of thrombus. cerebral angiogram confirmed occlusion of the superior sagittal sinus (sss) torcula and bilateral transverse sinuses. intravenous heparin was initiated; however, due to further deterioration with brain herniation, endovascular administration of tissue plasminogen activator (rt-pa) assisted with thromboaspiration with penumbra catheter was performed, followed by continuous infusion of rt-pa ( mg/hr) via microcatheter in the sss for days. a repeat angiogram showed near complete recanalization of the sinuses. heparin was continued, but he developed heparininduced thrombocytopenia, and was switched to bilvalirudin. his hospital course was complicated with intraventricular hemorrhage, acute respiratory distress syndrome, methicillin-resistant staphylococcus aureus (mrsa) bacteremia, and takasubo's cardiomyopathy. he had residual right facial nerve palsy and hemiparesis related to pontine ischemia. his prothrombin gene mutation was positive for one copy. he was ambulating with assistance prior to discharge to acute inpatient rehabilitation. cerebral venous sinus thrombosis is a rare complication of retrosigmoid resection of cpa tumor. aggressive treatment with endovascular rt-pa administration into the venous sinuses may be life-saving, but carries significant risks in the fresh post-operative period. many lives have been lost due to the loss of the airway in critically ill patients. the introduction of the video laryngoscope has been a useful tool that has saved many lives in recent years. one of the limitations of the video laryngoscope is that despite being able to see the vocal cords and the airway beyond it may be difficult to advance the endotracheal tube into the airway. we present a novel approach using a bougie to simplify this problem. a cohort of ten patients in a community critical care unit with difficult airways were intubated using this new technique in a nonrandomized fashion over a period of six months. a video laryngoscope was used in each case with patients sedated and paralyzed with usual agents used for rapid sequence induction. historically, the bougie when used with standard laryngoscopes is introduced into the airway by line of sight and the endotracheal tube is advanced over the bougie. with a video laryngoscope a direct line of sight is not available and passing the bougie is challenging because of a degree angle from the open mouth to the airway. this new technique involves lubricating both the metal stylet with the degree turn and a french x cm bougie and advancing them to the end of the endotracheal tube. the bougie is then advanced into the airway through the endotracheal tube under direct vision through the video laryngoscope. the endotracheal tube is then advanced into the airway over the bougie. all ten patients were intubated without difficulty and without complication. this new technique should be considered as an option in securing the airway in critically ill patients. further validation testing by other investigators is warranted regarding this new technique to determine if a randomized controlled trial is justified. francis r. ventilator-associated pneumonia (vap) remains a problem in traumatic brain injury and high-risk surgery patients. we use early non-bronchoscopic broncho-alveolar lavage (screening-bal) in the surgical intensive care unit (sicu) to identify ventilated patients with bronchiolar bacteria prior to hours. we reviewed results of these screening-bals in neurotrauma patients from / to / . all ventilated patients in the sicu underwent screening-bal - hours after intubation; quantitative cultures (> cfu/ml) were used to identify positive specimens. clinical pneumonia was defined as clinical pulmonary infection score (cpis)> and subsequent positive diagnostic-bal. continuous and dichotomous data were compared from the screening-bal results and clinical diagnosis of pneumonia. screening-bals were performed in neuro-trauma patients (mean iss . ± . ) with an average head abbreviated injury score (hais) of . ± . . thirty-three of these were positive for organisms ( %). twenty-four clinical pneumonias were diagnosed and in of these patients the causative organism identified was the same organism in the screening-bal ( . % agreement; kappa . ; p = . ). one patient with a negative screening-bal developed clinical pneumonia. the median day to develop pneumonia was . ( , ). the hais was higher in patients with a positive screening-bal ( . ± . vs. . ± . ; p = . ). there were no significant differences in the age, icu length of stay, iss, or hais in patients with a positive screening bal vs. the patients that developed a clinical pneumonia. positive screening mini-bal results are associated with the development of vap by the same organism. screening bal in neuro-trauma patients may be a mechanism to identify patients who are at-risk for developing pneumonia later in their hospitalization and early identification of the causative agent. further studies are warranted to determine if intervention on these results changes clinical course. human rabies is a relatively rare disease in the united states, with approximately cases diagnosed annually. the most common exposure in the u.s. relates to bats, however canines and other animals have also been implicated. the typical incubation period from exposure to development of symptoms is - months, while periods of up to years have been described. we present an atypical case of human rabies presenting after a prolonged incubation period in the united states. we describe a case of a year old brazilian man without prior medical history who presented with progressive sensory symptoms leading to encephalopathy and ultimately death. extensive workup revealed no other causes of his symptoms, and brain tissue samples sent to the cdc at the time of his death confirmed a diagnosis of rabies by direct fluorescent antibody testing. in addition, sequencing of the virus confirmed a variant found in canines in brazil. the patient had not traveled to brazil in over years, and had no confirmed exposure other than an encounter with a wild dog in brazil without reported bites or scratches before immigrating. because the viral genotype has not been previously identified among animals in the united states, this case represents the longest confirmed human rabies incubation in the united states to date. characterization of the illness revealed loss of evoked potentials, electroencephalography amplitude attenuation, mr spectroscopy changes of the deep nuclei, and an atypical inflammatory response on pathologic testing. we speculate that either an atypical immunologic response or the patient's recent anabolic steroid use may have mediated delayed progression. this case underscores the importance of keeping human rabies in the differential diagnosis of rapidly progressive encephalomyelitis, even without an exposure history, or with a remote exposure history. the full outline of unresponsiveness (four) score has been validated as an alternative to the glasgow coma scale (gcs) in the evaluation of stuporous and comatose patients and predicts long-term outcomes. the utility of serial four score and gcs by nurses in detecting changes in neurologic exam in the neurocritical care unit (nccu) and whether high frequency monitoring after the first assessment is beneficial has not been studied. the electronic charts of consecutive patients with surgical and non-surgical brain pathology admitted to a nccu were reviewed, yielding observations of gcs, fourscore, and cranial nerve assessments. changes in neurologic exam promoting notification of a provider were abstracted from nursing notes. of patients (m:f: : , age: + yrs), had semi-elective neurosurgery, -ischemic/hemorrhagic stroke, encephalopathy/infection, -subarachnoid hemorrhage, -traumatic brain injury, -seizures, -other. admission median gcs was (iqr- ); median fourscore was ( ). comparison of q - h fourscore vs. qdaily fourscore readings showed no significant difference in fourscore by frequency of measurement (p= . ). in occurrences of change in neurologic exam resulting in provider notification, changes in mean fourscore and gcs from hours prior to the event were . (sd- . ) and . ( . ) respectively; p= . ). from hours prior to event, changes in mean fourscore and gcs were . ( . ) and . ( . ) respectively; p= . ). in one cerebral herniation event, neither scheduled fourscore nor gcs changed. use of the fourscore for serial monitoring and early detection of worsening of neurologic condition performs similarly to gcs and is less sensitive than subjective assessment of trained nccu nurses. the utility of incorporating the fourscore into the on-going nursing assessment paradigm of all nccu patients requires further evaluation. there may be subsets of patients or conditions (with lower sumscores than in our cohort) for which daily or more frequent monitoring has predictive value. a technique for real time, non-invasive blood flow monitoring would be a major asset to clinicians in neurocritical care. we studied the ability of a new hybrid technology employing ultrasound tagged near infrared spectroscopy (ut-nirs) to detect changes in cerebral blood flow (cbf) as compared to measurements by xenon single photon emission computer tomography ( xe-spect). twelve healthy volunteers were enrolled in the study. a cerox monitor (ornim medical ltd. israel) provided continuous ut-nirs monitoring of regional tissue oxygen saturation (sto ) and regional cerebral blood flow index (cfi). xe-spect (ceraspect; dsi, waltham, ma, usa) was then used to measure cbf at baseline, minutes and minutes after acetazolamide injection. ten subjects completed the study. significant increases in cbf as measured by both ut-nirs cfi and xe-spect cbf were noted minutes after acetazolamide injection. at minutes following injection, xe-spect cbf had returned to baseline while ut-nirs cfi remained elevated compared to baseline. a significant correlation between ut-nirs cfi and xe-spect cbf values was found at minutes but not minutes after acetazolamide injection. specificity and sensitivity for detecting an increase in cfi following acetazolamide injection were calculated using a receiver operating curve (roc), with an area under the curve of . (+/_ sem . ). no statistically significant changes in ut-nirs sto were noted following acetazolamide injection. ut-nirs cfi can detect increased cbf following acetazolamide injection, correlates with a gold standard, xe-spect, and the roc curve analysis demonstrates excellent discrimination. the difference in the measurements at minutes may be explained by different ratios of gray matter to white matter in the regions of interest as assessed by the two techniques. ut-nirs cfi can be more sensitive to changes in cerebral perfusion than simple regional tissue oximetry. financial support: dr gress is a member of the scientific advisory board of ornim medical ltd and holds stock options in the company. level of coma has traditionally been measured clinically (e.g. glasgow coma scale, four score, etc.), or with neurodiagnostic tests (e.g. eeg). developing more objective, longer term measures of coma could improve quantitation of arousal and modification of response to therapy. we used a post-cardiac arrest (ca) rodent coma model to test -d bodily acceleration as a wireless, continuous measure of early movement during coma arousal, and compared it to eeg based markers validated previously. five adult wistar rats (male, - gms) underwent eeg electrode implantation wk prior to asphyxia-induced min ca. four hours after resuscitation, rats were attached to a wireless eeg-accelerometer system. wideband and sub-band eeg were analyzed to yield iq, an entropy based and previously validated measure of coma arousal. we defined activity as the variability in -d acceleration as quantified by the standard deviation of acceleration. we found a significant positive linear correlation between accelerometer activity and full band eeg iq (r= . ± . , mean ± sd). when eeg sub-bands were divided into two categories ( . - hz and - hz), accelerometer activity had better correlation with higher frequency sub-bands (r= . ± . vs. r= . ± . ). during individual sub-band analysis, we were able to find a moderate correlation with the higher frequency iq - hz (r= . ± . ). these results suggest that -d acceleration based activity, measuring early subtle movements during coma arousal, correlates with eeg iq. this relationship was stronger for higher frequency sub-bands. this suggests that subtle motor activity quantitated by an accelerometer may be an acceptable indirect measure of arousal. such accelerometer-based systems also have the advantage of being more objective and affordable while also offering longer term monitoring. therefore, accelerometer-based monitoring for coma arousal may have clinical applicability in intensive care units. recent literature emphasizes the impact of vancomycin concentrations on patient outcomes, especially in serious infections such as central nervous system infections (cnsi) and pneumonia. achieving adequate concentrations is challenging in the critically ill due to changes in volume of distribution and clearance. we investigated the impact of a pvds in our neurologic units. retrospective chart review comparing outcomes of pvds (rph-group) to pre-implementation control group (md-group). adult inpatients receiving vancomycin on neurologic units (neuro icu and floor) were included in a month pre/post period. rph-group patients receiving vancomycin not consulted to pvds were excluded. outcomes evaluated number of vancomycin levels and proportion within goal range ( - mcg/ml). in md-and rph-groups, and patients were enrolled, respectively. rph-group had a higher percentage of patients with weight > kg and crcl > ml/min. icu patients accounted for % and % of the md-and rph-groups, respectively. common indications were cnsi and pneumonia in both groups. levels were drawn in md-group versus levels in rph-group. a higher percentage of levels were within goal range in rph-group ( %) versus md-group ( %, p = . ). amongst patients with cnsi, rph-group had a higher percentage of levels within goal range ( % vs. %, p = . ). icu patients in rph-group had a higher percentage of levels within goal range ( vs. %, p = . ). in icu patients, younger age (p = . ) and crcl > ml/min (p = . ) trended toward initial subtherapeutic levels despite receiving ~ mg/kg/day of vancomycin. implementation of the pvds in neurologic units resulted in higher attainment of therapeutic concentrations. in icu patients, addition of a loading dose or higher daily doses of vancomycin may need to be employed by the pvds to ensure achievement of target concentrations. intraventricular therapy (ivt) with polymyxin b (polyb), an antibiotic with similar pharmacological action to colistin (polye), by external ventricular derivation (evd) has the main goal of offering major bioavailability of the drug, since its use by intravenous and direct action are restricted by the blood-brain barrier, with penetration of only %. the patient of the present report had arterial venous malformations followed by hemorrhagic stroke, which caused elevated intracranial pressure. the objective is to show an example of the effect of ivt polyb in a patient with meningoencephalitis infection by multidrug-resistant gram-negative bacteria (a. baumannii and p. aeruginosa), that are common in the icu. a literature review was made on the subject of therapy with polyb about the pharmacological characteristics, nephrotoxicity and neurotoxicity. a comparative table of the resistance profile of the strain treated in this study was created, with the intrinsic resistance of the species. also, the development of liquor evolution (culture and routine) of the patient before the treatment was monitored, until negative liquor. the effectiveness of evd, the colonizer germ and monitoring of the serial aspects of the liquor were analyzed. the patient was treated with intravenous and intrathecal administration of polyb (ivt) from november th to november th. on / / , therapy with intravenous polyb was started: ui( . ui /kg/d) once a day, on every day of treatment; and ivt by evd: ui in solution once a day during the first three days, and on alternate days during all the treatment. as a result of the use of intrathecal polyb associated with intravenous, effectiveness was proven in the routines of liquor negative for such germs, not showing any reports of neurotoxity and nephotoxity. ivt polyb proved to be very efficient on treating meningoencephalitis quickly. no toxic effect was associated with the drug. enhancing the level of alertness in comatose patients after acute brain injury is a very challenging problem. the use of alerting agents like modafinil is reasonably established for tbi patients in the chronic phase but not in the acute settings. we retrospectively reviewed the use of these agents at our center over a five year period to determine efficacy and use patterns in the acute brain injury settings. a chart review for patients who were admitted to the nicu at dumc during ( ) ( ) ( ) ( ) ( ) and treated with an enhancing agent (modafinil, methylphenidate) for decreased level of alertness secondary to an acute brain injury. electronic records were then reviewed to confirm the intended use of the agent, and a number of clinical data elements was recorded. patients were found to meet study criteria and data elements were extracted. patients received modafinil, received methylphenidate. the average gcs was on admission and at discharge. average delay in trialing alerting agents was ( . ) days and in most cases the agents were used within a few days of withdrawal of care or discharge to hospice. outcomes varied widely with ( . %) going to nursing home, ( . %) going to rehab, . % going home and . % to hospice or death. sah was the most common injury ( . %) followed by ich ( . %), sdh ( . %) and tbi ( . %). review of documented gcs during acute hospitalization showed no significant changes during the period of alerting agent trial for any diagnosis other than tbi. in tbi a significant points improvement was seen on average. our data showed that starting methylphenidate or modafinil for the purpose of improving the level of consciousness in acute brain injury patients is not effective except for patients with traumatic brain injury. based on these observation alternative agents like l-dopa should be explored. nurses in the neurocritical care unit (nccu) are responsible for performing serial neurological exams to establish baseline and potentially detect patient deterioration. nurses spend considerable time doing frequent neurological checks but the current neurological exam is open to subjectivity. we want to quantify the agreement between nurses doing these exams. over the course of one week we tracked the neurological exams of patients admitted to the neurocritical care unit. we compared exams between the off-going and on-coming nurses. each exam consists of single elements, loc, orientation, right and left pupil size, reaction and description, characteristics of speech/communication and motor response in all four extremities. grouping right and left pupils gave element-groups. we examined change of shift (cos) opportunities. when there was more than one variation of an element-group a thorough chart review was performed to identify clinical indicators, such as medications given, to determine if there was a true clinical explanation for the variation. cos exams were the same between nurses % of the time whereas % of exams had a single variation and % contained or more single variations. of the cos opportunities with multiple variations in element-groups only exams showed a clinical reason for the change. that leaves exams with multiple unexplained variations. this accounts for % of overall total exam opportunities. nearly % of the time nurses do not agree on the neurological exam of a patient when examined before and after cos. inconsistency in terminology and methods between nurses may hinder accurate communication. a comprehensive literature search did not reveal a standard neurological exam for nccu nurses. further discussion needs to take place between neuro-nurses across the nation with the goal of defining terms and developing a national standard for the serial neurological exam performed by nurses. electrical impedance spectroscopy (eis) is novel, portable, easy-to-implement device that aims to provide rapid, affordable point-of-care detection, assessment, and monitoring of acute brain injury. an adaptation of "passive" electroencephalography (eeg), eis relies on non-invasive measurement and modeling of the conduction of minute electrical currents applied transcranially across a spectrum of frequencies. our purpose was to test of the feasibility of eis to distinguish the impedance differences between normal subjects and brain injury attributable to acute/subacute intracranial hemorrhage or subacute ischemic stroke. we performed a prospective, observational, proof-of-principle study of patients admitted to our neurosciences intensive care unit for ischemic stroke or intracranial hemorrhage, and healthy volunteers. -minute eis recordings were obtained for each patient. the eis device delivered a small "white-noise" alternating current through a pair of stimulation electrodes; voltages were recorded across three bilaterally symmetric electrode pairs in an eeg montage. log-log plots of impedance (y-axis) as a function of current frequency (x-axis, range hz- khz) were produced for each set of electrodes per patient. mean age was years (range - ); % ( / ) were female. of these brain-injured patients: (a) among all patients with subacute hemorrhage (days old), impedances dropped at higher current frequencies; (b) among all patients with subacute ischemic stroke (days old), impedances increased at higher frequencies; and (c) in one patient with acute hemorrhage (hours old), impedances were not significantly different at higher frequencies but evolved to the subacute hemorrhage pattern (a) at a day- follow-up recording. all brain-injured patients were distinguishable from normal control volunteers. eis is a noninvasive, portable diagnostic modality that has potential for clinical applications in multi-modal neuromonitoring and far-forward battlefield/ambulance arenas for diagnosing and monitoring acute and subacute brain injured patients. future development requires clinical validation, standardization, hardware and software optimization, and graphical user interface development. financial support: this work is supported by national institute of biomedical imaging and bioengineering point of care center for emerging neurotechnologies (poc-cent), subaward u eb - and by an "innovation gra hypertonic saline (hs) improves cerebral edema, blood flow, and is inexpensive. however, use of hs is complicated by reports of induced renal dysfunction and associations with increased blood-stream infection. we hypothesize hs alters renal perfusion leading to a state of relative renal insufficiency. with institutional review board approval, we retrospectively reviewed our hospital's use of hs since march of , and prospectively since october . comparisons were made between admission diagnoses, changes in creatinine (cr), and formulation of hs received ( % nacl, % nacl/sodium acetate mix, and . % nacl) to patients receiving normal saline or lactated ringers. intervariable associationswere calculated between using pearson's correlation coefficients. patients of the retrospective portion were identified. the data presented represents the first patients with data. there were significant differences in the apache ii scores and glasgow coma scale (gcs) scores between the different formulations of hs. the overall correlation of chlorine (cl -) and sodium (na + ) with creatinine (cr), and within each of the saline types, were not significant. when dichotomized by the diagnosis, significant correlations appear. traumatic brain injury (tbi) patients demonstrated moderate correlation between na + & cr of . . stroke patients demonstrated small correlations between na + & cr, and c l-& cr ( . for both). patients receiving hs outside the neurocritical care unit (nccu) demonstrated a small but significant correlation between cl and cr at . . patients receiving hs have lower gcs and higher apache ii scores. elevations of na + or cl in stroke, na + in tbi, and cl in non-nccu patients correlating with elevations in cr. as reductions in renal function predict mortality, therapies precipitating kidney injury are concerning. cl -, a potent renal vasoconstrictor, reduces renal blood flow. prospective comparisons of hs formulation and renal function are needed to further assess if formulation affects outcome and cost. first recognized after rapid initiation of nutrition in prisoners of war during world war ii, refeeding syndrome (rs) is the manifestation of fluid and electrolyte disturbances precipitation systemic dysfunction. here we report a case of rs in a patient with duchenne's muscular dystrophy (dmd). a case report and literature review. a -year-old male with past medical history of dmd, chronically ventilated and feed via a percutaneous endoscopic gastrostomytube, presented with pneumonia, sepsis, and status epilepticus. he was treated with broad spectrum antibiotics, early goal-directed therapy, and hours of electrographic seizures suppression with a midazolam infusion. admission labs demonstrated a minimally low albumin ( . g/dl), mild hypokalemia ( . mmol/l), and the presence of urinary ketones. enteral nutrition was started post-admission day (pad) one. pad found elevated serum glucose and precipitous drops in potassium, phosphate, calcium, and magnesium refractory to replacement. pad three attempts to wean the patient to his home ventilator setting failed, and he remained encephalopathic. enteral nutrition was changed to a more elemental, peptide-based formulation, and multivitamin with thiamine was added. electrolyte abnormalities persisted. pad , it was learned the family had reduced the patient's daily enteral nutrition by approximately half over six months to have him fit within his wheelchair. learning this, enteral feeds were reduced by half, advanced at a reduced rate reaching goal in days, and electrolyte abnormalities resolved commensurately. over the next three days, the patients mental status returned to baseline and ventilation improved. no cardiac or hemodynamic complications occurred, but his infections resolved slowly. a significant concern in the critically ill, the constellation of problems associated with refeeding syndrome have systemic implications. these are centered on increased cellular uptake of phosphorus following the reintroduction of carbohydrates. the role of dmd in refeeding syndrome is uncertain, and has not been previously reported. to determine hospital mortality and complication rates associated with surgical clipping and endovascular coiling of cerebral aneurysms in children, and to evaluate the trend of utilization of these procedures over the recent years in various us hospitals. from the kid's inpatient sample database for the years through , we identified a cohort of children admitted with the diagnoses of intracranial aneurysms and aneurysmal subarachnoid hemorrhage. hospital-associated complications and in-hospital mortality were compared among the clipping and coiling treatment groups. a multivariate logistic regression analysis was used to identify independent variables associated with hospital mortality. cochrane-armitage test was used to assess the trend of hospital utilization of these procedures in various hospital subtypes. after data cleansing, children were included in the analysis. two hundred ( %) children had aneurysm clipping and ( %) had endovascular coiling procedures. the coiled group was younger ( . ± . versus . ± . )and had even gender distribution. hospital mortality was higher in the clipped population, . % versus . % (adjusted odds ratio . ; % ci . , . ; p = . ). in addition, hydrocephalus, status epilepticus and pulmonary complications were higher in the clipped population (p < . ). lastly, the length of hospital stay as well as the hospital charges was higher in the clipped population (p < . ). the rate of hospitals' use of the endovascular coiling has increased in various types of hospitals over the years included in this study (p < . ). the trend in mortality rates among the clipped population remained higher ( . %- . %) compared to the coiled group ( - . %). endovascular coiling of cerebral aneurysms in children is associated with fewer deaths and complications, shorter hospital stay, and less hospital charges compared to clipping. the trend of hospitals' utilization of coiling procedures has increased during the recent years. understanding and managing complex physiologies is a critical, but difficult, problem in the neruologicial-icu. most of the information that must be assimilated in the icu exists at the level of raw data, individual test results and observations, and individual clinician notes. this mass of data obscures a holistic view of the patient, hides the development of trends, makes it difficult for clinicians to notice interactions between different variables. graphical displays and patient summaries enhanced or outperformed traditional text displays in numerous studies (elson & connelly, ; balas et al. ) , but this work hasn't yet been extended to support intracranial pressure (icp). the aim of this effort was to develop an interactive icp-specific data visualization using cognitive engineering principles. the visualization is designed to transform and consolidate complex multimodal physiological data into integrated interactive displays. we have developed a drill-down interactive visualization to enable clinicians to manage icp and identify blood pressure target goals that will ensure adequate cerebral perfusion and thereby create and maintain an optimal physiologic environment for the comatose injured brain to heal. using high-resolution physiologic monitoring data, this drill-down screen depicts the status of cerebral autoregulation using methods well described in the clinical literature (czosnyka, smielewski et al. ; jaeger, schuhmann et al. ) additionally, the drill-down provide graphical display of bloodpressure, intracranial pressure, and brain oxygen tension over time. with this interactive visualization, along with medication and lab data, the clinician can determine the target brain oxygen tension for a specific patient and whether to intervene on blood pressure, intracranial pressure or a combination of both in order to achieve a brain oxygenation goal (i.e., goal-directed therapy). the next step in this project is to conduct an experiment comparing this visualization against standard methods. nicom is a novel technique of monitoring hemodynamic status which is based on bioreactance technology. ventricular outflow causes changes in the phase of radiofrequency waves as they cross chest. measuring the phase shift enables calculation of flow. technique is entirely non-invasive. retrospective analysis of collected data. we describe the use of nicom in a tertiary care neuroscience intensive care unit. patients were monitored on the nicom from january until june for an average of days. diagnoses of patients monitored on nicom were: sah - , ischemic stroke - , ich , tbi - , sdh- , brain tumor- , spinal surgery- and others. % of patients were on mechanical ventilation, % were treated with pressors. in the first hrs of monitoring, there were plr (passive leg raising) tests and fluid challenges performed to measure fluid responsiveness. patients ( %) were fluid responsive and ( %) had an intervention. selected cases will be presented nicom system is safe and can be useful in the neuroicu setting. it can be used in intubated patients with sepsis, unexplained hypotension, hypertensive therapy in sah or during hypothermia therapy. it is also useful in non intubated, alert patients, were fluid status has to be monitored closely. although nicom is a seemingly simple-to-use technology, there were multiple clinical challenges including education of the staff, proper test performance and consistent charting. inconsistent machine calibration, use of compression stockings during a plr, and untimely sensors changes were the main problems. in the neuroicu patients with increased icp, use of fluid challenge can be safer than plr. repeated staff training resulted in more consistent data. limited information is available regarding the current state of informatics in various ncc units. we sought to assess the current state and needs for informatics infrastructure to help determine priorities and future directions of informatics research in neurocritical care. a survey instrument was developed and with the support of the neurocritical care research consortium chair, distributed to the participants/registrants of the nd neurocritical care research conference. a response rate of % ( of ) was achieved. most responders worked in an academic medical center ( . %), level trauma center ( . %) and/or mixed multi-bed (mean= . ) neuromedical/neurosurgical icu ( . %), commonly treating ich ( . %), sah ( . %), ischemic stroke ( . %), and traumatic brain injury ( . %). acquiring, integrating, storing and analyzing mm data in a comprehensive informatics architecture for clinical and research use is stated as important but is rarely achieved due to financial and technical barriers. a centralized dissemination of technical assistance and a societal statement prioritizing informatics to advance ncc research may help facilitate future adoption. access to neurocritical care units (nccus) in the mountain west is geographically limited. we evaluated practice patterns among providers in this region and hypothesized that hospital size and distance from nccus impact decisions to transfer patients with critical neurological illness. surveys were sent to hospital providers with varying degrees of access to nccus in the mountain west, to examine what factors influence decisions to transfer patients with critical neurological illness. the survey queried location, hospital size, locally represented specialties, patterns of transfer, frequency of illness presentation, influences for and against decisions to transfer such as timeframes and perceived futility, and awareness of nccus and services they provide. responses were received. responses were grouped by distance from the closest nccu and by hospital size. results showed that futility in outcome has a strong influence on decisions against transfer for smaller hospitals and hospitals that require air transport (p< . ). notably, distance required to transfer is not a strong factor in the decision to transfer patients (p= . ). for larger hospitals and hospitals within ground transport range of a nccu, patient condition, patient risk during transfer, and specialized intensivist support are less influential in transport decisions. patient transfer for critical neurological illness originates from hospitals with varying size and geographic access to nccus. while distance required to transfer does not appear to be a significant limitation, perceived futility in outcome is a strong influence against deciding to transfer. among providers in smaller hospitals at greater distance from nccus, significantly more providers have never heard of nccus or services provided. these findings suggest that therapeutic nihilism regarding critical neurological illness in smaller hospitals at greater distances from nccus influences patient outcomes. patients and providers in these locations may be significantly impacted by further education about neurocritical care and implementation of tele-neurocritical care services. neurocritical care is a multidisciplinary specialty whose participants originate from diverse medical backgrounds. review of the growing body of literature is essential for clinicians and strategies for continuing education may be expected to be unique for this field. this exploratory survey aims to define how the neurocritical care team (ncct) educates itself. a fifteen question survey was sent to all neurocritical care society members and responses were gathered over a one month period. basic statistical analyses of rates and comparisons of response rate proportions were conducted. surveys were returned ( %). % of respondents were physicians, % were non-physician team members, and % were physicians in training. regardless of background or training, individuals seek published literature through a combination of electronic-print media outlets ( %) rather than a singular approach. however, % spend the most time reading journal articles. % of ncct members review the same journals monthly and allocate individual manuscript time contingent upon interest. neurocritical care ( %), critical care medicine ( %), and new england journal of medicine ( %) are the most commonly reviewed journals. % of ncct members do not attend a journal club. academic neurointensivists ( %) and fellows ( %) are most and nurses are least ( %) likely to attend. participation in ncc subspecialty ( %) or general critical care ( %) clubs is more common than neurology ( %) or neurosurgery ( %). responders rate national meetings ( %) as their most influential educational experience. attending physicians ( %) are more likely than trainees and non-physicians ( %) to consider personal literature review most valuable (p < . ). % of all ncct members attended last year's ncs annual meeting, compared to sccm ( %) and regional conferences ( %). ncct members infrequently attended (< %) general topic neurological or neurosurgical national conferences. despite diverse backgrounds, ncct members seek continuing medical education through common subspecialty specific methods. financial support: none the contributions and perceptions of staff regarding nurse practitioners (nps) and physician assistants (pas) in neuroscience icus throughout the country are not well known. the objectives of this study were to determine the impact of neuroscience nps and pas and assess demographics of icus. all members of the neurocritical care society were asked to complete a survey to obtain their perception regarding the addition of nps and pas to the icu team. participants rated the abilities of nps and pas to promote a team environment, anticipate or prevent neurologic deterioration, address patient or staff concerns in a timely manner, safety, and communicate effectively on a - likert scale. in addition, members were asked to provide basic demographics and background information on the type and size of icu, type of providers in charge, and the role of nps and pas in their icu, including procedures performed, documents written, and number of patients per provider. both quantitative and qualitative data was collected and analyzed. a mantel-haenszel chi square and ordinal logistic regression model were used to determine the relationship between the background information and the perception of the abilities of nps and pas. the study cohort composed of % of ncs members. additional responsibility of nps and pas was associated with higher scores in safety, ability to promote a team environment, address patient or staff concerns, communication, and most importantly the ability to anticipate or prevent a neurologic deterioration (p< . for all). number of nps and pas, number of years of employment of nps and pas, number of procedures, and amount of documentation also positively affected safety. additional responsibility of nps and pas has strong potential to improve staff, patient, and family satisfaction, safety, and prevent neurologic deterioration. nps and pas should be utilized to the full extent of their role. we conducted a survey study in an academic, co-managed neuro icu to explore family satisfaction regarding the care of their surviving loved ones and compared results with concurrent data from the hospital's closed medical icu (micu). over days, we administered the family satisfaction-icu instrument to neuro icu and micu patients' families at time of icu discharge. those whose loved ones passed away during icu admission were excluded. the capture rates of families from the neuro icu and micu were . % ( surveys) and . % ( surveys in our neuro icu, patients' families could be more satisfied with several aspects of care. further study is needed to determine ( ) whether a closed neuro icu model improves family satisfaction and ( ) whether instituting a system in which the neurointensivist team regularly meets with all available families daily improves perceptions of shared decision making, even in routine situations. non-funded prospective patient registries at any given institution rely largely on volunteer clinical personnel. presupposing that an all-inclusive database would be self-defeating in this type of environment, we designed and implemented a quality improvement (qi) database with intentional iterative design. neurointensivists identified by consensus the injury/disease related events and procedures that were most important to track for qi and for judging clinical intensity of our unit. we compiled a list of syndromes that were either commonly studied by principal investigators or were common primary diagnoses in our unit. for each syndrome, we identified commonly accepted grading or intensity scores. the clinical and translational science awards electronic data entry module, redcap, facilitated data collection. consecutive patients in our icu were entered upon discharge. weekly meetings served to adjudicate disease classification, grading scores (frequently based on consensus imaging review), and discharge disposition. opportunities to enter free-text items were allowed to enhance the intentionally iterative design. in quarterly reviews, we removed items that were consistently left blank and added standardized items corresponding to consistently annotated free-text items. since its implementation in january , the neurocritical care qi patient registry has accrued separate entries. consensus-driven iterative changes to the registry have resulted in complete data entry. participation at weekly registry meetings has been consistent and enthusiastic, routinely drawing - physicians ( - fellows, - attendings). qi projects have been enabled to date. resource limitations may be a practical hindrance to achieving all-inclusive databases outside of funded clinical studies. an iterative design driven by consensus in the described approach can result in a rich database with complete data entry and continued volunteer participation. future incorporation of supplemental information sources via enterprise-wide clinical data warehouses may achieve more complete databases that comply with standardized ideals such as the common data elements. many neurology residency programs have begun implementing mandatory rotations through neurocritical care (ncc) as part of the curriculum. the added experience was thought to be beneficial for residents after graduating the program; however, we wondered how it might affect residents and patients during residency. we thought to survey residents about their programs and the amount of time they spend in ncc rotations. we also wanted to know how they felt the extra time spent in these rotations affected their consulting habits, and therefore their ability to manage cases on their own. all neurology residents in the united states were the target population for this survey. a list of neurology residency programs was obtained from the american medical academy's freida database. the names and email addresses of program directors were generated, and they were contacted by email with a link to an online survey. the respondents were neurology residents ( pgy- , pgy- and pgy- residents). of the respondents, . % stated that ncc was a mandatory rotation in their program while the remaining . % said that it was not. of those who had mandatory ncc rotations, . % said they were for - weeks duration, while . % agreed they should be - weeks long. when asked how often they ask for consultations from other specialties, residents who had mandatory rotations through ncc were more likely to say they usually do not consult other specialties, while those who did not have mandatory rotations were more likely to consult for all non-neurological issues. the survey results demonstrated that neurology residents who have mandatory rotations in ncc are more confident in their abilities to manage their own patients. this is thought to promote continuity of care and may reduce medical errors as well as healthcare cost. a botulism epidemic in a maximum-security prison cell-block posed numerous logistical dilemmas for which telemedicine served as a bridge to management. inmates in a high-security prison cell-block brewed batches of "pruno" by fermenting fruit, raw potato, and granulated sugar in reusable bags that were passed throughout the cell-block. one of the batches was contaminated with type a botulism. twenty-nine inmates were potentially exposed, but the actual exposures were initially indeterminable due to the inmates' fears of incrimination. the index case developed nausea, emesis, diplopia, and ptosis approximately six hours after exposure and presented to the emergency department (ed) two days later with generalized weakness, dysarthria, dysphagia, hypophonia, and dyspnea. he required intubation and was admitted to the neurocritical care unit (nccu). four additional inmates presented with similar symptoms within several hours of the index case. two required intubation and all were admitted to the nccu. within twenty-four hours of admitting the first five cases, nine additional inmates developed symptoms. five were evaluated in the ed; three were admitted to the nccu and two were discharged to the prison infirmary and monitored using telemedicine. two patients were initially evaluated and monitored with telemedicine at the prison. the remainder of the cell-block was evaluated by prison infirmary staff. botulinum toxin type a was confirmed with bioassay and cultures in these patients, but classic electrodiagnostic findings were absent. the eight inmates admitted were treated with hepavalent botulinum antitoxin (h-bat). obtaining the antitoxin required collaboration with the cdc for transport from several sites around the country. inmates were followed post-discharge using telemedicine and showed improvement. this botulism epidemic presented a logistical logjam. initial telemedicine evaluation and subsequent monitoring played a key role in managing nccu access and optimizing security resources for the prison, ed, and nccu. intrahospital transport of neurocritical care unit (nccu) patients is associated with accidental line removal, unplanned extubation, and hemodynamic instability. further, because patients must be accompanied by a nurse during intrahospital transport, there is an inherent reduction in home unit staffing which reduces direct patient care and monitoring for other nccu patients. the purpose of this project was to assess the impact of a neurocritical care transport nurse (ntrn) on patient safety, improved direct patient care time and improved staff satisfaction. the -month ntrn pilot program was initiated in our bed nccu. for three months, the ntrn worked five -hour shifts per week. the ntrn accompanied patients during intrahospital transports, assisted with admissions, functioned as resource nurse in the nccu, and relieved nurses for meal breaks. data was collected in real time and included time-inmotion data, adverse event records, and a pre-post work-flow surveys. the ntrn completed intrahospital transports with were zero safety events. the mean length of time for intrahospital transport prior to the pilot was significantly greater than transport by the ntrn ( vs. minutes; p<. ). the mean time it took nurses to stabilize a new admission/post-op patients was reduced from minutes to minutes. staff surveys were overwhelmingly positive with % of nurses reporting the ntrn saved them time; % reported increased opportunity for meal breaks, and % attributed reduced overtime due to the ntrn program. individual nurses reported that the ntrn program saved them an average of . minutes each shift ( . hours per shift). the ntrn pilot program was associated with fewer safety events, increased staff satisfaction, more rapid attention to patient needs and reduced overtime. the program should be implemented full time and evaluated for potential costsavings. many factors are associated with time delays to reperfusion in endovascular treatment for acute ischemic stroke (ais). we assessed if a prototypical neurointensive care unit layout where both the angio suite and ct scanner are inside the unit can reduce times to reperfusion. we compared time from ct to groin puncture (gp) in patients that were transferred from outside hospitals (osh) directly to the nicu versus those who went through our emergency department (ed). we retrospectively reviewed patients from a prospectively maintained database from october -june who underwent endovascular therapy for ais. a univariate analysis was performed to compare the patients' characteristics between the two populations and to identify differences in time intervals between ct imaging and gp. a total of patients were included in our analysis. ( %) patients were from osh. patient characteristics in both groups were similar except for osh patients had significantly less history of hypertension ( % vs %, p< . ) but had longer time intervals from last known normal to gp (median mins vs. median mins, p < . ) and lower pretreatment aspects ( % < vs. % < , p < . ). patients' transferred from osh had significantly lower times from inhouse ct to gp as compared to patients from the ed ( . +/- mins vs. +/- mins). although there was an increased number of non-contiguous multimodal imaging studies performed on ed patients compared to those from osh ( % vs %, p< . ), exclusion of these patients still resulted in a significant shorter time frame between ct to gp ( . +/- mins vs. . +/- . mins) among osh transfers. the design of an integrated biplane angio suite within the nicu reduces the times from ct imaging to gp, thereby lowering the times to reperfusion, and potentially, patient outcome. sepsis is a challenge for the intensive care unit (icu), being the main cause of death during hospitalization. it was performed a longitudinal and individualized intervention authorized by the hsja ethics committee applying the campaign 'simple actions save lives' in which educational adhesives worked as a guide for washing hands and flags for high contaminated locations. a decontamination routine of monitors, control panels, ventilators and infusion bombs was established every hours; and continued education for the health team was intensified during the intervention. two groups were created, patient enrollments in periods of days before and after the intervention, more than hours of hospitalization: group a with patients and group b with patients. the hospital infection incidence decreased by % and vap by . %. urine culture was positive in , % of those patients (n= ) in group a and in . % (n= ) in group b (a . % decrease ). the cultures of catheter tip were positive in . % (n= ) of catheters in group a, which used catheter in total, and none in group b, which used catheters. the sepsis incidence decreased by . %. septic shock was detected in . % (n= ) of patients in group a. there was a drop of the costs between groups (r , . , . %). the cost of campaign material was r$ . . this intervention was a simple form to decrease the related number of infections in the neurovascular icu, having spent irrelevant values when compared to treatment of these clinical tables. intracranial pressure (icp) management guidelines have been established; however there is no data documenting actual icp management practices in the united states, or the degree to which clinicians comply with existing guidelines. the primary aim of this study is to explore nursing and medical practice patterns associated with icp monitoring and management. a prospective multi-center non-randomized observational design was used.the study sample was composed of consented nurse/patient dyads, with dyads enrolled per study site. study patient subjects included were over age , had icp monitoring in situ, and were diagnosed with intracranial pathology. nurse subjects included were those assigned to the patient, who routinely worked in the unit, and had completed their orientation training. each dyad consented to a hour observational period, where data was collected on nurse interventions for icp management. dyads (n= ) were enrolled at hospitals between august and may . patients were primarily male %, mean age of years, and non-hispanic. nurses were primarily female %, non-hispanic, and a mean of . years of critical care experience. we observed distinct nursing/medical interventions hypothesized to reduce icp. although csf diversion and limiting stimulation were the most frequently used interventions, there was not a consistent hierarchical approach to initiating icp reduction interventions. wide variances in nursing and medical treatment patterns were observed for icp treatment threshold, first-line therapy, and the order in which interventions were initiated. despite established guidelines, variability exists throughout the u.s. in how physicians and nurses monitor and manage icp. more research is needed to compare intervention techniques to determine the impact these differences have on outcomes in patients requiring icp management. administrative data are being increasing being used to measure quality of care, for public reporting, and in pay for performance. administrative data are inexpensive, readily available, and target clinical outcomes. the aim of this study was to evaluate the use the use of administrative data in identifying potentially preventable events and iatrogenic complications in patients admitted to an academic medical center with a primary diagnosis of acute stroke. administrative data for all adults patients (> years of age) with a discharge diagnosis of stroke , . , . , . , . , . , . , . , . , . , . , . , and ) were evaluated from january -december for complications based on administrative data by looking at secondary diagnoses that were not present on admission using data from the university healthsystem consortium database. both the agency for healthcare research and quality (ahrq) quality indicators (qis) for inpatient conditions and known codes for other complications such as catheter associated urinary tract infection, pneumonia, and deep vein thrombosis or pulmonary embolus (not associated with surgery) were used to identify potential events. of the cases reviewed, many cases had at least one complication. the leading cause of potentially preventable events were related-to-infection (central line associated bloodstream infection, sepsis, catheter associated urinary tract infection, and aspiration and/or hospital-acquired pneumonia). the ahrq qi only captured a fraction of the events. patients with subarachnoid hemorrhage had the highest mortality, followed by intracranial hemorrhage. several of the deaths occurred in low risk patients and had at least one potentially preventable complication. when reviewing flagged records, a small number of events reflected opportunities to improve documentation and/or coding, with the majority of remaining events associated with opportunities for improvement. administrative data may be a useful adjunct to quality improvement efforts. financial support: co-deputy project lead for the ahrq qi project (ahrq sub-contractor). continuous video-eeg (cveeg) monitoring is often utilized in the evaluation of impaired consciousness. nonconvulsive seizures may be distinguished from metabolic disorders when triphasic waves (tw) are recorded. however, rhythmicity detected on cveeg may call into question the presence of electrographic seizures. the following case describes the transient resolution of rhythmic tws after acute administration of glucose in a patient with hypoglycemic encephalopathy. case report reviewing clinical, laboratory and electroencephalographic features of a patient with metabolic encephalopathy secondary to hypoglycemia. a -year-old woman with type- -diabetes and treated osteomyelitis of the foot presented with altered mental status. she was intubated and stuporous. cranial nerves were intact. all four extremities withdrew to noxious stimulation. plantar responses were flexor. mri brain exhibited leptomeningeal enhancement consistent with meningitis. serum bg= mg/d, and csf glucose= mg/dl. month after antibiotic treatment, she was following commands. repeat mri revealed complete resolution of leptomeningeal enhancement. during recovery, she developed sudden onset stupor with left facial movements, and underwent cveeg monitoring. eeg showed generalized, polymorphic delta/theta slowing intermixed with tws, without electrographic correlate of facial movements. during cveeg, tw activity increased in rhythmicity and frequency, coinciding with worsening hypoglycemia, with a nadir bg= mg/dl. electrographic activity was not induced or exacerbated by stimulation. administration of ml of d ( g d-glucose) resulted in transient resolution of tws within minutes, which corresponded to a bg= mg/dl. however, background slowing remained on cveeg, with gradual reemergence of infrequently occurring tws despite normoglycemia. mental status returned to baseline approximately hours after bg stabilization. rhythmic triphasic wave activity due to hypoglycemia may be distinguished from electrographic seizures after acute correction of bg, with corresponding transient resolution of triphasic waves. however, clinical response to correction of metabolic dysfunction may be delayed for up to hours. continuous-iv-midazolam (civ-mdz) is recommended for treatment of refractory status epilepticus (rse) but doses are controversial. here we compare a historical cohort (n= ) treated with low dose to a subsequent cohort of patients treated with high dose civ-mdz for rse. following the analysis of the historical cohort ( - neurology , ( ) : - ) we changed our protocol for rse allowing for higher civ-mdz doses and collected consecutive cases ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . exclusion criteria: cardiac arrest; prior treatment with a different civ-aed. we collected data on baseline characteristics, civ-mdz doses, seizure control, complications, hospital course, and outcome. high dose was compared to low dose civ-mdz on an intention to treat basis using logistic regression analysis with the significance level set at p< . . baseline characteristics were similar between groups. median maximum civ-mdz dose was . mg/kg/h (iqr . , ) for the high and . mg/kg/h (iqr . , . ) for the low dose group (p< . ), but duration of civ-mdz was the same between the two groups (median hours). "withdrawal seizures" (within hours after civ-mdz discontinuation) were less frequent in the high dose group ( % vs %, or . ; %-ci . - . ). "breakthrough seizures", "ultimate civ-mdz failure", and complications were not different. discharge mortality was lower in the high dose group ( % vs %, or . , %-ci . - . ) after controlling for age, etiology, and apache- scores. at months, mortality was similar between the two groups. lower death or vegetative state rate for those treated with high dose civ-mdz was seen at months ( % vs %; or . ; %-ci . - . ), but this finding is limited by missing -month functional outcome data in both groups. high dose civ-mdz treatment for rse can be performed safely in an icu setting and may be more efficacious in controlling seizure activity. outcome data are promising and warrant further prospective study. the clinical utility of free valproic acid (vpa) levels is unclear, and the actual free fraction (ff) of vpa in hospitalized patients is not well established. our goal was to assess and compare the total levels, free levels, and ff of vpa in inpatients and outpatients and to determine factors that may influence the ff. retrospective chart review of paired total and free vpa levels in inpatients and outpatients. demographical, laboratory, and concomitant interacting medication data were collected and analyzed. paired total and free levels were categorized based on their status in regards to the therapeutic range (i.e., subtherapeutic, therapeutic, or supratherapeutic) and whether the paired levels were concordant or discordant (e.g., both levels in therapeutic range, or mismatched). linear regression was used to assess the impact of variables on the ff. logistic regression was used to determine if variables predicted the likelihood of having discordant paired levels. inpatients had a significantly higher median ff compared to outpatients ( . % vs. . % respectively; p < . ). total levels were found to be a poor predictor of free levels (r = . ) in hospitalized patients. inpatient free levels were discordant with the therapeutic status indicated by the total level % of the time. in a linear regression model, albumin (p < . ), total protein (p < . ) and co-administration of phenytoin (p= . ) and carbapenems (p= . ) were found to significantly and independently impact the ff. multiple logistic regression indicated albumin as a significant predictor of the total and free levels being discordant in regards to therapeutic status (or . [ %ci . - . ], p< . ). inpatients had a significantly higher ff compared to outpatients. inpatient free levels were frequently discordant with the total levels in terms of the therapeutic status. decreasing albumin was a significant predictor of discordance between the free and total levels. increased continuous eeg utilization in the icu has generated an interest in faster acquisition and interpretation of eeg data. limited electrode arrays (lea) coupled with quantitative algorithms have been leveraged for this purpose. however, previous studies with lea's have suggested an inherent error rate produced by a reduced number of electrodes. the aim of the current project was to test a novel lea and determine if multiple montages could correct any error rate. with approval from our irb, short de-identified eeg segments were retrospectively collected from clinical ceeg archives. segments contained one of five primary findings: normal, diffuse slowing, periodic epileptiform discharges (peds), seizure and burst suppression. all files were reformatted into an electrode array containing a lateral chain and central electrode bilaterally. segments were distributed to four experienced neurophysiologists in two phases. in phase , segments were interpreted in a single anterior-posterior bipolar montage and compared to the original read. in phase , fifty frequently misread segments from phase were reinterpreted using four additional montages. in phase , eeg interpretations were reviewed yielding a sensitivity of % for seizure and % for peds, burst suppression, and normal. the specificity was greater than % in all cases. the sensitivity and specificity for diffuse slowing was % and %. in phase , eeg interpretations were collected with no significant improvement noted in the detection of any eeg finding. in agreement with past studies, this trial suggests that leas contain a base error rate engendered by the reduced number of electrodes. this error rate is maintained regardless of the number of available montages. the implication of these findings suggests that studies examining the use of lea's for use in seizure detection and neurophysiologic algorithms should calculate an error rate specific to the electrode array before algorithm testing. the incidence of nonconvulsive status epilepticus (ncse) and other electrographic features in comatose post-cardiac arrest syndrome patients treated with therapeutic hypothermia (th) is still under investigation. the objective of this study is to determine the incidence of ncse and other electrographic features and correlate with neurologic outcome and survival. review of consecutive subjects treated with th and receiving continuous eeg (ceeg) monitoring between may and december . demographic data, survival, and functional outcomes using cerebral performance category (cpc) scale were prospectively recorded. forty eight patients were included, with mean age of years (sd ), majority were males (n= , %) and experienced out-of-hospital cardiac arrest (n= , %). ventricular fibrillation was the initial cardiac rhythm in patients ( %). all patients received th. twenty seven patients ( %) died. seventeen patients ( . %) had good neurologic outcome (cpc or ). ncse occurred in patients ( . %), both of whom died. periodic epileptiform discharges occurred in patients ( . %), ( %) of whom had poor neurologic outcome or death (cpc - ) compared to % poor outcome in whom periodic epileptiform discharges did not occur (nonsignificant). burst suppression occurred in patients ( . %), all ( %) of whom had poor neurologic outcome or death compared to . % poor outcome in whom burst suppression did not occur (p < . ); and severe background attenuation occurred in patients ( %), ( %) of whom had poor neurologic outcome or death compared to % poor outcome in whom severe background attenuation did not occur (p< . ). ncse occurred in . % of post-cardiac arrest patients undergoing therapeutic hypothermia. outcomes are poor in postcardiac arrest patients undergoing therapeutic hypothermia with ncse, burst suppression or severe background attenuation. larger prospective studies are needed to further evaluate and characterize ceeg findings in comatose postcardiac arrest patients undergoing th. encephalopathy is a frequent occurrence in the critical care setting. previously, we have shown that patients with a primary neurologic injury and encephalopathy are at high risk for ceeg seizures. patients with a presumed metabolic etiology of encephalopathy have been poorly characterized. the purpose of this study was to identify the frequency and underlying etiology of ceeg seizures that occur in critically-ill patients with a presumed metabolic etiology. we retrospectively reviewed prospectively collected ceeg and clinical data on consecutive patients monitored from january , , to december , . we identified those patients with ceeg seizures (n= ) and included in this study only those patients with metabolic etiologies. eeg seizures were defined as evolving rhythms in frequency, distribution, and/or morphology at hz or greater for more than seconds duration. statistical analyses were performed with jmp . . sixty-six ( . %) patients were identified as having metabolic causes for ceeg seizures with the most common etiology being sepsis ( . %) which linearly increased (r = . ) in detection from in to in . other etiologies included liver failure ( . %), posterior reversible encephalopathy syndrome (pres; . %), electrolyte/glucose derangement ( . %), drug overdose/withdrawal ( . %), and renal failure ( . %). . % of the ceeg seizures were without clinical signs. a linear increase in ceeg seizures occurred with a decrease in level of consciousness (r = . ). the majority ( . %) of patients were eventually discharged for rehabilitation, but . % expired prior to discharge. this retrospective study shows an increase of ceeg detected seizures in patients with a presumed metabolic etiology from to . this increase in seizures is likely due to increased targeted monitoring. this highlights the value of using ceeg database information to target at risk populations. our results should guide the use of ceeg monitoring in the metabolic patient particularly those with septic encephalopathy. medically induced burst suppression on eeg is often seen in critically ill patients who are sedated for treatment of status epilepticus, cerebral edema, and in patients with anoxic brain injury or post cardiac arrest undergoing hypothermia treatment. previous studies have demonstrated that the majority of these patients have poor prognosis. we decided to investigate if specific eeg patterns during burst suppression in these patients would correlate with different outcomes. we retrospectively identified patients with medically induced burst suppression out of patients who had continuous eeg monitoring (ceeg) from january through december in our neuro icu. neonates and children were excluded. all eeg tracings were independently reviewed by two electroencephalographers and classified into discrete seizures, status epilepticus (se), interictal epileptiform discharges (ied), burst suppression, and epileptic bursts defined as burst suppression with ied within the burst activity. primary outcome was cerebral performance categories (cpc) at hospital discharge. of the patients, were identified to have epileptic bursts-one se, eight anoxic brain injury, two ischemic stroke, hemorrhagic stroke, five other medical conditions. the mortality rate of patients with epileptic bursts was % compared to % for those without. only % in each group had good neurologic recovery defined as cpc score of - . patients with epileptic bursts on average had longer duration of monitoring ( days versus ) due to refractory seizures and, subsequently, increased number of aeds ( . vs . ) used. similar to previous findings, the patients in our study had poor prognosis. our findings additionally show that epileptic bursts in this patient population correlated with more refractory seizures and a higher mortality rate. the presence of epileptic bursts may be used as an adjunctive indicator for prognosis in patients who are in medically induced burst suppression. larger population study is underway. epidemiologic studies in epilepsy using large administrative databases depend on accurate icd- -cm classification. we sought to determine the accuracy of icd- -cm code . (grand-mal status) for diagnosing status epilepticus (se) after hospital admission. a case-control study at an academic institution was conducted. twenty-one subjects with discharge icd- -cm code . (grand-mal status) and consecutive admissions without the code of interest were randomly selected. se was defined as neurologist documentation of continuous clinical seizure activity for five minutes or longer and/or two or more discrete clinical seizures without inter-ictal return to baseline (clinical diagnosis) and/or eeg consistent with se by board certified neurophysiologist interpretation (eeg diagnosis). all cases and none of the controls met our pre-defined criteria of se. therefore, the sensitivity, specificity, positive predictive value (ppv), negative predictive value, and accuracy of the code was %. when the diagnosis relied on clinical criteria alone, the sensitivity decreased to % with ppv of %. when the diagnosis was made by eeg criteria alone the sensitivity decreased to % and ppv of %. the icd- -cm code . is both accurate and specific for the diagnosis of se after admission at an academic institution. clinical definitions of se and the prevalence of the disease may affect the sensitivity and ppv of icd- -cm code . for the diagnosis of se. the results of our study require further validation in other cohorts. refractory status epilepticus (se) has been linked to significant morbidity and mortality. when pharmacological treatment fails, ketogenic diet has shown to suppress seizure activity in children and is gaining acceptance as an adjunctive treatment in adults. while case reports exist, there are no standard guidelines for implementing ketogenic diet in adult neurocritical care patients. the purpose of this abstract is to demonstrate a standard guideline for ketogenic diet utilization in a neurocritical care unit. a performance improvement project was undertaken to standardize ketogenic diet administration in enterally fed neurocritical care patients with medically refractory se. the guidelines include patient selection, team communication, patient monitoring, family education, patient transitions out of intensive care and measures for patient outcome from this treatment. patients admitted with se are initiated with standard pharmacologic treatment; if treatment does not result in se cessation, then ketogenic diet is reviewed. discussion with the patient's family is required to review long-term implications and potential lifestyle choices related to diet after critical illness. a standard checklist within the guidelines assures communication to all necessary organizational departments including appropriate consults. daily monitoring and discussion in patient rounds evaluates daily patient progress. team communication is focused on diet tolerance, medication carbohydrate content, concurrent pharmacologic se management and patient progression. since , after implementation of the standardized guideline, seven adult se patients have been treated with ketogenic diet. mean age was . years; range - years; two patients were male. ketosis was achieved in six of seven patients and five of six patients sustained resolution of se after ketosis was achieved. our organizational experience indicates that coordinated team care, family education, goal planning and a standardized guideline contribute to successful implementation of ketogenic diet. further research is needed to determine overall effectiveness of this therapy. status epilepticus (se) is a potentially life-threatening condition that is frequently under-recognized, may be refractory to initial treatments, and often requires admission to general intensive care units (icus) we hypothesized that admission of patients with se to the neurosciences icu (nicu) vs the medical icu (micu) might correlate with surrogates for improved patient outcome. we performed a single-center, retrospective cohort study of patients with se admitted to the nicu vs the micu in our institution between - . admission to either icu depended on bed availability and emergency medicine preference. clustering methods were used for analyses, taking into account multiple visits of the same patient. there were visits for patients with definite or probable se [ ( %) in the nicu and ( %) in the micu]. apache ii scores were significant higher in the micu group ( . vs . , p= . ). more continuous eegs were ordered in the nicu ( % vs %, p< . ). ceeg was ordered more frequently in complex partial/non-convulsive and less in convulsive clinical presentations. the nicu had a higher rate of complex partial/non-convulsive se and the micu of generalized convulsive se ( % vs % and % vs %, p< . ). admission diagnoses differed, with the nicu having a higher rate of stroke and the micu a higher rate of toxometabolic etiologies ( % vs % and % vs %, p< . ). after adjusting for covariates, no difference was found in the icu or hospital length-of-stay and modified rankin scale at discharge. management differences occurred in micu vs. nicu-managed se, possibly based on variabilities in presentation and etiology. however, no reduction in length-of-stay or different discharge outcomes between the icus was found. hongki song , taechon kang , dongjin shin although levetiracetam(lev, s-(oxo- -pyrrolidinyl)butanamide, keppra®, ucb pharma) has been reported to be well tolerated and effective in se refractory to benzodiazepine (bdz), there was little preclinical or clinical data concerning the outcomes of lev in comparison to dzp, and vpa in se-induced neuronal death. to address this relevant lack of information, we have performed the preclinical study to investigate the effect of diazepam (dzp), valproate (vpa), and lev alone, and the efficacy of lev as an add-on treatment with dzp on the se-induced neuronal death. dzp and vpa. however, it is noticeable that lev as an add-on drug with dzp could not alleviatese-induced neuronal damage as compared to effective to protect neuronal damages from se, as compared to dzp. in contrast to lev, vpa( and mg/kg) as an add-on drug with dzp significantly reduced se-induced neuronal damage as compared to dzp alone, and showed the similar effect of vpa ( mg/kg) alone. these findings indicate that, unlike vpa, lev may negatively interact with dzp, and suggest that lev may be more effective to prevent se-induced neuronal death as a first line drug than as a second line therapy after bdz treatment, and that lev as an add-on drug with bdz may not provide any additional benefit to outcome of se. temkin and colleagues found that phenytoin exerted a beneficial effect by decreasing the rate of seizures by % during the first week after a traumatic brain injury. the purpose of this study was to determine the need for monitoring and titrating to therapeutic free phenytoin levels in patients receiving phenytoin for prophylaxis within days following a traumatic brain injury. this was a retrospective study of patients for a traumatic brain injury (tbi), who met the inclusion criteria and received phenytoin for seizure prophylaxis for days following injury. eligible patients were divided to two arms: patients with phenytoin levels (n= ) and patients without levels (n= ). the primary outcome measure was the incidence of seizures in those that were monitored for free phenytoin levels and those that were not monitored for free phenytoin levels. the secondary outcome measure was the appropriateness of phenytoin dosing in regards to initial loading and maintenance dose. a total of seizures occurred in the entire study population. both seizures transpired in patients with phenytoin levels. patient was diagnosed with a seizure event on day , with free phenytoin obtained on day at a therapeutic level of . mg/l. patient had a witnessed seizure on day , with free phenytoin level obtained on day also within therapeutic range at . mg/l. there was no incidence of seizure in patients who were not monitored for phenytoin levels. inconsistent phenytoin loading and maintenance doses were identified. this study suggests that monitoring phenytoin to therapeutic levels for seizure prophylaxis did not demonstrate a decrease in the occurrence of seizures. we are unable to make recommendations given the inherent limitations of our study. a large prospective, randomized trial is needed to clarify the need for monitoring phenytoin to therapeutic levels. seizure prophylaxis for nontraumatic intracerebral hemorrhage (ich) and aneurysmal subarachnoid hemorrhage (sah) is common practice in the intensive care unit(icu). typical antiepileptics include phenytoin (ptn) and levetiracetam (lvt). previou studies have suggested worse long term outcomes with icu ptn use, but such data is lacking for lvt. in addtion, few studies have compared lvt to ptn for seizure prophylaxis in ich or sah patient in the icu setting. we hypothesize that seizure prophylaxis with lvt, as compared to ptn, for patients admitted with ich and sah will result in similar outcomes at hospital discharge as measured by the modified rankin scale (mrs). this study is a single center retrospective review from - , to ultimately include approximately adult patients with the diagnosis of sah or ich who received seizure prophylaxis with either lvt or ptn. basic demographic, past medical history, severity of illness scales; length of mechanical, icu and hosital length of stay; seizure occurrence, use of continuous electroencephalogram, data will be collected, in addition to other variables. patients with prior seizure history or seizure on presentation, do-not-resuscitate hours within hours of icu admission, will be excluded. to date, our analysis includes patients (lvt = and ptn = ). comparing ptn to ltr, univariate analysis of demographics, baseline clinical characteristics and outcomes were similar between the two groups (all p> . ). in our initial univariate analysis, functional outcome at discharge was similar between ptn and lvt when used for seizure prophylaxis in patients admitted with ich or sah. subsequent analysis will include additional patients (approximately ) with multivariate adjustment. cerebral microbleeds (cmbs) are commonly found in patients with microvascular pathology such as primary intracerebral hemorrhage, cerebral amyloid angiopathy, and ischemic stroke. however, to our knowledge, there have been no reports of cmbs or their acute appearance in patients with status epilepticus (se). here we describe two patients admitted to our neuro-intensive care unit with generalized tonic-clonic seizures. laboratory tests were unremarkable except for mild pleoc onset and did not showed abnormal findings. seizures continued despite multiple anti-epileptic drugs including phenytoin, valproic acid, topiramate, clonazepam, pregabalin, lacosamide, phenobarbital, levetiracetam, and continuous infusion of propofol, ketamine and midazolam (up to . mg/kg/hr in the first patient and . mg/kg/hr in the second patient). followup . -tesla susceptibility-weighted imaging revealed new cmbs ( lobar [ frontal, parietal, temporal, occipital, and insular], deep [ corpus callosum and deep/periventricular white matter], and infratentorial [ brainstem and cerebellum]) in the first patient (performed days after initial imaging) and new cmbs ( lobar [ frontal, parietal, temporal, and occipital], and deep [ corpus callosum and deep/periventricular white matter]) in the second patient (performed days after initial imaging). multimodal neuromonitoring was available between initial and follow-up imaging in the second patient and suggested metabolic distress (lactate-pyruvate ratio > ), cerebrovascular dysautoregulation (pressure reactivity index > . ), brain tissue hypoxia (brain tissue oxygen partial pressure < mmhg), and fluctuations of blood pressure (variance, mmhg) and cerebral perfusion pressure (variance, mmhg). cmbs may develop acutely in patients with refractory se, which may point towards microvascular disturbances in refractory seizures. further prospective studies are necessary to explore the pathophysiology and clinical implications of new cmbs in se. synthetic cannabanoids, often sold as "spice" and various other labels, are a popular product sold in incense shops and through the internet. when inhaled, consumers often report experiences similar to marijuana use, and have thus become a popular street substitute for marijuana. unfortunately, with increasing use, there has been an increase in the number of patients presenting to emergency departments due to toxic effects of these products. we describe a year old gentleman with history of bipolar disorder but no history of neurological disease who presented to the emergency department with altered mental status and tachycardia who subsequently had a witnessed tonic-clonic seizure. patient received appropriate workup for his potential toxicity. we also performed a literature search on "spice" incense found in his backpack on presentation. patient had admitted to smoking "spice" incense on questioning. patient's negative drug screen, negative workup, as well as symptomatic improvement on phenytoin supported the source of his seizure as the toxic effect of inhaled "spice". we also on literature review discovered several other cases similar to this patient's case. "spice" or synthetic cannabanoid-induced toxicity is an emerging etiology of new-onset seizure and does not appear on conventional drug screens. critical care professionals should be aware of this product to recognize and appropriately treat this toxicity. refractory status epilepticus (rse) is associated with high morbidity and mortality. etiological heterogeneity and refractoriness to treatment remain a challenge for the treating intensivist. here we present a patient with rse and folic acid (fa) deficiency. brain metabolism was hourly analyzed using cerebral microdialysis (cma -analyzer; cma -catheter). fa concentrations of brain extracellular microdialysate (famd-ec) and serum (faserum) were analyzed using elecsysfolateiii® -assay. in vitro recoveryof fa was calculated using cerebrospinal fluid (csf). a -year-old male was referred to our neurocritical care unit with se refractory to levetiracetam ( g/d) valproic-acid ( . g/d) and , mg/kg bw/h midazolam continuous infusion. the patient had a history of short bowel syndrome (sbs) after small intestine resection five months prior. admission electroencephalography showed continuous rhythmic epileptiform activity over the right hemisphere despite adding ketamine continuous infusion ( , mg/kg bw/h) and lacosamide ( mg/d). neuroimaging demonstrated diffusion-weighted-imaging (dwi)-hyperintensities over the right hemisphere. csf was normal, common causes of rse were unlikely after extensive laboratory and csf studies. fa serum was found to be lower ( . μg/l; . - . μg/l) at day two of rse. after thiopental anesthesia ( hours) and parenteral fa substitution ( mg/d), the patient was successfully weaned without electrographic or clinical seizures. repeated imaging of the brain at day showed improvement of dwi-hyperintensities. glutamate levels in md ec decreased overtime. the patient could be extubated and fully recovered to the functional level before rse. fa serum increased by % to . μg/l, post hoc analysis of fa md-ec revealed an increase by % (from . μg/l to . μg/l). in vitro recovery of fa was %, therefore calculated fa brain / fa serum ratio was initially , which is comparable to previous animal studies. brain extracellular folic acid can be measured using cerebral microdialysis. although causality cannot be proven, fadeficiency may have influenced the course of rse in our patient. the management of inter-ictal eeg patterns such as sirpids (stimulus-induced rhythmic, periodic or ictal discharges) in comatose intensive care unit (icu) patients remains poorly understood whether these are secondarily injurious to brain or simply a of marker of underlying brain injury. we describe cases of brain-injured patients with sirpids with ictal spect imaging and in regards to aggressive neuroicu management and patient outcomes. case series, n= . case # -a -year old female suffered a cardiac arrest and remained comatose after days. continuous icu eeg demonstrated nonconvulsive seizures (ncsz) and status (ncse) with up to hz maximal bilateral centroparietal head spike and wave by day # which was refractory to initial iv levetiracetam, iv lacosamide, iv phenytoin but finally responded to iv phenobarbital load ( mg/kg) and propofol infusion. sirpids were noted despite these medications with any form of tactile or auditory stimulation. we performed ictal (stimulation provoked sirpids) and interictal technetium- -spect which was negative for hyperintense focus. case # -a year old female was admitted comatose for subarachnoid hemorrhage secondary to aneurysm rupture. she received a left-sided hemicraniectomy with operative clipping of the aneurysm and drainage of a small left subdural hematoma. on postoperative day (pod) # , ceeg showed left frontotemporal sharp waves. she was placed on leviteracetam, lacosamide, benzodiazepine, propofol infusion, and phenytion. by pod # , ceeg revealed left frontal sharply countoured discharges when the patient was stimulated by nail bed pressure on examination, consistent with sirpids. by pod # an ictal spect scan showed broad areas of hypoperfusion in the left hemisphere due to infarcts but there were no findings suggestive of a seizure focus scintigraphically. spect-scan negative sirpids may be helpful in terms of deescalating aggressive brain-metabolic suppressive therapies such as propofol and barbiturates, but larger, outcome-based studies are needed. thromboelastography (teg) is point-of-care test that allows for rapid global assessment of coagulation. teg analyzes whole blood, not plasma, which better accounts for the effects of cellular components on hemostasis. we sought to determine whether there is evidence of hypercoagulability by teg and whether it correlates with discharge outcome after aneurysmal subarachnoid hemorrhage. ten patients with moderate-to-severe sah were prospectively enrolled in an irb-approved observational study of serial thromboelastography. teg analysis, using kaolin activated citrated samples, was performed on post-bleed days , , , and . thrombus velocity curves, including the maximal rate of thrombin generation (mrtg), time to maximal rate of thrombin generation (tmrtg), and total thrombin generation (ttg), were plotted for each patient. a hypercoagulable state was defined a priori as a g value of > dynes/cm or a maximum amplitude (ma) of greater than mm. secondary outcome measures included discharge disposition. mean age of patients was . +/- . years. / patients were women and / were discharged home. the mean g parameter was within the normal range ( . dynes/cm ) on day , demonstrated a hypercoagulable profile on day ( . dynes/cm ), peaked on day ( . dynes/cm ), remained hypercoagulable on days ( . dynes/cm ) and day ( . ). the day g value was significantly different from the day value (p= . thromboelastography may identify a transient hypercoagulable state that peaks around post-bleed day in patients with sah. this state reflects accelerated thrombin generation and correlates with discharge disposition. defining a hypercoagulable state in patients with sah may lead to better risk stratification and novel therapeutic interventions. financial support: this study is supported in kind by haemonetics. they supply teg machines, kits and reagents. they have neither participated in study design nor are they aware of these preliminary results. intravenous sedation has been associated with impaired cognitive recovery following critical illness but its influence on recovery following asah remains unknown. data from consecutive patients with asah admitted to columbia-presbyterian hospital and enrolled into the shop database between / - / were analyzed after exclusion of deaths and unemployment prior to hemorrhage. employment status at year was obtained through self report or through patient surrogate and trichotomized (same level, decreased level, unemployed). proportional odds models were used to test the association between the use of continuous intravenous sedation with employment and cognitive function at year after controlling for baseline demographics (age, race, occupational level, admission hunt hess grade) and hospital complications (pneumonia, infarction from vasospasm). proportional hazards model was used to examine the association of sedation with time to return to work. patients who had the primary outcome data of employment status at year were analyzed. in multivariate analysis, exposure to continuous intravenous sedation was significantly associated with worse employment status at one year (or= . , ci= . - . , p= . ). poor judgment (or= . , ci= . ,- . , p= . ) and apathy (or= . , ci= . - . , p< . ) at one year were significantly associated with worse employment status but not with sedation exposure. with multivariate proportional hazards model, sedation was a significant risk factor of unemployment (hr= . , ci= . - . , p= . ). among those who returned to work within year, patients who received intravenous sedation returned to work significantly later than those who did not (median vs. days, p= . ). patients who received continuous intravenous sedation following asah had worse one year employment status and returned to work later. although poor judgment and apathy was associated with worse employment status, they were not associated with sedation exposure. future studies should investigate the effects of intravenous sedation exposure on cognitive and functional recovery following brain injury. despite an improvement in mortality, many survivors of asah still have significant disability and impairment in quality of life. we investigated predictors of unemployment at year among survivors of asah. data from consecutive patients with asah admitted to columbia-presbyterian hospital enrolled into the shop database between / - / were analyzed after exclusion of deaths and unemployment prior to hemorrhage. employment status at year was obtained through self-report or through patient surrogate and trichotomized (same level, decreased level, unemployed).pre-morbid occupational level was trichotomized (full time, part time, housewife). proportional odds models were used to test the association between baseline demographics, pre-morbid and discharge functional status with employment status at one year. proportional hazards model was used to test the association of these factors with time to return to work. a total of patients had the primary outcome data of employment status at year. patients ( %) remained unemployed, patients ( %) worked at a decreased level, while patients ( %) were employed at the same level. after controlling for age, modified fisher scale, and discharge functional status, ethnicity (p= . ) and pre-morbid occupational level (p< . ) were significantly related to employment status. hispanics (or= . , ci= . - . ) were less likely to be employed than other minority groups with caucasian as the reference group. caucasians working full time pre-morbidly provided the greatest odds for employment (or= . , ci= . - . ) over part time employees (or= . , ci= - . ) and housewives (reference) among those who returned to work at year follow-up, patients who were employed at the same level returned to work sooner that those employed at a decreased level (median: vs. days, p= . ). unemployment among survivors of asah remains problematic, especially among certain underrepresented minorities. future studies should investigate modifiable factors which impede successful reintegration to the work force. cerebral vasospasm after aneurysmal subarachnoid hemorrhage (sah) remains a major cause of death and disability. delayed cerebral ischemia (dci) after sah is likely multi-factorial, but eventually leads to altered cerebral blood flow (cbf) and cerebral infarction. neurointerventional treatment is used for medically refractory vasospasm, but with limited data on efficacy and impact on cbf and clinical/dci outcomes. patients with sah scheduled for neurointerventional treatment of refractory vasosasm were consented for intraprocedural cbf monitoring. we measured regional cbf using two sodium iodide scintillation scalp detectors approximating the cortical vascular territory of the treated vessel. a . ml saline bolus of - mci of -xe is injected through the coaxial catheter immediately before and after endovascular treatment. tracer washout is recorded under stable physiologic conditions for . minutes. cbf is calculated using the initial slope index, the monoexponential slope of tracer washout from - seconds after isotope injection. data were analyzed including standard corrections for remaining activity and physiologic parameters (cortexplorer cbf a, ceretronix, denmark). mean arterial blood pressure, paco , serum hemoglobin, and delivery of anesthetic agents were monitored. we calculated change in cbf expressed as a mean + standard deviation using repeated measures anova before and after endovascular treatment. a total of sah patients with refractory vasospasm were enrolled in the study. moderate to severe angiographic spasm was reported in % of subjects. treatment included ia verapamil in ( %), angioplasty only in ( %), and both in ( %). mean change in cbf was + ml/ gm/min, an average of % change in regional cbf. in our prospective study of patients with endovascular treatment for refractory vasospasm, we detected a mean change of % in quantitative cbf using the intra-arterial -xe washout method. without significant radiographic evidence of large vessel change at the time of measurement, increases in cbf may be related to the microcirculatory effects of treatment. early detection of cerebral vasospasm (vs), a common complication of subarachnoid hemorrhage (sah) enables prompt initiation of treatment. screening and detection of vs is done by repeated neurological examinations and transcranial doppler (tcd) monitoring, while angiograms are used for definitive diagnosis. this study aims to test the ability of a novel nirs based cerebral-oximetry method to detect vs in the post sah period. -hess score of - were enrolled. patients underwent neurological examinations, tcds and had - minute nirs monitoring sessions daily. whenever vs was suspected, angiography was performed. clinical event was defined as the combined endpoint of angiographically proven vasospasm, flow velocity > m/s over mca or aca territories, or neurologic deficit manifested rformed using the cerox , utilizing ultrasound tagged light (utl). pathologic cerebral oximetry was defined as having cerebral saturation below % for more than % of recording time and aut > second%. patients were analyzed, of whom had angiographic vasospasm. these were correctly detected by both nirs and tcd. of combined events over the aca territory, nirs detected / events. nirs also detected desaturations in / remaining cases, when no clinical or imaging event was detected. of combined events over mca territory, had an increase in desaturation auc, and / cases with no event had increase in desaturation events. both cases of angiography proven vasospasm were detected by nirs as an increase in desaturation auc, and by tcd as increase in flow velocities. cerebral oximetry using utl based nirs is comparable to tcd in detecting cerebral vasospasm, and may be superior in early detection of clinical neurologic worsening. extracellular fluid volume (ecfv), the main determinant of total circulating blood volume, is determined by the mass balances of na+ plus k+ (mbnk). in patients with aneurysmal subarachnoid hemorrhage (asah), diminished ecfv and reduced circulating blood volume are risk factors for worsened neurologic outcomes. maintenance of a normal ecfv based on nurse entered fluid balance (fb) has been reported to be difficult. the purpose of this study was to describe the time course of fluid and electrolyte mass balances over days in a cohort of patients receiving hypervolemic or normovolemic therapy. data from a randomized trial were secondarily analyzed. the intensive management of pressure or volume expansion in subarachnoid hemorrhage trial randomized patients to receive either a normovolemic or hypervolemic fluid management protocol. the standardized fluid management protocol included maintenance iv fluids with rate adjustments or boluses based on -hourly fluid balance and cvp (when available) with a target net positive fluid balance of - l in the hypervolemia group, and < . l in the normovolemia group. mbnk was calculated using published formulae. fb and estimated mbnk were compared between groups using random-effects generalized least square regression. baseline characteristics were similar between groups. fb was higher in the hypervolemia group than in the normovolemia group (mean difference: ml/day, %ci: - , p= . ). mbnk was also higher in the hypervolemia group (mean difference: meq/day, %ci: - , p= . ). average daily fb did not reach the target in the hypervolemia group. mbnk was negative on / days in the hypervolemia group, and / days in the normovolemia group. hypervolemic therapy resulted in higher net fb and mbnk compared to normovolemic controls, but was relatively ineffective at generating a consistently positive fb or expanded ecfv. our results support the notion that hypervolemia is difficult, if not impossible, to maintain in asah patients. exposure to hyperoxia is commonly seen but it is largely unknown whether hyperoxia is beneficial or harmful in patients with subarachnoid hemorrhage (sah). we hypothesized that hyperoxia may be associated with increase in the risk of delayed cerebral ischemia (dci) and poor -month outcome after sah. we analyzed data from single center, prospective, observational cohort database between and . patient nical ventilation, and ) arterial partial pressure of oxygen (pao ) measurements. patients expired within two weeks were excluded. hyperoxia was defined as the highest quartile of an average area under the curve of pao until the development of dci (pao mmhg) or until the post-bleed day (pao three months. of patients, no baseline characteristics were clinically contributing to hyperoxia. ninety-seven ( . %) patients developed dci. outcome data were available in patients, and poor outcomes were observed in ( . %) patients. the hyperoxia group had significantly higher incidence of dci (p = . ) and poor outcome (p = . ). after adjusting for modified fisher scale, hyperoxia was independently associated with dci (adjusted or, . ; % ci, . - . ; p < . ). after adjusting for age, smoking, alcohol consumption, previous stroke, previous heart disease, hunt-hess scale, aneurysm size, acute physiology and chronic health evaluation ii score, serum glucose, hyperoxia was found to be independently associated with poor outcome measured at months (adjusted or, . ; % ci, . - . ; p = . ). our data suggest that exposure to hyperoxia after sah is associated with dci and poor -month outcome. exact mechanism and the clinical implications can be explored by further investigations. advances in management of aneurysmal sah (asah) including refinement of neurosurgical techniques, availability of endovascular options and evolution of neurocritical care have led to improved outcomes following aneurysmal sah. we evaluated outcomes in asah patients admitted to our institution(s) over the past decades. prospectively collected data of aneurysmal sah patients admitted to the johns hopkins medical institutions between - was reviewed. we compared surivavl to discharge and functional outcomes at first clinic appointment post discharge ( - days) in patients admitted between - (phase =p ) and - (phase =p ) respectively using dichotomized gos (good outcome: gos - ). consecutive asah patients were included in the analysis (p . %; p . %). there were higher rates of poor grade hunt & hess (p %, p %; p< . ), admission gcs < (p : %, p %, p< . ), known medical comorbidites (p %, p %; p= . ), associated intraventricular hemorrhage (p %, p %, p< . ) and an older population in phase (p : . , p . ; p < . ) admissions. overall in-hospital mortality was low ( . %) and there was no significant difference between the periods in survival to discharge (p> . ). good outcomes were more common in phase ( . %) compared to phase ( . %); this difference was statistically significant after correction for other confounding factors following multivariate analysis (p< . ) with -fold greater adjusted odds of good outcomes in phase . our institutional experience over decades confirms that patients with asah have shown significant outcome improvements over time. hyponatremia in hospitalized patients has been associated with increased mortality, while chronic mild hyponatremia may impair attention and gait. hyponatremia after aneurysmal subarachnoid hemorrhage (sah) is common, yet its effect on cognitive outcome remains unclear. we aim to demonstrate the domain-specific cognitive effect of hyponatremia on patients after sah. we retrospectively analysed data from consecutive patients enrolled in our columbia university sah outcomes project between april and november . subjects were excluded if withdrawal of care of death occurred in the first three days. hyponatremia was defined as a sodium level < meq/l at any time during hospitalization. univariate and multivariate analyses were performed by a poisson regression, and a preset alpha of < . was set for statistical significance. a total of were included in the study. hyponatremia developed in subjects ( %). their mean age was years (sd+/- ), and subjects were men ( %). median time to onset and nadir of hyponatremia were (iqr - ) and days . univariate analysis associated hyponatremia with worsened modified rankin scale at discharge (rr= . , ci . - . ), three-month telephone interview of cognitive status (tics) (rr= . , ci . - . ), three-month barthel index (rr= . , ci . - . ), and three-month lawton instrumental activities of daily living (rr= . , ci . - . ). after adjustment for age, gender, hunt and hess grade, rebleeding, delayed neurologic ischemic deficit, and generalized cerebral edema, hyponatremia was associated with worsened three-month tics (rr= . , ci . - . ). by one year, hyponatremia was not associated with either functional or cognitive impairment. hyponatremia-related injury after sah appears to be associated with cognitive rather than functional impairment at three months. early and aggressive reversal of hyponatremia may expedite cognitive recovery among survivors of sah. financial support: dr ortega is supported by the spotrias fellowship funded by the national institute of neurological disorders and stroke (ninds)-p ns .dr mayer consults for actelion pharmaceuticals.there are no studies have shown that decreased quality-of-life (qol) after sah is a significant problem. the factors that predict poor qol after sah remain unclear. we sought to identify predictors of a poor quality of life months after sah. we prospectively studied -month qol in a cohort of patients consecutively admitted with sah between july and may . admission clinical scores, radiographic, surgical, and acute clinical course was documented during hospitalization. twelve months after sah qol was assessed using the sickness impact profile (sip). reduced qol was defined as two standard deviations below population-based normative values on the sip. univariate statistics were used to identify candidate predictors of poor qol, and to identify significant concurrent symptoms. backwards stepwise logistic regression was used to generate multivariable models of reduced qol. at months, % of survivors who participated in the follow-up survey ( / ) reported reduced qol. univariate admission factors associated with reduced qol were non-white race/ethnicity, high school education or less, poor clinical grade, loss of consciousness, hydrocephalus, pneumonia, and cerebral infarct from any cause. multivariable analysis revealed that poor hunt-hess grade (or . ; ci % . - . ), non-white race/ethnicity (or . ; ci % . - . ), and years or less of education (or . ; ci % . - . ) were significant admission risk factors for poor qol. common significant co-morbidities associated with poor qol at months included greater unemployment, not currently driving, more financial difficulties, current symptoms (e.g., headaches), marital difficulties, fear of recurrent sah, and dissatisfaction with rehabilitation. poor qol affects as many as one-third of sah survivors, and is predicted by poor admission clinical grade, non-white race/ethnicity, and lower educational status. further research is needed to determine if improved access to support and rehabilitation services for high-risk patients groups can improve qol after sah. biochemical mediators alter cerebral perfusion potentially resulting in neurological decline and delayed cerebral ischemia (dci); a significant cause of morbidity and mortality following aneurysmal subarachnoid hemorrhage (asah). estrogens (estrone-e and estradiol-e ) are mediators that have demonstrated neuroprotective properties that could play a role in dci however few studies have evaluated the impact of estrogens on outcomes in humans following asah. this study sought to examine the association between cerebrospinal fluid (csf) e and e levels and dci following asah. csf samples were collected after hemorrhage on adult asah patients [ -males, -pre and -post-menopausal females) admitted to the nv-icu enrolled in a nih study (ro nr ). up to csf samples per patient were selected for analysis representing days - after hemorrhage. samples were analyzed for e and e using liquid chromatography-tandem mass spectrometry. dci was operationalized as radiographic/ultrasonic evidence of impaired cerebral blood flow accompanied by neurological deterioration. statistical analysis using sas(v . ) included group based trajectory and multiple logistic regression. e was detected in more csf samples than e ( % vs %). group based trajectory identified distinct populations over time for both e ( % e high) and e ( % e high) values using censored normal model. non-weighted chisquare analysis identified differences between e trajectory groups by hh (p=. ) and dci (p=. ). using log metabolite levels, higher csf e measurements were associated with higher hh (p=. ) and fisher (p=. ) scores. csf e levels were not associated with dci (p=. ). there were no differences between csf e and severity of injury or dci.there was a significant relationship between csf e and e concentrations (p<. ). these findings provide evidence that estrogen metabolites are measureable in csf and may be associated with severity of injury. future studies are warranted to further explore these findings and their association to outcomes. high-grade spontaneous subarachnoid hemorrhage (sah) patients are monitored in the icu for up to days, as they are at risk for complications. the diagnosis of treatable complications such as vasospasm of cerebral arteries, cardiac arrhythmias and neurogenic stress cardiomyopathy is often delayed by the limitations of monitoring capabilities. we hypothesized that changes in heart rate variability (hrv) would correlate with the onset of these conditions following sah. we applied computational methodology to a cohort of sah patients in a single neurointensive care unit, examining hrv profiles to identify biomarkers of vasopasm, cardiomyopathy and impending respiratory failure. hrv was quantified for individual min epochs of the electrocardiogram waveform ( hz). qrs complexes were identified and the interbeat (rr) interval time series was constructed. mean, standard deviation and coefficient of variation of rr intervals, as well as the ratio of low frequency to high frequency power spectral density and standard poincare statistics were quantified. vasospasm occurred in ( %), stress cardiomyopathy in ( %) and respiratory failure in ( %) of patients. in a sah patient with takotsubo's cardiomyopathy and respiratory failure, we found a decrease in hrv that predated the discovery of cardiomyopathy as well as the onset of respiratory distress by several hours. the early clinical detection of vasospasm, cardiomyopathy and impending respiratory failure from on-line ekg hrv analysis would be of tremendous clinical value. in the face of changing autonomic influences in the critically ill postaneurysmal subarachnoid hemorrhage patient, the finding of an early signal prior to clinical detection of respiratory failure is encouraging. a larger and more highly annotated dataset may be required to increase the signal to noise ratio to realize the clinical potential of hrv-based biomarkers. retrospective analyses have found an association between transfusion and vasospasm, medical complications and mortality in subarachnoid hemorrhage (sah) patients. yet, none of those studies assessed the timing of transfusion, whether it occurred before, or, after vasospasm or complications. we sought to clarify whether transfusion could be considered a cause or consequence of vasospasm and complications. this interim analysis indicates that transfusion is not associated with vasospasm or infection when timing of transfusion is considered; fluid overload was more common after transfusion. the most dismal sequelae of aneurysmal subarachnoid hemorrhage (asah) are the development of cerebral vasospasm and consecutive delayed infarctions. their severity is linked to the clinical grade of the initial hemorrhage and the amount of blood in the basal cisterns. together, they represent the major cause of unfavorable clinical outcome and death in asah patients. from retrospective data, a promising method to reduce the incidence of vasospasm is the use of a lumbar drain to remove the blood from the subarachnoid space. the recently completed lumas trial addressed the safety of this approach in good-grade asah patients ( ). however, so far prospective data from subjects being at high risk for vasospasm and delayed infarction is lacking. we present the protocol of the earlydrain study, a prospective randomized multicenter trial comparing an intervention group with early continuous lumbar csf drainage to a control group receiving standard neurointensive care only ( ). eligible for participation are adults suffering from asah of all clinical grades who receive aneurysm treatment within hours of ictus. primary endpoint is the modified rankin score at six months. secondary endpoints include mortality, angiographic vasospasm, cerebral infarction, transcranial doppler sonography (tcd) mean flow velocity and rate of shunt insertion at six months after hospital discharge. the earlydrain study had recently been launched and, at abstract submission, patients of planned were enrolled. interim safety analysis did not reveal any concern on the use of lumbar drains after aneurysmal sah. up to now, ten centers in germany, switzerland and canada are participating. interested centers willing to join and contribute are still much appreciated. patients with aneurysmal subarachnoid hemorrhage (asah) require management in centers with neurosurgical expertise necessitating emergent interhospital transfer (iht). our objective was to compare outcomes in asah ihts to our institution with asah admissions from our institutional emergency department (ed). data for consecutive patients with asah admitted to johns hopkins medical institutions between and were analyzed from a prospectively obtained database. we compared in-hospital mortality and functional outcomes at first clinical appointment post-asah ( - days) using dichotomized glasgow outcome scale (good outcome: glasgow outcome scale - ) in ed admissions with ihts. a total of consecutive patients with asah were included in analysis (ed . %, iht . %). direct ed admissions had a higher incidence of poor hunt and hess grade ( / ) and major medical comorbidities, with no significant differences between the groups in age, intraventricular hemorrhage, and hydrocephalus. in-hospital mortality for ed admissions ( . %) was significantly lower than that for ihts ( . %), with . times greater adjusted odds of survival after multivariate analysis (p = . ). emergency department admissions had nearly -fold greater odds of good outcomes (odds ratio, . ; p b . ) after multivariate analysis. our institutional ed sah admissions had significantly better outcomes than did ihts, suggesting that delays in optimizing care before transfer could deleteriously impact outcomes. left ventricular (lv) systolic abnormalities occur commonly after subarachnoid hemorrhage (sah). cardiomyopathy associated with sah can include either predominate apical lv systolic dysfunction (cm-apical) or predominate basal lv systolic dysfunction (cm-basal). we aimed to determine if outcomes and diastolic function were different between patients with various forms of lv dysfunction after sah. patients hospitalized for sah between and were eligible for our study. those patients with a history of heart failure, myocardial infarction, or a documented acute coronary process were excluded. echocardiograms were reviewed and a wall motion score was provided for each of lv segments. patients were classified as cm-apical if the average wall motion score for apical segments was greater than the average wall motion score for basal segments. patients were classified as cm-basal if the average wall motion score for basal segments was greater than the average wall motion score for apical segments. of patients with sah had an echocardiogram. patients had normal lv function, cm-apical and cmbasal. the in-hospital mortality was not different between those with no echocardiogram or those with an echocardiogram who had normal lv function, cm-apical or cm-basal. patients with cm-apical were more likely to have shock and pulmonary complications, whereas patients with cm-basal were more likely to have sepsis. during a median follow up of . years, patients with cm-apical had the worse survival. patients with cm-apical and cm-basal had impaired lv relaxation as compared to those with normal lv systolic function. in-hospital mortality is not different between those patients with normal lv systolic function, cm-apical, or cm-basal. cmapical is associated with shock and pulmonary complications and a worse long term survival. further work evaluating the response to medical intervention and the differences in hemodynamic profiles of patients with cm-apical and cm-basal is warranted. therapy using sodium nitroprusside (snp) intrathecal (intraventricular) aims for a more effective approach for prophylaxis and treatment of cerebral vasospasm associated to a subarachnoid hemorrhage (sah). qualitative study whose objective was to analyze clinical cases to specific approach for cerebral vasospasm related to sah. two patients, the first one is a years old female with aneurysm rupture of the left posterior communicating artery, sah fisher iii, hunt hess . the second one is years old male with artery rupture of the middle cerebral artery, sah fisher iii, hunt hess , both were submitted to embolization, leading to acute hydrocephalus, in which external ventricular drainage (evd) was established. through the evd, a prophylactic intrathecal protocol was instituted ( ml snp with , ml of normal saline , % solution applying ml nps through the evd each hours for hour by infusion pump). patients evolved well with no neurologic or motor sequel and with a modified rankin scale = . the third patient was a years old male with aneurysm rupture in anterior communicating artery, sah fisher iii, hunt hess , severe vasospasm per operative in the left middle cerebral artery (mca), treated by angioplasty with balloon. starting the treatment protocol of cerebral vasospasm by lombar catheter: dosage mg ( ml) snp, solution with ml snp at ml of normal saline , % applying ml through the lombar catheter each hours for hour by infusion pump. patient without complication with modified rankin scale = . the cost for prophylactic therapy for days was u$ , ; if the patient had developed clinical vasospasm, the cost for a day treatment would be an average of u$ . , , having a great impact on morbidity, mortality and cost of hospital stay. angiography does not reveal a source of bleeding in - % of those with subarachnoid hemorrhage. these patients usually have a benign course and favorable outcome, especially those with a perimesencephalic pattern of bleeding (pm-sah); more diffuse bleeding has been associated with higher risk of vasospasm and neurological disability. we evaluated whether amount or pattern of bleeding better predicts risk of neurological complications and outcome. methods angio-negative sah patients were prospectively studied over seven years. six were excluded when a vascular etiology was identified on repeat angiography. pattern of bleeding, amount of cisternal (hijdra score) and ventricular blood (ivh score), and ventriculomegaly (bicaudate index) were assessed. neurological outcomes included hydrocephalus, angiographic vasospasm, and delayed ischemic neurological deficits (dind, based on clinical deterioration). functional outcome was assessed at -year using the modified rankin scale (mrs). bleeding was perimesencephalic in ( %), diffuse in ( %), cortical in and ct-negative in . patients with diffuse bleeding had higher hijdra ( [iqr - ] vs. [ - ]) and ivh scores ( [ - ] vs. [ - ]), and bicaudate index ( . [ . - . ] vs. . [ . - . ]) than those with pm--v ( % vs. %, p= . ) and require ventriculostomy ( % vs. %) and shunt placement ( % vs. %, both p= . ). moderate-severe angiographic vasospasm developed in % diffuse vs. % pm-sah (p= . ), while dind only occurred in those diffuse bleeding ( %). neither hijdra nor ivh score was higher in those developing vasospasm, across or within bleeding patterns. those with diffuse sah were less likely to be discharged home ( % vs. %, p= . ) or achieve minimal disability (mrs - , % vs. %, p= . ). angio-negative sah can result in hydrocephalus, vasospasm, cerebral ischemia, and residual disability. this is more likely in those with diffuse bleeding, a disparity not explained by a greater volume of cisternal or intraventricular bleeding. independent of the cholesterol lowering effects of hydroxymethylglutaryl conenzyme a reductase inhibitors(statins), there has been much debate about their protective effect against delayed cerebral ischemia (dci). various ongoing trials are aimed at assessing their effectiveness against dci after primary subarachnoid hemorrhage (sah). there is scanty literature on dci in patients who were on statins prior to the occurrence of sah. a retrospective chart review was done after approval from the institutional review board. data was collected from july to april using the icd code for sah. patients with sah secondary to avm, trauma and surgery were excluded. demographics, baseline characteristics and occurrence of clinical dci were collected. admission home medication list was used to identify patients on statins prior to admission. all statistical analysis was done using sas. a total of patients with primary sah were included. out of patients, ( . %) were on home statin. only ( %) patients within this group developed dci while ( . %) patients in the statin naive group developed dci (p= . ). this difference persisted even after correcting for age (p= . ), sex (p= . ), race (p= . ), smoking (p= . ), history of diabetes (p= . ), stroke/tia (p= . ), peripheral vascular disease (p= . ), hypertension (p= . ), hyperlipidemia (p= . ), home calcium channel blocker use (p= . ) and fisher grade (p= . ). a multivariate logistic regression analysis with backward selection further confirmed that the only significant factor affecting vasospasm was prior statin use (p = . ). the above findings suggest that prior statin use reduces the rate of dci after sah. though the known confounders were taken into consideration, the possibility of unknown confounders cannot be completely excluded. a larger prospective study may be required to verify these effects. the potential clinical implication of this would be to put patients with unruptured and untreated aneurysms on long-term statins. patients sometimes report that surviving a near-death experience results in enhanced appreciation of the preciousness and joy of life. we sought to determine how frequent the "stroke of insight" phenomenon occurs after sah. we prospectively enrolled sah patients between and and followed up survivors with a telephone interview at and months. patients were asked "do you enjoy life more, about the same, or less than you did before your brain hemorrhage?" surrogate responses were not analyzed. global functional outcome was evaluated with the modified rankin scale (mrs) and qol with the sickness impact profile (sip). of survivors who responded to the survey, the majority ( %, n= ) reported that they enjoyed life more since the hemorrhage, whereas only % enjoyed life less. enhanced life enjoyment was associated with female gender and white (versus non--hess grade. patients with enhanced life enjoyment were more likely to report improved marital status ( % versus %, p< . ), and were less likely to have rumination on their illness (p< . ). improved life enjoyment was associated with better sip qol scores ( . ± . versus . ± . , p< . ), but had no relationship with concurrent disability on the mrs (p= . ). remarkably, % of those reporting that they enjoyed life more were unable to walk without assistance (mrs or ). the majority of sah survivors enjoy life more after their hemorrhage. increased life enjoyment has no relationship with physical disability and handicap, but is associated with improved qol. informing patients of the "stroke of insight" phenomenon may be a simple and effective way to set positive expectations and promote recovery after sah and similar life-threatening illnesses. parenteral diclofenac infusion is commonly used in neurocritical patients and has been shown to effectively decrease body temperature after aneurysmal subarachnoid haemorrhage (asah). hemodynamic side effects and in specific the effect on brain homeostasis are understudied. twenty-one asah patients with multimodal neuromonitoring of intracranial pressure (icp), brain tissue oxygen tension (p b to ), and cerebral metabolism (microdialysis, md) receiving parenteral diclofenac infusions were analyzed in a prospective observational cohort study. mg diclofenac diluted in cc normal saline was administered at the discretion of the attending neurointensivist. we analyzed core body (cbt) and brain temperature (bt) over hours and hemodynamic (cardio-, cerebrovascular) and cerebral metabolic parameters over hours after intervention. ten-minuteaverage files of cardio-and cerebrovascular parameters and hourly files of md datasets were analyzedusing a generalized estimating equation.a pre-intervention baseline was calculated for every parameter. one-hundred-twenty-three parenteral diclofenac infusions over min (iqr - min) were analyzed. cbt and bt decreased to a minimum of . ± . °c and . ± . °c, h and h after diclofenac infusion (baseline . °c± . °c and . ± . °c, respectively, p< . ). hemodynamic side effects included a % reduction of map (by ± mmhg) and cpp (by ± mmhg) resulting in increased use of vasopressors in % of interventions (p< . ). p b to significantly decreased from ± mmhg baseline by % (p< . ) resulting in brain tissue hypoxia (p b to < mmhg) in % of interventions and % (n= ) of patients. in none of the interventions with baseline p b to above mmhg, brain tissue hypoxia was observed. baseline-p b to below mmhg was independently associated with brain tissue hypoxia during intervention (p< . ). there was a trend towards higher brain tissue lactate-pyruvate ratio and lower pyruvate after parenteral diclofenac after sah is associated with hemodynamic side effects and may result in brain tissue hypoxia without significantly affecting brain metabolism. the impact on outcome needs further investigation. delayed cerebral ischemia (dci) is a complication of subarachnoid hemorrhage (sah) with significant mortality/morbidity. digital subtraction angiography (dsa) can detect cerebral vasospasm which is a surrogate marker for dci. there is emerging data that perfusion computed tomography (ctp) is useful in detecting dci. we have compared the utility of ctp and dsa in detecting dci. patients with primary sah admitted to two academic institutions between july and april were identified. patients with clinical dci who underwent dsa or ctp (image processing through vitrea®) were included. the area of perfusion abnormality was traced out to generate cerebral blood flow (cbf), mean transit time (mtt) and cross sectional area. abnormal cbf and mtt values were compared to normal symmetrical areas in the opposite hemisphere. dsa reports were reviewed to identify radiologic vasospasm. out of patients, had clinical dci( . %). in those with dci, / patients that underwent ctp had abnormalities ( . %) compared to / patients that had vasospasm on dsa ( . %; p= . ). median abnormal cbf was . ( . - . ) ml/ gm/sec compared to . ( . - . ) ml/ gm/sec in area of normal perfusion (p= . ). median abnormal mtt was . ( . - ) seconds compared to the normal area of ( . - ) seconds (p< . ). median interhemispheric cbf and mtt difference was . ( . - . ) ml/ gm/sec and . ( . - . ) seconds respectively. median area of abnormal perfusion was . ( . - . ) cm . seventeen patients underwent ctp and dsa. a normal ctp excluded vasospasm on dsa. perfusion abnormalities involving an area of less than . cm did not have vasospasm on dsa. ctp is a useful indicator of dci and is comparable to dsa. in patients with clinical dci and a normal ctp, dsa is unlikely to pick up vasospasm. as the area of perfusion abnormality increases (greater than . cm in our subset of patients), dsa is more likely to show vasospasm. aneurysmal subarachnoid hemorrhage (asah) is more common in women than in men. current knowledge on potential gender differences after an asah occurred is sparse, albeit of clinical relevance. retrospective cohort study including patients with asah admitted to a neurovascular center at a major academic center at the university hospital of bern, switzerland. patients below age and with non-aneurysmal sah were excluded. we included consecutive patients with asah between january , and february , . women were older than men (median age years [interquartile range [iqr] - ] versus [iqr - ], respectively, p= . ), and progressively overrepresented with increasing age ( . % of women for the whole cohort). of note, in the swiss population the proportion of both genders between and years is similar, with women being slightly overrepresented at older ages. global disease severity at admission, measured by the acute physiology and chronic health evaluation (apache) ii score, was higher in women than in men (median score points versus [iqr - ], p= . ) even after correction for age. the apache ii score independently predicted an unfavourable outcome and mortality as opposed to gender. we found no differences between genders in the adopted aneurysm-securing strategy, intensive care interventions (administered drugs, rates of endotracheal intubation, tracheostomy, length of mechanical ventilation and placement of an external ventricular drainage). women and men with asah confirmed to be similar in terms of medical history, clinical / radiological severity of asah, complications and outcome. in conclusion, this study confirms that women with asah outnumbered men, especially at higher age. global disease severity on admission is higher in women and predicts, independently from gender, unfavourable outcome and mortality. finally, this study finds new relevant similarities between genders. complications of aneurysmal subarachnoid hemorrhage (asah) may include hypertension and neurogenic myocardial stunning. subsequent management often involves beta blockade. high fisher grade asahs may also be complicated by cerebral vasospasm, which could have pathophysiologic influence from sympathetic nervous system stimulation or inhibition. we investigated any relationship of beta blockade to the incidence of radiographic vasospasm in asah by retrospectively examining adults admitted to the sicu at loma linda university medical center between / and / , excluding those who expired within days of admission because of inability to assess outcomes. three groups were isolated relevant to beta blockade: were never beta blocked (no/no), were started on a beta blocker after admission (no/yes), and were continued on their home beta blockers (yes/yes). records were analyzed for the development of vasospasm with or without resultant infarction, death, and discharge status. outcomes were evaluated using multivariate analysis through logistic regression and adjusted for potential confounders. odds ratios were calculated setting the or for no/no patients to . one hundred and forty five patients had vasospasm, consequently infarcted, and died or required care in a longterm facility. patients in the no/yes group had significantly increased radiographic vasospasm ]. however, despite increased incidence of vasospasm, these patients had significantly fewer deaths or need for long term care [or . ( . - . )], with decreased tendency for infarcts ]. in the yes/yes group, there was a trend toward increased vasospasm ] that led to infarction )], with decreased mortality or need for long term care in a facility [or . ( . - . )]. the use of beta blockers in asah is associated with increased incidence of radiographic cerebral vasospasm. however, despite the increased rate of vasospasm, the use of beta blockers was associated with improved discharge characteristics. patients with subarachnoid hemorrhage (sah) frequently undergo continuous electroencephalography (ceeg) monitoring in the icu. we describe commonly encountered eeg patterns in sah patients with clinical correlation. patients with primary sah admitted to two academic institutions between july and april were identified. records were reviewed to note the presence of intraventricular hemorrhagic extension (ivh), intracerebral hemorrhagic extension (ich), location of subarachnoid blood, occurrence of delayed cerebral ischemia (dci), patient outcomes and length of stay (los). eeg reports were reviewed and classified as to the presence of arrhythmic continuous slowing (acs), rhythmic and periodic slow activity of triphasic morphology (tw), epileptiform activity (ea), and coma pattern. patients with metabolic causes for tw were excluded. of patients, had a routine eeg or ceeg monitoring.thirteen ( . %) exhibited non-metabolic tw, ( . %) had ea, ( . %) had acs, patient had coma pattern and had normal eeg. the presence of subarachnoid blood around the basal cisterns did not influence eeg patterns.in patients with ivh, the presence of tw patterns was significantly more common than other patterns ( . % vs. . %;p= . ). ea was associated with dci ( . %) as compared to non-epileptiform patterns ( . %;p = . ).ea was more common in patients with ich without statistical significance( . % vs. . %;p= . ). median los in patients with tw, ea and acs were ( - ), . ( - ) and . ( - ) days respectively without significant difference. patient outcomes were similar among all groups. non-metabolic tw are scantly reported in the literature and typically associated with diencephalic and brainstem lesion. in patients with sah, the presence of ivh and not cisternal blood was associated with non-metabolic tw. dci was significantly associated with the generation of epileptiform activity and the presence of ich seemed to favor an epileptiform pattern. eeg patterns did not influence los or outcome in our subset of patients. adenosine is an endogenous purine nucleoside that causes transient heart block in the av node when administered parenterally. we describe our experience with cases of severe intraoperative aneurysm rupture in which adenosine was administered to allow for control of the intraoperative bleeding. over a year period, we have treated approximately aneurysms with open microsurgery. two-thirds were unruptured. severe intraoperative aneurysm rupture that could not be readily controlled occurred in cases. of the aneurysms had recently bled, case was an unruptured aneurysm. in all cases, the amount of bleeding precluded safe application of temporary clips. an intravenous infusion of adenosine ( mg) was given in all cases. in , there was significant bradycardia and hypotension culminating in a brief cardiac pause ( - seconds), allowing for rapid dissection and clipping of the aneurysm. in cases, there was bradycardia and hypotension, but no cardiac arrest. in cases, there was limited bradycardia and hypotension, and a second dose ( mg) was required to slow the heart enough to allow for aneurysm treatment. in such cases, the adenosine allowed us to clear the field adequately to apply temporary clips in a precise fashion, and then to clip the aneurysms properly. poor response to the initial dosing was not related to patient size or other identifiable factor. adenosine has been used safely in our experience to allow for management of severe intraoperative aneurysm rupture. in most cases, there is a meaningful cardiac pause. in some instances, patients are less sensitive, and the dose must be repeated to achieve the desire effect. no adverse cardiac or pulmonary events were associated with the use of adenosine in our series. intraventricular hemorrhage (ivh) is an established independent predictor of poorer outcome in subarachnoid-and intracerebral-hemorrhage. though, limited knowledge exists regarding the pathophysiologic mechanisms that may lead to cerebral injury and poorer outcome. this is the first report presenting in vivo data on cerebral perfusion and brain tissue metabolism during the occurrence of ivh and after intraventricular fibrinolysis (ivf). a -year-old woman with severe subarachnoid hemorrhage (sah), hunt&hess grade , modified fisher scale , was admitted to our neuro-critical care unit. within the first hours an extraventricular drainage was placed and a left-sided mca aneurysm was coiled. after obtaining informed consent from the legal attorney, the patient received invasive multimodal neuro-monitoring, consisting of a cerebral blood flow (cbf)-and microdialysis-probe placed into the ipsilateral frontal white matter. within hours after probe placement we observed a significant drop of cerebral blood flow (cbf below ml/ g/min) and an increase in l/p-ratio without significant changes in cerebral perfusion-or intracranial-pressure. imaging revealed a re-hemorrhage into the ventricular system with blockage of the foramina of monro and acute hydrocephalus. consequently, therapeutic ivf was undertaken with mg of rtpa which lead to sufficient clot resolution. after ivf we normalization of cerebral perfusion and metabolism. this is the first report on ivh and its potential mechanisms that may contribute to secondary injury in the human brain. a decrease of cerebral blood flow and disturbance of cerebral metabolism was documented during the occurrence of ivh, supporting existing hypotheses of global impairment. moreover, we could document profound treatment effects of ivf leading to a restored cbf and a stable aerobic metabolism in the investigated brain tissue. many patients with aneurismal subarachnoid hemorrhage (sah) present with acute, labile, hypertension and may be at risk for rebleeding. clevidipine, a novel, ultra-short acting dihydropyridine has been used in cardiac surgery, acute hypertensive emergencies and patients with intracerebral hemorrhage, but not in sah patients. the clash study (clevidipine in aneurismal subarachnoid hemorrhage) is a prospective evaluation of the efficacy and safety of clevidipine in controlling systolic blood pressure (sbp) before the aneurysm is secured. the primary endpoint is the number of patients achieving sbp target within minutes. post-hoc, sbps pre-infusion, during-infusion and postinfusion were compared using a generalized estimating equation. we present the first patients enrolled: men and women, mean h&h and fisher . , aneurysms coiled and clipped. mean sbp upper and lower goals were ± . and ± . mmhg. analyses included , sbp data points. all patients reached sbp target within . ± min using an infusion rate of . ± . mg/hour. the mean preinfusion, during-infusion and post-infusion sbps were . ± . , . ± . and . ± . mmhg (pre-infusion vs during-infusion p < . , pre-infusion vs post-infusion p < . , during-infusion vs post-infusion p < . ). after the st sbp control readings, sbp was above the upper target goal . ± . % and below the lower . ± . % of the time. icp did not increase during infusion (n= ). no patient rebled. in one patient the infusion was stopped temporarily times due to sbp below the target range. there were ( . %) sbp values < mmhg and none < mmhg. clevidipine controlled sbp in all patients with sah in < min and kept sbp within the selected range in . % of the time without any patient rebleeding. financial support: research grant from the medicines company to conduct this study. aneurysmal subarachnoid hemorrhage (asah) is associated with numerous adverse sequelae. patients who survive the initial hemorrhage are at high risk for delayed secondary brain injury, including cerebral infarction, neuronal cell death, white matter abnormalities, and hydrocephalus. resulting in focal neurological deficits, cortical dysfunction, and both longterm cognitive and psychosocial deficits referred to as sah-induced "delayed neurological deficits" (dnds). review of the literature revealed that heparin had previously been advocated to reduce complications of asah. here, we report on our favorable experience with the use of heparin prophylaxis in the management of patients who are at a high risk for developing sah-induced dnds. a retrospective chart review of patients that presented to the university of maryland medical center were reviewed between january and may . inclusion criteria were patients with fischer grade iii sah due to rupture of a true saccular aneurysm and were treated by surgical clipping within hours of the patient's ictal event. exclusion criteria were patients who had a localizing deficit related to an intracerebral hematoma from the ictal event. included in this study were patients that were started on an intravenous infusion of heparin and an additional patients that served as matched controls. none of the patients exhibited heparin-induced thrombocytopenia (hit). the heparin regimen used appeared to be safe. patients administered low-dose iv heparin experienced significantly fewer occurrences of ischemia-related ct hypodensities as well as symptomatic vasospasms than case controls. retrospective analysis of our clinical experience with constant iv infusion of low-dose heparin in patients at high risk for sah-induced dnds indicates early use of low-dose iv heparin infusion may be safe and perhaps beneficial in patients having undergone surgical clipping. further study with a double-blind placebo-controlled trial is warranted to establish the role of heparin in the prevention of sah-induced dnds. subarachnoid hemorrhage patients (sah) may experience cardiac biomarker elevation in serum troponin and b-type natriuretic peptide (bnp). we hypothesized that elevations in these cardiac biomarkers after sah are predictive of increased patient mortality. we retrospectively reviewed the medical records of all non-traumatic sah patients admitted from march to march including medical history, modified fisher scale on initial head ct scan, initial glasgow coma scale (gcs), serum troponin t and bnp within hrs of admission. survival data was dichotomized as either alive or dead by chart follow-up. values (> pg/ml) versus normal values against alive or dead status. we identified sah patients, with initial measured troponin, and with initial measured bnp.the mean age was (range - ) and % male. modified fisher grade was - in %, and grade - in %. the initial gcs mean was (range - ), % of patients had intracranial aneurysm, while % were 'angiogram-negative' sah. twenty sah patients died, with a mean of days post sah (range - ), six from cardiopulmonary or multiple organ failure, from sah, and unknown/other. elevated troponin was seen in % ( of ) with a mean = . (range, . - . ), and elevated bnp in % ( of patients) with a mean = (range, - ). patients with elevated levels of troponin had a greater chance of death (p= . ). patients with elevated levels of bnp also had a higher mortality (p= . ). the data demonstrate a statistically significant association with elevated cardiac biomarker elevation and risk of subsequent death after sah, which occurs not only during the immediate post sah period but after initial hospitalization. delayed cerebral ischemia (dci), length of stay and glasgow outcome scale (gos) following angiogram-negative sah (ansah) are infrequently and inconsistently described in the literature. furthermore ansah are generally considered to have a better prognosis than aneurysmal sah (asah). ansah subgroups include benign perimesencephalic sah (pmh) and aneurysmal-type or diffuse sah. we report and compare outcome data of patients presented with diffuse ansah and diffuse asah. a retrospective chart review of patients who presented to academic institutions between july- and april- who met the criteria for diffuse spontaneous sah were reviewed. the patients were further divided into ansah (n= ) and asah (n= ). delayed cerebral ischemia rates, length of stay and discharge gos were compared and analyzed between two groups using sas statistical software. discharge gos scale was dichotomized in good outcome (gos - ) out of patients, a total of ( . %) patients meet the criteria of diffuse ansah and ( . %) meet the criteria of diffuse asah. demographics and baseline characteristics including age, sex, race, hypertension, diabetes, gcs on presentation, hunt & hess score and fisher grade among two groups were comparable. overall % (n= ) of ansah and % (n= ) of asah showed dci (p= . ). mean length of stay was days in nasah and days in asah. good outcome was seen in % (n= ) in nasah and % (n= %) in asah groups (p= . ). in our patient cohort of ansah, % of patients had dci. even though it is less then asah group it is considerably higher then previously reported in the literature. furthermore length of stay and discharge gos between two groups were comparable. this study indicates that diffuse ansah is not a 'benign' condition and warrants a low index of suspicion for complications with a multidisciplinary approach to management. transcranial doppler (tcd) is a common method used to measure cerebral blood flow velocities and estimate flow resistance related to intracranial pressure (icp). we present the case of a patient with subarachnoid hemorrhage and clipped aneurysm, who, while undergoing tcds, rebled. a year old man presented with sudden-onset severe headache and neck pain. ct of the head showed a subarachnoid hemorrhage (sah) with intraventricular extension and obstructive hydrocephalus. an anterior communicating artery (acom) aneurysm was found and clipped and a ventriculostomy was placed. after surgery there was an interval decrease in the sah. eight days after the original event the patient re-bled during a tcd test because of clip failure. tcd waveforms were captured before, during the bleed and post treatment with mannitol and csf drainage from the ventriculostomy. prior to the bleed. icp was mm hg, the left mca flow velocity was cm/sec and the pulsatility index (pi) . . during the bleed the icp increased to and pi to . - . , with the waveform showing a narrow peak and decreased diastolic and mean velocity. mannitol g was given and the ventriculostomy was opened to drain. within minutes the icp decreased to mm hg, the pi improved to . , the waveform widened and the velocities returned to previous levels (video will be provided with the abstract showing the tcd changes). repeat ct of the head showed increased sa blood and extensive new intraventricular hemorrhage; catheter angiogram a malpositioned clip. the acom aneurysm was coiled successfully. we present this unique case of tcd capturing the dynamics of a real-time intracranial aneurismal bleed with significantly elevated icp. our data demonstrated the tcd pi, flow velocities and waveforms changed dramatically during the rebleeding and improved quickly with treatment. transcranial doppler (tcd) is the least invasive method to detect cerebral vasospasm but is unable to interrogate vessels beyond the circle of willis and is highly operator-dependent. we tested a novel technique whereby we record the miniscule pulsation of the skull gated with cardiac contraction and compared it to tcd in patients with subarachnoid hemorrhage. skull accelerometry was performed using a prototype device designed by jan medial, inc. (mountain view ca). the device has highly sensitive accelerometers that couple through plastic feet to the patient's scalp, arrayed with detectors over the forehead, at midline occiput, each over the temporal bones, and on the patient's vertex. they are held in place with a plastic strap. paired tcd recordings and accelerometry epochs (typically minutes of recording) were compared in patients with and without spasm. a total of accelerometry recordings were obtained in subjects with subarachnoid hemorrhage who had paired tcd recordings. this allowed distinct pairings of data sets (right, left, posterior). a unique signature was identified by a fast fourier transform waterfall technique revealing a shift in accelerometry signals to higher frequencies (representing a "bruit" of sorts) in patients with tcd identified vasospasm. an analytic model was created based on the first recordings, and validated using the remaining recordings. this revealed % sensitivity and % specificity for detection and localization of spasm. highly sensitive skull accelerometry detects a shift toward higher vibration frequency in patients with vasospasm-a cranial "bruit". this technique may be a highly sensitive tool for the detection of cerebral vasospasm following subarachnoid hemorrhage. a prospective, blinded validation study is on going to measure this novel tool's performance characteristics in a larger sample of patients. financial support: research grant from jan medical, inc. j.n. is year-old hispanic male prisoner previously healthy presented to our institution altered due to diffuse subarachnoid hemorrhage (fisher grade iv) and a bi-lobed "mickey mouse" right m middle cerebral artery (mca) ruptured aneurysm. initially, j.n.'s hunt and hess grade level of on arrival, but declined to a in the ed. j.n. was intubated and an external ventricular device was placed. the anatomy of the aneurysm was complex in nature measuring mm in maximal dimension with the superior lobe measuring . mm and the inferior lobe measuring . mm. based on the complex anatomy of the aneurysm, a -vessel angiogram was planned to treat the aneurysm with a trans-arterial coil-embolization approach. a x mm septal balloon was used with a synchro microwire, with the balloon been placed across the neck of the inferior aneurysm. the superior aneurysm was accessed with a sl- microcatheter and coiled in the usual fashion. the sl- microcatheter was then re-directed to the inferior aneurysm and coiled similarly. post-angiographic images showed complete obliteration of the aneurysm with a small neck residual to protect en passé branches. evaluation of the literature is scant with reports of bi-lobed aneurysm with the classic description of "mickey mouse" or "mirror" aneurysm. trans-arterial coil-embolization provided a safe, rapid, and effective method for coiling a complex bilobed aneurysm with no major thrombo-embolic events. trans-arterial coil-embolization is a procedure used in the treatment of gross hematoma and fistula in human and the veterinary population. to our knowledge, there is no report of trans-arterial coil embolization for the treatment of bi-lobed aneurysm posted within the usual medical research engines. our institution is presenting a novel endovascular technique in the treatment of a classic bi-lobed mickey mouse aneurysm. j.n. was able to recover fully and eventually discharge to the infirmary in federal prison. the routine practice of therapeutic hypothermia is advocated in the management of comatose survivors of out-of-hospital cardiac arrest (ohca), particularly if ventricular fibrillation is the initial rhythm. potential benefits of hypothermia were evaluated for comatose survivors after ohca due to aneurysmal subarachnoid hemorrhage (sah). following return of spontaneous circulation (rosc), therapeutic hypothermia was induced for comatose sah patients except for those with devastating brain damage on brain ct and cardiac arrest over minutes. immediately after diagnosis and evaluation of cardiac function, cooling was promptly initiated by nasogastric lavage with iced water and surface cooling under general anesthesia. the ruptured aneurysm was obliterated by surgical clipping with wide decompressive craniectomy. core temperature was maintained at -urokinase was injected via cisternal drain and nicardipine and fusdil hydrochloride were intravenously administered to prevent cerebral vasospasm. clinical outcome was assessed according to the glasgow outcome scale (gos) months later. six women, aged between and years, were eligible during the past years. their glasgow coma scale was after resuscitation. electrocardiogram on arrival was asystole in and pulseless electrical activity in patients. myocardial stunning was detected in patients by echocardiogram. surgery and hypothermia treatment were uneventfully conducted. postoperative mri revealed extensive cerebral ischemia in and vasospasm-related ischemic lesion in patient. their gos was good recovery in , severe disability in , persistent vegetative state in , and death in patients. therapeutic hypothermia was feasible for ohca patients due to sah. since neurogenic stunned myocardium could be a possible cause of cardiac arrest in sah, beneficial effects of induced hypothermia are expected just like cardiogenic cardiac arrest. appropriate prognostication methods are warranted for decision making to treat or not. autonomic shift (as), characterized by increased sympathetic nervous system activation, has been implicated in neurologically mediated cardiopulmonary dysfunction and immunodepression following stroke. however direct measurement of autonomic nervous system dysfunction is difficult to obtain routinely in critically patients. we investigated the prevalence of as defined by readily available clinical parameters and determined the association of as with subsequent infection in a cohort of patients with aneurysmal sah (asah). data were obtained from a single center cohort study of asah patients admitted from january , through april , . as was defined as at least one early routine clinical marker of neurologically mediated cardiopulmonary dysfunction (based on electrocardiogram, echocardiogram, cardiac enzyme testing or clinical diagnosis of neurogenic pulmonary edema). exclusion criteria were beta-blocker treatment a known pre-existing abnormal electrocardiogram. multivariable logistic regression models were developed to evaluate the association between as and subsequent infection after adjusting for other covariates. a total of patients were included (mean age , % male). autonomic shift was seen in / ( %), and infection was seen in / ( %). autonomic shift was associated with subsequent infection on unadjusted analysis (or= . , % ci . , . ). however, on multivariable analysis adjusting for other predictors of infection, there was no significant association between as and subsequent infection (or . , % ci . , . ). age, clinical grade, aneurysm location and presence of ich were all identified as independent predictors of infection following asah. we identified evidence suggestive of as based on readily available clinical markers in % of patients with asah. however, as defined by these clinical criteria was not an independent predictor of infection. additional studies may be warranted to determine the optimal definition of as and to determine the clinical significance of this finding. we have previously studied the effects of falling temperature on the incidence of asah at our institution over days observing , asah. we previously reported that every degree decrease in temperature was associated with . % increase in risk of asah [relative risk (rr), . , p = . ]. we looked within the same data using other metrics to identify patterns in temperature changes which might result in physiological stress that increases the incidence of asah admissions at our institution. we developed a mathematical equation based on the premise that degrees fahrenheit is the ideal external temperature for humans. our formula measured the variation above or below ° as a percentage of ° for every day of days of observation. the relationship of absolute differences between tmax and tmin was examined to see if daily temperature variation was associated with increasing incidence. the odds ratio for incident asah relative to ° was . (ci . - . ) p= . . likelihood of incident asah increased as the ratio of tmax to ° fell below zero (i.e. experienced colder temperatures). intraday variation as measured by the absolute difference between tmax and tmin was strongly associated with increasing incidence, p= . , or . , ci ( . - . ). a smaller, not larger, difference between tmax and t min was associated with increased likelihood of asah admission. colder daily maximum temperatures relative to ° f, and smaller intraday temperature fluctuations are associated with increased asah admissions at our institution. smaller daily temperature ranges correspond to seasonal periods with the least daylight in this region, and may represent sudden arrival of cold weather in warm months. both metrics support the hypothesized increased likelihood of asah with falling environmental temperatures. these new methods may assist in the development of new algorithms for asah predictions based on temperature. near-infrared spectroscopy (nirs) is a noninvasive means of measuring cerebral regional mixed arteriovenous (av) brain oxygenation. we hypothesized that frontal nirs would correlate against more established modes of vasospasm monitoring and systemic variables for severe aneurysmal subarachnoid hemorrhage (asah). case report we describe a year old male who presented with coma (gcs= , e m v t) after severe asah (modified fisher ) from a ruptured giant basilar aneurysm ( . cm x cm) who developed severe diffuse vasospasm with no change on clinical examination. frontal nirs monitoring was applied in addition to map, cpp, cbf (hemedex tm ), cardiac output (co), spo , core temperature, continuous quantitative eeg (qeeg) with alpha delta ratio (adr) monitoring, along with daily tcd. the patient developed severe diffuse vasospasm and underwent angioplasty of the mca, aca, and pca arteries and received intra-arterial verapamil. pearson's correlation coefficient was used to analyze trends in variables pre-and post intervention. values were recorded over a four-day period. calculated correlation coefficients revealed invasive cbf to right nirs r= . (p= . ) and left r= . (p= . ) but was contralateral to the cbf probe, co to right nirs r= . (p= . ) and left r= . (p= . ). coefficients with weak or negative correlation included arterial map to right nirs r=- . (p= . ) and left r=- . (p= . ), noninvasive map to right nirs r=- . (p= . ) and left r= . (p= . ), spo to right nirs r=- . (p= . ) and left r=- . (p= . ). noninvasive map to arterial map r= . (p= . ), noninvasive map to cpp r= . (p= . ), and arterial map to cpp r= . , (p= . ). nirs correlates with ipsilateral invasive cbf values (r= . , p= . ) and trends with cardiac output. nirs did not correlate with map, cpp, spo , tcd or qeeg adr data. larger prospective studies are needed to validate these preliminary results. this case report describes the use of intraventricular nicardipine in a pediatric patient for the treatment of severe cerebral vasospasm following sah from traumatic pica dissection. intraventricular nicardipine has been suggested as an adjuvant to standard therapies in adults with aneurysmal sah but its use has not been described in pediatric patients. a year-old boy was transferred from an outside hospital for treatment of severe sah following sports related head injury. he was found to have a dissecting pica psuedoaneurysm which was treated endovascularly. bilateral ventricular drains had been placed for hydrocephalus. his neurological examination declined on hospital day and ct angiogram demonstrated severe vertebrobasilar vasospasm. intraventricular nicardipine was administered in addition to treatment with transluminal balloon angioplasty, induced hypertension and nimodipine. the patient received mg intraventricular nicardipine twice daily for days and the dose was then increased to mg every hours for a total of days. both ventricular drains were clamped for min following administration. he tolerated doses without hemodynamic effects, elevations in intracranial pressure or evidence of ventriculitis. after improvement in clinical examination and mean cerebral blood flow velocities by tcd, intraventricular nicardipine was stopped. he was discharged to acute rehab and was ambulatory and preparing to restart school at age appropriate grade level at month follow up. intraventricular nicardipine was safely administered in this year-old patient with severe vasospasm following sah with a good outcome. intraventricular nicardipine should be considered as an adjuvant to standard therapies for vasospasm in pediatric patients, though further studies are needed to evaluate safety and efficacy in both pediatric and adult patients. the benefit of early tracheostomy has been well described. patients with aneurysmal subarachnoid hemorrhage (asah); however, represent a distinct population to which traditional weaning parameters may be difficult to apply. the purpose of this study is to identify admission characteristics of asah patients that predict need for tracheostomy. this was a retrospective cohort analysis of consecutive asah patients. we excluded patients with a history of symptoms longer than hours prior to transfer, expired within hours, or no ct scan available prior to cerebral angiography. we collected data including: demographics, co-morbidities, neurologic exam, labs, ejection fraction % on echocardiogram, modified fisher scale, and hijdra scale. chi-square or wilcoxon tests were performed where appropriate with subsequent multivariate analysis of statistically significant variables. the data set included tracheostomy patients and non-tracheostomy patients. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] ,p=< . ). the modified fisher and all components of the hijdra scale were significantly higher in the tracheostomy group. the bicaudate index was significant ( . vs. . ,p= . ); however, presence of hydrocephalus using this index was not. in the multivariate analysis older age, lower albumin, higher pco and presence of ventricular blood by hijdra scale remained significant predictors. neurologic status on admission, advanced age, burden of systemic illness, and intraventricular hemorrhage are associated with increased risk of tracheostomy. further research in this patient population on the benefits of early tracheostomy (lower mortality, less ventilator days and less intensive care unit days) is warranted. patients with subarachnoid hemorrhage(sah) have variable outcomes, some of these leading to major disability. established guidelines advocate administration of nimodipine to patients with sah. several recent trials have investigated the utility of statins and magnesium, however there has not been much data showing clinical benefit. we present data of patients with primary sah who had therapy with magnesium, nimodipine and simvastatin for prevention of delayed cerebral ischemia (dci). patients with primary sah admitted to two academic institutions between july and april were identified. all patients received therapy with magnesium, nimodipine and simvastatin for dci prophylaxis. outcomes were categorized as good in those with glasgow outcome scales (gos) of - and poor in those with gos - . chi-square analysis was used to compare outcomes between age, sex, race, hunt-hess scores ( - vs - ), presence of vasospasm and glasgow coma scale (gcs) on presentation (below or above ). of patients identified with primary sah, . % had a good outcome. the mean age for patients with a poor outcome was . (sd . ) when compared to . (sd . ) in patients with a good outcome (p= . ). among those with a gcs - on admission, . % had a good outcome while in those with less than only . % had a good outcome (p< . ). when comparing hunt-hess scales, . % of those with grades between - had good outcomes, while . % of patients with grades - had poor outcomes (p< . ). among those who developed dci, . % had a good outcome as compared to . % had poor outcomes (p= . ). age and race failed to show any difference in patients with good and poor outcomes. we present our data on therapy with nimodipine, magnesium and statin for prophylaxis against dci. age, admission gcs, hunt-hess scale and occurrence of dci were predictors of patient outcome. intraoperative rupture during the surgical treatment of a previosuly unruptured intracranial aneurysm is a rare event. we describe our experience with intraoperative aneurysm rupture in this setting. we reviewed all cases of unruptured aneurysms treated by a single surgeon from july, to june, and identified those patients who suffered intraoperative aneurysm rupture. of unruptured aneurysms treated during this period, there were instances of intraoperative aneurysm rupture ( . %). in our experience, rupture occurred during dissection of either a perforator ( cases) or a major efferent vessel ( cases) from the aneurysm dome or of the dome from adherent overlying cortex ( case). in one instance, the aneurysm ruptured during removal of the anterior clinoid process. in cases, blunt rather than sharp dissection was being employed. in cases, bipolar electrocautery and gentle tamponade successfully sealed the rupture point. in cases, a clip placed across the bleeding site well up on the dome of the aneurysm controlled the bleeding and allowed for completion of the dissection and proper clipping. in the last case, the administration of adenosine was utilized to stop the bleeding and allow for proper clip placement. intraoperative angiography confirmed adequate aneurysm obliteration in each case. there were no clinical consequences associated with these intraoperative ruptures. intraoperative rupture during elective surgery for a previously unruptured aneurysm is uncommon. in our experience, rupture was typically associated with blunt dissection on the dome of the aneurysm. the use of bipolar electrocautery, clipping of the bleeding point, or intravenous adenosine infusion were successfully used to control bleeding in our cases. the neurovascular surgeon should be prepared to address this unlikely event, should it occur. aneurysmal subarachnoid hemorrhage (asah) is a life-threatening form of hemorrhagic stroke which is more common in women than men, typically between ages - . over the course of our nursing practice, we have observed a trend of pre-menopausal asah female patients who experience the onset of their menses during the initial week of hospitalization. we became curious as to whether there is a correlation between asah and an earlier onset menses than a normal - day cycle. retrospective, single-center review of the medical record of pre-menopausal females ages - years who were admitted to our neuroscience intensive care unit with the diagnosis of asah. chart review was specific to documentation of the onset of menses during the first week of hospitalization, medical/gynecological history with regard to last menstrual period, usual menstrual cycle characteristics, contraceptive use, past surgical history, and pertinent medications. over a month period (june -june ), we identified asah patients with being female. of the female asah charts screened, we found study patients. nine of ( %) females had documentation of starting their menses during their initial week of hospitalization for asah, much earlier than a normal range of the menstrual cycle of - days. one patient had menses documented on hospital day . this small retrospective study suggests that asah may disrupt the "normal" menstrual cycle of pre-menopausal females. to our knowledge, this is the first description of this gender and disease specific phenomenon. a prospective study is planned to better understand the role asah has on hypothalamic-pituitary-ovarian-uterine physiology. introduction - % of patients with spontaneous subarachnoid hemorrhage can have normal cerebral angiogram. vasospasm, hypoperfusion or thrombosis may hide the aneurysm. dynact is a promising new technique which may help in these cases. we present a case report that highlights the ability of dynact in identifying a thrombosed aneurysm that was undetected with routine cerebral angiogram. a year old female presented with the worst headache of her life. ct scan of the brain showed subarachnoid hemorrhage (sah) in suprasellar cistern, extending into the anterior interhemispheric fissure, bilateral perisylvian, prepontine cistern and right perimesencephalic cisterns along with extension in to the third and fourth ventricles. after the placement of an external ventricular drain, the patient was immediately taken to angio suite where a biplane cerebral angiogram showed - mm saccular aneurysm at right middle cerebral artery bifurcation and an unremarkable vasculature otherwise. repeat imaging using dynact showed the presence of a mm ruptured and thrombosed aneurysm at the right mca bifurcation. the thrombosed aneurysm was visualized and clipped surgically. this case report highlights the promising utility of dynact in identifying the culprit aneurysms. treatment of severe cerebral vasospasm in subarachnoid hemorrhage remains challenging. with failure of noninvasive therapy, endovascular modalities may be undertaken, albeit with limited efficacy; balloon angioplasty can be used only for proximal, focal spasm and intra-arterial calcium-channel blocker (ccb) bolus infusion has transient vasodilatory effects. we present a patient with severe vasospasm after subarachnoid hemorrhage, who demonstrated significant angiographic improvement with continuous infusion of intra-arterial verapamil over hours. a female in her mid- 's with sickle cell anemia presented with a hunt and hess , fisher grade iv subarachnoid hemorrhage secondary to a ruptured right posterior communicating artery. on initial assessment, the patient was localizing with only her upper extremities. the aneurysm was completely coil embolized and standard triple-h therapy maintained. on post-bleed day , the patient developed left-sided hemiplegia. angiography demonstrated critically severe, diffuse right anterior and posterior circulation vasospasm. angioplasty could not be performed due to microwire and balloon inaccessibility of stenosed anterior and posterior circulation vessels. subsequently, two microcatheters were positioned with their respective tips in the petrous right internal carotid artery (ica) and v segment of the right vertebral artery for continuous machine controlled intra-arterial verapamil infusion. dosing consisted of administering mg/hr verapamil into the right vertebral artery and mg/hr into the right ica. the patient was placed on a heparin drip and taken to the neurointensive care unit for monitoring. after hours of continuous ia verapamil infusion, angiography demonstrated significant improvement in right anterior and posterior circulation vasospasm, with only residual diffuse moderate stenosis. unfortunately, no corresponding clinical improvement was noted. prolonged infusion of intra-arterial ccb's may provide extended angiographic improvement in severe vasospasm refractory to conservative treatment and unsuitable for balloon angioplasty. with systematic study of such techniques, optimal agents and dosing for sustained vasodilation and clinical optimization may be defined. vasospasm remains a significant cause of morbidity after subarachnoid hemorrhage (sah), inducing delayed ischemic events. sah typically results in numerous complications including severe, treatment-refractory headache. fioricet® (acetaminophen mg/butalbital mg/caffeine mg) is a commonly used analgesic medication for the treatment of headache in sah. caffeine has been shown to reduce cerebral blood flow. the purpose of this study was to determine if there is an association between fioricet® administration and early vasospasm. a retrospective, medical record review was conducted, and patients were identified using the university health consortium (uhc) database. patients were included if they had an aneurysmal sah with a presenting hunt and hess grade of i-iv. data points included occurrence of clinical vasospasm, daily amount of fioricet® and other analgesics, daily pain scores, and patient demographics. a univariate analysis was performed to determine the association between extent of fioricet® exposure and early vasospasm (within the first days) after sah. a multivariate analysis was performed accounting for amount of fioricet® use, patient age, and hunt and hess grade. the population characteristics were typical of the sah population. patients who experienced clinical vasospasm received more fioricet® than those who did not have vasospasm (mean . + . tablets/day versus . + . tablets/day (p= . )). the odds ratio for vasospasm with regards to fioricet® use when controlled for age and hunt and hess grade was . ( % ci . - . ). the multivariate analysis did not yield any statistically significant associations with vasospasm. there was a significant association between fioricet® exposure and vasospasm in our univariate analysis. however, when correcting for age and sah severity, the association is not significant. thus, the data do not currently support a clear causal association. this preliminary data will be used to support a comparative study investigating headache treatment in sah. isolated complete third nerve palsy (tnp) in the setting of a subarachnoid hemorrhage (sah) is most commonly seen secondary to a posterior communicating artery (pcom) aneurysm. however, this same clinical picture with a negative angiogram and otherwise negative imaging studies becomes extremely rare. although trauma has been described as one of the most common causes of isolated tnp, concomitant post-traumatic sah and late onset isolated complete tnp has never been reported. we report a case of a delayed onset complete tnp after traumatic sah. case report. a year-old male with type- diabetes mellitus presented to the emergency department with painless diplopia and left eye ptosis three days after sustaining a fall with closed-head injury without loss of consciousness. his non-contrast head ct scan showed a fisher grade subarachnoid hemorrhage. upon arrival and throughout his hospitalization, the patient had a glasgow coma scale (gcs) of . his neurological exam revealed findings consistent with isolated complete thirdnerve palsy (tnp) involving the pupil. his neurological examination was otherwise normal. diagnostic digital subtraction angiography (dsa) was negative as it was his brain mri for aneurysm or vascular lesion. mri did however show traumatic sah pattern and small subdural hematomas consistent with trauma. laboratory findings (esr, crp, ace, c-anca and p-anca) did not raise suspicion of secondary vasculitic or ischemic causes of tnp. the patient was discharged five days after admission with no further complications but without any improvement of tnp signs and symptoms. this case illustrates an atypical presentation of traumatic sah with delayed-onset, isolated complete tnp. to our knowledge, this is the first case with these features described in the literature. his atypical presentation may represent the combination of both diabetes and traumatic injury to the cranial nerve iii in the subarachnoid space, rather than either etiology alone. diringer section of neurocritical care improved clinical outcomes after aneurysmal subarachnoid hemorrhage (asah) have been demonstrated for patients treated at high volume centers. these centers treat only % of all asah. it is common for asah patients to be transferred to high volume comprehensive stroke centers after presentation to a community hospital. this study aims to determine if the hospital of presentation has impact upon asah outcomes. a -year retrospective analysis of asah treated in a comprehensive stroke center was undertaken. the comprehensive stroke center consisted of a neurocritical care unit, dedicated vascular neurosurgeons, and endovascular and neurocritical care specialists. demographic and outcome data were collected on all asah patients who had a confirmed and secured aneurysm, survived > days from admission, and completed tcd monitoring and observation for complications of vasospasm. univariate and multivariate analyses were evaluated for differences in mortality, complications, incidence of vasospasm, discharge disposition, and length of stay. patients were included ( direct and transfer). baseline parameters known to influence outcome (age, medical complications, glasgow coma scale, fisher and hunt and hess grade) were similar between the two groups. transferred patients developed ultrasound defined vasospasm more frequently ( % versus %; p< . ) and had a greater delay in time to surgery ( . versus . days; < . ). adjusting for key predictors, direct admit patients spent . fewer days in the icu compared to transferred patients (t=- . , p= . ). multivariate analysis showed that the likelihood of vasospasm was significantly higher for transfer patients (or . , ci: . - . , p = . ). longer in-hospital stays and decreased rates of home discharge were observed in transferred patients (p< . ). mortality rates were not statistically different (transfer . %, direct . %, p= . ). asah patients admitted directly to a comprehensive stroke center have better outcomes than those transferred from lower acuity facilities. numerous advances have been made in the management of subarachnoid hemorrhage (sah) and its complications, including symptomatic vasospasm. however, the optimal management of vasospasm in patients without neurological deficit remains uncertain. we performed an electronic survey of members of the neurocritical care society (ncs) to elucidate clinical practice in this regard. an electronic survey with ten questions about different aspects of sah management was formulated. our institutional review board and ncs approved the survey. three scenarios were presented for good grade sah patients without evidence of delayed cerebral ischemia (dci): those with either normal tcd values, vasospasm on tcd, or vasospasm on angiography. members answered the survey (response rate of %). up to % of respondents utilized transcranial doppler (tcd) measurement to diagnose vasospasm, while % ( % ci, - %) used clinical examination and % ( % ci, - %) used angiography (ct or catheter). in good grade sah patients with no evidence of dci, % ( % ci, - %) of respondents indicated using nimodipine in all three scenarios. in the subset with normal tcd values, % ( % ci, - %) recommended use of hypervolemia, % ( % ci, - %) hemodilution and % ( % ci - %) induced hypertension. however, in the subset with vasospasm on angiography and no referable clinical symptoms, % ( % ci - %) recommended the use of hypervolemia, % ( % ci, - %) hemodilution, % ( % ci, - %) induced hypertension and % ( % ci, - %) endovascular therapy with intra-arterial vasodilators, angioplasty or stents. from the sample above, it appears that good grade sah patients without neurological deficit but radiological vasospasm are treated aggressively. this is not supported by current literature or guideline recommendations, which imply little benefit of aggressive therapy in such patients. further studies are needed on the optimal management of this subset of patients, in whom the effects of vasospasm remain unclear. key: cord- - dx dkv authors: humphreys, hilary; winter, bob; paul, mical title: immunocompromised patients date: - - journal: infections in the adult intensive care unit doi: . / - - - - _ sha: doc_id: cord_uid: dx dkv the ominous prognosis of cancer patients with or without neutropenia in need of critical care has led to reservations with regard to admission of cancer patients to the icu. however, significant improvements in icu and in-hospital survival of cancer patients in icu have been demonstrated in studies in recent years [ – ]. risk factors for mortality have shifted from those related to the underlying condition to those related to the severity of acute illness similar to other critically-ill patients. neutropenia per se and the underlying malignancy (solid and hematological) do not have an impact on the outcome of patients in icu. recent chemotherapy is associated rather with improved survival [ , – ], while organ dysfunction, severity of disease scores, need for vasopressor treatment, need for mechanical ventilation immediately or after noninvasive ventilation, no definite diagnosis and a non-infectious diagnosis are associated with mortality [ – , ]. invasive aspergillosis is also associated with very high mortality rates in icu (see below). in several studies, admission to icu in the early stages of sepsis or other acute event was associated with better survival than admission later, after development of organ dysfunction. performance status is perhaps the most important and only variable relating to the underlying condition that is correlated with icu death. the prognosis remains guarded for certain cancer patients, including patients after allogeneic hematopoietic stem cell transplantation (hsct) with active uncontrolled graft versus host disease, those with relapse of the primary disease after allogeneic hsct and special cases of solid cancer including pulmonary carcinomatous lymphangitis and carcinomatous meningitis with coma [ ]. associated rather with improved survival [ , [ ] [ ] [ ] , while organ dysfunction, severity of disease scores, need for vasopressor treatment, need for mechanical ventilation immediately or after noninvasive ventilation, no de fi nite diagnosis and a noninfectious diagnosis are associated with mortality [ ] [ ] [ ] ] . invasive aspergillosis is also associated with very high mortality rates in icu (see below). in several studies, admission to icu in the early stages of sepsis or other acute event was associated with better survival than admission later, after development of organ dysfunction. performance status is perhaps the most important and only variable relating to the underlying condition that is correlated with icu death. the prognosis remains guarded for certain cancer patients, including patients after allogeneic hematopoietic stem cell transplantation (hsct) with active uncontrolled graft versus host disease, those with relapse of the primary disease after allogeneic hsct and special cases of solid cancer including pulmonary carcinomatous lymphangitis and carcinomatous meningitis with coma [ ] . an "icu trial" consisting of patient admission and re-assessment after - days has been suggested for cancer patients [ ] . outcomes were better associated with the hemodynamic and respiratory status after the fi rst stabilization phase than at the time of admission. another study supporting this concept showed that organ failure scores predicted survival more accurate on day six than at admission [ ] . all patients who required initiation of mechanical ventilation, vasopressors, or dialysis after days in the icu died. an early invasive diagnostic strategy should be pursued in immune compromised patients, since the differential diagnosis is broad including infectious and noninfectious etiologies and the spectrum of infectious agents is large. this includes bronchoalveolar lavage (bal) with or without lung biopsy for pulmonary disease, functional endoscopic sinus surgery (fess) for sinusitis/ rhinocerebral disease, endoscopy for colitis, biopsies from liver nodules, etc. some infectious conditions by organ system to be considered in immune compromised patients are provided in table . . in additions, patients presenting with respiratory insuf fi ciency should be evaluated for community-acquired respiratory viruses using pcr, direct antigen tests and cultures of respiratory samples. these include in fl uenza, parain fl uenza, adenovirus, respiratory syncytial virus (rsv), and human metapneumovirus. empirical antibiotic treatment is recommended for neutropenic cancer patients (neutrophil count < /mm or < , /mm and expected to decline to < /mm ) with fever, diarrhoea or suspected infection [ ] . intravenous empirical treatment for high-risk patients should provide broad coverage against gram-negative (including pseudomonas aeruginosa ) and gram-positive bacteria. vancomycin should not be administered routinely, but is reserved for patients with hypotension or other hemodynamic compromise, those with a source of infection likely to be caused by staphylococci (skin/ soft tissue, catheter-related and pneumonia). antibiotic treatment should not be automatically discontinued with neutrophil recovery, even if infection has not been con fi rmed during neutropenia. rather repeated patient examination, imaging and microbiological evaluation for suspected sources of infection should be performed after neutrophil recovery to exclude new or exacerbations of pre-existing infections. among patients with documented infections during neutropenia, neutrophil recovery may be associated with "deterioration" in the status of the patient. local signs and symptoms of infection are frequently exacerbated. thus, pulmonary in fi ltrates may increase with new onset respiratory compromise (see figs. . and . ), an abscess may appear or enlarge or local signs of catheter-related infection may become manifest. in this case, treatment should not necessarily be changed or expanded. this is the normal response to neutrophil recovery. an immune reconstitution in fl ammatory response (iris), originally described among patients with hiv following treatment initiation (see below), has also been described among cancer patients following neutrophil recovery [ ] . this syndrome represents an overly robust and dysregulated in fl ammatory response resulting in re-appearance or deterioration in clinical signs and symptoms of infection. it occurs usually later than the initial worsening following neutrophil recovery, days to weeks after immune reconstitution. diagnosis is dif fi cult and is based mostly on negative cultures and biomarkers for the initial infection and treatment is with corticosteroids. a speci fi c syndrome of adult respiratory distress syndrome (ards) has been described following neutrophil recovery in hematological cancer patients [ ] . the only independent risk factor for ards is pneumonia during neutropenia. the importance of administering chemotherapy, if needed, cannot be overemphasized, even during an acute infection. while inducing immune suppression during an acute infection is counter intuitive, it is the underlying malignancy that is most commonly responsible for infection among cancer patients. without control of the underlying malignancy the long term outcomes of most or all infections remain ominous. close liaison with hematologists/ oncologists is recommended for oncological patients admitted to the icu [ ] . cancer patients, especially hematological cancer patients are frequently thrombocytopenic as part of their underlying illness or as a result of chemotherapy. while randomized controlled trials have not shown an advantage to a threshold higher than × /l for thrombocyte transfusions, these studies did not include critically ill patients [ ] . a higher threshold should probably be used ( - × /l) in critically ill hematological cancer patients, especially with sepsis or with pulmonary involvement. pulmonary and intracerebral hemorrhage are frequent terminal events in these patients and prophylactic transfusions may prevent mortality. neutrophil transfusions have not been shown to improve survival for patients with severe neutropenia as part of the management of acute infections. however, when sub-grouped according to the dose of neutrophils transfused, survival was improved with average neutrophil doses of × . this dose can be obtained by pre-treating donors with granulocyte growth stimulating factors (g-csf) [ ] . neutrophil transfusions should be reserved for severely neutropenic patients (< / ml ) for whom the neutrophil count is expected to increase in a few days, as a bridge until bone marrow reconstitution. neutrophil transfusion is probably futile when there is no expectation that the natural neutrophil count will increase. hematological cancer patients may be hypoglobulinemic as part of the underlying hematological malignancy or following chemotherapy. there is no evidence from high-quality studies that intravenous immuneglobulins (ivig) reduces mortality in sepsis in general and in cancer patients speci fi cally [ ] . in one randomized controlled trial speci fi cally assessing patients with hematological malignancies, there was no survival advantage with ivig [ ] . ivig is used in some centers for infection prevention among patients with multiple myeloma or chronic lymphocytic leukemia, known hypogammaglobulinemia and recurrent respiratory infections [ ] . patients with hiv may be seen in the icu as the fi rst presentation of their disease or following an infectious complication after diagnosis. highly active antiretroviral therapy (haart) has changed the epidemiology of hiv such that the latter group of patients is rare nowadays in locations where treatment is available (and depending on patient's compliance). clearly, the change in prognosis of hiv with haart has led to a shift in management such that hiv patients are offered maximal treatment, including full icu support, organ transplantation in the appropriate circumstances, or chemotherapy if needed. the impact of haart availability on mortality has been shown also in icu, where predictors of mortality in the haart era are no longer hiv-related [ ] . a thorough discussion of the management of hiv patients is beyond the scope of this book. however, we will address a few critical decisions in the management of infections with suspected or known hiv. administering antiretroviral therapy in the icu is dif fi cult [ ] . all antiretrovirals except zidovudine are available only as oral preparations, most only as tablets. beyond the poor bioavailability of orally administered drugs in the critically-ill patient, absorption and side effects of speci fi c antiretrovirals frequently depend on the provision of concurrent oral feeding. drug interactions are common; for example proton-pump inhibitors and histamine- blockers are contraindicated with protease inhibitors (pis). all nucleoside reverse-transcriptase inhibitors (nrtis), except for abacavir, require dose adjustment for renal failure. several pis require dose adjustment for hepatic impairment [ ] . thus, fi xed drug combination usually cannot be used in patients with renal and hepatic impairment; individual drugs must be dose-adjusted and administered separately. drug-related adverse effects are common, although few may be relevant in the critical care setting. nrtis (mainly stavudine, didanosine, and zidovudine) may induce lactic acidosis. abacavir-related hypersensitivity is a serious adverse event and this drug should be administered only after genetic testing for hla-b* . the most common infectious scenario encountered in the icu will be the recently diagnosed patient presenting with an opportunistic infection. the question in this scenario is whether to initiate antiretroviral therapy early while treating the acute infection or after its successful management. aside from the practical dif fi culties in the administration of haart in icu, there is the fear of iris with worsening of the underlying infectious process during immune reconstitution. iris can occur between days to weeks after initiation of haart [ ] . although logically predicted by rising cd counts, it can occur before signi fi cant cd cell count increase or viral load suppression [ ] . there are few randomized trials to guide the strategic decision of early vs. deferred haart initiation during infection (table . ). three trials have shown a clinical bene fi t for early, but not immediate antiretroviral drug initiation (e.g. within weeks of starting anti-infective treatment), for patients mostly with pulmonary tuberculosis and pcp [ ] [ ] [ ] . one study showed no difference in outcomes for patients with pulmonary and extrapulmonary tuberculoisis [ ] . in contrast two trials assessing hiv patients with meningitis showed no bene fi t or increased harm with early initiation of haart initiation [ , ] (table . ) . there is no direct evidence on timing of haart initiation in the critical care setting. summarizing the evidence from existing trials, it seems that the initiation haart about weeks after anti-infective therapy directed at the opportunistic infection is reasonable for patients with pulmonary infections, including tuberculosis. this allows the time for patient stabilization, hiv drug resistance testing and involving an hiv specialist in the management and all treatment decisions. with tuberculosis or cryptococcal meningitis, the start of haart should probably be deferred for longer. in previously treated hiv patients, the question is whether to continue or stop haart in icu. discontinuation could result in the selection of anti-viral resistance because of the different half-lives of the drugs included in the combination and functional monotherapy with the long-acting antiretrovirals. an expert recommendation is to try and continue haart for patients with virological suppression (plasma hiv rna below the limit of detection) [ ] . in other patients, haart can probably be discontinued after consultation with an hiv expert. hiv/ hepatitis b co-infected patients require special consideration. antiretroviral treatment active against hepatitis b (lamivudine, emtricitabine, and tenofovir) should not be discontinued for fear of exacerabations of hepatitis b after discontinuation. adrenal insuf fi ciency is common among hiv patients and should be evaluated in all patients admitted to the icu. testing of stress cortisol concentration and lowdose adrenocorticotropic hormone (acth) corticotropin stimulation test ( -microg of acth) is recommended [ ] . solid organ transplant (sot) recipients require life long immune suppression to prevent rejection. this immune suppression affects mainly the t-cell lymphocyte function. consequently, opportunist infections seen most frequently among sot recipients include herpesvirus infections, mainly cmv, pneumocystis pneumonia and more rarely fungal infections. ebv-associated post-transplantation lymphoproliferative disease (ptld) is a special entity. in the fi rst month after transplantation, most infections will be healthcareassociated, related to the surgical site, catheter or post-operative mechanical ventilation. lung transplant recipients are frequently colonized before transplantation by bacteria and pneumonia is very common in the fi rst year after transplantation (mostly in the fi rst month) and is associated with a high relative risk of death [ ] . donors may also be colonized with antibiotic resistant bacteria [ ] . prophylaxis for a more prolonged period (i.e. days) compared with non-transplant surgery (i.e. - doses of antibiotics) should be guided by the presence of pre-existing antibiotic-resistant bacteria in the recipient or the donor. all antibiotics continued after transplantation should be reviewed early with a view to discontinuation if the recipient is clinically well and there is no other evidence to suggest infection. antibiotics can be discontinued - h after transplantation if culture of donor and recipient samples is negative and the patient is stable. antibiotic prophylaxis in liver transplantation should provide a therapeutic concentration in the wound and within the biliary tract. in a european survey, all liver transplant centres administered antibiotic prophylaxis for liver transplantation, using a variety of different antibiotic regimens for a median of days after transplantation [ ] . given the shortage of organs, transplant centers are increasingly using marginal donors, sometimes with documented infections at the time of death, which might have been previously treated or not. studies describe non-inferior outcomes for recipients receiving organs from donors with clinical infections, including bloodstream infection and meningitis [ ] [ ] [ ] [ ] . treatment directed against the donor's isolate/s was given to recipients. procurement of organs from previously untreated patients with meningitis has not been described. pneumocystis pneumonia (pcp) caused by pneumocystis jirovecii most commonly affects patients with cellular immune de fi ciency, including lymphopenia or qualitative defects in lymphocyte activity, rather than patients with neutropenia or neutrophil dysfunction. susceptible patients therefore include patients with: multiple myeloma • chronic lymphocytic leukemia • following hsct with graft versus host disease (gvhd hematological cancer • patients receiving anti-lymphocyte antibodies such as rituximab and alemtuzumab (mainly lymphoma) sot recipients mainly during periods of high-corticosteroid therapy or anti-• lymphocyte antibody treatment for rejection non-immune-reconstituted hiv patients. • haart has changed the epidemiology of pcp such that most patients are now not hiv-positive. pcp is more severe and is associated with higher mortality in non-hiv patients. prophylaxis with trimethoprim-suphamethoxazole (tmp-smx) given daily or thrice weekly is highly effective in pcp prevention and patients who are receiving tmp-smx prophylaxis presenting with a clinical picture suspected of pcp probably do not have pcp. compliance with prophylaxis in the period before admission should be ensured by history taking, since discontinuation of pcp prophylaxis for adverse events is common and protection from pcp is reliable only while this drug is taken. less is known about the ef fi cacy of other prophylaxis agents, including dapsone or pentamidine, and their administration should not rule out the possibility of pcp in the appropriate clinical setting. pcp presents with dyspnea, tachypnea and hypoxia. lung imaging shows bilateral interstitial or ground glass in fi ltrates. initially the chest x ray may appear near normal but a high-resolution ct scan will show these opacities better. with more severe disease bilateral diffuse in fi ltrates can be seen also on the chest x-ray. the radiological picture is similar to than seen with cmv pneumonitis and actually coinfection of pcp and cmv is not uncommon. a diagnosis of one does not rule out the existence of the other and a search for cmv infection should be performed when pcp is diagnosed, especially in hematological cancer and sot patients. the interval from symptom onset to diagnosis of pcp was - days in one study [ ] . diagnosis is established most commonly by examination of bal fl uid, but it is possible also with induced sputum (table . ). giemza stain or immuno fl uorescence stain with human monoclonal anti-pneumocystis cyst antibodies will demonstrate p. jirovecii trophozoites or cysts. pcr is more sensitive but less speci fi c; p. jirovecii was identi fi ed by nested pcr in % of people dying suddenly of non-infectious reasons, representing low-level colonization [ ] . in the appropriate clinical scenario a positive pcr probably mandates treatment, but in other cases pcr results may represent colonization. tmp-smx is considered the most effective therapy for pcp [ ] . it is administered using high doses of - mg/kg/day of the trimethoprim component and - mg/kg/day of the sulphamethoxazole component, divided in four daily doses. clinical response may be delayed until day or later and treatment should be continued for days. adverse effects are common and include mainly rash and tmp-smx-induced leucopenia. hematologists or oncologists may be reluctant to use tmp-smx in patients with neutropenia for fear of delaying neutrophil recovery. leucovorin (folinic acid) can attenuate the hematologic adverse effects of tmp-smx, but should probably not be used during active pcp infection since it has been shown to increase death and failure rates in hiv patients [ ] . alternative agents include the combination of primaquine mg/ day and clindamycin mg thrice daily, a combination of dapsone with trimethoprim, atovaquone alone or intravenous pentamidine alone. each medication has its own adverse effect pro fi le which should be considered on a patient-by-patient basis before treatment and monitored for during treatment. adjunctive corticosteroid treatment for patients with hypoxemia (room air pao < mmhg) is based on evidence of improved survival in hiv patients, but it is recommended in other immune compromised patients with severe pcp [ ] . the dose recommended is mg prednisone twice daily for days, mg/day for the next days and mg/day until day . the classical risk factors for invasive aspergillosis include severe prolonged neutropenia, the immune de fi ciency state following allogeneic hematopoietic stem cell transplantation, particularly in the fi rst year after transplantation and with gvhd and more rarely following sot, mainly lung transplantation. however, currently, invasive aspergillosis is also reported among other patient populations in the icu not "classically" considered as immune compromised. these include patients with chronic lung disease, cirrhosis, burns and others [ ] . post-mortem studies show that invasive aspergillosis is under-diagnosed in the icu. therefore, in this setting, positive respiratory cultures for aspergillus sp . should not be automatically disregarded. aspergillus sp . may cause infectious, saprophytic and allergic syndromes. herein, we will address three of the more important infectious syndromes seen in icu: invasive aspergillosis, aspergillus tracheobronchitis and chronic necrotizing aspergillosis. invasive aspergillosis, the classical condition described in immunocompromised patients, involves the lungs, sinuses with or without cerebral extension and skin mostly. both contiguous extension disregarding normal anatomical barriers (as in the extension from the respiratory sinuses to the brain) and hematogenous dissemination (causing lung infarction) may occur. chest and sinus x-rays are notoriously insensitive for the diagnosis of invasive aspergillosis and ct is the imaging of choice. during neutropenia fi ndings are usually lacking or minimal, but after neutrophil recovery lesions frequently increase in size even with adequate treatment and control of systemic infection (fig. . ) . respiratory deterioration should also be expected at the time of neutrophil recovery. the classical signs of cavitation and crescent formation are usually observed at later stages of the disease (fig. . ) . lung hemorrhage is a feared complication, especially after biopsy, and thus attention should be given to correcting thrombocytopenia during invasive aspergillosis (see above). criteria for the diagnosis of invasive aspergillosis have been suggested [ ] . these consist of at least one host risk factor and one clinical fi nding (table . ). to diagnose probable invasive aspergillosis laboratory con fi rmation is needed in addition to host and clinical criteria (table . ) and for proven disease histological con fi rmation is necessary. aspergillus spp . appear as narrow, non-septate, acutebranching hyphae. given the dif fi culties in obtaining histological specimens in cancer patients that are severely thrombocytopenic, diagnosis usually relies on culture, direct stains, pcr and galactommanan (gm, a cell wall component of aspergillus spp. and penicillium spp ). pcr and gm can be tested in serum or in bal fl uid. as can be seen in table . , the sensitivity and speci fi city are slightly higher in bal, favoring the performance of bal for patients with suspected invasive aspergillosis. aspergillus tracheobronchitis represents infection of the major airways, with erythema, ulceration, nodules and pseudomembrane formation [ ] . it has been described mostly among lung transplant recipients, but also among patients with copd and chronic necrotizing aspergillosis (or "semi-invasive aspergillosis") consists of a more chronic and diffuse form of lung infection, resembling pulmonary coccidioidomycosis or histoplasmosis [ ] . it has been described among patients with chronic lung disease, diabetes mellitus, aids and with chronic corticosteroid therapy. the existence of the syndrome is important to recognize for patients presenting severe respiratory diseases and positive respiratory culture of aspergillus sp ., without the classical features of invasive aspergillosis. the primary recommended therapy for the infectious syndromes described herein is voriconazole [ , ] . voriconazole is available both in oral and intravenous formulations. blood level concentrations should be monitored, since currently recommended dosing frequently results in subtherapeutic concentrations [ ] . many other antifungals are active and recommended for the treatment of invasive aspergillus infections; [ , ] fl uconazole is the only azole inactive against aspergillus sp . (see chap. on antifungals). treatment failure and mortality rates are very high, especially with ongoing immune suppression. because of the ominous prognosis combinations of antifungals have been suggested as primary or salvage therapy. in one small randomized controlled trial, the combination of liposomal amphotericin b with caspofungin resulted in a higher rate of favorable response than liposomal amphotericin b, with no deaths in the combination arm ( / vs. / with monotherapy [ ] . the most common combination reported in observational studies was voriconazole and caspofungin, but at this time no conclusions can be drawn on the effects of this combination over monotherapy [ ] . . the patient in the case vignette underwent bronchoalveolar lavage (bal) with lung biopsy. cmv was isolated in cultures of the bal fl uid. cmv antigenemia was tested after neutropil recovery (the pp antigen is present in neutrophils which are required for cmv antigenemia assessment) and was negative. direct immuno fl uorescence and pcr for p. jirovecii in bal fl uid were negative. lung biopsy demonstrated diffuse alveolar damage with eosinophlic alveolar foam compatible with pcp. a methamine-silver and immunohistochemical stains for pcp were negative, as was the immunohistochemical stain for cmv. the patient was diagnosed with pcp based on the clinical presentation and histological sensitivity and speci fi city values refer to the diagnosis of probable or proven ia gm galactomannan, ci con fi dence interval a values refer to a gm cut-off of . optical density index fi ndings. cmv co-infection could not be ruled out. the positive cmv culture in bal fl uid could re fl ect cmv reactivation and infection in the presence of immune suppression, without disease. . the patient was empirically treated with high-dose trimethoprim-sulfamethoxazole and intravenous gancyclovir with no adverse events and these were continued after the results of the tests discussed above. . the dose of prednisone was increased and tapered down following the recommendations for severe pcp. . respiratory insuf fi ciency improved gradually until the patient was discharged with normal saturation on room air. notable was the appearance of pulmonary in fi ltrates and respiratory distress only after neutrophil recovery, although fever started during neutropenia and probably re fl ected the same infection. this exacerbation after neutrophil recovery is similar to the immune reconstitution syndrome seen with hiv patients after start of haart. the prognosis of acute respiratory failure in critically ill cancer patients survival in neutropenic patients with severe sepsis or septic shock icu and -month outcome of oncology patients in the intensive care unit prognosis of patients with acute myeloid leukaemia admitted to intensive care impact of neutropenia on the outcomes of critically ill patients with cancer: a matched case-control study impact of recent intravenous chemotherapy on outcome in severe sepsis and septic shock patients with hematological malignancies the icu trial: a new admission policy for cancer patients requiring mechanical ventilation characteristics and outcomes of patients with cancer requiring admission to intensive care units: a prospective multicenter study intensive care of the cancer patient: recent achievements and remaining challenges clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: update by the infectious diseases society of america the impact of the host on fungal infections risk factors for acute respiratory distress syndrome during neutropenia recovery in patients with hematologic malignancies prophylactic platelet transfusion for haemorrhage after chemotherapy and stem cell transplantation granulocyte transfusions for preventing infections in patients with neutropenia or neutrophil dysfunction intravenous immunoglobulin for treating sepsis and septic shock igma-enriched immunoglobulin in neutropenic patients with sepsis syndrome and septic shock: a randomized, controlled, multiple-center trial immunoglobulin prophylaxis in hematopoietic stem cell transplantation: systematic review and meta-analysis short-and long-term outcome of hiv-infected patients admitted to the intensive care unit intensive care of patients with hiv infection clinical features and serum biomarkers in hiv immune reconstitution in fl ammatory syndrome after cryptococcal meningitis: a prospective cohort study early antiretroviral therapy reduces aids progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial timing of antiretroviral therapy for hiv- infection and tuberculosis timing of initiation of antiretroviral drugs during tuberculosis therapy time to initiation of antiretroviral therapy between weeks and weeks of tuberculosis treatment in hiv- infected patients. results from the time study. in: paper presented at the nd european congress of clinical microbiology and infectious diseases timing of initiation of antiretroviral therapy in human immunode fi ciency virus (hiv)-associated tuberculous meningitis early versus delayed initiation of antiretroviral therapy for concurrent hiv infection and cryptococcal meningitis in sub-saharan africa adrenal insuf fi ciency in critically ill patients with human immunode fi ciency virus pneumonia after lung transplantation in the resitra cohort: a multicenter prospective study impact of bacterial and fungal donor organ contamination in lung, heart-lung, heart and liver transplantation antimicrobial prophylaxis in liver transplant patients-a multicenter survey endorsed by the european liver and intestine transplant association the use of liver grafts from donors with bacterial meningitis intrathoracic organ transplantation from donors with meningitis: a single-center -year experience donors with positive blood culture: could they transmit infections to the recipients? clinical signi fi cance of donor-unrecognized bacteremia in the outcome of solid-organ transplant recipients clinical picture of p. jirovecii pneumonia in cancer patients pneumocystis colonization is highly prevalent in the autopsied lungs of the general population an of fi cial american thoracic society statement: treatment of fungal infections in adult pulmonary and critical care patients adjunctive folinic acid with trimethoprim-sulfamethoxazole for pneumocystis carinii pneumonia in aids patients is associated with an increased risk of therapeutic failure and death aspergillus infections in the critically ill revised de fi nitions of invasive fungal disease from the european organization for research and treatment of cancer/invasive fungal infections cooperative group and the national institute of allergy and infectious diseases mycoses study group (eortc/msg) consensus group use of pcr for diagnosis of invasive aspergillosis: systematic review and meta-analysis evaluation of pcr on bronchoalveolar lavage fl uid for diagnosis of invasive aspergillosis: a bivariate metaanalysis and systematic review galactomannan detection for invasive aspergillosis in immunocompromized patients accuracy of bal galactomannan in diagnosing invasive aspergillosis: a bivariate metaanalysis and systematic review treatment of aspergillosis: clinical practice guidelines of the infectious diseases society of america monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients liposomal amphotericin b in combination with caspofungin for invasive aspergillosis in patients with hematologic malignancies: a randomized pilot study (combistrat trial) the role of combination antifungal therapy in the treatment of invasive aspergillosis: a systematic review key: cord- -xhx pzhj authors: nan title: nd world congress on pediatric intensive care rotterdam, the netherlands, – june abstracts of oral presentations, posters and nursing programme date: journal: intensive care med doi: . /bf sha: doc_id: cord_uid: xhx pzhj nan we present the results of a prospective population-based audit of paediatric intensive care activity in two comparable communities with markedly different delivery systems. in the trent region of the uk ( . million people), children receive intensive care largely without the supervision of a paediatric intensivist in a variety of hospitals, few of which have designated paediatric intensive care units (picus). critically ill children otherwise receive intensive care in children's wards, special care baby units (scbus) or adult intensive care units. in the australian state of victoria ( . million people), children receive intensive care almost exclusively in one centre -a picu staffed by full time paediatric intensivists. the two regions are otherwise demographically comparable. in both groups, data were collected on all children admitted to an intensive care unit between / / and / / and children who received intensive care (defined by levels of intervention and nurse dependency) in other sites during the same period. values of each variable at first contact with the icu, and the highest and lowest values over the first hours were recorded. the principal outcome was survival to discharge from the intensive care unit. severity of illness was assessed using pim (paediatric index of mortality) and prism. risk-adjusted mortality was compared using flora's z test and logistic regression. the rate of utilisation of intensive care (> admissions in each region) were similar. there was some variation in case mix between the two groups, but crude mortality rates were similar ( . % in trent and . % in victoria). however severity corrected data and other measures of picu performance were dramatically better in' the centralised delivery system. the substantial excess mortality in the trent region provides strong evidence for the benefits of centralisation of paediatric intensive care services. there are considerable difficulties in evaluating the efficiency and effectiveness oflcare in children presenting with respiratory failure during acute medical illness. optimal outcomes for such episodes include survival and the shortest length of stay (los) in intensive care with negligible risk of readmission. we have tried to determine whether or not the time course of acute severe medical illness with respiratory failure is predictable. study i (n= ): a retrospective study of intubated and mechanically ventilated children (> days, < years) with acute severe medical illness. measures: diagnosis, intensive care los in calender days, and survival. results: the underlying diagnosis fell within one of three broad categories: respiratory disease (n= , mortality . %), central nervous system (cns) disease (n= , mortality . %), and systemic inflammation or multisystem (sims) disease (n= , mortality . %. the los in survivors was: respiratory -median (interquartile range) ( - ) days, cns ( - ) days, £p, £ ( -g) days. :i'~'-+cen diag~,~is-rc!ated-grnnp~ (drgs) were identified ( respiratory, cns, sims disease) and each have been characterised by mortality and los. study ii (n= ): a prospective study of patients supported by the hypothesis that los for the above drgs was predictable (compared with study i data). in certain instances attributable causes for variances in los were identified: e.g. disease severity, timing ofdrug therapy, and associated disease. with daily paediatric risk of morality scoring within each drg, four profiles of instability were identified. discussion: the time course of acute severe medical illness with respiratory failure is predictable and variance may be attributable to specific care or diagnostic factors. we are now developing a means of linking drg-specific clinical care pathways with an integrated computerised decision support and education facility at the bedside. the objective of this open, prospective study was to assess the relation between basic patient characteristics as well as effectiveness of treatment on the one hand and resource utilization in pediatric intensive care on the other. as universal, non-monetary indicators of resource utilization we used the therapeutic intervention score system (tiss) and length-ofstay (los), from which indicators for total resource utilization per admission (tisstot) and average daily resource utilization (tiss-mean = tisstot/los) were obtained. overall admissions, totalling days, were included. mortality was . %; non-survivors accounted for . % of overall resource utilization. in non-survivors, both total resource utilization per admission and average daily resource utilization were higher, whereas los was not different from survivors'. severity of illness, surgical status, the presence of substantial chronic comorbidity, emergency admission and transfer from another hospital constituted the major predictive determinants of tisstot (r:= . ) and tissmean (ra= . ) in multiple regression analysis (p< . ). hence these indicators are appropriate non-monetary measures of resource utilization, a considerable proportion of which are determined by a concise set of basic clinical characteristics. subsequently we analysed the relation between effectiveness of care and resource utilization by assessing severity of illness corrected mortality in low, medium and high resource users, respectively. these categories were delineated by percer/tiles of resource utilization (< p , p -ps , > ps ). despite on average long los and high resource utilization in the high risk group, a relatively low standardized mortality was found, probably warranting prolonged intensive treatment in this patient category. summary: objective:the primary purposes of intensive care are to provide treatments to patients with life-threatening physiological dysfunction or to monitor and observe patients perceived to be at significant risk of dying. this collaborative study was performed to describe our patients and their outcome. in order to improve our results we tried to identit~ high risk groups, patients and methods: picus entered the study, the data included all the admissions with > hs. during a days period between the l°june and the th september . the records included: age, sex, weight, mechanical ventilation (mv), post-operative condition (p.op), malnutrition, diagnosis, length of stay, prism score and outcome. student test, mann-whitney or wileoxon were performed for univariate analysis. fisher exact test or chi square for dicotomic variables. risk group analysis was performed by logistic regression, odds ratio and % confidence interval. results: patients entered the study. mean age was . months (ds hh¢# ) and median months. we found significant statistical differences in calculated ,is observed mortality rate comparing malnourished with euthrofic patients; mechanical ventilated (mv) with non mv patients. no differences in ter ~,h of stay or di~ noses were found. effect of the un sanctions on the morbidity rate araong the iraqi small children ( below years old of age ) in bagdad. abdulsamad a.abood / institute of medical technology, bagdad. meningitis is essentially a childhood disease (i). the risk of infection are increased by powerty and overcrowding ( ). the impah'ed immunity may be an important pathogenic factor underlying the susceptibility to infections in undernourished subjects ( ). in general, malnutrition is a man made disease and it begins quite in the womb and ends in the grave (i). small children, below years of age were admitted to the pediatric hospital in washash with meningitis over cold months in i , in contrast to only child admitted with meningitis over the same period in . all of the children who admitted in were frankly undernourished, % of them were infected with enterobacteriae, because they were exposed to faulty hygiene and lack of asepsis. these facts showed precisely that our small children had suffered at most from the un_ sanctions against iraq, because of food, milk and drug shortage, since years which had resulted a severe undernutrition among them, which impaired their immune status. m wells, of riera-fanego, j lipman. baragwanath intensive care unit, university of the witwatersrand, south africa. background the use of prism or other scoring systems in the icu is of great importance for evaluating the efficacy and efficiency of a particular icu, the prism score was developed and validated in the usa and europe but has recently been shown to be inaccurate in a south american population, a south african population as well as several european studies. part of the poor performance of the prism score is as a result of differences in the case mix between the reference population and other paediatric icus. since scoring systems should generally be used only in populations similar to the reference population from which the prediction model was developed, a modification of the prism score is necessary to improve its discriminatory ability in a wide range of patient groups, aim to improve the predictive power of the prism score in a south african paediatdc icu population. patients & methods we analysed prism, demographic and clinical data collected prospectively from consecutive paediatrie icu admissions. the prediction of actual mortality by prism was evaluated by standard statistical methodology (goodness-of-fit test and receiver operating characteristic (roc) analysis), the components of the prism logistic regression equation (prism score, operative status and age) and the physiological variables making up the prism score in addition new variables analysed (nutritional index, the need for inotropes and institution of mechanical ventilation) were subjected to discriminant analysis to determine their association with outcome. results the goodness-of-fit test showed a significant failure of prism to accurately predict mortality over a wide range of expected mortality (chi [ ] = , p = ). prism underpredicted mortality at lower prism scores, but overpredicted mortality in patients with high prisms. similarly roc annysis indicated apoor predic~jve power (az = . ± . ), with an area under the curve significantly less than that for the prism reference population (p = ), prism showed equally poor discriminatory function at all age groups and diagnosfic categories. '~mth the addition of an index of nutrifional status (proportional weight-far-age), and indicators of early respiratory and cardiovascular failure to the logistic regression formula, and a recalibration of the acute physiological score component, the roc can be improved to . ± . , with a good fit described by the goodness-of-fit test (cn ] = , p = . ). discussion the prism score is not accurate in our patient population has been recalibrated in view of the poor discriminatory function that we have shown. part of the inaccuracy derives from the different demographic characteristics of our icu population and a different pattern of diseases. in addition to assessments of acute physiological aberrations, an assessment of nutritional status and early respiratory and cardiovascular failure significantly improve the discriminatory ability of the prism score, these parameters have been devised with a view to improving the accuracy of prism in our population, while not decreasing its accuracy in icus similar to the reference population. in interviewing parents regarding how physicians have communicated bad news, the response i have received is that it has not infrequently been done without appropriate care, understanding and compassion. personal experience and the lessons learned from parents, chaplains and others who deal extensively with these situations have provided me with an approach that has been supportive, compassionate, and caring. an especially difficult communication situation for the intensivist occurs when the parents have to be informed of the death of their child. for the parent, death is the hardest loss of all -the ultimate unalterable loss. circumstances surrounding the death are an important consideration (e.g., a fatal crash caused by a drunken driver, a prolonged illness, a suicide, aids). each produces a different grief reaction. the physician needs to inform parents of their child's death sympathetically coming right out with the news and leaving details until later. allow pauses and time for the paren~ to express sorrow and grief, the best communication may be thoughtful silence and a tender touch. there is disbelief that this happened. it is necessary to repeat oneself. acknowledgment of the parent's "feeling terrible" and the physician's acknowledgment of how terrible he/she feels that the life of the child could not be saved is an important first step in the parent's dealing with this tragic loss. with prolonged resuscitation, it is helpful to have a member of the icu team talk to the parents while the resuscitative efforts are ongoing so that the parents are not left unsupported at this time. a progress report should be delivered in a caring, lucid, and sensitive.manner, indicating that every effort is being made to save the life of their desperately injured child. after a child has died, it is helpful to the family if the physician maintains some contact with them. this should take the form of follow-up telephone calls at approximately , , and months. this can help to screen for depression in the parents. in giving bad news to the family and making every effort to support them through this tragic time, it is necessary to remind oneself that the intensivist has personal needs for dealing with grief and will also require support to pass through this stage. direct evidence that child mortality is lower in specialist pediatric icus comes from studies. a study in oregon (ccm ; : - ) found that mortality adjusted for severity of illness was % of expected in pediatric units and % of expected in general units (p< . ). a study in holland (ccm ; : - ) found that mortality in high risk patients was % of expected in tertiary pediatric units, and % of expected in nontertiary units (p< . ). a third unpublished study, has found that children in victoria (who almost all receive intensive care in a pediatric icu) have a much lower standardised mortality rate than children in the trent region of the uk (where many children receive intensive care in adult icus). there is indirect evidence that icus looking after many children are likely, on average, to perform better than icus looking after few children: numerous studies in many specialities have found that units looking after many cases of a particular disease have better results than units with few cases. see luft hs, "hospital volume, physician volume, and patient outcomes", happ, ; and farley d, medical care ; : - . compared to general icus, medical and nursing staff in pediatric icus are likely to be better at looking ~fter children, and plcu rmos have greater skills in pediatric intubation, ventilation, iv drip insertion and drug doses. picus are more likely to have appropriate equipment to manage children -especially for uncommon but life-threatening situations. icus in pediatric hospitals are more likely to have physicians and surgeons with pediatric expertise available for consultation at all times. the american academy of pediatrics, the society of critical care medicine, the british paediatric association and the australian nh&mrc have all said that children should receive intensive care in'specialist pediatric units. the weight of authoritative opinion, and direct and indirect evidence is strongly in favour of looking after children in dedicated pediatric icus. neurological deficit showed higher cbf values ( . / . ml/ g/ rain.) than the patients with good outcome (mean cbf . sd + . ; cbf . sd _+ . ml/ g/rain}. discussion: in asphyxia decrease of ph is due to reduced tissue oxygenation and indicates the severity of metabolic derangements. co reactivity in newborns with perinatal asphyxia correlates with the lowest ph and therefore may reflect severity of asphyxia. continuous monitoring of cerebral activity is carried out in our unit on all admissions at risk of cerebral dysfunction, a number of monitors are commercially available and we report our experience with the cfam which provides in addition to amplitude integrated eeg analysis, continuous raw eeg display and frequency distribution. bilateral recordings are commenced as soon as possible and continued while clinically indicated. forty one children ranging in ages from weeks to years were monitored for periods from hours to i days, diagnoses included traumatic brain injury ( ), sepsis/meningitis/encephalitis ( t), status epilepticus ( ) and miscellanous others ( ). results are tabulated below. patients status epilepticus * beta activity * background voltage * < i o/zv or more of above * (*z p < , ) asymmetry developed in children, all of whom died. positive predictors of good outcome included a mean background activity of > zzv, the presence of faster frequencies (usually ) in response to sedative drugs and the absence of seizures. all monitoring is performed by the picu staff and increasing expertise in interpretation has resulted in earlier therapeutic and diagnostic interventions. regional it was previously found that histamine, a vasoactive mediator, accumulated in brain compartments (kov~ics et al neurosci lett : ) , and antihistamines prevented brain edema formation (dux et al. neuroscience : ) in asphyxiated newborn pigs. in the present study we investigated the effect of intracarotid histamine injection on the blood-brain barrier (bbb) permeability, left internal carotid artery of newborn pigs ( - h; , - , g; ketamine anesthesia, mg x kg ) was catheterized through the external branch and different doses of histamine ( , - , xi - , - , x , m, respectively, in groups of animals; n= in each) diluted in . ml isotonic saline was injected into the vessel through rain. bbb permeability was determined for a small (sodium fluorescein, sf, da) and a large (evans blue/albumin, eba, kda) tracer ( %, mlxkg , rain circulation time for both dyes) concomitantly in frontal, parietal and occipital cortex, hippocampus, and periventrieular white matter both on left and right sides h after the challenge. then, intravascular dyes were removed by perfusion and bbb permeability for both tracers was quantified by fluorescence spectrophotometry (wavelengths for excitation and emission were nm and nm for sf; and nm and nm for eba, respectively). histamine injection, in doses higher than . m, significantly (p< . ; kruskal-wallis one way anova on ranks followed by dunn's test) increased bbb permeability for both tracers in each brain region. changes in left hemisphere were more intense (p< . ) than those in right one after the doses of xi - and - m in each region, i m histamine administration induced similar edema in both sides. increased intracarotid histamine levels resulted in a dose-dependent vasogenic brain edema formation. histamine might have a pathogenetic role in neonatal hypoxicischemic cerebral injuries. supported by otka f- and h-u.s,-jfno. , $ in coma caused by traumatic brain jnjury, an indication of the likely outcome is provided by the best motor response to pain in the first .$ hours after the insult. in a study in our picu, the proportion of children who died or had a severe disability was % in who had no response to pain, % in with an extensor response, % in with a flexor response, and % in who localized in response to pain. the long term outcome of traumatic brain injury appears to be worse in children < years old. other risk factors in traumatic brain injury are absent basal cisterns, midline shift or subdural haemorrhage on ct scan (or loss of grey-white differentiation in nontraumatic injury); or an intracranial pressure > mmhg despite hyperventilation, mannitol and barbiturate infusion. apart from brain death, there are two findings implying such a poor prognosis that consideration should be given to stopping treatment: first, after traumatic injury, the absence of any motor response to painful stimulus in the cranial nerve distribution (providing drug effects and a post-ictal state have been excluded); and second, in acute brain injury from trauma, infection, hypoxia, or ischaemia, the b{lateral absence of short-latency somatosensory evoked potentials (providing brain stem haemorrhage, subdural and extradural effusions, and decompressive craniectomy have been excluded). in children over months of age, recovery from prolonged coma or a vegetative state is exceedingly rare when more than months have elapsed after traumatic brain injury, and when more than months have elapsed after nontraumatic injury. overproduction of nitric oxide (no) via an inducible isoform of" no synthasc (inos) produces profound vasodilatation in adult septic shock. high nitrate levels have been reported in hypotensive children with sepsis syndrome ]. cardiovascular collapse is a prominent feature of severe meningocoecai disease (mcd). however, systemic vascular resistance (svr) was slightly higher in a group of non-survivors ~ and the rote of no in ivicd remains unclear. children with a presumptive diagnosis of mcd were enrolled. parental consent was obtained. blood was drawn on admission and hrly thereafter. plasma was separated immediately and stored at - °c. the final concentrations reported represent the product of nitrite and nitrate (nox). nox was measured spectrophotometrically using the greiss reaction. children were studied (median age (range); m ( - )). the diagnosis of mcd was confirmed in children, of whom had a glasgow meningococcal score (gms) of" ~ . in this group with severe mcd there were deaths. peak nox was significantly higher (,. ( - ) vs ( - )nmol/ml, median) and systolic btood pressure was significantly lower in children with severe mcd than mild mcd (p< . . wilcoxon rank test). there was a significant correlation between peak nox and gms (spearman's rank correlation r= . (p= . )) and prism (r= . (p: . )). nox production from adm.ission onwards was also higher in the severe mcd group (p: . , kmskal ~wallis). we have demonstrated that plasma nox levels are elevated in children with mcd, correlate directly with the severit ' of disease and are inversly related to systolic blood presssure. similar to hypotensive septic syndrome, mcd appears to be associated with an up-regulation of the l-arginine-no pathway.. non-survivors with mcd have higher svrs and may be relatively hypovolaemic. in our group of severe mcd there was a significantly lower systolic pressure and increased no formation. excess inos expression at different stages in mcd may contribute to the pathology of the disease. the identification of agents which can boost and/or inhibit no reiease may therefore represent different treatment strategies for mcd. u. merz, th. peschgens, g. kusenbach, m. b hle, h. h rnchen in this controlled, prospective study ventilated premature infants with a birth weight < g were randomized to receive treatment with dexamethasone (dex) either on day of life or on day of life. dex was given over days tapering from . mg/kg/day to . mg/kg/day. the infants treated with dex on day of life could be weaned earlier from the ventilator -in median after days (range - ) versus days (range - ) in the [ate treatment group (p = . ). the need for supplemental oxygen was shorter in the early treatment group -in median days (range - ) versus days (range - ) (p = . , ns). the incidence of chronic lung disease was lower in the early treatment group - of infants ( . %) versus of patients ( . %) (ns). to evaluate the long-term efficacy of early dex treatment we performed a respiratory function test in the age of - months using an infant whole body-plethysmograph. the intrathoracic gas volume (itgv), the airway resistance (r.w) and the airway conductance (gaw) were measured and no significant differences could be detected between the groups. the frequency of adverse effects due to dex therapy was found to be without significant differences between the early and the late treatment group. we conclude that early dex treatment had short-term improvements in pulmonary outcome in our study population, long-term efficacy however, remained unproven. several factors contribute to the development of chronic lung disease (cld) in premature infants including structural immaturity of the lung, mechanical ventilation, and oxidative stress. reactive oxygen species are formed during normal cellular metabolism but they are generated in higher concentrations during inflammation or inhalation of high oxygen concentrations. to study the relationship between increased oxidative stress, antioxidants and the development of cld we examined ventilated premature infants with birth weights below t g. infants developed severe chronic lung disease of prematurity (cld), defined by radiological signs of cld and an increased oxygen requirement at a postconceptional age of weeks, and infants had moderate cld with an increased oxygen requirement on day but not at an age of weeks. ventilator settings (fio , peak inspiratory and mean airway pressure) and the incidence of early-onset-sepsis were significantly higher in the severe cld group than in infants with moderate cld or without cld (n= ) during the first week of life. plasma concentrations of the two antioxidative substances bilirubin and uric acid (ua) were comparable in all groups during the first days of life. however, on day seven bilirubin and ua were significantly decreased in the plasma of infants with severe and moderate cld compared to the non cld group (p<o. ). there was no difference between both cld groups. in serially obtained tracheal aspirate fluids (taf) malondialdehyde (mda) was measured by hplc as an indicator of lipid peroxidation reflecting oxygen injury of the lung. ua was found in higher concentrations in taf than bilirubin. ua has been proven to be a potent antioxidant, capable to react especially with hydroxyl radicals and hydrochlerous acid, which play an important role in the induction of lipid peroxidation. infants with severe cld had significantly higher mdnua ratios in taf from day to compared to the non-cld group (p<o. ). mdnua ratios in taf of infants with moderate cld were significantly higher from day on but still lower than in the severe cld group. in addition, the ratio oxidized / reduced glutathione was significantly increased in taf of infants with cld compared to infants without cld between day and . the data support the hypothesis that an imbalance of oxidative stress and antioxidant defense contributs to the onset of cld at the end of the first week of life. introduction. rocuronium bromide (roe), a neuromuscular blocking agent with an onset time dose to that of succinyleholine l'z, has been studied in american society of anesthesiologists' physical status (asa) i or ii pedlatrie patients under non-critical elective conditions. there is a paucity of studies looking at the pharmacodynamics of roc under emergent conditions, involving pediatric patients who are asa iii or iv, without the use of adjuvant inhaled anesthetics ~. methods. with approval of our committee on clinical investigations (irb), roe . mg/kg was administered to asa iii/iv pediatric intensive care patients (age days to months; m:f= : ) on intravenous sedation. the time to reach % a~d % of b~elinc tetanie stimulus response was recorded using a r.elaxogra'ph/qmt- nerve stimulator/recorder (datex, helsiaki). depth of clinical relaxation at the % level was recorded. results. the time from rapid bolus to % was . + . see with a range of - see; and to % was . + . see, with a range of - see. at the % level, excellent clinical relaxation was seen. conduslon. in critically ill children, use of roe at . mg/kg produces rapid onset of neuromuscular blockade and excellent clinical relaxation, such that roe should be considered for rapid sequence intubation. int anesth clin. ; ( ): - . anesthesiology. ; ( ) computed tomography of the chest (ct) in mechanically ventilated adults can detect intrathoracic pathology not appreciated on chest radiographs (cxr) and influence intensive care management. no such data exists for ventilated children. aims: ) to assess if ct provides additional information over cxr regarding extent and nature of intrathoracic disease in ventilated children. ) to determine whether such information alters clinical management, inclusion criteria : ventilated children with cxr changes inconsistent with their respiratory status underwent ct if either a) pao :fio ratio < and/or mean paw> cm h or b) there was an unexplained increase in ventilatory requirement. methods : high resolution ct was performed in patients and spiral ct in patierits, to ensure minimal transport related morbidity, patients were transferred to the ct scanner by a specialised mobile intensive care team. results: in / patients ct demonstrated greater extent of disease than appreciated on cxr but did not significantly alter clinical management. in / patients ct provided additional information regarding the nature of disease present, in / children this involved a further diagnosis and in / children the exclusion of a suspected pathology. new information led to a positive therapeutic intervention in children, prevented inappropriate manoeuvres in , and had no significant effect on acute management in children. conclusions: initial data suggests that in a selected group of mechanically ventilated children chest ct can add to the sensitivity and specificity of intrathoracic diagnosis provided by the chest radiograph and directly influence acute management. case selection criteria and choice of the most appropriate protocol requires further study. pressure control ventilation (pcv) utilizes a decelerating flow pattern which may improve gas distribution and lead to alveolar recruitment. in contrast, volume control ventilation (vcv) employs a constant flow. in children, the effects of pcv as compared to vcv are unclear. the purpose of this study was to determine how these two modes compare in terms of dynamic compliance (cdyn). peak iaspiratory pressure (pip), and mean airway pressure (paw) at equivalent minute ventilation. methods: sixteen infants and pediatric patients ranging in age from day to years were studied. diagnoses included ards ( ), postoperative cardiac surgery ( ), head trauma ( ), and resfrictive lung disease ( ). patients were randomized to pcv ( ) or vcv ( ). initial measurements of gas exchange (abg's) and respiratory mechanics (ventrak, novametrix medical systems) were obtained after a minute stabilizadon period. respiratory mechanics included pip, peep, paw, delivered tidal volume, and cdyn (avolume/apressure). the patients were then crossed over to the alternate mode of ventilation holding delivered tidal volume, peep, inspiratory time, minute ventilation, and fio constant. data were collected after minutes, in each mode the absence of intrinsic peep was confirmed. to assure that the measurements were not affected by changes in clinical status, the patients were returned to the initial mode of ventilation and measurements repeated (final) . patients were ventilated with a siemens c or sv . reselts: data were analyzed using -way analysis of variance with repeated measures. ~ < . vs. vcv) vcv pcv ~ initial ] final ! cdljn . _+ . . _+ . * . _+ . . _+ . i , pip + . l-_t. * _+ , +- , paw . _+ . . i-_ . * . + . . -!-_ . pao _+ +- _+ _+ discussion: at the same minute ventilation, the decelerating flow pattern of pcv resulted in a % increase in cdyn and an % increase in paw while decreasing pip by %. the lack of a significant change in oxygenation may be a result of the limited time in each ventilator mode as well as the inclusion of patients with both normal and abnormal lungs. there was no significant difference in initial and final measurements indicating patient stability. the beneficial effects of iecre~l~iug cdyn and paw while decreasing pip indicate that pcv may be a preferable mode of ventilation in patients with lung injury. further randomized studies examining the effect of pcv on respiratory outcome measures in pediatrics are indicated. prolonged positive pressure ventilation following repair of cdh is associated with a high prevalence of iatrogenic lung injury, in our unit dudng - late deaths after repair of cdh were due to chronic lung disease. since babies requiring assisted ventilation for more than days following surgery were transferred to a cnep chamber to limit lung injury. cnep of - cm of h was combined with positive pressure ventilation via an endotracheal tube dudng the transition phase. immediate reduction of peak inspiratory and positive end pressures were possible and following extubation respiratory support was maintained by cnep v~th appropriate inspired oxygen. overall outcome: [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] n= deaths before surgery (%) ( ecmo during - / who were ventilated for more than days received cnep and there were no deaths and no chronic lung disease in that group. cnep assisted ventilation may be an important management option for babies who require prolonged respiratory support to avoid the adverse effects of chronic positive pressure ventilation, introduction so far modes of liquid ventilation (lv) have been used in experimental animals and, exceptionally, in humans: . total liquid ventilation (tlv)-functional residual capacity (frc) is filled by perfluorocarbons (pfc), and slow tidal volume (tv) breathing is performed by pfc. . partial liquid ve, ti,la~ion (page) -only frc is filled by pfc. gas tv is delivered by conventional mechanical ventilation (cmv), high frequency jet ventilation (hfjv) or high frequency oscillation (hfo). the aim of our study is to present our limited experience with page in newborns and infants. page was used in two groups of infants: , in infants with brain death before disconnection from cmv, because recipients for organ transplantation were not available. these infants have relatively normal lungs (fio~ less than . ). infants stayed on page for hour, during that period no ventdator manipulations were made. after page, infant were switched to cmv for next hours. . very critically diseased infants with ards (rds) - on ecmo more than days, before cannulation for ecmo, on hfo because of intractable respiratory failure, preoxygenated rm (miteni, italy) was used in the doses up to ml/kg intratrachealy. blood gases and parameters of pulmonary mechanics were followed (dynamic compliance -c dyn, airway resistance -raw, bicore monitor). page was combined with no inhalation ( - p.p.m, in infants). in both groups ad hoc an approvement from e local ethical commission and informed parental consent were obtained. in the first qroud with relatively normal lung parameters of oxygenation drops after pfc instilation intratracheally and stayed depressed for - hours. slight pco retention occured in both cases during page. c dyn increased almost double during page period, raw drops transitorily after pfc instilation but in minutes they were identical like in prepage period, parameters of oxygenation (peo /fio ) after - hours after page improved and were better than in prepage period. after that time infants were disconnected and died. in the second group no improvement of oxygenation was seen in one ecmo baby, in spite ()f transient improvement of c dyn. in the second ecmo baby, oxygenation improved and flow of pump could be decreased by more than %. none of these babies, however, survived, improvement was only transient in spite of repeated dosis of pfc. in these babies serious problems were to maintain the adequate frc by liquid, because of severe air leak, in babies on hfo/hfjv with severe ards/rds the improvement of oxygenation were seen in all the cases immediately after pfc instiletion for the period of - hours. after that period, pfc dose had to be repeated. two babies of this group survived. conclusion. page is going steadily from tabs to clinical practice. it is simple, could be performed anywhere, cheaper than tlv. however, because liquivent -perflubren (aliance pharmaceutical) is not available in europe, rm of (mitenti, italy) is the only solution, which could be currently used here. before the widespread use of page in clinics, liquid network among most nicus and picus must be built up, the criteria for page must be defined and ethinal-legal problems resolved as well. after resolution of these particular problems page can be life saving procedure for very special part of critically ill newborns end infants. catherine caronia, peter silver, laura nimkoff, cad quinn, jack gorvoy, and mayer san. division of pediartic critical care, medici,, schneider children's hospital, new hyde park, ny , imroduetiun: cystic fibrosis (cf) patients awaiting lung transplantation present a therapeutic dilenuna when severe respir, aory decompemalion occurs, endotracheal intubation and mechanical ventilation is known to have no long term benefits and is associated with high morbidity and mortality. noninvasive respiratory support appears to be a beneficial alternative. methods: we instituted bipap (respironics, inc,, murrayville, pa) in end-stage cf patients who were admitted to the pediatric icu with severe respiratory decompeusation. all patients were awaiting tung transplantation. after a control period, bipap was applied via a tight fitting nasal or facial mask, using the spo~aneous breathing mode, expiratory pressures were set at - cm hhzo. inspiratory pressures were started at cm ~i o and increased in cm i-i increments until the patient's respiratory comfort was achieved and substantiated by non-invasive monitoring. patients were instructed to use bipap during night sleep and whenever subjectively required, data are reported as mean _+ s.d. results: all patiems utilized nocturnal bipap for - hours/day during a follow-up period of - months. compared to their pre-bipap status, the patiems' oxygen requirement and respiratory rate both oz~ cundusion: bipap tl~rapy improves the respiratory status of decompeusatir!g end-stage cf paacnts. it is well tolerated for long term use at home, and provides an extended period of respiratory comfort and stability for cf patients awaiting lung transplantation. l. bindl*, g. kiihl**, p. lasch***, appel**, j.m er**** and the "arbeitsgemeinschaft ards im kindesalter" background acute respiratory distress syndrome (ards) is a therapeutic challenge in pediatric intensive care in view of the high mortality, in about german paediatlic hospitals founded a working group aiming on collaborative clinical research in this field. aims and methods the aim of both a prospective and retrospective survey conducted in german pediatric intensive care units in was to accumulate data on the epidemiology, risk factors, natural history and treatment strategies in a large group of pediatric ards patients who were treated in the tt~ee year period from to .all patients had acute bilateral alveolar infiltration of noncardiogenic origin and a po ~io ratio < mmhg. the influence of sex, underlying disease and single organ failure was analyzed using the fischer's exact test, the influence of additional organ failure on mortality was tested with the cochran-mantel-haenszet statistics. results patients were reported giving an incidence of cases per admissions to pediatric icus. median age was month. in % of the cases, ards was associated with a pulmonary, in % with a systemic underlying disease. in % immunocompetence was impaired. mortality was % and not dependent on age, sex and triggering event. the number of associated organ failures, however, strongly influenced mortalib,. mortafity in immuno-compromised patients was t %. the analysis of treatment modalifies employed in the patients revealed a lack of uniform therapeutic strategies. on the other hand, the patients were exposed to interventions not yet supported by controlled trials. conclusions the observation of the lack of uniform treatment strategies led to the elaboration of recommendations on ventilator therapy and patient monitoring within the working group. the data gathered in this survey provide the basis for the design of prospective multicenter studies urgently needed to evaluate innovative treatment modafities in pediatric ards. recurrent apnea and respiratory failnre due to severe lower respiratory tract disorders such as bronchiolitis or pneumonia are the most common reasons for mechanical ventilation during respiratory syncytial virus (rsv) infection. acute respiratory distress syndrome (ards) has been described as a complication of severe rsv infectionj in contrast to the low mortality rates associated with rsv infection (< %), mortality rates in the range of - % have been reported in pediatric patients with ards. however, studies on ards are usually lumped in respect to causation and the disease course of rsv induced ards has not been previously studied. we examined the lung function abnormalities of infants with rsv induced respiratory failure requiring assisted ventilation, measurements included respiratory mechanics, maximal expiratory flow-volume curves and lung volumes, ards was defined clinically using the criteria which were recently proposed by the american-european consensus conference on ards~: acute disease onset, pao /fio~ ratio _< mrn hg, bilateral infiltrates on chest radiograph and absence of clinical evidence of left atrial hypertension. we calculated the murray lung injury scores modified for use in pediatric patients from total respiratory system compliance, radiographic findings, ventilator settings and blood gas results. we identified infants with severe restrictive lung disease that fialfilled the clinical criteria fbr classification as ards. all had lung injury scores above . which is the recommended cut-off for a diagnosis of ards, twenty-seven infants had obstructive disease consistent with a clinical diagnosis of bronchiolitis. the ards patients were significantly younger, had a longer time of assisted ventilation (p < . ) and a greater proportion of infants with preexisting illnesses (p= . , odds ratio = . ) when compared to the patients with obstructive disease. with the exception of one immunodeficient patient, none of these infants died. given the low mortality despite a clinical picture of severe lung injury, there is evidence that rsv induced respiratory failure may represent a relatively benign cause of ards in pediatric patients, bachmann an audit of patients with severe acute bypoxic respiratory failure (ahrf) receiving highfrequency oscillatory ventilation (hfov) in our unit ( n= , mortality %) revealed that sub-groups with severe underlying disease (n= , mortality %)and those with mu~pie organ failure ( > systems failing, n= mortality %) accounted for all the deaths beyond the neonatal period. v~ therefore hypothesized that in a modem paedistric intensive care unit (picu): a) children greater than one month of age with ahrf do not die in the absence of severe, pre-existing disease or multi-organ dysfunction syndrome, b) respiratory parameters alone will predict outcome poorly in ahrf. method prospect~/e sty/of all adm~ns to our tertiary picu. data it, citing the respiratory parameters (oxygena~n index [ol] , aiveolar-artedal oxygen tension gradient , pao /fio ratio) were collected hourly from the bedside charts throughout admission. patients were included in the study if ahrf was present at admission either none or in combination with other organ dysfun~on. ahrf was defined as the acute (< hour) onset of respiratory dysfunctk:~l with a pao /fio ratio.< for six consecutive hours dunng the first hours of admission (with no evidence of left anal hypertension), x-ray review defined a sub-group of patients with acute respiratory distress syndrome (ards) by the presence of bilateral interstitial infiltrates. results to date children (ages - months, weight . - kg) have been admitted in ahrf. of these also had ards. the overall mortality was . % ( / ), and greater in the ards group than the non-ards group ( t , . % vs, , . %, p< o. ) . it was not possible to predict survivors from non-survivors on the basis of the seventy of the respiratory failure alone, the a-ado on the day of admission (best in hours) was not significantly different between survivors and non-survivors: (mean, + sd)( mmhg +_ , vs mmhg _+_ ). kdl non-survivors were immunodeficient (n= ), previously extmrnsly premature infants (< ),(n= ) or suffedng fcom chronic metabolic or gastrointestinal disease (n= ). no previously normal child died. conclusion the severity of respiratory failure does not allow predioljon of outcome in our patients. we believe that this reflects that modem picu is so effective at providing respiratory support that pre-existing pathology alone de~ prognosis. this suggests that an abnormally regulated host response or abnormal persistence of a pathogen may be required to induce lung injury of sufficient severity that the resulting respiratory failure cannot be supported in a modem picu. introduction: postural changes (supine to prone) is a therapeutic intervention that could be useful in children with adult respiratory distress syndrome. objective: to determine the effects of postural changes in the oxygenation of young children with ards. method,s: a prospective stud ," was performed in eleven subjects aged to months (mean= ) with the diagnosis of ardsreceiving vendlatory support. (mean peep and fio of and . respectively). postural changes was performed every - hours, during a period of time ranging from to days. arterial blood gases were determined before and - n~n after the postural change, no modification in the mechattical ventilation other that changes in the fio were performed. the oxygenation was determined by the index pao /fi (p/f). to study the differences between the oxygenation mean, before and after the postural changes the wilcoxon test for paired samples was used, results: changes were performed ( from supine to prone and from prone to supine). a % increased p/f ratio was obtained after the change from supine to prune. although, not all the patients receiving postural changes improved their p/f. six of them (group i) showed an improve in the p/f when changed from supine to prone, returning to their base line when positioned from prone to supine. no improvement on the p/f was observed in the remaining subjects (group ii)after postural changes (table ) . during the maneuver no complications were observed. two patients had a pneumothorax, not related with the postural change. conclusions: postural changes (supine to prone) is an easy way to improve oxygenation in some children with ards. change to prone change to supine introduction: the common noninvasive diagnostic efforts to identify possible obstruction of the intrathorucic airway, are of limited value. invasive procedures such as bronchoscopy and bronchography may also be noncontributory and entail risks. we evaluated the usefulness of d-ct in the diagnosis and management of pediatric patients with suspected intrathoracic airway obstruction (itao). methods: we used a diagnostic algorithm (see diagram) in patients with suspected itao resulting in respiratory distress. three-dimensioual imaging of the tracheobronchial tree was reconstructed, following high speed spiral ct scan, by specific computer software (advantage window computer work station, general electric, milwaukee, wisconsin). non-ionic contrast medium was injected, in some patients, to delineate the intrathoracie large vessels.. results: eight patients were studied. in patients the d-ct revealed intrathoracic airway abnormalities. these patients underwent further invesive studies which confirmed the following diagnoses: patients had bronchomalacia, had bronchial stennsis due to a dilated pulmonary artery mad patients had subglottie stenosis extending to the thoracic cavity. three patients had no significant disruption in the configuration of the tracheobronchial tree and thus did not require invasive diagnostic procedures. conclusion: computer reconstruction of three dimensional images of the tracheobronehial tree is a safe and reliable diagnostic tool for itao. ards and ecmo; preliminary data from a randomized clinical trial. j fackler, c steinhart, d nichols, d bohn, m heulitt, t green, l martin, k newth, m klein, j ware. many suggest ecmo be considered experimental for ards and undertaken only with careful data collection and reporting. a mtflticenter pediatric rct is in progress to determine whether ) ecmo and/or ) permissive hypercapnia, offer significant advantage for the treatment of ards. methods: all patients aged wk to yr (without congenital heart disease) are eligible for study. data collection begins when a patient receives at least % oxygen and a peep of cm h for hours (stage t). if the predicted mortality reaches % within days (stage ), eligible patients are asked for written consent for randomization. patients are excluded from randomization with significant chronic lung disease, immune compromise, cardiac disease; or profound acute central nervous system damage. the prime outcome variable is survival. at the studies onset, pts were estimated to be required so that pts were randomized per arm. results: patients are enrolled from centers. data are complete on . patients never reached stage (i.e. % mortality). patients improved and died. of the latter, had randomization exclusion criteria even if stage was reached. patients reached stage . had exclusions from randomization and all died. eight patients ( survivors were eligible for randomization; consent was obtained in no case. two patients received ecmo. overall survival is % ( / ). in patients without randomization exclusions, survival is % ( / ). morbidity m survivors (discharge -admission popc or pcpc score >_ ) was seen in none of the stage surviviors and % ( / ) of those who reached only stage !. conclusion: the rct requires completion. the records of hospital in-patients at king faisal specialist hospital and research center who received external cardiac massage as part of their cardiopulmonary resuscitation were reviewed. success of resuscitation was analyzed as ( ) short term (restoration of spontaneous circulation), and ( ) long term (discharge from hospital). of such patients, ( . %) survived the initial resuscitation, and ( . %) were discharged. success of outcome was not related to age, location of patient, time of day, or rhythm at arrest, including asystole. longer resuscitation time was associated with less chance of restoration of spontaneous circulation (p< . ), but not associated with hospital discharge rate. results for patients with congenital heart disease were similar to those with other medical or surgical conditions. in this series, . % of ward in-patients survived to discharge, compared to two "*;'~r ~r;~' ,.,.'her,, the r-e~ult~ were c/ "'~d ~, ~,°(. overall, % of patients who survived the initial resuscitation were discharged from hospital. where resuscitation continued for more than minutes, . % of patients had tong term survival. outcome from asystole was no worse than for other cardiac rhythms, we believe that previous reports of poor outcome from asystole in pediatric cardiac arrest should noi influence decisions to stop resuscitation for pediatric in-patients prematurely. successful restoration of spontaneous circulation with long term survival can be achieved after prolonged resuscitation. abdelmoniem~ lindsey jahusou~,mariano fiallos, university of florida, prudential drive, suite jacksonville, florida usa central acidosis is well recognized as a marker of inadequate tissue perfusiou, and ventilation. however, obtaining central venous blcod is difficult and fraught with complications in the child undergoing cardiopuimonary resuscitation. intraosseous blood may be used instead of central venous blood to judge ph and pcoz during short durations of cardiopulmonary resuscitation and during hemorrhagic shock. the purpose of this study is to compare the ph and pcoz status of intraosseous and central venous during prolonged cardiopulmonary resuscitation after fluid and drug infusion. we hypotbesized that there would be no difference in ph and pco values of simultanecusly obtained intraosseous and central venous blood samples. eighteen ( ) introduction: cardiopulmonary arrest (cpa) in children is usually preceded by a deterioration of cardiac or respiratory function due to sepsis, dehydration and hypovolemia. early recognition of clinical and laboratory signs followed by immediate intervention are essential for prevention of cpa. the purpose of the present study was to identify factors which contributed to high rates of mortality from cpa in patients admitted to a paediatric intensive care unit (p cu). methods: a prospective study was done of all non-surgical patients with cpa who were admitted to the picu, hospital baca ortiz, quito ecuador from january to october . clinical and laboratory variables before and after admission to the picu, time from hospital admission to picu admission and the pediatric risk of mortality score (prism) were recorded on a questionnaire designed specifically for this study. results: of the non-surgical patients admitted to the picu, ( %) were admitted after developing cpa on the general pediatric wards. mean age was + . months, with of patients under months of age. initial diagnoses upon picu admission included meningitis (n= ), respiratory failure (n= ), congenital heart disease (n= ), severe neurological impairment (n= ), end stage neoplastic disease (n= ), hypovolaemic shock (n=l), peritonitis (n=l) and sepsis (n=l). mean time from hospital admission to p cu admission was _+ . hours. the mean prism score upon hospital admission was + . (score > = > % mortality). % ( / ) of the patients died. one of the three survivors had severe neurologie injury. prior to picu admission, patients experienced tac~,cardia (n= ), hypotension (n= ), neurological deterioration (n= ), respiratory, distress (n= ), oliguria (n= ), bradycardia (n= ), metabolic acidosis (n= ), hyponatremia (n= ), hypokalemia (n= ), hypocalcemia (n= ) and severe hypoglycemia (n= ). there were serious delays from the time of development of clinical and laboratory abnormalities to the time of admission to picu. conclusion: in the critically ill pediatric patient, rapid recognition of clinical and laboratory signs of deterioration, followed by immediate intervention, are required to prevent end stage shock and cpa. we found serious delays in intervention following development of important premonitory clinical and laboratory abnormalities in patients less than months of age on the general pediatric wards, which iikely contributed to the dismal % mortality rate. hospitals throughout ecuador should institute immediate improvements in ctinical supervision, and provide training in paediatric advanced life support (pals) to decrease excessively high rates of and mortality from cpa. intraosscous access is recommended by the american heart association and american academy of pediatries as a means of rapid access to the vascular system for childhood emergencies. bone marrow and fat embolism is a concern and has been reported post intraosseous infusion in stable animals but has never been studied in animals subjected to cardiopuimonary resuscitation. we undertook this study to investigate the incidence and magnitude of lat and bone marrow embolism with the use of intraosseous infusion during prolonged cardiopuhaonary resuscitation and after fluid and drug infusion. we hypothesized that there will be no difference in the magnitude of fat embolism between cardiopulmonary resuscitation only and other cxperirnental conditions. thirty-one ( ) piglets were anesthetized, mechanically ventilated, and instrumented (carotid artery, pulmonary artery and intraosseous earmulas ). the animals then underwent bypoxic cardiac arrest followed by chest compressions with the mechanical thumper (michigan insmunents) and mechanical ventilation for a minimum of minutes. the animals were divided in groups: a (n= ) which had no intraosseous, ~'oup b (n= ) had intraosscous with no infi~ion, and groups c (n= ), d (n= ), e (n= ) had intraosseous with infusion of adrenaline, normal saline and sodium bicarbonate, at cessation ofcardiopulmonary resuscitation, representative lung samples were collected fi'om upper and lower lobes of each lung, embedded in ocp and firozen immediately. ltmg specimens were stained using oil red-o dye and observed for fat globules and bone marrow elements. the amount of emboli present was rated as a percentage in relationship to iung tissue, by a pathologist blinded to the experimental groups. buffy coat specimens were collected before and at cessation of cardiopuimonary resuscitation, stained with oil red-o dye and observed for fat globules. percentage of fat present were compared using analysis of variance. fat globules were seen in the prebronchial blood vessels and in intravascular areas throughout all lung fields. there was no difference in appearance or distribution of fat globules between groups. quantity varied in the different groups[(a) %, (b) %, (c) % (d) %, (e) %], but were not statistically significant (p = . ). fat globules in the buffy coat were few and inconsistent with lung findings. fat and bone marrow emboli were present in all experimental conditions, the use of the intraosseous cannula does not increase the magnitude of embolization during cardiopuimonary resuscitation. the decision to use the intraosscous route should not be influenced by the risk of embolization. tzareva iv/,, md*, nedialkova r, md**, *dept. of pathophysiol, *~dept. of child surg. and icu, emergency medical institute pirogov, sofia, among children with blunt abdominal trauma, treated in emi pirogov during the last five years, children had serious disturbances of the basic vital functions, connected with the trauma, and most often with massive haemorrhage, for this reason being an object of reanimation and intensive care. in the group of children who survived - , predominated the trauma of only one abdominal organ (mainly the spleen, rarely the kidneys, the intestine) and only children had injuries of more than one abdominal organ. in the same group, in children the abdominal trauma was combined with chest or head trauma or bone fractures. in the group of children who died - , a profound combined trauma was present. the haemodynamic parameters in all children showed a characteristically significant tachycardia along with normal or even high blood pressure, while hypotonia was present in only % of the children on the first trauma day. despite the fact that only . % of the children had direct chest injury as well, the gas exchange was considerably disturbed - ' of the children were hypoxemic during the first, and % during the third trauma day -in % significant -below . kpa ( mmhg). together with the markable decrease in haemoglobin levels, this determines the pronounced disturbance in oxygen transport. during the first trauma day all the children were acldo~c, and a metabolic alkalosis was present during the following days. twelve of the children with severe combined trauma died within several hours, with the symptoms of irreversible haemorrhagic shock, or in the next - days, developing multiple organ failure. in conclusion, the intensive therapy of children with severe abdominal and combined trauma, should take in consideration the special haemodynamical trauma answer in children, and requires dynamic monitoring of the most influenced homeostatic parameters -blood gases, acid-base metabolism, haemostasis. introduction: endocrine emergencies, other than diabetic ketoacidosis, are uncommon causes of pediatric intensive care unit (picu) admissions. we report our experience of children diagnosed of adrenal insuficiency (ai) admitted in the picu, during the last four years. subjects: five eases of ai requiring intensive care unit admissions are presented. four females anna male, with ages ranging from days to years, none of them had a previous systemic or endocrine diseases that could suggest al the initial clinical manifestations were: dehydration ( ), vomits ( ), abdominal pain ( ), seizures ( ), lethargy ( ) and hyperpigmentation in the muco-genitat area in a newborn male and ambigna genitalia in a newborn female. the reason for their admission in the p cu were: shock in two subjects; three because of hyperkalemia and hyponatremia (k/na: . / ; / ; , / meq/l); and two with severe hyponatremia (na: ; meq/l). laboratory findings: severe hyponatremia ( ), increased concentration of urinary sodium and chloride ( ); metabolic acidosis ( ); hyperkalemia ( ); increased levels of urea ( ) and hypoglycemia ( ). in all of them, the electrolytes abnormalities did not normalize with replacement and only normalized after the administration of hydrocortisone. tile ai was due to: autoimmtme disease in two subjects, congenital adrenal hypoplasia, congenital adrenal hyperplasia secondary to alia hydroxylase deficiency and in one no etiology was found, at the present time, comments: aiis an uncommon disease in the pediatric age. anearly diagnosis is crucial, as if the treatment is delayed could lead to patients death. in subjects with arterial hypotension and electrolytes abnormalities refractory to the usual treatment, they should be treated with corticosteroids, if no etiology is found. although, previously samples must be obtained to make the diagnosis, : denotes the number of cases. gerbaka b; hakme c; akatcherian c. toxics are frequently involved in domestic accidents during childhood; among non medical products ingestion, carbohydrate poisoning is a serious injury often made possible by inadequate stocking. over years, children aged years and less were examined in the emergency department of hotel-dieu de france hospital for carbohydrate ingestion. , % are boys; age goes from months to years (moan = , years). kerosene is found in , % of cases; all were admitted (mean = , days). , % were symptomatic on first examination but % of all children presented signs of gastric ( %) or respiratory ( , %) irritation sometime during their history; , % had neurological signs and , % presented some fever. leucocytosis is found in % of cases; , % of the children received antibiotics. chest x ray was abnormal in , % of cases: mainly parahilar infiltrates were found, all children survived; , % with a normal course ( , days of hospital stay) whereas those who presented complications (severe pneumonia, coma) stayed in the hospital for days (mean) with short course of assisted ventilation for two of them; long term follow up was not possible. we fonnd nick's criteria for hospital admission to be of value: -symptomatic children with normal x ray } to hours monitoring -asymptomatie children with x ray abnormality } -symptomatic children with x ray abnormality: hospital admission -asymptomatic children with normal x ray : no admission. these criteria would have helped to avoid admission in children and would have allowed a short t hours stay for more. we found chest x ray to be mandatory in carbohydrate ingestion; other tests were not helpful, aside arterial blood gases measurement in case of respiratory involvement; we now also advocate more restriction in antibiotic use. prevention remains efficient and should be stressed on. severe liver failure [slf] is a rare but severe condition in infants. we report our experience. patients: slf was defined as liver insufficiency with hepatic encephalopathy and a decrease in the level of factor v to below %. between and , infants (mean : mo) were admitted for slf (neonates excluded). main causes were metabolic disorders ( . %) (tyrosinemian= , hemochromatosis n= , reye's syndrome n= , other n= ), virus-induced flf ( . %) and hematologic diseases ( . %). in cases, the causes remained undetermined. results: olt was contraindicated in cases because of multiple organ failure (n= ), or underlying disease. all of them died within days after admission. patients had no indications for olt, all but one are alive. ( of them was transplanted later for tyrosinemia and died lately (virus induced-slf). among the t infants who underwent emergency olt, are alive and died because of primary non function of the graft. conclusion: slf in infants admitted before their first birthday is a severe condition with an overall mortality rate reaching %. inherited metabolic disorders are the first cause of slf at this age. contraindications for olt are frequent because of underlying disease or multiple organ failure. a number of children undergo primary graft failure after liver transplantation. it is unknown if there is any increased morbidity or mortality following retransplantation. this study seeks to explore these issues. methods: a pediatric intensive care/iiver transplant database is in formation. records of all liver transplant patients are reviewed and abstracted. this data is then computerized to allow analysis. this data provides the source for this study. statistical analysis was performed via student's t-test where appropriate. results: of the patients who have thus far received at our center orthotopic liver ransplants, the records of who underwent transplants form the basis for this review. twenty-three patients underwent multiple transplants, required one additional, three required organs, and one patient survived after a fourth organ transplant, there was no significant difference in age at first transplant between those who received multiple organs and those who did not ( vs, months, p=ns). the anesthesia time for the procedure did not significantly increase tbr subsequent transplants ( . vs, , hours), nor did time in the intensive care unit (t . vs. . days), nor did time on the ventilator ( . vs. . days) subsequent transplants did not predispose to having more bleeding in the intensive care unit for usage of packed red blood cells or platalets was not significantly altered ( vs ml and vs ml respectively). patients who required retransplantatior~ did receive mere fresh frozen plasma (ffp)daring their first transplant than in the subsequent ones ( vs ec, p < . ). however ffp use was not significantly different than patients who did not require retransplant. patients who underwent retransplant had a markedly increased mortality ( %) than the overall mortality for liver transplants at our center ( %), conclusion: children who require another liver transplant have a markedly increased mortality. bleeding and prolonged icu stay is not significantly different between the first and subsequent transplants, fulminant hepatic failure and ortothopic liver transplantation.dr.sasb n,j;centeno,m;entin,e;acarenza,m;ciocca, m:gofii,j;bianco,g;weller, g;imventarza,o. unidad de cuidados intensivos.hospital de pediatria "dr.j.p. garrahan" .buenos aires.argentina. introduction:fulminant hepatic failure (fhf) is a clinical syndrome, defined by the development of hepatic encefalopathy within weeks from onset of illness in a previously healthy person.by far,the most comun cause of pediatric fhf in all series, is acute viral hepatitis.we report our experiences with the pediatric fhf and ortothopic liver transplantation (olt) as attemative of treatment. patients: childrens with fhf diagnosis were admitted at the picu from / / to / / .symptomatic treatment was given to all children and all were put on list for olt,) following the king's college criterion (protrombina time,age,atiologies,bilirrubin,and encefalopathy state). results:etiologic causes corresponded to the childrens were: , hav ( %); , noa nob ( %); ,autoinmune ( %).the age was mean: years (range: month- years).seventeen patients were transplanted, chidmn were discarded because:no donors: ;withdrow of the list: ,because sepsis in and bleeding of cns ;and no admission at list: because genetic syndrome ,massive intestinal necrosis, ,mitral valvulopathy and sepsis, . patients ( %) had at least one complication dudng the post operative period.the most frequent was the acute renal insufficiency(ari) and patients requiered continuos hemofiltration.the gtobal mortality rate was %.the mortality of patients without olt was % and the mortality of patients with olt was %, patients dayed because sepsis, ( candidiasis) and the others because mof.the actuarial survival at year is % and the follow up of months. conclusions:the fhf is a very severe and frequent disease at picu. supportive treatment only is associated with a very poor prognosis and high mortality rate.the most frequent etiology in our country is the hav. the olt is applicable in this cases and is a valid alternative of treatment (mortality in our series %).the ari is the most frequent complication during the post opeative period.in argentina,due the high prevalence of hav,prevention must be considered the main and only way to avoid this catastrophic illness.- to assess the efficacy of gastric intramucosal ph (phi) for evaluation of tissular perfusion and prediction of hemodynamic complications m critically ill children. patients and methods: thirty critically ill children ( boys and girls) whose age ranged from month and years old were studied. a tonometry catheter was placed in the stomach of all patients at their °admission in pediatric icu. intramucosal ph measures were made at the admission and each - hours during the study: a total of determinations were made. the catheter was removed after extubation and/or checking of hemodyrmmic stability of the patient. the intramucosal ph was derived from application of the henderson-hasselbaeh formula using the pco value from the tonometer and the arterial bicarbonate. values of phi between . and . were considered normal. the relationship between phi and severity of patient measured through prism, presence of major (cardiorespiratory arrest, shock) and minor (hypotension, hypovolemia or arrhytlmtias) hemodynamic complications, mortality and stay in the picu, was analysed. results: the admission value of phi was . -t- . (range . - . ). five patients ( %) had an admission phi < . . no relationship was found between an admission phi < . and a higher incidence of hemodynamic complications. sixteen patients ( %) showed some values of phi < during their evolution. patients with phi < . had a higher number of hemodynanuc complications than the rest (p< . ). every cardiorespiratory arrest (cra) and shock cases were related to a phi < . . patients with major complications (cra and shock) had a phi lower (p= . ), as well as a higher number of measurements of low phi (p= . ) than patients with minor hemodynamie complications. the value of phi lower than presented a % of sensibility and % of specificity with regard to hemodymanic complications. there was no relationship between phi < . and prims score and stay in picu. patients with phi < . presented a prims higher than the rest of patients (p< . ). conclusions: the phi value may be an early sign of presence of hem dyaaimc complications in the critically ill child. we tested the hypothesis that gastric intramural ph (phi) can be used as an early sign of failure m weaning pediatric patients because the blood flow from nonvital areas is diverted to meet the increased demands of respiratory muscles. methods: children (mean age ( . _+ . ) years + sd) who were thought by their physicians to be weanable from mechanical ventilation (mv.). these patients were ventilated on serve c ventilators, receiving ranitidine, and had intestinal tonometer (tonometrics, inc.) minutes before obtaining a sample.. all children were placed on pressure support (ps) at levels judged to overcome the resistance of the endotracheal tube and ventilatory circuit ( em h.,o). a sample of arterial blood and a sample oftonometer were obtained during vm and weaning (ps). phi, hemodynamic and respiratory data were recorded during vm and weaning we did not interfere with the primary caretaker's decisions regarding extubation. patients were considered to be successfully weaned if they were able to sustain spontaneous ventilation for more than hours after extubation. paired t-test were used to compare the values obtained during mechanical ventilation with those obtained during weaning trials. unpaired ttest were used to compare values from the group that was successfully weaned (a=i ) with those from the group that were not (b= ). results: we did not find statistical differences in any of those variables mesured during mv for patients who were successfully weaned(group a) and those who were not (group b). gastric phi was in group a: . + . (vm) and + . (weaning); in group b: . _+ . (vm) and . t _+ . (weaning). discussion: although we did not find differences in gastric phi during vm, the group a had a lower value than group b because of the number of cardiac patients ( %) and transfusion therapy, in fins group. in group b % of patients showed a problem in upper airway (subglottic edema, and enlarged tonsils). we found it after extubation. conclusion: ) gastric phi is a good predictor of risk in critically ill patients but maybe because of the small size of the sample, in our study is not of practical value as a predictor of failure in weaning pediatric patients from vm. ) this test is not a predictor of problems in upper airway~ important etiology of failure weaning in children. objectives: i-to determine the prognostic value of the gastric intramueesal phi in mortality and multiple organ dysfunction (sdmo) in critically ill children. -to compare this value, with the pediatrics risk index mortality score (prims). methods: aprospective study was performed with critically illcbildren, aged from mouth to years. the athnittiug diagnosis was: post-surgery ( neurosurgery, spinal fusion and thoracic or abdominal surgery), sepsis, polytraumatism, adult respiratory distress syndrome and with miscellaneous. all the subjects were monitorized on picu admission and treated for their underlying condition. gastric intramucnsal pt{ was measured following the tonometric method, ou admission and every - hours depending on the patients state. the severity of the clinical condition was evaluated using the the prims, on admission (prims-i) and during the first hours, when the clinical condition deteriorate, the worse score was utilized for the statistical analysis (prims- ). to perform the statistical analysis the subjects were divided in two groups, one with the phi< . and the other with phi> . .aunivariate analysis (student's tand wilcoxon two tailed test, chi-square) and multivariate analysis were used. results: out of the subjects dyed. of children developing multiorgan failure (mof) expired. % of the patients admitted to the picu with sepsis, ards and miscellaneous had a phi < . . in contrast, with % of post-surgical and none of the postqraan~atism. the mortaliry rate, in children with a phi< . was % (ci %: . ; , ) and . % (ci %: , ; . ) in children with phi> . (p= . ). mofwas observed in , % of children withphi< . v.s, . % with phi > . .no relatiouship was observed between the phi and the score of prims-i and . perforating an unconditional logistic regression analysis, two independent variables have mortality predictive value: the phi and the prism- . (table i) following induction of anaesthesia, a laser doppler probe (moorsoft instruments ltd) was inserted cm into the patient's rectum, the probe's special design ensuring that the optical prism lay against the mucosa. continuous monitoring of rectal mucosal perfusion ("flux") was continued throughout the operation. after rain cpb at °c, "steady state" readings of nasopharyngeal temperature, mean femoral arterial pressure (map) and flux were recorded over a further min before cpbinduced core cooling to - °c. steady state was defined as a rain period with no change in core temperatures or map. other rain steady state recordings were taken immediately prior to low flow, immediately prior to rewarming and after rewarming to °c, before initiation of any vasoactive drugs. the cpb flow rate was kept at m l k g - min q, the pcv at _+ %, the p~co at . + . kpa and the pro at + kpa. results: initial warm and rewarm map (both mmhg) were significantly lower ( = . ) than during the cold cpb periods ( & mmhg). the mean cold flux before ( ) and after ( ) low flow were both significantly lower (p= . ) than the mean initial warm cpb flux ( ). the mean rewarm cpb flux ( ) was significantly lower than all other flux values (p= . ). there were no siglaificant correlations between map and flux except at the first warm cpb period (r= , , p= . ). conclusions: although hypothermia significantly reduces rectal mucosal perfusion, rewarming produces an even greater reduction in gut perfusion which, considering that mucosal oxygen constmaption is highest during this time, may prove crucial in the postoperative development of mof. therapy aimed at improving gut perfusion during cpb should be directed at the rewanning period in particular. abstract this work is aimed at establishing a clinical procedure for the diagnosis of enteritis necroticans (en), even at the communal level, and to define criteria for diagnosis able to distinguish between acute forms. subjects and method : cases admitted at the institute for protection of children's health dpch), having characteristic symptoms, were examined clinically, by roentgenography of the abdominal cavity, with the analysis of the blood (total protein, electrolytes, hematocrite) and cultures of intestinal fluid and faeces. through surgical operations, the pathological lesions were observed and recorded. results: common epidemiological features: the average age is - years old ( - ) ; male/female : . ; in % of the cases, the disease occurred after a meal rich in protides. the acute toxic form accounted for % : severe shock appearing early, with very severe dehydration associated with profoundly decreased blood protein concentration and lowered natriemia as well. the lesions of the small intestine were expanded, all of them were necrotic. in the surgical form ( %), the predominant feature was an obstruction -peritonitis syndrome, the peritoneal fluid showed a characteristic inflammatory reaction. for the rest of cases % were the internal form, the shock syndrome was less severe, the abdominal distention was light and disappears gradually, the inflammatory reaction of the peritoneal fluid was not so characteristic. conclusion (ino) is a selective pulmonary vesodilator that is rapidly inactivated compared to intravenous vasodilators. these qualities make ino an attractive agent for the treatment of pulmonary hypertension (pittn). the efficacy of ino has been studied in persistent fetal circulation, acute respiratory distress syndrome (ards), and congenital heart disease (chd). potential adverse effects oflno include: nitrogen dioxide (no toxicity, methemoglobinemia, and platelet dysfimction. our objective was to evaluate the safety of ino in pediatric patients (pts). methods: pediatric pts. with phtn from ards or chd were studied under an established, approved protocol conforming to fda guidelines tbr an investigational new drug. informed consent was obtained for each child prior to treatment. no was sequentially titratad from parts per million (ppm) to , , , and ppm at ten minute intervals. parameters monitored before and during therapy included nitric oxide (no) and no~ concentrations (cone.), mean arterial blood pressure (map), and percent methemoglobin (mhg). no and noz levels were continuously monitored using an inline dr~ger electrochemical detection device. ~,litp was continuously measured with an indwelling arterial catheter. mhg was measured by co-oximetry. a mhg level e % or no cone. ~ ppm were considered adverse effects by study criteria. pretreatment map was compared to map at and ppm ino using paired t-tests. ap value < . was considered statistically significant. results: thirty-two mechanically ventilated children with phtn ( with ards, with chd) were studied. five pts. were treated following cardiopulmonary bypass. methemoglobin (met-hb) levels were routinely measured in two prospective clinical studies on no inhalation in pediatric patients with pulmonary hypertension following heart surgery with extracorporeal circulation and in pediatric and neonatal ards patients, the observed differences between the groups prompted in an in vitro study, red blood cells (rbc) of patients sampled before and after surgery with and without extracorporeal circulation (ecc), respectively, were incubated with ppm no for rain, met-hb, atp, and nadht nadph concentrations were compared, during therapeutic exposure no increased met-hb from . - -_ . to . _+ . % in cardiac surgery patients and from . ± , to . ± . % in ards patients (p < . ). rbc's having undergone ecc were more susceptible to met-hb formation (p< , ) whereas intracellular coenzymes did not differ neither between the groups (table) nor before and after no exposure. ecc predisposes to increased methemoglobinemia upon exposure to no both in vivo and in vitro. our data suggest a reduced activity of met-hb reducing enzymes rather than diminished availability of energetic substrates, variation of the inhaled nitric oxide concentration with the use of a continuous flow ventilator. anne pmc de jaegere ~, frans im jacobs , nico gc laheij , john n van den anker t . dept. of paediatrics ~, central instrumentation , sophia children's hospital, erasmus university rotterdam, rotterdam, the netherlands. objective: to investigate the homogeneity of nitric oxide (no) concentration in a delivery system with a continuous flow ventilator. design: bench study, setting: biomedical laboratory. interventions: a nitrogen/nitric oxide (njno) gas mixture was injected at three different sites in the patient circuit: just before and just behind the humidifier, and centimetres before the y-connector. ventilator flow ( , , l/rain), ventilator rate ( to , increments of ) and compliance of the testlung ( . ; . ; . ml/cm h ) were changed. carbon dioxide (co ) instead of n /no was injected at the same points in the circuit. measurements and main results: a) though the flow ratio of the njno and the ventilator gas were kept constant, the no concentration ([no]) raised with increasing ventilator rates. the increase in [no] was up to % when the n /no injection site was close to the y-connector of the ventilator circuit. minimal changes in [no] were noticed when the n~/no was mixed to the ventilator gas before the humidifier. b) analysis of the ventilator flow pattern showed variations at different places in the ventilator circuit. the magnitude cf the p, ow change depended on the meas~:rement site. the closer to the expiratory valve the highest the flow change was. the duration of the flow change was inversely proportional to the adjusted ventilator flow. c) real time measurements of the co concentration ([coz]) showed variations during tile respiratory cycle. these [co ] variations were higher when the co gas was blended closer to the yconnector. conclusions: the ventilator flow variations in relation to the fixed side flow of the n /no gasmixture result in changes of the inhaled [no] during the respiratory cycle. the no concentration during inspiration is always higher then during expiration. this could not be detected with the available monitoring system. to ensure a constant [no] by blending a njno gas balance in a continuous flow ventilator, the site of injection should be as close as possible to the inspiratory outlet. nitric oxide, a potent and selective pulmonary vasodilator, has recently been successfully used to treat pulmonary hypertension of variable etiology in infants and children. side-effects and complications in infants are so far not well known. we describe here two cases in which prolonged ( and- days respectively) high-dose ( - ppm) nitric oxide was used to treat refractor~¢ pulmonary hypertension. one patient was a newborn infant with pulmonary hypertension secondary to a large leftsided diaphragmatic hernia. nitric oxide was begun under conventional ventilation (babylog ) at hours of life with a slight initial improvement in oxygenation. he was then placed on oscillation with the same nitric oxide concentration due to worsening respiratory failure. he died on th day of life. monitored nitric dioxide concentration never exceeded ppm. the other patient was a months old infant with severe pulmonary hypertension due to a complete atrioventricular septal defect. he required high-dose nitric oxide to come off cardiopulmonary bypass after surgical repair of his heart defect. he slowly improved over the week following surgery but developped suddenly respiratory failure due to massive pulmonary hemorrhage and died. surprisingly, a particular autopsy finding in both infants was a massive acute necrotizing tracheobronchitis. we conclude that nitric oxide is an excellent and sometimes lifesaving treatment of pulmonary hypertension in infants. tracheobronchitis has not yet been reported as a possible complication of nitric oxide administration. we suggest that caution needs to be taken with prolonged high-dose administration and this possible complication to be looked for at autopsy. introduction: permissive hypereapnia (ph) is a beneficial strategy for patients with acute respiratory distress syndrome (ards) to minimize barotrauma by decreasing the peak inspiratory pressure (pip). hypercapnia and hypoxia cause pulmonary vasoconstriction, pulmonary artery (pa) hypertension, and, thus, an increased afterload to the right ventricle. this increased afterload may result in increased right ventricular (rv) work load and subsequent rv dysfunction. one therapeutic approach is the use of inhaled nitric oxide (inn), a selective pa vasodilator. the objectives of this study were to test the hypothesis that in a swine model of ards with ph, inn would improve rv work load and not change intrinsic rv contractility. methods: in swine ( - kg), ards was induced by surfactant depletion. hypercapnia was achieved by decreasing the pip while increasing the peep to maintain a constant mean airway pressure, inn was administered in concentrations of , , and ppm in a random order. pulmonary blood flow (qpa) was determined by an ultrasonic flow probe. rv total power (tp) and stroke work (sw) were calculated by fourier transformation of the pa pressure (ppa) and qpa data. preload recruitable stroke work (prsw), a preload and afterload independent measure of ventriculur contractility, was determined by a shen-subtraction method and vena caval occlusion. respiratory failure with pulmonary hypertension in piglets gerfried zobel*, bernd urlesberger*, drago dacar**, siegfried rtdl*, fritz reiterer* and ingeborg friehs** depamnents of pediatrics* and cardiac surgery**, university of graz,austria objective: to evaluate gas exchange, pulmonary mechanics and bemodynamic data during partial liquid ventilation (plv) combined with inhaled nitric oxide (no) in acute respiratory failure with pulmonary hypertension. design: prospecfive~ randomized, controlled study. setting: university research laboratory. subjects: twelve piglets weighing to kg. interventions: acute respiratory failure with pulmonary hypertension was induced by repented lung lavages and a continuous infusion of the stable endoperoxane analogue of thromboxane. thereafter the animals were randomly assigned either for plv or conventional mechanical ventilation. initially perfhiorocarbon liquid ( ml/kg) was instilled into the endotracheal tube over min followed by - ml/kg~. all animals were treated with different concentrations of no ( - - ppm) inhaled in random order. measurements and results: continuous monitoring included ecg, cvp, mpap, map, san and svo measurements. during plv pao /fio increased significantly from _+ . mmhg to ± mmhg (p< . ) within rain, while pao ]fio remained constant at -+ . mmhg. qs/qt decreased significantly from -+ % to -+ % (p< . ) during plv and did not change during conventional mechanical ventilation. static pulmonary compliance (cstat) increased significantly ff~m . r± . to . _+ . ml/cmh /kg (p< . ) during plv and decreased slightly from . _+ . to . e . ml/cmh /kg during conventional mechanical ventilation. the infusion of the endoperoxane analogue resulted in a sudden decrease of pao /fio from _+ to _+ . mmhg in the plv group and from ± to +_ . mmhg in the control group. inhaled no significandy improved oxygenation in both groups (pao /fio : _+ mmhg during plv and +_. mmhg during conventional mechanical ventilation). during inhalation of no mpap decreased significantly from -+ m ± mmhg (p< . ) in both groups. there was no significant change in oxygenation and mpap during inhalation of and ppm no. conclusions : plv significantly improves oxygenation and pulmonary compliance in acute respiratory failure. the additional application of inhaled no further improves oxygenation and pulmonary hemodynamics when acute respiratory failure is associated with severe pulmonary hypertension. inhaled no is very effective in improving oxygenation and pulmonary blood flow even at low doses. the work was supported in part by grants of the austrian nationalbank nr . as in neonates, severe respiratory failure in infants and children can be aggravated by pulmonary hypertension, resulting in further deterioration of oxygenation due to increasing intrapulmonary shunting. we analysed the influence of inhalational nitric oxide (ino) in treatment, course and outcome of severe ards in a pediatric population. since infants and children (age: - months) with ards and oi > (mean value: . ± ) underwent a trial with ino (concentration: , , , and ppm) to prevent further respiratory failure. patients had a significant improvement of their oxygenation (rise of pa > mm hg) for at least hours (responders); mean best ~fficient no dose: . ppm. the non-responders had only a short-term improvement or ino had no effect. in responders and nonresponders there was no significant difference with regard to age, underlying disease, ards severity, time on mechanical ventilation, blood gases and ventilator settings before notrial, nor was there a different grade of pulmonary hypertension (estimated by echocardiography). the only difference was an higher ol in the group of the non-responders: . ± .i vs. . ~ . , p < . . in the group of the respenders there was a secondary deterioration of lung function after i - days on ino in children (transient responders): in these patients, as well as in the group of the non-responders, alternative modalities of treatment (hfov and/or ecmo) became necessary. children ( %) died: transient respenders and non-responders. in infants and children with ards due to different underlying diseases ino can acutely lead to a significant improvement of oxygenation in about % of the cases. the right selection of patients for no therapy and the influence of ino on the survival rate of ards in childhood has to be evaluated in further studies. and pediatric cardiology, university of graz, a- graz purpose: after fontan procedure cardiac output is critically dependent on the pulmonary vascular resistance. even minor elevations of the pulmonary vascular resistance may significantly decrease cardiac output. inhaled no is an effective, selective pulmonary vasodilator in experimental and clinical situations of pulmonary hypertension. the aim of this study is to evaluate the effects of inhaled no on oxygenation and pulmonm , circulation in children after a bidirectional glenn-anastomosis (n-~) or a fontan-like operation (n= ). material and methods: from june t to january children with a mean age of . +~ . (sem) yrs and a mean body weight of . -+ . (sem) kg were treated with inhaled no after glenn-or fontan-like operations. all but one had complex cardiac malformations with single ventricle. all children were mechanically ventilated with an fin > . . inhaled (no) was applied using a rrdcrdproeessor based system which additionally allowed measurement of no/nox using the chemihimniscence method. methemogtobin concentrations were determined times a day. the major indication for postoperative inhalation of no was a high (> mmhg) transpulmonary pressure gradient (tpg--cvp-lap). severe myocardial dysfunction of the single ventricle was excluded by echocardiography. results: the mean duration of mechanical ventilation was . _+ . (sem) days the. mean dose of inhaled no was . -+ . (sem) ppm, the mean duration of no-inhalation was _+ (sem) hours. the mean methemoglobin concentration was . -+ . (sem)%. hemodynamic data and arterial oxygen saturation before inhaling no and minutes later are given in table acute hypoxaemic respiratory failure (ahrf) in children occurs in a heterogenous group of diseases with pulmonary pathophysiological processes ranging from reversible physiological intrapulmonary shunting to fixed structural lung damage. we hypothesized that inhaled nitric oxide (ino), a selective pulmonary vasodilator, might identify those patients with potentially reversible disease, i,e, large response may indicate a greater likelihood ef reversibility and thus survival. a retrospective review of the early response to ino in infants and children (aged month to years, median months) with severe ahrf( with ards). the mean p(a-a)o , pao / fio , oxygenation index (oi) and acute lung injury (all) score prior to the commencement of ino were +_ . , +_ . , _+ , and . +_ . respectively, the magnitude of response to ino was quantified as the % change in oi occurring within minutes of ppm ino therapy. this response was compared to patient outcome data. results. there was a significant correlation between response to ino and patient outcome, kendall tau b r= , , p< . (table) conclusion. in ahrf response to ino appears te define a subgroup of patients with improved outcome compared to nonresponders. we speculate that response to ino may be useful in selecting patients with potentially reversible lung disease for special support therapies such as ecmo. randomised controlled trials are needed to define the role of ino in paediatric ahrf. between may and december , patients (pts) were treated for mas. treatment groups were: group i only : pts; group i conventional mechanioal ventilation (cmv): pts; group ii hfo: pt; group iv hfo+no: pts. therapy was stepwise intensified until oxygenation improved ( i -) ii -) iii --) iv). "high volume strategy" was used with hfo (mawp - cm h ). the initial no-concentration was - ppm, with rapid reduction down to - ppm once oxygenation improved. results: one pt (group it) died of hypoxic-ischemic encephaiopathy (termination of therapy); all other newborn babies survived. in group iv pt and showed barotrauma prior to hfo. pt , and were treated with additional mgci (max. mg serum concentration . - . mmol/i). following the identification of inhaled nitric oxide "no) as a selective pulmonary vasodilator (frostell et al ) [ .+ , + . data are compared to baseline values within each group. *=p< . , **=p< . , ***=p< . l among patients who fulfilled ecmo criteria, improved with no and did not required extracorporeal life support. tltree out of ecmo patients eventually survived. conclusions: m our study low-dose of irthaled no showed a variable effect on oxygenation in newborns with acute respiratory failure. an acute response to no appeared to be correlated with a better short-term outcome and the avoidance of extracorporeal support in ecmo candidates. differently, lack of acute and/or sustained response was associated with death or need for ecmo. although the nature and severity of the underlying disease or the degree of prematurity may play an important role in these patients, we believe lack of acute response to no may be an early predictor of bad outcome, prompting toward alternative treatments such as ecmo or liquid ventilation. *picea s., °bartuli a.,°dionisi-vici c., *dello strologo l., §villani a., §bianchi r., ^salvatori g.,*rizzoni g, °sabetta g. *div. of nephrology, °div. of metabolism, §intensive care unit, ^div. of neonatology. "bambino gesfl" children research hospital. rome, italy. successful prevention of handicaps or death in newborns with ~ depends on rapidity and efficiency of treatment. poor response to nutritional and/or pharmacological treatment requires extracorporeal removal of nh . efficiency and cardiovascular tolerance are often difficult to obtain with peritoneal or hemodialysis in neonates. we report the results of cavhd in newborns with hc. methods: vascular access: femoral vessels. blood flow: - ml/min, dialysate flow: - ml/h. filter: amicon minifilter plusrm(polysulfone membrane; . sq.m.). no ultrafiltrate(uf) production, patients: case with carbamoytphosphate synthetase deficiency (body weight -bw-: . kg) showed hc at day , a relapse of hc occurred at day due to an infectious event. case and (bw: . and . kg), both affected by propionic aeidemia, showed hc at day and day , respectively. plasma nh (~tg/dl) decrease is shown in the complications: transitory ischemia of arterial cannulation limb and transitory thrombocytopenia occurred in case ; surgical repairing of artery after cavt-id was necessary in case ; no cardiovascular instability was observed during cavhd . outcome,'all patients recovered from hc in less than day: case : alive, mild b)iootonia at mos; case : dead after days from cavhd withdrawal for pulmonary hemorrhage; case : alive, normal development at mos. conclusions: ) in newborns with hc, ca~q-id provides good cardiovascular tolerance,high efficiency and quick removal of nh , even without uf production (i.e. only by diffusion). this allows easier management (no need of fluid and electrolyte balance). ) arterial complications seem frequent in neonates treated by cavhd. venovenous circulation could overcome this problem. vb nguyen, m jokie, c leeaeheux paediatric intensive case service, hospital university centre, avenue c te de nacre, caen cedex, france background, the implication of polymorphonuclear neutrophils (pmns) in the physiopathology of children's haemolytic.uraemie syndrome (hus) becomes more and more evident. the purpose of the present study is to role out their impact among other pronostie elements during the course of the disease. patients and methods. diarrheal prodrome and its duration, patient's age, maximal blood nitrogen level, anuria and dialysis time, extra.renal involvements, white enll and pmn counts and thrombopenia duration have been retrospectively analysed in infants with good outcome and in another children with unfavorable outcome. results. neither diarrhoea or its duration, nor children's age, nor blood nitrogen level, nor anuria or dialysis time had any predictive value for the disease evolution in the acute phase of our patients. adversely, extra-nenal involvements was accompanied by severe and complicated courses of the disease (p< , ). the elevation of white cells and pmns (heyon x /i) and pmns (more than x / ) as well as its persistence beyon a week were most frequently observed in complicated forms (p< , , p< , and p< , , respectively). a transient thrombopenia (less than day@ in patients with elevated counts of white cells may be a filrther obvious sign of an unfavorable course of the disease ( < , ). conclusion. the elevated count of white cells and pmns, either alone or associated to one rapid regeneration of platelets, seems enabled to predict an unfavorable evolution of the hus in children. msud results from an inherited impairement of catabolic pathway of branch chain amino-acids. high leucine blood levels may induce acute brain dysfunction. this dramatic complication led us to propose leucine removal procedures as continuous hemofiltration. patients and methods three newborns in acute msud onset were treated by hf, hdf and hd. extracorporeal circulation was performed through a . fr catheter, a circuit with a blood pump (priming volume = ml). patients and procedures characteristics are summarized below in the sucralfate (an aluminium salt of sucrose octa sulfate) is used to prevent and treat upper gastrointestinal bleeding in critically ill patients. with minimal absorption, the potential for side effects is thought to be limited, though aluminium toxicity has been reported in patients with chronic renal failure. these patients may already have had high body stores of aluminium. we report critically ill children with high serum concentrations of aluminium following sucralfate therapy. all had renal impairment. the normal aluminium level is < . gmol/l and in patients with chronic renal failure < . ].tmol/l. none of these patients had known preexisting chronic renal disease. cpb was conducted under deep hypothermia (t,° °c) and cardiocirculatory arrest (cca) or under hypothermia (t,° °c) and low-flow perfusion. continuous holter-electrocardiograms (h-ecg) were recorded from the ilranediate postoperative (po) period on for hours. h-ecg were also recorded prior to the operation and before discharge. following dr were observed: snpraventricutar (sv) and ventricular (v) extrasystoles (es) (> / h), sv and v tachycardia (svt and vt), accelerated junctional rhythm (ajr) and junctional ectopic tachycardja (jet), and nd and rd degree atrioventricular block (avb and avb ). the incidence of po dr was % in the pre-op h-ecg, % on the st, % on the rid, % on the rd po day and % befbre discharge. compared to the pre-op findings, an increased incidence of sves, ves, svt and avb on the st po day was observed, whereas vt and a jr or jet were exclusively observed po. all types of dr were observed up to the rd po day. ty e of dr before discharge was similar to pre-op findings and there was no definitive avb . considering patient groups according to the most frequent isolated op-procedure, the incidence of dr on the first po day was % after asd ii-closure (n= ), % after stthaortal vsd-closure (n=lg), % after correction of a complete avsd (n= ), % after correction of a tetralogy of fallot (n= ) and % after fontan-operation (n= ). incidence and type of dr were not significantly different between groups. longer cpb-dttration and use of cca were risk factors for po ves and vt (p< , and p< , , respectively) whereas use of cca and degree of hypothermia were risk factors for the development of a jr and jet (p< , and p< , , respectively). -our results indicate that po dr after cpb in children m'e frequent but mainly transient. in our series, specific cpb-related parameters are of greater influence than surgical procedure itseif for the development of dr and are discriminant risk factors for particular types of dr. the course of anp, cgmp/anp (as indicator for atrial natriurefic peptide biological activity), and no and no (as indicator for endogenous nitric oxide (no) synthesis) was investigated in i infants (median age months) undergoing cardiopulmonary bypass (cpb). patients were divided into groups according to whether they had (group , n= ) or not (group , n= ) preoperative heart failure (hf) and pulmonary hypertension (pht). group patients had preoperatively significantly higher levels of anp (p< . ), cgmp (p< . ) and no and no (,p< . ) but had significantly lower cgmp/anp (i < . ) than group patients. during cpb, anp was significantly higher in group patients ~< . ). as compared with prebypass values, cgmp/anp was reduced in both groups during cpb (p< . ). cgmp/anp inversely correlated with duration of cpb and aortic clamping time (p< . , respectively). no and no were significantly higher in group than in group patients (p< . ) without any intraindividual change during cpb. from the early postoperative period on anp, cgmp/anp and no and no were similar in both groups. after cpb, anp correlated in both groups with blood pressure (p< , ) and diuresis (p< . ). no and no inversely correlated with pulmonary arterial pressure immediately after cpb ( < . patients after a fontan-type of procedure have elevated central venous pressures (cvp) leading to congestion in the gastrointestinal system and often ascites. purpose of this study was to evaluate whether this causes a different postoperative gastric mucosal ph (phi). methods: we evaluated a series of patients, who underwent cardiac surgery with cardiopulmonary bypass (age: days to years (mean , yrs), weight: . to kg (mean . kg). a commercially available tonometer (tonometics®) for sigmoidal use in adults was inserted into the stomach after induction of anesthesia. the phi measurements were done according to manufacturer recommendations we compared three groups of patients: ) aeyanotic (n= ), among them p with vsd and p with avsd; ) cyanotic (n= ): tof: p, tga: p; ) cyanotic after a fontan-type procedure (n= ). phi were measured at picu arrival and after h. fudhermore we compared lactat levels at these time points. differences between the groups were evaluated with one way anova on ranks with pairwaise multiple comparisons (dunn's method). the relationship between cvp and phi was investigated by regression analysis. results: the median phi for groups i, and were . , . and . at ardval and . , . and . after h respectively. at picu arrival group was significantly (p< . ) different from groups and . there was no significant difference between the latter two groups, after h group was different from group , there were no other significant differences. the median lactate levels for groups t, and were . , , and . at ardval and . , . and . after h respectively. at ptcu arrival group was significantly (p< . ) different from group , after h there were no significant differences. there was a weak negative correlation between cvp and phi: r= - . ; p< . . conclusion: patients after a fontan-type of procedure have lower phi than patients after other cardiac surgical procedures, however, this is only in part due to the elevated cvp and venous congestion. eleven children were investigated months (median) after postoperative mof. iviof was defined as the failure of at least two vital organ systems (kidney, liver, lung, central nervous system) in addition to cardiac insufficiency and high fever. underlying surgical procedure was repair of tetralogy of fallot (n= ), fontan-(n= ) or seuning procedure (n=l). all patients fulfilled criteria for mof in the first postoperative (po) days. six patients needed peritoneal or hemodialysis for days (median) during the po period. one patient showed cerebral infarction due to thromboembolism in the territory of the right internal carotid artery immediately after the operation. the follow-up protocol consisted of extensive investigations of heart-, renalliver-, and lung functions as well as complete neurological and psychological examinations. all patients had adequate cardiac examination. lung function was normal in all but patients who had an obstructive syndrome. only patient showed an isolated decreased creatinine clearance. abnormalities of the liver ftmction tests were only noticed in patients after fontan procedure. severe neurological sequels such as paraplegia (n = ) and diplegia (n-i) were observed in of the patients. the remaining children presented with a delayed graphomotorical and speech development associated with normal intelligence. -in our series the most frequent and severe sequels after postoperative mof were neurological. -abnormal liver fimction tests are more likely to be a consequence of the fontan hemodynamics than a sequel of mof. the optimal dosing schedule of surfactant therapy for the treatment of neonatal respiratory distress syndrome (rds) remains unclear. goal: surfaetant function and the concentration of phospholipids (pl) in tracheal aspirates are compared in a prospective randomized trial involving neonates with rds who received either two or more ( or ) doses of survanta. methods; ventilated neonates < w with rds were treated with survanta oo mg/kg if fio >_ % or mean airway pressure _> , cm hzo, after h a nd dose was given (same criteria), if the support still exceeded the criteria h after the nd dose, the patient was randomized to no extra dose (two}, or to an extra dose of survanta (morel (and a th dose h later; same criteria), pl was measured in tracheal aspirates and corrected for dilution with the urea method. "active" large aggregates and "non-active" small aggregates of surfactant were separated by centrifugation and quantified. surface tension of the large aggregate fraction was measured by pulsating bubble surfactometer, results: neonates were randomized, x two and x more ( x and x doses), gestational age was , ± , w and birth weight ± g. most patients had severe rds with initial ventilation: rate . _+ , , peak inspiratory pressure (pip) , -+ . cm hzo, fio . ± . %. at randomization: rate . ± . , pip . -+ . cm hzo, fio . ± . %, and h after randomization: rate . ± . , pip . _+ . cm hzo, fio . ± . %, without signif, differences between the groups. there was relapse (again fio _> % within h) in group two and t bpd in group more. in total, tracheal aspirates were analyzed. pl was not signif, different before randomization (two . ± . vs more . ± . /jmol/ml), but neither after randomization (two . -+ . vs more . ± ,o /~mol/ml). there was no difference in the % small aggregates (two . ± . vs more . ± . %), the surface tensions (ran/m) were not signif, different (each time two vs more): before randomization . ± , vs . -+ . , in the h after randomization . ± . vs . -+ , , or - h after randomization . -+ . vs . ± . , or - h after randomization . _+ . vs . -+ . . conclusion: neonates who received more than two doses of survanta did not have higher pl, nor a better surfactant function than neonates who received only two doses of survanta. continuation of the trial is necessary to evaluate clinical outcome. may not indicate need for treatment p.c. clemens s.j. neumann university of hamburg, department of pediatrics, klinikum schwerin, wismarsche str.. , d- schwerin. aim of the study: the finding of elevated tsh and decreased t in the newborn usually is classified as "transient hypothyroidism", thus the elevation of tsh is classified as consequence of the lowered t . but on the other hand several data sets show that tsh elevation as well as low t , one independently of the other one, are associated with different kinds of perinatal stress. each of these laboratory deviations, if not associated with the other value being abnormal too, is generally accepted not to be an indication for treatment. from this we conclude, that more pefinatal stress, as in intensive care neonates, may produce tsh elevation as well as low t , but only coincidentially, not the tsh elevation being the consequence of low t , thus not to be classified as "hypothyroidism", thus not indicating treatment. if this hypothesis is right, we should find an association of increasing pefinatal stress with an increasing number of neonates from tsh and t normal via tsh or t abnormal to high tsh and low t . method: in the newborn screening program in germa w we determine primarily tsh, and only in the neonates with elevated tsh, in addition we determine t . thus in our study we asked whether we find an association of increasing perinatal stress with an increasing number of neonates from tsh normal via tsh abnormal while t normal to high tsh and low t . definitions for this study were: tsh elevation = > mu/ (as usual in the german screening programs), t lowered = < p_g/dl perinatal stress score was or or or in dependency of the neonate having stress in none to all of the following three categories: (a) forceps or vacuum extraction or sectio co) birth weight below g (c) at the th day existence of a relevant neonatal disorder (rds, ictems gravis, infection/sepsis, vitium cordis with hemodynamic relevance, severe malformation). results: our data of neonates show a high significant association (chi = , p < . ) of, on one hand, perinatal stress score with normal tsh, versus, on the other hand, perinatal stress score or with high tsh and low t . discussion: facing the background given above, in the intensive care newborn, the constellation of high tsh and low t may be only a coincidential addition of two independent abnormalities. in tbese cases -the high tsh not being the consequence of low t -the classification as "hypothyroidism" is not justified, thus a therapy not indicated. on the other hand of course there exist rare cases with high tsh as consequence of low t thus with hypothyroidism tlms with indication for therapy. unfortunately we have no criteria, that enable a certain discrimination of these two categories thus in respect to the question of therapy or not. conclusion: further research has to be done to learn how to discriminate the coincidential high tsh and low t from the causal constellation of high tsh and low t . until we have certain discrimination criteria we have to treat both groups of neonates. few studies have focused on fa composition of surfactant pc in preterm infants before and after surfactant therapy. methods: tracheal aspirates were collected in venttlated mfants from birth until extubatlon ( / _ /twk ga, .+ g bw). after lipid extraction, t.l.c,, and methylation, fas of pc were quantified by gaschromatography. intralipid a ( . % linoleic acid, : • ) was started h after birth. results: six infants developed respiratory distress syndrome (rds) and received survanta r i mg/kg (sr), all doses within h after birth (ix s r n=l, x s r~ n= , x s r n= ). one child did not develop rds. in alt patients, the patmitate % in pc was ~ % (before sr<=natural composition), increased to ~ % after s r, and remained > % for i h after lx s a, . .+i . h after x, and . .+ . h after doses. in patients, intubated long enough, the palmitate % decreased with a half-life of . _+ . h to a new plateau which was still higher than baseline after week. linoleic acid % was . _+ . (with rds), decreased after s r~ and returned to baseline due to the decrease in patmitate %. thereafter the linoleic acid % increased linearly with . % per h, in patient even up to . %. other fas did not increase after return to baseline. in neonatal medicine the current parameters, arterial oxygen saturation and arterial oxygen pressure, are poor indicators for oxygen delivery and oxygen demand. the purpose of this study was to obtain venous blood samples from the inferior vena cava in stable neonates with respiratory failure and to determine a parameter that reflects more adequately the balance between oxygen delivery and oxygen demand. "l~e study included neonates requiring mechanical ventilation tbr severe respiratory insufficiency. an umbilical venous and arterial catheter were inserted in the inferior vena cava and in the aorta respectively. paired blood samples were obtained at the time that the patients were hemodynamically stable. fifty paired arterial and mixed venous blood samples were analyzed. jnear regression analysis showed the following correlations: in a neonatal intensive care unit adjacent to a delivery room caring for mothers per year, (with a referral of mostly for preterm delivery), virtually every neonate <ls g was seen by the same ophtalmologist, j.o. the incidence of retinopathy of prematurity (rop) was in - of ii cases ( preterms <ls g with % surviving to discharge, and % rop in survivors; % if less than weeks). in - , cases of rop were diagnosed by the same ophtalmologist. were born at less than weeks, of which ( %) survived to discharge, and among those survivors, rop was present in ( %), with rates varying from % at weeks to % at . objective: to compare a method of teicoplanine (teico) infusion using an electrical syringe-pump with a manual injection. methods: infusion of teico was simulated through a standart neonatal i.v. system. the infusion system consisted of an life care infusion pump (abbo'it lab.) with its i.v. set for maintenance intravenous fluid (flow < mi/h) connected to a -way stopcock. an meter extension tubing (vygon lab.) was placed between the stopcock and a neonatal catheter, an another meter tubing (injection tubing) was connected to the stopcock. the volume of the injection circuit was . ml. simulations were realised for weights ( or kg), with a doses of mg/kg and a injected volume of , ml to ml. our goal was to perform a complete infusion in minutes. we compare one method of infusion with an electrical syringe-pump with manual methods: a: teico was infused with a syringe-pump pilot c (becton & dickinson lab.) according to a protocol using ) a priming before connecting the syringe to the tubing (for immediate starting of infusion), ) a programmed volume injected in minutes (the drug volume was greater than the dose prescribed to avoid loss of teico into the syringe), ) a ml wash out was performed over minutes with the syringe pump. b: teico was manually injected in a few seconds in the tubing followed by a ml wash out over minutes. c: idem as b but a nu site valve (medex) was connected to the proximal end of injection tubing to avoid leakage between removal of the teico syringe and connection of the wash out syringe. during each run, serial samples were collected every ten minutes over a one hour period. the samples were assessed using hplc method. results: the amount of drug delivred at minutes was calculated and expressed as a perventage of the total amount of teico prescribed. results are a mean of to rons. a b c kg . + , % , + . % , -+ . % kg -+ , % -+ , % . -+ % conclusion: with a drug volume injected < circuit volume and a valve, a direct i.v. administration of the drug in the circuit followed by a wash out seems an accurate alternative to drug infusion conbroled by a syringe pump and is easier to perform. doxapram hydrochloride is a central and respiratory stimulant which is used in neonatal intensive care units to treat caffeine-resistant apnoes of the newborn. routinely, doxapram is administered intravenously. oral administration would be much easier but data on bioavailability after oral administration are limited (two studies) and show a large variation. we therefore studied the oral bioavailability of doxapram in preterm infants. doxapram treatment was started with an intravenous loading dose of , mg/kg during minutes, followed by a continuous infusion of mg/kg/h. after h the intravenous administration was changed to continuous oral administration with the same dosage, blood samples were collected h after both the intravenous and oral administration and analyzed by hplc-assay. apnoea rates per hours were listed before and after starting doxapram treatment. the median apnoea rate per hours declined from to after both the intravenous and oral administration. the oral bioavailability of doxapram is between and %, indicating that the oral route can be used effectively in these infants . there were no differences in the decline of the apnoea rate after intravenous versus oral administration of doxapram, infasurf r has been comnared with exosurf r in two studies: one as drodhvlaxis and the other a rescue trial. similar. althouah non-sianificant benefits were found for the natural surfactant. in trials there was a sianificant reduction in dulmonarv air leaks for . : % ci . - . for babies treated with natural comnared to svnthetic surfactants. for trials ( babies~ comdarina natural and synthetic surfactants for rds { comdarina survanta r and exosurf r. and one infasurf r and exesurfr% neonatal mortalitv was sianificantlv reduced (or . : % ci . - . with natural compared to synthetic surfactant treatment. in two further trials different natural surfactant drenarations were compared. reduced oxvaen needs for hours after treatment were found for r r infasurf and curosurf respectively when each was compared to survanta r. andarent lonaer-term benefits from these surfactants were not statisticallv sianificant. further trials will be needed to ascertain differences between various surfactant preparations. introduction bacterial meningitis is a common cause of admission in the paediatric age group, and one which still carries a high morbidity and mortality. these complications are strongly associated with a delay in antibacterial therapy. a significant proportion of these patients require mechanical ventilation; it is in this particular group of patients that survival is greatly diminished. the identification of risk factors for mechanical ventilation associated with bacterial meninges may help improving survival by shortening the delay to icu referral. the paediatdc risk of mortality score (prism) is the most widely used scoring system in the paediatric icu literature; the accuracy of prism on predicting outcome in meningitis has been shown to be poor. aim we aimed to describe our population of patients with bacterial meningitis requiring ventilation, and then to identify predictors of survival. methods this study was conducted at the baragwanath hospital in south africa which is an universityaffiliated institution with end average annual paediathc admission of patients. baragwanath icu admits non-neonatal paediatdc patients per year. a retrospective chart review from january to december of consecutive paedistdc icu admissions with bacterial meningitis was performed. results approximately cases of bacterial meningitis are admitted to the general paediatric wards every year; this constitutes ± % of all admissions. the mortality of these patients is + %. during this time ( m, f) patients ( %) were accepted for icu admission, with a mortality of . %. the median age was months (range days to years). the median delay to hospital admission was hours, and the median delay to icu admission was a further hours. the median duration of tcu stay was hours ( for non-survivors, for survivors). the main presenting features were convulsions ( %), altered mental state ( %), fever ( %), respiratory symptoms ( %), headache ( %), and diarrhoea and vomiting ( %). the most common indications for icu admission were seizures ( %), coma ( %), shock ( %), respiratory failure ( %) and acidosis ( %). in % of patients there was a cardiorespirstory arrest prior to admission. the most common organisms in the csf was pneumococcus ( %), haemophilus influenza ( %) and e coli ( %). the presence of leucopenia (wcc < ), a low platelat count (< ), acidaemia (ph< . ), and the need for inotropic support were strongly associated with nonsurvival. tachycardia and hypotension were not significantly essorjsted with poor outcome, as has been previously reported. discussion early diagnosis of meningitis and prompt institution of antibiotic therapy requires a high level of clinical suspicion. paediatric patients with bacterial meningitis that require mechanical ventilation have a poor prognosis. there is little evidence to suggest that nomsurviva[ can be predicted prior to icu admission, but a rapid deterioration requiring ventilation and inotrepic support with evidence of severe sepsis (low platelet count, leucopenia) is nmost invariably associated with a fatal outcome. the long term functional outcome of these patients make this disease even more devastating; the rote of icu in the management of these patients has yet to be fully estanished. objective and study design: a retrospective study was pertbrmed for all patients diagnosed with hemorrhagic shock and encephalopathy syndrome (hse) during to . soroka medical center is the only medical facility in the southern negev region of israel serving a population of - , residents, consisting primarily of jews and bedouins. results: patients ( bedouins and jews) were diagnosed with hse. main features on arrival included profound shock and coma with con~alsions. active bleeding and/or disturbing coagulation tests with falling heuroglobin levels and thrombocytopenia was noted in every case. all infants developed diarrhea shortly after arrival. elevated urea, creatinine and liver enzymes was noted in all cases. annual incidence tbr inlhnts < year of age was : , for bedouins and . : , for jews. patients ranged in age from - wks and arrived at the hospital late night/early morning ( : am-ll: am), during winter/early spring (november-april). all were healthy prior to admission, with short prodromal symptoms of upper respiratory tract or gastrointestinal infection noted in cases. most infants had markedly elevated body temperature on arrival. a history of overwrapping and/or excessive hearing was obtained in of infants. bacteriological and virological cultures were negative in all infants. one infant died and neurological sequelae were observed in all survivors. the high prevalence of hyperpyrexia during sleep in the presence of negative microbiological results with no evidence of excessive hearing, and the high incidence of rise among a closed, culturally isolated society known to have a high incidence of congenital malformations, may support previous assumptions that hse results from hyqperpyrexia, originating in most cases from a "physiologic" heat induced trigger which starts and peaks during the night in previously healthy infants with susceptible, predisposing genetic underlie. approximately % of hospitalised infants with respiratory syaacytial virus (rsv) infection require mechanical ventilation. our general practice is not to use specific antiviral therapy. we have undertaken studies of rsv-infected mechanically ventilated patients without underlying congenital heart disease or immunodeficiency. study i (n= ): a retrospective review of infants (mean post-conceptual age weeks; median duration of intubation was days (interquartile range - ). blinded review of chest x-rays during the first three days of mechanical ventilation revealed a spectrmn of lower respiratory tract findings from marked diffiase consolidation in all zones without hyper-inflation (n= ) to gross hyperinfiation without consolidation (n= ), with the remaining patients have an intermediate picture (n= ). death occurred only in patients who were at the poles of this continuum ( / consolidation and / hyperinflation). patients at these poles could be differentiated by gender predominance, birth gestation, alveolar-artarial (a-a) oxygen gradient (p< . l), oxygenation index (p< . l), peak inspiratory pressure (p< . ), and intubation days (p< . ). study ii (n= ): prospective audit of infants with the aim of verifying the above differentiation. separating patients based on their early x-rays and a-a gradient we confirmed the above predictable difference in duration of supportive therapy (consolidation v intermediate: ( - ) v ( - ) p< . ). severe lower respiratory tract rsv-infecrion in young infants results in different distinctive partems of disease with characteristic radiological and clinical features, and each has a predictable timecot~se. conflicting reports on special therapy should be interpreted with respect to these observations before making conclusions about the efficacy of any specific treatment. the clinical data of children wich suffered from a severe mycosis between jan. -dac. and wich were treated with amphotericin b in spanish hospitals were collected. mean age was + . years; were mate ( %) and female ( %). the most common underlying diseases were leukemimymphoma ( %) and congenital heart defects ( %). the major pathogens isolated were candida albieans ( %), other candida ( %) and aspergillus ( %). and liposomal amphotericin (la) in ( %). in the ca group, the starting dose was , ~ , mg/kg, reaching a maximal dose of . + , mg/kg after . + days. maintenance time was + days and the cumulative dose: ~ rag. in the la group, the starting dose was . ± mg/kg, reaching a maximal dose of . _+ . mg/kg (p< . ) after + days. maintenance time was ~ days (p< . ) and the cumulative dose _+ mg (p< . ). the reasons for la use were: elective in % of cases, previous renal failure in %, and ca inefficacy in %. hepatic or renal function impairment was two times more frequent in la group than in ca group, the antifungal efficacy was % for ca and % for la. therapeutic failure or toxicity induced withdraw of ca in % of cases, vs, , % for la (p< , ). mortality was not different in both groups ( vs. %), adverse effects were related to ca in events vs, only one in la group (p< , ). the commonest side effects in ca patients were fever ( %), chilis ( %) and nausea ( %). in ca group, cases ( %) developped analitical anormalities related with amphotericin, vs. cases ( %) in la patients (p< . ). in the first group, the commonest serum alterations were hypokaliemia ( %), raised creatinine ( %) and bilirrubin ( %). in the second one, hypokaliemia presented in % of cases (p< . ), raised bilirrubin in % and creatinine in % (p< , ), the antifungal efficacy of la is at least the same of ca. from the clinical and analitical points of view, la is much less toxic than ca. la can be used at a greater dose than ca and is safe in children with renal failure. laurence desplanques -serge gottot -christian dageville d~artement de sant~ publique -facult~ xavier bichat - rue henri huchard paris -france -the french << reaped ~> network was created to implement a nosecomial infections (ni) quality care program in nicu and picu, the first objective was to describe the annual ni incidence rate in each icu population : all patients stayed more than hours in icu. methods : n] criteria were defined by the reaped group according to cdc criteria. all data were collected by a medical and nursing team. all infection data were validated by an external investigator. results : patients were admitted over a months period. % were newborns. ni were identified among patients. the overall ni incidence rate (ir) was . % and . °/ person day (from . to . °/ according to age, lowest rate for newborns). septicemia ( % of ni) and pneumonia ( % of ni) were the two main ni. according to age, the septicemia ir varied from . to . °/oo catheter day (lowest rate for newborns) and the pneumonia ir from . to . °/ ventilator day (lowest rate for newborns). there were very few other infections (uti : %, ir : . °/ catheter day). gram positive cocci were isolated in % of septicemia ( % of them were coagulase negative staphylococcal). gram negative bacilli were isolated in % of pneumonia ( % of them were pseudomonas). % of ni were caused by candida, mostly septicemia. the septicemia and pneumonia ir varied according to unit even after adjustment for age. discussion the aminoglycoside antibiotics are frequently used in newborns for the treatment of severe infection and sepsis due to gram-negative microorganisms. the currently recommended dosage schedule for tobra ( . mg/kg q h) does not take into account differences in gestational or postnatal age during the first weeks of life. we questioned the validity of these recommendations and studied the population kinetics of tobramycin to establish predictive equations that enables the clinician to select the appropriate initial dosing schedule. methods tobra trough (t= ) and peak values (t= ) were taken on day - after birth in newborns. tobra was administered as a -minute intravenous infusion already in an adapted dosage schedule: . mg/kg q h in infants with gas < weeks; . mg/kg q h in infants with gas between - weeks and . mg/kg q h in infants with gas > wks, tobra concentrations were analyzed by tdx-assay, a one-compartment model was assumed and non-linear mixed effect modelling (using nonmem) was applied to the data, a trough level < mg/l and a peak level between and mg/l was required, with the present dosage scheme % of the trough levels were too high and almost % of the peak levels too low. calculations showed that the following dosage schedule should result in optimal levels of tobra. preterm infants gas < wks: mg q h preterm infants gas - wks: . mg q h preterm infants gas > wks: the currently recommended dosage schedules for toeira result in high trough and low peak levels. prolongation of the dosing interval and increasing the amount of drug per dose according to the above scheme will improve tobra level control. since january british clinicians have been conducting a randomized controlled trial of neonatal ecmo. mature infants (>- weeks gestation and birthweight kg) with severe cardiopulmonary failure have been randomized to receive continued care in their referring institution or referral to a designated ecmo centre for further management. we now present the preliminary results which have prompted closure of recruitment to this trial. the final outcome will be assessed as intact survival against death or severe disability at one year of age for all the recruited patients. patients were categorised by diagnosis such as isolated persistent fetal circulation, secondary persistent pulmonary hypertension of the newborn or congenital diaphragmatic hernia and by severity of illness at the point of first contact with the clinical coordinators of the trial -judged primarily by the oxygenation index ( before randomization). patients were randomized ( in each arm). hospital outcome data are reported for all patients and year outcomes on t ( survivors). at this stage of the babies allocated to ecmo are known to have died compared to of those allocated to conventional management (rr . ; % ci . - . ; p= . ). fewer deaths have been obsea-ved amongst ecmo allocated babies in all the diagnostic categories used. a % incidence of disability and impah~nent has been observed amongst survivors. this rate is similar in both groups and the survival advantage is not offset by an increased rate of disability or impairment following allocation to ecmo. we consider that these data combined with those available from other studies provide conclusive evidence that the survival to discharge from hospital is substantially higher in patients allocated to ecmo than in comparable infants not so allocated. therefore recruitment to this trial has been closed whist awaiting complete one year outcome data. sigston pe, goldman ap. #keating j. crook r. ~e dj~. great ormond street hospital for children nhs trust, and ~biochemistry department, kings college hospital, london, united kingdom. isoflurane is a safe and effective means of long term sedation in both children and adults in the intensive care setting. the use of isoflurane, by adding it to the sweep gas allows the use of this volatile anaesthetic agent in patients on ecmo, enabling rapid control and weaning of sedation. a potential problem with the long term use of isoflurane is fluoride ion accumulation with the possibility of renal toxicity, the purpose of this study was to assess plasma fluoride levels in patients receiving prolonged isoflurane on ecmo. method: fifteen infants and children (aged day - years, median weeks) receiving ecmo support for either cardiac or respiratory failure were recruited to this study. the patients were sedated with isoflurane as well as intravenous agents (morphine and midazolam). isoflurane was administered ( % - %) via a calibrated vaporiser to the sweep gas, adjusting the level to maintain adequate sedation. blood samples were obtained on a daily basis for plasma inorganic fluoride assay. the relationship between plasma fluoride and amount of isoflurane administered, as %-hours (vaporiser setting in % x hours) was calculated by linear regression. results: the duration of ecmo ranged from to (mean ) hours, during which the amount of isoflurane administered varied from to (mean ) %-hours. blood samples were anaiysed, demonstrating individual peak plasma fluoride levels of . to . #mol/ , mean , p.molli (toxic threshold = gruel/f). the plasma fluoride positively co;related with the %-hours of isoflurane (r = . , p = < . ). conclusion: this study shows that although there is a dose related accumulation of inorganic fluoride ions in patients sedated with isoflurane on ecmq, the peak fluoride levels are well below the suggested toxic threshold. merzel y, lev a, bar yosef g, halbertal m, lorber a ecmo center, picu, emek medical center, israel. the mortality rate of pediatric patients with acute myocarditis is - % according to the severity of myocardial damage. a month old gzrl presented with high fever, respiratory and cardiac failure. diagnosis of acute myocarditis was made and the patient was ventilated with high pressures and fio of . . she required high doses of inotropes. echocardiography revealed a dilated la and lv with severe mr. lvedd was mm and lvsf %. calculated oxygenation index was . she was resuscitated after a cardiac arrest. she was commenced on ecmo (using biomedicus centrifugal pump and avecor oxygenator) at a flow of ml/kg/mm with immediate improvement of hemodynamlcs, oxygenation and pc . resptratory assistance and vasoactive drugs were reduced. the patient was transported by air, on ecmo, to the ecmo cevter. she developed arf and cvvh-d was performed. cardiac fimction started to improve after days. ecmo was discontinued on day . echo revealed lvedd mm and lvsf %. ippv was discontinued on day . on discharge, a month later, her lvedd was mm and lvsf %. she behaves normally for age without neurologic or other medical sequellae. literature search revealed no case of acute myocarditis, as severe, that was treated successfully. survavors of disease this severe usually suffer dilated cardiomyopathy and permanent disability. the use of ecmo allows myocardial rest which prevents long term myocardial damage. introduction ecmo is increasingly used in the care of critically ill newborns. despite the frequent use of betalactam antibiotics in the treatment of these infants there are no data available on the dispbsition of cefotaxime (ctx) and amoxicilfin (am) d ring ecmo. the purposes of this study were to determine the pharmacokinetics of these two drugs in infants on ecmo and consequently formulate appropriate dosing regimens. we therefore studied the pharmacokinetics of ctx ( mg/kg ql h) and am ( mg/kg q h) in term infants on day after birth, blood samples were taken before (t-o) and . , , , , (am) and t h (ctx) after the intravenous bolus injection and analyzed by hplc-assays. . ctx mg/kg q h results in adequate serum levels of ctx in fullterm infants on ecmo, am mg/kg q h results in very high serum trough levels. recalculation based on the known volume of distribution and elimination serum half-life of these infants resulted in the following dosage recommendation: mg/kg q h. persistent pulmonary hypertension of the new-born (pphn) is characterised by rapid fluctuations in pulmonary artery pressure (pap) and a clinical impression of stifflungs. lung mechanics were measured in term infants, mean age . +_ . days who were paralysed and ventilated within the first three days of life. fourteen infants had pphn with systemic or suprasystemic pap measured by echocardiography. in these patients, the respiratory system resistance was . % higher (p < . ) and compliance . % lower (p = . ) during systemic or suprasystemic pap compared to when the pulmonary hypertension had resolved. in contrast, there were no changes in resistance in the infants with respiratory distress syndrome (rds) and no pulmonary hypertension or in the seven infants with normal lungs, where two readings were taken hours apart. the changes in lung mechanics interfered with mechanical ventilation, resulting in a . mmhg rise in paco (p= . ) during pulmonary hypertension. inhalation of nitric oxide ppm resulted in a % decrease in respiratory system resistance and an improvement in oxygenation. the bronchial and vascular smooth muscle was increased by % in postmortem lung samples from eight infants with pphn compared to six age matched post-mortem controls with normal lungs (p< . ). these findings suggest a co-constriction and co-hypertrophy of bronchial and vascular smooth muscle during pphn. anatomically the pulmonary vasculature and bronchi lie in close proximity to each other. thus mediators such as endothelin- released locally may act on both vascular and bronchial smooth muscle to produce the observed vasoconstriction, bronchoconstriction and smooth muscle hypertrophy. prince of wales children's hospital university of new south wales, randwick, n.s.w. australia. introduction an increasing mortality in asthmatic children has been reported. the increased severity of asthmatic illness leads to an increased demand for icu admission, and a corresponding increased need for mechanical ventilation. geographic end environmental factors are thought to be partly responsible for differences in disease sevedty throughout the wodd. for this reason, epidemiological studies from diverse areas are important, risk factors for icu admission, and for the institution of mechanical ventilation should be identified, to optimise icu admission criteria and to avoid unnecessary delays in admitting at-risk patients. aim to document the clinical characteristics of ventilated and non-ventilated asthmatic patients admitted to icu. methods this is a retrospective study of all paediatric asthma icu admissions from january to december . results there were patients admitted to the icu for acute severe asthma in the study period. the male:female ratio was : , the mean age . • . months, the mean prism . - . %, and the mean duration of admission . hours. there was no seasonal variation in admissions. only % ( / ) patients required mechanical ventilation. in % of all patients this was the first presentation with asthma. there were some significant differences between ventilated and non-ventilated patients (see table) . there was a significantly higher incidence of concomitant and nosocomial pneumonias in the ventilated patients ( . % vs . %) as well as segmental lung collapse ( . % vs . %). there were no deaths. discussion the need of mechanical ventilation significantly increases the morbidity of and duration of icu stay of asthmatic patients. younger asthmatic paediatdc patients have a significantly higher risk of ventilation. the need for ventilation is predicted principally from a worsening pco and respiratory acidaemia, which is often independently interpreted by the clinician as respira ory exhaustion. this study has shown that icu admission is important in the management of young paediatdc patients with acute severe asthma and respiratgry fa!!ure. intravenous salbutamoi in the emergency, department management of severe asthma in children. g.j.browne,a. perma,x. phung,m.soo westmead hospital, sydney, australia. it is postulate that if an initial intravenous loading dose of salbutamol is given in severe asthma, a more rapid clinical response will occur, reducing requirements for continued high doses of nebulised salbutamoi with fewer side effects. this double blinded study was conducted in the emergency department of westmead hospital a university hospital in sydney, australia. all children with severe asthma had initial nebuliser therapy ( rag of salbutamol with ml of saline). if asthma remained severe minutes later, they were given a dose of intravenous hydrocortisone ( mg/kg) and either normal saline or salbutamol microgm/kg intravenously. frequent nebulised salbutamoi therapy continued during the initial first hour if clinically indicated. continuous respiratory and haemodynamic monitoring occurred in the first hours. serum potassium and glucose determinations were made at study commencement and hour after intravenous therapy. salbutamol determination was made at study commencement. children remained clinically monitored for the next hours, with their ongoing treatment determined by clinical response. children with severe asthma months to years of age were studied, with given intravenous salbutamol and given intravenous saline. the intravenous satbutamol group (ivsg) showed rapid reduction in asthma severity scale in the first hours, with reduced need for high frequency nebuliser therapy ( _< hourly), occurring . hours.earlier. no clinically significant side-effects were found in either group, although, tremor more frequent in the [vsg. biochemistry and salbutamol concentrations were similar in both groups. the use of intravenous salbutamol (i microgm/kg) in the management of severe childhood asthma is a safe and effective therapy with no significant side-effects and the potential to abort severe asthma attacks in the emergency department. intravenous terbutaline in picu piva j., amantra s, rosso a., zambonato s, giugno k, maia t. introduction: the admission to a picu of children with respiratory failure secondary to an acute obstructive lower airway disease is a common event, especially during winter seasons. these diseases have several causes, but most of them (especially asthma and chronic airway disease) have a good response to the administration of b -adrenergic drugs. objective: to find the dosis of intravenous terbutaline that is safe, efficient and with minimal adverse effects when used in children admitted to a picu with acute obstructive lower airway disease and respiratory failure. material and methods: we study the records of all children that were admitted to our picu during the winter of . only the patients that had respiratory failure and acute lower airway disease and who needed the use of iv terbutaline were selected. the records were divided in two groups: less than months and more than a year old these two groups were compared in the following aspects: the minimal and maximal dosis, and the length of time of use of iv terbutaline, frequency of tachycardia, hypokalemia, and mechanical ventilation. to establish any difference in the two groups we use the t exact test of fisher and x , with p< . , results: during the period of study were admitted patients to the picu, and ( , %) of them used of iv terbutaline. the mean age was . + . month, used iv terbutaline during . + . days ( . to days), the initial rate was . + . p~g/kg/min, and the means of therapeutic dosis was . +l. ~g/kg/min (ranged from . to . ). twelve ( . %) patients had tachycardia art obstacle to the increases in the rate of use of iv terbutaline during any time. mechanical ventilation was necessary in patients ( . %) and ( . %) patients died. the children under year of age used initial dosis of iv terbutaline lower than the children up of year old ( . p.g/ kghnin x . ~tg &g/rain, p< . ), but without difference in the length of use, the maximal dosis, the rate of mechanical ventilation and tachycardia. the frequency of hypokalemia was most common in the group of children under year of age. acute respiratory failure during status asthmaticus may require mechanical ventilation. current therapy includes paralysis, pressure control ventilation (pcv) and permissive hypercapnia to limit pulmonary barotranma and its hemodynamic consequences. asthmatic children exert a significant amount of respiratory effort during exhalation. with paralysis, this expiratory effort is lost. unloading the inspiratory work of breathing while maintaining the patient's expiratory eftbrt using pressure support ventilation (psv), may be beneficial. methods: children receiving pcv (peak inspiratory pressure (pip) = kpa. rate breaths/min) and pco > kpa were switched to psv. children were initially ventilated with psv . kpa and peep = . kpa (servo c). all children received beta agonist therapy, ipratropium and anesthesia with ketamine or inhalational anesthesia, and were breathing spontaneously. respiratory parameters and blood gases are shown be~bre psv, within minutes (start) and when the ph had normalized (during). data are presented as median and range, * p < . compared to before psv. results: children with hypercarbia during pcv responded to psv, normalizing pcos and ph within hours. the mean respiratory rate decreased from a median of ( - ) to ( - ) while the pip was decreased to . ( . - . ) kpa within hours. the i:e ratio also significantly decreased. conclusion: psv permitted patients to active/y exhale while unloading the inspiratory work of breathing. perhaps this strategy shifts the patient's respiratory effort from inspiration to exhalation, thus permitting the child to meet the excess work of breathing caused by bronchoconstriction. maged z. youssef, peter silver, laura nimkoff, and mayer sagv. division of pediatric critical care medicine, schneider children's hospital, new hyde park, ny . introduction: mechanical vemiladon of patients with severe bronchospasm can be difficult, due to poor chest compliance and increased airway resistance. ketarmne is a cormnonly used anesthetic agent that has been shown to have bronchodilator properties. the purpose of this study was to determine ifa continuous infusion of ketamine had an effect on the oxygenation and chest compliance of children with severe lironchospasm who were mechanically ventilated. methods: a retrospective chart review was conducted of pediatric patients in severe bronchospasm who were mechanically ventilated in our picu and treated with a continuous ketamine infusion. all patients were receiving aggressive bronchodilator therapy and adequate sedation prior to keramine. patients were excluded if any new bronchodilator or sedative agents were started within hours of initiation of ketamine treatment. all patients were simultaneously treated with benzodiazepines. for each patient, the pao /fio ~ ratio and dynamic compliance [tidal volume/(peak imp. pressure -peep)] was determined immediately prior to ketamine, and at , , and hours post-ketsmine initiation. data are presented as mean ± s.d., and were a~yzed using one way anova and the multiple comparison method of bonferroni. patients (age . ± . yrs.) received * p< . ketamine for severe bronchospastu during mechanical ventilation in our picu. both . .xto-* * the pao /fio ratio and dynamic . . -.... . compliance increased significantly following initiation of the ketamine infusion (see figure) . the mean ketamine dose was ± mcg/kg/min, and the -, mean infusion duration was ± too-[/ hours. one patient required glycopyrrotate ~' to control excessive airway secretions, and " one patient required an additional dose of o--j i ~-~ ~/me diazepam to control hallucinations after i cessation of ketamine. all patients were t~n~,mr~ *~am~ successfully weaned off mechanical ~l~s ~,~s~on ventilation and discharged from the picu. conclusion: continuous ketamine infusion to mechanically ventilated pediatric patients with refractory broncliospasm results in a significant improvement in oxygenation and dynamic compliance of the chest. reports of adults with status nsthraaticus document significant morbidity and mortality, whereas studies in children have had more varied results. different centers report mechanical ventilation (mv) in to % of admissions, occurrence of pneumothoraces or paeutuomediastinums in to %, and mortality in up to % of patients ~'t . we retrospectively reviewed status asthmaticus admissions to the pediatric intensive care unit (picu) between january and december . seventy-five of these patients were admitted fr~an the emergency department of chla (er admit). the mean length of stay in the picu was . days and the mean length of stay in the hospital was . days. based on patients who had arterial blood analyses, patients had hyperoapnia (pco > ). all patients received oxygen, inhaled albuterol (alb), and cortieosteroid therapy. ninety-five percent of patients also received methylxanthine (mx) therapy. of the admissions, patients ( %) required mv. only of these patients were admitted through our emergency department, whereas the remaining patients were intuhated at outside facilities. twenty-three cases required intr:wenous beta-agonist therapy, either isoproterenol osop) or terbutaline (terb). h~ff of the ea.~es re~%wed were complicated with hypokalemia (k+< . ). c,', ,~lications ofpoeumothoraces or pneumomediastinums were seen in % of ,'r:u~ported patients, but in only % of er admit patients. only % of these were in mechanic.all, )atients. there were no deaths in the review. respiratory mechanics measurements 'are useful in mechanically ventilated children to optimize ventilator settings. nevertheless, the transducers used to measure flow (f) and pressure (p) remain expensive. objective. to evaluate the performances of piezoelectric p transducers ( us dollar) in measuring f and p. methods. we used a previously described monitoring system measuring respiratory parameters [ ] . in this study f was obtained by a differential piezoelectric p transducer (_+ . cmi-i , honeywell) whose sensitivity has been reduced to +_ cmh by an electronic amplification equipment and p by a piezoelectric p transducer (_+ (). cmhzo, honeywell) connected to a grid pneumotachymeter &nt) ffleisch or ). volume (v) ( to ml) obtained by numeric integration off ( . to l/rnin ) and p ( to cmh ) were respectively delivered through a calibrated seringe and an electronical manometer (pic premier) and calculated by the computer. bland and altman analysis was used for assessment of results bias. coefficient of repeatability (cr) was estimated by the standard deviation of repeated measurements of the parameters as calculated in a oneway analysis of variance. results. mean difference (mdi between injected v ( to ml) and measured v using pnt was . ml, sd = . ml. difference and mean v were not correlated. sd of repeated v measurements were not correlated to v. cr was . ml. mdif between injected v ( to ml) and measured v using pnt was lrd, sd = ml sd of repeated v measurements were not correlated to mean v. cr was ml. mdif between injected p and measured p was . cmi-i , sd . cm h sd of repeated p measurements were not correlated to mean p. cr was . cmh . conclusion. inexpensive piezoelectrical transducers can be used to measure f and p and evaluate respiratory mechanics in ventilated children. previous studies have already shown the problem of the reproducibility of pft in preterm ventilated babies. were studied preterm ventilated babies {mean weight gr) in the first week of life in clinically stable condition, measuring flow, airway pressure and esophageal pressure simultaneously. each baby was studied twice with an interval of one hour and each study was done increasing the rate till to inhibit spontaneous breaths. none sedative has been used. only mechanical breaths were analyzed. compliance and resistence were calculated with a computer system using the linear regression method. we expressed quantitatively the intrapatient variability as the percentage of variation of tidal volume, compliance and resistence between the two studies in each baby. then intraclass correlation coefficient test (icc) was applied to confirm qualitatively our results (total agreement = , good reproducibjtity > . ). we h~£ed, an a eept~ble ~efiabirl¢, ~-~r;= '~ . during mechanical ventilation, an air leak (al) and plateau phase duration (pl) may influence dynamic and static compliance (cdy and cst, respectively). this study evaluated the effect of al and pl on two methods of measuring c.dy and est. methods. intubated, ventilated patients in a pediatric intensive care unit were evaluated after obtaining informed consent. patients were intuhated with a cuffed endotracheal tube and ventilated with a serve ( ventilator. cdy and cst were determined using the serve ands~rmedics . objective: evaluate the repercussion in respiratory mechanics and arterial blood gases and the impact of the ventilator adjustments on the auto-peep magnitude. material and methods: the measurement of the auto-peep was performed using an eletronic-pneumatic controlled device with a oclasion valve installed between endotracheal canutla and the ventilator circuit. the d~'ice was connected to a solenoid to detecte the end of inspiratuo phase and thus, the activation of the oclusion valve. the signs of pressure and flow were monitorized using a diferential transducer and it was processed using a pc computer and tmeumoview® software. the stud were divided in phases: phase a. where the ventilator adjustments was performed using the routine of the unit and phase b, where the targets of mechanical ventilation were to minimize the auto-peep. static compliance (crs) was ineasured by the single-breath occlusion technique, using a mean of ten occlusions for analysis. passive respiratory resistance measurements and the tidal breathing flow-volume loops were also obtained., while the ventilatory settings were siguificantly reduced soon atier ecmo was started. before ecmo crs measured in all patienls was . _+t). ml/cmh /kg (mean_+sem). for each patient the ecmo course was divided into four periods, proportional to the duration of the treatment, and the best ~alue of crs in each period was chosen for analysis. as shown on the figure. crs significantly improved (*p< , ) from the second half of the ecmo course in the group of patient that finally were successfidly weaned from ecmo. no change ill compliance was measured in the group of patients who failed to respond to the extracorporeal hmg support our data suggest that compliance measurements during ecmo can be useful togelher with overall clinical evaluation to predict both outcome and duration of cxtracorporeai support in the neonatal and pediatric population. objectives: brain temperature determines the amount of neuronal damage caused by hypoxic insults. thus measuring brain temperature at standardised conditions is in request. we investigated whether brain temperature of neonates varies with head insulation environmental temperature, body activity and time course. patients and methods: we investigated non-invasive brain temperature analogues in healthy prematures tess than two weeks of age in an incubator (gestational age . + . wks; x + sd, weight + g). we measured nasopharyngeal temperature (tnasoph) by a thermistor placed in the nasopharynx via a feeding tube, zero-heatflux temperature (zht) at the temple by a thermistor and healflux transducer, insulated by two pads, as well as rectal and incubator temperatures. patient activity was documented by video taping. measurements were performed during periods of increased insulation ) by turning the head with its measuring site on to the mattress ( ( ) ( ) - ( ) ( ) ( ) ( ) . ( ) ( ) { ) ( ) ( ) - ( ) ( ) ( )i ( ) ( ) ( ) ( ) . ( ) ( ) t ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) web (lmg/kg) at rain ( ) - ( ) ( ) ( ) ( ) - ( ) the vehicle had no effect. paf caused dose dependent rise in ao and pa pressure and reduction in flow to lpa (up to % like the vascular endothelium, the endocardial endothelium (ee) has a significant impact on adjacent myocytes, and may critically alter myocardial function.~ we have previously shown that ee cells are capable of sensing and responding to hypoxia by the release of prostacyclin (pgl). potassium channels in other cell types have been reported to be oxygen sensitive. to determine whether potassium channels modulate the ee hypoxic response, we investigated the effects of three potassium channel inhibitors on hypoxia-induced pg] release from ee cells. methods: ovine endothelial cells were harvested and passaged onto ,~ microcarriers. cells were constantly perfused with normoxic and hypoxic kreb's solution, and with three potassium channel blockers: glibenclamide (gb, #g/ml), tetraethyl-antmonium (tea, ram) and aminopyridine ( ap, i mm), perfusate was assayed for prostacyclin (ria). data were compared by analysis of variance. * p<. compared to normoxic control; # p< . compared to hypoxic control. adrenaline is extensively used for resuscitation in neonates with rds. however, effects of adrenaline on systemic, pulmonary and cerebral hemodynamics have not been defined in newborns with rds. thirteen anesthetized, and ventilated newborn piglets were subjected to repeated saline lung-lavage series while mean systemic arterial pressure (abp), mean pulmonary arteriat pressure (pap), mean left atrial pressure (lap) and mean central venous pressure (cvp), cardiac output and blood flow in the internal carotid artery (ica) were measured. systemic vascular resistance (s~), pulmonary vascular resistance (pvr) and cardiac index (ci) were calculated. sixty minutes after luug-lavage, the adrenaline group (a) (n= ) received adrenaline as a continuous infusion of . lag/kg/mi, while the control group (c) (n= ) received saline. none of the varlables were changed by saline. however, significant increases in abp (p< . ), pap (p< . ), ci (p< . ) and svr (p< . ) were observed after administration of adrenaline, whiie pvr and ica were not modified. mean±sd for abp/pap (p/a), fvr/svr (p/s) and ci (ml/mirdkg) were: ratios of pap/abp and pvpjsvr significantly increased following infusion of adrenaline. these data suggest: ) the cerebral perfusion is preserved during the infusion of adrenaline; ) effect of the adrenaline infusion on the systemic circulation is more pronounced than its effect on the pulmonary circulation in newborn piglets with surfactant deficiency. s demirak~a, ch knothe, kj hagel, j bauer department of pediatrics, justus-liebig-university giessen, frg inhaled no is a short acting selective pulmonary vasodilator. we studied the effects of ppm no and % oxygen during heart catheterization in children (age - years, median years) with heart defects and elevated pulmonary vascular resistance index (pvri) in order to asses the value of no as a tool of decision making for corrective cardiac surgery. patients were eligible for testing when they were more than one year old and had a pathologically elevated pvri in a previous heart catheterization. intubation, 'anesthesia and muscle paralysis were performed in all patients during testing of pulmonary reagibility. calculations of pulmonary vascular resistance and flow were based on the fick method. response to no was assumed when pvri declined more than %, of the patients were responders to no. effects of no and oxygen on pvri, mean pulmonary arterial pressure (mpap) and pulmonary vascular flow (qp) in all responders are described in the table below. cardiac surgery was offered to all responders, and of them were successfully operated. surgery is planned in another patients and parental consent for surgery was not given in one patient. in ebstein disease, during the first days of life, the ability of right ventricle to propel blood to the pulmonary artery is impaired due to high pulmonary vascular resistances. the flow is mainly directed to left atrium through tricuspid insufficiency, right atrium and foramen ovale. to decrease pulmonary resistances and increase pulmonary blood flow, high frequency oscillations, mechanical ventilation, nitric oxide and prostaglandin are required. after few days, a forward circulation is normally established. we cared two newborns with ebstein disease where this approach was hindered by a large pulmonary valve insufficiency. both of them were diagnosed in utero, showing a large tricuspid insufficiency with a non opened pulmonary valve and a ductal left to right shunt. one fetus was hydropic. at birth, blood stream from the ductus arteriosus was directed to the right ventricle through the pulmonary valve insufficiency then to right atrium, left atrium and ventricle, aorta and ductus arteriosus. a low pulmonary blood flow was demonstrated by low mean velocities ( cm/sec). a high reverse flow was seen in descending aorta with a negative flow in the renal artery. both of these newborns were oliguric because of ductus arteriosus steal. pulmonary blood flow doppler evaluation allowed different strategies of ventilation, switching between hfo and conventional ventilation, modulation of pge doses, inhaled pulmonary vasodilators (nitric oxide) and surfactant. the hydropic baby died, the other survived after weeks of intensive care complicated by supraventricular arythmia (wpw). in conclusion, during neonatal period, in ebstein disease, a large pulmonary insufficiency leads to a vicious circle where lungs are excluded, inducing severe asphyxia and high pulmonary resistances. the blood is backward propeled from the aorta through the ductus arteriosus to the right ventricle and atria, then left cavities to aorta. arec must be considered when pulmonary blood flow does not increase despite optimal therapy. guti~rrez-larraya f*, mandoza a*, velasco jm*, zavaneua ( **, gatindo a ~, s&nchez-andrede r, s&nchez jl***, mellon a***, mar f***. pediatric cardiology*, pediatric cardiac surgery**, pediatric intensive care unit***. hospital de octubre. madrid. background: transesophageal pacing (tp) is effective and sate both for diagnosis and treatment of pediatric arrhythmias. material and methods. eleven consecutive patients are included. a tri or quaddpolar or f temporal transvenous catheter with an interpolar distance of to mm was advanced through the nares and positioned to the point with the largest amplitude of atrial deflection, surface ecg and a bi or monopolar electregram were recorded simultaneously, selecting filters when needed ( to mhz). pacing was performed with a programmable stimulator (medtronic ) beginning with ms and increasing ma to and then increasing up to . ms. narula method was selected to diagnose sinusal node disfunction (snd) and overdrive pacing to treat tachyarrhythmias. results. tp was useful in all the patients and no complications were observed: in patients a snd was diagnosed (one needing a definitive pacemaker), in two patients with atrial ratter (ripe ) sinus rhythm was recovered, in one patient with a postoperative junctional ectopic tachycadia we were able to get atrial synchrony with marked bemodinamic improvement, and patients with paroxysmal supraventricular tachycardia sinus rhythm was easily and quickly restored ( of them recquirad repited episodes of tp until pharmacelogycal levels of antiarrhythmic drugs were raised). mean age and weight were months and . kg (one patient had . kg). there was a close relation between height and depht insertion (r= . ). mean stimulation parameters were , ms and . ma. discussion. in experiencied hands tp is an effective and safe way to treat and diagnose cardiac arrhythmias even in newborns. it should be tried before endovenous pacing is stablished and it is faster than pharmacologycal treatment. bailing g., eicken a., sebening w., vogt m., schumacher g., bl~hlmeyer k.; kinderkardiologie, deutsches herzzentrum m nchen, germany to assess the outcome of balloon valvuloplasty in infants with cardiac failure caused by critical aortic stenosis a retrospective study was performed. between and neonates, aged - days (median d), weight .t - , kg (median , kg) with critical valvar aortic stenosis were dilated by balloon (aovp) as the first line treatment. patients received prostaglandin el, needed inotropic drugs and mechanical ventilation. associated cardiac lesions : persistent ductus arteriosus (pda) in patients (restrictive pda in cases), a mitral regurgitation (mivr) in cases ( severe and moderate or mild mivr), angiographic findings of endocardial fibroelastosis (efe) in patients, mitral stenosis (mivs) in , coarctation of the aorta (coa) in , and finally a small musculary ventricular septum defect (vsd) in i patient. vascular approach for ballooning : a. axitfaris in cases ( %) a. femoralis in t ( %) and v. femoralis in cases ( %). the median ratio between inflated balloon and aortic valve diameter was , . dilatation was achieved in all cases. the peak systolic gradient across the aortic valve (pre aovp) ranged from to mmhg (median mmhg) and was reduced to to mmhg (median ; gradient reduction is significant (p < , )). aortic regurgitation (aovr) was absent or mild in , moderate in and severe in patient after aovp. children survived (actual suwival rate: %; early mortalffy: n = ; late mortality: n = ). mid term follow up ( - , years; mean , years) showed an increase of the systolic peak doppler gradient across the aortic valve (median mmhg) but no increase of aovr. re-interventions (re-aovp: n = , commissurotomy: n = , mitral valve replacement n = , resection of subaortic stenosis: n = , resection of coarctation: n = ,vsd-closura: n = ) were performed in patients. rv contractility and pulmonary vascular mechanics(pvm) in immature animal models are poorly underslood. we developed an acute rv injury model to measure rv contractility and pvm in response to commonly used cateehalamines. ten anesthetized piglets ( - kg) were instrumented with micromanometers in the lv, rv, pa, and la. a pulmonary artery flow probe was placed to measure cardiac output(qpa). ultrasonic dimension crystals were sutured to the myocardium and dynamic chamber volumes estimated using shell subtraction methodology. rv injury was induced with - cryoprobe injuries at - to - °c for - minmes each. da at mg/kg/min, db at mg/kg/min, and ep at . mg/kg/min were infused in random order. rv contractility was evaluated by calculating a load independent measure of contractility, the preload recmitable stroke work(prsw), during vena caval occlusions. to describe pvm, input resistances), characteristic impedance(z ), total pewer(tp), and efficieacy f=qimo"p) were measured. measurements were made pre-and post-injury, during infusions, and between infusions. clyoablation decreased prsw ( . _+ . to . + . , p< . ). at the end of the experiment, prsw remained depressed to this level indicating stability of the model. one factor contributing to organ dysfunction for infants undergoing repair of congenital heart defects (chd) is their "inflammatory response" to cardiopulmonary bypass (cpb). this response is characterized by an increase in cytokine release, complement activation and endothelial injury. modified ultrafiltration (muf) is a method for removing tissue water and inflammatory mediators by rapid ultrafiltration followin~ cpb, muf may acutely improve post-operative end organ function. in this study, we evaluated the effects of muf on the pulmonary and cerebral function of infants undergoing cpb for repair of chd. we prosnecrivety randomized infants (.~ mos) to either muf (n= ) or no muf (n= )(control) following correction for chd. the study intervals were ) before cpb, ) immediately after cpb, and ) minutes after cpb. pulmonary function was evaluated by measuring dynamic compliance (cdyn) and airway resistance (raw). for pts (mue= pts; control= pts) exposed to a period of deep hypothermie circulatory arrest (dhca), cerebral metabolism (cmro ) was calculated at each interval using the xe clearance technique for cerebral blood flow measurements and arterial and jugular bulb saturation measurements to calculate cmro . a reduction in cmro has been consistently demonstrated after dhca. the effects of muf on cdyn and on cmro are shown below: p< . vs pre-cpb; # p< . vs post-cpb • p--o. vs. post-cpb this study demonstrates that immediately following exposure to cpb, muf will improve pulmonary compliance. raw was not different between groups. there was no significant difference in hours of post-op ventilation for either group. in those pts exposed to dhca a trend towards better cerebral metabolic recovery compared to control was demonstrated. this is the first technique applied to infants undergoing dhca where cmro after cpb was greater than precpb measm~s. although this may be beneficial to postoperative hemodynamics, ventilatory management and long-term neurologic recovery, more patients and longer follow up will be necessary to verify such an effect. the effects of conventional mechanical ventilation (cmv) on left ventricular (lv). diastolic filling in neonates are not well established. one approach to improve lv filling is the use of cmv to provide a phasic increase in airway pressure {thoracic augmentation). this phasic increase in airway pressure may result in an increase in lv filling similar to that which occurs with cpr. thoracic augmentation has not been evaluated in neonates with ventricular dysfunction who frequently demonstrate increased heart rates. attempts to maintain low peak airway pressures during cmv may result in a prolonged inspiratory time that occurs over multiple cardiac cycles. this may alter lv filling in the later cardiac cycles. to determine the effects of inspiratory time on lv diastolic filling, infants were examined with doppler echocardiography less than hrs after surgery for the arterial switch procedtme. pulsed doppler recordings of the millal valve (mv) were obtained with the inspiratory time adjusted to occur over cardiac cycles ( sec.). a pressure transducer was placed in line with the ventilator, and the respiratory cycle was recorded superimposed on the doppler tracing to provide accurate determination of inspiration and expiration. doppler recordings were obtained from the apical -chamber view and the following measurements were made: peak e and peak a velocities, eia ratio, and deceleration time. compared to the expiratory phase of cmv, the initial beat during the iuspiratory phase of cmv resulted in an increase in mv peak e (. +-. vs . -+ . m/s, p< . ) and peak a (. + . vs . -+ . m/s, p< . ) velocities with no change in mv deceleration times (p<. ). compared to the initial beat during tile inspiratory phase, the third beat during the inspiratory phase resulted in decreased peak e (. + . vs . + . m/s, p< . ) and peak a (. + . vs . + . m/s, p< . ) velocities with no difference in deceleration times. thus, cmv augments lv filling during the initial phase of inspiration. however, as the increase in airway pressure is distributed over multiple cardiac cycles, lv filling falls below baseline levels. these observations indicate that while thoracic augmentation may be beneficial, to optimize lv filling the inspiratory time of cmv must be < cardiac cycles. energy expenditure in pediatric orthotopic liver tranaplantat~on, to determine the actual calorie requirements of critically ill children and evniuate the correlations between measured, stress-p~lictod and repleted energy exponditttm and the severity of illness. des/gn: a prospective, dinlcal study. se~ng: tertiary care pediatric icu in a university hospital. patients: ten patients aged to months with disorders prompting picu admission, including sepsis, respiratory failure, solid organ transplantation, and cardiovascular surgery. inta~entions: all patients were studied within hrs of major surgery or transplantation, or following acute illness. all patienls were severely stressed clinically and all but two were intubated by cuffed tubes, in three of them, still in a stress state, the study repeated on the third day of the disease, energy expenditure mensurements (mee), as well as illness seventy scoring systems, mtfltisystern organ failure scores and various anthropemetric and clinical indices of nutritional status, the stress-predicted energy expenditure (s-pee), the basal metabufie rote (pbmr), the repleted energy (re) and the recommended dietary allowances (rda) were measured or calculated in each patient. multiple regression analysis was used to analyze the data. measurements and main results: although the mean mee was significantly lower than the mean s-pee ( . + kcal/kg/day vs. . : kcal/kg/day, p<. ), it did not differ significantly from the pbmr (mean difference - . kcal/kg/day, range - . to + . kcal/kg/day). the s-pee/mee ratio ranged from . to . , while the re/rda ratio ( . : kcal/kg/day)/( . : kcal/kg/dny) ranged from only . to . . the prism/tiss ratio was not correlated better with mee than the diagnostic category (r~=. vs.. , respectively). the re was positively correlated withthe mee (rz=. , i)=. ) while negative oarrelatian has been found between mee and age, mid-arm circumference, triceps skinfotd and the use of vaseactive agents (r~. , - , -. , p<. and -. resp~lively). concl.m~: if s-pee is used for caloric repletion in the stressed oritic~ly fll el~d, these patients will be substantially overfed by as much as %. although pbmr appears to approximate the mee by ± %, other clinical and nutritional indices should also be ennsidered. objective: to deter .mine..t.he metabpli.c and.nutritional state of mechanically ventilated intants and children m relatmn wlm severity or msease. patients and methods: mechanically ventilated infants and children, median age months (range days to years), were studied. severity of illness was assessed using prism, prism-ii~ and fiss-scores. oxygen consumption (vo ), energy expenditure (mee) and respiratory quotient (rq) were determmed by mdirect calorimetry. total urinary nitroger(tun) and creatinine excretion, levels of albumin and crp were aetermmed in patients. in these patients daily caloric intake and substrate utilization were assessed. they were categorized in subgroups: a partial feeding (recent admission to p cu); b complete feeding. results: mee of the total group (n= ) a) i=intake g/kg/day (% total intake); u=utilization g/kg/day (% total production). nitrogenba]ance was negative in all patients in group a (mean - . -- : mffkg/day) and positive in all but one patient in group b (.mean . ± .d n~g/..kg/day;p= . ). no significant correlations were round between creatinine height index, crp, albumine, jun vs v u /kg conclusions: the mean measured energy expenditure does not exceed predicted resting energy expenditure, but ~ere is a wide range. in a majority ot patients with complete feeding h.igh carbohydrate intake resulted, in high kq and lipogenesis. in patients witla partial teeding the highly negatwe nitrogen'balance suggests that in the early phase of diseasean higher protein intake should be provided. severity of illness scores ann oiocnemicm markers of physiologic stress correlatedpoorly with oxygen consumption. leite,hp; iglesias, s; faria, c; ikeda, a; albuquerque, mp; carvalho, wb pediatric icu -s~o paulo federal university -s~o paulo, brazil objectives: ) to evaluate patterns of use and monitoring of nutritional support in critically ill children; ) to evaluate an education program in nutrition support given throughout the resident physician training in the pediatric icu. patients and methods: records of patients receiving nutritional support during were reviewed. aider this first phase, knowledge and understanding of the role of nutrition support was conveyed to the residents through didactic lectures. in a second phase thedata were reevaluated in children who were given nutrition support in . results: from a total of days ofthempy, the single parenteral route was utilized in , %, the digestive route (tube feeding or oral route) in , %. of this time. a previous nutr~ional assessment was performed in children; no patient had the nutr~on goals set. the nitrogen to nonprotein calories ratio ranged among : and : . only , % of the patients had their estimated caloric needs supplied and this goal was achieved only in those patients who were on enteral tube feeding. patients did not achieved their goals for vitamins. the supply ofoligonleme~s was adequate except the zinc. nutritional monitoring parameters including weight, serum albumin and serum triglycerides were performed in almost all the patients but without uniformity. the reevaluation ofthase parameters showed adequacy of protein and micronutrients supply; however deficiency in nutritional monitoring and infrequent enteral feeding were still detected. conclusion: there were lacks in the implementation of nutritional support, which were partially corrected in the rid phase of the study, although the training of residents may have contributed to give them cognitive skills, it didn't changed policies and procedures as desired. we recommend reinforcement of the education program concerning basic nutritional aspects, and the organization ofa multidisciplinary team in charge of coordinating the providing of nutritional support. plasme free fatty acids (ffa) are the meier energy source for mast tissues. during fasting ffa are released from the breakdown af triglycefides in edipose lissue (at). lipalysis, le. the rote of release o/ ffa, has been megsured in humans by means of stable isotope techniques using labeled pa or glyeerd as traces. no information is avoilob!e io dale on the ro of la. we infused albumin hound u c-pa and u c-la in critically ill infants, receiving kcel/kg/doy of iv glucose end na oral feeding (weight . ,i., kg;, range . - . ; ego : days, range ) and measured simultaneously the ra of pa and la from (he isotopic enrichment of plasma fea by gas chromatography-mass speclrome|ry ai : , : and : hours from tile shod of the infusion. a subcutaneous gluted at biopsy was obtained far fatty acid (fa) composition. we intended to ( ) in fie infants sbjdied atipa ~'os hi her than attla (~p<o.o )' and ihe ra of pa was higher then thai of la (~p= . §). however the ratio el the re's to the respeclive fa in at was higher for la than far pa (*p= . ). in conclusion the ra af la was higher then expected from ~he fa composition of at. we speculate [hat la is preferentially released during tipolysis and its contributuion to the energy metnbolism of the sick infonl could io !orger than what: is normai!y assumed from ihe fa composilion of at and of plasma fea. preoperative starvation can be prevented in infants undergoing non gi surgery by continuing feeds till as long as it is safe to do so. some gi disorders require withholding of feeds for a long period. for these and for infants already suffering from pem~ parenteral feeds are given preoperatively. peroperatively nutrition is maintained by ensuring adequate glucose supply in the infusion fluid and its smooth metabolism. proper placement of feeding tubes are also carried out peroperatively. postoperative early resumption of oral feeds is ensured by new techniques of anaesthesia and pain relief and methods to ensure early return of peristalsis. enteral feeds of pre digested substances and feeds through transanastomotic tubes and through gastrostomies and jejunostomies can prevent starvation in many situations. parenteral feeding is carried out only when enteral feeding is not possible, for example in necrotising enterocolitis~ gastroschisis, short gut syndrome, high enteric fistula and acute pancreatltls. the artedal ketone body ratio (akbr) is established as a valuable tool in the management of adult patients undergoing surgery for severe liver disease.the redox theory emphasises the central role of the liver in preserving homeostasis and the importance of the hepatic mitochonddal redox potential (nad+/nadh) in monitoring liver function and integrity.the akbr (plasma acetoacetate/ hydroxybutyrate) is a measure of hepatic mitochonddal redox status, reduced ratios associated with poorer outcome. the venous ketone body ratio (vkbr) is influenced by peripheral ketone utilisation and therefore thought unreliable in assessing hepatic redox its use has been dismissed as no correlation with the ratio in hepatic venous blood was found. inspite of this. vkbr is used in the diagnosis of lactic acidoses and respiratory chain defects. the objective of this study was to determine the relationship between the akbr and vkbr in a paediatnc intensive care population. children admitted to the paediatdc intensive care unit, with indwelling arterial and central venous lines as part of their routine care, were recruited for the study. the median (range) age was . years ( - . years) with prism score ( - ), simultaneous akbr and vkbr were measured. suppression of ketogenesis was confirmed using a rapid -hydroxybutyrate strip test (ketofilm, genzyme diagnostics) pdor to sampling. the median vkbr . (range . - . ) was lower than median akbr . (range . - , ), there was good agreement between artedal and venous ratios, bland-altman analysis giving a % confidence interval for relative bias of - . to - . . there was a significant correlation between vkbr and akbr r , , p, . (intercept . , slope , ) conclusions; values for akbr tend to be higher than vkbr, however there is a consistent relationship in critically ill children. in paediatdc patients in whom ketogenesis is suppressed, vkbr may be considered equivalent to akbr. this simple test may prove to be a useful adjunct in predicting mortality in cdt{cally ill children. to understand the present status of pediatric intensive care in china, we conducted a survey between october and december, , involving hospitals in provinces and municipalities. the results showed that there were totally icus for pediatric patients, including pediatric icus (picu), neonatal icus (nicu) and pediatric surgical icus (sicu), with total of beds. the physicians to bed and nurses to bed ratios were : . and : . respectively. the average number of equipment per bed was . ventilator, . multi-fnnction monitor and . infusion pump. very few of the icus had portable x-ray machine, biochemical and blood gas analyzers, and hemodialysis machines. the most frequently treated diseases/conditions were pneumonia, intracraniat infections, post-operation and sepsis in picus, and neonatal pneumonia, hypoxic ischemic encephalopathy and sclerema in nicus. pneumonia and respiratory failure accounted for . % and . % of all the diseases/conditions treated in the icus and the mean case fatality rate of respiratory failure was . %. the results of the survey suggest that there is shortage of tcu beds and modern equipment, and treatment is often delayed due to excessively strict criteria for mechanical ventilation. a set of simple, and nationally acceptable criteria for evaluation of severity and cure of the diseases/conditions is urgently required. the medical reports of children were reviewed and each admission was analysed in terms of age, sex, diagnosis, management within the hosp~al, length of hospital stay and type of poisoning. the youngest age was days and the oldest was years. hundred and twelve ( . %) of the children were girls and ( . %) were boys. the most common ( . %) reason of admission was intoxication among all of the cases and the greatest group ( . %) of the poisoned children had ingested medication which was followed by another group of patients ( . %) who had eaten mushrooms. the peak incidence of drug ingestion was salicylate intoxication ( %). forty drug poisoninigs were accidental while was intentional. the majority ( . %) of the cases that committed suicide was between and t years old, and the main cause of suicide was being unsuccessful at school. we conclude that poisoning -especially salicylate intoxication -is still a major problem in turkey and we believe that emphasis on the need to stere all kinds of drugs in a secure place and re-examination of a chin resistant packaging should help to reduce childhood poisoning significantly which is a preventable condition. included were all patients who died in the hospital, except those treated in the neonatal icu (predominantly premature and sga newborns) and those who died in the emergency room. among a total of hospital admissions (excluding the neonatal icu and emergency room), patients died ( . %). of these patients ( %) died in the pediatric icu, ( %) in the ward and ( %) in the operating room. a chronic underlying disease was present in ( %). withholding or withdrawal of therapy was implemented in ( %) children, ( %) died due to failed cpr, ( %) were brain dead and ( %) died following a dnr order. justification for therapeutic restrictions in the patients of the dnr and w/w groups was imminent death in ( %), lack of future relational potential in ( %) and excessive health burden in ( %). withdrawal or withholding of therapy was carried out by extubation in %, vasoactive drugs were stopped in %, and mechanical ventilation was withdrawn in %, analgetics and sedatives were frequently used (in % and %, respectively). hence decisions concerning restrictions of treatment are common in pediatric practice, mostly due to imminent death. patients in which treatment was restricted were characterised by a longer hospital stay, a worse prognosis, a higher frequency of chronic underlying diseases and a lower acute mortality risk. despite restrictions of intensive therapy, most patients were allowed to die in the pediatric icu. background microalbuminuria (mca), a subclinical increase in urinary albumin, reflects glomerular and overall vascular permeability " . an increase in urinary excretion of albumin occurs after burns and trauma. transcanillary albumin escape rate is also increased in response to elective surgery and in critically ill adult patients . we investigated a possible relationship between urinary albumin levels and clinical instability, as measured by pediatric risk of mortality (prism) scores. method we studied consecutive patients (median age of months, range - ). patients whith nephropathies or any abnormality of urine analysis were excluded from the analysis. prism scores, mca (mg. - ) (immunonepbelometric) and urinary creatinine (cu) (mmol.l -!) (jaffb) ( hour collection sample) were determined within hours from admission to the picu. the mca/cu ratio (mg.mmol. "l) was used to correct for urine output variability. diagnoses included respiratory failure ( ), postoperative ( ), neurologic ( ), sepsis ( ), trauma ( ) and miscellaneous cases ( ). pearson's correlation was performed to correlate data. results and conclusions. mean prism score and mca/cu were . ± . sd and - sd, respectively. a significant correlation was found between mca/cu and prism scores (r= . , p< . ). our observations show that, independently of the initial insult, the paediatric unstable patient may have increased capillary permeability, which is correlated with the degree of physiological derangement, as measured by prism scores. microalbuminuria can be rapidly determined since it is routinely used in the management of diabetic patients, it is inexpensive, simple to measure and blood-spearing. therefore, it might have a role in the clinical assessment of capillary permeability and transcapillary albumin escape worldwide the demand for paediatric intensive care services exceeds the supply. in developing countries sporadic access to such services alters expectation of care and can lead to children being either mechanically or handventilated in general paediatric wards. the outcome of children requiring ventilation in a major teaching hospital in india was reviewed.children were ventilated on an adult intensive care unit (aicu) if a bed was available, otherwise in the general paediatric wards. over a year period children were ventilated on aicu with deaths. yearly mortality rates varied between - %. over a month period patients were ventilated on the paediatric wards. of the p~tients over weeks of age died (chi squared .t >p> . ) reasons for the higher mortality rate on the paediatric ward likely include the higher patient:nurse ratio, and more limited resources. a predictor of mortality based on simple physiological observations without the need for expensive blood tests and including chronic health status would be a useful tool. the establishment of a paediatric intensive care unit is proposed to redress the balance of care. to assess the performance of the pediatric intensive care unit of hospital dona estef~nia by an international standard score, the authors did a prospective study of consecutive admissions to the unit during a period of months. mean age was . _+ . months; mean lengh of stay was . + . days. the effectiveness and efficiency were determined by the admission prism. admission efficiency was defined by two criteria: a) mortality risk > % or b) the administration of at least one intensive care unit-dependent therapy. the cumulative observed mortality was . % and the expected mortality was . %, with a standardized mortality ratio (smr) = . . the overall performance of the prism score-based predictive model was found to be good (goodness-of-fit test x [ ] = . ;p= . ). of patients admitted, combining the two criteria (icudependent therapy and mortality risk) an admission efficiency of ( . %) was found, equating to ( . %) of cu days. conclusion: in our study the assessment of the admission efficiency and of the effectiveness of the unit was possible by using the prism score of admission. there was no significant difference between mean values for otiss and ntiss)in level l patients (p= . paired t-test).for level and patients mean value of ntiss was greater than otiss (p< . ). there was a significant correlation between levels using either ntiss or otiss (mean difference level and , level and , ( p < o.oool). conclusions: a new tiss has been developed and used in a picu. nurses were able to accurately score the interventions on their shift. the assignment of patients to intensive care levels correlates with tiss values allowing a quantitative measure of severity. objective : to compare the rate of cerebral palsy (cp) between monochorionic-twins, dichorionic-twins and singletons born at to weeks' gestation. design : two-year prospective cohort study. setting : geographically defined study (region of franche-comt~., france). main outcome measures : type of plasentation was obtained by anatomopathological, or macroscopic examination of placenta and comparison of twins' blood-groups. neurological assessment was performed at two years of age (uncorrected for gestational age) by family doctor (pediatrician or physician), or neonatologist of the icu at tertiary center. sample : of i survivors aged of two years ( % follow-up rate), born between / / and / . triplets and chromosomic malformation were non included. results : thirteen ( %) of the singletons had cp.vs / ( %) of dichorionic twins and / ( %) of monochorionic twins (p= . ). four of the monochorionic twins ( %), / dichorionic twins ( %) and / ( %) nngletons suffer from quadriplegia (p< . ).in a multivariate approach, monochorionic twin placentation was the strongest risk-factor of cerebral palsy (or= . , ic % = a- , p< . ). others risk-factors of cp were : lack of father's profession (or , p< . ), maternal antecedent of abortion (or . , - , p< . ), vaginal delivery (or . , - , p< . ), hyaline membrane disease (or . , . -t , ~ . ). discussion : this is the first population-based study to uplight the role of monochorial twin-placentation as a strong risk factor of cp for premature infants. cp is more severe in monochodonic twins than in other infants. mecanism of cerebrat deficiency is not clear since none of our infants with cp was survivor of an in utero cotwin's death, and none of these infants was exposed to twin to twin transfusion syndrome. were these monochorionic-twins affected by an undiagnosed neurological structural defect that could lead both to prematurity and handicap remains an open question, a vital role of the intensivist is to ensure that knowledge and practice are imparted to trainees in the icu so that patients receive optimal care. teaching effectiveness varies widely leaving gaps in knowledge and practice in the trainee. being an effective teacher should not be a "gift" of a privileged few. the icu provides a fertile ground for using a variety of methods for teaching, e.g. didactic, at the bedside, emergencies, and in the performance ofproeeaures. in this environment, much can be learned. we have embarked upon a program to facilitate this learning process. i) teaching needs to be recognized as the foundation of good clinical care, i.e., patient related, and in its ability to generate discussion and research investigation. ) teaching structurally has many components including the speaker, audience, varying situations, and the message delivered. ) establishment of a program using these components to enhance teaching abilities at all levels, a) evaluate base-line teaching skills initially, b) individualize interventions to improve teaching skills, e) demonstration of learned skills with re-evaluation. this process is analogous to the analysis of a clinical disorder in a patient which, once recognized, interventions are then instituted and then re-evaluated. ) instill the desire to use these attained skills to teach and interest others to teach. teaching excellence should be recognized through awards, honors, and academic advancement. a major emphasis of this program is to provide participants with skills necessary to teach thought processes, decision-making skills (what to do, what to avoid) and implementing appropriate management during stressful emergency situations common to the picu. introduction: many" e-mail based discussion groups exist on the internet to provide medical professionals with a rapidly responsive medium for the international exchange of ideas relating to patient care. several such lists each serve more than a thousand professionals in more than countries, each distributing a dozen or more messages each day to every subscriber. there is very little known about the time being spent by professionals interacting with these lists, and very little known about the impact of the discussions on patient care. we wished to test the hypothesis that these discussion groups provide infortuation which is being used to change the care of individual patients and the general approach to patient problems. methods: in early january a pilot electronic survey was sent to a small fraction (n= ) of the memberships of e-mail discussion groups, picu@its.mew.edu, and nicu-net@u.washington.edu (the full memberships of both. groups (n=t for nicu-net, n= for picu) will be surveyed in early february of ). participants were asked for demographic information, experience and skill level relating to e-mail, time spent with the discussion groups, perceived usefulness of different types of discussions, and the ways in which the discussions were used clinically. the pilot study was analyzed for construct validity by correlating an overall assessment question with a summary of the specific questions. scale reliability was measured by cronbach's alpha statistic. results: the pilot survey response rate was ( %). the majority of respondents were male physicians, with an average age of +_ years, who had completed subspecialty training in intensive care, and were working at a university-affiliated hospital. most had been using e-malt for more than months, and considered themselves moderately adept in that use. % felt that the list helped weekly to keep them informed about current issues and practices in their field(s), and % felt that, at least monthly, they used information from the list(s) that was not readily available in medical journals. overall, % agreed that the list improved their professional competency. when asked to compare the value of months of membership on an e-mail discussion group with more traditional educational media, % compared it with attending a national conference, and % compared it to a journal subscription. cronbach's alpha was . , construct validity testing yielded coeff=. , p <. . conclusior~: internet-based e-mail discussion groups for health care professionals can be an important part of a strategy for maintaining professional competency. despite the very low cost of this medium for most, the value is felt to be comparable to that of t~r more expensive forums for education. further study will include distribution of the full survey in early february of . fronk shann, tony slater, gale pearson and the pim study group we have developed a new score for predicting the risk of mortality in children admitted to intensive care. the score is calculated from only seven variables collected at the time of admission to icu: mechanical ventilation (yes/no), booked admission after elective surgery (yes/no), the presence of any one of specified underlying conditions, both pupils fixed to light (yes/no), the base excess, the pao divided by the fio , and the systolic blood pressure. most scores used to predict outcome in intensive care require the collection of a large number of variables (so many icus do not calculate them routinely), and they use the worst value of each variable in the first hours in intensive care. this means they appear to be more accurate than they really are (about % of child deaths in icu occur in the first hours -so they are diagnosing these deaths rather than predicting them), and they blurr the differences between traits (a child admitted to a good unit who recovers will have a low score; but the same child who is mismanaged in a bad unit will have a high score -the bad unit's high mortality rate will be incorrectly attributed to its having sicker patients). pim was developed in the picu at the royal children's hospital in melbourne, and has been tested in six other picus in australia and one in the uk. objectives: to study the characteristics of the muhiorgan dysfunction syndrome (mds) in children. methods: a retrospective study with all the children with mds diagnosed from january to june is presented. children fulfilled the wilkinson criteria (i). in all of them the number of organs affected and the prims score were determined during the first hours. several groups were performed according to the clinical diagnosis, the hospital of origin and the order of organs affected. results: the subjects studied were an % of the pediatric intensive care unit admissions. of them expired ( %). no differences in age, sex and weight were observed between the children dying and the survivals. the most common causes of mds were sepsis, both nosocomial ( %) and medingococcal (i %) and acute respiratory failure. sixty-fivepercent of the patients were from the hospital wards and the remaining were directly admitted to the pigu from the emergency room. the systems affected were: respiratory ( %), cardiovascular ( %), hematologic ( %), central nervous system ( %), renal ( %) and (hepatic) liver ( %). the organs initially failing were: heart ( %), tung ( %) and central nervous system ( %). the children dying had a larger number of organs with failure than the survivors ( . v,s. . , p< . ).the prmis score was higher in the children expiring than in the survivors ( . v.s. , p < . ). s.mmary: the mds is a common pathology in picu, with a high mortality, the mortality is higher in children with a larger number of organs affected and a higher prism score. sepsis is the most common etiulogy. methods : from june ist to july th , all patients admitted to the pediatric icu were included. the score was measured at day (d ) and day (d ) and we used variables. for each organ system, we defined categories : dysfunction or failure, which we respectively confered or points. results : patients were admitted : newborns, children. were medical and were surgical patients. ( %) patients had two or more organ failure at the admission, ( , %) patients died, which ( %) in the first hours. the mortality rate was the same for children with two or more organ faiiure at d and d : / ( , %) at d , / ( , %) at d . the mean score is different for children who survived or who died : , versus , at d ; , versus , at . when the score is > , the mortality rate is significant. conclusion : in this study, there is a good correlation between the score of severity and the mortality rate but we have few included patients. we need a prospective multicentric study to assess these results and we must compare this score to other scores of severity used in picu. back.qround: injury to the central nervous system is the cause of death in the majority of pediatric trauma victims, studies have identified a wide range of factors associated with poor outcome from brain injury. however, when single features are analyzed, they are not sufficiently accurate predictors. few studies have used a multivariate analysis of these factors and pediatric outcome, methods: clinical and radiographic features of comatose children after traumatic brain injury were analyzed, clinical parameters, the initial cranial ct scan, and demographic characteristics were analyzed for an association with death or vegetative survival at months. a tree diagram in which risk factors may differ within the study subpopulations was constructed using recursive partitioning. results: chitdren with a motor score _< had an -fold increased risk of poor outcome compared to those with motor scores > . among patients with scores of _< , those with abnormal pupillary reflexes experienced a -fold increased risk of death compared to those with normal pupillary reflexes. among patients with a motor score > , an intracranial diagnosis code (no pathology, mild shift _< mm, swelling, shift > mm, surgical mass lesions, or non-operative mass lesions) was highly predicative of poor outcome at months. children with ct findings other than normal or mild swelling had a -fold increased risk of poor outcome. of children with swelling, shift or mass lesions, the pupillary light reflex was associated with outcome. children with abnormal pupils had a -fold increased risk of poor outcome. discussion: a few clinical and radiographic features stratified comatose children into fairly distinct risk groups. information available early after traumatic brain injury in comatose children provides useful prognostic information on the likelihood of death or devastating injury. a retrospective study of children with the diagnosis of epidural hematoma was made during - period. ages ranged between days and years ( % less than year, % between and years, and % older than years), % of them were admitted at the picu. % of the cases were due to falls, % to road traffic accident and % to other causes. on admission gcs was less than in % of the cases and more than in %. diagnosis was made during first hours in % of patients and delayed more than hours in % of them. neurologic impairment was present at admission in % of patients, and delayed in %. even so, % remained without impairment. radiological findings at first ct were skull fracture ( %); epidural hematoma localization was: in the right side ( %), frontal area ( %), temporoparietal ( %) and occipital (t %). associated lesions were: several ( %) or unilateral ( %) cerebral contusions, diffuse brain oedema ( %), unilateral hemispheric oedema ( %) and % showed shifted middle line. four patients died, half of them during the first hours. fully recovered ( . %) and have sequelae of different nature : were left with severe motor disability ( %); at the follow-up t have some degree of neurodisability. next datas keep correlation with death or neurosurgical impairment: only were significative multiple cerebral contusion (p= . ) and brain oedema (p= . ), gcs less than at the admission (p-- . ), shock (p= . ) and remaining cerebral contusion in control ct correlated with death or diasability at discharge. on the other hand, neither surgical drainage volume nor first or highest levels of icp ( cases),nor pupillary abnormalities ( cases) correlated with worse prognosis. conclusion: gcs equal or less than an shock are main factors related to worse prognosis, also multiple cerebral contusions in ct and diffuse brain oedema. the results of a modified gcs were compared to outcome and intensive therapy in children (mean age , t , years) with head and associated injuries ( , % of all cases) of different causes (traffic accidents, falls). the gcs was regularly used inn the course of intensive therapy. according to our own and other experiences the gcs was divided in stages: stage ( - points), stage ( - points) und stage ( - points) palhuiugy wile sp, tdhlg c~'lcb al blood ~ w. sabgcqucntl}. rhc slat,: rerltncd to t tl, iiltlils. the p st,~pem~v~ b}i~g wij!!,:q ! ,:_a!~p!ica!j n~:. ri~;¢ ill the level of sensibflizatjou lo tile cerebn~ anhgrns up to t. -o was flofcd iu i,alicnts. there wa.~ al~ iuclt~a~e ill cerebral vdociij,. ~m d~;'ati a il~ p¢fiphc~ai re~ista/isc of the large ce~'bral ve~ds. neur h;~c ~:yn'.pt,m~at !a~, (s::mno!en~', _r_uscu!~r l~:pot ni& !ryper*'flema) was nbserwed tu lt~ese pal~enls o. cbruc~l ~ nnds. rile ple~c.ut abse~vafion~ suggesl ihal die ~tttdy at" ihe stale ~f hematocr~chcplm/itic bm~ic~ in ckil&en with on emergensy is of abviou.~ !?ece~sib; in co~.te ctin g severe pa~ lo ~-i~mnediately f u wing ne ,:~per,'~fion. background: reconstruction of the heart by three-dimensional ( d) echocardiography provided new information on anatomy of complex congenital heart defects, we assessed the utility of d ultrasound in detecting morphological changes in cerebral anatomy in newborns before and after cardiac surgery. methods: transfontanel cross-sectional ultrasound, scans were obtained in standardized coronal and median sagittal planes. subsequently, rotational scanning was used to acquire the multiple sequential crosssections of the brain. for rotational scanning, a conventional mhz transducer was rotated degrees.scanning took less than one minute and required no sedation, data was stored in the image processing computer which allowed for off-line three dimensional reconstruction of different brain regions.twelve infants aged - (median ) days were assessed before and after cardiac surgery, results: cavity of lateral ventricle, choroid plexus and the periventricular brain parenchyma could be reconstructed in all. accurate estimation of size and volume of lateral ventricle, aqueduct, and other ultrasonographic visible pathological brain lesions could be performed. reconstruction of various brain areas was accomplished in - minutes. the localisation and extension of severe periventricular hemorrhage which was detected preoperatively in one infants was better visualized than in conventional ultrasonography. epicortical and subarachnoidal space could be reconstructed in all and allowed detection of hemorrhage in one case which was not detected by conventional ultrasound. conclusion: d reconstruction of different areas of the brain may provide additional quantitative information on size and volume of the internal ventricle and choroid plexus, and better understanding of the topographical aspects and the extension of intra-and periventricular hemorrhage than conventional cross-sectional ultrasound. introduction: intracranial cerebral blood has been estimated to be % venous, the invasive measurment of venous blood saturation in the jugular bulb provides quantitative information on cerebral oxygen supply and consumption. however, routine oxymetric measurement of blood saturation in the jugular bulb by insertion of a catheter line into the internal jugtdar vein is an invasive procedure which has limited use especially in infants and young children. thus the aim of this study was to investigate the correlation between the non-invasive spectroscopic measurement of rso and the oxymetric determination of the blood saturation in the jugular bulb in infants and children undergoing routine cardiac catheterization.. methods: during routine cardiac catheterization infants and children (age day- year, median , year) the rso was measured continuously using a two chanel cerebral oxymeter (invos a). the sensor was placed in standardized location at the left temporal head side. after the routine oxymetric blood sampling in the superior vena cava the oxymetric catheter was manupilated into the left jugular bulb. after control of the catheter position simultenuous values of the rso were documented. results: over a range of ( - %) sjo , a significant linear correlation was found between the spectroscopic measurement of rso and the oxymetric determination of venous blood saturation in the jugular bulb (r= , , p< , ) and the superior vena cava (r= , , p< , ). no significant correlation was found between rso and the arterial blood saturation in the descending aorta and as well as to the standared hemodynamic parameters. conclusion: meusurement of rso by mrs may provide continuous non-invasive information on cerebral venous blood saturation and thereby possibly on cerebral oxygen supply and consumption in infants and children. these may be of clinical value particulary during and immediately after heart surgery by means of non-pulsatile cardiopulmonary bypass. information on refractory status epilepticus (rse) from developing countries is scarce. we analysed cases of rse admitted over last yrs. the objective was to study etiology end evaluate efficacy of diezepam infusion. median age of the patients was . years irange . months to t . yrs); % were boys. onset of seizures was -t hours (median hours) prior to hespitalisation. the glasgow coma scale score ranged from . (mean+sd + ). the commonest underlying causes were acute cns infections ( / , %; bacterial meningitis, , encephalitis, ) and epilepsy ( / , %). oiazepam infusion in incremental dose (range . - . mg/kg/min) was used in patients over . _+ . days. seizures were controlled n ( %), mechanical ventilation was required in ( %)only, while none had hypotension; % patients survived. thiopental infusion (holus mg/kg followed by . mglkg/min, and increments of . mg/kg/min till seizure control) was used in patients over . _+ . days; seizure were controlled in all, but five patients needed mechanical ventilation, six developed hypotension needing infusion of vasopressoi drugs, out of ( %) died, overall mortality was %, mainly due to acute cns infections (n- ) and prolonged se. the patient was a -year-old gift di~aosed of dov,~'s s~drom¢, tetralogy of fallot. (t.f.) before admission a vasovagal crisis after coughing and vomiting was seen, and she was taken to the emergency room. mother said she had eyanosis in the mucous membranes of the mouth with exercise.on physical examination, she ~as afebrile, normal fundi and neurologic examination was normal. a harsh systolic murmur was hear~ with decrased intensity during bradycardia. chest rx disclosed a decreased pulmonary vascular markings. ecg: synus rhythm, with bradycardia and nodal escape rhyflmas. she was transferred to our picu because of severe h ,pertomc seizure, lost conciousness, and deeembrate poslamng~ ~t cyancx~is. the episode lasted for ~weral seconds, and ceased v~th diazepam. on admission she was lethargy, and neurologlc exammation showed weakness of left leg without babinski, and normal funduscopic. the patient had two episodes of bradycardia and isoproterenol was begun. during those episodes the patient was cyanotic, and the murmur was heard with the same intensity. act scan disclosed a tight parieto-temporai abscess with midline shift, lnmediately after the diagnostic ct, we administered antibiotics, antiedema treatment and it was drained. the abscess culture was negative. a ct control disclosed air and midlme shift. ~ the next two days she had three episodes of h oxia and c'yauosis ceased with o@gen, morphine and propanolol the patient died during a fourth episode. discussion: arrhytmias are uncommon in patients with tetralogy of fallot before surgery. in our case the first diagnosis was sick sinus syndrome vs bradycardia secondary to cyanotic episodes. the incidence of cerebral abscess in children with congenital heart disease (chd) is approximately %. tetralogy of fallot is the most common associated lesion, and is unusual in children under years of age. conclusion: ) brain abscess is a rare complication of patients with cyanotic chd, but should be suggested in patients with °'apparent" sick sinus syndrome. in patients with down's syndrome, t.f.,with cyanotic episodes, and difficult neurologic exploration, a brain ct scan is recommended. guillain-ba~re syndrome (gbs) is an acute autoimmune reaction, directed primarily toward the myelin encasing the peripheral motor nerves= this reaction causes a delay or block in nerve conduction. the presentation often can be very subtle but is followed by rapid loss of neuromuscular power, leading to acute respiratory distress, resulting from weakness of muscles and aspiration pneumonia. there were boys - , , and i i years old with gbs, treated in our icu. two of them due to the respiratory distress were intubated nasotracheally and ventilated mechanically with servo- ooc (siemens-elema, sweden) ventilator. duration of ventilation was i i and days, respectively. plasma exchange was performed in all cases. the numbers of plasma exchange sessions were - in each case. mean amount of plasma exchanged per session was , ml/kg. plasma was substituted with albumin, plasma or saline. the most important aspect of the management of patients with gbs in the icu involves the airway care, prevention and treatment of aspiration pneumonia and the mechanical ventilation if respiratory distress presents. endotracheal intubation should be performed whenever there is evidence of retention of pulmonary secretions, refractory to chest physical therapy, weakness of protective reflexes of the airway, leading to aspiration pneumonia and (or) atelecr~sis. cardiac arrhithmias too, is a main threat to the circulatory stability in gbs. therapeutic plasmapharesis has been shown to be beneficial, reducing the time for weaning from the ventilator and for achieving independent ambulation. however, plasma exchange is expensive and not without significant risks for the patient. some authors find that plasmapheresis is not effective for patients with fulminant course of gbs and blocking of nerve conduction. recent studies have demonstrated that intravenous high-dose immunoglobulin can be equally effective. there were no significant complications associated with plasma exchange. all presented patients survived without residual disability. tetraparesis associated with long-term paneuronium use in an infant. paneuronium is a muscle relaxant used in ventilatory management of patients with respiratory distress in intensive care unit. after the end of sedation some patients were found to have severe tetraparesis. paresis was accompanied by complete areflexia and diffuse atrophy of alt extremity muscles. this neuromuscular complication is caused by prolonged high-dosage pancuronium treatment. in the last years, numerous reports have linked the use of pancuronium bromide with prolonged paralysis, disuse atrophy and areflexia. this side-effect is well known in adults patients but rare in a pediatric intensive care unit. we describe one pediatric observation of tetraparesis after prolonged pancuronium treatment in a -month-old girl, this female infant developed respiratory distress syndrome and was intubated and mechanically ventilated. to decrease chest wall rigidity pancuronium bromide was administered during days. (she received approximately mg of pancuronium bromide). on day the drug was discontinued and the patient had severe tetraplegia and areflexia with normal head movements. electromyograpliy showed absence of any disorder of neuromuscular transmission. this infant showed a recovely of muscles after months. the other causes of peripheral neuropathies were eliminated. electroencephalograms and head scans were normal. the recovery pattern observed in our patient correspond to the process of regeneration after axonal degeneration. it is suggested that these neuromuscular complications were caused by prolonged high-dosage pancuronium treatment (associated with cortieoid and aminoglucosides). polyneuropathy syndrome in adult lc.u. appeared in literature in and is extremely common in long stay cases. the etiology of these disorders remains elusive. it is tempting to ascribe them to administration of drugs (muscle relaxants, steroids, aminoglycosidea), plolonged immobility, malutrition, sepsis and ischemia associated with reperfusion injury. to our knowledge there is only one case report of similar condition in a children i.c.u. (pascucci ) we present a serie of previously healthy children, aged months to years, who admitted in i.c.u with respiratory failure and who following weaning from m.v, remained in profound diffuse hypotonia with proximal and distal muscle weakness for various length of time, recovery of muscle strength occured in a week or months {the longest i months), all children, except one, - days before admission developed symptoms of either respiratory or upper airway infection with fever. on admission viral and bacterial cultures were positive in cases (haemophilus influenze, herpes virus). during treatment patients became septic. muscle histological and neurophusiological investigations have not been done. considering the multifactorial nature of the aquired nmd in adult critically ill pts, is impossible to attribute the muscle weakness of our pts to any specific cause, in conclusion, our findings suggest the need for further investigation of nmd in critically ill children treated in i.c.u. a van esch, ha van steen~l-m , ir ramtal, g derksen-lubsen, idf habbema. febrile status epilepticus (fse) is a prolonged and serious febrile seizure. little is known about the outcome of fse in neurologically normal children. this survey involved patients between months and years of age who had visited due to their first fse, the sophia children's hospital during the period of january till december . patients with a history of neurologic disorders were excluded. patients were identified, % were male. the cause of the fever remained unknown in % of the cases. in all case the fse was generalized and it most frequently occurred at night ( %). the mean age at fse was t. years ( . - . ), the mean temperature . °c ( . - °c). the mean follow up time was . year. twelve children ( %) had neurologic sequelea. the neurologic sequelae varied from speech deficit ( case mild, v - year delayed; case moderate > year delayed) to severe retardation and epilepsy ( cases). speech deficit was detected after a mean period of months (range - ), age, gender, temperature, family history and time of onset were no significant risk factors for neurologic sequelae. duration of seizure [rr . ( . - . )] and more than two drugs to treat fse (rr . (t. - . ) were related to neurologic sequelae. we recommend that fse children should be followed for at least a year to detect possible speech disorders properly and start early intervention. unusual presentation of myasthenlg gra%qs ibtza e. modesto ,v~ abe~gochea a, sanch]s l all, go l varas k folgado s, garcia e. p. .c.u. la fe, valencia. spain case report: the patient was a -year-o!d gift transferred to our pic because of severe respiratory failure. the patient, convaleseem of ehiekenpox, came into contact with horse manure previous afternoon. in the morning, she was lethargy, and irritability, with poor finding, and ~ an episode of coughing, cyanosis and acute respiratory failure after mucous vomiting when she was drinking milk. on admission she had severe respiratory distress, respiratory acidosis, and the sat was %. she was mtubated without difficulty, and was transferred to our p.i.c.u. physical examination reveals stable hemodynamies, pupils equal, round, reactive to light, normal fandi, and muscle relaxation. crusted vesicles diseminats~d. rhonehi over both lungs. hepatomegaly (+) and splenomegaly (+). ~lhe urine, hematologic, and c.s.f. laboratory findings were normal. c.t. scan of the brain, e.e.g., and ekg. revealed no'abnormalities. rx chest disclosed a retrocardiac atelectasis. speci~ts of stool and blood were obtained for cultures and study of c. botul#num toxins. pending receipt of these results, a broad-speotmm antibiotic and acyctovir was begun. the initial differennal diagnosis consisted of laryngospasm associated with aspiraqlon, botulism, and postmfecfious varicella encephalitis. after hours, weatm~ was begun. the neurologic examination showed a low modified glasgow coma ~ale (mgcs), generalized hypotouia and muscle weakness. these data suggested three diagnoses, posfnfecfious encephalitis, residual neuroumsoaar blockade, and excessive doses of sedative and analgesic drugs. after hours she regained skeletal muscle poxver and ufltlcient respiratory effort, the mcgs was acceptable, and blood gases were normal. she was given n~-tigmine and atropine, and her tr~ma was extubated. an acute respiratory failure ocurrs ram. after. chest radioga'aph disclosed a left inferior lobe atelectasis. after hours weaning begun~and the same episode w~as seen. at this point her mother stated that the girl showed weakness of the eyelids or extraneular muscles. it suggested myasthenic syndrome vs ~-barr syndrome. c. botul#num toxins were negative, chotinesterase level ~as normal. edrofoinum test ~as positive. anti-acetyleholine receptor antibodies were negatives. e.m.g. confirmed myasthenia gravis (congenital vs juvenile serenegative). pyridostigmine was begun and the trachea was extubated without complications. conclusion: din the differential diagnosis of weamng failure we must consider ~c gravis~ )myasthenia gravis could resemble encephalitis, because of low ocs, overall if is triggered by viral infection. )in some diseases (this case) gcs could not he an aemuate index of mental state. a burguet*, a menget*, e monnet**, a gasca-avanzi*, c fromentin*, h allemand**, jy pauchard*, ml dalphin*. * r animation infantile potyvaiente chu st jacques besancon cedex. ** d~padement de sant publique besancon cedex, france, objective : to point out that strabism is) of one-year-old premature is a good predictor of a poor neurological outcome at two years of age. design and setting : two-year prospective cohort study and geographically defined study (region of franche-comte, france). main outcome measures : neurological assessment was performed at one and two years of age (uncorrected for gestationnal age). a mailing questionnaire was sent to the famity and fuu-filled by thefamily doctor (pediatrician or physician), or neonatologist of the icu at tertiary center, s was diagnosed at one year of age by the examinator but s was not used to diagnose cerebral palsy (cp). sample : of survivors ( %) evaluated at one and two years of age. results : correlation of one and two years neurological evaluation is weak (kappa= . ). correlation of s at one year and cp at two year is fair (kappa= , ). the goal of this paper is to review evidence related to hypothesis that the "waiting" axons and cells of the transient subplate zone may participate in the structural plasticity of the human cerebral cortex after perinatai brain damage (kostovic et al, metabot brain res : , t ) and to correlate this phenomenon with different forms and mechanisms of structural plasticity. it is our basic assumption that all lesions occuring during cortical histogenesis will lead to more or less pronounced structural reorganization. here we show that various components of the subplate zone participate in several forms of the structural "plastic" responses in the human cortex: modification of convolutional pattern, changes in size of cytoarchitecturat areas~ columnar reorganization, dendritic and synaptic plasticity. the etiological factors which induce lesions and subsequent plastic changes act via the following pathogenetic mechanisms: * disturbances of radial unit formation (rakic); * changes in ingrowth of afferent fibres; * changes in the rate of normally occuring reorganisational events, depending on the critical period for a given histogenetic event. in the present study developmental lesions (localized perlventricular leukomalacia and haemorrhages) were demonstrated by ultrasound in live-born infants ranging between to weeks of gestation. in younger infants ( - w) who died shortly after birth, examination revealed lesions of the white matter with the preservation of the subplate zone. in infants who died one week of more after the lesion, we have observed localized micropolygyria, cavities, condensed layer vi -subplate zone, and columnations of the cortical plate. these changes are less prominent if the lesion occurs after diminishment of the subplate zone (after w). since in the fetal cortex the subplate zone serves as predominant source of growing fibers, transient neurons, trophic factors and contains cellular substrata for migration, this zone is the most likely candidate for major types of structural plasticity. in conclusion, cerebral cortex of the low -birthweight infants is more susceptible to the various lesions but shows vigorous structural plasticity and conspicuous functional recovery due to the growing, transiently located neuron at elements. the mortality due to meningoccocal sepsis is high in spite of important progress in emergency and intensive care medicine. during the last decade multiple scoring-systems have been developed in order to establish a therapeutic approach and to evaluate the final outcome of a meningococcal infection. different clinical and biological data (shock, ecchymosis, peripheral wbc and platelet count, coagulopathy, acidosis, meningism, etc) are taken into consideration and the importance given to these data depends on the scoring-system used. a review of the different scoring-systems is given and a clinical case is presented. we report the case of a year old male, who was transfered to our icu hours after onset of temperature and skin rash. the parents described a fast deterioration of his condition. the boy presented wide spread ecchymosis, high temperature, no signs of meningism, circulatory insufficiency and shock, coagulopathy and low peripheral wbc and platetet count. disseminated intravascular coagulopathy developed promptly. the glasgow meningococcal septicemia prognostic score (gmss) was used and the obtained score reached the highest level ( / ). this corresponds to a % mortality. the patient required mechanical ventilation for days. at admission he received human albumine, fresh frozen plasma, dexamethason, dopamine, dobutamine and a continuous infusion of adrenaline. antibiotical treatment consisted of ceftdaxone. the evolution was favorable and the infant fully recovered. retrospectively the gmss was compared to other meningococcal scoring scales which gave the same mortality ( %). we conclude that the scoring-systems are important to evaluate the seriousness and to assess the therapeutic approach, but they should be used cautiously even when % mortality is predicted by several risk evaluations scoring-systems. the aim of this study was to assess the haemodynamic status on admission and the critical care management of children presenting with meningococcat infection. this was a retrospective study of the charts of consecutive admissions. mean age was . years (+/- . ). the average duration of symptoms prior to admission was . hours (+/- . ). on admission . % were hypotensive, . % had clinical signs of haemodynamic instability and . % of cases that had a blood gas analysis on admission had a metabolic acidosis (bases excess < - .q): the mortality rate was . %. % of patients that died were hypotensive on admission and all had a metabolic acidosis. of the survivors . % were hypotensive on admission, % had clinical signs of haemodynamic instability, % required invasive pressure monitoring and . % were ventilated and received inotropic support. this study demonstrates that at the time of presentation with meningococcal infection children had a high incidence of established haemodynamic instability. successful management of this infection is dependent on early presentation and initiation of therapy and on aggressive support of the cardiovascular and vital organ systems. dept. of intensive care medicine and dept of infectious diseases, our lady's hospital for sick children, crumlin, dublinl , ireland. jude. pediatric intensive care unit, ch&u, lille-france. more than % of children surviving sip (defined as purpura with shock) have snli. objective. to search for a specific hemostatic profile in children with snli. patients and methods. between may and march , children with sip were admitted to our picu : ( . %) died and ( . %) ranged in age from to months (mean : ) survived, of them ( . %) with snli (defined as the need of a surgical procedure). in survivors, two hemostasis studies (between h and h , and h later) included the determination of coagulation factors (routine tests), protein c (pc : amidolytic activity, biogenic), total protein s (ps : elisa, stago), c b binding protein (c bbp : laurell's technique, stago), antithrombin (at : chomogenic test, stago), and plasminogen activator inhibitorl (pail : chromogenic test, biopool). three severity scores were determined at admission : french group of pediatric intensive care, gedde-dahl, and crp. statistical analysis used the wilcoxon's test. results. at admission (lst sample) severity scores and at , pc, ps, c bbp levels were not different between the group with snli and the group without snli ; quick time ( - % vs ± % ; p = . ), vti+x ( . % vs - % ; p = . i) and pall ( - ui/m! vs . ui/ml ; p = . ) were lower in the group with snli. on the nd sample there was no difference between the two groups. kinetics of hemostatic abnormalities was not different between the two groups. conclusion. in the literature, intravascular coagulation (dic), low fibronectin and at were identified as predictors of snli, and a negative correlation was found between the mean size of the skin lesions and pc activity, at , and total ps. in this series, apart from dic, there were no specific hemostatic abnormalities that support the use of treatments such as pc, at , and pail antibodies administration to prevent snli. further studies including more children are needed. the aim of study was to investigate the efficacy of intravenous immunglobulin with enriched igm content pentaglob/n /biotest/. in our pediatric intensive care unit ten septic children /group i/-their average age , years /sd:o, /, of them with gramm negative and one with gramm positive blood cultures, and two with unindentified bacteria-were treated with basis sepsis therapy and pentaglobin. the application of pentaglobin was as follows: , ml/kg loading dose for one hour, followed by a continuous intravenous infusion , - , ml/kg/hour depending on body temperatura /lanser scheme/ for - hours. another ten septic patients /control-group ii/the mean age , years/sd:o, /, their blood cultures were gramm negative bacteria , positive , and the bacteria was not indentified in two cases -were treated with only the basis therapy. results: the duration of intensive treatment decreased from an average , days /sd: , min -max days/ to , days /sd: , min -max days/ in the group treated wit pentaglobin. the difference was significant /x p< , /. in the group i nobody died, but three in the group ii. conclusion: the pentaglobin therapy can improve the efficacy of the basis therapy of sepsis. sinus bradycardia after an episode of sepsis is a rare symptom complex decribed in children with hematologic malignancies. we present a case of postsepsis bradycardia following severe typhlitis and septic shock in a year old boy with relapse common all. blood and ascitic fluid specimen grew clostridium species and pseudomonas aeruginosa. at surgery there was a necrotic gangrenous terminal ileum and cecum, requiring ileocecal bowel resection with ileostoma. while clinically recovering from sepsis he developed bradycardia for hours. extensive diagnositic procedures was given and the heart rate slowly increased to normal range of age. postsepsis bradycardia in children with hematologic malignancies after an episode of sepsis is self-limiting and after careful differential diagnostics warrants an expectative attitude. nitrate level is known to be enhanced during sepsis. serum nitrate is the stable metabolic end-product of endogenous nitric oxide generation. nitric oxide has demonstrated to be a powerful anti microbial final mediator and also a key molecule driving to the lethality of one of the most common complication of sepsis; the endotoxic shock. such facts prompted us to investigate the possible diagnostic and/or prognostic value of monitoring serum level in high risk, presumptive and confirmed sepsis patients. additionally we have explored the usefulness of this mediator as index of therapeutic response. in our study it is demonstrated that there is an important relationship between nitrate level and the occurrence of neonatal sepsis. septic newborn group showed fold higher nitrate level than that of healthy control group. in addition, the group of patients with high risk of sepsis which finally became septics, exhibited fold higher nitrate level at - hours before the first symptoms appeared, when compare with those who did not develop sepsis. however in the presumptive sepsis group, there was no difference between the patients which finaliy ,&'ere considered septics and those which not. in all septic cases, after days of a successful therapy with antibiotics, the level of nitrate diminish fold. our results suggest the utility of monitoring nitrate as index for the diagnosis of neonatal sepsis. the potential benefits of exchange transfusion, plasma exchange, and haemofiltration have all been described in children with overwhelming sepsis. however, little hard evidence exists to prove the benefits of any of these techniques. i have treated five patients with plasma exchange (pe), having been asked to see all these patients at a point when it was felt death was inevitable. two of the patients had staphylococcal, two meningococcal and one enterococcal septicaemia. all patients showed a dramatic haemodynamic improvement following pe with improvement in blood pressure, reduction in inotrope requirement and improvement in tissue perfusion. three patients survived. one of the patients with staphylococcal sepsis and both of the patients with meningococeal sepsis had developing gangrene of the limbs which showed remarkable reperfusion with pe. in two of the patients measurements of cardiac output (co) and systemic vascular resistance (svr) showed ~a reduction in co and a rise in svr over the course of a pe despite the reduction or cessation of vasoconstricting inotropes. many believe haemofiltration is of value in septic shock. a trial with a no treatment limb is difficult to achieve. i believe we now have enough evidence to justify a controlled trial of haemofiltration versus plasma exchange in patients with septic shock and unstable haemodynamic status whilst on inotropic support. during the next several days, cough and chest pain suggested pulmonary embolism confirmed by radiologic evaluation. echocardiographic examination showed multiple thrombosis of the superior vena cava, right atrium and ventricle and pulmonary artery. estimated protein c level was . % (normal range - %); identical deficiency was found in patient's mother and elder sister. cvc was removed, and alter -month heparin therapy and supstitution of protein c with fresh frozen plasma, there was almost complete thrombolysis of the great vessels and cardiac chambers. we conclude that invasive diagnostic and therapeutic procedures in such patients may result in higher risk for severe thrombosis at unusual sites, and numeuos further complications bronchopulmonary dysptasia (bdp) is a chronic pulmonary disease of preterm and term babies treated with mechanical ventilation for respiratory problems of different origin and requiring oxygen therapy days after birth. bpd is a disease affecting the growth and development of pulmonary tissue. such pulmonary }esions heal by squamous metaplasia leading to scar formation and fibrous tkssue r~growth, the pediatric intensive care unit makes the survival of babies w~h very low birth weight ( - g) possible. with the increase in their aulyival, the number of complications in low birth weight babies increases as well. bdp is a very serious complication. therefore the importance of early diagnosis and treatment of bdp must be stressed in order to reduce the consequences. babies with bdp must be under medical suveillance for at least years as the disease needs at least that long for complete resolution. tn the icu of pediatric department at madbor teaching hospital: during the past two years ( - ) newborns were treated with mechanical ventilation. the neonatal and postnatal death rate of all newborns admitted to our icu was , %o.ln the two years from to , newborns were admitted to our icu ( %~ of all newborn babies at maribor teaching hospital), with birth weight - g. in the icu, the survival of these babies and parallel to it the number of complications is increasing. during the mentioned -year period, babies with very low birth weight ( - g) survived: in and in t . in - %, first or second stage bdp was treated,there was no case of third of fourth stage bdp. the treatment consisted of eary removal from mechanical ventilation, oxygen therapy~ intensive treatment of infection, volume and caloric intake contro}, corticosteroid treatment throught weeks with decreasing doses, diuretic end antioxydant therapy. the children are to be reevaluated at the age of and months and again at i and years. oeure j van der, markhorst do, haasnoot k department of pediatrics, pediatric intensive care unit, free university hospital, amsterdam, the netherlands. case summary a %-month . kg girl of african origin was admitted to the pedfatric irtensive care unit with pneumonia and progressive respiratory irlsuffjderey. she was intubated and ventilated by pressure regulated volume controijed ventilation (servo c, siemens, soma, sweden). maximum conditions were inspiratory minute volume . l, peep cm h~o ahd % ~. chest x-ray showed bilateral interstitial consolidation. material obtained by broncho-alveolar lavage showed preumocystis car}nil htv-serology (elisa and westerll blott) and p -antigerl were positive, confirming the diagnosis of pediatric aids. she was then treated with high dose co-tllmoxazoie, penthamldine, z{(~ovudire and steroids iv. because of thee x-ray features, high need for o ( %, pad mm hg), not responding to elevatiofi of peep (max cm h=o) and pao /fio = < (s ). m acute respiratory distress syhdrome (ards) was diagnosed. because conventional ventilation (cv) failure, hfo-v ( ooa, serisor medics,yorba linda, ca) was initiated. starting mean airway pressure (map) of cm h~o was based or map of the cv, oscillatory pressure amplitude (dp) of was, at ii~itial frequency of . hz, adjusted ur~til chest wall vibrations were visible, it was required to raise map to cm h and dp to before optimal lung volume and ventilation were achieved and need for o reduced within hours, this was monitored by frequent blood-gas analysis and chest x-rays. map and dp could slowly be reduced, after a good response the first day, gradually demand reduced and the patient could be weaned from the ventilation. map, dp, fi and oxygenation index (map x pa ~jfio ) are shown in table i. chest x-ray follow-up showed gradually improving lung features, with marked improvement of aereation. after days hf -v she could be succesfully detubated when a map of cm h was acmeved. results : sianificant increase in ventilato~ rate and mean airway pressure was noticed after the change to savi. no differences in oxygenation, co partial pressure and systolic, diastolic or mean blood pressure between imv and savi periods were noted. in infants however an improvement in pao /p .ol/ and decrease in paco was observed after the switch to savi. these babies had a lower initial a/a oxygen tension ratio and required higher initial ventilator rate /p<o. / in comparison to the rest of the studied patients. conclusion:infants with low a/a po ratio who need high initial ventilator rate are likely to obtain benefit from savi.. fumimare hatori, haruo uchida, masao katayama, and rika muto department of anesthesia and critical care medicine chiba children's hospital, chiba city, japan. purpose: this study was made to find out whether the heat and moisture exchangers (hme) was effective enough to humidify in the respiratory management for children. patients: the study population consisted of patients who were provided with artificial airway. they were divided into the two groups: ii with heated humidifier (a) and i with hme (b). methods: hme could be used for those without pulmonary complication and with less leakage around the endotracheal tube. in both a and b groups, (i) we have measured relative humidity, temperature, and absolute humidity at the endotracheal tube connector. for these measurements, humidity sensor system was utilized. ( ) any troubles and complications caused by the artificial airway were investigated. results: (i) in group a, we confirmed the mean values as the relative humidity of . %, the temperature of . ~c, and the absolute humidity of . mg/l. in group b, they were . %, . °c, and . mg/l respectively. no difference was noted between the two groups as to the relative humidity, but the temperature and absolute humidity were lower in group b with a significant difference (p< . ). ( ) in neither of the groups, any respiratory complications such as obstruction or stenosis of the artificial airway were noted. in pediatric icu, hme can be used without any problems under given conditions. titei: objective: evaluate the precision, reproductibility and aplicability of a new device to measure auto-peep in pediatric patients during mechanical ventilation. material and methods: it's an electromc-pneumatic eontolled device with an oclusion valve and a pressure monitor installed between endotracheal canulla and the ventilator circuit. the measurements were performed with a sollenoid conected with to the ventilator to detect the end of inspiration phase and the actwation of the oclusion valve. the signs of pressure and flow were moniturized using a difere~rtial transducer and it was processed using a pc computer and a pneumoviaw® software. the auto-peep also displayed in the ventilator pressure monitor. results: we submitted children with neuromuscular disease or respiratory distress in this study. the incidence of auto-peep was %, with variability between , to cmh . all the measurements were performed times to verify the precision and the reproduetibility and evaluation of the pressure and flow curves. conclusion: the device is low cost, easy to use and can be used without the pneumotacograph. the auto-peep measurement can be done during mechanical ventilation with time cycled, pressure limited and continuous flow, the most commom ventilator used in pediatric patient. resistance was modeled by endotracheal tube (ett) sizes ( . , , , ), and compliance by test lungs ( and ml/crnh ), for each resistance -compliance arrangement, we measured tidal volume (vt) at various frequencies, peak to peak (p-p) and mean airway pressures. results vt increased when ett size increased with all ventilators in accordance with fredberg results (jap, ; : - ) . the maximum vt delivered was smaller with the hfv-babyiog than with the ohf or the sm a at a given frequency (figure on the left). increasing p-p resulted in a linear increase in vt delivery in the - % range of maximum p-p (figure on the right). hfv-babylog didn't provide significant vt increase when p-p was set above % and vt deliven/decreased when mean airway pressure decreased. --i ~ sm a a number of ventilatory parameters had been analyzed with russia-produced monitor humitemp htm (servisinstrument j,-s. co) in newborn infants with rdsn of t-iv stages on cmv, cppv, imv, and cpap steps using respirators of various kinds (stephan-staxel, bear- , newport rezee, sechrist). parameters investigated were: temperature of inspired mixture (t), relative and absolute humidity (rh and ah, respectively), static compliance (c), expired tidital volume (vte), expired minute volume of ventilation (mve). the monitor read these parameters in following ranges; rh-from to %; ah-up to mg/i; mve-up to . i/mini vte-from to ml; t-accurate to %; c-from . to t ml/cm h . continuous monitoring time ranged from to hours, it was noted, that during this time the monitor and transducers had no malfunctions, and it's using didn't require additional calibration, it was found, that humidifiers mr and mr (fisher, paykel) couldn't maintain parameters t and ah continuously (these values varied from , to . c and from , to . mg/i, respectively, when heating regulator position was unchanged). changes of parameters c depended clearly on cppv conditions and rdsn severity (with rdsn of stages i-ii c value ranged from . to . ml/cm h ; and with stages iit-tv-from . to . ). tn newborn suffering from rdsn of stages ii-ltl and ill-lv with pip> mbar, fi > , , peep= - mber, c-from . to . ml/cm h , effectivity of exosurf therapy was studied. in newborns in - hours of therapy pip decreased to . - . , and c increased to , - . ml/cm h . in newborn infants with aad > mmhg and c from , to . mltcm h positive effects of exosurf on lung compliance were not observed. in newborns the monitor had revealed decreased of c (from . - . to , - . ml/cm h ), manifested clinically by pneumothorax. in general, monitor htm made possible; ), to estimate the adequacy of cmv-parameters and regimes in newborn infants; ). to select optimal t and ah values in the respiratory outline in dependence on lung damage severity and infused volume; ). to reveal rdsn severity; ), to optimize indications and adequacy of surfactaot therapy; ). to diagnostieate the air leakage syndrome; ). to effects to some agents (broncholytics, spasmolytics); ). to obtain objective indications for imv/simv and cpap regimes. albano communication is an important aspect of human development and existence, and an inability to vocalise can be a problem in ventilatordependent patients. we present our experience with speaking aids as a means of enhancing verbal communication in four ventilatordependent children in our paediatric intensive care unit. the age of the children ranged from months to years, and the period of ventilation ranged from months to months via a tracheostnmy. they require continuous flow generated pressure limited or control ventilation at rates of - bpm. the reasons for ventilation include tetraptegia following a shrapnel injury; tetraplegia following congenital cervical spine damage; tetraplegia following atlanto-axial subluxation; and critical illness polyneuropathy following adult respiratory distress syndrome from prolonged ventilation for a severe head injury. the first three patients have passy-mnir one-way speaking valves and the final patient has a bivona foam cuffed tmcheostomy tube with a talk attachment in view of recurrent aspiration. an improvement in quaiity of speech has been shown by independent assessment. we will review the present literature on this subject and discuss the advantages and disadvantages of these two types of speaking aids in the light of our experience. the prognosis of antenatally diagnosed cdh is closely related to the degree of ph. there have been attempts to correlate antenatal or postnatal criteria to mortality: none have been demonstrated to be predictive of lethal ph. the aim of this retrospective study was to determine whether antenatal or early postnatal data could correlate with the findings of post-mortem examinations. patients and methods: between july and july , cdh patients have been antenatally and postnatally managed at our institution. twentythree infants underwent a post-mortem examination. ph was assessed by using the lung weight to body weight ratio (lw/bw) and the radial alveolar count (rac). antenatal results: cdh diagnosis was made at weeks of gestation (wg) ( - ). twenty-eight patients had a left sided cdh, had a right sided cdh, and one had a bilateral cdh. herniated organs were stomach none (n= ), or liver alone (n= ), or both stomach and liver (n= the patient was a -yenr-old girl with chronic renal insufficiency see~ to renal dysptasm, two months before admission a kidney trar~ptant was performed. one morah later she showed acute graft rejection with serum ereafinine (cr) level of . mg%. the rejection was unreslxmsive to an increased steroid dosage, and okt was begun with resolution of the rejection. one week arer, new rejection episode was seen marestxmsive to an increased steroid dosage, and transp~ ~s performed five days before admission to our ptc. hemedialysis and peritoneal dialysis (p.d.) each other day, was indicated (g.r.f.< ml/rnin). four days before admission t ~ rose to °c. "lhe diagnosis of opporttmistic pneumoma was made on the basis of tach ,pr',e~ hypoxi~ and diffuse interstitial infiltrates. senma ~ was positive for cytomegaloviras (cmv), and stool culture for c albicans. pentamidine, ganciclovir (dhpg), arai-cmv gamma globulin, eritromicine and amphotericin b was administered. on admission in our picu, trachea was mmbated, (a-a) o gradient was , paofffio~: , lung injury score > with peep level of cm hzo. she had normal fiver function. during te next days she had fever and developed ards. bal was negative. p.d. was of little efficiency. we adjusted pentanfdine, and dhpg doses for severe renal failure, with supplements after hero, sis, and at~rp.d.. during ~ next days she was afebrile, and the chest became radiologlcally normal. after ten days on menhani~al ventilation (mv.), the patient was extubated. cr. level was . rag%, (a-a) oz gradient was , and paoyfioz was , the patiem was discharged with chronic ambulatory p.d. discussion: opportunistic pneumonia is a major complicalaou in imm~romised children, specially after kidney tvansplaraafion. c m.v. infection can result at~r okt administration. in the treatment dhik} dose must be adapted to the degree of renal insu~cieney, with supplements after hemedialysis, and after pd. pneu~y~tis cann# tmeumov~ is ehemeterized by ventilafion-perfusion mistmaeh, decreased pulmonary compliance, hypoxia arld elevated (a-a) oz gradient, with diffuse interstitial infiltrates. in our ease bal was negative. although we did not find the etiology the prevoclons eombh~ation of arairmcrobiat therapy, along with m.v., and supportive measures were the most effective trealme~. conclusion: ) in patients with severe renal failure and life-threatening infections, we must co~ider drug adjuslments. ) in our patient we gave dhpg supplements at~r pd. with excett~at results, although p.d. was of little effiele~. introduction: endotracheal intubation and mechanical ventilation have become an important treatmem for many diseases accompanied by respiratory failure. with the frequent use of this treatment modality, an increasing number of complications associated with endotracheal intubation have gained clinical significance. material and methods: a transversal study was realized to find the prevalence of pulmonary aspiration with endotracheat tubes in infants and children. aspiration was assessed by applying two dyes (evans blue, er)¢rosine sodic) on the tongue and searching for the dye during suctioning in the endotracheal aspirate. the factors, that potentially have influenced the aspiration, including weight, age, sex, cause of respiratory failure, main pressure airway (map), level of consciousness, presence of swallowing and body position were evaluated. all the variables studied had their association with aspiration tested by chi-square method with relative risk considering a confidence interval of %. the results were adjusted by multivariate analysis. results: the overall prevalence of aspiration was . %. among all children who aspirated, compared to those who did not, there was a statistically significant difference in the presence of swallowing (p= . ). the odds ratio to aspiration in the presence of swallowing was . (t. - c.i. %) and the relative risk . . aspiration was not significantly affected by sex, weight, age, cause of respiratory failure, map, level of consciousness and position of the body during the ventilation. conclusion: the endotracheal intubated children frequently aspirate as intubated adults and that preventive measures are ineffective. the presence of swallowing movements is the main risk factor to aspiration of oropharingeal content in intubated patients. clinical features and shortterm outcome skling, rp gie pneumonia is the second most important cause of death in young south african children. the clinical features, intensive care course and outcome of children being ventilated for pneumonia in the developing world is unreported. aim: to describe the clinical findings, aetiology and shortterm outcome of children younger than months with pneumonia requiring ventilation. the data of all babies under the age of six months with a lower respiratory tract infection admitted to the paediatric icu for ventilation were prospectively collected over a period of months. tracheal aspirates and blood specimens were submitted for viral and bacterial cultures. results: forty-seven babies aged to days were ventilated for pneumonia. twenty-six infants had been born prematurely; t had been ventilated during the neonatal period and had bpd. the median duration of symptoms was day, the most common being cough, tachypnoea, apnoea and cyanosis. five babies ( %) died. the mean duration of ventilation was days (range - days) and of ward stay after icu discharge days (range - days), blood euttures were positive in children ( %). viruses were cultured in children ( %). conclusion: ) fifty-five percent of children below months requiring ventilation for pneumonia were premature infants, of whom % had been ventilated during the neonatal period. ) the median duration of symptoms prior to admission was day. ) ninety percent of the children survived and were discharged from hospital. ) viral pneumonia was responsible for % of the admissions. mechanical ventilation and atrial natriuretic factor release ulloa santamarfa, e, p rez navero jl, ibarra de la rosa i, espino hernladez m, velasco jabalquinto mj, frfas p rez m. picu. reina sofia children's llospital. c rdoba. spain. mechanical ventilation effects on renal function decreased diuresis and natriuresis due several factors including anf. several studies have demostrated anf released due increaasing pressure in right atrium. on the other hand, mechanical ventilation, overall peep modality, inhibits peptide release althougt cvp increased is found. this study was designed to demostrate anf stimulation is due rigth atrium stretch which be higher during mechanical ventilation instead of atrium pressure. we desing a prospective study including patients, age range months- years with congenital heart disease. all of them were admitted at pediatric intensive care unit after extracorporeal surgery and were assisted by mechanical ventilation. hemodinamic state was stabilized in all patients and nor renal neither neurological diseases were found. after hours with mechanical ventilation, plasmatic levels of anf were measurement, pvc, pericardical pressure were assessment; all patient were sedated with midazolan and paralized with neuromuscular blocking agent; mechanical ventilation technique was as follow: imv between and , tidal volume and fi o enough to mantain respiratory parameters in normal range. afterwards, at least twentyfour hours in spontaneous breathing, the study was made again in each patient. atrial stretch was assesssment according to following equation: transmural pressure= cvp -pericardial pressure. cvp were significantly higher with mechanical ventilation than when the patient was breathing by himself. ( . +__ . vs . + . mm hg; p< . ). however, transmural pressure during mechanical ventilation were lower than during spontaneous breathing ( . +__ . vs . +__ . mm hg; p < . ) equal, plasmatic anf levels were lower during mechanical ventilation ( . + . vs . + . pg/rnl; p< . ). in conclusion, anf secretion decreases during mechanical ventilation, even with cvp higher. anf release would depend on atrial stretch meassured by transmural pressure, lower in patients with mechanical ventilation and it would not depend on atrial pressure. the paediatric intensive care unit shaikh zayed hospital, lahore is an acute care area devoted to the care of critically sick children upto the age of years. in a bedded unit with limited equipment, constant care is ensured by the presence of at least one nurse aed one doctor round the clock. in this setup we have the facility to ventilate - children at one time, between sep. and dec. , out of patients admitted to icu, ( . %) were below yr of age, while ( %) were below month of age. life support was discontinued in ( . %). total mortality was ( . %), major mortality was in - month age group ( . %), and month to month ( . %). majority of the patients were of sepsis ( . %), cns disorder ( , %) followed by respiratory problems ( . %). it seems therefore that the major indicatiou for ventilation was overwhelming septicemia leading to multiple organ failure, rather than purely respiratory problems. high frequency oscillation (hfo) in the therapy for ards in pediatric patients requiring aggressive conventional mechanical ventilation (cmv) -routine or experimental mode ef pre ecmo therapy. fedora m., nekvasi~ r, vobruba v., srnsky p,, zapadlo m. dpt. critical care medicine, nicu and ecmo center, university children's hospita! brne, nicu of university hospital prague, czech republic. introduction: pediatric patients ( males, female, average age . months, average body weight , kg) with severe ards ventilated with aggressive regimen of pcv or prvc were connected to hfo (sensormedics ) as the last "rescue" therapy due to uncontrollable respiratory failure before intended ecmo. in the course of hfo of them were given no in the concentrations of - p.p.m., were subjected repeatedly to surfactant replacement therapy (alveofact). results: ecmo was needed in no patient, patients survived, patient was disconnected from the ventilator because of brain death in spite of conspicuous improvement of oxygenation and other parameters, some relevant parameters hours before and hours after starting hfo are given in table ~ in all the cases, the disconnection from hfo was carried out through the simv regimen, never directly to cpap. table : the levels of blood gases, oxygenation index (oi), aado ,map,fio and pao /fio ratio hours before and hours after starting hfo. conclusion: although none of the patient had to be subjected to pediatric ecmo, hfo should be carried out only in workplaces having the immediate possibility of using this method in the case of hfo failure. speculation: should not hfo be used ir pediatric patients with ards earlier than aggressive cmv? can hfo ce considered standard, not experimental method of therapy? refractory hypoxemia in premature patients is characterized in a persistent elevation of pulmonary vascular resistance, with right to left shunt through the ductus arteriosus and or foramen oval. we report the case of a vlbw patient (ga w, bw g) who present a severe hypoxemia related to hyaline membrane disease and a pulmonary and systemic infection to group b streptococcus, refractory to conventional ventilatory support and surfactant therapy, associated to hemodynamic failure falling in ecmo criteria used for term infants. a rescue therapy with hfov (sensor medics a) is decided at h of live, the table resume the patient's evolution before and after hfov. at w of postgestational age the patient present a fio of . with a chest x ray compatible with a cld type l at discharge no oxygen requirements was needed and actually he's doing well. conclusion: hfov, using an adequate alveolar recruitment strategy, was effective in the rescue of a severe hypoxemic respiratory failure with a rapid off of ecmo criteria entry in our vlbw premature patient, during the united nmioffs embargo ~nst yugoslavia the prevalence of the ast}nnafic ~acks in c~dldren aratsed. the mo~t common causes have beem dramm~e worsening of life standard, ecom~c disaster in global community, gr~ number of refugees from the other parts of former yugodavia. it wm obviom that mcio-ecoumnical conditions took a part in the exacerbations of previously known cldldhood asthra~, ~av~ of micro-and m~mclimaflc changes, psychosocis] and emotional cryses, lack of medics-m~nts for p~ve~on and tl~rspy of acute asflanatic attacks. about % of d-dldv~ tmslod in our picu for these year~ exp~dvncod ~vcr~ attack for the flint time iu ~jzeir lifts. it has been cu~ ~%~ children in mspir~ry picu of our hos~mt. the scut~ revere attack (more ~asn ~/o of hight clinical score) was detected in % of all children admitted with respirak~ problems. from tl~ mmlysss we exclu&d: bmncldolifis, ~i anomalies, ~eve~ i~ccqions. concerning our drug supplies (which wc~e reduced), we started our therapy by administration of oxygen, ~ta -ago~dst inhalations (but sometimes we had the solution for jet nebulizcm only for o~e inhalation per p~cnt), mwinophyllin and mefl~ylpr~ini~done in/ravenously. % of ih~ asthmatics needed repea~ doses of muinophyl~n pinch.ally, tnch.,ding the fluids. the bronchodilak)r msponm was poor ~r~cl slow, hospital stay in picu was for days and for days in other units sl~rwsvds. tim ~ of their stable condifio~ was hard at borne (or refugees camps), without p~ventkm, so they came bsvk to hospital for morn than times in % of cases, dtrdng ~e je last motlfl~s file dtustion improved, concerning tim drugs supply for prevention, and we hope that these lifc~restening conditions wouldd~ introduction: the incidence of ards is increasing as survival of critically ill patients is higher. the application of new therapeutic modalities have increased the survival rates in (ards) adult patients. objective: to study the therapeutic efficacy of new tleamlents in children with ards material and methods: a retros~ctive study was conducted from to . children with severe ards, (lung severity score > , ) (r), aged days to years, were included. the diagnosis were as follows: interstitial pneumonitis, non interstitial lung infection, with lung aspiration and with clinical sepsis. patients had different tipes of cancer and to suffer inmunodeficiency disease, the first subjects (group t) were treated with conventional measures. from october of new therapeutic modalities were introduced, including: less agressive ventilatory support, postural changes (prone to supine) in subjects, administration of corticosteroids in patients, rfitric oxide in , pe~ssive hypercapnia and administration of exogeans sarfactant in one, pao /fio , d(a-a)o , oxigenation index (oi) and the score of respirator), severity disease were similar in both groups. the two groups evolntiou was compared. results: -ten patients died, from group i and from group ii ( % v.s. : %,ns). -the evolution time, either to exitus or weaning from ventilatory support was higher in group ii ( . v.s. . days in group i, ns), -the incidence of barotrauma was observed in subjects ( . %), from group i and from ii. of these patients % expired. -during the course of the disease, ( %) patients had more than one damaged organ. only in one subjet mof was considered to be the main cause of death. the majority of the patients expired because of their respiratory disease, although, % of them met criteria of mof. -fifty percent of the subjects were infected at the time of death. stmmry: a trend toward a higher survival rate is observed in the subjects receiving the new modalifies therapeutic intervention (corticosteroides, postural changes and permissive hypercapnia). our results are not significative,probably because of the small number of subjects studied. a new doubleaurae~t two-stage et-tube (dl-ett) was desig~aed and tested in the rabbits with acute king injury under conventional mechanical ~entilation_ ventilation efficiency of dl-ett was emrrpared with that of canveniionally t~sed single lumen et-tube (sl-ett). meth~s: dl-ett was specially made out of two sl-ett. vertical crosssections at the distal end of two et-tube (td _ rmn portax) were adhered with each other to form a tracheal stage lumen wifu id . mm the two remained uncut parts of the tubes corlntithted the oval s~ge with two separate imnens. dl-ett and sl-ett were randomly applied to five adult paralyzed rabbits with acute lung injury (by . nffkg oleic acid. iv). a bird inter vetffttator (bird products corporation) was used for time-cycled pressure-limited ventilation at /min of respiratory rate, ern h of peak i_~piratory pressure, l: of ire ratio, ljmin. of flow rate and . of fich. peak inspirntory pressure, mean mrway pressure, posi ve end-expiratory pressure at tip of et-mbe and bemodynamics were measured and recorded continuously. arterial blood and expired gas were measured ~by avl blood gas analyzer) after each stabilization t.~iod of minntes. _analysis w~as by prated t test. result: dl-ett acaltety improve cos removal at all amman. pa(?oz was decreased by t . +_t. (p< . l) and physiologic dead space fraction (v~zvt) reduced by % +- . % (p< . t), compared with dl-ett. there were no significant change in arterial oxygenation. conelus|on: the double-lumen two-stage et-tabe significantly increases ventilation effmiency with simple operation in rabbits v, ith acute hmg injury, lts availability may influence future clinical management of ~ennated patient~. this ~muly was fimded by the science and technology. commiuee of beijing municipality. analis of hemostasis alterations on different coagulation cascades in children with septic shock has shown that coagulation disorder character is dependent on lung affection rate. the initial manifestation of the respiratory distress-syndrome (rds) are characterized by the obvious activation of blood thrombin potential, moderate coagulopathy and not sharply marked endoteliosis, the witlebrand's factor (wf) increase tot - %. progress in the clinical picture of "shock lung" leads to chronometric and structural hypocoagulation with potential hypercoagulation in "mix-test", high level of firbin derivative, thrombocytopenia with thrombocytopaty and the wf increase to ~ %, terminal stages of the rds, as a rule, are characterized by potential hypercoaguletion absense, depletion of at-lit and plasminogen, prevalence of antithrombin and antiaggregating activity, obvious endoteliosis (the wf to increase - %). the arteriowenous difference according to index of the thromboelastography (teg) in the rds ill-iv rates was , % less than in the - rates, disorder of lung filtering ability in severe rds is confimed also by minimal arterio-venous difference of activated euglobulin lyses (ael) in children with the rds ill-iv rates is only , %, while the patients whit rds i-i rates have the ael-activity in arterial blood , times as much than in venous blood. the use of then allows to determine the potential hypercoagulation rate, the at-ill level and fibrinogen quantity during the anticoagulant therapy and also the character of the x-factor activation and thrombocytic hemostasis. the effective therapy component of septic genesis rds in children is the controled coagulation method with the use of the individual selected heparin doses in according to desagregants, kryoplasma, proteolisis inhibitors and trombolytics. it is necessary to avoid the heparintherapy for children with the rds complicated with producting coagulopaties and termal phases of blood disseminated intravascular coagulation (dic). bronchoseopy has been used for evaluation of the potential problems of the airways and for investigation the bronchial specimens for diagnostic purposes. regent technical advances result in performing this procedure at the bedside manner and in critically ill patients. we have performed hronehoaeopy during last three years on pediatric patients with respiratory problems, in % of cases the opentube hroneh seopy was performed (for diagnostic as well as for therapeutic reasons) and collected secretions or bioptic material were examined. the indieatiuns were: acute upper respiratory problems, chronic wheezing, inspiratory strider, tracheal or bronchial bleeding, chronic eongh, retractable atelectssis, severe pulmonary infections, lymph node perforation in lung tuberculosis and soquells like bronehiectssis and fibrosis. our results were: anatomical malformations in %, mueosal oedema with chronic inflammation and thick secretions in %, easuos masses in %, granulation tissue and purulent secretions in foreign bodies and bronehieetasis in %, and only % of eases were normal finding. our exlxdenees pointed that this invasive procedure in carefully selected patients has important role in establishing the diagnosis and in the- introduction: tbg has been a useful investigation in the management of ventilator-dependent infants in our experience. one ml of contrast was hand ventilated into the respiratory tree via their nasotracheal tubes and their anatomy and dynamics demonstrated on radiological screening. case descriptions: three infants who were difficult to ventilate requiring high airway pressures, high peep and a significant oxygen requirement had tbgs. the ages ranged from to months. two cases were complicated by complex cardiac lesions. in all cases there were frequent episodes of desaturation, where hand ventilation proved difficult and various intermittent lobar collapses occurred. microlaryngobronchoscopies (mlb) performed on the infants by experienced paediatric ent surgeons failed to identify the airway problems. more than one mlb was frequently done. concern about introducing contrast into the airways of infants with limited cardiorespiratory reserve combined with an uncertainty about how much extra intbrmafion would be gained often led to a delay in investigation. when performed these fears proved groundless, the anatomy and pathology of the airways were demonstrated in full and the correct therapeutic plan started. in two cases tracheostomy and peep producing patency of bronchomalacic segments allowed weaning to low levels of ventitatory support. in one case tracheal reconstruction was undertaken and in the cardiac cases the respiratory component of the ventilatory dependence was fully assessed. at the age of months, a baby boy with a history of minor respiratory problems, was admitted to hospital with an upper airway infection and severe dyspnoea. shortly after arrival at the icu he had a total airway obstruction. after intubation there were still difficulties to establish a normal gas exchange, and he was tranferred to the regional picu. ct scan and bronchoscopy verified a congenital tracheal stenosis affecting the whole trachea except the upper mm below the vocal cords. the diameter was estimated to less than ram. an unsuccessful attempt was made to dilate the extremely rigid stenosis with a balloon. after the procedure he had a respiratory and circulatory arrest, and he was put on ecmo as a bridge to surgical correction. after stable days on ecmo, surgery was performed during ecmo with a tracheal homograft transplantation. immediately after surgery, ecmo was discontinued. a silastic dumont type stcnt was inserted inside the homogra~, and a nasotracheal tube was placed inside the stent for assisted intermittent mechanical ventilation. repeated bronchoscopies were performed to remove granulation tissue and secretions. at months of age, the stem was removed with an endoscopic procedure. however, the trachea was still soft and collapsable, and another silicon stent was placed inside the trachea for another months period, after removal he had some respiratory problems and he was treated with nebulized salbutamol, mcemic epinephrine and steroids. he was discharged from the hospital at months of age and his condition is now stable. this is the first procedure of its kind in sweden. it was accomplished by international and multidisciplinary collaboration. ecmo may be a bridge to corrective surgery and long time stenting may be necessary in the postoperative period. post mtubation laryngitis ( pil ) is still a frequent complication, occurmg in l - % of intubated patients. inhaled racemic epinephrine has for long been used as an accepted therapy, but this drug is not always available. the authors undertook a randomized, double-blind, placebo-controlled trial to determine the efficacy of inhaled l-epinephrine(le) in the treatment of plu in the period between july/ and may/ , patients were submitted to endotracheal intubation for ventilatory support. atter the extubation procedure patients were considered for enrollement if they met the following criteria: clinical signs of laryngeal estridor and a downes and rafaelly score for upper respiratory obstruction equal to or higher than patients with primary upper respiratory disease were excluded all patients enrolled reeieved either inhaled l-epinephrine % or normal saline. dexametasene ( , mg/kg/day) was given to all patients in both groups. after inhalations, au patients were monitored for a period of - minutes and monitoring included cardiac and respiratory rate, mean arterial blood pressure, arterial blood gases and the dowries and rafaelly score. statistical analysis included, qui-square with the fisher correction test and the z-test for paired variables. thirty eight patients ( , % ) met the criteria for enrollment, to the le group and to the placebo group.there were no significant differences in both groups in regard to age, sex, initial score ( , x , ) and endotracheal tube diameter. the period of ventilatory support and tracheal intubation was significantly higher in the le group ( , x , , p = , ). the follow-up score showed a significant drop only at minutes after the inhalations (p = , ). re-intubation due to laryngitis, occured in patient of the le group and in of the placebo group with no statistical sxgnificance (p = , ). no difference was observed on the monitored hemodynamic variables during the minutes, except for the mean arterial pressure at minutes, being heighar on the placebo group (p = , ). we concluded that, although the l-epinephrine group showed a trend in better scores post-inhalation and fewer re-intubations due to laryngitis, the results were not statistically significant. we especulate that the period of intubation may have affected our results. similarlly there were no differences in the incidence of adverse effects between both groups. objectives:to evaluate the complications of endotracheal intubation in children with upper airway obstruction due to epiglottitis or croup. methodes: during a year period ( - ) all patients with epiglottifis or croup were reviewed to determine the complications of endotracheal intubation, especially upper airway obstruction due to granulomas. results: patients were reviewed. in children (mean age . years) with epiglottitis the mean duration of intubation was . days ( - ). no complications were seen. in patients (mean age . years) with croup the mean duration of intubation until the first extubation was . days ( - days). elective extubation was performed if an airleak was present or after days without airleak but in the absence of fever and obvious secretion. reintubation was not necessary in children ( . %). in this group the mean duration of intubation was . days ( - ). in patients ( . %) reintubation was necessary because of severe upper airway obstruction due to granulomas. mean duration of intubation until the first extubation was . days ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . there seems to be a difference in duration of intubation between these two groups with croup, however it is not significant (p > . ). all the patients with granulomas could be successfully extubated after microlaryngeal surgery, with a mean intubation period of . days ( - ). revealed no complications, where as endotracheal intubation in children suffering from croup showed a high incidence ( . %) of granulomas. however laryngeal steepsis and other serious complications were not sesn~ patients ( days averagely] was obviously seen in ~he peak =one of fl, f resonance and in the zone of high freq,-~ncy :r, ~;~e composition while cases( day~ average;y] :~bowed no abnormality both clinically and isryngoscopica!~y. / patients with catheter placement for more than week~ end p~tie,~ts for less than weeks had t;~ryngeal abnormal change in their larynges,abnormal changes of sound spectrogram were all seen in patients with placement for mope than weeks. our data suggest= ca] the complication of endotracheal intubation was increases with increasing length of time of catheter placsm. entjbut aeriuoa complication is rare i (b] the time limit of pernasal endotraoheal catheter placement is weeks within which the procedure is • comparatively safe and effective means for maintaining e tong term artificial airway. in a -year period ( ) ( ) ( ) ( ) ( ) ( ) ( ) we diagnosed tbm as an apparent dilatation of the trachea and main bronchi ih four premature infants on continued mv for respiratory distress syndrome (rds). the infants were three boys and one girl with gestational age (ga) - weeks and body weight (bw) - g. mv was provided by bourns cub time-cycled and pressure-limited ventilator to attain normal gas tensions. no jet ventilation was used. chest radiographs were reviewed for a complete evaluation, and for the evaluation of the airway. after the intial subjective diagnosis of tbm, the width of the tracheal and main bronchial air column was measured at the lower level of the first and the third thoracic vertebal body it , t ) and near the carina; the width of the main bronchi below the carina was also measured. in all infants, tbm became apparent close to the lh day, that is, after - weeks of mv. therefore, for the time period from birth to the th day the following ventilatory parameters were reviewed and analyzed: ( ) the percentage of total ventilation time when more than % o concentration was required, ( ) the peak inspiratory pressure, ( ) the positive end-expiratory pressure, and ( ) the duration of high frequency ventilation ( - breaths per minute). also noted were the apgar scores ( and min after birth), the duration of hypotension (systolic bp below mmhg) and circulatory instability, the presence of systemic or tracheal conatal or later infection, the duration of mv, and the final clinical outcome. the records were also reviewed for other possible pertinent data. rigid respiratory endoscopy in children fraga j, amant a s, piva j, nogueira a, palombini b. introduction: the respiratory endoscopy is an important procedure to diagnose and treat many airway's diseases in children. although have had advances in radiologic investigation exams and pulmonary function tests, the direct anatomic visualization of airway is important to the management of many respiratory problems. objective: evaluation the respiratory endoscopies performed with a rigid bronchoscope in a pediatric reference hospital. material and methods: we study the records of all children that were submitted to respiratory endoscopy under general anesthesia from march to march . age, sex, clinical to indicate the procedure, diagnosis and complications of endoscopy were registered. results: three hundred and fifty six respiratory endoscopies were performed. the most common indications for endoscopy were strider ( %), suspected foreign body ( %), atelectasis ( %) and difficult tracheal extubation ( %). the most frequent diagnosis were laryngomalacia ( %) and subglottic stenosis ( %) in the glottic and subglottic areas, and foreign body ( %) and tracheomalacia ( %) in the tracheobronchial area. normal endoscopy was performed in ( %) of the children. only three slight complications of the endoscopy were observed. two patients presented bradycardia during the exam, and the third need tracheal intubation due to post-endoscopic subglottic edema. conclusion: the rigid endoscopy in children is efficient and has no serious complications. near drowning; indicators of acute and long term prognosis bernardien t.mj. thunnissen t, reinoud j.b.j. gemke , loes veenhuizer?, krijn haasnoot , a.johannes van vugh department of pediatrics, ~wilhelmina children's hospital, utrecht, sophia hospital, zwolle, and ~free university hospital, amsterdam, the netherlands. in this retrospective study factors that affect short and long term prognosis after submersion were analysed. all patients that were admitted to a tertiary pediatric icu between january i, and january i, were included. of patients, aged - years, died in the icu, one after hospital discharge. survivors and non-survivors showed significant differences with respect to central temperature, pupillary reactions, arterial ph, pediatric risk of mortality (prism) score and therapeutic intervention scoring system (tiss) upon admission (p < . ). non-survivors more frequently required mechanical ventilation, bicarbonate administration and active reheating. ards was seen in patients ( %), invariably within hours after admission. no patients with cardiac arrest on" admission snrvived without sequelae. hypothermia appeared to have no protective effect on hypoxic damage. survivors with persistent sequelae _> months after discharge had significantly higher prism and t ss scores (mean and , respectively) than those with complete recovery (mean and , respectively). long term cognitive problems were present in / survivors ( %) and emotional disturbances in / ( %). in conclusion, a concise number of clinical and laboratory parameters, representing acute severity of illness, are important prognostic indicators for survival and health status of children after submersion. there were ( %) bronchoscopies, and ( %) were oesophagoscopies.the average age was , years for bronchoscopies, and years for oesophagoscopies. the outcome of the patients was good. no complications were observed. extraction is recomended in every symptomatic patient. orphenadrine is an anticholinergic drug mainly used to decrease symptoms of parkinson disease. orphenadrine has a peripheral and central effect and overdose can result in athetoid movements, convulsions, cyanosis, coma, arrhythmias, shock and cardiac arrest. physostigmine is a specific antagonist of the peripheral and central effects and can be a useful antidote. we report the case of a two and a half year old female who was transfered to our icu for general convulsions. the little girl had, three hours before admission, accidently ingested rag of orphenadrinehydrochlodde (disipal®), which was her grandmothers anti-parkinson medication. three hours after ingestion she presented neurological signs: confusion, unstable walking, and periods of aggression. generalized tonic-clonic seizures appeared who were rebel to administration of multiple anti epileptica but ceased after iv administration of diazepam and endotracheal intubation and ventilation. an episode of ventdcular tachycardia responded well to the iv administration of tidocaine. the levels of orphenaddne in the serum were high at admission ( pg/l) and were present in the blood up to hours after ingestion. high serum levels are, in the literature, associated to a high mortality rate. physostigmine was administered three times at a . mg/kg dose in the first hours. we decribe the noted effects of physostigmine on the different symptoms. the patient survived and could leave the icu after one week. in conclusion: orphenadrine poisoning is a very complicated medical problem associated with high mortality. in severe intoxication, the benefit of physostigmine more than counterbalances its side effects. objective: to define the optimal volume of dilution for endotracheal (et) administration of epinephrine (epi) design: prospective, randomized, laboratory comparison of four different volumes of dilution of endotracheal epinephrine ( . , , and ml of saline) setting large animal research facility ofa universi~ medical center subjects and interventions: epinephrine ( . mg/kg) diluted with four different volumes ( , . . and i rot) of normal saline was injected into the et tube of five anesthehzed dogs. each dog served as its own control and received all four volumes in different sequences at ieast one week apart. arterial blood samples for plasma epinephrine concentration and blood gases.were collected before and . , . . . _ . . , . . , . , . , and minutes after drug administration. heart rate and arterial blood pressure were continuously monitored. measurements and main results: higher volumes of diluent ( and i ml) caused a significant decrease of pao , from :!: tort to ±i torr, compared to the tower volumes of diluent ( and ml), from ± torr tu +_ torr (p< . ). these effects persisted for over minutes. mean plasma epinephrine concentrations significantly increased within seconds following administration for all the volumes of diluent. mean plasma epinephrine concentrations, maximal epinephrine concentration (cmax), and the coefficient of absorption (ka) were higher in the ml and ml groups. the time interval to reach maximal concentration (tmax) was shorter in the ml and ml groups. yet these results were not significantly different. heart rate. systolic and diastolic blood pressures did not differ significantly between the groups throughout the study. conclusions: dilution of endotracheal epinephrine into a ml volume with saline optimizes drug uptake and delivery, without adversely affecting oxygenation and ventilation. the aetiology and outcome of paediatric out-of-hospital cardiac arrest was studied during a -year period in southern finland served by physician staffed emergency care units. the files of prehospital patients less than years old without palpable pulse and spontaneous respiration were analysed retrospectively. fifty patients were declared dead on the scene (dos) and resuscitation (cpr) was initiated in patients. the sudden infant death syndrome was the most common cause of arrest ( %) in the dos patients as well as in patients receiving cpr ( %). asystole was the initial cardiac rhythm in % of the patients in whom cpr was attempted. eight of the hospitalised patients were discharged, of them with mild or no disability, with moderate disability and one in vegetative state. in multivariate analysis the short duration of cpr (< minutes) was the only factor significantly associated with better survival. due to various aetiologies the survival rate from prehospital paediatric cardiac arrest is quite low. on the other hand, hypothermic near-drowning victims seem to have a relatively good prognosis. duration of cpr less than minutes was the best predictor of intact survival, our study supports the previous findings of the importance of early and effective resuscitation efforts for establishing ventilation and perfusion on the scene. in our system well trained physician staffed emergency care units are able to provide immediate and effective als on the scene. on the other hand, these units also appear to be able to refrain from resuscitation when the prognosis is pessimistic. objective: to assess the normal ,gastric intramucosal ph ~hi) by tonometry in healthy children patients and methods: twelve healthy children ( males and females) with age rmaged from months to years scheduled for minor plastic or urologic surgery. children were previously medicated with midazolam ( . mg/kg) and atropine ( . mg~) both i.m.. anaesthetic induction was standardized with -n ( %) administered via facial mask and increased halotane concentrations (up to %). all patients got an endotraeheal tube after iv. administration of femanile ( mcg:jkg) and vecuronium ( . mg/kg) or suxametonio ( mg/kg), pmaesthesia was maintained with o -n ( - %) and isofluorane ( . - %). during surgery, children needed mechanical ventilation and the others maintained spontaneous breathing. ekg, heart rate, blood pressure, and pulse oximetry were moniterized. after anaesthesia, a sigmoid tenometry catheter (tonometrics, inc.) was inserted in the stomach of the patients by direct visualization with laryngoscope and magyll clamps. children were all maintained normoventilated and with normal cardiorespiratery variables. cadet's balloon was £~led with . ml of saline. thirty minutes after the insertion rrd was extracted and rejected, just afterwards the remanent . ml was extracted and immediately analyzed. simultaneously an arterial gasometry by puncture was performed. gastric phi was calculated by the henderson-hasselbalch's equation using the pco obtained from the tenometry catheter and the bicarbonate value obtained from the arterial gasometry. results: average gastric phi was . -i- . , range ( . - . ). objective: demons~ating intramucesai ph (phi) alterations during transport of patients from operative room to pediatric intensive care unit (picu), material and methods: phi measurements were performed with gastric tonometer catheter in t patients undergoing cardiac surgery with cardiopulmona d" bypass (cpb), there was mate and female, the average age = yl ra, average weight = , kg, average time of cpb = rain. the measurements were made at the end of the surged' and when the patients had arrived in the picu statistical aualysis: average and ~andart deviation and test "t" student. objetive: to asses the efficacy of gastric iatramucosad ptt (phi) and arterial lactate levels to evaluate splacalc tissular perfusion in an experimental model of intestinal ischemia. suneets ~nd methods: twelve piglets weights t - kgs. undergoing orthot~ie liver trasplantation. the intestinal ischemia was induced by aortic damping. tonometry catheter (tonometrics inc.) w~s placed in the stomach after artaesthesia and ot intubation. phi ~s determined times and lactate levels was determined fi times in stages: i) pre-ae~hepatic stage (twice: before surgery and before aortic clamping ); ii) end anhepatic stage (only phi): iii) reperfusion stage (a , , and minutes). the phi was derived from application of the henderson-hassdbach formula using the pco value from the tonometer and the arterial bic~rbonate. all pipets received raaitidiila before sttrgery. values of phi above , and lactate levels between and mg/dl were considered nortrm. the results were statistically anaj.izated with anova and bonferroni tests. results: the phi was normal on pre anhepatic stage (> , ) and lactate levels were slightly increased ( , +_ , and , ± , mg/dl ns) . in relalion to we-anhepatics values, phi decreased signncatly at the mid of anhevatic stage ( , _+ , vs , _+ , p< , ), phi remain low in stage iii, at rain ( , + , p< , ) and min(g -+o, p< , ). arterial lactate levels increased significatly in relation to levels in stage i, at rain ( , _+ , p< ,o ) arid rain ( , ± , p< , ) of reperfusion stage. there is a slight improvement on phi and lactate ievels at and t rain althought the differences did not reach significance. cnmments: phi and arterial lactate levels propperly reflect hypoperfusion on the experimental model of acute intestinal isdlemia. b~kground : the paediatrie gallbladder diseases generally described are calculous ¢hol~tstitis, cystic duct obstruction, congenital anomaly of the biliary tract, and inflammation. in the neonatal period, noulithogenie gallbladder disease could be also due to erythroblastosis or hyperalimentation. obieetive : we describe an other type of disease affecting the gallbladder in neonates thought to be related to their vascular vulnerability. methods : four patients with abnormal gallbladder ultrasound not related to classical observations were included. we have studied and reviewed the biological and clinical data, the ultrasound findings and their evolutions. results : four patients, to ~.k-old neonates ~ffth a birthweight be~,een , and , kg, were intubated and under total parenteral nutrition for to days. none of them were symptomatic on repeated clinical evaluations. one newborn developped hypotensien on umbilical bleeding at hours of life. in two cases, signs of cholestasis were discovered : the total bilirubin level has risen to mg/dl; the direct bilirubin level was , mg/dl while the urina were dark and the ~o~,ls :mcolour~. the c~mplct~ ~crology as a!! the culvare~ remained negative. the ultrasound explorations were atypical : in the four eases, an initial increasing broad and thickness of the wall of the gallbladder with an hyperecbogenie inside content, which was not sludge, was discovered. in three eases the images resolved in ten to fifteen days. in one ease, an asymptomatie thrombosis of the vena portu which remained patent was discovered. in this case, at one month, the ultrasound showed images encountered in chronic ebolecystitis and, at one year, the gallbladder appeared atrophic. none of them underwent surgery. conelusiou : the gallbladder diseases are multifactorial. besides the prematurity, the infections, the total parenteral nutrition, the premature neonate is exposed to vascular vulnerability affecting also the gallbladder and this may explain our findings. progress in prognosis of pts with b-nhl had followed the use of multimodality chemotherapy (ct). with the prolonged survival, there are comlications due to myetosupression & desease process. the syndrome of neutropenic enterocolitis (ne) is one of the ominous problems because ofpts increased susceptibility to infection & overwhelming sepsis. this material included neutropenic pts ( - years) with the stages iil& iv of b-nhl who were treated with the modifired bfm- (mtx g/m in -h inf.); males, females. seventeen episodes of ne were observed & only after the first courses of ct ( of after tst, %; of after nd, %). the symptoms existed to days. wbc ranged from to in l~tl (median, ). the first signs of ne were directly correlated to the beginning of the neutropenia & the recovery of neutrophils led to the disappearance of abdominal recovery of neutrophils led to the disappearance of abdominal pain. the conservative treatment included gastrointestinal tract decompression, broad spectrum antibiotics initially, volume & electrolyte substitution, nutritional support, correction of acid-base balance, symptomatic treatment. sixteen pts were treated nonoperatively, died. on autopsy the transmural bowel necrosis due to thrombosis of branches of a.mes.sup, was found. the bowel perforation occurred in one patient, he was undergone laparotomy & hemicolonectomy & survived. we conclude that ne is a frequent complication in neutropenic pts with the st. lii& iv of b-nhl. it occurs after the induction courses of ct. close observation by surgeons, oncologists & pediatric intensivists is mandatory. conservative treatment is effective & more preferable until leucopenia resolves. operation is necessary only for those.with perforation. near infrared spectroscopy as a tool for evaluation of intestinal perfusionpresentation of an animal model. c. scheibenpflug, p. buxbaum and a.m. rokitansky the recent development of and investigations in the so called near infrared spectroscopy ( nirs --transcutanous emission and simultaneous registration of intensity of spectralcolours depending upon modulations of tissue perfusion ) enable physicians to measure and qualify organ perfusion and nowadays is mainly used to control cerebral as well as skeleton muscular blood flow in trauma patients at intensive care units ( icu ). today intestinal perfusion, hypoperfusion , cell damage caused by reperfusion injury, bacterial and toxin translocation are serious problems in critically ill patients at an icu. paediatric intensive care physicians put major concern on intestinal perfusion, which for. instance gains more and more importance, especially in the neonatal period for example as an etiologic factor for necrotizing enterocolitis. we established an animal model, in which we measured intestinal perfusion by nirs under various invasive and noninvasive conditions. methods and results will be referred. for preliminary conclusion we propose near infrared spectroscopy ( nirs ) also as a potent diagnostic tool to determine early intestinal malperfusion in order to prevent lethal outcome. fm'ther investigations in animals as well in paediatric iritensive care patients should be done to estimate our efforts. introduction: following the acute phase of necrotising enterocolitis (nec) starvation of the gut for a period up to weeks is a generally accepted treatment modality in many centres. objective criteria to refeed these patients are hardly available. recently the double sugar test has become available as a parameter for (ab)normal gut permeability ~' . aim of the study: to evaluate the changes in permeability of the small bowel in patients with nec and controls before introduction of enteral feeding. methods: a lactulose! rbarrmose (i/r) test was performed in two groups. group was studied - times within a -week period of starvation (n= , mean gest. age , range - weeks). in group seven different control patients were studied (mean gest.age , range - weeks). the test was performed by giving a patient after at least a hour fast ml/kg bodyweight l/r solution and determination of the /r ratio in a -hour urine sample by chromatography. results: objective: to evaluate the prognostic factors in the response to nitric oxide (no) in children with acute respirator/ distress syndrome (ards) and/or pulmonary hypertension (pht). patients and methods: critically ill children received no inhaled for ands and/or pht treatment. patient before and after cardiac surgery ( cardiac transplants), with bronchopneu~onia, multiple trauma, sepsis and cardiorespiratory arrest. patients showed /j~ds and pht, in with associated ards. we analyzed age, sex, diagnosis, pao , pa /fi , oxygenation index, pht, shock, and sepsis as prognostic factors and response factors to n . results : after no administration oxygenation did not improve in patients ( . %) and pht did not diminishe in one children ( %). patients survived ( %), / ( . % with /d%ds) and / ( %) with pht. the four patients with isolated pht survived , and the patients with pht and ards dead. patients after cardiac surgery presented less mortality ( . %) than the rest of patients ( . %). patients with shock presented higher mortality ( . %) than the rest of patients ( . %). there are no differences in response to no in respect of sex, age, diagnosis, shock, and sepsis. survivors showed higher increase of pao /fi . ± . to no than non-survivors . ± . (n.s). patients with pht showed higher increase in pa /fi to no administration ( ± . ) than patients with ards ( . ± . ), (n.s), but patients with ards showed a higher increase in !, ± . , than patients with pht . ± (p < . ). patients with pa /fi < i showed less increase in pa /fi , . ± . , than the rest of patients . ± . (n.s) conclusions: i. mortality of isolated pht treated with no is less than patients with ap~s. patients with shock and those with pht and ards showed higher mortality. . we have not found any clinical or analytical factor to predict clinical response to no administration. patients showed ards, and severe pht after cardiovascular surgery, in with associated ards. we registered respiratory assistance, blood gases, pao /fi , the oxygenation index (oil, and mean pulmonary pressure/ mean systemic pressure (pap/sap) before and after no inhalation. we measured continuous concentration of no and no by electrochemical method (noxbox, bedfont, airliquide). results: no administration improved oxygenation mean pao from ± tm~g to i ± ~g (p < . ), mean pa /fi fr<xa ~ to £± (p < . )and i from ± to ± (p < . ). patients did not improved with no administration. the oxygenation improved in the first five minutes and the best oxygenation was achieved with - ppm. there is no significant change in pac . pap/sap diminished from ± % to ± % ( p< . ), in one patient there is no response. the no administration was maintained between ~ minutes to days. the effect of no on pulmonary pressure and oxygenation was maintained without change during all the time it was administrated. n concentration were always less than ppm y metahemoglobinaemia less than . %. there are no side effects secondary to no administration. patients survived ( %). concluaions:l.administration of no improves oxygenation in children with ~/eds and diminishes pht after cardiac surgery. .no effect is fast and maintained during the evolution. high frequency oscillatory ventilation in combination with inhaled nitric oxide g~thberg sylvia, md, edberg k e md, phi), dept of paediatric intensive care, children's hospital, s- g teborg, sweden background: for man), years severely sick infants with congenital heart malformations or acute lung disorders have died due to pulmonary hypertension, hypoxia and multiple organ failure. today there are several therapeutic facilities coming up for these infants. ecmo progranunes have been introduced in severul centres as well as improved venlllatory techniques, as high frequency oscillatory ventilatior~ (hfov), which provides adequate ventilation with less risk for hmg injury.. in , the endothelium derived relaxing factor was identified as nitric oxide (no), and extensive studies have sho~-a that inhaled no reduces pnimonm o vascular resistance and improves oxygenation in hypoxic infants with pulmona~ hypertension. material.. from july to january , we have treated severely hypoxic children with combined ttfov-no. seven were newborn, with cdh, one with mas, one with irds, one with paediatric ards due to rsv infection and one with poor oxygenation atler open heart surgery. were between month and years and all had ards of differentorigin but one who was hypoxic after open heart surgery. method: hfov was given by means of sensormedics a oscillatory ventilator to patients, and dr~ger babylog was used in one case. mean airway pwssures varied from - cm h . oscillatory pressures varied from - cm h and ventilatory rates from - hz. fi o varied from , - , . no was administered by nomius classic. no and no was measured in the inspiratory limb with an electrcchemieal device. noconcentration varied from to ppm and the no -concentration between - , ppm. methemoglobin was never more than , % (average , ). duration of treatment varied from to days. combined trealment with hfov and inhaled no improved oxygenation and carbon dioxide elimination in out of treated childretl patients died, due to their underlying congenital heart disease, one of asphyxia due to rsv-infection and one of cdh with progressive hypoxia and multiple organ failure. combined treatment with hfov and inhaled no improves oxygenation in severely hypoxic children. treatment should be slarted early to reduce the risk for chronic lung injury following barotranma and high oxygen concentrations. we speculate that the combined hfov-no may reduce the use of ecmo, and that it may improve outcome in ceotres where ecmo programmes are not introduced. apart from its vasodilative properties nitric oxide appears to act also in physiologic immune defense. intracetlular concentrations of no synthesized by macrophages are in the range of above those produced by vascular endothelium. we investigated the bacteriostatic effect of nitric oxide at concentrations used during inhaled therapy for pulmonary vasodilation in neonates. ten different strains of five species were used (staph. anrens, staph. epidermidis, strop. group b [gbs], e. coil and pseudomenas aeruginosa), which are ~e most often tracheally isolated bacteria in mechanically ventilated premature infants and neonates. we compared bacterial growth of cultures applying three different concentrations of nitric oxide ( ppm. ppm, ppm) m the growth of the same strains in room air for a duration of hours. no bacteriostatic effect was demonstrable at no concentratioes of ppm. e. coil showed decreased bacterial growth at ppm and ppm, however without reaching statistical significance (p= . ). at nitric oxide concentrations of i ppm staph. epidermidis and gbs grew significantly less as compared to colonies of the same strains in room air. no effects were found regarding the growth of staph. aureus and pseudomonas aneruginosa. we conclude that nitric oxide has a selective bacteriostatic effect on some of the most often trachealb, isolated bacteria in premature infants and neonates. this effect appears to be dose-dependant and occurs in the upper range of dosages used with inhaled no therapy. further research is required in order to examine the mechanisms of action as well as specific interactions between different strains of bacteria and nitric oxide. the no,box monitor (bedfont, kent, uk) is used to monitor nitric oxide (no) and nitdc dioxide (no ) during no administration in ventilated neonates. according to the manufacturers specifications the monitor can be applied in cases where airway pressures range from to mbar. we investigated in-vitro the accuracy of the no monitor in a range of ventilatory conditions. using a dr~ger babylog we ventilated an artificial lung. no was administered { ppm no in % nitrogen) with a mass flow controller to the inspiratory tube, at a distance of cm from the y-piece. the no target value was set to ppm. the ventilator was operated in both cpap and ippv modes at different settings. the no sampling tube was placed on two different locations; in the inspiratory tube dose to the y-piece; in the expiratory tube haft way between the y-piece and the ventilator. the no-monitor was ca)ibrated with ppm no at mbar. fig. and show the sensitivity of the no-monitor for respectively static pressure (cpap) and pulsatile pressure (ippv) with the sampling tube located in the inspiratory tube. fig. shows the resur for pulsatile pressure with sampling in the expiratory tube. we conclude that the accuracy of the bedfont no-monitor is dependent upon airway pressure and sampling site, the latter possibly caused by incomplete mixing, pressure and no are linearly related when sampling occured further away from the administration site. based on this study we suggest to place the sampling tube in the expiratory tube. during neonatal care the clinician should be aware of varying inaccuracies depending on the respiratory pressures. hypothesis: availability of therapy with inhaled nitric oxide (ino) decreases ecmo use in patients referred .to a tertiary care hospital for treatment of respiratory, failure unresponsive to conventional therapies. background: at children's hospital of wisconsin (chw) treatment for patients who have failed conventional treatment for respiratory failure, sometimes called "rescue" therapy, has included ecmo since and high frequency oscillatory ventilation since . ino has been in experimental use at chw since may of i and has resulted in the perception of a decreased need for ecmo therapy in those patients referred for rescue therapy. this study was designed to tbst the validity of that perception. study type: retrospective cohort. methods: the medical records of all patients referred to chw from /lj to / / for rescue therapy for severe respiratory failure were included in the chart review. data were collected regarding diagnoses, illness severity, hospital course including interventions and complications, and outcomes. exclusion criteria w~ere the finding of structural heart disease or congenital diaphragmatic hernia as the basis for hypoxemia. qualification for ino treatment included an a-ado - or oi ~- for two hours or -> for twelve hours and echocardiographic demonstration of persistent pulmonary hypertension of the newborn. patients were classified into two groups based on the availability of ino at the time of their hospitalization. results: in the time period of the study, patients were referred for possible ecmo therapy. twelve patients greater than weeks old, with congenital diaphragmatic hernia and with congenital heart disease were excluded from this analysis, leaving patients for study, ino availability reduced ecmo use from of ( %) patients in the ~ino unavailable" group to out of ( . %) patients in the "ino available" group, p=& by fisher's exact test. the fact that the two groups were composed of patients of similar severity of illness is reflected by comparable rates of ecmo and ino rescue therapy ( % vs. %). conclusion: by providing an alternative rescue therapy, ino has reduced the need for ecmo in this group of neonates referred for respiratory failure. introduction: true hepatnrenal syndrome (his) is defined an acute renal failure {arf) in the presence of severe liver disease without other known causes of renal failure. hrs is frequently seen in the course of hepatic cirrhosis• in children, cirrhosis is rare; however, arf can be seen in combination with aseites and liver dysfunction• we describe patients with hepatic dysfunction and aseites in combination with ar~ and abnormal sodium-water handling, leading to the diagnosis of hrs. pathophysiology: three factors are considered in the pathogenesis of hr~: i) hepatic dysfunction, ) deranged hemodynamics, including abnormal blood pressure, reduced effective arterial blood volume and abnormal blood flew distribution, and ) neuro-humoral dysrsgulatiom, including elevated levels of aldosteron, renin, angiotensin-ll, ade, vasodilatim nitric oxide and vasoconstrictor peptide endothelin-l. the main pathogenetic feature is decreased cortical renal blood flow, decrease of glomerulur filtration rate (gfr), vastly increased sodium retention, uliguria, and azotemia. treatment: therapy is based on counteracting sodium and fluid retention by highdose aldosteron antagonists and loop diuretics, improving renal perfusion by lowdose dopamin, and strict restriction of fluid and sodium. interventions as paracenteals of aacites or n peritoneo-systemic shunt are associated with high morbidity and poor outcome in children. reversal of hem by conservative measures can only be attained at early stages of hrl liver transplantation is the only definitive treatment that can reverse ere at advanced stages. patients: the described patients developed severe ascites with insidious renal dysfunction and abnormal sodium-water handling during admission at picu and fullfilled clinical criteria fur hrs. treated according to the cited principles, all patients showed improvement of gfr, with increased natriuresis and gradual decrease of ascites. eventually, renal function normalised completly. conclusion: ere deserves greater recogmitimn in the picu population; diagnosis can be suspected on clinical criteria. with this increased awareness, therapy tun be instituted at an early phase, with better prospects for recovery. positive outcome of hem depends on early recognition of the clinical picture, understanding of the pathophysiology, and early institution of consistent treatment. mtx is an antimetatxflite widely used as chemotherapeutic agents. high dose ivitx (i to ~m ) administered as a prolonged intravenous infusion (over - hours), is often used to treat malignant paediatric diseases. major complications of this treatment are myelosuppression, orointestinal mucositis, dermatitis and impairment of anal function. we report two cases of mtx overd~age occurred in two children ( -year-old. month-old) t~ted for acute lymphoblastic leukaemia. they were treated by cavh and the mtx bhk~d levels rapidly decreasedavoiding multisystemic involvement. establishment of alkaline diuresis and monitoring of plasma mtx levels during treatment is essential to prevent nephrotoxicity. however. leuco',cnn rescue may not prevent the development of potentially lethal toxicities in patients with mtx concentrations persistantl} exceeding t mm. in theses cases, em'ly treatment of mtx intoxication may pm~cnt myelosuppression and reducerenal damage. the goal is to lower the concentration to below mmoll, at which time rescue agents aleme would be expected to be cllcctive. respective indications of these remo',at mctny.:is are still discussed : hacmt~ialysis t~ eharc(~l haemoperfusion should be prolx',sed for massive and acute intoxication. however, rebound has been reported after combined hcmodialysis and hemoperfusion. exchange transfusion may be proposed as a treatment for prolonged and moderate intoxication. peritoneal dialysis is an incflbedve method for remo~ al of mtx. cavh was used in our icu. cavh is a simple method for blood purification and n':dy iluid control. use of cavh was never be reported in this indication to our knowledge. simplicity, rap~d application and gco.l clinical tolerance are the main advantages of this technique. the technique presents ~peclal advantages in terms of low priming volume of extracorporeal circuit, low blood flow, low rate heparinisation. our results show a decreaseof plasma mtx concentration and a rapid reduction of halfqite of elimination (t hours over the period of cavh). moreover, we didn't delec~d rebound after stopping prc,xedure. small size of the i:ratients may present sometime special problems, but these technical problems can be overcome, no severe complication (needing, inlection) were observed during filtration, in summary, aggressive intravenous fluid hydration and alkaliniaation of the urine coupled with careful monitoring of renal function and plasma mtx concentrations during and al'tcr infusion along with lem~overin rescue has reduced the inndcace of life-threatening toxicity after highdose mtx. however, some mtx inu>xication still occurred, leading to se~em toxicity, particularly nephrotoxicity. in these cases, we think that cavh (or cavhd) is a reliable, rapid method without rcix~und increase in plasma mtx concentration or important adverses effects compared to other procedure removal. gouyon jb, germain jf, semama d, pr vot a, desgres j preliminary limited data suggested that hemofiltration and hemodiafiltration may be valuable in some neonates with decompensation of maple syrup urine disease (msud). venovenous hemofiltration (vvhf) and hemodiafiltration (vvhdf) were performed with a new neonatal hemo(dia)filter (miniflow , hospal) on anesthetized rabbits infused with branched-chain amino acids (leucine, isoleucine and valine) and c~-keto-isocaproate. the bcaa and aketo-isocaproate blood levels were close to those previously observed in neonates with msud when extracorporeal blood purification was required. vvhf and vvhdf performances were assessed with two different blood flows (qb = . and . ml/min). vvhdf was performed with dialysate flow rates (qd = , , . , . and . l/h). thus, each animal was submitted to successive procedures. within each studied period, clearances of the bcaa were strictly similar. bcaa clearances obtained by vvhf were similar to ultrafiltrate rates (respectively, . - . and . - . ml/min at high and low qb ; p < . ). the ~x-keto-isocaproate clearances obtained by vvhf were . - . and . - . ml/min at low and high qb (not significantly different). whatever qd value, the vvhdf procedures always allowed higher bcaa and c~-keto-isocaproate clearances as compared with the corresponding v'~hf period with similar qb. bcaa clearances obtained by vvhdf with a . l/h dialysate flow, were . - . mljmin and . - . ml/min at iow and high qb, respectively. the concurrent a-keto-isocaproate clearances were . -,. , ml/min and . _+ , ml/min. at both qb regimens, bcaa clearances provided by vvhdf were markedly higher than values previously obtained with peritoneal dialysis in human neonates with msud. the management of renal failure in the newborn is difficult. when dialysis is instituted peritoneal dialysis (pd) is usually the technique of choice. this is can be problematic and impossible in some patients with pre-existing intra-abdominal pathology. continuous arterio-venous haemofiltration (cavh) has been described in infants but sick preterm infants are not able to support the circuit. i have devised a means of having pumped haemofiltration in small/preterm infants (phis/pi) and describe its use in nine patients ranging in size from to gms for periods of to days. vascular access was achieved through or guage cannulae in either a peripheral artery and a central vein or through two central veins. blood was pumped out using an ivac infusion pump and through a gambro fh haemofilter. a second ivac pump was used to remove haemofiltrate from the filter and a third to infuse replacement solution. removal rate was set to give a clearance of mls/min/ . sq.m and blood flow rate set to between and times the removal rate. heparin was infused into the circuit to prevent clotting of the filter. biochemical and fluid balance control was achieved in all infants. guaranteed fluid removal allowed the administration of full nutritional support. four patients died when treatment was withdrawn because of an untreatable underlying problem. one recovered renal function but died some weeks later from unrelated problems, three survived and recovered renal function and one patient is still on treatment. this system allows a secure means of achieving fluid and electrolyte control in the preterm infant. the use of this technique may allow haemofiltration to become as applicable to preterm infants as it is to older children and adults. unibrtunately, children often receive no treatment, or inadequate treatment for pain and painful procedures. this prospective, multicentric study focuses on the efficacy, safety and side effects of novalgin (metamizol sodium) for this indication. patients and method: novalgin was administered to children, aged between - years, with acute, postoperative or procedural pain. novalgin ( - mg/kg) was given - hourly iv or im respectively, in some cases ( ) in combination with opioids (tramadol , piritramid , butorphanol ). the pain relief was assessed by six-step verbal rating scale (vrs) from to , vital signs were monitored, the side effects, that occured were recorded. results: pain relief was good (vrs less ) in children - . % of study patients. novalgin was very well tolerated, only one patient had adverse reaction -hyperpyrexia following intravenous application of the drug. discussion: novalgin (metamizol sodium) is safe and effective drug in the management of acute pain in children with low incidence of side effects. obie~qve: a prostx~tive study comparing simultaneous, indepeadent ratings conducted by intensi~ sts using an american (comfort) and an european chartwig) sedation scale for mechanically ventilated pediatric patients. measurements and results: the study comprised observations in mechanically ventilated pediatric patients (aged days to years) in a pediatric intensive care unit (from march to january . each patient was sedated by his/her managing physician with opiates, benzodiazepines, barbiturates, used isolated or in combination. each observation consisted of a -mid period of oly~ervatien of the patient in his or her pediatric icu bed, after each observation, the comfort (analyses dimensional physiologic and behavioral subscores -range to paints) and hartwig (analyses dimensional behavioral subsenres -range to points) were performed by the intensivist. we established the comfort scores ~ correspanding to adequate (range to ), excessive (range to ), and inadequate (range to ) sedation; and, hartwlg scores z correslxmding to adequate (range to t ), excessive (range to , and inadequate (range to ). statistical mmlysisj: agreement rate (kappa) and p <. was considere d s!l~nificant. comfort ( . %) ( , %/ ( . %) hap, twig , ( . %) ( . %) ( . %) to the comfort score, the average for adequately sedated, inadequately sedated, and too sedated was . +- . , z _+ . , and a.+_l , respectively. and to the ha~twig scorn, the average for adequately sedated, inadequately sedated, and too sedated was . :k-' . , . -&l , and . l- . , respectively. conclnsion: in our study there were no significantly statistical difference when you apply a more complex scale (conff'ort) or a less complex scale (hartwig) to assess the sedation of mechanically vemilated pediatric patients. the application of local and intravenous morphine infusion after surgery of urinary tract eva nemeth , m.d. semmelweis medical university , first oepartment of paediatrics , budapest , hungary in±roduction:continuous analgesia with morphine may be ~egaroed as a safe and effective method of pain relief during postoperative period. subjects and methods: children /mean age . years/ underwent elective ureteroneoimplanta±ion were randomly selected to receive either morphin intravenously of lo ug/kg/h /group one/ or bladder morphineinfusion ug/kg/h /group two/ after surgery. all patients were prospectively evaluated during their s±ay in the postanaesthetic care unit. cardiac and respirafory rates,blood pressure,sa ~,degree of alertness,pain perception and complaints of the paticnto ~cr~ recorded hourly. pruritus,nausea and vomiting,voiding difficul-±ies,sedation,dysphoria were systematically sough and quoted. statistical analysis was performed by chi square test. results:postoperative analgesia was the same in the two groups,but side effects were less in the bladder morphine group,because of the lower se morphine concentration.the differentes weren't significant in two groups. conclusions:the administration of bladder morphine infusion is a safe and effective method in children. objetive: compare the evaluations of sedation level made by physicians and nurses with the visual analog scale (vas) and the comfort scale (cs) in pediatrics patients receiving difforents modes of intravenous sedation. material ~ method." file evaluations were made by an attending physician and nurse with the vas and by another physician (always the same) using the cs. the observations were divided following the sedation mode: one drug (fentanyl or midazolan), two continuous drugs, one continuous and one intermi~ent drug and two intermittent drug (fentanyl and midazolan). the groups were compared using the t-student test. the groups also were compared between the percentual of agreement of the evaluations of sedation level made by physicians and nurses with the cs and vas using the x . results: we didnk find any statistical difference between the observations made by physicians and nurses with the vas in the differmts modes of intravenous sedation, the average of the observations using the cs betwom one drug and two drugs modes didnk exhibit also statistical difference. the observations made by physicians mad nurses using the the vas when compared with the cs didn't show statistical difference between the sedation level. we found statistical difference only in percentual of concordance of sedation level between physicians and nurses when compared the one and two drugs modes of sedation. conclusion: we didn't find differences in the observations made by physicians and nurses in the sedation level, only in concordance pereentua/ of observations when compared two modes of sedation. the observations using the cs (more complex) didnk show differences when compared with the vas. effects of age, concurrent administration of other pharmacologic agents, and disease [cardiac(n= ) & pulmonary(n= )] on the pk & pd of b were evaluated in volume overloaded infants aged days- mo (n= ). single doses of . , . , . , . , . , , , . , . & . mg/kg iv were given over - min after baseline evaluation. age was used as a continuous vadable to determine its effects on the variability in the pk & pd of b. values for pk parameters were compared between patients in cardiac and pulmonary disease groups. hierarchical multiple regression analyses were used to determine the effects of age, disease and other pharmacologic agents on the variability of bumetanide excretion rate (ber) and pd responses, e.g. urine flow rate (ufr) & electrolyte excretion. cit, cir & cinr increased with age (p< . ) while t, decreased markedly in the first monthe of life (p< . ). ber normalized for dose increased with increasing age. patients with pulmonary disease exhibited significantly greater clearance and shorter t~= (p< . ) than those with cardiac disease whereas vd~ was similar in both groups. the administered dose of b was the primary determinant of ber but increasing age also contributed. penicillin antibiotics decreased ber. dose response curves for ufr and electrolyte excretion were similar between disease groups. more of the variability in ber and pd responses could be accounted for in the pulmonary group than the cardiac group but this was not statistically significant. conclusion: the pk of bumetanide were influenced significantly by age and disease. differences in pk between patients with pulmonary and cardiac disease were primarily due to differences in total clearance. age and the administered dose of b were positive determinants of ber and pd responses while penicillin antibiotics had a negative impact on both, once b reached its site of action, no differences in pd responses were detected between disease groups. the pharmacodynamic effects of bumetanide were evaluated in volume overloaded infants (n= ) aged days- months. single doses of . , . , . , . , , , . , . , . & . mg/kg iv were given over - rain. bumetanide concentration in blood (n=l ) & urine (n= ) samples were quantified by hplc. baseline urine samples were collected over - hours prior to drug administration. determinations of urine volume, electrolytes (na ", k +, ci, ca ++ and mg++), creatinine and osmolality were performed before and at - , - , - , - , - and - hours after bumetanide dosing. changes in urine flow rate and electrolyte excretion were plotted as a function of bumetanide excretion rate which was considered the effective dose of the drug. peak bumetanide excretion rate increased linearly with increasing doses of drug and showed no evidence of approaching a maximum. time course patterns for urine flow rate and electrolyte excretion were similar for all dosage groups. urine flow rate and electrolyte excretion increased lineady up to a bumetanide excretion rate of approximately #g/kg/hr and either plateaued (urine flow rate) or declined at bumetanide excretion rates > #g/kg/hr. bumetanide had no detectable effect on serum electrolyte concentrations, conclusion: maximal diuretic responses occurred at a bumetanide excretion rate of about ;~g/kg/hr. higher bumetanide excretion rates produced no increased diuretic effect. peak bumetanide excretion rate of about #g/kg/hr corresponded to bumetanide doses of . - . mg/kg. neonates using an electrical syringe-pump. authors: tr~luyer j.m., sertin a., bastard v., settegrana, c., bourget p., hubert p. background and objective: many problems can be observed with drug administration by i.v. route, especially in neonates. so we evaluate different protocols of teico delivery using an electrical syringe-pump. methods: we simulate infusion of teico with a syrlnge-pump (pilot c, becton & dickinson lab.) trough d standart neonatal i.v. system. for weights ( or kg) we used doses of teico ( mg and mg/kg) and a dose volume _< . ml. our goal was to perform a complete infusion in minutes. the infusion system consisted of an life care infusion pump (abbott lab.) with its lv. set for maintenance intravenous fluid (flow _< ml/h) connected to a -way stopcock. an meter extension tubing was placed between the stopcock and a neonatal catheter. an another meter tubing (injection tubing) connected the teicoplanine syringe to the stopc, ock. the volume of the injection circuit (from the syringe to the distal part of the catheter was . ml methods of injections were assessed: a: injection of the predetermined volume of teico in minutes with no wash out. b: idem as a but the teico was injected in minutes, followed by a wash out ( ml / minutes). c: twice the required volume was introduced in the syringe and the volume to infuse was programed in minutes, followed by a wash out ( ml/ minutes). d: ]dem as c but a priming was performed before connecting theteico syringe to the tubing. during each run, serial samples were collected every ten minutes over a one hour period. the samples were assessed using hplc method. results: the amount of drug delivred at minutes were calculated. the results are a mean of to runs and expressed as the percentage of the total amount of teico prescribed. a , % , % b % , % c a % , % d , % % conclusiom for accurate and reliable intermittent drug infusion with a syringe pump it is mandatory to use a precise protocol of administration and to take in account ) a priming (for immediate starting of infusion), ) a drug volume greater than the dose prescribed and a programmed volume injected, ) a wash out of the tubing (with a volume ~ , x volume of tubing injection) caz is an antibiotic with activity against the major pathogens responsible for neonatal bacterial infections. we previously reported the pharmacokinetics of caz in preterm infants on day of life which showed that the clearance of caz increased with increasing gestationat age (ga). mean serum half-life of infants with gas < wks was . h. we wanted to investigate the effect of postnatal age on caz pharmacokinetics, we therefore studied caz pharmacokinetics on day - of life in preterm infants with gas < wks. caz ( mg/kg) was administered as an intravenous bolus injection. blood samples were coilected before (t = ), and . , , , , and h after the caz dose and analyzed by hplcassay, the pharmacokinetics of caz followed a one-compartment open model. during newborns with complex congenital heart defects requiering either htx or palliative staged single ventricle repair were admitted to our hospital: hlh n= , unbalanced cavsd, tga with hypopl. rv and hypoplastic aoa. tga with hypopl. rv, sas and dextrocardia. /i children had been admitted with cardiogenic shuck and mukiorgan failure due to intermittend closure ofductus arteriosus; in / stabilization failed. parents were informed about the known and unknown risks of the always palliative surgery; in cases parents denied further therapy. one pafiem with hlh underwent orthotopic htx at the age of month after the ducms art. had been stunted in the newborn period. month later he is still in favourable condition and without any sign of acute organ rejection. / underwent first stage of palliative single ventricle repair: norwood -op. ( ) ( n= ), damus-kaye-stansel -procedure ( ). the clue to adequate postoperative management was to archieve a balanced distribution of flow to systemic and pulm circulation, that is to protect the single ventricle from volume overload and to guarantee sufficient oxygenation and pulmonary development as well. with the centralvenous sato at about % provided maintaining the arterial sato at about _+ % is corresponding with a qp/qs of : . using modified bt-shunts of . mm resp. a central anrtopulm, shunt of mm in one case l severe puim. hypertension, surgery at weeks of age ) there was no excessive pulm. blood flow and no need to increase pvr with inspired co . one child ( norwood at weeks, preexisting pnim_ edema ) developed severe pulur hypertension and parenchymal pulm. dysfunction after prolonged bypass and multiple transfusions due to intraoperative bleeding: hypoxemia could be managed successfully by implanting a second shunt of mm hh later and temporarily using prostacyclin and no; at sternum closure dd later the second shtmt was banded to ram. follow-up ranges - month: all children are at home being assigned for second stage operation at about month of age. establishing clinical practice guidelines has become increasingly important in the current health care environment. significant effort has been focused upon development of post-operetive critical care pathways. however, benchmark data upon which such pathways should be based has not been well reported. length of mechanical ventilation (lmv) and length of stay (los) for children following cardiac surgery, for example, is poorly described. we prospectively recorded the lmv and los in patients who underwent cardiothoracic surgery between / / to / / . only patients who belonged in any one of five categories of congenital heart disease (ventricular septal defect _+ other septal defects (vsd), atrioventricular (av) canal, tetralogy of fallot (tof), transposition of great arteries (tga), and single ventricle physiology (fontan)) were included. eight non-survivors were excluded from the analysis. all patients were admitted to an intensive care unit cu) post-operatively where mechanical ventilation was managed by pediatric intensivists. lmv was defined as the period from post-operative admission to planned extubation. length of stay (los) was defined to be from le from the icu. cytokine patterns during and after cardiac surgery in young children. especially in children, cardiac surgery with cardiopulmonary bypass (cpb) can cause a systemic inflammatory response. this process is thought to be mainly a result of inflammation induced by surgery and exposure of blood to an artificial surface, and of reperfusion injury during weaning of bypass. complement activation, degranulation of granulocytes, induction of free oxygen radicals, endotoxemia and release of cytokines, are important contributing factors. we studied cytokine patterns before, during and after cpb in young children admitted for complex surgery or for septal defect correction. in the first group, significant amounts of il- and il-lra could be detected preoperatively. these findings could reflect the already existing hemodynamic dysregutation. in both groups, cpb procedure upregulated the circulating pro-inflammatory cytokines il- / , but not il- b. at the same time, il-lra became detectable. therefore, we suggest that in these patients the production of the anti-inflammatory cytokine il-ira was not induced by the preceding acnvity ot pro-inflammatory cytoidnes. during cpb, we noticed a sharp decline in the capacity of the leucocytes to secrete il- / . the ex-vivo production of il-lra however, was only slightly attenuated. we conclude that there is a differential regulatory pathway for the induction of il- / and il-lra. in addition, we studied the influence of dexamethasone administration on the cytokine pattern. administration delayed the appearance of il- / and il-ira in the plasma, interestingly, it did only interfere with the ex-vivo production of pro-inflammatory cytokines. the latter supports our hypothesis that production of il- / and of il-lra is regulated by two independent pathways, ( %) of pts. % ofpts < months of age developed metabolic alkalosis as compared with % ofpts > months of age.the infants with metabolic alkalosis received more citrated blood products and furosemide. following cardiac pulmonary bypass the highest ph-values and be-values were observed - hours and - hours, respectively. ii. prospective study: metabolic alkalosis was registerd in t children ( %), of those < month ( %) developed metabolic alkalosis and % of those elder than monms.durmg the postoperative course patients younger than months developed the highest ph-and base excess values after and t hours, in the subset of the older patients maximum ph and base excess was found after and hours, respectively. in one case the top level ofph-value exceeded . , the base excess + mvalb. conclusion: children undergoing cardiac surgery with cardiopulmonary bypass often develop metabolic alkalosis.in contrast to previous reports, we did not observe an association between metabolic alkalosis and mortality, nor greater frequency of cardiac arrythmias or prolonged mechanical ventilation. in context with decreasing serum lactate levels, our data show positive correlation of metabolic alkalosis with postoperative improvement of liver function. respirator, mechanics and weaning outcome in children undergoing cardipvascular surgery. vassallo j., cernadas c., saporiti a., landry l., rivello g., buamsha d., rufach d., magliola r. mechanical ventilation (mv) and acute respiratory failure are common events in children unergolg cardiovascular surgery (cvs), the development of new techniques helped to measure some of the main respiratory mechanics (rm) in a non invasive fashion. our goal was to evaluate the predictive value of these measurements in weaning (w) outcome in these patients, patients and methods: we prospectively evaluated children considered clinically to be ready for w with < kg and > hs mv. patients with diaphragm paralysis and those who failed w because of upper airway obstruction were excluded. before patient extubation the following measurements were recorded during spontaneous ventilation (cpap/t piece) using the cp neonatal pulmonary monitor bicore (lrvine, ca): total respiratory system static compliance (cssr) and resistance (rts), rapid shallow breathing index (rsbi). maximal inspiratory negative pressure (pi max) was measured using an unidirectional expiratory valve. threshold values predicting w success (ws) were: cssr > . ml/cm h , rts < cm h /l/sec, rsbi and pi max > - cm t . w failures (wf) -patient reintubation within the following hs, these values were compared between w success and failures using fisher exact test. an apriori level of statistical significance was chosen at p < . . considered, an increase in tnf-a levels is observed after cardiac surgery (p< . ) with a return to previous values after hours (p< . ). hours after cpb, similar values are observed in groups ii and ill, but there is a further increase in serum tnf-a levels in group i when compared with both other groups (p< . ). we found no statistically differences in any other moment. there was a significant correlation between serum tnf-o levels determined hours after surgery and cpb duration (p< , ). conclusions: cpb in childhood provokes a significant increase in serum tnfa levels, in newborns the inflammatory response is maintained hours after surgery. this enhancement of serum tnf-e levels indicates the existence of a relevant inflammatory response in these patients. introduction: cardiac surgery appears to induce a systemic inflammatory response. we have investigated the behaviour of il- i~ and il- before and after cardiac surgery. patients and methods: we studied serum il- and il- levels from children with congenital heart disease ( boys and girls), aged from days to years, undergoing open heart surgery, before cpb (d we found no statistically differences in the il-i levels in the different groups and moments. there is a significant increase in il- immediately after surgery (p< , ) with similar levels hours after cpb and a significant decrease (p< . ) hours after cpb. preoperatory il- levels were higher in the groups i and tl than in group i (p< . ). hours after cpb serum il- levels in group were significantly higher when compared with group (p< . ). conclusions: cpb in childhood induces a significant transient increase in serum il- levels, strongly relevant in newborns. cpb was not associated to a significant modification in serum il- levels. thus, cpb in childhood induces a dissociated behaviour in the proinflammatory il- and il- & pathways. obiective, to evaluate the effects of amg receipt on the clinical condition during the first hours after birth (t ), the morbidity and mortality in immature outborn neonates. methods. we studied outborn neonates with ga to wks, admitted during the years to . eighteen neonates exposed to amg (ga: , +lwks, bw: _+ g) and neonates did not (ga: , _+ wks, bw: _+ g). results. amg-exposed neonates compared to those not exposed had lower incidence of apgar score at min _< ( % vs %, p<. ), lower incidence of ph t < . ( % vs %, p<. ), decrease need of bicarbonate ( % vs %, p<. ), lower fio (fio min> : % vs %, p<. and fio max > : % vs %, p<. ), lower incidence of intubation ( % vs %, p<. ), lower requirements of surfactant ( % vs %, p<. ) and lower mortality ( % vs % p<. ). there were no differences between the two groups for the following parameters: type of delivery, hypothermia hypoglycemia and anemia during admission, hypernatremia, hypotension (map< mmhg), need of dopamine and or plasma , incidences of ptx pda sepsis nec severe rop major ivh (plus pvl) and bpd and duration of intubation. conclusions. the main beneficial effects of amg receipt on the immature outborn neonates were the decrease of mortality and the decrease of surfactant need. there was no effect of amg receipt upon other severe morbidity in this high risk group of neonates. premature babies are very sensitive on homeostatic disturbances, and often develope intracranial haemorrhage (ich). ultrasound scan of the bram shows four grades of ich: -grade i -only periventricular hyperechogenic areas -grade ii -haemorrhage ham the lateral ventricles -grade ili-dilated lateral ventricles -gtrade iv -intracerebral haemorrhage. the purposes of this study were: to show the incidence of ich in premature babies and its correlation with the gestational age, . to determine the severity of ich . to present the outcome &those babies. in the study were included premature babies successively-born at the department of gynecology and obstetrics before gestational week (g.w.) and grouped in three groups: less than g.w., - g.w., - g.w. to all of them was performed ultrasound scan of the brain. results : . the incidence of ich hi premature babies is % and there is ingh level of correlation with the gestational age: -babies born before t~ g.w. have % incidence of ich and graduated : i grade - %, ii grade - %, iii grade - %, iv grade - % -babies old between - g.w. have incidence of % : i grade - %, i[ grade - %, iii grade - %. -babies older than g.w. have incidence of %: i grade - %, ii grade %, iii grade - % . sixty of premature babies have died and it is . % lethality. in all died ilffant was confirmed the grade of ich diagnosed by ultrasotmd scan of the brain. d. maksimo~ c. z.braiko~ic, n.vunjak. p. ivanovski ( ~iversi~, children's hospital. belgrade, yugosla~, ia infantile intracranial hemorrhage is the most frequent and serious manifestation of late hemorrhagic disease of the newborn caused by ,,~tamm k deficiency in earl?,, ti~fancy. in the last two years, we recorded five cases of infantile intracranial hemorrhage due to "dtamin k deficiency, despite routine prophylax~s (intramuscular vitamin k, mg) , with bpieal clinical presentation: age was - days (average days): vomiting, poor feeding, lethar~'irritabiljty, palor, bulging t ntanelle and convatsiones were present in most cases.two patients developed signs of hemorrhagic shock, with hemoglobin level less than g. . in ~ f \qi level was less than % of predicted value. there was no evidence of head trauma or liver disease in none of patients. four inlants were breast fed, while one, who had diarrheal disea.se, was on adapted milk formula. routine therapy wa.s given (including vitamin k and fresh frozen plasma). two patients were discharged with no sequellae, one developed posthemon'hagic hydrocephalus as a complication and two patients died. late hemorrhagic diseo.se of the newborn is sill/ a significant cause of morbidib' and mortality in earl ' infancy, despite different approaches to prophylaxis developed in recent years. background: neonatal hearing screening in at risk newborns can detect % of the children with a congenital hearing loss. automated abr hearing screening (algo- ) has been introduced for healthy newborns. the aim of this study is to test the validity of this algo- screener in at risk newborns in a neonatal intensive care unit. subjects: at risk newborns (median gest.age: . wks, median birthweight g) selected according to the criteria of the american joint committee on infant hearing. interventions: algo-i automated abr-hearing screening at a level of db was performed in the neonatal intensive care unit. when bilaterally referred, further audiologic screening and/or therapeutic intervention took place. when passed uni-or bilaterally, children enrolled in a) a nation wide screening programme (ewlng) at the age of months and b) in a half yearly follow-up programme in which hearing and speech-and language development were observed according to egan an illingworth. results: screening without disturbance from ambient noise or from routine technical equipment was possible in the incubator, even during nasal cpap therapy. ( %) newborns passed algo- screening. ( %) did not pass bilaterally. of with a congenital rubella died shortly after screening.in of bilateral congenital hearing loss of -> db was confirmed. of the newborns passed were still alive at the age of year. ewing screening was performed in of ( , %). / passed, of had passagere conductive hearing loss, in / no further investigation was performed. all children enrolled in the i/ yearly follow-up programme had normal speech-and language development. in this study all at risk newborns with bilateral congeni "tai hearing loss were detected with algo- screening. screening results showed no false negatives at follow-up. the algo- infant hearing screener can be used as an valid automated abr-screener to detect hearing loss in at risk newborns in a neonatal intensive care unit. gancia gp, bruschi l pnlito e, ferrari g, rondini g -divisione di patologia nc~matate e turapia intensiva -irccs policlinico s. mattco -pavia, italy latrogenic esophageal perforations (iep) in preterm and term infants are seldom reported in litteraturc, in association with difficult endotracheal (et) intubation (with or without stylets), insertion of gastric tube, and pharyngeal suctioning with stiff catheters. crieopharyngeal muscle spasm caused by instrumentation may also lead m a narrowing of lumen, with increased risk of local injury. we report iep observed in intubatcd, mechanically ventilated newborn infants ( male, female, all outborn). a common feature of iep was inability to pass a nasogastric (ng) tube into the stomach, mimicking e~)phageal atresia.~se : birth weight (bw) (i g, gestational age (ga) wk, sepsis. before admission to n cu, the baby underwent multiple et inmbations, because of inappropriate securing of et robe. bloody secretions in pharynx were observed. the endoscopy showed a large lesion at the end of proximal third of the esophagus, case : bw g, ga wk, rds. chest x-ray (cxr) showed a retrostcrnal air leak: the ng tube was stopped }~etwcen d and d and soluble contrast was seen in upper mediastinum.case : bw (/g, ga wk, rds. the endo~opy showed an esophageal lesion. cxr showed a paravertebral route of ng tube and a right pneumothorax.case : bw (i g, cz ,.v!:. rd c. ~!,'.::;;: ::':'_'rvt!~' s l" ~k':.rvrx. cwr, d,,,,vs ~,,mr~e, ~n rhe upper mediastinum and abnormal route of ng tube through a false passage. surgical intervention is needed in case of mediastinitis or mediastinal abscess: conservative management included broad spectrum antibiotics, total parenteral nutrition, antireflux therapy and, if necessary, drainage of air leaks. enteral feeding has been stopped lor days and cautiously resumed after radiographic study. [x~cal sequelae and death are uncommon, but iep occur in newborns with high risk of death due to prematurity and other diseases. in our patients, et intubation has been performed by experienced personnel: therefore the lack of skills in resu~itative procedures is not always the main factor of iep. prevention of iep requires appropriate materials (et tubes, laryngoscope blades, suction catheters), and procedures (positioning of the infant with correct neck estension, firm et placement). sedation and pain control may help to prevent the muscle spasm. aggressive treatment has improved the tong-term outcome of extremely low birth weight neonates (elbw) but it has also increased the chances of iatrogenic lesions. reviewing the charts of our neonates we observed a high number of vascular injuries. from to , neonates were admitted to the neonatal intensive care unit (nicu); of them were elbw ( . %). studying the charts of these elbw we observed cases ( m - f) with vascular lesions ( . %). mean gestational age of these patients was . weeks (rain -max ). mean weight at birth was g . mean weight at diagnosis was g ( - ). in the same period patients with vascular injuries were reported in the neonates over g ( . %). the injuries observed in elbw group were: arteriovenous fistula ( bilateral) at femoral,level, carotid lesion and limb ischemic lesions. aetiology was in cases by venipuncture, in one case umbilical catheter and in the case of carotid lesion a wrong surgical maneuver. no general simptoms were observed. the vessels were repaired with microsurgical technique in six cases: the carotid lesion and five arteriovenous fistula; one case was solved with thrombolitic drugs; an amputation at knee level was required in one case after a long period of medical treatment. the last neonate with an arteriovenous fistula was only observed for parent's will. at follow-up (clinical and by ecodoppler) out of neonates presented normal vascular function without sequelae. from our experience elbw neonates have more chances than older neonates to develop iatrogenic vascular lesions. we advocate an aggressive microsurgery and/or medical treatment to obtain good results and prevent late sequelae. a retrospective comparison between natural surfactants l.j.i.zimmermang m.c.m,van oosten. dept. pediatrics, div. neonatofogy, sophia children's hospital/erasmus university, rotterdam, the netherlands. aim: retrospective comparison of alvofact (in ) versus survanta (in ) as rescue treatment for neonatal respiratory distress syndrome (rds). methods: both surfactants were given at an initial dose of mg/kg (except for alvofact mg/kg for mild rds grade mi). repeat doses were attowed (survanta mg/kg, alvofact mg/kg) up to a maximum of mg/kg, all parameters and outcome criteria were strictly defined beforehand. the initial response (good,mild,no response,relapse) to surfactam therapy was defined on the basis of the decrease in fio . results: there were no signif. differences in patient population and initial parameters: ga ( . +_ . vs a _+ , wks), birth weight (t _+ vs -+ g), severity of rds (grade ill-iv: . % vs . %), apgar scores, cord blood gases, initial ventilatory settings. in ' however, the initial surfactant dose was administered earlier than in ' ( . -+ . vs . _+ . hrs postpartum, p= . ). although the average total cumulative dose was equal in ' and ' ( . -+ , vs . _+ . mg/kg), more doses of alvofact were given compared to survanta { . _+ . vs . _+ . , p=o.o ) and more patients in ' received more than two doses than in ' ( % vs % of patients). there was no difference in the incidence of non-putmonarycomplications. aivofact ( there was a better initial response to survanta and a better respiratory outcome in : in the group < g the duration of ventilation was half in , and in the group >~ og the duration of extra o need was half in as compared to . we speculate that the main reason for this difference is the earlier and initially higher dosing used with survanta compared to that used with alvofact which was given in the same total cumulative dose but over a larger time span. background: e×ogerlous sur&ct~t raplacem~t treatmem has become rou~ne k~ the t~eatme~t of respira~"¢ dim'~ syndrome (i~ds) of pr~e~tur~, wh~eas its effica w th odi~ respiratory diseoses is sdi being wader mvesugatio~. objective: "eac~ mt ereat isto report ottr results of prospect/re, non-randomized "re~-o.e" study oe suffact~t replacement in outhom premamae infa~t~ with rds reruirmg me~aical ventilatioa (nfv). p~tien~ and metho .s: from j-aly to june , / ; ( %) out~ ~¢ infaats, at a mesa age of z , horn's ( boys, ~rls; ~ gestafioan age -+ . weeks, mera~ birth weight _+ g, ~ . i" at minutes) with rds, requiring mv, received bov~e-suff~amt (survanta, ros~/aboti, laboratotie~ columbus, ohio) eadotracheally, as was recomm~aded by maaufacturer. as the c,~:ttrol group o~bom premature infants (ot~ of ; %, admitted with rds from euiy to eune ) were saelected ~d who did not receive surfaaam, compared with ~hctant ~'oup they were admitted for treatmeat e~'li~" aft~" daliv~:y (at the age . :: . hours vs. . +- hours), but they did not diff~ in othe~ baseline dam'a~eri~cs at ~ti~ion. entry crkeda for ~¢fa~aut ~hcadou were fractional i~firat o~ oxtgem r~emeats -fio > . - . , ratio au-lerlal to alveolar oxygea pre~are~ao ~ao < , ~ad oxyge~at,~ i~.dex -ol > . primary o~comes were deter~caned by ~hanges m exs'ge~ab, c~ ~r~d vmtilatic~ ~ the following variable~; ( ) fi'aaic~ of i~spired oxtge~ (fio ); ( ) mesa nnvay presmzre (map) ( ) pag ~ao ratio, ( ) oxyge~ion index (oi). commo~ comphcadces of prem,musty ~d con~ol mechamcal v~ati]al~on (pater dumas merios.s, intracr~nlal haemcrn:hage, air leak, br onchop ulmrmm'y dy~pl~a ~d death) were reg~ded as sec~d,~y outcomes. r~suas: in warfactaat group we observed slg~ .c~t improve~aeat (p< . ) in oxygea~thia md veaatilation at hours all~ e~try k~to the m~dy in compari~ion to nons~fa~m" group. compa~on of secondao' outcomes in ~ts with p,.ds showes table l we did not observe ~y major acute hfe fl:u-eattming complicatlola,s m sxlrlhct~mt grou~ tr/lmediately after stu'~actsmt rcplacemev_t therapy. the duramm of mechmucal ven~ation ~ad oxygen lreau~ent m survivals of both groups did not dafter gmficautl y a-ore ead~ other. condusion: l!a premature mthats with rds treated with surfaaaat replacemeaat therapy we observed decrease m mc~de~ce of tme'~m~o~oraces add de~th (p< . and p< . ), whe~e~s m othe~ observed variables thee was uo ,igmfi~t d~=ecce infectious complications during the therapy of respiratory insufficiency in neonates with birth weight less than g in the course of yearsretrospective study. zitek infants on cmv, cppv, and imv were administered exosurf in dose of - mg/kg twice endotracheally (see table) . in newborns ( . %) hours after surfactant admin fi value decreased by . %, and after hours -by . % compared with initial value; pip and peep values decreased by - cm h and - cm h after hours, and by - cm h and - cm h after day, respectively accompanied by mean decrease of aado from , to . mmhg, qs/qt decrease from . to . % (see table) . mean time of cmv, cppv was . days, imv- - hours, cpap - - hours. respiratory therapy in newborns ( . %) was complicated by pneumothorax (bilateral -in infants chorioangioma is a rela~ively rare placentai malformation associated with considerable mortality and morbidity. a chorioangioma can be regarded as an arterio-venous shunt in the circulatory system of the fetus. this causes volume loading eventually resulting in cardiomegaly and high output cardiac failure. a female neonate (gest age wk, birth weight g, - . sd) was born with an apgar score of and after and rain respectively. the placenta showed multiple chorioangioma. ultrasound of the heart showed a hypertrophic cardiomyopathy. she developed severe hypertension ( / mm hg), treated with nitroglycerine and nitropruside. finally blood pressure decreased when enalaprillic acid was given ( . mg.kg ). we measuered the activity of the renin-angiotensinsystem. an elevation in renin-angiotensin system is shown probably to compensate for the low resistance circulation before birth, hypothesis: the instantaneous cut off of a large arteriovenous shunt did not result in a fast downregulation of the renin-angiotensin system resulting in hypertension. hypertension should be added to the list of complications of chorioangioma of the placenta. the authors studied cases of children's septicemia with blood culture yielding staphylocucetts aurens. the age of patients varied from months to years ( , % from years downward), % of the children caught their disease in the hot season (may to october). the deaths also occured in this season: , % ( / ). following were the anatomo-dinical lesions. -skin %, muscle , %, bone , %, joint . %. -viscera : lung %, heart . %, cerebrum . %, kidney . %, fiver , %. -simple lesion skin-muscle-bone joint: %, no death in this group. the concomitant lesions of the soft tissue,bone-joint and viscera : % with one viscera, % with two viscera, % with three viscera and % with four viscera. -bone lesion : mainly on the long bones ( % on the tibia, % on the femur, the remainder being the mandible ( ) and the humerus), inflammation of' the hip joint was the main one. -i,ung lesion had forms pneumatocele ( cases), bronchopneumonia ( cases), pleural effusion ( cases), multimicroabcess bursting into the pleura ( cases), most multimicroabcesses were lethal : / ( , %), -heart: all thethreelay~rs got le@~r~, % had or layers alrected and death ensued. -cerebrum : the meninges had three forms of lesions purulent meningitis ( cases), obturafing embolns of brain vessels ( cases) and cerebral abcess (one case). the characteristic clinical sign was paralysis and meningismus, phlebothrombosis of eavcrnous finus ( cases)was mually ther~sultofalxil vdfi:h burst there were cases of death with lesion of the meninges and cases of obturating embolns of brain vessels. -the main sign of lesion of the kidney was a change in the components of urine: % got proteinuria, % had leucocytes in their urine, % had erythrocytes in their urine, the urea in their blood increased (over rag%) in . % of cases.the lesion of the kidney seemingly had little relation to death. seven cases of ictertts due to an increase of direct bilirubinemia and a decrease of blood-albumin. -the biological characteristics of the pathogen staphylococci showed that all the isolated specimens had positive coagulaza ; the specimens from the dead patients were less semiti~e to, mad ~t to mali~ overag death rate was . % ( / ). the fungal infection to fusariun species in immunocompromissed child have been reported in the literature with a rare, severe and high, mortality rate in spite.of the use of antifungal drugs. we report a case of successful treatment of a severe disseminated fusariun infection in a ll-year-old boy with acute lymphocytic leukemia (lla-l ), after use a chemotherapy followed by absolute granuloeytopenia. the patient developed fever, skin lesions, pneumonia and fungaemia. fusariun species was cultured from the blood, necrotic skin lesions and lung secretion. the child developed multiple organ system disfunctiou in spite of use broad spectrum antibiotcs and antimycotic therapy needing. uci during days. the patient receive suport treatment (mechanical ventilation, inotropie d~.ugs, diuretics, imunestimulants, blood components, a broad spectrum antibiotes and antifungal agents). we absorved a gradual recovery in the white blood cell count and regression on the sites of infection. the association of preeoce diagnostic and the terapentic with increase in the white blood cell count was the most important in a successful treatment. a year old african-american child suffered a severe pulmonary injury in a house fire. initial survey revealed % total body surface burns, soot on the face, and bloody endotracheal secretions. initial chest radiograph revealed diffuse, bilateral infiltrates. severe respiratory failure with an oxygenation ratio of rapidly developed. he developed a pneumomediastinum and subcutaneous emphysema. although transient improvement occurred with inverse i:e ventilation and surfactant, he became more hypoxic (sac as low as %) and acidotic. on day post injury, he was placed on venc~venous extracorporeal life support (ecls). on ecls day he was decannulated. chest radiograph on ecls day showed an opacity in the left chest. ultrasound of the left chest was consistent with atelectasis rather than pleural fluid. flexible bronchoseopy failed to reveal any obstruction in the left lung. a computed tomography (ct) seen of the chest, which was performed after decannulation, revealed a large loculated collection of fluid in the left, anterior chest. under ct guidance, a f cope loop catheter was inserted and cc of thick blood was removed, follow-up ct performed immediately after this procedure revealed minimal change in the size of the fluid cavity. over the next hr, we instilled urokinase , units over minutes every two hours. a minute dwell time was allowed before draining the fluid. repeat ct scan done at the end of the urokinase infusion showed a marked decrease in the size of the fluid cavity. act scan was not performed prior to decarmulation because the ecls circuit tubing was too short to allow appropriate positioning of the child in the ct scanner. after a ct scan revealed loculated pleural fluid, a simple drainage procedure was diagnostic but inadequate treatment. we were able to successfully dissolve the thrombus after hr of urokinase therapy even though the thrombus was > days old. we suggest that large loculated plenral thrombi which develop as a complication of ecls therapy may be successfully managed with urokinase infusion. introduction: haemorrhages, particularly intracranial, are major complications experienced in - % of neonates treated with extracorporeal circulation. an induced thrombocytopenia and impaired platelet function play a key role in the increased bleeding tendency observed in these patients. the aim of the present study was to establish a dose-respons curve for the effect of a synthetic protease inhibiting agent, nafamostat mesilate (fut- ), on platelet membrane glycoprotein density and platelet activation during experimental perfusion. methods: two identical extracorporeal life support (ecls) circuits were primed with fresh, heparinized human blood and circulated for h. four different concentrations of fut- ( . mg/l blood/h; . mg/l/h; . mg/l/h+ % bolus at the start of the perfusion and & mg/l/h+ % bolus) were used in different perfusion experiments. a total of eight paired experiments were performed. platelet count, plasma betathromboglobulin levels and platelet membrane density of glycoprotein ib and lib/ilia were followed as well as plasma concentration of haemoglobin. results: a protective effect of the agent on platelet count, plasma concentration of btg and platelet membrane gpib could be observed during the first hours of the perfusion when a bolus dose was added. no positive effect could be recorded with the two lower doses used. plasma concentration of haemoglobin was higher in all the fut-circuits compared to the control circuits. conclusion: the addition of a bolus dose of fut- at the start of the perfusion seem to induce a protective effect on platelets during the first hours of perfusion. extracorporeal membrane oxygenation (emco) is a form of invasive cardiopulmonary support that can provide imporary physiologic stabilisation in reversible circulatory failure and or respiratory failure. we reviewed our expierence with extra corporeal membrane oxygenetion in children aged day to year between and . two neonates was succesfully decanulated, but died - well after decanulation due to septic complictions. one child years old, one neonates died on day and day" respectively while still on emco. complication which were and encountered were heavy bleeding in case (child), (neonate) and raceway rupture in case (neonate). problems which are specific developing countries like indonisia are: high cost ( . us for days) difficulty in transportation (transporting intubated baby) from the orgin hospital, lack of knowledge and understanding of the primary physician and nm-ses and difficulty organizing in hours emco team. resnratory mon tor/ng in picu z,zjvkovic, s. mihailovic, o, tosev respiratory monitoring in pediatric intensive care unit picu) provide the importartt informations for understanding of the pathophysiology of the clinical signs, aid with the diagnosis, and assist in therapeutic management and predicting prognosis. pien in children's hospital for ~flmonary diseases and tuberentosis remained for the t~s't two end a half years relatively limited for diagnomic tools and therapeutic regimens, mostly because of the poor fmnaeial suptx~rt. the number of children admitted for aurae asthmatic at.lzek~ severe pneumonias, bronehiolitis, complicated pulmonary tuberculosis, foreign bodies and exacerbations of ehronit'. pulatonary diseases was t . for all patients the respirator' monitoring system means: physie~d examination, ehe~ x rays, capillary bltxxl gas mmlyses (vevv few ehiktren experienced itwasive arterial blt~.~'i gases), noninvasive oxyntctry, measuring of the vital capacity in coopo-able patients, as~d capnography. later on, after the imtial critical illness, a complete hmg fimction tests was performed, as well ,~s bronehoscopy in selected eases, (~lr experience revealed that abotrt % of ehil&en heos suecessthl outcome, without s~lllens , instead they had been tremted in limited conditions. ']'he rest of our patients were previously diagnosed ~s ettronie pulmonary patients, with high risk score system ibr having seqnells 'llae mortality rate were , %. the continuous blood gas monitor, pasatrend (biomedical sensors, ltd., high wycombe, bucks, england) has the capability of measuring ph, pco , and po via an indwelling optical absorption optodelclark electrode sensor that is placed through an intra-arterial catheter. we evaluated the accuracy of the sensor in radial and femoral locations in critically ill pediatric patients. methods: the simultaneous values of ph, pcoz, and po recorded from the paratrend monitor were compared to values measured by standard arterial blood gas analyzer (coming , ciba-corning diagnostics, medfield, ma). criteria for the elimination of data points included a core vs. sensor temp. gradient, and sensor pulled back beyond accepted insertion distance. mean time of monitoring per sensor was hours (range . - . hrs). mean time of radial monitoring was hrs (range . - . hrs) and of femoral monitoring was . hrs (range . - . hrs.). linear regression and bland-altman analysis for bias and precision for each parameter were calculated. results: a total of patients (age range weeks to years) had paired samples of ph, pens, and poz made by the sensor and blood g&s analyzer. the range of measurements were ph . - . , pco, . -i . t(n r, and po - torr. the paratrend monitor demonstrated accuracy that is comparable to the accepted standard of blood gas analysis in a group of critically ill pediatric patients manifesting wide variation in ph, pen , and poz..this technique appears m be very useful especially in the extreme values of the parameters measured. funding provided by biomedical sensors. understanding of pulse oximetry d.semple, l.e.wilson. royal hospital for sick children, edinburgh, eh lf, scotland, uk. pulse oximetry is a useful, non-invasive monitor, routinely used on the itu and increasingly often on the general wards. we used a questionnaire incorporating questions on the theory and clinical uses of the pulse oximeter to assess understanding of pulse oximetry in medical and paramedical staff doctors indicated grade, speciality, pulse oximetry tuition and neonatology experience. doctors, itu nurses, t medical students and physiotherapists completed the questionnaire. some confusion existed between the principles of pulse oximetry and transcutaneous oxygen measurement. wide variations in the lowest acceptable saturation in fit children were seen ( - %), with around % of respondents in all groups accepting values of % or less. some potentially serious mistakes were made in the evaluation of oxygen saturations in the clinical scenarios. there were widespread variations in correct responses at all grades of medical staffing. nurses scored well on more clinically-orientated questions but relatively poorly on theory. only % of doctors (mostly senior grades) had received tuition in putse oximetry. neonatology rotations appeared to confer little additional knowledge on pulse oximetry. few doctors and nurses receive tuition in the use of pulse oximetry a significant proportion of nurses and doctors, of all grades, exhibited a lack o{" understanding of the principles of pulse oximetry. this may result in unsafe use of the equipment and put patients at risk. one can see from the table that blood composition in uv and ua differens in some characteristics, and similar in sgp magnitude. venous-asterlal gradients "gas functiomals" between uv and ua represent the measure of difference in this characteristics. the gradient cari be positive, zero -order or negative and change both in value and in sign but not reach apo (positive) and apco (negative) in absolute significance.minimization of "gas functionals" deviations atom the zero is achieved due to"mutual replacement acts" between po and pco in uv and ua blood. we suggest that presented tests can be useful in full evaluation of gas exchange in newborns. (pap) in the context of pulmonary hypertension is oft desired but rarely achieved. inhaled nitric oxide (no) has been shown to produce this desirable effect, but is relatively difficult to administer or monitor. we wondered whether np, chemicaily related to no but more stable in solution, would produce similar physiologic effects when administered in the convenient modality of nebulization. methods: piglets were anesthetized, mechanically ventilated, and surgically instrumented. systemic blood pressure (bp), pap, and cardiac output (co) were monitored continuously. after postoperative stabilization, . % nac} nebulization was begun, and pulmonary hypertensiorr was induced by reducing fio from . to . . the piglets were monitored for minutes during this hypoxic phase, next, without altering fio or ventilator settings, np ( mg/ml, dissolved in . % nacl, flow ipm) was substitued for . % nacl in the nebulizer circuit. np was nebulized for mins. results: during hypoxia, pao fell from to mm hg. pap rose during hypoxia from to torr (p< . ). ,^fhile bp and co did not change significantly. pap fell during nebulized np in each piglet, (mean apap = to torr; p< . ; mean reduction of hypoxia-induced rise in pap = %; range: to %; p < . ). pvr/svr fell by % during np nebulization (p< . ), while bp and co did not fall significantly ( to tort; to mllkg-min), the reduction in pap began within minutes of the onset of nebulized np, and appeared to reach a plateau by minutes. no tachyphylaxis to nebulized np was noted. nebulized np did not significantly affect pap, bp, or co under normoxic conditions. conclusions: ) like no, np selectively reduced hypoxia-induced pulmonary hypertension without altering systemic bp, ) unlike no, np can be administered by nebulizer, a technique familiar to virtually all health-care providers, and potentially adaptable to both intubated and non-intubated patients. } nebulized np may be beneficial in clinical contexts where inhaled no is impractical. dang phuong kiet and nguyen xuan thu examining cases of purulent pericarditis with various clinical forms treated by surgery, the authors drew the following experiences for their diagnosis. t. clinical factors. purulent pericarditis appeared like a cardiac tamponade in a septicemia due to staphylococci with dassieal symptoms: severe dyspnea, tachycardia, faint heartsound, big liver, prominent cervical vein ; rentgenography of the chest showing enlargement of the cardiac silhouette, a diminution of ventricular pulsations, ~i clear lung field. by an emergency operation, ml of diluted blood were drained. purulent pericarditis and pleural effusion appeared at the same time but at first tile symptoms of purulent pericarditis were masked by the predominant symptoms of plearal efihsion. after the pleura was drained, its pus was no more, the general state was relatively stabilized but there still were big liver, dyspnea, enlargement of the cardiac silhouette while central venous pressure increased. purulent pericarditis appeared late. in the first stage (about weeks) there was no suspected sign. later on gradually appeared such symptoms as dyspnea (during serum transfusion for instance). central veinous pressure also raised. the heart chest diametre increased at first (up to - %) then decreased (down to below % ) but the liver kept on swelling together with the particular changes of electroeaediegramme. now the pericardium had no more pus but get fibrous (up to ram) thus constricting the heart and its main arteries ike pick syndrome). . diagnostic values of electrocardiograms : common signs of ecg related of these purulent pericarditis were: a diminution of voltage, a widespread elevation of the st segment, the tf wave flattened and inverted. however, what should be stressed was : the diagnostic values of an electrocardiogram for purulent pericarditis was mainly in the dynamics of their signs: in the first week, the voltage diminished corresponding to a pericardium containing pus, while the st segment went up then seemed parallel to the fibrosis of the epicardium, the liver swelled, the central velnous pressure increased, the heart/chest dimension ratio decreased, the st segment went down, the t wave became more flat and inverted. between and neonates, aged - days (median ), weight , - kg (median , ) with critical valvar pulmonary stenosis were scheduled for balloon dilation (psvp), children ( %) were on pge and ( %) needed mechanical ventilation. after stepwise dilation a final balloon : pulmonary valve (pav) ratio of % ( - ) was achieved, there was a significant correlation (p< , ) between an adequately sized balloon and freedom of reintervention. two valves could not be passed, four neonates underwent surgical procedures (brock n = , commissurotomy n = ), two children ( %) died of sepsis. / patients ( %) were successfully palliated by psvp in the first month of life. the rv : systemic pressure value fell from % ( - ) to % ( - ), complications included transient dysrhythmias, transient hypoxia, vessel occlusions;- right ventricular outflow tract perforation. in / patients follow up data is available. the residual systolic peak doppler gradient over the pav on the last out patient visit ( - months after psvp) was - mmhg (median ). four children needed repea.ted psvp to months after the initial intervention. conclusion: psvp of critically ill newborns is possible. the risk of mortality is relatively low. psvp in neonates with an adequately sized balloon is a challenging alternative to surgical treatment. post hypoxic-ischemic (hi) reperfusion induces the formation of non protein bound iron (npbi), leading to production of the reactive hydroxyl radical. it was investigated if the ironchelator deferoxamine (dfo) could reduce free radical production and improve neonatal myocardial performance after hi. severe hi was produced in newborn lambs and changes from pre-hl values were measured at , and min post-hi for (mean) aortic pressure (mean pao), cardiac output (co) and stroke work (sw). left ventricular (lv) contractility and co were assessed by measuring lv pressure (tip-manometer) and volume (conductance catheter), using inferior caval vein occlusion to obtain slope (ees) and intercept of the end systolic pv relationship (v ). npbi, reduced and oxidized vitamine c ratio (vcred/ox) and lipid peroxidation (mda) were measured from sinus coronarius blood. lambs received dfo ( mg/kg i.v.) immediately post-hi, control lambs (cont) received a placebo. results: mean pao was stable, co and sw decreased up to and % respectively in cont as compared to pre-hi. in both dfo-groups co and sw remained within the normal range. ees and v decreased in all groups post hi, but did not differ between groups. npbi and mda were higher at min post hi (p<o. ), vcred/ox was lower at min post-hi (p<o.o ) in cont as compared to dfo-group, indicating more oxidative stress in cont. conclusions: dfo reduced the oxidative stress of the heart and prevented co and sw to drop, suggesting a positive effect of iron chelation on the myocardium after h{. from we published reports with analysis of performance of the heart as a whole organ.while analysing the heart performance as a whole, we recognize three block in it located intrapericardially: l."atrial"block -left (la) and rigth (ra) atriums; ."aorta-pulmonary" block-aorta 'bulb (a) and pulmonary artery(pa); .ventricular "three-chambered" block (vb) consisting of: -left (lv) and right (rv) myocardial chambers, both frith blood outflow into "aorta-pulmonary" block vessels, and -spongy (venous) myocardial chamber with the blood outflow through coronary sinus (cs) and thebesiau vein (tv) into "atrial" block. the following conceps are introduced for vb functions assessment "common" systole and "common" diastole of "three-chambered" vb. the process of normal "common" vb systole: -begins with blood ejection from vb spongy chamber into the "atrial" block; -continues with blood outflow from rv and lv into "aorta-pulmonary" block wi~ venous minimums -x-coiiapses -~btmation iu "a~riai" block; -completes with "three-chambered" vb general emptying. at this period the following blood volumes are transferring: -two-from rv and lv(their stroke volumes)into"aor~o-pulmonary"block; -two-from "spongy" chamber .into "atrial" block; -two-from systemic and pulmonary veins into "atrial" block during the process of so called "systolic" membrane suction (at pulling atrio-ventricular valves into rv and lv chambers as blood ejects out of them). it appears to be the regulation of blood inflow to "atrial" block by blond outflow from "three-chambered" vb into "aorto-pulmonary" block. objective: to evaluate the efficacy and complications of transpyloric enteral nutrition(ten) in critically ill children patients and methods~ from june to january children (i boys and girls), aged from days to years (mean l. ± . years) were treated with ten. patients were included after cardiac surgery, with acute respiratory failure, and after cerebral surgery. the indication of ten was mechanical ventilation in patients and failure of nasogastric nutrition in patient. children ( %) had previously received parenteral nutrition. and i fg enteral tubes was inserted into duodenus through nasogastric intubation en patients and by endoscopy in patients. rx and ph determination were used as methods to control tube situation. children received adapted formula, caseine hidrolisate, and enteral formulas. (in patients the nutrition formula was changed during ten). patients were supported with mechanical ventilation during ten, received midazolamperfussion(range to mcg/kg/min), fentanyl (i - . mcg/kg/h), and vecuronium ( . - . mg/kg/h). resulte: ten was used during to days (mean . ± . days). mean maximmnvolume ad~iniateredwas ± ml/kg/day (range ) .patients with midazolam, fentanyl and vecuronitml tolerated ten similar than children without sedatives. complications were diarrhoea patient, abdominal distension and/or important gastric fed residuals patients. pulmonary aspiration or respiratory complications were no registered. ten was ended in one patient due to diarrhoea, in due to change to oral or nasogastric nutrition, children continue yet with ten and was discharged of picuwith ten. conolusion: ten is an useful method of nutritional support in critically ill children with mechanical ventilation and/or nasogastric intolerance. introduction: the enteral nutritional support of the critically ill child may reduce the morbidity and mortality by attenuating, the hypermetabolic and catabolic response, decreasing the gut translocation and the septic complications, improving the bowel mucosa integrity and the wound healing. the aim of this study was to show the safety and tolerance of en. methods: we enrolled consecutive patients admitted to our unit from may to december , mean age . years (range imonth to i years). the prism, mechanical ventilation, inotropic use, opiates and other drugs were recorded. the en was delivered by continuous infusion across a polyuretane tube.we kept the patients head elevated °, and we used cisapride routinely. the gap betweeen admission and the en beginning, average time to meet the nutritional objective, en duration, selected formula, patients outcome and complications were recorded. results: prism groups were - = patients; - = ; - = ; - = ; - = . two patients with mof (multiorgan failure) died. % needed mechanical ventilation.the average time elapsed from picu admission to initiation of en was . days (range to ) and the average duration of the en was . days (range to t ). the average time to meet the nutritional objective was days (range to ). the selected formula were: lactose free infant formula in patients, elemental diet in , pediasure in and jevity in . we recorded vomiting in patients, diarrhea in and constipation in . none of them forced the en suspension. we didn't recorded any case of ~spiration or pneumonia. we found no relation between drugs, selected formula and complications. we think that en may be a safe and well tolerated procedure at the picu setting. generation of free radicals in iipid emulsions used in parenterai nutrition (pn) has been described recently. this seems to be due to high polyunsaturated fatty acid content. we studied lipoperoxidation status and antioxidant parameters presurgically and through the postoperative period ( days) in a group of twelve children (ranging from months to years of age), who underwent heart surgery and received nutritional support with pn. malondiaidehyde (mda), an end product of lipid peroxidation was used as a marker of oxidative stress. it was determined by the yagi spectrofluorometric method. antioxidant activity was measured with an assay based on the inhibition of spontaneous autooxidation of a brain homogenate, and vitamin e in serum by the technique of hansen and warick. erythrocyte mda release fonowing incubation in hzo in vitro was used as a functional measure of tissue vitamin e levels. data were compared using one-way variance analysis. there was not significant differences in the plasma mda production among the values obtained before surgery ( :t: . nmol/ml), postoperative pre-pn ( . +_ . nmol/ml) and through the course of pn ( . : . nmol/ml). levels of vitamin e previous to surgery were , : . #g/ml and decreased to . _+ . #g/ml at hours post-surgery before starting pn. while receiving pn, concentrations of vitamin e increased progressively up to + . l #g/ml (p = . ). pre-surgicai plasma antioxidaut activity values ( :i: %) dimiuished in the first postoperative day ( _+ . %) and then showed a clear increasing tendency, directly correlated with that observed in vitamin e levels. the measurements of the maximal percentage of mda release of erythrocytes in vitro, showed an inverse relationship with plasma vitamin e levels and with the plasma antioxidant capacity: preoperative . + . % and postoperative descending from . + % to _+ . %. our results indicate that during surgery and within hours postsurgery, a decline in antioxidant defenses occurs, in the postoperative period, while patients are on pn and taldng into account our obtained data: the unaltered mda values, the rise of plasma vitamin e levels, the recovery of both functional erythrocyte membrane antioxidant protection and the plasma antioxidant activity, they do reflect that during the intravenous administration of lipid infusions, oxidative damage does not occur, probably due to the addition of vitamin e to pn solutions in order to avoid autooxidation of lipid emulsions. garnitine is one of the essential nutrient in the diet of newborn infants. mother's milk represents the natural eamitine source for the newborn infants. we studied enteral earnitine intake in premature infants eutrophic (eu) and hypotrophic (hy), fed with mothers milk trough consecutive days-from fifth to tenth day of life. mean gestational age was (range - ) weeks for eu and (range - ) weeks for hy. birth weight was ranged - g for eu and - g for hy (p < , ). breast milk carnitine concentration was , i.tmol/i in mothers milk delivered eutrophic babies, and singnificant higher mean coenetration , l.tmol/i, of hypotrophic premature infants (p< , ). breast milk earnitine concentration was ranged between , - , ~moi,'l, and daily carnitine excretion was between , - , p.mol/i, mean , +- , i p.molll. the daily mean carnitine intake was from - , mgkg/d, in eutrophic and , - , mg/kg/d, in hypotrophic premature infants, in milk volumene intake from - mllkgld., the results of this study suggest that premature infants should be fed with own mothers mitk in eady neonatal pedod in attempt to prevent camitine deficiency. keto-acids and parenteral lipid admlnistration. castorina m., antuzzi d., ricci r., rendeli c., polidori g. pediatric intensive care unit -catholic university -roma (italy). some metabolic studies have suggested that the administration of mediumchain tltgticerides (mct) might induce a marked increase in ketone body concentrations; the aim of this study is to evaluate the effective ketogenetic risk of infusing mct emulsions in total parenteral nutrition (tpn). two groups of seriously infected children were examined: a- septic infants were given to tpn with a % of long-chain tryglicerides ( lct). b- septic infants, in wich the lipid source in tpn consisted in a - mixture of lct and mct. the children in the different groups showed similar severity and therapeutic scores (prism, tiss, ~, f~ , f~ ); the lipid intake was the same, corresponding to - . g, ckg bodyweight/day. in all patients a sample of urine was taken six times a day for the whole time of tpn the urine samples were screened by the diphenylhydrazone test, and the ketoacids excretion was confirmed by a chromatography. the urinary excretion of -keto-acids equivalent to p-ohphenyl-pymvate (mcg/ml urine) is summarized in the no significant increases in frequence and/or in severity of acid-base disturbances were found in all studied patients in consequence of the lipid infusion. the patients of b-group showed a lower excretion of -ketoacids. the c~-keto-acids excretion was ever unsignificant and seemed to be correlated with the illness severity more than with the lenght of the tryglicerides chain. this observations let us suppose that the mct, at employed doses, can be safely administred also in childen with metabolic acidosis and/or serious illness. reye syndrome cayetano heredia hospital, lima, peru five patients with reye syndrome were studied; included were those diagnosed from january to march and treated at cayetano heredia hospital. the age of presentation varied from z. to months. the syndrome occurred more frequently in males ( / ); the time of illness at the presentation varied from to lo days, and the following features were found: fever ( / ), akeration in mental status ( / ), seizures ( / ), gastrointestinal illnesses (diarrhea) ( / ), and respiratory insufficiency ( / ) --in this case ventilator)-support was needed, in all cases hepatomegaly, intracranial hypertension, hypokalemia hyponatremia, metabolic acidosis, hyperammonemia and elevation of hepatic enzymes were found. coagulation blood tests were abnormal in three patients. cerebrospinal fluid (csf) showed hypocellularity in all cases (less than cells/ram ). the cultives were negative, and the final diagnosis was confirmed by hepatic biopsy. no deaths were due to reye syndrome. a contribuhon to the study of reye's syndrome the aulhors analysed records of patients meeting all the clinical, biochemical and anatomic criteria put forward by hutrealoch~ and samaha ( ) who were ireated at the emergency and resusdlation depammlt tithe ipch in years. the average age of the children was years (the ~umgest monks and the driest year~ most of lhon ( / ) came from lhe countryside to lhe lmfia~ willfin hours of file oulbreak. a few days previously the patients w¢~ld have fever (some of ahem wilh diarrhea or cough) ,,rod vomit then rapidly fidl into coma and c~nvuksien. they ~me to the imtia~ with the signs of typical increased inlracranial pressure ( stages - according to lovejiy for most cases) but the liver was unllkely big. the main biocheafical dmnge of the blood was acute hepatic thilure -the bllod glucose decreased : (ha the aver~ , n~% ( ) ~ not measured in five cases (glucose a"aces). -the blood ammonia ino~ased riven to microg/dl fin lhe average , n = ) -the percentage of p~in was low, in the average , % (n-- ), % at the lowest (a case ofmekaa lasling five days was ctwed with vitamin k). -got and gpt enzymes increased - times (n= ) besides, tht~re was decompcmated addt~is with lhe average valnes ph = . ; pcoz = ~ mmhg and eli = - ~ ~, (n~). the charadaislic dumge in the ¢~'ebrospinal fluid was a low glucose tx~acenwalien h the average of k mg/dl ( cases of glucose it'aces) ; meanwhile protein decreased in the average of mg/dl ( cases below mg/dl). besides ~here was no inflammatory lesion ~tion) : very serious brain oedona and fatty degeneration of live~ scatteredly or parllally.microso~ically (biopsy and necropsy) in file brain appeared bright space around blood arteries and glioma extended v'lrdmw -robin space, with no inflammatory reaction. liver.-the sa~dure was intact there was no " "mtlammal~s ' cell, the kupffer cells did not show hyperplasia but show a heterogenous deg~nerafion~eart: also showed a fatty degencralion in some areas of the myocard eellkidney: the ihtty degenerati~l scattetedly in the tubular cell. pano~as:fatty degeneration scattetedly in file pancreatic cell. two cases of liver biopsy for lhe rid lime (check before leaving file inslitute) found that fatty degeneration was r~tta~ nearty ff~pletely. the exact muse remained unknown. objectives: to analyse whether there exists serum and urine electrolyte disorder in children with respiratory failure, methods: we have made prospective study of children in our icu during a month period, electrolyte concentrations were measured in serum and urine collected during hours (sodium-na, potassium k, chloride-ci, calcium-ca, magnesium-mg and phosphorus-p). results: average values in serum were: na . +/- , (rv: - ) mmol/i, k . +/- . ( . - . )mmol/i), cl . +/- . ( - ) mmol/l, ca .t +/- . ( . . )mm /i), mg . +/- . ( . - . )mmol/i. average electrolyte levels in hours urine were: na . ~/~ . ( - )mmol/day. k . +/- . ( - )mmol/day, ci . +/- . ( - )mmol/day, ca . +/- . ( . - . )mmol/day and p . +/- . ( . - )mmol/day. conclusions: average serum ci and ca levels were decreased in children with respiratory failure. in urine, average k, ci, ca and mg levels were decreased and urine p concentration was increased. we concluded that serum and urine electrolite disbalance may be expected in children with respiratory failure. the nurse is going to kill me! (icu syndrome) anita duvndam ~, sonia v.d,sluis ~dpt. of pediatrics, div. pediatric intensive care, sophia children's hospital, rotterdam dpt. of pediatrics, div. pediatric tntensive care, juliana children's hospital, the hague. content description: this presentation will provide the critical nurse with background information concerning the identification, the prevention and management of the critical ill child who has developed the icu syndrome. the results of a questionnaire concerning the occurrence of icu syndrome on a picu will be presented. behavioral objectives: at the end of this session the participant will be able to: . describe four clinical symptoms of the tcu syndrome, . identify major sources of picu environmental stress, . discuss nursing's unique role in helping the child to cope with the icu syndrome, . discuss nursing's unique role in preventing icu syndrome. content outline: the icu syndrome is a situation in which the individual is not able to deal with changes in observation and interpretation of both quantity and of patterns of sensory perceptions. in other words the borders between the inner and outer world becomes unclear for the person. the exact incidence of the icu syndrome in the critical care setting is unknown, we have limited knowledge of the occurrence of the icu syndrome in critical ill children. yet critical ill children in our hospitals sometimes show the symptoms of icu syndromes. to be able to identify the occurrence of icu syndrome we developed a questionnaire. the thesis of the questionnaire was: does the icu syndrome occur in critical ill children in the age between three and ten, who have been intubated and/or ventilated in a picu? eighteen questionnaires have been send out to parents of critical ill children in two hospitals. the response was percent. conclusions: . most of the children were anxious (n= ), showed regression (n= ) or had sleeping problems (n-lo) during the stay on the picu. . children showed the same problems after discharge. . there is no relationship between environmental factors and symptoms of the tcu syndrome during the stay. . there is no relationship between preexistential behavior and symptoms of the icu syndrome during the stay. because the lack of a scientific definition for the icu syndrome in children and good criteria for diagnosis, we were not able to get an answer to our thesis. more research is needed. continuous veno venous haemofiltration (cvvh) was adopted as a first line renal replacement therapy in our paediatric intensive care unit (picu) some three years ago. ~/he process of introduction and development of cvvh proved to be an exciting challenge for nurses as indeed it was for the whole multidisciplinary team involved. we have successfully used cvvh in the treatment of over infants and children, weighing between - kg. the range of conditions treated is ever increasing. to date we have not only used cvvh for patients in renal failure and fluid overload, but also to gain biochemical control in tumour lysis syndrome-and metabolic disorders. other distinct patient benefits in comparison with more conventional means of renal replacement therapies are that, it is a continuous controlled treatment being extremely effective in creating 'space' for nutrition, which is especially important in the fluid restricted, catabolic patient. of paramount importance in providing this level of service is the education and training necessary to impart the skills and knowledge for nurses to become expert practitioners in this field. we now have a teem of highly advanced practitioners who have developed their nursing skills to provide even more holistic care for their patients. this group are embracing new challenges and responding positively to the developing service whilst expanding their knowledge base. this paper will discuss the advantages and disadvantages of cvvh as we have experienced, relating i t to the wide variety of patients we have treated. we wish to share how cvvh has become an accepted role of the picu nurse and how the service has been successfully implemented. integrated care pathways (icp's) define the optimum course of events in the care of a patient with a specific condition, within a set timescale. aims and methods: icp's and case management (cm) were introduced to evaluate and improve clinical practice. icp's were developed for patients undergoing surgery for atrial septal defect (asd) ventricular septal defect (vsd) and fallots tetralogy. they were based on the median experiences of the last patients. patients have been managed using icp's. results: analysis of variation from the icp's shows a reduction in the following potentially avoidable causes of variation: delay in extubation has been reduced from % to %, and patients ( %) were extubated earlier than the median. prolonged stay on the intensive care unit (icu) has decreased from % to %, and patients ( %) were discharged to the ward a day earlier than the median. the number of patients receiving inadequate post operative analgesia has decreased from % to %. delayed feeding after operation has been reduced from % to %. unavoidable delays in extubation and discharge from icu occurred in patients ( %) because of haemodynamic instability" or lung problems. cm utilising individualised pathways for these patients has reduced variation in care which can improve patient outcomes. pathways have been developed for other conditions and it is anticipated that approximately, % of patients will be treated using an icp revision of icp's results in continuous evaluation and improvement of the care provided, conclusions: the use of icp's and cm has improved patient care and decreased avoidable delays and variations. the future development of other icp's, combined with a case managed model for selected patients, is seen as a viable method of continuously improving patient care. this paper is a retrospective audit of children who received continuous veno venous haemofiltration (cwh) whilst on the paediatrie intensive care unit (picu), data was collected over a month period from may to january . the girls and boys were aged from day to ½ years (median ½ years) and weighed between , and kg (median . kg). length of admission to picu was to days (median days). sepsis syndrome was diagnosed in cases: of these had bowel necrosis and meningoceccal disease. eight patients had an underlying haematological, oncolngical or immune disorder. the remaining children had inborn errors of metabolism ( ), nephrotic syndrome ( ), or cardiac failure ( ). cvvh was instituted for a variety of reasons. muttiorgan dysfunction was present in % of patients, % had acute renal failure, . % tumour lysis syndrome, . % uncontrollable metabolic acidosis with hyperammoneemia and % required fluid management. treatment was continued for between hours and days (median ½ days). haemofiltration was successful in achieving its desired effect in all except one patient. . % of children with haematological, ontological or immune disorders died despite successful haemofiltration. survival was higher in cases of septicaemia ( . %), nephrotic syndrome ( %) and errors of metabolism ( %). overall mortality was . %. this was attributed to the severity of the underlying disease process rather than the effectiveness of cvvh as a renal replacement therapy. asynchronous defibrillation and synchronized cardioversion deliver direct currents of high amplitude through the chest, to stop ventricular fibrillation or to convert life-threatening arrhythmias. since the human body is partially conductant, it should be possible that after a brief delay of time, a derivation of this monophasic defibrillation pulse is measurable in regions of the defibrillated body, other than the traject between anodal ("sternum") and cathodai ("ape~;") paddles. one could also estimate that health care personnel in the immediate environment of defibrillatoty shocks, are always at risk to possible electric injury. accidents might occur when health care personnel do not stand clear from the patient during firing and create an additional electric path from this patient through their own body. most likely, the nonisolated parts creating a transversal eiectric path, will be the hands of the caretaker. since defibrillation generates touch voltages up to v and - a in ved, short delay's ( to millisec), the total body resistance during skin to skin or skin to paddle contact, is calculated to be as [ow as ohm (percentile tank for the entire population). an experimental protocol was developed to evaluate the conducted currents during defibrillation. mature pigs with a weight of up to kg. were used as animal models. the:,, had barbiturate anaesthesia, inotropic support with dobutamine at l micmgrams/kg bodyweight and all had a sinasat rhythm at the begining of the test-rounds. synchronized defibrillation at j (approx. . j/kg) and asynchronized -at j (whenever ventricular fibrillation or ventricular tachycardia occurred), were attempted, through latero-lateral placed and firmly pressed defibrillation paddles and/or adhesive multi-function electrodes. gel pads were choosen as contactmedium to cross the skinpaddle barrier. subdermal electro-myography needle electrodes were put at different parts and regions of the pig's body, but not between the paddles. these electrodes were coupled to a resistance device of ohm and a measuring computer. we measured monophasic and low current pulses up to , a during the defibrillation burst. thus conducted currents are high enough to produce accidental electric shocks when additional electric paths are created by the caretaker. "llaese are usually harmless, but in some "worst case" (wet or transpiring hands, rings,...) or in association with defectuous equipment, peak currents might be harmfull, and can produce pain, bums, apnae or cardiac (transient or persistant) arrhythmias. maria skogbv. karin mellgren, lars-g ran friberg, g sta mellgren, hans wadenvik. g teborg, sweden. bleeding complications in extracorporeal circulation is partly due to perfusion-induced platelet dysfunction. the aim of this study was to evaluate an in vitro model for investigation of platelet function parameters in an extracorporeat system. study: two complete extracorporeal life support systems were perfused with fresh heparinized human blood for hours. piatetet membrane glycoprotein changes, platelet granule release and platelet count were followed. eight paired experiments were performed. one of the circuits was perfused by a roller pump (polystan) and the other by a centrifugal pump (biomecicus), other components were identical. results: a continuous increase in glycoprotein (gp) ib-negative platelets was seen in both circuits. a marked increase of plasma beta-thromboglobulin concentration and a decrease of the intracellular pool of serotonin was observed, indicating a marked release of alpha as well as of dense granules. the plasma concentration of glycocalioin increased in parallel with a reduced platelet surface expression of gpib, suggesting that the loss of gpib is caused by proteolysis rather than by a downregulation of this receptor protein. conclusion: hours of ecls perfusion induces pronounced platelet degranutation and causes changes of important membrane receptors. this is in accordance with clinical studies, suggesting that our in vitro model does mirror the platelet exhaustion observed in a clinical reality. no significant difference was observed between the two pumps. the purpose of this study was to examine signs of distress exhibited by several patients following the discontinuation of opioids and benzodiazepines (o & b) in a -bed pediatric intensive care unit. the authors compiled a list of all cases of possible withdrawal reactions reported by nurses in the study setting over a one-year period. five cases were selected for study in terms of their wide diversity of relevant circumstances. the cases were examined through a retrospective chart review. data pertaining to analgesic and sedative administration, along with nurses' reports of behavioral distress, were transcribed and coded. a remarkable pattern of behavioral distress was clearly associated with discontinuation of o & b. cessation of benzodiazepines was associated with severe distress. these reactions were characterized by various combinations of crying, irritability, tremors, grimacing, gagging, vomiting, or feeding problems. some of these persisted in spite of large amounts of bolus drug administration. these signs were manifested for to days following cessation of o & b. these findings demonstrate that the rapid weaning of o & b infusions, sometimes following short-term therapy, can cause severe withdrawal reactions. the particular course that a specific patient will follow will likely be modulated by underlying manifestations of "icu psychosis" and unresolved pain and emotional distress. hermana tezano mt, pilaf orive j, latorre garcia j, lizarraga azparren ma, lopez bayon j ucip hospital de cruces. bilbao. spain a female child, one year old, was referred to our unit from another hospital because she had ischemic syntomsjn her right forearm wich started three days before. she had ~i downs syndrome and fallot's tetralogy with a systemic-pulmonary by-pass. nine days before the admission in our hospital she was undergone to a cardiac catheterization by arterial and venous femoral punctures with no incidences. on the admission to the picu her forearm was cold and pale with absence of cubital and radial pulses and slow capilary filling. treatment with heparine was started unsucessfully in the firsts hours, so uroquinase was added that later was changed to rtpa plus brachial plexus blockade. by the time me arterial tlux became more and more evident (doppi~) il bccuute aiat) evident a regional aedema witch made necessary a fasciectomy &the wrist. she also developped necrotic delimitted areas that included her first and fifth fingers. she was discharged from the picu after days and a week later she went to the operating room where an amputation of the distal phalange of the fifth finger was made. the etiolgy of this ischemic picture can't be attributed to the catheterization itself, but probably it should be due to some attempts in arterial puncture in its course, attempts that could be guess by the little marks noticed at the elbow flexure when she was admitted. long maintenance of cardiovascular funtion by assisted ventricular device with membrane oxigenator hermana tezanos mt, pilar orive j. latorre garcia j, lizarraga azparren ma lopez bay n j. ucip. hospital de cruces. bilbao. spain a little girl of three and a half years came to the intensive care unit from the operating room. affected of great vessels transposition with a pulmona~' banding corrected vith rastelli technique, it became impossible to discharge her from the by-pass circulation. it was assumed that this factt was due to a transient myocardial disfunction dfter the surgeon x~ent through the technique and found no wrong step in it. at the picu admission she had an ejection fraction belox~ % (echncardiografy), and was manteined on veutricular assistance with a circuit consisting ofa plate's membrane oxigenator, a bio-medicus pump and pvc rubber tubes, with monitoring of pulmonary', right and left atrial pressures. initially she needed a ventncular support of . l/min with dopamine. dobutamine and adrenaline; gradually the ejection fraction rose to % aliowing a decrease in the mechanical and inotropic support. the organic function ,.'.-as preserved but x-ray of the thorax showed images of pulmonary aedema with an increase in the needs until a fi of . . even though she was placed in a transplant program, she was remouved when the ejection fraction rose to % on the lth da of the evolution. there were no signs of infection (profilactic coverage). on the fifhteen postsurgery day. with a good cardiac sound and an ejection fraction of at least %. it was considered the withdrawal of the ventficular support, but unsucessfully despite the increase ofinotropic drugs, so she died. we think that our patient is a good example of the posibiti~ to mantain x~ith ecmo during a prolonged period of time a potential transplant receiver without major complicatios. joan wierema; ma )an mourik. sophia children's hospital, department of pediatric surger,j, rotterdam, the netherlands. the success of an ecmo program is heavily determined by the organizational structure and the daily availability of both well trained nurses and physicians. until now there is no general guideline to determine the optimal training schedule to set up an ecmo program. objective: to evaluate the set-up of an ecmo program in an area without direct availability of perfusionists of cardiothoracic surgeons. description of the progress: during the preparation of the ecmo program which started november , different phases are identified. first phase, acquisition of experience by training abroad of one physician, staff member of the icu, physician acting as a fellow and one icu nurse with theprimary task to serve as an ecmo coordinator and train the nursing start. in the second phase animal experiments were performed by paediatric surgeons, staff physicians, fellows and nurses. third phase, start of the actual ecmo program, priming by one trained nurse and ecmo fellow, daily care of the patient by nurses, icu nurse taking care of the patient related activities, ecmo trained nurse taking care of the circuit. fourth phase, transition of the tasks for priming the system from the ecmo fellow to the ecmo nurse and changing daily care for the ecmo patient now including the circuit by trained icu nurse with special legislation for ecmo. ongoing training of to nurses working for at least half a year in the icu. during an ecmo run direct contact between the ecmo nurse and one of the staff members; patient data: in a year period neonatal ecmo cases were performed with an overall mortality of %, ranging from over % in meconium aspiration to % in congenital diaphragmatic hernia. in other patients pediatric ecmo (age range month - months) mortality was %. conclusions: ecmo can be established without perfusionists or cardio surgical back up once a predetermined training schedule is available, resulting in comparable results with the international ecmo registry both for neonatal as well as for pediatric cases. mechanical ventilation at home makes normal development of the child with chronic respiratory failure possible. the parents must be encouraged to accept the treatment at home; therefore, they should be enabled to take care of their children all by themselves and the continuous professional support has to be offered to them. it must be stressed that the nurse is the link between the diseased child and his family introducing them into the process of the medical care at home. all the equipment needed for the mechanical ventilation of the child at home (ventilator, suction device, pulse oxymeter, oxygen tanks) has to be provided before the child is discharged. it is paid by the national insurance company. the maintainance service workers will make the necessary installations available and they will renew oxygen and compressed air weekly. the ventilation assembly must not interfere with the childs activities. the related dispensary and nursing service should be notified of the child's condition and the list of the required material (suction tubes, cannulas, desinfectants etc.) has to be made. our experience is so far -from the nursing and medical point of view -satisfactory, however the social status of the parents needs further regulations, omphalocele. mourik m, sophia children's hospital, department of pediatric surgery, rotterdam, the netherlands. in patients with (giant) omphalocde operative closure is impossible due to the lack of intra-abdominal space and a variable degree of pulmonary hypoplasia. consequently conservative treatment allowing epithelialization is the treatment of choice with a high risk of infection and/or sepsis due to a sometimes very long stay in the icu. this conservative treatment consists of daily application of an antibiotic containing powder on the cele which is covered by sterile gauzes. furthermore the enteral intake is started as soon possible. objective: to evaluate whether this treatment renders a high risk for serious infections. patient characteristics: in a year period patients with a giant omphalocele were admitted; mean birth weight g ( - g) mean gestational age . ( - weeks). overall mortality ( %). patients had to be ventilated for a median duration of t days ( , - ). results: patients were discharged at the mean of days following birth ( - ) following complete epithelialization of the omphalocele. following the initial stabilisation period parents were involved in daily care of all patients even during artificial ventialation. enteral intake was started at a median of days ( - ). colonization of the omphalocele was observed within - days in all patients. although infectious periods were observed at regular intervals, sepsis was the primarily cause of death in only of the patients who died, in conclusion: nursing care to prevent sepsis in patients with (giant) omphalocele is feasible for a long period of time and can be performed with simple measures, since june , we have been using nasal cpap in the treatment of respiratory disorders in newborn infants (severe apnea syndrom, tachypnea, hyaline membrane disease). in newborns presenting hyaline membrane disease, we have used cpap and administered surfactant therapy to premature babies out of . clinical data were : mean ga : . + weeks. mean bw : + g. mean administration time was hours. before administration, mean fio was . + . , mean pao . + . kpa and mean a/ao ratio . . all babies were intubated for administration of surfactant (curosurf) and were extubated after half an hour to hours after administration. this treatment failed for seven babies and they were ventilated by oscillation ventilation ; all babies survived. complications : we have observed pneumothorax in cases and cerebral hemorrage. mean duration time of nasal cpap was hours for the babies without assisted ventilation. nurses in charge of babies with nasal cpap should be aware of neonatal care, of the possibility of surfactant administration and of complications during this type of treatment. therefore nurses should know very well the use of nasal cpap, the monitoring during this treatment, the fixation of the system on the baby, nursing of the babies during this treatment and finally should take care of the baby physical and psychological well being. as a conclusion, nurses in intensive care neonatal units should know the possibility of treatment of rds by nasal cpap and should be aware of baby-nursing. emco in the postcardiotomy infan_t : a simplified circuit and reduced management grillet lsabelle, bosson christa, goelz andrea, helmer pascale, icu nurses, tschaut rudy perfusianist aldo castaneda institute, clinique de genolier, suisse to improve postoperative survival of infants with repaired cardiac tessions but severe residual cardiopnlmonary dysfunction, emco was used in infants, ranging in age from l days to months and in weight from , kg to , kg. diagnosis included tga / intact ventricular septum ( ) (both subiected to rapid arterial switch operation because of unsuitable lv function) and tga +vsd ( ). "['he emco circuit included a sarns roller ump, a medtronic minimax plus hollow fiber oxygenator and tubing ( / - / inch) with bioactive surfaces, an arterial canula fr., venous canulas : right atrial fr, left atrial fr., an air oxygen mixer and a sarns heater. the act was kept between - sec. after the infant was connected to emco by the surgical team and the perfusion technologist, the patients were being cared for and controlled exclusively by the cu nurse assigned to the patient and the physician on call for the icu, pump flows of - ml / kg / mln were targeted to insure an adequate urine output, a brisk capillary fill and physiologic left and right atrial pressures. sodium nitroprusside was used to control systemic hypertension while all other inotropic drugs were discontinued. inspired oxygen fraction on the ventilator was reduced to , at a respiratory rate of - breaths per minute. body temperature was maintened close to normal. when the heart started to eject again, inspired oxygen was increased to about , . the preparation for weaning from emco was done by the icu nurse: including oxygen fraction and ventilator rate. weaning from emcowas coordinated by the medical / surgical team and the perfusion technologist. the duration of emco in the patients ranged from to days. three patients ( %) were saccessflly weaned from emco. one of the three died within hours from neurologic complications, unrelated to the emco. the other patients ( both with tga + vsd ) are long term survivors and are doing well. neither the survivors nor the patients who died bad hemorrhagic complications, despite the fact that of the were placed on emco because of failure to wean from cardiopulmonary bypass. the simplified emco circuit worked reliably throughout this experience and no complications occurred nor could any shortcoming be ascribed to the use of this reduced, cost effective management team. years of praciical experience wiih exiracorporeal membrane oxygenation (echo) -the viewpoint of the nursing siaef monika schindler in a training program was started for the introduction of echo in the kinderklinik of mannheim/germsny. years later ( ) the first european echo patient, a days old newborn baby, ~as treated successfully in our institution. with echo, more treatment modalities ~ere available after failure of conventional therapy in eases of severe lung diseases like meeonium aspiration syndrome, congenital diaphragmatic hernia, sepsis/pneumonia, primary persistent pulmonary hypertension of the newborn and -in infants and children -ards (acquired respiratory distress syndrome) due to multiple underlying illnesses. in the first ards patient, a years old girl, was treated successfully ~ith ecmo in mannheim. until now patients (age: i day - years) were treated with echo in our institution; additional patients were transferred to us from other institutions for therapy with echo, but could be treated ~ieh alternative moda]ities of therapy like improved conventional ventilatory support, high frequency oscillatory ventilation (hfov) and inhaled nieric oxide (no), unexpectedly the more ~ide-spread use of hfov and no -also in other ~ntensive care units -did not lead to a reduction of the echo frequency in our hospital. due to this long ecmo practice, which is helpful in many critical situations, a certain routine came up in the nursing staff of our intensive care units; but ecmo continues to be a maximum strain for all co-workers and implies an high personnel and material/financial-expense. but in our opinion the improved survival rates in severe respiratory failure-( % in neonates and % in infants and children, estimated survival rates under continued conventional management: < %) by the use of echo justifies this expense, even in times of less financial support for public health. • analyse the differences between each urdt. method : ni criteria were defined by the rt~a ped group according to cdc criteria. all data were collected by a nursing and medical team. data vere dealed with epi info software. all u-dections data were validated by an external mvestigatol : patients who stay more than hours in an icu were included over a months period. % were newborns, % infants and , % children. ni were idenlified among sll patients, the overall ni incidence rates was , % and , person day, septicemia was the first cause of ni ( %). staphylococcus epidermidis were isolated in % of septicemia cases. pneumonia was the other main ni ( %) with gram negatwe bacille isolated m % ( % of them beei,ng fseudomonas) accordmg to age, the septicemia mcidence rate varied from , ~., to . %,, catheter/day and pneumonia incidence rate from , %, to , % ventilation/daywith the lowest rate for newborns. : this survey was possible thanks to the collaboration between laboratories, bacteriologist, physicians and nurses, and allowed each concerned unit to work together in~tead of every one in his own field. 'lhe results of this survey bring changes in attlhades and empower the different team work the next step is to analyse the ditferent nurses procedures of indwelling central venous catheter in each unit ar)d implement a ni quatity care. program in all nicu anti picu. v~,~jl~j~'v~y : new born in~ra-v~ nous drugs ~md lheir pr~taration mcounter a lot of risk ~)f utters, due to inadapted conditionn~ng to podia)eric and minimal amount injec~.~d, th~ study t~ed to evaluate degrees of do.~age er~o~ dye tt) dru~ preparaek, n i~ nc,:,~atol~gy and to come out w~th ~ method of dihttion able to reduce risk to minima (errors _< %) at the ~eme t~me, ¢o~,~x-tueaces on cost were studioj methnd~ : amikacine was choosen because this antibiotic is regularly ~,~l in neonatology unit and its dosage is easily used by standardiaud method, amikacine doses ( , mg doses and , mg doses) were prepared" by nurse~ form mg for m) vial. each dose w'a~ diluted to obtain mi volume, tallowing usual ward method, for each dilution, amikacine con<entrati('m and it,s volume was measured and used equipment for preparation wa~ regi~tred. "first s utj(m" were prepared diluting ~t'~ mg amikacine pouder inn ) ml glucnse solution bag (viaflex baxter bag with transfer cap), from tho~e "first solution" doses at mg and doses of ~ rng were prepared, amik~cine coc, cenir,)tmn for each preparabon and their volume were measured, ai,~n ntttl~,ber of seringe were tounted. first soiuhon staeiiity was conrroieo aher one week conservation at + '>c. amjkacine concentration were measured by fluorescence process (tdx abbott) after sample dilurion. on a mg/l sample, tovhnical reliahility show~ > ~ % of result mpmductlon and < % of variation due to dilutions. results : when amikacine injection werv pro.pared from araikacme /) mg for mt vial > % do~ge, ermr~ were found in / cases ; ~ % in ,t ,to cases. if preparation is done from amikacine "~it'st soltltion", les.--concenvr~tcd, it i~ more preci,,,e and only one dosage error ~ % ( , %} is found in eli studied doses. in add)inn to )hal if doses were wep,m-'d from one "first soiatiol~' bag, the cost economy sl~ouid b~" of fr~, and ii dos~$ were prepared tram the same bag the saving mtmey should be o{ i its .cencluslon : .ur survey shows th~t h' ntu)nato|ogy the u~ of a "first sohation which can be kept fi~r one week is enable to reduce dosage erroes and i~ co,~tsavmg, regarding [,v. admimst'rahon method the survey is still on, introduction: so-called vein of galen m~iformations ale rare in~racranial embryologycal anomalies, repl~senti~g tess than of symptomatic intracranied artefiovenoas l~alform~tions. the spontlneous prognosis is ~s~u~lly fatal, because of cardiac frilure due to left-to-right shunt thrq~ugh the fistula. recent developments of new techniques of treatment of the malformation and its cardiac consequence have led to a revolution in the practical approach of children w~th galen malformation. our fukfose is to contribute, with our persoaal series of s newborns and infal~ts admitted in our unit after endov~,scular embolization, to a better management of these children. such a management requ!res a rnultidisciplinary approach. intensive care are required prior to embollzation for patients with cardiac failure or cardiogenic shock and after cmbolization in order to insure cardiac and cerebral hemodyna.mic stabilities. this overlooking suppose for the nursing team to understand: prior to embolization : heart failure and cardiogenic shock. after cmbolization : evaluation of neurological and hemodynamic consequences of this proccdure, without forgetting the nursing and psychologic aspects, in concl'iision, this last ten yerrs, these new approaches give to the patients and their famitiy a good reason to hope a total recovew, in our exl)erience, the global mortality is % aad % of children #j-e neurologically normal after embolizafion, ii ii~ i ~ii i ii i i l i iiii~ i ~i iii i background: venous oxygen saturation (svo z) reflects the residuai oxygen after tissue oxygen extraction and represents the relation between tissue oxygen supply and demand. we studied svo and arterial lactate during progressive isovolemic anemia to assess the relation between svo and tissue hypoxia. subjects: ten - day old anesthetized ventilated piglets sao and svq were measured continuously by a fiberoptic catheter (oximetrix, abbott lab.) in the carotid and pulmonary a~epy tissue hypoxia was confirmed by a reduced vo, and an increase in lactate. conclusion: svo reflects better a reduced dp obtained by progressive anemia surfactant replacement improves gas exchange in early-stage adult respiratory syndrome (ards) [ , ], but not in late-stage ards [ ] . we report the first case of successfull treatment of ards after repeated instillation of surfactant.a ten year old boy, weighing kg, presented with hemorragic shock. biphasic-positive-airways-pressure ventilation was performed (evita ii, dr~ger, germany). he had recieved nine units of packed red blood cells and underwent surgical exeresis of two bleeding gastric ulcus. post-operatively, a cardiac arrest required cardiopulmonary resuscitation for three minutes. hemodynamic status was subsequently stabilised. the chest-radiograph showed infiltrates of both lungs without signs of cardiac failure. on the third day, the patient became severely hypoxic with a pao /fio ratio of . gas exchange was not improved by high ventilator settings. peak inspiratory pressure (pip) and ventilatory rates were cmh~o and breaths/min respectively. inspiratory:expiratory time was : and the positive end expiratory pressure (peep) cmh . after increasing the peep level to cmh , we instilled over minutes, mg/kg of porcine surfactant (curosurf, serene france), in two equal volumes in both main bronchus,the spo~ rose to % within rain, the fie could be reduced to . . twenty four hours later, gas exchange worsened again (pao /fio ratio ). we increased the peep from to cmh , and instilled a second dose of surfactant ( mg/kg). again, fie could be reduced within minutes (spo ; fie . .). the patient was weaned from the ventilator and extubated on the tenth day. follow-up at four month showed normal lung function.we demonstrate improvement in oxygenation after repeated exogenous surfactant administrations. we assume that in early-stage ards, surfactant may potentiate shunt-reducing effect of peep as it has been demonstrated in experimental model of ards [ ] , and allow decrease in fie . in case of secondary deterioration, we think that a second dose of surfactant should be administered. . weg jg, balk ra, tharratt rs, et al. ,lama : : - . . spragg rg, gillard n, pdchman p, et al. chest t : : - . . haslam pl, hughes da, mcnaughton pd. et al. lancet : - . . huang yc, caimulti sp, fawcett ta, et al. jappl physiol : - % (ref) . the aim of this study was to verify these data: patients/~lethods: all pts admitted to our multidisciplinary nicu/picu in were included if they were in respiratory failure recruiting conventional mechanical ventilation (cmv) with peep >_ and 'fig -: % or high-frequency oscillation ventilation (hfo) with mean airway pressure _> t cm h for or more houm. diagnosis, maximal ventilatory parameters, barotrauma, organ/ system failures, mechanism of death and glasgow oulcome scale (gos) and months after study entry were prospectively collected. results: patients were admitted to the unit, o whom required mechanical ventilation for a mean duration of . days. overall mortality was %, patients fulfilled study criteria. survivors had gos , pts with preexisting neurological impairment survived with gos . neonatal diseases included hyaline membrane disease ( ), meconium aspiration syndrome ( ) and cardiovascular surgery ( ), pediatric diseases included bacterial ( ) and viral ( ) pneumonia, aspiration ( ) and cardiovascular surgery beyond the neonatal period ( ). - ) . patients and methods: cefotaxim was used as a prophylactic agent in patients in life threatening situations (e.g. multitrauma, neurosurgery atc.). more than % children required cefotaxim for the treatment of severe infections (epiglotitis, meningitis, sepsis, pneumonia mainly in immunodeficient and neutropenic patients) in monotherapy or in the combination with the other antimicrobial agents. results: cefotaxim as a prophylactic drug was successful in all cases ( %). the effectivity of treatment of infections was . % ( patients). the change of antibiotic therapy required patients ( . %). patients ( . %) died, but only in of them ( . %) the obduction confirmed infection. conclusion: we conclude that cefotaxim is very effective and safe antibiotic and represents "golden standard" in the treatment of severe infections in childhood. in order to improve nursing quality, we recently adapted nursing care to the "five nursing functions" (activities of daily living, accompagnment in crisis, treatment, prevention and research) as described by the swiss red cross in accordance to the new educational guidelines of the european community, the aim of this study was to document complications of "treatment nursing function".methods: all treatment complications were prospectively collected by the nursing and medical staff. the nursing staff included patient (pt) name, time of occurence and exact description of complication, proposal for prevention and information of parents. the medical staff reported type of complication together with pt information, diagnosis, medication, treatment and interventions, outcome and referral, all complications were discussed in monthly meetings including nursing and medical staff.results: from january until december , pts were admitted to the picu/nicu for nursing days ( % of total bed occupancy). pts needed endotracheal intubation for an average of . days and pts required nasal cpap. complications in pts were noted ( per pi): inadequate check-up of equipment ; accidental extubation ( in intubated pts); bedsores ; false drug dosing ; wrong drug ; umbilical bleeding ; wrong transfusion setup ; nasal septal necrosis ). there was no mortality due to these complications. exact documention of treatment complications and their meticulous discussion within the medical and nursing staff may improve "treatment nursing function". however, documentation and evaluation of nursing within all "five nursing functions" will be nessecary in order to achieve optimal nursing care. cardiac output determination by thermodilution, using iced injectate has been shown to be valid and reliable in pediatric patients. it has been demonstrated in adult patients that there is no difference in cardiac output values when using room temperature injectate as compared to iced temperature injectate. the purpose of this study is to examine the effect of injectate temperature on cardiac output values in pediatric patients. our study consisted of sixteen pediatric patients who had oximetric thermodilution catheters in place after cardiac surgery and who had cardiac output determined using both iced and room temperature injectate. with each patient, cardiac output was measured once on the day of surgery and again the following day. in each case cardiac output was measured using both iced and room temperature injectate. statistical analysis included a two-way, repeated measures analysis of variance for each individual injectate administered and no significant differences were found in cardiac output. no statistically significant differences were found between groups with regard to the order of injectate administration or volume of injectate used (i,e., or cc's). the correlation coefficients between groups for cardiac output measurements at each injectate administration time, and for the average measurements across times, ranged between . to . (p < . ). preliminary data analysis suggests that cardiac output measurements for children are not effected by the temperature of injectate. a lenghty stay at a paediatric intensive care unit will always have sideeffects on a child's well-being and will put a high strain on the parents. in order to minimize the side-effects longterm intensive care unit opened in at the childrens' hospital. admitted children are all ~ongterm-ill and technically-dependent and the ventilatory support can alter from a tracheostoma to cpap or portable volume ventilator. nutritional support is applied by gastrostomies. a homelike atmosphere surrounds the children, they share a dormitory, a living-room and a dining-room the main purpose is to send the child home with or without technical equipment. this can only be implemented by giving structured education (theory and practice) to all categories involved. the multi-disciplinary team consists of one anaesthesiologist, head nurse, clinical specialist, rn nurses, nurses, one habilitation doctor, one social worker and therapists. twenty-four patients have been admitted to licu during these six years. length of stay was from one day to four years. four are presently staying at the trait. the assessment of pain in children ( - yrs) is still difficult, because children of this age have limited language and cognitive skills. to standardize the assessment of postoperative pain and distress in the intensive care unit an observational mstrument was needed that met several criteria. it should be easy to use in daily routine care. be suitable for the i.c. situation, and in children of - hrs of age. the comfort scale, an observational instrument designed to assess distress in infants in i.c. units, met these criteria. to accommodate the use of the comfort scale in the i.c. units and in research, nurses should be trained to use the scale. an additional requirement was that the inter-rater reliability should be sufficiently high, (cohen's kappa > . ). objectives: ) to introduce the comfort scale in the i.c.u.; ) to examine whether this instrument can easily, be incorporated into routine care; ) to investigate the inter-rater retiabtlity. methods: the comfort scale is an -item instrument specifically designed for use in pediatric i,c, units and contains both physiological items (heart rate, blood pressure) and behavioral items (e.g., alertness behavior, calmness/agitation, body movement, facial expression respiratory response, muscle tension). the observation period is minutes. the scale is supplemented with an item on crying tbr children who are not mechanically ventilated. groups of t.c. nurses were trained by means of video's and observations at the wards. after the training, each nurse completed scores with other nurses, after which the cohen's kappa was computed. when the kappa's for the items met or exceeded our . criterium, a new group of nurses was trained. results: to date, nurses have been trained. nurses find the comfort scale easy" to administer and a valuable addition to routine care in the i.c. unit. the cohen's kappa's were higher than . for all items that the inter-rater reliability was high. the comfort scale is feasible in postoperative care in the i.v. and is considered a valuable instrument to improve and maintain high postoperative quality of care in the i.c. unit. introduction:children with neuro-muscular disease are believed to have a higher resting energy expenditure (ree), because of their increasedwork of breathing.the influence of nocturnal nasal mask ventilation on energy metabolism and nutritional state of these children has not been studied so far.objective:l,ls the ree inereased? . s there an influence of nasal mask ventilation on the ree? .what is the nutritional state? .what is the estimated total energy expenditure(ete) in relation to the caloric intake? methods:a pilot study of patients( - years) .the following measurements were performed:l.anthropometry. .bioelectric impedance- .ree was measured by indirect calorimetry during the day (in bed) with and without nasal mask ventuation,ree was compared with predicted ree according to schofield(pee), .caloric-intake and activities were recorded during hour before measurement. .total energy expenditure was calculated as follows:measured ree x estimated activity factor. results:tin all children weight for height was too low, <p . .aii children had a low % of fat. .according to the healthy group, ree is not increased. ,nasal mask ventilation lowered ree in patients, in patient we measured a clear decrease.conclueion:l.anthropometry and indirect calorimetry were helpful in evaluating the nutritional state. .there is no increased ree,in t patient there is clearly effect of nasal mask ventilation. .when caloric intake was related to ree and level of activity patients had too low caloric intake. .the influence of nocturnal nasal mask ventilation and nutritional assessment should be evaluated longitudinally. increasing awareness that the neonate can percept pain and suffer following surgical procedures, has major impact on pain management. in our unit continuous morphine infusion (t /~g/kg/hr) was introduced from january as a standard medicatton following surgical procedures. before morphine was given as a bolus (i.m., i.v., rectal) of /~g/kg up till four times a day. repeated gifts of morphine were only gwen following observation by the nurse that the child experienced pain. aim of the study: to evaluate pain management before and tbllowing introduction of a continuous morphine infusion for postoperative pain in our icu. patients and methods: term born babies with isolated oesophageal atresia and tracheo-oesophageal fistula were included in the study. the total amount of morphine (/~£/kg/ hours); number of days morphine was given; duration of artificial ventilation was evaluated in a case control study. res ults: - - central venous catheters (cvc) have been increasingly used also at our picu, university medical centre ljubljana. besides advantages, the cvc has brought numerous risks of complications; the catheter sepsis occurs most often and can be fatal for the patient. for example, in we dealt with children aged - years or in other words . cvp per a child treated at our picu. a specialized unit for preparing parenteral natrition started to function in the university medical centre pharmacy in . after that we equipped a special room for preparing other necessary infusion mixtures and organized a team of nurses -"catheter nurses".their tasks comprise: managing cvcs, replacing and installing infusion systems and mixtures made at pharmacy, preparing drugs and some necessary infusion mixtures in special room, permanent training and co-operation with related disciplines, pharmacy, epidemiology, microbiology, etc. all registered nurses at picu have been trained for this work. the routine is as follows: in the morningafter the doctor's visit, we first check the cvc and change the dressings; according to the nurse's observations, the doctor decides whether there is a need to remove or replace the cvc. if the catheter site is inflamed, swollen, or purulent, a swab is taken for microbiological culture and the area cleaned. in case of systemic infection signs, cvc has to be replaced, blood culture taken and the infection treated with antibiotics. the dressings are always changed by two tmcatheter nurses together. afterwards the infusion mixtures for the next hours are prepared for each child. the infusion mixtures which will not be used immediately are kept on + °c; before application they are, of course, warmed to at least room temperature. finally the "catheter nurse" supplies the cvc with new infusion mixtures made at our pharmacy. our observations show that such work requires responsibility and is demanding; but our pemanent care lessens the number of complications. thus the described scheme fulfilled our expectations. perl- perative management of neonates with hypoplastic left heart syndrome muir warren, blondel maryse, foltz rhonda, farine martine, icu nurses, the aldo castaneda institute, clinique de genolier, switzerland both the pre-operative and post-operative physiology of patient with hypoplastic left heart syndrome is critically determined by the puhnonary-tosystemic resistance ratio. a high ratio results in minimum volume work for the right ventricle but is at the expense of important hypoxemia. a low ratio is reflected in minimum hypoxemia but an unfavorable increase in excess ventricular volume work. a resistance ratio of approximately results in an arterial oxygen saturation of % - %, a qp/qs of , and ventricular volume work only twice normal. this latter physiology appears best for oxygen delivery and systemic perfusion with tolerable volume work. carbon dioxide (co ) in the inspired gas is known to increase pulmonary vascular resistance without significantly influencing systemic resistance in the range of to tort partial pressure. hyperventilation with no co in inspired gas decreases pulmonary vascular resistance. thus, managing co may be useful to modulate the pulmonary-to-systemic resistance ratio, in the tast months, patients with hypoplastic left heart syndrome were managed by a norwood procedur e. patients with endotracheal entubation pre-operatively had co added to inspired gas to modulate the pulmonary-to-systemic flow ratio. patients had co added to inspired gas post-operatively. all but patient had characteristically large pulmonaary-to-systemic flow ratio with oxygen saturation mean % preoperatively, even in those patients receiving co , co was accompanied by elimination of metabolic acidosis pre-operatively. the most comlnon partial pressure of co added post-operatively was torr. po ranged from mmhg to mmhg. all surviving patients developed a metabolic alkalosis ( mean) when treated with co . there were deaths, one from drug toxicity, one from excessive post-operative hemorrhage, two from sepsis or mocardial insufficiency. only one patient benefited from catecholamine support which can increase systemic resistance unfaborably. in this experience co was felt to be an important adjunct in some patients pre-operatively and most patients postoperatively to faborably modulate the critically important systemic-topulmonary flow ratio, to maximize oxygen delivery and systemic perfusion, while minimizing excessive right vantricular volume work. key: cord- - qfecv h authors: velasquez, t.; mackey, g.; lusk, j.; kyle, u. g.; fontenot, t.; marshall, p.; shekerdemian, l. s.; coss-bu, j. a.; nishigaki, a.; yatabe, t.; tamura, t.; yamashita, k.; yokoyama, m.; ruiz-rodriguez, j. c.; encina, b.; belmonte, r.; troncoso, i.; tormos, p.; riveiro, m.; baena, j.; sanchez, a.; bañeras, j.; cordón, j.; duran, n.; ruiz, a.; caballero, j.; nuvials, x.; riera, j.; serra, j.; rutten, a. m. f.; van ieperen, s. n. m.; der kinderen, e. p. h. m.; van logten, t.; kovacikova, l.; skrak, p.; zahorec, m.; kyle, u. g.; akcan-arikan, a.; silva, j. c.; mackey, g.; lusk, j.; goldsworthy, m.; shekerdemian, l. s.; coss-bu, j. a.; wood, d.; harrison, d.; parslow, r.; davis, p.; pappachan, j.; goodwin, s.; ramnarayan, p.; chernyshuk, s.; yemets, h.; zhovnir, v.; pulitano’, s. m.; de rosa, s.; mancino, a.; villa, g.; tosi, f.; franchi, p.; conti, g.; patel, b.; khine, h.; shah, a.; sung, d.; singer, l.; haghbin, s.; inaloo, s.; serati, z.; idei, m.; nomura, t.; yamamoto, n.; sakai, y.; yoshida, t.; matsuda, y.; yamaguchi, y.; takaki, s.; yamaguchi, o.; goto, t.; longani, n.; medar, s.; abdel-aal, i. r.; el adawy, a. s.; mohammed, h. m. e. h.; mohamed, a. n.; parry, s. m.; knight, l. d.; denehy, l.; de morton, n.; baldwin, c. e.; sani, d.; kayambu, g.; da silva, v. z. m.; phongpagdi, p.; puthucheary, z. a.; granger, c. l.; rydingsward, j. e.; horkan, c. m.; christopher, k. b.; mcwilliams, d.; jones, c.; reeves, e.; atkins, g.; snelson, c.; aitken, l. m.; rattray, j.; kenardy, j.; hull, a. m.; ullman, a.; le brocque, r.; mitchell, m.; davis, c.; macfarlane, b.; azevedo, j. c.; rocha, l. l.; de freitas, f. f. m.; cavalheiro, a. m.; lucinio, n. m.; lobato, m. s.; ebeling, g.; kraegpoeth, a.; laerkner, e.; de brito-ashurst, i.; white, c.; gregory, s.; forni, l. g.; flowers, e.; curtis, a.; wood, c. a.; siu, k.; venkatesan, k.; muhammad, j. b. h.; ng, l.; seet, e.; baptista, n.; escoval, a.; tomas, e.; agrawal, r.; mathew, r.; varma, a.; dima, e.; charitidou, e.; perivolioti, e.; pratikaki, m.; vrettou, c.; giannopoulos, a.; zakynthinos, s.; routsi, c.; atchade, e.; houzé, s.; jean-baptiste, s.; thabut, g.; genève, c.; tanaka, s.; lortat-jacob, b.; augustin, p.; desmard, m.; montravers, p.; de molina, f. j. gonzález; barbadillo, s.; alejandro, r.; Álvarez-lerma, f.; vallés, j.; catalán, r. m.; palencia, e.; jareño, a.; granada, r. m.; ignacio, m. l.; cui, n.; liu, d.; wang, h.; su, l.; qiu, h.; li, r.; jaffal, k.; rouzé, a.; poissy, j.; sendid, b.; nseir, s.; paramythiotou, e.; rizos, m.; frantzeskaki, f.; antoniadou, a.; vourli, s.; zerva, l.; armaganidis, a.; riera, j.; gottlieb, j.; greer, m.; wiesner, o.; martínez, m.; acuña, m.; rello, j.; welte, t.; atchade, e.; mignot, t.; houzé, s.; jean-baptiste, s.; thabut, g.; lortat-jacob, b.; tanaka, s.; augustin, p.; desmard, m.; montravers, p.; soussi, s.; dudoignon, e.; ferry, a.; chaussard, m.; benyamina, m.; alanio, a.; touratier, s.; chaouat, m.; lafaurie, m.; mimoun, m.; mebazaa, a.; legrand, m.; sheils, m. a.; patel, c.; mohankumar, l.; akhtar, n.; noriega, s. k. pacheco; aldana, n. navarrete; león, j. l. Ávila; baquero, j. durand; bernal, f. fernández; ahmadnia, e.; hadley, j. s.; millar, m.; hall, d.; hewitt, h.; yasuda, h.; sanui, m.; komuro, t.; kawano, s.; andoh, k.; yamamoto, h.; noda, e.; hatakeyama, j.; saitou, n.; okamoto, h.; kobayashi, a.; takei, t.; matsukubo, s.; rotzel, h. b.; lázaro, a. serrano; prada, d. aguillón; gimillo, m. rodriguez; barinas, o. diaz; cortes, m. l. blasco; franco, j. ferreres; roca, j. m. segura; carratalá, a.; gonçalves, b.; turon, r.; mendes, a.; miranda, f.; mata, p. j.; cavalcanti, d.; melo, n.; lacerda, p.; kurtz, p.; righy, c.; rosario, l. e. de la cruz; lesmes, s. p. gómez; romero, j. c. garcía; herrera, a. n. garcía; pertuz, e. d. díaz; sánchez, m. j. gómez; sanz, e. regidor; hualde, j. barado; hernández, a. ansotegui; irazabal, j. m. guergué; spatenkova, v.; bradac, o.; suchomel, p.; urli, t.; lazzeri, e. heusch; aspide, r.; zanello, m.; perez-borrero, l.; garcia-alvarez, j. m.; arias-verdu, m. d.; aguilar-alonso, e.; rivera-fernandez, r.; mora-ordoñez, j.; de la fuente-martos, c.; castillo-lorente, e.; guerrero-lopez, f.; lesmes, s. p. gómez; rosario, l. e. de la cruz; pertuz, e. d. díaz; hernández, a. ansotegui; romero, j. c. garcía; sánchez, m. j. gómez; herrera, a. n. garcía; ramírez, j. roldán; sanz, e. regidor; hualde, j. barado; león, j. p. tirapu; navarro-guillamón, l.; cordovilla-guardia, s.; iglesias-santiago, a.; guerrero-lópez, f.; fernández-mondéjar, e.; vidal, a.; perez, m.; juez, a.; arias, n.; colino, l.; perez, j. l.; pérez, h.; calpe, p.; alcala, m. a.; robaglia, d.; perez, c.; lan, s. k.; cunha, m. m.; moreira, t.; santos, f.; lafuente, e.; fernandes, m. j.; silva, j. g.; rosario, l. e. de la cruz; lesmes, s. p. gómez; herrera, a. n. garcía; romero, j. c. garcía; pertuz, e. d. díaz; sánchez, m. j. gómez; sanz, e. regidor; echeverría, j. g. armando; hernández, a. ansotegui; hualde, j. barado; podlepich, v.; sokolova, e.; alexandrova, e.; lapteva, k.; kurtz, p.; shuinotsuka, c.; rabello, l.; vianna, g.; reis, a.; cairus, c.; salluh, j.; bozza, f.; torres, j. c. barrios; araujo, n. j. fernández; garcía-olivares, p.; keough, e.; dalorzo, m.; tang, l. k.; de sousa, i.; díaz, m.; marcos-zambrano, l. j.; guerrero, j. e.; gomez, s. e. zamora; lopez, g. d. hernandez; cuellar, a. i. vazquez; nieto, o. r. perez; gonzalez, j. a. castanon; bhasin, d.; rai, s.; singh, h.; gupta, o.; bhattal, m. k.; sampley, s.; sekhri, k.; nandha, r.; aliaga, f. a.; olivares, f.; appiani, f.; farias, p.; alberto, f.; hernández, a.; pons, s.; sonneville, r.; bouadma, l.; neuville, m.; mariotte, e.; radjou, a.; lebut, j.; chemam, s.; voiriot, g.; dilly, m. p.; mourvillier, b.; dorent, r.; nataf, p.; wolff, m.; timsit, j. f.; ediboglu, o.; ataman, s.; ozkarakas, h.; kirakli, c.; vakalos, a.; avramidis, v.; obukhova, o.; kurmukov, i. a.; kashiya, s.; golovnya, e.; baikova, v. n.; ageeva, t.; haritydi, t.; kulaga, e. v.; rios-toro, j. j.; perez-borrero, l.; aguilar-alonso, e.; arias-verdu, m. d.; garcia-alvarez, j. m.; lopez-caler, c.; de la fuente-martos, c.; rodriguez-fernandez, s.; sanchez-orézzoli, m. gomez; martin-gallardo, f.; nikhilesh, j.; joshi, v.; villarreal, e.; ruiz, j.; gordon, m.; quinza, a.; gimenez, j.; piñol, m.; castellanos, a.; ramirez, p.; jeon, y. d.; jeong, w. y.; kim, m. h.; jeong, i. y.; ahn, m. y.; ahn, j. y.; han, s. h.; choi, j. y.; song, y. g.; kim, j. m.; ku, n. s.; shah, h.; kellner, f.; rezai, f.; mistry, n.; yodice, p.; ovnanian, v.; fless, k.; handler, e.; alejos, r. martínez; romeu, j. d. martí; antón, d. gonzález; quinart, a.; martí, a. torres; llaurado-serra, m.; lobo-civico, a.; ventura-rosado, a.; piñol-tena, a.; pi-guerrero, m.; paños-espinosa, c.; peralvo-bernat, m.; marine-vidal, j.; gonzalez-engroba, r.; montesinos-cerro, n.; treso-geira, m.; valeiras-valero, a.; martinez-reyes, l.; sandiumenge, a.; jimenez-herrera, m. f.; helyar, s.; riozzi, p.; noon, a.; hallows, g.; cotton, h.; keep, j.; hopkins, p. a.; taggu, a.; renuka, s.; sampath, s.; rood, p. j. t.; frenzel, t.; verhage, r.; bonn, m.; pickkers, p.; van der hoeven, j. g.; van den boogaard, m.; corradi, f.; melnyk, l.; moggia, f.; pienovi, r.; adriano, g.; brusasco, c.; mariotti, l.; lattuada, m.; bloomer, m. j.; coombs, m.; ranse, k.; endacott, r.; maertens, b.; blot, k.; blot, s.; amerongen, m. p. van nieuw; van der heiden, e. s.; twisk, j. w. r.; girbes, a. r. j.; spijkstra, j. j.; riozzi, p.; helyar, s.; cotton, h.; hallows, g.; noon, a.; bell, c.; peters, k.; feehan, a.; keep, j.; hopkins, p. a.; churchill, k.; hawkins, k.; brook, r.; paver, n.; endacott, r.; maistry, n.; van wijk, a.; rouw, n.; van galen, t.; evelein-brugman, s.; taggu, a.; krishna, b.; sampath, s.; putzu, a.; fang, m.; berto, m. boscolo; belletti, a.; cassina, t.; cabrini, l.; mistry, m.; alhamdi, y.; welters, i.; abrams, s. t.; toh, c. h.; han, h. s.; gil, e. m.; lee, d. s.; park, c. m.; winder-rhodes, s.; lotay, r.; doyle, j.; ke, m. w.; huang, w. c.; chiang, c. h.; hung, w. t.; cheng, c. c.; lin, k. c.; lin, s. c.; chiou, k. r.; wann, s. r.; shu, c. w.; kang, p. l.; mar, g. y.; liu, c. p.; dubó, s.; aquevedo, a.; jibaja, m.; berrutti, d.; labra, c.; lagos, r.; garcía, m. f.; ramirez, v.; tobar, m.; picoita, f.; peláez, c.; carpio, d.; alegría, l.; hidalgo, c.; godoy, k.; bakker, j.; hernández, g.; sadamoto, y.; katabami, k.; wada, t.; ono, y.; maekawa, k.; hayakawa, m.; sawamura, a.; gando, s.; marin-mateos, h.; perez-vela, j. l.; garcia-gigorro, r.; peiretti, m. a. corres; lopez-gude, m. j.; chacon-alves, s.; renes-carreño, e.; montejo-gonzález, j. c.; parlevliet, k. l.; touw, h. r. w.; beerepoot, m.; boer, c.; elbers, p. w. g.; tuinman, p. r.; abdelmonem, s. a.; helmy, t. a.; el sayed, i.; ghazal, s.; akhlagh, s. h.; masjedi, m.; hozhabri, k.; kamali, e.; zýková, i.; paldusová, b.; sedlák, p.; morman, d.; youn, a. m.; ohta, y.; sakuma, m.; bates, d.; morimoto, t.; su, p. l.; chang, w. y.; lin, w. c.; chen, c. w.; facchin, f.; zarantonello, f.; panciera, g.; de cassai, a.; venrdramin, a.; ballin, a.; tonetti, t.; persona, p.; ori, c.; del sorbo, l.; rossi, s.; vergani, g.; cressoni, m.; chiumello, d.; chiurazzi, c.; brioni, m.; algieri, i.; tonetti, t.; guanziroli, m.; colombo, a.; tomic, i.; colombo, a.; crimella, f.; carlesso, e.; gasparovic, v.; gattinoni, l.; neto, a. serpa; schmidt, m.; pham, t.; combes, a.; de abreu, m. gama; pelosi, p.; schultz, m. j.; katira, b. h.; engelberts, d.; giesinger, r. e.; ackerley, c.; yoshida, t.; zabini, d.; otulakowski, g.; post, m.; kuebler, w. m.; mcnamara, p. j.; kavanagh, b. p.; pirracchio, r.; rigon, m. resche; carone, m.; chevret, s.; annane, d.; eladawy, s.; el-hamamsy, m.; bazan, n.; elgendy, m.; de pascale, g.; vallecoccia, m. s.; cutuli, s. l.; di gravio, v.; pennisi, m. a.; conti, g.; antonelli, m.; andreis, d. t.; khaliq, w.; singer, m.; hartmann, j.; harm, s.; carmona, s. alcantara; almudevar, p. matia; abellán, a. naharro; ramos, j. veganzones; pérez, l. pérez; valbuena, b. lobo; sanz, n. martínez; simón, i. fernández; arrigo, m.; feliot, e.; deye, n.; cariou, a.; guidet, b.; jaber, s.; leone, m.; resche-rigon, m.; baron, a. vieillard; legrand, m.; gayat, e.; mebazaa, a.; balik, m.; kolnikova, i.; maly, m.; waldauf, p.; tavazzi, g.; kristof, j.; herpain, a.; su, f.; post, e.; taccone, f.; vincent, j. l.; creteur, j.; lee, c.; hatib, f.; jian, z.; buddi, s.; cannesson, m.; fileković, s.; turel, m.; knafelj, r.; gorjup, v.; stanić, r.; gradišek, p.; cerović, o.; mirković, t.; noč, m.; tirkkonen, j.; hellevuo, h.; olkkola, k. t.; hoppu, s.; lin, k. c.; hung, w. t.; chiang, c. c.; huang, w. c.; juan, w. c.; lin, s. c.; cheng, c. c.; lin, p. h.; fong, k. y.; hou, d. s.; kang, p. l.; wann, s. r.; chen, y. s.; mar, g. y.; liu, c. p.; paul, m.; bougouin, w.; geri, g.; dumas, f.; champigneulle, b.; legriel, s.; charpentier, j.; mira, j. p.; sandroni, c.; cariou, a.; zimmerman, j.; sullivan, e.; noursadeghi, m.; fox, b.; sampson, d.; mchugh, l.; yager, t.; cermelli, s.; seldon, t.; bhide, s.; brandon, r. a.; brandon, r. b.; zwaag, j.; beunders, r.; pickkers, p.; kox, m.; gul, f.; arslantas, m. k.; genc, d.; zibandah, n.; topcu, l.; akkoc, t.; cinel, i.; greco, e.; lauretta, m. p.; andreis, d. t.; singer, m.; garcia, i. palacios; cordero, m.; martin, a. diaz; pallás, t. aldabó; montero, j. garnacho; rey, j. revuelto; malo, l. roman; montoya, a. a. tanaka; martinez, a. d. c. amador; ayala, l. y. delgado; zepeda, e. monares; granillo, j. franco; sanchez, j. aguirre; alejo, g. camarena; cabrera, a. rugerio; montenegro, a. pedraza; pham, t.; beduneau, g.; schortgen, f.; piquilloud, l.; zogheib, e.; jonas, m.; grelon, f.; runge, i.; terzi, n.; grangé, s.; barberet, g.; guitard, p. g.; frat, j. p.; constan, a.; chrétien, j. m.; mancebo, j.; mercat, a.; richard, j. c. m.; brochard, l.; soilemezi, e.; koco, e.; savvidou, s.; nouris, c.; matamis, d.; di mussi, r.; spadaro, s.; volta, c. a.; mariani, m.; colaprico, a.; antonio, c.; bruno, f.; grasso, s.; rodriguez, a.; martín-loeches, i.; díaz, e.; masclans, j. r.; gordo, f.; solé-violán, j.; bodí, m.; avilés-jurado, f. x.; trefler, s.; magret, m.; reyes, l. f.; marín-corral, j.; yebenes, j. c.; esteban, a.; anzueto, a.; aliberti, s.; restrepo, m. i.; larsson, j. skytte; redfors, b.; ricksten, s. e.; haines, r.; powell-tuck, j.; leonard, h.; ostermann, m.; berthelsen, r. e.; itenov, t. s.; perner, a.; jensen, j. u.; ibsen, m.; jensen, a. e. k.; bestle, m. h.; bucknall, t.; dixon, j.; boa, f.; macphee, i.; philips, b. j.; doyle, j.; saadat, f.; samuels, t.; huddart, s.; mccormick, b.; debrunnar, r.; preece, j.; swart, m.; peden, c.; richardson, s.; forni, l.; kalfon, p.; baumstarck, k.; estagnasie, p.; geantot, m. a.; berric, a.; simon, g.; floccard, b.; signouret, t.; boucekine, m.; fromentin, m.; nyunga, m.; sossou, a.; venot, m.; robert, r.; follin, a.; renault, a.; garrouste, m.; collange, o.; levrat, q.; villard, i.; thévenin, d.; pottecher, j.; patrigeon, r. g.; revel, n.; vigne, c.; mimoz, o.; auquier, p.; pawar, s.; jacques, t.; deshpande, k.; pusapati, r.; wood, b.; pulham, r. a.; wray, j.; brown, k.; pierce, c.; nadel, s.; ramnarayan, p.; azevedo, j. r.; montenegro, w. s.; rodrigues, d. p.; sousa, s. c.; araujo, v. f.; leitao, a. l.; prazeres, p. h.; mendonca, a. v.; paula, m. p.; das neves, a.; loudet, c. i.; busico, m.; vazquez, d.; villalba, d.; lischinsky, a.; veronesi, m.; emmerich, m.; descotte, e.; juliarena, a.; bisso, m. carboni; grando, m.; tapia, a.; camargo, m.; ulla, d. villani; corzo, l.; dos santos, h. placido; ramos, a.; doglia, j. a.; estenssoro, e.; carbonara, m.; magnoni, s.; donald, c. l. mac; shimony, j. s.; conte, v.; triulzi, f.; stretti, f.; macrì, m.; snyder, a. z.; stocchetti, n.; brody, d. l.; podlepich, v.; shimanskiy, v.; savin, i.; lapteva, k.; chumaev, a.; tjepkema-cloostermans, m. c.; hofmeijer, j.; beishuizen, a.; hom, h.; blans, m. j.; van putten, m. j. a. m.; longhi, l.; frigeni, b.; curinga, m.; mingone, d.; beretta, s.; patruno, a.; gandini, l.; vargiolu, a.; ferri, f.; ceriani, r.; rottoli, m. r.; lorini, l.; citerio, g.; pifferi, s.; battistini, m.; cordolcini, v.; agarossi, a.; di rosso, r.; ortolano, f.; stocchetti, n.; lourido, c. mora; cabrera, j. l. santana; santana, j. d. martín; alzola, l. melián; del rosario, c. garcía; pérez, h. rodríguez; torrent, r. lorenzo; eslami, s.; dalhuisen, a.; fiks, t.; schultz, m. j.; hanna, a. abu; spronk, p. e.; wood, m.; maslove, d.; muscedere, j.; scott, s. h.; saha, t.; hamilton, a.; petsikas, d.; payne, d.; boyd, j. g.; puthucheary, z. a.; mcnelly, a. s.; rawal, j.; connolly, b.; mcphail, m. j.; sidhu, p.; rowlerson, a.; moxham, j.; harridge, s. d.; hart, n.; montgomery, h. e.; jovaisa, t.; thomas, b.; gupta, d.; wijayatilake, d. s.; shum, h. p.; king, h. s.; chan, k. c.; tang, k. b.; yan, w. w.; arias, c. castro; latorre, j.; de la rica, a. suárez; garrido, e. maseda; feijoo, a. montero; gancedo, c. hernández; tofiño, a. lópez; rodríguez, f. gilsanz; gemmell, l. k.; campbell, r.; doherty, p.; mackay, a.; singh, n.; vitaller, s.; nagib, h.; prieto, j.; del arco, a.; zayas, b.; gomez, c.; tirumala, s.; pasha, s. a.; kumari, b. k.; martinez-lopez, p.; puerto-morlán, a.; nuevo-ortega, p.; pujol, l. martinez; dolset, r. algarte; gonzález, b. sánchez; riera, s. quintana; Álvarez, j. trenado; quintana, s.; martínez, l.; algarte, r.; sánchez, b.; trenado, j.; tomas, e.; brock, n.; viegas, e.; filipe, e.; cottle, d.; traynor, t.; martínez, m. v. trasmonte; márquez, m. pérez; gómez, l. colino; martínez, n. arias; muñoz, j. m. milicua; bellver, b. quesada; varea, m. muñoz; llorente, m. Á. alcalá; calvo, c. pérez; hillier, s. d.; faulds, m. c.; hendra, h.; lawrence, n.; maekawa, k.; hayakawa, m.; ono, y.; kodate, a.; sadamoto, y.; tominaga, n.; mizugaki, a.; murakami, h.; yoshida, t.; katabami, k.; wada, t.; sawamura, a.; gando, s.; silva, s.; kerhuel, l.; malagurski, b.; citerio, g.; chabanne, r.; laureys, s.; puybasset, l.; nobile, l.; pognuz, e. r.; rossetti, a. o.; verginella, f.; gaspard, n.; creteur, j.; ben-hamouda, n.; oddo, m.; taccone, f. s.; ono, y.; hayakawa, m.; iijima, h.; maekawa, k.; kodate, a.; sadamoto, y.; mizugaki, a.; murakami, h.; katabami, k.; wada, t.; sawamura, a.; gando, s.; kodate, a.; katabami, k.; wada, t.; ono, y.; maekawa, k.; hayakawa, m.; sawamura, a.; gando, s.; andersen, l. w.; raymond, t.; berg, r.; nadkarni, v.; grossestreuer, a.; kurth, t.; donnino, m.; krüger, a.; ostadal, p.; janotka, m.; vondrakova, d.; kongpolprom, n.; cholkraisuwat, j.; pekkarinen, p. t.; ristagno, g.; masson, s.; latini, r.; bendel, s.; ala-kokko, t.; varpula, t.; vaahersalo, j.; hoppu, s.; tiainen, m.; mion, m. m.; plebani, m.; pettilä, v.; skrifvars, m.b.; son, y.; kim, k. s.; suh, g. j.; kwon, w. y.; ko, j. i.; park, m. j.; cavicchi, f. zama; iesu, e.; nobile, l.; vincent, j. l.; creteur, j.; taccone, f. s.; tanaka, h.; otani, n.; ode, s.; ishimatsu, s.; martínez, l.; algarte, r.; sánchez, b.; romero, i.; martínez, f.; quintana, s.; trenado, j.; vondrakova, d.; ostadal, p.; kruger, a.; janotka, m.; malek, f.; neuzil, p.; yeh, y. c.; chen, y. s.; wang, c. h.; huang, c. h.; chao, a.; lee, c. t.; lai, c. h.; chan, w. s.; cheng, y. j.; sun, w. z.; kaese, s.; horstmann, c.; lebiedz, p.; mourad, m.; gaudard, p.; eliet, j.; zeroual, n.; colson, p.; ostadal, p.; mlcek, m.; hrachovina, m.; kruger, a.; vondrakova, d.; janotka, m.; mates, m.; hala, p.; kittnar, o.; neuzil, p.; jacky, a.; rudiger, a.; spahn, d. r.; bettex, d. a.; kara, a.; akin, s.; dos reis miranda, d.; struijs, a.; caliskan, k.; van thiel, r. j.; dubois, e. a.; de wilde, w.; zijlstra, f.; gommers, d.; ince, c.; marca, l.; xini, a.; mongkolpun, w.; cordeiro, c. p. r.; leite, r. t.; lheureux, o.; bader, a.; rincon, l.; santacruz, c.; preiser, j. c.; chao, a.; chao, a. s.; chen, y. s.; kim, w.; ahn, c.; cho, y.; lim, t. h.; oh, j.; choi, k. s.; jang, b. h.; ha, j. k.; mecklenburg, a.; stamm, j.; soeffker, g.; kubik, m.; sydow, k.; reichenspurner, h.; kluge, s.; braune, s.; bergantino, b.; ruberto, f.; magnanimi, e.; privato, e.; zullino, v.; bruno, k.; pugliese, f.; sales, g.; girotto, v.; vittone, f.; brazzi, l.; fritz, c.; kimmoun, a.; vanhuyse, f.; trifan, b.; orlowski, s.; albuisson, e.; tran, n.; levy, b.; chhor, v.; joachim, j.; follin, a.; champigneulle, b.; chatelon, j.; fave, g.; mantz, j.; pirracchio, r.; diaz, d. díaz; villanova, m.; aguirregabyria, m.; andrade, g.; lópez, l.; palencia, e.; john, g.; cowan, r.; hart, r.; lake, k.; litchfield, k.; song, j. w.; lee, y. j.; cho, y. j.; choi, s.; vermeir, p.; vandijck, d.; blot, s.; mariman, a.; verhaeghe, r.; deveugele, m.; vogelaers, d.; chok, l.; bachli, e. b.; bettex, d.; cottini, s. r.; keller, e.; maggiorini, m.; schuepbach, r.; fiks, t.; stiphout, c.; grevelink, m.; vaneker, i.; ruijter, a.; buise, m.; spronk, p. e.; tena, s. altaba; barrachina, l. galarza; portillo, j. h. rodriguez; aznar, g. pagés; campos, l. mateu; sellés, m. d. ferrándiz; tomás, m. arlandis; muncharaz, a. belenguer; skinner, l.; monsalvo, s.; olavarria, e.; stümpfle, r.; na, s. j.; park, j.; chung, c. r.; park, c. m.; suh, g. y.; yang, j. h.; witter, t.; brousseau, c.; butler, m. b.; erdogan, m.; dougall, p. c. mac; green, r. s.; abbott, t. e. f.; torrance, h. d. t.; cron, n.; vaid, n.; emmanuel, j.; siddiqui, s. s.; prabu, n.; chaudhari, h. k.; patil, v. p.; divatia, j. v.; solanki, s.; kulkarni, a. p.; gutierrez, l. a. rincon; bader, a.; brasseur, a.; lheureux, o.; vincent, j. l.; creteur, j.; taccone, f. s.; hempel, d.; stauffert, n.; recker, f.; schröder, t.; reusch, s.; schleifer, j.; breitkreutz, r.; sjövall, f.; perner, a.; møller, m. hylander; moraes, r. b.; borges, f. k.; guillen, j. a. v.; zabaletta, w. j. c.; ruiz-ramos, j.; ramirez, p.; marqués-miñana, m. r.; villarreal, e.; gordon, m.; sosa, m.; concha, p.; castellanos, a.; menendez, r.; ramírez, c. sánchez; santana, m. cabrera; balcázar, l. caipe; escalada, s. hípola; viera, m. a. hernández; vázquez, c. f. lübbe; díaz, j. j. díaz; campelo, f. artiles; monroy, n. sangil; santana, p. saavedra; santana, s. ruiz; gutiérrez-pizarraya, a.; garnacho-montero, j.; martin, c.; baumstarck, k.; leone, m.; martín-loeches, i.; pirracchio, r.; legrand, m.; mainardi, j. l.; mantz, j.; cholley, b.; hubbard, a.; frontera, p. ruiz; vega, l. m. claraco; miguelena, p. ruiz de gopegui; usón, m. c. villuendas; lópez, a. rezusta; clemente, e. aurensanz; ibañes, p. gutiérrez; aguilar, a. l. ruiz; palomar, m.; olaechea, p.; uriona, s.; vallverdu, m.; catalan, m.; nuvials, x.; aragon, c.; lerma, f. alvarez; jeon, y. d.; jeong, w. y.; kim, m. h.; jeong, i. y.; ahn, m. y.; ahn, j. y.; han, s. h.; choi, j. y.; song, y. g.; kim, j. m.; ku, n. s.; bassi, g. li; xiol, e. aguilera; senussi, t.; idone, f. a.; motos, a.; chiurazzi, c.; travierso, c.; fernández-barat, l.; amaro, r.; hua, y.; ranzani, o. t.; bobi, q.; rigol, m.; torres, a.; fernández, i. fuentes; soler, e. andreu; de vera, a. pareja rodríguez; pastor, e. escudero; hernandis, v.; ros martínez, j.; rubio, r. jara; torner, m. miralbés; brugger, s. carvalho; eroles, a. aragones; moles, s. iglesias; cabello, j. trujillano; schoenenberger, j. a.; casals, x. nuvials; vidal, m. vallverdu; garrido, b. balsera; martinez, m. palomar; mirabella, l.; cotoia, a.; tullo, l.; stella, a.; di bello, f.; di gregorio, a.; dambrosio, m.; cinnella, g.; rosario, l. e. de la cruz; lesmes, s. p. gómez; romero, j. c. garcía; herrera, a. n. garcía; pertuz, e. d. díaz; sánchez, m. j. gómez; sanz, e. regidor; hualde, j. barado; hernández, a. ansotegui; ramirez, j. roldán; takahashi, h.; kazutoshi, f.; okada, y.; oobayashi, w.; naito, t.; baidya, d. k.; maitra, s.; anand, r. k.; ray, b. r.; arora, m. k.; ruffini, c.; rota, l.; corona, a.; sesana, g.; ravasi, s.; catena, e.; naumann, d. n.; mellis, c.; husheer, s. l.; bishop, j.; midwinter, m. j.; hutchings, s.; corradi, f.; brusasco, c.; manca, t.; ramelli, a.; lattuada, m.; nicolini, f.; gherli, t.; vezzani, a.; young, a.; carmona, a. fernández; santiago, a. iglesias; guillamon, l. navarro; delgado, m. j. garcía; delgado-amaya, m.; curiel-balsera, e.; rivera-romero, l.; castillo-lorente, e.; carrero-gómez, f.; aguayo-dehoyos, e.; healey, a. j.; cameron, c.; jiao, l.r.; stümpfle, r.; pérez, a.; martin, s.; del moral, o. lopez; toval, s.; rico, j.; aldecoa, c.; oguzhan, k.; demirkiran, o.; kirman, m.; bozbay, s.; kosuk, m. e.; asyralyyeva, g.; dilek, m.; duzgun, m.; telli, s.; aydin, m.; yilmazer, f.; hodgson, l. e.; dimitrov, b. d.; stubbs, c.; forni, l. g.; venn, r.; vedage, d.; shawaf, s.; naran, p.; sirisena, n.; kinnear, j.; dimitrov, b. d.; hodgson, l. e.; stubbs, c.; forni, l. g.; venn, r.; londoño, j. gonzalez; cardenas, c. lorencio; ginés, a. sánchez; gubianas, c. murcia; sánchez, e. clapes; sirvent, j. m.; panafidina, v.; shlyk, i.; ilyina, v.; judickas, s.; kezyte, g.; urbanaviciute, i.; serpytis, m.; gaizauskas, e.; sipylaite, j.; sprung, c. l.; munteanu, g.; morales, r. c.; kasdan, h.; volker, t.; reiter, a.; cohen, y.; himmel, y.; meissonnier, j.; banderas-bravo, m. e.; gómez-jiménez, c.; garcía-martínez, m. v.; martínez-carmona, j. f.; fernández-ortega, j. f.; o‘dwyer, m. j.; starczewska, m.; wilks, m.; vincent, j. l.; torsvik, m.; gustad, l. t.; bangstad, i. l.; vinje, l. j.; damås, j. k.; solligård, e.; mehl, a.; tsunoda, m.; kang, m.; saito, m.; saito, n.; akizuki, n.; namiki, m.; takeda, m.; yuzawa, j.; yaguchi, a.; frantzeskaki, f.; tsirigotis, p.; chondropoulos, s.; paramythiotou, e.; theodorakopoulou, m.; stamouli, m.; gkirkas, k.; dimopoulou, i. k.; makiko, s.; tsunoda, m.; kang, m.; yuzawa, j.; akiduki, n.; namiki, m.; takeda, m.; yaguchi, a.; preau, s.; ambler, m.; sigurta, a.; saeed, s.; singer, m.; jochmans, s.; chelly, j.; vong, l. v. p.; sy, o.; serbource-goguel, j.; rolin, n.; weyer, c. m.; abdallah, r. i.; adrie, c.; vinsonneau, c.; monchi, m.; mayr, u.; huber, w.; karsten, e.; lahmer, t.; thies, p.; henschel, b.; fischer, g.; schmid, r. m.; ediboglu, o.; ataman, s.; naz, i.; yaman, g.; kirakli, c.; su, p. l.; kou, p. s.; lin, w. c.; chen, c. w.; lozano, j. a. benítez; sánchez, p. carmona; francioni, j. e. barrueco; ferrón, f. ruiz; simón, j. m. serrano; riad, z.; mezidi, m.; aublanc, m.; perinel, s.; lissonde, f.; louf-durier, a.; yonis, h.; tapponnier, r.; richard, j. c.; louis, b.; guérin, c.; mezidi, m.; yonis, h.; aublanc, m.; lissonde, f.; louf-durier, a.; perinel, s.; tapponnier, r.; richard, j. c.; guérin, c.; marmanidou, k.; oikonomou, m.; nouris, c.; loizou, c.; soilemezi, e.; matamis, d.; somhorst, p.; gommers, d.; hayashi, k.; hirayama, t.; yumoto, t.; tsukahara, k.; iida, a.; nosaka, n.; sato, k.; ugawa, t.; nakao, a.; ujike, y.; hirohata, s.; mojoli, f.; torriglia, f.; giannantonio, m.; orlando, a.; bianzina, s.; tavazzi, g.; mongodi, s.; pozzi, m.; iotti, g. a.; braschi, a.; jansen, d.; gadgil, s.; doorduin, j.; roesthuis, l.; van der hoeven, j. g.; heunks, l. m. a.; chen, g. q.; sun, x. m.; he, x.; yang, y. l.; shi, z. h.; xu, m.; zhou, j. x.; pereira, s. m.; tucci, m. r.; tonelotto, b. f. f.; simoes, c. m.; morais, c. c. a.; pompeo, m. s.; kay, f. u.; amato, m. b. p.; vieira, j. e.; suzuki, s.; mihara, y.; hikasa, y.; okahara, s.; morimatsu, h.; kwon, h. m.; moon, y. j.; lee, s. h.; jung, k. w.; shin, w. j.; jun, i. g.; song, j. g.; hwang, g. s.; lee, s.; moon, y. j.; kwon, h. m.; jung, k.; shin, w. j.; jun, i. g.; song, j. g.; hwang, g. s.; ramelli, a.; manca, t.; corradi, f.; brusasco, c.; nicolini, f.; gherli, t.; brianti, r.; fanzaghi, p.; vezzani, a.; tudor, b. a.; klaus, d. a.; lebherz-eichinger, d.; lechner, c.; schwarz, c.; bodingbauer, m.; seemann, r.; kaczirek, k.; fleischmann, e.; roth, g. a.; krenn, c. g.; malyshev, a.; sergey, s.; yamaguchi, y.; nomura, t.; yoshitake, e.; idei, m.; yoshida, t.; takaki, s.; yamaguchi, o.; kaneko, m.; goto, t.; tencé, n.; zaien, i.; wolf, m.; trouiller, p.; jacobs, f. m.; kelly, j. m.; veigas, p.; hollands, s.; min, a.; rizoli, s.; robles, c. m. coronado; de oca sandoval, m. a. montes; tarabrin, o.; gavrychenko, d.; mazurenko, g.; tarabrin, p.; garcia, i. palacios; martin, a. diaz; mendez, m. casado; orden, v. arellano; noval, r. leal; mccue, c.; gemmell, l.; mackay, a.; luján, j.; villa, p.; llorente, b.; molina, r.; alcázar, l.; juanas, c. arenillas; rogero, s.; pascual, t.; cambronero, j. a.; almudévar, p. matía; domínguez, j. palamidessi; carmona, s. alcántara; castañeda, d. palacios; abellán, a. naharro; lucendo, a. pérez; pérez, l. pérez; rivas, r. fernández; sanz, n. martínez; ramos, j. veganzones; villamizar, p. rodríguez; javadpour, s.; kalani, n.; amininejad, t.; jamali, s.; sobhanian, s.; laurent, a.; bonnet, m.; rigal, r.; aslanian, p.; hebert, p.; capellier, g.; contreras, m. r. diaz; mejías, c. rodriguez; ruiz, f. c. santiago; lombardo, m. duro; perez, j. castaño; de hoyos, e. aguayo; estella, a.; viciana, r.; fontaiña, l. perez; rico, t.; madueño, v. perez; recuerda, m.; fernández, l.; sandiumenge, a.; bonet, s.; mazo, c.; rubiera, m.; ruiz-rodríguez, j. c.; gracia, r. m.; espinel, e.; pont, t.; kotsopoulos, a.; jansen, n.; abdo, w. f.; gopcevic, a.; gavranovic, z.; vucic, m.; glogoski, m. zlatic; penavic, l. videc; horvat, a.; martin-villen, l.; egea-guerero, j. j.; revuelto-rey, j.; aldabo-pallas, t.; correa-chamorro, e.; gallego-corpa, a. i.; granados, p. ruiz del portal-ruiz; faivre, v.; wildenberg, l.; huot, b.; lukaszewicz, a. c.; simsir, m.; mengelle, c.; payen, d.; sanz, n. martinez; valbuena, b. lobo; de la fuente, m. valdivia; almudena, p. matía; pérez, l. pérez; carmona, s. alcántara; abellán, a. navarro; simón, i. fernández; muñoz, j. j. rubio; ramos, j. veganzones; carmona, s. alcantara; almudevar, p. matia; abellan, a. naharro; lucendo, m. a. perez; perez, l. perez; dominguez, j. palamidessi; rivas, r. fernandez; villamizar, p. rodriguez; wee, s.; ong, c.; lau, y. h.; wong, y.; banderas-bravo, m. e.; olea-jiménez, v.; mora-ordóñez, j. m.; gómez-jiménez, c.; muñoz-muñoz, j. l.; vallejo-báez, j.; daga-ruiz, d.; lebrón-gallardo, m.; rialp, g.; raurich, j. m.; morán, i.; martín, m. c.; heras, g.; mas, a.; vallverdú, i.; hraiech, s.; bourenne, j.; guervilly, c.; forel, j. m.; adda, m.; sylla, p.; mouaci, a.; gainnier, m.; papazian, l.; bauer, p. r.; kumbamu, a.; wilson, m. e.; pannu, j. k.; egginton, j. s.; kashyap, r.; gajic, o.; yoshihiro, s.; sakuraya, m.; hayakawa, m.; hirata, a.; kawamura, n.; tsutui, t.; yoshida, k.; hashimoto, y.; chang, c. h.; hu, h. c.; chiu, l. c.; hung, c. y.; li, s. h.; kao, k. c.; sibley, s.; drover, j.; d’arsigny, c.; parker, c.; howes, d.; moffatt, s.; erb, j.; ilan, r.; messenger, d.; ball, i.; boyd, j. g.; harrison, m.; ridi, s.; muscedere, j.; andrade, a. h.; costa, r. c.; souza, v. a.; gonzalez, v.; amorim, v.; rolla, f.; filho, c. a. c. abreu; miranda, r.; atchasiri, s.; buranavanich, p.; wathanawatthu, t.; suwanpasu, s.; bureau, c.; rolland-debord, c.; poitou, t.; clavel, m.; perbet, s.; terzi, n.; kouatchet, a.; similowski, t.; demoule, a.; diaz, p.; nunes, j.; escórcio, s.; silva, g.; chaves, s.; jardim, m.; câmara, m.; fernandes, n.; duarte, r.; jardim, j. j.; pereira, c. a.; nóbrega, j. j.; chen, c. m.; lai, c. c.; cheng, k. c.; chou, w.; lee, s. j.; cha, y. s.; lee, w. y.; onodera, m.; nakataki, e.; oto, j.; imanaka, h.; nishimura, m.; khadjibaev, a.; sabirov, d.; rosstalnaya, a.; akalaev, r.; parpibaev, f.; antonucci, e.; rossini, p.; gandolfi, s.; montini, e.; orlando, s.; van nes, m.; karachi, f.; hanekom, s.; andrade, a. h.; pereira, u. v.; filho, c. a. c. abreu; costa, r. c.; parkin, m. s. w.; moore, m.; andrade, a. h.; costa, r. c.; carvalho, k. v. silva; filho, c. a. c. abreu; min, h. j.; kim, h. j.; lee, d. s.; choi, y. y.; lee, e. y.; song, i.; kim, d. j.; e, y. y.; kim, j. w.; park, j. s.; cho, y. j.; lee, j. h.; suh, j. w.; jo, y. h.; kim, k. s.; lee, y. j.; ferrero-calleja, j.; merino-vega, d.; gonzález-jiménez, a. i.; sigcha, m. sigcha; hernández-tejedor, a.; martin-vivas, a.; gabán-díez, Á.; luna, r. ruiz-de; de la calle-pedrosa, n.; temprano-gómez, i.; afonso-rivero, d.; pellin-ariño, j. i.; algora-weber, a.; fumis, r. r. l.; ferraz, a. b.; junior, j. m. vieira; kirca, h.; cakin, o.; unal, m.; mutlu, h.; ramazanoglu, a.; cengiz, m.; nicolini, e. a.; pelisson, f. g. f.; nunes, r. s.; da silva, s. l.; carreira, m. m.; bellissimo-rodrigues, f.; ferez, m. a.; basile-filho, a.; chao, h. c.; chen, c. m.; chen, l.; hravnak, m.; clermont, g.; pinsky, m.; dubrawski, a.; varas, j. luján; montero, r. molina; sánchez-elvira, l. alcázar; díaz, p. villa; delgado, c. pintado; ruiz, b. llorente; guerrero, a. pardo; galache, j. a. cambronero; sherif, h.; hassanin, h.; el hossainy, r.; samy, w.; ly, h.; david, h.; burtin, p.; charpentier, c.; barral, m.; courant, p.; fournel, e.; gaide-chevronnay, l.; durand, m.; albaladejo, p.; payen, j. f.; chavanon, o.; ortiz, a. blandino; pozzebon, s.; lheureux, o.; brasseur, a.; vincent, j. l.; creteur, j.; taccone, f. s.; fumagalli, f.; scala, s.; affatato, r.; de maglie, m.; zani, d.; novelli, d.; marra, c.; luciani, a.; de zani, d.; luini, m.; letizia, t.; pravettoni, d.; staszewsky, l.; masson, s.; belloli, a.; di giancamillo, m.; scanziani, e.; latini, r.; ristagno, g.; kye, y. c.; suh, g. j.; kwon, w. y.; kim, k. s.; yu, k. m.; babini, g.; ristagno, g.; grassi, l.; fumagalli, f.; bendel, s.; de maglie, m.; affatato, r.; masson, s.; latini, r.; scanziani, e.; reinikainen, m.; skrifvars, m.; kappler, f.; blobner, m.; schaller, s. j.; roasio, a.; costanzo, e.; cardellino, s.; iesu, e.; cavicchi, f. zama; fontana, v.; nobile, l.; vincent, j. l.; creteur, j.; taccone, f. s.; park, m.; you, k. m.; suh, g. j.; kwon, w. y.; ko, s. b.; kim, k. s.; xini, a.; marca, l.; lheureux, o.; brasseur, a.; vincent, j. l.; creteur, j.; taccone, f. s.; beane, a.; thilakasiri, m. c. k. t.; de silva, a. p.; stephens, t.; sigera, c. s.; athapattu, p.; jayasinghe, s.; padeniya, a.; haniffa, r.; santiago, a. iglesias; sáez, v. chica; ruiz-ruano, r. de la chica; gonzález, a. sánchez; kunze-szikszay, n.; wand, s.; klapsing, p.; wetz, a.; heyne, t.; schwerdtfeger, k.; troeltzsch, m.; bauer, m.; quintel, m.; moerer, o.; cook, d. j.; rutherford, w. b.; scales, d. c.; adhikari, n. k.; cuthbertson, b. h.; suzuki, t.; takei, t.; fushimi, k.; iwamoto, m.; nakagawa, s.; mendsaikhan, n.; begzjav, t.; lundeg, g.; dünser, m. w.; romero, d. gonzález; cabrera, j. l. santana; santana, j. d. martín; padilla, y. santana; pérez, h. rodríguez; torrent, r. lorenzo; kleinpell, r.; chouris, i.; radu, v.; stougianni, m.; lavrentieva, a.; lagonidis, d.; price, r. d. t.; day, a.; arora, n.; henderson, m. a.; hickey, s.; costa, m. i. almeida; carvalho, j. p.; gomes, a. a.; mergulhão, p. j.; chan, k. k. c.; shum, h. p.; yan, w. w.; maghsoudi, b.; tabei, s. h.; masjedi, m.; sabetian, g.; tabatabaei, h. r.; akbarzadeh, a.; saigal, s.; pakhare, a.; joshi, r.; pattnaik, s. k.; ray, b.; rousseau, a. f.; michel, l.; bawin, m.; cavalier, e.; reginster, j. y.; damas, p.; bruyere, o.; zhou, j. c.; cauwenberghs, h.; de backer, a.; neels, h.; deblier, i.; berghmans, j.; himpe, d.; barea-mendoza, j. a.; portillo, i. prieto; fernández, m. valiente; gigorro, r. garcia; vela, j. l. perez; mateos, h. marín; alves, s. chacón; varas, g. morales; rodriguez-biendicho, a.; carreño, e. renes; gonzález, j. c. montejo; yang, j. s.; chiang, c. h.; hung, w. t.; huang, w. c.; cheng, c. c.; lin, k. c.; lin, s. c.; chiou, k. r.; wann, s. r.; lin, k. l.; kang, p. l.; mar, g. y.; liu, c. p.; zhou, j. c.; choi, y. j.; yoon, s. z.; gordillo-brenes, a.; fernandez-zamora, m. d.; perez-borrero, l.; arias-verdu, m. d.; aguilar-alonso, e.; herruzo-aviles, a.; garcia-delgado, m.; hinojosa-perez, r.; curiel-balsera, e.; rivera-fernandez, r.; lesmes, s. p. gómez; rosario, l. e. de la cruz; hernández, a. ansotegui; herrera, a. n. garcía; sanz, e. regidor; sánchez, m. j. gómez; hualde, j. barado; pascual, o. agudo; león, j. p. tirapu; irazabal, j. m. guergue; pérez, a. gonzález; fernández, p. alvarez; amor, l. lopéz; albaiceta, g. muñiz; lesmes, s. p. gómez; rosario, l. e. de la cruz; hernández, a. ansotegui; sanz, e. regidor; sánchez, m. j. gómez; calvo, s. aldunate; herrera, a. n. garcía; hualde, j. barado; pascual, o. agudo; león, j. p. tirapu; corona, a.; ruffini, c.; spazzadeschi, a.; marrazzo, f.; gandola, a.; sciurti, r.; savi, c.; catena, e.; ke, m. w.; cheng, c. c.; huang, w. c.; chiang, c. h.; hung, w. t.; lin, k. c.; lin, s. c.; wann, s. r.; chiou, k. r.; tseng, c. j.; kang, p. l.; mar, g. y.; liu, c. p.; bertini, p.; de sanctis, f.; guarracino, f.; bertini, p.; baldassarri, r.; guarracino, f.; buitinck, s. h.; van der voort, p. h. j.; oto, j.; nakataki, e.; tsunano, y.; izawa, m.; tane, n.; onodera, m.; nishimura, m.; ghosh, s.; gupta, a.; de gasperi, a.; mazza, e.; limuti, r.; prosperi, m.; bissenova, n.; yergaliyeva, a.; talan, l.; yılmaz, g.; güven, g.; yoruk, f.; altıntas, n. d.; mukherjee, d. n.; agarwal, l. k.; mandal, k.; palomar, m.; balsera, b.; vallverdu, m.; martinez, m.; garcia, m.; castellana, d.; lopez, r.; barcenilla, f.; kaminsky, g. e.; carreño, r.; escribá, a.; fuentes, m.; gálvez, v.; del olmo, r.; nieto, b.; vaquerizo, c.; alvarez, j.; de la torre, m. a.; torres, e.; bogossian, e.; nouer, s. aranha; salgado, d. ribeiro; brugger, s. carvalho; jiménez, g. jiménez; torner, m. miralbés; vidal, m. vallverdú; garrido, b. balsera; casals, x. nuvials; gaite, f. barcenilla; cabello, j. trujillano; martínez, m. palomar; doganci, m.; izdes, s.; besevli, s. guzeldag; alkan, a.; kayaaslan, b.; ramírez, c. sánchez; balcázar, l. caipe; santana, m. cabrera; viera, m. a. hernández; escalada, s. hípola; vázquez, c. f. lübbe; penichet, s. m. marrero; campelo, f. artiles; lópez, m. a. de la cal; santana, p. saavedra; santana, s. ruíz; repessé, x.; artiguenave, m.; paktoris-papine, s.; espinasse, f.; dinh, a.; el sayed, f.; charron, c.; géri, g.; vieillard-baron, a.; marmanidou, k.; oikonomou, m.; nouris, c.; dimitroulakis, k.; soilemezi, e.; matamis, d.; ferré, a.; guillot, m.; teboul, j. l.; lichtenstein, d.; mézière, g.; richard, c.; monnet, x.; pham, t.; beduneau, g.; schortgen, f.; piquilloud, l.; zogheib, e.; jonas, m.; grelon, f.; runge, i.; terzi, n.; grangé, s.; barberet, g.; guitard, p. g.; frat, j. p.; constan, a.; chrétien, j. m.; mancebo, j.; mercat, a.; richard, j. c. m.; brochard, l.; prīdāne, s.; sabeļņikovs, o.; mojoli, f.; orlando, a.; bianchi, i.; torriglia, f.; bianzina, s.; pozzi, m.; iotti, g. a.; braschi, a.; beduneau, g.; pham, t.; schortgen, f.; piquilloud, l.; zogheib, e.; jonas, m.; grelon, f.; runge, i.; terzi, n.; grangé, s.; barberet, g.; guitard, p. g.; frat, j. p.; constan, a.; chrétien, j. m.; mancebo, j.; mercat, a.; richard, j. c. m.; brochard, l.; kondili, e.; psarologakis, c.; kokkini, s.; amargianitakis, v.; babalis, d.; chytas, a.; chouvarda, i.; vaporidi, k.; georgopoulos, d.; trapp, o.; kalenka, a.; mojoli, f.; orlando, a.; bianchi, i.; torriglia, f.; bianzina, s.; pozzi, m.; iotti, g. a.; braschi, a.; lozano, j. a. benítez; sánchez, p. carmona; francioni, j. e. barrueco; ferrón, f. ruiz; simón, j. m. serrano; spadaro, s.; karbing, d. s.; gioia, a.; moro, f.; corte, f. dalla; mauri, t.; volta, c. a.; rees, s. e.; petrova, m. v.; mohan, r.; butrov, a. v.; beeharry, s. d.; vatsik, m. v.; sakieva, f. i.; gobert, f.; yonis, h.; tapponnier, r.; fernandez, r.; labaune, m. a.; burle, j. f.; barbier, j.; vincent, b.; cleyet, m.; richard, j. c.; guérin, c.; shinotsuka, c. righy; creteur, j.; taccone, f. s.; törnblom, s.; nisula, s.; vaara, s.; poukkanen, m.; andersson, s.; pettilä, v.; pesonen, e.; xie, z.; liao, x.; kang, y.; zhang, j.; kubota, k.; egi, m.; mizobuchi, s.; hegazy, s.; el-keraie, a.; el sayed, e.; el hamid, m. abd; rodrigues, n. j.; pereira, m.; godinho, i.; gameiro, j.; neves, m.; gouveia, j.; e silva, z. costa; lopes, j. a.; mckinlay, j.; kostalas, m.; kooner, g.; dudas, g.; horton, a.; kerr, c.; karanjia, n.; creagh-brown, b.; forni, l.; yamazaki, a.; ganuza, m. sanz; molina, j. a. martinez; martinez, f. hidalgo; freile, m. t. chiquito; fernandez, n. garcia; travieso, p. medrano; bandert, a.; frithiof, r.; lipcsey, m.; smekal, d.; schlaepfer, p.; durovray, j. d.; plouhinec, v.; chiappa, c.; bellomo, r.; schneider, a. g.; mitchell, s.; durrant, j.; street, h.; dunthorne, e.; shears, j.; caballero, c. hernandez; hutchison, r.; schwarze, s.; ghabina, s.; thompson, e.; prowle, j. r.; kirwan, c. j.; gonzalez, c. a.; pinto, j. l.; orozco, v.; patiño, j. a.; garcia, p. k.; contreras, k. m.; rodriguez, p.; echeverri, j. e. title: esicm lives : part three: milan, italy. – october date: - - journal: intensive care med exp doi: . /s - - - sha: doc_id: cord_uid: qfecv h nan months is better than cole's formula. therefore, we conducted a retrospective analysis to investigate our hypothesis. methods: the ethics committee of our hospital approved this retrospective study. we included consecutive patients aged < years who underwent tracheal intubation under general anesthesia in our hospital from august to october . we collected the following data from the anesthesia records: age in months, height, weight, type of a tracheal tube, and id and od of tracheal tube. patients who were intubated using a cuffed tracheal tube or had incomplete data were excluded. we developed a regression formula for calculating id and od based on age in months and calculated the coefficient of determination r by using a regression analyses. a difference of . mm in the actual and predicted tube size was considered clinically permissible. then, we compared the rate of a clinical permissible estimation of the cole's formula and our new formulas used by multiple comparison analysis and a p value less than . was considered statistically significant. results: a total of pediatric patients received general anesthesia during the study period. of these, patients were excluded because they did not meet the inclusion criteria. finally, we included patients for this analysis. the regression formula for predicting id by based on age in months was id = . × age in months + . , and the coefficient of determination r was . . the regression formula for predicting od based on age in months was od = . × age in months + . , and coefficient of determination r was . . the rate of a clinical permissible estimation of our id and od formulas were significantly higher than that of the cole's formula ( %, % and %, respectively; p < . ). conclusions: our results showed that the prediction of id based on age in months is more useful than that using cole's formula. in addition, estimation of od based on age in months might be more rational because od varies according to the type of the tracheal tube used. these results should be confirmed in a future prospective study. introduction: survival among out-of-hospital cardiac arrest (ca) relies primarily on bystanders and their knowledge of basic life support (bls) manouvers [ ] . many medical societies and organizations recommend teaching bls at schools as part of the educative program [ ] ; being this a reality in north european countries, but not yet an education standard issue in others including spain. moreover, less is written about the perception of ca and cardiopulmonary resuscitation (cpr) among the general population, and even less in school age. objectives: describe the perception and knowledge about ca and cpr among a teenager school population in barcelona, spain. methods: prospective, descriptive study carried out between - and - among teenagers school population, based on surveys before and after bls -cpr classes. during this period , th classes were held, in different schools in barcelona. before attending the class , each pupil was asked to answer a survey with questions related to previous knowledge of sudden death, ca, and cpr, and their attitude towards them. the class consisted on a threehour theorical and practical instruction based on the european resuscitation council guidelines, adapted for laypersons. practices were held with an instructor (ratio instructor:pupil : [ ] [ ] [ ] , with the little anne mannequins (laerdal®). after the class, a new survey (post intervention) was distributed, with questions related to the new concepts and skills learnt, the attitude toward ca and cpr. results: we have instructed pupils ( . (± . ) years, . % female). the . % had heard about sudden death and ca before the class. regarding starting cpr: % said they were not capable of doing it, and . % suggested they would be able to do cpr but in a wrong manner. in a ca scene . % would contact the emergency service and start cpr, . % would call and wait, and . % would only do cpr. after attending the classes . % declared had understood the theorical concepts and practical skilles taught; . % would changed positively their attitude towards cpr; and . % would be prone to start maneuvers. conclusions: cpr and ca remain a well known issue among teenager population in barcelona, as long as being an interesting topic. nevertheless they do not feel capable of starting maneuvers. the concepts taught during the class were easy to learn , and after the intervention the majority were prone to start cpr. this population is adequate to teach cpr. introduction: to meet the need of patients family members and staff we started to guide visiting children at our adult icu in the st elisabeth hospital (ez) in tilburg years ago. to do so we developed a guidance leaflet for parents with practical instructions and information. additionally, practical advice is given, such as what to say to the child and what to expect when visiting. the leaflet is subdivided in developmental stages. furthermore we developed a book "mees op bezoek", in which a child visits his father at the icu. pictures show what children can expect, which helps prepare the child for visiting at home. an instruction box is present at the icu with icu materials such as an iv catheter, a pulse oximetry or a tracheal tube. these materials give children a tactile experience of the icu. the box is divided in two parts; the second part contains guidance materials for when a patient may die. pedagogical staff are available to support parents, children and staff. if there are more profound problems a referral to our children's psychologist is possible. we made some improvements to our waiting area to make it more appealing to children. we instructed and educated our nurses and doctors on how to use these materials and how to guide children. we recently merged with the twee steden hospital in tilburg (tsz), in this hospital there was no program to guide children. with the merger we also wanted to introduce our "child as a visitor program" at the icu on location tsz. we wanted to know if there were differences of opinion between the nursing staff on guidance of children. introduction: critically ill children are underfed early in their pediatric intensive care unit (picu) stay and this may contribute to worse outcomes. acute kidney injury (aki) occurs in % of all picu admissions and the risk of acute and chronic malnutrition is high in these patients with aki, and the presence of malnutrition in the context of aki has been associated with more severe clinical deterioration and organ dysfunction. critically ill children with aki are at high risk of underfeeding. objectives: to evaluate the effects of protein feeding on the resolution of aki. methods: this is a retrospective study of critically ill children admitted from / - / to the picu. patients with a diagnosis of end stage renal disease requiring renal replacement therapy or had received a kidney transplant were excluded. nutritional status assessed by weight and height who z-scores after admission and caloric and protein intakes calculated from i.v. fluids and parenteral and enteral nutrition for the first days of admission. energy and protein needs estimated by schofield and a.s.p.e.n., respectively. aki was defined by prifle (creatinine only) and persistent aki was defined as patients who did not resolve their aki during the first eight days of picu stay. introduction: sedation and analgesia are important components of postoperative management of neonates who underwent cardiac surgery. excessive or inadequate sedation may have a significant adverse effect on patient outcome. objectives. we aimed to determine which drug regimen would be most effective with less side-effect and better outcome. methods: from march till march we conducted a randomized controlled prospective study in neonates with congenital heart disease who underwent arterial switch operation in our clinic. inclusion criteria: ) gestational age more than weeks, ) birth weight over g, ) age -up to days, ) absence of concomitant diseases and surgical complications. patients were randomized into cohorts: patients ( %) were given infusion of dexmedetomidine with morphine boluses (study group) and patients ( %) were randomized to the standard regimen -infusion of morphine with diazepam boluses (control group). results: in both groups there were no differences in pre-and intraoperative indexes, duration of mechanical ventilation, sympathomimetic support, and time of infusion of dexmedetomidine/ morphine. in study group time of icu stay - . h -was significantly shorter than in control group - h (p- . ). onset of peristalsis and start of feeding in study group was earlier than in control group - st vs -d day (p- . ) and -d vs . -day (p- . ), respectively. in the control group there were more patients who had complicated feeding (start after -d day, bloating or vomiting) - ( %) vs ( %) in the study group. we did not observe any decrease of mean blood pressure and heart rate in the study group as it could be expected. conclusion: use of dexmedetomidine with morphine hydrochloride boluses for postoperative sedation and analgesia is effective and facilitates feeding process in neonates, leads to earlier onset of peristalsis and start of feeding, decreasing icu stay. impact of positive end expiratory pressure on cerebral hemodynamic in paediatric patients with post-traumatic brain swelling treated by surgical decompression s.m. pulitano' , s. de rosa , , a. mancino , g. villa , , f. tosi , p. franchi , g. conti introduction: asthma exacerbation is one of the most common diagnoses seen in the pediatric ed. several adult randomized controlled trials have shown that administration of high concentration oxygen leads to rise in carbon dioxide and increases admission rates. however, there are no studies in the pediatric population comparing the effects of high concentration oxygen versus titrated oxygen therapy in asthma exacerbation. objectives: we evaluated the effects of transcutaneous carbon dioxide (tpaco ) in high concentration oxygen therapy versus titrated oxygen therapy to maintain saturation between to % in pediatric patients with acute asthma exacerbation in the ed. methods: children to years with previously diagnosed asthma with moderate to severe asthma exacerbation (asthma score > ) were randomized to high concentration oxygen therapy ( % oxygen via face mask at > l/min.) or titrated oxygen therapy (titrated up from % via a blender continuously) to maintain saturations between to % while receiving their nebulized treatments. exclusion criteria included disorders with hypercapnic respiratory failure, unconscious patient, history of congenital heart disease, pregnancy, history of smoking or using sedatives and depressants. asthma therapy was provided per the ed physician. asthma score, tpaco , pefr (age > years) were measured at the start of the study and every minutes for the first hour then every minutes until disposition decision. the primary outcome was increase in tpaco with high concentration oxygen therapy. secondary outcome included rate of admission to the hospital. results: patients were enrolled with mean age of . years. % were males and % had poorly controlled asthma with mean asthma score of . . there were patients enrolled in the high concentration oxygen group (hcot) and patients in the titrated oxygen group (tot). the minute tpaco were not statistically different( . ± . hcot v. . ± . tot,p = . ); whereas, the minutes tpaco was statistically different( ± . hcot v. . ± . tot, p = . ). the minutes tpaco was . ± . hcot v. . ± . tot, p = . . at minutes, % of the patients had a rise in tpaco in hcot v. % in the tot(p = < . ), and at minutes % had a rise in tpaco in hcot v. % in the tot(p = < . ). the asthma score was similar in the two groups at minute ( . ± . hcot v. . ± . tot, p = . ); whereas, the minutes asthma score was lower in the tot( . ± . hcot v. . ± . tot, p = . ). the rate of admission to the hospital was . % in hcot v. . % in the tot. conclusions: high concentration oxygen therapy in pediatric asthma exacerbation leads to significantly higher carbon dioxide levels. it also causes rise in carbon dioxide from the baseline which increases the asthma scores and rate of admission. introduction: in critically ill patients, temperature measurement is a routine important care task and can lead to important decisions. rectal temperature and bladder temperature are now used as a continuous body temperature measuring method in the pediatric intensive care, but these practices have several disadvantages including the patient´s discomfort, the risk of organ injury and the inaccurate measuring caused by the sensor position. a new temperature monitoring system m tm spot-on tm (spoton) is a non-invasive zero-heat-flux thermometer designed to estimate core body temperature from the skin surface. although the usefulness and accuracy of spoton system in adult patients have been demonstrated, there are no reports on pediatric intensive care patients. objectives: the aim of this study was to evaluate the effectiveness of a new temperature measurement system attached to the forehead, and compare it to rectal temperature sensors in terms of correlation and accuracy. methods: pediatric patients weighing less than kg, who were managed in our icu during the period from february to march , were enrolled in this study. core temperature was measured and recorded at every minute from the both thermistor of a rectal thermal probe and with spoton in these patients. the data when the forehead sensor or rectal probe was taken out for nursing care was excluded from statistical analysis. results: sets of data of children (mean bw g) were examined retrospectively. in all patients, spoton showed higher than the rectal temperatures. the spoton temperature was analyzed to be . degrees ( % limits of agreement of ± . ) higher temperature than the rectal one with a moderate correlation(r = . ). discussion and conclusion: rectal temperature measurement is the gold standard method for pediatric patients in icu despite several complications of rectal injury. our children´s study demonstrated the slightly higher temperature in the spoton than rectal temperature with a substantial correlation. one possible explanation could be that the abundance of brain blood flow of children affected the results. our study concluded that spoton system could be used as a highly reliable noninvasive core body temperature measurement for small pediatric patients. introduction: viral bronchiolitis (vb) remains one of the leading causes of hospitalization in early childhood. despite the heavy burden of vb on the healthcare system, little is known about the incidence of acute respiratory distress syndrome (ards) in this cohort of patients. in , the pediatric acute lung injury consensus conference (palicc) published guidelines for the definition, management and research in pediatric ards (pards) ( ) . objectives: to study the incidence and prevalence of pards in vb and to study the association between pards and specific picu outcomes such as incidence of mechanical ventilation, noninvasive ventilator settings length of picu stay in this group of patients. methods: this is a retrospective single center observational cohort study that examined children - years of age admitted to the picu with vb and respiratory failure (rf) from - . palicc criteria were applied to define pards. clinical and demographic data was collected. patients with a diagnosis of congenital heart disease or pre-existing chronic lung disease were excluded. data was expressed as median with iqr ranges. test of bivariate association were performed using mann whitney u test and chi square test. a two tailed p value of ≤ . was used to denote statistical significance. results: out of patients with rf, with vb met study criteria. eighty of these ( %) patients admitted for vb met the criteria for pards or at risk for pards. out of these patients, ( %) met criteria for pards and ( %) met criteria for "at risk of pards". median age was ( , ) months and the median weight was . ( . , . ) kgs. most common etiology for vb was respiratory syncytial virus (rsv) % followed by rhinovirus ( %). there was no statistically significant difference in age, weight, and etiology of vb in patients with pards and those "at risk of pards." patients with pards had longer hospital and picu length of stay (los) and more likely to receive diuretics compared to those "at risk for pards" ( ( , ) vs ( , . ) , p = . ; ( , ) vs ( , . ), p < . ; and % vs %, p = . respectively). nineteen ( / , %) patients with pards received invasive mechanical ventilation with a median duration of ventilation of ( , ) days. conclusions: almost a quarter of children with vb developed pards or were at risk of pards. the presence of pards in children with vb was significantly associated with longer picu and hospital los compared to those "at risk of pards". children with vb are a high risk group for the development of pards. introduction: mean platelet volume(mpv) seems to be a marker of platelet activation and may be related to severity of illness. changes in mpv and platelet count(plc)could be used for disease prognosis and mortality in icu patients. we hypothesized that mpv changes and plc could be used as prognostic tools in pediatric surgical intensive care units(psicu). objectives: to study the association between mpv changes and mortality and morbidity in psicu. also to study the relation between plc and psicu mortality and morbidity. methods: this descriptive observational study was conducted on consecutive pediatric surgical patients who admitted to psicus at cairo university hospitals starting from / - / / .after approval by research ethics committee,informed consents were obtained from parents and pediatric cases aged from month- years and stayed for > h were enrolled.mpv and plc were obtained and recorded at baseline(preoperative values),on the day of icu admission(day ), st , nd , rd , th and th days.to measure daily mpv changes; (Δmpv) was constructed and computed where Δmpv = ([mpvday(x) − mpvday ( )]/mpvday( ) × %. pediatric index of mortality(pim)score was calculated on day and the pediatric logistic organ dysfunction(pelod)score was recorded daily. results: patients who developed icu complications (fever, sepsis, pneumonia, required mechanical ventilation, needed vasopressors or blood transfusion); showed higher Δmpv compared to non complicated cases (fig. ) . this association was statistically significant on days (p value = . ), (p value < . ), (p value < . ) and (p value = . ) of icu stay but it´s insignificant on day (p value = . ).according to receiver operating characteristics(roc) curve analysis, the sensitivity of Δmpv to detect complications on day was . % but its specificity on day was . %.patients who developed icu complications showed lower plc compared to non complicated cases (fig. ) .this association was statistically significant on days (p value < . ), (p value < . ) and (p value < . ) but it was insignificant on day (p value = . ), (p value = . ) and (p value = . ). on other hand, the sensitivity of plc to detect complications day was . % but the specificity was . %, while the sensitivity of plc to detect complications day was . % but the specificity day was %. conclusions: mpv dynamics and plc have prognostic roles and could be used in determining several complications in critically ill pediatric surgical patients. plc is a more specific and sensitive tool to detect complications than mean mpv dynamics. introduction: limited information exists regarding the association between functional status at icu admission at and outcomes. objectives: we hypothesized that initial functional status assessment as well the amount of physical therapy delivered would be associated with outcomes in icu survivors. methods: we performed a retrospective cohort study in one boston teaching hospital on , adults who received critical care from to and survived hospitalization. all patients had a formal evaluation by a physical therapist in the week prior to icu admission and at hospital discharge. the exposure of interest was functional status determined by a licensed physical therapist based on the functional mobility sub scales of the functional independence measure. all patients received physical therapy to improve functional performance. the primary outcome was -day all-cause mortality. we used logistic regression to describe how -day mortality differed with functional status at icu admission. negative binomial regression was utilized to describe how functional status at hospital discharge differed with functional status at icu admission, the extent of physical therapy received and hospital length of stay. results: the cohort was % male, % non-white and had a mean age of . years. % of the cohort had sepsis, % had acute kidney injury, % had respiratory failure and % were surgical cases. the median [iqr] hospital length of stay was [ , ] days. the -day mortality rate was . %. functional status at icu admission was robustly associated with -day mortality. in a logistic regression model adjusted for age, gender, race, surgical patient type, deyo-charlson index, acute organ failure, sepsis, length of stay and the extent of physical therapy received, the second lowest and lowest quartiles of functional status at icu admission was associated with a . in critically ill patients, decreased functional status at icu admission is associated with increased -day mortality. increased intensity of physical therapy is associated with improved mortality outcomes. both functional status at icu admission and the intensity of physical therapy contribute to functional status determined at hospital discharge. introduction: patients admitted to critical care are shown to lose significant muscle mass, with the degree of muscle loss as high as % in the first week for those in multi organ failure (puthucheary, ) . early rehabilitation has been demonstrated as a safe and effective method of improving functional status at the point of critical care discharge and reducing both icu and hospital length of stay (mcwilliams et al., ) , although the specific impact of this on muscle mass has not been reported. objectives: this study aimed to analyse the impact of enhanced physiotherapy incorporating early mobilisation on the rate of muscle decline for patients admitted to critical care. methods: patients admitted to a large uk teaching hospital during the trial period and ventilated for ≥ days were included in the study. patients were randomised to either enhanced physiotherapy or standard care groups as part of a larger rct. baseline measurements were taken on the day of recruitment and then repeated at critical care discharge. muscle mass was measured using ultrasound to calculate cross sectional area of quadriceps and biceps. to ensure validity , measures were taken and the average of these taken as the final value. all scans were reviewed for agreement by therapists trained in muscle ultrasound. results: patients were included in the analysis. patients in the enhanced physiotherapy group mobilised earlier and achieved a higher level of mobility at the point of critical care discharge (see table .) all subjects demonstrated a reduction in muscle mass of both quadriceps and biceps over the course of their critical care stay. the extent of muscle loss was however lower in those receiving the enhanced physiotherapy, although this did not reach statistical significance (quads % vs %. p = . ; biceps % vs %, p = . ). conclusions: a programme of enhanced physiotherapy appeared to be associated with a lower rate of muscle loss in both biceps and quadriceps in comparison to standard care. an appropriately powered rct is required to assess these findings. introduction: survivors of critical illness experience a range of impairments after intensive care, including physical, cognitive and psychological compromise. the provision of information using a diary to describe the intensive care unit (icu) experience is one strategy that has been proposed to improve psychological health. objectives: the purpose of this study was to explore similarities and differences in patients' and relatives' perceptions of information containing strategies, including icu diaries, to assist recovery after critical illness. methods: an exploratory mixed-methods study was undertaken in an australian tertiary hospital with general icu patients admitted for ≥ days and their relatives. semi-structured interviews were conducted - months after icu discharge. transcripts were analysed using content analysis. results: twenty-two patients and relatives consented to participation and completed interviews prior to reaching data saturation. patients were usually male ( %) and aged ± years. patients raised similar themes to relatives, although with diverse opinions. themes of wanting to have a diary kept and considering they would find a diary helpful were consistent across a majority of participants, although with a minority expressing a desire to 'move on' and would not have liked a diary kept. differences between patients and relatives arose in the areas of the purpose, content, ownership and timing of delivery of a diary. patients viewed the diary as a therapeutic tool while relatives considered it as an information sharing mechanism, including as a mechanism to demonstrate to the patient 'how sick he really was' and 'what he put us through'. possibly as a result of these differences, patients considered that ownership of the diary rested with them while some relatives envisaged shared ownership. patients were more likely to note that the diary should not be provided to them until some weeks after icu while relatives considered an early time point soon after icu discharge to be appropriate. patients were more likely to raise concerns about the potential negative impact of information sharing strategies including diaries and return visits to the icu. conclusions: patients and relatives expressed common themes related to information sharing strategies after icu, but with some important differences. differences in purpose, content, ownership and timing of delivery of a diary suggest there is a need to consider whether the same intervention meets the needs of both groups of stakeholders. introduction: in the intensive care unit (icu) several patients are disturbed in their cerebral function due to their critical illness and medication, leading to discomfort, agitation, restlessness, pain and delirium. rocking chair mobilization therapy (rcmt) is a chair with good seating comfort which gives rhythmic movements. rocking chair studies have shown concrete results to improve patient satisfaction, balance and well-being in patients who suffered from dementia ( ) . however, no studies have evaluated the value and the effect of rcmt for critically ill patients in the icu. objectives: the purpose of the study was to evaluate whether rcmt could be used in the rehabilitation of critically ill patients in the intensive care. the focus was to explore the impact of rcmt on critically ill patients comfort, pain, agitation and delirium. methods: the evaluation took place in a medical/surgical icu in denmark in the period from may to july . patients ≥ years, who were physically stable and had the ability to be mobilized to chair could participate in the evaluation. the rcmt session lasted minutes.each session with rcmt was evaluated by registration of patient consciousness (richmond agitation and sedation scale (rass)), pain (numeric rating scale (nrs) - or by critical-care pain observation tool (cpot)), delirium (cam-icu) before and after the session. patient comfort was assessed by the patients as well as by the nurses during the session. results: sessions with rcmt were evaluated. males and females, age between and years, participated in the evaluation. the results showed a decrease in patient agitation level and an increase in patient consiousness. patients´with rass > decreased from before the session to after the session. patients with rass ≤ − decreased from before the session to after the session. a decrease in delirium where patients were assessed cam-icu positive before the session and patients after the session. a decrease in pain where six patients scored nrs > before the session compared to one patient after the session and patients had cpot scores > before the session compared to patients after the session. assessment and evaluation of comfort by patients themselves and by the nurses, who cared for the particular patient, showed that rcmt was associated with a high degree of patient relaxation and comfort. conclusions: promising results gives reason to recommend rcmt for critically ill patients in the icu, as an alternative holistic nonpharmacological intervention to stimulate patients´bodily awareness and enhance patient comfort and rehabilitation. introduction: critical illness and immobility in the intensive care unit (icu) lead to a loss of muscle mass and reduced exercise capacity for many years following hospital discharge. [ ] nutritional management of the critically ill is challenging and most nutritional studies are focused in this period. nutritional recommendations are for a high protein diet to minimise muscle breakdown and support protein synthesis during rehabilitation. nevertheless, during the rehabilitation period little is known of patients' protein intake and physical functioning. objective: to investigate physical functioning, frailty and dietary protein intake after months of icu discharge. method: our icu is recognised as a therapy rehabilitation centre and the only icu member of the uk rehabilitation outcomes (uk-roc). patients cognitive and physical functioning is assessed as part of their rehabilitation therapy with the functional independence measure (fim) score [ ] . the fim contains items on motor ( ) and cognitive ( ) functions that are scored on a -point ordinal scale based on the amount of assistance a person requires to perform specific activities. the fim scores on icu discharge and also on return to the rehabilitation clinic after months were assessed. in addition, frailty was assessed based on a scale ranging from very fit to very severely frail, terminally ill [ ] and patients were asked to complete a protein food frequency questionnaire. results: twenty patients were assessed. data are reported as mean and (standard deviation). patients were male % and . years ( . ). paired t tests of the changes in fim scores from discharge showed significant increments; . ± . (p = . ) and . ± . (p < . ) for motor and cognitive scales respectively. nevertheless, patients reported that they were "vulnerable to moderately frail" in the frailty scale. dietary intake was also inadequate with a protein intake of . g/kg ( . ). objectives: physiotherapy rehabilitation is a recognised component of icu care. the intensive care society -core standards recommends that rehabilitation is 'at a level that enables the patient to meet their rehabilitation goals for as long as they…are able to tolerate it'. in order to investigate and measure the terms 'tolerate' and 'level', physiological measurements and their relationship with self-perceived exertion and tolerance were analysed. methods: the project was registered with guy's & st.thomas' nhs foundation trust, clinical audit group, (project no. ). a convenience sample, of icu patients undergoing active physiotherapy led rehabilitation, were observed between july and september . a modified exertion scale was used to measure patients' perceived effort. patients also rated tolerance of the session using a tolerability scale, created based on the exertion scale. sessions were timed, heart rate, blood pressure and oxygen saturation were monitored and the cardiovascular impact of the session measured using heart rate reserve (hrr). results: nine rehabilitation sessions were observed; mean length of minutes (range - ). minimum target hrr (> %) was achieved, but not sustained, by patients, while peaked within a normal target hrr ( - %). of the patients, were able to use the tolerability scale and the exertion scale. there did not appear to be a relationship between hrr and either perceived scale measurements. there did appear to be a link between perceived exertion and perceived tolerability with of the patients scoring within points. conclusions: reported perception of exertion and physiological markers could both indicate the 'level' patients are working at. we were able to measure effects of rehabilitation on heart rate. the majority of patients were able to use exertion and tolerance scales. however, the change in heart rate was not great enough to suggest a training effect, despite their exertion scores implying high effort levels. to fulfil the icu society recommendations, a good understanding is needed of how hard patients are working during rehabilitation. further research is needed to determine why there may be disparity between heart rate and patient-reported measures of exertion; and if either is a useful guide for exercise prescription with icu patients. introduction: critically ill patients are at risk of developing deconditioning, muscle atrophy and functional impairments long after hospital discharge. there is evidence demonstrating benefits of mobilization in critically ill patients -improved functional outcome and reduced icu and hospital length of stay. however, there is limited information about how these advances are translated to clinical practice. objectives: to obtain a baseline data on patients who are eligible for mobilisation in icu and how many of these patients are optimally mobilised in icu. this would enable us to undertake a clinical practice improvement project (cpip) using the plan-do-study-act (pdsa) implementation strategy to optimise mobilisation in at least % of all eligible icu patients. methods: setting. -bedded intensivist led closed surgical icu. the mobilisation team composed of physiotherapists, bedside nurses and respiratory therapists who worked along with an intensivist. prospective audit conducted to collect data on the patients who met the eligibility criteria of mobilisation over a -month period. cpip team results: our audit revealed that at baseline, only % of all eligible patients were optimally mobilised. rca revealed a total of barriers and through multi-voting and pareto-charting, we identified the top barriers to change. key barriers identified were: . mobility not being a part of the daily review routine . staff were unsure of the eligibility criteria . lack of knowledge the benefits of optimal mobilisation in the critically ill. the team proposed following strategies to overcome the barriers: . combined icu multi-disciplinary handover rounds with the lead consultant asking the question "can this patient be mobilised?" for every patient reviewed. . providing a bedside decision-making algorithm on eligibility criteria, displayed within visibility of staff's work area. . undertake sharing session with ground staff on the importance and benefits of optimising mobility of the critically ill. conclusions: our audit revealed that less than half of eligible patients received early mobilisation. our cpip -a quality improvement initiative identified barriers in translating knowledge into clinical practice. through various tools of cpip, we identified the key barriers and strategies to overcome these barriers and thereby achieving the goal of optimising mobilisation in icu patients. introduction: bed rest and immobility during critical illness may result in profound physical deconditioning. the multidisciplinary team in intensive care includes physiotherapists, who are responsible for performing diagnoses and procedures for critically ill patients, such as ventilation, respiratory monitoring and assessments of musculoskeletal, neurological, metabolic and cardiovascular diseases, and for the prevention and treatment of the effects of prolonged immobility. objectives: to evaluate the influence of physiotherapy on quality indicators in the intensive care unit of the sagrada esperança clinic in luanda, angola. methods: a retrospective before-after study was designed to assess some quality indicators within the intensive care unit between july and september , where there were no physiotherapists specially trained for respiratory care, and from january to march , where the physiotherapists integrated a multidisciplinary team. the quality indicators analyzed were: the average duration of mechanical ventilation, prevalence of ventilator associated pneumonia and the rate of ventilated patients with non-invasive ventilation. the study population comprised patients for and for . in this study the patientsć ategorization was made by age, sex, pathology and also according with the patient classification systems saps and sofa. the statistical analysis used the systems spss version for a % significance level. results: the results obtained after analyzing the two homogeneous groups according to age, gender, type of admission and severity influencing the physiotherapy care in icu quality indicators, in the sagrada esperança clinic, highlights the decrease of the average number of days with mechanical ventilation but it is not observed a significant relation between physical therapy and this indicator (p = : ). furthermore, it is also observed a decrease ventilator associated pneumonia, and a significant relation between this indicator and the respiratory physiotherapy. last, there is a strong relation between the increase on the number of patients without invasive ventilation and physiotherapy (p = . ). conclusions: in this study it is demonstrated the respiratory therapy influences in some quality indicators, namely regarding the reduction of ventilation associated pneumonia and the promotion of non-invasive ventilation in the icu of the cse. introduction: the incidence of candidemia has increased in icu patients ( ) . in addition, there are differences in epidemiology among different countries. we have previously shown an increased proportion of nonalbicans candida species in our icu ( ) . objectives: to identify the variables associated with candidemia due to non-albicans candida species, as well as with fluconazole-resistant strains in a multidisciplinary icu. methods: all icu patients with candidemia were prospectively studied over two time periods ( - and - ) . demographics, illness severity, clinical and laboratory variables were recorded. sofa score value on icu admission subtracted from the value on the day of candidemia occurrence was defined as delta sofa. patients with c. albicans candidemia were compared to those with non-albicans candidemia. also, patients with fluconazole-resistant candidemia were compared to those without fluconazole resistance. results: among patients with icu-acquired candidemia, in patients candidemia was due to c. albicans and in patients to non-albicans species. c. parapsilosis was the most common ( %) followed by c. albicans ( %). the median time from icu admission to candidemia onset was and days for c. albicans and nonalbicans respectively, p = . . similarly, the median time for candidemia due to fluconazole sensitive isolate was days and days for fluconazole resistant, p < . . resistance to fluconazole was % and % in c. albicans and in non-albicans species respectively, p < . ).presence of shock on candidemia day (or . ; ci: . - , p = . ) and the delta sofa score (or . ; ci: . - . , p = . ) were independently associated with candidemia due to c. albicans. independent risk factors for fluconazole resistant isolates were the length of icu stay before the development of candidemia (or . ; ci: . - . , p = . ) and the presence of shock on candidemia day (or . ; ci: . - . , p = . ). previous fluconazole exposure ( patients) was not associated with fluconazole resistance. conclusions: this study confirms the predominance of non-albicans candida species, in our icu patients with candidemia, with high prevalence of fluconazole resistance. early onset of candidemia and the presence of shock were most likely due to c. albicans whereas late onset was associated with fluconazole-resistant non-albicans species. these findings may be of value for empiric antifungal treatment selection. introduction: invasive aspergillus infections are well-known complications of immunocompromised states, chronic obstructive pulmonary disease and haematopoietic stem cell transplant. bacterial coinfection is well described in influenza literature but there is scarce data on invasive aspergillosis complicated severe influenza infection. objectives: the aim of this study is to describe the clinical and demographic characteristics of patients with aspergillus isolation in severe influenza a(h n ) pneumonia. methods: prospective, observational, multicenter study conducted in spanish icus from to . all individuals with severe primary influenza a(h n ) pneumonia requiring invasive mechanical ventilation were included in the study. influenza a(h n ) patients without coinfection were compared with those with aspergillus isolation in respiratory samples. all serotypes were confirmed using rt-pcr at icu admission. patients´demographic, clinical, radiologic features, laboratory values, icu and hospital length of stay (los) and outcomes were recorded. discrete variables are expressed as counts (percentage) and continuous variables as medians with th to th interquartile range (iqr conclusions: the mortality rate was significantly higher in h n patients with aspergillus isolation in respiratory samples. diagnosis of invasive aspergillosis in critically ill patients in the post-influenza era must be re-evaluated. clinical studies should be conducted in order to know the clinical significance of aspergillus isolation in respiratory samples in intubated patients with primary influenza a(h n ) pneumonia. methods: this prospective, monocentric, study performed over months assessed the value of a twice weekly dosage of fungal biomakers (candida serology iga, igm, igg, ß-d-glucan (bdg) and mannan antigens) in icu patients after lt. proven/probable/possible infection was defined according to the eortc/msg criteria. colonisation was defined by presence of candida sp in respiratory samples without any sign of invasive infection. the study was approved by the ethical committee. results are presented as means. results: we analysed icu patients after lt. % had a candida sp colonisation while an invasive infection was proven in ( %) patients. candida albicans was cultured from % of the pulmonary samples. % of the invasive infections were related to c. glabrata. results of biomarkers dosages are presented in the table. positive candida igg serology was observed in % of the cases. mortality rate at -months after lt was % in the immunised patients versus % in nonimmunised patients. an invasive candidiasis (ic) was present in % of the immunised patients versus % in non-immunised patients. at least one bdg dosage was positive in % of the cases. bdg dosage value decreased after surgery, reaching a non-significant value after the th day. in proven ic, bdg measurements reached concentrations > pg/ml, days before initiation of antifungal treatment. no patient had positive mannan antigen measurement. conclusions: a twice weekly dosage of bdg seems to be useful in the decision making process for early initiation of antifungal therapy in lt patients. the cutoff for a significant value of bdg needs to be defined. pre-transplantation assessment of candida igg serology could help to identify patients at risk of post-operative fungal infection. introduction: the antifungal (af) therapy strategy (pre-emptive vs culture based treatment) in intensive care unit is a matter of debate [ ] . the necessity to not delay the initiation of the af in invasive candidiasis (ic) must be balanced with the cost and risk of selecting resistant pathogens when af are prescribed too widely. burn patients are at risk of ic because of the frequent use of antibiotics and immunodeficiency. objectives: to evaluate our antifungal (af) therapy strategy in suspected or proven ic in terms of prognosis and risk factors of ic. methods: observational, descriptive, retrospective study conducted from june to september in the saint louis hospital burn unit. inclusion criteria: patients treated with pre-emptive (severe sepsis or septic shock with candida sp colonization) or curative (proven, pic) af. the outcome was the pic (candidemia and/or positive peritoneal sample). clinical characteristics, organ supports, af treatments and outcome were collected and compared between pic and suspected ic (sic). the results are presented in median (iqr) or n (%). results: patients were admitted during the study period including with a total body surface area (tbsa) > %. treated with af including pic ( %). in those patients: age ( - ), tbsa ( - ), sapsii ( - ), absi ( - ) and sofa ( - ). renal replacement therapy ( %), mechanical ventilation ( %), parenteral nutrition ( %). inhospital mortality = % ( % sic vs % pic, p = . ). patients with pic ( %) were treated before the ic diagnosis ( because of filamentous infection before the pic). the delay between admission and af treatment initiation was days. patients characteristics, organs supports were not significantly different between pic and sic at the treatment initiation except for the sapsii (pic ( - ) vs sic ( - ), p = . ). patients ( %) received an echinocandin as a first-line treatment. ( . - . ) sites were monitored for candida colonization the week before treatment initiation. patients with pic had higher colonization index than those with sic ( % vs %, p = . ) and a candida score significantly higher ( vs ( . - . ) respectively, p = . ). a semiquantitative estimation of the fungal inoculum had no predictive value. conclusions: in this study, the majority of pic were treated after diagnosis confirmation. only / ( %) patient treated preemptively did declare a pic. the outcome was not different when the treatment was initiated after confirmation. the results of this study highlight the difficulty to identify patients at highest risk of ic, and question the strategy of preemptive treatment in this population. objectives: we wanted to determine whether pct guided antibiotic rationalisation could reduce fungal colonisation and antifungal usage. methods: we undertook a retrospective observational study at a nine bedded icu department in the united kingdom. we collected data on all patients admitted to the unit in the year prior and post the introduction of pct guided rationalisation of antibiotics. we used the pharmacy database to assess the use of antibiotics, correcting for changes in costs over this time. we used the microbiology database to assess the rate of patients colonising fungal species and those requiring treatment. results: since the introduction of pct, the average expenditure on antibiotics per icu admission fell . % (p . ). the rate of icu patients colonised with a fungal species fell from . % to . % (p < . ). the incidence of patient's prescribed systemic antifungal therapy fell from . % to . % (p < . ). conclusions: we demonstrated a significant reduction in patients colonised with fungal species and those requiring anti-fungal therapy since introducing pct guided rationalisation of antibiotics. a prospective randomised controlled trial is required to assess whether this equates to improved patient outcome. ), median days. c. albicans was the most commonly isolated species (sp) ( , %), candidemia was the most common diagnosed infection. the sp isolated in blood cultures (bc) were: , % c. albicans, , % c. haemulonii, . % c. parasilopsis. we had + bc for trichosporon asahii. catheter -related infection by c. albicans, c. parasilopsis, and candida haemulonii was diagnosed in patients. positive urine samples were found mostly for c. albicans . %. the most frequently factors associated with fungal infection were: > than days in the icu . %, urinary catheter . %, broad-spectrum antibiotic exposure . %, indwelling central venous catheter (cvc) . %, feeding tube . %, total parenteral nutrition . %, invasive mechanical ventilation . %. to highlight an association with acinetobacter baumannii in . % of our patients. doctors chose fluconazole in . % as a first line of therapy. an antibiogram was performed and the susceptibility was confirmed. icu mortality rate, . %. conclusions: in our environment, c. albicans continues to be the species that causes the largest number of invasive candidiasis. prolonged stay in the icu is an important risk factor to develop fungal infections. even with the particular features of a burn patient, their complexity, and the negative impact of each infection; fluconazole keeps having an important role in the treatment as a first line. the effect of introduction of daily chlorhexidine bathing on healthcare-associated infections and acquisition of multi-drug resistant organisms e. ahmadnia introduction: it has been suggested that daily bathing with chlorhexidine impregnated cloths may significantly reduce the acquisition of multi-drug resistant organisms (mdros), incidence of central line associated bloodstream infections (clabsis), and the development of intensive care unit (icu) acquired bloodstream infections [ ] . however, more recent data have failed to support daily bathing of critically ill patients with chlorhexidine for these purposes [ ] . objectives: to determine if the implementation of a daily chlorhexidine bathing regimen affects acquisition rates of mdros, the incidence of clabsis, and icu bacteraemias. methods: a quality improvement project was conducted at a bedded adult critical care unit within a uk university hospital (incorporating major trauma, medical, and surgical patients). during the year control period (december to november ), all patients were bathed using soap and water. during the subsequent intervention period (december to november ), all patients were bathed using % chlorhexidine impregnated cloths (clinell, gama healthcare). the acquisition of mdros, incidence of clabsis and icu bacteraemias were recorded during these periods ( months pre-and months post-chlorhexidine for clabsis, one year for the other outcomes). results: the study covered patient bed days ( pre-and post-introduction of chlorhexidine bathing). there were an identical number of mdro acquisitions in each group ( ), giving rise to an mdro acquisition rate per bed days of . in the control group compared to . in the chlorhexidine group (p = . ). clabsi incidence per bed days was higher in the control group compared to the chlorhexidine group ( . vs . ; p = . ). the incidence of significant bacteraemias per bed days was similar in the the two groups ( . before and . during chlorhexidine bathing; p = . ), but the incidence of bacteraemias due to skin commensals per bed days was lower in the chlorhexidine group ( . vs . ; p = . ). conclusions: at our large university hospital icu with a heterogeneous patient population, the introduction of routine daily chlorhexidine-impregnated cloth bathing appears to significantly reduce the incidence of bacteraemias due to skin commensals and demonstrates a non-significant reduction in clabsis. given the uncertainties surrounding diagnosis in the icu, the effect seen may be of benefit in reducing the use of antibiotics to cover for these skin commensals -both in terms of antibiotic stewardship and health economics. introduction: the current cdc guideline published in for the prevention of intravascular catheter-related infections recommends skin preparation with a greater than . % chlorhexidine with alcohol solution before cvcs or acs placement and with dressing changes, which was changed from % chlorhexidine recommended in the guideline. however, few studies investigated the superiority of % chg over either . % chg or % pvi for the prevention of catheter colonization as cdc guideline recommends. objectives: efficacy comparison of three antiseptic solutions [ % aqueous povidone-iodine (pvi), and . % and . % alcoholic chlorhexidine gluconate (chg)] for preventing intravascular catheter colonization. this was a open-label, multicenter, prospective, randomized controlled trial conducted at icus in japan. the intravascular catheters included central venous catheters (cvcs) and arterial catheters (acs). patients aged > years of age undergoing cvc and ac insertion in icu were randomized to receive one of three antiseptic preparations pre-insertion. catheters were removed when no longer necessary or if catheter-related infection was suspected. after catheter removal, distal tips were cultured using semi-quantitative/ quantitative techniques. catheter colonization and catheter-related bloodstream infection (crbsi) incidences were compared. results: while a total of catheters were randomized, several catheters were excluded due to withdraw of their informed consent and lack of cultured catheters after randomization, and ( %) catheters were included in the full analysis ( . % chg n = , . % chg n = , and % pvi n = ). the median catheterization duration was . days ( % ci: . - . days); no significant intergroup differences were observed (p = . ). catheter-tip colonization incidence (per catheter days) was . , . , and . events in % pvi, % chg, and . % chg groups, respectively (p = . ). catheter colonization risk was significantly higher in the % pvi group. no significant intergroup differences crbsi probability were observed introduction: spontaneous intracerebral hemorrhage (ich) is the most fatal stroke subtype worldwide caused by spontaneous vascular rupture due to hypertension or amyloid angiopathy. an accurate prediction of ich outcome would assist both families and physicians to decide therapies and monitorization at an early stage. objectives: to evaluate the relationship between the hematoma volume and location with mortality and functional outcome in patients with spontaneous ich. methods: we performed a prospective observational study, included patients admitted in icu with spontaneous ich. we determined hematoma volume at admission with kothari modified formula (axbxc/ ) and divided them in two groups according the location as infratentorial or supratentorial. we collected gcs, sofa, apache ii and graeb at admission, medical history and complications during the first week in the icu. we established modified rankin scale (mrs: poor outcome > ) and glasgow outcome scale (gos, poor outcome < ) at icu discharge. we used %, mean (sd) and median (minimal/maximum). t-student and χ (p < . ) were used for the univariable analysis. we conducted a multivariable analysis for mortality with binary logistic regression ( % ci, or) p < , . roc curve was determined for the volume of hematoma associated with mortality (ic % p < . ). results: we enrolled patients. % were men, mean age (± . ) years. global mortality was . %. . % were supratentorial and . % infratentorial. mean apache ii (± , ) and gcs . (± , ) and median sofa ( - ) and hematoma volume , cc . there were no significant differences between the two groups (infra and supratentorial) except ich volume (p . ) and length of stay (los)-icu (p . ). in the univariable analysis worse outcome with mrs was related with the volume of the hematoma (p , ) but not with gos (p , ). variables associated with mortality: gcs (p . ), apache ii (p . ), graeb (p . ), sofa (p . ), los-icu (p . ) and ich volume (p . ). after the multivariable analysis we determined hematoma volume was an independent risk factor for mortality (or , ; % ci , - , ; p . ). according the location we obtained a significantly association with mortality in the supratentorial group (p , ). we performed a roc curve of this group and obtained an auc , ( % ci , - , ; p . ) with cutoff point of , cc . conclusions: hematoma volume and los-icu are greater in supratentorial ich. the hematoma volume is associated with a worse outcome at icu discharge and a supratentorial ich volume above . cc is related to higher risk of mortality. introduction: aneurysmal subarachnoid hemorrhage (sah) is an acute cerebrovascular event, which leads to devastating consequences, high mortality and is an important cause of neurologic disability among survivors. incidence is reported between to / and mortality rates vary widely, ranging from to % among different authors. many complications associated with sah, such as delayed cerebral ischemia or hydrocephalus, also play a role in the poor functional outcome in survivors. paulo niemeyer state brain institute is a reference and high-volume center for sah, located in rio de janeiro, brazil, receiving patients from all over the state. objectives: the aim of the study was to describe the characteristics of patients with sah admitted to the icu, as part of a large prospective ongoing study, and to evaluate the factors associated with outcome. methods: from july to march , every patient admitted to the icu with aneurysmal sah, years and older was enrolled in the study. data were collected prospectively during hospital stay. the primary endpoint was mortality and dichotomized functional outcome, (poor outcome defined as modified rankin scale - ) at hospital discharge. results: a total of patients were included. the median age was ( - ), patients ( %) were female. demographic characteristics are presented in tables and . twenty-nine patients ( %) were treated by clipping, and patients ( %) were hydrocephalic and needed an evd. an intracranial pressure monitor was inserted in patients ( %). nine patients ( %) developed sepsis or septic shock during icu stay and pneumonia was present in ( %) patients. rebleeding was diagnosed in patients ( %), vasospasm was present in ( %) patients, post-surgical deterioration was diagnosed in ( %) patients and ( %) patients developed dci. twenty-two ( %) patients were mechanically ventilated. hospital mortality was % ( patients); and patients had unfavorable ( %). in univariate analysis, factors most frequently seen in patients with unfavorable outcome were rebleeding ( % vs %, p = . ), vasospasm ( % vs %, p = . ), post-surgical neurological deterioration ( % vs %, p = . ), dci ( % vs %, p = . ) and pneumonia ( % vs %, p = . ). although not statistically significant, there was a trend towards the association between sepsis/septic shock ( % vs %, p = . ) and unfavorable outcome. conclusions: sah is associated with high morbidity. neurological complications such as rebleeding, vasospasm, post-surgical neurological deterioration and dci, as well as clinical complications (eg. pneumonia) were associated with unfavorable outcomes. therapeutic interventions to prevent neurological and systemic complications may have an impact on clinical outcomes. introduction: the management of patient into the icu after been submitted to a cns resection is an important challenge. surgery is indicated for diagnosis, to reduce tumor bulk and to manage raised intracranial pressure. primary brain tumors are classified based on their cellular origin and histologic appearance. the most common malignant brain tumor is glioblastoma multiforme, this group have a poor prognosis. objectives: the goal was to make a descriptive analysis about the evolution of patient submitted in the icu for postoperative control following a surgical resection of intracranial tumors. methods: a retrospective and observational study was conducted on all elective consecutive surgical procedures for tumor resection admitted into the icu. we analyzed variables related with the tumor, predisposing pathology, surgical data and evolution in the icu. we considered as an unfavorable evolution the death into the first month after the intervention or the decrease in two points or more of the canadian´s scale score (css). is a comparative study analyzed by student´s t-test, anova of one factor and pearson´s chi-square test. comparative study expressed by: mean difference, relative risk and confidence intervals at %. results: we analyzed patients over of years ( - ) . of the total, . % are high-grade gliomas, . % low grade gliomas, , % meningiomas , . % metastasis and . % other type of tumors. average age is . years (sd . ), it is significantly lower in the low-grade gliomas, and in the group of other tumor types compared to other groups. . % are men , the most common in men ( . %) and meningiomas and other tumors in women ( . % and . % respectively) gliomas. . % are supratentorial location. average size is . ml (sd . ) . the average score in the preoperative karnofsky scale is . (sd . ) . the average income apache is . points (sd . ). an unfavorable evolution is observed in . % of patients ( . % per patient died and . % decline in the css) after one month , with no differences between different types of tumors. the percentage of deaths in the first month is higher in those undergoing surgery for metastasis ( . %, rr . , ci . to . ) . mortality at two years of intervention is . %, being higher in sifnificativamente undergoing metastasis ( %; relative risk . , ci . to . ) and high-grade gliomas ( . %; relative risk . , ci . to . ). conclusions: patients undergoing brain tumors have a significant risk of poor outcome , which is significantly higher in metastatic patients from the first month of intervention and in patients undergoing high-grade gliomas at two years. introduction: nosocomial infection (ni) is still an issue in neuroritical care. objectives: we analysed ni in a preventive multimodal protocol in patients with acute brain disease. method: we performed a -year prospective observational cohort study in patients (pts) with acute brain disease admitted to an eight-bed adult neuro-intensive care unit (nicu). we defined our preventive multimodal protocol as: ) keeping a hygienic and epidemiological regime including isolation of pts with multi-drug resistant bacteria ) correct antibiotic policy, and ) regular microbiological screening. there were ( . %; wound . %, respiratory . %, urinary . %, bloodstream . % and other . %) pts with ni. we compared ni group pts with the control group of pts and searching predictors of ni in univariete analysis. we did not find differences in age (p = . ), male (p = . ), weight (p = . ) or body mass index (p = . ), but there were more stroke pts and fewer tumour pts (p < . ). ni pts stayed in nicu longer (mean . vs . , p < . ), on admission had lower glasgow coma scale (mean . vs . , p < . ), higher therapeutic intervention scoring system (tiss, p < . ), acute physiology and chronic health evaluation ii (p < . ), and crp (p < . ); in the nicu they had higher crp (p < . ) and nicu mortality (p < . ); on discharge they had worse glasgow outcome scale (p < . ) and higher tiss sums (p < . ). ni pts had more accesses, which were strong predictors of ni: artery (odds ratio [ conclusions: our study confirmed that nosocomial infection is associated with worse outcome and higher cost, and that accesses are still risk factors in a preventive multimodal protocol. the predictive value of emergency triage codes on the outcome of aneurysmal subarachnoid hemorrhage introduction: outcome of patients with aneurysmal subarachnoid hemorrhage (sah) was associated in different studies with different variables (baseline illness severity, physical status, treatments, complications), but the relationship between outcome and triage assessment in the emergency setting has never been evaluated. emergency triage in italy is carried out with color codes: red (immediate life-saving intervention needed), yellow (urgent intervention needed), green (delayed intervention is sufficient), white (not urgent). objectives: to study the relationship between triage severity codes assigned to patients with sah in an italian emergency setting and the outcome expressed as modified rankin score (mrs) at hospital discharge (good outcome for mrs ≤ , poor outcome for mrs > ). methods: a retrospective clinical study included patients with aneurysmatic sah admitted to emergency departments of bologna catchment area, and then to intensive care unit (icu), from january to january . aneurysm coiling or clipping was performed after neuroradiological diagnosis and clinical stabilization, excluding patients too ill to benefit. intensive care treatment was carried out according to current practical guidelines. demographic, clinical and interventional data, complications, severity scores and outcome scores were recorded. the following parameters were considered in univariate analysis: age, sex, clinical condition on arrival in the emergency department (triage code, gcs, wfsn scale, vomiting and seizures) aneurysm clipping or coiling and other neurosurgical interventions, hydrocephalus, vasospasm, cerebral infarction (ct scan), fever, sepsis, acute respiratory failure with p/f ≤ , cardiovascular complications (hypotension requiring vasopressor therapy, acute cardiomyopathy, arrhythmias requiring treatment); the outcome variable was modified rankin score > at hospital discharge. results: poor outcome (mrs > ) was observed in % of triage green codes, % of yellow codes, % of red codes. the univariate analysis showed the statistically significant (p < . ) association with mrs > for the following variables: triage red code, wfsn scale > , acute respiratory failure, cardiovascular complications, sepsis. on logistic regression analysis, the red code assigned in the emergency department, cardiovascular complications and sepsis were associated with poor outcome. conclusions: the severity of general clinical conditions after subarachnoid hemorrhage needing immediate life-saving intervention, feature labelled "red code" in the emergency triage, was associated with poor outcome (mrs > ), while the other triage codes did not show any significant correlation with outcome. cardiovascular complications and sepsis during hospital stay were other variables associated with mrs > . evaluation of intracerebral hemorrhage (ich) score in patients admitted in intensive care by supratentorial brain hemorrhage l. perez-borrero introduction: intracerebral hemorrhage is a stroke subtype with high mortality and significant disability among survivors. objective: to evaluate in our area the intracerebral hemorrage (ich) score in patients with spontaneous supratentorial brain hemorrhage. methods: multicenter prospective observational study in three hospitals in andalusia (spain). we studied all patients with supratentorial brain hemorrhage admitted to the regional hospital of malaga (between to introduction: within the clinical importance of the sah, there are factors described in the scientific literature that speak of an unfavorable evolution of the disease. our hypothesis is based on trying to demonstrate if only one therapeutic intervention could alter the significance of these factors. objectives: analyze the sociodemographic, laboratory findings, clinical and radiological factors that influence prognosis at months in discharged aneurysmal sah patients treated with endovascular intervention. methods: we performed a retrospective longitudinal observational study of all patients who were diagnosed with an aneurysmal sah in icu services of hospitals between march st and november th . they were treated by endovascular intervention. after being discharged from icu and after months of neurologic follow-up. patients were divided into two groups, one formed by those who presented a favorable outcome (ef) and the other by those who didn´t (ed). the variables studied were age, sex, hbp, dm, smoking and dyslipidemia. at the time of admission po , pco , leukocytosis, hyperglycemia and hypertension was determined as well as sodium, magnesium and chlorine plasma levels. the clinical status of patients on admission was assessed using the hunt-hess and wfns scales. the severity of sah was determined by ct using the fischer scale. the aneurysm was located by four vessel angiography. the time between the sah clinic presentation and the procedure was recorded, as well as if aneurysmal occlusion was complete or not. as for the complications, we took into account the presence of fever, hydrocephalus, vasospasm and infarction. results: for the study, patients who underwent acute endovascular sah treatment using coils, were selected. female sex was the predominant sex % vs . % between ed and ef, respectively. the age group most frequently found was between and years ( % for ed and % for ef). logistic regression analysis determined as associated with a worse outcome factor: hyperglycemia on admission(or . , % ci . - . , p = . ), clinical status on admission determinated by hunt-hess (or . ci . - %, p = . ) and wfns scales (or . , % ci . - . , p = . ). the presence of fever on admission also has proven to be a poor prognostic factor (or . % ci . - , p = . ). conclusions: clinical factors for aneurysmal sah patients treated with endovascular procedure that have shown relation with the clinical outcome at six months are: poor clinical grade on admission, hyperglycemia and fever. these data are similar to those found in the literature and support the idea that the therapeutic decision (surgical or endovascular) is not the determining factor for the evolution of these patients, however, the ones mentioned above could be. background: conflicting results have been obtained by studies attempting to assess the risks of ischemic stroke in patients with venous thromboembolism, while the long-term risk of stroke in survivors of venous thromboembolism remains unexplored. objective: we evaluated whether the risk of ischemic stroke in patients hospitalized with venous thromboembolism is higher when compared to the general population. methods: one million patients from national health insurance beneficiaries in taiwan were sampled. there were , patients who had been hospitalized with diagnosis of venous thromboembolism and , unexposed subjects. all adult patients were followed from january to december to evaluate if ischemic stroke was diagnosed. cox regression models were applied to compare the hazards adjusted for potential confounders. results: after controlling for age, gender, urbanization level, socioeconomic status, diabetes, hypertension, coronary artery disease, hyperlipidemia, history of alcohol intoxication, malignancies, congestive heart failure, atrial fibrillation, smoking, peripheral artery disease and charlson comorbidity index, the adjusted hazard ratio of ischemic stroke was significantly increased in patients with venous thromboembolism ( . ; % ci, . - . ). a subgroup analysis based on patients who survived longer than months in the cohort also revealed higher hazard ratio in the patients with venous thromboembolism. ( . ; % ci, . - . ). conclusion: the possible risk of ischemic stroke is significantly higher in patients hospitalized with venous thromboembolism than in the general population. introduction: status epilepticus (se) is a common neurological emergency with considerable associated health-care costs, morbidity and mortality. , se is defined as a prolonged seizure or multiple seizures with incomplete return to baseline. , the overall mortality of se is around % with convulsive status epilepticus representing about - % of all cases. status epilepticus severity score (stess) is a prognostic score that relies on four outcome measures (age, history of seizures, seizure type and extent of consciousness impairment) determined before treatment institution that ranges between and . objective: evaluation of stess as a prognostic measure of functional impairment, neurologic motor deficits and -day mortality. methods: retrospective observational study of patients with se admitted at a general intensive care unit (icu) from to . age, gender, saps ii/iii, type of se, length of stay, number of anti-epileptic drugs, duration of se, functional impairment, neurologic motor deficits and -day mortality were collected through the icu informatics database -picis®. data is presented as mean ± sd and we used logistic regression to correlate stess with study variables. statistical analysis was performed using xstat ®. results: sample included patients, , % male, age , ± , years, saps ii , ± , , saps iii , ± , , icu length of stay , ± , days and hospital length of stay , ± , days. convulsive se represented , % of cases. stess score`s mean was , ± , . se lasted more than day in , %. electroencephalogram was performed in , % of the patients. , % of the patients needed two or more anti-epileptic drug for se. at hospital discharge , % had functional impairment and , % had neurologic motor deficits. mortality was , % at days. there was a correlation between stess and mortality (or = , ; roc = , ), functional impairment (or = , ; roc = , ) and neurologic motor deficits (or = , ; roc = , ). the number of antiepileptic drugs and se duration had no correlation significance. conclusions: we found an excellent correlation between stess and mortality in our study. besides this, we also found this score to be a good prognostic tool for functional impairment and neurologic motor deficits. we consider our main limitations the sample size and lower mortality. despite we recommend using stess as an outcome predictor. introduction: in order to determine optimal airway protection measures in early postoperative period after fossa posterior surgery (pfs), it is important to carry out a prognosis of neurological dynamics based on the preoperative neurological exam. we have designed neurological evaluation scale (nes). objectives: our study was aimed at determining the potential of nes to predict brain stem deterioration in early postoperative period after pfs based on the assessment of the preoperative neurological status. methods: the prospective study was carried out during the period from december to june and included patients operated for fossa posterior tumors (fpt). to be included in the study, patients had to be over years old and operated for fossa posterior non infiltrative paraxial tumors. we examined all patients before and after the operation, immediately after the extubation in icu. nes provided complex neurological assessment with an emphasis on the brain stem function. postoperative nes points were subtracted from the preoperative points -ab-criterion (abc). positive abc corresponds to intensification of neurological deterioration. negative or zero abc corresponds to neurological improvement. all neurological symptoms were grouped in nes blocks according to their relation to cns. results: we divided all patients in two groups depending on their abc, which revealed that the patients with positive abc had reliability less nes points before operation compared to the patients with negative or zero abc. we found out the frequency of occurrence of each nes block for inclusion in the full neurologic status. we discovered that caudal stem affection occurred more frequently in the patients with more nes points. we evaluated the probability of neurological impairment or regression of neurological symptoms depending on abc with sensitivity , % and specificity %. we created a prognostic model, which could predict the discharge from clinic outcome on the basis of the nes blocks points assigned during the early postoperative period. conclusions: we revealed neurological features of postoperative period in patient after fps. our data could predict neurological outcomes, and be useful in optimization tactic of airway protection. and those who died ( . ± ; . ± and ± . ± vs ; . ± and . ± respectively) but difference was not significant. an inverse correlation between inflammatory biomarkers (pct, crp and il- ) and igm endocab was detected. il showed a higher correlation, but without statistically significant differences. icu mortality rate was %. conclusion: igm endocab were detected in septic shock caused by gpb, it could be explain by a bacterial translocation. patients with major endotoxaemia have higher consumption of antibodies and therefore lower levels of igm endocab that is associated with a worse prognosis. the relationship between the neutrophil/lymphocyte ratio and mortality in the severe sepsis patients y. conclusions: sp compliance is below recommended but the mean hobe reaches the lower limit of the recommendation. the factors affecting sp compliance differ according to the method used for data collection and include other factors than patient's clinical condition. politics targeting to increase its compliance should address various areas of care such as team and professionals, resources and equipment and re-consider clinical indications for sp. the project was funded by the °national award of nursing research from marques de valdecilla hospital (spain). gained to collect staff opinions and anonymised patient data. ed, or and icu professionals were surveyed following a pilot to determine options, ranking and scoring criteria a priori where needed. anonymous patient data from intubated patients who were cared for in the ed, or and icu within their first hours were collected. this included physiological observations and supportive care standards around a, b and c. results: the most striking differences in staff opinion involved the preferential use of artificial colloid-based fluid resuscitation in sepsis ( % ed staff; % or staff; % critical care staff); the value and significance of recording end tidal co ( % ed staff; % or staff; % critical care staff); and the potential preferential use of flowdirected fluid boluses rather than pressure-directed fluid boluses in critically ill patients ( % ed staff; % anaesthetic staff; % critical care staff). when observing supportive care standards the largest differences were in the use of stress ulcer prophylaxis (only prescribed in critical care); patient positioning (head-up: % patients in cc; % in ed); the recording of sedation level ( % ed; % anaesthetic; % critical care) and the recording of ventilator parameterstidal volume, peak pressure and et-co -( % ed; % anaesthetic; % critical care) . finally, in respect to patient pathophysiology, all groups were under ventilated and over oxygenated. mean arterial pressure was most divergent from baseline in the ed. however, changes in pathophysiology were related to interventions (fluid boluses, analgesia, surgical interventions, inotropes, pressors) rather than location. despite the divergent views regarding the relative value of flow monitoring, observed fluid boluses were predominantly triggered by pressure changes in all three locations. conclusions: differences in staff attitudes; application of standards and patient pathophysiology were identified between care locations. the influence of variation in resources and professional composition of teams (nurses:doctors) on these results requires further work. it remains uncertain whether more uniform approaches would improve patient outcomes. lung comet score (lcs) for evaluation of extravascular lung water (evlw) in intensive care unit (icu) patients undergoing renal replacement therapies (rrt) a. taggu methods: a prospective observational study was conducted on patients in icu needing rrt. exclusion criteria were age < years, pregnant, amputees, cardiac pacemakers, pre-existing lung diseases and ascites. lung comet score as per validated technique , bia measurements and baseline data were collected pre and post dialysis. lung comet score and other covariates were fitted into a regression model using bia as the standard test. based on bia delta hydration relative (hs rel), patients were divided into normohydration and hyperhydration using a cut-off of %. results: a linear regression model in predialysis state showed that only lcs could significantly predict lung water (const . , coef. . , p value . ). in the postdialysis state lcs perfectly predicted lung water (const . , coef., . ; p value . ).bland altman plots showed good agreement between lcs and hydration status (bia) pre and post dialysis. the lcs > nearly perfectly predicted hydration status in both pre and post dialysis states. conclusions: lung comet score is a good surrogate of evlw and reliably predicts reflects hydration status pre and post dialysis in icu patients. introduction: treatment withdrawal in intensive care is common ( ) . whilst significant research attention has focused on how treatment is withdrawn and what information is communicated to families ( ) introduction: micro-aspiration of subglottic secretions is considered a major pathogenic mechanism of endotracheal tube-associated pneumonia (etap), either postoperative pneumonia or ventilatorassociated pneumonia. endotracheal tubes (ets) with taper-shaped cuffs have been proposed to provide a better seal of the extraluminal airway, thereby preventing micro-aspiration and possibly etap. objectives: to perform a systematic review and meta-analysis to assess the efficacy of ets with taper-shaped cuffs in the prevention of etap. methods: a systematic search of medline, embase and central/ cctr was conducted in march . eligible trials were randomized controlled clinical trials (rcts) comparing taper-shaped cuffs with standard, cylindrical-shaped cuffs in intubated patients. all studies reporting the incidence of etap were included. inclusion of trials was irrespective of publication status, date of publication or language. random-effects meta-analysis calculated the risk ratio (rr) and % confidence interval (ci) for the incidence of etap between both groups using the mantel-haenszel method. results: three rcts, given a total of patients, met the inclusion criteria. one trial was published as a conference abstract only ( ), while the others were published in full ( , ) . none of the trials was blinded for the intervention. patients were allocated to the intervention arm and to the control arm. etap episodes occurred in the intervention group and in the control group. the pooled rr for the incidence of etap was . ( % ci, . - . ; z = . p = . ). conclusions: the use of endotracheal tubes with taper-shaped cuffs did not show to reduce the incidence of etap. however, the number of available studies is small, and there is an inherent risk of bias due to the unblinded designs. background: understaffing of icu's can have serious adverse consequences both for patients and for nurses, and therefore it is important to have an adequate number of nurses on the ward. nurses however are in short demand and resources are scarce. being able to predict the nursing workload for a certain group of patients may help to allocate nursing capacity as efficiently as possible and thus to reduce costs, without endangering the patients safety and nurses' health. nas is a validated tool for the measurement of nursing workload in an intensive care unit. goal: this study was conducted to investigate whether it is possible to predict the nursing workload for a homogeneous group of patients, admitted after an in or out of hospital cardiac arrest and to assess the effects of baseline characteristics, vital parameters and admittance time on this workload. method: we performed a retrospective analysis of nas scores of all ihca and ohca patients admitted to our icu from october until september during the first hours of stay. the nas was recorded per patient per nursing shift. we furthermore recorded patient characteristics and vital parameters. results: during this period patients, males and females, were admitted to the icu after cardiac arrest. the mean age at admission was . years (sd = . ). the mean nas at admission was . (sd = . ). patients admitted in the evening shift had a significantly higher nas compared to patients admitted in the night shift ( . ; sd = . vs . ; sd = . (p = . )), but no significant difference was found with the day shift (mean nas day shift: . ; sd = . ). after admission the workload decreased in all patients by a mean of . points (sd = . ; p < . ). a higher sofa score, a higher peep and a lower ph at admittance resulted in a higher nas score on average over time (p < . ). conclusions: the nursing workload at admission of patients after cardiac arrest is fairly predictable, with no clinically significant difference between shifts , necessitating a nurse-to-patient ratio of at least : . after the first shift it is almost always possible to decrease the nurseto-patient ratio to : . the nas was influenced by severity of illness. these results can be used to assess the needed nursing staff for the treatment of these patients for the first days after admittance. introduction: major trauma and severe sepsis are both leading causes of admission to the resuscitation rooms in emergency departments across the world. despite obvious differences in precipitating mechanism, there are surprising similarities between subsequent pathophysiology: both disorders lead to disorders of the macrocirculation, microcirculation and host inflammatory response ( , ) . objectives: here we compare the baseline epidemiology, pathophysiology, operational and clinical management of intubated resuscitation room patients with these two critical illness syndromes (major trauma/septic shock). the results will be used to facilitate the design and planning of a study to test the feasibility/effectiveness of advanced monitoring systems (thromboelastography, oesophageal doppler flow monitoring, echocardiography, and microcirculatory monitoring) in the resuscitation room management of critically ill patients with these conditions. methods: institutional approval was gained to collect anonymised patient data over a -month period from a mixture of written and electronic records. where appropriate, significance was tested by mann whitney u (sigmaplot . ). results: patients, intubated pre-hospital or in ed resus, were identified with trauma or sepsis diagnoses. trauma patients were commoner (n = ; %) and more likely to be intubated prehospital ( / ; . % vs / ; %). lactate profiles were similar in the two groups at start and end of resus episode ( figure ). patients with major trauma were more hypertensive but equally tachycardic when compared with patients with severe sepsis/septic shock. patients with septic shock/severe sepsis (median minutes vs minutes) spent longer in resuscitation room, but received less documented consultant-level review ( . % vs . %). imaging of major trauma patients was with ct ( / ; %) and ultrasound ( / ; . %) in contrast to septic patients ( / ct; . %; / , % us). icu and hospital mortality was higher in patients with sepsis ( . % vs . %), but death in resus only occurred in the trauma population. only two patients, both with facial trauma, would have had a relative contraindication to the proposed advanced monitoring. conclusions: this novel preliminary work has highlighted some important differences between the epidemiology, outcomes, pathophysiology and clinical/operational management of intubated patients with severe sepsis versus major trauma. these will influence the conduct and outcome measures of any trial of advanced monitoring in this setting. however, contraindications to any of the advanced monitoring technologies being considered were rare and no obvious barriers to the planned study of advanced monitoring were identified. introduction: in our -bedded gicu, demand for beds has increased while recruitment of icu trained nurses has decreased. there is enduring evidence of links between workload and stress [ , ] , with high levels of burnout reported in icu nurses [ ] . there has been a shift towards measuring what makes people positive and engaged [ ] , rather than why people reach the extreme state of burn out. it is important to understand factors that affect work engagement to develop strategies that enhance nurse retention and improve the quality of icu patient care. objectives: to examine the impact of an education initiative for novice icu nurses on work engagement for the icu nursing staff and organisational resource use. methods: a pre -post design was used to collect data from all icu nurses at the start of the education programme and at months following he intervention. work engagement was measured using the self-report item utrecht work engagement scale (uwes) [ ] with an open question to capture staff experiences. organisational impact was measured using levels of sick leave, % staff turnover, use of agency nurses and staff recruitment. results: fifty three icu nurses completed the pre-intervention survey ( % response) and completed the post-intervention survey ( % response). respondents had reasonable years of icu experience (mean . , sd . ) and time in current post (mean . , sd . ). internal consistency for the uwes was high (alpha . ). levels of work engagement (mean [sd]) increased ( . , [ . ] vs . [ . ]) but did not reach significance and remained in the 'average' band as judged by the scale authors [ ] . when examined by senior and junior nurses, the increase was similar. organisational measures showed decrease in sick leave, turnover, agency use and increase in recruitment of experienced icu nurses. qualitative feedback was positive, with perceptions of improvement in unit morale due to time being invested in the individual and reduced stress and workload for shift leaders. conclusions: providing education for the newest icu recruits can have benefits for the whole icu team. however, it is important to examine how work engagement might be further improved. the incidence of silent aspiration on intensive care n. maistry royal brompton and harefield nhs foundation trust, rehabilitation and therapies, london, united kingdom intensive care medicine experimental , (suppl ):a introduction: the incidence of dysphagia on intensive care is an area of growing research. dysphagia is associated with aspiration pneumonia and increased icu bed days. in general, speech and language therapy (slt), makes recommendations based on the results of a clinical bedside swallowing evaluation, despite the unreliability of this method . this is largely due to the difficulty accessing gold standard assessment methods such as videofluoroscopy (vf) and fibreoptic endoscopic evaluation of swallowing (fees) . referral for these assessment methods are based on a local defined criteria. this study evaluates the incidence of silent aspiration identified by vf and fees in a bedded tertiary cardio-respiratory intensive care unit. objectives: to determine the incidence of silent aspiration, defined as "aspiration before, during, or after swallowing in the absence of cough or visible signs of choking and distress ," in icu patients assessed by vf or fees between july and june . method: data was retrospectively reviewed for month period from all icu referrals made to slt for swallowing evaluation. all patients received a clinical bedside swallowing evaluation. the results are presented as percentages and counts for patients receiving vf and fees that silently aspirated. results: a total of patients were referred for swallowing assessment and % ( / ) had a vf or fees. there were males and ages were . ± . years. in this group, patients had videofluoroscopic assessments and patients had fees. in the vf group % silently aspirated whilst in the fees group the values were %. patients ( %) silently aspirated during objective assessment, impacting on how and when oral feeding was commenced. conclusion: this study suggests that silent aspiration is highly prevalent in this population group. consequently, vf and fees should be part of standard routine assessment in the management of critically ill patients. delerium related incidents at the icu and nursing aspects a. van introduction: at the icu of vu university medical center (vumc) nurses are frequently confronted with delirium , . delirium is known to be present in - % of mechanical ventilated patients and - % in non-ventilated patients. immediate consequences are falling incidents or for patients to remove tubes and iv lines that are necessary for treatment. in literature, this is stated as a result of treatment, but often data is missing. consequences of removal are increased risk of complications , prolonged mechanical ventilation, los and increased morbidity/mortality . objectives: to measure the frequency of removing tubes, lines and falling incidents related to delirium. methods: a multidisciplinary focus group was formed ( ) in order to properly diagnose, prevent and/or treat delirium due to the high prevalence. the first steps were increasing awareness and implementing the cam-icu score. to clarify delirium-related incidents a one year period was set in which the dedicated senior nurse informed and trained the nursing staff regarding delirium and potential risks. to register delirium-related incidents a modified report button was built in the epr (metavision, imd soft) and used beside the regular incident reporting system . results: after one year, individual patient incidents were reported concerning falling or tube or iv line removal. this included gastric tubes, airway tubes, iv/cvc/arterial lines, other lines and fall incidents. in % of the cases the patient was diagnosed with delirium. out of patients received medication or were fixated before the incident despite a % cam-icu registration rate. because the focus group doubted about underreporting nurses were interviewed if the results corresponded with their experience. they were unanimous that there was hardly any underreporting. discussion: despite therapy or fixation delirium-related incidents occur on a weekly basis at our icu, causes harm and increases nursing workload. although the incidence rate is presumed to be low, there is no feeling of satisfaction. further improvement is necessary due to the high risks for the patient. therefore, we need to be able to diagnose incidents faster so we can start treatment sooner. although the cam-icu score was implemented, compliance is insufficient. increasing compliance is the first step to further improvement. the follow-up question is whether delirium-related injury can be reduced when cam-icu compliance improves. second step is to investigate the effectiveness of our fixation protocol. prospective study to determine the predictors of extubation success a. taggu introduction: timely extubation is crucial in critically ill patients. traditional indices like rapid shallow breathing index are considered as accurate during the spontaneous breathing trial. multiple other proposed parameters like diaphragm thickness, fluid balance and cardiac indices have been shown to predict succesful extubation in the recent years. objectives: to assess the reliability of the parameters in predicting successful extubation. methods: a prospective observational study done on adult patients eligible for extubation as decided by the attending intensivists. exclusion criteria: pregnant and tracheostomised patients. along with baseline parameters, following measurements were taken pre and post extubation. . cardiac parameters including simpsons method for ejection fraction, e/a, e/e' (lateral) for diastolic function, tapse and tad for right ventricular function. all recordings were taken just before extubation and within six hours post extubation. . just before extubation,high frequency linear ultrasound probe was used to measure the right sided dt at the zone of apposition (zoa) between th to th intercostal spaces in mid-axillary line.the change in dt fraction(Δdtfrac_pre%) was calculated as dt(end-inspiration)-dt(end-expiration)/dt (end-expiration)x .rsbi was simultaneously recorded. . fluid balance hours were recorded. figure ) . we found no significant difference on mortality when limiting the results just to trial employing cvvh at hemofiltration rate lower or higher then ml kg − h − . conclusions: blood purification with cvvh might be associated with a significant reduction in mortality when performed in patients with sepsis or ards. this is the first meta-analysis suggesting beneficial effects of cvvh on mortality and we could suppose that the beneficial effects of cvvh in these inflammatory conditions could arise from the immunomodulatory properties of hemofiltration. further high-quality randomized controlled trials adequate powered for mortality are needed to clarify the impact of cvvh on these inflammatory conditions. the authors declare no support or funding and no potential conflict of interest. we defined extreme hyperbilirubinemia as a state of total bilirubin above mg/dl and selected all patients whose serum total bilirubin increased above mg/dl at least once during their stay in the intensive care unit. we investigated the overall clinical course of the patients and compared the differences between one group with normalization of total bilirubin (recovery group) and the other group without normalization (non-recovery group). furthermore, we evaluated the association between prognosis and various clinical factors, including the peak total bilirubin levels, increasing rate of total bilirubin (vi), results of laboratory analyses related to hepatic function, and clinical features at the time of extreme hyperbilirubinemia. these data were analyzed using chi-square test and cox and logistic regression analyses. introduction: propofol is widely used in critical care sedation due to its pharmacological properties which allow serial neurological examination ( ) .hypo tension is a common side effect of propofol infusion, which affect patient outcome. introduction: propofol is a common intravenous drug used during anesthetic induction and sedation because of its rapid onset and short duration. its downfall, however, is that patients experience injection pain so severe that they recall induction as the most painful part of the sedation process. among numerous reports in efforts to decrease propofol injection pain, the most effective combination of drug and non-drug intervention evaluated through a quantitative systematic review revealed to be pretreatment with . mg/kg lidocaine in combination with a tourniquet for venous occlusion. the majority of these reports conclude that a single method is insufficient in eliminating propofol injection pain. objectives: we evaluated the effect of heated carrier fluids ( °c) in decreasing propofol injection pain. methods: a randomized controlled clinical trial was conducted in patients (asa or ), ages to . patients were allocated into groups (n = ) each. group w received ml of heated carrier fluids for minutes prior to mg/kg propofol injection; group l received ml of heated carrier fluids for minutes prior to lidocaine pretreatment and mg/kg propofol injection: and group c (control group) received ml of room temperature fluids prior to mg/kg propofol injection. propofol injection pain was evaluated using the verbal pain score (vps). results: group w and l showed significant reduction in the incidence and severity of injection pain compared to group c (p < . ). vps was significantly lower in group w (p = . ) and l (p = . ) compared to group c. there was no statistical difference between group w and group l (p = . ). there was statistically significant difference in mean blood pressures measured after mg/kg propofol injection among groups. conclusions: both heated carrier fluids and combination of lidocaine pretreatment effectively reduced propofol injection pain. objectives: we conducted a prospective cohort study to clarify the epidemiology and the nature of aes in surgical inpatients in japan. methods: the japan adverse event (jet) study was a prospective cohort study which had evaluated aes and medical errors (mes) at tertiary care hospitals. the medical and surgical wards were stratified according to hospital and whether they were medical or surgical wards, and study wards were randomly selected. intensive care units (icus) were all included. we included all adult patients aged > = years old who were admitted to any of the selected study wards ( medical, surgical, and icus) over a -month period. the primary outcome of this study was the epidemiology and the nature of aes and mes in the patients who had operation during the study period. trained nurses placed at each participating hospital reviewed all charts daily on weekends, along with laboratories, incident reports, and prescription queries to collect any potential event. they also collected the characteristics of the patients in the cohort. independent physician reviewers evaluated all potential events and classified to whether they were aes or mes, as well as to their classification, severity and preventability. introduction: whereas the importance of low tidal volume to avoid ventilator-induced lung injury (vili) in patients with ards is well known, several uncertainties still exist regarding how to set positive end-expiratory pressure (peep). many approaches have been considered, but no one showed a clear effectiveness in terms of outcome. recently a ventilator strategy using esophageal pressure to estimate the transpulmonary pressure has been proposed by talmor and colleagues . although they found an improvement in arterial oxygenation, it was not explored whether the increase in oxygenation was due to lung recruitment. objectives: the aim of this study was to assess whether the peep set to maintain a positive end-expiratory transpulmonary pressure (p l ) is associated with an increase in lung recruitment estimated by lung ultrasound score (lus) . methods: patients with moderate and severe ards were enrolled. for the first hours, peep was set according to the acute respiratory distress syndrome network standard-of-care recommendations (phase a). it was then adjusted according to measurements of esophageal pressure for the following hours (phase b) to maintain a positive p l at the end of expiration. the primary end point was the improvement in lung recruitment assessed with lung ultrasound. [ ] no data are available on the relationship between opening pressures and disease severity. objectives: to describe lung recruitment as a function of the transpulmonary pressure in mild, moderate and severe ards. methods: ards patients underwent a low-dose end-expiratory ct scan at peep cmh o and three end-inspiratory ct scans at the plateau pressures reached starting from peep cmh o, cmh o and cmh o. in each of the ct slices, lung profiles were manually delineated, excluding hilar structures. thereafter, quantitative analysis of ct scan images was performed and the gas and tissue fractions were computed. we defined the recruitability as the difference of not inflated tissue between and cmh o, that we arbitrarily assumed to be the "full recruitment". [ ] the grams of recruited tissue were computed across the pressure intervals at which the ct scan were performed, as the differences of not aerated tissue. airway and esophageal pressures were continuously measured and transpulmonary pressure was computed as: driving airway pressure (cmh o) -(esophageal plateau pressure (cmh o) -esophageal end-expiratory pressure at peep (cmh o) [ ] . results: thirty-three patients were studied, with mild, with moderate and with severe ards, according to the berlin definition. [ ] as reported in the table and fig. , the amount of tissue which can be opened between and cmh o was %, % and % respectively in mild, moderate and severe ards). mild ards patients nearly completed recruitment at approximately cmh o transpulmonary pressure while in moderate and severe ards recruitment continues up to cmh o transpulmonary pressure. conclusions: at the clinically recommended plateau pressure of cmh o, in severe ards, up to / of the lung tissue recruitable at cmh o, stays always closed. beyond contributing to the gas exchange impairment (depending on the perfusion), these "always" collapsed regions may also act as stress risers at their interface with aerated regions, though they are theoretically protected from the mechanical ventilation. introduction: extracorporeal membrane oxygenation (ecmo) is a rescue therapy for patients with acute respiratory distress syndrome (ards) by providing additional oxygenation, and removing carbon dioxide thus permitting less injurious mechanical ventilation settings that have been shown to protect the lungs from additional injury. objectives: to evaluate associations between distinct ventilator settings during ecmo, and outcome of ards patients. methods: individual patient data analysis of observational studies in adult ards patients receiving ecmo for refractory hypoxemia. multilevel multivariable logistic regression models and cox-proportional hazards models were used to determine which settings and parameters had an independent association with the primary endpoint all-cause mortality. results: nine studies with patients were selected ( figure ). initiation of ecmo was accompanied by significant decreases in tidal volume, positive end-expiratory pressure (peep), plateau pressure (pplat), and driving pressure (Δp = pplat -peep), respiratory rate and minute volume (figure ), and resulted in higher pao to fio ratios, higher arterial ph and lower paco ( figure ). higher age, lower body mass index, and higher lactate were associated with all-cause mortality after multivariable adjustment. Δp, both before and during the first three days of ecmo, demonstrated an independent association with all-cause mortality ( conclusions: in this series of ards patients receiving ecmo for refractory hypoxia, Δp and fio were the only ventilatory variables that had an independent association with outcome. these findings indicate the potential for improvement in the management of patients with ards undergoing ecmo. lungs were analysed for wet-to-dry ratio, bal protein, static compliance, spo and histology. to detect the timing of injury, rats received evans blue dye (ebd- mg/kg iv) at the initiation and were euthanized immediately before lung deflation or at , , or min afterwards ( /group). terminal bal analysed for ebd absorbance. ultrastructural impact was studied by electron microscopy on lungs sampled from rats euthanized before deflation, and at and min after deflation. hemodynamic data was obtained by echo performed at baseline (peep cmh o), immediately before and after deflation, and at mins after deflation. rv pressure was measured with a millar catheter. results: wet-to-dry ratio ( . ± . vs . ± . ; p = . ) and bal protein ( . ± . vs . ± . ; p = . ) was higher; and static compliance ( . ± . vs . ± . ; p = . ) and spo ( ± . vs ± . ; p = . ) were lower in intervention vs control. histology revealed collapse, hemorrhage and neutrophil accumulation in the intervention group. bal evans blue demonstrated that microvascular leak was absent before deflation and was maximal by min of deflation. ultrastructural analysis showed that sustained inflation caused minimal swelling of epithelium and endothelium before deflation; deflation resulted in major cellular and interstitial edema, and endothelial injury. hemodynamic data showed that rv and lv were under-filled during inflation. upon deflation, rv output, pulmonary vascular resistance, rv systolic transmural and diastolic pressures increased precipitously. rv/lv ratio increased progressively. conclusion: sudden deflation after sustained inflation with peep causes protein leak, inflammation, hypoxemia, reduced compliance, endothelial injury and rv failure. the mechanism appears to be endothelial injury resulting in microvascular leakage, pulmonary hypertension and rv failure. significance: deflation injury may be an important entity to prevent when using sustained inflation manoeuvres and may explain -in partwhy several important rcts in ards have been negative. low dose steroids reduce short term mortality in septic shock patients: results of an individual patient data meta-analysis r. introduction: previous research has suggested that the use of low dose steroids may be beneficial during septic shock. however subsequent inconsistent results explain the lack of consensus amongst doctors around the world about whether treatment with low dose steroids does improve the overall recovery and survival in patients with septic shock. we hypothetize that the lack of consistent evidence on the effect of low-dose steroids on short term mortality may be related to underpower. treated for septic shock. objectives: the primary objective of the present study was to estimate the effect of three different therapeutic regimens (hydrocortisone alone, hydrocortisone plus fludrocortisone, neither hydrocortisone nor fludrocortisone) on -day mortality in patients treated for septic shock using an individual patient data meta-analysis. methods: individual patient data meta-analysis including the major recent randomized controlled trials comparing early lowdose short course hydrocortisone and fludrocortisone to placebo (ger-inf ( )), hydrocortisone alone to placebo (corticus ( )) or hydrocortisone to hydrocortisone and fludrocortisone (coiitss ( )) in septic shock patients. the primary outcome measure was all cause -day mortality. secondary outcomes measures were day mortality, resolution of organ dysfunction (as measured by the time to reach a sequential organ failure assessement score < ), time to vasopressor and mechanical ventilation discontinuation, intensive care unit and hospital lengths of stay as well as the rate of superinfection. treatment effect on the primary outcome was quantified using relative risk and estimated using targeted maximum likelihood estimation. results: a total of , patients were enrolled in the trials. when compared to the placebo, hydrocortisone + fludrocortisone significantly reduced -day mortality (rr = . , %ci = . - . , p < . ). hydrocortisone + fludrocortisone was also superior when compared to the placebo and hydrocortisone pooled together (rr = . , %ci = . - . , p = . ). hydrocortisone + fludrocortisone significantly decreased -day mortality (rr = . , %ci = . - . , p < . ) in the nonresponders, while it was associated with an increase in -day mortality in the responders (rr = . , %ci = . - . , p = . ) ( figure ). hydrocortisone + fludrocortisone was also superior when considering secondary outcomes such as vasopressor discontinuation or lengths of stay. conclusions: in this individual patient data meta-analysis including the major randomized controlled trials on the subject, we found that an early short course of low-dose hydrocortisone and fludrocortisone decreases -day mortality and improves recovery from organ failure in septic shock patients non responding to a corticotropin stimulation test. introduction: statin therapy during intensive care unit (icu) stay has been associated with a reduction in all-cause hospital mortality in some studies. this association was especially noted in septic patients. however, potential benefit needs to be validated in randomized, controlled trials. objectives: the purpose of this study was to compare the effect of simvastatin plus standard therapy on mortality and total icu length of stay (los) to that of standard therapy alone in critically ill septic patients. methods: a prospective randomized, open label, controlled pilot clinical trial was conducted on patients diagnosed with sepsis/severe sepsis as defined by the american college of chest physicians (accp). hundred patients met the study criteria and were randomized into two groups; a standard group who received standard treatment and simvastatin group who received the standard treatment plus mg simvastatin. primary outcomes were days icu mortality and total icu los. plasma c-reactive protein (crp), total creatine kinase (ck) and liver enzymes [alanine aminotransferase (alt) and aspartate aminotransferase (ast)] were measured as secondary outcome measures. results: a total of patients completed the study. simvastatin was well tolerated, with no increase in adverse events between the two groups. total icu los was significantly lower in the simvastatin group. however, the number of patients with days icu mortality in the simvastatin group was lower compared to standard group; but survival failed to reach statistical significance. similarly, plasma creactive protein failed to reach statistical significance between the two groups conclusions: treatment with simvastatin mg in patients with sepsis/severe sepsis is safe and associated with an improvement in number of deaths and icu los but without subsequent improvement in survival. the use of anapnoguard system in intubated critically ill patients a randomized controlled study introduction: the anapnoguard system (ag) (hospitech respiration ltd., petach-tikva, israel) is an innovative respiratory guard system that continuously monitors and controls the cuff pressure by measurements of co levels above the cuff, and allowing simultaneous rinsing and aspiration of subglottic secretions. objectives: to determine the safety and clinical efficacy of ag system compared with usual care in critically ill patients. methods: prospective, single centre, open-label, randomized, controlled feasibility and safety trial. sixty patients, without pneumonia, were randomized to be intubated with the ag tube and connected to the system (n = ) or with a conventional tube (n = ) combined with subglottic secretion drainage and manually control of tracheal cuff pressure (p cuff ). primary outcome was the rate of adverse events. other outcomes included the rate of mechanical complications, the level of icu staff satisfaction, the incidence of ventilator-associated pneumonia (vap), the quality of p cuff control, and the amount of ss drained. results: out of patients enrolled in the study, were included in the analysis ( per each group). both groups were similar at randomization in demographic characteristics, icu admission diagnosis, main comorbidities and severity of illness. no device-related adverse events occurred in any of the two groups. no differences were detected using ag system vs conventional tubes in terms of post- introduction: during sepsis, intrinsic stress responses may become maladaptive and contribute to poor outcomes. targeted intervention with β-blockade to 'de-stress' such patients may be beneficial. we developed a -h rodent model of fluid-resuscitated faecal peritonitis in which mortality (occurring between and h) can be predicted at h by a low stroke volume (auroc . ), and where survivors are clinically improving by study end. [ ] objectives: to investigate the impact of β-blockade on outcomes in predicted survivors and nonsurvivors of faecal peritonitis. methods: instrumented, fluid resuscitated, male wistar rats ( - g) had sepsis induced by intraperitoneal injection of faecal slurry ( . ml/kg). at h, under brief isoflurane sedation, echocardiography was performed to differentiate predicted survivors from nonsurvivors based on a stroke volume cut-off of . ml. rats in each prognostic group were then randomised to receive either esmolol ( μg/kg over min followed by μg/kg/min infusion) or matching placebo ( . % nacl) until h. animals were observed for up to h, and time of death was recorded. the study was powered to detect a mortality reduction in predicted nonsurvivors from % to % with esmolol, with a power of . and type- error of . . results: rats were randomised after prognostication to receive either esmolol or placebo. at h, predicted survivors and nonsurvivors were clinically indistinguishable (both groups appeared only mildly unwell), though predicted nonsurvivors (stroke volume < . ml) had lower cardiac output ( ± vs. ± ml/min), higher heart rate ( ± vs. ± bpm) and blood pressure ( ± vs. ± mmhg) and more haemoconcentration (haemoglobin . ± . vs. . ± . g/dl) (all p < . ). survival was significantly improved by esmolol in predicted nonsurvivors (p = . ), but worsened in predicted survivors (p = . ). conclusions: mortality was approximately halved in predicted nonsurvivors by esmolol, but doubled in predicted survivors. early prognostication appears key in identifying the subset(s) of animals (and, potentially, patients) who might benefit from additional treatment, while avoiding iatrogenic harm in those that would naturally survive. mechanisms by which esmolol impact upon mortality are under investigation. introduction: endotoxins (lipopolysaccharides, lps) have become interesting targets in extracorporeal therapies. lps is a major constituent of the outer cell wall of gram-negative bacteria and strongly triggers inflammatory responses in humans at concentrations as low as ng/kg body weight. although the elimination of lps is promising for the supportive therapy of sepsis and liver failure, endotoxin neutralization using endotoxin adsorbents is controversial. objectives: we could recently show that endotoxin inactivation by low-dose polymyxin b (pmb; ng/ml) could be applied for endotoxin inactivation in blood [ ] . aim of this study was to establish an adsorbent-based system which combines constant pmb release for endotoxin inactivation and effective cytokine adsorption during extracorporeal treatment. methods: we established an adsorbent-based pmb release system which ensures a constant pmb level in plasma during extracorporeal therapies. a polystyrene-divinylbenzene based cytokine adsorbent (cg c) with nanostructured pores was coated with a defined amount of pmb by hydrophobic interactions. the endotoxin inactivation and cytokine adsorption was tested in an in vitro model using fresh donated blood which was stimulated with ng/ml lipopolysaccaride from e. coli. results: in plasma or blood an equilibration between the free and bound form of pmb will lead to a constant pmb level in plasma. the pmb release experiments in plasma clearly show that the adsorption and desorption is a function of the ratio pmb concentration: adsorbent surface. furthermore the pmb release depends on the protein concentration of the plasma. it makes a big difference whether the pmb coated adsorbent is used in plasma or in fractionated plasma where the hydrophobicity is much lower. the experiments suggest that the pmb coating of the cg c adsorbent doesn´t influence the cytokine removal which can take place in parallel. the ability of lps inactivation by the pmb coated cg c adsorbents was similar to pmb which was infused directly into the plasma. conclusions: our in vitro model shows that the combination of cytokine removal and controlled pmb release by the same adsorbent results in a strong suppression of inflammatory effects in blood. objective: management of hemodynamically stable pulmonary embolism (pe) with right ventricular (rv) dysfunction is still controversial. the objective of our study is to evaluate the effectiveness of local intraarterial thrombolysis (lit) in this group of patients and analyze its complications. patients and methods: prospective study (january -december ). patients included had been diagnosed of pe by computed tomography (ct), were hemodynamically stable [systolic arterial pressure (sap) > mmhg] and had a clinical suspicion of rv dysfunction (biventricular quotient in ct > or elevated levels of troponin i), that was confirmed afterwards by the presence of at least one of the following findings in the echocardiogram: subjective alteration of rv contractility, rv basal diameter (four chamber view) > mm, tricuspid annular plane systolic excursion (tapse) < mm or estimated systolic pulmonary artery pressure (spap) > mmhg. lit was done with a urokinase infusion (bolus dose of . ui followed by a perfusion of . ui/h) administered thru a pulmonary artery catheter, placed with radiological guidance, using an antecubital puncture. patients received simultaneous systemic anticoagulation with unfractionated heparin. after - h of treatment, and before ending the urokinase infusion, a radiological control was done using angiography or ct. within the seven days after lit, patients underwent a follow-up echocardiogram. statistical analysis was performed with student´s t test for parametric paired data, wilcoxon´s test for non parametric and stuart-maxwell for qualitative values. results: eighty-seven patients were included and their general data are detailed in fig. . mean treatment time was , ± , h. ninety percent of patients experienced a radiological improvement ( . % a complete/almost complete resolution and, . % a significant improvement). only , % didn´t improve radiologically. the evolutions of the different rv parameters studied are shown in fig. . minimum fibrinogen and platelet values where , ± , mg/dl and x ± . x cells/mm . eighteen patients ( , %) suffered form hemorrhagic complications that, in cases, where puncture site hematomas and, in six occasions ( , %) required an early interruption of the treatment. three patients ( , %) received a blood cell transfusion of ≤ blood units. mean icu and hospital stays where ± , and ± , days. all patients survived. conclusion: in our group of patients, lit rapidly improved the function and decreased the hemodynamic strain of the rv, while being associated with a low incidence of major complications. introduction: atrial fibrillation (afib) is associated with higher shortterm mortality in critical illness, but it is still uncertain whether afib independently contributes to unfavorable outcome. objectives: the aim of this study was to test the hypothesis that afib during critical illness is independently associated with increased in-hospital and long-term risk of death. methods: the frog-icu study was a prospective, observational, multicenter cohort study designed to investigate outcome of critically ill patients. heart rhythm was assessed at inclusion and during icu stay with digital ecg recordings. among patients who had any afib during icu stay, newonset and recurrent afib were diagnosed in patients without and with previous history of afib, respectively. primary endpoints were in-hospital and -year mortality. covariate adjusted logistic regression models and cox proportional hazards models were used to evaluate the association between afib and in-hospital mortality or -year mortality, respectively. in-hospital mortality was adjusted for independent covariates (age, gender, simplified acute physiology score (saps ii), treatment with inotropes or vasopressors, serum lactate level, high-sensitive troponin i, b-type natriuretic peptide), -year mortality was adjusted for covariates (age, gender, saps ii, history of congestive heart failure, treatment with inotropes or vasopressors, serum lactate level, c-reactive protein and serum creatinine). results: the study included critically ill patients. the study population consisted of patients for whom data about heart rhythm during icu stay was available. afib occurred in patients ( %). newonset afib (n = ) had higher in-hospital mortality ( %) compared to no afib ( %, p < . ) or recurrent afib ( %, p = . ). newonset afib showed increased in-hospital risk of death after multivariable adjustment compared to no afib ( introduction: the incidence of the supraventricular arrhythmias is increased in septic shock patient, and it is associated with worse short and long term prognosis. objective: to test that propafenon could be a feasible antiarrhythmic in the absence of contraindications. methods: patients with septic shock who received antiarrhythmic drugs for supraventricular arrhythmias were included over months. the patients were divided into the three groups according to antiarrhythmic agent: amiodarone (group ), propafenon (group ) and metoprolol (group ). in the first h the type of arrhythmia, dosages, cardioversion rates, demographic, haemodynamic, laboratory parameters were recorded. mortality was compared between the groups and between the cardioverted vs those remaining in acute and chronic arrhythmias. clinical studies; presumably due to an impairment of myocardial oxygenation and ventricular filling. a randomised control trial of heart rate (hr) control in septic shock showed an increase of survival for the patients receiving esmolol . an animal study observed a similar improvement of survival and an increase in left ventricular (lv) contractility when esmolol was associated with norepinephrine (ne) . however beta-blockers therapy in sepsis is still debated considering its negative inotropic side effect. ivabradine, a pure bradycardic agent, blocking selectively the if channels in the sinus node, could represent a safer option for hr control. objectives: compare the hemodynamic tolerance of hr control either with intravenous (iv) ivabradine or esmolol perfusion, in a large animal model of septic shock. methods: we used a closed chest swine model of fecal peritonitis. analgesia and sedation were provided by sufentanil and sevoflurane. hemodynamic monitoring included arterial blood pressure (abp); continuous cardiac output (cco); lv maximum rate of pressure (dp/dtmax) and lv elastance (e-lv); mixed venous oxygen saturation (svo ) and arterial lactate (lac). after the development of septic shock, fluid resuscitation was started and animals were randomised in groups of pigs: ivabradine (ivb), esmolol (esm) or control. ivabradine was administered with an iv bolus of , mg/kg that could be repeated at , mg/kg, aiming an hr between and beats per minute (bpm). continuous iv perfusion of esmolol was started at mg/kg/h and adapted to reach the same hr range. after hours of hr control, a fixed dose of , mcg/kg/ min ne was introduced in all groups. results: all animals developed an hyperdynamic distributive shock, including tachycardia above bpm. hr control between and bpm was successful in both ivb and esm groups. ivb administration didn't affect abp, cco, dp/dtmax, e-lv, svo or lac. esm perfusion tended to decrease abp, cco and svo ; e-lv and lac were unaffected but dp/ dtmax decreased markedly. under ne perfusion, e-lv was similar in all groups but dp/dtmax was lower in esm group. conclusions: in septic shock, hr control with an iv administration of ivabradine doesn´t alter global organs perfusion and cardiac function. esmolol perfusion, in order to achieve the same goal, reduces lv dp/dtmax and didn´t enhance lv contractility in association with ne. introduction: patients in critical care settings are often at risk of developing hypotension, which can lead to poor outcomes such as increased morbidity and mortality. current hemodynamic parameters for monitoring such hypotension often exhibit pronounced changes only when the hypotensive event is already occurring or when it is too late. we have developed a hypotension probability indicator (hpi™) to predict hypotensive episodes based on machine learning techniques. the hpi™ model was trained on~ icu and or patients. the objective of this study is two-fold: ) to test the accuracy of hpi™ to predict events on a completely independent test data set of icu patients, not used in the development of the algorithm; and ) to compare timing of interventions in response to an event to the timing of detection of an event by hpi™. methods: data used in this study came from the mimic ii mit research database. arterial pressure waveforms of patients were analyzed for hpi™ and then tested for event detection and prediction accuracy. all features of the hpi™ as well as other hemodynamic parameters for comparison were calculated using flotrac (edwards lifesciences, irvine, ca). a hypotensive event was defined as any time period where map < mmhg for at least minute. an roc analysis was performed to assess auc, sensitivity, and specificity of the hpi™ to identify an event during the event, and , , and minutes prior to the start of event. next, clinical records of the patients were reviewed for any drug or fluid interventions during start of event to minutes after an event and the elapsed time from start of event to intervention time was calculated. a drug or fluid intervention was defined as any bolus or iv infusion start. in addition, the time at which hpi™ probability of event > . prior to the start of an event was also calculated for comparison. data are presented in median [ - th percentiles]. conclusion: in conclusion, hpi™ can accurately detect an event up to minutes prior. hpi™ may serve as a useful addition in the care of critically ill patients by potentially facilitating earlier intervention either in response to an event or serve as a decision support and direct a physician's attention to potential oncoming events when hpi™ is high. this statement is valid for both in-hospital as well as out-of-hospital cardiac arrest. regardless of the location of the cardiac arrest, there are at least four factors that appear to be of major importance for survival. the first is the time from collapse to delivery of treatment; the second is the quality of cardiopulmonary resuscitation (cpr); the third is the patient's co-morbidity and the fourth is the aetiology of the ca and the presenting rhythm. the present study will focus on the first three parts of the chain of survival, time from collapse to call/cpr/defibrillation. objectives: to describe the number of survivors following inhospital cardiac arrest (ihca) in sweden during one year and, based on estimations and assumptions, calculate the potential number of additional lives saved following improvements in the chain of survival. there was a strong inverse relation between delay to call for the rescue team and delay to treatment and survival. if delay from collapse to a/call and, b/start of cpr were reduced to < minute in patients with a longer delay than that and if c/time from collapse to defibrillation was reduced to < minutes among those with a longer delay than that: a/ ; b/ ; and c/ further lives could potentially be saved. we speculate that about additional lives (one per hospital beds each year) could theoretically be saved by improved adherence to guidelines regarding the first three components in the chain of survival in swedish hospitals yearly. conclusions: in , approximately patients (four per hospital beds) were successfully resuscitated following ihca in sweden. there was a strong negative relation between collapse and call for rescue team/cpr/defibrillation and -day survival. with reduced delay times a further lives (one per hospital beds) could theoretically be saved each year in sweden. the study was supported by grants from the laerdal foundation of acute medicine in norway (jh) and the scientific council of halland (fh). prophylactic versus clinically-driven antibiotics in comatose survivors of out-of-hospital cardiac arrest -a pilot study s. results: proportion of patients on antibiotics was significantly greater from day to in prophylactic group while there was no difference on days to . peak c-reactive protein in prophylactic group was significantly smaller ( ± vs. ± mg/l; p = . ). there was no difference in peak white blood cell count ( . ± . vs. . ± . ; p = . ), procalcitonin ( . ± . vs. . ± . microg/l; p = . ) and cd . except for positive mini bal on day ( % vs. %; p < . ), there was no significant impact on other microbiological samples and x-ray signs of pneumonia ( % in each group). use vasopressors/inotropes ( % in each groups), duration of mechanical ventilation ( . ± . vs. . ± . days), tracheal intubation ( . ± . vs. . ± . days), icu stay ( . ± . vs. . ± . days), survival ( % vs. %) and survival with good neurological outcome ( % vs. %) were also comparable. conclusions: tracheobronchial aspiration was documented in more than a quarter of comatose survivors of ohca using bronchoscopy on admission. in the absence of aspiration, prophylactic antibiotics reduced peak crp and the incidence of positive mini-bal on day and had no significant impact on other introduction: survival to discharge after in-hospital cardiac arrest (ihca) is poor ( − %) and has not improved despite developments in modern medicine. data on the aetiology of in-hospital cardiac arrests is very limited, and conducted studies include ihca patients resuscitated in emergency departments, intensive care units and high dependency units. objectives: to determine the underlying causes of ihcas occurring on general wards and investigate, whether the aetiology is independently associated with six months survival. methods: a prospective observational study between - in a finnish university hospital. we included all adult ihca patients on general wards who were attended by icu´s medical emergency team. definite aetiology was determined from the autopsy records and medical records. no autopsies were conducted solely for study purposes. the local ethics committee approved the study protocol (approval no: r ). results: the cohort consisted of patients, of which ( %) were male. median age of the patients was ( , ) years. altogether ( %) ihcas were monitored/witnessed, first rhythm was shockable in ( %) cases and ( %) patients survived six months. autopsy was conducted in ( %) cases. aetiology was determined as cardiac in events, of which were due to acute myocardial infarction and due to acute myocardial ischaemia without infarction. congestive heart failure was the third most prevalent reason in cardiac sub cohort ( ). altogether ihcas were considered non-cardiac; most common causes were pneumonia ( ), exsanguination ( ), pulmonary embolism ( ) and peritonitis ( ). cardiac ihcas were more commonly preceded by subjective symptoms (e.g. chest pain, respiratory distress) than non-cardiac ihcas ( % vs. %, p = . ), while objective vital dysfunctions preceded ihcas as often in both sub cohorts ( % vs. %, p = . ). in a multivariate logistic regression model monitored/witnessed event, shockable primary rhythm and low age-adjusted charlson comorbidity index score were factors independently associated with -day survival, but the aetiology (cardiac vs. non-cardiac) was not. conclusions: aetiology of ihcas on general wards is cardiac in % of the events. ischaemic reasons for ihcas were twice as common as shockable primary rhythms in this study. subjective symptoms and objective vital dysfunctions often precede general ward ihcas. however, neither the aetiology nor the presence of antecedents, but low comorbidity, observed arrest and shockable primary rhythm are factors associated with a favorable outcome. reducing in-hospital cardiac arrest by implementation of innovative early warning information system in a tertiary medical center introduction: in-hospital cardiac arrest (ihca) is a common and high-risk issue with less than % surviving to hospital discharge. most patients show signs of clinical deterioration in the hours before ihca. as a result, the development of vital signbased early warning system was designed to detect early signs of clinical deterioration before ihca attack in order to trigger early intensive care. objectives: in this study, we investigate the impact of the implementation of an innovative early warning information system on the rate of ihca and survival rate in ihca patients. methods: a multidisciplinary team among intensivists, cardiologists, emergency physicians, and nursing staffs in a tertiary medical center was organized since may . the key interventions include automatic national early warning score (news) calculating information system, nurses and physicians computer-based reminding alarm if news ≥ or more than highest scores among previous measurements, real time early warning screen saver and electric board, in service education and early warning monitor team. all patients admitted between january and january were enrolled. total , patients were divided into three groups: pre-interventional group from jan to april (n = , ), interventional group from may to june (n = , ) and post-interventional group from july to jan (n = , ). the definition of in-hospital cardiac arrest is the number of in-hospital cardiac arrest per thousand admitted patients. we compared the rates of ihca, hours survival rate and discharge survival rate in ihca patients among these groups. results: the rate of in-hospital cardiac arrest improved from . ‰ in pre-interventional group, to . ‰ in interventional group and to . ‰ in post-interventional group (p < . ). the hours survival rate in ihca patients increased from . % in pre-interventional group, to . % in interventional group and to . % in postinterventional group (p < . ). the discharge survival rate in ihca patients also increased from . % in pre-interventional group, to . % in interventional group and to . % in post-interventional group (p < . ). conclusions: the study demonstrated that implementation of early warning information system and innovative strategies could attenuate the rate of ihca, hours survival rate and discharge survival rate in ihca patients. introduction: although prolonged unconsciousness after cardiac arrest (ca) is a sign of poor neurological outcome, limited evidence shows that a late recovery may occur in a minority of patients. objectives: we investigated the prevalence and the predictive factors of delayed awakening in comatose ca survivors treated with targeted temperature management (ttm). methods: retrospective analysis of the parisian region out-of-hospital ca registry ( - ). in adult comatose ca survivors treated with ttm, sedated with midazolam and fentanyl, time to awakening was measured starting from discontinuation of sedation at the end of rewarming. awakening was defined as delayed when it occurred after more than h. results: a total of patients ( % male, mean age ± years) were included, among whom awoke. delayed awakening occurred in / ( %) patients, at a median time of h (iqr - ) from discontinuation of sedation. in / ( %) late awakeners, pupillary reflex and motor response were both absent h after sedation discontinuation. in multivariate analysis, age over years (or . , % ci . - . ), postresuscitation shock (or . [ . - . ]), and renal insufficiency at admission (or . [ . - . ]) were associated with significantly higher rates of delayed awakening. conclusions: delayed awakening is common among patients recovering from coma after ca. renal insufficiency, older age, and postresuscitation shock were independent predictors of delayed awakening. presence of unfavorable neurological signs at h after rewarming from ttm and discontinuation of sedation did not rule out recovery of consciousness in late awakeners. grant acknowledgment none note: this abstract has been previously published and is available at [ ] . it is included here as a complete record of the abstracts from the conference. introduction: viral infections play a key role in preventable deaths of children globally, and can be antecedents to bacterial pneumonia and sepsis. diagnosis of viral infection is often problematic due to non-specific clinical presentation. we developed a host immune response gene expression signature to distinguish systemic inflammation due to viral infection vs. bacterial or noninfectious causes. objectives: to define and validate the host immune response gene expression signature against multiple independent datasets. methods: four public geo datasets describing transcriptomic responses to viral infection were used to identify biomarkers, ranked by auc, which could separate affected from unaffected subjects. biomarkers that also responded (auc > . ) to non-viral causes of systemic inflammation were removed. remaining biomarkers were then ranked for performance in other geo transcriptomic datasets for viral infection; those with mean auc > . were retained. next, a greedy search was applied to the merged ( + ) viral geo datasets to identify the best combinations of biomarkers for discrimination of viral infection. the signature was then validated using independent datasets. results: a -gene signature (comprised of isg , il , oasl, adgre ) had auc . across the merged ( + ) viral geo datasets. this signature was validated in additional geo datasets covering a wide variety of viral pathogens including a time-course study of respiratory syncytial virus (rsv) in children (fig ) , and in two independent datasets of our own: adults from the emergency department (fig introduction: using a tourniquet to temporary cut off blood supply to the arm (remote ischemic preconditioning -ripc) has been shown to result in myocardial protection and reduced incidence of aki in patients undergoing cardiac surgery. however, a recently performed large multi-center trial in cabg patients showed no beneficial effects on clinically relevant endpoints [ ] . animal studies have shown an`early window of protection' in the - hours after ripc as well as a`late window of protection` - hours after ripc. several mechanisms have been suggested to mediate the protective effects of ripc, of which attenuation of the immune response is an important candidate, although this has hitherto also only been shown in animal studies [ ] . objectives: to determine the effect of single and repeated ripc, thereby investigating both the early and late windows of protection, on the inflammatory response during endotoxemia, a standardized, controlled model of systemic inflammation in humans in vivo. methods: we performed a randomized controlled study in healthy non-smoking male volunteers. subjects were assigned to either the single-dose ripc group, multiple-dose ripc group, or the control group (n = per group). the single-dose ripc group received dose of ripc, consisting of cycles of -minute ischemia of the arm followed by minutes of reperfusion just before administration of ng/kg lipopolysaccharide (lps). the multiple-dose ripc group received one dose of ripc per day on the days before the endotoxemia experiment day, and dose just before lps administration. results: lps administration resulted in a typical increase in body temperature, flu-like symptoms, and hemodynamic changes, with no differences between groups. administration of lps resulted in a sharp increase in plasma levels of the proinflammatory cytokines tnf-α, il- , and il- as well as the antiinflammatory cytokine il- . no differences in plasma levels of these cytokines were observed between the different groups ( figure ). conclusions: in the present study, we demonstrate that ripc does not affect the in vivo inflammatory response induced by administration of endotoxin in humans. these results implicate that ripc does not exert direct anti-inflammatory effects and that the previously observed protective effects are mediated through other mechanisms. furthermore, the absence of immunomodulatory effects of ripc in the present study tempers expectations of using ripc as an immunomodulatory treatment strategy in patients. introduction: sepsis-induced immune alterations are associated with secondary infections and increased risk of death ( ). mesenchymal stem cells (mscs) have been described as a novel therapeutic strategy for the treatment of diseases related to inflammation and tissue injury with their potent modulatory effects on immune system ( ) . objectives: in this study, we evaluated the immune-modulatory effects of human dental follicle mesenchymal stem cells (hd-mscs) on lymphocytes which are isolated from peripheral blood samples of sepsis and septic shock patients. methods: according to the international sepsis definitions conference ( ), patients divided into two groups as sepsis (group i, n = ) and septic shock (group ii, n = ). peripheral blood mononuclear cells (pbmcs) were isolated from venous blood samples of group i, group ii and healthy subjects named as group iii, n = . anti-cd /cd pbmcs were co-cultured with df-mscs, ifn-g stimulated df-mscs and with no mscs about hour. cd + cd + foxp + t cells levels (treg), lymphocyte proliferation and apoptosis were evaluated with the flow cytometry. results: df-mscs and ifn-g induced df-mscs cultures significantly supressed proliferation in sepsis group when compare to septic shock group(p < , ). conclusions: mscs demonstrate their effects on immune system by increasing the number and activity of regulatory t cells (treg) ( ) .in our study, mscs suppressed lymphocyte proliferation and apoptosis but increased the rate of treg cells in sepsis cocultures. this effect was more obvious with ifn -g stimulation. these responses were not seen in septic shock patients´blood samples and might be explained with anergy. our findings revealed that df-mscs application has immunoregulatory effects in sepsis. this approach opened a new area to work how will mscs be used to reduce organ dysfunctions and mortality in the clinical practice. introduction: inhibition of mitochondrial complex i is described in human and animal sepsis. , this may be responsible, at least in part, for the decrease in mitochondrial functionality seen in sepsis. we have recently demonstrated that the mitochondrial uncoupling agent, dinitrophenol (dnp) failed to increase body temperature and oxygen consumption (vo ) in septic rats, as was seen in healthy controls. this suggests that uncoupling is active in sepsis and can contribute to fever. we further postulated that the blunted effects of dnp in sepsis may be related in part to upstream mitochondrial inhibition. objectives: to determine if complex i inhibition by metformin in healthy rats can prevent the increment in temperature and oxygen consumption (vo ) by dnp, and thus mimic the pattern seen in sepsis. methods: vo was measured in awake, cannulated male wistar rats (approx g body weight) in metabolic cages (oxymax, columbus instruments). sepsis was induced with an intraperitoneal injection of faecal slurry at time . sham control animals received no slurry. fluid resuscitation ( ml/kg/h crystalloid) was started at hours and continued throughout the whole experiment. half the septic and sham animals were treated with an iv infusion of metformin ( mg/kg) between hours - . at and hours, all animals received iv dnp ( mg/kg). arterial blood gases, echocardiography and core temperature were measured at times , and , and and hours (i.e. before and after the two doses of dnp). mean arterial pressure was recorded continuously. wilcoxon rank sum test was used to compare groups and two-way anova to compare changes in continuous variables from baseline between groups. p values < . were considered statistically significant. results: pretreatment with metformin completely prevented the increase in temperature and vo induced by dnp in sham animals at hours and reflected that seen in non-metformin treated septic rats ( figure ). the reduction in myocardial contractility (stroke volume and vmax) seen in the septic animals treated with dnp was prevented by complex i inhibition at h. metformin was metabolically well tolerated, with no increase in blood lactate. conclusions: inhibiting complex i with metformin prevents the uncoupling effect of dnp in sham animals. this mimics the pattern seen in septic animals and confirms that both complex i inhibition and pre-existing mitochondrial uncoupling could be active in septic rats. objectives: the inflammasome is a multiprotein complex that stimulates cytokines release such as interleukin- β (il- β) and il- , involved in the inflammatory response. our aim is to quantify the state of activation of the inflammasome complex in septic patients, as well as to study possible differences in the cytokines levels in sepsis and septic shock, its temporary evolution, and its prognostic value. methods: prospective study including patients admitted to the icu with sepsis or septic shock during months. on days , and , il -β serum levels and real-time expression of nlrp inflammasome (nucleotide-binding oligomerization domain, leucine rich repeat domain containing protein and pyrin) were determined by elisa and real time-pcr respectively. demographic variables, severity scores on icu admission (apache ii and sofa), sepsis focus and mortality were collected. statistical analysis: t-student, kruskal-wallis and u-mann-whitney test as appropriate. results: there were included patients (severe sepsis and septic shock ). overall mortality was % ( patients). the levels of il- β on day ( . ± . vs . ± . pg/ml; p < . ) and nlrp inflammasome ( . ± . vs . ± mrna arbitrary units; p < . ) were significantly higher in septic shock patients than in sepsis, with no differences in the following days set ( and ). the il- β and nlrp inflammasome levels decreased significantly on days and compared to first day (p < . ), without differences between survivors and deceased patients. conclusions: in septic patients, inflammasome activation complex occurs, with higher levels detected in septic shock. decreased levels of il- β and nlrp inflammasome in septic process have been observed during evolution, actually without relation with mortality. introduction: according the consensus conference on weaning from mechanical ventilation, intubated patients should pass a spontaneous breathing trial (sbt) to assess their readiness to be extubated. objectives: to characterize patients who are extubated without any sbt and to compare them to patients who had at least sbt during their weaning period. methods: the prospective multicentre observational wind (weaning according new definition) study was performed from april to august . ventilation and weaning modalities were daily assessed until discharge in all intubated patients admitted to the participating icus. we defined ) weaning attempt (wa) as a spontaneous breathing trial (sbt) or an extubation (with or without sbt), ) successful weaning as an extubation without death or invasive mechanical ventilation within days. variables are presented as mean ± standard deviation, median [interquartile range] or number (percentage). comparisons were made using chi test, exact fisher tests, student t-test or wilcoxon rank sum test as appropriate. all statistical tests were two-sided and p value ≤ . were considered significant. results: among the patients included, patients had at least wa comprising patients whose first wa was a sbt and who had another type of first wa. these patients with no sbt had a total of wa: ( . %) planned extubation without sbt, self-extubations ( . %), wa while tracheostomized ( . %) and sbt after their first wa ( . %). the majority of patients with self-extubation had a successful weaning not requiring reintubation ( . %). almost a quarter (n = ) of the patients who were extubated without any sbt had a decision of withholding or withdrawing invasive mechanical ventilation, representing . % (n = ) of the deceased patients. we then excluded patients with a decision of limitation and patients with a self extubation to compare patients who had a planned extubation with or without sbt as first wa (table ) . patients with no sbt were younger, less severe and were more often admitted for unplanned surgery: they had an easier weaning with a lower (but non significative) rate of reintubation, a shorter duration of invasive mechanical ventilation and a shorter length of stay in the icu. conclusion: patients who are extubated without sbt seem to belong to three different groups: self-extubation, terminal extubation and patients in whom physicians anticipate an uneventful weaning and extubation. among the patients with a planned extubation and without any limitation decision, clinical judgment regarding weanability appears to be effective as this group of patients had a good outcome with a low reintubation rate. this study benefited of a grant of the non-profit association départementale des insuffisants respiratoires (adir) of the haute normandie, france introduction: decrease in diaphragmatic maximal relaxation rate (mrr) occurs early in the process of diaphragmatic fatigue and well before the diaphragm fails as a force generator; its measurement would, therefore, be especially valuable in icu patients during a weaning trial. however, the use of oesophageal pressure catheters for that purpose impedes wide clinical use. on the contrary, m-mode sonography, allows non-invasive, real-time measurement of the speed of the diaphragmatic motion. objective: purpose of our study was to investigate a possible correlation between diaphragmatic mrr traditionally acquired with transdiaphragmatic pressure (pdi) catheters (mrr-pdi) and an echo equivalent mrr (mrr-echo) acquired during different breathing conditions. methods: the slope of mrr was measured from the initial steepest part of the descending pdi curve simultaneously with the slope of the initial steepest descending part of diaphragmatic excursion with m-mode sonography. the protocol entrained four consecutive stages: i) breathing spontaneously during t-piece trial, ii) breathing spontaneously with performance of sniff-like maneuvers, iii) breathing with resistances of cmh o/l, and iv) breathing with resistances of cmh o/l with performance of sniff-like maneuvers. statistical comparisons between slope recordings from the two methods were performed with pearson correlation, while bland and altman plots were obtained in order to demonstrate reliable agreement between methods at each different breathing condition. results: a total of separate breaths during the four previously reported breathing conditions from six icu patients were recorded. table summarizes the slopes measured from mrr-pdi and mrr-echo as means ± standard deviations (sd), and their linear correlations with p values. statistical significant correlations were observed in all four stages; i) pearson correlation coefficient r = . , p < . , r = . , ii) r = . , p < . , r = . , iii) r = . , p < . , r = . , and iv) r = . , p < . , r = . . bland and altman plots demonstrating differences of measurements against means, as well as confidence intervals (means of differences ± sd) were obtained for each breathing condition. graph represents the bland and altman plot for spontaneous breathing with sniff-like maneuvers without resistances. high r indexes, indicating high agreement between the two methods were noted: i) . , ii) . , iii) . , and iv) . . the results of our study suggest a statistical significant correlation and reliability between diaphragmatic mrr measured from pdi tracings and the assumed diaphragmatic relaxation rate calculated from simultaneous m-mode sonographic recordings. clinical studies are required to confirm the potential of this non-invasive index of diaphragmatic mrr to be used as a predictor for weaning success. grant acknolwedgement none declared. introduction: high flow nasal cannula oxygen therapy (hf oxy) has been recently shown to decrease re-intubation rate, as compared with low flow oxygen therapy (lf oxy). [ ] , [ ] objectives: to assess the effects of hf oxy as compared with lf oxy on diaphragmatic electrical activity (eadi), respiratory rate (rr), tidal volume (vt) and gas exchange in the post extubation period. our hypothesis was that hf oxy, as compared with lf oxy, would improve gas exchange and decrease eadi. methods: patients underwent a crossover study immediately after extubation. each patient was submitted to three consecutive steps of hour each, according to an on-off design: ) hf oxy; ) lf oxy; ) hf oxy. oxygen fraction was maintained stable throughout the study. the eadi was continuously monitored through eadi cathether (maquet, solna sweden). the heated and humidified hf oxy was delivered through nasal cannula at flow rates of - l/min, (f&p, auckland new zealand). results: rr remained similar throughout the study, vt was significantly higher during the lf oxy step as compared with the hf oxy steps. oxygenation significantly improved during the hf period, whereas paco remained unchanged throughout the study (table ). eadi was significantly higher during lf oxy ( figure ) conclusions: since the eadi is correlated to work of breathing, our physiological data suggest that hf oxy significantly reduces wob while improving oxygenation in the post extubation period. further studies are required to define if diaphragm unloading may explain the favourable results of hf oxy in clinical trials. introduction: i non-invasive mechanical ventilation (niv) has been seen to play a major role in decreasing intubation rates in patients with severe exacerbation of chronic obstructive pulmonary disease and congestive heart failure. unsuccessful niv has been found to be independently associated with increased mortality in patients with arf. the niv failure and their impact on mortality in patients with inlfuenza infection is unknown. objectives: ) to describe non-invasive ventilation failure (nivf) rate, ) to identify risk factor for nivf using chaid (chi-square automatic interaction detection) and ) to determine if nivf is associated with icu-mortality. methods: secondary analysis in , patients with influenza requiring mechanical ventilation(mv). three groups were considered: ) patients with niv who failed (group a); ) patients with niv who succeeded (group b); and ) patients with invasive mv (group c). cox analysis was used to assess survival. risk factors for nivf were obtained using chaid. conclusions: niv failure is frequent and independently associated with icu-mortality in patients with influenza. chaid analysis might be a promising tool to assist in clinical decision-making. introduction: acute kidney injury (aki) after liver transplantation is a common complication with an incidence of approximately % [ ] , resulting in high morbidity and mortality. to increase the possibilities to prevent or treat aki after liver transplantation, it is essential to increase the knowledge on changes in renal physiology after liver transplantation. objectives: the aim of this study was to gain insights into renal perfusion, filtration and oxygenation in the immediate postoperative period in patients undergoing liver transplantation and to compare these data to those obtained from a group of patients undergoing major surgery with no postoperative renal impairment. methods: informed consent was obtained preoperatively from twelve patients with normal renal function accepted for liver transplantation. glomerular filtration rate (gfr) was measured preoperatively by plasma clearance of cr-edta. the patients were studied after liver transplantation in the icu in the immediate postoperative period, sedated and mechanically ventilated. systemic haemodynamics and renal variables where obtained during two -min periods. renal blood flow (rbf) and gfr were measured by the renal vein retrograde thermodilution technique and by renal extraction of cr-edta (=filtration fraction, ff), respectively. arterial (a) and renal vein (rv) blood samples were taken for measurements of arterial (cao ) and renal vein (crvo ) oxygen contents. renal oxygen consumption [rvo = rbf x (cao -crvo )], renal oxygen delivery (rdo = rbf x cao ) and renal oxygen extraction [ro ex = (cao -crvo )/cao )] were calculated. sixty-three patients undergoing uneventful cardiac surgery with no postoperative renal impairment served as controls. results: cardiac index ( %) and systemic oxygen delivery index ( %) were higher and systemic vascular resistance index was lower (− %) in the liver transplant group compared to controls (p < . ). rbf was % higher and renal vascular resistance was % lower compared to controls (p < . ). in the liver transplanted group, gfr was % lower compared to the preoperative value (p = . ), accompanied by a % increase in serum creatinine (p < . ). after surgery, when compared to controls, gfr and ff was % and % lower, respectively (p < . , p < . ), and rvo and ro ex were % and % higher, respectively, in the liver transplanted patients (p < . , p < . ). conclusions: despite the hyperdynamic systemic circulation, gfr is considerably reduced immediately after liver transplantation, most likely caused by a post-glomerular renal vasodilation decreasing upstream glomerular filtration pressure. renal oxygenation is impaired after liver transplantation due to the high rvo , which was not met by a proportional increase in rdo . introduction: acute kidney injury is common in critically ill patients and associated with increased short and long-term mortality. most published studies have focussed on patients with severe aki. little is known about the long-term outcome of patients with less severe aki. our objective was to determine the outcome of patients with different stages of aki at and years after admission to the intensive care unit (icu). we retrospectively analysed the data of all adult patients admitted to a multi-disciplinary icu in a teaching hospital in the uk between march -may . patients with chronic dialysis dependent renal failure were excluded. patients were categorised according to their maximum stage of aki during stay in icu as defined by the serum creatinine criteria of the kdigo classification. apache ii and sofa scores were used to describe severity of illness on admission to icu. in patients with > admission to icu, we only included the first admission in the analysis. results: data of adult patients were analysed of whom % had aki during their stay in icu. patients with any degree of aki had a higher mortality at and years but they were also sicker on admission to icu. conclusions: any stage of aki during critical illness is associated with an increased risk of mortality at and years. mortality is highest in patients with aki ii and iii. more work is necessary to explore the relationship between aki and long-term outcome and to identify independent risk factors for mortality. introduction and objective: observational studies of intensive care unit (icu) patients with acute kidney injury have shown a negative correlation between accumulation of fluids and survival [ ] . it is unknown whether rapid removal of accumulated fluids is feasible and beneficial. therefore we wish to perform a pilot trial of forced fluid removal vs. standard care in critically ill patients with high-risk acute kidney injury and severe fluid overload. methods: the ffaki-trial is a pilot, multicenter, randomized clinical trial recruiting adult intensive care patients with high-risk acute kidney injury and fluid overload defined as > % of ideal bodyweight. to reduce the signal-to-noise ratio we only wish to include patients with a high baseline risk of persistent renal failure. baseline risk will be calculated using a newly developed model, the renal recovery score (rrs), to predict the chance of recovering renal function within days. in-and exclusion criteria are shown in tables and . patients are randomized to either forced fluid removal or standard care for the entire icu stay. forced fluid removal is done by infusion of furosemide and/or fluid removal with continuous renal replacement therapy. the fluid removal rate is adjusted times daily to achieve a therapeutic goal of net negative fluid balance ≥ ml/kg/h. physiologic tolerance to fluid removal is continually evaluated according to predefined criteria of hypoperfusion: lactate ≥ mmol/l, mean arterial pressure < mmhg or mottling beyond the edge of the kneecaps. in case of hypoperfusion, fluid removal is suspended until all criteria have been resolved for a minimum of hour. the flow chart for the experimental ffaki-treatment is seen in figure , , . the primary outcome is cumulative fluid balance days after randomization. by inclusion of patients we are able to detect a difference of . l between groups (α = . and β = . renal recovery score ≤ %. fluid overload defined as a positive fluid balance ≥ % of ideal body weight. able to undergo randomization within hours of fulfilling the other inclusion criteria introduction: enhanced recovery pathways have been a focus for patient optimisation of morbidiy and mortality in the post-operative patient. significant mortality improvement was seen following the implementation of the emergency laparotomy pathway quality improvement care (elpquic) bundle with an adjusted risk of death from . % to . % ( ). the first national emergency laparotomy audit (nela) has since been published demonstrating a -day mortality of % and recommending access to pathways that identify need to escalate care ( ) . however acute kidney injury (aki) in critically unwell patients remains a major source of mortality, of up to %, and morbidity ( ). it is not yet clear whether enhanced recovery pathways, specifically those that utilise early goal directed therapy, affect the incidence of aki. objectives: to determine if there was a difference in incidence of combined aki pre and post implementation of an enhanced recovery protocol, one that had already demonstrated a significant mortality benefit. methods: a subgroup analysis of the data gathered via the elpquic bundle was performed ( ). we obtained buy-in from the participating centres and requested an extrapolation of values from their raw data. if required further data was obtained via the hospital's electronic path system. all data was reviewed by a second investigator. we defined the baseline creatinine as the best available preoperative creatinine from the past year. the data recorded included creatinine at baseline, post-op, worse recorded creatinine between day and day , make , p-possum and -day mortality data. ckd stage was identified via mdrd equation with age, gender and baseline creatinine. patients with aki were stratified according to kidgo stages of akin. primary outcome was the incidence of aki in each of combined pre and post elquic patient population. secondary outcome included the stage specific incidence of aki. results: there was no significant difference between the cumulative incidence of akin pre and post elquic implementation on day post-op ( . % vs . %, p = . ) or day post-op ( . % vs . %, p = . ). conclusion: this multi-centre cohort subgroup analysis demonstrates that the implementation of a quality improvement care bundle does not affect the incidence of aki. this is in contrast to the clear mortality benefit that such a care bundle has provided and provides stimulus to discover what factors may yet improve aki, and so further improve these patients outcome. introduction: it is now well documented that critically ill patients are exposed to stressful conditions and experience discomforts from multiple sources. improved identification of the discomforts of patients in intensive care units (icus) may have implications for managing their care, including consideration of ethical issues, and may assist clinicians in choosing the most appropriate interventions. objectives: the primary objective of this study was to assess the effectiveness of a multicomponent program (mcp) of discomfort reduction in critically ill patients. the secondary objectives were to assess the sustainability of the impact of the program and the potential seasonality effect. methods: we conducted a multicenter, cluster-randomized, controlled, single (patient)-blind study involving french adult icus. the experimental intervention was the implementation of the mcp including the following steps: identification of discomforts, immediate feedback to the healthcare team, and implementation of targeted interventions under control of local champions who received monthly feedback and organized monthly meetings with their healthcare team. all icus started with a -month period with no intervention, and then they were randomized to one of two groups: icus with mcp implemented during a -month period (experimental group) and icus without any programm during the same period (control group). to assess the sustainabilty of the impact of the mcp, the study was completed with a second -month period during which the mcp was no longer applied in the experimental group. the primary endpoint was the monthly overall score of self-reported discomfort from the french -item questionnaire on discomforts in icu patients (iprea) (range from to , the lowest possible level of discomfort to the highest). the secondary endpoints were the scores of each item of iprea. results: at the end of the -month period, taking into account the clustering design, the monthly overall discomfort score was lower in the experimental group ( parents were asked to consent to being contacted months after discharge, at which point they were asked to complete the pedsql, a generic measure of quality of life. the pedsql enables a total score, physical health summary score and psychosocial health summary score to be calculated, with possible scores ranging from - and higher scores equating to better quality of life. results: parents of children aged - . years (median age: . years; ( %) males), the majority of whom had had an emergency picu admission due to sepsis (n = , %) or respiratory problems (n = ; %), completed the pedsql months after discharge from picu. for the group overall the total score was . (sd . ), physical health summary score was . (sd . ) and psychosocial health summary score . (sd . ). babies aged - months (n = ) had total scores (m = . , sd = . ) comparable to those of healthy norms (m = . , sd = . ). however older children in all age groups had lower total scores than healthy norms. whilst % ( / ) of babies had scores of more than one standard deviation below the score of healthy norms, which is recognised as being of clinical significance, this rose to % ( / ) of children aged - years and % ( / ) of children aged - years. of note is that children ( %) aged - years had been admitted to picu for reasons related to trauma or neurological concerns whereas no child aged - months had been admitted for those reasons. conclusions: children who have had an emergency admission to picu are at risk for impaired quality of life months after discharge. the risk appears to be greater for children of years and older which is likely to be at least partly attributable to the underlying reason for their admission. evaluating quality of life outcomes in the longer term after picu discharge is warranted and identification of potential risk factors will enable interventions to be targeted to optimise outcomes after an emergency admission to picu. introduction: cognitive dysfunction is an important long-term complication of critical illness associated with reduced quality of life, increase in healthcare costs and institutionalization. delirium, an acute form of brain dysfunction that is common during critical illness has been shown to be associated with long-term cognitive dysfunction( ). objectives: the aim of this prospective cohort study was to estimate the prevalence and severity of cognitive dysfunction in survivors of critical illness and to evaluate if delirium duration is an independent determinant of the severity of cognitive dysfunction. methods: included were all adult patients admitted to a -bed medical surgical icu over a -month period(from march to february ).we excluded patients with preexisting cognitive dysfunction; those that in the evaluation by the psychologist on admission to the icu had evidence of impaired cognition through the mini mental state examination and patients who could not be reliably assessed for delirium owing to blindness, deafness or language deficit and patients for whom informed consent could not be obtained. after at least months of hospital discharge patients were assessed for cognition using a validated battery of tests including: )the digit span, forward and backward; ) the rey auditory verbal learning test (ravlt); ) the clock drawing test (cdt); ) the verbal fluency test; and the mini mental state examination. we classified patients as having mild or moderate impairment if they had either two cognitive test scores . standard deviation (sd) below the mean or one cognitive test score sd below the mean; we classified patients as having severe cognitive impairment if they had or more cognitive test scores . sd below the mean or two or more cognitive test scores sd below the mean. results: enrolled in the clinical trial were patients and patients were eligible for the cohort (fig. ) . four hundred and thirteen patients were tested ( - ) months after discharge. table shows demographic and clinical data of these patients. cognitive impairment was identified in ( . %) patients; ( . %) had mild or moderate and ( %) severe cognitive dysfunction (table ) . eleven( . %) patients with delirium for days or more presented severe cognitive dysfunction. in logistic regression analysis the duration of delirium for days or more was not an independent predictor of cognitive dysfunction(p = . ). conclusions: this investigation in an unselected population of critically ill medical and surgical patients demonstrates that cognitive dysfunction is a frequent and severe long-term complication in survivors of critical illness. on the other hand, unlike other studies we couldn't demonstrate that the duration of delirium is an independent determinant of cognitive impairment. table positive determinants of the evolution of the eq-index were time and admission glasgow score (p . and . respectively) while age, duration of mv and weakness were negatively associated (p . , . and . ) ]. eq-eva paralleled eq-index changes. conclusions: after icu discharge, patients suffered frequent longterm consequences that negatively affect their hrqol. alterations in mobility, daily activities and personal care exhibited the greatest deterioration. prevalence of pain, anxiety and depression was high even before icu admission, aggravated after -year post-discharge ( % of patients) duration of vm was the only intra-icu variable that affected hrqol. pre-icu conditions as age and the extent of neurological injury and, after icu, time and weakness, were also independent determinants. the present study was supported by the argentinian society of critical care (sati) introduction: diffuse axonal injury (dai) is a common event following traumatic brain injury (tbi), which is likely related to worst long term outcome. diffusion tensor imaging (dti), a magnetic resonance imaging (mri) technique that investigates white matter integrity, is recognized as a useful tool to quantify dai extent in tbi and possibly predict outcome. few studies explored whole brain longitudinal changes of dti-derived parameters in single subjects following tbi. methods: patients with severe tbi underwent brain mri including dti ( directions, b = , voxel size x x ) - weeks and year after trauma. age-matched healthy controls underwent the same dti protocol. we used region of interest (roi) automated analysis (www.mristudio.org) covering the entire brain to quantify white matter integrity. the roi fractional anisotropy (fa), mean diffusivity (md), axial diffusivity (ad) and radial diffusivity (rd) were extracted. abnormalities were defined as dti values more than standard deviations below or above the mean values of controls for each roi. results: tbi patients with a median age of (iqr - ) and a median gcs score of (iqr - ) were included. had diffuse injury according to marshall classification. regions with increased md and reduced fa were more than expected in both early and late scan (p < . binomial test), while ad and rd abnormalities were less common. more than % of the patients had increased md in the early scan in the frontobasal girae, corona radiata and thalami; in late scans md abnormalities were larger and more diffuse, affecting also all frontal and temporal girae and corpus callosum. fa was frequently reduced in the corpus callosum, internal capsule and fronto-basal girae in early scan, while in late phase reductions were similar but more widespread, also including the central girae, cerebellum and inferior longitudinal fascicles. the number of regions with abnormal md increased over time (p < . mann-whitney), whereas for fa it was not statistically different. an inverse correlation between the number of roi with altered md at early scan and outcome evaluated with gose was found (p < . , spearman r). the present results indicate that early alterations of mean diffusivity and fractional anisotropy persist or worsen (for md) at year after tbi, suggesting an ongoing loss of white matter integrity and gliosis. the more frequently affected regions were the frontal girae, corpus callosum, corona radiata, inferior longitudinal fascicles and cerebellum. the number of roi with early abnormal mean diffusivity is inversely correlated with outcome. all patients underwent ssep, aep and tms the day before operation. after operation, all patients were delivered to icu intubated and mechanically ventilated. patients demonstrated full recovery from anesthesia with regaining consciousness, passed spontaneous breathing test (sbt) and gained points on cst without deficiency. these patients had none or low level of dysphagia and were successfully extubated after operation. these patients formed st group. patients had a neurogenic dysphagia and formed nd group. we performed ssep, aep and tms on all patients immediately after admission to icu. results: we revealed no clinical or electrophysiological points that could have predicted neurogenic dysphagia before operation. in our research, we found the ep values which were different for the first group and for the second group. the aep and tms data were not informative. we found instrumental the ssep values that reflected perioperative cct dynamics, lat p , amp n , auc n -n , auc n -n . these ssep values were used to create a prognostic rule through logistic regression and roc-curves. as a result, we were able to predict neurogenic dysphagia in early introduction: eeg monitoring during the first hours robustly contributes to the prediction of either poor or good outcome in comatose patients after cardiac arrest [ ] . quantitative eeg (qeeg) measures can be useful to visualize evolution of the eeg over hours. we recently proposed the cerebral recovery index (cri), an index based on a combination of five qeeg measures grading the severity of hypoxic brain damage on a scale from zero to one to facilitate prognostication [ ] . objectives: to evaluate the prognostic accuracy of a revised cri, after optimalization by the use of a random forest classifier instead of a manually chosen feature combination and the addition of four qeeg measures, resuscitation parameters and patient characteristics. methods: in this prospective cohort study, consecutive comatose patients after cardiac arrest were included in two intensive care units. continuous eeg was recorded during the first three days. outcome at months was dichotomized as good (cpc - ) or poor (cpc - ). nine qeeg measures were extracted: alpha to delta ratio, signal power, shannon entropy, delta coherence, regularity, the number of burst/min, mean and max burst correlation, and fraction of burst correlation > . . these measures were combined with patient characteristics and resuscitation data, including sex, age, initial heart rhythm, in-versus out-of-hospital-cardiac-arrest, and presumed cause of cardiac arrest. patients were randomly divided over a training and a validation set of respectively and patients. within the training set, a random forest classifier was fitted for each hour after cardiac arrest. based on results in the test set, two thresholds were chosen: one for predicting poor neurological outcome and one for predicting good neurological outcome. subsequently, the revised cri was evaluated in the validation set. results: poor outcome could reliable be predicted with the revised cri (with % specificity) in the validation set with a sensitivity of and % at respectively and hours after cardiac arrest. good neurological outcome could be predicted with a sensitivity of and % at a specificity of and %. conclusions: here we show that a combination of qeeg and clinical measures, extracted and combined by a random forest classifier, provides reliable, objective prognostic information. this revised cri can be used for the prediction of both poor and good neurological outcome, thereby poor outcome can be reliable predicted (without false positives) with relatively high sensitivity. the revised cri is expressed as a single index between and , which can be used in real time at the bedside, even by professionals who are not trained in eeg interpretation. introduction: continuous electroencephalography (ceeg) allows real-time monitoring critically-ill patients neurophysiology and to detect non-clinical seizures in comatose patients, delayed cerebral ischemia after subarachnoid haemorrhage, and guide therapies for status epilepticus. the application of ceeg is still limited because it requires awkward analysis by experienced neurophysiologists of huge amount of eeg tracings. quantitative eeg (qeeg) techniques, i.e.amplitude integrated eeg (aeeg) and density spectra array (dsa), have been developed to simplify the complexity of eeg interpretation, to allow rapid evaluation of cerebral background electrical activity and the power spectrum of the eeg frequencies derived from raw data eeg. these developments offer the potentiality to transform an instrument interpreted by neurophysiologist afterwards in a monitoring tool useful to icu staff. objectives: to test the hypothesis that eeg-nonexpert neurointensivists can obtain real-time reliable information from qeeg after training under the supervision of an in-house neurophysiologist. to describe the implementation of qeeg monitoring in neurointensive care units. methods: the implementation occurred in sequential phases. ceeg was recorded using surface electrodes according to the international - system, on a bipolar longitudinal montage in patients with brain injury. qeeg-naïve neurointensivists, after a short training from a neurophysiologist followed by daily supervision for the study period, were subjected to a baseline test evaluating aeeg and dsa traces. each panel consisted of raw eeg data and qeeg tools: the color density spectral array (dsa), amplitude integrated eeg (aeeg) and the burst suppression rate (bsr). after this evaluation, daily qeeg evaluation was performed by the neurointensivists and reviewed by the neurophysiologist. results: from july to april we monitored patients ( ± years, male) admitted for brain trauma ( %), stroke introduction: it has been noted the importance of job satisfaction in healthcare services and the consequences resulting therefrom, such as increasing the quality of care services provided and satisfaction of their users. objectives: to develop a model of influence of human resource management directed to the quality management and organizational excellence in the organizational results, from the perspective of healthcare staff. methods: we carried out a research study, of a transversal nature, whose study population were a total of ( , % physicians, , % nurses and , % nurse assistants) icu staff. a personal questionnaire was used to measure, through likert scales of points, the application of human resource practices of high commitment (hr), the quality of service provided to the patient (quality), the satisfaction with the capacity of the service (capacity), the personal satisfaction with the work done (satisfaction) and the affective commitment with the organization (commitment). results: the measure models of these five constructs were validated by confirmatory factorial analysis, whose results were satisfactory. the measurement model of hr is a second order construct which is introduction: in the period between - , a successful implementation project was finished aimed at strict blood glucose level (bgl) regulation in the intensive care unit (icu) [ ] . we hypothesized that glucose control would afterwards slack and that implementing other measures to modify behavior would be required to regain adequate glucose control. methods: a prospective study was performed in a -bed mixed medical-surgical icu of a university affiliated teaching hospital. all bgl values were extracted from the icu database in years following the implementation project until december . following the project, bgl targets were set at a range of - mg/dl, nurses' instructions for keeping bgl values in target were not changed. after . years, an automated warning system was implemented in the patient data management system that triggered a centrally placed monitor with feedback about the need for obtaining a bgl value, based on the actual value compared to the previous one. the primary outcome measure was mean bgl. secondary endpoints were sampling frequency, bgl within predefined targets, incidences of severe hypoglycemia, and hyperglycemia. the analysis was restricted to patients with at least two blood glucose measurements. these indicators were analyzed over the course of time using the xmr control chart, a tool belonging to statistical process control. results: data of patient admissions were evaluated, which corresponded to , bgl measurements. the bgl sampling interval (figure ), mean bgl and percentage of severe hypoglycemia all increased after introducing nurses' instruction and decreased significantly after monitoring feedback (p < . ). percentage of severe hypoglycemia events, which is associated tosafety, decreased with some delay after nurses' instruction and remained unchanged ( . % on average) and stable after introducing monitoring feedback. percentage of "in range" measurements of both normoglycemia ( - ) and protocol recommended ( - ) decreased after nurses' instructions and then increased after feedback monitoring. mean of per patient's standard deviation as a measurement of variability remained unchanged and stable after nurses' instruction and even decreased after monitoring feedback. conclusion: even after successful implementation of a bgl control system, behavior changed within months with inherent worsening of bgl control. an automated warning monitor in a central location was able to restore bgl control in the icu. using objective: the overall objective of this research program is to use the kinarm to define the neurocognitive phenotype of icu survivors (i.e. required invasive mechanical ventilation and/or vasoactive agents for hemodynamic support). this group is compared to healthy age-and gender-matched controls, as well as active control groups. these active control groups were patients ) pre-and ) post-cardiac surgery, and ) patients postcardiac arrest. methods: participants performed tasks on the kinarm that ranged from simple sensorimotor tasks to more complex executive tasks. for each task, - performance metrics were recorded. these metrics were compared to a normative database of age-and gendermatched controls and z-scores were generated. a composite score for each task was generated using a score derived from maholanobis distance, with increasing scores representing worse performance. cluster analysis was applied to these performance metrics using euclidian distance. (fig. ) . conclusions: serial mlt measurements significantly underestimate muscle wasting in critical illness and are not related to development of muscle weakness. in comparison, changes in rf csa reflect changes in 'gold standard' methods of assessing muscle mass, and are related to loss of muscle mass and function in critically ill patients. there is significant evidence that electronic prescribing can significantly reduce the errors, however implementation of it is a long term project and is not feasible in attempt to improve medicines safety over short period of time. therefore we aimed to improve safety of a current paper based system. multidisciplinary intervention was chosen as this approach has been previously demonstrated to reduce medication errors on icu . objectives: evaluate effect of multidisciplinary intervention to improve medicines safety. methods: over the course of months following interventions were introduced: development and implementation of new icu specific iv infusion chart, prescription checks during nursing handover, introduction of daily pharmacy handover and on-site feedback, additional medicines training for current staff and new medicines safety induction module for new-starters. outcome data was based on monthly spot audits carried out by pharmacy staff. comparison is made between quarter and quarter after the start of intervention. chi-square test was used to compare the two datasets. results: there were prescriptions analysed in q and in q . we observed a five-fold reduction in prescription validity errors from . % to . % (p < . ). and nearly ten-fold reduction in administration of medicines against non-valid prescriptions from . % to . % (p < . ). pre-printed icu specific iv infusion chart eliminated errors related to variable dilutions, choice of diluent, incorrect or inconsistent infusion rates. month-by-month trends are presented in figure . conclusion: multidisciplinary intervention has resulted in significant improvement in medicines safety. introduction: the concept of frailty has been defined as a multidimensional syndrome characterised by the loss of physical and cognitive reserve that predisposes to adverse events. the prevalence of frailty amongst the critically ill is unknown, however it is probably increasing. this audit aimed to look retrospectively at our admissions to intensive care, to categorise them into frail or non frail, and evaluate how frailty correlated with icu length of stay and mortality methods: a retrospective case note review of all patients admitted to intensive care over a six month period in the victoria infirmary and then queen elizabeth university hospital in glasgow. classification of frail or non-frail was done using a combination of the clinical frailty score (cfs) and edmonton frailty scale. [ , ] . once classified into frail and non-frail we looked at icu outcome, length of stay, apache, weight on admission, lowest albumin and admission haemoglobin and compared the frail population to the non-frail population. results: two hundred and eighty four patients were admitted to intensive care in this time period. of those, were over the age of years. of the patients, patients were deemed to be frail, and were deemed to be non-frail using the cfs. approximately % of the patients admitted to intensive care are over the age of . there was no significant difference found in mortality, icu length of stay or hospital stay, apache or weight between the two groups. [see table ] conclusions: we know that the utilisation of intensive care resources by older people is rising. our data shows that almost % of those admitted to icu are over the age of . interestingly, there is no significant difference between the non frail and frail groups of patients admitted to intensive care. this may be because of small sample size. the length of stay of the frail patient is shorter and this may be because as intensivists we are better at treatment limitation in this group of patients. no difference in overall mortality suggests that the patients we deem suitable for intensive care who are frail do as well as the non-frail cohort as the selection process for admission has been adequate. patients deemed to be frail are more likely to be dependant on care if they survive, with % requiring some sort of support on discharge. most studies show that frailty is associated with increased mortality so it is indeed interesting that this audit has shown no difference between the two groups. figure shows a significant increase in admissions among the elder groups along the five-year periods. the severity scores increased significantly as shown in figure (p < . ). icu lenght stay also decreased significantly (table ) introduction: in our intensive care medicine (icu) department we used a database (gespac) with uniform and quality data for all admissions from to , which allows us to study the evolution of severity scales and the clinical activity by age and type of patient. objectives: to describe the effectiveness of severity scales used in our icu over years by age and type of patient. methods: a retrospective, single-center and descriptive study was conducted from to . all patients admitted consecutively were included. patients with lenght of stay less than hours were excluded.the severity scales we analyzed were mpm , mpm , saps , apacheiii. patients were divided in groups of age by quartiles (< years, - years, - years, > years). the type of patient was classified in medical and urgent or scheduled surgery. we used descriptive statistics. qualitative variables are expressed as percentages and quantitative variables are expressed as means and standard deviations (± sd) and roc curves for the analysis of discrimination. we used spss v . results: we included patients, were men ( %), mean age was . years (sd . ). icu mortality was . %. in figure we show curve roc corresponding to the severity scales for all patients, mpm has a significantly worse discrimination respect to the other scales. mpm , saps and apache iii have a similar behavior. in table we show the severity scales effectiveness by age groups. in table we show the severity scales effectiveness by type of patients. we observed a decrease of effectiveness of severity scales over time, however this effectiveness remains optimal in all the severity scales except for mpm . introduction: we implemented a critical care epr using the quadramed system on the th sept . our objective was to evaluate whether the epr had improved the quality of our documention and the responsiveness of our notes. methods: we evaluated the patient record from hospital days prior to the implentation of the epr and hospital days months after using and refining the system. results: the proportion of completed nursing risk assessments did not change after implementation of the epr. they depend on the user to shedule their completion. safety checks for arterial and cvc lines were well established and changed little. there was an improvement in the percentage of shift checks completed when they were automatically sheduled. the system provides a date, time and audit trail for each entry. the user traceability in the medical notes increased. the presence of the author´s name improved from % to %, the date from % to %, the time from % to %, and signature from % to %. legibility improved from % to %. the proportion of entries with a contact number dropped from % to %. the nursing care plans in the paper notes were better completed than the medical notes, but still improved. the presence of the nurse´s name increased from % to %, the date from % to %, the time from % to % and the signature from to %. legibility was % in both groups. the quadramed system provides automatic calculations of early warning scores and fluid balances.the more complicated the calculation, the greater the improvement. integration of data: · the increase in data points that cross populate is: + · the allergy advice populates all the sheets compared to an average of on paper (excluding the drug chart). · the average number of scheduled events (that instruct staff to perform functions) has gone from to . conclusions: . the largest improvement came in the accessibility of the notes. they can now be accessed within one minute from any pc in the trust. previously a standard time to deliver notes was two days, reducing to one day in an emergency. . correct filing of the epr notes and the search facility reduced the average time to complete the audit by minutes per patient. . the user audit trail and traceability improved in both medical and nursing paperwork, more so in the former. this is explained by a baseline of lower documentation standards in the medical group. . the typed out notes are now legible. . there was a large improvement in the quality of data calculations that are now up to %. . there was a large increase in the number of scheduled events, but this these only lead to an improvement in documentation when they were automatically scheduled by the computer. there was no improvement when user scheduling was required. we noticed very high levels of satisfaction regarding the professional care (frequency of communication, physician skill and competence, understanding information, honesty and facilities of getting information) and overall with care. satisfaction was even higher when we considered the usefulness of the ecp. every respondents supported it as a complement to daily information but it was only supposed to replace verbal information in , %. % did not access the website because of sufficient verbal information or cultural or age-related difficulties. the access was mostly via computer ( , %) followed by smarthphone ( , %). particularly desired were daily updates, an established timetable and more detailed information. there were no statistically significant differences in the need of web access among families living near the hospital and not or prior experience with icu familiar admission. conclusions: ecp appears to decrease the level of anxiety of families, improves perceived quality and can help to combine patient care with their work and personal responsibilities without replacing the daily evolution provided by physicians. introduction: neuroimaging shows promise for determining early prognosis after cardiac arrest (ca). nevertheless, conventional mri sequences, as t -weightened sequences, are currently considered not precise enough to detect brain structural anomalies in this context, and therefore are supposed to be unable to accurately predict outcome . objectives: we hypothesize that the combined use of cortical thickness measurement and subcortical grey matter volumetry could provide an early and accurate in vivo assessment of the structural impact of cardiac arrest (ca), and therefore could be used for longterm neuroprognostication in this setting. methods: prospective study undertaken in five intensive critical care units affiliated to the university in toulouse (france), paris (france), clermont-ferrand (france), liège (belgium) and monza (italy). high-resolution anatomical t -weighted images were acquired in anoxic coma patients ( +/− days after ca) and matched controls. patients were followed up one year after ca. cortical thickness was computed on the whole cortical ribbon and deep grey matter volumetry was performed after automatic segmentation . brain morphometric data was employed to create multivariate predictive models using learning machine techniques ( figure ) . results: patients displayed significantly extensive cortical and subcortical brain volumes atrophy compared to controls. a dissociated vulnerability to anoxic insult was observed: subcortical volumes were related to ca duration and cortical thickness values were linked to the time to mri acquisition ( figure ) the accuracy of a predictive classifier, encompassing cortical and subcortical components has a significant discriminative power (auc = . ). the anatomical regions which volume changes were significantly related to patient's outcome were: frontal cortex, posterior cingulate cortex, thalamus, putamen, pallidum, caudate, hippocampus and brainstem ( figure ) conclusions: these findings are consistent with the hypothesis of pathological disconnection within a striatopallidal-thalamo-cortical mesocircuit induced by ca and pave the way for the use of combined brain quantitative morphometry in this setting. clinical and electrophysiological correlates of absent somatosensory evoked potentials after post-anoxic brain damage: a multicentre cohort study conclusions: our data confirm that bilateral absence of n reflects severe post-anoxic cerebral damage and therefore frequently correlates with concordant clinical and eeg signs of poor outcome. however, our study also identified a subset of patients with discordant signs, in whom clinical examination and/or eeg were reactive despite bilaterally absent n . our findings raise further questions on outcome prognostication after ca and underline the importance of multimodal assessment in this setting. the response time threshold for predicting favorable neurological outcomes in patients with bystander-witnessed out-of-hospital cardiac arrest introduction: it is well established that the period of time between when a call in made to emergency medical service (ems) to the point when ems arrive at the scene (i.e., the response time) affects the survival outcomes in out-of-hospital cardiac arrest (ohca) patients. however, the relationship between response time and favorable neurological outcomes remains unclear. we therefore aimed to determine a response time threshold in bystander-witnessed ohca patients that is associated with positive neurological outcomes and to assess the relationship between the neurological outcomes and response time in ohca patient. methods: this study was a retrospective, observational analysis of data from , episodes of bystander-witnessed ohca between and in japan. we used classification and regression trees (carts) and receiver operating characteristic (roc) curve analysis to determine the threshold of response time associated with favorable neurological outcomes (cerebral performance category or ) one month after cardiac arrest. results: both carts and roc analyses indicated that a threshold of . min was associated with improved neurological outcomes in all bystander-witnessed ohca events from cardiac origin. furthermore, bystander cardiopulmonary resuscitation (cpr) prolonged the threshold of response time by min (to . min). the adjusted odds ratios for favorable neurological outcomes in ohca patients who received care within ≤ . min was . ( % confidential interval: . - . , p < . ). conclusions: a response time ≤ . min was closely associated with favorable neurological outcomes in all bystander-witnessed ohca patients. bystander cpr prolonged the response time threshold by min. methods: patients with established out-of-hospital cardiac arrest (ohca) who underwent cardiopulmonary resuscitation with subsequent return of spontaneous circulation were retrospectively enrolled. two hundred and eight dic patients diagnosed by the japanese association for acute medicine (jaam) dic criteria were divided into two subgroups with hyperfibrinolysis ( ) and without hyperfibrinolysis ( ). the definition of hyperfibrinolysis was made by a fdp level > μg/ml. platelet count, global markers of coagulation and fibrinolysis were measured times after admission to emergency department (t , - ; t , - ; t , - ; t , - hr). the outcome measure was the hospital all-cause mortality. results: patients with hyperfibrinolysis had higher dic, sirs, and sequential organ failure assessment (sofa) scores associated with higher prevalence of mods, leading to a higher mortality rate of . % in comparison to patients without hyperfibrinolysis ( . %). stepwise logistic regression analyses confirmed that dic, sofa scores, and lactate levels are independent predictors of patient death. hyperfibrinolysis also predicted patient death. tissue hypoperfusion (as indicated by lactate level) is a main determinant of hyperfibrinolysis. receiver operating characteristic curves showed a significant discriminative performance of dic scores for patient death. kaplan-meier curves showed that dic, especially dic with hyperfibrinolysis, significantly affected patient death. conclusions: dic with the fibrinolytic phenotype during the early phase of post-cpr more frequently results in sirs and mods, and affects the outcome of ohca patients. hypoxia/ischemia during cardiac arrest and cpr are considered to be the cause of increased fibrin(ogen)olysis. the association between tracheal intubation during pediatric inhospital cardiac arrest and survival l.w. andersen , , t. introduction: tracheal intubation is common during pediatric inhospital cardiac arrest, although the relationship between intubation during cardiac arrest and outcomes is unknown. objective: to determine if intubation during pediatric in-hospital cardiac arrest is associated with improved outcomes. methods: this was an observational study of prospectively collected data from united states hospitals participating in the get with the guidelines -resuscitation registry. we included pediatric patients (age < years) with index in-hospital cardiac arrest. we excluded patients who were receiving invasive mechanical ventilation and/or had an invasive airway in place at the time chest compressions were initiated. the exposure was tracheal intubation during the cardiac arrest. the primary outcome was survival to hospital discharge. secondary outcomes included return of spontaneous circulation and neurological outcome. a favorable neurological outcome was defined as a score of - on the pediatric cerebral performance category score. patients being intubated at any given minute (from to minutes) were matched with patients at risk of being intubated within the same minute (i.e. still receiving resuscitation) based on a timedependent propensity score calculated from multiple patient, event, and hospital characteristics. modified poisson regression with adjustment for matching and clustering were then performed to obtain risk ratios. results: patients were included. of these, ( %) were intubated during the cardiac arrest. in the time-dependent propensity score-matched cohort (n = ), survival was lower in those intubated compared to those not intubated during cardiac . ], p = . ) between those intubated and not intubated during cardiac arrest. the association between intubation and decreased survival remained in the majority of our sensitivity and subgroup analyses conclusions: tracheal intubation during in-hospital pediatric cardiac arrest was associated with decreased survival to hospital discharge. these findings challenge the present resuscitation paradigm for pediatric in-hospital cardiac arrest. introduction: substantial proportion of patients who suffered cardiac arrest do not respond to conventional cardiopulmonary resuscitation. recently, extracorporeal cardiopulmonary resuscitation (ecpr) has been introduced as a potentially life-saving procedure in refractory cardiac arrest. objectives. the aim of our study was to evaluate the relation between ecpr survival, lactate levels and blood ph. methods: eligible patients for this analysis had to undergo ecpr after at least ten minutes of unsuccessful cardiopulmonary resuscitation with a minimum of three defibrillation attempts. for extracorporeal life support (ecls) we used cardiohelp system (maquet, germany) or levitronix centrimag blood pump (levitronix, usa). lucas ii system (physiocontrol, sweden) was used for chest compressions during ecls insertion and cannulas were placed with percutaneous puncture under fluoroscopy or ultrasound control. blood lactate and ph levels measured before ecls insertion and after hours were used for this study. results: we analyzed data from patients treated with ecpr for refractory cardiac arrest. the mean age of our patients was years ( - ). out-of-hospital cardiac arrest occurred in patients, patients suffered from in-hospital arrest. thirty-day mortality in our group was % and % of patients recovered with good neurological outcome. percutaneous coronary intervention was performed in ( %) patients. baseline value of lactate was . ± . mmol/l, initial ph . ± . . in comparison with survivors, patients who died had significantly higher initial lactate levels ( . ± . vs. . ± . ; p < . ) and lower baseline ph ( . ± . vs . ± . ; p < . ). moreover, survivors had significantly lower lactate levels after hours. conclusions: ecpr represents virtually the last chance to survive refractory cardiac arrest. the levels of blood lactate and ph are significantly associated with clinical outcomes of ecpr. introduction: post-cardiac arrest survivors treated with therapeutic hypothermia (th) remain comatose after rewarming. in contrast to survivors without th, neurological prognostication is imprecise due to a persistent sedative effect [ ] . objectives: we aimed to evaluate clinical signs and findings that could predict neurological recovery and determined the optimal time for prognosis. methods: we retrospectively reviewed database of post-arrest patients treated with th in our hospital from to . cerebral performance category (cpc), neurological signs and findings in eeg and brain ct were evaluated. neurological recovery was scored as favorable neurological outcome, namely normal cerebral function(cpc ) and moderate disability(cpc ) or unfavorable neurological outcome, namely severe disability(cpc ), vegetative state(cpc ) and death(cpc ). neurological signs and findings in eeg and brain ct, which possibly predicted neurological recovery, and the optimal time to evaluate neurological status were analyzed. results: th was performed in post-arrest patients. approximately % ( / ) of th-patients survived and % of the survivors had favorable neurological outcome. findings predicting unfavorable outcome at discharge were lack of pupillary response and/or gag reflex after rewarming, and the absence of at least one of the brainstem reflexes, no eye opening or motor response worse than pain withdrawal (m ≤ ) on the seventh day. (table ) myoclonus and seizure could not be used to indicate poor prognosis. one of survivors with myoclonus had full recovery and % of the survivors with seizures regained consciousness upon discharge. findings of eeg and brain ct showed that the patients with burst-suppression eeg pattern or brain swelling became vegetative or died, but the prognostic values of these findings were inconclusive. conclusions: our study showed that the simple neurological signs helped predict short-term neurological prognosis of comatose survivors undergoing th. the most reliable signs which determined unfavorable outcome were the lack of the pupillary light response and gag reflex. the optimal time to assess prognosis was either at to hours or days after return of spontaneous circulation. physicians can use these neurological signs to evaluate the prognosis of postcardic arrest survivors treated with th. objectives: procalcitonin (pct) and presepsin are biomarkers associated with severe infections. we asked, if they could be used to reflect the severity of the post-cardiac arrest syndrome and to predict poor outcome. a significantly greater increase in procalcitonin from admission to h was observed in patients with eventual poor outcome compared to those with a favorable one (p < . ). presepsin levels were on average constantly higher in patients with poor outcome but did not show any statistically significant changes in repeated measures analysis of variance. conclusions: plasma procalcitonin may be a useful tool for the evaluation of long-term outcome of out-of hospital cardiac arrest patients at the icu. on the contrary, presepsin did not provide clinically relevant additional predictive value in the study setting. introduction: prognosis of cardiac arrest survivor is mainly determined by ischemic brain injury. post-cardiac arrest state is characterized by elevated circulating cytokines and hemodynamic instability, called as a sepsis-like syndrome. in many critical ill diseases such as acute pancreatitis and sepsis, a low serum level of high-density lipoprotein (hdl) and apolipoprotein a- (apoa ) were associated with poor outcomes. objectives: in this study, we examined whether a serum level of hdl and apoa at intensive care unit (icu) admission is associated with a neurologic outcomes in cardiac arrest survivors. methods: this study was a retrospective observational study conducted in a single tertiary urban hospital icu. all admitted patients following cardiac arrest were screened during from march to december . patients younger than years and without admission lipid panel were excluded. neurologic outcome was determined by hospital discharge cerebral performance categories (cpc). good neurologic outcome was defined as cpc and . note: this abstract has been previously published and is available at [ ] . it is included here as a complete record of the abstracts from the conference. we analyzed all patients admitted on hospital ward that were assisted by the ihca team. patients admitted less than hours on ward and patients not eligible for resuscitation were excluded. demographic data (age and gender) were collected. we analyzed the type of patient (medical or surgical), the schedule in which the ihca happens (weekdays from hours am to hours pm and the rest, every day from hours pm to hours am, weekend and holidays), ihca witnessed, the ihca team time reaction, ihca established or not at ihca team´s arrival, return of spontaneous circulation (rosc) and hospital mortality. statistics:qualitative variables are expressed as percentages and compared using the x -test; quantitative ones are expressed as means and standard deviations (± s.d), and analyzed using student´s t-test. multivariate logistic regression was performed, with hospital mortality as the dependent variable. the level of significance was placed at p < . . the statistical analysis was performed using specific software ( ibm spss statistics for windows, version . . armonk, ny: ibm corp). results: patients were assisted by the ihca team and patients were included. in figure we described the characteristics of the study population. the beginning of cardiopulmonary resuscitation (cpr) maneuvers were immediate on ward, according to ihca protocol. the arrival of ihca team was less than minutes in all cases. table shows an assosciation between hospital mortality and the capability of anticipation of ihca situations (schedule, witness, pre-cardiac arrest …). table shows the persistence in the multivariate analysis of the relationship of these factors with the hospital mortality. conclusions: the number of activations of ihca team is remarkable, mortality of these patients is very high despite being patients on ward without a bad expected outcome. the improvement in the factors associated with the capability of anticipation of ihca situations (schedule, witness, pre-cardiac arrest …) could lead to an improvement in the prognosis of ihca. , and vessels with diameter smaller than μm were defined as small vessel. serum level of endothelial cell specific molecule- (endocan) was measured at specific time points. the hemodynamic parameters, the inotropic equivalent score, and prognosis of the patients were recorded. results: patients were iinvestigated in this preliminary report. they were equally divided into two groups (survival and nonsurvival) according to -day mortality. the baseline patient characteristics were not significantly between the two groups. the perfused small vessel density and proportion of perfused vessels at h were higher in the survival group than in the non-survival group. the endocan level were higher in the non-survival group than in the survival group, but the difference was not significant. conclusions: our results revealed that the perfused small vessel density were higher in the survival group than in the non-survival group. it encourages further studies to investigate whether aiming to improve microcirculation can improve outcomes in patient with venoarterial ecmo life support system. demographic data, sedation and vasopressor dose were recorded. enteral feeding was started as soon as possible. the cumulative grv was recorded up to a maximum of days, with a cut-off value of ml used to define intolerance to enteral feeding (ief). all data is presented as median(p -p .) statistical analysis was performed by stats . with mann-whitney u test and chi-square test. results: data from patients were recorded. baseline demographic data were similar in the groups. the average grv and the doses of midazolam were the highest in patients with vv ecmo, while the number of days with ief and the doses of na were the highest in the va ecmo group (table ) . overall, grv and number of days with ief tended to be higher in survivors (n = , grv ( - ), days with ief ( - )) than in non-survivors (n = , grv ( - , days with ief ( - )). conclusion: early enteral feeding is feasible during ecmo, in spite of impairments of gastrointestinal function potentially related to sedation and/or vasopressor treatment. extracorporeal membrane oxygenation for refractory cardiogenic shock in patients with peripartum cardiomyopathy a. chao results: six patients with confirmed ppcm were found. two ( %) patients died of neurological consequences (cerebral infarct and hypoxic encephalopathy) and their left ventricular (lv) ejection fraction remained about %. one patient underwent heart transplantation. the other three patients weaned off ecmo and their lv function began to improve on day . they were discharged uneventfully. conclusions: ecmo can provide an effective and simple treatment for critical ppcm with a satisfactory result. patients supported by ecmo whose heart function did not begin to recover on day and had neurological complications had a poor prognosis. introduction: the use of venoarterial extracorporeal membrane oxygenation (va-ecmo) for prolonged cardiopulmonary resuscitation (cpr) and severe cardiogenic shock after cpr has widely increased ( ). bleeding complications, due to necessary therapeutic anticoagulation and cpr/sirs induced coagulopathy are common ( ) . targeted temperature management (ttm) has shown positive effects on neurological outcome after cpr. although optimal target temperature is not exactly known, ttm remains a recommended approach in patients after cpr ( ). objectives: to determine the incidence of bleeding complications in patients after cpr, who are on va-ecmo and treated with ttm (target temperature °c) simultaneously. methods: we conducted a retrospective observational study from jan to dec and extracted relevant clinical data from electronically medical records. outcomes of interest were d-mortality and incidence of bleeding complications within hrs of cpr. demographic data, (anti-)coagulation status and need for transfusion were also analyzed. results: a total of patients received va-ecmo during the study period of which patients ( , %) underwent cpr before ecmo. of these, patients ( %) were treated with ttm. the median age was yrs (range - yrs) and patients were male ( %). sofa score on admission was ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . patients received cpr mainly because of either acute myocardial ischemia (mi) ( ; %) or malignant dysrhythmias not attributable to acute mi ( ; %). ecmo implantation was performed within hrs ( . - hrs) of cpr and ecmo duration was . hrs ( - hrs). ttm was implemented within hrs ( - hrs) of cpr and the duration of simultaneous treatment with va-ecmo and ttm was . hrs ( - hrs). introduction: during initial resuscitation of patients with shock, last consensus recommend to target a mean arterial pressure of at least mmhg. however, there is no recommendation for the mean arterial pressure target in in the particular setting of extra corporeal cardio pulmonary resuscitation patients in the first hours following a refractory cardiac arrest. objectives: therefore, we conducted an experimental study to assess the effects of two different levels of mean arterial pressure for macrocirculatory, microcirculatory and metabolic functions. methods: randomized animal study in university research laboratory. in fourteen male pigs, a myocardial infarction was induced by a surgical ligature of the inter-ventricular coronary artery, triggering a refractory ventricular fibrillation. after twenty minutes of standardised cardiopulmonary resuscitation, extra corporeal life support was initiated to restore the circulatory flow. then, animals were randomly allocated to a high mean arterial pressure group (high map, - mmhg) or to a standard mean arterial pressure group (standard-map, - mmhg). evaluations at baseline, just before and six hours after ecls initiation were focused on ) lactate, ) amount of fluid infused and ) microcirculatory parameters (sidestream darkfield imaging, renal and liver functions). results: the two groups were similar at baseline and also at time of ecsl initiation including for the lactate levels ( objectives: the goal of our study was to assess the factors associated with percutaneous cannulation success or failure during ca. methods: this was a prospective observational monocentric study conducted between may and february including all consecutive patients with ca (no return to spontaneous circulation after minutes of cardio-pulmonary resuscitation) and an indication of ecls (low-flow below minutes). femoro-femoral cannulation ( fr for arterial cannula and fr for venous cannula, maquet®) was performed using the seldinger technique under ultrasound (us) guidance. patient characteristics, physician's a priori about cannulation conditions (ranging from (expected very easy) to (expected very difficult)) and us measures of femoral vessels diameter were recorded. the primary endpoint was the time to ecls initiation (icu admission -ecls running) and was analyzed using a stepwise multivariable linear regression. as a secondary analysis, we also explored the differences between the patients with a time to ecls initiation < min and all others (> minutes or cannulation failure conclusions: our data suggests that the level of care patients receive does not affect baby being with its mother. however, level patients are admitted to a general critical care unit and not captured in this review. the results also suggest that maternal well-being is affected by and/or affects whether baby is with her, however the % confidence intervals overlap. the above data does not take into account babies being in special care baby units and therefore not able to join their mothers at their bedside (this data will be recorded in the future). when this data is recorded it is expected that a high proportion of babies who are able to be at their mother's bedside during amc will be there. the introduction: high levels of job satisfaction are associated with decreased turnover intention, burnout incidence and absenteeism among health care professionals. moreover, turnover and burnout negatively impact on quality of care and healthcare costs. as the intensive care unit (icu) represents a highly complex and stressful environment, prevention of conflicts among team members as well as improvement of communication and job satisfaction can as such reduce burnout risk. objectives: this study explores the relationship between communication -and job satisfaction and the impact on burnout and turnover intention among icu nurses. %, / ). an average job satisfaction of . / was found. . % ( / ) had a score ≤ on job satisfaction, indicating significant dissatisfaction. icu nurses were most satisfied with the trust received from their supervisor ( . %) and least with the information about accomplishments and/or failures of the organization ( . %). . %, ( / ) had a low, . % ( / ) an average and only . % ( / ) a high turnover intention. % of the icu nurses had an indication for burnout. . % of the nurses had a low experience of their personal accomplishment. conclusions: in this survey icu nurses had a reasonable job satisfaction. they are most satisfied with the trust received from supervisors. despite a low indication for burnout risk, a quarter of icu nurses report low personal accomplishment. this may represent a particular focus for both preventive and interventional actions, which should preferably be developed through and in conjunction with the supervising staff. introduction: in the swiss diagnosis related groups ((swiss)-drg)) was implemented in intensive care units (icu). its impact on hospitalizations has not yet been thoroughly examined. we compared the number of icu admissions according to clinical severity and referring institution, screened whether implementation of swissdrg affected admission policy, icu length-of-stay (los) or icu mortality. methods: retrospective single center cohort study conducted at the university hospital zurich, switzerland between january and end of . demographic and clinical data were retrieved from a quality assurance data base. conclusions: drg introduction had not affected icu admissions policy, except for an increase of in-house patients with a low clinical severity of disease. drg had neither affect icu mortality nor icu los. interactive gaming as part of mobilisation programs is feasible in the icu, but specific explanation about the usefulness of these games to patients is crucial for improving motivation and engagement t. introduction: in recent years, light sedation has gained attention as part of standard daily care in the intensive care unit (icu). consequently, patients are increasingly engaged in their rehabilitation process. particularly early mobilization is associated with shorter time on the ventilator, shorter icu length of stay and better survival [ ] . interactive gaming may be a challenging way of engaging the patient in his own rehabilitation program. few data are available for the use of these interactive games in the icu envirnoment as part of daily routine physiotherapy, although one study showed that it was safe [ ] . we developed a trolley with a wii (tm) device that can be easily used when the patient is mobilized in a chair. we hypothesized that this would be associated with increased motivation to participate in interactive gaming by our patients. methods: the wii device was used with different games. participating patients were offered to play games of their own choice as part of the mobilisation program to improve their strength and coordination. no extensive explanation about the potential usefulness of these interactive games was given to the patients. after finishing the games, a specific survey was administered addressing motivation and affects on mental health. scores were obtained using a likert scale (range - ). results are shown as median and interquartile range {p -p ] results: at the time of abstract submission, participating patients had finished a cycle of games. some of the patients liked to use the wii device, particularly because a choice in games made it more interesting to use. other patients, however, felt they were required to participate. tennis, bowling and boxing were most frequently used. the use of the wii was programmed in the daily mobilization schedule together with a physiotherapist, or just with the attending icu nurse. in general, patients were not that enthusiastic about the wii-games (median score [ - ]), were not convinced that playing these games improved their well-being (median score [ ] [ ] [ ] [ ] ), and most felt that they did not have a choice but to participate (median score [ ] [ ] [ ] ). conclusion: interactive gaming with the wii-device is feasible in icu patients. however, thorough explanation of the potential usefulness of these games is required to engage and motivate patients to participate. methods: descriptive and retrospective study. we include all patients admitted in icu during (previous to rrt establishment) and (year of rrt establishment), and who were discharged to the ward. we analysed the icu and hospital mortality in both groups. results: in we admitted patients ( , % from the ward and , % from the other places like emergency, other icu or other hospitals), with a icu mortality of , % and hospital mortality of , %, with a hospital mortality after icu discharge of , %. in we admitted patients ( , % from the ward and , % from the other places), with a icu mortality of , % and hospital mortality of , %, and a hospital mortality after icu discharge of , % (p = . ). conclusions: after the first year of rrt establishment in our hospital, we appreciate that the continuation of patients after icu discharge, decrease the hospital mortality ( , % versus , %, p = . ). the number of patients admitted in icu from the ward decrease in ( , % versus , %), maybe because we did a previous assessment of this patients, with a stabilization in the ward and avoiding the icu admission. objectives: to identify outcomes and prognostic factors in hm patients admitted over -years to a general intensive care unit in a specialist haematology centre. (figure ). patients with - organ failures had significantly worse outcomes than those with - organ failures (p < . ) or . [ . - . , ci %]. median apa-che ii, sofa and saps ii scores were , and , respectively. median apache ii (p < . ), sofa (p < . ) and saps ii (p < . ) scores were greater in those ventilated for - days vs. ≥ days. conclusions: apache ii scores and mortality were greater than described in similar hm populations. given the severity of critical illness in our cohort, we suggest that admission to icu earlier in the acute illness may improve outcomes. poorer outcomes were observed in those with > organ failures and in ventilated patients. the survival of / rd of patients on icu for ≥ days to hospital discharge suggests that -day trials of icu in hm patients are unlikely to reliably distinguish between survivors and non-survivors. background: dedicated intensive care unit (icu) physician staffing was associated with a reduction of icu mortality in the general medical and surgical icu. however, limited data were available on the role of a cardiac intensivist in the cardiac intensive care unit (ccu). we compared the clinical outcomes in adult patients admitted to ccu before and after implementing the cardiac intensivist-directed care. methods: we enrolled , consecutive patients admitted to a ccu at samsung medical center, from january to december . in january , ccu was changed from a low-intensity staffing model to highintensity staffing model which managed by a dedicated cardiac intensivist. we divided eligible patients into low-intensity group (n = ) and highintensity group (n = , ). the primary outcome was ccu mortality. results: high-intensity group had significantly lower ccu ( . % vs . %; p < . ) and hospital ( . % vs . %; p < . ) mortality compared to the low-intensity group. the decrease in ccu ( . % vs . %; p = . ) and hospital ( . % vs . %; p = . ) mortality in high-intensity group were consistent in (low-intensity group , high-intensity group ) patient with profound cardiogenic shock treated with extracorporeal membrane oxygenation. kaplan-meier survival curve showed significant higher cumulative survival rates in highintensity group at year follow-up (log rank test, p < . ). ccu ( . % vs . %; p = . ) and hospital re-admission rate ( . % vs . %; p = . ) were decreased as well after conversion to highintensity although these results were not statistically significant. conclusions: dedicated cardiac intensivist was associated with reductions of ccu mortality in patient with cardiovascular disease requiring critical care. introduction: opioids are commonly given to alleviate pain and distress in patients admitted to the intensive care unit (icu) patients or undergoing major surgery. previous studies have shown that patients who are already taking opioids prior to surgery or icu admission are more likely to experience an extended duration of opioid use postoperatively or post-discharge ( ). however, it is unknown whether patterns of opioid usage differ between patients who are admitted to the icu and those undergoing a surgical procedure. objectives: the objective of this study was to describe opioid use in critically ill patients before and after icu admission and to compare it with preoperative and postoperative opioid use in a surgical population. methods: retrospective review and comparison of adult patients admitted to the icu or undergoing surgery at a tertiary care center between january , and december , . we divided the populations based on their degree of opioid use into "non-user", "intermittent", and "chronic" opioid users as previously described ( ). we assessed opioid use at months prior to icu admission or surgery, at discharge, and monthly for months thereafter. patients admitted to icu who had surgery were categorized under the icu population. to assess for risk of monthly chronic opioid use, a cox-proportional hazards model was postulated that allowed for recurrent events to account for patients irregularly requiring opioids over the course of the study period. the model showed that the risk of chronic opioid use was . times greater for those with prior chronic opioid use compared to patients who were non-users. there was no difference in risk of chronic opioid use between the icu and surgery group. conclusions: our findings suggest that icu and surgical patients have similar risk of prolonged chronic opioid use post-discharge. chronic opioid use prior to icu admission or surgery is the strongest predictor of chronic opioid usage at and after discharge. a single-centre cohort study of national early warning score (news) and blood gas derived biomarkers in patients with acute medical illness introduction: empirical combination antibiotic therapy for treatment of severe sepsis is a matter of debate. the proposed rationale for using a combination of two or more different antimicrobials is several fold. first, it allows for a broader empirical coverage with a higher likelihood of targeting the causative organism. second, it may decrease the development of resistance to the antibiotics used. third, a combination of active drugs potentially cause a synergistic effect increasing the efficacy of bacterial eradication. the surviving sepsis campaign recommends combination therapy in some patient populations and certain type of infections but the quality of the evidence supporting empirical combination antibiotic therapy is weak and does not include high quality randomised clinical trials (rcts). objectives: to assess benefits and harms of empirical mono-vs. combination antibiotic therapy in adult patients with severe sepsis in the intensive care unit (icu). methods: we performed a systematic review according to the cochrane collaboration methodology, including meta-analysis, risk of bias assessment and trial sequential analysis (tsa). we included rcts assessing empirical mono-antibiotic therapy versus a combination of two or more antibiotics in adult icu patients with severe sepsis. we exclusively assessed patient-important outcomes, including mortality. two reviewers independently evaluated studies for inclusion, extracted data, and assessed risk of bias. risk ratios (rrs) with % confidence intervals (cis) were estimated and the risk of random errors was assessed by tsa. results: thirteen rcts (n = , ) were included; all were judged as having high risk of bias. there was no difference in mortality (rr . , % ci . - . ; p = . ) or in any other patient-important outcomes between mono-vs. combination therapy. in tsa of mortality, the z-curve reached the futility area, indicating that a % relative risk difference in mortality may be excluded between the two groups. for the other outcomes, tsa indicated lack of data and high risk of random errors. conclusions: this systematic review of rcts with meta-analysis and tsa demonstrated no differences in mortality or other patientimportant outcomes between empirical mono-vs. combination antibiotic therapy in adult icu patients with severe sepsis. the quantity and quality of data was low without firm evidence for benefit or harm of combination therapy. introduction: de-escalation antibiotic in sepsis is associated with reduced costs and bacterial resistance. however, often it is not done. objectives: we designed this study with the primary objective to evaluate the prevalence of de-escalation in patients with severe sepsis or septic shock in an academic public hospital in south brazil. secondarily we evaluated antibiotic adequacy and cultures positivity. methods: we analyzed prevalence of de-escalation, antibiotic adequacy and culture positivity in severe sepsis and septic shock patients in an intensive care unit. results: of the patients included, de-escalation could have been performed in % of cases ( patients), but was implemented in only % of cases ( patients). among patients who received deescalation, half was for antimicrobial spectrum narrowing. the mortality was not different between patients with or without de-escalation ( . % versus . %, p = . ). empirical antimicrobial therapy was adequate in % of cases. pathogens were isolate in % of all cultures and . % of blood cultures. conclusion: the rate of empiric antibiotic adequacy was high, reflecting active institutional policy of monitoring the epidemiological profile and institutional protocols of antimicrobial use. however, the antimicrobial de-escalation could have been higher than reported. de-escalation did not impact mortality. there are few data in the literature regarding the care of severe sepsis patients in developing countries. this data can contribute to adequate treatment in this scenario. introduction: despite recent advances, appropriate initial amikacin dose in critically ill patients is still challenging. relationship between pharmacokinetic/pharmacodynamic (pk/pd) parameter peak concentration (cmax)/minimum inhibitory concentration (mic) in critically ill patients is not clear. objectives: we assessed the impact of amikacin pharmacokinetic and pharmacodynamic parameters on clinical and microbiological outcome in these patients. methods: observational prospective study. adult patients (> years) admitted to an intensive care unit (icu) with a gram negative documented infection and treatment with amikacin were included (study period: september -april ). amikacin blood samples were taken to hours after treatment started. amikacin concentration were determined using indiko® (thermo fisher scientific), and drug adjustment were based on the recommendations given by the pharmacokinetics unit (pharmacy service). clinical response, defined as sign and symptoms presented at the moment of infection diagnosis (fever, chest radiography alteration, infection biomarkers elevation and hemodynamic instability), was evaluated. ji-square and u-mann whitney test were used to compare results between treatment responders and notresponders. . mean initial dose was mg (sd: , )/day, equivalent to . ( . ) mg/kg/day. with that dose, patients ( , %) reached a cmax/mic value higher than . final treatment response was higher for those patients with amikacin cmax/mic value > ( , % vs , %; p = . ). no significant differences were reached in early treatment response (initial h) ( , % vs , %;p = , ) or days mortality ( , % vs , %;p = , ). cmax/mic values was not associated with toxicity-related treatment discontinuation ( , vs , ; p = , ). conclusions: initial cmax/mic value is associated with clinical response in those patients treated with amikacin. high initial amikacin dose may be necessary to optimize pk/pd parameters. method: in a bed mixed icu from october , to september , nosocomial infections (pneumonia, urinary tract infections, catheter-related bacteremia (crb) and secondary nosocomial bacteremia) were prospectively collected. envin-helics diagnostic criteria were applied. etiology, inflammatory response to infection, antibiotic treatment (atb t) and treatment modifications according to culture results, were analyzed. sdd was applied to all admitted patients requiring endotracheal intubation over hours. for each groups categorical variables were summarized as frequencies and percentages and number in means and standard deviations (sd) or median with interquartile ranges (iqr).percentages were compared, as appropriate, with the fisher´s exact test or x test and medians with the wilcoxon test for independent samples. for those variables that were associated with de in the univariate analysis were entered into a logistic multidimensional analysis. the model obtained was expressed by p-values and odd-ratios, which were estimated by confidence intervals at %. a hypothesis test was considered statistically significant when p-value was less than . . results: ninety patients ( , %) had atb de and did not. there were no significant differences in demographics or type of admission in both groups (fig. ) . mortality was lower in patients receiving de antibiotic (atb) ( , %, p: . ). in the multivariate analysis, icu mortality and urinary tract infection were the only variables found significant (fig. ) de was performed in out of ( , %) with crb and in out of ( , %) who had nosocomial pneumonia. the atb t was inadequate in out of infections ( , %). targeted therapy was performed in out of patients ( , %) and in out of infections, at least once occasion ( , %). finally, atb were targeted prescribed. in all studied patients with de, this was performed in patients once, in patients twice and in patients three times. the number of antibiotics used was and atb de was performed in occasions. frequency of atb used and of theirs de is shown in fig. of note, meropenem was de in , %. conclusions: patients who received atb de compared to those that did not had a significant lower icu mortality. the factors independently associated to de were icu mortality and urinary tract infection. inadequate atb t in our icu occurred in . % of nosocomial infections. atb de was performed in patients. targeted therapy was applied to , % of infections. the most commonly used antibiotics were meropenem ( , %), levofloxacin ( . %) and piperacillin-tazobactam ( , %). meropenem, was de in , %. introduction: antimicrobial prescription represents a major challenge for clinicians in the daily practice especially in certain difficult clinical scenarios. thus, in critically ill septic patients, prompt and adequate antimicrobial therapy reduces morbidity and mortality objectives: we set out to assess the impact on in-hospital of antibiotic de-escalation in patients admitted to the icu with severe sepsis or septic shock. methods: collaborative study enrolling patients admitted to the icu with severe sepsis or septic shock from two different cohorts. the first one, a spanish prospective and observational cohort and the second one, a multicenter non-blinded, randomized and non inferiority trial conducted in france. severity was estimated by the use of the predicted mortality rate at icu admissionfor every included patientby implementing the likelihood of death logit formule defined according to the apache ii and saps ii scores criteria and taking this cuantititative variable into account as a confounder factor in the regression model. de-escalation was defined as discontinuation of an antimicrobial agent or change of antibiotic to one with a narrower spectrum once culture results were available. to control for confounding variables we performed a multivariatebinomial logistic regression analysis adjusted by wald test. results: nine hundred and one patients with severe sepsis or septic shock at icu admission were treated empirically with broadspectrum antibiotics. eight hundred and seventeen patients were evaluated ( died before cultures were available). de-escalation was applied in patients ( . %). we found no differences in hospital long of stay between de-escalation group comparedto those who did not received it. we also found a significant lower hospital mortality in de-escalation group in front of the others ( . vs. . %; p < . ). by multivariate analysis (adjusted by severity scores-apache and saps), factors independently associated with in-hospital mortality were age (odds-ratio [or] . ; % confidence interval [ci] . - . ), and sofa score at icu admission (or . ; % ci . - . ), whereas de-escalation therapy was a protective factor (or . ; % ci . - . ) as well as urinary focus (or . ; % ci . - . ). analysis of the patients with etiological diagnosis revealed that the factors associated with mortality were age and sofa and conversely de-escalation therapy was a protective factor (or . ; % ci . - . ) conclusions: de-escalation therapy for septic critically ill patients is a safe strategy associated with a lower mortality. efforts to increase the frequency of this strategy are indeed justified. introduction: at the population level, both vancomycin and aminoglycosides are known to be nephrotoxic. the risk of nephrotoxicity might even be higher when combining the agents together ( ). nonetheless, in septic patients, the benefit in terms of sepsis control may outweight the risk of nephrotoxicity. thus, being able to appraise the risk/benefit ratio at the patient level would be of great interest to better tailor individual treatment. objectives: capitalizing on recent statistical innovations in personnalized medicine, our goal was to develop a patient-centered estimation of the impact of the association vancomycin/aminoglycosides on the kidney function. methods: our data come from a cohort study performed between and in the departments of anesthesia, critical care and cardiovascular surgery at a french teaching hospital. this study included all consecutive patients operated for an acute endocarditis ( ). the primary endpoint was postoperative evolution of the kidney function as evaluated by the akin score (stade : elevation in serum creatinine (srcr) ⩾ . μmol/l or ⩾ , xbaseline; stade : elevation in srcr ⩾ xbaseline; stade : elevation in srcr ⩾ xbaseline or creatinine ⩾ μmol/l with increase > μmol/l or need for rrt). the impact of vancomycin/aminoglycosides on kidney function was estimated using targeted maximum likelihood estimation on a risk difference (rd) scale. the association between patient characteristics and the individual effect of the drugs on the kidney function was estimated using conditional recursive partitioning (ctree). results: patients were included in the study. their baseline characteristics are described in table . at a population level, we confirmed the strong association between vancomycin + aminoglycosides and the risk of kidney dysfunction (rd = . , %ci: . - . , p < . ). however, at the patient level, this effect was very variable and could be predicted based on patients characteristics (r = . ) (figure ). conclusions: the individual impact of vancomycin + aminoglycosides on kidney function may be very different than the overall effect at the population level. innovant statistical approaches may be used to identify patients in whom this drug combination is safe, and others in whom it may seriously threaten kidney function. introduction: catheter-related bloodstream infection (crbsi) is one of the most frequent nosocomial infections in critically ill patients, resulting in a significant increase of morbidity and mortality. that is why it is essential to detect crbsi precociously so that optimal treatment can be initiated as soon as possible. objective: our objective is to evaluate the effectiveness of rapid non-invasive tests that may allow clinicians to detect colonisation of the central venous catheter (cvc) as a source of bloodstream infection in critically ill patients, permitting catheter withdrawal and the initiation of early goal-directed antibiotic therapy. methods: over the course of eight months, we selected for evaluation those critically ill patients admitted to our icu who developed fever (> °c) without source, to whom the clinician in charge decided to withdraw the cvc. before extraction, we obtained a skin smear at the insertion site, in addition to a catheter-hubs smear. we sent both smears, along with the catheter tip and blood cultures, to the microbiology laboratory. these results indicate that our test has a negative predictive value of %. to evaluate the degree of association between our test and the gold standard, we calculated the contingency coefficient, which resulted in , out of a maximum , (p < , ). this shows the strong validity of the combination of skin and catheter-hub cultures as a diagnostic method for cvc colonisation. conclusions: the combination of skin and catheter-hub cultures is a rapid and very effective method for detecting the colonisation of cvc as a possible source of bloodstream infection in critically ill patients. while a negative result, which can be obtained within h, would prevent the need for cvc withdrawal, a positive result would not only enable the removal of the likely source of infection, but it would also allow for, if the intensivist deemed it necessary, the initiation of early goal-directed antibiotic therapy. this would mean, in more than % of cases, starting optimal treatment at least hours prior to the diagnosis of crbsi from blood cultures. results: introduction: piperacillin/tazobactam (ptz) is a β-lactam-β-lactamase inhibitor combination with a broad spectrum of antibacterial activity. βlactams are time-dependent antibiotics and their effectiveness is in association with the duration of free drug concentrations over the minimum inhibitory concentration (t > mic) of organisms. prolonged infusion has a pharmacokinetic (pk) advantage compared to intermittent bolus dosing, a continuous infusion lower dose of g ptz may be as effective as a higher dose of intermittent bolus ptz. objectives: in this study we intend to evaluate the continuous infusion of / grams of ptz along with a loading dose of / , grams in patients admitted in a tertiary icu. methods: between october and december eight patients had piperacillin plasma concentration monitored during treatment with continuous ptz infusion in a monocentric prospective observational study. patients received a loading dose of / , grams of ptz followed by infusion of / grams, reconstituted in ml sodium chloride , % and transferred to braun space infusion system®. the pump had a flow rate of ± ml/h. blood was always extracted from the contralateral arm to the infusion, over hours at predetermined times. serum piperacillin/tazobactam concentrations were determined using an hplc method ( ). after extraction, samples ( μl) were injected into a xbridge c column (waters, spain) and were scanned by an uv detector at nm with gradient elution. mobile phase was composed by acetonitrile and a solution of tetrabutylammonium bisulfate ( g/ l). penicillin g was used as internal standard (sigma aldrich, spain). results: patients have been examined ( men and women). the average age was ± , the weight was ± kg, the creatinine clearance ± ml/min and the apache ii score , ± , . the mean concentrations of ptz in serum are represented in the next figures. conclusions: in this icu patient group, our results suggest that continuous infusion of ptz at / g per day is sufficient to obtain therapeutic plasma-concentrations in critical care patients with infections caused by ptz sensitive bacteria with a mic lower than mg/dl. however, in our group there were three patients with levels of mg/dl, which are not sufficient for bacteria with mic lower than mg/dl; these three patients are neurocritical. in conclusion, further studies in this are needed, especially studies regarding the association between piperacillin therapeutic drug monitoring and clinical outcome. introduction: ultrasound guided internal jugular vein cannulation is recommended technique in current anaesthesia and intensive care practice. however, classic short axis view has inherent problem of needle visualization during venous access. in contrast, medial oblique view may enhance needle visibility during venipuncture and decrease overlap between ijv and carotid artery and thereby increase the safety of us guided ijv cannulation ( ) ( ) . objectives: to compare the safety and efficacy of medial oblique view and in-plane technique as compared to short axis view and out-of-plane technique during us guided ijv cannulation. methods: two hundred patients aged between - yrs of either sex and american society of anesthesiologists' physical status i-ii who were undergoing any surgery under general anaesthesia requiring an internal jugular vein cannulation, enrolled for this prospective randomized controlled trial. three patients were excluded due to us machine malfunction. in patients of group m, ijv cannulation was performed with medial oblique probe position and in plane approach. in patients belonging to group s, ijv cannulation was done in out of plane approach with the us probe in short axis position. primary outcome was needle and guide-wire visibility during procedure. results: needle visibility (entire needle tract and needle tip) was significantly higher during ijv puncture in medial oblique probe position ( of patients in group m versus of patients in group s; p = . ). guide wire visibility during insertion was also higher when medial oblique probe position was used ( of in group m versus out of ; p = . ). first insertion success rate for ijv puncture, incidence of posterior wall of ijv puncture and time to cannulation were similar both the groups. no serious complications such as carotid artery puncture, haematoma formation and pneumothorax were reported. conclusions: medial oblique view may increase safety of us guided ijv cannulation in comparison to short axis view by increasing needle visibility during puncture. resuscitation "philosophy" shifted from being heart oriented towards brain oriented since its delay may increase neurological deficits . recent studies are highlighting the role of the bystander-cpr as a critical variable affecting ocha neurological outcome. , objectives: two step prospective interventional observational study to assess the role of the bystander-cpr in affecting neurological outcome in our ohca population. introduction: there is a clear rationale for monitoring microcirculatory behaviour during shock since it is the anatomical location of oxygen and substrate exchange, and may not correspond to global haemodynamics. and yet despite over a decade of research and technological advances such monitoring has not reached clinical bedside utility. analysis of the data is performed offline and too time consuming for clinical use. there is an urgent need for a system to assess the microcirculation at the bedside. we present a novel -point grading system (the point-of-care microcirculation (poem) scoring system) that can be used at the bedside (using sublingual microcirculatory monitoring). objectives: to assess the inter-user variability of the novel poem scoring system amongst doctors and nurses who may use such technology for clinical practice, and to benchmark poem scores against traditional offline computer analysis. methods: the poem score is an ordinal scale from (worst) to (best), and calculated based on assessment of individual video clips. online calculator found at: www.poemscore.com. thirtytwo naïve study participants from two uk teaching hospitals (birmingham and london) participated in a standardised -hour interactive training session in how to assign poem scores based on microcirculatory video clips from sublingual incident dark field (idf) videomicroscopy imaging. they were then asked to assign scores for different video sequences (each of varying clinical status, played in a random order). they were blinded to clinical status. inter-user consistency and agreement were assessed using intra-class correlation coefficient (icc) analysis. blinded expert poem scores were also validated against offline computer analysis of the same clips using traditional microcirculatory parameters, and the time taken to assign each was recorded. results: raters showed good inter-rater consistency (icc . , % ci . , . ) and agreement (icc . , % ci . , . ) for assigned poem scores. expert poem scores correlated well with offline analysis but took far less time to assign (mean times of minutes versus minutes; p < . ). conclusions: a new -point ordinal scale of microcirculatory function has been tested amongst 'front line' emergency physicians and nurses at two large uk teaching hospitals, and has minimal inter-user variability, even after just hour of training. poem scores take a matter of minutes to assign, and correspond well to computer-analysis variables. we present for the first time a bedside microcirculatory grading system that is quick, reliable, and gives potentially meaningful clinical parameters that might guide resuscitation. prospective randomised trials utilising goal directed therapy using the poem score are required to test its reallife clinical utility. introduction: vocal cord palsy is a known postoperative complication following cardiothoracic surgery. , . although the incidence is relatively low its existence cannot be ignored and thus its identification necessary in order to avoid any further complications and maintain patient wellbeing. this study aims to look at the incidence of vocal cord palsy following cardiothoracic surgery in a tertiary referral centre and highlight the importance of the speech and language therapist's role in working with this cohort. objectives: to measure the incidence of vocal cord palsy post cardiac and thoracic surgery and to identify the consequent effects. methodology. a retrospective analysis, within a tertiary cardiothoracic centre. data for all patients who underwent either a cardiac or thoracic surgical procedure between december and april and were referred to speech and language therapy (slt) was collected. vocal cord palsy was identified by fibreoptic endoscopic evaluation of swallowing (fees) or bronchoscopy. results: a total of patients were seen by the slt. patients with vocal cord palsy were identified by fees and bronchoscopy; % and % respectively. six patients assessed presented with vocal cord palsy; patients were post cardiac surgery ( / ) and post thoracic surgery ( / ). the consequence of vocal cord palsy was dysphonia in all the patients and dysphagia in two thirds of patients. the median duration that patients experienced dysphagia was days (range - days) and dysphonia was days (range - ). conclusion: this review highlights the high prevalence of vocal cord palsy post cardiothoracic surgery. vocal cord palsy led to high levels of dysphagia and dysphonia. early identification of these is imperative to ensure patient safety and optimise recovery and quality of life. ) . . % were over years old at the moment of the surgery. figure shows previous cardiac clinical history figure shows other relevant comorbidities. it was first surgery in . % of the patients. , % of the cases were valvular surgery (with or without cabg); , % were isolated cabg; , % thoracic aortic surgery; , % were other surgeries (congenital disease surgery, post ami complications, pericardiectomy). tables and summarizes the results of the application of sf- questionnaire in the patients interviewed in the follow up in the comparative analysis we found worse qol in women than men (p = , ), and a negative correlation between age and qol (p = , ). women in our study were significantly older than men (p = , ). we found no differences between the type of surgery and the postoperative qol, or between surgery or extracorporeal circulation duration and qol. there was a relationship between nyha degree during the follow up and the sf health score prognostic scores showed an inverse relationship with qol, but with a low correlation; pearson coefficient − , (euroscore), − , (saps ). conclusions: in our study, involving hospitals in andalusia (south spain), , % of cardiac surgery patients didn´t show any activity limitation or only a slight limitation before years of follow up. perceived quality of life decreases as age increases or worsens the functional status of the patients. conclusion: concsultation for the severely ill cases in the wards take very much time of the intensivits. it was seen that consultation request was mostly emergent and due to respiratory problems and sepsis. maybe we need another system like rapid response team for decrease the insivists work and decrease the mortality amd morbidity. the limitation of the beds in icu is one of the most important problem, and there must be more empty beds for inhospital emergencies. an external validation study of the qsofa score to predict inhospital mortality in medical patients with infection and derivation of a new enhanced score using automatically available variables: news-hazard l. introduction: sepsis has recently been redefined as´life-threatening organ dysfunction caused by a dysregulated host response to infec-tion´. it is one of the leading causes of mortality internationally. earlier identification of sepsis means more timely management, reduced length of hospital admission, and prevention of septic shock; ultimately reducing sepsis associated mortality. ( ) there is currently no standard diagnostic test for sepsis. distinguishing sepsis from alternative, uncomplicated infections is pertinent to ensuring an appropriate clinical approach. systemic inflammatory response syndrome (sirs) criteria have been used since to define sepsis (sepsis . ). however they have been found to lack sensitivity or specificity. the quick sequential organ failure assessment score (qsofa) is an emerging initial assessment method that uses three simple bedside criteria to measure organ dysfunction; altered mental status, respiratory rate ≥ and systolic blood pressure ≤ mmhg. the aim is to facilitate earlier recognition of sepsis outside of itu by prompting the clinician to think, and adequately screen for sepsis. in cases, the diagnosis of pneumococcal meningitis by culture or pneumococcal crp in csf was confirmed. in all cases, pneumococcus antigen was positive. therefore, there were no false negatives. in cases pneumococcal meningitis was not diagnosed, being the final diagnosis a non-pneumococcal bacterial meningitis or another pathology. in all cases, pneumococcus antigen was negative. therefore, there were no false positives. in conclusion, in our sample of patients, the sensitivity and specificity of the test for s. pneumoniae antigen in csf was %. the ppv and npv were also %. conclusions: in our series, the sensitivity and specificity of the test for s. pneumoniae antigen in csf by immunochromatography ( binaxnow® test ) was %. the vpp and vpn were also %. these results are similar to those reported previously in the literature. knowing the reliability of this fast, simple and inexpensive test, will allow to remove unnecessary isolation and to establish a more specific treatment and a better prognoses of the disease. evaluation of sensitivity and specificity of different criteria using for diagnosis of burn sepsis and without these (group № , n = ). logistic regression was performed to identify the independent factors for the prediction of early death ( days and less). we examined sensitivity and specificity with area under the receiver operating characteristic curve (roc auc). results: there were no significant differences between two groups for demographics, burn size, inhalation injuries. fatal outcome came early in the group № (mean icu length of stay , days vs days, p < , ). organ dysfunction at day was significantly higher in the group № (mean sofa , vs , ; p < , ). there were no significant differences in aba, fsbi and cdbs between two groups, and the highest auc were for cdbs by the day (auc , % ci , - , vs , % ci , - , and , % ci , - , for cdbs, aba and fsbi, respectively). sirs criteria were significantly higher in the group № , auc was , ( % ci , - , ) but specificity and sensitivity was too low (for sirs criteria is , % and %, respectively). independent factors for early death include: more than % immature neutrophils at the day , sofa more than by the day , thrombocytopenia less than by the day . conclusion: patients without specific pathomorphological signs of sepsis have more severe organ dysfunction, greater number signs of systemic inflammation and earlier fatal outcome. diagnostic model of sepsis by chinese experts has more sensitivity and specificity for diagnosis of burn sepsis confirmed by autopsy. immature neutrophils count, thrombocytopenia and sofa score are stronger risk factors for early death. the value of neutrophil to lymphocyte count ratio in diagnosing blood-stream infection s. involved microorganisms: s. pneumoniae and n. meningitidis in communitary abm, s. epidermidis and gram-negative bacilli in nosocomial abm. when comparing both groups, only we observed difference in the c-reactive protein at admission ( ± , in nosocomial abm vs , ± , in communitary, p , ). there were differences with other variables but were not statiscally significant. so, we observed a higher mortality in nosocomial abm group but the difference was not statistically significant (p , ). global icu mortality was % ( ) and hospital mortality was , % ( ). conclusions: the demographic and bacteriological profiles of patients with acute bacterial meningitis have changed in the last years mainly due to the expansion of neurosurgical procedures. still has a high morbidity and mortality. the detection of microbial dna but not cultured bacteria is associated with increased mortality in patients with suspected severe sepsis -a european multi-centre observational study m. introduction: sepsis is a leading cause of worldwide mortality. blood culture results poorly discriminate the mortality risk in critically ill patients with sepsis. here we aimed to determine whether the detection of microbial dna in the blood stream of patients with suspected sepsis was associated with mortality. we performed an analysis of data collected during the rapid diagnosis of infections in the critically ill (radical) study ( ) . patients were considered eligible for this study if they developed suspected sepsis and were either in or were referred for treatment to one of nine intensive care units (icus) in six european countries. when initial blood cultures were taken for clinical indications an additional blood sample was obtained for a culture-independent polymerase chain reaction/electrospray ionization-mass spectrometry (pcr/esi-ms) assay. the results of the pcr/esi-ms test were not communicated to the treating clinicians. results: of the patients analysed in the original study outcome data, blood culture results and pcr/esi-ms results were available for patients (table ) objectives: to evaluate if a "bundle" consisting of a sirs and organ failure (sof)-triage, flow chart response and alert system, and a sirs/ sepsis training course for all wards nurses improved clinical observations, lead to fewer patients developing severe sepsis, decreased length of stay in the high-level care (los) and increased survival. methods: a before and after intervention study in one emergency and community hospital within the mid-norway sepsis study catchment area. all patients with confirmed blood stream infection (bsi) and evidence of sepsis have been prospectively registered continuously since . the severity of sepsis, observation frequency of vital signs, treatment data, los and mortality were retrospectively registered from the patients' medical journals until end . results: the pre-intervention group was patients with confirmed bsi from jan to dec (n = ) whilst the postinterventions group was recruited between nov to dec (n = ). the nurses' observation frequency of vital signs increased in bsi patients with and without severe organ failure comparing these periods. the post-intervention group had, in average, . days shorter los. patients admitted without severe organ failure in the post-intervention group had a lower probability of developing severe organ failure ( . , % ci . - . ) than the pre-intervention group. adjusted for differences in disease severity the post-intervention group also had higher odds of surviving days (or . , % ci . - . ). conclusion: a sepsis specific triage-, flow chart alert and treatment system was an effective tool to increase ward nurses recognition and early treatment of patients with confirmed bsi. in addition to increased survival, the shorter los is important from a hospital perspective in term of resource utilization. this study was supported by the liaison committee between nord-trøndelag hospital trust and nord university introduction: the endotoxin activity assay (eaa™; spectral diagnostics inc., toronto, canada) is a rapid in vitro diagnostic test of the neutrophil's reaction to endotoxin and reflects the endotoxemia ) . recently, eaa is used to confirm endotoxemia such as in the euphrates (evaluating the use of polymyxin b hemoperfusion in a randomized controlled trial of adults treated for endotoxemia and septic shock) trial study in north america ) . however, eaa has not been routinely used to diagnose sepsis, yet. objectives: our hypothesis is eaa is useful to diagnosis for new definition's sepsis due to gram-negative infection. methods: the present study is a single-center retrospective observational analysis. of all adult patients in whom eaa was measured at our medico-surgical icu from july to july , patients with new definition's sepsis in were included in this study. new definition's sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection which is identified with total sofa score of or greater ) . patients were divided into two groups, ) with gram-negative organisms in some cultures and ) with no gram-negative organisms in any cultures. age, sex, body temperature (bt), wbc, crp, procalcitonin (pct), sofa score, and eaa values were compared between two groups. values are expressed as mean ± sd. data was analysed by chi-square test and unpaired students t-test. p values less than . were considered significant. results: five hundred and twenty seven patients ( men and women; mean age . ± . years) were studied. there were ) patients with gram-negative infection and ) patients with no gram-negative infection. eaa values and sofa score were statistically significant differences between gram-negative infection and no gram-negative infection ( . ± . vs. . ± . , p = . , . ± . vs. . ± . , p < . , respectively). pct was different but did not reach to statistically differences between two groups ( . ± . vs. . ± . , p = . ) and age, sex, bt, wbc were no significant differences between two groups. patients and methods: mechanically ventilated patients with severe sepsis/septic shock, treated in icu, were included in this prospective observational study. exclusion criteria were mechanical ventilation for more than hours prior icu admission and brain death. clinical and laboratory data were recorded, on a daily basis. thrombocytopenia was defined as a plt below x /μl. thrombocytopenia was considered as mild ( x /μl ≤ plt < x /μl), moderate ( x /μl ≤ plt < x /μl), or severe (plt < x /μl) depending on plt counts. serum levels of ifnγ, il- , icam, vcam, and soluble urokinase plasminogen activation receptor (supar) were estimated by using luminex xmap technology. results: fifty-six out of ( %) patients enrolled in the study were thrombocytopenic at the time of admission in icu. the overall incidence of thrombocytopenia during icu hospitalization was %, while mild, moderate, and severe thrombocytopenia developed in ( %), ( %), and in ( %) respectively. patients with severe thrombocytopenia had higher apache score, higher serum icam, il- and supar levels, higher incidence of bacteremia and higher probability to present with septic shock as compared with patients with normal platelet counts. moreover, severe thrombocytopenia was associated with statistically significantly higher hospital mortality. patients with severe thrombocytopenia showed significant higher serum icam (p < . ), il- (p = . ), and supar (p < . ) levels respectively, as compared to patients with normal platelets count, or patients with mild or moderate thrombocytopenia. in multivariate analysis, higher apa-che score, thrombocytopenia, and higher serum supar levels were statistically significantly associated with a higher risk of icu mortality. enrolled patients were stratified in different groups according to their apache ii score (apache ii > ), plt counts (plt ≤ . ) and serum supar levels (supar > . ). in multivariate analysis, this new scoring system remained the only and most significant factor associated with statistically significantly increased icu mortality [or = . , ( % ci, . to . ), p < . ]. conclusion: severity of thrombocytopenia in severe sepsis and septic shock parallels the severity of inflammation and subsequent endothelial dysfunction and is associated with higher mortality. the and il- α, were measured and compared between immediately before the first pmx-dhp therapy, before the second pmx-dhp therapy and after pmx-dhp therapy. human cytokine elisa plate array i (chemiluminescence) are used the plate which of cytokine capture antibodies are coated on wells respectively. each cytokine value is shown as relative light units of luminescence. values were expressed as mean ± sd. data were analyzed by wilcoxon signed-ranks test. a p < . was considered as statistically significant. results: all results were provided in about hours after starting this assay. one measurement of all cytokines costed $ . . tnf-α and mcp- values were significantly decreased between immediately before and after the second pmx-dhp therapy ( . ± . vs. . ± . , . ± . vs. . ± . , p < . , respectively). il- , il- and mcp- were also significantly decreased between before the second and after pmx-dhp therapy ( . ± . vs. . ± . , . ± . vs. . ± . , . ± . vs. . ± . , p < . , respectively). there were no statistically significant differences between before and after pmx-dhp therapies in other cytokines. the present study has some limitations because of a retrospective analysis and numbers of patients. however, human cytokine elisa plate array i is a fast and low-cost assay compared with the previous elisa method. and several cytokines are evaluated with one sample at the same time. this assay could be useful especially for the clinical research because small volumes of sample allow to several cytokines' information at the bedside. introduction: critical illness-acquired myopathy in rats is characterized by homogeneous muscle atrophy ( ). conversely, histological abnormalities are heterogeneous: oxidative muscles show patchy alterations (myofascitis, necrosis), while glycolytic types demonstrate normal patterns. akt and mtor are key proteins of the anabolic pathway, leading to myocyte growth when activated. conversely, ampk and foxo are key proteins of the catabolic pathway, leading to myocyte atrophy when activated. whether anabolic or catabolic pathway activation is dependent on skeletal muscle type (i.e. oxidative and glycolytic) during critical illness is unknown. objectives: to characterize activation of the anabolic and catabolic signalling pathways in a long-term rat peritonitis model by skeletal muscle type. methods: male wistar rats were followed for up to weeks after intraperitoneal injection of the yeast cell wall constituent, zymosan or n-saline. soleus (oxidative, slow twitch muscle), and gastrocnemius (mixed glycolytic-oxidative, fast twitch muscle) were harvested from both zymosan and control groups at , and days after the insult. expression of phospho-(p-) and total proteins were assessed by western blots. expression of akt, p-akt (p-threonine , active form), mtor, p-mtor (p-serine , active form), ampk, p-ampk (pthreonine , active form), foxo , and p-foxo (p-threonine , inactive form) were assessed at all time points. results: weight loss was not statistically different in soleus versus gastrocnemius in the zymosan group (− ± % versus − ± %, p = . ) at day . gastrocnemius displayed a decrease in p-akt at day , and an increase of p-akt and p-foxo at day . soleus displayed an increase of p-akt, p-ampk, and p-foxo at day , and an increase of p-ampk, and p-foxo at day . results are detailed in the table . conclusions: in a rodent model of long-term peritonitis, both oxidative and glycolytic muscles display little change in the anabolic signalling pathway. ampk (an autophagy activator) is activated while foxo , (an autophagy and ubiquitin-proteasome system activator) is inhibited up until day in oxidative but not glycolytic muscle. introduction: esophageal pressure (p es ) guided setting of peep has been described in ards patients either to avoid expiratory alveolar collapse or to promote maximum inspiratory recruitment . the proportion of ards patients that may benefit from maximum recruitment strategy and its effects regarding dead space (v d /v t ), shunt, driving pressure (dp), transpulmonary driving pressure (tpdp) and expiratory transpulmonary pressure (tpp exp ) remain unclear. methods: we included moderate and severe ards patients under mechanical ventilation and paralyzed, in the first hours after reaching ards criteria. patients were monitored with esophageal balloon catheter and ventilated with express study settings for hour after recruitment maneuver. then peep was modified to obtain an inspiratory transpulmonary pressure (tpp insp-p ) based on p es between and cmh higher peep in group b led to higher plateau pressure and tpp insp-p , positivation of tpp exp without increase in v d /v t (p = . ), shunt (p = . ), dp (p = . ), tpdp (p = . ) or oxygen stretch index (p = ). however agreement between tpp insp-p and tpp insp calculated from respiratory motion equation and chest wall elastance (tpp insp-e ) was weak with band-altman bias (tpp insp-e -tpp insp-p ) = . ± . [ %ci − ; ]. conclusions: p es measurement in moderate to severe ards patients distinguishes groups of patients in whom peep appears to be taylorized without side-effects. however physiologic studies should assess reliability of transpulmonary measurement based on either p es or chest wall elastance. introduction: to optimize mechanical ventilation different targets are used including tidal volume (tv), peak and mean airway pressure and peep. however, prevention of alveolar collapse not only depends on intra-pulmonary, but also on the extra-pulmonary pressure (epp). epp can be estimated by measuring esophageal pressure (ep). ventilator strategies aiming at optimized trans-pulmonary pressure tpp (difference between intra-and extrapulmonary pressure: tpp = tip-tep) have been shown to improve outcome. tpp-guided ventilator setting might be useful in patients with liver cirrhosis and ascites. however, the impact of paracentesis on tpp is poorly investigated. objectives: to investigate the impact of high volume paracentesis (hvp; ≥ ml) on tpp and on other parameters of pulmonary and circulatory function. methods: analysis of hvp-procedures in patients ventilated with the avea viasys ventilator (carefusion, usa) capable to measure ep via an esophageal tube. haemodynamic monitoring with the picco- -device (pulsion medical systems se, feldkirchen, germany) was available during measurements. intra-abdominal pressure iap was determined by intra-peritoneal (iap_p) and intra-vesical (iap_v) pressure measurement. high grade esophageal varices had been excluded endoscopically before measurement of ep. statistics: spss . results: male, female patients, aetiology of cirrhosis alcoholic (n = ), viral ( ) and cryptogenic ( ) . age ± years, apache-ii ± , sofa ± , meld ± . paracentesis of ± ml resulted in marked increases in inspiratory ( . ± . vs. . ± . ; p < . ) and expiratory (− . ± . vs. - . ± . cmh o; p < . ) tpp. in parallel inspiratory ( . ± . vs. . ± . cmh o; p < . ) and expiratory ( . ± . vs. . x ± . cmh o; p < . ) ep significantly decreased. paracentesis resulted in decreases in iap_p ( . ± . vs. . ± . mmhg; p < . ), iap_v conclusions: paracentesis markedly increases inspiratory and expiratory tpp in parallel with a decrease in iap. increased iap before paracentesis resulted in markedly decreased inspiratory and endexpiratory tpp despite ventilation according to the ardsnet guidelines. to avoid decreased end-expiratory tpp and alveolar collapse in patients with increased iap, paracenteses and/or higher peep-setting should be used. iap and its changes markedly confound cvp, but neither gedvi nor ci. introduction: if the proportional assist ventilation(pav) level is known, then muscular effort can be estimated from the difference between peak airway pressure and peep (△p) during pav. namely, p mus, peak, aw = (p aw, peak -peep) x ( -gain)/gain. pressure time product estimated from airway (ptp aw ) = p mus, peak, aw x inspiratory time/ x respiratory rate [ ] . objectives: validation of this hypothesis by using the esophageal pressure time product calculation. methods: eleven mechanically ventilated patients who received esophageal pressure monitoring under pav were enrolled. patients were randomly assigned to seven pav assist levels ( - %, pav means % pav gain) for minutes. maximal muscular pressure (p mus, peak, es and p mus, peak, aw ) and pressure time product (ptp es and ptp aw ) estimated from △p and esophageal pressure were determined from the last minute of each pav level. results: pav significantly reduced the breathing efforts of patients with increasing pav gain (ptp es . ± . at pav vs. . ± . cmh o•sec/min at pav , ptp es, peepi . ± . at pav vs. . ± . cmh o•sec/min at pav , p < . ). p mus, peak, aw overestimate p mus, peak, es in pav of low gain (pav ) and underestimate in pav of moderate to high gain (from pav to pav ). linear regression analysis revealed that the slope ptp es, br (ptp es per breath)/p mus, peak,es for ptp es, peepi is . (r = . ), for ptp es is . (r = . ), and ptp aw, br (ptp aw per breath)/p mus, peak, aw for ptp aw is . (r = . ). conclusions: adjustments should be made when extrapolating ptp aw into ptp es . an additional % should be added when extrapolating ptp es from p mus, peak, aw and an additional % should be added when extrapolating ptp es, peepi from p mus, peak, aw , assuming p mus, peak, es and p mus, peak, aw are equal. introduction: airway occlusion pressure is a noninvasive measure of motor neural output. if the airway is occluded, the change in pressure in the pleural space and at the airway open, both are equivalent objectives: we studied the similarity of effort and work of breathing measure with pesophageal (peso) at regular cycles, versus inadvertent airway pressure (paw) occluded during end-expiration (paw_occl). methods: esophageal, airway pressure and airway flow, sampling hz, were registered in patients during weaning time, with levels of sedation ramsay , at pressure support ventilation (psv) with differents levels of assistance (high: - cmh o, medium: - cmh o, low: - cmh o). respiratory effort was quantified using pressure-time product (ptp/min) with esophageal and occluded cycle (figure ), and wob_occlusion, using the occlusion pressure with the flow of preceding, not occluded, cycles ( figure ). the work of breathing esophageal referent (wob_peso, j/l)) is obtained from integral of peso versus differential of volume. also we are calculated Δ peso and Δ paw_occl as additional parameter. for all data, the bland-altman analysis and linear regression was applied. the results are expressed as mean ± sd, the comparison was made by t-test. results: a total of paired measures were obtained. the mean comparison of the respiratory effort and work did not show showed statistical differences for all data, except for low assistance (table ) . a good correlation between both measures methods was observed for ptp and wob (r = , and , ; respectively). the mean bias was for ptp and wob: , (± , ) cmh o*sec/min and , (± , ) j/l, respectively; and the % limits of agreement were − , to , cmh o*sec/min and − , to , j/l, respectively; this indicates wide dispersion. conclusions: airway occlusion pressure is a noninvasive procedure that could be useful to assess the effort and work of breathing patients during mechanical ventilation. introduction: chest wall elastance (ecw) is thought to increase in prone (p) as compared to supine (s) position in ards patients ( ) ( ) ( ) . this makes respiratory system elastance (ers) not reflecting lung elastance (e l) . little is known about the changes of ecw, e l and lung resistance (r l ) when moving the patient from the supine to the prone position via the lateral (l) position ( ) ( ) . objectives: the goal of present study was to measure ecw, e l and r l in ards patients in s, l and p position during the proning procedure. methods: ards patients intubated, sedated and paralyzed with an indication of p positioning were included. mechanical ventilation was delivered in volume controlled mode with constant flow inflation. end-inspiratory pause of . sec was set during the breathing cycles. ventilator settings were unaltered during the procedure. airway and esophageal pressures and airflow were continuously measured during minutes in s, then during minute in l and minutes in p. the side for the lateralization was that selected by routine practice (in the opposite side from central venous line). prone positioning was performed manually by caregivers. ecw, e l and r l were obtained by fitting the first order equation model to flow and pressures signals. values are expressed as mean ± sd. results: fifteen patients ( males) of ± years, saps ± and sofa ± were included ± days after ards criteria ( moderate and severe) were met. tidal volume averaged ± . ml/kg predicted body weight, peep ± cmh o, fio ± %, pao /fio ratio ± mmhg. the cause of ards was pneumonia in cases, undetermined in cases. side positioning was the right in and the left in patients. the results are shown in the table . conclusions: during prone positioning in ards patients, as compared to s we observed an increased r l and e l in l and increased ecw in p. introduction: driving pressure of respiratory system (Δp) is defined as the difference between plateau pressure (pplat) and total positive end-expiratory pressure (peeptot) measured after endinspiratory and end-expiratory occlusion, respectively, on airway pressure signal. Δp has recently been shown as a strong predictor of mortality in patients with acute respiratory distress syndrome (ards) ( ) . most of the studies involved in this demonstration measured pplat . sec after onset of endinspiratory pause according to the arma trial ( ) and used peep set on the ventilator (peepvent) instead of the peeptot. this does not take into account slow decay of airway pressure after endinspiratory occlusion and instrinsic peep, respectively. objectives: the aim of the study was to compare Δp when pplat was measured at different times after end-inspiratory pause and whether peeptot or peepvent were used. our hypothesis was that Δp was *p < . versus supine **p < . versus supine higher with pplat measured at . and peepvent than with any other combinations of pplat and peeptot. methods: a retrospective analysis of patients with ards in whom respiratory mechanics was measured. most of the patients had recordings at two levels of peepvent. data were analyzed with acqknowledge software. pplat was measured at . , and seconds after end-inspiratory pause. peeptot was measured after a -sec end-expiratory pause. the low-peep and high-peep measures pertained to peepvent ≤ cmh and peepvent > cmh , respectively. the primary outcome was the comparison of Δp calculated as pplat . sec -peepvent : Δp reference versus Δp computed as pplat sec -peeptot: Δp physiologic . the values are expressed as mean ± sd and are compared by using signed rank test for paired values, anova for repeated measures and bland-altman. results: twenty-three patients were analyzed. Δp reference was significatively higher than Δp physiologic in low and high peep groups: . (± . ) vs . (± . ) cmh o (p < − ) and . (± . introduction: end expiratory lung volume (eelv) is reduced in ventilated patients especially in patients with acute respiratory failure (arf). recruitment maneuvers and different levels of peep are used to restore eelv and to improve oxygenation. however; no matter how useful is the value of eelv in clinical practice his bedside measurement at baseline, at different levels of peep and after recruitment maneuvers is cumbersome. we measured the eelv with two techniques and we noted the technical problems and pitfalls. methods: we measure the eelv in patients with arf at two levels of peep ( and cm h o) with two techniques. with a dilutional nitrogen wash in and wash out method using the carescape r ventilator (ge) and by measuring the expired lung volume after a sudden release of peep to zero peep (zeep). specifically after min of stabilization at each level of peep we performed an expiratory hold and we decrease the ventilator frequency to zero to obtain sufficient time for a complete expiration. therefore, by releasing the expiratory hold we permit the return of the lung to his passive lung volume at zeep(passive frc).the expired volume was calculated by the integration of the expiratory flow. we call this volume Δeelv. correlation and agreement fig. (abstract a ) . variation of driving presure at low peep between the two methods with the bland and altmann analysis were performed. results: mechanically ventilated patients were studied. at zeep eelv was low ( ml) % of the predicted. good correlation was found between the two methods ( ± and ± ml respectively) when eelv was measured at cmh o of peep(r = o. , p < . ). on the contrary at cmh o of peep a wider variability and less agreement was noticed between the eelv values( ± vs. ± , r = . , p < . ). technical problems with carescape were spontaneous breathing attempts or asynchrony in the patient-ventilator interactions leading to instable vo -vco measurements. on the contrary with the release of peep method high expired volumes from peep to zeep induced high expired flow exceeding the lit/sec, thus affecting the linear sensitivity of the ventilator's pneumotachograph. conclusions: the measurement of the eelv remains a precious parameter for the ventilatory management of the icu patients but his measurement is still far away to be accurate by both techniques at bedside. low end-expiratory trans-pulmonary pressure is associated with lung collapse p. somhorst, d. introduction: the open lung concept aims to reduce lung injury due to cyclic opening and closing of alveoli. finding the 'optimal' peep to maintain an open lung proofs difficult and patient-specific. we hypothesize that targeting positive trans-pulmonary pressure (ptp) at end of expiration (ptpee) may prevent collapse. we used electrical impedance tomography (eit) clinically to optimize peep, visualizing over-distention and collapse. objectives: to show the association between collapse and low ptpee, as visualized by eit. methods: we retrospectively analyzed data of ten patients with acute respiratory distress syndrome (ards) who underwent measurement of the ptp and eit due to clinical considerations. a peep trial was performed to identify optimal ventilator settings. esophageal pressure (pes) was measured using endo-esophageal pressure balloons (cooper surgical, germany, or sidam, italy). the ptp was calculated as the continuous difference between the airway pressure and pes. eit was measured at the th/ th intercostal space (dräger, germany) and analyzed using specialized software (dräger, germany). collapse is defined as a local decrease in ventilation after a reduction in peep; over-distention is a local decrease in ventilation after an increase in peep. results: collapse was associated with a lower ptpee at lower peep levels. for most patients ( / ), collapse occurred when ptpee was ≤ cmh o. collapse was also present at a peep level of cmh o. inversely, we showed that collapse and over-distention can occur simultaneously (fig. ) . the ptpee was strongly correlated to the peep level (r = . , p < . ; corrected for each individual patient). the overall regression is shown as a dashed line. conclusions: for most ards patients, collapse did not occur when ptpee was above + cmh o. in addition, peep increase in order to prevent collapse may induce over-distention due to heterogeneity in the ventilation distribution in each patient. introduction: medical experts recommend keeping plateau pressure below cm h o to avoid ventilator-induced lung injury in patients with acute respiratory distress syndrome (ards). transpulmonary pressure (ptp), the difference between alveolar and pleural pressure, has been measured as a surrogate for plateau pressure for lung protective strategies. however, placement of an esophageal balloon catheter is required to measure esophageal pressure. objectives: we investigated the relationship between ptp and ventilator waveform parameters according to the strength of spontaneous breathing effort. methods: eight patients (four patients with ards and four with non-ards) mechanically ventilated with avea® were included in this study. an esophageal balloon catheter (avea® smartcath® esophageal balloon) was placed to measure esophageal pressure. we evaluated the relationship between Δptp (difference between inspiratory and end expiratory ptp) and peak inspiratory flow, or ti ratio (percentage of time until peak negative esophageal pressure to total inspiratory time). spontaneous breathing effort was categorized as strong or weak and was analyzed with inspiratory waveform using voxr data management software. results: although there was no significant relationship between Δptp and peak inspiratory flow (r = . , p = . ), a significant correlation was found between Δptp and ti ratio (r = . , p = . ). median Δptp and ti ratio were significantly higher in patients with strong spontaneous breathing effort compared with those with weak breathing effort ( . vs. . cmh o, p = . , and . vs. . , p = . , respectively). in patients with strong spontaneous breathing effort, median Δptp was higher in the ards group compared with the non-ards group ( . vs. . cmh o, p = . ). conclusions: measuring ti ratio and ventilator waveform parameters may be helpful to estimate ptp. appropriate sedatives, analgesics, or muscle relaxants may be required to limit ptp in cases of higher ti ratio in patients with ards. in vivo calibration of the esophageal balloon catheter: a simplified procedure f. introduction: a calibration procedure has been recently proposed to obtain reliable esophageal pressure (pes) measurements in mechanically ventilated patients [ ] . this procedure helps optimizing esophageal balloon filling and removing esophageal artifacts, but is timeconsuming. objectives: to test accuracy of a simplified procedure, designed according to average values of esophageal elastance (ees) and minimum appropriate filling volume (vmin) previously observed [ ] . methods: in patients under pressure controlled ventilation, pairs of end-expiratory and end-inspiratory calibrated pes values (pes,cal) were obtained with the standard procedure, consisting in measure of ees and detection of vmin and vbest (filling volume associated with the largest tidal swings of pes): pes,cal = pes -ees * (vbest -vmin). "simplified" calibrated pes values (s-pes,cal) were also obtained with a simplified procedure based on detection of vbest and on the assumptions that ees = cmh o/ml and vmin = ml: s-pes,cal = pes -(vbest - ). we used the nutrivent catheter (sidam, italy), equipped with an esophageal balloon that is cm long and has a ml nominal volume. results: in the conditions tested, vmin was . ± . ml, vbest . ± . ml and ees . ± . cmh o/ml. at optimal filling volume (vbest), difference between pes and pes,cal was . ± . cmh o (range . - . ). s-pes,cal strictly correlated with pes,cal (r = . ; p < . ); difference between s-pes,cal and pes,cal was − . ± . cmh o (figure ) . conclusions: when optimal filling of the esophageal balloon is adopted in mechanically ventilated patients, absolute values of pes are affected by significant esophageal artifact. a simplified calibration procedure seems to be adequately accurate in removing this artifact and suitable for clinical use. introduction: mechanical ventilation unloads the inspiratory muscles in case of high work of breathing to prevent development of muscle injury and patient discomfort. on the other hand, over-assist is associated with disuse atrophy and patient-ventilator asynchrony. two indices for assessing respiratory muscle effort have recently been published. patient-ventilator breath contribution (pvbc) index provides an estimation for the percentage of the total work of breathing performed by the patient related to the total work of breathing (patient + ventilator). neuromuscular efficiency (nme) or pressureelectrical activity index (pei) expresses how much pressure the inspiratory muscles generate (pmus) for each microvolt of diaphragm electrical activity (eadi). objectives: the aim of the current study was to assess the repeatability of both pvbc and nme and investigate how these indices changes in time in ventilated icu patients. methods: we included mechanically ventilated adult icu patients with a dedicated naso-gastric feeding tube for assessing diaphragmatic emg activity (eadi catheter). pvbc and nme were calculated at inclusion, after , and hrs and repeated times each with a -minute interval. pvbc was calculated by (tidal volume no assist/ eadi no assist)/(tidal volume assist/edi assist). nme was calculated by measuring change in airway pressure divided by amplitude of the electrical activity during end expiratory occlusion (delta paw/edi). results: the repeatability coefficient (rc) of pvbc and nme was % and . cm h o/uv respectively. median pvbc at t = was % and decreased until % at t = . in the same period, the mean nava level decreased ( . until . ) and mean eadi peak increased ( . until . uv). five patients had a pvbc index > %; four of them had a calculated pressure support (mean eadi peak x nava level) < cmh o. the median nme was . conclusions: we showed a repeatability of % for pvbc and . cmh o/uv for nme. this means that the absolute difference between two repeated measurements lies between this value with a probability of %. for example, with a calculated pvbc of % it is expected that % of the subsequent measurements will be between - %. nme was much more heterogeneous which indicates that neuromechanical coupling changes during icu stay in an unpredictable manner. pressure developed by the diaphragm in our patients appears within physiological limits. use of sigmoid regression for determining the optimal balloon volume in esophageal pressure monitoring: a bench and clinical feasibility study introduction: esophageal pressure (p es ), which has been used as a substitute for pleural pressure, is commonly measured by catheter with air-filled balloon. the accuracy of measurement depends on the proper balloon volume (v b ). assessment of optimal v b is difficult in clinical settings because the surrounding pressure of the balloon cannot be directly measured. in the present study, we introduced a sigmoid fitting method for determining the optimal v b . objectives: to assess the accuracy of optimal v b measured by sigmoid fitting and to evaluate the feasibility of this method in clinical practice. methods: six randomly selected esophageal balloon catheters (cooper catheter, cooper surgical, usa) were tested in a bench model with the lung and the pleural cavity during simulated mechanical ventilation. the balloon was progressively inflated in . ml increments from to . ml, and pressure in the balloon pressure (p b ) and in the pleural cavity (p c ) were measured. balloon transmural pressure (p tm ) was calculated as p b -p c . balloon pressure-volume was fitted by a sigmoid regression: v b = a/[ + e -(p-b)/c ], where a = the vertical distance of the upper asymptote, b = the pressure at the midpoint between zero and a, and c = the pressure range with the greatest volume change ( figure a shows a sample curve). the optimal v b was predicted by zero p tm and zero (p b -b). bland-altman´s analysis was used to assess the accuracy of the optimal v b predicted by p tm and p b . the balloon catheter was introduced into lower third of esophagus in patients with mechanical ventilation, and the balloon was inflated as the same sequence as that in the bench study. p es and v b were also fitted by the sigmoid regression ( figure b shows a sample curve) and the optimal v b was predicted by zero (p es -b). at each v b , dynamic occlusion test was performed, and ratio of changes in p es and airway pressure (Δp es /Δp aw ) was calculated. results: in the bench study, the best-fit coefficient r of sigmoid regression ranged from . to > . with a median (interquartile range, iqr) of . ( . , . ). the natural logarithmically transformed bias (and lower to upper limit of agreement) in optimal v b predicted by p tm and p b was − . (− . to . ). in the clinical study, v b tests were performed. r of sigmoid regression ranged from . to > . with a median (iqr) of . ( . , . ). the optimal v b was . ( . , . ) ml. the b value (r = . , p < . ) and predicted optimal v b (r = . , p = . ) significantly correlated with respective p es measured at the v b with the best Δp es /Δp aw ratio. conclusions: in the determination of balloon pressure-volume response, the performance of nonlinear sigmoid fitting was excellent in introduction: the use of more physiological tidal volumes ( - ml/ kg of ideal body weight) during general anesthesia can minimize the risk of lung injury but may be associated with increased atelectasis. a recent meta-analysis has suggested that high driving pressure and peep level changes that result in an increase of driving pressure are associated with more postoperative pulmonary complications ( ). there is no consensus, however, on how to tailor the level of peep to best suit each patient. objectives: our primary objective is to evaluate the variability of peep titrated by eit in healthy patients submitted to elective abdominal surgery. our secondary objective is to compare the consequences on lung mechanics and on the formation of atelectasis during abdominal surgery in two groups: titrated peep or peep of cmh o. methods: forty patients will be allocated into two groups: laparoscopic (n = ) or open surgery (n = ). after induction of anesthesia and neuromuscular blockade, and before insufflation of abdominal cavity, all patients will be submitted to a recruitment maneuver (rm) in pressure-controlled ventilation mode for two minutes followed by a decremental peep titration starting at peep of and diminished in steps of cmh o. optimal peep is defined as that with the best compromise of atelectasis and overdistention as measured by eit. patients in each subgroup will be randomized to one of two ventilatory strategies during intraoperative period: ( ) peep chosen by the peep titration procedure (titrated peep); ( ) peep set at cm of h o (peep ). a chest ct will be performed one hour after extubation. a density range of − to + hounsfield units (hu) was used to define atelectasis. results: thirty nine patients have been recruited. the median of titrated peep was (iq - ) (table ) . a weak correlation between bmi and titrated peep (r = . ) is shown in figure . lung compliance was significantly lower and driving pressure was significantly higher at baseline, with peep = and before rm, when compared to same measures using titrated peep during peep titration (table ) . during surgery, compliance (p < , ) and driving pressure (p < , ) were also significantly different between peep and titrated-peep group ( figure ). lung collapse evaluated through lung ct after extubation presented less non-aerated lung tissue in patients submitted to mechanical ventilation under eit-titrated peep. conclusions: in this sample of patients, the individualized value of peep titrated by eit had a great variability. peep titrated by eit was able to reduce both lung collapse and driving pressure. introduction: lung protective ventilation strategies could improve clinical outcomes in patients undergoing surgery. these strategies did not include specific goals for oxygenation. there is increasing recognition of potential harmful effect of hyperoxia in critically ill patients. however, little is known about current oxygen management during surgery. objectives: to describe current oxygen administration during general anesthesia in japanese hospitals. methods: a multicenter cross-sectional study was conducted. we screened all consecutive adult patients (≥ years) who received general anesthesia from to september or from to november at the participating hospitals (each participating hospital could choose whichever was more convenient). ventilator settings and the corresponding vital signs were collected hour after the induction of general anesthesia. we investigated the prevalence and risk factors for excess oxygen exposure ( . ± . . ± . . ± . ± . driving pressure with titrated peep (cmh o) . ± . . ± . ± . . ± . fig. (abstract a ) . driving pressure background:. acute kidney injury (aki) is common and is associated with significant morbidity and mortality after liver transplantation (lt). although the creatinine value is highly specific to estimate renal dysfunction, an inadequate sensitivity of creatinine level is demonstrated, particularly in early stage aki. cystatin c is founded to be a stronger predictor of the risk of cardiovascular events and death than creatinine. we aimed to determine whether pretransplant serum levels of cystatin c predict -day major cardiovascular events (mace) and all-cause mortality in lt recipients with normal serum creatinine values. methods: between may and october , consecutive lt recipients (mean age: years; % male; % living-donor lt) who have pretransplant creatinine level < . mg/dl were retrospectively evaluated. the -day mace was a composite of troponin i > . pg/ml, arrhythmias, congestive heart failure, death, cerebrovascular accidents. results: there was a . % -day mace event and . % of lt recipients were dead during a median of . years follow-up. mean values of cystatin c and creatinine were . ± . mg/dl and . ± . mg/dl, respectively. the risk for a -day mace event increased significantly with increasing quartiles of cystatin c; hazard ratios ranged from . to . for the highest versus the lowest quartile (p < . for trend). the kaplan-meier curves showed that the highest quartile (cystatin c > . mg/dl) had a significantly worse survival rate than the lowest quartile (cystatin c < . mg/dl) (logrank p = . ). however, pretransplant creatinine level showed neither increasing mace event rate nor worse survival rate with increasing quartiles of creatinine values (p = . for trends, log-rank p = . , respectively). conclusions: our results demonstrate that pretransplant cystatin c levels were significantly and progressively associated with -day mace and all-cause mortality in lt recipients with normal serum creatinine values, in contrast, the creatinine levels were not significant and gradual predictor of adverse clinical outcomes. were decreased (p < . ), and prevalence of postoperative aki was increased (q : %, q : %, q : %, q : %, respectively, p < . ). odds ratios for aki ranged from . to . for the highest versus the lowest quartile (p < . for trend). on the multivariate logistic analysis, low map was an independent risk factor of the postoperative aki (p < . ), after adjusting factors of age, sex, body mass index, diabetes, hypertension, creatinine, qtc interval, meld score, b-type natriuretic peptide, beta blocker uses, intraoperative red blood cell uses, postreperfusion syndrome, and cyclosporine uses. conclusions: our results demonstrate that pretransplant low map was significantly and progressively associated with the postoperative aki in lt recipients with normal serum creatinine values, therefore, our findings may assist in determining the optimal perioperative management of patients to prevent postoperative aki. introduction: patients undergoing cardiac surgery often develop, in the post operative period, pulmonary impairment and abnormalities gas exchanges ( ) . lung ultrasound (lus) examination may detect main pulmonary abnormalities at the bedside of the patient ( ). to increase bronchial drainage and help lung reaeration, physiotherapy treatment is daily applied starting from the first day after cardiac surgery. objectives: our study was to evaluate if physiotherapy treatment was able to induce changing in lung ultrasound pattern in the postoperative patients. compared total loss of aeration, before and after treatment, we identified a significant increase of rearation after physiotherapy (p = , ) evaluated with wilcoxon test. conclusions: our results confirm an elevate rate of loss of aereation in patients after cardiac surgery. physiotherapy may induce increase of reareation when evaluated with lus even thought it is not able to reduce consolidation. introduction: the therapy of malignant liver diseases has changed over the last years. during this period the frequency of liver resection has increased with great improvement in morbidity, mortality and long-term survival. [ ] thereby, the duration of liver transection and the amount of perioperative blood loss are of great importance for postoperative recovery time and therefore they are measures for choosing the optimal resection method. [ ] furthermore, the release of cytokines, chemokines, and stress hormones correlates with postoperative infection and organ dysfunction [ ] . to minimize cell damage and limit apoptotic cell death the so called heat shock response is initialized by various body cells as countermeasure to increased stress levels [ ] . moreover, pittet et al. showed a positive correlation between the small heat shock protein (hsp ) serum levels and survival after severe trauma. [ ] objectives: measurement of hsp could give an insight about pathological mechanism and their counter regulations of the liver. furthermore the hsp serum level should be correlated with the transection speed of the two resection methods cusa and stabler. . immediately after collection, samples were aliquoted, snap frozen and stored at − °c until further analyzation. to quantify hsp in serum commercially available elisa kits from r&d (duoset ic) have been used according to the manufacturer's protocol. furthermore the duration of transection and the resection surface expressed as cm /s were recorded. results: during surgery a significant increase in hsp levels was detected in patients undergoing stabler hepatectomy or cusa resection (n = , p < . ). during postoperative icu stay, hsp concentrations decline to levels comparable before surgery. the transection speed was significant faster in patients undergoing stapler resection compared to the cusa method (p < . ). the mean length of icu stay after liver resection was in both groups days. conclusions: our data show increased levels in serum of hsp , which might reflect the body's countermeasure to increased systemic stress levels during hepatectomy. moreover the hsp levels are in both groups equal high during surgery even though the resection conducted with the stabler is significant faster than cusa. introduction: performing laparoscopic surgery using carboxipneumoperitoneum usually accompanied with a moderate increase of the concentration of carbon dioxide at the end of expiration, as well as higher peak airway pressure that easily manages to compensate by the correction of ventilation parameters. in the postoperative period marked a fairly long recovery of baseline respiratory function associated not only with the post-operative pain, but with the restriction of the lung as a result of intraabdominal hypertension. objectives: assess the impact of prolonged pneumoperitoneum during laparoscopic surgery on respiratory function and to follow the dynamic of its rehabilitation. the study included patients ( men and women) in the age of . years (min , max ), operated in moscow municipal hospital № . the volume of surgical procedures: gastric resection (n = ), gastrectomy (n = ), pancreatoduodenal resection (n = ), hemicolectomy (n = ), resection of the sigmoid colon (n = ), anterior resection of rectum (n = ). depending on the surgical access patients were divided into two study groups: st -basic -(n = ) group -laparoscopic procedures, nd -control -(n = ) group of traditional laparotomy. all patients were under equal anesthesia during surgery: combined general anesthesia (sevoflurane + fentanil) and epidural infusion of . % ropivacaine solution, as well as myoplegia; postoperative multimodal analgesia: nonsteroidal anti-inflammatory drugs, antispasmodics, epidural analgesia. a study of respiratory function was carried out in four stages: -before surgery, - nd, - th, - th day after surgery. results: in patients of both groups to the second stage of study determined a significant reduction of volume parameters of respiratory function (vc, fvc, fev, fev , mef, mvv etc.). for example vc decreased in patients of group by % against the initial values, and % of patients in group (dynamics presented in the diagram). similarly changes in vc there is a decrease of all volume parameters: fev for the second phase decreased by . % in group and % in group ; mef decreased by . % and . % in the first and second groups, respectively. however, in addition to a statistically smaller decrease in the absolute values of volumetric parameters of respiratory function in the st group, we found them more intense recovery. conclusions: reducing the volume indicators of respiratory function after extensive laparoscopic surgery is less than after similar in volume laparotomy. recovery of acquired restrictive respiratory disorders is more intense and after laparoscopic surgery. at the same time in either group studies we have not observed a complete rehabilitation the initial levels of respiratory parameters, even after days after surgery. introduction: critically ill patients sometimes need laparoscopic surgery. it has been reported that steeped head-down position could increase intracranial pressure during robotic surgery. but we don´t know whether mild trendelenburg position and carbon dioxide pneumoperitoneum cause intracranial hypertension. we conducted a prospective observational study. objectives: the aim of our study was to investigate the change of optic nerve sheath diameter (onsd) in head-down position during carbon dioxide pneumoperitoneum. methods: we included patients scheduled to undergo laparoscopic gynecological surgery. exclusion criteria were ocular disease and central nervous system diseases. onsd were measured mm sagittal behind the globe we assessed onsd after tracheal intubation (t baseline), after pneumoperitoneum and trendelenburg position (t ) and every minutes (t , t , t , t ). anesthetic management were standardized. results: twenty seven patients were enrolled in this study. four patients were excluded from analysis because it was difficult for us to measure onsd. the degree of head-down angle was . ± . . onsd is significantly higher than baseline after pneumoperitoneum and trendelenburg position ( figure ). conclusions: carbon dioxide pneumoperitoneum and trendelenburg position increased intracranial pressure even if the head-down angle was mild. introduction: monitoring the anticoagulant effect of unfractionated heparin (ufh) is mandatory. this monitoring can be done by the mean of the activated partial thromboplastin time (aptt) or by anti-xa levels measurements. compared with anti-xa levels testing, aptt is more frequently impacted by preanalytic variables and biologic factors (increased levels of acute phase reactants, consumption coagulopathy) often encountered among critically ill patients. we studied the agreement of both tests results in unselected critically ill patients. objectives: to study the agreement of both tests results in unselected critically ill patients. methods: aptt and anti-xa levels were simultaneously monitored in patients treated by continuous intravenous infusion of ufh. blood samples were drawn into sodium citrate tubes (greiner bio-one sas, france). aptt was measured with triniclot automated aptt reagent (tcoag, ireland) and anti-xa levels with bio-phen heparin (lrt) (hyphen biomed, france) . an aptt of - times the control and anti-xa levels between . - . iu/ml were defined as therapeutic. results: forty-four patients (mean age . ± . years; mean sap-sii . ± . ) were included. reasons for admission were medical in , surgical in . the indications for ufh therapy were atrial fibrillation ( ), venous thromboembolism/pulmonary embolism ( ), thrombophilia ( ), acute coronary syndrome ( ), arterial thrombosis ( ). paired measurements of aptt and anti-xa were performed on page of samples. linear regression analysis was used to evaluate the relationship between aptt and anti-xa. the correlation between aptt and anti-xa levels was low (r = . ) concordant aptt and anti-xa values were observed in ( . %) data pairs. aptt was discordantly high in ( . %) data pairs and discordantly low in ( . %) ones. considering anti-xa as gold standard, monitoring anticoagulation treatment by aptt leads to a high risk of misdosing. aptt is frequently impacted by biologic factors. although less commonly, anti-xa levels can also be influenced by biological cofounders. poor correlation between aptt and anti-xa could result from lterations in fii and fviii activity. conclusions: use of aptt and anti-xa levels to guide heparin therapy may lead to different estimates of ufh concentration in the same patient. both aptt and anti-xa have limitations when used for ufh monitoring and may not accurately assess anticoagulant status. further investigation (using thromboelastometry or thrombin generation assays) could be useful to determine the optimal anticoagulation testing protocol in critically ill patients. note: this abstract has been previously published and is available at [ ] . it is included here as a complete record of the abstracts from the conference. introduction: the severe capillary leak-induced respiratory and renal failure limit large-volume resuscitation with crystalloids and blood components. the combined use of low volumes of crystalloids and "damage control resuscitation" (dcr), a blood product resuscitation goal of a : : ratio of packed red blood cells (prbc), fresh frozen plasma (ffp) has recently been applied to obstetric patients in hemorrhagic shock. another important consideration is the association of ffp with the risk of transfusion-related acute lung injury (trali), a major cause of death after transfusion. this risk is not present with the use of prothrombin complex concentrate (pcc) as the antibodies responsible for trali are removed during the manufacturing processes. methods: our research involved patients with massive bleeding after cesarean section. patients were divided into groups: st group contained patients as a treatment of massive bleeding with coagulopathy was scheduled pcc in a dose of ml/kg ( iu/kg), packed red blood cells (prbc). nd group ( patients) received fresh frozen plasma (ffp) in a dose of ml/kg and prbc. basic infusiontransfusion therapy was administered according to the protocols of hemorrhagic shock treatment in obstetrics. evaluation of the functional state of the hemostasis system was carried out using lowfrequency pyezoelectric thromboelastography (lpteg) on admission to hospital and every hours after the patient´s admission until normalization of hemostasis state. results: according to lpteg indicators obstetric patients with massive bleeding has a statistically significant abnormality in all parts of hemostatic system: platelet aggregation -intensity of contact coagulation (icc), the coagulation -intensity of coagulation drive (icd), clot maximum density (ma) and fibrinolytic activity -index of retraction and clot lysis (ircl introduction: both anaemia and transfusion of red cells (as defined by who criteria) ( ) have been associated with adverse outcomes, and the potential for anaemia to be a marker of a greater disease burden is frequently raised in discussion. cohort studies of patients aged > years demonstrate that anaemia is associated with increased mortality ( ) . anaemia is also associated with a variety of morbidities in older people, being linked with an increase in hospitalisation, poorer physiological, physical and cognitive function, development of alzheimer´s and parkinson´s diseases, depression, falls and hip fracture rates. we aimed to investigate whether anaemia was associated with adverse outcomes, increased lengths of stay and increased overall mortality in our icu cohort. we also thought it would be interesting to know if there was a difference in haemoglobin level depending on the specialty in which the patients were admitted -hereby defining the physiology of their anaemic process. methods: we conducted a retrospective review of all patients over the age of years that were admitted to the victoria infirmary, glasgow between / / and / / using the wardwatcher national database. we looked at admitting specialty (medicine or surgical), haemoglobin at admission, length of stay and hospital mortality. results: patients were included in the analysis, however full data set was available for patients. the patients were more predominantly male with similar numbers in the medical and surgical groups. medical patients were slightly younger, but with higher physiology scores and mortality. there was no statistical difference between length of stay in intensive care between the two groups. medical patients had a higher admission haemoglobin but this did not trend with outcome or length of stay. (see table ) conclusions: interestingly, and not as expected, it seems that admission haemoglobin to intensive care is not associated with outcome in the elderly population. it is noteworthy that discussion continues in the literature regarding the definition of anaemia in this age group as the population used to generate the who criteria did not include any over ´s. admission haemoglobin levels did not seem to correlate with apache, length of stay or outcome. however, the medical patients with more likely chronic anaemic state had higher apache-ii scores, were younger with higher mortality than the surgical admission who were older, had better outcomes but were more significantly anaemic on admission to intensive care. introduction: because of the substancial morbidity and mortality provoked by massive bleeding, a protocol to guide treatment of this event in each hospital is required. objectives: the aim of this study was to determine whether implementation of the massive transfusion protocol (mtp) was associated with a change in clinical practice or mortality. conclusions: the number of patients is greater in post-mtp group and apache score is lower in the same group since we are warned of these patients at an early stage. there were no differences in clinical practice regarding the administration of blood and hemostatic products.no change in mortality could be documented using the protocol. we have not found any statistically differences probably in part due to the sample size. introduction: discontinuation of life sustaining treatments (lst) is an accepted approach for certain icu patients. there are different ways of limiting lst, and while terminal extubation (te) is one of them, it may lead to dyspnoea and respiratory distress, which can be regarded as morally troublesome. table shows the characteristics of the patients included. conclusions: denial of admission to an intensive care unit due to lst decisions was associated with a high morbidity and mortality. mortality, apache ii and charlson index were significantly lower in the group of patients refused admission to an icu with a non invasive treatment recommendation. introduction: donation after circulatory death (dcd), refers to the procurement of organs from patients whose death is diagnosed and confirmed after circulatory arrest. in the netherlands the timeframe for dcd to proceed is set at two hours. a considerable number of potential donors after circulatory death are lost because they do not die within the specified timeframe after withdrawal of life-supporting treatment (wlst). identification of those dying within hours after wslt results in efficient utilization of the organ procurement teams, hospital resources and above all fulfillment of family expectations. objectives: the aim of this study is to determine factors predicting time to cardiac circulatory death after wslt within hours. methods: in this single-center study we retrospectively evaluated potential and actual dcd iii donors. patients younger than years of age, and clinically brain dead patients in whom relatives requested a dcd procedure, were excluded. univariate logistic regression analyses were performed to establish the effect of different predictors. results: only ( %) converted into actual donor partly due to the fact that cardiac death did not occur within hours. univariate analysis showed an association between the following predicitors and death within introduction: family refusal of organ donation from dbd (donors after brain death) is a limiting factor of the whole donation process and plays an important role in shortage of organs available for transplantation. although croatia is a state with presumed consent when it comes to dbd (donors after brain death) organ donation, family is always informed about the possibility of organ donation after it is verified that the deceased is not registered in the non-donor registry. if the family objects organ donation, their decision is always respected. objectives conclusions: main reason for refusal of organ donation in our hospital is unknown wish or opposition of the deceased person. no family refused donation due to fear of organ trafficking which is an encouraging fact. although refusal rate in our hospital is %, which is higher than croatian average of %, we could not clearly identify contributing factors. we also could not confirm the hypothesis that additional education of transplant coordinators lowers refusal rate. a more detailed prospective evaluation is needed in order to further reduce refusal rate in our hospital. impact of brain injury (bi) and bi with brain death ( the course was aimed to spanish health professionals (nurses and doctors), with a total duration of . hours. it consisted of a small theoretical introduction followed by several workshops, which included: donor after circulatory death management protocol through high fidelity simulator, family interview, preservation and perfusion procedures with extracorporeal membrane oxygenation in animal models. the students sat a pre-course self-assessment -question test to evaluate their knowledge about cdcd. at the end of the course they filled out a survey, offering their opinion on different sections: content, usefulness, documentation and educational support, organization, duration and overall assessment. the score ranged between one, the most negative value, to . average score was analyzed. a survey was sent to students working in different hospitals to evaluate the impact of the course in the cdcd programs at their hospitals. results: students completed the course, their characteristics are in table . students did the pre-course test, with an average score of . points. filled out the survey, results plotted in table . feedback trough the after-course survey was received from students. % of the students worked at hospitals without a cdcd program, established after completing the course. % of these students considered that the course contributed to the development and implementation of cdcd program. all professionals who worked at centers where there was already a cdcd program felt that the course contributed to its improvement. conclusions: despite the fact that there was a high knowledge on the subject among the students, they showed interest and enjoyed the course. the course had a high impact because it helped improving and developing cdcd programs in several hospitals. we believe that this course, based on high-fidelity simulaton training, has been one of the factors that has promoted controlled donation after circulatory death in spain in the last years introduction: the demand for donor lungs thoroughly exceeds the supply.this situation and the application of a strict group of selection criteria, has made donor lung shortage a major problem. to overcome this scarcity, some studies have examined the possibility of using lungs from older donors with mixed results [ ] [ ] [ ] [ ] objective: using as a starting point the favourable clinical evolution of a recipient of a year old lung, we reviewed all of our donors from the last years that were dismissed strictly because advance age (> years) methods: retrospective (feb -jan ) and descriptive study. all donors of a spanish tertiary hospital were analysed. we selected all patients excluded for donation and reviewed their contraindication to serve as lung donors. demographic data and comorbidities, reason for icu admission, icu length of stay, respiratory parameters, days of mechanical ventilation, respiratory cultures and antimicrobial therapy were collected. results: during the period studied we identified potential donors that translated into real donors and only of them ( , %) served as lung donors. after analysing the ( , %) patients that were not considered as lung donors, we identified ( , %) that had been dismissed strictly because advance age. all patients studied were brain death donors. demographic data and comorbidities, reason for icu admission and icu length of stay are detailed on figure .last mean po /fio recorded was , ± (peep , ± , ) and last mean pco recorded was , ± , mmhg. median days of mechanical ventilation were ( - we recorded the main characteristics of the donors, the most important periods in the process and the evolution of liver receptors admitted to the icu. results: patients were admitted. the mean age was , ± , . most were male ( / ). reason for icu admission more frequent: haemorrhagic stroke ( ) . the icu stay until list decision was , ± , days. the cares at the end of life (list) were performed in the first four patients in the uci, and another patients in the operating room, intervening in all of them intensivists who had participated in the previous treatment. the time from extubation to significant hypoperfusion of organs (sbp < mmhg) was minutes, the time to cardiac arrest was , minutes, and to the beginning of the cold perfusión was , minutes. liver transplants were performed without complications in the icu, and the icu stay was days ( , ). the higher alt level was ± , . of the liver transplants are well and with functioning organ today (one died in hospital ward unexpected cardiac arrest). kidneys were obtained from these donors. the maastricht iii donors provide valid organs for transplantation and the intensivists play an important role both in the detection as in the development of care at the end of life. the first transplants had long functional prolonged warm ischemia, which has been reflected in graft function, but the performing of list in operating room, the ultrafast extractions and the presence of the receptor in the hospital are improving the viability of organs, so the results of the last donors are better. thus, maastricht iii donors must be considered today as an additional source of organs for transplantation. ( ), cisatracurium was administered at a constant and high posology without monitoring the depth of neuromuscular blockade. objectives: to assess if the monitoring of the train-of four (tof) and the management of cisatracurium posology by nurses according to an algorithm can ensure an effective neuromuscular paralysis and allow to decrease cisatracurium consumption during ards methods: we conducted a prospective study in medical icus. all the patients with a pao /fio < for more than hours and requiring a continuous perfusion of cisatracurium were included. neuromuscular blockade was monitored by a tof at the adductor pollicis. nurses followed an algorithm of adaptation of cisatracurium posology depending on the tof with an aim of / . the initial posology was based on the maximal doses recommended in anesthesiology and on the patient ideal body weight. this posology was increased and a bolus done each time that the tof was > . the interruption of nmbas was decided by physicians. the initial and final posology and the daily consumption of cisatracurium, the need of performing boli, the results of tof and the occurrence of adverse events such as patient/ventilator asynchrony were noted. effective cisatracurium consumption was compared to the theoretical posology that would have been administered if the patient had been treated according to the acurasys study protocol (i.e. , mg/h). we also evaluated the economic impact of the reduction of cisatracurium consumption. introduction: sepsis-associated acute respiratory failure is frequent, occurs early and is associated with significant mortality. with the increasing use of noninvasive techniques, timing of intubation can vary and may lead to a difference in outcome. objectives: the objectives of this study were ) to draw on practitioners' current practice and perspectives to understand and identify practice variation in intubation and ) to develop an explanatory theoretical model that demonstrates the relationship of various factors contributing to practice variance. methods: between march and july , using a grounded theory approach, we conducted semi-structured interviews with providers involved in intubation and audio recorded them. the interview guide focused on clinicians' perspectives on and practices of intubation in patients with sepsis and impending respiratory failure. results: eighteen interviews were conducted with intensivists, fellows, nurse-practitioners, respiratory therapists and registered nurses. intubation perspective and practice varied dependent on three domains: patient's characteristics, clinician's characteristics, and organizational structure. patient factors included nature of acute illness, underlying comorbidities, clinical presentation, and patient's values. clinician factors included background, training, experience and practice style. system factors included of standardized policies and protocols, hierarchy and team dynamics. although most clinicians agreed that intubation is needed in case of persistent respiratory distress, altered mental status, or shock, they disagreed on when to initiate it. in different contexts, intubation could be considered as preemptive (prophylactic), therapeutic ('just in time'), and as a rescue. assessment, reassessment, and time-limited trial off noninvasive techniques matter. based on these results, we propose a model regarding intubation in sepsis consisting of the steps in the decisional process, a classification of the categories of timing of intubation, and decisional context factors that impact the timing of intubation. conclusions: in patients with sepsis-associated acute respiratory failure, variability of intubation was a natural phenomenon and appeared case-driven. intubation timing should be adjusted based on explicit consideration of each patient situation, their fitness, the cadence and trajectory of their respiratory failure, the team's proficiency in providing noninvasive and invasive ventilator support, and emphasis on clear, frequent closed-loop communication of the treatment plan and rationale within the entire critical care team. ( ) . objectives: to determine the efficacy of rhtm in septic patients with severe respiratory failure. methods: we performed sub-analysis of a retrospective observational study (japan septic disseminated intravascular coagulation study, j-septic dic study), which was conducted in intensive care units in japan. among septic patients enrolled in this original trial, we selected septic patients with severe respiratory failure and compared patients based on rhtm treatment (rhtm group and control group). propensity score analysis was performed between two groups. outcome was the number of ventilator free days. results: patients (rhtm, n = , control, n = ) were analyzed in this trial. after adjusting for baseline imbalances by propensity score analysis, vfds increased significantly in rhtm group (rhtm group: . ± . days vs. control group: . ± . days, p = . ). conclusions: in this analysis, rhtm improved outcomes in septic patients with severe respiratory failure. we need further evaluation. results: during the study period, totally ards patients with pathologic diagnosis of dad were eligible for analysis. these patients were divided as mild (n = , . %), moderate (n = , . %) and severe ards (n = , . %) by berlin definition and the hospital mortality rate were not significantly different between these three groups ( . %, . % and . %, p = . ). according to the etiology, these dad patients were divided into known etiology group (n = , . %) and unknown etiology group (n = , . %), and the hospital mortality rate had no significant difference ( . % vs . %, p = . ). the known etiology group had higher percentage of male and lower pao /fio ratio than unknown etiology group ( . % vs . %, p = . ; . ± . vs . ± . , p = . ). the multivariable logistic regression revealed sequential organ failure assessment (sofa) score at the time of open lung biopsy was the only predictor of hospital mortality (odds ratio . , % confidence interval . - . ; p = . ). in terms of glucocorticoid treatment, there was no significant difference in glucocorticoid use, timing from ards to glucocorticoid use, dose and duration between survival and nonsurvival patients. conclusions: for the ards patients with dad, sofa score was the predictor of hospital mortality but glucocorticoid treatment did not improve the survival rate. introduction: ventilator associated pneumonia (vap) is a known complication of mechanical ventilation. aspiration of oropharyngeal secretions results in infection that leads to significant morbidity, mortality and cost . use of sub-glottic secretion drainage (ssd) devices have been shown to decrease both the incidence of vap and intensive care unit (icu) days , . there have been safety concerns associated with use of ssd devices and herniation of tracheal tissue into the suction port . a study in sheep showed significant tracheal injury associated with continuous suction . human studies have shown conflicting results regarding the risk of tracheal injury , . objectives: to determine the risk of tracheal injury using an ssd device versus a standard endotracheal tube. methods: patients undergoing tracheostomy in the icu were enrolled in the study. patients were intubated in the icu, operating or emergency room, pre-hospital, or referring hospitals. intubation conditions and duration of intubation were documented. at the time of tracheostomy, a bronchoscopy was performed and the presence and degree of tracheal injury were noted. patients were followed to hospital discharge and decannulation, otolaryngology consults, and discharge or death were recorded. results: patients were intubated with a malinckrodt evac ssd device and were intubated with a standard endotracheal tube. patients were found to have a tracheal injury ranging from mild erythema to severe ulceration; / ( %) in the evac group and / ( %) in the standard group (rr - . ; % ci . to . ). / ( %) patients were reported to have injury at the site of the suction port; were reported to have mild edema and erythema and had mild to moderate ulceration. of the patients with tracheal ulceration at the suction catheter port, were decannulated successfully without further complication and patient died prior to termination of mechanical ventilation. conclusions: there was no significant difference in the risk of tracheal injury with ssd devices compared to standard endotracheal tubes. the degree of injury was similar in both groups. a small introduction: vap rates in brazil are higher than those listed in europe and eua.no municipal hospital moyses deutsch since implemented the protocol, applied the five strategies to reduce vap, however we maintained vap density with little reduction and we never zero target . objectives.objective of the study was to examine the effect of healthcare improvement ventilation bundle institute in addition to focusing on three strategies : oral decontamination with chlorhexidine (odc), the head elevation and awakening daily in the incidence of vap in a unit intensive care. methods: the study was conducted in a -bed, medical-surgical icu. criteria for nosocomial pneumonia are those from the cdc. strategy was to implement the ihi's ventilator bundle , focused and optimized in the first three the goals were the icu team adhesion of % achieved in six month after bundle implementation and % after one year of follow up. these measures included five strategies to prevent ventilator-associated pneumonia: - °elevation of the head of the bed, -adequate sedation level (rass − a − ), -oral decontamination with chlorhexidine . %, -dvt/pe prevention and -peptic ulcer prophylaxis . from january on, the icu nursing staff and ict performed a daily checklist in order to observe the five issues accomplishment. if any item was found to be inadequate it was promptly corrected. results: in january and december , adhesion to the whole bundle was % and % respectively. vap density was proportionally lower to bundle adhesion in the same period, per ventilation/day and respectively. in we achieved zero vap in both semesters. conclusions: initial vap rates were extremely high even for brazilian benchmarks. although we could not implement expensive technologies like continuous aspiration of subglottic secretions, icu team and ict efforts were crucial for satisfactory results, as well the administrative board support, which turned this issue an institutional priority. our goals are to reduce even more, implementing ''ventilator bundle-getting to zero'' program, maintaining a continuum effort to sustain these results. introduction: ventilators-associated pneumonia (vap) and its prevention is a significant concern for ventilated patients in the acute care. objectives: to determine if the knowledge and awareness of "ventilator bundle" helped in the prevention of ventilator associated pneumonia in the patients admitted to hospital. methods: a prospective observational study that evaluated vap rates from august through october were evaluated. all the adult medical patients who were intubated and ventilated in medical wards from august through october in the year were included in the study. during the period of june to july the staff nurses were educated and made aware about the problem of vap and the use of ventilator bundle in helping to prevent this vap. patients who expired within hrs of admission, who were transferred to intensive care unit within hrs, and those who were diagnosed with pulmonary embolism or metastasis were excluded from this study. intervention. the concept of "ventilator bundle' was introduced after educating the nursing staff and the medical personnel through group discussions."chula ventilator bundle" is a package of evidence -based interventions that include: ( ) clean equipment and environment; ( ) hand hygiene and elevation of patient's head of bed to - degrees; ( ) use . % chlorhexidine as a part of oral care every hour; ( ) labor over weaning and extubation each day; ( ) aspiration precaution protocol. measurement. demographic data was collected from the patient data files. vap was diagnosed when it met the (clinical non-invasive) diagnostic criteria. incidence of vap and protocol compliant were calculated. results: a total of were on mechanical ventilator for a vary period of - days. average age was . ± . with . % of male. introducing the concept of "chula ventilator bundle to prevent ventilators-associated pneumonia" significantly reduced the vap rate per ventilator days from % to % in the medical group ( medical wards). it significantly reduced the incidence of oral cavity problem ( . ± . vs. . ± . , p = < . ). ventilator bundle compliance was . %. conclusions: however, ventilator bundle compliance was less than %, introducing the concept of "chula ventilator bundle" helped us to reduce the incidence of vap and the incidence of oral cavity problem. grant acknowledgment quality improvement center, king chulalongkorn memorial hospital introduction: patient-ventilator asynchrony is a mismatch between patient and ventilator inspiratory and expiratory time. it is associated with prolonged duration of mechanical ventilation (mv), increased need for tracheostomy and increased mortality. five main patterns of asynchrony are described, without universal agreement on definition. studies on patient ventilator asynchrony have quantified asynchrony at heterogeneous time points and during periods of various durations. in addition, most of these studies were of single centre type. objectives: the aim of the present study was to evaluate the factors associated with and the prognosis impact of asynchrony, according to two methods of quantification: visual inspection of airway flow and pressure signal and a computerized method integrating electromyographic activity of the diaphragm (eadi) as a maker of patient inspiratory time at the early phase of weaning. methods: ancillary study of a multicentre, randomized controlled trial comparing neurally adjusted ventilator assist to pressure support ventilation at early phase of weaning. airway flow, pressure and eadi were recorded during minutes , , and hours following inclusion. asynchrony were quantified according to two methods: ) "flow-and-pressure" based on the visual inspection of the flow and pressure signals ) "eadi-based" with analysis of the eadi signal in addition to the flow and pressure signals. asynchrony index (ai) was calculated as the number of asynchronous breaths divided by the total number breaths multiplied by . results: patients mechanically ventilated for days ( - ) were included, men ( %), aged ( - ) years, saps ii ( - ), % were mechanically ventilated for de novo hypoxemic respiratory failure. prevalence of ineffective efforts was higher with flow-and-pressure method than with eadi-based method. auto-triggering, doubletriggering, premature and late cycling were more frequently observed with eadi-based method than with flow-and-pressure method. ai and the total prevalence of asynchrony were significantly lower with the flow-and-pressure method than with the eadi-based method (table ) . no significant difference in term of gender, age, saps , charlson score or length of mv prior to inclusion was observed with severe asynchrony (ai > %) severe asynchrony was not associated with difference in term of hospital length of stay, duration of mv and day- mortality. icu length of stay determined by the flow-and-pressure method was shorter in patients with ai ≥ % ( ( - ) vs ( - ), p = . ). conclusions: the prevalence of patient ventilator asynchrony varies according the methods and definitions used to quantify asynchrony, which suggests the need for a consensus statement in asynchrony's definition. patient ventilator asynchrony was not associated with a poorer outcome. introduction: tracheostomy is a frequent procedure in intensive care units, in the us over the past decades utilization rose substantially, driven by surgical patients [ ] . the optimal timing for tracheostomy in critically ill patients remains a topic of debate. objectives: to analyse tracheostomy utilization and trends in an intensive care unit (icu) and to determine the impact of tracheostomy timing (early vs late) in critically ill patients on duration of mechanical ventilation, icu stay, overall hospital stay and mortality. methods: retrospective study including all critically ill patients who underwent tracheostomy in an icu from to . the sample was stratified in two groups, according to time of invasive mechanical ventilation until tracheostomy: early tracheostomy (≤ days) and late (> days). results: over the study period a total of tracheostomies were performed, representing , % of the admissions in the icu. tracheostomy was more common in medical patients ( . %). mean time until tracheostomy was days. there was no tendency in tracheostomy rates and timing over the years. early and late tracheostomy groups did not differ significantly by gender, age, sofa score and type of admission. in the early tracheostomy group there was a statistically significant reduction in the length of invasive mechanical ventilation ( days vs days, p < . ) and icu stay ( days vs days, p < . ), with impact in icu and hospital mortality. conclusions: early tracheostomy was associated with reduction in invasive mechanical ventilation days and icu stay, with possible implications in long term morbidity and health care costs. reinforcing that tracheostomy timing should be considered in the decision process, when evaluating risks and benefits. introduction: development of critical care medicine has been decreasing mortality of critical illness. however, - % of survivors suffer functional impairment or icu-acquired weakness (icu-aw). in order to address interventions in icu-aw, it is essential to know when icu-aw developed in addition to its incidence and risk factors. objectives: to assess the onset of icu-aw and its incidence and risk factors in the icu of tokushima university hospital. methods: prospective observational study. critically ill adults were enrolled when they were mechanically ventilated at least days. patients younger than years old, with neuromuscular diseases, central nervous system disorders, and pregnancy were excluded. after we determined feasibility of communication, medical research council (mrc) sum score was measured as soon as possible. when mrc score was less than , we diagnosed patient as icu-aw. basic profiles, underlying diseases, apache ii score, administration of neuromuscular blocking agents (nmba) and corticosteroids, and laboratory data were recorded. introduction: severe traumatic brain injury (stbi) remains as the most significant medical and social problem due to high prevalence and mortality, primarily among young and employable population. the leading problem of intensive care of stbi is the prevention and elimination of intracranial hypertension (ich). one of the methods of ich elimination is mechanical ventilation as a component of complex therapy. among the various methods and modes of mechanical ventilation high-frequency jet ventilation (hfjv) is particularly distinguished, which is enduring "the second birth". in hfv transpulmonary pressure and the pressure in airways is much lower than one during traditional methods, the negative pressure in pleural cavity is maintained during inspiration phase and spontaneous breathing. objectives: comparative assessment of efficacy of different modes of mechanical ventilation in patients with stbi. methods: we studied the cerebral perfusion during various modes of mechanical ventilation in patients with stbi. mean age was ± . the general status in admission was severe, glasgow coma score was ± . all patients had traditional intensive care with different modes of respiratory support: controlled mechanical ventilation -cmv (n = ); synchronized intermittent mandatory ventilation -simv (n = ); hfjv (n = ). the efficacy of all modes were assessed by arterial blood gases analysis (sao - - %, pco - . - . mmhg). intracranial pressure were measured invasively and was ± mmhg. all patients regularly had clinical and neurological examination, control of laboratory tests (common blood count, arterial blood gases, arteriovenous gradient of o (avdo ) and oxygen saturation in jugular vein (sjo ). cerebral hemodynamics was studied by transcranial dopplerography. the registered parameters were mean linear velocity of cerebral blood flow (vm), pulsatile index (pi) and overshoot coefficient (oc). results: there were significant differences in parameters of cerebral hemodynamics in various modes of respiratory support: cmv: vm - . most patients found mobilisation to be a positive experience and the beginning of their recovery. however, mobilization was described as a difficult component of the care, mainly due to pain, tiredness and dizziness. almost all patients commented on the benefits of participation in physiotherapy, which was verified by physical improvements and progression in their abilities. although most improvements discussed were physical, two patients also described the psychological benefits that occurred in the sessions. they reported that the physiotherapists 'built them up' and encouraged them. one patient described a mind shift that occurred once she had mobilised out of the bed. she described it as being able to see what she was capable of. it was described as a precious and muchneeded service, without which some patients felt they may not have survived or recovered as quickly. methods: this retrospective study was performed in a -bed medical icu in spain from to . all patients admitted to the icu during this period were included in the study. cci patients were defined as those with more than days of icu stay. data were collected in ways: review of a prospectively elaborated database, review of electronic records, and telephone survey evaluating the functional status of survivors, one year after their discharge from the icu. results: during the study period, patients ( females − %) were considered cci. the characteristics of these patients are shown in table . all the studied patients needed prolonged mechanical ventilation (median days), defined as > hours/day of ventilator support for > consecutive days. the follow-up period is drawn in figure . the in-icu mortality was %. in the first year, patients ( %) were alive. most patients improved their quality of life over a year, with approximately % of them displaying some help for dressing or to performing the transfer of themselves. symptoms of anxiety and depression improved during the first year, being present in up to % (of the patients), but in % if we refer to the presence of nightmares or hallucinations. % these patients were transferred (discharge) to a rehabilitation center and % needed hospital readmission within the follow-up period. conclusions: for cci patients in-hospital mortality rate is still high after discharge from the icu. however, more than one third of them are alive one year after their hospital stay and in an almost independent condition. efforts focused on early specific therapeutic strategies after icu admission to prevent the progress of the acute disease towards chronic critical illness and to improve the outcome must be explored. [ ] [ ] [ ] [ ] . at icu, . % had delirium, . % needed blood transfusion and . % renal replacement therapy. patients worsened in all parameters of the five dimensions of the eq- d after -days: the extreme problems level increased in the mobility dimension from . % at icu to . %, self-care from . % to . %; usual activities from . % to . %; pain/discomfort from . to . and anxiety/depression from . % to . %. the dependence observed in the katz index worsened in days when . % of patients were dependents before icu admission increasing to . % after days. about family members, . % were spouses and . offspring, their mean of age was . ± . years and . % had previous experience of icu. we observed that they presented more symptoms of anxiety ( %) and depression ( . %) at icu when compared days after ( . %) and ( . %), symptoms of anxiety and depression respectively. conclusions: the most common eligibility conditions of cci were sepsis followed by mechanical ventilation. we observed a great mortality on days and among survivors a worsen quality of life with more dependence in their activities of daily living. we also observed that family members suffered more while in icu stay. introduction: tracheostomy is a favored alternative option for providing prolonged mechanical ventilation and safety airway used for more than years. despite its numerous advantages, tracheostomy may have severe complications as being an invasive method for presenting respiratory tract patency. besides, the tracheostomized patients usually have prolonged icu stay, high mortality and morbidity arise from concomitant comorbidities. objectives: the aim of the study was to evaluate the frequency, patient characteristics, complications and the prognosis related with our percutaneous tracheostomy practice. methods: hospital electronic records and icu files of the patients with percutaneous tracheostomies performed in our bed anesthesiology icu were evaluated between january and december . ethic consent was obtained from local ethic committee. the patients who were discharged with home type mechanical ventilator or their relatives were contacted by phone for getting information about their health status or related complications. (tables and ) . conclusions: the blood serum sodium levels at admission, especially hypernatremia, may also be used as an independent predictor of outcome in the surgical critically ill patients. introduction: who estimates that the worldwide dengue fever incidence is about tens of thousands of cases every year. as taiwan is situated in the high risk subtropical region, dengue fever has virtually become a seasonal infectious disease. climate warming, demographic movement and the higher probability of increase in intermittent rainfall in recent years have added many factors unfavorable to dengue fever prevention. years of prevalence and the emergence of different types have also caused the risk of mortality for dengue fever to become relatively high.of the total , confirmed dengue fever cases in , there were deaths (with a mortality rate of . per thousand), marking the largest outbreak over nearly one decade in taiwan. objectives: analysis was conducted on the confirmed severe cases of dengue fever or dengue hemorrhagic fever reported to this hospital over the period between july and september , in terms of gender, age, history of chronic diseases, warning signs and diagnostic criteria for severe conditions. methods: retrospective case study was also conducted to identify risk factors in dengue fever and dengue hemorrhagic fever as well as predictors of death among dengue fever cases for statistical analysis. results: according to the results, those susceptible to infection concentrated on older people aged over (with an average age of ); in total cases had chronic diseases (with an average rate of . %), among which hypertension and diabetes constituted the majorities; and based on symptoms, fever accounted for . % while gastrointestinal bleeding was the most common at . %. of the cases, there were deaths, with an average apache ii score of . and an average mortality rate of . %. conclusions: this study shows that patients with chronic diseases aged over will have times higher risk of death if infected with dengue hemorrhagic fever. it is therefore suggested that older people aged over and patients with chronic diseases who are infected with dengue hemorrhagic fever must be closely monitored in clinical practice to pinpoint the best time for treatment and effectively reduce mortality rates. to sum up, effective use of knowledge about risk factors and prognostic factors in dengue hemorrhagic fever can help epidemic prevention organizations to focus their limited resources on high risk groups and increase the effectiveness of prevention. cardiorespiratory instability risk escalation patterns: an association study with risk factors and length of stay l. chen (fig. ) . % of them belong to "late onset" types whose risk escalated ≤ minutes before cri onset, but with different initial rr levels (low, medium and high). % of patients belonged to "early onset" type with gradual escalating risk starting about hours before overt cri, and % falling into a "persistently high" type. the mean rr during the first hours of sdu stay are . , . and . for "late onset" types; . for "early onset" type, and . for "persistently high" type, comparing with baseline rr of . for cri negative patients. the mean rr derived in the first -hours after admission is strongly associated with risk escalation patterns observed (p-value < . ), specifically, patients of "persistently high" type were more likely to have higher mean risk levels at sdu admission . risk escalation patterns were not significantly associated with age, cci or sdu los. however, they are significantly associated with hospital los (p = . ). conclusions: there is potential "risk stratification value" of vs collected during initial hours of sdu stay in predicting the cri risk escalation patterns later on, which may in turn predict hospital los. these insights may guide monitoring resource allocation for cri management. - . ] mmol/l and most of patients were on vasopressors therapy. coronary angiography was performed in / ( %) patients with a cardiac cause; continuous renal replacement therapy was initiated in out of the patients ( %) developing acute kidney injury during the icu stay. patients showed a full neurological recovery during the icu stay ( %) but only were still alive with intact neurological function at months ( %); / after ohca ( %) and / ( %) after ihca. eight patients ( %) with irreversible brain damage had organ function suitable for donation and were eventually explanted. conclusions: ecpr provided acceptable survival rate with good neurologic recovery in refractory cardiac arrest. these patients underwent several additional therapeutic interventions, which, in case of irreversible brain damage, could stabilize extra-cerebral organ function and potentially provide some available organs for donation. post-resuscitation treatment with inhaled argon improves outcome even after a prolonged untreated cardiac arrest in a porcine model introduction: after the initial success of cardiopulmonary resuscitation (cpr), the majority of patients die, mainly due to postresuscitation (pr) cardiac failure and ischemic brain damage. inhaled argon has shown neuroprotective effects in a porcine model of cardiac arrest (ca) of short duration. objectives: to investigate the effect of post-resuscitation treatment with inhaled argon on outcome in a preclinical porcine model of prolonged untreated ca and cpr. we hypothesized that argon would ameliorate post-resuscitation neurologic dysfunction. methods: the left anterior descending coronary artery was occluded in pigs ( ± kg), and ventricular fibrillation (vf) was induced. after min of untreated vf, cpr, including mechanical chest compression, ventilation and adrenaline administration, was performed for min prior to defibrillation. following successful resuscitation, animals were subjected to hr ventilation with (a) % argon - % o (n = ) or (b) % n - % o (n = ). hemodynamics were continuously monitored and systolic myocardial function (i.e. ejection fraction (ef), shortening fraction (sf)) was assessed by echocardiography. serial blood samples were obtained for blood gas, serum neuron specific enolase (nse) and plasma high sensitive cardiac troponin t (hs-ctnt) assays. animals were observed up to hr for assessment of survival and neurological recovery (cerebral performance categories (cpc) scale). results: twenty animals were successfully resuscitated and enrolled in the study (table ) . ventilation with argon did not have any detrimental effects on respiratory gas exchange during the hr ventilation (table ) . animals receiving argon showed a significantly lower heart rate and higher mean arterial pressure and stroke volume compared to controls during the hr of observation (table ) . animals treated with argon presented also a significantly better recovery of systolic myocardial function, as represented by the higher sf at hr compared to controls (table ) . nine of the resuscitated animals in the argon group survived for h in comparison to out of in the control group. animals treated with argon presented a significantly better neurological recovery (cpc . ± . ) in contrast to animals in the control group ( . ± . , figure ). lower circulating levels of hs-ctnt (median: ng/ml vs. ng/ml, p < . ) and nse (median . ng/ml vs. . , p not significant) were observed in the animals ventilated with argon compared to controls. conclusions: in this severe model of ca, post-resuscitation treatment with argon allowed for improved hemodynamics, myocardial function and neurologic recovery, without detrimental effects on respiratory gas exchanges. munich, germany, which is staffed with physicians working at a university hospital in the specialities anaesthesia or surgery. ( ) test if there is a difference between specialists and residents in pain treatment of trauma patients. methods: after ethics committee approval, retrospective analysis of the protocols of our prehospital emergency service location in munich, germany of - . statistical calculation was done using logistic regressions with stata (college station, tx, usa). results: documented trauma cases. trauma cases could be assessed for frequency of oligoanalgesia, which was present in of these cases (see figure , dashed frames), leading to an relative frequency of % of cases. there was no difference in frequency between residents and specialists (table ) . relatively more trauma cases where handed by specialists, while documentation of pain was better in residents (table ) . documentation of pain, however, was insufficient, since pain assessment at hospital admission was documented in % of possible cases of oligoanalgesia only. conclusions: frequency of oligoanalgesia in trauma patients seems to vary in different systems, since it was much lower in munich compared to switzerland ( % vs. %, respectively). there are several possible explanations: data from swizerland was from an air resuce service while our data is from a ground based system. second, in our system possibility of treatment by a specialist was much higher ( % residents in switzerland). third, documentation in our system was inadequate. theoretically, frequency of oligoanalgesia could increase up to % if all cases without adequate pain documentation were counted as oligoanalgetic. to assess appropriate numbers improvement in documentation is essential. of the attempted resuscitations were immediately unsuccessful, resulted in rosc ( sent to icu for post-resuscitation care, whilst remained on the ward). at hours (both in icu) were still alive. defibrillation was attempted in cases. intubation was attempted on occasions. in ( %) of the resuscitation attempts cpr was the only intervention reported while ( %) received more than vial of adrenaline, or defibrillation, and or intubation. interviewees reported that in ( %) of these patients they were 'not at all' or only a 'little bit surprised' by the patient having a cardiac arrest (fig ) . they further described the chances of a successful outcome as 'unlikely or very unlikely % of the time and likely or very likely only . % of the time (fig ) . conclusions: perspectives of junior doctors interviewed suggest many cardiac arrests were not a surprise and that the probability of rosc following attempted resuscitation was unlikely. there is high incidence of patients receiving cpr attempts before death in hospitals across sri lanka with dnar practices remaining uncommon. outcomes remain poor, with rosc after cardiac arrest being . % and survival at hrs . %. of the unsuccessful resuscitation attempts, defibrillation and or repeated adrenaline was reported in . % of cases. introduction: pro-coagulatoric effects after cardiac arrest and consecutively appearing microthromboses have been considered major contributors to morbidity and mortality after cpr [ ] . in contrast, recently published data suggest that - % of patients after out-ofhospital cardiac arrest (ohca) present with hyperfibrinolysis during and after cpr [ ; ] . the interpretation of these inconsistent observations remains unclear and complicated, because of methodological differences and lacking analytical approach in the underlying studies. fibrinolytic activation might be the physiological reaction to restore perfusion after hypoperfusion due to microthromboses. this leads to the question, if the duration of no-flow (time without chest compressions) after cardiac arrest influences the level of coagulation activation and subsequent fibrinolysis during cpr. objective: to investigate the influence of a delayed onset of cpr on the extent of fibrinolysis and the function of the coagulation system measured by rotational thrombelastometry (rotem). methods: after approval of the local authorities (nds. laves, approval g - ) cardiac arrest was induced in anaesthetized female göttingen minipigs via rapid ventricular overpacing resulting in ventricular fibrillation (vf). in order to simulate a bls-cpr in animals (cpr-group), chest compressions (cc) and ventilation were started after min of vf ( : -ratio, fio = . ). in order to simulate consecutive als-cpr, continuous cc ( min − ) and ventilations ( min − , fio = . ) were started minutes later. no cpr was started in the remaining pigs (non-cpr-group). blood samples for a complete rotem analysis (rotem delta® analyzer, tem int. gmbh, munich, germany) and laboratory analyses were taken before induction of vf (baseline) and , and min after vf. all parameters were investigated for normal distribution (shapiro-wilks-test). statistical significance of differences (p < . ) was investigated using the unpaired t-test (normal distributed parameters) and the mann-whitney-u-test (notnormal distributed parameters). results: figure summarizes laboratory and rotem results. in no group maximum lysis increased significantly after cardiac arrest ( figure ). maximum clot firmness (mcf) in fibtem analyses decreased significantly in both groups (figure ), but plasma fibrinogen levels (measured using the clauss method) remained stable. introduction: perception and knowledge of hospital staff involved in an emergency evacuation of hospitalized patients is usually low. this is especially remarked in an icu due to the complexity of moving patients who depend on invasive monitoring and organ support due to acute illness. objectives: to analyze the differences between different members of icu staff about their perception and knowledge of self-protection and evacuation plans. methods: a quantitative, descriptive and cross-sectional study was carried out by a fully structured and self-administered survey in public and private icu staff through a total sample of participants. they were asked to complete a questionnaire about their perception and knowledge of self-protection and evacuation plans in the icu. this study pretended to analyze the differences between participants, taking into account their demographic and occupational characteristics and their level of satisfaction and commitment to their jobs. results: on a rating scale from to , icus workers perceive that their preparation and knowledge were too low to meet a possible emergency that could require an evacuation, although they were aware of the need to make an update. however, they state that the different icus where they work do not have these plans, and, consequently, they do not feel prepared to act in an emergency situation, even though they think this type of situation may occur. the significant differences (p < , ) were observed when levels of satisfaction and commitment to their jobs were high. the results of this study showed that there is a need for more knowledge in the area of emergency training. this should be the basis for the development of educational programs and also promoting awareness of icu staff on self-protection and evacuations plans. integrating nurse practitioners and physician assistants in the icu: results of a national survey r. kleinpell rush university medical center, chicago, united states intensive care medicine experimental , (suppl ):a introduction: an increasing number of intensive care units (icus) are integrating advanced practice providers (app) including nurse practitioners (nps) and physician assistants (pas) to meet workforce demands to care for acute and critically ill patients. although these roles are established ones, limited information is known about the specific care models used in icu settings. this information is crucial in objectively evaluating the effectiveness of app roles. objectives: to address this gap, a national survey was conducted targeting nps and pas, including those working in icu settings. methods: a web-based survey was used to assess domains including role components (i.e. direct care management; care coordination; performing procedures; education; quality assurance; research); role responsibilities (i.e. practice autonomy, prescriptive authority, credentialing and privileging delineations) unit-level organization (i.e. physician staffing models, components of the multidisciplinary care team); and hospital organization (i.e. academic status, bed size, location, payer-mix). results: a total of apps responded to the national survey including nps and pas. the respondents reported working in a variety of settings including hospitals, clinics, urgent care centers and specialty practice sites. a total of reported working in an icu setting. of these, reported / coverage of acnps and pas in the icu. main role components included patient care management as part of the multiprofessional icu team; teaching to patients, families and healthcare staff; involvement in quality improvement and research initiatives and administrative components such as committee work. specific aspects include conducting history & physical exams, ordering and interpreting diagnostic test/labs; providing care coordination, performing specialty procedures such as wound care or other specialty care. major areas of impact that were identified included continuity of care, improving evidence based practice care, reducing hospital length of stay, preventing hospital readmissions and promoting patient, family and staff satisfaction. the results of the study provide information from a large national sample of nps and pas that identifies the comprehensive care components of the role as well as areas of impact, highlighting the value of app care. globally, this information can be useful to other countries who are considering use of nps and pas in the icu. national health care resources. with icu beds, the reserves of the system are often overwhelmed. the responsibility for a rational management and distribution of these costly resources burdens the admitting intensivist. intensivists not using protocols expressed a strong desire ( %) to introduce protocol based criteria for admission. conclusions: the most important factors influencing decisions about admission (or refusal of admission) in the icu are bed availability and prognosis of the underlying disease. socioeconomic and religious criteria are clearly of marginal significance. drug abuse and severe psychiatric disease do not emerge as compelling causes of biased decisions. it appears that the intensivist's decisions are largely individualized, as application of admission protocols is limited among the icus. however, the responses documented in this survey strongly indicate that introduction of such protocols would be welcome by a majority of our colleagues. conclusions: it is essential that non-cardiac surgery should be delivered in the most appropriate clinical setting. in scotland, adults with moderate to complex congenital cardiac disease are managed by the scottish adult congenital cardiac service (saccs), based at the golden jubilee national hospital (gjnh), near glasgow. [ ] existing guidelines have established when patients should have elective non-cardiac surgery performed at gjnh. however, many surgical specialties are not routinely available at gjnh, the bed occupancy rate is high and with an increasing saccs population there is a need for appropriate patients to receive optimal care at their base hospital. additionally, urgent and emergency non-cardiac surgery ought to be performed at the base hospital. while nitric oxide is a core cardiac therapy we have shown that it is scarce in scotland and unfamiliar to many icus. there is a need for a national discourse and consensus to ensure that nitric oxide is more widely available as part of a bundle of optimal cardiac critical care. this should include education, material resources, clinical guidelines and perhaps cardiac critical care outreach services to support general icus. introduction: scarcity of intensive care unit (icu) beds has long been a problem. among other things, it increases the work load of emergency department (ed), contributing to its crowding and probably to worst care, jeopardizing outcomes. despite the plausibility of this premise, studies aren't consensual about the impact on outcome of delayed icu admission from ed. hospital de são joão is a portuguese tertiary care center. ed receives around adult admissions per year, and is spatially organized according to manchester triage priorities. emergency room (er) receives patients from the street and all patients from other areas of the ed that need critical care. it is staffed by trained personnel and is equipped with level iii icu material. intensive care department is composed by level iii and level ii icu beds objectives: assess if there's a link between time spent in ed and outcome of patients admitted to level ii and/or iii icu beds. methods: this is a retrospective study analysing older than years old patients admitted to icu from ed from st january to st december . we excluded patients transferred from other hospitals. demographic and clinical data was collected from records. we selected hospital outcome (dead, alive, transferred), hospital length of stay, icu length of stay, vital status at and days after admission and ed and er duration as outcomes. simplified acute physiologic score (saps) ii and sequential organ failure assessment (sofa) were calculated by considering the worst values in the first hours of hospital admission. we performed a descriptive analysis, with median and interquartile ranges presented for continuous variables and proportions for categorical variables. for analysis of subgroups we did a chisquare or mann-whitney test. statistical analyses were done on ibm-spss (version ). a p-value of < , was considered significant. results: adults were assisted in ed in this period, with a median length of stay of minutes. were admitted to icu beds, which accounts for , % of all adults cared for in ed. around % of patients admitted in icu were treated in the er at some point of their ed care. patients admitted to icu stayed around minutes in ed. the more severe the disease, the least time spent (p = , ). patients treated in er were significantly more likely to be admitted quickly in icu (p < , ). taking in consideration the time spent in the ed, we found an opposite relation with global outcome, meaning that patients staying longer periods in ed had lower icu mortality and lower length of stay in icu. there was no association with hospital mortality. conclusions: time spent in ed had no negative impact on outcome. however, given the fact that the majority of patients admitted to icu beds were cared in a devoted area with trained staff and full level iii equipment, we hypothesize that what might impact the most on outcome is provision of early critical care. determination of icu bed requirement using resampling k.k. introduction: planning for icu-bed provision, with a statistical confidence level, required the average number of critically-ill patients, their average icu length of stay (los), and the fluctuation/variance of these two parameters. the actual icu bed occupancy would under-estimates the variance, as icu could never exceed its full capacity. with an under-estimate, the predicted icu bed requirement would be inaccurate, with a tendency of under estimation. objectives: estimate the bed requirement to cover . % of time, by resampling of admission/discharge entries in , for the two busiest icus in hong kong (~ admissions/year each) methods: we assumed that the chance of an icu admission was identical in a period of four weeks before and after a certain date. based on this assumption, a computer simulation of icu admissions was performed as if the year happened again. in brief, we pooled patients admitted on a particular date in , and those admitted on the same day of week in the previous four and subsequent four weeks. then patients were randomly selected from the pool to simulate icu admission on that particular date. a mechanism (not described here) was in place to handle the public holidays. the hourly icu occupancy was calculated using the actual icu los of the selected patient. re-sampling for the whole year was repeated times to provide the estimates required. results: the actual hourly medians of icu occupancy were % and %. they were close to that obtained using resampling ( % and %). as predicted, the distributions of the actual occupancy were skewed to left, indicating a negative bias on the variance estimates. the observed standard deviations of the two icus' occupancy were . % and . % respectively. after resampling, the distributions became more symmetrical, and had higher standard deviations of . % and . % (both p = . ). the . percentile occupancy in reality were % and %, while that from resampling were significantly higher at % and % (both p = . ). this corresponded to three or four additional icu beds in each icu. conclusions: in conclusion, using a simple and conservative assumption, resampling could provide valuable insight for icu bed planning. introduction: the number of available intensive care unit (icu) beds are limited while the request for the beds are high. thus rationing the admission to icu is necessary especially in developing countries where the resources are limited. also models are needed to estimate and re-estimate regularly, shortage in the number of icu beds in any hospital. in the current study we tried to design a model for estimating shortage in the number of intensive care beds in a developing country tertiary university hospital after an initial delphi consensus study. objectives: designing a model for estimating shortage in the number of icu beds in a hospital. methods: initially the standard indications for icu triage were extracted from the literature. four intensivists were served as steering committee and the initial questionnaire were further prioritized by experts with three rounded delphi method and formed a standardized checklist for icu triage. indications were considered as critical, important, and all indications. then a cross-sectional study being performed during a -month period from august to september for all admissions to nemazee hospital, a tertiary healthcare center affiliated to shiraz university of medical sciences. cardiac, transplantation and pediatrics patients were excluded from the study, as to be studied separately. the checklist were filled every day by an observing physician and any indications for icu admission were marked in the questionnaire. decision making for requesting icu admission were performed by the specialized physicians of each ward regardless of the results of completed checklists.the results were further assessed according to the mentioned criteria and the reliability and viability was calculated. finally assuming that there was no available icu bed-days, the required icu bed-days were compared with the total icu bed-days of the hospitals, to estimate the shortage of icu beds. results: totally patients were admitted and studied.the required bed-day regarding critical indications, important indications, and all indications for icu admission was , , and . by comparing the required bed-days with available bed-days of the hospital, beds were calculated as shortage of icu beds. the results of the current study indicate that our center has deficiency in the number of icu beds. it seems that a checklist is not only useful for prioritizing patients but also it is useful for estimating the required number of the icu beds.the actual number of shortage is greater as three group of patients were not included. transfer delay from intensive care unit: retrospective analytical study in an indian tertiary care hospital s. k introduction: there lies scarcity of intensive care unit (icu) beds in every tertiary care hospitals, and on top of it delayed transfer of patients from icu to wards is further increasing the burdensome. numerous factors affect in making delayed transfer, which in itself is a risk factor for patient related morbidity and mortality, especially the after hour transfers. objectives: the aim of the study was to analyze the hours of transfer delay and their effect on readmission rates in the icu. methods: we conducted a retrospective study of patients transfer from our icu to the wards over last one year (jan-dec' ).data collected from the icu database by the secretarial staff during the study period and divided into following categories of transfer delays: results: there were patients admitted to our icu during the study period of which patients were shifted to the wards. the average delay in shifting was around . hours ( - . hrs).delayed transfer of more than hrs was found in % patients and the percentage of after-hours transfer was % of the total transfers. there were readmissions into the icu within hrs of shift out among patients transferred in after hours as against in patients transferred during routine hours. conclusions: prevalence of delayed discharge from icu was significant, especially the after hour discharges, which has got an impact on readmission rate as well. discharge delay should be considered as an important quality indicator for critically ill patients to decrease the morbidity and mortality in icu patients. further studies are warranted to identify factors associated with delayed discharge. introduction: critical illness (ci) and stay in an intensive care unit (icu) are known to induce physical and functional changes. bone is often forgotten in survivors. limited published data reported an altered bone metabolism in case of prolonged icu stay [ ] and a decreased in bone mineral density (bmd) in the year following icu admission [ ] . clinical impact of these changes is still not well described. objectives: our retrospective study aimed to assess incidence of any new bone fractures (bf) two years after a severe ci. methods: patients admitted in our icu during were screened. adults > years (y) old with an icu length of stay (los) > days (d) were included. lost to follow-up were considered exclusion criteria. patients who died in icu or who died during the follow-up period (fup) with an icu los ≤ d were also excluded. demographic data, medical objectives: pulmonary arterial hypertension (pah) is associated with reductions in health-related quality of life (hrql). the patient care still played an important role in improvement of hrql, even though more drug therapy was identified in recent decade.. in this study, we investigated to provide quality care for patients with pulmonary arterial hypertension via multidisciplinary care model. methods: a multidisciplinary team was organized.in a tertiary medical center, including intensivists, cardiologists, pulmonologists, cardiac surgeons, rheumatologists, chest surgeons, rehabilitation physicians, psychologist, pharmacologists, hospice care physicians, nutritionist, social workers and nursing staffs. the key interventions include home based rehabilitation therapy, hours hot line care, pah care nurse training program, hospice care information and consultation, phychological care and autogenic training, prompt pah referral system, social care connections, on-line self pah risk assessment system, on-line and innovative mobile apps patient instructions, facebook patient care group and ourdoor pah patient education program. the pah patients were divided into three groups: pre-interventional group from may to dec , interventional group from jan to june and post-interventional group from july to feb . hrql was measured using the short form health survey (sf- ) in all enrolled subjects. results: the average physical compartment scale of sf- , including physical functioning; role limitations due to physical health, pain and general health improved from ± in pre-interventional group, to ± in interventional group and to ± in post-interventional group (p < . ). the average mental compartment scale of sf- , including role limitations due to emotional problems, energy/fatigue, emotional well-being and social functioning, improved from ± in pre-interventional group, to ± in interventional group and to ± in post-interventional group (p < . ). conclusions: the study demonstrated multidisciplinary care model could improve hrql of patients with pulmonary arterial hypertension. blood pressure management with urapidil for patients with aortic dissection is associated with less esmolol usage than nicardipine j.-c. zhou sir run run shaw hospital, intensive care medicine, hanghzou, china intensive care medicine experimental , (suppl ):a introduction: acute aortic disease is a common but challenging entity in clinical practice. titration the blood pressure and heart rate to a target level is of paramount importance in the acute phase regardless of whether the patient will undergo a surgery or not eventually. in addition to the initially intravenous β-blockers, parenteral infusion of nicardipine and urapidil are the most common used antihypertensive therapy currently in mainland china. however, few empirical data was available with respect to the different effect on patients' outcome of the two antihypertensive strategies, especially given the deleterious reflex tachycardia of vasodilators which may increase force of ventricular contraction and potentially worsen aortic disease. objectives: to evaluate the difference of the abovementioned two antihypertensive strategies on the outcome of patients with aortic disease. methods: all patients with new diagnosed aortic diseases presented to our hospitals from january , to june , were retrospectively reviewed. the antihypertensive strategies and their association with patients' outcomes were evaluated with logistics regression. results: a total of patients with new diagnosed aortic disease were included in the study. of them, patients received urapidil while patients received nicardipine antihypertensive therapy. patients with nicardipine were more quickly to reach the target blood pressure level than those treated with urapidil (median vs mins, p = . ). after adjustment for patient demographics, comorbidity, involved extend of aorta, interventional strategies, antihypertensive therapy with nicardipine (with urapidil as reference) for patients with aortic disease was significantly associated with high esmolol cost (or: . , %ci: . - . , p = . ) and longer icu length of stay (or: . , %ci: . - . , p = . ). however, there was no significant correlation between nicardipine use and icu mortality (or: . ; %ci, . - . , p = . ). conclusions: although nicardipine achieved the target blood pressure level more quickly than urapidil for patients with aortic disease, it was associated with more esmolol use and longer icu length of stay. introduction: postoperative bleeding is one of the most common complications of cardiac surgery. excessive perioperative bleeding continues to complicate cardiac surgery with cardio-pulmonary bypass (cpb) in spite of improvements in extracorporeal oxygenation and surgical techniques. even bleeding after cardiac surgery has variable causes, we thought the applying isth scoring system may be able to predict the postoperative excessive blood loss in patients after cardiac surgery with cpb. objectives: the aim of present study was to examine the effectiveness of international society on thrombosis and hemostasis (isth) scoring system in patients with cardiac surgery. methods: the medical records of patients undergoing elective cardiac surgery using cpb between mar. and feb. were retrospectively reviewed. these demographic and clinical characteristics, perioperative laboratory findings, and postoperative complications were assessed using computerized databases from our institution. isth score was calculated in icu and patients were divided with overt dic group and non-overt dic group. results: among patients with cardiac surgery, patients with overt dic group (n = ) or non-overt dic group (n = ) were enrolled. mean dic scores at icu admission was . ± . (overt dic group) and . ± . (non-overt dic group) and overt dic was induced in % ( / ). overt dic group had much more ebl for hrs (p = . ) and maintained longer time of intubation time (p = . ) conclusions: in spite of limitation of retrospective design, management using isth score in patients after cardiac surgery seems to be helpful for prediction of the post-cpb excessive blood loss and prolonged tracheal intubation duration. renal failure, . % vs %, p ≤ , ; respiratory failure, . % vs . %, p ≤ , ; mechanical > h . % vs . %, p ≤ . ventilation. the variables that reached statistical significance in the multivariate analysis as predictors of mortality were apache ii or . ( % ci . - . ), p = . , euroscore or . ( % ci , - . ), p < . ; acute respiratory failure or . ( % ci . to . ), p = . ; acute renal failure or . ( % ci . - . ), postoperative bleeding or . ( % ci . to . ), p < . conclusions: mortality in this group is similar to other series, being patients with more comorbidities, with the highest score in the euro-score and apache ii and more often subjected to mixed surgery. the euroscore, apache ii, respiratory failure, renal failure and postoperative bleeding, predict higher mortality. methods: we measured rea as ratio of pulmonary pressure at the dicrotic notch (dypap) and stroke volume (sv) [ ] and rees as ratio of the difference between mean pulmonary artery pressure (mpap) and wedge pressure (pcwp) and end systolic volume (resv) (mpap-pcwp/resv) [ ] after the induction of anaesthesia (t ) via pulmonary artery catheter (swanganz f and vigilance ii monitor by edwards lifesciences), after weaning from cpb (t ) and h after in icu(t ) in patients. results: measure of rvac has been demonstrated feasible in all four patients undergoing cardiac surgery. as expected all the patients were found uncoupled (rvac > ) before surgery, immediately after weaning from cpb rvac worsen and in icu it was restored to the basal. conclusions: in this preliminary analysis we demonstrated the feasibility of measuring rvac in critical patients undergoing cardiac surgery, to our knowledge this is the first report in this field. as expected rvac is very much influenced by cpb although further investigation is needed to confirm the utility of this technique to monitor the right heart in such patients. introduction: detection of tissue hypoperfusion is paramount in the management of va ecmo. arterial to pulmonary artery co difference has been demonstrated to be an early marker of hypoperfusion in the shock patient [ ] and during hypothermic cardiopulmonary bypass [ ] , objectives: in this report we investigated the accuracy and feasibility of mixed venous to arterial co difference as an early marker of perfusion mismatch during va ecmo. methods: in a patient treated with va ecmo for refractory cardiac arrest due to acute myocarditis we performed serial measurements of pulmonary artery to arterial co difference as well as svo , map, urine output and lactate level. results: during reduced perfusion periods, assessed by elevated lactacidemia (> mmol/l) we observed high > co difference which is concordant to literature [ ] . during episodes of reduced systemic perfusion, demonstrated by increase of serum lactic acid we were able to early detect hemodynamic derangement (avg minutes) by identifying elevated (> mmhg) co difference. conclusions: this case report underlines the importance of pulmonary artery to arterial co difference as an early marker of hypoperfusion if compared to lactate level in the intensive care unit. to our knowledge this is the first report on venous to arterial carbon dioxide difference in va ecmo. further investigation is needed to confirm those preliminary results. introduction: many studies have shown clinical benefits from sdd for critically ill patients. however, there is still doubt concerning the emergence of antimicrobial resistance in the long term. previously no evidence to support this view was found but long-term effects of sdd on antimicrobial resistance on the unit level is understudied. , objectives: to determine the incidence of antimicrobial resistance in aerobic gram-negative potentially pathogenic micro-organisms (agnbs) to the components of sdd and frequently used i.v. antibiotics on icu-level over a year period with unchanged antibiotic policy. methods: this is a single-center observational cohort study in a dutch -bed adult intensive care unit in a teaching hospital. all consecutive patients admitted to the icu between january and december were included when at least one culture was taken during icu-admission. data on all cultures taken during icu stay were collected from the hospital database. susceptibility testing was performed following the guidelines of the 'clinical and laboratory standards institute' (csli) until and 'the european committee on antimicrobial susceptibility testing' (eucast) from until . incidence rates of antimicrobial resistance to tobramycin, ciprofloxacin, polymyxin b or cefotaxime were calculated per year. only icuacquired resistant pathogens were selected by excluding resistant pathogens in cultures taken on day -day . patients at risk were defined as all admissions with a length of stay longer than days. differences between the incidence in the first and last year of the study were tested using chi-square test. results: data of . cultures was analyzed containing . agnbs. the number of admissions with a length of stay more than days was . in admissions newly acquired resistance to cefotaxime was found, in to polymxin b, to tobramycin and to ciprofloxacin. figure presents incidence rates per year. in - date of discharge to the ward was unknown and therefore incidence rates could not be calculated for these years but absolute numbers were comparably low. there was no significant difference in incidence of icu acquired resistance in cefotaxime (χ = . , p = . ), polymyxin b (χ = . , p = . ), tobramycin (χ = . , p = . ) and ciprofloxacin (χ = . , p = . ) between and . conclusions: the incidence of newly acquired agnb resistant to cefotaxime, polymyxin b, tobramycin and ciprofloxacin continues to be low during a year unchanged antimicrobial policy of sdd. the increase in resistance in the society may impact these numbers and should be studied. results: overall, icu and h mortality rates were and %. . % of the pts ( / ) became infected in the early postoperative period. (icu and h mortality rate and % respectively). crpk infections were present in pts ( . % of the entire series, . % of the infected pts). sarcopenia ( % vs %, p = . ) and meld ( + vs + , p = . ) were significant preoperative risk factors. icu and h mortality rates were % and % in crpk pts, % and % in non -crkp infected pts respectively : while icu mortality was not different (p = . ), h mortality was significantly higher in crkp pts (p = . icu vs h, ci . - . ). if compared to non -crkp pts , crkp pts were more often in septic shock ( % vs %, p = . ) and more frequently underwent crrt ( % vs % p = . ). intraabdominal infections were largely represented ( %) among crkp pts. blood loss and transfusion needs, early gratt dysfunction and reolt were more represented in infected vs non infected pts. however, no differences were found when crkp and non-crkp transplanted pts were compared. conclusions: crkp infections are on the rise also in italy. post olt mortality is high and strategies able to control crkp are urgently needed to be implemented. introduction: the prevalence of antibiotic-resistant pathogens in icu conditions makes it difficult to treat these infections, and treatment becomes impossible in some cases. acinetobacter baumannii is important infectious agent icu patients, which effective antibiotic therapy is currently limited. objectives: we aimed to determine the range of a.baumannii associated infections among icu patients, to summarize the level of resistance to antimicrobial drugs, and provide an overview of strategies to prevent the spread of resistance. methods: a prospective microbiological study of the prevalence and antibiotic resistance of a.baumannii strains isolated from adult icu patients hospitalized to the tertiary hospital after cardiac surgery from to . results: a total of isolates from icu patients were included to the study. . % of the isolated strains ( ) were gram-negative, among which . % ( ) of a.baumannii isolates. strains of a. baumannii showed a high level of resistance to the iii generation cephalosporins ( . % to ceftazidime, . % to cefotaxime, . % to ceftriaxone). resistance to carbapenems was at %. investigation of antimicrobial activity of ciprofloxacin showed the resistance in . % of strains, to levofloxacin - . %. the lowest level of resistance recorded to doxycycline - . % and polymyxin - . %. conclusions: rapid microbiological diagnostics (including the results of antibiotic resistance), strict adherence to infection control, the appointment of an effective regime of antibiotic therapy, optimization schemes appointment of antibiotics, all of which are the most important priorities for the effective fight against a. baumannii associated infections in icu patients. in order to reduce the emergence and spread of drug-resistant strains in the icu, it is strongly recommended to carry out microbiological monitoring and optimization of the use of antibiotics in each hospital. therefore local resistance surveillance programs have the greatest value in the development of appropriate therapeutic recommendations for specific types of patients and infections. introduction: acinetobacter spp. are opportunistic, nosocomial pathogens that may colonize the surfaces in intensive care units. their tendency to harbor multi-drug resistance and to develop resistance mechanisms to commonly available drugs make their treatment a challenge. carbapenem resistance, and newly reported colistin resistance has led to a search for new treatment options. there are in vitro studies which report synergistic effect with rifampicin in combination therapies. objectives: we aimed to present and discuss the results of our patients who were infected with either panresistant ( patients) or only tigecycline susceptible ( patients) acinetobacter spp. and were treated with rifampicin combination regimens. methods: patients reported to be infected with colistin resistant acinetobacter spp. and treated with rifampicin combination regimens upon decision of the responsible teams were traced from the intensive care unit (icu) records between the years and retrospectively. their demographic data, liver function tests, icu and hospital outcomes were recorded. results: there were a total of patients, were women. mean age was . . in patients pulmonary site was the source. nine patients had positive blood cultures. mean sofa score at the start of therapy was . ; all were intubated, and ( %) were on vasopressor therapy. combination regimens comprised of at least antibiotics and all regimens included rifampicin and tigecycline. at the end of first week, mean sofa score was . . of these ( %) survived to hospital discharge. patients who were lost had higher initial and follow-up sofa scores. initial and follow-up liver enzymes and renal function tests were similar to their basal values in patients who survived; unlike the patients who were lost. when lost patients were re-evaluated: the first patient had irreversible lung fibrosis due to bleomycine; in the second patient; combination treatment was delayed until days after the cultures were performed; the third patient had been admitted to icu with acute renal failure and acute respiratory distress syndrome, after autologous stem cell transplantation for multiple myeloma. conclusions: when the importance of accurate antibiotic choice is taken into account for treatment success; rifampicin combinations may be considered as an appropriate treatment option for infections caused by colistin resistant acinetobacter strains. introduction: carbapenem resistant enterobacteriacae (cre) emerged in recent years as one of the most challenging group of antibiotic resistant pathogens. polymyxins are considered as the last resort for the treatment of infections with carbapenem resistant gram negative bacilli (gnb). inadequateor extensive use of colistin leads to emergence of colistin resistance, increasing mortality and morbidity and necessitating prudent use of alternative antibiotics. fosfomycin, a phosponic acid derivative which acts by disrupting bacterial cell wall synthesis, is a broad spectrum antibiotic. it is available as sodium/disodium formulation for intravenous use and is showing promising result against multi drug resistant(mdr)/pan drug resistant (pdr) pathogens. methods: a total of eight colistin resistant (mic ≥ ) gnb were isolated from icu patients with nosocomial mdr infections during a period of one year. all eight isolates were klebsiella pneumonia. among these isolates five were from blood and three from endotracheal aspirate. all the isolates were sensitive to fosfomycin in vitro. all of these patients had multiple co-morbidities with recent history of colistin exposure. intravenous fosfomycin was given as a combination therapy. results: among the five bacterimic patients, three recovered completely from sepsis. one patient took discharge against medical advice and the only one bacterimic patient who died during the course of therapy was later on diagnosed to have azole resistant fungemia as super infection. the patient with ventilator associated pneumonia also responded well after initiation of fosfomycin therapy. average duration of antibiotic therapy in all these cases was ten days. conclusions: based on the evidence of clinical experience and available studies, intravenous fosfomycin therapy may be considered as the last option for the treatment of mdr gnb infection where there is documented colistin resistance and where there is literally no other choice of antibiotic therapy. the success of the therapy is encouraging in selected group of patients. further research on intravenous fosfomycin use specially against mdr pathogens and on the effectiveness and safety of the drug in the treatment of patients with such infections may be warranted. introduction: patients at the intensive care units have an increased risk of infection due to their underlying diseases or conditions, impaired immunity, and exposure to multiple invasive procedures (surgery, mechanical ventilation, central venous catheters, artherial catheters, urinary tract catheters). multidrug-resistant organisms infection has become a public health problem and has been associated with increased morbidity, mortality, and costs. objectives: to analyze the principal features of postsurgical patients with colonization or infection by multidrug-resistant organisms, acquired before the admission at the intensive care unit. methods: retrospective observational study, descriptive, case series, collected from / / to / / in a -bed hospital, with a -bed polyvalent intensive care unit in fuenlabrada, madrid, spain. the hospital is attached to resistance zero project, with screening at admission and every week in all patients (pharyngeal, rectal, nasal, wounds and bronchial suction). postsurgical patients have been identified with multidrugresistant organisms isolation in screening in the first hours of admission to the intensive care unit. studied variables: age, sex, adjusted charlson comorbidity index, barthel index, apache ii, saps , days of hospitalization prior to icu, days of antibiotic treatment administered before icu, previous days of parenteral nutrition, prealbumin, surgical wound infection, multigrug-resistant organisms identified sample. statistical analysis: spss . categorical in frequencies and percentages, mean and standard deviation or median and interquartile range. analysis kolmogorov smirnov, shapiro wlik and qqplot to normality. confidence intervals (ci) % by t student for normal variables, boot stramp to not normal. results: in months we identified postsurgical patients with multidrug-resistant organisms in screening at the admission or before the admission to the intensive care unit. multidrug-resistant organisms identified: pseudomonas aeruginosa ( . %), esbl enterobacteriaceae ( . %), mrsa ( . %), stenotrophomonas maltophilia ( . %). isolated on: surgical wound ( . %), bronchial suction ( . %), peritoneal fluid ( . %), exudates monitoring ( . %), blood ( . %). antibiotic therapy: carbapenem ( . %), piperacilina-tazobactam ( . %). conclusions: in our study the risk of prior acquisition of multidrugresistant organisms at the admission to the intensive care unit in postsurgical patients was characterized by long hospital stay, high comorbidity and dependence, malnutrition, prolonged use of broadspectrum antibiotic, parenteral nutrition and surgical wound infection. introduction: the emergence and dissemination of klebsiella pneumoniae carbapenemase (kpc) is of great concern. outbreaks have been reported in different types of intensive care units (icu). in brazil, there have been reports of kpc since . we recently experienced a large outbreak at our hospital. risk factors for kpc colonization and outcome of icu patients are still to be determined. objectives: to study the differences between patients who acquired from those who did not acquired kpc during their stay in the icu, focusing on risk factors and outcomes. introduction: patients with a prolonged weaning represent a small part of the total icu population but this prolonged state has many implications on their later recovery and can highly impact health expenditures. objectives: to better characterize patients with prolonged weaning and assess factors associated with their survival. methods: the prospective multicentre observational wind (weaning according new definition) study was performed from april to august . ventilation and weaning modalities were daily assessed until discharge in all intubated patients admitted to the participating icus. we defined ) weaning attempt (wa) as a spontaneous breathing trial (sbt) or an extubation (with or without sbt), ) successful weaning as an extubation without death or invasive mechanical ventilation within days. we considered patients as having a prolonged weaning if weaning was not terminated at days following their first wa. conclusions: in this multicentre international prospective cohort, . % of the patients entering the weaning process had a prolonged weaning with a high mortality rate of . %. the only baseline factor associated with death were previous immunodeficiency and chronic cardiac failure. these patients highly impact the icu workload as they receive mechanical ventilation for a median duration of days and their median length of stay in the icu is days. patients with a prolonged weaning spend a long icu time after the end of weaning without mechanical ventilation raising the issue of the need for specialized units. introduction: ineffective efforts (ie), defined as the inability of patient's inspiratory effort to trigger a ventilator-delivered breath, is a commonly encountered asynchrony, and has been reported to adversely affect patient outcome , , . the incidence of ie depends on several factors, including patient population, ventilator settings, and the observation period, which in most studies so far was limited , . objectives: aim of this study was to investigate the incidence of ineffective efforts, using continuous recordings, in critically ill patients mechanically ventilated only on assisted mode and their potential effects on patient outcome. methods: adult critically ill patients hospitalized in the icu of the university hospital of heraklion on mechanical ventilation for > h were enrolled. patients were studied when they were on assisted ventilation for > hour and expected to remain on assisted ventilation for the next hours. patients were studied again on the rd and th day if they remained on assisted ventilation. continuous h measurements were obtained using a monitor validated to identify ineffective efforts (pvi monitor) . the output of pvi monitor data was processed before analysis to optimize data quality and re-sampled to a time-series with the number of ies calculated in uniform intervals of secs while preserving the total number and duration of ies . the ie index was calculated as previously described. because ie occurred in clusters, the concept of ie event was introduced, to describe variable periods of time containing ie > % of breaths. ie events were characterized by their duration and power (number of ie) . introduction: the neural timing during mechanical ventilation can be obtained from conventional airway flow tracing, or invasive esophageal and gastric signal; however, it is difficult clinical practice and could be imprecise. the first derivative of airway flow signal show line segments with distinctly different slopes and with welldefined the inflections points, therefore this closely indicate the respiratory times, it can be calculated easily. objectives: to evaluate the accuracy of the derivative of the flow signal (df) as method for measurement of the respiratory times compared with esophageal-gastric signals. introduction: providing appropriate levels of pressure support (ps) at the bedside is challenging. physicians should avoid both over-support, which increases the risk of lung trauma, muscle atrophy and prolonged weaning; and under-support, which increases the risk of patient discomfort and respiratory muscle fatigue. the latter can be determined by the using the tension time index of the inspiratory muscles (tti es ) derived from measurement of esophageal pressure. tti es values higher than . indicate fatiguing patient effort. the beacon caresystem (mermaid care, denmark) advises on level of ps using physiological models of lung mechanics, pulmonary gas exchange, respiratory drive, acid-base status and muscle function; along with clinical preference functions quantifying the risk of muscle atrophy, patient stress, and lung trauma. mathematical models are tuned to measurements allowing advice to be patient specific. objectives: this study investigates the variation of tti es and other indices of respiratory muscle function induced by an increase/decrease of the level of ps, and whether the consequent advice proposed by the beacon system results in appropriate patient effort. methods: ten patients with acute respiratory failure residing in an icu in ferrara, italy, have currently been included for this analysis. an esophageal balloon was inserted and its correct position determined by the occlusion test. the advice of the beacon system was followed for an hour from states of over-and under-support defined as % and % of baseline ps. the level of peep was kept constant throughout the study. data were analysed in terms of tti es and esophageal pressure developed in the first ms of an occluded inspiration (p . ) results: the baseline tti es values of . ± . were consistent with absence of fatiguing effort in all patients but one. as expected, reducing/increasing the level of ps resulted in tti es and p . increase or decrease, respectively. in patients the reduction of ps was associated with impending muscle fatigue. the levels of ps proposed by the beacon system resulted in tti es of . ± . , slightly higher than obtained by the treating physician, but always below the values indicating muscle fatigue, a part from the patient in which the tti es indicated fatigue at baseline. of note, this new value of tties was not associated with a significant variation p . , which implies that the proposed level of ps was not associated with an increased respiratory drive or higher transpulmonary pressure conclusion: these initial results indicate that beacon caresystem responds appropriately to over-and under-support avoiding muscle fatigue and excessive p . . the use of vo level changes as a predictor for weaning success in the mechanically ventilated patients introduction: experimentally, hyperchloraemia may induce vasoconstriction of the renal afferent arterioles and tubular dysfunction, potentially resulting in acute kidney injury (aki). the clinical implications of these findings are not well established, especially in septic patients. objectives: to investigate whether chloride serum and urinary concentrations as well as chloride load, output, balance and urinary anion gap are associated with the development of aki in septic patients. methods: retrospective analysis of an institutional database including all patients admitted to the intensive care unit (icu) for severe sepsis and septic shock from january to june . inclusion criteria were length of stay in the icu ≥ hours and complete data available on serum and urinary samples for at least days. patients were excluded if they had anuria on icu admission, continuous bladder irrigation, if they were on hemodialysis (of recent onset and chronic) and if they were kidney-transplanted. demographics and data on outcome were also analysed from the database. we collected chloride levels on daily blood (bcl) and urinary (ucl) analyses; chloride load (cl) was calculated by considering the amount of chloride present in the iv fluids administered daily to the patient, while chloride balance (cb) was calculated as: cl -co, where co is chloride output (ucl * daily urine output). creatinine clearance (crcl) was calculated on -hr urinary collection. aki was defined according to standard criteria. conclusions: most of septic patients developed aki and this complication was associated with a significant reduction in renal chloride elimination. the impact of such findings on the management of fluid therapy in this setting remains to be further evaluated. introduction: plasma interleukin (il- ) is associated with acute kidney injury (aki) in sepsis. il- receptor (il- r) is not expressed in the kidney. circulating il- in a complex with soluble il- r (sil- r) activates ubiquitously expressed transmembrane signal transducing glycoprotein on renal epithelial cells. this il- trans-signaling is associated with mortality in experimental sepsis. objectives: to study il- trans-signaling in patients with sepsis in a clinical intensive care setting. methods: in septic patients showing first organ failure at intensive care unit (icu) admission ± hours, we measured plasma il- and sil- r at admission and hours later. our primary endpoint was aki during the first five icu days by kdigo criteria. mann-whitney's, spearman's correlation and chi square tests were used. results: plasma il- was significantly higher in patients with aki at h (p = . ) and h (p < . ). plasma il- correlated with kdigo stage at h (r = . , p = . ) and h (r = . , p < . ). plasma sil- r did not differ between aki and non-aki groups. using cut-off values of pg/ml of il- and pg/ml of sil- r at h (detected by youden method), the combination of low il- and low sil r was associated with non-aki (p < . ). conclusions: combination of low il- and low sil- r in plasma is associated with decreased incidence of aki, suggesting that il- transsignaling contributes to septic aki. . % for the non-aki group (or = . ; % ci, . - . , p < . ). multivariate analysis indicated that the bpv was well associated with aki (adjusted or = . ; % ci, . - . , p < . ) while the mean blood pressure was not (adjusted or = . ; % ci, . - . , p = . ). conclusions: elevated blood pressure variability is associated with increased risk of aki in septic patients. this understanding may be helpful to develop requirement for stabilising blood pressure in the bp management of septic patients. introduction: acute kidney injury (aki) is a frequent and serious complication of sepsis in intensive care units (icu). according to acute kidney injury criteria (akin), the most current diagnostic criteria for aki is an abrupt (within hrs.) reduction in kidney function currently defined as an absolute increase in serum creatinine of more than or equal to . mg/dl, or . fold from baseline or a reduction in urine output (documented oliguria of < . ml/kg per hr. for > hr.). by time of occurrence of these criteria actual kidney insult has occurred & probably this leads to late intervention for kidney protection &/or renal replacement therapy (rrt). so early prediction of aki by using biomarkers like urinary angiotensinogen could help patients to benefit from a quicker and more appropriate therapy. urinary angiotensinogen appears quite promising due to its reported correlation with the intrarenal angiotensinogen and angiotensin ii levels which play a major role in molecular mechanisms of aki. objectives: the aim of this work was to evaluate the role of urinary angiotensinogen as a possible predictor of aki in patients with severe sepsis. methods: the study was carried on adult patients who were admitted to the department of critical care medicine, at the alexandria main university hospital and who suffered from severe sepsis. patients were categorized into two groups according to aki development; non aki group which consisted of patients (group i), and aki group which consisted of patients (group ii). patients were excluded if they have chronic kidney disease, already started rrt, received angiotensin convertase enzyme inhibitors (acei) or angiotensin receptor blockers (arbs), or septically shocked. urinary angiotensinogen and creatnine were withdrawn once from each patient on the day of admission to calculate urinary angiotensinogen/creatinine ratio (uancr, ng/mg). akin staging was assessted daily for seven days. results: there was a significant difference between the two studied groups regarding uancr ratio on admission (p < . ), whereas this introduction: acute pancreatitis with organ dysfunction is termed severe acute pancreatitis (sap) and complex sap if local complications develop (such as infected pseudocyst). we receive tertiary referrals of complex sap patients to our unit, who often have multiple ct scans. muscle wasting is known to occur in critically ill patients ( ) and can be quantified by measurement of the cross-sectional area (csa) of para-spinal muscles at the third lumbar vertebral level on ct imaging. aki is one of the most common causes of death in sap patients ( ) and is a risk factor for developing ckd ( ). kdigo guidelines suggest using creatinine changes to detect aki ( ) but creatinine changes may be inaccurate in the presence of musclewasting (myopenia) ( ). objectives: to utilise measurements of l para-spinal muscle csa (l mcsa) from complex pancreatitis patients between april -december and compare these to changes in plasma creatinine during their icu stay. methods: patients were identified from our icu patient database (wardwatcher software) and additional clinical details including creatinine/egfr level on ct-scan days, were acquired from electronic databases. images were exported from our pacs system as dicom files and analysed using imagej software (ref) in duplicate by two independent users, average values were used. for patients who had no renal-replacement therapy (rrt), between-scan l mcsa and creatinine change were paired and analysis was with excel (ms) and graphpad (prism). results: patients met inclusion criteria. patients had ≥ ct scans in icu, enabling serial estimation of l mcsa. / ( . %) patients did not have rrt in icu. there was no statistically significant difference in overall (start to end of icu) % change of l mcsa between patients who did/did not have rrt. there was also no correlation between overall (start-to-end of icu) % creatinine change and % change/day l mcsa: r = − . , p = . . for between-scan data (n = ): the median (iqr) % creatinine change/scan was − . % (− . to − ) and the % l mcsa change/ scan was − . % (− . to − . ). however, there was no correlation between % l mcsa change and % creatinine change between scans ( r = − . , p = . ). conclusions: l mcsa (relating to lean muscle mass) was shown to decrease in complex severe acute pancreatitis (sap) patients. however, there was no correlation with change in l mcsa and change in creatinine. this suggests that normal/stable creatinine values may be falsely reassuring in the context of muscle mass loss (myopenia) and ongoing aki could be under-diagnosed. acknowledging myopenia and interpreting creatinine value in context is therefore vital. introduction: continuous renal replacement therapy (crrt) is the most common therapy in critical ill patients with acute renal failure, having circuit coagulation as the most frequent complication. the crrt circuit requires careful anticoagulation to avoid coagulation and bleeding complications. critically ill patients with acquired antithrombin (at) deficiency, may have a shorter filter lifespan. objectives: evaluate the relation between the modification of at levels from baseline and circuit survival during ccrt. we would like to determine the existence of an at critical level, related to the risk of the clotting filter. methods: we started an observational study with prospective data collection in a university hospital. from october to april , patients were included, with filters in total. we measured the level of at activity at the beginning (basal at), daily, and at the moment of circuit coagulation. we divided the patients in two groups depending in their at´s basal level (< % or > %). then, we observed the percentage of change in at from baseline, and we divided the patients in tertiles to obtain three comparable groups. the main outcome measure was filter lifespan of first circuit and the correlation with at´s levels. results: low at´s basal level (< %) has significant association with longer filter life span (p = . ). we obtained three groups according to a percentage changes of ± % in at from baseline. one group declined the at´s basal level ( % decrease), other had little changes (between % decrease and % increase) and the last one had an increase ( % increase). the group which presented the highest percentual increase showed the largest median survival time to circuit coagulation ( hours; % ci: - ). we observed a significant association (p = . ) between the greater percentage change in at from baseline, and a larger time intervals to circuit coagulation. conclusions: the circuit lifespan shows a narrow correlation with evolution of at´s levels since the start of crrt until filter clotting. at measurement should be considered an essential factor during crrt. calcium supplementation was required with filters ( %) in patients ( %). in these patients, the median supplementary calcium dose (in addition to replacement fluid ca) was . mmol/hr ( . - . ). of those were initiated with calcium with only requiring further calcium in the next filter and did not ( patient who started on calcium only used filter). one patient in the citrate group was discontinued for alkalosis. no patients were discontinued for hypocalcaemia. conclusions: post dilution rca, using replacement fluid which contains calcium, in patients with a relative contraindication to heparin, reduces need for post filter calcium supplementation and provides acceptable filter life. mortality risk factors in continuous renal replacement therapy in a university hospital from colombia c. introduction: acute kidney injury (aki) occurs in more than % of critically ill patients, % need renal replacement therapy, preferring continuous therapies. however mortality seems not to change with this technology. the research available focus on the right time to start therapy, but only evaluating renal dysfunction characteristics. objectives: to identify mortality risk factors at the start of continuous renal replacement therapy (crrt) for acute kidney injury and early mortality risk factors in this patients. methods: a cohort study was performed in patients over years old with aki who required crrt in the intensive care unit of a university hospital in bogota colombia between and . the crrt was provided with aquarius® edwards® technology, polyethersulfone membrane of . and . m (aquamax®) and replacement fluids with lactate (premixed®). modality selection were guided by the hospital guideline. sample size calculation was estimated selecting cases (death) for each variable associated with mortality. a description of demographic and clinical variables was performed, bivariate analysis with mortality and early death defined as death within hours of onset of crrt, and finally we proceed to perform a multivariate prediction analysis. we considered statistically significant p value < . . results: a total of patients required crrt during the period, ( . %) patients were excluded, (age under years old, incomplete data and chronic kidney disease on dialysis). the mean age was . years (± . ), . % men. the most frequent cause of aki was sepsis in . % of cases. a total of crrt days were conducted with a median of days per patient (range - ). mean charlson comorbidity index was . (± . ), apache ii score . (± . ), total non-renal sofa had a median of (range - ) at the time of starting therapy. the hospital mortality was . % and early mortality was . %. in multivariate analysis: age (p = . ), sofa (p = . ), days door-support (p = . ) and the presence of hypotension (p = . ) were independent risk factors for hospital mortality with an area under the curve of . . for early death lactic acid levels (p = . ), glucosa (p = . ) and age (p = . ) were independent risk factors with an area under the curve of . . conclusions: patients with aki on crrt have high mortality. age, multiple organ dysfunction, hypotension and time door-support were independent mortality risk factors. low levels of glucose and high lactate at onset of crrt are independent risk factors of early death. pediatric formulas for the anesthesiologist the role of bystanders, first responders, and emergency medical service providers in timely defibrillation and related outcomes after out-of-hospital cardiac arrest: results from a statewide registry kids save lives-training school children in cardiopulmonary resuscitation worldwide is now endorsed by the world health organization (who) acute skeletal muscle wasting in critical illness enhancing rehabilitation of mechanically ventilated patients in the intensive care unit: a quality improvement project pdf . nice quality standard (qs ) stroke in adults the sentinel stroke national audit programme (ssnap) interventions to improve the physical function of icu survivors core standards for intensive care units icu early mobilization: from recommendation to implementation at three medical centres revista brasileira de terapia intensiva invasive pulmonary aspergillosis is a frequent complication of critically ill h n patients: a retrospective study isolation of aspergillus in three h n influenza patients. influenza other respir viruses grant acknowledgement supported by fucap and ciberes effect of daily chlorhexidine bathing on hospitalacquired infection chlorhexidine bathing and health care-associated infections: a randomized clinical trial outcome of elderly patients undergoing intracranial meningioma resection -a systematic review and meta-analysis references . an expanded definition of the adult respiratory distress syndrome acute respiratory distress syndrome: the berlin definition jama h n influenza a virus-associated acute lung injury: response to combination oseltamivir and prolonged corticosteroid treatment epidemiology, co-infections, and outcomes of viral pneumonia in adults: an observational cohort study. medicine (baltimore) survival from severe pandemic h n in urban and rural turkey: a case series prognostic importance of neutrophillymphocyte ratio in critically ill patients: short-and long-term outcomes. the american journal of emergency medicine reversal of neutrophil-to-lymphocyte count ratio in early versus late death from septic shock the association between the neutrophil-to-lymphocyte ratio and mortality in critical illness: an observational cohort study the mortality risk of over hydration in haemodialysis patients ultrasound assessment for extravascular lung water in patients undergoing hemodialysis. time course for resolution sufficient sleep quality easily measured: a multicenter centre study in dutch icus rd international symposium on intensive care and emergency medicine using nursing activities score to assess nursing workload on a medium care unit nurse staffing levels and the incidence of mortality and morbidity in the adult intensive care unit: a literature review nursing activities score in the intensive care unit: analysis of related factors. intensive and critical care nursing organisation and management of intensive care : a prospective study in european countries impact of performance obstacles on intensive care nurses' workload, perceived quality and safety of care and quality of working life burnout syndrome in critical care nursing staff work engagement: an emerging concept in occupational health psychology diagnostic accuracy of clinical swallow assessment for oropharyngeal aspiration: a systematic review the cruelest lies are often told in silence critical review: is the endoscopic swallowing assessment (abstract a ). lactate (sepsis vs trauma) jaundice in the intensive care unit cooling techniques for targeted temperature management post-cardiac arrest thermoregulatory catheter-associated inferior vena cava thrombus ivtm intravascular temperature management catheter specifications prediction of postoperative pulmonary complications in a population-based surgical cohort lung ultrasound: routine practice for the next generation of internists relevance of lung ultrasound in the diagnosis of acute respiratory failure* assessment of hemostasis after plasma exchange using rotational thrombelastometry (rotem) prevention of pain on injection of propofol: systematic review and meta-analysis prevention of pain on injection with propofol: a quantitative systematic review mechanical ventilation guided by esophageal pressure in acute lung injury ultrasound assessment of antibiotic-induced pulmonary reaeration in ventilator-associated pneumonia ards definition task force endotracheal tubes cuff pressure control: does the co matter? minerva anestesiol incidence and outcome of in-hospital cardiac arrest in the united kingdom national cardiac arrest audit delayed awakening after cardiac arrest: prevalence and risk factors in the parisian registry diaphragm ultrasound as a new index of discontinuation from mechanical ventilation critical ultrasound journal ventilator-induced diaphragm dysfunction: time for (contr)action! the course of diaphragm atrophy in ventilated patients assessed with ultrasound: a longitudinal cohort study critical care effect of postextubation high-flow nasal cannula vs conventional oxygen therapyon early non-invasive ventilation treatment for severe influenza pneumonia use of a pathway quality improvement care bundle to reduce mortality after emergency laparotomy the first patient report of the national emergency laparotomy audit acute kidney injury enhances outcome prediction ability of sequential organ failure assessment score in critically ill patients médecine intensive et réanimation development and validation of a questionnaire for quantitative assessment of perceived discomforts in critically ill patients the emotional and cognitive impact of unexpected simulated patient death the efficiency of instructional conditions: an approach to combine mental effort and performance measures long-term cognitive impairment after critical illness satisfacción laboral de los profesionales sanitarios de un hospital universitario: análisis general y categorías laborales the nurse satisfaction, service quality and nurse retention chain: implications for management of recruitment and retention grant acknowledgement am: moulton foundation hospital/kcl the very elderly admitted to icu: a quality finish? crit care med a global clinical measure of fitness and frailty in elderly people cognitive, functional, and quality-of-life outcomes of patients aged and older who survived at least year after planned or unplanned surgery or medical intensive care treatment outcome of elderly patients with circulatory failure. int care med understanding and reducing disability in older adults following critical illness mechanical ventilation in a cohort of elderly patients admitted to an intensive care unit preferences of current and potential patients and family members regarding implementation of electronic comunication portalls in intensive care units caring for the family of the critically ill patient the carina as a radiological landmark for central venous catheter tip position duration of resuscitation efforts and survival after in-hospital cardiac arrest: an observational study duration of cardiopulmonary resuscitation and illness category impact survival and neurologic outcomes for in-hospital pediatric cardiac arrests duration of prehospital resuscitation efforts after out-of-hospital cardiac arrest neurologic prognosis after cardiac arrest magnetic resonance imaging markers of parkinson´s disease nigrostriatal signature disruption of posteromedial large-scale neural communication predicts recovery from coma james mcdonnell foundation, the belgian american education foundation, university milano bicocca. fig. (abstract a ). study flowchart intensive care medicine experimental neurological prognostication after cardiac arrest strategies for improving survival after in-hospital cardiac arrest in the united states: consensus recommendations: a consensus statement from the cardiopulmonary resuscitation with assisted extracorporeal life-support versus conventional cardiopulmonary resuscitation in adults with in-hospital cardiac arrest: an observational study and propensity analysis early extracorporeal membrane oxygenator-assisted primary percutaneous coronary intervention improved -day clinical outcomes in patients with st-segment elevation myocardial infarction complicated with profound cardiogenic shock the current use of impella . in acute myocardial infarction complicated by cardiogenic shock: results from the uspella registry mechanical circulatory support in cardiogenic shock cardiac transplantation research database group, long-term outcomes of cardiac transplantation for peripartum cardiomyopathy: a multiinstitutional analysis cardiopulmonary resuscitation with assisted extracorporeal life support versus conventional cardiopulmonary resuscitation in adults with in-hospital cardiac arrest: an observational study and propensity analysis patient safety, satisfaction, and quality of hospital care: cross sectional surveys of nurses and patients in countries in europe and the united states nurses' widespread job dissatisfaction, burnout, and frustration with health benefits signal problems for patient care early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial feasibility and observed safety of interactive video games for physical rehabilitation in the intensive care unit: a case series is admission to the intensive care unit associated with chronic opioid use? a -year follow-up of intensive care unit survivors survival to icu discharge in ventilated patients intensive care medicine experimental modified early warning score with rapid lactate level in critically ill medical patients: the views-l score impact of matrix-assisted laser desorption ionization time-of-flight mass spectrometry on the clinical management of patients with gram-negative bacteremia: a prospective observational study. clinical infectious diseases : an official publication of the infectious diseases society of america impact of rapid organism identification via matrix-assisted laser desorption/ionization time-of-flight combined with antimicrobial stewardship team intervention in adult patients with bacteremia and candidemia. clinical infectious diseases : an official publication of the infectious diseases society of america impact of rapid identification of acinetobacter baumannii via matrix-assisted laser desorption ionization time-of-flight mass spectrometry combined with antimicrobial stewardship in patients with pneumonia and/or bacteremia. diagnostic microbiology and infectious disease an international cross-sectional survey of antimicrobial stewardship programmes in hospitals continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial hplc determination of plasma free and total tazobactam and piperacillin effectiveness of polymyxin bimmobilized fiber column in sepsis: a systematic review crit care predicting functional impairment in brain tumor surgery: the big five and the milan complexity scale *p. ferroli the "medial-oblique" approach to ultrasoundguided central venous cannulation-maximize the view, minimize the risk medial-oblique" probe position for ultrasound-guided internal jugular vein cannulation: a crossover study improving survival from sudden cardiac arrest: the "chain of survival" concept practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the quality standards subcommittee of the american academy of neurology association of bystander interventions with neurologically intact survival among patients with bystander-witnessed out of hospital cardiac arrest in japan performance of the revised atlanta and determinantbased classifications for severity in acute pancreatitis rational fluid therapy for sepsis and septic shock what do recent studies tell us? review article surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock fluid type and the use of renal replacement therapy in sepsis: a systematic review and network meta-analysis. int care med the third international consensus definitions for sepsis and septic shock fernández-ortega regional university hospital in málaga rapid diagnosis of infection in the critically ill, a multicenter study of molecular detection in bloodstream infections, pneumonia, and sterile site infections grant acknowledgement supported, in part cytokines and signaling molecules predict clinical outcomes in sepsis the application of esophageal pressure measurement in patients with respiratory failure mechanical ventilation guided by esophageal pressure in acute lung injury ecmo criteria for influenza a (h n )-associated ards: role of transpulmonary pressure mechanical ventilation guided by esophageal pressure in acute lung injury fig. (abstract a ) grant acknowledgment national cheng-kung university hospital grant a assessment effort and work of breathing by airway occlusion pressure versus esophageal pressure hospital universitario reina sofia, intensive care unit airway occlusion pressure effects of the prone position on respiratory mechanics and gas exchange during acute lung injury effects of prone position on alveolar recruitment and oxygenation in acute lung injury prone position reduces lung stress and strain in severe acute respiratory distress syndrome lateral positioning of ventilated intensive care patients: a study of oxygenation, respiratory mechanics, hemodynamics, and adverse events the effect of lateral position on oxygenation in ards patients : a pilot study the open lung concept of mechanical ventilation: the role of recruitment and stabilization selecting the 'right' positive endexpiratory pressure level esophageal and transpulmonary pressures in acute respiratory failure spontaneous breathing during lung-protective ventilation in an experimental acute lung injury model: high transpulmonary pressure associated with strong spontaneous breathing effort may worsen lung injury relationship between activation of the sympathetic nervous system and renal blood flow autoregulation in cirrhosis hepatorenal acute kidney injury and the importance of raising mean arterial pressure a fig. (abstract a ) rotational thrombolelastometry produces potentially clinical useful results within min in bleeding emergency department patients: the deuce study thrombelastography and rotational thromboelastometry early amplitudes in trauma patients with clinical suspicion of severe injury a prospective study of anaemia status, haemoglobin concentration and mortality in an elderly cohort a experience with a hospital-wide implementation of a massive transfusion protocol: before and after a references . experience with a massive transfusion protocol in the management of massive haemorrhage rodríguez villamizar hospital universitario puerta de hierro majadahonda recommendations for end-of-life care in the intensive care unit: a consensus statement by the american college of critical care medicine end-of-life care practices in patients dead as a result of a devastating brain injury and organ donation in spain prediction of potential for organ donation after cardiac death in patients in neurocritical state: a prospective observational study causes of family refusal for organ donation development of the croatian model of organ donation and transplantation evaluation of organ procurement in an area under the influence of a training program grant acknowledgment none. a non-heart beating donor program: seville's experience l. martin-villen , the variables analyzed were: total number of queries activation, of pd, of eligible donors (ed) and of real donors (rd). rd attendance times were registered and we defined out-of-hospital time (from cardiac arrest to hospital arrival), inof-hospital time (from hospital arrival to cannulation onset), cannulation time (beginning of cannulation to perfusion onset) and perfusion (from perfusion onset to the first organ removal). we registered number and type of valid organs and tissues, number of family members or judicial negative, number of non-real-donors (nrd) and its causes regarding attendance times, the median time was (icr - ) minutes for out-of-hospital, (icr - ) minutes for in-of-hospital, ( - ) minutes for cannulation and ( - )minutes for perfusion controlled donation after circulatory determination of death in spain rodriguez villamizar puerta de hierro hospital, intensive care unit, majadahonda, spain correspondence: j. veganzones ramos -puerta de hierro hospital the use of lung donors older than years: a review of the united network of organ sharing database marginal donor lungs: a reassessment liberalization of donor criteria may expand the donor pool without adverse consequence in lung transplantation the human organ transplant act. legislative acts and guidelines, ministry of health amendment of the human organ transplant act lebrón-gallardo regional university hospital in málaga grant acknowledgment this work was funded by the innovation awards from the department of medicine recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysis a successeful strategy to reduce ventilator getting started kit: prevent ventilator associated pneumonia. cambridge ma: institute for healthcare improvement umr_s and hôpital pitié-salpêtrière, respiratory division and medical icu trends in tracheostomy for mechanically ventilated patients in the united states outcome of patients with cirrhosis requiring mechanical ventilation in icu the impact of organ dysfunction in cirrhosis: survival at a cost? does intermediate care improve patient outcomes or reduce costs abbreviations: tbs, tracheobronchial secretions aki, acute kidney injury hd, hemodialysis a patient perceptions of physiotherapy in icu: a qualitative study m dimensionamento da equipe de enfermagem da uti-adulto de um hospital ensino -rev. eletr. enf critérios para admissão de pacientes na unidade de terapia intensiva e mortalidade patient acuity rating: quantifying clinical judgment regarding inpatient stability identification of deteriorating patients on general wards; measurement of vital parameters and potential effectiveness of the modified early warning score the epidemiology of chronic critical illness in the united states impact of chronic critical illness on the psychological outcomes of family members tracheostomy procedures in the intensive care unit: an international survey percutaneous tracheostomy: a yr prospective evaluation of the single tapered dilator technique can outcomes of intensive care unit patients undergoing tracheostomy be predicted? respir care safety and complications of percutaneous tracheostomy in a cohort of mixed icu patients prognostic consequences of borderline dysnatremia: pay attention to minimal serum sodium change. crit care are the dysnatremias a permanent threat to the critically ill patient? a explore the dengue-related risk factors and death factors in dengue hemorrhagic fever epidemic in taiwan diabeted with hypertension as riak factor for adult dengue hemorrhagic fever in a predominantly dengue serotype epidemic: a case study characteristics of dengue epidemics in taiwan modelling risk of cardio-respiratory instability as a heterogeneous process grant acknolwedgment nih ninr r nr during two years, we included all patients with more than days of stay in a medicalsurgical icu. previous informed consent , we collected demographics data, baseline functional status (barthel scale), mortality intrauci, at hospital and one-year of hospital discharge chronic critical illness a comparison between -dimentional speckle tracking & color-tissue doppler imaging for the assessment of left ventricular global longitudinal systolic strain and strain rate in outcome prediction of sepsis grant acknolwedgment italian ministry of health, italy (convenzione n. /gr- - ); and fondazione sestini exclusion criteria: do not resuscitate order. protocol: data were collected anonymously according to the utstein style. follow-up: months long using registry office and telephonic interview. data: age, sex, cerebral performance category (cpc good moderate disability, severe disability, unconscious), site of cardiac arrest, presumed etiology, initial rhythm (shockable or unshockable), witnessed event, monitored, cpr started within minute. primary end points: return of spontaneous circulation (rosc), survival to hospital discharge and cpc - . secondary end points: months survival and cpc - . statistics: numerical data are expressed as mean ± standard deviation or median (interquartile range), as percentage if ordinal data. chi-square test for ordinal data and t student's test for numerical data were performed. p significant if < . . results: cardiac arrests, cpr was carried out in cases ( %) secondary end points: . % alive at months; . % of them with cpc - . conclusions our experience reflects some aspects common with other european countries: less monitored events as well as more frequent cardiac arrests in unmonitored wards . rrt allowed a reduction of cardiac arrests thus reducing their incidence without modifying mortality incidence and outcome of in-hospital cardiac arrest in the united kindom national cardiac arrest audit epidemiology and outcomes of in-hospital cardiopulmonary resuscitation in the united states effectiveness of rapid response teams on rates of inhospital cardiopulmonary arrest and mortality: a systematic review and meta-analysis national intensive care surveillance, quality secretariat building, castle street hospital for women correspondence: a. beane -network for improving critical care systems and training (nicst), colombo, sri lanka intensive care medicine experimental fig. (abstract a ) fig. (abstract a ) authors thank tem international for providing a rotem analyzer for the study. references . the consort extension for cluster trials mcf fibtem & plasma fibrinogen references . extracorporeal membrane oxygenation for ards in adults cardiopulmonary resuscitation with assisted extracorporeal life-support versus conventional cardiopulmonary resuscitation in adults with inhospital cardiac arrest: an observational study and propensity analysis critical care in resource-restricted settings on behalf of the task force for mass critical care. evacuation of the icu. care of the critically ill and injured during pandemics and disasters: chest consensus statement icu fire evacuation preparedness in london: a cross-sectional study fire on an intensive care unit caused by an oxygen cylinder national questionaire survey on what influences doctors; decisions about admission to intensive care the faculty of intensive care medicine/the intensive care society acute care toolkit . high-quality acute care. royal college of physicians united kingdom; golden jubilee national hospital, department of anaesthesia there is a need for general (non-cardiac) intensive care units (icus) to facilitate more elective and emergency surgery for these patients. inhaled nitric oxide, a selective pulmonary vasodilator, may be required for this purpose. objectives: we wished to determine the availability of inhaled nitric oxide in general scottish icus we excluded tertiary paediatric, cardiothoracic and neuro-critical care units. an online survey was distributed followed, if necessary, by a telephone survey. caldicott guardianship approval was not required. results: four ( %) general icus had nitric oxide immediately available adult congenital heart disease (grown-up congenital heart disease) audit of critical care in scotland scottish adult congenital cardiac service a references . triage of patients consulted for icu admission during times of icu-bed shortage a then performed a cross-sectional survey by visiting each facility, and determining characteristics for each facility critical care in low-income countries functional compromise reflected by sarcopenia, frailty, and nutritional depletion predicts adverse postoperative outcome after colorectal cancer surgery sarcopenia is a predictor of outcomes in very elderly patients undergoing emergency surgery oudemans-van straaten hm, beishuizen a. low skeletal muscle area is a risk factor for mortality in mechanically ventilated critically ill patients acetate-versus lactate-based balanced colloids used as priming solutions for cardiopulmonary bypass: an experimental pilot study h. cauwenberghs , a. de backer , h. neels , i. deblier correspondence: h. cauwenberghs -zna middelheim general hospital methods: following irb approval, male non-diabetics gave consent and were randomly assigned to receive either succinylatedgelatin g (geloplasma®) in meq na+, meq k+, meq cl-, meq mg++, meq lactate (sid ) or succinylated gelatin g (isogelo®) meq na+, meq k+, meq ca, meq cl-, meq mg++, meq acetate and bonferroni corrected. results: demographics were comparable. acid-base variables changed similarly throughout without significant differences between groups (sig shown in figure ). by contrast, glucose levels rose very significantly in the lactate group and persisted post cpb (figure ). oncotic pressure, diuresis, osmolarity and oxygen uptake did not differ between groups. discussion. concerning acid-base variables and secondary endpoints the perioperative period stewart's textbook of acidbase pl effects of intravenous solutions on acid-base equilibrium: from crystalloids to colloids and blood components seric pro-adrenomedullin levels in low cardiac output syndrome (lcos) after cardiac surgery we measured am at time-points (t -t ): before surgery; at admission; h and h after surgery. continuous data were showed as average (sd) and categorical ones in percents. comparisons were performed with kruskall-wallis and anova tests. the roc approach was used to assess the predictor capacity of am. all analyses were performed with stata . the ethical committee approved the study. results: patients were included. the average of age was ± . years, and were women . %. the median (iqr) for euroscore was ( - ). comorbidities were hypertension ( %), diabetes mellitus ( %) and atrial fibrillation ( . %). on-pump surgery was performed in the % and the coronary bypass was the most frequent ( %). the incidence of low cardiac output syndrome was %. am levels (mmols/l) were: . ± . (before surgery) postoperative pro-adrenomedullin levels predict mortality in thoracic surgery patients consensus on circulatory shock and hemodynamic monitoring. task force of the european society of intensive care medicine canadian cardiovascular society position statement on the management of thoracic aortic disease guidelines for the diagnosis and management of patients with thoracic aortic disease early and midterm outcomes following surgery for acute type a aortic dissection importance of blood pressure control after repair of acute type a aortic dissection (abstract a ). pro-adm levels t -t bleeding complications associated with cardiopulmonary bypass prospective validation of the international society of thrombosis and haemostasis scoring system for disseminated intravascular coagulation towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation hospital regional, intensive care, malaga, spain; hospital serrania, ronda, spain; hospital regional, intensive care, málaga, spain; hospital infanta margarita, intensive care, cabra, spain; hospital virgen del rocio, intensive care we analyze differences in the postoperative incidence of af in both groups. results: cohort of patients, mean age . ± . years. . % was elective surgery. euroscore . ± . points. icu mortality was . %.prior to surgery, . % and . % taking statins present a history of af. . % postoperative af episode presented. the patients treated before surgery with statins had af . % vs . % (p = . ) the sample was divided among the patients who died and those who do not. demographic variables, prognostic scales,type of surgery,early complications, icu stay and mortality were compared.the variables that reached statistical significance in the univariate analysis were analyzed in multivariate logistic regression. data expressed as mean and standard deviation, percentage, mean difference, odds ratio and corresponding confidence intervals. statistical significance level of p < . . results: a total of patients were analyzed, ≥ years ( . %) of which died( . %) predictors of postoperative complications in octogenarians undergoing cardiac surgery a ventricular assist devices, transfusion and health-related quality of life %,median rbc transfused ventricular assist devices and increased blood product utilization for cardiac transplantation. stone ml et all bleeding complications and blood product utilization with left ventricular assist device implantation. schaffer jm et all after completion of cardiac surgery. the patients were divided into two groups: aged < and age ≥ years. association analysis of demographic, clinical, therapeutic factors and complications during icu stay. univariate analysis using chi square (fisher if applicable) and t student. data expressed as percentages, means, estándar desviation (sd), mean differences (dm), odds ratio (or), and confidence intervals % (ci %) results: a total of significant differences in cardiac arrest cardiac surgery in octogenarians: a case series outcomes and cost of cardiac surgery in octogenarians is related to type of operation: a multiinstitutional analysis aortic valve replacement with and without coronary artery bypass graft surgery in octogenarians: is it safe and feasible? short-and long-term outcomes in octogenarians after coronary artery bypass surgery diagnosing and treating the failing right heart matching dicrotic notch and mean pulmonary artery pressures: implications for effective arterial elastance. the american journal of physiology university hospital of pisa, department of anaesthesia and critical care medicine, cardiothoracic and vascular anaesthesia venous-to-arterial co differences and the quest for bedside point-of-care monitoring to assess the microcirculation during shock model of pco gap during hypothermic cardiopulmonary bypass central venous o( ) saturation and venous-to-arterial co( ) difference as complementary tools for goal-directed therapy during highrisk surgery patients: closed-vs. opensystem the closed-system pivc was composed of catheter with inteof pivcs, the incidence of bacterial colonization and pivcs-related complications (phlebitis, extravasation, catheter occlusion and hematoma) were recorded. the protocol of the study was approved by the irb of tokushima university hospital. results: ninety-one closed-system pivcs and open-system pivcs were evaluated. the median indwell time did not differ between the closed-and open-system pivcs (median were identified from the database of the microbiological laboratory of the hospital and were included in this study as cases. demographic data, severity of illness, risk factors for colistin-resistance (described in previous studies), clinical management and hospital outcome of all cases were recorded. mdr -resistant to at least one agent from different classes. pdr -resistant to all classes. results: of kp ( . %) and of ec ( . %) isolates were colistin resistant. of ( . %) of kp and of ec ( . %) isolates were colistin resistant colistin-resistant isolates of klebsiella pneumoniae emerging in intensive care unit patients: first report of a multiclonal cluster risk factors associated with the isolation of colistin-resistant gram-negative bacteria: a matched case-control study combination antibiotic treatment versus monotherapy for multidrug-resistant, extensively drug-resistant,and pandrug-resistant acinetobacter infections:a systematic review in vitro synergistic activity of tigecycline and colistin against xdr-acinetobacter baumannii woodlands multispeciality hospital references . combatting resistance in intensive care: the multimodal approach of the spanish icu "zero resistance" program. garnacho montero et als during a kpc outbreak in the -bed icu of a tertiary university hospital in rio de janeiro, brazil. all patients admitted to the icu were included in the study and classified as case (kpc yielded from any biological material, either considered as colonization or infection) or control (all other patients who did not have kpc isolation). both groups were compared according to demographic data, comorbidities, sepsis diagnosis, type and time of life support, sofa and saps iii scores at icu admission, length of stay (los) at icu and hospital, and hospital costs, icu and hospital mortality. results: patients were admitted during the studied period. patients had kpc samples isolated from different biological material conclusions: during a kpc outbreak in the icu of an academic tertiary hospital in rio de janeiro, the isolation of kpc associated with colonization or infection was associated with greater icu and hospital los, more requirements of life-organ support, higher icu and hospital mortality rates impact of carbapenem resistance on the outcome of patients' hospital-acquired bacteraemia caused by klebsiella pneumoniae first report of kpc- -producing klebsiella pneumoniae strains in brazil attributable mortality rate for carbapenem-resistant klebsiella pneumoniae bacteremia zero resistance" (rz) program was swabs (nasal, pharyngeal, axillary and rectal) were routinely performed to all patients admitted, besides diagnostic cultures when needed. furthermore, we analysed other pathological variables and comorbidities. the difference between groups of mrb was made by chi-square test for qualitative variables and the kruskal-walls test for the continuous ones. statistical significance was set at p < . . results: admitted. in patients were identified one or more mrb ( in total). patients ( , %) were esbls carriers, ( , %) mrsa, ( , %) p aeruginosa, ( , %) acinetobacter spp and ( %) others mrb carriers. in cases ( , %) the presence of a mrb caused infection. nasal swabs detected % of mrb carriers ( % of all mrsa), pharyngeal swabs % ( , % of mrsa), axillary swabs % ( % of mrsa, % of acinetobacter), and rectal swabs % ( % of esbls, , % of acinetobacter). in cases ( %) just the axillary swab was positive, and in cases ( %) the rectal was the only swab able to detect a mrb. diagnostic cultures (blood, urine, bronchoaspirate, surgical wound and others) detected mrb in less than %. the checklist did not detected neither colonization nor infection by mrb in ( %) patients ( % mrsa, , % acinetobacter, % of esbls). all patients with p aeruginosa had rf, but one. there was no statistical significance between groups of mrb and other comorbidities. conclusions: the surface cultures realized at admission detected % of mrb not detected by diagnostic cultures ):e . a enteral paramomycin to eradicate colistin and carbepemenase resistant microorganisms in rectal colonization to prevent icu multiresistant nosocomial infections university hospital of gran canaria dr. negrín, pharmacy department hospital of getafe, intensive care unit microbiology unit, section biology pathology and health products ) received catecholamines and ( %) were immunocompromised. icu mortality was . % and did not differ between esbl carriers and non-carriers. the rate of esbl colonization at admission and esbl acquisition were . % and . %, respectively. escherichia coli was the most frequently observed bacteria. the results of the univariate analysis for esbl acquisition are presented in table . in multivariate analysis, igs-ii and icu length of stay were strongly associated with esbl acquisition (table ). discussion and conclusion: the observed rate of esbl carriage on admission was comparable to other rates in french icus ( %). despite the unfavourable twin-bed architecture of our icu, the incidence of esbl acquisition was . % which was actually lower than transmission rates previously published in other icus. esbl acquisition was strongly associated with icu length of stay and severity score at admission. this study is fully consistent with previous ones challenging the geographic isolation in a non-epidemic setting and suggests that environmental contamination may not play a substantial role in the transmission of esbl-pe wipo was diagnosed with lus if, on at least one upper or lower part of both sides, the lus profile moved from a (normal) to b (interstitial oedema) or from b to "b+", where b+ consisted in at least a doubling of the b lines number. the reference diagnosis of wipo was established on other criteria by experts blind for lus. results: wipo occurred in ( %) sbt. among cases with wipo, the lus profile did not change during sbt in one case, changed for lus signs of pulmonary oedema in cases (true positives) and changed but without typical lus signs of wipo in one case university hospital of lausanne, intensive care and burn unit saint michael's hospital and keenan research centre, interdepartmental division of critical care a introduction: many different tools are found to predict weaning success us) assessed excursions of the right hemi-diaphragm could be a useful measurement for prediction success in weaning from mechanical ventilation (mv us was performed after patient met weaning criteria (according to local protocol) and it was decided to discontinue mv. patients with neuromuscular disorders and diaphragmatic paralysis were excluded. measurements were performed once on pressure support ventilation (ps ≤ cmh o, peep ≤ cmh o). the right hemi-diaphragms of patients were evaluated by m-mode ultrasonography (esaote mylabgamma ac - mhz convex probe). the average diaphragm excursions value (de avg ) was estimated from sequential measurements. the rapid shallow breathing index (sbi), dynamic compliance (c dyn ), minute ventilation (m v ) and spontaneous tidal volume (v t spont) were obtained from the ventilator (servo i , maquet) table ) with best de avg cut-off value . mm (sensitivity % , specificity %). conclusions: our findings suggest that right hemi-diaphragm excursions assessed with m-mode ultrasonography is more accurate predictor of weaning success than other common weaning criteria weaning from mechanical ventilation diaphragm dysfunction assessed by ultrasonography: influence of weaning from mechanical ventilation a cycling-off guided by real-time waveforms analysis (intellisync+): pilot study on next-generation psv anesthesia and intensive care methods: in patients under psv, intellisync + was compared to to default setting, ets opti decreased cycling delay and unassisted efforts at ps basal, but these favorable effects were not maintained at ps + . further optimization (ets opti ) decreased cycling and trigger delay but did not affect unassisted efforts. when intellisync + was activated, cycling delay was shorter and values of trigger delay and unassisted efforts were at least as low as with optimized settings of ets. table summarizes the results obtained in the conditions tested. conclusions: bedside optimization of ets guided by waveforms on the ventilator screen improved pvi. increase of pressure support level worsened pvi and mandated re-optimization of ets a characteristics and factors associated with prolonged weaning. a sub-analysis of the wind study g upres ea irib saint michael's hospital and keenan research centre, interdepartmental division of critical care objectives: to determine a predictor of weaning success with a faster reaction time than respiratory rate & pulse rate. methods: patients ( male, female) on mv > days were included in our study diagnosed with sepsis (n = ), pneumonia (n = ), pancreonecrosis (n = ), obesity hypoventilation syndrome (n = ), intestinal obstruction (n = ). oxygen consumption (vo ) monitoring in different stages of mv support reduction was recorded using e-covx evaluation of mortality over time in patients receiving mechanical ventilation the use of mechanical ventilation in intensive care unit in russia: national epidemiological survey ruvent- a prospective, blinded evaluation of indexes proposed to predict weaning from mechanical ventilation a randomized, controlled trial of the role of weaning predictors in clinical decision making cpf) using ventilator built-in flow-meter to predict extubation success: a single centre study f. gobert , , h inclusion criteria were: age > years, intubation > h, no withdrawal decision of life supporting care, eligible for scheduled weaning trial and then scheduled extubation, mechanical ventilation from evita xl ventilator (dräger, germany) and patient's agreement to participate. once daily checked criteria for weanibility were present, patients were switched to a standardised pressure support ventilation (inspiratory pressure = cmh o, peep = cmh o, fio = . ) for h (if no chronic respiratory failure-crf), h (if crf) or h (if neuromuscular crf). the procedure of cpf measurement was explained to the patient, who was encouraged to cough as strong as possible just before extubation. cpf measurements were done by freezing ventilator screen and scrolling the cursor to the maximal value of cpf during expiration and tidal volume (tv) in preceding inspiration. three measurements were averaged. early extubation success rate was defined as the proportion of patients who were alive and not reintubated h after scheduled extubation. median values were compared by using non parametric tests. diagnostic performance of cpf and tv was assessed by using area under curve (auc) of the roc method. after having defined cut-off values for cpf and tv, we described the performance of a test combining cpf and tv values to predict the early extubation outcome. results: during the study period, patients were admitted to our icu of who were intubated and patients included (fig ). between the patients who succeeded and the patients who failed extubation, median cpf was − . l/min and − . l/min, respectively (p = . , fig a), median tv . l and . l, respectively (p = , , fig b), and auc averaged . and . , respectively (fig a). bi-dimensional analysis showed a synergistic effect of cpf and tv to predict early extubation success (fig b). the combination of thresholds (cpf < − l/min and tv > . l) grant acknolwedgment the study has been supported by the sigrid juselius foundation, päivikki and sakari sohlberg foundation the third international consensus definitions for sepsis and septic shock acute renal failure in critically ill patients: a multinational, multicenter study relation between mean arterial pressure and renal function in the early phase of shock: a prospective, explorative cohort study grant acknolwedgment this study is supported by the national key technology r&d program of china conclusions: in patients with chronic renal impairment who undergo cardiovascular surgery requiring cpb, a lower level of preoperative shp is independently associated with higher risk of paki. a urinary angiotensinogen as a possible predictor of acute kidney injury in severe sepsis s we aimed to compare the incidence of aki according to rifle (risk, injury, failure, loss of kidney and end-stage kidney disease united kingdom intensive care medicine experimental ):a introduction: cytokine elimination during continuous hemofiltration (chf) depends largely on the character of the filter membrane a references ( ) (kidney disease outcomes quality initiative. kdigo clinical practice guidelines for acute kidney injury antithrombin supplementation for anticoagulation during continuous hemofiltration in critically ill patients with septic shock: a case-control study acquired deficit of antithrombin and role of supplementation in septic patients during continuous veno-venous hemofiltration the influence of venovenous renal replacement therapy on measurements by the transpulmonary thermodilution technique effect of the venous catheter site on transpulmonary thermodilution measurement variables the influence of haemodialysis on haemodynamic measurements using transpulmonary thermodilution in patients with septic shock: an observational study when drugs disappear from the patient: eliminaiton of intravenous medication by hemodiafiltration cardiac arrest in intensive care unit: case report and future recommendations omni® (b. braun, melsungen, germany), a new third generregional citrate anticoagulation. we collected patients' characteristics, filter life time, circuit pressures, interruption of therapy duration and reasons (alarm types), achieved and targeted renal dose, metabolic parameters (serum creatinine and potassium levels and arterial base excess). in addition, we adminof total therapy time) in cvvhd-citrate mode. mean achieved renal dose was . ml/kg/hr corresponding to % of the targeted dose in cvvh-heparin mode and . ml/kg/hr corresponding to % of the targeted dose in cvvhd-citrate mode. in both rrt modes, excellent metabolic control and adequate fluid balance were achieved. overall, the interface, design and ease of use were evaluated by users as excellent. conclusions: crrt in both cvvh and cvvhd modes could be provided using omni® in a safe and efficient way in ten critically ill patients. users provided positive feedback regarding therapy setup, management and user interface. a intermittent haemofiltration outside itu led by the intensive care team. experience at a tertiary cardiothoracic centre s following modification of the aquarius haemofilter (nikkiso), we designed and implemented a protocol for rca with stand alone citrate administration pre filter (acd-a (acid citrate dextrose formula-a) containing mmol/l of citrate) and post dilution cvvhf using calcium containing replacement fluid (accusol containing . mmol/l ca) and, when needed, supplementary calcium depending on systemic ica. the protocol can deliver or mls/kg/hr of crrt. we compare the efficacy of this new protocol, which we have initially implemented in patients with a relative contraindication to heparin, to a historical cohort of patients who received crrt with prostacyclin and or pre-dilution cvvhf but would not have been contraindicated for rca. we also present relevant biochemical data. methods: a prospective audit of the first adult critically ill patients receiving rca with post dilution cvvhf. crude comparison was made with a historical group of consecutive critically ill patients who received crrt without heparin prior to the introduction of the rca protocol. patients were excluded from the rca protocol and the comparison if they had, severe acute liver injury. data is presented as median (range) with non parametric analysis and filter survival as a kaplan meier for the event´filter clotting´and censored for medical cessation or technical failure. results: there were filters used in patients who received rca and in in the comparison group respectively. one patient ( filters) from the rca group was excluded from the filter survival analysis due to a triglyceride level of . mmol/l, causing repeated filter failure epidemiology of acute kidney injury in critically ill patients: the multinational aki-epi study conclusions: there is no relationship between copd patients, bmi, age and extubation failure. this new formula combine parameters, dtf*rsbi, as a good parameter for extubation.methods: we used the administrative claims data of all diagnosis procedure combination (dpc) hospitals in japan from april , to march , , and retrospectively reviewed the number and outcome at discharge of patients who were on ecmo support. results: we identified , patients who received ecmo support during the -year study period. the average age was . , and only . % of the patients were under years old. the most common diagnosis was acute coronary syndrome, followed by cardiac arrest and pulmonary embolism. the overall survival rate at discharge was . % [ %ci . - . ]. among the , acute care dpc hospitals, ecmo support was provided in hospitals ( . %), and therefore the annual ecmo patient volume per hospital was . , which is much lower than international standards for ecmo centers. adjusted odds ratio for discharge alive stratified by annual ecmo volume per hospital were . [ %ci . - . ] and . [ %ci . - . ] for medium ( hospitals treating to patients) and high volume centers ( hospitals treating or more patients), respectively, compared with low volume centers ( hospitals treating or less patients). conclusions: ecmo support was administered to many adult cardiac patients, and provided in a substantial proportion of acute care hospitals in japan. no significant patient volume effect for survival discharge was found. funding from the american nurses association impact grant is gratefully acknowledged. history and icu related data were analyzed. basal fracture risk before ci was calculated using the frax tool (https://www.shef.ac.uk/frax). in january , referent family doctors were contacted by phone to check out new bf occurred during the years after icu discharge. data are expressed as median (min-max) or percentages. unpaired data were compared using mann-whitney test (p < . = significant). results: from the patients admitted in , had an icu los ≤ d, were < y, died in icu or died after an icu los ≤ d and were lost to follow-up. we analyzed patients who were alive in january and patients who died outside icu during the fup after an icu los > d. regarding alive patients ( % males), admission was mainly related to cardiovascular, respiratory and neurological failure, or trauma. age was ( - )y, simplified acute physiologic score (saps ii) was . ( - ), icu los was ( - )d. according to the frax tool, the -y probability of major osteoporotic bf (major frax risk) was . ( - )%. nine patients ( men) developed bf in . ( - ) months after ci, equivalent to a % risk of new bf y after ci. a context of fall at home was noted in every case. age, icu los and saps ii of these patients were not statistically different from non-fractured patients. their major frax risk was ( - )%, significantly higher than non-fractured patients (p = . ). finally, among the dead patients, only one y man experienced hip fracture at the th month after ci. conclusions: present incidence of new bf in the y following severe ci with a prolonged icu stay is similar to previously published data [ ]. patients who experienced new bf after ci had a higher frax risk than the non-fractured patients. influence of ci or icu stay on bf risk is thus questioned. however, to be relevant, our results need to be compared to a control population: this work is ongoing. conclusions: we detected a rise in pro-adrenomedullin levels after cardiac surgery. the results suggest that am could be useful for lcos prediction. more data are necessary to confirm the role in the prediction of relevant outcomes. conclusions: the icu stay and early complications evaluated not differ between the two groups , except for acute renal failure and higher mortality, despite the use of shorter times in cardiac surgical in octogenarians. there is a progressive decrease in coronary artery bypass surgery in recent years in this group probably in favor of percutaneous techniques.high-risk patients who require intensive perioperative management,should be identified to reduce the incidence of postoperative complications.conclusions: previous renal replacement treatment and the colonized patients' long stay at icu increase the transformation of the vre colonization into vre infection. strategies to reduce the duration of icu stay of vre-colonized patients are the main objects to controlling vre infection rate. identification of sirs/sepsis signs by ward nurses reduces -days mortality in patients with sepsis m. torsvik , l.t. gustad , , i.l. bangstad , l.j. vinje , j.k. damås , , , e. solligård , , , a. mehl , , nord university, faculty of health science, levanger, norway; nord-trøndelag hospital trust, levanger hospital, internal medicine, levanger, number of patients had ulceration at the site of the suction port but did not suffer any complication as a result. drainage of pleural effusion with small bore tube in mechanically ventilated patients s.j. lee , y.s. cha , w.-y. lee correlate with decannulation failure but future studies are necessary in this field. objectives: to weight all sharps containers in a cardiac intensive care over a one-week period. to then review the financial implications of the cost of this waste. to review ways to redistribute this waste.methods: all closed sharps containers were weighed. research the cost implications of different waste types from the waste management team within the trust. look into ways of reducing this waste. results: a total of items where weighed, totaling . kg, costing £ . . this can be broken down in six l chest drain boxes, weighing . kg, costing £ . . four l sharps bin, weighing . kg, costing £ . . l sharps bin, weighing . kg, costing £ . , and thirty-nine l sharps bins, weighing . kg, costing £ . . this would take eight weeks to produce a tonne. producing around . tonnes a year costing £ , . . compared to other types of waste: sharps containers: £ per tonne clinical waste: £ per tonne domestic waste: £ per tonne recycling: £ per tonne clinically objects that aren't sharps are placed in sharps bins, for example arterial blood gas syringes, this item could be put into a clinical waste bin. while this suggests education is needed there are other methods to reduce sharps bin wastage. these include: having needle only sharps bins, and solidifying chest drain bottles post removal.conclusions: this cardiac intensive care unit produces a volume of high-cost waste. a large proportion of this waste can be redistributed to other types of waste. this could make the unit more efficient, and reduce it's environmental burden. this audit suggests that it should be looked at other types of waste and other departments in the same manner on other units. in the bloodstream infection density related to hemodialysis catheter in the hospital moyses deutsch was . , which represents patient in its entirety. due to this high rate, it was necessary to review all related process through institutionalized and supervised practice, minimizing the risks of hemodialysis procedure and maintenance of the catheter, in order to directly reduce the length of hospital stay, morbidity and hospital costs. objectives: objective of this study was to evaluate the application of strategies according to ihi to reduce infection of the bloodstream related to cvc hemodialysis. methods: the study was conducted in a -bed, medical-surgical icu. criteria for infection catheter related bloodtream infection are those from the cdc. strategy was to implement the permanent education of employees, highlighting the importance of prevention of infections;training of new employees as the hemodialysis routine and safe and aseptic techniques; optimize other measures that can reduce the risks, such as early removal of invasive devices.raise awareness of nursing staff about the importance of their role in the prevention of infection, such as maintenance of the catheter with use of aseptic techniques; disseminate monthly for teams infection rates; make benchmarking with other services; the goals were the icu team adhesion of % achieved in six month after bundle implementation and % after one year of follow up. from june on, the icu a effect of therapeutic hypothermia on mitogen activated protein kinase pathway in the brain tissue of a swine cardiac arrest model y. c objective: to investigate the change in mitogen-activated protein kinase pathways in the brain tissue after therapeutic hypothermia in swine cardiac arrest model. design. prospective animal study setting. university animal laboratory subjects. male domestic pigs (n = ) interventions: after the return of spontaneous circulation by cardiopulmonary resuscitation following min of no flow time induced by ventricular fibrillation, pigs were randomly assigned to one of four groups (sham, normothermia, hr of therapeutic hypothermia, hr of therapeutic hypothermia). therapeutic hypothermia (core temperature - °c) was maintained and the pigs were then rewarmed for hr. at hr after the return of spontaneous circulation, the pigs were sacrificed and brain tissues were harvested. measurement and main results: we measured the tissue levels of p , jnk, and erk pathway expressions in swine brain hippocampus of the four groups. the phosphorylated p to p ratio and phosphorylated jnk to jnk ratios were significantly increased in all of the intervention groups, relative to the sham group. but the phosphorylated erk to erk ratio was increased only in the therapeutic hypothermia groups (p-value = . in the hr of therapeutic hypothermia group and p-value = . in the hr of therapeutic hypothermia group, both compared to the sham group). conclusions: normothermia activated the p and jnk pathway. and did not activate the erk pathway in ischemia-reperfusion injury after cardiac arrest. therapeutic hypothermia, however, did not attenuate the activation of the p and jnk pathways, but activated the erk pathway, which seemed to be dose dependent with the duration of therapeutic hypothermia. effect of permissive hypercapnia on outcome of cardiac arrest in a porcine model of cardiopulmonary resuscitation g. babini , g. ristagno figure ). pigs in the hypercapnic group showed a trend towards longer survival. etco and pco were significanlty higher in the hypercaninc group compared to the normocpanic one (table ). ph and po trended to be lower in the hypercapnic group during the hrs of observation. hypercapnia was associated with significantly higher mean arterial pressure during the post-resuscitation (pr) period ( lesser neuronal degeneration was seen in the frontal cortex in the hypercapnic group compared to the normocapnic one (figure ) . neurological recovery was equivalent in the two groups ( figure ). conclusions: permissive hypercapnia after resuscitation was associated with better mean arterial pressure and lesser neuronal degeneration in pigs. grant support. laerdal foundation for acute care, norway introduction: pain is the main indication for utilisation of the physician staffed prehospital emergency service in germany. data from switzerland showed that oligoanalgesia (inappropriate treatment of pain with nrs > ) is common in trauma patients. objectives:( ) determination of the frequency of oligoanalgesia in trauma patients at our prehospital emergency service location in objectives: assessment of characteristics and outcomes of patients who suffer cardiopulmonary arrest resuscitated in a tertiary hospital, inside and outside intensive care unit, according to utstein style.methods: a prospective cohort study was performed according to utstein style. every arrest occurred in the hospital "virgen de las nieves" (granada, spain) for a period of years (july/ -june/ ) were included. all arrest occurred in all areas of the hospital were included, except those in operating rooms and anesthesia recovery room (not attended by the resuscitation team) and those commenced in the prehospital setting. we also excluded patients in whom no resuscitation attempt was made or those suspended either by existence of a living will, by orders dnr or considered futile. the variables were grouped according to the location (inside or outside the icu). chi test was performed when the dependent variable was qualitative and a t-student test when it was quantitative.results: during this period a total of patients suffered at least one episode of arrest and they were resuscitated. most frequent sex was male ( . %) with a median age years ( . ± . years; interquartile - years). the cardiac origin was the most common aetiology ( . %). the icu was the area most frequent location ( . %). when comparing the characteristics of icu arrests with the rest of the hospital, significant differences were observed. it was most likely to have a shockable initial rhythm (χ : . ; p = . ), younger age ( , ± , vs , ± , years; t = , ; p = , ), shorter interval to defibrillation ( , ± , vs , ± , min; t = , ; p = , ), shorter period until start of resuscitation ( , ± , vs , ± , min; t = , ; p < , ) and shorter total duration ( ± , vs , ± , min; t = , ; p < , ). however, no differences were found in coronary aetiology, sex, recovery of spontaneous circulation and hospital survival ( . % vs . % in icu).conclusions: despite higher frequency in initial shockable rhythms and lower intervals until defibrillation and resuscitation in the icu, no differences were found in initial recovery or hospital survival. delayed onset of cardio-pulmonary resuscitation (cpr) does not induce hyperfibrinolysis in a piglet model of ventricular fibrillation -a pilot study in göttingen minipigs n. introduction: pulmonary arterial hypertension (pah) is a disease with gradually increased pulmonary vascular resistance and pressure, often leads to right ventricular (rv) failure and death. excessive proliferation of pulmonary arterial smooth muscle cells (pasmcs) is regarded as the major cause of the remodeling of pulmonary artery, whereas the underlying mechanism is largely unclear. caffeic acid phenethyl ester (cape) is the main component of propolis, which is known as a versatile compound of antimitogenic, anticarcinogenic and anti-inflammatory potentials. objectives: to investigate the effects of cape on the improvement of the hemodynamic function in pah animal model and to explore the underlying mechanisms in in vitro pasmcs. methods: animal model of pah symptom was induced in - grams sprague-dawley rats by subcutaneous injection of monocrotaline (mct, mg/kg). weeks later, the mct-induced pah rats received intraperitoneal administration of cape with various dosages of or mg/kg once per day, for further weeks. hemodynamic functions, including rv systolic pressure (rvsp) and fulton index, were measured before sacrifice. the lung tissues were harvested for examining the vascular remodeling of pulmonary artery. to investigate the molecular mechanisms, in vitro cultured human pasmcs challenged with either % oxygen level or recombinant human pdgf ( ng/ml), followed by the treatment of cape in or mm. the change of expression level and phosphorylation of the cellular signaling molecules, including erk, akt, nf-kb, or hif- a, were analyzed by semi-quantitative pcr and western blotting, respectively. results: in mct-induced pah rats, cape significantly improved the hemodynamic values of rvsp, fulton index, and attenuated the severity of pulmonary vascular remodeling. furthermore, the administration of cape critically reduced the expression levels of hif- a, nf-kb and pdgf molecules in the lung of mct-induced pah rats. in vitro assay showed that an increased expression level of hif- α and pdgf genes in hpasmcs was observed under hypoxia or pdgf stimulation, which was significantly suppressed following cape treatment. for chemical inhibition, we indicated that cellular signaling molecules erk, akt and nf-kb were involved in the up-regulation of hif- a and pdgf genes, which were responsible for the proliferation of hpasmcs exposed to hypoxia or pdgf stimulation. in addition, cape also significantly promoted the number of apoptotic cells and the number of cell arrested in g phase of hpasmcs by tunel assay and sa-b-galactosidase staining, respectively. conclusions: we showed evidence that the natural compound cape could provide therapeutic benefits on the reversal of experimental pah rats. importantly, the results further indicated that the hif- a-mediated pdgf expression is a positive feedback mechanism underlying the pathogenesis of pah, which was regulated by the akt/erk/nf-kb signaling. right ventricular arterial coupling after cardiac surgery: a preliminary report p. introduction: right ventriculo-arterial coupling (rvac), defined as the ratio of end-systolic elastance (rees) to pulmonary arterial elastance (rea) is considered a sensitive method to assess right heart performance [ ] . objectives: in this study we aim to identify the feasibility of measuring rvac in hemodynamic deranged patients undergoing complex/ emergency cardiac surgery using cardiopulmonary bypass (cpb) as an experimental model of further hemodynamic impairment. objectives: this study aims to determine the frequency of the vre colonization and the transformation into infection and the risk factors, which lead to infection. methods: the patients who were hospitalized for at least hours in tertiary mixed type icu between and and had vre colonization and vre infection during or following their hospitalization were included in the study and their medical records were examined retrospectively. vre rectal swab sample was taken from each patient at his arrival and once a week afterwards. when negativity was detected in the rectal swab sample, which had been taken total times successively from those with positive vre; that patient was considered vre negative. their demographic data, apa-che ii scores, invasive procedures, treatments (corticosteroid, antibiotics, etc.), nutrition types, laboratory results and icu outcome were recorded. results: vre colonization was detected in of patients ( . %) admitted to icu. vre infection developed in of vre-colonized patients ( . %). among these infected patients; it was (n = ) . % primary bloodstream infection, (n = ) % urinary tract infection, (n = ) % . pneumonia. in vre colonized patients ( . %) and infected patients ( %), the most frequent factor was e. faecium. in % of the vre-colonized patients, vre became negative in their stay at icu. previous renal replacement treatment was significantly higher in statistical terms in the vreinfected group ( . %) when compared to vre-colonized group ( . %) (p < . ). in the vre-infected group, colonization with vre lasted longer than week in patients ( . %) were determined. demographic data, apache ii scores, treatments, nutrition types, previous antibiotic usage and types, invasive procedures, laboratory results and icu outcome were similar between the vre-colonized and infected patients.objective: to assess the value of enteral paramomycin to decontaminate patients with rectal colistin and/or carbepemenase resistant microorganisms colonization to prevent the development of icu nosocomial infections methods: all consecutive patients admitted to the icu from october to september , expected to require tracheal intubation for longer than hours, were given sdd with a -day course of intravenous cefotaxime, plus enteral colistin, tobramycin, nystatin in an oropharyngeal paste and in a digestive solution. oropharyngeal and rectal swabs were obtained on admission and once weekly. rectal swabs colonized by colistin and/or carbepemenase resistant microorganisms were treated with enteral paramomycin gram every hours a day, in order to eradicate them and prevent nosocomial infections. categorical variables were summarized as frequencies and percentages and the continuous ones as medians and interquartile ranges (iqr) or means and standard desviations. statistical significance was set at p ≤ . . results: we applied paromomycin treatment to colonized patients with rectal colistin resistant microorganisms. all of them had colonization by extended spectrum beta-lactamases (esbls). also, all of them but two were klebsiella pneumonia. out of these two, one patient was colonized by enterobacter spp and other one by escherichia coli. demographic data and type of admission are shown in fig. . forty out of ( , %) of the studied patients the rectal swab became negative. five out of the patients were colonized by carbapenemases producing microorganisms and one of these died with persistent multirresistant rectal colonization. only out of the patients that negativized the colonization received concurrent susceptible iv antibiotics. only of the paromonycin treated patients developed a mediastinitis infection due to one of the treated microorganisms. finally, patients died in the icu. conclusion: our data show that enteral paramomycin is effective in treating rectal colistin and/or carbepemenase resistant microorganisms colonization allowing clinicians preventing the development of icu nosocomial infections. introduction: diaphragmatic thickness increases as lung volume increases towards tlc. it has been shown that in healthy subjects, diaphragmatic thickness, increases as lung volume increases, above . of the vital capacity (vc). in mechanically ventilated patients, different levels of peep are used to improve oxygenation. there is no information about the diaphragmatic thickness when in icu patients, lung volume increases with peep towards tlc. methods: in patients with acute respiratory failure (arf) and lower lobe atelectasis detected by lung echo, two levels of peep ( and ± cmh o) are used to increase lung volume and to improve oxygenation. end expiratory lung volume (eelv), and diaphragmatic thickness was measured at baseline (zeep) and at the two levels of peep. eelv was measured with a nitrogen indirect dilution method and diaphragmatic thickness at the zone of apposition with echography using a mhz linear probe. statistical analysis was performed by one way anova and normal distribution by colmogorof-smyrnof test. results: patients ( m and f) with a mean age of ± were studied. diaphragmatic thickness at baseline was , cm and eelv at ml ( %) of the predicted ( ml). at the intermediate and high level of peep diaphragmatic thickness did not change significantly ( . and . cm, respectively, p = . ) and eelv increased at % ( ml) and % ( ml) of the predicted. the increase in lung volume induced by peep was at % and % of the predicted vc ( ml). mean pao /fio ratio did not change significantly conclusions: mechanically ventilated patients for arf have a severe reduction in their eelv or frc. the use of peep reestablishes partially the eelv, but not to his normal levels(predicted frc). despite high levels of peep, diaphragmatic thickness remained constant because the increase in eelv never attained the % the vital capacity.introduction: the majority of patients entering the weaning process from mechanical ventilation (mv) in the intensive care unit (icu) will have a short and simple weaning (sw) successfully terminated within hours, while other may take up to one week (difficult weaning) or longer. studies have shown that using a sedation or a weaning protocol could reduce the length of mechanical ventilation and the weaning duration. objectives: to describe factors associated with sw and particularly assess if sedation and weaning protocol are associated with the proportion of patients having a sw. methods: we used the data from the wind (weaning according new definition) study, a prospective multicenter observational study performed in france ( icus), spain ( icus) and switzerland ( icu) from april to august . ventilation and weaning modalities were daily assessed until discharge in all intubated patients admitted to the participating icus. we defined ) weaning attempt (wa) as a spontaneous breathing trial (sbt) or an extubation attempt (with or without sbt), ) successful weaning as an extubation without death or invasive mechanical ventilation within days. we considered patients as having a sw if weaning was successfully terminated within h following their first wa. having a protocol for sedation or for weaning (or both) was asked to each center. quantitative and qualitative variables are presented as mean (standard deviation), median [interquartile range] or number (percentage) as appropriate. comparisons of proportions were made using chi or exact fisher tests and continuous variables were compared using student t-test or wilcoxon rank sum test as appropriate. we performed a multivariable analysis of factors associated with sw by means of a logistic regression, forcing both sedation and weaning protocols in the final model. all statistical tests were two-sided and p values of . or less were considered significant. results: among the patients included, patients entered the weaning process and we only kept in the present analysis the patients who did not have any decision of withholding or withdrawing mechanical ventilation. among these patients, ( %) had a sw and ( %) had a weaning duration longer than hours. main clinical characteristics are shown in table . conclusions: in this study of patients with a daily assessment of the weaning process, hospitalization in an icu using a sedation protocol or a weaning protocol (as declared by the center) was not associated with a higher proportion of patients having a simple and short weaning. admission for planned surgery, younger age, lower sofa score at admission and shorter duration of ventilation before any weaning attempt were associated with a higher proportion of simple and short weaning. this study benefited of a grant of the non-profit association départementale des insuffisants respiratoires (adir) of the haute normandie, france. introduction: during weaning from prolonged ventilation overload of diaphragm as main breathing muscle should be avoided. clinical criteria are used for determining the end of the spontaneous breathing trial (sbt) in the context of a discontinuously concept for weaning. in addition the patients subjective feeling of breathing exhaustion plays an important role. in incommunicable patients lacks this possibility for feedback.continuous monitoring of diaphragm electrical activity could give information of respiratory muscle effort during sbt. objectives: in tracheotomized patients undergoing prolonged weaning the relationship between the protocol-based definition of the end of a sbt and the course of the electrical activity of the diaphragm (eadi) should be examined. methods: prospective observation study conducted in a beds intensive care unit in an early rehabilitation clinic. patients that were not communicable because of stroke ( ), cerebral hypoxaemia ( ), traumatic brain injury ( ) have been included. using an eadi-catheter usually applied in nava (neurally adjusted ventilatory assist)-ventilation, peak of diaphragm electrical activity (eadi peak) was continuously recorded minutes before disconnection from ventilator up to minutes after reconnection. the weaning protocol contained two possibilities for terminating of the sbt: reaching clinical signs of ventilation exhausting or reaching a previously fixed time limit. results: median duration of mechanical ventilation at study start was days and days at successful weaning ( / patients, died). sbt have been recorded, terminated because of exhaustion, by time limit. median duration over all was minutes (exhaustion: / time limit: ). with multiple regression analysis, the relationship between the duration of the sbt and the eadi peak was examined. looking at all sbt, which were terminated due to exhaustion, shows that the duration of the sbt has a highly significant impact on eadi ( p < . ). the mean increase of eadi peak was . μv (absolute) and . (relatively). in sbt terminated because the time limit has been reached, there was no significant correlation between the time and course of eadi peak. conclusions: continuous recording of the electrical diaphragmatic activity during weaning of prolonged ventilation in incommunicable patients can be used as supplementary parameter in monitoring the respiratory function. introduction: patient-ventilator asynchronies are associated with poor outcome. it was suggested that bedside analysis of ventilator waveforms may help detecting different types of asynchrony and setting properly the ventilator [ ] . objectives: to test accuracy of a "waveform" method, based on specific signs on airway pressure (paw) and flow curves, in detecting spontaneous respiratory activity and asynchronies in patients under pressure support ventilation (psv).methods: recordings ( min each) of esophageal pressure (pes), paw and flow were obtained in obstructive ( %) and restrictive ( %) patients under psv with clinical evidence of poor patient-ventilator interaction. tracings of breaths were visually analyzed for detection of spontaneous respiratory activity both with pes (reference method) and without pes (waveform method) by different operators. breaths were defined as assisted, unassisted or autotriggered, and assisted breaths as delayed triggered, early cycled or delayed cycled. the waveforms method was applied in a selection of tracings ( min, breaths) by different operators for assessment of inter-rater agreement. results: the reference method detected autotriggered ( . %), unassisted ( . %) and assisted ( . %) breaths; among assisted breaths, delayed triggered ( . %), delayed cycled ( . %) and early cycled ( . %). table shows sensitivities and specificities ( % ci) of the waveform method in evaluating patient-ventilator interaction. the waveform method detected the start of patient's inspiration and expiration with a bias of − and − ms and a precision (± . sd) of and ms respectively. absolute agreement among operators was almost perfect for unassisted breaths, strong for delayed triggered, delayed cycled and early cycled breaths, and weak for autotriggered breaths. conclusions: the waveforms method is a reliable, accurate and reproducible method to assess patient-ventilator interaction and could help optimal setting of the ventilator. automation of this method may allow continuous monitoring of ventilated patients and/or improved breath triggering and cycling.methods: we studied a group de mechanically patients during the weaning time, at pressure support ventilation (psv) with different levels of assistance (high - cmh o, medium - cmh o, low - cmh o). esophageal, gastric, airway pressure, and airway flow were registered, samplig hz. we determined the phase difference (Φ) relationships between the neuronal times obtained from derivative flow versus esophageal or gastric signal respect to machine cycle, by calculating the phase delay, dividing by the cycle time of ventilator* °. times (t) definitions: t = onset inspiratory effort, t / = effort maximum. data were analyzed by descriptive statistical methods and are expressed as mean ± sd, medians, interquartile range (irq, - % quartile), and coefficient of variation (cv). the comparisons were performed by mann-whitney test. the relationships between measurement methods was examined using single linear regression and bland-altman analysis. results: patients were studied. for all data angle phase Φ median (irq): t : , (− , to , ), t / : − , (− , to , ). the mean comparison of t and t / between pes and df did not showed statistical differences for any level of support, and correlation r > , . the cv for all data at the t of pes and df: % and %, respectively; and for the t / of pes and df: % and %, respectively; without differences between levels of assistance. table below show results from bland-altman analysis. figure show representative tracing of df with well-defined inflection points (arrows) at t and t / , as the onset inspiratory flow and transition from inspiratory to expiratory flow. conclusions: the derivative of flow signal is useful to measure with accuracy neuronal and cycling times, it´s more homogeneous and precise than obtained for esophaeal or gastric pressure for all levels of assistance. the derivative of flow signal is a non-invasive signal which can be calculated easily and useful by conventional ventilator. introduction: sepsis has been defined as organ dysfunction as a result of the inappropriate host response to infection. [ ] renal function is often injured at the early stage of sepsis. [ ] autoregulation, which plays an important role in maintaining an adequate renal blood flow against changes in blood pressure, could be impaired during sepsis, [ ] thus resulting in aki if blood pressure fluctuates greatly. objectives: to investigate if there is any relationship between blood pressure variability (bpv) and aki in septic patients. methods: clinical data of patients admitted to our bed medical icu between / and / were reviewed. continuous records of blood pressure were analysed. blood pressure variability was calculated as the coefficient of variation (cv) of mean arterial pressure in the first h of admission. aki was defined by the kdigo definition according to creatinine change and urine output criteria. [ ] results: adult patients with sepsis (age: . ± . years old; apache ii score: . ± . ; male: . %) who stayed at icu for more than three days were identified. aki was presented in ( . %) of them (stage : n = ; stage : n = ; stage : n = ). the bpv was . ± . % for the patients with aki versus . ± . % for the others (p < . ). icu mortality was . % for the aki group compared to difference was not statistically significant regarding creatinine level on admission (p = . ). moreover, there was a positive correlation between uancr ratio on admission with akin staging and creatinine level of the all studied patient in the follow up days. the cutoff value of uancr on admission to predict later occurrence of aki during icu stay was . ng/mg: at this level, ( . % sensitivity and . % specificity). conclusions: urinary angiotensinogen is a new promising biomarker in early prediction of aki in patients with severe sepsis. acute kidney injury in patients with severe sepsis or septic shock: a comparison between the "risk, injury, failure, loss of kidney function, end-stage kidney disease" (rifle), acute kidney injury network (akin) and kidney disease improving global outcomes an st and polymethyl methacrylate (pmma) membranes have strong adsorption capacity. cytokines play important roles as the main mediators affecting critically ill patients. however, differences in the cytokine elimination by specific membranes during chf have not yet been fully investigated. objective: the objective of this study was to determine the elimination of cytokines by an st and pmma membrane filters during chf in a pig sepsis model. methods: piglets (n = ) weighing - kg were anesthetized and administered μg/kg endotoxin. the baxter sepxiris (an st membrane) and the toray hemofeel . w (pmma membrane) were used as hemofilters. samples were taken at , , , and hours after endotoxin administration, and the inlet plasma, outlet plasma, and filtrate concentrations of tnf-α, il- β, il- , and il- were measured. clearance values were calculated for each cytokine. results: endotoxin administration induced increases in the inlet plasma concentrations of all cytokines measured. the an st membrane filter showed higher adsorption and clearance of il- than the pmma membrane filter at hours after endotoxin administration (an st: . ± . ml/min; pmma: − . ± . ml/min; p < . ). however, the pmma membrane filter showed higher adsorption and clearance of il- β than the an st membrane filter. il- did not appear in the filtrate of the pmma membrane filter, while il- was not eliminated in the filtrate of the an st membrane filter. in addition, the filtrate concentration of tnf-α increased after its plasma concentration decreased with the pmma membrane filter. conclusions: shiga et al. previously reported the efficacy of cytokine absorption by an st membrane filters during continuous hemodiafiltration, and matsuda et al. reported the efficacy of cytokine absorption by pmma membranes. however, the cytokine absorption efficacy by these two membrane filters had not been directly compared. the results shown here confirm that there are differences in cytokine adsorption by the an st and pmma membrane filters. introduction: continuous renal replacement therapy (crrt) in intensive care is a cornerstone in the supportive treatment arsenal. its influence on thermodilution cardiac output measurements, and the possible influence of central venous dialysis catheter(cvdc) position, has been studied but the results are of uncertain clinical impact ( ) ( ) ( ) . there have been case reports describing the possibility of direct aspiration into a cvdc of drugs given in adherent central venous catheter(cvc) ( , ) . objectives: the aim of this study was to investigate if different positions of central lines influence infused noradrenaline during continuous renal replacement therapy (crrt) in an experimental animal model. methods: ten anesthetized piglets received a cvc in the right jugular vein and two cvdcs (one via the same jugular vein as the cvdc and the other through a femoral vein). after randomization the crrt was started in either one of the cvdcs and a nitroprusside infusion was started in an auricular vein. the dose was titrated until the mean arterial pressure (map) was mmhg and then kept constant during the rest of the experiment. after reaching the intended blood pressure an infusion of noradrenaline was started and titrated with the goal of increasing the blood pressure to a map of mmhg during minutes. after a washout period the crrt circuit was changed to the other cvdc and the experiment was repeated. results: the median dose of noradrenaline with the crrt in the jugular vein was . (iqr . ) and in the femoral vein . (iqr . ) μg/kg/min (p = . ). conclusions: during crrt, the noradrenaline dose needed to reach a target blood pressure in hypotensive piglets was twice as high with the cvc and cvdc close together, compared with cvc and cvdc on opposite sides of the diaphragm. this suggests that there is a possible clearance of noradrenaline and that the clearance is affected by catheter positioning a first evaluation of omni, a new device for renal replacement therapy p. schlaepfer , , j.-d. durovray , , v. plouhinec , c. chiappa , r. bellomo , a.g. schneider introduction: due to the lack of conventional dialysis facilities in our centre, intermittent renal replacement therapies (irrt) are led and performed by the itu team. this team comprises a group of specialist outreach nurses with the support of intensivists. irrt are performed nocturnally by itu nurses in level areas according to our hospital policy. objectives: to describe the use and results of irrt in level areas in patients that have left itu with established aki. these therapies are directed and performed by specialist intensive care nurses with the support of the itu medical team. methods: retrospective observational study that included those patients admitted to level areas at harefield hospital during that were transferred to level areas still requiring irrt. demographic variables were collected, along with the indication and duration of irrt and results. results: patients were admitted to harefield hospital level areas during , of which patients required continuous renal replacement therapies (crrt). this population included patients admitted after cardiac and thoracic surgery, heart or lung transplantation, mechanical circulatory devices, out of hospital cardiac arrests (oohca) and medical admissions from the cardiology or cardio-thoracic surgical wards. demographic variables were collected, along with the indication and duration of crrt. of those patients still required intermittent renal replacement therapies at their discharge to a level area. of them ( . %) were male and the group was a median age of . years. of them ( %) were hypertensive and ( %) were diabetic. as shown in figure , the most frequent reason for admission to intensive care was cardiac surgery ( . %, patients), followed by lung transplantation, heart transplantation and medical admissions from the transplantation ward. the reasons for admission to intensive care in the general crrt group are also shown in figure . the most frequent indication for initiation of crrt was metabolic acidosis ( . %, patients), followed by a combination of uraemia and fluid overload ( . %, patients), uraemia ( . %, patients) and fluid overload ( . %, patients) as shown in figure . the median time of rrt was days days whilst the median time of filtration in the general rrt group was days. the in-hospital mortality (after discharge from itu) was . % and was . % in the general crrt group. no complications were associated with the use of intermittent renal replacement therapies in level areas. conclusions: the group of patients that required intermittent renal replacement therapies beyond their discharge from itu had longer itu and hospital lengths of stay. these therapies were performed safely in level areas by the itu team, allowing these patients to leave level areas to continue their care. key: cord- -li pwigg authors: nan title: esicm monday sessions october date: - - journal: intensive care med doi: . /s - - -x sha: doc_id: cord_uid: li pwigg nan methods. for the present investigation, healthy male volunteers with a mean age of ± . years were recruited for a cardiovascular screening exercise stress test prior to inclusion for the study. during the lbnp protocol, the subjects were exposed to sequential increasing negative pressures of - , - , and - mmhg while resting in a supine position with their legs sealed in the lbnp chamber at the level of the iliac crest. in addition to continuous registration of cardiac output (co) and mean arterial pressure (map), sublingual perfused vessel density (pvd) ( ) and microvascular flow indices (mfi) ( ) were measured using sidestream dark-field (sdf) imaging before (t ), during (t ; - mmhg), and after (t ) lbnp. results. there were no significant differences in mean co and map in our subjects. introduction. fever management remains controversial in sepsis. control of thermal balance might improve vascular tone but fever could play a role in host defence. objectives. the aim of this multicentre randomised controlled trial was to determine primarily whether external cooling might accelerate the weaning of vasopressors in patients with septic shock. patients with septic shock treated with epi/norepinephrine infusion and fever over . °c were enrolled in centres when also requiring mechanical ventilation and sedation. patients received external cooling to reach normothermia ( . - °c) during h (n = ) or had fever respected (n = ). a goal of mmhg for mean arterial pressure was used in the two groups. a similar algorithm was used for weaning of vasopressors. the main end point was the number of patients achieving a % decrease in the initial dose of vasopressor in the two groups. shock reversal was defined by vasopressor withdrawal for at least h. at inclusion the two groups (cooling/respect of fever) were similar for age ± versus ± years, saps iii ( ± vs. ± ), sofa score ( ± vs. ± ), and body core temperature ( . ± . vs. . ± . °c). a similar number of patients received steroids and a pc before enrolment. body temperature became significantly lower in the cooling group within the h of treatment: . ± . vs. . ± . at h and . ± . vs. . ± . °c at h (p \ . ). the decrease in vasopressor was more rapid in the cooling group (fig. ). shock reversal was vs. %, p = . and in-hospital mortality was vs. % in the cooling and the respect of fever groups respectively. conclusions. these preliminary results show that treating fever using external cooling in septic shock patients allows a more rapid decrease in the dose of vasopressor without apparent adverse effect. grant acknowledgment. aphp-scr . we set up to describe the antibiotic treatment regimens prescribed for patients with severe sepsis in spanish icus and to analyze the potential therapeutic benefit of combination therapy. methods. edusepsis subanalysis, including all patients with severe sepsis admitted to the participating icus during months, in three periods between november and june . there was analyzed the time between the presentation of sepsis and the initiation of antibiotic treatment and empirical antibiotic used in terms of focus and origin of sepsis (community/nosocomial). we also studied the combination therapy compared to monotherapy, assessing the impact on outcomes of combination therapy in particular. the results are presented as frequencies (percentage) or mean ± standard deviation. results. there were included , patients with severe sepsis (age . conclusions. combination therapy is not associated with a better outcome in this large cohort of patients with severe sepsis. nevertheless, there is room for improvement since % of patients did not receive antibiotic therapy within the first h from admission, as recommended by the ssc. introduction. tracheostomies are increasingly common in hospital wards and can lead to significant patient harm. this is partly due to bed pressures in uk critical care units and the increasing use of percutaneous and surgical tracheostomies for critical care patients. commonly, hospital wards lack the infrastructure to care for tracheostomies safely. objectives. analyse tracheostomy-related critical incidents reported in the uk over a year period. we wished to identify themes and make recommendations to improve patient safety. methods. the search was conducted from st october to th september and was conducted in february to allow time for incidents to be submitted. the selected incidents were then incorporated into an access database (microsoft office ) and the description of each incident was read and reviewed. we analysed tracheostomy-related critical incidents reported to the uk national patient safety agency over a year period, identified by key letter searches. we categorized the records to identify recurring themes and then performed root cause analysis where possible. results. we identified , incidents from the npsa incident database originating from hospital wards during the study period having the defined letter sequences. of these incidents, were associated with tracheostomies; directly affecting patients with the remaining not directly affecting individual patients. in the incidents where patients were directly affected ( %) were associated with some identifiable patient harm of which ( %) were associated with more than temporary harm. in incidents ( %) some intervention was required to maintain life and in cases the incident may have contributed to the patient's death. there were cardiac arrests and respiratory arrests described in these incidents. of the incidents, involved equipment and there were blocked or displaced tracheostomy tubes described. note: an individual incident could be classified in multiple fields conclusions. we were able to identify themes in incident reports associated with tracheostomies and identify areas where care could be improved to reduce risks to patients. there were a number of recurrent problems that contributed to incident evolution or severity that would be potentially avoidable. these include: introduction. the study of computerized thoracic tomography patterns can be of great help in the diagnosis of the causes of acute respiratory failure in the icu patients. we hypothesized that the consecutive analysis of a series of thoracic cts will contribute to the management of these critically ill patients. objectives. to study, over a three-month period, the thoracic cts performed in the adult icu in the albert einstein hospital in são paulo, brazil. methods. from may st to august st, , all the thoracic cts were analyzed by two radiologists from the albert einstein hospital staff according to a pre-established protocol: ( ) presence of parenchymal consolidations; ( ) ground-glass opacities; ( ) septal thickening; ( ) atelectasis ( ) pleural effusions; ( ) pneumothorax ( ) pneumomediastinum; ( ) subcutaneous emphysema; ( ) presence of nodules; ( ) presence of masses; ( ) presence of cysts; ( ) emphysema; ( ) bronchial thickening. results. hundred and sixteen thoracic cts were performed and analyzed over the study period, from ( . %) males and ( . %) females. the mean age of the patients was . ± . years. thoracic ct analysis revealed: ( ) parenchyma consolidations: ( . %); ( ) ground-glass opacities: ( %); ( ) septal thickening: ( . %); ( ) atelectasis: ( . %); ( ) pleural effusions: ( %) ( ) presence of pneumothorax: ( . %); ( ) pneumomediastinum: ( . %); ( ) subcutaneous emphysema: ( . %); ( ) nodules: ( . %); ( ) presence of masses: ( . %); ( ) presence of cysts: ( . %); ( ) emphysema: ( . %); ( ) bronchial thickening: ( . %). conclusions. thoracic ct is a useful tool for a detailed analysis of the lung parenchyma, specially in the detection of ground-glass opacities, consolidations and atelectasis, improving the diagnostic possibilities and management of acute respiratory failure. s. wolf , , a. rieß , j.f. landscheidt , c.b. lumenta , l. schürer , p. friederich charite campus virchow, department of neurosurgery, berlin, germany, klinikum bogenhausen, neurosurgery, muenchen, germany, klinikum bogenhausen, anesthesiology, muenchen, germany introduction. extravascular lung water index (evlwi) may present a valuable marker for the severity and treatment of acute lung injury and acute respiratory distress syndrome. measured by single indicator transpulmonary thermodilution and indexed to predicted body weight, a threshold of ml/kg is currently regarded as the upper limit of normality. however, so far only critically ill patients were studied and data from subjects with normal cardiovascular function is lacking. objectives. to prospectively investigate evlwi in patients without cardiopulmonary compromise. methods. patients requiring elective brain tumor surgery were equipped with a transpulmonary thermodilution device (picco . , pulsion medical systems ag, munich, germany). triplicate evlwi measurements were performed after induction of anesthesia (time point ), before (time point ), during (time points and ) and after surgery (time point ) as well as after extubation (time point ) and before discharge from the neurosurgical icu (time point ) . data were recorded electronically and investigated with a random effect model to cope for multiple measurements per individual. results. valid measurements were performed in patients ( female/ male, fig. ). no patient showed clinical signs of over-hydration or cardiopulmonary failure and all were discharged regularly from the icu on postoperative day one. indexed to predicted body weight, females had a mean evlwi of . (sd . , range - ) ml/kg and males had a mean evlwi of . (sd . , range - ) ml/kg (p \ . ). % of the measurements in females and % in males exceeded the threshold of ml/kg. no significant differences were between the different time points of measurement (p = . ) or during anesthesia and after extubation (p = . ). conclusions. measured with single indicator transpulmonary thermodilution and indexed to predicted body weight, evlwi frequently shows values above the previously established normality threshold of ml/kg in patients without cardiopulmonary compromise. females present significantly higher values than male patients. as we are not aware of any abnormal hemodynamic profile for brain tumor patients, we propose our findings as a close approximation to normal values for evlwi. introduction. cardiovascular dysfunction is though to be common during weaning from mechanical ventilation. however, its precise incidence is unknown in this setting. in addition, the respective impact of systolic and diastolic dysfunctions on the weaning process have not been studied. objectives and methods. this is an ancillary study of the ''bnp for the management of weaning'' clinical trial. patients were ventilated with an automated weaning system as soon as they tolerated pressure support ventilation with an fio b %, a peep level b cmh o, and a total inspiratory pressure b cmh o. a total of patients underwent transthoracic echocardiography (tte) at day (initiation of weaning). in addition, serial tte were performed in a subgroup of patients to explore left ventricle filling pressures variations during daily weaning trials (low-pressure support with zero end-expiratory pressure). filling pressures were assessed using the ratio of early transmitral peak velocity (e) over early diastolic mitral annular velocity (e ). results. day tte revealed a systolic (ejection fraction \ %) or diastolic dysfunction (defined as e \ . cm/s) in half of patients. treatment during weaning included diuretics ( % of patients), vasodilators ( %) , dobutamine ( %), amiodarone ( %) and betablockers ( %). diastolic dysfunction was more prevalent in patients with difficult or prolonged weaning as compared to those with simple weaning (weaning duration \ days). serial tte revealed a greater increase in e/e ratio during failed weaning trials as compared to successful trials. conclusions. when treated, systolic dysfunction does not seem to jeopardize weaning. in contrast, diastolic dysfunction is associated with difficult/prolonged weaning. during failed weaning trials, there is a more pronounced increase in filling pressures as compared to successful trials. introduction. monitoring and determination of fluid responsiveness in a critically ill patient who presents with circulatory compromise and septic shock is essential but often, challenging and difficult. continuous haemodynamic monitoring using arterial pulse contour analysis is less invasive compared to the thermodilution method using the pulmonary artery catheter. objectives. we aim to assess the utility of stroke volume variation as measured by the flotrac Ò device (edwards lifesciences, irwine, usa) as a predictor of fluid responsiveness in patients with septic shock. we studied mechanically ventilated adult patients with septic shock in the medical intensive care unit (icu) of a university hospital. haemodynamic parameters including stroke volume variation (svv) and stroke volume (sv) were recorded using radial arterial pulse contour analysis (flotrac Ò pressure sensor versions . and . ) before and after a crystalloid fluid challenge. fluid responsiveness was defined as an increase of c % in sv after the fluid challenge. results. the sensitivity, specificity, positive predictive value and negative predictive value of a svv of c % to predict fluid responsiveness were respectively . , . , . and . %. the area under the receiver operator characteristic curve for the prediction of fluid responsiveness using svv (pre) was only . . similarly, there was no correlation between svv (pre) and the absolute change in stroke volume (spearman's rho - . , p = . ). conclusions. our study's findings call for caution with the use of svv measured via versions . and . of the flotrac Ò device to predict fluid responsiveness in patients with septic shock. further studies are now required to assess if recent software upgrades may provide more accurate svv measurements in severely septic patients. objective. our objective was to assess the recent literature with respect to cco monitor validation. in particular we wished to determine if study protocols reflected the dimension of time. we looked at four different cco monitors: vigileo tm , picco tm , pulseco tm , and oesophageal doppler (odm). human validation studies of cco monitors were sought through the ovid interface, generating over , hits. manufacturers' websites were also searched. case reports were excluded, as were abstract-only publications, letters, and studies over years old. ultimately, studies were included. a full reference list and search strategy is available from the authors. a recent article provided suggested criteria for assessment of cco monitors [ ] : this was used to generate a proforma. to check for interobserver bias, a subselection of five studies was assessed by the three authors independently; no differences were found. the authors summarised the remaining studies individually. results. results are summarised in table . w rows do not add up because some studies evaluated more than one monitor researchers have yet to address the necessity of validating cco monitors with respect to their realtime functionality. while most studies give an assessment of bias based on essentially static measurements, fewer than half document sampling time or directional change reliability. response time and response amplitude to a step change in cardiac output are important variables which may influence patient treatment; in the vast majority of studies, these have not been assessed. in this respect, all four monitors have yet to be validated. this study offers two perspectives: one, for clinicians to realise that the cco monitor in their intensive care unit may not have been as extensively validated as they think; another, for researchers, to realise that work is still to be done. initial distribution volume of glucose rather than right ventricular end-diastolic volume is correlated with cardiac output following cardiac surgery j. saito , h. ishihara , e. hashiba , h. okawa , t. tsubo , k. hirota hirosaki university graduate school of medicine, anesthesiology, hirosaki, japan, hirosaki university graduate school of medicine, division of intensive care, hirosaki, japan introduction and objectives. rational decision making for cardiovascular and fluid management in critically ill patients requires reliable assessment of cardiac preload. we have reported that initial distribution volume of glucose (idvg) measures the central extracellular fluid volume and has potential as an alternative preload variable ) . idvg can be approximated rapidly and simply in any icu using a conventional blood glucose analyzer ) . right ventricular end-diastolic volume (rvedv) has been shown to be a better indicator of cardiac preload than cardiac filling pressure ) . this study was intended to determine whether idvg, rvedv, pulmonary artery wedge pressure (pawp) or central venous pressure (cvp) are correlated with cardiac output (co) during the early postoperative days following cardiac surgery in the absence of apparent congestive heart failure. methods. twenty-nine consecutive patients who underwent cardiac surgery such as coronary artery bypass grafting (either off-pump or on-pump: n = ), valve surgery (n = ) and aortic arch replacement (either hemi or total: n = ) were studied. patients associated with excess hyperglycemia ([ mmol/l), arrhythmias or mechanical cardiovascular support were excluded from the study. a volumetric thermodilution pulmonary artery catheter for continuous monitoring of co and rvedv was placed in the operating room. immediately after cardiovascular variables were recorded, idvg was determined using the incremental plasma concentration at min after administration of glucose ( g) as described previously ) . three sets of measurements were performed; on admission to the icu and daily at a.m. on the first postoperative days. the relationship between either volumetric or static variables and cardiac index (ci) was evaluated throughout the study period. a p value. was considered statistically significant. results. all but one patients required vasoactive drugs during study period. indexed idvg (idvgi) had a moderate correlation with ci (r = . , n = , p \ . ), even though indexed rvedv (rvedvi) had a slight correlation with ci (r = . , n = , p = . ). a linear correlation was also obtained between changes in idvgi and those in ci (r = . , n = , p \ . ). however, changes in rvedvi had not a correlation with those in ci (r = . , n = , p = . ). neither pawp nor cvp had a correlation with ci (r = - . , n = and r = - . , n = , respectively). although cardiac dysfunction has a significant impact on determining co early after cardiac surgery, our results demonstrate that idvg rather than rvedv is correlated with co. idvg has potential as being an alternative indicator of cardiac preload following cardiac surgery. (spv) are reliable predictors of fluid responsiveness in controlled mechanically ventilated patients [ ] . ppv and spv are calculated using an intra-arterial catheter. it is unknown whether an arterial pressure signal obtained with the nexfin tm system [ ] using only a finger cuff can be used to calculate ppv and spv. objectives. to validate ppv and spv measured with a finger cuff. methods. after their arrival on the icu, sedated and mechanically ventilated patients after coronary artery bypass graft surgery (cabg) were included. intra arterial pressure (iap) was measured using an arterial catheter inserted in the radial artery, and non-invasively, using the finger cuff of the nexfin tm monitor (bmeye, the netherlands). we took the mean value of ppv and svv in a -min time interval before and after the administration of a fluid challenge. agreement of the ppv and spv measured by the finger cuff and from the iap signal were assessed using the method described by bland and altman. results. nineteen patients were included and twenty-eight volume challenges were analyzed, resulting in simultaneous measurements. ppv and spv measured by the finger cuff correlated with ppv and spv from iap (r = . , p \ . and r = . , p \ . , respectively), see figure . the mean bias was - . and - . % for ppv and spv respectively, and limits of agreement were - . and . % for ppv and - . and . % for spv (see figure ). there was no correlation between the bias and the mean value of the two measurement methods. the correlation between changes in ppv and spv measured by the two different methods was r = . (p \ . ) for ppv and r = . (p \ . ) for spv. conclusions. in ventilated icu patients, ppv and spv can be reliably calculated using the nexfin tm monitor. reference(s). ( ) kramer, a., et al., chest, . ( ) . ( ) eeftinck schattenkerk, d.w., et al., am j hypertens, . ( ) . introduction. the transpulmonary thermodilution (tptd) technique with integrated pulse contour analysis (picco Ò -system) enables continuous monitoring of cardiac index (ci) after calibration by tptd [ ] . this monitoring technique is applied in patients with lung failure who undergo prone positioning (pp) which has been shown to potentially improve pulmonary gas exchange [ ] . objective. we sought to determine the influence of a modified pp ( °) on the accuracy of pulse contour derived ci (pcci) without recalibration by tptd. patients: after approval by our institutional review board and written informed consent by a legal surrogate we studied critically ill patients ( #, $, age - years) who were mechanically ventilated due to acute lung injury following lung contusions or acute respiratory distress syndrome. methods. all patients were prone positioned and had received an extended haemodynamic monitoring (picco Ò , pulsion medical systems ag, munich, germany). before turning from supine position (sp) to pp, ci was measured by tptd (tptdci) and pcci was calibrated. ten minutes after positioning, pcci was read from the monitor and then recalibrated by tptd. after - h, pp was ended and measurements were performed analogously to prone positioning. volume management between the respective time points remained unchanged. linear regression analysis and bland-altman plots were used for statistical analysis. all data are given as mean ± standard deviation, range in brackets. results. the tptdci in sp was . ± . ( . - . ) l/min/m . after proning, a pcci of . ± . ( . - . ) l/min/m and a tptdci of . ± . ( . - . ) l/min/m were measured. linear regression analysis revealed a correlation coefficient of r = . (p \ . ). mean bias (tptdci-pcci) was . ± . l/min/m . immediately prior to turning back to sp, tptdci was . ± . ( . - . ) l/min/m . after re-positioning, the pcci was . ± . ( . - . ) l/min/m and tptdci was . ± . ( . - . ) l/min/m , with a mean bias of . ± . l/min/m . the correlation coefficient was r = . (p \ . ). conclusion. pcci is only marginally influenced by prone positioning and is reliable without recalibration by tptd. however, in case of greater differences a recalibration by tptd is nevertheless recommended. objectives. the aim of this study was to analyze the clinical agreement between the intermittent bolus thermodilution technique (tdco) and apco in patients with non-traumatic intracranial hemorrhage requiring intensive care. methods. this was a prospective observational clinical study in a university level icu. we studied adult patients with non-traumatic intracranial hemorrhage, who for clinical indication underwent co monitoring by the tdco (pac, . fr, criticath tm sp h td catheter, becton-dickinson, singapore). in parallel, arterial pressure waveform was applied using the radial arterial pressure curve (flotrac/vigileo tm , version . and . , edwards lifesciences, ca, usa). tdco measurements were done approximately every h and when needed. the length of data recording was depending on the need for tdco monitoring and icu stays but was no longer than days. every tdco measurements and the simultaneous apco values were recorded and included into the analysis. results. data pairs were obtained. overall, mean co was . (sd . ) l/min for tdco and . (sd . ) l/min for apco. mean bias between tdco and apco was . l/min ( fig. ), % limits of agreement . to . l/min and the percentage error %. there was a large interindividual variation in mean bias and percentage error (minimum to maximum, - . to . l/min and - %, respectively). the bias was significantly greater if patient received norepinephrine ( . vs. . l/min, p = . ) but not if patient received dobutamine ( . vs. . l/min, p = . ) . only a small correlation between the bias and the rate of norepinephrine infusion was detected (q = . ). when cardiac index of . (l/min/m ) was used as a cut off value for need for intervention, the sensitivity and specificity for apco were . ( % ci . to . ) and . ( % ci . - . ), respectively. conclusions. according to our results the second generation of flotrac Ò /vigileo Ò monitoring system underestimates the tpco and the sensitivity is poor. there is also a large interindividual variation in bias. the use of norepinephrine may provoke the error. objectives. to compare cardiac output techniques to the reference tte method, which allows accurate measurement of the aortic flow section and of velocity time integral of aortic pulsed wave doppler signal to measure co. methods. monocentric prospective study included patients requiring invasive blood pressure and hemodynamic therapeutic intervention. tte co measurement was performed with aortic diameter measured in parasternal long axis view at the the aortic leflets, and velocity time integral measured using five apical view averaged on cardiac cycles. tod co was measured only when the pac insertion was decided. tte, uscom Ò , mostcare Ò and vigileo Ò were performed in all patients. each value was the average of successive cardiac cycles with consecutive measurements. each patient could have several measures. results. mechanically ventilated patients ( ± years; sofa ± . ) were investigated allowing to obtain measurements ( under norephinephrine). diagnostics: brain injury (n = ), sepsis(n = ) and others (n = ). patient had the methods ( measurements), patients had techniques ( measurements), patients had techniques ( measurements), conclusions. all methods correlated more or less with tte co, with a slope close to identity, and a low intercept. the best correlation was obtained between mostcare Ò and tod. agreement for almost all methods was large, within an acceptable range. for the pulse contour method, mostcare is correlated better than vigileo with tte co. the arterial signal has to be accurate as possible and requires a high quality chain for measurement avoiding overdamping or underdamping to allow effective signal digitalization. introduction. the lithium indicator dilution technique is attractive in paediatric intensive care because it is non-invasive. however, it requires calibration. the reliability of cardiac output measurement data rests on the reproducibility of the calibration factor (cf). objectives. to establish the number of calibrations (= x) that are required in a paediatric patient material, if the coefficient of variation for the calibration factor does not increase by % or more by (x + ) calibrations. to establish x it is also required that % of the patients do not show an increase in cv by % or more and that % of the patients show an increase in cv by % or more at (x + ). hemodynamically stable sedated and ventilator treated children under intensive care with a body weight of - kg were included. to perform calibration, . mmol/kg of lithium chloride was injected intravenously and the concentration of lithium ions in arterial blood was analyzed by a lithium selective electrode. the calibration process was repeated times and the cf as well as lithium indicator cardiac output (lidco) were calculated. results. results from children with a mean body weight of . kg are presented below. cv was below % throughout the investigation. introduction. stroke volume variation has been shown to be a better indicator of fluid responsiveness than static indices such as cvp or paop. a limitation of dynamic parameters is arrhythmias which produces abnormal svv. beat-to-beat variations reflect altered cardiac filling times not the effects of mechanical ventilation in fluid responsive conditions. a recently developed enhanced algorithm (newsvv) helps eliminate this limitation. newsvv rejects ectopic beats using multi-parameter signal recognition and restores the respiratory variation of the signal using spline-based interpolation. objectives. to evaluate the performance of the new arrhythmia rejection svv algorithm to predict fluid responsive from patient data with frequent arrhythmias. methods. newsvv was developed from data collected in a porcine model to limit the impact arrhythmias had on svv. comparing the current standard svv (svvstd) algorithm (flotrac-vigileo system edwards lifesciences, usa) with the newsvv showed a significantly improved sensitivity and specificity. ( ) in this preliminary study sets of patient data with frequent pvcs and atrial fibrillation (afib) were ran through the new algorithm and compared to the data from svvstd. in one patient fluid boluses ( - cc platelets and packed red blood) during a period of afib caused newsvv to decrease from to % and co to increase from . to . l/min, while svvstd algorithm did not show a significant change (varying randomly between and %). a second patient had non-paroxysmal afib. svvstd showed abnormally high values ranging between and %. patient was a non-responder to fluid and had a co ranging between and l/min. newsvv showed more realistic value of % depicting a non-responder range. the third patient had periods of afib followed by normal sinus rhythm (nsr). svvstd algorithm had abnormally high svv values ([ %) during the afib. during nsr, both algorithms correlated well with svv of %. (fig. .) conclusions. the newsvv algorithm improved svv with ectopics and afib and shows promise in eliminating a limitation of svv in those conditions. further studies are needed to fully evaluate the performance in patients with arrhythmia receiving fluid challenges. rd esicm annual congress -barcelona, spain - - october s methods. mechanically ventilated pigs (median weight kg) under general anesthesia were investigated. after instrumentation, baseline values were obtained after at least h of stabilization. ''shock'' phase (simulation of aaa rupture): ( - ) ml/kg of blood was gradually withdrawn and hemorrhagic shock maintained for h. abdominal cavity was filled with warmed saline to abdominal pressure of mmhg. ''clamp'' phase: infrarenal aorta was cross clamped for min and hemodynamics was resuscitated with shed blood and fluids. ''post-surgery'' phase lasted h and pigs were subsequently sacrificed. hemodynamics was obtained at baseline, every min for first h of hemorrhage, every h until postoperative phase and every h till the end of the study. data are presented as median (iqr), appropriate non-parametric tests were used for statistical analysis. results. baseline co measured by pac was ( - ) ml/kg/min. both vigileo ( - ) ml/kg/min (p = . ) and lidco ( - ) ml/kg/min (p = . ) differed significantly. the course of co is shown in fig. , all values are presented as a difference to baseline. the median difference between pac and vigileo was ( - )% and for lidco ( - )%. study limitations: both devices were designed for co estimation in humans but we do not expect huge differences in arterial system properties in pigs. young pigs reacted to hemorrhage by severe sinus tachycardia which caused failure in some co measurements but at least pigs are presented at every timepoint. conclusions. absolute co values obtained by both vigileo and lidco differ significantly from pac. unlike lidco rapid, flotrac/vigileo was able to track changes in co during severe hemorrhage. grant acknowledgment. iga mzcr ns - and vz msm . introduction. most important role of postoperative sedation is suppressing stress of the patients in icu. urinary -hydroxy- -deoxyguanosine ( -ohdg) can be a good biomarker for oxidative stress in clinical research. the aim of this study is to assess the free radical production under sedation in icu and compare the production between with midazolam and dexmedetomidine. subjects and methods. subjects were twenty-five patients with sedation after neck malignant tumor operation and ventilated for h in icu. patients with renal failure were excluded from this study. all patients received fentanyl ( lg/kg/day), fifteen patients were with midazolam ( . mg/kg/h: m-group) and ten patients were with dexmedetomidine ( . - . lg/kg/h: d-group) we examined the concentration of urinary -ohdg by high performance liquid chromatography (hplc) method with coolaray system every morning in icu. results. the average value of urinary -ohdg of healthy human volunteer is ng/ml. the values of urinary -ohdg were less than ng/ml in the both groups and no significant differences were observed between the groups in this study. conclusions. postoperative sedation with both midazolam and dexmedetomidine were effective in suppressing oxidative stress in icu patients. poorly controlled pain in the postoperative period can lead to slow recovery and life threatening complications, especially in elderly patients. it has also been suggested that the quality of postoperative analgesia could decrease delirium incidence and reduce duration of hospital stay in the elderly patients. however, the ideal postoperative analgesia management of elderly surgical patients in intensive care units remains to be determined. since, continuous epidural analgesia provides the required level of analgesia to support early mobilization and significant reduction in pulmonary and cardiovascular morbidity in the early postoperative period, we postulated that the use of low dose of continuous epidural morphine might improve postoperative analgesia and reduce undesirable side effects in elderly patientstherefore, the present study was designed to evaluate the effects of morphine administered via epidural patients controlled analgesia and intravenous tramadol + metamizol on postoperative pain control and side effects in elderly patients after major abdominal surgery. objectives. the purpose of this study was to compare the analgesic efficacy of morphine administered via epidural patients controlled analgesia (epca) with our standard analgesic for postoperative pain treatment, intravenous tramadol + metamizol in eldery patients undergoing major abdominal surgery. methods. forty patients older than years undergoing major abdominal surgery were randomly assigned to two groups. group i received epidural morphine mg at the end of surgery and used a patients controlled analgesia device programmed to deliver morphine . mg/h, . mg per bolus. group ii received intravenous infusion of mg tramadol plus mg metamizol in ml electrolyte infusion. the patients in group ii received ml of the infusion solution as a loading dose over min (corresponding to mg tramadol plus . mg metamizol) postoperative analgesia was tested at rest on a visual analogue pain scale ( = no pain, = worst possible pain) at , , , and h after surgery. patients' satisfaction, arterial oxygen saturation, respiratory rate, episodes of nausea, vomiting, pruritus and dizziness were also noted. results. both groups obtained adequate pain relief, and there were no between-group differences in pain scores. there were no significant respiratory differences but the patients in the epidural group were more sedated. in the tramadol metamizol group patients were treated for ponv while of the patients in the morphine group showed ponv. we conclude that combination of tramadol and metamizole provided postoperative analgesia equivalent to that provided by epidural morphine in early postoperative period. the both analgesic regimens were safe and suitable for the management of postoperative pain in elderly patients. h. poon , j. hulme sandwell and west birmingham hospitals nhs trust, birmingham, uk, sandwell and west birmingham hospitals nhs trust, intensive care medicine and anaesthesia, birmingham, uk a substantial amount of patients in intensive care units (itu) receive an inappropriate level of sedation with a tendency for over-sedation. although the ideal itu sedation practice is not known, many units use a protocol-based approach incorporating best practice consensus. the use of daily interruption of sedation infusions can reduce oversedation and is included in our current guidelines. objectives. the audit assesses compliance to our current protocols for sedation scoring and adjustment of sedation infusions. provision of sedation breaks in patients sedated more than -day is evaluated. methods. retrospective review of itu inpatients' daily record charts during june and july at sandwell and west birmingham hospitals nhs trust in two -bedded itu. charts were reviewed. results. our guidelines recommend hourly sedation scoring from h to midnight and hourly scoring from midnight till h; at , and h. % of the reviewed charts did not have a recorded hourly score. % did not have hourly scores overnight. % of the charts contain ramsay score - or - ; % of the charts contain ramsay score or . per protocol, sedation infusion is stopped at ramsay score - or - but in % of cases this did not occur. a sedation bolus should be given at a score of or . % did not receive a recorded bolus. our guidelines advocate restarting a sedation infusion at a lower rate after it has stopped and the patient is less sedated and increasing the rate after a bolus is given. however, correct infusion rate adjustments were only performed in % of cases. often, rates were changed but without first stopping, or administering a drug bolus. out of sedation days, there were only true daily breaks. conclusions. there is a tendency to over-sedation in our itu; less so under-sedation. common practice deviates from protocol and there is poor documentation. scores are recorded less often than protocol: there may continuous assessment by nursing staff that is not recorded. boluses are given more often than documented on patient charts. review of the current guidance is required to address appropriate frequency of formal scoring, nurse-led compulsory sedation breaks and pharmacokinetic education about the necessity to stop or bolus before infusion rate alterations. introduction. daily interruption of sedation has been shown to decrease length of stay in icu . recent national guidance in scotland promotes dis as part of a care bundle to decrease ventilator associated pneumonia. a week retrospective first round audit was completed prior to the introduction of dis and demonstrated % of patient hours where sedation could be improved. a second round audit of current practice was therefore undertaken to assess the impact of dis on sedation levels. our aim was to identify the frequency of periods where sedation levels were undesirable and investigate any clinical reason behind these. objectives. to assess whether dis would improve sedations levels of our patients already managed with a simple sedation algorithm (sa) aiming at a ramsay sedation score level - . methods. six months following the introduction of dis, a second period of weeks was studied retrospectively where the icu daily charts were examined to look at: demographic data, sedation score, and whether dis had been successfully carried out. results. cases were identified: males and females with an average age years and similar illness severity scores to the first group. dis was carried out on patient days, omitted on days and contraindicated on a further . , patient hours were examined. ( %) were excluded due to contraindications such as refractory hypoxia, drug overdose, and end of life care. the remaining patient hours were compared to the first round group [ , patient hours with contraindications ( %)] using the mann-whitney test as shown in fig. . conclusions. we could not demonstrate any difference in sedation levels following introduction of dis on our unit. we found a large proportion of patients where dis was unsuitable. introduction. delirium, an acute and fluctuating disturbance of consciousness and cognition, is a common manifestation of acute brain dysfunction in critically ill patients, occurring in up to % of ventilated patients in the united kingdom . delirium is independently associated with more deaths, longer hospital stay, and higher overall cost . hypoactive delirium is much more common, is easily missed and is associated with a worse prognosis than hyperactive delirium . objectives. the aim of our project was to quantify the presence of delirium on our critical care unit and to survey the practice of delirium assessment within our region. we conducted a prospective audit at the critical care unit, birmingham city hospital, uk. we used the confusion assessment method for the intensive care unit (cam-icu) to assess for delirium daily on all our patients for a period of weeks. simultaneously, we conducted a telephone survey to elicit the delirium assessment practice of the other units within the west midlands region of the unite kingdom. results. we carried out our assessment on patients over a -week period, which resulted in assessments ( were on non ventilated patients and on ventilated patients). assessments could not be completed because of deep sedation or language barrier. in total we had assessments positive for delirium giving an incidence of % for those patients we could fully assess. all of the patients with a positive assessment had hypoactive delirium. the telephone survey revealed only three of the twenty units in our region routinely assessed for delirium. none of the units had a formal management protocol/guideline for delirium. conclusions. delirium is a significant problem on our critical care unit. the incidence was lower than that reported in the literature this might be because firstly we were unable to assess a number of patients due to the patients being deeply sedated, and secondly we noted many of the patients during the assessment period were high dependency patients with minimal organ dysfunction. despite a large number of recent publications on delirium and increasing awareness amongst critical care professionals most of the units in our region do not routinely assess for delirium. without regular assessment most delirium will go unrecognised and thus opportunities to instigate preventative measures and early management will be missed. methods. six patients aged - years old ( females) who all sustained brain injury with cerebral oedema alongside other traumatic damage (i.e., fractures, abdominal trauma) are hereby presented. upon admission to the icu all patients received large propofol doses ( - ml/h of propofol infusion %), in an attempt to lower cerebral metabolic demand along with vasopressors to maintain a normal mean arterial pressure. three to days following admission all patients developed metabolic acidosis (base deficit ranged from - to - mmol/l), hyperkalemia (potassium concentration ranged from . to . mmol/l), evidence of muscle cell degradation (creatine kinase and myoglobin concentrations ranged from , to , u/l and from , to , lg/l, respectively) and lipaemia (triglyceride concentrations ranged from to . mmol/l). at that time all patients were clinically stable and usual laboratory tests as well as cultures were inconclusive, hence a diagnosis of pris was suggested. results. three out of six patients developed global left ventricular dysfunction, which was documented by echocardiographic evaluation, with normal cardiac enzymes, while all patients developed acute renal failure. cardiac and renal failure were observed within - h following the manifestation of the above abnormal laboratory findings. continuous hemofiltration was initiated promptly on a daily basis in all cases, while the administration of propofol was discontinued. abnormal laboratory findings normalized within - days, while cardiac and renal function gradually ameliorated within a week, following therapy in all cases. no deaths were recorded. conclusions. the initiation of continuous hemofiltration therapy is a crucial therapeutic tool for the elimination of propofol and its potentially toxic metabolites in cases of pris and may have a beneficial effect upon survival in these cases. l. zurong , w. yichun intensive care unit of hunan province tumor hospital, changsha, china objectives. our purpose was to compare the analgesic properties, effect, and side effects of intravenous butorphanol and fentanyl during chest tube removal in cardiac surgery patients. seventy-four patients with cardiac surgery were enrolled before chest tube removal. each patient received standard doses of either fentanyl ( lg) or butorphanol ( mg) before chest tube removal in a double-blind manner. pain intensity and pain distress were measured before analgesic administration, immediately after chest tube removal, and min later pain quality was measured immediately after chest tube removal. level of sedation was measured before and min after chest tube removal. results. the fentanyl (n = ) and butorphanol (n = ) groups were identical with respect to age, race, sex, and weight. pain intensity, pain distress, and sedation levels did not differ significantly between groups. however, procedural pain intensity (mean . , sd . ) and pain distress (mean . , sd . ) scores for all were low. patients remained alert, regardless of which analgesic was administered. conclusions. if used correctly, either fentanyl or butorphanol can substantially reduce pain during chest tube removal without causing adverse sedative effects. thus, clinicians may choose either safe and effective analgesic interventions during chest tube removal. introduction. delirium is defined as an acute alteration of mental status, with either a disturbance of consciousness or a change in cognition which develops over a short period of time and fluctuates during the course of the day. reported prevalence of delirium in critical care varies widely from to %. despite this, delirium remains grossly under-recognised and is often thought to be temporary and of little consequence in critical care. it is however one of the most frequent complications and, after adjusting for age, gender and severity of illness is an independent risk factor for prolonged length of stay and mortality ( ) . current recommendations are for the assessment and diagnosis of delirium using simple validated tools ( ) . pharmacological intervention should be considered when reversible precipitating factors have been corrected. haloperidol is considered the drug of choice. objectives. the purpose of this study was to detect knowledge and awareness of delirium, attitudes and behaviours towards its assessment and pharmacological management in critical care units of two large uk teaching hospitals a -point survey was distributed to all senior medical and nursing staff employed in critical care at the leeds general infirmary and the james cook university hospital, middlesbrough. a total of questionnaires were collected after four follow up rounds via web-based survey tool ''survey monkey''. results. the survey detected a significant awareness of the problem delirium poses in icu. the vast majority ( %) of practitioners did not screen for delirium routinely. of the % who screened only in used screening tools that were appropriate, the majority lacked the knowledge of suitable methods to do so. % of respondents felt that they required tools to aid diagnosis of delirium in their unit. the pharmacological management of delirium varied significantly, with a wide range of drugs used, suggesting the need for guidance. the majority of respondents ( %) felt that they needed guidelines for treatment of delirium, % felt that guidelines would change their practice. despite an awareness of the problem delirium poses in icu, data from this survey shows a lack of knowledge of assessment and treatment. given that most respondents needed guidelines, we have developed a delirium treatment protocol and implemented the confusion assessment method for icu (cam-icu) training package for all staff in the james cook icu. following its implementation we plan to re-evaluate in the hope that the awareness of delirium can be met with the appropriate knowledge to implement a sustained change in practice. results. patients were included, male ( %), mean apache ii score ± . midazolam was suspended in % after h. maximum dose of sufentanyl was mcg/kg/h. bilirrubin and creatinin did not change from initial values and there was no effect in enteral nutrition tolerance. bis values improved % from ± to ± (p = ns) and there were less hemodynamic effects as well as less necessity of amines and sedatives. results are shown in table . conclusions. sufentanyl is an efficient and safe sedative that reduces necessity of more sedatives, amines and generates adequate sedation without renal or hepatic effects. a.s. puxty , j. kinsella , k. anderson glasgow royal infirmary, department of anaesthetics, glasgow, uk etomidate is a sedative agent often used for the induction of critically ill patients. it is, however, a controversial drug with effects on the steroid axis that have been suggested may lead to a poor outcome. so far this has only been proven in infusions of the drug. despite this some have called for its withdrawal altogether objectives. to determine the attitude of anaesthetists and icu consultants in five hospitals in a major uk city towards the use of etomidate. methods. an online questionnaire was constructed using surveymonkey (portland, oregon, usa). this was then sent out to all anaesthetists in glasgow via an e-mail link. a reminder was sent after weeks. trainees from one of the hospitals were unable to be contacted via e-mail and so hard copies of the questionnaire were sent to them. of a total of anaesthetists in glasgow (trainees and consultants), ( %) completed the questionnaire successfully. of those answering the questionnaire, . % were sho level, . % spr, . % consultants and . % sas grade. these respondents sub-specialities/specialist interest were: general ( %), pain ( %), icu ( . %), obstetrics ( . %) and cardiac ( . %). overall ( % ci - )% of respondents were concerned about etomidate's effect on steroid synthesis, although when asked about induction of an emergency laparotomy ( - )% would still use it [with ( - )% avoiding it and ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) % responding that they were never involved in emergency laparotomies]. of those using etomidate, ( - )% would avoid it in a septic patient, and a further ( - )% would give steroid cover. the most common reason for using etomidate was cardiovascular stability [ ( - )%]. other reasons given were simple dosing ( [ - ] )% and habit ( [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] )%. more than one reason was allowed. looking for differences between groups the following was found: while icu consultants reported more concern over etomidate ( vs. %, p = . ), there was no difference in etomidate usage in emergency laparotomy ( % of general vs. % of icu consultants, p = . ). trainees were more likely to have their habit changed by the recent literature on etomidate ( vs. %, p = . ). conclusions. there is concern among anaesthetists and icu consultants regarding the use of etomidate but usage has not changed markedly by most. further evidence of harm would likely need to be demonstrated before abandonment of the drug. introduction. nociception and requirement of additional analgesia before painful procedures in icu are difficult to anticipate. under anaesthesia, the direct pupil light reflex reflects the sympatho-vagal balance and remains altered by pain and sedative drugs. the pupillometry is a reproductive, non invasive method based on automated flash light device assessing pupillary variations [ ] . to study pupillometric parameters to anticipate the tolerance to painful stimuli (surgical debridement). methods. eligibility criteria: sedated patients (morphinomimetics + benzodiazepines, bps = ) in days after invasive surgery for cervical necrotizing fasciitis (cnf), complicated or not with mediastinitis, requiring a surgical debridement three times a day. clinical evaluation performed before and during debridement: heart rate (hr), mean arterial pressure (map) and behavioral pain score (bps) [ ] . pupillometric test before debridement (calibrated bright flash of one-second at lux, (neurolight, id med) with recording of pupillary parameters: minimum and maximum diameter, variation rate, latency, velocity. noxious procedure was defined as an increase of at least one point of the bps (change in facial expression, upper limb movement or ventilator synchrony). the additional analgesia was decided blindly from pupillometric values. analysis compared two groups defined on bps variation induced by the procedure: group with dbps c and group with dbps = . comparison of pupillometric parameters before procedure between the groups. results expressed as median (interquartile range, iqr), mann-whitney test, significance at p \ . . . patients with cervical cellulitis of which complicated by mediastinitis, h/ fratio = / , age years ( ), igs ( ). in this population, during the procedure, hr and map were unchanged, the bps increased significantly [from ( ) to ( ) , p = . ] but remained unchanged in patients ( %) (group = high tolerance). pupillometric parameters before procedure before procedure group (n = ) group (n = ) p conclusions. all pupillometric parameters, except latency, were discriminant for subsequent debridement tolerance with significantly lower values in the group without pain experience. the pupillometric test seemed adapted to this clinical practice for evaluation of nociception status and may help for rationalizing analgesia for short noxious procedures. introduction. delirium is an acute and fluctuating change in mental status, with inattention and altered levels of consciousness. the incidence of delirium in orthopedic patients was ranges from . to %. delirium may present before or after the patient undergoing surgical procedure and has demonstrate increasing risk, including mortality. objectives. the purpose of this study was to compare the effectiveness and tolerability of intravenous propofol versus midazolam infusions in postoperative agitation/delirium therapy with using an epidural infusion for postoperative analgesia after major orthopedic surgeries in high-risk patients with chronic renal failure. with the institutional ethic committee approval; eighty-two high-risk chronic renal failure patients (asa iii, bun [ mg/dl and serum creatinin value [ ) after a major hip or knee operations with a diagnosis of agitation/delirium were eligible for the study in the postoperative period. richmond agitation sedation scale (rass) or confusion assessment method for the icu (cam-icu) were used for sedation/orientation levels. all agitated patients had an lumbar epidural catheter was inserted preoperatively in combination with spinal anesthesia intraoperatively. after the surgery the catheter was loaded with . % mg bupivacaine at the t to l sensory levels and a continuous infusion of . % bupivacaine was commenced at - ml/h in combination with patient controlled analgesia of meperidine ( mg/bolus). for agitation/delirium therapy in group p (n = ) propofol was used with intravenous loading dose of - mg/kg in a bolus and followed by continuous infusion at - mg/kg/h and group m (n = ) midazolam was used with intravenous loading dose of . - . mg/kg in a bolus and followed by continuous infusion at . - . mg/kg/h to ensure a target of rass in + and - values. hemodynamic parameters (heart rates, systolic and diastolic blood pressures), oxygen saturation with sedation-agitation scales were monitored periodically for h. adverse events were recorded. p \ . showed statistically significant. results. the groups were demographical comparable (p [ . ). group p patients reached the target rass scores earlier in group p (p \ . ). hemodynamic values were significantly higher in group m (p \ . ). the epidural bupivacaine consumption was significantly lower in group p with a limited analgesic requirement (p \ . ) and n treatment required adverse events was seen in group p (p [ . ). conclusions. intravenous propofol infusion may be an effective and safe approach adjunct to epidural analgesia for possible postoperative agitation/delirium treatment after major orthopedic surgeries in high-risk patients with chronic renal failure. introduction. ventilator-associated pneumonia (vap) is the most common nosocomial infection among the critically ill patients admitted in the intensive care units (icus). implementation of the available international evidence-based guidelines and recommendations to prevent and manage vap into the clinical setting may not be adequate leading to suboptimal patient care and increased vap rates. objectives. to assess the implementation of selected vap prevention strategies, and to learn how vap is managed by the intensivists practicing in the indian subcontinent. methods. three hundred -point questionnaires were distributed during an international critical care conference. ( . %) were returned and ( %) questionnaires of delegates from india, nepal and sri lanka were analyzed. most of the intensivists ( . %), reported using vap bundles in their icus with a high proportion including head elevation ( . %), chlorhexidine mouthcare ( . %), stress ulcer prophylaxis ( . %), heat and moisture exchangers (hme, . %), early weaning ( . %), and hand washing ( . %) as part of their vap bundle. use of subglottic secretion drainage (ssd, . %) and closed suction systems (css, . %) was also reported by many intensivists, whereas, use of selective gut decontamination was reported by only . % of respondents. most common method for sampling used for diagnosis of vap was endotracheal suction by ( . %) intensivists, and only . % intensivists reported using protectedsample brush. gram negative organisms (pseudomonas, acinetobacter) were reported to be the most commonly isolated organisms. majority of respondents ( . %) reported using proton pump inhibitors for stress ulcer prophylaxis. majority ( . %) believed that vap contributed to increased mortality in their icus with . % treating vap with an antibiotic course lasting for - days. de-escalating therapy was considered, in patients responding to treatment, by . and . % considered adding empirical mrsa coverage and . % considered adding nebulised antibiotics in certain high risk patients. overall there was good concordance regarding vap prophylaxis among the intensivists with a majority adhering to evidence based recommendations and guidelines. even though the gap between recommended guidelines and the actual clinical practice is closing, we could identify certain issues like the choice of agent for stress ulcer prophylaxis, use of hme, ssd and css, where there still exists some practice variability and opportunities for improvement to provide better patient care. objectives. to reassess the value of individual levels and dynamic alteration of procalcitonin (pct) in predicting the outcome of ventilator-associated pneumonia(vap) patient. methods. forty adult patients with vap were studied and divided into two groups according to their outcome at day after diagnosis of vap: death and survival. serum pct levels were measured on days , and (d , d , and d , respectively) and their alteration between different days (kinetics, pct) were calculated. to control the study, acute physiology and chronic health evaluation ii (apache ii), sequential organ failure assessment (sofa), and clinical pulmonary infection score (cpis) and c-reactive protein (crp) were also recorded and analyzed. all parameters have been investigated as independent variables in relation to -day death as dependent variable. results. the increase of pct levels on day , and were significantly predictive of death in univariate analysis with area under curve (auc) and % ci of . ( . , . ), . ( . , . ) and . ( . , . ), respectively. however, kinetics of pct levels among day , and did not show a significant difference between favorable and unfavorable outcomes (p [ . ). multivariate analysis revealed that only sofa ( ) conclusions. neither pct individual levels nor their kinetics during vap course can predict patient outcome. comprehensive evaluation of patients with multiple methods, in combination with pct levels, may increase predictive accuracy in the future. grant acknowledgment. we have no competing interests. introduction. the presence of new or progressive radiological infiltrates, pyrexia, leukopenia or leukocytosis, and the presence of purulent tracheal aspirates are key features defining the presence or absence of vap. the incidence of vap is dependent upon the number of diagnostic criteria applied, and the demographics of the critical care population to which it refers. a uk government directed ''patient safety first'' campaign in the uk, has highlighted vap as a complication related to mechanical ventilation that can be reduced through the introduction of a ''care bundle''. however, benchmarking between different units has practical limitations. objectives. selective data presentation can distort the perceived occurrence of critical events in order to deliver performance targets. we compared the incidence of vap between a neurosurgical and general intensive care unit in the same hospital. a variety of denominators were applied to explore the potential for data manipulation to realise performance targets a local database of neurosurgical and general intensive care admissions, covering a month period, was analysed retrospectively results. and subjects were admitted to gitu and nitu respectively in the month period. ( %) and ( %) subjects were ventilated for more than days. table summarises the demographics and measures of performance between the two units. a p value . was considered significant. parametric and non-parametric tests were applied as appropriate. . vap is associated with not only mortality but also considerable morbidity, prolonged duration of ventilation and increased cost of hospitalisation. to determine the incidence of vap in patients ventilated at the qensiu, to calculate mv resource utilisation, and to ascertain whether vap relates to outcome in acute sci. we undertook a retrospective case note review of all patients ventilated at the qensiu during a year period. patients were identified using a local computerised database. the qensiu receives referral of patients with sci from the whole country (pop * . m). vap was defined pragmatically as deteriorating gas exchange more than h following mv, coupled with a raised crp or wcc, together with either a positive sputum sample or new infiltrates on cxr. statistics: descriptive, median (range); analytical, mann-whitney u and fisher's exact test as appropriate. death occurred in % of patients, and was significantly greater in the group who were retrospectively assigned to the vap cohort: vap vs survival of the deaths, occurred following discharge from the unit ( of whom developed a subsequent vap). conclusions. vap incidence was apparently high in this patient population ( %), particularly in comparison to the reported general icu population incidence ( - %) . this may partially reflect our pragmatic diagnostic criteria, applied retrospectively. vap was also associated with an increase in mortality following discharge in patients with sci. a modified vap bundle adapted to sci patients is being developed locally, based on recent recommendations . introduction. the implementation of a prevention programme with feedback to nurses and healthcare workers (hcw) was associated with better outcomes and increased compliance [ ] . to assess the effects of feed-back in a study based on implementing a variables care bundle to prevent vap. a multicenter and prospective study was carried out in icus. the element care bundle consisted in hands hygiene, oral hygiene, monitoring cuff pressure, sedation vacation/adjustment and avoid ventilator circuits changing. beweekly feed-back displaying posters with information was carried out to update hcw in the compliance of the prevention measures and vap incidence. a questions with open answer questionnaire was performed months after the implementation of the feed-back in all icus to assess the knowledge of the compliance measures, vap incidence, opinion of the study and improvement suggestions. results. questionnaires were obtained. the median experience in intensive care was . years (sd . - . ). % of the staff was aware of the study: . % agree that was useful, . % disagree and . % didn't know. regarding if they thought that in their units they had a high vap incidence, . % answered that they did, . % answered negatively and . % didn't know. asking about the knowledge of the prevention measures' compliance . % answered right, . % said they knew but didn't specify the percentage, . % didn't know and . % didn't answer the question. finally, about the vap incidence, . % answered right, . % said they knew but didn't specify it, . % didn't know and . % didn't answer the question. . % added comments, the most relevant was: . % of the respondents wanted more verbal information. conclusions. poster feed-back failed to improve compliance on vap care bundle due to lack of information. our survey suggests to implement other communication strategies based on direct verbal interaction to improve implementation. objectives. to compare the effectiveness of two different methods of oral dental hygiene on ventilator-associated pneumonia (vap) prevention using the cpis (clinical pulmonary infection score). methods. twenty-seven critically ill patients, aged - years were studied. patients were randomly separated in groups: group (n = ) received oral care with tooth brushing using the bass technique followed by lavage with chlorhexidine . % (chx) solution in nacl . % (chx:nacl . % = : ). hexetidine . % (hex) was used for oral lavage alone in group (n = ). demographics, sofa, apache ii, gcs and cpis scores were recorded upon patient admission. on days , , and , bal and tongue surface cultures were obtained. the endpoints taken into account were the cpis on days , , , and as well as the number and species of bacteria cultivated. a cpis c was considered positive for vap. two-way anova, t test for independent samples, mann-whitney u, pearson correlation and kruskal-wallis tests were used for statistical analysis. p \ . was considered statistically significant. patient data analysis showed that both groups were homogeneous. on days , and there were more negative tongue surface cultures in the chx group than in the hex group (p = . ). even though the cpis did not differ significantly between the groups, a strong tendency of faster and greater reduction in the chx group was observed. moreover, a continuous gradual improvement of the cpis score was recorded in both groups on days , and . the overall incidence of vap was similar in both groups: group , . % (n = ) and group , . % (n = ). the same bacteria (p \ . ) developed in both bal and tongue cultures on days (p \ . ) and (p \ . ). nevertheless, the cpis was positive for vap only in the above patients on day , while day was totally free of vap. conclusions. even though the cpis improvement was more remarkable in group , both group scores showed parallel improvement overtime, the chx group being in a slightly more propitious position. diligence in patient oral care seems to be an additional effective practice for vap prevention, independently of the method used. introduction. specific patterns of cytokine gene expression are reported to be associated with the occurrence of infection in humans [ , ] . it is unclear whether these characteristic profiles are a consequence of an established disease process or precede the infective process. objectives. our primary endpoint was to determine whether hospital acquired pneumonia was associated with differential gene expression of ifn-c, tnf a and il- family of cytokines. secondary endpoint was to identify whether alteration in gene expression preceded the clinical onset of infection. methods. consecutive patients undergoing elective thoracic surgery were recruited. hospital acquired pneumonia was diagnosed as per nnis guidelines, independent of study investigators. mrna and protein levels were analysed pre operatively, h and days post operatively. . patients had an uncomplicated recovery. patients developed hospital acquired pneumonia. il- , il- , il -p , il- -p , il- -p , tnf-a, and ifn-c mrna and protein levels of il- , il- , and ifn-c in peripheral blood were analysed before surgery, h and day post surgery. il- p mrna levels were reduced in the pneumonia group ( , ; , - , ) compared to non pneumonia group ( , ; , - , ) day post surgery (p = . ). ifn-c mrna levels were reduced in the pneumonia group ( ; - , ) compared to non pneumonia group ( ; - , ) (p = . ) day post surgery. absolute copy numbers of mrna per million copy numbers of b-actin are quoted. all values are quotes as median and th to th centile range. patients with postoperative hospital acquired pneumonia exhibit distinct patterns of cytokine gene expression. these distinctive patterns manifest before the clinical onset of pneumonia. objectives. the aim of this study was to evaluate the impact of the implementation of a ventilator bundle on the incidence of vap in our intensive care unit (icu). methods. prospective, observational study. during a year period (january - ) a ventilator care bundle based on the cdc and canadian guidelines , was applied to each patient requiring more than h of mechanical ventilation (mv). the ventilator care bundle consisted in:hand hygiene. use of barrier precautions. preference of noninvasive ventilation (niv). orotracheal intubation. semirecumbent position. continuous aspiration of subglottic secretions. manteinance of the endotracheal cuff pressure. oral care with chlorhexidine. daily sedation vacation and assessment of readiness for weaning. no scheduled ventilator circuit changes. ventilation circuit maintenance. stress bleeding profilaxis. we followed general measures for infection control:single patient room. microbiologic surveillance. monitoring and early removal of invasive devices. program to reduce antimicrobial prescriptions. for each ventilated patient the following data was registered:age, apache ii, the reason of admission, risk factors, use niv, mv duration, timing of tracheostomy, time of diagnosis of vap, microbiological data, length of stay and mortality in icu. the compliance with the bundle was registered in a check list. the application of the ventilator care bundle impact was compared with historical data. . ventilated patients were included. the median age was years. the mean apache ii was . ± . . the reason of admission was in a % medical and % surgical. the most frequent risk factors were: age [ years, emergency surgery, pulmonary disease and immunosuppression. niv was used in %. the median duration of mv was days. tracheostomy was done in . % patients with a delay of ± days. there were late-onset vap episodes and the rate of vap per , ventilator days was . . the vap were caused by candida albicans, enterobacter aerogenes and pseudomona aeruginosa. the length of icu stay was . days. mortality was % (only one patient with vap). the rate of compliance with ventilator care bundle was %. the rate of vap per , ventilator days after implementation of the bundle decreased significantly (table ) . there is currently no consensus on the diagnostic criteria for ventilator associated pneumonia (vap) which has led to significant variation in the reported incidence ( - %) . icus need a reliable and accurate diagnostic system so that the efficacy of measures to reduce the incidence of vap can be assessed, and if vap is to be considered as a quality indicator of performance. objective. to establish a process to diagnose vap that can be used for continuous surveillance and to assess the effect of new therapeutic interventions. method. potential diagnoses of vap were identified prospectively by a senior intensive care doctor and clinical data was collected to calculate a modified clinical pulmonary infection score (cpis) . each case was subsequently reviewed at a multidisciplinary team (mdt) review forum with intensive care and microbiology clinicians. the case details, modified cpis and semiquantitative microbiological culture results were used to reach a consensus view on the diagnosis. a pilot audit performed over a week period in , gave a vap incidence of % ( vaps; ventilated patients; ventilator days) . a change to our ventilator care bundle was subsequently instigated, with the addition of chlorhexidine paste to daily mouth care before repeat surveillance. result: patients were admitted to the critical care unit over days. patients were ventilated during a total ventilator days. patient episodes were identified as potential vap and discussed at the mdt forum. cases were diagnosed as vap (incidence . %) and patient diagnosed as tube associated pneumonia. the other cases were excluded either due to clinical circumstances (n = ) or absence of positive microbiology (n = ). conclusion. we have developed a process for identifying and diagnosing vap within our critical care unit that continues to be used for ongoing surveillance. collaboration between the intensive care team and the microbiology department, along with a mdt forum, has been fundamental to this process. our data highlights the difficulty in diagnosing vap and the need for multidisciplinary expertise. of the patient episodes prospectively identified as potential vap, were deemed not to be vap when clinical data and results were available for review at the mdt forum. the reduction of vap incidence between the pilot study and subsequent screening suggests benefit from the introduction of oral chlorhexidine, however we recognise other contributing factors. controversially, icus in the uk are increasingly being asked to provide data on vap incidence as a quality indicator. we believe that we have a process that is robust and allows us to accurately monitor the incidence of vap. introduction. bacterial biofilm within the internal surface of the endotracheal tube (ett) may contribute to ventilator-associated pneumonia. the gene expression pattern of those bacteria, embedded within biofilm matrix, greatly differs from their planktonic counterpart and allows survival benefits and increased virulence. to compare biofilm production capability of planktonic versus sessile methicillin-resistant staphylococcus aureus (mrsa) retrieved from within etts, and to assess whether antimicrobials can hinder those processes. ultimately, to study any change in planktonic versus sessile bacterial dna. we previously developed a model of pneumonia in pigs mechanically ventilated up to h and challenged into both lungs with mrsa. from those studies, etts of pigs, treated with placebo (n = ), linezolid (n = ) or vancomycin (n = ) were retrieved. distal and medial parts of each ett were processed ( samples). the planktonic mrsa strain, inoculated to the pigs, was compared with sessile mrsa strains, retrieved from the internal surface of the etts, in capability to form biofilm, assessed through the adhesion-to-aplaque method for gram-positive bacteria. the optical density of biofilm was measured using a microplate reader at wave length k = nm and results are proportional to the planktonic control strain (value = ). pulsed-field gel electrophoresis (pfge) was used to determine potential bacterial dna recombination. introduction. ventilator-associated pneumonia (vap) is a common complication in mechanically ventilated patients and is associated with increased morbidity, mortality and costs. treatment-related risk factors associated with vap, include prolonged duration of mechanical ventilation, lack of antiseptic techniques, improper patient's position, inappropriate cuff pressure, peptic ulcer prophylaxis, and deep sedation. objectives. the aim of this study is to evaluate the presence of these risk factors and their association with vap development in a multidisciplinary icu. one hundred and fifty-seven critically ill patients consecutively admitted to a multidisciplinary icu, were prospectively studied. forty-one of them, developed vap ( m/ f age: ± years, apache ii score on admission ± , sofa score on admission ± ). inclusion criteria were intubation \ h prior to icu admission or after h of admission. exclusion criteria included: prior hospitalization in another icu, icu stay\ h, brain death, age \ years old and pregnancy. bronchial secretions, samples from the pharynx and gastric secretions were collected from each patient times weekly (on days , and ). we also documented the known risk factors for vap; sedation depth (using the ramsay scale), cuff pressure, head-bed elevation, reintubation, ventilator circuit changes, tracheostomy, the presence of levin, deep venous thrombosis and stress ulcer prophylaxis, three times weekly per patient results. in this selected sample of patients, the incidence of vap was per , ventilation days. out of this sample, % underwent at least one endotracheal tube change, % had at least once their ventilator circuit changed, % underwent a tracheostomy, % had levin, % did not have head-bed elevation above °, % had ramsay scale or , % had cuff pressure b cmh o, % did not received deep venous thrombosis prophylaxis and all of them received h -receptors antagonists, as gastric ulcer prophylaxis. these results indicate that several risk factors for vap, do indeed apply for the cases under study and that the incidence of vap is relatively high. therefore, the implementation of preventive strategies and the reinforcement of vap bundles can result in beneficial effects on the appearance of vap, in the monitored icu. introduction. pulmonary inflammatory response and progressive ards may complicate posttraumatic ali. clrt by a motor-driven bed is used in trauma patients to improve gas exchange and to prevent from ventilation-associated complications. we investigated the effect of clrt on the inflammatory response in the posttraumatic course. to assess systemic and pulmonary cytokines (interleukin (il- , il- ), intercellular adhesion molecule- (icam- ) before and days after begin of clrt. conventionally positioned patients served as a control group. after approval by our institutional review board trauma patients presenting with ali (pao /fio \ ) were prospectively randomized in clrt (n = ) and control group (n = ). cytokines were assessed from serum (s) and broncho-alveolar lavage (bal) after admission at the icu and on day , respectively. results. the mean age was ± years and mean injury severity score was ± . pulmonary gas exchange improved significantly in clrt in comparison with conventional positioning on day . changes in cytokine levels are presented in table (median and / percentile values, * = p \ . within groups and $ = p \ . between groups, wilcoxon and mann-whitney-u test). serum il- and il- levels were reduced statistically significant on day in both groups, but this effect was significantly more pronounced in clrt-group. in bal cytokines tended to be increased in clrt and control group on day . icam- levels were increased in s and bal after days treatment. conclusions. the early use of clrt reduces the systemic inflammatory response (il- , il- ), but has no influence on regional pulmonary cytokine expression. clrt might be a helpful tool for stabilization in trauma patients with ali. objectives. the aim of this study was to compare the performance of adaptive support ventilation (asv) with and without closed loop control by end tidal co (etco ) (asvco ) to that of pressure control ventilation (pcv) and volume control ventilation (vcv) during simulated ards and to compare the ability of all modes to manage etco , tidal volume (v t ), and plateau pressure (pp) as respiratory mechanics, peep and minute volume changed. methods. asv and asvco were compared to a v t of ml/kg in vcv and pcv using the michigan instruments test lung set up with co titrated into one of the test lung chambers. the compliance of the system was set at and ml/cmh o and resistance at . cmh o/l/min. at baseline ventilation co was titrated to establish a co production of ml/kg pbw/min ( kg) or ml/min. after stabilization and data collection co production was increased to ml/ min and then to ml/min then decreased to ml/min. after each co adjustment and stabilization period data was collected. statistical analyses were performed by anova or kruskal-wallis tests where appropriate, a p value. was considered significant. overall etco level in asvco ( . ± . mmhg) was higher than in other modes (asv . ± . , vcv . ± . , pcv . ± . mmhg) (p \ . ). at the lowest compliance etco in asvco ( . ± . mmhg) was higher than in vcv ( . ± . mmhg) and pcv ( . ± . mmhg). overall v t was similar in all modes except that v t in asvco ( . ± . ml/kg) was lower than in vcv ( . ± . ml/kg) (p = . ). at the lowest compliance v t in asv ( . ± . ml/kg) and asvco ( . ± . ml/kg) were lower than in vcv ( . ± . ml/ kg) and pcv ( . ± . ml/kg) (p \ . ). overall, pp in asv ( ± . cmh o) and asvco ( . ± cmh o) were lower than in vcv ( conclusions. our high mortality in this group of patients despite improved oxygenation concurs with published data. however, potential improvements with adherence to ph and oxygenation targets could be made to ensure optimal use of hfov as a lung protective strategy. objectives. this randomized cross-over controlled study was designed to assess safety, gas exchanges, and ventilator outputs obtained with intellivent Ò as compared to adaptive support ventilation (asv) ( ) in icu ventilated patients with acute respiratory failure. methods. the study was approved by ethic committee and inform consents were obtained by next-of-kin. intubated, sedated and ventilated patients were included (age = ± years, saps ii = ± , and ali/ards and normal lungs patients, respectively). patients were ventilated using a g (hamilton medical, switzerland) with a dedicated software. asv and intellivent Ò were delivered in random order for two periods of h with half an hour of washout in between. tidal volume (v t ), peak pressure (ppeak), spo , and etco were continuously recorded. blood gas analysis and plateau pressure (pplat) were measured at the end of each period. a paired t test was used to compare ventilation and oxygenation parameters between asv and intellivent Ò period. no patient was removed from intellivent Ò for major safety issue. intellivent Ò delivered a lower mv ( . ± . vs. . ± . l/min, p = . ), peep ( ± vs. ± cmh o, p = . ), fio ( ± vs. ± %, p \ . ), vt/pbw ( . ± . vs. . ± . ml/kg pbw, p = . ), and pplat ( ± vs. ± cmh o, p = . ) than asv. static compliance, pao /fio ratio and paco were not different between asv and intellivent Ò . with both asv and intellivent Ò , v t was between and ml/kg pbw in all the patients. figure is showing the distribution of mean of individual breath by breath peak pressure during the two recording periods. conclusions. intellivent Ò delivered lower volumes and pressures than asv for equivalent results on gas exchange suggesting more efficient ventilation. introduction. during neurally adjusted ventilatory assist (nava) pressure applied to the airways by the ventilator is moment-by-moment proportional (according to a proportionality factor called ''nava gain'', unit: cmh o/lv) to the electrical activity of the diaphragm (eadi, unit: lv), as measured through a modified nasogastric tube with a multiple array of esophageal electrodes. independently from its physiological correlation with real diaphragm activity, eadi and its variations are the only variables through which different nava gains may affect patient respiratory pattern. objectives. we explored how eadi influence the effect of varying the nava gain on tidal volume and peak airway pressure. we included twelve patients recovering from acute respiratory failure. all patients, connected to a servo-i ventilator (maquet critical care, solna, sweden) able of delivering both psv and nava, underwent to a random application of increasing gains ( . - - . - - . - - cmh o/lv) during nava and increasing pressure support ( - - - cmh o) during psv. each level was maintained at least min. all changes in eadi, tidal volume (vt), and peak airway pressure (paw peak ) were referenced respect to their respective values at nava gain . . introduction. lung protective ventilation strategies is considered 'gold standard' for patients with acute respiratory distress syndrome (ards). high-frequency oscillation (hfo) has been used as a rescue measure and claimed to protect the lungs from ventilator induced lung injury ( ) . theoretically hfo should be considered early in the course of ards. objectives. we were interested to determine the time course to achieve optimal gas exchange with early hfo and its impact on the use of other adjunctive therapies; inhaled nitric oxide, prone positioning and extracorporeal oxygenation or carbon dioxide removal. after ethical approval, a total of adult patients with ards were enrolled in this prospective observational study. the oscillation (metran co. ltd, - , -chome, kawaguchi, saitama, japan) was started when fio [ . or level of peep [ cmh o were required on a conventional ventilator. hfo frequencies, cycle volume and bias flow were altered until optimal gas exchange achieved. the pattern of gas exchange was observed for the first h and other adjunctive therapies were used when required. the following parameters were recorded: duration of hfo, arterial blood gases during the first h, frequency of need for other therapies, incidence of barotraumas, and re-requirement of hfo once weaned from. a total of patients (age between - years, male:female ratio = : ) were ventilated - days with conventional ventilator before start of hfo. duration of hfo varied from to days ( median). there was a significant improvement in pao at - h (p = . ) following the onset of hfo (fig. ) . the number of patients requiring other therapies are very low; inhaled nitric oxide n = , prone positioning n = , both prone positioning and nitric oxide n = , ecmo/novalung n = . seven patients required re-hfo once weaned and another two developed pneumothoraces requiring chest drainage. conclusions. the data of this study demonstrates that significant improvement in gas exchange occurs in patients with ards following - h of hfo. early oscillation also appears to reduce the need for other adjunctive therapies. further studies of early hfo strategy are warranted. introduction. neurally adjusted ventilatory assist (nava) is a novel method for patient triggering of pressure support. instead of relying on conventional pressure or flow triggering, the peak diaphragmatic emg signal (edi) is used to precisely synchronise patient demand with ventilatory assist. although, the physiology and science underpinning nava has been described, less is known about its clinical application and efficacy ( ) . in particular, clinical superiority over conventional pressure support has not been established. objectives. here, we describe the clinical, nursing and operational lessons learnt from the introduction of nava platforms (servo-i, maquet) into a -bedded central london intensive care unit over years. in parallel we present some novel data from an observational cohort study examining the effect of nava on sedation use and ventilator days. a protocol for the safe measurement of edi in critically ill ventilated patients was developed through multidisciplinary review and discussion. a year registry of clinical lessons and adverse events from the introduction of nava was kept. in a parallel observational cohort study we examined three populations of ventilated patients (n = ) matched for apache ii, oxygenation index and compliance. group had no nava catheter; group had edi signal measured during conventional pressure support; and group utilised the edi signal to act as a neural trigger to drive ventilatory support. results. the measurement of edi was not associated with a difference in hospital mortality. there was a significant reduction in sedation use, muscle relaxation, ventilator days and icu days in patients with a nava catheter (fig. ) . however, there was no significant difference in any of these parameters with edi measurement guiding conventional pressure support versus nava. ventilator days in nava versus pressure support conclusions. in this study we show that neurally adjusted ventilatory assist can be safely and effectively be introduced into a 'non-expert' intensive care unit. we further show that reductions in sedation use and ventilator days appear to be related to the earlier introduction of sedation holds and reductions in ventilatory assist (with consequent earlier spontaneous breathing trials) in order to acquire an edi signal rather than due to an intrinsic advantage gained by improved patient-ventilator synchronisation with nava. the causes of the respiratory failure were: infections n = ; . % (immunodeficiency n = , tuberculosis n = , aplastic anemia n = , congenital cardiomyopathy n = , sepsis n = ), rsv infection-bronchiolitis n = ; . %, bronchopulmonary dysplasias n = ; . %, leukemias n = ; . %, burn-ards n = ; . %. the mean duration of hfov was . days ( h to days). the parameters of ventillation ranged: fio : - %, mean pressure: - cmh o, dp: - cmh o. the i time and hertzs ranged within the acceptable for age limits. closed suction circuit was used. we didn't notice any side effects from cardiovascular system or distension of the thorax. eadi and respiratory effort indices decrease when assistance increases in nava. nava should also theoretically allow perfect synchronization between the patient and the ventilator, and no asynchrony has been described with this mode. nava level adjustment at bedside, however, is still a matter of research. we assessed breathing pattern, respiratory effort indices, and patient-ventilator synchronization throughout a titration of nava and of pressure support ventilation (psv). we assessed breathing pattern, respiratory effort indices, and patient-ventilator synchronization throughout a titration of nava and of pressure support ventilation (psv). methods. physiological study conducted in seven patients (preliminary results) during the weaning. airway pressure (paw) and flow, esophageal and gastric pressures and the eadi were continuously recorded. for each patient, the following levels of assistance were consecutively applied: in psv: - - - - cmh o; in nava: . - - . - - . - - - - cmh o/mvolt. results are given as median and [ th- th percentiles], and tidal volume (vt) in ml/kg of predicted body weight. results. the increase from the lower to the higher level of assistance was associated with an increase in vt from . [ . - . ] to . [ . - . ] ml/kg in psv and from . [ . - . ] to . [ . - . ] objectives. we describe technical possibilities, tolerance and gas exchange with combination of oscillation device with nimv. a specific oscillator device (sensor medics, vyasis) was selected to change conventional airflow to oscillatory airflow. connected by ''t'' piece with oscillatory devicerespiratory circuit-face mask. we selected bipap ventilator (vision resp inc), facial mask. bipap mode (iap/epap cmh o) to achieve stable mechanical ventilation (t ). a progressive increment in rate of oscillation (hz) and power oscillation to achieve airflow change (t ). to evaluate the differences of peepi during the release phase, referred to mechanical pressure release from p high to p low , and the inspiratory work of breathing (wob) during p high among currently available aprv ventilators, using a lung model (ttl , mi). methods. the six aprv ventilators were evaluated in this study: ) nellcor puritan-bennett (puritan-bennett), ) evita xl (drager), ) servo i (maquet), ) avea (viasys), ) g (hamilton) and ) engstrom (ge healthcare). ventilator settings in aprv ventilators were set as follows: p high /p low cmh o/ cmh o, t high /t low . s/ . s. when evaluated peepi during the release phase, t low was diminished by steps of . s from . to . s. the inspiratory pressure-time product (ptp), as an index of wob, was directly measured under with tidal volume/respiratory rate of ml and /min. measurement for each setting was performed in a random order. three breaths were analyzed and averaged for each measurement. the results are shown in fig. objectives. to perform bench study to test the hypothesis that ett or trach can reduce the insufflated (vti) and/or exsufflated (vte) volume as provided by coflator Ò . methods. coflator Ò is connected to a pneumatic model (ttl, michigan instruments) via ett mallinckrodt . , . , . , . , . ) or trach (mallinckrodt . , . , . ) . the set up is tested in conditions of compliance (c ml/cmh o) and resistance (r cmh o/l/s): c r , c r , c r , c r . the device is set in manual mode, at the highest inspiratory flow, inspiratory/expiratory time / , s pause after expiration. three pressures are used, , and cmh o in both inflation and deflation. a baseline condition without any tracheal prothesis nor r served as reference. airflow and pressure upstream ett or trach are measured (biopac mp ). five insufflations followed each by an exsufflation are performed in each condition. the data are analyzed by using a linear mixed effects model where ett or trach, and pressure have fixed effects and c or r a random effect. the dependent variable is vti and vte. the main end-point is the slope of the relationships between vti or vte and pressure. results. the vti-pressure slope was significantly lower with any ett than baseline at both c ( fig. a and b). the same was true for trach. even though these differences were statistically significant the reduction in vti from the baseline averaged ml with etts as a whole. the vte-pressure relationships were similar for ett and trach and showed no difference from baseline at c ( figure d ). however, at c , the relationships are scattered ( figure c ). moreover, expiratory pressure of - and - cmh o were not reached for ett . , . and . and trach . and . . conclusions. ett and trach slightly but significantly change the performance of the device. however, small sized ett or trach in c condition substantially modify the efficacy of the exsufflation. these findings desserves assessment in patients for relevance. rd esicm annual congress -barcelona, spain - - october s though humidified high flow nasal canula oxygen (hfnc) has been widely studied in pediatric population, few data in adult is available and its and its precise indications and actual benefits in these patients remains unknown. two studies have shown that hfnc generates a low level of positive airway pressure contributing to decrease the work of breathing. one study has reported a favourable effect on comfort and oxygenation of hfnc as compared to venturi mask and in another preliminary one, fewer patients using hfnc went on requiring non invasive ventilation. objectives. to evaluate the efficiency of hfnc (optiflow, fisher and paykel, auckland) in critical care patients with acute respiratory failure. methods. prospective single centre study in a university hospital intensive care unit. all patients exhibiting acute respiratory failure (arf) as defined by clinical signs and/or failure of haematosis, regardless of the aetiology, were eligible. hfnc was used at a mean output of ± l/min and a mean fio of ± % throughout the study period. results. thirty-five patients were included. the mean age was . ± . years old and mean saps ii is ± . pulmonary infection was the most common aetiology of arf. hfnc was used ± days. all but one patient were discharged alive from icu. optiflow significantly reduced respiratory rate (p \ . ), heart rate (p \ . ), dyspnea score (p = . ), sus clavicular recession and thoraco abdominal asynchrony, and improved pulse oxymetry (p = . ). there was no significant difference in ph, pao , paco on arterial blood gazes performed before and , and h after hfnc use. the pao /fio ratio at and h after hfnc initiation was higher than before use of hfnc (p = . ). patients ultimately intubated exhibited a higher respiratory rate min ( . ± . vs. . ± bpm, p = . ) and min ( with an incidence of up to % in routine sonography [ ] , pleural effusion is one of the most common complications in intensive care patients. the use of bedside d ultra-sound to detect pleural effusion is fast, practicable and minimises radiation exposure [ ] . however, sonographical volumetry tends to be imprecise, and ct imagingbased volumetry is the more accurate method to quantify pleural fluid in intensive care patients [ ] . objectives. the aim of this study was to compare the accuracy of d and d ultra-sound volumetry of pleural effusion in intensive care patients. methods. icu patients designated for thoracentesis because of radiological support for pleural effusion were examined both with d and d ultra-sound \ h before and after the intervention. effusion volume was calculated with the formula ''volume [ml] = sep [mm] '' [ ] for d measurements and compared to the d volumetry by the ge d view software. the difference of volumetry before and after intervention was compared to punctured volume (gold standard). the device used for u-sound measurements was the ge voluson i. . within the group under survey (n = ), eight patients were on the respirator. mean punctured volume was ml ( ml; ml). mean absolute value of deviation from punctured volume (gold standard) was ml ( . %) for the d measurements and ml ( %) for d measurements. biggest difference between methods was found between ml and ml punctured volume. none of the methods generally measures higher volumes than the other. conclusions. the size of deviations from gold standard in both directions in d measurements suggests that the method is not reliable in predicting pleural effusion volume. d measurements are more likely to predict the right effusion volume, making the method a better diagnostic tool than d u-sound measurements. although thoracocentesis was found to be safe for mechanically ventilated patients [ ] and d volumetry may not change the therapeutic decision, which depends on high-risk patients' overall clinical condition, it could nevertheless help to avoid unnecessary interventions and thus improve patient safety. ongoing work analyses results for a group of patients with ct imaging-based volumetry of pleural effusion as gold standard. we study the utility of deltacvp changes during pressure support ventilation (psv) as an indication of respiratory effort. patients after several t-trials failures were on psv. the level of ventilatory assistance was changed in order to set the psv. no aditional interventión was used in the management of these patients. we registered data from the ventilator and beside monitor (vt, rr, p , deltacvp) in two levels of ps. optimal-ps, as the lowest support without respiratory distress and with the middle of this level -psv. the inspiratory trigger was used with the highest sensibility without autotrigger, the inspiratory ramp was changed in every patient and expiratory was flow-cycled at % of the peak inspiratory flow. results. patients n, acute on chronic respiratory failure, n, heart failure, n, recovery of acute respiratory failure. age ± years, admission apache ii ± and they needed weaning with ps after ± days with control mechanical ventilation. the respiratory mechanics in this time were cst.rs ± ml/cmh o and raw.rs ± cmh o/l/s. the ramsay score was ± ( ) ( ) ( ) ( ) ( ) . when the optimal level of ps was decreased from ± to ± cmh o, all patients showed respiratory distress, and the variables studied changed significantly: p : . ± . to . ± . cmh o, deltacvp . ± . to . ± . cmh o, vt decreased from . ± . to . ± . l and rr increased from ± to ± bpm (p \ . ). the correlation between p and del-tacvp was . (p = . ). central venous pressure swing provided information about the respiratory effort and may be useful during pressure support ventilation. introduction. the use of a tidal volume of ml/kg of predicted body weight is part of the management of patients presenting with ards ( ) and prevents ventilator induced lung injury in icu patients undergoing mechanical ventilation ( ) . the setting of tidal volume is based on patient height. height seems to be more often estimated by the icu staff than actually measured ( ). objectives. our study aimed to assess the accuracy of the visual estimation of patient height and its impact on ventilator settings. thirty-two patients admitted to a surgical icu were prospectively included in this observational study. patients had their height visually estimated by icu staff members ( doctors, nurses and nurse-assistants) and then measured. we also measured the knee height from which height can be extrapolated. we then compared the mean estimated height for each patient to the actual measured height with the use of bland and altman plots and the consequences of the measurement error on the tidal volume setting. in most patients visual estimation overestimates the actual height. the measurement errors result in an increase in the tidal volume up to + ml/kg. this remains true whatever the subgroup studied: all patients (bias: . ± . , % ci: - . ; . ), male patients (bias: . ± . , % ci - . ; . ), female patients (bias: . ± . , % ci . - . ) and whatever the type of assessor. extrapolated height from knee height results invariably in an underestimation of actual height (bias - ± . , % ci - . ; . ). our results prove that neither visual estimation nor knee height measurement are reliable surrogates for measured height. therefore, measuring patient height should be mandatory in critically ill patients in order to minimise ventilator-induced lung injury. methods. , respiratory acts were recorded in icu patients selected because of severe asynchrony with the ventilator (g , hamilton medical) during psv. by visual analysis (va) of airway pressure and flow trajectory, ineffective efforts and inspiratory/expiratory delays were detected. the results of va were compared with those provided by a new algorithm based on the automatic analysis (aa) of flow trajectory. results. va identified ineffective efforts ( % of patients acts). among , assisted acts, average inspiratory and expiratory delay was ± ms and ± ms, respectively. significant inspiratory and expiratory delay ([ ms) occurred in , ( %) and in acts ( %), respectively. automatic analysis was able to identify , of , patients acts ( %). in , cases ( %), both inspiratory muscles contraction and relaxation were detected. in acts ( %) only relaxation was identified. compared with va, inspiratory and expiratory delay of aa was ± and ± ms, respectively. aa recognized the start and the end of patient's effort before the ventilator in , ( %) and , ( %) of assisted acts. sensitivity and specificity of aa in detecting ineffective efforts, inspiratory delays [ ms, expiratory delays [ ms were and %, and %, and % respectively. the new algorithm proved to be efficient as a real-time, continuous monitoring system of patient-ventilator interaction. the advantage over traditional flow and pressure based triggers has to be tested. introduction. mechanical ventilation remains as one of the most difficult safety issues in the icu, but parameters commonly monitored by ventilators only depict the most extreme risks for patients. new computerized approaches may manage exhaustive data and may include ''intelligent'' software that mirrors expert decision making. to test the clinical usefulness of a new computerized system as a herald for clinically significant alarms and its possible impact in outcome. methods. twenty-five mechanically ventilated patients were continuously monitored in a single mixed icu in a university-affiliated hospital. we recorded age, diagnosis, pao /fio , apache ii and sofa on admission. the computerized system grabs and process data from different devices, usually a monitor and a respirator, and evaluates the most relevant events in a ventilated patient. all the algorithms were designed and validated with the clinical staff. data of ventilated patients were recorded at the icu during months and a total of , , breaths from different patients, each of them with a register of at least % of total ventilation time, were collected. data include biomedical signals (waves and trends) as well as all the clinical events detected by the system, including trapped gas at end-expiration, presence of secretions, double-cycling, asynchronies during expiration, pulse pressure variation in patients not triggering the ventilator and stress index ([ . or . ) in those ventilated with square airflow. outcome variables were icu length of stay, hospital stay and mortality. statistical analysis included multiple regression models for length of stay and mortality. [ ] [ ] [ ] [ ] [ ] [ ] [ ] , icu length of stay . days [ . - ] , hospital length of stay days . the frequency of alarms were: trapped gas at end-expiration: . %, presence of secretions . %, double-cycling . %, asynchronies during expiration . %, stress index [ . . %, stress index . . %, and pulse pressure variation . %. multiple regression analysis found pao /fio associated with length of mv and close to significance with hospital stay and mortality, but any of the computerized alarms reached yet the level of significance. conclusions. the computerized system is able to detect and review more clinically significant problems than clinical routine. however, its impact to define patient outcomes warrants further investigation. objectives. we have assessed the ability of the ventilator t-bird vs and ltv- to deliver to a lung model with ards a set tidal volume (vt) at different simulated altitudes. we used a decompression chamber to mimic the hypobaric environment at a range of simulated cabin altitudes of , , , and , m ( , , , , , feet). ventilators were tested with realistic parameters. vt was set at and ml in an ards lung model. the positive end expiratory pressures (peep) were set at and cmh o. pressure drop across the pneumotachograph was measured by a differential pressure transducer (enertec tm ). the spirometer was checked at each altitude using a calibration syringe. the inspired oxygen content (fio ) was %. respiratory rate was breaths/min. the ratio inspiratory time/expiratory time was / . the protocol included three measurements for each simulated altitude. comparisons of preset to actual measured values were accomplished using a t test for each altitude. a significant difference was defined by p \ . . the standard deviation for the three measurements obtained at each altitude was consistently less than ml. respiratory rate delivered was breaths/min in all cases. variation of peep did not change the volume delivered. the t-bird vs showed a decrease in volume delivered. comparisons of actual delivered vt and set vt demonstrated a significant difference starting at , m for a vt set of ml, at , m for vt set of ml. at these altitudes, the variations between vt set and delivered were more than %. with decreasing barometric pressure, the ltv- showed mostly an increase in volume delivered. comparisons of actual delivered vt and set vt demonstrated a significant difference at , m for a vt set of ml, at , m for vt set of ml. the delivered tidal volume remained within % of the set vt. assuming that the patient is ventilated at sea level and gas exchange is normal, the movement to altitude would result in an increase in tidal volume which might in fact represent a clinical event. conclusions. the ltv- met the trial targets in all settings, whereas the t-bird-vso did not compensate well for altitude and progressively delivered lower volumes as barometric pressure decreased. such variations between delivered and set vt suggest lack of efficacy of altimetric correction in hypobaric conditions in some devices. the ltv showed a moderate increase in volume delivered for ards lung model with increasing altitude, but maintained the delivered volume within % of the set vt up to , m. the accuracy of the vt delivery was superior with the ltv- than with the t-birdvso . oxygen therapy is commonly used to correct residual oxygenation impairment in the post-extubation period. this is usually done through a venturi mask which allows to deliver predetermined fractions of oxygen humidified with bubble humidifiers. the low humidity delivered by such devices and the use of an oro-nasal mask may, however, reduce patient's comfort, possibly resulting in mask displacement or removal and consequent oxygen desaturations. nasal high-flow (nhf) oxygen therapy allows to deliver high-flow oxygen, humidified with heated humidifiers and delivered through nasal cannulae, with the potential to improve comfort and efficacy. objectives. in patients requiring oxygen therapy after extubation, we compared nhf vs. venturi mask in terms of oxygenation and comfort. patients who were mechanically ventilated for more than h, passed a spontaneous breathing trial, and had pao /fio \ at the end of the trial were randomized to receive oxygen with nhf or venturi mask after extubation. exclusion criteria were: tracheostomy, age \ , pregnancy, or anticipated need for noninvasive ventilation after extubation. in both groups, fio was set to obtain spo between and % ( - % in copd patients). with nhf, flow rate was set at l/min. arterial blood gases, respiratory rate, and discomfort were assessed at , , , , , , and h. discomfort was assessed by asking patients to rate their discomfort with the used device by using a numerical scale from (no discomfort) to (maximum imaginable discomfort). discomfort symptoms were also assessed for the dryness of the delivered oxygen (dryness of the mouth, throat, nose, difficulty to swallow and throat pain). incidence of desaturations and interface displacement was also assessed. objectives. to evaluate the optimal humidifier water temperature when using a helmet for noninvasive positive pressure ventilation. oxygen. each was sequentially tested in the following order: using the helmet without humidification at ambient temperature, with humidification with unheated chamber water, and with humidification with the chamber water at , , and °c. at each setting, after a min stabilization period, measurements were taken. comfort level at each setting was evaluated using a visual analog scale (vas) rated zero (most comfortable) to ten (least comfortable). temperature and relative and absolute humidity inside the helmet, and vas scores statistically significantly increased as the humidification chamber water temperature increased. the lowest vas, . ± . , was obtained when water in the humidifier chamber was at ambient temperature. conclusions. for patient comfort during cpap using a helmet, the most desirable conditions are likely to obtained by humidifying without heating, that is by leaving the water in the humidifier chamber at room temperature. introduction. the physiological and clinical effects of non-invasive ventilation (niv) on acute post-operative respiratory failure are relatively unknown. the aim of this study was to determine the prediction factors for failure in the use of niv with a helmet in this context. the use of niv was assessed for a period of years, in a post-operative intensive care unit (icu). demographic data was collected, as well as arf and arterial gas readings. haemodynamic changes were assessed using picco tm technology and the clinical development of patients was recorded. all patients who developed acute respiratory failure (arf) were treated using niv as their primary care, and the two groups for the study were determined in this way, depending on whether the technique was successful, or the patients required intubation. the risk factors that determined failure in the application of niv were subsequently determined. of the patients presenting with post-operative arf treated with niv using a helmet, did not require intubation ( . %). following a multivariate analysis using logistic regression, we determined that there are four independent risk factors for the failure of niv. the primary causes of respiratory failure are as follows: acute respiratory distress syndrome (ards) and pneumonia, and in second place, the high initial evlwi (extravascular lung water index) value, as a protective factor, is the increase in the po /fio ratio after the first hour of niv application. conclusions. niv using a helmet could provide an effective alternative to conventional ventilation in selected patients with post-operative arf. -jaber s, delay objectives. analyze niv practice in emergency departments. we have development an international epidemiology survey (march ) by electronic questionnaire to know niv organization, equipment and training in emergency departments (phase i). design. international multicenter prospective. we have enrolled information from hospitals: spain ( ); italy ( ); india ( ); usa ( ); slovakia ( ); turkey ( ); germany ( ); australia( ); chile ( ); singapore ( ); finland ( ) during to analyze noninvasive practice in prehospital and emergency medicine, equipment, interfase, ventilatory modes and common clinical applications. major results during month period analysis were: noninvasive mechanical ventilation were applied in prehospital: ( ) ( . %). nimv commonly was applied follow a objective pprotocol of nimv: ( ) ( ) ( . %). global rate indication of niv were copd exacerbation ( %) and cardiac pulmonary edema ( - %). all niv applications were successful applications in emergency departments (avoid eti %) with minor complications ( . %) (skin nose lesion). equipment more relavant were (cpap devices ( %) and facial mask ( %) was more frequent, follow total face( %); nasal mask ( %); helmet ( %); type ventilary mode: cpap ventilatory mode was frequent used as first line ( % ( ) suggest niv should be started within h of not responding to the maximal medical therapy for acute type respiratory failure patients. following an earlier audit presented as an abstract at esicm ( ) , which looked at possible delays in starting niv, protocols were implemented to start niv earlier at russells hall hospital acute admissions unit. objective. the aim was to assess the delays in starting the appropriate patients on niv at admission looking at impact on adverse outcomes. method. data was collected retrospectively using bts niv audit tool. cases admitted with type respiratory failure in our hospital between january and march who needed niv were included in the audit. delay was subdivided into a) door to first arterial blood gas (abg) sampling b) abg to decision for niv and c) from decision to actual starting of niv. results. the mean time to get an abg from admission was min. cases with delay more than h skewed the data. the median time, which was more representative of the usual delay between admission and first abg, was min. our audit showed that out of ( %) patients had abg within an hour compared to out of ( %) in the last audit. although noninvasive ventilation (niv) has been widely used in patients with acute on chronic respiratory failure (acrf) due to chronic obstructive pulmonary disease (copd), series studying patients with pulmonary restriction due to morbid obesity (mo) are rare ( ) , despite the disease is highly prevalent in our environment. objectives. the aim of our study is to analyze and compare the effectiveness of niv in patients with copd and om. we analyzed all patients admitted to icu for a period of years with diagnosis of acrf due to copd or mo and treated with noninvasive ventilation. niv success was defined as the avoidance of endotracheal intubation, survival in icu and at least h on a medical ward with no signs or symptoms of respiratory failure. variables are expressed as means ± standard deviation and percentages. comparison between variables by pearson's v test and student t. we analyzed survival and hospital readmission per year (log rank test). during the study period, patients were admitted with exacerbation of copd and with mo. all patients were treated with two levels of pressure. age differs between copd and om, ± and ± years, respectively (p = . ), as well as the percentage of men, . adaptive support ventilation (asv) Ò (hamilton galileo) has been shown to result in better patient synchrony, reduced weaning times and reduced work load for the icu staff ( , ) . but, data is lacking on its efficacy, especially as non invasive ventilation (niv) due to the concern of being closed loop ventilation. also, little is known about the risk factors of late niv failure in patients who improve initially ( objectives. to assess end tidal co monitoring in patients with hypercapnic exacerbations of copd requiring niv methods. simultaneous measurement of paco and petco was performed in groups of patients. paco was measured using arterial blood gas analysis and petco was measured using non-invasive capnography. the groups were; phase a: mechanically ventilated patients post coronary artery bypass graft, used to establish the reliability of the end tidal carbon dioxide monitor in a homogenous group of previously well patients. phase b: patients with copd who did not have symptoms associated with an exacerbation, used to assess the use of a non invasive sampling device and assess the sampling method in stable copd patients. phase : patients with a hypercapnic exacerbation of copd requiring niv. capnography was monitored continuously in this group and petco values were calculated based on a mean value min before and after the arterial blood gas sample. this was to avoid any sampling error as it was impossible to isolate the exact moment of arterial puncture. agreement between the sampling methods was assessed using the bland-altman method. phase a objectives. we aimed to evaluate the possible harm of niv failure in routine practice among spanish icus. methods. we extracted patients with acute respiratory failure requiring either invasive or noninvasive mechanical ventilation in spanish icus during the -month period of the validation of the sabadell score ( ). we recorded demographic parameters and treatments received during the icu stay. patients were followed until hospital discharge or death. results. we analyzed , patients, of whom , ( %) received only invasive mechanical ventilation (imv) and ( %) received niv. niv succeeded in % of patients, but the other % required intubation. niv failure was more common in neurologic ( %) and post operatory ( %) and less frequent in coronary patients ( %). mortality was lower than predicted in niv patients ( vs. %) and similar to predicted in imv patients ( vs. %). mortality was lower than predicted in patients in whom niv was successful ( vs. %) and (similar or slightly lower than to predicted) in those in whom niv failed ( vs. %). conclusions. routine use of niv seems to confer a benefit, even when it fails and intubation is needed. reference(s tables and shows the parameters on respiratory muscles. introduction. the effectiveness of non-invasive ventilation (niv) in the setting of hypoxemia de novo remains controversial. it has been detected that patients in whom niv fails and intubation is required have a high mortality. otherwise, in patients in whom niv avoids intubation, survival rate is also high. to identify the factors involved in success or failure of niv in critically ill patients with hypoxemia de novo. we retrospectively studied all the patients admitted in our -bed intensive care unit (icu) from january to december with the diagnosis of hypoxemia de novo. do-notintubate patients were excluded. the indication of niv was at medical discretion, as well as intubation criteria. we defined the hypoxemia de novo as acute non hypercapnic respiratory failure due to a different cause from cardiogenic pulmonary edema. we defined two groups of patients: ) niv failure, patients who required intubation, and ) niv success, patients who did not require intubation. we collected demographical variables (age and gender), etiology of the hypoxemia, severity scores on admission (saps ii and sofa), glasgow coma scale (gcs), respiratory rate (rr), pulsioximetry (spo ), ph and fio , before and h after starting niv, episodes of nosocomial respiratory infection, length of stay (los) in icu and icu mortality. we compared both groups using the mann-whitney non-parametric test. p \ . was statistically significant. we studied patients ( women and men) with a mean age of ± years. the etiology of respiratory failure was: ards (n = ), pneumonia (n = ) and others (n = ). there were patients in the niv failure group ( %), and in the niv success group ( %). niv failure rate was higher when hypoxemia was due to ards (p = \ . ). objectives. this retrospective analysis aimed to assess outcomes following instigations of niv in a variety of clinical conditions. outcome data for copd/apo and non-copd/apo groups were compared. we assessed whether outcomes differed between these groups. in addition we wished to assess how outcomes varied across non-copd, non-apo conditions. objectives. the aim of this study was to compare patient's respiratory effort with three different noninvasive ventilators currently used on critical care patients and selected from a bench study. six patients treated by niv to prevent respiratory failure after extubation were included. each subject was successively submitted to a randomly assigned min-period of ps-niv with three different ventilators: bipap vision (respironics), elisée (resmed) and oxylog (dräger medical). these ventilators have different performances in a bench comparison. ventilatory settings were adjusted for the first ventilator and maintained for the followings. ps level was increased in order to obtain a tidal volume of - ml/kg of body weight (ps ± cmh o). flow, airway and oesophageal pressures were recorded. the oesophageal pressure time product (ptpoes) and tidal oesophageal swing (dpoes) were measured to evaluate patient's respiratory effort. results. no significant differences in tidal volume, respiratory rate and autopeep were found between ventilators. the dpoes and ptpoes, however, were significantly higher with oxylog as compared to bipap vision and elisée , as expected from the bench comparison. there are limited data on niv s efficacy in hypoxic respiratory failure. objective. to investigate the epidemiology and outcomes of patients administered niv as first line respiratory support in a mixed medical-surgical icu over a year period (jan -dec ), in an academic medical center. methodology. data abstraction from icu database, clinical care manager and chart review. results. surgical patients (sp) and medical patients (mp) were administered niv. the sp were % male, and had a median age of years. the mp were % male, and had a median age of years. % of sp were admitted with type respiratory failure (t rf pao \ kpa), % were admitted with type respiratory failure (t rf paco [ kpa) and the remainder were admitted with respiratory distress (rd). % of mp were admitted with t rf (pao \ kpa), % were admitted with t rf (paco [ kpa) and the remainder were admitted with rd. the median length of stay (mlos) was days for sp (range - ); the mlos for mp was days (range - ). sp were commenced on niv on average . h after admission (range - h), and remained on niv for a median of . (range - ) h. % of surgical patients required intubation, and the mortality rate was . %. mp were commenced on niv on average h after admission (range - h), and remained on niv for a median of (range - ) h. % of medical patients required intubation, and the mortality rate was %. logistic regression was applied to all datasets. among medical and surgical patients there was no correlation between the type of respiratory failure, initial blood gas or ph and the need for subsequent intubation, or risk of death. hematology patients had a mortality rate of % and accounted for % of overall deaths. oncology patients also had a % mortality rate, and accounted for % of overall deaths. amongst the mp that presented with hypoxemia, the intubation rate was % and the mortality rate was % (although not all patients that died were intubated). amongst the mp that presented with hypercarbia, the intubation rate was % and the mortality rate %. summary. niv successfully prevented intubation in more than % of patients. patients presenting with hypoxic respiratory failure were no more likely to be intubated than those presenting with hypercarbia. two-thirds of hematology and oncology patients treated initially with niv subsequently died. a microdialysis system was composed and the time delay of the system, recovery time, was introduced and tested with a fluids switching method. twelve sd rats were divided into ir or control group. myocardial ir was induced by ligating ( min) or releasing ( min) the suture underlying lad. mycrodialyisis probe was implanted into the left ventricular myocardium perfusion area to be occluded. dialysate samples were collected every min. blood samples were drawn at the beginning and at the end of the procedures. dialysate calcium concentration ([ca++]i) was detected with an atomic absorption spectrophotometer. serum calcium and ctnt were detected. recovery time for the microdialysis system was min, recovery rate was %. [ca++]i showed no changes during ischemia and descended immediately after reperfusion,reached the lowest level at min after reperfusion, then escalated slowly while keeping lower than control with significant difference. there was no difference in serum calcium at the beginning ( objectives. to evaluate the causes, incidence and impact on outcome of admission hyperlactatemia in patients admitted to a general micu. methods. data were retrospectively collected from the patient records for all adult patients admitted in the micu during the -months period. data regarding patient demographics, probable cause of hyperlactatemia, presence of shock on admission, need for organ support and icu outcome were recorded. patients were divided into two groups based on admission lactate levels: high lactate, with levels of mmol/l or more and normal lactate, with levels less than mmol/l. patients in these two groups were compared in terms of need for organ support and icu mortality. the efficacy to discriminate between survivors and non-survivors was assessed by area under the receiver operating characteristic curve (auroc). introduction. during critical illness alterations in blood flow are thought to predispose to organ dysfunction and hemodynamic therapy is often targeted at maintaining organ perfusion. however, abnormal blood flow distribution during critical illness may cause regional blood flows to correlate poorly with systemic haemodynamics ( ) . currently, our understanding of blood flow distribution during critical illness in humans has been limited by the invasiveness of established techniques for its measurement. objectives. phase-contrast mri (pc mri) represents an entirely non-invasive, contrastfree, method of measuring blood flow in major blood vessels ( , ) . we sought to apply this technique to technique to the measurement of organ blood flow in the critically ill. in a pilot proof of concept study, we measured renal and portal blood flow by pc mri critically ill humans with sepsis, multi-organ dysfunction and acute kidney injury (aki). in individuals cardiac output was measured by thermo-dilution in the icu, in the remaining patients we measured cardiac output (ascending aortic flow) and also descending thoracic aortic blood flow using pc mri techniques. we studied critically ill individuals with severe sepsis and aki. when studied, were mechanically ventilated, were on continuous haemofiltration and required vasopressors. transport and mri examinations were carried out without complication. in these patients, median cardiac index was . l/min/m (range . - . ), median renal blood flow ml/min ( - , ) and median renal fraction of cardiac output . % ( . - . ). median portal blood flow was ml/min ( - , ). descending aortic blood flow (measured in patients) ranged between and % of cardiac output (median %). conclusions. phase-contrast mri can efficiently and safely assess organ perfusion during critical illness in man. near simultaneous measurement of cardiac output enables organ blood flow to be assessed in the context of the global circulation. preliminary observations suggest renal blood flow is consistently reduced as a fraction of cardiac output in established aki. pc mri may be valuable to future investigation of organ dysfunction and vasoactive therapies in sepsis and critical illness. objectives. we were interested in the effects of the higher pco -levels on the microcirculation of infants with birh weights \ , g. data were collected from infants, who were randomized either to treatment with permissive hypercapnia or normocapnia. inclusion criteria were a birth weight between and , g, a gestational age from rd to th+ weeks, intubation during the first h of life and no malformations. the pco target range was increased stepwise and was mmhg higher in the intervention group. skin microvascular parameters were assessed noninvasively with sdf on the right arm every h during the first week of life and on the th day. results. pco (auc: ± vs. ± ) differed significantly between the two groups (p = . ). functional vessel density (fvd) was significantly lower in the intervention group on the th day of life ( ± vs. ± cm/cm ; p = . ). the proportion of small vessels increased in the control group whereas they decreased slightly in the intervention group, but did not reach stat. sig. increasing target pco lead to a temporary hyperdynamic flow in both groups. conclusions. pco -levels influence significantly the microcirculation in preterm infants. elevation of pco -levels leads to a decrease in fvd, presumably due to shunting and vasoconstriction and might cause temporarily hyperdynamic flow. methods. blood from healthy volunteers were diluted with hes, albumin %, rl or autologous plasma to obtain a final hematocrit of %. in vitro wbv measurements were made by the rheolog tm device (rheologics, exton, pa), a new viscometer with a u-formed capillary. the flow rate (determined by the rate of change in height of the columns of blood) is directly related to the pressure drop across the capillary tube. the shear rate (from , to s - ) and viscosity of the sample can be mathematically derived. results were expressed as median values (with - % intervals) and compared by anova with bonferroni correction. a p value . was considered as statistically significant. hemodilution with rl and albumin decreased significantly the wbv for all shear rate compared with autologous plasma and hes ( fig. ). conclusions. in contrast to albumin and ringer's lactate, hes and autologous plasma increased the whole blood viscosity, suggesting that these solutions may be preferred in severe hemorrhagic shock to better preserve plasma viscosity and microcirculation. we divided into two groups the randomly selected sample from the scope of patients come through open-heart operation assisted with extracorporeal support at the university of pécs: therapeutic (continuous blood gas monitoring/cdi- ) and control (intermittent sampling) group. after the retrospective data collection we carry out the analysis with (prevalence) frequency and confidence interval calculation and khi square test. results. the following accompanying diseases occurred significantly higher rate in the therapeutic group: ami (p = . ), kidney disease (p = . ), chronic pulmonary disease (p = . ), and the aggregation of the accompanying diseases showed also significantly high degree (p = . ). the long interval operations occurred significantly higher rate (p = . ) in the therapeutic group, and the times of the aorta clinch (p = . ) and the perfusion (p = . ) was also significantly longer. despite of that during the perfusion in a significantly more cases remained the rates in the normal range concerning to the therapeutic group (ph: p \ . ; be: p \ . ; pco : p \ . ), and the prevalence of the restart of the heart showed also significantly higher rate (p = . ). the continuous blood gas analyses assure reliable and the postoperative recovery assisted ecc circulation support. this assists considerably for keeping the parameters in the physiological limits even in the higher rate of the incidences of complex operations and accompanying diseases. this could contribute to lower incidence of side effects, preventing the causeless elevation of the postoperative hospital charges. objectives. describe the changes in capillary perfusion after erythrocytapheresis during severe falciparum malaria. we report two cases of severe falciparum malaria and describe the evolution of the sublingual capillary perfusion after erytrocytapheresis. the sublingual microcirculation has been studied with sidestream dark-field imaging (microscan; microvisonmedical tm , amsterdam). the device was applied on the lateral side of the tongue and the video images ( - captures of - s.) of capillary perfusion were recorded. the microcirculatory scores were analysed offline: small vessels (\ lm) density (number of vessels/mm), percent of continuously perfused small vessels (ppv%) and mean flow index (mfi). mmol/l. the capillary perfusion has improved: capillary density increased ( . /mm), the proportion of perfused vessel increased ( %) and flow was continuous in most vessels (mfi: ). clinical evolution was rapidly favourable and the patient was discharged from the intensive care unit. case . severe falciparum malaria with high parasitemia ( %) and acute renal failure. before erythracytapheresis: macrohemodynamic parameters were normal but microcirculation was reduced: vessels density ( . /mm) with % of small vessels perfused and the flow was slow in most vessels (mfi: . ). after erythracytapheresis: parasitemia decreased ( . %). sublingual microcirculation has improved with an increase in small vessels density ( . /mm) among which . % were perfused with a continuous flow (mfi: ). the patient had a good outcome. conclusions. microcirculation monitoring should be assessed specifically in some critically ill patients, even if macrocirculatory parameters are in the normal range. during severe plasmodium falciparum malaria, this monitoring could be specifically important to assess the effect of erytrocytapheresis therapy on tissue perfusion. rd esicm annual congress -barcelona, spain - - october s objective. perioperative myocardial infarction (pomi) is associated with significant mortality and morbidity in cardiac surgery. the primary objective of this prospective multicenter study is to investigate whether monitoring of coronary sinus metabolic markers can reliably predict ischemia and pomi faster than conventional monitoring. method. patients undergoing cardiac surgery were monitored perioperatively using a transjugular implanted microdialysis catheter (cma microdialysis) to study the metabolic changes of the heart. coronary sinus (sc) samples of lactate, pyruvate and glycerol were obtained continuously through -h post-operatively. pomi was defined by ckmb c u/ l and troponin t c . lg/l. a total of patients met the criteria for pomi. patients showed at least one adverse event during the postoperative course. lactate, lactate-pyruvate-ratio and glycerol levels in the sc sharply increased up to h before rise of cardiac enzymes. analyses of regression and discriminate analyses showed statistically significant (p \ . ) relationships between elevated metabolite values and the occurence of pomi. roc analysis revealed that lactate, lp-ratio and glycerol from the sc are sensitive markers to predict pomi and postoperative clinical events. conclusions. coronary sinus metabolic markers are sensitive and early predictors for the detection of perioperative myocardial infarction and severe complications in patients undergoing cardiac surgery. beginning disorder can be detected far earlier than with any existing monitoring device. perioperative red blood cell transfusions (btx) are commonly used in patients undergoing cardiac surgery to correct for anemic conditions caused by blood loss and hemodilution associated with cardiopulmonary bypass circulation and anesthesiological procedures. however, several studies have shown btx might have adverse effects on patient outcome. the goal of btx is to correct anemia and to ensure an improvement in the oxygen delivery to the parenchymal cells by the increased presence of red blood cells in the microcirculation. the aim of this investigation was to test the hypothesis that btx during onpump cardiac surgery have a beneficial effect on sublingual microcirculatory perfused vessel density, and oxygenation. methods. adult patients undergoing on-pump cardiac surgery were selected for this study. sublingual microvascular flow index (mfi), detected vessel length (dvl), and functional capillary density (fcd) were assessed using sidestream dark-field (sdf) imaging in patients. sublingual reflectance spectrophotometry was applied in patients to monitor sublingual tissue oxygen saturation. in group a, btx resulted in increased fcd and dvl as depicted in fig. . mfi for small and medium microvessels was not affected by btx (fig. ). in group b, reflectance spectrophotometry demonstrated increases in microcirculatory hemoglobin and oxygen saturation ( fig. ). the main findings suggest that leukoreduced btx improves the systemic circulation and oxygen carrying capacity of the microcirculation by increasing fcd and thereby reducing diffusion distances without increasing significantly the convection of red blood cells. this reduction in diffusion distances causes an increase in microcirculatory oxygen saturation. d.m.j. milstein , k. yürük , r. bezemer , c. ince academic medical center at the university of amsterdam, translational physiology, amsterdam, netherlands aims. anemia is a common adverse effect of oncologic diseases as is the therapeutic options required for their treatment. however, as blood transfusions are directed at correcting for anemia and intrinsic hypoxic conditions, little evidence exists claiming that blood transfusions have successfully resolved anemic challenges as storage can significantly deteriorate rbc function. the aim of this study was to investigate the influence of rbc transfusions on sublingual microcirculatory perfusion and tissue oxygenation in anemic oncology patients. methods. eight consecutive ambulatory patients scheduled to receive packed rbc transfusion bags were selected for this study. baseline sublingual microcirculation functional capillary density (fcd) was measured using sidestream dark-field (sdf) imaging prior to and after min of the completion of the last infused blood bag. sublingual mucosal oxygen saturation (sto ) was measured at the same anatomical location and time points using near-infrared spectroscopy (nirs). results. figures and capillary refill time (crt) is a generally accepted method of assessing the circulatory status of a patient. we have previously showed that using . s as the upper limit of normality in critically ill patients could discriminate patients with a more unfavourable outcome . however, this upper limit of normality was defined based on variation of crt in an adult healthy population . the best crt in critically ill patients, therefore, should still be redefined. objectives. we aimed to define the best crt as predictor of organic and metabolic dysfunction in an intensive care unit (icu) population. methods. capillary refill time was measured by applying firm pressure to the distal phalanx of the index finger for s, and a chronometer recorded the time of returning to normal colour. we performed receiver operating characteristic curve (auc) to detect the best crt consistent with severe organ and metabolic dysfunction, as evaluated by sequential organ failure assessment (sofa) [ and acidosis (lactate [ mmol/l and be\ - meq/ l), respectively. in addition, we performed logistic regression analysis using the cutoff crt as binary to investigate its estimated odds ratio (exp(b)). of patients included in the study (age ± ; male), had circulatory shock, of whom had septic shock. mean crt in all patients was . ± . . figures and show the roc curve for sofa score[ and metabolic acidosis, respectively. using the best crt value, logistic analysis revelled the following estimated odds ratio: for sofa score[ : exp(b) = . ; p = . ); for metabolic acidosis (exp(b) = . ; p = . ). roc curve for crt relative to sofa score [ roc curve for crt relative to acidosis conclusions. we found that . s is the best time to define prolonged crt in critically ill patients, and that using this crt cutoff value could discriminate patients with a more severe organ and metabolic dysfunction. introduction. impairment of microcirculation in acute situations is associated with organ failure and depends on macrocirculation but also on specific factors ( ) . micro-perfusion, assessed by tissue hemoglobin saturation (sto measurement) or micro-blood flow (laser doppler, ld) are easy to use and non invasive methods. the obtained data could be an end point in critical care resuscitation or optimization. objectives. to assess the impact on microcirculation of cardiovascular (cv) support on the basis of mean arterial pressure (map) and cardiac output (co), to evaluate when microcirculatory parameters improved or not the modifications observed in map and co. methods. observational study: measure of co, map, svco , and lactate, thenar nirs (inspectra ; hutchinson technology) baseline sto , with performance of an arterial occlusion test ( mn, mmhg) so calculate occlusion-os and reperfusion slopes-rs ( ). similarly, forearm skin blood flow velocity (ld, blf d, transonic systems) basal ld, and post-ischemic peak velocity ldmax) ( ) were measured. data were collected before and after cv optimization (fluid loading, vasoactive or inotropic drugs). patients were defined: macrocirculatory responders (r) when co increased more than % versus nonresponders (nr); microcirculatory responders (rs+) when rs increased more than % versus nonresponders (rs-). statistical analysis: nonparametric tests (wilcoxon and mann-whitney test). results. patients ( % in shock) were studied. had sepsis ( %), hemorrhage ( %), pulmonary oedema ( %), or other ( %). therapeutic optimization challenges were performed: fluid challenges ( ml, . % nacl), dobutamine c/kg/min, nitrates, diuretic, electric shock and an increase in dosage of norepinephrine. in r group (n= , %), co was increased associated with map (p \ . ), svco (p = . ) and decreased lactate (p = . ). the micro-oxygenation improved with an increase of rs ( . [ . - . ] vs. . [ . - . ]%/s, p = . ) as microperfusion did: increase in ldmax ( . [ . - . ] vs. . [ . - . ] tpu, p = . ). in the nr group, both the macro or the microcirculation did not change. since no microcirculatory differences between r and nr were observed, patients with good or poor microcirculation could not be detected. the study based on microcirculatory responses showed % of responders (rs+). in this group, baseline sto (p = . ), basal ld (p = . ) and ldmax (p = . ) increased in a large amount in association with an improved co and map (p = . and p = . ). in the rs-group, co and map were also improved (p = . and p = . ). conclusions. improvement of macrocirculatory parameters can improve microcirculation but not in all patients. improvement in microcirculation may also be a target, regardless the effects on macrocirculatory parameters. this concept has to be tested prospectively. introduction. hypothermia is regularly used for brain protection after resuscitation from cardiac arrest but its impact on cardiovascular function, however, is not well defined. objectives. the aim of this study was to evaluate the cardiovascular response to mild therapeutic hypothermia and rewarming in a large animal model. seven anesthetized, mechanically ventilated and invasively monitored sheep were cooled with a cold intravenous saline infusion, ice packs and nasal cooling (rhinochill system, benechill, ca) to achieve a core temperature of - °c (the basal temperature in sheep is around °c). after maintenance of this temperature for h, sheep were progressively rewarmed to baseline temperature. a positive fluid balance was maintained during the entire study period to avoid any hypovolemia. the sublingual microcirculation was observed using sidestream dark-field (sdf) videomicroscopy and the proportion of perfused vessels (ppv) and perfused vessel density (pvd) evaluated using a semi-quantitative method. results. during cooling, systemic and pulmonary artery pressures did not change, but cardiac output decreased significantly along with the increase in vascular resistance. left and right ventricular stroke work index decreased reflecting altered ventricular function. nevertheless, there was an increase in mixed venous oxygen saturation (svo ), reflecting a decrease in oxygen extraction. sublingual microcirculation analysis showed a significant decrease in ppv and pvd. all the variables returned gradually to baseline during the rewarming phase. conclusions. in this intact healthy large animal model, the alteration in cardiac function during hypothermia was well tolerated because of the simultaneous decrease in oxygen requirements. arterial pressure was maintained by an increase in systemic vascular resistance associated with a reduction in peripheral microcirculatory density. grant acknowledgment. *rhinochill system was supplied by benechill, inc. objectives. to evaluate consequences of hypoxemia occurence on intestinal microcirculatory perfusion in mice submitted to controlled hemorrhage. tracheotomized and ventilated balb/c mice were submitted to systemic hypoxemia (pao = mmhg) during h. controlled hemorrhage to mean arterial pressure of mmhg was associated (from th to th min). groups were constituted: hh = hypoxia and hemorrhage, hr = hemorrhage, hx = hypoxia, cl = control (neither hypoxia nor hemorrhage). a segment of ileon was exteriorized through an abdominal midline incision. it was opened along the antimesenteric border and placed on a specially designed piedestal to facilitate observation of the villi with transilluminating and epifluorescent microscopy. the bowel segment was superfused with krebs solution maintained at °c. villous perfused density (dvp), red blood cell velocity in villous tip arteriole (vart) and villous capillaries (vcap) were observed after fitc-labeled erythrocytes were intravenously administered. mice were included in each group. leucocytes adhesion to intestinal wall venules ( - lm) was observed in a separated set of experiments including also mice per group. number of adherent leucocytes (l adh ) and leucocytes flux (l fl ) were observed in each group. measurements and arterial blood gases were collected at , , min (t ). data were expressed as mean ± sem and were compared by analysis of variance (anova). introduction. despite remarkable progress in hemodynamic monitoring, clinical examination, assessment of peripheral perfusion and comparison of surface and body core temperature still are diagnostic cornerstones of critical care. infrared non contact thermometers provide accurate measurement of body surface temperatures. the picco device using an arterial line with a thermistor tip in the distal aorta-in addition to transpulmonary thermodilution (tptd)-provides continuous body core temperature. objectives. therefore, it was the aim of our study to evaluate the predictive capabilities of surface temperatures and their differences to body core temperature regarding ci, svri and parameters of microcirculation. in icu-patients body core temperature was measured four times per day using a picco-catheter (tp), a thermistor-tipped urinary catheter (tu) and an ear thermometer (te) (thermoscan; braun). additionally, surface temperatures were determined on the great toe, finger pad, forearm and forehead using an infrared non contact thermometer (thermofocus; tecnimed). furthermore capillary refill time (crt), lactate and scvo were measured and peripheral perfusion was clinically assessed (normal, pale, mottled). immediately afterwards tptd was performed to obtain ci and svri. statistics: spss . . spearman correlation. compared to tp, t forehead (- . ± . °), t forearm (- . ± . °), t finger pad (- . ± . °) and t toe (- . ± . °) were significantly lower (p \ . for all comparisons). in multivariate analysis tptd-derived ci ( . ± . l/min sqm) was significantly correlated (r = . ) to the difference ''tp-t forearm '' (p \ . ), ''tp-t finger pad '' (p = . ), crt (p = . ), scvo (p = . ) and map (p = . ). tptd-derived svri was multivariately associated (r = . ) with ''tp-t forearm '' (p \ . ) and map (p \ . ). scvo was independently correlated to the difference ''tp-t finger pad '' (r = . ; p \ . ). lactate was independently correlated (r = . ) to crt (p \ . ). the roc areas were . and . for (tp-t forearm ) and (tp-t finger pad ) to predict ''ci \ . '' and ''scvo \ '', respectively. the sensitivity, specificity and negative predictive value of ''tp-t forearm [ . °'' were , and % regarding a ci \ . l/min/sqm. .) measurement of surface temperatures using non contact infrared thermometers and comparison to body core temperature provides useful data on macro-and microcirculation. .) the differences (tp-t forearm ) and (tp-t finger pad ) were independently associated to tptd-derived ci and svri, and ci and scvo , respectively. .) crt was independently associated to lactate level. v. shilov , a. astakhov ural state postgraduate medical academy, chelyabinsk, russian federation introduction. actuality of this problem consists of different disturbances of heart rhythm and heart conductivity (from sinual bradycardia and ventricular extrasystolia till sinuatrial arrest and fibrillation of ventricles) provoked by traction of oculomotorial muscles and pressure on eyeball. this reaction is called oculocardial reflex (ocr). it is necessary to note there is no definite strategy of ocr prevention. objectives. this study was conducted to estimate the possibility of the control of haemodynamic effects of ocr. the haemodynamics and hydrobalance were investigated with electric current probe ( and khz) using monitoring complex of cardiorespiratory system and hydratation of tissues -km-ar- «diamant». data documentation was carried out at stages of evisceroenucleation: . before anesthesia and surgery; . at induction; . during the intubation; . at eyeball mobilization and oculomotorial muscles traction; . while deepening of endotracheal anesthesia by inhalative anesthetics during - min after preceding stage; . at the end of surgery, after the extubation. results. the study confirmed ocr reflex, to appear at eyeball extraction and to manifest as bradycardia, cardiac output decreasing heart productivity, but peripheric vessel resistansce does not change. monitoring-controlled gradual deepening of inhalative anesthesia during - min has restored the haemodynamic data to normal eliminated ocr vessel reactions. hydrostatic changes took place only at the end of the operation, after the extubation. it manifested ad increasing of extracellular liquid confirmed by decreasing of low-frequent impedance. intracellular liquid remained intact. it seems the most possible, hydrostatic changes of extracellular liquid to depend on crystalloid infusion in blood vessels up to , ml during anesthesia and they eliminate with hypovolemia. conclusions. thus we can conclude that vascular manifestations of hemodynamics in ocr at eyeball extraction or active oculomotorial tractions may be eliminated with gradual deepening of inhalative anesthesia and monitoring of registed date of haemodynamic and hydrobalance. probably it's necessary to optimige the anesthesia using of pterygopalatal and pterygoorbital blockade to prevent ocr before the induction as retrobulbal anesthesia may be an ocr trigger. f. corradi , c. brusasco , a. vezzani , f. altomonte , p. moscatelli university of genoa, anesthesia and intensive care, genoa, italy, ospedale maggiore di parma, anesthesia and intensive care, parma, italy, azienda ospedaliera universitaria san martino, emergency medicine, genoa, italy introduction. despite improvements in trauma care, uncontrolled bleeding is the leading cause of potentially preventable early in-hospital deaths contributing to to % of trauma-related deaths ( ) ( ) . about % more deaths occur within the second/third hour after injury due to occult major internal haemorrhage. failure to recognize this situation may in part be due to lack of sensitivity of hb/hct levels, arterial blood pressure, heart rate, respiratory rate, injury severity score and markers of hypoperfusion (lactate and base excess) in initial assessment of blood loss. to study if early changes in spleno-vascular resistance index predict the development of hypovolemic shock after trauma. a prospective observational study conducted in adult haemodinamically stable patients admitted to the emergency department because of suspected or definite severe trauma and retrospectively divided into groups depending on whether or not they developed haemorragic shock requiring blood transfusion. doppler ultrasound measurements of splenic arterial branches at ilum were obtained and splenic doppler resistance index (sdri) was recorded at admittance (within h from trauma) and related to arterial blood gas analysis (haemoglobin, base deficit, lactate, co , ph), heart rate, and outcome in the first h (intensive care unit admittance, blood transfusion, sepsis, mortality). results. statistically significant differences between patients who developed shock within h and those who did not were the following: higher sdri ( . ± . vs. . ± . , p \ . ), lower base deficit (- . ± vs. . ± meq/l, p = . ) and higher lactate ( . ± . mmol/l vs. ± mmol/l p = . ). auc's of roc analysis were significant for sdri (auc = . , ci . - . , p \ . ) and lactate (auc = . , ci = . - . , p = . ), and borderline for bd, hr, hb, and ph. by multivariate analysis, sdri at admittance resulted to be the only good independent predictor of hypovolemic shock and bleeding (p \ . ), whereas haemoglobin, base deficit, heart rate, lactate and ph were not significant. in trauma patients with stable haemodynamic conditions at admittance spleen constriction occurs very early under heavy adrenergic stimulation in response to occult bleeding and can be non-invasively detected by sdri. the present study proposes sdri as a non-invasive measurement of changes in splanchnic circulation to detect blood loss and occult hypovolemia, which may help activate early surgical or radiological intervention for patients with major trauma and guide therapy to optimize splanchnic perfusion. introduction. approximately % of patients require temporary circulatory support due to cardiogenic shock following cardiac surgery. these patients are at risk of a mismatch between oxygen delivery and demand and carry a substantial mortality and morbidity risk. mixed venous oxygen saturation (svo ) is the still the ''gold standard'' for the determination of the ratio between systemic oxygen delivery and consumption (do /vo ratio) in cardiac surgery patients. a nonivasive technique is thought to be cerebral near-infrared spectroscopy determining cerebral oxygen saturation (rso ). purpose. the present analysis aims to compare rso and svo levels in adult patients undergoing ecmo therapy for postoperative cardiogenic shock. methods. data were collected hourly for the first h post operatively. each patient was equipped with a pulmonary artery catheter (pac) for continuous determination of svo connected to a vigilance ii-monitor (edwards lifesciences, irvine, usa) and an invos monitoring system (somanetics, troy, usa) to determine rso . data were analyzed by parametric testing and bland-altman analysis. a total of patients were enclosed. all svo values were in a range between and %. in this range, the linear correlation coefficient between svo and rso was r = . (p \ . ). the correlation coefficient for svo values below % was r = . (p \ . ) and r = . (p \ . ) for svo levels equal or higher than %. bland-altmann analyses of all collected oxygenation data (n = ) revealed a bias of . % (mean % ci: . to . ) and limits of agreement ( . standard derivation) of . to - . % (upper % ci: . to . ; lower % ci - . to - . ) for the raw data of the whole group ( figure ). bland-altmann analyses of svo values below % (n = ) showed a bias of . % (mean % ci: . to . ) and limits of agreement ( . standard derivation) of . to - . % (upper % ci: . to . ; lower % ci - . to - . ). bland-altmann analyses of svo values equal or higher than % (n = ) revealed a bias of - . % (mean % ci: . to . ) and limits of agreement ( . standard derivation) of . to - . % (upper % ci: . to . ; lower % ci - . to - . ). interestingly, despite svo values [ %, we noticed events in patients with rso values less than % for more than min. all events had been associated with arterial co levels below mmhg, whereas no other changes in hemodynamic or oxygenation parameters could be determined. conclusions. this pilot study suggest for the first time that rso highly correlates with svo in patients undergoing ecmo therapy due to refractory cardiac and/or pulmonary dysfunction. therefore determining rso may be a noninvasive alternative to monitor global tissue oxygenation under this condition. additionally, it was noted that cerebral hypoxia may be present despite a svo c mmhg. rd esicm annual congress -barcelona, spain - - october results : during severe hypothermia ( °c) cardiac index (ci), stroke index, mean arterial pressure and indexes of lv contractility (prsw and dp/dtmax) were reduced. after rewarming all variables remained reduced, except for ci that returned to prehypothermic values due to increased heart rate. systemic vascular resistance (svr), lv isovolumetric relaxation time (tau) and oxygen content in arterial and mixed venous blood increased during °c, while lv end diastolic pressure (lvedp) was constant. after rewarming svr and lvedp were reduced, while tau and the blood oxygen contents normalized. troponin-t and tnf-a were constant during °c but increased after rewarming. albumine plasma concentration was reduced during °c and remained so after rewarming. conclusions. surface cooling to °c followed by rewarming caused reduction of systolic, but not diastolic lv function. there were no signs of inadequate global oxygenation throughout experiments. the posthypothermic increase in troponin-t may reflect degradation of myocyte troponins secondary to a hypothermia-induced calcium overload. the increase in tumour necrosis factor alpha together with a posthypothermic reduction of plasma albumin concentration may indicate that the cooling and rewarming initiated an inflammatory response. we studied patients, mean age . ± . years, % male. the etiology of cardiogenic shock was: % (n = ) dilated cardiomyopathy, % (n = ) acute myocardial infarction, % (n = ) acute cardiac allograft rejection and % (n = ) acute myocarditis. the duration of ecmo support was . ± . h. weaning was possible in % (n = ) and the ecmo was used as a bridge to transplantation in % (n = ). -day survival was and . % of our serie were discharged from the hospital. in cases the ecmo was withdrown as a result of a limiting treatment decision. objectives. to describe the characteristics of patients with ca and its management with moderate hypothermia using arctic sun Ò device with hydrogel patches. descriptive, observational and retrospective study of patients who suffered ca and received moderate therapeutic hypothermia ( °c) according to the protocol implemented in a coronary intensive care unit of a tertiary hospital. we collected patients from june to april , first months of this therapy in our hospital. moderate therapeutic hypothermia is applied using the arctic sun Ò device consisting of hydrogel patches applied to the skin covering % of the body surface. the device is connected to a temperature control console, measuring core temperature with an urinary catheter. we analyzed demographic characteristics, cardiovascular risk factors and other relevant comorbidities. we collected data about the ca, its initial treatment and its icu management with moderate hypothermia, analyzing length of events and systemic and neurological outcome at discharge from icu. we also collected data about the infectious complications during the icu stay. results. during this period, moderate therapeutic hypothermia was applied to patients with a mean age of ± years. . % were male. the most frequent cardiovascular risk factor was cigarette smoking, present in % of individuals. the ca cause was an ami by % of cases; however, myocardial infarction or angina was documented before the event only in . % of patients. the ca event was outside the hospital in . % of cases and the initial heart rate recorded was ventricular fibrillation in . % of cases. the average ca length was . ± min. obtaining a temperature of °c took between and h from the ca in most cases; and this temperature was maintained for an average of ± h. the average time of induction of hypothermia was . h. the re-heating was performed between . to . °c per hour, averaging h to reach temperatures of . °c. midazolam sedation was performed in all patients and severe chills required muscle relaxation with cisatracurium in . % of patients. infectious complications occurred in . % of patients, the most common site of infection was respiratory. the average stay was days. at the time of icu discharge, average gcs was and the average gos was . mortality was . % ( patients). -implementation of a therapeutic hypothermia protocol is feasible. -infectious complications are common, being respiratory ones the most observed. -the arctic sun Ò device is quick and safe for induction of moderate therapeutic hypothermia. rd esicm annual congress -barcelona, spain - - october s objectives. up to now, it is not clear, however, whether mild hypothermia influences also markers of oxidative stress and nitric oxide production. methods. eleven patients after out-of-hospital cardiac arrest were included into this study, all were treated with mild hypothermia using endovascular system thermodard xp. target core temperature °c was maintained for h, re-warming rate was set at . °c per hour, followed by normothermia of . °c. blood samples for measurement of nitrotyrosine and nitrates/nitrites were taken at admission and then every h for days. during hypothermia the levels of nitrotyrosine and nitrates/nitrites were comparable with baseline values. in re-warming period serum levels of both parameters gradually increased and in normothermia the levels were significantly higher as compared with hypothermia: nitrotyrosine . ± . vs. . ± . lm/l, p = . ; nitrates/nitrites . ± . vs. . ± . lm/l, p = . . our results revealed that during mild hypothermia in cardiac arrest survivors the levels of nitrotyrosine and nitrates/nitrites are significantly lower. these data indicate that the reduction of oxidative stress and suppressed nitric oxide production may be involved in the protective effect of hypothermia. grant acknowledgment. this study was supported by the grant of the czech ministry of health, nr. . new volumetric variables of preload, such as total end-diastolic volume index (tedvi) and active circulation volume index (acvi) and central blood volume index (cbvi), have been shown to be good predictors of fluid responsiveness. during acute changes of intravascular volume, such as hemorrhagic shock, these variables allow a more accurate intervention. objectives. the aim of our study was to investigate the changes in tedvi, acvi, cbvi in a juvenile model of hemorrhagic shock. seven anesthetized ponies ( - months of age) were studied at normovolemia (base), after blood withdrawal to mean arterial pressure (map) of mmhg (hemo), after infusion of norepinephrine to a map of mmhg (ne), and after retransfusion (resu). tedvi, acvi, cbvi were measured by ultrasound dilution (ud) technology with costatus device. data were analyzed using kruskal-wallis analysis and dunn's t test. comparison of fluid load agreement by blant altman. results. tedvi and acvi had significant change during hemo and resu status. percentage of tedvi and acvi changes agreed with percentage of blood volume removed/ infused with bias and limits of agreement (loa) % (- . , . ) and - . (- . . %) respectively. ne administration induced map and cvp significant changes, whereas tedvi and acvi remained unchanged. cbvi showed high variability and seemed to be inconsistent on the identification of the volume status. conclusions. in this animal model, tedvi and acvi were superior to cbvi in accurately reflecting hemorrhage and were also suitable to predict fluid responsiveness. ne administration did not affect the volumetric variables tedvi and acvi. ( ). objectives. we sought to identify independent predictors of post-arrest neurological recovery, and of survival to hospital discharge with neurological recovery. in the course of a pre-planned interim analysis, we analyzed the data from participants of nct . this three-center, double blind, placebo-controlled, clinical trial is ongoing (estimated enrollment = patients) and aims to asses the efficacy of combined vasopressin and epinephrine during cardiopulmonary resuscitation (cpr) and of steroid administration during and after cpr. post-arrest neurological recovery was defined as glasgow coma scale score[ documented at least once by study-independent physicians in patients not receiving sedation for at least h. we identified a total of patients who were subjected to at least one post-arrest assessment of their neurological status. subsequently, we used backward stepwise logistic regression, and assessed the following potential predictors: cause of cardiac arrest (cardiac vs. non-cardiac); area of cardiac arrest occurrence (monitored vs. non-monitored); use of therapeutic hypothermia; number of cpr cycles; mean arterial pressure and serum lactate at min following resuscitation; and patient group allocation. results. the sole independent predictor of post-arrest neurological recovery was the occurrence of the cardiac arrest in an area of monitored patient care (i.e., intensive or coronary care unit, and operating or emergency room): odds ratio: . , % confidence interval = . - . ; p = . . the sole independent predictor of survival to hospital discharge with neurological recovery was the serum lactate concentration at min after resuscitation: odds ratio: . ; % confidence interval = . - . . conclusions. the results of this preliminary analysis suggest that post-arrest neurological recovery seems to depend more on the use of pre-arrest patient monitoring rather than the employed cpr protocol. also, patients with lower, early post-arrest serum lactate concentration seem to have a better chance of surviving to hospital discharge without concurrent, severe neurological deficits. reference(s). to quantify the attribution of intra-operative defibrillation on markers of myocardial injury (ck, ck-mb, tnt and hfabp). methods. single centre prospective study in which elective cabg patients were included in a month period in . patients with valve, emergency, off-pump surgery or rethoracotomies were excluded. patients were grouped as having had defibrillation or no defibrillation during surgery. serum levels of ck, ck-mb, tnt and hfabp were analyzed in blood samples taken at arrival on the icu and at , and h after admission to the icu. levels of these biochemical markers were compared using a paired t test. results. all data presented as mean ± standrad deviation conclusions. atrial fibrillation is a common problem associated with morbidity and mortality in critically ill patients; however, evidence-based recommendations are lacking leading to variability in treatment. our audit confirmed variability and low compliance to nice in treating new af. inconsistency in using appropriate first line drugs for rate control and inadequate thromboprophylaxis reflects lack of familiarity with nice guidelines. educating itu medical staff and promoting the use of well validated, easy to remember chads scoring system might improve compliance with nice guidance. also,promoting hemorr hages scoring system for assessing risk of bleeding and carat tool to guide prescribing antithrombotics may allow itu physicians to anticoagulate more patients with af with less fear of bleeding complications. in patients with acute coronary syndromes (acs) combined antiplatelet and anticoagulant therapy is recommended in addition to percutaneous coronary revascularization. heparins and glycoprotein iib/iiia receptor inhibition can be associated with immune-mediated thrombocytopenia of clinical significance in less than %, resulting in major bleedings and increased mortality rate. to evaluate the incidence of thrombocytopenia and its impact on in-hospital complications-bleedings, reinfarctions, in-hospital heart failure and mortality in patients with acs. retrospective evaluation of patients admitted during months, fulfilling the criteria for acs: rest chest pain up to h, changes in standard ecg with or without st-elevation with or without elevated serum troponin i. serum troponin i was estimated by immunochemical method (boehringer, mannheim, germany, normal levels . lg/l). patients were treated by combined antiplatelet therapy, heparins and percutaneous coronary revascularization. platelets were estimated by automatic analyzer sysmex xe , kobe, japan (normal levels - /l). thrombocytopenia was defined as platelet count less than /l or a drop in platelet count of more than % during inhospital stay. we registered demographic, laboratory, clinical data and in-hospital mortality. we included acs patients, . % ( / ) with and . ( / ) without stelevation ( . % men, mean age . ± . years). mean admission troponin i was . ± . lg/l, platelet count . ± . /l. in-hospital thrombocytopenia was observed in . % of patients. in thrombocytopenic patients in comparison to non-thrombocytopenic ones we observed significantly increased mean age ( . ± . vs. . ± . years, p = . ) and admission serum creatinine ( . ± . vs. . ± . lmol/l, p = . ), significantly decreased admission systolic blood pressure ( . ± . vs. . ± . mmhg, p = . ) and hdl-cholesterol ( . ± . mmol/l vs. . ± . mmol/l, p = . ), significantly increased bleedings ( . vs. . %, p = . ), in-hospital heart failure ( . vs. %, p = . ), but nonsignificantly increased reinfarctions ( . vs. . %), arrhythmias ( . vs. . %) and in in-hospital mortality ( vs. . %). thrombocytopenic patients were less likely treated by percutaneous coronary revascularization ( . vs. . %, p = . ). admission thrombocytopenia in comparison to normal admission platelet count was associated with significant increase in inhospital mortality ( vs. %, p = . ) and icu-mortality ( . vs. . %, p = . ). conclusions. thrombocytopenia, observed in more than % of acs patients, was associated with in-hospital complications and mortality, especially thrombocytopenia on admission. introduction. stress cardiomyopathy, also known apical ballooning or takotsubo cardiomyopathy (tts), has been recognized for several years. this syndrome is characterized by transient systolic dysfunction of the apex or mid segments of the left ventricle (lv) in the absence of coronary artery disease. several forms of mostly physical stress may evoke this syndrome. in this case we describe a very uncommon cause for tts in an unusual situation. a -year-old woman without cardiovascular history found her husband non-responsive in bed. after resuscitation he was admitted to icu. visiting her husband, she complained of chest pains, shortness of breath and hyperventilation. physical examination revealed no abnormalities but her ecg showed deep negative t-waves in leads i, ii, iii, avf, v -v . her troponin t level was . lg/l (ref \ . ), nt-pro-bnp was , ng/l (ref \ ). ck was ng/l with ckmb of ng/l. echocardiography showed very poor lv function with the typical apical ballooning of the lv along with hyperkinesis of the basal ring ( fig. ). there was no coronary artery disease. she was admitted and treated with beta-blockers. within days, the enzymatic changes normalized and echocardiography showed improved lv function with and normalization of the apical segments. she made full recovery within weeks. discussion. icu admittance has significant impact on family members. in the acute phase of the illness, most medical attention goes to the admitted patient. especially when prognosis is poor, stress to the family may be considerable. mostly spouses and relatives with female gender are at the highest risk for depression and anxiety disorders . in contrast, little is known about the occurrence in relatives of broader physical symptoms like pain and nausea or even acute onset severe medical conditions requiring treatment. in our case the wife experienced pain, anxiety and nausea along with hyperventilation. however, the underlying disease was a severe cardiomyopathy requiring admittance and treatment. the tts cardiomyopathy is known to icu physicians in relation to subarachnoid hemorrhage, but most likely not in the context of severe emotional stress. in summary, we stress the importance for intensive care physicians to be alert to the fact that despite many diverse symptoms related to stress and anxiety, relatives can develop acute medical conditions as well. a retrospective observation study. demographic profiles, operative data and short term outcomes in the icu were reviewed in the patients who underwent beating-heart (b-h) operation. we also compared b-h operation group ( - ) and conventional cardiac arrest (c-a) operation group (before ). both groups of patients were similar with respect to preoperative demographics (age, co-morbidities, lv function). in the b-h operation group, mean age was years ( - ). preoperative mean nyha functional class was . . and the mean lvef was . %. patients underwent single valve operation, and the rests needed combined valve operation or cabg. patients were included in the c-a operation group, with mean age of years ( - ), nyha functional class of . and mean lvef of . %. in the b-h operation group, no dc shock was needed, whereas % of the patient with c-a operation needed dc shock after aortic unclamp. in the single aortic valve replacement, b-h operation group had a tendency of shorter assist perfusion time after intracardiac procedure ( . vs. . min). in the icu, inotropic support (maximum dose of dopamine) was much less ( . vs. . r) than conventional c-a operation (p = . ) and additional iabp support was not required ( vs. % in c-a operation). low cardiac output syndrome was not encountered in the b-h operation group ( vs. % in c-a operation). no major postoperative complication was encountered except ventricular tachycardia in one patient. there was no day mortality ( vs. % in c-a operation). conclusions. in our series, valve surgery on the beating-heart had a superior postoperative hemodynamics and lower associated morbidity compared to conventional cardiac-arrest operation. this procedure is recommended especially in the patients with impaired lv function. ( ) objectives. does hrt measured during daytime or nighttime predict: one-year all-cause mortality in acs?; hospital readmission within one-year? methods. secondary analysis of the immediate aim study, prospective clinical trial of patients presenting to the emergency department (ed) with symptoms of acs (n = , ): holter recordings of patients, positive for acs and admitted to the hospital, started min (median time) after arrival in the ed; -year follow up after hospital discharge in % of the sample; recordings scanned to exclude artifact and non-sinus rhythm. hrt analysis performed using research software at the washington university heart rate variability lab; hrt parameters measured: ) turbulence onset (to), which characterizes the initial rate acceleration after a ventricular premature contraction (vpcs); and ) turbulence slope (ts), which characterizes the subsequent oscillation in heart rate. results. holter recordings eligible for hrt analysis; eliminated due to unanalyzable rhythm, \ vpcs needed to calculate hrt, or recording time \ -h. patients were diagnosed with ua, with nstemi, and with stemi. patients died and were re-hospitalized during follow up. hrt measures were dichotomized into low and high-risk groups based on previously reported cutpoints: to \ % normal, to c % abnormal; ts [ . ms/beat = normal, ts b . abnormal. chi square statistics calculated. findings include: abnormal -h ts significantly associated with -year mortality [odds ratio (or) . (p = . )]; re-hospitalization significantly associated with both abnormal -h to (or . , p = . ), and -h ts (or . , p = . ); abnormal night ( - ) to and day ( - ) ts also significantly associated with -year mortality (or . , p \ . for both); abnormal daytime to (or . , p = . ) and ts (or . , p = . ) each significantly associated with re-hospitalization. conclusions. patients with acs who have a ts \ . measured over h or during the daytime are at higher risk of dying within year after hospitalization. those who either have to c % or ts b . have a greater risk of re-hospitalization. assessment during the daytime only might provide sufficient information for risk stratification. hrt measured close to acs symptom onset may aid in risk stratification. objectives. we tried to find a correlation between trs and the severity of coronary artery disease (cad) found in coronary angiography. we analyzed all consecutive patients with nsteacs admitted to intensive care unit from june to december . all patients were stratified at admission with trs. pci were performed when it were indicated. for the study we grouped patients according to trs and the severity and extend of cad. considering the trs the patients were classified into three categories: trs - , trs - and trs - and considering the results of the coronary angiography were grouped into three categories: normal angiogram, one or two vessel disease and three vessel or left main disease. we excluded patients without pci. qualitative variables are expressed as absolute value and percentage and quantitative variables are expressed as means ± standard deviation or median ± interquartile range when correspond. comparisons between groups were made with the v or fisher's exact test for categorical variables and mann-whitney test for quantitative variables. a total of patients were admitted with nsteacs during the period of the study and underwent to pci. age median were higher in patients with trs - than other groups ( . years ± . p \ . ). men percentage and in-hospital mortality were similar in all groups (pns). between groups there weren't significant differences in prevalence of diabetes, hypertension, dyslipidemia, smoking, mean first troponin i and mean highest troponin i (pns). the v for all comparisons were . (p \ . ). normal angiogram were most likely found in patients with trs - than in those with trs [ (p \ . or , % ci . - ). one or two vessel disease were found more often in those with trs - than in those with trs\ o [ (p \ . or . , . three vessel or left main disease were found more often in those with trs - (p \ . or . , % ci . - . ). conclusions. the relationship between trs and clinical outcomes (recurrent angina, acute myocardial infarction and death) is well known but its relation with the extent and the severity of cad is not well determined. in our study we found a correlation of trs with the number of vessels affected in coronary angiography, making the trs as a good predictor of the extent and the severity of cad. a.b. ratnaparkhi , j. walton freeman hospital, anaesthetics, newcastle upon tyne, uk introduction. acute onset atrial fibrillation (af) is common phenomenon in the intensive care unit. atrial fibrillation poses risk for thromboembolism. practice of commencing anticoagulation after acute onset af varies in different intensive care units. anticoagulation comes with its own side effects in the already compromised patients in the intensive care unit. this regional audit was carried out in intensive care units of the north east region of the uk. to assess the practice of use of anticoagulation after acute onset of atrial fibrillation in the intensive care units. postal questionnaire were sent to the intensive care units of the north east region of the uk including two cardiac surgical intensive care units. the questions asked were; is there a protocol in your unit? are you aware of any guidelines? if yes, which guidelines? do you commence anticoagulation for acute onset af? what do you use for anticoagulation and in what dose? after what duration of onset of af you consider starting anticoagulation? how long do you continue anticoagulation? do you commence anti platelet therapy? we also put six clinical scenarios with acute onset atrial fibrillation. the aim was to assess if the units consider stroke risk stratification for commencing the anticoagulation. one example is; how would you manage anticoagulation for a year old patient with hypertension and diabetes, presented with sepsis following pneumonia. results. we received responses from out of intensive care units. the management of anticoagulation strategy was different in different unit. two units were aware of the nice guidelines, one unit was aware of the accp guidelines and two units were aware of the other guidelines. ten units responded that they commence anticoagulation for acute onset af. commonly used anticoagulation was low molecular weight heparin. four units use anticoagulation within less than h of the onset of af. there was no fixed duration for the continuation of the anticoagulation. different units consider various factors before commencing anticoagulation. conclusions. use of anticoagulation in acute onset af varies in the different units. each unit takes into account different factors for the commencement of anticoagulation. this audit highlights the possible need for the evidence based protocol for the use of anticoagulation in acute onset af in intensive care units. objectives. to study of the clinical features and analytical features of those patients with dilated cardiomyopathy treated with ecmo as a bridge to cardiac transplantation in order to determine which parameters are useful to predict the outcome methods. a retrospective study from december to december . all patients were divided into two groups: the a group: patients who died before transplantation; the b group patients who got transplantation. several clinical and analytical characteristics are compared before starting ecmo, at and h after the onset and immediately before withdrawing (''end time'') ecmo treatment (either for transplantation or for death). qualitative variables are expressed as % and quantitative ones a mean and standard deviation (sd). chi square and t student test are used as appropriated. a p \ . denotes statics significance. there are statistically significant differences between patients who died and patients who survived to be transplantated. the presence of multiorgan failure and severe tissue oxygen hypoperfusion, and its persistence after initiated treatment, denotes a worse prognose. the study of this differences could be useful to decide which patients benefit of ecmo treatment. objectives. to measure the diagnostic contributions of routinely used (nt b type natriuretic peptide (nt probnp), cardiac troponin i (t), ddimeres (dd), c-reactive protein (crp) and procalcitonin (pct)) and new biomarkers(mid-regional pro-atrial natriuretic peptide-(mr-proanp), pro adrenomedullin (pro adm), pro endothelin (pro et) and copeptin [pro vasopressin (cp)] for diagnosing infection in patients with severe acute dyspnea. we designed a prospective study of patients admitted in the emergency department and in medical intensive care unit in a university hospital. inclusion criteria were acute dyspnea with spo b % and/or respiratory rate (rr) c b/min. patients with obvious myocardial infarction or pneumothorax were excluded. clinical-biological data were recorded and biomarkers sampled. an independent blinded expert panel classified the patients according to all the data including response to treatment and outcomes blindly to biomarkers' results. the roles of biomarkers were assessed quantitatively and then using terciles of the distribution. the contribution of the biomarkers in the diagnosis was assessed using auc-roc curves and by multiple logistic regression taking into account other clinical and biological explanatory variables. objectives. to compare differences between a group of patients with lmca treated with percutaneous coronary intervention (pci) and others with cabg. to evaluate direct results and make a long term prognosis analyzing mayor cardiovascular complications (mcc) rate. observational retrospective study that includes a total of patients with lmca submitted to ca between january and december : patients ( %) were treated with pci and compared to patients ( %) treated with cabg. in the total of the pci cases drug-eluting stents were used. we exclude patients in cardiogenic shock and those with protected left main coronary artery. results. average age of the patients was . ± . . in the pci group most of the patients were older than years. in the cabg group there was a majority of male patients ( . vs. . %, p = . ) without significant differences in the rest of demographic information. in the pci group (p = . ) there were more previous record of acute myocardial infarction (ami) and pci found, and also a greater percentage of patients with lvef\ % (p = . ). average euroscore of patients from the pci group were greater than those from the cabg group. complete revascularization was obtained more frequently in the cabg group. in the cabg group (p = . ) the number of days between diagnosis and therapeutic strategy as well as the days hospitalized were greater. in the multivariate analysis, the type of therapeutic strategy wasn t associated to mortality when hospitalize. the median follow-up period was months. according to the classification ccs (p = . ), there was no significant difference in the grade of angina. tendency to a greater restenosis of stent, greater mortality during follow-up and greater mcc without statistically significant. in the multivariate analysis surgical strategy was associated to a lower mortality during follow-up (or . objectives. our objectives were to analyze the characteristics of the patients who were done a cardiac catheterization, the differences of the procedure and the incidence of complications. methods. we randomized consecutive patients referred to the hospital for cardiac catheterization since august until october . results. among patients, the age (mean ± sd) was ± . years and more frequently male ( . %). . % were angioplasty. the radial approach was used in patients ( . %; . % with f arterial sheaths and . % with f), and the femoral approach in patients ( . %). there was no difference in the baseline characteristics of the patients. the time required for the procedure and the fluoroscopy time were longer in the radial group (p = . ). a cross over was more often necessary in the radial group ( patients, . %) due to radial artery spasm, deviousness, loop, unstable catheter or artery dissection. only one patient required cross over from femoral to radial approach ( . %) due to serious deviousness in iliac artery. the intravascular ultrasound (ivus) and rotablator always were done by femoral approach. the incidence of complications was higher in the femoral approach group ( . vs. . %, p = . ). in the radial approach group, the most important complication was wrist haematoma ( % radial artery occlusion checked with allen test), however the femoral approach complications were: inguinal haematomas ( . %), big haematomas required blood transfusions ( . %), femoral artery pseudoaneurysms ( . %), arteriovenous fistulas ( . %), retroperitoneal haemorrhages ( . %), strokes ( . %). these complications increased the hospital stay ( . ± vs. . ± . days, p = . ). conclusions. the radial approach reduces peripheral arterial complication rates and allowed earlier ambulation, so also reduces the hospital stay. however, needs higher learned time, and the size of the artery can limit several procedures (ivus/rotablator on the other hand, the development of bundle branch block after that procedure has been associated with higher rates of complete av block, syncope, and sudden cardiac arrest at long term. objectives: our aim is to describe the incidence of cardiac conduction problems after pavi and to identify possible risk factors associated with these conduction problems. patients and methods. a total of consecutive patients who underwent a pavi were included in our analysis. the indication for pavi was a severe symptomatic aortic valve stenosis in patients who were rejected or had a high risk for conventional savr. permanent pacemaker implantation was performed in case of the presence of complete heart block or symptomatic bradycardia, persisting after at least the second postprocedural day. data are expressed as mean value ± sd for continuous variables and as numbers with percentage for categorical variables. between the variables selected for predicting av block after pavi (basal valvular area, annulus diameter, valsalva sinus diameter, left and right bundle branch block), the only independent predictor was the last one (or . , % ci . ( ). implementation of care bundles have been advocated to reduce the infection rate ( ). objectives. the aim of the study was to identify the effect of the introduction of the central venous catheter (cvc) bundle on crbsi rate on our critical care unit over a threeyear period. retrospective audit on the rate of crbsi for a months period before the implementation of the cvc bundle provided baseline data. prospective audits for the corresponding months were carried out after the cvc bundle was firmly embedded in clinical practice. the data was collected based on the information recorded in our clinical information system (cis). the cvc bundle consisted hand hygiene, barrier precautions on insertion, % chlorhexidine skin preparation, using femoral site as last resort, daily review of necessity of central access, daily inspection of insertion site, use of tpn on a dedicated port and maintaining asepsis when accessing the line. robust educational program was rolled out during the implementation phase for medical and nursing staff. compulsory elements of the care bundle were recorded in our cis. we collected data on overall compliance with the bundle, mean dwell time, number of crbsis, site of infection and whether the patient left the unit with a cvc line in situ. for statistical analysis chi-square test and wilcoxon test were used. our main results are summarised in table . lines removed prior to transfer (n) we have seen a significant increase in the compliance with the bundle and it resulted a significant and sustained reduction in mean dwell time, cvc related infection rate and number of patients transferred to the ward with cvc lines (all p \ . ). the bundle resulted in bigger scrutiny for cvcs, hence the reduction in the number of lines inserted. conclusions. our data shows that implementation of care bundles can significantly and sustainably reduce the rate of crbsi on the icu in a real life setting. our previously unacceptable infection rates were reduced and now are comparable with the recently published data ( ) . evidence-based catheter-care procedures, guided by healthcare workers perceptions and including bedside teaching, reduce significantly the crbsi rate and demonstrate that improving catheter care has a major impact on its prevention. to evaluate the incidence of catheter-related bloodstream infection (cr-bsi) and of the use of central venous catheters (cvc) after an intensive improvement program aimed at reducing cr-bsi. before-and-after study in patients admitted to a -bed medical-surgical icu from january through december . in we implemented an improvement program (analysis of barriers, creation of a working group, review of protocols, and implementation of an educational program and checklist) and a set of measures to reduce cr-bsi during cvc insertion and maintenance based on provonost et al.'s model ( ) . in the postintervention period, we suspended the use of the checklist and evaluated the degree of completion of the online training module ''bacteremia zero program'' and analyzed the staff turnover rate. we have monitored cr-bsi using the ''estudio nacional de vigilancia de infección nosocomial en uci'' (envin-uci) criteria since . we calculated the incidence rate ratio of cr-bsi and cvc utilization ratio for , , and . we compared the incidence rate ratios using the epitab module from the stata program and utilization ratios using chi-square tests. results. nine cr-bsi were diagnosed in , one in , and five in . the incidence rate ratio of cr-bsi in these periods was . , . , and . %, respectively. the incidence rate ratio in the postintervention period ( . %) was significantly lower than in the preintervention period ( . %) ( . : % ci . - . , p = . .) the increase in incidence rate ratio between and was not statistically significant ( . vs. . %, p = . ). the pre-and post-intervention cvc utilization ratios were . and . , respectively (no significant differences). during the year , and for existing staff in , rotating residents, nurses (turnover rate %), and nurse's aides (turnover rate %) joined the icu. the training module was completed by % of the new nurses and none of the physicians or nurse's aides. conclusions. the program was effective; its effectiveness may be related to the intensity of the measures. a low preintervention incidence rate ratio does not preclude the usefulness of an improvement program. introduction. in the intensive care unit (icu) the bloodstream infections (bsi) related to the central venous catheters (cvcs) represent a serious clinical complication and are a substantial economic burden. although the data are still somewhat controversial, the use of antibiotic impregnated cvcs is one of the generally accepted approaches in reducing the risk of bsi [ , ] . objectives. in order to determine the efficacy of antibiotic impregnated cvcs in our clinic we evaluated retrospectively the data of the cultures of cvcs and blood obtained from patients during their stay at icu within the last years (january till august ). conclusions. surprisingly, there was no difference in the incidence of the cvc and bloodstream infections in both groups. we can conclude that the strategy of using mrimpregnated cvcs did not reduce the incidence of catheter related bsi. although earlier studies have indicated that mr-impregnated cvcs are cost saving [ ] , our data add further proof to the suggestion that the cost effectiveness of these catheters is at least uncertain. results. from all patients, ( . %) developed infection from any reason during the icu stay. patients developed crbsi, . % of the total patient number and . % of the patients who developed any infection. we recorded episodes of bacteremia due to cvc during days of cvc placement stay, . % while the standard limit is four episodes of crbsi per , days cvc placement. during the year , we chanced our practice in order to avoid as risk factors as we can, using only antimicrobial/antiseptic impregnated catheters, improving our hand hygiene and aseptic technique, using only chlorhexidine and semipermeable polyurethane dressings and making catheter replacement at scheduled time intervals as a method to reduce crbsi. the previous year the recorded crbsi incidence was . % respectively. conclusions. the incidence of intravascular catheter related infection is recorded above the standard limits for second consecutive year assuming that we have to improve further our surveillance policy. on the other hand, the incidence is recorded smaller than the incidence of the previous year according to the change to our practice, assuming that our reforming policy, although not fully effective, still is better for the prevention of intravascular catheter related infections. introduction. intravenous catheter related blood stream infection is a major factor contributing to in hospital morbidity and mortality and extending hospital stay by days and expenditure by , to , lb . the incidence of central line associated blood stream infections (cr-bsi) in our unit was audited in and a comprehensive infection prevention program that included staff education, hand hygiene, maximal sterile barrier precautions and daily assessment of the need for a central line was introduced. we are also taking part in the national audit project matching michigan. objectives. assess the effectiveness of the infection prevention programme and re-audit the incidence of cr-bsi methods. data was collected daily for a period of months. this included the number of patients with central venous catheters in the unit, the number of lines removed or re-sited, the indications for line change, the site of line insertion and incidence of line infection. the lines were reviewed daily and removed if indicated clinically (pyrexia or raised white cell count) or if not required. results. over a period of months central lines were used amounting to line days. the lines inserted were subclavian (sc)- ( . %), femoral (f)- ( . %) and internal jugular (ij)- ( . %). the percentage of lines removed for clinically suspected cr-bsi reduced in this period from to . %. the average duration of stay for the lines were sc . days, ij . days and f days which was shorter than our previous audit showed. the percentage of microbiologically proven cr-bsi also dropped from . to . % ( from internal jugular lines and one from a femoral line). conclusions. introduction of simple and cost effective practices decreased the prevalence of cr-bsi in our unit by a factor of five. daily review of lines led to earlier removal of central lines once they were no longer required. the unit being a neurointensive care unit has a greater proportion of patients in whom femoral lines are often the only option. our survey proves that with strict adherence to guidelines and following infection control protocols diligently the risk of cr-bsi from all line types can be reduced. conclusion. this study implies that the scale of crbsi may be higher than is currently recognised and that the blood culture positivity rate for crbsi is %( / ). as concurrent antibiotic therapy may reduce blood culture and cvc tip positivity, the blood culture rate of % suggests that crbsi has an inherently high blood culture positivity rate despite concurrent antimicrobial therapy. ( ). in this context, we tested the introduction of chlorhexidine(chx)-impregnated sponges ( ) ( ), acinetobacter baumannii . % ( ), serratia marcescens . % ( ), stenotrophomonas maltophilia . % ( ), escherichia coli . % ( ) jai salmonella enteritidis . % ( ) . production of extended-spectrum beta-lactamases (esbls) was detected in % of klebsiella spp. and e. coli strains, overproduction of ampc beta-lactamases was recognized in . % of enterobacter spp., while only one k. pneumoniae strain was found to produce metalloenzyme. all eight strains of p. aeruginosa were susceptible to aminoglycosides, ciprofloxacin and carbapenemaces, both strains of s. maltophilia were susceptible to ticarcillin/clavulanate and trimethoprim/sulfamethoxazole. among a. baumannii isolates, . % were susceptible only to colistin. in total, . % of isolates were susceptible to imipenem and ciprofloxacin. conclusions. gram-negative bacteremia, in particular in the critically ill, is associated with significant morbidity and mortality. significant susceptibility to ciprofloxacin and imipenem was demonstrated. empiric treatment regimens should be based on unit-specific data. ben objective. to assess whether implementation of a national safety program to prevent cvc-related bacteremia had an impact on rates of devices-associated infections acquired in icu. methods. prospective, multicenter, incidence, surveillance study of vap, crb and uti carried out from - - to - - . simultaneously, a bundle for prevention of cvcrelated bacteremia and a comprehensive safety program were introduced at the national level. infections were diagnosed according helics definitions. the follow-up was carried out until discharge from the icu or to a maximum of days. the severity was assessed by the apache ii score. the rates are expressed as incidence density (id) per , days of risk factor. rates are compared with those of previous years ( ) ( ) . introduction. acute kidney injury (aki) is one of the most dreaded complications of severe malaria. occurs as a complication of plasmodium falciparum malaria in less than % of cases, but the mortality rate in these cases may be up to % [ ] . to evaluate the incidence of aki and compare akin and rifle classification systems with regard to hospital mortality. a retrospective analysis based on medical records of adult patients with severe plasmodium falciparum malaria admitted in the general icu of clínica sagrada esperança, in luanda, angola, from january to december . criteria for diagnosis included the standard who definition for severe malaria. only changes in serum creatinine were used to define the presence of aki by both criteria. logistic regression was used to access the association of each rifle and akin with hospital mortality. data are presented as odds ratios with % confidence intervals (ci). we enrolled patients. thirty-nine ( . %) were males. the mean age recorded was . ± . . the mean apache ii score was . ± . , with a mean predicted dead rate of . %. the mean sofa score on admission was . ± . . the mean length of stay in the icu was . ± . days. rifle allowed the identification of more patents than akin as having aki ( . vs. . % there was no statistic association between corticosteroids therapy and length of icu stay less than days (p = . ), duration of mechanical ventilation less than days (p = . ), severe infection (p = . ), re-intubation (p = . ), tracheotomy (p = . ), nosocomial infections (p = . ), myopathy (p = . ) or mortality (p = . ). although there is a tendency for a higher prescription of corticosteroids in dni patients with severe infection, the difference did not reach statistical significance. the use of steroids is neither associated with a better outcome nor with a higher frequency of adverse events or side effects, namely critically illness myopathy or nosocomial infections. ozbek introduction. q fever, a zoonosis due to coxiella burnetii, is more frequent and severe in men than women, despite a similar exposure. here we explore whether the severity of c. burnetii infection in mice is related to sex differences in gene expression profiles. methods. experimental study analyzing the transcriptome of c bl/ j mice. ten females and males were sterilized at weeks of age. after weeks, males and females ( intact and castrated animals of each gender) were killed. the other series of mice were injected intraperitoneally with c. burnetii organisms and sacrificed at day one after infection. organs were aseptically excised and stabilized in rnalater. total liver rna was retrotranscribed and labelled with cy . labelled cdna were hybridized onto whole mouse genome oligo microarray k (agilent). raw signal data were normalized with the quantile method. the significance analysis of microarrays test was used to study the gene expression in uninfected and infected mice. supervised analyses were carried out with r with the library bioconductor. pca was used to visually explore global effects for genome wide trends, unexpected effects and outliers in the expression data (library made ). in another set of experiments, mice ( intact males, castrated males, intact females and castrated females) were killed at , , and days after c. burnetii infection (same protocol). liver rna was analyzed by rt-pcr to confirm microarray results. results. multiclass analysis (sex and infection) identified , modulated genes (fdr = %, |fold change| [ . ) . we found that % of the genes are specifically modulated in males or females. only % of the genes are sexindependent. castration showed that sexual hormones are responsible for more than % of this sex-specific differential expression. the reduction of gene expression modulation upon castration is seen almost exclusively in males. functional annotation of male specific signature identified groups of keywords linked to cellular adhesion, signal transduction, defensins and cytokines and jak/stat pathway. functional annotation of female specific signature identified two group of keywords linked to intracellular metabolism and circadian rhythm. these results were confirmed by rt-pcr. the increased susceptibility to infection in males may be related to the overexpression of il and stat . the modulation of the circadian rhythm in female is linked to a more efficient bacterial clearance. conclusions. this study showed for the first time that the sexual dimorphism observed in q fever is reflected by sex related gene modulation, and is under the control of sexual hormones. this study also showed that the circadian rhythm seems to play an important role in infection in mice. this work open the way for deciphering the role of sex and circadian rhythm in human infections. the author's report a p.aeruginosa sepsis with skin and heart involvement in a previous healthy woman. a years old woman without a pertinent medical history came to the hospital after days with high fever ([ . °c), vomiting and diarrhea. at admission she was in septic shock with multiple organ disfunction (hemodynamic, cardio respiratory and renal) and presented genital skin lesions (round, ulcerated, painless lesions with necrotic black eschar and erythematous margin-ecthyma gangrenosum). the laboratory tests showed bicytopenia (leucocytes and platelets), hepatic necrolysis and elevated troponin t, associated with t wave inversion in anterior leads in the ecg. the ecocardiogram showed apical dyskinesis with normal systolic function suggesting tako-tsubo cardiomyopathy. hemocultures ( ) were positive to pseudomonas aeruginosa and skin lesions biopsy showed vascular ulcers with local p. aeruginosa inflamation. results. besides the fluid challenge and supportive therapy she began empirically piperaciline-tazobactam with rapid improvement of the clinical picture. she needed vasopressors (norephynefrine and dopamine) for h. the skin lesions have resolved in days and cardiac treatment was conservative and symptomatic. the patient was discharged from the intensive care after days. conclusions. ecthyma gangrenosum although relatively uncommon, was first considered a pathognomonic sign of p. aeruginosa sepsis, but now we known that other bacterias can have the same presentation. tako-tsubo cardiomiopathy or broken heart syndrome is a stress-induced cardiomiopathy characterized by transient systolic dysfunction that mimics myocardial infarction but without coronary disease. although the unusual p. aeruginosa clinical presentation sepsis should be treated with prompt supportive measures and the most adequate antibiotic. objective. we undertook this study to determine the relative frequency of meningitis and sepsis in a paediatric intensive care and to define the clinical and laboratory features at the time of admission and the outcome of these children. we reviewed the medical records of patients with sepsis and meningitis, in our paediatric intensive care, from to . results. among these patients % had meningitis, % had sepsis, % patients had bacteraemia, and % had meningitis and sepsisage ranged from month to years old ( % were - years old. boys %, girls %. temperature at the moment of admission was in % patients greater than °c. leucocytosis was noted in % (from , to , / mm ) and leucopenia % ( , - , /mm ) % of the patients had petechiaes, % had a positive lumbar puncture and % who did not have lumbar punctures had diffuse intravascular coagulationthe species of microorganism were in % meningococcus group b, in % no organism was found, in % were pneumococcus, and meninococcus group d in %. on admission, % of our patients had seizures. the duration of hospitalization in our picu was % (average length of stay from to days) % had hemodynamic instability, and % had a normal arterial pressure. from the patients who had hemodynamic instability, needed only fluids %, and % needed fluids and inotropes % of the patients received intravenous ceftriaxonewe had no mortality. conclusion. meningitis and sepsis remain a serious problem in picu. with the existing guidelines of therapy and prognostic signs at the moment of admission in picu we have a better outcome. howitz introduction. community acute bacterial meningitis is a relatively common disease. three bacteria are responsible in most cases: streptococcus pneumoniae (adults), neisseria meningitidis (older children and young adults) and listeria monocytogenes (in the elderly, alcoholics and immunosuppressed). the mortality rate ranges between and % and is higher in case of pneumococcal meningitis ( %) due mainly to increased intracranial pressure and the intense inflammatory reaction that produces pneumococcus in the cerebrospinal fluid. objectives. to study epidemiology, aetiology, clinical and evolution in acute meningitis in the adult community in our icu. methods. retrospective and descriptive study of patients admitted to a tertiary icu with beds from january to december . a total of patients of whom were males ( . %) and women ( . %). the mean age was . years (range: - ). the apache ii at admission was determined in of the patients with an average of points, which is associated initially with a good prognosis. the glasgow coma scale was found in % of the cases the majority ranging between and with a range: - . the average stay in icu was . days. patients died ( . %). risk factors include: infections in otolaryngology: cases ( . %) alcohol: case ( . %) and states of immunosuppression: ( . %) of which: there were two diabetic patients ( . %); hiv: ( . %) were chronic treatment with corticosteroids in one case ( . %); advp: case ( . %) liver transplantation: one case ( . %) and other case cerebrospinal fluid leak ( . %). in patients (% . ) found no risk factor. the most common complication was the need for endotracheal intubation and mechanical ventilation in a . % of patients, hydrocephalus followed by . %. hearing sequelae were found in patients ( . %) and persistent vegetative state in case ( . %). the outcome was favorable and without sequelae in cases ( . %). the etiology was bacterial germs and virus in cases in . bacteria, not unknown in cases ( %). filiated of the causative agent in the majority ( . %) were streptococcus pneumoniae, followed by neisseria meningitidis in cases ( . %), listeria, staphylococcus aureus, e. coli and mycobacterium tuberculosis were isolated in one case each ( . %) . in relation to the vhs virus was found in one case ( . %) and unable to filial the rest. conclusions. community acute meningitis is a disease with low prevalence and mortality in our environment. the agent most commonly streptococcus pneumoniae, clearly associated with increased morbidity. the most frequent complication was the need for endotracheal intubation and secondly hydrocephalus. mortality was associated with longer hospital stays and lower glasgow at the beginning, but not with age. rd esicm annual congress -barcelona, spain - - october s evaluated factors: patient characteristics, signs, symptoms, abscess location, time between symptoms and hospital admission and surgery, lab results, microbiology, antibiotic therapy, apache , saps , sofa, length of icu stay, surgical re-intervention, duration of mechanical ventilation, infectious complications, critical illness myopathy (cim), renal replacement therapy (rrt), re-intubation, tracheotomy, mortality. descriptive statistics were used to analyze data. objectives. to assess ventriculitis (vg) and to study outcome and disability indices in patients admitted in icu due to cerebral hemorrhage (spontaneous or traumatic). we prospectively studied patients hospitalized due to cerebral hemorrhage in the icu of university hospital of thessaly, between and . patients were followed for median follow up of ( - ) days. on admission, the neurological status of patients was described by the glasgow coma scale; disability was evaluated at months by the rapid disability rating scale (rdrs). results. one hundred twenty-one patients ( male) were studied; median (iqr) age was ( - ) years, gcs before intubation ( ) ( ) ( ) ( ) ( ) ( ) objectives. to analyze characteristics of patients diagnosed with infective endocarditis in a third-level hospital from january until december , evaluating the echocardiography findings, the therapeutic strategy used, and both morbidity and mortality rates in hospital and during long term follow-up. observational retrospective study of consecutive patients with following duke criteria with a mean follow-up of ± months. conclusions. this study showed a low mortality of sepsis and its sequential stages in children with meningococcal disease admitted to the picu, which was probably associated with the early use of antibiotics (up to the sixth hour) and aggressive fluid esuscitation. diagnosis and treatment of infections in critically ill patients: - background. about one-third of hospital mortality in critically ill patients occurs after intensive care unit (icu) discharge. post icu deaths may arise from incomplete resolution of the primary condition or from the development of new complications. some authors have recently hypothesized that unresolved or latent inflammation and sepsis may be an important factor that contributes to death following successful discharge from the icu. aim. the aim of our study was to determine the ability of the clinical and inflammatory markers at icu discharge to predict post-icu mortality. a prospective observational cohort study was conducted during a -month period in an bed polyvalent icu. acute physiology and chronic health evaluation (apache) ii score, simplified acute physiology score (saps) ii, sequential organ failure assessment (sofa) score, c-reactive protein (crp), body temperature and white cell count (wcc) of the day of icu discharge were collected from patients who survived their first icu admission. results. during this period patients were discharged alive from the icu. a total of patients ( . %) died in hospital after icu discharge. there were no differences in clinical and demographic characteristics between survivors and nonsurvivors. c-reactive protein levels at icu discharge were not associated with hospital mortality (mean crp concentration of survivors = . introduction. early diagnosis of bacterial infection can be challenging in critically ill patients, however prompt recognition and initiation of antibiotics improves outcome. serum procalcitonin (pct) has been proposed as a more reliable marker of bacterial sepsis than white cell count (wcc) or c-reactive protein (crp), however there is no consensus in how it should be used and pct measurement has not disseminated widely into critical care practice in the uk. to identify if clinical recommendations based on procalcitonin levels are being followed. we retrospectively studied pct use between october and december . assay results were interpreted as: . ng/ml, possible local bacterial infection . - . ng/ml, possible bacterial systemic infection, moderate risk of severe sepsis . - ng/ml, likely systemic bacterial infection, high risk of severe sepsis \ ng/ml, almost exclusively severe bacterial sepsis or septic shock. , this was compared to changes in antibiotic prescribing which were identified from our local audit database and used as a surrogate marker for clinical suspicion of sepsis. to provide context we also compared this to crp and wcc trends in a larger sample from june to december . results. forty-four episodes had matched antibiotic prescribing data and pct results. a further episodes provided synchronous wcc and crp data. pct assays were typically requested on day (median, interquartile range - ). distribution of pct results pct value (ng/ml) . . - . - [ number (%) ( ) ( ) ( ) ( ) there was poor concordance between pct and both wcc and crp trends and also when wcc and crp trends were compared. pct assays did not have significant correlation with antibiotic prescribing. pct conclusions. our study suggests pct results did not influence clinical practice. pct testing may be of greater benefit if used with a protocol with guidance for clinicians based on assay levels. routine and serial quantitative pct testing protocols may also be useful to guide antibiotic initiation and duration, particularly in cases of greater diagnostic uncertainty, for example traumatic brain injury. , references. introduction. procalcitonin (pct) is a reliable marker for diagnosis of infection after cardiac surgery, except in patients who previously received antibiotics, but its diagnostic role in patients with post-sternotomy pre-sternal wound infection and mediastinitis has not been studied in detail. ( ) . objectives. this retrospective study focused on the role of pct in the differentiation between poststernotomy pre-sternal wound infection and mediastinitis. methods. all patients (n = ; age: median , - years) who underwent surgical treatment due to poststernotomy superficial pre-sternal wound infection and mediastinitis between january and september were included in the study. procalcitonin (pct), c-reactive protein (crp) and leukocyte counts were routinely measured within the last h before surgical wound revision. body temperature and hemodynamic parameters were evaluated immediately before operation. bacteriologic samples were also routinely taken intraoperatively. results. the primary cardiac operation was cabg (n = ), cabg and valve procedure (n = ) and others (n = ). time between primary operation and wound revision was in median days (range sensitivity, specificity, positive and negative predictive value for diagnosing sepsis are presented in table . roc curves and auc are presented in figure . roc curves and auc conclusions. patients with sepsis have significantly higher levels of crp, pct, il- and lbp on admission to the icu as compared to patients with sirs. pct is more usefull in differentiating between sepsis and sirs than crp, il- and lbp. b. ergan arsava , s. bilekli , n. alayvaz aslan , e. er , a. topeli hacettepe university, ankara, turkey introduction and objective. the incidence and mortality of bacterial infections significantly increase with age. aging is associated with an impaired immune response, which causes not only an increased susceptibility for infections, but also a poor inflammatory response against them. procalcitonin (pct) is an inflammatory biomarker used as a diagnostic and prognostic tool in bacterial infections. there is no data regarding the diagnostic yield of pct in elderly patient populations. in this study we sought to identify the relationship between age and the magnitude of pct response in patients admitted to the intensive care unit (icu). methods. patients, who were admitted to icu between january and december , with the diagnoses of severe sepsis, pneumonia and chronic obstructive pulmonary disease exacerbation (copde) were included into the study. patients' demographics, apache- scores, admission pct values, intensive care and hospital outcomes were extracted from a database of prospectively collected clinical data. results. we studied a total of admissions ( female/ male, mean age ± standart deviation . ± . years). median (interquartile range-iqr) apache score was ( - ); the icu and hospital mortalities were . and . %, respectively. median (iqr) admission pct levels were . ( . - . ) ng/ml in patients with severe sepsis (n = ), . ( . - . ) ng/ml in patients with pneumonia (n = ) and . ( . - . ) ng/ml in patients with copde (n = ). there was a negative correlation between age and pct levels (spearman correlation coefficient: r = - . , p = . ); the median (iqr) pct levels were . ( . - . ) ng/ml in patients\ years-old and . ( . - . ) ng/ ml in patients c years-old (p = . ). in subgroup analyses it was found that the inverse correlation between age and pct levels mainly arised from patients with severe sepsis (r = - . , objectives. we intend to define the role of pct in the initial evaluation of the patient with a suspected sepsis admitted to the icu. preliminary data from a prospective observational single centre study (polyvalent icu in a third level university hospital). the ethics committee of the centre has approved this study. we included all patients admitted to our unit with diagnosis of sepsis since june- . we measured pct (lgr/ml) at admission and at the second and third day of stay beside the routine screening for the source of infection. then we analyzed the relation of pct with culture results. chi-square and anova have been used for the analysis. (fig. ). pct at admission showed an auc of . ( . - . ) for discriminating bacterial infection. we detected higher mortality in those patients with bacterial infections and sustained high levels of pct the third day ( fig. ) (p \ . ). figure , conclusions. in the initial approach to the septic patient, pct does not seem in our experience useful as an aid in decision-making but an early decrement of serum levels can be a marker for response and for a better outcome of patients with bacterial infections. ( - ) b-d-glucan (bg) assay in early detecting ici in critically ill pts and assess its reliability on arterial blood specimens compared to venous blood specimens. methods. all pts admitted to the -bed icu of our university hospital, between th of february and th of march , harboring an arterial line for more than days and suspected to have an ici, were prospectively enrolled. from all the pts, two blood samples drawn from the arterial line and direct femoral site were simultaneously obtained and subjected to both conventional cultures and bg assay determinations. candida colonization index (cci) and candida score (cs) were also calculated. results. during the study period, from admissions, pts were enrolled. bg assays, cutaneous and mucosal swabs and urine cultures were collected. in pts bg assays resulted negative from either arterial line and femoral site. all but one did not develop ici. in pts bg assays resulted positive. four of these pts did not develop ici, whereas the other six developed ici ( fungemias and mediastinitis). the positive and negative predictive values (ppv, npv), sensitivity (se) and specificity (sp) of bg assay, cci, and cs are shown in table . among pts with ici, (median sofa score value ± . ; median saps ii value . ± . ) had at the diagnosis bg levels c pg/ml and developed septic shock; two of them died within few days. in contrast, the clinical course of pts with bg assay below pg/ml was not complicated by septic shock (median sofa score . ± ; median saps ii value ± . ) and a rapid clearance of bg levels was observed. in addition, we observed a % agreement between arterial line and femoral site bg assays (positive and negative). in particular, we detected bg levels from arterial site specimens that did not significantly differ by those obtained from femoral site specimens (p = . ). conclusions. although conventional mycological culture remains the gold standard for ici diagnosis, we showed that bg assay seems to be a diagnostic tool that may help physicians in early detecting ici. sampling blood from the arterial line was shown to give a simple and adequate specimen to be used for bg assay. further studies are in progress in order to define the role of bg as a surrogate marker for an early diagnosis of ici. objectives. to assess which marker, if any, and at which cut-off value could add diagnostic information to enhance clinical assessment in the difficult context of long-term icu-patients. methods. long-term ([ days) critically ill patients prospectively enrolled in the general icu of a university-hospital. all patients were daily assessed by the attending physician for the accp-sccm classification. c-reactive protein (crp, mg/dl), procalcitonin (pct, ng/ ml), and interleukin- (il- , pg/ml) were measured after patient's discharge on daily stored sera. an independent overall clinical evaluation after patient's discharge, aware of the clinical course but blinded against biomarker's measurement, an ''a posteriori'' accp-sccm classification, was chosen as reference standard for all comparisons. results. we studied clinical variables and biomarkers in patient-days ( patients). the day by day accp-sccm classification of the attending physician overestimated the severity of the inflammatory response to infection. discriminative ability of each biomarker for diagnosis of sepsis is shown in table . methods. icu patients ( males and females) with new onset of fever and leukocytosis within the first days of icu admission were prospectively included in the study. exclusion criteria: age \ or [ years old, heart or renal failure, hypertension, copd, pregnancy and head trauma. serial plasma samples were taken on days , and after the onset of fever for procalcitonin and bnp levels measurement. procalcitonin and bnp values were correlated with severity scores (apache ii and sofa), progression to septic shock and final outcome. statistical analysis was performed. results. patients included in the study were divided in three groups according to clinical and laboratory findings: sirs, sepsis and septic shock. procalcitonin value on days and and bnp value on days , and was significantly associated with sofa max value and with sofa value at the first day of fever, but not with apache ii. there was found no correlation between procalcitonin value on days , and and final outcome. bnp value on days and was significantly associated with final outcome (p = . and . respectively). the optimal cut-off bnp value on day was estimated to be pg/ml (sensitivity = %, specificity = %). the optimal cut-off bnp value on day was estimated to be pg/ml (sensitivity = %, specificity = %). procalcitonin value on days , and was not able to differentiate between patients with sirs and those with sepsis. also procalcitonin value on days , and was not significantly associated with progression to septic shock. bnp value on day was useful in differentiating between patients with sirs and those with sepsis (p = . ). the optimal cut-off bnp value was estimated to be pg/ml (sensitivity = %, specificity = %). bnp value on days and was significantly associated with progression to septic shock (p = . ). the optimal cut-off bnp value on day was estimated to be pg/ml (sensitivity = %, specificity = %). the optimal cut-off bnp value on day was estimated to be pg/ml (sensitivity = %, specificity = %). conclusions. in icu patients with new onset of fever during the first days of icu hospitalization, bnp value on days and seems to be a good predictor of icu mortality and progression to septic shock. also bnp value on day may be useful in differentiating between patients with sirs and those with sepsis. in our study procalcitonin value on days , and was not found useful in predicting progression to septic shock nor the final outcome. due to the small number of patients included in our research, further studies are needed to confirm these findings. objectives. as c-reactive protein (crp) is regarded a marker for both inflammation and infection we decided to analyse the pct and eo status next to every crp request of critically ill patients, during month. a two-side immunoassay (sandwich principle) for procalcitonin, using both anti-katacalcin and anti-calcitonin (see fig. a ) was used for quantitative analysis of procalcitonin with the roche modular e . pct concentrations [ . lg/l were regarded as positive. crp was measured by immunoturbidimetric analysis using the roche modular p. a positive blood culture was regarded as infection, with exclusion of the coagulase negative staphylococcus aureus since this organism doesn't induce pct expression. every crp request of the icu during month was accompanied by a pct, wbc, and eosinophil count. conclusions. pct at randomly measured at the icu doesn't seem to contribute to an earlier diagnosis of sepsis. pct measurement seems to be useful only when sepsis is suspected and a blood culture request has been summoned. however, its non-specificity for infection, as demonstrated by the high number of pct-positive, no blood-culture requested patients (concerning mostly post-cardiac arrest and post-heart surgery patients), makes it difficult to apply routinely. the recently displayed effort of various companies to market pct in combination with cd and neopterin (other potential markers of infection) supports the conclusion that not one marker by itself can substitute the golden standard of blood culture today. objectives. in this prospective observational study we sought to investigate the role of serum c-reactive protein (crp) and procalcitonin (pct) in the diagnosis and prognosis of patients admitted to the icu with suspected h n infection. all patients older than year-old, presenting with severe acute respiratory disease (cough, fever and respiratory distress) admitted to the icus of an university hospital in southeast brazil were included in this study. serum levels of crp and pct were measured at inclusion and at day , and . were also were also significantly higher (p \ . and p = . , respectively) independently from the presence or not of a co-infection. conclusions. as a conclusion, in our experience, some severe forms of influenza a/ h n with respiratory failure had elevated levels of pct and/or crp in the absence of proven bacterial co-infection. low values were unusual in the presence of co-infection but high values are not synonymous of co-infection and may be related to the severity of the disease. a large prospective randomized study is needed to assess the clinical interest of these biomarkers during the next pandemic of influenza. methods. descriptive study of pregnant with influenza a admitted in the obstetric section icu. the study period runs from september to january . during this period patients were admitted. entry criteria (%): gestosis %, complicated postoperative gynecology and obstetrics , postpartum hemorrhage , acute respiratory failure in influenza pneumonia: . , sepsis and others respiratory failure respectively, others (pregnant myocardial infarction, trauma, renal failure, arrhythmias and heart failure) . acute respiratory failure due to influenza pneumonia was assessed using severity criteria the ats/idsa (major criteria ( ) were admitted in icu cases of severe influenza pneumonia, nasopharyngeal specimens confirmed with rt-pcr positive for influenza a (h n ): pregnant in icu og, and women and men general icu. the average age of pregnant was ± years, average stay days. % were in the rd trimester and one in the nd trimester (week ). two-third pregnancy and two primiparous. the apache ii on admission ranged between and . only one patient with pre-existing disease (diabetes type ). admission due: acute respiratory failure complicating pneumonia multilobar in %, with more than days of typical symptoms (fever [ °c, malaise, myalgia, headache and respiratory symptoms), no starting oseltamivir within h symptoms. caesarean was performed at %; % in the first h of admission and one after days (week ) intrauci, posterior cerebral hemorrhage fetal death. all newborns free of viral disease. invasive mechanical ventilation (mv) in the first h in patients and did not require. required aggressive parameters %: bipap, alveolar recruitment and prone. a percutaneous tracheostomy for weaning. the average duration of mechanical ventilation: ± days complications: barotrauma (pneumothorax and a pneumomediastinum ). % required vasoactive drugs. one patient with acute renal failure that required extracorporeal clearance techniques (hdfvvc), recovering renal function, deep vein thrombosis complicated with shaldon catheter. one brain death by massive subarachnoid hemorrhage. nosocomial infections in patients, most common germ staphylococcus epidermidis catheter and candida sp in urine. initial empiric coverage with ceftriaxone and clarithromycin, as well as oseltamivir. conclusions. during pregnancy, especially in the second and third quarters, there is an increased risk of complications associated with infection by influenza a virus h n , highlighting pneumonia, with more rapid progression to severe respiratory complications. objectives. the aim of this study was to describe baseline characteristics, management and outcomes of critically ill patients with influenza a (h n ) infection who were treated at icu. we performed a retrospective observational study which included critically ill patients with influenza a (h n ) infection admitted to icu between rd november and th march . the primary outcome measure was mortality. secondary outcomes included the rate of influenza a (h n )-related critical illness and introduction of mechanical ventilation as well as intensive care unit (icu) length of stay and hospital length of stay. in the early th century, burns patients were dying of multi-organ failure due to dehydration and hypovolaemia [ , ] . the parklands formula was devised to guide fluid resuscitation and prevent multi-organ failure from occurring. however, over enthusiastic fluid resuscitation will lead to other complications [ ] . objectives. we aimed to assess the adequacy and complications of fluid resuscitation in the st h of a burns patient admitted to our icu, a tertiary centre for burns intensive care. • a retrospective medical case notes audit on all patients admitted to our icu in with [ % tbsa (total burns surface area). • st h of burns resuscitation initiated by the referring hospital and our icu compared to the parkland's formula. • statistical analysis by spss . results. patients audited. • mean duration of transfer from burn injury to our unit = . h • mean age = years, burn area %, length of stay . days • day mortality = % • % had an inhalational injury • no statistical difference between the emergency department (ed) estimation of tbsa and whiston icu. • mean iv fluids given . l but the actual predicted requirement is . l, therefore an excess of . l (p \ . ) • average urine output during this period was . ml/kg/h suggesting that this amount was adequate. iv fluids in the st h conclusions. excessive amount of iv fluids in the st h is associated with prolonged ventilation and length of stay but is not associated with increased day mortality. the mean amount of fluid required in the st h is approximately ml/kg/h which is consistent with other studies [ ] . urine output is still an accurate marker of resuscitation. there was no statistical difference between the determination of tbsa by the ed and burns surgeons, contrary to other studies [ ] . introduction. icu-acquired hypernatremia appears to be associated with mortality in the icu . to reduce iatrogenic rise of serum sodium the use of balanced colloids has been advocated. objectives. aim of this study was to establish the incidence of clinically relevant hypernatremia on our icu and to evaluate the change in incidence of hypernatremia due to the introduction of a natriumacetate based colloid solution. we performed a single centre retrospective study in a -bed mixed icu with all available medical specialities except neurosurgery. sodium measurements of all patients were analyzed during a -month period prior to and after a switch from sodium-based (s) to natriumacetate -based (na) colloids. s contains a % kda polystarch with a mmol/l na and mmol/l cl concentrations (voluven Ò ). na contains a % kda hydroxyeethylstarch with a mmol/l na and mmol/l cl concentrations (volulyt Ò ). serum sodium measurements were routinely performed -hourly. by protocol colloids were provided to a maximum of l/day, independent of bodyweight. patients with hypernatremia at icu admission were excluded. data are expressed as mean ± sd. comparison of na concentrations between groups was performed with a t test for independent samples and comparison of incidence of hypernatremia with a pearson chi-square test. results. patient characteristics and number of samples are summarized in table . after the introduction of na mean serum sodium concentration in the total icu population decreased significantly from . ± . to . ± . , p = . . the incidence of serum na[ mmol/ l decreased from . to . %, p = . . the percentage of patients with at least one na measurement[ mmol/l did not change significantly: . % (s) versus . % (na), p = . . introduction of a natriumacetate based colloid solution in stead of a sodium-based colloid solution reduces the overall incidence of clinically relevant hypernatremia; however, the number of patients with such hypernatremia did not change significantly. patients admitted to intensive care frequently have a metabolic acidosis with previous studies demonstrating an association between the degree of acidosis and outcome. hyperchloraemia is a significant cause of metabolic acidosis and there is increasing interest in the adverse consequences associated with it, which include hypotension, renal dysfunction, impaired gut perfusion and increases in inflammatory cytokines. previous studies, however, have failed to show that hyperchloraemic metabolic acidosis (hcla) has a significant effect on survival. to assess whether patients with hcla had a worse prognosis than our general intensive care unit (icu) population, and the factors associated with the development of hcla. consecutive admissions to the intensive care unit over a month period were studied. patients with a base deficit[ mmol/l and a serum chloride[ mmol/l on the same arterial blood sample during their icu admission were classified as having an episode of hcla. apache ii scores on admission, length of stay on the unit, mortality rates and reason for admission were collected. hospital survival was investigated by logistic regression analysis, controlling for illness severity (apache ii) and admission category, and displayed as a kaplan-meier curve. of patients entering the unit during the retrospective study period, had an episode of hcla, with an odds ratio of death of . ( % ci . , . ) compared with those without hcla. after controlling for apache ii score on admission, and admission category the odds ratio reduced to . but was still statistically significant (p = . , % ci . , . ). the development of hcla was significantly more associated with medical than surgical admissions with an odds ratio of . ( % ci . , . ). within the surgical admissions, the occurrence of hcla differed significantly with the urgency of surgery, with an odds ratio of . ( % ci . , . ) for emergency surgery versus elective surgery. those with hcla had a longer median duration of stay and were overrepresented in the group of patients whose length of stay was c days. kaplan-meier graph showing survival to days conclusions. the results demonstrate that hcla occurs frequently in a general icu population and is associated with a significantly worse outcome. this is in contrast to previous studies which have demonstrated acidosis secondary to lactate and an elevated strong ion gap are associated with poorer outcomes, but not hyperchloraemia. a. dumoulin , a. janssen , j.j. de waele , j. decruyenaere , e.a. hoste universitair ziekenhuis gent, gent, belgium increased creatinine clearance or hyperfiltration has been reported in icu patients. enhanced renal clearance of antibiotics in patients with hyperfiltration may result in suboptimal antibiotic serum concentrations, and so affect patient outcomes. there are only limited data on the incidence of hyperfiltration in icu patients. objectives. assess the epidemiology of hyperfiltration in a cohort of icu patients. single center retrospective cohort study, including adult patients hospitalized during the period / - / in the bed icu of the ghent university hospital, a tertiary care center. data were retrieved by a specially designed electronic alert from the electronic icu database. urinary creatinine clearance (ccr) was calculated as ( h urine volume) (urinary creatinine)/([creatinine day - + day ]/ )/time. we retrieved the initial ccr, and the minimum and the maximum ccr. hyperfiltration was defined as a ccr c ml/min. patient days with anuria were excluded from the analysis. data are reported as median (interquatile range). patients with neurological disease. several factors may interfere with water and sodium homeostasis in these patients, including factors that are also present in other icu patients. in addition, these patients may develop a syndrome of antidiuresis (siad), or salt wasting syndrome (sw). the latter by secretion of brain natriuretic peptide (cerebral salt wasting syndrome (csw)), release of atrial natriuretic peptide in volume overload, or renal salt wasting. objectives. assess the epidemiology of hypona in icu patients with neurological disease. methods. retrospective single center study. data were retrieved from electronic icu databases. inclusion criteria were age c years, hypona (\ mmol/l), and neurological disease. only the first episode of hypona was considered. siad and sw was assessed with tonicity balance on data of the preceding h in patients with urinary sodium[ mmol/l, in whom other etiologies were excluded. sw was defined as negative salt balance and negative fluid balance, and siad as positive fluid balance. to evaluate the prevalence of anaemia among patients attended at the emergency room (er) and to estimate the need of an early diagnose and efficient treatment. observational transversal trial in which days in june were randomly chosen. all patient attending to the er is included. paediatric, gynaecologic and traumatic cases fall out of this research. anaemia was diagnosed according to who criteria. comparison means statistics methods for quantitative variables and chi square for categorical variables were used. prevalence data for the entire cohort, for men and women separately and for different age bands, medical history, anaemia related medication and red blood cells data were extracted. results. patients were interned through the er channel. % men, mean age . ± . years old (median ), and , % were subject of blood analysis using classification proceedings. from the analysed . % were anaemic. . % of them were under years old, % aged from to and . % elderly patients (over years old). most frequent co-morbidity was chronic obstructive pulmonary disease (copd) (n = , . %) and most related drug aspirin (n = , . %). % of the sample had a bleed but only . % needed red blood cell transfusion. we found statistic difference in mean age, antiplatelets therapy use, bleeding episode, need for transfusion, creatinin value and hospitalisation. anaemia classification according to vcm: microcytic . %, normocytic %, macrocytic . %. conclusion. unknown anaemia detection in the er and its following treatment could be a strategy to further reduce allogeneic blood transfusion. the presence of disorders of sodium balance on icu admission could be independently associated with mortality. we decided to study if the existence of dysnatremias at the time of icu admission could be related to mortality in critically ill patients. we conducted a retrospective study in a mixed icu with a database of , adults admitted consecutively over a period of years ( - ) . most patients ( . %) had normal sodium levels ( b na b mmol/l) on icu admission. the frequencies of borderline ( b na b mmol/l), mild ( b na \ mmol/l), and severe hyponatremia (na \ mmol/l) were . , . %, and . %, respectively. the frequencies of borderline ( \ na b mmol/l), mild ( \ na b mmol/l), and severe hypernatremia (na [ mmol/l) were . , . , and . %, respectively. all types and grades of dysnatremia were associated with increased raw and risk-adjusted hospital mortality ratios. multiple logistic regression analysis showed an independent mortality risk rising with increasing severity of both hyponatremia and hypernatremia. odds ratios and % confidence interval (ci) for borderline, mild, and severe hyponatremia were . , . and . , respectively. odds ratios and % ci for borderline, mild, and severe hypernatremia were . , . , and . respectively. conclusions. this observation suggests the possible correlation of natremia on icu admission with hospital mortality and confirms that both hypo-and hypernatremia present on admission to the icu could be independent risk factors for poor prognosis in icu populations. ( ) . a relationship between mortality and delay from time of pars trigger to critical care admission for patients not requiring surgery has recently been described ( ) . objectives. this study was to test the hypothesis that in cases of emergency laparotomy, prolonged physiological deterioration pre-operatively is associated with higher hospital mortality. we reviewed notes of patients that underwent emergency laparotomy between july and february at the northern general hospital, sheffield, uk. time at which patients triggered (pars c ), time of arrival in theatre and hospital mortality were recorded. two-tailed fisher's exact test was used to test null hypotheses that a delay of more than h after pars trigger does not affect hospital mortality. . patients had an emergency laparotomy during this period. of notes retrieved by our patient record service, were incomplete. of remaining patients patients did not trigger, of whom died ( . % mortality). patients triggered, died ( . %). amongst patients that triggered, arrived in theatre within h, of whom died ( . % mortality); of the patients that arrived in theatre after h died ( . % mortality). the odds ratio of death for those with a prolonged pre-operative deterioration (n = ) compared to those without (n = ) was . ( % ci . - . , p = . ). the number needed to treat early to save one life was . conclusions. our data suggest that in cases of emergency laparotomy, those who trigger pars pre-operatively have higher hospital mortality than those who do not. specifically, our data indicate that patients triggering pars c should arrive in theatre within h of first triggering. nothing is known about the effect of the duration of icu-related therapies on acute outcome. to identify the importance of the duration of invasive ventilation and of renal replacement therapy for acute prognosis of surgical patients treated in an intensive care unit (icu). we performed a retrospective analysis of prospectively collected data of an icu patient cohort linked to a local database. adult patients (n = , ) admitted to a -bed icu at a university hospital in munich, germany, between and who had an icu length of stay of more than days and who were followed-up until the end of the acute phase after icu admission. cox-type additive hazard regression models were used to analyse linear, nonlinear or time-varying associations of therapeutic variables with survival time. duration of different invasive therapies was evaluated by constructing specific vectors, which tested potential effects of time-dependant variables on outcome after a lag time of days. . patients ( . %) were still alive at the end of the acute phase after icu admission. during the acute phase, . % of the patients required invasive ventilation, and . % a continuous renal replacement therapy. besides the underlying disease and disease severity at icu admission, the need for invasive ventilation or renal replacement therapy was associated with poorer outcome. duration of invasive ventilation shortened survival (with a lag of week), if treatment lasted for more than days (non-linear association). in contrast, duration of renal replacement therapy was unimportant for acute prognosis. conclusion. prolonged duration of invasive ventilation, but not of renal replacement therapy is inversely related to acute survival. objectives. to identify the prognostic importance of preceding invasive ventilation, renal replacement therapy and catecholamine therapy for long-term survivors after surgical critical illness. we performed a retrospective analysis of prospectively collected data of an icu patient cohort linked to a local database. adult patients (n = , ) admitted to a -bed icu between and , who had an icu length of stay of more than days, were followedup until the end of the second year after icu admission. hazard function was explored by weibull modelling and likelihood ratio tests. cox-type structured hazard regression models were used to analyse linear, non-linear or time-varying associations of therapeutic variables with -year survival time of a patient subgroup, which had survived the period of high hazard. hazard rate declined exponentially up to day after icu admission, and became constant thereafter. patients reached this stable stage of their disease forming the study population. of these patients ( . %) were still alive at the end of the second year after icu admission. underlying diseases were major determinants for long-term outcome. long-term mortality was significantly associated with the acute extent of physiological derangement during icu stay (maximum apache ii score), but was independent from the duration of preceding invasive organ support. in surgical patients with a prolonged icu length of stay, an exorbitant mortality exists for about half a year after icu admission. later on, life expectancy of surviving patients is largely determined by the underlying disease and, to a minor degree, by the acute extent of homeostatic disturbance during icu stay. the duration of preceding invasive therapies does not limit long-term survival. b. rozec , a. desdoits , k. asehnoune , c. lejus , y. blanloeil chu nantes, hôpital laënnec, anesthesia and intensive care, nantes, france, chu nantes, hotel-dieu, anesthesia and intensive care, nantes, france postoperative stroke could be an endpoint in non-cardiac surgery morbidity studies [ ] . therefore, its frequency established in old studies and considered higher than in the non surgical population remains to be estimated more precisely. objectives. the aim of this evaluation was to calculate the frequency of stroke, firstly in a prospective study, and secondly in a review of the literature. strokes diagnosed in the prospective follow-up ( days) of surgery for hip fracture was confirmed by a neurologist and a ct-scan. retro and prospective studies (except abstract) published in journals (pubmed, ovid) from to were included in the analysis. statistics:% ic , multivariate analysis (effects of population size, date of publication, type of surgery, patient age, prospective vs. retrospective studies were evaluated). results. mean pre-operative possum scores between the two groups showed no significant differences. continuous measurements taken by the odm showed a mean stroke volume increase of mls at the end of surgery (paired t test, p-value = . ). ( . %) patients following implementation compared to ( . %) prior to implementation required post-operative critical care admission. following odm implementation, critical care los was reduced from . to . days and post-operative length of stay within hospital was also significantly reduced by . days. introduction. local (skeletal muscle necrosis) and remote (lung neutrophil infiltration) ischemia-reperfusion injury (ir) have been described in animals [ ] and humans after aortic surgery. postconditioning with cyclosporina (csa) was recently shown to prevent skeletal muscle infarction in pig latissimus dorsi muscle flaps [ ] . objectives. the aim of this study was to investigate local (gastrocnemius muscle, gc) and remote (lung and liver) ir in rats exposed to aortic cross-clamping with special focus on mitochondrial respiratory chain complexes activities and reactive oxygen species (ros) production. we also investigated whether pharmacological post-conditioning with csa would be protective in this setting. methods. anaesthetized (isoflurane) and mechanically ventilated wistar rats underwent laparotomy and were randomly assigned to one of the following groups: sham (n = ), ir (n = , clamping of the infrarenal aorta for h followed by h of reperfusion), ir+csa (n = , mg/kg csa administered intraperitoneally and min prior to reperfusion). maximal oxidative capacities (vmax) and complexes i, ii and iv of the mitochondrial respiratory chain were determined using glutamate-malate (vmax) and succinate (vsucc) as substrates in the gc permeabilized fibers and freshly harvested liver and lungs isolated mitochondria. tissue superoxide anion production was assessed with dihydroethidium (dhe) in thin sections of frozen gc. data are expressed as mean±sem and analyzed with anova followed by newman-keuls post-hoc test; a p value. was considered significant. esophagectomy with gastric tube reconstruction is associated with frequent postoperative complications due to a (surgery induced) systemic stress response, provoked by the overproduction of proinflammatory cytokines. in elective postoperative esophagectomy patients, we previously showed that levels of serum crp are associated with the occurrence of postoperative complications and reduced survival. plasma ngal (pngal) and urine ngal (ungal) are early predictors of acute kidney injury, however sepsis/sirs seems to accelerate their production even in the absence of aki. objectives. we examined the role of pngal and ungal as early indicators of postoperative complications at the icu in patients undergoing elective esophagectomy surgery methods. in a prospective follow-up cohort study, data of a total of patients admitted to the icu following elective esophagectomy with gastric tube reconstruction were collected in the period from september to april . patients who developed aki at the icu were not included in this study. postoperative pngal and ungal levels were determined at consecutive time points and the relation between the course of postoperative serum pngal and ungal, development of complications and outcome of the patients was investigated. in our experience, assisted by dv robot radical prostatectomy, despite requiring longer surgery time, was shown to be safer than conventional radical prostatectomy, with a significant less blood loss during surgery, less need for blood transfusion, fewer postoperative complications, included need to reoperate, and also a shorter length of hospital stay than conventional radical prostatectomy. objectives. the aim of the study was to evaluate safety and effectiveness of m infusion, impact on fluid balance and urine output (uo) and also whether we can avoid cvc line insertion. we conducted a prospective analysis of patients (pts) treated with m who were admitted to the shdu between oct and aug . demographic data and vital parameters were collected through the individual questionnaires before ( ) introduction. an ever increasing number of patients over the age of year are being admitted to critical care units [ ] . with no marked expansion in the number of critical care beds in our hospital and in the health region as a whole, this may lead to a huge strain on the service provision, with less availability of beds to treat elective and other emergency admissions. to determine the factors that affect outcome following admission to critical care of patients aged years and above(medical and surgical). methods. ethical approval was sought but deemed unnecessary as our study was observational (non-interventional). we prospectively looked at the number of patients (age year and above) who were admitted to icu/warrington general hospital over the period of year. our unit is a modern, -bedded general icu with an annual admission rate of approximately ( level and level care). we examined data that was related to the source of admission, gender, apache scores, the use of vasopressors (including inotropes) and the need for ippv in the first h of admission. we analysed the effect that each factor had on patient mortality (applying chi-square and z tests). we followed the patients up for months post-discharge from icu. the final report produced results that showed icu, hospital and -month mortality. results. there were admissions during the period st may - th april . last set of mortality data was obtained in september . female: male ratio was : . the overall -month mortality was %. in our study, patients admitted through a&e, theatre and ward had mortality rates of , and % respectively. patients who received vasopressors (including inotropes) in the first h had a significantly lower mortality than patients who did not receive any vasopressor support ( vs. %). invasive ventilation in the first h of admission was associated with significantly higher mortality rates ( vs. %). in this patient cohort, the overall -month mortality is higher than the general icu population. factors that determine mortality include the source of admission to icu, the need for vasopressor support and invasive ventilation in the first h of admission. introduction. the optimization of oxygen delivery (do ) is an intervention with fluids and inotropics to achieve supranormal goals of do during surgery, before disturbances of perfusion occur and oxygen debt accumulates. oxygen debt is directly linked to multiple organ failure and death. we aimed to evaluate the temporal pattern of oxygen debt in the intraoperative period in patients included in two studies of goal directed therapy to supranormal values of do . oxygen debt was calculated from data obtained from high risk surgical patients included in two randomized controlled trials were analysed. , the oxygen deficit was calculated by subtraction of the basal vo value from subsequential values of vo obtained during surgery and after the icu admission. the oxygen debt was calculated by the product of oxygen deficit and time (minutes) between measurements. patients treated with supranormal goals of do ([ ml/min/m ) using fluids and dobutamine showed lower levels of oxygen debt during icu stay. the peak of oxygen debt was , ml/m at min of surgery in the control group in comparison to , ml/ m in the protocol group. in the second study, the peak of oxygen debt occurred at min in the volume group ( , ml/m ) which was significantly higher than in the dobutamine group ( , ml/m ). higher oxygen debt during peroperative period correlated with poor outcome as shown on the original studies. conclusion. the use of supranormal goals of do with dobutamine and fluids in the peroperative period results in lower oxygen debt. post-operative nausea and vomiting (ponv) is a common problem in the patients undergoing laparoscopic surgery. the release of serotonin during surgical procedure may induce ponv. we investigated if postoperative increase in plasma serotonin metabolite was associated with ponv after gynecologic laparoscopic surgery. objectives. the patients who experienced nausea after gynecologic laparoscopic surgery (ponv group, n = ) and patients who had no or mild nausea (control group, n = ) were enrolled into this study. postoperative nausea was assessed during h in post-anesthetic care unit and ondansetron was administered if needed. blood samples were obtained before anesthesia and h after surgery. plasma serotonin metabolite ( -hydroxy indole acetic acid, -hiaa) was analyzed using high performance liquid chromatography (hplc) assay. perioperative change of plasma -hiaa and the degree of nausea were compared between groups. results. the degree of post-operative nausea varied from to ( mm visual analogue scale, vas) and median value was ( - ) in control group and ( - ) in ponv group (p \ . ). average -hiaa concentration of all patients increased after surgery ( . ± . to . ± . ng/ml, p \ . ). baseline plasma -hiaa concentrations were similar between groups, however, -hiaa of ponv group increased higher after laparoscopic surgery compared with control group ( . ± . to . ± . ng/ml vs. . ± . to . ± . ng/ml, p = . ). conclusions. the patients who experienced post-operative nausea showed more increase in -hiaa concentration. ponv after gynecologic laparoscopic surgery may be associated with a peripheral release of serotonin. introduction. the intracavitary ecg method is an easy, accurate and inexpensive methodology for real time positioning of the tip of central venous catheters. in particular, when the ecg method is performed using not the guidewire but the saline-filled catheter as electrode, the methodology is completely safe and can be applied to any central venous access device (vad). we have tested a new specific device (sapiens tls, romedex) which simplifies and standardizes the ecg method; it consists of a hardware (a small box with cables connecting it to a pc and to ecg electrodes) plus a software (which can be used on any pc). we tested the sapiens tls in patients who underwent positioning of central vads ( totally implantable ports, piccs and tunnelled catheters, all inserted by ultrasound guided venipuncture). our goal was to position the tip of the catheter at the cavoatrial junction: the length of the catheter was estimated by anthropometric measurements and the correct positioning was achieved by the intracavitary ecg method during the procedure. the final position was checked by a post-procedural chest x-ray. there was no insertion-related complication. the intracavitary ecg method was easily performed in all cases. at the final x-ray control, % of all tips were correctly positioned at the cavo-atrial junction (± cm), confirming the accuracy of the intracavitary ecg method. the anthropometric measurement tended to overestimate the length of the catheter both in port insertions ([ cm in % of cases) and in picc insertions ([ cm in % and [ cm in % of cases). conclusions. the intracavitary ecg method as performed with the sapiens tls was more accurate than the anthropometric measurement in terms of correct positioning the tip of the catheter during the procedure. the sapiens tls simplified the method, by standardizing the ecg tracking, and making it easy (no need of ecg monitor, no need of ecg commuter since the sapiens tls displays simultaneously the surface ecg and the intracavitary ecg). also, the sapiens tls allows the print-out of the intracavitary ecg reading for documentation, as well as the storing of the ecg reading in a computer-based database. previous studies have shown that hypernatremia impact graft function after orthotopic liver transplant (olt). the purpose of this retrospective investigation was to determine whether differences in serum sodium values after olt influenced postoperative short-term patient outcomes. objectives. the study was aimed at exploring the incidence of hypernatremia after orthotopic liver transplantation (olt) in order to provide critical monitoring and intensive care services. clinical and sicu laboratory data were collected; serum sodium was assessed an average of three times per day. hypernatremia was defined as two daily values of serum sodium above mmol/l. from to , we analyzed patients with hypernatremia after olt. the major outcome was death in the icu after days. conclusions. in sicu, olt patients are easy to suffer from hypernatremia ( . %) and have high mortality ( . %). hypernatremia is associated with an increased risk of death in patients with olt. early active fluid infusion is crucial, besides optional continue venovenous hemofiltration (cvvh). cywinski objectives. the aim of this study was to determine the value of blood lactate sequential dosages during the first postoperative hours for the diagnosis of gd. we conducted a retrospective study on consecutive patients admitted in icu after lt, between july and june . lt with auxiliary or splited grafts were excluded so were patients with septic or cardiogenic shock occurring during the first h after lt. criteria for gd diagnosis were: sgot [ , u/l with pt \ % between d and d , or re transplantation or death between d and d . demographics and biological data (transaminases, pt, serum bilirubin) were recorded between d and d . hopital bicêtre, kremlin-bicêtre, france, hôpital saint-louis, paris diderot university, biostatistics, paris, france, hôpital hôtel-dieu, medical intensive care unit, nantes, france, hôpital gabriel montpied, nephrology and transplantation, clermont-ferrand, france, hôpital edouard herriot, medical intensive care unit, lyon, france, conclusions. in kidney transplant recipients, arf is associated with high mortality and graft loss rates. increased pneumocystis and bacterial prophylaxis might improve these outcomes. early icu admission might prevent graft loss. a. umgelter , k. lange , p. büchler , h. friess , r.m. schmid technical university of munich, transplantationszentrum münchen rechts der isar, ii. medizinische klinik, münchen, germany, technical university of munich, transplantationszentrum münchen rechts der isar, chirurgische klinik, münchen, germany introduction. the shortage of donor organs in the eurotransplant region results in late allocation at a time when liver disease is already very advanced. the severe condition of patients at that stage negatively affects outcomes of orthotopic liver transplantation (olt). to support decision-making in these situations, clinical data are urgently needed. objectives. to evaluate outcomes of liver transplantation (olt) in icu-patients with multi-organ failure due to advanced acute on chronic liver failure (aclf). methods. in our centre, patients on the waiting list for olt are not automatically excluded from the procedure, if their condition deteriorates to multi-organ failure. a consensus of the team in each individual case is based on criteria such as the previously manifested will of the patient, exclusion of current infection, absence of neurologic damage or other organ damage expected to impair the possibility of rehabilitation. we retrospectively analyzed a database comprising data from evaluation for the waiting list of all patients transplanted in our center since implementation of the meld-score for allocation. only cirrhotic patients treated on our intensive care unit before transplantation were included. patients treated on the icu before retransplant for primary graft failure were excluded from analysis. data are presented as median ( th - th percentile). wilcoxon or mann-whitney u tests were used for comparisons of paired and unpaired data, respectively. results. from january until september patients ( m, f; age ( - ) years) fulfilled inclusion criteria. cirrhosis was due to alcohol (n = ), hcv (n = ), alcohol+hcv (n = ), alpha- -antitrypsin deficiency (n = ), budd-chiari-syndrome (n = ) or cryptogenic (n = ). upon icu admission icu, apache ii scores were ( - ), sofa scores ( - ); meld ( - ). after ( - ) days on the icu, directly before transplantation, sofa scores had deteriorated in all patients to ( - ) and meld scores to ( - ). patients had renal replacement therapy and patients were on single-pass albumin dialysis. the -day-mortality was %, hospital mortality % and -year mortality %. in hospital survivors, surprisingly, sofa scores ( ( - ) vs. ( - ); p = . ) and inr ( . ( . - . ) vs. . ( . - . ); p = . ) upon admission to the icu were significantly higher than in non-survivors. there were no significant differences in age, gender, meld scores or use of extracorporeal treatment in survivors vs. non-survivors. conclusions. liver transplantation in selected cirrhotic icu-patients with multi-organ failure is not medically futile. outcome, however, is much worse than usually considered acceptable. objectives. this work tries to study the clinical profile and the results with the immediate postoperative outcome of patients suffered from pancreas-kidney transplantation (pkt) and only pancreas transplantation (pt) admitted in our intensive care unit (icu) setting. methods. prospective study during years (from to ). we recorded epidemiological, demographical and clinical data, surgical and postsurgical complications, therapy, morbidity and mortality rate, length of stay in icu, organs survival, etc. the data were expressed in mean±typical deviation, median and percentages. results. we recorded patients. table expresses some of the data. the mean age was . ± . years old male . %. pkt from unic deceased donor: %. pt: %. the mean ischemia time was . ± . h for the kidney and . ± . for the pancreas. the most frequent surgical complications were bleeding ( . %), technical difficulties ( . %) and anesthetic complications ( . %). postoperative immunosuppression consists in methyl-prednisolone, tacrolimus, mycophenolate mofetil and thymoglobulin (as our protocol recommends) and was administered to the % of the patients. prophylactic antibiotic and antiviral therapy (ampicillin, ceftriaxone, fluconazole and gancyclovir) was given to almost the % of the patients. table expresses the blood test results. the mean insulin requirements per day during the stay in icu was ( - . ) iu. table represents the complications in the icu. the first leading cause of reoperation was vascular thrombosis ( %) followed by intraabdominal bleeding ( %). conclusion. the clinical profile of this patient in our setting is a years old man, with high blood pressure, retinopathy, dialysis, pancreas-kidney transplant recipient, with unic decesed-donor. he needs no insulin or minimal requirements. the principal complication is pancreatic vascular thrombosis that frecuently leads to removal of the graft. ( ) . in a clinical practice, a specific marker to evaluate and predict ischemic-reperfusion injury in liver transplantation (olt) is not available. poor organ perfusion and high pct levels appeared to predict early graft failure only in the cardiac donor ( ) . objectives. we evaluated pct as a predictor of ischemic-reperfusion injury in liver transplantation and pdr, as a predictor of complication and graft outcome. methods. prospective study. patients (age, child-pugh score, aetiology of liver cirrhosis) undergo liver transplant. bilirubin levels and pdr ( . mg/kg of ig in a central catheter with limon system Ò , pulsion medical system, munchen, germany) was measured once a day for postoperative days (pod). on the same day, aspartate aminotransferase (ast/gpt) and alanine aminotransferase (alt/got) were measured. sofa score was as a patient severity score. serum level of pct, c-reactive protein (crp) was collected at the liver reperfusion time and from the st to the rd pod. warm and cold ischemia time was collected. statistical analysis was performed with wilcoxon, spearman tests (p \ . ). linear correlation was performed too. a small rise on pct levels were observed early after olt, with a peak in the st day after olt. it was associated neither with hepatic post-olt dysfunction nor with other non infective complications. pct increased significantly after liver reperfusion (p \ . ) and correlate with pdr on the nd pod, but not correlation were found with crp, white blood cells, or liver enzymes after olt. crp levels increased rapidly after olt. pct increasing after liver reperfusion correlated with child-pugh olt (r = . at nd pod) in the recipients. the cold ischemia time did not correlate with pct serum levels after liver reperfusion as well as the warm ischemia time. a negative correlation was found between pdr and liver function in the recipient. pdr did not correlate with child-pugh score. the cold ischemia time well correlated with ast and alt on the first day after transplant (r = . ). it negatively correlate with pdr (r = - . ) at the same time. the warm ischemia time did not correlate with pdr, ast and alt. the same results were found between pdr and liver enzymes and lactates. no correlation was found between pdr and sofa score. conclusions. pct peak in the recipient at reperfusion and early post operative was not predictive of graft dysfunction or other non infective complication. it may represent a marker of ischemia-reperfusion injury. crp levels increased rapidly after olt and it could be an expression of surgical procedure, and it doesn't correlate with pct. objectives. the aim of this prospective observational study was to describe the kinetics of ngal following renal transplantation and to assess its ability to predict delayed graft function. introduction. lung transplantation is the recognized therapy for end-stage respiratory failure. many serious medical complications have been described occurring from months to years after lung transplantation, often necessitating admission to an intensive care unit (icu), which has been associated with a high mortality. we examined the factors associated with mortality. methods. all patients admitted to the general intensive care unit between and following lung transplantation were included in this retrospective study. data was collected regarding demographic parameters, intensive care unit stay and outcome. over the study period, forty patients were admitted to the icu. the main pretransplant diagnosis was idiopathic pulmonary fibrosis followed by chronic obstructive pulmonary disease. the majority ( %) of patients required mechanical ventilation during their icu stay. the main reason for icu admission was septic shock in patients ( %) of cases. an organism was isolated from of these patients; in cases, the organism was shown to be multi-drug resistant. the icu mortality was . %. non-survivors were characterized by a higher admission sofa score (p = . ), an admission diagnosis of sepsis ( . vs. . % for all other diagnoses, p \ . ), and a requirement for mechanical ventilation (p = . ). in addition, the incidence of chronic rejection was significantly higher in the non-survivors (p = . ). conclusions. severe sepsis remains the most important factor associated with a poor outcome. new strategies are required to alter the course of this common complication of lung transplantation. (the % of the infections were respiratory) and ( %) patients presented pulmonary allograft rejection. according to our immunosuppressive protocol, we started with methylprednisolone and tacrolimus and we added mycophenolate later. the ccd length of stay was ( - ) days and the median days of mechanical ventilation were ( - ). thirteen ( %) patients died, basically due to refractory respiratory failure, multiple organ dysfunction syndrome and haemorragic shock. conclusions. in our large series of lung transplantation a remarkable incidence of complications has been observed. despite this complications, lung transplanted patients presented an excellent short term outcomes. introduction. acute kidney injury (aki) poses a massive challenge after kidney transplantation, especially when kidneys from brain dead adult donors are transplanted into small paediatric recipients. inflammation mediated by cytokines is a key event in experimental models of ischaemic aki. objectives. the aim of this study was to investigate whether remote ischaemic preconditioning (ripc) reduced the inflammatory cytokine load and apoptosis in the kidney after transplantation. methods. kidneys were harvested from eight -kg brain dead donor pigs and transplanted into two groups of -kg recipient pigs after h of cold ischaemia. in one group (+ripc, n = ) ripc was performed before the -h reperfusion period, while no ripc was performed in the other group (-ripc, n = ). non transplanted kidneys from brain dead pigs served as controls. concentrations of tnf-a, il- , il- , and il- in renal tissue were determined by an immuofluorometric assay. renal apoptosis was quantified by immunohistochemistry for activated caspase- . high concentrations of tnf-a, il- , il- , and il- were detected in renal cortex in all three groups. no statistical differences between the two transplanted groups were found for any of the cytokines. compared to controls higher cortical levels of il- (control vs. -ripc, p = . , control vs. +ripc, p = . ) and lower levels of il- (control vs. -ripc, p = . , control vs. +ripc, p = . ) were found in transplanted kidneys. no differences were detected for tnf-a or il- . transplantation significantly increased the number of apoptotic cells in both glomeruli and tubuli (control vs. -ripc, p = . , control vs. +ripc, p = . ). no difference was found between recipients, (p = . ). conclusions. in transplanted kidneys from brain dead donors exposed to h of cold ischemia and ±ripc, we found increased tubular and glomerular apoptosis, but no increase in pro-inflammatory cytokines. the levels of il- were higher in transplanted kidneys compared to controls. remote ischaemic preconditioning did not modify cytokine load or apoptosis in the kidney graft. objectives. we present the case of a patient with confirmed hit and the management of its status during the perioperative period of the cardiac transplantation. a years old patient with a cardiac myxoma was operated under heparin anticoagulation. thrombocytopenia is noted at day after surgery. an enzymelinked immunosorbent assay (elisa) was performed and since the result was positive, the treatment was changed to lepirudin. the hit was confirmed by a heparin-induced platelet activation (hipa) test. the internal jugular vein thrombosis was observed. the post operative evolution was marked by the necessity of the implantation of a ventricular assisted device. the patient was submitted to two sessions of plasmapheresis which turned the antibodies negative. the patient underwent heparin anticoagulation during the surgery time and bivalirudin as the post operative treatment. the antibodies remained negative. two months later, the cardiac transplantation was performed; heparin was used for anticoagulation during surgery. due to a restored renal function, danaparoid was used postoperatively. conclusions. hit is a serious complication of heparin therapy. the diagnosis is difficult. when hit is strongly suspected, a non-heparin anticoagulant is recommended. the choice of the anticoagulant depends on the hepatic and renal function. plasmapheresis is a solution for the antibody purging prior to cardiac surgery. objectives and methods. a nationwide qualitative study investigating their perception of the meaning of professionalism, and how they learn to behave professionally was performed. all eight dutch icm training centres participated. the moderator asked participants to clarify the terms professionalism and professional behaviour. next, participants were asked to explore the questions 'how do you learn the mentioned items?' and 'what ways of learning do you find useful or superfluous?' qualitative data analysis software (maxqda ) facilitated analysis: an inductive approach applying open, axial and selective coding principles was used. results. fellows across eight groups participated. results relating to the subtopics 'elements of professionalism' and 'teaching and learning of professionalism' are described consecutively. elements of professionalism relevant to intensivists: the elements most frequently addressed were communication, keeping distance and boundaries, medical knowledge and expertise, respect, teamwork, leadership and organization and management. medical knowledge, expertise and technical skills seem to become more tacit when training progresses, and relate to ethical, cultural and legal dilemmas originating in the specific icu context, and working as a multidisciplinary icu team member. teaching and learning professionalism: topics can be categorised into the themes workplacebased learning, by gathering practical experience, by following examples and receiving feedback on their actions, including learning from own and others' mistakes. formal teaching courses (e.g. communication) and scheduled sessions addressing professionalism aspects were also valued. conclusions. the emerging elements considered most relevant for intensivists were adequate communication skills, and keeping boundaries with patients and relatives. the specific icm context, and working as multidisciplinary icu team member substantially influenced the icm fellows' perception of professionalism. whereas medical knowledge, expertise and technical skills seem to become more tacit when training progresses, professionalism issues continue to be learned during icm training. professionalism is herein mainly learned 'on the job' from role models. formal teaching courses and sessions addressing professionalism aspects were nevertheless valued, and learning from own and others' mistakes was considered especially useful. selfreflection as a starting point for learning professionalism was stressed. the latter can e.g. be stimulated by means of assessment, structured feedback and use of portfolios, for which guidelines are now being developed within the cobatrice project. introduction: during the past decades there has been an increase in mass casualty events with changing geopolitical and climate situations. in a mass casualty event comprehensive care for the individual is expected [ ] . to meet these obligations further education in disaster medicine seems obligate [ ] . therefore the german home department responsible for mass casualties passed a concept for student education in disaster medicine [ ] . objectives. the introduction of a summer academy ''disaster medicine'' (sadm) is a first approach at charité university of berlin to establish a curriculum for disaster medicine. the sadm is sponsored by the german academic exchange service (daad) for years. the enhancement of student education in disaster medicine is supposed to raise the level of skills and knowledge of future physicians in the face of mass casualties [ ] . international participants and an interdisciplinary approach are keystones of the sadm concepts. in a globalized world international networking should enable students to exchange knowledge about the handling of mass casualties in different parts of the world. disaster medicine needs an interdisciplinary approach [ , ] . psychological aspects are always a key factor in the successful handling of mass casualties. the teaching concept of sadm consists of four parts: e-learning ahead of a week training session, emergency medicine training, disaster medicine training and excursions to evaluate already existing disaster concepts. the concept will be evaluated [ ] using a knowledge test, a skills test and a structured written interview concerning motivation and satisfaction of the students. conclusion. the support of the daad for three consecutive years allows a further evolution of this concept by integrating the evaluation results. the sadm should enable future physicians to meet the challenges of mass casualties with greater confidence and skills. educational programs are being set up to provide training and skills in these core subjects for dental care professionals. objectives. to evaluate dental practitioner (dp) skills and knowledge prior to a day continuous medical education (cme) training session, and assess training efficacy at the end of the session. methods. nine ( ) multiple choice questions concerning medical emergencies and pain treatment were handed out to dps at the beginning of cme training sessions over a year period in metropolitan france. after the day training session, the same multiple choice was taken again and collected for statistical analysis (kruskall-wallis test). examination before and after cme, p \ . we evaluated dps and obtained a % answering rate. before the cme session, the correct answer rate was below % for several items, like the european emergency telephone number or performing back blows before the heimlich manoeuver for severe choking, and below % for identifying vasovagal malaise by bradycardia, giving insulin for diabetic malaise or treating anaphylactic shock by epinephrine. more worrisome still is the fact that nearly out of dps would prescribe non steroidal anti inflammatory drugs (nsaids) during late pregnancy. the overall impact of cme was highly significant (p \ . ), showing real efficacy but correct answering rates after cme still remained between and %, which leaves room for improvement. further studies are under way to evaluate long term memorization of cme sessions in order to determine their optimal frequency. conclusions. medical skill and proficiency evaluation before cme training sessions for dps allows to target the training sessions and to evaluate their efficacy in the short run. introduction. the positive impact of immediate bedside echocardiography for rapid diagnosis and management of acute hemodynamic disturbances in the critically ill patient is well established. it is advocated that peri-resuscitation echocardiography should be an integral part of training for all intensivists. however, a major challenge for the intensive care clinician is access to appropriate echocardiography training outside of specific fellowship programmes. objectives. one suggestion to meet this training need is to combine supervised practical instruction with self-learning through the use of on-line educational tools. the internet is ideally suited to studying echocardiography as e-tutorials serve to convey theoretical principles whilst stills/video clips aid image recognition and interpretation. here we review currently available web based learning resources. methods. an online search was performed using google Ò and yahoo Ò search engines with the following key words: echocardiography, tte, toe, education, training, programme, courses, on-line, web-based, critical care. the resulting hits were screened to identify relevant sites and these were then evaluated independently by each author before an overall consensus was reached. one author had no previous echocardiography training whilst the other had passed the american national board of echocardiography perioperative transesophageal echocardiography examination. a total of sites were identified for evaluation (see table ); these are listed below with a brief description. conclusions. our search demonstrated a number of sites dedicated to facilitating echocardiography training. these varied from those which were essentially atlases, to those with a modular learning programme supported by interactive discussions and self assessment. some were targeted at the beginner seeking a basic understanding of echo whilst others were aimed at the enthusiast preparing for examinations. with growing interest in critical care ultrasound it is likely that we will see the use of such resources increasing. however echocardiography is a practical skill and it is essential that on-line learning is conducted in parallel with supervised bedside training in a process of 'blended learning'. . to determine level of supervision for trainees in the elective mri setting as compared with critical care transfers to mri. . to gain insight into the learning resources used by medical staff on mri to allow existing training to be improved. methods. two online surveys were conducted in february , with invitations to participate via e-mail. the survey population included all anaesthesia and intensive care medicine consultants in the local tertiary neurosciences centre and all trainees for these specialties in the northern ireland deanery. first year trainees were excluded. results. the response rate was % for consultants and % for trainees. in total, consultants responded with over % having no experience of mri at consultant level, even though % worked in areas where mri skills could be required. trainees completed the survey, with % having experience of mri in the elective setting, all of whom had been directly supervised by a consultant. % of trainees had experience of critical care transfers for mri, but this was in an unsupervised capacity more than % of the time. despite this, % of trainees did not feel competent to work in mri unsupervised. web based learning was found to be a poorly utilised mri training tool, particularly among consultants. conclusion. we have demonstrated a need to formalize training for mri in our institution and for trainees in the local deanery. we propose to meet this need by a combination of e-learning and experiential sessions with defined competencies. this should increase the cohort of physicians who can provide optimal care , in this unique environment and subsequently improve both service delivery and patient safety. was not a priority in health systems. following the report: ''to err is human. building a safer health system'', by the institute of medicine, which had a great impact on the media, ''patient safety'' is included as an strategic line in most health systems. training in patient safety is essential to implement safety culture and as a result improve it. for that reason we developed a training program ( courses) in for physicians and nurses from our icu. objetive. patient safety training program assessment. methods. we designed a h course ( % practical), using simulated scenarios common in icu clinical practice. we pointed out the relevance of human factors such as teamwork and communication, and its leading role in the genesis of error. we discussed a ''sentinel case'', using the root-cause analysis method, and analysed an icu process through failure mode and effects technique. adverse events reported to the department website were reviewed. participants and instructors discussed specific aspects about insertion of central venous catheter, prevention of nosocomial infection and improvement of security in the different groups of icu patients, highlighting the need for fidelity to the established protocols for this purpose. finally, participants completed a survey that assessed various aspects in a score from to . results indicated the most and least interesting aspects and suggestions for improvement were included. results. assessment surveys were analysed. participation rate was %. overall results: appropriate and clear targets, accomplished goals and utility ( . ) , appropriate content objectives and organization ( . ) , time invested in development activity and oral presentations ( . ), faculty competence ( . ) , interest and faculty adaptability to the group needs ( . ), degree of satisfaction and practices ( . ) . most interesting comments: practice of root-cause analysis ( . %), continued participation and motivation ( . %), practices with hps and group discussions ( . %), importance of human factors ( %), theory and practice good balance ( . %). least interesting comments: too condensed contents ( . %), few scenarios ( . %)suggestions: do it again( . %), enhance preventive medicine sessions ( . %), increase course duration ( . %). conclusions. overall assessment was positive. adaptability and competence of teaching staff have been the most valued aspects; too condensed contents and oral presentations were the least valued. practice of root-cause analysis ease of participation, ongoing motivation, hps scenarios and group discussions are the most appreciated activities. final comment: good acceptance has encouraged us to continue in to complete participation of all interested professionals. introduction. our intensive care unit (icu) was one of the first to initiate a humanization program in daily routine in . since then, the program suffered changes, the icu grew up in number of beds and complexity and had great renewal of the members of our interdisciplinary group. objectives. to improve our knowledge we continually re-evaluated the stress factors for the patients from our staff members' perspective, putting them in the patients place. methods. between january and march of , a research form was used with the interdisciplinary icu team. the following items were analyzed: profile of the interviewed, evaluation of the environment of the icu and the stress factors for the patients. the results were compared with the questionnaire form filled by the patients after icu discharge, as a part of our quality improvement program. results. about . % of our icu team answered the research (n = ). the mean age is . years (sd . ), . % of female, . % married, . % protestants and . % catholics and icu professional experience of . years (sd . ). our icu is noisy for . %, very illuminated for . %, easy-going for . %, organized for . %. in a preview research we found closed results. according to the team, factors that bother the patients are: noise ( . %), bed bath ( . %), loneliness ( . %), lack of privacy ( . %), anxiety ( . %), distortion of time perceptions ( . %) and fear ( . %). the patients (n = ) described as main complaints after icu discharged: distortion of perceptions of time ( . %), anxiety ( . %), sleeplessness ( . %), noise ( . %), loneliness ( . %), fear ( . %), pain ( . %)bed bath ( . %) and lack of privacy ( . %). the study showed differences of icu team opinions and the patients' complaints. when the team is placed in the patient's perspective they may experience a better view of how harmful is an icu and how much we can do to improve it. this is our daily challenge: take care with quality, respect, affection and always search for improvement. introduction. endotracheal intubation is a routine procedure to protect the airway in critical care, that is performed by a wide variety of clinicians from different specialities with different levels of experience in airway management. serious complications can result from misplacement of an endotracheal tube (ett) in a main stem bronchus. a widely recommended method for the prevention of this complication is bilateral auscultation of the lungs; but this method frequently provides only inconclusive results ( ) . other routinely used tests to verify correct endotracheal tube placement include observation of symmetric chest movements, and inserting the ett to a specific depth, but it remains unclear which of these tests detects endobronchial intubation best. objectives. we therefore designed this study to determine which bedside method has the highest sensitivity and specificity for detecting endobronchial intubation in adults and whether sensitivity and specificity increases as a function of the anesthesiologist's experience. methods. surgical patients were randomized to two study groups. in the first, the ett was fiberoptically positioned . - -cm above the carina, whereas in the second group the tube was positioned in the right main stem bronchus. first year residents and experienced anesthesiologists randomly performed only one of the following tests to verify the position of the tube: ) bilateral auscultation of the chest (auscultation); ) observation and palpation of symmetric chest movements (observation); ) estimating the position of the ett by the insertion depth (tube depth); and, ) a combination of all three mentioned tests (all three). results. patients ( female/ male) with observations by experienced and inexperienced anesthesiologists were included in the study. tube depth and all three had a higher sensitivity ( . and ) in detecting endobronchial intubation than auscultation ( . ) and observation ( . ) (p \ . ). experience increased the sensitivity only for auscultation, with % of first year residents versus % of experienced anesthesiologists detecting endobronchial intubation by auscultation correctly. the optimal ett insertion depth was found to be cm in women and cm in men. we conclude that auscultation alone is inadequate for assessment of correct ett insertion depth, and that checking for symmetric chest movements is of little use. our results suggest that the hierarchy of the methods used to assess the correct ett insertion depth should be changed and that clinicians should rely more on depth of ett insertion than on auscultation. this is especially true for physicians with less experience in airway management and in situations where auscultation is difficult or impossible. min usa) , uses a new probe measuring hemoglobin saturation at a lesser depth ( vs. mm before), with more data output ( value/ s vs. value/ . s). the new device contains automated software to compute parameters such as occlusion and reperfusion slopes of sto obtained during and after a vascular occlusion test (vot). objectives. to compare nirs parameters obtained with the devices used simultaneously in healthy volunteers and critical care patients to test if the new device gave similar results than the older one. methods. micro-oxygenation parameters were collected simultaneously with the different nirs models, one on each thenar eminence, before (baseline) and during a min upper arm (brachial artery) vot in patients ( septic shock (g ), trauma (g )), compared to healthy volunteers (hv)(g ). nirs probes were then shifted to the contra lateral thenar eminence and a second vot was performed. sto occlusion and reperfusion slopes from both devices were calculated in all groups by the same software, using linear adjustment (r c . to be valid); p \ . was considered significant. following parameters were collected in patients: saps ii and sofa scores, macrohemodynamic (heart rate (hr), mean arterial pressure (map), central venous pressure (cvp), cardiac output (co) and svo (mixed venous o saturation) or scvo ), and metabolic parameters (ph, base excess, and lactate). results. median ± iqr. patients (g and g ) did not differ for macrohemodynamic or metabolic data, except map ( ( - )mmhg vs. ( - )mmhg; p = . ). baseline nirs sto values were similar for both groups and for both devices, but were lower than in hv. during vot, reperfusion slopes were also lower in patients than in hv regardless the device used. the minimum sto during vot, occlusion and reperfusion slopes were significantly different between the devices: intraclass correlation coefficient (icc) . , . and . , respectively, and bland and altman poor agreement and large bias. conclusions. data obtained with model largely differ from those obtained with model , regardless of the studied population for both sto baseline and slopes. these differences appeared more pronounced in hv than in patients. such differences may result from muscle depth, number of data output allowing to more precise linear adjustment, or the minimum value reached during occlusion. it becomes hazardous to compare data obtained with these devices either in hv or in critically ill patients. crrt is used increasingly for the management of acute renal failure in critically ill patients. one major problem with crrt is coagulation of the filters, leading to decreased efficacy and increased costs. regional anticoagulation with citrate is an effective and established form of anticoagulation during crrt in critically ill patients ( , ) . objectives. the aim of this study was to investigate the filter life span during regional anticoagulation with citrate and regarding cost effectiveness. methods. this observational, retrospective study was performed in a mixed surgical and trauma icu in a university hospital. clinical characteristics are shown in table . citrate crrt was performed using commercially available equipment and fluid solutions (multifiltrate Ò with integrated cica Ò -system; fresenius medical care; germany). to maintain stable metabolic and hemodynamic conditions we used an internal standard protocol for citrate crrt. reimbursement for crrt is calculated on procedure related rates (according to german drg). data are shown as mean or median and standard deviation. results. f patients treated with citrate crrt from april through december were evaluated ( table ). the mean circuit lifetime of crrt for all patients was ± h (fig. ) . mean daily costs per patient were calculated as eur and mean benefit for crrt as eur (table ) . commercially available interstitial glucose sensors have already been evaluated for this purpose with promising results. however, because of the range of medications administered in the icu, potential interference with sensor performance must be characterized. to minimize the undesired offset caused by these medications, an interference rejection membrane (irm) was uniquely developed for a new subcutaneous glucose sensor for in-hospital monitoring. the novel irm was studied within the icu setting to gain a realistic picture of its performance in clinical use. objectives. acetaminophen is known to be an interfering agent for electrochemical sensors. to study the functionality of the new irm, the effect of acetaminophen on sensors worn by critically ill patients was assessed. sensor signals were characterized to identify any undesired response from the medication. methods. icu patients simultaneously wore - -day sensors that were connected to ipro tm (medtronic diabetes, northridge, ca) recorders to gather blinded sensor glucose values. patients were given acetaminophen or a mix of hydrocodone and acetaminophen during their icu stays; staff charted the exact time of each medication administration. to assess whether a signal offset would be introduced by the acetaminophen, min of sensor signals before and after medication administration were compared. the period of min was chosen based on acetaminophen's pharmacokinetic profile and the time to reach maximal plasma concentration. the normalized medians for the signal segments before and after each acetaminophen delivery were calculated. the medians formed vectors, each with elements representing signal characteristics before and after the medication deliveries. a paired t test was used to compare the vectors and assess for any effect (p \ . ) on sensor performance. across the patients evaluated for this study, acetaminophen and a mix of hydrocodone and acetaminophen were administered a total of times. one sensor was not available during a medication delivery; thus, occurrences of acetaminophen administration were analyzed. no effect on sensor signals could be identified in the instances of acetaminophen delivery. no statistically significant difference was observed between the signal segments before and after administration (p [ . ). conclusions. this study demonstrates that a novel irm effectively reduces the undesired interference of acetaminophen on a continuous glucose sensor signal during clinical use. although this analysis was focused on acetaminophen, the outcome suggests that the irm may also effectively suppress interferences from other medications administered in the icu. [ ] . however, assessing elastance requires a highly invasive vena-cava occlusion maneuver and left and right ventricle pressure/volume waveforms, which are not typically available in an intensive care unit (icu) and may raise ethical issues in regular use. a validated, lumped-parameter chamber cardiovascular system (cvs) model is used to evaluate a time-varying elastance estimate at the bedside using standard clinical measurements. objectives. to assess time-varying elastance at the bedside for the left and right ventricles using available icu data, and prove the concept on a porcine model of pulmonary embolism. five pigs had pulmonary embolism (pe) induced via injection of blood clots over h, developing full pe in stages from a healthy state. at each state several data sets were taken ( in total over pigs), measuring aortic and pulmonary artery pressure waveforms (p ao (t), p pa (t)), left and right ventricular volume and pressure waveforms (vlv(t), vrv(t), plv(t), prv(t)). at each cardiac state in inducing pe, the time-varying elastances are estimated as elv = plv/ vlv and erv = prv/vrv. these values are correlated to readily measured quantities (pao and gedv). these correlations are used to approximate time-varying elastances erv* and elv* for use in a clinically validated -chamber cvs model. note these approximations are load dependent and thus change with cardiac state. a fivefold cross validation was used to validate the model. a time-varying elastance is generated from data from pigs and used to simulate the fifth pig. simulated pv loops are compared to the originally measured pv loops to validate the approach. results. p ao (t) and elv were highly correlated over the data sets (r = . to r = . ). p ao (t) and elv, gedv and erv are also well correlated (r = . to r = . in this case we report the worldwide first use of the novel deltastream-dp -system (medos corp.) in a patient suffering from acute right heart failure due to pulmonary embolism following cardiac surgery. in a year-old male patient days after mitral valve reconstruction cardiac arrest occurred during physiotherapy treatment. after failure of restoring circulation, a short-term ecls system (lifebridge Ò ) was implanted under cardiopulmonary resuscitation by inserting cannulas in venous and arterial femoral vessels and then switched immediately to the dp -deltastream system. ct-scan revealed the diagnosis of a massive central pulmonary embolism. transesophageal echocardiography showed a dilated failing right ventricle. a thrombolytic therapy was carried out by administering mg alteplase. following ct-scan showed reduced thrombus burden. the deltastream system was carried out for h. ptt was maintained to . -fold under i.v. heparine therapy. pump blood flow was held at a maximum of . l/min ( , - , r/min) for days. despite transesophageal echocardiography showing improved left ventricular function the ecls flow was maintained for further days focussed on the improvement of right heart. further on the pump flow was reduced every h and the system could be explanted after days in now stable cardiolpulmonary situation. the patient was discharged on day at home in good state without any neurological dysfunction. overall duration of the ecls deltastream therapy was h. no system related major complication occurred during the time. even in maximum blood flow of . l/min no relevant hemolysis was measured. ldh level was only slightly elevated to - u/l. introduction. airway management has progressed dramatically in the last years but the most significant advance has been video laryngoscopy. several devices have been introduced since, the most important currently available are the glidescope Ò , c-mac Ò , mcgrath Ò , pentax airway scope Ò , airtraq Ò , among others. a common practice has been to abandon direct laryngoscope intubation (dli) after attempts and move onto advance airway devices such as video laryngoscopy which is becoming the first choice when available. although dli is successful in the majority of patients, poor glottic exposure is more likely to require prolonged or multiple intubations attempts and therefore be associated with complications such as oxygen desaturation or airway and dental injuries. in the intensive care environment an airway should always be considered a difficult airway due to scarce time to perform assessment, to make decisions and to act. should the use of video laryngoscopy be implemented as a routine for airway management in a critical care setting ? objectives. the purpose in this study was to describe for the first time the use of video laryngoscopy, specifically the vel , as a routine choice for airway management in the intensive care environment. single center, prospective observational study, from november to february , was conducted in our intensive care facility, which involved utilization of the vel for all tracheal intubations, no exclusion criteria, rapid sequence intubation (rsi) was the standard procedure. information was recorded by the operator assistant on the same day identifying timings of intubation, number of attempts, success or failure and the difficulties encountered. vel was developed in our institution in and later adopted as a standard airway management by the department of anesthesia. the device has an original mccoy blade with an attached port that holds a channel for the displacement of an optical shaft mm long, . mm in diameter with a °angle view (tekno-medical Ò germany) which is assemble to a video camera (telecandx ii, karl storz, germany), an external light source and to a -in monitor. results. there were tracheal intubations performed by operators, crash intubations and rapid sequence intubations. all intubation attempts were successful, mean number of attempts . the median time to successful intubation was s with no complications. subjective assessment post intubation showed that in all cases vocal cords were view in full, all operators manifested to feel comfortable with the handling of the apparatus but felt dependent on a assistant specially to maintain view while maneuvering the endotracheal tube. conclusions. routine airway management with vel in critical care setting is effective with a high rate of success and most important, with a positive impact for patient safety. introduction. hypovolemia is a common complication in many clinical scenarios and its detection is considered of prime importance. in previous clinical studies, tissue oxygen saturation (sto ) measured by near-infrared spectroscopy (nirs) has been explored for this purpose; however, results are disappointing. it has been suggested that the sensitivity of nirs for detection of hypovolemia might be improved when nirs is applied in combination with a vascular occlusion test (vot). nirs in combination with a vot, consisting of a -min period of arterial occlusion followed by reperfusion, allows quantification of muscle deoxygenation during ischemia (sto downslope; a measure of muscle oxygen consumption rate) and muscle reoxygenation after ischemia (sto upslope; a measure of microvascular reperfusion rate). objectives. in the present study we applied multi-site and multi-depth nirs in combination with a vot in a model of simulated central hypovolemia; lower body negative pressure (lbnp). eight healthy male subjects, with a mean ± sd age of ± years, participated in this study. the lbnp protocol consisted of a stepwise increase of lbnp from to - mmhg. stroke volume (sv), heart rate (hr), cardiac output (co), and mean arterial pressure (map) were continuously measured using near-infrared finger plethysmography (nexfin). multi-depth nirs, with probing depths * and * mm, was performed on forearm and thenar for the measurement of sto . three-min vots were performed by rapidly inflating a pneumatic cuff around the left upper arm before application of lbnp and at lbnp = - mmhg. vot-derived sto traces were analyzed for baseline, downslope, and upslope. . from baseline to lbnp = - mmhg, sv decreased from ± to ± ml (p \ . ), hr increased from ± to ± bpm (p \ . ) and co and map were maintained around baseline level. forearm sto baseline decreased significantly from ± to ± (p \ . ) and ± to ± % (p \ . ) for the and mm probing depth, respectively. forearms sto downslope, measured with the and mm probe, decreased from - . ± . to - . ± . %/min (p \ . ) and - . ± . to - . ± . (p \ . ), respectively. forearm sto upslopes remained unchanged during lbnp. vot-derived sto parameters measured on the thenar did not shown any changes as a result of lbnp. conclusions. vot-derived sto parameters measured on the forearm seem to be more sensitive to the hemodynamic changes associated with lbnp compared to sto parameters measured at the thenar. grant acknowledgment. this project was supported in part by hutchinson technologies inc. introduction. hypovolemia is a common complication in many clinical scenarios and its detection is considered of prime importance. in previous clinical studies, near-infrared spectroscopy (nirs) has been explored for this purpose; however results are conflicting due to inconsistencies in methodology with respect to nirs probing depth and site. objectives. in the present study we applied multi-site and multi-depth nirs in a model of simulated central hypovolemia; lower body negative pressure (lbnp). fifteen healthy male subjects, with a mean ± sd age of ± years, participated in this study. the lbnp protocol consisted of a stepwise increase of lbnp from to - mmhg. stroke volume (sv), heart rate (hr), cardiac output (co), and mean arterial pressure (map) were continuously measured using near-infrared finger plethysmography (nexfin). multi-depth nirs, with probing depths * and * mm, was performed on forearm and thenar for the measurement of tissue oxygen saturation (sto ). . from baseline to lbnp = - mmhg, sv decreased from ± to ± ml (p\ . ), hr increased from ± to ± bpm (p \ . ), and co and map were maintained around baseline level. forearm sto decreased significantly from ± . to ± . % (p \ . ) and ± . to ± . % (p \ . ) for the and mm probing depth, respectively. thenar sto measured with the mm probe remained unchanged, but measured with the mm probe, a decrease from ± . to ± . % (p \ . ) could be observed. conclusions. forearm sto seems to be more sensitive to (simulated) hypovolemia compared to thenar sto and the sensitivity of nirs seems to increase for increasing probing depth. grant acknowledgment. this project was supported in part by hutchinson technologies inc. introduction. sidestream dark field (sdf) is a microcirculatory imaging modality implemented in a hand-held microscope for the non-invasive bed-side visualization of the human microcirculation. despite the many studies showing the importance of microcirculatory imaging in intensive care patients the introduction of sdf imaging into routine clinical practice remains cumbersome. one of the challenges is the need for automatic analysis of the images which currently is subjective and time consuming. objectives. in the present study, we introduce a rapid automated software method for automatic quantification of microvascular density, a key microcirculatory parameter, based on sdf image contrast analysis. methods. twenty-five sequential sdf images (duration = s, resolution = pixels) were isolated from an sdf movie clip, stabilized, and averaged. subsequently, the mean ± sd gray scale intensity in a sliding pixel window was calculated and the sdvalue was assigned to the window center pixel, creating an sdf contrast image. this is a simple and rapid algorithm for vessel wall detection as a pixel window at a tissue-vessel junction will have a high sd-value due to the presence of both light tissue cells and dark red blood cells. conclusions. here, we introduce and validate a rapid automated method for quantification of microvascular density in sdf images. as this algorithm detects vessel walls rather than vessel lumen, smaller and larger vessels have similar contribution to the microvascular density assessment. a limitation, however, is that vessel diameters cannot be detected with this algorithm. the preliminary results confirm the proof of concept of the sdf image contrast analysis software, however, further research is required for its optimization. the criteria believed to be necessary for the implementation of hcs in practice were that his name would be written{ ( )}, the document dated{ ( )} and signed{ ( )}. physicians in private practice wanted date(p = . ) and signature(p = . ) more often than in institution. ( ) physicians thought that the patient must be competent at the designation' time of hcs, especially those who possess advances directives(p = . ) and a hcs(p = . ) themselves. ( ) thought the hcs should know about the patient's wishes regarding treatment and care objectives. conclusions: more than / of physicians did not know who the hcs is. more than / thought hcs useful and at least / would encourage a patient to designate one before heart surgery. about % thought that being a hcs is a too high responsibility and that the hcs could not be the best representative when needed. the potential fear this topic might induce is a barrier for this minority. introduction. the use of a daily goals chart has been shown to improve communication between the multi-disciplinary team leading to an increase in understanding of daily patient goals and a decrease in length of patient stay on the intensive care unit (icu) [ ] . we have used a daily goals chart on our icu since . we wanted to assess the value of this initiative in a general adult icu. methods. the royal cornwall hospital is a large uk district general hospital. we conducted the survey over a week period in the icu. each day, after the morning multidisciplinary ward round, the consultant in charge was asked to give the main goals for each patient. these were compared with those written on the daily goal chart, or stated by the house medical and nursing staff. they were graded as complete match ( % of consultant goals matched), partial match ( - % matched) or non match (\ % matched). results. surveys were conducted. the daily goals sheet matched the consultant completely on ( %) occasions and partially on ( %) occasions. in comparison, the combination of house medical and nursing staff had complete match on ( %) occasions and partial match on ( %) occasions. house medical staff had a % complete or partial match, house nursing staff had a % complete or partial match. overall house staff understanding of the goals set on the ward round is far better than that recorded on the goals chart. the goals related by medical and nursing staff showed differences that reflected their differing clinical priorities. combining results of all staff led to higher levels of complete match than either group independently. low levels of non-matches indicate that there is good overall understanding and communication within the team. use of daily goals charts is an effective aid to augment communication on the icu multidisciplinary ward round. objectives. to assess the effectiveness of an icu diary on post-icu psychological symptoms of patients (pts) and their families. single centre prospective study. three periods: = control ( to / ), = diary ( / to / ), = control ( / to / ). all the pts admitted c days for the first time to our medical-surgical icu were included. during the intervention period, the diary was filled both by the caregivers and the pts' relatives, without directives except for the first (medical summary) and the last (recovery wishes) ones. at icu discharge, their families were asked to fill a satisfaction questionnaire (ccfni) and the hospital anxiety and depression scale (hads), and to be contacted by phone to assess peri traumatic stress disorders [dissociation and impact of event scale-revised (ies-r)], hads at months and year after icu discharge. we excluded pts if they or their family refused to participate, were not fluent in french, or if their family was not present around the day of icu discharge. the optimal theoretical content of the diary was determined by a delphi technique involving a panel of icu and non-icu caregivers and a voluntary visitor. the content of the diaries was analysed and linked to the outcome measurements. of the admitted patients, were included. after exclusion of pts, formed the basis of the study. the content of diaries and the results of ies-r are under analysis. the year data is not yet available the saps ii at admission, icu and months post icu mortality were not significantly different between the three periods. the family satisfaction score was high and was not significantly different between the three periods. included: patients with failure of two or more organs in the first h, admitted to icu during . excluded: neurocritical and politrauma patients. contact year following discharge from; questions were asked about the patients' different perceptions during their stay in icu. if it was not possible to contact the patient, the next of kin was asked. results. patients included. general characteristics during admittance to icu: % male; age . ± . ; sofa * ± . ; apache ** ii . ± . ; apache ** iv ± . ; length of stay in icu: . ± . days; . % on invasive mechanical ventilation and . % on non-invasive mechanical ventilation. data collection was carried out over a period of ± . months, on average months (range: - months). . % ( patients) had died at the time of contact. the person interviewed was the patient in . % of the cases, the spouse in . % and immediate family (patient s parent/child/sibling) in . % of the cases. overall, . % do not have any memory of their stay in icu. for . %, the experience was unpleasant and for . % of patients the memory is very unpleasant. . % experienced fear, . % disorientation, . % a feeling of lack of hygiene, . % a feeling of suffocation/drowning (with the endotraqueal tubes, etc.), . % a lack of privacy (nudity, etc.) and . % pain during procedures. . % were very grateful for our phone interview. . % were satisfied with the staff. conclusions. in patients with high severity scores during their time in icu, less than half have memory of their stay after year. in those who do, the feeling of fear and disorientation predominates. to determine the occurrence of communication failures in clinical icus, identifying their main detection tools and disclosing their effects on patient condition. a prospective cohort was conducted in four icus of a -bed academic, tertiary-care urban hospital in sao paulo, brazil, enrolling critical ill patients older than years from july to august . communication failures were identified by daily direct observation of medical and nursing rounds and also by chart reviews. the association between communication failures and adverse event occurence was determined using multivariate logistic regression. results. among the enrolled admissions, as much as admissions ( %) were affected by communication failures, with occurrences. the vast majority of the communication problems was not registered in patient charts, and could only be identified during the medical and nursing direct monitoring. none of the identified communication failures caused patient harm. nine out of ten communication issues involved exclusively members of the multidisciplinary icu health team, patients and their relatives being seldom included in this scenario. despite communication failures are considered important adverse event risk factors, no association was identified between these two variables. conclusions. the incorporation of direct observation as a research tool for identifying untoward events was essential to the detection of communication failures in our study. almost half of the studied admissions was affected by communication flaws, most of them involving exclusively the healthcare team. nevertheless, these figures are underestimated, since the research team remained in the studied icus for no more than h a day. although patients were not harmed fortunately, the presence of these communication issues suggests the existence of important gaps in the provision of critical care. the issue regarding communication deficiencies in icus setting affecting patient safety deserves attention. relatives of patients in the intensive care unit (icu) are exposed to considerable stress . effective communication with relatives has been shown to provide support and minimise stress whilst improving their wellbeing and decision making for critically ill patients . furthermore, satisfaction is dependent on communication by a senior caregiver . no published guideline or recommendation exists for when relatives should be first spoken to, how often they should be updated, or how these conversations should be documented. to determine how well relatives of patients in the icu are kept informed and to assess the quality of documentation. we retrospectively analysed data from the metavision Ò clinical information system of patients staying over days during / / - / / on the -bed icu at the nnuh. data obtained from the 'relatives communication' page included: when relatives were first spoken to, how often they were spoken to (according to the number of entries made) and the members of staff involved in the conversations. these variables were analysed in relation to patient outcome and length of stay on the icu. . patients were analysed. communication with relatives was not documented in % of patients. % of communication was carried out by a consultant. discussions were more likely to occur with relatives of patients who died; % compared to % of patients discharged to the ward. similarly, relatives of patients who died were spoken to more frequently; % were talked to on more than one occasion compared to % of patients surviving to discharge. relatives were more likely to be spoken to with an increased duration of admission on the icu; communication occurred with only half the relatives of patients staying - days, compared to % of those staying more than days. two-thirds of relatives of patients staying more than days were not communicated with until after the fourth day of admission, although the majority of these were spoken to on numerous occasions and all were seen by a consultant. relatives of patients dying on the icu are more likely to be communicated with, and are updated more often than those of patients surviving to discharge. a delay in communication with relatives of patients staying more than days on the icu was noted, but conversations occurred more regularly and involved a consultant. we suspect that our results demonstrate a lack of documentation rather than actual communication; auditing relatives' satisfaction with communication on the icu may help clarify areas for improvement. assessment of satisfaction with the quality of care provided to patients hospitalized in intensive care units, in most cases, is transferred to the relatives of the same, given the context of the patient himself unable to speak. the diagnosis of the needs of families of critically ill patients has been the subject of several studies. aiming to assess the needs of relatives of patients admitted to the picu (polivalent intensive care unit), we conducted studies in particular through an adapted version of the questionnaire ccfni (critical care family needs inventory) developed from the adaptation made by johnson and col. ( ) and focus group. one of the needs identified in these studies was to improve information about what happens in the picu. with this in mind we designed a manual to support relatives in order to improve communication and understanding in the context of the intensive care unit. objectives. this study aims to assess the impact on the level of family satisfaction of a manual we've created. the manual is available from january to all visitors at the entrance of that unit. the questionnaire was mailed to all families who had a family member hospitalized in the picu during the year following the introduction of the manual. together followed a letter to present the study and a stamped and addressed envelope for their return. beyond the satisfaction and access to the manual or not, were collected socio-demographic data from relatives and socio-demographic and clinical data of patients. we obtained responses, representing % of all potential families. questionnaires were returned because of address failure ( . %). statistical analysis was performed using spss Ò v. . results. the satisfaction of family members who had access to the manual was better in all dimensions tested (support, comfort, information, access, trust), and with a statistically significant difference (p \ . ). this difference was clearer in the fields support (med , / . ) and information ( . / . ). conclusions. the impact of the manual on the improvement of family satisfaction was positive in the various dimensions assessed. the questionnaire of family satisfaction monitoring and understanding of information given through a manual created by us can contribute to a better understanding of the needs of families and hence for the continued improvement of service quality. johnson introduction. the burnout can be defined in its multidimensionality: emotional exhaustion, understood as a feeling of exhaustion and failure of the person to give more of herself; depersonalization, in which the person's relationship with patients and with colleagues becomes cold, distant and guided by some cynicism, lack of personal and professional completion, which may manifest itself, on one hand, by the sense of incompetence and inability to respond to requests or, on the other hand, by the sense of omnipotence. the provision of intensive care can lead to health care provider's physical, psychological and emotional exhaustion, which may develop to burnout. we notice the absence of specific studies on this syndrome, in portuguese intensive care units. objectives. the study here presented intend to identify the levels of burnout of physicians and nurses working in portuguese intensive care (adult polyvalent units in the north of the country), and to identify factors that can lead to the development of burnout in the portuguese physicians and nurses working in that setting. the methodology presented consist of application of a questionnaire for self fulfilment with items: , socio-demographic data of the study population; , experiences in the workplace; , maslach burnout inventory-general survey. for the application of methodological tools, we requested the authorization by the competent institutional bodies: the board, ethics committee and directors of services. the professionals who participated in the study were asked informed consent, whether in formal or informal. in addition, each instrument was accompanied by a cover sheet of the same. we have also done observation of the work contexts, and interviews. in this study we will focus on the results of the questionnaire. . sample: hospitals with a total of intensive care units. professionals participants in the study , physicians nurses. the mean ages of respondents , of professional experience years and of experience in intensive care were years. mbi preliminary results:distribution of levels of burnout by occupational category: at the moment, portuguese physicians and nurses who work in intensive care units seam to have medium levels of burnout, obtained through the mbi. results show higher levels at emotional exhaustion in nurses never less in general they showed higher personal and professional completion than physicians. depersonalization were higher in physicians. the results presented here underline the importance of promoting the prevention of burnout at intensive care. the development of the burnout syndrome in physicians and nurses in intensive care has serious consequences, both for themselves, or the consequences that entails for patients and their families. introduction. the hospitalization of a member of the family in the intensive care unit (icu) usually occurs in an acutely and inadvertent way, leaving little time for a family adjustment. facing the stressful situation, the family may feel disorganized, helpless and with difficulties to mobilize themselves, enabling the rise of different types of needs. the scope of those needs leads to the alleviation of tension and uncertainties that could provide to the family the stability needed to cope with the situation disease . to identify the needs of care of family members with persons admitted to the icu. methods. this is a transversal study, held in two icus (a public one and a private one) in the city of feira de santana, bahia, brazil, after approval by ethics and research committees. the relative person is understood by the person who had consanguinity ties or who was closest to the patient, who lived with him and had close relationships. relatives were interviewed when his relative was over h of hospitalization. the the brazilian adaptation of the critical care family need inventory (inefti) was used for measuring the degree of importance, once it has items distributed in five dimensions. descriptive statistics were used for analysis. the inefti reliability was satisfactory (cronbach a = . ). results. the needs of care considered most important by family members were those related to the security dimension, expressed by the items ''to know what are the chances of improvement of the patient'' ( . ± . ), ''to be informed about everything that relates to the evolution of the patient'' ( . ± . ) and ''to feel that hospital people care about the patient'' ( . ± . ). in the category information, the item ''be able to talk to the doctor everyday'' ( . ± . ) obtained more average. in the category proximity was consider more important to ''see the patient frequently'' ( . ± . ). the needs of the categories support and comfort categories showed lower scores. these results are similar to those presented by literature , , what confirms the appreciation of the family to the aspects related to the recovery of the hospitalized relative, in detriment of their own needs. conclusions. having security, information and being around its ill relative is what the families need. the security is provided by the conviction that the person receives the best care in the pharmacological, technological and human aspects, and can be perceived by the information transmitted by the team and by the proximity established in the interaction with the sick relative. a collaborative project was developed between the itu clinical staff of a large, inner city teaching hospital, palliative care clinicians and an academic department of palliative care. qualitative data collection included: (i) semi-structured interviews with staff and relatives of patients thought to be at the end of life; (ii) focus groups with staff (iii) observation of care and (iv) clinical note review. data was analysed using the framework approach to identify key themes. results. semi-structured interviews were carried out with staff and focus groups took place. a total of relatives, representing patients thought to be at the end of life, were interviewed. half the patients represented were female, with diagnoses including infection, hypoxic brain injury, malignancy and liver failure. the participants were aged - and included a range of ethnic groups and religious affiliations. non-participant observations of care took place for and clinical note review for of these patients. data from the interviews with staff describe that an existing withdrawal of treatment document was working well but could be developed further along with suggestions for amendments. the interviews with relatives, observations and review of clinical notes show key themes: communication, decision-making, patient and family needs, and symptoms and their management. through discussion at itu end of life group meetings, a consensus was reached to pilot a complex intervention comprising an amended withdrawal document; a psychosocial assessment; education and awareness-raising; palliative care team input and increased psychosocial support. the psychosocial assessment document was deemed valuable to all patients and was rolled out for all patients admitted to itu. initial evaluation shows greater staff awareness. documentation of end of life issues and the collaborative research process has improved communication between itu and palliative care staff. introduction. consumer-centric healthcare is a key component of nhs policy. when patients are critically ill, family members act as surrogates. family members alone may inform patients of events that occurred, and provide physical, emotional and socioeconomic support during rehabilitation. thus, high family satisfaction (fs) is important. the fs-icu instrument was developed in canada to quantify family satisfaction and benchmark intensive care units (icus). we have piloted and validated previously an adaptation of the fs-icu such that its language was appropriate for the uk . to date, no intervention has demonstrated improvement in the fs-icu for a critical care unit. we hypothesise that provider-driven interventions fail to recognise central issues. co-production is a framework that enables creation of parity between providers and consumers by validating both individual worth and specialised knowledge . there are no published data on the use of co-production in intensive care. we undertook to co-produce interventions targeted to improve family satisfaction. the fs-icu instrument will be used as an objective measure of their efficacy. objectives. to co-produce some interventions targeted to improve family satisfaction and to use the fs-icu instrument as an objective measure of their efficacy. methods. fs-icu questionnaire responses were used to highlight potential areas for service development. focused interviews with families provided detailed descriptions of the ''the way the icu works''. these data were used to build exercises for a workshop of service users and providers which aimed to co-produce service developments. results. fs-icu questionnaires were received over the months to april ( % response). quality and consistency of communication between icu doctors and relatives; the level of relatives' inclusion in decision-making processes; and the icu waiting room atmosphere were identified as needing improvement. four families were interviewed in detail. workshop participants included trust directors, managers, clinicians, nurses, patients and their families. proposed interventions from the workshop included: development of a non-clinical family liaison officer role with a dedicated contact number; increasing focus on managing patients' and relatives' expectations of care delivery; specific improvements to the waiting room area. intensive care patients' relatives provided a unique insight into the icu functioning that should be utilised as a resource. co-production was used to design service improvements that may not have been obvious from a provider perspective. workshop transactions were empowering for both staff members and patients' families, generating social capital that creates and improves social provider-consumer networks, now and in the future. to evaluate the degree of satisfaction of icu patients regarding their icu stay. as the result of a fund sponsored by former patients and their relatives, our dept of intensive care is able to provide a small team of assistants to welcome and accompany the relatives of icu patients. one role of this team is to collect and evaluate impressions and criticisms from patients and relatives shortly after the icu stay. we studied a convenience sample of icu patients who stayed in our multidisciplinary dept of intensive care between september and april . the evaluation included simple questions about the welcome (friendliness of the personnel, explanations), quality of care (including pain control, attention to patient needs, availability of nurses and speed of response) and comfort (temperature, light, noise). data were analyzed using non-parametric (mann-whitney) and chi tests. we collected answers from of patients ( were incapacitated, had died and declined), including unplanned admissions and patients after major surgery. more than % of the patients were very satisfied with all items, except for information provided by the attending physician ( % of patients) and the room temperature ( % of patients) (figure ). post-icu enquiries can provide valuable feed-back information that could improve the quality of care in the icu. introduction. previous research suggests that family members of critically ill patients hospitalized in the icu frequently suffer from severe anxiety. a survey conducted in our unit-a -bed, university-affiliated tertiary-care, closed, general icu with restricted visiting hours-revealed a willingness of family members to participate in a support group. such a group was recently introduced and we report on our initial experience over the last year. methods. the purpose of the support group was to provide a forum where family members could freely raise any topic related to the care of their loved one as well as to family-related issues. the meetings were held weekly in the icu and chaired by a senior nurse and the unit social worker. family members were informed of the meetings when the patient was admitted to the icu and notifications were placed in the family waiting room. all family members were encouraged to take part and to raise any topic they felt was relevant. results. since its introduction in , there has been an increase in the percentage of a family representative attending the meetings from to %. the most frequently raised issues included staff-family interaction (especially lack of empathy), lack of information regarding the patient's status and prognosis, and the lack of adequate visiting hours. in addition, other issues included technical aspect related directly to the family, in particular, overcrowding and lack of privacy in the waiting room. finally, participants wanted to learn skills in order to cope with their new and uncertain circumstance. we have noted an ongoing readiness of family members to take part in the support group. the issues raised have and will allow us to make appropriate changes and to improve the current situation. in particular, the meetings help us to identify family members at risk who require more immediate and personal attention. introduction. the soap study suggested outcomes of cancer patients admitted to icu are similar to those without cancer in contrast to other reports . we wanted to compare this with our own experience. ( ) to determine critical care and hospital outcome of patients with malignancy referred to critical care in the previous years. ( ) to identify any factors influencing treatment decisions and survival after admission. retrospective chart review of patients undergoing treatment for malignancy admitted to icu for medical or surgical reasons from may to feb . leukaemia patients were not included as they are treated at a different hospital by a different group of clinicians. demographic information, tumour/treatment related factors e.g neutropenia, preadmission status and critical care diagnoses e.g. sepsis, were collected in addition to patient outcomes. results. patients were identified ( . % of all critical care admissions). itu mortality was . % (n = ), however only . % (n = ) survived to hospital discharge (comparable overall unit mortality: - %, hospital mortality: %). hospital survivors were younger (median . vs. years), and more non-survivors had pre-existing comorbidities, sepsis, ali and required more organ support (all ns). there was no difference between the groups regarding cancer treatment. non-survivors had a longer stay in critical care and treatment withdrawal/limitation decisions were more common suggesting these were often based on lack of medical progress whilst on icu rather than diagnostic nihilism. hospital mortality in patients with malignancy is higher in our specialist centre than reported for a europe wide cohort ( . vs. % overall and % in the medical subgroup). the majority of our patients were medical and not post-surgical unlike in the soap study. this may account for the greater mortality as a larger proportion of our patients had ali, sepsis, neutropenia and required inotropes. numbers admitted to critical care are much smaller than the . % reported in the soap study, suggesting some referral and admission triaging by the oncologists and the icu team. our results are similar to single centre french (hospital survival rate . vs. . %) and brazilian studies ( . vs. %), although a majority of our patients did not receive mechanical ventilation. , a diagnosis of cancer or active treatment for it should not be the major determinant of critical care support, but the patient's general premorbid status and the extent of organ failures appear to be important factors in decision making as for any other critical care patient. figures from the soap study for non specialist centres do not appear to reflect the experience of specialist oncology centres. historically there has been a negative perception of the prognosis for patients with haematological malignancies requiring admission to the intensive care unit (icu). however, advances in chemotherapeutic regimes and haematopoietic stem cell transplantation (hsct), along with improved monitoring and supportive measures have suggested that outcomes for these patients have improved [ ] . establishing key prognostic indicators predictive of outcome may be useful in identifying patients most likely to benefit from icu therapy. the aim of this study was to describe clinical outcomes and identify prognostic factors in patients with haematological malignancy requiring admission to icu. following research approval, a retrospective cohort study was undertaken in a -bedded specialist cancer icu over a -year period (october -september . recorded patient variables included demographics, haematological diagnosis, reason for icu admission, hsct, apache ii, admission laboratory data, number of organ failure, use of invasive mechanical ventilation, renal replacement therapy (rrt) and vasopressors. the primary outcome was in-hospital mortality. key prognostic variables in determining inhospital mortality were identified using univariate and multivariate analysis. results. patients with haematological malignancies were admitted to the icu during the study period: mean age . (sd . ); . % female; haematological diagnosis ( . % leukaemia, . % lymphoma, and . % myeloma); . % emergency admissions and . % were post-hsct. mean apache ii was . (sd . ), mean number of organ failures . (sd . ), % required invasive mechanical ventilation, . % rrt and . % vasopressor therapy in the first h of icu admission. icu, in-hospital and -month mortality were . , . and % respectively. significantly higher mortalities were seen in patients who were mechanically ventilated ( vs. % non-ventilated patients p \ . ), on vasopressor support ( vs. % no vasopressor support p \ . ), neutropenic ( vs. % non-neutropenic p \ . ) and in multi-organ failure defined as c organ failures ( deaths vs. deaths in patients with b organ failure, p \ . ). univariate analysis revealed mechanical ventilation, vasopressor support, albumin \ g/l, neutropenia, platelet count \ /l and multi-organ failure were all significant with p values . , . , . , . , . and. respectively. multivariate analysis revealed that multi-organ failure was the only independent prognostic predictor of in-hospital mortality. conclusion. mechanical ventilation, apache ii, vasopressor support, albumin\ g/l, neutropenia, platelets \ /l and multi-organ failure all had a significant association with mortality; however multi-organ failure was the only independent factor that predicted poor outcome. c.y.c. michael , a. vasu , s. eillyne tan tock seng hospital, emergency department, singapore, singapore introduction. coronary heart disease is the leading cause of mortality and morbidity for both women and men. although men are affected in greater numbers, women have been shown to have worse outcomes and higher mortality. objectives. this study aims to examine gender differences in risk factors, angiographic severity, treatment and in-hospital mortality after stemi. methods. in this retrospective study, the medical records of patients with an admitting diagnosis of stemi from tan tock seng hospital, emergency department (ttsh ed) between st january and st december were reviewed. we extracted the data from the electronic records of the emergency case notes and inpatient discharge summaries. results. of the patients studied, ( . %) were women and ( . %) men. four hundred and forty-nine ( . %) patients underwent coronary angiography. one hundred and seventy ( . %) patients did not undergo coronary angiography, majority ( . %) were elderly aged c years (men . % and women . %). between women and men, there was no significant difference between the number and distribution of diseased coronary vessels (including triple vessel and left main stem diseases). regardless of age, men were frequently treated with a coronary artery stent ( . %). elderly women (aged c years) were more often treated conservatively ( %) while those younger women (aged b years) were frequently treated with a coronary artery stent ( . %). in-hospital mortality rate was significantly higher for women than men ( . vs. . %, p = . ). amongst the patients treated conservatively, elderly women had the highest in-hospital mortality when compared to the other patients (women c years . vs. women b years . %; men c years vs. men b years . %). compared to men, women were significantly older (p \ . ; % ci . - . ) , more likely to have a history of hypertension ( . vs. . %; p \ . ), diabetes ( . vs. . %; p \ . ), hyperlipidemia ( . vs. . %; p = . ), peripheral vascular ( . vs. . %; p = . ) or ischemic heart diseases ( . vs. . %; p = . ) and less likely to be smokers ( . vs. . %; p \ . ) or consume alcohol ( vs. . %; p \ . ). conclusions. elderly women who were treated conservatively had the highest in-hospital mortality during the early management of stemi. hôpital saint-louis, ap-hp, paris diderot university, hematology department, paris, france introduction. aml is considered as an oncology emergency as a proportion of patients experience life threatening complications within the first hours or days after diagnosis. early death had been shown to be statistically related to high white blood cell (wbc) and monoblastic leukemia - , with leukostasis and lysis syndrome as the most deadful events. objectives. to evaluate the relationship between timing of icu admission and outcomes in high risk aml patients at the earliest phase of the malignancy (before any chemotherapy) methods. retrospective study in a tertiary care teaching hospital. adult patients with newly diagnoses aml from to were included. patients admitted for an immediate life sustaining therapy (ventilation, vasopressors or renal replacement therapy) were excluded. patients admitted directly to the icu (early admission) were matched for age, wbc and fab subtype with patients primarily admitted in hematology ward. datasets were extracted from medical charts. results. patients were included ( early admitted to the icu and admitted first to the wards). median follow up was . months. median age was . years ( - ). fab m or m was retrieved in % of the patients. karyotype was favorable for % and poor for %. median wbc was l - . no statistical difference was seen for demographic and hematological parameters between early admitted patients and matched controls. among the patients admitted first to the wards (controls), were subsequently admitted to the icu (lately admitted) and remained in ward during the entire treatment course (never admitted). the median time between diagnostic and icu admission of this last group was ( - ) days. strikingly, patients lately admitted had more frequently dyspnea,oxygen requirement, high respiratory rate, low diastolic arterial pressure and lower first h urine output. lately admitted patients were less likely to receive the complete dose of induction chemotherapy ( vs. %) furthermore, late admission resulted in increased use of invasive mechanical ventilation ( vs. %) and vaso-active drugs ( vs. %). these differences resulted in longer stay in icu and decreased survival. conclusion. patients at the earliest phase of high risk aml who are lately admitted to the icu experience worse outcomes, with increased use of life-sustaining therapies and higher mortality, compared to patients early admitted to the icu. physiologic parameters at the time of aml diagnosis such as respiratory rate, diastolic blood pressure, spo , or oxygen need are likely to help clinicians distinguish those patients at risk of late icu admission and subsequent adverse outcomes. studies are needed to assess the right place for newly diagnosed aml with physiological abnormalities but no organ dysfunction. atrial fibrillation (af) is the most common sustained tachyarrhythmia in the community. it has a prevalence of * % in those over years of age ( ) . the chronic health consequences of chronic af are significant. it can cause impaired cardiac function, a fivefold increased risk of stroke and decreased life expectancy ( ) . af is also the commonest arrhythmia in the critically ill, though a recent systematic review ( ) was unable to recommend evidence based standards due to the heterogeneity of the studies. objectives. a retrospective cohort study to assess the impact that chronic af has on the outcome from critical illness. methods. all patients admitted with chronic af between / / and / / were identified. we recorded age, apache ii and predicted hospital mortality, actual icu and hospital mortality, past medical history, admitting diagnosis, medication, echo findings, anticoagulants given, therapy instituted, and any further events between icu and hospital discharge. the only data collected for the patients who did not develop af was their age, apache ii and predicted hospital mortality and actual icu and hospital mortality. data analysis using chi square test and mann-whitney u test were used where appropriate. results. patients were admitted to the icu over the study period, of which had a history of chronic af ( . %), the remaining results are shown in table . chronic af had a prevalence of . %, in keeping with previous studies, and the mean age in the chronic af group was significantly higher. interestingly, there was no difference in icu and hospital mortality between the groups. despite the chronic af group being older with significantly worse apache ii scores. indeed the hospital mortality ( . %) of those patients admitted with chronic af was over % less than predicted hospital mortality ( . %). why patients with chronic af are outperforming expectation is not clear. it could be that apache ii is over estimating the severity of illness in these individuals, or is there something about the way chronic af is treated that affects the response to critical illness, for example, anticoagulation therapy? one of the major outcome measurements in burns centers is still mortality after severe burns. there are many predictive factors in admission as well as factors that are related with all the course of the disease responsible for survival after severe burn. many centers have a minimum standard of burn survival or la (the body surface area that kills % of people) and also have generated computer models of death probabilities based on age and tbsa (total body surface area) burned. objectives. to evaluate the outcome of the severely burned patients treated in the burn center and to develop a predictive model for survival from major burns in albania. the medical records of all acute burn patients admitted to the burn center of the university hospital center ''mother teresa'' in tirana, albania are reviewed retrospectively. statistical analyses are conducted using spss version . logistic regression is used for the prediction of death probability for two risk variables, tbsa burned and age. based on the index of evidence the variables are grouped in significant strata, from to for each variable. logistic regression equation is: where z = , - , age - , age - , age - , age + , tbsa - , tbsa - , tbsa - , tbsa after calculating the probability of death for each record, we have done respective grouping according the mortality from - %. results. during - are admitted altogether , patients in the burn center. overall mortality in icu is . % with a significant reduction during the years, up to . in . row burn mortality is . for , persons per year. la for children is % tbsa; for adults % tbsa and for aged % tbsa. based on probability of death, we notice that older age and larger burn size are associated with a higher like hood of mortality. figure gives an overview of death probability in our burn center. conclusions. the mortality reduction speaks up for a better work of our staff toward the patients. the predictive model may assist all the burn team to identify the crucial determinants of clinical outcome to establish a real basis for treatment standards and to allow future comparisons of new treatment strategies. ( ) in mechanically ventilated (mv) critically ill patients. methods. prospective observational multicenter study during weeks in november . consecutive patients admitted to the participating icus and requiring mv for at least h were included. maximal, minimal and mean intra-abdominal pressure (iap), were recorded on day , , and . iah was defined as mean iap c mmhg/ h at least day. following risk factors were recorded if evident during the first icu day or immediately before: respiratory failure, abdominal surgery with fascial closure, damage control laparatomy, major trauma/burns, prone positioning, gastroparesis, ileus, colonic pseudo-obstruction, ascites, hemo/pneumoperitoneum, intra-abdominal fluid collection, acidosis (ph \ . ), hypothermia (core t°\ °c), massive transfusion ([ u of packed red cells/ h), massive fluid resuscitation ([ l/ h), coagulopathy, oliguria and sepsis. results. patients from icus were included; mean apache ii score on admission was . ( . ) and -day mortality %. mean number of iap measurements was . per day. iah occurred in patients ( . %). only pt ( . %) had none of the studied risk factors, nevertheless % of them still developed iah. of the patients with or more risk factors, only . % developed iah (table ) . objectives. to describe the icu admission of our hospital for serious complications of hematology patients in the last years. compare the characteristics of these patients throughout the study period. analyze mortality and their evolution from their admission to the icu. the evolution of hematologic patients has improved in recent years due to better supportive treatment, sometimes involving the use of specific treatments in the icu. a retrospective study of medical records of all patients with hematologic diseases were admitted to our icu from april until may . we excluded patients admitted for channeling central catheter, diagnostic tests and bone marrow transplants. we selected a total of patients ( % male) with a mean age of years (range - ). the main hematological diagnoses were the most common aml ( %), acute lymphatic leukemia ( %), lymphoma (non-hodgkin's lymphoma) ( %), coagulopathy ( %), myelodysplastic syndrome ( %) and myeloma multiple ( %). the principal reason for admission in the unit were: acute respiratory failure ( %), followed by sepsis ( %) and less cns and cardiac problems ( and %) respectively. as important risk factors of neutropenia and peripheral blood stem cells after transplantation. the icu mortality reached . %. the average stay was . days. conclusions. the transfer to the icu allows a high percentage of hematological patients survive severe complications and the benefit continues after discharge. the mortality of icu patients in our series has not changed over the past years, keeping both the characteristics of patients transferred. the consensus among the services of hematology and intensive care is essential to select and treat the best candidates to benefit from support in the icu and to improve current survival results. a retrospective (from to ) and prospective (from to ) analysis of obstetric patients (pregnant or postpartum admissions) admitted in our ccd was performed. results are expressed as mean (standard deviation) or frequency (percentage). chi and t student tests were used for statistical analysis according to the different variables (spss . , inc. chicago, il), accepting a p-value . as significant. results. obstetric patients were included. mean maternal age was . ( . ) years and mean gestational age was . ( ) weeks. apache ii score was . ( ) . ( . %) patients were admitted to ccd due to an obstetric cause. the main diagnosis of this group were thrombotic microangiopathies ( . %) and hemorrhagic shock ( . %). thrombotic microangiopathy included ( %) eclampsia-preeclampsia, ( %) acute fatty liver, ( %) hellp syndrome and ( %) ptt-shu. in the remaining . % ( patients) the main reason for ccd admission not related to the pregnancy was respiratory failure ( . %). from the whole population included, patients ( . %) required mechanical ventilation (mv) with a mean duration of . ( . ) days. furthermore, ( . %) patients required surgical intervention ( . % hysterectomy). the ending of pregnancy was made in patients ( . %), most cases by caesarean . % ( patients). mean length of stay in ccd was . ( . ) days. maternal mortality was . % ( patients), basically in the non-obstetric group ( vs. ) . conclusions. this is a large series of young obstetric critically ill patients with a low mortality. however, a non-depreciable part of the population included presented important morbidity. objectives. to identify the association of co-morbidities with mortality. methods. retrospective analysis of clinical process of diagnosing patients with severe sepsis/septic shock admitted to the intensive care unit (icu) in the period of november to october . we collected demographic data, co-morbidities, and mortality in the icu hospitalization. statistical tests used were student's t and chi-square. we analyzed patients admitted with this diagnosis, median age of years and females . %. in . % ( patients) appear co-morbidities, distributed as follows: hypertension . %, . % diabetes mellitus, cerebrovascular disease . %, . % chronic kidney disease; . % neoplasic disease and chronic obstructive pulmonary disease . %. the mean age ( . , p \ . ) was higher in this group. the overall mortality in the icu was . % that has not increased significantly to . % in the group with comorbidities, and the overall in-hospital mortality was . % and rise significantly to . % (p \ . ). conclusions. in our study, around - patients had co-morbidities and these facts and the age were those who contributed to higher mortality. the factors of greatest weight are those related to metabolic disease. the characterization of chronic illness in the icu is important in future larger epidemiological studies to better characterize this group of patients and the factors predictive of mortality to decrease the suffering of the patient and plan for admission to intensive care units. one year mortality of patients treated with an emergency department based early goal directed therapy protocol for severe sepsis and septic shock: a before and after study. introduction. despite the advances in respect to the development of objective criteria for admission of patients with hematologic malignancies to intensive care unit (icu), no evidence exists that they contributed to a reduction in the mortality, which depends from the aggressiveness of the cancer itself, its complications and even as a consequence of therapy. since the decision to admit one of these patients in icus involves a complex decision-making process, it becomes imperative to identify predictors that may help the clinician to discriminate the patients who may benefit from intensive care than those in which intensive care will be associated with just a prolongation of an agony. objectives.: to identify early prognostic factors in the admission of patients with hematological malignancy, admitted in the icu of a central university hospital. analysis of data prospectively collected and registered in a database of patients with hematological malignancy, admitted to the icu between january and december . we collected for each patient demographic and clinical data (age, sex, length of stay, origin, previous treatment, stage of disease at admission, type of malignancy and aggressiveness, organ dysfunction at admission, co-morbidities, reason of admission), general severity scores (saps ii and apache ii) and organ dysfunction scores (sofa at admission to the icu, maximum sofa score and delta sofa). specific variables were correlated with mortality at the icu and hospital discharge. results. patients ( males and females) fulfilled the inclusion criteria. the average age was ± . years ( - years). the type of hematological malignancy was acute leukemia ( . %), multiple myeloma ( . %), myelodysplastic syndrome ( . %), chronic leukemia ( . %), low grade non-hodgkin lymphoma ( . %), high grade non-hodgkin lymphoma ( . %). the average length of stay in the hospital was . ± . days. most patients were admitted from the department of hemato-oncology ward of the hospital ( . %), . % of the emergency department and . % of another hospital. the icu mortality was . %, with a corresponding hospital mortality of . %. the discriminative capacity of the severity scores, as assessed by the area under the roc curve (aroc) was . for saps ii and . for apache ii. for the delta sofa calculated for each organ dysfunction, progression of respiratory dysfunction/failure and cardiovascular failure demonstrated the best discriminative power (aroc of . ). conclusions. none of the variables showed a statistically acceptable relationship with icu or hospital mortality. the general severity indices saps ii and apache ii demonstrated a better discriminative power than the multiple organ failure scores. however, in this group of patients,it is still difficult to know objectively what factor or combination of factors may be useful in deciding the admission of the patient in an icu. recently due to new developments in interventional gastroenterology and new therapeutic options for treatment, gastroenterological and hepatological (geh) admissions to acute care settings has been decreased. for general intensive care units (icu) gastroenterological and hepatological (geh) diseases consititutes the minority of icu admissions. so we planned to find the incidence and clinical course of admissions due to geh complaints in a medical icu. objectives. main objective is to analyze clinical and epidemiological features of patients admitted to icu with geh disorders. other objectives are to analyze the mortality rate and the factors contributing mortality in these patients. and who stayed for more than h were included. the prospectively developed data including demographics, prognostic scores and clinical features of patients were analyzed retrospectively. patients with geh disorders consituted % of patients admitted to icu. one hundred thirthythree patients with an age of [ - ] years and gender of % male were included. more than half of these patients ( %) did not have any chronic geh disease. the patients were admitted most often from the emergency department ( %). the most frequent admission diagnosis was gastrointestinal bleeding ( %) followed by hepatic diseases including hepatic failure and acute hepatic encepahalopathy, biliary tract infection ( %), pancreatitis ( %) and enteric diseases including massive diarrhea and bowel obstruction ( %). on admission median apache ii and glasgow coma scores were [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , respectively. acute kidney injury (defined by rifle criteria risc, injury or failure) was found in (% ) patients. the most common rifle class was class failure ( %). during icu stay patients ( %) needed renal replacement therapy and patients ( %) received mechanical ventilation. nosocomial infection developed in ( %) patients and icu aqıired severe sepsis occured in ( %) patients. icu and hospital mortality were % and % respectively. length of icu and hospital stays were [ ] [ ] [ ] [ ] [ ] [ ] and [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days respectively. respiratory failure requiring mechanical ventilation, acute renal failure on admission and severe sepsis in the icu were found to be the independent factors determining mortality in these patients (p = . , p = . and p = . respectively). patients with geh constitued % of patients admitted to icu. they usually do not have any chronic geh disease. gastrointestinal bleeding is the most frequent admission diagnosis. respiratuar and renal failure on admission and severe sepsis occured in the icu are the major determinats of mortality in these patients. introduction. in recent years described series with hematological patients in icu, but these studies are often limited because they are retrospective, single center in a few patients divided over many years. to determine the characteristics of mortality in this group is very important to assess their management in the icu. objective. to analyze prognostic factors associated with icu mortality of patients (pts) with hematologic malignancies admitted to the intensive care unit (ptu). method. an observational, transversal, prospective, multicenter oct conducted between june and october . we conducted a descriptive analysis, chi-square, bivariate and logistic regression including variables with a value of p \ . with the sas statistical pauet to assess the factors influencing mortality in icu. we included patients from icus. the mean age was years. the apache ii at admission was . ± . ) and the first day sofa ± . . ( . - . ). the crude mortality icu was . % ( pts). we divide related mortality by infectious etiology ( %) versus other causes ( %). in univariate analysis the variables significantly associated with mortality were: males p \ . , hematology plant from . , . multiple myeloma, respiratory failure at admission . , tachycardia, . , . hypothermia, tachypnea , apache ii c , more than two organ failures . , presence of ards \ . , invasive mechanical ventilation (imv) \ . , niv . , . transfusion (of all products: red cells, platelets and plasma), acquisition intrauci infection . , days longer stay in icu . . the presence of neutropenia was not associated (p = . ) at a significantly higher mortality, or personal history, septic shock, bone marrow transplant or other reasons for admission to the icu. table describe the independent factors associated with mortality in logistic regression analysis. variables classics such as septic shock or neutropenia not associated with mortality. and the independent variables associated with increased icu mortality were: vm, ards, severity and need for transfusion of blood products. results. patients were identified. major haematology diagnoses were acute leukaemia %, nhl % and lymphoma %. mean time to icu admission was . days with % admitted within h. the commonest reasons for icu admission were respiratory failure %, sepsis % and acute renal failure %. the mean number of organs supported was . . % of patients had c organ failure. mean apache ii score was . . increasing organ failure correlated with increasing mortality. patients with or organ failure had % mortality. mean icu stay was days with % having an icu stay of less than h. icu mortality rate was . %. . % received invasive ventilation, . % failed non-invasive ventilation (niv) and required invasive ventilation, . % had niv only and % received no respiratory support. vasoactive support was given to . % and rrt to . %. invasive ventilation and niv were associated with a higher mortality; and % versus % in spontaneously ventilating patients. vasoactive support was associated with more organ failure, longer icu stay and higher mortality. rrt was associated with a higher mortality versus %. patients with a documented poor haematological prognosis had a higher mortality but also more organs supported. conclusions. from this study invasive ventilation, cardiovascular support and multiorgan failure are strongly associated with increased mortality. the need for rrt was not an independent predictor of mortality. close collaboration is needed between the specialities to allow early resuscitation and critical care support to avoid delayed admissions with multi organ failure. introduction. the prescription of stress ulcer prophylaxis (sup) in critically ill patients is relatively commonplace due to the association between physiological stress and gastrointestinal (g.i.) bleeding. however, recent guidelines recommend that only patients who are mechanically ventilated, and/or have a coagulopathy warrant prophylaxis. they also state that histamine receptor blockers (h rb's) can be used primarily for sup ( ). objectives. the aim of this audit was to compare prescription practice of sup at the itu/hdu at mayday hospital with those set out in the guidelines and to calculate the potential cost savings resulting from following these guidelines. methods. data prospectively collected from consecutive admissions to mayday hospital itu/hdu between october and november . . data was collected on patients, had a g.i. bleed on admission, and were already on sup so were excluded. of ( %) patients with major risk factors were prescribed sup, compared with of ( %) patients with no major risk factors. proton pump inhibitors (ppi's) were prescribed preferentially to h rb's; versus . the cost of sup during the audit period was £ , . if we had only prescribed it to those at high risk the cost would have been £ , . , and if we had only used h rb's the cost would have been £ . . prescribing of sup in our unit does not reflect quenot's guidelines. this not only represents an increased cost but there are increased rates of nosocomial pneumonia and c. difficile diarrhoea associated with sup ( , ) . there is little evidence showing the superiority of ppi's over h rbs in the prophylaxis of bleeds; and there is evidence of an increased rate of the aforementioned infections with ppi's as compared to h rb's ( ). we prescribed ppi's to a significant majority of our patients; however, it is our opinion that our current unit practice is not dissimilar to that of the rest of the uk. we would encourage all critical care units to review their sup prescribing as our results show that significant savings can be made with judicious prescription of these drugs. . surprisingly little is published on the cost of drug treatment for critically ill patients. critical care is expensive, mainly due to the high staff ratio, expensive equipment but also due to a significant reliance on pharmacological management, which is usually funded with a limited drug budget. objectives. to explore the relationship between drug expenditure, patient acuity and outcome. methods. data was generated by retrospective analysis of consecutive patients admitted to our bedded general adult icu/hdu in a london teaching hospital, during february . patients were excluded from analysis if they were present in icu for less than h. the first and final ccu days stay were not included so that only full days were analysed. daily drug-use per patient was manually extracted from the computerized icu management system (cis, qs, ge medical). costs of prescribed drugs, fluids and parenteral nutrition (pn) were calculated from the pharmacy computer system and analyzed using regression analysis (spss ver ). results. the patient characteristics and outcomes of the patients are described in table table patient characteristics and outcomes age ( - )* gender (male n and %) ( %) apache ii score . ( . )** tiss score/patient . ( . )** length of ccu stay (days) ( - )* ccu survival (n and %) ( . %) daily drug cost for each patient's stay £ . (£ . - . )* daily drug cost for ccu and hospital survivors n = £ . ( . - . )* daily drug cost for ccu survivors who died in hospital n = £ . ( . - . )* daily drug cost for ccu non-survivors n = £ . ( . - . )* *median (interquartile range), **mean (standard deviation) the median daily drug cost was £ . . of note, the drug cost was highest for ccu nonsurvivors compared with survivors and also compared with patients who died in hospital after ccu discharge (p = . ). multivariate regression analysis demonstrated that median daily drug cost/patient = - . + . (mean tiss score) + . (apache ii score), r = . %; i.e median daily drug cost/patient was positively associated with tiss and apache ii score explaining % of the variation in cost seen. conclusions. this is the first study to show that daily drug expenditure in all general ccu adult patients correlates with patient acuity. median daily drug costs/patient were found to be £ . . this parameter would make an interesting comparison with other units both nationally and internationally. daily drug costs can be predicted on the basis of apache ii and tiss scores. furthermore, this may be further refined to develop a quality marker of daily drug cost in relation to survivors and non-survivors. material, methods and results. all patients admitted to the icu of neurotrauma, which underwent a tracheostomy after admission. data were collected: affiliation, cause of admission, average stay, indication of tracheostomy, tracheostomy time delay from its indication, place of performance of the procedure (icu or operating room), perioperative complications (event during transfer to operating room, event during surgery: hypoxia, hypotension, arrhythmia, bleeding, premature extubation, false cannulation, cardiac arrest, pneumothorax or death), and postoperative complications in the first week (bleeding, difficulty in changing cannula, stomal infection, pneumothorax, death conclusions. tracheostomie is a simple surgical technique and . % of tracheostomíes could be safely performed in the icu, saving hours of scheduled interventions in the operating room. there were no serious event during the transfer to the operating room or during the performance of tracheostomy. tracheostomized patients in icu, had a higher incidence of hypotension during surgery, although this complication in any case was serious or required treatment with vasoactive amines. when the tracheostomy is performed in the operating room, the delay shows a tendency to be higher, although this difference is not ss introduction. the concept of tight glyceamic control in critically ill has led to the rise of number of insulin infusion protocols designed to keep the blood sugar (bs) in predefined range. at the same time monitoring practices and patients populations vary greatly between intensive care units and thus so do the results. the matter is complicated by the absence of a widely agreed common glyceamic control indicators against which protocols can be evaluated and compared ( ). to establish the quality of glyceamic control in two different intensive care units. to compare the quality of glyceamic control between two intensive care units, with different glyceamic protocols and blood sugar measurement practices. we conducted retrospective non-randomized population study comparing quality of glyceamic control in two independent and non-related intensive care units. time spend in pre-defined glyceamic range was chosen as a quality indicator for both units ( , ) . data was collected from the electronic database and point of care bs measuring devices. the frequency distribution was analyzed to establish the patient-to-patient variability and a degree of bs deviation from the target value. results. units were different in method of sampling, frequency of sampling, target for optimal glyceamic range and instigated insulin protocol. data was collected on patients ( , bs measurement) in itu and patients ( , bs measurements) in itu . mean bs was . (sd = . ) mmol/l in itu and . (sd = . ) mmol/l in itu . conclusions. the performance of both protocols were satisfactory- . and . % of the time patients spend with bs less than mmol/l in itu and itu respectively. the quality of glyceamic control on both itus is similar in terms of proportion of time spend in different glyceamic bands, with the exception of the longer time spend in a hyperglyceamic state in itu . this study confirms the notion for a need of unified approach for evaluating quality of glyceamic control for in-patient populations. with an icu mortality of . % and in-hospital mortality of . %. the median transfusion threshold was a platelet count of /l with yearly medians ranging from . /l to /l. the % of platelet transfusions complying with bcsh guidelines increased from . to . % during the year study period. the specialties with the highest platelet requirement were general surgery ( . %), haematology ( . %) and general medicine ( . %) as a % of total units transfused. the yearly median threshold for haematology patients fell from . /l in to x /l in , increasing guideline compliance from . introduction. numerous protocols (e.g. glycaemic control, hhh, renal rescue) have been introduced into icu. these protocols involve blood sampling to assess gases, haemoglobin, glucose and electrolytes. this may result in anaemia and subsequent transfusion and adverse clinical outcome ( , ) . reducing blood loss due to sampling is an important blood conservation strategy ( ) . currently, our icu processes over , blood samples per month. objectives. to study the indications for blood gas sampling in our icu and identify strategies to reduce sampling. methods. we performed a prospective, observational study over week in . the nurses completed a questionnaire per shift per patient to assess the primary and any secondary reasons for each sample. subsequent management changes, haemoglobin levels, active bleeding, and transfusion were also recorded. results. blood samples from patients and questionnaires were analysed ( % of the nursing shifts). the range was - samples per patient per h shift with a mean of . the secondary reasons showed that many samples were also being used for potassium ( %) and glucose ( %) monitoring. only % of samples changed management (potassium %, ventilatory settings %, glucose %). haemoglobin levels dropped by an average of g/dl per week per patient with no active bleeding. units of blood were transfused during the study period. conclusions. our study shows that reasons for sampling are often relatively weak and sampling is promoted by icu protocols. frequent sampling does not change management for a large proportion of samples and may cause anaemia. there are financial implications to frequent sampling-at the time of the study each sample cost £ . (€ . ) to process. each unit of blood transfused cost £ (€ ). we have considered ways to reduce sampling including changing the glucose protocol to capillary sampling, using ml syringes, increased use of end tidal co monitoring, protocol redesign and education of staff. reference(s it has been reported that tight glyceamic control is associated with net savings in terms of length of stay on the itu and critical care bed occupancy ( ) . whilst it might be true for the overall length of stay, there is as yet, an un-quantified effect of frequent blood sugar measurement on the overall available nurse-patient time ( ) . there is finite amount of nurse-patient time within any given shift and so prioritizing nursing care will be an important factor in critically ill and high dependency patients. this is specifically important for any saving to be realized from the introduction of automated blood sugar measurement devices ( ). objectives. to quantify the amount of nursing time devoted to glyceamic control on itu or post-operative critical care environment based on data from four cohort studies on quality of glyceamic control in three intensive care units. a mathematical model, which takes into account frequency of blood sugar measurements and time to take each measurement was developed. stochastic analysis was used to calculate interdependency between quality of glyceamic control and the frequency of blood sugar measurements. introduction. introduction of trans-catheter aortic valve implantation (tavi) has been the latest technological advance in minimizing surgical stress and improving the chances of high-risk patient undergoing a successful aortic valve intervention ( ) . the latest technology comes at considerable cost, which relates to both-the cost of the tavi valve and to it's delivery system. currently, there are no randomized controlled trails addressing the issue of cost-effectiveness of tavi versus surgical avr ( ) . to build a cost-effectiveness model for patients undergoing either a tavi procedure or a surgical avr based on the level of care: level (ward based care), level (high dependency unit) and level (intensive care unit) during in-hospital stay, taking into account the rate of post-operative complications in both groups. methods. tavi patients were matched against patients who had previously undergone surgical avr. the groups were matched for demographic and physiological risk factors, as well as euroscore. a decision analytical tree was constructed based on the length of stay in hospital and post-operative complications. a markov model was built and the effectiveness was measured in terms of improvement in nyha class, which was translated into the quality adjusted life years (qaly) ( ) . results. the average in-hospital cost for tavi was £ , versus £ , for the surgical avr. the cost did not include the theatre time cost. in the surgical avr group the in-patient mean cost was greater than respective cost of the tavi group due to longer overall length of stay as in-patients. patients in the avr group spent more days in level and level care as compared to the tavi group. conclusions. the shorter length of stay and reduced rate of post-operative complications in the tavi group has got the potential to substantially reduce the overall in-patient cost and offset high cost of the valve. the effectiveness arm of the models did not differ for both groups, due to the lack of published literature, and raises a need for a qaly assessment for the effectiveness of tavi. the rate of post-operative complications in surgical avr group (higher rate of stroke and need for cardiac pacemaker) substantially affected the projected long-term cost. objectives. to determine if interventions for permanent pacing (ppm) and change of generator are more efficient in small hospitals. retrospective, transversal, observational study, measured through five diagnosis related groups (drg) that make up the casemix of pacemakers from the spanish minimum basic data set in , descriptively analyzing demographic variables (age, gender), clinical (number of secondary diagnoses (nsd) and procedures (np), mortality) and management (total, preoperative length of stay, access, discharge, hospital size), defining inefficient stays exceeding days the average. a bivariate study contrasting quantitative variables and comparisons between nominal and categorical, evaluating the independent association between short stay and different covariates studied building a binary logistic regression model, introducing as independent variables those that were significant in the bivariate as well as those considered that might be associated with the dependent variable. introduction. blood products are in short supply and with an ageing population the demand is likely to increase. blood use has been shown to be declining within the surgical specialties and intensive care, however overall use has remained unchanged. this audit looks at the use of packed red cells amonsgst medical inpatients to determine appropriateness. to determine if red cell use is appropraite among medical inpatients methods. medical blood transfusions were examined between august and august . patients were selected and pre and post transfusion haemoglobins were determined along with chronicity of anaemia. transfusions with haemoglobins of c . g/dl triggered a case note review. over months , patients were transfused , units. , units ( %) were given to medical patients ( %), of which patients were reviewed receiving transfusions. average age was . in patients pre transfusion haemoglobin was b g/dl ( %) and in patients c . g/dl ( %). in the group b g/dl patients had acute anaemia and had chronic anaemia. in the group c . g/dl patients had acute anaemia and had chronic anaemia. patients were not transfused and had absent data. out of case notes only were available. patients were transfused for acute anaemia, for chronic anaemia of which patients had cardiac disease, had haematological disorders, patients had iron deficiency anaemia and patient was folate deficient. conclusions. chronic anaemia in the over s accounted for the majority of transfusions. documentation was substandard. transfusions in chronic anaemia may be reduced by up-to-date guidance on transfusion triggers and alternative strategies to the use of blood products. ( ) results. the commonest indication for pct was long-term mechanical ventilation ( %) followed by airway protection ( . %). . % patients had platelets count\ lac while . % had severe thrombocytopenia (\ , ). . % patients had an additional coagulopathy (hepatic failure and multiple organ failure), with inr [ . was present in . % and deranged aptt in . % patients. pct was safely performed in all these patients. the patients received platelets or fresh frozen plasma(ffp) before the procedure to optimize coagulation. only . % had minor bleed through stoma, which was stopped in - min requiring gauze compression. conclusions. pct under videobronchoscopic guidance has low haemorrhagic complication rate in patients with deranged coagulation profile. platelets/ffp should be transfused before the procedure in these patients. introduction. blood components transfusion is common in the critically ill patient, as in the acute bleeding or the acute illness with multiorganic failure context. as any medical intervention, it has clinical indications and associated risks. clinical guidelines have evolved in a restrictive direction, suggesting that decision should be based on particular clinical situation and not only on analytical results. objectives. understand our transfusional practice and how close it is to clinical recommendations, as a quality indicator of our intensive care unit (icu). retrospective study using the icu patients data base. the population consists of patients with more than h icu stay in . the variables analysed are sex, age, diagnostic class (medical, surgical, trauma), saps ii score, mortality, number of transfusional events (erithrocyte concentrate, platelets, fresh frozen plasma and albumin) and the concordance to our hospital clinical guidelines. results. the population is of patients, % of male gender, with an average age of years-old. the admission diagnostic is medical in % of patients, with an average saps ii score of , median icu stay of days and a mortality rate of %. % (n = ) of patients received any kind of blood component transfusion, mostly erithrocyte concentrate ( % of patients), followed by albumin ( %). the populations of transfused patients is older ( vs. years-old), has a longer icu stay ( vs. days), higher saps ii score ( vs. ) and mortality rate ( . vs. . %) . pretransfusional values are hemoglobin of . g/dl, , platelets/ul, and albumin of . g/dl. the level of concordance with recommendations is high for erithrocyte concentrate ( %), platelets ( %) and fresh frozen plasma ( %) but not for albumin ( %). conclusions. the level of transfusion is high in icu patients. the population who received transfusion has a more severe clinical condition and higher mortality rate. the level of concordance with recommendations is high with the exception of albumin, which use is still less standardized. with increasing acuity due to escalating icu bed demand, but the impact on patient safety is unclear. sdu continuous non-invasive physiologic monitoring of hr, rr, bp and spo identifies cardio-respiratory instability often unnoticed by caregivers. causes may be alarm fatigue and/or high sdu nurse-to-patient ratios which make bedside monitoring insensitive. instability may become more resistant to intervention the longer it occurs. the impact of instability duration upon sdu patient outcomes is understudied. objectives. the study purpose was to determine the impact of cardiorespiratory instability duration experienced by in-patients being cared for on a monitored sdu upon hospital length of stay (los) and hospital charges. prospective study of monitored patients on a -bed trauma sdu over weeks. noninvasive continuous monitoring data were downloaded from bedside monitors and analyzed for vital signs (vs) beyond local instability criteria: hr\ or [ , rr\ or [ , systolic bp \ or [ , diastolic bp [ , spo \ % . vs time plots of unstable patients were further assessed to judge instability as mild or serious. instability duration categorized as: none, [ ] [ ] [ ] [ ] [ ] [$ k) . relationships between instability duration and outcomes analyzed with chi-square for mild and serious instability. conclusions. there has been a marked improvement in the overall recording of sews since the previous study. it is of concern that respiratory rate was again the least well recorded parameter as this has been shown to be the best physiological predictor of impending cardiopulmonary arrest , . this may be because respiratory rate is not provided by the automated monitoring devices available on the general wards in our hospital, and must be calculated manually. it demonstrated an increase in mortality even when tiss scores were taken into account as an independent risk factor. since these publications critical care outreach and the use of early warning scores have become common place; however it was felt that time of discharge was still impacting on patient outcome. to review our post-unit mortality and readmission rate, with particular focus on the time of discharge. conclusions. our mortality and readmission data compare favourably with a recent publication. there is a clear difference in mortality related to time of discharge; however this is for evening discharges as compared to night discharges in previous papers. [ ] [ ] [ ] [ ] the time of discharge may represent logistical issues of planned discharges or early discharge decisions due to pressure for beds. overnight discharge is an uncommon occurrence in our unit; this evidence suggests that previous concern about night discharges should be extended to evening discharges. transferring critically ill patients is a challenging task in the day to day activities of the critical care team. safe accomplishment of these transfers relies on skills of the persons accompanying and the resources available. guidelines have been produced by various professional bodies [ , ] to safely accomplish these transfers. the competency document released by the royal college of anaesthetists, uk requires that junior trainees have appropriate knowledge, skills, attitude and behaviour in the principles of safe transfer of critically ill patients [ , ] . to obtain information about trainee's perspective, experience and knowledge in transfer of critically ill. a web based online survey was sent to all the anaesthetic/itu trainees in the west midlands region of the uk. results. total number of respondents were . of these, . % had less than months of anaesthetic training before undertaking a transfer. only % had formal training on transfer of critically ill patients. % of the trainee's didn't have any competency based formal assessment of their skills, attitudes and behaviour in transfer of critically ill patients. majority of them ( %) felt that every one should undergo formal training before undertaking transfers. while % of the respondents have undertaken transfers during their training, only % have experienced some form of critical incident during these transfers. more than % of these adverse events were related to equipment failures while % were due to patient deterioration. nearly % of the trainees were not aware of terms and conditions of the insurance cover for these transfers. conclusions. this survey highlights the deficiencies involved in training the trainee's for transfer and the transfer itself. the results demonstrates that majority of the trainees would prefer to attend specific transfer courses before venturing out on an actual transfer. we hence recommended the following for implementation: improvement of training process for those undertaking transfers; regular monitoring of this process; regular analysis of critical incidents and acting upon it; making the insurance compulsory for those undertaking the transfers. greek hospitals, including initial management of critically ill patients and primary care for a growing proportion of the population. the impact of ed length of stay (los) on patient outcome has not been covered adequately by existing surveys so far. objectives. the aim of this study was to determine the association between ed overcrowding and outcomes for critically ill patients. in the present study, we included medical and surgical pts that all of them were intubated promptly to ed of general hospitals of athens gr, for months. pts survived [ h were divided into groups: ed boarding \ h (group a) and ed boarding c h (group b). demographics, apache ii, diagnosis, los, and icu and hospital mortality were recorded. ed boarding time was measured in min. groups were compared using chi-square, mann-whitney, unpaired student's t tests and stepwise regression analysis. the collection of data lasted months. results. in the ed, critically ill patients with a mean age . ± . years and apache ii score . ± . were intubated. pts were males and were females with a mean age . ± . and . ± . years, and apache ii score . ± . and . ± . respectively. main diagnosis was multi trauma ( ) objectives. we sought to assess the baseline characteristics and outcomes of the patients presenting af as a cause of met call activation. using the met database of one tertiary teaching hospital, we retrospectively reviewed all patients for which the met diagnosis was atrial fibrillation. we reviewed their clinical history, immediate treatment and outcome. these data were compared to those of a control group of randomly selected met calls with patients being matched for age, gender and ward of origin (surgical or medical). objectives. to ascertain the proportion of preventable in-hospital cardiac arrests occurring at university hospital lewisham. furthermore, to identify any common predictors of poor outcome that were apparent prior to those arrests and whether these are potentially modifiable. a case note review was performed on the cohort of patients who suffered inpatient cardiac arrests and who were admitted for icu (level- ) care post-resuscitation. these patients were identified using our quarterly feedback from the intensive care national audit and research centre (icnarc) case mix program dataset between april and september . we found that half ( out of ) of our in hospital cardiac arrests resulted in death despite level- care post arrest within the audit period. of these in-hospital arrests were deemed preventable from case note review and trust cardiac arrest call audit forms when available. in addition, in the preventable sub-group an arterial blood gas sample was not obtained in out of , %. in all of these cases, the icu outreach team was not aware of the patient prior to the arrest. conclusions. in keeping with widely published data regarding survival to discharge after in-hospital cardiac arrest, the high mortality rate of % for this cohort of patients emphasises the importance of early recognition of abnormal physiology and timely intervention. with the sensitivity, specificity and validity of ews yet to be validated and no clear benefit proved from the introduction of met/outreach teams, an alternative strategy for earlier recognition of critically ill patients is needed. our data suggests that arterial blood gas sampling, an essential investigation central to the recognition of critically ill patients is being consistently overlooked and is an important factor influencing outcome. results. attended patients were , , with mean age of , years, and women represent , % of them. most demanding services were internal medicine ( %) followed by general surgery, haematology and nephrology. global data may be seen in table . with regards to admissions to the icu of these patients, table depicts the proportion between requested admissions, and refusals. introduction. tradicionally, critical care interventions are highly intensive, expensive and brief. critical illnesses and interventions that we use, can both contribute to posticu disability: catheter-related bacteraemia, polineuropathy, resistant organism, nutricional problems, complications of tracheostomy, prolonged analgesic. all these factors and a premature discharge from an ever full icu, can even have an impact on occult mortality after discharge from icu (between and %). in our unit a follow up program have been implanted. when patients are about to be discharged from icu, icu clinicians selected those considered to be recoverable but fragile enough to have poor prognosis. objectives. to quantify the workload that a after icu follow-up entails, and to determine if this program impacts on mortality posticu. prospective and interventional study carried out during a months period. at a beds medical uci of a teaching hospital in malaga icu, patients were enrolled in the follow up program. we assessed prognosis with sabadell score and severity of illness with apache ii score; and registered our interventions after discharge from icu. the final endpoint was status at hospital discharge: survivant or dead. we did interventions in patients: we changed a venous catheter ocasions ( % of patients), changed analgesic schedule times ( . %), stopped antibiotics times ( %), modified parenteral nutrition times ( %) . we searched and treated sources of sleep deprivation (delirium, anxiety or insomnio) in patients ( %); treated tracheostomy complications in patients. mortality of patients enrolled in this program was . % ( patients) even if the mean expected mortality by apache ii score was [ %. conclusions. in our study, implementation of a continued follow-up program after icu discharge in selected patients, carried out by icu staff, was associated with an important decrease of mortality. encouraging clinical results and a non-excesive workload for icu staff justify continuing this follow-up. objectives. various therapeutic protocols were used for the management of sepsis including hyperbaric oxygene (hbo) therapy. it has been shown that ozone therapy (ot) reduced inflammation in several entities and exhibits some similarity with hbo in regard to mechanisms of action. thus, we designed a study to evaluate the efficacy of ot in an experimental rat model of sepsis and to compare these effects with hbo. methods. forty male wistar albino rats were divided into sham, sepsis+cefepime (control), sepsis+cefepime+hbo (hbo), and sepsis+cefepime+ot (ot) groups. sepsis was induced by an intraperitoneal injection of . cfu escherichia coli; hbo was administered twice daily at . -atm pressure for min; ot was set as intraperitoneal injections of . -mg/kg ozone/oxygen gas mixture once a day. the treatments were continued for days after the induction of sepsis. at the end of experiment the lung tissues and blood samples of the study animals were harvested for biochemical and histopathologic analyses. results. lung tissue myeleperoxidase activities and oxidative stress parameters, and serum proinflammatory cytokine levels, il- b and tnf-a, were found to be ameliorated by the adjuvant use of hbo and ot when compared with the antibiotherapy alone group. histopathologic evaluation of the lung tissue samples confirmed the biochemical outcome. some measures indicated significantly more efficacy of ot than hbo. conclusions. our data presented that both hbo and ot reduced inflammation and injury in the septic rats' lungs; a greater benefit was obtained for ot. these findings suggest that it may be possible to improve the outcome of sepsis by using ot as an adjuvant therapy. objectives. to investigate the regularity for change of paf, tm and vwf in septic rat, and the protective effects of statins on vascular endothelium. methods. fifty-four male sd rats were randomized into simvastatin with lps group (group a, n = ) and lps group (group b, n = ) and control group(n = ). they were respectively accepted ml/kg normal saline (ns) abdominal injection for both control group and group b, ml/kg simvastatin abdominal injection for group a, then h later, total male sd rats from group a and group b were respectively accepted lps ( mg/kg weight) abdominal injection to establish sepsis model and ml/kg ns abdominal injection for control group. thereafter, detected the serum concentration of von willebrand factor (vwf), thrombomodulin(tm) and antithrombin (at-iii) at different point of time ( , , and h after lps abdominal injection) in both group a and group b by elisa, the endothelial cells from thoracic aorta was observed with electron microscope. under electron microscope scanning, endothelial cells in septic rats from group b were found disarranged. under transmission electron microscope, endothelial cells were found to be in prophase of apoptosis characterized by unclear cell membrane, thickened cellcell conjunction, disappeared desmosome and microfilament, dissolved or vacuolized organelles and agglutinated and evaporated chromatin gathering under the karyolemma, but the karyorrhexis were not found. no similar changes were found in group a. ( ) introduction. sepsis induced lymphocyte apoptosis is believed to play an important role in the pathogenesis of sepsis and in the development of the immunesuppresion observed in septic patients. lymphocyte apoptosis not only decreases the number of functional lymphocytes but may also modify the immune response towards an anti-inflammatory state. erythropoietin (epo) has recently been recognized as a multifunctional cytokine with antiinflammatory, antioxidative, and antiapoptotic properties. objectives. this study aimed to test whether epo could mitigate peripheral blood mononuclear cell (pbmc) apoptosis and whether epo could modify the dynamic changes in lymphocyte-subsets in a porcine model of acute endotoxemia. methods. twenty-eight anesthetized and mechanical ventilated pigs were randomized to one of three groups: ) epo group, epo administered h prior to endotoxemia (n = ); ) placebo group, vehicle administered h prior to endotoxemia (n = ); ) sham group, animals only anesthetized and mechanical ventilated. endotoxemia was induced by an infusion of lipopolysaccharide (lps). after h the lps infusion was reduced to a maintenance dose and the animals were fluid resuscitated. pbmc were isolated at time , , , and min of endotoxemia. apoptosis in pbmc and relevant lymphocyte subsets were assessed by staining with -amino-actinomycin d ( aad) and annexin v using multicolor flow cytometry. apoptotic lymphocytes in spleen were quantified by immunohistochemical staining for activated caspase- . endotoxemia increased the number of apoptotic mononuclear cells in both blood (p = . ) and in spleen (p = . ), but with no significant modifying effects of epo. the numbers of both cd + (t-helper) and cd + (cytotoxic) t-cells declined during endotoxemia. cd + cells, defining b-lymphocytes, demonstrated a biphasic response with an immediate decline followed by an increase in number of b-cells. the dynamic changes in the lymphocyte subsets were not modified by epo. , and reduced the number of circulating leucocytes. epo had no modifying effects on these dynamic changes. furthermore, epo did not mitigate apoptosis in pbmcs analyzed by flow cytometry or in spleen lymphocytes analyzed by immunohistochemistry. this study does not support that epo confer protection against lymphocyte apoptosis. objectives. aim of this study was to investigate the effects of combined, recombinant human activated protein c (rhapc) and ceftazidime (cef) in our established model of acute respiratory distress syndrome (ards) and septic shock methods. thirty sheep ( - kg) were operatively prepared for chronic study, and were randomly allocated either to sham, control, rhapc, cef, or rhapc/cef groups (n = each). after tracheostomy, acute lung injury and sepsis was produced in all groups, following an established protocol ( , ) , except the sham group that received the vehicle. the sheep were studied for h in an awake state and were ventilated with % oxygen. pao /fio ratio was determined intermittently. cef ( g) was administered intravenously and h post injury. rhapc was given as a continuous infusion ( mcg/kg/h), starting h post injury. the animals were resuscitated with ringer's lactate solution to maintain filling pressures and hematocrit. lung tissue was obtained during necropsy and analyzed for myeloperoxidase (mpo) using a commercially available kit. statistical analysis: two-way anova and student-newman-keuls post hoc comparison. data are expressed as mean ± sem. significance p \ . . . mpo levels (mu/mg protein) were ± in sham and significantly increased in the control group ( ± *). the rhapc ( ± *) and cef group ( ± *) increased significantly vs. sham and tended to be lower than controls, but not statistically significant. mpo levels of combined rhapc/cef ( ± *) showed no difference to sham, but were significantly lower than controls or rhapc or cef alone. conclusions. combined administration of rhapc and ceftazidime in ards associated with septic shock improved oxygenation more than cef or rhapc alone, and prevented the onset of ards. seleno-compounds, such as sodium selenite (na seo ) show conflicting clinical results in the treatment of sepsis. efficacy, as well as mechanism of action of na seo , are unclear, with prevailing opinion that it acts as an anti-oxidant. however, na seo has also oxidant properties that could have a paradoxical therapeutic role in septic shock by reducing over-activated phagocytic cells. indeed, in septic sheep, high dose na seo injection as bolus rather than continuous administration resulted in a beneficial effect on survival time, macro and microcirculation ( ). objectives. to investigate at the endothelial level the mechanism of action of a bolus injection of a high oxidative dose of na seo . in male wistar rats, lipopolysaccharide (lps, mg/kg) or normal saline were injected intraperitoneally, followed h later by either an intravenous bolus injection of na seo (corresponding to . mg/kg se) or normal saline. after h of lps, extravasation of fluoroisothiocyanate-dextran and leukocyte-endothelium interaction in venules of the cremaster muscle were quantified by intravital microscopy. results. na seo did not alter systemic haemodynamic variables as compared to lps rats. there were no intergroup differences in fluoroisothiocyanate-dextran extravasation. lps significantly decreased leukocyte rolling when compared to control animals (p \ . ). bolus injection of na seo did not alter leukocyte rolling but decreased leukocyte adhesion and extravasation levels to control values. our results in endotoxemic rats suggest that a toxic dose of na seo may have a beneficial effect of on leukocyte-endothelium interaction without a significant effect on plasma extravasation. objectives. to design a model of sepsis in pigs characterized by an unchanged q t over time. methods. after a h fasting, pigs (weight - kg) were sedated with ketamine ( mg/ kg) and midazolam ( . mg/kg) i.m. animals were tracheostomized and anesthetized (propofol mg/kg iv bolus, followed by mg/kg/h), atracurium ( . mg/kg/h) and fentanil ( lg/kg/ h). the internal jugular vein, carotid artery and pulmonary artery were catheterized for iv fluid administration and monitoring. a lumbotomy was performed and an ultrasonic blood flow and a laser-doppler microvascular flow probes were placed in the left renal artery and on the kidney surface to measure renal artery blood flow (rabf) and renal cortical blood flow (rcbf), respectively. a cystostomy was performed to collect and measure urine output (uo). sepsis was induced by the iv administration of live e. coli ( . our previous study showed that citrulline (cit) supplementation during endotoxemia improved microcirculatory flow and endothelial function, and prevented glycocalyx degradation as a consequence of increased arginine (arg)-dependent vascular nitric oxide (no) production. during sepsis the availability of arg, the substrate for endothelial no production, is tempered as a consequence of increased inflammatory no synthase (inos) activity. the reduced endothelial nos (enos) activity and vascular no production is believed to result in endothelial and vascular dysfunction. a shortage of arg availability for enos is considered the main cause of the dysfunction. previous studies have indicated cit as an important, if not exclusive, mediator for enos-derived no production. cit is a substrate for argininosuccinate synthetase, an arg-producing enzyme that co-localizes with enos in the caveolae, thus directly and exclusively supplying arg to enos. objectives. we investigated whether cit supplementation during an ongoing endotoxemia rescues the enos-derived no production in endothelial cells, thereby providing a mechanistic explanation for its positive in vivo effects. mice received a continuous intravenous endotoxin (lps, lg total) infusion for h alone or an h lps infusion with cit ( . mg total) during the last h of endotoxin infusion. after the h infusion, the mice were sacrificed, arterial blood was sampled and the carotid arteries were removed. no production in the carotid arteries was measured ex vivo with -photon fluorescence microscopy, using a fluorescent copper-based no probe. amino-acid concentrations in plasma were measured by hplc. results. both cit and arg plasma concentrations were significantly increased in the lps-cit group compared with mice treated with lps alone (p \ . ). in vivo cit supplementation led to detectable levels of no production ex vivo in carotid smooth muscle cells (smc) and endothelial cells (ec) by using the no-probe with -photon fluorescence microscopy. while ec-derived no production was absent in the carotid arteries of mice treated with only lps, the smc-related no signal was undisturbed. no production in the ec of the lps-cit group was not blocked by the inos inhibitor , w, suggesting enos to be responsible for the observed effect. furthermore, ex vivo incubation of the carotid arteries of the lps-cit mice for min with extra cit ( mg/ml) resulted in prominently increased no production in the carotid ec, whilst this effect was not observed in the carotid arteries of lps without cit treated mice. conclusions. cit supplementation during murine sepsis rescues the enos-derived no production in carotid artery endothelial cells, providing a mechanistic base for the positive effect of cit supplementation on endothelial no synthase during endotoxemia. grant acknowledgment. objectives. investigated the mechanism involved in the clearance of bacteria observed after rpaf-ah treatment in sepsis model. mice were subjected to clp model, after min, the mice were treated with rpaf-ah. the cfu counts and measured of mediators were determined. results. the numbers of bacteria (cfu) recovered in the peritoneal fluid was inhibited in rpaf-ah treated group ( . / . ), suggesting a more efficient clearance of bacteria after rpaf-ah treatment. direct incubation of s. typhimurium, e. coli and s. aureus failed to affect bacterial growth indicating lack of a direct effect of paf-ah on bacteria. administration of rpaf-ah in ccr (receptor for mcp- /ccl ) deficient mice failed to increase bacterial clearance after clp, suggesting that mcp- signaling is involved in this phenomenon. rpaf-ah treatment also failed to increase bacterial clearance in inos deficient mice and no levels were found to be elevated ( . ± . / . ± . ) in peritoneal fluid of the mice treated with rpaf-ah after clp surgery. synergism for no production was also seen when macrophages stimulated with e. coli were treated with rpaf-ah+mcp- and correlated with better bacterial killing by macrophages. peritoneal macrophages from knockout mice for mcp- , stimulated from lps+ifn inhibited no levels when compared to wt mice ( . ± . / . ± . ). this results indicating that, excessive mcp- favors macrophage production of no and hence the ability of macrophages to deal with invading bacteria. conclusions. we conclude that the increase in bacterial clearance is important for the protective effect of rpaf-ah in sepsis and that exist a signaling involving mcp- /ccl and no in this system. introduction. disturbances within the microcirculation represent an important factor in the pathogenesis of multiple organ dysfunction during systemic inflammation and sepsis [ ] . dehydroepiandosterone (dhea) has immunomodulatory effects and improves survival in several animal models of trauma, hemorrhage and sepsis but also causes potent vasodilatation [ ] . to maintain efficient microcirculation we combined dhea with sodium orthovanadate (sov), which augments vascular contraction. furthermore, sov has been identified to attenuate tissue injury and improve survival related to inflammatory response [ ] . objectives. we investigated whether the combined administration of dhea and sov has beneficial effects to microcirculation in experimental sepsis. we divided sixty male lewis rats into six groups: control group; ethanol (solvent) treated control group; dhea ( mg/kg) + ( . mg/kg) treated control group; endotoxemic group (lps mg/kg); dhea + sov treated endotoxemic group; dhea ( mg/ kg) + sov treated endotoxemic group. two hours after lps challenge we performed intravital fluorescence microscopy of the intestinal wall in order to study leukocyte adhesion and functional capillary density (fcd). tnf-a, il- a, il- and infc, gm-csf and mcp were measured at baseline and following h of endotoxemia in all experimental groups. in comparison to untreated rats subjected to endotoxemia the treatment with dhea (both dosages) and sov resulted in a significant reduced number of adhering leukocytes in intestinal submucosal venules. furthermore, the mucosal functional capillary density was significantly improved. we did not identify any changes in cytokine plasma levels. conclusions. the study demonstrated beneficial effects of combined treatment with dhea and sov within the intestinal microcirculation in experimental endotoxemia. concomitant administration of sov permitted to reduce dhea dosage and prevent potential vasodilation without affecting anti-inflammatory dhea action. . spronk pe, zandstra df, ince c: bench-to-bedside review: sepsis is a disease of the microcirculation. crit introduction. sepsis is a disease of the microcirculation and impairment of the intestinal microcirculation during sepsis may cause a breakdown of gut barrier function thus releasing bacteria and their toxins into the systemic circulation [ ] . consequently, the protection of the intestinal microcirculation represents a pivotal therapeutic target in severe systemic inflammation. cannabinoids that interact with cannabinoid receptors (cb r and cb r) have been shown to have immunomodulatory properties in in vivo and in vitro studies and the endocannabinoid system has been shown to be involved during systemic inflammation [ ] . objectives. the aim of the present study was to examine the effects of cb receptor modulation on the intestinal microcirculation in experimental sepsis (endotoxemia) using intravital microscopy (ivm). we studied four groups of animals (lewis rats, n = per group): healthy controls (con), endotoxemic animals ( mg/kg lipopolysaccharide; lps), endotoxemic animals treated with cb agonist, hu ( mg/kg iv), and endotoxemic animals treated with cb antagonist, am ( . mg/kg iv). intravital microscopy of the intestinal microcirculation was performed following h lps/placebo administration. leukocyte adhesion and functional capillary density (fcd) were measured offline in a blinded fashion. results. following h of endotoxemia, a significant increase of leukocyte adhesion in the intestinal submucosal venules (e.g., v venules: con . ± . n/mm , lps . ± . n/mm , p\ . ) was observed. capillary perfusion of the muscular and mucosal layers of the intestinal wall was significantly reduced (e.g., circular muscular layer: con . ± . cm/cm , lps . ± . cm/cm ). treatment of endotoxemic animals with the cb receptor agonist, hu , further increased leukocyte adhesion (v venules: . ± . n/mm ), whereas cb receptor inhibition by am significantly reduced leukocyte activation (v venules: . ± . n/mm ) and restored capillary perfusion (circular muscular layer: . ± . cm/cm ). conclusions. the data support the hypothesis, that cb receptor signalling is involved in the impairment of the intestinal microcirculation during sepsis. blocking cb receptor signalling reduces leukocyte activation and improves capillary perfusion in acute endotoxemia in rats. the long-term effect of modulating cb receptors in more clinical sepsis models needs further investigation. [ ] . this study compares dobutamine and levosimendan for the treatment of circulatory failure in septic shock and assesses survival benefits. objectives. in this controlled randomized doubleblinded study anaesthetized and ventilated pigs ( . ± . kg) were enrolled after approval by the local governmental commission. methods. by continuous infusion of endotoxin (escherichia coli serotype :b , sigma-aldrich; . ± . lg/kg/h) over a time period of . ± . h, septic shock was induced. hemodynamic stabilization was performed by either use of the vasopressor norepinephrine alone (control group; n = ) or in combination with levosimendan ( . lg/kg/min; n = ) or dobutamine ( . lg/ kg/min; n = ). in a setting of h of measurements and treatment heart rate (hr), map, central venous pressure (cvp), pulmonary artery pressure (mpap) and cardiac output (co) were recorded continuously and evaluated hourly. beside norepinephrine requirement and mixed venous oxygen saturation (svo ) mean survival time and survival rate within the measurement period were analysed. results. after endotoxinemia septic shock was marked by reduction of co and svo [p \ . ]. mean survival time and survival rate were superior in levosimendan treated animals ( table ). norepinephrine consumption was lowest in the levosimendan group. after h, co of surviving animals was highest in the levosimendan group and statistically different compared with the control group. comparison of parameters hr, map, cvp and mpap showed no differences between treatments. conclusions. the complementary use of the calcium sensitizer levosimendan provides potential survival advantage in endotoxemic septic shock. beside an increase in co, improvement of regional organ perfusion or protection could be an explanation and has to be shown by further analysis. reference(s methods. the study group consisted of patients with shock on vasopressor support and control group had normotensive patients. arterial and capillary samples were taken simultaneously and were tested immediately at the bedside. the results of the paired measurements were analysed as a scatter plot by bland and altman method and were expressed as a correlation coefficient. values were considered to disagree significantly when the difference exceeded %. results. mean arterial and capillary sugars (mg/dl) in study and control groups were . ± and . ± . , and . ± . and . ± , respectively. on bland-altman analysis, % in study group and % in control group were out of range (acceptable limit \ %) [ figures , ] . correlation between capillary and arterial values was less in the study group (r = . , p . vs. r = . , p \ . ). in addition, the disagreement between capillary and arterial values was more than % in % of the patients in the study group vs. % in control group (p = . ) (iso standard \ %). conclusions. capillary blood glucose monitoring can be applied reliably to patients in icu. however, caution must be exercised in patients with shock in whom arterial blood may be preferred. rd esicm annual congress -barcelona, spain - - october objectives. our primary objective was to evaluate the safety and efficacy of a single oral high dose vitamin d supplementation in an intensive care setting over a one-week observation period. methods. , iu (corresponding to . mg) of cholecalciferol (d) dissolved in ml herbal oil or matched placebo (pbo) were given enterally (via nasogastric feeding tube or swallowed) to patients with vitamin d deficiency [ (oh)d b ng/ml] in the medical icu. results. baseline characteristics including age, sex and saps ii were balanced between the two groups (mean age ± years, % male, saps ii ± ). mean serum (oh)d levels at baseline were ± ng/ml in both groups. the mean serum (oh)d increase in the intervention group was ng/ml (range - ng/ml). two patients showed a small ( ng/ml) or no response ( ng/ml) attributable to gastrointestinal dysfunction after prolonged hypoxia and gastrointestinal gvhd after allogeneic stem cell transplantation. the time course of the (oh)d response is given in figure . introduction. considerable controversy has emerged as to whether tight glucose control (tgc) is warranted in all critically ill adult patients. recently, a new blood glucose upper limit ( mmol/l) has been assessed as more appropriate. rather than blood glucose target ranges, algorithms used to achieve tgc should be numerically evaluated before initiating clinical trials (preclinical validation test). our purpose was to assess performances of tgc algorithms in realistic virtual icu patients. we compared numerically the nice-sugar algorithm (n-s) and the cgao system (cgao) used in the ongoing cgao-rea study [clinicaltrials.gov, id:nct ] . a set of virtual patients constituting the test bench was built with ) real data coming from patients controlled with cgao before starting cgao-rea and ) a non-linear pharmaco-dynamic glucoseinsulin system model where patient endogenous glucose clearance and insulin-sensitivity were time varying parameters. in order to anticipate how algorithms would manage glycaemic control in clinical settings, delayed controls and inaccuracy of glucometers were implemented. the overall performance of each algorithm over the whole stay was assessed according to standard scores. results. the percentage of time in the target range [ . - . mmol/l] with n-s was less than % for almost all patients. in insulin-sensitive patients, glycemic fluctuations and sometimes severe hypoglycemia are induced by n-s (fig. ). the mean time in the target range with cgao was about % and variability scores were significantly lower than with n-s. mean glucose and standard deviations were always lower with cgao than with n-s. a numerical test bench constituted of realistic virtual icu patients, whose features were defined from real data obtained in patients under glycemic control, enabled to determine the best algorithms candidate for further evaluation in clinical settings. according to this approach, the algorithm used to achieve tgc in nice-sugar would not have been selected for such a large clinical trial while cgao reached the first validation step in simulation. we recommend that further glucose control studies focus not only on the target range but also on the algorithmic properties. introduction. there has been much debate in recent years about the appropriate level of blood glucose for intensive care patients with proposals of different levels of glucose control using insulin infusions. one risk of intensive glucose control is hypoglycaemia and this has been proposed as a measure of quality of care given by delivering the protocol safely. the nice-sugar trial found that intensive glucose control increased mortality among adults in intensive care. objectives. the aim of our study was to record hypoglycaemia and study it's relation to insulin therapy. insulin therapy on our unit follows the recommendations of the nice-sugar trial. methods. hypoglycaemia was recorded as a blood glucose level\ mmol/l. levels were detected using the blood gas analyser (radiometer m). data was recorded at the time of hypoglycaemia to provide an explanation using the innovian system which is the paperless patient record system on our unit. data was obtained over a period of months between october and december . data recorded included adverse events which were defined as worsening shock and/or increasing inotropic support. feeding status at the time of hypoglycaemia was recorded. results. there were a total of admissions over this period and there were a total of , blood glucose measurements. incidents of hypoglycaemia were recorded, of which patients were on insulin and were not. of the patients who were on insulin, had adverse events at the time of hypoglycaemia. all these patients died within h of the adverse event. all except one was on full feed. the others had minimal feed due to poor absorption. of the patients who did not have adverse events, were discharged and one died days after the hypoglycaemic event due to worsening sepsis. of the patients on insulin, there were iatrogenic errors where feeding was stopped and the insulin was left on. none resulted in any adverse outcome for the patients. of the patients who were not on insulin therapy, had adverse events at the time. died within h of the adverse event and died days later. the remaining patients were discharged. none of the patients were on full feeding protocol. conclusions. our findings suggest that hypoglycaemia in our unit is not primarily related to insulin therapy. it is related to adverse events and possibly inappropriate feeding at the time of hypoglycaemia. hypoglycaemia, in the absence of insulin therapy, is associated with a poor outcome. use of hypoglycaemia as a quality indicator should be interpreted with caution. introduction. vitamin d deficiency seems increasingly prevalent. pleiotropic effects of vitamin d like immunomodulation and effects on muscle strength may be of special importance to critically ill patients [ ] . however, vitamin d deficiency has only been studied in small and selected groups of icu patients [ ] . objectives. to prospectively determine the prevalence of vitamin d deficiency in winter and summer and relate vitamin d status to outcome in cohorts of critically ill patients. results. vit d was measured in patients admitted in winter and patients admitted in summer (table ). mean vit d was significantly lower in winter than in summer. in winter, % was deficient, % severely deficient. in summer, % was deficient, % severely deficient. predicted mortality was higher in winter and higher in vit d deficient patients. observed mortality was lower than predicted in all groups, but not different between groups. including both vit d and season in a multiple regression analysis, winter (p = . ) and not vit d (p = . ) was related to predicted mortality. introduction. glucagon-like peptide- (glp- ) lowers blood glucose via stimulation of insulin and suppression of glucagon secretion, as well as slowing gastric emptying. we have previously shown that exogenous glp- attenuates hyperglycaemia in non-diabetic critically ill patients [ , ] . however, islet cell function in critically ill diabetic patients may be so disturbed that pharmacological doses of glp- have no effect in this group. objectives. the aim of this study was to evaluate the effect of exogenous glp- on glycaemic excursions during intraduodenal nutrient infusion in critically ill patients with preexisting type- diabetes mellitus. methods. nine critically ill, mechanically ventilated, patients with pre-existing type- diabetes ( m: f, age ± years, hba c . % ± . %, bmi ± kg/m , apache ii on day of study ± , days in icu on day of study ± ) received iv infusions of glp- ( . pmol/kg/min), and placebo, from t = - min on separate days in a randomised, double-blind, fashion. between t = - min a liquid nutrient (ensure) was infused intraduodenally at a rate of kcal/min via a naso-enteric feeding catheter. blood glucose concentrations were measured by glucometer at min intervals. data are mean±sem and comparisons are using student's t test. results. prior to the commencement of iv infusions there was no difference in blood glucose between the groups (at t- min: glp- : . ± . mmol/l vs. placebo: . ± . mmol/ l; p = . ). during fasting, glp- had no effect on glycaemia (at t = min: glp- : . ± . mmol/l vs. placebo: . ± . mmol/l; p = . ). however, glp- attenuated the overall glycaemic response to the nutrient (auc - min : glp- : , ± mmol/l.min vs. placebo: , ± mmol/l.min; p \ . ), as well as the peak blood glucose (glp- : . ± . mmol/l vs. placebo: . ± . mmol/l; p \ . ) conclusions. exogenous glp- is effective in reducing the glycaemic excursions that occur with enteral nutrient critically ill patients with pre-existing type diabetes mellitus. these data indicating that further studies using glp- , or its analogues, are warranted in this group. , , , , whilst raising concerns regarding an increased risk of hypoglycaemia. , , . locally most units adopt a protocol that reflects the practice of the original study. objectives. this study was conceived due to concerns around the safety of tight glycaemic control (tgc). our objectives were to measure adherence to our local policies and ascertain our true rates of hypoglycaemia. methods. this study was designed as a retrospective audit on four critical care units in the cheshire and mersey critical care network. each site used the same audit tool but adapted it to allow for differences in local practice and protocols. data pertaining to the prescribing and administration of insulin was collected daily over a week period (the time of data collection varied from day to day). the doctors and nursing staff were unaware of the audit and the data was collected by the ward pharmacist who suggested modifications to therapy if it was deemed inappropriate or unsafe. results. patient days worth of data was collected with blood glucoses checked in this period. % of patients receiving insulin had insulin prescribed. only % of blood glucoses were within the target range set by the local protocol. however, of all the results only . % were ''low'' as defined by the local protocol, and only . % ( / ) were hypoglycaemic episodes as defined in the greet van den berghe paper of (\ . mmol/l). conversely, . % were above the target range. in the trusts that recorded how many of these levels were[ mmol/l (a proposed alternative upper limit), the rates were and %. in response to a blood glucose the policies suggest dosage adjustments/maintenance. on only % of occasions were the adjustments made correct. insulin infusions appeared to be managed safely by nursing staff. insulin, if given, was always prescribed and hypoglycaemia (blood glucose \ . mmol/l) occurred on only one occasion. although safe, adustments often didn't follow the protocols and the patients' blood glucose were within the target range only % of the time, potentially negating many of the perceived benefits of tgc. reasons for non-compliance with the protocols was difficult to objectively establish reference(s). introduction. diabetes mellitus has been associated with an increased risk of adverse outcomes after coronary artery bypass grafting. hemoglobin a c is a reliable measure of long-term glucose control. it is unknown whether adequacy of diabetic control, measured by hemoglobin a c, is a predictor of adverse outcomes after coronary artery bypass grafting. material and method. we evaluated consecutive diabetic patients who underwent primary, elective coronary artery bypass grafting at the anadolu medical center. hba c levels of all patients with diabetes mellitus were measured and value of % or greater was used as a threshold for uncontrolled hyperglycemia. all the peroperative variables were recorded and then, statistically evaluated. the statistical analysis was realised by t test for parametric variables and chi-square test for nonparametric variables. results. there were consecutive patients that underwent elective coronary artery bypass graft surgery between january and april . among them, patients had diabetes mellitus and others not. there were no significant differences between groups regarding each adverse outcomes (table ) . although, ( . %) of total surgical site infection in patients had been seen in diabetic patients, there were also no significant differences between groups regarding the rate of infections (table ). there was no early postoperative mortality in diabetic patients. insuline treatment (iit) , by implementing a completely nurse driven protocol as in the leuven i study, to achieve tight glucose control in our -bed medical(cardio-)surgical icu and non-ventilator beds. in the last year, the benefit of iit and the possible detrimental effects of hypoglycemia on survival have been heavily debated. objectives. the goal is to analyze our daily practice in all icu patients and compare this with the intensive treated groups from the leuven , visep en nice-sugar trial. methods. we compared mean morning blood glucose levels and the percentage of patients who had a hypoglycaemia, defined as glucose below . mmol/l, from to . the frequency of control and the insulin dosage was comparable to the leuven study. enteral or parenteral feeding was started at admission. no standard intravenous glucose was used. glucose was measured with arterial blood samples on the abl flex radiometer as poct. results. in our patients, the mean morning blood glucose was higher than in the leuven study and comparable to the visep and nice-sugar. the percentage of hypoglycemia on our icu was lower in comparison with the visep and nice-sugar. this may be explained by the availability of a poct on our icu which allows quick adjustments of the insulin dosage. conclusions. effective tgc with sprint resolved organ failure faster, and for a greater percentage of patients who had similar admission and maximum sofa scores, compared to a matched retrospective conventional control cohort. these morbidity reductions mirror the reduced mortality seen with sprint. these results suggest that reduced organ failure, assessed by sofa, is a fundamental element in reduced mortality when tgc is implemented effectively. introduction. tight glycaemic control was reported to reduce mortality in selected surgical critically ill patients and lowering of blood glucose (bg) levels was recommended as a means of improving patient outcomes ( ) . however, this approach has been linked with significant risk of hypoglycaemia. recently, several studies have confirmed significant associations between variability of bg levels and patient outcomes ( ). objectives. to evaluate the association between bg variability and hypoglycaemia in a mixed adult icu. methods. retrospective analysis of the prospectively collected and stored bg measurements over a year period, during which tight glycaemic control was targeted in all patients. every day we have calculated the bg coefficient variation as expressed by sd/mean bg level. we have divided the patients into low, medium and high variability groups ( - , - and [ , respectively) . hypoglycaemia was determined if bg was below . mmol/l. for statistical analysis chi-square test and pearsons correlation test was used. results. patients were admitted over the -year period, providing daily data points. bg variability was high in daily measurements ( . %), medium in ( . %) and low in ( . %). hypoglycaemia occurred in measurement points ( . %). hypoglycaemia was observed at all points ( %) when bg variability was high vs. . % when bg variability was medium and . % when bg variability was low and this difference was statistically significant (p = . ). we observed a significant correlation between increased bg variability and hypoglycaemia (r = . , p = . ). conclusions. increased bg variability as expressed by coefficient variation is associated with hypoglycaemia, when measured daily in a mixed icu population employing tight glucose control. decreasing the variability of the bg concentration may be an important dimension of glucose management. if reducing swings in the bg concentration is a major mechanism behind the beneficial effects of glucose control, it may not be necessary to pursue lower glucose levels with the associated risk of hypoglycemia. ). there were two major outliers which may skew the results in favour of the hypothesis. if these two results are removed (fig. ) the statistical significance remains strong (n v * p \ . ; **p = . ; ***p = . )). standard multiple regression analysis found the most useful predictors of t [mid] were 'time with aki' and 'serum urea' (beta coefficient . and . (p \ . ) respectively). crcl, serum creatinine and urine output did not add further predictive statistical power. conclusions. this study demonstrates a reduction in the hepatic metabolism of midazolam associated with aki. this effect is related most strongly to the length of time the patient has suffered with aki. our results are similar to the ncepod report. even with multiple recommendations by ncepod and the national institute for clinical excellence (nice) recognition of the critically ill remains poor. detection of organ failure risk is vital to implement preventative strategies. we found a delay in aki recognition and a lack of risk assessment. observations, included in admission protocols, were recorded, but investigations outside of these, were often absent. nice suggest management should be physiologically and not diagnosis based but few patients had a documented physiological plan. we suggest improving under and postgraduate education to increase awareness of aki. this could occur as an extension to the national, acute life-threatening events recognition and treatment course. an aki admission protocol may allow identification of at risk patients and instigate appropriate monitoring, investigation and management. improved ward based fluid monitoring and management would reduce deterioration. incorporation of a physiological monitoring plan on the icu observation chart may reduce preventable aki. there was no effect in patients with extensive stroke and high severity of a glasgow score ( - points in an observational prospective study, a total of patients who admitted during months in a medical and surgical intensive care unit and didn t have any recent history of renal replacement therapy were included in the study. ( %) of all patients was in aki (acute kidney injury) group according to the akin (acute kidney injury network) definition. the mean of age in aki group was more than non-aki ( . ± . , . ± . respectively; p \ . ); and had worse condition according to apache ii (acute physiology and chronic health evaluation ii) score ( . ± . vs. . ± . ; p \ . ). the aki patients stayed longer in icu rather than non-aki patients ( . ± . vs. . ± . days respectively; p \ . ); with more mortality rate ( . vs. %; p \ . ). also the mechanical ventilation days, time of vasoacive drugs and the use of dobutamin were more in aki group (p \ . ; p = . and p = . respectively). the aki was a significant predictor for mortality using the multivariate logistic regression (or adj = . ; %ci: . - . ); and had the same sensitivity as the apache ii score in prediction of mortality (sen. = . ). objectives. the purpose of this study was to evaluate renal function in children with congenital heart disease (chd) undergoing cardiac surgery with cpb. we conducted prospective, non randomized observational study at the tertiary care university children's hospital -bed surgical icu. study protocol was approved by hospital ethics commission. the study included patients with chd with body weight from . to kg (mean . ± . kg) and age from days to years (mean age months). there were patients with ventricular septal defect (vsd), patients had atrioventricular septal defect (avsd), two had total anomalous pulmonary venous drainage (tapvd), one had tetrology of fallot (tof), one had transposition of great arteries (tga), and one had aortic stenosis, requiring ross operation. urine was collected in the postoperative period during the first h after surgery for determination of clcr. the serum creatinine (scr) level was determined by jaffé s method (cobas analyzer, roche). harrison am et al. [ ] shows that estimated creatinine clearence (clcr) using schwartz formula does not accurately predict clcr. therefore we used standard formula for clcr calculations. urine output, inotrope score, duration of aortic cross clamping and cardiopulmonary bypass was recorded. we applied rifle criteria to assess renal functions, using clcr as a variable reflecting glomerular filtration rate (gfr). objectives. evaluate whether a real-time alert of worsening of rifle class, through the physicians' dect telephone system, would affect therapeutic interventions for aki and progression of rifle class. single centre, prospective intervention study during a -month period in our bed surgical and medical icu. three study phases were compared: a . -month control phase (con ) where physicians were blinded for the electronic alerts, a -month intervention phase where electronic alerts of worsening rifle class were made available to the physicians through the dect telephone system (int), followed by a second . month control period (con ). pasw statistics was used for statistical analysis and a double sided p value of . was considered as significant. at study entry, before and after to receive antioxidant or placebo concentration the blood was drawn, to posterior determination of thiobarbituric acid reactive species (tbars), protein carbonyls, total nitrite concentration and il- . results. the use of nac+dfx decreases oxidative damage parameters. patients at antioxidant arm have, despite not reaching statistical significance, a decrease on plasma il- levels h after the start of treatment. as observed to oxidative damage parameters, il- returned to the placebo levels after the end of antioxidant administration. the nitrite levels increased h after nac+dfx, returning to placebo levels and h. the incidence of arf using the rifle criteria was not significantly different in the two arms, and this was also true to a number of secondary end points, none of which showed significant differences between the treatment arms. analyzing the subgroups of the sofa score we observed at day a worse cardiovascular sofa in the nac+dfx arm ( . ± . vs. . ± . , p = . ) and a better renal sofa in antioxidant treated patients ( . ± . vs. . ± . , p = . ). conclusions. we demonstrated that nac + dfx administration was able to decrease plasma markers of oxidative damage and to a minor extend il- plasma levels. we believe that the use of antioxidants could be an alternative adjuvant therapy to prevent arf in critical ill patients with hypothension. table were found to be independent risk factors for postoperative aki: objectives. we aimed to access prospectively whether the use of antioxindants has beneficial effects in renal function of critical-ill patients undergoing imaging studies with intravenous radio-opaque agents (ivca). patients were recruited from those hospitalized in a tertiary intensive care unit between and . inclusion criteria were: a) requirement for imaging studies with ivca b) no use of renal replacement therapy. patients were randomized to receive before and after imaging, either antioxidants (n-acetyl-cysteine , mg and ascorbic acid g and ml ns . %) (sg) or cc ns . % (cg). renal function was assessed by serum levels of creatinine and cystatin c assessed before and at , h following administration of ivca. patients were followed until discharge. systatin c was measured by elisa. conclusions. the results of this study suggest that the use of preventive antioxidant therapy may protect critical-ill patients from contrast-induced nephropathy. our preliminary results have to be confirmed in larger cohorts. acute coronary occlusion is the leading cause of cardiac arrest. because of limited data, the indications and timing of coronary angiography and angioplasty in survivors of out of hospital cardiac arrest are controversial. objectives. using data from the parisian region out of hospital cardiac arrest (procat) prospective registry, we performed an analysis to assess the impact of an invasive strategy on hospital survival. between january and december , survivors of out of hospital cardiac arrest were referred to a tertiary center in paris, france. in survivors with no obvious extra-cardiac cause of arrest, an immediate coronary angiogram followed if indicated by coronary angioplasty was performed at admission. the prognostic value of pre-hospital and in-hospital characteristics on in-hospital mortality was evaluated using logistic regression analysis. results. at least one significant coronary artery lesion was found in ( %) therapeutic hypothermia has been shown to improve survival and neurological outcome in patients who have suffered out-of-hospital cardiac arrest and in whom the initial rhythm was ventricular fibrillation (vf) [ , ] . international guidelines now recommend the use of therapeutic hypothermia as part of post-resuscitation care in patients fulfilling the above criteria [ ] . objectives. we surveyed current practice regarding the use of therapeutic hypothermia for post resuscitation care in northern ireland (ni) intensive care units. a questionnaire was devised, reviewed and agreed by each author prior to posting to the lead clinician in each of northern ireland's adult intensive care units. a % response rate was obtained. we asked about the existence of a protocol for cooling, which patients were cooled, duration of cooling, by what particular method(s) cooling was achieved and how temperature was monitored during cooling. results. out of ( %) adult icus in ni institute therapeutic hypothermia routinely as part of their post-resuscitation care. only out of the units ( %) have a protocol for institution and maintenance of hypothermia. all units that utilise hypothermia do so regardless of the initial cardiac rhythm. out of ( . %) icus target a temperature of - °c with out of ( . %) targeting a temperature of - °c. all units utilise surface cooling methods with out of ( %) also using cold intravenous fluids occasionally. out of ( %) units cool for - h, ( . %) unit - h and unit - h. all units use more than one method of temperature monitoring during cooling. all units sedate patients during cooling and out of ( . %) also routinely curarise patients during cooling. the units that do not currently use therapeutic hypothermia cited lack of resources/funding as the main obstacle to adopting this evidence based practice. conclusions. the practice of therapeutic hypothermia post cardiac arrest has been embraced by the majority of icus in ni. there appears however to be variation in the target temperature and duration of hypothermia once instituted. icus that cool patients appear to do so regardless of initial cardiac rhythm. regional protocolisation of this therapeutic modality may help standardise practice across ni icus. reference(s we compared our data with those from retrospective audit [ ] . the method of th was via surface cooling technique together with cold intravenous saline infusion but not ivcd. total patients presented with cardiac arrest: underwent th ( ooh vf/vt and ooh non-vf/vt). in , there was an overall improvement in adherence to the audit standards, as shown in table : table : table hospital survival rate of th % gcs of the survivors at icu discharge / ( %) / ( %) / ( %) / ( %) conclusions. introduction of ivcd has led to an improved compliance with local and ilcor th guidelines. although the total numbers are small, there has been an increase in the patients discharged with gcs from our icu using ivcd. there are areas that require further improvement, notably the time to reach target temperature and prevention of rebound hyperthermia. work continues on protocolised evaluation of neurologically damaged survivors. rd esicm annual congress -barcelona, spain - - october s target temperature management after out-of-hospital car-diac arrest, an international, multi-centre, randomised, parallel groups, assessor blinded clinical trial-rationale and design of the ttm-trial n. nielsen , , and the ttm-trial study group helsingborg hospital, department of anesthesia and intensive care medicine, helsingborg, sweden, lund university, department of clinical sciences, section of anesthesia and intensive care medicine, lund, sweden introduction. experimental studies and previous clinical trials suggest an improvement in mortality and neurological function with induced hypothermia after out-of-hospital cardiac arrest (ohca). previous trials have included highly selected populations and the optimal target temperature is not known. objectives. to evaluate differences in efficacy and safety with target temperature management at and °c for h after ohca of presumed cardiac cause. methods. intervention: patients will be managed with h of temperature control at versus °c according to randomisation. temperature control will be delivered with temperature management equipment at the discretion of the trial sites. to facilitate cooling, when applicable, and to stabilise the circulation all patients will be treated with ml/kg of crystalloid infusion ( °c or room temperature according to treatment arm). design. randomised trial with : concealed allocation of ohca patients to temperature control for h at versus °c with blinded outcome assessment. sample size is based on a relative risk reduction of % with a risk of type- error of % and a power of % with a % loss to follow-up. conclusion. this study demonstrated that health care professionals, despite guidelines, are hyperventilating simulated cardiac arrests patients. suboptimal ventilation was a problem across all the backgrounds investigated; although doctors performed best here, they were still found to be hyperventilating to an unacceptable level. hyperventilation has a number of deleterious physiological effects and is associated with poor outcomes. increased training, awareness and recertification may be the answer, and certainly improves short term compliance with guidelines. however, these effects may be short lived and other changes may be needed. a reasonable course of action may be the use of paediatric ( l) self inflating reservoir bags as a first line device. this simple measure may ensure delivery of more guideline consistent ventilation, independent of the level of experience. extracorporeal life support (ecls) has been proposed as the ultimate heroic rescue measure in prolonged cardiac arrest unresponsive to conventional cardiopulmonary resuscitation. ecls effectiveness in out-of-hospital cardiac arrest remains to be addressed. decision to discontinue cpr due to medical futility is based upon presumed prolonged anoxia, with existing guidelines for termination. however, even when ecls is implemented, failure to maintain stable hemodynamic conditions due to marked capillary leak frequently results in patient's death. to evaluate the usefulness of routine laboratory parameters in the decision to treat refractory cardiac arrest patients with ecls . methods. sixty-six adults with witnessed cardiac arrest of cardiac origin unrelated to poisoning or hypothermia undergoing cardiopulmonary resuscitation without return of spontaneous circulation (duration: min [ - ], median, [ - %-percentiles]) were included in a prospective cohort-study. ecls was implanted under cardiac massage, using a centrifugal pump connected to a hollow-fiber membrane-oxygenator, aiming to maintain ecls flow c . l/min and mean arterial pressure c mmhg. introduction. due to the human lifespan increasing, people are living longer. cardiac arrest (ca) in old people could be seen as a natural end of life process and cardio-pulmonary resuscitation (cpr) in this setting as a disturbance. therefore, the question of prognosis in patients has been raised when performing cpr in the elderly. data from the s found month mortality in % of patients over suggesting that cpr in elderly people could be futile ( ) . the recent progresses in the management of resuscitated patients, such as mild hypothermia, were not evaluated in patients older than years ( , ) . in a recent study, we found that age [ years was an independent pejorative prognostic factor ( ) . hence there is virtually no data of prognosis factor of elderly patients after ca. our aim was to determine the prognosis factors in patients older than years successfully resuscitated. methods. all patients admitted to icu for ca with successful rosc were consecutively included between and . ca data were prospectively entered in a registry according to utstein recommendations. patients were managed following standardized procedures. good prognosis was defined as cpc or at icu discharge. factor associated with a good outcome were identified using multivariate analysis. results. among , patients admitted for ca, were older than years. median age was . years ( - ), ca was from cardiac origin in % of patients and . % had a vt/vf initial rhythm. mean no flow (nf) and low flow (lf) were . (± . ) and . min (± . ). mean blood lactate and creatinine level at admission were . mmol/l (± . ) and lmol/l (± ). . % of patients presented post-resuscitation shock (prs) and . % were treated with hypothermia. conclusions. ca in elderly patients is associated with an in-icu % good outcome rate. this should promote the cpr in non-severely disable elderly patients with ca regardless of their age. we plan to collect the -month mortality and the functional status of survivors. introduction. post-resuscitation phase is often characterized by a ''sepsis-like'' syndrome, which may be associated with the development of organ dysfunction. microcirculatory abnormalities play a key role in sepsis-related organ failure; however no data are available on microvascular function after cardiac arrest (ca). objectives. the aim of this study was to investigate peripheral microcirculation during and after therapeutic hypothermia (th) in ca patients. methods. this prospective, observational study included patients treated by th after ca. sublingual microcirculation was evaluated using sidestream dark-field (sdf, microscan, the netherlands) videomicroscopy at hypothermia and normothermia in all patients. at least images of s each from separate areas were recorded at each time point and stored under a random number to be analyzed, using a semi-quantitative method, by an investigator blinded to time and condition. thenar oxygen saturation (sto ) was measured using a tissue spectrometer (inspectra ; hutchinson, usa). a vaso-occlusive test was performed at hypothermia and normothermia by rapid inflation of a pneumatic cuff around the arm to evaluate sto reperfusion rate, reflecting microvascular reactivity. results. compared to hypothermia, measurements at normothermia showed a significant increase in functional capillary density (fcd) from . ± . to . ± . n/mm (p = . ), the proportion of small perfused vessels (ppv) from ± to ± % (p = . ) and mean flow index (mfi) from . ± . to . ± . (p = . ). fcd and ppv values were significantly correlated with body temperature. sto reperfusion rate was largely decreased when compared to healthy volunteers, but it did not change over the study period (from . ± . to . ± . %/sec) and showed large inter-individual variability. the same was found for sto (from ± to ± %). conclusions. mild hypothermia is associated with decreased fcd and ppv in the sublingual area when compared to normothermia. microvascular reactivity is decreased but changes are unpredictable. introduction. acute posthypoxic myoclonus (phm) occurs in deeply comatose patients, soon after a hypoxic episode. it is characterized by generalized, severe body jerks with violent flexor movements, but more focal myoclonus is reported too ( ) . acute phm and status myoclonus are considered to have a poor prognostic outcome ( , ) . although the cerebral cortex is known to be the most common origin of myoclonus in ambulant patients ( ) , the origin of acute phm is uncertain ( ) . to determine whether acute phm originates from damage in cortical or subcortical structures. for this study patients with myoclonus in the first h after admission were selected from the propac ii study, a prospective cohort study including patients admitted after cpr and treated with hypothermia. exclusion criteria: pre-existing disease with life expectancy\ months and severely disability before cpr. baseline characteristics were used from the main database. additional data of eeg and ssep recordings made after rewarming were collected. eegs were evaluated for presence of epileptic activity, status epilepticus, generalized periodic discharges, burst suppression pattern, iso-electric or low voltage amplitudes and reactivity of the background pattern. data collected from sseps: n potential, giant potential (defined as a potential five times the size of a normal potential) and p /n amplitudes (done by jhk). the glasgow outcome scale (gos) was used to assess outcome after months, poor outcome was defined as a gos of - (death, vegetative state, severe disability), good outcome as a gos of - (moderate disability, good recovery). . from a total of patients included in the propacii study, ( %) patients developed myoclonus. baseline characteristics of this group: age , % male, time to rosc min, primary cardiac arrest in patients, hypoxic arrest in . ssep recordings were available from patients. n potentials were present bilaterally in % ( ) and giant potentials were seen in % ( ) of the patients with a present n potential. eegs were made, epileptic activity was seen in % ( ) and a status epilepticus in % ( ), thus % of the eegs did not show any type of epileptic activity. good outcome was seen in % of the patients, poor outcome in %. mortality was %. conclusions. the results of this study show that acute phm is found in % of patients admitted after cpr and treated with hypothermia. it did not necessarily lead to a poor outcome, but we did not have information about the type of myoclonus. the available data seem to support the idea that the myoclonus originates mainly from subcortical structures, given the low number of patients with eegs showing epileptiform activity and sseps with giant potentials, which can be seen in cortical myoclonus ( ). introduction. the international liaison committee on resuscitation, the american heart association and the european resuscitation council recommend that mild therapeutic hypothermia improve neurological outcome in unconscious adult patients with return of spontaneous circulation (rosc) after out-of-hospital cardiac arrest (ohca) due to ventricular fibrillation (vf) or ventricular tachycardia (vt). in our intensive care unit (icu) we use mild hypothermia in all patients following cpr with successful rosc regardless of initial rhythm. in this study we compared the effect of mild therapeutic hypothermia at neurological outcome and mortality between the patients who had ohca due to vf or vt and them who had ohca due to a different initial cardiac rhythm as asystole or pulseless electrical activity. the study protocol was approved by the local ethics committee on human research. a total of patients were admitted to our icu with rosc after ohca between may and december . therapeutic hypothermia was initiated after admission in icu by intravenous infusion of cold saline ( °c , ml bolus) followed by intravenous cooling device (coolline catheter, coolgard alsius corporation irvine, ca, usa). the target temperature was °c maintained for h followed by slow active re-warming over a minimum period of h ( . °c per hour). intravenous anesthesia was induced in all patients by a combination of propofol and remifentanyl with dose adjustment as needed. to prevent shivering, patients received muscle relaxation by iv administration of sisatracurium every h. the primary end point was the neurological outcome at months according to the pittsburgh cerebral performance category (cpc). secondary end point was mortality at months. prehostital cooling procedures were not applied. nine of the patients ( %) of the group of the patients who had ohca due to vf or vt had favourable neurological outcome cpc or as compared with of ( %) of the group of the patients who had ohca due to a different initial cardiac rhythm. mortality at months was % ( of patients died) in the group of the patients who had ohca due to vf or vt as compared with % ( of patients died) in the group of the patients who had ohca due to a different initial cardiac rhythm. in patients who had ohca due to vf or vt mild therapeutic hypothermia inproves the neurological outcome and reduces mortality as compared with the patients who had ohca due to a different initial cardiac rhythm. objectives. we aimed to compare therapeutic hypothermia using either surface or endovascular techniques in terms of efficacy, complications and outcome at our institution, a bedded tertiary referral icu. a local research ethics committee reviewed the proposed study and waived the need for a full ethics submission, as the study met the national criteria for service evaluation. data were collected from patients undergoing therapeutic hypothermia following cardiac arrest over a . year period by retrospective casenote review and interrrogation of the carevue (phillips uk) database. therapeutic hypothermia was initiated in the icu using iced hartmann's solution, followed by either surface (n = ) or endovascular (n = ) cooling; choice of technique was based upon endovascular device availability. the target temperature was - °c for to h, followed by rewarming at a rate of . deg h - . the mean age was ± years; % of arrests occurred out of hospital, and % were ventricular fibrillation/tachycardia. endovascular cooling provided a longer time within the target temperature range (p = . ), less temperature fluctuation (p = . ), better control during rewarming ( . ), and a lower -h temperature load (p = . ). endovascular cooling also produced less cooling-associated complications in terms of both overcooling (p = . ) and failure to reach the target temperature (p = . ). after adjustment for known confounders, there were no differences in outcome between the groups in terms of icu or hospital mortality, ventilator free days and neurological outcome. conclusions. endovascular cooling provides better temperature management than surface cooling, as well as a more favorable complication profile. the equivalence in outcome suggested by this small study requires confirmation in a randomized trial. introduction. ventricular assist devices (vads) are successfully used in patients with end stage heart failure, usually as a bridge to transplantation or recovery, but increasingly as destination therapy as well. a major threat for patients with a vad is the frequent occurrence of, mainly thromboembolic, stroke, with a reported incidence of up to %. manufacture guidelines for anticoagulation therapy are based on relatively small observational studies and common sense rather than evidence, and as a consequence anticoagulation protocols vary widely between centers. objectives. the aim of this systematic review was to provide more evidence in order to determine the optimal anticoagulation protocol to prevent stroke in patients supported with a vad. a systematic search in pubmed and embase was performed in which we included all types of vads. all types of anticoagulation drugs applied to prevent thromboembolism were included and divided in three categories; heparin, coumarins and antiplatelets. we included references with a full text available, written in english, dutch, german or french, and which described patients with a stroke or tia. our primary outcome measure was defined as the onset of any type of stroke. two authors evaluated independently the results of this search; doubtful references were evaluated by two other authors. after critical appraisal articles were selected as relevant, which include cohort studies, case-control studies and trials, totaling patients with vad support between and . the mean age was years (range - ) and the mean duration of support was days ( - ). stroke occurred in - % patients supported by vad, with an incidence of - /patient-year. the majority of strokes occurred within the first year. six types of anticoagulation protocols were used that combines drugs from one or all three categories. most protocols used a combination of all categories ( , patients with a total follow up of , days) and had an average stroke incidence of . events/patient-years. the lowest average stroke incidence was reported in studies that used only antiplatelets ( . events/patient-years) and the highest in which only heparin was used ( events/patientyears). we could not detect a decreased risk for stroke in patients with vad support when coumarines or heparin were used instead of or in addition to antiplatelets. antiplatelets should be part of an anticoagulation protocol to prevent stroke in patients supported by vad. a.m. de la torre , c. marco , d.j. palacios , a. pedrosa , i. lopez de toro , v.a. hortigüela hospital virgen de la salud, toledo, spain objectives. to analyze the difference between two groups of patients with ich considering severity, treatment, evolution and mortality. methods. description retrospective study of admitted patients between st of january of to st of december and st of january of to st of december in the icu of virgen de la salud hospital (toledo) with the diagnosis of ich. there are patients in the group of - and patients in the groups of - without any difference of age. regarding comorbidity between the two groups no differences can be found regarding the previous presence of hta, but regarding diabetes and dislipemy, we do find a higher prevalence on the second group ( . vs. . %, p \ . and . vs. . %, p \ . respectively). reviewing the presence of anticoagulated patients, no differences of significance can be found, but a trend ( . vs. . %, p \ . ). regarding the location of the hemorrhage, the most frequent is the basal ganglia ( . vs. %), existing no differences amongst the two groups. we don't find differences either in the presence of a intraventricular component, whether it is neither supratentorial nor infratentorial. there are differences between the ich score of both groups with p \ . : with a score of ( . vs. conclusions. an increase in the comorbidity can be observed in the included patients, which can be due to a better screening of these pathologies. we also find that the ich score is higher than in the - sample, which is attributed to the admittance in the icu of patients with the ultimate goal of organ donations. in the evolution, it can only be observed a longer stay in patients from the second sample, likely because they are more serious patients with a higher ich score. the analysis of the two groups has not been conclusive when it comes to assessing the improvements that might have come out in these last years, although it is necessary a deeper analysis of the data. introduction. sodium dysbalances are frequent medical complications in patients with subarachnoid hemorrhage (sah). hyponatremia is more frequent but it is associated with better outcome than hypernatremia. the aim of this study was to observe differences in outcome between hyponatremic and hypernatremic patients with sah. we performed the prospective years study in incidence of hyponatremia (serum sodium \ mmol/l) and hypernatremia (serum sodium [ mmol/l) in patients (pts) with sah. we compared the incidence of cerebral complications, glasgow outcome scale (gos) upon discharge from the neurointensive care unit (nicu) and in mortality nicu. results. there were ( %) pts with dysnatremia, more patients had hyponatremia ( , %), less hypernatremia ( , %). between these groups there were no diferences in stay in nicu (p = . ), duration of dysnatremia (p = . ), fluid intake (p = . , ml/day), daily sodium intake (p = . , mmol/day) and fluid output (p = . , ml/day). hyponatremia was more frequent on admission (p \ . ) and connected with higher diuresis (p \ . ). hypernatremic pts received more antiedematic therapy (p \ . ). hypernatremia was arised in pts with significantly lower glasgow coma scale (p = . ). these pts had more cerebral complications (p = . ), worse glasgow outcome scale upon discharge from nicu (p \ . ) and higher mortality in the nicu (p = . ). conclusion. dysnatremia is frequent in patients with sah ( %). hyponatremia occurs more often, but hypernatremia is connected with worse outcome. objectives. to analyze clinical, epidemiologic and outcome differences and to identify predictor factors of mortality at discharge from icu of patients admitted after craneoencephalic trauma (cet) according to glasgow coma scale (gcs) score. observational prospective study of patients admitted in the intensive care unit (icu) after cet. we classified the traumatic brain injury, according to gcs score of b or c points groups. we analyzed clinical and demographic data during icu stay, as well as physiological, functional and emotional data measured with paecc scale (project for the epidemiological analysis of critical patients) at discharge from icu. qualitative variables are expressed as a percentage and quantitative variables as mean and standard deviation. we used chi test, t-student and multivariate analysis as required with a maximum alpha error of %. we analyzed patients, . % male. at admission . % had gcs b . traffic accidents ( . % in gcs c and . % in gcs b ) were the most frequent cause of cet. there was a higher rate of out hospital hypotension in the gcs b group (p = . , or . , % ci . - . ). cranial computed tomography (ct) scan findings in the gcs c group were diffuse injury i and ii ( . %) after marshall classification versus . % in the gcs b group (p = . ). fewer complications were detected in patients in the gcs c vs. gcs b group ( . vs. . %, p = . , or . , % ci . - . ). icu mortality rate was significantly lower in the gcs c group than in the gcs b group ( . vs. . , p \ . ). predictors of mortality were gcs at admission (p = . ), ct findings type iii, iv and v (p = . , . and . respectively), complications (p = . ), tracheotomy (p = . ), days on ventilator (p = . ), apache ii (p = . ) and the length of icu stay (p = . ). best overall score in paecc questionnaire at discharge from icu was better in the gcs c vs. gcs b group. ( . ± . vs. . ± . , p = . ). conclusions. patients with lower gcs at admission presented higher rate of prehospital hypotension, more severe ct findings, more complications at icu, worse physiologic, functional and emotional outcome, and higher rate of mortality, than patients with gcs c . factors associated with increased mortality were coma level, type of findings in ct, complications, prolonged mechanical ventilation, length of icu stay, apache ii, and the need for a tracheotomy. objectives. the aim of our study was to estimate the influence of hyperhaes infusion on haemodynamic regulation. we examined patients with severe brain trauma (gcs score \ , sedation, artificial ventilation). the bp, stroke volume (sv) and their variability (bpv, svv) were determined by the bioimpedance method. additionally we determined the peripheral pulse (pp) and its variability (ppv) using plethysmography curve registration. special attention were paid to the p ( . - . hz) and p ( . - . hz) bands of bpv, svv and ppv, connected with volume state, breathing, and autonomic regulation, especially baroregulation. all the comparisons were made before and after min. of the infusion of hyperhaes ( ml). all patients had the autonomic dysfunction: the waves of baroregulation (p ) had low power compared with healthy. hypovolemia was moderate: sv ( ± . ) and pp ( ± . ) were slightly decreased, but bp were ± . mmhg. the bp increasing was registered as the first reaction on the infusion of hyperhaes ( ± . mmhg). the same time pp increased more then twice and became ± . , and p of ppv decreased from ± . to ± . , that reflected the improving of the volume state. although sv did not rise significantly, the increasing of p were estimated in svv, as a marker of the baroregulation restoration. conclusions. the infusion of hyperhaes in severe brain trauma not only decrease the range of hypovolemia, but restore the baroregulation as a significant part of autonomic regulation, needed for cerebral perfusion support. introduction. continuous measurement of intracranial pressure (icp) using intraparenchymal sensors has become part of the standard management of patients at risk of developing intracranial hypertension. whilst reliability has been explored previously little is published on the accuracy of depth to which the sensor is placed. a difference in sensor location has been shown to affect the reliability of icp readings and could impact negatively on patient management ( ). to determine whether icp sensors (codman, j&j) placed by neurosurgical staff were within the optimum depth of cm from the cortex. methods. consecutive patients were identified from a prospectively collected neuro icu database who had had a ct of the head (cth) performed whilst an icp sensor was in situ during . the depth of the sensor tip on cth was measured and patients were stratified according to whether they had surgery or no surgery to determine any differences between open and percutaneous placement. of the icp sensors ( %) were placed deeper than cm. the greatest incidence of deep placement was in surgical patients / ( %) and in craniotomy patients % of these were deeper than cm conclusions. this investigation has shown that the majority of patients admitted to our neuroicu have less than optimally placed icp sensors. inappropriately deep sensors appear more common in surgical patients, particularly following craniotomy. the impact of this on patient outcome is unknown and would require further study. this study has highlighted we need to implement new methods to improve the accuracy of our icp sensor placement. graduated marks on the sensor sheath during manufacture may assist accurate placement. conclusions. if icp is largely used, it remains below %. % of the cases have been monitored with at least techniques suggesting an acceptance tendency for a multimodal monitoring. among these techniques, the control of pco seemed considered important as the use of tcd to assess perfusion and vessel tone. on-going analysis of these data will provide information on the therapeutic strategy performed and the impact on outcome. introduction. raised intracranial pressure (ricp) can be evaluated sonographically by measuring the optic nerve sheath diameter (onsd). a wide variation in the threshold measurement of onsd for ricp has been reported in literature. it is likely that exaggeration of the hypoechoic edge artifact around the dura by high frequency ([ mhz) linear transducers and uncertainty over whether to measure -mm behind the papilla or behind the globe (posterior margin of sclera) could have resulted in such differences. to determine the optimal site of measurement of onsd by correlating it with ricp determined clinico-radiologically. we also evaluated if different sonographic appearances of the onsd could be used qualitatively to determine the presence or absence of ricp. methods. initially, in order to precisely delineate the anatomical dura sonographically and assess optimal cursor placement, cadaver orbital preparations were studied before and after subarachnoid fluid insufflation. scans were then done by a single sonographer using a - mhz linear transducer on healthy volunteers and patients admitted to the medical/ neurosurgical intensive care units. onsd was measured at locations; -mm behind the papillae and -mm behind the globe. in each location measurement was made within the anatomical dura and another between the echogenic margins of retrobulbar fat as described in literature. four patterns (fig. ) of the nerve sheath were identified based on the appearance of the csf space and edge artifact. ricp was diagnosed by clinically correlated computed tomography of the brain. an independent sample t test was done to correlate measurements with ricp. classification of optic nerve sheath appearances results. / ( %) scans were done on patients with ricp. all measurements independently correlated with ricp (p \ . ); albeit cut-offs differed substantially ( table ) . the presence of a type pattern (fig.) in both eyes strongly suggested ricp ( % positive predictive value) whilst its absence in both eyes ruled out ricp ( % negative predictive value). methods. three years after the introduction of the concept of bs in our icu, a questionnaire was sent to people directly involved in the nursing of critically ill patients to study the current practice during the previous month. responses were received from persons, a % response rate. ( %) persons had practiced bs. only ( %) employees used calming bath and ( %) an invigorating bath. guided oral care and guided suction was performed respectively by ( %) and ( %) nursing persons. orientative positioning was used by ( %) nurses. everybody is very satisfied with the instruction manual which can be found in each room. ( %) persons estimated to be well informed about bs. others wanted more practice course and training at the bedside. conclusion. pattern suggested an increasing interest in bs since its introduction. initial touch is well implemented. more effort is needed for continuous education and training. introduction. admittance to hospital for surgical treatment, is often linked with insecurity and anxiety for many patients. to most patients, the postoperative care unit constitutes an unknown environment, and can represent a frightening experience. research has shown that preoperative information leads to subjective outcome as anxiety reduction, and objective outcome as shorter hospital stay and less intake of pain medication. few studies, however, have addressed patients' experiences with preoperative information about the early postoperative phase. objectives. the purpose of this study was to describe patients' experiences with preoperative information about events they may experience during their stay in the postoperative unit. patients' experiences may contribute to increased knowledge about this topic. the study design was exploratory-descriptive, and a semi-structured interview based on thematic guide was used. nine patients met the inclusion criteria, and they had an average age of years. they were admitted to elective surgery for cancer and their stay in the postoperative unit varied from to . days. the interviews were conducted - days after surgery and transcribed verbatim. the data material was subjected to qualitative content analysis. results. experience with information before surgery and in the early postoperative phase, was categorized into four themes: being prepared before surgery, reactions to differing experience, discomfort and pain, management of some self-care activities and experiences with the environment of the postoperative unit. conclusions. the patients received a fair amount of information before surgery, but only limited information concerning what to expect while in the postoperative unit. the patients' information needs differed and patients with former experience with surgery were more prepared for what to expect. the patients got mainly verbal information and most of this was given the day before surgery. o.m. peters-polman , m. van roosmalen , j.e. tulleken , j.g. zijlstra umc groningen, intensive care, groningen, netherlands, arup nederland, amsterdam, netherlands, umc groningen, groningen, netherlands background. who guidelines concerning sound levels in hospitals requires a maximum of db in daytime, a nighttime sound level below db to allow good sleep quality and peak levels that do not exceed db at all times. in an icu environment, apart from being critically ill, patients are exposed to typical icu environmental noise. sleeping cycles disturbed by illness are further disrupted by care providers performing procedures and taking vital signs and alarms with delirium as a common result. we describe the acoustic environment in our mixed icu. we conducted an observational study in which we continuously measured the sound level (db), frequency and repetition of sound in our icu. we used a splnet microphone and noise monitoring system which was placed, after informed consent, at the ear level of the patient. results. noise sources are numerous and consist of human voices, doors slamming, pagers, telephones, shoes and equipment alarms. there is a round the clock continuous background noise of - db, staff conversation with levels of - db and peak levels up to - db, mainly due to alarms. these levels of sound are comparable to loud conversation at meter distance ( - db), walking along a motorway ( - db) or standing next to a roaring engine ( db). conclusion. who guidelines clearly state maximum sound levels of db in daytime, db at night and peak levels of db. the sound level in our unit is exceptionally and unacceptably high throughout day and night and requires a behavioral intervention. further research on the influence of these noise levels on our patients is necessary. objectives. this study has been achieved in order to realize the comparison of efficiency of manual and mechanical compression techniques used for the maintenance of haemostasis after femoral sheath removal. methods. this study was planned and applied as a randomized controlled trial. the study was executed at a military education and research hospital in turkey between january and march . data collecting form was prepared by the investigators after the literature examination. the form consists of questions which are evaluating the demographic data of patients, the compression time, the pain level (before sheath removal, during the manual/ mechanical compression and after the sheath removal), the complications occurring in femoral zone, the mobilization/discharge period and the problems (bruise, oedema, hemorrhage and etc.) occurring the th day after the discharge. the patients have been called up in order to evaluate the problems occurring on the th day. the persons that were applied mechanical compression have constituted the experimental group and the patients that were applied manual compression have formed the control group. the patients volunteer to participate to the study have been informed in regard with the implementing procedures before the application. descriptive statistics were shown in numbers and percentages for the variables obtained by counting and in mean ± standard deviation for variables obtained by measurement. results. the average of age is . ± . in the experimental group and is . ± . in the control group. the average of compression time is . ± . min in the experimental group and is . ± . min in the control group (p \ . ). the average of mobilization time after sheath removal is . ± . min in the experimental group and is . ± . min in the control group (p \ . ). it has been observed a lower pain level during compression and after sheath removal in patient that were applied mechanical compression in comparison to the patients that were applied manual compression(p \ . ). when the groups were compared in terms of femoral zone complications while no haematoma was observed in the experimental group, haematoma has been occurred in the . % (n = ) of the control group. conclusions. the mechanical compression provides an earlier mobilization and earlier discharge of the patient. this study shows that mechanical compression is a method as safety as the manual method in order to obtain a haemostasis a correlational survey was conducted in public hospitals located in athens. critical care nurses completed anonymous questionnaires , , yielding a response rate of %. greek critical care nurses believe that open visiting increases family's satisfaction ( . %), exhausts family members ( . %) and provides emotional support to the patient ( . %); nevertheless the effects of visiting depend both on patient and family ( . %). furthermore open visiting hampers the planning of adequate nursing care ( . %) and is not a helpful support for the caregivers ( . %) while increases their physical and psychological burden ( . %). critical care nurses' attitudes toward visiting hours were rather negative and they didn't want to liberalize the visiting policy of their unit ( . %). there was a positive correlation between nurses' beliefs and attitudes regarding visiting (r = . , p \ . , r = . , p \ . ). the factors ''working experience'', ''adequacy in staff'' and ''the number of shifts'' were found to be independently correlated and they predicted the score of the scales of the questionnaire. greek icu nurses have rather negative beliefs and attitudes toward visiting and open visiting policy. this will be a challenging barrier to overcome when imposing new flexible policies in icus . objectives. our aim was to elucidate potential mechanisms for the beneficial effects of rhapc on ali, as assessed by microarray analysis of lung tissue after sepsis induced by clp in rats. methods. sepsis (n = ) was induced in rats by clp. a sham-operated group (n = ) underwent laparotomy and closure without clp. a clp group (n = ) received subcutaneous saline ( ml/kg) and a clp + apc group (n = ) additionally received mg/kg rhapc. twelve hours postoperatively, lung tissue was preserved in mrna later until mrna isolation by promega total rna kit and analyzed using illumina beadarray. data were log variance stabilized and quantile normalized using the lumi package in r and the limma package was used for group comparisons and false discovery rate correction. data were further analyzed using panther and david. the clinical outcomes of this study showed a marked attenuation of the sepsisinduced increase in lung permeability in rats treated with rhapc . although no formal statistical significance was reached for the gene expression changes between the clp and the clp + apc groups, there was a clear attenuating effect of rhapc on the changes in gene expression caused by sepsis reflected in generally lower fold change values and fewer significantly differentially regulated genes in the clp + apc versus sham group compared to the non-treated clp vs. sham group ( vs. genes). nevertheless, there were only genes of which the fold change difference between clp versus sham and clp + apc versus sham was more than one, indicating that although there was a large difference in the number of differentially expressed genes, the difference in fold change between these genes was small. conclusions. these data suggest that the rhapc treatment of septicemic rats does not only cause a down regulation of specific pathways as argued by previous investigators, but leads to a global reduction in the inflammatory response at a mrna level. introduction. septic shock guidelines recommends the use of recombinant human activated c protein (acp) in high risk mortality patients. the aim of our study is to describe the clinical characteristics, and the outcome of patients treated with acp in our hospital. methods. retrospective and descriptive study which includes patients with severe sepsis/ septic shock treated with pca in a tertiary hospital intensive care unit (icu) over years ( - ) . we analyze epidemiological data, reason for admission, infectious focus and agent, severity scores, organ failure, complications, stay and mortality. we used chi-square analysis to compare categorical data and student's t test to compare continuous variables. conclusions. in our study most patients were admitted from emergency department, with organic failure caused by pneumonia. we haven't detected deaths related with acp complications, even in patients undergoing surgery. we found as prognostic factors for mortality: organ dysfunction, acp indication, renal failure, pao /fio relation, amount of vasopressors, bicarbonate and base deficit levels, apacheii and icu stay. objectives. to analyze changes on hemodynamics in patients with severe sepsis treated with high volume hemofiltration ( ml/kg/h) vs. patients treated with very high volume hemofiltration ([ ml/kg/h). we conducted a prospective randomized trial from january to november in patients admitted into icu with a diagnosis of septic shock in which hf was indicated. patients were randomized to one of each group of therapy. the control group received high volume hemofiltration therapy and the experimental group received very high volume hemofiltration. the hemodynamic parameters were measured at the admittance in icu and every h onwards. results. data of patients were collected ( men and women) mean age ± years old. the hemodynamic parameters registered at the admittance and during the therapy had no significant difference between the groups. the control group received hf therapy during . ± . days and the intervention group . ± . days. there wasn't any difference either in the administration of vasoactive drugs between both groups. the most significant difference between the groups was the -day survival rate, . % of the experimental group against . % of the control group (p = . ). from these results we can conclude that very high volume hemofiltration therapy should be the therapy of election because it improves the survival of patients with severe sepsis without impairing the hemodynamic parameters. we have to point out the importance of the nursing staff in the assembly and management of the equipment as well as in the patient care and thus avoiding potential complications. introduction. the use of herbal products is increasing, and may result in increased drug-herb interactions or form a potential for adverse reactions in cardiovascular surgery patients. objectives. the aim of this study was to describe the utilization patterns for herbal products in patients with cardiovascular disease. methods. this was a descriptive study which was carried out among adult patients presenting to cardiovascular surgery department for elective cardiac surgery between september and april in a research and training hospital. after giving informed consent, patients were interviewed by researchers using a structured survey instrument in the preoperative period. results. interviews were conducted with patients (mean age . ± . , range: - years), % of them were married, % were men, and % of the patients had high school or university education. the majority ( %) had coronary artery disease and most of the patients ( %) had concomitant diabetes mellitus and hypertension. the most common used drugs were anti-hypertensives, nsai's, and anti-aggregants. most patients ( %) reported the regular use of drugs. eighty-nine ( %) among the surveyed patients reported the use of herbal products. the most common used herbal products were garlic ( %), apple vinegar ( %), lavandula stoechas ( %), cratageus ( %) and ginger-honey mixture ( %). the average educational degree of herbal product users was found to be higher when compared with the others. many patients report being informed about those products from television, internet, newspapers, herbal-stores personal communications, and report the use of those products after the diagnosis is made. none of those patients have informed physicians or nursing staff about the use of those herbs. the demographic variables of patients and the herbal-product usage has failed to show a statistically significant difference (p [ . ). conclusions. the use of herbal products is common among the patients with cardiovascular diseases. health professionals should be aware of the usage of those products in order to prevent possible adverse reactions and drug-herb interactions. introduction. nurses employed in the icu operate in a complex environment, under time pressure, and with limited information available. thus, errors are inevitable and, besides their adverse consequences, they offer the potential for learning . in this concept, properly copying with errors is a prerequisite for avoiding their recurrence and improving nursing practice. objectives. our aim was to investigate how error-copying strategies are associated with constructive and defensive changes in icu nursing practice. methods. questionnaires were completed (a % response rate) from nurses employed in the icus of adults, children, and the coronary care unit of two greek hospitals, between january-june . ''ways of copying'' scale as revised by wu et al. was used for evaluating copying strategies. this includes copying subscales, each ranging between and . constructive changes in response to error included items (paying more attention to detail, keeping better patient records, reading patient notes more carefully, seeking advice, discussing with colleagues about similar situations, devoting more observation on patients, reading for covering knowledge deficiencies), while defensive changes included items (getting more worried, feeling less confident at work, being more likely not to discuss errors, being less trusting of others, thinking to leave profession.). a four-point likert scale ( - ) was used for evaluating each item, and points were summed to estimate total scores of constructive and defensive changes. . . % of participants were female and . % were registered nurses. mean (±se) age was . ± . years and mean icu experience was . ± . years. multiple linear regressions with constructive and defensive changes in practice as dependent variables and copying strategies as independent variables are summarized in table . participants were more likely to make constructive changes if they coped by seeking social support (p = . ) and accepting responsibility (p = . ). at the same time, they were more likely to make defensive changes if they coped by escape-avoidance (p = . ). reasons for high risks are e.g. sedation and analgesia, immobility, malnutrition and hemodynamic or oxygenation problems as well as poor identification or unsystematic assessment of the risks. in our unit, we performed a months retrospective review of pressure ulcer risks for all patients (n = ) using jackson-cubbin calculator. the risk point level in this instrument is and below. patients of ( %) exceeded the risk limit already in the icu admission phase. objectives. to change care practices of pressure ulcer prevention and care with action research. with the measurement tool nurses are able to identify patients at risk of developing pressure ulcers during the whole icu in-patient time, and to prevent risks of pressure ulcer in an early stage. with the assessment tool, the measurement is systematic which enables the benchmarking and have effects on material recourse planning and cost caused by pressure ulcers. the study unit is a -bed icu for adults taking care annually circa , patients with multiple disorders. firstly, the jackson-cubbin pressure area risk calculator was translated into finnish. a few changes which have an effect on pressure ulcer risk were added; weight limits were also defined with bmi values, hyperbaric oxygen therapy was added in deducted points as well as h limit for blood transfusions and limits for hypothermia from celsius or under. secondly, standardized guidelines for different risk levels were developed; if patients have a high risk specialized mattresses should be used and changes of positions and beds should be stressed. thirdly, an electronic evolution form for patient information system was planned and implemented. finally, a systematic education program for icu personnel including special lectures, material demonstrations and familiarization by the nurse responsible for wound care was started. results. after the development project and systematic education the knowledge of personnel about pressure ulcer risks and care has increased. risk points are counted once a day for every patient using the electronic form. all the mattresses at the icu have been changed to medium and high risk mattresses and are chosen for a patient related to the risk assessment points. conclusions. a reliable assessment scale, systematic measurement and continuous evaluation and education are crucial for identification of high risk pressure ulcer patient at the icus. with a systematic measurement and recognizing high risk patients we can also improve patients' quality of life and reduce the cost caused by pressure ulcers. reference(s ) is considered to be one of the main agents in gram negative sepsis. in recent years several adsorption dispositives have been designed in order to achieve low blood endotoxin levels with a theorical clinical improvement. toramyxin (polymixine b fixed to polyesthirene fibers) and alteco lps adsorber (polyethylene discs) are two of these dispositives. both are used with h sessions for several days until patient clinical improvement. • design a nursery prothocol with the most important procedures in gram negative septic shock patients with acute renal failure that undergo adsorption cartridge therapy. • evaluate initial experience in the use of endotoxin adsorption cartridges. methods. nursery prothocol with special attention to the settlement and management of the cartridge therapy, based on library references and practice guidelines. once prothocol was stablised, prospective observational study was started from january till january . inclusion criteria were: patients admitted to our intensive care department with gram negative confirmed septic shock and acute renal dysfunction requiring continuous renal replacement therapies (crrt). adsorptive cartridge were added and several parameters were studied: heart rate, mean blood pressure, vasopressor support (norepinephrine), pao / fio , and lactate. the information was analyzed in excel. results. nursery protocol was correctly applied in all patients and showed to be basic in the maintenance and early complication detection. hemodynamic improvement that allowed norepinephrine lowering dose and normalized lactate levels with no changes in pao /fio . patient (toraymyxin): years man, acute pancreatitis with septic shock. patient (toraymyxin): years man, pneumococic pneumonia and klebsiella septic shock. patient (alteco): years man, acute pancreatitis with enterobacter cloacae septic shock. patient (alteco): years woman, acute peritonitis with e. coli septic shock. results of a program to reduce catheter-related blood-stream infection in the icu: two years' follow-up a systematic review comparing the relative effectiveness of antimicrobial-coated catheters in intensive care units benefits of minocycline and rifampicin-impregnated central venous catheters which antimicrobial impregnated central venous catheter should we use? modeling the costs and outcomes of antimicrobial catheter use when is hit really hit? anticoagulative management of patients requiring left ventricular assist device implantation and suffering from heparin-induced thrombocytopenia type ii -hit happens: diagnosis and evaluating the patient with heparininduced thrombocytopenia informe del registro mami - grupo de trabajo de la sociedad europea de cardiología (esc) sobre marcapasos y terapia de resincronización cardíaca moreno millán e. variación de la estancia preoperatoria en españa según grupos de edad, sexo y modo de acceso hospitalario reference(s). . association of anaesthetists of great britain & ireland. safety guideline on interhospital transfer intensive care society: guidelines for the transport of the critically ill adult competency-based st st training and assessment. a manual for trainees and trainers. royal college of anaesthetists training and assessment of competency of trainees in the transfer of critically ill patients adverse events experienced while transferring the critically ill patient from ed to the icu a modified mccabe score for stratification of patients after intensive care unit discharge: the sabadell score surviving intensive care. edicion taurine and niacin block lung injury and fibrosis by down-regulating bleomycin-induced activation of transcription nuclear factor-kappab in mice antioxidants and sepsis: can we find the ideal approach? post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. a scientific statement from the international liaison committee on resuscitation therapeutic hypothermia after cardiac arrest: unintentional overcooling is common using ice packs and conventional cooling blankets it's well known that normobaric hyperoxia (nh) increases arterial and brain oxygen tension. however the influence of nh on intracranial pressure (icp) and cerebral metabolism in patients to investigate the dynamics of icp, jugular bulb saturation (svjo ), brain oxygen tension (pbro ) and cerebral metabolism during nh in patients with ich icp monitoring and tissue microdialysis were used in all patients, svjo monitoring -in , pbro -in . microdialysis and pbro catheters were placed in lesioned (les) and intact (int) brain tissue. icp, svjo , pbro , glucose and glycerol levels, lactate/pyruvate ratio dynamics during fio ) to ± mmhg (ð \ . ) (fio . ) and ± mmhg (ð \ . ) (fio . ) cerebral metabolism didn t change significantly, except glycerol level increase in lesioned brain tissue from ( ; ) mlmol/l (fio . ) to ( ; ) mlmol/l (fio . ) and ( ; ) mlmol/l (fio . ). fio . : glucose (int) - . ( . ; . ) mmol/l, glucose (les) - . ( . ; . ) mmol/l, lactat/piruvat (int) - . ( . icp was stable during investigation ( . ± . mmhg nh is accompanied by pao and pbro increase and doesn't influence icp and cerebral metabolism in ich patients with normal vo /do relationships effects of anesthetics oc cerebral blood flow and cerebral metabolic rate isoflurane preconditioning improves long-term neurologic outcome after hypoxic-ischemic brain injury in neonatal rats this no-profit trial has been supported by depuy/ hemedex, providing the probes. no other economical support has been received effect of equiosmolar solutions of mannitol versus hypertonic saline on intraoperative brain relaxation and electrolyte balance a comparison of % hypertonic saline and mannitol for brain relaxation during elective supratentorial brain tumor surgery hypertonic resuscitation and blood coagulation: in vitro comparison of several hypertonic solutions for their action on platelets and plasma coagulation effect of the combination of mannitol and ringer acetate or hydroxyethyl starch on whole blood coagulation in vitro no well defined threshold for transfusion or target hemoglobin (hb) level for these patients exists. objectives. to examine associations of anemia and transfusion with adverse outcomes in patients with sah, and better define hb level thresholds associated with these. methods. retrospective, observational study of consecutive patients with sah admitted to icus at mayo clinic in jacksonville and rochester, usa, over -year period. data included demographics, nadir hb, blood transfusion, ali/ards, vasospasm, radiographically confirmed cerebral infarction, apache and wfns. primary outcome was association of anemia and transfusion with death and secondary outcomes were vasospasm, cerebral infarction and ali/ards. results. we identified patients, mean age was (± ), ( %) were females. mortality was %. seventy-two ( %) of patients were transfused. ( %) patients had vasospasm and ( %) cerebral infarction. there was a strong association between transfusion and increased mortality (p = . ), vasospasm (p = . ), cerebral infarction (p \ . ) and ali/ards (p \ . ) outcome prediction in mild traumatic brain injury: age and clinical variables are stronger predictors than ct abnormalities comparison of simultaneous continuous intracranial pressure (icp) signals from a codman and a camino icp sensor therapeutic actions may correct abnormal values and perform potentially cerebral blood flow/oxygen extraction coupling. objectives. aim of this study was to describe the incidence and the type of bedside icu monitoring devices used in the management of patients with severe tbi in french icu's. methods. multicentric observational study including patients having severe tbi (glasgow coma scale (gcs) \ ) picked on scene by a mobile medical unit for pre-hospital care (samu). inclusion period: months general hospital of athens, department of intensive care unit o poder na relação enfermeiro-utente relacionamento enfermeiro, paciente e família: factores comportamentais associados à qualidade da assistência investigação qualitativa em enfermagem: avançando o imperativo humanista the experiences of families of critically ill patients in greece: a social constructionist grounded theory study. intensive and critical care nursing visiting hours policies in new england intensive care units: strategies for improvement this study was supported by a post graduate programme in nursing surviving the nursing shortage: developing a nursing orientation program to prepare and retain intensive care unit nurses clinical utility of apc-pci (activated protein c-protein c inhibitor) complex as predictors for severity and prognosis in sepsis: preliminary study republic of korea introduction. recently human recombinant activated protein c (drotrecogin alfa [activated]) has been shown to reduce mortality in severe sepsis. in severe sepsis, conversion of protein c to apc (activated protein c) is impaired due to endothelial dysfunction. apc level is related to coagulation cascade known to be important in sepsis pathophysiology. objectives. in this preliminary study, we checked apc-pci (activated protein c-protein c inhibitor) complex level to evaluate protein c activation using apc-pci elisa kit they were admitted asan medical center (seoul, korea) medical intensive care unit (icu) between sep and . , respectively. apc-pci level had no statistically difference among sepsis, severe sepsis, septic shock ( . , . , . ng/ml, p = . ). between hospital survivor group and non-survivor group there was also no difference in apc-pci level ( . , . ng/ml but apc-pci level was tended to decrease in severe sepsis, septic shock group as compared to sepsis group activated protein c versus protein c in severe sepsis endogenous protein c activation in patients with severe sepsis efficacy and safety of recombinant human activated protein c for severe sepsis septic critical patients to evaluate the experience with drotrecogine alfa (da) in septic critical patients (scp) in a analysis of scp admitted in an icu unit between december and which received treatment with da. patients were included or excluded on the approved specifications fda and emea. inclusion criteria were septic patients and apache ii score c and/or two or more organ dysfunction (od) thirty-eight patients were eligible od: respiratory %, renal %, cardiovascular %, metabolic %, hematologic %; sdra . , vmc . , vni, . , all patients received empirical antibiotic treatment in the first h according to epidemiologic characteristics. microbiology: some germens were isolated in patients ( %) mortality (%) by presumed site of infection day /day : respiratory / , abdominal / , urologic / ; skin / . average hours drug administration was h. da was administrated at % of the patients between hour and hour , the other % between hour y critical septic patient treated early with empirical antibiotics, the best standard care and da have a low mortality rate. more early da administration was associated to lower mortality the treatment of severe sepsis in france: overview of a -year survey period bichat hospital, surgical intensive care unit lariboisière university hospital, medical intensive care unit cochrane database leptin is an adipocyte-derived cytokine regulating energy homeostasis, metabolism as well as immune-inflammatory processes. leptin also has thermogenic actions and regulates enzymes of fatty acid oxidation. leptin is significantly increased in response to acute infection and sepsis and exerts direct effects on cd + t-lymphocyte proliferation, macrophage phagocytosis, and secretion of inflammatory cytokines such as il- and tumor necrosis factor (tnf) a. we measured leptin in blood of septic patients we measured leptin serum levels in septic patients leptin levels in septic patients (mw = , . ng/ml ± sem = , . ng/ ml) are significantly higher compared to healthy controls (mw = , . ng/ ml ± sem = , . ng/ml, p \ . ). serum levels of leptin were significantly higher on day (mw = , . ng/ml ±sem = , . ng/ml) and day (mw = , . ng/ ml ± sem = the aim of this multi-centre retrospective observational study was to resuscitation bundle the above preliminary data indicated that an experienced use of rhapc, when compared to other survey ( ), was associated with a reduction of serious bleeding events, a more frequent off-label use and a similar mortality rate. the concomitant adherence to evidence-based guidelines improved significantly the patient survival ) macias et al. sources of variability on the estimate of treatment effect in the prowess trial: implications for the design and conduct of future studies in severe sepsis use of drotrecogin alfa (activated) in italian intensive care units: the results of a nationwide survey acute lung injury (ali) is one of the most frequent complications of sepsis. although coecum ligation and puncture (clp)-induced sepsis is a frequently used model, we found only three microarray studies of clp-induced sepsis - , of which one looked at lung tissue . none of them had examined the effects of recombinant human myocardial transcriptional profiles in a murine model of sepsis: evidence for the importance of age molecular signatures of sepsis: multiorgan gene expression profiles of systemic inflammation sepsis gene expression profiling: murine splenic compared with hepatic responses determined by using complementary dna microarrays endothelin- in endotoxin-and sepsis-induced lung injury activated) in real-life clinical practice for management of severe sepsis in surgical patients in patients with severe sepsis and multiple organ dysfunction, major surgery is not a contraindication for early ( - h after surgery) daa administration retrospective, observational, descriptive cohort study in patients with severe sepsis and multiple organ dysfunction treated with daa the principal focus of sepsis differed between the two groups (p \ . ): in the surgical group it was the abdomen ( . %) followed by the skin and soft tissues %) followed by the urinary tract ( . %) in the perfusion period, the distribution of severe/ moderate hemorrhages in the surgical group was %/ . vs. . %/ . % in the medical group. we found no differences between groups in death from any cause at days ( . vs. . %; rr ; % ci . - . ; p = . ). nevertheless, at days overall mortality had increased in both groups, although this difference was not statistically significant: the percentage of increase with respect to the -day mortality was % in the surgical group and % in the medical group in patients with severe sepsis and multiple organ dysfunction, major surgery is not a contraindication for early ( - h after surgery) daa administration. given our findings at days, studies including a wider period from the initiation of daa administration are necessary to evaluate the cost-efficacy efficacy and safety of recombinant human activated protein c for severe sepsis recombinant human activated protein c, package labeling and hemorrhage risk reference(s). iom. to err is human incidence of adverse events and negligence in hospitalized patients matrix metalloproteinase- promotes repair after ventila-tor-induced lung injury supported by the parker b. francis foundation, physician services incorporate, ontario thoracic society and canadian lung association sepsis-induced immuno-endocrine dysfunction impact of arginine-vasopressin (avp) and apelin (apl) exogenous administrations in a rodent model because the corticotrophic pathway is disturbed during circi, with acth-cortisol dissociation, alternative physiologically nondominant pathways such as the vasopressinergic/apelinergic axis, become essential to the hpa adaptation to stress. objectives. seeking the impact of arginine-vasopressin (avp) and apelin (apl) exogenous administrations on: acth & corticosterone blood contents, and respective pituitary and adrenal gland receptor expression (v b, apj) in a rodent model of endotoxin challenge. methods. a rodent model of endotoxin (lps e. coli :b , mg/kg i/p)-induced hpa axis has been selected to study the committment of avp/apl and related receptors (v b/ apj). rats (n = ) were equipped with subcutaneous osmotic minipumps (alzet, ) containing: saline, apl- ( , , , lg), or avp ( . , lg) for h. results. without lps challenge, exogenous apl administration did not alter acth & corticosterone blood contents whereas high dosage of exogenous avp significantly increased corticosterone blood content (p \ . vs. control). lps i/p challenge induced a huge increased of blood acth & corticosterone, both culminating at . h ( -and -fold increases respectively, p \ . vs. baseline), which was normalizing at h for acth whereas corticosterone remained high. this dissociation validates the model, matchs with human observations, and suggests non acth-dependent corticosterone release after lps challenge apl administration completely reversed the above down-regulation while avp also partially restored apj pituitary expression by almost % in a dose-dependent manner, and to a lesser degree in the adrenal gland (p \ . vs. lps). selective non-peptide v b (ssr ) and peptide apl antagonists (f a) substitutions confirmed the above effects were directely mediated. conclusions. apl and avp pituitary neuronal and bloodstream contents behave differently, and blood acth & corticosterone contents were dissociated, after acute lps challenge. apl as well as avp exogenous administrations were able to reverse (partially for the later) the lps-induced apj down-regulation in both pituitary and adrenal glands. reference(s) supported by the esicm young investigator award from infection diagnosis to therapy an antimicrobial stewardship program (asp) is a method of optimizing antimicrobial prescribing, altering antimicrobial resistance, reducing costs, and improving patient care. the intensive care unit (icu) is an ideal environment for the application of an asp given the complexity of the patient population, the ecology of resistant organisms, and the fact that selection of inappropriate antimicrobials or delays to determine the impact of the introduction of an icu asp on prescribing, patient outcomes, resistance, and costs we implemented an asp in a -bed medical surgical icu of a university-affiliated hospital. the asp team used prospective audit with interaction and feedback providing suggested changes in therapy (e.g. antibiotic choice, dose, duration) on a daily basis. asp provided consultation on all icu patients not followed by the infectious diseases consult service. parameters collected included demographic data, details of antimicrobial regimens, culture results, defined daily doses (ddd)/ patient days and antimicrobial costs mean monthly antibacterial ddd/ patient-days post-asp was reduced by . % ( . vs. . , p \ . ). the implementation of the asp was associated with a . % decrease in mean monthly antibiotic costs/ patient-days ($ vs. $ ) for a total cost reduction of $ , . in terms of prescribing and resistance, the introduction of asp was associated with a reduction in the prescribing of anti-pseudomonal agents (compared with antibiotics not covering pseudomonas) (mean monthly ratio . vs. . ), mrsa vs. mssa covering antibiotics (mean monthly ratio . vs. . ) and improved susceptibility pattern for pseudomonas aeruginosa as demonstrated by increases of , and % to tobramycin, meropenem, and piperacillin-tazobactam susceptibilities, respectively. there was no difference in icu mortality rate the asp team worked collaboratively with the icu team to improve antimicrobial therapy and as a result improved overall antibiotic usage and resistance patterns of important icu microorganisms, and decreased antimicrobial costs. appropriate and judicious antimicrobial use guided by an asp is beneficial to the icu can pct and/or crp help identify associated bacterial infection in patients with influenza pneumonia? procalcitonin (pct) is a recognized marker of bacterial infection and might be a prognostic marker in lower respiratory tract infections. objectives. to determine if pct and/or c-reactive protein (crp) levels at admission in intensive care unit can help identify associated bacterial infection in patients with influenzae pneumonia. methods. a nationwide registry (reva) was set up in france during the h n influenza pandemic. levels of pct and crp at icu admission were compared between patients presenting with influenzae pneumonia associated or not with a bacterial coinfection. results. patients were included, of whom received antibiotics prior to hospitalization. of the remaining patients, ( %) had documented bacterial co-infection. the bacteria involved in the co-infections were streptococcus pneumoniae (n = , . %), staphylococcus aureus (n = , . %), streptococcus a group (n = , . %). figure shows the initial values of procalcitonin and crp. median values for both pct ( . vs. . ng/ml, p \ . ) and crp ( vs. mg/l, p = . ) were significantly higher in patients with bacterial coinfection. the area under the roc curve was . and . , respectively for pct and crp. a cutoff of[ . ng/ml for pct (sensitivity % and specificity %) best identified patients with bacterial co-infection. for crp, a cutoff of[ mg/l (sensitivity %, specificity %) best identified patients with bacterial co-infections. comparison of the h n pneumonia and bacterial pneumonia group revealed no differences except for a higher saps in the latter pro endothelin (pro et) and copeptin (pro vasopressin cp)) for diagnosing infection in patients with severe acute dyspnea. methods. we designed a prospective study of patients admitted in emergency department (ed) and medical intensive care unit (icu) in a university hospital. inclusion criteria were acute dyspnea with spo b % and/or respiratory rate c b/min. patients with obvious myocardial infarction or pneumothorax were excluded. all clinical and biological data were recorded and biomarkers sampled. an independent blinded expert panel classified the patients according to all the available data including response to treatment and outcomes blindly to biomarkers' results. the roles of biomarkers were assessed quantitatively and then using terciles of the distribution. the contribution of the biomarkers in the diagnosis was assessed using auc-roc curves and by multiple logistic regression taking into account other clinical and biological explanatory variables. results. consecutive patients ( % male, med age years, day mortality %) were enrolled. the final diagnosis was severe sepsis for ( . %) (pulmonary: n = , non-pulmonary n = ). the parameters independently associated with infection lead to a clinico-biological model with an auc = . and a good calibration (p (hlchi ) = . ) and included temperature, arterial pressure, cyanosis, stupor and coma, orthopnea, localized chest sound abnormalities, pao /fio ratio and localized infiltrate on chest x ray although new biomarkers were different between septic and non septic patients with severe acute dyspnea, only mid pro-anp may add a significant contribution. further analysis about the prognostic value of these biomarkers is ongoing grenoble university hospital and brahms diagnostic czech republic, st faculty of medicine charles university and thomayers' hospital, anesthesiology and intensive care medicine fluid management with cvp is still common despite lack of efficacy. objectives. implement stroke volume maximisation during major surgery using odm guided fluid challenges. assess impact of odm use on central venous line insertion rates. identify and overcome barriers to adoption of odm technology. methods. nhs technology adoption centre project (ntac) supported an implementation project at hospitals. the audit into central catheter use during major surgery was undertaken at manchester royal infirmary. fourteen anaesthetic consultants volunteered to champion odm use to guide targeted fluid challenges with hes / . (voluven, fresenius kabi) within a range of major surgical procedures (colo-rectal, hepatic, pancreaticobiliary, urological, reno-pancreas transplant and emergency surgery). prospective data was collected for patients who underwent major surgery between with no significant differences in preoperative risk, intervention patients had enhanced post-operative outcomes. cvc insertion reduced after anaesthetists had the opportunity to use odm to guide fluid therapy. reference(s) clinically used fluids modify in vitro phenotype and function of circulating immune cells peri-operative fluid loading, i.e. ''hemodynamic optimization'', reduces post-operative complications and hospital length of stay. mechanisms involving perfusion have been studied, but fluid could also alter phenotype and function of circulating immune cells, and consequently the systemic inflammatory response induced by surgery blood from control donors has been diluted in crystalloid fluid (isotonic saline, wsio), colloids (hydroxyethyl starch (hes kd, . %) and % albumin solution (alb)), or autologous plasma, which corresponds to clinical situations in programmed anesthesia and surgery. two dilution levels have been studied, to achieve - g/dl hemoglobin (dilution ) and - g/dl (dilution ) )* cd mono (sites/cell) , ( , ) , ( , )* , ( , ) , ( , )* , ( , )* cd b pmn (sites/cell) alb only increased ord, but not activation and adhesion markers. conclusions. wsio had clear anti-inflammatory properties, whereas colloids were more inflammatory, with a dissociation of the effects between different types of fluids. mechanisms have to be precised, especially regarding physico-chemical, immuno-inflammatory and metabolic regulations. reference(s). none. grant acknowledgment. plan quadriennal outcome-related factors federacion panamericana e iberica de sociedades de medicina critica y terapia intensiva (fpimcti) our aim was to conduct a multicenter study to evaluate the epidemiology of delirium in intensive care units (icu) a -day point-prevalence study was performed with the aim of describing in icus from countries in south and north america and spain % were admitted to the icu due to medical causes and sepsis was the main diagnosis (n = , . %). patients were sedated and only ( . %) patients could be evaluated with the cam-icu. the prevalence of delirium was . % (n = ). as compared to patients without delirium, those with the diagnosis of delirium had a higher severity of illness at admission as demonstrated by higher sofa increased use of invasive devices such as central venous catheter (p \ . ), arterial catheter (p = . ) and urinary catheter (p = . ) were more frequent in patients with delirium. on multivariate analysis, delirium was independently associated with increased icu mortality in this one-day international study, delirium was frequent in icu patients and associated with increased mortality and icu los. the main modifiable risk factors associated with the diagnosis of delirium were the use of invasive devices and sedatives the study was funded by the federacion panamericana e iberica de sociedades de medicina critica y terapia intensiva (fpimcti). the fpimcti has used in part an educational grant from hospira recent studies suggest that increased blood glucose variability (bgv) is associated with icu mortality . hypothermia is known to induce insulin resistance, thus potentially increasing bgv. no studies however have examined the effect of therapeutic hypothermia (th) on insulin requirements and bgv. objectives. to examine the effect of th on bgv and its relationship to all patients were treated with intravenous insulin (blood glucose target - mm), according to a written algorithm, with nurse-driven adjustment of insulin dose. for each patient, standard deviation of repeated blood glucose samples was used to calculate bgv. two time-points, comparable in duration, were studied: th (stable maintenance phase, i.e. - h, core temp ± °c) vs. normothermia (nt, i.e. after rewarming, stable normothermic phase, core temp ± °c). mortality and neurological recovery (glasgow-pittsburgh cerebral performance categories, cpc, dichotomized as good = cpc - vs. poor = cpc - ) were assessed at hospital discharge. statistical analysis was performed with anova for repeated measures therapeutic hypothermia is associated with increased insulin requirements and higher blood glucose variability, which in turn correlates with worse prognosis in patients with post-ca coma. strategies aimed to maintain stable glycemic profile and avoid blood glucose variability might contribute to optimize the management of th and may translate into better outcome glucose variability is associated with intensive care unit mortality therapeutic hypothermia post cardiac arrest has been shown to improve survival and neurological outcome . there are approximately , treated cardiac arrests in the uk each year with one-eighth we aimed to establish if implementation of an agreed care bundle including therapeutic hypothermia reduced mortality and improved neurological outcome patients were categorized according to initial cardiac rhythm, ventricular fibrillation/tachycardia (vf/vt) or non-vf/vt. we recorded the degree of implementation of the post cardiac arrest care bundle, comprising; coronary reperfusion, haemodynamic optimisation, control of ventilation, blood glucose, temperature and seizures. data was compared with survival to discharge and neurological function there were ihas, male (mean age . years) and female ( . years) and oohas, male ( . years) and female ( . years). the predominant presenting rhythm in oohas was vf/vt ( . %) compared to ihas which was non vf/vt ( . %). underlying co-morbidities included - °c) was achieved in % of vf/vt oohas compared to . % of vf/vt ihas. the complete care bundle was delivered to . % of oohas and . % of ihas survival rates were higher in all patients with complete bundle of care versus those with an incomplete bundle independent of location or rhythm ( . vs. . % p = . ). this improval in survival was also demonstrated in vf/vt arrests receiving the complete bundle of those patients who had a vf/vt arrest, survival with full neurological recovery (gcs on discharge) was higher in those receiving therapeutic hypothermia . versus % where therapeutic hypothermia was not achieved adherence to the post cardiac arrest care bundle led to significantly improved outcome following both vf/vt and non vf/vt arrests. there was a trend towards therapeutic hypothermia improving neurological outcome on discharge reference(s). . the hypothermia after cardiac arrest study group. mild therapeutic hypothermia to improve the neurological outcome after cardiac arrest royal sussex county hospital intensive care unit, brighton, uk for patient data h. altemimi , s. altaf , j. brown , s. al-juboori , v. jadhav queen elizabeth hospital, kings lynn, medical assessment unit, kings lynn, uk introduction. the medical assessment unit (mau) in our district general hospital (with beds) provides assessment and treatment of acute medical patients from general practice (gp) referals and the emergency department (ed). patients arriving in mau are first triaged by the nurses before assessment by junior doctors. the early warning score (ews) is an indepenently verified scoring systems used to prioritise patient assessment. appropriate referal to critical care outreach teams and intensive care units can be triggered by nurses or doctors according to the ews score. clear and seemless referal pathways and communication between those involved with acutely unwell patients is essential. objectives. to measure key performance indicators in the mau and identify specific areas for improvement. methods. retrospective audit of all admissions to medical assessment unit during week in . the following parameters were recorded for patients admitted. patient ages ranged from to : [ . of these, only were reviewed within h. . % of patients reviewed within min. conclusions. in the uk, early warning scores have been developed to trigger early review. the most sophisticated intensive care becomes unnecessarily expensive terminal care when the pre-icu system fails to refer in a timely manner. our results showed that when a patient was recognised as being unwell, they were seen rapidly by the outreach team. however, not all new admissions had their ews documented, overlooking an important opportunity to risk stratify patients before formal medical clerking. our critical care outreach team have prominent role in education to identify abnormal physiology early, and take action as appropriate. immunological host reactions are primarily believed to determine the clinical course of this disease. an overwhelming inflammatory response to microbial invasion may be involved in the pathogenesis of sirs, sepsis and multiple organ failure. it is important to block the inflammatory response and stop or alleviate sepsis injuries. immunotherapy is regarded as effective approach to improve the immunological function. objectives. immunomodulation in the critically ill is an appealing notion because of the abnormal immune responses. the aim of this study is to evaluate the immunomodulation and its mechanism to improve immune function and prognosis in sepsis. methods. experimental part:clp model were divided into three groups including sham group, control group and experimental group. control group only used antibiotic and experimental group used antibiotic plus immunomodulation. blood collection were made after clp model in , , and h. lymphocyte counting, cd +, cd + t lymphocyte and cd /cd ratio were checked. the apoptosis of lymphocyte in thymus and spleen and survival rate were checked. clinical part: prospective analysis seventy patients conformed to the enrolled standard. it was divided into two groups at random. one was control group with regular therapy, the therapy group with ulinastatin plus thymosin-a in a week. the immune index before and after therapy in the , st, rd, thday was observed. results. experimental part: lymphocyte, cd + t lymphocyte and cd /cd ratio in experimental group increased more significant than in control group (p \ . ). lymphocyte apoptosis index of thymus and spleen in control group increased more significant than in experimental group (p \ . ). h-survival rate in experimental group was higher than in control group. clinical part: cd + t lymphocyte, lymphocytes and hla-dr cd + had more significant increase in therapy group than in control group (p \ . ). twenty patients died in the control group and thirteen patients died in the therapy group (p \ . ). conclusions. immunomodulation in sepsis can improve immune function and alleviate the lymphocyte apoptosis and extend the survival time. in recent years, the antiinflammatory effects of niacin by reducing nuclear factor jb (nf-jb) activation have attracted attention. however, the protective effects of niacin on the development of acute lung injury and systemic inflammatory response during sepsis have not been studied.objectives. we performed this study to determine whether niacin attenuates acute lung injury (ali) and improves survival during sepsis and the beneficial effects of niacin are associated with the down-regulation of nf-jb pathway.methods. lipopolysaccharide (lps) at a dosage of mg/kg was injected into the tail vein to induce endotoxemia in rats. then, vehicle, low dose niacin ( mg/kg), or high dose niacin ( mg/kg) diluted in distilled water with same volume ( ml/kg) was administered once to the rats through orogastric tube, respectively. we observed the survival of the subjects. at h post-lps injection, we measured serum tumor necrosis factor-a (tnf-a), interleukin- (il- ) levels, lung cytoplasmic phosphorylated inhibitor jb-a (p-ijb-a), ijb-a, nuclear nf-jb p expressions, nf-jb p dna-binding activity, and ali occurrence.results. high dose niacin improved survival during sepsis. niacin induced dose-dependent reduction of serum tnf-a, il- levels, lung cytoplasmic p-ijb-a, nuclear nf-jb p expressions, nf-jb p dna-binding activity, and ali occurrence in endotoxemic rats. in contrast, niacin preserved lung cytoplasmic ijb-a expression dose-dependently in endotoxemic rats.conclusions. niacin attenuated acute lung injury and improved survival during sepsis in rats. the protective effects of niacin were associated with the down-regulation of nf-jb pathway. niacin can be considered as a therapeutic agent for sepsis. f. barbani , m. boddi , r. cammelli , a. cecchi , e. spinelli , m. bonizzoli , a. peris university of florence, postgraduate school of anesthesia and intensive care, florence, italy, university of florence, department of critical care medicine and surgery, florence, italy, careggi teaching hospital, anesthesia and intensive care unit of emergency department, florence, italy introduction. acute kidney injury (aki) is a frequent complication in critically ill patients. there is emerging evidence that aki can lead to chronic kidney disease and that even only partial renal recovery after aki is associated with a higher long-term mortality.objectives. we investigated whether measurement of renal resistive index (rri) by ultrasound could predict renal function recovery after aki.methods. rri has been determined in patients who had been admitted (jan -feb to our mixed intensive care unit (icu) and referral trauma center (careggi teaching hospital, florence, it) and developed aki. rri measurements were performed within h from aki diagnosis, according to rifle criteria. renal recovery was defined as the return to the normal renal function parameters.results. patients studied were ( male vs. female) with a mean age of . ± . years. aki was due to sepsis (n = ), shock (n = ), rhabdomyolysis (n = ), abdominal compartment syndrome (n = ) and major surgery (n = ). mean length of icu stay was ± days. at discharge patients showed a complete recovery of renal function, while patients had persistent altered renal function parameters or needed renal replacement therapy (rrt); mortality rate was . % ( / ) . rri measured at aki onset was significantly higher in patients with persistence of renal failure than in patients with complete renal recovery ( . ± . vs. . ± . , p \ . ). rri [ . had a sensitivity of % ( % ci - %), a specificity of % ( % ci - %) and a positive likelihood ratio of . ( % ) for persistent renal dysfunction at the discharge.conclusions. our findings suggest that doppler-based determination of rri at the onset of aki can identify those patients who are at greater risk for no complete recovery of renal function. further studies on larger populations are required to confirm these preliminary results so to promote therapies dedicated to this high risk population.conclusions. apache score on admission, hypothermia and mean arterial pressure are not statistically significant, but age approached significance at % level in ccu survival. blood sugar control is not statistically significant at % level but approached significance as p value was less than . for ccu survival. for hospital survival,age is significant at % level; apache score on admission and mean arterial pressure are significant at % level while cardiac index, hypothermia and glycaemic control are not statistically significant . in the intensive care society (ics) published a care bundle for the management of patients following cardiac arrest . the american heart association now recommends regionalisation of post-resuscitation care following out of hospital cardiac arrest (ohca), in a centre capable of providing rapid therapeutic hypothermia, h emergency angiography and percutaneous coronary intervention (pci) as necessary . objectives. the audit's purpose was to evaluate work load, treatment and outcomes of ohca on the icu following publication of the ics care bundle and inception of a h pci service in our hospital. methods. retrospective audit of ohca patients admitted to icu from / to / to examine number admitted, cause of arrest, treatment and mortality. predicted mortality from the icnarc model was used to calculated standardised mortality ratio (smr). comparison was made with an audit of ohca patients between / and / . the sample was subdivided into subgroups with cardiac and non-cardiac cause for ohca. the chi-square test was used in analysis. results. comparison conclusions. we demonstrated: . a significant increase both in the absolute number of ohca and the proportion due to cardiac causes, due in part to in-region transfers for emergency angiography/pci. . a significant increase in the use of angiography and pci, increasing use of therapeutic hypothermia and iabp. . improved survival from previous audit. . better than predicted survival, particularly in the 'cardiac' group. this audit lends support for the protocolised icu care of post-ohca patients in a regional centre able to offer h emergency pci. there is scope for increased use of cooling for arrests of all causes, and extending provision of angiography/pci to vf arrests and those of unknown cause . reference(s). . despite all the research, education and training that has gone into the field of cpr during the last years, survival rates remain bleak for the majority of patients . so, what is lost in translation? much of the problem is that what the medical community is being trained to do is not being replicated in clinical practice . given this discrepancy, along with the deleterious outcomes, we conducted a manikin-based study to assess the quality of ventilation delivered during simulated cpr, in a large uk centre. objectives. to demonstrate whether uk-based medical personal were adhering to ventilation guidelines and to see how this result varied across specialities. methods. a simulated cardiac arrest scenario was undertaken by (a- . , power- %) participants from a range of medical specialties. participants were asked to asynchronously ventilate our manikin for a period of min during which time tidal volumes (tv), minute volume (mv) and ventilation rates (vr) were recorded. to help limit outside influence, at no point during the trial was any feedback about ventilation technique or als principals discussed with the participant. results. the mean and sd across the sample population for the mv, vr and tv were . l min - (sd . ), . min - (sd . ) and ml (sd ) respectively. comparison of groups can be seen in table introduction. mild hypothermia reduces cerebral blood flow (cbf) without concurrent increase of cerebral oxygen extraction rate in the first h after cardiac arrest, indicating a lower cerebral metabolic activity with a preserved metabolic coupling.objectives. the aim of this study was to assess the cerebral blood flow and cerebral oxygen extraction in patients treated with prolonged hypothermia, as previously was performed in newborn infants with perinatal asphyxial encephalopathy . patients were included after restoration of spontaneous circulation (rosc) after asystole, pulseless electrical activity based circulatory arrest or after rosc after ventricular fibrillation based prolonged resuscitation. in this prospective observational study comatose patients after cardiac arrest were treated with prolonged hypothermia for h. after h patients were passively rewarmed. mean flow velocity in the middle cerebral artery (mfv mca ), reflecting cbf, was measured after , , , , , , , , and h after admission to the icu by transcranial doppler (tcd). jugular bulb oxygenation (sjbo ) and arterial oxygenation were measured at intervals of h. introduction. isoflurane is a volatile anesthetic known for its direct vasodilating effect on cerebral vessels, producing a cbf increase. moreover, it has been shown in animal studies that isoflurane has neuroprotective properties, inducing tolerance to ischemia when used as a preconditioning agent. at the present time, isoflurane is not used as a sedative agent in neuroicu because of the fear of an increase in intracranial pressure (icp) caused by the increase in cbf. however, sah patient at risk for vasospasm may benefit from an increase in cbf. the ischemic risk will peak at day - , leaving a window of opportunity for neuroprotection. objectives. we decided to measure rcbf during traditional intravenous sedation with propofol and during volatile sedation with isoflurane in sah patients not having intracranial hypertension. the clinical trial was approved by the hospital irb and registered on trial.gov (nct ). we enrolled sah (fisher - , wfns b ) patients, monitored with an intraparenchimal icp device and a thermal diffusion probe (tdp, hemedex) for the assessment of rcbf. an icp [ mmhg was an exclusion criteria. cerebral and haemodynamic parameters were assessed at steps:step during sedation with propofol - mg/kg/ h; step : after h of sedation with isoflurane . - % mac administered through an anesthetic conserving device; step after h of propofol re-started at the same infusion rate. in all patients sedation with isoflurane produced an increase of rcbf although not yet significant in the population (step : ± ml/ g/min; step : ± step : ± ). jugular vein oxygen saturation, sjo , was significantly higher at the end of the isoflurane step (step : ± %; step : ± ; step : ± ). icp did not change significantly and remained below the pathological threshold (step : . ± ; step : . ± ; step : ± mmhg).conclusions. the small population of this pilot study phase causes a lack in statistical significance, however our data already suggest that isoflurane induces a marked cerebral vasodilatation and an increase in rcbf compared to propofol. patients with a normal icp did not develop an intracranial hypertension. at short and long term and its correlation with severity scales, scales of quality of life and endovascular treatment m there is not a consensus about which scales should be used to define the outcome after aneurysmal subarachnoid hemorrhage. objectives. the purpose of this study was to determine the risk factors and impact on functional outcome and quality of life months after spontaneous sah due to ruptured intracranial aneurysms. methods. we performed a prospective study of patients with aneurysmal spontaneous sah admitted to our centre from july to august . diagnosis of sah was done by ct and ethiological diagnosis by brain angiography. we paid attention to previous pathological history, clinical characteristics at admission and radiological characteristics. the severity was measured by the hunt-hess (hh), wfns, graeb and fisher scales. the months outcome was assessed by the glasgow outcome scale (gos) and modified rankin scale. the basic activities of daily living were evaluated with the barthel index. moreover, patients were asked about their subsequent incorporation to their previous occupation. we divided our population into two groups depending on the clinical grade at admission (hunt-hess scale): group i, hh , or ; and group , hh or . long-term followed up continues. results. during the year of study a total of patients have been included. the mean age of patients was years with a prevalence of % in women, being arterial hypertension and smoking history the main factors of related risk. the angiography was performed in . % of the patients. an aneurysm was confirmed as the origin of the bleeding in . %. poor clinical grade at admission (hh or ) was associated with apache ii, sofa, glucose, more sah computed tomography on admission, and infection and icu stay. there is % mortality in the series. after a months period, group patients (hh or grade) had a severe disability and functional dependence to perform instrumental and basic activities of daily living (p = . ). only % of patients were able to return to their previous occupation months after the initial bleeding. scales and outcome by clinical grade at admission introduction. aneurysmal subarachnoid hemorrhage (asah) remains a therapeutic challenge due to unacceptably high levels of mortality and morbidity. for survivors of the initial insult, cerebral vasospasm and related delayed ischemic deficits are the major determinants of final outcomes. traumatic sah (tsah) occurs in as high as % of patients with tbi, and is associated with a twofold increase in risk of death. statins may be an alternative for conventional treatments of vasospasm due to their beneficial pleiotropic effects on cerebral vasomotor reactivity as well as absence of negative haemodynamic influence.objectives. the goal of our study was to examine the effects atorvastatin therapy on cerebral vasospasm after asah and tsah as well as on short term outcomes of icu patients (length of stay and severity of condition upon discharge from icu). hypertonic saline infusion is an alternative to mannitol to decrease intracranial pressure before craniotomy [ , ] . previous studies have demonstrated that both hypertonic saline and mannitol interfere negatively with various components of blood coagulation [ , ] . normal blood coagulation capacity is essential during craniotomy and, therefore, we created an in vitro model to examine the effects of hypertonic sodium chloride and mannitol solution on whole blood coagulation. fresh citrated whole blood, withdrawn from volunteers, was diluted with . , . or . % sodium chloride solution or % mannitol to make vol.% and vol.% hemodilution in vitro. the diluted blood and undiluted control samples were analyzed with thromboelastometry (rotem Ò ) using two activators, tissue thromboplastin without (extem Ò ) or with cytochalasin (fibtem Ò ). all the study solutions with the same vol.% hemodilution induced comparable decrease in hematocrit. in extem Ò analysis, alpha-angle was smaller in the mannitol group than in the . % or . % sodium chloride group after vol.% dilution (p. ). in vol.% hemodilution, alpha-angle was also more decreased, and clot formation time more delayed in the mannitol group than in the . , . or . % sodium chloride groups in extem Ò analyses (p \ . ). maximum clot firmness (mcf) in extem Ò analysis was similar with all the study solutions after vol.% dilution, but after vol.% dilution mcf was weaker in the mannitol group than in the other groups. mcf was also weaker in . % than in . % sodium chloride group after vol.% dilution. in fibtem Ò analysis, mcf was stronger in the . % sodium chloride group than in the mannitol group after both dilutions (p \ . ). a or vol.% dilution of % mannitol disturbs whole blood coagulation more than equiosmolar . % sodium chloride. this disturbance seems to be attributed to overall clot formation and strength but also to pure fibrin clot firmness. . % sodium chloride might be more favorable than mannitol before craniotomy in patients with high bleeding risk. introduction. delayed cerebral ischemia (dci) is a major complication after aneurysmal subarachnoid haemorrhage (sah), occurring in around % of patients and increasing case fatality . - -fold. induced hypertension, alone or in combination with haemodilution and hypervolemia (triple-h), is used around the world as a therapy in the treatment of dci, but its efficacy in improving outcome is not based on a randomised clinical trial. objectives. to investigate the outcome of induced hypertension versus no induced hypertension in patients with dci after aneurysmal sah. study design a multi-centre, single blinded, randomized controlled trial. study population patients admitted after recent sah with a treated aneurysm and dci based on the onset of a new focal deficit and/or a decrease of the level of consciousness of at least point on the glasgow coma scale with exclusion of other causes of deterioration, will be randomized to either hypertension (n = ) or no hypertension (n = ). interventions in the intervention group, blood pressure will be raised with norepinephrine or additional dobutamin in case of low cardiac output. when clinical improvement occurs, hypertension will be continued for h, after which the dose norepinephrine will be tapered daily, but resumed in case of clinical deterioration. when no clinical improvement occurs within h, induced hypertension will not be continued. patients in the reference group will be treated according to the standardised sah treatment protocol of the participating centre including oral nimodipine and normovolaemia without haemodilution. main outcome measurement the modified rankin scale at months after the sah, will be compared between patients who were randomized to induced hypertension and patients who were randomized to no induced hypertension. objectives. to investigate brain metabolism at different serum glucose levels.methods. six patients with aneurismal sah and vasospasm were enrolled in the study (age . ± . ; male/female / ; . cerebral microdialysis was used in all patients. microdialysis catheters were placed into ''lesioned'' (brain tissue perfused by involved artery) and ''intact'' brain tissue. glucose levels in arterial blood (glu art ) and in brain interstitial fluid were compared. we analyzed brain glucose levels, intracranial pressure (icp), lactate/pyruvate (l/p) ratio, pao , paco and cerebral perfusion pressure (cpp) at blood glucose levels b mmol/l (group i, n = ), . - mmol/l (group ii, n = ), . - mmol/l (group iii, n = ), c mmol/l (group iv, n = ). we found out tight correlation between glucose levels in arterial blood and in ''lesioned'' brain tissue (n = ; r = . ; p \ . ) and weak correlation between gluart and glucose levels in ''intact'' brain tissue (n = ; r = . ; p \ . ). pao , paco , icp and cpp were comparable between groups. glu art was . ± . mmol/l in group i, . ± . mmol/l in group ii, . ± . mmol/l in group iii and . ± . mmol/l in group iv. normal glucose levels in arterial blood (group i) were accompanied by low glucose levels in ''intact'' ( . ± . mmol/l) and ''lesioned'' ( . ± . mmol/l) brain tissue. arterial blood glucose elevation has led to significant increase in brain glucose levels. but brain glucose levels were in normal ranges during hyperglycemia. glucose levels in ''intact'' brain tissue: . ± . mmol/l (group ii), . ± mmol/l (group iii), . ± . mmol/l (group iv). glucose levels in ''lesioned'' brain tissue: . ± . mmol/l (group ii), . ± . (group iii), . ± . (group iv). we didn't find out any significant differences in l/p ratio at different blood glucose levels. however, low glucose levels in ''intact'' brain tissue (b . mmol/l; . ± . mmol/l; n = ) were accompanied by significant increase of l/p ratio ( . ± . vs. . ± . at normal brain glucose levels (c . mmol/l; . ± . mmol/l; n = )). we didn't notice any significant differences in l/p ratio in ''lesioned'' brain tissue at different brain glucose levels, opposite to intact brain tissue. l/p ratio was . ( . ; . ) at glucose levels in ''lesioned'' brain tissue b . mmol/l ( . ± . mmol/l; n = ) vs. ( . ; ) at glucose levels in ''lesioned'' brain tissue c . mmol/l ( . ± . ; n = ).conclusions. hyperglycemia is not accompanied by high glucose levels and brain metabolism impairment in ''intact'' and ''lesioned'' brain tissue in severe patients with aneurismal sah. low glucose levels in ''intact'' brain tissue are related with significant increase of l/p ratio. introduction. the national confidential enquiry into patient outcome and death report found that less than % of patients with a severe head injury received a standard of care that was judged to be good [ ] . our intensive care unit (icu) at the royal cornwall hospital, a large district general hospital, is one of the few non-neurosurgical centres in the uk to use intracranial pressure (icp) monitoring. we aimed to assess if the practice of icp monitoring in our non-neurosurgical centre was valuable and safe. retrospective audit of case notes and charts of all patients admitted with traumatic brain injury receiving icp monitoring over a year period from st january until st january . a total of patients who had icp monitoring for traumatic brain injury were identified. the codman tm strain-gauge catheter was used in all cases, ( %) were male, ( %) were female. mean age was years (range - ). median reported gcs at the scene of injury was (range - ), median gcs prior to intubation was (range - ). median apache score was (range - ). all patients were discussed with the neurosurgical referral centre. patients were monitored for a median of days (range [ ] [ ] [ ] [ ] . icp was raised in patients ( %). elevation of icp triggered the following interventions: patients ( %) received hyperosmolar agents, patients ( %) were treated with therapeutic hypothermia, patients ( %) with barbiturate coma and none of the patients received steroids. patients were transferred to a neurosurgical centre ( % of patients with elevated icp, % of total). complications comprised one minor intracranial haematoma and one monitor failure. review of documented care bundles for head-injury patients revealed: head-up tilt in %, gastric protection in %, normoglycaemia in %, early enteral nutrition in %, appropriate thromboprophylaxis in %, appropriate sedation in % and appropriate analgesia in %. % survived to hospital discharge.conclusions. in our audit the majority of patients received specific treatment for raised icp, which might have gone undetected without invasive icp monitoring. at the same time most patients were managed without neurosurgical intervention. in light of the paucity of neurocritical care beds [ ] this approach appears to help to select a suitable subgroup of patients needing transfer to a specialist centre. our data adds weight to the evidence that icp monitoring is a valuable and safe monitoring modality in a non-neurosurgical icu if used appropriately within established guidelines and in collaboration with a neurosurgical referral centre. introduction. assessment of injury severity and prediction of outcome represent major challenges following severe traumatic brain injury (tbi). objectives. this study was aimed to evaluate relationships between cerebrospinal fluid (csf) levels of purported biomarkers of tbi including glial fibrillary acidic protein (gfap), ubiquitin c-terminal hydrolase (uch-l ) and alpha-ii spectrin breakdown product (sbdp ), and partial pressure of brain tissue oxygen (ptio ) as well as brain temperature during the first h and up to days post-injury.methods. twenty-seven severe tbi patients with csf drainage and invasive monitoring (licox probe) have been studied with quantitative csf-elisa for sbdp , uch-l and gfap on admission and every h up to days. in the first h, biomarker levels decreased while those of ptio increased. all three biomarkers correlated with ptio (p \ . , p = . and p = . , respectively). after the first h, there were statistically significant changes in levels of the three markers as well as in levels of ptio (p = . , p \ . , p = . , p \ . , respectively). however, the correlation between biomarkers and brain tissue oxygenation was sustained and, for uch-l improved (p \ . ). no significant correlations between biomarker levels and brain temperature were found. the results indicate that cfs levels of sbdp , uch-l and gfap are related to ptio following severe tbi. future studies are on their way to unravel whether these biochemical markers and ptio measurement could serve the better care of the head injured. introduction. this was a pilot study to compare the cerebral neurochemical changes in patients with traumatic brain injury (tbi) who underwent conventional blood glucose level (bgl) control and intensive bgl control with continuous titrated insulin.objectives. to demostrate that intensive glycaemic control using insulin induced a decrease of cerebral glucose.methods. this prospective, randomized study was conducted in traumatic brain injury patients in a surgical and trauma intensive care unit. patients admitted over an -month period with tbi were prospectively divided into two groups according to the method used for bgl control: the intensive group consisted of patients who underwent continuous titrated insulin infusion to maintain a lower normoglycemic level of - mmol/l, and the conventional group consisted of patients whose bgl was maintained at between . and . mmol/ l using conventional sliding scale bolus subcutaneous insulin administration. data on cerebral haemodynamics, interstitial brain oxygenation (ptio ( )) and neurochemical monitoring were collected via microcatheters inserted in the penumbral region. we analyzed , cerebral microdialysis samples. in patients treated with intensive insulin therapy, there was a reduction in microdialysis glucose by % of baseline concentration compared with a % reduction in patients treated with a conventional blood glucose level control. intensive insulin therapy was associated with increased incidence of microdialysis markers of cellular distress, elevated glutamate ( ± vs. ± %, p \ . ), elevated lactate/pyruvate ratio ( ± vs. ± %, p \ . ) and low glucose ( ± vs. ± %, p \ . ), and increased global oxygen extraction fraction. cerebral microdialysis glucose was lower in nonsurvivors than in survivors ( . ± . vs. . ± . mmol/l, p \ . ).conclusions. intensive glycaemic control using insulin induced a decrease of cerebral glucose and an increase in microdialysis markers of cellular distress. in patients with severe brain injury, tight systemic glucose control is associated with increased mortality. introduction. we have previously used c-flumazenil positron emission tomography to show that selective neuronal loss in the thalamus is pervasive after traumatic brain injury (tbi) and correlates with functional outcome, findings that are concordant with previous post-mortem data. the mechanisms responsible are unclear, but may involved global hypoxia/ischaemia as well as retrograde degeneration.objectives. we hypothesised that early brain tissue oxygenation would correlate with late diffusion tensor imaging (dti) abnormalities in the thalamus, and therefore, help to provide an explanation for late neuronal loss. nine patients underwent brain tissue oximetry (pbo ) following acute tbi, using a licox pbo probe, sited in structurally normal frontal white matter. mean pbo was calculated for the duration of their intensive care admission. at a median of . months (range - days) they underwent magnetic resonance imaging, including dti. apparent diffusion coefficient adc (maps) were created, adc calculated in regions of interest in the frontal lobes, splenium of the corpus callosum and thalami, and correlated with mean pbo using spearman's rho. ethical approval was obtained from the local research ethics committee, and assent from next-of-kin was obtained in all cases.results. mean pbo was inversely related to adc in both frontal lobes (r = - . and - . ; p = . and . ), and with the adc in the thalamus bilaterally (r = - . and - . ; p = . and p = . ). in contrast, no correlation was seen between mean pbo and adc in the splenium of the corpus callosum, a common site of traumatic axonal injury (tai; p = . ).conclusions. the inverse correlation of mean pbo associated with adcs in the monitored brain region is unsurprising, but the correlations observed with contralateral regions and deep grey matter suggest that the burden of tissue hypoxia has a significant impact on secondary neuronal loss across the brain. in contrast, the lack of correlation with adc changes in an area at risk of tai suggests a less significant impact of hypoxia on the progression or maturation of tai. the correlations with measures of thalamic microstructural injury are particularly significant, since they establish a clear link between acute physiology, tissue fate in key brain regions, and clinical outcome. introduction. earlier studies have suggested that autonomic dysfunction is associated with poor outcome in traumatic brain injury (tbi).objectives. this study was performed to assess changes in baroreceptor sensitivity and heart rate variability as indices of autonomic dysfunction in relation to icu management variables during early tbi.methods. ten patients ( females/ males) with a median age of (interquartile range, iqr, - ) admitted to icu following tbi were prospectively studied for the first consecutive days. all patients were sedated and mechanically ventilated with icp monitoring in place. high fidelity signals at hz were sampled for ecg and invasive arterial pressure (radial) to monitor baroreceptor sensitivity (brs) based on three or more consecutive beats in which successive systolic pressure and rr intervals increased or decreased with the threshold set at mmhg and ms, respectively. heart rate variability (hrv) was analysed by fourier transformation in the low (lf, . - . hz) and high frequency (hf, . - . hz) domains. the lf/hf ratio and total power ( . - . hz) were also calculated for hrv. management variables included use of inotropes, vasopressors, icp, use of decompressive craniectomy, icu length of stay (los) and mortality. statistical significance was set at p \ . using mann-whitney one-way anova and spearman correlation tests. median days (and iqr) were . ( - . ) for inotropes, . ( - ) for vasopressors and . ( - . ) for icu los. brs and lf, hf, lf/hf ratio and total power were all depressed throughout early icu management with no significant changes in the first week. no significant correlations were found between brs/hrv and days on inotropes/vasopressors or icu los. four patients underwent decompressive craniectomy and one patient died while in icu. no correlation was found between these events and brs or hrv changes brs, hrv and icp data conclusions. both brs and hrv were depressed early following tbi but did not correlate to icu management variables. while autonomic dysfunction is evident early in the icu treatment of tbi, no evidence to support an association between severity of impairment and icu outcome was found in this pilot study. introduction. in neurocritical care, raised intracranial pressure (icp) is associated to a poor outcome and its detection still leads the therapeutic management of the patients suffering from head pathologies.objectives. although invasive devices are recommended to detect intracranial pressure (icp), we investigated the correlation and the reliability with non-invasive ultrasound techniques as the optic nerve sheath diameter (onsd) assessed by ultrasonography and the pulsatility index (ip) measured by transcranial doppler sonography (tcd). we included patients suffering from intracranial hypertension, sedated and mechanically ventilated and control individuals, chosen among healthy people. all the patients had icp measured invasively either by external ventricular drains (evd) or intraparenchymal catheter. everyone underwent non-invasive measurements of onsd bilaterally and simultaneous medial cerebral artery ip assessment at the side of the best window.results. onsd had a significant difference between volunteers ( . ± . mm) and patients ( . ± . mm). ip's were . ± . for the control individuals and . ± . for the patients (media icp = ± mmhg) and also revealed a significant difference. onsd strongly correlated with icp (y = . x + . , p \ . , r = . ) whereas ip had some correlation but without statistical significance (y = . x + . , p = . , r = . ). onsd was found wider (p = . ) within patients with both icp and ip abnormal. a strong correlation was found between onsd and ip (y = . x + . , p = . , r = . ). however, we could not find the best cut-off values of onsd and ip for predicting an icp [ mmhg.conclusions. ip and onsd correlated with icp with a stronger reliability results of the latter, suggesting the possibility to integrate their use in the case of icp invasive monitoring would be contraindicated or not available. we studied the effects of normothermic therapy during the acute phase of traumatic brain injury.methods. twenty patients ( males, ± years old) who were admitted in the intensive care unit due to traumatic brain injury (glasgow coma scale upon admission - , marshall scale ii to iv) were studied. if patients' core temperature was above . °c, a cool line Ò , alsius corporation, irvine, ca. usa intravascular heat exchange central venous catheter (coolgard Ò device) was inserted via the femoral or the subclavian route, in order to achieve and maintain a target temperature of °c. intracranial pressure (icp) was measured (a) invasively by means of a intraparenchymal catheter (camino, camino laboratories, san diego, ca, usa) and (b) noninvasively by means of transcranial doppler sonography (tcd), using a philips hd xe (philips medical systems; bothell, wa, usa) equipped with a mhz transducer and a mhz linear transducer. estimated icp was calculated by tcd using the equation proposed by czosnyka and colleagues and the pulsatility index (pi = vs -vd/vm) was assessed in the middle cerebral artery bilaterally. all measurements were conducted at baseline and repeatedly on a daily basis for the next days and the average values were used in the statistical analysis.results. target temperature (t: . ± . °c) was achieved within the next h of the catheter insertion. at baseline (t: . °c) pulsatility index (pimean) was . ± . , icpmean/invasive was ± . mmhg and icpmean/noninvasive was . ± . mmhg. invasive and noninvasive icp values correlated significantly (r = . , p \ . ). following ± h from the insertion of the catheter the above parameters were significantly decreased as compared to baseline values (pimean = . ± . , icpmean/invasive = ± . mmhg, icpmean/noninvasive = . ± . mmhg, respectively; all p \ . ). out of patients, progressed towards brain tamponade, remained in a persistent vegetative state and were discharged with normal consciousness and motor deficits. however, due to the small number of patients no analysis could be performed to estimate the possible impact of normothermic therapy on the survival of these patients. these preliminary results suggest that normothermia during the acute phase of traumatic brain injury may decrease icp and ameliorate cerebral blood flow. introduction. extracranial organ dysfunctions are extremely common in patients with severe traumatic brain injury (tbi). although it has been shown that development of tbiinduced multiple organ failure (mof) is associated with a poor outcome, the underlying mechanisms leading to mof after tbi have not been investigated.objectives. to investigate in vitro the effect of plasma from tbi patients developing different degrees of organ failure on human endothelial cells.methods. ten consecutive severe tbi patients were included. gcs, iss and sofa score were recorded at admission; sofa was also recorded after days. plasma samples were obtained at the same time points. adhesion of freshly isolated human neutrophils on spontaneously transformed human umbelical vein endothelial cells (ecv ) was evaluated after h in vitro stimulation with % of plasma collected from tbi patients days after admission. expression of intercellular adhesion molecule- (icam- ) was assessed by immunofluorescence. to determine the impairment of the endothelial cell barrier function, trans-endothelial electrical resistance (teer) and permeability to fitc-dextran were measured. plasma from healthy volunteers were used as control. data are expressed as mean ± sd. results from different experiments were compared by unpaired t test.results. ten male patients were enrolled, mean age ± , gcs ± , iss ± , sofa was . ± . on admission and ± . on day . plasma derived from tbi patients increased the adhesion of neutrophils on ecv cells ( ± vs. ± cells/field, p \ . ), induced a significant reduction of teer ( . ± . ohm/cm vs. . ± . ohm/cm , p \ . ) and caused a concomitant increase of endothelial permeability to dextran ( . ± . vs. . ± . %, p \ . ) compared to control (healthy plasma). a visual up-regulation of icam- expression was also observed. there was a significant correlation between delta sofa score (day -day ), calculated excluding gcs, and neutrophil adhesion on endothelial cells exposed to plasma from tbi patients (p = . , r = . ).conclusions. plasma from patients with tbi causes the increase of endothelial permeability and neutrophil adhesion, which correlates with the development of extracranial organ dysfunction expressed by sofa. these results suggest a mechanism potentially responsible for the development of mof after traumatic brain injury.grant acknowledgment. fondi universitari ex- %, regione piemonte-ricerca sanitaria finalizzata. objectives. the aim of this study is to describe indications of dc and outcomes in our unit.methods. it is a retrospective revue collecting patients who had a dc for severe icht between january and july . inclusion criteria were: icht refractory to medical management due to cerebral oedema. we define intractable icht as intracranial pression (icp) over cmh o, pupil modification, neurologic deterioration persisting more than min despite medical management or ct scan findings. exclusion criteria were imminent cerebral death, icht due to an acute hematoma, tumour, hydrocephalus and prediction of short life expectancy. objectives. historically, research has targeted problems experienced several months post discharge from critical care, namely using data from follow up clinics \ months after the critical illness. in contrast, this study aimed to review data from patients recently transferred from critical care to the wards. this data can then be compared with patients' progress after earlier rehabilitation. methods. this was a prospective, longitudinal study, involving long stay critical care patients ([ days), between april - . this cohort included all patients nursed within our itu/hdu, regardless of speciality, age or gender. all reviews took place whilst the patients were still hospitalised. the study used qualitative data, using specifically designed questionnaires which highlighted the type of long term problems our patients suffered. these were developed using data from previous informal patient interviews and the had (hospital anxiety and depression) questionnaire. the latter was considered too intrusive for the ward environment. a data base was used to list the frequency of these problems to provide quantitative data. a total of patients were reviewed over years. the qualitative data highlighted different, common morbidities, in addition to disease specific morbidities. between, april - , % of patients demonstrated at least physical or psychological problems and % displayed or more. the quantitative data showed the most prevalent morbidities were: poor mobility at %, nightmares %, loss of appetite % and insomnia %. year showed similar findings, plus global weakness at %.conclusions. this research showed significant post critical illness morbidities in this cohort which appeared to impact on the patients' recovery on the wards. the challenge for our follow up is to target support and rehabilitation whilst the patients are in critical care and then re-evaluate the results. if this expedites a return to a near normal quality of life, it will have improved the efficacy of our service and may impact on follow up care in general. . it may affect the balance of family and change their roles and responsibilities, mainly due to the separation from their relative imposed by hospitalization. this admission may also generate other discomforts to the family, as relationship problems, emergence of diseases, lack of financial resources for expenditures now installed, anxiety, depression, fear and irritability . objective. to get to know the discomfort that characterizes the changes experienced in the daily life of families who have a relative in icu. method. this is a qualitative study, conducted in a general icu of a large hospital in the city of salvador, bahia, brazil, from august to october of . nine relatives of people hospitalized for at least h in icu were interviewed. the data were analyzed by the use of procedures of analysis of grounded theory. results. the hospitalization of a family member in icu produced discomfort for her, as the uncertainty of recovery, the fear of loss and the sudden physical separation of the relative. the interaction between the huge discomfort of life threat and the separation from the relative, in turn, spawned other discomforts in the daily lives of families, expressed by two categories. the first one, having difficulties to answer psychobiological needs, meant for the family member the experience of sleep deprivation, loss of appetite and constant concern with the relative. the second one, suffering a discontinuity in the daily life, meant to the family the disruption of daily activities with the relative, irritability front other family members, removal of the routine of home, loss on work performance and studies and difficulties to enjoy the leisure and recreation.conclusion. the coping of illness and hospitalization of a relative in intensive care produced discomfort for family members, characterized by changing of the routine of the daily life and care for oneself. the family's attention is primarily directed toward the ill relative. it starts to experience the routine of a hospital and disrupts the organization of familiar and personal life, it finds itself suffering a break from daily life. the discomfort experienced by the family can be minimized by practices of the healthcare team, which provide care, information, support, safety and convenience. (fig. ). this is a unique opportunity to study the effects of nursing environment on sleep quality and quantity in icu patients. to study the effects of nursing environment on sleep quality and quantity in icu patients. a total of patients will be included in this ongoing study: ten subjects who were admitted to the old, ward-like icu (fig. ) , and ten patients who will be admitted to the new, single-room icu (fig. ) . objectives. in order to understand the family's perception of nursing care, the authors undertook this study, assessing the family satisfaction and use the results to increase the quality of care.methods. this is a qualitative study of inductive nature. data was collected along the time of the study by in-depth interviews, to six relatives of each patient, after discharge the intensive care unit. for data analysis we followed the steps of the phenomenological method, according to max van manen ( ) . results. from data analysis, the results were divided in categories: ) relative needs; ) icu environment; ) relative's feeling; ) nurses role and ) suggestions. all this categories were grouped in a central theme called ''being a relative in a general intensive care unit''. the results show that relatives of patients admitted to the intensive care unit often require complete knowledge of the medical condition of the patient, a specific area for that purpose and a comfortable waiting room. they express the need to be near the patient and participate in care. they feel fear and anger with the situation that inevitably are forced to live and think, mostly, that nurses are effective and efficient in meeting the needs of the patient and family. conclusions. it is essential to promote attitudes and behaviors that provide comfort, safety and privacy for relatives, and acknowledge that they have a role in the process of care, reinforcing their importance in decision making process.introduction. heart failure (hf) is a complex syndrome that commonly affects elderly patients in whom it has a major impact upon longevity and quality of life. it is usually associated with symptoms such as dyspnoea, fatigue, and fluid retention, and results in frequent episodes of hospitalisation.objectives. this study was planned to examine the relationship between self-care behaviors and quality of life in patients with hf.methods. this study was planned and applied as a descriptive and a cross-sectional study. introduction. the hospitalization of a relative in icu, especially when it's unexpected, is considered a too stressful experience for the family, usually compounded by the disruption of daily life. from the relative's hospitalization at the icu, the family will necessarily interact with health practices, the rationality that underlie it and institutional objects that may be a source of comfort or discomfort , .objectives. to understand the situations defined as comfort to relatives of people in critical state of health and the sense of comfort in this situation.methods. this is a qualitative study conducted in the general icu of a large hospital in the city of salvador, bahia, brazil, from june to october of . fourteen family members of persons hospitalized for at least h in icu were interviewed by a specific questionnaire. all recorded interviews were transcribed and the data were analyzed by the use of procedures to encode the data of grounded theory. seven categories expressed the experience and sense of comfort for the relatives who had a person hospitalized in the icu: ) security: confidence of relatives in technical-scientific and humanistic team and in the possibility of recovery of the person who is hospitalized, ) reception: comfort experienced by the family by being treated as a person by the professional of icu when they interact with a supportive attitude, ) information: comfort experienced by the family when it feels conscious of the reality of the health condition of their relative and to receive guidance about the unit s routine, ) social and spiritual support: comfort experienced by the receiving of help and support of the family, friends and religion, ) proximity: the comfort of being close of the relative and being able to enjoy the interaction established between them, ) convenience: comfort experienced in interacting with pleasant elements and support of basic needs of the family, offered by the environment and physical structure of the hospital; ) integration with itself and the daily: the possibility of the family member to take care of himself, to help the relative and to give continuity to the family routine as it did before the hospitalization.conclusions. the comfort is a positive, subjective and dynamic experience, which changes in time and space, which is the result of the interactions that the individual sets with himself, with those around him and with the situations he faces, without losing view that every family is unique and can experience this process in a proper way. to ascertain the perceptions of icu nurses' about the needs of families of critically ill patients methods. this is a transversal study. the data were collected in four icus in the city of feira de santana, bahia, brazil, after approval by ethics and research committees. all clinical nurses of icus were interviewed. the brazilian adaptation of the critical care family need inventory (inefti) was used for measuring the degree of importance of needs of family members, valued at increasing levels from to . descriptive statistics were used for analysis, needs with a mean score [ were defined as having the greatest importance.results. the nurses identified % of needs as important for family members. the items related to security ''to be sure that the best possible treatment is being offered to the patient'' ( . ± . ), and the information ''to talk to the doctor every day'' ( . ± . ), were pointed out as the most important, with consistent results with the literature. some needs of support ''to have general guidelines on the icu at the first visit'' ( . ± . ) and comfort ''to have a bathroom near the waiting room'' ( . ± . ) were also identified as important. however, the needs of proximity, like being close to their relative was not identified as important to the family for all nurses.conclusions. the nurses identified the need for security and information as important, however the wish that the family has to be near their relative was not considered important, as described in the literature , , . a movement of nursing towards the family can be perceived, so nurses should plan their interventions based on knowledge of the demands of the family in order to promote care for the relief of immediate distress and anguish, which will consequently encourage the recovery of the ill relative reference(s). nurse educator, realized that with an ongoing critical care nursing shortage world wide, even when retention is high, some turnover is inevitable necessitating an orientation tool to guide charge nurses in assigning new hires to critically ill patients. impetus for this clinical orientation tool arose from observations that new hires were often overwhelmed or disengaged at the bedside, and patient assignments did not consistently foster the development of critical care skills. the orientation tool reflected a staged approach to patient assignments; gradually exposing the new hire to progressive levels of complexity. embedded within the tool were guidelines specifying performance competency expected of new hires at month intervals in their first year of critical care practice. evaluation at this stage involved on the spot interviews. use of the tool began in january . since its introduction, this tool has guided patient assignments for newly hired nurses. in six cases, nurses moved through the stages more quickly than anticipated. reports from staff nurses, clinical educator, patient care coordinator and nurse manager suggest that anxiety and stress of novice critical care nurses related to the complexity of patient assignments have decreased, and that the tool's structure provides clear goals and has enhanced satisfaction with the consolidation experience. our goal was to ensure the tool facilitated an optimal learning experience, structured around orientation standards and leading to the development of confident, competent practitioners. future plans for on-going evaluation include: formal surveys with present msicu staff, and exit interviews with nurses new to critical care who have left their msicu positions prior to the introduction of the orientation tool. ( ) has previously been claimed to show an association between improvement of score (or lack of) over time and survival status ( ) . severe sepsis in patients is associated with considerable mortality. activated protein c (apc) is a mediator of the inflammatory and coagulation systems, which has shown decreased mortality in severe sepsis ( ) beyond h sofa scores showed further distinct improvement over the apc infusion period in the survivor group, whereas minimal improvement was seen in the non survivors.change in daily sofa scores conclusions. our analysis appears to agree with levy's previous findings of increasing sofa (albeit modified) scores and mortality. we, however, looked at a different treatment period, (apc infusion rather than first day of sepsis) but, nonetheless, found the same association of increasing score and mortality and decreasing score and survival. the mean age in survivor group was considerably less than that in non survivors and this age discrepancy largely accounts for the difference in mean apache score ( points) between groups. the depicted trend in sofa scores is more apparent beyond the initial h of treatment, and suggests that improving sofa scores and outcome prediction is possible beyond the previously reported h. our numbers are small, but lend support to the predictive potential of repetitive sofa scores and outcome.objectives. this real-life registry was implemented to describe clinical characteristics of patients treated with drotrecogin alfa (activated) (daa) in france and the use of this drug.methods. this national multicenter observational study, proposed to intensive care units (icus) which used daa, was conducted by data abstraction from hospital files of patients admitted in icus and treated by daa. two sets of data were obtained: a) retrospective data collected between january st, and beginning of the prospective phase in each site; b) prospective data for patients treated until november . this current analysis aimed to describe the patients retrospectively enrolled and treated between january and april . statistical analysis was mainly descriptive. conclusions. this study showed a good concordance between the target population and population treated by daa in terms of treating patients with higher disease severity. patients treated in real-life had a particularly severe sepsis as shown by the saps ii score of and high number of organ dysfunctions at time of infusion initiation. the -month observed mortality was lower than the predicted hospital mortality of % with this level of saps ii. introduction. mortality in severe sepsis is variously described, but is often up to % ( ) . activated protein c (apc), a mediator of the inflammatory and coagulation system has shown a decrease of hospital mortality from . to . % ( ) at year post apc we found that patients ( %) out of were still alive ( patients are still less than year post apc and therefore not eligible for consideration). conclusions. this study is limited in size, but demonstrates further favourable evidence to support the administration of apc for patients with severe sepsis, and appears to contradict the cochrane findings ( ) . we have shown that our hospital survival has improved since initial report ( ) . we attribute this improvement in smr to better targeting of apc to the more severely ill septic patients (as evidenced by the increased apache score).longer term survival data was also encouraging, % of our patients were alive at year, post apc. this should be considered against an initial predicted survival to hospital discharge (never mind year) of . %. we find this result very promising, it would appear that initial survival advantage with apc is in fact sustained beyond hospital discharge. objectives. medication errors reported in a self reporting medical incident system were systematically analyzed to identify root causes and obtain preventive measures methods. all medication incidents received within year in a -bed mixed icu, were analyzed by trained persons in analyzing medical adverse events. the systematic approach consisted of five steps. . description of the incident in a causal tree. . all causes were classified into the main categories according to the prisma incident analysis tool (technical failure, organization failure, human failure, patient related and non classified). . all medication errors were categories into the broad stages of medication process (prescription, transcription, preparation, dispensation and administration). . the recovery phase of all near miss were analyzed. . development of an action matrix based on the most suitable solution (equipment, procedures, information/communication, training and motivation) for each root cause. . incidents/near miss were recorded. % were medication or fluid therapy related incidents/near miss. human intervention ( %), verification ( %) and organizational/ protocol ( %) were the most common causes of medication incidents/near miss. % of all errors occurred in the administration phase and % in the prescription phase. the most suitable solution for the recorded medication errors are shown in fig. . conclusions. this systematic approach reveals that introduction of new equipment, such as a patient data management system (pdms), and improvement of the procedures are the most important actions to reduce medication errors in our icu. objectives. this study is a descriptive study which is carried out in order to determine the perspectives of newly graduate and experienced nurses on medication errors working in a military education and research hospital. methods. this study was planned and applied as a descriptive and a cross-sectional study. study was executed at a military education and research hospital in turkey between july and august . totally nurses were involved, of those were newly graduate and were experienced nurses. data collection form which has been prepared by the researches in order to determine the perspectives of nurses on medication errors consists of two parts. the first part consists of questions prepared in order to determine the ages, departments, educational levels, experiences and some informative characteristics of the nurses. in the second part there is questionnaire form on perspectives of the nurses on medication errors which was prepared by gladstone in . the study was applied after written ethical approval of the ethical committee of the military education and research hospital and application permission of the nursing department. the application was realized by surveying on volunteer nurses after making necessary explanations about the aim of the study and the application procedures to the participants. the data were analyzed using percentages, mean ± standard deviation, chisquared test and independent-samples t test. conclusions. in this study among the causes of drug errors; tiredness and exhaustion of nurses is stated in the first place. it is thought that rearrangement of working hours of the nurses, reduction of long working hours by the nursing administration will be effective on preventing drug errors. ( ). to test the basic knowledge and practical implementation of picco measurements by icu personnel. descriptive trial in which (para)medical icu personnel were asked to participate in a written or online survey ( questions based on the information found in the manual of the picco system).results. so far, persons have participated: nurses and medical doctors ( were residents in training), all of them actively working in an icu. in total, % of the respondents knew that a picco co measurement is performed intermittently by transpulmonal thermodilution and on a continuous basis by arterial pulse contour analysis. about % is convinced that a picco measurement is an invasive procedure, while in fact it is considered minimally invasive. opinions are divided upon the indications for picco measurement. some participants do not know that the measurement of extravascular lung water provides valuable additional information in pts with acute hypoxic respiratory failure and some even believe that picco can also measure pulmonary capillary wedge pressures. the basic knowledge on co calibration is insufficient: % do not know that the temperature of the injection fluid should best be below °c and only % know that the volume of the calibration fluid depends on the patients' weight. % faulty believe that the patient has to be in the supine position to perform a measurement and % is not informed on the fact that the co obtained should not differ more than % from the mean co value. only % of the respondents carry out a rapid flush test before each picco measurement and only % know that the calibration fluid has to be injected in less than s to obtain a correct measurement. finally, % believe that it is necessary to input the cvp value to calculate a correct co, although % of the respondents correctly knew what to do in case the delta t°is too small and % could correctly interpret the thermodilution curves displayed in the survey.conclusions. from these data we can conclude that a big variation exists in the knowledge on the basic principles and the practical implementation of picco measurements. some confusion exists with regard to the terminology used. we conclude that (as with any new technique) high quality education on picco measurements is necessary for icu personnel. this education can be facilitated by a good protocol, that can be implemented by nurses and doctors at the bedside to avoid human errors. a.c. beers vu university medical center, intensive care, amsterdam, netherlands health insurance companies in the netherlands sign exclusive contracts with hospitals. patients are more critical and independent. they consciously choose a particular hospital or treatment. this is why our management gave high priority to the subject of customer service in their long term policy plan.objectives. in january a project group was launched, which aimed for a number of specific improvements but also by increasing awareness and enthusiasm for customer experience amongst employees. the project is focused on the experience or perception of patients and visitors.methods. the first step was a baseline measurement by hcg (hospitality consulting group). this measurement included interviews with employees from different icu locations and an online survey that was completed by employees, next of kin and other visitors. this resulted in a high score for commitment of staff towards patients and visitors. remarkably, employees thought that aspects for example reliability, professional care and privacy would be valued higher by customers. they attach more importance to how they are received, to empathy and sympathy. respondents also mentioned other things for improvement for example better signage, improved telephone access, better information about rules and procedures, unambiguity in approach, a better visibility of staff and a pleasant and hygienic department. . several improvements such as product, behavior and environment were achieved: we employed family counsellors, developed an information folder and started a pilot for an improved name badge. we can still make improvements in awareness, behavior and addressing each other on this subject. this year we plan to come to an agreement on standards, competencies and control by means of several management training sessions and workshops for employees. we can measure changes in patient satisfaction by family evaluation surveys or an instrument called netto promotor score. the netto promotor score (nps) indicates how many respondents will recommend our ward or hospital to their family and friends. to quote fred lee: ''if a service is provided as expected, patients or visitors will not remember it, they are merely satisfied. satisfied patients will forget a service quickly, have no story to tell to their family and friends and are not really loyal to your organisation. therefore you must create an unforgettable experience, because an experience that remains in memory, is told to others.'' reference(s). critically ill medical, post-surgical, and trauma patients are at greater risk for hyperglycemia with associated increase in mortality and morbidity. tight glycemic control (tgc) has been well documented as a method to control hyperglycemia by managing blood glucose fluctuations through carefully controlled continuous insulin infusion. in order to determine the amount of time it takes within practice for nurses to implement effectively a tgc protocol within the critical care unit, we conducted a pilot time-in-motion study to elucidate the effect on workload. a time-and-motion study was carried out at a hospital located in london, uk in order to document the time associated with tgc activities. a timing workflow, used to capture the key steps involved with effective tgc implementation when utilizing blood gas analyzers for the determination of whole blood glucose (bg) and the time required to complete each step, was designed and then validated by ccu staff. ccu staff was trained on the timing workflow and mechanism. independent observers shadowed ccu nurses, observing when a blood glucose measurement was taken, which steps were completed, and the length of time required to complete each step. other data such as time of the previous bg measurement and status of the last bg test was collected for analysis purposes. during the past few years, the increased incident rate of medical errors occurring in hospitals under governing of hong kong hospital authority has contributed significant attention from the public and health care policy makers. in such a situation, promote patient safety culture becomes paramount for all health care professionals and hospital settings. interdisciplinary teamwork is important in the intensive care units. the benefits of good teamwork have been well documented in the literatures. they included fewer delays, increase in working moral, increased in job satisfactory and decreased in medical errors. in relation to patient safety, fewer errors occur when there is strong teamwork because patient care activities are planned, well organized and standardized. therefore, substantial attention should be given to decrease of medical errors and nurture patient safety culture within high-risk areas such as icus. objectives.• to examine the perception of teamwork and patient safety culture of doctors and nurses between icus and within icu • to investigate the relationship between teamwork and patient safety culture of icu doctors and nurses methods. a cross-sectional surveyed of doctors and nurses in three intensive care units with various size, level of care and staff to patient ratio of hong kong hospitals. totally icu doctors and nurses have been included in this study. a modification of safety attitudes questionnaire developed by sexton and colleagues in was adopted. results. the overall response rate was . %. there were no significant difference of perception of teamwork and patient safety attitude among studied icu's doctors and nurses. however, icu (a) and icu (c)'s doctors demonstrated more positively and showed significant different in perceptions of teamwork (p = . ; . ) than nurses. regarding patient safety attitude, icu (a)'s doctor also showed significant difference (p = . ) and rated more positively than nurses working in the same clinical area. a highly statistically significant association between patient safety attitude and teamwork was shown in the spearman rho statistics with r s ( ) = . , p = . . conclusions. the rate of agreement on teamwork and patient safety attitude were higher in icu doctors. they were more likely to perceive effective teamwork and patient safety in the working area. nurses tended to rate both items lower. as teamwork has been shown to have strongest relationship with patient safety issues, more attention should be given to improve teamwork for icu nurses. tnf is upregulated within the alveolar space early in the course of ventilator-induced lung injury (vili), and plays a major role in the pathogenesis. we previously found in knockout mice that two tnf receptors play opposing roles during vili, with p promoting but p preventing pulmonary oedema. this suggests that specific blockade of the p receptor within the alveoli is a potential therapeutic strategy for vili. domain antibodies (dabs) are the smallest antigen-binding fragments of the igg molecule, which may have advantages over complete antibodies due to their small size (short half life, enabling regional delivery) and monovalent binding (no receptor cross-linking). objectives. we tested the effects of an intratracheally (i.t.) delivered dab that binds to and inhibits the mouse p receptor (biopharmaceutical r&d, glaxosmithkline), on pulmonary oedema and inflammation during vili. methods. c bl mice were ventilated with a high-stretch protocol (plateau pressure . - . cmh o, tidal volume - ml/kg, peep cmh o, o with - % co ). immediately after the start of high-stretch, mice were given an i.t. bolus of non-specific 'dummy' dab or p -specific dab ( lg in ll) and ventilated for up to h ( -hit model). as a -hit model, ng lps was included in the dab bolus. respiratory elastance (ers) and blood gases were monitored, and bal performed at termination. in the -hit model, lung cell suspension was analysed for intravascular margination of neutrophils (pmn), and bal fluid (balf) assessed for pmn infiltration and alveolar macrophage (am) activation using flow cytometry. results. high-stretch ventilation produced deteriorations in ers and po , and high balf protein in both models. treatment with the p -specific dab substantially attenuated all of these changes in the -hit model (table ). in the -hit model, p blockade prevented deteriorations in ers and po , and significantly decreased pmn margination, intraalveolar pmn infiltration and icam- expression on ams (table ) . introduction. ventilator-induced lung injury (vili) triggers a variety of molecular responses within the lungs. however, the contribution of these pathways to lung repair has not been identified.objective. to identify the molecular mechanisms involved in lung repair after vili.methods. vili was induced in mice by ventilation using high pressures ( cmh o) without peep for min. after this, pressure was decreased to cmh o and peep increased to cmh o for h more to promote lung repair. we quantified histological damage, protein content in alveolar lavage (balf) and different molecules in lung tissue (collagen, matrix metalloproteinases- and - , tnfa, ifnc, il- , il- , mip- and lix) in the different conditions (baseline, after injury and after repair). additionally, survivors and non-survivors to the repair phase were compared. the effects of the differentially released mediators were studied in a wound model using murine alveolar cells cultured in presence of balf obtained from ventilated animals, and human alveolar cells and balf from ventilated patients. results were compared using an anova, with a significance level of p = . . . mice were studied ( at baseline, after injury and after repair). high pressure ventilation caused lung tissue injury, with significant increases in balf protein content, mmp- , mmp- , tnfa and mip- , and a significant decrease in il- . during the repair phase, tissue injury was partially reverted, balf proteins and levels of tnfa decreased, but mmps and mip- persisted elevated. mortality during the repair phase was %. survivors showed lower levels of collagen and higher levels of mmp- ( ± vs. ± units, p \ . ) and mip- ( ± vs. ± pg/mg protein, p \ . ).blockade of mmp- , but not mip- , delayed wound closure in both murine and human alveolar cells cultured in presence of balf from ventilated mice or patients respectively.conclusions. vili is partially reversible by decreasing airway pressures and increasing peep. mmp- promotes epithelial repair.grant acknowledgment. universidad de oviedo (unov- -becdoc), ficyt (cof- - ). introduction. critically ill survivors present significant long-term brain-related morbidity. excessive end-inspiratory stretch during mechanical ventilation (mv), even in healthy lungs, may promote alterations in the local and the systemic inflammatory cascade. the effects of ventilator-induced systemic inflammation on brain structures are unknown. to characterize the role of the ventilatory pattern (high vs. low tidal volume (vt)) in the development of local or systemic inflammatory response and regional neuronal brain activation in rats. brains were processed for c-fos immunohistochemistry, as a cellular marker for activated neurons, in the following regions: thalamus, cerebral cortex, amygdala, hippocampus, hypothalamus, and caudal striatum. data were analyzed using one-way anova (p \ . ). results. map and lung compliance remained stable and in the normal range in both groups. pao decreased and paco increased at h in lvt. mv animals presented high levels of systemic and lung inflammatory mediators compared with baseline levels. hvt significanly increased tnfa and il- in plasma when compared with lvt group. in the lungs mv increased il- , il- , il- b and mip- proteins, irrespective of the vt level (lvt or hvt). mcp- only increased in hvt lungs, while tnfa lung levels are similar in ventilated and non-ventilated animals. a significant increase in the number of c-fos immunopositive neurons was only found in retrosplenial cortex and thalamus in hvt animals as a sign of neuronal activation of those areas. none of these two areas were activated in lvt or in control animals. mechanical ventilation produced a moderated systemic and lung inflammation in the context of a preserved lung function. high tidal volume ventilation promoted differential neuronal activation in the brain compared with lvt animals. these findings suggest a novel cross-talking mechanism between lung and brain in the context of experimental acute lung injury.grant acknowledgment. mec bfu - /bfi, fundació parc taulí. jl-a is senior researcher program i isciii, and ciberes. ( ).in an ex vivo perfused human lung preparation injured by e. coli endotoxin, allogeneic human mscs or the conditioned medium restored normal fluid balance ( ).objectives. we wished to evaluate the potential for mscs to modulate inflammation and enhance repair after ventilator induced lung injury (vili). adult male sprague-dawley rats were anaesthetised, orotracheally intubated and subjected to injurious mechanical ventilation. following the development of vili, animals were recovered and extubated. thereafter the animals received two intravenous injections of mscs ( . million cells) or vehicle immediately post injury and at h. the extent of the inflammatory response and recovery from vili, as measured by systemic oxygenation, respiratory static compliance, lung wet:dry ratio and lung lavage inflammatory cell infiltration, was assessed at h. mscs reduced inflammation and enhanced repair following vili. msc treatment improved respiratory static compliance, reduced total lung water as assessed by wet:dry ratio, and decreased bronchoalveolar lavage total inflammatory cell and neutrophil counts, from , cells/ml to , cells/ml (ci . - . ) (fig. ). there was a trend towards better oxygenation in the msc group.conclusions. these findings demonstrate the potential of mscs to modulate inflammation and enhance repair following vili. further analysis of our work, including bal cytokine assay and histological assessment of injury, will provide insight into the utility of mscs to enhance repair in the lung. to determine the role of vagus nerve signaling in vili and establish whether stimulation of the vagus reflex can mitigate lung injury from high volume ventilation.methods. first we demonstrate that disruption of the cap reflex by bilateral vagotomy results in worsening lung injury in a mouse model of high-volume-induced lung injury. in a clinically relevant rat model of injurious ventilation following hemorrhagic shock/resuscitation (hs; model of lung ischemia/reperfusion injury), we then tested the hypothesis that electrical and pharmacological stimulation of the vagus nerve can attenuate injurious effects of vili. finally, to determine the molecular mechanisms by which stimulation of the cholinergic response mitigates vili, we exposed human bronchial epithelial cells (beas b) to cyclic stretch ( cycles/min, pka) in the presence of specific agonist or antagonist of the subunit of the acetylcholine nicotine receptor. vagotomy exacerbates lung injury from high volume ventilation in mice as demonstrated by increased wet-to-dry ratio, infiltration of neutrophils in bronchoalveolar lavage fluid and lung tissues, and increased tissue levels of interleukin- . vagotomy exacerbated while vagus stimulation attenuates lung injury in rats after ischemia reperfusion injury ventilated with either high or low volume strategies. treatment of both mice and rats with the vagus mimetic drug, semapimod, resulted in decreased lung injury. vagotomy also increased pulmonary apoptosis whilst vagus stimulation (electrical and pharmacological) attenuated vili-induced apoptosis. in vitro studies suggest that vagus-dependent effects on inflammation and apoptosis are mediated via the a nachrc-dependent effects on cyclic stretch-dependent singling pathways c-jun n-terminal kinase (jnk) and fas (tnf receptor superfamily, member ).conclusions. stimulation of the cholinergic anti-inflammatory reflex may represent a promising alternative for the treatment of vili.introduction. so far, histological data on critical illness myopathy (cim) primarily refers to muscle biopsies taken during protracted critical illness (after weeks), repeatedly describing pronounced type-ii muscle fibre atrophy.objectives. we speculate that type-ii fibre atrophy develops during early critical illness in patients with non-excitable muscle membrane which predicts cim. ( ) methods. due to their elevated risk for cim, critically ill patients with sofa scores c on of consecutive days within the first days after icu admission were eligible for inclusion into this prospective, observational study. preexisting iddm or neuromuscular disorder, pregnancy, bmi c kg/m , age \ years, or pretreatment[ days on other icu constituted exclusion criteria. surgical muscle biopsies were taken from vastus lateralis muscles between day and after first sofa c and postprocessed according to standard procedures (isopentane, liquid nitrogen, atpase/toluidineblue staining). we assessed muscle membrane excitability after direct muscle stimulation, abnormal muscle membrane excitabilty indicating cim ( ). after quantifying fibre-type specific median cross sectional areas (csa) with imagej-software, we compared fibre-type specific csa in patients with and without non-excitable muscle membrane. nonparametric tests (mann-whitney u) were used for statistical analyses, results expressed as median and ( th/ th) percentiles for continuous variables. . patients were enrolled and subsequently biopsied. patients were evaluated for muscle membrane excitability, of whom % (n = ) showed non-excitable muscle membrane. reliable csa quantification was obtainable for patients.type-ii but not type-i muscle fibre csa during early critical illness was significantly decreased in patients with non-excitable muscle membrane ( , lm compared to , lm for type-ii, p = . ; , lm compared to , lm for type-i, p = . ; n = ). furthermore, non-excitable muscle membrane was associated with significantly lower mrc scores after end of sedation ( . ( . / . ) vs. . ( . / . ) , p = . , n = ). in patients showing non-excitable muscle membrane after direct muscle stimulation we could observe selective type-ii fibre atrophy as early as within the first days after icu admission (day - after st sofa c ). our findings demonstrate that nonexcitable muscle membrane indeed is associated with a histomorphological correlate previously linked to cim. these results highlight the need to focus on early critically illness in order to investigate pathophysiological aspects of cim. bacterial sepsis is a major threat in neonates born prematurely, and is associated with elevated morbidity and mortality. little is known on the innate immune response to bacteria among extremely premature infants. objectives. identify innate immune defect in premature infants as risk factor for the development of neonatal sepsis. methods. we compared innate immune functions to bacteria commonly causing sepsis in infants of less than wks of gestational age, infants born between and wks of gestational age, term newborns and healthy adults. levels of surface expression of innate immune receptors (cd , tlr , tlr , and md- ) for gram-positive and gramnegative bacteria were measured in cord blood leukocytes at the time of birth. the cytokine response to bacteria of those leukocytes as well as plasma-dependent opsonophagocytosis of bacteria by target leukocytes were also measured in the presence or absence of interferon-c. results. leukocytes from extremely premature infants expressed very low levels of receptors important for bacterial recognition. leukocyte inflammatory responses to bacteria and opsonophagocytic activity of plasma from premature infants were also severely impaired compared to term newborns or adults. these innate immune defects could be corrected when blood from premature infants was incubated ex vivo h with interferon-c. conclusions. premature infants display markedly impaired innate immune functions, which likely account for their propensity to develop bacterial sepsis during the neonatal period. maturation of the innate immune response to bacteria can be induced by interferon-c ex vivo and represents a promising strategy to prevent neonatal sepsis. the anaphylotoxin c a impairs neutrophil phagocytosis in animals and humans with sepsis. although dependency on the phosphoinositol -kinase delta (pi kd) pathway has been identified , , greater understanding of the mechanism will allow novel therapeutic options. objectives. to test the hypotheses that c a mediates its effect on phagocytosis by impairing rhoa activation, and that similar defects will be found in neutrophils from critically ill patients. methods. the mechanism was dissected using an in vitro model of c a-mediated neutrophil dysfunction, treating healthy human donor neutrophils with c a at concentrations found in sepsis ( nm). phagocytosis was assessed by zymosan particle uptake. neutrophils exposed to zymosan were assayed for rhoa activity, a key mediator of actin polymerisation in phagocytosis . phagocytosis by neutrophils from critically ill patients was investigated, looking for correlations with a marker of c a exposure (cd , the main c a receptor) , an examination of the rhoa and actin polymerisation response to zymosan, and the ability of gm-csf to restore phagocytosis ex-vivo. results. c a inhibited phagocytosis of zymosan by healthy donor neutrophils (reducing from to %, p \ . ) and also impaired rhoa activation (figure) . blocking pi kd, using inhibitor ic , prevented the inhibition of rhoa by c a, and prevented the reduction in phagocytosis. treatment with gm-csf restored phagocytosis and rhoa activation (fig. ). neutrophils from patients with critical illness showed a strong correlation between phagocytosis and surface cd expression (r = . , p \ . ), consistent with our previous findings . patient neutrophils failed to up regulate rhoa or polymerise actin in response to zymosan, in marked contrast to cells from healthy donors (p = . and p = . respectively). ex-vivo gm-csf was able to improve phagocytosis by patient neutrophils from to %, p \ . . conclusions. these data demonstrate that c a inhibits rhoa activity through pi kd, inhibiting phagocytosis. gm-csf is able to reverse this inhibition. similar effects are seen in neutrophils from critically ill patients, providing new avenues for therapeutic intervention in critical illness. host infection triggers an innate immune response leading to a systemic inflammatory response, often followed by an immune dysfunction which impairs the lung defence mechanisms in mice and increases susceptibility to secondary p. aeruginosa pneumonia. activation of the toll-like receptor (tlr)-dependent signalling pathways influences the magnitude of the initial pro-inflammatory phase of sepsis. contribution of tlr signaling to the subsequent development of post-infective immunosuppression has been poorly studied.objectives. to investigate the relative contribution of tlr and tlr in lung defence towards p. aeruginosa in the setting of sepsis-induced immune dysfunction. we used wild-type (wt) c bl /j mice and littermates deficient for tlr (tlr ko), tlr (tlr ko) or both tlr and tlr (tlr ko). these animals were subjected to a sublethal polymicrobial sepsis (cecal ligature and puncture, clp) followed by a secondary p. aeruginosa pneumonia at day post-clp . we evaluated -day survival and the lung response and h after instillation through lung histology, quantification of protein level, cell recruitment and myeloperoxydase (mpo) activity. lung expression of tlr , tlr and tlr was assessed through quantitative rt-pcr. bacterial lung clearance was evaluated through quantitative culture of bronchoalveolar lavage fluid (balf). bacteremic dissemination was assessed through quantitative blood cultures. finally, we measured cytokines in the balf and in the whole lung. post-septic wt and tlr ko mice displayed high susceptibility (mortality rate %) towards secondary pneumonia. in contrast, post-septic tlr -deficient mice (either tlr ko or tlr ko), survived the secondary pulmonary infection (mortality rate \ %). in wt mice, clp increased lung expression of tlr , but neither of tlr nor tlr . tlr ko mice displayed improvement in lung bacterial clearance and reduction in bacteremic dissemination as compared to wt mice. with regard to pulmonary inflammation, tlr ko mice displayed decreased alveolar damage. furthermore wt and tlr ko mice displayed differences in the pulmonary release of cytokines. thus tlr ko mice exhibited increased production of tnf-a and ifn-c and a decreased production of il- .conclusions. in a model of polymicrobial sepsis followed by p. aeruginosa pneumonia, tlr deficiency improves survival by promoting efficient bacterial clearance and decreasing pulmonary inflammation. tlr -dependent mechanisms that specifically contribute to lung defence in the setting of sepsis-induced immune dysfunction are currently investigated. infection is a serious complication in critically ill patients, who can be in a state of secondary immunodeficiency due to a severe illness. apart from common nosocomial pathogens, highly unusual microorganisms may be found in these patients, i.e. pathogens whose cultivation requires specific conditions, and/or agents which are difficult to cultivate. molecular biology-based methods (pathogen-specific probes with real-time pcr detection, or universal system pcr detection with subsequent sequenation) make diagnosis faster and more accurate.objectives. i) to assess an agreement of investigation results using classical microbiology techniques and molecular biology-based methods; ii)to evaluate the clinical effect of the diagnoses based on the frequency of changes in antibiotic therapy as a direct result of molecular detection of ''pathogens'' (mpd) and to assess the effect of this change by evaluating a -day trend of inflammatory parameter concentrations i.e. of procalcitonin (pct) and c-reactive protein (crp). a total of samples (blood, bal, tracheal aspirate, urine, cerebrospinal fluid and secretions from abdomen drains and thoracic punctures) were taken from icu patients (aged - ). these were investigated simultaneously, both by classical microbiology and microbial methods, using the system of pathogen-specific probes with real time pcr for agents. each sample was tested simultaneously with the universal pcr detection system for bacteria and fungi with the subsequent sequenation.results. an agreement between the two compared examination methods was found in % of samples and disagreement in % of the samples. % of the results were classified as ''not possible to interpret''. in % of the samples, mbm detected the presence of other agents, which were not confirmed by cultivation. in % of cases, the mdp results did not contribute to the decision to change the atb. in % of cases, a modification of atb treatment followed; a change, reduction or stopping the administration of the drug. in % of cases, atb was changed without any direct connection to the results. in % of patients who underwent the change in atb treatment, a decrease in inflammatory parameters occurred (pct and crp), however, in % there was an increase. the remaining % are divided equally between those ''without any change'' and ''data not available''.conclusions. the advantage of septic-state diagnostics using molecular biology techniques, as opposed to classical microbiology methods, is the fast availability of the examination results ( - h) , and its high sensitivity and specificity. proving the presence of agents in biological material does not necessarily signify its pathogenicity. however, in combination with a thorough assessment of the clinical progression, including laboratory indicators of inflammation, it is of considerable benefit in decisions about the efficacy of antibiotic therapy. common antibiotics and the number of patients on high or low intensity crrt recruited were: ciprofloxacin ( , ) , meropenem ( , ), piperacillin-tazobactam ( , ) , vancomycin ( , ). the clearance of individual antibiotics varied approximately -and fold within a single crrt regimen for high and low flow rates, clearance, estimated using ccrt extraction ratios for the two flow rates, differed significantly: meropenem ( vs. ml/min; p = . ) and vancomycin ( vs. ml/min; p = . ). using dialysate clearances, significant differences for vancomycin ( vs. ( ) objectives. to perform a meta-analysis on incidence and outcome of intra-abdominal hypertension (iah) in different icu populations, the evolution of iap over time and the correlation with organ failure and fluid balance (fb)methods. pts admitted to icu with iap measurements (gastric or bladder) were included. data from existing databases were collected on , pts from centers ( countries [ ] . recently, it was demonstrated that % hes / . induces increased inflammation and leads to more tubular damage compared to % hes / . in an ex-vivo kidney perfusion model [ ] . we investigated whether different hes solutions lead to disturbed cell proliferation or to increased apoptosis in murine kidney cells. we performed a large cohort study on prospectively collected data over a year period ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . data were extracted from the cub-réa network , a french regional database in which icus from paris and its suburb prospectively record data using standardized coding methods. cancer patients with septic shock were selected through keywords including the malignancy status on one hand (''hematological malignancy'', ''cancer'', ''cancer with metastasis''), and ''septic shock'' or the combination of ''septicemia'' and ''shock'' on the other hand. extracted variables included demographic characteristics, type of malignancy, requirements for organ failure supports (vasopressor therapy, mechanical ventilation, renal replacement therapy) and severity-of-illness score (saps , , , , however, some studies have suggested little effect on morbidity or mortality. , clarification of any differences would improve pre-operative risk assessment, providing more information for the clinician and patient. it would also aid resource planning in the critical care unit. we hypothesized a proportional increase in the extremes of bmi occurring over the -year study period. we analysed data collected prospectively between april and april on patients undergoing cardiac surgery in our unit using the patient analysis and tracking system (pats Ò ) database. the patients were grouped according to bmi. for each group we calculated organ specific complication rates, re-operation and readmission rates, itu and postoperative length of stay and overall mortality. we studied the change in mean bmi of patients over the year period. in comparison with normal bmi range ( . - . ), patients with bmi range \ . had significantly increased rates of peri-operative myocardial infarction (mi) ( conclusions. both the high and low extremes of bmi range show significant increases in complication rates compared to normal bmi patients undergoing cardiac surgery. the bmi group - . shows significant increase in re-operation, readmission and mortality rates.there is a year on rear increase in the bmi group [ . this suggests a greater demand for resources particularly in the intensive care unit as the population with a higher morbidity and mortality increases. we would welcome an opportunity to present a detailed analysis of our findings. with advances in critical care medicine, more patients are surviving intensive care units stays. patients admitted to critical care may experience morbidity that affects their life after discharge . in addition to any physical morbidity, treatment in critical care may also be stressful and psychologically traumatic for patients .objectives. to describe the psychological outcome of patients surviving icu admission at months. a second end-point was to find possible relationships between patients' background and intensive care variables, post-traumatic stress and depression disorders.methods. retrospective analysis of data from icu follow-up clinic. data were collected in questionnaires (ptss- and beck inventory) during an interview at months after discharge of icu in the last years. statistics analysis: pearson's chi-square or fisher's exact test, significance for p \ . . . patients were interviewed, mean age was ± , % were male and . % were trauma victims. mean icu length of stay was ± days and sapsii score ± . . % of patients had less than years of education. concerning previous health status . % were healthy and . % were dependent for daily living activities. . % were retired. more than % had new complaints after discharge. only . % of the previously professionally active patients resumed their work and only % of the retired were able to maintain their normal activity. almost % of patients had new psychiatrics symptoms and only . % were being followed by psychiatry: % were on benzodiazepines and . % on anti-depressants. . % of the patients had symptoms suggestive of diagnosis of post-traumatic stress disorder (ptsd) having a ptss- superior to . regarding beck inventory, % were considered to have a depression, with . % having moderate to severe depression. after the interview % were oriented to a psychiatric consultation. % of depressive patients had new symptoms (p \ . ). of the previously active patients who did not resume normal activities, a significant (p \ . ) part was depressed ( . %). the same is true for the retired patients ( . %), p = . . longer hospital and icu lengths of stay were related with development of depression (p = . and p = . , respectively). patients with higher sapsii were more prone to develop ptsd. women had more ptsd than men (p = . ). patients in risk of ptsd and depression were younger (p = . ; p = . , respectively). as with depression these patients also had more new complains and did not return to work. introduction. mild hypothermia improves outcome after cardiopulmonary resuscitation (cpr). modes of action for it are manifold, though one way might be reduction of basal metabolic rate (bmr). therapeutic hypothermia was able to reduce bmr in patients with traumatic brain injury and critically ill patients with fever.objectives. in the present study we investigated the metabolic effect of therapeutic hypothermia in patients after successful cpr.methods. patients after cpr were treated with therapeutic hypothermia ( °c) for h and subsequently rewarmed with a rate of . °c per hour until °c was reached. all patients received standardized sedoanalgetic medication and neuromuscular blockers. indirect calorimetry was performed at , . and °c, as well as between . and . °c and - h after cpr. for statistical analysis repeated measures anova, linear and logistic regression were used. a linear relation between bmr and temperature was detected ( kj/m / . °c; p \ . ). therapeutic hypothermia ( °c) was associated with a reduction of bmr by ± % compared to °c. in this regard no difference was found between patients with good and bad neurological outcome (good outcome vs. bad outcome: ± vs. ± %; p = . ). concerning substrate oxidation rates only fat oxidation rate showed a temperature dependency ( g/day/ . °c; p \ . ). in contrast to protein oxidation rate (good outcome vs. bad outcome: ± vs. ± g/day; p = . ) patients with good neurological outcome had a significantly higher fat oxidation rate (good outcome vs. bad outcome: ± vs. ± g/day; p = . ) and a significantly lower glucose oxidation rate (good outcome vs. bad outcome: ± vs. ± g/day; p = . ) as compared to patients with bad neurological outcome.conclusions. in patients after cpr mild therapeutic hypothermia ( °c) was associated with a reduction of bmr by %. a linear relation between temperature and bmr was detected. fat oxidation rate was temperature dependent in contrast to protein and glucose oxidation rate. a significant difference in glucose and fat oxidation rates was found between patients with good and bad neurological outcome. objectives. our goal was to determine whether its institution after resumption of spontaneous circulation (rosc) improves survival and neurological recovery in an experimental model of cardiac arrest in rabbits.methods. ventricular fibrillation was induced in anesthetized rabbits. after -min of untreated fibrillation, cardiopulmonary resuscitation was attempted using external massage, electric shocks and intravenous epinephrine. after rosc, rabbits randomly underwent either normothermic life support (control group with conventional ventilation until weaning) or hypothermic support with rapid cooling (tlv group). in this last group, a °c hypothermia was induced by -min of tlv using a perfluorocarbon. subsequently, the perfluorocarbon was removed from the lungs and rabbits were conventionally ventilated with maintenance of hypothermia during h. rabbits were further warmed and weaned from ventilation. in both groups, hemodynamic and biochemical parameters were monitored, as well as survival and neurological recovery. after days, survivors were finally euthanized for post-mortem analyses. neurological dysfunction was assessed by a - % scoring system evaluating reflexes, postural reactions and behaviour ( %: no dysfunction; %: brain death).results. ten rabbits were randomized to the control group and to the tlv one. defibrillation was obtained using . ± . and . ± . electric shocks, respectively. subsequent rosc was observed after . ± . and . ± . min, respectively. oesophageal and tympanic temperatures were rapidly reduced in the tlv group, achieving . ± . and . ± . °c within -min versus . ± . and . ± . °c in control, respectively. in the tlv group, rabbits returned to normothermia within - h after the hypothermic episode. throughout follow-up, no significant difference in blood pressure was observed between both groups (e.g., ± and ± mmhg in control vs. tlv at h after cardiac arrest, respectively) whereas heart rate was decreased throughout hypothermia in tlv vs. control (e.g., ± vs. ± beats/min at h following cardiac arrest, respectively). lactates's concentration and epinephrine dosages were not significantly different between groups. importantly, neurological dysfunction was significantly attenuated in tlv vs. control (e.g., ± vs. ± % after h). in control, / ( %) rabbits survived throughout the follow-up and the others died or should be euthanized earlier following severe disability. in the tlv group, survival was significantly increased as / rabbits survived to the entire follow-up ( %).conclusion. ultra-fast cooling induced by tlv after rosc improves survival and neurological recovery following -min of experimental cardiac arrest in rabbits.grant acknowledgment. (ca) . th involves at least h of induced hypothermia ( - °c), mechanical ventilation and sedation. th may affect sedation through changes in pharmacology. still, no clinical studies have investigated the use of sedation during th. objective. to compare the efficacy of two sedation protocols for patients treated with th. methods. open, randomised, controlled, population based study of patients treated with th ( - c for h) after ca in two norwegian university hospitals. patients were randomised to sedation with remifentanil + propofol (rp) or fentanyl + midazolam (fm). baseline characteristics (age, sex, bmi, saps-ii) and cardiovascular variables during study drug infusion (blood pressure, heart rate, use of fluids, vasopressors and inotropic drugs) were recorded. the primary end point was defined as time from stop of sedation to extubation. results. sixty patients were randomised. one patient was withdrawn by next of kin. baseline characteristics were similar in the two groups. for two patients in the rp group, and one in the fm group, study drugs were stopped shortly after allocation due to cardiovascular instability. the rp group had lower heart rates and more patients needed noradrenaline infusions than the fm group ( . ( . ) (mean(sd)) vs. . ( ) beats/min, p = . , and vs. patients, p = . , respectively). other circulatory variables were similar. reasons to not stop sedation or not extubate after stop of sedation were; cessation of icu treatment (n = ), need for mechanical ventilation (n = ), inadequate awakening (n = ), seizures after stop (n = ), and other (n = ). sedation was stopped according to protocol in of patients. median (range) time from stop of sedation to extubation for the patients who could be extubated according to protocol was . ( - . ) vs. . ( . - . ) h in the rp and fm group, respectively, p = . . ''cerebral performance category'' on day - was similar in the two groups. conclusions. time to extubation after cessation of sedation was significantly shorter in patients sedated with rp compared to fm. however, the benefit from a short time to extubation is limited by that only one-third of the patents can be extubated according to protocol. the rp group had lower heart rates and needed more noradrenaline. no major differences were observed for outcome.grant acknowledgment. ntnu. increased blood glucose variability during therapeutic hypo-thermia and neurological recovery after cardiac arrest key: cord- -vbzy hc authors: damjanovic, v.; taylor, n.; williets, t.; van saene, h. k. f. title: outbreaks of infection in the icu: what’s up at the beginning of the twenty-first century? date: - - journal: infection control in the intensive care unit doi: . / - - - - _ sha: doc_id: cord_uid: vbzy hc surveillance cultures are the only cultures that allow the distinction between secondary endogenous and exogenous infections. these types of infection are the two known to cause outbreaks. secondary endogenous infections can be controlled by enterally administered antimicrobials and should be integrated into the routine infection control measures. exogenous infections can be controlled by topically applied antimicrobials and hygiene. two recent sets of publications were taken into consideration when preparing our analysis of infectious outbreaks in the intensive care unit (icu). the first concerns the emergence of severe acute respiratory syndrome (sars) and avian flu in , and a spread across the world of a novel influenza caused by swh n in . these viral infections had a major impact on intensive care and are described in chap. . this chapter is dedicated to describing outbreaks caused by bacteria and fungi, with references to secondary infections associated with flu and sars [ , ] . the second publication concerns the ''international study of the prevalence and outcomes of infection in intensive care units'' published in december [ ] . although this is a point-prevalence study, it provides information about the global epidemiology of infection in icus. unfortunately, it could not give insight into outbreaks of infection in icus, so we searched for specific publications describing such outbreaks. in the second ( ) edition of this book, we analysed the usefulness of molecular techniques in selected outbreaks [ ] . the majority of outbreaks occurred in the last decade of the twentieth century. however, reports were usually published several years later. a similar pattern was observed when we analysed outbreaks published in the first decade of the twenty-first century: the actual outbreaks occurred a few years earlier. indeed, the above-mentioned point-prevalence study was conducted on may but published in december [ ] . therefore, for accuracy, this analysis indicates when outbreaks actually happened and when they were subsequently published. acinetobacter outbreaks were selected to illustrate this point ( fig. . ). in addition to the reported outbreaks, a number of publications considered many relevant aspects of infection and outbreaks in icu. some of these are included in this chapter. we analysed publications, the majority of which met the definition of an outbreak in neonatal (nicu), paediatric (picu) and adult (aicu) icus and reported since . the main objective of this analysis was to find out whether there were any new features in the outbreaks of infection in icu at the beginning of the new century, including those influenced by new viruses. we searched medline for outbreaks published between january and september . the search terms used were intensive care unit, adult icu, paediatric icu, neonatal icu and outbreaks. we used the same framework as in the second edition of this book; however, outbreaks were not presented separately per icu type but according to causative organisms, in the following order: methicillin-resistant staphylococcus aureus (mrsa), vancomycin-resistant enterococci (vre), aerobic gramnegative bacilli (agnb), pseudomonas spp., acinetobacter spp. and fungi, together with the selected features searched (table . ). the number of analysed outbreaks is stated, but only selected outbreaks are shown and listed in the references. we retrieved reports on six outbreaks [ ] [ ] [ ] [ ] [ ] [ ] published since ; five occurred in aicus and one in an animal icu. reports of two outbreaks were published in and three in , all occurring between and . one report published in did not report the actual time of the outbreak. these outbreaks are summarised briefly according to their countries of origin. a paper from italy published in reported a unique experience of controlling a mrsa outbreak of months' duration in a medical/surgical aicu in using enterally administered vancomycin in mechanically ventilated patients [ ] . another report from italy, published in , described the identification of a variant of the ''rome clone'' of mrsa responsible for an outbreak in a cardiac surgery icu, which occurred in in a hospital in rome. this strain had decreased sensitivity to vancomycin and was resistant to many antibiotics [ ] . a study from germany published in described the occurrence of mrsa in icu in terms of endemic and epidemic infections followed from january to june .this study involved icus, of which ( %) had mrsa infections. outbreaks (three or more mrsa infections within months) were registered in icus, clusters (two mrsa infections within months) in further units and single events in [ ] . a publication from spain showed that enterally administered vancomycin can control endemic mrsa in icus without promoting vre. this study was carried out over a -month period from july to and published in [ ] . in , a report from canada presented a recent outbreak of mrsa carriage in an animal icu. this finding appears important, as the strain responsible for the animal outbreak was indistinguishable from a strain in humans commonly isolated in canada and the usa. infection control measures, including active surveillance of all animals in the icu, were used to control the outbreak. as transmission of mrsa within the unit occurred without infections and did not persist for a prolonged period of time, staff screening was surprisingly not initiated [ ] . a paper from china published in described an mrsa outbreak due to an increased there have been ten outbreaks in aicus published since : eight were caused by vre, one was sensitive to vancomycin and one was sensitive to vancomycin but resistant to linezolid. we selected seven reports and summarised them according to the countries of origin and time of events and publishing. a paper from pakistan published in was the country's first experience with a vancomycin resistant enterococcus faecium outbreak in the icu and nicu. the outbreak occurred in , lasted month and all but one isolate was of a single clone [ ] . all isolates were resistant to gentamicin, ampicillin and tetracycline but sensitive to chloramphenicol. six patients were colonised and four infected, with positive blood cultures; two of each died before specific therapy could be started ( % mortality rate). in , a report from italy described an outbreak of vre colonisation and infection in an icu that lasted months ( - ) [ ] . fifty-six patients were colonised by e. faecium, and e. faecalis was detected in only two cases. because of the low pathogenicity of vre, the authors questioned whether it was worthwhile to have a specific vre surveillance programme. for the lowbury lecture, pearman reported the australian experience with vre, which he described as ''from disaster to ongoing control''. this was the first outbreak of vre, which was caused by e. faecium in an icu and hospital wards and lasted months in . a vigilant vre control programme prevented the epidemic strain from becoming endemic in the hospital [ ] . an outbreak due to glycopeptide-resistant enterococci (gre) in an icu with simultaneous circulation of two different clones was reported from france in . the outbreak lasted several months in without infections, but the significant colonisation caused organisational problems in the icu [ ] . an outbreak of vre in an icu was reported from china in . the outbreak was caused by e. faecium and lasted months ( - ) . a detailed molecular analysis showed that genetically unrelated isolates had transferred vancomycin resistance by conjugation [ ] . a paper from korea reported an outbreak of vre in a neurological icu. vre was mainly isolated from urine specimens associated with the presence of a foley catheter. of patients colonised with vre, only two had active infection [ ] . in , a report from spain presented an outbreak of linezolid-resistant e. faecalis in an icu and reanimation unit [ ] . this was the first report of a clonal outbreak of linezolid-resistant e. faecalis in spain. the strain was sensitive to imipenem, vancomycin, teicoplanin and rifampicin. most patients were exposed to linezolid within a year ( ) ( ) . the use of linezolid began in . the increase in its use continued until when a mutant was identified by molecular analysis. fourteen reports on outbreaks were retrieved since . eight were caused by klebsiella pneumoniae, four by serratia marcescens, one by enterobacter cloacae and one by simultaneous infection of e. cloacae and s. marcescens. three klebsiella, three serratia and the remaining two were selected for analysis. we discuss pseudomonas and acinetobacter outbreaks separately. an outbreak of klebsiella infection in nicu and picu was published from spain in ; this outbreak occurred in - and lasted year [ ] . the outbreak was polyclonal. two predominant clones of klebsiella harboured a special gene (shv ) for the beta-lactamase enzyme responsible for multi-drugresistant klebsiella. according to the authors, this type of klebsiella was not reported previously in spain. another clone harbouring two different genes responsible for multidrug resistance but dissimilar from the above was reported. a report from the netherlands published in described an outbreak of infections with a multi-drug-resistant klebsiella strain [ ] associated with contaminated roll boards in operating rooms. this outbreak in showed how an unusual source of the outbreak can be revealed by systematic surveillance. in , a polyclonal outbreak of extended spectrum beta-lactamase (esbl)-producing k. pneumoniae in an icu of a university hospital in belgium was reported [ ] . this was a -month outbreak that occurred in with isolates. there was one predominant clone, two clones with several isolates and four with unique isolates. the cause of the outbreak was not clear but was associated with a dramatic increase in the number of imported carriers during the previous weeks. an outbreak caused by esbl-producing e. cloacae in a cardiothoracic icu was reported from spain in [ ] . the outbreak occurred in , lasted months, and involved seven patients. molecular analysis revealed two clones responsible for the outbreak: one carried a single esbl; the other carried two esbls. both clones showed resistance to quinolones and aminoglycosides. the outbreak was brought under control by the implementation of barrier measures and cephalosporin restrictions. an outbreak was reported from germany in [ ] in both the nicu and picu, lasted from september to november and involved patients. two epidemic strains were associated with cross-infection in groups of five and ten patients, respectively. two epidemic clones were detected from the surfaces of an icu room, but an original source was not identified. the outbreak was stopped by routine infection-control measures. a report from malaysia in described an outbreak of serratia infections that lasted days in an aicu [ ] . the single outbreak strain was found in insulin and sedative solutions administered to patients. an outbreak of s. marcescens colonisation and infection in a neurological icu that occurred from may to march was reported from a dutch university medical centre in [ ] . the outbreak strain was traced to a healthcare worker (hcw) with longterm carriage on the hands. the skin of the hcw's hands was psoriatic. the epidemic ended after the colonised hcw went on leave, with subsequent eradication treatment. a heterogeneous outbreak of e. cloacae and s. marcescens infections in a surgical icu was published by a group of authors from san francisco, usa [ ] . the outbreak lasted from december through january . molecular techniques ruled out a point source or significant cross-contamination as modes of transmission. the authors concluded that patient-related factors, such as respiratory tract colonisation and duration of central line placement might have played a role in this outbreak. several reports have been published on infections caused by multi-drug-resistant pseudomonas spp. in icus since . we retrieved reports; not all were outbreaks, as some were described as endemic infections. in addition, one outbreak was caused by burkholderia cepacia. we selected a few outbreaks that we believed would represent the main problems occurring in icus, such as multidrug resistance, clonality, transmission source and mode and infection severity. in , a publication from norway reported an outbreak of multi-drug-resistant p. aeruginosa associated with increased risk of death [ ] . the outbreak occurred from december to september , was monoclonal and the strain was introduced into the icu early in and was maintained thereafter. all patients were ventilated. the strain was resistant to carbapenems, quinolones and azlocillin. in infected patients, ten of whom died, pseudomonas was found in one or all specimens, such as respiratory secretions, ventilator tubes, connection tubes and the water catcher of the ventilator system. the bacterium was also isolated from water taps. in addition to enhanced control of infection measures, complete elimination of the outbreak was achieved after water taps were pasteurised and sterile water was used when a solvent was needed. in , french authors published a report on the epidemiology of p. aeruginosa in an icu [ ] . although between and the prevalence of p. aeruginosa infections reached % of all hospital-acquired infections, the authors did not call this an outbreak, despite the fact that this was twice the national prevalence of % observed in icus. however, this high prevalence prompted the authors to conduct a prospective epidemiological study from july to february . we selected this study as a good example of activities necessary to prevent a major outbreak. the authors described how systematic surveillance was carried out (oropharyngeal and rectal swabs on admission and twice weekly afterwards). this practice revealed that during the study period, the overall incidence of p. aeruginosa carriage was %: % on admission and % acquired in the icu. in addition / ( %) patients developed the infection. the authors also pointed out that intestinal carriage was a prerequisite for colonisation or infection. genotyping analysis of isolates indicated that % belonged to genotype , % to genotype and that remaining isolates were not genetically related. it has also been shown that mechanical ventilation was associated with p. aeruginosa carriage and ineffective antibiotics significantly increased the risk of colonisation and infection in icu. the authors concluded that not only do endogenous sources account for the majority of colonisation or infection due to p. aeruginosa but that exogenous sources may be involved in some instances. in an epidemic setting, the authors' stance was to reinforce standard barrier precautions. however, the main message of this study is the necessity to adopt and pursue preventive measures. in , an outbreak of severe b. cepacia infections in an icu was reported from spain [ ] . the outbreak occurred over a period of days in august when b. cepacia were recovered from different clinical samples associated with bacteraemia in three cases, lower respiratory tract infection in one and urinary tract infection in one. samples of antiseptics, eau de cologne and moisturising milk available on treatment carts were collected and cultured. b. cepacia was isolated not only from three samples of the moisturising body milk that had been applied to the patients but also from two new hermetically closed units. all strains recovered from environmental and clinical samples belonged to the same clone. the cream was withdrawn from all hospital units, and no new cases of b. cepacia developed. the authors concluded that the presence of bacteria in cosmetic products, even within accepted limits, may lead to severe life-threatening infections in severely ill patients. we retrieved publications on acinetobacter outbreaks, of which were not strictly outbreaks, and actually not reported as such, but rather described general epidemiology, antibiotic resistance, infection control or treatment options. most of these problems are dealt with in relevant chapters of this edition. following our approach, we summarise only a few outbreaks, which appeared to offer some new findings or insights. a report from italy described an outbreak of infusion-related a. baumannii bacteraemia in an eight-bed icu [ ] . from june to july , six cases were identified. all patients received parenterally administered solutions prepared by icu nurses, which was subsequently proven to be the source of infection. three patients died from sepsis despite treatment with a combination of meropenem and amikacin, which were shown by laboratory tests to be synergistic. this high mortality rate ( %) was explained by the authors as being due to persistent bacteraemia related to the repeated infusions of contaminated solutions. once aseptic preparation was carried out in the hospital pharmacy, this outbreak was controlled, and further infusion-related nosocomial bacteraemia was prevented. from the usa, a publication in reported an outbreak of multiresistant acinetobacter colonisation and infection in an icu [ ] . the strain was sensitive only to polymyxin. the outbreak lasted an entire year between and and involved patients, of whom were infected and colonised. the arrival of a colonised burn patient ([ % total body surface area) from an outside hospital was responsible for the outbreak. although on typing two strains were found, the only identified primary source was the original burn patient. ten deaths resulted from infections ( % of infected patients). the authors claimed that this outbreak served as a model of eradication of multi-drug-resistant organisms, as the acinetobacter was eliminated from all icu patients by multidisciplinary measures that included the following: cohort and contact isolation of all colonised and infected patients; introduction of strict aseptic measures such as hand washing, barrier isolation, equipment and room cleaning; sterilisation of ventilator equipment; and individual dedication of medical equipment to each patient. a paper was published from australia in regarding carbapenem-resistant a. baumannii [ ] . we selected this publication as an illustration of an extensive molecular analysis rather than for a critical review of the outbreak, which occurred in an icu between and . based on their findings, the authors claim that antibiotic-resistant genes are readily exchanged between co-circulating strains in epidemics of phenotypically indistinguishable organisms. in conclusion, they recommend that epidemiological investigation of major outbreaks should include whole-genome typing as well as analysis of potentially transmissible genes and their vehicles. finally, we found a paper in a journal from kuwait not found by our internet research [ ] . the authors reported three different outbreaks of multi-drug-resistant a. baumannii infections involving patients aged - years that occurred in an icu in the course of year between and . the outbreak was polyclonal and successfully controlled with tigecycline, to which two causative clones were sensitive. three additional distinct clones were isolated from the environment. due to lack of appropriate surveillance cultures, no explanation was offered for the origin of epidemic clones. subsequently, in a letter to the editor, our interpretation that ''…microbial gut overgrowth increased spontaneous mutation, which led to polyclonality and antibiotic resistance in the critically ill'' was accepted by the authors [ , ] . thirteen publications were retrieved from medline, five of which described outbreaks of remarkable findings. the remaining papers reported some important aspects of fungal species, colonisation, infection and treatments, predominantly as surveys, and as such were not included in our analysis. outbreaks presented here were caused by uncommon opportunistic fungi. two reports described icu outbreaks caused by hansenula anomala, an opportunistic yeast first reported from a liverpool, uk, nicu in [ ] . in , a report from croatia described an outbreak in a surgical icu [ ] . h. anomala was isolated from blood taken from eight patients between august and december . all patients were treated with antifungal therapy; three died from complications of underlying disease. the introduction of strict hygienic measures stopped the spread of infection, but the outbreak ceased with the introduction of a new batch of cotton from another manufacturer, which was used for venipuncture-site disinfection. however, the authors could not find evidence for infection source and transmission route. the second report, from brazil ( ), describes an outbreak in a picu [ ] . the authors reported their finding as an outbreak of pichia anomala, a newly introduced name for h. anomala. from october to january , children developed p. anomala fungemia. the median age was . year, and the main underlying conditions were congenital malformations and neoplastic disease. the overall mortality rate was . % despite treatment with amphotericin b. during a -week period in april , when new cases occurred, surveillance cultures revealed that . % of patients were colonised with yeasts, but no single patient was found to be colonised with p. anomala. thus, no source was found at that time. the outbreak was not controlled until orally administered prophylaxis with nystatin and topical application of an iodoform to venipuncture sites were started. an extraordinary outbreak of invasive gastritis caused by rhizopus microsporus in an adult icu was reported from spain in [ ] . over a -week period (between november and march ), gastric mucormycosis was diagnosed in five patients, four of whom were admitted to icu with severe communityacquired pneumonia and one with multiple trauma. the main symptom was upper gastrointestinal haemorrhage. isolated filamentous fungi were identified as r. microsporus var. rhizopodiformis and were detected in gastric aspiration samples and traced to wooden tongue depressors used to prepare medication for oral administration (and given to patients through a nasogastric catheter) and in some tongue depressors stored in unopened boxes unexposed to the icu environment. the outbreak was terminated when contaminated tongue depressors were withdrawn from use. this outbreak was attributable to the % mortality rate; wooden material should not be used in the hospital setting. in , an outbreak of three cases of dipodascus capitatus infection in an icu was reported from japan [ ] . the index case was pulmonary infection with a fulminant course of fungal infection, which resulted in death, in a patient with acute myelocytic leukaemia who shared a room for at least week with the two other patients, suggesting the possibility of transmission. one of the other two patients died from multiple organ dysfunction. the presence of d. capitatus might have been due to contamination in the respiratory icu. in all cases, d. capitatus was identified in sputum, deep tracheal aspiration samples, blood and urine samples. the authors concluded that d. capitatus should be added to the lengthening list of opportunistic fungal pathogens that can cause infection in immune-compromised patients, with the danger of transmission and potential outbreak. an outbreak of saccharomyces cerevisiae fungemia in an icu was reported from spain in [ ] . during the period from to april, three patients with s. cerevisiae fungemia were identified. the only identified risk factor was treatment with a probiotic containing this yeast. the three patients received the product via nasogastric tube for a mean of . days before the culture was positive. surveillance cultures for the control patients admitted at the same time did not reveal any carriers. all three patients died from causes unrelated to s. cerevisiae. discontinuation of use of the product for treatment or prevention of clostridium difficile-associated diarrhoea in the unit stopped the outbreak of infection. in conclusion, the authors warned that the use of s. cerevisiae should be carefully reassessed in immune-compromised or critically ill patients. an outbreak is defined as an event where two or more patients in a defined location are infected by identical, often multi-drug-resistant, microorganisms transmitted via the hands of hcw, usually within an arbitrary time period of weeks. there are two different types of infection involved in outbreaks: secondary endogenous and exogenous. outbreaks of secondary endogenous infections are invariably preceded by outbreaks of carriage of abnormal flora, whereas outbreaks of exogenous infections are not preceded by outbreaks of abnormal carriage. these two types of outbreaks each require a different type of management: enterally and topically administered antimicrobials for secondary endogenous and exogenous outbreaks, respectively. ongoing surveillance efforts, i.e. throat and rectal swabs on admission and twice weekly thereafter, to monitor the efficacy of systematic decontamination of the digestive tract (sdd) and to identify the emergence of antimicrobial resistant threats, is an intrinsic component of any decontamination programme. in this sense, a well-designed programme contains an intrinsic degree of protection against antibiotic-resistant organism emergence. surveillance cultures of throat and rectum are more sensitive in detecting resistance than are diagnostic samples [ ] . additionally, there is a close relationship between surveillance and diagnostic samples. once a resistant microorganism reaches overgrowth concentrations, i.e. c /ml saliva and/or gram of faeces, diagnostic samples become positive [ ] . in our review, outbreaks were selected to illustrate the situation at the beginning of this century. as a matter of fact, the majority of the outbreaks was related to the previous decade. however, biased or not, our analysis described outbreaks that occurred after and nine from last century, although the outbreaks were published in this century (fig. . ). this suggests that some new problems indeed emerged in this century. it is important to record the number of papers retrieved according the causative organisms: mrsa six, vre ten, agnb , pseudomonas spp. , acinetobacter spp. and fungi . perhaps, against our expectation, agnb organisms-in particular, opportunists such as pseudomonas and acinetobacter-prevailed significantly, for which there must be a reason. if we take mrsa as an example, all around the world, this drug-resistant pathogen has been a primary focus for nosocomial infection control and treatment for years. thus, there are fewer outbreaks. an extensive study from germany that involved icus showed that cluster and single mrsa infections were significantly more common than actual outbreaks ( icus compared with , respectively) [ ] . to our knowledge, there were no similar studies for vre and agnb, but one would anticipate similar findings and interpretation. on the other hand, opportunistic pathogens such as pseudomonas spp., acinetobacter spp. and fungi often caused unexpected outbreaks, particularly in immunocompromised patients. they originated from external sources and were difficult to treat because of their resistance to multiple antibiotics. our search for specific features relevant to published outbreaks revealed some new, and confirmed some older, trends (table . ). probably the best example of how new viral infections-such as sars-can change the rate of bacterial and fungal infections in icus came from the experience in china [ ] . there was a significant increase in the rate of mrsa and candida spp. acquisition in an icu during the sars period. it may be anticipated, therefore, that in the future, sars and influenza viral infections would lead to complex icu outbreaks. we pointed out earlier how using molecular techniques revealed that many outbreaks were due to more than one clone [ ] . our analysis confirms this, although the origin of different clones remained obscure in all reports in which polyclonality was detected. however, we recently put forward a hypothesis that microbial gut overgrowth is responsible for increased spontaneous mutation leading to polyclonality and antibiotic resistance [ ] . furthermore, extensive use of molecular techniques not only revealed a number of new genes responsible for antibiotic resistance [ ] but showed that genetically unrelated organisms readily exchange antibiotic resistance genes [ , ] . yet further, a new trend is related to the sdd concept. two studies, one from italy and one from spain, reported the use of enterally administered vancomycin to control and prevent, respectively, mrsa outbreaks [ , ] . this is further evidence that the principle of sdd can be used with antimicrobials directed specifically to the causative organism. as early as we reported how selective decontamination with nystatin successfully controlled a candida outbreak in an nicu [ ] . among older trends, surveillance cultures, or lack of them, are still prominent. even in there were authors responsible for infection control in hospitals and icus who claimed that ''…surveillance cultures of all patients with potential to develop infection are difficult and very costly…'' [ ] . some time ago ( ), we expressed an alternative view in response to an identical attitude [ ] . needless to say, lack of surveillance cultures not only delays the recognition of an outbreak and its control but also precludes the understanding of the pathogenesis of the majority of outbreaks. surveillance cultures are also crucial for detecting outbreaks of exogenous pathogenesis, i.e. without carriage. on the other hand, the source of an exogenous outbreak is readily identified with molecular techniques. some of these outbreaks are striking, such as one from this analysis in which acinetobacter-contaminated parentally administered solutions were repeatedly infused to patients, leading to a very high mortality rate of % [ ] . in conclusion, new trends as well as old confirm what we indicated in the previous edition of this book, which is that to control and prevent icu outbreaks, surveillance cultures and sdd should be integrated in routine infection-control measures. severe acute respiratory syndrome: another challenge for critical care nurses h n influenza is here international study of the prevalence and outcome of infection in intensive care units outbreaks of infection in intensive care units-usefulness of molecular techniques for outbreak analysis enteral vancomycin to control methicillinresistant staphylococcus aureus outbreak in mechanically ventilated patients identification of a variant 'rome clone' of methicillin-resistant staphylococcus aureus with decreased susceptibility to vancomycin, responsible for an outbreak in an intensive care unit occurrence of methicillin-resistant staphylococcus aureus infections in german intensive care units effectiveness and safety of enteral vancomycin to control endemicity of methicillin-resistant staphylococcus aureus in a medical/surgical intensive care unit cluster of methicillin-resistant staphylococcus aureus colonisation in a small animal intensive care unit increase in methicillin-resistant staphylococcus aureus acquisition rate and change in pathogen pattern associated with an outbreak of severe acute respiratory syndrome emergence of vancomycin-resistant enterococcus faecium at a tertiary care hospital in karachi outbreak of vancomycin-resistant enterococcus spp. on an italian general intensive care unit lowbury lecture: the western australian experience with vancomycin-resistant enterococci-from disaster to ongoing control glycopeptide-resistant enterococcus outbreak in an icu with simultaneous circulation of two different clones molecular characterization of outbreak-related strains of vancomycin-resistant enterococcus faecium from an intensive care unit in beijing incidence and risk factors of infections caused by vancomycin-resistant enterococcus colonization in neurosurgical intensive care unit patients nosocomial outbreak of linezolid-resistant enterococcus faecalis infection in a tertiary care hospital outbreak of shv- beta-lactamase-producing klebsiella pneumoniae in a neonatal-pediatric intensive care unit in spain outbreak of infection with a multiresistant klebsiella pneumoniae strain associated with contaminated roll boards in operating rooms intensive care unit outbreak of extended-spectrum beta-lactamase-producing klebsiella pneumoniae controlled by cohorting patients and reinforcing infection control measures nosocomial outbreak due to extended-spectrumbeta-lactamase-producing enterobacter cloacae in a cardiothoracic intensive care unit nosocomial neonatal outbreak of serratia marcescens-analysis of pathogens by pulsed field gel electrophoresis and polymerase chain reaction using pulsed-field gel electrophoresis in the molecular investigation of an outbreak of serratia marcescens infection in an intensive care unit outbreak of serratia marcescens colonization and infection traced to a healthcare worker with long-term carriage on the hands a heterogeneous outbreak of enterobacter cloacae and serratia marcescens infections in a surgical intensive care unit an outbreak of multidrug-resistant pseudomonas aeruginosa associated with increased risk of patient death in an intensive care unit epidemiology of pseudomonas aeruginosa and risk factors for carriage acquisition in an intensive care unit mosturizing body milk as a reservoir of burkholderia cepacia: outbreak of nosocomial infection in a multidisciplinary intensive care unit clinical and molecular epidemiology of an outbreak of infusion-related acinetobacter baumannii bacteremia in an intensive care unit eradication of multi-drug resistant acinetobacter from an intensive care unit hospital gene transfer in a polyclonal outbreak of carbapenem-resistant acinetobacter baumannii role of tigecycline in the control of carbapenemresistant acinetobacter baumannii outbreak in an intensive care unit origin of epidemic clones of acinetobacter in the critically ill control of acinetobacter outbreaks in the intensive care unit infection and colonisation of neonates by hansenula anomala hansenula anomala outbreak at a surgical intensive care unit: a search for risk factors an outbreak of pichia anomala fungaemia in a brazilian pediatric intensive care unit outbreak of gastric mucormycosis associated with the use of wooden tongue depressors in critically ill patients an outbreak of dipodascus capitatus infection in the icu: three case reports and review of the literature saccharomyces cerevisiae fungemia: an emerging infectious disease colonization with broadspectrum cephalosporin-resistant gram-negative bacilli in intensive care units during a nonoutbreak period: prevalence, risk factors, and rate of infection microbial gut overgrowth guarantees increased spontaneous mutation leading to polyclonality and antibiotic resistance in the critically ill selective decontamination with nystatin for control of a candida outbreak in a neonatal intensive care unit candida colonisation as a source of candaemia the multiple value of surveillance cultures: an alternative view key: cord- -j vrvqf authors: fong, i. w. title: issues in community-acquired pneumonia date: - - journal: current trends and concerns in infectious diseases doi: . / - - - - _ sha: doc_id: cord_uid: j vrvqf pneumonia is one of the most commonly diagnosed infectious diseases and is the third most frequent cause of death worldwide. accurate statistics of community-acquired pneumonia incidence globally or in countries of various regions are lacking. although the clinical diagnosis of pneumonia is not difficult, the etiology diagnosis to guide targeted specific antimicrobial therapy still poses a challenge even with novel molecular methods. this has led to different approaches and guidelines for the empiric treatment of community-acquired pneumonia, often with broad-spectrum antimicrobial agents which may play a role in fostering the worldwide development of antibiotic resistant bacteria. severe community-acquired pneumonia, seen mainly at the extremes of age and in persons with chronic underlying diseases, is associated with high mortality of – %. pneumonia severity tools, such as curb- , have been developed over the past decade to assist emergency department physicians to recognize, admit, and implement rapid antimicrobial therapy in severely ill patients. the evidence for the beneficial effects of these tools will be reviewed in this chapter. issues in the management of severe community-acquired pneumonia that are discussed include: combination with newer macrolides [irrespective of microbial etiology], value of adjunctive therapy such as corticosteroids and statins. cough reflex, and mucociliary clearance of foreign material and invaders of the tracheobronchial tree. local production of immunoglobulins [iga, igg, and ige] in the mucosa of the respiratory tract provides another layer of protection against invading microbes. the relative proportion of iga and igg in the respiratory tract changes with the location, greater ratio of iga to igg in the nasal mucosa, trachea and bronchial tree and reversed ratio in the alveoli with greater proportion of igg [ ] . iga may be more important in protecting against viral infections, as it can neutralize several respiratory viruses such as rhinovirus, influenza, and respiratory syncytial virus [ ] . but it may be involved in the mechanisms of preferential bacterial adherence. whereas, most individuals with iga deficiency do not have increased respiratory infections, those with igg or certain igg subclass deficiency have recurrent respiratory infections [ ] . igg limits the invasion of microorganisms in the epithelium by opsonization and complement fixation and the concentration can increase a hundred-fold in the respiratory tract in the presence of infection and increased vascular permeability. protection of the respiratory tract from microbial invaders is a complex process that involves many immune cells: dendritic cells, b and t-lymphocytes, neutrophils and macrophages and their secretory products [immunoglobulins, cytokines, opsonins, enzymes, and oxygen metabolites]; and nonimmune opsonins such as surfactant, fibronectin fragments, and possibly c-reactive protein [ ] . recent studies indicate that progranulin, an autocrine growth factor expressed in a variety of tissues and cell types, plays a protective role in lung immunity during bacterial pneumonia [ ] . elevated progranulin levels were observed in clinical and experimental bacterial pneumonia and it mediated host defense in both gram-positive and gram-negative bacterial pneumonia. the healthy mucosa is colonized by a complex milieu of microorganisms, not exclusively aerobic and anaerobic bacteria, that probably plays an important protective role against invading pathogens. these normal microbes prevent the establishment of invading pathogenic microbes in the respiratory epithelium, the first step to induce infection. in the past decade, there has been marked interest and research on the role of the normal microbiome of the respiratory tract in health and disease. this has been facilitated by modern sophisticated, molecular, multiomics techniques. recent studies of the human microbiome, including the respiratory tract, have demonstrated that the resident microflora is much more abundant and diverse than previously realized; including many species of nonculturable bacteria, viruses [virome], fungi, and protozoa. present data indicate that the microbiome of the gut and the lungs are linked, by immune cells and mediators, and maybe important and associated with the pathogenesis of respiratory diseases [ ] [ ] [ ] . the bronchial tract harbors a complex and dynamic microbial milieu of about species, which overlaps with the oral microbiome [ ] . the lung is also colonized by airway microbiota that resembles the microbiome of the mouth but not the nostrils at a lower density. studies [ ] [ ] [ ] have linked dysbiosis of the respiratory microbiome with asthma and chronic lung diseases such as cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease [copd] . however, there is no data as yet on association with acute pneumonia. it is generally believed, that cap occurs from aspiration of pathogenic microbes colonizing the nasopharynx in situations where there is defect of the normal airway defenses. inciting factors that may play a role in the development of pneumonia include preceding viral upper respiratory tract infections [seen in nearly % of bacterial cap]. these minor infections can result in defect in mucociliary function and clearance of aspirated bacteria and allow adherence of pathogens to the mucosa. it is quite possible that upper respiratory virus infections can result in dysbiosis of the commensal respiratory microbiome. cigarette smoking can have a similar effect on airway defense and has been associated with dysbiosis of the resident microbiota. although numerous microorganisms can cause lung involvement or pneumonia [estimated about ], only several have been associated with cap in children or adults. in clinical practice the identification of etiologic microbes in cap is usually achieved in < % of cases. sputum cultures are often nonspecific and difficult to interpret because of contamination of oral-pharyngeal commensals, and blood cultures are positive in only - % of adults and even less in children with bacterial pneumonia [ ] . urinary antigen detection of streptococcus pneumoniae may improve the sensitivity compared to culture [ - % sensitive], but can be false positive from colonization in children [ ] . in recent years studies have applied molecular assays for viruses and bacteria for microbial diagnosis. results have indicated that the etiology of cap may vary with age. in children < years of age cap is most commonly due to viruses [mainly respiratory syncytial virus or rsv], especially in the absence of lobar consolidation and effusion [ ] ; but even with extensive testing a pathogen cannot be identified in - % of children with cap [ , ] . in a recent study of children < years of age hospitalized for cap without an identifiable etiology and asymptomatic controls, metagenomics [next-generation sequencing] and pan-viral pcr were able to identify a putative pathogen in % of unidentifiable cases from nasopharyngeal and oropharyngeal swabs [ ] . putative viral pathogens included human parainfluenza virus , human bocavirus, coxsackieviruses, and rhinovirus a and c. human bocavirus was the most commonly detected virus [ %] . it is plausible that these viruses were causing upper respiratory tract disease that resulted in cap from bacterial pathogens. although cultures and pcr for bacterial pathogens were obtained, endobronchial secretions were not routinely obtained. in a meta-analysis of detection of viruses by pcr in childhood cap, the pooled incidence was . % with mixed infection in . % [ ] . rhinovirus, rsv, and bocavirus were the three most common viruses in childhood cap. respiratory viruses were detected in . % of patients aged ≤ year, . % of patients - years, and . % of children aged ≥ years [ ] . it was estimated that more than half the viral infections were probably concurrent with bacterial infections. the etiology inference of identifying viruses in the upper respiratory tract in children with cap is still unclear. although higher viral loads can . microbial etiology of community-acquired pneumonia be found in children with pneumonia compared to controls with some viruses, the utility to diagnose viral pneumonia with quantitative pcr was equivocal [ ] . it is still the opinion of experts that most cap in children with radiographic alveolar infiltrate is due to bacteria, predominantly s. pneumoniae. previous studies have reported an association of upper airway density of s. pneumoniae and pneumococcal pneumonia, and nasopharyngeal bacterial load with this pathogen is significantly higher in viral infection compared with no viral infection [ ] . in a case-control study from seven developing countries, colonization density of s. pneumoniae in the upper airway was compared in children [< years of age] with proven pneumococcal pneumonia and controls [ ] . pneumococcal colonization density > . log copies/ml was strongly associated with confirmed pneumococcal pneumonia, with a sensitivity of % and specificity of % but not sufficiently accurate for clinical diagnosis. the same group of investigators also assessed the colonization density in the upper respiratory tract and confirmed pneumonia with haemophilus influenzae, moraxella catarrhalis, staphylococcus aureus, and pneumocystis jirovecii. there was an association of colonization density [ . log copies/ml] and h. influenzae confirmed pneumonia, with a sensitivity of % and specificity of %, but not with the other respiratory pathogens [ ] . in adults, the microbial diagnosis of cap with conventional microbiology, urine antigen detection and commercial pcr for viruses in two prospective studies in the usa have had low yield [ , ] . each study failed to identify a respiratory pathogen in about - % of cases, pneumococci was found in < % of cases, respiratory viruses in - %, and atypical organisms in about % of cases in one study [ ] . a prospective study of hospitalized patients with cap in the netherlands, using similar investigative techniques but added real-time pcr for "atypical organisms" [mycoplasma pneumoniae, legionella pneumophila, coxiella burnetii, and chlamydophila sp.], identified s. pneumonia in %, c. burnetii in %, h influenzae in %, and atypical bacteria including legionella in % [ ] . some european studies have used advanced microbiological techniques with identification of pneumococcus in - % of cases and identification of a pathogen in % of cases [ , ] . in norway, bacterial etiology was found in % and viruses in %, including viral-bacterial coinfections [ ] . a prospective study from china, beside viral culture and nucleic acid amplification assessed paired sera for antibody response, and viral etiology was established in . % of cap [ ] . in a review and meta-analysis of the incidence of viral infections in adult cap, incidence ranged from . to . %; lower tract samples were associated with higher viral yield and the three main viruses were influenza virus, rhinovirus, and coronavirus [ ] . in a similar review by other investigators, the pooled proportion of patients with viral infection was similar, . %, but in studies that obtained lower respiratory samples the proportion increased to . % [ ] . more recently in britain, adult patients with confirmed pneumonia admitted to two tertiary-care hospitals had cultures and comprehensive molecular testing [multiplex real-time pcr for respiratory viruses and bacteria] from sputum [ %] and endotracheal aspirate [ % or cases] [ ] . an etiology agent was identified in % with molecular testing compared to % with culture-based methods. bacterial pathogen was detected by pcr in % and culture in % but most patients [ %] received antibiotics before admission. viruses were present in % of cases but % were co-detected with bacterial pathogens. it was surprising that h. influenzae was the most common bacteria in . %, followed by pneumococcus in . %, m. catarrhalis in . %, s. aureus in . %, klebsiella pneumoniae in %, and atypical organisms in < % [ ] . it is questionable that mere detection of a pathogen is sufficient to attribute causality, unless there is evidence of acute immune response, as most specimens were sputa and not aseptically collected endotracheal secretions. the high incidence of h. influenzae could represent oropharyngeal colonization with non-typeable strains, high prevalence of copd [about %] and high proportion of older patients above years of age [ . %] . the low prevalence of atypical organisms [mycoplasma and chlamydophila pneumoniae] is not surprising as the patients had severe pneumonia requiring hospitalization. it is likely that mildmoderate cap receiving ambulatory treatment would have a higher proportion of the atypical bacteria. a similar but smaller study in japan used conventional methods and real-time pcr for diagnosis of cap [n = ] from sputa and nasopharyngeal swabs; molecular methods detected a causative organism in % versus % with conventional methods [ ] . s. pneumoniae was most frequently identified, followed by h. influenzae and m. pneumoniae [ %] . pneumococcus is the most important bacterial cause of cap, responsible for most cap mortality in severe cases, but rates of detection have varied from to %. rapid diagnosis of pneumococcal etiology could lead to initiating treatment with a narrow-spectrum antibiotic such as penicillin, which would be cost saving, with decreased risk of superinfection with clostridium difficile and lower rate of predisposing to multiresistant bacteria. sputum gram stain at presentation is an inexpensive, rapid, easy to perform test that is underused in clinical settings to assist in the diagnosis and treatment of cap. in a prospective study of patients with pneumonia [ cap], the utility of sputum gram stain was assessed from good quality samples [ ] . the sensitivity and specificity of gram stain were . % and . % for s. pneumoniae, . % and . % for h. influenzae, . % and . % for m. catarrhalis, . % and . % for k. pneumoniae, and . % and % for s. aureus. unfortunately about % of patients with pneumonia had no or poor quality sputum, which limits the overall diagnostic value. hence, this simple test should be routinely used in the diagnosis of cap whenever purulent sputum is available. detection of pneumococcus c-polysaccharide in urine by immune chromatography is increasingly being used for evaluation of patients with cap. in a large observational, multicenter, prospective study of patients admitted to hospital for cap, pneumococcal infection was diagnosed in %, with % of the cases diagnosed exclusively by urinary antigen test [ ] . the sensitivity and specificity were % and . %, respectively. a combination of different methods, however, appears to be more sensitive. using quantitative [q] pcr on blood samples, multiplex immunoassay for urine antigen and multiplex immunoassay for serologic antibody responses against serotypes were able to detect pneumococcus in % of cases and % more patients than conventional methods [ ] . the qpcr of blood samples, however, was not more sensitive than blood culture. how can we interpret these studies utilizing comprehensive molecular methods for etiology diagnosis of cap? finding viruses or pathogenic bacteria from nasopharyngeal and sputum specimens may not prove of causality in pneumonia, as they clearly can just be causing upper tract infection or colonization without producing lower respiratory disease. however, the absence of any specific pathogens from theses assays can effectively exclude them as etiology agents, since nearly all cap is a result of aspiration of upper airway microbes. a combination of tests such as sputum gram stain and culture, blood culture, urinary antigen and antibody response to the microbe[s] may be the most specific and reliable methods of determining causality, but are not highly sensitive nor provide rapid results to affect management. future research should focus on rapid, readily available, and inexpensive tests for etiologic diagnosis of cap that could be used in emergency departments. such methods may use immunoassays that could detect various bacterial pathogens or antigens semiquantitatively from sputum, blood, and urine in the form of a dipstick, similar to that of a urinalysis test. in most cases of cap, the diagnosis should be straightforward, but since the advent of chest radiograph there has been no significant advance in diagnostic methods. typical mild cases of cap with clinical symptoms of recent cough, fever, and the presence of chest crackles may be treated empirically without a chest x-ray or blood tests. however, normal chest examination can be present in about % of cap. chest radiograph is the standard investigation to confirm pneumonia in suspected cases and should be done in moderate-severe cap even in the presence of typical chest findings, to define the extent of lung[s] involvement, assess for presence of parapneumonic effusion or possible empyema, and the presence of pulmonary cavitation or abscess. the presence of necrotizing pneumonia restricts the etiologic diagnosis to a few bacteria and usually requires a longer duration of therapy. diagnosis of cap can be difficult in some more complicated cases, often severe cases with multi-organ failure or dysfunction requiring intensive care. in these situations, the difficulty lies in the interpretation of the chest x-ray. problems arise from differentiating pneumonia from pulmonary edema, hemorrhage, atelectasis, and acute respiratory distress syndrome [ards]. computerized tomography [ct] scan may or may not be able to differentiate these conditions. bedside ultrasonography has been used for diagnosing pneumonia but is less reliable than radiography, with sensitivity ranging from % to % and specificity of % to % [ ] . ultrasound is more useful for defining the presence and severity of associated pleural effusion. investigators have also assessed the value of molecular biomarkers in severely ill patients to differentiate cap from noninfectious cause of lung infiltrates. in a study of patients admitted to the intensive care unit [icu] with suspected cap genome-wide transcription profiling of blood leucocytes was investigated. expression of proinflammatory and anti-inflammatory pathways was similar between patients with and without cap, and blood concentrations of biomarkers such as procalcitonin, interleukin [il]- , and interleukin il- were not discriminatory [ ] . further analysis revealed that the ratio of two genes, faim and plac , was best for distinguishing cap from no-cap. the faim :plac ratio provided a positive predictive value of . % and negative predictive value of . %. however, the clinical utility for management in seriously ill patients is questionable and further studies are needed. the risk of cap and invasive pneumococcal infection in adults increases with older age, number of comorbidities, cigarette smoking, and the combination of the above [ ] . proton pump inhibitors [ppi], a commonly prescribed medication, in this high-risk population also may add to the risk of cap. a systematic review of studies with , cases of cap reported a . -fold increased risk of cap, with the highest risk in the first days after initiating a ppi [ ] . cap is the most common infectious disease leading to hospitalization in the icu and the leading cause of mortality in patients with infection [ ] . severe sepsis may be present in about one-third of patients presenting with cap at a hospital. predictors of severe sepsis and assessment for these factors are important on arrival in the emergency department [ed], to facilitate rapid treatment and close monitoring to avoid high fatality. in a prospective multicenter cohort study of hospitalized cap patients, . % presented with severe sepsis [ ] . [ ] . other comorbid conditions such as cardiovascular disease may not predispose to severe sepsis but may result in higher mortality and morbidity. previous studies indicate that cap is associated with increased cardiovascular complications. in a multicenter prospective cohort of patients hospitalized for cap, [ ] . various scoring systems and biomarkers have been developed to identify severe cap, assess prognosis for mortality risk and to assist physicians in making decisions on hospital and icu admission. these scoring systems were designed for the use in non-immunosuppressed patients. the most commonly used scoring system is the curb- score, which is based on five easily measurable factors [see table . ]. the presence of each factor was given a score of to a maximum of . in the initial study of patients in the derivation cohort and a separate validation cohort, the day mortality was . - . %, . - . %, . %, . %, and % for , , , , or factors [ ] . based on these data, it was suggested that that cap patients with a score of - could be treated as outpatients, those with a score of should be admitted to hospital, and those with a score of or more should be assessed for icu care. however, another large study of patients with cap reported a mortality of . % with a curb- score of [ ] ; which suggests even score should be an indication for hospital admission. but a healthy -year-old person without other factors or significant comorbid illness could be treated with outpatient antibiotic. in a more recent study, however, curb- had very good accuracy for predicting the -day mortality among patients with cap discharged from the er [ ] . among all er encounters the curb- threshold of > was . % sensitive and . % specific for predicting mortality, with a . % negative predictive value. a simplified version without blood test to measure blood urea nitrogen [bun], designated crb- , can be used in the doctor's office to assess severity of cap. if i or more score is present then the patient is referred to the hospital for admission. the crb- score has not been extensively evaluated but was found to have good predictive value in patients with cap [ ] . the pneumonia severity index [psi] assessment is based on the presence of variables and is divided into five strata of increased risk for short-term mortality at presentation [ ] . low-risk patients with cumulative mortality of < % falls in the class i-iii, whereas patients in class iv and v have higher mortality risk of % to %. although several large studies have validated its predictive utility, it is more complex to calculate, less user friendly than curb- , and the predictive performance is similar in prospective comparison [ ] . hence, curb- is more commonly used by ed physicians to assess cap severity. the british thoracic society and the national institute for health and care excellence [nice] guidelines recommend curb- and crb- for severity assessment in cap [ , ] . bun blood urea nitrogen disposition of patient based on total score: - treat as outpatient; admit to hospital for and above for patients hospitalized for cap risk prediction can be used to assess the need for icu care, mechanical ventilation, and mortality. monitoring the c-reactive protein [crp] during hospitalization may be useful in predicting response and the risk of death. in a retrospective multicenter study of patients with cap admitted to three dutch hospitals, the highest mortality risk was seen in patients who failed to demonstrate a decline in their crp by % after days of treatment, irrespective of the actual value and initial curb- score [ ] . this study should be validated by a larger prospective study. three scoring systems have been developed to identify severe cap in hospital and the need for icu management. these include the severe community-acquired pneumonia score [scap], smart-cop, and the infectious diseases society of america/ american thoracic society [idsa/ats] severity criteria [see table . ]. all three systems utilize a combination of clinical criteria [shock, altered mental state, and respiratory failure], routine blood tests, and arterial blood gas results. a scap score of ≥ [at least one major and two minor criteria] was superior to curb- in predicting progression to more severe pneumonia [ ] . further validation study showed that the scap score was just as accurate as other prediction scoring systems for predicting icu admission, progression to severe sepsis, treatment failure and need for mechanical ventilation [ ] . the smart-cop scoring system was assessed in a prospective study of episodes of cap requiring hospitalization, with more than % of patients over years old [ ] . each factor led to accrual of one point, except low systolic blood pressure, poor oxygenation, and low arterial ph, each subscribed two points. smart-cop score of ≥ points identified % of patients who received intensive respiratory or vasopressor support [ ] . the predictability of smart-cop was less accurate in younger adults < years of age, as it failed to identify the need for these critical measures in % of patients in this age group [ ] . the idsa/ats severity system is based on two major criteria and nine minor criteria [ ] . any one of the major criteria, septic shock requiring vasopressors and requirement for mechanical ventilation, are universally accepted and are self-evident. three or more of the minor criteria indicate need for icu management. a validation study of patients with cap, not meeting the major criteria, found the minor criteria were equivalent to the smart-cop scoring system for predicting need for mechanical ventilation, vasopressor support, and icu care [ ] . recently, other investigators have modified the idsa/ats minor criteria by excluding four infrequent variables [leucopenia, hypothermia, hypotension, and thrombocytopenia] but adding age ≥ years [ ] . the modified version best-predicted mortality, but it is unclear whether it is as useful for predicting need for icu care and vasopressor/ventilation support. various blood biomarkers have been studied as prognostic predictors in cap and these include procalcitonin [pct], crp, proadrenomedullin [pro-adm], presepsin [scd -st], copeptin, and cortisol. the pct was the most extensively studied in a total of studies with pneumonia patients. although elevated pct level was a risk factor for death in cap, particularly patients with a low curb- score, the commonly used cutoff, . ng/ml, had low sensitivity in identifying patients at risk of dying [ ] . in a systematic review and meta-analysis of the prediction value of various biomarkers in , cap patients, they demonstrated moderate-good accuracy to predict mortality but had no clear advantages over cap-specific scores [ ] . curb- should be the standard prediction score applied to patients seen in hospital ed with cap, the main contentious issue is whether or not patients with a score of should be admitted or treated as outpatients. it may be reasonable to admit patients with one factor, other than age years alone. using age alone for admission has no supporting evidence for almost every medical illness. however, patients years or older with significant comorbid illness, such as underlying cardiovascular disease, should be admitted and monitored. once patients are admitted to hospital the idsa/ ats guidelines maybe the most appropriate to use on deciding on further care in the icu, although scap and smart-cop scores are suitable as well. empiric treatment of cap is designed to treat common bacterial respiratory pathogens [s. pneumoniae, h. influenzae] and atypical bacteria [m. pneumoniae, c.pneumoniae], but recent etiology studies suggest that a large proportion of cap is due to no pct threshold discriminated viral from bacterial etiology with a very high sensitivity and specificity [ ] . a contentious issue in the empiric management of cap is the routine coverage for atypical bacteria with a macrolide, as m. pneumoniae and c. pneumoniae infection are usually associated with self-limited course and recovery. whereas, north american guidelines for outpatient treatment of cap list a macrolide as first choice [ ] european guidelines do not [ ] and consider macrolides as second choice for penicillin-allergic patients. moreover, coverage for atypical bacteria routinely in the management of cap has not been proven to be beneficial. in a systematic review of trials and with randomized patients, no advantage was found for regimens covering atypical bacteria in the major outcomes tested-mortality and clinical efficacy [ ] . macrolide as a sole therapy for cap maybe inadequate to cover pneumococcus, as the prevalence of macrolide resistance has been increasing and is currently up to %, although the clinical significance is uncertain [ ] . for patients with moderate-severe cap being hospitalized, north american and european guidelines [ , , ] recommend initiating broad-spectrum therapy of a β-lactam agent [often ceftriaxone] and a macrolide or a respiratory quinolone alone. the macrolides have immunomodulatory effects and anti-inflammatory properties that may improve outcome even for pneumococcal infection. even in gram-negative sepsis and ventilator-associated pneumonia, clarithromycin has been reported to restore the immunoparalysis and improve outcome [ ] . a recent systematic review of antibiotic therapy for hospitalized adults with cap has been published [ ] . several key aspects of antibiotic therapy can be summarized: ( ) eight observational studies showed that antibiotic initiation within - h of hospital arrival was associated with decreased mortality; ( ) stepping down from intravenous to oral therapy once patients are stable shortens hospital stay without affecting outcome; ( ) choice of empiric antibiotics on outcome was mixed and inconclusive. six of eight lowquality observational studies [with up to , patients] found that the combina- . treatment of cap tion of β-lactam and macrolide was associated with reduced short-term mortality over β-lactam monotherapy. the three largest studies were all retrospective in design. three observational, mainly retrospective, studies found reduced mortality with quinolone monotherapy compared to β-lactam monotherapy [ ] . however, in prospective randomized, trials the results have not confirmed superiority of combination with a macrolide nor quinolone over β-lactam monotherapy. in the first trial in switzerland, adults with moderate-severe cap admitted to six acute care hospitals were randomized to β-lactam monotherapy or a macrolide combination [ ] . the mortality, icu admission, length of stay, and recurrence of pneumonia within months were not different between the treatments. in the second prospective multicenter dutch trial, patients with cap admitted to non-icu wards were allotted to one of three treatments by a cluster-randomized, crossover design with strategies rotated in -months period [ ] . monotherapy with a β-lactam was non-inferior to strategies with β-lactam macrolide combination or quinolone monotherapy for months mortality, length of stay, or any complications. quinolones when used can be given orally from the onset if the patients can take oral medications, since they are fully bioavailable. idsa guidelines had recommended initial intravenous therapy for severe pneumonia, but well-conducted observational study confirms that intravenous route is not necessary for severe cap [ ] . the duration of treatment for cap is not well established. idsa/ats guidelines recommend at least days treatment in patients who are stable and have been afebrile ≥ h [ ] ; the british guidelines advice days for mild-moderate and - days for moderate-severe cap [ ] ; and the nice guidelines recommend days for mild and - days for moderate-severe cap [ ]. in a recent multicenter randomized trial from four teaching hospitals in spain, the duration of antibiotic treatment was studied in hospitalized patients with cap [ ] . after days of treatment, the intervention group stopped antibiotics if they were afebrile for h and had no more than one cap-associated sign of instability, and the duration of antibiotics in the control group was determined by physicians. there was no significant difference in the outcome between the two groups. thus, the idsa/ats guideline is safe to implement in hospitalized patients with cap. current data indicates that amoxicillin for outpatient treatment of mild-moderate cap for days is the preferred therapy. macrolide monotherapy should be avoided due to high and rising resistance of s. pneumoniae. furthermore, moderate macrolide resistance in m. pneumoniae has now been reported with analysis for resistant mutation genes [ ] . amoxicillin/clavulanic acid maybe preferable to cover β-lactamase strains of h. influenzae and m. catarrhalis in the elderly and subjects with copd or chronic bronchitis. patients admitted to hospital for moderate-severe cap, not requiring icu care, can be treated with a β-lactam monotherapy [commonly ceftriaxone] but amoxicillin/clavulanic acid can be used or respiratory quinolone orally. whenever pneumococcus is shown to be the etiologic agent, penicillin should be used as there is no evidence that the outcome is adversely affected for penicillin nonsusceptible [relative resistance] strains in cap even with bacteremia. in patients with severe cap requiring icu care, a β-lactam [ceftriaxone] with a macrolide or a quinolone alone is suitable. in this setting, the macrolide is used for l. pneumophila infection until this organism can be excluded. severe cap has a high mortality [about %] despite adequate antibiotic therapy, thus adjunctive therapy has been studied and used empirically to try and improve the outcome. combination with a macrolide for macrolide-resistant bacteria is a form of adjunctive therapy. comparative studies on the inflammatory response of patients with severe and non-severe cap can be useful to guide adjunctive therapy. in one such study, the severe cap group showed higher plasma levels of pro-and anti-inflammatory cytokines but in contrast, lower sputum concentration of proinflammatory cytokines [ ] . moreover, neutrophils from severe cap patients showed reduced respiratory burst activity compared to the non-severe group. these results indicate that patients with severe cap fail to mount a robust local inflammatory response but instead produce a heightened systemic inflammatory response [ ] . it has been suggested that statins, primarily indicated for dyslipidemia and cardiovascular disease, have modulation effects on the cytokine cascade and could be useful in severe cap. in a previous review of the immunomodulatory effects of statins in cap, experimental and clinical studies were identified [ ] . statins attenuated pulmonary inflammation by reducing cytokine release and expression, modulating neutrophil function, and by protecting against disruption of lung integrity. observational studies suggested a decrease in mortality due to cap in current statin users but randomized studies are lacking [ ] . a randomized, double-blind, placebo-controlled trial of simvastatin for cap was initiated in spain but was terminated after enrolling patients because of slow enrolment [ ] . however, after h of statin, there was no difference in concentrations of cytokines compared to patients on placebo. thus, the benefit of statins in cap remains unknown. corticosteroids [steroids] have been studied for its anti-inflammatory effect in severe cap in an attempt to reduce mortality, ards and need for mechanical ventilation and icu care with inconclusive results. although steroids have been shown to improve outcome and decrease risk of respiratory failure in pneumocystis pneumonia, it failed to improve outcome in a major, definitive randomized controlled trial in patients with all cause sepsis [ ] . in a previous review of this topic in , it was concluded that steroids should not be used in cap because of insufficient evidence of the beneficial effect and potential harm [ ] . since then, two other randomized, placebo-controlled trials of adjunct steroids in cap have been reported. the first study from spain randomized patients to intravenous methylprednisolone or placebo for days. there was less early treatment failure [composite end . adjunctive therapy for severe cap points defined by the study] in the steroid treated group but no difference in mortality [ ] . the second study from switzerland randomized patients to either prednisone mg daily or placebo for days. prednisone shortened the time to clinical stability by about . days without an increase in complications but did not improve mortality [ ] . in the past - years four systematic reviews and meta-analyses of the value of steroids in cap have been published. in the first report, ten randomized controlled trials [rct] with cases of hospitalized cap were reviewed. mortality was decreased in the severe-case subgroup and patients requiring icu care. length of icu decreased by . days and length of hospital stay by day [ ] . in the second review in , trials were included with patients and concluded that steroids may reduce mortality by %, need for mechanical ventilation by %, and hospital stay by day [ ] . were included in the analysis. steroids treatment was associated with reduced ards and reduced length of icu stay but no effect on mortality [ ] . none of the four studies found significant adverse events with steroids except for hyperglycemia. in moderate-severe cap adjunctive macrolide is not beneficial. further randomized studies are still needed for the more severe cases at risk for icu management. steroids may be beneficial to reduce mortality, ards and mechanical ventilation for the severe cap but the results are not conclusive. thus, it would be premature to use steroids routinely in severe cap, pending larger rct in this subgroup of patients admitted to hospital. in the most recent review and meta-analysis of steroids in hospitalized patients with cap, with analysis of cases from six trials, steroids reduced time to clinical stability and length of hospital stay by day but did not reduce mortality and increased risk of hyperglycemia and cap-related rehospitalization [ ] . the state of the art is reminiscent of the data of steroids in sepsis/septic shock, when steroids appeared to be effective in reducing mortality based on small rcts but was proven ineffective in larger, definitive trials. at least three large trials registered on clinical trials.gov are expected to enroll a total of patients and are scheduled for completion by october will provide more definitive data on the use of steroids in cap. future trials should investigate the effect of adding nonsteroidal anti-inflammatory agents [nsaids] for the treatment of cap. in a recent open randomized trial from hong kong, patients hospitalized with severe influenza a [h n ] with pulmonary infiltrates had significantly lower -day mortality and shorter hospital stay after treatment with naproxen-clarithromycin [ days] + oseltamivir than oseltamivir, both groups received beta-lactam antibiotics [ ] . in the past - years, marked reductions in the total burden and mortality of pneumonia in children < years of age have occurred worldwide. this has been attributed to a number of factors, improved healthcare and social-economic conditions in low earning countries, and major contribution due to increased vaccination against measles, pertussis, s. pneumoniae and h. influenzae type b with conjugate vaccines. however, similar reduction in cap has not been realized in adults. smoking cessation may reduce the risk of cap in chronic smokers but permanent cessation is difficult to achieve. the world health organization estimates that > billion of the world's population smoke and smoking is a strong risk factor for invasive pneumococcal disease and bacterial pneumonia [ ] . in most temperate countries peak incidence of cap occurs in the winter during the peak influenza season. thus universal yearly influenza vaccination may decrease the incidence of cap in children and adults for influenza and bacterial pneumonia. previous studies have shown that influenza vaccination is effective in preventing hospitalization for acute respiratory illness associated with confirmed influenza. estimates ranged from % to % among children, % to % among all adults, and % to % for adults years or older [ ] [ ] [ ] [ ] . however, most of these studies did not specifically assess the effect of influenza vaccination on the prevalence of cap. in a prospective observational multicenter study of hospitalization for cap over . years in four us sites, patients were hospitalized for cap. among children and adults, only those with confirmed influenza-associated pneumonia had lower odds of having received influenza vaccine [ ] . indicating that influenza vaccination reduces cap from influenza complication, including secondary bacterial pneumonia. the introduction of the -valent and subsequent -valent s.pneumoniae conjugate vaccine [pcv ] in children in resource-rich countries has resulted in the decline of pneumococcal pneumonia in children and adults as well, through herd protection [ ] . the -valent pneumococcal polysaccharide vaccine [ppv ] has been available for > years and is recommended in many countries for high-risk patients, but its efficacy in preventing cap is debatable. three recent reviews and meta-analysis of the benefit of ppv in preventing pneumococcal cap in adults have been published with inconsistent conclusions. one review found no proof that ppv can prevent pneumococcal cap in the elderly population [ ] . another study reviewed seven randomized trials involving , subjects and concluded that the ppv vaccine provided weak protection against all cause pneumonia [ ] . the third review, however, reported that ppv vaccine effectiveness in preventing invasive pneumococcal disease was % for cohort studies and % for case-control studies [ ] . but lower for prevention of cap, % reduction in trials, % for case-control studies and % effectiveness for cohort studies. however, the conjugate vaccine appears to be more effective in adults. in a large placebo-rct involving , adults years of age and older, the community-acquired pneumonia immunization trial in adults [capita], the pcv vaccine was assessed [ ] . the vaccine efficacy in preventing vaccine-type pneumococcal cap was . % and % in preventing invasive pneumococcal disease, but not effective in preventing cap from any cause. more effective treatment is clearly needed for smoking cessation worldwide to prevent lung cancer, cardiovascular disease, copd and many associated cancers and illnesses, including possible cap. although universal annual influenza vaccination is now recommended for children and adults, the rate of vaccination in all countries has been low [< - % of the population]. improved and more effective, long lasting influenza vaccines [given by nasal or oral route] are needed to facilitate greater compliance and herd immunity. in the meantime, physicians should encourage annual influenza vaccines for all. pcv should be offered to all elderly and high-risk adults for cap. pending the development and marketing of a -valent conjugate pneumococcal vaccine, it is reasonable to administer the ppv as well several months later. global, regional, and national incidence, prevalence, and years with disability for acute and chronic diseases and injuries in countries, - : a systematic analysis for the global burden of diseases study community-acquired pneumonia: the us perspective clinical and economic burden of communityacquired pneumonia in the veterans health administration, : a retrospective cohort study burden of community-acquired pneumonia in north american adults national hospital discharge survey incidence, direct costs and duration of hospitalization of patients hospitalized with community acquired pneumonia: a nationwide retrospective claims database analysis the incidence rate and economic burden of community-acquired pneumonia in a working-age population defense mechanisms of the respiratory tract contribution of progranulin to protective lung immunity during bacterial pneumonia microbiome effects on immunity, health and disease in the lung linking microbiata and respiratory disease respiratory microbiata: addressing clinical questions, informing clinical practice the modern quest for the "holy grail" of pneumonia etiology diagnostic tests for agents of community-acquired pneumonia pediatric infectious disease society of america et al ( ) the management of community-acquired pneumonia in infants and children older than months of age: clinical practice guidelines by the pediatric infectious disease society and the infectious disease society of america what is the role of respiratory viruses in community-acquired pneumonia in ambulatory pneumonia? what is the best therapy for influenza and viral causes of communityacquired pneumonia? cdc epic study team et al ( ) community-acquired pneumonia requiring hospitalization among us children viral pathogen detection by metagenomics and pan-viral group polymerase chain reaction in children with pneumonia lacking identifiable etiology incidence of viral infection detected by pcr and real-time pcr in childhood community-acquired pneumonia: a meta-analysis is higher viral load in the upper respiratory tract associated with severe pneumonia? findings from the perch study association between nasopharyngeal load of streptococcus pneumoniae, viral coinfection, and radiologically confirmed pneumonia in vietnamese children density of upper respiratory colonization with streptococcus pneumoniae and its role in the diagnosis of pneumococcal pneumonia among children aged < years in the perch study colonization density of the upper respiratory tract as a predictor of pneumonia---haemophilus influenzae, moraxella catarrhalis, staphylococcus aureus, and pneumocystis jirovecii can an etiologic agent be identified in adults who are hospitalized for community-acquired pneumonia: results of a one year study community-acquired pneumonia requiring hospitalization among us adults microbial etiology, outcomes, and costs of hospitalization for community-acquired pneumonia; an observational analysis etiology of community-acquired pneumonia: increased microbiological yield with new diagnostic methods etiology of community-acquired pneumonia and diagnostic yields of microbiological methods: a three year prospective study in norway respiratory virus is a real pathogen in immunocompetent community-acquired pneumonia: comparing to influenza like illness and volunteer controls incidence of respiratory viral infections detected by pcr and real-time pcr in adult patients with community-acquired pneumonia: a meta-analysis viral infections in community-acquired pneumonia: a systematic review and meta-analysis comprehensive molecular testing for respiratory pathogens in community-acquired pneumonia identification of pathogens by comprehensive real-time pcr versus conventional methods in community-acquired pneumonia in japanese adults validation of sputum gram stain for treatment of community-acquired pneumonia and healthcare-associated pneumonia: a prospective observational study sensitivity, and positivity predictors of the pneumococcal urinary antigen test in community-acquired pneumonia detection and serotyping of pneumococci in community-acquired pneumonia patients without culture using blood and urine samples accuracy of lung ultrasonography in the diagnosis of pneumonia in adults: systematic review and meta-analysis a molecular biomarker to diagnose community-acquired pneumonia on intensive care unit admission redefining risk categories for pneumococcal disease in adults: critical analysis of the evidence risk of community-acquired pneumonia with outpatient proton-pump inhibitor therapy: a systematic review and meta-analysis risk factors for community-acquire pneumonia in adults in europe: a literature review predictors of severe sepsis among patients hospitalized for community-acquired pneumonia cardiovascular complications and short-term mortality risk in community-acquired pneumonia relationship between serum vitamin d concentrations and clinical outcome of community-acquired pneumonia severe thinness is associated with mortality in patients with community-acquired pneumonia: a prospective observational study defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study prospective comparison of three validated prediction rules for prognosis in community-acquired pneumonia curb- performance among admitted and discharged emergency department patients with communityacquired pneumonia crb- predicts death from community-acquired pneumonia a prediction rule to identify low risk patients with community-acquired pneumonia thorax : . national institute for health care excellence. diagnosis and management of communityacquire pneumonia in adults failure of crp decline within three days of hospitalization is associated with poor prognosis of communityacquired pneumonia development and validation of a clinical prediction rule for severe community-acquired pneumonia prospective comparison of severity scores for predicting clinically relevant outcomes for hospitalized with community-acquired pneumonia smart-cop: a tool for predicting the need for respiratory or vasopressor support in community-acquired pneumonia predicting the need for mechanical ventilation and/or inotropic support for young adults admitted to the hospital with community-acquired pneumonia severe community acquired pneumonia: validation of the infectious disease society of america/american thoracic society guidelines to predict an intensive care unit admission validation of the infectious disease society of america/american thoracic society minor criteria for intensive care unit admission in community acquired pneumonia patients without major criteria or contraindication to intensive care unit care modified idsa/ats minor criteria for severe communityacquired pneumonia best predicted mortality prognostic value of procalcitonin in pneumonia: a systematic review and meta-analysis biomarkers for predicting short-term mortality in community-acquired pneumonia: a systematic review and meta-analysis diagnostic and prognostic utility of procalcitonin in patients presenting to the emergency department with dyspnea procalcitonin as a marker of etiology in adults hospitalized with community-acquired pneumonia infectious diseases society of america/ american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (review) the effect of macrolide resistance on the presentation and outcome of patients hospitalized for streptococcus pneumoniae pneumonia effect of clarithromycin in inflammatory markers of patients with ventilator-associated pneumonia and sepsis caused by gramnegative bacteria: results from a randomized clinical study antibiotic therapy for adults hospitalized with community-acquired pneumonia. a systematic review ) β-lactam monotherapy vs β-lactam-macrolide combination treatment in moderately severe community-acquired pneumonia: a randomized noninferiority trial antibiotic treatment strategies for community-acquired pneumonia in adults association between initial route of fluoroquinolone administration and outcomes in patients hospitalized for community-acquired pneumonia duration of antibiotic treatment in communityacquired pneumonia: a multicenter randomized clinical trial mycoplasma pneumonia: current knowledge on macrolide resistance and treatment contrasting inflammatory responses in severe and non-severe community-acquired pneumonia the immunomodulatory effects of statins in community-acquired pneumonia: a systematic review the effect of simvastatin on inflammatory cytokines in community-acquired pneumonia: a randomized, double-blind, placebo-controlled trial hydrocortisone therapy for patients with septic shock immunomodulatoy adjuvant therapy in severe community-acquired pneumonia effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial adjunct prednisone therapy for patients with community-acquired pneumonia: a multicenter, double-blind, randomized, placebo-controlled trial adjunctive systemic corticosteroids for hospitalized community-acquired pneumonia: systematic review and meta-analysis corticosteroid therapy for patients hospitalized with community-acquired pneumonia: a systematic review and meta-analysis efficacy and safety of adjunctive corticosteroids therapy for severe community-acquired pneumonia in adults: an updated systematic review and meta-analysis efficacy and safety of steroids for community-acquired pneumonia: a systematic review and meta-analysis corticosteroids in patients hospitalized with community acquired pneumonia: systematic review and individualized patient data metaanlysis efficacy of clarithromycin-naproxen-oseltamivir combination in the treatment of patients hospitalized for influenza a [h n ] infection. an open-label randomized, controlled, phase iib/iii trial cigarette smoking and invasive pneumococcal disease. active bacterial core surveillance team influenza vaccine for community-acquired pneumonia vaccine effectiveness against severe laboratory-confirmed influenza in children: results of two consecutive seasons in italy effectiveness of the - seasonal vaccine in preventing confirmed influenza hospitalization in adults: a case-case comparison, case-control study vaccine effectiveness against laboratoryconfirmed influenza hospitalization among elderly adults during the - season association between hospitalization with community acquired laboratory-confirmed influenza pneumonia and prior receipt of influenza vaccination impact of infant -valent pneumococcal conjugate vaccine on serotypes in adult pneumonia efficacy of ppv in preventing pneumococcal pneumonia in adults at increased risk---a systematic review and meta-analysis efficacy of -valent pneumococcal polysaccharide vaccine in preventing community-acquired pneumonia among immunocompetent adults: a systematic review and meta-analysis of randomized trials the effectiveness of pneumococcal polysaccharide vaccine [ppv ] in the general population of years of age and older: a systematic review and meta-analysis polysaccharide conjugate vaccine against pneumococcal pneumonia in adults key: cord- - cl gk authors: humphreys, hilary; winter, bob; paul, mical title: lower respiratory tract infections date: - - journal: infections in the adult intensive care unit doi: . / - - - - _ sha: doc_id: cord_uid: cl gk lower respiratory tract infections are common and are important in the critical care setting either because they precipitate admission to the critical care unit, e.g. severe viral pneumonia or because they complicate the course of a patient with significant underlying disease or following major surgery, e.g. after multiple trauma. furthermore, respiratory failure requiring artifical ventialtion is a well recognised reason for critical care support but it can be difficult to determine if this is due to an underlying non-infectious condition such as chronic obstructive pulmonary disease (copd), infection or a combination of both. the early diagnosis and management of respiratory infection combined with appropriate ventilatory support aids prognosis and the efficient use of critical care facilities given the number of patients affected. lower respiratory tract infections are common and are important in the intensive care setting either because they precipitate admission to the intensive care unit, e.g. severe viral pneumonia or because they complicate the course of a patient with signi fi cant underlying disease or following major surgery, e.g. after multiple trauma. furthermore, respiratory failure requiring arti fi cal ventialtion is a well recognised reason for intensive care support but it can be dif fi cult to determine if this is due to an underlying non-infectious condition such as chronic obstructive pulmonary disease (copd), infection or a combination of both. the early diagnosis and management of respiratory infection combined with appropriate ventilatory support aids prognosis and the ef fi cient use of intensive care facilities given the number of patients affected. community acquired pneumonia (cap) is common with an estimated incidence of - cases/ , population annually [ ] representing . % of uk icu admissions [ ] . community acquired pneumonia requiring icu admission has a high mortality (icu). in a study of , cases of cap admitted to uk intensive care units, icu mortality was . % and ultimate hospital mortality . %. mortality was . % in those admitted to the icu within days of hospital admission rising to . % in those admitted at - days and . % in those admitted after days following hospital admission [ ] . at presentation many patients with severe cap will already be developing multiple organ failure. identi fi cation of the critically ill pneumonia patient is essential to the early and effective management of this condition. severity-of-illness scores, such as the curb- (confusion, uremia, respiratory rate, low blood pressure, age years or greater), or prognostic models, such as the pneumonia severity index (psi), can be used to identify patients with cap who might bene fi t from icu admission. in some studies, signi fi cant numbers of patients with cap are transferred to the icu in the fi rst - h after admission. mortality and morbidity among these patients appears to be greater than those among patients admitted directly to the icu. the most recent modi fi cation of the british thoracic society (bts) criteria includes fi ve easily measurable factors [ ] . multivariate analysis of , patients identi fi ed the following factors as indicators of increased mortality: confusion (based on a speci fi c mental test or disorientation to person, place, or time), bun level mmol/l ( mg/dl), respiratory rate breaths/min, low blood pressure (systolic, < mmhg; or diastolic, mmhg), and age years. this gave rise to the original acronym curb- . in the derivation and validation cohorts, the -day mortality among patients with , , or factors was . , . , and . %, respectively. mortality was higher when , , or factors were present and was reported as . , , and %, respectively. the authors suggested that patients with a curb- score of - be treated as outpatients, those with a score of be admitted to the wards, and that patients with a score of often required icu care. direct admission to an icu is required for patients with septic shock requiring vasopressors or with acute respiratory failure requiring immediate intubation and mechanical ventilation. decisions on direct admission to an icu or high-level monitoring unit should be based on a number of parameters and is recommended for patients with three or more of the following a relatively small number of pathogens account for the majority of cases of cap with streptococcus pneumoniae consistently shown to be the commonest pathogen in europe and north america although in at least one third of cases no de fi nite causative organism is isolated [ ] . a survey of studies of severe cap found the following pathogens: s. pneumoniae - %; legionella spp., - %; staphylococcus aureus - %; and gram negative enteric bacilli - % [ ] . historically, cap was divided into so-called 'typical' and 'atypical' and was said to produce different presentations. 'typical' pneumonia was caused by pneumococci and was said to present with fever of greater than °c, pleuritic chest pain, lobar consolidation, and a left shift of granulocytes. 'atypical' pneumonia had a more gradual onset with diffuse interstitial or alveolar pattern on the plain chest x-ray. studies, however, have shown that clinical overlap between the different pathogens is great and that symptoms and plain chest radiology can not reliably differentiate between the different pathogens [ ] . in severe cap the situation is even more dif fi cult. in the uk intensive care national audit and research centre ( www.icnarc. org ) case mix database viral pneumonia accounted for % of cases admitted to critical care units with cap accounting for % of cases. however, no organism was isolated in % of cases where the primary admission diagnosis was pneumonia. the bts recommends the following investigations for all severe cases of cap [ ] : • blood cultures • sputum or lower respiratory tract sample for gram stain, routine culture, and antibiotic susceptibility tests • pleural fl uid analysis , if a pleural effusion/empyema is present • pneumococcal antigen test on sputum, blood, or urine • investigations for legionella including urine for legionella antigen -sputum or lower respiratory tract samples for legionella culture and direct immuno fl uorescence initial and follow up legionella serology -• direct immuno fl uorescence on appropriate samples, e.g. bronchoscopy sample or equivalent for respiratory viruses (e.g. in fl uenza in season, adenovirus, respiratory synctial virus, etc), chlamydia species, and possibly pneumocystis jirovecii ( carinii ) • initial and follow up serology for pathogens dif fi cult to culture such as however, there is no good evidence that this strategy alters the outcome of severe cap and studies disagree about the impact of microbiological testing on outcome [ ] . the american thoracic society recommendations for inpatient, icu antibiotic treatment are a beta-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) plus either azithromycin or a fl uoroquinolone. for penicillin-allergic patients, a respiratory fl uoroquinolone and aztreonam are recommended. for community-acquired methicillin-resistant staphylococcus aureus infection, vancomycin or linezolid are suggested [ ] . the bts guidelines recommend the combination of amoxicillin/clavulanate with clarithromycin and the optional addition of rifampicin, which provides additional cover, especially against staphylococcus aureus and legionella spp. patients with hypoxemia or respiratory distress should receive a cautious trial of non-invasive ventilation (niv) unless they require immediate intubation because of severe hypoxemia (arterial oxygen pressure/fraction of inspired oxygen [pao /fio ] ratio, < mmhg or kpa) and bilateral alveolar in fi ltrates [ ] . patients with underlying copd are most likely to bene fi t from niv [ ] . patients with cap who were randomized to receive niv had more than a % absolute risk reduction for intubation [ ] . inability to cough may limit the use of niv, but intermittent application of niv may allow for its use in patients with productive cough without excessive sputum production. prompt recognition of a failed niv trial is important, as patients who require intubation after a prolonged niv trial have a worse outcome. within the fi rst - h of niv, failure to improve respiratory rate and oxygenation or failure to decrease carbon dioxide partial pressure (pco ) in patients with initial hypercarbia predicts niv failure and warrants prompt intubation. niv provides no bene fi t for patients with adult respiratory distress syndrome (ards), which may be indistinguishable from cap among patients with bilateral alveolar in fi ltrates. patients with cap who have severe hypoxemia (pao /fio ratio, < ) are also poor candidates for niv [ ] . the optimal ventilator strategy for patients with severe cap has not been established. both volume controlled and pressure controlled modes have been used with varying levels of positive end expiratory pressure (peep). although there is a signi fi cant incidence of ards in patients with cap it is unclear whether the ardsnet lung protective strategy should be applied in all patients [ ] . in patients with cap who fail to respond to initial treatment, broncho-alveolar lavage identi fi es pathogens in - %. although the yield is relatively low, it is recommended that bronchoscopy is performed in severe cap where the diagnosis is not established or where treatment is failing [ ] . once the patient is intubated and ventilated this is relatively easy to perform although often associated with transient deterioration in oxygenation. the diagnosis should be reviewed and other conditions presenting with x-ray in fi ltrates such as cardiac failure and pulmonary infarction excluded. culture results may be available by this stage and may necessitate a change in therapy. the possibility of immunosuppression should be considered with the consequent possibility of an opportunist pathogen, e.g. pneumocystis jirovecii ( carinii ) and a history of recent foreign travel excluded which might impact on the choice of empirical antibiotic therapy. pathogens may vary from country to country and tuberculosis does occasionally present as severe cap. therefore this diagnosis should be considered in the relevant settings or geographical areas. most cases of in fl uenza are self-limiting and are characterized by the sudden abrupt onset of fever, malaise, headache and a non-productive cough. this syndrome is usually easily distinguishable from the common cold caused by coronaviruses, rhinoviruses, para-in fl uenza viruses, etc. the elderly and those with chronic underlying diseases such as ischemic heart disease are more at risk of complications from in fl uenza, including death. however, when a pandemic occurs, as in with h n , other groups of patients were at risk of more severe disease as they had not been exposed to a radically new virus, different to those viral strains that circulated previously. early diagnosis is important and the threshold for suspicion should fall during the in fl uenza season or during a pandemic. then every patient requiring critical care support with respiratory failure should have a throat swab in viral transport medium or nasopharyngeal aspirate, and a good quality lower respiratory sample, e.g. broncholaveloar lavage (bal) or equivalent, sent for viral studies, i.e. immuno fl uorescence or the polymerase chain reaction (pcr). in fl uenza-related pneumonia is similar to other forms of viral pneumonia although the recent pandemic h n strain originating from mexico had some different features. the australasian experience was published by the australia new zealand intensive care society group [ ] . a total of patients with con fi rmed infection with h n infection ( . cases per million inhabitants; % con fi dence interval [ci], . - . ) required admission to an icu in australia or new zealand. of the , . % were under and . % were pregnant. the obese were also adversely affected; . % of icu patients had a body-mass index of more than . the median icu stay was . days, . % required mechanical ventilation for a median of days and . % had died within a month of presentation. higher numbers than usual for viral pneumonia received treatment with extracorporeal membrane oxygenation (ecmo). of patients who required mechanical ventilation, . % were subsequently treated with ecmo. this parallels the situation in uk (richard firmin, personal communication). a recent paper [ ] matched patients referred for ecmo in the uk with patients from a pool of , patients from the icnarc casemix program using three different techniques and found a mortality of around % in patients who were referred for ecmo and around % for the matched controls. during the - h n in fl uenza a pandemic, the united states centers for disease control and prevention and other agencies around the world released guidelines for the use of antivirals for patients with con fi rmed or suspected infection [ ] . for most patients a neuraminidase inhibitor (e.g. oseltamivir) is recommended and this should be started as soon as possible to improve patient outcome and assist in reducing transmission. healthcare-associated pneumonia is de fi ned as new onset of pneumonia more than h after admission to a healthcare facility and may occur in either the open ward environment or in association with mechanical ventilation, i.e. associated pneumonia (vap). infection acquired in an acute hospital compared to that acquired in a long stay institution is more likely to be antibiotic-resistant and due cognisance needs to be taken of this when treating empirically. vap was historically associated with the overgrowth of aerobic gram negative bacilli but is now increasingly characterized by infection with gram positive organisms such as staph aureus including methicillin-resistant staphylococcus aureus (mrsa) as well as resistant strains of acinetobacter spp and enterobacteriaceae resistant to extended-spectrum beta-lactam agents such as third generation cephalosporins. there is a lack of a clear and clinically accepted de fi nition for vap. there is also a difference between research de fi nitions including the need for invasive lung sampling such as protected specimen brushing (psb) or bal, and clinical de fi nitions stressing increased oxygen requirements, new in fi ltrates on chest x-ray, purulent tracheal aspirates etc. the presence of new chest x-ray in fi ltrates plus one of the three clinical variables (fever, i.e. ³ °c, leucocytosis or leucopenia and purulent secretions) is useful for clinical screening and has high sensitivity but should where possible be followed by invasive respiratory sampling ideally before commencing antibiotics. protected specimen brushing with a threshold on quantitative culture of cfu/ml, or bronchoalveolar lavage with threshold of cfu/ml have been said to be equivalent for the diagnosis of ventilator associated pneumonia [ ] . however, - % of patients meeting the above clinical criteria for vap will not have the diagnosis con fi rmed by alternate objective methods such as quantitative cultures of psb or bal samples [ ] . in some studies vap appears to be an independent risk factor for death, with a doubling of the mortality rate directly attributable to vap [ ] . this is, however, dependent on the patient population and the infecting organism [ ] . critical care length of stay is increased by a mean of . days, and the excess costs can be as high as $ , per patient with vap [ ] . recent attempts to limit vap include the use of ventilator care bundles which include a number of the following, avoidance of endotracheal intubation and reintubation, a preference for niv, semi-recumbent positioning, continuous aspiration of subglottic secretions and oral decontamination [ ] . these interventions have been shown to reduce ventilator days and length of stay in a number of studies such as that by crunden and colleagues [ ] . despite showing a reduction in mortality in some studies and critical care unitacquired respiratory infections in many others, selective decontamination of the digestive tract (sdd) has failed to make the jump into mainstream practise outside the netherlands [ , ] . this is partly due to the perceived additional costs of the topical regimens and microbiological surveillance (although offset by the reduced need for therapeutic antibiotics to treat infections) and concerns about antibiotic resistance. many of the larger studies have taken place in the netherlands, a country characterized by admirably low levels of antibiotic consumption and antibiotic resis-tance, e.g. mrsa but in settings where antibiotic resistance is more common, there is understandable concern about the long-term implications on the spread and dissemination of dif fi cult to treat pathogens. sdd is also discussed in chaps. and . prompt initiation of appropriate antibiotic therapy is the cornerstone of vap management and requires knowledge of the local likely fl ora and antibiotic resistance patterns. iregui et al. found a higher mortality rate in patients in whom administration of adequate antibiotic therapy was delayed by approximately h ( . % vs. . % mortality, p < . ) after meeting criteria for the diagnosis of vap [ ] . because of the importance of adequate initial antibiotic therapy in reducing the mortality from vap, especially when patients are at risk from drug resistant organisms, initial therapy should be broad and known to be effective against pathogens such as pseudomonas aeruginosa and mrsa, and tailored using local knowledge. recent north american guidelines suggest that the use of three antibiotics: two drugs of different classes active against pseudomonas, and a third for mrsa [ ] . as previously mentioned copd is a signi fi cant complicating factor in cap. copd is one of the most frequent comorbidities in patients admitted to hospital for cap with respiratory failure [ ] . a prospective study of cap in patients in intensive care units in spain showed that copd was the most frequent comorbidity encountered [ ] . copd patients also fare badly compared with non-copd patients [ ] . another spanish study compared copd patients with non-copd patients and showed that icu mortality (odds ratio (or) . ; % con fi dence interval (ci) . - . ) and mechanical ventilation (or . ; % ci . - . ) rates were higher than in non-copd patients. the icu mortality was % for copd patients initially intubated and % for those who failed non-invasive ventilation [ ] . copd patients also present more frequently with organisms such as pseudomonas aeruginosa and strains of moraxella catarrhalis resistant to fi rst-line therapy, e.g. co-amoxycalv, and empiric antibiotic therapy may need to account for this. noninvasive ventilation (fig. . ) is routinely used in the management of hypercarbic respiratory failure in copd and guidance was produced by the royal college of physicians (uk) in conjunction with the bts and the intensive care society recently [ ] . niv in a number of settings has been shown in a number of randomized controlled trials to reduce the rate of intubation and mortality in copd patients with decompensated respiratory acidosis (ph < . and paco > kpa) despite maximal medical therapy. all units admitting such patients should have local protocols and training in place to offer niv to patients presenting in respiratory failure in the context of copd. infection of the paranasal sinuses is more common in critically ill patients than often realised by clinicians working in the area. it occurs in - % of all critically ill patients and - % of endotracheally intubated patients may develop sinusitis, the variation largely being accounted for by differences in diagnostic criteria [ ] . nasotracheal rather than orotracheal intubation appears to be a risk factor although nasogastric intubation may be a confounding factor. plain radiographs of adequate diagnostic quality are often dif fi cult to obtain in critical care patients and ct scanning is often required to make a radiological diagnosis which should be supplemented with microbiological samples to con fi rm the aetiology [ ] . nosocomial sinusitis is usually caused by gram-negative bacilli or is polymicrobial. pseudomonas aeruginosa represents . % of isolates, with the most common gram-positive isolate being staph. aureus ( . %); fungi represent . % of isolates [ ] . treatment usually involves a combination of appropriate antibiotics, removal of intranasal foreign bodies and drainage [ ] . . if he has severe community-acquired pneumonia by any criteria, he has an estimated mortality of - % depending on the results of further investigations. he is highly likely to require intensive care admission. . bacterial pneumonia is the most common and the pneumococcus accounts for - % of cases in most series but a substantial proportion will have no organism isolated . if he is known or suspected of having copd then niv may reduce the morbidity and mortality associated with intubation. its place in routine pneumonia management is less well de fi ned. severe community-acquired pneumonia community-acquired pneumonia on the intensive care unit: secondary analysis of , cases in the icnarc case mix programme database de fi ning community acquired pneumonia severity on presentation to hospital: an international derivation and validation study community-acquired pneumonia a fi ve-year study of severe community-acquired pneumonia with emphasis on prognosis in patients admitted to an intensive care unit infectious diseases society of america. guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia noninvasive ventilation in severe hypoxemic respiratory failure: a randomized clinical trial noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease acute respiratory failure in patients with severe communityacquired pneumonia: a prospective randomized evaluation of noninvasive ventilation predictors of failure of noninvasive positive pressure ventilation in patients with acute hypoxemic respiratory failure: a multi-center study the acute respiratory distress syndrome network. ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome utility of fi beroptic bronchoscopy in nonresolving pneumonia critical care services and h n in fl uenza in australia and new zealand referral to an extracorporeal membrane oxygenation center and mortality among patients with severe in fl uenza a(h n ) updated interim recommendations for the use of antiviral medications in the treatment and prevention of in fl uenza for the - season ventilator-associated pneumonia in a surgical intensive care unit: epidemiology, etiology and comparison of three bronchoscopic methods for microbiological specimen sampling role of quantitative cultures of endotracheal aspirates in the diagnosis of nosocomial pneumonia clinical and economic consequences of ventilatorassociated pneumonia: a systematic review the attributable morbidity and mortality of ventilatorassociated pneumonia in the critically ill patient oral decontamination with chlorhexidine reduces the incidence of ventilator-associated pneumonia an evaluation of the impact of the ventilator care bundle selective decontamination of the digestive tract clinical evidence in intensive care antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care clinical importance of delays in the initiation of appropriate antibiotic therapy high prevalence of obstructive airways disease in hospitalized patients with community-acquired pneumonia: comparison of four etiologies antibiotic prescription for community-acquired pneumonia in the intensive care unit. impact of adherence to idsa guidelines on survival for the capuci study investigators, et al. implications of copd in patients admitted to the intensive care unit by community acquired pneumonia chronic obstructive pulmonary disease: non-invasive ventilation with bi-phasic positive airways pressure in the management of patients with actute type respiratory failure. concise guidance to good practice series hospital-acquired sinusitis is a common cause of fever of unknown origin in orotracheally intubated critically ill patients acute pranasal sinusitis in critically ill patients: guidelines for prevention, diagnosis and treatment key: cord- - xvzvdg authors: nan title: national scientific medical meeting abstracts date: journal: ir j med sci doi: . /bf sha: doc_id: cord_uid: xvzvdg nan zero months months months months group a . . * . ** . "* . ** zero months group b . . ** values are means; *p< . and **p< . l~ most other studies show neutral effects on insulin sensitivity, with minimal incidence of glucose intolerance. this may be partly explained by the diversity of age, diagnosis (whether insufficiency or deficiency state), other pituitary deficiencies and replacement therapy, and possibly by dosage ofgh utilised in these studies. clostridium difficile-associated disease (cdad) is primarily a nosocomial condition. community-acquired disease has been described but the incidence is low "). during a recent outbreak, we prospectively reviewed all new cases of cdad to determine what proportion of cytotoxin positive cases were community or hospital acquired. during a month study period, cases were identified. history of diarrhoeal episodes were recorded for each case. selected isolates were typed using pyrolysis mass spectrometry (pms). community-acquired cdad was defined as diarrhoea, on or within hours of admission, in association with a positive stool cytotoxin test for c.difficile and in the absence of hospitalisation within days. sixty-five cases ( %) were hospital acquired. fifteen patients ( . %) had cdad on admission; ( %) were community acquired, ( . %) had been recently hospitalised ( at st. james's hospital, at other hospitals). pms typing of faecal isolates revealed that predominant strains were responsible for the hospital outbreak; one of these strains was also isolated in community-acquired cases. this study suggests that the incidence of communityacquired cdad may be higher than previously reported. we suggest that all newly admitted or transferred patients with diarrhoea should be screened for this organism. several studies have confirmed that activated protein c resistance (apc-r) occurs in - % of thrombosis patients and is therefore more common than congenital deficiencies in the inhibitors of coagulation such as atii , proteins c and s. homozygosity for the factor v (fv) gene mutation is associated with a - fold increased risk of venous thrombosis while heterozygosity is associated with a - fold increased risk. the mutation, however, is highly prevalent in the general population, a prevalence of % has been reported in several european countries. its frequency in the population of northern ireland (ni) has not yet been reported. we screened a group of generally healthy elderly individuals (av. age . ; range - yr on several occasions for apc-r using an assay based on the prolongation of activated partial thromboplastin time by the addition of apc. a mean ratio of . (range . - . ) was measured. seven individuals ( . %) had ratios < . (av. . ; range . - . ). these subjects were then analysed for the fv mutation by pcr amplification and restriction analysis. the individuals with the lowest ratios (av. . ; range . - . ) were found to be heterozygous for the mutation. none of these individuals were deficient for protein c, protein s or atiii. the frequency of apc-r ( . %) within this ni elderly group is similar to that reported by others in the uk whose studies would have included a generally younger population. the successful ageing of these individuals perhaps underlines the low risk associated with heterozygosity. alternatively a higher prevalence of the mutation may exist in the general population of ni, where the incidence of heart disease is one of the highest worldwide. the insulin-like growth factor ii gene (igf ) is imprinted. thus, in contrast to most genes where both maternal and paternal copies (alleles) are transcribed into rna and expressed, gf is normally only expressed from the paternal copy (monoallelic expression). alterations causing biallelic expression of igf may lead to excess growth factor production, and thus, to tumourigenesis. this study evaluated igf expression in a series of childhood cancers. to date tumours have been evaluated using pcr based methodology ( wilm's tumours, rhabdomyosarcomas, miscellaneous). dna was extracted and a polymorphic site apal within the igf gene was amplified and digested. this identified samples as heterozygous for igf , meaning that separate maternal and paternal alleles were distinguishable. rna from these informative samples was extracted, pcr amplified and restriction digested, to identify monoallelic versus biallelic profiles at the expression level. samples with normal imprinting (monoallelic) displayed allele a ( bp) or allele bl/b ( / doublet). biallelic samples displayed both alleles. using this approach / informative wilm's tumours and / rhabdomyosarcomas demonstrated biallelic expression. in conclusion, biallelic expression of igf was detected in a significant number of wilm's tumours and rhabdomyosarcomas, and should be considered; with other genetic alterations, as a candidate mechanism in tumourigenesis. the proinflammatory cytokines, tnf~, il and il- , may mediate host metabolic and immune responses to cancer possibly leading to paraneoplastic phenomena such as cachexia. the cellular origin of these cytokines in the cancer patient, in many cases, remains unknown. we examined proinflammatory cytokine levels intracellularly, using flow cytometry, in pbmcs from oesophageal cancer patients (n= ) and age and sex matched controls (n= ). tnf~ and il- levels were significantly increased (p< . ) in pma stimulated t cells and monocytes from the cancer patients when compared to the healthy controls. these results were confirmed using standard elisa assays. following cotlagenase digestion, increased levels of tnfa and il- ,were detected in oesophageal tumour infiltrating t cells when compared to cells from normal mucosa. there was also increased production of tnf~ and il- , but not il-ib, in malignant epithelial cells when compared to normal and halothane and maintained by % nitrous oxide-oxygen, . - . % halothane, with spontaneous ventilation. tc rose marginally in group and fell in group (not significant, ns). tp in groups and at induction and and minutes were, respectively, (mean + sem, celsius) . + . vs . + . , ns; . + . vs . + . , ns and . + . vs . + . , (p< . ). overall incidence of shivering-was .%, but not significantly different between the groups. the data suggests that preemptive application of the space blanket increases tp in paediatric patients during general anaesthesia and tends to conserve tc. chronic actinic dermatitis (cad) an uncommon, eczematous, photosensitive eruption is diagnosed on history, clinical examination, skin biopsy and abnormal light tests. drug induced photosensitivity may look identical clinically, have a similar history and patients with cad may be treated with potentially photosensitising drugs. we therefore reviewed all patients with cad and compared their monochrumator light tests with patients who had drug induced photosensitivity. phototesting was performed on unaffected skin of the back with an irradiation monochromator; the minimal erythema dose (med) determined for a series of wavelengths between and nm, in patients with drug induced photosensitivity and patients with cad. of ten females, four males with drug induced photosensitivity, age range - (mean yrs), ten ( %), were photosensitive in the uva range ( - nm), the implicated drugs including, quinine, sparfloxacin, amiodarone, doxycycline, mefenamic acid, nalidixic acid, fenbrufen, diclofenac, enalpril and prochlorperazine maleate. three patients with rosacea were photosensitive to doxycycline. the re/nainder ( %), were tested after discontinuation of the drug and their light tests were normal. in the cad group, (four males and three females), age range - (mean . yrs), three patients ( %), were sensitive to uva, uvb and visible light, four ( %) to uva and uvb. in conclusion, uva dissociated from uvb photosensitivity seems a relative but not absolute sign of drug induced photosensitivity. this pattern of light tests should prompt a detailed drug history to elucidate the causative agent. phototesting should be performed while on the offending drug as testing days or weeks after discontinuation will give normal results. patients at risk of bone fractures by measuring bone mineral density (bmd) and markers of bone turnover and to assess the correlation of these with the severity of cld. twenty three patients with cld had bmd measured by dual-energy x-ray absorptiometry scanning of hip and lumbar spine. bone formation was assessed using serum levels of procollagen type peptide, osteocalcin and bone alkaline phosphatase, and bone resorption was assessed using hour urinary excretion of hydroxyproline, pyridinoline and deoxypyridinoline. % and % of patients had evidence of osteoporosis at the lumbar spine and femoral neck respectively. biochemical results showed that % of patients had an increase in all bone resorption markers and % had an increase in markers for bone formation. bmd at the lumbar spine was lower in patients with cholestatic liver disease compared to patients with other types of'liver disease (p= . ). no correlation was found between bmd and patient age, bilirubin, albumin, inr or duration of liver disease. conclusions: osteopenia occurs in up to % of patients with cld due to a high bone turnover state where bone resorption exceeds formation. osteoporosis is most severe in those patients with cholestasis. a detailed profile is presented of all leukaemia and multiple myeloma (icd-o code ) patients registered by the southern tumour registry during the -year period / "). annual age-adjusted rates of . and . per , were seen for males and females respectively. these levels indicate a lifetime (up to yr) risk of in for males and in for females. the main morphological sub-types registered were multiple myeloma ( %), cll ( %), aml ( %) cml ( %) and all ( %). one, two and five-year survival rates were examined; age at diagnosis and lesion type were extremely significant factors in relation to patient outcome. the overall incidence levels indicate that irish rates were relatively high by internatiomil standards r we assessed effects of reducing the volume of hyperbaric bupivacaine by giving half the volume as isobaric bupivacaine. when using . % hyperbaric bupivacaine for spinal blockade, the segmental spread and cardiovascular effects of the block have been shown to be dependent on the volume of local anaesthetic injected. patients undergoing elective surgery were studied in a prospective, randomised, double-blind trial: group ( patients) received their local anaesthetic as two equal aliquots of . % hyperbaric bupivacaine and . % isobaric bupivacaine respectively; group ( patients) received their local anaesthetic as two equal aliquots of . % hyperbaric bupivacaine. there was no significant difference found between the two groups with regard to maximal height of block (group , mean (range), t (t -ti ); group , t (ts-t )), rate of onset of blockade, or time to maximal blockade (group , mean (sem), . ( . ) rain; group : . ( . ) min). there was no difference found between each group in either cardiovascular stability or vasopregsor usage. the administration of a mixture of . % isobaric bupivacaine and . % hyperbaric bupiv/~caine confers no advantages over administration of the same volume of . % hyperbaric bupivacaine alone. propofolis used as a sedative during regional anaesthesia. providing titrateable sedation, it can compromise haemodynamic stability. a propofol ketamine combination provides stable haemodynamics during total intravenous anaesthesia, avoiding emergence phenomena m. we compared two sedative regimes in patients having spinal anaesthesia. following informed consent, patients, asa i-ii, undergoing spinal anaesthesia were randomized to one of two groups (n= ). group i (propofol-ketamine) received loading doses of . mg/kg propofol, . mg/kg ketamine followed by an infusion of . mg/kg/h and . mg/kg/h respectively. group ii (propofol) received bolus . mg/kg and infusion . mg/kg/h. subsequent infusion rates were titrated to effect using a sedation score. heart rate, blood pressure, oxygen saturation, end tidal c and oxygen requirements were recorded. observation continued for the recovery period and patients visited the following day. data were analysed using t-test, chi test and anova. groups were demographically comparable. sedative and respiratory indices were similar for both groups. there was no difference in total propofol requirements between the groups; group i - _+ mg, group ii - _+ : mg (mean _+ sd). there was a large difference in mean arterial pressure, being much lower in the propofol only group. both groups had an uneventful recovery without emergence phenomena. our results do not confirm the described additive effect of andketammc . ketamine.with propofol for sedation propofol ' =~ ) confers haemodynamic stability during spinal anaesthesia. we designed a controlled study to investigate whether there is a direct relationship between the degree of postoperative pain and the development of negative middle ear pressure in adults following tonsillectomy. middle ear pressure was measured by tympanometry. pressures were classified as type a (o to - mmh ), type b (flat) or type c (- to - mmh ) tympanograms. patients with type a tympanograms, undergoing tonsillectomy were enrolled in the study. patients had daily tympanometry whilst in hospital and then weekly until amrmalisatign. a questionnaire incorporating visual analogue pain scores was filled in at the same time. a control group of patients with type a tympanograms, undergoing appendicectomy and endotracheal intubation was used. follo~v up was available on patients. patients ( %) developed type c tympanograms, patients %) type b and ( %) patients remained unchanged. no member of the control group developed any change in middle ear pressure (chi squared = . , p < vol. , irish journal of supplement no. medical science . ). there was no relationship between pain scores for throat pain or otalgia and the development of negative middle ear pressure. patients recorded higher pain scores for throat pain at day then day , only of this group had negative middle ear pressure. middle ear pressure reverted to normal at day in / patients and in the remaining / it was normal at day . this study demonstrates the development of transient negative middle ear pressure following tonsillectomy in % of patients. this change is unrelated to the degree of postoperative pain nor is it associated with otalgia. postoperative ward analgesia remains suboptimal. this may be partially related to inadequate early use of opioids to attain minimum effective analgesic concentration (meac). we examined the incidence and predictors of severe postoperative pain on admission and discharge from our postoperative recovery room (rr). verbal pain scores were obtained in a pilot study of patients on rr admission and discharge. procedures were classed as open cavitary, laparoscopic, orthopaedic, ent or body surface surgery. intraoperative use and dosage of narcotics and nonsteroidal (nsaid) analgesics, anaesthetists' experience (prefellowship or post-fellowship nchd, consultant) were noted, and rr opioid usage recorded. pain scores and analgesic use were examined using mann-whitney, ~ analysis and logistic regression. moderate or severe pain was experienced by % of patients on either arrival or discharge. median intraoperative morphine dosage was mg. opioid use was slightly (median morphine dosage mg, p < . ) higher in patients undergoing cavitary surgery; these patients had the highest pain scores on rr arrival and departure. patients ( %) received > mg morphine intraoperatively. discharge scores of / or higher occurred in patients ( %). opioid usage and pain scores were unrelated to level of training. nsaid use/nonuse was unassociated with differences in opioid use or rr pain scores. no morbidity attributable to analgesic use (desaturation, slow respiratory rate) occurred. nonattainment of meac is frequent after open cavitary surgery. conservative opioid dosages continue to be employed despite inadequate early postoperative pain relief; this does not change with increasing experience. reporting such findings in departmental audit may help to alter perioperative management; such data may serve as a baseline for future interventional studies. diclofenac is frequently used for analgesia after tonsillectomy. recently concern has been expressed about the effect of diclofenac on prolonging bleeding time. one recent retrospective study found its use in tonsillectomy was associated with an increase in reactionary haemorrhage. we designed a randomised controlled study to compare the effects of rectal diclofenac and im pethidine given at induction with pethidine alone, in children undergoing tonsillectomy. fifty nine patients were entered into the study. there were males and females, mean age years, range ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . patients were randomised according to chart number. thirty five patients received rectal diclofenac after induction. twenty four patients acted as controls. there were no significant differences in operating time or operative blood loss between the two groups. in the recovery room the diclofenac group was significantly less restless than tl~e control group (p < . , chi squared test), with less crying, movement and agitation. there was no difference in postoperative recovery and no primary or reactionary haemorrhage. one patient in the diclofenac group developed a secondary haemorrhage. this study demonstrates a significant reduction in restlessness in the recovery room in children receiving rectal diclofenac. no increase in reactionary haemorrhage was demonstrated. diclofenac remains a safe and effective analgesic agent in children undergoing tonsillectomy. elderly patients have decreased dose requirements for many drugs compared to the young. few studies have examined dose requirements of opioids in the elderly when administered via patient controlled analgesia (pca) . we compared the pca morphine requirements between young and elderly patients. records were retrospectively analysed from , consecutive patients receiving pca for post-operative pain. inclusion criteria (i) age less than years or greater than years, (ii) upper abdominal surgery, and (iii) morphine pca usage. patients fulfilled the inclusion criteria. patients were young and were elderly. the mean age in the young was years and in the elderly was years. % were female in the younger group, % were female in the older group. pain scores at rest and on movement were similar in both groups . and . respectively in the young, . and . in the elderly. (p > . , students t-test). morphine usage over hours was + . mg in the young, and + . in the elderly. (mean + s.d.) (p.< . , students t-test). elderly patients required significantly less morphine via pca to achieve the same pain scores as the young. these findings are consistent with studies showing decreased requirements of other drugs in elderly. the erythrocyte sodium-lithium countertransport (slc) is abnormal in essential hypertension and some other forms of cardiovascular disease (cvd) but the considerable overlap in its activity in patients with these conditions and in normotensive healthy subjects remains a strong point against its possible utility as a marker for cvd. we sought to address this issue in greater detail. twenty-nine hypertensive patients ( with family history of cvd) aged . + . years (mean + se) and normotensive subjects ( with family history of cvd) aged . + . years, participated after informed consent. slc were determined in , , , and mm sodium chloride; and the vmax and km of the transporter determined. hypertensive and normotensive individuals with family history of cvd (n = ) had higher slc activity ( . + . vs . + . , p < . ), greater vmax ( . + . vs . + . mmol/lcell.h, p < . ) and lower km . mm (median) vs . (p < . ) than hypertensive and normotensive subjects without such a history (n = ). however, none of these parameters was sufficiently discriminatory as evidenced by the considerable overlap in the scattergrams for the two groups. on the other hand not only was the median quotient vmax/km significantly different . vs . (p < . ), but also the scattergram separated the two groups. this may reflect an effect of hereditary factors on the identified rate-limiting step in the transport system. capsaicinadministration results in depletion of substance-p sensitive nerves. this study was carried out to observe the impact on the morphology of mitral valve endothelium. the experimental group received capsaicin i.p. on day four of life; control animals received drug vehicle only. animals were anaesthetised by chloral hydrate and hearts were removed following perfusion of % glutaraldehyde, and were routinely processed for scanning electron microscopy. normal endothelial morphology showed an ordered and structured pattern, with large raised nuclei covered in discrete microappendages: no zoning was observed over the valve surface. following capsaicin administration, valves were seen to be torn and possessed a denuded endothelium. nuclear bulges changed in both apparent height and area, with the surface partially denuded of microappendages. one month following systemic administration of capsaicin to neonatal rats, a serious alteration of mitral valve endothelium morphology and integrity had occurred. depletion of substance-p may have resulted in mechanical insufficiency of the mitral valve. this study was funded by the health research board. with expanding applications and increasingly aggressive stress protocols, concerns about the safety of dobutamine stress echocardiography (dse) have arisen. the purpose of this study was to analyse prospectively the safety, adverse event profile, and complication rate of dse. prospective data was recorded in a consecutive series of patients undergoing dse for diagnostic evaluation of chest pain, for risk assessment following myocardial infarction or for detection of hibernating myocardium. the maximum dose of dobutamine used was mcg/kg/min in . % of patients and mcg/kg/min in . %. atropine was used in . % long-term outcome following coronary artery bypass grafting may be related to the prevalence of major risk factors and their treatment following surgery. we aimed to establish the prevalence and current management of coronary risk factors in a group of consecutive patients attending our hospital. this is a report of the first patients. data was collected by a structured patient interview, chart review, physical measurements and blood sampling. there were male and female patients, average age . years. the mean length of time since surgery was . years. thirty-nine patients had a recurrence of angina and this occurred on average ll months after surgery. as regards risk factors, were active smokers, were ex-smokers and only had never smoked. two thirds of the patients were taking regular exercise; only took no exercise at all. seventy-two percent of patients had a cholesterol greater than . mmol/l, yet only of the patients were on lipid lowering drug therapy and a further were on a lipid towering diet. twenty-nine patients had a systolic bp > or a diastolic bp > and of these were on antihypertensive therapy. seventy-seven patients were overweight but most of these had received specific advice regarding weight reduction in the preceding year. our results show a high prevalence of treatable risk factors in this high-risk group with inadequate treatment in many cases. new combined primary and hospital care strategies for cardiac rehabilitation and long-term secondary prevention of coronary heart disease are required. if the goal of modern therapy of acute myocardial infarction (ami) is preservation of myocardium, the occurrence of cardiac failure could be regarded as a treatment failure. in recent studies of iv thrombolysis and primary ptca the frequency of left ventricular failure (lvf) following ami has been as low as . %. this very low rate might be explained by selection bias in patients recruited to randomized trials. the purpose of this study was to examine the frequency of lvf in a consecutive alterations in nitric oxide (no) synthesis have been implicated in cardiomyopathy, ischaemic heart disease and septic shock. recent work has suggested a possible role for nitric oxide in cardiac arrhythmogenesis. the effects of inhibiting no synthesis with l-name (n c -nitro -l -arginine methyl ester) on cardiac electrophysiology have not been fully determined. the dominant frequency of electrically induced ventricular fibrillation was determined in l anaesthetised pigs ( - kg) using a fourier transform. the dominant frequency ( . _+ . hz in lead ii) was not altered by treatment ( . _+ . hz) with l-name in a group of pigs ( - kg) the effect of l-name ( mg/kg) was assessed in relation to energy required to defibrillate. there was no significant difference in the energies required to achieve successful defibrillation on % of attempts between the l-name group ( . _+ . j) and the control group ( . _ . j), and on % of occasions, l-name ( . + . j) and control ( . _+ . j). the results show that inhibition of no synthesis has no significant effect on the dominant frequency of ventricular fibrillation or on the efficacy of defibrillation in the pig heart. received either mg ( pts) or mg ( pts) oral flecainide followed by a maintenance dose of mg bd. all pts were euthyroid. none had significant hypertensive, valvular or ischaemic heart disease. pts had normal echocardiograms, had mildly dilated atria. of the pts ( %) converted to sinus rhythm, within hrs and at and days respectively. subsequently, he was found to have paralysis of all the muscle groups of his right upper limb apart from some flexor movements in his fingers with areflexia and sensory loss over the c /c dermatomes. the findings were thought to be in keeping with a brachial plexus.lesion. an mri scan showed a "haematoma" or "fibrosis" around the brachial plexus~ emg studies revealed a complete lesion from c /c with evidence of partial function at c and a good function at c . despite physiotherapy, at follow up months later there was no improvement in the emg findings. though brachia~ plexus injury has always been considered a complication of central venous line insertion <l), there have been no cases described, in the literature in the last years. central lines are mandatory irt major surgical cases but one must always be aware of the possible complications caused by them. body weight (bw) in icu patients fluctuates due to alterations in body mass ( ) and water ( ) and is usually estimated rather than measured. we hypothesised that (i) estimated weights are inaccurate and (ii) changes in true body mass (tbm) are masked by changes in water content. on admission, icu patients whose expected length of stay (los) was > days were placed on a bed incorporating load cells (accuracy of _ . kg). bw was estimated by icu staff. mbw was then recorded hourly under standard conditions. changes in mbw due to pack insertion/dressing changes were excluded. we calculated tbm as mbw minus cumulative fluid excess, corrected for insensible losses c ~. patients received standardized nutritional support from day and urinary nitrogen on day was calculated we studied patients whose mean (sd) age, mbw, los and apache ii score were . yr ( . ), . kg ( . ), . days"( . ) and ( . ) respectively. mean error in estimated weight on admission was . % (nurses) and . % (doctors). mean protein and calorie intake was g and kilocals/day. mean decrease in mbw during icu stay . kg/day (range . kg (gain) to . kg). mean reduction in tbm was . kg/day (range . - . kg/ day) and this correlated with urinary nitrogen loss (r= . ). in icu, (i) estimated weight is significantly inaccurate and should not be used in physiological calculations and (ii) rapid and significant decreases in body mass occur which may be underestimated due to fluid accumulation. dopamine appears to influence pituitary function and is associated with decreased circulating human growth hormone and insulin-like growth factor i m which could exacerbate catabolism, and therefore wasting, during critical illness. at hrly intervals from admission, patients whose expected length of stay exceeded days, were weighed (measured body weight, mbw) under standardized conditions,-using a bed incorporating electronic load cells (accuracy + o. kg). standard demographics, apache ii score and use of dot~amine by infusion was recorded. changes in weight due to removal./ insertion of prostheses, packs/dressings were excluded mbw was converted to true body mass (tbm) using measurements of cumulative fluid balance ( ml = kg) and insensible lossr patients received nutritional support, starting on day , based on their admission mbw. there were no significant differences in mean age, weight, length of icu stay, admission apache ii scores and mean daily protein/calorie intake between patients who had received dopamine by infusion (group d) and who had not (group nd). mean (sd) decreases in mbw during icu stay were . ( . ) kg/day (group d) and . ( . ) kg/day (group nd) (p< . i). mean decrease in tbm was . ( . ) kg/day and . ( . ) kg/day respectively (p< . ). thus group d were losing an additional . kg body mass per week relative to group nd. the use of dopamine by infusion is associated with an accelerated loss of lean body mass during critical illness. adhesion of polymorphonuclear leucocytes (pmns) to pulmonary endothelial cells is an initial step in the inflammatory process characterising the adult respiratory distress syndrome. previous studies using human umbilical vein endothelial cells (huvecs) have suggested that lipopolysaccharide (lps) is a potent stimulus for pmn adhesion to endothelial cells. the aim of this study was to investigate the effect of lps on pmn adhesion to human pulmonary artery endothelial cells (hpaecs). human pmns were coincubated with hpaecs _+ lps ( . - mg/ml) with % serum for hour. the effect of phorbol myristate acetate (pma) ( ng/ml) was also examined. percentage adhesion stimulated by pma was + sd. lps did not significantly increase adhesion at any of the concentrations used. to confirm the activity of lps pmns were incubated at ~ with . - mg/ml lps + % serum for hour and labelled with flourescent antibodies to the mac adhesion molecule complex (cd /cd lb). facs analysis indicated upregulation of both cd and cdllb. thus in the system used, lps did stimulate pmn adhesion molecule expression, indicating that the lack of adhesion reflects a difference in hpaec response to lps compared to that reported for huvecs. this work was supported by the health research board ireland. although inhaled corticosteroid therapy is of undoubted benefit in the management of asthma, dysphonia is a recognised sequela. this study was designed to examine longitudinally the effect of inhaled steroids on the voice and vocal cords of newly diagnosed and previously untreated asthmatics. twenty subjects were recruited and underwent voice and vocal cord assessment prior to and months after starting inhaled steroid treatment. the assessment consisted of ) rating dysphonia using a visual analogue scale, ) acoustical analysis of the voice and ) videostroboscopic examination of vocal cord activity. prior to commencing inhaled steroid therapy for their asthma subjects had normal voices, subjects were mildly hoarse and one was moderately hoarse. vocal cord pathology was noted in subjects, patients had vocal cord nodules and the remainder were noted to have mildly oedematous cords together with a glottic chink. at month follow up, improvement in voice was noted in subjects, one patient felt more dysphonic but there was no change in vocal cord appearance. one subject was noted to have developed a mid glottic chink with no associated change in voice. one subject had clearing of mild vocal cord oedema and improvement in voice. this study demonstrates that % of subjects commencing inhaled steroid therapy for asthma have mild vocal cord pathology. voice is more likely to be improved following use of inhaled steroids for months then made worse. although the relationship between elastin degradation and emphysema is well known, recent evidence suggests that a more complex process of pulmonary remodelling occurs within the emphysematous lung. the aim of this study was to assess the extent of extracellular matrix remodelling by ultrastructural examination of its two major components, elastin and collagen. emphysema was induced in rats by the intratracheal administration of porcine pancreatic elastase ( . u/g body weigh and human lungs were obtained at surgical resection for lung carcinoma. emphysema was confirmed histologically in both animal and human samples by measurement of the mean. linear intercept. matching sections were immersed in . m naoh and % formic acid to digest elastin and collagen respectively. scanning electron microscopy with stereo-pair imaging allowed -d visualisation of elastin and collagen frameworks. the distribution of emphysema was primarily panacinar in rat lungs a'nd centriacinar in human lungs. as expected in both types of emphysema, elastic lamellae were disrupted and perforated with multiple fenestrations. accompanying this disintegration was a marked increase in thickness of collagen fibrils which in some cases coalesced irish journal of medical science imparting a sheet-like appearance to the airspace walls. unique to human centriacinar emphysema, collagen formed helices which spiralled around alveolar septae to form bulky walls between adjacent airspaces. in conclusion, these findings lend support to the novel concept of aberrant collagen remodelling in the pathogenesis of emphysema. small cell lung carcinoma (sclc) is the most aggressive of the four common cell types of lung carcinoma. less than % of patients with sclc are alive two years after diagnosis. staging procedures, treatment regimens and survival results were reviewed in a small regional centre to make a comparison with larger treatment centres. thirty-one cases of sclc seen by one physician from to were reviewed. staging was clinical. treatment was undertaken in conjunction with the local oncology and radiotherapy services. % of patients had limited disease where as % had extensive disease at diagnosis. in patients with limited disease, % were alive at months and there was a % long term survival rate i.e. greater than three years. average length of survival in limited disease was days. survival results were comparable with those treated with chemotherapy alone and combination chemotherapy and radiotherapy. in patients with extensive disease the best results were from those treated with a combination of chemotherapy and radiotherapy with art average survival of days. these figures compare favourably with those from larger multidisciplinary centres. the factors contributing to our relative success may relate to continuity of care achieved in a smaller centre. nasal cpap is a very effective therapy for osa, but is cumbersome, and compliance varies. we prospectively evaluated consecutive osa patients treated with ncpap, who were asked to complete questionnaires before, and to months after starting therapy. this stttdy intended to examine both the patient's subjective response to ncpap and their bed-partner's impressions also. replies were received in ( %) patients. patients were divided i~to groups depending on whether they had a bed-partner, and according to their response to an initiat question assessing overall improvement in sleep quality and daytime al'ertness with ncpap, ranging from (minimal/none) to + (excellent). patients were called responders if they scored > . group a ( pts, %) were responders with bed-partners; group b ( pts, %) non-responders with bed-partners; group c ( pts, %), were responders ( pts, %) and nonresponders ( pts, %) without bed-partners; and group d ( pts, %) had stopped ncpap. nine questions were directed at the bed-partner, and assessed their perception of changes in both the patient's and their own sleep quality, daytime alertness, mood and quality of life, and also to changes in the relationship between patient and bed-partner following institution of ncpap. these questions scored from - (worse) to + (marked improvement). significant improvement in all parameters for the patient (mean + sd = . + . ) were noted in group a. in addition, group a bed-partners reported ~ubjective improvement in the same parameters ( . + . ). group b improvements were less, ( . + . in patients, and . + . in partners). overall, the data indicate a subjective success of therapy in % of patients, but the bed-partner's replies indicate this figure underestimates the true response rate. furthermore, the results show significant improvements in the bed-partner's sleep quality, daytime alertness, mood and quality of life, indicating that successful treatment of osa patients with ncpap also gives significant benefits to their bed-partners. vincent's hospital, dublin. neutrophil collagenase (mmp ) is a member of the matrixmetalioproteinases (mmps), a family of highly homologous zinc endopeptidases which play a crucial role in many physiological processes. the aim of this project was to develop a purification system for mmp from purulent sputum and raise polyclonal antibodies. after initial extraction, contaminating proteins were removed with a zinc chelate affinity column. mmp was then separated, from another closely related mmp, gelatinase b, on a q sepharose ion exchange column using a nacl gradient. the final purification step was carried out with an orange sepharose affinity column. sds-page analysis indicated the presence of purified protein with bands corresponding to latent neutrophil collagenase ( kd) and products of coll~igenase autodegradation at lower molecular weights ( kd & kd). a fold increase in specific activity was observed, with a % final yield, which provided mg quantities of pure enzyme. this work is funded by forbairt and the. irish american partnership. cd is a protein first described as a surface marker on hodgkin's lymphoma cells. recently cd has been demonstrated on th -type t lymphocytes (produce il- , , , l and ), which have a pro-inflammatory cytokine profile. but is not found on thl-type t lymphocytes (produce il- and ifn-gamma). its ligand, cd l, has also been described, cd -cd l interaction has been shown to aid the development oft lymphocyte clones into a th rather than a th phenotype. th -type cytokines are inextricably linked to the aetiology of inflammatory airway disease. firstly we investigated serum cd levels in various patient groups. we have demonstrated significant differences in serum cd levels in the following groups, atopic asthmatics (mean = iu/l, n = ), non-atopic asthmatics (mean = iu/l n = ) and atopic rhinitis/dermatitis (mean = iu/l n = ) and normal controls (mean = iu/l, n = ). secondly we cultured peripheral blood mononuclear cells from allergic individuals and normals. when these cultures were stimulated with house dust mite antigen (der p ) and il- or der p with both il- and i - , surface expression of cd on t lymphocytes could be demonstrated using fluorescent staining and flow cytometric analysis, after days culture in the allergic individuals but not in normals. the presence of i - in the culture increased the degree of surface cd expression. these results are important as they show that allergic individuals have an expandable population of memory t lymphocytes which respond to allergen by expressing cd and developing th- phenotype. most work on cd and th- cytokines has hitherto been carried out an t cell clones. we have developed a relatively simple in vitro system of looking at t lymphocyte response to allergen which will allow the testing of novel therapeutic interventions with a view to modulating the immune response in allergic disease. our work also suggests that even non-allergic patients with inflammatory airway disease may have increased th activity, which has not been shown previously. scimitar syndrome is a rare congenital disorder consisting of a spectrum of abnormalities including hypoplasia of the right pulmonary artery, dextroposition of the heart, anomalous pulmonary venous drainage of the right lung into the inferior vena cava and anomalities of the right diaphragm. bronchiectasis and respiratory tract infections on the right side are the usual clinical presenting features. a year old male patient was referred to the outpatient clinic with a history of recurrent chest infections which were slow to resolve following antibiotic therapy. physical examination revealed decreased air entry, coarse crepitations and a prolonged expiratory wheeze in the right lower lobe. the only abnormalities on routine biochemical and haematological screening were an elevated esr of and a slightly raised white cell count of . a chest x-ray revealed hypoplasia of the right lung when compared to the left. in addition to this there was a vascular shadow present in the right lower robe representing an anomalous pulmonary vein which appeared to drain to below the diaphragm on the night side. bronchoscopy showed a normal left bronchial tree. on the right, no apical segment was detected in the right lower lobe. otherwise no endobronchial lesion was seen. a dynamic computerised axial tomographic scan of the thorax was performed. this showed a dilated anomalous right lower pulmonary vein which was clearly seen to enter the inferior vena cava below the diaphragm. in addition the right lung was again noted to be hypoplastic when compared to the left. these findings were pathognomonic of the scimitar syndrome. "the patient was treated symptomatically and is presently stable. conclusion: scimitar syndrome, with its wide spectrum of abnormalities should be considered when reviewing plain chest x-ray in patients with recurrent right lower lobe respiratory tract infection. recent studies indicate that the ability of circulating neutrophils to regulate surface levels of adhesion molecules may be altered in disease situations. the aim of this study was to determine if changes in neutrophil responsiveness accompanies chronic inflammation in cf. neutrophils in blood samples from cf patients and age-matched control subjects were analysed by flow cytometry for expression of l-selectin and mac- (cd lb) following stimulation by interleukin- (il- ) and fmlp. as expected, both il- and fmlp provoked a decrease in surface levels of l-selectin and an increase in cdi lb levels. however, the magnitude of these changes was significantly lower in cf patients than in control subjects (table) . these results suggest that chronic exposure to inflammatory stimulii in vivo may alter neutrophil responsiveness in cf. given the emphasis on rational prescribing, we reviewed drug use in a bedded long-stay unit. prescribing patterns were analysed on an appointed day thereby obtaining a "snapshot" of prescribing practices. one hundred and ninety four long-stay residents, with a mean age of , were on drugs, the maximum number of drugs per patient was , the minimum and the average . . sixty percent of prescriptions fell within one of the following therapeutic categories:-central nervous system (cns) preparations ( prescriptions), analgesics ( ), gastrointestinal preparations ( ) and cardiovascular preparations (i ). there were ,prescriptions for respiratory drugs and only prescriptions were for antibiotics. the most commonly prescribed cns preparations were anti-psychotics ( ), benzodiazepincs ( t ), anti-depressants ( ). % of all analgesics prescribed ( ) were nsaids. the most commonly prescribed h blocker was cimetidine ( ). nuseals aspirin ( ), digoxin ( ) and captopril ( ) were the most commonly prescribed cardiovascular drugs. % of drugs were issued on an as required basis, i.e. "prn". the most commonly prescribed prn therapeutic classes were analgesics ( prescriptions) followed by gastrointestinal ( ) and cns preparations ( ). these results contrast with prescribing patterns in hospitals and general practice and may provide an insight into the challenges and realities of management in long-stay units. supported by the health research board. evaluation of physician requests to hospital based clinical pharmacist for ( ) drug information, ( ) possible adverse drug reaction (adr) was undertaken over a two year period from jan ' to dec ' (admissions - , , opd attendances - , ). overall requests were made. ( ) drug information: advice/information on new drugs, formulation, dosage, safety consideration prior to drug prescribing was given in cases. ( ) suspected adr: a total of suspected adverse drug reactions were investigated. in cases, no adr link was established, after extensive literature/data base search. adr's were confirmed in cases of which were reported to n.d.a.b. regular on-going interaction between physicians and clinical pharmacy allowed critical analysis of new drugs and heightened awareness of, potential adverse drug reactions in current clinical practice. we previously demonstrated that commonly prescribed medications are not easily identified by patients, doctors or nurses in the hospital setting o, ~. we then investigated the ability of hospital pharmacists, in all, to identify the same commonly prescribed branded and generic drugs. correct identification as follows:-bendrofluazide k ( / ), cimetidine ( / ), diazepam mg ( / ), diazepam mg generic ( / ), digoxin ( / ), ferrous sulphate ( / ), frusemide ( / ), mefenamic acid ( / ), paracetamol ( / ), prednisolone ( l/ ), temezepam ( / ), theoph /lline ( / ). pharmacists had % correct answers compared with % for nurses and % correct for doctors. the pharmacists had no difficulty recognising drugs with brand names written on them e.g. cimetidine, but like nurses and doctors had difficulty identifying the plain white tablets e.g. prednisolone. generic drugs were tess well recognised. a number stated that they were unwilling to definitively identify medication with no clear marking. pharmacists were also asked to list the top prescribed drugs, l got / correct and got / correct. in contrast out of doctors got / correct, got right and only got right. we conclude that hospital pharmacists are generally better than doctors or nurses at identifying commonly prescribed drugs but their knowledge of the top prescribed drugs is not as good at that of doctors. all professionals need assistant in this important task. suggesting reduced activity or more iranians with inherited variants of cholinesterase. one iranian subject with very low activity (dibucaine number below , atypical) had a history of apnea. these data indicate that the frequency of atypical and heterozygote genes for cholinesterase activity leading to prolonged apnea with succinylcholine (suxamethonium) is much higher in iranian than irish populations. this study emphasises the importance of ethnic pharmacology. it is has been advocated that funding for the prescibing of methadone in general practice should be provided separate from the indicative drugs budgeting scheme on the assumption that this may act as a disincentive to g.p.s to take on care of drug addicts. the objective was to analyse the current level and cost of methadone prescribing in general practices in the eastern health board over a six month period. there was a review of methadone prescriptions for gms patients from jan. to jun. . , persons received prescriptions. , scripts were issued. the age-specific prescribing rate for the total population was / , (males /i , , females / , ). males aged - years had the highest age specific rates ( / , ). the cost of methadone prescriptions amounted to s for the six months there was a trend towards an increase in the number of g.p.s who prescribed methadone over the period. only four of the g.p.s ( . %) who prescribed methadone issued in excess of scripts for the period studied. for a small number of g.p.s methadone prescribing is a significant cost item on their budget. in the light of this, government policy should be reviewed with a view to excluding methadone from the indicative drug budgeting scheme. sciences, mashhed, lran. there is increasing evidence that some of the wide variation in the response to medicines has a genetic origin which may be expressed on a racial basis. to further study inter-ethnic differences in pharmacology we compared the activity of an enzyme responsible for the breakdown of endogenous substances and drugs -serum cholinesterase (pseudocholinesterase), dibucaine and fluoride numbers -in irish and iranian healthy subjects. irish subjects had significantly higher serum cholinesterase activity ( . + . vs . + . u/ml, mean + sem, p < . drug prescribing data may reflect changes in therapy and disease pattern. we reviewed current drug use among patients (n = ) in a dublin teaching hospital in "snapshot" fashion on a designated day, and compared it with that obtained in . in , patients received an average of . different drugs each, with % on or more and % on none. by , the average was . (range i - ), with % on or more. the percentage of patients receiving heparin fell from % to %, due mainly to a reduction in use on the medical side. the proportion of patients prescribed hypnotics fell from % to %, while ssri's are now the most used anti-depressants. antibiotic choice changed from amp/amoxicillin to coamoxiclav and the cephalosporins. diuretics remained the most frequently used cardiovascular agents, accounting for % of all drugs used and prescribed for around one quarter of patients. digoxin use remained constant, and by , % of patients were on anti-platelet doses of aspirin. at least four different agents were in use in each of calcium antagonist, beta blocker and ace inhibitor classes. some of these changes in therapy reflect therapeutic advances, changes in disease management, greater choice of therapy and amendment of less than desirable therapeutic practices. on the other hand, some may reflect fashion or pharmaceutical promotion, rather than change as a consequence of evidence-based practice. acknowledgements: pharmacy staff, st. james's hospital and the health research board. studies of in vivo endothelial function in humans have usually involved intraarterial cannulation and the subsequent administration of substances that stimulate the endothelium to produce nitric oxide (no). such techniques are invasive and potentially hazardous. an alternative non-invasive method would be of benefit. animal studies have indicated that reactive dilation of vascular beds may be at least partially endothelium dependent. this study aimed to determine whether reactive hyperaemia in the human forearm was an endothelial dependent process with the potential to be used as a non-invasive method of stimulating the endothelium. ten volunteers underwent brachial artery cannulation and randomly received either placebo or n-monomethyl-l-arginine (l-nmma) ( ~mol/min), an no synthase inhibitor, for minutes. following this reactive hyperaemia was induced by the inflation of an arm cuff to mmhg for minutes and the response to this was measured by strain-gauge plethysmography. when flows had returned to baseline the process was repeated with the remaining substance. results were analysed by repeated me~isures anova. l-nmma resulted in significant reduction of basal forearm blood flow (p< . ). there was no significant difference in reactive hyperaemia with either l-nmma or placebo. in conclusion, no does not contribute to reactive hyperaemia in the human forearm. dublin . home-based infusion therapy has been widely recognised as the optimum for treatment of disease states that require daily intravenous therapy from a patient-care aspect. conditions necessitating intravenous therapies in hiv disease include: cmv retinitis, intractable cryptosporidial diarrhoea, azole-resistent candidosis, nutritional support with total parenteral nutrition, chemotherapy for aids-related malignancies and palliative care in the terminal phase of the disease. the need for such therapies is increasing as patient survival improves. in , the home-infusion service was set up in recognition of the need to treat patients, requiring intravenous therapy, in the home environment. this has been brought about by the development of small, light-weight pumps suitable for ambulatory use, the development of a service for aseptic compounding and the availability of permanent in-dwelling venous catheters. we describe the impact of this service on our patient cohort. to date, sixty-five hiv positive patients have received parenteral therapy at home. patients' age, sex, risk group, cdc stage, cd count, indication for therapy, complication rate and response to treatment are described. the provision of this service has reduced the number and length of patient admissions with associated improvement of quality of life. in addition, it recognises that patients prefer to be treated in the home environment aided by a co-ordinated multidisciplinary approach. since blood alcohol levels over mg/ ml are now illegal for vehicle drivers we have investigated if the commonly held "safe" limit of two drinks will bring the young adult over the legal limit and if this amount of alcohol will affect their psychomotor skills. following informed consent healthy volunteers, nonhabitual drinkers on no medication ( male, female), with a median age of (range - ) years participated and refrained from alcohol for at least days. each drank within minutes two standard drinks ( . ml each ) of . % vodka ( . units of alcohol) plus ml of orange juice at about minutes after a standard mid-day meal. their psychomotor performance was estimated by the number connecting technique at minutes after alcohol consumption and they were also asked to rate their feelings (which included alertness, clear-headedness, competence and attentiveness) using a visual analogue scale of to . blood samples at one and two hours later were collected from the antecubital vein and analysed on the same day for alcohol content using enzymatic methods. mean (+ sem) blood concentrations of alcohol at and hours respectively were . + . and . + . mg/ ml. in males and . + . and . + . mg/l- ml in females. values were significantly higher in females. blood concentrations in females were also higher (p < . ) than in males when expressed per kg body weight. while the blood alcohol in both the genders was considerably lower than the current legal limit in ireland their psychomotor skills as estimated from their task completion time and their answers to questionnaires were indicative of an impaired cns function. thus while drinks may keep many subjects below the legal limit, there is considerable inter-individual variation with females showing higher concentrations and both genders have evidence of impaired performance at these lower levels. a non-linear approach was used to develop an hrv parameter, robust to both data non'-st~itionary and missing data points. unlike the standard chaos approach, using higher dimensional embeddings and time-delays, we employed a onedimensional correlation integral plot. the parameter thus obtained, allows an estimate of the spatial spreading of the attractor (ssa) or spatial variation of rr intervals along a straight line. heart rate data from volunteers ( : to : hr), ~ifter oral placebo or propranolol mg, investigated the ability to detect drug effect. vitamin e (~-tocopherol) is the most important dietary antioxidant in lipid and cell membranes and its intake reversely relates to the incidence of coronary heart disease and certain cancers. estrogen regenerates oxidized tocopherol radical in vitro m but such interaction has not been investigated in postmenopausal women receiving estrogen containing hormone replacement therapy (hrt) although estrogen containing oral contraceptive may reduce plasma vitamin e levep. we studied healthy post-menopausal women (aged - ) ammenorrheic for at least one year. fifteen subjects took a combination of harmogen provera therapy and acted as a control group. blood samples were taken from all subject at baseline and after weeks. in the hrt group, serum fsh levels were greatly reduced ( . + . vs . + . iu/ , p < . , mean + sd, after hrt) with an increased serum oestradiol level (< - . vs . + . umol/ , p < . ). no change occurred in the control group. vitamin e status, measured either as plasma or red cell ~-tocopherol respectively showed no change in both groups (hrt group . + . vs . + . , . + . vs . + . gmol/ , p > . ). we conclude that in post-menopausal women, weeks estrogen containing hrt did not alter vftamin e concentrations in vivo. we assessed the clinical benefit of the newer markers of bone formation: osteocalcin (oc), procollagen carboxyterminal peptide (picp), bone alkaline phosphatase (balp), and bone resorption: carboxyterminal telopeptide of type collagen (ictp) and urinary deoxypyridinoline crosslinks (dpd) over traditional assays such as total alkaline phosphatase (talp) and urinary hydroxyproline (oh/pr) in patients with primary hyperparathyroidism (phpt). patients were sampled basally, then at , , , and hours post surgery and again at . , , and months post op. the mean basal p cp level was + ug/l (normal: - ) this increased to a peak at h ( +_ ug/l), then declined to normal at weeks ( + ug/l). mean basal urinary dpd levels were raised at . + . nm/mm cr. (normal . - , ), they had normalised by months to . -+ . nm/mm cr. mean balp levels were always normal, although normal the yearly mean oc level was significantly lower than the basal value. mean ctp, oh/pr and talp levels were always normal. therefore bone turnover in phpt is best assessed by the newer markers picp and dpd. we have previously described seasonal variation in fibrinogen with higher levels in winter. as fibrinogen is an acute phase reactant, the winter rise may be a response to seasonal infections. the present study investigates this hypothesis by examining seasonality infibrinogen and markers associated with infection: white cell count (wcc), interleukin- ( l- ), human herpes virus (hhv ) and herpes simplex virus (hsv) antibodies. monthly blood samples from healthy volunteers age and over were measured for fibrinogen, wcc, il- , hsv and hhv reactivation over a year time period. a rhythmometric method was used to examine the data for seasonality. statistical significance was measured using the fstatistic. a highly significant seasonal variation (sv), peaking in mid-february, was found for fibrinogen (n= ; sv= . g/ ; f= . ; p< . ). no significant seasonal variation was present for measures of wcc (n= ; sv= . e /l; f= . ; p> . ), hhv (n= ; sv= . au; f= . ; p> . ), hsv (n= ; sv= . au; f= . ; p> . ) or il- (n= ; sv= . pg/ml; f= . ; p> . ). the present investigation does not support the hypothesis that seasonal variation in fibrinogen is a direct effect of the acute phase response, initiated by a seasonal variation in level of infection. the explanation for the seasonal changes in fibrinogen remains unknown. increased plasma homocysteine and reduced plasma antioxidants are risk factors in the development of vascular disease. design: subjects drawn from elderly people living in the community (median age yr, range - yr; female). total plasma homocysteine, vitamin c, gamma tocopherol, retinol and beta carotene were measured by high pressure liquid chromatography. homocysteine levels in elderly males [median (range) = . um ( - . ), n= were significantly higher than in vol. , supplement no. irish journal of medical science elderly females [ . um ( . - . ), n= ]. these values were also higher than in a younger ( - years) male cohort [mean = . um, n= ]. no correlations to vitamin concentrations were found, nor was there a correlation to age within the elderly cohort. within the elderly females, a significant negative correlation with age was found in vitamin c, gamma tocopherol and beta carotene (p< . ). however a significant increase in retinol was noted. a very strong correlation between vitamin c and gamma tocopherol levels was noted in the elderly population sample (p< . after multiple regression). conclusion. homocysteine levels in the elderly are higher than in samples of a younger population. a gender difference is maintained in the elderly. the provision of extended care forms one part of a spectrum of health care for older people. in the eastern health board area all patients over the age of must be assessed by the multidisciplinary geriatric team prior to placement. we report on the experience of the total number of referrals for assessment for extended care to one department of geriatric medicine in a bed teaching hospital. ninety-eight patients listed for extended care in . the mean number of days between listing for long term care and placement was _+ days (range to ). almost one quarter of patients died while in hospital awaiting long term care: this underlines the frailty of patients who are admitted to hospital and request long term care. two patients were transferred to other institutions and patients were able to get home. of the remaining patients ( %) were placed in statutory or voluntary long term care accommodation and only % were eligible (usually financially but in some cases due to significant disability) for nursing home care using the terms of the nursing home act. patients who are listed for long term care through a general hospital are in general very frail, they tend to have a very extended length of stay and the provisions of the nursing home act only apply to a minority. these findings underline the need for provision of adequate statutory and voluntary extended-care places within the eastern health board area. there are over screening assessments for cognitive function and choosing the most appropriate may be difficult. increasingly the importance of behavioural dysfunction is recognised. can any of the cognitive assessments help to predict behavioural dysfunction.'? we compared and contrasted the folstein mini mental state examination (mmse) and the cognitive assessment schedule (cas) of the clifton assessment procedures for the elderly (cape) and compared them with the behavioural rating scale (brs) of the cape. the study was carried out on a total of referrals to the occupational therapy departments by geriatricians in the meath hospital and st. james's hospital. all subjects were over and medically stable. the time scale involved was may-july . the mmse and the cas were administered within the one sitting and each was timed. brs was rated the same day by either a staff or family, member. the average time to complete the mmse ( + s) was longer than the cas ( + s) but this was not statistically significant. the mmse and cas were significantly correlated (r = , p < . ). the cas was significantly correlated with the behaviour scale (r = , , p < . ) whereas the mmse was not. these results suggest that equivalent assessments of cognitive function may be made with the mmse or cas, but a low cas score will be a better prediction of behavioural dysfunction. a spectrum of neurological and myopathological changes are associated with patients in intensive care units. we observed several patients post discharge from icu who presented with unexplained dysphagia which we suspected may be associated with the neurological complications of sepsis. the particular complication of dysphagia as a neurological manifestation of sepsis has not been documented. our descriptive study presents a series of three patients with persistent dysphagia which may represent a similar phenomenon. we selected patients for the study ranging from - years of age and on the basis of medical history including icu stay, sepsis, and intubation. all patients presented with dysphagia as observed on videofluoroscopy. we studied the video findings in-depth in order to ascertain if similar swailow patterns were present in these patients and if this could be correlated with their medical history. each of the three patients presented with similar dysphagia signs. the oral phase of the swallow was moderately atypical but the pharyngeal phase was significantly atypical. it was felt that intubation alone was not the sole causative factor of this dysphagia. the polyneuropathy associated with sepsis in icu may explain the atypical swallow patterns observed in these patients. the severity of the persistent dysphagia can cause serious respiratory and medical consequences. there is a need for further investigation of this phenomenon to identify patients who are at risk. little attention has been paid to the prevaience and phenomenology of behavioural disturbances among medical patients despite awareness of the high prevalence of cognitive vol. , supplement no. impairment in this patient population. we screened consecutive admissions to a department of acute geriatric medicine. patients were evaluated over a week period using a modified version of the brief agitation rating scale. medication use, cognitive function and impact on nursing time were also measured. the prevalence of behavioural disturbance in this population was / ( %). the most frequent behavioural abnormalities were restlessness ( ), complaining ( ) and screaming ( ). the most common underlying disorders were dementia, stroke disease, personality disorder and paranoid psychosis. the behavioural disturbance was only documented in the medical notes in patients ( %) and in only cases was a psychiatric consultation sought. these findings demonstrate that behavioural disturbances are not only common but also under-documented in elderly medical patients and there is a need for training in the detection and management of behavioural symptoms in this patient group. in lower limb trauma where there is severe compound fracture, the successful treatment of this depends on adequate bone and soft tissue debridement. as a result, subsequent bone defects can lead to instability and often require large amounts of bone grafts, and major soft tissue reconstruction is reaquired to obtain skin cover. large soft defects can by reduced bv primary bone resection and shortening of the limb. this will improve the chance of bone healing if performed in the presence of an external fixator, then lengthening at a site away from the traumatised area can gradually restore limb length. two cases are presented to demonstrate .the effect of compression / distraction techniques on soft tissue and bone injuries in these difficult situations. wegener's granulomatosis -wg ( ), churg strauss syndrome -css ( ), polyarteritis nodosa -pan ( ) and unclassified ( ). using the chc definitions, the diagnoses were wg ( ), microscopic polyangiitis -mpa ( ), pan ( ) and undefined ( ). there was concordance in only patients (all wg). there is significant discordance between these two criteria sets. since the acr criteria does not recognise mpa, they tend to overdiagnose wg. in addition, the chc criteria cannot be applied without a biopsy and therefore surrogate features which predict the underlying histology are required to allow more practical application of the chc definitions. the objective was to determine the value of examination of dried freshly produced saliva, under light microscopy, in patients with xerostomia related to secondary sjogrens syndrome. ten patients with known connective tissue disease or rheumatoid arthritis attending rheumatology clinic were enrolled into the study, all with symptomatic xerostomia and dry eyes. all had an abnormal schirmer's test. five normal patients were enrolled, all of whom were without clinical evidence of rheumatological disease. control patients were enrolled who had no clinical evidence of rheumatological disease, a salivary sample was collected and examined by light microscopy. serum was also examined for the presence of anti-ro/la, rheumatoid factor, and anti-nuclear factor. all ten patients demonstrated 'reindeer horn' type ferning of saliva, a pattern of shorter thicker clubbed branches of crystallised mucus, in contrast to the normal ferning pattern of the healthy subjects. conclusion: we have shown in this preliminary report that light salivary microscopy is a simple test easily performed in an outpatient setting which could be a useful diagnostic procedure in sjogrens syndrome. recently, two sets of criteria have been proposed for the nomeclature of primary vasculitides, the american college of rheumatology (acr) classification criteria and the chapel hill consensus conference (chc) definitions. the aim of this study was to determine the concordance of these two systems in a cohort of patients with primary systemic vasculitis. patients with systemic vasculitis were recruited who had a biopsy proven diagnosis or, who had typical clinical features associated with a postive antineutrophil cytoplasmic antibody (anca). the case notes were reviewed and patients were classified according to both sets of criteria. twenty-six patients were recruited, of whom had a positive biopsy. applying the acr criteria, the diagnoses were, primary pulmonary hypertension (pph) typically affects young individuals, and has a high morbidity and mortality. secondary pulmonary hypertension complicating connective tissue diseases likewise carries a poor prognosis. we evaluated the acute and chronic effects of ketanserin, a selective serotonin type- receptor antagonist in patients with pulmonary hypertension in the acute study ketanserin was administered as a peripheral venous infusion during right heart catheterisation. following encouraging results during catheterisation oral administration of ketanserin mg daily in divided doses was instituted. in patient , a year old female with probable pph, serial cardiac catheterisations over a year period showed a significant, sustained reduction in both mean pulmonary artery pressure from mmhg at baseline to mmhg at year (normal - mmhg) and pulmonary vascular resistance units at baseline to units at year (normal < units). in patient , a year old female with limited scleroderma (crest) echocardiography after month's oral ketanserin showed a reduction in estimated peak right ventricular systolic pressure from mmhg at baseline to mmhg (normal range - mmhg). the acute and long term response to ketanserin with improyement in pulmonary haemodynamics in these patients suggests that if a beneficial effect is detected during catheterisation long term oral therapy may be worthwhile. levels were low (< . iu/ ); normal though above average (>- -< iu/l) and moderate high (> -< iu/l) respectively. gonadotrophins for ovarian stimulation were commencing initially at iu for group a & b and at iu for group c. ivf performance was poor in most aspects (total follicles, oocytes & embryos transferred) in group b comparing with group a or c; the cumulative ongoing pregnancy rate (pr) over ivf cycles in group b; was % comparing with . % in group a (p < . ) however there was no significant difference in pr in group c ( %) comparing with other two groups. cycle day fsh screening is predictive of follicular development in ivf. high initial dose of gonadotropins help to improve the pregnancy rate in the presence of moderate high level of fsh. the purpose of this study was to evaluate patient satisfaction with antenatal care provided in the perinatal day centre (pndc). a self administered questionnaire was administered to consecutive patients. the main indications for referral were suspected small-fordates ( %), non-proteinuric hypertension ( %), glucose tolerance testing ( %), reduced fetal movements ( %) and post-term evaluation ( . %); % were nulliparae. thirty-two percent of patients were reviewed in the pndc on the day of referral; the rest within days. twenty eight percent of patients lived more than miles from the hospital and % spent more than minutes in travelling there. eighty five percent of patients scored their level of satisfaction with the service provided in the pndc as > out of ; only . % would have preferred admission; % said that they would prefer to visit the pndc times per week to avoid admission. the main area of dissatisfaction related to the waiting time for review prior to discharge, with . % of patients waiting over hours. patients attending the pndc report a high level of satisfaction; changes to reduce the visit duration have been introduced. to examine the change of taking-up the essential preconceptual measurements; rubella immune status, cervical cytology and prophylactic folic acid intake; following specific advice and publicity through general public meetings with new patients prior to in vitro fertilization (ivf) programme. in we studied new couples for ivf for the presence of some specific pre-conceptual data (group a). in this study we follow-up the same intake in another new women interviewed to commence ivf programme from january till september (group b). in group (b) the taking-up measurements were dramatically improved. however, % and % stilldid not have rubella immunity test and cervical cytology performed; compared to % and % in group (ai respectively (p< . ). while folic acid intake was sustained at > % in both groups. following specific advice the rate of taking-up of preconceptual measurements prior commencing ivf programme was improved. there is a future need for continuous enhancement of the publicity and advice regarding the importance of preconceptual measurements. the aim of this study was to introduce icsi to ireland for treatment of specific cases of male factor infertility. following an introductory proving period using the bovine model, thirtyeight couples with infertility attributed to the male were selected for an icsi attempt. ovulation induction, oocyte retrieval and luteal management were as described for conventional ivf tm. the average age of patients selected for icsi were . + . years and . + . years for the female and male respectively, with an average duration of infertility of . + . years. a year old woman presented with a three day history of parasthesia in her lower limbs and difficulty walking. neurological examination revealed sensory loss in her limbs and truncal ataxia. rombergs sign was positive. pelvic examination revealed a large pelvic mass that was distinct from the uterus. routine blood investigations were normal. csf culture, ct brain and serum electrophoresis were negative. anti-purkinjie cell antibodies were not present. ca- levels were elevated at micrograms/litre. laparotomy revealed a cm left ovarian tumour. a total abdominal hysterectomy, bilateral salpingo-oophorectomy and omentectomy was performed. histology revealed a poorly differentiated clear cell adeno-carcinoma of the left ovary. the capsule was intact and peritoneal washings were negative. she made a good postoperative recovery. she received six courses of carboplatin without ill effect. her neurological symptoms resolved. subacute cerebellar degeneration can occur as a paraneoplastic disorder in ovarian carcinoma. the mechanism by which cancer can cause neurological disorders is not fully understood. paraneoplastic cerebellar degeneration occurs with or without the presence of purkinjie cell antibodies. the aim was to review all red cell transfusions in gynaecological surgery in . a retrospective review of blood bank records and individual charts was carried out. patients underwent gynaecological surgery; ( %) were cross matched and ( . %) were transfused. units were transfused. there were no single unit transfusions. the mean number of units transfused per patient was . this accounted for % of all units transfused this year. % of patients were undergoing elective surgery. the overall cross match/transfusion ratio was . intraoperative difficulty was recorded in % of cases. % of patients were transfused perioperatively and % postoperatively. the percentage of patients requiring blood transfusions in the the main individual operation categories was as follows: radical surgery: %; total abdominal hysterectomy and salpingo-oopherectomy, %; vaginal hysterectomy and repair, %; subtotal abdominal hysterectomy, %; vaginal hysterectomy alone . %; and total abdominal hysterectomy alone %. adverse reactions to transfusions were seen in % of patients. conclusion: the majority of patients transfused were undergoing elective surgery. vaginal hysterectomy was associated with greater blood loss than abdominal hysterectomy. only half of all units cross matched were transfused. dilatation and curettage (d+c) is the most common operation performed in the u.k. the liberal use of d+c has been criticised. the objective of this study was to evaluate the use of outpatient endometrial pipelle biopsy and determine its safety in terms of detecting abnormalities. complications and financial costs were also evaluated. data was reviewed from an active gynaecological unit from february to january , using theatre and outpatient records. a total of d+cs and endometrial pipelle biopsies were performed in this period. malignancies were detected by d+c and by pipelle biopsy. a total of and benign abnormalities were detected by each method respectively. there was a higher complication rate in the d+c group but the failure rate was higher in the endometrial pipelle biopsy group. the monetary savings over this period is estimated at s there were no missed malignancies to our knowledge over the year period since endometrial pipelle bioposy was introduced to this hospital. our study indicates that outpatient endometrial pipelle biopsy appears to be safe, efficacious and economical. while ultrasound findings may sometimes be in conflict with clinical examination, it is the case that there are instances when ultrasound findings have, following subsequent laparotomy, been found to be wholly incorrect. it is therefore not surprising that there remain some gynaecologists who view ultrasound with scepticism, preferring to rely solely of their clinical findings. there have been few studies that directly compare clinical, ultrasound and surgical findings in the detection of pelvic masses. the objective of the study was firstly to directly compare the reliability of clinical and ultrasound examination findings in the detection of pelvic masses proven by subsequent laparotomy and secondly to determine the accuracy of ultrasound in detecting malignancy. this was as a retrospective review of women who underwent a laparotomy because of a pelvic mass between january to february . information was obtained from theatre and patient records. real time abdominal ultrasound was used. findings at laparotomy were correlated with clinical and ultrasound findings. the sensitivity and specificity of ultrasound in detecting a uterine mass was % and % respectively. this contrasts sharply with clinical examination (sensitivity = % and specificity = %). similar findings were obtained when ultrasound was compared to clinical examination in detecting ovarian masses. ultrasouud is capable of predicting benign disease with reasonable confidence but the prediction of malignancy is less reliable. in conclusion, ultrasound is more sensitive and specific in detecting pelvic masses compared to clinical examination. vincent's hospital, dublin. osteoporosis occurring during pregnancy or lactation is a rare event despite the homeostatic demands of the foetus for calcium. we investigated the case of a year old woman who, immediately following vaginal delivery of her first child, developed severe back pain due to a vertebral compression deformity of the second lumbar vertebrae. bone mineral density (bmd) was measured by dual-energy x-ray absorptiometry. calcium metabolism and bone turnover were studied. there was a severe reduction in bmd in the spine (z-score = - . ) and f e m o r a l neck ( z -s c o r e = - . ); but, serial measurements showed no further reduction in bmd. indices of calcium metabolism and bone turnover were normal. pregnancy-induced osteoporosis is a severe but self-limited disorder in calcium homeostasis of unknown aetiology. women with low bmd prior to pregnancy may be at increased risk. in view of increased demand, supplemental calcium and vitamin d should be considered during pregnancy and lactation. crumlin, dublin . the aim of this study was to assess the clinical status on admission and the critical care m a n a g e m e n t of children p r e s e n t i n g with m e n i n g o c o c c a l i n f e c t i o n . t h i s was a retrospective study of the charts of consecutive admissions. mean age was . years (+ . ). the average duration of symptoms prior to admission was . hours (+ . ). on admission . % were hypotensive, . % had clinical signs of haemodynamic instability and . % of cases that had a wood gas analysis on admission had a metabolic acidosis (bases excess < - . ). the mortality rate was . %. % of deaths were hypotensive on admission and all had a metabolic acidosis. of the survivors . % were hypotensive on admission, % had clinical signs of cardiovascular compromise, % were admitted to the high dependency unit, % required invasive pressure monitoring and . % were ventilated and received inotropic support. in this study children presenting with m e n i n g o c o c c a l infection have a high incidence of cardiovascular instability. successful management is dependent on early presentation and initiation of therapy and on aggressive intensive care monitoring and support of the cardiovascular i and vital organ systems. the normal crying curve and incidence of colic for term infants are well known. we studied prospectively the crying pattern and the incidence of colic in preterm'infants to determine if prematurity influenced these behaviours. the subjects were consecutive preterm infants admitted to the cork neonatal units for two and a half months from july . a continuous hour diary was completed on each infant by the neonatal nurses, when the babies were on full oral feeding and no longer required intensive care. the parents completed the diaries 'after discharge. colic was defined according to wessel's rule of threes. two unwell babies were excluded. the duration of follow up was from to weeks. fifty infants were recruited and completed the study ( lost to follow up and one withdi'awn due to sepsis). their mean (range) gestational age was ( - ) weeks and birthweight was . ( . - . ) kg. the mean (range) age of crying onset was x(y-z) weeks; crying, peak 'was x(y-z) weeks and crying offset was x(y-z) weeks. one baby developed colic in the period of follow up. conclusions: the incidence of wessel's colic was less than expected in these preterm babies. the crying pattern according to chronological age was different from that clescribed in term babies. in general preterm babies had a delayed onset of crying, but the pattern became similar to term babies when allowance was made for gestational age. the findings'suggest that the crying patterns of early infancy have a developmental basis. we re-evaluated children who had had rs ( - ), with their closest-age siblings using the wechsler scales, coopersmith self esteem inventory and achenback child behaviour checklist (acbc) (duffy j. et al ). the rs patients' means were consistently lower than that of their sibs. however, comparison of mean raw data, using "t-tests", yielded significant differences only in the acbc scores, in that rs children exhibited significantly more problem behaviours than their sibs (p= . ). after categorisation of iq data, further comparisons between the groups (using x ), found rs patients were significantly more likely to score "below average" in tests of verbal iq compared to their sibs (p= . ). age of onset and clinical stage were also found to be more important predictors of outcome. children less than year of age at onset of rs had significantly lower iq scores on all measures of cognitive ability (p= . ) and more problem behaviours (p= . ) than children over year of age. no significant differences were found in comparison with sibs. clinical stage to which rs progressed affected only verbal iq scores. children in whom consciousness had been impaired had significantly lower iq scores than both their sibs and rs children in whom consciousness was less impaired (p= . ). in conclusion outcome remains cautiously positive, with / rs children attending mainstream schools or in employment without apparent difficulties. a national breastfeeding policy was introduced by the department of health in . factors identified for promotion of breastfeeding were based on the who/unicef "ten steps for successful breastfeeding". we present clinical cases which suggest that one step may need to be modified. the charts of breastfed babies admitted to the special care baby unit were reviewed for one year following the introduction of the national breastfeeding policy to this hospital. thirteen term breastfed babies were admitted because of fever and dehydration. none of the babies had water or bottle feed supplements. ten of the thirteen mothers were primigravida. eleven babies were admitted in the six months following the introduction of an exclusive breastfeeding policy. the nursing staff were then alerted to the risk of dehydration, but two further babies of mums committed to exclusive breastfeeding were admitted in the subsequent six months. routine biochemistry, haematology and a limited septic screen was performed in all babies. three of the thirteen babies had lumbar punctures. the mean (range) weight loss on admission was . ( . - )%. the mean (range) plasma sodium level was . ( - )meq/ and the mean (range) urea was . ( . - . )meq/t. there was no growth from the cultures of the blood, urine, csf and swabs. all the babies were given intravenous fluids and parenteral antibiotics for hours. the outcome was satisfactory in all babies and breastfeeding was reestablished in eleven of the thirteen babies. conclusions: the common factor to these babies was inadequate fluid intake prior to admission associated with stricl~ adherence to the policy, and avoidance of all supplements including water. we conclude that the who/unicef step "not to give food or drink other than breastmilk unless medically indicated" is too restrictive in the immediate postpartum period. . % of children reported headache in the previous months . % of girls and . % of boys reported headache (p < . ). . % of children reported daily headache . % of children reported weekly headache . % of children reported monthly headache . % of children reported headache less often than monthly the percentage of children with headache at each frequency, other than daily, increased with increasing age. in girls headache showed a marked rise at ages , and years. reported prevalence of headache in the past year in to year old aberdeen children was % and % was recorded for swedish children aged , , and years old. this study is the first community based prevalence study of headache in irish schoolchildren. our aim was to test the hypothesis that there is no correlation between the type of feeding & swallowing disorder the child has with the neurological diagnosis or the radiological findings. a further purpose was to develop a classification of the feeding & swallowing disorders which would guide us towards a management plan. a retrospective analysis of the data collected between the years - from the feeding & swallowing clinic at booth hall children's hospital was done. children were included in our study ages ranged from months to yrs. all the children were assessed by the members of the feeding & swallowing team and had videofluroscopic assessment by the same radiologist. neurological signs, speech therapy assessments & videofluroscopy findings were compared between children with spastic quadriparesis & those without. significant differences were noted. a clinical classification was devised using cluster analysis. we conclude that there is no causal relationship between the neurological diagnosis & the type of dysphagia. there are three distinct groups of children who require different strategies of clinical management. surveillance commenced in january to continuously monitor the incidence of surgical site infections (ssi). employing modern optical scanning technology (formic for windows version . , formic limited, london) a questionnaire was designed, which required minimal completion time. the questionnaire includes relevant data based on the american national nosocomial infections surveillance system for ssi including the ssi risk index. surveillance commences at the time of surgery and continues until the patient's discharge. optical scanning technology allows rapid reading of surveillance questionnaires thereby bypassing the bottleneck of manual data entry. by october , details of , procedures had been recorded. the crude ssi rate for these patients was . %. the patient risk index used demonstrated that there were increased chances of developing ssi in certain patient groups. seventy-nine per cent of ssi had presented by the th post-operative day. the length of stay increased by an average of days in patients developing ssi. regular feedback to individual surgeons, theatre and ward staff maintains awareness and highlights possible problems. we recommend optical scanning technology to all those engaged in surveillance work. this system would be especially useful were data collected is transported from outlying hospitals to a central receiving centre for collation and analysis. in francis crumpe published a paper ~ in which he described the therapeutic effect of poisonous mussels (psp) on a case of tetanus. he obtained the mussels from tralee ship canal on the occasion of its infrequent emptying, and entertained the idea of using them in tetanus after treating a young girl with psp who recovered after hours. prior to the use of psp he described it's paralytic effect in two cockrels who both recovered. in concluding his successful use of psp he speculated as to the clinical nature and role of the toxin tralee ship canal was opened in . the water was relatively stagnant and would have contained plenty of nutrients. as such it would have been an ideal habitat for toxic algae which may have been brought across the atlantic as spores in bilge water . the emptying of the canal may well have been done at times of algal blooming. this is the first irish report of psp and a most remarkable use of saxitoxin (?) in the treatment of tetanus, antedating the current management by seventy years. this study was carried out to quantify the published research on smoking in irish medical journals; to ascertain the type of research carried out; and to identify the authors of that research. during the years under study, papers explicitly dealing with smoking were published. only papers appeared in forum. there was a decline in published papers in the eighties with a resurgence in the early nineties. of the papers, a majority were observational and ten were editorials. only one paper dealt with smoking cessation, and one with preventive work. general practitioners were poorly represented as authors. one doctor (prof. r. mulcahy) published at least one paper on smoking in each quinquennium since . this study underlines the relative insignificance of smoking as a topic for research in ireland. a major sea change in attitude will be required if the government's targets for smoking cessation are to be realised, particularly if they are to be achieved by relying on the medical profession. radiology represents a major cost centre within a hospital. lack of awareness of cost amongst doctors may result in the inappropriate requesting of radiology services. this study assesses doctors knowledge of the cost to a tertiary referral hospital of commonly performed radioj'ogical procedures and investigations. doctors were asked to estimate the cost of items namely -chest,x-ray, arch aortogram, ultrasound abdo., lumbosacral spine, barium enema, ct brain, ct abdo., ultrasound abdomen, i.v.p. and percutaneous gastrostomy tube insertion under radiological screening. doctors in st. vincent's hospital were surveyed. doctors as a group overestimated the cost of all individual tests, by margins ranging from % (i.v.p. & gastrostomy insertion) to % (ct brain/ct abdo.) the total cost to the hospital of all items was s consultants'overestimated this total cost by %, followed by registrars, interns and s.h.o's who overestimated the total cost by margins of %, % and % respectively . conclusion: doctors tend to overestimate what radiological procedures and investigations cost a public hospital, often by quite wide margins. thus, any excessive requesting of radiology services by docto.rs is not due to a lack of awareness of their true cost to the hospital. (ded) in dublin. secondly, to identify the major cancers contributing to years of potential life lost (ypll) for the ehb, each cca and ded in males and females. in ireland little work has been done to date on disease specific premature mortality. crude death rates weight all deaths equally; in comparison, ypll emphasise deaths among younger persons and provide a measure of the burden of premature mortality. premature mortality for the deds in dublin for the years and was estimated using ypll, which was calculated by subtracting the date of death form . ypll due to each of the major disease groups were ranked for each ded. seventy-one thousand four hundred and sixty-eight & ) years of potential life were lost in dublin in the and . . % of ypll was due to injury and poisoning, . % to cancer, . % to circulatory disease. however, when the major cause of ypll was established for each ded, injury and poisoning was the number one cause of death in . % of the deds; cancers %, congenital and perinatal conditions . % and circulatory disease %. by emphasising deaths in younger individuals ypll is a valuable tool for planning and monitoring local health promotion initiatives. serum total homocysteine (thcy) levels are inversely associated with dietary intake of folic acid and b vitamins and raised levels have been linked with chd. we have examined the association between thcy concentration and the risk of chd in middle-aged men in british towns. we used a nested case control study design, within an ongoing prospective study, thcy concentration was measured in serum samples, stored at entry to the study, from incident cases of myocardial infarction and controls. cases and controls were frequency matched by town and age group. levels of homocysteine [geometric mean ( %c ) were significantly higher in cases than'controls: homocysteine . ( . - . )gmol/l vs . ( . - . )lamol/l; p = , . there was a graded increase in the relative risk (odds ratio; or) of chd in the nd, rd and th quartile of thcy (or . , . , . ; trend p = . ) relative to the first quartile. adjustment for age, town, social class, body mass index, smoking, physical activity, alcohol intake, hypertensive status, serum cholesterol and serum creatinine did not attenuate this association, (or . , . , . ; trend p = . ). the findings suggest that thcy is an independent risk factor for chd with no threshold level. in summer , a diagnosis of cryptosporidiosis was made in a child who had visited a pet farm. this child had participated in a summer project involving children and nine adults. reports of a similar illness among other project members, prompted an outbreak investigation. a cohort study consisting of two phases was initiated. % ( / ) of project participants responded to a self-administered questionnaire in the first phase. thirteen children met the case definition, of whom seven had cryptosporidium detected in their stools. illness was significantly associated with having visited a pet farm. (p< . ). % of those ill sought medical attention, of whom two were hospitalised the second phase of the cohort study was conducted among those who had visited the pet farm. % ( ) were interviewed. illness was significantly associated with play in sand, to which animals had access, at a stream's edge beside a picnic area (p< . ). contact with various animals was not statistically significantly associated with illness. however the small numbers involved may have obscured such an association. this outbreak highlights a potential hazard for children visiting pet farms and also that cryptosporidiosis is a significant but often overlooked cause of morbidity in healthy children. managers of pet farms need to be aware of the potential for transmission of disease to visiting children. strict implementation of hygiene measures is essential to minimise risk. the mrc vitamin trial highlighted the importance of folic acid in the prevention of neural tube defects(l). since , the department of health has recommended periconceptional folic acid supplements. the objective of this study was to document the knowledge and behaviour of women in child bearing years to periconceptional folic acid. a cross sectional community survey was conducted using an interviewer administered questionnaire in dublin. three hundred and thirty five women took part in the study. approximately two thirds / ( . %) had heard of folic acid. knowledge was significantly associated with higher social class and higher education (p< .o ). few / ( . %) had been advised to take folic acid before pregnancy. only / ( . %) of the women in the study were currently taking folic acid supplements. three quarters of the group ( . %) would be willing to take periconceptional folic acid supplements if they knew it would reduce the risk of malformations. the majority ( . %) would prefer to take folic acid in tablet form. this study clearly shows that few women in childbearing years have been advised on folic acid. however, if advised appropriately the majority would be willing to take periconceptional folic acid in tablet form. future publicity campaigns involving all health professionals should address these issues. unstable intra-articular fractures with or without dislocation of the phalangeal joints often lead to joint stiffness ana loss of function. nine patients with comminuted intra-articular phalangeal fractures were treated in our unit by dynamic external fixator using "pins and rubber bands traction system". the mean age was . years, and the follow-up average was . months. five patients had full and good range of motion in the involved joints. three patients had poor results, and one patient underwent open reduction one week following the original procedure. the technique and our results are discussed. this dynamic frame is compact, comfortable for the patient, easy to apply and allows early mobilisation. careful selection of patients and close follow-up in the first few weeks are needed. this study examines how gp's store and handle vaccines. all gp's in a health board region were invited to take part. gp's were interviewed in their practice premises about how they dealt with vaccines fridges were examined and temperature recorded post interview. oral polio was taken from randomly selected fridges for potency testing. cold chain monitors and freeze watch indicators were used to monitor batches of vaccine stored. of the gp's, ( . %) agreed to participate, used fridges to store vaccine, store vaccine at room temperature. of the fridges, ( . %) had the power supply safeguarded, ( . %) had thermometers, ( . %) had vaccine only stored therein. during defrosting, vaccine was inadequately protected in ( . %). of the gp's who use multi-dose vaccine vials, ( . %) keep them for further use at the end of a day/session, store them at room temperature. ( . %) fridges had temperatures outside the recommended range. ( . %) coldchain monitors indicated vaccine exposed to more than ~ ( %) of the oral polio samples showed a reduction in total titre of live virus, however, none were below the minimum acceptable. this study indicates that vaccine potency could be seriously compromised due to breaks in the cold-chain and suggests the need for guidelines to be drawn up, implemented and monitored to ensure the integrity of immunisation schemes. comparison was made with a study carried out in . in addition the range of antimicrobial agents tested included new oral cephalsporins and quinolones that were not then available. three hundred microorganisms isolated from mid stream urine (msu) samples were examined by standard microbiological techniques. antimicrobial susceptibility testing to antimicrobial agents was performed on significant pathogens (> organisms per ml) by disc diffusion test, and minimum inhibitory concentrations of antibiotics was carried out by e test on organisms found resistant by disc testing. by comparison with resistance amongst e.coli, the most commonly isolated pathogen, had increased for the following: ampicillin by % to %, co amoxyclav by . % from %, trimethoprim by % to % and nitrofuradantin by % from %. no increase in resistance occurred to cephradine ( %), or nalidixic acid ( . %). resistance to cefixime, ofloxacin and ciprofloxacin, was %, no resistance was encountered to cefotaxime. for proteus species resistance to ofloxacin, ciprofloxacin and cefotaxime was %, and for enterobacter sp %. enterococci were sensitive to ampicillin and augmentin but the numbers were small. pathogens isolated from patients domiciled in the inner city were significantly more resistant to nalidixic acid ( %), cefotaxime ( %), cefixime ( %), ofloxacin and ciprofloxacin ( %) than those isolated from patients in rural areas. the purpose of this study is to examine the relative importance of obstetric complications ( c%) in the aetiology of schizophrenia and mania. using the dublin psychiatric case register, birth records of patients with an icd- diagnosis of schizophreniaor mania were obtained. these records were evaluated, for obstetric complications using two scales, the lewis, owen and murray scale (lom) it~ and the parnas scale . the mothers of those going on to develop schizophrenia did not differ from those going on to mania as regards maternal age, parity, social class, or period of pregnancy. however, males who developed schizophrenia when compared to males developing mania, experienced significantly more oc's when rated by the lom scale (p= . ) and.more frequent oc's on the parnas scale (p< . ) of greater severity (p= . ). no significant differences were found between females with schizophrenia and those with mania. dublin. the aim was to evaluate the diagnosis, symptomatology and level of functioning of patients presenting with a first episode of psychosis to a catchment area service and a private psychiatric hospital. all patients presenting with a first episode of psychosis were assessed using the scid-p,,the positive and negative syndrome scale (panss) and the global assessment of functioning scale (gaf). fifty-eight patients ( male, female) ranging in age from to years (mean + sd = . + . ) were included in the study. the mean total panss score was . (sd + . ) and was strongly correlated with the gaf score (p < . ) but independent of age (p = . ). males had a significantly lower gaf score compared to females (p = . ) but there was no gender difference in the total panss score (p = . ), twenty-five patients ( %) had a lifetime prevalence of drug abuse or dependence but only patients ( %) had signs of drug abuse or dependence in the month prior to presentation. level of functioning was strongly influenced by the severity of psychopathology. substance abuse is common in individuals presenting with a first episode of psychosis. the aim was to evaluate the presence of involuntary movements in patients presenting with first episode psychosis to a catchment area service and a private psychiatric hospital. patients presenting with first episode schizophrenia and schizophreniform psychosis were assessed for involuntary movements using the involuntary movements scale (a.i.m.s.). patients ( m., llf.), age range - years (mean= . years.) were included in the study. one patient ( . %) satisfied the strict criteria of schooter and kane for spontaneous dyskinesia. patients ( m., if.), had minimal involuntary movements in at least body areas, predominantly orofacial. the total a.i.m.s. score was positively correlated with the number of days spent in hospital per year of follow up (p= . ). the group with involuntary movements were found to have spent more days in hospital per year of follow up, v. days (p= . ). for patients with first episode schizophrenia or schizophreniform disorder spontaneous dyskinesia is not common. however involuntary movements at presentation may be a predictor of poorer outcome. psychiatry has moved from custodialcare towards care in the community. adequate reprovision will have to be made in order to discharge the remaining continuously hospitalized patients. the objectives of this study were to describe a.n entire long-stay hospital population, to examine the differences between the old and new long stay groups within this populatian and to evaluate the needs for community residential and day care facilities in order for hospital closure to take place. the study group consisted of the total long-stay population of st. davnet's hospital, monaghan. the patients were assessed using the community placement questionnaire (cpq) one hundred and twenty four patients were included in the study. fifty-six were female and % were single. the mean age of the total group was . years. the majority suffered from schizophrenia. the assessment revealed a globally disabled group with multiple handicaps. the new long-stay group were disabled as the old long-stay group. the patients were characterised into four groups with regard to placement recommendations. these were a specialist unit for chronically disturbed geriatrics, a geriatric unit, a high support hostel and a medium support hostel. the remaining population of this hospital were highly dependent with multiple handicaps but would live in community with adequate support. there is little difference between the needs of the old long-stay and those of the new long-stay. failure of the immune system to identify self peptides is likely to lead to the development of an autoimmune reaction. susceptibility to autoimmunity is strongly influenced by genes clustered in the hla region (chromosome p) particularly class i (a, b and c) and class ii (d, q and p). it has been suggested that there is an autoimmune component in the aetiology of schizophrenia. of many conflicting reports from case/control studies using hla antigens the most consistent finding has been an increased frequency of hla-a (now split into a /a ). additionally, a susceptibility locus for schizophrenia has been reported near the hla locus. to attempt to confirm the hla a hypothesis, we have genotyped a preliminary sample of familial schizophrenic probands and unrelated controls at the hla-a region, using a pcr-ssop technique. the frequency of hla-a (the major component of a ) in patients and controls respectively was . % vs . %. these findings do not support the hypothesis. some of the discrepancy may be due to unspecific cross-reactions produced by commercial antisera used in the microlymphocytotoxicity method of previous studies. however it is also possible that the hla associatton with schizophrenia may reflect linkage disequilibrium with unidentified gene(s) within the hla region which is less strong in the irish population. schizophrenia is a common mental disorder affecting about % of the general population with a devastating disturbance of mind and personality. family, twin and adoption studies have demonstrated that the disease is largely genetic with a polygenic mode of: transmission. dopamine receptors have been implicated in the aetiology of the disease. as yet dopamine genes have been identified (d -d ). in particular the d receptor is expressed in the limbic regions of the brain, implicated in the control of emotions. association studies of a d polymorphism (glycine to serine substitution at position ,) with schizophrenia have produced conflicting findings, many of which, however, have demonstrated a significant excess of homozygosity, or excess of the -l genotype at this polymorphism. in this study, familial schizophrenics and irish unrelated controls were genotyped. the result show a small increase in the frequency of the - genotype which did not attain statistical significance (patients, . % vs. controls, . %). homozygosity (alleles - and - ) was also slightly increased in the patients (patients, . % vs. controls, . %). the small increase in the frequency of the - genotype and of homozygosity in the patients is in keeping with earlier findings but suggests that the effect, if any, of d sequence variation in the development of the disease is small. lack of information about general practitioners' (gp's) ability to prescribe psychotropic medication may affect patients' compliance. in this study, out of patients attending a psychiatry out-patient clinic completed a questionnaire which documented how many had run out of medication, the steps taken if they had and the role each patient thought their gp played in their treatment. % indicated that their gp knew what their current medication was but only % thought that their gp could provide them with a prescription if they did not have one from the clinic. this figure was similar in those who had ( %) and had not ( %) run out of medication in the past. on running out of medication, % of patients waited until their next appointment, % attended their gp and the remainder either contacted the department or went to a chemist. in conclusion, many patients do not appreciate the entitlement of their gp's to prescribe psychotropics for them. literature regarding whether or not the social class distribution of patients with psychiatric illness may differ from the general population remains controversial. we sought to clarify this by examining social class at the time of birth, to see whether patients with serious psychiatric illnesses (schizophrenia and mania) differ from the general population. paternal occupation of schizophrenic patients, and manic patients, from the dublin psychiatric case register, were obtained from birth registration details and categorised according to central statistics office criteria, the same-sex previous live birth was used as a matched control. there was no difference between the social class of patients with schizophrenia or mania (p= . ). neither patients with schizophrenia (p=b. ) nor mania (p= . ) differed from controls in social class distribution. paternal social class was found to be related to amount of time spenr in hospital (p< . ', mean= . ), and educational age (p< . , mean= . ) and "age at onset of the illness" (p= . , mean= . ). these results suggest that social class of origin may not be related to the development of either schizophrenia or mania. however, social class of origin may be relevant in terms of presentation of schizophrenia for treatment. cognitive function is widely recognised to be impaired in schizophrenia but there is an ongoing debate as to whether this impairment is generalised or localised, progressive or static, similar in both sexes, or related to symptoms. using the positive and negative syndrome scale (panss)'we measured psychopathology in chronic in-patients ( m, f; mean age . + . ) who satisfied feighner criteria for schizophrenia. subsequent to this, we assessed their global cognitive function using the mini-mental state examination (mmse) and their frontal cognitive function using a new instrument, the executive interview (exit). poor performance on the exit was associated strongly with increasing severity of negative (r=- . , p< . ) but not positive (r=-- . , ns) symptoms,'in both males (r=-- . , p< . ) and females (r=-- . , p< . ). overall exit performance declined modestly with increasing age (r=-- . , p< . ) but this phenomenon was co'nfined to females (r=-- . , p< . ; males: r=-- . , ns). mmse performance was also associated with negative symptoms (r=-- . , p< . ) but decreased mm:e prominently with age (r=-- . , p< . ) and showed no gender difference. frontal dysfunction in schizophrenia appears to be intimately related to negative symptoms over the course of severe chronic illness, and may reflect among males a more static' trait deficit than is accessed by the mmse. this study was supported by the stanley foundation. while determinants of the course of schizophrenia are unclear, emerging evidence suggests that the longer psychosis proceeds unchecked before initiation of anti-psychotic therapy, the poorer may be long-term outcome. we have reported that, among older in-patients, increasing duration of initially untreated psychosis in the pre-neuroleptic era was associated with a deterioration to a state of muteness (after controlling for intervening variables). the current survivors of this population have now been examined more extensively using the positive and negative syndrome scale (panss), the mini-mental state examination (mmse) and the executive interview (exit). among these patients (mean age . + . ), after controlling for age and for the duration and continuity of subsequent antipsychotic treatment, increasing duration of initially untreated psychosis was associated with greater severity of negative symptoms (p< . ) and with lower scores on the mmse (p< . ) but not with executive dysfunction on the exit (p= . ). increasing duration of initially untreated psychosis appears to be associated with the evolution of more prominent negative symptoms and cognitive impairment in a manner consistent with an active, morbid process in schizophrenia that can be ameliorated by anti-psychotic drugs. this study was supported by the stanley foundation and the health research board. patients who are selected and who agree to participate in the royal college examinations play an important role. as psychiatrists and exam organisers, we should be aware of the potentially stressful experience which this might present. the purpose of our study was to elicit attitudes to the exam, and also knowledge of the examination procedure. a questionnaire comprising questions was circulated to patients who had participated in the royal college examinations. responses were received from ( %) of the patients. there were males and females in the responding group. none of the patients had previously participated in the examinations. all of the respondents (n= ) felt that the candidate had been polite towards them during the interview. % (n= ) of the patients were nervous prior to the examination, and this group was predominantly female (n= ). % of the patients (n= ) did not know that they would receive payment for their participation. % (n=l ) did not know that they might be physically examined as part of the examination procedure. % (n= ) of the patients described experiences which had been upsetting for them the results of our study suggest that on the whole patients tolerate the exam procedure quite well. one of the central issues concerning physiotherapists in stroke rehabilitation is the emergence of abnormal tone. rehabilitation involves re-establishing a normal postural control mechanism (ncpm)"~. abnormal tone may develop in the presence of severe sensory and proprioceptive loss. the patients' attempts to move and find a stable base can lead to compensatory movement patterns and asymmetrical postures. positioning is used by physiotherapists to influence the distribution of muscle tone and facilitate symmetrical postures. it is essential that the patient is made aware of his 'position in space' as failure to do so presents no feedback regarding movement resulting in inertia ~ ~. standardised positioning charts have been used in hospitals. the physiotherapist liaises with nursing staff regarding correct use on a hour basis. this study looked at the role of a more individualised approach to positioning in the form of a photograph. patients were randomised to two positioning groups group a standard vs group b photograph, and their positioning was scored by a 'blinded' research physiotherapist over an eight week period. the results of a pilot study on a small number of patients revealed that nursing staff preferred a positioning chart individually tailored to the patient's problems. from a physiotherapy perspective, improved postural awareness correlated with better positioning scores in group b. the prevention of compensatory movements, posture is critical in stroke rehabilitation, the use of an individualised positioning chart requires further evaluation. we discuss the case of a fourteen year old boy who presented with bilateral ptosis present since birth, microcephaly and pigmentory retinopathy"!. he was found to have mild facial and proximal limb weakness. creatinine kinase and ldh were raised. muscle biopsy showed ragged red fibres consistent with a mitochondrial myopathy ~ ~. electron microscopy showed abnormal mitochondria. the term mitochondrial myopathy describes a diverse range of clinical disease ~ ~ and this is discussed. she developed a vasculitic skin rash with pruritis and oedema associated adenopathy, low grade fever and mouth ulcers. lab tests showed leucocytosis, eosinophilia and abnormal liver function. skin biopsy indicated an inflammatory picture without vasculitis. ct thorax confirmed axillary and para-aortic adenopathy. lymph node biopsy confirmed a reactive lymphadenopathy. the aim of. this study was to assess the characteristics of patients referred for pudendal nerve studies over a one year period. consecutive patients were asked a standard questionnaire and nerve studies were performed as described by kiff and swash m and swash and snook~ k of the patients, only were male. the age range was from to (mean ). presented with constipation and with faecal incontinence. two had both symptoms. bladder incontinence was presented in of patients. of these, faecal incontinence was the cardinal symptom in patients, constipation in . patients were nulliparous. of the remaining , had a history of complicated births involving forceps ( ), caesarean section ( ), post partum haemorrhage ( ), breech without forceps ( ) . patients had pelvic surgery and one had major trauma. of patients had bilaterally delayed pudental nerve terminal motor latency (pntml). of people had unilaterally delayed pntml, were right sided, were left sided. had normal studi~s. the range of measurements was . - . ms with a mean of . ms. in conclusionl delayed pntml was seen in of patients with constipation and of with faecal incontinence. pelvic surgery and a complicated obstetric history were significant. urological symptoms were also a common association. the p component of the middle latency-auditory evoked potential is attenuated in response to the second of paired clicks in a normal population. in schizophrenia, this attenuation is minimal. in alzheimer's disease (ad), the results have varied between centres depending on the frequency of the stimuli and the interclick interval. we studied ad patients, elderly controls (ec) and young controls (yc) using a paradigm of sets of paired clicks. in contrast to previous studies, our study demonstrates significantly larger absolute p generation and recovery amplitudes in ad patients compared to elderly controls and young controls. the purpose of study was to establish a simple screening vol. , irish journal of supplement no. medical science test to identify asymptomatic intracranial aneurysms (icas). an association between atherosclerosis and icas is recognised. elevated serum lipoprotein (a) [lp(a)] is an independent risk factor for atherogenesis. we aimed to assess the degree of correlation between serum lp(a) and the occurrence of sporadic ruptured aneurysms and familial asymptomatic aneurysms. lp(a) levels were measured in (a) patients with icas and normal controls, (b) first degree relatives of patients with familial subarachnoid haemorrhage (sah). icas were detected by cerebral angiography. patients with sporadic icas had significantly elevated lp(a) levels when compared with matched controls. mean level was . mg/dl in patients and . mg/dl in controls. in the familial studies, out of i subjects with asymptomatic icas had elevated lp(a) levels. one young female with elevated lp(a) had a pre-aneurysmal dilatation at operation. six out of subjects without icas had elevated lp(a) levels; four of these were in the second or third decade of life and may yet develop aneurysms. conclusions: lp(a) has potential as a biological marker for icas. follow-up studies are required on angiographically negative subjects. we have begun a genetic case-control study to establish if particular apoprotein (a) gene polymorphisms can be correlated with the occurrence of icas. post mastectomy breast reconstruction has undergone several changes in the recent years. attitudes have changed towards the problem from both the patient and the reconstructive surgeon, as aesthetic outcome receives a greater emphasis than previously. there is a shift towards using autologous tissue as a means of reconstruction; these new technically difficult procedures entail a longer learning. centralization of this type of reconstruction in highly specialized centres only will serve the patient better. we share our experience of post mastectomy breast reconstruction spread out over the past five years. seventy-eight consecutive cases of breast reconstruction are included in the study. different techniques of breast reconstruction were used with a recent switch to transverse rectus abdominis myocutaneous (tram) flap; we feet that tram flap is the gold standard of breast reconstruction as far as the ultimate cosmetic result is concerned. ours is only a moderate sized study compared to some published, yet it is representative of the experience of most of the plastic surgery units in the british isles. clinically significant paraneoplastic neurologicaldisorders are rare, most are associated with small cell lung, female genital tract and breast carcinoma. the malignancy is often silent and the neurological manifestations vary from encephalomyelitis, cerebellar degeneration, sensory neuropathy to neuromuscular block. prognosis is usually poor. pathogenesis is thought to be related to cross reaction with neurons of antibody produced to tumour antigens. detection of these antineuronal antibodies in serum has assisted diagnosis of paraneoplastic encephalomyelitis in which anti-hu antibodies are present and cerebellar degeneration, in which anti-yo are found. in our lab, we used avidin-biotin-complex immunocytochemistry to detect anti-hu (cortical neuron antibodies) and anti-yo (purkinje cell antibodies) in patients' sera. tests were performed on human frontal cortex and cerebellum, at in and in , dilutions, with positive and negative controls. of sera, were positive. two patients had repeat positives; in one, antibody titre rose in the second sample. subsequent patient review showed positives ( patients) had identifiable carcinoma with paraneoplastic cns signs, had no identifiable malignancy but had no other cause of their cns disorder and are being followed up; details of one patient were unavailable. these results are similar to other centres. the proliferation of tumour cells despite the presence of tumouricidal mediators could be due induction of a heat shock response, a universal cellular defence mechanism in host cells and possibly tumour cells. protection may be mediated either by increasing intracellular levels or surface expression of heat shock proteins (hsp). the aim was to assess the effect of heat shock induction on tumour cell protection against host effector cells. the heat shock response was induced in sw colorectal cells by either sodium arsenite ( - ~tm for hr) or by hyperthermia ( ~ for rain). monocyte (m )-mediated cytotoxicity or flow cytometry to evaluate surface expression of hsp and hsp were assessed. cytotoxicity showed a significant decrease in all treated groups (p< . ) when compared to the control value. there was also a significant decrease in all groups (p< . ) when compared to the ~ value. no significant alteration in surface expression of either hsp or hsp was seen. conclusion: heat shocking tumour cells significantly protects them from m -mediated tumour cell lysis. since the flow cytometric data indicate that there is no concomitant increase in surface expression of hsp and hsp on the tumour cell following heat shock, it can be inferred that induction of intracellular hsp levels are responsible for the protective effect on the tumour cells. a week qol study in consecutive advanced cancer patients was undertaken to compare the subjective question fact-g with simple subjective global tools (visual analog, categorical scales: vas, cas), objective tools (spitzer qli and ecog performance status) and verbatim patient description. we anticipated the high drop out rate enrolling to achieve complete study patients for statistical purposes. the study sample appeared representative of the advanced cancer population in the usa. generally qol was satisfactory despite the severity of illness. there were significant differences in all measures between those who described qol in verbatim responses as positive and negative, particularly cas, vas, and qli (p< . ). there were significant intercorrelations between qli and ps (observer rated), vas and cas (subject rated) respectively (p< . ). taking patient description as the gold standard, simple, global qol measures e.g. vas or cas are as effective as multidimensional ones (fact-g and qli). irish journal of medical science males had more dysphagia. survival from diagnosis was greater for females </= years (female median months, male median months, p< . ). anorexia was associated with reduced survival since diagnosis in the total population and in males. anorexia anddysphagia were associated with reduced survival from referral. advanced cancer patients were polysymptomatic. symptom prevalence differed with age, gender and cancer site. the pattern of g symptoms was related to gender and severe weight loss. specific symptoms were associated with reduced survival. there was a gender difference in survival favoring females. the administration of recombinant interleukin- (rll- ) is limited by the induction of increased microvascular permeability. the in vivo antineoplastic effects of taurine in combination with rll- were investigated and its impact on the associated vascular leak was examined. lung metastases were established in mice via tail vein injection. ten days after injection mice were randomized into treatment groups. on day the mice were sacrificed; lungs were removed, weighed and metastases counted. treatment of tumour-bearing mice with rll- alone resulted in a significant reduction in tumour nodule incidence compared to a control group, while the~group recei'~ing rll- + taurine showed an even fuither reduction in the incidence of lung nodules. animals receiving rll- showed a significant increase in mean wet lung weight compared to control lung weight, while mean wet lung weight of the rll- + taurine group was significantly less than that of the rll- group.and comparable to control values. animals receiving ril- + taurine in vivo demonstrated significantly enhanced splenocyte-mediated antimelanoma activity ex vivo compared to animals receiving rll- alone. thus taurine may have an important role in modulating both metastatic growth and the associated toxicity of rll- immunotherapy. a prospective analysis of symptoms in , patients on initial referral to the palliative care service of the cleveland clinic was made using the paradox relational database. the median number of symptoms per patient was (range - ). the most frequent symptoms were pain %, easy fatigue %, weakness %. anorexia %, > % weight loss %, lack of energy %, dry mouth %,'eonstipation %, dyspnea % and early satiety %. patients years and under had more pain, sleep problems, depression, anxiety, vomiting and headache (all p< . ).'the prevalence of early satiety, nausea, vomiting and anxiety were greater in females; dysphagia nd hoarseness in males. patients with >/= % weight loss had more gi symptoms; of these females had more nausea, early satiety; the progn.o'stic significance of abnormalities in the p tumour suppressor gene and in the expression of its protein in colorectal carcinoma may be influenced by the method of analysis used. we studied p abnormalities in patients with colorectal cancer followed for more than years. single-strand conformation polymorphism analysis (sscp) was used to detect alterations in exons - of the p gene. paraffin sections were examined immunohistochemically for p overe,xpression with the monoclonal antibody do- (dako) both with and without microwave antigen retrieval. abnormalities of the p gene were found in % of cases by sscp analysis but were unrelated to age, sex, tumour size or differentiation. outcome was unrelated to sscp abnormalities (p= . ). overexpression of p protein was seen in % of cases by immunohistochemistry without microwave antigen retrieval and in % of cases with microwaving. poor long-term survival was related to immunohistochemical expression of p protein either with (p= . ) or without (p= . ) microwave antigen retrieval. these results suggest that immunohistochemical detection of the p protein product may be more useful than sscp analysis of the encoding p gene in identifying those at high risk of colorectal cancer recurrence and death. dublin . the anti-tumour activity of tumour infiltrating lymphocytes (tils) is known to be poor and therapeutic manipulation of these cells has met with little success. suppressor macrophages (smo) influence t cell cytotoxicity and proliferation. we hypothesized that smo are a component of the lymphoreticular infiltrate and that these cells may be related to lymphocyte numbers within the tumour. tgf-b may influence macrophage phenotype. colorectal and breast tumours were obtained within an hour of resection. tumours were dissaggregated with collagenase and dnase for three hours. antibodies was used to identify smo (rfd and rfd ) and t cell subsets (cd and cd ) by flow cytometry on the resulting cell suspension. pre-op blood was collected from patients and tgf-b levelsdetermined by elisa. conclusions: we have shown for the first time that smo, defined by the antibodies rfd and rfd , are present within breast tumours. we have also shown that the balance of t cell subsets is different in these tumours and may be related to smo content. circulating tgf-b levels are increased in breast cancer and associated with greater smo numbers. this was not found to be the case in colorectal cancers. these results imply the existence of a fundamental difference in the make-up of the lymphoreticular infiltrate between these cancers. swelling of the upper limb is an uncommon but well irish journal of medical science recognised complication of breast cancer treatment. in severe cases, patients have limited arm function and feel disfigured. in a pilot study, the incidence of arm swelling following complete axillary clearance in the immediate post-operative period and at long term follow-up was investigated. arm volume measurements were performed using an opto-electronic volometer (bosl medizintechnick, hamburg). both ipsilateral and contralateral arm volumes were assessed. the expected volume of the ipsilateral arm volume was calculated using the formula vr = v = mls for right handed people and v = vr = mls for left handed people (vr and v = volume of the right and left arms respectively). the difference between the expected and actual volume of the ipsilateral arm was expressed as a percentage of the expected volume. twelve patients undergoing axillary clearance for breast cancer were prospectively evaluated pre-operatively, hours and days post-operatively. a second group of patients who had had axillary clearance at least months previously (range to months) were also evaluated. there was no significant change in arm volume in the immediate post operative period. clinically detectable arm welling was found on patients who had undergone axillary clearance at least months previously but none had any impairment of arm function. we conclude that axillary clearance can be performed safely and that arm swelling is an uncommon complication. a larger study is planned to investigate factors such as the influence of pectoralis minor division, duration of the operation and the number of axillary nodes retrieved on upper limb volume. epidermal growth factor (egf) is a potent mitogen and has been shown to accelerate healing of epithelial damage both in the skin an.d the gut. in the skin egf is not produced locally as the requisite mrna is not present but egf receptors are present on the surface of basal keratinocytes. egf is produced in various sites in the gi tract including the submandibular salivary glands. we have hypothesised that as there is upregulation of salivary egf production in some enteropathies a similar situation may occur in disorders of the skin with an associated enteropathy. using a sensitive radio-immunoassay, egf activity was estimated in stimulated saliva from patients with various skin disorders, patients with gastrointestinal disease, patients with mixed dermatological and gut disease and normal healthy volunteer controls. elevated egf activity was found in the following groups of patients : skin cancers, psoriasis, acne, oesophagitis and ulcerative colitis. the hypothesis of up-regulation of salivary egf production in skin associated enteropathy was rejected but the discovery of elevated egf activity in skin cancers and psoriasis may have aetiological and therapeutic implications. the malignant fibrous histiocytoma (mfh) is considered an uncommon malignancy. its potential for invasion, metastasis and death of patient has been reported in literature. it can be confused with other tumours including fibrosarcoma. salient histologic features include cells of both the fibrocytic and histiocytic series. mfh with its high recurrence rate and lethal potential merits an aggressive evaluation and treatment. we present unusual case of recurrent mfh treated in our unit with an open question as to what qualifies to be adequate primary surgical excision. the recommended management of localised merkel cell carcinoma has been wide surgical excision, combined with adjuvant radiotherapy in selected cases. the risk of recurrent regional disease is reported to be between % and %. a year old woman with merkel cell tumour on the cheek is presented; this patient was treated exclusively with radiotherapy to a total dose of gy over days. the tumour regressed rapidly during the treatment, and there were no signs of local or regional recurrence. the patient is still alive and free of disease for months. immune in origin with a heightened cutaneous immune response to ultraviolet light. the coexistence of cad and pbc is a new association which has not previously been documented and may not be fortuitous given the similar pathogenesis of both diseases. chronic actinic dermatitis (cad) is a rare photosensitive disorder which primarily affects elderly men resulting in an eczematous reaction to ultraviolet-radiation and sometimes visible light. the pathogenesis has been attributed to an autoimmune process, possibly in response to a photoallergen which has yet not been identified. we report a year old female patient who developed cad four years after being diagnosed with primary biliary cirrhosis (pbc). abnormal monochromator irradiation tests were detected with narrow band ubv, uva and in addition visible light wavelengths. phot provocation tests induced florid vesicular eczema and multiple patch and photo-patch tests were positive, findings typical of cad. immunoglobulin g was elevated at mg/dl and liver histology was typical of pbc with an elevated anti-mitochondrial antibody. routine biochemical and immunological tests were ~ormal and porphyrin screen was negative. azathioprine mg/day induced remission of cad. pbc is an auto-immune disorder where cell-mediated immunity is impaired, suggesting that sensitized t lymphocytes may cause damage to bile ducts. the pathogenesis of cad may be auto- we present two cases of cutaneous polyarteritis nodosa (pan) associated with seronegative arthritis: the first patient, a year old male presented in complaining of a year history of pain, stiffness and swelling affecting his right ankle. he also noted intermittent tender nodules on the dorsum of his foot and over his ankle over the preceding three years. the second patient, a year old male, presented .in complaining of a month history of tender nodules on his shins, and pain and swelling of his right ankle. skin biopsies of the nodules in both cases showed medium vessel vasculitis consistent with polyarteritis nodosa. neither patient had any symptoms or signs to suggest systemic involvement. the only abnormality. n laboratory investigations for vasculitis was elevated esr. x-rays showed periosteal elevation and new bone formation in case , and were normal in case. . bone scan demonstrated increased uptake at the talo-navicular joint in case and at the fight ankle in case . synovial biopsy and mri confirmed the presence of an inflammatory arthropathy in patient . joint involvement has been a prominent feature throughout the course in both cases requiring aggressive treatment with vol. , irish journal of supplement no. medical science cyclophosphamide and systemic corticosteroids in case . cutaneous pan is a localised cutaneous vascular disorder with a benign chronic relapsing course. in one reviewl, of patients had arthralgias but an association with arthritis has not been emphasized in the literature to date. we conclude that this condition may present as a seronegative arthropathy in which the joint symptoms may be the most prominent feature and aggressive immunosuppresive therapy may be required for control. cardiac transplantation patients have an increased risk of skin disease. in our centre, heart transplants were performed with a year survival of %. eighty three patients are now alive and have required dermatological assessment. the mean age of patient was . years, (range - years); males, females. skin infections were diagnosed in of patients. drug side effects, including sebaceous hyperplasia and steroid acne, were common. in the patients who developed skin cancer, mean time from transplant to development of lesions was . years. eleven of patients had non melanoma skin cancers (nmsc), squamous cell carcinomas (scc), basal cell carcinomas (bcc), giving scc/bcc ratio of : . three of patients had multiple skin cancers, one had tumours. nine of patients had actinic keratoses, two thirds of whom had sccs. nineteen of patients had viral warts, two of whom had sccs. viral warts, premalignant and malignant lesions were located on sun exposed sites. skin complications of cardiac transplantation though mild were very common. the observed incidence of nmsc in age matched cardiac transplant recipients, appears much higher than the expected incidence of . per , population (national tumour registry ). regular dermatological assessment of cardiac transplant patients is necessary to detect skin disease and early skin cancer. the increased incidence of warts and skin cancer in renal transplant recipients {rtr} is well known. the oncogenic potential of unusual human papilloma virus {hpv} types has been postulated from warts and in both premalignant and nonmelanoma skin cancer (nmsc). the possible etiological role of sun-exposure in facilitating the development of hpv associated skin disorders is also suggested. a clinical study to assess the risk factors for development of these lesions in rtr attending the dermatology servic& age and sex matched haemodialysis patients were similarly examined as controls. male and female patients with a mean duration of transplant of . years, range to years. a total of nmsc (range to ), scc and bcc, ratio . : , were excised from rtr of which over % had viral warts, mosle commonly occurring on sun exposed sites and always predated the development of neoplastic lesions. both were associated with mean duration from transplantation, years for warts and . for skin cancer and not the type of immunosuppressive treatment. none of the control patients had similar findings. conclusions: the close clinical association of viral wart lesions and development of skin cancer in these patients suggests a close relationship to immunosuppression, in addition to exposure to ultraviolet radiation. this study highlights the high rate of nmsc in rtr. these patients justify early and regular skin assessments soon after transplantation with advice on sun protection. sensitivity to ultraviolet (uv) light may be established by exposure to broad band uva and uvb radiation. the minimal erythema dose (med) can be determined at individual wavelengths using a monochromator. uv action spectra of photosensitive disorders may thus be constructed. we examine the value of this process in distinguishing two clinically similar photosensitive disorders. the radiation from a xenon arc is separated into component wavelengths using the monochromator. each wavelength is focused on unaffected skin, on the patient's back. the patient is exposed to a range of doses of w radiation. the med is determined for a series of wavelengths from to nm. chronic actinic dermatitis (cad) and drug induced photosensitivity are photosensitive disorders which may have similar clinical history and presentation. ten cad and drug induced photosensitivity patients were tested. uva photosensitivity was seen in % of the latter group. the remaining % had normal mlts as the implicated drug had been discontinued prior to testing. cad patients were sensitive to both wa and wb radiation. forty-three percent of these patients were also sensitive to visible light ( to nm). monochromator light test (mlt) results show that uva photosensitivity dissociated from wb photosensitivity is indicative of a drug induced light sensitive disorder. sensitivity to both wa and wb however indicates a diagnosis of cad. mlts can therefore distinguish between clinically similar photosensitive disorders. bartholomew's hospitals, london. patients with mpd have an increased incidence of both thrombosis and haemorrhage suggesting a pivotal role for; platelets in these conditions. this study aimed to examine platelet activation antigen expression in stable patients with mpd and to examine the predictive value of these antigens prospectively. patients with mpd had p selectin and gp measured using a refined minimally manipulative flow cytometric technique. expression of p selectin -median . % (inter quartile range . - . ), control . % ( . .- . ) and gp -median . % ( . - . ), control- . % ( . - . ), were significantly elevated p< . . patients were followed for a median of months. % experienced thrombosis and % bleeding during follow up. at entry to the study % of patients had previously experienced thrombosis, median disease duration deaths, of which were caused by thrombotic events in which the mpd was a major risk factor. increased expression of p selectin or gp expression failed to predict thrombosis or bleeding in this study. nor was any significant retrospective relationship demonstrated. however, previous thrombotic events were strongly associated with future events (p< . ). this association was independent of disease, duration, age and medication. not surprisingly disease duration was also correlated with thrombotic/bleeding events. taurine levels fall in gut mucosal cells during critical illness. however, taurine transport into human intestinal cells is poorly understood. the aim was to establish the efficiency of taurine uptake by enterocytes, and to examine uptake under stressful conditions. to investigate efficiency of taurine uptake, confluent caco- cells were incubated for time points up to h. in a second study, cells were incubated for h with medium containing dexamethasone and / or cytokines. media for both studies was supplemented with [ h]-taurine. radioactivity was related to mg/ml protein to calculate rate of taurine uptake for each time point. study : uptake exhibited a steady linear response which approached saturation at h. maximal uptake occurred at h after which the rate levelled off. study : dexamethasone alone reduced taurine uptake by . % (p< . ) and in combination with tnf-c~ and ifn ~/ it decreased transport by . %. (p< . ). lps alone impaired uptake by % (p< . ). conclusion: we have established the time course over which taurine transport reaches its maximum rate in caco- cells, and that corticosteroids and cytokines significantly impair uptake of taurine in these cells. elderly individuals have an increased risk of infection suggesting that immune responsiveness is altered with age. changes in the level of proinflammatory cytokine production may be an important indication of any such age related change. using flow cytometry we examined intracellular tnfet, il-lf~ and il- in pbmcs from normal healthy volunteers of different ages ranging from up to yr (n= ). tnf and il levels from pma stimulated cd positive cells (t cells) were shown, using this technique, to increase in an age dependent manner (p< . ). no il- was detected in any t cell sample. no significant differences were observed between the different age groups for tnfa, il- g or il- in cd + cells (monocytes). the age related changes detected by flow cytometry have been confirmed using conventional elisas. this novel method of proinflammatory cytokine detection has detected increased tnf and il levels in t cells from elderly healthy volunteers which may help explain some of the exaggerated inflammatory responses seen in elderly patients. detection of proinflammatory cytokines by conventional elisa or bioassay is problematic due to the presence of naturally occurring biological inhibitors. flow cytometry allows the simultaneous detection of both intra and extracellular antigens thus intracellular cytokine levels can be quantified while cell surface markers allow cell type identification. a range of monoclonal antibodies were examined for tnfcx, il-lg and il- using saponin permeabilisation oft cells (cd ), monocytes (cd ) and epithelial cells (ber-ep ). t cells and monocytes were grown in ~culture, t~p :to hr with or without pma activation, and intracellular cytokine levels were shown to increase with time, with the stimulated samples producing more cytol<ine than the spontaneous.samples (p< . ). elisas performed on these same samples (n--: ) correlated well with the flow cytometric results (r= . ). tnf~x, il- and il- are detectable !n monocytes while only tnfa and il- have been detected in tcells and epithelial cells using this methodology. this novel technique will allow us to identify the cytokine producing cell while also avoiding the influence of the extracellular millieu, thus being useful for a number of research and diagnostic applications. all the viral hepatitides are said to be common in the middle east. hepatitis a viru s (hav) seroprevalence is said to be % in the adult population of gulf countries. hepatitis b, c and d seroprevalence are taken from blood banks data which are biased by selection criteria and the background of blood donors. very little is known about hev in the uae. vol. , supplement no. irish journal of medical science the aim was to investigate the seroprevalence of hav, hbv, hcv, hdv & hev in the uae. we prospectively recruited volunteers drawn from all the uae, socioeconomic classes and from different age groups in both sexes. each donated ml. of venous blood and using an indirect enzyme immunoassay were tested for total ig to hav; hbsag using monoclonal antibody t.o hbsag; for hcv antibodies using recombinant antigens hc- , hc- , c- and ns- , ( rd generations); for total ig to hdv and for total ig to hev. positive samples were retested in duplicate for confirmation. this large sero-epidemiological study clearly shows that hav is decreasing in the uae. hbv is low but significant, hcv is similar to southern european countries, hev is lower than expected and hdv does not exist in hbsag carriers in the uae. reactive oxygen and nitrogen species produced by inflammatory cells plays a role in tissue injury and inflammation. taurine, a bamino acid present in high concentrations in leukocytes functions as an anti-oxidant by scavenging the mpo derived oxidant, hypochlorous acid, to form taurinechloramine. experimental colitis was induced in male sprague-dawley rats and randomised into two groups. one group received tap water whilst the second group was supplemented with taurine ( %). these groups were sub-divided into those receiving tnbs/ ethanol (n= ) or saline (n= ). an increase in wcc count, particularly neutrophils was found in colitis. tat~rine was found to reduce the severity of the disease (ns) usin.g a colon macroscopic score. in the first group, respiratory burst activity was reduced in animals that had developed colitis (p< . ) although mpo activity was augmented (p< . ). nitric oxide production was . and . fold respectively higher in inflamed and non-inflamed areas of the colon than that by normal colonic mucosa. animals supplemented with taurine demonstrated attenuated m po activity (p= . ). administration of taurine did not lead to a reduction in nitric oxide production. thus, taurine appears to have a beneficial role in reducing the severity of disease. a reduction in mpo and respiratory burst may be beneficial in reducing tissue damage. to women subsequently identified by a national screening programme which revealed to be positive for rna of hepatitis c, type lb. were referred to this centre for evaluation. had moderate activity by modified knodell index, mean (_+ . ), bridging fibrosis and a mean alt of ( - ). six months dual therapy was administered. two patients withdrew due to depression ( ) and hyperthyroidism ( ). one patient di d not respond. seven responded with normalisation of alt and negative pcr. eight patients showed improved histology (kai +_ . ), fibrosis was unchanged. adverse reactions in the treated group included marrow suppression ( ) and thyrotoxicosis ( ) . at six months follow up four remain in remission with normal alt negative pcr, three have relapsed, (pcr positive, mean alt ( - ). we conclude that despite adverse prognostic indicators in this homogenous group with chronic hepatitis c, lb and long disease duration, dual therapy with interferon and ribavirin achieved results comparable to prolonged high dose interferon in patients with more favourable initial prognoses. the aim of the study is to evaluate a day course of azithromycin in combination with omeprazole in eradication of h.pylori. twenty-four patients with proved h.pylori infection and peptic ulcer disease were treated with omeprazole mg daily for months plus azithromycin mg daily for days. h.pylori was diagnosed on the basis of clo test and histology. this was done at the beginning and months after the treatment. eradication was defined as negative clo test as well as negative histology. out of patients, patients were lost to follow-up. only patients were analysed. sixteen patients responded to treatment and had successful eradication as well as healing of their ulcers. these included patients with gastric ulcers ( . %), patients with duodenal ulcers, patients with gastric and duodenal ulcers and patients with non-ulcer dyspepsia. five patients did not respond including with non-ulcerative dyspepsia. duodenal ulcers and gastric ulcer. however their ulcers have healed and symptoms relieved and they were treated with other h.pylori eradication regimes. conclusion. in this small study we have shown that azithromycin mg oncedaily for days is an alternative safe effective and well tolerated monotherapy for eradication of h.pylori. it has been suggested that hepatitis c virus (hcv) infection is associated with a high prevalence of autoimmune disease, but that this risk may be diminished in patients who received a low viral load at initial infection. the aim was to determine the prevalence of symptoms, signs and markers of autoimmune disease in a group of women vol. , irish journal of supplement no, medical science infected with hcv contaminated anti-d immunoglobulin. patients, mean age . years (range - yrs) were examined. patients ( %) were rheumatoid factor positive. ana was positive in patients ( %) but titres were / in / . thyroid globulin antibodies were found in patients ( %) with also being tm positive. further patients were positive for thyroid microsomal ab. prevalence of apa, ara, sm were %, % and % respectively. one patient had cryoglobulins detected while antibodies against mitochondria and lkm-i were not found only one patient of was symptomatic. these levels of antibodies are no greater than levels in the general population and similar to other groups infected with hcv contaminated anti-d. these results further support the hypothesis that either low viral innoculum or long duration of infection may in some way result in a low level of autoimmunity. a previous study (ilan et al, arch int. med., ; : - ) suggested that lga deficiency disposes towards hepatitis c virus (hcv) infection in some patients. it has also been suggested.that iga deficiency may occur as a result of the viral infection as a secondary event. the aim was to determine the prevalence of selective and partial lga deficiency in patients with hcv infection using a radio-immunodiffusion technique. serum lgg and igm levels were also examined. immunoglobulin levels were measured in patients, women and men, mean age . years (range - years) infected with blood between and . none of the patients were found to have selective or partial iga deficiency. mean iga = . g/l (range . g. - . g/l). furthermore no patient exhibited deficiency of igg or igm. conclusion : no evidence of iga or other immunoglobulin deficiency exists among this group of patients with hcv infection. while it may be possible that lga levels decrease following infection, no evidence exists that this phenomenon persists in the long term. hereditary non-polyposis colorectal cancer (hnpcc) is the most common form of hereditary colon cancer and accounts for up to % of the overall cancer incidence. the disease is inherited in an autosomal dominant manner andis characterised by predominantly right-sided tumours. hnpcc is caused by mutations in one of four mismatch repair genes. these genes are homologues of the bacterial mismatch repair systerfi and their function is to detect and correct defects in dna. the hmsh gene is reported to account for up to % of cases, hmlhi, hpms and hpms account for %, % and % of cases respectively. we have collected eighteen irish hnpcc families which satisfy the amsterdam criteria for the disease. we have screened the entire hmsh gene in eight of these families. a combination of single strand conformational analysis (sscp) followed by dideoxy sequencing was used to detect defects in the dna. sequence analysis revealed the presence of a novel polymorphismin exon in one family and a possible splice site mutation in the remaining ten families, using a novel mutation detection technique. departments of medicine and immunology, university college hospital, galway. serial iga gliadin antibody (igaga) studies are used as a surrogate for repeated small intestinal biopsy to monitor dietary compliance in treated coeliac patients. we have correlated igaga levels with indices of hyposplenism (platelets and erythrocyte "pits") to determine if either index can be used to monitor adherence to a gluten free diet. the study population of biopsy proven coeliacs was stratified according to dietary status into gluten free diet (groups a) and normal diet (group b). the iga gliadin antibody titres were significantly lower in group a than group b ( . : units p = . ). in group a gliadin antibody titres showed a statistically significant correlation with both platelet (p = . ) and pits count (p -- . ) ; in group b gliadin antibody titres correlated with platelet counts only (p - . ). those ona gluten free diet were further subdivided according t ~ reported degree of adherence to the diet (strict diet -sgfd, lax'diet -lgfd). significantly higher gliadin antibody titres were found in lgfd than sgfd ( . ; . p = . ), but the ptatelet and.pit counts were similar in the two groups. igaga is superior to platelet or pit coums in monitoring dietary'compliance in coeliac disease. hospital, galway. iga endomysial antibodies (igaea) are said to be more specific and sensitive indicators of coeliac disease than iga gliadin antibodies (igaga). initially the igaea substrate was monkey oesophagus and more recently umbilical cord. a new commercial product has becomeavailable using primate smooth muscle (accu track -diagnostic slides). we have undertaken a preliminary study to compare the performance of this lgaea assay and igaga elisa in treated and untreated coeliacs, coeliac relatives and controls. the study population consisted of biopsy-proven coeliacs who were stratified according to "reported" dietary status into good gluten free diet (group a), poor gluten free diet (group b) normal diet (group c) and unaffected coeliac relatives (group d) and controls (group e). elevated igaga (> units) were found in the following groups : a %, b %, c %, d %. igaea were positive in a %, b %, c %. with respect to igaga positivity, there were false positive igaeaa %, b . %, c % and false negative -a %, b %, c %, d %. in this preliminary study in untreated coeliac patients the performance of the igaea test was on a par with the igaga assay. alt and fibrosis may be associated with a non-alcohol steatohepatitis and these processes may be synergistic. finally, number and type of riba bands is not a predictor of inflammatory activity. ~stepping hill hospital, stockport, uk sk je. royal oldham hospital, rochdale rd., oldham ol jh. we investigated upper gut bleeding in patients aged years and over. a proforma addressing demography, drug therapy, clinical status, timing of endoscopy / surgery, and outcome was used. consecutive patients (median age years, range - ) were studied over months. ( %) underwent gastroscopy with a % diagnostic yield. patients had severe oesophagitis, had oesophageal malignancy, had gastric ulcers - of which are malignant and had duodenal ulcers. ulcerogenic drugs were implicated in patients. patients were referred for surgery, operated upon with one postoperative death. had haemoglobins of g/dl or less. all malignant lesions were inoperable. the overall mortality was % reducing to % if neoplasla were excluded. co-morbidity influenced mortality. patients were discharged with a median hospital stay of days. information on cause of bleeding greatly influenced management. the prognosis of gut haemorrhage in the very old need not be so poor. a few require surgery but the majority respond to active medical resuscitation which is a key factor in determining outcome. we advocate low threshold for endoscopy, judicious use of ulcerogens and adherence to guidelines on management of upper gut haemorrhage. haemochromatosis (hh), a common recessively inherited disorder of iron metabolism is closely linked to the hla-a locus on chromosome . linkage studies have demonstrated a close association between (hh) and the hla alleles, a and b ("ancestral haplotype"). heterogeneity at the molecular level may account for the variance in clinical phenotypic expression. the aim was to evaluate phenotypic expression of hh in the presence/absence of the a -b ancestral haplotype. probands ( m: f) from unrelated irish families were investigated. phenotypic variability was assessed with regard to l) age; ) % trans.sat.; ) serum ferritin; ) liver bx iron grade; ) body iron stores and )symptomatology. three males were homozygous for a b , were heterozygous for a b and were non-a b . symptomatology, trans, sat., serum ferritin and liver bx grade were not influenced by homozygousity or heterozygousity for a b . conclusion: there were no significant differences in phenotypic expression on comparison of the three haplotype groups. no predominant genotype appears to be responsible for phenotypic severity in irish families indicating the possibility of multiple mutagenicity of the hh gene. of riba positive anti-d associated chronic hepatitis c patients, were pcr positive but had surprisingly mild disease. the disease status of the pcr negative patients was hitherto uncertain and is the subject of this study. / riba positive patients referred to this centre were biopsied because of elevated alt ( ) or florid symptoms which dated from inoculation ( ). histological activity index * , , , , , (f), (f), , (f), , , , , , , , no bile duct damage, lymphoid follicles or aggregates was observed. / had mild periportal fibrosis (f), of these had steatohepatitis with obesity ( ) and impaired glucose tolerance ( ) suggesting dual pathology. we conclude that riba positive, pcr negative patients have minimal disease activity. elevated the association between the hla locus and haemochromatosis (hh) has allowed early identification of affected siblings. it is unclear what proportion of subjects who are predicted to be homozygous or heterozygous for the disease by hla typing develop the disease. studies correlating clinical features with hla type in families from ireland -a putative source of this celtic trait have not been described. the aim was to correlate clinical, biochemical and pathologic features of hh with hla typing in first degree relatives of probands. initial analyses identified homozygous (hh), heterozygous (hn) and normal (nn) individuals. however, / hn individuals had stainable iron on liver biopsy, confirming hh. further hla analysis revealed homozygous x heterozygous matings and identification of all disease haplotypes within each pedigree allowed final classification of hh, hn and nn individuals. vol. . supplement no. conclusion: this study demonstrates the importance of hla typing in the clinical management of families with hh, furthermore, in multiply affected families the incidertce of homozygous x heterozygous matings is high indicating the high degree of "pseudodominance" in the irish population. the degree of acute hepatic failure after severe trauma and sepsis is related to the extent of hepatocyte (hc) damage and cell death resulting from either necrosis or apoptosis. we have previously demonstrated that tnf-ct and lps can directly lead to hc necrosis, but not apoptosis. recent, studies have shown that reactive oxygen intermediates (roi) and nitric oxide (no) are capable of inducing apoptosis in eukariotic cells. however, it is unclear whether roi or no are involved in hc cell death. the aims of this study were to evaluate the role of no and roi in hc cell death (apoptosis vs necrosis). hcs were isolated from sprague-dawley rats, and cultured with the no donor, sodium nitroprusside (snp) or the roi generation system, hypoxanthine-xanthine oxidase (hx-xod) and h . the effect of lps, tnf-t~, and ifn-y alone or in combitmtion with different antioxidants and the no synthase inhibitor, n-methyl arginine (nma) on hcs was also assessed. snp caused a dose-dependent increase in hc apoptosis. roi generated by hx-xod and h did not induce hc apoptosis, but were responsible for hc necrosis. tnf-ct alone failed to induce hc apoptosis, but when ~combined with antioxidants resulted in increased hc no production and apoptosis. this effect was attenuated by nma. snp also induced hc damage and hc necrosis. moreover, tnf-ct-mediated hc damage and necrosis could be further reduced by the combination of antioxidants and nma. these results indicate that roi preferentially induce hc necrosis, but not apoptosis. induction of no resulted in both hc apoptosis as well as hc necrosis, which suggest that overproduction of no may be detrimental during the sirs. irish journal of medical science intervention was not uniform. mean albumin was . g/ . mean weight was . kg. poor cognitive status greatly increased the requirement for dietetic consultation time. lack of dietetic resources results in inadequate monitoring of these patients following discharge. this study highlights the need for a dedicated clinical nutrition service, for medical services for older people. periconceptual consumption of folic acid has been shown to decrease the incidence of neural tube defects. the preventative strategy of universal food fortification with folic acid presents the possible risk of masking the diagnosis of cobalamin deficiency in pernicious anaemia. in addition, the ultimate longterm effect of universal exposure of adult or foetal cells to a synthetic substance, ie. folic acid, is unknown. in this study, the threshold oral dose of folic acid in a number of foods above which metabolically-unaltered vitamin appeared in serum postprandially was determined in a young and elderly population by microbiological assay of serum pre-fractionated by hplc. subjects on a five-day regime of fortified cereal and bread along with their normal unfortified diet. were shown to have a threshold level of ~g/d, abovewhich unaltered folic acid appeared in the serum. individuals given folic acid in either isotonic saline, milkor white bread exhibited a threshold level of ~tg per serving. from patterns of food consumption in ireland, even moderate levels of fortification are likely to lead to some population groups being exposedto excessive amounts of un-altered folic acid in serum. many older people are nutritionally compromised. there is clear evidence that: nutrition intervention reduces morbidity m and mortality in older patients. to identify the spectrum of nutritional abnormalities referred for dietetic intervention and the problems associated with nutritional assessment, elderly patients were alphanumerically selected from files of the department. of nutrition and dietetics. the most common dietetj.c interventions were: use of supplements %; high protein high calorie diet %; nasogastric feeding %; reduction fat %; iron/thiamine assessment %; high fibre diet %; diabetic diet %; nutrition swall w programme %; lipid lowering diet %. some % referred required nutritional supplements, but the profile of an increase in oxidative stress in cystic fibrosis patients has been suggested. activated neutrophjls in the presence of chronic lung inflammation in addition to increased activity of the electron transport chain in cfmay. increase free radical generation. antioxidant protection against free radical attack is likely to be compromised as a i'esult of deficiencies in fat soluble antioxidants vitamins. in the present study stimulated thiobarbituric aoid reacting substances (tbars) were measured to determine the ability of plasma to withstand lipid peroxidation. copper was used to in!tiate the breakdown of lipids to lipid hydroperoxides and eventually to aldehydes, mainly malonyldialdehyde (mda). pooled cf plasm a and pooled control plasma were incubated for , , , , and min. mda complexes with thiobarbituric acid which absorbs at approximately rim. there is a lag phase where antioxidartts vol. , irish journal of supplement no. medical science in the plasma or tissue protect against lipid peroxidation, then a log phase where the protective effect is overcome and finally the reaction reaches a plateau when lipid peroxidation is complete. absorbance at nm was measured in all samples and zero order and first derivative spectra were obtained. the lag phase appears to be longer in the pooled cf plasma compared with controls. plasma t~-tocopherol levels were within the normal range in both groups, indicatin~ an alternative protective effect in cf. mild hyperhomocysteinaemia is an established risk factor for heart disease. a source of homocysteine in humans is the essential amino acid methionine found in protein of animal origin. in an -week study weekly fasting plasma homocysteine levels were examined in a group of healthy male subjects (n= ) under normal dietary conditions (weeks to ) and in response to graded increased methionine intakes (weeks , , ). nutrient intakes, including methionine, were calculated from x -day food records. under normal dietary conditions weekly mean plasma homocysteine levels were not significantly different (anova) from each other ranging from . + . to . + . ~tm/ . doubling daily methionine intakes (supplementing with mg/ kg/d) did not result in a significant increase in plasma homocysteine ( . + . ~m/ ), however, significant increases were achieved when diets were supplemented with methionine at levels of and mg/kg/d resulting in mean plasma homocysteine levels of . + and . am/ + . , respectively. mean plasma homocysteine levels returned to baseline ( . + . ~tm/l) days post supplementation. we conclude that supplementary methionine results in a significant increase in plasma homocysteine only when levels of five times the normal dietary intake are reached. this study is evaluating the use of a synthetic construct which encompasses primer binding sites for lpl and a variety of cytokine and other transcripts, to quantify lpl expression in cultured human monocyte-derived macrophages. following isolation of total rna at various times during cell culture, its reverse transcription (rt) using random hexamer primers generating first strand cdna and specific amplification of lpl cdna targets by polymerase chain reaction (pcr), generates products identifiable on gel electrophoresis. quantitation of message is obtained by incorporating the pawl construct in the rt assay in varying quantities as an internal standard with known amounts of monocyte-macrophage rna (l~tg). pcr amplification of this construct yields size distinguishable products from that produced by the monocyte-macrophage lpl cdna transcript. pcr conditions for the assay have been optimised at cycles of denaturation (tmin @ ~ annealing ( . min@ ~ and extension (lmin@ ~ lpl mrna has been detected in cultured monocytes and macrophages throughout their differentiation. also increased expression of monocyte lpl mrna has been observed following hr incubations with chylomicrons ( t~g/ x mononuclear cells/ ml)-when compared with controls. interestingly, little or no lipase mrna was detectable in circulating monocytes using identical pcr conditions to preparations of mrna from the day and day cultured cells. this methodology will now permit investigation of the factors controlling lpl expression in cultured human monocytic cells. replacement growth hormone (gh) therapy in adult hypopituitarism is attracting increasing interest. in markussis (l) detected premature atherosclerosis by ultrasonography in the untreated patient we have shown plaque regression with patients on replacement gh (norditropin) in a -month trial. females and males were recruited, mean age . years. at each timepoint plaque characteristics were measured by duplex ultrasound. patients showed a large reduction in plaque size (mean %) after four months treatment (p value < ~ l). similarly, highly significant values in cholesterol, hdl and ldl and apo a are achieved. chol hdl ldl apo a pretreatment . . . posttreatment . w . w . w ~ w achieve a high degree of statistical significance (p< . ). the significant reductions achieved in plaque characteristics in six patients studied who showed plaque formation correlates with other parameters traditionally accepted as reducing cardiovascular risk. hypertension is found in approximately % of patients with cushing's syndrome, but the mechanism is poorly understood. previous studies in our unit have examined levels of exchangeable sodium, plasma renin and angiotensin ii and cardiac sensitivity to phenylephrine. one previous study has demonstrated enhanced pressor responsiveness to noradrenaline in a group of patients with cushing's syndrome due to adrenal adenoma. we have investigated the blood pressure response to noradrenaline in patients with pituitary dependent cushing's syndrome and in controls matched for age, sex and bmi. noradrenaline was infused for minute intervals at five different concentrations between . and . mcg.kg.min -~ multiple systolic and diastolic readings were recorded and the infusion was stopped if the systolic pressure became > mmhg, diastolic _> l mmhg or the systolic pressure rose > mmhg. basehne blood pressure in the patients with cushing's disease (cd) was / + / compared with / + / mmhg in the normal controls (nc). in of the patients with cushing's disease, the test had to be stopped before completion of the protocol, whereas this was necessary in only one control subject the change in blood pressure from basehne to the blood pressure value recorded either at the time the test was stopped or at the peak blood pressure reading during equivalent noradrenaline infusions was compared between the matched pairs. the mean change in diastolic pressure was + mmhg in cd compared with + in nc (p< . ). there was no statistically slgmficant difference in either systolic pressure ( + vs + mmhg) or mean arterial pressure ( + vs + mmhg). these results demonstrate an increased diastolic pressor response to noradrenahne tn cushing's disease. increased pressor sensitiwty to uoradrenaline may contribute to the elevated blood pressure seen in cushing's disease. increased plasma homocysteine (thcy) is an independent risk factor for premature vascular disease. patients with insulindependent diabetes have an increased prevalence of cardiovascular disease. accordingly, we measured plasma thcy concentration in such patients ( - y), randomly selected, and in control subjects. in controls, thcy was higher in males than in females (supine: geometric mean ( % ci): , . ( . , ) v . ( . , . ) i.tmol/l, p< . ), as previously described, but there was no gender difference in patients. male patients, without microvascular complications, had lower thcy than controls (supine: . ( . , . ) v . ( . , ) ~mol/l, p< . ), but values in female patients without complications were similar to those of female controls, thcy significantly correlated with age in diabetics but not in controls, thcy increased in patients with increased severity of microvascular complications, partly due to the effect of age. thcy was higher when standing.than when supine in both controls ( ( . , . ) v ( . , . )lalmol/l, p< . ) and patients ( . ( . , . ) v . ( . , . )l.tmol/l, p< . ). the absence of gender difference, the association between thcy and age, and higher levels with increasing microvascular complications suggest thcy could be of pathogemc significance in iddm patients, despite unexpectedly low levels in male patients without complications. differences.between supine and erect samples may be due to haemodilution of albumin-hound thcy in the latter a review of the treatment outcome of thyrotoxicosis with standard dose/doses of radio-active iodine (sdrai) in consecutive patients presented to the endocrinology department, uchg, from december -december was analysed. the mean pre-treatment levels of free thyoxine (ft ) was correlated with the treatment outcome. there was statistically significant difference in the pre-treatment ft between responders and nonresponders to the first dose rai (p = . ). response with hypothyroidism and/or euthyroidlsm was considered successful treatment / ( %) responded to a single dose rai; / ( . %) and / ( %) responded with euthyroldism and hypothyroidism respectively / ( . %) and / ( . %) responded to the second and third doses of rai respectively giving a total response rate of . % and % respectively. interestingly, / ( . %) patients failed to respond even to the fourth dose rai / ( . %) patients with t toxicosis ( females and male). two responded to the first dose (one with hypothyroidism and the other with euthyroidism), the remaining required a second dose, which produced the same results. no statistically significant difference in the response rate between t and t toxicosis (p = . ) was observed. inherent in the st. vincent declaration targets is the need for continuous data collection and audit. we present preliminary information from the mater database, the first prospective audit of patients from a homogenous irish population. , iddms ( m: f) were identified with the following characteristics (mean + sd), age . + . years, duration of dm + . years, bmi . + . (males) and . + . kg/m (females), hbalc . + . % (n< . %). no male:females differences existed in the above nor in macrovascular complication rate . % (predominantly peripheral vascular &sease and lschaemic heart disease). however, males were more likely to be current smokers ( % vs %, p = ). hypertension rates ( . m vs . %f), cholesterol > . mmol/ ( . m vs . %f) were similar but more males had cholesterol < . mmol/l ( . m vs . %f, p < . ). clinical nephropathy was present in . % of males vs . % in females (p< ) . % had clinical peripheral neuropathy. retinopathy will be described elsewhere. . % of females and . % of males had a history of hyperthyroidism and . % of females vs . % of males of hypothyroidism. . % had history of psychiatric disease. conclusion although not a population based study, care of iddm in ireland is almost totally hospital clinic based cigarette smoking is identified as the major problem to be addressed patients with diabetes meltitus (dm) are at a higher risk of developing vascular complications, including coronary artery disease (cad). we performed a detailed analysis of predictors of cad and its seventy in patients with dm and chest pain patients in total single vessel cad (svd) in , double vessel (dvd) in , and triple vessel (tyd) in on cine contrast angiography clinical, biochemical and dobutamme stress echocardiographic findings are tabulated below for patients with angiographically proven coronary artery disease. patients with tvd had a longer duration of dm ( years) and were more likely to have retinopathy ( %) the sensitivity of dse was excellent for severe disease. conclusion' duration of dm, retinoapthy, and a positive dse were the best predictors of severe cad in a diabetic population with chest pain the haemodynamic hypothesis for the pathogenesis of diabetic microangiopathy argues that an initial increase in microvascular flow leads to sclerosis and disturbed microvascular autoregulation. we have recently demonstrated impairment of vasoconstrictor responses to endothelin- , a potent endothelium-derived constrictor substance, in niddm and have suggested that this could contribute to the initiation of microangiopathy the purpose of this study was to determine whether responsiveness to endothelin-i is also impaired in iddm. non-specific vascular smooth muscle contraction was assessed using high dose serotonin eleven patients with iddm and control subjects underwent forearm blood flow (fbf) measurement by venous occlusion plethysmography in response to local infusions of endothelin- ( pmol/min for minutes) and serotonln ( la g/min for minutes) control subjects showed slow onset vasoconstriction in response to endothehn- reaching maximum at minutes (p< . ) the diabetic group did not respond to endothelin-i group differences were significant (p= . ). the two groups showed similar vasoconstriction in response to serotonln. in conclusion, vasoconstriction in response to endothelin-t is impaired m iddm non-specific vascular smooth muscle contraction is preserved. impaired vascular responsiveness to endothehn-i is a possible common mechanism for the pathogenesls of microanglopathy in ddm and niddm. we measured total corrected (tca) and standardised ionised calcium (lca) in a population of intensive care ( cu) patients (with a mean age of + years, % male) to determine the prevalence of abnormalities in circulating calcium and its possible determinants severity of illness was measured by the apache ii score (acute physiological and chronic health evaluation). for comparison of ica we examined subjects undergoing arterial gases which proved to be normal and non-critically hypoxlc subjects ica was measured on arterial gas samples and corrected for ph % of icu patients had a total ca (unadjusted) of < mmol/l. after adjustment for serum albumin, % of icu patients had an tca < mmol/ % of icu patients had a serum phosphate of < . mmol/ ica in controls was . + . mmol/ and . + . mmol/ in hypoxlc non icu patments (ns) ica in icu was lower: . + . (< . ). tca and lca were not slgmficantly related. tca and ica did not sigmficantly differ between patients who died and who survived in the icu, and they were not related to apache ii score. belfield, dublin . from july to june there was a -fold increase m the annual number of specimens submitted to the virus reference laboratory because of a perceived risk of contracting hiv through a needlestick injury, blood splash, human bite, or through occupational exposure. needlestick-associated specimens also comprise an increasing proportion of 'at-risk' specimens, rising from . % m the year july -june to . % in the year july -june . between july and june a total of patients had specimens submitted for hiv antibody testing after a perceived'exposure to hiv of these only patients had more than specimen taken. although the time of putative exposure is rarely avadable, the median interval between st and nd postexposure specimens for these patients is months with / ( %) lying between to months. if the risk of hiv refection from a needlestlck injury is assessed as sufficient to warrant serological investigation, the timing and number of blood samples are important. a negative report from a single early specimen may not indicate an absence of infection a basehne specimen and follow-up specimens at weeks, months and at a minimum of months post-exposure are recommended appropriate serology for other viral mfections (hepatitis b and hepatitis c) should also be considered. since the beginning of a significant sustained increase in the numbers of hepatitis a cases has occurred. the number of cases m was against in . this reverses the continuous fall observed over previous years. the reason for this increase remains unidentified at present this increase has occurred following a dramatic increase in the total number of hepatitis a igm tests carried out by the vrl since february/ march the increase in the number of tests carried out since this time is primarily attributable to increased hepatitis testing following receipt of hepatitis c-contaminated rhesus anti-d immunoglobuhn. analysis of the age profiles of the positive patients and of all the referrals indicates that . % of positive results were found m patients aged yr or less whdst % of all hav igm tests were performed on individuals aged yr or greater. this raises the question whether greater selectivity should be employed when requesting hepatitis a tests studies report compliance rates ranging from to % in hiv negative patients there has been no comprehensive study of compliance in hiv positive patients. accurate measurements of compliance are not easy; easy measurements of comphance are not accurate "). to determine the compliance rate in hiv posmve patients attending st. james hospital, dublin, one hundred consecutive patients attending the service were interviewed (homosexual , ivdu , heterosexual ). the questionnaire was divided into three sections. firstly, a medical review was completed by the clinicmn which included demographic data, cd count, cdc staging, karnofsky index and prescribed medication. secondly, the pharmacy detailed the medication dispensed to each patient. the third section comprised a patient interwew to determine adherence to, and understanding of prescribed drug therapy. we report an overall comphance rate of %. this was unevenly distrtbuted between the two main patient groups ( % in homosexuals, % in ivdu) the following factors were found to mfluence compliance: number of medications, cdc stage, karnofsky index, dysphagia, educational and socio economic factors. we also found that poor patient understanding of the prescribed therapy significantly affected compliance. the aim was to determine the incidence of stds in patients presenting for hiv testing at the department of genito-urinary medicine, saint james's hospital. a retrospective analysis of all patient notes who presented for hiv testing between july ' and december ' was undertaken. according to clinic policy all patients had been screened for the following stds; neisseria gonorrhoea, chlamydia trachomatls trlchomonas vagmalis, candida, human papilloma virus, herpes simplex virus syphilis and hepatitis b in addition intravenous drug users (ivdus) were also screened for hepatttls c all patients underwent pre test counselhng. sex, age, risk groups and diagnoses were noted. patients presented for hiv testing, of whom % were male, % female, wtth an average age of . years. of the total, % were, or had previously been ivdus. of the total ivdus, were heterosexual males were bisexual and were females . % of the male patients were homosexual and % btsexual there were posmve hiv tests ( % of total); males and female. in this group there were patients with hepatitis c, all of whom were ivdus. no other stds were detected in the hiv negative group hepatitis c was diagnosed in , hepatttis b in , anogenital warts in , herpes gemtalis in , syphilis in , n. gonorrhoea in , t. vagmalis in i, c. trachomatls m , g vaginalis in and candldlasis in . this study confirms the importance of std screening in all patients requesting a hiv test. of the total testing for hiv, % had a concurrent std diagnosis although no stds were identified in the hiv positive group this may be more a reflection on the makeup of the irish hiv positive population, the majority being ivdus, rather than a difference m the mode of sexual toxoplasmosis is the most common opportumstlc infection of the central nervous system in aids patients. in clinical practice the diagnosis depends on clinical, radiographic and serological findings coupled to chnical response to therapy brain biopsy is not routinely performed. in this retrospective review, we describe our experience with diagnosing toxoplasmosis we examined (a) the clinical demographics and presentation, radiographic findings, response to therapy and patient outcome (b) role of polymerase chain reaction (pcr) in detecting toxoplasma gondii from blood and csf samples (c) the usefulness of serology in diagnosing acute infection. all cases diagnosed as toxoplasmosls based on the above criteria were reviewed. pcr to detect toxoplasma gondn dna used primers to the b gene giving a bp amphficatton product serological tests used were sabln-feldmen dye test and latex agglutination. there were cases diagnosed ( m, f, cd - ; cdc iv ). panents unknown to be hiv posmve presented with cerebral toxoplasmosis patients were not receiving continuous systemic prophylaxis against pce diagnostic value oft gondii pcr in blood and csf showed a sensmvlty of %, specificity of %, ppv was % and npv was % determination of lg subtype was of limited value % ( ) of patients were seronegatlve of whom % ( ) had histologically proven disease of these latter cases were pcr negative the dye test was of poor predictive value this review confirms the need to combine all parameters in making a diagnosis of toxoplasmosis in lmmunocompromlsed hosts. the performance of the newly developed, rapid and fully automated m~croparticle enzyme immunoassay abbott imx hiv- /hiv- rd generation plus assay for the detection of antibody to hiv- and hiv- including subtype o m human serum or plasma was assessed the assay was evaluated by testmg specimens from blood donors, diagnostic populations and hospitalized patients, hiv seroconverslon panels confirmed hiv-positive specimens, and potentially interfering specimens. the abbott imx hiv- /hiv- rd generation plus assay showed an overall apparent specificity of . % (lower limit of % ci . %) in the tested blood donor populations (n= t). this comparable to the specificity found for the abbott imx hiv-i/hiv- rd generation plus eia ( %) and the axsym h v- /hiv- assay ( %). the apparent sensitivity of the abbott imx hiv-i/hiv- rd. generation plus assay is at least equivalent to that of the abbott imx hiv-i/hiv- rd generation plus eia and the axsym hiv-i/hiv- assay. of hiv-i seroconversion panels tested, the abbott imx hiv- /hiv- rd generation plus assay detected seroconverslon earlier on up to panels, depending on the comparison assay. among specimens from asymptomatic and symptomatic hiv patients, the abbott imx hiv- /hiv- rd generation plus assay detected ( ) including specimens characterized as hiv- subtype o. the abbott imx hiv- /hiv- rd generation plus assay is an extremely sensltlve and highly specific assay for the early detection of antibody to hiv- /hiv- and shows at least an equivalent performance to the abbott imx hiv-i/hiv- rd generation plus eia and the axsym hiv- /hiv- assay. the fully automated imx instrument system offers ease of use and rapid results on a widely accepted and reliable platform. streptokinase (sk), a kd protein produced by group c b hemolytic streptococci, is a widely used thrombolytic agent. anti-sk antibodies arise either as a result of therapeutic administration of sk or following natural mfection with streptococci although the clinical significance of antl-sk antibodies is not clear, there is evidence that some anti-sk antibodies arising from natural infections can interfere with sk activity tn vtvo, resulting in thrombolytlc failure. to facilitate further investigations of these antibodies, we have developed and validated a highly sensitive functional assay, which measures sk neutralisatlon activity of serum independently of other circulating inhibitory factors in the sample, and a rapid and convenient enzymeimmunoassay for the detection of anti-sk antibodies. analysis of over random serum samples from the local blood bank with the enzymeimmunoassay showed the prevalence of antl-sk antibodies to be approximately %. all the positive samples and an equal number of the negative samples randomly selected were analysed by the functional assay the agreement between the results of the two assays was excellent indicating that our enzymelmmunoassay was a convement method for detection of anti-sk antibodies which could neutrahse sk activity m vitro irish journal of medical science tuberculosis drug therapy, isolation precautions and prophylaxis. conventional methods of detection such as microscopy and culture either lack sensitivity and specificity or are timeconsuming. in this study we investigated the use of a pcr based diagnostic assay for the detection of m. tuberculosis in sputum samples this assay has been developed by bioresearch ireland (bri) and raggio italgene. sputum samples were lysed and pcr amplified using an m. tuberculosis complex-specific primers. the results obtained using the bri/c-trak tm technology were initially compared to the amplicor system (hoffman la roche). both probe detection methods represent fast and reliable methods for the detection of m. tuberculosts in clinical samples. this test is designed to eliminate the possibility of obtaining false negatives. strongyloldes stercoralis infection in humans ts endemic in the tropics. as travel is becoming more common, it will be seen more frequently. two cases of this infection in irish people are described. case i. a year old women had travelled and worked in poor rural areas of mexico for one month, three years before presentation. two and a half years later she developed abdominal discomfort, anorexia and sore throat. myalgia, arthralgta and a transient skin rash began to appear in the next month. eosinophilia, mild anaemia and raised liver blood tests were noted. elisa test for strongyloides was positive but parasites were not seeri in the faeces. ivermectin was given and the patient feels better. case ii. a year old nurse had arthralgia, fatigue and some weight loss for months'. on two occasions in the last four years, she had been travelling extensively in s.e. asia for a total of four months. she was admitted to hospital because of acute fever and loin pain. a urinary tract infection was diagnosed. absolute eosinophil count was i'aised . x ^ / . esr was mm/hr. strongyloides elisa was positive and treatment administered as above. strongylotdes is the most important nematode in the returned tropical traveller. it can multiply and persist within the body for long periods of time and it can cause hypertnfection syndrome, a protean fulminating infection of bowel, lungs, blood stream and brain, in those who are lmmunocompromised. diagnosis can be difficult by stool microscopy. thlabendazole has side effects but ivermectin is safe and effective. june , there was an outbreak of c.difficde-associated diarrhoea (cdad) at st. james's hospital. the aims of this study were to determine the incidence and outcome of cdad in hiv positive and negative patients we prospectively reviewed all patients with diarrhoea, a positive c.difftcile cytotoxin assay, and in whom no other infectious cause for diarrhoea was identified demographic data, history of diarrhoeal episodes, risk factors and outcome were recorded. the incidence of cdad in hiv negative patients was . per hospital admissions, compared to per admissions m hiv positive patients. the average number of courses of antibtotlcs received, in hiv negative patients prior to the onset of symptoms was . , and % of this group were exposed to third generation cephalosporins. hiv positive patients received an average of . courses of antibiotics and no patients received third generation cephalosporins. there were no deaths due to cdad in hiv positive patients however hiv negative patients died from severe pseudomembranous colitis in conclusion we documented a unexpectedly low incidence and complication rate of cdad in hiv positive patients this is surprising considering their multiple hospital admissions and exposure to ant~microbial and chemotherapeutic agents. the number of new positive hiv specimens detected at the virus reference laboratory has risen from a cumulative total of m july of to in september of . we examined our data to determine the proportional make up of these positives by major risk group. in august . % of positive specimens were from intra venous drug abusers (ivda) by september ivda made up % of the total positive hiv specimens. positive specimens from homosexual individuals rose fro.m l % of total positives in august to . % in september there were no recorded positive specimens from heterosexual exposure in august but in september . % of positive specimens recorded heterosexual exposure. a further category which includes blood donors, haemophiliacs, transplant patients and organ donors made up % of total positives in august and in september made up . % of total positives. we further examined our data in order to show when these changes occurred by ascertaining how many new positive patients have been discovered per year in each of the main risk groups. see in the united kingdom echovlrus type (echo- ) is regularly isolated, with nearly reports annually to the central public health laboratory. reports increased during - and overall it is the second most commonly reported echovlrus in the u.k. echo- epldemiology is different to that of other enteroviruses; over % of patients with echo- tsolated are less than years of age echo- shows distinctive and unique cytopathogenic features in tissue culture, and based on sequence analyses, it seems to belong to a separate subgroup of picornaviruses. echo- has been associated with respiratory symptoms in premature infants, myocarditis and severe encephalitis. in an outbreak of acute flaccid paralysis associated with echo- was described in jamaica in six patients, four of whom died. we describe three cases of sudden death in infants associated with echovirus type infection case i: s d. born / / ; birth asphyxia and death at two days of age; echo- isolated on from spleen. this study assessed the antibiotic sensitivity of organisms causing urinary tract infections (uti) among genito-urinary medicine (gum) clinic attenders in order to determine whether it is worthwhile giving tetracycline for dipstick (nitrite) positivity, even in the absence of clinical features of uti. we looked retrospectively at laboratory confirmed uti's diagnosed among gum clinic attenders over a period of eight months. we assessed antibiotic sensitivities of the organisms involved, and determined how many dipstick positive urines which were left untreated turned out to be real uti's. % of uti's were due to coliforms and % of these were sensitive to tetracycline. % of uti's were due to staphylococcus saprophyticus, % due to beta haemolytic streptococcus group b, % due to enterococcus, % due to proteus species and % due to coagulase negative staphylococci. % of nephur positive urines were left untreated. % of these were nitrite positive. failure to treat a positive urine dipstick which turned out to be a uti necessitated a further clinic visit for adequate treatment. nitrite positive urines should be treated as a uti, even in the absence of clinical features of uti, either with trimethoprim or tetracycline. the number of untreated uti's and unnecessary extra visits to gum clinics would have been reduced with the use of judicious antibiotic therapy for nitrite positive urines. strains of enterococci resistant vancomycin have been reported with increasing frequency. in , we investigated an increase in the frequency of vancomycin-resistant enterococcus faecium (vref) among patients in the haematology/oncology unit using pulse-field gel electrophoresis (pfge) to genotype these isolates and to assist in establishing the source of these vref. eighteen clinical isolates of vref from blood, urine sputum and-faeces and two environmental isolates were collected from separate patients between march and july . minimum inhibitory concentrations (mics) to several antibiotics including teicoplanin and vancomycin were determined by agar dilution. pfge were performed following smal restriction endonuclease digestion. antimicrobial susceptibility testing revealed high level resistance to vancomycin and teicoplanin; mics > mg/ l and > mg/l respectively. this antibiogram is consistent with the van a phenotype. pfge of all isolates revealed identical patterns indicating clonal spread of vree subsequent implementation or infection control measures reduced the frequency of vref isolation. pfge proved useful in demonstrating clonal spread of vref and.in emphasising the need for infection control measures. a prospective audit of baeteraemia in our bed teaching hospital was carried out from february to march . clinical and microbiological data were collected on episodes of bacteraemia in patients. of these ( %) were hospital acquired and ( %) community acquired. urinary tract and respiratory tract sources were implicated in % and % of community acquired episodes, making e. coli and s. pneumoniae the commonest community acquired isolates ( % and % respectively). other gram negative bacilli accounted for % and s. aureus for %. coagulase negative staphylococci were the commonest hospital acquired isolate ( %) followed by s. aureus ( %), e. coli (i %) and enterococcus spp. ( %). enterobacter spp. were the second commonest gram negative isolate ( %). central venous cannulae were implicated in % of hospital acquired cases. urinary tract infections accounted for %. % of which were catheter related. invasive diagnostic procedures (angiography, prostate and liver biopsies, sinography) were implicated in t episodes. gentamicin resistance was found in % of hospital acquired aerobic gram negative bacilli and mrsa accounted for % of hospital acquired s. aureus. these figures are higher than expected but may be explained by outbreak of mrsa and gentamicin resistant entercobacter spp. which occurred during the study period. the past severalyears have seen a significant increase in the recognition of moraxella (branhamella) catarrhalis as a respiratory pathogen (~). the pathogenic mechanisms employed by the organism are largely unknown, but adherence may play a role ~ ~. in our investigation the haemagglutinating ' activity of isolates of m. catarrhalis was determined by a microtitre method. no isolate agglutinated horse, chick or sheep red blood cells (rbc). seventeen isolates agglutinated human rbc, x~hile of these isolates also agglutinated rabbit red. blood cells. haemagglutination of human and rabbit red blood cells was inhibited by porcine mucin. galactose inhibited the haemagglutiriating activity of the isolates which agglutinate both human and rabbit rbc and yet bad no effect on the haemagglutinating activity of the isolates which haemagglutinate human rbc alone. .electron microscopy studies of the bacteria demonstrated a diffuse outer fibrillar layer on the surface of haemagglutinating positive isolates, thislayer was subsequently removed following trypsin treatment, as was the haemagglutinating activity. a kda trypsin sensitive protein appears to be associated wfth haemagglutinating properties. mrsa is an increasingly important cause of morbidity, and is spreading from large hospitals to smaller community-based facilities and nursing homes. the objective of this survey was to obtain an indication of the size of the mrsa problem in ireland prior to introducing national mrsa control guidelines. a survey of all microbiology laboratories in ireland was carried out over two weeks in spring . for patients from whom mrsa was isolated during the study period standard demographic and clinical data were requested and period prevalence/ discharges was calculated. all microbiology laboratories surveyed responded. mrsa was isolated from patients during the week period. the period prevalence of mrsa/ , discharges was . . males aged + had the highest rate of infection ( / discharges). half of all isolates were from patients in surgical or medical wards, but % were from community-based sources e.g. gps, nursing homes, hospices. thirty-two percent of mrsa patients were infected rather than colonised. mrsa is clearly a substantial problem in ireland. while it is largely a hospital problem at present, the increasing trend for day procedures and shorter stays means that infection will increase in the community. a survey in a university hospital in the usa revealed % of mrsa cases to be communityacquired. tonsil core specimens were cultured for bacteria including mycoplasma, chlamydia and ureaplasma urealyticum in children undergoing tonsillectomy for recurrent acute tonsillitis. serology for chlamydia and mycoplasma pneumoniae was obtained in of the children. the polymerase chain reaction (pcr) was used to investigate the presence of chlamydia pneumoniae in core tonsil tissue. ureaplasma urealyticum was cultured in three children ( . %) and mycoplasma salivarium in two children ( . %). culture was negative for chlamydia pneumoniae and mycoplasma pneumoniae. the complement fixation test for chlamydia species was positive in / children ( %) indicating previous infection. specific immunofluorescence testing for c. pneumoniae was positive for lgg (titre> ) in / ( %). igm antibody to c. pneumoniae and antibodies to c. trachomatis and c. psittaci were not detected. ninechildren ( %) had titres > to m. pneumoniae. pcr failed to demonstrate c. pneumoniae. aerobic and anaerobic bacteria were cultured from all specimens. the culture of ureaplasma urealyticum in . % of our patients indicates a higher rate of colonisation then previously thought. this study irish journal of medical science demonstrates past infection with c. pneumoniae in % and with m. pneumoniae in % of children with recurrent tonsillitis. however c. pneumoniae and m. hominis do not play a significant role in childhood recurrent tonsillitis. multiply resistant enterococci are increasingly common causes of serious infection in hospitalized patients. high level gentamicin resistance (mic > mga) in enterococci further compromises the therapy of such infections. we have identified seven clinical isolates of enterococcus hirae demonstrating high-level gentamicin resistance (hlgr: mic > i mg/ ). to our knowledge this is the first report of hlgr for this enterococcus species. plasmid analysis has demonstrated the presence of a single, large plasmid in all seven isolates, as well as several smaller plasmids in some of the isolates. filter mating experiments have revealed that in all seven cases, hlgr was transferred to a laboratory recipient e. faecalis jh- by conjugation. plasmid analysis of transconjugant strains confirmed transfer of the large plasmid in all cases. based on restriction enzyme profiles, two distinct conjugative plasmids were identified for the e. hirae isolates investigated. at present we are using southern blot techniques with oligonucleotide probes designed to hybridise to the hlgr determinant found in other species of enterococcus. the results will confirm whether or not the same resistance determinant is responsible for the dissemination of hlgr in the genus enterococcus. dublin . aminoglycosides remain commonly used in the treatment of severe gram negative infection and have conventionally been given on a twice or thrice daily basis. single daily dosing offers advantages with respect to less nephrotoxicity, better bactericidal activity, convenience, nursing time, cost and should avoid subtherapeutic dosing which has a significant impact on outcome. we reviewed serum gentamicin assays from january to december to assess potential toxicity and subtherapeutic dosing in patients who received once daily gentamicin and those who received multiple daily dosing. assays were performed in the study period. of those were random assays and not included. there was a trend towards significantly less potentially toxic levels in the once daily group compared to the multiple daily group (p< . ). once daily dosing produced significantly less subtherapeutic dosing (p< . ). over % of peak assays in the once daily group were in the recommended range. we conclude that current practice of multiple daily dosing of gentamicin leads to significant underdosing and more potentially toxic trough levels. measurement of trough assays only in patients who are treated with once daily aminoglycosides is sufficient and will have considerable cost savings. respiratory, syncytial virus (rs virus) is a major respiratory pathogen of infants less than year old. it occurs in annual epidemics during the winter and early spring in temperate climates. during rs virus epidemics a significant number of infants less than months old are hospitalised with symptoms of bronchiolitis and pneumonia. rs virus exists in two antigenically distinct subgroups, a and b which are known to cocirculate in the same community during the same rs virus season. there is much debate regarding the virulence of one strain over the other. using a panel of monoclonal antibodies specifically directed against the two rs virus strains, rs virus isolates from specimens sent to the virus reference laboratory, university college dublin, over seven consecutive rs virus seasons ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) were typed and the rs virus subgroup predominance monitored. subgroup a was the most predominant of the rs virus isolates accounting for . % of the total and was found to be the predominant rs virus strain in six out of the seven rs virus seasons studied. subgroup b predominated in a season in which the number of rs virus detections peaked much later than normal. treatment of fungal infections in patients in intensive care unit (icu.) is usually empiric. the aim of this study was to identify candida species isolated from i.c.u. patients and to test their susceptibility to antifungal agents to enable more directed therapy. forty candida sp. from patients in i.c.u. were isolated from the following sites, blood culture ( ), central venous catheter ( ), chest drain fluid ( ), wounds ( ), catheter urine ( ), bronchial lavage ( ), sputum ( ). strains were identified by standard procedures. minimum inhibitory concentrations of amphotoeracin b, -flucytosine and fluconazole were obtained by agar dilution test and e test. the isolates were identified as c.albicans ( ), c.glabrata ( ), c.krusei ( ), c.tropicalis ( ), c.parapsilosis ( ), c.kefyr (i). all the candida species were sensitive to amphoteracin b (mic = -< mg/l), and flucytosine (mi c= < mg/l). c.albicans and c.parapsilosis were fluconazole sensitive (mic = - mg/l). four of eight c.glabrata were fluconazole resistant (mic = > mg/l). c.krusei, c.tropicalis and c.kefyr were also resistant (mic = > mg/l). wbilst there were no major discrepancies between the agar dilution test and the e test, the agar dilution test was laborious and required a high degree of skill. the e test was easier to read and more reliable results were obtained provided the inoculum was carefully standardised. this study shows that azole antifungals should not be ganglion is probably the commonest tumour encountered in the hand and the wrist. it often arises from tendon sheath or lining of a joint capsul. the treatment can be surgical or nonsurgical, the latter includes aspiration with or without injection of steroids. surgical treatment of ganglion can pose a difficult situation to deal with. it requires hand surgeon to deal with one such problem, we present a year old man with tender mass in the hypothenar eminence. during surgical exploration it was obvious that the ganglion was infiltrating the wall of the ulnar artery, and the histology proved this later. the clinical features, management arid the outcome of this unusual case are discussed. ischaemic preconditioning (ipc) of the myocardium with repeated brief periods of ischaemia and reperfusion (i-r) prior to prolonged ischaemia significantly reduces subsequent infarction. following ipc two "windows of opportunity" (early and late) exist during which prolonged ischaemia can occur with reduced myocardial infarction, we investigated if ipc of skeletal muscle prior to flap creation improved subsequent flap survival and perfusion in either early or late windows. the latissimus dorsi muscles (ldm) of sprague-dawley rats were used. group : (control, n= ). the ldm was elevated as a thoracodorsatly based island flap group : (early ipc, n= ). the ldm was preconditioned with two minute episodes of normothermic global ischaemia with intervening minute episodes of reperfusion prior to elevation. group : (late ipc, n= ). the ldm was elevated hours after ipc ischaemia was created by occlusion of the thoracodorsal artery and vein and the intercostal perforators having previously isolated the muscle on these vessels. muscle perfusion was assessed by a laser doppler perfusion imager. one week after flap elevation the percentage of muscle necrosis was measured by computer-assisted planimetry ipc significantly reduced muscle flap necrosis (table) in both early and late windows. muscle flap perfusion was similar in all groups. this study compares the biochemical, serological and histopathological findings in women with chronic hepatitis c virus (hcv) infection with age-matched women with established autoimmune hepatitis (aih). there is increasing evidence of autoimmunity in hcv liver pathology. because of different treatment regimens for hcv (d-interferon) and aih (steroids, immunosuppression), clear distinction between the two diseases is desirable. liver enzymes (alt, ast, alkaline phosphatase), antinuclear factor (anf), anti-smooth muscle (asm) and antimitochondrial (ama) antibodies are compared for both groups of patients. liver biopsies from all women were compared using the grading and staging system of ishak et al ( ) . the results show that while some women in both groups show elevated liver enzymes, positive anf and asm autoantibodies, the values are much higher in aih. similarly aih patients show overall more severe disease on liver histology. both groups demonstrate poor correlation between histological features and autoantibody titre. we conclude that distinction between hcv and a!h is usually possible with liver histology and serology. some women with chronic hcv and positive autoantibodies however," demonstrate a histological and serological picture suggesting that chronic hcv may be mediated by an immunopathogenic mechanism. irish journal of medical science terminal changes only, showed lymphocytic meningitis and of these also had perivascular lymphocytic inflammation (cd positive) in the subependymal regions, brainstem and choroid plexus. two brains showed purulent meningitis and one case had central pontine myelinolysis probably related to profound metabolic disturbance. basal ganglia mineralization, hiv encephalitis (hive) or hiv leucoencephalopathy (hivl) were not present. these findings differ considerably from those described in us cases, in whom the majority have evidence of hiv within the cns. relatively early death from systemic infection may account for the lack of hive/hivl in these cases. the lymphocytic meningitis and perivascular inflammation may represent an immuno-allergic reaction, previously reported as "early" changes, regarded as important in inducing vascular damage which allows subsequent entry of h v into the brain. the aim of this study is to assess apoptosis in areas of interface hepatitis and spotty necrosis in hepatitis c virus (hcv) infected liver biopsies, and to correlate the degree of apoptosis with severity of histological activity. liver biopsies were randomly selected from a group of type lb hcv positive women. these patients were diagnosed by recombinant immunoblot assay (riba) test and the presence of hcv rna was confirmed using the polymerase chain reaction (pcr). apoptosis was demonstrated in the biopsies by the oncor apoptag in-situ hybridisation technique. the average number of apoptotic hepatocytes per portal tract, and within the parenchyma per x objective, was determined. the modified histological activity index (h.a.i.) was used to score each biopsy. comparison of the results shows that increasing numbers of apoptotic hepatocytes are consistently associated with increasing scores for interface hepatitis and spotty necrosis. it is concluded that apoptosis occurs in hcv infected livers and that it correlates with increasing histological activity .indicating a significant role for apoptosis in the pathogenesis of hcv liver disease. and university of edinburgh, scotland. paediatric aids represents only % of cases worldwide, in most published series parental iv drug use was the main risk factor, cns pathology was a late feature of the disease and antiretroviral treatment had been given. we studied eleven brains from romanian children with probable postnatal hiv infection using standard neuropathological stains and immunostains for lymphocyte markers and hiv p antigen. death was due to systemic infection, mostly pneumonia or gastroenteritis; antiretroviral treatment had not been given. three cases showed we studied the role of the p and bcl- genes in the pathogenesis of post-transplant lymphoproliferative disease (ptl). ten cases were examined by immunohistochemical and molecular methods. immunohistochemistry was performed using standard and antigen retrieval methods, with the p do- and the bcl- oncoprotein clone antibodies. dna was extracted from paraffin blocks and subjected to pcr, and single-strand conformation polymorphism (sscp) analysis searching for mutated p genes. samples showing any evidence of aberrant migrations were further analysed by direct sequencing. pcr was also used to detect bcl- gene rearrangements. we employed a technique called representational difference analysis to search for previously undescribed translocations or deletions which may be involved in breast carcinogenesis. dna was isolated from both invasive ductal carcinoma of the breast and normal tissue from the same patient. following restriction enzyme digestion and tigation of oligonucleotide linkers, pcr was carried out on both tumour and normal dna using oligonucleotide specific primers to obtain a representation of each genome (amplicons). digestion with the same restriction enzyme removed the original linkers, and a second set of oligonucleotides were ligated to normal amplicons only. the tumour derived amplicons were subtractively hybridised to the normal and subsequent pcr was used to isolate fragments unique to the normal dna (difference products). this was possible since oligonucleotides were ligated to normal dna only. following a series of further subtractive hybridisations and subsequent amplifications, purified difference product was obtained. difference products in the size range - bp were obtained. following further rounds of subtractive hybridisation and amplification, purified difference product will be sequenced and characterised by comparison with known gene sequences. the chromosomal location of the affected gene will be established by in-situ hybridisation and somatic ceil hybridisation, using the difference product as probe. protein s is secreted by osteoblasts and case reports of reduced bone mineral density in patients with total protein s deficiency have lead to the hypothesis that this inherited disorder is associated with generalised osteoblast dysfunction predisposing to osteoporosis ~. we have assessed bone formation in patients ( male and female) with total protein s deficiency and controls ( male and female) using two recently available sensitive markers; serum osteocalcin (oc) and serum procollagen carboxyterminal peptide (p cp), both secreted by the osteoblast. the mean total protein s level amongst the patients was _+ % (ref range - %), mean oc was . ng/ml (ref ~'ange . - ng/ml) and the mean picp was . + uga (ref range - ug/ ). in the control group, mean oc was . _+ ng/ml and the picp was + ug/ . there was no statistical difference between both groups using either marker. in conclusion bone formation as assessed by serum osteocalcin and p cp appears to be normal in patients with total protein s deficiency. hereditary spastic paraparesis (hsp) is a variably expressed neurodegenerative disorder which exhibits clinical and genetic heterogeneity. hsp can be inherited in an autosomal dominant (ad), autosomal recessive (ar) or x-linked manner. ad-hsp has been linked to a number of loci. we have ruled out linkage to these loci in a large irish family affected with ad-hsp. the aim of this study was to determine whether ad-hsp is linked to spinocerebellar ataxia loci (sca), sca-i & sca-ii. ad-hsp can be clinically similar to sca. dna was extracted from blood taken from co-operating family members. microsatellite markers spanning the sca-i and sca-ii loci were amplified by pcr. individuals were genotyped and linkage analysis was carried out using the linkage set of programs. significantly negative lod scores were obtained for both sca-i and sca-ii loci. d s gave maximum exclusion of cm on either side of the sca-i locus with a lod of - . at a recombination fraction of . . d s gave maximum exclusion of cm on either side of the sca-ii locus with a lod of - . at a recombination fraction of . . other markers examined also outruled linkage to these loci. we conclude that the gene for ad-hsp is unlinked to the major sca loci. serum vitamin b is frequently measured in the investigation of anaemia, and in screening neurological and other disorders. frequently, patients are found with low serum vitamin b level with a normal hb and without clinical abnormalities relevant to vitamin b deficiency. this study was carried out to determine the significance of a low serum vitamin b level. vitamin b measurements were carried out over an month period using a chemiluminescence method (abbott imx). clinical data was obtained retrospectively. of the samples ( . %) representing patients had a low serum vitamin b level (> pg/ml) with a mean of pg/ml ( - ). data was available on patients. ( %) had a hb below the normal range with median serum vitamin b level of pg/ ml ( - ). ( %) had a normal hb, mcv and mchc with a median serum vitamin b of pg/ml ( - ), and had a normal hb with an abnormal mcv or mch. lft's, autoantibodies, schillings test and bone marrow examination data will be presented. in conclusion in patients with a low serum vitamin b level, there was no significant difference in the b levels in those patients with a normal or a low hb concentration. it would appear that serum vitamin b is a poor discriminatory test but that changing the normal range may not help in screening. low serum vitamin b on its own may not appear to provide adequate grounds for lifelong replacement therapy. of in for males and in for females. as expected the overall incidence of hodgkin's was lower with one third of male and one quarter of female lymphoma cases affected by the disease. a distinct age specific pattern is evident depending on lesion type. marked variation in incidence levels were noted throughout the study region. an extremely varied pattern is evident in the survival rates for lymphoma patients. the cork and kerry rates for malignant lymphoma are relatively low when compared with international levelstzl obstetric complications and schizophrenia: methodology and mechanisms perinatal complications and clinical outcome within the schizophrenia spectrum ) negative symptoms, cognitive impairment and duration of initially untreated psychosis in schizophrenia davnet's hospital, monaghan, and royal college of surgeons in ireland retinal pathology in kearns sayre syndrome mitochondrial dna and disease mitochondrial myopathies: clinical features, investigation, treatment and genetic counselling phenytoin induced pseudolymphoma. a report of a case and review of the literature cutaneous reactions in head injured patients receiving phenytoin for seizure prophylazis hydantoin induced pseudopseudolymphoma branhamella catarrhalis: an organism gaining respect as a pathogen correlation between branhamella catarrhalis adherence to oropharyngeal cells and seasonal incidence of lower respiratory tract infections ) epidem ology and survival rates for all lymphoma patients registered in cork and kerry over the eight year period an indepth review of all lymphoma (icd -o code ) patients registered by the sourthern tumour registry during the eight year period / ~l annual age adjusted rates of . . and . per , were seen for males and females respectively. these levels indicate a lifetime (up to yr) risk references . cancer, the irish experience cancer incidence in five continents volume v immunohistochemistry for bcl- oncoprotein without antigen retrieval gave negative results, but with antigen retrieval, showed positive staining in out of cases. no bcl- rearrangements were detected by pcr. the combination of sscp and sequencing confirmed only wild type dna in all cases, p immunohistochemistry by standard methods revealed positive staining in only one out of nine samples analysed. when the antigen retrieval method was employed for this antibody, positive staining was seen in > % of tumour cells in four further cases.our results suggest that p does not play major role in ptld. bcl- overexpression but not rearrangement may contribute to the development of ptld. transplant arteriopathy (ta) is the major cause of death in cardiac allograft recipients. the pathogenesis is unclear. we have previously shown a plasma cell predominance in the infiltrate of ta, leading us to hypothesise a role for epstein-barr virus (ebv) infection in its pathogenesis. an association between cytomegalovirus (cmv) and ta has previously been suggested. the aim of the study was to investigate the role of epstein-barr virus (ebv) and cytomegalovirus (cmv) in the pathogenesis of ta.we performed pcr for cmv and ebv dna and protein (lmp) in seven cases of ta, involving cardiac allografts. restriction mapping was used to confirm that pcr products were either cmv or ebv dna respectively.cmv dna was found in four cases. ebv dna was found in six of the seven cases and ebv lmp staining was present in six cases. ebv was detected in all cases by either pcr or ihc.our results suggest that ebv infection may play a pathogenic role in transplant arteriopathy. the evidence for a similar role for cmv ~s less strong. st. vincent's hospital. hereditary spastic paraplegia (hsp) is a neurodegenerative disorder characterised by progressive spasticity, primarily of the lower limbs. it can be inherited in an autosomal dominant (ad), autosomal recessive or x-linked manner~ we have identified a large irish family (family a) affected with ad hsp that cosegregates with dementia. three. loci have previously been identified that are linked to ad hsp in families of different ethnic origin. the locus on chromosome is reported to be the major hsp locus. the aim of the present study was to examine family a for linkage to the chromosome hsp locus.dna has been extracted from blood taken from all co-operating family members for genotyping. polymorphic microsatellite markers from chromosomal region p - have been amplified by pcr, electrophoresed on a denaturing polyacrylamide gel and detected by silver staining. linkage analysis was carried out using the linkage series of programs. linkage analysis excluded the hsp gene from the chromosome p locusl the most significant marker was d s , with a lod score of- . for recombination fraction . , thereby excluding approximately cm either side of this marker. negative lod scores were also obtained for the other markers chosen (d s , d s , d s , d s ) excluding cm, cm, cm and cm respectively.the current study has therefore successfully excluded linkage of ad hsp in family a to the major locus on chromosome p. further studies are underway to exclude linkage of hsp in this family from other candidate loci, prior to carrying out a genome wide search. the presence of dementia in this family in association with hsp suggests that a new and as yet unidentified gene is responsible. vincent's hospital. eye and ear hospital, dublin. ched is a corneal endothelial dystrophy characterised by diffuse bilateral corneal opacities resulting in impaired vision. both autosomal dominant and autosomal recessive modes of inheritance have been described. another endothelial dystrophy, posterior polymorphous dystrophy (ppmd) has been linked to qll.we have used homozygosity mapping to analyse a pedigree with autosomal recessive ched for linkage to ql. . all affected individuals are offspring of consanguinous matings. homozygosity mapping is based on the principle that these offspring would be homozygous for genetic markers near the disease gene. homozygous regions would be random between different offspring of these matings, except at the di-sease locus shared by affected offspring.dna was extracted from blood taken from family members, of which have ched. allele frequencies were determined in pooled dna from affected individuals. pooled dna from unaffected individuals was used as a control. at the disease locus, a shift in allele frequencies towards a single homozygous allele would be observed in the affected dna pool. pooled dna was genotyped by pcr for polymorphic microsatellite markers in the region of qll. pcr products were separated on a polyacrylamide gel and visualised by silver staining. similar allele frequencies were observed at these loci in both dna pools demonstrating independent assortment of alleles. in addition, affected and unaffected family members were individually genotyped at these loci and no significant loss of heterogeneity in the affected individuals at these loci was observed. these data indicate exclusion of linkage of the ched gene to qll. key: cord- -xez zso authors: stephens, r. scott title: icu complications of hematopoietic stem cell transplant, including graft vs host disease date: - - journal: evidence-based critical care doi: . / - - - - _ sha: doc_id: cord_uid: xez zso hematopoietic stem cell transplant (hsct) is an essential treatment modality for many malignant and non-malignant hematologic diseases. advances in hsct techniques have dramatically decreased peri-transplant morbidity and mortality, but it remains a high-risk procedure, and a significant number of patients will require critical care during the transplant process. complications of hsct are both infectious and non-infectious, and the intensivist must be familiar with common infections, the management of neutropenic sepsis and septic shock, the management of respiratory failure in the immunocompromised host, and a plethora of hsct-specific complications. survival from critical illness after hsct is improving, but the mortality rate remains unacceptably high. continued research and optimization of critical care provision in this population should continue to improve outcomes. non-infectious complications of hsct. respiratory failure is the most frequent cause of intensive care unit (icu) admission after hsct, most frequently from an infectious cause. the patient was placed on high-flow nasal cannula (hfnc) for oxygenation support and started on a norepinephrine infusion for hemodynamic support. antibacterial coverage was changed to meropenem, levofloxacin, and vancomycin, and voriconazole was added for antifungal coverage. her central line was removed. her respiratory status continued to decline, and endotracheal intubation and mechanical ventilation were required h after admission. she was placed on volume assist-control with a tidal volume of ml/kg predicted body weight, and bronchoscopy with bronchoalveolar lavage (bal) was performed. the bal fluid was initially bloody, but cleared with sequential aliquots. microbiologic studies of the bal fluid were positive for respiratory syncytial virus and pseudomonas aeruginosa. she was maintained on low tidal-volume ventilation and vasopressors were weaned off. her white blood cell count slowly began to recover, and her respiratory status began to improve. she was extubated on hospital day and was discharged from the icu on hospital day . hematopoietic stem cell transplant (hsct) has become an essential therapeutic modality in the treatment of malignant and non-malignant hematologic disease. in , more than , hscts were performed in the united states, including approximately , autologous hscts and more than allogeneic transplants [ ] . allogeneic transplants are associated with more morbidity and mortality than autologous transplants, and are further categorized based on conditioning regimen (myeloablative [ma] vs non-myeloablative [nma]), donor-recipient relation (related vs unrelated), hla matching (full match vs haploidentical vs mismatched), and stem cell source (bone marrow, peripheral blood, umbilical cord blood). in general, nma regimens are associated with less peri-transplant morbidity and mortality than fully ablative transplants. in both ma and nma transplants, the cytotoxic conditioning regimen required in hsct rapidly induces neutropenia by injuring hematopoietic precursor cells within the bone marrow [ , ] . neutropenia persists until donor cell engraftment or bone marrow recovery. the period of aplasia and neutropenia places the hsct patient at high risk for infectious complications. in addition to the lack of immune cells, the mucosal barrier of the intestinal tract is disrupted by chemotherapy, creating portals through which enteric pathogens can enter the bloodstream [ ] [ ] [ ] . the respiratory system is also more susceptible to infection, with qualitative and quantitative dysfunction of alveolar macrophages, lymphocytes, and neutrophils [ ] [ ] [ ] . even after the marrow and mucosal surfaces have recovered, the immunological consequences of hsct can cause further complications requiring critical care. refinement of transplant techniques over the last decades has dramatically decreased transplant-related mortality, but approximately % of hsct patients require critical care [ ] and earlier icu admission has been associated with improved survival rates [ , ] . still, icu mortality in allogeneic hsct patients remains approximately % [ ] . the early complications of hsct (day - ) are predominantly infectious in nature, and patients typically present to the icu with septic shock or respiratory failure. the latter is the most common reason for icu admission after hsct [ ] . non-infectious complications also occur, and can involve nearly any organ system. neutropenic fever, defined as any fever higher than . °c or a sustained fever greater than . °c for more than h with an absolute neutrophil count (anc) less than cells/ mm , occurs in more than % of patients undergoing hsct [ , ] . no organism is identified in about % of neutropenic fevers [ , ] . bacteremia is documented in up to % of patients. gram-positive bacteria are most commonly isolated [ , ] (table . ), while gram-negative infections confer a higher mortality risk [ ] . fungal infections, particularly candida and aspergillus species, are frequent, especially in prolonged or profound neutropenia [ ] . approximately % of allogeneic hsct patients will develop severe sepsis during the engraftment period [ ] , and mortality is approximately % in those who go on to develop septic shock [ , , ] . mortality predictors include concomitant graft-vshost disease (gvhd), respiratory failure, positive blood cultures, and multi-organ failure [ , ] . neutropenic fever and sepsis are medical emergencies, and appropriate empiric antibiotics must be started without delay: ideally within min of presentation [ , , ] and potentially within min [ ] . empiric antibiotics must cover common organisms and should be tailored to patientspecific culture data and institutional epidemiology [ , ] . appropriate empiric antibiotics include an anti-pseudomonal penicillin or cephalosporin (e.g. piperacillin/tazobactam or cefepime, respectively), or a carbapenem [ , ] . vancomycin is not routinely indicated but should be added in the presence of a suspected catheter-related infection, soft tissue infection, oral mucositis, pneumonia, known colonization with resistant gram-positive organisms, or hemodynamic instability [ , , ] . aminoglycosides should not be added to an anti-pseudomonal beta-lactam unless required by allergies, resistant organisms, or refractory hemodynamic instability [ , , [ ] [ ] [ ] . fluoroquinolones, which are frequently used as prophylaxis in hsct patients, should not be used as empiric monotherapy due to the likelihood of resistance. in hemodynamically unstable patients, anti-pseudomonal beta-lactams should be escalated to a carbapenem and consideration should be given to the addition of an aminoglycoside or aztreonam [ , , , ] . vancomycin should be added if not already part of the regimen, and anti-fungals with activity against yeasts and molds (e.g. liposomal amphotericin, caspofungin, or voriconazole) should be strongly considered in all unstable patients [ , , , ] . identification of infectious organisms and control of infectious sources are essential to optimize outcomes but the infectious workup should not delay antibiotic administration. blood cultures and respiratory cultures should be obtained and sinus, head, chest, and abdominal imaging performed as indicated [ , ] . abdominal pain or diarrhea associated with fever suggests neutropenic enterocolitis (typhlitis) which can lead to intestinal necrosis [ , ] . in the hemodynamically unstable patient with a central venous catheter, early catheter removal is associated with improved survival [ ] ; infected or potentially infected catheters should be removed without delay. acute respiratory failure and acute respiratory distress syndrome (ards) are major problems after hsct [ , ] . data from the s indicated that - % of patients undergoing hsct experience a respiratory complication [ ] . more recent data suggest that more than % of patients undergoing allogeneic transplant develop ards with a mortality rate of - % [ , ] . most cases of respiratory failure and ards after hsct are related to infection, either a primary pulmonary infection or sepsis [ ] . common pulmonary infections and associated risk factors are shown in table . hsct [ , ] , and is associated with significant mortality, especially with progression to lower respiratory tract infection [ ] [ ] [ ] . in some cases, antiviral therapy with agents such as oseltamivir (influenza) or ribavirin (respiratory syncytial virus) is indicated [ ] . bacterial pneumonias are also common and may occur as a co-infection or secondary infection with a respiratory virus. fungal and other opportunistic infections such as pneumocystis jirovecii must also be considered [ ] . as in immunocompetent patients, treatment of ards centers on treatment of the underlying cause while providing supportive care with low tidal volume mechanical ventilation. neuromuscular blockade and prone positioning should be considered in patients with an arterial po : fio ≤ mmhg [ ] [ ] [ ] . non-invasive ventilation (niv) is frequently used as firstline respiratory support in hsct patients [ ] . however, early studies which showed a mortality benefit in immunosuppressed patients with using niv compared to invasive mechanical ventilation were limited by relatively few numbers of hsct patients and extremely high mortality in the control groups [ , ] . it is nearly impossible to control delivered tidal volume with niv and high delivered noninvasive tidal volumes are linked to higher rates of niv failure [ ] . more recent data suggest that niv may not be beneficial in hsct patients and heated humidified high-flow oxygen may be a better option [ , [ ] [ ] [ ] [ ] [ ] . chest computed tomography (ct) scanning should be performed in all patients with respiratory symptoms [ ] . the presence of respiratory failure, respiratory symptoms, or abnormalities on chest imaging should prompt evaluation for a respiratory infection. in many cases a non-invasive evaluation is appropriate, but bronchoscopy may be indicated in some patients [ , , ] , and bronchoscopic findings that lead to a change in management are associated with improved outcomes [ ] . two specific forms of respiratory failure after hsct warrant special mention: diffuse alveolar hemorrhage and idiopathic pneumonia syndrome. diffuse alveolar hemorrhage (dah) occurs in up to % of patients and is associate with poor outcomes [ , ] . diagnosis is most commonly made by observation of progressively bloody aliquots of bronchoalveolar lavage. steroids are the mainstay of treatment of dah, with some evidence that efficacy is greatest at doses < mg/day of methylprednisolone equivalent [ ] . idiopathic pneumonia syndrome (ips) is a form of noninfectious lung injury after hsct and is clinically defined by diffuse alveolar injury when infection, cardiac dysfunction, renal failure, and volume overload have been excluded [ ] . ips can have many manifestations, including ards, pulmonary capillary leak, dah, or cryptogenic organizing pneumonia. ips is thought to affect up to % of patients after myeloablative allogeneic hsct, and only ~ % of patients after non-myeloablative hsct. median time of onset of ips [ , ] is days after hsct and mortality ranges from - % in all patients, with nearly % mortality if mechanical ventilation is required [ ] . though the pathophysiology of ips is incompletely understood, research indicating a pathogenic role for tnf-α has led to the use of the anti-tnf-α antibody etanercept to treat ips, with mixed clinical results [ ] [ ] [ ] [ ] . the single randomized placebo-controlled trial in adults included only patients and showed no benefit to etanercept when added to steroids (methylprednisolone mg/kg/ day) [ ] . neurologic complications are frequently encountered after hsct [ ] . intracerebral hemorrhages are a constant threat in thrombocytopenic patients. infections of the central nervous system (cns), including viral, bacterial, and fungal, can occur, and may require modification of antibiotic regimens to ensure cns penetration. seizures and generalized encephalopathy can occur, often with cryptic causes. posterior reversible encephalopathy syndrome (pres) is increasingly recognized, especially in patients receiving tacrolimus-based gvhd prophylaxis. any of these complications may be life-threatening, and close collaboration with neurology and neurocritical care specialists may be required. acute kidney injury (aki) is common after hsct and affects up to % of patients, with higher incidence after allogeneic transplant than autologous transplant [ , ] . in addition to the usual icu causes of aki such as septic shock, there are many specific contributors to the risk of aki in hsct, including preparative chemotherapeutic regimens, nephrotoxins (e.g. tacrolimus, cyclosporine, antimicrobials), elevated cytokine levels, gvhd, and hepatic sinusoidal obstruction [ ] . hemorrhagic cystitis arising from chemotherapy toxicity or viral infection can cause significant blood loss and obstructive nephropathy due to blood clots. management of aki primarily consists of limiting exposure to nephrotoxins (if able) and maintaining adequate hemodynamics. if hemorrhagic cystitis is present, continuous bladder irrigation with a three-way catheter should be considered. the requirement for renal replacement therapy is ominous and portends a high mortality rate [ ] . hepatic veno-occlusive disease (vod), also known as sinusoidal obstruction syndrome, primarily occurs after myeloablative hsct, but can occur after a non-myeloablative transplant [ ] . vod is thought to be caused by damage to the hepatic endothelium and leads to obliteration of hepatic sinusoids and hepatocyte necrosis. incidence of vod is thought to be approximately %, though estimates vary. diagnosis is based on clinical findings (table) including hepatomegaly, elevated bilirubin ascites, and weight gain [ ] . there are limited therapeutic options for vod, and the prognosis is poor. a major complication of allogeneic hsct is graft-versushost disease (gvhd), which is divided into acute and chronic forms. acute gvhd is a major contributor to peritransplant morbidity and mortality, and is caused by donororigin t-cells recognizing recipient tissues as foreign and instigating an immune response against the transplant recipient [ ] . acute gvhd generally occurs within the first days after transplant and can affect the skin, mucosa, intestinal tract, and liver. grading is based on severity of clinical manifestations, which include skin erythema or maculopapular rash; nausea, emesis, or diarrhea, and elevated bilirubin levels ( fig. . , table . ) [ ] [ ] [ ] [ ] . acute gvhd can progress to frank epidermal desquamation, massive diarrhea and hematochezia, and fulminant liver failure, respectively. severe skin acute gvhd behaves much like a burn injury, and the expertise of a burn center may be required. corticosteroids are the mainstay of treatment for acute gvhd, and the prognosis of steroid-refractory disease is poor [ , ] . prophylaxis against gvhd is an essential part of allogeneic transplant regimens and includes a variety of modalities, including calcinuerin inhibitors, anti-metabolites, and post-transplant cyclophosphamide [ ] . as gvhd prophylaxis has improved, more patients are presenting with grade ii or grade iii acute gvhd (and fewer are presenting with grade iv acute gvhd), the incidence of hepatic acute gvhd is decreasing, and overall mortality from acute gvhd is decreasing in patients treated with tacrolimusbased gvhd prophylaxis [ ] . chronic gvhd is the major cause of non-relapse-related mortality after hsct [ ] . despite its name, chronic gvhd is defined clinically, rather than by time after transplant, and can present at any time during the transplant course. by years after transplant, up to - % of patients will have some manifestation of chronic gvhd [ ] [ ] [ ] . though the biology of chronic gvhd is complex and incompletely understood, clinically it mimics autoimmune disease [ ] . while diagnostic criteria include effects on the skin, oral mucosa, eyes, liver, gi tract, joints, genitals, and lungs, chronic gvhd can affect almost any organ system and is staged according to severity of organ involvement [ ] . selected manifestations and diagnostic criteria are in table . . of the manifestations of chronic gvhd, the most relevant to the icu physician is pulmonary chronic gvhd. the only recognized manifestation of chronic pulmonary gvhd is bronchiolitis obliterans syndrome (bos), which is diagnosed by documentation of the new onset of an obstructive ventilator defect (fev : fvc < . and fev < % predicted) and air trapping (documented by expiratory ct scan or pulmonary function tests) in the absence of an explanatory pulmonary infection [ ] . bos results from a b c d peribronchiolar fibrosis and obliteration of small airways resulting in the characteristic obstructive physiology [ ] . interstitial and subpleural fibrosis may also occur, resulting in concomitant restrictive physiology. bos occurs in approximately - % of all patients after allogeneic hsct, and % of those with chronic gvhd, but is likely underdiagnosed [ , , ] . inhaled corticosteroids appear efficacious in improving fev in established bos [ ] . systemic steroids are also commonly used to treat bos and most patients are maintained on anti-gvhd immunosuppression with tacrolimus, sirolimus, or a calcineurin inhibitor [ ] . the combination of inhaled fluticasone, azithromycin, and montelukast (fam) appears to slow the decline in lung function with bos [ ] but has not yet been proven in a randomized controlled trial. while fam is standard therapy for established bos, recent data argue strongly against using azithromycin as prophylaxis against bos due to decreased survival due to a higher rate of hematologic relapse [ ] . though fam has been shown to decrease the progression of bos, mortality due to progressive lung disease remains high, and patients typically present to the icu with respiratory failure. unfortunately, with end-stage bos, there are no effective therapeutic options. a select few patients may be eligible for consideration for lung transplantation, but this is unusual, hsct is increasing in volume and importance as a therapeutic modality, and the volumes of hsct patients requiring critical care is accordingly continuing to increase. there is good reason to think that the pathogenesis of critical illness is substantially different in the immunosuppressed hsct patient. yet our understanding of critical illness in this population is limited, and many practices are extrapolated from the general critical care population without direct evidence in the hsct population. in response to this, research agendas for critically ill hematology and oncology patients have been proposed [ ] . neutropenic sepsis is typically thought of as an uncontrolled variant of non-neutropenic sepsis. however, the real picture is likely much more complicated, and neutropenic sepsis and respiratory failure may be very different from their nonneutropenic counterparts. even the phrase "neutropenic sepsis" is a misnomer, as the hsct myelopreparative regimens also result in pancytopenia. leukopenia, including neutropenia, lymphopenia, and monocytopenia, dramatically changes not only the acute response to infection, but the regulation of the adaptive immune response and the resolution and repair of injury [ , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] . platelets are increasingly recognized to play a vital role in the defense against bacterial, viral, and fungal infections, and like leukocytes, are integral to the development and resolution of organ failure [ ] [ ] [ ] [ ] [ ] . not surprisingly, thrombocytopenia is associated with poor outcomes in critical illness [ ] . taken together, these data strongly support the notion that common critical care conditions, such as sepsis and respiratory failure, may differ dramatically in hsct patients compared to "normal" patients. encouragingly, survival in neutropenic sepsis appears to be improving, but still lags that of non-neutropenic patients [ , , ] , and more research is needed. drug-resistant and multi-drug resistant (mdr) organisms are an increasing problem in hsct patients, and the situation shows no sign of improving [ , , ] . vancomycinresistant enterococcus (vre) bacteremia affects up to % of patients after hsct and is associated with poor outcomes [ ] [ ] [ ] . similarly, mdr gram negative infections, particularly carbapenem-resistant enterobacteriaceae (cre), are associated with high mortality rates in allogeneic hsct patients [ ] . successful treatment cre infections is challenging, and requires early use of multi-drug antibiotic regimens, typically including aminoglycosides, carbepenems, and polymyxins. however, none of the available regimens are particularly effective, and new antimicrobials are desperately needed. an increasingly recognized complication of hsct is hsctassociated thrombotic microangiopathy (hsct-tma) [ ] , which has some features in common with betterknown microangiopathic processes such as thrombotic patients can present to the icu with acute kidney injury and neurologic changes in addition to hemolytic anemia and thrombocytopenia [ , ] . management is predominantly supportive, with blood pressure control, cessation of any possible pharmacologic instigators (tacrolimus or cyclosporine), and renal replacement therapy playing major roles. recent case reports have suggested a possible role in some patients for the anti-cd antibody rituximab or the anti-complement antibody eculizumab, though neither of these agents has been definitively proven effective [ ] . as noted above, advances in transplant techniques have allowed the increased use of alternative donors, including related haploidentical donors [ ] [ ] [ ] . similarly, peripheral blood stem cells (pbsc) are increasingly used for transplant instead of bone marrow stem cells [ ] . however, the use of peripheral blood results in a larger number of donor t-cells included in the transplanted stem cells. this higher t-cell dose can result in a profound syndrome of fevers, vascular permeability, hemodynamic instability, acute kidney injury, and respiratory failure. this constellation of findings is associated with elevated levels of inflammatory cytokines and has accordingly been labeled as cytokine release syndrome (crs). while most associated with chimeric antigen receptor (car) t-cell therapy [ ] , crs is increasing recognized after pbsc transplant and is associated with poor outcomes [ ] . emerging data suggest that anti-il- therapy with tocilizumab may improve outcomes, but more research is needed [ ] . hsct continues to grow as a therapeutic modality and the pool of both potential donors and recipients continues to increase. as hsct volumes increase and the complexity and potential toxicity of hsct regimens expands, the number of critically ill hsct patients will increase [ ] . in response to this growing icu volume, some centers continue to admit hsct patients to general icus, but many high-volume transplant centers have developed specialty hsct icus. while specialty hsct icus have a number of potential benefits, there are few data to support (or dissuade) their development. development of best practices for the provision of critical care to hsct patients, including the optimum icu organization is an important area for study [ ] . great progress in the critical care of hsct patients has been made, but with continued basic and clinical research and further development of the sub-specialty of oncologic critical care, outcomes for critically ill hsct patients should continue to improve. current uses and outcomes of hematopoietic cell transplantation (hct): cibmtr summary slides hematopoietic stem cell compartment: acute and late effects of radiation therapy and chemotherapy the significance and regulatory mechanisms of innate immune cells in the development of sepsis mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview inflammatory response to mucosal barrier injury after myeloablative therapy in allogeneic stem cell transplant recipients mucosal barrier injury, fever and infection in neutropenic patients with cancer: introducing the paradigm febrile mucositis deactivation of alveolar macrophages in septic neutropenic ards monocyte deactivation in neutropenic acute respiratory distress syndrome patients treated with granulocyte colonystimulating factor bronchoalveolar lavage during neutropenic episodes: diagnostic yield and cellular pattern critical care of the hematopoietic stem cell transplant recipient outcomes of critically ill patients with hematologic malignancies: prospective multicenter data from france and belgium--a groupe de recherche respiratoire en reanimation oncohematologique study managing critically ill hematology patients: time to think differently critically ill allogenic hsct patients in the intensive care unit: a systematic review and meta-analysis of prognostic factors of mortality clinical practice guideline for the use of antimicrobial r. s. stephens agents in neutropenic patients with cancer: update by the infectious diseases society of america diagnosis and empirical treatment of fever of unknown origin (fuo) in adult neutropenic patients: guidelines of the infectious diseases working party (agiho) of the german society of hematology and medical oncology (dgho) recent changes in bacteremia in patients with cancer: a systematic review of epidemiology and antibiotic resistance current epidemiology and antimicrobial resistance data for bacterial bloodstream infections in patients with hematologic malignancies: an italian multicentre prospective survey severe sepsis in hematopoietic stem cell transplant recipients * survival in neutropenic patients with severe sepsis or septic shock prognosis of neutropenic patients admitted to the intensive care unit management of sepsis in neutropenic patients: updated guidelines from the infectious diseases working party of the german society of hematology and medical oncology (agiho) cohort study of the impact of time to antibiotic administration on mortality in patients with febrile neutropenia surviving sepsis campaign: international guidelines for management of sepsis and septic shock: beta-lactam versus beta-lactamaminoglycoside combination therapy in cancer patients with neutropenia beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis liposomal amphotericin b for empirical therapy in patients with persistent fever and neutropenia. national institute of allergy and infectious diseases mycoses study group caspofungin versus liposomal amphotericin b for empirical antifungal therapy in patients with persistent fever and neutropenia neutropenic enterocolitis: new insights into a deadly entity the prognostic impact of abdominal surgery in cancer patients with neutropenic enterocolitis: a systematic review and meta-analysis, on behalf the groupe de recherche en reanimation respiratoire du patient d'onco-hematologie (grrr-oh) acute respiratory distress syndrome in patients with malignancies acute respiratory distress syndrome during neutropenia recovery pulmonary complications of bone marrow transplantation outcomes of stem cell transplant patients with acute respiratory failure requiring mechanical ventilation in the united states epidemiology of acute respiratory distress syndrome following hematopoietic stem cell transplantation pulmonary infections complicating hematological disorders febrile neutropenia: significance of elaborated screening for respiratory viruses, and the comparison of different sampling methods, in neutropenic patients with hematological malignancies viral pneumonia in patients with hematologic malignancy or hematopoietic stem cell transplantation mortality rates of human metapneumovirus and respiratory syncytial virus lower respiratory tract infections in hematopoietic cell transplantation recipients bcsh/bsbmt/uk clinical virology network guideline: diagnosis and management of common respiratory viral infections in patients undergoing treatment for haematological malignancies or stem cell transplantation management of rsv infections in adult recipients of hematopoietic stem cell transplantation management of respiratory viral infections in hematopoietic cell transplant recipients and patients with hematologic malignancies fungal pneumonia in patients with hematologic malignancy and hematopoietic stem cell transplantation ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome neuromuscular blockers in early acute respiratory distress syndrome prone positioning in severe acute respiratory distress syndrome immunocompromised patients with acute respiratory distress syndrome: secondary analysis of the lung safe database noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure the intensive care medicine research agenda on critically ill oncology and hematology patients failure of noninvasive ventilation for de novo acute hypoxemic respiratory failure: role of tidal volume noninvasive ventilation during acute respiratory distress syndrome in patients with cancer: trends in use and outcome effect of noninvasive ventilation vs oxygen therapy on mortality among immunocompromised patients with acute respiratory failure: a randomized clinical trial acute respiratory failure in patients with hematological malignancies: outcomes according to initial ventilation strategy. a groupe de recherche respiratoire en reanimation onco-hematologique (grrr-oh) study high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure diagnostic strategy for hematology and oncology patients with acute respiratory failure: randomized controlled trial diagnostic bronchoscopy in hematology and oncology patients with acute respiratory failure: prospective multicenter data outcome of alveolar hemorrhage in hematopoietic stem cell transplant recipients low-, medium-and high-dose steroids with or without aminocaproic acid in adult hematopoietic sct patients with diffuse alveolar hemorrhage an official american thoracic society research statement: noninfectious lung injury after hematopoietic stem cell transplantation: idiopathic pneumonia syndrome etanercept and corticosteroid therapy for the treatment of late-onset idiopathic pneumonia syndrome high-dose corticosteroids with or without etanercept for the treatment of idiopathic pneumonia syndrome after allo-sct tnf-receptor inhibitor therapy for the treatment of children with idiopathic pneumonia syndrome. a joint pediatric blood and marrow transplant consortium and children's oncology group study (asct ) the impact of soluble tumor necrosis factor receptor etanercept on the treatment of idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation randomized, double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor: enbrel (etanercept) for the treatment of idiopathic pneumonia syndrome after allogeneic stem cell transplantation: blood and marrow transplant clinical trials network protocol risk factors for icu admission and icu survival after allogeneic hematopoietic sct mini-review of kidney disease following hematopoietic stem cell transplant a multicenter, retrospective study of acute kidney injury in adult patients with nonmyeloablative hematopoietic sct hepatic veno-occlusive disease after hematopoietic stem cell transplantation: risk factors and stratification, prophylaxis, and treatment venoocclusive disease of the liver following bone marrow transplantation acute graft-versus-host disease -biologic process, prevention, and therapy graft-versus-host disease international, multicenter standardization of acute graftversus-host disease clinical data collection: a report from the mount sinai acute gvhd international consortium atlas of graft-versus-host disease: approaches to diagnosis and treatment improved survival after acute graft-versus-host disease diagnosis in the modern era high-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease the biology of chronic graft-versus-host disease: a task force report from the national institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease late acute and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation pathophysiology of chronic graftversus-host disease and therapeutic targets national institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: i. the diagnosis and staging working group report bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation-an increasingly recognized manifestation of chronic graft-versus-host disease bronchiolitis obliterans syndrome epidemiology after allogeneic hematopoietic cell transplantation budesonide/formoterol for bronchiolitis obliterans after hematopoietic stem cell transplantation fluticasone, azithromycin, and montelukast treatment for new-onset bronchiolitis obliterans syndrome after hematopoietic cell transplantation effect of azithromycin on airflow decline-free survival after allogeneic hematopoietic stem cell transplant: the allozithro randomized clinical trial neutrophils in critical illness neutrophil recruitment and function in health and inflammation impaired lung repair during neutropenia can be reverted by matrix metalloproteinase- the role of neutrophils in immune dysfunction during severe inflammation neutrophil-mediated suppression of influenza-induced pathology requires cd b/cd (mac- ) role of circulating lymphocytes in patients with sepsis neutropenic sepsis is associated with distinct clinical and biological characteristics: a cohort study of severe sepsis platelet tlr activates neutrophil extracellular traps to ensnare bacteria in septic blood blood platelets and sepsis pathophysiology: a new therapeutic prospect in critical ill patients? ann intensive care thrombocytopenia impairs host defense in gram-negative pneumonia-derived sepsis in mice platelets in pulmonary immune responses and inflammatory lung diseases small but mighty: platelets as central effectors of host defense thrombocytopenia is associated with a dysregulated host response in critically ill sepsis patients clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: update by the infectious diseases society of america clinical impact of pretransplant multidrug-resistant gramnegative colonization in autologous and allogeneic hematopoietic stem cell transplantation impact of vancomycin-resistant enterococcal bacteremia on outcome during acute myeloid leukemia induction therapy colonization, bloodstream infection, and mortality caused by vancomycin-resistant enterococcus early after allogeneic hematopoietic stem cell transplant early vancomycin-resistant enterococcus (vre) bacteremia after allogeneic bone marrow transplantation is associated with a rapidly deteriorating clinical course the global challenge of carbapenem-resistant enterobacteriaceae in transplant recipients and patients with hematologic malignancies emerging concepts in hematopoietic stem cell transplantation-associated renal thrombotic microangiopathy and prospects for new treatments hematopoietic stem cell transplant-associated thrombotic microangiopathy outcomes of related donor hla-identical or hla-haploidentical allogeneic blood or marrow transplantation for peripheral t cell lymphoma outcomes of nonmyeloablative hlahaploidentical blood or marrow transplantation with high-dose post-transplantation cyclophosphamide in older adults hla-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide peripheral-blood stem cells versus bone marrow from unrelated donors management of the critically ill adult chimeric antigen receptor-t cell therapy patient: a critical care perspective severe cytokine-release syndrome after t cell-replete peripheral blood haploidentical donor transplantation is associated with poor survival and anti-il- therapy is safe and well tolerated key: cord- -cyhcbk j authors: nan title: ps - date: - - journal: intensive care med doi: . /s - - -y sha: doc_id: cord_uid: cyhcbk j nan in our -bed icu-cum-hdu of a -bed tertiary referral cancer centre, medical oncology admissions increased from < % of total admissions to over % in the last years. we audited outcomes in these patients to determine prognostic factors that may aid patient selection and management. methods. consecutive admissions ( males, females, age > years) from february , to february , were prospectively studied. the total sofa score on day (sofa ), the highest sofa score of the first three days (max ) and the change in sofa score between day and day (delta ) and between day and day (delta ) were calculated. predictors of outcome were identified using univariate and multivariate binary logistic regression. results. patients had solid tumours , had leukemia, lymphoma, myeloma, and had other diagnoses. mean age was . ± years and apache ii score was . ± . . icu mortality was % and hospital mortality . %. / patients ( . %) with icu stay < day died. overall length of icu stay was . ± . days. in survivors vs. nonsurvivors, sofa , delta and delta (median, interquartile range) were . ( . to . ) vs. . ( . to . ; p< . ), - . (- . to ) vs. . (- . to . ; p< . ) and (- . to . ) vs. . (- . to . ; p< . ), respectively. several factors were associated with mortality on univariate analysis (table ) . on multivariate analysis, only need for vasopressors (or . , p= . ) and max (or . , ci . - . , p= . ) were independently associated with hospital mortality, while type of cancer and leucopenia were not. for patients staying > days, no factor predicted hospital mortality, but sofa (or . , ci . - . , p= . ), delta (or . , ci . - . , p= . ) and delta (or . , ci . - . , p= . ) predicted icu mortality. usually, the cgr transfused in our icu are old (about % of rbc are stocked more than days). icu outcome is independently associated with the number of rbc transfused, but not with their age. this result in contradiction with previous report could possibly be explained by the systematic leucodepletion performed before storage in france, contrary to precedent studies where rbc were not leukodepleted. we compared them with ≥ years old and an icu stay < days patients, the differences in icu mortality, apache ii, age, gender and the necessity for renal replacement therapy (rrt) were not significant (see table) . the survivors patients (≥ years old and an icu stay ≥ days) were more older and ( ' %) were still alive one year later. when we analyzed the overall patients, according their stay < or ≥ days, did not find statistically significant differences between both groups in the mortality (p= ' conclusion. icu mortality rates in elderly patients with a stay < or ≥ days at icu were comparable. the year-survival of elderly patients with a long-term intensive care unit stay was high. results. seventy patients were admitted to our icu with the diagnosis of acute pancreatitis during study period and of them were later confirmed as having sap. the average icu length of stay in patients with sap was days compared to days in patients with mild form of the disease. pancreatic infection was present in patients. the mortality rate in the group with sap was % compared to , % in the group with mild acute pancreatitis, p< , . the most common etiology of patients with sap was biliary and this was similar both in survivors and non-survivors. the most common cause of death in the group with sap was multiple organ dysfunction/failure syndrom(mods/mof) in % followed by bleeding complications in %. twelve patients with sap ( %) underwent the surgical intervention. mortality in the group of patients who underwent a surgical intervention was % ( patients). , +/- , , +- , apache ii score( mean+/-sd) , +/- , , +- , * necrotising form (%) infected necrosis (%) ct guided fnab (%) * p > . conclusion. the patients with mild form of acute pancreatitis had low mortality rate (similar to general ward population) despite positive icu admission criteria in our case series with fifty per cent development of severe form with organ dysfunction/failure later on. apache ii score was better predictor of mortality in patients with sap than presence, extent or infection of pancreatic necrosis. patients with higher risk for development of severe form of acute pancreatitis should be admitted to multidisciplinary icu prior to definitive diagnostic evaluation of pancreas. further studies are warranted. conclusion. absi is an aprropiate score for estimating the probability of death in critical brun injury patients. preexisting cardiac and liver diseases have a little influence on mortality and its addition to the absi variables don't predict mortality more accurately. poisoned patients constituted up to , % of all icu admissions in our hospital. demographic data and specific poisons have been presented at the table. the total poisoned mortality rate was , %. methyl alcohol poisoning has a higher mortality than others poisoning. conclusion. childhood poisoning is usually accidental and is usually associated with a low morbidity and mortality. in adults, self-poisoning is usually deliberate suicide or parasuicide) and has a higher morbidity and mortality rate. ( ) the most important part of the poisoned patient's care are the general supportive management and specific antidotes therapy. it has abundantly been demonstrated that duration of mechanical ventilation can be reduced by the use of protocols for weaning and sedation [ , ] . utilization of the required sedation scales and adherence to protocols, however, is poor in daily practice, as has been shown in recent studies [ , ] . it has been proposed to use daily checklists to improve the quality of care [ ] . to improve adherence to the established guidelines for weaning and sedation in our icu, we included two questions in a checklist printed on patients' charts which had to be answered daily by the physician on duty: conclusion. the checklist as a daily reminder to observe established weaning and sedation protocols may have significantly accelerated weaning from mechanical ventilation. we carried out a prospective and descriptive study in patients admitted to our icu from to . we defined tolerance as the need to use more than mg/h, at least for four hours, or the need either to use or to change to other sedatives to obtain a to level on the ramsay scale ( ). the appearance of tolerance in the first hours was considered as tachyphylaxis or early therapeutic failure to this sedative. in our sedation protocol we use propofol preferably in patients who need frequent neurological consciousness evaluations, or in patients whose sedation is expected to have short to medium duration, and who have haemodynamic stability. also, we use propofol as a sequential strategy when early weaning from ventilation is expected. all patients received analgesic drugs. during this time, we admitted patients, of them needed mechanical ventilation and in patients we administered continuous analgesic and sedative infusions. continuous propofol infusions were administered in patients at some point of their sedative strategy, and ( % of the sedated patients) received propofol for more than hours. tolerance development was observed in patients, % of the patients sedated with propofol. in thirty-seven of them, this situation was present in the first hours (early therapeutic failure). conclusion. in our sedative protocol for propofol use, the incidence of tolerance in patients sedated with this drug was %, which is substantially less than the usual described midazolam tolerance. most of these cases ( %) happened in the first hours. diabetes mellitus (dm) with its chronic and acute complications puts patients suffering from the disease at increased risk. none of the scoring systems used for risk prediction in intensive care units accounts for diabetes as a risk factor, although, in everyday practice, patients with dm admitted to icus may be recognized as those with higher risk. not much data is available on how much risk can be attributed to diabetes. we have compared course and outcome of patients with dm with non-diabetics to try to answer this question. we have analyzed data from the "croicu.net", national pilot-project which collects data on patients from icus in croatia. data collected during the first months (nov -dec have been analyzed. adult patients from icus in university hospitals were included; three most frequent admission diagnoses were selected for comparison of diabetic and non-diabetic patients. the diagnosis of dm had to be established prior to admission according to the usual criteria. icu mortality and icu length of stay (los) were primary outcome measures. incidence of organ failure was a measure of disease course. in the analysed period there were admissions to the analysed icus, ( . %) with documented dm prior to admission. patients with md did not differ significantly from non-diabetics in age or sex distribution. overall mortality was higher for dm patients ( . % vs. . %), as was los ( . vs. . days). three most frequent diagnoses were: sepsis (n= ; . %), pulmonary oedema ( ; . %) and myocardial infarction (n= ; . %). patients with diabetes had significantly higher mortality and higher los in all three subgroups. in the sepsis subgroup, patients with diabetes had higher incidence of organ failure and higher number of failing organs. in the other two subgroups, the differences were not significant. in multivariate analyses which was performed separately for all three diagnoses and included dm, age, apache ii score and sofa score, diabetes mellitus was shown to be an independent predictor of mortality and los in all three cases. although some chronic effects of diabetes mellitus can be included in multiparameter scoring systems such as apache ii score, the disease itself is not scored. we have shown on three most common diagnoses in icus of university hospitals that diabetes mellitus is an independent predictor of mortality and los and that it has significantly higher incidence of organ failure in sepsis. patients with dm should be given appropriate attention as high risk patients in the icu. introduction. neuromuscular abnormalities are common in critically ill patients with systemic inflammation and organ failures. we assessed the incidence of a clinically diagnosed critical illness polyneuro-myopathy (cipm), and its potential impact on mortality and long-term neurological outcome. methods. consecutive critically ill patients on mechanical ventilation for hours and with the presence of or more sirs criteria were prospectively studied. based on daily clinical neurological examinations, cipm was defined as symmetric limb muscle weakness [ or more muscle groups, m or less (mrc)] without other explanation than cipm in patients with normal neurology at icu admission. a barthel index (score for activities in daily living) was performed at day and months after icu discharge. after months a neurological examination was also performed. . cipm was diagnosed in patients ( %). patients with suspected cipm had a prolonged icu stay and a high mortality. the barthel index was significantly lower in this group at day but improved over the next six months. of patient who survived could be reached months after discharge and of them were clinically examined. at this time the most compromised activity in daily living is climbing stairs. patients with a clinical diagnosis of cipm have a high mortality. if they survive, they are severely limited in simple daily activities one month after icu discharge, but improve later. host infection by pathogens triggers innate immune response leading to a systemic inflammatory response, often followed by a paradoxical compensatory antiinflammatory response. this immune dysfunction can impair the eradication of primary infections and favor the emergence of nosocomial sepsis. dendritic cells (dcs) have a central role in initiation and control of innate and adaptative immune responses to infectious challenges. dcs might contribute to sepsis-induced immunodepression. indeed, depletion of dcs has been reported in secondary lymphoid organs of patients who died from sepsis and in animal models of lethal sepsis. in order to investigate the mechanisms of sepsis-induced immunodepression, we studied quantitative and functional features of dcs in a murine model of sublethal sepsis. we developed a sublethal murine model of polymicrobial sepsis through cecal ligature and puncture followed by short course of antibiotics and volume resuscitation. we isolated splenic dcs by immunomagnetic procedure and generated bone marrow-derived dcs (bmdcs) by -day culture of medullar progenitors in the presence of gm-csf before stimulation with lps to induce maturation. we counted spleen dcs and studied the following functional features of spleen dcs and bmdcs in the early (day ) and late (day ) phases of sepsis : maturation (expression of mhcii, cd and cd through facs analysis), production of cytokines (tnf-alpha, il- , il- ) and priming of cd -positive t-cell lymphocytes ( h-thymidine proliferation assay in allogeneic mixed lymphocyte reaction). upon anesthesia induction with isoflurane sepsis was initiated by cecal ligation and double puncture in groups of c bl/ j-mice per group [ g, g, g] (clp). control mice underwent laparatomy and manipulation of the cecum only (sham). , and hrs post-surgery in and g mice and hrs post surgery in g mice single cell suspensions of thymus and spleen were analyzed by means of cell surface staining and flow cytometry. fluorescence-labeled antibodies included cd , cd , cd , b , igm, igd, cd , cd . data are presented as mean+sem. results. similar to previous results, thymi primarily demonstrated a time-dependent reduction of cd +cd + double-positive cells which was more pronounced during severe sepsis ( + g). at hrs post-clp cd + cells and cd + t-cells recovered to values of sham mice in g animals, which previously recovered fastest with highest survival rates of about %. in contrast cd + cells and cd + cells, respectively, raised to maximum levels at hrs in g animals. concerning spleocytes cd + and cd + cells were similarly reduced to about % and % after hrs and to % and % in g and g mice compared to sham mice. splenocytes of g-treated mice, which could only be investigated at hrs postclp showed no difference to sham mice. as far as b cells are concerned no significant differences between the groups or different time points could be detected. relative numbers of peripheral t cells expressing the early activation marker cd or cd were clearly more pronounced at hrs compared to hrs in and g mice. in g treated mice cd and cd positive t cells were significantly higher at hrs compared to sham mice. a mild clp model is more appropriate to study during murine sepsis. the rapid occurrence of peripheral activated t cells suggest a very early function of the adaptive immune system during sepsis. considering a milder disease course of g mice they seem to more efficiently use their t cells to fight the infection. thymocyte data suggest a block in lymphopoiesis from cd -cd -to cd +cd +. b cells are not likely to play a major role in polymicrobial murine sepsis. further studies have to be performed to elucidate the turnover and the homing of lymphocytes during sepsis. endotoxaemia is associated with intestinal perfusion deficits and gut barrier failure. regional sympathetic blockade by means of thoracic epidural anaesthesia (tea) has been shown to positively affect intestinal microcirculation during endotoxaemia. this study tests the hypothesis that the microvascular changes observed with tea go along with an increase in overall gastrointestinal blood flow. in addition we investigated whether the use of tea influences gut barrier function. after approval of the animal care committee rats were anaesthetised (urethane/ketamine), hemodynamically monitored and mechanically ventilated with room air. lidocaine % or normal saline were administered as a bolus ( µl) and subsequent continuous infusion ( µl x h − ) via an epidural catheter (tip at t / , spread t -t ). organ blood flow (n = rats) was measured by the fluorescent microspheres technique at baseline, min after epidural infusion, and min and min after the infusion of endotoxin (e. coli lipopolysaccharide, . mg x kg- x h − ) or normal saline. for assessment of gut barrier failure rats (n = ) received a bolus infusion of endotoxin ( mg x kg- ) or normal saline and epithelial permeability to low molecular fluorescein isothiocyanate-dextran ( kd) was quantified using a ligated loop of terminal ileum after hours of normotensive endotoxaemia. in hypodynamic shock models pure o breathing was shown to redistribute blood flow in favour of hepato-splanchnic organs and to improve survival. in contrast, this therapeutic approach has not yet been evaluated in hyperdynamic septic shock, since an increased production of o radicals, which is directly related to the increased o partial pressure, is considered as harmful. therefore, we investigated the effects of pure o breathing on hepato-splanchnic macro-and microcirculation, energy balance and tissue cell death during porcine fecal peritonitis. after induction of fecal peritonitis, pigs were randomly ventilated for h with % o (n= ) or an fio adjusted to yield a sao > % (n= ). before as well as at and h of peritonitis we measured cardiac output as well as hepatic artery and portal vein (pv) flows (ultrasound flow probes), microcirculation in the intestinal wall (laser doppler flow), intestinal wall oxygenation, portal and hepatic-venous acid-base status, and lactate/pyruvate (l/p) ratios. apoptosis was analysed post-mortem in liver biopsies with the tunel assay. within group effects were analyzed using a friedman anova on ranks, intergroup differences with an unpaired rank sum test. at the end of experiment the contribution of both pv and total liver blood flow to cardiac output was significantly higher in the hyperoxic animals than in the control group (qliver/co ( ; )% vs. ( ; )%, p= . ; qpv/co ( ; )% vs. ( ; )%, p= . , respectively), which was concomitant with attenuated regional venous metabolic acidosis and lower hepatic-venous l/p-ratios. intestinal wall microcirculation and oxygenation did not significantly differ between the two groups. the hyperoxic animals presented with a markedly reduced number of apoptotic cells in the liver. our results show that early % o ventilation redistribute blood flow in favour of the hepato-splanchnic system even in peritonitis-induced hyperdynamic septic shock. furthermore, the hepatic energy balance is improved and the morphologic integrity of the liver better maintained under these conditions. grant acknowledgement. supported by the eli lilly-esicm sepsis elite award, the alexander-von-humboldt-stiftung, and the deutscher akademischer austauschdienst glucocorticoids are known as strong modulators of immune response that play an important role in patophysiology of sepsis and inflammation. they have strong influence on the development of immune system, its effector functions, and trafficking of immune cells.the biological activity of glucocorticoids depends not only on their plasma concentration, the number of receptors and the responsiveness of the target cells but also on the local metabolism of glucocorticoids that is predominated by b-hydroxysteroid dehydrogenase ( hsd). two isoforms of hsd are known. the isoform hsd operates in vivo predominantly as a nadph-dependent reductase that locally increases glucocorticoid concentration (cortisol, corticosterone) by reduction their -oxo derivatives (cortisone, dehydrocorticosterone) . the isoform hsd is a sole nad+-dependent dehydrogenase that inactivates biologically active glucocorticoids to their inactive -oxo derivatives. the aim of this study was to investigate peripheral metabolism of glucocorticoids in immune cells and tissues in experimental model of sepsis and inflammation. sepsis was induced in balb/c mice and wistar rats by intraperitoneal administration of lipopolysaccharide or pooled fecal inoculum. in these animals and in healthy controls we measured expression and activity of hsd in lymphatic nodes, peripheral blood leukocytes and alveolar macrophages. activity was measured by incubation with corticosterone and -dehydrocorticosterone, following hplc determination. the abundance of hsd mrna was measured by semi-quantitative real-time rt-pcr. for years etomidate has been known to cause adrenal insufficiency in the critically ill and is a confounder when studying corticosteroids in septic shock. subgroup analysis of a prospective, randomized, placebo-controlled study of corticosteroids in septic shock. patients underwent a short high dose acth test before study drug administration. patients received d treatment with hydrocortisone (hc) or placebo (p). the affects of etomidate administration on acth responsiveness and d mortality were studied. results. patients were enrolled. overall . % patients died in the hc group and % in the p group (p= . ). in total % of patients received etomidate. received etomidate before baseline [ % hc group + % p group] and in after baseline [ % hc group + % p group]. overall, more of the patients receiving etomidate were acth nonresponders [ % vs %] . no mortality differences was seen between patients receiving etomidate at any time during study and those who did not receive etomidate [ . % vs. . %](p= . ). there was a possible trend towards a difference in mortality between patients who received etomidate in the hrs before randomisation [ % hc vs. % p] or not receiving etomidate during this time period [ % hc vs. % p](p= . ). etomidate was commonly used in patients in the corticus study. etomidate was associated with an increased likelihood of adrenal hyporesponsiveness in all patients. there was no increase in mortality associated with etomidate administration at any time, there was a trend towards increased mortality in those who received it in the hours before trial baseline. this result comes from an underpowered subgroup and should be considered exploratory. d. pestaña* , e. martinez-casanova , a. buño , r. madero , a. criado anestesia-reanimación, análisis clínicos, bioestadística, hospital universitario la paz, madrid, spain introduction. steroids are indicated in septic shock patients when relative adrenal insufficiency is suspected. our aim was to study if the measurement of total proteins ( ) and eosinophil count ( ) improves the accuracy of cortisolemia to predict the hemodynamic response to steroid treatment in this setting ( ). we analysed data from consecutive surgical patients with criteria of septic shock receiving steroid treatment. four criteria were chosen to define hemodynamic improvement based on the combination of noradrenaline (na) withdrawal (at and h) and an increase of the hemodynamic index (hi = mean arterial pressure/na dose) of % at h and of % at h. the accuracy of the baseline cortisolemia to predict the hemodynamic response to steroid treatment following the four criteria was determined by roc curve analysis. the largest area under curve (auc) was found for the noradrenaline withdrawal or an increase of the hi > % at h after starting the steroid treatment (table ) . this criteria was met by patients ( %) and was associated with a lower mortality ( . % vs . %, p= . , % sensibility and . % specificity). however, no clear cortisolemia cut-off value for the diagnosis of adrenal insufficiency based on the hemodynamic response could be found. neither the basal proteins nor the eosinophils improved the accuracy of cortisolemia to predict a hemodynamic improvement. mortality was also related to age (p= . ), apache ii (p= . ) and sofa score (p= . ). neither basal cortisolemia nor lactate were related with icu mortality. twelve septic shock patients admitted to the icu < hours after family consent were enrolled. we excluded all patients in use of steroids in the preceeding months, etomidate, espironolactone, oestrogens, oral contraceptives, ketoconazole or any other drug known to suppress adrenal function; aids, pregnancy, history of disease of the hypothalamic-pituitaryadrenal axis, shock of other etiologies. after a baseline serum cortisol was obtained, a ld ( ug) corticotropin stimulation testing was performed. subsequently, serum cortisol at and min was measured. four hours later, another bc was obtained. then, a hd ( ug) corticotropin stimulation testing test was performed and serum cortisol was again measured after and min. results. both baseline serum cortisols were similar. delta hd cortisol was higher than delta ld cortisol ( . ± . vs. . ± . ug/dl, p= . ). five patiens had a bc < ug/dl, but only one showed rai in both tests. concordance between ld and hd tests was % ( / ). it was strong for responders ( %, / ) but weak for non-responders to ld test ( %, / ). the preliminary results of our study suggest that a ld test is a more sensitive test than a hd test. a further study comparing treatment of rai defined by a ld or a hd test is still needed. the potassium channels (kc), atp-sensitive k+ (katp) channels and calcium-activated potassium (bk) channels, may be implicated in shock induced vasoplegia. the aim of our study was to demonstrate that the potassium channels are overexpressed in experimental shock independently of the etiology. three rats models of shock were used : peritonitis by caecal ligation and perforation (clp, n= ) observed at h, ischemia-reperfusion model (hemorrhagic shock + resuscitation + laparotomy, n= ) observed at h, and pressure fixed hemorrhagic shock (n= ) observed at h. these three models were compared to a control group. we performed quantitative real-time pcr (lightcycler technology -roche -and sybr green -sigma) and western blot on aorta and mesenteric arteries. we studied the expression of the vascular smooth muscle katp channels -kir . and sur b subunits -and bk channels -bk alpha subunit. we assessed the inflammatory syndrome in studying inos expression. we were able to detect kir . , sur b, bk alpha and inos arnm in both vessels. quantitative real-time pcr results (reference gene : beta-actine) clp clp ir ir hs hs aorta mesenteric aorta mesenteric aorta mesenteric inos . ± . * . ± . * . ± . * . ± . * . ± . * . ± . * expression kir . . ± . . ± . * . ± . * . ± . * . ± . * . ± . * expression sur b . ± . . ± . * . ± . * . ± . * . ± . * . ± . expression bk alpha . ± . * . ± . * . ± . * . ± . * . ± . . ± . expression * : p< . vs control group conclusion. various potassium channels are activated and up-regulated during shock independently of the etiology. thus, potassium channels likely play a major role in sepsis but also in prolonged and severe hemorrhagic shock and in ischemia reperfusion. (cars) . a predominantly anti-inflammatory reaction induces immunosuppression with impaired host defense. application of gm-csf to patients with major surgery or sepsis has been proposed to improve host-defense. in this study we investigated the differential effects of gm-csf production in an ex-vivo model. and lps on the tnf-a. whole blood of healthy donors (age - years, mean years) was used to determine optimal concentrations and incubation time for lps. the immunomodulating properties of gm-csf (leukine ® (sargramostim), berlex)) were investigated in whole blood of healthy donors ( - years, mean years) and icu patients suffering from sepsis. six of the patients had immunoparalysis as defined according to local standards by a monocytic hla-dr expression of < mfi and an ex-vivo stimulation test of < pg/ml after lps incubation (dpc biermann, bad nauheim , germany), whereas the other displayed a hla-dr expression of > mfi and a ex-vivo stimulation test of > pg/ml. samples were primed either with gm-csf, gm-csf simultaneously or lps prior to incubation. tnf-a and il- concentrations were determined with the immulite chemoluminescence immunoassay system (dpc-biermann, bad nauheim, germany). leukocyte phenotyping was performed by dual-colour flow cytometry using whole blood lysis technique and monoclonal antibodies. in healthy donors, ex-vivo stimulation with lps leads to a massive increase of tnf-a production. however, if whole blood is incubated with gm-csf hours prior to the lps challenge, the tnf-a production is significantly increased. the simultaneous incubation with lps and gm-csf leads to a significant decrease in tnf-a levels in the same patient population. gm-csf stimulation of whole blood hours after the production. in patients lps challenge causes no significant change in tnf-a levels of with sepsis and endogenous tnf-a < pg/ml, gm-csf pre-incubation production, whereas patients leads to a significant increase in ex-vivo tnf-a had a blunted ex-vivo reaction to lps with higher endogenous levels of tnf-a stimulation. both the sequence of stimulation with either gm-csf or lps and the presence or absence of systemic tnf-a determine the ex-vivo cytokine response of whole blood. hence, it may be speculated that . the administration of gm-csf prior to the inflammatory stimulus would be most efficient, and that . the lack of stimulation effect in patients with high endogenous tnf-a may mirror endotoxin tolerance. the most common acquired causes of weakness and muscle wasting in the critically ill patient in the intensive care units (icu) are critical illness polyneuropathy and critical illness myopathy. there is significant clinical and neurophysiologic overlap between the two conditions, such that the term critical illness polyneuropathy and myopathy (cipnm) is often used. over a -mo period, critically ill patients who needed prolonged intensive care were studied. clinical manifestations include delayed weaning from the respirator not explained by pulmonary complications, muscle weakness and prolonging of the mobilization phase. included patients were classified as having mof, sirs and sepsis according to established consensus definitions. the occurrence of a positive emg for cipnm, as defined by an electrophysiologist who was blinded for treatment allocation, was analyzed during icu stay. variables recorded at baseline and during follow-up included patient demographics, principal diagnosis, routine blood tests and microbiological culture results. levels of tnf-alpha, il- , il- , il- , procalcitonin (pct) and c-reactive protein concentrations were repeatedly measured by elisa. all patients were divided in: patients without cipnm at any time (group a, n= ), with a positive emg during icu stay (group b, n= ), and with a diagnosis of cipnm since the admission (group c, n= ). emg testing demonstrated severe acute denervation with striking involvement of proximal muscles in patients. patients died of complications of sepsis. critically ill patients without cipnm showed serum il- levels lower (p < , ) than those with a diagnosis of cipnm while no differences were found as concerned serum il- levels. il- and tnf-alpha did not show any difference between the two groups. il- levels resulted higher in groups a and b (p < , ) while il- levels were higher in group a (p < , ). in the group b, we observed a characteristic pattern of il- and il- serum concentrations that may be important for clinical outcome. il- levels were higher than il-l in patients with worse clinical outcome. the opposite pattern was observed in those with a good prognosis. no differences in clinical and laboratory variables were observed between patients with and without cipnm. pct appeared to be most helpful in differentiating patients with sepsis from those with sirs (p < , ), exhibiting a greatest sensitivity ( %) and specificity ( %). conclusion. the analysis of the serum cytokines il- , il- , tnf-alpha and il- to standard indicator did not improved the predictive power of detecting cipnm but may contribuite to explain its pathogenesis. high dose glucocorticoids are known to induce muscle weakness. we investigated in a pilot study the occurrence of cip/cim in septic shock patients treated with low dose hydrocortisone (hc). patients were enrolled in the randomized controlled study of hc in septic shock (corticus) and received hc ( mg q h for days, tapered until day ) or placebo (pl). electrophysiological testing (ep) consisted of the assessment of compound muscle (cmap) and sensory nerve action potentials (snap), spontaneous activity (spa), and muscle membrane excitability investigated by direct muscle stimulation (dms). clinical muscle weakness was defined by a medical research council scale (mrc) below . cmap and snap were categorized based upon normal age related values. ep results were categorized as unspecific (cim or cip or both) when cmaps and spas were pathological in >/= muscles. presence of cip was defined by pathological snaps in >/= nerve, and cim by dms values < mv. data are shown as mean and %ci, chi square test and mann-whitney-u-test were performed for statistical analysis. from jun -feb , patients were enrolled in sites: hc and pl. median time for ep assessment was days ( - ) after study enrolment. pl and hc patients had unspecific electrophysiological signs; pl patients, but only hc patient had reduced snaps indicating cip. in patients dms could be performed, / pl and / hc patients showed reduced muscle membrane excitability indicating cim. in patients (pl , hc ) evaluation of mrc score was possible. muscle strength did not differ between placebo [ . ( / . )] and hc group [ ( . / . )]. none of the parameters reached statistical significance. conclusion. the frequency of cip/cim diagnosed by electrophysiological examination was higher in patients who received placebo. the clinical diagnosis of muscle weakness assessed by mrc scale was not different in both groups. with limitations of the small sample size, this first prospective evaluation showed no impact of hc on the development of cip/cim in this cohort of patients with septic shock. surviving sepsis campaign guidelines recommend treatment with hydrocortisone in septic shock patients requiring vasopressor support. however, the association of fludrocortisone remains controversial. the objective of the study was to determine if the association of fludrocortisone in patients with septic shock and adrenal insufficiency treated with hydrocortisone is related to an improved outcome. from a database including patients with septic shock requiring vasopressor support, we retrospectively studied patients who fulfilled criteria for adrenal insufficiency (baseline cortisol less than µg/dl and/or an increase after injecting µg synacthen less than µg/dl). all patients included received treatment with hydrocortisone (h) or hydrocortisone plus fludrocortisone (h+f) for at least h. data are presented as mean ± standard deviation. groups were compared by using student's t test for continuous variables and chi-square test for categorical variables. long rank test and kaplan-meier curves were used to analyze time to shock reversal and mortality. forty-eight patients received hydrocortisone (h group) and hydrocortisone plus fludrocortisone (h+f group). overall mortality was % ( patients). both groups were comparable in baseline clinical and demographic characteristics. no differences were found in age (mean age ± ), gender, weight ( ± vs ± , p , ) (kg), infection site and severity scores: saps ii ( ± vs ± , p , ), apache ii ( ± vs ± , p , ) and sofa max ( ± vs ± , p , ). both groups presented no differences regarding baseline ( ± vs ± ,p , ), stimulated ( ± vs ± , p , ) and delta cortisol values ( , ± , vs , ± , , p , )(µg/dl). we did not find differences between both groups in norepinephrine(ne)maximal dose received(µg/kg/min), time to shock reversal (days of ne use), time of mechanical ventilation, icu and in-hospital length of stay (days) and mortality ( prospective, randomized, double-blind, placebo-controlled study of -day mortality in patients with septic shock for less than hr who underwent a short high dose acth test in centres in european countries. patients received -day treatment with hc ( mg q h for days, q h for days, q hr for days) or placebo (p). serum electrolytes levels were obtained at baseline, day (d ), day (d ), day (d ) and day (d ) from randomisation. from mar -nov , patients were enrolled. baseline serum sodium were ( ) mmol/l and ( ) mmol/l in the hc and p group respectively. serum sodium peaked at d ( mmol/l) and remained elevated up to d ( mmol/l) in the hc group. in the placebo group, serum sodiumpeaked at d ( mmol/l). the mean change in serum sodium were, in hc treated and p treated patients respectively, at d : . ( . sd) vs . ( . ) mmol/l; d : . ( . ) vs . ( . ) mmol/l; d : . ( . ) vs . ( . ) mmol/l; and at d : . ( . ) vs . ( . ) mmol/l. the difference between groups reached statistical significance at day (p= . ). there were no significant changes in mean potassium levels over time between the two treatment arms. according to the guidelines for the management of severe sepsis and septic shock, low doses of steroids are recommended in septic shock patients requiring vasopressors, despite adequate fluid replacement. the aim of this retrospective case control study was to assess the effectiveness of low doses of hydrocortisone in patients with late septic shock and mods. the study was held in a bed multidisciplinary icu of a tertiary hospital. twenty four norepinephrine dependent (> . γ /kg/min) patients, fulfilling the criteria of septic shock, were enrolled in the study. patients were divided in groups according to the continuous administration of mg hydrocortisone for days (group a: pts) or conventional treatment (group b: pts). end points of the study were, the within days vasopressors weaning, evolution of mods and -day as well as -day survival. mods was described by sofa score. statistics : statistical analysis was computed by using paired t-test and linear regression analysis. groups were similar regarding demographics ( ± vs ± y), initial sofa score ( ± vs , ± ), initial norepinephrine dose ( . ± . vs . ± . γ /kg/min) and mean elapsed time from the onset of shock ( . ± . vs . ± . days). an early and significant decrease in norepinephrine dose (p< . ), was observed in all group a pts, while no difference was detected in group b pts. this decrease was associated with hemodynamic stability. on days and mean abp was significantly higher in group a pts (p< . , p< . ). weaning from vasopressors within days was achieved in pts in group a ( . %) and pts in group b ( . %). seven day mortality was . % in group a vs % in group b while -day mortality was % and % respectively. in the treatment group a positive correlation between the within days shock reversal and survival (cor coeff = . , r = . , p= . ) was found. there was no relation between the time elapsed from the onset of shock to the steroid administration and survival (p= . ). oxygenation parameters (fio /po ), sofa score and creatinine did not differ between groups. wbc in group a pts were significantly higher (p< . ) only on day . no significant adverse effects were detected. in late septic shock patients with mods the administration of low doses of hydrocortisone is associated with decreased vasopressors requirements, hemodynamic improvement and beneficial effect on survival. the within days shock reversal was a good predictor of survival. introduction. early microcirculatory impairment followed by mitochondrial dysfunction may combine to produce multi-organ failure in sepsis. we recently reported that tissue oxygen tension (tpo ), the balance of local o supply/demand, is variably affected in four different organs (kidney cortex, liver, muscle, bladder) at h' post-endotoxin challenge ( ). we seek to measure temporal changes in tpo in these organs in a resuscitated rat model for up to h following the onset of faecal peritonitis. here we present our -hr timepoint results with assessment of the impact of fluid loading. methods. male wistar rats (approx g weight) with tunnelled right jugular venous cannulae in situ received i.p. injection of faecal slurry. fluid ( : mixture of % glucose/ % hetastarch; ml/kg/h) was started h later. at h, rats were anaesthetised with isoflurane, and then instrumented with a left common carotid arterial line and tissue po probes (oxford optronix, uk) sited in thigh muscle, between right and left liver lobes, in the left renal cortex and within the bladder lumen. after -min stabilisation, recordings were made of bp, tpo , and end-diastolic volume (edv) and cardiac output (co) by echocardiography (vivid , ge healthcare, bedford, uk). this was performed before (bi, baseline instrumented) and after fluid challenge (f) of ml/kg bolus of % hetastarch given to optimise lv filling. comparisons were made against sham-operated animals that underwent instrumentation but received no i.p. injection. notwithstanding considerable volume resuscitation beforehand, left ventricular filling and output were significantly reduced at h in this faecal peritonitis model. despite the % reduction in output, baseline tpo values were similar in bladder and renal cortex compared to sham animals but showed a decreased trend in muscle and a significant reduction in liver. fluid loading restored cardiac output to control values, however only muscle and liver tpo increased, albeit not significantly. these data suggest a combination of microcirculatory and mitochondrial dysfunction with each predominating in different organ beds at this timepoint. confirmation is required using complementary techniques. microcirculatory dysfunction leads to inadequate tissue oxygenation and multi organ failure during sepsis or septic shock. aim of this study was to compare non-invasive assessment of tissue oxygen saturation (sto ) with systemic oxygenation using mixed venous oxygen saturation (svo ) as an indicator in an established model of porcine septic shock. in a prospective animal study anaesthetised, ventilated pigs ( . ± . kg) were investigated. animals received g/kg/body weight faeces into abdominal cavity to induce sepsis and were observed over hours. volume therapy was administered to maintain a central venous pressure of mmhg. svo measured by co-oxymetry (radiometer, copenhagen) was obtained hourly after induction of sepsis. at the same time quadriceps muscle sto was measured by near-infrared spectroscopy (nirs) (inspectra tm , hutchinson, usa). correlation was analyzed by linear regression analysis. a total of measurements were performed in animals. sto was significantly correlated with the svo . r = . (r = . ) (p< . ) and y = , x + , . comparing the change in sto and svo of two successive measurements reveals a correlation of r = . (r = . ) (p< . ). changes in sto and svo were parallel in % of two successive measurements (both measurements changed at the same time in the same direction). although there is a significant correlation between sto and svo in our experimental septic shock model, paired sto and svo changed in the same direction only in %. thus, svo may not be estimated on the basis of sto in treatment of experimental septic shock and tissue oxygenation may not be estimated on the basis of svo either. whether a combination of sto and systemic oxygenation measurements is a useful monitoring approach in sepsis needs to be revealed. grant acknowledgement. inspectra device was provided by hutchinson. systemic immune response syndrome (sirs) frequently develops in critically ill patients and may lead to multiple organ dysfunction or failure even in the presence of normal or normalized global hemodynamic parameters, mainly due to tissue dysoxia and microvascular dysfunction. near infrared spectroscopy (nirs) is a validated method for the assessment of tissue oxygenation but its accordance with routine parameters has not yet been sufficiently studied. aim: to compare nirs parameters to routine monitoring parameters of the critically ill. thirty two consecutive critically ill patients (age= ± years, male/female= / , length of icu stay= ± days) were enrolled. all patients were evaluated with nirs and the occlusion technique within hours of icu admission. all patients were mechanically ventilated and were sedated. routine hemodynamic parameters (mean arterial pressure= ± mmhg, central venous pressure= ± mmhg, heart rate= ± ), full blood analysis (hemoglobin= . ± . g/dl, white blood cells= , ± , /dl) and arterial blood gases analysis were recorded. sofa, apache ii and saps iii ( ± ) scores were assigned on icu entry day. tissue oxygen saturation (sto %) was continuously monitored before, during and after -min occlusion of the brachial artery via pneumatic cuff inflated up to mmhg above measured systolic arterial blood pressure. (elwi) has been demonstrated to predict mortality and to correlate to pao /fio -ratio and to the compliance of the lungs in patients with sepsis and ards. however, with an increasing number of obese patients, there is the question which body weight should be used for indexation of elwi. therefore it was the aim of our study, to investigate the correlation of elwi to pao /fio -ratio and oxygenation index (mean airway pressure* / pao ) using different weight parameters for indexation. in patients of a medical icu with a body mass index > kg/m , measurements of extravascular lung water were performed using the picco system (pulsion, munich; . . software). extravascular lung water was indexed using the actual body weight (abw), predicted (pbw), ideal (ibw) and adjusted body weight(adbw) , respectively. these data were correlated to pao /fio -ratio and oxygenation index. spearman correlation, spss-software. the highest correlation to pao /fio -ratio was found using adbw, the highest correlation to oxygenation index for elwi adjusted to pbw. .) although the extent of correlation varied within smaller limits (- , to - . and . to . , respectively), the distribution of the patients within "normal", "modestly elevated" and "significantly elevated" elwi would have changed markedly using different indices. .) with regard to impaired respiratory function in the patients of our study, pbw, ibw and adbw seem to more accurately reflect "functional" extravascular lung water than abw with % of the patients in the normal range. our objective is to analyse the hemodynamic profile and the extravascular lung water in the first stages of severe acute pancreatitis (sap) that are admitted at the intensive care unit (icu), through the collected data by transpulmonary thermodilution. observational and prospective study, in which -sap-diagnosed patients consecutively admitted at the icu were analyzed. all of them were monitorised at their admission with continuous cardiac output system picco ® (pulsion medical systems). demographic variables, general (apache ii and sofa) and specific (balthazar) severity scores as well as the development or not of respiratory failure, were collected. the ordinary hemodynamic parameters [heart rate (hr), mean arterial pressure (map), cardiac index (ci), vascular resistances (svri)] were determined on days , , and as well as preload parameters [intrathoracic blood volume index (itbi), global end-diastolic volume index (gedi)], extravascular lung water index (elwi) and pulmonary vascular permeability index (pvpi) according to picco ® methodology. the results are expressed as means±sd and percentages. the non-parametric mann-whitney test for quantitative variables was performed and statistical significant level was established at p< . . age was ± years with a majority of males ( %). the biliar was the most frequent cause ( %). apache ii= ± and sofa= ± . all patients showed an alteration determined by ct scan (balthazar grading system) degree c or higher. seven patients ( %) needed mechanical ventilation in the first hours. hospitalary mortality was of %. on day , the ci ( . ± . l/min/m ) and the rvsi ( ± din.seg.cm - .m ) were at normal parameters and only patients needed vasopressor support. however, on days and , the preload parameters were low (itbi= ± ml/m and gedi = ± ml/m ) and improved on the th day (itbi= ± ml/m and gedi = ± ml/m ). patients with respiratory failure and mechanical ventilation showed neither higher elwi nor higher pvpi than the rest (day , elwi: . ± . vs . ± . ml/kg; pvpi: . ± . vs . ± . ; p=ns). in our population, certain hypovolemia degree in the first stages of the disease was found, corresponding to the development of the third space. the respiratory failure associated is not mainly due to an extravascular lung water increase or to a permeability increase. . ( . - . ) . ( . - . ) . cpo after dobutamine (w) . ( . - - ) . ( . - . ) . poap: pulmonary occlusion arterial pressure, swi: stroke work index. conclusion. cpodelta after dobutamine challenge is a good predictor for mortality in ss. septic shock is a common disorder with a high mortality. recent guidelines for the haemodynamic management of severe sepsis have emphasized the importance of aggressive volume resuscitation in the initial phase. central venous pressure (cvp) and pulmonary capillary pressure (pcp) are common end-points for volume resuscitation, however these cardiac filling pressures are poor predictors of fluid responsiveness in septic patients. right ventricular end diastolic volume index (rvedvi) is a better predictor of preload, and it allows the identification of patients with right ventricular (rv) dysfunction and dilation (> - ml/m ), as well as predicting mortality. we correlated rvedvi with pcp, cvp and hypoperfusion variables during septic shock initial management. longitudinal, prospective and observational study. demographic, haemodynamic (rvedvi, pcp, cvp) and hypoperfusion (lactate, base deficit) variables were obtained. descriptive statistics with mean ± sd (numerical variables) and frequencies and percentages (categorical ones). comparisons between groups with u mann-whitney test and x and fisher exact test as needed (statistically significant value if p< . ). results. patients (mean age ± )were divided in: survivors n= (rvedvi ± ml/mt ) and non-survivors n= (rvedvi ± ml/mt ). early dilation of rv predicts survival with a sensibility of % sensibility and specificity of %. methods. ten patients with severe sepsis ± yr, patients with septic shock ± yr and polytrauma patients with hemorrhagic shock ± yr, who remained in icu more than hours were included in the study. serial bnp measurements were performed for at least days. consecutive hemodynamic measurements were done using a right ventricular ejection fraction (rvef) thermodilution catheter (edwards). transthoracic echocardiography was performed in the first two days. . bnp values ( st day) was dramatically elevated in septic shock ( ± pgml- ), significantly elevated in severe sepsis ( ± pgml- ), but within normal limits in hemorrhagic shock ( ± pgml- ) (p< . ). inotropes (noradrenaline) were similar in patients with septic or hemorrhagic shock on day . bnp levels did not correlate with pulmonary arterial wedge pressure, right atrial pressure, rvef or left ventricular ef (lvef) measured by echocardiography. eleven patients with septic shock, with sepsis and with hemorrhagic shock died during days. bnp decreased gradually in survivors from septic shock after day . septic shock survivors had lower apache ii, and increased rvef and lvef compared to non-survivors ( ± , ± and ± vs ± , ± and ± respectively, all p< . ), but not bnp ( ± vs ± pgml- ). in conclusion, bnp is significantly elevated in sepsis, mainly in patients with septic schock, probably indicating the level of inflammation severity. inotropes, shock and myocardial stretch, as it is expressed from hemodynamic parameters, do not seem to be implicated to bnp release. sepsis and septic shock are major causes of mortality and morbidity in the icu. if inflammatory mediators responsible of sepsis remain elevated or if there is a poor cardiac function, septic myocardial dysfunction may occur, increasing morbidity and mortality. brain natriuretic peptide (bnp) is an adequate biomarker for cardiac failure so our objective was to determine its utility in predicting myocardial dysfunction in septic patients. the role of hemofiltration, its dose and biological effects in sepsis remain a contentious issue. although some beneficial effects on systemic hemodynamics and reduced vasopressor requirement were reported, the potential of hemofiltration to prevent sepsis-related disturbances of microcirculation and energy balance has not been evaluated. therefore, we investigated the effects of standard hemofiltration (hf, ultrafiltration rate ml/kg/h) and high volume hemofiltration (hvhf, ml/kg/h) during h hyperdynamic porcine septic shock. in mechanically ventilated and instrumented pigs fecal peritonitis was induced by inoculating autologue feces. h after induction of sepsis pigs were randomly assigned to three groups: ) controls (n= ), ) hf (n= ), ) hvhf (n= ). before, , and h after the induction of peritonitis we measured, in addition to systemic and regional hemodynamics, ileal mucosal and renal cortex microvascular perfusion (ops and laser doppler flowmetry). energy balance was determined by measuring arterial lactate pyruvate (l/p) and hepatic venous ketone body (kbr) ratios. in the control group hyperdynamic septic shock resulted in a progressive deterioration of intestinal mucosal and renal cortex microvascular perfusion despite well-maintained regional blood flows. altered microcirculation was paralleled by gradually increased l/p and kbr indicating disturbed energy balance. compared to six animals in the control group, only three and two pigs required noradenaline support in hf and hvhf group, respectively. however, neither hf nor hvhf blunted the sepsis-induced alterations in microvascular perfusion and cellular energetics. in this clinically relevant model of septic shock, the protective systemic hemodynamic effects of early hemofiltration did not translate into the improved microvascular perfusion and energy metabolism. hvhf did not confer any additional benefit. the value of hemodynamic improvement as a surrogate marker for efficacy of hf is therefore ambiguous. patients in prolonged septic shock show enhanced pressor sensitivity to vasopressin(vp) yet decreased response to norepinephrine(ne). as both act via g protein-coupled receptors and activate the inositol phosphate cascade to increase vascular smooth muscle(vsm) ca + levels, the reason for this disparity is uncertain. we postulate that these drugs may have diverse effects on different ca + mobilisation pathways during sepsis. we investigated this using specific modulators of ca + release and influx on contractile responses to vp and ne in mesenteric arteries from septic and sham-operated rats. sepsis was induced in awake, fluid-resuscitated wistar rats by ip injection of fecal slurry. paired sham controls received no injection. rats were sacrificed after h, and mesenteric arteries mounted on a wire myograph to measure isometric tension responses to vp and ne. the contributions of sarcoplasmic reticulum(sr) ca + release and ca + entry through the store-operated channel(socc) were assessed by removing and returning extracellular ca + respectively. the contribution of the voltage-gated ca + channel(vgcc) was assessed by applying vp/ne in the presence of nifedipine. contractions were significantly enhanced to vp but depressed to ne in septic vessels . in all arteries, constriction to both agonists relied predominantly on extracellular ca + influx rather than sr ca + release. ne responses were more sensitive to extracellular ca + removal in septic vessels. the ca + influx in response to ne was almost entirely vgcc-mediated, with a negligible contribution from soccs in both sham and septic arteries. soccs contributed significantly to vp contraction however, and socc-rather than vgcc-mediated influx of ca + predominated in septic arteries. patients in prolonged septic shock show enhanced pressor sensitivity to vasopressin (vp) yet decreased responsiveness to norepinephrine (ne). we have reproduced this pattern in ex-vivo contractile responses of resistance arteries taken from rats subjected to a clinically realistic septic insult ( ). we hypothesise that an underlying mechanism is vp-mediated sensitisation of the vascular smooth muscle contractile apparatus to calcium. to investigate this, we performed simultaneous wire myography and fluorescence microscopy to examine the relationship between contractile response and intracellular calcium concentration ([ca + ]i). sepsis was induced in conscious, tethered, male wistar rats by intra-peritoneal injection of faecal slurry. paired sham controls received no such injection. both groups received ml/kg/hr of intravenous fluid. after hours, animals were sacrificed, and rd order mesenteric arteries dissected and mounted on a wire myograph (danish myo technology). arteries were loaded with a fluorescent calcium indicator (fura- , mum) for hour and imaged by fluorescence microscopy. [ca + ]i and isometric tension kinetics were measured simultaneously in response to vp ( nm) and ne ( mum). ]i was higher in arteries taken from septic rats. tension responses to vp were significantly enhanced in septic arteries, however the associated increases in [ca + ]i were comparable in septic and sham groups. tension responses to ne were significantly decreased in septic arteries, with a similar degree of depression in delta [ca + ]i. data were analysed for statistical significance using un-paired t tests. conclusion. the higher baseline [ca + ]i in the vascular smooth muscle of septic arteries suggests an abnormality of intracellular calcium storage. the ability of vp to produce a greater contractile response in septic compared to sham arteries, despite an equivalent degree of [ca + ]i elevation, implies sensitisation of the contractile apparatus to the effect of vp. there was contractile hyporesponsiveness to ne in the septic vessels and no evidence of calcium sensitisation to this agonist. these findings provide one potential explanation for the hypersensitivity to vp observed in patients with septic shock. mitochondrial dysfunction and compromised cellular energetic status are associated with poor outcome in septic patients [ ] . maintenance of mitochondrial function is mediated in part by activity of transcription factors nrf- and nrf- , the transcriptional co-activator pgc -alpha and mitochondrial transcription factor alpha (tfam). these markers of mitochondrial biogenesis were elevated in a rodent model of endotoxaemia [ ] . in an ongoing study in critically ill patients, we have investigated the relationship between cellular energetics and mitochondrial biogenesis. with ethics approval and appropriate consents, critically ill patients were recruited within h of icu admission. age-matched control patients were undergoing elective hip surgery. muscle biopsies were taken from vastus lateralis. atp and creatine compounds were determined by hplc of perchloric acid extracts and standardised to total creatine [total cr = phosphocreatine (pcr) + creatine (cr)]. mrna levels for pgc -alpha, nrf- and tfam were determined by rt-pcr and standardised to s mrna. data were analysed for significance using one-way anova. the ratio of pcr/cr was significantly decreased in both survivors and non-survivors. mrna levels of the mitochondrial biogenesis markers pgc- alpha and nrf increased in survivors but not in non-survivors. a similar pattern was observed with the mitochondrial transcription factor tfam, although statistical significance was not reached. ( ) the decreased pcr in both survivors and non-survivors indicates increased demand for atp in the acute phase of critical illness. ( ) increased levels of markers of mitochondrial biogenesis in survivors indicate that maintenance of mitochondrial function, specifically atp synthesis, may be crucial to recovery. failure to maintain adequate mitochondrial function through biogenesis may contribute to atp depletion and mortality. local metabolic changes are not well investigated in sepsis and sirs. our aim was to describe subcutaneous metabolic changes using microdialysis (md) concurrently with systemic hemodynamics over days in patients with sepsis/sirs and circulatory failure. methods. patients with severe sepsis/sirs were recruited. at inclusion, all patients had circulatory failure despite resuscitation according to the rivers concept. cardiac index (ci), intrathoracic blood volume index (itbvi), extravascular lung water index (evlwi), blood lactate (p-lac), md lactate (md-lac) and md lactate-pyruvate ratios (md-lac/pyr) were analysed - hourly. data were tested for differences over time using anova. patients were subdivided into sepsis and sirs groups, and intergroup differences were tested using the rank sum test. mean apache scores were & for sepsis & sirs respectively. sofa decreased from . to . with no difference between sepsis & sirs. ci increased over time and itbvi, evlwi, p-lac & md-lac decreased. md-lac & p-lac were maximal at day . lactate concentrations were generally higher in md than in blood, and in the sepsis group. severe sepsis and septic shock have been recognized as a serious clinical problem that shows an increasing incidence and that is responsible for substantial morbidity and mortality in intensive care units. sepsis has been defined as the systemic host response to infection with an overwhelming systemic production of both pro-and anti-inflammatory mediators. continuous hemofiltration has been suggested as possible therapeutic option that may remove the inflammatory mediators. on the other hand, hemodialysis and hemofiltration were reported to influence cardiac electrophysiological parameters and to increase the arrhythmogenic risk. therefore, in this study we have investigated the effects of hemofiltration on electrophysiological properties of the septic pig heart. methods. pigs of both sexes were divided into groups: ) control group without hemofiltration; ) control group with conventional hemofiltration ( ml/kg/hour); ) septic group without hemofiltration; ) septic group with conventional hemofiltration ( ml/kg/hour); ) septic group with high-volume hemofiltration ( ml/kg/hour). in septic groups, the sepsis was induced by fecal peritonitis and maintained for hours. hemofiltration was applied for the second hours of this period. ecg was measured just before and after -hours period of sepsis in septic groups and at the same time points in non-septic groups. action potentials were recorded in isolated ventricular preparations obtained from the hearts at the end of experiments. . rr and qt intervals were significantly shortened by sepsis in all septic groups, in non-septic groups they were not influenced by the experiment. action potential duration (apd) was also significantly shortened by sepsis (septic group without hemofiltration vs. control group without hemofiltration) at all cycle lengths tested ( , , ms). both conventional and high-volume hemofiltration in septic groups shortened apd further at slow pacing rates. hemofiltrate obtained in septic groups by both conventional and high-volume hemofiltration prolonged significantly and reversibly apd at all pacing rates. substitution solution alone had no effect on apd. neither hemofiltration nor hemofiltrate in control, non-septic groups influenced apd. we conclude that the hemofiltration in septic groups and the septic hemofiltrate influence significantly the electrophysiological properties of the heart, probably due to removal/content of various inflammatory mediators in the septic hemofiltrate. introduction. the precise mechanism by which multiorgan failure develops in severe sepsis and septic shock remains unclear. potential mechanisms include alterations of microvascular flow distribution, mitochondrial dysfunction and treatment effects. we investigated the effects of lps and different catecholamines on oxidative respiration of rat skeletal muscle fibers and hepatocytes. muscle fibers (m. gastrocnemius) were isolated from anesthetized male wistar rats ( - g). human hepatocytes (hepg cells) and human monocytes (monomac -mm ) were also used. to avoid systemic effects of endotoxin and catecholamines, experiments were performed in vitro using the skinned-fiber technique. the mechanically dissected muscle fibers were incubated with lps ( µg/ml) for h. after h of lps incubation, norepinephrine, dopamine, and dobutamine ( µm each) were added. monocytes and hepatocytes were treated with different concentrations of lps only. mitochondrial respiration was determined after permeabilization with saponin, using a clark type electrode (oxygraph k, orobros instruments, innsbruck, austria). septic shock is associated with severe cardiac dysfunction, whose mechanisms remain only partly defined. recent data suggested that it might be triggered by the direct action of microorganisms and their products on the heart itself. we previously shown that flagellin (flag), the protein monomer from bacterial flagella, is a potent activator of nf-κb-dependent pro-inflammatory signaling in cultured cardiomyocytes. therefore, the aim of the present study was to evaluate whether flag might induce such an inflammation in the heart in vivo and contribute to cardiac dysfunction. h c cardiomyocytes were stimulated with recombinant salmonella muenchen flag ( - ng/ml, min to h). in vivo, balb/c mice were injected (tail vein) with - µg flag ( min to h). the effects of flag were evaluated by its ability to activate nf-κb, and to induce transcription of tnfα and mip- cytokines. in vivo, cardiac neutrophils recruitment was evaluated by myeloperoxidase (mpo) activity. the expression of the flag receptor tlr was also determined. in vivo physiological measurements: left ventricular pression-volume curves. a microtip pressure-volume (pv) catheter (spr- ; millar instruments) was inserted into the left ventricle (lv) via the right carotid artery. the pressure and volume signals were continuously recorded and heart rate, cardiac output, end-systolic and end-diastolic volumes, stroke volume, ejection fraction and end-systolic and end-diastolic pressures were measured. load-independent indices of lv systolic and diastolic functions were determined by the slope of the end-systolic, respectively end-diastolic pv relationships in conditions of rapidly reduced preload (transient compression of the vena cava). . flag activated nf-κb in cardiomyocytes in vitro and in vivo, and also upregulated the transcription of tnfα and mip- . flag also increased cardiac neutrophils recruitment. flag induced significant increases in end-systolic and end-diastolic lv volumes, indicating cardiac dilation, and a significant reduction of the load-independent indices of lv systolic function (end-systolic pv relationship, espvr, and maximal elastance, emax), indicating significant lv systolic dysfunction. in contrast, no change in the slope of the end-diastolic pv relationship (edpvr) was noted. bacterial flagellin induces a prototypical inflammatory response in cardiomyocytes in vitro and in the myocardium in vivo. these effects are associated with a profound alteration of the lv systolic function in vivo, suggesting that flagellin may represent a critical mediator of cardiac dysfunction in septic shock. current guidelines recommend either dopamine (da) or norepinephrine (ne) as the initial vasopressor in septic shock (ss), but the management of moderate to severe ss is still controversial. to explore this issue is important, because pharmacodynamic differences between vasopressors might be irrelevant in mild cases, but could potentially affect outcome in more severe patients. beside clinical implications, there are also economical considerations since these drugs are not cost-equivalent. this subject may be specially important for developing countries. the aim of our study was to compare ne vs da as the exclusive vasopressor for established moderate to severe septic shock (requirements of > . mcg/k/min of ne or > mcg /k/min of da to maintain map to mmhg) multicentric rct involving nine polivalent icus from argentina, brazil and chile, randomizing moderate to severe ss patients to ne or da titrated to target map or maximal dose of mcg/k/min ne or mcg/k/min da. after inclusion patients were switched blindly to the assigned drug. the study could be stopped if severe hypotension or arrhythmias developed. epinephrine was used as a rescue drug. main outcome criteria were day mortality, organ dysfunctions and adverse effects (ae). the study was stopped early after randomizing patients because of low enrollment rate. only patients were evaluable. main results are shown on the table. adverse effects with da were cases of atrial fibrillation (af) and supraventricular paroxysmal tachycardia (spt), which were considered serious in cases. aes with ne were two af and one spt, which resolved with no drug suspension. aes occurred more frequently with higher doses of da. conclusion. the use of dopamine as exclusive vasopressor for established moderate to severe septic shock appears to be associated with a worst outcome and more adverse effects. this should be explored in a future better powered rct. although arterial blood pressure (abp) is a widely used guide for hemodynamic therapy in sepsis, few data exist on its association with mortality and on critical abp limits that should be maintained. in this retrospective cohort study, clinical, hemodynamic, and laboratory parameters were extracted from a prospectively collected database in sepsis patients. the severity and duration of hypotension was calculated by the area under the curve (auc) of systolic arterial blood pressure (sap), mean arterial blood pressure (map), and mean perfusion pressure (mpp = map -central venous pressure). laboratory parameters included the most aberrant variables during the icu stay. urine output per hour during the first hours and need for renal replacement therapy were recorded. the sepsis-related organ failure assessment (sofa) score was calculated from given clinical and laboratory parameters. binary and linear regression models were corrected for the severity of disease by inclusion of the saps ii (excluding sap count) as a covariate and were used to examine the association between abp and day-mortality or organ function. similarly, a binary logistic regression model including saps ii as a covariate was used to determine the best discriminating cut-off limit of abp in regards of day-mortality. the goodness of fit of each limit was assessed by the r -value according to the nagelkerke method. . sap and map were recorded for . ± . hours, mpp for . ± . hours. there was a significant association between day-mortality and the auc of sap (p< . , r = . ), map (p< . , r = . ), mpp (p< . , r = . ). the area under map mmhg and mpp mmhg was associated best with day-mortality. one or more episodes of map < or mpp < mmhg increased day-mortality by . (ci % . - . , p= . ) and . (ci % . - . , p= . ), respectively. there was a linear association between time under the critical map and mpp limit and day-mortality. while abp was significantly associated with the sofa score, arterial lactate levels, and renal function, no association with liver function or troponin i was observed. the critical map and mpp limits for the need for renal replacement therapy were mmhg (r = . , p< . ) and mmhg (r = . , p< . ), respectively. during early sepsis, abp is associated with day-mortality and organ function. mpp shows the best association with mortality and may be a new resuscitation target. animal models of traumatic brain injury (tbi) are used to elucidate sequelae underlying human head injury in an effort to identify potential neuroprotective therapies. although human tbi is a highly complex multifactorial disorder, animal trauma models tend to replicate only single factors involved in the pathobiology of clinical head injury and may thus partly underlie the discrepancy between preclinical and clinical trials of neuroprotective therapeutics. we here present our experience with a large animal model of tbi which was designed to closely resemble the forces impacting the brain in e.g. traffic accidents. anesthetized, mechanically ventilated instrumented sheep (n= ) were placed in prone position with the head resting on a support to allow free lateral movements of the head. a left-temporal head impact was then delivered by mechanical stunning device (mk , schermer, germany), which is approved for euthanasia of domestic lifestock. a captive bolt with a mushroom-shaped head is propelled from the muzzle of the stunner against the skull by the discharge of blank cartridge inserted in a chamber behind the proximal end of the bolt. depending on the charge and the positioning of the stunner, this device delivers an intracranial atmospheric pressure of approximately bar in sheep at a bolt velocity of approximately ms- . to prevent skull fractures, a steel plate was attached to the left temporal fossa. a fiberoptic intracranial pressure (icp) catheter and a brain tissue oxygen (pbro ) probe were introduced in the parietal white matter. unilateral ultrasound flowprobes were attached to the internal carotid artery to measure cerebral blood flow. after measurements, sheep were killed and the brains removed for neuropathological examination. brain injury was characterized by a marked increase in icp from ± to ± mmhg (mean values ± standard deviations) hours after head impact. intracranial hypertension was accompanied by a significant decrease of cerebral blood flow. pbro significantly decreased from ± to ± mmhg. the decrease in sinus venous oxygen saturation did not reach statistical significance. in instrumented control animals (n= ), parameters remained unchanged. neuropathological examinations revealed the presence of multifocal traumatic subarachnoid hemorrhage in , and diffuse axonal injury in out of animals. while interstitial brain edema was found in all sheep brains, contusion zones were present only in a minority of the animals. the pathobiological characteristics of the head impact model presented here closely resemble the alterations frequently found in human tbi. the relatively high variability of neuropathological changes after head impact may be seen as a disadvantage of this model. non-neurologic organ dysfunction triggered by infection represents a frequent and independent predictor of poor outcome in traumatic brain injury (tbi) patients admitted to intensive care units ( ). because tbi itself significantly increases susceptibility to infection ( ) and infection is a potentially modifiable risk factor, we developed a combined experimental model of tbi and sepsis in the rat. controlled cortical impact (cci) was produced in left parietal cortex by using a mm diameter tip (velocity m/sec; depth mm). sepsis was induced contemporarily by cecal ligation and puncture (clp). the outcome was evaluated in terms of mortality, neurological function (via the morris water maze (mwm) and beam balance (bb) tests)and histologically. rats were subdivided into groups: sham, cci, clp, and cci + clp. -day mortality was % in sham, % in cci and % in clp group respectively. adding clp to cci increased mortality up to % (p< . vs cci and p< . clp alone). at h and week post-injury mwm and bb test performance was significantly worse in cci and cci + clp than in sham and clp groups (p< . ). lesion volume was similar in injured groups. ca cell loss in left hippocampus was unaffected in the sham and clp groups, while it was % in cci and % in cci + clp groups (p< . cci vs cci + clp). our results show that the occurrence of systemic sepsis exacerbates mortality and cerebral damage in rats subjected to traumatic brain injury. t. j. p. lieutaud* , j. rhodes , p. j. d. andrews anesthesiology and intensive care medicine, hospices civils de lyon, lyon, france, anesthesiology and intensive care medicine, university of edinburgh, edinburgh, united kingdom introduction. human recombinant erythropoietin (epo) appears promising in different brain injury models but its cellular mechanisms remain poorly understood. following brain trauma injury (tbi), inflammation (il- b) and chemokine expression (mip- , neuropath appl neurobiol ) are important. the aim of this study was to measure the effects of acutely administered rhepo on il- b and mip- after tbi. methods. with home office approval, under isoflurane anesthesia rats sd were subject to lateral fluid percussion tbi ( . - . atm) (dixon j neurosurg ) of the left parietal cortex. epo ( , or iu/kg) or placebo were injected in a random and double blinded manner by the intra-peritoneal (ip)route. the ipsi-and contra-lateral cerebral cortices were removed h later and homogenized. il- b and mip- were measured in the surnageant using elisa kits. results are expressed as pg/mg of protein (mean ± sem). there was a significant increase in il- b and mip- in the ipsilateral cortex in comparison with the contralateral side for both proteins analyzed. neither nor and iu/kg rhepo did not exhibited any significant effect (figure ). conclusion. this study confirms that inflammation is important and occurs early after lfp-tbi. epo did not display significant effects on two of the main inflammation mediators. the purpose of this study was to evaluate the effects of agmatine on histopathological damage following traumatic injury using a clinically relevant model of diffuse axonal injury (dai) on the rat. a total of male sprague-dawley rats weighing - g were anaesthetized and subjected to head trauma using marmarou's impact-acceleration model. the rats were then separated into two groups; one group was treated with agmatine and the other group was treated with saline for up to four days immediately after the head trauma. rats from both groups were killed one, three or eight days post-injury. the brains were examined histopathologically and scored according to the neuronal, vascular and axonal damage. there were no significant histopathological differences between the control and agmatine-treated group after one or three days (p> . ), but evaluation after eight days revealed a significant improvement in the group treated with agmatine (p< . ). our data indicate that agmatine has a beneficial effect in diffuse axonal injury and should be tried for therapeutic use in the management of this condition. d. morii*, y. miyagatani critical care department, national hospital organization kure medical center, kure, japan the disadvantageous effect of haemorrhagic shock on head trauma related mortality are well known. thus, efficacious shock treatment is a surely significant measure against the development of secondary brain damage. the small volume resuscitation by hypertonic saline has been shown to promote systemic and cerebral haemodynamic benefits. similarly, many clinical studies have demonstrated the effects of long-term mild hypothermia on outcome of traumatic brain injury. in this study, we evaluated the new strategy consisting of therapeutic mild hypothermia and hypertonic saline therapy to the multiple trauma patient with severe traumatic brain injury. severe multiple trauma patients (iss>= , head ais>= ) were studied to evaluated the efficacy of therapeutic hypothermia ( . ˚c for h) and hypertonic saline therapy (na+: meq/l for the first h , meq/l for to h, meq/l for to h) which were applied to them in parallel with massive blood transfusion . we evaluated glasgow coma scale (gcs), injury severity score (iss), the probability of survival (ps), the volume of blood transfusion, infusion and urine volume during the first days, and glasgow outcome scale (gos). we monitored the extent of brain swelling by head ct. four male patients (age: ± y.o., mean±sd) were examined. the characteristics of injury mechanism were explosion , mva , fall . on admission, gcs, head ais, iss and ps were . ± . , . ± , ± and . ± . , respectively. the sum of blood transfusion, infusion, and urine volume during the first h were ± ml, ± ml, ± ml. no patient was died and their gos on posttrauma day was . ± . . the combined therapy of therapeutic hypothermia and hypertonic saline to multiple trauma patients with brain injury may lead to good outcome in spite of the necessity of a large quantity of blood transfusion and infusion. recent data suggest that commonly used anaesthetic agents, e.g. propofol, cause neurodegeneration in the developing brain. the intention of our study was to investigate the effects of propofol on primary neuronal cultures referring to the cell survival rate. primary cortical neuronal cultures were prepared from wistar rat embryos at days gestation. to test the effect of propofol on neuronal survival, cultures were exposed to µl gibco neurobasal-a medium per well with propofol at a concentration of mg/ml for , , , , , and hrs. cell viability was assessed using the methyltetrazolium method (mtt) and was related to untreated cells as controls. all cells were kept in normoxia. after three and six hours of exposition to propofol cell viability values of the propofol treated cells were significantly higher ( . ± . %, p= . and . ± . %, p= . , respectively) compared to untreated control cells ( %). after hours, values were decreasing to levels of the control cells ( . ± . %). after , and hours of exposition to propofol, in contrast, cell viability was significantly reduced ( . ± . %, p= . , . ± . %, p< . and . ± . %, p< . ) compared to controls. at high concentrations, propofol has a time-dependent effect on the viability of primary cortical neurons. during the first hrs propofol has a potential neuroprotective effect, whereas it seems to cause neurodegeneration in the period of to hrs of exposition. e. paramythiotou* , j. papanikolaou , p. ntagiopoulos , a. armaganidis , a. karabinis icu, attikon university hospital, icu, george gennimatas hospital, athens, greece multiple trauma patients constitute a significant majority of admissions in a general icu. brain injury is often present in those patients. the aim of our study was to investigate demographic, clinical and management characteristics in trauma patients suffering a brain injury in a five year period. in a retrospective study all trauma patients hospitalized in the -bed multivalent icu of a bed -tertiary hospital between st jan and th dec suffering a traumatic brain injury were enrolled. recorded data included age, gender, cause of the injury, icu length of stay, initial glasgow coma score (cgs), submission or not to an emergent neurosurgical intervention, all cause mortality and neurological outcome. a total of trauma patients were hospitalized during the study period. tbi was present in patients ( . %). among them, were women ( %) and ( %) were men. their mean age was . years (range - ). icu length of stay (los) ranged between two and days (mean . days). traffic road accidents were the cause in cases ( . %) while tbis ( %) were due to fall from a height on the ground which happened either accidentally or as a result of a suicide attempt. the rest cases ( . %) were due to accidents during work. mean glasgow coma score was seven (range - ). an extradural hematoma was present in p and a subdural one in p. intracerebral hemorrhage was noticed in p, hemorrhagic contusions in p (with or without diffuse axonal injury) and a traumatic subarachnoid hemorrhage in p. twenty nine patients were submitted to craniotomy and p were submitted to unilateral or bilateral decompressive craniectomy. mean los was . d for p submitted to a surgical intervention versus d for the other group. barbiturates were used in p ( %). a total of patients survived ( . %). death was due to neurological cause (herniation of brain stem and subsequent cerebral death) in p. other causes of death included sepsis, multi organ failure, severe injury in other organs, and hemorrhage from upper gastrointestinal tract. a poor neurologic outcome (mean glasgow outcome score < ) was noticed in % of patients. almost two thirds of trauma victims suffer from a cerebral injury. most of them are young males, victims of traffic road accidents. the injury is often severe and one third of patients are submitted to a neurosurgical operation. though overall mortality is rather low, long duration of treatment is often required and severe disability is present in a not negligible number of patients. in the majority of the intensive care units (icu), several of the admissions involves patients with primary nervous system illnesses. a great progress of the technologies used in the icu in the last few decades had reduced neurological illnesses mortality and morbidity. since september of we had beginning an longitudinal e prospective coort study verifying the characteristics of the patients years older that had been admitted in the icu for primary neurological cause (clinical or surgical). the study occurred in a private hospital icu with beds. we recorded patients until the moment. the number of neurological patients corresponds % of the admissions in the unit. the average age of this group of patients is significantly lesser of the remain icu patients ( vs. years), however does not have difference estatistically significant between apache ii ( vs. ) and the mortality ( vs. %) of the neurological patients and others. the stay of length in the unit is bigger ( , vs. , ) . we also recorded mechanical ventilation time length ( % ventilated patients with for average time days). in ventilated patients, % was tracheostomyzed (on average in days). % developed sepsis ( % with septic shock). the patients were divided and analised in several goups (for example: trauma, surgery, central nervous sistem infection, vascular disease,...). neurology was one of the most benefited specialties with the intensive care units progress and evolution. however, high mortality and morbidity caused by the neurological illness, and the social and economic impact that its sequels cause, still deserve the attention of the involved professionals cares of these patients in the acute illness. n. baffoun* , w. gdoura , h. ouragini , k. baccar , m. lamourou , t. chaoua , r. souissi , c. kaddour , n. ben romdhane , s. mahjoub anesthesia and intensive care, national institute of neurology, departement of haematology, chu la rabta, tunis, tunisia trauma victims develop frequently various degrees of haemostatic disorders. the severity of such post traumatic coagulopathie is considered to be major detrimental factor of outcome. the aims of our study were: to identify the origin of such disorders, time course and their correlation with mortality. our aim was identification of coagulopathy disorders and relation to outcome in severely head injured. prospective study,june -march . included:critically ill isolated closed severe head trauma. collected data:demographics,management prior and during icu hospitalization (sedation, catecolamin drug use, blood product transfusion, intra-cranial pressure monitoring, neurosurgical emergency surgery etc.),ct-scan results, daily worst glasgow coma scale, admission simplified acute physiology score ii. we inserted an arterial catheter for invasive pressure monitoring, a central venous catheter and a unilateral jugular bulb in front of the most damaged brain hemisphere(cf. ct-scan). jugular bulb thrombosis was prevented by continuous infusion of ml per hour isotonic serum without heparin. blood samples were obtained simultaneously from the central venous line(k) and jugular bulb(b) at admission, th, th hour, and then in case of neurological aggravationt or daily till th day. we measured platelet count,prothrombin time (pt),activated partial thromboplastin time (act),fibrinogen concentration (fib), prothrombin fraction + (f) and thrombin anti-thrombin complex (tat). during the study only central venous blood samples (pt, act, fib and platelet count) could be available if necessary. otherwise blood samples were centrifuged and preserved refrigerated for post hoc analysis. statistical analysis by student's t test, paired t test for paired results and analysis of variance. significance set as p< , . results. n= ; survivors(s) and deaths (ns). no differences between s and ns in demographics,management modalities, admission gcs( ± ), ct-scan,saps ii ( ± vs ± , p= , ). b vs simultaneous k platelet count was significantly lower in all drawn blood samples,with a trend to decrease overtime. s vs ns at day and day : ± vs ± (p= , ). admission b thrombin fractions was higher in ns( ± vs ± , p= , ). b day tat was higher in ns: ± vs , ± p= , . no difference for other tests between b vs k and s vs ns for different paired tests. pro-coagulant factors (f and tat) are valuable prognostic factors at day in closed isolated severe head trauma. severe traumatic injury is a multisystemic disease where normal homeostatic mechanisms are lost. this situation involves an increase in physiological needs. usually these patients present anormalities in the hypothalamic-hypophyseal axis, which become neuroendocrine dysfunctions with deteriorated physical or neuropsychological secuelae. the aim of this study is to improve our knowledge about this part of the axis in acute phase of politraumatism. methods. an observational prospective study was carried out, with patients who were admitted to our icu with a critical traumatic injury, for six months. demographic and epidemiological data were registered. apache-ii (acute physiology and chronic health evaluation system) and apache-iii scores during the first three days were measured. tiss (therapeutic intervention scoring system) score during the hospital stay was recorded. also gh (grown hormone), igf- (insulinlike-grown-factor- ) levels and nitrogen urinary losses in the first three days after traumatic event were measured. statistical data were analysed with the spss . program. in our study , % ( cases) were men and , % ( cases) were women. the average age was , years old. the hypothalamic-hypophyseal-somatotrophic axis role in the first three days was characterized by a progressive increase in gh levels and a progressive decrease in igf- levels. connections between average hormonal levels in the first three days and apache-ii, apache-iii and tiss scores during this time were studied. a good inverse connection between igf- and prognosis was shown si (spearman index) - , , - , p value , and , respectively with apache-ii and apache-iii. this appropriate connection could not be shown with tiss score sp - , p value , ; but the connection between gh and tiss was better, sp , p value , . conclusion. gh levels increase and igf- levels decrease in the first three days after acute trauma. lower igf- levels can mean a worse prognosis. there are no connections between igf- and sanitary resources used (tiss score) but these connections seem to get better when gh levels are higher. trimodal distribution of deaths and the golden hour concepts are in part responsible for the genesis of all modern trauma systems but these concepts have been challenged recently. our aim was to describe distribution of death in trauma using data from a trauma system and discuss what can be done from the organizational point of view to improve outcome. all traumatic deaths occurring between and in a trauma system were. data on age, gender, time and place of injury, time of first and second hospital arrival, cause of trauma and type of accident, hospital characteristics, dominant injury and time of death were collected for this study. for mortality distribution the variable time was transformed applying a natural logarithm. results. deaths occurred over a period of months. % at the scene, % in the level i trauma centre, % in level iii trauma centre and the remaining in level iv/v trauma centre. death distribution using a logarithmic scale in minutes showed four peaks: deaths at the scene, deaths in the first hours, deaths in the first two days and finally deaths in the second week that we referred as minutes, hours, days and weeks peak (image ). we found statistically significant differences in age and dominant injury concerning timing of death. a tetramodal pattern of death distribution could be described. our data support the need to focus on the treatment of severe head injuries namely in the intensive care environment. anaemia is usually detected in critically ill patients. red bloos cell transfusion is not free of risk. we want to start an alternatives to transfusion protocol but fist we tryed to dercrive our critically ill patients anaemia. our objectives were to: study the red blood cell and iron metabolism in the icu patients at admission. observe changes in these parameters across the first seven days after admission. observe rbc transfusion and his relation whit morbidity and mortality. find transfusion predictors at the admission moment. during tree mounths of , we include all the admissions in a trauma and neurocritical icu of our hospital that stay in unit more than hours. at the moment of admission we determinated haematocrit, (hto), haemoglobin (hb), and reticulocytes (%retic) levels, iron metabolism, folic acid, b , epo and creatinin (kr) we repeated determinations seven days after admission if patient was still in icu. adverse events occurred during icu stay were also registered (mainly infections) together the number of rbc transfusions (with hb levels before and after administration). we included in the study patients. severe traumas ( %), neurocritical patients ( %), tumoral neurosurgery ( , %) and other patients ( %) . average age was . years and apacheii . ± . points. % were males . results of admission blood determinations and seven days after are exposed in table i . there is a tendency to decrease in hto and hb parameters, but not significant. the only parameter we observe difference statistically significative was the reticulocites rate (%retic), significative lower days after admission. (p< . ) in graphic we describe anaemia groups in admission and the evolution of anaemia groups seven days after admission. we appreciated that no anaemia group suffers a severe decrease. % of patients were transfused during their fist week stay. average levels of pre-transfusional hb were . g/dl . we analysed transfusion predictors. hto and hb levels at admission predict transfusion. there is no other analytical parameter at admission that predicts transfusion. we also detected tracheal intubated patients at admission and patients with inotropic drugs perfusions at admission were significative more transfused (p< . and p< . ). conclusion. the high mortality rate in our patients is related to the initial gcs and cranial cat at the moment of admission. it is necessary to continue the study to determine the influence of the rest of the variables in the mortality rate of these patients. introduction. traumatic brain injury, subarachnoid hemorrhage (sah) and spontaneous intracerebral hemorrhage (ich) are associated with systemic inflammatory response syndrome (sirs). early diagnosis of sepsis versus sirs is frequently difficult in neurointensive critical care units. procalcitonin (pct) has been used as a predictor marker of bacterial infection in different groups of patients. there is variable and scarce information about pct in neurocritical patients. the aim of this study was to evaluate the utility of serum pct in the early diagnosis of fever from bacterial infectious origin in patients with acute brain hemorrhage. we made a prospective diagnostic study between july and january . we analyzed serum level of pct and c-reactive protein (crp) on consecutive patients with diagnosis of sah, ich or tbi who have fever during the intensive care unit admission. we excluded patients with antibiotic therapy previous to admission. pct and crp were blindely measured from samples of serum extracted within hs of fever onset and within hs of antibiotic administration. blinded to pct and crp results and according to previously defined criteria patients were classified in two groups: proved bacterial infection (pbi) and non proved bacterial infection (npbi). serum pct was measured by immunochromatographic semiquantitative method brahams pct-q (brahams diagnostica, berlin, germany). its sensitivity is . ng/ml. we analyzed sensitivity, specificity, positive predictive value (ppv) and negative predictive value (npv) of serum pct and crp for diagnosis pbi. we defined negative serum pct as < . ng/ml and negative crp as < mg/l. we studied patient, with sah ( %) and with ich ( %). ten patients had pbi ( %, %ci - %). pbi were pneumonia ( ), urinary tract infection ( ), meningitis ( ) and central line associated blood infection ( ). two patients had simultaneous infection sources. there were bacteremic infections. pct was positive in patients in pbi group ( pneumonia and bacteremic central line associated blood infection) and in of npbi. sensitivity was % ( %ci - %), specificity % ( %ci - %), ppv % ( %ci - %) and npv % ( %ci - %). crp was positive in pts, pbi and in npbi. sensitivity was % ( %ci - %), specificity % ( %ci - %), ppv % ( %ci - %) and npv ( %ci - %). in this study serum pct had an adequate ppv to diagnose pbi, without false positives results. however, it has a low negative predictive value to diagnose pbi. due to the results obtained, we consider that the quantitative pct assay with a sensitivity limit of . ng/ml should be used for the future study to evaluate the role of pct as a predictor marker of acute bacterial infection in patients with acute brain hemorrhage. in different published series cerebral infarction occurs in - % of patients with symptomatic vasospasm after subarachnoid hemorrhage (sah) despite maximal therapy. standard triple-h treatment is associated with life-threatening side-effects (such as myocardial ischemia and pulmonary edema) and has not been properly validated. milrinone, a phosphodiesterase iv inhibitor, has few side effects and exhibits inotropic, vasodilatory and immunomdulatory properties besides inhibiting platelet aggregation and thromboxane a synthesis. we present our experience using our m&h protocol (milrinone and homeostasis) in patients with vasospasm. it consists of cvp-guided normovolemia (maintain cvp=or> ), aggressive temperature control, maintenance of normal serum sodium and step-wise interventions based on symptoms (milrinone . - . mg/kg bolus plus infusion, levophed and angiogram plus intra-arterial milrinone). we retrospectively reviewed the charts and imaging studies of patients diagnosed with symptomatic vasospasm based on the development of focal symptoms and the results of angiographic and doppler studies. cerebral infarction was defined as a new hypodensity on ct scan appearing at least days after aneurysm clipping or coiling. conclusion. among the different physiological scores, the sah-pds was most strongly associated with the major outcomes and the h&h score was better than the other aneurysmal bleed scores. the strong association of physiological scores with outcomes suggest that interventions targeting physiological derangements may improve outcomes in sah patients. contrast induced nephropathy (cin) is the acute deterioration of renal function due to parenteral administration of radio-contrast media. cin is defined as an increase in serum creatinine concentration of > µmol/l ( . mg/dl) or % above baseline within hours after contrast administration. [ ]epidemiologic data in neurosurgical patients undergoing endovascular coiling are sparse and only one study in stroke patients reported figures of % prevalence. [ ] cin is associated with increased morbidity, length of hospital stay and costs. pre-existing renal failure and the dose of contrast media are known risk factors for the development of cin in cardiac patients where the condition is well-described. [ ]although the pathogenesis of cin is not entirely clear, several mechanisms for contrast-induced renal injury have been proposed, including alterations in renal medullary perfusion, direct cytotoxicity and oxygen-free radical generation. [ ] we conducted a twelve month retrospective electronic patient record based review of data from patients presenting to the hospital for endovascular coiling. renal dysfunction was based on increase in serum creatinine of µmol/l ( . mg/dl) or % above baseline within hours after contrast administration; the incidence of contrast induced nephropathy was investigated. peri-operative care and post-operative management were analysed. a multi-variate analysis of risk factors was conducted and statistical tests done using microsoft excel. . patients visited our hospital neurosciences unit and underwent endovascular coiling over a one year period (sept -sept ). the incidence of contrast induced nephropathy was %. . % had pre-existing renal disease and . % needed haemofiltration on intensive care for renal failure post-operatively. the odds ratio for developing cin in patients with diabetes mellitus was . ( . - . ) p= . . the odds ratio for developing cin with pre-existing kidney disease was . ( . - . ) p= . . the development of cin did not show any correlation with patient age, emergency or electively performed procedure or the number of coils used. no anti-oxidants were given for prophylaxis and no protocol for peri-operative hydration was used though fluids were administered intra-operatively. conclusion. cin is a common cause of acute renal functional impairment and accounts for significant morbidity in patients undergoing endovascular coiling. patients with pre-existing renal failure are at high risk; other predisposing factors should be identified. there is some evidence regarding use of peri-procedural hydration and anti-oxidants and, therefore, management protocols should be developed. open prospective observational study. were studied patients treated by embolization after spontaneous intracranial aneurysm rupture. included: embolization complicated by rupture of aneurysm during the obliteration procedure. rupture was ascertained by extravasation of contrast. current results of period ranging from july till october . thirty two patients embolized for aneurysms. one patient pesented a rupture during the embolization: she was a y.o female; she came to our institution's emergency suffering from acute headache, nausea vomiting and a mild meningism. she got no neurological defect (wfns grade i). ctscan showed a mild sah (fisher class ). an angiography followed, confirming presence of a mm ruptured pericallosum aneurysm. during embolization procedure, a sudden hemodynamic instability (bradycardia, unstable blood pressure) was noticed and rerupture of aneurysm confirmed by extravasation of contrast medium. this complication occurred during placement of the first coil. the procedure continued successfully and aneurysm was completely obliterated by three coils. ctscan performed immediately after end of the procedure showed no massive cerebral haemorrhage (class fisher). the patient was thereafter transferred to our icu where she was extubated. she developed a transient neurological defect (right hemiparesis). she was discharged alive without any disability. aneurysmal perforation during embolization seems to be a rare event. in our case it doesn't cause much damage, but clinical severity is variable and far from being predictable. re-bleeding can result in severe intracranial hypertension and ultimately brain death. aneurysm thrombosis complicated procedures, and was fatal for both (respectively and days after embolization) due to massive ischemia (aneurysm of the internal carotid artery) and refractory intracranial hypertension (aneurysm of anterior communicating artery). those two patients got respectively wfns grade / fisher classification: iii/ and ii/ . the patient with wfns grade iv got a successful uncomplicated procedure days after the initial insult and partial clinical recovery. he continued to improve and was discharged alive from hospital without major neurological disability (gos: good, modified rankin scale = ). conclusion. endovascular coiling could be an efficient therapeutic tool. incidence and outcome of procedures complications is still to be determined. strategy in patients with high wfns grade is certainly try embolization because of too risky surgery. right management timing is still to be determined. the quantitative estimation of blood loss helps in the choice of the best treatment tactics. the purpose of the study is to evaluate the ability of central blood volume index (cbvi, volume in heart and lungs and large vessels divided on body weight) and total end diastolic volume index (tedvi, sum of the end-diastolic volumes of the atria and ventricles divided on body weight) to reflect the magnitude of a hemorrhage. normo-volumic values of cbvi and tedvi were measured in cardiac icu cardiac patients, pigs and rats with weight range of . kg to kg. blood loss in the order of - ml/kg ( - steps) was applied in rats and pigs. ultrasound dilution technology utilizes the decrease in blood ultrasound velocity caused by injecting isotonic saline, and can be used in species of any size. cardiac index (ci), cbvi and tedvi were measured by hcp (transonic systems inc., usa) before and after blood loss. a disposable extracorporeal av loop filled with heparinized saline was connected between an existing artery catheter and central venous catheter. reusable ultrasound sensors were clamped on to the arterial and venous limbs of the loop. a peristaltic pump (nipro, japan) was used to circulate the blood from the artery to the vein at - ml/min for - min. measurements were obtained by injecting . - ml/kg (max ml) of isotonic saline. at the conclusion, the av loop was flushed with heparinized saline. in normo-volemic situations indexes are in the range of cbvi = - ml/kg and tedvi = - ml/kg, despite times differences in weight. a dramatic blood loss of - ml/kg in experimental animals produces the same magnitude - % decrease in cbvi and tedvi. severe dysphagia associated with silent aspiration and the danger of asphyxia requires translaryngeal intubation or tracheostomy. the aim of the study was to apply the clinical screening test (cst) and fibrooptic evaluation of swallowing test (fest) to determine the best method of upper airway protection. it was a prospective cohort study during the period of - . it included patients operated for fpt. all patients were delivered to icu intubated and mechanically ventilated after operation. after full recovery from anesthesia, returning to consciousness and passing spontaneous breathing test (sbt) (if not -mechanical ventilation continued) they underwent cst of points. the patients who passed cst without deficit were considered to have none or low level of dysphagia. the patients who passed cst with some deficit were considered to have dysphagia. all the patients were extubated and underwent fest. in patients with poor cst, icu crew was ready to perform translaringeal intubation immediately if necessary. patients with severe cases of dysphagia underwent tracheostomy and received cuffed tracheostomy tubes to prevent aspiration and ensure free air passage. on the next day after performing tracheostomy, swallowing rehabilitation therapy began. tracheostomiesd patients underwent fest every week. after passing fest with blue dye, decanulation was possible. results. patients of total group who did not recover consciousness or did not pass sbt in hours after operation were determined for prolonged artificial ventilation and were excluded from further study. the patients who passed cst without any deficit were successfully extubated and showed absent or mild dysphagia in fest. patients passed cst with deficit and after fest were divided into three groups by the level of dysphagia -mild, -intermediate and -severe. the regress of swallowing disorders was evaluated by fest every week. in the first group the earliest recovery was in three days, in the two other groups none recovered earlier than after three weeks. the latest recovery was determined after a year of swallowing rehabilitation therapy. two patients were not decanulated at all. postoperative recovery made possible to reduce rs. but insufficient rs exhaust the patient and may result in secondary impairment of the brain. the aim of the study was the analysis of different respiratory strategies in these patients to choose the best. it was a prospective cohort study of patients after removal of pft with complicated postoperative period during and no significant difference in± - . the age of the patients was severity of complications and neurological status. all patients included into study demanded rs after operation because of low rd. all patients had bulbar palsy syndrome (bps). patients with bps were tracheostomiesed. after full recovery from anesthesia and returning to consciousness ventilation modes were simv+ps or cpap+ps (ventilator pb ). rr (respirator and patient), tv, ps, fio , peep, pao and paco and neurological status were evaluated and registered daily. the criteria of readiness to wean were determined as: pao /fio > , peep< , ps< - , spo > %, rr< , fio < %, gcs> . weaning was successful if patient could breathe spontaneously for more than hours without neurological deficit arise. patients were divided into groups: . simv+ps ventilation (respirator rr - % of total rr) - cases; . cpap+ps ventilation - cases; . failed extubation in first hours - cases. all patients of the group were ventilated in simv+ps after reintubation. the patients of the group were extremely unstable and the modes of ventilation were corrected - times per day. duration of ventilation was minimal in the group with maximum replacement of spontaneous breathing with artificial ventilation -simv+ps (table ). in this group was minimal number of breathing disorders (minimal number of ventilator mode corrections) and patients were most stable. in first group was tendency to regress of bps ( %) and there wasn't cases of arising neurologic deficit. but in the group there was increase of bulbar palsy syndrome in % cases and no regression. c. a. eynon* , p. collins neurosciences icu, wessex neurological centre, southampton, wessex regional transplant, queen alexandra hospital, portsmouth, united kingdom the management of severe brain injury in the uk is undergoing significant change. national recommendations are that all severely brain-injured patients are referred to specialist centres. protocolised guidelines for the management of brain injury have resulted in improvements in mortality and morbidity. with this has come a reduction in the numbers of brainstem dead patients suitable for solid organ donation. however, there still exists a group of patients for which continued treatment is felt to be futile and who may be suitable as solid organ donors following death by cardiorespiratory criteria. all deaths during a -month period were audited prospectively. when patients did not fulfill the requirements for brainstem testing, futility in continuing medical treatment was determined by the supervising consultant neurosurgeon, neurointensivist and senior nurse. in such patients, treatment other than comfort care was withdrawn. patients (< yrs) where medical treatment was to be withdrawn were considered for nhb organ donation. . patients died during a -year period. patients had death confirmed by brainstem tests of which became solid organ donors. patients were potential nhb donors. nhb donation was considered in cases and offered to the family in . in one case the next of kin were untraceable, in one case the coroner refused permission. consent for donation was obtained from the family in / cases. nhb organ donation occurred in cases. in the remaining cases, patients died outside the time window for organ retrieval, in one the next of kin withdrew permission and in one the coroner did not grant permission. of the patients who died outside the time window for nhb organ donation, subsequently donated tissue. a total of kidney transplants, liver transplants and one double lung transplant were performed from nhb donors. conclusion. the number of brainstem dead patients is declining in the uk. patients in whom continuation of medical care is felt to be futile can provide a source of solid organs suitable for tranplantation. successful transplantation of solid organs from potential nhb donors occurs in a significant proportion of cases. feedback from family members has been supportive regarding the decision to donate. the studies on treatment of patients with head injury and brain damage, with sudden cardiac arrest due to various reasons revealed, that it is very useful to introduce neuroprotective therapy in those patients. it allows to decrease the consequences of local and global brain ischemia. the aim of the study was to present the efficacy and tolerance of treatment with amantadine sulphate (amantix, merz, germany), as a neuroprotective therapy. in the intensive care unit, between and we monitored a group of patients with consciousness disorders, in the age of . +/- . , with average bmi of . +/- . . the level of coma's deepness and its reasons were different. the examination plan, methods used, choice and classification of patients were carried out based on previously prepared protocols. the minimal period of treatment with intravenous infusion of amantadine sulphate was days, however, if possible, the therapy was continued for days. after this period the patients received amantix in tablets. many additional therapeutic measures from different groups were used in those patients. an endotracheal intubation and ventilation were necessary in all of the patients. amantix was used as treatment's supplementation in the dose of x mg/day. at the admission the patients were classified with the use of gcs (glasgow coma scale). in order to evaluate the effects of use of the preparation, some specific function of the patients were examined before the use of amantix and after finishing of the therapy. the examination was carried out by the intensive care unit doctors, neurologist and nurses taking direct care of the patients. the results were compared with the control group of patients, age , +/- , . those patients were treated with the use of standard methods. all of the collected data were worked up statistically. the authors revealed statistically important difference in gcs grading between the groups. the average gcs score in amantix group at the admission was: . +/- . , and at the discharge: . +/- . . analogically, in the control group the admission score was: . +/- . , and at the discharge: . +/- . . in patients using amantix we have noted the presence of side effects, usually it was hiperactivity. patients were transferred to different wards. patients died. the average hospitalization period in the amantix group was: . +/- . , and in the control group: . +/- . days. . this has been fuelled by increasing evidence demonstrating either sub-optimal care or poor end of life decision making as antecedants to cardiac arrest calls on acute wards. outreach and medical emergency teams have developed as a result, but their effectiveness remains unproven [ ] . at southend, development of a critical care outreach service began in . the aim of this study was to establish the trends in cardiac arrest call rates from the acute wards in the years prior to, during and after the introduction of the outreach team, to assess any potential impact this may have had. hospital switchboard records were analysed retrospectively to provide data relating to the date, time and location of ward cardiac arrest calls occurring between january and december . arrest calls to all acute wards except the critical care unit were included. the data collected was then related to hospital inpatient activity (in terms of completed in-patient consultant episodes, supplied by the hospital's information department) to enable meaningful interpretation of the observed trends. table summarises the results from the medical and surgical wards separately and then together to present data for the hospital's acute wards as a whole. the data shows an upwards trend for the years prior to and during the establishment of the outreach service, and a falling trend subsequently. conclusion. the establishment of a comprehensive outreach service that promotes all aspects of outreach critical care (expediting appropriate and preventing inappropriate critical care admissions, following up patients post critical care discharge and promoting critical care skills throughout the hospital) is likely to lead to a reduced frequency of cardiac arrest calls. however, this effect may take years and not months following introduction to be manifest. we suggest all outreach services should collect and present this simple data locally to demonstrate the potential impact of their activities. intracerebral haemorrhage (ich) represents - % of all strokes. the acute and subsequent blood pressure management presents a therapeutic dilemma. it is necessary decrease high systolic blood pressure, but there is the risk of decrease cereb. objective: can the regional cerebral oximetry helps us to determine individual adequate blood pressure? ral perfusion pressure and risk of ischemia developing. methods. regional oxymetry is the method of measurement the cerebral oxygen content based on near-infrared spectroscopy, which is carried out by means of the invos device (in vivo optical spectroscopy). this method is non-invasive, delivers continuous information and it allows the possibility of emergency therapeutic response. rso is transcutaneous monitoring of regional cerebral saturation with hemoglobin oxygen (rso ) in mixed blood in the frontoparietal regions, which represents interface beetween the basin of the anterior and middle cerebral arteries. the normal value of rso is beetwen - % in a majority of the population, and every change from the baseline in both directions by more than - % signifies the risk of ischemia for the observed tissue. during a twelve-month period all pacients admitting with ich in our neurointensive care unit (nicu) were managed by regional cerebral oximetry (n = ). arterial blood pressure was monitored and was corrected farmacologically. the functional outcome of patients when discharged from the nicu and after six month were evaluated by the glasgow outcome scale, barthel index and modified rankin scale. data was collected retrospectively for comparison with pacient which didn't monitor by rso . we found correlation between discovery of patological rso values and age, initial gsc and volume of ich. there are less septic and hemodynamic complications in the group with monitoring rso . using this method, the probability of successful improving outcome all patients with intracerebral haemorrhage will be estimated. there is the need for guidelines regarding the blood pressure managemet of these patients. elaborated data are available on iccollege.be. of ( , %) icu directors, representing icu beds completed the extended query. main findings were: visits limited < h/day ( h + h ) ; hcp dedicated to family ( %) children admitted from y of age ( %) ; family accompanied by hcp during resuscitation ( %) ; no witnessed resuscitation procedures ( %) ; scare possibilities for family to stay during night ( %) ; insufficient bad news delivery ( , %) ; poor team psychological support ( - %). icu physicians completed the follow-up simplified query. main findings were: psychological support for family ( , %) and team ( , %) ; post-resuscitation debriefing ( , %) ; identification of dedicated hcp ( , %) ; use of ( , %) and written ( , %) dnr-orders ; comprehension of ( , %) and family witness ( , %) of patients' will ; structured bad news delivery ( , %) ; witnessed resuscitation ( , %) and invasive procedures ( , %) ; children accepted < y ( , %). in belgium, although there's obvious concern from the majority of icu's to communicate with relatives, recommendations for psychological team support, teaching bad news delivery, schedule of visits and witnessed procedures are made. sudden death constitutes an important sanitary problem. early diagnosis and advanced cardiorrespiratory live support are considered the most important factors related with short term prognosis. the objective of this study was to analyze the prognosis, clinical characteristics and evolution of patients who initially recovered after an episode of out-of/hospital or in-hospital cardiac arrest and who were admitted to a medical-surgical intensive care unit (icu). sixty three consecutive patients were included and retrostectively studied when they were admitted to a medical-surgical icu. for two years, from april of until april of , sixty three consecutive patients were included. eighteen of the patients were women ( . %) and were men ( %). cpr was given out of hospital to patients, and patients suffered sudden death on a conventional hospital ward and patients in special units (surgery, coronary, emergency room, etc.). the etiology of the arrest was considered to be of probable primary cardiac origin in % of the episodes and the rest of the origin of arrest was considered secondary to other pathologies (respiratory, sepsis. . . ). mortality in icu was . % and , % were discharge alive but of that percentage of patients only % were released without important neurological damage. patients recovering following cardio-pulmonary arrest out of hospital and hospital ward had greater mortality than those who suffered an event in a monitored area ( %).(p< , ) the lengthy resuscitation times (greater than minutes), elevated apache ii scores and advanced age is associated with greater mortality. recovered cardiac arrest is a pathology with high mortality and morbidity in intensive care. in our series only % were released alive without severe neurological damage. the existing condition of the patient and the excessively long resuscitation times were decisive factors in these results. we conducted a retrospective case-note study in a six-month period at an innercity district hospital (distant from any international airport), and report three patients who deteriorated about the time of overseas travel by air. results. case . a retired gentleman of -years with progressive idiopathic pulmonary fibrosis requiring home oxygen therapy travelled by air without a medical escort. he deteriorated shortly after his arrival at the family home in the uk. he presented to the emergency department in respiratory failure requiring non-invasive ventilatory support. he died during prolonged hospitalization. case . a -year old woman with obstructive sleep apnoea reduced her diuretic prescription without her physician's knowledge prior to a long-haul flight. she deteriorated with acute shortness of breath shortly after her arrival at the family home in the uk. she was brought by her family to the emergency department where she was found to be in cardiogenic pulmonary oedema, requiring non-invasive ventilation. she survived hospitalization and was discharged with home oxygen therapy. case . a -year old man collapsed in the street explaining to passers-by that he had swallowed some packages. he had a travel ticket from the airport in his possession but was able to give no other history. he was taken to the emergency department and required intubation due to extreme agitation. he was found radiographically to have ingested multiple wrapped packets. he required laparotomy to remove differently coloured packs some of which had ruptured releasing their contents. urinalysis revealed cocaine metabolites. he subsequently made an uneventful recovery after extubation and transfer to a surgical ward. patients may present to hospitals distant from international airports with clinical deterioration consequent upon risks associated with long-distance air travel. ( ) prospective observational study of a cohort including every septic patient admitted in a medical icu of an university hospital from may to december . demographic, clinical, laboratory and therapeutic variables were registered. a clinical examination assessing motor deficit and tendon reflexes was daily performed in order to check cipnm criteria. univariate and multivariate logistic regression tests were used. . septic patients were included with age ± , apache ii score ± , maximum sofa score . ± , icu mortality %, in-hospital mortality %. patients survived at least days. patients did not require mv and none of them developed cipnm. finally the analysis was performed with the patients who survived at least days and required mv, with a cipnm incidence of %. variables were included in the univariate analysis. after multivariate analysis, it was found that several variables were significantly related with risk for the development of cipnm (odds ratio, or; % confidence interval, ic; signification level of change in log likelihood, p): . mv length (days): or . patients in the icu often develop an acute neuromuscular disorder characterised by difficulty of weaning from mechanical ventilation and associated with variable degrees of muscular weakness including quadriplegia [ ] . often associated with steroid treatment, neuromuscular blocking agents (nmba) and septic patients, the pathogenesis of cim is poorly understood [ ] . originally thought to be neuropathic in nature, however, today myopathy is more often diagnosed [ ] . to further clarify this point we present a series of patients. between and a retrospective study was carried out on patients diagnosed with cim and whose muscle samples were analysed in the dept. of neuropathology of chuvi, spain. in the clinical studies special attention was paid to the neuromuscular status apache ii, and treatments with steroids, nmba,total parenteral nutrition (tpn)and insulin. all patients underwent electromyographic studies and biopsy and in those with sensitive neurography an abnormal nerve biopsy. of the patients, were women and were men, all aged between and , (mean ± ). in three of the patients admission to the icu was not necessary. all save two received prolonged high doses of steroids and two were on chronic treatment of steroids. only one was treated with nmba for more than days. two patients were diabetic with no electromyographic signs of neuropathy. seven needed insulin to control glucemia during the critical period. received tpn, and had sings of sepsis. muscle biopsy showed signs suggestive of cim (atrophy of both types, alteration of the intermiofibrilar pattern) and in some cases miofagia and thick filament loss. in two cases there was discrepancy between neurophysiologic and biopsy findings (muscle and nerve). the seven patients that survived the acute illness showed neuromuscular symptoms on release from hospital. follow up was possible on three patients for , and years respectively. all recovered muscle strength, the electromyography normalized and currently have normal independent daily life activities. the aim of this clinical trial is to study cip in icu patients (pts) after surgical procedures. we enrolled retrospectively icu pts ( men ( . %), women ( . %) who underwent at least one surgical procedure under general anaesthesia and developed cip. all of them were mechanically ventilated and stayed > days. underlying diseases: multiple trauma , complicated surgery , pancreatitis . mean age: . ± . years. operation sites: abdomen , cns , orthopaedics , thorax , other . mean anaesthesia time: ± min. in all pts an electromyogram was performed twice, as well as daily neurological examination. we analyzed several parameters predisposing to cip. conclusion. ) sepsis predisposes to cip, but cip can be appeared without sepsis ( . %). ) age and serum albumin values do not predispose to cip (p< . ); however the early implementation of a nutritional protocol is useful. ) although not well correlated, we try, if possible, to avoid neuromuscular agents. ) high pgl predispose to cip (p< . ); it is important to maintain pgl < mg%. ) cip prolongs lmv (p< . ), los in icu (p< . ) and los in hospital (p< . ), but does not increase mr significantly (p< . ). s. kjaergaard* , s. e. rees intensive care, anaesthesia and intensive care, region north jutland, aalborg, center for model-based medical decision support, aalborg university, denmark ( ) is accepted as the gold standard method of describing pulmonary gas exchange. in the clinical setting, if any, only very simple one-parameter models are used. the parameters of these varying upon changing the fio . in a previous paper we have compared the miget with a simpler model, and shown that this simpler model is a good fit to the inert gas data obtained from the miget experiment ( ) . this study explores whether the simpler model can reproduce oxygenation data in an oleic acid lung damage model upon changing the fio and compared these results with those obtained using the miget. seven pigs were used for the study. lung damage was induced by an intravenous infusion of oleic acid. six inert gases were infused to estimate the distribution of v/q-ratios of the miget model and dead space, shunt and a parameter describing v/q mismatch, i.e. fa , of the simpler model ( , ). measurements were taken at five different ventilator settings. the two models were then used to simulate arterial oxygenation data when the model-parameters along with measurements of mixed venous blood gases at different values of fio were given as input to the models. both models can be used to simulate sao at varying fio . this is shown in the figure where the models have been used to simulate sao at varying values of fio (miget "+", simple "squares") ranging from . - . . it shows that the models simulate identical values of sao with a mean difference = - . +/- . . since the miget and the simpler models provide both equally good fit to the inert gas data ( ) and precise predictions of arterial oxygenation, they might be interchangeable in a clinical setting where only a limited amount of data are accessible. in addition, the parameters of the simpler model can be obtained quickly and non-invasively ( ). the model could therefore have applications a clinical situation. ethanol may be used in the management of toxic alcohol poisonings , or as sedation in alcohol withdrawal. ethanol may be a component within drug formulations, for example nimodipine infusion or chemotherapeutic agents . ethanol flush has also been used to restore the patency of occluded catheter lumens . in clinical practice, ethanol should only be infused via a pcvc and not a peripheral venous cannula, as the high osmolality of ethanol can cause thrombophlebitis. given anecdotal reports of pcvc deterioration during ethanol infusion , , this study applied a bench testing method and statistical modelling to develop clinical practice guidelines at our institution. the test solutions used were: dextrose (d) %; ethanol (e) %, %, %, %, % and %. each test solution was perfused through pcvcs. a total of pcvcs were perfused. (b) hour perfusion. the test solutions used were: d %, e %, e % or e %. each test solution was perfused through pcvcs. after perfusion, the strength of all pcvcs was assessed. the pcvc was attached to a force gauge. a known force was applied to the pcvc and the pcvc length was measured. this was repeated for increasing forces until the pcvc broke. length-force relationships were plotted and were described statistically using linear mixed effects models. . this bench test model produced reproducible data. the pcvcs were not directly traumatised by the testing apparatus. (a) minute perfusion. pcvcs perfused with e % , e % or e % perished with obvious structural deterioration. two distinct length-force relationships were described on linear mixed effects models: e %, e % or e % weakened the pcvcs , whilst d %, e %, e % and e % had no effect upon pcvc structure (p< . ) (b) hour perfusion. the pcvcs did not perish. on linear mixed effects models, e % and e % weakened the pcvcs, whilst d % and e % had no effect (p< . ). conclusion. this model quantifies the effect of ethanol infusion upon pcvcs. this has not been demonstrated previously. the infusion of e % e % or e % via pcvcs should be avoided. infusion of e % and e % for hours weakens pcvcs. nimodipine and other drugs using ethanol as a carrier vehicle should be infused via pcvcs with caution. these potential hazards should be outlined in individual pcvc package inserts and drug product information leaflets. ( ) in septic shock patients tissue microcirculation is altered despite an increased tissue oxygen tension ( ). microcirculatory distress could be one of the earliest stages in the progress of sepsis to multiple organ failure, and microcirculatory shunting could be an important contributing factor to this development ( ) . sofa score has been suggested to clinically assess the level of organ dysfunction( ). we've done a prospective observational study to determine if changes in the rate of thenar muscles tissue deoxygenation during stagnant ischemia in patients with severe sepsis and septic shock are related to changes in organ dysfunction using the sofa score. fourteen septic shock patients were included in a preliminary study during the first days of sepsis evolution. , hutchinson?thenar muscle sto was measured noninvasively by nirs (inspectra technology, usa) before and during upper limb ischemia. sto decrease (downslope) after limb ischemia were analyzed during first and fifth day after icu admission. changes in sto downslope, sofa score, cardiac output, lactate and the use of vasoactive drugs between first and fifth days were recorded. we found good correlation between ∆sto downslope and ∆sofa between the first and the fifth day. (spearman's rho = - , ; p< , ). our results are in accordance with those reported by pareznik( ) wich correlated isolated values of sto with sofa in septic shock patients but moreover we show that changes in both variables during evolution are also correlated. in septic shock patients, thenar muscle ∆sto downslope is well correlated with changes in ∆sofa, a clinically accepted tool to measure organ dysfunction evolution during sepsis. ∆sto downslope monitoring could be not only a good marker of microcirculatory state but also a good indicator of organ dysfunction evolution during sepsis and consequently a potentially therapeutic objective. one of the important tasks that the anesthesiologist should perform is to monitor the functions of body organs; lung airway pressure is among the most important ones. a real-time continuous monitoring device which would be designed in a small volume and is portable could be used by anesthesiologists for this purpose. so, this device could improve the quality of anesthesia care while being efficient and cost containing. the device consists of four consisting parts as follows: sensors (pressure transmitter and gas velocity transmitter), processors (two avr microprocessors), monitor and software. software simulation: the performance of the monitor was controlled through a simulation process with matlab-simulink software (the mathworks inc. ma, usa),( ). the monitoring device demonstrated acceptable results, both clinically and at the lab assessments. the study demonstrated this device as an effective, reliable and cost containing device. a. rodríguez salgado* , a. socias , b. comas , a. llompart , i. losada , p. ibáñez , m. borges intensive care unit, emergency department, internal medicine, h. son llàtzer, palma de mallorca, spain since we have a global computerized system on our hospital we used it to develope an integral and multidisciplinary working protocol for the early recognition of sepsis and its appropiatte therapy. prospective study conducted in a four-hundred bed teaching hospital with medical and surgical areas and the support of a global computerized system and on line internet conexion among areas. a computerized protocol to improve management of sepsis was developed. it automatically produces an annotation on the medical chart and a serie of analytics forms when activated. additionally clinical guidelines on sepsis management can be consulted. it was started on january , and here we present all patients included until january . during the study period patient were included in the protocol, with a mean age of , ( , ) y, , % were male. we have observed an ascending tendence in the number of patients included in the protocol, having arised from patients on january to on january . the protocol was activated at the icu in ( , %) cases, at the emergency department in ( , %) and at hospitalization units in ( , %). two-hundred and two ( , %) patients were admited at the icu. though initially the protocol was exclusivelly directed to patient with severe sepsis or septic shock, lately some patients with sepsis have been included. so, ( %) had sepsis, ( , %) severe sepsis and ( , %) septic shock. only ( . %) had fever and ( . %) had arterial hypotension at the protocol entry. sepsis was community-adquired in ( , %) cases, nosocomial-non icu adquired ( , %) cases and icu adquired in ( , %). the the most frequent site of infection was the lung in ( , %) patients, followed by the abdomen in ( , %) patients. isolation of the causal microorganism was achieved in ( %) patients. blood cultures were positive in ( . %) cases. forty seven ( %) had organ disfuntion (od), ( . %) od, ( . %) od and ( . %) or more od. mean lactate levels were , ( , ) mmol/l, , ( , ) mmol/l and , ( , ) mmol/l at the activation moment, at and a hour respectively. mean c-reactive protein levels were , ( , ) mg/l. eighty-five ( , %) patients deceased, of whom ( %) had sepsis, ( , %) severe sepsis and ( , %) septic shock at the moment of activation. conclusion. it is possible to implement a global multidisciplinary computerized protocol for identification and management of the sepsis, although this is a laborious and continual process. t. kyprianou* , g. panayi , d. zeinalipur-yazti , m. dikaiakos intensive care unit, nicosia general hospital, ngo, intensive care forum, dept of computer science, universiy of cyprus, nicosia, cyprus introduction. the physiological condition of icu patients is marked by rapidly evolving and frequently life-threatening derangements as well as 'silent' yet important alterations in homeostasis. reliable monitoring i.e. the capability to collect, store, process, and share inpatient monitoring data along with physicians' remarks can bring tremendous benefits to all aspects of intensive care medicine (practice, research, education). currently, grid infrastructures assemble an extensive collection of resources and expertise (egee grid: + sites around the world with more than , cpu's - pb of storage, adequate for storing and managing icu-related data. we present the design and implementation of the intensive care window (ic-window), a software tool that enables the retrieval and integration of data from patient-attached medical sensors. ic-window follows a modular design to retrieve data from different patient monitoring devices. the tool includes a full-edged interaction protocol and graphical user-interface to interact with the phillips intellivue mp monitor. ic-window is implemented in the context of icgrid (intensive care grid), a novel data-grid framework that utilizes the egee infrastructure to enable the seamless integration, correlation and retrieval of 'clinically interesting episodes' across intensive care units clusters. we present preliminary data from software's use in icu patients. conclusion. ic window belongs to a new generation of tools that could improve dramatically intensivist's capabilities as offers virtually unlimited storage capacity for every possible type of patient's data. in the future we plan to extend the ic-window application to communicate with other medical devices found within the icu. this will provide an open platform for the aforementioned applications. introduction. strict glycemic control by lowering blood glucose levels to - mg/dl reduces the intensive care unit (icu) mortality, morbidity, duration of the hospital stay, and overall medical care costs. to provide an intelligent system for tight glycemic control, the eu-project "closed loop insulin infusion for critically ill patients (clinicip)" was started in january . three different sensor technologies -two based on an enzymatic reaction with immobilised glucose oxidase using either amperometry or fluorimetry as transducer and another based on reagent-free infrared spectroscopy -have been developed to continuously monitor the glucose levels in the subcutaneous interstitial body fluid. monitoring of the subcutaneous interstitial fluid is realized using a microdialysis catheter cma from cma microdialysis ab as a body interface to all glucose sensors. experiments were carried out at the center for medical research (graz, austria), lasting up to h with the probands starting under fasting condition, but receiving later their normal diet. after microdialysis probe implantation, the perfusate (either % mannitol solution or elo-mel) flow rates were around µl/min. for reference measurements, dialysate samples were collected. in parallel, blood glucose concentrations in venous blood samples, collected under arterialised conditions with the arm resting in a hot box, were determined using a glucose analyzer from beckman instruments. a clarke error grid analysis of the results from all three sensors has shown all values in clinically acceptable zones. the blood reference and sensor measurements were further compared using bland-altman plots. owing to the tubing connecting the catheter outflow and sensor, the lag times for the sensor readouts were between and min. for the electrochemical and infrared sensors a simultaneous micro-dialysis recovery rate determination has already been implemented for improving the correlation of the sensor readout to the whole blood levels. some observational studies suggest that the use of pulmonary-artery catheters to guide therapy is associated with increased mortality. we performed a randomized trial to study outcome benefit of using pulmonary artery catheter (pac) in ards patients when compared to standard care using central venous catheter (cvc). the subjects were ards patients on mechanical ventilator who were assigned either to pac (pac group), or cvc (cvc group). the base-line characteristics of the two treatment groups were similar. the primary outcome was icu and in-hospital mortality from any cause. the pac group had a significantly lower icu mortality than the cvc group ( vs , p value= . ) but there was no difference between the groups in in-hospital mortality (one case mortality in cvc group). there were no significant differences between pac and cvc groups in urine output ( . ± . vs. . ± . ), use of vasopressors ( . ± . vs. . ± . ), and length of hospital stay ( . ± . vs. . ± . ) respectively. our findings suggest that pac can be used in ards patients for better hemodynamic assessment that may result in reduced icu stay and mortality rate. ethanol may be used in the management of toxic alcohol poisonings , or as sedation in alcohol withdrawal. ethanol may be a component within drug formulations, for example nimodipine infusion or chemotherapeutic agents . ethanol flush has also been used to restore the patency of occluded catheter lumens . in clinical practice, ethanol must be infused via a pcvc, as its high osmolality can cause peripheral thrombophlebitis. given anecdotal reports of pcvc deterioration during ethanol infusion , , this study applied a bench test and a statistical model to develop clinical practice guidelines at our institution. each cm triple lumen pcvc was perfused with a single test solution only. (a) minute perfusion. the test solutions used were: dextrose (d) %; ethanol (e) %, %, %, %, % and %. each test solution was perfused through pcvcs. a total of pcvcs were perfused. (b) hour perfusion. additional pcvcs were perfused with d %, e %, e % or e %. after perfusion, the strength of all pcvcs was assessed. the pcvc was attached to a force gauge. a known force was applied to the pcvc and the pcvc length was measured. this was repeated for increasing forces until the pcvc broke. length-force relationships were plotted and were described statistically using linear mixed effects models. . this bench test model produced reproducible data. the pcvcs were not directly traumatised by the testing apparatus. (a) minute perfusion. pcvcs perfused with e % , e % or e % perished with obvious structural deterioration. two distinct length-force relationships were described on linear mixed effects models: e %, e % or e % weakened the pcvcs , whilst d %, e %, e % and e % had no effect upon pcvc structure (p< . ). (b) hour perfusion. the pcvcs did not perish. e % and e % weakened the pcvcs (p< . ). not been demonstrated previously. the infusion of e % e % or e % via pcvcs should be avoided. infusion of e % and e % for hours weakens pcvcs. nimodipine and other drugs using ethanol as a carrier vehicle should be infused via pcvcs with caution. these potential hazards should be outlined in individual pcvc package inserts and drug product information leaflets. ( ) introduction. inadvertent esophageal intubation may lead to serious complications such as hypoxia, cardiac arrythmias and death. auscultation of breath sounds may be an inaccurate method to determine correct endotracheal tube placement of endotracheal tube placement. vibration response imaging (vri) is a novel non-invasive technology that measures vibration energy of lung sounds during respiration. as air moves in and out of the lungs, vibrations propagate through lung tissues and are recorded by sensors spacially distributed on the patient's back over the lungs and a dynamic image is created. a year old female patient presented with lung cancer. plain chest radiograph and ct scan revealed a large left lung mass comparable for a neoplasm. she was admitted for left lung lobectomy. after informed consent was obtained, she underwent vri before and after intubation. the esophagus was inadventently intubated and recognized immediately after the vri recording was obtained. the patient went on to have a successful operation. analysis of the vri data obtained during esophageal and tracheal ventilation are compared along with a normal vri image. during esophageal ventilation most of the vibrations ( %) were detected by the upper sensors and the least by the lower sensors ( %) (fig. ) . following the endotracheal intubation as well as in a normal image, the vibrations were more evenly distributed with the sensors from the middle region receiving more vibrations. quick detection of inadvertent esophageal intubation is crucial to prevent serious complications but commonly used methods of confirmation such as auscultation and plain chest radiograph are inaccurate or do not provide timely results. vri is a novel technology that offers the potential to quickly identify inadvertent esophageal intubation in the or and perhaps other settings. the acapella ® is a small hand-held vibratory device that combines the resistive features of the positive expiratory pressure (pep) and the vibratory features of a flutter valve to mobilize secretions in the airway. vri is a novel dynamic imaging technique that measures vibration energy of lung sounds generated during respiration. in this study, our aim is to determine, using the vri, what regions of the lungs receive the most vibrations when the acapella is being used. a second vri recording was performed on a healthy volunteer during normal breathing (first three breaths) and while using the acapella device (last four breaths). the vri recordings were obtained in second periods of respiration. dynamic digital images and numerical raw values for vibration energy are analyzed and compared any regions of interest. . vri images at maximal expiration while using acapella show increased total vibration intensity. when the distribution of expiratory vibration is examined, it appears that vibration from the acapella goes more to the lower lung regions (figure and ) . asymptomatic catheter-related central vein thrombosis (cvt) which is diagnosed by venographic studies is mentioned to be as high as %. moreover, when thrombosis occurred, the risk of catheter related sepsis was declared to be . % higher. in this prospective study we aimed to diagnose cvt early as possible, its incidence and risk factors. icu patients (pts) that needed a central venous access for at least hours without chemotherapeutic agents administration were included in this prospective study. the catheters were inserted via internal jugular or subclavian vein at bedside under aseptic conditions using the seldinger technique. diagnosis of vein thrombosis was detected by color doppler ultrasound examination performed in less than h after catheter removal (picture). the protocol was approved by the ethic committee. three hundred and thirty eight pts ( f, m), mean . years old ( - years), were included in the study. catheters mean duration time was . days and duration of insertion mean time was . min ( - min). in pts catheter insertion was performed with a single puncture, in pts with double and in pts with three and more punctures. catheter localization was : in pts right subclavian vein, in pts left subclavian vein, in pts right internal jugular vein and in pts left internal jugular vein. catheter related thrombosis was diagnosed in pts ( . %) while catheter infection was seen in patient ( . %) (table). generally the chemotherapeutic agents administered via the central vein catheter have thrombogenic effect. when we study our cvt diagnosed pts we found out that all of them were over years old, the mean catheter duration time was . days (table) . but these results were not statistically significant when compared with the other pts under years old and more than . days of mean catheter duration time. out of pts who were not under anticoagulant therapy had cvt while out of pts under anticoagulant therapy had cvt diagnose which was found statistically insignificant (p> . ). our results show that patients under anticoagulant therapy have a three fold more cvt risk ratio than the others who are not using this anticoagulant therapy. patients under anticoagulant therapy have to be followed more closely regarding to cvt. the provision of good glycaemic control is thought to have some beneficial aspects in critical care patients. we have previously described the introduction of a web-based insulin dose calculator program to support the control of blood glucose in critical care. the aim of this study is to describe a modified version of a calculator program based on van de berghe's studies. this allows nursing staff to enter blood glucose values together with the insulin infusion rate into a calculator. the calculator then provides a recommended insulin infusion rate to control blood glucose with the added ability to recommend small bolus doses of insulin when appropriate, store blood glucose concentrations, insulin rates, bed number and the date and time of calculation. we also modified our feeding protocol to restrict the target enteral feed from kcal to kcal per day and removed the night time rest period. we studied the data stored by the program which was used for all patients admitted to a -bedded intensive care unit (approximately % of whom have neurological injuries) between june and may . overall there were patients admitted (mean apache ii score [sd +/- ], with a mean age of years [sd +/- ]. patients died prior to icu discharge. there was a total of patient days with recorded calculation data points. the mean blood glucose concentration was . mmol ( ci . - . ). there were episodes of treated hypoglycaemia of which were on an insulin infusion. there were two troughs in the time of data entry that corresponded with staff handover. there was no diurnal variation in blood glucose concentration or in insulin infusion rates, although this did peak slightly in the early morning. the mean value of the insulin infusion rate was . units / hr (sd +/- . ). in normal subjects there is a decreased level of endogenous insulin in the early morning, that is only partly lost with constant nutrition. from this study we concluded that the web based insulin calculator facilitates the dosing of insulin in critical care in an economic manner. the lack of diurnal blood glucose concentration variation, suggests that once daily estimation of blood glucose may be an acceptable method of monitoring blood glucose concentrations in critical care. systemic inflammatory response syndrome (sirs) is a common entity in the intensive care units. early institution of an appropriate antimicrobial regimen in infected patients is associated with a better outcome. both c-reactive protein (crp) and procalcitonin (pct) are accepted sepsis markers. however, there is still controversy concerning the correlation between serum concentrations, infection and sepsis severity. objective:to determine the clinical aplication of procalcitonin (pct) and c-reactive protein (crp) plasma concentrations in the detection of sirs related to infection and sepsis and the assesment of severity of sepsis. desing: prospective observational study. setting: medicosurgical intensive care unit. patients: over a period of months (january-february ), forty seven consecutive adult patients admitted in a intensive care unit for an expected stay > hrs.and sris symtoms and signs. informed consent was obtained from all patients. measurements: pct and crp plasma concentrations and white blood cell counts , apache ii y sofa within the first h . each patient was examined at the time of enrollment and was classified in one of the following four categories according to the accp criteria: siris and sepsis group (sepsis, severe sepsis and septic shock). statistical analysis: were performed with spss . . differences in continuous variables between infected and non infected patients were compared with the nonparametric mann-whitney test. and lineal.regressión. pct levels were significantly higher in the severe sepsis(p= , ) and shock septic group (p< , ). pct and cpr levels no weren found differences between sepsis of less gravity group and noninfectious sirs. pct and crp levels are significantly correlated to the severity of organ dysfunction (sofa y apache ii). pct and crp levels were significantly higher withing short space of time in patient with infection than in patients with non-infectious sirs, but for sepsis of less gravity, pct and crp plasma values not differentiate between sepsis and non-infectious sirs. investigators have reported microcirculatory alterations in critically ill patients using various techniques. persistent microvascular alterations might be associated with the development of organ failure and death. in this study, microcirculatory blood transit time was measured in intensive care patients using micro-channel flow analyzers and related to the severity score and mortality. thirty-one patients were included in this study. mean apache-ii score was . . patients were divided into two groups, group l (apache-ii< , n= ) and group h (apache-ii>= , n= ). in both groups, blood transit time was measured using microchannel flow analyzers (mc fans). the micro-machined silicon chip is utilized in these instruments to simulate human capillary blood flow. microcirculatory alteration was presented as a blood transit time (second) of heparinized blood through micro-channel array under the pressure difference of cmh o. hematocrit, white blood cell (wbc) count, platelet count, and labolatory data were obtained at the same time. blood transit time was significantly longer in group h comparing that in group l ( . +/- . sec, . +/- . sec, p< . ). wbc count was larger in group h comparing that in group l ( +/- /ul, +/- /ul, p< . ). triglyceride (tg) and immunogloblin (igg/m/a) levels were significantly higher in group h comparing these in group l. none of the group l patients died, however, hospital mortality rate was . ? in group h. blood transit time through micro-channel array was prolonged in patients with high apache score )wbc, tg, and immunogloblin levels might be associated with patients blood fluidity. ) micro-channel flow analysis may become a valuable tool to monitor microcirculation in critically ill patients. a. roman* , t. el mahi , c. hanicq , d. gnat , f. vertongen , e. stevens intensive care, clinical chemistry, chu saint-pierre, brussels, belgium bedside glucose monitoring is mandatory for icu patients under tight glycemic control. point-of-care (poc) glucometers are based on glucose-dehydrogenase coupled with pyrroloquinoline-quinone/ferricyanide (gd/pqq)or phenanthroline-quinone/nad (gd/pqnad), or glucose-oxydase/ferricyanide (go) enzymatic methods for whole blood measurements. the laboratory reference method is hexokinase for measuring the plasma glucose levels. some drugs and metabolites can interfere with poc methods. the aim of this study was to evaluate the effect of the uric acid levels on the accuracy of these bedside methods. in this prospective observational study, arterial blood glucose was measured simultaneously on the accu-chek inform roche (gd/pqq), on the precision pcx abbott (gd/pqnad), on the rapidlab bayer (go) and each value was compared with the reference laboratory result. measures were done in adult icu patients. uric acid was obtained only once a day. a bland-altman analysis was done. biases were expressed as the poc minus the laboratory result. data were also analysed using linear regression. spearmann's rho squares were calculated to evaluate the uric acid level effect on the difference between poc and laboratory methods. the uric acid level range was . to . mg/dl. the biases, the % limits of agreement between each poc method and the reference method, the r of spearmann for the correlation between uric acid level and the difference of result glucose level for each poc method are shown in table . the accu-chek inform overestimates moderately the glucose level while the precision pcx and the rapidlab underestimate it slightly. the wilcoxon ranked test with bonferroni correction gave a p < . for comparing the bias from the accu-chek to the bias from the precision pcx, p < . when compared to the bias obtained for the rapidlab. no statistical difference between the precision pcx bias and rapilab was found. the r of spearmann correlating the effect of the uric acid level and the difference between the accu-chek and the reference method was . . the weak effect of the uric acid level of the patient on the overestimation of the glucose measured by the accu-chek can be summarized as : glucose difference(accu-chek-laboratory) = . x uric acid (mg/dl) - . . for the other poc glucometers, such correlations were absent. a patient presented with severe acidosis, point-of-care (poc) lactate of mmol/l, suspicion of mesenteric ischemia and potential need for laparotomy. however, plasmalactates was < mmol/l, and ethylene glycol (eg) ingestion was subsequently diagnosed. we, therefore, wished to determine why discrepant lactates occur and if this "lactate-gap" could be clinically useful. we phlebotomized blood, added various concentrations of eg metabolites, and tested with the five most common lactate analyzers. the pressure-volume(p-v)curve of the respiratory system defines the mechanical properties of the lung and the chest wall by relating airway pressure(paw)in no-flow conditions with lung volume at the same pressure level. objective:to evaluate a new technique for p-v curve tracing. two p-v curves were obtained in ali/ards patients using the continuous positive airway pressure (cpap) method and an automated system built into a commercial ventilator (p-v tool , galileo, hamilton). for the cpap method, ventilators were switched to cpap and pressure was raised from to cmh o in cmh o steps and then decreased while respiratory inductive plethysmography measured lung volume. for the automated method, we selected the automatic pv mode(galileo, hamilton)with flow l/m and maximum pressure of cmh o. lung-volume and airway-pressure data were recorded. p-v pairs were fitted to a mathematical model. lower (lip) and upper (uip) inflection points on the inspiratory limb and maximum curvature point on the deflation limb were obtained. correlation between methods was calculated using bias and % agreement limits for lips and uips and the intraclass correlation coefficient (icc) for absolute agreement for each pressure level. no adverse events were observed. p-v curves were equivalent for each method, with icc > . for each pressure level. bias and precision for lip and uip were:lip . ± . cmh o and uip . ± . cmh o. the automated method for tracing p-v curves is equivalent to the cpap method. easily applicable at the bedside, it avoids ventilator disconnection and can obtain both inspiratory and deflation limbs of p-v curves. introduction. hypoxic hepatitis (hh) is a common cause of acute hepatic impairment. however, few is known about the degree and duration of the reversal of the liver impairment. therefore we assessed the liver function by indocyanine green (icg) clearance via limon (pulsion medical systems, munich, germany) in patients with hh. icg clearance was assessed in critically ill patients fulfilling the criteria of hypoxic hepatitis. mean apache iii score was ± . nine patients were male. icu survival was %. icg -plasma disappearance rate (pdr) (normal range: - %/min) and the retention rate of icg extrapolated to minutes (r ) were obtained on the day of development of hh and till day five. nine patients with decompensated liver cirrhosis child c requiring intensive care therapy served as control group. results. icg-pdr and r expressed as mean ± standard deviation were . ± . %/min and . ± . %, respectively ( patients), on the day of development of hh. icg-pdr and r were . ± . %/min and . ± . %, respectively, in the control group and was comparable to the hh group (p=ns). icg-pdr and r improved continuously from time of development of hh to day five ( patients alive and at icu) and were comparable to the course of laboratory data during observation period (table ) . exhaled breath condensate (ebc) is a non-invasive means of collecting samples of airway lining fluid from the lower respiratory tract and monitoring respiratory diseases. we have used ebc acidification to study the effects of mechanical ventilation. ebc was collected ( - minutes at - o c: ecoscreen, jaeger). immediately after collection and as soon as the sample returned to room temperature, we measured conductivity and ph before and after deareation with helium ( minutes). results are expressed as median (interquartil range). we have applied spsswin with spearman correlation and mann-whitney test. our earlier evaluations of a decision support system for tight glucose control (tgc) in the critically ill utilising model predictive control (mpc) documented clinically acceptable performance with hourly bg sampling. the mpc advises on insulin infusion based on blood glucose (bg) measurements and carbohydrate content of parenteral and enteral nutrition. in the present study, we evaluated an improved version of the mpc (v . . to . . ), which extends the advice by suggesting the time of the next bg measurement in the range from half-to four-hourly to reduce nurse workload. patients were admitted at one medical (mug; n= ) and two surgical (kul: n= ; cup: n= ) icus. patients were followed for a minimum of hours and up to hours. we evaluated safety of tgc (hypoglycaemia frequency), efficacy (mean bg; hyperglycaemic index, hgi; and time spent in the target range . - . mm), and efficiency (time between bg measurements). nonparametric statistical tests evaluated differences among icus. one hypoglycaemia (bg < . mm) occurred in one subject at mug and in another at cup. there was no hypoglycaemia at kul. bg was within the target range but differed among icus with values of . ( . - . ), . ( . - . ), and . ( . - . ) mm [median ( strict glycemic control of plasma glucose has become general practice in most icus. frequent glucose control is required to titrate the amount of insulin infused and detect episodes of hypoglycemia. for practical reasons bedside glucometry is often used. aim of our study was to determine the accuracy of several glucose point-of-care (poct) devices in critically ill icu patients. arterial blood samples from unselected icu patients were collected and glucose measurements were performed on a bloodgas analyzer (glucose-oxidase; rapidlab bloodgas analyzer, bayer diagnostics) and three different poct devices (gdh-pqq, accu-chek sensor, roche diagnostics), gdh-nad+ (precision, abbott diagnostics) and modified gdh (hemocue). results of paired measurements were compared in three ways. paired values were plotted on a bland-altman plot. the pearson correlation coefficient (r) between the different methods was determined by linear regression. each pair was also analysed using the international organization for standardization (iso) criteria: -glucose > , mmol/l value within % of reference -glucose ≤ , mmol/l value within . mmol/l of reference. comparison between accu-chek and rapidlab of samples from unselected icu patients (n= ) showed a good correlation (r = . ). bland-altman analysis and analysis by iso criteria revealed clinical significant differences in . % of pairs. in all cases the poct values were higher than the values from the bloodgas analyzer. comparable results were found using the precision and hemocue: although correlation was high, analysis by iso criteria showed differences in / ( . %) and / ( . %) of pairs. a clinically important inaccuracy was found between poct devices and bloodgas glucose measurements in critically ill icu patients. in the most cases values from poct devices were false high, increasing the risk of hypoglycemia. in the context of an insulin infusion protocol for aggressive glucose control in sedated icu patients poct devices are potentially dangerous and should be avoided. acute hyperglycaemia associated with insulin resistance is common in critically ill patients. acute tight control of blood glucose is considered important, although difficult to perform in routine care. we developed a software to implement tight glycaemic control (cgao): after each glucose level measure, the cgao advises a new insulin pump rate and the schedule for the next glucose control, gives indication for correcting any hypoglycaemia episode, and presents numerous parameters describing the quality of glycaemic control. in a retrospective case control study, we compared the software cgao (lk , igny, france) used routinely in our unit since may with our previous method for glycaemic control based on daily medical prescriptions. patients without cgao (group pres) were randomly selected from our prospective intensive care database (admission after january , ) and matched : for sex, age, simplified acute physiologic score (saps ii), medical or surgical category, history of type diabetes, and length of stay (los) with patients for whom we used cgao. type diabetic patients or patients with los < days were excluded. endpoints were average glucose level, hyperglycaemic index calculated above . mmoles/l, fractions of time (ft) resp. with normoglycaemia [ . - . mmoles/l] and hyperglycaemia [> . mmoles/l], cumulative duration of hypoglycaemia [< , mmoles/l], average insuline requirements per day, and mean sampling interval for glucose control. we included patients (mean age: ± years, saps ii: ± , surgical: %, type diabetic: %), permitting to compare cgao patients with pres patients. a. sigalas*, d. w. patch, a. k. burroughs, j. p. o'beirne liver transplantation and hepatobiliary medicine, royal free hospital, london, united kingdom recently a number of studies have reported that relative adrenal insufficiency (rai) is common in critically ill cirrhotics. depending on the definition used the prevalence of rai in critically ill cirrhotics has been reported to be - %, whilst in patients immediately post liver transplantation the incidence of rai has been reported to be %. given the high prevalence of rai in critically ill cirrhotics and patients undergoing liver transplantation, we hypothesised that adrenal function impairment may be a feature of chronic liver disease per se. the aim of this study was to define the prevalence of impaired adrenal function in patients with stable cirrhosis. we also examined whether the use of the µg or µg acth tests was associated with different responses. methods. patients with biopsy proven cirrhosis (or compatible imaging and biochemistry) underwent adrenal function testing with the µg (n= ) or µg(n= ) short synacthen tests (sst). patients were those with stable cirrhosis undergoing evaluation for transplantation or assessment for tips insertion for refractory ascites. patients with a recent history of infection or bleeding were excluded. . patients underwent adrenal function testing. the median age of the group was (iqr - ). the commonest cause of cirrhosis was alcohol in %. disease severity was measured by meld and childs-pugh scores. the median meld was (iqr . - . ) and the median childs-pugh score was (iqr - ). patients ( %) showed a baseline cortisol < nmol/l and an increment < nmol/l following sst. patients ( %) had an increment in cortisol < nmol/l following sst. patients ( %) had a baseline cortisol < nmol/l. overall abnormalities in the sst (low baseline, peak or increment) were seen in patients ( %). there were no significant differences in the frequency of abnormalities in the sst between the µg or µg sst groups. in multivariate analysis only meld score significantly predicted abnormalities in the sst. the above data suggest that adrenal dysfunction is a frequent finding in patients with stable cirrhosis and is correlated with liver disease severity. the underlying mechanism of this finding is unknown but may account for the very high frequency of rai in critically ill cirrhotics. the direct relation between glucose and lactate levels in critically ill patients has hardly been studied. we studied the relation between glucose and lactate in general and during hypoglycemia. intensive insulin therapy was performed with the nurse-centered grip computer system that aimed at a glucose level of . mmol/l or less. glucose and lactate were routinely measured together. all hypoglycemias detected over a -month period at the surgical icu were analyzed. hypoglycemia was divided in mild ( . thru . ), moderate ( . thru . ) and severe (<= . mmol/l) hypoglycemia. . , glucose/lactate measurements were analyzed in patients. glucose and lactate both were not normally distributed. after taking these distributions into account no evident relationship between simultaneous measurements of glucose and lactate was seen. hypoglycemias were identified ( mild; moderate; severe). lactate showed a with a nadir value two hours after the hypoglycemia. the magnitude of hypoglycemia was not related with lactate response. evidence accumulates that improved glucose control in intensive care patients results in better outcome. improved glucose control requires rapid point of care glucose measurement. however, the reliability of point of care glucose measurements has been questioned. this study was done to evaluate the accuracy of accucheck point of care glucose measurement in intensive patients as compared to glucose measurement by the central hospital laboratory. the unit is a bed mixed closed format icu. glucose regulation is performed by nurses for all patients using a computerised protocol( ). for this study, paired glucose measurements were randomly done in patients in the icu, only when glucose measurement was clinically indicated and only if workload permitted the extra task. the accucheck inform device (roche diagnostics) measures whole blood glucose in a single drop of blood. the central laboratory uses glycoseoxidase vitros to measure glucose in serum. from patients paired measurements were obtained (table ) . central laboratory glucose measurement was generally higher than accucheck glucose measurement. the mean difference was , mmol/l. correlation coefficient r was , . the difference was more than , mmol in % of cases. blood samples were mostly ( %) derived from arterial lines. the correlation and bland altman plots are presented in figure . related literature was examined for benchmarking purposes. data collection was carried out over a one month period, two days a week, in the icu. each blood sugar level (bsl) was recorded and ensuing action chosen on adjusting the insulin infusion rate, and resultant information analysed. a survey was carried out on nursing staff regarding their views on the protocol. statistical analysis was carried out using microsoft excel ® . the bsls were in the target range of . - . mmol/l . % of the time (n= ). the proportion of bsls that complied with the surviving sepsis guidelines target of less than . mmol/l was good at . %. the incidence of severe hypoglycaemia, defined as less than . mmol/l, was low at . %. compliance with the action chosen on adjusting the insulin infusion rate was high at . %. total compliance (action and timing) with the protocol was %, and a relationship between compliance and achieving target bsls was shown. in general, a positive view of the protocol was obtained from the nursing staff regarding the protocol. the amnch icu insulin infusion protocol is effective at achieving tight glycaemic control in a safe manner. the low incidence of severe hypoglycaemia and high proportion of bsls complying with the surviving sepsis guidelines illustrates this. compliance with the protocol is achievable, demonstrated by the high level of compliance on action taken on the insulin infusion rate and the survey responses. however the timing of bsl checking needs to be addressed in future drafts of the protocol, as this is an area that needs improvement in terms of feasibility and compliance. further changes and auditing of the protocol are necessary to ensure consistency and improvement of the tight glycaemic control. introduction. intensive insulin therapy might be able to reduce mortality and/or morbidity in critical patients. besides adherence to strict protocols this strategy implies multiple, accurate measurements of glycemia. gold-standard laboratory assessment isn't able to provide immediate readings and capillary or arterial blood samples may differ too much when bedside reflectance meters are used, particularly in shock patients. our aim was to assess the accuracy of two methods of blood glucose analysis (bedside "glucometer" using capillary and arterial blood) in two groups of critical ill patients (shock and non-shock). prospective non-randomized, cohort study, in a university hospital general icu. a group of consecutive icu patients with shock syndrome and vasoactive amines and another contemporary patients without shock, were included (shock-sg and non-shock-nsg groups). for each patient to "triplets" of blood samples were collected in a h period, and included concomitant samples of blood drawn from fingerstick (cap) and non-heparinized arterial line(art). drops of capillary and arterial blood were analyzed with a bedside glucometer (glucotouch ® , lifescan), and a sample of arterial plasma was sent to laboratory for glycemia determination (lab). . total group had a median age of years, mean saps ii of , . sg was older (median age - vs ys) and more ill (mean saps ii , vs , ) than the nsg. total mortality was , % (sg- , %; nsg- , %). in the sg , % had septic and , % cardiogenic shock. in the nsg , % had politrauma and , % pneumonia. a total of "triplets" were studied. non parametric wilcoxon test was applied to test agreement between cap-lab and art-lab paired samples. although we've found a highly significant correlation (spearman r> , ) between cap-lab and art-lab values, agreement were rejected by -tailed wilcoxon signed ranks test, both in total, sg and nsg (p= . ). an error grid-analysis using iso for blood glucose determination showed that , % of cap and , % of art determinations had a deviation more than % the reference lab value in the sg. in the nsg % of cap and % of art samples had more than % deviation. this study show that the glucometer we used had an unacceptable accuracy, both in shock and non-shock patients, far from the iso criteria that imposes only % of values can be more than % apart the reference value. glucose control is a major issue in the icu and standard procedures for its determination are still lacking. introduction. arginine (arg) is a precursor of the vasodilator nitric oxide (no), while asymmetric dimethylarginine (adma), derived from proteolysis of methylated arg residues, is a no synthase inhibitor. accumulation of adma is related to oxidative stress, impairing its degradation, and to renal-and liver failure. accumulation is associated with increased mortality ( ). aim of this study was to evaluate the relation between plasma arg, adma, arg/adma ratio, organ failure and survival in patients with shock. we measured plasma concentrations of arg, adma and lactate, sofa scores and hospital mortality in septic (ss) or cardiogenic shock (cs) patients on d , d and d of icu admission. patients were enterally fed with impact (arg-enriched). values are presented in mean ± sd or median (iqr). for regression analysis, arg, adma and arg/adma were log transformed. of the patients, had ss, cs. mean age was ± yrs, sofa ± , apache ii ± . . hospital mortality was %, predicted mortality was ± %. at d , median (iqr) of arg was ( - ) mumol/l (normal range - mumol/l), adma . ( . - . ) mumol/l, arg/adma ( - ) and lactate . ± . mmol/l. arg and arg/adma at d were inversely related to lactate (r = . , p < . , for arg; r = . , p < . for arg /adma), and to sofa scores. the table presents the relation between arg and arg/adma to sofa score during sampling, and of arg and arg/adma on day to maximum sofa score. apneic oxygenation (ao) is apllied during several operations in thoracic surgery and some procedures in th icu. retention of co often leads to hypoxemia, limiting the tolerable time in ao. this experimental study was designed to evaluate the effects of recruitment maneuver on oxygenation, co retention and survival times ao. following the ethic committee approval, male sprague-dawley rats were anesthetized, tracheostomized, cannulated via the a. carotis and ventilated with pressure controlled ventilation (peak pressure: cmh o, frequency: /min, cm h o peep) for minutes. following the basal (t ) arterial blood gas sample, they were randomized into groups and disconnected from the ventilator: in group (n= ), rats underwent ao with a cannula inserted to carina (o -flow: . l/min), in group (n= ), recruitment maneuver ( cm h o (peep) ventilation pressure during seconds) was performed before ao. in control group (group , n= ), data were recorded after apnea (this group was stopped after the first subjects have died during the study period). further arterial blood gas samples were drawn in st, rd and th minutes, and ph, po , pco , hco and be values were recorded. survival times after the initiation of ao were also investigated. kruskal-wallis test was used to compare the values in different times, and mann-whitney-u the values in different groups. there were no significant difference in t values. compared to t values, there was a significant decrease in po and a significant increase in pco during rd and th minutes in all subjects, with a less change in g . there was a significant difference between g and g in po after and minutes p< . ; table ), the difference in pco was not significant. survival time in g was significantly longer (g : , ± , min; g : , ± , min; p< . ). to investigate potential prognostic factors and to predict extent of risks for postoperative pulmonary complications by logistic regressive analysis, and to evaluate the role of non-invasive ventilation in reducing the incidence of complications in elderly patients. stair-climbing test was carried out with asa score, fev , changes of spo and hr et al were noted at the same time. logistical regressive analysis based on the parameters above were used to assess the relation between potential prognostic factors and postoperative complications. patients with limited pulmonary reserves were selected using the equation, and protective effect of non-invasive ventilation on these patients was assessed. incidence of postoperative pulmonary complications for high-risk patients with non-invasive ventilation was . %, and incidence of pulmonary complications for high-risk patients without non-invasive ventilation was . %. there was not a significant difference between these two groups with low-risk (p> . ). conclusion. the mathematical model of logistic regressive analysis using stair-climbing testing combined with other parameters is a simple, reliable method to predict the cardiopulmonary reserved function in elderly patients. non-invasive ventilation can effectively reduce the incidence of postoperative pulmonary complications for high-risk patients, but it has no effect on patients with low-risk. continuous epidural analgesia (ea) and intravenous analgesia (ia) are widely used for postoperative thoracic pain control. the aim of this study is to compare the advantages and the disadvantages of both analgesic techniques. ropivacaine . % to mg/h using thoracic epidural catheters (ea) vs intravenous analgesia with remifentanyl . µgr/kg/min (ia). one hundred patients, undergoing pulmonary surgery, were recruited and divided, after randomization into groups. patients included in ea group had an epidural thoracic catheter placed at th -th space, received ropivacaine . % by continuous infusion (rate ml/h). patients included in ia group received an ev continuous infusion of remifentanyl (rate . µgr/kg/min for hours). rescue medication consisted of morphine mg ev at patients demand. analgesia at rest and while coughing as evaluated by visual analogue scale (vas). haemodynamics, motor blockade (bromage scale) and side effects such as nausea, vomiting and pruritus were observed. the follow-up took place after weaning and every hour to hours at rest and coughing. data are reported to media ± standard deviation (sd). analgesic effects were compared by using chi square statistics (p< . ). both groups showed good analgesic effects. remifentanyl seems to decrease the incidence of side effects and the need of rescue analgesia. conclusion. )our data show that both analgesic techniques are able to guarantee a good pain relief after thoracotomy. )epidural analgesia was more difficult to perform and it showed less acceptance by patients. non-invasive ventilation (niv) has become an effective treatment to reduce morbidity and mortality in patients with acute respiratory failure. its application has been restricted to critical care o intermediate care areas, and little data is available on its usefulness in the post-anaesthesia care units (pacu). the aim of this study is to document our experience after eight patients treated in the pacu. we undertook a retrospective audit of patients treated with niv between october and december . data of past medical history, age, asa physical status, surgical procedure, anaesthesia modality, type of respiratory failure, ventilatory mode, and time of niv were recorded. we also recorded side effects related to niv application. descriptive statistical analysis was used. eight patients were included. the mean age was . ± . (sd) years. five patients were classified as asa ( . %), two as asa ( . %), and one as asa ( . %). three patients had morbid obesity, two chronic heart failure, and two chronic obstructive pulmonary disease. general and regional anaesthesia were employed in and cases respectively. type of surgery was thoracic ( %), urologic ( %), and plastic ( %). there was one case of abdominal surgery and another one of oral surgery. hypoxemic failure was detected in three patients ( . %), and cpap was applied in these cases. bipap was applied in cases of hypercapnic ( . %) or global ( %) respiratory failure. the mean time of niv was . ± . (sd) minutes. no complications related to niv occurred. no patient required either intubation or transfer to the icu. all of them were transferred to the surgical wards the same day. conclusion. niv can be safely applied to selected patients in the pacu, to treat respiratory failure after either general or regional anaesthesia. it is an effective method to avoid intubation and icu stays, with minimal side effects. further studies should be conducted to analyze the clinical and economic impact of niv in the pacu. the routine use of volatile anesthetics in intensive care medicine has been limited so far due to technical difficulties and the need for an anaesthetic machine. the new anesthetic conserving device (anaconda)can provide a safe application of isoflurane or sevoflurane under intensive care conditions. this system is a modified heat and moisture exchanger which includes activated carbon fibres and works as a miniaturized vapor with recirculation. we studied the effectiveness of sevoflurane sedation in operative intensive care patients undergoing mechanical ventilation. we included ventilated patients (neurosurgery, septic patients) in our retrospective analysis. the anaesthetic conserving device (anaconda-system) replaces the common heat and moisture exchanger in the ventilator circuit. the volatile anaesthetic is continuously applied in liquid status via a syringe pump to the minivapor where the anesthetic is vaporized. the expired anaesthetic gas is stored in the carbon filter and about % are resupplied into the breathing circle. first experiences with sevoflurane at our institution with a mean application time of . ± . hours per patient, showed a mean dose of . ± . ml sevofluran to achieve the individually targeted sedation level. . ± . minutes after the end of sevoflurane application, the patients could be neurologically evaluated or transferred to spontaneous breathing or extubated. no relevant side effects like nausea, vomiting or elevated enzymes were observed. we could demonstrate a safe application route, no development of tolerance as well as short wake-up times after long-term sedation with sevoflurane. the current literature suggest that volatile anaesthetics present an alternative for long-term sedation on intensive care units, providing optimized pathways from a medical as well as from an economical viewpoint. safety and effectiveness of sedation and analgesia in permanent pacemaker implant (ppm) is of special concern, due to age and comorbidity of the implanted patients. remifentanil pharmacological properties appear to be of interest in this setting. to date, there are no reports describing the use of remifentanil in this procedure, without the use of mechanical ventilation. consecutive patients in whom a ppm or other procedures, such as pacemaker battery change, was scheduled were included. a sedation and analgesia protocol for ppm implantation was performed: metoclopramide premedication, remifentanil infusion ( mg/ml), local anaesthesia with mepivacain %, magnesic metimazol administration at the end of procedure, and remifentanil infusion withdrawal minutes later. remifentanil infusion was initiated at a rate of mcg/min, increasing the rate to attain a sedation ramsay scale grade or , to a maximum of mcg/min. remifentanil failure was defined as the need to administer a different sedation after the maximum dosage was attained. adverse effects, lenght of infusion and dosage were recorded. .two hundred and thirty-six consecutive patients were included. the men age was , ± , . procedures: bicameral pacemaker , %, unicameral , %, battery change , %, other , %. infusion description and adverse effects are showed in tables and . serious adverse effects were resolved with remifentanil infusion withdrawal. all the procedures were completed. remifentanil is safe and effective as sedation and analgesia for ppm implantation, even for old patients, with the dosages used in our protocol. nausea is the most frequent adverse effect. serious adverse effects are uncommon and can be resolved with infusion withdrawal. glass psa, gan tj, howell s. a review of the pharmacokinetics and pharmacodynamics of remifentanilo. anesth analg ; : s -s . peripheral arterial occlusive disease (paod) can cause intense neuropathic/ischemic limb pain in patients (pts) with end stage renal disease (esrd). although fentanyl may be an excellent choice in esrd due to the absence of active metabolites, the use of fentanyl as pca in esrd has never been reported. we used iv fentanyl pca for ischemic lower extremity pain in esrd patients ( m, f), of whom were scheduled for amputation. pts received iv fentanyl pca via a gemstar (abbott) pump. initial settings were mcg bolus, min lockout, no basal, and dose was adjusted as needed to achieve visual analogue scale (vas) score < . pca started hours preamputation and continued postoperatively for h in pts ( pts had epidural postoperative analgesia and one terminal cancer pt did not have surgery). pain was assessed twice daily with vas. the mcgill pain questionnaire (mpq) -total ranked rating index (pri(r)), was administered immediately before and h after pca started. sedation was assessed twice daily on a four-point scale: ) agitated, ) awake, ) roused by voice and ) unarousable. pain scores were compared with paired t-test. group data are presented as mean ± sd. mean sedation score was in men and in women. we did not observe respiratory depression in any patient. the aim of this study was to determine risk factors for relapse, and for icu-mortality in patients with ventilator-associated pneumonia (vap) related to nonfermenting gram negative bacilli (nf-gnb). retrospective case-control study based on prospectively collected data. vap diagnosis was based on clinical, radiographic and microbiologic (endotracheal aspirate ≥ cfu/ml) criteria. patients with monobacterial vap related to nf-gnb were eligible. patients with subsequent superinfection or persistent pulmonary infection were excluded. patients with relapse of nf-gnb vap were matched ( : ) with patients without relapse according to duration of mechanical ventilation before vap occurrence. univariate and multivariate analyses were used to determine risk factors for relapse, and for icu-mortality in cases and controls. . patients were eligible. patients were excluded for superinfection. no persistant infection was diagnosed. ( %) patients developed a relapse of nf-gnb vap, and were all successfully matched with controls. pseudomonas aeruginosa was the most frequently isolated bacteria ( %), followed by acinteobacter baumannii ( %) and stenotrophomonas maltophilia ( %). no significant difference was found between cases and controls with regard to age ( ± vs ± ), male gender ( % vs %, p = . ), and surgery ( % vs %). however, saps ii at icu admission ( ± vs ± , p = . ) was significantly lower in cases than in controls. duration of adequate antibiotic treatment for first vap episode was significantly shorter in cases than in controls ( ± vs ± d, p = . ). inadequate initial antibiotic treatment was the only variable independently associated with relapse of vap related to nf-gnb (or [ % ci] = . inadequate initial antibiotic treatment is independently associated with relapse of vap related to nf-gnb and with icu-mortality. ∆ radiologic score and saps ii at day after vap diagnosis are independent risk factors for icu-mortality in these patients. s. blot* , j. solé-violán , j. blanquer , j. almirall , a. rodriguez , j. rello icu, ghent univ hosp, ghent, belgium, icu, dr negrin hosp, gran canaria, respiratory care, clinic hosp, valencia, icu, mataró hosp, barcelona, icu, joan xxiii univ hosp, tarragona, spain practice guidelines suggest processes of care such as timely pulse oximetry monitoring and antibiotic therapy, as quality indicators for the management of communityacquired pneumonia (cap). the objective of this study was to determine whether postponed initial processes of care such as pulse oximetry monitoring delays initiation of antibiotic therapy and adversely affects intensive care unit (icu) survival in patients with severe cap. a prospective observational multicenter study was conducted including patients with cap admitted to the icu in hospitals. a secondary analysis was conducted to evaluate processes of care and icu survival. postponed blood culture sampling, arterial blood gas sampling and pulse oximetry monitoring was predictive for delayed antibiotic administration (p< . ). linear regression analysis demonstrated that a delay of > h in blood culture sampling was associated with a delay of . h ( % confidence interval [ci], . - . ) in antibiotic therapy, a delay of > h in blood gas sampling with a delay of . h ( % ci, . - . ), and a delay in pulse oximetry monitoring of > h with a delay of . h ( % ci, . - . ). a delay in antibiotic administration of > h was associated with increased mortality in univariate analysis (relative risk [rr], . ; % ci, . - . ), but not after adjustment for disease severity. a delay in pulse oximetry monitoring of > h was associated with increased mortality in univariate analysis (rr, . ; % ci, . - . ) and after adjustment for disease severity (hazard ratio, . ; % ci, . - . ). in patients with severe cap timely executed processes of care are associated with a short time to antibiotic administration and reduced risk of death. appropriateness of antibiotic therapy is associated with reduction of bacterial load. c-reactive protein (crp) is a valid biochemical surrogate. our objective was to determine the correlation of bacterial load, measured by quantitative tracheal aspirate (qta), with crp as an indicator of inflammatory response in episodes of lower respiratory tract infection. to evaluate whether appropriateness of antibiotic treatment influences microbiologic (qta), biochemical (crp) and clinical resolution criteria (temperature, wbc, sofa and po /fio fraction). prospective cohort study. sixty-five intubated patients with monomicrobial lower respiratory tract infection were included. crp and bacterial load variation were evaluated through the ratio between d and d measures. a qta was performed on lower respiratory tract onset (d ) and h afterwards (d ). its logarithm value (logqta) was recorded. logqta correlated positively with crp, temperature and wbc. logqta has decreased significantly more from d to d in patients receiving appropriate empirical antibiotic therapy compared to those with inappropriate treatment (logqta ratio . vs . , p< . ). mean crp levels showed a similar pattern, decreasing from d to d in patients receiving appropriate empirical antibiotic treatment, but not in episodes with inappropriate treatment (crp ratio d /d . vs . , p< . ). ancova showed that crp level on d was significant lower in patients with appropriate antibiotic treatment compared to inappropriate empiric treatment ( ± mg/l vs ± mg/l, p< . ). the best cut-off to predict appropriateness of antibiotic therapy is a crp levels reduction of % on d (auc= . ). conclusion. c-reactive protein correlates with bacterial load and is a valid biochemical surrogate of bacterial burden in lower respiratory tract infection. follow-up measurements of crp anticipate the appropriateness of antibiotic therapy. a. günther* , p. schenk , m. maggiorini , a. betbesé , p. f. laterre , n. fedorovskiy , f. j. h. taut , r. g. spragg university of giessen, lung center, giessen, germany, , medical university vienna, vienna, austria, , universitätsspital zürich, zurich, switzerland, , hospital sta cruz y san pablo, barcelona, spain, , hôpital saint luc, brussels, belgium, , city clinical hospital n , moscow, russian federation, altana pharma ag, a member of the nycomed group, konstanz, germany, , uc san diego, san diego, united states the formal diagnosis of ards requires the acute onset of a severe impairment in oxygenatio(pao /fio <= mm hg), exclusion of a hydrostatic cause, and the presence of diffuse bilateral opacities. pneumonia is one of the most common underlying reasons for development of ards, but when only unilateral opacities are present, these patients fail to fulfil ards criteria. it is currently not known whether fulfilment of the formal ards criteria has any impact on -day mortality in patients with pneumonia suffering from severe gas exchange abnormalities. the valid study, a randomised, double-blind study in intubated and mechanically ventilated patients with severe respiratory failure (pao /fio <= mm hg) due to pneumonia or aspiration of gastric contents investigates the effect of rsp-c surfactant (venticute ® ) on mortality. the study does not require a formal diagnosis of ards for patient enrolment. however, the presence or absence of ards is documented. we conducted univariate and multivariate logistic regression analyses using preliminary blinded data from the first patients randomised with a diagnosis of pneumonia. the prognostic value of the formal diagnosis of ards was determined. univariate logistic regression analysis failed to identify a significant correlation (p= . ) between the formal diagnosis of ards and mortality at day . pao /fio was more likely to be associated with mortality (p= . ) as was the number of quadrants on chest radiograph that showed opacities (p= . ). age and apache ii score were highly associated with mortality (p< . ). multivariate logistic regression identified age (p< . ), the number of involved quadrants (p= . ), and apache ii (p= . ) as independent factors affecting -day mortality. conclusion. the prognosis of ventilated patients with pneumonia is not dependent on the formal diagnosis of ards. instead, age, apache ii score, and the number of lung quadrants with radiographic opacities are more predictive of outcome. bernard gr et al. intensive care med. ; : - . to determinate the clinical-epidemiological characteristics and risk factors for postsurgical pneumonia (psp) after lung cancer resection in a university hospital. a retrospective case-control paired study ( : ) was performed in cases of lung cancer collected from to . definition of psp case was a new or changing radiographic infiltrates with two or more of the following criteria: fever > o c, wbc> mm or/and purulent secretions. control group was formed by patients matched by age and lung cancer stage. . patients were evaluated ( psp and controls). overall, data of both groups were: age ± yr, males ( %), smoking habit (active or past smokers) patients ( %), copd patients ( %) and weight loss over kg in patients ( %). incidence of psp was %, crude mortality rate and attributable mortality estimated for psp was % and %, respectively. in the psp group, we found the following isolates ( %): p. aeruginosa ( %), s. viridans ( %), h. influenzae ( %) s. pneumoniae ( %) and undeterminated ( %). psp was associated with low bmi (p= . ), low fev (p= . ), stage iiia (p= . ), anaesthetic time (p= . ), pneumonectomy (p= . ), thoracic pain (p= . ), reintubation (p= . ) and haemorrhage (p= . ). conclusion. the incidence of psp in our series is low but with a high mortality. identification of risk factors (some of them suitable for medical intervention) may improve the management of lung cancer patients treated with surgery. j. karhu* , h. syrjälä , p. ylipalosaari , j. laurila , p. ohtonen , t. i. ala-kokko anesthesiology, division of intensive care, infection control, surgery, oulu university hospital, oulu, finland introduction. scap (severe community acquired pneumonia) and hap (hospital acquired pneumonia) requiring icu treatment have been shown to be associated with significantly higher mortality compared to those not requiring icu treatment ( , ). we compared pneumonias acquired outside the icu to that acquired in the icu, during mechanical ventilation (ventilator-associated pneumonia, vap). patients admitted into a mixed university level icu during a month period whose icu stay was longer than hours were included. the occurrence of scap, hap and vap were prospectively assessed. the following information was collected: age, severity of underlying disease on admission, underlying malignancy and recent use of immunosuppressive therapy. the length of icu and hospital stay as well icu, hospital and day mortalities were recorded. a total of patients fulfilled the inclusion criteria during the study period. there were a total of pneumonias. majority of the pneumonias were scap ( / ), while there were hap and vap cases. patients with hap tended to be older ( . , p= . ) and a larger proportion of them had malignancy ( %, p< . ), compared to vap ( years, %) or scap ( years, %). there were no significant differences between the mean admission apache ii scores (scap . vs. hap . vs. vap . ) . the icu length of stay was longest in vap; while the hospital stay was longest in patients with hap (table ). the survival rates were highest in hap, although this did not reach statistical significance. in apache ii and age adjusted multivariate logistic regression analysis vap (or . , % ci . - . , p= . ) and scap (or . , % ci . - . , p< . ) remained significant risk factors for hospital mortality together with immunosuppression (or . , % ci . - . , p= . ). heart surgery in infants is often associated with pulmonary inflammatory process. at the same time, the blood level of pro-inflammatory factors: interleukin- (il- ) and interleukin- (il- ) is increased. the number of polymorphonuclear leukocytes (pmn-elastase) and neutrophils is raised as well. a qualitative evaluation of the factors, cellular composition analysis of nonbronchoscopic trachebronchial lavage (ntl) combined with clinical findings can help early diagnose pneumonia. the objective of the study was to reveal the peripheral blood level of pro-inflammatory cytokines (il- , il- ), the activity of pmn-elastase and α antiprotease inhibitor (α -pi), as well as examine the ntl cellular composition and cytokine level in infants before and after heart surgery. we studied infants aged from days to months, weighting between . and kg. patients underwent cardiopulmonary bypass surgery, patients were operated on without cardiopulmonary bypass. in cases a clinical diagnosis of pneumonia was made between and days postoperatively. early postoperative survival was %. the peripheral blood cytokine concentration in operated infants pre-and postoperatively is presented in the study (table ) . a significant increase in pro-inflammatory factors after surgery can be observed. we examined the ntl of infants who underwent heart surgery and who did not develop pneumonia. we noticed that the number of neutrophils increased significantly in all patients after cardiopulmonary bypass surgery, sometimes reaching %. we consider it as a sign of pulmonary inflammatory process. the number of nonviable alveolar macrophages before and after surgery exceeded %. it indicates a decrease in cellular pulmonary protection. the pmn-elastase peripheral blood activity was . ± . iu/ml preoperatively and ± . iu/ml postoperatively; the α -pi level was . ± . iu/ml and . ± . iu/ml, respectively. conclusion. thus, an increase in the peripheral blood level of pro-inflammatory cytokines was observed in infants who underwent heart surgery. at the same time, the ntl relative number of neutrophils was increased. an early detection of the mentioned factors appears to be a diagnostic marker of the pulmonary inflammation reaction onset. all colistin resistant gram-negative isolates from patients hospitalized in a -bed icu during one-year period were retrospectively recorded. demographic data, the underlying disease, prior antimicrobial therapy, microbiological data and the clinical and bacteriological response to treatment were recorded. the antimicrobial susceptibility of the isolates was determined using the disk-diffusion (kirby-bauer) method, the vitek ii system and the etest method (ab biodisk, solna-sweden). interpretation of the susceptibility results was in accordance to the clinical and laboratory standards institute (clsi). nine patients with infections caused by colistin resistant gram-negative isolates were recorded. all patients had prolonged icu stay, were under mechanical ventilation and had a significant exposure to antibiotics including colistin for mdr gram-negative bacteria. three k.pneumonia isolates producing metallo-beta-lactamases (mbl), two k. pneumonia isolates producing extended spectrum b-lactamases (esbl) and mbl, two acinetobacter baumannii isolates susceptible to tetracyclines, one pandrug resistant (pdr) acinetobacter baumannii and one pdr pseudomonas aeruginosa were recorded. the bacteria were isolated from bronchial secretions in four cases and from the blood stream in five patients. in five patients antibiotic treatment was based on susceptibility tests, with clinical and bacteriological success. antibiotic combinations including colistin plus meropenem or colistin plus cefepime were provided in patients harbouring pdr isolates. these patients failed to respond to treatment and had a fatal outcome. the overall clinical success and survival rate was . % at days. conclusion. the development of colistin resistant strains with increasing mortality rates urges for the continuous surveillance on these highly resistant organisms and the strict implementation of infection control practices. ventilator-associated pneumonia (vap) is one of the most severe infections in the icu, continuing to complicate a high percentage of the patients receiving mechanical ventilation and leading to increased morbidity and mortality, especially when it is due to highrisk pathogens. our aim was to study the incidence and outcome of vap due to mdr bacteria in our icu. prospective, epidemiological study, in a mixed icu of a tertiary care hospital. all patients admitted from august to march were included. lower respiratory tract samples of all patients with suspicion of vap were cultured. standard diagnostic criteria were followed. statistical analysis was performed with spss v. . during the months period of the study patients were admitted. their mean age was years and % of them were male. their mean apache score was and the average duration of stay in the icu was days. forty-two episodes of vap due to mdr bacteria were recorded in patients. the bacteria isolated from lower respiratory tract samples were acinetobacter baumanii, pseudomonas aeruginosa, klebsiella pneumoniae and enterobacter cloacae, while in cases concomitant bacteremia was recorded. the mean time from admission to the icu to diagnosis of vap was days. positive outcome was noted in % of cases and was found to be reversely related to the apache ii score (p= . ), to days of stay in the icu (p= . ) and to multi-organ failure (p= . ). of the patients with vap, had normal renal function before the lung infection. of these, developed renal failure due to the lung infection and had to be started on renal replacement therapy. the mortality of these patients was significantly higher than for the patients who did not develop renal failure (p= . ). regarding the crude mortality of patients with and without vap, this was found to be . % and . % respectively (p= . ). (pa) is not a frequent pathogen in this setting but could be associated with poor prognosis. in our population of patients undergoing cs, we compared risk factors and prognosis of pa-eop with eop due to others micro-organisms. this retrospective study performed on years ( - ) involved patients (pts) who underwent cs with cardiopulmonary by-pass. diagnostic of pneumonia was based on clinical and laboratory criteria: t˚> . , purulent tracheal secretions, wbc> , /mm , chest x-ray changes and microbiological criteria (broncho-alveolar lavage> cfu/ml). pre, per and postoperative risk factors, empiric antibiotic, and prognosis of pa-eop were compared with those obtained for eop due to others germs. the groups were compared using chi-square. p< . was considered significant. over the studied period, eop occurred in pts (incidence %), including pts ( conclusion. in our experience, pa-eop following cs seems to be more frequent than what was previously reported. criteria for prediction of pa-eop remain to be assessed. in case of pa eop, empiric antibiotic is often inappropriate with a possible increased risk of mortality. these results lead us to modify our empiric broad-spectrum antibiotic treatment and to take into account pa, especially in severe forms of eop and in copd pts. antibiotic exposure and timing of pneumonia onset influence ventilatorassociated pneumonia (vap) isolates. the first goal of this investigation was to evaluate whether trauma also influences prevalence of microorganisms. a retrospective, single-center, observational cohort study. . vap isolates in a multidisciplinary icu documented by quantitative respiratory cultures and recorded in a -month database were compared, based on the presence (t) or absence of trauma (at). causative microorganisms were classified in four groups, based on mechanical ventilation duration (> days), and previous antibiotic exposure. one hundred eighty-three patients developed episodes of vap ( trauma). methicillin-sensitive staphylococcus aureus (mssa) was more frequent ( . % vs . %, p< . ) in trauma, whereas mrsa was more frequent ( % vs . %, p< . ) in nontrauma. no significant differences were found between trauma and nontrauma patients regarding prevalence of other microorganisms. in trauma patients, mssa episodes were equally distributed between early and late-onset vap( % vs %) but no mrsa episode ocurred in the early-onset group. conclusion. trauma influences the microbiology of pneumonia and it should be considered in the initial antibiotic regimen choice. our data demonstrate that patients with trauma had a higher prevalence of mssa, but the overall prevalence was sufficiently high to warrant an s. aureus coverage for both groups. on the other hand, since no mrsa was isolated during the first days of mechanical ventilation on trauma patients, mrsa coverage in these patients is only necessary after ten days of admission. a retrospective study of a hiv patient's cohort that stays in icu with acquired community pneumonia in the period between january and december . data analyzed included age, clinic stage, years of disease evolution, antiretroviral therapy, cd levels and viral charge at the hospitalization, positive hcv and/or hbv, severity scores and microorganism isolated. chi-square analysis was used to compare categorical data. continuous data was compared using student's t-test. prognostic factors of mortality were studied by multivariate logistic regression analysis. . fifty-three patients were studied. % were males. the average age was ± years. the most frequently risk practice was intravenous drug addiction ( % we prospectively collected data regarding demographics and microbiology of bacteremias. blood cultures were obtained on clinical suspicion of bacteremia and followed up on days , , and th. severity of illness scores, apache and sofa were recorded at baseline and days , , and th. improving hand hygiene is a cost-effective way of decreasing hospital-acquired infection rates. in this study we recorded opportunities for and compliance to hand hygiene in our icu. four trained nurses and a doctor monitored opportunities for hand hygiene performance (hand antisepsis and glove use) as well as compliance to the cdc guidelines in our icu for days. the procedure was anonymous, involved all icu personnel and was performed in -min sessions, throughout all shifts. we collected opportunities for hand hygiene, mostly related to nurses ( %). compliance to hand antisepsis was %, higher in nursing and assistant staff ( % and %, respectively) compared to doctors ( %). compliance was lowest before contact of healthcare staff with a patient or his inanimate environment ( % and %, respectively). the activity index (=the need for hand antisepsis performance) for the nursing staff was high ( opportunities per hour per nurse in the morning shift, ie opportunities per shift). however, no significant correlation was found between compliance rate and activity index of the staff (r=- . , p= . ). alcohol-based hand-rub was used in % of the cases. technique of antisepsis performance was uniformly poor and mean duration of the procedure was low ( . seconds). compliance with glove use guidelines was % and was high in all staff categories and all types of opportunities. is an aerobic non-fermenting gram negative bacillus. it is generally considered an opportunistic pathogen. s. maltophilia is increasingly recognised as a cause of nosocomial infection among ventilated and immunocompromised patients, and in those receiving broad spectrum antibiotics. s. maltophilia infections are commonly resistant to multiple antibiotics including beta lactams, quinolones, aminoglycosides and carbapenems. reported mortality rates for patients with bacteraemia due to s. maltophilia vary from - %. the mid western regional hospital, limerick, ireland, is a bed hospital located on three sites. the intensive care unit(icu) is a seven bed medical and surgical unit with approximately admissions per year. the s. maltophilia clusters prompted epidemiological investigation, restriction fragment-length polymorphism typing (rflp) of genomic dna of outbreak strains, and finally, instituting revised infection control measures to limit spread. we conducted a retrospective chart review of affected patients noting admission apache ii scores, medical co-morbidity, immunocompetence, antibiotic history, and patient outcome. we collected cultures of icu cubicle/ room surfaces, sinks, ventilatory equipment, and water sources. patients and environmental isolates were examined by rflp typing. this preliminary analysis suggests that pct can be use to accurately early identify sepsis only at levels above ng/ml and then use them to decide to rapidly beginning the use of antibiotic. in patients with pct below ng/ml we cannot use them to exclude the diagnosis of sepsis. with the cutoff , ng/ml we found the same analysis. other studies with more samples are necessary to confirm this conclusion. during these three years patients were hospitalized in total. one hundred and thirty one ( . %) were hospitalized less than h and were excluded. a total of bacteremias were observed. forty -four bacteremias were catheter related bloodstream infections. fifty five were due to gram negative microorganisms (pseudomonas aeruginosa %, acinetobacter baumanni %, klebsiella pneumonia %). in the following table, resistance to broad spectrum antimicrobials is presented during these three years. infection in patients with severe stroke is an important problem and the sensitivity and specificity of its diagnosis with clinical criteria are deficient. fever is a common event and, as leucocytes or c-reactive protein, its specificity is very low in this kind of patient. our objective was to evaluate the utility of a biological marker such as procalcitonin (pct) in the diagnosis of infection in patients with severe stroke. we followed patients with severe stroke receiving mechanical ventilation because of coma. during the first days of evolution nih and apache ii scales were registered, we measured pct and c-reactive protein on days and and if infection was suspected microbiological samples were collected. infection was diagnosed if the patient fulfilled the cdc criteria. mann-whithney u and x-square tests were used. twenty-six cases corresponded to haemorrhagic stroke. baseline characteristics were: mean age years, % males, glasgow scale ( - ), nih scale ( - ), apache ii ( - ), temperature . o c ( - . ), leucocytes /mm ( - ), pct . ng/ml ( . - . ) and c-reactive protein . mg/dl ( . - ). on the third day of evolution cases of ventilator-associated pneumonia were diagnosed. when compared with the noninfection group there were no differences in baseline characteristics and on the infection day we only found differences in pct, . ng/ml in front of . ng/ml; p < . . seventeen ( %) of the patients without infection presented a temperature o c sometime during the follow-up and in all cases pct did not show any change. these results indicate that pct is a useful tool in the diagnosis of infection in patients with severe stroke. the ongoing challenge of accurately diagnosing infection in the icu motivates a search for novel molecular diagnostics. we reported recently that microarray analysis of circulating leukocytes can be used to derive a "riboleukogram", which captures the dynamics of the host response to and recovery from ventilator-associated pneumonia (vap). in the current study, we tested the hypothesis that the informational content of circulating leukocytes differs, thereby allowing one to rank leukocyte populations on their potential to contribute to rna diagnostics for pneumonia. sixteen patients ( male, female) at risk for vap were entered into our irbapproved study that collects blood and clinical data every hours for up to days. four of the sixteen patients developed vap as diagnosed and treated by the attending icu physician. previously reported blood protocols were used to isolate buffy coat, enriched neutrophil, and enriched monocyte populations by using negative selection. cellular purity was assessed by facs for one of the vap patients. genome-wide expression analysis was performed on rmanormalized signal from affymetrix u . plus genechips. edge software (fdr= . ) was used to determine changes in mrna abundance over time for each cell population. during the -day window in which each of the four patients (all males) developed vap, significant changes in gene expression were observed (table) , but the information content (number of genes altered) varied across leukocyte populations. these differences were not due to signal variance (coefficient of variation, cv) or differences in the number of samples available for analysis. moreover, only . % of the monocyte gene list overlaps with the neutrophil list, arguing that neutrophil contamination of monocyte populations is insufficient to explain the -fold difference in gene number. the aim of the present study was to evaluate the relationship between the cytokine expression in bronchoalveolar lavage fluid and bacterial burden in mechanically ventilated patients with suspected pneumonia. mechanically ventilated patients with suspected pneumonia admitted in icu from november to january were prospectively enrolled. fiberoptic bronchoalveolar lavage (bal) was performed with ml of sterile isotonic saline in aliquots of ml, local anesthetic were not used. bal samples for microbiologic quantitative cultures and bal cytokines: interleukin (il) , il , tumor necrosis factor-alpha (tnf-alpha), granulocyte colony stimulating factor (g-csf) and granulocyte-monocyte colony stimulating factor (gm-csf) were measured. . patients were included, most of the patients ( . %) were with prior antibiotic therapy. patients ( . %) had a positive bacterial culture defined than a diagnostic threshold of > colony-forming unit/ ml. the concentration of tnf-alpha was significantly higher in the group of patients with positive bal (table ) . it has been demonstrated in a swine model that therapeutic hypothermia ( ˚c) facilitated transthoracic defibrillation. however, the mechanisms leading to reduced defibrillation threshold (dft) remain unclear. we hypothesized that therapeutic hypothermia promotes the wavefront organization of ventricular fibrillation (vf), therefore facilitating defibrillation. methods. by using a two-camera optical mapping system, epicardial activation patterns of vf were studied in isolated rabbit hearts at baseline ( ˚c), -min therapeutic hypothermia ( ˚c), and -min rewarming ( ˚c). in additional hearts, dft (voltage required to achieve % probability of successful defibrillation, n= hearts) and apd (action potential duration)/conduction velocity (cv) restitutions (n= hearts) were determined at these stages. results. comparing with at baseline ( ± %) and rewarming ( ± %), there was a higher percentage of vf duration containing organized repetitive activities during hypothermia ( ± %, p< . ). however, there was no significant difference of dft among these stages ( ± , ± , and ± v, p= . ). the electrophysiologic characteristics of ventricles at these stages were summarized in table . in brief, hypothermia prolonged apd, decreased cv, and subsequently shortened wavelength. hypothermia also failed to flatten the slope of apd restitution. furthermore, apd dispersion at the epicardial surfaces of both ventricles and cv heterogeneity among epicardial lines were all enhanced by hypothermia. (pt) with acute coroanry syndrome (acs) at admission is a associated with a high mortality. the mechansims are poorly understood. we sought to determine an interrelation between no coronary reflow after percutaneous coronary intervention (pci), the likelihood of developing cardiogenic shock, death in hospital and plasma glucose level at admission. we performed a prospective analysis of consecutive pt presenting with an acs in our emergency room. we recorded basis data (gender, age, bmi), cardiovascular risk factors, burden of coronary artery disease (cad), coronary blood flow after pci, killip-classification, left vetricular ejection fraction, probabilty of developing cardiogenic shock and the likelihood of dying in-hospital. our findings suggest that elevated bs at admission is a useful risk marker to identify pt with a high risk to develop coronary no reflow-phenomenon after pci. this may be due to increased inflammatory activity and hypercoagulability. if one dies in cardiogenic shock, these pt present always with elevated bs at admission. prull mw, trappe hj. activation of blood coagulation in nstemi: does diabetes mellitus matter? intensivmed . we measured serum cortisol levels before and minutes after a , mg corticotropin stimulation test in pts with cs following acute myocardial infarction (mi) and in a control group of pts with uncomplicated mi at day , , , , , and after onset of shock/mi. rai was defined by an increase in serum cortisol levels in response to corticotropin of less than µg/dl. data were correlated to vasopressor-need and interleukin (il) levels (il ,il ,il ,il ). baseline cortisol levels in pts with cs were significantly higher than in control pts especially on day ( ± vs ± , p= . ). in cs-pts the test-series were stopped at day to because the physician in charge started a therapy-trial with hydrocortisone due to increasing vasopressor need. three other pts died within the seven day period. rai was observed only at day in of the cs-pts but in none of the control pts (p= . ). these cs pts with rai had higher il- and il- levels at baseline ( during tidal mechanical ventilation, an end-expiratory pause abolishes the cyclic increase in intra-thoracic pressure. this may produce a transient increase in cardiac preload and then in cardiac output in volume responsive patients. our objective was to test whether the effects of an end-expiratory pause on cardiac index and pulse pressure may help in detecting fluid responsiveness in patients with acute circulatory failure. in mechanically ventilated patients with an acute circulatory failure and no spontaneous ventilator triggering who were deemed at volume expansion, we performed a -sec end-expiratory pause. we continuously measured the systemic arterial pressure and the pulse contour-derived cardiac index (picco device) at baseline, during the last seconds of the end-expiratory pause and after a ml saline administration. volume expansion induced an increase in cardiac index ≥ % in patients (classified as responders). in these patients, volume expansion increased the cardiac index by ± % from . ± . l/min/m . before volume expansion, the end-expiratory pause had induced an increase in cardiac index by ± % and in pulse pressure by ± % as compared to the baseline values. by contrast in the non-responders, before volume expansion the cardiac index and the pulse pressure did not change during the pause as compared to baseline ( ± % and ± % increases, respectively). importantly, an increase in cardiac index ≥ % during the end-expiratory pause predicted fluid responsiveness with a sensitivity of % and a specificity of %. a pause-induced increase in pulse pressure ≥ % detected fluid responsiveness with similar sensitivity and specificity ( % and %). in responders, a second end-expiratory pause was performed again immediately after volume expansion. in patients, the increases in cardiac index induced by this second pause induced had dropped below %. in the remaining responders, the second pause induced an increase in cardiac index still higher than % ( ± %). in these patients, the pause-induced increase in cardiac index was abolished by a second ml saline administration. conclusion. an increase in cardiac index and in pulse pressure during an end-expiratory pause enables to detect fluid responsiveness in critically ill patients with mechanical ventilation and acute circulatory failure. , and tissue doppler imaging measurements of the mitral annulus velocities like early (ea) peak diastolic velocity. the aim of the study was to examine which echocardiographic index is the best marker of preload by making the hypothesis that a good measure of preload should increase with fluid-induced increase in stroke volume (sv) but not with dobutamine-induced increase in sv. comparison of the capacity of the intra thoracic blood volume index (itbvi) and the central venous pressure (cvp) to predict fluid responsiveness in critically ill patients with acute circulatory failure (systolic blood pressure < mmhg or vasopressor requirement). methods. this prospective interventional study performed in a surgical intensive care unit of a tertiary university hospital included ( males) mechanically ventilated and sedated patients with acute cardiovascular failure requiring cardiac output measurement (transpulmonary thermodilution technique)and a fluid challenge. intervention: fluid responsiveness was defined as an increase in stroke index (si = cardiac output/heart rate/body surface area) ≥ %. receiver operating characteristic (roc) curves were generated for itbvi and cvp. in eligible patients, could not be included because of cardiac arrhythmia (n = ) or moribund status (n = ) or protocol violation (n = ). the cause of acute circulatory failure was septic shock in ( %) patients, haemorrhagic shock in ( %) patients, and systemic inflammatory response syndrome in ( %) patients. fluid challenge induced an si increase ≥ % in ( %) patients (responders(r). no statistical difference was shown between responders and non responders for cvp and itbvi. the areas under the roc curves of itbvi and cvp were . [ % ci: . - . ], and . [ % ci: . - . ], respectively, without any statistical difference (p = . ). the best cut of value for cvp and itbvi were mmhg (sensitivity = %; specificity = %) and ml.m- (sensitivity = %; specificity = %), respectively. the relative changes in si and ci were correlated with relative changes in itbvi (r = . , p = . ; r = . , p = . respectively) but no correlation was found between relative changes in si and ci and relative changes in cvp (r = - . , p = . ; r = . ; p = . ). conclusion. itbvi is similar to cvp to predict fluid responsiveness in critically ill patients with acute circulatory failure. the pulse pressure variation (ppv) is used to predict fluid responsiveness in mechanically ventilated patients. nevertheless false positive of this parameter have been reported especially in patient with right ventricular dysfunction. the peak systolic velocity of tricuspid annular motion (sta) assessed by doppler echocardiography (dec) is a parameter of right ventricular systolic function. the aim of the study was to find out whether sta can discriminate between false and true positive of vpp. methods. mechanically ventilated patients were prospectively included. all patients had a measurement of ppv> %. a dec was realised before and after infusion of ml of colloid solution. patients were separated into groups as they were responders (r) (at least % increase in stroke volume (sv)) or non-responders (nr) to fluid infusion. all data are expressed as mean [standard deviation]. the comparison of demographic, hemodynamic and echocardiographic parameters in r and nr patients was performed using a t-test. a p value < . was considered statistically significant. roc curves were plotted. a threshold value of sta was calculated with roc curve. in the resting patient, pulse pressure (pp = systolic -diastolic pressure) is mainly related to arterial stiffness and stroke volume index (svi). the dynamic effects of fluid loading on pp are poorly documented and were studied in the critically ill using arterial tonometry. we tested the hypotheses that i) arterial stiffness was unchanged after fluid loading, ii) pp changes paralleled svi changes such that pp increased in fluid-responders only, and iii) aortic pp was more indicative of svi changes than radial pp. twenty-two critically ill patients ( f), mean age(sd), ( ) years, were prospectively included. radial pressures were calibrated from brachial cuff pressures. radial applanation tonometry (sphygmocor ® ) allowed us to estimate aortic pp, left ventricular ejection time, and the augmentation index which quantifies wave reflection. the svi was calculated by transpulmonary thermodilution. the arterial stiffness was estimated from the aortic pressure curve using standard formula. fluid challenge ( ml saline . %) was required by the patient's hemodynamic status. data were obtained before and immediately after fluid loading. responders had increases in svi > %. baseline mean values were as follows: svi = ( ) ml.m- , heart rate= ( ) bpm, mean arterial pressure (map) = ( ) mmhg, radial pp = ( ) mmhg, aortic pp = ( ) mmhg. after fluid loading, svi increased from ( ) to ( ) ml.m- and map increased from to ( ) mmhg (each p < . ). arterial stiffness was unchanged ( . ( . ) vs . ( . ) mmhg.ml- . m ) as well as heart rate, left ventricular ejection time, radial and aortic pps and augmentation index. there was a positive linear relationship between the svi changes and the changes in radial pp (r = . ) and aortic pp (r = . ) (each p < . ), not map (r = . ). when responders (n= ) and non responders (n= ) were compared, the increases in map were similar while the changes in pp were higher in responders (radial: mmhg, %; aortic: mmhg; % ) than in non responders. (radial: - mmhg, - . %, aortic: - mmhg; - . %) (each p< . ). given the unchanged arterial stiffness throughout the fluid infusion, the changes in aortic pp (and slightly to a lesser extent radial pp) paralleled the changes in svi. both radial and aortic pps increased in responders but not in non responders, while map similarly increased in the two groups. the capability of arterial pp changes to track svi changes during fluid loading appears promising but deserves a further large scale study. new device may be used in intensive care unit to measure cardiac output (co) by arterial pulse pressure waveform analysis , but comparative studies with co thermodilution in cardiac surgery have shown large bias between the methods . aim of this study is to evaluate in critical ill patients not submitted to cardiac operation -cardiac output (co wave) obtained using flo track tm vigileo . -the correlation with co obtained by thermodilution (co therm). methods. critical care patients admitted to a general intensive care were enrolled in the study . all patients were mechanically ventilated ( tv - ml /kg pl press < cmh ) and connected to an integrated monitoring system ( flow trac tm / vigileo tm , ewdards lifescience ,irvine ,ca, usa ) that attaches to an arterial cannula . a central venous catheter and a pac ( thermodilution catheter ; arrow international , inc ., reading ,pa,usa ) was inserted via the jugular internal vein . after haemodynamic stabilization co wave was calculated from an arterial pressure based algorithm that utilises the relationship between pulse pressure and stroke volume , primarily based on the standard deviation of the pulse pressure waveform. at the same time a co therm. determination was performed by triple injection of ml of iced isotone na cl into the central line of the pac. every patients had two co determination at two time point. for each measurement of co therm corresponding simulataneous co wave was documenteted . a regression analysis and bland altman analysis was used to compare the two methods of co determination. a total of co determination was performed in patients . co vigileo correlated co thermodilution with r = . , p< , . at table are reported the bland altman's results. the left ventricular ejection fraction (lvef) as measured by echocardiography is considered as the reference estimate of the lv global contractility at the icu bedside. the transpulmonary thermodilution technique (picco system) continuously provides a measure of the cardiac function index (cfi), which is the ratio of cardiac output over global end-diastolic volume. thus it could be considered as a marker of cardiac global contractility and could enable a continuous monitoring of this key parameter. we tested whether cfi could actually behave as an indicator of lv systolic function by testing if it fulfilled the following criteria: (i) increase with inotropic stimulation, (ii) no alteration by fluid loading, (iii) correlation with the echographic lvef and (iv) ability to track the changes in lvef during inotropic stimulation. in patients ( cases) with an acute circulatory failure, we simultaneously measured the echographic lvef (transthoracic -chambers apical view) and the cfi at baseline, after a ml saline administration in a group of cases and after -min of dobutamine administration in a group of cases. volume expansion did not alter lvef significantly ( ± % vs. ± % at baseline) nor cfi ( . ± . vs. . ± . min- at baseline). by contrast, dobutamine infusion induced a significant increase in lvef from ± % at baseline to ± %(+ ± %) and in cfi from . ± . at baseline to . ± . min - (+ ± %). considering the whole set of cfi:lvef pairs of measurements (n= ), a significant correlation was observed between cfi and lvef (r= . , p< . ). importantly, a cfi value < . min - predicted a lvef value higher than % with a sensitivity of % and a specificity of %. in patients receiving dobutamine, there was a significant correlation between the changes in cfi and the changes in lvef induced by dobutamine infusion (r= . , p< . ). our study demonstrates that cfi fulfilled the criteria that are required from a bedside indicator of lv contractile function: it was increased by inotropic stimulation while it was not altered by volume expansion, it was fairly correlated with the echographic lvef and it was able to track the changes in echographic lvef with reliability. this suggests that the continuous monitoring of cfi provided by transpulmonary thermodilution could help in assessing the effects of inotropic therapy and could alert the physician in case of abrupt lv contractile deterioration. passive leg raising (plr) is a predictive test of preload responsiveness in patients with acute circulatory failure. it could predict fluid response to fluid loading in mechanically ventilated patients. critically ill patients have an increased risk of lower extremity deep venous thrombosis. elastic compression stocking (ecs) is frequently used in association with unfraction or low molecular weight heparin. the aim of this study was to evaluate the effect of the elastic compression stocking on the plr test variations. methods. patients undergoing cardiac surgery were included. all of them were anaesthetised and mechanically ventilated (tidal volume ≥ ml/kg). pre-operative left ventricular ejection fraction was > % for all patients. they were monitored with central venous pressure (cvp), invasive blood pressure and esophageal doppler. hemodynamics parameters were obtained before and after plr, without and with elastic compression stocking respectively (ssv = systolic stroke volume, co = cardiac output, ppv = pulse pressure variation and sbp = systolic blood pressure). results are presented as median [inter quartile range](iqr) and compared with mann whitney test. . table represents hemodynamics variations after plr without and then with elastic compression stocking. second table represents hemodynamics effects of the elastic compression stocking in supine position (sp). conclusion. this study shows a clear improvement in gut permeability after surgery. the effects of early feeding shall be assessed in a future study. methods. descriptive-prospective study. pre and post-class question -survey (administered one week before and after). the transplant co-ordination team gave informative classes in secondary schools, - / - . . surveys collected; pre/ post-class: % of eso ( years old), % bachiller ( years old) and % ciclo formativo ( years old) / post-class: % eso, % bachiller and cf % . % had some prior awareness and % broad knowledge. massmedia is usually sole information channel ( %), ticked in all cases. other sources were: family, school and peers. regarding attitude to donation: we found no differences in refusals between own donation or relatives'( %); or in doubts % - %. related to transparency and parity of the health system: % believed equality did not exist and % had doubts. % felt this inequality was worse abroad. % are convinced that organ trafficking exists and % assume it is possible. pre-course standpoint by course is showed in figure . % had prior knowledge about spanish transplant law. following classes the students claim higher awareness ( %). in general they maintain their standpoint on donation, % have reconsidered their previous attitude. regarding transparency and equality, % maintain doubts and % are convinced of its absence. on trafficking: % assume it is possible, % occurs exclusively abroad, uniform group distribution. post-course attitudes by course are in figure . despite an in-depth discussion about the law and its consequences (presumed consent), they generally disagree and some consider this too extreme , refusing to accept that donation is an obligation (only % agree) and believing that it should be an optional act of solidarity ( %). conclusion. knowledge about donation and transplant in urban areas is slanted, due to information sources ( usually mass media ) and a warped (tv-dominated) perception of the health system's transparency and equality. a considerable number of students still refuse donation or maintain their scepticism, despite a decrease following classes. however, our desire is not to convince them to become donors, we simply wish to provide decision-making tools. generally college students ,without gender differences, are the most resistant to the process, having the greatest incidence of refusals and doubts about transparency, equality and organ trafficking. ( - ) . c (pao /fio ) / peep day . ( . - . ) . ( . - . ) . c (pao /fio ) / peep day . ( . - . ) . ( . - . ) . c (pao /fio ) / peep day . ( . - . ) . ( . - . ) . c conclusion. the pao /fio ratio on day one is useful to predict mortality, but not in the subsequent days. the (pao /fio )/peep index is a better predictor in later days, specially on the third and seventh day of mv. a. roch* , l. fouché , j. forel , d. blayac , c. aglioni , d. lambert , j. carpentier , l. papazian réanimation médicale, dar, hôpitaux sud, réanimation, hôpital laveran, marseille, france introduction. general anesthesia promotes atelectasis of the dependent parts of the lung. we evaluated the differential effects of neuromuscular blocking agents (nmba) on consolidation formation in healthy or injured lungs. methods. pigs ( ± kg) were anaesthetized with pentobarbital, fentanyl and ketamine in order to prevent spontaneous ventilation and ventilated using volume controlled ventilation (vt ml/kg, fio . ) for hours after randomization into groups: healthy lungs ventilated without (hzeepno) or with nmba (cisatracurium, hzeepnmba), healthy lungs ventilated with nmba and peep (hpeepnmba) and injured lungs ventilated without (tweenpeepno) or with nmba (tweenpeepnmba). lung injury was induced using instillation of . ml/kg of . % tween . injured lungs were ventilated with peep , fio . and vt ml/kg. after lung removal, six sections of equal thickness were obtained from the right lower lobe and from the upper. sections were photographed and analyzed using a software (sigmascan pro , spss inc). the areas of consolidated, edematous and normal parenchyma were measured on each section and then added to obtain the percentage of consolidated lung. . nmba use induced a two-fold increase of the consolidation (from ± to ± %)that was totally prevented by peep . the deleterious effect of nmba on derecruitment did not occur in injured lungs. consolidation was located to the dependent parts in healthy lungs and nmba extended consolidation towards more cephalad parts. in injured lungs, consolidated parenchyma was diffuse and its cephalo-caudal distribution was not affected by nmba. pao to fio ratio was affected neither by nmba nor by peep. * p< . vs hzeepno and hpeepnmba; **p< . vs hzeepno and hzeepnmba. conclusion. nmba increase dependent lung consolidation during volume-controlled ventilation of healthy lungs. this effect is prevented by a moderate peep level. in contrast, nmba do not increase the extent of pathologic lung areas in injured lungs ventilated during a -h period. th esicm annual congress -berlin, germany - - october s m. amigoni* , m. scanziani , g. bellani , g. balconi , e. zanotto , s. masson , n. patroniti , r. latini , a. pesenti dept of experimental medicine, milano-bicocca university, monza, cardiovascular research, istituto di ricerche farmacologiche mario negri, milano, italy introduction. surfactant dysfunction seems to play a pivotal role in the deterioration of gas exchange and lung mechanics that occurs in ali/ards following aspiration pneumonitis. we investigated the effects of exogenous surfactant administration in a murine model of unilateral acid-induced lung injury. we instilled . ml/kg bw of . m hydrochloric acid in the right bronchus of anesthetized and mechanically ventilated mice (vt - ml kg- bw, rr min- , fio and peep of . cmh o). mechanical ventilation was stopped minutes after injury; animals were then placed in an oxygenated chamber (fio . ). after ', hr or hrs from acid instillation, the mice were reintubated and received a single bolus of surfactant in the injured lung at a low or high dose. each animal was again mechanically ventilated for minutes, placed in oxygenated chamber until full awakening. acid-injured mice instilled at the same time and with the same volume ( ml/kg bw) of sterile saline ( . % nacl) were used as controls. lung mechanics, blood gas analysis, and lung myeloperoxidase activity (mpo) were assessed hrs after acid aspiration. no effect of surfactant administration was present upon oxygenation hrs after the injury. at the opposite the high dose group showed a significantly better compliance at hrs, when compared to both the low dose and control groups. this effect was present only in the late ( hrs) administration group. mpo activity did not change after surfactant treatment in the right (injured) lung while in the controlateral, it tended to be lower in both low and high dose when treatment administration occurred at hrs (n= /group: n right lung ± left lung . ± . ; s(low dose) right lung . ± . left lung . ± . ; s(high dose) right lung . ± . left lung . ± . ). pulmonary aspiration is associated with significant morbidity and mortality . several risk factors for aspiration have been highlighted in the literature . the aims of this study were to: (i) identify specifically which patient factors predispose to aspiration and (ii) determine the outcome of patients admitted to our inner city hospital intensive care unit (icu) with a diagnosis of aspiration. we identified patients with a diagnosis of pulmonary aspiration on our icu over a year period (august - ), by using our institution's icnarc (intensive care national audit and research centre) database. of these patients' case notes were able to be retrieved and reviewed in detail. patient demographics, risk factors for aspiration, number of ventilated days, icu & hospital length of stay and mortality were analysed. we also looked at any documented signs that supported the diagnosis of aspiration. median age of the patients was years (range - ). / patients ( %) were male. the main risk factor was a reduced glasgow coma score ( / patients, %): the median score was (range - ). the following risk factors were also identified: obesity ( / patients, %), excessive alcohol intake ( / , %), acute cerebrovascular event ( / , %) and cardiorespiratory arrest ( / , %). the following signs were most frequently observed: perioral vomitus ( / patients, %), acute hypoxaemia ( / , %) and a new radiographic infiltrate ( / , %). one patient exhibited all three markers. all patients required mechanical ventilation. the median duration of ventilation was days (range - ). the median length of icu stay was days ( - ) and the median length of hospital stay was days ( - ). icu mortality was % ( / patients) while hospital mortality was % ( / ). patients who presented to our inner city icu with aspiration had risk factors that included impaired conscious level, obesity, a recent cerebrovascular event or cardiorespiratory arrest. signs that supported the diagnosis of aspiration were the presence of perioral vomitus, acute hypoxaemia and a new radiographic infiltrate. icu and hospital length of stay were both prolonged, but icu and hospital mortality were no higher than our institution's overall rate. a high index of suspicion should be applied to these patients at risk of aspiration, to facilitate the early initiation of appropriate care. reference(s). . hickling k. a retrospective survey of treatment and mortality in aspiration pneumonia. int care med ; : - . . kozlow j. epidemiology and impact of aspiration pneumonia in patients undergoing surgery in maryland, - . crit care med : - . t. tagami* , s. kushimoto , t. atsumi , r. oyama , k. matsuda , m. kawai , h. yokota , y. yamamoto surgery, tokyo metropolitan saiseikai central hospital, critical care medicine, nippon medical school, tokyo, critical care medicine, yamanashi prefectural central hospital, yamanashi, japan introduction. restoration of intravascular volume by massive fluid administration without pulmonary edema formation is one of the biggest challenges in the early treatment of burn shock. although it is not easy to predict the development of the respiratory failure before the treatment, the hallmark of the edema is increased capillary permeability which may be possible to measure by the pulmonary vascular permeability index (pvpi). the aim of the present study was to clarify whether the pvpi is predictable indicator of pulmonary edema formation in patients with burn. we studied mechanically ventilated patients with burn involving more than % of the body surface area that were treated at intensive care burn unit between july and january . all patients had a central venous catheter and a thermistor-tipped arterial thermodilution catheter (picco system) for hemodynamic management. we measured the extravascular lung water index (evlwi) and the pulmonary vascular permeability index(pvpi) as soon as the picco catheter was inserted. infusion volume was calculated according to the parkland formula. only crystalloid fluid (lactated ringer's) was infused during the first hours after the thermal injury. we investigated the medical records and defined the respiratory failure during the period of burn shock as a clinical syndrome of acute respiratory distress associate with pulmonary rales and radiographic evidence. inclusion criteria were: )acute onset and rapid progress, )oxygenation index (pao /fio ratio< and ) bilateral infiltrates on chest x-ray. those are the part of the standard criteria of acute respiratory distressed syndrome. the pvpi was significantly higher in the patient with respiratory failure (n= pvpi: . ± . ) than in patient without respiratory failure(n= pvpi: . ± . ) before the fluid treatment. there was no significant difference between the groups in terms of evlwi at the beginning ( ml/kg vs . ml/kg). although the evlwi increased after hours in the patient with respiratory failure, it did not change in patient without respiratory failure( . ml/kg vs . ml/kg). the pvpi increased before the evlwi increased in patient with respiratory failure. the pvpi is considered to be the predictable value to identify the risk of respiratory failure during the period of burn shock. ultrasonography allows observation of diaphragm. in healthy subjects, a correlation was found between its excursion and the tidal volume. in addition, diaphragm thickness variation measured in the zone of apposition has been used to evaluate paralyzed diaphragm. we assessed the accuracy of these indexes to assess diaphragmatic function and respiratory workload. five patients were studied in spontaneous ventilation (sv) and during noninvasive ventilation at different levels of pressure support (ps). diaphragmatic excursion (e) was carried out subcostally. diaphragm thickness was measured in the zone of apposition and the thickening fraction (tf) was calculated as tf = (thickness at inspiration -thickness at expiration)/thickness at expiration. diaphragmatic pressure time product per breath (ptpdi) was measured by assessment of esophageal and gastric pressure. ptpdi and tf both decreased as the level of pressure support increased (fig and ) . a positive correlation was found between ptpdi and tf(r= . ; p= . ; fig ) . in addition, there was also a significant correlation between tidal volume and e (r= . ; p< . ; fig ) . ultrasonography of the diaphragm could be applied in intensive care to assess diaphragmatic function. tf and ptpdi decrease as the level of pressure support increases. these results suggest that tf could help to assess diaphragmatic contribution to respiratory workload. reference(s). ( ) fantus g. metformin's contraindications: needed for now frequency of inappropriate metformin prescriptions systematic review and meta-analysis of studies of the timing of tracheostomy in adult patients undergoing arteficial ventilation catheter infection is a common concern in the intensive care unit (icu). recent works have pointed that the site of catheters is related to this problem. we analysed data obtained from our data base to confirm the results of previous works. methods. catheters were inserted in a surgical-medical icu, along five years. semiquantitative cultures were obtained if the catheter was kept in place more than hours and it was no longer necessary, the catheter was withdrawn because of fever of unknown origin or an infection was suspected at the point of insertion. every catheter site, culture and germ was registered in our patient data base. we studied the following variables: type of catheter, site and results of cultures. statistical analysis: variables were compared by chi-square. a p< , was considered statiscally significant. results. a total of . catheters were registered (venous catheters , arterial ). rate of germs was as follow: gram-positive , %, gram-negative , %, fungi %, contaminated flora , %. site and germs were not statistically associated. table shows type, site and rate of infection of cultured catheters. femoral arteries were more frequently cultured than radial arteries (p< , ); no differences were found for cultured venous catheters. femoral arteries were infected more frequently than radial (p< o, ); yugular and femoral venous catheters were more frequently associated to infection. (sc) in non neutropenic patients is increasing with a high cost and mortality. we define the clinical and epidemiological profile of patients admitted to our icu and the microbiological aspects of the pathogen. mortality analysis was done, including sevilla score system (sss). we include patients admitted in icu from to with candidas ssp (cd) positive blood cultures (bacter system). we analysed demographic factors, reason for admission to the unit, associated risk factors, need of multi-instrumentation or parenteral nutrition, value of apache ii, and length of stay in the icu. the kind of cd diagnosed, its sensitivity profile, and the existence or not of previous wide spectrum antibiotic or antifungic therapy were determined. the sevilla score system was applied and correlated with mortality. chi square, t-test and multivariant analysis were made. there were . % male patients, with years old median age and with a length of stay longer than days. the reason for admission was sepsis ( %), surgery ( . %), acute respiratory failure ( . %) and trauma patiens ( %). apache ii median was . points.risk factors related with fungal infections were diabetes ( . %), neoplasia ( %), steroid therapy ( , %), a length of stay longer than days ( %) and antibioticoterapy. none had neutropenia. % of patiens received antibioticoterapy previous to diagnosis, . % parenteral nutrition and % of them underwent multi-instrumentation. patient isolation was achieved in % of them ( % in period - ). candida albicans was isolated in . % of cases against . % of candida nonalbicans, specially c. parapsilosis , %. first antifungal therapy was fluconazole ( %), caspofungin ( . %) and lipid amphotericins ( . %). we found a significant increase of sc cases along the years, ( % in - vs . % in - , p< . ), being unresponsive to azoles . %. mortality was specially high ( . %), unrelated with cd type; those with high/moderate sss risk had a significative higher mortality (p< . ). candida albicans was more frequently found in septic patients while candida nonalbicans was gaining place in patients under parenteral nutrition (c.parapsilosis).conclusion. ) systemic candidiasis affects men admitted with sepsis or surgery, with a high apache ii index, multiple organ failure, multi-instrumentation and more than two weeks intensive care unit stay. ) we observe a progressive incidence of non albicans candidiasis (c. parapsilosis). ) type of candida ssp did not affect mortality. ) c. albicans was more frequently isolated in septic patients, while candida nonalbicans was predominant in cases with parenteral nutrition. ) mortality was greater in moderate/higher sss risk group. f. alvarez-lerma* , m. palomar , p. objetive: to present changes of multiresistance markers in icu-acquired infections. a prospective, cohort, multicenter study. all patients admittted to the participating spanish icus between the years and were included. patients were followed until discharge from the icu or up to a maximum of days. the following infections were studied: mechanical ventilation-related pneumonia (mv-p), catheter-related urinary tract infection (cr-uti), and primary bacteremia (pb). markers of multiresistance were those defined by the cdc ( ) of a total of , pacientes included in the study, , ( . %) developed , infections ( . %) during their stay inthe icu, in which a total of , pathogens were identified.multiresistance markers are shown in table . pulse pressure variation greater than % predicts fluid responsiveness in patients ventilated with large tidal volumes. the aim of this study is to evaluate the influence of a low tidal volume on the capacity of pulse pressure variation (deltapp) to predict fluid responsiveness.methods. this is a prospective interventional study that took place in a -bed university hospital medico-surgical icu. the study included eighteen mechanically ventilated critically ill patients with a low tidal volume ( - ml/kg) requiring fluid challenge. fluid challenge was performed with , ml crystalloids or ml colloids. complete hemodynamic measurements including deltapp were obtained before and after fluid challenge. overall, the cardiac index increased from . ± . to . ± . l/min/m (p < . ). it increased by more than % in patients (responders). pulmonary artery occluded pressure was similar ( . ± . vs. . ± . mmhg, p= . ) but deltapp higher in responders than in non-responders ( ± % vs. ± %, p= . ). fluid responsiveness was equally predicted by deltapp (roc curve area . ± . ), pulmonary artery occluded pressure ( . ± . ) and right atrial pressure ( . ± . ) (p=ns). the best cutoff value for deltapp was % with a sensitivity of % and a specificity of %. the preliminary results suggest that deltapp is not a better predictor of fluid responsiveness then paop or rap in mechanically ventilated patients when tidal volume is - ml/kg. if used, a lower critical value may help to predict fluid responsiveness. svv and ppv are proven influenced by the different airway pressures due to depth of tidal volume and peep. the effect of respiratory rate or respiration frequency on svv and ppv is however unclear. aim of this study was to evaluate the effect of respiration frequency on svv and ppv in mechanically ventilated patients. after obtaining informed consent, (coronary bypass grafting) patients were studied immediately after surgery. cardiac output (co), svv and ppv were assessed by arterial pulse contour analysis (lidco, lidco ltd). all patients were ventilated in pressure controlled mode (settings: fio . , tidal volume ml/kg, peep cmh o, frequency min- ) and sedated with propofol. in this study svv and ppv were evaluated with fixed ventilator frequencies of , and min- . this protocol was repeated to times (before and after volume loading of ml) in each patient. during the study the mean airway pressure was maintained constant by adjusting inspiration time. collected data points are described in means (sd) and evaluated using anova. in six patients (female/male ratio / ) after coronary bypass grafting, mean age (± . ) years [range - years], data points by fixed respiratory frequencies could be analysed ( / , / and / ). all measurements were performed in hemodynamically stable conditions, hr mean (± . ) min- , map . (± . )mmhg, cvp . (± . )mmhg and co . (± . ) l/min (p for all ns). mean airway pressure . (± . )mbar (levene statistics, p = . ), for resp-f . (± , )mbar, resp-f , (± , )mbar and resp-f . (± . )mbar. on fixed respiratory rates svv and ppv were unchanged: for svv (resp-f ) . (± . )%, (resp-f ) . (± . )%, (resp-f ) . (± . )%, p = . , for ppv (resp-f ) . ( . )%, (resp-f ) . (± . )%, (resp-f ) . (± . )%, p = . . in ventilated cardiothoracic surgical patients, svv and ppv were not influenced by forced changes in respiratory frequencies between and min- . (svv) has been studied as a dynamic preload marker to predict fluid responsiveness in critically ill patients. patients undergoing major abdominal surgical procedures with the aid of pneumoperitoneum may have a difficult preload management, due to either a preoperative hypovolemic status or an excessive intraoperative fluid loading to maintain an adequate volume and tissue perfusion. the aim of this study was to use the svv to optimize the fluid management in patients undergoing major abdominal robot-assisted laparoscopic surgery. methods. patients (asa score - ; mean age . +/- . ) were prospectively enrolled. cardiac index (ci), stroke volume variation (svv), and central venous saturation (scvo ) were calculated with the vigileo system. gastric carbon dioxide pressure (pgco ) was measured with a gastric tonometer. before the induction of anesthesia, ml/kg normal saline solution was administered. later, colloids were infused whenever a svv > % resulted. hemodynamic variables and pgco were measured before, during, and after the end of surgery. the total amount of intraoperatively administered fluids (iaf) was calculated. subsequently, the iaf was compared with theoretical iaf using the formula proposed by miller. analysis of variance and student's t-test were applied. mean surgery time was . +/- . hours. ci ranged from . to . liters/min/m . scvo ranged from % to %. the pgco ranged from . to . mmhg. anova did not show significant variations of ci, scvo and pgco . mean baseline and postoperative svv% were +/- . and . +/- . , respectively. with respect to preoperative values, anova showed a significant reduction for svv%. moreover, at the end of surgery the svv% resulted less than % for each patient. the total amount of fluid was . +/- vs . +/- . ml/kg per hour (calculated vs theoretical, respectively. p< . ). no patient showed signs of hypoperfusion. no complication or death occurred.onclusion. the vigileo system seems to be a reliable tool to provide indications for fluid administration and volume responsiveness. it could be useful especially in major surgical procedures at risk of fluid overfilling. svv continuously monitored may help physicians to avoid fluid overloading in patients undergoing major abdominal robot-assisted laparoscopic surgery. recently, the preload parameters global enddiastolic volume gedv and intrathoracic blood volume itbv measured with transpulmonary thermodilution were convincingly shown to be superior to the historically used central venous pressure . the extravascular lung water evlw was shown to be a prognostic marker in critically ill patients . however, in our clinical experience, we failed to achieve the proposed normal ranges for gedv/itbv indexed to body surface area in a substantial number of patients. as hypothesis, we investigated the dependence of transpulmonary thermodilution parameters on the patient's age. we retrospectively analyzed the transpulmonary thermodilution data in a series of patients treated on our neurosurgical intensive care unit. diagnosis was predominantly severe subarachnoid hemorrhage, but included traumatic brain injury and polytrauma, too. itbvi and gedvi were measured with the picco ® system (pulsion medical systems ag, munich, germany). measurements were performed with cc iced saline injected repeatedly in a central venous line. all data was stored online and pooled for analysis. mean patient age was . (sd . ) years. pooled thermodilution measurement sequences consisting of single injections were analyzed. mean gedvi was (sd ) ml/m , mean itbvi was (sd ) ml/m and mean evlwi was . (sd . ) ml/kg. younger patients had lower mean values calculated by linear regression, with an increase of . ml/m for gedvi and . ml/m for itbvi per patient year. evlwi was independent of age.conclusion. the thermodilution data from our patient collective contrasts the use of fixed age-independent normal values for gedvi and itbvi but not for evlwi. this data set, however, comprises a neurosurgical patient collective and may not be validly extrapolated to other clinical surroundings. . michard f., et al.: chest ; : - . sakka, s., et al.: chest : - thirty mechanically ventilated patients with severe sepsis or septic shock (age ± ; apache-ii score ± ; male) requiring invasive hemodynamic monitoring due to cardiovascular instability were included in a prospective observational trial. the study was performed in a university hospital setting with a -bed medical intensive care unit (icu) and a -bed anaesthesiological icu. volume-based hemodynamic parameters were assessed using the single-pass thermal-dye transpulmonary dilution technique. simultaneously, ivc diameter was measured throughout the respiratory cycle by transabdominal ultrasonography. we found a statistically significant correlation of both inspiratory and expiratory ivc diameter with central venous pressure (p= . and p= . ), extravascular lung water index (p= . , p< . ), intrathoracic blood volume index (p= . , p= . ), the intrathoracic thermal volume (both p< . ), and the pao /fio oxygenation index (p= . and p= . , respectively).conclusion. sonographic determination of ivc diameter is useful in the assessment of volume status in mechanically ventilated septic patients. this approach is rapidly available, non-invasive, inexpensive, easy to learn and applicable in almost any clinical situation without doing harm. ivc sonography may contribute to a faster, more goal directed optimisation of fluid status and may help to identify patients in whom deleterious volume expansion should be avoided. it remains to be elucidated whether this approach influences the outcome of septic patients. a severe burn injury is associated with hypermetabolism and catabolism that has been shown to persist for over months post injury. propranolol has been shown to reduce hypermetabolism during the acute hospital course. the effect of propranolol, a nonselective beta blocker, on respiratory variables in children with severe burns has not been established. beta-blockade is associated with a known risk of bronchoconstriction in children with hyper-reactive airway disease, but it is not known whether the effects are also seen in severely burned children. the purpose of this study was to determine the effect of propranolol, given during acute hospitalization, on respiratory variables. forty-six patients with burns > % total body surface area (tbsa) were enrolled into the study and randomized to receive propranolol at . mg/kg/day (n= ) or placebo (n= ). administration of propranolol was started the day following the first operation and continued for three weeks. respiratory variables were measured by a flow transducer attached to a bicore cp respiratory monitor. all patients were breathing spontaneously and non-intubated. study variables included respiratory rate (rr), minute ventilation (mv), tidal volumes (vt), and peak inspiratory/expiratory flow rates (pifr/pefr). baseline measurements were taken at rest before the drug or placebo was initiated. follow-up measurements were performed at the end of the study period. data were analyzed using paired t-test within groups and un-paired t-test between groups. data are reported as mean ± sd. significance was accepted at p< . . the mean age in both groups was ± years. as expected, heart rate was reduced by approximately % in the propranolol group compared to placebo (p< . ). there was a significant increase in pefr from . ± . to . ± . l/s in the propranolol treated group (p= . ). in contrast, neither placebo nor propranolol significantly affected rr, vt, ve or pifr. results indicate that short term administration of propranolol showed significant effects on pefr suggesting increased pulmonary conductance. further studies on the effects of propranolol on gas exchange and lung compliance are needed. grant acknowledgement. funded by nih grants p -gm and ko -hl a. storesund* , e. wallestad , l. rygh postoperative section, surgical department, surgical department, haukeland university hospital, bergen, norway international studies point out that to work with agitated children, described as restless and disorientated are particularly stressful for the child, parents and caregiver. this project is based on the assumption by nurses in the post anaesthetic unit (pau) that there was a noticeable post anaesthetic agitation difference between the children who received long-term opioids initially and in the end of the operation (refill, a) compared to those who only got long-term opioids in the beginning of the operation (no refill, b). the main purpose of this project was to examine whether there were any difference in postsurgical agitation between the refill and no refill group. further, this project seeks to uncover if there are any factors that can be improved per-and postoperative for these patients. we observed post anaesthetic children, lip-(n= ), cleft-(n= ), and palateclosure (n= ), adeno-(n= ), & adeno-tonsillectomy (n= ). these children were recruited using a convenience sampling strategy at the pau at haukeland university hospital, norway, over a week period in - . a pilot-tested fixed cross sectional designed questionnaire was utilised by the nurse responsible for each patient. several statistical tests by the use of spss made it possible to analyse and answer the research question: are children who only get long-term opioids in the initial anaesthetic phase (b) of the operation more agitated than those who where also given a refill of long-term opioids (a)? we found that / got refills of long-term opioids (a), / did not get refills (b), % were recorded as missing values. t-test result = , is greater than , , hence there is no statistically significant difference between the two groups. levene's test tells us that the two variances are not significantly different (levene's test sig= , ). there were no significant relationships between the parameters recorded. however, there was a tendency that more preoperative anxious children got refills ( / ) compared to non-anxious children ( / ) (fisher's exact test p= , ). the latter results may conceal the agitation-scores in the two groups; refill and non-refill-group. this possible bias may have been eliminated if the patients had been randomized to either refill or non-refill. the present study confirms previous observations by others indicating no singular factors can explain why some children experience agitations and others do not. analysis of the parameters studied did not discover any statistical significant relationships. thus, how to minimise the cohort of children who experience post anaesthetic agitation still remains a recurrent challenge. pulmonary hypoplasia with severe cardiorespiratory dysfunction is often the leading cause of death in neonates with congenital renal disease and oligo-anhydramnios. aim of the study was to determine whether ino is effective to improve respiratory function in these critically ill neonates. we retrospectively reviewed the charts of all newborns who were admitted between february and september with the diagnosis of oligo-anhydramnios of renal origin. during this period all patients were treated according to a standardised algorithm. they were intubated either if post cpr or if fio had to be increased above . . mg/kg of bovine surfactant were applied for improvement of ventilation. pre-and postductal oxygen saturation were measured simultaneously with target values of - %. if fio remained above . a transthoracic echocardiography was performed. the presence of a ductal or atrial right to left shunt or a difference in oxygen saturation between the pre-and postductal measurements of > % led to the diagnosis of pulmonary hypertension and to the initiation of ino therapy. further, ino was applied as a rescue therapy if oxygen saturation remained below % despite a fio of . and optimization of ventilator settings and therapy with catecholamines. all patients had informed parental consent. the patient population (n= ) included children receiving ino of whom suffered from obstructive uropathy and two had polycystic kidneys, whereas patients did not receive ino treatment. in this group there were children with obstructive uropathy and born with polycystic kidneys. all data are presented as median (range). we concentrated on the group receiving ino. in this group mortality was . %. therapy was started at an age of . ( - ) hrs. initial dose of ino was . ( - ) ppm with peak dose of . ( - ) ppm. ino led to a decrease of oxygenation index (oi) from . ( . - . ) to . ( . - . ). five children suffered from obstructive uropathy. three of them had a favourable long-term outcome, one child died immediately, whereas one child was initially stabilized but finally succumbed to its underlying disease. two children demonstrated genetically determined pulmonary hypoplasia due to the presence of polycystic kidneys. both children died within the first three days despite ino treatment. children with obstructive uropathy and severely impaired oxygenation seem to benefit from ino therapy. patients suffering from a hereditary renal and pulmonary hypoplasia did not respond favourably to ino therapy and had a fatal outcome. a. khaldi*, k. menif, a. bouziri, a. hamdi, s. belhadj, n. ben jaballah pediatric intensive crae unit, children's hospital, tunis, tunisia the use of high-frequency oscillatory ventilation (hfov) and ino resulted in a decline in the need for extracorporeal membrane oxygenation (ecmo) in near-term and term neonates with persistent pulmonary hypertension (pphn). association of hfov and ino is actually an accepted treatment modality even in non-ecmo centers. however, because not all neonates respond to hfov + ino, identification of factors related to a poor response is very important for prognosis and for early transfer to ecmo canters if possible. the objective of this study was to identify the risk factors predicting poor shortly outcome in near-term and term neonates with pphn treated with hfov and ino in a tertiary care pediatric intensive care unit in a university hospital. we conducted a prospective clinical study including all neonates with gestational age ≥ weeks with echocardiographic signs of pphn. patients with pulmonary hypoplasia or congenital diaphragmatic hernia were excluded . patients were ventilated with conventional mechanical ventilation (cmv) with ino ( - ppm). hfov were instituted if patient required, on conventional ventilation (cmv)+ino, a fraction of inspired oxygen (fio ) . , and a mean airway pressure > cm h o to maintain adequate oxygenation or a peak inspiratory pressure > cm h o to maintain tidal volume between and ml/kg of body weight. hfov were used in association with ino in seventy infants (gestational age, ± , weeks), after a mean duration of cmv of ± hours. arterial blood gases, oxygenation index (oi), and alveolararterial difference in partial pressure of oxygen (p[a -a]o ) were recorded prospectively before and during hfov. there were a rapid and sustained decreases in mean airway pressure (map), oi, and p[a -a]o during hfov (p ≤ . ). this improvement, along with decreased need for oxygen, was sustained through the subsequent course of hfov. sixty-six infants ( %) were weaned successfully from hfov. five infants ( %) were classified as meeting treatment failure and died from their underlying disease. treatment failure was associated with lack of improvement in p[a -a]o and oi at hour of hfov (p < . ) and the presence of intractable shock requiring epinephrine or norepinephrine (p= , ). in near-term and term neonates with pphn, the association of hfov and ino lead to a rapid and sustained improvement in gas exchange in the most cases. the magnitude of improvement of oi and p[a -a]o at hrs can predict outcome early. early burn sepsis is notable for the complexity of diagnostics, malignant course and high lethality. the problem remains actual for the children who got a severe burn trauma (more than % body surface area). purpose to define procalcitonin test (pct) effectiveness for early sepsis diagnostics for children with thermal trauma. during the period of time from january up to april there were children in our clinic with extensive burns from %up to % body surface area (bsa) at the age from months to years old. patients at the age from months to years old with the burns from % to % bsa were included in our research. all the children got surgery in shortest time after trauma (tangential excision with authodermoplastics), antibacterial, and infusion therapy. from the moment of registration in icu all the patients, who were suspected to have sepsis, simultaneously with traditional examinations (blood analysis, bacteriological investigation) were taken pct analysis with the help of "pct-express test" (brahms, germany). . patients ( , %) were diagnosed sepsis, children died. these patients pct level was from to ng/ml; together with this all the patients had increasing quantity of leucocytes, acceleration the level of c-reactive protein, fever. ( %) patients had no sepsis, so pct figures fluctuated in the bounds of , ng/ml. among these patients traditional markers of inflammation were increased. no trustworthy difference is found as for the level of leucocytes and c-reactive protein figures between the patients without infectious complications and with sepsis. only with the help of pct the beginning of sepsis and sirs manifestation can be differentiated.conclusion. . burn trauma itself is not the reason for pct increase. pct level increases in cases of burn injuries as the sign of infectious complications joining. . with the help of traditional sepsis markers it is difficult to differentiate sirs manifestation and first stages of infectional complications in case of thermal trauma. . in cases of severe burns pct test is a highly sensitive method of sepsis early stages diagnostics. . surgery treatment at early stages after trauma allows to avoid development of severe sepsis. h. knoester* , m. b. bronner , a. p. bos , m. a. grootenhuis pediatric intensive care unit, psychosocial department, emma children's hospital, amc, amsterdam, netherlands introduction. improved survival in children with critical illnesses has led to new disease patterns due to long-term complications and effects of the original illness and its treatment. as a consequence, health related quality of life (hrqol) has become an important outcome measure in pediatric intensive care unit (picu) survivors. little is known about hrqol in picu survivors,. hrqol evaluation could contribute to improvement of support after discharge. the purpose of this study was to assess hrqol in picu survivors. october all parents of children, acutely admitted to our picu were invited to complete hrqol questionnaires, and months after discharge. hrqol in children from - years of age was evaluated with a dutch validated questionnaire, the tno-azl preschool children quality of life questionnaire (tapqol). the tapqol covers domains of hrqol; norm data from the general dutch population are available. data analyses was done by non-parametric testing (patients versus norm group) and by calculating effect sizes (difference in mean scores between the patients and the norm group divided by the standard deviation of the scores in the norm group). effect sizes give an indication of changes in hrqol in comparison with the norm group. . of ( . %) eligible patients were evaluated. statistically significant differences with the norm group were found on domains, and months after discharge (more lung problems and worse liveliness) and on domain months after discharge (better appetite). moderate ( . ) and large ( . ) effect sizes were found on five respectively four domains and months after discharge: indicating worse hrqol on lung problems, sleeping problems, motor functioning, anxiety, positve mood and liveliness; and indicating better hrqol on problem behaviour. no statistically significant changes over time were found for all domains and months after discharge. our results indicate that hrqol in young picu survivors is decreased in some domains of physical and emotional functioning. these problems do not diminish over time. positive evaluation by parents regarding appetite and problem behavior could be influenced by response shift (changing of internal standards and values due to confrontation with a life-threatening disease). more research is necessary because of the small study group and to determine the influence of risk factors such as length of stay, age of the child at admission, severity of illness and physical sequelae of the disease and its treatment on hrqol. hrqol evaluation can be a useful tool as part of screening after picu survival to determine the necessity for follow-up care. coarctation of the aorta is not an uncommon congenital heart defect. one of the possible postoperative complications is the so-called postcoarctectomy syndrome (mesenteric arteritis). the purpose of the present study is to assess the changes in gut flow through the dual sugar permeability test. five patients have been included in the study until now. median age month ( . - ) and median weight . kg ( - ). premedication and anaesthesia was the same for all the patients. the test solution contains -o-methyl-d-glucose, d-xylose, l-rhamnose and lactulose. patients received ml/kg of the test solution after induction of anaesthesia, at and hours after the initial dose. urine production is measured during a three-hour period after each instillation. the sugar content is analysed by capillary gas chromatography (normal values l/r = . , omdg and xylose - %). a. monsel , p. durand , v. haas , c. beaujard , p. rouleau , s. el aouadi , d. benhamou , k. asehnoune* anesthesie reanimation, reanimation pediatrique, anesthesie réanimation, hopital de bicetre, bicetre, anesthesie réanimation, chu hotel-dieu, nantes, france pediatric epidural anesthesia (ea) is considered to be without hemodynamic impairment in children. however, when compared with information relating to adults, little is known about the hemodynamic effects of epidural anesthesia on the cardiac output (co) in infants. using transesophageal doppler (ted) monitoring of co, we prospectively studied infants < kg who were scheduled for abdominal surgery. during sevoflurane general anesthesia, ted monitoring of co was performed before and after lumbar ea with . ml/kg of . % bupivacaine and : , adrenaline. co, arterial blood pressure, and heart rate were measured before and , , and minutes after performance of ea. in patients anesthetized with sevoflurane and sufentanil, ea resulted in an increase in stroke volume by % (p< . ) and a decrease in heart rate by % (p< . ). ea also induced a significant decrease in systolic, diastolic, mean arterial blood pressure and systemic vascular resistances by %, %, %, and % respectively. conversely, co remained unchanged. the increase in sv observed is probably explained by optimization of afterload due to the sympathetic blockade induced by ea. these results confirm that ea provides hemodynamic stability in infants weighing < kg and support the use of ea in this pediatric population. bleeding is the most frequent complication during extracorporeal life support (ecls) after pediatric cardiac surgery. we would like to present our experience with ecls and recirculation blood saving, volume auto-regulation system using the law of connected vessels based on converted cpb set in infants after cardiac surgery with significant bleeding. since to ecls in the postoperative period was performed ( , % of all cardiac operations in this period). the significant bleeding (> ml/kg/h) was noted in pts. in most recent pts the volume recirculation system was implemented, whereas in previous patients blood was sucked out the circuit. the retrospective analysis of data was carried out. there were infants with single ventricle anatomy and with two-ventricle anatomy. there were no significant differences with respect to age, weight and prevalence of single ventricle anatomy between groups. the indication for ecls was cardiac arrest in , low cardiac output in , hypoxemia in and sepsis in patients. the overall mortality rate was %. the mortality did not differ significantly between groups ( , % versus % in non-recirculation group; p= , ). there was significantly lower number of blood products transfusions(p< , ), lower number of surgical explorations(p< , ) lower mean lactate level hours after ecls institution p(< , ) and shorter ecls duration (p< , ) in the recirculation group. the system of blood recirculation in children with bleeding on ecls is simple, highly effective in stabilization of the haemodynamics and no-cost consuming. it can reduce necessity of chest exploration, blood product transfusions and duration of support. t. tunc* , t. topal , m. kul ,Ö.Öngürü , a. korkmaz , s.Öter neonataloji bilim dali, fizyoloji anabilim dali, patoloji anabilim dali, gülhane askeri tip akademisi, ankara, turkey necrotizing enterocolitis (nec) is the most common gastrointestinal emergency in the premature infant. the major risk factors in nec include prematurity, hypoxia, enteral feeding, and bacterial colonization. these factors predispose at-risk infants to an exaggerated intestinal inflammatory response leading to ischemic bowel necrosis. experimentally induced ischemia and reperfusion (i/r) of the intestine is a model which can be appropriately used to imitate nec. n-acetylcysteine (nac), erdosteine (erd) and alpha-lipoic acid (ala) are well-known antioxidants with similar structural properties. in the present study, the effectiveness of these three sulfur-based antioxidants against intestinal i/r-injury was evaluated.methods. one month old male spraque-dawley rats were randomly divided into five groups (n = for each): i/r (control), i/r+nac, i/r+erd, i/r+ala and sham-operated group without i/r. animals were operated at a temperature of o c under ketamine anesthesia. ischemia was provided by occluding the superior mesenteric artery via a microvascular clamp. collateral vessels of the small intestine were ligated to prevent collateral circulation. min of ischemia was followed by min of reperfusion. nac ( mg/kg/day, i.p.) was administered first min before operation and followed once daily for days. erd ( mg/kg/day, oral gavage) administration was begun days before operation and continued daily doses. ala ( mg/kg/day, i.p.) was injected only one time h before operation. at day after operation the ileum was resected and the rats were sacrificed. protein oxidation (carbonyl content, pco), lipid peroxidation (malondialdehyde, mda), superoxide dismutase (sod) and glutathione peroxidase (gsh-px) were measured in the ileal tissue. oxidative and antioxidant parameters of resected ileal segment (mean ± sd) groups as a clinically relevant model to nec, our experimental i/r protocol resulted with marked rise in oxidative stress levels and fall of antioxidant enzymes activities. these changes were ameliorated with the antioxidants used. among all, ala presented the strongest and nac the weakest effect. this outcome promises beneficial usage of these sulfurbased antioxidants against oxidative stress which plays an important role in nec pathogenesis. a. khaldi* , k. menif , a. bouziri , a. hamdi , s. belhadj , n. ben jaballah pediatric intensive crae unit, children's hospital, pediatric intensive crae unit, children's hospital, tunis, tunisia high-frequency oscillatory ventilation (hfov) may significantly improve oxygenation and outcome in newborns with respiratory dysfunction and beyond the neonatal period in patients with a variety of diffuse alveolar diseases. in small airway disease like respiratory syncytial virus (vrs) bronchiolitis, hfov is considered potentially hazardous because of the risk of air trapping. however, a few studies had reported utility of hfov in children with acute hypoxemic or hypercapnic respiratory failure caused by vrs and failing optimal conventional mechanical ventilation (cmv). the objective of the study is to evaluate the effectiveness and safety of hfov in pediatric patients with acute respiratory failure due to rsv and failing cmv. we conducted, over -year period (october to october ), a prospective clinical study in a tertiary care pediatric intensive care unit. fourteen ( ) patients (ages to days) with acute respiratory failure due to rsv bronchiolitis and failing optimal cmv were included. passage to hfov was indicated for severe hypoxemia in patients (median alveolar-arterial oxygen difference [p(a-a)o ]: [ - ] mmhg, median oxygenation index [io]: [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] ) and for severe hypercarbia in patients (median ph: , [ , - , ] , median paco : [ - ] mmhg). hfov was instituted after a median length of cmv of ( - ) hours. ventilator settings, arterial blood gases, oi and p(a-a)o was recorded before hfov (h ) and at a predetermined intervals during hfov and compared using the one-friedman rank-sum procedure and a two-tailed wilcoxon matched-pairs test. after starting hfov, a distinct decrease in fio at hrs that continued to hrs (p< , ). in all patients, there were significant decreases in oi and p(a-a)o at hrs, that were sustained up to hrs (p< , ). target ventilation was achieved in all cases and paco significantly decreases after hr of hfov (p= , ) and remained within the target range thereafter ( - mmhg). the median maximum pressure amplitude used on hfov was ( - ) cm h o and the median maximal paw was ( - ) cm h o. no significant complications associated with hfov were observed. twelve patients ( %) survived to hospital discharge without supplementary oxygen. tow patients ( %) died from septic shock. in pediatric patients with either hypoxemic or hypercapnic acute respiratory failure due to rsv bronchiolitis, hfov can be used successfully and safely if conventional ventilation fails to improve gas exchange. however, randomized controlled trials are needed to identify its benefits over conventional modes of mechanical ventilation. and are influenced by numerous factors like patient's disease severity, policies of the treating unit, religious and cultural traits, education and awareness of the patient's family, financial status of the family and legal provisions. majority of published studies on eol reflect either european or american ethos; that is either physician's paternalistic approach about the patient or patient's autonomy and self determination,( , ) about this sensitive process. studies on eol which reflect the influence and pivotal role of closely knit indian family on eol decision making are scant. we retrospectively analysed the eol decisions taken by the family in our icu as majority of the patients which merit eol care were not in a condition of decision making. setting- bedded multidisciplinary icu of a bedded tertiary care teaching hospital in pune in india. case papers of all icu admissions during one year i.e. st january to st december where eol decision was documented, were reviewed. data collected included demographics, underlying disease process, duration of aggressive treatment till eol consent, duration between eol decision and death, consenting person's relation with the patient, organ failure & level of life sustaining supports at decision and mode of payment of the treatment. during the study period patients died in our icu of which eol decision and consent was explicitly documented in cases which constitute study population. average age of the patient was years (range to ), average duration of active treatment till eol consent was . hours(range to ),average duration between consent and death was . hours(range to ). . % consents were signed by close relatives( son/daughter, brother/sister, spouse, father/mother) and . % were by other relatives( cousins, son in law/daughter in law). at the time of eol decision . % patients were having glassgow coma scale and below, . % patients were on mechanical ventilation, . % were on vasopressors and . % were needing renal replacement. metastatic disease ( . %) and traumatic or vascular brain injury( . %) were the commonest causes of death. only . % patients had medical insurance or employer assistance as a mode of payment for the treatment and in . % cases family members were the payers. withholding of non beneficial life sustaining therapies as eol process was practised in . % of the total icu deaths. all ( %) eol decisions as well as directive requests and consents were signed by patients' relatives, reflecting the importance of close family ties in indian eol practices. our objective was to study frequencies of withholding and withdrawing treatment and time until death in a dutch university hospital icu. between october and february we collected data of all patients that died. data were collected from patient files and during interviews with the doctors and nurses who were responsible for the patient at the time of death. we analyzed which treatments were withheld or withdrawn and calculated the time until death following withholding or withdrawal. preliminary results show that of admissions, patients died ( %). nonsurvivor's (median age years [range - ]) median length of stay was days (range minutes - months). in patients ( %) treatment was withdrawn and in patients ( %) treatment was withheld but not withdrawn. of all patients ( %) were mechanically ventilated of which ( %) were weaned and extubated before death. in of these patients it was decided not to intubate again and other patients not to intubate at all (median time until death: hours). in ( %) ventilator-dependent patients mechanical ventilation was withdrawn; ( %) were extubated. the median time until death after ventilator withdrawal was minutes. when patients were also extubated, it was minutes (p= , [mann-whitney test]). in patients mechanical ventilation was not withdrawn, but fio was decreased to . (median time until death minutes). in patients ( %) inotropic medication was withdrawn (median time until death minutes). in cases, the withdrawal of inotropic medication was combined with the withdrawal of mechanical ventilation. in patients ( %) it was decided not to increase inotropic support (median time until death : hours). in patients ( %) the decision was made not to resuscitate in case of cardiac arrest. median time of this decision before death was hours. in the patients that died treatment was withdrawn in the vast majority of patients. withdrawal of mechanical ventilation and/or withdrawal of inotropic support were most often used. a considerable number of patients died within minutes following withdrawal of therapy. r. veiga* , g. silva , g. campello , c. dias , c. granja intensive care department, hospital pedro hispano, matosinhos, biostatistics and medical informatics, faculty of medicine, porto, portugal the high mortality of critically ill patients underscores the need for icu teams to recognize end-of-life care as an integral component of critical care. besides survival, the success of intensive care should also include the quality of lives preserved and the quality of dying. the aim of this study was to evaluate the incidence and type of end-of-life decisions in critical patients that died in an icu. retrospective analysis of all patients that died in the icu in the period of january to december and evaluated the following variables: demographic characteristics (age, gender); co-morbidities: (heart failure, chronic obstructive pulmonary disease (copd), diabetes mellitus, neoplasia, chronic renal disease, hiv/aids, alcoholism); reason for admission; saps ii; length of icu stay (icu los) and type of end-of-life decisions. three concepts were defined in order to classify the end-of-life decisions: comfort care: a change from curative therapy to comfort care therapy; limited therapy: maintenance of curative therapy but without escalating it (e.g. not raising rate of vasopressor agents, no renal substitution); without previous end-of-life decisions: when no attitudes toward end-of-life care were considered. given the diminished number of patients in the without previous end-of-life decisions group we decided to evaluate them apart from the other two groups.results. two-hundred and twenty seven patients were admitted in the icu and of them died ( %). reason for admission in those who died was septic shock/ severe sepsis ( %), post-cardiac arrest ( %); cardiogenic shock ( %); acute respiratory distress syndrome ( %). the most common co-morbidity was alcoholism ( %), followed by diabetes mellitus ( %), neoplasia ( %), heart failure ( %) and copd ( %). forty seven patients ( %) died after comfort care decision, eleven patients ( %) after limited therapy decision and four ( %) patients died without previous end-of-life decisions. comparing the groups comfort care and limited therapy we found significant differences in the following variables: hemorrhagic shock at admission ( % vs. %) (p= . ); saps ii ( vs. ) (p= . ); icu los ( . days vs. . days) (p< . ). patients in the limited therapy group had more admissions with hemorrhagic shock, a higher severity score and stayed less time in the icu. this analysis suggests that end-of-life decisions in this group express their higher severity. patients of the comfort care group presented less severity and stayed longer in the icu. their shift of curative therapy to one designated to provide comfort care reflects an absence of a clinically favorable response. the low percentage of patients without previous end-of-life decisions is consistent with previous reports and should be seen as a positive issue. non invasive positive pressure ventilation (nippv) is widely accepted as an initial approach to providing ventilatory support to many patients with acute respiratory failure (arf). palliative approaches focused on the quality of life and comfort; represent a challenge for family's physicians and the patients. nippv is an attractive option to treat acute respiratory failure in end stage patients when the failure is irreversible and it is a final outcome of the primary disease. the approach to providing ventilatory support to patients with arf, to relieve them from the sensation of dying suffocate without intubating them because they don't wish it either, is very challenging. after institutional approval and patients consent, we conducted a prospective observational study of patients that fulfilled the criteria. cases received nippv ( with end stage cancer and with pulmonary fibrosis). when nippv was ordered we recorded: respiratory rate, heart rate, arterial blood pressure, neurological status and arterial blood gases, before nippv initiation (baseline data) and then st, th and th hour. at the time of initiation of nippv, all patients were alert and cooperative with nippv. analgesia and/or sedation were used when it was necessary. pao , pco and ph measures were analyzed using statistical methods. percentage changes from baseline (pre-nippv) of these measures were used as dependent variables. (mean value of measurements at different time points was used). dependent variables (percentage of pao , pco and ph) were regressed on time, for each patient. in all cases the results were statistically significant, with p-values ranging from a low of . to a high of . . for all patients, the regression coefficient for the percentage change was positive; indicating that the percentage change was increasing with time. we can remark that pao increases over time, pco and ph p values > . . we believe that nippv via helmet cpap is a means of potentially ensuring the highest quality of end-of-life care. nippv can be applied for palliative care, and it might be used to keep patients whom developed acute respiratory failure comfortable before the inevitable. decisions regarding the resuscitation status of patients are among the most difficult facing healthcare professionals, patients and families. these groups often need to discuss decisions regarding resuscitation yet their understanding and expectations can differ greatly. this study sought to determine the knowledge and beliefs of doctors, nurses and the general public regarding resuscitation decisions.methods. an observational study was designed. three study groups (doctors, nurses and general public) were interviewed using a face-to-face interview by a single interviewer and questionnaires completed. questions examined opinion, factual knowledge and knowledge of the ethics surrounding hospital resuscitation attempts. . doctors, nurses and general public were randomly selected. % doctors, % nurses and % of public correctly estimated survival to discharge following in-hospital resuscitation attempt. the remainder overestimated survival. . % of doctors and % of nurses consider resuscitation decisions to be made too infrequently. deficiencies were identified in doctor and nurse knowledge of the ethics governing resuscitation decisions and public opinion was found to conflict with ethical guidelines. public understanding of the nature of cardiopulmonary arrests and resuscitation attempts, and of the implications of a dnar order is poor. . % of public report television medical dramas as their primary source of information on such matters. knowledge regarding resuscitation principles, outcomes and ethics is poor among both healthcare staff and the general public. these knowledge differences may not be appreciated or addressed in discussions regarding resuscitation and this reduces the likelihood of meaningful discussion and acceptable decisions. there is a need for educational initiatives to address these deficiencies. public apprehension surrounding this subject needs to be identified and corrected during discussions and this could be facilitated with a patient information leaflet. [ ] poor communication during this process may lead to unnecessary anger and a delay in the grieving process that could linger for many years to come. giving the family the option to be present during resuscitation offers a more compassionate and family-centred approach to this crisis. this option of family presence however is frequently met with resistance and uncertainty by health care workers who may view the family's presence as increasing their risk of making a mistake or worse, being sued. a study in the uk estimated that out of one-hundred-and-sixtytwo uk emergency departments family witnessed resuscitation was allowed by % for an adult patient and % for a child. [ ] another us study also found that amongst patients in emergency departments, % preferred to have their family present during resuscitation. [ ] a survey was conducted amongst the doctors, nurses and paramedics who work in two uk eds to assess their attitudes and beliefs. experience, life support training, years in practice, consent issues, ethical factors and concerns regarding medico legal implications were sought for. a -point likert scale was used and mean scores analysed using microsoft excel. . staff were surveyed. % of doctors, % of nurses and % of paramedics believed in the concept in trauma fwr. in cardiac arrest patients, % were in favour of it, % opposed to it and % undecided. % of staff believed that litigation was possible with family witnessed resuscitation. % of respondents thought that critical incident de-briefing would be of benefit to assist staff dealing with stress. fewer doctors believed in cardiac fwr compared to nurses (p= . ) and paramedics (p= . ). in trauma, difference was non-significant. as health care professionals caring for families in the emergency departments, we need to recognize the need for compassionate family-centered care. with a well trained and motivated team equipped with effective, well thought out guidelines, there is considerable benefit for family members and staff in this difficult situation. thorough information about the events that are going to take place in the icu after an elective procedure might facilitate the awakening process and weaning from the ventilator, mitigating patient's anxiety and increasing their comfort. the aim of this study was to analyze the impact of preoperative information on the patient's perceptions and reactions to the usual inconveniences, such as orotracheal tube (ott), associated with the first postoperative hours in the icu. prospective, cohort study with a group of cases (a) and a control group (b). duration: two months. inclusion criteria: all patients undergoing elective cardiac surgery. there were no exclusion criteria. setting: cardiac surgical icu of a tertiary hospital. the survey was made in the first hours. the study was blinded for the doctors in charge of the patients. the characteristics of both groups are presented as a/b with the p value into brackets. the quantitative variables are shown with the mean value and the qualitative variables as a percentage. the number of patients included was : cases (a) and controls (b). age: , / , years ( , ); men: / %( , ); time receiving sedative drugs: , / , hours ( , ); total hours with ott: , / , ( , ); hours with ott after stopping sedation: , / , ( , ). the first patient's perceptions were: discomfort related to ott in , / , % ( , ); surgical pain in , / , % ( , ); thirst in , / , % ( , ); welfare or calm in , / , % ( , ), and nothing in , / , % ( , ). additional sedatives were required in , / , % ( , ). information was considered very useful in , %. patients valued very positively the provided information. in addition, this information had a significant impact on the tolerance to the ott, requirement of additional sedatives, and in the sense of welfare. there were not differences in the time under sedative drugs or in the perception of thirst or pain. a multiparameter questionnaire was sent to icu. each questionnaire comprised informational topics groupe into categories (table). one relative per patient was asked to quote (yes/no) within days after admission, each item, i.e. if he would like to find information on that item in an ib. if "no" was quoted, he was asked to say why (closed answers). demographic data on patient and relatives were correlated to the scores (nbre of "yes"), in each item category (factor analysis with varimax rotation followed by stepwise multiple linear regression). . questionnaires were analyzed (patients: age ± year, saps : ± , sofa: ± ). table: % of positive response for each item ("would you like information on this topic in an icu booklet?") grouped into categories. "no" answers were mostly explained by "i trust the team to manage information about this" (median: %, range: - ). mulitvariate analysis showed that demographics data describing patient condition (age, saps , chronic disease) correlated (p< . ) with "yes" score of the items comprized in "icu rules" (table) but not with other items grouped in other information categories. conclusion. interestingly, as a whole, most items were highly wished in a booklet, suggesting that - % of relatives express a plea for transparency in face of "difficult icu issues", without taboo. only the "yes score" to "icu rules" items correlated with patient status whereas items from other topics did not. this sounds, as relatives visiting the most severe patients may consider visiting rules as crucial. other items did not correlate to profiles, and may thereby be considered as societal standard requirements in terms of information. in / , our -bed medical icu signed a convention with the asp iroise association defining hv's role and presence. the association, a member of a national network of hv associations, works with our university hospital. four hvs took alternate turns in the icu one afternoon per week. hv were free to meet any conscious patient or any family member who wished so; icu staff also asked them to meet patients or families who seemed particularly distressed. hv wrote a brief commentary in a special transmission logbook which could be consulted by the staff and gave feedback about their visits whenever needed. patients (pts)and families (fam)who met an hv were sent a questionnaire either in / or in / . pts were admitted during the period of study: the hv met pts ( , %) and families ( , %). people answered the questionnaire ( , %): pts and fam: spouse, parents, sister, children( no answer). ethics consultation has been introduced into the practice of medicine during the last decades as a way to help physicians and nurses come to a decision about a medical treatment where value-laden conflicts are involved. the primary goal is helping to identify, analyze, and resolve ethical problems. the aim of this study was to evaluate ethics consultation in a dutch university hospital intensive care. intensivists, residents, fellows and nurses can consult a clinical ethicist specialized in intensive care for advice in value-laden situations. we evaluate ethics consultation on our icu between january and april . the clinical ethicist was consulted times. in / cases ( %) advice was asked before withdrawal of life-sustaining therapy. in this category / ( %) cases concerned palliative care. in / cases ( %) the independent advice was in confirmation with the physician's view. in / cases ( %) advice was sought in cases were there was doubts to proceed with intensive care therapy. in four cases relatives wanted to withdraw therapy, where the intensivist did not consider this as futile. in / cases ( %) the advice was in accordance with the treatment plan. in cases ( %) questions about information asked by non-relatives. all advises were followed. cases concerned triage, cases withholding therapy, brain death declaration, a deadly iatrogenic complication and in patients a question concerning emergency research. in ( %) cases a lawyer specialized in health care was consulted. in the cases about 'withdrawal of therapy', the advise could be given within minutes in % of the cases. ethical advise by a clinical ethicist specialized in intensive care can be additional, affirmative and reassuring, and improves quality of care. in most cases advice could be given immediately. . deferred consent has been proposed as a surrogate for a priori subject or proxy consent. the aim of this report is to evaluate the practicality and efficacy of a deferred consent procedure in an ongoing dutch multi-centre clinical trial. screening logs were collected from two participating centres of a clinical trial that is currently conducted to evaluate the efficacy of early lactate-directed therapy and that uses deferred consent. screened patients were analyzed for eligibility and reasons for exclusion. ( %) were not reported to the study investigators, patients ( %) were not included for medical-ethical reasons (e.g. treating clinician deemed risk/benefit ratio of the study intervention unacceptable), in patients ( %) study participation was practically impossible (e.g. unavailable study materials) and the reason was unknown in patients ( %). only patients (or their relatives)( %) refused informed consent. in an ongoing dutch multi-centre emergency clinical trial using deferred consent, only % of patients or their relatives refused informed consent. deferred consent in emergency research is practical and facilitates a high inclusion rate. adult respiratory distress syndrome (ards) and peep have been linked to right ventricular dysfunction (rvd). this has been attributed to elevated pulmonary artery pressure (pap) and pulmonary vascular resistance (pvr) due to ards as well as increased intrathoracic pressure due to peep therapy. we wondered if rvd was a late phenomenon in ards or could also be detected during early peep treatment of hypoxia in patients with multiple ards risk factors. pulmonary embolism is a highly prevalent disease associated with severe morbidity and mortality. although the hemodynamic changes induced by pulmonary embolism are known, the alterations in respiratory mechanics after an embolic event are not completely understood. the aim of this study was to evaluate acute changes in hemodynamics, static and dynamic respiratory mechanics and lung histology induced by an experimental model of pulmonary microembolism. ten large white pigs (weight - kg) were instrumented with arterial and pulmonary catheters and pulmonary embolism was induced in pigs by injection of polystyrene microspheres (diameter ∼ µm), in order to obtain a pulmonary mean arterial pressure (pmap) of twice the baseline value. five other animals were injected with saline and served as controls. hemodynamic and respiratory data were collected and pressure x volume (pxv) loops of the respiratory system were performed by a quasi-static low flow method. animals were followed for hours and after death lung fragments were dissected and sent to pathology. the average amount of microspheres necessary to generate microembolism was . ± . mg/kg. pulmonary embolism induced a significant reduction in stroke volume ( ± ml/min/bpm pre vs ± post, p< . ), an increase in pmap ( ± mmhg pre vs ± post, p< . ) and pulmonary vascular resistance ( ± mmhg/l/min pre vs ± post, p< . ). respiratory dysfunction was evidenced by significant reductions in pao /fio ratio ( ± pre vs ± post, p< . ), dynamic lung compliance ( ± ml/cmh o pre vs ± post, p< . ) and increase in dead space ventilation ( ± pre vs ± post, p< . ). pxv curves of the respiratory system were affected by embolism, with shift of the loops to the right and consequent reduction in static compliance and pulmonary hysteresis. pathology depicted inflammatory neutrophil infiltrates, alveolar edema, collapse and hemorrhagic infarctions. pulmonary microembolism induced by polystyrene microspheres is associated with cardiovascular dysfunction, as well as respiratory injury characterized by decrease in oxygenation, dynamic and static lung compliances and pulmonary hysteresis. pathology findings were similar to those verified in inflammatory-induced acute lung injury. the similarities between respiratory and histologic features of this model and those from conditions associated with lung inflammation suggest that pharmacologic and ventilatory interventions already used to treat acute lung injury may also be tested in pulmonary embolism. the presence of patent foramen ovale (pfo) is frequently underdiagnosed in icu patients suffering from refractory hypoxemia. however, it is relatively common in the general population. we examined the prevalence of pfo in mechanically ventilated icu patients with refractory hypoxemia and abnormal chest x-ray findings. over a period of five years, mechanically ventilated patients with refractory hypoxemia and abnormal chest x-ray findings were examined with transesophageal echocardiography (tee) for the presence of pfo as a contributing factor to their hypoxemia (right to left intracardiac shunt). all patients were ventilated with tidal volume - ml.kg - and peep between - cmh o. their mean pao /fio ratio was ± mmhg. the coexisting pathology consisted of: ards ( cases), massive pulmonary embolism ( cases), copd ( cases), cabg surgery with rv infarction ( cases), cerebrovascular accident ( case) and pulmonary oedema due to fluid overload ( case during a two-month period we investigated the possibility of opening of the foramen ovale during a recruitment maneuver in either patients with ards or in patients with atelectasis and a pao /fio ratio< . we enrolled consecutive patients (ards: cases, patients with atelectasis and hypoxemia: cases), likely to benefit from a recruitment maneuver. mean pao /fio ratio was and mean compliance was ml.cmh o - prior to the maneuver. all data regarding the mechanical properties of the lung were recorded from the ventilators monitor screen. after deficits of intravascular volume had been addressed and hemodynamics had been optimized, a baseline transesophageal echocardiographic study using contrast material was performed to rule out the possibility of a foramen ovale already patent prior to the maneuver. the recruitment inflation pressure was chosen as the lesser of cm h o or the peak pressure at ml.kg - tidal volume. the ventilator was then adjusted to deliver this high inflation pressure for secs. five seconds after the onset of inflation, ml of a contrast material were injected through a central venous line with the transesophageal probe already in place to detect the passage of the material to the left atrium. passage of the contrast material to the left side of the circulation was detected using two dimensional echocardiography. we found that the sustained high inflation pressure resulted in foramen ovale opening in patients, whereas it did not produce such a result in patients. in of the studied patients, the baseline transesophageal study revealed a patent foramen ovale before recruitment was attempted. no adverse effects following the recruitment maneuver were noted. mean pao /fio ratio was and mean compliance was ml.cmh o - twenty minutes after the recruitment maneuver, with only one of the recruited patients showing a significant improvement in oxygenation.conclusion. patent foramen ovale may be a contributing factor of refractory hypoxemia in icu patients. opening of the foramen ovale is not an unlikely event during a recruitment maneuver. acute respiratory distress syndrome (ards) remains a major problem in critically ill patients, with mortality rates of - %. to date, no specific treatment has been shown to decrease mortality, but this may largely be due to the heterogeneity of the populations meeting the ards criteria.objectives: to evaluate patients who died with a clinical diagnosis of ards and who had a postmortem examination in order to: -define the pathological alterations associated with the syndrome, with particular reference to the typical pattern of diffuse alveolar damage (dad); -evaluate whether etiologies or precipitating factors were missed; and -speculate whether a lung biopsy could have guided the clinical management. three year ( ) ( ) ( ) review of all patients with ards (using the aecc criteria) who had a postmortem examination. comparisons between ante-and post-mortem diagnoses were classified as major and minor discrepancies using the goldman classification. results: of a total of admissions, patients had a clinical diagnosis of ards. of these, died; had a postmortem examination and of these had complete data for analysis. the main causes of death were multiple organ failure in ( %) and refractory hypoxemia in ( %). postmortem lung examination revealed dad in ( %) patients ( associated with a lung infection), (broncho)pneumonia without dad in ( %), invasive pulmonary aspergillosis without dad in ( %), and other diagnoses in ( %). major unexpected findings were found in ( %) patients, classified as goldman class i errors and class ii errors. the class i errors included cases of invasive pulmonary aspergillosis.conclusion. ards as a syndrome, can be due to various pathological patterns; at autopsy, only half of patients with ards have typical dad. special attention should be paid to the possibility of aspergillosis; in this setting, lung biopsy may have a role. g. s. georgieva*, s. kurata, c. zhu, a. bilali, t. imai critical care medicine, tokyo medical and dental university, tokyo, japan development of efficient lung preservation method has been anticipated and we elucidated that positive pulmonary venous pressure (pvp) ( mmhg) prevented ischemia-reperfusion (i/r) injury in isolated mechanically ventilated rat lungs. the aim of this study is to determine whether cpap accompanied with mmhg of pvp would be effective for prevention of i/r injury. after tracheostomy rats were ventilated at strokes /min with air ( % c ) and with peep of . cmh , cannulated to the left atrium and pulmonary arteries (pas), and perfused with krebs -henseleit solution supplemented with albumin ( %) ( . ml/g/min). the lungs and heart "en block" were isolated and placed in a chamber; right and left bronchus as well as pas were dissected which permit each lung to be ventilated and/or perfused selectively by selective occlusion of each bronchus and/or pa. after min control condition, the left lung (ll) was maintained under cpap (selective occlusion of left broncus); the control right lung (rl) was ventilated with peak airway pressure of cmh above peep;perfusion to the both lungs was stopped (ischemia). pulmonary venous outflow was elevated so as to be applied mmhg to the left atrium during ischemia. after -min ischemia, reperfusion with mmhg pvp and both lung normal ventilation were resumed for min. perfusion pressures of rl and ll was measured at the beginning and at the end of the experiment by occlusion either the left or right pulmonary artery, as appropriate. albumin content in bronchoalveolar lavage fluid (balf) separately for each ll and rl, and lung weight were measured. protein content in balf was calculated as (mg of protein)/(ml of balf)/(g of lung dry weight). all the data were compared by wilcoxon's rank-sum or mann-whitney u-test and expressed as mean +/-sd. in i/r lung maintained at cpap, wet/dry and balf as well as perfusion pressure increased compared to the control rl. conclusion. cpap( . cmh ) and mmhg pvp cannot prevent ischemic lung injury despite constant distention of pulmonary vasculature and alveolar space. this suggests that gas exchange during ischemia would be necessary for escaping from i/r injury. potential peripheral airway obstruction is of importance for the choice of ventilatory strategy in acute lung injury (ali). use of a limited expiratory time counteracts early regional expiratory collapse but might cause hyperinflation in case of significant peripheral obstruction. the aim of this study was to assess regional expiratory time constants and gas trapping in early ali. ten anesthetized pigs were ventilated in volume-controlled mode with i:e ratios of either : or : at a rate of breaths per minute. starting from the end-inspiratory level, sequential computed tomography (ct) exposures were performed during passive, uninterrupted expiration to the atmosphere. the procedure was performed before and after oleic acid-induced lung injury (oai) had been induced in the lower lobe on one side. the gas volume of bilateral dependent and non-dependent regions of interest (rois) was calculated from radiographical attenuation values. the expiratory time constant was calculated from a mono-exponential decay of roi gas volumes during expiration. gas trapping in injured and non-injured regions were compared. during ventilation with i:e ratio : , oai caused overall compliance to decrease from +/- . to +/- . ml/cmh o (p< . ). dependent, injured regions showed a shorter time constant and a lower volume of gas than dependent non-injured regions regardless of whether the preceding end-inspiratory volume had been increased or not by application of a limited expiratory time. in non-dependent, non-injured regions, the gas volume was similar on both sides after both patterns of ventilation. one of the additional approaches in the therapy of the acute respiratory distress syndrome (ards) is the use of a pumpless arteriovenous extracorporeal membrane oxygenator (interventional lung assist (ila)). the aim of our study was to test the effects of an ila system on hemodynamics and gas exchange during resuscitation and to establish whether ila should be kept open or clamped under these circumstances. the study was designed as a prospective experimental study. the experiments were performed on pigs ( to kg body weight). the pigs were anesthetized and mechanically ventilated. one femoral artery and one femoral vein were cannulated and connected with ila. acute lung injury was induced by repeated bronchoalveolar lavage until arterial partial pressure of oxygen (pao ) was lower than torr for at least min during ventilation with % o . ventricular fibrillation was then induced by an indwelling pacemaker. manual compressions of the thorax were started at once and continued for minutes. in animals, ila was kept open, in the other it was clamped immediately. statistical analysis was performed using graphpad prism. two-way analysis of variance was applied and significance was accepted at p values < . . the data is given as mean ± sd. with a mean systolic arterial pressure in the group with ila open of ± mm hg and ± mm hg with ila clamped and mean blood pressures of ± mm hg with ila open and ± mm hg with ila clamped the blood pressure did not differ between the two groups. endtidal carbon dioxide decreased from ± torr with ila open and ± torr before intervention to ± torr and ± torr, respectively. the arterial partial pressure of carbon dioxide (paco ) was significantly lower in the group with the ila system open ( ± mm hg versus ± mm hg at minutes) and the pao was higher (although significant only at minutes, mm hg ± mm hg versus mm hg ± mm hg). the blood pressure generated with thorax compressions did not differ significantly between the two groups and endtidal co was also in the same range. therefore we assume that circulation was not significantly affected by ila and that the shunt caused by the ila system did not deteriorate circulation. paco was significantly lower in the group with the ila system open and pao was higher. our results indicate that the ila system was not harmful during resuscitation, it even might have a beneficial effect.grant acknowledgement. the study was partially supported by novalung, hechingen, germany. respiratory failure -miscellaneous - increased thorax rigidity and high intraabdominal pressure reduce the stretch ability of the thoracic cage and modify the regional lung function. this phenomenon is often seen in intensive care patients, e.g. with abdominal compartment syndrome. objective of this study was to determine the effect of decreased thoracic cage compliance on regional distribution of spontaneous ventilation in different postures by the non-invasive method of electrical impedance tomography (eit). for this survey we examined ten healthy male spontaneously breathing volunteers (mean age ± sd: ± years; body weight: ± kg, height: ± cm). the compliance of the thoracic cage was restricted by external abdominal and thoracic corsets respectively. the eit examinations were performed with the goe-mf ii eit device (viasys healthcare, höchberg, germany). sixteen self-adhesive electrodes ( m red dot , m health care, borken, germany) were applied on the chest circumference in one transverse plane and used for rotating electrical current injection and voltage measurement. the eit data were acquired at a rate of scans/s. impedance data and spirometry were obtained during spontaneous ventilation in three body positions (sitting, left and right side). statistical analysis was performed using repeated anova with bonferroni's multiple comparison test and student's t test. p values < . were considered significant.results. the regional distribution of ventilation in subjects without restrictions revealed a close match with physiologically expected values. thoracic and abdominal restrictions led to reduction of ventilation in the dependent lung areas. the non-dependent lung areas were not affected. the fractional ventilation in the dependent lung areas was reduced in the right side position from . ± . % to . ± . % (thoracic restrictions) and . ± . % (abdominal restrictions), in the left side position from . ± . % to . ± . %, and . ± . %. thoracic and abdominal restrictions of the thoracic cage reduce ventilation only in the dependent lung regions in spontaneously breathing healthy volunteers. eit is a suitable method for non-invasive determination of regional lung ventilation. k. raymondos* , k. vieweger , j. ahrens , m. przemeck , m. homann , s. piepenbrock anaesthesiology, medical school hannover, anaesthesiology, annastift, johanniter-unfall-hilfe e.v., ortsverband wasserturm, hannover, germany germany are still performed with ambulances in that only limited monitoring and usually only volume-cycled emergency ventilators can be used. we established an intensive care ambulance system and evaluated the transfers of critically ill patients performed with this system. we prospectively recorded interhospital-transfers. the ventilatory modes before and during the patients' transfer and further characteristics of the interhospital-transfers were evaluated. transport ventilation was performed with the raphael ® silver ventilator (hamilton medical ag, rhäzüns, switzerland) with that also pressure-support ventilation (psv), airway pressure release ventilation (duopap ® /aprv) and the combination of both could be used. indications for the interhospital-transfers included ischemic ( . %) and other ( . %) cardiac diseases, cerebral diseases ( . %) of which % required neurosurgy, pulmonary disease ( . %) and others ( . %). ( . %)% of the transferred patients received ventilatory support, patients ( . %) breathed spontaneously with and patients ( . %) without oxygen insufflation. the majority of the mechanically ventilated patients received ventilatory modes supporting spontaneous breathing before ( . %) and during the transfer ( . %). the patients were transferred in minutes ( minutes - hours) over a distance of km ( - km) (median (range)). at least motor syringe pumps were needed during the transfer of patients ( . %). monitoring during the transfer was similar or more extended compared to the monitoring in the hospital prior to transfer (ecg % vs. %, pulse oximetry % vs. %, non-invasive blood pressure % vs %, intraarterial pressure % vs % and capnography % vs. %). most ventilated patients received weaning techniques and most of these ventilatory modes were continued during the transfer. these ventilatory modes and a more extended monitoring including intraarterial pressure monitoring and capnography cannot be applied in emergency ambulances. the less invasive ventilatory modes and the extended monitoring enable a less invasive and safer interhospital-transfer as the intensive care treatment and monitoring prior to transfer is maintained or even extended during the transport. a. sánchez*, m. palomar, r. alcaraz, a. socias, d. moreira intensive care unit, hg vall d'hebron, barcelona, spain introduction. some series have shown the bad prognosis of patients with pulmonary fibrosis (pf) who require admittance at icu for respiratory failure. there are doubts of the benefit of the ventilatory support if the precipitating cause is not well defined. lung transplant (lt) could be a therapeutical option. the aim of this study was to analyze the prognosis of the patients with pf who are admitted to an icu of a hospital with lt program.methods. case-series, observational study of patients with pf and acute respiratory failure admitted to the icu of a third level hospital with lt programm between january until june . information about the cause of pf, clinical course, current status, ventilatory support, length of stay, pulmonary functional tests, possibility of trasplantation, complications and mortality was collected. . patients ( men, women) with pf ( idiopathic pf, connectivopaty and due to radiotherapy) were admitted for acute respiratory failure (arf) to our icu. mean age was , ( - ) years. the median duration of illness from diagnosis until admittance was , ( - ) years. apache-ii score was ( - ). the precipitating cause of arf was identified in patients: bacterial pneumonia was documented in patients; had a pulmonary embolism; fungic infection and cases were due to the progression of the disease. in cases the precipitating cause could not be identified. mechanical ventilation (mv) was required by patients ( , %) during an average of , ( - ) days with a mortality rate of , %. pa o /fi o at admittance ( - ) mm hg; and paco at admittance ( - ) mm hg. respiratory functional studies were available in eleven patients with a fev of . ( . ) l and fvc of . ( . ) l. patients ( %) died during their stay at icu. the cause of death was multi-organic failure in ( . %); refractary hypoxemia in ( . %) patients and of them died while the transplantation was being performed. mean length of stay was ( - ) days. patients were included in the urgent lt list and were transplanted. no donor was found in cases and died on the waiting list. there were performed single-lung and double-lt. mean age was ( - ) years. the time from the admittance until transplantation was ( - ) days. of them ( %) required mv with a mortality rate of , %. from this group ( , %) patients died during their stay at the icu. of the patients died while the transplantation was being performed.conclusion. literature shows a bad prognosis of patients with pf who need admittance to an icu for arf. in our experience the survival was % so the existance of a lt programm could offer a chance to these patients. m. e. lugarinho*, p. p. souza intensive care unit, hospital de clinicas mario lioni, rio de janeiro, brazil introduction. acute kidney insufficiency (aki) worsens the outcome in critical ill patients. we investigate whether the presence of aki had any effect on lenght of mechanical ventilation and mortality rate. observational, prospective study in a -bed general intensive care unit (icu) from january to december . the inclusion criterion was invasive mechanical ventilation for more than hours. aki was defined as the presence of dialysis during the icu stay. patients were then separated into aki and non-aki patients (control group). the primary end point was duration of total length of mechanical ventilation and the secondary end point was the icu mortality. a total of patients were studied: with aki and non-aki. the groups were similar in regard to age, sex, and apache ii score. the median (interquartile range) duration of mechanical ventilation [ - ] versus [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days, (p< , ). the icu mortality rate were significantly greater in the aki patients: % versus , % (p< , ).conclusion. this study shows that renal insufficiency has serious impact on the duration of mechanical ventilation and morbi-mortality in critically ill patient. these data elicits the poor outcomes of mechanical ventilated patients who demands for dialytic methods. it will be useful in end of life discussions and decisions in our icu. introduction. -ht a-r-agonist -oh-dpat has been shown to counteract morphine induced ventilatory depression, while opiate antinociception remained unaffected. repinotan-hcl, another -ht a-r-agonist, is unlike -oh-dpat suitable for the use in humans. it was hypothesized that repinotan-hcl is capable to antagonize ventilatory depression without impairing anti-nociception in rat. with approval from local animal care committee, rats were anesthetized with sevoflurane and tracheotomized to record respiratory rate (rr), tidal volume (vt) minute ventilation (mv). inguinal vessels were catheterized to monitor arterial blood pressure and apply drugs iv. nociception was assessed by tail-flick reflex. morphine was administered at increments of mg/kg until a target % reduction of rr was achieved. subsequently, repinotan-hcl was added cumulatively at increasing doses ( . , . , , , µg/kg, n= ). another group received nacl . % to serve as control (n= ). morphine ( . ± . mg/kg) depressed rr to - ± %, and tfr was abolished with first dose of morphine in any experiment. repinotan-hcl antagonized ventilatory depression dose-dependently, mcg/kg repinotan-hcl re-established ventilation almost at pretreatment level (rr + . ± %, p< . , -anova, compared to control). tfr remained absent throughout repinotan administration. repinotan functionally antagonized morphine-induced ventilatory depression, while suppression of nociceptive reflex sustained. -ht a-r-agonists such as repinotan-hcl appear to be promising candidates to stabilize spontaneous breathing. a. makowski* , b. misztal , c. plowright , k. safranow anaesthetics, medway maritime hospital, gillingham, united kingdom, biochemistry, pomeranian medical university, szczecin, poland vapotherm's (vap) patent pending membrane technology makes higher flows from to lpm possible by saturating breathing gases with water vapor at body temperature. fio is ranging from . - . . heat and humidity allow nasal flow to be well tolerated by the patients. high flow in animal study caused small amount of peep. can we achieve desired therapeutic goal in treatment of respiratory failure (rf) with this very simple, non-invasive method? we investigated effectiveness and hospital outcome of patients with rf treated on vap at surgical hdu between december and march . data were taken during retrospective investigations. we analysed type and reason of rf as well as respiratory rate (rr), fio , flow, arterial blood gases (abg). data were collected before (bef) vap was commenced, hour after, and every day of treatment. we also recorded length and outcome of vap therapy and patient satisfaction. data were analysed with wilcoxone and also spearman's rank correlation tests. the patients ( % female, % male) at age - ( . ± . ) were treated - ( . ± . ) days. we applied vap therapy for . % patients with type i rf and . % with type ii rf. the reasons of rf were pneumonia in . %, sepsis in . % pulmonary oedema in . %, copd in . %, others in . %. for . % patients there was a sufficient and definite treatment whereas . % required mechanical ventilation and icu admission. the . % of patients were satisfied with therapy. the . % survived and were discharged from the hospital. high flow and small amount of peep reduce work of breathing and significantly decrease rr. after effective vapotherm therapy we observed in abg significant increase of oxygen saturation and pao . vast majority of patients were satisfied during the treatment. in critically ill patients who need long-term mechanical ventilation, early tracheostomy may facilitate weaning and shorten the length of stay in intensive care ( ). however, there are no clinical tests that identify patients as being at an increased risk for prolonged ventilatory support; clinicians must predict the duration of arteficial ventilation by their clinical experience. in our surgical intensive care unit we conducted a prospective clinical study to determine if there was an association between different clinical parameters (age, body mass index, gcs, saps score, vasopressor use, pao /fio ratio) and long-term mechanical ventilation. furthermore, we examined the positive predictive value of clinicians' prediction; to do that, clinicians had to indicate whether they considered prolonged mechanical ventilation as the most likely (but not always certain) outcome or not. we enrolled patients and collected date on days - th and th of treatment. prolonged meshanical ventilation was defined as at least more days on respirator. none of the examined parameters could be used alone to predict long-term mechanical ventilation. overall sensitivity of clinicians' prediction was . %, and positive predictive value was . %. . % of patients died, . % was weaned from respirator ( . % extubated) within days despite predicted by clinicians as having prolonged ventilatory need. suprisingly, the best positive predictive value ( . %) was found on the day of admission, the worst ( . %) on day ; the difference was not significant (p= . with chi-square test). this result could be explained by the fact that most patients in the study group were ventilated on day , but only a few on day .conclusion. prediction of prolonged mechanical ventilation was found to be very inaccurate, and did not improve in the course of first week of treatment. however, in our department where many neurosurgical patients are treated, only a minority could be extubated within days when long-term ventilatory support was predicted. as selection of patients who need tracheostomy seems not to be better after one week of treatment than at an early stage, there can be a reason for early tracheostomy if we anticipate prolonged arteficial ventilation. n. abidi , h. thabet* , o. béji , h. elghord , n. brahmi , m. ben othmen , n. kouraichi , m. amamou intensive care medicine, emergency medicine, centre d'assistance médicale urgente, tunis, tunisia introduction. acute exacerbation of copd is a frequent cause of admission in icu and usually have a poor outcome. such a patient consume a large amount of resources particulary if they need endotracheal intubation. the aim of this study is to report epidemiological, clinical features,treatment and outcome of patients admitted in icu for acute exacerbation of copd. a retrospective study was carried out of consecutive admisions in icu over a years (from january to december ). american thoracic society criteria are usued to define copd. exacerbation is defined as a worsening of copd symptoms. a total of patients were included in this study with episodes of acute exacerbation. mean age was ± , years. the sex ratio was , (m/f: / ). eighty percent were current tobacco users. seventy two percent had one or more associated comorbities mainly cardiovascular disease. according to copd severity , % of patients were in stage iii. , % were receiving home oxygen and ( %) were previously mechanical ventilated. on icu admission severity score are apache ii ± ; igsii ± . patients ( %) have a shock and ( , %) have a coma (gcs< ). treatment consist of starting non invasive ventilation (niv) for patients ( %); patients ( %) need immediate intubation and mechanical ventilation. failure of niv was noted for patients. in the course of hospitalisation in icu main complications were: nosocomial infection for patients ( , %), barotrauma patients ( , %) and thromboembolic complications for patients ( , %). the median icu stay was , ± , days and mortality was , % ( patients). the main cause of mortality were septic shock ( cases, , %) and ards ( cases, %). in this retrospective study patients admitted for exacerbation of copd need a mechanical ventilation in , %. failure of niv were %. main complications were nosocomial infection ( , % of cases). mortality is high , % but not different for patients admitted in icu for other disease. it is described, that gelatin leads to red blood cell (rbc)-coating, which is protective against shear stress in extracorporeal circuits. ( ) an increase of mean corpuscular volume (mcv) without an increase in mean corpuscular hemoglobin content as well as a reduction of red blood cell (rbc) counts can be assumed to reduce pulmonary oxygen transfer. increased rbc aggregability (accelerated blood sedimentation rate, bsr), as could occur due to coating, impairs microcirculation. since adequate oxygen delivery is important in ventilated patients to counteract metabolic acidosis, we compared rbc features in acidotic pigs undergoing hemofiltration. healthy pigs (male, dlxde, - kg) were anesthetized, received acid infusion ( . m) and low tidal ventilation with fio > . resulting in normoxic acidosis (ph . - . ; paco - mmhg). tris-hydroxymethylaminomethane (tham) was infused to titrate a ph of . - . . either hes or gel (n= - /colloid-group) was infused additionally to crystalloids (colloid to crystalloid ratio was : ). samples were collected before acid and colloid infusion (bs), after induction of acidosis (baseline acidosis, bsa), and after h of continuous acidosis ( ha). thereafter, acid infusion was stopped and tham was infused with . mol/kg/h for h in order to normalize ph-values. final values (fv) were taken. parameters investigated were: paco , rbc counts, mcv, and bsr. the fio /pao ratio was also determined. compared to hes application, gel infusion was associated with a reduction in rbc count, an increase in mcv and an accelerated bsr from bsa until fv. values did not recover from initial deterioration (bsa) even not after normalization of ph (fv). based on the healthy lungs in this porcine model, these changes did not impair pao /fio ratio. whether increases in mcv were due to gel coating or due to unhampered swelling of rbcs during acidosis could not determined. however, in acidotic pigs gel induced unfavorable effects concerning rbc features with respect to rheology while hes did not. in individuals with impaired pulmonary function and hypodynamic state the described difference between the two types of colloids could become crucial with respect to total oxygen delivery. perctaneous dilational tracheostomy (pdt) has become more common procedure used in intensive care. however, several complications, such as hemorrhage, posterior tracheal wall injury, tracheal stenosis have been recently reported. the aim of this study was to confirm whether the ultrasound can easily and clearly delineate the pretracheal anatomy and identify the potential problems for pdt. we also examined the accuracy in identifying the correct puncture level between and tracheal cartilages blindly (by hand). we studied patients and volunteers. before ultrasound scanning, the circumference of the neck was measured and the puncture level between and tracheal cartilages was marked blindly in each subject. in ultrasound scanning, we examined the relationship of the thyroid to the trachea, aberrant vascular anatomy in the pretracheal region, counted the number of extrathoracic tracheal rings. the distances from the skin to cricothyroid ligament and anterior tracheal wall at the level between and tracheal cartilages were estimated and the relationship between depth of trachea and circumference of the neck was analyzed by simple regression. we also checked the level of trachea pointed by operator blindly was correct or not by comparing the level identified by ultrasound images. the mean age and circumference of the neck were ± years (range: - ) and ± cm. ultrasound examination of the trachea and thyroid was easily carried out in each subject except subjects. approximately extrathoracic tracheal rings could be imaged with ultrasound. anterior jugular veins were seen in subjects ( %) and six were near the midline. the depth of trachea between and tracheal cartilages were varied in each subject ( . - . cm) and there were stastistically relatioship between circumference of the neck and depth of trachea (r = . , p= . ). the accurate decision of trachea level was made in % of the subjects.conclusion. this study showed that: ) ultrasound can delineate the neck structure and detect variations related to the complication of pdt; ) blind identification of the puncture level for tracheostomy without ultrasound was not necessarily correct. our results demonstrated that the routine use of ultrasound could be recommended before pdt. introduction. fluid therapy system of critically ill patients is very variable, and it is based in the interpreting of differents physiologic parameters with a double aim, by one hand keep an adequate perfusion of vital organs, and the other hand avoid overload volumen. our objective was analyze changes in critically ill patients fluid therapy when we including evlw in treatment protocol and evaluate response in short time. observational and prospective study in a neurotraumatological icu. we included consecutives patients that were admited with acute lung injury/adult respiratory distress syndrome and/or septic patients who needed monitoring with central venous and arterial catheterization with picco system. we made a therapeutic reassessment of the fluid therapy and/or vasoactives after we knew evlw when one of the following events in the patient evolution hapenned: hypoxemia, hypotension, olyguria/anuria, or its addition. response in short time was also evaluated. our sample included patients and determinations( patients with determinations, patient with determination and patient with determination). after we knew evlw we changed initial therapeutic plan in . %; this change affected fluids in . % and vasoactives in . %. evlw in patients who therapeutic plan was modified was . ± . and if therapeutic plan was not modified, evlw was . ± . (p< . ). association is observed between evlw value and decision about fluids, so when we decided increase fluids was . ± . ; if the decision was decrease fluid, evlw was . ± . and in the cases that diuretics were added . ± . , in all cases statistics significant was found. no differences was observed in evlw values about vasoactives decision. we found improvement of initial event in short time after intervention in . %.conclusion. evlw determination affects in important way to fluids therapy plan in critically ill patients. we think that inclusion of evlw contributes to a more racional management of these patients. patients who had received ino were identified from icnarc records. hospital notes and icu charts were reviewed. data collected included diagnosis, apache ii and unit and hospital outcome. the pao /fio ratio (in mmhg) was recorded prior to starting ino (day ) and subsequently on days - using the data from the time at which oxygenation was best in each hour period. . patients received ino. patients received it for treatment of hypoxaemic respiratory failure, and for treatment of pulmonary hypertension. mean apache score was . on admission (survivors . ; non-survivors ) . the mean pao /fio ratio was . on day and improved to . on day . in unit survivors, the mean pao /fio increased from . to . on day , compared with unit non-survivors in whom it increased from . to . . ( %) of patients were responders to ino (defined as a > % increase in pao /fio ratio). unit and hospital survival figures for responders and non-responders are presented below. hospital surviviors (n= ) hospital non-survivors (n= ) responder (n= ) ( %) ( %) non-responder (n= ) ( %) ( %) fisher's exact test ( tailed) p= . conclusion. ino was used in patients with more severe hypoxia than those included in randomised trials. ( ) in this review, responders were found to have a significantly reduced unit mortality and a reduced hospital mortality compared with non-responders. we believe ino may be a valuable therapy in ards patients with severe refractory hypoxaemia, and that studies in this subgroup of patients are warranted. outcome predictors of hfov in severe ards are not well studied. we prospectively evaluated the outcome predictors of hfov in adult ards. methods. ards patients receiving mechanical ventilation as per the ardsnet protocol with po /fio ≤ inspite of peep≥ cm and fio ≥ . ,were considered for hfov. continuous distending pressure(cdp),frequency ,amplitude, inspiratory time and bias flow of hfov were optimised with the help of frequent blood gas analysis. weaning from hfov to pressure support ventilation was attempted once po /fio ratio remained ≥ with cdp≤ cm &fio ≤ . . responders(r) were defined as patients who were successfully weaned to a state which required no ventilatory support for > hrs. non responders(nr)were defined as patients who could not be weaned off ventilatory assistance. results. out of total patients were r & were nr. both the groups were similar prior to hfov as shown in table. improvement in po /fio ratio and oxygenation index (oi) at hrs & hrs in r group was statistically significant as compared to that in nr group. we could show that chaotic variation of pressure support improves pressure support ventilation (psv), and named this new mode noisy psv. in this work, we compared noisy psv to conventional biphasic positive airway pressure ventilation (bipap), which has been claimed to be a "gold standard", in experimental acute lung injury. after approval by the local animal care committee, juvenile pigs ( . - . kg) were anesthetized and mechanically ventilated (dräger evita xl lab; volume controlled ventilation, vt = ml/kg; fio = . ; peep = cmh o). after induction of acute lung injury by saline lung lavage ( ml/kg), lungs were recruited and a decremental peep trial was performed to determine the optimal peep according to the elastance of the respiratory system (ers). thereafter, spontaneous breathing was resumed and animals were randomly assigned to noisy psv or bipap groups (n= each group). the ventilator settings were as follows -bipap: fio = . ; plow = according to peep of minimal ers; phigh = titrated to generate vt of ml/kg; thigh = s; tlow = s -noisy psv: fio = . ; peep = according to peep of minimal ers; mean pasb = titrated to generate vt of ml/kg. noisy psv was accomplished by means of remote control of the evita xl lab by a laptop, which generated a sequence of respiratory cycles with different pressure support levels (mean = pasb; sd = % of mean). gas exchange, respiratory parameters and hemodynamics were measured at baseline, injury, after resuming of spontaneous breathing (baseline ) and during an observational period of h. statistical analysis was performed with general linear model statistics adjusted for repeated measures using baseline as covariate. significance was accepted at p< . . bodyweight, peep and number of lavages as well as hemodynamics did not differ significantly between groups. oxygenation and co elimination were significantly improved with noisy psv (p< . both). analysis of respiratory parameters revealed significant lower mean airway pressures with noisy psv as compared to bipap (p< . ), as well as increased mean peak airway pressure, spontaneous respiratory rate, and mean tidal volume (p< . all).conclusion. this study represents the first evaluation of the recently developed noisy psv combined with peep levels titrated according to lowest ers. noisy psv was found superior to conventional bipap with regard to gas exchange and respiratory parameters. further experimental studies are necessary to determine the potential role of noisy psv in intensive care therapy. we investigated if chaotic variation of pressure support (noise) can improve the performance of pressure support ventilation (psv) in experimental acute lung injury (ali). with approval of the local animal care committee, pigs weighing to kg were anesthetized, intubated and mechanically ventilated (volume-controlled mode, fio = . , peep= cmh o, tidal volume= ml/kg). following that, ali was induced by surfactant depletion, and biphasic intermittent positive airway pressure (bipap) was initiated with: lower cpap (cpaplow) = cmh o, higher cpap (cpaphigh) titrated to obtain tidal volumes of - ml/kg, respiratory rate set to obtain paco between - mmhg. then, depth of anesthesia was decreased to allow spontaneous breathing, and animals were ventilated with two different modes ( hour each, random sequence): ) traditional psv, with pressure support level set at cpaphigh -cpaplow; ) noisy psv, with random variation of pressure support and mean value set at cpaphigh -cpaplow, and standard deviation set at % of the mean value (normal distribution). gas exchange, inspiratory drive (p . ) and inspiratory pressure time product of esophageal pressure (ptp) were assessed. helical computed tomography (ct) of chest was performed at end-expiration and the hyperaerated, normally aerated, hypoaerated and non-aerated lung compartments were calculated in animals. patients with respiratory failure treated with vm with fio . were included. after minutes of oxygen therapy, arterial blood gases were collected and patients were asked to quantify (from to ) three items: dyspnea, dry mouth and general confort. then, vm was changed for hfnc (optiflowtm, fisher & paykel, new zeland) . the same variables were collected after minutes using hfnc. results are expressed as median (interquartil range). we have applied spsswin v . with wilcoxon test. patients n= ( m), age ( - ). in the moment of inclusion, one patient ( %) presented mods and sofa score was ( . - . ). during their evolution, five patients ( %) finally need endotracheal intubation. main results are presented in the following tables: a computer-driven system (cds) has been recently used to optimise psv to patient's needs during weaning. in some pts, the cds fail to find a "comfort window" despite stepwise increase in pressure support (ps) levels. for these pts, cds could further increase respiratory muscle workload. we speculate that failure to adapt respiratory rates (rr) and vt following changes in ps levels might identify a subset of pts unlikely to benefit from the cds.to test this hypothesis, we used a bedside test before switching ventilated pts to a closed-loop algorithm of psv. we studied pts at initiation of weaning with psv using the smallest ps level resulting in rr≤ , vt> ml/kg. we collected baseline values and assessed changes in vt (dvt), rr (drr) during min after cmh o-increase and decrease in ps levels. then, a cds session was started at the baseline ps level. we searched for correlations between dvt, drr, and outcome (failure/success) of the cds sessions. a cds session was deemed successful when the system detected criteria for separation of the ventilator or when psv was efficiently adjusted by the cds within h after starting the session. in pressure support ventilation auto-peep is considered a major contributor to the inspiratory work of breathing. measurement of auto-peep requires esophageal pressure tracings, which are not routinely available. the presence of auto-peep is likely, when flow is interrupted at end-expiration, a pattern well-established in controlled ventilation. we studied expiratory flow-volume relationships as substitute for detection of auto-peep in patients on pressure support ventilation. in patients successively admitted to our icu respiratory mechanics were obtained from consecutive breaths on pressure support ventilation. auto-peep was considered present when in flow-versus-time recordings flow was interrupted at end-expiration. from flow-volume relationships expiratory time-constants were calculated and related to actual expiration times. all measurements were obtained with a nico-computer; for analysis a computer program analysis plus was used (both respironics/novametrix, inc.). in of the patients flow at end-expiration was interrupted suggesting the presence of auto-peep (interrupted flow group). in the remaining patients flow was zero at end-expiration (zero flow group). in the flow-volume curves of patients in the interrupted flow group versus the zero flow group end-expiratory flows varied between . - . l/s and . - . l/s respectively. the expiratory time-constants ranged from . - . s in the interrupted flow group and . - . s in the zero flow group. the ratios between expiration times and expiratory time-constants varied between . - . and . - . for the interrupted and zero flow groups respectively . the means and standard deviations for both groups were:means +/-sd in patients on pressure support ventilation with interrupted flows at endexpiration higher expiratory time-constants and lower ratios between expiration times and time-constants were found, suggesting the presence of auto-peep. these variables can be used as substitute for detection of auto-peep. non invasive ventilation (niv) is the delivery of assisted mechanical ventilation to the lungs, without the use of an invasive endotracheal airway. niv has decreased the need for invasive mechanical ventilation and its attendant complications. acute cardiogenic pulmonary edema (acpe) is defined as an episode of acute heart failure accompanied by severe respiratory distress and oxygen saturation < % on room air before all treatment. our study aimed to asses the respiratory effects of a device that delivers a continous positive airway pressure via face mask in patients with severe acpe, the feasibility of using this technique in an emergency department (ed) and estimed the need of endotracheal intubation (ei). we evaluated a series of patients consecutively treated in our ed for acpe, from june to december . a peep level of cm h o delivered by cpap-boussignac device (vygon, ecouen, france) was used in all patients. fio was estimed to range from to %. clinical and blood gas parameters were recorded at entry and also after minute and hour of treatment. all patients were treated with standard medical therapy. the average of age was years ( - ), were male and were female. the inclusion criteria for niv were: ph < , but > , , paco > mmhg or an acute augment of - mmhg, respiratory rate > /min, pao /fio < mmhg on room air and score kelly max . resolution of respiratory distress occurred from to minute ( media minute). all patients showed an improve of clinical and emogasanalytic impairment. only patients needed ei and were transferred in icu. patients were treated in ed and after normalization and stabilization of their vital signs they were discharged in other medical departments ( cardiology department and pneumology department). the rate of ei was %.conclusion. cpap delivered using boussignac device is feasible in an emergency care setting. it can quickly improve respiratory distress in acpe patients and reduce the need of ei. in clinical practice niv is being used as a sole respiratory support modality or in the weaning period in at least % of arf patients admitted to emergency department. the remaining patiens need imv as primary and secondary forms of respiratory support. failure of niv seems to predict higher mortality rates. as a conclusion we need both support modalities and the physician has to use them carefully according to patients condition and their expertise. methods. medline, pubmed, cochrane, & cinahl databases ( to were searched using the terms: aprv, bipap, bilevel & lung protective strategy, individually and in combination. reference lists of identified papers were also examined. two independent reviewers determined eligibility of papers based on predefined criteria. database searching yielded citations, of which were selected on review of title and abstract. data were abstracted onto pre-designed forms from experimental studies and discussion articles on further review. of the experimental studies, used a randomised design, were cohort studies and case series. aprv was the named mode in ( %) studies, bipap in ( %), and inverse mandatory pressure release ventilation in one study. extreme inverse inspiratory:expiratory (i:e) ratio was used in ( %) aprv compared to bipap studies (p = . ); ( %) aprv and ( %) bipap studies used mild inverse ratio (up to : ). a : ratio was used more often with bipap ( , % vs , %, p = . ) as was a normal i:e ratio ( , % vs , %, p = . ). in adult studies, mean inspiratory pressure was cmh o (aprv) and cmh o (bipap) (p= . ). mean expiratory pressure was . cmh o for both modes (p= . ). seven aprv studies described synchronisation, ( %) stated the mode did not synchronise to patient effort. all bipap studies that described synchronisation stated it was available.conclusion. aprv assumes inverse ratio ventilation (irv). some studies advocate extreme irv with short release times to improve gas exchange, haemodynamic stability, renal and splanchnic blood flow( ). extreme irv was used in only % of aprv studies, % described an i:e ratio of : . further, ventilator settings used for studies of aprv may be indistinguishable from bipap studies ( , ) . given the variation in ventilatory settings described, uncertainty of optimal settings may exist. commercial ventilator branding may further add to confusion. generic naming of ventilatory modes, as with drug prescribing, combined with consistent definitions of the parameters that define the modes, may avoid confusion, improve consistency of patient response and assist the implementation of these modes into clinical practice. pav is intended to normalize neuro-ventilatry coupling by assisting each breath in proportion to patient effort, but requires reliable measurements of elastance (e) and resistance (r). pav+ allows to (a) automatically and non invasively measure e and r, and (b) continuously adjust ventilatory support accordingly. aim of our study was to test the physiological effects of pav+ versus cmv (ardsnet lung protective strategy) in a model of ards. in pigs ards was induced through chloridric acid inhalation ( ml/kg). at t (after damage) each pig was randomly assigned to pav+ or cmv. gas exchange and lung ct scan at (t ) hours were compared with those obtained at t (delta = t -t ). data are mean +/-standard deviation; *) p < . pav+ versus cmv cmv pav+ ∆ hyperinflated areas (cm ) +/- +/- ∆ normally aerated areas (cm ) - +/- +/- * ∆ poorly aerated areas (cm ) +/- +/- * ∆ nonaerated areas (cm ) +/- - +/- * ∆ pao /fio - +/- +/- * ∆ paco (mmhg) +/- - +/- * our data suggest the ability of pav+ to improve gas exchange, principally through an increase in normally aerated areas. the impact of pav+ on ventilator induced lung injury deserves further investigation.grant acknowledgement. university of bari. introduction. the major advantage of high-frequency oscillatory ventilation (hfov) to conventional mechanical ventilation (cmv) is delivery of smaller tidal volumes to an optimally recruited lung. assuming there is a save window in the pressure volume curve of the lung between a lower zone with atelectasis and a upper zone with overdistension, surpassing this zone would result in either cyclic recruitment and decrecruitment, overdistension, or both. in diseased lungs this safe window may be too small to harbor the relatively large tidal volumes of cmv. co removal (v'co ) and therefore paco is a function of frequency (f) and alveolar delivered tidal volume (vt): v'co = f x vt . it is an inherent technical feature of all oscillators that vt at maximal power decreases as frequency increases. in addition, pressure swings fall down the endotracheal tube and the airways. this fall in pressure swings is a function of frequency and mechanical properties of the respiratory system. as a result of both phenomena vt delivered to the alveoli decreases substantially at higher frequencies. up till now oscillation is set at a fixed frequency, in adults at hz, in children and neonates at hz. paco is regulated by adjusting the power, and thus the pressure swings (delta p) and the delivered volume. if the maximum power has been reached, decreasing the frequency can lower the paco further. we calculated vt required to keep v'co constant at different oscillation frequencies and measured the delivered vt at maximal power as function of frequency with the sensormedics a. . vt needed to keep v'co constant and maximal delivered vt can be plotted against oscillatory frequency. by increasing frequency, vt needed to keep v'co constant and maximal delivered vt both decrease. however, a point is reached at which the required vt to maintain v'co equals the maximal delivered vt. at this point vt has its lowest possible value to maintain paco . at higher frequencies the delivered volume of the oscillator is lower than required and paco would rise above the pre-arranged level. we advocate a ventilatory strategy with the oscillator set at its maximal power and the frequency to be adjusted according to the paco . with this strategy the lowest vt is delivered to the alveoli with the largest safety margins between atelectasis and overdistension. automatic tube compensation (atc) compensates the resistance caused by the endotracheal tube. tube resistance is defined by the equation hagen-poiseuille: r = ( x x l) / π x r . (r= resistance, = viscosity, l= length of the tube, r= radius of the tube). atc is designed to lower the work of breathing in intubated spontaneous breathing patients by creating a higher initial flow and therefore a higher peak pressure. the aim of this study was evaluate the consequences of atc during controlled mechanical ventilation without spontaneous breathing activity on peak pressure distal of the tracheal tube, in comparison to the set pressure. moreover, the time needed to reach the set inspiratory pressure distal of the tube with and without atc was assessed. in an experimental laboratory setting using an artificial lung the maximum pressure in the ventilator (draeger evita ), proximal and distal of the tube with and without % inspiratory atc in a tube id , and a tube id , were measured. the time needed to reach the set inspiratory pressure distal of the tube with and without % inspiratory atc were compared. baseline ventilator settings were bipap, asb , peep mbar, i:e-ratio : , fio %, rise time seconds. a set of measurements where performed for each of the following settings: pressure constant group (pcg): frequency of respectively: , and a minute at a fixed pinsp of mbar. frequency constant group (fcg): pinsp of respectively: , and mbar at a fixed frequency of a minute. no peak pressure were measured at any time distal of the tube regardless of frequency or set pressure. the pressure distal of the tube never exceeded the set pressure level in the ventilator. the time needed to reach the set inspiratory pressure distal of the tube was significant shorter during atc. (see table) conclusion. there is no danger of creating a higher pressure distal of the tube than the set inspiratory pressure at any time during the use of atc % with the draeger evita . with the use of atc the set inspiratory pressure at the distal end of the tube is reached more quickly. atc creates a faster rise time on the tracheal level, resulting in a higher mean airway pressure. key: cord- -kv vxmcw authors: bambi, stefano title: evolution of intensive care unit nursing date: - - journal: nursing in critical care setting doi: . / - - - - _ sha: doc_id: cord_uid: kv vxmcw the specialties of critical care medicine and critical care nursing arose to provide special treatment and care to the most severely ill hospital patients. however, critical care medicine does not seem to have made any major therapeutic progress in the past years. the reduction of mortality in intensive care units (icus) is due essentially to improvements in both supportive care and the relevant technologies. in future, increases in the number of icu beds relative to bed numbers in other hospital wards will probably be contemplated, even in a scenario of decreasing costs; clinical protocols will be computerized and/or nurse-driven; more multicenter and international trials will be performed; and organizational strategies will concentrate icu personnel in a few large units, to promote the flexible management of these healthcare workers. moreover, extracorporeal organ support technologies will be improved; technology informatics will cover all the bureaucratic aspects of healthcare work, aiding the staff in workload assessment; and critical care multidisciplinary rounds and follow-up services for post-icu patients will be implemented. lastly, a better continuum of care between the pre-hospital phase, the emergency care phase, the icu phase, and the post-icu phase should be achieved. also, policies should be drafted to manage sudden large demands for critical care beds in mega-emergencies. the main lines of discussion in critical care nursing research should include nursing research priorities in critical care patients, holistic approaches to the patient, the humanization of care, special populations of icu patients, and challenges related to critical care nursing during emerging outbreaks of infectious diseases. recently, professor jean-louis vincent (along with other luminaries in the field of intensive and critical care medicine), has published articles that consider the history and perspectives of intensive care medicine and intensive care units (icus) [ ] [ ] [ ] . the fields of critical care medicine (ccm) and critical care nursing arose to provide special treatment and care for the most severely ill hospital patients [ ] . these patients need high levels of surveillance, intensive nursing care, and biomedical technology to support and monitor their vital functions and failed organs/systems. this type of care is carried out in icus, which are specific spaces, separated from other hospital areas, set up to receive critically ill patients and provide highly specialized medical and nursing competences and skills [ , ] . however, in the past years, despite the increasing amount of research in ccm, major therapeutic progress does not seem to have been made in the field [ ] . the reduction of mortality achieved in icus is due essentially to improvements in supportive care and in the relevant technologies [ ] . some therapeutic progress has been shown in the following fields [ ] : • protective strategies for mechanical ventilation in acute respiratory distress syndrome (ards) • increasing employment of noninvasive ventilation (niv) • reduction of (long-term) sedation use • enteral nutrition preferred to parenteral nutrition • less invasive monitoring systems • reduction in blood transfusions • reduction in anti-arrhythmic medications • greater attention to the use of antibiotic drugs • early and active patient mobilization. however, greater steps have been made in the process of care, including all the healthcare professionals involved with the critically ill patients, the environment, the "interpretation" and organization of the work [ ] . such achievements that can positively affect patient outcomes are [ , ] : • multidisciplinary outcome-oriented teamwork. the icu staff now goes beyond critical care nurses and doctors, and includes physiotherapists, pharmacists, infectious disease consultants, nutritionists, and psychologists. • implementation of protocols for weaning of patients from mechanical ventilation; sedation; nutrition; glucose control; vasopressor and electrolyte-targeted infusion; patient positioning; and early mobilization/ambulation. • processes of cure and care driven by the "time is tissue" motto (early diagnosis and treatment of critical illnesses produces better patients outcomes). • utilization of continuous renal replacement therapy (crrt) to better manage the intake and removal of fluids during the hyperacute phase of critical illnesses and the later phases, in which there can be the need to remove fluids. • early mobilization of patients to prevent ventilator-associated pneumonia (vap), deep vein thrombosis (dvt), pressure ulcer (pu), and delirium. • increased utilization of clinical risk management tools (incident-reporting systems, morbidity and mortality reviews, and audits). • humanization of icu scenarios through open visiting policies and ethical approaches to the issue of end-of-life (eol) care. • more awareness of the limited (or even absent) evidence for the effectiveness of many therapeutic and interventional options now used in the icu (e.g., albumin, pulmonary artery catheter, tight glycemic control, dopamine). • more awareness of the need to prevent cross-infections and device-related infections. • implementation of the concept of an in-hospital medical emergency team and an outreach team philosophy. • greater understanding of the role of intra-abdominal hypertension and compartment syndrome in multi-organ failure and patient outcomes. • establishment of multicenter and international patient registries for specific pathologies (e.g., trauma, cardiac arrest, etc.), in order to improve quality assurance programs and benchmarking. technology has made great contributions to the availability of monitoring and interventional options, together with providing higher standards of safety for patients, being user-friendly, and, in some cases, with devices being smaller and lighter in weight than in the past [ ] . what about the future of icus? vincent [ ] envisions increases in the number of icu beds relative to the number of hospital beds in other areas, even in a scenario of decreasing costs. the shortage of intensivists could be "compensated" for by computerized or nurse-driven clinical protocols, but the nursing workload would then increase, and nursing staff numbers should be adequate to deal with this increase [ ] . more multicenter and international trials will be performed to test drugs and treatments, offering greater evidences to use in ccm [ ] . furthermore, pharmacological treatments for critically ill patients should be improved through strategies such as [ ] : • selecting samples for research in critically ill populations, taking into account biological and clinical variables • promoting the early administration of drugs during the initial manifestations of diseases and also before the admission of patients to the icu • performing phase trials to test new generic drugs • implementing cell-based therapies and therapies that will enhance the resolution of organ failure. organizational strategies should involve the use of inclusive models, concentrating icu personnel in a few large units, and promoting the concept of centralization to improve patient outcomes and to provide flexible management of healthcare workers [ ] . extracorporeal organ support technologies will be improved [ ] . information technology should cover all the bureaucratic aspects of healthcare work, improving handover, drug prescriptions, and data collection with a network consisting of patient monitoring systems, point-of-care systems, clinical records, and charts [ ] . in addition, computerized systems could provide real-time calculation of staffing needs, based on the nursing workload and patient risk prediction and stratification, improving triage for icu admission and discharge [ ] . this kind of progress could be time-saving and prevent mistakes, and it could also leave more time for doctors and nurses to care for their patients at the bedside [ ] . multidisciplinary rounds should become the norm. patient follow-up post-icu stay could become the source of valuable information employed to direct interventions that recover the patient's quality of residual life and improve the quality of care in the icu [ ] . a better continuum of care between the pre-hospital phase, the emergency care phase, the icu phase, and the post-icu phase should be implemented. at the same time, adequate data collection and analysis models are needed, to accurately evaluate the effectiveness of interventions delivered to patients in the whole healthcare path of the critical illness [ ] . in addition, policies should be drafted to manage increasing demands for critical care beds in the event of maxi-emergencies [ ] . discussing future perspectives in critical care nursing is not a simple issue. however, four main lines of discussion can be addressed: priorities in critical care nursing research, holistic care and humanization of care issues, specific populations of icu patients requiring competent and expert nursing care, and icu nurses' preparedness during outbreaks of emerging infectious diseases. across (and beyond) all the above considerations, this chapter will provide an overview of current and more meaningful issues for critical care nursing, noting the areas that require particular consideration and further investigation. nursing research plays a central role in scientific production, increasing the disciplinary body of knowledge. the main problems related to research in critical care settings are related to the small sample numbers and the large number of variables that are difficult to control. moreover, research findings are not simple to retrieve. hence, some large nursing associations, such as the american association of critical-care nurses (aacn) and the european federation of critical care nurses associations (efccna), have promoted the identification of priorities in nursing research and are developing international networks to support multicenter designed studies. according to an american professional task force, priorities in critical care nursing research should be oriented toward [ ] : • development of methods for fast recognition of acute patients at high risk of rapid deterioration • minimally invasive organ support technologies • new approaches to enhance patient comfort while reducing changes of consciousness • effective process and outcome measurements for critical illness research and palliative and eol care. the areas of nursing interest in healthcare service research should cover [ ] : • strategies to improve communication and coordination of care • tools, processes, and programs to promote knowledge transfer and implementation • factors related to an effective learning environment • strategies for the application of clinical risk management concepts and methods • assessment of the distressing effects of interventions on the patient and their family. on the european side, the efccna, through a delphi study design, has identified research topics in different domains [ ] . the priorities of nursing research in critical care settings noted in that study mainly cover patient safety issues, the impact of evidence-based practice (ebp) and the workforce on patients' outcomes, the comfort/well-being of patients and relatives, and the impact of eol care on staff and their practice [ ] . the five research topics with the highest ranking scores were [ ] : • interventions to reduce nosocomial infections in the icu • pain management and pain assessment • exploration of the extent of anxiety, fear, and stress in icu patients, and strategies to reduce their occurrence • prevalence and prevention of critical incidents in the icu (medication errors, adverse events) • impact of the icu nurse-patient ratio on patient outcomes. some authors have also proposed new strategies to increase effectiveness in the production and local dissemination of scientific knowledge, reducing the distance between researchers and clinicians. such strategies involve the "tripartite model," based on synergy among universities, hospitals, and single hospital wards [ ] . the american college of critical care medicine guidelines for support of the family in the patient-centered icu rely on the concept that relatives are essential resources for patients' health [ ] . these guidelines refer to major concepts such as "flexibility," "single-case basis evaluation," and "open icu" [ ] . the open icu philosophy is based on the reduction/elimination of temporal (liberalization of visiting policies), physical (overcoming the imposed barriers to physical contact between relatives and patients), and relational restrictions (trust-based relationship between icu staff and families) [ , ] . this progressive change of view toward a "holistic" approach to the cure and the care of the patient-family as a whole, greatly challenges icu staff [ ] . some authors promote open visiting policies as a standard, as well as promoting the adoption of patient-centered outcomes (not only survival) [ ] . evidence on the influence of programs for the implementation of open icus on patient mortality, length of stay (los), infection risk, and the mental health of patients and their relatives is currently lacking, and the influence of such programs needs to be investigated [ ] . further, the efforts of icu teams to improve the relationship climate inside the icu will require addressing according to the indications arising from the research results. recently, some authors have hypothesized that open icu programs and the presence of family members during cardiopulmonary resuscitation could also play a role in reducing the rates of opposition to organ donation [ , ] . more studies are needed to confirm this hypothesis, introducing important scenarios with potential lifesaving effects for future icu patients [ , ] . animal-assisted therapy (aat) is defined as "the use of human-animal bond to attenuate stress and improve mood" [ ] . aat works on the interaction between humans and pets, with the aim to reduce stress and feelings of isolation and depression [ ] . areas of aat implementation range from simple social well-being to the improvement of language or motor functions [ ] . dogs are the most frequent animals used for aat, although rabbits and cats can also be employed, under the guidance of specially trained teams. adequate procedures that address hygiene guidelines, times of use, and safety measures are needed [ ] . although the introduction of aat inside icus has been referred to in the literature since the early s [ ] and finds enthusiasm among staff nurses [ ] , experience on its implementation in icus is very limited. a preliminary randomized controlled trial (rct) conducted on adult patients with advanced heart failure in the icu showed reductions of cardiopulmonary pressure, neurohormone levels, and anxiety during the visitation of a dog and a volunteer [ ] . another pilot rct study, performed on children (aged between and years), showed that the employment of dog visitations in the immediate postoperative period after general surgery facilitated the recovery of vigilance and activity after anesthesia and significantly reduced the perception of pain [ ] . this fascinating adjunctive therapy needs to be the target of more scientific research, to expand the areas of implementation and produce better evidence of its effectiveness than that currently available. working in an icu is not a simple matter [ ] . the icu work environment is complex, as a result of three different determinants involved: the physical environment, emotional environment, and professional environment [ ] . the physical environment is often challenging for healthcare professionals, generating stress. unfavorable (artificial) lighting, frequent irritating noises (e.g., monitor and device alarms), clumsily placed equipment, narrow patient units, and overcrowding are the main workplace stressors generated by the physical environment [ ] . human factor engineering is a discipline that can provide some solutions to these difficulties, improving work conditions for all members of the icu staff [ ] . the emotional environment in the icu is well portrayed by the metaphor of "a continuous hot and cold shower" [ ] . the emotional stress for healthcare workers is very high, owing to the high mortality and disability rates, the need for making fast life-or-death decisions, and the need to balance the effort to save lives with the realistic limits of technologies and medical/nursing sciences [ ] . these elements can easily lead to feelings of frustration, exhaustion, and (sometimes) anger, in the personnel, particularly in critical care nurses, because they are the professionals who are always on the frontline at the patient's bedside [ ] . anger, in particular, is an emotion that needs to be adequately addressed before it develops into hostility, aggression, and violence [ ] . some studies have reported that about a quarter of workers in the united states experience anger in the workplace [ ] . it is important for staff to recognize their own trigger points for anger, and to prevent negative feelings and their escalation; strategies that can be used for this are [ ] : • be constructive and practice open listening. • identify the signs and causes of anger. • use calming techniques. • maintain eye contact with the person who has triggered the anger and express genuine concern. • try to understand elements that could resolve the anger. the recent widespread implementation of the "open icu" concept has exposed nurses to additional emotional stressors arising from the family's feelings and needs, because the relatives spend more time in icu, at the patient's bedside. the consequent physical and emotional stress can cause depersonalization and/or avoidance behaviors, exhaustion, burnout, and higher turnover rates in icu personnel [ ] . some proposed solutions rely on teamwork learning programs (with the focus on interprofessional relationships). educational interventions and workshops aiming to provide psychological stress management tools and improve interpersonal social and communication skills have also been recommended [ ] . concerning the professional environment, work satisfaction seems to be the key to the adequate development and expression of positive potential in healthcare professionals. to increase work satisfaction, the icu environment should promote group cohesion, effective communication, autonomy, and supportive management [ ] . when teamwork is not effective, synergistic, and harmonious, burnout and errors can easily arise. burnout is a syndrome characterized by absenteeism, fatigue, reduced personal commitment, and low job satisfaction levels. team training programs and, above all, reduced staff workload can be effective in increasing work satisfaction levels, preventing the above-mentioned negative consequences [ ] . it has been found that most icu staff share the same definition of interprofessional work, that includes concepts as "shared team identity, clarity, interdependence, integration, and shared responsibility." [ ] nevertheless, except for critical events, the most common work interactions developed in the icu are synthesized as collaboration (interactions related to specific questions), coordination (working in parallel), and networking (acquiring skills and expertise, and consultations with others) [ ] . nurses and other icu team members are often frustrated by doctors not listening to them [ ] . it has been reported that the only event in which an icu staff acts as a team is during an emergency code. such behavior is well known in crisis resource management, but this behavior fails to be shown in daily practice and workflows [ , ] . therefore, the only way for the multidisciplinary icu team to achieve better outcomes is to develop a high level of trust, improve communication and discussion, and share clear and structured clinical and organizational information [ ] . currently, some authors recommend that future research be focused on the mechanisms that drive learning and interactions in the icu team, seen through the "magnifying lens" provided by the social sciences (organizational behavior, anthropology, and network science), taking into account that the composition of the icu team can vary largely from one shift to another [ ] . during the past years, the aacn has recognized the positive influence of healthy work environments on nursing staff outcomes and retention [ ] . the aacn has identified and promoted six standard elements that define a work environment as "healthy": "skilled communication," "true collaboration," "effective decision-making," "appropriate staffing," "meaningful recognition," and "authentic leadership" [ ] . despite the efforts of the aacn to disseminate these standards and improve nursing workplace environments, the results of two surveys, performed years apart, showed only a marginal improvement in communication [ ] . when icu nurses were surveyed in regard to the elements that provided them with work satisfaction, they responded that the main elements were related to nursing unit management; the relationships with and the organization of medical staff; rostering practices; nurses roles in icu patient care; and general relationships in the workplace [ ] . nurses and physicians are the two main professionals driving the workflows inside the icu. the relationships between the two professional groups are influenced by three components of the icu workplace environment, their specific roles, differences in expected patient outcomes, and levels of stress and workloads. therefore, conflicts between these two professional groups are not rare. however, to better understand this phenomenon, it is necessary to differentiate vertical conflicts (nursesdoctors) from internal conflicts among nurses (horizontal conflicts). a large multicenter study reported that % of conflicts within the icu team were nurse-physician conflicts, being the most common types of struggles within the icu team [ ] . hostility and lack of communication were the main causes of the conflicts [ ] . most conflicts arise around two main issues: eol decisions and communication matters [ ] . conflicts about eol decisions are one of the most important causes of moral distress in nursing staff, with profound effects on the workplace climate [ ] . disagreement with postoperative goals of care is another important cause of conflict between physicians and nurses [ ] . the need to keep relatives adequately informed about patients' conditions can also cause some tension between icu staff nurses and doctors [ ] . further, many nurse-physician conflicts emerge from procedural factors (related to team processes), organizational factors (related to the local unit or hospital), contextual factors (legal, social, and cultural features), relational factors (variables influencing the social relationship) [ ] , and, probably, anthropological factors (the idea of nursing as an oppressed discipline) [ ] . a simple but effective intervention to improve communication between icu nurses and doctors could be the introduction of a multidisciplinary daily round and daily planning of activities, to share objectives and desired clinical outcomes [ , ] . after a conflict has happened, the best strategy is to try first to resolve the problems with the individuals, taking the discussion back to the real subject of the conflict (often the patient or the organizational problem) and depersonalizing the situation [ ] . unprofessional, offensive, or unsuitable behaviors should not be tolerated by a team that has common shared values and should be referred to the internal disciplinary authority [ ] . to really understand the "internal world" of the "nurses' tribe" in depth (these anthropological terms can be used to describe the characteristics of nurses' relationships), one has to observe nurses' particular positive and negative internal relationship dynamics. nurses colleagues show strong bonds, forged by the unique, intense, and emotional challenges shared daily at their patients' bedsides. the shared experiences of their patients' pain, suffering, and death, as well as shared experiences of hope and healing, can bond nurses to their colleagues at deeper levels than those seen in other professions. but, similarly to the strong attachments between nursing colleagues, internal conflicts among nurses can be fierce. horizontal violence (hv) is one of the terms used for behaviors ranging from verbal and emotional abuse to physical violence perpetrated by workers against their peers inside an organization [ ] . the reported prevalence rate of this phenomenon among nurses ranges widely, from . [ ] to . % [ ] and is associated with important psychosocial [ ] and professional consequences. symptoms of posttraumatic stress disorder (ptsd) have been reported in nurses, and high rates of job leaving are recorded in those with shorter lengths of service [ ] . moreover, some authors suppose that there may be a relationship between hv and patient safety, owing to changes in the flows of clinical information among nurses [ ] . various researchers have advanced explanations for the origin and development of hv. the "oppressed group behavior theory" [ ] , interpersonal, intrapersonal, evolutionary, and biological models offer different views about the emergence of this phenomenon [ ] , but, currently, none of these models has been completely validated. the key elements of these theories and models are [ , ] : • "lack of self-esteem" • "generational and hierarchical abuses" • "actor-observer effect" • "nursing as an oppressed discipline" • "working practices depriving rights/privileges" • "aggression leading to aggression" and "development of cliques". despite the high rates of the hv phenomenon and the perceived relevance of its effects by nurses, the solutions proposed have been limited to position statements [ ] and guidelines [ ] released by some nurses associations, as well as ideas on team building [ ] and self-esteem augmentation [ , ] , education programs, and an educational tool-kit to identify and resolve workplace bullying and harassment [ ] . interventional studies of solutions (e.g. the implementation of zero tolerance policies [ ] ) are lacking. hence, there is a need to focus nursing research on hv prevention, because it is difficult to eradicate the problem once it becomes part of the structure of a group. during the delivery of care, critical care nurses should pay attention to the particular features appropriate to specific patient populations, as shown in the framework summarized in fig. . . recent epidemiological data has shown that about . billion people worldwide are obese (i.e., have a body mass index [bmi] higher than kg/m ), with an increasing trend [ ] . the fight against this harmful condition requires powerful prevention programs, and such programs need political commitment [ ] . morbid obesity (bmi > kg/m ) is a condition affecting about . % of the united states population (data from ) [ ] . morbid obesity is often associated with potential complications in the icu, such as difficult airways and/or ventilation, and challenging peripheral and central venous access [ ] . frequent comorbidities are obstructive sleep apnea, diabetes, insulin resistance, low levels of vitamin d, hyperlipidemia, and hypertension [ ] . moreover, respiratory and cardiovascular impairments can be frequent, both seen with a chronic inflammatory state. in particular, the respiration of these patients can be affected by increased work of breathing and chest wall resistance and high chest wall resistance, increased intra-abdominal pressure, co production, and oxygen consumption, and the possibility of muscle weakness [ ] . cardiovascular impairment can be caused by increasing levels of circulating blood or co , risk of heart failure and dysrhythmias, hypertrophy, and other myocardial structural alterations [ ] . additionally, hypercoagulability and late wound healing can be expressions of metabolic changes due to obesity [ ] . lastly, the pharmacokinetic and pharmacodynamic characteristics of most drugs can change in these patients [ ] . currently the association between higher bmi class and patient outcomes in icus is still controversial ("obesity paradox") and requires more accurate comparisons between the obese bmi classes and "normal" bmi subjects [ , ] . however, bmi calculation alone is not sufficient to stratify patients, since it does not take into account differences in body composition (adipose tissue, lean tissue, body fluids) [ ] . from the logistical and nursing care points of view, morbidly obese patients present challenges for bed and stretcher weight limits and dimensions, and for patient repositioning and transfers. standard hospital beds can bear weights of up to - kg, but morbidly obese patients are often beyond these body weight limits [ ] . sometimes radiological examinations cannot be performed, owing to the limits of radiological stretchers. standard radiology beds can hold weights of - kg, while in patients over these weight limits, the performance of a computerized tomography (ct) scan or magnetic resonance imaging (mri) can require special equipment (beds bearing a weight of up to kg for ct and up to kg for mri) [ ] . all this information is useful for planning the nursing and medical care of these patients, considering the complex physiopathological, logistical, and safety factors that characterize their stay in critical care units. airway management can be very difficult. the "ear-to-sternal notch positioning" (so-called ramped position) can improve the management of intubation in these patients, when there is no suspicion of cervical spine injury. this position can be obtained by rolling layers of bedsheets under the patient's shoulders, until the back elevation reaches the desired alignment [ ] . ventilation can be improved using the "beach chair" position or anti-trendelenburg position at °. these solutions allow better diaphragmatic excursion and prevent the risk of microinhalation. in morbidly obese patients, the supine position and trendelenburg must be avoided because of the risk of "obesity supine death syndrome" [ ] . during mechanical ventilation (mv), tidal volume according to ideal body weight (ibw) should be used, since the size of the lungs does not depend on the real body weight of the patient. also, for these patients the limit of cmh o for plateau pressure has to be respected to prevent ventilator-associated lung injury [ ] . it is sometimes difficult to insert vascular catheters in morbidly obese patients. echocardiographic insertion techniques are greatly limited owing to the large stratification of adipose tissue [ ] . so arterial and venous catheters are often maintained in place for a longer time than recommended, exposing patients to a high risk of infection and other kinds of complications [ ] . hypocaloric nutrition is indicated in obese patients. in the higher bmi classes, the aim is to reach - % of the patient's energy requirements. protein supply in patients with bmi ≥ should be ≥ . g/kg of ibw, except for those with renal failure [ ] . some pharmacological considerations should also be taken into account. reduced peak serum levels and increased clearance time can be recorded for lipophilic drugs [ ] . the doses of highly lipophilic medications should be calculated according to the real weight, while the doses of minimally lipophilic medications should be calculated according to the ibw. increased creatinine clearance in obese patients can reduce the levels of medications excreted by the kidneys [ ] . altered absorption through intramuscular, intradermal, and subcutaneous pathways is typical in obese patients [ ] . beyond preventing the deterioration of vital and organ functions, nursing care has to be directed toward the provision of adequate staff numbers, special beds, and equipment to facilitate patients' repositioning and early mobilization, with particular attention paid to the development of "traditional" pu and device-related pu [ ] . finally, during their clinical practice, critical care nurses need to pay attention to aspects related to the emotional support needed by obese patients and the social stigma they experience, as obesity still has a negative social connotation. indeed, some stereotypes and prejudices portray obese persons as being shorttempered and nasty [ ] . verbal and emotional abuse of obese patients perpetrated by healthcare workers has been reported in the literature; it is mandatory for healthcare workers to avoid behaviors that blame patients who are unable to control their unhealthy or excessive eating habits [ ] . the percentage of the world's population aged over years has increased from % in to % in , and in the percentage is projected to be up to %, with a large proportion of people over years old [ ] . older people (aged over years) admitted to icus are the subject of complex ethical debates related to poor outcomes and the poor quality of residual life after intensive care [ ] . moreover, interest in financial issues has emerged in recent years (especially owing to the worldwide economic crisis), since medical costs rise exponentially in people older than years [ ] . another factor is that, in any kind of patient, deciding to withdraw treatment and organ support is surely more difficult than deciding to apply some kind of advance care directive (such as "do not resuscitate", or do "not intubate" orders). therefore, discussions about the ways to offer and employ intensive care support in elderly patients are influenced by ethical, cultural, and political variables, and such discussions are far from ended [ ] . in a recent canadian multicenter prospective cohort study, conducted by heyland et al. [ ] on patients ≥ years old admitted to icus, the mortality rate in the icu was % and the in-hospital mortality was %. patients died at a median of days after icu admission. no predictors for prolonged time of intensive care support were found by the authors [ ] . frailty indexes or advance care directives had little influence on the decision to limit life-support measures [ ] . many other studies have shown a mortality trend of over % to years after hospital discharge in very old icu patients [ ] . heyland et al. [ ] , studying recovery after a critical illness in patients aged ≥ years, found that % of the surviving patients achieved physical recovery months after hospital admission. physical recovery was significantly associated with younger age, lower acute physiology and chronic health evaluation ii (apache ii) score, lower charlson comorbidity score, and a lower frailty index [ ] . comorbidities in older patients probably play an important role in survival rates and quality of life (qol) after intensive care [ ] . to improve the care of these frail patients, professional integration between intensivists and geriatricians is recommended [ ] . more research in older patients is needed to explore care, life-sustaining therapies, eol problems, icu effectiveness, and qol after a critical illness [ ] . critical care nursing in older patients should take into account these patients' comorbidities, with the frequent presence of chronic diseases such as diabetes, chronic obstructive pulmonary disease, congestive heart failure, and end-stage renal disease. another typical complication seen in this population is "geriatric syndromes," including pus, incontinence, falls, functional decline, and delirium [ ] . the other big issue in the aging population is the concept of frailty. frailty, a condition that arises owing to reduced physiological and sensorial/cognitive reserves, typically in older people, plays an important role in the occurrence of adverse events and outcomes [ ] . some authors, in discussing the consequences of nursing care in critically ill older patients, have pointed out new challenges, such as environmental modifications, the need for education and training in healthcare staff, changes in their own professional attitudes, and collaboration with experts in geriatrics [ ] . functional assessment and awareness of existing medications are two key elements on which a nursing care plan should be based, also providing an "after icu perspective" to critical care nursing [ ] . critical care nursing assessment of vulnerability in frail elderly patients should be multidimensional [ ] . physiological assessment is directed toward the patients' sensorial status, level of mobility, and chronic pathologies. psychological assessment should focus on the identification of cognitive changes, dementia, and psychiatric conditions. lastly, an evaluation of social conditions and social supports is needed [ ] . the data collected can help critical care nurses to plan adequate strategies for the prevention of complications and for the support of older patients in the icu and to draft personalized discharge planning [ ] . common negative events that should be prevented in these patients are falls, abuse, malnutrition, hypothermia, depression, fear, low levels of self-care, and loss of autonomy [ ] . historically, the presence of psychiatric disorders in icu patients was not well recognized or well managed [ ] . only in recent times has this trend been reversed. the most frequent psychiatric clinical problems in icu patients are delirium, anxiety-panic-agitation loop, depression, psychosis, and persecution ideation [ , ] . the causes of these problems are mainly metabolic and electrolyte disorders, infections, head injuries, withdrawal syndromes, and vascular conditions [ ] . the high level of stress during an icu stay can itself be the source of a patient's psychological impairment [ ] . according to some authors, certain environmental variables trigger the establishment of these conditions. high sound levels and loud noises, lack of sleep and rest, impairment of circadian rhythms, procedure-related pain, and in intubated patients, the impossibility of speaking, are typical features of the icu environment [ ] . care efforts should be oriented toward [ , ] : • maintaining patients in single icus. • guaranteeing low levels of technological noise and quiet voices. • providing calendars, clocks, and other tools for patients' time and space orientation. • improving the quality of the patient's sleep and rest and reducing light levels at night. • promoting relatives' visitations and contact with patients. • establishing an empathetic relationship with patients (and their relatives). early physical rehabilitation plays a fundamental role in the prevention of conditions such as delirium [ ] . for patients who survive after icu admission and a hospital stay, ptsd symptoms are frequent and very disturbing [ ] . however, except for delirium, the other psychiatric disorders noted above are rarely considered by staff nurses in the icu. nurses have to be aware of the importance of promptly recognizing psychiatric emergencies, which can sometimes be deadly [ ] . psychiatric emergencies can be related to overdoses of psychotropic medications, but are not limited to overdosing [ ] . in fact, the withdrawal or interruption of drug treatment can be the cause of a psychiatric emergency [ ] . delirium, drug toxicity, uncontrolled schizophrenia, agitation, and suicidal attempts are typical psychiatric emergencies [ ] . common psychiatric emergencies in the icu are agitated delirium, overdose of psychiatric medication, neuroleptic malignant syndrome, and serotonin syndrome [ ] . often non-specific signs and symptoms, such as tachycardia, diarrhea, fever, and seizure, can hinder the rapid recognition of these emergencies [ ] . almost all of the above-mentioned psychiatric emergencies in the icu require treatment with specific medications, and quick action by nurses [ ] . although deaths caused by oncological illnesses have diminished since the s, cancer is still the second most common cause of death, after heart illnesses, accounting for % of deaths in the united states [ ] . recent estimates from europe, for , indicated . million new cases of cancer and . million deaths caused by the disease [ ] . icu admission criteria for patients with cancer have changed over the years, from an approach excluding "do not resuscitate" patients to offering the chance to recover from an acute on chronic event owing to the illness or the toxic effects of pharmacological treatments [ ] . traditional oncology emergencies requiring icu treatment are currently treated in oncology or medical-surgical units [ ] . these emergencies, owing to the illness or its therapy, are, mainly, tumor lysis syndrome, superior vena cava syndrome, and malignant spinal cord compression [ ] . currently, oncological complications requiring assessment and support in the icu are cardiac and respiratory failure, severe bleeding and coagulopathies, and sepsis [ ] . specifically, these complications can be pneumonia, venous thromboembolism, ards, pulmonary toxicity associated with chemotherapy and radiation, malignant pericardial effusions, heart failure, dysrhythmias, prolonged qt syndrome, gastrointestinal bleeding, disseminated intravascular coagulation, sepsis, and hypersensitivity reactions [ ] . admitting cancer patients to the icu makes sense for improving short-term survival rates after a critical care illness [ ] . furthermore, some recent general achievements and progress in icu use support the admission of these patients; such items are: more "open" admission policies, niv, diagnostic strategies in acute respiratory failure, treatment of acute renal failure, blood component transfusion policies, diagnostic strategies in neurological complications, and treatment of organ failure in macrophage-activation syndrome [ ] . however, cancer patients can also die in the icu. the qol of oncology patients who die in an icu seems to be worse than that of patients who die in a hospice or at home [ ] . moreover, relatives of oncology patients who have died in an icu can be affected by symptoms of ptsd [ ] . one big challenge to the implementation of high-quality eol care in the icu is to incorporate palliative care early in the care plan [ ] . palliative care aims to relieve symptoms and pain related to the treatment and the illness and to take into account the spiritual and psychological spheres of the patient and his/her relatives, independently of the severity and progression of the illness [ ] . there are some hindrances to the implementation of eol care in the icu [ ] : • mission of the icu (lifesaving and restoring patients' qol) • culture of the icu (death-denying and difficult-to-manage communication on prognosis) • goals of the icu (technology-oriented to implement lifesupport treatment, relegating the holistic approach to a low priority) • environment of the icu (an open space is a more frequent architectural configuration than a single patient rooms unit) • competing priorities for nurses' time (dying patients considered a low priority; difficulties in managing the relatives' needs and requests for information about their loved ones). a key element in eol care in the icu is the nursing management of symptoms of discomfort and pain. often these patients are treated with all the organ support that the icu can offer (mv, hemodynamic pharmacological support, crrt, artificial nutrition, etc.) [ ] . moreover, large numbers of invasive devices are often in place, causing procedural pain, discomfort, and delirium. the most frequent symptoms presented in these patients are dyspnea and pain [ ] . the withdrawal or withholding of organ-or life-support treatments is complex, and often a long time is required for making the decision, with the involvement of the patient, the healthcare professionals, and relatives (as proxy decision-makers) [ ] . at the same time, there are important implications of such decisions, related to ethical debates and influenced by religion, national culture, and national laws. however, the key to the successful implementation of oncology patient care in the icu can only be a real commitment to interprofessional collaboration among nurses, doctors, palliative care and oncology specialists, cultural-linguistic mediators, and spiritual care providers [ ] . without adequate information, meaningful collaboration, and realistic goals of care for the patients, the risk of moral distress for critical care nurses is quite elevated [ ] . in [ ] . an outbreak is defined as "a sudden increase in incidence compared with the "normal" morbidity rates for any certain disease in a given area" [ ] . the consequences of the "sudden" features of an outbreak can be disruptive, causing chaos, panic, and insecurity. increasing levels of stress and anxiety related to work can be experienced by healthcare personnel. in some extreme cases, inadequate preparedness for a disease outbreak can lead to hospital closure [ ] . the term "outbreak" can also refer to the cross-transmission of multiresistant microorganisms inside hospital wards (e.g., acinetobacter baumannii and clostridium difficile), as well as referring to pandemic or epidemic diseases (e.g., sars, h n reaction to a disease outbreak in the icu must be twofold: increasing the competencies and skills of the icu staff in disease management and implementation of safety measures to contain the spread of the infection, as well as implementing adequate isolation procedures [ ] . education and training about infection control for critical care nurses should include [ ] : • training modules about the fundamentals of quarantine and isolation, routes of infection transmission, and infectious disease prevention and control • basic pediatric intensive care protocols • high-fidelity simulation of the management of high-risk and complex scenarios • debriefing and teach-back models • certification of the successful completion of education, and annual recertification. however, the key to reaching a safe and optimal care setting depends on the availability of a robust hospital epidemiology program [ ] . many microorganisms responsible for recent outbreaks of viral infections can be deadly, not only for patients (even when they receive the best care) but also for the healthcare staff. for infectious diseases transmitted through respiratory droplets, the icu is a high-risk setting, owing to the performance of aerosol-generating procedures (suctioning, intubation, niv, and bronchoscopy). patients needing multiple procedures pose a high risk of contamination for healthcare staff [ ] . the ebola virus outbreak has set a new standard of infection control precautions (maximum isolation). together with contact, droplet, and airborne precautions (table . ), the need to prevent accidental exposure of all body surfaces emerged, with the provision of adequate protective clothing. furthermore, a dedicated staff member, present as a trained observer, directly puts on and takes off the protective clothing and equipment from the care personnel to reduce the risk of mistakes and self-contamination [ ] . lastly, suitable protocols are needed to disinfect the care environment and to manage infected waste, and, in some cases, the architectural design of hospital areas has been modified [ ] . currently, the employment of full protective body suits and powered air-purifying respirators is mandatory for the care of patients infected by ebola, mers-cov, and sars-cov [ ] . this kind of equipment requires high standards of training and periodic retraining [ ] . achieving an optimal level of proficiency in donning and removing the personal protective equipment for this kind of infective threat is critical. studies have been performed comparing the effectiveness of different training programs for the management of full protective body suits [ ] . however, there are still debates about the actual adequacy and effectiveness of the protective equipment used in the prevention of ebola transmission [ ] . the special training should be conducted while the critical care nurse is performing invasive procedures typical of critical care settings: intubation, mv (closed-system endotracheal tube suctioning and placement of a bacterial filter on the expiratory side of the ventilator circuit) [ ] , venous access introduction (ultrasound guided), crrt, and bedside imaging, with the nurse using the full protective equipment in a high-containment unit (negative-pressure room) under biosafety level - isolation conditions [ ] . working inside a high-containment unit requires the nurses to place their own safety before the patient's needs, to move slowly, to pay great attention to sharp objects, and always to think before acting [ ] . all the nursing care and procedures should be performed in pairs: one nurse cares for the patient and the other checks for breaches in personal protective equipment, disinfects the environment, and manages the waste appropriately, covering all the containers to avoid splashing [ ] . training programs also have to cover some important psychological features of this kind of nursing care: fatigue, fear, a sense of impotence, and the social consequences of the risks the nurses are exposed to. in regard to the prevention of disease transmission, each institution should draft protocols for the management of laboratory tests, the handling of biological specimens, and imaging testing. surgery and specialist consultations should also be considered in the safety management procedures. lastly, the healthcare teams that will provide care for these high risk infected patients should be previously assigned, on either a voluntary or an obligatory basis [ ] . take-home messages • in future icus will probably see increases in the number of icu beds relative to the number of beds in the rest of the hospital and the staff shortages could be "compensated by" computerized and/or nurse-driven clinical protocols. more multicenter and international trials will need to be performed, and pharmacological treatments for critically ill patients should be improved through various strategies. • priorities in critical care nursing research are: the development of methods for the rapid recognition of acute illness in high-risk patients; new approaches to enhancing patient comfort while reducing changes of consciousness; effective process and outcome measurements for critical illness research and palliative and eol care; focus on patient safety issues; the impact of ebp and the workforce on patient outcomes; the comfort/well-being of patients and their relatives; the impact of eol care on staff and nursing practice. • critical care nursing should, in particular, take into account the special needs of different patient populations, such as oncology patients, elderly patients, morbidly obese patients, and psychiatric patients admitted to the icu. • forthcoming and highly challenging issues for icu nurses are those related to critical care management during outbreaks of emerging infectious diseases. thirty years of critical care medicine critical care -where have we been and where are we going? critical care: advances and future perspectives organizing critical care for the st century new strategies for effective therapeutics in critically ill patients critical care societies collaborative/usciitg task force on critical care research. multisociety task force for critical care research: key issues and recommendations research priorities of adult intensive care nurses in european countries: a delphi study the priorities in the nurse research in critical care clinical practice guidelines for support of the family in the patient-centered intensive care unit: american college of critical care medicine task force open intensive care units: the case in favour the "open" icu: not just a question of time open intensive care units: a global challenge for patients, relatives, and critical care teams critical care in the near future: patient-centered, beyond space and time boundaries family presence during cardiopulmonary resuscitation could make more natural organ donation open visiting policies in intensive care units may not affect consent to organ donation nonpharmacological interventions to manage common symptoms in patients receiving mechanical ventilation what criteria should be used for pet therapy in critical care? are you aware of any hospitals doing this? animal-assisted therapy in the intensive care unit. a staff nurse's dream comes true animal-assisted therapy in patients hospitalized with heart failure post-operative benefits of animal-assisted therapy in pediatric surgery: a randomised study the intensive care unit work environment: current challenges and recommendations for the future suggestions for handling anger in the workplace beyond the team: understanding interprofessional work in two north american icus teamwork in the icu-do we practice what we preach? teamwork in the icu: from training camp to the super bowl the nurse leader's role in supporting healthy work environments the healthy work environment standards: ten years later what makes a good intensive care unit: a nursing perspective prevalence and factors of intensive care unit conflicts: the conflicus study resolving communication challenges in the intensive care unit understanding nurse-physician conflicts in the icu the strange and conflicting world of nursing lateral hostilities among nurses employed in intensive care units, emergency departments, operating rooms, and emergency medical services. a national survey in italy work-related factors and violence among nursing staff in the european next study: a longitudinal cohort study workplace bullying: a systematic review of risk factors and outcomes bullying of staff registered nurses in the workplace: a preliminary study for developing personal and organizational strategies for the transformation of hostile to healthy workplace environments horizontal violence and the quality and safety of patient care: a conceptual model oppressed group behavior: implications for nursing bullying, harassment, and horizontal violence in the nursing workforce. the state of the science the effect of oppressed group behaviours on the culture of the nursing workplace: a review of the evidence and interventions for change a literature review of conflict communication causes, costs, benefits and interventions in nursing behaviors that undermine a culture of safety standards for establishing and sustaining healthy work environments. a journey to excellence lessons learned from a lateral violence and team-building intervention undergraduate nursing students' level of assertiveness in greece: a questionnaire survey irish nursing students' changing self-esteem and fear of negative evaluation during their preregistration programme dealing with bullying and harassment at work-a guide for rcn members eliminating lateral violence in the ambulatory setting: one center's strategies rethinking and reframing obesity preface: obesity identifying obstacles for the obese trauma patient obesity in critical illness: what weight or why weight? critical care management of obese patients bariatric patients in emergency department: a challenge for nursing care the very old icu patient: a neverending story very elderly patients in the icu: should there be a line in the sand? elder care in the icu: spin bravely? the very elderly admitted to icu: a quality finish? recovery after critical illness in patients aged years or older: a multi-center prospective observational cohort study geriatric trauma: a clinical and ethical review care of older people in critical care: the hidden side of the moon vulnerability of older patients in critical care psychiatric disorders in intensive care units psychiatric issues during and after intensive care (icu) stays treatment of four psychiatric emergencies in the intensive care unit psychiatric emergencies in the intensive care unit providing a "good death" for oncology patients during the final hours of life in the intensive care unit cancer incidence and mortality patterns in europe: estimates for countries in caring for the critically ill patient with cancer oncologic emergencies: new decade, new perspectives intensive care of the cancer patient: recent achievements and remaining challenges the meaning of our work: caring for the critically ill patient with cancer critical care in resource-restricted settings a review of critical care nursing and disease outbreak preparedness task force on management and prevention of acinetobacter baumannii infections in the icu adapt or perish -a relentless fight for survival: designing superbugs out of the intensive care unit critical care medicine after the - ebola outbreak: are we ready if it happens again? personal protective equipment for the ebola virus disease: a comparison of training programs uncertainty, risk analysis and change for ebola personal protective equipment guidelines caring for the critically ill patient with tuberculosis ebola at the national institutes of health: perspectives from critical care nurses key: cord- -p q f c authors: nan title: posters_monday_ october date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: p q f c nan a huge variability in excess risk of death, ranging from to %, from ventilator associated pneumonia (vap) have been reported in the literature [ ] . this large between-study variation can be attributed to difference in definitions but also to incorrect estimation by standard statistical methods, i.e. inappropriate adjustment for informative censoring and time dependent confounders. the aim of this study was to take into account above statistical shortcomings and to assess the excess risk of vap by using an extension of a recently developed techniques from the field of causal inference [ ] . materials and methods. data was retrieved from a large longitudinal, high quality multi-centric icu database from france (outcomerea). a random sample of consecutive patients ventilated [ h from icus over a year period were included. vap was defined as clinical suspicion plus at least one positive proximal or distal sampling with quantitative count using classical thresholds. only the first vap episode was taken into account. we considered discharge from the icu as a competing risk and estimated the attributable -day icu mortality of vap by comparing the counterfactual cumulative incidence of death for the entire population under different hypothetical infection paths. baseline characteristics indicating underlying co-morbidity and longitudinal (daily measured) severity of illness indicators together with all other known confounders until vap developed were taken into account through the use of a marginal structural model [ ] . results. a total of , icu patients were included. mean (sd) age and saps ii score were ( ) and ( ), respectively. seventeen and % were admitted after scheduled and emergency surgery respectively, % were medical patients. forty-two percent had an underlying chronic illness (knaus). nine percent received dialysis in the icu. a total of ( %) patients developed vap within days of admission ( and % within and days, respectively). crude icu-mortality rates in patients with and without vap were and %, respectively. when taking into account all the confounders, we found a . % increase ( % ci . - . , p = . ) in the hazard of -day icu-death per additional day since the development of vap. provided vap could have been prevented in the whole population -day mortality would have decreased by . %. conclusion. the excess risk of death from vap estimated by marginal structural models is lower than commonly reported in the literature. this indicates that underlying comorbidities and the evolution of severity of illness until vap are insufficiently taken into account by current standard statistical methods. reference (s) . . rello et al ( ) introduction. the intensive care society (uk) has recently published national guidelines regarding many aspects of percutaneous tracheostomy management [ ] , however, these guidelines do not make any recommendations regarding antibiotic prophylaxis during the procedure. we recently audited uk practice and have established that only % of the units give prophylactic antibiotics for patients known to be colonised with methicillin-resistant staphylococcus aureus. the low rate of antibiotic use is surprising given that pneumonia and/ or bacteraemia following pt is frequently caused by organisms (non-mrsa) that colonise the patients' skin and/or airway [ , ] . objective. to establish the incidence of mrsa positive sputum and/or blood cultures following pt in patients colonised with mrsa in their nose or throat. methods. we audited all the patients who had pt performed between and who were known to be colonised with mrsa in their nose or throat, (but who had negative sputum cultures) before pt was undertaken. we wanted to find how many of these patients developed mrsa positive sputum and/or blood cultures in the first week following their pt. results. from a total of patients admitted to critical care between and only seven mrsa colonised patients required pt. all of these patients had mrsa colonised throat or nose with negative sputum and blood cultures prior to the pt. no patients were given prophylactic antibiotics during the pt as this was our standard practice. four ( %) developed mrsa positive sputum cultures in the first week following the procedure. one ( %) developed mrsa bacteraemia on day following pt. over the same period there were no case of mrsa bacteraemia in the mrsa colonised patients who did not undergo pt. microbiology bacterial biofilm has been observed in the surface of the endotracheal tube (ett) in mechanically ventilated patients and recent studies relate the presence of biofilm with the incidence of ventilator-associated pneumonia (vap). acinetobacter baumanii is a gramnegative opportunistic nosocomial pathogen involved in the production of vap, and capable of biofilm formation on abiotic surfaces. objective. to analyse the presence of biofilm in the ett by using scanning electron microscopy (sem) and to identify the microorganisms contributing to its formation in patients admitted in an icu endemic for a. baumanii. methods. from march to september , consecutive patients admitted to our unit and mechanically ventilated were included in the study. etts after extubation were (a) sent to microbiological culture, and (b) fixed with % paraformaldehyde- % glutaraldehyde for one hour, dehydrated with increasing ethanol concentrations, and processed for sem. etts were observed under sem to assess the presence and extension of the biofilm, and to recognize bacterial or fungal forms. results. there were males ( %) and females ( %) with a median age of years (range - ).the median apache ii score in the first h was (range - ). the median duration of intubation was days (range . causes of intubation were coma in patients ( %), respiratory failure in ( %), and heart failure in ( %). the microbiological isolations showed: a. baumanii ( %), staphylococcus non aureus ( %), pseudomonas spp. ( %), streptococcus viridans ( %), staphylococcus aureus ( %), enterococcus faecalis ( %), candida albicans ( %), and others ( %). under the sem, biofilm was identified in the % of all cases and was abundant in ( %), regular in ( %), and scarce in ( %). morphological identification of microorganisms observed under sem showed: cocci in ( %), bacilli in ( %), and yeast in ( % introduction. hospital-acquired infection is often linked to the standard of ward cleaning however the impact of increased quality of cleaning and deep cleans are unknown. objectives. this study aimed to determine the effect of enhanced cleaning on local contamination rates of hospital pathogens and whether this results in a reduction in patient colonisation. a cross-over one-year study was performed in the intensive care units (icu) of two teaching hospitals, which screened patients weekly for mrsa. in randomized two-month periods and in addition to conventional cleaning using detergent and mops, high contact areas were cleaned twice daily by a team of trained hygiene technicians using microfibre cloths. using contact plates, samples were taken at nine sites around the bed area and ward over bed-days per week. hand hygiene was encouraged and compliance audited. results. only . % of the planned , local samples were missed and this was equal between study phases. average hand hygiene compliance was similar between enhanced and standard phases [hospital a . % ( / ) vs. % ( / ) and hospital b . % ( / ) vs. . % ( / )]. patient characteristics were similar during standard and enhanced cleaning periods. of the sites tested, samples taken from bed rails were most likely to be contaminated with mrsa (or = . ; % ci: . - . ) followed by nurses' hands (or = . ; % ci: . - . ). analysis of these site-samples also confirmed that enhanced cleaning significantly reduced environmental contamination (or = . ; % ci: . - . ; p \ . ). the effectiveness of enhanced cleaning in removing mrsa contamination did not vary with the sample site. a sub-group analysis of samples only taken from nurses' hands showed a non-significant reduction in mrsa hand contamination associated with enhanced cleaning although associated uncertainty was large (or = . ; % ci: . - . ; p = . conclusions. this is the first prospective controlled study examining the effectiveness of enhanced cleaning in preventing spread of multiresistant pathogens within icu. although both environmental and hand contamination were reduced, enhanced cleaning of high contact surfaces was not associated with a reduction in cross infection. conclusions. isd of secretions reduces the incidence of vap in patients receiving. css alone, or in combination with isd has no significant effect on incidence of vap. hence, isd may be recommended for vap prevention, considerations other than prevention of vap should determine the choice of the suction system in a mechanically ventilated patient. to show a mortality benefit, larger, multi-center trials may be required. decreasing incidence of ventilator-acquired pneumonia (vap) is increasingly regarded as a priority in icu quality programs. subglottic secretion suctioning (sss) has been associated with a decreased risk of vap. a previous metaanalysis concluded that sss reduces the risk of vap, but it included only five randomized controlled trials (rct), and sss is still underused, perhaps considering the available evidence is insufficient. we planned a systematic review and metaanalysis of sss for vap prevention. pubmed, embase and cdsr were searched for rct studying the influence of sss on vap incidence. additional outcomes were mortality (within icu or hospital), icu and hospital stay, mechanical ventilation duration and time from intubation to vap diagnosis. additional references and sources of information were searched, and authors were contacted as necessary. rct were found, but one of them was excluded for not having enough data for analysis. rct were analysed, including , patients. quality of the rct was only moderate. qualitative outcomes were homogeneous between studies, so were analysed by a fixed effects model; quantitative outcomes were very heterogeneous, and were analysed by a random effects model. compared to control, sss decreased vap incidence (rr . ; % ci . - . ), but not mortality (rr . ; % ic . - . ). sss delayed vap onset for . days ( % ci . - . ), shortened mechanical ventilation for . days ( % ci . - . ) and decreased icu length of stay for . days (ic % . - . ). in two rct, no differences were found in the hospital length of stay. conclusion. sss reduces vap incidence and delays vap onset, shortening mechanical ventilation and icu length of stay, but not decreases icu or hospital mortality. data from rct support the use of sss as an adjunctive tool to prevent vap. introduction. in comparison to ventilator-associated pneumonia (vap), less data are available on ventilator-associated tracheobronchitis (vat). however, vat may be associated with considerable morbidity [ ] . aim. to investigate prospectively the incidence and outcomes of vat. we studied prospectively all patients who received mechanical ventilation in the general intensive care unit of a tertiary hospital in greece between september-november . vat diagnosis required temperature ([ °c) or leukocyte count [ . per ml or leukopenia \ . per ml) (at least one of these) plus new onset/change of purulent endotracheal secretions. vap diagnosis required the aforementioned criteria plus appearance of new and persistent pulmonary infiltrates on chest radiography. microbiological documentation was based on the growth of microrganisms in bronchial aspirations ([ . cfu) or bal ([ . cfu) . results. forty-six patients were included, median (iqr) age was ( . years. eleven ( %) patients presented vat, presented vap and patients presented none of these two disorders (np). there were no significant differences between vat and vap cases in terms of baseline characteristics (diagnosis, respiratory compliance, apachee, murray score), occurrence of sepsis or ards and microbiology; pseudomonas aeruginosa, acinetobacter baumannii, staphylococcus aureus and klebsiella pneum. were the most common bacteria in both vat and vap. patients who presented vat or vap had significant longer hospitalization and mechanical ventilation duration (days) compared to , ( - ) vs. ( - ), (p = . )] and [ ( - ) , ( - ), ( - ) , (p = . ), respectively]. icu mortality was , , %, for patients with vap, vat and np, respectively (p = . ). conclusions. incidence and microbiological pattern was similar in vap and vap in these case series. both vat and vap were associated with longer hospitalizations and mechanical ventilation duration. further analysis with a larger cohort of patients is required to give conclusive remarks. reference (s) . . nseir s et al ( ) nosocomial tracheobronchitis in mechanically ventilated patients: incidence, aetiology and outcome. eur respir j : - . g. c. choutas , v. g. nolas , a. kalantzi , a. moutzouri , g. k. anthopoulos intensive care unit, \ \ [ [ general air force hospital, athens, greece introduction. endotracheal suctioning is an essential part of care for patients receiving mechanical ventilation, to keep the airways free from bronchial secretions, assuring ventilation and oxygenation. there are two types of suction systems. in the open system, endotracheal suctioning requires disconnecting the patient from the ventilator and introducing a single-use sterile suctioning catheter into the endotracheal tube. closed systems are changed every and h. to determine whether ventilated patients treated with css in an intensive care unit (icu) differ as to airway bacterial colonization and colonization of the suction system based on cultivation of both bronchial secretion and suction catheter tip and if cultivation of suction catheter tip is adequate in place of bronchial aspirate cultivation. methods. patient, incubated and ventilated in the icu ward were studied in a period of one year ( to ) , on admission to the icu a css (trach care mac) was connected. closed multi-use catheters were changed daily. two-pass endotracheal suctioning was performed as needed. ba cultures were obtained on admission and the next day. radiographs taken before, during, and after ba and css cultures were graded for pneumonia and a modified score for vap. of the patients css samples ( . %) and ba samples ( . %) were sterile. airway colonization with gram-negative bacteria and fungi occurred in the majority of the patient . % and gram-positive bacteria in %. cultivation of css revealed gramnegative bacteria and fungi occurrence . % and gram-positive bacteria in . %. with the current sample no significant difference was found between the positive results of trach care tip cultivation and ba cultivation p = . . objectives. to reduce the use of sedatives and to decrease the amount of time spend on a ventilator by specific ramsay-instructions and checks for sedation-protocol-adherence. methods. in april , after introductional lessons to doctors and nurses, we started and collected data for months. a yellow reminder was attached to the medical-instructions-form and doctors were requested to fill in the ramsay-score on a daily basis. once in a week patients and records were screened to assess protocol-adherence. each nurse and each intensive care-unit received feedback on their compliance to the bundle-elements. the total amount of sedatives per month was divided by the number of ventilator days, resulting in an average dose midazolam/propofol per ventilator day. the median and interquartile range of ventilator days/patient was also calculated and all data were compared with the same period in . we accomplished a reduction in the use of sedatives and costs. introduction. ventilator associated pneumonia (vap) often occurs in patients who are mechanically ventilated. the incidence rate varies between and % for patients in the intensive care unit. it has been the second most common hospital-associated infection after that of the urinary tract. the diagnosis of vap is difficult because of different existing definitions. hypothesis. our hypothesis was, that lowering vap incidence rate, could be done by a bundle of five interventions. the purpose of introducing multiple ventilatory interventions as a bundle, was to lower vap incidence rate by %. methods. during the last months of all patients who were ventilated [ h, were investigated for vap. the diagnosis of vap was done according to the criteria supposed by the dutch working group on infection prevention. a new infiltrate on chest x-ray after h ventilatory support in combination with fever, leucocytosis, increased need for oxygen and culture of blind bronchial secretion c cfu/ml. a ventilator bundle was introduced on all icu wards as inspired by the institute of healthcare improvement. five interventions were introduced: head of bed [ °, reduction of sedatives as low as possible according to prescribed ramsay score, assessment of readiness to extubate, cuff-pressure measurement times a day with application of cuff pressures between and cm h o, and oral care with chlorhexidine . % times a day. icu nurses were trained in the first months of . the last months of were used to evaluate the bundle intervention in comparison with the last months of . results. patients were included in and in . after introduction of the ventilator bundle, the incidence per , ventilator days decreased from . % to . % per , ventilator days. introduction. continuous positive airway pressure (cpap) may improve oxygenation in patients with mild to moderate acute hypoxemic respiratory failure (ahrf) and avert further deterioration and need for intubation. objectives. aim of our study was to assess the physiologic effects produced by the addition of periodic hyperinflations (sigh) to cpap in patients with ahrf. we studied patients with non-cardiogenic ahrf. four trials of one hour each were performed at a constant fio % during ( ) spontaneous breathing (sb) via a venturi mask, ( ) cpap , ( ) cpap ? sigh/min of cm h o for s (cpap sigh ), ( ) cpap . cpap, via helmet, was maintained at cm h o troughout the whole study period. pao /fio ratio (p/f), paco , ph, respiratory rate (rr), arterial blood pressure (abp), heart rate (hr), dyspnea and patient comfort (by means of separate visual analog scales) were measured at the end of each trial. results. overall, p/f was significantly (p \ . ) improved by cpap (cpap ± mmhg, cpap sigh ± mmhg, cpap ± mmhg), as opposed to sb ( ± mmhg). overall, the sigh did not significantly improved p/f. in the six patients with bilateral infiltrates, however, the rate of improvement in p/f significantly (p \ . ) augmented with the introduction of a sigh as compared with those with monolateral infiltration ( vs. % respectively, being % the increase from venturi to cpap ). paco , ph, rr, hr, abp, dyspnea and comfort were not significantly different between trials. conclusions. in patients with ahrf, cpap improves oxygenation without affecting hemodynamics. the addition of a sigh to cpap further improved oxygenation only in patients with bilateral pulmonary infiltrates. background. adaptive support ventilation (asv) is a novel electronic ventilator protocol that incorporates the recent and sophisticated measurement tools and algorithms. the target tidal volume and respiratory rate are continually adapted to patient's respiratory physics and varying medical conditions. in injured lung, the asv should actively adjust ventilatory parameters achieving minimal work of breathing to meet the lung protective strategies. but there were little literatures describing its efficacy when applied to korean population. methods. from may to january , we observed initial mechanical ventilation parameters in patients receiving asv due to various causes ( lung injuries including community acquired pneumonia, hospital acquired pneumonia, interstitial lung diseases, pulmonary tuberculosis and idiopathic cases; without lung injury which comprise trauma cases, strokes, suicidal attempts and other cases). the mean age of studied population was . years (male:female = : ). the data were collected within the first h of mechanical ventilation. conclusion. as expected, adaptive support ventilation delivered smaller tidal volume and higher respiratory rates for injured lungs. asv efficiently operated in korean ali patients without any serious drawbacks and favorably adjusted the tidal volume and respiratory rates combination in relation with rcexp to meet lung protective strategies. introduction. neurally adjusted ventilatory assist (nava) is a mode of mechanical ventilation that uses the electrical activity of the diaphragm to control the ventilator obtaining an improved patient-ventilator synchrony and an efficient unloading of the respiratory muscles. nava is characterised by a variability of the breathing pattern and the absence of a constant flow, which makes impossible the determination of reliable data of respiratory mechanics by using the rapid occlusion method. we have previously demonstrated that the least squares fitting method (lsf) could be used during pressure support ventilation (psv), provided that the level of ps is sufficiently high to unload the inspiratory muscle. hence we made the hypothesis that ( ) reliable data of respiratory mechanics can be obtained by applying the lsf method during nava and ( ) the lsf method should work better during nava because of the characteristics of the flow and pressure traces. methods. ten patients undergoing mechanical ventilation for acute respiratory failure were enrolled. they were ventilated using randomly either psv or nava with the the same peepe and tidal volume (v t ). data of resistance (r rs ), elastance (e rs ) and total positive end expiratory pressure (peep tot ) were obtained by fitting the equation paw = r rs v ? v t / c rs ? peep tot during inspiration, because of the possible presence of expiratory flow limitation. the coefficient of determination (cd) of the applied equation was used to compare data obtained during nava and psv, the higher being the cd, the better the quality of the data. moreover patients were sedated and ventilated in volume controlled ventilation (acv) with the aim of calculating data based on rapid occlusion method and compare them with those obtained with lsf method by using the bland-altman analysis. ( ) data obtained with lsf were statistically more reliable during nava (mean cd: . ± . ) than during psv (mean cd: . ± . ; p \ . ). ( ) the cd obtained at every level of nava was always higher then . . on the contrary, the cd obtained at low level of psv was less than . due to the presence of inspiratory muscle activity. ( ) the bland-altman analysis demonstrated lower bias and higher precision between traditional data and those calculated during nava (bias: . ; limit of agreements: - . / . ) compared to psv (bias: . ; limit of agreements: - / . ). conclusion. the application of the lsf method during nava allows calculation of reliable data of rrs, ers and peeptot, which are independent of the level of nava applied. this is of clinical relevance since psv allows calculation of reliable data only at high level of pressure support. it appears that the influence of inspiratory muscle activity on respiratory mechanics is less relevant during nava ventilation, suggesting a more physiological ventilation during nava both in terms of timing and of delivering adequate level of assist throughout each breath. introduction. nava is a new spontaneous-assisted ventilatory mode based on the detection of diaphragmatic electrical activity (eadi) and its feedback to adjust ventilator settings. nava uses the eadi, an expression of the respiratory center's activity, to initiate pressurization, set the level of pressure support and cycle the ventilator into exhalation. therefore, nava should theoretically allow near-perfect synchronization between the patient and the ventilator. however there are few data documenting these effects in intensive care patients. to determine whether nava can improve patient-ventilator synchrony compared to standard pressure support (ps) in intubated intensive care patients. comparative study of patient-ventilator interaction during ps with clinician determined ventilator settings and nava with nava gain (proportionality factor between eadi and the amount of delivered inspiratory pressure) set as to obtain the same peak airway pressure as the total pressure obtained in ps. a min continuous recording with each ventilatory mode was performed allowing determination of trigger delay (t d ), patient neural inspiratory time (t in ), duration of pressurization by the ventilator (t iv ), excess duration of pressurization (t i excess = t iv -t in /t in ) and number of asynchrony events by minute: non-triggering breaths, auto-triggering, double triggering, premature and delayed cycling. results are given in mean ± sd. p is considered significant if . . . ± . . ± . . ± . n asynchrony/minute . ± . . ± . * . ± . respiratory rate (min - ) . ± . . ± . na * p \ . conclusion. compared to standard ps, nava improves patient ventilator interaction by reducing td and the overall incidence of asynchrony events. there is also a strong trend in reducing delayed cycling. this ongoing trial should provide evidence that nava can indeed improve patient-ventilator synchrony in intubated patients undergoing ps. introduction. high fio and hyperoxia may induce pulmonary injury and may increase oxidative stress. guidelines suggest a target arterial oxygen tension of kpa [ ] . a canadian questionnaire study found considerable variation in the attitudes, beliefs and practices of intensivists in the management of oxygen therapy [ ] . however, the actual response of intensivists to hyperoxia in patients has never been studied. in this retrospective database study we investigated adherence to guidelines concerning oxygen therapy in a dutch academic intensive care. all arterial blood gas (abg) data from mechanically ventilated patients from to were drawn from an electronic storage database (metavision) of a mixed -bed icu in a university hospital in amsterdam. mechanical ventilation settings at the time of the abg as well as the successive abg were retrieved. the statistical analysis was carried out with spss . . results. . abg's from mechanically ventilated patients were retrieved including corresponding ventilator settings. in . ( %) of the abg's po was[ kpa. initial ventilator settings and adjustments based on abg's of this group are shown in table [data represent median ( th/ th percentile)]. in % of the lowest fio group, fio was exactly %. in only % of cases with po [ kpa the fio was decreased. hyperoxia was accepted with no adjustments in ventilator settings if fio was % or lower. introduction. major patient ventilator asynchronies are frequent during non-invasive ventilation (niv) especially due to leaks.niv can be delivered using icu ventilators or specifically designed niv ventilators. although icu ventilators are traditionally used for invasive mechanical ventilation, specific niv modes have been recently implemented. the impact of these niv modes as well as niv ventilators on patient ventilator asynchrony is unknown. our objective was to compare the incidence of patient ventilator asynchrony between invasive or niv mode of icu ventilators and niv ventilators. patients and methods. icu patients with acute respiratory failure requiring niv were studied during three randomized consecutive min-periods of niv: icu ventilator with and without niv mode and niv ventilator. we used two icu ventilators: evita xl (dräger) and engström (general electrics) and niv ventilator: bipap vision (respironics). flow and airway pressure were continuously recorded to determine breathing pattern. to detect major patient ventilator asynchrony we used surface diaphragmatic and/or sternocleidomastoid electromyogram allowing to assess neural patient's inspiratory time and to define asynchronies: ineffective triggering, auto-triggering, double-triggering, prolonged and short cycles. asynchrony was quantified using an asynchrony index as previously described. results. these preliminary results concern ten patients ( males and female) with a mean age of ± and a saps of ± . reason for niv was acute exacerbation of copd (n = ), acute pulmonary edema (n = ) and post-extubation (n = ). at time of study, ph was . ± . , paco ± mmhg and pao ± mmhg. ventilatory settings were set by the clinician and kept constant during the three periods with a ps level of ± cm h o and a pressurization ramp of ± ms, a peep level of ± cm h o and a fio of ± %. using icu ventilators, inspiratory trigger was l/min and cycling off was % when adjustable. median asynchrony index was . % ( . - . ) using icu ventilators versus . % ( . - . ) using niv mode and . % ( . - . ) using bipap vision (p = . between invasive and niv mode, p \ . between niv mode and bipap vision). asynchrony index was greater than % in three patients using invasive mode, two patients using niv mode and no patient using bipap vision. auto-triggering was the main asynchrony. conclusion. niv ventilator (bipap vision) allowed a marked reduction in patient ventilator asynchrony during niv as compared to niv mode currently available on new generation of icu ventilators. grant acknowledgement. this study was supported by a research grant from respironics. a. armaganidis , k. stavrakaki-kallergi , c. sotiropoulou , a. koutsoukou , j. milic-emili , c. roussos athens university, athens, greece prevalence of expiratory flow limitation (efl) was estimated using the negative expiratory pressure method (nep) in anesthetized, paralyzed mechanically ventilated patients in icu. patients were studied in supine position at zero positive end-expiratory pressure (peep). a nep device especially designed and in build in an evita -draeger respirator, allowed the application of a pressure equal to- cm h o, starting at ms after the onset of expiratory flow and sustained throughout the end of the expiratory time set on the ventilator. patients were categorized in two groups: . non efl ( patients without flow limitation), in whom nep elicited an increase of expiratory flow over the entire expiratory flow-volume (v -v) curve. . efl ( patients with efl), in whom part or the expiratory v -v curve during nep was superimposed on the baseline v -v curve. half of our patients ( %) were flow-limited. no patient without pulmonary disease was found flow-limited, except of a percentage of morbidly obese patients ( %). efl was recorded in % of icu patients with pulmonary diseases: % of ards patients, % of patients with respiratory infection, % of asthmatics and % of patients with copd. time constant (s) and inspiratory flow (v insp) were found to predict the severity of flowlimitation expressed as efl % v t . objective. tidal volume (v t ) administered to ards patients can be adjusted depending on body weight. body weight may be estimated, measured or calculated for an ideal or a predicted value based on different formulas [ , ] . besides, those formulas require the measurement of height and may differ depending on gender. we hypothesized that v t value (ml/kg of body weight) may be different and show intrameasure variability depending on the method used. methods. ards patients were included prospectively in the first h after icu admission. the ventilatory parameters were selected by the attending physicians that were foreign to the study. all patients were ventilated by volume controlled-assisted mode. five independent observers estimated the weight (estw) of each patient. they also measured height with a metric tape for calculate the predicted body weight (pbw) [ ] and the ideal body weight (ibw) [ ] . after previous measurements, patients were weighed once with a calibrated scale (scaw). results were compared using analysis of variance. results. patients were studied, % women (age . ± . , saps ii . ± . ; apache ii . ± . ). ventilation parameters at inclusion: v t /scaw (ml/kg) mean ± sd . ± . . ± . . ± . . ± . . ** mean ± sd mean ± standard deviation, min minimum, max, maximum, pbw (men) or . (female) ? . (height in centimetres - . ), ibw (height in meters) , mean diff average of the intraindividual differences of calculated/estimated weight, range intraindividual difference in weight (estimated/calculated) expressed as minimum and maximum * estw versus pbw p \ . , pbw versus ibw p \ . , pbw versus scaw p = . ** v t /estw versus v t /pbw p \ . , v t /pbw versus v t /ibw p \ . , v t /pbw versus v t /scaw p \ . conclusions. our data show that there is no gold standard method for estimate or calculate body weight to adjust tidal volume in ards patients. recommendations based on pwb and ibw not guarantee that tidal volume administered is really those that we want to administrate. reference (s) . . ardsnet. nejm ; : - . . stewart te et al ( hôpital raymond poincaré ap-hp, service de réanimation médicale, garches, france, hôpital saint-louis, paris diderot university, paris, france, centre hospitalier d'etampes, etampes, france, université versailles saint quentin en yvelines, versailles, france rationale-objectives. dyspnea is a major respiratory symptom, which can reveal a severe disease. additionally, it can also result from an inappropriate ventilator setting in mechanically ventilated patients. if these patients are nowadays more and more conscious, prevalence of dyspnea and its clinical, biological and radiological correlates has never been assessed in this population. prospective cohort study conducted in two medical intensive care units (icu) during months. all patients intubated more than h and conscious have been included. the first day when the patient regained consciousness, dyspnea, anxiety and pain were assessed using a visual analogic scale (vas). if dyspnea was found, patient was asked if he experienced ''air hunger'', and/or ''excessive respiratory effort'' and if dyspnea vas was improved after ventilator setting has been changed. demographic, clinical, biological and chest x-ray data and ventilator settings have been collected. results. patients were included (age: ± years; simplified acute physiology score ii (saps ii): (iqr - ). reasons for mechanical ventilation included acute respiratory failure (n = , %), neuromuscular diseases (n = , %), coma (n = , %), and exacerbation of chronic obstructive pulmonary disease (n = , %). dyspnea was present in ( %) patients and was qualified as ''air hunger'' in patients ( %), ''excessive effort'' in ( %) and both in ( %). age, saps ii, reason for mechanical ventilation, respiratory rate, clinical examination, x-ray chest, pao /fio ratio, paco were not statistically different between patients with and without dyspnea. anxiety . ); p \ . ), assist controlled ventilation [ . ( . - . ) ] and diastolic blood pressure ; p = . ) were independently associated with dyspnea in multivariate analysis. ''air hunger'' tended to be associated with controlled ventilation (p = . ) whereas ''inspiratory excessive effort'' was significantly associated with low inspiratory flow, severe hypoxemia (median pao /fio ratio: , p = . ) and marked hypercapnia (median paco : mmhg, p = . ). in % of breathless patients, of ventilator resetting decreased dyspnea. length of icu stay was greater in patients with dyspnea (p = . ) whereas extubation within three days and icu mortality did not differ between the two groups. conclusions. dyspnea is frequent in mechanically ventilated patients and is strongly associated with anxiety, more frequently when controlled ventilation is used and is often reduced after ventilator resetting. assessment of dyspnea in conscious mechanically ventilated patients should be routinely performed in order to improve patients' comfort. methods. an experimental study design was used with a group of first year health care provider students. the students were divided into two groups related to familiarity of the location of exam. a part of students (n = ) were examined in demonstration room (dr) and the other part of students (n = ) in public place (pp) . every student received the same number of training hours ( h) and the same training method in demonstration room. during this exam the students performed a min long, single person cpr related to erc guideline. their performance was measured with calibrated ambu cpr software and the adapted point system of brendan b. spooner's scale. v and t test were used for comparison. p values less than . were considered statistically significant. we did not find difference between dr and pp groups in the correct sequence of bls steps, hand position, adequate frequency and depth of chest compression. between groups of characteristics of ventilation were not significant differences observed. it is first critical point in bls process to assess the quality of patients' spontaneous breathing; therefore it is crucial that the duration of check breathing may be sufficient long. the duration of checking for breathing was significantly (p = . ) shorter in dr groups than pr groups. in the pp groups time interval between chest-compression cycles were significantly (p = . ) longer-more than s-than in dr group. conclusions. the altered location of bls final exam shortens duration of checking for breathing which determines bls providers' decision making on starting chest compressions. the students may be full of confident in the well-known place represented by the shorter time of checking for breathing. the changed place of exam extended time interval between chestcompression cycles, therefore weaken the continuity of chest compressions, and decrease the chance of return of spontaneous circulation. aims. this paper reports an evaluation of the student experience of using a clinical competence assessment tool (ccat) in postgraduate critical care nursing education. the focus is on the perceptions of students in relation to the validity, reliability and usability of the assessment tool. the domains of competence assessed are based on five domains outlined by an bord altranais ( ) . they are: professional/ethical practice, interpersonal relationships, practical and technical skills, utilising a holistic approach to care, clinical decision making and critical thinking skills and organisation and management of care. the assessment process encompasses three clinical assessments and clinical competence is measured using the developmental process of novice, advanced beginner, and competent as described by benner ( ) . students are asked to reflect on their own learning needs prior to each assessment. the assessment includes a discussion on the knowledge that underpins practice thereby showing the integration of theoretical and practical knowledge. questionnaire was administered to all students who recently completed a graduate diploma in nursing studies (critical care) at a specific third level institution. results. the evaluation of the ccat as a mode of competence assessment in postgraduate critical care nursing education was generally positive from the students' perspective. some students considered the holistic nature of the ccat document to be a limitation, suggesting that their level of competency could have been better addressed with a tool that was more oriented toward critical care rather than being so 'broad' in nature. overall respondents considered that the ccat helped them to identify learning needs and found the use of the tool to be a positive experience and easy to use although some respondents considered that the wording of some of the sub-domains and indicators was difficult to interpret. competence assessment is about ensuring the delivery of safe and competent patient care. in order to determine competence a valid and reliable tool is needed. this small scale study presents the views of post registration critical care nursing students on using a competence assessment tool. the findings of this study cannot be generalised, however they do provide insight for educators and students using competence assessment tools in programmes preparing registered nurses for specialist nursing practice. the use of a holistic assessment process needs further explanation. students need to be encouraged to move away from the reductionist approach, which is focussed on tasks and move towards a broader understanding of competent practice. reference (s) . . an bord altranais ( ) requirements and standards for nurses registration education programmes, nd edn. . benner p ( ) from novice to expert excellence and power in clinical nursing practice. addison-wesley, california. to assess the usefulness of a web-based interactive learning package designed to supplement an undergraduate acute care course (very basic) taught to final year medical students. a web-based interactive learning package was developed to supplement a highly rated traditionally taught -day acute/critical care course consisting of pre-course reading, lectures, skill stations and interactive tutorials [ ] . the additional web-based package consisted of narrated lectures, interactive lessons, videos and animations to demonstrate practical procedures and clinical signs, self assessment quizzes and a question and answer forum. topics covered included arterial blood gas sampling and interpretation, acute metabolic disturbances, non-traumatic coma, acute respiratory failure and sepsis. both the package and the course are available to other medical schools free of charge. usefulness of the package was assessed by examining activity logs, a student questionnaire, formal focus group (conducted by an investigator not involved in course preparation or teaching), comparing the results of a post-course mcq based summative assessment with historical controls and comparing results of formative assessment included in the package with the summative assessment. results. over , student-activities were logged by students during the two week course. students completed the questionnaire. with regard to usability, [ % agreed or strongly agreed that interactive lessons and self assessment ran smoothly without faults, with a corresponding score of [ % for narrated lectures and ease of browsing. with regard to usefulness, c % agreed or strongly agreed that the question and answer forum was useful in clarifying areas of doubt and narrated lectures improved understanding of the course material; [ % agreed or strongly agreed that the content as a whole was useful in preparing the respondent to work as a doctor, interactive lessons improved their understanding of how to apply their knowledge, and their understanding of arterial blood gas interpretation and self assessment exercises improved their understanding of the course material. participants in the focus group indicated that the resources provided in the website were useful for learning, specifically the animations, narrated lectures and the question and answer forum. suggestions for improvement included improving the quality of the video and animations, increasing the range of topics covered and ensuring consistency with the printed course manual. there was no correlation between formative and summative assessments but, compared to historical controls, performance in the summative assessment improved ( vs. %, p \ . ). conclusions. the package provided a useful supplement to a traditionally delivered acute care course. introduction. faculty development refers to that broad range of activities that institutions use to renew or assist faculty in their roles. it includes activities that improve an individual's knowledge, skills and attitudes in important areas in teaching, education, research, leadership, administration and career development. in this abstract we will introduce one of the most important methods of faculty development programs. a meeting by the authors ''organizing group'' was conducted to decide on a topic for our workshop and discussed the planning and designing process. we decided on conducting a workshop on clinical teaching methods. a scientific and organizing committee was established, and accordingly work loads and assignments were distributed among them. we gave this workshop a title of ''i am the best clinical educator…are you!? our target audience was acute care management providers, with a capacity of up to participants. we gave a specific time and location of this event. venue was arranged. computers for group work, audiovisual and other logistics were provided. after summarizing the main points for the workshop the organizing committee distributed an invitation letters throughout the higher management and educational leaderships. an address remark was done through invitation from the organizing committee. hot and cold beverages and break lunch meals were provided. posters on the workshop were distributed through out the institution. folders with educational materials were provided for each candidate. pre-course registration was done. once the program for the workshop was finalized a reminder was sent out to the participants on the date and venue for the workshop. participants attended on time, folders, badges with usbs were handed out. a questionnaire was distributed to the audience to estimate their learning experiences and approaches towards teaching styles and methods which were used in their practice. certificates of attendance with cme credit hours were distributed. results. candidates attended this faculty development workshop. % were nurses and % were physicians, during this workshop, three topics were distributed over three groups, one group on how to break bad news. second group about how to conduct microteaching and the third group about how to give feedback. each group was evaluated by three members of the organizing committee, each group was ranked accordingly. all were performed by role play. at the end of the workshop an evaluation form was filled % responders. a five performance scale was used. the strength of the workshop was innovativity and ranked as strongly agree. the only weakness was the place constraint. conclusion. we concluded that a well organized workshop using role play, interactive sessions are effective modality for faculty professional development programs among acute care providers with high satisfaction rate. only of the respondents ( %) indicated they did understand the statistics they encountered in journal articles and % felt it was important to understand these concepts and that they would like to access more easily to biostatistics training. a patient is referred to a higher centre when services are needed to maintain continuity of care.there are guidelines for the safe inter and intrahospital transport of critically ill patients but no guidelines are available for the minimal mandatory content of interhospital referral notes of critically ill patients.this problem is manifold in developing countries. objective. to educate the critical care physicians regarding the deficits in the physicians referral notes with which critically ill patients are referred from one centre to another. it is a prospective observational study on out of hospital referred patients transferred to our intensive care unit (icu) over a period of year. after permission from the institutes ethical committee we reviewed the referral summaries of these patients at the time of icu admission regarding the information available of clinical details, course in the previous hospital and therapeutic interventions. patients with more than h of hospitalization before transfer were included in the study. introduction. in japan, closed icus have been gradually increasing at university hospitals. a closed icu is necessary for a university hospital not only for the hospital activity but also the education of medical students and the training of fellows. they can learn how to manage the circulation and respiration status of severely ill patients in icu. it is indispensable for effective education to ensure sufficient proper icu staffs. but the present condition of our country is that there are not so many intensivists enough to perform both of clinical duties and education of students and fellows. each icu of university hospitals is endeavoring to increase the number of intensivists. one of the popular methods is the announcement on web site to promote interest of young fellows. regrettably, the homepage of the japanese society of intensive care medicine has no such specific pages. each icu of university hospitals has to create attractive its own pages in the homepages of the hospitals. [ ] . most subjects are taught using lectures and group tutorials and the theory is applied in clinical areas to facilitate greater understanding of the newly acquired knowledge. there is no reported best practice mechanism for teaching medical ethics in a practical setting to medical students. objectives. the routine use of an ethical checklist has been proposed as a tool for the medical team to consider ethical issues on critical care [ ] . its use as a tool for teaching medical ethics within critical care has not previously been reported. the aim was to use this checklist to facilitate learning providing clinical case material for discussion in daily tutorials. one medical student (sm) undertook a one week period of study to learn about ethics in critical care practice. the checklist was used to review patient notes, guide further discussion with patients, when observing the professional behaviours and communication of the multidisciplinary team, and as a guide for case based discussions. results. the complexity and severity of patient conditions in critical care makes it the ideal setting for learning about ethics. sm considered more ethical dilemmas in this practical attachment than in the previous years of clinical placements. the checklist allowed identification of possible ethical issues relating to each patient and a deeper understanding of the patient's health care needs. it was used for daily tutorials to discuss the ethical principles and observed professional behaviours in a similar way to a discussion of clinical diagnosis and management of a patient case with a supervising doctor on a normal clinical attachment. complex issues such as capacity to consent, end of life treatments or resource allocation were seen in relation to ongoing care. on ward rounds it was observed that their conduct in an open environment could at times potentially compromise patient confidentiality. there was also a benefit from the consideration of ethics issues in a real time basis which allowed exploration and reflection on personal moral or spiritual beliefs and how they may differ from those of the patients and other medical professionals. conclusions. using an ethical checklist allowed application of theoretical lecture and workshop material to real life situations. by discussing the cases and observed behaviours with a senior critical care doctor it is possible for trainee staff to appreciate how difficult medical management decisions are made, and to improve the acquisition of the skills necessary to start to assess and discuss ethical issues surrounding a patient's care confidently. introduction. accurate data on patient's weight and height are important for management in intensive care units (icus). unfortunately, weight beds or bed scales are not available in a significant number of icus and these variables are often estimated by health care personnel. the accuracy of such estimations is poorly described. objective. to investigate the accuracy of visual estimation of weight and height in critically ill patients. methods. prospective study conducted in a -bed mixed medical and surgical icu. patients were consecutively weighed by an unblinded physician with a stretcher scale (t metric), and measured by a physical therapist using a measuring tape. the ideal weight was calculated using the ardsnet's formulas for predicted body weight. medical staff (ms), internal medicine resident (imr), nursing staff (ns), physiotherapist (pt) and nutritionist (nu) were asked to estimate patient actual weight, ideal weight and height. they were blind to the estimations during all the protocol. estimations in each healthcare group were computed as means, medians and percentage of error from actual and ideal weight and height, respectively. anova test was used to compare mean estimations between the groups. there were no significant differences between the groups in estimation of either weight (p = . ) or height (p = . ). conclusion. weight estimations from healthcare personnel are often inaccurate. there are no significant differences in accuracy between the estimations of weight and height in different healthcare groups. an effort should be made to weigh all critically ill patients. intraabdominal hypertension (iah) is often diagnosed in icu and it can lead to abdominal compartment syndrome, multiple organ failure and death [ ] . in clinical setting biochemical signals based on which iah is considered severe or detrimental on visceral tissues are scarce. currently, the only clinically relevant signal is decreasing hourly diuresis. in an attempt to find an early sign of metabolically relevant signal on clinically marked iah we investigated abdominal wall metabolite concentrations. previously high lactate/pyruvate has been detected in dialysate from rectus abdominis muscle (ram) in animal models of iah [ ] . in the present experiment we hypothesized that laparoscopic surgery which induces iah could lead to clinically significant increase of l/p ratio as a signal of anaerobic metabolism caused by iah and insufficient tissue perfusion. introduction. among the techniques proposed to assess microperfusion and oxygenation, nirs sounds to be convenient [ ] . if baseline measurements do not provide useful information for outcome of micro-vascular impairment, functional evaluation using vascular occlusion test (vot) seems to be promising [ ] . technological development of the nirs device (inspectra models and , hutchinson technology, hutchinson, minn) proposes to use a new probe measuring hemoglobin saturation at less depth than previously ( vs. mm between fiberoptic) with more data output ( value/ s vs. value/ . s) associated with an automated software to compute occlusion and reperfusion slopes. objective. to compare nirs results obtained, using the two different probes, at day of septic shock (ss) in two groups of patients having similar clinical characteristics. methods. patients (g ) and patients (g ) were included within the first h of ss. macrohemodynamic: heart rate (hr), mean arterial pressure (map), central venous pressure (cvp), cardiac output (co) and svo (mixed venous o saturation), ph, base excess, and lactate were collected as saps ii and sofa scores. baseline sto at thenar eminence was continuously monitored and a min upper arm(brachial artery) vot was performed. sto occlusion and reperfusion slopes were calculated manually in g (probe mm) using linear adjustment (r c . to be valid) or calculated by the software in g (probe mm) using the same method, p \ . was considered significant. results. median ± iqr. the two groups did not differ for macrohemodynamic nor for metabolic data (table ) . nirs data surprisingly were largely significantly different between the two groups for both baseline and slopes ( background. hypovolemia and hypovolemic shock are life-threatening conditions that occur in numerous clinical scenarios. near-infrared spectroscopy (nirs) has been widely explored, successfully and unsuccessfully, in attempt to function as an early detector of hypovolemia by measuring tissue oxygen saturation (sto ). in order to investigate the measurement site-and probe-dependence of nirs in response to hemodynamic changes, such as hypovolemia, we applied a simple cardiovascular challenge; a posture change from supine to upright, causing a decrease in stroke volume (as in hypovolemia) and a heart rate increase in combination with peripheral vasoconstriction to maintain adequate blood pressure. methods. multi-depth nirs was used in nine healthy volunteers to assess changes in peripheral vascular tone in the thenar and forearm in response to the hemodynamic changes associated with a posture change from supine to upright. a posture change from supine to upright resulted in a significant increase (***) in heart rate. thenar sto did not respond to the hemodynamic changes following the posture change, whereas forearm sto did. in the forearm, sto was significantly lower (***) in the upright position with respect to the supine position. conclusion. the primary findings in this study were that ( ) forearm sto is a more sensitive parameter to hemodynamic changes than thenar sto and ( ) cerebral hyperperfusion syndrome, caused by inflow at normal blood pressure into maximally dilated fine vessels, is a recognized complication of carotid endarterectomy (cea) strict blood pressure control in the early postoperative period can minimize the risk of cerebral hyperperfusion. until yet, diagnosis of cerebral hyperperfusion mainly relies on intermittent postoperative examinations (spect; ct angiography). non-invasive absolute cerebral oxygen saturation (scto by fore-sight technology) was validated to jugular bulb saturation (sjo ) monitoring with a constant difference of % higher for scto values. previously, sjo monitoring after severe head injury indicated cerebral hyperemia. in this study, we evaluated scto monitoring after carotid surgery as possible continuous on-line monitoring of cerebral hyperperfusion. fourteen pts scheduled for cea were monitored for h postoperatively after cea. bilateral scto monitoring was started before induction of anesthesia and maintained until h postoperatively. intra-operative eeg monitoring guided the decision to intraluminal shunt insertion. strict blood pressure control was applied at maintaining normotensive levels throughout the clamping procedure. early postoperative care focussed on strict maintenance of normotensive blood pressure. in no pt, any change in eeg was observed after carotid clamping. in all pts, ipsilateral scto significantly decreased after carotid clamping, without any scto value below %. we observed no changes in contralateral scto . mean clamping time was min ( - min). in all pts, clamp release restored ipsilateral scto to baseline values. in all pts, emergence from anesthesia was uneventful, without any new neurological deficit. in of pts, significant increases (scto [ %) in ipsilateral scto were observed in the postoperative period (m scto . %), without any changes in contralateral scto . this increase occurred at a mean of . h after carotid declamping with a mean duration . h. in these pts, we could not make any significant correlation to arterial blood pressure, as none of these pts needed more aggressive antihypertensive control. we noted that of these pts suffered from diabetes mellitus, while of pts revealed high ([ %) contralateral stenosis. further data will have to reveal the importance of these comorbide factors. non-invasive cerebral oximetry, enabling absolute cerebral oxygen saturation monitoring, could provide on-line estimation of cerebral perfusion state after cea. this could allow bedside detection (and eventual therapeutic interventions) of cerebral hyperperfusion after cea. introduction. analysis of microcirculatory alterations obtained by side-stream dark field (sdf) is time consuming. automated analysis with modern softwares could accelerate this process and help to quantify blood flow velocity. however, perfusion detection is based on the contrast between pixels and this may be influenced by image settings. objective. we aimed to compare data obtained with a new software to the traditional semi-quantitative analysis of sdf images. methods. we selected from our database six images of poor sublingual microcirculatory perfusion and six images of good microcirculatory perfusion registered by the sdf technique (microscan; microvision medical, amsterdam, the netherlands). the proportion of perfused vessels [ppv = (number of vessels with continuous flow/number of all vessels) ] \ % was used to define microcirculatory perfusion. total vessel density (tvd) was determined automatically by the software ava . (microvision medical) and also by the semi-quantitative technique, considered as the gold-standard (number of capillary crossing three equidistant vertical and horizontal lines divided by the total length of these lines). ava software was also used as default definitions or set to optimize analyses according to manufacturer instructions. vessels falsely detected (false positive = fp) or missed (false negative = fn) by the software, in comparison to the semi-quantitative evaluation, were also counted. results. tvd was significantly higher by the ava software either on default or on optimized mode than by the semi-quantitative method, and these differences were present with good or poor perfusion images (table ) . overall fp rate was %, and it was greater in poor perfusion images ( %). optimization of the ava set parameters attenuated fp rates both in poor and good perfusion images, at the expense of increasing fn rates (table) . due to intrinsic characteristics of the software, the mean total grid length was significantly lower in the ava than in the semi-quantitative analysis ( . vs. . introduction. perfusion index (pi) is the proportion of constant absorbed light compared to pulsatile absorbed light emitted from a pulse oxymeter. it ranges from a value below up to depedant of peripheral perfusion. it is measured primarily to evaluate the signal quality for the pulse oxymeter and is displayed by some pulse oxymeters to be acknowledged by the clinician. the pi changes with vasodilation and vasoconstriction. however, intubation is a stimulus able to increase endogenous catecholamines and thus leading to vasoconstriction possibly declining the perfusion index. therefore we found intubation with a double lume tube in a thoracic surgery setting as a suitable setting to evaluate changes in perfusion index as a reaction to intubation. after informed consent, we enrolled seven patients undergoing lung surgery requiring an double lume tube. they were monitored as it is standard of care in our institution with invasive blood pressure, ecg, and a pulse oxymeter displaying the pi. (radical , masimo, irvine, ca) the patients received the medication to induce anesthesia calculated adequately to their body weight. midazolam, propofol and fentanyl where used to anesthetize the patient, cisatracurium was used for muscle relaxation to facilitate intubation. pi, pulse and arterial saturation were recorded every minute from prior to induction until after successful intubation. a baseline value was recorded prior to induction and compared to the value minutes after induction. then the pi measured next to intubation was compared to the pi after induction and analysed using students t test. introduction. anticoagulation strategies for albumin dialysis suppose a difficult compromise between risk for bleeding and a high tendency to clot in the circuit. even thought the sessions are short, a premature clotting is a serious event because the lost of blood (high priming volume) and a high cost of the systems. we intended to demonstrate that the classical approach based in heparin is not adequate in these patients and should be substituted for a different strategy (mixed low dose of heparin plus epoprostenol). methods. data of a prospective registry of all cases treated in our centre (a third level, teaching hospital) with albumin dialysis (mars system). initially we used non-fractionated heparin at - u/(kg h) in patients without coagulation problems, epoprostenol [ - ng/ (kg min)] in cases with risk or thrombocytopenia and no anticoagulation when high risk for bleeding or contraindication for anticoagulation. after an intermediate analysis of our registry we detected a high number of filters clotted when heparin was used and changed our approach to use as first indication a mixed protocol with non-fractionated heparin [ u/(kg h) ] plus epoprostenol [ ng/(kg min) ]. data are presented as percentages. analysis was performed with chi-square test. to detect variables related to coagulation a stepwise backward logistic regression analysis was performed. we registered patients with a total of sessions. selecting only the first session for each patient to validate the first choice for anticoagulation, we used heparin in cases and detected the loss of filters ( . %) because clotting. after the change to mixed anticoagulation we used this as first indication in patients and in only ( . %) the sessions were prematurely ended because clotting (p ns). the rest of patients received isolated epoprostenol in cases (with - %-cases of premature clotting) and no anticoagulant in five cases (with - %-premature clotting). between the cases with heparin as first choice, three episodes of mild and one episode of severe bleeding were detected while no patients in the mixed group presented bleeding complications (p ns). in a logistic regression analysis over all registered sessions using coagulation of filters as dependent variable and type of patient, anticoagulant, arterial pressure, inr, tpta, platelets, haematocrit or bilirubin as independent variables, none of these was included in the regression model. even though more studies are necessary to validate this conclusion, a mixed protocol based in low dose heparin plus epoprostenol could be adequate as first indication for non-complicated patients submitted to a mars treatment with lower risk for bleeding than the classical approach of isolated non-fractionated heparin. optimizing oxygen delivery in critically ill patients is vital for the promotion of aerobic cellular metabolism. current practice includes the measurement of variables such as partial pressure of arterial oxygenation (pao ), cardiac index (ci) and percentage of oxygenated haemoglobin in arterial blood (sao ). these parameters reflect global oxygen delivery. the real point of interest is the end point of the oxygen cascade; oxygen utilisation in tissue mitochondria. near infrared spectroscopy (nirs) has been developed in an attempt to measure tissue oxygen saturation (sto ) in peripheral muscle microcirculation. manufacturers state normal values as ± %. it uses four wavelengths near the infrared spectrum ( - nm) to measure sto , a ratio of oxygenated haemoglobin to total haemoglobin. it is continuous and non-invasive. sto has proven efficacious in predicting oxygen delivery in trauma patients and claims to have been successfully used to guide early resuscitation [ ] . objectives. we were interested in assessing whether sto had a role in measurement of oxygen delivery in the intensive care population, and how it compared to the parameters currently used to predict oxygen delivery. we had particular interest in the usefulness of nirs in septic patients, where the pathophysiology of tissue oxygen utilization is disrupted. patients from a general, adult intensive care unit were enrolled over an month period. all patients had lidco monitoring. exclusion criteria were gtn, atrial fibrillation and patient refusal. mm sto probes were sited on the thenar eminence. serial recordings of sto , cardiac index, hr, sao , map, and pao were recorded. sto results were compared to more traditional parameters of oxygen delivery. sixteen patients were recruited, all met criteria for sirs and shock. four were excluded with incomplete data. results were analysed for individual patients and as a collective series. we found: • no statistical correlation between nirs and sao or pao . • a weak and clinically insignificant correlation between cardiac index and nirs (p \ . ). • supra normal nirs readings (normal [ %) were not infrequently gained in patients where all other parameters were indicating severe shock and poor oxygen delivery. conclusion. theoretically nirs has potential to be beneficial in measuring oxygen delivery. our results demonstrate that nirs is not accurate for our septic population. we found poor correlation with current methods used to predict oxygen delivery and it may well be more misleading than beneficial. more traditional methods of intensive care monitoring, although sometimes invasive, appear to provide a more accurate representation of a patient's oxygen delivery. background. urine output is a crucial parameter of renal function and fluid balance. conservative urine output monitoring harbors problems such as subjective reading, sampling time errors and nursing workload. an electronic urine collection device was introduced into the icu and connected to a computerized information system. this created a more reliable and accurate means for urine output monitoring and the ability to develop new calculated parameters. . to evaluate the effects of introducing an electronical urine collection device into a fully computerized icu. . to evaluate new parameters that were created by the combination of the device and a computerized data management system. patients included were all admitted to the icu at rambam medical center, haifa, israel, during the years - . urine production and flow were monitored continuously by the urinfo Ò device (med-dynamix, israel), a novel electronic urinometer, connected to a patient data management system (imdsoft, israel). graphical analysis of urine production was done and derived parameters continuously calculated. comparison was done to the conventional mechanical urine collection system. variables studied were: measurement accuracy, sampling time accuracy, nursing workload before and after the implementation process. correlation between derived parameters and conventional renal function measurements such as plasma creatinine and creatinine clearance time. results. the conservative urine output measuring system demonstrated percentage error span in range of - %, compared to a range of - % percentage error in measurement after implementation of the computerized system. before implementation, sampling time error span was found to be - min, while no sampling time error was present after implementation due to the automated recording system. time consumed by the workload of the conservative urine output monitoring system was measured at - min per nursing shift ( h). the computerized system eliminated this workload completely. derived parameters evaluated were continuous urine flow (in cc/min or cc/h), urine production acceleration rate (calculated via the slope of the ''up-rise'' in cc/min ) and the peak urine production rate (cc/min). these parameters were able to demonstrate immediate changes in renal function, hours before conventional measurements and calculations would show them. conclusion. implementation of a computerized urine monitoring system can lead to improved accuracy in renal function monitoring and eliminate a significant amount nursing workload. use of derived calculated parameters may lead to earlier detection of renal malfunction and thus lead to earlier intervention. ( g/ , ml), cica dialysate k tm (na mmol/l, k . mmol/l, mg . mmol/l, cl . mmol/l, hco mmol/l, glucose anhydrous . g/l, ph * , ) and calcium chloride mayrhofer tm cacl , mol/l. the filter was an ultraflux av s tm , the material of the bloodline tubing system was medical grade soft pvc. in three circuits used in two different patients we found an opaque white precipitation starting at the cacl side port growing along the line with the direction of the bloodflow up to a maximal mm wide and mm long stripe. to identify the composition of the white stripes we included histological examination of hematoxylin-eosin stained sections and lyophilisation with wet chemical analysis. blood samples were simultaneously taken from the venous port of the cvvhd circuit and the arterial line of one patient. results. histology showed **an organic material in form of calcific deposit, covered with coagulated blood. chemical analysis identified this deposit as calcium phosphate. the results of the blood samples are shown in table . calcium phosphate precipitates may have reached patient circulation and been deposited in the capillary bed of the lungs or other organs. no histological examinations of tissue were taken and adverse events could not be attributed to the described phenomenon. citrate anticoagulation was stopped and switched to combined heparin-epoprostenol sodium anticoagulation. conclusions. the combination of the fluids and materials used in this specific cvvhd circuit with citrate anticoagulation resulted in some patients in a detectable calcium phosphate formation in the circuit. physicians using the described setting should be aware of the phenomenon and stop citrate anticoagulation as soon as a deposit occurs. in vitro studies, using different compositions and concentrations of dialysate and substitution fluids and simulating different patient conditions (ph, ph, hb, alb,…) should clarify, which solutions could safely be used. in addition the material of the circuit should be investigated, since surface characteristics have been identified to influence the formation of a calcium phosphate layer [ ] . reference (s) objective. the aim of this study was to assess, in a medical population of critically ill patients, whether intraabdominal pressure at admission was an independent predictor for mortality and to evaluate the effects of intraabdominal hypertension on organ functions. all patients admitted to the medical icu of the hgu gregorio marañón over a period of days were studied prospectively. patients who fulfilled two or more risk factors for wsacs (diminished abdominal wall compliance, increased intra-luminal contents, increased abdominal contents and/or capillary leak /fluid resuscitation.) were included. iap was measured via a foley bladder catheter, according to the modified kron technique. data recorded on admission were the patient demographics with, acute physiology and chronic health evaluation ii score (apache ii), and type of admission; during intensive care stay, sepsis-related organ failure assessment score (sofa) and clinical concomitant factors and conditions. intraabdominal pressure were measured at least daily together with fluid balance. patients were followed throughout their hospital stay. forty-four patients were included in the study (age - , apache ii . . half were admitted for cardiopulmonary disease. twelve ( %) had pancreatic or gastrointestinal disease. twenty-two ( %) had severe sepsis or septic shock. the incidence of iah was %. mortality was %. the cause of the iah was capillary leak syndrome/fluid resuscitation in % of cases. there was no relationship between the presence of iah and the number of organ failure during admission. the only variables associated with mortality of the patients were sofa and apache ii. the presence of iah was not a factor associated with increased mortality, although these results may be confounded by sample size. conclusions. there is an unusually high incidence of iah in the population of critically ill medical patients with two or more medical risk factors for wsacs. however, unlike in other populations, our study does not demonstrate that the iap monitoring allow detecting a group at higher risk of developing multi-organ failure or death. background. drainage of ascitic fluid is a common practice in order to relief the respiratory discomfort of patients. the aim of the present study was to determine abdominal compliance after ascitic fluid removal by transcutaneous drainage. methods. twelve patients presenting with ascitic fluid were included. all patients had transcutaneous blind drainage with a wide catheter. the ascitic fluid removed was recorded, while the intraabdominal pressure (iap) was measured as proposed by wsacs. iap was measured before and min after the puncture. abdominal compliance (cabd) was calculated. results. the pre-drainage iap was . mmhg (ranging from . to . mmhg, sd . mmhg), while the post-drainage was . mmhg (ranging from . to . mmhg, sd . mmhg). the mean volume of ascitic fluid removed was ml (ranging from to , ml, sd ml). cabd after drainage was ml/mmhg (ranging from to ml/ mmhg, sd ml/mmhg). a linear correlation was found between ascitic fluid removal and iap variations. conclusion. the drainage of ascitic fluid reduces iap, facilitating in this way respiration. moreover, iap variation seems be in linear relation with the volume of ascitic fluid removed. this linear relation between iap and volume may probably predict the cabd quite accurately and vice versa. however, larger studies are necessaries in order to safely draw predicting diap-dv (cabd) diagrams, and determine the optimal ascitic fluid removal in order to achieve best comforting of the patient and slower fluid reformation. introduction. use of stroke volume variation (svv) to guide fluid therapy in preload responsive state has been studied well in patients undergoing cardiac or neurosurgery during anaesthesia. use of this dynamic monitoring variable has not been studied much in septic shock. we undertook this prospective study to evaluate utility of svv to optimize preload in patients with septic shock and ards. setting. bedded medical surgical icu of a bedded tertiary care centre in pune, india. inclusion criteria: ( ) patients with ards (po /fio b ), svv readings were taken every h with flotrac-vigileo system after confirming abolishment of spontaneous breaths by sedation or paralysis and increasing tidal volume transiently to ml/kg. fluid boluses were given to keep svv \ % for h after enrollment. attempts were made to reduce vasopressor doses keeping map c mmhg. results. patients with average age . ± . years and apache ii score . ± . were studied. each patient received an average . ± . l fluid in h after enrollment to keep svv below %. svv at h after enrollment was . ± . % improvement in microcirculation was evident as plasma lactate reduced from . ± . (at h) to . ± . mmol/l (at h) there was no worsening in pulmonary edema as po / fio increased from . ± . (at h) to ± . (at h) only out of patients needed renal replacement therapy. in patients, vasopressors could be stopped completely in . ± . h. of them survived till discharge from the icu and died of ards. in patients, vasopressors could not be weaned off completely and all of them succumbed. overall survival rate was %. conclusion. svv guided fluid therapy is a promising modality for pre load optimization in mechanically ventilated patients with septic shock and ards. introduction. cardiovascular function is an important determinant of outcome in sepsis, and heart rate (hr) has been associated with cardiovascular risk and mortality in large patient cohorts [ ] . to investigate the association between hr and or day mortality in septic shock. methods. this study is a post hoc analysis of septic shock patients who were included in the control group of a multicenter trial [ ] . demographic and clinical data, average hr and catecholamine requirements during septic shock, occurrence of acute circulatory failure, and day mortality were documented. a binary logistic regression model adjusted for the simplified acute physiology score ii (excluding hr) was used to investigate the association between mean hr and acute circulatory failure or / day mortality. a multiple logistic regression model was applied to identify independent risk factors for developing hr critical for outcome. conclusions. hr is associated with and days mortality in septic shock. hr persistently exceeding bpm during septic shock seems associated with a significant risk of death. introduction. different colloids can be used for treatment of hypovolaemia in septic pts. recently, small-volume resuscitation was introduced for initial therapy of severe hypovolaemia and shock. the concept of small-volume resuscitation encompasses the rapid infusion of a small dose of . % nacl/colloid solution [ ] . however, in septic pts hypovolaemia often associates with acute lung injury (ali). therefore in these pts great importance has influence of colloids on oxygen transport. objectives. the aim of the study was to evaluate and compare the effects of hhes and hes on oxygen transport in pts with sepsis and ss. methods. hypovolaemic pts with sepsis and ss were enrolled in the study. pts received - ml/kg ( ml) hhes ( . % nacl ? % hes) (fresenius kabi) within min and pts received hes / (voluven, fresenius kabi) ml/kg. in all pts before and after infusion the parameters of oxygen transport was measured by pulmonary arterial catheter and transpulmonary thermodilution (pulsion medical system). after infusion of hhes oxygen delivery index (ido ) increased because of increase of cardiac index (ci) despite of decrease of hemoglobin (hb) levels and absence of changes of arterial oxygen content. extravascular lung water (evlw) and shunt increased significantly immediately after hhes infusion, but this increase was not accompanied by deterioration of pao /fio . introduction. severe sepsis is characterised by a wide array of haemodynamic changes including increased capillary leak, vasodilatation, vascular hyporeactivity and myocardial depression. the resultant tissue hypoperfusion is an important catalyst of multi-organ failure [ ] . to further develop our understanding of the underlying mechanisms, we have developed and characterised a fluid-resuscitated mouse model of intraperitoneal polymicrobial sepsis. objectives. to assess alterations in cardiac performance in mice at , , and h following faecal peritonitis. methods. sepsis was induced in week old male mice (n = ) by intraperitoneal (i/p) injection of dilute faecal slurry. sham animals (n = ) received n-saline i/p. animals were fluid resuscitated at time ( ml/kg . % saline), and at and h ( ml/kg . % saline- % dextrose each time). under a minimum concentration of isoflurane to achieve light anaesthesia, peak velocity, stroke distance, heart rate and fractional shortening were measured in the short axis plane by echocardiography at the , and h timepoints. in separate sham and severe septic mice (n = per group) the cardiac response to intravenous colloid boluses was assessed at and h. results. we clinically characterised septic animals into 'mild' and 'severe'. mice with severe sepsis showed a % drop in peak velocity and cardiac output at h (vs. and % falls in the mild septic and sham-operated animals, respectively, p \ . ). while mild septic animals showed recovery by hr, cardiac output in severely ill mice remained significantly depressed (due to both low heart rate and stroke volume) compared to mild septic and sham animals [*p \ . ( fig. ) ]. stepwise . ml boluses of intravenous fluid at h in severe septic animals led to restoration of cardiac output to baseline ( h) values. however, in the h septic animals, fluid challenge produced an initial improvement in cardiac output followed by deterioration [ fig. purpose. myocardial dysfunction has been well-documented in sepsis even in hyperdynamic state, and may develop and contribute to morbidity and mortality. nicaraven, a radical scavenger, has been shown to protect the coronary endothelial and myocardial function from ischemia and reperfusion injury due to hydroxyl radical scavenging activity. the purposes of present study were to determine the effects of nicaraven on cardiac function and cytokine production in lipopolysaccharide (lps) induced sepsis. methods. this protocol was approved by our institutional committee. following arterial and venous cannulation and tracheostomy, rats ( - g) were anesthetized with pentobarbital, and mechanically ventilated with a control mode (v t = ml/kg, rr = rpm). after baseline measurements, rats (n = ) were administrated with lps ( mg/kg, intravenously) and randomly assigned to following two groups: the nicaraven group treated with nicaraven [ mg/(kg min), intravenously] and the control group treated with saline. the left ventricular pressure and volume were measured with the pressure and conductance catheter every one hour. cardiac function, including cardiac output (co), ejection fraction (ef), and maximal elastance of left ventricle (e max ) were analyzed with a computer soft. blood was collected, centrifuged ( , g, min, ) , and stored (- °c) from rats every h after operation to measure plasma concentration of tnf-a, il -b and macrophage migration inhibitory factor (mif) using enzyme-linked immunosorbent assays kits. blood lactate concentration was also measured. data were analyzed by repeated measure anova. results. the co in the nicaraven group was kept significantly higher than the control group (p \ . ). the ef and e max in the nicaraven group were also kept significantly higher than the control group (p \ . ). arterial lactate, tnf-a, il -b and mif were significantly lower in the nicaraven group versus the control group (p \ . ). conclusion. the current study indicates that the treatment with nicaraven improved cardiac dysfunction and reduced plasma concentration of cytokines, and improved lactic acidosis in septic model. methods. this protocol was approved by our institutional committee. following arterial and venous cannulation and tracheostomy, rats ( - g) were anesthetized with pentobarbital, and mechanically ventilated with a control mode (v t = ml/kg, rr = rpm). after baseline measurements, rats (n = ) were administrated with lps ( mg/kg, intravenously) and randomly assigned to following two groups: the oxytocin group treated with oxytocin ( iu/kg iv and followed by the continuous infusion of mg/(kg min), intravenously) and the control group treated with saline. the left ventricular pressure and volume were measured with the pressure and conductance catheter every h. cardiac function, including cardiac output (co), left ventricular peak pressure (lvpp), and cardiac work (cw) were analyzed with a computer soft. blood was collected from rats every h after operation to measure plasma concentration of blood lactate. data were analyzed by repeated measure anova. results. the co in the oxytocin group was kept higher than the control group but there is no significance (p \ . ). the lvpp and cw in the oxytocin group were kept significantly higher than the control group (p \ . ). arterial lactate was significantly lower in the oxytocin group versus the control group (p \ . ). conclusion. the present study indicates that the treatment with oxytocin improved cardiac dysfunction and reduced plasma concentration of lactate in septic model. introduction. conventional hemodynamic monitoring parameters like heart rate, mean arterial pressure (map), and central venous pressure may be misleading in assessment of circulating blood volume in severely septic patients. inadequate blood volume may compromise renal blood flow leading to acute kidney injury (aki). stroke volume variation (svv) is a sensitive indicator of relative preload responsiveness and has high sensitivity and specificity when compared to conventional indicators of volume status and their ability to determine fluid responsiveness. to assess the efficacy of svv guided fluid therapy in preventing aki in patients with severe sepsis on ventilatory support. mechanically ventilated patients with septic shock who had undergone resuscitation based on surviving sepsis campaign guidelines and still requiring vasopressor support were enrolled. patients with pre-existing renal failure were excluded. a total of patients were randomized to receive fluid therapy according to conventional indices or svv, in the first h after mechanical ventilation. svv was measured with flotrac vigelio after abolishing spontaneous ventilation by sedation and paralysis if required. fluid boluses were given to keep svv less than %. vasopressor therapy was optimised to maintain map [ mm hg. patients were followed during their icu course with respect to development of aki, need for renal replacement therapy (rrt), length of icu stay and icu mortality. aki was diagnosed as per the rifle criteria. primary outcome measure was development of aki. results. patients in both groups were similar with respect to age (p = . ), sex (p = . ), and admission apache ii score (p = . ). incidence of aki was / ( . %) and / ( . %) in conventional and svv groups, respectively (p = . ). there was no statistically significant difference in terms of need for rrt, icu length of stay and icu mortality ( [ ] . moreover, pnu- a (pnu), an inhibitor acting through the poreforming subunit of the channel, did not affect bp in our awake peritonitis rat model [ ] . given that vasoconstrictors, including ne, inhibit k atp channel activity [ ] , we speculate that the high sympathetic tone seen in sepsis [ ] objectives. the goal of this study was to determine if hfav improves microcirculatory alterations in ss patients. methods. by using side dark field videomicroscopy (microscan Ò , microvision medical) we evaluated sublingual microcirculation in ss patients who according to our local protocol care [ ] underwent a h-hfav as rescue therapy for refractory septic shock. hemodynamic parameters and microcirculation were assessed at baseline, after h of hfav, and h after stopping hfav. microcirculation assessments were performed at to different sublingual areas ( - s/image). images were analyzed according to recent consensus [ ] by semiquantitative scores of flow (mfi, mean flow index and ppv, proportion of perfused vessels), density (tvd, total vascular density; pvd, perfused vascular density), and heterogeneity (het mfi) of small vessels (\ lm introduction. disturbances within the microcirculation represent an important factor in the pathogenesis of multiple organ dysfunction in sepsis and septic shock [ ] . gender-specific effects may modulate the septic pathophysiology [ ] . therefore, we studied sepsis-induced changes within the intestinal microcirculation in randomly cycling and ovariectomized female rats. objectives. we hypothesized that estradiol (e ) and dehydroepiandrosterone (dhea) may have a beneficial effect on the microcirculation during experimental sepsis and resubstituted these hormones in the ovariectomized animals. methods. fifty female rats were divided in to five groups of ten animals. group received sham laparotomy without further treatment. in group - we induced experimental sepsis (colon ascendens stent peritonitis-casp model). animals of groups - were additionally ovariectomized weeks before sepsis induction. in group we administered mg/kg estradiol immediately after and h following casp surgery. the animals of group received mg/kg dhea immediately after sepsis induction. twenty-four hours after casp surgery intravital microscopy was performed to study leukocyte-endothelial interactions and functional capillary density. blood samples were taken for the measurement of estradiol, dhea and inflammatory cytokines. results. in ovariectomized rats subjected to casp the number of activated leukocytes was significantly increased in comparison to sham and not ovariectomized casp animals (p \ . ). in ovariectomized rats treated with e leukocyte adhesion was significantly reduced in comparison to untreated ovariectomized rats subjected to casp (p \ . ). the same observation was made in ovariectomized rats treated with dhea. in addition, in ovariectomized rats subjected to casp the functional capillary density was significantly decreased in comparison to sham and casp groups (p \ . ). in ovariectomized rats treated with e or dhea functional capillary density was completely restored. the results demonstrate the role of e and dhea in the sepsis-induced changes within the microcirculation. a rapid, non-genomic effect of both e and dhea is suggested [ ] . dhea may play a role through conversion to e or through direct acting on the e receptor. further investigations should be done to elucidate the underlying mechanisms. both e and dhea appear to be a promising adjunct for the prevention and treatment of sepsis-induced multiorgan failure. liver is involved in the production of no. the aim of this experimental study was to evaluate the time course of hepatic no production at the onset of hypotension occurring during septic shock. methods. male wistar rats were anesthetized with isoflurane Ò , and mechanically ventilated. a first group (sepsis group) underwent a cecal ligature and puncture (clp) peritonitis, the second one (control group) a laparotomy only. animals were euthanized at different times: h after surgery, at shock onset, and h after shock. shock was defined by systolic blood pressure lower than mmhg. each rat of sepsis group was matched with rat of control group. liver perfusion was measured using a direct laser doppler flowmetry probe. no generated in the liver was measured using a pulse voltametric method. results. rats were studied ( in each group). in sepsis group, shock occurred at ± min after clp. in sepsis group, a significant decrease of hepatic perfusion was identified h after clp ( fig. ) whereas hepatic no production was increased only at the time of shock onset (fig. ). intra hepatic no production conclusion. this study shows a time shift between hepatic perfusion disturbance, hepatic no production and shock onset in a septic animal model. introduction. microvascular blood flow alteration is a key element of severe sepsis and septic shock [ ] . one study show that microvascular alterations in septic patients could be improved with a nitric oxide donor nitroglycerin [ ] . studies in human have shown that infusion of magnesium sulphate has endothelium dependent and independent vasodilation properties, increase of red blood cells deformability in specific conditions. we hypothesized that combination of nitroglycerin with magnesium sulphate and order of priority influence microvascular improvement in patients with severe sepsis and septic shock. methods. ten septic patients who had already been fluid resuscitated randomly assigned to one of two groups. one group received magnesium sulphate infusion g/h with nitroglycerin . mg/h infusion added after min. another group received nitroglycerin . mg/h infusion with additional magnesium sulphate g/h infusion after min. if required we added crystalloids and use norepinephrine. sublingual microcirculation was evaluated using side dark field videomicroscopy (microscanÒ, microvisionmedical) . each patient's microcirculation was evaluated by examining different sublingual areas ( - s/image). in all patients measurements were obtained at baseline, at and min. images were analyzed by semiquantitative scores of flow (mfi, mean flow index; ppv, proportion of perfused vessels) and density (tvd, total vascular density; pvd, perfused vascular density). capillaries were defined as microvessels with a diameter \ lm. data are presented as median values (percentiles ; ). . the median age of the patients was ( ; ) years. in both groups we see tendency progressively increase of pvd, ppv and mfi after drug alone and combination after min, but pvd has tendency to be higher [ . ( ; . ) n/mm vs. . ( . ; . ) n/mm , p = . ] after min. in group, where magnesium sulphate infusion was given first. combination of magnesium sulphate with nitroglycerin, when magnesium sulphate is given first, has tendency to higher potential for improving of microcirculation in severe sepsis and septic shock patients, but further studies are needed to obtain more detailed results. severe sepsis remains one of the leading causes of death in critical care, with around % of patients dying within one month of diagnosis. rapid diagnosis and therapy of sepsis improves survival [ ] . in november the whittington hospital introduced a hospital severe sepsis guideline, based on the first surviving sepsis campaign guideline [ ] . the sepsis guideline was published on the hospital intranet and specified actions to be completed within the first h of the diagnosis of severe sepsis or septic shock [ ] . objectives. to assess whether publication of a sepsis guideline on the hospital intranet, coupled with departmental educational campaigns, improved the management of severe sepsis. the whittington hospital is a university associated general hospital in london. we audited the early management of severe sepsis and septic shock before and after the introduction of the new hospital sepsis guideline. the 'before' phase comprised patients with severe sepsis or septic shock admitted to critical care between november and november . the 'after' phase comprised patients with severe sepsis or septic shock admitted to critical care between january and november , after introduction of the guideline. data was retrospectively collected from case notes and observation charts. the audit tool compared immediate, , and h actions following diagnosis against the hospital guideline. the main outcome measures were compliance and day mortality. compliance was defined as the average of the percentage compliance with each of the items specified in the guideline. results were compared by chi squared. compliance with the severe sepsis guidelines was only % after publication of the hospital sepsis guideline, compared with % before publication (p. )! there was similarly no significant difference in day mortality (before %, after %, p. ). publication of a sepsis guideline on the hospital intranet, coupled with departmental teaching sessions, failed to improve compliance with surviving sepsis recommendations, perhaps because the guideline competes for attention with over other guidelines on the intranet. next we will implement an interdepartmental educational programme to try and improve guideline compliance. as guidelines proliferate it is difficult to ensure they are followed, but failure to implement a published hospital guideline may represent a significant clinical and medicolegal risk. methods. the icu is an intensivist-led bed intensive care in a bed non-academic teaching hospital. hospital mortality from sepsis in icu-patients was . % in . patients are treated under modern icu conditioning, including continuous venovenous hemofiltration and a lung-protective ventilation strategy including prone position. an intensive insulin therapy protocol for glycemic control is used. in the period between march until june , we prospectively screened all patients admitted to the icu for (severe) sepsis, without the knowledge of the nurses and most of the doctors. all severe septic patients were included in our surviving sepsis database. after h, we examined how many targets of the resuscitation and management bundles were applicable and reached. in the period between march until june , patients were admitted to the icu. twenty-two of them were suffering from severe sepsis ( . %), of which had a septic shock. focus of the sepsis was abdominal in patients ( %), pulmonary in five patients ( %), urogenital tract in five patients ( %), meningitis in one patient ( %) and catheterrelated in one patient ( %). table shows us the applicability and achievement of the bundle elements. only in one of the patients all targets were reached. however, mean individual bundle element performance was . % (sd . ). all patients received fluid resuscitation when indicated, and all patients on mechanical ventilation were ventilated in a lung-protective manner with plateau pressures \ cm h o. only percent of patients had glucose levels within the target range. scvo was never measured, though it was indicated in patients. one patient had an apache iiscore c and had no contraindications for administration of activated protein c. treatment was not considered for this patient by the attending physician. of these patients suffering from severe sepsis, three died within days after the diagnosis ( . %). introduction. the surviving sepsis campaign (ssc) guidelines give a group of interventions (''sepsis bundles'') expected to improve the outcome of patients with severe sepsis [ ] . objetives: the aim of this study was to evaluate the impact of the implementation of the ssc guidelines on the mortality in our intensive care unit (icu). methods. prospective, observational study. during one year period (january -january ) the sepsis bundles were applied to each patient with severe sepsis-septic shock and they were followed up until discharge. we considered as ''time o'' (the time of delay of the implementation of the sepsis bundles) the time of admission of the patients in the icu. for each severe septic patient the following data was registered: time delay, apache ii and sofa scores at icu admission, diagnosis, the rate of compliance with the resucitation and management bundles, microbiological data, evolution of levels of serum lactate, empiric antibiotic therapy, length of stay and mortality in icu. the application of guidelines impact on mortality was compared with historical data years before implementation in our icu ( . %) and spanish icu ( . %) [ ] . a total of severe septic patients were included in the study. ( . %) patients had severe sepsis and ( . %) septic shock. the median age was years. the mean apache ii was . (± ) and sofa was . (± . ). the main sources of infection were abdomen ( %), lungs ( %), urinary tract ( . %) and soft tissues ( . %). the most common clinical diagnosis related to an episode of severe sepsis was peritonitis ( %). a microbiological diagnosis of the infection was reached in . % and the infections were mostly caused by gram-bacilli. once the antibiogram was obtained, the initial treatment was considered appropriate in . % patients. the rate of compliance with sepsis bundles was %. the length of icu stay was . days. mortality was . %. the implementation of the sepsis bundles decreased icu mortality significantly ( . % before implementation vs. . % after implementation). non survivors were older (median age ± . ), had higher apache ii (mean . ± ) and sofa (mean ± . ), % had septic shock, . % had negative cultures and an increased on the levels of serum lactate in h. age, apache ii and sofa scores and the increased on the levels of the serum lactate were useful tools to predict mortality. conclusion. implementation of the surviving sepsis campaign guidelines was associated with a reduction in icu mortality. introduction. the objective of this before-after study is to assess the impact of a protocol of care for severe sepsis in a french emergency setting. methods. two months periods were surveyed before and after the initiation of a protocol of care for severe sepsis and septic shock. after the control period (p : november -february ), a procedure for early recognition, aggressive treatment and standardized antibiotherapy of severe sepsis was initiated. a campaign to raise medical physicians and nurses awareness concerning this new strategy of care was performed. the intervention period (p : november -february ) assessed the impact of these actions. . patients with severe sepsis or septic shock were included during p ( % of patients with a suspected infection and . % of all non trauma admissions) and during p ( . % of patients with a suspected infection and . % of admissions). the age and the proportion of patients with co-morbidities were similar during the p and the p periods ( years in median versus years, and vs. %, respectively). and % of the patients lived in long term care facilities. severe sepsis and septic shock were correctly identified by the emergency team in / ( . %) during p and in / ( . %) in p (p = . ). the delay between the admission in the emergency department and the administration of antibiotics was in median equal to h min in p and h min in p (p = . ). adequate iv fluid resuscitation was administered to % of patients in p and % of patients in p (p = . ). during p , % of patients did not qualify for admission to the intensive care unit compared to . % in p . hospital mortality did not change from . % ( / ) in p to . % ( / ) in p (p = . ). conclusion. the introduction of a standardized treatment protocol in an emergency department allowed a better recognition of severe sepsis with earlier adapted treatment . the study was not powered to demonstrate a reduction of the mortality in this elderly population. multiple studies have shown that early detection and therapy is crucial for the prognosis of a severe septic patient. many hospitals have joined the surviving sepsis campaign and its fight for the decrease of mortality in severe sepsis and have implemented the severe sepsis bundles into their daily practice. other institutions such as ours had so far not taken this step, perhaps because the process is hard and time consuming. we have tried to find an easy way to audit the implementation of severe sepsis bundles and its change in time in an institution without a set system and database for the implementation of severe sepsis bundles to help us prove, that a systemic change in clinical practice is essential. we have decided to use the first step of the resuscitation bundle-the measurement of lactate and audit the lactate requests in blood samples with elevated inflammatory markers in our hospital laboratory information system. we retrospectively audited the number of lactate requests in blood samples with c-reactive protein (crp) c mg/l and its evolvement in time between and before and after the introduction of surviving sepsis guidelines and severe sepsis bundles in our regional hospital with beds. we compared the total number of blood samples with elevated crp c over mg/l with or without procalcitonin request in our institution with the number of blood samples with crp c mg/l and lactate request (both arterial and venous) in the hospital laboratory information system. . the total number of lactate requests in samples with crp c mg/l had increased in time, the incidence widely differed between departments. the main increase was in patiens from intensive care units, the number of lactate requests in samples from general wards, emergency department and intermediate (step down) units had also increased ( lactate requests in samples with crp c mg/l- , % in and lactate requests in samples- . % in ) but still remains insufficient. surprising was that procalcitonin was in non icu patiens with crp c mg/l requested more often than lactate. although many lectures and seminars on severe sepsis bundles and the guidelines for the management of severe sepsis were organised in our intitution between the year and , it was not sufficiently effective. conclusion. retrospective audit in the hospital laboratory information system of the number of lactate requests in samples with elevated inflammatory markers appears to be a fast and a very easy first step for auditing how the surviving sepsis guidelines and severe sepsis bundles are implemented in your institution. the results help to quantify the present state, its change in time and may serve as an impulse to make systemic changes in the system of early detection and therapy of septic patients. introduction. early goal-directed therapy (egdt) is the accepted gold standard for resuscitation in septic shock [ , ] . international guidelines for the treatment of septic shock [ ] set an initial h limit to accomplish this goal. to test the hypothesis that egdt with fluids and vasopressors has better patient outcomes if each intervention is completed within h. thirty septic shock patients from the spring of and from spring were reviewed prospectively (n = ). septic shock was defined as a lactic acid c mmol/l and/or hypotension unresponsive to fluids. apache ii and sofa scores were calculated. patients were subjected to the hospital septic shock protocol according to guidelines [ ] . firstly, egdt compliance was met if the following interventions were achieved within h: lactate levels drawn, map c mmhg and cvp c mmhg; and secondly, if antibiotics were given\ h, blood cultures were taken before antibiotics and if ml/kg fluid bolus was administered prior to vasopressors. in patients / interventions were performed in time (''egdt-compliant''). the other were deemed ''egdt-noncompliant''. outcomes were mortality rate and discharge destination. fisher test was used in statistical analysis. . mr was % amongst the compliant and % amongst the noncompliant and admission to long-term care facilities (ltcf) was and %, respectively. neither one of these differences was statistically significant. a power analysis revealed that patients are required to attain statistical significance for mortality. discharge home was the same in both groups. there was no difference between groups in the number of new tracheostomies or new hemodialysis. conclusions. in a us community teaching hospital, compliance with guidelines in the treatment of septic shock had a trend towards lower mortality and higher discharge rates to ltcf but the difference was not statistically significant. larger numbers are needed for the benefits/effects of egdt-compliant therapy to reach statistical significance in the treatment of septic shock in this hospital setting. improve the survival rate of septic patients by means of education and implementation of a sepsis operative protocol including the activation of a specific consultation by an intensivist and an infectious disease specialist (i.e. sepsis team, st). aim of this study was to describe the first months activity of st, with a focus on the patients not admitted in intensive care unit (noicu). methods. the sepsis operative protocol, introduced in clinical practice in june , provides for specific instructions for the early identification and management of septic patients and for the early activation of the st for patients with severe sepsis or septic shock admitted in non-intensive departments. the st consultation ought to support the departmental health personnel in the management of septic patient and allows an early intensive care admission in case of shock or if mechanical ventilation is needed. to assess st activity, we evaluated in noicu patients the correct st activation rate, the number of st activations for each patient, the rate of central venous catheter insertion (cvc) and the days mortality. results. from june to december , the st was activated for patients ( . patients per month) whose ( %) were admitted to icu and ( %) were considered too sick to benefit. in ( %) of the remaining patients, st was properly activated: patients with severe sepsis and with septic shock. thirteen patients ( %) had no sepsis and ( %) had sepsis without organ dysfunction. % of st activations originated from medical departments (including emergency department) and % from surgical departments. the number of st activations for each single patient was ± . the days mortality was . % in patients with sepsis, % in patients with severe sepsis and % in patients with septic shock. conclusion. the rate of correct activation of st and the number of activations for each patient were acceptable considering that more than % of the activations refers to septic patients and that a mean of activations was sufficient for patient management. mortality rates observed are slightly lower than those reported by others, but further data are needed to evaluate the impact of st on patient outcome. a. estella , l. pérez fontaiña , j. i. sanchez angulo , e. moreno hospital of jerez, emergency and critical care unit, jerez, spain clinical evidence suggests that an early diagnosis and treatment of severe sepsis has been shown to improve outcome. frequently the initial management of septic patients occurs outside of the icu. objective. to describe clinical characteristics and outcome of septic shock patients admitted in icu and to compare mortality according origin prior admission in the icu (emergency department versus medical or surgical wards). consecutive patients with septic shock admitted in icu from july to november were registered. age, icu length of stay, source of infection, isolated bacteria, blood lactate concentration, apache ii score and mortality were collected. patients were classified according the origin prior admission in icu. . consecutive septic patients were admitted in icu during the time of study, global mortality was %. patients were admitted from medical or surgical wards and patients from the emergency department. mean age was years, male and female, icu length of stay was . ± . days, the mean apache ii score at admission in icu was . ± . abdominal infection, . %, was the commonest source of infection followed by pulmonary and urinary infection, . and . % respectively. patients ( %) had a positive bacterial culture, the mean baseline lactate level was . ± . mmol/l p \ . ( . ± mmol/l in the medical and surgical wards group versus . ± mmol/l in the emergency department group).there were not differences in clinical characteristics according origin prior admission in the icu except for lactate level, and mortality, . % in the medical and surgical wards group and . % in the emergency department group (p \ . ). conclusion. there were not differences in clinical characteristics, icu length of stay, source of infection, isolated bacteria and apache ii score between groups. mortality was lower in the group of patients admitted in icu from the emergency department than the group admitted from medical and surgical wards. although very high circulating concentrations are detectable in plasma, it is not known which organs actually produce the cytokines. we hypothesized that key abdominal organs affected by sepsis such as the kidney and liver produce cytokines and tested this hypothesis by measuring cytokine flux. materials and methods. pigs ( - kg) were randomised to control (n = ) and endotoxin (n = ) groups. hemodynamic measurements using picco and pulmonary arterial catheters and arterial blood gases were collected hourly. portal, hepatic and renal arterial blood flows were measured with transit time probes. arterial and venous cytokine concentrations (tnfa, il- b, il- and il- ) were measured from samples taken from each respective organ. cytokine flux was calculated as: organ blood flow (venous-arterial cytokine concentration difference). endotoxemic pigs had significant increases in heart rate (p \ . ) and mean pulmonary arterial pressure (p = . ) and decreases in cardiac output (p = . ). in contrast, these hemodynamic variables remained stable in the control animals. renal, hepatic and portal vein flows decreased significantly in all endotoxemic animals but remained stable in the control group. renal [ml/(kg min)]:control . ± . , . ± . , . ± . , . ± . versus endotoxin . ± . , . ± . , . ± . , . ± . for baseline, t = , , , respectively. portal [ml/(kg min)]: control . ± . , . ± . . . ± . , ± . versus endotoxin . ± . , . ± . , . ± . , . ± . for baseline, t = , , , respectively. hepatic [ml/(kg min)]: control . ± . , . ± . , . ± . , . ± . versus endotoxin . ± . , . ± . , . ± . , . ± . for baseline, t = , , , respectively plasma cytokines tnfa was detectable in very low concentrations (\ pg/ml) in of the endotoxemic animals, and none of the control animals. il- b, il- and il- increased significantly with time peaking at t = , and respectively in the endotoxin group. in the control group only few animals showed a cytokine response, in numbers insufficient for statistical analysis. in the endotoxin group there was a negative cytokine flux in the renal circulation, maximal at t = [- . ± . for il- b and - . ± . for il- (pg/ml), respectively]. there was a positive cytokine flux for il- reaching its peak at t = ( . ± . pg/ml). a similar pattern was seen in the hepatic ? portal circulation with maximal flux for il- b and at t = (- . ± and - . ± . pg/ml, respectively). for il- there was a positive flux peaking at -= ( . ± . pg/ml). although there was a negative il- b and il- cytokine flux in the renal, portal and hepatic circulations indicating net uptake, and vice versa for il- , none of these values reached statistical significance. conclusions. these data do not support that cytokines are produced nor consumed in the kidney and liver during endotoxemia. discussion. non-survivors show more severity at the beginning and during their icu stay, more altered biological markers and a higher mean glycemia, but do not show significant difference either at initial glycemia, history of diabetes, hypoglycemia event or insulin treatment. elevated mean glycemia appears to be a factor independently associated with higher mortality. hyperglycemia prevalence in critically ill patients is very high and the controversy whether it is a mortality marker or a mediator still remains. our results would justify starting an intensive insulin protocol and its subsequent analysis. the interest of continuous scvo was proven in the management of severe septic patients [ ] , but the place of discontinuous scvo remains unclear. objectives. to compare continuous scvo to discontinuous scvo concerning the number of therapeutic interventions in the management of severe sepsis (ss) and septic shock (ssc). methods. prospective randomized comparative study. inclusion criteria: age [ years, ss or ssc [ ] . two groups were defined: continuous scvo (c group) monitored by a central venous oximetry catheter (edwards lifescience x hs, irvine, usa), and discontinuous scvo (d group) measured on blood samples drawn every h and at the request of the treating physician. the hemodynamic management of these patients was based on the algorithm established by rivers [ ] . the primary endpoint was the number of therapeutic interventions (fluids, transfusions, inotropic drugs) triggered by a scvo \ %. non parametric tests (chi-square and mann whitney) and repeated-measures anova were used in statistical analysis (p \ . was considered significant). results. patients were included in a polyvalent intensive care unit (icu). the two groups were comparable concerning age, sex, weight, height, apache ii score, mods on admission and mechanical ventilation (mv). there were no statistical differences between the two groups concerning: mortality, duration of icu stay, duration of mv and the evolution of mods and plasma levels of lactate from day to day . the therapeutic interventions data are shown in table . introduction. the calcium activated potassium channel (bkca) exists in smooth muscle cells in most vascular beds and is believed to be important in sepsis induced hypotension and vascular hyporeactivity [ ] and also in neutrophil killing and macrophage production of proinflamatory cytokines. however the latter two roles have been disputed [ ] and we have found that bkca expression is not upregulated in aorta from septic mice using real time polymerase chain reaction. as its role in sepsis remains uncertain we sought to determine whether null mice for the bkca channel were (a) resistant to hypotension and (b) showed improved survival in a clinically relevant model of fecal peritonitis. methods. bkca null mice (based on balc) were obtained from jax Ò mice. agematched litter mates homozygous for bkca were wild types (wt). mice (age - weeks) had tethered arterial and venous lines inserted under isoflurane anesthesia. the tether enabled mice to roam cages freely whilst continuous blood pressure (bp) traces were obtained. h post surgery, echocardiogram and intraperitoneal injection of rat slurry was administered under anesthesia. fluid resuscitation of . ml/h voluven/ % dextrose ( : ) was given. at and h echo was recorded and mice culled with mesenteric arteries dissected for myography. data expressed as mean(sem) and statistical analysis anova. results. genotypic study and whole cell patch clamp recording in aortic smooth muscle cells confirmed bkca current was absent in null mice. fecal peritonitis induced equivalent hypotension in both wt (n = ) and bkca null mice (n = ) at - h (fig. a ). echocardiography at h post slurry showed no difference in cardiac output between wt- . ( . ) and bkca null mice- . ( . ) ml/min and no difference or improvement cf time (fig. b) . thus this fall in bp is due to reduction in total peripheral resistance not myocardial depression. in addition / of the bkca null mice died prior to h as opposed to / wt. hence myography was only performed on wt mesenteric arteries which were hyporeactive to norepinephrine (p = . , fig. c ). conclusion. there is no evidence from this transgenic mice study of fecal peritonitis that inhibition of the bkca channel would be beneficial for the treatment of hypotension in septic shock or would improve survival. reference(s). introduction. pro-and anti-inflammatory responses play a key role in the pathophysiology of sepsis [ ] . phosphodiesterase (pde) inhibition could play an anti-inflammatory role in this setting [ ] . previously, it was shown that among the three inhibitors of pde five currently available (sildenafil, vardenafil, tadalafil), only tadalafil could exhibit anti-inflammatory properties on endothelial cells (ec) stimulated by modified oxidized ldl or tnf alpha [ ] . to assess the potential anti-inflammatory role of tadalafil in ec stimulated by lps. methods. thp- cells ( . /ml in rpmi) were incubated alone (control group) or in the presence of either tadalafil ( lm; eli lilly, in, usa), lps from e.coli :b ( ng/ml; sigma-aldrich, inc.) or both. tnfa production, as a marker of inflammation, was measured in the supernatant (elisa assay; roche, mannheim, germany) after h of incubation ( independent experiments in quadruplet). comparisons were made by one-way anova, with bonferroni's post hoc test (mean ± sem). results. production of tnfa increased significantly after stimulation by lps alone compared to control ( . ± . -fold over the control, p \ . ) or tadalafil ( . ± . vs. . ± . -fold over control, p \ . ). levels of tnfa were significantly reduced in the lps ? tadalafil group, compared with the lps group ( . ± . vs. . ± . -fold over the control, respectively; p \ . ) (graph ). we hypothesized that daa provides varying protective effects in different organs as indicated by higher amounts of epcr in early murine sepsis. methods. sepsis was induced by cecal ligation and puncture (clp) in male nmri-mice (n = , body weight ± g). animals were randomly assigned to vehicle infusion (control), or clp sepsis with daa infusion [daa; lg/(kg hr)]. a third group received only sham operation and vehicle infusion (sham). h prior to clp all mice were given a permanent central i.v.-line and an arterial transmitter (pa-c , st. paul, mn, usa) to measure heart rate (hr) and mean arterial pressure (map). clp was adjusted to survive h. after h hearts, livers and kidneys were fixed in formalin and embedded in paraffin. immunohistochemical analysis of the paraffin sections was performed using the avidinbiotin-peroxidase complex (abc) method. for analysis an anti-mouse epcr antibody (clone , natutec, frankfurt, germany) was used (dilution : ) after heat pretreatment. anti-epcr positive cells were counted in fields in light microscopy (original magnification: . ) of each tissue and the average was recorded. data are presented as mean ± sd. *p \ . was considered significant. results. there were no significant differences in hr between the groups (sham ± per min; daa ± per min; control ± /min). map was significantly higher in sham group ( ± mmhg; p = . ) and non-significantly higher in daa group ( ± mmhg) when compared to control ( ± mmhg). anti-epcr positive cell count in heart tissue was significantly higher in sham-treated mice ( . ± . cells; p \ . ) and daa mice ( . ± . cells, p = . ) compared to controls ( . ± . cells). in kidney tissue epcr positive cells were significantly more in sham group ( . ± . ; p = . ) compared to control, but not in daa group ( . ± . ). liver samples showed no significant differences (sham . ± . ; daa . ± . ; control . ± . ). conclusion. our data showed higher amounts of epcr in murine sepsis undergoing daa therapy in heart and kidney tissues, but not in the liver when compared with control animals. this suggests that daa provides different effects in early experimental sepsis. background. caspofungin treatment is often initiated in hypovolemic shock patients, what could affect its pharmacokinetics and efficacy. the present study investigated the influence of hypovolemic shock and fluid loading on the plasma pharmacokinetic parameters and the pulmonary penetration of caspofungin in a pig model. after anesthesia and mechanical ventilation, pigs ( ± kg) were bled to induce a -h deep shock and resuscitated for h using normal saline based on hemodynamic goals. a -h perfusion of mg caspofungin was started at the beginning of the resuscitation period. lungs were removed h after the initiation of hemorrhage. sixteen animals were used as controls without hemorrhage. caspofungin concentrations were measured using high performance liquid chromatography method. in the shock group, the volume of removed blood was ± ml/kg and a volume of ± ml/kg of saline was infused through the resuscitation period. conclusion. hypovolemic shock followed by fluid loading in pig results in a significant decrease in plasma caspofungin exposition. it resulted in a decrease in the pulmonary concentration of caspofungin without affecting its diffusion to the lung. future investigations should focus on the interest for monitoring of plasma caspofungin concentrations in icu patients and on optimal dosing in these patients. objectives. the present study was designed to assess the effects of mps from septic origin on systemic hemodynamics as well as on the inflammatory, oxidative and nitrosative stresses. methods. forty healthy rats were randomly allocated to three groups: animals inoculated with mps isolated from control rats (cmps), animals inoculated with mps isolated from sham rats (shmps) and animals inoculated with mps isolated from rats with peritonitis (smps). rats were anesthetized, mechanically ventilated and were infused with the same amount of cmps or shmps or smps. we measured heart rate (hr), mean arterial pressure (map), carotid artery blood flow (cbf) and portal vein blood flow (pbf). hemodynamic parameters were recorded during h, and then animals were sacrificed. aorta and heart were harvested for further in vitro tissue analyzes. . the cellular origin (phenotype) but not the circulating concentration of mps was different in septic rats, characterized particularly by a significant increase in leukocyte derived mps. . smps but not cmps or shmps decreased mean arterial pressure without any effect on carotid artery and portal vein blood flows. all rats survived in the cmps and shmps groups whereas three rats died before the end of the experiment in the smps group. . rats inoculated with smps exhibited an increase in superoxide ion production and nf-kb activity, over-expression of inos with subsequent no overproduction and decrease in enos activation. pulse blood pressure recordings conclusions. rats with sepsis induced by peritonitis exhibited a specific phenotype of mps which could play a detrimental hemodynamic effect as a systemic vasodilatation. inoculation of smps in healthy rats decreased map likely by up-regulating nf-kb activity with subsequent inos, no and superoxide anion overproduction. these data confirm a proinflammatory detrimental role of mps in the vascular pathophysiology of septic shock. introduction. heat shock proteins (hsps) play an active part in modulating intracellular responses to stress. in the classical model for their activation de-repression of heat shock transcription factor (hsf ) occurs as a result of the titration of hsps away from hsf by misfolded proteins [ ] . however, hsps may change in many diseases without any changes in the levels of denatured proteins [ ] . objective. we propose that hsps are activated, in part, by a membrane dependent calcium channel receptor, possibly transient receptor potential vanilloid type- (trpv ). capsaicin, a known inducer of trpv , and capsazepine, a selective antagonist, were used on different mammalian epithelial cell lines. cells were pre-treated with micromolar concentrations of capsaicin or heat shock (hs) followed by treatment with capsazepine. results. capsaicin or hs induced hsf activation and the consequent accumulation of hsp , and chaperones. pre-treatment with capsazepine prior to hs or capsaicin abolished the heat shock response (hsr). capsazepine treatment prevented capsaicininduced stabilization of ikb and cell to cell adhesion and induced apoptosis. capsazepinemediated blockage of the heat shock response was reproduced with egta. moreover, treatment with trpv sirna resulted in a similar response to capsazepine. conclusion. hsr-sensing and signaling in mammalian cells depends, in part, on the transient entry of calcium by way of membrane dependent calcium channel receptor. these hsr modulators may hold promise in treating inflammation in the future. introduction. hydrogen sulphide gas, or its intravenous donor-sodium hydrogen sulphide (nahs), are promising therapeutic agents in ischaemia-reperfusion and haemorrhagic shock [ ] . we studied nahs in a short-term endotoxaemia model as relatively little is known about its effects during sepsis. methods. under isoflurane anaesthesia, male wistar rats (approx g weight) underwent left common carotid and right jugular venous cannulation for blood sampling/continuous bp monitoring and fluid administration, respectively. animals were kept normothermic on a heating mat. tissue oxygen tension (tpo ) was monitored using oxylite probes (oxford optronix, oxford uk) placed in thigh muscle. after a -min stabilization period, fluidresuscitated rats [ ml/(kg h)] were subjected to iv lps ( mg/kg over min). comparisons were made against animals receiving nahs ( . mg/kg bolus given immediately after lps, followed by a mg/(kg h) infusion). echocardiography (vivid , ge healthcare, bedford) and blood gas analysis were sequentially performed. sham-operated, non-septic animals also received nahs (n = ) or placebo (n = ). at the doses given, nahs had no effect on either sham-operated animals (data not shown), nor on the endotoxic rats (table ) . data shown as mean (±se). timepoints chosen reflect the biphasic response to endotoxin: = baseline, = initial hypotensive phase, = maximal recovery, = end of experiment. conclusion. nahs does not improve haemodynamics, tissue oxygenation nor shockrelated biochemical parameters in a severe model of fluid-resuscitated endotoxaemia. we will further investigate the effects of dose and time of therapeutic intervention in this model, in addition to testing it in a long-term septic model. intestinal endothelial and epithelial barrier dysfunction remain severe clinical problems as they may contribute to the development of sepsis and multiorgan failure. we have recently established an isolated rat small intestine model with access to vasculature, lumen and lymphatics for study of inflammatory changes in fluid balance [ ] stable for min, rendering it less suitable for examination of changes in gene and protein expression profile. the aim of this study was to assess the long term functional and metabolic stability of this model. adult female wistar rats were anaesthetized, small intestines cannulated and perfused vascularly ( . ml/min) and luminally ( . ml/min) and placed in a warm humidified chamber for up to h. arterial, venous and luminal pressures as well as venous, luminal and lymphatic effluent flows and intestinal weight were recorded continuously. as measures of metabolic integrity, oxygen consumption, lactate/pyruvate ratio and galactose uptake from luminally administered lactose were analysed every min. structural and barrier integrity were assessed as histostability score (mesenteric and antimesenteric fraction of fully epitheliated villi), wet/dry weight ratio and translocation of vascularly applied fitc albumin to lumen and lymphatics. data were compared using paired t tests. ± . / . ± . ml/(min g) dry weight (**)) as well as galactose uptake ( . ± . / . ± . mg/(min g) dry weight (n.s.)) were very stable with time pointing towards high metabolic stability. during the whole experiment, luminal effluent flow was slightly lower than applied ( . ± . ml/min, min) resulting in net liquid absorption over the whole time period ( . ± . / . ± . ml/min (n.s.)), and lymph production stayed in the physiologic range ( . ± . / . ± . ml/min (n.s.)). the organ weight did not change with time which, together with the balanced luminal fluid flow and end experimental wet/dry weight ratio of . ± . (compared to . ± . at the beginning of the experiment (**)), indicate absence of edema. minimal leakage of vascular fitc albumin to the lumen ( . ± . %) and a histostability score of . ± . show integrity of the vascular-luminal barrier until the end of the experiment. the isolated small intestine model presented earlier [ ] displays excellent long term physiologic, metabolic and histologic stability and opens up a wide field of applications including inflammatory gene transcription and protein expression. introduction. mitochondria play a major role during ischemia-reperfusion as well on cytotoxic pathways as protective such as ischemic preconditioning. the aim of this study is a better understanding of the mitochondrial pathophysiologic response to several oxygen regimens in an isolated mitochondria model. mitochondria were isolated from rat heart. enriched mitochondrial pellets were conditioned in presence of glutamate ( mm) and malate ( mm) inside the oxygraph chamber during min. oxygen partial pressures were: mmhg for control group; to mmhg for hypoxia group and mmhg for anoxia group. then, after a min oxygenation period, several measurements were realized: oxygen consumption (vo ) were measured with or without adp ( mm) (state and of mitochondrial respiration); calcium retention capacity (crc); mitochondrial membrane potentiel (dwm). to explore the involvement of reactive oxygen species (ros), mitochondrial vo were measured in presence of a specific mitochondrial antioxidant drugs (xbj). all results were expressed in percent of variation in comparison to control group [median (minimum-maximum)]. the different groups were analyzed using a kruskal-wallis, a mann-whitney with a bonferroni correction or a sign test when necessary. after hypoxia and reoxygenation the mitochondrial function was altered. this impairment of mitochondrial function was not found after anoxia and reoxygenation. this difference in mitochondrial function between hypoxia and anoxia suggests the involvement of ros. this hypothesis was confirmed by the effect of the antioxidant xbj that reestablished after hypoxia the same level of vo than after anoxia. [ ] . superoxide dismutase (sod) catalyses the dismutation of superoxide oxygen free radicals to oxygen and hydrogen peroxide (h o ). the therapeutic potential of exogenous sod administration in ards is evidenced by demonstrations of efficacy in acute lung injury models [ ] . anti-oxidant defenses, particularly the extracellular sod isoform, extracellular sod (ec-sod), are downregulated by endotoxin [ ] . we proposed that ec-sod delivered via a novel viral vector would ameliorate lung injury caused by lipo-polysaccharide (lps) pulmonary instillation. methods. three groups with nine rats per group were randomised to receive either adenoassociated virus expressing ec-sod (aav-ec-sod), adeno-associated virus coding for no product (aav-null), or vehicle control, days prior to planned lps instillation. a model of lipo-polysaccharide (lps) induced acute lung injury by pulmonary instillation was established in male sprague dawley rats. twenty-four hours following lps delivery, animals were anaesthetized and mechanically ventilated and their baseline compliance and oxygenation recorded. there was a statistically significant improvement in the oxygenation of animals recieving aav-ec sod as compared to aav-null or vehicle control (mean pao = . vs. . and . , respectively). there was a significant increase in amount of ec-sod as determined by real time pcr in the group who were administered aav-ec sod. no significant differences in static compliance or bronchoalveolar lavage cells counted were noted. conclusion. aav delivered ecsod is protective in a animal model of lps induced acute lung injury. the down regulation of the ec sod system seen in the systemic inflammatory response [ ] and its subsequent replacement exogenously may explain our findings. further work will focus on other components of cellular anti-oxidant pathways and confirmation of down regulation of ec sod in our injury model. aims. the endothelial specific angiopoietin (ang)-tie ligand-receptor system has been identified as a non-redundant mediator of endothelial activation in experimental sepsis. binding of circulating ang- to the tie receptor physiologically protects the vasculature from leakage, whereas binding of ang- antagonizes tie signaling and disrupts endothelial barrier function. we tested whether administration of exogenous recombinant ang- improves survival and attenuates multi organ failure in a lethal murine sepsis model. to induce septic acute kidney injury and to evaluate survival time cecal ligation and puncture (clp) was performed in twenty sv mice. half of the mice received an intravenous application of recombinant human ang- ( lg) immediately before clp and every h thereafter. in the other half, saline was administered in the same fashion. for tissue assessment (western blot, immunohistological) clp was induced in versus (ang- vs. saline) additional mice; animals were sacrificed after h. laparotomy served as sham control (n = ). further, a panel of cytokines has been assessed with a cytometric bead array (cba) system after h. . ± . mmol/l, p \ . ) were lower in ang- treated septic mice compared to controls. similar results were obtained at h after clp. renal tissue revealed that saline treated mice exhibit a marked loss of expression of vascular endothelial (ve)-cadherin, a major component of endothelial adherens junctions. in contrast, loss of ve-cadherin expression was prevented by ang- (pre-) treatment (wb densitometry: ang- : . ± . ; saline: . ± . ; p = . ). however, contrary to previous reports, intravenous injection of exogenous ang- enhanced not only the expression of adhesion molecules (icam- , vcam- ) in renal vasculature, but also circulating cytokine levels (tnfa, mcp- , il- , il- ). conclusions. our study demonstrates that administration of exogenous recombinant ang- improves survival time in a lethal experimental sepsis model. enhanced survival was accompanied by an improvement in microcirculatory function, probably via stabilization of adherens junctions. however, ang- injection deteriorated expression of vascular adhesion molecules and raised plasma cytokine levels. although ang- may have utility as an adjunctive agent for the treatment of septic multi-organ failure, additional dose-finding and efficacy studies are required. adaptive immune responses to infection. in contrast to neutrophils, macrophages or lymphocytes, there are virtually no data on the time course of circulating dcs in septic shock (ss). using a novel specific and sensitive assay, we analyzed the evolution of circulating myeloid (mdcs) and plasmacytoid (pdcs) dcs in ss. we enrolled immunocompetent adult patients with ss (n = ), shock from other etiologies (nss, n = ) and with sepsis without organ dysfunction (s, n = ). age-matched healthy controls (hc) served as reference for mdcs and pdcs. blood samples ( ll) were drawn on the day of shock, then after and days. dcs were counted using the dc-labelling kit trucount Ò assay (bd biosciences). cd c? cd -(mdc) and cd c-cd ? (pdc) cells were selected by flow cytometry (facscanto tm , bd biosciences). hla-dr mean fluorescence index (mfi) was measured. age, sex ratio, saps ii, sofa score, nosocomial infection (ni) and mortality rates did not statistically differ between ss and nss pts. at day , mdcs and pdcs counts were significantly lower in ss and nss pts as compared to hc and s ( fig. ). pts with ss had significantly lower mdcs and pdc counts than nss at days and . hla-dr mfi of mdcs and pdcs was lower in ss pts compared to hc (p = . and . , respectively). interestingly, of the ss pts developed ni after a median time of ( . - ) days in the icu. whereas mdcs increased in pts without ni, mdcs counts remained low at day in pts who developed ni: mdcs counts and their relative variation between day and were significantly lower in pts who developed ni than in those who did not (p \ . ). logistic regression analysis indicate that a negative mdcs relative variation is associated with an increased risk of nosocomial infection with an or ( . - ) (p = . ). figure conclusion . ss is associated with quantitative and qualitative abnormalities of circulating mdcs and pdcs as early as day , independently of the haemodynamic injury. the persistence of low counts of mdcs after ss is associated with the advent of nosocomial infection during the icu stay, suggesting that dcs play a role in the development of sepsisinduced immunosupression. introduction. liver dysfunction is common in sepsis but its mechanisms are unclear. the aim of the study was to evaluate the effects of lps on cultured primary human hepatocyte respiration over time. methods. human hepatocytes were isolated and cultivated from human liver resection specimens. cultivated cells were exposed to lps ( lg/ml) for , and h. after incubation, cells were trypsinized and respiration rates were measured using a high-resolution oxygraph (oxygraph- k, oroboros instruments, innsbruck, austria). glutamate ? malate (g ? m), succinate (s) or ascorbate/tmpd (a/t) were used as substrates to test the function of complex i, ii and iv, respectively. human hepatocyte mitochondrial function in the cells treated with lps for h exhibited a significant reduction in the maximal complex ii-dependent mitochondrial respiration [control: ± vs. lps: ± pmol/(s million cells) ( table ) ]. after and h of lps incubation no significant reduction in cellular respiration was observed ( and h: n = and h: n = ). statistics: paired t test, *p = . control vs. lps ( h incubation). introduction. acute kidney injury (aki) in critically ill patients is a frequent clinical problem and a rising incidence has been reported over the past several years. recently two consensus definition for aki have been developed: rifle [ ] in by the acute dialysis quality initiative workgroup (second conference) and akin [ ] in . insofar akin and rifle criteria have been applied in large retrospective studies, limited to the initial days of icu. nefroint is an italian initiative for an observational prospective multicenter study to evaluate epidemiology of aki in italian icus employing rifle and akin classifications. a pilot study has been performed in one of the centers enrolled. objectives. primary endpoints of nefroint are: application and comparison of rifle and akin criteria for aki definition in a prospective observational study; estimate, along such criteria, of aki incidence in critically ill patients; correlation of aki stages with prognosis. method. an observational prospective multicenter study has been designed, in italian adult icus (medical and surgical). all incident icu patients have been enrolled over a month period. exclusion criteria was age \ years, or icu stay \ h. data collection about patients was performed on a web-based electronic case report form. data included icu admission diagnosis, daily urine output ( h interval), daily laboratory data. sepsis events diagnosed on clinical and/or microbiological basis where as well marked for each patient. severity scores have been calculated at admission and daily. aki patients had higher severity of illness scores and higher serum creatinine values on admission. they also were older and more likely to have a respiratory diagnosis as reason for icu admission. conclusions. nefroint is an initiative aimed at comparing rifle and akin scores to promote a uniform use of a single definition of aki that will render subsequent studies comparable. early aki recognition could potentially allow implementation of timely corrective interventions, and hopefully prevent progression to more severe stages. aim. sepsis and septic shock remain the most important causes of acute kidney injury (aki) in critically ill patients and account for more than % of cases of acute renal failure (arf) in intensive care units (icu). its mortality varies with the severity of sepsis from % to %. the aim of this preliminary study was to investigate the differences in the course and prognosis of aki that was induced by community and hospital acquired sepsis. method. patients with sepsis induced aki were included in the study. rifle criteria were used to define aki. clinical and laboratory characteristics of the patients were compared with student t test and chi square tests. results. forty-one patients were included in the study and of them had community acquired septic aki (akic). ninety percent of the patients received mechanical ventilation (mv). etiologies of sepsis were mostly community acquired pneumonia and ventilator associated pneumonia. age, gender, admission apache ii scores and sofa scores at the time of aki diagnosis were similar across the groups (p [ . ). hospital acquired septic aki (akih) developed later when compared to community acquired septic aki ( th and rd days of sepsis respectively, p . ). akih was significantly and more frequently associated with oliguria ( vs. %, p . ), bacteremia ( vs. %, p . ), nephrotoxic antibiotic usage ( vs. %, p . ) and tend to progress more frequently to acute renal failure( vs. %, p . ) compared to akic. akic episodes were more frequently ( vs. %, p . ) and rapidly ( vs. days, p . ) reversible. mean blood pressure and scvo % were significantly lower and more vasopressor and steroid therapies were required during akih episodes compared to akic (p \ . ). while length of mv and mortality rates were similar, duration of hospitalization was significantly longer in the akih group ( vs. days, p . ). conclusion. these results suggest that, akih has worse clinic and prognosis than the akic so further and larger studies are necessary to investigate the preventive and therapeutic approaches. introduction. severity-of-illness or organ dysfunction scores are inaccurate to predict outcomes in patients with acute kidney injury (aki), even when specific aki scores are used. in recent years, the third versions of simplified acute and physiology score (saps ) [ ] and of mortality probability model (mpm -iii) [ ] scores were developed, and information on their use in patients with aki is scarce. objectives. to validate the use of saps and mpm -iii at the start of renal replacement therapy (rrt) in patients with aki. prospective cohort study conducted in the icus of three tertiary-care hospitals. data used to calculate the scores were collected at start of rrt. discrimination was assessed by area under receiver operating characteristic (aroc) curves and calibration by hosmer-lemeshow goodness-of-fit test. a total of consecutive patients were included between january and july . the mean age was . ± . years. the main contributing factors for aki were ischemia/shock ( %), sepsis ( %), contrast/nephrotoxins ( %), rhabdomyolysis ( %) and urinary tract obstruction ( %) (a patient could have more than one contributing factor). eightnine ( %) patients received rrt on the first day of rrt and ( %) thereafter; continuous rrt was used as first indication in ( %) patients. the icu and hospital mortality rates were and %, respectively. the mean saps score at the start of rrt was . ± . points. both the standard equation of saps and mpm -iii scores tended to underestimate mortality. discrimination was better for saps [aroc = . ( % ci, . - . )] than for mpm -iii [aroc = . ( % ci, . - . )], as was the calibration. however, mortality prediction and calibration improved when the customized equation of saps for countries from central and south america was used. in multivariate analyses, both higher prognostic scores and length of icu stay prior to rrt were the main predictive factors for hospital mortality. conclusions. the saps score at the start of rrt was accurate in our cohort of patients and seems a promising instrument for predicting hospital mortality critically ill patients with aki. objectives. the aim of this study was to investigate the effect of hes administration on kidney function compared with other colloids or crystalloids. methods. systematic review and meta-analysis of the effects of hes administration on kidney function. inclusion criteria for the study were prospective randomized trials comparing hes to control with reporting on variables of kidney function. aims. during the initiation phase of experimental acute kidney injury (aki), subtle but devastating changes, such as loss of brush borders, disruption of tubular cell polarity and cytoskeletal changes are detectable only to a certain extent by routine histologic methods. for this reason, subjective and moderate reproducible semi-quantitative scoring of tubular changes (e.g. vacuolization, detachment, cast formation, and necrosis) still remains the method of choice to quantify the extent of experimental aki. lectins are glycoproteins which are able to bind carbohydrate structures specifically. it has previously been shown that immunolabeling of the lectin phaseolus vulgaris erythroagglutinin (pha-e) is highly specific to the brush border of proximal tubular epithelial cells of rats, mice, and humans. the aim of this study was to ( ) develop a simple and fast lectin (pha-e) based staining protocol ( ) to objectively quantify, and ( ) to analyze brush border loss in a murine model of septic aki. methods. septic aki in mice (n = ) was induced by cecal ligation and puncture (clp). animals were sacrificed h after clp.sham operated (n = ) and healthy animals (n = ) served as controls. in order to specifically stain the tubular brush border, binding of biotinylated lectin pha-e was visualized by the biotin-avidin-complex (abc) glucose-oxidase (go) method coupled to tetranitroblue tetrazolium (tnbt) in -lm paraffin sections of renal tissue. the mean brush border area of five randomly chosen, non-overlapping cortical highpower fields was analyzed by planimetric software. lectin pha-e staining was highly selective for brush border of proximal tubules (black colour). virtually no staining was present in glomeroli and medulla. the xx software reliably identified lectin-positive areas, as confirmed by image overlay controls. we found a significant difference between sepsis induced aki, sham operated animals, and healthy mice (clp: . ± . ; sham: . ± . ; healthy controls: . ± . pixel ratio; p \ . ). our findings with the pha-e staining protocol correlated significantly with the conventional semi-quantitative scoring system (r = . , p \ . ). conclusion. the here presented lectin pha-e staining method followed by computerassisted planimetric quantification of brush border area is a highly reproducible and objective tool to analyze early histological changes during septic aki in mice. when an imbalance between oxygen supply and demand exist, anaerobic respiration commences and a metabolic acidosis develops. base excess and lactate have been used to identify a higher risk group of patients who should be admitted in icu prior to development of multiple organ failure. and at a time when appropiated therapy may previne the decline to death. acute kidney injury failure is a common complication in critically ill patients and it always difficult separate the acid base effects of critical illness per se from those of aki. the aim of this study was to examine wheter values of base excess or lactate taken on admission of patients with aki to a intensive care unit indicate prognosis and if wheter this can be used as screening tool for future intensive care admissions. we restropectively examinated data from patients with aki. to define the unique acid base characteristics of aki patients, we used a control group. the matched group consisted of icu patients wihtout aki matched for apache ii score. the base excess and lactate were collected at admission and then at h. a total of patients were enrolled at study over a month-period. there were no difference with respect age, sex and apache score between groups. the icu survival rates were % to the aki group and % to control group. the value of base excess with the best predictive prognosis ability was - mmol/l to the aki group and- . (p \ . ) to the matched group and the corresponding value for lactate was higher than . to both groups. the combination of these two markers on admission to the intensive care unit led to a sensitivity of % and specifity of % for mortality. conclusion. both base excess and lactate, or the combination of the two, can be used to predict day mortality in patients admitted to the intensive care unit. in patients with aki a different cut off of base excess should be used.these variables could be utilized to identify patients who have a higher risk for mortality to whom resources could be better directed. nonthyroidal disease (ntd) is a common finding in patients who are critically ill or on dialysis or with cardiovascular disease. its presence has been associated with inflamatory conditions. the aim of this study was to analyse the posible association of ntd with the development of acute kidney injury (aki). secondary targets where to estimate the incidence of ntd in a polyvalent icu and observe the realationship between the levels of t and some inflamatory markers: c reactive protein (crp), albumin and cortisol. during months in , after approval of the local ethical committee, we prospectively determined the following parameters in every patient admited to the icu: t , t , tsh, serum creatinine (scr), crp, albumin and cortisol. after excluding patients who died or were discharged before h, patients were studied. the degree of aki was calculated using the rifle scale. at admission the values of the analysed parameters were (mean ± sd): t . ± . pg/ml; t . ± . ng/dl; tsh . ± . liu/dl; scr [ ] . its incidence ( - %) is rising due to increasing numbers of ct scans and contrast studies conducted, and the higher prevalence of risk factors such as chronic renal impairment, diabetes mellitus and old age. although usually selflimiting, cin can be associated with a need for ongoing dialysis or increased mortality [ ] . to highlight the problem of contrast induced nephropathy and the difficulties in interpreting the current evidence for possible prevention strategies. we present the case of a year old man admitted to intensive care with acute pancreatitis. he underwent eight contrast-enhanced abdominal ct scans and received nacetylcysteine (nac) for all but one of these, after which he developed acute renal failure which did not recover. we also present a review of evidence for various proposed strategies. results. several studies have examined possible renal protective strategies around contrast administration. saline and bicarbonate have been shown to be beneficial when given pre-contrast [ , ] . theophylline has been shown in meta-analysis to have a significant beneficial effect, but heterogeneity of methodology between studies makes it difficult to clarify the degree of benefit achieved [ ] . nac has shown benefit in of trials. twelve meta-analyses showed inconsistent results, with showing nac to be beneficial. none showed harm. we analysed the heterogeneity of methods, endpoints and patient groups that makes these studies difficult to compare. critically ill patients may be considered at even greater risk of cin. only one study has specifically looked at this group. strategies such as volume loading may be inappropriate in some patients and there may not be time for nac for h pre-contrast. we were unable to find specific guidelines for the prevention of cin in critically ill patients. conclusion. the evidence for strategies to prevent cin specifically in critically ill patients is unclear. we review the current literature and propose renal protective strategies including hydration, nac and theophylline for this patient group based on the evidence available. objectives. the present study addresses the issue of how the different modes of rrt are currently used and performed. we conducted a prospective observational study in three portuguese intensive care units (icu). patient demographics, type of rrt used and outcomes were collected. we studied patients who were treated with rrt for rf, with a median age of years and a saps-ii score of . ± . , a sofa score of . ± . at admission; patients ( . %) were treated with continuous replacement therapy (crrt), patients ( . %) with sustained low-efficiency dialysis (sled)and patients ( . %) were initially treated with crrt and latter with sled. using the rifle criteria for the stratification of acute renal dysfunction at the beginning of the rrt we observed: risk- ( . %), injury- ( . %), failure ( . %), loss- ( . %), esrd- ( . %). we used anticoagulation in almost all patients ( . %). among patients who received anticoagulation, heparin was the most common choice ( . %), followed by low molecular weight heparin ( . %), and by sodium citrate ( introduction. in the intensive care unit (icu), severe sepsis and multiple organ failure are frequently associated with renal failure. continuous veno venous hemofiltration (cvvh), which is used as renal replacement therapy, also removes circulating inflammatory mediators. standard cvvh is currently prescribed with a substitution flow of ml/(kg min). theoretically, when hemofiltration is performed with higher volumes, buffer balance will be restored more rapidly, while also more inflammatory mediators will be removed. this may result in faster stabilisation from septic shock. indeed, animal-and some human studies show promising results, but have several (methodical) limitations. to evaluate hemodynamic and metabolic changes during hv-cvvh in patients with septic shock in comparison to (standard) cvvh. we performed a retrospective, observational, single-center study. all patients admitted with septic shock who were treated with cvvh in the period until were included. cvvh was defined as a substitution-flow b , ml/h, hv-cvvh as[ , ml/h. the decision to start with lv-cvvh or hv-cvvh was made by the attending icu-physician on an intention-to-treat basis. statistical analyses were performed with spss . introduction. haemostatic changes in critically ill patients are complex due to simultaneous pro-and anticoagulant processes. routine ptt and aptt assays monitoring clot formation poorly reflect hypo-or hypercoagulant state, especially during anticoagulation. endogenous thrombin potential (etp) comprises an in-vitro system for measuring thrombin generation beyond clot formation and may be more informative. objective. to assess whether etp has a role in monitoring systemic anticoagulation and predicting circuit clotting in critically ill patients receiving cvvh. methods. in a prospective study in an -bed general icu, we included patients with acute renal failure (arf) requiring cvvh (postdilution, - l/u). patients received a bolus of , iu of nadroparin followed by iu/h. samples of arterial and postfilter blood were taken at baseline and , , and h after start of cvvh to measure aptt, ptt, anti-xa and etp. we compared patients with early circuit clotting (circuit life £ lower quartile) and those with normal circuit life. median baseline arterial etp-area under the curve (auc) was ma (iqr - ma) (normal values - ma). baseline etp-auc was positively related to antithrombin and inversely to ptt, aptt, anti-xa (p \ . ) and sofa score (p = . ). median circuit life was . h (iqr - h). at baseline, the four patients with early filter clotting (£ h) had prolonged ptt and aptt, higher sofa score and a tendency to lower etp (table ) . during cvvh and nadroparin infusion, arterial and postfilter ptt and aptt were prolonged (p \ . ), antixa lower (p = . ) and etp-maximal concentration (cmax) lower (p \ . ) when circuits clotted early. while arterial etp-auc tended to be lower (p = . ), postfilter etp-auc was not different between groups. in critically ill patients with arf requiring cvvh with nadroparin anticoagulation, baseline etp is lower than normal and inversely related to organ failure and (a)ptt, probably reflecting consumption of coagulation factors. within the cvvh circuit, etp-auc and anti-xa show opposing patterns. the concurrence of early filter clotting with prolonged (a)ptt, lower antixa, lower etp and higher sofa score emphasizes the role of severity of disease and associated coagulation activation and heparin resistance in circuit clotting. introduction. nadroparin is a low-molecular-weight heparin (lmwh) used to prevent clotting in the extracorporeal circuit during cvvh. in renal failure lmwh accumulates and is associated with more bleeding (ref) . whether nadroparin is removed by hemofiltration and whether the anticoagulant activity accumulates during continuous infusion is controversial. objective. to study the kinetics and removal of anti-xa activity during continuous infusion of nadroparin in patients requiring cvvh using a cellulose tri-acetate filter. methods. in a randomized crossover trial in an -bed general icu, patients with acute renal failure (arf) were randomized. in group , postdilution cvvh was initiated at filtrate flow of l/h (blood flow (bf) ml/min), which was converted to l/h (bf ml/min) after min; in group , l/h was converted to l/h. patients (\ kg) received a bolus of , iu nadoparin followed by iu/h. samples of arterial blood, postfilter blood and ultrafiltrate were taken at baseline, h after the start and min, , and h after the conversion to measure anti-xa activity. results. fourteen patients with arf were equally randomized. patients in group had higher median sofa scores ( vs. , p = . ), baseline coagulation markers were not significantly different. arterial and postfilter anti-xa values are presented in fig. . during cvvh arterial anti-xa tended to decrease in time (p = . ). the median ratio of postfilter to arterial anti-xa was . (iqr . to . ). there were large differences between patients; differences between groups were not significant, except for postfilter anti-xa at h, which was significantly higher in group ( l/h) (p = . ) . anti-xa activity was not detectable in the ultrafiltrate. conclusions. critically ill patients receiving nadroparin during cvvh showed no signs of accumulation of anticoagulant activity, although extracorporeal removal of anticoagulant activity could not be demonstrated. apparantly, nadroparin is cleared by these patients despite renal failure. the differences in anti-xa between patients may be related to severity of disease. introduction. unfractionated heparin (ufh) is used as the first-line agent for anticoagulation of the extracorporeal circuit during continuous renal replacement therapy (crrt) in % of icus in the uk (uk) [ ] . its use is monitored with serial measurements of activated partial thromboplastin time (aptt) or its ratio (apttr) in % of icus [ ] . there is, however, considerable variation in practice [ ] . anticoagulation is useful for prolonging haemofilter life and facilitates the provision of continuous therapy, but must be balanced against the risk of haemorrhage, which has been correlated with increasing apttr [ ] . most icus in the uk use an apttr target of . - . [ ] , despite recent guidance that a target range of . - . provides adequate filter life with less risk of bleeding [ ] . objectives. to investigate the adherence to our local target range for ufh therapy (apttr . - . ) and the occurrence of over-anticoagulation in our patients. ]. there were apttrs ( %) which were above our target range, and incidences ( %) where the apttr was greater than or equal to . . the apttr was greater than . on occasions ( %). conclusions. this study was conducted in an icu which delivers crrt at a higher than average frequency [ ] , and which consistently has a standardized mortality rate below the national average. despite this, there was wide deviation from our target apttr range and a considerable incidence of significant over-anticoagulation, which may place our patients at risk of haemorrhage. the vast majority of apttrs were in excess of recent guidance [ ] . regional citrate anticoagulation (rca) may provide longer filter life with a lower incidence of bleeding [ ] . its use is increasing worldwide [ ] , though it is not commonly used in the uk [ ] . we are investigating the possibility of introducing rca in our icu. in the meantime, we will set a lower apttr target for our patients. we prospectively studied patients who received cvvh from july to december . age, gender, admission diagnosis, and apache-ii were obtained and the patients were divided into three groups: low dose heparin group, low molecular weight heparin group (lmwh), and no anticoagulation group (normal saline washing) based on assessment of coagulation status. for each circuit, circuit life, bleeding, platelet count, pt, inr, aptt, creatinine and urea were collected before and after crrt. results. seventy-seven critically ill patients with acute renal failure were treated with crrt and circuits were observed. among these circuits, received unfractionated heparin (ufh) anticoagulation, received lmwh anticoagulation and received no anticoagulation. the mean circuit life ( . ± . h) in low dose ufh group, was significantly longer than in lmwh ( . ± . h) and in no anticoagulation group ( . ± . h). there was no significant difference in baseline patient pre-crrt hb, creatinine and urea among three groups. the inr and pt and aptt in baseline were significantly higher in no anticoagulation group compared to the other two groups (p \ . ). the platelet count was significantly lower in the no anticoagulation group compared to ufh group and lmwh group in baseline and during crrt. there was no significant difference in the filter pt, aptt, among the three groups during crrt. the clearance of creatinine and urea during crrt were no significant difference among the three groups. bleeding complication secondary to crrt were no significant difference among the three groups. objectives. the purpose of the study was to assess the duration of time spent off therapy during the first five days of crrt in post-traumatic arf, and to identify the reasons for this. ullevaal between january and december , were retrospectively reviewed. the hospital is the regional trauma referral centre for approximately . million adult ([ years) persons. according to the local treatment protocol, dialysis filters were routinely changed after h due to time-out. individuals were identified and data collected using several institutional registries. patients were grouped according to presence of rhabdomyolysis based on peak serum creatine kinase levels exceeding , u/l or not. categorical data were compared employing two-sided pearson chi-square test, whereas continuous data were analyzed utilizing two-tailed mann-whitney u test. results. patients were included during the study period. during the first five days of therapy there was a total of dialysis days, and the total number of pauses was . the median duration of crrt was . h per day, giving a downtime of . h per day. the number of pauses per day was significantly larger in patients with rhabdomyolysis compared to patients without rhabdomyolysis ( pauses in dialysis days vs. pauses in dialysis days, p \ . ). this resulted in a shorter duration of crrt in rhabdomyolytic compared to non-rhabdomyolytic persons ( . vs. . h per day, p \ . ). overall the reasons for pauses during crrt were filter clotting ( %), therapeutic procedures ( %), catheter problems ( %), filter time-out ( %) and diagnostic examinations ( %). patients with rhabdomyolysis had more pauses due to therapeutic procedures ( vs. %, p = . ), whereas non-rhabdomyolytic persons had more pauses due to catheter problems ( vs. %, p = . ) and filter time-out ( vs. %, p \ . ). the number of pauses per day stayed relatively stable during the first five days of crrt, but the reasons for pauses changed during the study period. conclusions. this study indicates that trauma patients with rhabdomyolysis had more frequent dialysis pauses during the first days of crrt than those without rhabdomyolysis, resulting in shorter duration of dialysis therapy. the reason for this was more frequent use of therapeutic procedures, i.e. surgery and radiological interventions, in rhabdomyolytic compared to non-rhabdomyolytic persons. grant acknowledgement. the author is supported by institutional grants. introduction. treatment of acute pancreatitis is aimed at correcting any underlying predisposing factor and at the pancreatic inflammation itself. hypertriglyceridemia is an uncommon cause of pancreatitis. a serum triglyceride level of more then , to , mg/ dl is an identifiable risk factor. interestingly, serum pancreatic enzyme levels may be normal or only minimally elevated in such cases. severe necrotizing pancreatitis is associated with a high rate of complications and significant mortality. the reduction of triglyceride level to below , mg/dl effectively prevents further episodes of pancreatitis. this study aimed to determine the effectiveness of plasma exchange (pe) in reducing triglyceride levels during an acute attack of hyperlipidemic pancreatitis (hlp). methods. prospective, observational study including six patients hospitalized with hyperlipemic pancreatitis treated with plasmapheresis between and in the medical icu of a teaching hospital in malaga. demographic data, apache ii score, organ support needed and prognosis were prospectively collected. a total of hypertriglyceridemic patients with the complication of acute pancreatitis received one or two consecutive sessions. mean age was ± years and mean apache ii was ± . icu mortality was %. we performed sessions. the development of multiorgan failure in patients with hyperlipemic necrotizing pancreatitis was associated with grave prognosis ( %), needed mechanical ventilation, vasoactive agent and renal replacement therapy. however, we had a good outcome in the majority ( %) with a effective reduction of triglycerides after the session of plasmapheresis (pe). four of six patients ( %) recovered completely in a single session. two patients developed intraabdominal abscess, requiring more than one consecutive session and surgical debridement of infected necrosis and died due to both septic shock and multi-organ failure. the respective mean removal rates during a single pe for triglyceride were %. conclusions. the best treatment of hypertriglyceridemic pa is a drastic reduction of tg-s to normal. experiences with plasmapheresis are limited. we report six patients of hypertriglyceridemic necrotizing pancreatitis with mildly elevated amylase and lipase, treated successfully with plasmapheresis. in summary, pe treatment is an effective method to clear lipids and enzymes from plasma in a single session for most hlp patients. the presence of multisystem organ failure appears to be a more important indicator of outcome than does the presence of infection. results. sixteen ( %) patients were female and ten ( %) were male. the median age was years old. the median apache ii score was . . mechanical ventilation ( %), vasoactive agents ( %) and renal replacement therapy ( %) were the most common forms of organ support needed. sessions of plasmapheresis were performed. ( %) patients had been diagnosed with thrombotic thrombocytopenic purpura (ttp), six ( %) patients had hyperlipemic pancreatitis, five ( %) patients had pulmonary-renal syndrome (prs), three ( %) patients had guillain-barré syndrome (gbs) and two ( %) had myasthenia gravis. we obtained a decreased in the values of apache ii score following the plasmapheresis performed. there were six death ( % mortality) due of the severity of the disease. the number of complications were minimal and commonly described in the literature and there was a low mortality as a result. conclusion. results indicate that the performance of plasmapheresis was on a heterogeneous sample of patients with neuroimmunological diseases, rheumatology diseases and hyperlipemic pancreatitis. we conclude that plasmapheresis is a safe treatment which can be made by the staff trained in intensive care in any moment with a wide spectrum of clinical indications and with a minimum adverse effect. the aim of the study is to evaluate that early treatment of septic shock with cpfa may improve patient outcome. methods. twenty septic patients who were admitted to the icu have been enrolled in this study. cpfa treatment was performed immediately after septic shock was diagnosed (early group h after diagnosis). every patient had - cpfa treatments for h with q blood = ml/h, q ultrafiltration = ml/(kg h) and q plasma = % of q blood. we measured the plasma concentration of procalcytonin (pct), blood lactic acid levels, crp, serum creatynine, wbc and pao /fio ratio. the apache ii score, hemodynamic parameters, norepinephrine dosage were evaluated before cpfa (t ), t (after first cycle), t (after second), t (after third cycle) and t (after h). introduction. the development of electrolyte disturbances in intensive care patients could be prevented by the use of better adapted dialysis fluids. a common problem is hypophosphatemia which has been shown to occur in up to % of the patients. correction by intravenous phosphate supplementation is known to improve respiratory muscles, cardiac index, oxygen delivery to tissues and insulin resistance. lately it has been reported that phosphate can be added directly to the dialysis fluid. this facilitates phosphate handling, but there is a risk of precipitation with calcium. an additional problem is that the amount of phosphate required to correct total body deficit varies and repeated serum measurements are needed to establish phosphate insufficiency. the process is time consuming and leads to treatment delay and excessive cost. objectives. this study evaluated the possibility to achieve and maintain normal phosphate balance over time by using a new phosphate-containing dialysis fluid. objective. the purpose of this study was to evaluate the impact of different dialysate and replacement flows in the acid-base balance of the blood. furthermore we tried to assess the way partial pressure of oxygen (po ) in the blood is affected by high flow crrt. methods. this was a prospective observational study. thirty consecutive critically ill patients that were admitted in our icu and required crrt during their course were enrolled in the study. for each patient, blood flow, dialysate and replacement flow as well as ultrafiltration adjustments were performed by the responsible intensivist. any time that the clinical condition required a modification in any of these parameters, and after a period of time of no less than h, a simultaneous blood sample was drawn from both the arterial and the venous part of the circuit and the samples were analysed by a blood gas analyzer. arterial and venus samples were then compared for differences in ph, po and pco concentration. results. in total we performed measurements in patients. mean patient age was . years, mean apache ii score was , mean icu stay was days and mean crrt days was days. overall, ph in the venous line of the circuit was higher, pco was lower and po was lower as well compared to the respective values in the arterial line of the circuit, with no difference reaching a statistical significance. concerning the blood flow, we observed that when using high hemodiafiltration flows the difference in oxygen partial pressure between the arterial and the venous line of the circuit was greater, but again it did not reach statistical significance. conclusion. the use of crrt may influence the po in the returning blood. although we did not reach statistical significance in our study, there was a definite trend towards lower po in the venous line of the circuit when high flow crrt was applied. introduction. renal failure (rf) is a common complication in critically ill patient and is associated with high mortality and has a separate independent effect on risk of death. the continuous renal replacement therapy (crrt) is physiologically superior; however, there is lack of strong evidence to prove a clinical benefit. hybrid therapies (sled) that combine the benefits of intermittent haemodialysis and continuous therapies have emerged in the past few years. objectives. the aim of this study was to assess what type of renal replacement therapy (rrt) used and relate them to severity of the illness and outcome we conducted a prospective observational study in three portuguese intensive care units (icu). patient demographics, type of rrt used, saps ii and sofa score at admission and when we started the rrt and outcomes were collected. we studied patients who were treated with rrt for rf, with a median age of years and a median saps-ii score of ; patients ( . %) were treated with continuous replacement therapy (crrt), patients ( . %) with sustained low-efficiency dialysis (sled) and patients ( . %) were initially treated with crrt and latter with sled. aim. tetanus is traditionally treated with very high doses of diazepam and morphine. it often required prolonged periods of paralysis and was associated with very high mortality and prolonged periods of ventilation. magnesium sulphate (mgso ), due to its effects on neuromuscular and autonomic system should be effective in controlling muscle rigidity, spasm and autonomic instability in patients affected with tetanus. we introduced an icu protocol using mgso as first line treatment. we wanted to evaluate our patient outcome following the introduction of our protocol. we retrospectively analysed the effects of introduction of mgso in our intensive care for management of tetanus. aim. electrolyte disturbances were often seen in patients in intensive care unit (icu). hypomagnesemia is not enough described but can be contributed in icu mortality. the aim of this study was to define the prevalence of hypomagnesemia in critically ill patients and to evaluate its relationship with duration of mechanical ventilation day, length of icu stay and mortality. a prospective study was done on patients with respiratory failure admitted to the icu between . . and . . . total serum magnesium level, electrolyte levels, albumin, total protein, and lactate levels were evaluated at the admission. patients demographic features, accompanying neurological and cardiac diseases, apache ii score, duration of mechanical ventilation, and the length of icu stay and mortality were recorded. at admission % of patients had hypomagnesemia. a positive correlation was found between serum magnesium and calcium level (p = . ), but there was no relationship between other laboratory tests. also there was no relationship determined between hypomagnesemia and duration of mechanical ventilation, and the length of icu stay and mortality (p [ . ). conclusion. electrolyte levels are important in critically ill patients. however routine monitoring of serum magnesium level is not necessary. so we should increase the case number and also evaluate the serum magnesium level with urine magnesium level to see the effects of hypomagnesemia. method. medical records of copd patients who underwent invasive mechanical ventilation (imv) were reviewed. the patients' age, sex, body mass index (bmi), apache ii scores at admission, previous diagnosis of hypothyroidism or hyperthyroidism, history of thyroid replacement therapy or antithyroid medications, and the serum thyroid stimulating hormone (tsh), free triiodothyronine (ft ), and free thyroxine (ft ) at admission were recorded. the primary outcome measure was prolonged mv (pmv), which was defined as dependence on mv for [ days. the outcome and the relation between the serum thyroid levels were evaluated. results. ninety-five copd patients were included, % were male, with a mean age of . ± . years. bmi's of the patients were . ± . and the mean value of apache ii score was . ± . . only two patients ( %) had a history of hypothyroidism. two more patient were diagnosed hypothyroidism at admission and treated with thyroid medications. the patients treated with thyroid replacement therapy were liberated from mv successfully. patients ( . %) could not be weaned. serum ft level ( . ± . ) of the patients, who could not be weaned, was statistically lower than other group who could be liberated (p = . ).however there was no statistical difference between serum ft and tsh levels and two groups. hypothyroidism is an uncommon cause of ventilator dependent respiratory failure with an incidence of %, but it is treatable, so it should be considered in patients who can not be liberated.more prospective studies are also needed to evaluate the significance of hypothyroidism in patients with respiratory failure and failure to wean. smoke inhalation injury represents an important prognostic factor in patients admitted in the hospital after smoke exposition. objectives. we determined whether initial antithrombin (at) levels help in diagnosis and prognosis of sepsis after smoke inhalation. smoke inhalation was diagnosed according to classical clinical and laboratory findings in patients admitted in the hospital with suspected inhalation after smoke exposition. at levels, coagulation parameters (fibrinogen levels, prothrombin time (pt), activated partial thromboplastin time (aptt) and liver function tests were determined on admission and correlated each other and with outcome of the patients. . initial at and fibrinogen levels were significantly lower in patients with severe smoke inhalation compared to control (p \ . ). initial at levels were lower in the ones who developed septic complications with disseminated intravascular coagulation (dic) compared to those without dic (p \ . ). initial at levels were significantly lower in patients who died as compared to survivors (p \ . introduction. x-ray finding of pleural effusion is fairly common in icus. this may vary from mild to massive effusions and of different etiologies. epidemiological and outcome data for this icu problem are scarce in literature. the objective of this study was to find how common this finding is in our icu, their respective etiologies and any bearing on icu mortality. a single centre, prospective, observational study conducted in two mixed medical and surgical icus in kolkata, india. over six month period (october to march ) all consecutive patient admissions to these two icus were screened for a x-ray evidence of pleural effusion, either on admission or during their icu stay. as per icu protocol apache ii scoring were done in all patients. those with effusions were grouped according to etiology. finally in icu mortality were observed for those with or without an effusion. a total of icu admissions were studied. among these patients were found to have x-ray evidence of pleural effusion. median apache ii score was (iqr - ) among the study population with predominant ( . %) medical admissions. incidence of bilateral effusions were a total of ( %). the common causes of pleural effusion include chronic kidney disease (n - %), heart failure (n - %), pneumonia (n - %), post operative (n - %), chronic liver disease (n - %) and rest others (e.g. trauma, pancreatitis, pte, malignancy). the overall icu mortality was ( . %) and ( . %) in groups with and without effusion respectively with a p value of . , showing number of deaths in pleural effusion group were significantly higher. our study showed x-ray finding of pleural effusion quite common in icu patient population even many a times being bilateral. in this small study the overall icu mortality were also higher in pleural effusion group, but a wider multicentric study is needed. introduction. acute lung injury (ali) is a clinical manifestation of respiratory failure caused by lung inflammation and the disruption of the alveolar-capillary barrier. to prevent alveolar edema, it is of critical importance to preserve the physical integrity of the alveolar epithelial monolayer which is regulated by the balance between centripetal forces arising from cytoskeletal tension and cell-cell and cell-matrix tethering forces [ ] . intercellular junctions, such as tight junctions are closely related to actin cytoskeleton-related barrier regulation. proteins of the coagulation cascade such as thrombin (thr)-that stiffens [ ] and contracts [ ] alveolar epithelial cells (aec)-or activated protein c (apc)-an endothelial barrierprotective agent [ ] -could modulate this balance of forces in the epithelial monolayer. to study the combined effects of thr and apc on the barrier integrity through the tight junction zo- of aec by western blotting and immunofluorescence. methods. aec (a ) were incubated for h with apc ( lg/ml) or vehicle (control). subsequently, thr ( nm) or medium was added to the cell culture. for zo- western blotting, cell lysates were first ultracentrifuged ( , g, min, °c) to obtain membrane and cytosol fractions. then the samples were subjected to western blotting and the amount of zo- fractions was calculated by densitometry. for zo- immunofluorescence, aec were grown on glass coverslips and fixed in . % formaldehyde solution. zo- antibody was used to localize the tight junction and the zo- integrated optical intensity was then measured. . treatment with apc did not induce significant changes in any zo- amount of fraction protein analyzed by western blot. thr induced a *fivefold increase ( ± % of control values) in zo- membrane fraction while no changes were detected in zo- cytoplasm protein content ( ± % of control values). by contrast, apc concentration of lg/ml showed a clear tendency to reduce the effects induced by thr on zo- membrane fraction ( ± % of control values). for zo- inmunofluorescence, apc and thr treatments resulted in different patterns of zo- in the cell-cell contacts. after thr challenge cells showed discontinuous staining of zo- compared to untreated cells indicating a disruption of alveolar monolayer. conclusions. the increase in zo- amount of membrane fraction after thr challenge lends support to a protective mechanism avoiding cell-cell contacts disruption. treatment with apc reduced the increased zo- amount of membrane protein induced by thr suggesting an improvement of the barrier integrity in this model. ( ) interleukin- (il- ) is said to be involved in organ injury. we investigated the il- values of septic acute lung injury (ali) and acute respiratory distress syndrome (ards) patients. the subjects were patients during the -year period from to from whom it was possible to collect a blood specimen within approximately h of the onset of septic ali or ards. their mean age was years, and their mean apache ii score was . their sofa score was , and their mean pao /fio (p/f) ratio was . the p/f ratio was in the ali group and in the ards group. there were cases ( . %) in the -day mortality group, and cases ( . %) in the -day mortality group. the value of il- in died group was significantly higher than in survived group ( , ± , vs. , ± , pg/ml; p \ . ), and in the ards group also significantly higher than in ali group ( , ± , vs. , ± pg/ml; p \ . ). these results suggested that il- may play an major role in progression of ards in respiratory disorder as multiple organ failure (mof). [ ] . it is well-known that the pathophysiological mechanisms and factors involved in the liberation of no and the activation of inflammatory responses differ between aud and non-aud patients. objectives. the main hypothesis of this study is that ards patients with aud and non-aud differ in their response to the application of evidence based algorithms with respect to no response (aud patients are more frequent non-responders). patients with ards (meeting aecc criteria) were included in this ethically approved study. patients with severe chronic lung fibrosis and/or bridging for lung transplant were not included. patients were allocated to aud and non-aud patients. the auddetection was performed by the published algorithm [ ] . statistical analysis: wilcoxon-mann-whitney and chi-quadrat test was used. results. so far, patients with ards were included. prevalence of aud was % in our ards patients. baseline characteristics are given in table . frequencies of no nonresponse, extracorporeal lung support and mortality are given in table . frequency of no non-response was in tendency different: % in aud patients versus % in non-aud. overall mortality was % in aud patients versus % in non-aud patients. introduction. acute lung injury (ali) is a critical illness characterized by increased vascular permeability and impaired gas exchange leading to death in some cases. inflammation plays a pivotal role in the induction and maintenance of ali and is therefore therapeutic target to treat ali. rho, a small gtpase, is involved in the regulation of inflammation through the activation of recruitment of neutrophils to the site of inflammation and through activation of transcription factors such as nf-kb. we hypothesized that a rho kinase (rock) inhibitor, y- may be beneficial to dampen the inflammatory response in ali. male sd rats were intravenously pre-treated with either saline or rock inhibitor (y- , mg/kg). ali was induced by intratracheal instillation of mg/kg e. coli lipopolysaccharide (lps). control rats received saline intratracheally. h after the induction of ali, lungs were harvested and analyzed for myeloperoxidase (mpo) activity and expression of the proteins ijb, inos and enos. bronchoalveolar lavage fluid (balf) was used to assess total protein concentration as a measure of vascular permeability. pre-treatment with the rock-inhibitor resulted in significantly decreased levels of lps-induced mpo expression and prevented the upregulation of both lps-induced inos and enos expression. furthermore, lps-induced degradation of ikb was attenuated by pretreatment with y- . finally, y- improved vascular permeability by decreasing the lps-induced protein concentration in the balf. conclusion. inhibition of rho-kinase decreases lung inflammation and vascular permeability in acute lung injury and may therefore be a good approach to treat patients suffering from ali. we hypothesized that due to the cyclic changes of pulmonary air content there are po oscillations also in the mixed venous blood (pvo ), potentially influencing pao oscillations. in each of three healthy pigs of kg, anesthetized and ventilated with constant minute volume we studied three different tidal volume settings ( , and ml/kg) resulting in different respiratory rates. a calibrated oxygen probe (fiber optic, fluorescence-quenching probe, foxy-al ; ocean optics, dunedin, fl, usa) was inserted into the pulmonary artery through a fr catheter. the catheter position was previously controlled by pressure tracing. pvo was sampled with temperature compensation at hz with a multi frequency phase fluorometer (mfpf , tau theta, fort collins, co, usa) after a generated timestamp to synchronize with the electric impedance tomography (eit) signal (goettingen goemf ii, viasys healthcare, the netherlands) sampled at hz. eit and pvo were simultaneously recorded for min during each tidal volume setting and analysed with and without low pass filtering at the heart rate. we obtained pvo oscillations with amplitudes between to mmhg with the main frequencies matching the respiratory rate. ventilation with tidal volumes of ml/kg provided higher pvo amplitudes than ventilation with ml/kg. these results are preliminary and the source of the measured pvo oscillations is not clear. alternate backflow from the superior and inferior vena cava due to changes in intrathoracic pressures during mechanical ventilation may be responsible for these oxygen partial pressure oscillations in the mixed venous blood. conclusion. mixed venous oxygen partial pressure oscillates in accordance to the respiratory rate. whether arterial po oscillations are due to cyclic recruitment and derecruitment of the lung or to corresponding mixed venous oscillations remains to be evaluated. [ ] and in neonates [ ] . to our knowledge this is the first validation of the model using a large cohort of samples from intensive care patients. aim. to assess the ability of the severinghaus equations [ ] to estimate values for po and so in critically ill adult patients. methods. , sequential blood gas samples were analysed to validate the severinghaus oxygen dissociation curve, of these , measurements had a so b . % and were included in subsequent analyses. bland-altman plots were used to examine the agreement between measured po and that calculated from the severinghaus equations, and between measured and calculated so , both with and without correction for ph. the differences between measured and estimated values were analysed using paired t tests with a p value \ . considered significant. results. the severinghaus oxygen dissociation model accurately reflects the relationship between po and so observed in clinical samples. there is reasonable agreement between the measured and calculated values for po and so , with the majority of values falling between the lines of % agreement. there was a statistically significant difference between observed and calculated values of po even when adjustment for ph was made (p \ . ), however the mean difference between the groups was not clinical significant ( . mmhg when ph adjusted). there was also a statistical difference between measured and calculated values of so (p \ . ), again, however, this difference may not be considered clinically significant ( . %). patient data and severinghaus oxygen dissociation conclusions. the severinghaus equations accurately reflect the oxygen dissociation curve in critically ill adult patients and whilst they provide values for po introduction. zinc (zn) is an essential trace element, which plays a role in many biological functions including immune function. development of respiratory infections and changes in respiratory tract cells may be affected by low zn levels. in critically ill children mortality of septic shock and degree of organ dysfunction were associated to low blood zn levels , . our aim was to study serum zn in the beginning of acute respiratory failure (arf) and its association to development of organ failures and day mortality. during an -week study period (from april to june ) adult patients with arf were treated in intensive care units (= finnali-cohort). after consent blood sample for zn analysis was drawn at baseline). samples were taken in zn-free tubes, freezen and stored in - °c for analysis. all samples were analyzed with an atomic absorption spectrophotometry in the oulu university hospital laboratory. the range of normal values is - lmol/l. organ failures were assessed by daily maximal sequential organ failure assessment (sofamax) score. results. serum zn samples were obtained during h after the baseline with median time of h. only zn values were within and two over the normal range. median (iqr) serum zn levels were . ( . - . ) and . ( . - . ) lmol/l for survivors (n = ) and nonsurvivors (n = ), respectively, with no significant difference (p = . ). in patients with or without infection (pneumonia, respiratory infection or sepsis) during h prior to arf, zn levels were . ( . - . ) and . ( . - . ) lmol/l, respectively (p = . ). zn levels were significantly lower (p \ . ) in patients with cardiovascular sofa - than - , . ( . - . ) and . ( . - . ) lmol/l, respectively. a significant correlation of zn level and daily sofamax (spearman's q - . , p \ . ) was found (fig. ) . conclusions. low serum zn levels were detected in almost all patients with arf. no association to day mortality was detected to support the earlier findings with pediatric critically ill patients. however, we found a significant correlation to organ failure development in adult patients with arf. mountaineering is closely related to a range of adverse influences. the overriding factor that affects a climber may be the hypobaric hypoxia, which is compensated by hyperventilation and other adaptive changes in the pulmonary and systemic circulation. west ( ) theoretically predicted hypoxemia combined with respiratory alkalosis [ ] , and low oxygen saturation ( … %) has been observed on peak broad, karakorum [ ] . lack of adaptation is known as mountain sickness (occurrence … % [ , ] ), which may be alleviated by acetazolamide. the importance of understanding pathophysiology of mountaineering is dictated by the gradual expansion of western consumer-oriented society to higher altitudes. the goal of our study was to obtain precise information on changes in arterial blood gas composition, acid-base status, and degree of hemoglobin desaturation relative to altitude. materials and methods. experienced athletes-four males between and years and female years attempted to ascend mt. makalu ( , m) in april-may . acetazolamide , bid was used from april till may . femoral arterial blood rather than radial arterial blood was analyzed before reaching base camp ( background. ventilator associated lung injury is a complication of mechanically ventilated patients. knowledge about pathological pathways comes from animal studies, which are necessary to generate hypotheses to be tested in humans. various experimental methods of inducing acute lung injury (ali) have been used in animal models. the results of animal studies and human research appear to be conflicting; however, this may be a consequence from the different animal models used as such for comparison. we hypothesized that effects on gas exchange, respiratory mechanics, histo-pathologic lung damage and systemic inflammation are depending on the model of ali used. in five groups of pentothal anesthetized rats acute lung injury was induced by either lung lavage or hydrocloric acid aspiration. rats were then ventilated with lung protective settings in pressure controlled mode with positive endexpiratory pressure (peep) of cm h o or breathing spontaneously with continuous positive airway pressure (cpap) = cm h o for h. blood pressures, cardiac output, pulmonary mechanics and gas exchange were measured. results. the tidal volume was . ± . ml/kg in ventilated and . ± . ml/kg in cpap groups. respiratory rate and minute ventilation were constant in ali animals and controls, but showed variability in spontaneous breathing animals. only half of the cpap animals with ali survived [ h. no significant differences were found for pco , cardiac output or blood pressure between models, but mean arterial pressure decreased in ali. in the lavage and aspiration model, pao was lower after induction of ali ( ± and ± mmhg, respectively) than controls, and increased in lavage ( ± mmhg) but not the aspiration model ( ± mmhg) after h (p \ . ). dynamic compliance of the respiratory system decreased permanently after induction of ali to . ± . ml/cm h o (lavage) and . ± . ml/cm h o (aspiration) as compared to controls, which maintained at . ± . ml/cm h o after h. the lungs from five additional anesthetized, unassisted breathing animals, taken directly after induction, showed significant atelectasis, neutrophil infiltration and interstitial and alveolar edema (diffuse alveolar damage (dad) score . ± . ), as compared to control animals without ali (dad . ± . in ventilated, . ± . in cpap, respectively). the dad was higher in aspiration ( . ± . ) than in lavage ( . ± . ) induced ali, with no significant differences between ventilated and cpap animals. no hyaline membranes were observed. conclusions. anesthesia induces significant alveolar inflammation, which is partially reversible by use of peep. the ali model of acid aspiration induces persistent changes in gas exchange, respiratory mechanics and alveolar damage, which are more severe and consistent than those induced by the lavage model. background. acute lung injury (ali) is characterized by exaggerated inflammation and a high metabolic demand. mechanical ventilation can contribute to ali, resulting in ventilator induced lung injury (vili). a suspended animation-like state induced by hydrogen sulfide (h s) may reduce metabolism and co production, allowing for a lower minute ventilation to maintain gas exchange, thereby decreasing vili. h s may also limit lung injury via reduction of inflammation. the effect of h s-induced suspended animation on myocardial function is unknown. methods. in rats, vili was induced using a peak inspiratory pressure (pip) of mmhg and zero peep. controls were ventilated with a pip of and peep of mmhg. respiratory rate was adjusted to maintain normocapnia. suspended animation was induced by infusion of a h s donor, controls received saline. blood gases were drawn, bronchoalveolar lavage fluid (balf) was collected, lungs were removed. aortic flow was measured. statistics include kruskal-wallis and mann-whitney u. introduction. alveolar oedema is a hallmark of ards and ali. fluid clearance and the influence of anaesthetics on oedema resolution are poorly understood on a molecular level in the injured lung. oedema resolution is mediated by osmotic water reabsorption, following active sodium reabsorption via the apically located epithelial sodium channel (enac), driven by sodium-potassium-adenosin-triphosphatase (na ? /k ? -atpase). objectives. our aim was to investigate the influence of mac (= . vol%) sevoflurane on mrna and protein levels of enac and na ? /k ? -atpase in injured alveolar epithelial cells (aec). methods. primary culture of aec was stimulated with lipopolysaccharide (lps, lg/ ml) and exposed to normal air containing % co with or without sevoflurane. mrna levels were measured at h using the taq-man real-time pcr method. additionally, proteins for western blotting were analyzed at , and h (n = ). in the presence of sevoflurane mrna level of the a -subunit mrna of na ? /k ? -atpase in control cells was downregulated by % (p \ . ). a-subunit na ? /k ? -atpase protein expression, however, was not influenced by lps or sevoflurane at all time points. mrna of c-enac was decreased by % in the presence of sevoflurane and by % upon stimulation with lps. in the lps-sevoflurane group downregulation was even more pronounced with % (p \ . ) after h, but not statistically different from the lps group. on the protein level of c-enac protein expression a first change was observed at h with a downregulation of % upon lps exposure (p \ . ). sevoflurane did not have an effect of this transporter protein. previous studies have shown that halothane decreases na ? /k ? -atpaseand sodium channel activities in alveolar epithelial type ii cells [ ] . despite this finding for halothane, we could not see similar effects for the volatile anaesthetic sevoflurane. our results suggest that neither the driving force of alveolar oedema resolution, the sodium potassium atpase, nor c-enac, which is considered the rate limiting step in sodium coupled water reabsorption are influenced by sevoflurane and lps in an in vitro model of ards. to further characterize the impact of sevoflurane on water transport, functional analysis of these two transporters have to be performed. grant acknowledgement. objectives. we evaluated the effects of two nebulised sfa perfluorohexyloctane (f h ) and perfluorobutylpentane (f h ) at different dosages ( ml/kg vs. . ml/kg) on pulmonary mechanics and gas exchange in healthy lungs. design. after approval by the local animal care committee, prospective, randomized animal study. subjects. thirty-five new zealand white rabbits. interventions: tracheotomised and ventilated juvenile rabbits were nebulised intratracheally with either a high or a low dose of two different sfa (f h low/high and f h low/high ) or saline (nacl). ventilated healthy animals served as controls (sham). arterial blood gases, lung mechanics, heart rate and blood pressure were recorded prior to nebulisation and in min intervals during the -h-study period. results. immediately after starting aerosol therapy p a o /f i o -ratio and dynamic lung compliance decreased in all groups, with the exception of the f h low group which behaved like the sham group. although p a o /f i o -ratio showed a continuous improvement in the other groups over time respiratory mechanics still remained impaired. high dose groups with nebulisation of liquid perfluorohexyloctane (f h high ), perfluorobutylpentane (f h high ) or saline (nacl) showed no significant differences neither in oxygenation, blood pressure nor in pulmonary compliance and resistance. in contrast to f h high , there were no residues of f h high detectable in bronchoalveolar lavage. regarding f h low we were not able to detect any adverse effects on gas exchange or pulmonary mechanics. additionally, wet-dry-ratio of apical lung tissue samples revealed no significant edema. conclusions. high dose aerosolized sfa ( ml/kg), either f h or f h , equals effects of high dose inhalation of saline. when comparing the low-dose sfa-groups, there is a convincing discrepancy in favour of f h . f h low impairs pulmonary function, whereas a low dose application of f h (low) shows no interference. this may be due to the faster evaporation of f h . a new sfa-based pulmonary drug delivery system for lipophilic or water-insoluble substances could be developed on the basis of a low-dose application of f h . objects. hypertonic exposure reduces cell volume and thereby creates a relative excess of plasma membrane (pm). as a result the lipid bilayer of the pm can simply unfold with a minimal increase in lateral tension when an externally imposed shape change demands it. to test this hypothesis, we determined the effects of osmotic pressure on the susceptibility of deformation injury and pm wound repair. we measured deformation injury and repair responses of a . cell culture media were consisted of x hmem and mannitol (v/v / ) with osmolarity of (iso), (hyper) and mosm (hypo). cells conditioned with media were either stretched or deliberately injured with a scalpel. the fraction of wounded and healed cells was measured using a dual label method. . ( ) exposure to a hypertonic environment tends to lower the susceptibility of a to deformation injury ( . ± . % for iso, . ± . % for hyper), while exposure to a hypotonic environment uniformly increases it ( . ± . % for hypo) in stretch injury. introduction. the migration of polymorphonuclear leukocytes (pmns) into the lung plays a critical role in the development of acute lung injury (ali). adenosine receptor a (a ar) is one of four g protein-coupled adenosine receptors that has been demonstrated to modulate pmn trafficking in various models of inflammatory disorders including sepsis and asthma. however, the role of a ar in ali has not been investigated systematically yet. the objective of this study was to determine the role of the a ar in a murine model of lpsinduced lung injury and in an in vitro transmigration system with human cells. methods. the migration of pmns into the different compartments of the lung was determined by flow cytometry in adult male c bl/ mice (wildtype [wt] ) and homozygous a receptor knockout (a ko) mice. we used chimeric mice that were generated by transferring bone marrow between wild-type and a ko mice to differentiate the role of a on hemopoietic and nonhemopoietic cells. furthermore, microvascular permeability was assessed by the extravasation of evans blue and the release of chemotactic cytokines into the alveolar airspace was determined by elisa. paraffin-embedded sections of the lung were stained for pmns after lps inhalation to illustrate their accumulation in the lung. in a human in vitro assay, we quantified neutrophil transmigration across an epithelial monolayer (a cell line). in all murine in vivo experiments and in the in vitro transmigration assay, we assessed the effectivity of the specific a -agonist cl-ib-meca. all statistical analyses were performed by using anova. p \ . was considered statistically significant. results. inhalation of lps significantly increased the number of pmns in wt and a ko mice in all lung compartments. no differences in pmn counts were observed between wt, a ko, and chimeric mice. pretreatment with cl-ib-meca led to a significant decrease of pmns in all lung compartments of wt mice but not in a ko mice. pharmacological activation of a ar diminished the lps-induced microvascular permeability in wt mice but not in a ko mice. upon lps-inhalation, a ko mice exhibited significantly higher levels of the cytokines cxcl und cxcl / in the alveolar airspace than wt mice. in wt mice, pretreatment with cl-ib-meca reduced levels of tnfa and il- significantly. transmigratory activity of human pmns across an epithelial monolayer was reduced when a was activated in pmns. in contrast, pretreatment of the epithelial cells did not inhibit migration of pmns. introduction. lung overdistention during mechanical ventilation causes an increase in pulmonary vascular permeability, which is characterized by interstitial and alveolar edema secondary to a diffuse endothelial and epithelial injury. thrombopoietin (tpo), a humoral growth factor that stimulates the proliferation of megakaryocytes, has also been identified as a pro-inflammatory mediator in various clinical conditions. the receptor of tpo, c-mpl, is constitutively expressed on endothelial cells and may modulate the permeability of the endothelium. we investigated the contribution of tpo in the development of acute alveolar edema formation by mechanical stretch. in an ex-vivo model of mechanical ventilation (mv), lungs of c bl mice were ventilated for h with high stress pressure cycled ventilation (end inspiratory pressure = cm h o, peep = cm h o, i:e ratio = : ) and perfused with % bovine serum albumin rpmi medium at a rate of ml/min, in the presence or absence of tpo ( mg/ml). following ventilation, lung elastance was measured and protein concentration was analyzed in the bronchoalveolar lavage. data are mean ± se. mechanical ventilation (mv) to treat patients with ards or acute lung injury (ali) has the end objective to increase the dynamic functional residual capacity (dfrc), thus increasing overall functional residual capacity (frc). simple methods to estimate dfrc at the end of expiration for a given positive end expiratory pressure (peep) would provide a valuable metric to track and modulate therapy. however, such methods do not exist and current methods are time-consuming and relatively invasive. methods. this study utilizes a constant stress strain ratio for an individual patient's volume responsiveness to peep to estimate dfrc at any peep. the estimation model identifies two population parameters from clinical data to estimate a patient-specific dfrc, b and mb, where b captures physiological parameters of frc, lung and respiratory elastance and varies depending on the peep level used, and mb is the gradient of b versus peep. dfrc was estimated at different peep values ( , , , , ) cm h o, and compared to the measured dfrc for ali/ards patients to validate the model. patients and methods. in a years period patients ( males, females) with haematological malignancies were admitted in icu. malignancy type, reason for admission, haematological profile, requirement for invasive ventilation, bronchial and blood cultures and survival rate were recorded. results. patients suffered from: hodgkin's lymphoma ( ), non-hodgkin's lymphoma ( ), chronical lymphocytic leukaemia ( ), acute myelogenous leukaemia ( ) and multiple myeloma ( ) . admission to icu was precipitated by: emergency surgical procedure ( ), respiratory failure ( ), sepsis ( ), pulmonary oedema ( ) and coma ( ) . pulmonary infiltrates was the main finding in chest x-ray. bronchial secretions cultures were positives in patients while blood cultures were positives in patients. apache ii score ranged from to (average . ) and the icu days ranged from to (average . ). all the patients required invasive ventilation. all the patients with sepsis and serious neutropenia were died, while the total mortality was / ( . %). conclusion. the admission of patients suffering from haematological malignancies in icu is associated with high mortality. immunosupression that renders them susceptible to infections, thrombocytopenia, and invasive ventilation are factors that contribute to this. early recovery of bone marrow and non invasive ventilation could improve the outcome in these patients. in liver transplanted patients, immunosuppressive therapy can increase the risk of infections and post-operative arf. nimv has been proposed as an alternative technique to reduce complications related to endotracheal intubation. the aim of our study was to evaluate nimv in liver transplanted patients, developing arf in the post-operative period. materials and methods. in this study we evaluated liver transplanted patients, developing postoperative arf. measurements of respiratory and haemodynamic parameters were performed at baseline, after h and at the end of the treatment. we evaluated intubation rate, nimv tolerance, length of stay in the icu (los), icu and hospital mortality. results. ( %) out of patients were successfully treated with nimv, while ( %) failed and were intubated. we observed no significant differences among groups in gas exchange, but rr was significantly reduced in the success group during treatment (p \ . ). in both groups we found no significant differences in pao /fio initial improvement, but the success group showed a significantly higher rate of pao /fio sustained improvement (p \ . ). no significant differences between the two groups were found in terms of hours and days of nimv. success and failure groups were significantly different in saps ii (p \ . ) los (p \ . ), icu and hospital mortality ( vs. %, p \ . , vs. %, p \ . ). reasons for nimv failure were not related to respiratory causes, but acute systemic causes such as septic shock and mods. conclusions. nimv can represent a valid alternative to invasive mechanical ventilation for the treatment of postoperative arf in liver transplanted patients; in nimv success patients reduced los and mortality can be expected. the influence of body posture on expiratory flow-limitation (efl) was estimated in flowlimited, mechanically ventilated patients using the negative expiratory pressure (nep) method. a device especially designed and in build in an evita -draeger respirator allowed the application of a pressure equal to- cm h o, starting at ms after the onset of expiratory flow and sustained throughout the end of expiration. patients were considered flowlimited, if despite the application of nep part or the expiratory flow-volume curve was superimposed on the baseline curve. patients were studied in supine and in semi-seated position ( ) at baseline and then min after administration of bronchodilators ( mg of inhaled salbutamol) with a nebulizer connected to the inspiratory port of the ventilator. supine position was significantly related to the occurrence of efl (p = . ). efl was abolished in % of our patients when changing from supine to semi-seated position, while in general a significant improvement of efl was noticed (from to % of v t , p = . ). significant improvement of efl was achieved as well (p = . ) after bronchodilative therapy. peepi was the only variable significantly related to efl improvement when changing body posture from supine to semi-seated, while for bronchodilative therapy, none of the variables studied was significantly related to efl improvement. l. c. woodson , university of texas medical branch, anesthesiology, galveston, usa, shriners hospital for children, anesthesiology, galveston, usa aims. laryngeal injuries are common among burn patients and can result in long term functional deficits. we have included careful laryngeal examination with our initial fiberoptic bronchoscopic evaluation of burn patients. the goal has been to allow early identification of laryngeal injuries and to facilitate laryngology consultations. methods. digital video recordings were made of upper airway endoscopies performed during airway management on admission or at the time of anesthesia for initial wound excision. these recordings were used to identify laryngeal injuries and to facilitate laryngology consultations. a wide variety of laryngeal injuries were identified and the digital recordings (which can be communicated by email) greatly facilitated laryngology consultations. in many cases these recordings guided therapeutic interventions and were often sufficient to avoid a separate exam under anesthesia. diagnosis of thermal necrosis provided an indication for early tracheostomy. identification of the mechanism of mechanical airway obstruction (e.g. supraglottic edema, fibrinous exudates, granulomas, vocal fold dysmotility) resulting in failure of a trial of extubation frequently guided therapy. early identification of posterior glottic damage provided more timely corrective laryngological interventions. educational use of these videos helps increase awareness of risks of laryngeal injury in thermally injured patients. aims. the most used weaning predictor f/v t ratio, is not a consensual predictor. when it was reported on the first time, this ratio was considered highly sensitive and specific. but others papers seems to disagree with it, suggesting other cutoff values to determine weaning failure in specific populations, as the elders. advanced age is thought to be an import associated factor in the intensive care unit (icu), but its effect on the weaning process is unclear. no studies have found strong evidence that conventional weaning parameters are reliable for this population. the widest used weaning criteria, f/v t ratio, does not seems to keep the same performance in this kind of population. the main purposes of this study were to identify the possible differences of the f/v t ratio measured in a spontaneous breathing trial, between an adult and an elderly group. we designed a protocol to study the variation, sensibility and specificity of the frequency-to-tidal volume ratio between an adult group (ag; up to years) and an elderly group (eg; older than years) in a daily weaning screening trial. methods. the study cohort comprised patients ready to undergo weaning trial. the parameters studied were: weaning success ( h of spontaneous ventilation after extubation), respiratory rate (f), tidal volume (v t ), frequency/tidal volume ratio (f/v t ), gasometric and ventilatory parameters. the weaning method was spontaneous breathing trial (sbt). measurements were made in the beginning of sbt (t ) and min after (t ). we analyze possible differences in the sensibility and specificity of the f/v t ratio between elderly and adults and compare with previous values already published. the chi-square test, anova and the t test were used in the statistical analysis. weaning success was . % in eg and . % in ag (p = . ). the baseline characteristics were similar. comparisons of ag and eg at t and t showed statistical differences in weaning criteria: f, v t and f/v t ratio. conclusion. weaning success in our study was low, but similar to the described in other trials. elderly patients showed higher f and lower v t . consequently, f/v t ratio was lower too. the area under the roc curve for f/v t ratio was smaller than already published. results. / ( %) were successfully extubated and patients required re-intubation. the demographic data showed no differences in age, bmi, apache ii, icu admission diagnosis or sex distribution between groups (table ) . patients who failed extubation had small but statistically significant differences in vital capacity (vc), peak negative inspiratory pressures (pnip), pao /fio ratios (pf) and were ventilated longer prior to extubation. paradoxically, patients failing extubation had positive end expiratory pressures that were statistically but not clinically significant higher. the ratio of respiratory rate to tidal volume (f/vt) was not significantly different. patients failing extubation were also more likely to have weaker cough, gag, level of consciousness as measured by glasgow coma scale and more secretions ( table ). having no cuff leak did not predict failure of extubation. the most common reasons for reintubation were secretion retention and/or absence of cough ( %). pressure support ventilation (psv), a widely used assisted mode, has the purpose to avoid diaphragm disuse allowing the patient to generate spontaneous inspiratory efforts optimizing comfort and work of breathing. however, still little is known about the individual response of respiratory muscles under these conditions. we hypothesized that respiratory muscles of patients ventilated with clinic psv might result, at least sometimes, excessively unloaded. we performed an observational study in the intensive care unit on patients ventilated with psv set by the clinician in charge. twenty intubated, mechanically ventilated patients ( ± years old) during the weaning phase entered the study. the patients had no sedation at least for the last h. respiratory timing, tidal volume (v t ), peak airway pressure (paw peak ), electrical activity of diaphragm expressed as percentage of its maximum (edi/ edi max ), inspiratory (ptpes) and diaphragm (ptpdi) muscle effort were measured during min of clinic psv. results. we found that seven out of twenty patients generated a negative pes swing only during the psv inspiratory triggering phase (psv t ) in comparison with the remaining patients in whom pes was negative throughout most of the mechanical breath (psv n ). in the psv t group, pes swing was either flat or positive after inspiratory triggering. therefore, in the psv t group both ptpes /min and ptpdi /min were fivefold lower than normal values. v t / predicted body weight (pbw) was significantly higher in the psv t versus psv n group (see table ). during weaning with psv: ( ) a significant number of patients ( %) showed a pes shape similar to that observed during pressure assist/control modes, and inspiratory muscle effort abundantly lower than normal, both indicating excessive inspiratory muscle unloading; ( ) among the variables used to set psv, only a high v t /pbw (higher than ml/kg) hallmarked excessive unloading; ( ) due to the ample prevalence of the phenomenon, the question whether high levels of inspiratory muscle unloading can cause detraining and prolonged mechanical ventilation merits an answer from further research. introduction. the liberation from mechanical ventilation (mv) should be done as soon as possible in order to avoid complications and the risks associated with prolonged unnecessary mv, such as ventilator-associated pneumonia, ventilator induced lung injury, and increased icu and hospital stay. this procedure should be carried out properly and safely. objective. evaluate the extubation success rate, mv time and weaning time using a daily weaning screen followed by a spontaneous breathing trial (sbt). patients who were ventilated for more than h were subject to this procedure, which was carried out by respiratory therapists. methods. in our icu, between february and august of , all intubated patients who were ventilated for more than h underwent a daily weaning screen, which contained variables such as hemodynamic, gas exchange, consciousness and resolving the need for mv. if these variables were stable, these patients were submitted to a sbt and were extubated if they did not show any signs of respiratory discomfort or hemodynamic changes for at least min. conclusion. the use of a daily weaning screen followed by a sbt was associated with a high extubation success rate and a very short weaning duration with % of unsuccessfully extubations. c. chatt , d. pandit , g. raghuraman birmingham heartlands hospital, critical care, birmingham, uk, birmingham heartlands hospital, birmingham, uk aim. the aim of the study was to assess the impact of pmv on the course of weaning in mechanically ventilated patients. we wanted to assess the optimal pressure support at which pmv can be initiated which would enable prolonged use of pmv without affecting the duration of respiratory support. method. data on all patients who were mechanically ventilated for greater than eight days were obtained from icnarc database, who underwent tracheostomy as part of their weaning process. satisfactory level of pressure support was achieved (between and cm h o) pmv was introduced into the patient's breathing circuit and spontaneous ventilation was attempted. we applied mann whitney u tests for parametric data, fisher exact tests for non-parametric data and anova was used to compare the three groups with different pressure supports at initiation of pmv. a p value \ . be statistically significant. results. patients who were ventilated for greater than eight days identified. of these, patients were excluded because they did not have a tracheostomy during their period of ventilation. of the remaining patients, pmv was used in patients ( %). there were no significant differences between the demographic data (sex, age) or the data on admission to intensive care (apache ii score, ratio of medical to surgical patients) and duration of mechanical ventilation between the two groups. however, there were significant differences in the mortality, total respiratory support days after tracheostomy and length of stay in intensive care and length of hospital stay between the two groups. in the group on pmv, no record of aspirations was found documented on the intensive care charts. in patients in whom pmv was used (n = ), pmv was initiated at cpap (continuous positive airway pressure) in patients ( %). patients ( %) had pmv initiated at a pressure support of b cm h o and in patients ( %) pmv was initiated at a pressure support of [ cm h o. there was a significant difference in the duration of mechanical ventilation post tracheostomy (p = . ) and the length of hospital stay (p = . ) between the two groups, with the cpap group being ventilated for a shorter duration but with a longer stay in hospital the same difference was shown when comparing three groups of pressure support when pmv was commenced (cpap, pressure support b cm h o and pressure support [ cm h o). however, in the pressure support [ cm h o group we observed that the duration of use of pmv was lower than in the other two groups despite longer duration of mechanical ventilation and total respiratory support days. although this was not statistically significant, it could be clinically significant. our study suggests that use of pmv at pressure support b cm h o could increase the duration of its use without affecting the length of mechanical ventilation. we would therefore recommend weaning to a pressure support b cm h o before pmv is commenced in the acute setting. no data are available concerning the oxygenation target to aim during the weaning phase from mechanical ventilation. also, in opposition to ards patients there is no clear recommendation for the upper limit of spo to maintain during weaning. this study is part of a research project on peep and fio settings automation during mechanical ventilation. methods. this observational study was designed to assess the spo target aimed during the weaning phase of invasive mechanical ventilation (fio b . and peep b cm h o). patients were recruited in icus from several countries (canada, france, italy, tunisia, argentina). the following data were prospectively collected by the respiratory therapists at each round during a months period: spo , fio , peep level, ventilatory mode, anatomic site of the pulse oxymetry sensor, quality of the spo signal. results. data from centers ( icus) from quebec city, canada, and center from créteil, france are available. patients were prospectively included. , observations were performed. the mean level of fio was . ± . with fio c . and . in . % and . % of observation times respectively. the mean level of peep was . ± . cm h o and was below, equal or above cm h o in . , . and . % of the cases respectively. the most frequent ventilatory modes were pressure support ( %), simv ( %) and acv ( %). the pulse oxymetry sensor was applied on a finger of the hand in . % of the cases and was deemed of good quality in % of the time. the mean spo was . ± . % for the whole population and was . ± . % for patients with fio c . . spo was higher than % in % the observations. desaturation with spo below % were recorded in . %. the spo signal was deemed available by the bedside nurse in . ± . % of the time. conclusion. this study demonstrates that spo levels may be maintained at high levels unduly. this may have an impact on the weaning phase of mechanical ventilation. this study also shows that the spo signal availability was high enough to be used in a closed-loop oxygenation system. introduction. automated weaning systems are viewed as a challenge to weaning decision-making autonomy by some clinicians. clinician perceptions of the utility of such systems may influence uptake in to practice. to assess the perceived utility of the automated weaning system, smartcare/ ps. a survey was generated based on comprehensive literature review and -year's experience using smartcare/ps. survey pilot testing was conducted with senior clinicians experienced in smartcare/ps weaning in an independent icu. questions addressed perceived system usability and appropriateness of automated weaning, system benefits and disadvantages, as well as patient indications deemed suitable and unsuitable for smartcare/ps weaning. participants were also asked to indicate if they would continue using smartcare/ps on trial completion. the survey was administered to clinicians on completion of a randomized controlled trial conducted to compare smartcare/ps to non-protocolized weaning . of staff surveyed, surveys were returned by nurses and doctors (response rate %). eight respondents had no experience with smartcare/ps despite the year trial duration, leaving surveys with evaluable responses. the majority of respondents perceived smartcare/ps was easy to activate ( / , %) and to use once activated ( / , %). the system was observed to wean appropriately by / ( %) respondents; experienced smartcare/ps to wean inappropriately. comments on inappropriate weaning identified clinically unacceptably increases of pressure support (ps) for patients with profound tachypnea and complicated lung pathology. smartcare/ps' ability to reduce the overall duration of weaning was questioned by all but / ( %) respondents. ps adjustment according to patient requirements was the most frequently perceived benefit ( / , %). most respondents did not perceive any advantage of smartcare/ps for patient comfort / ( %), assessment frequency ( / , %) and automated control of weaning ( / , %). less control over weaning was the most regularly cited disadvantage of smartcare/ps ( / , %). system issues such as program abortion without identifiable reason and mandatory peep reduction prior to a spontaneous breathing trial to assess readiness for separation were less frequently cited disadvantages [ / ( %) and / ( %) respondents respectively]. most respondents ( / , %) felt smartcare/ps was best suited for weaning postoperative patients and should be avoided for patients with neurological dysfunction ( / , %). only / ( %) respondents stated they would not continue to use smartcare/ps. clinicians demonstrated moderate acceptance of smartcare/ps. more work is needed to identify those patients more likely to benefit and confirm the overall utility of smartcare/ps as a weaning tool. introduction. physician approaches to ventilation withdrawn varies among physicians whereas the prompt recognition of respiratory failure reversal and usefulness of weaning protocols in reducing duration of mechanical ventilation (mv) have been largely demostrated as nursing staff attend patients h a day its leadership in this process can be effective and safe. objective. to demonstrate that a nurse-directed protocol to withdraw mv could reduce a % its duration. prospective sequential study performed in two periods. during de first period ( months) data concerning weaning definite criteria appearance, duration of mv, reintubation or need for nonninvasive ventilation (nimv) and demographic data were collected to all mechanically ventilated patients blinded by attending nurses and physician. after a three months phase of staff training there was a second months period where weaning criteria were checked al each nurse working shift during the first days of mv. when criteria were fullfilled a min of spontaneous breathing trial was perfomed and tracheal tube removed if there were no intolerance criteria. same data as the first phase were collected. we used mann-whitney s u test to compare mv duration, time to reach weaning criteria (trwc) and extubation delay (mv duration minus trwc). weaning failure was compared using x square. data are presented as median ( - percentile). results. patients were screened ( in the first period and in the second) but only patient reached weaning criteria in the first days ( in the first period in the second), . % men, aged ( - ) years. aim of this study is present our experience about elective bedside pdt with the blue-rhino kit over an year period, in order evaluate its efficacy in terms of intraoperative and postoperative complications. patients and methods. the study included a total of consecutive icu patients requiring tracheostomy. all pdt were performed by icu staff physicians at patients' bedsides, using a blue rhino kit. the following data were recorded: age, sex, simplified acute physiology score (saps) ii, fraction of inspired oxygen (fio ) before the tracheostomy, days on mechanical ventilation before the tracheostomy, bleeding, tracheal tear, subcutaneous emphysema, pneumothorax, wound infection, hypotension, lowering sao during the procedure, inability to complete the procedure, and procedural mortality. distance follow-up included fiberoptic bronchoscopy to evaluate tracheal stenosis. results. there were a total of ( . %) complications (tracheo oesophagel fistula and bleeding). forty -one patients died in the icu ( %), although none of these deaths were related to technique complications. mean duration of the procedure was . ± . minutes. the pdt performed at bedside in the icu, using the blue rhino kit is a simple and safe procedure that offers many advantages in terms of safety and efficacy. objectives. questioning the need for several specialized physicians or extra assistance to perform a single percutaneous tracheostomy using fibrescopic tracheoscopy, we performed a prospective study into the complication rate of percutaneous tracheostomy without tracheoscopy on our mixed medical and surgical icu. , consecutive patients were included after having received a percutaneous tracheostomy. indication for tracheostomy was always a long anticipated duration of mechanical ventilation. if no contra indications were present, percutaneous tracheostomy was performed. if contra indications against the use of percutaneous tracheostomy without tracheoscopic control were present, tracheoscopy was performed to ensure maximum patient safety. the mean age at the time of receiving a tracheostomy was . ( - ) years. the cohort consists of male patients en female patients. only ttwo percutaneous tracheostomy were performed under fibrescopic control due to contra-indications for an uncontrolled procedure. in procedure, sixteen minor, and no major complications were encountered. this resulted in a . % minor complication rate. conclusions. the number of complications in our group is approximately the same as those which are suggested in international literature where tracheoscopy was performed during percutaneous tracheostomy. none of the complications encountered could have been prevented by the use of tracheoscopy. therefore we postulate that in the hands of an experienced team and in adherence to strict guidelines, percutaneous tracheostomy can safely and successfully be performed without tracheoscopy. objective. to assess the risks and complications associated with the bedside pdt in our years experience of over pdts in icu. pdt is a relatively newer technique and has been introduced as an alternative to open tracheostomy as a safer and convenient procedure. however, the risks and complications of the pdt have not been highlighted in the icu of a developing country. a retrospective analysis of the data gathered from patients undergoing pdt was done in a -bedded tertiary level multidisciplinary icu of a teaching hospital. the data was collected between april and march . all intubated patients with indications for elective tracheostomy, as well as patients who required emergency tracheostomy were included in the study. demographic and other clinical details of the patients who underwent pdt were collected. griggs [ ] technique was most commonly adopted while other adopted techniques were ciaglia [ ] , white tusk/blue rhino tapered dilator and percutwist technique. a total of , pdts were done in , patients, over a period of years. of the , patients ( %) were males and ( %) were females. the mean age of patients was . years. the average duration of intubation before pdt was . days. ( %) pdt were done bedside in icu while ( %) were done in wards, coronary care unit, high-dependancy unit and liver transplant unit. griggs technique was adopted in ( . %), ciaglia in ( . %), white tusk/blue rhino tapered dilator technique in ( . %) and percutwist technique in ( . %) patients. long-term ventilation was the most common indication in ( . %) followed by airway protection in ( . %), facilitation of weaning in ( . %) while airway obstruction/difficult intubation was observed in ( . %) patients. pre-procedure coagulopathy was observed in ( . %) patients, ( . %) were morbidly obese while ( . %) required emergency tracheostomy. no complications were observed in ( . %) patients. procedural complications were seen in ( . %) patients. bleeding from the site was the leading complication affecting ( . %) patients. difficult tube placement was seen in ( . %) patients, premature extubation in ( . %), false passage in ( . %), guidewire dislodgement in ( . %), subcutaneous emphysema in ( . %), arrhythmia in ( . %) and bleeding requiring transfusion was seen in ( . %) patients. no procedure related mortality was observed. conclusion. on the basis of this large single centric study we found that pdt is a safe, reliable and convenient procedure which can be easily performed bedside by experienced intensivists. results. of the recipients who underwent pdt, were liver, kidney and heart transplant recipients. the respective mean values for age, weight and apache ii score were . ± . years, . ± . kg, and ± . all pdts were performed at bedside by experienced staff anesthesiologists with direct bronchoscopic guidance. in all cases, the indication for pdt was prolonged mechanical ventilation due to acute respiratory failure. the mean time from transplant to pdt was ± months and the mean duration of endotracheal intubation before pdt was ± days. twelve patients had coagulopathies. the calculated lung compliance and pao :fio ratio improved after pdt ( . ± . vs. . ± . ml/cm h o, p = . and ± vs. ± , p = . respectively). transient hypoxemia (n = ) and mild extratracheal bleeding (n = ) were the only early complications. there were no procedural failures and no pdt-related late complications and deaths. conclusion. the results suggest that percutaneous dilational tracheotomy is an efficacious and safe technique for prolonged airway management with improved ventilatory mechanics in solid organ transplant recipients. a. vianna , g. cabral , r. azambuja , g. carleti , t. balbi , g. pereira clinica são vicente, rio de janeiro, brazil aims. we studied diferent aspects of tracheostomy procedures performed in intensive care units (icus) located in the municipality of rio de janeiro and compared them with the medical literature. a questionnaire was elaborated and sent through email to the coordinators of every icu in the city of rio de janeiro in the period of july to august . the questionnaire was sent to the coordinators of the icus located in rio, and was answered by ( . %) of them. among the studied icus, ( . %) are public, ( . %) are private, and ( . %) are part of university hospitals. ( . %) are medical/ surgical, ( . %) are medical, and ( . %) is a surgical unit. the average number of beds is ± . . the decision to perform the procedure is taken by the icu team in ( . %), by the patient's primary team in ( . %), and by both in ( . %). tracheostomy is performed by a surgeon in ( . %) units, by an intensivist in ( . %), and by both in ( . %). the procedure is performed at the bedside in ( . %) of the icus. the most frequent indications for tracheostomy are: prospect of prolonged mechanical ventilation, coma, and airway protection. . % of are performed between the first and second week of mechanical ventilation, and % between the second and third week. control chest x-ray is performed in . % of the units. surgical tracheostomy is available in all the studied units. only ( . %) units perform percutaneous tracheostomy. the reasons given for the preference for surgical tracheostomy were the lack of a qualified team for performing the percutaneous tracheostomy or material needed for this procedure. all icus that perform the percutaneous procedure use the ciaglia technique with bronchoscopic guidance. late followup is performed in ( . %) of the studied units. the study showed great differences between the tracheostomy protocols used in the hospitals of rio de janeiro and those found in the medical literature. in particular, the use of percutaneous tracheostomy is still infrequent in the icus of rio. on all the patients, aged at least years or more, admitted to our postoperative icu since january through december , we collected demographic profiles, operative data and short and long-term outcomes. spss . was used for statistical analysis and p \ . was considered the level of significance. a total of patients ( . %), . % males and with a median (iqr) age of ( - ) were admitted to our post-operative icu over the study period. iddm was recorded in the . % of the population, copd in the . %, hypertension in the . %, chronic renal failure in the . % and arteriopathy in the . %. out the total population, . % of patients, with a median (iqr) pre-operative crs of ( - ) underwent a coronary-artery bypass grafting (cabg) surgery, whereas . % of them, with a preoperative median (iqr) nyha of ( . - ) needed a valve replacement (vr) and . % of them combined (cabg ? vr) operations; moreover, . % of patients underwent other type of cardiac and aortic surgery. overall median (iqr) post-operative mechanical ventilation length was ( . - ) hrs. while no statistically significant difference was recorded in terms of mv duration among the four surgical groups. overall recorded mortality rate was %, with the lower . % for cabg and the higher . % for vr (p = . ). kaplan meier curves showed no differences in survival likelihood at th (log rank = . , p = . ) th (log rank = . , p = . ) and th (log rank = . , p = . ) days after surgery among the different surgical groups. conclusions. the outcome after heart surgery in octogenarians is excellent; the operative risk is acceptable and the late survival rate is good. therefore, cardiac surgery should not be withheld on the basis of age alone. introduction. re-do cardiac operations have been reported to be increasing in incidence and are associated with a higher operative risk [ ] . this study aimed to determine the impact on intensive care provision. methods. data from , procedures spanning twelve years (april -march ) was examined. the re-do operations were further analysed by gender, age, pathology (new, progressive, combined) , duration between procedure, theatre time, length of stay, complications and mortality. as the number of cardiac operations performed has increased over the twelve year period, the relative incidence of re-do procedures have remained stable at . %. operative length at re-do was significantly longer (mean min vs. ) however anaesthetic time pre surgical incision was not significantly increased. subsequent length of stay on the intensive care or high dependency unit increased by % (mean . vs. . days), with higher complication rates affecting all systems (except post operative myocardial infarction). renal and pulmonary complications showed the most significant increases. renal related complications occurred in % and pulmonary in . % of cases which represents an and % increase on first operation rates. infection rates were also significantly increased at double that of the initial procedure. the total hospital stay was found to be % longer (by . vs. . days, respectively) while in hospital mortality increased from . % at initial procedure to . % at re-do. mortality rates were further elevated in the presence of renal failure post operatively, as re-do valve mortality increased from . to % and re-do cabg from . to % in this subgroup. conclusion. these results, combined with the stability of percentage re-do surgery over the twelve year period, enable specific planning and management of intensive care provisions. the knowledge of extended theatre times and subsequent stay in intensive care/high dependency units has a further impact on the throughput of routine cases. the data also highlights the increased costs associated with these patients, as they not only require longer hospital stays but also suffer increased complications requiring more investigations and interventions. specific costing therefore applies to this subgroup of intensive care patients. objectives. we aimed to assess hrqol at days after surgery in relation to preoperative hrqol. we compared patients with decreased hrqol to patients with unchanged or increased hrqol to identify disparities between these two groups. a prospective cohort study including patient scheduled for cardiac, vascular, abdominal and orthopedic surgeries in a tertiary hospital was performed. patients filled-out a hrqol questionnaire (sf- ) the day before surgery and days after. preoperative, intraoperative, postoperative data were collected. changes of pre-and postoperative physical component summary ( simultaneus kidney-pancreas transplantation is the best treatment option for type diabetic patients with chronic kidney disease. currently, the medical and surgical complications have decreased significantly, although these represent a high risk of morbidity and mortality in the short term. objectives. this study sought to investigate the incidence of medical and surgical complications, the clinical characteristics and prognostic factors influencing graft and patient's survival in a recent cohort of pancreas-kidney recipients. patients and methods. the present study included patients who received simultaneous pancreas-kidney transplantation in our center from january to february . we studied demographic, clinical and immunological characteristics of patients, and surgical and medical complications during his admission to intensive care unit. results. the average age of recipients was . years and mean age of donors was . years. the median cold ischemia time was . h ( % confidence interval - ). the average stays on the waiting list was . days. % of patients were extubated within the first h. % of patients required transfusion during their icu admission, amine infusion was started at % patients in the early hours. during follow-up, surgical reintervention in the immediate postoperative occurred in % of the patients. major surgery complications reported in the literature are graft thrombosis, although in our serie there have been only kidney graft thrombosis and pancreas graft thrombosis. only % of patients died within the first months posttransplantation surgery. conclusion. surgical complications after pancreatic transplantation remain a significant concern. hence we our results add further evidence to support the notion that the double and simultaneous pancreas-kidney transplant is in fact the treatment of choice in selected patients with end-stage renal failure due to type diabetes mellitus. a. shono , t. mihara , y. murakami , j. ota , f. kono , y. saito shimane universiy hospital, anesthesiology, izumo, japan pulmonary catheter is widely used for cardiac surgery. the complications of indwelling pulmonary catheter, such as perforation of pulmonary artery, pulmonary embolism, are well known. however, the thrombosis associated with introducer sheaths has received much less attention. we evaluated the incidence and risk factors for internal jugular vein thrombosis (ijvt) associated with introducer sheaths for pulmonary catheter after cardiac surgery. methods. the patients who underwent cardiac surgery and insertion of introducer sheaths ( . f) at right internal jugular vein (ijv) were included. ultrasonographic evaluations of ijvt were performed prior to insertion and daily until introducer sheaths removal. we investigated demographic data, underlying disease, length of surgery, use of cpb and iabp, complications during cannulation and duration of catheterization. coagulation status (pt, aptt, platelet count, d-dimer) and cardiac index at before and after surgery were also recorded. the student's t test, v test, and fisher's exact test were used for statistics and p value of . was considered significant. results. patients were included in this study. mean age of patients was ± years (range - ), mean duration of catheterization was ± days. ( . %) patients developed ijvt which occurred only one day after insertion. the incidence of ijvt was related to presence of underlying disease (relative risk, . ; % confidence interval, . to . ) and was unrelated to emergency operation, the use of iabp and cpb, number of insertion attempts. there were significant differences between patients with or without ijvt in duration of catheterization ( . ± . vs. . ± . days, p = . ), cardiac index at day after surgery ( . ± . l/(min m ) vs. . ± . l/(min m ), p = . ), the value of d-dimer at day after surgery ( . ± . vs. . ± . lg/ml, p = . ). no clinical symptoms related to ijvt were found in observation period. our results demonstrated that ijvt associated with introducer sheaths was a frequent complication and cardiac index was significantly lower in patients with ijvt. though the incidence of ijvt was higher in patients with prolonged catheterization, it developed even on day after surgery and was usually asymptomatic. this risk should be carefully considered when the insertion of pulmonary catheter is chosen for cardiac surgery. methodology. it is a prospective study of patients admitted to our icu after undergoing robotic radical prostatectomy (da vinci) in the time interval going from january up to april . we analyzed clinical and demographic data, the length of stay in the icu and hospital, the need for blood transfusion, surgical times and the complications suffered during hospital stay. data are expressed as mean, median or percentage, using the student's t test and chi-square to compare averages and detect possible associations between variables. results. seventy three patients underwent surgery with a median of years. mean surgical time was min. in recent months this time is reduced to min. the mean haemoglobin at admission ( . g/dl) was significantly higher than when dismissed ( . g/ dl), p \ . . an average of two units of concentrated red blood cells was transfused in the surgery room in . % of patients. only one patient required transfusion at the icu. cardiac or renal mild complications appeared in . % of patients. this could not be associated with age. the median of mechanical ventilation length was h. one patient required conversion to open surgery due to profuse bleeding. there was no hospital mortality and no need for reoperation. mean stay at icu was day, significantly less than those patients who suffered complications (p \ . ). the median stay in ward was days. conclusion. robotic radical prostatectomy (da vinci) has a very low associated morbidity, minimal blood transfusion requirement and short is the stay at the icu and hospital, in contrast to published data with open surgery. there was no hospital mortality. objectives. to evaluate short-and long-term outcome in patients undergoing coronary artery bypass grafting (cabg), who received an intra-aortic balloon pump (iabp) prior to surgery. methods. between january and june , all patients (n = ) who received an iabp prior to on-pump cabg in our center were included. patients received the intra-aortic balloonpump for vital indications (i.e. either unstable angina refractory to medical therapy or cardiogenic shock; group ; n = ) or for prophylactic reasons (group ; n = ). a cox proportional hazards model was used to identify predictors of long-term all-cause mortality. compared with the euroscore predictive model, observed -day mortality in group ( . %) was not significantly higher than predicted ( . %). a dramatic decrease in -day mortality occurred in group (median predicted mortality was . % and observed was %, p \ . ; fig. introduction. physiological abnormality is associated with adverse outcome and a high percentage of patients admitted to icu have abnormal physiology in the hours prior to admission [ ] . track and trigger systems are used to enable timely intervention to a deteriorating patient. the mews system is used in our level care general wards with more intensive monitoring in our level care facilities. objectives. we hypothesised that the mews for patients admitted from the general wards were being inadequately documented and that this be may influencing outcome. we therefore also hypothesised that patients admitted from the level care general surgical and medical wards in our hospital had a poorer outcome following icu admission than those admitted from sites of level care, such as the high dependency unit (hdu), emergency department and theatre recovery. we undertook a prospective week audit of all patients admitted to our district general icu. all patients' case notes and monitoring charts were reviewed by an icu consultant with additional data (e.g. apache ii scores) obtained from the ward watcher icu database. day mortality data was obtained from the hospital's sci patient database. we then compared the data with that available for patients admitted over the previous year ( ) background and aim of study. aorto-femoral bypass (afb) is widely used for the patients with peripheral vascular disease (pvd). nevertheless, there is no consensus about the type of anesthesia for this difficult group of patients. we hypothesized that continuous spinal anesthesia (csa) will be more secure and suitable for the patients with pvd combined with pulmonary and cardio-vascular co-morbidities. the aim of our study was to compare alterations of the mean arterial pressure (map) and delivery of oxygen (do ) during afb and in the early postoperative period under the influence of ga and csa. after approval of our hospital helsinki committee prospective randomized study was performed between and : male patients with pvd were included in our work. risk of anesthesia was equal to the third degree according to asa scale. in the first group of patients (n = ) ga with mechanical ventilation was employed. in the second group of patients (n = ) csa was used. both groups of patients were similar with respect to age and co-morbidities (copd % in both groups, ischemic heart disease and arterial hypertension). for ga we used propofol, midazolam, fentanyl, and isoflurane. bupivacaine was used for csa. in combination with mental sedation by intravenous midazolam. map was measured directly through radial artery catheter and do with the help of tetrapolar rheovasography. both parameters were measured during fixed points: before the operation, at the end of induction of anesthesia, after cross clamping of the aorta, after release of aortic clamp, first hour after operation, h after operation and h after operation. mann-whitney test was used for statistical analysis of our results. in the patients with csa during the operation and in the early postoperative period, map was lower but statistically non significant. map was lower statistically significant only during the cross clamping of the aorta and in the first postoperative hour, most probably due to the influence of the sympathetic block. at the same time do had almost no difference in both groups. only in induction stage it was lower in the ga group that most probably was connected with negative influence of propofol on cardiac output. conclusions. both methods of anesthesia ga and csa gave us opportunity to preserve stable map and do during afb that we performed in this difficult pvd patients with copd and cardiovascular co morbidities. over the last few decades, several scoring system have been developed for use in critically ill patients, not only to assist therapeutic decision making but also to guide resource allocation and quality of care. to evaluate the tiss- in surgical intensive care unit (icu) patients and the possible relationship between tiss- and the type of surgery, severity of illness, and outcome in these patients. prospectively collected data from all patients admitted to a postoperative icu between st march and th june were analyzed retrospectively. a-priori subgroups were defined according to gender, age, saps ii score, sofa score, surgical procedures, and the occurrence of major morbidity or death in the icu or in-hospital. a total of , patients were admitted during the study period ( . % male, mean age . years) constituting , observation days. the highest tiss- scores were observed on the day of admission. the highest tiss- was observed in patients who underwent cardiothoracic surgery, the lowest in neurosurgical patients. during the first week in the icu, tiss- was correlated to the severity of sepsis syndrome; however tiss- scores remained elevated only in patients with severe sepsis/septic shock. tiss- score was correlated to saps ii (r = . , p \ . ) and sofa score (r = . , p \ . ) throughout the icu stay and was consistently higher in non-survivors than survivors during the first weeks in the icu. conclusions. the highest tiss- scores are observed on the day of admission to the icu with marked variations according to the type of surgery. tiss- correlates well with the severity of sepsis syndrome and outcome in these patients. our data could be helpful in icu planning, risk stratification, and resource allocation in the surgical icu setting. introduction. pain and opioids for treatment of pain can affect immune function in cancer patients, which may in turn influence metastatic capability of a primary tumour during and after surgical excision. it is also been shown morphine has a direct effect on cancer cells, but results of these studies have been conflicting. we therefore aimed to determine effect of morphine, commonly used in anaestehsia and intensive care, on in vitro breast cancer cell migration using two breast cancer cell lines. we used two cell lines: mcf is er positive breast cancer cell line while mda-mb- is er negative, less differentiated and more invasive. cells were incubated with or without morphine (concentrations - ng/ml) for , and h, corresponding to clinically relevant concentrations and exposure times. cell proliferation was determined using an mts (promega inc.). h cell migration was determined using a -well flourescent kit (chemicon). results were compared using independent sample t test for differences between the groups. morphine had positive effect on cell proliferation, which was greater in mda-mb- cells. proliferation of mda-mb- was increased the most at h incubation and higher concentrations ( and ng/ml caused and % increase in proliferation at h incubation and up to % increase at h incubation). proliferation of mcf cells was increased by % in and h incubation periods. morphine caused an increase in migration of both cell lines, which was again more evident with mda-mb- cells at higher concentrations of morphine ( , % and % increase with , and ng/ml respectively). our experiments have shown morphine has potential to directly stimulate breast cancer cell proliferation and migration in vitro, especially in less differentiated breast cancer cell line. further studies are needed to determine its effect on other metastatic mechanisms such as invasion and gene expression as well as the implication of these results for clinical practice. objectives. aim of this study was to evaluate the predictive value of nt-probnp levels and inflammatory markers (crp, il- , tnf) on late mortality in patients who underwent thoracic surgery for lung cancer. methods. patients median age ( ± years) without history of heart disease or renal failure. the blood tests for nt-probnp, crp, il- and tnf analyses were drawn one day preoperatively, h, h and days postoperatively. patients' demographic data, laboratory results and mortality were collected and assessed. results. nt-probnp at h was significant higher in non-survivors ( , ± , pg/ ml) compared to survivors ( ± pg/ml, p = , ). furthermore, nt-probnp at h was associated with survival in the cox-regression analysis (p = . , hr = , , % ci: , - , , units: pg/ml). crp preoperatively was significant higher in non-survivors ( ± mg/dl) versus survivors ( ± mg/dl, p = , ). il- preoperatively was significant higher in non-survivors ( ± pg/dl) compared to survivors ( ± pg/dl, p = . ). conclusions. high nt-probnp levels at h postoperatively, associated with increased mortality in patients undergoing thoracic surgery but there was no relation ship between crp, il- and mortality. introduction. the occurrence of post-operative delirium in elderly orthopaedic patients is associated with neurological complications and cognitive decline [ ] . although the etiology of the decline is less understood, cerebral ischemic events may be involved [ ] . high plasma concentration of n-methyl-d-aspartate (nmda) receptor antibodies (nr ab) has been proven highly predictable for occurrence of the postoperative neurological events in cardiac surgery [ ] . objectives. the aim of the present study was to investigate the predictive value of blood levels of nr ab for postoperative delirium, cognitive dysfunction or any other neurological complications after hip and knee replacement surgery. methods. the study enrolled consecutive patients, aged over , requiring acute or elective knee or hip replacement surgery. cognitive impairment was evaluated by minimental state evaluation (mmse) test administered before and after surgery. daily postoperative delirium was evaluated by confusion assessment method for intensive care unit (cam-icu). plasma levels of nr ab were recorded before surgery, at the moment of hospital discharge ( - days postoperative) and weeks after discharge. all other possible risk factors for postoperative delirium were also recorded. cognitive decline was present in patients ( %) before surgery and in patients ( %) at the moment of hospital discharge (p \ . ). plasma levels of nr ab were . ± . ng/ml preoperatively, . ± . ng/ml at the moment of hospital discharge and . ± . ng/ml weeks postoperatively, with no significant differences. conclusions. the incidence of cognitive decline in elderly patients after othopaedic surgery was significantly higher when compared with the preoperative status but there was no correlation between the cognitive decline and the plasma levels of nr ab. methods. patients older than years, whose performed endoscopic, colonoscopic or both procedures, under sedation performed by the intensive care deparment of the hospital del tajo. data were collected for months. demographic characteristics, medical history, asa (american society of anesthesiologists classification), drugs bolus and total dosages, respiratory and hemodynamic data, the length of procedure and recovery, and complications were collected. tolerance was assessed by endoscopist, with a (very bad) to (very good) scale. quantitative data are expressed with mean and standar desviation, and qualitative data with percentage. results. procedures were included. table shows main characteristics. tolerance and complications are referred in table . the . % of the procedures were appropriate ( or ) . the main complications were vomiting ( . %) and hallucinations ( . %). there were only incidences of respiratory depression and of hypotension. background. the authors hypothesized that the efficacy and quality of a remifentanil (r)-based regimen versus a piritramide (p)-based analgosedation in major post-surgical patients with renal and hepatic impairments still more potent even if prevention of narcotic induced hyperalgesia (nih) [ ] was done. the nih was made by sulphate magnesium (m), ketamine(k) or clonidine(c). methods. patients were randomly allocated to receive a blinded infusion of either r at a rate of . l/(kg min) (± . ) (g : n = ) or p at . mg/(kg h) (± . ) (g : n = ) coupled to an hypnotic sedation of propofol. r and p were titrated in icu after surgery, to achieve an optimal sedation as defined by a sedation conclusions. the remifentanil-based regimen allowed a more rapid emergence from sedation and facilitated earlier extubation diminishing total icu hospitalisation time and cost. even if we prevent the narcotic induced hyperalgesia by used of magnesium, ketamine or clonidine, needs of tramadol in rescue still lower in the remifentanil group due to its high power coupled with its high fexibility compared to piritramide. its reducing, by the way, risks of tramadol's metabolites accumulation in case of renal or leaver impairment. a ''fast track'' approach to cardiac surgery has significantly shortened the length of icu stay. however, quick awakening from anesthesia and subsequent extubation after discontinuation of sedative drug sometimes cause instability of hemodynamics, such as increase of bp or hr. dexmedetomidine (dex), a agonist, is a sedative drug that can be continuously infused during weaning and extubation. the aim of this double-blind study was to evaluate the effect of dex on time to extubation and hemodynamics during weaning from mechanical ventilation after cardiac surgery. with irb approval and informed consent, the patients undergoing cardiac surgery were randomly divided into two groups, dex group [infusion of . lg/(kg h) of dex] and saline group. drug administration was started at sternal closure and continued h. ramsay sedation score, times to extubation, systolic blood pressure, heart rate, respiratory rate, pulmonary artery pressure, central venous pressure, cardiac index were examined. we analyzed these parameters on icu admission, when the patients opened their eyes on order, at immediately before extubation, min, h, and h after extubation. unpaired t test was used for statistics and p value less than . was considered significant. results. patients were included in this study (n = in the dex group, n = in the saline group). there were no significant differences between two groups in age, length of surgery, length of anesthesia, and total dose of propofol and fentanyl. time to extubation was ± min in the dex group and ± min in the saline group (mean ± sd), which were also no significant differences. ramsay sedation score were maintained and no patients needed additional sedative drug during assisted ventilation in the dex group. althought mean systolic bp and mean pa, mean cvp, rr were similar in both groups during infusion. hr at eye opening, immediately before and after extubation were significantly lower in the dex group than in the saline group. conclusion. our results demonstrated that the infusion of . lg/(kg h) of dex decreased hr during weaning from mechanical ventilation. dex could not only provide adequate sedation but also suppress the stress response after cardiac surgery. dex is a useful sedative drug for preventing instability of hemodynamics on fast track approach. however, most anxiolytics impair intellectual function. dexmedetomidine (dex) is an alpha agonist that may offer sedation without overt cognitive decline. we performed a comparison between dex and propofol (pro), a drug often used for icu sedation. methods. prospective, randomized, double-blinded, cross-over study of awake and intubated brain-injured (bi, n = ) and non-bi ( ) icu patients, each receiving pro and dex using a cross-over design with periods of baseline (analgesic use fentanyl only), drug a, interval washout (fentanyl only), drug b. sedation was titrated to a score of or - (calm, cooperative) on the rass and hopkins nics scale. cognitive testing was performed at each study period using the validated -pt hopkins ace cognitive battery. objectives. we evaluated the effect on final outcome of a treatment regimen with lowdose haloperidol initiated when a positive cam-icu occurred as a quality improvement project. methods. the cam-icu was previously implemented in daily care in all patients who stayed[ h in our bed medical-surgical icu. in the first months of the study (period ), the cam-icu was used as an adjunct to daily care and the treatment of delirium was left to the physician on an intention to treat basis. subsequently, a month study pause was defined. thereafter, in the second months of the study (period ), the cam-icu was judged to indicate the presence of delirium and haloperidol was directly started with a loading dose of mg iv with subsequent daily dosing of . - . - mg iv (age \ ) or - oversedation is still common in many intensive care units (icu) despite the demonstrated benefits associated with sedation sparing strategies, including shorter duration of mechanical ventilation, and shorter length of stay in the icu and hospital. our aim was to observe whether a minimal sedation policy could be feasible in a multidisciplinary department of intensive care. prospective observational study over a two month period (december , to january , ) in a -bed medico-surgical department of intensive care of a university tertiary hospital. all adult patients who stayed in the icu for more than h were included. data were collected on duration, type, dose, and indication for sedative and opiate analgesic agents. self extubation was used as a safety surrogate. disease severity was assessed by the apache ii score within the first h of admission. statistical analysis was performed with spss software (spss incorporation, chicago, il, usa). a total of patients (male %) with a median age of years were included; ( . %) received some sedation, the majority [ ( . %)] during mechanical ventilation. midazolam ( %) and propofol ( %) were the most frequently used sedative agents. the most common indications for sedation were: early postoperative ( %), severe respiratory failure ( . %), short term procedures ( . %), and withdrawal syndrome ( . %). the median percentage of time during which patients received mechanical ventilation without sedation was . %, and was not related to severity as assessed by the apache ii score (rho . -p = . ). in the group of patients who required sedation for longer than just short procedures or uncomplicated postoperative care ([ h), the median percentage of time during which patients received mechanical ventilation without sedation was . %. analgesic opiates were often required ( %), predominantly by continuous infusion ( %). morphine was the most frequently used agent ( %). self-extubation occurred in patients, but only needed re-intubation. conclusion. in a mixed medical-surgical population of critically ill patients, a strategy of minimal or no sedation (''sedationless'') is feasible and without major adverse effects. we propose that comfort, hemodynamic instability, and mechanical ventilation should be abandoned as usual indications for sedation. grant acknowledgement. drs received grants from the doctoral fellowship program of capes/ brazilian ministry of education and from the federal university of rio de janeiro. r. russai the royal free hospital, anesthetics, northwood, uk postoperative cognitive dysfunction (pocd) is reported to occur frequently after cardiac surgery, even in low-risk patients. predictors of neurocognitive deficits can suggest the potential etiology and outcome of patient that has developed pocd. there is a wide range of neurological manifestations from subtle cognitive impairment to deadly stroke. over a period of weeks a population of patients underwent cardiac surgery in our hospital. we have looked for any signs of pocd in correlation with the possible etiology. data have been collected prospectively focusing on past medical history (pmh), possible contributors, manifestation, complications and treatment. pocd has occurred in patients ( male, female) with age range of to years (median age years), of whom % has had pmh of neurological impairment (predementia; cerebrovascular disease). multifactorial etiology was found: respiratory failure %, morphine %, tramadol %, renal failure %, remifentanyl %. in patients no related causes were recognised. all patients showed confusion as leading manifestation, although in patients confusion presented in combination with aggressive behaviour ( ), cognitive dysfunction ( ), paranoia ( ). in occasions pocd resulted in major complications such as difficulties in airway management ( ), removal of cvp line ( ), removal of arterial line ( ). the majority of patients ( ) required pharmacological treatment with single or multiple drugs therapy, the most common used was haloperidol ( % pts). the average length of stay in itu was . days, and the average length of hospital stay was . ( - ) days. conclusion. pocd is a common and potentially devastating complication with a complex and broad etiology, which may affect the rehabilitation process and the final outcome. early diagnose is essential for personalise treatments and therefore preserve in both life quality and life expectancy. introduction. sedation and analgesia is given to the icu patient for adaptation to the intensive care environment. however, side-effects of drugs used are increasingly acknowledged as negative factors increasing the risk of delirium, vasopressor therapy, prolonged ventilation and length of stay. objectives. the purpose of the proposed study was to study the practice of sedation in norwegian icu's and the challenges experienced by nurses and physicians. a national postal survey for clinicians in all norwegian icu's was conducted in september and october . all intensive care units treating mechanically ventilated patients for more than h (n = ) were included. two respondents from each unit ( intensive care nurse and icu physician) were invited to answer the questionnaire. the survey was based on two previous danish surveys. questions on practice and perceived problems were scored on a numeric rating scale and a lickert scale, as well as a few questions with response categories based on theme. results. the response rate was % (n = ). all icus were represented with nurses with formal education in intensive care and physicians specialized in anesthesiology as respondents. written protocols are not routine in norwegian icus, but half of the departments titrated sedation according to a scoring system, most commonly maas. the most commonly used sedatives were propofol and midzolam, while fentanyl and morphine were the most used analgesics. the main indication for sedation was to achieve tolerance to ventilation and to treat other bothersome symptoms. side-effects were reported to be frequent with both sedatives and analgesics. the most frequent side effects (% reported as often present or always present) with sedative agents were circulatory instability ( %), delayed awakening ( %) and sleep disturbances ( %), while the most frequent side effects experienced with analgesics were gastrointestinal problems ( %), circulatory instability ( %) and delayed awakening ( %). the main indication for tracheostomy was reported as longterm ventilation and the wish to reduce sedation. discussion/conclusion. written protocols were not routinely used. side-effects of sedation are perceived as a problem by the majority of clinicians, leading to circulatory instability and delayed awakening. tracheostomy is used first of all to be able to reduce longterm ventilation and sedation. these results indicate a potential for new sedative agents and analgesics with fewer side-effects and more focus on the use of sedation protocols. [ ] and has been associated with gaba agonist use [ ] . delirious patients may not be overtly agitated, so signs of delirium must be actively sought. the confusion assessment method for the intensive care unit (cam-icu) is a validated and easy to use screening tool [ ] . in a recent study on this bed medical and surgical intensive care unit (icu), more patients who had received gaba agonists were delirious compared with those who were sedative free [ ] . however, the percentage of patients having at least one episode of delirium was lower than expected ( %), perhaps because they were screened only once daily and in the daytime. we repeated this study with twice daily assessments (morning and after dark) and a larger number of patients in order to obtain a more accurate prevalence of delirium and confirm an association with gaba agonist use. methods. two doctors attached to the icu received a min tutorial on using the richmond agitation and sedation score (rass) and the cam-icu assessment tools. the cam-icu was performed on all rousable patients (rass score [ - ) twice daily (morning and after dark). the following information was also noted: ( conclusion. this study shows that the prevalence of delirium on this unit is comparable with published research [ , ] and higher ( . vs. %) [ ] when patients were screened after dark as well as in the daytime. the study shows that any sedating drug was associated with significantly increased prevalence of delirium. the unexpected higher prevalence of delirium in the patients receiving non-gaba agonists versus gaba agonists cannot be explained by haloperidol use to treat delirium. results. there were patients in the icus. the mean age was . years old with a predominance of chinese ( . %) and a slight male predominance of . %. forty-six per cent of the patients were mechanically ventilated and . % had tracheostomy done. there were an average number of devices per patient. sedation was administered in . % of the patients with no sedation scales used in a quarter of these patients. only . % of the sedated patients were on sedation protocol. the majority of patients ( . %) were monitored hourly and on propofol ( %) and midazolam ( . %). up to . % of sedated patients did not have daily interruption of sedation. there were no significant difference noted in the use of sedation between medical and surgical icus. slightly more than a third of patients were given analgesia (n = ) with no analgesia scales used in a third of these patients. one third of them were administered with paracetamol and about a third with morphine. patients in surgical icus were more likely to receive analgesia compared to medical icus patients. most of these patients ( . %) were monitored hourly. only patients were on neuromuscular blockade. there was no usage of any formal delirium assessment tools at all with . % of the patients being assessed for delirium based on clinical judgement of the caring team. only % of the patients had some form of sleep promotion in the icu. conclusions. this national multi-center study reveals several deficits in the adult icu with regards to sedation, analgesia and delirium assessment and management. several initiatives should be implemented to improve patients' safety and quality of care in the icu. methods. this study was conducted in patients who visited emergency care center following caustic ingestion during a period ranging from january of and august of , in whom a retrospective analysis of medical records was performed. findings for the esophageal lesion were classified according to the change of the esophageal wall and the infiltration of periesophageal soft tissue. also, clinical, laboratory, and endoscopic data from this patients were reviewed. the correlation between the degree of esophageal damage seen on ct scans and esophageal constriction seen on esophagography were then evaluated. a total of cases of caustic ingestion were identified (age range, - years). the most common caustic agent ingested was acid ( %). the most frequent cause for ingestion was attempt of suicide ( %) as opposed to accidental ( %). the findings of thoracic ct in patients were follows: first-degree esophageal injury in ( . %), seconddegree in ( . %), third-degree in ( . %), fourth-degree in ( . %). fourteen patients ( . %) developed caustic esophageal stricture. the degree of esophageal damage got closer to grade iv, the more prevalent esophageal constriction became. this correlation was statistically significant (p \ . ). of the total patients, underwent endoscopy in the early stage after they visited emergency care center. an analysis of the correlation between the degree of esophageal damage seen on endoscopy and that seen on ct scans was performed. this revealed a significant correlation (p = . , r = . ). conclusions. thoracic ct grading suggesting periesophageal soft tissue infiltration and fluid collection (grade iii to iv) rather than only edema (grade i) may be associated with stricture formation. early ct grading was very safe and useful for predicting the development of stricture induced by caustic ingestion. conclusion. in our area critical care transport teams provided safe transfers for critically ill patients.adequate preparation, strict adherence to checklists and adequate personal are the key of optimal solving of problems. introduction. although endovascular repair of traumatic aortic injury (ertai) has revolutionized the practice of vascular surgery, many questions still remain unanswered. endoleaks, coverage of the left subclavian artery, stent fold/collapse, access complications and durability are the most important complications associated with the procedure. we describe our experience with stent fold/collapse after endovascular repair of blunt aortic injury in otherwise healthy and young patients. from january to december , patients (mean age years, mean apache score , mean length of stay days) who underwent endovascular repair of a blunt aortic injury were admitted in our icu. every day clinical examination and invasive blood pressure monitoring were employed for all our patients. when persistent hypertension was detected, transthoracic (tte) and transoesophageal echocardiography (tee) were initially used, followed by spiral computed tomography (ct) and angiography as confirmatory methods. of the patients, ( %) developed a pressure gradient of [ mmhg at the level of the stent that was initially investigated with continuous wave doppler at the descending thoracic aorta (suprasternal view). the complication presented with refractory hypertension (requiring more than two classes of antihypertensives in high doses) and difficult weaning. the cause of hypertension in of those patients was a stent collapse, while in the other patients the stent appeared folded but not collapsed. endograft revision by open surgery was necessary in of the patients. conclusion. the absence of especially designed grafts for the treatment of blunt aortic injury and the subsequent use of oversized grafts are associated with severe complications. refractory hypertension after ertai can be a manifestation of poor stent alignment and/or stent collapse. echocardiographic monitoring proved to be a useful tool in the early diagnosis of this kind of stent-graft complication. as far as we know, it is the first time that echocardiography is described in the relative literature as an early diagnostic technique for this serious complicationction. facing an aging population, the number of interventions of the french emergency medical service (ems) among very elderly is increasing. a previous retrospective study showed that except from out-of-hospital cardiac arrest survival to discharge was remarkably high after ems intervention for life-threatening pathology [ ] . the aim of the present study was to evaluate prospectively outcomes of very elderly patients managed by ems. methods. after irb approval, we conducted a prospective study over year, including all patients aged years or more managed by our physician staffed ems department. characteristics of patients including previous medical status (mccabe and knaus scoring systems), functional independence (katz adl scale), clinical conditions, the index de gravité simplifié ambulatoire (igsa) severity score were recorded. patients were followed until their hospital discharge. the -month mortality was recorded as well as the adl score. data are expressed as mean ± sd, median [iqr] or percentage of patients and compared using univariate and multivariate analysis. a p \ . was considered the threshold for significance (*). results. of the patients included, died on-scene, were transferred to the hospital and patients were left on scene because of significant improvement in medical status making hospitalization unnecessary, or on the contrary in near-death situations. mean age was ± years ( men). their adl was ( - ) and % of patients were living at home. main conditions were pneumonia (n = ), acute coronary syndrome or chest pain (n = ) and acute pulmonary oedema (n = ). at months, survival rate was % (n = ). the proportion of patients living at home was % and adl among survivors was ( - ) (vs. ( - ) initially for this subpopulation, p = . ]. when compared with deceased patients, survivors were significantly younger ( ± vs. ± years*), had lower adl penetrating anterior chest wounds causing cardiac injury are typically fatal, with only % of patients surviving to reach hospital. while the majority of patients with thoracic trauma can be managed conservatively or with simple intercostals catheter, a small but significant number of blunt ( %) and penetrating ( - %) injuries, require emergency resuscitative mediam sternotomy as a component of initial resuscitation. case report. a years old men, fall from meters high, while working in a truss. he was immobilized with semirigid cervical collar and backboard in the scene and transport to our trauma center, witch was a h car-distance. anesthesiologist team was present since the initial management in emergengy room (er) and act according to advanced trauma life support principles. in primary survey, patient was paraplegic, had a gcs of / , a normal respiratory rate, a slight hypotension and a slight tachycardia. when surgeon places a chest drainage, it drains immediately more than , ml blood, and the patient vital signs started to fade, to extreme bradicardia. the patient was then intubated with a rapid sequence intubation, with a single lumen endobronquial tube, and ventilated with protective lung ventilation. hypotension postinduction was promptly treated with vasoactive drugs (nor-adrenaline and dobutamine) and ongoing volume resuscitation. an emergency resuscitative mediam sternotomy incision was perfomed in the er and reveled a clavicule and sternum fracture and laceration in the braquiocephalic artery which has repaired. maintenance was performed with total intravenous anesthesia with fentanyl and nondepolarizing muscle relaxant. monitoring include standard monitoring plus direct arterial and central venous pressures. during the surgical procedure we treat massive blood loss, with multiple transfusions of units of red blood cells (unmatched type-specific), seven units fresh plasma, and pools of plaquets, fibrinogen and cryoprecipitate. at the end of the surgery, still ongoing blood loses, made us suspect of coagulopathy, and to use octaplex Ò . it was also performed a nasal tamponade, to stop severe epistaxis and suture a major scalp wound with evidence of basal skull fracture. patient was transferred to an intensive care unit (icu) ventilated.we was extubated at the th day post-operative. after days, he still remains in icu, because he is recovering from lumbar spine fixation for a total fracture-dislocation of d -d . discussion. although he remains paraplegic, we think emergency sternotomy have had a significantly impact in this life-threating situation. the use of cell-saver Ò would have been beneficial, but it was unavailable in er. we included only patients attended in this unit by icu personnel. these patients belonged to the area assigned to cruces which has been reference centre of the northern area of spain until december . we collected all the information needed from the clinical history and the treatment sheet, and used the spss . programme to perform the statistic analysis. results. we found patients that meet the severely burned patients criteria and that were attended by the icu personnel in colaboration with the plastic surgey unit. their medium age was . ± . years, % of those patients were men, and the medium burned body surface was ± . %. these patients remained hospitalized in this unit during a medium time of . ± . days. during their stay, the % of them needed mechanical ventilation, % presented acute renal failure, % had a pao /fio less than , and . % suffered some kind of infection. methods. prospective and observational study developed in a burn unit, in which were included all patients with total surface body area burn (tsba) [ % and/or inhalation syndrome who were admitted in our unit from march to december . we used transpulmonar thermodilution by means of monitor picco Ò in a total of measurements per patient (admission and every h). we collected measurements of cardiac index (ci), intrathoracic blood volume (itbv), extravascular lung water (evlw), inhalation syndrome or not (it was diagnosed by broncoschopy), percentage of tsba and abbreviated burn severity injury score (absi) in a total of patients.the average change of measurements of ci, itbv and evlw was studied in the following determinations and their association with few factors with a general and lineal model of mixed effects longitudinal data unbalanced. results. the evolution of thermodilution measurements was the following (graphic ) cardiac index: ci = . , ci = . , ci = . , ci = . , ci = . , ci = . , ci = . , ci = . , ci = . , ci = . . intrathoracic blood volume: itbv = , itbv = , itbv = , itbv = , itbv = , itbv = , itbv = , itbv = , itbv = , itbv = . extravascular lung water: evlw = . , evlw = . , evlw = . , evlw = . , evlw = . , evlw = . , evlw = . , evlw = . , evlw = . , evlw = . . in our serie, % of patients were male and the average age was . ( - ). nine out of all the patients ( . %) suffered inhalation syndrome, the average absi was . ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) and the average of tsba was % ( - %). mortality in our serie was % ( patients).ci and itbv measurements increased significantly while the reanimation advanced (ci p . ) (vsit p . ). in evlw we only find significantly differences in post hoc study between first measurements and fourth one (p . ), th (p . ), th (p . ), th (p . ), th (p . ) and th (p . ).in the evlw/itbv ratio (permeability index = pi) we did not observe significantly changes in the evolution.the inhalation factor did not change ci outcomes neither magnitude nor in the measurements evolution (p . and p . respectively), the same form, itbv (p . and p . respectively), but inhalation modified evlw (p . ) and the permeability index was in the signification stadistic limit (p . ).mortality was higher in patients who ci was lower and evlw was in higher values. conclusions. thermodilution in the reanimation period in critically ill burn patient shows significantly haemodynamic changes in the evolution that can help to adapt the treatment.the inhalation syndrome only modified the measurements of evlw significantly in this period but it influenced neither ci, itbv nor pi. introduction. one major issue in trauma management is to get every patient directly from the scene to the appropriate hospital for the injury he sustained. patterns of interfacility transfers have been thouroughly investigated in trauma system settings, but scarce data are available about transfers in non trauma system settings. objectives. this study aims to assess interfacility transfers that eventuate in the abscence of a formal trauma system and to estimate the potential benefits from the implementation of a more organized process. the 'report of the epidemiology and management of trauma in greece' is a one year project of trauma patient reporting throughout the country. it provided data concerning the patterns of interfacility transfers. in greece there is no formal trauma system employed and to our knowledge, all available data concerning the epidemiology of trauma in the country are either extrapolations of relevant data from other countries or based on police reports and individual hospital reports. in this study, we attempted to evaluate the paterns of interfacility transfers, information reviewed included patient and injury characteristics, need for an operation, intensive care unit (icu) admittance and mortality. trauma patients were devided in two groups, the transfer group was compared to the non-transfer group. analysis employed descriptive statistics and chi-square test. interfacility transfers were furthermore assessed according to each health care facility's availability of five requirements; computed tomography scanner, icu, neurosurgeon, orthopedic and vascular surgeon. results. data on , patients were analyzed; . % were treated at the same facility, whereas . % were transferred. in transferred group there were more male, the mean age was lower than that of the non transferred group and the injury severity score was higher. transferred patients were admitted to icu more often, had a higher mortality rate but were less operated on compared to non-transferred. the transfer rate from facilities with none of the five requirements was . %, whereas the rate of those with at least one requirement was . %. facilities with at least three requirements transferred . % of their transfer volume to units of equal resources. conclusions. the assessment of interfacility transfers can reflect current trends in a nontrauma system setting and could indicate points for substantial improvement. results. , patients included, , injuries analyzed. average age was . , . % men. . % were car accidents, % falls, . % motorcycle, . % run over and . % bicycle. . % had one injury, . % two and . % three. most frequent injury was tbi ( . %), thoracic traumatism ( . %) and ortophaedic ( . %); severe tbi was . %. ctrate according to marshall classification was . % ii, . % v and . % iii. iss averaged , higher in dying patients than in the survivors ( ± . vs. . ± . ; p \ . ). of the non mechanical-ventilated patients, . % were so in the first h following admittance. during this, . % patients were given blood transfusions, platelets . %, plasma . % and prothrombinic complexes . %. in the first h . % underwent surgery, most frequent was neurosurgery ( . %). complications: nosocomial pneumonia ( . %), catheter related bloodstream infection ( . %), acute kidney injury ( . %), ards ( . %), cns infection ( . %). . % renal replacement therapy. invasive ventilation was used in . % with . ± . days, non invasive ventilation in . %. average stay in the icu was days. . % of the patients were transferred to a ward. . % were transferred to another hospital. gos on discharge was higher than on . %. % died in icu, % brain death. tbi as a main injury showed a . % mortality rate. depending on trauma type, mortality was higher in fall ( %) and run over ( . %). if due to car accident ( . %), motorcycle ( . %) or bicycle ( . %), mortality in icu was lower (p \ . ). prehospitalary variables related to mortality were age, gcs \ and a motor component \ , pupil alteration, shock, respiratory failure, prehospitalisation intubation and iss (p \ . ). on arrival to hospital, the variables were: haemodynamic instability in the first h, transfusions need and number, marshall iv-vi, mechanical ventilation (p \ . ) and initial fibrinogen (p \ . ). evolutive variables related to a higher mortality rate were days of stay, invasive ventilation, tracheostomy and the show up of complications (catheter related sepsis -p \ . -, nosocomial pneumonia, acute kidney injury, ards, renal replacement therapy (p \ . ). in a logistic regression model, prehospitalisation variables having an influence on icu mortality rate were age (or . ; p \ . ), mydriasis (or . ; p \ . ), gcs-motor component (or . ; p \ . ), shock (or ; p \ . ) and iss (or . ; p \ . ). conclusions. multiple trauma patients show a high need of resources, with many peaks of treatment involving a high monitorization and handling. many of the variables are related with a higher mortality rate in icu: iss, mydriasis, gcs motor component and shock. introduction. trauma systems are multifactorial modules that incorporate any aspect of traumatic injury from the very moment of the injury to the final outcome. a significant prerequisite for the development of a trauma system is the trauma registry. trauma registries are the actual core of any trauma system since they provide valuable information about the standard of care offered to the patients and are amenable to quality control and statistical evaluations, which in turn allow improvements and amendments in the definite care. contrary to what is common practice in the usa, trauma registries in european countries are in embryonic stage. in our country with no actual trauma system, the epidemiology of trauma and the reports on care outcomes are based on police reports and national emergency service reports. objectives. the purpose of this study was to assess the possibility of a national trauma registry in greece and to provide accurate data on the epidemiology of trauma in the country. methods. the project, entitled ''report of the epidemiology and management of trauma in greece'', was initiated in october and lasted for twelve months. all the national representatives of the hellenic society of trauma were invited to participate. the representatives are certified surgeons employed in hospitals receiving trauma. data presented here are those reported from two tertiary care facilities in athens and twenty eight other primary and secondary hospitals around the country. inclusion criteria were defined as trauma patients with documented need for admission in the hospital, patients that arrived dead or died in the emergency department of the receiving hospital and patients that required transfer to a higher level center. in total . trauma patients were included in the study in twelve months time. of them . % (n = , ) were male, aged . ± . (mean ± sd) and . % were female (n = ), aged . ± . (mean ± sd). as expected and reported in most trauma registries, males are leading in all subcategories of iss. the age group - years incorporates . % of the total injuries, in accordance to the axiom that trauma is the disease of the young. conclusions. trauma registries are the cornerstone of any trauma system. even in a non-trauma system setting, registries are a valuable tool for quality control of the provided health care and for further development of the health care system. objectives. determine the impact of rurality in epidemiology, injury severity, health care facilities, length of stay (los), mortality, functional outcome and quality of life in trauma patients. retrospective study in trauma patients that were admitted in our emergency room(er) between and . data was collected from the prospective trauma registry and follow-up registry months after the accident. we classified patients according to statistical national institute classification: urban areas-areas with more than inhab/km or have a place with more than , inhabitants; semi-urban areas-areas with more than inhab/km and less than inhab/km or have a place with more than , inhabitants and less than , inhabitants; rural areas-areas that were not classified as semi-urban or urban areas.patients were divided in three groups according to residence area: r (rural), su (semi-urban), u (urban). we studied several variables in order to find a relation with rurality: sex, age, type of injury, los in hospital and intensive care (icu), anatomic severity (ais), politrauma severity (iss), physiologic severity (rts), surveillance probability (triss index), pre-hospital care, previous admission in other hospital, icu admission and mortality. we report two outcome measures: euroqol to evaluate quality of life and extended glasgow outcome scale for functional outcome. we used qui-square test, t test, mann-whitney test, kruskal-wallis test for statistic analysis. results. , patients were admitted in the er. patients ( . %) were excluded with missing data related to residence area. we studied patients, where patients were from rural areas ( . %), from semi-urban areas ( %) and from urban areas ( . %). we find a statistical significant relation between rurality and pre-hospital care, previous admission in other hospital and icu admission. urban area patients had a higher incidence of pre-hospital care(r: . %; su: . %; u: . %, p \ . ). semi-urban and rural patients were admitted more frequently in other hospitals before admission in er (r: . %; su: . %; u: . %, p \ . ) and also had higher admissions in icu (r: . %; su: . %; u: . %, p \ . ). there were no statistical differences in the other variables studied. conclusions. rural trauma patients are similar from those that live in urban areas concerning epidemiology, injury severity and outcome. despite lack of pre-hospital care and higher previous admission in other hospital in rural patients, mortality between groups did not differed in our trauma centre. introduction. metformin-associated lactic acidosis (malta) is a rare but severe complication ( . / , patients/year) of metformin treatment in type-ii diabetes. metformin impairs neoglucogenesis and liver lactate clearance in the presence of a disease that enhances its production. although frequently used, there is no recommendations regarding hemodialysis in this poisoning. to study the prognostic factors of malta and the interests of blood metformin measurement. . on admission, patients presented profound lactic acidosis with arterial ph . ( . - . ), serum bicarbonate . mmol/l ( . - . ) and plasma lactate . mmol/l ( . - . ). early symptoms associated coma ( %), asthenia ( %), vomiting ( %), abdominal pain ( %), and diarrhoea ( %). renal function was significantly altered [creatinine clearance: ml/ min ( - ); p \ . ). all patients received massive alkalinization, / ( %) were hemodialyzed while / ( %) were mechanically ventilated and received catecholamines. six patients ( %) died in the icu. duration of icu stay was days [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . there was no significant differences regarding malta severity and treatments between suicidal and accidental poisonings. neither lactic acidosis severity nor acute renal failure were predictive of death. there was no correlation between prognosis and the time-course of plasma metformin concentrations, with or without dialysis. toxicokinetics showed significant tissue distribution when the patient was early admitted or plateaued concentrations if he was later admitted and survived, even though his situation improved and his lactates decreased. metformin dialysance suggested an interest for extra-renal elimination enhancement although its impact on survival could not be analysed based on this limited study. our study showed that malta is severe with elevated mortality in icu whatever the poisoning is accidental or intentional. metformin toxicokinetics are useful case by case to better understand the patient's outcome. the most important guidelines [ ] for trauma care recommend (us)-fast as the first step investigation to rule out major bleedings. however, us is less sensitive and accurate than multislice computed tomography (ct). the spreading concept that ''moderrn cts require little time'' often brings surgeons to ask for total body ct also in haemodynamically unstable patients. to understand how long it really takes to perform a total-body ct in patients suffering from major trauma (mt) we analysed the data of the ritg project, a pilot multicenter study to define the national standards for trauma care and establish a national trauma registry. methods. italian level trauma centers were involved into the first stage of the ritg project. data of all major trauma patients (iss [ ) who were admitted to either one of the three hospitals during a months period of time ( july - june ) were prospectively entered into the ritg database. time between hospital admission and the first scan were recorded for all patients. patients who, for any reason, were submitted to a ct with a delay of °or more were excluded. the time elapsed between the first scan and the patient's exit from the ct room was measured in a subset of pts from a single center equipped with a new generation ct next to the emergency room. during the study period mt patients were admitted to the three trauma center. patients were submitted to an emergency total body ct scan within . patients died before arrival in the ed. more died soon after admission and before the secondary survey. the interval times are shown in table . seven patients died in the ct room. the average interval between hospital admission and the first available scan was °. however, even where a new generation ct next to the er was used, the average time needed to stabilize the patients, get a correct position on the ct and start the scanning process was °as an average. in the most severely injured patients, who are frequently artificially ventilated, the time required to stabilize the patient and perform a total body ct scan is longer than expected and to a certain extent, independent from the ct scanner itself unless the very last technology as the sliding ct scanners are employed [ ] , thus ct should be considered with extreme caution in the unstable patients. in univariate analyses, survival to discharge was significantly lower with two of acute conditions (acute coronary syndrome and acute inflammation), and with five of chronic conditions (chronic heart failure, diabetes mellitus, kidney failure, hepatic cirrhosis and malignancy). recent surgery was strongly associated with higher odds of survival. the most consistent multivariate predictors of survival to discharge were liver cirrhosis (or . ; % confidence interval . - . ) and malignancy (or . ; . - . ). malignancy was not predictive for outcome after cpr attempts, whereas liver cirrhosis was predictive both in all dispatches and in dispatches involving cpr. recent surgery was strongly associated with higher multivariate odds of survival (or . ; . - . ) after cardiac arrest. in dispatches without cpr, absence of chronic conditions was associated with higher likelihood of survival (hr . ; % ci . - . ). increasing numbers of chronic conditions were significantly and continuously associated with lower survival (p for trend \ . ). advanced age only weakly predicted survival, but age c years was, along with malignancy, the strongest predictor of not attempting cpr in patients with cardiac arrest. conclusions. comorbidities are important determinants of survival after in-hospital met dispatches, with and without cardiac arrest. survival odds are lowest with malignancy and liver cirrhosis. recent surgery increases odds of survival by exclusion of those most severely ill. advanced age at best weakly predicts worse survival, but strongly predicts not attempting cpr. design. retrospective, cohort study. setting. emergency department (ed) and intensive care unit in a university hospital. measurements and main results. the study subjects included of consecutive severe trauma patients. a systematic review of the computer-based medical records of the patients was conducted to provide the base line characteristics and dic-related variables. the worst data of these variables were obtained at time points within h after arrival to the ed; time point , immediately after arrival at the ed to h after the arrival; time point , to h after the arrival; time point , to h after the arrival; time point , to h after the arrival. one hundred and forty one patients ( / , . %) diagnosed as jaam dic showed significant differences in the prevalence of multiple organ dysfunction syndrome (mods) and the outcome in comparison to the non-dic patients. a stepwise logistic regression analysis showed that the maximum jaam dic scores during the study period independently predicted the patient death (odds ratio . , % confidence interval . - . ). all of the patients who developed isth overt dic during the study period could be identified by the jaam dic criteria at early time points. the mortality rate and the incidence of mods of the patients with the isth overt dic were higher than those only met the jaam dic criteria. stepwise increases in the isth overt dic scores and the incidence of the isth overt dic were observed in accordance with the increases in the jaam dic scores. while the mortality rates were identical, there were marked differences in the incidence of mods and sequential organ failure assessment scores between the dic patients associated with trauma and sepsis. conclusions. the jaam scoring system has acceptable validity for the diagnosis of dic at an early phase of trauma. the jaam dic further exists in a dependent continuum to the isth overt dic. in addition to mods, other factors may affect the prognosis of the trauma patients associated with dic. introduction. in the uk, more than , units of fresh frozen plasma (ffp) are transfused every year. since there has been a reduction of % in its use, but it has been suggested that as many as % of transfusions in critical care may be inappropriate. there is significant morbidity associated with the transfusion of ffp. guidelines for the use of ffp do exist, but the indications for its use are limited. coagulation studies, such as prothrombin time (pt), abnormalities are often assumed to be a risk factor for bleeding prior to invasive procedures, but evidence suggests that ffp may not have a prophylactic role. in addition to this the pt or international normalised ratio (inr) were not intended to assess haemostasis in patients without a history of bleeding. review of the blood bank database between st january and st december revealed all prescriptions of ffp for patients on intensive care (itu). the case notes were analysed to find the indication and timings of administration and weight of the patient. the pathology database was examined to find the clotting studies immediately before transfusion. in patients received ffp; this was only . % of the total admissions to the itu. there were prescriptions and a total of units transfused. the mean prescription of ffp was . units and overall each patient received a mean of . units. the mean dosage of ffp was . ml/kg. the pt pre-transfusion mean was . ± . s with a median of . s. the aptt pre-transfusion mean was . ± . s with a median of . s. only . % of transfusions had not had a clotting screen done prior to administration of ffp. % of administrations were given prior to procedures being undertaken on the itu and a further % were given in preparation of the patient for the operating theatre. a significant number of patients are receiving ffp outside international guidelines. a third of transfusions were given for prophylactic correction of coagulopathy prior to an invasive procedure where there is least evidence for using ffp. most patients received a sub-therapeutic dose of ffp; there is ongoing debate on the correct dosage required to normalise coagulopathy, but it is likely to be greater than ml/kg. [ ] . little data exists on the demographics of mt and subsequent demand on a hospital's blood bank. we examined the mt requirements of a bedded tertiary referral hospital over a month period. objectives. to establish the mt demographic, speciality distribution, prbc demand and associated mortality; within a tertiary referral hospital over a month period. to assist with future mt logistics, planning, implementation and audit. methods. the hospital blood bank database was reviewed for cases of mt from jan to aug . inclusion criteria were the administration of c units of (prbc) within a h period. cross referencing with the laboratory records and medical notes was undertaken to establish patient demographics, hospital specialty, diagnosis, outcome and number of prbc transfused. results. patients received mt over a -month period; male ( . %) female ( . %). median age years (range - ). median mt of prbc was (range - ) units. units of prbc were transfused in the treatment of mt during the study period, accounting for a hospital expenditure of over € , . the main specialties associated with mt were the: emergency department ( patients, . %), cardiothoracic surgery ( patients, . %), and general surgery ( patients, . %). of the patients receiving massive transfusions ( . %), did not survive to hospital discharge. % of those patients who died, did so in the first h with a further % dying in the next h. % of the further deaths occurred within and % after thirty days. conclusions. mt in our establishment is associated with a high mortality and predominantly early deaths. recipients were generally elderly with significant co-morbidity. provision of prbcs and blood components for massive transfusion recipients, is challenging for blood bank services [ ] . the demand of mt, within our establishment, was predominantly within the acute specialties; emphasizing the need for close communication between them and the laboratory services. in light of this data we propose the implementation of a mt protocol together with continuous audit, to assess its effect on outcome. in the department of health updated the 'better blood transfusion' circular, a drive to decrease the use of blood products which have become increasingly scarce and expensive [ ] . there is evidence that blood product transfusions in icu patients are associated with an increase in morbidity, length of stay and mortality. there has been concern over the increasing use blood products and despite guidelines [ ] for their use, both national and local audits have demonstrated a high degree of inappropriate transfusion [ ] . derriford hospital is a -bedded tertiary referral centre. the blood bank database was examined for the use of blood products on icu from st january to st december . there was a steady rise in icu admissions from , patients in to , patients in . during this time there was a marked decline in both the transfusion of fresh frozen plasma (ffp) and cryoprecipitate. the decreased use of these blood products has occurred with only a very modest introduction of new pro-coagulant therapies, prothrombin complex concentrate (pcc) and recombinant factor viia (rfviia). usage of rfviia and pcc conclusions. our usage of blood products does not reflect the national trends of increasing use of cryoprecipitate and pcc with a small reduction in ffp transfusion, and is more in line with the hsc requirements for better use of blood products. this has been achieved with little use of the newer rfviia and pcc. the evidence for the use of all these blood products is not strong, particularly in critically ill patients. national guidelines exist for their use, but these are poorly adhered to. to test the hypothesis that transfusion of prbcs has a deleterious effect on clinically relevant outcomes in patients with septic shock receiving early goal directed therapy (egdt). retrospective cohort study of patients who presented in an academic center in septic shock and received egdt. data was collected on patients identified via the surviving sepsis campaign chart review database and linked to the project impact database. pearson chi square and fisher's exact test were used to test for clinical significance. primary outcome was mortality and secondary outcomes included mechanical ventilation days, intensive care unit (icu) length of stay, and hospital length of stay. . / patients presented via the emergency department. / patients received at least one prbc transfusion during their hospital stay. the two groups were balanced with respect to age, gender, apache ii, and baseline lactate levels. the prbc group had a mortality of . vs. . % in the no prbc transfusion group (p = ns). the prbc group also had more mechanical ventilation days ( . vs. . days, p = \ . ), longer hospital length of stay ( . vs. . days, p = \ . ), and longer icu length of stay ( . vs. . days, p = \ . ). conclusions. in this study, transfusion of prbc was associated with worsened clinical outcomes in patients with septic shock treated with egdt. this trial is limited by its small sample size and retrospective nature. however, the results are consistent with data from previous trials pointing to a deleterious effect associated with prbc transfusion. further studies are needed to determine the impact of transfusion of prbc within the context of early resuscitation of patients with septic shock, as the beneficial effects gained by an early and goal oriented approach to resuscitation may be lost by the negative effects associated with prbc transfusion. introduction. blood transfusion therapy (btt) is thought as one of transplantation of living cell, that means btt includes several risk such as infection and btt should be thought to derived from precious material by courtesy of donors. patients with traumatic cardiopulmonary arrest on arrival on the hospital (t-cpa) usually suffered from lethal hemorrhage and required rapid supplement of red blood cells for resuscitation of circulation and oxygen transport, that is to say btt. however, the prognosis of t-cpa patients is well known hopeless. the aim of this study is to evaluate the propriety of our strategy concerning btt for t-cpa patients. we retrospectively examined the medical records of t-cpa patients for the past years. we do btt until (the first period) for t-cpa patients regardless of rosc without any restriction. after then (the second period), we do btt case by case but only after rosc in principle. the rate of rosc, admission to icu, survive to discharge were compared between these two period, and were compared within the first period between the patients group who underwent btt (btt group) and the group who did not underwent btt (non-btt group). in blunt t-cpa and penetrating t-cpa patients, and % achieved rosc, and % admitted to icu, and and % were survive to discharge. in penetrating t-cpa in the first period, units of packed red cells (prc) were used before rosc for non-survivors. in the second period, no prc was used for non-survivor before rosc. in blunt t-cpa in the first period, prcs were used for non-survivors before rosc. in the second period no prc was used for non-survivors before rosc. concerning the effect of btt on the prognosis of t-cpa in all cases, the rate of rosc and admission to icu were statistically higher in the first period than in the second period (p = . and . ). however, there was no statistical difference in the rate of survive-to-discharge between these periods. there was a same tendency in witnessed cases. in cases with electrical rhythm on the scene, only the rate of rosc were higher in the first period (p = . ). restricted in the first period, only the rate of rosc was statistically higher in non-btt group than btt group in all cases, in witnessed cases, and in cases with electrical rhythm on the scene (p = . , . , and . ). however, there was no statistical difference in the rate of admission to icu and survive-to-discharge between these groups.. our retrospective serial study showed a possibility that btt before rosc for t-cpa improves the success rate of rosc but add no effect on the improvement of survival rate. btt is thought to be futile for t-cpa before rosc. management of refractory coagulopathy due to adult onset acquired autoimmune haemophilia. d. hendron , g. allen , m. brady , g. benson belfast city hospital, intensive care, belfast, uk, belfast city hospital, department of haematology, belfast, uk we report a case of life-threatening haemorrhage occurring as a result of a rare acquired condition caused by the production of an antibody to clotting factor viii. this necessitated administration of recombinant activated factor viia (novoseven) to bypass this step of the clotting cascade. a -year-old man presented to intensive care following ogd for acute upper gastro-intestinal haemorrhage, with recent haemoptysis and haematuria. ogd had demonstrated a large clot obstructing the oesophagus and extending through stomach into duodenum. this could not be removed and no bleeding points were identified. a coagulopathy was detected which failed to correct with administration of appropriate amounts of fresh frozen plasma, cryoprecipitate and activated prothrombin complex concentrate (apcc), necessitating clotting factor studies. this demonstrated a factor viii level of % with a detectable antibody inhibitor. acquired haemophilia was diagnosed and activated factor viia was administered resulting in rapid correction of coagulation studies and arrest of haemorrhage. it was necessary to continue daily activated factor viia at a dose of mg a day in addition to anti-inhibitor coagulant complex (feiba-vh)-an activated prothrombin complex with factor viii inhibitor bypassing activity. definitive treatment of the coagulopathy was chemotherapy with cyclophosphamide, vincristine and rituximab. this destroyed the factor viii inhibitor and returned his factor viii levels to almost %. laparotomy and gastrotomy were required to relieve the oesophageal obstruction from the accumulated clot. he was eventually discharged from hospital and remains well. acquired haemophilia is a rare haematological condition that presents with refractory haemorrhage and coagulopathy and these patients are likely to be referred to critical care services for ongoing support and management. it has an incidence of approximately . cases per million per year [ ] . underlying medical conditions can be identified in up to % of patients and include autoimmune disease, solid tumours, lymphoproliferative malignancies and pregnancy [ ] . international recommendations on the diagnosis and treatment of patients with this condition have recently been published and advise recombinant activated factor viia to control bleeding followed by a combination of corticosteroid and chemotherapy [ ] . the paucity of cases presents an obstacle for randomised controlled trials and therefore these recommendations are based on anecdotal evidence and expert opinion. reference (s) objective. to analyze the application of blood transfusion in critically ill trauma patients after wenchuan earthquake. a retrospective study was made in icu of huaxi hospital on patients who had received transfusion at least once during month after the earthquake. their primary diagnosis and clinical features and apacheii score were obtained at admission. non-active bleeding patients were classified into s group if operation was done during his icu stay, otherwise n group. the function of liver and kidney, and the state of circulation and oxgenation were compared between groups, as well as the hemoglobin level before each transfusion were investigated. a total of patients ( . %) had received transfusion at least once, among which were non-active bleeding. the average frequency was . ± . and . ± . , amount was . ± . ml and . ± . ml, the incidence of transfusion-related complication was . %( / ) and . %( / ) in active and non-active bleeding patients respectively. the apacheii score, mean arterial pressure, ast, serum creatinine, oxgenation index and hemoglobin level on day , , after admission to icu showed no statistically significant difference between s and n group. the frequency and amount of transfusion were similar also, while the hb level before each transfusion was significantly lower in n group ( . ± . g/l)than in s group ( . ± . g/l) (p \ . ). the incidence of transfusion-related and infectious complications, time with ventilator and the -day mortality were similar. conclusion. transfusion strategy is more strict in icu doctors than surgeons, while the similar result on organ function, incidence of complications and outcome raises the need for a more wide-accepted transfusion trigger. keywords. earthquake trauma transfusion trigger. extracorporeal life support (ecls) represents an ultimate rescue technique in poisonings. the optimal anticoagulation protocol remains unclear. objectives. we aimed to investigate the coagulation status at ecls decision in order to validate the best heparin protocol to administer. [ packs ( - ) ] and fresh plasma [ packs ( - ) ] transfusions were required within the first h. hemorrhages ( / ), thrombosis ( / ) or lower limb ischemia ( / ) seemed equivalent to previous series using more complicated anticoagulation protocols. conclusions. poisoned patients present at ecls time with important alteration in their clotting tests, associated with various degrees of hepatocellular failure, dic, defibrination, as well as dilution. a simple heparin protocol appears optimal to reduce complications in these critical situations. henna is the dried and powdered leaves of the henna plant. the plant is lawsonia alba and the powdered leaves are used to apply decorative designs over the skin. henna application is widely practiced in the arab and asian communities. they create fascinating designs over the skin, especially over the hands and feet. it is widely practiced during wedding ceremonies and at childbirth. g pd deficiency is common in the community of the arab world. lawsone, the chemical compound in the henna leaves, is capable of inducing severe acute hemolysis in g pd deficient cases. the compound is chemically related to naphtha. we report a case of acute sever hemolysis in a young girl who presented with dizziness and jaundice and diagnosed to have acute severe hemolysis. her symptoms had started while preparing for her wedding by henna application. the girl was g pd deficient, and found to have severe hemolysis resulting from henna application on her skin. very few cases have been reported of similar nature. the matter is also of tremendous practical implication in areas of g pd deficiency. the relevant literature is reviewed as well. background. lactate has prognostic use in critically ill medical and trauma patients, and is a core component in identification of early sepsis. elevated lactate levels in these patients prior to icu admission, e.g. in an a&e setting or pre hospital setting identify patients at risk of death and can trigger an earlier optimization of triage decisions and earlier targeted treatment. a range of poc methodologies for lactate measurement are available but there is little standardization between methodologies. stat sensor lactate is a new poc lactate meter based on a patented multiwell and multilayer electrochemical technology that incorporates control wells that measure and correct for common interfering substances. the electrochemistry technology is layered onto a gold platform providing a stable and robust surface for the electrochemical reaction kinetics. the aim of this study was to assess the performance and functionality of stat sensor lactate. whole blood venous samples were collected from adult patients admitted to a&e. samples were tested for lactate using statsensor lactate (nova biomedical) and the omni b bga (roche) routinely used for lactate measurement. precision was assessed using donated whole blood and spiked with a concentrated lactate solution. results. within run precision was acceptable at all levels tested. for the lowest level sample (mean . mmol/l) %cv for the two meters tested was ( . and . %) at the three other levels tested (mean . , . , . mmol/l) % cv precision was \ %. lactate values during the method validation ranged from . to . mmol/l by the reference method (nova . to . mmol/l background and objectives. this research work's intention is to describe the epidemiology in patients suffering from anemia who were interned into emergency room (er). a preliminary work will be conducted in which three days in june will be randomly chosen. during these days, all patients satisfying certain criteria will be registered. the criteria fitted to this work are the following: be using the emergency channel of the hospital, score any diagnostic and be over years old. paediatric, gynaecologic and traumatic cases fall out of this research. anemia was diagnosed according to who criteria. outcome. patients were interned through the aforementioned er channel. . % were subject of blood analysis using classification proceedings. from the latter, . % were diagnosed with anemia. age, intake of clopidogrel and/or aspirin, admission and place of admission resulted statistically significant among anemia patients versus non-anemia. anemia was to be found in . % of patients younger than years old, % of the times in patients between and and . % among patients above years old. according to vcm, . % were microcitic-anemia, % were normocític-anemia and . % resulted macrocític ones. conclusion. anemia is among a large share of patients coming into the hospital through emergency proceedings. its likelihood increases accordingly to the risk group analysed and dominating among the elderly population and among patients suffering from renal disfunction and non aggregated. most common are normocitic and macrocitic anemia-types. early identification and valuation could bear prognostic consequences. a. s. omar tawam hospital, critical care medicine, al ain, united arab emirates introduction. an elevated serum creatinin phosphokinae (cpk) and the presence of myoglobin in the urine characterize rhabdomyolysis. rhabdomyolysis had been described in various traumatic and non-traumatic conditions [ ] , there are few reports of its association with anaphylaxis. in this paper, we report cases of anaphylaxis both complicated with rhabdomyolysis. aim of the work. to discus the association between rhabdomyolysis and anaphylaxis and the value of early screening of cpk in such cases. setting. two patients were included in this review in multidisciplinary intensive care unit of tawam hospital/uae. the two patients survived, both developed rhabdomyolysis shortly after admission, evidenced by fivefold or greater increase in serum cpk [ ] . both patients had transient hypotension through the presentation, but none of them had persistent shock requiring vasopressors or complicated with acute renal failure. conclusion. we observed rapid increase in serum cpk in our two cases suggesting the potential benefits of early assessment of cpk in such patients which may amplify early goal guided management and avoiding logistic organ dysfunction. keywords. rhabdomyolysis, anaphylaxis. the blood oxygen and carbon dioxide levels are a direct measure of the effectiveness of ventilatory support in patients on mechanical ventilation. head injury patients require strict control of the cerebral homeostatic state. these patients also need careful management of sedation, maintaining a fine balance between patient comfort, hemodynamic instability and ability to assess conscious levels. biphasic intermittent positive airway pressure (bipap) ventilation is thought to be better tolerated by the patient allowing for spontaneous breathing at any point, thus reducing the amount of sedatives and muscle relaxants used. but the effectiveness of this ventilatory mode in achieving stable blood oxygen and carbon dioxide levels in this group of patients is not known. we hypothesised that bipap is more labour intensive to adapt to the target blood gas parameters as the volume delivery is not constant and that the blood gases may be more unstable in the initial resuscitation phase of head injury patients without conferring much advantages in terms of usage of sedatives and muscle relaxants. retrospective data collected from case record review of head injury patients with no primary respiratory insult, requiring mechanical ventilation with volume controlled synchronised intermittent mandatory ventilation (simv) was compared to the data from similar patients treated with bipap ventilation. both the data groups specifically looked at two time periods, the first h and - h after intensive care admission. blood gas parameters classified as hypocarbic, hypercarbic and/or hypoxic, use of muscle relaxants, number of episodes of raised intracranial pressure (icp) above mmhg as recorded in the intensive care chart every hour, number of episodes of cerebral perfusion pressure (cpp) below mmhg as recorded in the chart every hour was noted. need for muscle relaxant in the first h of admission was noted. the outcome was recorded as either ''alive'' or ''dead'' at the end of itu stay. the data was checked for normality of distribution and compared using non parametric tests (spss for windows). results. baseline characters were comparable between the groups. increased episodes of hypoxia ( . ± . vs. . ± % p = . ) and hypocarbia ( . ± . % vs. . ± . % p = . ) in bipap mode, compared to simv volume control mode. all measurements being percentages of total blood gases for that patient in the first h. there was no difference in the usage of muscle relaxant ( . vs. . % p = . ), raised icp, reduced cpp or mortality between the groups. conclusion. bipap mode of ventilation requires more intensive monitoring and changes in ventilatory settings before adapting to the target blood gas parameters in the first h of admission. at the same time the quoted advantage of using less sedatives and muscle relaxants is not significant. acute post-traumatic brain swelling is one variety of the pathological forms, which needs emergent treatment following traumatic brain injuries. we investigated the effects of clinical effects of decompressive craniectomy (dc) in patients with acute post-traumatic brain swelling (bs). seventy-four patients of acute post-traumatic bs with midline shifting more than mm were divided randomly into two groups: dc group (n = ) and routine temporoparietal craniectomy group (control group, n = ). the vital sign, the intracranial pressure (icp), the glasgow outcome scale (gos), the mortality rate and the complications were prospectively analysed. the mean icp values of patients in dc group at , , and h after injury were much lower than those of routine temporoparietal craniectomy group ( . ± . , . ± . , . ± . and . ± . mmhg vs. . ± . , . ± . , . ± . and . ± . mmhg, respectively). the mortality rates at month after treatment were % in the dc group and % in the control group (p \ . ). good neurological outcome (gos score of to ) rates year after injury for the groups were . and . %, respectively (p = . ). the incidences of delayed intracranial hematoma and subdural effusion were and %, respectively (p \ . ). in conclusion, dc has superiority in lowering icp, reducing the mortality rate and improving neurological outcomes over routine temporoparietal craniectomy. however, it increases the incidence of delayed intracranial hematomas and subdural effusion, some of which need secondary surgical intervention. therefore, the effects of dc in patients with acute post-traumatic bs should be further evaluated. we analyze among others variables: age, injury severity score (iss), abbreviated injury score (ais); admission and discharge glasgow coma score (gcs), extended glasgow outcome score (gose), complications, icu and hospital mortality. differences between groups were tested with students t test and v testing for statistical analysis. results. fourteen patients with intracranial hypertension were treated with decompressive craniectomy . compared with control group, patients with dc had a better gcs ( ± g ; ± g p = , ) and gose index not only at icu discharge ( ± g ; ± g p = , ) but also at hospital discharge ( ± g ; ± g p = . ). the mortality rate was lower in the craniectomy group (g : %, g ; % p = . ). conclusions. in our center, the use of dc for treat patients with severe tbi and refractory cranial hypertension (gcs b and pic c ) improved outcome and mortality significantly compared with medical conventional approach. method. in this retrospective study we present patients who underwent decompressive craniectomy following traumatic brain injury at king's college hospital between and . results. % of these patients presented at a&e with a glasgow coma scale of or below whereas the remaining % presented with gcs above and deteriorated following admission. the patients underwent decompressive craniectomy to reduce raised icp resistant to medical treatment (barbiturate coma excluded). the procedure resulted in significant decrease in icp. out of patients had the operation within h following their injury. we also found that dc in younger patients (\ years) was correlated with lower icp following the operation compared to older patients ([ ) . our study also showed that early dc (\ h) is correlated with a shorter stay in itu. conclusions. the findings of the present study are limited by its retrospective nature and small sample size which does not permit any definitive conclusions from these results. however, they form the basis for further investigation. we present the study with a review of the recent literature. introduction. the objective is to study the correlation of secondary icp indices with ct findings and outcome in tbi. a cerebrovascular pressure reactivity index (prx) can be determined as the moving correlation coefficient between mean icp and mean arterial blood pressure . it is a surrogate marker of cerebrovascular reactivity. the rap coefficient was calculated as the running correlation coefficient (r) between slow changes in pulse amplitude (a) and mean icp (p). it is a surrogate marker of pressure-volume compensatory reserve. all components of the icp waveform that have a spectral representation within the frequency limits of . to . hz can be classified as slow waves. methods. prospective observational study of patients with tbi at the royal london hospital. all patients were managed according to the local guidelines for the management of tbi . secondary indices derived from the icp waveform were analyzed by icm ? software. an initial ct was performed in all patients before admission to icu. marshall classification has been shown to predict mortality in tbi. we found a strong association between all these secondary indices and the initial ct findings. all these markers of cerebral haemodynamics correlate significantly with outcome in headinjured patients. conclusions. surrogate markers of cerebrovascular reactivity and pressure-volume compensatory reserve correlates with ct findings and outcome in tbi. these secondary icp indices may be used in the management of tbi. introduction. following the introduction of national guidance [ ] on the management of patients with head injury, the use computed tomography (ct) imaging of the head has increased markedly. the impact on anaesthetic and critical care services is unknown. . determine the impact of national guidelines on ct scanning in the head injured patient upon anaesthetic and critical care services in a university teaching hospital. . determine the incidence of acutely abnormal ct appearances in patients referred for ct scanning under the guidelines. . estimate in-hospital mortality in this population and its sub-groups. a case-note analysis was performed in october of consecutive emergency department (ed) patients who were recorded as having a ct head. of the cases, did not actually have ct head. details of the analysed subjects, indications for the scan and day mortality rates are reported in table . in patients with severe traumatic brain injury pro-and anti-inflammatory mediators are released into the systemic circulation. however, the relationship between the inflammatory response and the kind and duration of secondary insults remains unclear. objectives. the aim of this study was to investigate in severe traumatic brain injured patients the relationship between the systemic concentrations of pro-and anti-inflammatory mediators and the total duration of secondary insults occurring during the icu stay. methods. ten consecutive traumatic brain injury patients admitted to the icu were included. physiological variables were continuously recorded and analyzed minute-by-minute to identify the occurrence of secondary insults (intracranial hypertension, systemic hypotension, hypoxemia and hyperthermia) according to the edinburgh university secondary insult grading scale. serum samples were obtained at admission, , and h, in which pro-and anti-inflammatory mediators were analyzed by a bioplex assay. results. ten male patients were enrolled, mean age ± , gcs ± , apache ii ± , iss ± . patients were monitored for . days (median value, range - ; , total minutes recorded); intracranial hypertension occurred for , min ( . % of total period recorded, range . - %), hypotension occurred for , min ( . % of total period recorded, range . - %), hypoxemia occurred for min ( . % of total period recorded), not enough data were validated for fever. interleukin (il)- , il- beta, il- , il- and il- ra were in the detectable range. a significant correlation was found between the total duration of intracranial hypertension and the median value of il- (p \ . , r = . ), il- beta (p \ . , r = . ), il- (p \ . , r = . ), il- (p \ . , r = . ), and il- ra (p \ . , r = . ) measured during the period of observation. no correlation was found between these inflammatory mediators and the occurrence of hypotension or hypoxemia. no significant correlation was present between the baseline values of these inflammatory mediators and the severity indexes (gcs, iss and apache ii). conclusions. these results suggest that the duration of secondary insults such as intracranial hypertension was associated with a systemic inflammatory reaction, while the severity of injury on admission was not related to the initial concentrations of these inflammatory mediators. grant acknowledgement. aim. assessing behavioral responses to pain is difficult in severely brain-injured patients recovering from coma. we here propose a new scale developed for assessing pain in vegetative (vs) and minimally conscious (mcs) coma survivors: the coma pain scale (cps) and explore its concurrent validity, inter-rater agreement and sensitivity. methods. concurrent validity was assessed by analyzing behavioral responses of postcoma patients to a noxious stimulation (pressure applied to the fingernail) ( vs. and mcs; age range to years; non-traumatic and of traumatic origin). patients' were assessed using the cps and four other 'pain scales' employed in non-communicative patients: the 'neonatal infant pain scale' (nips) and the 'faces, legs, activity, cry, consolability' (flacc) used in newborns; and the 'pain assessment in advanced dementia scale' (pa-inad) and the 'checklist of nonverbal pain indicators' (cnpi) used in dementia. for the establishment of inter-rater agreement, fifteen patients were concurrently assessed by two examiners. results. concurrent validity assessed by spearman rank order correlations between the cps and the four other validated pain scales was good. cohen's kappa analyses revealed a good to excellent inter-rater reliability for the cps total and subscore measures, indicating that the scale yields reproducible findings across examiners. finally, a significant difference between cps total scores was observed as a function of diagnosis (i.e., vs or mcs). conclusion. the cps constitutes a sensitive clinical tool for assessing pain in severely brain injured patients with disorders of consciousness. this scale constitutes the first step to a better management and understanding of pain in patients recovering from coma. methods. study group: consecutive patients with cervical spinal cord injury admitted to icu. mean age: , years. patients asia a, asia b, asia c. the more frequent neurological level was c ( %). the requirement of mechanical ventilation was considered the key sign for establishing the diagnosis of severe respiratory failure. the blood gas values (po , pco , and pao /fio ) before and after connection to mechanical ventilation [mv(if needed)], were used to estimate the more probably mechanism of respiratory insufficiency. the increase of pco levels was considerate as a sign of neuromuscular weakness; the low po level before ventilation, and the persistence of pao /fio below normal values was considered a sign of v/q mismatch. for this purpose statistic analysis (mean values comparison using student t test) comparing blood gases before and after mechanical ventilation treatment was performed. results. ( %) patients developed severe respiratory failure. mean delay between admission and mechanical ventilation was h. previously to mechanical ventilation patients developed pulmonary atelectasis, and four pneumonia. the incidence en respiratory failure was significantly higher in patients with neurological level above c (p \ . ). conclusions. the incidence of respiratory failure is related with the severity of neurological deficit (relationship between incidence of respiratory failure and neurological deficit level). in addition, our data support that, besides the neuromuscular weakness (moderate increase of co levels), a significant v/q mismatch with shunting phenomena associated (significant hypoxemia no completely solved after mv) is involved in the respiratory failure of cervical spinal cord injured patients. . moderate and severe traumatic brain injury is more likely in middle aged men; more than one third present other major trauma and intensive first level medical treatment is required in most of them. . the most frequent complications found were infectious diseases like ventriculitis and vap. . independent mortality risk factors in moderate and severe trauma brain injury were age, high apache ii score, neuromuscular blocking drugs and icu los. . outcome was significantly improved after six months, and most of the patients only present mild disability and good recovery. nosocomial infections are leading causes of increased morbidity and mortality of severe brain injured patients [ ] . the mechanism underlying the susceptibility to the infections is a subject of great scientific interest and still to be clarified [ ] . it has been recently recognized that injury of brain induces a disturbance of balance between the central nervous and immune system [ ] . objective. the aim of this study was to investigate changes in frequency of lymphocytes subpopulation in peripheral blood of patients with severe brain injury during the course of intensive care treatment. human peripheral blood samples were taken from the severe brain-injured patients at day , and and peripheral blood mononuclear cells (pbmc) were immediately isolated by gradient density centrifugation. the percentage of lymphocytes subpopulation were analyzed by simultaneous detection of surface antigens using fluorochrome conjugated monoclonal antibodies directed toward cd , cd , cd , cd , cd , cd , cd . t lymphocytes were distinguished from the other lymphocyte subpopulation as cells labeled with anti-cd monoclonal antibody but negative for cd staining (cd ? cd - patients. eighty-seven patients with head injury, glasgow coma scale \ . measurements and main results. clinical and demographic data, and head ct scan were taken at admission. patients underwent advanced neuromonitoring and were treated according to brain trauma foundation guidelines. s b concentration was quantified at admission and , and h post-tbi (days , , and ). outcome was assessed months after discharge using glasgow outcome score. significant negative correlations were found between -year gos and s b concentrations on days - , but not on day (day , p = . ; day , p = . ; day , p \ . ; day , p \ . ). patients who deceased showed higher s b concentration than survivals for all the samples. good versus poor outcome (gos = - ) differed significantly on days and . logistic regression analysis showed that samples , and h post-tbi sample predicted death outcome. roc curve analysis showed -h sample was the strongest predictor for decease. poor outcome was only predicted by the -h sample. conclusions. s b levels h post-tbi was the strongest predictor for poor and fatal -year outcome, whereas levels at admission do not. a temporal profile of s b release from admission to h post-tbi is strongly recommended for use in identifying the subset of patients liable of developing a worse outcome. according to our results, s b protein might be an early, sensitive, accurate and useful biomarker for predicting long-term outcome in patients with acute severe tbi. grant acknowledgement. this research was made possible in part by the generous donation of protein s b electrochemiluminescence assay kits by roche diagnostics, mannheim, germany. introduction. brain intercellular fluid glycerol concentration as measured by microdialysis catheters has been recognized as an index of glial and neuronal cellular destruction. we present a data analysis correlating glycerol levels with intracranial pressure (icp), cerebral perfusion pressure (cpp), brain tissue oxygen partial pressure (pbtio ), lactate to pyruvate concentration ratio (l/p) and outcome. methods. data of head injured patients is presented. all had simultaneous monitoring of icp, pbtio and metabolic biochemistry by three brain intraparenchymal bolt catheters inserted via the same one burrhole (icp codman or camino, pbtio licox and microdialysis-cma). there was not a clear straight correlation of raised glycerol levels with bad outcome. however, glycerol elevation seemed to be a predictor of intracranial hypertension together with l/p raise. in subarachnoid hemorrhage patients glycerol elevation was an early sign of secondary ischemic insult. conclusion. multimodal monitoring with intracranial catheters is a useful clinical tool for management of critical neurosurgical patients. metabolic biochemistry as measured by microdialysis, and specially l/p and glycerol levels, can early predict incoming intracranial hypertension as well as secondary ischemia. the pulsatility index (pi), a parameter derived from the blood velocities along the cardiac cycle, has been used as an indirect way to evaluate intracranial pressure. the aim of this research has been to evaluate the accuracy of transcranial doppler sonography (through pulsatility index) in the inference of intracranial pressure. methods. population of the study group (high-pi-group): severe head injured patients (gcs at admission \ ; mean age . years; patients with diffuse injury (traumatic coma data bank) type ii ( %) and iii ( %)) who presented episodes of increase of pulsatility index (pi [ . ) in the acute phase of head injury. control group (normal-pi-group): severe head injured patients, with tcd recordings of normal pi (pi b . ). in all the patients the intracranial pressure (icp) was continuously monitored using a intraparenchymal device. all the tcd recordings are referred to the middle cerebral artery of the cerebral hemisphere were icp catheter was inserted. in the transcranial doppler recording, the pulsatility index was automatically calculated derived from the formulae: pulsatility index = (systolic velocity -diastolic velocity)/mean velocity. transcranial doppler sonography recordings of with pulsatility index c . (high normal value of pulsatility index) were correlated with the simultaneous icp value. the incidence of intracranial hypertension (icp [ mmhg) was analyzed in the high-pi-group, and compared with the incidence of intracranial hypertension in the normal-pi-group. methods. in a double-blind, randomized, placebo-controlled clinical trial, patients scheduled for elective cabg was randomly assigned into two groups. after matching inclusion and exclusion criteria and induction of general anesthesia, one group received intrathecal sufentanil (s) and the other group received the same dose of sufentanil plus supplemental bupivacaine (sb). except for this, all the cases were similar regarding anesthesia and surgery. mean arterial blood pressures were measured before and after induction of anesthesia, during the bypass time and after weaning from bypass were checked. also, the need of the patients for administration of inotropic agents after weaning was compared. results. there was more stable mean arterial blood pressure and less inotropic need after weaning from cardiopulmonary bypass in the sb group. also, the sb patients had a more stable hemodynamic profile during the bypass period; especially after the initiation of the bypass. less inotropic agents were needed after weaning in the sb patients. there was no difference between the two groups regarding the extubation time. discussion. the administration of intrathecal sufentanil plus bupivacaine seems to keep the hemodynamic status of the patients more stable than intrathecal sufentanil alone. methods. this study was approved by the hospital s ethics committee. prospective observational study including consecutive patients. preoperatory and postoperatory data were collected. interventions included blood samples for nt-pro bnp taken prior to operation, and and h in postoperative. troponin-i was taken and h postoperatively. blood obtained was processed for nt-probnp with cobas h system Ò point of care (poc) by roche diagnostics, with range from to , pg/ml. the serum nt-probnp level was also correlated with the logistic euroscore and ejection fraction (ef). serum ntpro-bnp and troponin i values were compared between patients with and without postoperative length of stay in the intensive cardiac unit (icu) [ h. and hospital [ days. all results are in median ± sd * p \ . , **p \ . tables ??? and ??? conclusions. preoperative euroscore and nt-probnp levels were higher in patients with ef \ %. the troponin i after surgery increased more in patients whose length stay in icu was longer. after surgery nt-probnp levels increased significantly,and they differ significantly between patients with length stay in icu for more than h and days at hospital. our data collection confirmed that measurement of nt-probnp is useful and helpful during postoperative period and it also predicted a higher possibility for a long stay in icu and a later hospital discharge. however, owing to the small size sample, these results must be regarded as preliminary. conclusions. in spite of the limitations of our trial, percutaneous aortic valve implantation appears to be safety. a high rate of maccv events were observed, essentially due to a disruption of the a-v conduction, in most cases transitional. despite the definition of ''inoperability'' is difficult, less-invasive aortic valve procedures will undoubtedly find a place within current cardiac surgical practice. objective. to describe the evolution of cardiac transplant patients, presenting clinical low cardiac output in the immediate postoperative period, and after handling routine, they are treated with levosimendán (lv). descriptive, prospective and observational in a postoperative care unit for cardiac surgery from a terciary hospital. study period: january -december . lv was used when the patient had inotropic dependence over h, to try to remove the amines or added to them in those cases that do not get these drugs with an adequate hemodynamics. bolus was used in occasions and then infusion of . - . mcg/ (kg min). we analyzed demographic variables, hemodynamic response to the input of the drug if you can reduce or discontinue other medications, clinical tolerance and side effects, overall development, the icu and hospital stay. we studied patients ( women and men). presented a mean age of . . before surgery, all of whom were in nyha functional class iii-iv. three patients were transplanted in emergency. in this series, there is a case without pulmonary hypertension (pah) pre-transplant, patients with mild htp and htp moderate to severe, with a transpulmonary gradient(gtp) between and mmhg. the patients with gtp [ mmhg had a positive reversibility test with sildenafil. ischemia time of surgery was . . in the immediate post, all the patients studied had low cardiac output syndrome by graft postoperative ventricular dysfunction, cardiac index measured by pulmonary artery catheter. in all patients echocardiography was performed to rule out a pericardial effusion with hemodynamic deterioration in cardiac cavities and showed ventricular dysfunction, right dominance in patients. in all patients we observed a good tolerance to the drug. in lv cases facilitated the withdrawal of the remaining. patients were used lv only after the withdrawal of treatment with inotropic dependence on it. in the remaining cases to be associated with other drugs. only two cases could not withdraw inotropic treatment after the lv infusion. in five patients with pulmonary arterial hypertension and prevalence of right ventricular failure, to reduce poscarga also added pulmonary arterial vasodilators. patients have a stay in icu between and days. one patient mortality. . the primary graft failure is a severe potential complication of post-cardiac, which is associated with a worse prognosis. . lv shows good tolerance, without serious adverse effects attributable to the drug, and facilitated the removal of amines and clinical recovery. . it is necessary to expand the case to confirm the results, and to establish the most appropriate indications and patterns of use of this drug. post-infarction ventricular septal defect (infarctvsd) is a rare but serious complication of myocardial infarction, usually quickly followed by low cardiac output. repair of infarctvsd is still a challenging procedure with a high risk of mortality. improvement of surgical outcome depends on results of large studies in this setting. the aim of this retrospective study was the evaluation of preoperative and surgical parameters influencing the -day mortality following surgical repair. conclusions. in this large study, pre-operative left ventricular function and troponin level were found to be the best predictors identifying patients at high risk for -day mortality following surgical closure of infarctvsd. both parameters may be helpful in deciding on the time of the operation and preoperative preparation. in contrast to other findings, in our cohort the location of the vsd (anterior vs. posterior) did not affect mortality. this may be due to improvement of surgical technique and perioperative management over time. adequate fluid therapy is the first step of hemodynamic optimization after cardiac surgery [ ] . cardiac surgery exposes patients to ischemia and reperfusion, which are well known risk factors for a systemic inflammatory response and increased capillary permeability in the lungs [ ] . it is still unclear what type of fluid should be given in the presence of increased pulmonary vascular permeability at hypovolemic status. objectives. aim of this study was estimate the optimal type of fluid for intravascular volume deficit treating without evoking pulmonary oedema. a prospective clinical study at the intensive care unit was performed on mechanically ventilated patients within h after elective cardiac surgery involving cardiopulmonary bypass. patients, divided into four groups, were subjected to fluid challenge according to the global end-diastolic volume index (gedvi) measurements with normal saline , ml or the colloids % gelatin, % hes / . or % albumin ml in min. hemodynamic and extravascular lung water index (evlwi), gedvi measurements were performed exactly before fluid challenge, afterwards and min after challenge. results. the change in evlwi did not differ between saline and colloid fluid challenge. gedvi increased by % in saline group, by % in % gelatine, in % hes / . and in % albumin. conclusions. all colloid fluid infusion leads to the greater increase in cardiac preload compare to normal saline (saline in four times larger volume). the change in evlwi did not differ between saline and colloid fluid groups and did not increase pulmonary oedema despite in the presence of increased pulmonary vascular permeability, when fluid overloading is prevented. introduction. the annual incidence of prosthetic valve thrombosis is up to - % (patients-year) despite the anticoagulant therapy. conventionally, the treatment of choice for this event was the surgical valve replacement. however, fibrinolytic therapy has become a valid alternative for the treatment of this serious complication, especially in high-risk surgery patients. to analyze the clinical factors, diagnosis and treatment management of patients with prosthetic valve thrombosis admitted to the acute cardiac care unit. we designed an observational-descriptive study, including patients admitted between and . clinical factors were analyzed: sex, age, prosthetic valve position, time from valve replacement, inr at admission, clinical features, diagnostic technique and treatment used. results. patients were included. . % were women, . % men. mean age was . ± . years. the highest incidence was at the tricuspid prosthetic valve position ( . %), followed by the mitral ( . %) and the aortic position ( . %). when a triple valve replacement was performed, the tricuspid position was the most often affected. mean time from the first valve replacement surgery was . ± . years. clinical features which led to the diagnostic were: acute heart failure ( . %), peripheral embolization ( . %), chest pain ( . %) and syncope ( . %). the diagnostic techniques used were transesophageal echocardiography (tee) and cinefluoroscopy in all the patients. inr at admission time was lower than adecuate anticoagulation recommendations in . % of patients. the most widely used treatment was the systemic fibrinolytic therapy ( . %), followed by surgery ( . %) and conservative treatment with heparin alone ( . %). the most widely used thrombolytic was rtpa in . % of patients, with a mean dosage of . ± . mg. one patient was treated with . mil. ui of streptokinase. unfractionated heparin was added to all patients whom received fibrinolytic therapy, with a mean dose of ± ui/h. a . % incidence of minor bleeding was found in the fibrinolytic group. there were no major complications due to fibrinolytic. total mortality rate was . %. our experience, suggests that systemic fibrinolytic therapy is safe and effective in patients with prosthetic valve thrombosis. objective. to describe the outcomes of patients with acute, refractory, non-ischaemic and not postcardiotomy, cardiogenic shock treated with extracorporeal membrane oxygenation (ecmo) and to evaluate whether survivors and non-survivors differed with respect to clinical characteristics, pre-ecmo treatment and laboratory values. design. in this retrospective cohort study, information is collected from a database with additional review of medical records. patients. consecutive adult patients, males, mean age . ± . year, presenting to hospital with non-ischaemic acute severe, refractory cardiogenic shock, supported by central or peripheral venoarterial (va) ecmo. measurements and main results. characteristics of survivors and non-survivors were compared using chi square test. twelve patients ( %) were transported to our institution on ecmo. eleven patients ( %) were weaned from ecmo, seven ( %) bridged to ventricular assist devices. in two patients ( %) ecmo support was withdrawn. mean duration of ecmo support was . ± . h. overall survival was %, and did not differ between patients with myocarditis (n = ), cardiomyopathy (n = ) and acute on chronic non-ischaemic cardiogenic shock (n = ). a larger proportion of the three patients with or more complications died as compared to the seventeen patients with less than complications ( % versus %, p = . ). pre-ecmo intra-aortic balloon counterpulsation (iabp) was used in patients, % survived, as compared to % of those who did not receive iabp (p = . ). we have not identified any other significant differences between survivors and non-survivors. conclusion. the survival of patients on ecmo in this unique heterogeneous patient cohort is similar to the survival of ecmo support for fulminant myocarditis in the literature. we recommend to institute ecmo early in all medical patients with acute non-ischaemic cardiogenic shock, refractory to conventional therapy, or to refer these patients in time to an ecmo centre. introduction. human parvo b virus is associated with a broad spectrum of clinical manifestations, mostly in children or immune-compromised patients. in adults, severe myocarditis due to this viral agent is a rare disorder, presenting as acute congestive heart failure. we describe a patient with rapidly progressive heart failure, needing circulatory support by extracorporeal membrane oxygenation (ecmo). methods. case report. a -year-old previous healthy female was admitted to our icu with nausea, vomiting, bradycardia and hypotension with a blood pressure of / mmhg. two weeks before admission, patient had signs of erythema infectiosum. on physical examination the patient was pale, with venous congestion, third heart sound and hepatomegaly. the initial electrocardiogram showed a slow, regular, ventricular rhythm. admission chest x-ray showed normal heart size with bilateral pleural effusion. echocardiography revealed dilated ventricles (rv and lv) with depressed systolic function and a thrombus in the rv apex. patient was initially treated with intravenous medical therapy, but unfortunately developed progressive cardiogenic shock. troponin levels, serum transaminases and bun were extremely elevated. it was therefore decided to implant a percutaneous ecmo by femoro-femoral cannulation which permitted to stabilize hemodynamic conditions while peripheral organ functions returned to normal range. progressive cardiac recovery was observed after days with a circulatory assistance with a mean flow rate of . l/min. as myocardial function improved, ecmo was gradually weaned and removed after days of support. however, atrioventricular conduction did not recover, necessitating implantation of temporary vvi-pacemaker, which was later replaced by a permanent ddd pacemaker system. pathology of the endomyocardial biopsy showed extensive lymphocytary infiltration with destruction of myocytes. parvo b dna-pcr was positive in both the biopsy and serum. these findings suggest that this patient developed severe myocarditis induced by parvo b viral infection. to our knowledge, parvo b viral infection is an uncommon cause of severe myocarditis in adult patients. sparse literature is available describing the use of ecmo in these adult patients. conclusion. this case report shows that parvo b virus should be recognised as a potential infective agent in adult patients presenting with severe myocarditis. furthermore, ecmo can be safely used to stabilize hemodynamics and peripheral organ perfusion in expectation of myocardial recovery in these patients. copeptin is easier to measure than vasopressin, and could be used as a marker of vasopressin release [ ] . the aim of the study was to compare plasma concentration of avp and cop during cardiac surgery, and specifically during post cardiac surgery vasodilatory syndrome (pcsvs). methods. two-month consecutive patients scheduled for cardiac surgery with cardiopulmonary bypass (cpb) were included in the study except patients suffering from chronic renal failure and under dialysis. blood samples were obtained from blood withdrawals routinely operated before cpb, during cpb and after surgery, at the postoperative hour (h ). these samples were used for avp and cop measurements. pcsvs, assessed as hypotension unresponsive to volume replacement therapy and without cardiogenic shock features, was treated with norepinephrine (ne). patients treated with ne have been compared to the others. statistical test consisted of variance analysis, non parametric test (mann whitney or wilcoxon) and linear regression. a p value of less than . (p \ . ) was considered statistically significant. results. patients have been included, out of which have been treated with ne. correlation between avp and cop plasma concentrations is significant (r = . , p \ . ). avp and copt concentrations increased significantly at h but the increase is less pronounced in ne-treated patients (fig. ) . ne-treated patients had lower preoperative left ventricle ef ( . ± . vs. . ± . %, p = . ), longer cpb ( . ± . vs. . ± . min, p \ . ) and clamping times ( . ± . vs. . ± . min, p \ . ), higher incidence of low output syndrome ( / vs. / , p \ . ) longer extubation time ( . ± . vs. . ± . h, p \ . ) and higher plasma cop before (t ) and during cpb (fig. ) . avp (ng/ml) et copeptin (cop, pmol/l), in patients. *p \ . ne versus others discussion. correlation between avp and cop is similar to that observed in other studies [ ] . the correlation coefficient is rather weak that is possibly related to avp dosage limitations (binding of avp to blood platelets, lack of antibody-specificity). increased cop plasma concentrations before and during cpb is observed in sicker patients undergoing more complex surgery, which seems to expose them to relative postoperative vasopressin deficiency and pcsvs. background. waiting list for heart transplantation has been growing up. high doses of cathecolamines has been an exclusion criterion for heart donation and norepinephrine use is still controversial. to assess if norepinephrine used on heart donors modify receptors outcome. methods. historical cohorts study from april to march . patients were divided in two groups: group : patients with local donors treated with norepinephrine (n = ). group : patients with local donors managed with other cathecolamines (n = ).cathecolamines were used at least for h and doses were between . and mcg/(kg min) if norepinephrine and between and mcg/(kg min) if dopamine or dobutamine. mortality risk factors published on the last international society for lung and heart transplantation guidelines were recorded. graft dysfunction risk factors were also collected. heart transplant outcome was measured by -day mortality, mortality rate at first, second, fifth and tenth years; and graft dysfunction incidence. chi-squared and t student test was used. multivariate logistic regression was used to evaluate norepinephrine impact on the outcome. mortality in group was . and % in group . no differences in mortality or graft dysfunction incidence were found in multivariate analysis. conclusions. norepinephrine used for donors management compared with dopamine and dobutamine does not increase mortality or graft rejection incidence in heart transplantation. groups were not uniform so further studies may be made to determine this association. introduction. coronary artery bypass surgery on cardiopulmonary bypass is associated with significant morbidity and mortality. with present technology, all arteries on the heart can be bypassed off-pump. the benefit of this technique is higher for patients whom are at increased risk of complications from cardiopulmonary bypass, such as those who have heavy aortic calcification, carotid artery stenosis, prior stroke, and compromised pulmonary or renal function. to evaluate the short-term follow up results of off-pump coronary artery bypass (opcab) and postoperative management of these patients admitted to our coronary care unit. we designed an observational study that included patients who underwent opcab from july to december . data were collected on preoperative age, sex, major cardiovascular risk factors, history of prior ami, number of affected vessels and ventricular function. after the surgery we evaluated: the extubation time, postoperative bleeding, troponin maximum level, need for blood transfusion, use of vasoactive drugs and intra-aortic balloon pump, development of renal failure, atrial fibrillation, neurological complications and reintervention. results. patients were included. . % were men and . % women. mean age was . ± . years. % of patients had one or more cardiovascular risk factor: hypertension was present in . %, smoking . %; diabetes mellitus . % and dyslipidemia in . %. there was prior myocardial infarction in . % of patients. prior coronary angiography showed . % of patients with vessels disease and . % of vessels disease. mean lvef was %. mean number of grafts was . . mean extubation time was . h. mean postoperative bleeding was estimated in cc. . % of patients needed blood transfusion; . % vasoactive drugs; and . % needed an intra-aortic balloon pump. . % of patients developed troponin t elevation with a mean level of . ng/ml. . % of patients developed atrial fibrilation, and . % renal dysfunction (two patients needed hemodialysis). there was no neurological complications. patient needed a reintervention. mean of intensive care unit stay was . ± . days. total mortality rate was . %. our experience shows that the off-pump coronary artery bypass graft surgery is a safe and effective technique for coronary revascularization, with low mortality and morbidity rates and reduced postoperative complications. objectives. to assess if deterioration of left atrial function in patients with severe sepsis and septic shock could predict mortality. we studied patients with severe sepsis or septic shock with mean age of . ± . . underlying echocardiographic parameters were measured on admission, th and th day, which comprised left ventricular ejection fraction (ef), and atrial function which is expressed as atrial ejection force (aef), with aef defined as the force that the atrium exerts to propel blood into the left ventricle (lv). all patients were subjected to bnp assay well. multivariate analyses adjusted for acute physiology and chronic health evaluation score ii (apache ii score) was used for mortality prediction. results. underlying source of sepsis was lung in patient ( %), blood in seven patient ( . %), abdomen in seven patients ( . %), while three patient ( %) had urinary tract infection (uti) as a cause of sepsis. only one patient had cns infection. severe sepsis was admission diagnosis for patients, patients were labeled as septic shock. look for days mortality. in-hospital mortality was . % ( patients) . admission ef showed significant difference between survivors and non-survivors . ± . versus . ± . % (p \ . ), on the other hand admission aef showed insignificant changes between the same groups . ± . versus . ± . k/dynes p = . , while bnp was significantly higher in the non-survivors , ± . versus . ± . pg/ml (p \ . ). multivariate logistic regression, the predictable variables for mortality was apache ii score, bnp then ef. conclusion. in septic patients, left atrial function unlike the ventricular function and bnp levels cannot be used as independent predictor of mortality. objectives. to analyse the relationship between plasma levels of nt-probnp and lcd diagnosed by echocardiograph during ss. methods. prospective observational cohort study. inclusion criteria: consecutive patients with ss [ ] . non inclusion criteria: creatinine clearance \ ml/min, years \ age \ years, cardiac surgery patients, pre existing coronary or cardiac insufficiency, neoplasia and systemic diseases. the evaluation of the left ventricular function was realised by a trans-thoracic or a trans-oesophageal echocardiograph on day . the lcd was defined by a left ventricular fraction of ejection \ % evaluated by teicholtz. the blood tests for nt-probnp analyses were drawn on days , , and . serum nt-probnp measurements were made automatically by elecsys analyser with the truss nt-probnp (roche diagnostics, myelan, france) by the electrochemiluminescence immunoassay method (eclia). data are expressed as mean ± sd and percentages. statistical analysis was performed by repeatedmeasures anova and roc curves (p \ . indicated statistical significance). . patients were included in a period of months (medical patients n = , surgical patients n = and trauma patients n = ), age = ± years, bmi = ± kg/m , apache ii = ± , igs ii = ± , duration of intensive care unit stay = ± days, mortality = %. lcd was observed in patients. the statistical analysis showed a significant elevation of nt-probnp in patients with lcd (table ) . on day , the area under roc curve was . , and the cut off value of nt-probnp predictive of lcd was , pg/ml (sensibility = %, specificity = %). introduction. fluid responsiveness can be predicted by the respiratory variation of arterial pulse pressure (ppv) or of pulse contour-derived stroke volume (svv) as well as by the changes in pulse contour-derived cardiac index during a passive leg raising manoeuvre (plr) or a tele-expiratory occlusion (teo). we evaluated the ability of an infrared photoplethysmography arterial waveform (cnap device) to estimate ppv. we also tested the ability of this non invasive estimate of ppv to predict fluid responsiveness compared to the invasive measure of ppv, to svv and to the plr and teo tests. in patients with septic shock ( ± years of age, receiving norepinephrine, saps = ± , lactate = . ± . mmol/l), we measured the response of cardiac index (pulse contour analysis, picco device) to fluid administration ( ml saline over min). before fluid administration, we recorded the ppv directly calculated from the non invasive arterial pressure signal (ppv ni ), the ppv directly calculated from the invasive arterial pressure signal (ppv i ), the ppv automatically provided by the picco device (ppv picco ), the svv automatically provided by the picco device, the changes in cardiac index induced by a plr test and the changes in cardiac index induced by a -s teo. results. five patients were excluded because the arterial curve could not be obtained by the cnap device due to excessive vasoconstriction. in the remaining patients, fluid administration increased cardiac index by more than % ( ± %) in ''responders''. the fluid-induced changes in invasive (? ± %) and non invasive (? ± %) mean arterial pressure were correlated (r = . , p \ . ). at bland-altman analysis, ppvni accurately reflected ppvi (bias %, limits of agreement ± %). for predicting fluid responsiveness in the patients, the receiver operating characteristics (roc) curves for ppv ni , ppv i , ppv picco , svv, plr and teo were . ± . , . ± . , . ± . , . ± . , . ± . , . ± . (all non significantly different). when considering only the patients ventilated with a tidal volume b ml/kg predicted body weight, were falsely classified as non responders by ppv ni , ppv i and two others by ppv picco and svv, but all four were well classified by plr or teo. in septic shock patients, provided that vasoconstriction is not excessive, the non invasive assessment of arterial pulse pressure seems valuable for predicting fluid responsiveness. introduction. mechanical ventilated patients often require inotropic support. however, the role of mechanical ventilation (mv) in myocardial depression is not well understood. septic patients often have impaired cardiac function and are in need of mechanical ventilation. we hypothesized that mv enhances sepsis-induced myocardial depression. objectives. in this study we investigated the influence of mechanical ventilation on cardiac function in an acute sepsis model. sepsis was induced in male wistar rats using ip injection of lps. healthy and septic rats were randomized to one of three ventilation groups; ( ) non-injurious ventilation with a tidal volume of ml/kg and cm h o peep (low tidal volume, ltv), ( ) injurious ventilation with a tidal volume of ml/kg and cm h o peep (high tidal volume, htv) and ( ) spontaneous breathing. arterial pressure was kept at least at mm hg. cardiac output (co, thermodilution method), central venous pressure (cvp) and mean airway pressure were measured in vivo. after h of ventilation, animals were sacrificed and cardiac function was measured ex vivo in a langendorff setup and expressed as developed pressure and ?dp/dt. cardiac wet to dry weight ratio was calculated. results. cardiac output in vivo was lower during htv ventilation than during ltv ventilation (p \ . ). cvp did not differ between ventilation strategies while mean airway pressure was higher in htv ventilation than in ltv ventilation (p \ . ). ex vivo, cardiac function of septic animals was depressed compared to healthy controls (p \ . ) in septic animals, cardiac function was better in htv ventilated animals than in non ventilated animals (p \ . ). ventilation lowered cardiac wet/dry ratio (p \ . ). developed pressure (p \ . ) and ?dp/dt (p \ . ) correlated inversely with cardiac wet/dry ratio. [ ] . perfusion may be also evaluated by other parameters such as lactate or venous-arterial pco gradient (delta pco ). objectives. to evaluate if early normalization of scvo after emergency intubation in septic patients persists over time and if it is associated with similar trends in lactate and delta pco . methods. ten septic patients subjected to emergency intubation for respiratory or circulatory failure and in whom scvo increased to [ % after the procedure. these patients were included in a large prospective study published elsewhere [ ] . patients used a common intubation protocol and we evaluated several perfusion related parameters before, min and h after emergency intubation. statistical analysis included friedman and wilcoxon tests. results. evolution of perfusion parameters after intubation is presented in table . five patients died during icu stay. as a whole, scvo remained stable in pts and decreased dramatically at h by[ % in non-survivor patients (lowest %). only pts had a high lactate before intubation that did not normalize at h (both non-survivors). delta pco exhibited erratic changes over time with no correlation with scvo changes and with mortality ( fig. ). introduction. venous to arterial carbon dioxide difference (pv-aco ) could reflect the sufficiency of blood flow in shock states. time evolution of pv-aco during early phases of resuscitation in septic shock has not been widely characterized. we proposed to describe the association between time course of pv-aco during the initial resuscitation and outcomes in septic shock. methods. patients with a new septic shock episode admitted to icu were included. general management was guided according surviving sepsis campaign recommendations. time (t ) was set when a central venous catheter was inserted to guide reanimation. simultaneous measurements of lactate and arterial-venous gases were obtained at t and h after (t ). pv-aco was calculated as the difference between venous co (blood samples drawn from a central catheter) and arterial co . a value of pv-aco [ was considered as high. survival at day was described for four groups: persisting high pv-aco (high at t and t ), increasing pv-aco (normal at t , high at t ), decreasing pv-aco (high at t , normal at t ) and persistently low (normal at t and t ). survival probabilities were estimated using kaplan-meier method. log-rank test was use to estimate a two-tailed p value for the differences in survival among groups. results. sixty septic shock patients were analyzed. mortality rate was . %. no demographic differences at baseline between survivor (s) and non-survivors (ns) were found. there were no differences in the amount of fluids administered at t and t . no significant differences in scvo at t for s introduction. septic shock (ss) has been defined as sepsis related hypotension despite adequate fluid resuscitation ? perfusion abnormalities such as lactic acidosis [ ] . despite this, an operationally simplified definition overlooking perfusion parameters, has been utilized in several landmark studies during the last decades [ ] [ ] [ ] [ ] . more recently, a new consensus reemphasized the pivotal role of hypoperfusion in ss definition and added low svo as a surrogate [ ] . several problems emerge from these apparently interchangeable definitions, including pathophysiologic and epidemiologic (incidence, outcome) issues. objectives. our aim was to evaluate if applicating different commonly used ss definitions to vasopressor-requiring septic patients leads to distinct outcomes. methods. we applied the two most utilized ss definitions to hypotensive septic patients managed with a ne-based algorithm [ ] for years, generating two major subgroups for analysis (fig. ) . statistical analysis included chi-square test. (fig. ) . pts of subgroup , exhibited persistent normal lactate levels with a mortality of . % which was similar regardless of svo [ or \ : p = . . (fig. ) . conclusions. commonly used ss definitions are not interchangeable and when applied to the same vasopressor requiring septic patients lead to statistically different mortalities. our data suggest that lactate and svo cannot be used indistinctly to define shock condition. a reappraisal of clinical septic shock definition appears to be necessary. objectives. to assess intra-and inter-observer agreement of ecg interpretation in adults with septic shock (vasst, nejm ; : ) . methods. patients were randomised to receive a blinded infusion of low-dose vasopressin or norepinephrine in addition to open-label vasopressors. eight icus participated in this ecg sub-study; and -lead ecgs were recorded at baseline (prior to study drug infusion), and h, and days after initiation of study drug. an intensivist (reader ) and a cardiologist (reader ), blinded to patient data and randomization group, interpreted all of the ecgs in duplicate, using a checklist. prior to ecg interpretation, a calibration exercise was performed to refine definitions and maximize inter-observer agreement; both readers reviewed ecgs (from the current study) representing the spectrum of normal to abnormal. cohen s kappa statistic was used to assess intra-and inter-rater reliability. methods. the model consists of eight elastic chambers including the heart and circulations. identification of the parameters is made only from measured pressures in the aorta and pulmonary artery, and the volume in the right ventricle. septic shock was induced in (n = ) healthy pigs with endotoxin infusion over min. right ventricular pressure-volume loops were recorded by conductance catheter and end-systolic ventricular elastance was assessed by varying right ventricular preload. consent was obtained from the university of liege medical ethics committee. errors for the identified model are within % when the model is identified from data, re-simulated and then compared to the clinically measured data. even with a limited amount of available experimental data to identify the parameters of the model, all simulated parameters trends match physiologically expected changes during endotoxic shock. in particular, a close match of the trends of the right ventricular end-systolic elastances are obtained, when compared to previously reported experimental results [ ] , including capturing of the peak after min and a decaying oscillation after min. conclusions. pig-specific parameters for the cvs model were accurately identified using a significantly reduced data set. this research shows the ability of the model to adequately and realistically capture the impact of pressure-volume changes during endotoxic shock. in particular, the model is able to aggregate diverse measured data into a clear, clinically and physiologically relevant diagnostic picture as the condition develops. this research thus increases confidence in the clinical applicability and validity of this overall diagnostic monitoring approach. background. conflicting data exist concerning the effects on the microcirculation of increasing mean arterial pressure (map) with norepinephrine (ne) in septic shock. nearinfrared spectroscopy (nirs) has been proposed as a tool to quantify microvascular dysfunction in patients with sepsis. by inducing a vaso-occlusive test (vot), a variety of nirsderived variables can be measured to assess local metabolic demand and microvascular dysfunction. this trial was conducted to test the effects of increasing map by ne on microvascular reactivity in patients with septic shock. after local ethical committee approval and informed consent, we enrolled patients in septic shock with an arterial pressure stabilized by ne. in addition to hemodynamic measurements, svo and blood lactate level, we measured thenar muscle oxygen saturation (sto ) and muscle tissue hemoglobin index (thi) by a tissue spectrometer (inspectra tm model , hutchinson technology inc, mn). serial vot (upper limb ischemia induced by a rapid pneumatic cuff inflation around the upper arm) were performed. we also recorded during the vot: basal sto , thi, the slope of the decrease in sto during the occlusion (desc slope; %/min) and the slope of the increase in sto following the ischemic period (asc slope; %/s). muscle oxygen consumption (nirvo i) was calculated as the product of the inverse of the slope value by the mean of thi over the first minute of arterial occlusion and is expressed in arbitrary units (u) (skarda shock ). all these data were obtained at different times: baseline and with map of mmhg, then at mmhg and mmhg of map by increasing the ne doses and finally to baseline . we report here data corresponding to the mean and sd of baseline and versus map mmhg analyzed by repeated measures analysis of variance (at % level) with bonferroni adjustment to account for multiple comparisons. increasing ne dose induced an increase in cardiac output (from . ± . to . ± . l/min, p \ . ) without any changes in heart rate and an increase of svo (from . ± . to . ± . %, p \ . objectives. to investigate: . the effects of ''successful'' protocolised resuscitation (egdt) on microvessel perfusion (particularly density). . whether there is different effects of egdt on the microcirculation of septic compared to critically ill non-septic patients and . whether there is a difference in the behaviour of ''true'' capillaries (i.e - lm) compared to larger microvessels ( - lm) at baseline or after resuscitation. prospective observational study in the emergency and intensive care departments of an urban teaching hospital. subjects: septic and critically ill control patients requiring shock resuscitation (map less than mmhg, ±cvp less than mmhg, ±central venous saturations less than %). all patients had invasive monitoring and identical cardiovascular targets. patients with known cardiogenic shock or pre-stabilised trauma were excluded. we performed sidestream dark field (sdf) videomicroscopy of sublingual microcirculation at the point of egdt initiation and again on attainment of at least out of cardiovascular goals. three sites were imaged for s and the clips were analysed randomly off-line to provide an average value for capillary density (total length and count per mm) and a semi-quantitative description of microvessel flow (continuous, intermittent or stopped) as previously described. vessels were grouped according to diameter as small ( - lm) and medium ( - lm). non parametric analysis was used for all within or between group comparisons, data is displayed as median values with [range]. *p \ . was considered significant. ( ) ( ) ( ) ( ) duration of occlusion (min), mean ± sd . ± . . ± . . ± . . ± . minimal sto (%), mean ± sd ± ± ± ± as expected, all septic shock patients, except one (for the vot fa % ) and two (for the vot a % ) had a recovery slope lower than normal when sto decreased to % during arterial occlusion. by contrast, when occlusion lasted min, many patients including patients who eventually died, were misclassified since their recovery slopes were in the normal range. these results could be due to the smaller decrease of sto and in turn a less strong hyperemic response when ischemia lasted only min. additionally, a significantly (p \ . ) shorter time to reach % was required when arm (compared to forearm) occlusion was performed. conclusion. when a vot is required for assessing microcirculatory disturbances in septic shock, we recommend performing it using an arm occlusion until sto reach %. aims. to analyze the correlation between sto (and its changes derived from a transient ischemic challenge) and global oxygen delivery (do ) parameters measured invasively using a pulmonary artery catheter (pac). observational study, performed in a -bed medical-surgical icu, at a university hospital. we recruited adult patients with cardiovascular insufficiency that required a pac placement for hemodynamic monitoring and resuscitation. we collected demographic data, and hemodynamic and oxymetric data derived from the pac. simultaneously, we measured sto and its changes derived from a vascular occlusion test (vot). results. twenty-two patients were studied. all the patients had a mean arterial pressure (map) above mmhg. the do index (ido ) range in the studied population was - mlo /(min m ). the mean svo value was ± %, mean cardiac index (ci) . ± l/ (min m ), and blood lactate . ± . mmol/l. the correlations found between sto and invasive oxygen delivery-related variables are shown in table . the sto -deoxygenation slope (deox) during the vot showed a significant correlation with svo (r . , p . ). we did not find any correlation between sto and global flow measurements, such as cardiac index (ci), but we found a correlation between sto and ido . this correlation seems related to the arterial oxygen content, and not to global flow. normal sto values could not rule out low ido and low ic states. therefore, sto seems to be poorly sensitive to exclude hypoperfusion states. in clinical practice there remains issues over the appropriate prescribing of antibiotics in patients with unproven sepsis. the prescribing of antibiotics is not without risk and creates a selective pressure on existing bacterial flora resulting in the emergence of virulent and resistant organisms [ ] . there is also a cost issue from the inappropriate prescription of antimicrobials [ ] . the diagnosis of sirs can be made with confidence [ ] , sepsis cannot and requires confirmation from microbial tests. empirical usage of antibiotic therapy is commonplace but not ideal. rapidly detectable, reliable markers of sepsis would help in directing antimicrobial therapy. objectives. the aims of this study are to determine the significance of % band forms in sirs patients suspected to have sepsis. can they be used as a diagnostic tool in conjunction with procalcitonin in order to direct antimicrobial therapy? methods. this is an observational study aiming to assess the ability of serum procalcitonin and percentage band forms in identifying nosocomial sepsis in patients with sirs. patients were recruited over an month period in a mixed medical-surgical university teaching icu. all patients had suspected sepsis arising 'de novo' and had not received prior antimicrobial therapy. patients had a septic screen performed along with baseline, and hpct and % band form count. introduction. pneumonia is the most frequent infectious complication after successfully resuscitated cardiac arrest (ca). however, diagnosis is difficult because of many clinical, biological and radiological confounding factors as well as the widespread use of therapeutic hypothermia. this could lead to a broad antibiotic prescription. to assess the utility of plasma procalcitonin (pct) measurements for diagnosis of early-onset pneumonia in successfully resuscitated ca. monocentric study (july -march with retrospective review of a prospectively acquired icu database focusing on all consecutive patients admitted for ca and surviving more than h. patients with an infection prior to ca or with an extra-pulmonary infection developing within days following admission were not studied. all files were reviewed to assess the diagnosis of early-onset pneumonia p(?), or not p(-) during the first days of icu stay. p(?) was defined by the presence of a new pulmonary infiltrate on chest radiography, persistent for at least h, associated with either positive quantitative culture of the endotracheal aspirates, either, in case of lack of bacteriological sample, conjunction of purulent sputum and hypoxemia (p/f \ ). pct was measured at admission, days (d) , and (brahms kryptor Ò ). among patients admitted for ca, were studied ( death before h, evolutive infections and incomplete samples). pneumonia was diagnosed in patients ( %), and antibiotics were prescribed in during the first days of icu stay. characteristics of p(?) and p(-) patients were (median, iqr): age ( - ) versus ( - ) (p = . ), ''no flow'' ( - ) versus ( - ) min (p = . ), ''low flow '' ( - ) versus ( - ) min (p = . ), shockable rhythm versus % (p = . ), cardiac etiology versus % (p = . ), therapeutic hypothermia versus % (p = . ), post-resuscitation shock versus % (p = . ) and icu mortality versus % (p = . ). using a threshold value of . ng/ml, negative predictive values were % at admission, % at d , % at d , whereas positive predictive values were , and %, respectively. patients with post-resuscitation shock had higher pct levels than those that did not require vasopressors: . versus . ng/ml at d (p \ . ), . versus . at d (p \ . ) and . versus . at d (p = . ). conclusion. diagnosic value of pct is poor in survivors of ca and pct should not be recommended to assess early-onset pneumonia. post-resuscitation disease could play a major role in the lack of specificity and predictive values. in acute community respiratory infection, low levels of procalcitonin (pct) have been shown to allow a marked reduction of antibiotic use. the aim of the study was to look for the same efficacy in case of suspicion of infection during icu stay. method. from april to december , patients hospitalized in the five intensive care units (icu) of the university hospital of liège in belgium, were prospectively randomized to either a procalcitonin guided approach to antibiotic therapy (pct group, n = ) or to a standard approach (ctrl group, n = ) when they were suspected of developing an infection. for pct group guided therapy only, the use of antibiotics was more or less strongly discouraged (pct level . or. lg/ml, respectively) and more or less recommended (pct level [ or[ . lg/ml, respectively) . number and duration of antibiotic treatments were recorded. diagnosis and treatment decisions were reviewed by infectious disease (id) specialists at the end of icu stay. results. there were no differences between groups in terms of age ( vs. ), saps ii score ( . ± . vs. . ± . ), type of patients (medical: vs. %, scheduled surgery: vs. %, emergency surgery: vs. %, trauma: vs. %), icu length of stay [ (iqr - ) vs. days (iqr - )] for pct and ctrl group respectively. suspicion of infection was either evoked on admission (in and %) or during icu stay (in and %) in pct group and ctrl group respectively. at the time of suspicion, pct levels was. lg/ l in . % of the infectious episodes in pct group and . % in ctrl group. episodes of suspected infection with pct level . lg/ml were recorded. clinicians decided not to treat % of these episodes (n = ). the remaining episodes were treated, of which % were eventually considered as probable or confirmed infections by id specialist (n = ). at the end of icu stay, id specialists classified infectious episodes of both groups as confirmed (n = ; . %), probable (n = ; %), possible (n = ; %) or absent (n = ; . %). for confirmed episodes of infection, pct levels were . lg/ml in as much as . % and above lg/ml in . %; for absence of infection, pct levels were . lg/ml in only . % and above lg/ml in . %. the ability of pct to discriminate between confirmed and probable infections on the one hand and possible or absent infection on the other hand, was tested by the measurement of the surface under the roc curve, which was . , which is too low to recognize pct as a valuable marker of infection. there were no difference in the number of treated patients ( vs. %) nor in the number of antibiotic days ( vs. %) between pct and ctrl group respectively. conclusions. procalcitonin level as an aid for the decision to treat infection in icu patients appeared not to be helpful. antibiotic consumption was not reduced using this tool in our study. introduction. respiratory infections, pneumonias in particular are a common cause of mortality in the intensive care unit (icu) patients worldwide. early identification and prompt management of these patients especially with associated sepsis is crucial in reducing the mortality. many clinical and laboratory markers have been studied extensively to predict the outcomes in them. there have been numerous studies on the clinical utility of serum procalcitonin (pct) in the past decade, in systemic inflammation, infection and sepsis. objective. to evaluate the role of serum procalcitonin, in predicting the outcomes of patients admitted in the icu with respiratory infections associated with sepsis. setting: bedded icu of a tertiary referral hospital. study design: prospective observational study. subjects: adult ([ years) patients admitted in the icu with lower respiratory tract infections with associated sepsis during the period july to january were prospectively followed up. primary outcome measure: day mortality. we measured pct levels using the brahms immunochromatographic technique(semiquantitative estimation) on the first day of admission into the icu . normal pct was taken as . ng/ml. patients were grouped into four groups-group a (pct \ . ng/ml), group b (pct [ . - ng/ml), group c (pct [ - ng/ml),group d (pct [ ng/ml). sepsis, severe sepsis, septic shock are defined according to the accp/sccm criteria. results. the overall mortality was . % with mortality of . , . , , and % in groups a, b, c and d, respectively. there is a statistically significant difference (p \ . ) in the mortality rates of groups c and d as compared with group a and b, but no difference was observed in the mortality rates between groups a and b and groups c and d .also significant statistically are the apache ii scores, septic shock and multiorgan failure incidence in the groups c and d as compared to groups a and b. conclusions. serum procalcitonin level [ ng/ml on the first day of admission in icu appears to be a good predictor of mortality in patients admitted with lower respiratory tract infections and associated sepsis. methods. in a retrospective study we assessed acutely ill patients investigated for pct and treated by a physician blinded for pct value. for each patient we also calculated new simplified acute physiology score (saps ii). we evaluated many clinical and instrumental parameters and diagnosis was done upon our usually clinical practice results. the mean age of patients (pt) was . yeats, shock was found in patients ( . %),median value of saps ii score was (iqr - ), and median estimated mortality from saps ii was % (iqr - ). bacterial infection was found in . % (septic shock . %, pneumonia . %, cholecystitis . %, pleural empyema . %, other infections . %) non infective disease in . % (pulmonary embolism . %, acute coronary syndrome . % heart failure . % other disease . %. a pct value [ . ng/ml was considered positive: so pct was elevated in . % of bacterial infection patients and in . % of non infective disease patients. we also compared pct values with antibiotic therapy and considered appropriate the administration if pct [ . ng/ml: there was discrepancy in . %. the review of these cases found medical decision wrong in cases versus ( . %); pt with pct \ . ng/ml had antibiotic therapy without bi and cases with pct [ . ng/ml did not have antibiotic therapy but had a bacterial infection. subsequent to this review discrepancy felt to . % (ci % . - . ) and was found especially in pt with pct \ . ng/ml. at cut off point of . the sensitivity was . (ci %: . - . ) specificity . (ci %: . - . ) or . and at point . the sensitivity was . (ci %: . - . ) specificity . (ci %: . - . ) or . , with high predictive positive value. all-causes mortality was . %. mortality if pct \ . ng/ml was . %, if pct . - . ng/ml was . %; if pct . - . lg/ml was . % and if pct [ ng/ml was . % without significant difference between bacterial infection and non infective disease group. comparing pct with saps ii score, area under roc-curve was not significantly different (pct . -ci %: . - . ) (saps ii . -ci %: . - . ). conclusions. pct in acutely ill patients is a useful marker to discriminate bacterial infections with high sensibility but low specificity and it may be useful to guide the therapy also with values higher than . ng/ml. our data suggest a real prognostic utility of pct in these patients, regardless of bacterial infections, but our efforts to elaborate a mathematical predictive model aren't still satisfying and further data are required in this setting. h. taniuchi , t. ikeda , k. ikeda , s. suda tokyo medical university, hachioji medical center, division of critical care medicine, tokyo, japan introduction. its apparent that detection of the causative bacteria is useful for the therapeutic strategy. however, conventional tests for the detection of the causative bacteria are not high sensibility. in order to diagnose sepsis or septic shock and start appropriate therapy rapidly, it's also important to know whether the infection is cause of gram negative bacteria, that is to say, whether the infection is cause of endotoxin. in this study, we investigate the severity level of sepsis and initiation criteria of direct hemoperfusion with polymixin b immobilized fiber column (pmx-dhp) treatment from the result of severity level by using endotoxin activity assay (eaa) and using measurement of procalcitonin (pct). subjects and methods. patients who developed severe sepsis or septic shock and admitted to icu were included. on the day of icu admission, a general blood biochemistry, eaa and pct levels, and apache ii and sofa score were measured. patients were evaluated retrospectively the relationship between the severity of sepsis and each measurements and investigated the relationship between the measurements and pmx-dhp. serum eaa level was measured using smart line eaa luminometers. serum pct level was measured using immune luminometric assay. results. the average age of the patients is ± , apacheii score was . ± . , sofa score was . ± . , the median pct was . ng/ml (range - ), eaa was . ± . . the underlying diseases of the enrolled patients were the abdominal infection ( patients), the urinary tract infection ( ), pneumonia ( ), the meningitis ( ), the soft tissue infection ( ) and other infection ( ) . the causative bacteria were gram positive bacteria ( ), gram negative bacteria ( ), virus ( ), and unknown ( ). there was no statistical correlations between eaa or pct level and apacheiiscore. there was no statistical correlations between eaa level and sofa score. although there was no statistical correlation between pct level and sofa score, the pct level tended to rise as pct level rises. we investigated the relationship between eaa and pct levels. there was also no statistical correlations between eaa and pct. we investigated the relationship between the causative bacteria (gram positive bacteria, gram negative bacteria and the others) and eaa or pct level. there was no statistical correlations between the causative bacteria and eaa level nor pct, that was contrary to our expectation that eaa level should be high for gram negative bacterial infection. we further investigated the relationship between whether or not the pmx-dhp was implemented and eaa or pct level. there was no statistical relationships. conclusion. high levels of the eaa and pct would not indicate the severe infection with gram negative bacteria, and the initiation of pmx-dhp. further study is needed, in which more patients will be enrolled and evaluated. introduction. sepsis still the major cause of death in the late post traumatic period in patients with major burns. early diagnosis of sepsis is crucial for management and outcome of critically burn patients. attempted in this study to assess whether plasma procalcitonin (pct) level was related to diagnostic and prognostic of sepsis in burned patients. patients and methods. pct was measured over the entire course of stay in patients with predictive signs of sepsis according to american college of chest physician. the patients were assigned to two groups depending on the clinical course and outcome: a = no septic patients, b = septic patients. optimum sensitivity, predictive values, and area under the receiver operating characteristic (roc) curve were evaluated. results. over a month period starting from july to december , patients were admitted. were investigated. in group a et in group b. procalcitonin was significantly higher in septic group . ± ng/ml compared to no septic group . ± . ng/ml. area under the curve was . on the day of sepsis diagnostic. pct cut-off value of . ng/ ml was associated with the optimal combination of sensitivity ( %), specificity ( %), positive predictive value ( %), and negative predictive value ( %). in survived septic patient the pct value was significantly lower than in deceased septic patients . ± . versus . ± . ng/ml. pct cut-off value for optimum prediction of outcome in septic patients was . ng/ml with sensitivity ( %), specificity ( %), positive predictive value ( %), and negative predictive value ( %). conclusion. procalcitonin appears to be a powerful marker of sepsis in burn patients. it is sensitive, specific, reliable and easy to measure. a high pct concentration ([ . ng/ml) would indicate poor outcome in septic patients. n. v. beloborodova , a. s. khodakova , a. y. olenin , s. t. ovseenko bakulev scientific center for cardiovascular surgery, moscow, russian federation objectives. accurate and timely diagnosis of sepsis remains challenging for clinicians. the diagnosis of sepsis is defined as typical symptoms of systemic inflammation (temperature, tachycardia, respiratory rate, leukocytosis) with clinical evidence of an infection site, but the criteria are met by a large number of intensive care unit (icu) patients. among studied biomarkers, serum procalcitonin (pct) has been described as one of the most promising predictors of bacterial sepsis, but in some clinical situations it is not enough. the search of reliable markers of sepsis is still in progress. in present study the significance of raised levels microbial phenylcarboxylic acids in serum of patients with sepsis are assessed. methods. the present study evaluated serum samples of patients (pts) with documentary sepsis, according to well known consensus criteria. the comparison groups were: no. - clinically healthy volunteers, no. - pts. with acquired heart diseases, no. - pts with ventilator-associated pneumonia. blood concentrations of phenylcarboxylic acids were determined by gas chromatography-mass spectrometry (gc-ms). results are presented as median and range of th and th percentiles. the statistically significant differences between the various groups were calculated using mann-whitney test. results. increased levels of phenyllactic (pla), p-hydroxyphenylacetic (hpaa), p-hydroxyphenyllactic (hpla) acids were observed in group of pts with sepsis. the level of hpaa was increased up to two orders in comparison with groups no. and [ . ( . - . ) vs. . ( . - . ) and . ( . - . ) lm, p \ . ). the levels of hpla and pla were increased up to one order [( . [ . - . ] table for illustration of importance of phenylcarboxylic acids blood level monitoring. introduction. acute kidney injury (aki) is a frequent complication of sepsis, and is associated with high mortality and morbidity rates. routinely used measures of renal function, such as levels of blood urea nitrogen (bun) and serum creatinine, increase only after substantial kidney injury occurs, resulting in delayed diagnosis of aki. therefore biomarkers, which enable early diagnosis, are needed. objectives. this clinical study was designed to investigate whether human interleukin- (il- ) and neutrophil gelatinase-associated lipocalin (ngal) are early predictive markers for sepsis-induced aki. urine and blood samples have been collected prospectively from icu patients, who met defined clinical criteria of severe sepsis. aki was defined by rifle criteria. urinary and serum levels of n-gal and il- have been quantified by elisa in patients with sepsis without aki (n = ) and in patients with sepsis induced aki (n = ). results. both, urinary il- and serum il- considerably increased (respectively, . and . -fold over the baseline) two days before the patients reached rifle risk. urinary ngal raised significantly ( . -fold over the baseline) one day before occurrence of aki, whereas serum ngal did not show any prior elevation. no increase in the levels of any of these markers could be found in patients who did not develop aki. conclusions. both urinary and serum il- seem to be sensitive early biomarkers for sepsis associated aki, while urinary ngal has less accuracy for aki prediction. objectives. to define a biomarker panel able to predict infection in case of severe acute dyspnea in emergency situations. we designed a prospective observational study of patients admitted in the emergency department (ed) and in medical polyvalent intensive care unit (icu) in a university hospital. inclusion criteria were acute dyspnea with spo b % and/or respiratory rate (rr) c b/min. patients with an immediate need of coronarography or with obvious spontaneous pneumothorax were excluded. five biomarkers were measured from blood sample at admission on ed or icu: nt b type natriuretic peptide (nt probnp), cardiac troponin i (ctni), ddimeres (dd), c-reactive protein (crp) and procalcitonin (pct). all clinical and biological data were recorded. an independent blinded data monitoring committee classified the patients according to all the available data including response to treatment and outcomes but blindly to biomarkers. the roles of biomarkers were assessed quantitatively and then using terciles of the distribution. the contribution of the biomarkers in the diagnosis was assessed using multiple logistic regression taking into account other clinical and biological explanatory variables. . patients were enrolled consecutively. the final diagnosis was: severe sepsis (n = ), acute heart failure (n = ), pulmonary embolism (n = ), copd (n = ), other causes (n = ). the days mortality was %. there was no significant association between infection diagnosis and dd, ctni, nt probnp. interestingly, a crp value of less than mg/l was not discriminant in predicting infection. adjusted on clinico-biological covariates selected, both pct with cutpoints of . and . ng/ ml (discrimination auc . ; p = . ) and crp with cutpoints of and mg/l (discrimination auc . ; p . ) were significantly associated with the diagnosis of sepsis. both biomarkers used simultaneously lead to a discrimination of the model (auc . ). conclusion. both crp and pct are able to predict the diagnosis of infection in case of severe acute dyspnea independently of clinico-biological variables. in this particular subpopulation, the best threshold for crp is higher than the standard one. an external validation is needed to prospectively validate the clinical utility of these findings. t. trefzer , i. nachtigall , a. weimann , c. de grahl , c. spies charite universitaetsmedizin berlin, campus virchow, department of anesthesiology and operative intensive care medicine, berlin, germany, charite universitaetsmedizin berlin, campus virchow, zentralinstitut für laboratoriumsmedizin und pathobiochemie, berlin, germany aims. infections are the most relevant icu-admission complication. crp and pct are labvalues used for diagnosis of infections. however, their use is often not evidence based. this study aimed to access whether the adherence rate increased after introducing an evidencebased standard operating procedure (sop). in an evidence-based sop was approved by experts of our department. in july it was made available to icu-physicians via intranet, which is accessible from every work station. altogether, we assessed sop-adherence rates of patients: in june (pre-sop), patients in august (one month post-sop) and in january ( months post sop). every crp and pct measurement was assessed for adherence to the standard operating procedure (sop). at first, the three periods were assessed for significant differences concerning the adherence. according to the percentage of sop-conform measurements the patients were then divided into two groups: the sop-group (c % of measurements sop conform) and the non-sop (nsop) group (\ % conform) in a second step, patients in the sop-and nsop-group were compared concerning icu scores (sofa, tiss, apacheii, saps) and outcome parameters (length of icu-stay, length of hospital stay, duration of mechanical ventilation, hospital mortality). statistics: p b . was considered as statistically significant; hospital mortality was assessed by a v test, icu scores and outcome parameters were compared using the mann-whitney u test. all parameters with p \ . were included into a logistic regression analysis. no change was observed concerning the implementation of the sop pre and postintroduction: . % in june , . % in august and . % in january . the non-conform pct-and crp-measurements resulted in additional costs of approximately . euros/year. the univariate analysis revealed significant differences in the sop-and nsop-group: the nsop-group had higher saps-, sofa-and tiss-scores, as well as increased length of icu-stay, length of hospital stay and duration of mechanical ventilation. logistic regression analysis revealed tiss score and length of hospital stay as an independent predictor for low sop adherence. conclusion. distribution of an evidence based sop without further education did not lead to a significant increase in adherence rates, but tiss score and length of hospital stay have shown to be independent predictors for low adherence to the sop. the significant higher tiss-scores in the nsop group might be a indicator for actionism of clinicians in the face of more severely ill patients. objetives. to asses the evolution of the risk-adjusted mortality rates of sepsis and septic shock in our icu in a ten years period. patients and method. analisys of prospectively recorded data of all pacients admitted with severe sepsis and septic shock in a bed icu during a period of years. patients were followed up until death or discharge from the hospital, excluding those with unknown outcome. mortality prediction was made using apache ii model with % confidence intervals. statistical analisys was made with spss . using anova test or t test to compare means and chi square test to compare categorical variables. results. from january to december a total of patients with sepsis were admitted, with an anual increase to reach % of all icu admissions. age and severity of illness increased anually as did sofa in the first h (sofa ) thus rising up calculated risk of death. from to mortality rate was between % ics of calculated risk of death, falling below inferior ic from and after . (fig. ). hospital mortality versus risk of death per year mortality was . % in the pre- period and . % from and on (p = . ) with non significant differences in apache ii, risk of death nor sofa , but with significantly greater age in the post- period ( . vs. . years p = . ). this non significant difference between the two periods of the study became significant when we analized the outcome in both sex. being significant in women (mortality . % in pre- period vs. . % in post- p = . ) but not in men ( . vs. . % p = . ). overall sepsis moratlity is lower in female without significant differences in age, apache ii score nor risk of death (table ) , being the only signifficant difference found in sofa ( . in male vs. . in female p = . ). introduction. low-grade systemic inflammation has been shown to play a key role in the pathophysiology of several chronic noncommunicable diseases [ , ] and may be attenuated by anti-inflammatory treatments such as administration of statins [ ] . so far, the association between acute systemic inflammation experienced during critical illness and long-term mortality after hospital discharge has not been investigated in intensive care unit (icu) patients. objectives. to assess the association between acute systemic inflammation, assessed by crp levels, and post-hospital mortality in non-surgical icu patients. methods. the study was performed as a prospective, observational follow-up study and included non-surgical critically ill patients with an icu length of stay [ h. patients who died during the icu or hospital stay, were \ years or pregnant, as well as patients discharged from the hospital with the plan to limit life support were excluded. demographics, chronic diseases, admission diagnosis, the simplified acute physiology score ii, length of icu stay, maximum crp levels during the icu stay (crpmax) and crp levels at icu discharge (crpdis) were documented. after a mean ± sd follow-up time of . ± . years, mortality and causes of death were determined. adjusted cox models were calculated to investigate the association of crpmax and crpdis with post-hospital mortality. a receiver operating characteristic analysis was used to identify optimal cut-off levels to predict post-hospital mortality. background. the prevalence of hiv infection is increasing worldwide as a public health problem. survival of hiv/aids patients has improved since highly active antiretroviral therapy, but sepsis has grown as an important cause of icu admission in this population. an international conference has set a system composed of specific risk factors, site and microbiology of severe infections and host response and organ dysfunctions (piro) to help identify patients at risk for sepsis. piro factors have not been classified for hiv/aids population yet. objectives. to identify predisposing factors, microbiology of infections, host clinical response and incidence of early organ dysfunctions of severe sepsis on hiv/aids patients, admitted to a specialized infectious diseases icu; to analyze long-term survival of hiv/aids critically ill patients. a prospective case-control study of septic and non-septic hiv/aids patients admitted between june and may was performed. demographic data, causes of admission, time since aids defining condition, cd cell count, and opportunistic infections were evaluated as predisposing factors to sepsis. microbiology and site of infections were registered. clinical response to severe infections was evaluated by ali/ards and shock incidence on day of icu admission. organ dysfunctions (sofa score) were reported soon after icu admission. icu length of stay, hospital and -month mortality were compared between septic and non-septic groups. a multivariate regression analysis was done to identify risk factors for icu mortality. kaplan-meyer survival curve was built. . icu admissions of hiv-infected patients were studied. half ( ) fulfilled criteria for severe sepsis diagnosis. septic group was younger ( . ± . vs. . ± . years, p \ . ) and had more female patients ( vs. %, p \ . ). time since aids diagnosis, cd cell count and opportunistic infections prevalence were not different. sites of infection were predominantly pulmonary ( %) and catheter-related ( %). ninety percent of infections were nosocomial. forty-three percent of septic patients presented bacteremia. pseudomonas sp, s aureus and enterobacteriacae were commonly identified, but five patients had mycobacterium tuberculosis isolated ( on blood cultures). multiple organ dysfunction syndrome was frequent, and incidence of cardiovascular, respiratory and hematological dysfunctions was significantly higher in septic group. longer length of icu stay ( . ± . vs. . ± . days, p \ . ) and icu mortality ( vs. %, p \ . ) was observed for septic patients. severe sepsis also influenced long-term survival, as mortality continues significantly higher after months (log rank . , p \ . ). conclusions. piro system is applied to septic hiv/aids patients. shock, ali/ards and hematological dysfunctions are prominent for septic hiv/aids population. septic hiv/ aids patients are at severe risk of short and long-term mortality. international guidelines for management of severe sepsis and septic shock suggest the use of recombinant human activated protein c (rhapc) in adult patients with high risk of death (apache ii c or multiple organ failure). the objective of this study is to analyse the characteristics and outcome of patients treated with rhapc in our medical intensive care unit. retrospective study of patients with severe sepsis/septic shock treated with rhapc between january to december . all of them were c years, with apache ii c and two or more organ dysfunction, and were treated on basis of a bundle for severe sepsis management: complete early goal-directed therapy, early administration of broadspectrum antibiotics; corticosteroids in vasopressors unresponsive patients and monitor for lactate clearance. chi-square analysis were used to compare categorical data. continuous data were compared using student's t test. prognostic factors of mortality were studied by means of multivariable logistic regression analysis. results. forty-one patients were studied. % were male. their mean age was ± years. % had comorbidities ( % immune pathology). severity scores. apache ii ± , sofa ± , % of patients had three o more organ dysfunction. % had septic shock. serum lactate level was . ± . mmol/l. the primary location of infections was: respiratory %, abdominal %, urinary %. . % were positive blood culture. % of patients needed mechanical ventilation ( ± days). % of rhapc infusions were not completed, mainly for bleeding risk ( %) and death ( %). . % of patients had bleeding event. at the end of the infusion % of patients remained with two or more organ dysfunction and % were vasopressors dependent. mean hospital stay was days and days in icu . days mortality was %, icu mortality . % and hospital mortality . %. analyzed data included age, comorbidities, primary location of infections, severity scores and serum lactate level. univariable analysis showed that statistically significant factors related to mortality were: apache ii ( ± vs. ± , p = . ), organ dysfunction number: vs. [ ( vs. %, p = . ) and primary location of infections: pneumonia versus others ( vs. %, p \ . ). a multivariable logistic regression analysis showed that age (or . , % ci . - . , p = . ), organ dysfunction number (or . , % ci . - . , p = . ) and serum lactate levels (or . , % ci . - . , p = . ) had statistically significant relationship to mortality. conclusion. in our study the patients with severe sepsis and septic shock remained with high vasopressors dependency and organ dysfunction at the end of the rhapc infusion. despite of rhapc therapy the mortality of patients was very high. the age and the severity at icu admission were independent prognostic factors of mortality. a higher incidence of severe sepsis in blacks compared to whites is well documented, however prior analyses do not discriminate whether this is due to a higher incidence of infections, a higher risk of developing organ dysfunction once infected, or both. objectives. we sought to understand whether higher severe sepsis incidence in blacks is due to higher infection susceptibility, higher risk of organ dysfunction once infected, or a combination of both. we analyzed , , hospitalizations from hospital discharge records of us states ( % of us population). we linked these records to us census data to generate age and sex-standardized incidence rates. we identified infections of bacterial and fungal etiology based on icd- cm criteria, including characterization by site and type of infection (gram negative vs. gram positive). we defined severe sepsis as documented infection plus acute organ dysfunction based on previous work by angus et al we estimated the risk of organ dysfunction among those hospitalized with infections using logistic regression, adjusting for age, sex and comorbidities (charlson score). fig. b ]. the combination of both events led to a % higher severe sepsis hospitalization rate for blacks ( . vs. . per , population, irr: . - . ). these differences persisted when stratified by sex, comorbidities, site and type of infection. infection incidence and severe sepsis risk conclusion. the higher incidence of severe sepsis among blacks is due to a higher hospitalization rate for infections, as well as a greater likelihood of organ dysfunction once infected. future interventions to reduce racial disparities in severe sepsis incidence should target both distinct events. grant acknowledgement. dr. mayr was supported by t hl - . objective. to describe recent epidemiological data and mortality risk factors of patients admitted to icu for severe pneumococcal pneumonia (pp). multicentric retrospective study (january -june ). prospective acquired data from patients admitted in french medical icu for severe pp were considered. patients with concurrent meningitis, severe copd with known sp colonization, hiv or aspiration pneumonia were not included. pp was defined by the combination of a suggestive clinical context, the presence of a new pulmonary infiltrate on chest radiography and a s.pneumoniae positive bacteriological sample (pulmonary quantitative culture, pleural fluid, blood culture or urinary antigen assay). all files were reviewed and approved by two independent investigators (nm, am). . patients were included. median age was ± . hospital survivors were significantly younger ( ± vs. ± , p = . ). sex ratio m/f was / , but male sex was associated with higher risk of death (male: vs. %, p = . ). active tabagism ( %) or alcohol abuse ( %) were more common than asplenia ( %). organ dysfunctions were mainly respiratory ( %), haemodynamic ( %) and renal failures ( %). low doses steroids were prescribed in % of patients with septic shock. icu mortality rate reached % ( % in the first days); hospital mortality rate was %. univariate analysis demonstrated that age, male sex, cirrhosis and organ failure support were strong predictors for icu mortality. multivariate analysis only highlighted age [or . ( . - . )], cirrhosis [ . ( . - . ) ] and renal replacement therapy [ . ( . - . )] as independent mortality predictors. activated protein c treatment was associated with decreased mortality [or . ( . - . )]. bacteremia had no impact on outcome. conclusion. this is the most important cohort of pp requiring icu admission. despite adequate antibiotherapy, mortality is still preoccupant. determination of factors related to the bacteria (virulence) or to the host (genetic susceptibility) could allow a better understanding of this important health problem. introduction. to identify the risk factors of mortality for patients with severe community-acquired bacteremic pneumococcal pneumonia. retrospective study realised in the intensive care units of two hospital medical centers. the studied population was patients with serious community-acquired bacteremic pneumococcal pneumonia. all the patients entered the intensive care units between january of and december of . study variables were: age, sex, concomitant pathology, toxic habits, pre-vaccinal ( - ) and postvaccinal periods ( ) ( ) ( ) ( ) ( ) ( ) ( ) , serotype and sensitivity of streptococcus pneumoniae to penicillin, the initial use of the non-invasive mechanical ventilation, the development of empyema pleural, apache ii and sofa scores during the first h after admission. results. the age average was of years. forty one percent of our patients required mechanical ventilation, and % had acute renal failure that required hemofiltration. average values of apache ii and sofa were . and . respectively. in hospital mortality of the series was of %. in patients with severe community-acquired bacteremic pneumococcal pneumonia: ( ) the presence of empyema pleural is an independent risk factor for mortality. introduction. procalcitonin (pct) is an interesting marker of pulmonary infection [ ] . it is useful as an help for infection diagnosis but also for treatment follow-up [ ] . besides, initiation of effective antimicrobial therapy is the strongest predictor of outcome in patients with septic shock [ ] . the aim of the study was to analyse whether kinetics of pct decline may reflect sensitivity of identified infectious agents to initial antimicrobial therapy (at). patients with diagnosis of severe pneumonia following major cardio-thoracic or vascular surgery were retrospectively included in the study. severe pneumonia was suspected as a combination of several manifestations including fever or hypothermia, hyperleucocytosis or leucopenia, new radiological infiltrate, and/or a clinical pulmonary infection score [ , pct [ ng/ml and pao /fio \ . initial antimicrobial treatment was chosen according to the guidelines in use in our institution for community-acquired or nosocomial infections. microorganism identification from endotracheal aspiration or bronchoalveolar lavage, and antibiotic susceptibility testing, allowed to classify patients according to appropriate (aat) versus inappropriate initial at(iat). pct was measured daily over days and its kinetics compared between both groups. data are expressed as median (extremes) or mean ± sd (decrease rate). results. patients aged ± ( - ), operated on vascular (n = ), thoracic (n = ), or cardiac surgery (n = ) have been studied from october to july . pneumonia occurred within the st to the st postoperative day (median . days), with a septic shock in cases and deaths at day . initial at was appropriate in % ( / ) patients. pct peak was not statistically different between aat versus iat patients ( . ± . ng/ml vs. . ± . , respectively) but pct decrease was significantly steeper and constant in iat patients (fig. ). pct decrease (%) from peak value over days discussion: the results suggest that absence of early decrease in pct within days may reflect failure of the at. conversely, an average decrease in pct plasma concentration of % in days seems to be a good marker of sensitivity of the causative infectious agent to the initial at. in case of unchanged pct within days at change should be considered. icu mortality was % for pts with rb early vap while it was % ( of cases) in those with sb or negative cultures (p = . ). mortality was higher than the predicted according to apache ii score in pts with rb vap ( vs. ± %, p \ . ). however, it was lower than predicted in those with negative or sensible isolates ( vs. ± %, p = . ). conclusions. rb were the most common cause of early vap among our patients. the burden of illness, los in icu before intubation and previous use of antibiotics were associated with early vap due to rb. inappropriate empiric therapy and mortality were higher among patients with early vap due to rb. to evaluate the performance of the saps piro model in patients with severe community acquired pneumonia (cap), over a period of years ( - ) , in a general icu in a central hospital. material and methods. we analysed data prospectively registered in an informatic data base, which contains information referring to all patients admitted in this unit. analysed were patients. discrimination was accessed by the area under the roc curve (aroc). calibration was evaluated by the by the hosmer-lemeshow Ĉ test. conclusion. implementation of a sedation protocol requires constant follow up and regular adaptation to prove efficient over time. constant feed back information to both the medical and nursing staff is mandatory. treatment of hyperactive delirium. hal haloperidol, bzd benzodiazepine, pro propofol, aa atypical antipsychotic, nd no drugs, na not answered discussion. there tends to be a general pessimism regarding obese patients within the intensive care community. our data indicates that this opinion could be misplaced. reduced ventilator days may reflect a reluctance to invasively ventilate obese patients. the apache ii scoring does not take into account the bmi which would eliminate any severity scoring bias. high bmi alone should not be a consideration in the decision regarding suitability for admission to critical care. during the last decades, a growing medical knowledges have changed the clinical approach to elderly patient diseases. they receive major surgery or intensive treatment for acute medical illness but often the recover is condictioned by the previous chonical diseases. this determines a long period to stay in intensive care unit (icu) because the slow improvement and cause an occupation of bed places. in our hospital, after a period of training performed by an intensivist (bc) and an internist (ag), icu patients who need a non invasive ventilation (niv) or tracheostomized elderly patients who have difficult weaning were admitted in a dedicated area in a medical department (md). this study desribes the results of one year of observation. in the last year, forty nine patients (age . ± . ; m f ) were transferred from icu to md. twenty three patients were treated with niv (age . ± . ; m f ), fourteen tracheostomized patients (age . ± . ; m f ) receive positive pressure ventilation because the difficult weaning in icu while twelve don't need any respiratory support. at the admission was performed a multidisciplinary plan and many specialists were involved (dietist,physiotherapist, pneumologist) and in invasively ventilated patients (ivp) was done a program of weaning. we follow all the patients until the discharge at home where someone need oxigenotheraphy, niv or mechanical ventilation. for the invasive ventilated patients we try to identificate significative differences beetween patients discharged at home and patients who died in hospital. data are given as mean ± sd and statistical analisis t test was performed results. patients underwent niv stay in hospital for . ± . days ( . ± . days in icu- . ± . in md) and ventilation was performed for the entire period in icu while for . ± . days in md. all the patients were discharged at home: twelve with niv, fourteen with oxygen. the lengh to stay in hospital for the ivp in wich weaning was failed in icu was . ± . days ( . ± . days in icu- . ± . in md). in md they continue the invasive ventilation for . ± . days. seven were weaned from ventilation after . ± . days, one was discharged at home with the ventilator while six died in hospital. patients who died were older ( . ± . vs. . ± . years-p . ), have more chronical diseases ( . ± . vs. . ± . -p . ), longer hospitalization ( . ± . vs. . ± . days-p . ), glascow coma scale ( . ± . vs. ). elderly patients often require a long period of recovery from acute ilness. in selected patients md could be a useful place where continue the treatment started in icu. in our study ivp who died had more chronical diseases and a more significative cognitive compromission. aim. documenting the qualitative and quantitative properties of administered and lost fluids is a common critical care monitoring practice. these nurse-registered fluid balances (fb) are used to optimize patient care and in clinical decision-making. this ''good clinical practice'' has also found application in research: recent studies reporting superior outcomes expressly refer to (negative) fb. we prospectively assessed the accuracy (review of all fluid balance charts and correction of arithmetic errors) and consistency (gold standard: body weight changes [bwc] registered with standardized measurements of body weight on admission and discharge [precision ± g]) of nurse-registered cumulative fb. total (tfb) and daily fb (dfb = total fb/los) were calculated. we analysed the unadjusted cumulative fb (unafb: without considering additional losses, i.e. perspiration/fever/liquid faeces) and the adjusted cumulative fb (adjfb: considering the above as proposed in the literature) in all patients (all) and in three subgroups (cardiaccerebral:card; septic:septic; others). exclusion criteria: lack of admission/discharge weight, incomplete fb data. we calculated l = kg. among patients admitted during the study period were eligible and analyzed. fb were inaccurate in cases ( %) (error range: - . to ? . l, mean arithmetic error ± sd: ? . ± . l, mean absolute error: . ± . l). the body weights at admission and discharge were . ± . kg and . ± . kg, with a bwc of . ± . kg ( . ± . kg per day). unatfb were . ± . l, unadfb . ± . l. adjtfb was . ± . l, adjdfb . ± . l. correlation (r ) and bland and altman was poor between bwc and unatfb ( . and - . ± . kg) and slightly better between bwc and adjtfb ( . and ? . ± . kg). the sd of the difference between bwc and fb per day of the icu stay was always [ kg. a multiple regression model including unatfb, duration of intubation, maximum temperature, estimation of liquid faeces, age and the calculated caloric deficit during the icu stay, only modestly improved correlation (r . ). compared to the two other groups, septic were significantly more severely ill, had a higher and longer fever, a longer los, larger bwc and cumulative fb, and presented larger differences between bwc and cumulative fb (poor correlation and bland and altman). though, consistency betwenn bwc and cumulative fb in card and other was still scarce. conversely, another multiple regression model (including only unatfb and the maximal temperature) in septic yielded an r of . . conclusion. fb are often inaccurate and they are not consistent with the gold standard of bwc. the correlation and the agreement with bwc of both adjtfb and unatfb are poor, with sd per icu day-stay[ kg or l. multiple regression models including several variables slightly improve correlation, yet remaining disappointing. consequently, clinical decisions should rather be based on other methods than fb. a prolonged hdu los was associated with a high sofa score for respiratory, hepatic and coagulation variables, preoperative ecg alterations, an increased urea and bmi and important bleeding. sofa score should be use in the first h to assess organ failure and a possible icu transfer for patients with an elevated score. evaluation of procalcitonin, neopterin, c-reactive protein, il- and il- as a diagnostic marker of infection in patients with febrile neutropenia financed by the following fellowships: rd / / from retics, fiss pi and fijc p-ef- reference(s). . bohoun c ( ) a brief history of procalcitonin biomarkers of sepsis: is procalcitonin ready for prime time? definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis procalcitonin assay in systemic inflammation, infection, and sepsis. clinical utility and limitations usefulness of procalcitonin for diagnosing complicating sepsis in patients with cardiogenic shock patients at our er, icu and wards of internal medicine and surgery meeting the ssc criteria were included. blood cultures were taken before administration of antibiotics, other cultures when appropriate. laboratory tests included wbc, crp, lactate, and pct. we categorized patients using bacteriological criteria group bacteriological proven infection (negative blood cultures but any other culture(s) positive) using chi square test there was no difference in survival, pct and findings on chest x-ray between the groups. with the mann whitney u test we found no differences in wbc, crp and lactate between survivors en nonsurvivors in a cohort of patients meeting the ssc criteria only % met bacteriological criteria for sepsis. wbc, crp, lactate and pct did not differ between patients with and without bacteriological proof of infection nor between survivors and non-survivors il rn and tnfr in the severity and outcome of community-acquired pneumonia to investigate whether polymorphisms within genes encoding for inflammatory or anti-inflammatory molecules are associated with susceptibility design. prospective observational, cohort study a cohort of , spanish caucasians with cap and subjects were genotyped for the following polymorphisms: tnfa - and - , lta ? sequential kaplan-meier survival analysis of tnfrsf b ? g/t polymorphism showed a protective role of the gt genotype. cox regression analysis adjusted for age, gender, hospital of origin and comorbidities showed that patients with gt genotypes had lower mortality rates compared with those patients with gg or tt genotypes (p = . our study does not support a role for the studied polymorphisms of the tnfa, lta, il and il rn genes in the susceptibility or outcome of cap. a protective role of heterozygousity for the functionally relevant tnfrsf b ? variability in genes involved in the inflammatory response in patients with community-acquired pneumonia to investigate whether polymorphisms within genes encoding for inflammatory or anti-inflammatory molecules are associated with susceptibility design. prospective observational, cohort study a cohort of , spanish caucasians with cap and , controlsinterventions: subjects were genotyped for the following polymorphisms: tnfa - and - , lta ? sequential kaplan-meier survival analysis of tnfrsf b ? tt versus gg/gt genotypes suggested a detrimental role of the tt genotype. longrank c tests at and days yielded p = . and . , respectively; cox regression for -and -day survival, adjusted for age, gender ghent university hospital, intensive care we aimed to describe the incidence and characteristics of healthcare-associated pneumonia (hcap) diagnosed at the emergency department of our university hospital compared to cap, hcap occurs in more debilitated or at-risk patients, is more frequently caused by nosocomial pathogens, and has worse outcome. nursing-home pneumonia is included within the definition of hcap but could have characteristics different from the other categories of hcap ) with a diagnosis of 'pneumonia'. episodes were categorized in cap and hcap according to the definition of the american thoracic society/infectious diseases society of america. within hcap, distinction was made between nursing-home pneumonia (nhp) and non-nhp hcap. severity of the pneumonia was assessed using curb- during the study period, episodes of pneumonia were diagnosed in patients; episodes ( %) were categorized as cap, and ( %) as hcap. within hcap, ( %), respectively ( %) episodes were further classified as respectively nhp and non-nhp hcap. median age of the patients was years ( - ) and % of patients were male median curb- pneumonia severity score in patients with cap and hcap was ( - ) and ( - ) respectively (p = . ); in nhp and non-nhp hcap, median curb in bivariate logistic regression analysis, both increasing curb- (or . , ci . - . ) and categorization as nhp (or . , ci . - half of the episodes of pneumonia diagnosed at our emergency department could be classified as hcap. severity of the pneumonia was higher in patients with hcap as compared to cap. categorization as nhp, but not as non-nhp hcap was independently associated with hospital mortality after adjustment for severity of the pneumonia medical intensive care unit community-acquired pneumonia (cap) is the leading cause of infectious death, severe sepsis and the seventh leading cause of overall death. severe cap (scap) is defined as need of aggresive intensive care unit (icu) management due to shock to describe the episodes of severe community-acquired pneumonia (scap) in a multicentric european study and to assess management practices and outcome of scap patients admitted to icu observational, prospective, multi-centre study conducted in icus of consecutive patients requiring invasive mechanical ventilation for an admission diagnosis of pneumonia or mv for [ h were recruited in each icu. statistic analysis was performed using spss years p \ . ) and presented a higher saps ii score at admission ( . sd . vs. . sd . p \ . ). patients were treated with monotherapy in . % and combination therapy . %. empirical antibiotic treatment was in accordance with idsa guidelines in ( . %) patients. combination was prescribed with macrolides in . % and quinolones in . %. in patients receiving combination therapy in accordance with idsa guidelines, a cox regression analysis adjusted by saps ii and age identified that macrolides use was associated with lower icu mortality when compared to the use of quinolones in patients with severe community acquired pneumonia who had therapy in accordance with the idsa guidelines, only combination therapy with macrolides was associated with better outcomes the eu-vap/cap project was endorsed by eccrn hospital de mataró, critical care, mataró, spain, hospital universitario germans trias i pujol, microbiology, badalona, spain, hospital de mataró, microbiology, mataró, spain, hospital universitario germans trias i pujol this leads to improved survival in a sterile acute lung injury model in wild-type mice, compared to mmp- knockout mice. we recently showed that mmp- deficient mice had better survival in a cecal ligation and puncture (clp) sepsis model than wild-type mice. in humans, functional genetic variations of the mmp- gene exist, but their relation to outcomes of severe infections, such as cap, is unknown. objectives. we hypothesized that functional human single nucleotide polymorphisms (snps) leading to increased mmp- levels are associated with worse survival and higher incidence of severe sepsis in patients with cap. methods. we examined data from genims, a multicenter prospective cohort study of patients with cap and analyzed potentially functional snps (rs , rs , rs ) in the mmp- gene in caucasians by polymerase chain reaction (pcr) the overall incidence of severe sepsis was . % (n = ), and . % of patients (n = ) died within days. the rs genotype distribution was significantly associated with -day mortality by armitage's trend test failure plot for rs conclusions. the non-synonymous rs snp is associated with -day survival in patients with cap. our findings suggests a trend towards a transcriptome analysis of ventilator associated pneumonia in trauma patients the sepsichip project the diagnosis of acute infection in the critically ill remains a challenge. transcriptional profiles (tp) of circulating leukocyte can be used to monitor the host response to infection. ventilator-associated pneumonia (vap) is a frequent complication of major trauma, raising morbidity and mortality data files were analyzed with r and bioconductor. unsupervised analysis was conducted using the dbf-mcl algorithm. supervised analysis was conducted using the significance analysis of microarray algorithm, using siggenes library. all statistical analysis used corrections for multiple comparisons. results. vap occurred in of the trauma patients ( . %). one hundred and fifteen samples were hybridized on husg k microarray ( sirs and sepsis samples for the patients who developed a vap, and sirs samples for those who did not). whereas clinical parameters (iss, chest trauma) discriminated trauma patients with or without vap, admission samples transcriptome analysis did not lead to the identification of prognostic markers. analysis of paired samples of the patients who developed a vap identified a transcriptional signature. these genes were involved in transcriptional regulation, cell survival, hemostasis and endocrine regulation. conclusions. by comparing whole blood admission samples, we were not able to identify transcriptional prognosis markers in trauma patients who did or did not develop vap. however, using vap as a model of sepsis in trauma patients, we identified a set of genes which may serve to diagnose vap in trauma patients to investigate the correlation between transfusion practice and the development of ventilator associated pneumonia (vap) in patients with traumatic brain injury (tbi) we analyzed which tbi individuals developed vap in regard to the transfusion practice and if the number of transfused prbcs increases the risk of pneumonia development. we counted the total amount of prbcs units received by each patient during icu stay, as well as those given before vap development. patient's data included: demographics, apache ii, iss, gcs, vap characteristics, duration of mechanical ventilation (mv), length of stay (los) and outcome. cpis and mods were calculated on the day of vap detection.statistical evaluation was performed using univariate and multivariate logistic regression, students t-test and pearson's chi square test %) tbi patients who developed vap received on average units of prbcs during icu stay, compared with non vap individuals who were transfused on average with two units of prbcs (p \ . ). vap patients received on average four units prbcs before vap development. after correcting for age, apache ii, gcs and iss, transfusion was independently associated with vap. the odds ratio for vap aspiration pneumonia (ap) in comatose patients (pts): clinical and microbiological findings ap is a common complication in comatose pts. we aimed to update data on their incidence standard guidelines were used for diagnosis and treatment of ap. daily chest x-ray were retrospectively reviewed. ap was diagnosed if pts met following criteria: persistent radiographic infiltrate within days following ti, and at least two of the following: purulent sputum, fever/hypothermia duration of mv was days ( - ) and length of stay in icu days ( - ) on the day of ap diagnosis, main pts characteristics were: saps ii %) received empirical antimicrobial therapy. main empirical antibiotics were coamoxiclav ( %) and third generation cephalosporin ( %) ) and mv duration ( vs. days, p \ . ), even considering only non-cardiac arrest pts. gcs h after ti and ap were associated with a [ days duration of mv in multivariate analysis ap was associated with higher overall -day mortality in univariate analysis ( vs. %, p = . ) but no longer in multivariate analysis mortality in the icu was . % with a corresponding hospital mortality of . %. a microbiological documentation was obtained in . % of the patients, with streptococus pneumonia being the most frequent ( % of the isolates). the cap was classified as localized in . %, unilateral mean (±sd) saps piro score was . ± . points, with a corresponding predicted mortality of . ± . % (standardized mortality ratio . ). the aroc was . ( . - . ). the value of the hosmer-lemeshow Ĉ test was saps piro presented a discrimination similar to the originally described. however, it significantly overestimated mortality sepsis mortality prediction based on predisposition, infection and response the piro-cap score was proposed earlier this year to stratify patients with severe community acquired pneumonia (cap) to evaluate piro-cap score in patients with severe cap, over a period of years we analysed data prospectively registered in an informatic data base, which contains information referring to all patients admitted in this unit survival curves were built as proposed by the original authors. outcome was evaluated at icu discharge overall, it was a severe population: . % of the patients presented at least one chronic disease, saps : . ± . points (predicted mortality . % ± . ), length of stay in the icu . ± . , icu mortality was . %. a microbiological documentation was obtained in . % of the patients, with s. pneumoniae being the most frequent ( % of the isolates). the cap was classified as localized in . %, unilateral icu mortality was piro-cap presented an excellent discrimination. however, mortality rates were greater than the ones described by the original authors in all groups (except group ), with the system significantly under-predicting mortality. consequently, we recommend caution in their widespread use. cumulative survival reference(s). clinical and biological assessments in icu patients delirium is a life-threatening, acute organ dysfunction with an incidence of % in uk mechanically haloperidol is recommended as treatment [ ] despite limited evidence base. objective. a national postal survey of consultant members of the uk intensive care society (ics) was performed to determine the current management of delirium in the ) drug treatment of hypoactive and hyperactive delirium as described by two clinical vignettes and ( ) level of agreement with five statements regarding delirium. results. six hundred and eighty one replies were received from , questionnaires senta response rate of %. twenty five percent of respondents routinely screen for delirium. only % use a validated screening tool, most ( %) of whom use the confusion assessment method, icu. hyperactive delirium is treated pharmacologically by %, the majority using haloperidol. hypoactive delirium is treated pharmacologically by %, with haloperidol again the most common treatment ( %) grant acknowledgement. intensive care foundation, intensive care society a practical algorithm to diagnose delirium in critical care-validity and reliability delirium occurs in up to % of critical care patients [ ], but often remains undiagnosed because standardized delirium monitoring is often dismissed as being too time-consuming or too complicated [ ]. the 'harvard flowsheet', derived from the 'confusion assessment method for intensive care unit' (cam-icu) [ ], provides a practical, algorithm-type handling advice to assess the four dsm-iv delirium criteria in a standardized fashion in intubated patients. it mostly allows for truncation of assessments to save time after approval from our institution's ethics committee, patients of a -bed surgical icu-department were screened in five sessions for delirium ( ) by a psychiatrist as the reference rater using the dsm-iv delirium criteria, and ( ) by two 'harvard flowsheet'-investigators, each unaware of other's ratings. motoric delirium subtypes were classified according to the richmond agitation sedation scale (rass) [ ], which was rated for the feature ('altered level of consciousness') of the 'harvard flowsheet'. patients were deemed as having hypoactive delirium if they were dsm positive by the reference rater and had rass - to , or having hyperactive delirium if their rass was between ? and ? . for interrater reliability the median time to complete the 'harvard flowsheet' in delirious patients was s (iqr, - s) vs. s ( - s)] in non-delirious patients. conclusions. the 'harvard flowsheet' has high sensitivity, high specificity and very high interrater reliability. false-negative ratings can occur infrequently and likely reflect the fluctuating course of delirium with intermittent lucid states a decrease of the overall cost of sedation and of sedation/day of mv followed protocol implementation and has been pursued each year: sedation cost which was greater than €/day in / has decreased to less than €/day in acute renal failure in critically ill patients: a multinational, multicenter study to evaluate current transfusion practice and the association between the age of red blood cells (rbcs) and outcome in critically ill patients design. prospective, multicenter observational study patients: critically ill adult patients receiving at least one unit of rbcs %)] revealed an unadjusted absolute reduction rate (arr) in mortality of % ( % ci - %). after adjustment for disease severity, patient age, other product transfusions, number of transfusions, pre-transfusion haemoglobin concentration, pre-icu transfusions, and cardiac surgery the odds ratio (or) for hospital mortality in critically ill patients in australia and new zealand transfusion of rbcs is delivered within current international recommendations. however, within such a practice patients enrolled included men and women, with mean age of ± years. there were ( %) liver transplantation, ( . %) renal transplantation and ( . %) pulmonary transplantation and ( . %) renal-pancreas transplantation. the days mortality for liver, renal, pulmonary and renal-pancreas was: ( . %), ( . %), ( . %) and ( . %). the mean saps score for liver, renal ic apache ii auc . % . - . , ic % . - . . conclusions. in these study, no differences were observed comparing saps and apache ii in the mortality prediction from liver, renal and pulmonary transplantation current opinion in critical care introduction of a rapid response team: why we are glad we met dew ma and members of the medical emergency response improvement team (merit) committee ( ) mature rapid response system and potentially avoidable cardiopulmonary arrest in hospital the effect of a rapid response team implementation in a private hospital adult patients often exhibit physiological deterioration hours before cardiopulmonary arrest to determine the effect of a rapid response team on the rate of in-hospital cardiac arrests, total and unplanned intensive care unit admissions, and icu and hospital mortality before and after implementation of a rapid response team standard criteria were used to activate the rrt and included acute changes in the patient's mental status, respiratory rate, heart rate, oxygenation, or blood pressure and hypoxia, chest pain, or worry from clinical staff. we measured: admitting diagnosis after rrt were a total the activations. the most common reasons for rrt activation were ventilator dysfunction ( %), cardiac changes ( %) and acute neurological changes ( %). % were transferred to icu and the main reasons were cardiac changes ( %), ventilatory dysfunction ( %) and acute neurological changes ( %) the rrt implementation was associated with decreases in rates of inhospital cardiac arrest, but was not associated with reductions in hospital or icu mortality the . lives campaign: setting a goal and a deadline for improving health care quality gender difference in critical care response team activations impact on outcome saudi arabia, king saud bin abdulaziz university for health sciences, riyadh, saudi arabia introduction. gender-related differences in outcome of ccrt intervention has been documented in the literature indicating that more men were admitted to the intensive care unit our center is the only center in the kingdome of saudi arabia which implements an intensivest-lead ccrt services h/ . the team is leaded by in house board certified in critical care medicine. ccrt services started in chest pain unit-viable option when risk of cardiac etiology is modest. multitudinous patient population brought together for structured survey and care at appropriate level what alters physicians' decisions to admit to the coronary care unit? m. camara , g. silva , s. silva , c. dias , j. nóbrega , e. maul hospital central do funchal, funchal, portugal introduction. procalcitonin (pct) and c reactive protein (crp) are markers of sepsis and the levels correlate with the severity of illness.aims. to evaluate the relationship of procalcitonin (pct) and c-reactive protein (crp) kinetics within the first days of sepsis with the appropriateness of antibiotic therapy and the outcome. a prospective cohort study, over months including patients with documented sepsis in our -bed intensive care unit. crp and pct were simultaneously measured four times (m -m ) during the first days of antimicrobial treatment. the pct and crp time course were analysed according to the appropriateness of the empirical antibiotic therapy as well as according to the patient outcome.results. between january and march of , patients were admitted to the icu. patients presented with sepsis on admission or during their stay. the most common infection site was the lung ( . %) followed by primary bacteraemia ( . %). gram-negative and gram-positive bacteria were isolated in the following proportion: . and . %, respectively. enterobacter, acinetobacter and escherichia were the most frequently isolated ( . % each). gram-positive sepsis was mainly caused by haemophylus influenzae ( . %). sepsis was polimicrobial in . % of cases. . % of the patients were given inappropriate antibiotics. the proportion of gram-negative bacteria isolated was significantly higher in patients who did not receive appropriate antibiotics. the magnitude of the pct and crp elevation was not associated with the appropriateness of antibiotic therapy. logistical regression analysis showed that infection without agent was an independent predictor of inappropriateness of antibiotic therapy.age, saps ii, apache ii and sofa were not associated with an unsuccessful treatment. regarding the absolute value of crp and pct there was no significant difference between successful or unsuccessful. multivariate analysis showed that dpct was not associated with antibiotic appropriateness and mortality.conclusions. although the sample is small, our study suggests that crp and pct kinetics are not associated with the appropriateness of antibiotic therapy and outcome. introduction. patients with hematological malignancy who need advanced life support in the icu because of a life-threatening complication may have a poor prognosis. that's why it is necessary to identify clinical, analytical and biological factors that can help doctors with the decision to admit these patients into the icu.objective. the aim of this study was to assess the utility of procalcitonin serum levels (pct) in predicting the outcome of patients with hematological malignancies admitted to the icu. a total of patients with hematological malignancy were admitted to the icu from january until march . epidemiological data were collected before admission, and patients were followed up clinically and analytically during icu stay. serum samples were collected from icu admission until a maximum period of days. pct values were measured by an immunofluorescent assay based on trace (time-resolved amplified cryptate emission) technology (kryptor pct, brahms ag, hennigsdorf, germany). mean age: (sd ); men/ women. among the patients included, hematological diseases were: non-hodgkin lymphoma ( patients), acute myeloblastic leukemia ( ), acute lymphoblastic leukemia ( ) , multiple myeloma ( ), chronic lymphoproliferative disorder ( ) , others ( ). twenty patients ( %) had previously received hematopoietic stem cell transplantation. thirty patients ( %) presented neutropenia at the moment of icu admission. the main causes for icu admission were respiratory failure in patients ( %) and septic shock in ( %). pct levels were not significantly higher in those patients that required mechanical ventilation. pct levels were significantly higher (p = , ) in those patients admitted because of septic shock. pct levels were lower in days , and in the patients who survived with respect to those who died: day : . ng/ml (sd . ) versus . (sd ); day : . (sd . ) versus . (sd . ) ; day : . (sd . ) versus . (sd . ). the differences were significant in days (p = . ) and (p = , ). there was a trend to have higher pct levels in those patients who had microbiologically documented infection respect to the rest; day : . ng/ml (sd . ) versus . (sd: . ); day : . (sd . ) versus . (sd . ) and day : . (sd . ) versus . (sd . ) .conclusions. serum pct levels are higher in patients with septic shock. serum pct measurement might be useful for predicting mortality in patients with hematological malignancy who require advanced life support. introduction. sepsis is a major cause of mortality in the intensive care unit (icu). efforts have been made to reduce the time needed to diagnose sepsis in order to reduce mortality from sepsis-related multiple organ dysfunction. procalcitonin (pct) has been reported elevated levels at the onset of bacterial infections and seemingly correlated to severity of infection. several clinical trials have detected a high pct level in patients with evidence of systemic bacterial infections, whereas relatively low pct levels occur in patients with only localized bacterial infections.objective. the aim of the present study was to assessed the ability of pct through sensitivity, specificity, positive and negative predictive value (ppv, npv) in patients with suspected sepsis, septic shock, inflammatory systemic response syndrome (sirs) and compared it with variables like crp, mortality, band%, renal failure, active cancer and an isolated bacterial cultures. finally we wanted to evaluate if exists a no infectious correlation in patients who received blood transfusions. we conducted an observational study including all patients admitted to the multidisciplinary icu of the abc medical center (tertiary reference hospital) to whom requested pct at admission in the suspect of sepsis and we followed their outcomes. total populations was patients (p). % were females and % were males. median age was years. of the total of pct sample % were positive and % were negative. the sensitivity and specificity in septic patients were and %. ppv and npv were and %, respectively. we did not found any statistical difference between positive value of pct and sepsis, septic shock, sirs, mortality, crp, band%, acute renal failure, acute lung injury, ards (acute respiratory distress syndrome), blood transfusions and active cancer. the mortality in the populations was %.conclusions. the pct has a wide range of diagnostic in the septic patients. in our study the rate of false positive was % and limited the use for sepsis diagnosis. we suggest that the better utility is for outcome biomarkers more than diagnosis biomarkers of sepsis. y. jin , c. guolong , iit study group of zhejiang province in china zhejiang hospital, hangzhou, china introduction. the use of intensive insulin therapy (iit) in severe sepsis and septic shock has been shown to decrease morbidity and mortality rates significantly when given to high risk surgical patients.objectives. the aim of this study was to assess the efficacy of iit in severe sepsis and septic shock patients in intensive care unit.methods. this is a muticentre, prospective, randomized and controlled study. we randomly assigned patients who admission to icu with severe sepsis or septic shock into three groups: a group (target range for blood glucose is - mg/dl); b group (target range for blood glucose is - mg/dl); c group (target range for blood glucose is - mg/dl as a control). primary end point ( -day mortality for any cause) and secondary end points (icu stay days, mv duration, apacheii scores and mods scores) were obtained serially for days and compared between the three groups. of the enrolled patients, were randomly assigned to group a and to group b and to group c; there were no significant differences between the groups with respect to base-line characteristics. -day mortality was percent in the group a and . percent in the group b assigned to iit, as compared with . percent in the group c assigned to conventional therapy (p = . ).during the interval from first hour to -day stay in icu, the patients assigned to group a and group b had a significantly lower apache ii scores( . ± . and . ± . vs. . ± . , p = . ) and mods scores( . ± . and . ± . vs. . ± . , p = . ) than those assigned to conventional therapy, there were no differences in icu stay days( . ± . , . ± . , . ± . , p = . )and mv duration( . ± . , . ± . , . ± . , p = . ) between the three groups. compared with the conventional therapy group, the group a had a higher rate of severe hypoglycemia [blood glucose level b mg/dl ( . mmol/l); . . vs. . %; p \ . ]. intensive insulin therapy provides significant benefits with respect to outcome and scores in patients with severe sepsis and septic shock in icu, on the other hand, intensive insulin therapy brings a higher rate of severe hypoglycemia. to determine the prognosis factors in elderly patients (c years) with severe sepsis admitted to an intensive care unit (icu).method. an observational, prospective and multicenter study was realized. it includes all the patients of the database edusepsis study (adults with severe sepsis admitted to spanish medical-surgical icus). the clinical and demographic characteristics of all patients including age, sex, origin of the infection, location of the patient at the moment of diagnosis of sepsis, apache ii modified score (apache ii score age excluded), number of organic failures, initial therapeutic strategy (measures of resucitación and measures of treatment), icu length of stay and hospital mortality were registered. the patient were classified in young cohort (\ years) and elderly cohort (c years). elderly cohort patients were also classified in young-old patients ( - years) and very-old patients (c years). descriptive comparative study of both cohorts was realized and multivariate logistic regression for the two subgroups of elderly patients was performed to study the risk factors of hospital mortality. a total of , patients wer enrolled ( . ± . years, apache ii modified score of . ± . , . ± . organic failures, hospital mortality . %). the elderly cohort (n = ; . %) presented a lower apache ii modified score ( . ± . vs. . ± . , p . ), higher abdominal infection as origin of the sepsis ( . vs. . %, p \ . ), higher nosocomial infection ( . vs. . %, p . ) and a lower application of measures at initial treatment ( . vs. . %, p . ) than the young cohort. there were not significant differences in the number of organic failures and days of stay in uci between both cohorts. the apache ii modified score (or . ; % ic . - . ; p \ . ), the nosocomial infection (or . ; % ic . - . ; p \ . ), the thrombocytopenia (or . ; % ic . - . ; p . ) and the acute renal failure (or . ; % ic . - . ; p . ) were associated independently to mortality in the subgroup of young-old patients. in the very-old patients only the apache ii modified score (or . ; % ic . - . ; p \ . ) was independently associated with higher mortality and in this population subgroup the application of measures of initial resuscitation was a protective factor (or . ; % ic . - . ; p . ).conclusions. the elderly patients (c years) admitted in the icu whith severe sepsis have higher mortality, more abdominal infections as origin of the sepsis and fewer application of measures of initial treatment than the young patients (\ years). nevertheless, in the subgroup of very-old patients (c years) the aggressive initial treatment decreases the mortality. objectives. the aims of this study were to determine the crude and related to bacteremia mortality rates in icu patients with bacteremia who receive appropriate empirical antibiotic therapy and to describe the factors associated to mortality in this appropriated treated patients material and methods. during a twelve years and a half period, from to , icu-patients with clinically significant bacteremia were prospectively evaluated. for purposes of this investigation, appropriate empirical antimicrobial treatment of a bloodstream infection (aeat) was defined as the microbiological documentation of infection that was effectively treated based on its antibiotic susceptibility at the time the causative microorganism were suspected. clinical and microbiological variables were recorded. logistic regression analysis was performed to determine the risk factors associated to global and associated to infection mortality. results. among icu-bacteremic patients, aeat was applied in patients ( . %). apache ii and sofa score were . ± . and . ± . , respectively and the incidence of septic shock was . % in this aeat patients. global and associated to infection mortality rates were . and . %, respectively in aeat patients. logistic regression analysis confirmed copd (or . ; % ci: . - . ) and age (or . ; % ci: . - ) as factors independently associated to global mortality and diabetes mellitus (or . ; % ci: . - . ) presentation as septic shock (or . ; % ci: . - . ) and serum levels of albumin (or . ; % ci: . - . ) as a protective factors for global mortality whereas factors as nosocomial origin (or . ; % ci: . - . ) and again serum levels of albumin (or . ; % ci: . - . ) were considered protective for related mortality to bacteremia conclusions. mortality rates remains excessively high in aeat bacteremic-icu patients. different factors were identified as predictive factors for global and associated to mortality in aeat patients. only serum levels of albumin seems to be an independent protective factor for both global and associated to infection mortalities. introduction. severe sepsis is hallmarked by organ hypoperfusion or dysfunction. the transition from severe sepsis to septic shock carries with it an increase not only in morbidity but also in mortality [ , ] . objectives. the aim of the study was to demonstrate the effect of shock at admission in sepsis comparing severe sepsis and septic shock admission diagnoses.methods. single center retrospective study in a bed mixed icu of a tertiary university hospital. during a -years period of study patients were unplanned admitted in the unit: the median was age of ( - ), the males were . % and the mean of sapsii was ± . we randomly select two groups: severe sepsis ( patients) or septic shock ( patients) at admission. statistical analysis of variables: v , mann-whitney test, unpaired t student test, cox regression. no statistical significant differences were found about age and sex between groups. about the origin of infection no statistical significant differences were found between groups, meanwhile the diagnosis respiratory infection appears to be more frequent in the severe sepsis group ( . vs. . %, p . ). the proportion of post-operative admissions (in surgical related conditions) was not different between groups. the sapss ii and sofa at h were higher in the septic shock group [ ( - ) vs. ( - ) , p \ . ]; ( - ) vs. ( ) ( ) ( ) ( ) ( ) , p \ , , respectively]. sofa at discharge appears to be higher in the shock septic group (excluding deaths) [ ( - ) vs. ( - ) (p . )]. the mortality and length of stay (excluding deaths) was higher in the shock septic [ . vs. . % (p \ . ); ( - ) vs. ( - ) (. ), respectively]. the ventilator associated pneumonia was not significantly different between groups. the probability of discharge, across an initial period of days, was lower in the septic shock group [hazard ratio . ( % ci: . - . )], mainly between the th and th days, as shown in the kaplan-meier plot (see graph ) .admission diagnosis: probability of discharge conclusions. septic shock at admission patients had a poorer outcome. the difference in the probability of discharge between groups was higher when mechanical ventilation related events are likely to occur [ , ] . we emphasize the importance of the institution of early goal-directed therapy in the wards and emergency departments prior to admission in an intensive care unit [ , ] .introduction. it is not clear whether patients with community acquired severe sepsis (cass) or hospital acquired severe sepsis (hass) have a same presentation. objectives. to evaluate the characteristics of a severe sepsis (ss) population admitted through the er (cass) and those coming from the ward (hass). all patients were treated by the same team of intensivists and er doctors in a shock room, so we could minimise the differences due to management. methods. all adult patients admitted to the medical icu were eligible if they met the criteria for ss. we collected demographic characteristics, apache ii and sofa score, comorbidities and immuno-compromised conditions. scvo or svo (if possible), lactate concentrations. the milestones of the surviving sepsis campaign (ssc) were measured regularly during the first h of treatment. the data collection went on in the icu stay too. treatment for septic shock was conformed to the recommendations of ssc. results. we enrolled pts with ss, including with cass and with hass. there was no difference in demographic features and comorbidities, including immuno-compromised conditions, haematological malignancy and chronic respiratory diseases .there were no significant differences in hemodynamic variables or indices of tissue perfusion like scvo (or svo ) and blood lactate levels, or in amounts of fluids infused or needs of vasopressor agents. the need for mechanical ventilation (mv) after the first has greater for hass than for cass patients, but during the icu stay the need for mv was the same for both groups; similarly, during the icu stay there was no difference in the need for extracorporeal renal support or need for adrenergic agents. at the beginning the scvo was around % for the entire population. after the first h both groups reached the target of %. at the admission % of patients had a scvo less than % ( . % for hass patients and . % for cass, without any difference between groups) and % of patients had a scvo higher than %. the mean svo for both groups was higher than % already at the beginning of the observational period. conclusion. only a half of pts with ss or sho had fever. the presence of fever is often associated with a positive microbiological diagnosis, but better prognosis. while hypothermia was often viewed in severe ill pts and was associated with a worse prognosis. to investigate the possible differences in characteristics and outcome between early and late-onset severe sepsis in surgical intensive care unit (icu) patients. we conducted a retrospective analysis of prospectively collected data from all adult patients ([ years) admitted to our -bed surgical icu between st march and th july .results. of , patients admitted to our icu during the study period, patients ( . %) had severe sepsis; ( . %) had early-onset and ( . %) late-onset severe sepsis. respiratory infections ( . vs. . %, p = . ) and infections of unknown origin ( . vs. . %, p = . ) were more frequently recorded in patients with late-onset than those with early-onset severe sepsis, whereas abdominal infections were more frequent in early-onset than in late-onset severe sepsis ( . vs. . %, p = . ). gram-positive infections were more frequent in late-onset than in early-onset severe sepsis ( . vs. . %, p = . ). the time of onset of severe sepsis was not independently associated with an increased risk of in-hospital death (early vs. late: or . % ci . - . , p = . ).conclusions. respiratory infections and infections of unknown origin were more frequently recorded in patients with late-onset than in those with early-onset severe sepsis, whereas abdominal infections were more frequent in early-onset than in late-onset severe sepsis. the time of onset of severe sepsis has no impact on mortality. objectives. to describe the causes, microbia spectrum, and prognosis of pregnancyassociated sepsis treated in icu in france along the last years. we conducted a retrospective study in a medico-surgical icu of beds in a non-teaching hospital in france where a high risk maternity unit was opened in . patients admitted between and for sepsis occurring during pregnancy or the post-partum period were included. the patients were excluded if the sepsis was due to a nosocomial icuacquired infection. charts were reviewed to collect data on sources of infection, microbia, maternal and fetal prognosis. data are shown as median (extremes) or percentage. data before and after were compared using non parametric tests.results. patients were admitted for pregnancy-associated sepsis ( % of total pregnancy-related icu admissions). included patients had the following characteristics on admission: age: ( - ) years, gravidity: ( - ) pregnancies, parity: ( - ) children, , . vasopressors, mechanical ventilation, and hemodialysis were required in respectively , , and % of cases.characteristics of infections are shown in table . microbiological data about bacterial infections, and specially infections of pelvic origin (chorioamniotitis, endometritis, septic thrombophlebitis), are shown in table .all urinary infections were due to e. coli. lung infections were most often documented clinically but not microbiologically.maternal mortality rate was % ( deaths before and deaths after ). for those infections that occurred in the pre-partum period, fetal mortality was %. after exclusion of fetal deaths that had occurred before icu admission, pregnancy was interrupted during icu stay in % of cases, resulting in fetal mortality of %.conclusions. despite of disappearance of post-abortum sepsis in france, sepsis remains a significant cause of icu admission during or after pregnancy, and a significant cause of maternal and fetal mortality.grant acknowledgement. none. introduction. the glasgow coma scale (gcs), universally used for assessing comatose states, has the advantage of ease of use making it accessible to all levels of clinical competence. there are, however, significant drawbacks. its relative subjectivity in the interpretation of verbal and eye responses and its mesencephalic limit in the rostro-caudal assessment of brain vitality. these two drawbacks limit its use particularly in icu intubated patients. we propose a new score, the sousse coma score (scs) that overcome the eye and verbal responses and explore the brain vitality up to brain death. the score ranges from (normal consciousness) to (brain death). the performance of this score was compared to a modified gcs (gcsm; gcs reduced to its only eye and motor components) and four score. our study interested prospective and consecutive comatose patients who were admitted to a medical icu, intubated and under ventilatory support. the level of consciousness was assessed at admission by physicians of different levels of competence. the inter-observer reliability was assessed by measuring the spearman correlation between the responses of different observers to the scs, gcsm, four score and their respective components. the prognostic predictive value of the three studied scores was assessed by the analysis of possible correlation with mortality and the roc curves. inter-observer reliability was excellent (spearman rho [ . ) for the three studied scores, but with better performance for the scs ( . , p \ . ) compared to the gcs ( . , p \ . ) and four ( . , p \ . ). the level of overall inter-observer reliability for gcs and four was paradoxically higher than that of their respective motor components. this is probably the result of a summation effect of their respective components.regarding the relationship between mortality and the studied coma scores, there was for all three scores a threshold below which mortality was %; / for scs, / for the gcs and / for the four. beyond this threshold, only the scs provides a highly significant correlation with the risk of death (spearman = - . , p = . ). a similar correlation was observed with the motor components of the gcs and four. a better correlation was found between mortality and the scs. the area under the roc curve, however, was poor for all three scores. in evaluating the minimally consciousness states and from eight value of scs, the gcs and four scores provided a wider and more subtle level of consciousness assessment. the scs provides a better inter-observer reliability and a better prediction of death while being easier to achieve. the apparently good inter-observer reliability of gcsm and four was simply the result of summation effect. however, scs was not very sensitive in detecting variations of the minimal consciousness states. the results of our study should be confirmed in larger multicenter studies for the external validation. introduction. the use of a sedation assessment scale and a sedation goal is recommended in critically ill adults [ ] . several studies have found a reduction of icu length of stay (los), of mechanical ventilation (mv) duration, and of cost [ , ] . but, durability and efficiency of such procedures over time have not been evaluated. a -bed medical icu in a university hospital. a sedation and analgesia protocol has been implemented since - . the sedation goal is prescribed each day by the intensivist; the ramsay sedation score is evaluated by the nurses every h and doses of drugs are adapted accordingly. we conducted an annual survey from to to evaluate the quantity of sedative drugs utilized, the impact on icu los and on mv duration, and cost of sedation; both the medical and nurse staff were regularly informed and the protocol was modified if necessary. u. guenther , j. weykam , u. andorfer , t. muders , h. wrigge , c. putensen university of bonn, anaesthesiology and intensive care, bonn, germany background. acute brain dysfunction (delirium and coma) is reported to occur in up to % [ ] , and to be associated with longer mechanical ventilation and stay in the icu, and increased -months mortality rates up to % [ ] . such outcome data, to the best of our knowledge, are predominantly given on medical patients with delirium incidences and mortalities much higher than we expected in surgical patients. this study assessed incidence and impact of acute brain dysfunction on length of stay on the ventilator and in the icu, and mortality in cardiac surgery patients. after approval from our local ethics committee, every patient admitted to our cardiac surgery -beds icu from october through november was daily monitored for delirium with the ''confusion assessment method for the intensive care unit (cam-icu)'' [ ] , level of consciousness was assessed with the richmond-agitation-sedation scale (rass) [ ] . acute brain dysfunction was diagnosed if patients were comatose without sedative medication or delirious. patients were contacted months later to obtain information about their further clinical course.results. patients were eligible for analysis [male , female , age, mean (iqr), ( - ) years]. % had acute brain dysfunction while in icu, these had significantly higher apache-scores on admission, higher tiss-and saps-scores, were longer mechanically ventilated [ ( - ) vs. ( - ) days, p \ . , mann-whitney test) and had longer stay in icu [ ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) vs. ( - ) days, p = . , mann-whitney test). patients were lost to follow-up; -months mortality in patients with acute brain dysfunction in icu was vs. % (p = . , log-rank test).discussion. incidence of acute brain dysfunction and mortality found here in cardiac surgery patients are lower compared to reports on medical patients. even though, duration of mechanical ventilation, length of stay in icu, and -months mortality were increased in patients with acute brain dysfunction in our icu.conclusion. these data emphasize the need for routinely monitoring of consciousness and delirium and to develop strategies to reduce incidence of acute brain dysfunction. introduction. the incidence of obesity is increasing globally, with billion overweight people (body mass index (bmi) [ kg/m ), and million of them obese [ ] (bmi [ kg/m ). the number of obese individuals presenting to critical care is likely to increase, but data on effect of obesity on outcome is conflicting [ ] . there is a general perception that obese patients are likely to have a higher incidence of adverse outcome in critical care. to investigate the effect of bmi on length of stay and mortality in patients admitted to critical care in city hospital, birmingham, uk.methods. an observational study was performed over a month period from february-april . pre-morbid data on bmi was collected from medical records and direct questioning of patients. apache ii score at h, critical care length of stay (los) and survival data to hospital discharge were collected. the figures were compared against their predicted mortality. readmissions, patients with a los \ h, patients \ years old and those without complete apache ii data were excluded. a total of patients were admitted. met the exclusion criteria, bmi data was unavailable for patients and apache data was unavailable for patients. patients were included in the final analysis. . % were female and . % were male. % of patients were above their ideal body weight, and % were obese. the obese cohort had a mean apache ii score of . with a mean los of . days and a mean hospital mortality rate of . %. the corresponding figures for the non-obese group (bmi \ ) was . , . days and . % (table ) . obese patients had reduced hospital mortality in comparison to predicted rates from apache ii scores. statistically, there was no increase in mortality of obese patients. the los and ventilated days were also comparable to the nonobese patients. introduction. managing glucose levels in critically ill hospitalised patients has been shown to play a role in improving clinical outcomes. as a result glycaemic control protocols are widely used in critical care settings and require rapid and frequent testing of patient glucose levels. poc glucose meters have migrated from ambulatory testing into hospital.there is increasing recognition that the clinical accuracy of nearly all commonly used glucose meters are affected by components or substances often present in the blood matrix of critical care patients giving rise to an increase risk of adverse incident. the aim of this study was to challenge the accuracy of a glucose meter designed to correct for these interferences.methods. paired random arterial whole blood samples were collected from icu patients admitted for [ h, samples were tested for glucose using stat strip glucose (nova biomedical) and the omni b bga (roche) routinely used for blood gas analysis.statistical methods: spearman rank correlation/regression, bland-altman analysis. results were compared to iso standard for glucose measurements. omni bga: correlation coefficient r = . , slope = . with intercept - . .bland altman plot for absolute glucose concentration showed that mean bias compared to reference was - . ± . mmol/l with limits of agreement - . - . mmol/l. study aim. to assess predictors of t and its impact on icu-, hospital-length of stay and costs in a cardiac surgical patient cohort admitted to our eight bedded icu, since through june .methods. all the pre-, intra-and post-operative variables were prospectively put into an electronic database. patients were divided into: ( ) ntg group, not needing a tracheostomy;( ) tg group, undergoing a tracheostomy. p values \ . were considered significant. out of a total of , patients with a median (iqr) age of years ( - ) ( ) from post-operative icu to the cardiac surgical ward and ( ) from the cardiac surgical ward to the rehabilitative one, increased significantly higher in the ntg group than in tg group (respectively: log-rank = . , p = . and log-rank = . , p = . ,). tg group showed a lower mortality ( . vs. . %, p = . ) than ntg one.conclusion. this study allowed us ( ) to define a predictive model for identifying patients that are likely to undergo a tracheostomy ( ) introduction. patients admitted to itu increasingly have significant medical comorbidities that require chronic therapy for adequate control . on admission to itu, acute medical problems take precedence and many long term medications, such as thyroxine, may be withheld or ceased. in chronic hypothroidism the patient is physiologically dependent upon ongoing administration of thyroxine. the optimal management of chronic medical conditions such as hypothyroidism within the itu may be essential to patient recovery and should be a quality assurance issue. to assess the prescription of thyroxine and the thyroid function in patients admitted to itu with previously diagnosed chronic hypothyroidism. a six year retrospective review of the electronic records of patients with hypothyroidism who were admitted to a bed tertiary referral hospital itu from to was performed. patients were included if they were admitted to the itu for a period of more than days and were on thyroid replacement therapy prior to itu admission. patient demographics, daily thyroid replacement dose/route, thyroid function tests (tsh and free t ) and rate and type of nutrition were obtained. patients were grouped by their worst recorded tsh according to predefined ranges . conclusions. patients did not receive their thyroid replacement for a significant proportion of their admission. this was predominantly due to either lack of prescription or lack of tolerance of enteral feed. the tsh was appropriate for the free t level. a significant proportion of patients ( %) did not have their tsh measured at all. of those that did, abnormal tests were inconsistently repeated or acted upon. having processes in place to ensure the appropriate prescription and adjustment of relevant chronic medications is essential in the provision of high quality care in itu.background. cell-free dna has been investigated as a diagnostic marker in many diseases, including acute conditions such as stroke, myocardial infarction, burns, sepsis etc. its serum and plasma levels have been shown to correlate with disease severity in all those. free circulating dna is released from dead cells (necrotic or apoptotic) and activated inflammatory cells. our hypothesis was that in acute pancreatitis free serum dna correlates with the extent of pancreatic necrosis and that it may be an early marker of severity. free dna was measured in sera from patients with acute pancreatitis at admission, on the first, fourth and seventh day following admission. severetiy of illness was assessed with atlanta criteria. on the first day following admission patients who would develop severe pancreatitis had significantly higher serum dna levels than those with mild disease (median . vs. . ng/ml respectively; p \ . ). this parameter showed very good characteristics as a potential predictor (area under roc curve . ). free serum dna was in correlation with the extent of pancreatic necrosis.conclusions. free serum dna correlates with the extent of pancreatic necrosis and is a potential early marker of severe acute pancreatitis.keywords. acute pancreatitis, cell-free dna, prognostic marker, pancreatic necrosis. introduction. the performance of general prognostic models in patients with transplantation in need for intensive care unit (icu) admission is poor, showing a tendency towards significant underestimation of the risk of dying. the objective of our study is to evaluate the acute physiology and chronic health score ii (apache ii) and simplified acute physiology score (saps ) and their days mortality prediction after liver, renal and pulmonary transplantation [ ] [ ] [ ] .methods. this is a prospective cohort study in a transplantation icu in porto alegre, brazil, during the period of may -december . clinical data of pos transplantation patients admitted at icu were collected at admission and saps and apache ii calculated with respective estimated mortality rates. the area under receiver operating characteristic curve (auroc) was obtained for both scores. objectives. to validate the saps model, over a period of one year, in a general icu. material and methods. we analysed data prospectively registered in an informatic data base (icdoc), which contain information referring to all patients admitted in this unit.we studied all the patients admitted in the year ( patients). excluded from the analysis were readmissions and one patient still in the hospital. analysed patients.results. discrimination was accessed by the area under the roc curve (aroc) and calibration by the hosmer-lemeshow ĉ test for the general equation and for regional equations (southern europe and mediterranean countries).the mean age of the patients was . ± . years. from the total of the patients, were medical ( . %), were scheduled surgical ( . %) and were emergency surgical ( . %). the mean icu and hospital mortality was . and . %. the mean saps score was . points ( - ). discrimination was good with an aroc of . ( . - . ).there was a statistical significant difference between the mortality predicted by the general equation and the observed mortality (ĉ = . ; p = . ); this discrepancy was not significant by using the regional equation (ĉ = . and p = . ). the saps overestimated hospital mortality with the predicted mortality by the regional equation getting closer to the observed mortality [standardized mortality ratio (smr) = . ] than the predicted by the general equation (smr = . ).conclusion. the saps model, particularly using the regional equation introduction. saps has been previously validated in our icu and it has been routinely used in hospital mortality prediction. as we have shown before, saps had a good accuracy regarding discrimination and calibration, with better predictions done by north american and western europe customized equations than the south american one [ ] . in a larger sample we have been observed deterioration in calibration model, especially among groups of lower probability of death, regardless of the equation in use. therefore we tested saps accuracy considering days mortality in comparison to hospital mortality. we considered consecutive admissions in a medical-surgical icu in a private tertiary hospital in sao paulo -brazil, in the period from january to november of . probability of death was derived from given equations of the original study [ ] . hospital and days mortality were considered as end point. discrimination was performed by the area under the roc curve (auroc) and calibration by the hosmer-lemeshow (hl) statistic. observed to expected (o/e) mortality ratio was also calculated. to assess factors concerning prognosis of patients older than years admitted to the icu: group a, to years old and group b, older than years. both groups were compared for the apache ii, admission group, lenght of stay, mortality and usual intensive care procedures (arterial and venous catheters, mechanical ventilation). statistical anlysis: quantitaive variables were expressed as mean and standard deviation (sd). student t test was employed for these variables. categorical variables were compared by the chi-square. p \ . was considered statistically significant. a total of patients were included in group a (mean age . , sd . ) and in group b (mean age . , sd . ). apache ii score was . for group a and . for group b (p = , ); predicted mortality was . and . % respectively (p = . ). ther were no differences for admission group or procedures among groups. mortality was significantly higher in group b ( . vs. . %, p = . ). when mortality was analyzed for admission groups, it was higher just in cardiological group, wich included ischemic cardiopathy, cardiac failure and arrhythmia ( . vs. . %, p \ . ). the investigation of the association between a differential access to intensive care services and patient or hospital outcomes is increasing markedly [ ] [ ] [ ] [ ] . objectives. the aim of this study was to compare demographic, clinical characteristics, and outcomes of patients admitted to tertiary-level intensive care units from a tertiary hospital ward (intrahospital transfer) to patients transferred from a secondary hospital ward (interhospital transfer). single centre retrospective study in a bed mixed icu of a tertiary university hospital. during the study period ( ) ( ) conclusions. the interhospital transferred patients are younger, but at admission severity of the disease is comparable.these findings, within this case mix of patients, suggest there are not significant differences in mortality, length of stay, icu-nosocomial respiratory infection or physiological disability at discharge between intrahospital and interhospital transferred patients to our unit. in this study we did not find a different impact in outcome considering these differential sources of admission. we prospectively analysed data of all patients (pts) undergoing cardiac surgery between january and june , and discharged from our icu by h from surgery. on all patients the following was collected:(i) demographics, risk factors and gravity scores anamnestic illnesses (ii) intra-operative variables [i.e. type of operation, cardiopulmonary by-pass (cpb) and aortic cross clamp (acc) times] (iii) icu-related variables. one-way anova test was used for continuous variables whereas, differences in proportions were compared using chi-squared test.a binary logistic regression model was used to estimate the effect of each considered risk factor on discharging from cardiac surgical to rehabilitative ward, considered as a dycotomous outcome (yes = early b days/no = late [ days). statistic analyses were performed using spss software. p values less than . were considered significant. on all the patients, aged c years, admitted to our post-operative icu since january through december , we collected demographic profiles, operative data and outcomes. a logistic regression model was set up to assess predictors of hospital outcome. a total of patients ( . %), . % males and with a median (iqr) age of ( - ) were admitted. the below table shows the outcome predictors (see table ). objectives. the purpose of this study was to evaluate prospectively in our medium the capacity of apache iii score to stratify prognostically critically-ill-patients upon their admission to the icu, not only with regard to hospital mortality, but also to hospital length of stay. study aim. to assess if cardiopulmonary by-pass (cpb), aortic cross clamp (acc) time and duration of mechanical ventilation (mv) may impact on icu and hospital length of stay in a cardiac surgical patient cohort admitted to our bedded icu, since through june . all the patient pre-, intra-and post-operative variable were prospectively put into an electronic database. on all patients the following was collected:(i) demographics, risk factors and gravity scores anamnestic illnesses (ii) intra-operative variables [i.e. type of operation, (cpb) and (acc) times] (iii) icu-related variables (i.e. duration of mechanical ventilation, use and type of inotropes. statistic analyses were performed using spss software. p values \ . were considered statistically significant. a total of , patients with a median (iqr) age of years ( - ) were admitted through the study period. . % underwent a cabg operation, whereas . % valve surgery and . % aortic and lung surgery. a bivariate analysis was performed considering as independents variables respectively the natural logarytm (nl) of ( ) cpb time, ( ) acc time, ( ) mv duration, whereas dependent variable was considered the nl of the total hospital stay. we showed that a linear correlation exists between total hospital stay (ln) and ( ) conclusion. this audit allowed us to assess that the longer is the cpb and acc time and mv duration the longer is likely to be the total hospital length of stay of the patients undergoing heart surgery. introduction. high-dependency units (hdu) were designed as a bridge between the operating theatre and the surgical ward for postoperative patients demanding a higher than standard level of care. the aim of our study was to determine the risk factors as well as the predictive value of four severity scores for a prolonged hdu length of stay (los). three hundred fifty-eight consecutive adult patients were included in the study for a period of months. asa, saps ii, possum and sofa scores were calculated for the first h following admission. the demographic and the scores variables were subjected to a univariate and, consecutively, a multivariate logistic regression analysis. a receiver operating curve (roc) model was used to determine the predictive value of the scores for a prolonged los. the presence of a patient for three or more days in the hdu was defined as prolonged stay.results. the median los was ( - ) days, patients were transferred to the intensive care unit and the in-hospital mortality was . % ( patients). the univariate logistic regression revealed the following variables as significant for a prolonged los (p \ . ): asa, possum preoperative, possum postoperative, possum total, possum cardiac, possum ecg, possum type of surgery, possum blood loss, sofa, sofa respiratory, sofa cardiovascular, sofa liver, sofa coagulation, igs ii, igs respiratory, igs urinary output, igs urea, igs potassium, igs bicarbonate, and bmi. seven variables were identified as having a statistically significant association with the los (table ) . according to the roc model, sofa score was the best predictor for a prolonged los, with an area under the roc (auroc) of . .warning systems and rapid response team: - s. saxena , s. jafrey , j. zwaal kingston hospital, anaesthetics, kingston, uk, kingston hospital, kingston, uk background. published data suggests that the patient group with the highest mortality in icus comprises those patients admitted from the hospital wards [ ] . studies have shown that in-hospital cardiac arrests are commonly preceded by physiological abnormalities [ ] . if admission to icu, is preceded by specific physiological derangement, then early identification of these high risk hospital in-patients may be possible. this may improve survival of patients. objectives. to determine . the effectiveness of new track and trigger pathway in identifying patients requiring icu admissions. . the impact of new system on outcome of icu admissions method. . retrospective case notes survey of all icu admissions from the ward over a month period. . the pathway is triggered when abnormalities are present in two or more of the following parameters: response to painful stimuli, respiratory rate, oxygen saturation, systolic blood pressure, and heart rate. . .triggering steps progress through involvement of junior medical staff and outreach teams at step , to more senior staff at step , to consultant involvement at step , depending on the level of deterioration of the patient. . forms were collected over a period of months. icu mortality: patients with abnormality at any time prior to icu admission: / ( %) icu mortality: patients with c abnormalities any time prior to icu admission: / ( . %) mortality of patients who were pathway followers: / ( %) mortality of patients who were pathway non-followers: / ( . %) average length of stay in icu who were survivors from pathway followers: days average length of stay in icu who were survivors from pathway non-followers: . days discussion. . there was low sensitivity of pathway for identifying icu admissions. . poor documentation of triggering events . pathway followed inadequately in majority of patients due to combinations of delay in, or absence, of triggering when indicated . lack of consultant involvement at step . no patients with chronic kidney disease admitted to intensive care have poor outcomes [ , ] . in % of cardiac arrest calls in our hospital were from the renal unit (personal communication.) at this time critical care outreach teams were recommended as means of improving intensive care outcomes through earlier ward assessment of critically ill patients [ ] [ ] [ ] . in modified early warning system (mews) charts to wards and a dedicated seven-day ward-based consultant led service ( - ) were introduced on our renal unit [ , ] . aims and methods. the impact of these change interventions was analysed. primary outcomes were the incidence of cardiac arrests calls to the renal unit, admission apache ii scores and icu mortality. secondary outcomes were age, sex, intensive care and hospital length of stay, in-hospital mortality, cpr prior to icu admission and emergency admissions to the renal unit. cardiac arrests, mortality rates and emergency admissions were compared with the v test; other outcomes via mann-whitney u test. a p value \ . was regarded as significant.results. the results are outlined in the table [ ] ; this group has a high mortality [ ] . deterioration in vital signs often precedes referral to critical care and this is evidenced by a rise in the patient at risk score (pars). higher pars may be associated with worse patient outcomes [ ] . most pars systems have a trigger value at which critical care input should be sought. we hypothesised that the duration of physiological deterioration prior to critical care admission would be associated with mortality and used the delay between pars trigger and admission as an estimate of this.methods. we collected data on over consecutive patients that had deteriorated on the ward and required admission to general critical care (hdu and icu) at both acute hospitals in sheffield. patients admitted to specialist facilities such as cardiac and neurosurgical units were excluded. those already triggering at time of hospital admission were also excluded. to assess if any of the ccrt activation criteria was associated with higher incidence of icu or hospital mortality. our hospital is bed tertiary care center. cohort analysis of prospectively collected data of each ccrt activation including demographic data of the patients and their outcome in terms of icu and hospital mortality and ccrt activation criteria. ccrt activation from st january to th september .the activation criteria for ccrt includes: threatened airway,tachypnea defined as respiratory rate more than or less than breath/min, hypoxemia defined as oxygen saturation less than % on oxygen flow l/min, arrhythmias defined as heart rate less than or more than beat per minute, hemodynamic instability if systolic blood pressure less than mmhg or more than mmhg, decrease level of consciousness defined as drop of gcs = or more points from baseline, seizure and serious concern about the patient.we analyzed each factor separately as independent predictor of icu and hospital mortality. [ ] . with this in mind efforts have been made to develop physiological early warning scoring systems which have been shown to predict subsequent outcome [ ] . we have recently introduced an early warning system (ews) chart for all patients in our hospital and we wanted to assess its impact on our icu admissions. to assess the calculation of the ews, the scores of patients admitted to icu and the compliance with guidelines regarding further intervention for patients who were ultimately admitted to icu.methods. chart review of twenty five consecutive emergency icu admissions, examining the ews in the h prior to admsission.results. ews charts were completed for % of emergency icu admissions; of these % of scores were calculated correctly. only % of ews had all parameters completed for all set of observations. the mean peak ews prior to icu admission was . with a range from to . higher peak ews was strongly associated with increased icu mortality: a ews of - was associated with mortality of . %, whereas a ews of - was associated with a mortality of % (see below). for each ews recorded specific action was required to be triggered according to the protocol. in % of cases appropriate action was taken, however, in % the required action was not taken and a number of patients were thought to have delayed referral to critical care as a result of this.conclusions. following this audit we have introduced a critical care outreach team and have embarked on an educational programme for staff with emphasis both on the complete and accurate recording of early warning scores and the necessity for appropriate action to be taken on the basis of these scores. aim. the quality of care prior to icu admission has been a focus of attention [ ] . mews had been chosen by the trust as a trigger device to identify deteriorating (sick) patients in the general wards. this retrospective study looked at the clinical characteristics of unplanned admissions to our icu and assessed the mews as a predictive tool to trigger early intervention in such cases.methodology. all patients who were non-electively admitted to our icu from the medical wards were included in the study (january-march [ ] score and standardised mortality ratio(smr) had occurred since the introduction of our nurse lead outreach serrvice and high dependency unit. this seemed counterintuitive so we decided to look at in futher detail and whether the phenomena of lead time bias occurred.objectives. primary end point was to assess if the apache ii scores and smr were different if assessed from the point of contact with outreach or hdu for patients admiitted to general intensive care. secondary endpoints looked at which physiological scores were most altered by these systems. a cohort prospective study was setup with ethics committee approval. all patients seen by outreach (group ) or on hdu (group ) prior to admission to general icu were included over a six month period. two sets of apache ii scores and mortality prediction were generated for each group, a 'pre' and 'post' score. the pre score was a h scoring period started from up to h prior to admission to icu on point of contact on hdu or by outreach. the post score was a period for scoring taken h from the point of admission to icu, ie the conventional apache ii score .therefore each patient had two sets of scores for apache ii and predicted mortality. the apache ii and predicted mortality scores were then compared using a two tail paired t test, the individual physiology scores were compared via a wilcoxon rank sum score. in total patients from hdu were included and patients from outreach were included.the primary question was answered as a significant difference in apache ii and smr was found in both groups. introduction. unplanned admissions to intensive care units (icu) are associated with an increased mortality. in order to identify in-hospital patients at risk of deterioration, several scores based on physiological parameters have been published. however, routine application of these parameters is not common in all european hospitals yet. the goal of this prospective study was to evaluate the efficiency of the current practice of handing over ward patients at risk for decompensation by physicians and nurses. furthermore, factors associated with admission to the icu or alarming of the physician on duty should be identified. the study was conducted at the university hospital of regensburg, germany on wards with predominantly gastroenterological and general medical patients ( beds). over a time period of months, the daily routine report of patients at risk to the physician on call after hours was recorded. in addition, the nurse assessment of patients at risk and the documentation of the decompensation defined by calling the physician on duty during the night were registered.results. patients were treated during the surveillance period. in total, patients ( women, men) with a mean age of ± years were either judged by the attending physicians or the nurses at risk for deterioration. patients suffered from decompensation during the night shift. of those, patients were correctly identified by physicians and patients by nurses, respectively. in patients ( %), an icu admission was necessary.discussion. only a small portion of patients reported at risk experienced a severe decompensation at night, defined as icu admission. interestingly, those were only in part correctly identified by the physician and nurse reports. a further evaluation of the correlation of those reports with the previously published ''early warning score'', and physiological parameters associated with decompensation are currently being performed in order to estimate the value of standardized patient assessment, and will be presented at the meeting. introduction. the need to implement a patient follow-up program after icu discharge arises from several facts: ( ) at icu discharge patients are now more fragile (aged, chronic comorbidities, complex). ( ) the demand for intensive care exceeds its availability. as much as % of patients die after discharge from the icu, many of them in spite of a low predicted mortality, perhaps due to premature icu discharge. ( ) compared to nursing care in the icu, the level of that received upon transfer to the floor, as measured by tiss- , may be reduced up to more than %. we believe that, in order to change icu behavior towards focus on long term outcomes, we need to increase global awareness of disability post-icu discharges, and expand the involvement of the icu team in key decision management outside the icu. we propose an alternative model of care for the critically ill patient. this involves an expanded role for clinicians with expertise in critical illness at several points along the continuum of care.objectives. due to lack of adequate clinical resources to care for some recoverable patients when are discharged to hospital wards after a long time in icu, we have planned a follow-up program focused in detecting risk factors associated to bad prognosis and, decreasing adverse events in general hospital wards. qualitative, prospective and interventional study realised during seven months (from march to september ), in the medical uci of a teaching hospital in malaga. we determined demographic data, icu admission reason, comorbidity index (charlson scale), follow-up reason (polineuropathy, tracheostomy, analgesia), family support in ward, difference in nursing activities score between icu and ward (tiss- ), intervention done out of icu with patient; satisfaction of patient, icu readmissions, reason to end follow-up and mortality at day after icu discharge. we enrolled patients in this analysis. comorbidity was charlson scale (very high) in . % of patients, apache-ii mean score points and mean expected mortality rate %. more than % of patients had five or more risk factors (age [ years, icu stay [ days, transfusions, inotropic drugs, mechanical ventilation, tracheostomy, kidney failure, parenteral nutrition, polineuropathy). nursing activities score in icu was . before discharge versus . in ward ( . % decreasement). mean follow-up were . (range - ).in hospital mortality rate was . %, rest of the patients were discharged at home. our study found the implementation of continue follow-up program from icu staff is associated with an important decreased of the mortality. encouraging clinical results and a non excesive workload for icu staff justify to continue this follow-up program in cases in which is going to be an important decrease in nursing care after icu discharge, and have bad prognosis risk factors. objectives. we examined the prevalence of adverse events (ae), suboptimal assessments of vital signs and whether there were advance directives prior to icu admission from the general wards among patients who died within days of icu admission. the patients were those admitted to the general icu from the general wards at the university hospital, lund in and who died within days after icu admission. there were patients with a mean age of years and a mean apache ii score of . we used the global trigger tool model for measuring ae (http://www.ihi.org). the frequency of vital functions assessments, and which parameters were controlled were studied in relation to patient status and the local routine for frequency of modified early warning scoring (mews).the patient records were also controlled for descisions to forgo treatment before admission to the icu. . patients ( %) suffered from at least one ae prior to icu admission. patients had an ae contributing to death, among those patients suffered from an ae that with a probability greater than % was deemed avoidable. seven of those patients suffered from a most likely avoidable ae contributing to death.vital signs were recorded inadequately in % of the patients in the h before admission to the icu. the vital signs most often recorded were blood pressure, heart rate and oxygen saturation, whereas consciousness and breathing frequency were the least recorded parameters.descisions to forgo resuscitation, or some other limitations due to ethical considerations were found only in % of the patients before admission to the icu.conclusions. patients admitted to the icu who died within days suffer from a considerable proportion of avoidable ae contributing to death. vital signs are not recorded in a satisfactory way during the h before admission to the icu in this most severely ill population. there are very rarely documented descisions to forgo treatment in this group of patients before icu admission. thus, poor control of vital signs in the general wards leads to severe and avoidable ae contributing to death. the lack of descisions to forgo treatment before icu admission in this group of patients most probably contributes to prolonged dying and suffering, and unnecessary intensive care. results. a significant correlation (p \ . ) was detected between the type of prehospital care and the early outcome among the patients. the majority of the patients was transported by ambulance services ( . %) from which half of the patients ( . % of the total) were seen by a paramedic and the rest by a physician beforehand. a relevant proportion of the patients visited the cpu without having been seen by medical personnel ( . %) before. a smaller group of patients was referred by an attending hospital physician to the cpu ( . %). . % of all patients were admitted to a cardiologic ward, . % to icu and . % underwent immediate cardiac catheterization. the rest was referred to other departments within the hospital, other hospitals or was discharged and no one died within h after admission to the cpu. almost half of the patients ( . %) who underwent immediate cardiac catheterization was transported by emergency physician car whereas half of the rest ( . %) visited the cpu as out-patient (p = . ). this very similar ratio can be seen within the patient admitted to icu ( . %). conclusion. the detection of the early symptoms of chest pain is an important prevention strategy for lay people because they can immediately turn to a chest pain unit ( . %) where almost half of them might have life threatening situation ( . %) requiring acute intervention (cardiac catherization or icu-treatment). the adequate in-time treatment can reduce the length of hospitalization and secure quicker recovery. key: cord- -g qaoub authors: lohan, rahul title: imaging of icu patients date: - - journal: thoracic imaging doi: . / - - - - _ sha: doc_id: cord_uid: g qaoub imaging in intensive care unit (icu) is integral to patient management. the portable chest radiograph is the most commonly requested imaging examination in icu, and, despite its limitations, it significantly contributes to the decision-making process. multidetector ct (mdct) is reserved for relatively complex and challenging clinical scenarios. bedside ultrasound is emerging as a promising imaging modality as it does not subject the patients to risks and resources involved in the transportation of these patients to the ct facility. ultrasound is an effective modality to triage patients and is being increasingly incorporated into the emergency and intensive care management algorithms. imaging in intensive care unit (icu) is integral to patient management. the portable chest radiograph is the most commonly requested imaging examination in icu, and, despite its limitations, it significantly contributes to the decisionmaking process. multidetector ct (mdct) is reserved for relatively complex and challenging clinical scenarios. bedside ultrasound is emerging as a promising imaging modality as it does not subject the patients to risks and resources involved in the transportation of these patients to the ct facility. ultrasound is an effective modality to triage patients and is being increasingly incorporated into the emergency and intensive care management algorithms. the commonly encountered disease states in icu setting are pulmonary parenchymal diseases, pulmonary thromboembolism, barotrauma, and pleural fluid. besides the evaluation of these conditions, imaging is routinely used for the assessment of various catheters and tubes commonly used in icus. the common pulmonary parenchymal disease processes in icu patients include hydrostatic pulmonary edema, acute respiratory distress syndrome (ards), atelectasis, pneumonia, aspiration, and pulmonary hemorrhage. pulmonary edema is an abnormal accumulation of fluid in the extravascular compartment of the lungs. the fluid accumulation depends on the capillary permeability and the oncotic pressure, as described by the starling equation, i.e., q = k (hpiv − hpev) − t(opiv − opev), where q represents the amount of fluid filtered and hp and op denote the hydrostatic and oncotic pressures of the intravascular (iv) and extravascular (ev) compartments. k represents the conductance of the capillary wall, determined by the resistance offered to the water flow by the capillary endothelial cell junctions [ ] . t represents the permeability of the capillary membranes to the macromolecules. lymphatic drainage is another pathway for handling excess water in the lungs. however, the lymphatic drainage needs time to be effective, and in the acute situation, it often fails to eliminate the excess fluid [ ] . classically grouped into cardiogenic and non-cardiogenic variants, the pulmonary edema can be divided into the following four types based on the pathophysiology [ ] ( almost all pulmonary edema presentations in critical care units are due to increased hydrostatic pressure or increased permeability with dad. the two common pathophysiological forms are further discussed. the two most common causes of increased hydrostatic pressure edema (hpe) in critical care units are left heart failure and fluid overload. besides renal and liver failure, overzealous hydration in settings of trauma and immediate postoperative care frequently contibutes to fluid overload. there are two distinct radiological phases of the pressure edema-the interstitial edema and the alveolar edema. the radiographic findings in the early interstitial phase include indistinctness of the intrapulmonary vasculature, peribronchial cuffing, and kerley lines. indistinctness of pulmonary vasculature is subtle but often the most useful radiographic sign of early interstitial edema in icu patients. with increasing intensity and duration of pressure gradient, edema extends into the alveolar spaces, resulting in nodular or acinar areas of increased opacity that coalesce into frank consolidation ( fig. . ). there is a good correlation between the increased pressure in the intravascular compartment as measured by the pulmonary capillary wedge pressure (pcwp) and radiographic appearances (table . ) [ ] . the vascular pedicle width is measured from the svc and azygos vein complex on the right to proximal descending thoracic aorta on the left. it can provide a reasonable estimate of intravascular volume status. increased width of vascular pedicle (> cm) thus may help in differentiating hydrostatic pulmonary edema from non-cardiogenic edema ( fig. . ) . the ct findings of hydrostatic pulmonary edema include smooth interlobular septal thickening, ground-glass opacities, consolidation, and pleural effusions ( fig. . ) . the distribution of densities often demonstrates gravity-based gradient, with abnormalities being most notable at the lung bases. atypical distribution or appearances similar to aspiration pneumonitis or pneumonia may be seen in presence of underlying chronic pulmonary disease, such as emphysema [ ] . acute respiratory distress syndrome (ards) represents the most severe form of permeability edema associated with dad [ , ] . in icu settings, the common primary pulmonary pathologies causing ards are pneumonia, aspiration, and pulmonary contusions. the common extrathoracic causes include drug toxicity, systemic inflammatory response syndrome, sepsis, shock, and abdominal trauma [ ] . clinically, ards is defined by recently created "berlin defi- (table . ) [ ] . ards involves three often overlapping and conflicting stages. the first or exudative stage is characterized by a rapidly progressing high protein content interstitial edema that quickly fills the alveoli and is associated with hemorrhage and hyaline membrane formation. the second or proliferative stage involves organization of the fibrinous exudate, regeneration of the alveolar lining, and thickening of the alveolar septa. the third or fibrotic stage manifests as varying degrees of scarring and formation of subpleural and intrapulmonary cysts. the radiographic findings in exudative phase are that of interstitial edema pattern, rapidly progressing to perihilar opacities and subsequently widespread alveolar consolidation ( fig. . ). in comparison to hydrostatic edema, . this gravitational distribution can be changed by patient's position (supine vs prone), suggesting a significant contribution from atelectasis [ ] . the atypical pattern comprises of dense consolidation in anterior (in supine position) nondependent locations. this may be seen in up to % of ards patients and is more common in ards with underlying primary pulmonary cause [ ] . "crazy paving," i.e., ground-glass opacities with superimposed inter-and intralobular septal thickening, may be seen [ ] . during the fibroproliferative stage, patchy heterogeneous areas of ground-glass opacification are seen with reticular changes. traction bronchiectasis and bronchiolectasis may be seen on ct. these findings early in the course of ards are associated with a poorer clinical outcome [ ] . subpleural and intrapulmonary cystic lesions may be observed in the fibrotic stage which can directly result in pneumothoraces [ ] . recurrent episodes of exudative phase in the proliferative and fibrotic stages often result in mixed radiologic findings. hrct of the patients recovered from ards on subsequent follow-up shows characteristic anterior lung fibrotic bands with sparing of posterior lungs. distinguishing imaging features between hpe and ards are described in table . . atelectasis, defined as a decrease in lung volume, is the commonest cause of radiographic parenchymal opacities in icu patients, particularly amongst the postoperative surgical icu patients. the atelectasis most commonly involves the left lower lobe ( %), followed by the right lower lobe ( %) and right a b to symmetrical central ground-glass opacities and bilateral pleural effusions at a later stage. note there is a gravity-based gradient of increasing density in the lungs upper lobe ( %) [ ] . obstructive atelectasis from impaired mucociliary clearance, increased secretions, and altered consciousness is often encountered in the icu patients. distal obstruction manifests as crowding of air bronchograms, whereas the proximal mucus plugging leads to lobar or even complete lung collapse ( fig. . ). compressive atelectasis from pleural effusion and cicatrization from fibrosis in later stages of ards are other forms of atelectasis seen in icu setting. the imaging findings include linear, band-like, or wedge-shaped opacities with signs of volume loss. mechanical ventilation and aspiration are two main risk factors for pneumonia in icu patients. ventilator-associated pneumonia can occur in up to % of patients after days of ventilation [ ] . the diagnosis of pneumonia in icu patients is often challenging as the airspace opacities seen on chest radiographs in these patients can be caused by atelectasis, aspiration, pulmonary hemorrhage, noninfectious lung inflammation (e.g., drug reaction), pulmonary edema, or ards [ ] . however, there are certain features that may favor pneumonia (table . ). air bronchograms typically associated with pneumonia result from the complete filling of the alveolar spaces around nonobstructed bronchi. however, when the airways get filled with mucus, air bronchograms are not seen on imaging which is often the case in critically ill patients (fig. . ). on ct, pneumonia can often be differentiated from atelectasis by lack of signs of volume loss. ct may provide additional clues to the possible causative agent of pneumonia. cavities, upper lobe or superior segment of lower lobe airspace disease, endobronchial spread (tree-in-bud densities), and findings of prior granulomatous disease point toward reactivation tuberculosis (tb). multiple peripheral lung nodules, solid as well as cavitary, in certain patients (long-term indwelling catheters, endocarditis, or history of iv drug abuse) suggest septic emboli [ ] . widespread bilateral predominantly central ground-glass opacities and cysts with or without spon-taneous pneumothorax in immunocompromised patients are features of pneumocystis jiroveci pneumonia (pcp), whereas focal areas of consolidation surrounded by a "halo" of groundglass suggest angioinvasive aspergillosis [ ] . intubation, diminished cough reflex, sedation, altered mental state, and enteric tube feeding predispose the icu patients to increased risk of aspiration. the different manifestations of the aspiration include chemical pneumonitis, pneumonia, and airway obstruction. aspiration of large amounts of severely acidic gastric contents can be fatal, resulting in a severe chemical pneumonitis and ards [ ] . aspiration is more common in the right lung, due to the vertical orientation of the right main bronchus. in the supine position, the frequently involved sites are the posterior segments of the upper lobes and superior segment of the lower lobe [ ] . the radiographic abnormalities commonly seen with aspiration are patchy ill-defined ground-glass opacities, nodular opacities, or consolidation in the dependent regions of the lungs (fig. . ). the opacities usually are seen over the first - days in aspiration pneumonitis demonstrating relatively rapid resolution on follow up radiographs. persisting opacities indicate progression to infectious pneumonia, and this is one important reason for following up the patients on radiographs. the ct better demonstrates the ground-glass changes or consolidation. areas of necrosis and cavitation can be seen when aspirates contain anaerobic organisms [ ] . tree-in-bud opacities present in the abovementioned dependent distribution are also frequently seen with aspiration [ ] . the pulmonary hemorrhage can be localized or diffuse. the localized form is often secondary to bronchiectasis, tumors, or some infections. the diffuse alveolar hemorrhage results from injury to the alveolar microcirculation leading to bleeding into the air spaces [ ] . this form is encountered in various autoimmune diseases, bleeding diathesis, vasculitis, certain drugs, and infections (invasive aspergillosis, mucormycosis). in icu patients, the culprit drugs often are systemic or catheter-directed thrombolytics (for myocardial infarction, pe, or stroke). the differentiation of pulmonary hemorrhage from pneumonia or pulmonary edema may be difficult. rapidly developing central and basilar predominant pulmonary parenchymal opacities sparing the costophrenic angles, along with drop in hemoglobin and hemoptysis (or blood in tracheal aspirate), should suggest the diagnosis of pulmonary hemorrhage. on ct scan, patchy ground-glass opacities, typically cloud-like opacities without significant interlobular septal thickening, are seen in the acute phase. in subacute phase, interlobular and intralobular interstitial thickening often develops [ ] . although the ct imaging features are nonspecific, the distribution of these findings, the temporal evolution of opacities, and the radiologic manifestations of predisposing disease (table . ) can help in arriving at the diagnosis [ , ] (fig. . ) . the prevalence of pulmonary embolism (pe) in critically ill patients is as high as % with only one-third of these cases being suspected clinically [ ] . besides the general risk factors for pe such as obesity, past history of venous thromboembolism, cancer, immobilization, trauma, and recent surgery; the icu patients are exposed to additional risk factors [ ] there are various radiographic signs (table . ) described for pe [ ] [ ] [ ] [ ] . although these signs are difficult to interpret, their timely recognition might alert the physician to the possibility of pe before it is suspected clinically (figs. . and . ). ct pulmonary angiography (ctpa) is now the reference standard for diagnosing pe in icu patients, with most icus moving away from the ventilation-perfusion scan and conventional invasive pulmonary angiography. ctpa not only detects pe by direct visualization of the thrombus in pulmonary arteries, it allows risk stratification by providing signs of right heart strain and quantification of thrombus burden. an rv/lv ratio > . - . has been shown to predict adverse outcomes similar to the echocardiographic measurements [ ] . newer ct techniques, such as dual-energy ct, can be used to assess functional lung perfusion [ ] as well as reduce contrast burden in icu patients who are prone to acute kidney injury [ ] . barotrauma, particularly the pneumothorax, remains a common icu complication despite continuously improving mechanical ventilation strategies of low tidal volumes and plateau pressures [ ] . the other forms of barotrauma are pneumomediastinum, pneumopericardium, pneumoperitoneum, subcutaneous emphysema, and interstitial emphysema. even a small pneumothorax can rapidly progress to tension pneumothorax in ventilated patients. the typical appearance of a thin curvilinear line, bordered by the lung on one side and pleural air space devoid of lung markings on the other, is often absent in the supine radiographs. in the supine position, air collects to the least dependent anteromedial pleural space (fig. . ) resulting in increased radiolucency at the bases and sharply elongated cardiophrenic and costophrenic sulci (the deep sulcus sign) [ ] . ct is useful for evaluation of loculated air collections and guides the proper placement of chest tube when pneumothorax persists. pneumomediastinum (fig. . ) in ventilated patients most commonly occurs from the rupture of the terminal airways. the pressure gradient between an alveolus and the interstitium directs the air from the ruptured alveolus to the perivascular and peribronchial fascial sheath. the fascial sheath at the lung root gives away letting the air escape into the mediastinum. with increasing severity, the air overflows into the subcutaneous tissues of the neck and into the retroperitoneum [ ] . pneumomediastinum can also be seen in tracheobronchial injury, following tracheostomy tube placement, asthma, and esophageal rupture. pleural effusion in icu patients is mostly transudative. despite being a common occurrence, it is difficult to detect small to moderate pleural fluid on the supine radiograph. in addition, differentiating it from other causes of lower zone opacities such as consolidation and atelectasis is often not possible. the costophrenic angle is often not blunted on the a b supine radiograph, and pleural fluid may only demonstrate diffuse hazy "veil-like" opacification from the layering of the pleural fluid (fig. . ). the apex is the most dependent location in supine patients and fluid may manifest as an apical cap [ ] . ct helps in differentiating pleural fluid from pulmonary parenchymal disease and better demonstrates the loculated pleural fluid collections. on ct, the thick enhancing visceral and parietal pleura suggests empyema often with a "split pleura" sign. hemothorax is suggested by increased attenuation of the pleural fluid, commonly - hu [ ] . ultrasound, readily available as a bedside imaging modality in most icus, is very useful in demonstrating loculations and in guiding fluid sampling as well a c b tubes, lines, and catheters are always present in icu radiographs. one major use of the radiographs in icu is to check their position and to evaluate any complications related to their insertion (table . ) . endotracheal tubes (ett) are used for short-term respiratory support with mechanical ventilation. the tip of endotracheal tube should be located about cm above the carina when the patient's head is in a neutral position [ ] . the neck flexion moves the tube inferiorly by up to cm, and the neck extension moves it superiorly by the same cm, hence the saying "the hose goes with the nose" [ ] . intubation of the main bronchi (most frequently right sided) may result in subsegmental atelectasis (fig. . ), segmental collapse, or complete collapse of the contralateral lung and puts the ipsilateral lung at risk of pneumothorax from overventilation. the too high a position of ett can lead to inadvertent extubation or damage to the larynx. overinflation of the endotracheal balloon cuff beyond the normal tracheal diameter chronically can lead to tracheal stenosis or may rarely result in acute rupture [ ] . the tracheal rupture however mostly occurs in the peri-intubation period, through the membranous trachea within cm of the carina [ ] . difficult intubation can occasionally result in hypopharyngeal injury (fig. . ). tracheostomy tubes are placed when long-term intubation is necessary. the tracheostomy tube tip should be approximately at mid-t level. the tracheostomy tube maintains its position during neck movements. pneumomediastinum can occur following an uncomplicated tracheostomy tube insertion. nasogastric tubes are the most commonly used for feeding, medication administration, and suctioning of gastric contents. the tip of a feeding tube should be ideally in the antrum of the stomach or distal to it (post-pyloric) to reduce the risk of aspiration. the proximal side hole of a nasogastric tube should extend beyond the gastroesophageal junction [ ] . the bedside chest radiograph is the most important investigation to detect tube malposition. the enteric tubes can coil within the pharynx or esophagus, resulting in high risk of aspiration, or very rarely esophageal perforations. the nasogastric tubes occasionally may terminate in the large airways ( fig. . ) where ectopic feeding can result in direct bronchopulmonary injury, pneumonia, pneumothorax, pulmonary laceration, and pulmonary contusion [ ] . the gastric feeding tubes are easier to insert than small bowel feeding tubes, allowing early initiation of enteral feeds, and are almost always placed at the time of icu admission. small bowel feeding tubes (nasojejunal or percutaneous jejunostomy) are reserved for patients who have high gastric residual volumes despite the use of prokinetics [ ] . the tip of the central venous catheter should be distal to the last venous valve, which is located at the junction of the internal jugular and the subclavian veins. on the cxr, the position of the valve corresponds to the inner aspect of the anterior first rib [ ] . a catheter is more likely to get blocked from thrombosis around it when its position is in proximal svc or at the thoracic inlet than in the distal svc or at the cavoatrial junction [ ] . the inferior border of bronchus intermedius serves as a good guide to the distal svc ( fig. . ) . on the cxr, the cavoatrial junction corresponds to the lower border of the bronchus intermedius, while the arch of azygos is located at the right tracheobronchial angle a b azygos location of a catheter tip can be identified by its characteristic orientation and position (fig. . c pulmonary artery catheters or swan-ganz catheters are placed primarily to measure pulmonary capillary wedge pressure, which helps to differentiate cardiogenic pulmonary edema from non-cardiogenic pulmonary edema. the catheter tip should lie in the main pulmonary arteries or the proximal lobar pulmonary artery (fig. . ) . the catheter tip should not extend beyond the pulmonary hilum on the chest radiograph [ ] . a further distal catheter tip increases the risk of arterial injury and pulmonary infarction. pulmonary infarcts may also occur secondary to persistent balloon occlusion or pericatheter thrombus. the proper position of the chest tube depends on the contents to be removed from the pleural cavity. the tip of the tube is directed toward the apex for pneumothorax and toward the lung base for fluid drainage (fig. . ). the side holes of the chest tube, identified on radiographs as interruptions of the tube's radiopaque line, should lie within the pleural space. an improper location of chest tube results in poor drainage and accumulation of air or fluid in the chest wall. the ineffective drainage may also result from tube kinking; blockage resulting from blood clots, pus, or debris in the tube; and apposition of the tip against the mediastinum [ ] . an intrafissural location of the tube may or may not affect its function; however, rarely it may result in herniation of lung parenchyma into the holes of chest tube leading to infarction [ ] . inadvertent parenchymal insertion of a chest tube (fig. . ) can lead to pulmonary laceration, hematoma, infarction, and bronchopleural fistula. besides the lung parenchyma, an inappropriately positioned chest tube can injure the heart, great vessels, diaphragm, liver, and spleen [ ] . interpretation of icu radiographs is a challenging task. important pearls for reporting icu chest radiographs are summarized in table . . on the absorption of fluids from the connective tissue spaces harrison's principles of internal medicine clinical and radiologic features of pulmonary edema revisiting signs, strengths and weaknesses of standard chest radiography in patients of acute dyspnea in the emergency department intensive care unit imaging acute respiratory distress syndrome: the berlin definition acute respiratory distress syndrome caused by pulmonary and extrapulmonary injury: a comparative ct study crazy-paving" pattern at thin-section ct of the lungs: radiologic-pathologic overview prediction of prognosis for acute respiratory distress syndrome with thin-section ct: validation in cases lobar collapse in the surgical intensive care unit ventilator-associated pneumonia thoracic imaging in icu chest ct for suspected pulmonary complications of oncologic therapies: how i review and report the many faces of pulmonary aspiration diffuse pulmonary hemorrhage: clues to the diagnosis manifestations of systemic diseases on thoracic imaging venous thromboembolism prophylaxis in critically ill patients venous thromboembolic disease: an observational study in medical-surgical intensive care unit patients on the roentgen diagnosis of lung embolism roentgen diagnosis of pulmonary embolism pulmonary embolism: roentgenographic and angiographic considerations correlation of postmortem chest teleroentgenograms with autopsy findings with special reference to pulmonary embolism and infarction prognostic value of echocardiography and spiral computed tomography in patients with pulmonary embolism diagnosing pulmonary embolism: new computed tomography applications reduced iodine load at ct pulmonary angiography with dualenergy monochromatic imaging: comparison with standard ct pulmonary angiography -a prospective randomized trial distribution of pneumothorax in the supine and semirecumbent critically ill adult pneumomediastinum revisited imaging of the pleura complex disease of the pleural space: radiographic and ct evaluation stateof-the-art: radiological investigation of pleural disease radiographic evaluation of endotracheal tube position chest radiography in the icu: part , evaluation of airway, enteric, and pleural tubes early radiographic signs of tracheal rupture chest radiography in the icu: part , evaluation of cardiovascular lines and other devices gastric versus post-pyloric feeding: a systematic review to clot or not to clot? that is the question in central venous catheters lines, tubes, and devices lung entrapment and infarction by chest tube suction key: cord- -u gsa lg authors: divatia, j. v.; pulinilkunnathil, jacob george; myatra, sheila nainan title: nosocomial infections and ventilator-associated pneumonia in cancer patients date: - - journal: oncologic critical care doi: . / - - - - _ sha: doc_id: cord_uid: u gsa lg nosocomial infections or healthcare-acquired infections are a common cause of increased morbidity and mortality among hospitalized patients. cancer patients are at an increased risk for these infections due to their immunosuppressed states. considering these adverse effects on and the socioeconomic burden, efforts should be made to minimize the transmission of these infections and make the hospitals a safer environment. these infection rates can be significantly reduced by the implementing and improving compliance with the “care bundles.” this chapter will address the common nosocomial infections such as ventilator-associated pneumonia (vap), catheter-associated urinary tract infections (cauti), and surgical site infections (ssi), including preventive strategies and care bundles for the same. the term "healthcare-associated infections" (hcais) is commonly used to refer to the whole spectrum of infections that a patient acquires from the healthcare environment including hospitals, intensive care units, hospice, nursing homes, etc. nosocomial infections or hospital-acquired infections (hais) are defined by the centers for disease control and prevention (cdc) as "those infections that were not present in carrier state or incubating state at the time of admission and manifest h after hospital admission" [ ] . these infections are often unrelated to the primary cause of hospital admission and can present even after the hospital discharge of the patients [ ] . as per the cdc criteria for surveillance, nosocomial infection sites can be of types affecting over infection sites that can be differentiated on the basis of microbiological and clinical criteria [ ] . patients in intensive care units (icus) are more vulnerable to nosocomial infections. the extended prevalence of infection in intensive care (epic ii) study showed a prevalence of infections within the icu as high as % [ ] . nosocomial infections are associated with worse outcomes including increased length of hospital stay, long-term disability, and increased mortality rate, and are associated with increased antibiotic use and antibiotic resistance [ ] . due to the multiple risk factors like immunosuppression, disrupted skin and mucosal barriers, recurrent hospital visits, exposure to multiple antibiotics, and the presence of invasive lines and other devices, cancer patients, irrespective of whether they have solid or hematologic malignancies, are at high risk for nosocomial infections [ ] . as cancer patients are increasingly being admitted to icus for management of diseaseand treatment-related complications, the incidence of nosocomial infections is also increasing in icus caring for cancer patients [ ] . the common nosocomial infections are catheter-related bloodstream infection (crbsi), catheter-associated urinary tract infections (cauti), surgical site infections (ssi), and ventilator-associated pneumonia (vap). this chapter will focus on vap, cauti, and ssi, and central line-related bloodstream infection will be dealt with separately. hospital-acquired infection is common across all parts of the world, with an estimated incidence of - % in developed countries and up to % in developing countries [ ] . data from the international nosocomial infection control consortium (inicc) suggests that among developing countries, the crbsi rates were . per , central venous catheters (cvc)-days, ventilator-associated pneumonia (vap) rates were . per , ventilator-days, and the catheter-associated urinary tract infection (cauti) rates were . per catheter-days [ ] . with increased awareness and constant vigilance, there has been a steady and gradual decrease in the incidence rates of hospital-acquired infections with a % reduction in central line-associated bloodstream infections (clabsi) rates and a % reduction in surgical site infections (ssi) [ , ] . table shows the national health safety network (nhsn) and inicc benchmarks for various hospital-acquired infections [ ] . although nosocomial infections can be caused by a variety of organisms including bacteria, virus, fungi, and parasites, bacterial infections are the commonest. these agents may be commensals in the patient or may originate from an exogenous source and spread via cross infection. hospital-acquired pathogens are often resistant to most antibiotics (multidrug resistant) or at times extremely drug resistant or pan drug resistant, thereby increasing the treatment costs, antibiotic use, and antibiotic resistance. this is evident from microbiology data demonstrating an increasing incidence of nosocomial infections that are caused by multidrug-resistant bacteria over the years [ , ] . the common pathogens are gram-negative bacteria including pseudomonas, klebsiella, and acinetobacter and gram-positive bacteria like methicillin-resistant staphylococcus aureus (mrsa), coagulase-negative staphylococci, and enterococci. invasive candidal infections also occur in those with indwelling catheters, lines or contaminated abdominal surgeries [ ] . the other common nosocomial organisms are clostridium difficile, vancomycin-resistant enterococci, anaerobes, and enterobacter. nosocomial infections result in an increased mortality and morbidity to the patients with a significant effect on the treatment cost due to the need for higher antibiotics and prolonged icu and hospital length of stay. these infections are responsible for - % of all death causes in neonates in developing countries and - % in the united states [ ] . as per the world health organization (who) report, nosocomial infections result in direct financial losses of approximately € billion in europe and $ . billion in the united states. the risk factors for developing nosocomial infections are: (a) patient factors such as extremes of age, immunosuppression due to malignancy, acquired immunodeficiency syndrome (aids), patients requiring emergency admission to the intensive care unit (icu), duration of stay more than days, chronic illness like renal failure, diabetes mellitus, chronic liver disease, presence of indwelling catheters, ventilation, total parenteral nutrition, trauma, abdominal surgeries, and impaired functional status [ , ] (b) organizational factors such as the poor environmental hygiene inside the hospital or icu, lack of efficient infection control measures, inadequate manpower such as an inadequate nurse to patient ratio or inadequate waste management staff, and inadequate equipment for patient use (c) iatrogenic factors such as ignorance regarding infection control practices, lack of training in infection control, etc. [ ] treatment and prevention of nosocomial infections strategies for the prevention of nosocomial infections as majority of the patient risk factors for developing nosocomial infections cannot be modified, care should be given for focused education and training to the hospital staff, by distribution of education materials regarding healthcareassociated infections and basic infection control policies including identifying the need of isolation, types of isolation, barrier nursing, hand hygiene, etc. [ ] an infection control committee should be formed headed by an infection control nurse and hospitalinfection control policies should be laid down. the infection control committee should be entrusted with the responsibility of formulating and implementing "care bundles" for common nosocomial infections that can be adopted from health organizations like cdc, who, etc. and modified as per hospital policy. across the world, implementation of such "bundles of care" and adherence to these bundles have been proven to significantly reduce nosocomial infections, especially in the developing countries [ , ] . the infection control team should conduct audits and give necessary feedback regarding compliance with hand-washing and other infection control policies. [ ] . an antibiotic stewardship program should be initiated with a multidisciplinary team, with members such as an infectious disease specialist, a clinical pharmacist with training in infectious disease, a clinical microbiologist, an information system specialist, and an epidemiologist, with a policy for regulating higher antibiotic prescription. review of practice of antibiotic prescription, ensuring environmental decontamination with surface cleaning, air filtration and decontamination of water source, increasing strength of healthcare personnel (improving nurse to patient ratio and increasing waste management staff), and regular training and feedback to hospital staff are some important measures that can be adopted at an institutional level for reducing the nosocomial infections inside the hospital. the treatment of common nosocomial infections and bundle of cares will be discussed under respective sections in the chapter. previously nosocomial pneumonia was considered as a spectrum of high-risk diseases comprising of ventilator-associated pneumonia, non-ventilator-associated hospital-acquired pneumonia, and healthcare-associated pneumonia. the terminology "healthcare-associated pneumonia (hcap)" was introduced by the infectious diseases society of america (idsa) in for patients in the community to be considered at high risk for mdr pathogens similar to those associated with hap. these patients, in spite of not being hospitalized, were still considered as high risk in virtue of their interaction with the healthcare system. over years, increasing evidence suggested that this could be a false assumption that also led to inappropriate use of antibiotics [ , ] . probably this group of patients needs to be considered as a high-risk group when they present to the emergency department with communityacquired pneumonia. hence the current guidelines do not consider hcap as a part of hap [ , ] . the current idsa guidelines recommend the use of two mutually exclusive termsventilator-associated pneumonia and hospitalacquired pneumoniathereby avoiding the terminology of "non-ventilator-associated hospital-acquired pneumonia." the terminology has been explained in fig. . nosocomial pneumonia (hap and vap) is the most common hospital-acquired infection in the developed world, with a prevalence of % [ ] . vap contributes almost % of all cases of nosocomial pneumonia and is a major cause of increased morbidity and mortality. the attributable mortality rates of vap range from % to % across both developing and developed countries [ ] . although hospital-acquired pneumonia (hap) is generally considered to be less severe than vap, patients who develop complications of hap have mortality rates similar to those of vap. in the icu, data suggests that treatment of vap is the main reason for antibiotic usage, with more than % of antibiotic use in icu being for vap [ ] . vap also significantly prolongs ventilation days, hospital length of stay, and treatment costs as compared to patients who do not develop vap. ventilator-associated pneumonia (vap) is defined as pneumonia occurring after - of intubation and ventilation, associated with a new or progressive infiltrate on chest x-ray along with fever, altered leucocyte count, and changes in sputum characteristics for which a definitive causative agent can be found [ ] . early vap occurs in the initial days of ventilation (within - h) and is more likely to be caused by antibiotic-sensitive bacteria. late vap (occurring after days) is likely caused by bacteria which are likely to be multidrug resistant. however, this distinction might not hold true always as patients who are hospitalized for more than days prior to intubation will probably harbor multidrug-resistant bugs [ ] . vap is the most common nosocomial infection in patients who are mechanically ventilated with rates of % being reported among patients admitted in multiple hospitals across the united states [ , ] . the international nosocomial infection control consortium (inicc) data from the developing world suggests that the overall vap rate was . per , ventilator days with a pooled crude excess mortality of . % [ ] . the incidence increases with duration of ventilation. the risk of vap is highest during the initial days of ventilation ( % per day), which gradually decreases over time ( % per day from fifth to tenth day and % afterward). older data suggested that most of the vap episodes occurred in the initial part of icu stay itself (early vap) probably because of the increased practices of short-term ventilation in majority of patients [ ] . recent studies however suggest the converse with an increase in the late vap rates (as much as % of total vap) [ ] . the data on vap is difficult to assimilate for surveillance reporting due to the technical issues in diagnosing vap from radiologic criteria alone and in differentiating vap from other conditions such as pulmonary edema or acute respiratory distress syndrome. hence the cdc has laid down a set of epidemiological definitions called ventilator-associated events (vaes). [ ] . this is a surveillance system to prevent underreporting of the complications (including vap) occurring in mechanically ventilated patients, irrespective of their origin or mechanism, and should not be used in the clinical management of patients. ventilator-associated events are defined for a period of weeks and require patients to be ventilated for a minimum of days, with at least days of clinical stability, to be assessed for vae. vaes are further classified into ventilator- ventilator-associated condition (vac) is defined as days of worsening oxygenation, assessed by an increase in peep requirement more than cm of h o or an increase infio requirement more than . , after an initial clinical stability (of h) or improvement. any vac associated with either a change in temperature or leucocyte count (fever > c or hypothermia < c, or leukocytosis > , / mm or leukopenia < , /mm ) and that requires addition of a new antibiotic for at least days is an infection-related ventilator-associated complication (ivac). an ivac, with a positive microbiological test from respiratory tract specimens, is called possible vap (pvap). a positive microbiological test is defined as a positive microbiological culture in specimens, meeting the threshold of quantitative or semiquantitative culture, without purulent respiratory secretions; or a representative lower respiratory tract sample that is visibly purulent, but the positive culture does not meet the thresholds as per quantitative or semiquantitative criteria; or positive pleural fluid culture or lung tissue culture or a positive test result for legionella or viruses implicated in respiratory diseases. organisms such as candida species, coagulase-negative staphylococcus (cons), and enterococcus species can be considered as positive microbiological test only if isolated from pleural fluid or lung tissue and not from sputum, endotracheal aspirates, bronchoalveolar lavage, or protected specimen brush specimens. positive microbiological test of normal/respiratory flora should be ignored [ ] . vap is defined as a pneumonia occurring in a patient on ventilator for at least calendar days before the onset of a vae, with same duration of ventilation, and the patient was on ventilator on the day of the event, or a day prior [ ] . a complex interplay between host factors, microbiology of the oropharyngeal flora, and the presence of endotracheal tube is responsible for the development of vap. this is summarized in fig. . after hospitalization and antibiotic administration, the normal flora of the upper respiratory tract is replaced by exogenous aerobic gramnegative flora due to alterations in host defense properties. these organisms colonize in the oropharynx from multiple sources (see table ). the normal cough reflex is hampered by the endotracheal tube, and these pathogens gain access to the lower respiratory tract through micro-aspiration along the endotracheal cuff, aided by the ventilator gas flow. the stomach is an important source of bacterial colonization. change in the acidic ph of the stomach due to drugs favors colonization with these virulent bacteria, and with regurgitation of gastric contents, they pool in the oropharynx and reach the lower respiratory tract by micro-aspirations. the risks are further increased in the absence of adequate cuff seal or with multiple attempts of intubation. these virulent bacteria are usually difficult to treat owing to the thick biofilm that they produce alongside the endotracheal tube. the presence of this biofilm hampers antibiotic penetration and increases antibiotic use and antibiotic resistance [ , ] . although increased pharyngeal colonization with virulent bacteria, micro-aspiration, and biofilm formation all contribute to the risk of developing vap, it is the host's immune response to these pathogens that determines whether vap will develop or not. immunosuppression is common in critically ill patients due to dysfunction of monocytes and t cells [ ] . apart from that, critically ill patients have an over expression of c a that leads to neutrophil dysfunction and reduced phagocytic activity, again predisposing them to severe infections [ ] . other contributory factors to the development of vap include advanced age, emergency intubation for surgery or trauma, severity of illness and organ dysfunction, immunosuppressant drugs, previous antibiotic exposure, presence of nasogastric tubes (resulting in sinusitis), and preexisting illness like diabetes mellitus, chronic lung disease, and chronic renal failure. the etiology for vap varies between icus and hospitals which highlights the importance of knowing local infection and susceptibility patterns. the duration of hospital stays before intubation, length of icu stays, and duration of ventilation are also significant as they determine the nature of flora causing vap (see table ). vap before days (early-onset vap) is often caused by microbes similar to the organisms causing community-acquired pneumonia like streptococcus pneumoniae, haemophilus influenzae, methicillin-sensitive s. aureus (mssa), and susceptible enterobacteriaceae [ ] . late-onset vap is usually caused by microbes from the hospital environment. they are usually the aerobic gramnegative bacilli like klebsiella, pseudomonas, acinetobacter, enterobacter, and e. coli, while mrsa is rarely implicated [ ] . the odds that they are multidrug resistant is high, and hence these infections are more difficult to treat. this difference between early and late vap may not always be clinically relevant, and there are increasing reports of lack of difference in microbiology and mortality across both groups [ , ] . patients who are previously exposed to healthcare environment such as those who received antibiotics within the preceding months, those who are currently hospitalized for more than days, those who are on immunosuppressants, or those who have immunosuppressive states such as chronic renal failure, diabetes mellitus, aids, etc. are prone to multidrugresistant infections irrespective of the onset of vap. vap is diagnosed in patients who are being ventilated or was on a ventilator recently and develops signs of infection such as fever or hypothermia, leukocytosis or leukopenia, and worsening in gas exchange along with the appearance of new infiltrates on radiologic imaging and changing nature (increase in purulence) of the tracheobronchial secretions [ ] . these signs are highly nonspecific and may be also associated with various noninfectious causes. moreover, the sensitivity and specificity of routine icu x-rays is much lower than the conventional x-rays. interobserver variability in interpreting x-ray findings also affects their accuracy as a diagnostic tool. hence the diagnosis of vap in icu lacks sensitivity and specificity and may result in both over diagnosis or underdiagnosis. however, if the clinical suspicion of pneumonia is high, empiric antibiotics should be administered immediately as delay in antimicrobial treatment leads to increased mortality [ , ] . to aid in the diagnosis and to rationalize the use of empirical antibiotic therapy for vap, a clinico-radiologic criterion was proposedthe clinical pulmonary infection score (cpis). the cpis (table ) consists of six clinical and laboratory parameters with scores range from to . a score has a sensitivity of % and a specificity of %, for the presence of vap [ , ] . although seemingly simple and straightforward, calculation of cpis score also varies substantially from observer to observer, hereby limiting its routine use in clinical trials [ ] . the current idsa guidelines suggest the use of clinical criteria rather than cpis score for initiating and stopping of antibiotics [ ] . a microbiologic diagnosis can be made by gram staining and culture of the tracheal aspirate or lower respiratory secretions obtained by direct/ non-direct bronchoscopic alveolar lavage (bal). bronchoscopic techniques like bal, mini-bal, and protected specimen brush (psb) specimens provide reliable lower respiratory tract samples, and quantitative cultures of these samples may help to differentiate colonization from true infections. technically it has the advantage of identifying the pathogens correctly, leading to less antibiotic exposure and thereby minimizing antibiotic resistance. however, bronchoscopy and sample collection require expertise and still result in false negative reports. blind sampling requires less expertise and infrastructure and is easy to perform. however, blind sampling is likely to produce false positive results with colonizing organisms, thereby increasing inappropriate antibiotic use and promoting antibiotic resistance. the available data remains conflicting with no benefits of one method over the other with respect to mortality, length of icu stay, and mechanical ventilation days [ , ] . the idsa recommends blind methods of sample collection, while the european guidelines recommend bronchoscopicdirected methods [ , ] . the threshold values for cultured specimens recommended by cdc for the diagnosis of pneumonia are mentioned in table . numerous biomarkers for infection/inflammation have been studied in vap including erythrocyte sedimentation rate (esr), c-reactive protein (crp), procalcitonin, pro-adrenomedullin, lps-binding protein, soluble-triggering receptor expressed on myeloid cells (strem-) , presepsin, etc. other than esr, crp, and procalcitonin, the use of other biomarkers is not widely practiced out of research field [ ] . procalcitonin, a precursor hormone of calcitonin, is actively produced by neuroendocrine cells in the lung and intestine on exposure to bacterial endotoxin and inflammatory cytokines. the level peaks at h and may aid in early identification of infections as compared to blood culture. procalcitonin is not useful in cases of viral or fungal infections and in cases of localized bacterial infections. it is also elevated in noninfectious conditions such as burns, major surgery, end-stage renal failure, etc. [ ] . procalcitonin testing is expensive and serial measurements make it even more expensive. based on the current data, procalcitonin levels should not be used to rule out an infection or influence the decision of antibiotic initiation. the main role of procalcitonin is in its role as a guide for early stoppage of antibiotics, thereby preventing unwanted exposure to antibiotics [ , ] . the current guidelines do not recommend the use of these biomarkers over clinical criteria for a diagnosis of vap [ , ] . idsa recommends coverage for methicillinsensitive staphylococcus aureus and gramnegative bacilli including pseudomonas for patients with suspected vap, pending culture and sensitivity reports [ ] . mrsa coverage is not usually required, unless there is an increased risk for mdr organisms such as recent antibiotic exposure, septic shock, acute respiratory distress cpis clinical pulmonary infection score, ards acute respiratory distress syndrome, pao partial pressure of alveolar oxygen, fio fraction of inspired oxygen, cxr chest x-ray table threshold values for cultured specimens used in the diagnosis of pneumonia bronchoalveolar lavage: more than colony-forming unit/ml protected specimen brush: more than colony-forming unit/ml nondirected bronchoalveolar lavage obtained from (blind) specimens: more than colony-forming unit/ml endotracheal aspirate: more than cfu/ml open lung biopsy/transthoracic or transbronchial biopsy: more than colony-forming unit/g tissue syndrome (ards) prior to the current episode of vap, acute kidney injury requiring renal replacement therapy, or in case of high infection rates of mrsa in the hospital, i.e., > - %. in patients without risk factors for gram-negative mdr infection, such as those without any structural lung disease or those who have not received antibiotics in recent past, a single antipseudomonal agent that also covers mssa will be appropriate. only in patients with underlying structural lung disease like bronchiectasis or cystic fibrosis or those having higher risk for mdr infection, dual antipseudomonal coverage should be given [ ] . recommended empirical antibiotics are those with antipseudomonal and mssa activity such as ceftazidime, cefepime, piperacillintazobactam, fluoroquinolones such as levofloxacin, carbapenems such as meropenem or imipenem, etc. aminoglycosides are not recommended as monotherapy for vap. in case mrsa is suspected, linezolid or vancomycin may be used. with the increased incidence of infections due to mdr gram-negative pathogens, there has been a resurgence of polymyxins in the treatment of vap. they may be particularly useful in places with increased baseline mdr acinetobacter rates [ ] and for empiric therapy in patients with septic shock or high risk such as neutropenic patients or those who have hypersensitivity to beta-lactams. current evidence suggests that different doses or dosage schedules might be required for various bacteria, depending on the pharmacokinetic/pharmacodynamic parameters [ ] . the idsa guidelines recommend the addition of nebulized colistin along with intravenous route for managing vap [ ] . regarding newer antibiotics, daptomycin is inactivated in the lungs and hence is not recommended for vap. tigecycline monotherapy in the doses as per the label is not recommended for hap or vap [ , ] . doxycycline and fosfomycin have not been studied for hospital-acquired mrsa as standalone treatments [ , ] . antibiotics should be changed according to culture and sensitivity reports and may be administered for a total duration of days, or fewer, perhaps guided by procalcitonin levels. the european guidelines for vap recommend a total treatment duration of - days for all immunocompetent hosts in the absence of complications such as empyema, lung abscess, or necrotizing pneumonia, if initial empiric therapy was adequate and their response to treatment has been good irrespective of the microbiological etiology. patients infected with pseudomonas, carbapenem-resistant enterobacteriaceae, and acinetobacter, those on antibiotics such as tigecycline and colistin, and immunocompromised hosts will require a prolonged duration of treatment [ ] . a simplified algorithm for antibiotic selection is shown in fig. guidelines for managing vap and hap were published by the ats and idsa in , while the european respiratory society/european society of intensive care medicine/european society of clinical microbiology and infectious diseases guidelines were published in . while addressing nosocomial pneumonia including hap and vap, both guidelines concur with each other except for a few points. the ats guidelines do not make any new recommendations regarding vap prevention and encourage the use of clinical criteria to decide on initiation and discontinuation of antibiotics rather than use of clinical pulmonary infection score (cpis) score. the ats guidelines recommend the usage of noninvasive or minimally invasive techniques for microbiological investigations of vap. risk factors for mdr pathogens are described by ats as prior hospitalization and organ failure such as septic shock ards and requirement of dialysis prior to vap onset. they recommend combination therapy for target therapy and set a duration of treatment for hap and vap as days. the european guidelines mention prevention strategies for vap but do not make any recommendation on the use of chlorhexidine for selective oropharyngeal decontamination. the european guidelines introduce the concept of "low probability of hap" and suggest the usage of cpis score to identify the same. they endorse invasive sampling over noninvasive sampling, as it might help to avoid overdiagnosis and unnecessary antibiotic exposure. the risk of mdr pathogens is described based upon local prevalence rates of mdr organisms and presence of septic shock. although they recommend days of treatment, they suggested prolonged treatment for selected patients. both guidelines agree on the need of appropriate empiric antibiotic treatment, the need for de-escalation, and the need to minimize antibiotic exposure [ , , , ] . the antimicrobial drug concentration in the lung is the most important factor that determines the efficacy of the antibiotic treatment. drugs delivered reach the lung parenchyma by bulk flow, permeation, active transport, and passive diffusion [ ] . patient factors such as parenchymal inflammation, volume of distribution, renal function, and drug factors such as water solubility, tissue penetration, molecular weight, inactivation of drug in local site, etc. are important factors in deciding the further efficacy of these drugs. hydrophilic drugs like beta-lactams, aminoglycosides, and colistin attain less concentrations in the lung even after administering of therapeutic dose, while linezolid, fluoroquinolones, and macrolides concentrate well inside the lung. hence the pharmacokinetic (pk) and pharmacodynamic (pd) parameters of drugs should be kept in mind while determining loading dose, dosing frequency, and dosing route. alternate routes such as nebulization may be tried as an additional measure to improve the lung deposition of the antibiotics [ ] . the exact time frame of when to expect resolution of symptoms of vap after initiation of treatment is unclear and varies upon the symptoms or signs that are being monitored for resolution. the lack of improvement in clinical condition and/or clinical parameters such as fever, tachypnea, oxygenation, etc. after initiation of treatment can be either due to poor response to treatment/persistence of infection or due to a secondary infection. typically, non-resolving pneumonia is common in elderly patients or in those with comorbidities, underlying immunosuppression, chronic lung disease, or infection with virulent/drug resistant pathogen. treatment factors such as inappropriate initial therapy (either drug or its dose, route, frequency, and duration) are other important factors responsible for vap. workup for non-resolving pneumonia should be undertaken, including microbiological workup for mdr pathogens and imaging for complications such as lung abscess or empyema, while ruling out noninfectious causes of fever and radiologic infiltrates. once an infective etiology is confirmed, optimizing antibiotics as per the pk/pd principles with a hike in antimicrobial coverage will be needed to manage non-resolving pneumonia [ ] . infection control programs form the most crucial step in the prevention of vap [ ] . vap rates can be reduced by proper decontamination of ventilatory equipment and practice of infection control measures during care of the mechanically ventilated patient. a brief outline of the steps to reduce vap is given below. . adherence to the five moments of hand hygiene as recommended by the world health organization (who) [ ] . avoiding intubation and re-intubation by the judicious use of noninvasive ventilation and high-flow nasal oxygen helps reduce the risk of development of vap. . preferring the use oral route than nasal route for intubation, thereby reducing the chances of nosocomial sinusitis and vap. . avoid routine stress ulcer prophylaxis as alteration in gastric ph is associated with increased microbial colonization in the stomach. . enteral feeding reduces the gut translocation of endogenous bacteria and reduces bacteremia. caution should be taken to avoid overdistension of the stomach and monitor gastric residual volumes if there are signs of feed intolerance. . daily oral hygiene with . - % chlorhexidine gel reduces the pathological colonization of oral flora. its role is supported by evidence of multiple meta-analyses of randomized controlled trials which are open-labelled trials [ ] . role of selective decontamination of the gut is controversial in areas with high antibiotic resistance. elevation of the head end of the bed by - has shown to reduce vap rates significantly and is recommended by many professional societies [ ] . continuous low-pressure suction of the subglottic secretions above the endotracheal cuff is useful [ ] . silver-coated endotracheal tubes may prevent bacterial colonization and biofilm formation though the current evidence is weak. [ ] iii. vap bundle the term "bundles" in critical care refers to collective group of practice statements, each with high level of evidence in itself; when practiced together, they result in better patient outcome by the consistent delivery of these practices and avoidance of individual preferences or practices [ , ] . infection surveillance, hand hygiene, semi-recumbent positioning, early extubation, ensuring adequate cuff pressure, and continuous subglottic suctioning have been proven to be simple and efficient methods that help to reduce vap rates significantly [ ] . the initial vap bundle suggested by ihi comprised of five components: head end elevation of bed, daily interruption of sedation combined with assessment of the likelihood of weaning, prophylaxis for stress ulcer and deep vein thrombosis, and daily oral care with chlorhexidine [ ] . table represents the suggested practice from scottish intensive care society [ ] . they differ from the classical institute for healthcare improvement (ihi) vap bundle by not suggesting peptic ulcer prophylaxis or dvt prophylaxis as they have no direct relation with vap rates. similarly, the implementation of a bundle for vap as proposed by the international nosocomial infection control consortium (inicc) also led to substantial reduction in vap rates in multiple countries including india, kuwait, saudi arabia, etc. [ , , ] . the bundle proposed by the inic consortium included the following elements: . adherence to guidelines for hand hygiene . patient nursing in a semi-recumbent position, with head of the bed elevated at - . use of weaning protocols and daily assessment of readiness to wean . regular oral care with chlorhexidine . minimization of the duration of mechanical ventilation and use of noninvasive ventilation if feasible . preferable the orotracheal route instead of nasotracheal route for intubation . endotracheal cuff pressure monitoring and attempts to keep it at least cm h o . care of ventilator circuits and removal of condensates from circuits while keeping the ventilator circuit closed . avoiding scheduled changes of ventilator circuits and changing them only if they are visibly soiled or malfunctioning . prevention against gastric overdistension . avoidance of stress ulcer prophylaxis similar to the inicc study, a spanish group reported successful reduction of their vap rates by more than half with the implementation of a vap bundle among icus across the country [ ] . the bundle they used is similar to other vap bundles and notably avoided the dvt and peptic ulcer prophylaxis of the ihi recommendation [ ] . they had seven mandatory recommendations including staff training in airway management, hand hygiene in airway management, monitoring cuff pressure, chlorhexidine oral care, positioning in bed, striving to reduce ventilator days, and discouraging scheduled changes of ventilator circuits. they also added "highly recommended measures" such as selective decontamination of the digestive tract, subglottic suctioning, and short-course antibiotics for patients intubated with altered sensorium. the data published seemed robust and the reduction in vap rates was sustained and significant. these data suggest that vap bundles are pragmatic, are easy to implement and adhere to, and are effective in reducing the vap rates substantially across the world including developed and developing countries. adapting evidence-based vap bundles that are tailor-made to suit the prevailing practices and hospital policies does not affect the effectiveness of the program [ , , ] . with an increased awareness against vap and with active infection control measures, the incidence of vap is on a declining trend. there has been an increased incidence in hap due to an increased use of noninvasive devices for respiratory support such as noninvasive ventilation and high-flow nasal oxygen [ ] . currently hap is one of the leading causes of nosocomial infections that in turn leads to prolonged hospital stay and increased treatment costs. a recent study found that the incidence of hap is . per patient days, occurring in both wards and the intensive care units [ ] . hap is classified into icu acquired and non-icu acquired hap, with icu acquired hap having an increased incidence of mdr pathogens increased incidence of septic shock, and worse outcomes as compared to non-icu hap [ ] . the term "non-icu acquired pneumonia (niap)" has been recently proposed and refers to a specific subset of hap patients who developed pneumonia outside icu and has an estimated incidence of . - . cases per admissions [ ] . hap differs from vap with respect to the microbiology, diagnostic investigations, and mortality. the microbiological diagnosis is by culture of a pathogen identified from a representative sputum sample. there are no data to suggest invasive sampling techniques like bronchoscopy over simple sputum collection; rather some data suggest that they may be harmful and do not improve outcomes [ ] . the use of rapid diagnostic methods such as polymerized chain reactionbased technologies in hap has yielded promising results especially in the choice of antibiotics and detection of antibiotic resistance. however further studies are needed to confirm the benefits of such systems over the possible disadvantages such as false diagnosis of colonization [ ] . the microbiology of hap differs from vap, and there seems to be an increased incidence of s. pneumoniae and respiratory viruses and a lower incidence of mdr gram-negative pathogens [ ] . the ats/idsa guidelines recommend antipseudomonal therapy for most patients with hap. this may lead to unnecessary use of broad spectrum antibiotic therapy [ ] . the ers guidelines suggest that antipseudomonal treatment is not necessary for initial empiric treatment of most patients with hap, in the absence of risk factors or septic shock [ ] . thus, hap patients need to be treated based on factors such as local epidemiology, surveillance cultures, presence or absence of mdr risk factors, and septic shock [ , ] . infections involving any part of the urinary system, from the urethra to kidney, are labelled as urinary tract infections. they comprise more than one third of all nosocomial infection. in the intensive care units, uti comprises of - % of all nosocomial infections and is the third most common nosocomial infection occurring in the icu [ ] . icu patients require a catheter for reasons such as immobility, strict intake output charting, etc. and retain it for prolonged duration. each catheter day is associated with a - % increase in the risk of acquiring a catheter-associated urinary tract infection (cauti). the cdc guidelines classify cauti as symptomatic urinary tract infection or asymptomatic urinary tract infection as follows: cauti is an infection occurring in a patient with an indwelling catheter of more than h duration before the event, with the catheter remaining in situ or removed h prior at the time of the event. signs and symptoms of infection such as fever, suprapubic tenderness, loin pain, andin those patients without the catheterincreased urinary frequency, urgency, and dysuria and a significant bacteriuria should be present [ ] . significant bacteriuria is defined as a urine culture with no more than two species of organisms identified, of which at least one of which is a bacterium which has a colony-forming unit count more than cfu/ml [ ] . the most common pathogens associated with cauti are enterobacteriaceae. in the setting of icus, candida, enterococcus, pseudomonas, klebsiella, and e. coli become increasingly prevalent and are often drug resistant [ ] . cauti as well as other nosocomial infections prolongs hospital stay, increases treatment cost, and increases mortality. as with an endotracheal tube for vap, the indwelling catheter is the main risk factor for uti. other risk factors include female sex, severity of current illness, age greater than years, presence of diabetes mellitus, altered rft with serum creatinine level more than mg/dl, location of catheter insertion, nonadherence to aseptic precautions of catheter care, etc. [ ] . laboratory examination will demonstrate pyuria irrespective of symptoms and urine wbc > cells/microl. quantitative urine wbc > cells/microl has low sensitivity but retains high specificity for the likelihood of getting a positive microbiological culture. a proper sample of urine should be sent for culture when cauti is for obtaining culture results. samples should be collected from the "needleless site" after applying aseptic precautions or with a needle from the aspiration port. the idea of changing the catheter before sample collection has been suggested in some studies but currently cannot be recommended [ ] . the empiric antimicrobial therapy for cauti depends on the presentation, i.e., whether they are symptomatic/asymptomatic and also upon the complications if any. antibiotics for asymptomatic bacteriuria do not prevent the progression to symptomatic cauti nor its complications. as the risk of antibiotic resistance is high, patients with asymptomatic bacteriuria are usually not treated with antibiotics except in pregnancy and in patients undergoing surgical procedures of the lower urinary tract [ ] . for symptomatic bacteriuria, the choice of antibiotic will depend on patient's risk factors for mdr infection and ongoing antibiotics. a -to day duration of intravenous antibiotic therapy is generally advocated and can be switched to oral route as per the sensitivity reports if the patient can tolerate oral medications [ ] . candiduria is a common occurrence among hospitalized patients, with candida being isolated from almost one third of the total samples among hospitalized patients. candiduria with symptoms and signs of infection including fever, leukocytosis or leukopenia, shock, etc. should be evaluated for disseminated candidiasis. treatment for otherwise asymptomatic candiduria is not required except in the high-risk population such as neutropenia or urinary tract instrumentation. imaging should be obtained in patients with diabetes mellitus or urinary tract abnormalities in case of persistent candiduria as they have a high risk for developing fungal balls. treatment should be guided by the culture and sensitivity reports. fluconazole - mg daily is recommended for susceptible strains for a total duration of - days. fluconazole-resistant strains should be treated with amphotericin b ( . - . mg/kg per day) for days. lipid formulations of amphotericin b do not penetrate the kidney and cannot be used for the treatment of fungal cauti. the data on efficacy of echinocandins is still evolving, and the preliminary data shows clearance of candiduria with micafungin. further data is required for making any recommendation [ ] . strategies for reducing cauti include strict aseptic techniques including hand hygiene for insertion and maintenance of catheters and maintaining a closed drainage system, monitoring the insertion of urinary catheters for appropriate indications, development of cauti bundles [ ] (table ) for placement, daily check list, early removal, encouraging other alternatives such as intermittent catheterization, and condom catheter. a recently conducted study in the united states demonstrated that a cauti bundle could reduce the catheter use and cauti rates in non-icu acute care settings [ ] . other methods proposed to reduce the incidence of cauti were to use urinary catheters coated with antibiotics or to use urinary catheters with silver impregnated in it. silver compound was found to reduce biofilm formation on the catheter significantly. however, the use of both types of catheter was not associated with a reduction in uti rates or any other meaningful benefit [ ] . surgical site infections (ssis) are those occurring at the incision site and/or extending to deeper tissue spaces or adjacent organs within days of a surgery or within days if the procedure involved prosthetic material implants. they are further classified into superficial ssi, deep ssi, and organ/space ssi (table ) [ ] . these are the most common healthcareassociated infections in patients undergoing surgery, with an incidence of about % [ ] . studies have estimated that more than half of these infections are preventable, if appropriate measures were taken [ ] . the most common organisms responsible for ssi are staphylococcus aureus (mrsa and mssa), e. coli, coagulase-negative staphylococci (cons), pseudomonas, etc. [ ] . the inicc data from developing countries shows a significantly higher incidence of ssi, as compared to the data from developed countries. the incidence rates reported by the inicc group are . % after hip prosthesis, . % after cardiac surgeries, . % in abdominal hysterectomy, . % in other abdominal surgery, and . % after ventricular shunt [ ] . patients at risk include those who are elderly patients; those with history of skin or soft tissue infection, recent radiotherapy, diabetes, obesity, alcoholism, and preoperative hypoalbuminemia; those who are current smoker; or those having immunosuppression. other risk factors include emergency procedure, wounds of increasing complexity, prolonged surgeries, contaminated environmental surfaces, lack of strict asepsis in the operating room, inappropriate antibiotic with respect to choice/timing/weight-based dosing, impaired glycemic control, etc. [ ] . maintaining strict asepsis during wound handling and timely administration of the correct antibiotics in appropriate doses are the most important factors to prevent ssi. other measures such as hand hygiene, skin antisepsis, avoiding shaving of hair (if necessary, to clip), and use of double gloves and other barrier devices are also recommended by various societies for reducing ssi. surgical antimicrobial prophylaxis (amp) is the administration of a short-course antibiotic to reduce the microbial burden at the time of skin incision. an ideal amp program has to select the antibiotics that are active against the likely pathogens at the surgical site and administer the optimum dose at correct time, so that adequate serum and tissue concentrations are achieved. it is recommended that the full dosa should be administered within min of the surgical incision and re-dosed as per the half-life of the drug or in case of blood loss more than one third of circulating blood volume. cefazolin as a single agent is the recommended drug of choice for cardiothoracic and upper gastrointestinal surgeries, surgery of non-obstructed small bowel, cesarean section, orthopedic surgery, spinal surgery, and neurosurgery. in patients with allergy to cefazolin, aminoglycosides such as gentamycin may be used. infective endocarditis prophylaxis is restricted to specific procedures in patients with few high-risk cardiac conditions. the cdc recommendation for prevention of ssi is outlined in table [ ] . table strong recommendations from cdc regarding prevention of ssi bath with water and soap on the night prior to surgery administer amp only if indicated, and amp to be administered in the correct time and correct dose such that optimal bactericidal concentration of the agents is established in the serum and tissues when the incision is made administer amp for all caesarean section procedures use an alcohol-based antiseptic agent for surgical site preparation unless otherwise specified avoid application of all antimicrobial agents including ointments, solutions, or powders to the surgical incision use of antibiotic (triclosan)-coated sutures strict glycemic control in the perioperative period with target blood glucose levels less than mg/dl in all patients irrespective of diabetic status maintain perioperative normothermia optimize tissue oxygenation by maintaining normothermia and euvolumia provide an increased fio during surgery and in the immediate postoperative period after extubation transfuse blood and blood products as per transfusion thresholds avoid additional amp after closure of the surgical incision in the operating room cdc centre for disease control and prevention, amp antimicrobial prophylaxis nosocomial infections increase patient's morbidity, hospital and icu length of stay, treatment costs, and mortality. they are also responsible for increased antibiotic use, leading to antibiotic resistance and outbreaks of multidrug-resistant infections. implementing and enforcing infection control measures is the pivotal step toward curbing the nosocomial infection. increased awareness, health education, and adhering to care bundles have been proved to be efficacious in reducing nosocomial infections. impact of the international nosocomial infection control consortium (inicc)'s multidimensional approach on rates of ventilatorassociated pneumonia in intensive care units in hospitals of cities of the kingdom of saudi arabia impact of the international nosocomial infection control consortium (inicc) multidimensional approach on rates of ventilator-associated pneumonia in intensive care units of two hospitals in kuwait prevention of ventilator-associated pneumonia guidelines for the prevention of ventilator-associated pneumonia and their implementation. the spanish "zero-vap" bundle the intensive care medicine research agenda on critically ill oncology and hematology patients american college of surgeons and surgical infection society: surgical site infection guidelines, update centers for disease control and prevention guideline for the prevention of surgical site infection update on surgical site infections: the new cdc guidelines use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (prorata trial): a multicentre randomised controlled trial canadian critical care trials group. a randomized trial of diagnostic techniques for ventilator-associated pneumonia /nhsn surveillance definitions for specific types of infections urinary tract infection (catheter-associated urinary tract infection [cauti] and non-catheter-associated urinary tract infection [uti]) and other urinary system infection healthcare-associated infections (hai) progress report|hai|cdc the impact of the international nosocomial infection control consortium (inicc) multicenter, multidimensional hand hygiene approach in two cities of india healthcare-associated pneumonia does not accurately identify potentially resistant pathogens: a systematic review and meta-analysis preventing catheter-associated urinary tract infections in the intensive care unit strategies to prevent ventilatorassociated pneumonia in acute care hospitals. infect control hosp epidemiol preventing ventilator associated pneumonia (vap) the impact of hospitalacquired infections with multidrug-resistant bacteria in an oncology intensive care unit hospital-acquired infections at an oncological intensive care cancer unit: differences between solid and hematological cancer patients ventilator-associated pneumonia (vap) -early and late-onset differences evaluation of the infectious diseases society of america/american thoracic society guideline criteria for risk of multidrug-resistant pathogens in patients with hospital-acquired and ventilator-associated pneumonia in the icu benchmarking local healthcare-associated infections: available benchmarks and interpretation challenges cdc definitions for nosocomial infections the epidemiology of nonventilator hospital-acquired pneumonia in the united states microbial profile of early and late onset ventilator associated pneumonia in the intensive care unit of a tertiary care hospital in bangalore, india colistin for lung infection: an update management of nosocomial pneumonia on a medical ward: a comparative study of outcomes and costs of invasive procedures diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: international clinical practice guidelines from the infectious diseases society of america ventilator associated pneumonia respective impact of implementation of prevention strategies, colonization with multiresistant bacteria and antimicrobial use on the risk of early-and late-onset vap: an analysis of the outcomerea network institute for healthcare improvement: how-to guide: prevent ventilator-associated pneumonia institute for healthcare improvement: evidence-based care bundles n.d institute for healthcare improvement, i. institute for healthcare improvement: how-to guide: prevent ventilator-associated pneumonia defining antibiotic dosing in lung infections trends in antibiotic use and nosocomial pathogens in hospitalized veterans with pneumonia at medical centers empirical antibiotic therapy for ventilator-associated pneumonia ventilator-associated pneumonia in the icu management of adults with hospitalacquired and ventilator-associated pneumonia: clinical practice guidelines by the infectious diseases society of america and the american thoracic society nosocomial infections and their control strategies nosocomial infections: epidemiology, prevention, control and surveillance severe sepsis bundles prevalence of and risk factors for hospital-acquired infections in slovenia-results of the first national survey the prevalence of and risk factors for healthcare-associated infections in slovenia: results of the second national survey. zdravstveno varstvo estimating health care-associated infections and deaths in u.s. hospitals reappraisal of routine oral care with chlorhexidine gluconate for patients receiving mechanical ventilation benefits and harms of treatment of asymptomatic bacteriuria: a systematic review and meta-analysis by the european association of urology urological infection guidelines panel impact of inappropriate antibiotic therapy on mortality in patients with ventilatorassociated pneumonia and blood stream infection: a meta-analysis early onset pneumonia: a multicenter study in intensive care units treatment failure in ventilator associated pneumonia subglottic secretion suction for preventing ventilator-associated pneumonia: an updated meta-analysis and trial sequential analysis silver-coated endotracheal tubes and incidence of ventilator-associated pneumonia the nascent randomized trial new guidelines for hospital-acquired pneumonia/ventilator-associated pneumonia: usa vs guidelines for prevention of hospital acquired infections effectiveness of a multidimensional approach for prevention of ventilator-associated pneumonia in adult intensive-care units from cities in india: findings of the international nosocomial infection control consortium (inicc) attributable mortality of ventilatorassociated pneumonia: a meta-analysis of individual patient data from randomised prevention studies comprehensive evidence-based clinical practice guidelines for ventilator-associated pneumonia: prevention antibiotic treatment of hospitalacquired pneumonia bronchoscopic or blind sampling techniques for the diagnosis of ventilator-associated pneumonia clinical practice guideline for the management of candidiasis: update by the infectious diseases society of america non-intensive care unit acquired pneumonia: a new clinical entity? antimicrobial catheters for reduction of symptomatic urinary tract infection in adults requiring short-term catheterisation in hospital: a multicentre randomised controlled trial randomized phase trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia diagnosis of nonventilated hospital-acquired pneumonia nosocomial infections in medical intensive care units in the united states surgical site infections, international nosocomial infection control consortium (inicc) report, data summary of countries international nosocomial infection control consortium report, data summary of countries for - : device-associated module impact of the international nosocomial infection control consortium's multidimensional approach on rates of ventilator-associated pneumonia in intensive care units in hospitals of cities within argentina a program to prevent catheter-associated urinary tract infection in acute care controlling antimicrobial use and decreasing microbiological laboratory tests for urinary tract infections in spinal-cord-injury patients with chronic indwelling catheters impact and effect of nosocomial infections: a review inhibition of daptomycin by pulmonary surfactant: in vitro modeling and clinical impact biomarkers in sepsis impact of quantitative invasive diagnostic techniques in the management and outcome of mechanically ventilated patients with suspected pneumonia immunoinflammatory response in critically ill patients: severe sepsis and/or trauma a systemic review on surgical site infections: classification, risk factors, treatment complexities, economical and clinical scenarios international ers/esicm/escmid/ alat guidelines for the management of hospitalacquired pneumonia and ventilator-associated pneumonia: guidelines for the management of hospitalacquired pneumonia (hap)/ventilator-associated pneumonia (vap) of the summary of the international clinical guidelines for the management of hospital-acquired and ventilator-acquired pneumonia estimating the proportion of healthcare-associated infections that are reasonably preventable and the related mortality and costs pharmacokinetics of antibiotics in the lungs international study of the prevalence and outcomes of infection in intensive care units the prevalence of nosocomial infection in intensive care units in europe procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. lancet infect dis national trends in patient safety for four common conditions nosocomial infections in the icu: the growing importance of antibioticresistant pathogens surgical site infections: control., causative pathogens and associated outcomes who|my moments for hand hygiene. who. world health organization ventilator-associated pneumonia: the clinical pulmonary infection score as a surrogate for diagnostics and outcome key: cord- -ftz a authors: richards, guy a.; schleicher, gunter; mer, mervyn title: viruses in the intensive care unit (icu) date: journal: tropical and parasitic infections in the intensive care unit doi: . / - - - _ sha: doc_id: cord_uid: ftz a whereas viruses are not usually considered to be important causes of icu admission this review has demonstrated this perception to be incorrect. viruses and their manifestations differ from continent to continent and hemisphere to hemisphere and it is essential that the intensivist be familiar with diagnosis and management of these ubiquitous organisms. infectious diseases in the developing world icu usually involve bacterial sepsis resulting from community-acquired pneumonia, pelvic inflammatory disease, ruptured abdominal viscus (traumatic or spontaneous), necrotising fasciitis, or more exotic infections such as malaria. despite their importance, viruses are rarely considered, except during outbreaks of hemorrhagic fever in which case they have short-lived notoriety. important viral infections in africa often differ from those found in the united states of america (usa). this chapter will focus on viral hemorrhagic fevers, influenza, varicella, viral hepatitis, cytomegalovirus, measles and the respiratory syncitial virus. the viral hemorrhagic fevers are generally characterized by a marked propensity for person-to-person spread and high mortality rates. this places them in the highest biohazard category (class ) and renders them liable to control by the state in countries that have the relevant bio-safety regulations. the viruses themselves are numerous ( , ) ( table ) and this chapter will confine discussion to those found in sub-saharan africa and some of those seen in south america and india. it is noteworthy that no cases of hanta virus have been reported in africa and in particular the hanta virus pulmonary syndrome ( ). the viruses known or considered to be associated with hemorrhagic fever fall into three groups with respect to the primary means of transmission and reservoir hosts (table ) . however, clinical manifestations are similar. they are febrile illnesses with an abrupt onset and usually with a short incubation period. headache, myalgia, lumbar pain, nausea, vomiting and diarrhea are frequent. hematological and serological findings are leukopenia (or leukocytosis), thrombocytopenia and elevated transaminases ( , , ) . coagulation profiles become progressively more abnormal and overt hemorrhagic features such as epistaxis; gingival bleeding and melena supervene from day onward. in those most affected, multiple organ system failure and death ensue. mortality is high, particularly with the filoviruses where marburg has a fatality rate of %, ebola zaire - %, with ebola ivory coast intermediate between these two ( ). the primary features of established illness are related to endothelial damage, hemorrhage and shock ( ). whereas direct cytopathogenesis appears to be a major mechanism of injury there is not extensive necrosis of endothelial cells ( ). endothelial dysfunction is more likely to be due to cytokine release as part of the systemic inflammatory response syndrome. hemorrhage may be related to disseminated intravascular coagulopathy (dic), but the presence of hepatic damage may confuse the picture. dic is a regular feature of marburg and crimean-congo hf but less frequent with arena-virus infections ( , ). shock occurs as a consequence of hypovolemia. only limited observations have been made in patients in whom shock persists after volume resuscitation and these have been contradictory with both an increased and a decreased systemic vascular resistance reported in association with a reduced cardiac index ( , ( ) ( ) ( ) . therapy is supportive and directed toward ensuring adequate oxygen delivery. hemorrhage is managed by replacement of appropriate clotting factors, platelets and blood as required, with monitoring of cardiac output mandatory given the uncertainty as to the etiology of hypotension ( , ). positive transfer of human antibodies has not been proven to be of benefit in filovirus infection but may be of value in cchf, although there has been no controlled trial ( ). it is of value in treatment of junin virus, with a reduction of mortality to - % from - % if initiated within the first days of illness ( ) and is also possibly of value in lassa virus infection ( ). promising results have been obtained with intravenous ribavirin in cchf in south africa and oral ribavirin in pakistan but the discontinuation of the intravenous preparation has prevented proper evaluation ( , ) . it is of particular value in lassa fever with a reduction in mortality from % to % if begun within days of onset of fever ( ). in addition, ribavarin has some benefit in argentine hf caused by junin virus and reduces mortality in hantan virus, which causes hemorrhagic fever renal syndrome in asia ( ). nursing and infection control are critical. it is possible that universal precautions may be sufficient to afford protection, however where a worry exists that airborne transmission is possible (this has been documented with the reston and zaire strains of ebola virus in monkeys ( )), high level barrier nursing may be preferable utilizing isolation, protective clothing plus hepa-filtered respirations. infection control extends to the transport of specimens and their examination in the laboratory, where procedures should be in place to manage these materials. influenza is increasingly being recognized as a cause of significant morbidity and mortality in the community, particularly among pediatric patients and the elderly ( , ). these viruses are subdivided into subtypes, which include host of origin, geographic location of first isolation, strain number and year of isolation ( ). the antigenic description is of the hemaglutinin (ha) and neuraminidase (na) and is given parenthetically. since major antigenic shifts have occurred in when the subtype replaced the subtype, in when the hong kong virus appeared, in when the virus reappeared and most recently in when the avian virus appeared ( , ). an epidemic was aborted in the latter case by eradication of the domestic bird population. pneumonia is the most common complication, which occurs in high-risk patients including those with comorbid illness such as cardiovascular or pulmonary disease, diabetes, renal failure, immunosuppression, the elderly, or residents of nursing homes. the pneumonia may be primary (of viral origin) or secondary (related to bacterial infection). primary viral pneumonia is the most severe, although the least common of the pneumonic complications and may occur in patients that are otherwise normal ( ). whereas secondary bacterial pneumonia has been reported to be the most frequent cause of death in previous pandemics ( ), this was not the case in the most recent outbreak in hong kong ( ). where secondary bacterial pneumonia occurs, the most common pathogens are s. pneumoniae ( %). s. aureus ( %) and h. influenzae. the incidence of s. aureus is significantly increased in influenza epidemic years ( ). other complications that may result in icu admission are rhabdomyolysis, encephalitis, transverse myelitis and less commonly reyes syndrome. management is supportive, though new antiviral agents may play a role, particularly if administered early. all currently available drugs should be started within days of onset of symptoms to be effective ( ). the practical effectiveness of drugs such as oseltamivir and rimantidine remains to be determined ( ). rsv is a frequently encountered, potentially severe infection in childhood. disease is less severe in adults but may be more severe in the elderly, and in those with comorbid disease or immunocompromise ( , ) . presentation is non-specific with fever, myalgia, arthralgias, wheeze and non-purulent or bloody sputum. x-ray changes are also non-specific and not helpful in the etiologic diagnosis of pneumonia. in one study in south africa, patients admitted to hospital with an acute lower respiratory tract infection were identified over a -month period ( ). of these, pneumonia was diagnosed in . %, bronchiolitis in . % and laryngotracheobronchitis in %. . % and % had moderate or severe disease respectively, the latter requiring admission to icu. rsv enzyme immunoassay was positive in . % of cases in all groups of diagnoses. viral culture performed in of the cases ( . %), grew rsv in . %, adenovirus in . %, parainfluenza in . % and influenza b in . %. diagnosis is made most frequently by rapid antigen detection, but is not a routinely performed investigation outside of research studies. enzyme immunoassays have sensitivities of - % and specificities of - % ( ). treatment of rsv is supportive although nebulized ribavirin has proven effective in infants ( ). this agent is not readily available in developing countries and it would be impractical to recommend routine enzyme testing for children or adults admitted to the icu. varicella pneumonia represents a severe complication of varicella and most frequently occurs in adults. estimates as to the incidence vary, with the highest being % of all adult cases and the overall incidence in the region of % ( - ). varicella pneumonia has been reported to carry an overall mortality of between and %. however, where mechanical ventilation is necessary, mortality is as high as % ( - ). risk factors include cigarette smoking, pregnancy, immunocompromise and male gender ( - ). whereas chickenpox is primarily a disease of childhood and less than % of reported cases occur in adults, more than % of all deaths take place in this group. recent evidence indicates that there is an upward shift in the age at which chicken pox is contracted and as a consequence it is possible that more critically ill patients with varicella may be seen ( ). varicella pneumonia causes an interstitial pneumonia with severe impairment of gas exchange. pathologically this manifests as a florid immune reaction characterized by an interstitial pneumonitis with mononuclear cell infiltrates, capillary endothelial cell destruction, intraalveolar exudates and hemorrhage, septal wall invasion by mononuclear cells and inflammatory changes in the bronchioles ( ). the pneumonitis appears to be due to the host response rather than to specific virally mediated tissue injury. whereas usual therapy involves support and acyclovir, the benefit of the latter is uncertain ( ). it is possible that acyclovir may hasten improvement in those that are less ill and do not require ventilation ( , ) but despite the recognition of limited efficacy it is still widely recommended as early primary therapy ( , ). a study performed in our icu indicates that corticosteroids may dramatically alter the course of the most severe disease and should be considered in addition to antiviral therapy along with appropriate supportive care in any previously well patient with life threatening varicella pneumonia ( ). little is known about the incidence and clinical cause of varicella pneumonia in hiv (human immunodeficiency virus) infected individuals ( , ) . patients with hiv or aids (acquired immunodeficiency syndrome) who are hospitalized with chickenpox appear to be at high risk for developing varicella pneumonia, which manifests in a similar clinical fashion to that in immunocompetent individuals. in a recent review conducted in a regional infectious diseases hospital affiliated to our institution, % of the patients who were hospitalized with chickenpox developed pneumonia ( ). this incidence is significantly greater than in any previously reported study in immunocompetent patients. immunocompromised patients with varicella pneumonia have previously been reported to do poorly, with mortality as high as %, despite prompt initiation of antiviral therapy and supportive care ( ). our experience suggests that response to adjunctive corticosteroid therapy in patients with hiv/aids is as favorable as in immunocompetent patients. interestingly, recurrent varicella pneumonia requiring acute treatment followed by secondary antiviral prophylaxis in an hiv-infected adult patient has been described, analogous to other aids complicating opportunistic infections ( ). the proportion of viral hepatitis infections that progress to acute liver failure caused by viruses is very low, occurring in less than % of patients with acute a or b hepatitis. however, viruses account for between - % of all cases of liver failure ( , ). most of these are related to hepatitis b (hbv) and a relatively smaller proportion to a (hav) or other newly identified viruses. fulminant hepatic failure is defined either as acute liver disease, occurring in the absence of pre-existing liver disease, which leads to encephalopathy within weeks of onset of symptoms, or as liver disease, which leads to encephalopathy within weeks of onset of jaundice ( ). clinical features are often non-specific, such as nausea and vomiting with progression to encephalopathy and coma. the prognosis is inversely proportional to the degree of encephalopathy. hepatitis a is an rna virus transmitted by the fecal-oral route. hepatitis b is a dna virus and accounts for % to % of virally caused fulminant hepatitis. transmission is via sexual contact, transplacentally, parenterally and in particular occupationally. hepatitis d is an incomplete rna virus that requires the presence of hepatitis b virus in order to infect an individual. it is an important cause of fulminant hepatitis and aggressive chronic hepatitis in hbv carriers ( ). hepatitis e virus is an rna virus transmitted by the fecal-oral route and possibly parenterally which for unknown reasons carries a high mortality from fulminant hepatitis in pregnant women and is also the commonest cause of fulminant hepatitis in india ( , ). hepatitis c virus is an rna virus of the flaviviridae family and is responsible for % of acute hepatitis, % of chronic hepatitis and % of end-stage cirrhosis in europe. % of patients infected with hepatitis c develop chronic infection consisting of either chronic hepatitis, fibrosis or cirrhosis. it is also not usual for it to cause a fulminant hepatic failure ( ) but this occurs only in areas with high hepatitis c serum prevalence ( ). the diagnosis of hav is made on the basis of the detection of high levels of igm antibodies in the serum. in fulminant hepatitic failure caused by hbv, the widespread hepatic necrosis that occurs as a consequence of immune mediated lysis of infected hepatocytes may result in igm antihepatitis b core (anti-hbc) being the only marker of hepatitis b, as hepatitis b surface antigen and hepatitis b dna may be absent from serum ( ). other viruses in the herpes group (cytomegalovirus, herpes simplex and ebstein barr virus), adenovirus and influenza virus may rarely cause fulminant hepatic failure. treatment involves identification of the cause and if possible, specific therapy. if facilities are available, patients with grade encephalopathy or greater should be transferred to a liver transplant center ( ). supportive therapy, involves hemodynamic management, ventilation, prevention and treatment of hemorrhage, dialysis, therapy of co-existent sepsis and electrolyte disturbance, and management of intracranial pressure ( ). orthoptic liver transplantation is not frequently available in developing countries, but in appropriate patients has been shown to improve survival significantly ( ). measles is a frequently encountered disease in the icu in developing countries. the presence of malnutrition and often the lack of an effective vaccination programme combine to convert this "harmless" childhood infection into a major killer. in one case series of patients admitted to an icu during a measles epidemic, were malnourished and none had been vaccinated. all required mechanical ventilation for pneumonia and ards, died and developed long-term sequelae, i.e. chronic lung disease, subacute sclerosing panencephalitis, hemiplegia or partial amputation of a limb ( ). young adults are not exempt from the ravages of this disease. in a study from greece, previously healthy young males were hospitalized with measles. had bacterial pneumonia on admission and developed pneumonia in hospital or post discharge ( ). in another study of adult patients admitted with measles diagnosed on clinical and serological grounds, required intensive care, six mechanical ventilation for approximately days, and two deaths occurred. prior vaccination history was not available ( ). it would be best to avoid measles entirely by means of vaccination, however once contracted a study conducted in south africa indicated that vitamin a supplements reduce morbidity and mortality significantly and concluded that these should be given regardless of the presence or absence of clinical evidence of vitamin a deficiency ( ). herpes encephalitis is the most common cause of fatal sporadic encephalitis in the united states, accounting for - % of the annual cases of viral encephalitis. no accurate figures are available as to the incidence of this disease in the developing world, however we see sporadic cases in our icu. this disease occurs in all age groups with the development of focal encephalitis with progressive oedema and necrosis. the syndrome is characterized by rapid onset of fever, seizures, focal neurological signs and impaired level of consciousness ( - ). in adults the etiology is herpes simplex type whereas in neonates type may also be involved and confers a worse outcome. brain biopsy is no longer a routine diagnostic test and polymerase chain reaction assays are considered the best non-invasive technique ( , ). this test is positive early in the disease and remains so during the first week. early aggressive antiviral therapy with acyclovir improves mortality and reduces subsequent cognitive impairment. acyclovir provides better outcome than vidaribine. whereas cmv is usually asymptomatic, severe morbidity may occur in the premature neonate and organ and bone marrow transplant recipients ( ). seronegative patients receiving a seropositive organ transplant will develop a primary infection in - % of cases ( , ). seropositive patients will develop cmv infection by superinfection or reinfection in - % of cases. primary infection is the most likely type and is also usually more severe. those who receive anti-thymocyte or antilymphocyte globulins and those who have bone marrow transplants also have more severe disease and a mortality of - % ( , ) . cmv infection occurs most frequently - weeks after transplantation. manifestations include, fever, hepatitis, leukopenia and thrombocytopenia. the most important condition resulting in admission to icu is interstitial pneumonitis. this is associated with variable changes in the chest radiograph, most commonly showing diffuse bilateral infiltrates, but focal consolidation or nodules may occur. in the developing world cmv is more frequently seen in association with hiv. despite the clear association with mortality in organ transplant recipients, in particular bone marrow transplants, the significance of cmv as a pathogen in patients with aids is unclear. autopsy studies demonstrate that although cmv pneumonitis is frequently present it is not commonly found as the sole pathogen ( , ). in addition bronchoalveolar lavage specimens are also positive for cmv in more than % of patients ( ). cmv has also been reported to be a potential cause of ventilator associated pneumonia in immunocompetent patients ( ) and it is suggested that cmv should be considered as a possibility in patients not responding to antimicrobials or if there is evidence of other hospital outbreaks of viral infection particularly in the pediatric wards ( ). diagnosis is made most frequently with an antigenemic assay incorporating antibodies directed at the pp matrix protein of the cmv virus ( ). this test has gained acceptance particularly in immunocompromised hosts and correlates with viremia ( , ). the polymerase chain reaction has an even higher sensitivity, but is not always widely available ( ). the mainstay of therapy for solid organ transplant is ganciclovir, which appears to reduce morbidity ( , , ) . in contrast, ganciclovir is not effective in bone marrow transplant recipients. it should not therefore be used as a single agent therapy in these patients ( , ) . it is possible that combinations with immunoglobulin or cytomegalovirus immunoglobulin may be of value ( , ). on november an unusual respiratory illness was reported in guangdong province, southern china, which was designated the severe acute respiratory syndrome (sars)( ). subsequent world -wide transmission was initiated by a doctor who traveled to hong kong, where he infected guests in the same hotel ( ). a global alert was issued by the who on / / , an unprecedented step, which nevertheless was proven to be appropriate when days later, as a consequence of this alert, similar cases were identified in singapore and canada. early international recognition of an impending crisis was precipitated in part by the detailed report by who clinician carlo urbani, who subsequently himself demised from sars ( ). local spread of this disease occurred in vietnam, canada, hong kong, singapore, china and taiwan. the organism. tissue culture isolation and electron microscopy resulted in rapid identification of the culprit virus as a novel coronavirus only distantly related to any that had previously infected humans ( , ). it is likely that it originated in animals, but it differs from all previously known coronaviruses in that most cause disease in only one host species whereas this virus appears also to have acquired the ability to infect humans. the high concentration of viral dna in the sputum suggested that droplet spread was the main mode of transmission. lack of antibody in the general community indicated that this virus had not circulated widely in humans. the rapid sequencing of the genome allowed early development of diagnostic tests. a number of pcr protocols have been developed ( ). these tests have high sensitivity, but a negative test cannot rule out infection. sars follows an unusual pattern in that during the initial phases of the illness, virus shedding is relatively low. because shedding peaks in respiratory specimens and stool only at around days after onset of clinical illness, tests of very high sensitivity, which do not yet exist, are necessary ( ). virus culture is extremely demanding and not useful for rapid diagnosis, however elisa, immunofluorescence and neutralization tests will soon be available commercially. detectable immune responses begin at day or but reliable antibody tests are available only after about day following onset of symptoms. seroconversion or a fourfold rise in titre indicates recent infection. diagnostic tests currently have severe limitations and extreme caution should be used before excluding the possibility of sars on the basis of a test alone. suspicious laboratory features include lymphopenia, thrombocytopenia and elevated lactate dehydrogenase levels ( ). from the perspective of clinicians, where local transmission has occurred, all cases of community-acquired pneumonia are suspect. otherwise a travel history to an affected country or contact with an infected patient is essential. the who case definition as of / / for a suspected or probable case of sars is a useful resource ( ). clinical features. in a recent study by peiris ( ), all patients became apyrexial within hours, but fever recurred in % ( patients) at a mean of . days (± . ). in only of these was nosocomial bacterial sepsis the cause. between days and , % of patients had another episode of fever. radiological worsening occurred in % of patients at a mean of . (± . days), % subsequently improved, % had remained unchanged at the time of writing and % had progressed further to a diffuse ground glass appearance at a mean of . (± . ) days. % developed desaturation of less than % in room air at . (± . ) days after onset of symptoms. % ( ) required icu at a mean of . (± . ) days of whom were intubated and required mechanical ventilation for ards. the development of ards had a bimodal pattern with a peak at days and another at days. on univariate analysis, the risk factors for development of ards were age, male sex, chronic hepatitis b carriage, raised creatinine and recurrence of fever. igg seroconversion had a % sensitivity at day even with corticosteroid therapy; however, nasopharyngeal viral rna detection was present in only % at presentation in the study by lee ( ) . % were admitted to icu, all for respiratory failure. mechanical ventilation was required in ( . %). died ( . %) all of whom had co-existing conditions. multivariate analysis defined age [odds ratio (or)/per decade of life . ( . - . ), p = . ; high peak ldh, o.r. per units . ( . - . ) p = . and a neutrophil count that exceeded the upper limit of normal at presentation, o.r. . ( . - . ) p= . ] as predictors of mortality. in those admitted to icu, dramatic increases in lung opacity, shortness of breath and hypoxia occurred at a median of . days (range to ). in a further study by booth ( ) , % were admitted to icu and of these died i.e. there was a . % -day mortality. diabetes, relative risk (rr) . ( % ci . - . ) p= . , and other comorbid conditions, rr . ( . - . ) p= . , were independently associated with outcome. treatment. viral amplification may be associated with cellular damage by cytolysis or immunopathological mechanisms ( ). once an immune response is mounted auto-immune tissue injury may occur. this has been the rationale for corticosteroid therapy in this condition ( ). interestingly sars behaves similarly to varicella, in that the disease is more severe in adults, pneumonic manifestations may occur some days after the onset of clinical symptoms and dramatic responses have been apparent after the use of corticosteroids (see varicella). whereas there has been concern regarding the use of corticosteroids there have also been many proponents, particularly from those at the coalface in hong kong. rivabirin was initially the antiviral of choice since it is an effective treatment of fulminant hepatitis in mice infected with the mouse hepatitis corona virus ( ). however, no anti-viral has been reported to be clinically effective in humans. this drug is extremely expensive in its intravenous form and health canada recently stated that it would no longer provide access to ribavirin because of side effects and lack of clear efficacy ( ). so et al ( ) have described a standard protocol for the management of sars which involves the administration of a combination of ribavirin and corticosteroids for those patients with: extensive or bilateral chest radiographic involvement, persistent chest radiographic involvement and high fever for days or worsening clinical, radiographic or laboratory findings, or oxygen saturation less than % in room air. late administration of corticosteroids appears to be less effective, correction of dose according to body weight results in more rapid improvement of symptoms in obese patients, and step-down within - days resulted in re-bound in some patients. steroids in this protocol were administered in high doses beginning with methylprednisone ( mg/kg mg x days) and weaning over days. there was no mortality and only required short periods of non-invasive ventilation. mortality. the who has revised its initial estimates of the case fatality rates on the basis of more complete data from china, hong kong, singapore and vietnam ( ). mortality varies according to age; being less than % aged years or younger, % aged - , % aged - and greater than % aged and older infection control. sars is highly contagious, specifically to health care workers and in particular where the index case is not immediately identified as having the disease. at the prince of wales hospital, a patient was admitted on the / / with "pneumonia" and was discharged well on the / / . on the / / however, health care workers became ill and a further potential cases were identified on that day. by march patients had been admitted to prince of wales hospital with sars, all traceable to this index patient ( ). in singapore similarly, initial transmission occurred from an index case to patients, of whom were primary contacts and of whom were health care workers ( ). in this latter case, singaporean media labeled this patient a super-spreader, a concept that, although as yet inadequately defined may possibly be correct ( , ). some patients do appear to spread the disease more readily and this may be related to the rate of shedding of viral particles. in toronto amongst cases ( %) were health care workers and the subsequent outbreak of at least patients occurred as a consequence of a cluster of unrecognized patients that had been admitted to north york hospital in toronto ( ). infection control measures should include negative pressure wards, the use of n masks, gloves at all times, disposable impermeable gowns and eye protection. hand washing after removal of gloves and avoidance of touching nose, eyes and mouth if at all possible are the most important practical measures ( ).hcws should be cohorted to decrease the number of people exposed and visiting should be strictly limited. alcohol, phenol and quaternary ammonium based disinfectants are highly active against coronavirus. certain features appear to enhance spread, in particular overcrowding of hospital wards, outdated ventilation systems and the use of nebulizers in the ward environment ( ). endotracheal intubation, open suctioning of respiratory secretions, the use of bi-pap and high frequency oscillatory ventilation in which air is forced around the face mask appear to be some of the most high-risk procedures numerous sources describing adequate infection control procedures are available, as well as those on the cdc website ( - ). the primary factor responsible for transmission seems to be inadequate training in or compliance with infection control procedures ( ). whereas viruses are not usually considered to be important causes of icu admission this review has demonstrated this perception to be incorrect. viruses and their manifestations differ from continent to continent and hemisphere to hemisphere and it is essential that the intensivist be familiar with diagnosis and management of these ubiquitous organisms. pathogenesis of viral hemorrhagic fevers viral hemorrhagic fevers in south africa: history and national strategy hantavirus pulmonary syndrome: a clinical description of patients with a newly recognized disease kass handbook of infectious diseases. exotic viral infections. porterfield js clinical practice and public health control virus induced endothelial permeability triggered by affected macrophages hemostasis and the complement system in argentine hemorrhagic fever cardiovascular and pulmonary responses to pichinde virus infection in strain guinea pigs a nosocomial outbreak of crimean-congo hemorrhagic fever at tyberberg hospital (part ii). management of patients unexpected ebola virus in a tertiary setting: clinical and epidemiologic aspects dose of neutralizing antibodies for argentine hemorrhagic fever endemic lassa fever in liberia. iv. selection of optimally effective plasma for treatment by passive immunization crimean-congo hemorrhagic fever treated with oral ribavirin lassa fever: effective therapy with ribavirin prospective, double blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome pneumonia and influenza during epidemics the viruses and their replication. in: fields virology pathology of fatal human infection associated with avian influenza a virus clinical features and rapid viral diagnosis of human disease associated with avian influenza a virus influenza a outbreak amongst adolescents in a ski hostel epidemiology of influenza bacterial pneumonia during the hong kong influenza epidemic of - influenza: prospects for control influenza pneumonia: a descriptive study an outbreak of respiratory syncytial virus in a bone marrow transplant center respiratory syncytial virus infections on an adult medical ward respiratory syncytial virus infection in children hospitalized with acute lower respiratory tract infection culture vs direct antigen assays for detection of microbial pathogens from lower respiratory tract specimens suspected of containing the respiratory syncytial virus a controlled trial of ribavirin in infants receiving mechanical ventilation for severe respiratory syncytial virus infection varicella pneumonia in adults: spectrum of disease varicella pneumonia varicella pneumonia in adults: spectrum of disease varicella pneumonia varicella-zoster virus pneumonitis early treatment with acyclovir for varicella pneumonia in otherwise healthy adults: a retrospective controlled study and review varicella pneumonia in adults: report of cases and a review of the literature chickenpox pneumonia: an association with pregnancy epidemiology of chickenpox in england and wales - chickenpox in adults corticosteroids in life-threatening varicella pneumonia recurrent varicella pneumonia complicating an endogenous reactivation of chickenpox in an hiv-infected adult patient clinical manifestations of varicella-zoster virus infections in human immunodeficiency virus-infected children varicella pneumonia in patients with hiv/aids viral causes and management of acute liver failure fulminant and sub-fulminant liver failure: definition and causes virus hepatitis update factors in spread of hepatitis e fulminant hepatitis in a tropical population: clinical course, cause and early predictors of outcome detection of hepatitis e but not c in sera of patients with fulminant hepatitis liver transplant in the management of fulminant hepatic failure severe complications of measles requiring intensive care in infants and young children bacterial pneumonia as a superinfection in young adults clinical and laboratory features of measles in hospitalized patients a randomized, controlled trial of vitamin a in children with severe measles herpes simplex encephalitis: a review viral encephalitis herpes simplex virus type i encephalitis diagnosis of herpes simplex encephalitis: application of a polymerase chain reaction to cerebrospinal fluid from brain biopsied patients and correlation with disease. national institute of allergy and infectious diseases. collaborative antiviral study group polymerase chain reaction for detection of herpes simplex virus encephalitis impact of cytomegalovirus infection on organ transplant recipients clinical patterns of cytomegalovirus disease after liver transplantation observations from transplantation contributing to the understanding of pathogenesis of cmv infection cytomegalovirus infection after allogeneic bone marrow transplantation viral infections in the intensive care unit the causes of death in patients with human immunodeficiency virus infection. a clinical and pathologic study with emphasis on the role of pulmonary diseases cytomegalovirus in patients with aids cytomegalovirus in lavage fluid of patients with aids an unexpected cause of ventilation associated pneumonia cytomegalovirus antigenemia as a useful marker of symptomatic cytomegalovirus infection after renal transplantation -a report of consecutive patients direct detection of cytomegalovirus in peripheral blood leukocytes. a review of the antigenemia assay and polymerase chain reaction ganciclovir for the treatment of renal transplant -associated primary cytomegalovirus pneumonia treatment of cytomegalovirus infections in renal transplant recipients with -( , -dihydroxy- -propoxymethyl guanine) ganciclovir treatment of cytomegalovirus disease in transplant recipients and other immunocompromised hosts ganciclovir for the treatment of cytomegalovirus gastroenteritis in bone marrow transplant patients (hydroxymethyl) ethoxymethyl] guanine in the treatment of cytomegalovirus pneumonia treatment of cytomegalovirus with ganciclovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplants granciclovir immunoglobulin combination therapy for the treatment of human cytomegalovirus -associated interstitial pneumonia in bone marrow allograft recipients centres for disease control and prevention update: outbreak of severe acute respiratory syndrome-world-wide identification of a novel coronavirus in patients with severe acute respiratory syndrome clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study clinical features and short term outcomes of patients with sars in the greater toronto area development of a standard treatment protocol for severe acute respiratory syndrome induction of post inflammatory cytokines in human macrophages by influenza a (h n ) viruses: a mechanism for the unusual severity of human disease ribavirin inhibits viral induced macrophage production of tnf, il- , the procoagulant fg prothrombinase and preserves th cytokine production but inhibits th cytokine response managing sars amidst uncertainty sars: experience at prince of wales hospital, hong kong preventing local transmission of sars: lessions from singapore. published on-line ahead of print global outlook of severe acute respiratory syndrome (sars) advisors of expert sars group of hospital authority. effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (sars) health canada infection control guidance for respirators (masks) worn by health care workers -frequently asked questions key: cord- -kck e ry authors: nan title: th annual meeting, neurocritical care society, october – , , vancouver, canada date: - - journal: neurocrit care doi: . /s - - - sha: doc_id: cord_uid: kck e ry nan aging is associated with greater stroke risk and diminished stroke recovery. while the effect of aging on stroke recovery is well defined, the influence of aging on neuronal network activity and its correlation with stroke recovery is poorly understood. to study this, we performed serial whole-cortex imaging of spontaneous and evoked neuronal activity before and after stroke in young and aged mice and correlated those findings to behavioral outcomes. young ( - m, n= ) and aged ( m, n= ) thy -gcamp mice, underwent behavioral assessment and imaging before and , , , and weeks after infarct. infarcts were induced via exposure of somatosensory cortex to a laser ( mw, m) after injection of the photosensitive dye rose bengal. imaging followed placement of plexiglas windows and consisted of awake ( m) and anesthetized sessions ( m) with gcamp excitation via flashing of a nm led and acquisition via an emccd camera ( . hz framerate). somatosensory activation was via forepaw shock ( ma at hz for s x blocks). behavioral response was assessed by quantifying forepaw use during cylinder exploration ( m). aged and young mice exhibited similar baseline contralateral forepaw use (aged . ± . %; young: . ± . %) and evoked somatosensory cort . ± . x - ). whole-brain gcamp flourescence power in delta ( - hz) and infraslow ( . - . hz) ranges was significantly (p< . ) lower at baseline in aged mice. after stroke, aged mice developed greater long-term dependence on the unaffected limb (wk : aged . ± . %; young: . ± . %) - ). -stroke decrement in whole-brain gcamp fluorescence power was observed in aged animals. stroke in aged mice is associated with a greater decrement in local network activation, global mechanisms underlying age-related differences. hypernatremia and hyperchloremia is common after moderate-severe traumatic brain injury (mstbi) from saline resuscitation, osmotherapy administration, fever with insensible losses, limited free water administration, and diabetes insipidus. in isolation, hypernatremia and hyperchloremia are independent predictors of mortality in critically-ill patients; but this association has not been studied in mstbi, or in combination as physiologically occurring in patients. we examined whether hypernatremia and hyperchloremia in combination are independent predictors of in-hospital mortality in mstbi patients. we retrospectively analyzed prospectively collected data of consecutive mstbi patients enrolled in the optimism-study over a -year period. a semi-automated process provided all sodium and chloride values from the index hospitalization. time-weighted-average(twa)-sodium and chloride representing their "burden" over the entire hospitalization were calculated using a published formula. univariate and multivariable logistic regression were applied adjusting for impact-model-variables as validated predictors of mstbi mortality, osmotherapy, icu length-of-stay and ventilatory days. of patients analyzed, ( %) died. unadjusted mortality rates had a dose-response relationship with increasing sodium and chloride ( % for twa-sodium - mmol/l and % for twa-sodium > mmol/l; % for twa-chloride - mmol/l and % for twa-chloride > mmol/l; all p< . ). separately, twa-sodium (per mmol/l increase adjusted-or . ; %ci . - . ) and twachloride (per mmol/l increase adjusted-or . ; % ci . - . ) independently predicted mortality. in combination, however, twa-chloride remained an independent predictor of in-hospital mortality (per mmol/l increase or . , % ci . - . ), while twa-sodium did not (c-statistic . ; hosmer-lemeshow p< . ). to our knowledge, this is the first study to show that when concomitantly adjusting for hyperchloremia and hypernatremia burden, only hyperchloremia is independently associated with early mortality in mstbi. while not proving cause-and-effect, this suggests that hyperchloremia, and not hypernatremia as previously reported, deserves further attention in mstbi. if validated, this may have treatment implications for mstbi patients in the acute care phase. hyperosmolar therapy, with hypertonic sodium chloride (nacl) solution is often used in the treatment of cerebral edema and elevated intracranial pressure. recent reports have demonstrated that in patients with subarachnoid hemorrhage (sah) treated with hypertonic nacl, hyperchloremia is associated with the development of acute kidney injury (aki). we report a trial which compared two hypertonic solutions with different chloride content on the resultant serum chloride concentrations in sah patients. a low chloride hypertonic solution for brain edema (acetate), is a single center, double-blinded, double-dummy, pilot clinical trial comparing bolus dosing of . % nacl versus . % nacl/na-acetate for the treatment of cerebral edema in patients with sah. randomization occurred once patients who received hypertonic treatment for cerebral edema and/or elevated intracranial pressure (icp) developed hyperchloremia (serum cl- group, and to the hypertonic nacl/na-acetate one. the groups were well balanced in terms of severity of the sah, age, gender and risk factors. differerences between the serum chloride and sodium measurements, assessed from randomization to maximum during the icu course, were comparable between the nacl and nacl/acetate groups (cl: . ± . vs. . ± . , p= . ; na: . ± . vs. . ± . , p= . , respectively). nacl/acetate had a more prominent effect on immediate post dose sodium (increase of . ± . vs. . ± . ,p< . ). the rate of aki was lower in the na-acetate group ( . % in the nacl group vs. . % in the na-acetate group, p= . ). hyperchloremia preceded aki in . % of the cases; however, the time interval between hyperchloremia and aki was only a median of . days ). intention to treatment analysis demonstrated that treatment with hypertonic nacl/na-acetate hypertonic versus standard hypertonic nacl solution for patients with mild hyperchloremia, resulted in less events of a -center trials are needed to corroborate these results. up to . million people in the united states are living with physical, cognitive, and psychological sequelae after tbi. patients that sustain a moderate to severe tbi (mstbi) are heavily reliant on caregivers during their inpatient stay and for post-discharge care. there are limited data on how best to support caregivers in their role. the purpose of this study was to develop a checklist based on qualitative data that can be utilized by caregivers and clinicians to re-examine the particular needs of the caregiver at different periods in the acute, subacute, and chronic timeframe. patients with mstbi and their caregivers were recruited from two intensive care units (icus) in one institution to participate in semi-structured interviews at hours, one month, three months, and six months post-injury. transcripts of each interview were analyzed by two investigators who independently coded responses using a predetermined code list adapted from previously identified needs and concerns of other similar populations. based on the particular coded segments, a checklist and a list of strategies were derived to address the needs and concerns of caregivers. a total of patient-caregiver dyads were enrolled from x-y, with interviews completed; interviews with caregivers and with patients. caregiver interviews resulted in unique codes that corresponded to varying caregivers' needs and concerns which were developed into a checklist and list of strategies. the needs and concerns of mstbi caregivers should be assessed over time to provide the support necessary to assist in the care of mstbi survivors. implementation of a checklist, as well as a list of strategies, can allow for tailored interventions that improve the transitions of mstbi survivors from the icu to subacute/chronic care environments. malignant cerebral edema (mce) develops in a subset of those with hemispheric strokes, precipitating neurological deterioration and death if decompressive hemicraniectomy (dhc) is not performed in a timely manner. however, prediction of which patients will develop mce is imprecise based on baseline clinical and radiographic features imaging quantifies development of cerebral edema. we employ a recurrent neural network that learns from serial clinical and imaging data to enhance early prediction of mce. we identified patients with hemispheric stroke who had nihss and ct scans performed at baseline automated algorithm; midline shift (mls) was measured at the level of the septum pellucidum. we trained a recurrent neural network that incorporates sequential data and compared its performance to those of traditional models. we tried to maximize sensitivity for predicting mce (dhc or death) while optimizing prediction of those not requiring dhc (negative predictive value, npv). nine patients required dhc or died from mce. a linear classifier incorporating age, baseline nihss, and serum glucose had high npv ( %) but only % sensitivity for mce. a probabilistic gaussian mixed model (gmm) improved sensitivity to %. incorporating -hour nihss into gmm improved prediction (sensitivity %, npv %). the neural network was able to predict all cases of surgery and all of those not requiring surgery with % accuracy prediction. recurrent neural networks incorporating sequential clinical and imaging data from the first -hours after stroke may enhance our ability to predict which patients will need dhc. our promising pilot evaluation of this approach study requires validation in larger external stroke cohorts. aneurysmal subarachnoid hemorrhage(sah) survivors live with long term residual physical and cognitive disability. we studied whether neuromuscular electrical stimulation(nmes) and high protein supplementation(hpro) in the first two weeks after sah could preserve neuromotor and cognitive function as compared to standard of care(soc) for nutrition and mobilization. sah subjects with a hunt hess(hh) grade> , assigned to soc or nmes+hpro. nmes was delivered to bilateral quadriceps and gastrocnemius muscles daily during two minute sessions along with hpro(goal: . g/kg/day) between post bleed day(pbd) and . primary endpoint was atrophy in the quadriceps muscle as measured by the percentage difference in the cross sectional area from baseline to pbd on ct scan. all subjects underwent serial assessments of physical(short performance physical battery,sppb) cognitive(montreal cognitive assessment scale,moca) and global functional recovery(modified rankin scale,mrs) at pbd , , and . twenty-five subjects(soc= ,nmes+hpro= ) were enrolled between december and january with no between group differences in baseline characteristics( years old, % women, % hh> ). median duration of interventions was days(range - ) completing % of nmes sessions and % of goal protein intake. no difference in caloric intake between groups, but hpro+nmes group received more protein( . +/- . g/kg/d v . +/- . g/kg/d,p< . ). muscle atrophy at pbd was less in nmes+hpro group( . +/- . % vs . +/- . % ,p= . ). on univariate analysis, higher atrophy was correlated with lower daily protein intake (r=- . ,p= . ); and worse month moca (r=- . , p= . ),sppb(r=- . ,p= . ) and mrs(r= . ,p= . ). nmes+hpro subjects performed better on sppb(p= . ), were observed to have a lower mrs(p= . ) and obtained a higher moca(p= . ) than soc at pbd . nmes+hpro may reduce acute muscle wasting in lower extremities with a lasting benefit on recovery after sah. to better understand whether nmes and/or hpro are responsible for observed benefits, a larger, multicenter study is underway. increasing authorization rates for organ donation is the best way to grow the number of organs available for life-saving transplants. in order to improve our authorization rates and thereby provide more organs for life-saving transplants, our organ procurement organization (opo) partnered with donor hospitals to -led donation conversations and intensified the focus on a collaborative donation process. ned in the the opo during the authorization process by providing a timely notification of a potential donor and by work together on the timing of the donation discussion. the overall authorization rate has improved from % in to % currently. during this time frame, --led conversations has been compelling and a significant factor in improving authorization rates. equally impactful to improved authorization rates has been a % increase in cases involving a collaborative donation process (measured by timely referral and collaborative mention of donation). developing a strong partnership between an opo and a donor hospital is paramount to a successful donation process. critical factors such as timely referral notification and collaboration regarding the timing of the donation discussion can positively influence authorization outcomes. moreover, we -led donation conversations will lead to further increases in authorization which results in more lives saved through donation. quantitative eeg analysis is one part of multimodal monitoring in the intensive care unit due to high temporal resolution and ease of deployment. previously we have shown that dynamical properties of eeg signals can be used to differentiate focal vs. diffuse causes of coma (kafashan et al., ) , and that the intrinsic reactivity of eeg signals -a measure of responsiveness of the eeg to endogenously rare events -correlates with gcs score (inri, khanmohammadi et al., ) . here, we explore the possibility of localizing brain lesions using these dynamical features of eeg signals. we collected retrospective data from comatose patients (gcs< ) defined to have a focal injury. the patients underwent eeg recordings and imaging for routine purposes at barnes-jewish hospital nnicu. index (inri) , which consists of identifying intrinsic events, obtaining brain-state trajectories, and quantifying brain-state trajectories. we then used a neural network-based classifier to map the inri to lesion location using supervised learning paradigms with cross-validation. we used imaging to identify anatomical location of lesions and project them to a two-dimensional headmap. we trained a neural-network classifier to predict d lesion location from the inri dynamics of each eeg channel. we then assessed the correlation between predicted location and actual location using a cross-validation protocol. predicted locations significantly correlated with injury location (r> . ) when compared to correlations with randomly selected patients (r~ ). the results point to a systematic change in underlying neuronal-dynamics induced by brain lesions, that was captured through eeg dynamics and the concept of intrinsic reactivity. here we developed and evaluated a framework to localize brain injury through novel analysis of eeg dynamics. the results here, together with our previous work, suggest brain injuries can be detected and localized using eeg recordings. to examine whether changes in intracranial pressure (icp) waveform morphologies can be used as a biomarker for early detection of ventriculitis. of consecutive patients enrolled prospectively in a hemorrhage outcomes study from to , ( %) patients required external ventricular drainage (evd). only the culture-positive ventriculitis seen in ( % of all evds) patients were included in current analysis. based on our es per week, and additionally if infection was suspected. evds were left open for drainage, with icp monitored hourly by clamping. using wavelet analysis, we extracted uninterrupted segments of icp waveforms. we extracted dominant-pulses from continuous high-resolution data using morphological clustering analysis of icp pulse (mocaip). then we applied hierarchical k-means clustering using dynamic time warping distance to obtain morphologically similar groupings. we applied a top-down approach to split the clusters further, which stops when the mean distance of the waveforms to the centroid is less than a pre-clusters and further-split clusters (when equipoise existed) were categorized for broad comparison by clinician consensus. we extracted , dominant pulses from . hours of evd data. , pulses ( . %) occurred before positive culture, , pulses ( . %) were during culture positivity, and , pulses ( . %) occurred after clinical diagnosis was made. k-means identified clusters, which were further grouped into meta-clusters: tri/biphasic (green), single-peak (yellow) and artifactual (red) waveforms. . % of dominant pulses were tri/biphasic before ventriculitis, which reduced to . % during and . % after (p< . ). one day before the first positive cultures were collected, the distribution of meta-clusters changed to include more single-peak and artifactual icp waveforms (p< . ). the distribution of icp waveform morphology changes significantly prior to the clinical diagnosis of ventriculitis, and may be a potential biomarker. inducing normothermia with temperature modulating devices (tmds) is often associated with significant shivering. we tested the ability of a novel transnasal tmd to induce and maintain normothermia with minimal shivering in endotracheally intubated (et) cerebrovascular patients. single center study utilizing coolstat transnasal cooling device to achieve core temperature reduction by inducing an evaporative cooling energy exchange in the turbinates and upper airway thru a high flow of dehumidified air into the nasal cavity and out the mouth. primary goal was the ability to induce normothermia(t<= . c) within hours in et patients with fever(t>= . c) refractory to acetaminophen. continuous temperature measurements were obtained from tympanic and core(esophageal or bladder) temperature sensors. safety assessments included continuous monitoring for hypertension, tachycardia, and raised icp(when monitored). ent evaluations monitored for any device related nasal mucosal injury. shivering was assessed every minutes using the bedside shivering assessment scale(bsas). duration of device use was limited to hours, as regulated by the e care for temperature management. ten subjects(median age: years, bmi: . kg/m , %men) were enrolled with normothermia achieved in % of subjects. one subject did not achieve normothermia and was later refractory to other tmds. median baseline temperature was . +/- . c, with a reduction noted by hours( . +/- . v. . +/- . , p< . ) and sustained at hours( . +/- . v . +/- . , p= . ). time to normothermia was . +/- . hours. the median bsas was (range: - ) with only episodes necessitating meperidine across hours of study monitoring. no treatment was discontinued due to safety concerns. ent evaluations noted no device related adverse findings. inducing normothermia with a novel transnasal tmd appears to be safe, feasible and not associated with significant shivering. a multicenter trial testing the ability to maintain normothermia for hours is currently underway. traumatic coma is thought to be caused by disruption of the subcortical ascending arousal network (aan). this hypothesis has not yet been tested because tools to map aan connectivity in living humans have only recently become available. we implemented high angular resolution diffusion imaging (hardi) on an mri scanner in the intensive care unit to determine whether patients presenting with traumatic coma have disrupted aan connectivity. we performed high angular resolution diffusion imaging (hardi) in patients with acute severe traumatic brain injury who were comatose on admission and in matched controls. we used probabilistic tractography to measure the connectivity probability (cp) of aan axonal pathways linking the brainstem tegmentum to the hypothalamus, thalamus and basal forebrain. to assess the spatial specificity of cp differences between patients and controls, we also measured cp within four subcortical pathways outside the aan. compared to controls, patients showed a reduction in aan pathways connecting the brainstem tegmentum to a region of interest encompassing the hypothalamus, thalamus, and basal forebrain (patients: median . , iqr [ . , . ] controls: . [ . , . ], p = . ). examining each pathway individually, brainstem-hypothalamus and brainstem-thalamus cps (pc < . ), but not brainstemforebrain cp (pc = . ), were significantly reduced in patients. only one subcortical pathway outside the aan showed reduced cp in patients. we provide initial evidence for the reduced integrity of axonal pathways linking the brainstem tegmentum to the hypothalamus and thalamus in patients presenting with traumatic coma. our findings support current conceptual models of coma as being caused by subcortical aan injury. aan connectivity mapping provides an opportunity to advance the study of human coma and consciousness. limited knowledge about the physiology underlying coma recovery has decreased clinicians' ability to identify patients likely to benefit from continued intensive therapy. machine learning using quantitative eeg (qeeg) has shown potential to improve outcome prediction in cardiac arrest, but the relationship between qeeg trends and coma recovery had limited evaluation in large multicenter studies. seven hospitals contributed clinical and eeg data from comatose adult subjects with cardiac arrest who underwent continuous eeg and targeted temperature management. qeeg features evaluated included background frequency, burst-suppression ratio(> %), epileptiform discharges, and entropy. we utilized random forests to predict good (cpc - ) vs. poor (cpc - ) outcome at -months. model performance was evaluated using the auc at h intervals up to h. we analyzed , hours of eeg (+ tb) for , subjects ( good outcomes). unfavorable eeg features were common in subjects with good or poor outcomes (epileptiform discharges: %, % and burst-suppression: %, %, respectively). epileptiform discharge frequency peaked after rewarming in subjects with good outcome ( spikes/min at h), but continued increasing during cooling and rewarming for those with poor outcome ( - spikes/min from h- h). shannon entropy was always higher in subjects with good outcome. burst-suppression strongly predicted outcome for all centers but during different times, while epileptiform discharges predicted outcomes in five centers, entropy in three, and alpha-background in only one. outcome prediction was best with qeeg during cooling rather than after rewarming (auc . vs. . at h and h, p< . ). maximal auc at h for individual centers ranged from . - . . early qeeg trends carry useful information for coma recovery prediction, but marked heterogeneity in qeeg trends across centers can limit performance and reproducibility of machine learning prognostication algorithms. coexistence of favorable and unfavorable qeeg features in the same patient is common, suggesting that generalizable models for coma recovery prediction must leverage temporal trends. human consciousness depends on ascending projections from the brainstem. brainstem lesion mapping studies have identified a coma-specific sub-region of the dorsolateral pontine tegmentum. however, loss of consciousness (loc) can also occur following injury to cortical regions remote from the brainstem, a phenomenon that commonly occurs after penetrating head trauma but remains poorly understood. andexanet alfa has been shown to reduce anti-factor xa activity however outcome studies are lacking. we compare the efficacy of four-facto -pcc) vs andexanet in patients with factor xa inhibitor related bleeding. retrospective study was performed january to march , including patients with factor xa inhibitor related bleeding of whom wer -pcc vs treated with andexanet. outcome was analyzed using glasgow outcome scale (gos) at discharge, presented as good (score - ) and poor ( - ); length of stay (los) and invariables, and t-test for continuous variables. -pcc or andexanet were included in the study. bleeding source --pcc; vs andexanet cases, % of total -pcc n= , andexanet n= ) and trauma ( -pcc -pcc group was . d vs . d in the andexanet group; icu stay corresponded to . vs . days, respectively. outcomes evaluated through gos did not differ -pcc group vs % in andexanet group, -pcc group vs . % on andexanet group, p= ). unexpectedly, in-hospital mortality was higher on andexanet group -pcc group ( . %); with a similar trend observed in the cns subgroup. -pcc as a factor xa inhibitor related bleeding reversal agent was as effective as andexanet based on outcome scale, constituting an essential option for hemostatic control as cost differences can limit the use of andexanet. the mechanism by which early administration of tranexamic acid (txa) reduces mortality in traumatic brain injury (tbi) is poorly understood. in-vitro models suggest the glycocalyx is preserved with early txa administration, indicating that txa may inhibit glycocalyx breakdown. we hypothesized that early txa administration would result in vascular endothelial preservation as evidenced by lower levels of thrombomodulin, syndecan- , icam, and vcam. we analyzed a subset of subjects from the prehospital txa for tbi trial, which examined the efficacy and safety of prehospital administration of txa compared to placebo in patients with moderate or severe tbi who were not in shock. blood samples were collected upon admission and at hrs. glycocalyx breakdown markers were quantified using a luminex analyte platform. clinical variables were compared using wilcoxon rank-sum tests for non-parametric continuous data and chitests for categorical data. differences in median marker levels were evaluated using t-tests performed on log-transformed variables. significance was set at . . data from patients [placebo (n= ), txa (n= )] were analyzed. groups were well-matched for age, sex, injury mechanism, admission injury severity score, head abbreviated injury score, and presence of intracranial hemorrhage (ich) on admission ct. no differences were observed in any median marker levels on admission or at hours. however, admission levels of syndecan- in patients with ich (n= ) who received txa were lower than those in the placebo group ( . pg/ml [ . - . ] v. . pg/ml [ . - . ], p= . ). no differences in thrombomodulin, icam, or vcam levels were detected at either timepoint in the ich subgroup. administration of txa early after injury may attenuate endothelial release of syndecan- in patients with moderate or severe tbi and ich, potentially suggesting a selective role for txa in endothelial gl despite a rapid increase in the use of the oral factor xa inhibitors rivaroxaban and apixaban over recent years, there remains no standard management for associated life-threatening hemorrhage. andexanet -approved reversal agent available but its place in therapy remains controversial due to its high cost and a lack of head-to-head trials comparing it to four-factor prothrombin complex -pcc). we conducted a retrospective review of adult patients admitted with ich associated with rivaroxaban or apixaban and -pcc for anticoagulation reversal between may and april . the primary outcome was hemostatic efficacy using the annexa- study rating system (excellent, good, or poor) based on initial and repeat non-contrast ct head imaging within hours. secondary outcomes included the occurrence of thromboembolic events and -day all-cause mortality. we excluded patients whose hematoma was surgically evacuated before the -hour ct or who received multiple reversal products. ich patients met the inclusion criteria: andexanet patients ( spontaneous and traumatic) and -pcc patients ( spontaneous and traumatic). ( %) andexanet patients achieved excellent -pcc patients ( -pcc patients, ( %) achieved good (p= . ) and ( %) achieved poor (p= . ) hemostasis. thromboembolic events following -pcc patients (p= . ). thirty-day all-cause mortality occurred in ( %) andexanet patient and ( %) -pcc patient (p= . ). -pcc for reversing ich associated with rivaroxaban and apixaban. limitations include our small sample size and -pcc in this population now that andexanet alfa is widely available. a quality improvement project was undertaken to understand the risks of central venous catheter associated venous thromboembolism (vte) in the neuroicu setting. all patients who were admitted to the neuroicu and required a central venous catheter from / / to / / were included in the study. all catheters were placed under ultrasound guidance using the seldenger technique. the site of catheter insertion, duration of dwell time and subtype were recorded for each catheter that was placed. catheters were categorized as cooling catheters, large bore and dialysis catheters, or standard multi-lumen infusion catheters. clinical suspicion for vte such as extremity edema or unexplained hypoxemia triggered the standard of care use of ultrasound and/or lung ct angiography for diagnosis. vtes with an appropriate chronology and in the same vascular distribution as the suspected catheter were categorized as catheter associated. catheters in patients were included in the analysis representing catheter*days. a total of catheter related vtes were observed in our cohort. in a mixed neuroicu cohort the overall vte rate was . per patient days which is in line with prior published rates. multi-lumen infusion catheters had the highest rate of vte ( . ± . ) and cooling catheters had the lowest rate ( . ± . ). surprisingly, the highest rate of vtes was observed in catheters placed in the subclavian vein across catheter types ( . ± . ). we observed that multi-lumen infusion catheters had a higher rate of vte compared with cooling and large bore catheters. this finding may be related to longer dwell times for multi-lumen catheters ( . ± . vs [cooling] . ± . and [large bore] . ± . ). the subclavian vein was the site with the highest rate of vte which may be related to more lateral approach taken with ultrasound guided subclavian catheter placement. patients on direct acting oral anticoagulants (doacs) have high mortality after intracranial hemorrhage (ich). prothrombin complex concentrate (pcc) has been used off-label to treat ich while on doacs. pccs effect on laboratory markers of anticoagulation have varied. whether or not a change in laboratory markers of anticoagulation impact outcome is unknown. retrospective, single center design assessing patients on doacs that presented with ich and received pcc. the primary outcome is to describe changes in anti-thrombelastography (teg) parameters before and after receiving pccs. hemostatic efficacy (defined by international society on thrombosis and haemostasis criteria), and thrombosis rate are also reported. thirty five patients were included. patients were . +/- . years old and % were male. . % had traumatic brain injury related hemorrhage, % had primary intracerebral hemorrhage, . % had subdural hemorrhage, and . % had subarachnoid hemorrhage. median glasgow coma score at was . units/ml +/- . units/ml. on average teg r time decreased +/- seconds and teg act time decreased +/- seconds. hemostatic efficacy was excellent or good in % of patients and poor in %. thrombosis rate was . %. overall mortality was %. there was a modest response in laboratory parameters after giving pcc to patients with doac associated ich. the mortality in this cohort was high. whether a laboratory response in coagulation dosing, laboratory response, hemostatic efficacy and patient outcomes. in critically ill patients with tbi, agitated behaviors may often be threatening for patients safety and for clinical teams. antipsychotics are commonly used for the acute management of these agitated behaviors. however, animal tbi models suggest that repeated use of antipsychotic agents reduce cognitive and functional recovery. it remains unknown if the use of these agents negatively impact the functional recovery of tbi patients. our objective was to describe the use of antipsychotic agents and agitation/delirium monitoring practices in critically ill tbi patients. we conducted a retrospective observational study of adult icus in canada that manage tbi patients. consecutive adult patients with moderate/severe tbi admitted to icu between january and december were included. data were collected using standardized forms for up to a maximum of days in icu or until transfer out of icu. the primary outcome was incidence of antipsychotic use. we included patients ( patient-days) with a moderate ( %) or severe ( %) tbi. the majority tbi included falls ( %), mva ( %) and assaults ( %). antipsychotics were used in % of patients for a total % of patient-days. quetiapine, haloperidol, olanzapine, and risperidone were used in a %, %, %, % of patient-days, mostly for agitation, an unclear reason or delirium ( %, % and % of total patient-days, respectively). a delirium monitoring tool was used % of patient-days whereas the rass and sas were used in % and % of patients-days, respectively. despite uncertainties regarding their efficacy and safety, antipsychotics are frequently used in critically ill moderate/severe tbi patients in canada, mostly for the management of agitation. sedation/agitation tools are mostly used for the monitoring whereas delirium tools are more rarely used. traumatic venous sinus thrombosis (tvst) is increasingly detected on neuroimaging in acute head trauma, and may be an important contributor to elevated icp refractory to standard medical/surgical treatment, and in turn, higher morbidity/mortality and more complex icu course. we sought to identify clinical and neuroimaging features predictive of refractory icp issues in tvst patients treated in an urban level i trauma center. retrospective query of electronic radiology database from to using the phrase "venous sinus thrombosis". cases were reviewed and scored by a fellowship-trained neuroradiologist to define degree of occlusion (partial vs complete) and cause of sinus occlusion (extrinsic compression vs intrinsic thrombus vs both). additional patient characteristics included demographics, mechanism of trauma, cerebral venous sinus involvement, laterality, skull fracture, extra-axial hemorrhage and invasive neuromonitoring. refractory icp was defined as at least one spontaneous icp elevation >= minutes during icu stay despite use of first tier therapies for icp control. odds ratios were computed and adjusted by multivariate logistic regression for patient age, gender and initial gcs to determine association with refractory icp. among patients with radiologic diagnosis of tvst, developed refractory icp ( / = . %). statistically significant variables associated with refractory icp included involvement of internal jugular vein (aor= . , % ci . - . ), involvement of transverse sinus (aor= . , % ci . - . ) and presence of temporal bone fracture (aor= . , % ci . - . ) . potentially protective factors included sinus pathology secondary to extrinsic compression (aor= . , % ci . - . ) and coexisting epidural hemorrhage (aor= . , % ci . - . ). involvement of the internal jugular vein or transverse sinus and temporal bone fracture may represent sensitive features of tvst predisposing to refractory icp issues, while extrinsic compression of a sinus alone was found to be protective. monitoring cerebral autoregulation in traumatic brain injury (tbi) patients can indicate an individual cerebral perfusion pressure (cpp) target for which autoregulation is best preserved (cppopt): this offers a precision medicine approach with hypothetical advantage over the current 'one size fits all' strategy. large retrospective data suggest that managing cpp close to cppopt has a benefit in outcome. a prospective evaluation of cppopt guided therapy is needed, but before performing an outcome study it is necessary to assess the feasibility and safety of such a protocol. the primary objective of cogitate (cppopt guided therapy assessment of target effectiveness) is to demonstrate feasibility of individualising cpp at cppopt in tbi patients, expressed as the percentage of monitoring time for which cpp is within mmhg of regularly updated cppopt targets during the first days of intensive care unit (icu) admission. secondary objectives are to investigate the safety (increases of the treatment intensity level) and physiological effects of this strategy (changes in autoregulation indexes, organ function parameters). cogitate is a phase ii non-blinded, randomised controlled trial currently ongoing in the icu of cambridge, leuven, nijmegen and maastricht. severe tbi patients requiring intracranial pressure directed therapy, are enrolled in the first hours after icu admission and allocated into two groups. in the intervention group the cpp target (cppopt) is calculated using a (modified) algorithm previously described by liu x et al. and clinically reviewed -hourly. the control group uses a fixed cpp target ( - mmhg). patient re have been recruited so far. randomising between a fixed and variable cpp is feasible. after completion of recruitment and follow up in terms of assessment of safety and physiological parameters, we will consider progressing to a phase iii study. selective reduction of non-classical monocytes has been associated with reduced neutrophil activation in murine traumatic brain injury (tbi) models. similarly, cd -/cd -t cells or double negative t-cells (dnt) may exacerbate ischemic brain injury. this study sought to assess the expression of peripherally isolated t-cells and monocytes after acute tbi. all patients admitted with primary tbi to the neurotrauma icu between november and november were eligible for study. consent was obtained and blood samples were obtained within hours of injury. samples were compared to healthy age-and sex-matched controls. conventional flow cytometry techniques gating on all patients admitted with tbi to the neurotrauma icu between november and november were eligible for study. consent and blood samples were obtained within hours of injury. samples were compared to healthy age-and sex-matched controls. conventional flow cytometry techniques, gating on cd + and cd + were employed to identify t-cell and monocyte populations, respectively. data were analyzed using cytometric fingerprint binning and t-sne embedding, which captures the set of multivariate probability distribution functions and generates maps that facilitate quantitative comparisons. patients were compared to controls. after computational analysis, distinct t-cell phenotypes were identified, of which were statistically significantly different between patients and controls expressed as a fraction of cd + cells. three of these eleven subsets had a cd -/cd -(double negative) phenotype that were depressed among patients: cd -/cd -/cd + . % versus . %, p= . ; cd -/cd -/ + . % versus . %; p= . ; cd -/cd -/ +/ + . % versus . %; p= . . there was a three-fold decrease in the fraction of type , non-classical monocytes in patients than in controls [ . (iqr . - . ) versus . (iqr . - . ); p= . ]. similar patterns in monocyte expression were observed for the patients who had repeat analysis at hours. in this preliminary study, there were notable reductions in dnt populations and non-classical monocytes in patients with acute tbi, which may suggest recruitment to the cns. prior studies suggest that dnt play a critical role in the perpetuation of cerebral ischemia after acute stroke and that type monocytes modulate neutrophilwarranted. much of the secondary injury that occurs after traumatic brain injury (tbi) results from coagulation derangements related to disseminated intravascular coagulation (dic). extracellular vesicles (evs) are small ( . transduction. evs are released from all cell types, including platelets, endothelium, and granulocytes which are responsible for dic. we hypothesized that specialized flow cytometry techniques could identify a unique ev signature of dic in acute tbi. ev fluorescence panels were created assessing for endothelial cells (cd +, cd +), platelets (cd , cd a+, cd b+), erythrocyte markers (cd +) as well as brain specific biomarkers (s b). using a modified flow cytometry instrument for detection of small particles, side scatter signal is used to estimate ev size. samples were treated with triton, which disrupts vesicular membranes, abolishing evs. samples were prepared in trucount tubes with a known number of lyophilized beads, which enabled the determination of the plasma volume. all combinations of positive/negative expression were counted. there was no significant difference in the total number of evs in the panels between the patients and controls. of combinatorial analyses in the first ev panel, the following were significantly elevated after bonferroni correction: cd +/cd + . evs/ul plasma v controls (wilcoxon rank sum p= . ); cd +/cd + . evs/ul plasma v . controls (p= . ); cd +/cd a+ . evs/ul plasma v . controls (p= . ). brain biomarkers were also elevated: s b . evs/ul plasma v. . controls (p= . ). evaluate whether this expression correlates with secondary microvascular brain injury. s b evs (membrane bound, not free soluble protein) are significantly elevated in tbi patients; if reproducible, the significance of this remains to be elucidated. diabetes insipidus (di) following transsphenoidal craniotomy may lead to significant metabolic derangements. serum sodium imbalances are frequent and important; both hypo-and hypernatremia can be devastating neurologically. a project aimed at improving di management through predictive assessments and ddavp protocols could potentially improve patient outcomes. however, few predictors for the postoperative development of di have been reported. after institutional irb exemption, the records of patients undergoing endonasal transsphenoidal craniotomy between july and december were retrospectively reviewed. demographics, preoperative medical or radiologic diagnoses, medications, and laboratory values as well as intraoperative blood loss, urine output, and ddavp administration were assessed for correlation with the incidence of postoperative development of di using logistic regression. development of postoperative di was defined as postoperative ddavp administration and/or ddavp use upon or after discharge from hospital. of the patients developed postoperative di. patients . , and . , respectively). similarly, patients with increased intraoperative blood loss, increased intraoperative volume administration, nd intraoperative ddavp or vasopressin administration were also more likely to develop postoperative di (pwith logistic regression modeling adjusted for associations between outcome and potential risk factors, patients having a documented or clinical suspicion for a preoperative endocrinopathy had seven times higher odds of developing postoperative di compared to their peers (p-value . , % ci . - . ). in administration, and ddavp were independently associated with an increased risk of postoperative di; the odds of postoperative di were seven times higher in patients with a documented or clinical suspicion findings. the seminal mechanical thrombectomy (mt) trials had a median age of years. though some of these trials included nonagenarians, there is little data on their outcomes. we aimed to compare the procedural, discharge outcomes and complications, of mt for acute ischemic stroke (ais) in patients with ais admitted to two comprehensive stroke centers were enrolled prospectively in a mt, procedural outcomes, complications, and discharge disposition were compared in propensity scorematched groups (matched for nihss, pre-stroke mrs, ivdefined as a discharge to home/acute rehabilitation. of the ais patients, / ( %) nonagenarians underwent mt compared to / ( %) ) were propensity score-matched with a median admission nihss of and , and median aspects ( % vs %, p= . ), whereas ica ( % vs %, p= . ), and m ( % vs %, p= . ) occlusions were similar between the two groups. time to groin puncture ( ± vs ± ; p= . ), revascularization time ( ± vs ± ; p= . ), complication rates ( vs . %; p= . ) and inhospital deaths ( % vs %; p= . ) were similar among the two groups. % of nonagenarians had we present one of the largest series of mt among nonagenarians with % successful recanalization rates. in propensity score analysis almost half of nonagenarians ( %) were discharged to home/rehab, which is comparable to a younger cohort ( %). aggressive management is warranted in the oldest of the old. early neurologic deterioration (end) occurs in up to one third of stroke patients and is associated with poor outcome. no consistent definition of end exists regarding degree of nihss decline and timeframe. we evaluated the definition of end, predictive factors, and day outcomes in a cohort of critically ill stroke patients. this study is a retrospective review of consecutive ischemic stroke patients with nih stroke scale (nihss) intervention factors were obtained. end was defined as a delta nihss > at hours from admission. reperfusion was defined as a thrombolysis in cerebral infarction (tici) score of > b, cerebral edema treatment as any icp-lowering therapy, and poor outcome as mrs > at days. multivariable logistic regression analyses were performed to assess factors associated with end and poor outcome. patients (median age years, % women, median nihss ) met study criteria. % experienced end. admission nihss, administration of tpa, receipt of intraarterial therapy, and successful reperfusion were not associated with end. end was independently associated with older age (p= . ), sex (p= . ), and treatment of cerebral edema (p= . ) after adjusting for cerebral herniation and tracheostomy. poor outcome was associated with older age (p= . ), higher delta nihss (p< . ), not receiving tpa (p= . ), and placement of percutaneous endoscopic gastrostomy tube (p= . ). end patients had a higher median day mrs (p< . ). end as defined by a delta nihss > at hours predicts poorer outcome, but was not associated with tpa or intraarterial therapy, which contrasts with prior literature. this variance could be attributed to the end timeframe defined as hours rather than the typical samples sizes and comparison of end timeframes could clarify observed findings. annexa- was a single-arm, prospective, open-label study of andexanet in patients presenting with major bleeding within patients with spontaneous intracranial hemorrhage (ich). brain imaging was performed at baseline, and at and hours post andexanet treatment. subdural hemorrhage (sdh) thickness and ich volumetric analysis was performed using quantomo software. co-primary efficacy outcomes were change in anti- of patients enrolled in annexa- , nontraumatic ich was present in patients, including intracerebral +/-intraventricular in patients, subarachnoid in patients and subdural in patients. in this cohort, mean age was years (sd . ) administration was . hours (iqr . - . ); median time from symptoms to ct was . hours (iqr . - . ); and median time from ct to andexanet administration was . hours ). median intraparenchymal volume was . ml (iqr . - . ). among efficacy evaluable patients (baseline anti-treatment overall. in patients treated < hours after baseline imaging, hemostatic efficacy was . %; - hours after baseline imaging, . %; > hours, . %. within days, death occurred in patients ( . %). andexanet reduced anti--or apixaban-associated nontraumatic intracranial bleeding and with a high rate of hemostatic efficacy up to hours after treatment. spontaneous intracerebral hemorrhage (ich) is associated with high rates of mortality. multiple scoring systems exist however the original ich score remains most commonly used. we hypothesize that patients undergoing scuba, compared to medically managed patients, would have lower -day mortality than predicted. we performed a retrospective observational cohort study of consecutive nontraumatic spontaneous ich patients treated at a single, tertiary care, academic center from december to june . patients for each patient based on the admission ich score. a total of ich patients were included. the median age was (q = , q = ), gcs ( , ), and nihss ( , ) . sixty-three were deep hemorrhages and had intraventricular hemorrhage. median pre-operative volume was . ml ( . , . ). the expected -day mortality was . % while the observed mortality was %. on -day follow up, a mrs of - was seen in % of patients. patients undergoing scuba have an absolute risk reduction of . % in mortality than predicted by the ich score. good outcome to moderate disability, defined as mrs - , was achievable in almost half the introduction andexanet (coagulation factor xa [recombinant] inactivated-zhzo), a specific reversal agent for factor xa % of patients with major bleeding in the annexa- trial. however, little is known about the clinical factors associated with a hemostatic response in patients with intracranial hemorrhage (ich) receiving andexanet. annexa- was a prospective, single-arm, open-label study of andexanet in patients with acute major treatment was rated by an independent adjudication committee as excellent, good, or poor/none based on pre-specified criteria. all ich patients with evaluable he were included in the analysis. univariate and indication for anticoagulation, baseline antianti-platelet use, time from last dose to andexanet (and other time intervals), neurologic function, and hematoma characteristics were performed to identify factors predictive of he. of ich patients enrolled, ( . %) had evaluable he. in patients with ich, baseline antitime from symptoms to andexanet were all significantly associated with he. in multivariate analysis, time from last dose ( . h for excellent/good; . h for poor/none), time from symptoms to andexanet ( . h for excellent/good; . h for poor/none), and time from symptoms to scan ( . h for excellent/good; . h for poor/none) were independently associated with he. in ich patients treated with andexanet in the annexa- study, various time intervals were predictive of hemostatic efficacy. these findings suggest that shorter time intervals are associated with lower he and are consistent with the known relationship between time from symptoms and the risk of hematoma expansion. alterations in functional connectivity are associated with persistent cognitive deficits in survivors of aneurysmal subarachnoid hemorrhage (sah), but causation remains unknown. therefore, we sought to and behavior could be assessed. we used functional optical intrinsic signal imaging to measure spontaneous hemodynamic fluctuations -operated (n= ) and sah (n= ) mice. we tested behavior using the morris water maze, open field test, y-maze, and rotarod. timepoints were from days to months. we used the anterior prechiasmatic injection model of sah. . ), and visual cortex ( . vs. . ) at day following sham procedure or sah, as measured by the proportion of brain surface with a correlation coefficient > . (sham vs. sah, respectively, p< . ). -independent ng sah. a global connectivity index remained decreased until month following sah ( . vs. . , p< . ). an interhemispheric connectivity index was also he hidden platform test on the morris water maze (p= . ) and open field test ( vs. m, p= . ) at approximately weeks. there were persistent deficits on the y-maze for at least months ( % vs. % alternation, p= . with repeated measures at and months). there was no significant effect of sah on rotarod performance. we studied whether high-protein supplementation (hpro) and neuromuscular electrical stimulation (nmes) after subarachnoid hemorrhage (sah) could be a safe and feasible approach to reduce muscle wasting and improve long term recovery. assigned to standard of care (soc) or nmes + hpro. nmes was delivered to bilateral quadriceps and gastrocnemius muscles during two -minute sessions daily along with hpro (goal . g/kg/day) between post bleed day (pbd) and . tolerability was measured during each nmes session by assessing for agitation or discomfort. safety measurements included increased heart rate, blood pressure, or intracranial pressure (when monitored) during nmes. stimulation sites were assessed after each nmes for muscle injury or skin trauma. hpro tolerability was assessed by monitoring for gastric retention or emesis. safety measures included aspiration and evidence of acute kidney injury. nmes and hpro were discontinued if subjects refused. the goals were to administer at least % of nmes and hpro. muscle wasting was assessed with serial ct scans of the thighs. twenty-five subjects (soc= , nmes + hpro= ) participated with no differences in baseline characteristics ( years old, % women, % hh> ). median intervention days were (range: - ), with % of nmes sessions completed. two subjects had transient muscle soreness but no other adverse events. no adverse events were associated with hpro. the hpro group received % of the goal and more protein than soc (mean difference: . +/- . g/kg/d, p< . ). muscle atrophy at pbd was greater in soc group ( . +/- . % vs . +/- . %, p= . ). nmes and hpro are safe and feasible after sah. a larger pilot study is underway to understand whether nmes and/or hpro may beneficially impact neuromotor recovery after sah. lipocalin- (ngal) is released by activated neutrophils and astrocytes and mediates neuro-inflammation and iron regulation in hemorrhagic stroke models. blood ngal is an early biomarker in human ischemic l and neurofunctional outcome in sah patients. magnetic luminex assay, r&d systems) and assessed modified rankin scale (mrs) every months. patients with renal or severe liver dysfunction, active malignancy or intracranial infections were excluded. poor outcome is defined as mrs> . vasospasm was defined as > % reduction any vessel caliber on cerebral angiogram. continuous variables were compared with student's t or wilcoxon rank sum test depending on data distribution. one-way anova was used for multi-group comparison. sah cohort has mean age of . years, % women, % with poor -month outcome and % developed vasospasm. higher plasma ngal on post--sah days - (p= . ) and (p= . ) are associated with poor -month outcome. higher plasma ngal on postand ngal on post-sah days -- . ) early elevation of plasma ngal on post-sah day is associated with vasospasm and poor -month -sah - are associated with poor -month outcome. larger population studies are needed to validate plasma ngal as a potential sah biomarker. patients with aneurysmal subarachnoid hemorrhage (asah) are at risk of rebleeding prior to aneurysm obliteration. while placebo-controlled studies have shown that administration of either -aminocaproic acid (eaca) or tranexamic acid (txa) can decrease rebleeding, there has not been a comparison of the two in this patient population. because of a national shortage of eaca in , our hospital changed to txa. the purpose of this study is to describe the outcomes of asah patients treated with either eaca or txa. this is a retrospective chart review of patients who presented with an asah between / / and / / and were treated with either eaca or txa to prevent aneurysm rerupture. descriptive statistics were used. there were patients with asah who received eaca and who received txa. the groups were eaca group and . % in the txa group. the average time from admission to drug initiation was . ± . hours in the eaca group and . ± . hours in the txa group. no patient in either group experienced aneurysm rerupture after receiving the drug. similar numbers of patients in both groups had cerebral ischemia (eaca: % vs. txa: %) and extracranial thrombosis (eaca: % vs. txa: %). although txa is known to lower the seizure threshold, we found no increased incidence of seizures (eaca: % vs. txa %). there was a modest cost difference in favor of txa vs. eaca. there does not appear to be any major differences in outcomes in patients with asah treated with either eaca or txa for the prevention of aneurysm rerupture and a slight cost savings favoring txa. a larger prospective study is required to confirm these results. outcome prediction after aneurysmal subarachnoid hemorrhage (asah) is based on scores, which are determined once at admission. however, the occurrence of delayed ischemic neurological deficits (dind) depends on multiple concomitant and continuously changing factors. the goal of the study was to establish an automated analysis pipeline to predict dind from multimodal data. multimodal data (patients' history, imaging and laboratory values among others) from patients with asah were analyzed. dind was defined as new ischemia or perfusion deficits in native or contrastenhanced ct/mri and/or cerebral vasospasm in conventional, ct-/mr-angiography. a ranking of the features was performed by univariate regression analysis. only cases with < % of missing values were included in the model. among the tested features, the top , with a false discovery rate < . , were selected. missing values were imput random forest machine learning algorithm was applied. the performance of the prediction was estimated on the fly by predicting the observations that were not used for building the tree ("out-ofbag") across all trees. the final data matrix contained events described by features from patients. in the final model, the out-of-bag estimate of error rate was %, which reflected a % accuracy. the importance plot for different features revealed the importance of some parameters known in the context of inflammatory response, which is linked to the pathophysiological cascade leading to dind. these included counts of leucocytes, monocytes, neutrophils, and lymphocytes. however, other laboratory parameters, such as zinc and selenium, appeared to be of high importance in the model, which was somewhat unexpected. machine learning algorithms may be helpful to filter out predictive features from a large number. these features might be subsequently investigated regarding their predictive value on the occurrence of dind after asah. innate inflammation is a recognized mediator of dci after sah. we have shown that neutrophils and the neutrophil-derived enzyme, myeloperoxidase (mpo), mediate memory deficits in dci. how mpo affects memory is unclear. there is evidence that mpo, and its substrate h o , may act through astrocytes or directly on neurons. here we test mpos action on astrocytes and neurons. primary neuronal and astrocyte cultures were developed from wt and c bl/ thy -gcamp mice. to test if mpo or h o are toxic to neurons or astrocytes, cells were incubated with mpo ( . u/ml), h o ( . %), and mpo/ h o and evaluated with live/dead cell viability assay (thermofisher). to test if neuronal firing is affected by mpo, the same experimental conditions were examined in c bl/ thy -gcamp using video microscopy. neuron activation was stimulated with kcl (final concentration mm). addition of h o led to death in neurons and astrocytes. mpo did not affect cell death in either group. interestingly, mpo/ h o showed less cell death than h o alone suggesting a neuroprotective benefit of mpo. in neurons, kcl administered to untreated neurons led to continuous firing as evidenced by intense calcium signal. mpo addition did not change the firing rate when compared to baseline. after . hours of mpo pretreatment, activation with kcl showed a suppressed firing rate suggesting neuronal depression. the addition of mpo/ h o showed the same firing rate suppression as mpo alone. this study suggests that mpo acts directly on neurons to decrease function. in our model of neutrophilinduced development of dci, mpo is released in the meninges, diffuses to the brain parenchyma and acts directly on neurons to affect memory. this needs to be tested more thoroughly in an in vivo model of sah. how mpo specifically affects memory in neurons is an area of interest in our laboratory. delayed cerebral ischemia (dci) is a feared complication of subarachnoid hemorrhage (sah), leading to worse outcomes. electroencephalography (eeg) provides a useful, continuous monitoring tool for dci risk (claassen ; kim ; rosenthal ) and late-onset epileptiform discharges (ed) have high predictive value for dci (kim ; rosenthal ) . however, optimal parameters to assess ed contribution to longitudinal dci risk are unknown. we hypothesize that the evolution of ed frequency after sah can provide early identification of those at high dci risk. we analyzed continuous eegs from patients with moderate to severe aneurysmal sah. ed were identified using a commercial detection algorithm (scheuer ). we calculated ed frequency (per hour) after sah and compared mean ed frequencies between dci and control patients. we also evaluation, we performed group based trajectory analysis (gbtm) and calculated hourly receiver operating curves (roc). ed rates were higher in both dci and control groups during the clinical dci "risk period" of day - . overall mean ed frequency were significantly higher in dci patients (t-test, p= . ), including only pre-dci ed assessment (t-test, p< . ). hourly mean ed rates remain higher in dci patients from days - . using gbtm, we identified three distinct trajectories associated with dci ( %, %, %, p= . ), with group number selection optimized based on bayesian information criteria. hourly area under the roc (auc) calculations of ed frequency yielded a maximum performance of . . natural history of ed frequency in all sah patients coincides with the "high risk" time-period of dci. patients with dci have higher mean frequencies that remain elevated throughout this dci risk period. gbtm and auc calculations suggest longitudinal analysis of discharge frequency can differentiate dci risk, but integration of other waveform characteristics are needed to optimize prediction. aneurysmal subarachnoid hemorrhage (sah) has high morbidity and mortality. time to aneurysm repair, whether earlier or later in the course of the disease, may impact outcomes. however, optimal timing remains controversial. our goal was to describe the association between time to aneurysm repair and mortality and functional outcome. this study was conducted in two reference centers -one in rio de janeiro and one in porto alegre july to march , every adult patient admitted to the icu with aneurysmal sah was enrolled in the study. data were collected prospectively during the hospital stay. patients were divided into four groups according to the moment of aneurysm repair after bleeding: < days, to days, > days and not repaired. the primary outcome was in-hospital mortality. dichotomous variables were analyzed using twomortality as the reference group ( to days). a total of patients were included. median age was years, mostly female ( %). in the univariate analysis hydrocephalus, rebleeding, postoperative neurological deterioration (up to hours after procedure), delayed cerebral ischemia, as well as mortality and poor outcome, were associated with the different timing of aneurysm repair. in the multivariate model for mortality, poor grade sah, hydrocephalus, post-procedure neurological worsening and dci were independently associated with higher mortality. additionally, late repair was associated with lower mortality (or . ) as compared with occlusion between to days. our study shows higher mortality in patients submitted to aneurysm occlusion procedure between days and after ictus, when compared to late repair. more studies are needed to define the best timing of aneurism repair in patients that are not submitted to early occlusion. the biological mechanisms that influence abnormal cortical neurophysiology after aneurysmal subarachnoid hemorrhage (sah) are uncertain. we hypothesized that soluble st (sst ), a plasma marker of the innate immune response, is associated with events of electroencephalography (eeg) deterioration including new epileptiform abnormalities (eas) or new eeg background deterioration. -approved biospecimen repository, we evaluated patients with at least days of eeg monitoring and an early sst measurement (collected < days following sah). eas were defined as sporadic epileptiform discharges, lateralized rhythmic delta activity (lrda), lateralized periodic discharges (lpd), or generalized periodic discharges (gpd). background deterioration was defined as decreasing alpha delta ratio (adr), relative alpha variability (rav) or worsening focal slowing. the association between sst level and eeg-identified eas or new background deterioration was compared using the wilcoxon rank sum test. patients met inclusion criteria. early sst was collected at mean . ± . days after sah; patients had a subsequent sst measurement at ± . days. ( %) patients developed new eas during eeg monitoring, ( %) developed new background deterioration, and ( %) developed neither. median sst in patients developing new eas was higher ( . ng/ml ]) than in patients who did not develop new eas ( . ng/ml ], p= . ). this association between elevated sst and new eas was not present for sst samples collected at later time points. there was no difference in sst levels between patients who developed new background deterioration ( . ng/ml ) compared with those who did not ( . ng/ml ], p= . ). among patients admitted with aneurysmal sah, elevated sst in the first days is associated with the development of new eas on eeg monitoring. this association was not present at later time points, suggesting that the early inflammatory response may be linked to abnormal cortical neurophysiology. glial-mediated inflammation occurring early after status epilepticus (se) in rodent models has been implicated in the subsequent development of spontaneous recurrent seizures (srs). while this suggests anti-inflammatory strategies may be a target for therapeutic intervention, the appropriate timing for such an intervention is unclear. the aim of this work is to define the timing of early inflammatory changes using pro-inflammatory mir- and anti-inflammatory mir- a as biomarkers in a kainic acid mouse model of se. se was induced in - week old male c bl/ j mice (n= per timepoint) using intraperitoneal injections of mg/kg kainic acid. the onset of se was defined as the first class seizure using a modified racine scale. the intensity of the se episode was estimated by the total number of discrete class v seizures observed. after hours, the se was aborted with diazepam, and hippocampal tissue was harvested at hr, hr, hr, hr and hr. rna was isolated using trizole (life technologies) followed by qrt-pcr analysis to define the steady-state expression levels of mir- and mir- a and their targets, socs we observed a > fold increase in expression levels of mir- , reaching peak levels at hours. expression levels of mir- directly associated with the intensity of se. the level of socs mrna expression decreases after the peak expression of mir- . as the levels of mir- a were only conclusions mirna- expression shows an early increase within hours of se, reaching a peak at hours. mir- a shows a non-mir- initiated after se to determine if this can prevent the development of srs. nurses routinely screen for changes in neurologic status with serial clinical assessments. the objective of this study was to employ mixed methods to determine inter-rater reliability (irr), protocol adherence, and acceptability of a new tool we developed called serial neurologic assessment in pediatrics (snap) compared to the glasgow coma scale (gcs). snap assesses mental status, cranial nerves, communication, and four-extremity motor function/strength, with scales for children < -months, -months to -ye -years-old. snap was designed for use in a diverse population, including patients who are intubated, sedated, and/or have developmental disabilities. irr of independent snap assessments by pairs of trained nurses was assessed with multilevel cohen's kappa and linear weighted kappa, calculated through clustered bootstrap method to account for multiple assessments. we assessed protocol adherence with standardized observations. we conducted semi-structured interviews to assess acceptability and feas we thematically analyzed interviews in accordance with modified grounded theory framework. critical care nurses performed paired snap assessments on patients ( < -months; months to --years). there was substantial agreement between nurses (average kappa= . < -months; . -months to --years), and irr was unchanged for children who were intubated, sedated, and/or had developmental disabilities. irr was unchanged based on degree of experience using snap and for day vs. night-shift nurses. nurses had % protocol adherence. snap was easier to use and more precise at describing neurologic status of patients who were intubated, sedated, and/or had developmental disabilities than gcs. % of nurses preferred to use snap over gcs. when utilized by nurses, snap has substantial irr, excellent protocol adherence, and is acceptable and feasible to i neurologic decline. several studies demonstrate significant gender disparities in professional societies for critical care and neurology, but data for neurocritical care is lacking. we examined gender representation trends within the neurocritical care society (ncs), the largest international professional society for this subspecialty. we hypothesized that female representation has increased with achievement of gender equality in . a multidisciplinary writing group obtained approval from the ncs executive committee and endorsement by the women in neurocritical care (wincc) section. after review by the rush university irb, access was granted for the following rosters: general membership, board of directors, officers, committees, annual meeting speakers, grant, fellowship and other award recipients. we differentiated between female, male and unidentified gender. available membership rosters from listed members, with gender unknown for > %. in , of members . % were females, . % males, and . % unidentified. as of , / presidents ( . %) and - , female committee members increased from % to %; female committee chairs increased from % to %. to date, / ( . %) christine wijman young investigator awardees were female with no female recipients of the best scientific abstract award ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . % of presidential citation awardees - % from -e representation in guidelines writing groups ranged between %- % ( - ), and - % in consensus statements writing groups ( ) ( ) ( ) ( ) ( ) ( ) . - % ( awardees were women. within the ncs, a longitudinal increase in female representation has occurred over the last years but gender equality has not been achieved. we recommend focused efforts to facilitate inclusion and gender equity within ncs. with the push toward using large data sets in critically ill patients, the use and management of registries is becoming more relevant. clinical registries provide insight about associations and patterns in diagnosis, disease, and treatment. the integrity of the data is of utmost importance. this poster describes the quality control and data management methods for maintaining the integrity of a multicenter trial registry. we employed modifications to van den broeck's method of data organization to clean and manage the end-panic registry. the data management consisted of five phases: ) screening phase, ) data organization , ) diagnostic phase, ) treatment phase, and ) missing data phase. the screening phase consisted of distinguishing missing and extraneous data elements, outliers, inconsistent patterns/distributions and unexpected analysis results. the data organization phase consisted of treating blank cells and highlighting errors with data input. the diagnostic phase was used to clarify the true nature of the data points, and make sure the data presented was biologically possible. the treatment phase consisted of correcting variables. the missing data phase consisted of determining whether the missing data was informative or noninformative. currently the multi-center registry houses ~ . million discrete data points from , patients. there was a high correlation between the texas, ohio and california locations, and npi, dvl, cvl, mcvl, and pupil size. there was a low correlation between the texas, ohio and california locations, and pupil latency and presence/absence of cataracts. missing data was informative for age, race and ethnicity, and distribution of missing data caused an inquiry into methods for collecting data and implementation plans for change. this interdisciplinary method for cleaning and managing the end panic registry was able to identify and rectify errors. we would recommend others to use the methods to build, clean and manage clinical registries. objective was to describe current state of quality improvement (qi) processes implemented in neurocritical care units (nccu). a -question-survey was sent to members (physician, nurses, and pharmacists) of the neurocritical care society. we describe factors affecting the presence of nccu qi, barriers to qi, awareness of stroke (stk, cstk), stroke get with the guidelines (gwtg), trauma quality improvement program (tqip) and american academy of neurology (aan) performance measures, and examined factors affecting satisfaction with current practices. the response rate was . %; . % of respondents were from us teaching hospitals, . % practiced in dedicated neurocritical care units, and . % in a program with a neurocritical care fellowship. . % reported a dedicated nccu qi program. comprehensive stroke center (rr . , % ci . - . , p = . ), dedicated nccu (rr . , % ci . - . , p = . ), and ncc fellowship programs (rr . , % ci . - . , p = . ) were more likely to report dedicated ncc qi staff. external ventricular drain infection was the most commonly tracked ncc qi metric ( . %). respondents indicated the highest level of awareness for cstk ( . %), stk ( . %), and gwtg ( . %), but indicated a relative lack of awareness for tqip ( . %), and aan ( . %) perform satisfaction with existing ncc qi were: presence of a hospital qi program (rr . , % ci . - . ), p = . ), presence of a formal ncc qi program (rr . , % ci . - . ), p = . , and dedicated ncc qi staff (rr . , % ci . - . ), p < . ). insufficient hospital ( . %) and departmental support ( . %) were reported common barriers to the successful implementation of an nccu qi program. a dedicated staffed nccu qi program occurs in a minority of neurocritical care units, and the lack of such programs may lead to clinician dissatisfaction. institutional and departmental support may be critical elements of a successful and satisfactory implementation of nccu qi. the development and implementation of a nurse driven rounding model was instituted in the neuro icu of an academic medical center to increase effectiveness of team communication, practice autonomy and integration of nursing input into the interprofessional care plan. clinical nurses and neuro-intensivists developed a structured rounding tool to guide the nursing presentation of clinical information on rounds. the interprofessional team underwent education on expectations and processes. the rounding tool underwent a number of revisions over a -month period based on feedback from all team members and evolving patient care priorities. all team member roles in the rounding process were clearly defined with nursing leading patient assessment and goals. nursing satisfaction surveys assessed nursing attitudes regarding autonomy, decision making and rn-md communication via a point likert scale; mean values for each question domain were compared pre-and post-implementation. in total, nursing surveys were analyzed, pre-implementation and nurses postimplementation. mean response values evidenced significant improvement across all domains in the post-implementation group: autonomy ( . vs . , p< . ), rn decision making ( . vs . , p< . ), p< . ) . survey participation was good in both groups ( % pre-and % post-implementation). nursing satisfaction across multiple important domains improved following implementation of a nurse driven structured rounding model. application of a nurse-facilitated, structured model creates a standardized reliable process that can be observed by all team members in order to deliver data driven, high quality, efficient and effective care. multiple models for program development and care delivery in pediatric neurocritical care (pncc) have been proposed with varying degrees of success. here we present a unique model for building a dedicated pediatric neuro-intensive care unit (pnicu) through creation of a community of practice (cop). cop represents a mechanism for collective learning and production of repertoire of best practices through knowledge sharing, development of social capital, and support for organizational change. we utilized a bolman and deal -frame for organizational functioning (structural, human resources, political, symbolic) to describe the development of our pncc cop. we evaluated our pnicu with the standards outlined by the neurocritical care society (ncs) for a level neuro-intensive care unit. structural factors included forming pncc leaders across specialties (neurology, critical care, neurosurgery, radiology, nursing), opening (in ) a state-of-the-art, unique pnicu which includes wired rooms for continuous eeg monitoring and multimodal neuro-monitoring, meeting / ( %) of ncs standards. human resource factors included creating core groups of physicians and nurses with a primary role in pnicu, providing ongoing education through workshops, lecture series, and certification including enls and tncc, meeting / ( %) of ncs standards. politically, a pncc fellowship-trained, board-certified physician serves as medical director coordinating conception of collaborative partnerships across multidisciplinary experts. simultaneous creation of other specialty cohorts in pediatric critical care aided in departmental acceptance for the program, meeting / ( %) of ncs standards. symbolically, we set forth our shared purpose and strong commitment to foster cop that advances knowledge and best practices for pncc. using cop principles, we have accomplished many of the ncs standards over a relatively short period of time. we plan to further develop the program with particular focus on education, certification, and expansion to include allied health professionals. our roadmap may be applicable to any institution interested in developing a pncc cop/pnicu. intravenous (iv) anti-hypertensive infusions are often used acutely in patients with intracerebral hemorrhage (ich). there is a lack of standardization of titration and variation in goal blood pressure, and therefore their use is associated with increased icu length of stay (los) and cost. we examined the use of anti-hypertensive infusions in ich patients in our institution and developed a quality improvement intervention to reduce duration of infusion, icu los, and cost. patients were included if they were admitted to our icu from september -march with an icd- diagnosis of non-traumatic ich and received iv antihypertensive infusions. interventions introduced starting in november included interdisciplinary task force formation, provider education, updated rounding checklist, and emr order with clear blood pressure target. the primary outcome measure was duration of anti-hypertensive infusions determined by retrospective chart review, and secondary outcome measures of icu los and cost data were obtained from our finance department. over months, mean antihypertensive infusion duration reduced from . hours (n= ) to . hours (n= ). icu los reduced from . to . days. proportion of cases with discordant blood pressure goal documentation reduced from . % to . %, while discordance in documented goals to actual orders reduced from . % to . %. there were no significant increases in countermeasures (infusion restarts, icu readmission, and aki due to blood pressure lowering). extrapolating from finance data, and our baseline infusion duration and icu los data, iv antihypertensive infusions cost ~$ /hour. our improvement suggested $ in estimated cost savings in months. icu accommodation cost was approximated at $ /hour, for an estimated $ additional cost savings. a quality improvement based intervention targeting management of hypertension resulted in reduced duration of anti-hypertensive infusions, icu los, and cost. the intervention was feasible and ongoing data collection is warranted to assess sustainability. mortality and long-term-disabilities secondary to stroke are high. educating high-risk population with early stroke symptoms has been outstanding. however, education of post-stroke consequences (requiring resuscitation codes and goals-of-care awareness) is lagging. this study evaluates the understanding of such concepts by the admitted stroke patients (high risk population) and visitors (general population). were asked to answer a preliminary question about their original code status then read a self-explanatory sheet followed by revealing their revised code and goals-of-care choices. we used within-group logistic-regression-analyses to determine changes of codes among original coders and types of novel codes among post-survey coders. this included proposition of new short-term resuscitation (str-strp [partial]) codes. we used between-group chi-square-analyses to determine differences in education between groups. the odds of changes in no-coders were . , . in patients and visitors, (p-value= . , < . ) respectively. the odds of changes in dnr-coders= . , . , partial-coders= . , . , full-coders= . , . times those of the no-coders respectively (p-value< . ). the odds of novel-dnr-coders= . , and . , , . , . , . times those of novel-no-coders respectively (p-value< . ). str-coders originated from other-codes> no-coders. between-group analyses showed %, % of patients versus visitors changed their code status respectively (p-value= . ). goals-ofcare choices indicated tolerance towards temporary measures (tracheostomy and feeding-tube placement) and hemiplegic disabilities without poor mentation among the majority (~ - %) as a target for continuing care. pre-event (stroke) documentation of code status was approved among the majority of participants ( %). there is a misunderstanding of the resuscitation codes among both admitted stroke patients and general population. however, the difference between both indicates reception of some education among the stroke patients. str-strp are a good alternatives for many people. pre-event documentation -stroke outcome awareness are needed. early integration of palliative care improves communication, decision-making and social support in patients with acute stroke in the neurocritical care unit. the primary objective of this study was to analyze how early palliative involvement impacts communication between the healthcare team and patients/families. in this ongoing prospective study, patients with moderate to severe ischemic and hemorrhagic strokes were randomized into control and intervention arms. the control arm received routine icu care and the intervention arm received an early palliative care consultation. study assessments with the patient or surrogate decision maker were obtained at day - , and day - of icu care. comparisons were made for total scores on the questionnaire on communication (qoc), decisional conflict scale (dcs), and hospital anxiety and depression scale (hads). we performed an interim analysis utilizing the student's t-test and chi -square test on spss , with results below as mean + standard deviation. of patients enrolled ( intervention and control), % and % were female (p = . ). the average age was + and + years (p = . ). the majority ( % and %) were ischemic strokes (p = . ). admission nihss was + and + (p = . ). there was no difference in total qoc ( + , + , p = . ), hads ( + , + , p = . ), or dcs ( + , + , p = . ) scores. when comparing responses to individual questions, a trend toward improvement in qoc responses was observed "using words you can understand" (p = . ) and "answering all questions about illness" (p = . ). early integration of palliative care may improve communication between healthcare providers and patients/families, specifically with regards to using appropriate language that is understandable. routine daily chest radiographs (cxr) in mechanically ventilated patients (mvp) are often performed in the icu for "monitoring" purposes, despite lack of specific indications. routine daily tests are of questionable value and may increase costs without clinical benefit. the society for critical care medicine and choosing wisely campaign promote indication-based test ordering. studies involving medical-surgical icus demonstrate that indication-based versus routine daily cxrs in mvps results in cost-savings without jeopardizing outcomes. we implemented a quality improvement initiative targeting reduction of routine daily cxrs in mvps in the nsicu. we convened an interprofessional team of attending physicians, fellows, medical students and nurse practitioners. we conducted educational campaigns promoting evidence-based cxr utilization practices. standardized discussion of indication for cxr was incorporated into rounds. iterative process improvements were adopted beginning june . cxr utilization rates in mvps were measured the first weeks of , and and compared pre/post-intervention. hospital length of stay (hlos) was evaluated to monitor for complications resulting in prolonged hospitalization. implementation of indication-based ordering strategies decreased cxr utilization in mvps in the nsicu without increasing hlos. value-based care quality improvement initiatives can reduce costs without compromising clinical outcomes. patients transferred from nsicu to lower acuity units are vulnerable to readmissions and hospital acquired complications. standardized handoffs may help reduce this risk within academic institutions where physician trainees possess varying levels of clinical experience. we sought to implement a standardized handoff (i-pass) within inpatient neurology, focusing on high risk patient populations. residents and attendings were surveyed about inpatient handoff practices to inform implementation of i-pass. an electronic survey was administered in to residents and inpatient attendings in neurology at university of north carolina (unc). handoff practices among inpatient services (wards, consults, nsicu, and epilepsy) were evaluated. surveys assessed perceived quality of handoffs, as well as problems with handoffs leading to adverse events. surveys were sent to physicians ( residents, inpatient attendings); responses ( residents, inpatient attendings) were obtained (response rate, . %). -six percent of residents and % of attendings reported that problematic handoffs had been the primary or contributing factor to one or more adverse events. overall quality of handoffs involving nsicu patients transferred to lower acuity units was reported as a concern, with % of residents indicating the quality of these handoffs to be poor. in ranking inpatient services for prioritization of handoff interventions, % of residents identified nsicu handoffs as either their first or second highest priority. we also found residents exhibited a self-performance bias, with % reporting that they provided all pertinent information during handoffs most of the time, and only % reporting that they received all pertinent information during handoffs most of the time. inpatient handoffs are perceived as problematic by residents and attendings, with handoffs involving transfer of nsicu patients identified as high priority for targeted intervention. unc neurology has since implemented i-pass protocols to improve the safety of handoffs involving nsicu patients. targeted temperature management (ttm) to - c is the standard of care for post-cardiac arrest patients. recent literature has demonstrated a new trend of worsening morbidity and mortality postarrest due to under-utilization of ttm. management of post-arrest patients is a multidisciplinary health care effort, and knowledge of ttm rationale and protocol varies. normothermia ( - . c) also could have neuroprotective benefit in other clinical scenarios and is another indication for ttm. we hypothesized that a focused educational intervention would improve ttm protocol compliance. a multidisciplinary team developed a standard educational presentation and a question exam given as a pre-and post-test to residents, fellows, and critical care nurses. baseline data on ttm use was established followed by month prospective data collection post-intervention. data was extracted from arctic sun® machines on all ttm cases (post cardiac arrest and normothermia). the primary outcome was compliance with the ttm protocol measured by correct temperature target goals and appropriate duration, assessed by chi-square analysis. the secondary outcome measure was individual score improvement, evaluated by -variable students t test. there was a total of ttm cases pre-intervention, and ttm cases post intervention. there was a trend toward increased ttm protocol compliance ( % to %), however this was not statistically from pre-test (n= ) to post-test (n= ) after the education presentation (p< . , ci . to . ) among all health care participants. the resident, fellow, and nursing scores increased from % to %, % to %, and % to %, respectively. educational interventions for physicians and nurses caring for post-cardiac arrest and neurocritical care patients improved knowledge gaps and helped improve compliance with ttm protocol. additional education and process improvement activities are warranted to further improve protocol compliance, which may improve patient outcome. identifying the appropriate level of care needed for a patient presenting with acute intracerebral hemorrhage (ich) is often imprecise. the utility of prior work in triaging patients is limited by exclusion of non-primary ich patients, which is often difficult to determine prior to admission. this study aims to identify which admission factors are associated with icu level of care on presentation. this is a single-center retrospective review of patients admitted to our institution with ich in , regardless of etiology. all patients were admitted to the neurocritical care unit (nccu). icu level of care was defined as the need for mechanical ventilation, administration of vasoactive or insulin infusions, continuous renal replacement therapy, ventriculostomy, treatment of cerebral edema, temperature management, management of status epilepticus, or neurosurgical intervention. logistic regression was used to identify characteristics associated with icu level of care. patients (median age , % female, median admission gcs , median ich volume ml, % with ivh, % lobar, % infratentorial) were admitted with ich. ( . %) required intensive care. the most common interventions required were mechanical ventilation ( patients, . %), antihypertensi with need for intensive care included age ( vs. ), admission gcs ( vs. ), deep location of ich ( . % vs. . %), ich volume ( ml vs. ml), and presence of ivh ( . % vs. . %). on multivariate analysis, age (p = . ), admission gcs (p < . ), and deep location (p = . ) were independently associated with the need for intensive care. among all patients presenting with ich, age, admission gcs, and location of hemorrhage may help identify ich patients who need icu level of care. the impact of emergency neurological life support (enls) course on provider knowledge and selfreported comfort in management of neurocritically ill patients in a low-middle income country such as cambodia is unknown and explored in this study. in-person enls courses with english to khmer translated slides were conducted in hospitals in phnom penh, cambodia in may, . wilcoxon signed rank test and matched paired t-test were used to examine pre and post-course scores on translated knowledge-based multiple choice tests. a descriptive analysis was performed to evaluate provider comfort in management of neurocritically ill patients pre and post-course and amongst individual enls modules. overall, / healthcare providers participated; ( . %) physicians and ( . %) nurses. thirtythree ( . %) had acquired base specialty training in cambodia, ( . %) had completed subspecialty training in critical care medicine and ( . %) previously cared for neurocritically ill patients. pre-test sores were % [iqr ]; post-test scores were . % [iqr ]. though not statistically significant, posttest scores were higher for providers who had base specialty training in cambodia ( . % vs. . %, p = . ), subspecialty training in critical care medicine ( . % vs. . %, p = . ) and previous experience caring for neurocritically ill patients ( . % vs. %, p = . ). most ( %, n = ) reported that enls training had prepared them for management of neurocritically ill patients. enls courses may enhance the knowledge and comfort of healthcare providers in managing neurocritically ill patients in low-middle income countries, however this may depend on prior experience and minimizing language barriers. the impact of enls courses on outcomes in neurocritically ill patients in low-middle income countries warrants further study. neurocritical care has become increasingly subspecialized.yet, due to limited availability of dedicated neurocritical care units (nccus), often patients may need to be admitted to icus other than nccus. this survey based study was conducted to explore self-reported knowledge in recognizing and managing some common neurological emergencies such as stroke, status epilepticus, raised intracranial pressure etc among critical care nurses at a comprehensive stroke center. in january , we engaged nurses from icu units in this qi project-which included medical, surgical, neurocritical care, cardiac and cardiothoracic units as well as post-anesthesia care unit (pacu) and interventional radiology units. using institutional redcap anonymized surveys were sent to the nurses.information on demographic and critical care work experience was recorded. all participants answered questions with a likert type scale on their knowledge of several common neurological emergencies. nurses ( females, males) participated in the survey. ( %) had been working in an icu for years or longer. their self-reported level of knowledge in managing neurological emergencies revealed that more than half the participants did not feel comfortable managing patients with evds, ich, sah, raised intracranial pressure, tbi and traumatic spine injury patients. more than % of nurses were not satisfied with their current level of training to deal with neuroemergency and supported the need for dedicated training/ study time. icu nurses report gaps in fundamental knowledge in recognizing and managing common neuroemergencies. this highlights the need for providing ongoing training and education about neuroemergencies to critical care nurses to help maintain competencies. simulation training has been increasingly adopted in critical care specialties to promote active learning and create a reproducible platform for feedback. the role of advanced simulation as a core component of training in neurocritical care remains unclear, which may be due to uncertainty about the degree of fidelity needed. our objective was to determine if trainee knowledge and/or confidence differs when using standardized patients as compared to a multi-media simulation platform in a neurocritical care concepts training course. methods junior neurology residents engaged in simulated neurologic emergencies: a right mca stroke case, status epilepticus case, and a pontine hemorrhage/coma case. the mca stroke and status epilepticus cases were portrayed by trained standardized patients for half of the residents (group sp), while the other half interacted with the manikin supplemented with video clips of pertinent neurologic exam findings (group mv). both groups interacted with the manikin for the pontine hemorrhage/coma case. before and after the course, residents completed a -question multiple-choice test on management of neurologic emergencies and a survey about their confidence in managing neurologic emergencies. a detailed task checklist was used to assess decision making during the simulations. both resident groups had statistically significant higher knowledge and confidence scores after their training sessions (knowledge: pre: % vs post: %, p< . ; confidence: average pre: . to post: . , p< . ). however, there was no statistically significant difference between the two groups in either knowledge or confidence. the task checklist demonstrated significant variations in treatment practices and provided individualized areas for teaching. this pilot study suggests that trainees' knowledge and confidence in the management of neurocritical care concepts increases following simulated encounters, regardless of whether an actor-patient or multi-media simulation platforms is used. use of a task checklist uncovered important variations in protocol adherence among novice physicians. the accurate evaluation and determination of brain death has broad consequences on life-saving organ donation, closure for families, and length-of-hospital-stay. we have observed a concerning variability of brain death testing knowledge and comfort amongst neurology attendings and trainees at our institution. we aimed to create and apply a combined didactic and simulation training program to increase the knowledge and comfort in brain death evaluation, using our approved institutional brain death policy as reference. we hypothesized that participants who attended the training would show a measurable increase in their knowledge and comfort in the clinical evaluation of brain death. an experienced neurointensivist (> years of clinical practice) presented a -hour didactic session on brain death criteria, evaluation, and pitfalls to neurology residents and attendings. a high-fidelity simulation was implemented to allow practicing the brain death examination. knowledge and comfort levels were measured before and after learners had attended both sessions using electronic -exact-tests were applied to examine changes in knowledge and comfort in brain death testing pre-and post-exposure to the educational sessions. participants ( residents, attendings) completed pre-exposure, and ( residents, attendings) have completed post-exposure questionnaires thus far. knowledge significantly improved from pre-to post-exposure ( % correct, range - % improved to % correct, range - %; p= . ). comfort levels in performing the brain death examination pre-exposure also increased from pre-to postexposure (pre: "very comfortable- %","somewhat comfortable- %","neutral- %","somewhat or very uncomfortable- %" to post: "very comfortable- %", "somewhat comfortable- %","very uncomfortable- %" [p= . ]). exposure to a single combined didactic and simulation session improved the knowledge and comfort levels immediately post--exposure questionnaire response rates, as well as measurements of knowledge retention over a -and -month period and accurate application in practice. the safety and benefit of early mobilization in general intensive care units (icu) has been found to improve outcome and decrease length of stay. however, there is a lack of literature on early mobilization in the neuro icu (nicu) specifically, due to the complexity of the patients in the nicu and their disease processes. traditionally, patients were kept on bedrest after subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, and neurotrama, due to neurologic limitations such as fluctuation in mental status, requirement for sedation and paresis. additional challenges associated with mobility in this population include the potential for positional changes to impact intracranial pressure physician comfort level and concern for adverse neurological outcomes such as vasospasm or increased bleeding also decrease mobilization. while it is imperative to be cautious with nicu patients, prolonged bedrest and restricted mobility come with its own set of complications including muscle atrophy, decreased activity tolerance, delirium, pressure sores, nosocomial infections and deep vein thromboses. we sought to develop an early mobilization guideline that would help multidisciplinary staff identify which patients in the nicu should be mobilized early. a nicu physical therapist and the director of the nicu identified criteria for patients who were appropriate/inappropriate for early mobilization. all patients in the nicu should be mobilized early with the exception of the following exclusion criteria: unstable respiratory status, status epilepticus, contraindication to holding sedation, rass - , changing/worsening neuro exam, icp > mm hg, mean arterial pressure < or > mm hg, oxygen saturation < %, acute myocardial infarction, > vasopressors, clinical vasospasm, perfusional state, guidelines on early mobilization in the nicu can optimize patient mobility while minimizing complications associated with mobilization. introduction delivery, nurses must develop leadership skills and serve as full, collaborative partners with physicians and health professionals ( ). registered nurse (rn) inclusion into rounds has been shown to: improve interdisciplinary collaboration, incorporate learning in the workplace, increase leadership skills and improve team members' perception of unit flow and culture. attending physicians, rns, neurocritical care fellows, nurse practitioners, pharmacists and respiratory therapists were surveyed via surveymonkey to examine opinions regarding current rounding processes and potential opportunities in the neurocritical care unit (nccu). responses were aggregated to create scores for each topic, with the priority areas being the lowest relative scores based on a -point likert scale. survey responses were collected from nccu staff members ( % response rate). based on survey results, priority areas to enhance rounding satisfaction included: increasing collaborative decision making, creating entire team efficiency, completing rounds in a timely manner, increasing engagement and minimizing extraneous conversations and activities. other targeted areas for improvement included reserving time for prolonged family meetings for post-rounds, as well as focusing educational time and consistently utilizing the rounding checklist. based on areas of opportunity, a multidisciplinary committee was developed. one item created to enhance processes was the development and implementation of an rn facilitated presentation tool. to support this, a standardized presentation script and handoff tool were created and executed. six-month follow up survey results are pending at the time of submission. strategies to improve communication in multidisciplinary rounds are key to decreasing errors and improving care delivery. it is likely that a systematic data presentation by bedside rns will improve: staff perceptions of rounds, collaboration among all multidisciplinary staff members and rounding efficiency. the department of neurosurgery has a readmission rate goal of less than . for the fiscal year and less than . for the fiscal year of . over the past four fiscal quarters there has been an increase in the department's readmission rate, always exceeding the institutional goal. all readmissions in the institution's dashboard for q and q for and q and q of were reviewed by way of chart review. these were divided into spine vs cranial, planned vs unplanned readmission, reason for readmission and consistency vs inconsistency with the institution's dashboard. in q the dashboard reported a readmission rate of . . the final calculated actual readmission rate was . . in q the dashboard reported a readmission rate of . . the final calculated actual readmission rate was . . in q the dashboard reported a readmission rate of . . the final calculated actual readmission rate was . . in q the dashboard reported a readmission rate of . . the final calculated actual readmission rate was . . the most common reason for unplanned n reason for planned readmissions were shunt placements after lumbar drain trials. the dashboard was correct in predicting planned vs unplanned readmissions . % of the time. the coding on the backend of the institution's dashboard is missing many staged and planned readmissions and is only accurate in coding planned vs unplanned readmissions half of the time. this is resulting in falsely elevated readmission rates. despite the initial uptrend in readmissions, the actual readmission rates of the department are down trending and always below the institutional goal. this likely translates to other departments within the hospital. there needs to be a more efficient way to improve the coding and accuracy of the institution dashboards. the critically-ill neurological patients managed by specialized neurocritical care team is associated with improved outcome. in korea, limited data are available on improved outcomes after initiation of neurointensivist co-management in neurocritical care units (ncu). we evaluated the impact of a newly appointed neurointensivist on the mortality of patients admitted to the ncu. the study was conducted in intensive care unit (icu) beds of a large academic tertiary care hospital. neurointensivist co-management was initiated in march . the retrospective observational study compared the outcomes of patients before and after neurointensivist co-management. a total of patients were included, prior to and after the initiation of neurointensivist comanagement. patients admitted after neurointensivist co-management were older and had higher apache ii scores. icu mortality was significantly decreased in patients managed by neurointensivist ( . % vs . %, p= . ). the length of icu stay and duration of ventilator days were shorted in patients without co-management. neurocritically ill patients managed by specialized neurointensivist showed better clinical outcomes despite increased severity. social media has changed the way individuals communicate with each other and has altered the way society obtains information. in the past ten years, multiple articles have been published highlighting the ability to utilize social media for education of medical, nursing and pharmacy students. to our knowledge, cross discipline education utilizing these platforms has yet to be evaluated. with over . to implement a pharmacist led, social media based nursing education program and evaluate the perceived value of this education. a curriculum consisting of basic pharmacy related issues was developed and topics were posted to the ok users weekly. a pre-and post-education survey was sent out evaluating the program's effectiveness. email. of those nurses who received the pre-and post-education survey, a total of % and % completed the survey respectively. of those who completed the survey % received education via -education survey, there were no statistically significant differences in nursing performance on fact based questions after receiving education (p-value > . on all assessment questions). overall, % of the respondents reported a positive learning experience and wanted to continue this method of education delivery. the educational content. this project demonstrates the potential of utilizing social media as a means of cross discipline education; however, the solitary utilization of this platform should be used cautiously as this did not improve performance on assessment questions. consequently, targeted temperature management (ttm), either to maintain normothermia or induce hypothermia, is often advocated as a therapy to improve outcomes in brain injured patients. the physiological pathways that promote fever associated brain injury, and how these pathways might be modulated by ttm, remain unclear. this study examined the effect of fever and hypothermia on cerebrovascular pressure reactivity, a validated proxy of cerebral autoregulation. we included patients treated for brain injury from a single academic center. all patients had intracranial pressure (icp), invasive brain temperature, and arterial blood pressure (abp) recorded patient, mean prx over all periods of fever (> °c), normothermia ( - °c), and hypothermia (< °c) were calculated. differences in mean prx during normothermia, fever, and hypothermia epochs were then analyzed using paired student's t-test. the relationship between prx differences and total time spent normothermic was analyzed using linear regression. spent at a normal brain temperature (p = . , r = . ). in contrast, hypothermia was not associated with impaired cerebral autoregulation (p = . ). this study supports the hypothesis that impaired cerebral autoregulation may be one mechanism through which fever worsens outcome in brain-injured patients. the effect of fever on cerebral autoregulation appears to be more pronounced in patients that spend a longer amount of time in a normothermic state. interestingly, hypothermia was not associated with reduced prx, suggesting that the possible benefits of therapeutic hypothermia do not occur by improving the autoregulatory state. veno-arterial extra corporeal membrane oxygenation (va-ecmo) provides hemodynamic support in patients with refractory cardiogenic shock. these patients have a % incidence risk of cerebrovascular complications according to the extracorporeal life support organization database. reliable neuroassessments and neuroimaging are often limited by heavy sedation and risks of transporting these patients. transcranial doppler (tcd) can be a useful tool for cerebral hemodynamic assessment in these patients. we present four va-ecmo patients where tcd spectral waveforms provided key information on cerebral blood flow despite non-pulsatile flow. interpretable spectral waveforms were obtained in three of four patients. extensive embolization obscured flow patterns in one patient but clear cerebral perfusion with non-pulsatile waveforms was seen in the rest. two of the three remaining patients had high intensity transient signals (hits), suggesting cerebral microembolization. one patient showed pulsatility in cerebral waveforms despite no gross change in cardiac output on echo that helped guide decision to initiate ecmo wean. ecmo settings included flow at - l/min, map - mmhg, and paco between - mmhg. mca mean flow velocities were comparable to the systemic bp, and ranged from - cm/s in three patients and - cm/s in one patient. one patient suffered cerebral edema and two expired from withdrawal of care on sedation after multisystem organ failure without a chance neurological or neuroimaging assessment. the fourth patient retained consciousness and the ability to follow commands, but died from a massive gi bleed. tcd spectral waveforms can be useful bedside tools for patients on va-ecmo to assess for cerebral perfusion patterns. presence of hits reflecting microembolization can guide perfusionists to check for pulsatile flow, their relationship with systemic hemodynamics and va-ecmo settings is needed. cranial ultrasonography has a long history of use in neonates, but inadequate windows have limited its use in adults. a hemicraniectomy provides an obvious window for point-of-care intracranial imaging, providing similar views traditionally seen on ct and mri. we describe a standard approach and settings, presenting sample imaging demonstrating key anatomic landmarks. the hemicraniectomy ultrasonography preset was created and optimized using a phased array transducer with a - mhz frequency range. imaging parameters were tested and saved for d grayscale mode, with an emphasis on tissue harmonic imaging, adaptive image processing, and dynamic range. axial views are obtained from the ipsilateral temporal window, approximating the pterion, adjusting the probe to display a well-aligned view using the lateral ventricles as a landmark. by convention, the probe marker is placed anteriorly. the depth and focus are set to visualize the brain he probe craniocaudally permits visualization of the entire cranial vault. parasagittal and coronal views are obtained by placing the probe at the vertex, off midline, ipsilateral to the hemicraniectomy. several structures are clearly visualized and are available as landmarks for orientation. the ventricular system can be easily identified as hypoechoic spaces similar in appearance to ct or mr imaging. the brainstem and cerebellum, with its associated folia and peduncles are also easily seen. the thalami are identified as strongly hypoechoic paramedian structures. pathologic findings that can be easily seen include hydrocephalus, hemorrhage, and edema. aneurysm clips are hyperechoic with streak artifact, and ventriculostomy catheters can be seen as subtle hypoechoic areas within the cortex. hemicraniectomy pocus can be used to visualize the intracranial vault to facilitate evaluation of structural lesions and pathology at the bedside. the authors advocate adding hemicraniectomy pocus to the neurocritical care imaging arsenal in patients where this view is available. pain assessment is a challenge in critically ill patients with impaired consciousness, either because of sedation or concomitant severe brain injury. automated pupillometry has been used to assess the response to noxious stimulation in such patients. skin conductance, which has been used in the operative setting, has not been tested in this setting yet. the purpose of the study was to compare the pupillary response and skin conductance to pain stimulation in critically ill unconscious patients. prospective ongoing study including adult (> years) patients admitted to the intensive care unit of a university hospital and who were unconscious (glasgow coma scale < with a motor response < ) for several reasons. automated pupillometry (algiscan, idpupillary reflex dilation during tetanic stimulation. the tetanic stimulation ( hz) was applied to the skin area innervated by the ulnar nerve and was stepwise increased from to ma until pupil size had increased by % compared to baseline. the maximum intensity value allowed the determination of a pupillary pain index score ranging from (no nociception) to (high nociception): a pupillary pain peak per second ( concomitantly to tetanic stimulation. twelve patients (median age [ranges= - ] years; male gender / ) were included so far; eight patients had a primary brain injury ( / anoxic injury) and others were sedated because of shock with concomitant respiratory failure. all patients were under continuous intravenous sedation and analgesia; / were on vasopressors and / on continuous neuromuscular blockade. median gcs at the moment of pain assessment was [ - ] and median ppi was [ - ]; patients ( %) had adequate pain control. no changes of skin conductance variables were reported during pain stimulation. skin conductance was unable to detect insufficient nociception in critically ill unconscious patients. the cerebral arterial time constant (tau) reflects the time it takes to fill the cerebral arterial bed with blood during one cardiac cycle, and is derived from arterial blood pressure (abp) and middle cerebral artery flow-s with/without vasospasm (vsp) and delayed cerebral ischemia (dci) after aneurysmal subarachnoid hemorrhage (asah). ( ) ( ) . angiographic vsp and dci were adjudicated by neurointensivists. artifact-free cerebral arterial compliance and resistance. statistical comparisons were made using a two-tailed mann-whitney u-test. of asah patients, ( %) developed vsp and ( % of vsp) developed dci. patients had unilateral and bilateral vsp ( & % of vsp). one patient with unilateral vsp was available for monitoring prior to diagnosis. this patient had increased asymmetry in tau over time prior to diagnosis (slope: . s/day, r¬ : . ). tcd measures in patients were available prior to angiographic diagnosis of bilateral vsp, showing initial marginal asymmetry similar to the unilateral vsp case, then slightly decreasing asymmetry over time (mean slope: - cm/s higher in dci (p< . ). tau was . s greater for dci patients, however this did not reach significance (p= . ). explore the relationship of tau asymmetries with vsp and dci after asah. these may provide further insights into the pathomechanisms of vsp and dci while also having potential as a tool for earlier diagnosis of these important complications. pupillometry is more accurate and has higher inter-rater agreement than subjective pupil size and reactivity estimation. limitations include using a single high-intensity flash to evaluate the direct pupillary response only. we present preliminary data on using virtual reality-based pupillometry (vrp) with graded-intensity flashes and bilateral pupillary recording to monitor patients with large hemispheric infarction (lhi). we utilized a virtual reality headset-based system, i-pas (neurokinetics, pittsburgh, usa) to perform pupillometry. a total of homogeneous illumination flashes ( . to . cd/m², . sec on, . - . sec off) were presented to each eye while infrared cameras recorded pupillary area (mm ) continuously at samples/sec. this permits measurement of latency, magnitude and velocity of direct and consensual pupil constriction and dilation at each light intensity. : we performed pupillometry as described above in patients admitted with lhi from middle cerebral artery strokes. patients required decompressive craniectomy (dc) during the hospital course while the other patients did not require dc. bilateral graded-intensity pupillometry detected subtle changes in pupillary reactivity (peak constriction velocity in mm /s) prior to clinical deterioration, which were very pronounced when compared to normal control performance. singleneuropupillary index (npi) did not detect a change in pupillary reactivity in all but the most severe deterioration. virtual reality-based, graded intensity pupillometry is feasible in the intensive care unit and appears ed to set cutoff values that may aid in clinical decision making. limited access to conventional eeg results in significant delays to important diagnostic information, especially in patients with suspected non-convulsive seizures (ncs). recently, the rapid response eeg technology has proven to be clinically valuable. however, the economic aspect of this new technology has not been studied in detail. we retrospectively reviewed the use of the rapid response eeg device in our small community hospital over months since its launch in december . we performed limited chart review and collected information regarding eeg diagnosis, length of stay, and transfer to mothership hospital. we evaluated the clinical and economic impact of the device by considering the patients' clinical outcome and the estimated cost of hospitalization (~$ - /day) and transfer ($ - , ). metrics are not precise and are only estimates. the device was used in a total of patients. the treating physician or the nurse applied the device with and one with post-anoxic burst suppression. in patients with status epilepticus, seizures were aborted successfully, and median length of stay was . (national average of days). all patients were treated locally without requiring transfer to the main university hospital. considering the cost of rapid response eeg infrastructure and disposables (<$ , ) compared to conventional eeg systems (~$ , - , ) and eeg technologists (estimated to cost ~$ , - , ), and estimated range of $ , to $ , in annual savings because of shorter los and lesser transfers, this new technology seems economically advantageous. rapid response eeg system enabled significantly faster and easier access to eeg and helped detect a relatively high number of patients with gross eeg abnormalities. adopting the rapid response eeg improved emergent ncs detection and treatment in a cost-effective manner. patients requiring neurocritical care frequently have neurologic fluctuations of uncertain significance. we hypothesized that severe and prolonged events of neurologic deterioration (nd) have the greatest impact on discharge neurologic status and serve as intermediate indicators of poor outcome. we extracted nurse-documented gcs scores from electronic health record (ehr) data of consecutive patients admitted to a neurosciences intensive care unit (icu) or undergoing intracranial pressure monitoring (april - ) best initial -hour gcs (bestgcs- h), ) maximum magnitude of gcs decline (maxgcsdecline), ) duration of the episode of maximum gcs decline (dur-max), and ) the maximum duration of any gcs decline >= points (max pt-dur). we fit a -fold cross-validated logistic regression model predicting the final gcs - (vs. - ) and tested it in a % hold-out sample. we then evaluated the rates of poor outcome for combinations of these parameters. , consecutive admissions ( , unique patients) met inclusion criteria ( % with severe bestgcs- h ( - ), % with moderate bestgcs- h ( - ), and % with mild bestgcs- h ( - )). bestgcs- h, maxgcsdecline, dur-max, and max pt-dur, respectively, were independently associated with poor discharge gcs (or per standard deviation were . [ %ci . - . ], . [ . - . ], . [ . - . ], and . [ . -with a -point maxgcsdecline, the rate of poor outcome was % for patients with a severe bestgcs- h and >= -hour max-dur; % for patients with a severe bestgcs- h and < -hour max-dur; . % for patients with a mild bestgcs- h and >= -hour max-dur; and . % for patients with a mild bestgcs- h and < -hour max-dur. both the magnitude and duration of nd events are independently associated with neurological status at discharge. these empiric, informatics-derived thresholds may serve as useful intermediate outcomes facilitating the testing of biological associations and therapeutic interventions aimed at promoting neurologic recovery. unit. deteriorati worsening. we hypothesized that nonearlier than clinical deterioration. we prospectively collected data from patients with acute brain injury who are at a high risk of perfusion disturbance (sah, mmd, and severe anterior circulation ischemic stroke) between may and may . non--ry seconds neurological worsening were assessed using perfusion imaging and were categorized as hypoperfusion group and hyperperfusion group. baseline compared. non-monitoring should be highlighted in patients with high risk of deterioration. intracranial cerebral pressure (icp) monitoring is an integral part of acute brain injury management. while invasive icp monitor is the gold standard, there are several medical conditions that preclude its placement. non-invasive icp assessment tests (e.g. optic nerve sheath diameter, optic nerve disk elevation, pulsatility index, pupillary reactivity etc) have moderate accuracy when used individually. the aim of the present study is to validate a multimodal approach for intracranial hypertension detection. in this prospective study, patients with acute brain injury who had an evd placement for both icp measurement and treatment were included since march . we measured bilateral optic nerve sheath diameter (onsd) by ultrasound, bilateral optic nerve disk elevation (onde) by ultrasound, bilateral middle cerebral artery (mca) pulsatility index (pi) by using transcranial doppler and assessed pupillary reactivity with or without pupillometer as part of multimodal assessment for measuring intracranial pressure. we assessed the correlation and agreement of these values with icp measured by the evd. we included measurements in patients with acute brain injury. the presence of two or more values of mean onsd greater than mm, unilateral or bilateral presence of onde and mean mca pi greater than . has % sensitivity ( % ci . - . ) and . % specificity ( %ci . - . ) for predicting icp greater than mmhg. non-invasive multimodal assessment can be easily done by bedside, requires minimal training and seems to correlate well with increased icp. raised icp following acute brain injury is associated with poor outcome. monitoring with early detection is important in reducing sustained icp crisis. previous studies demonstrated rheoencephalography (reg) reflects cerebrovascular reactivity and may substitute invasive monitoring techniques. we hypothesized using a correlation coefficient between slow spontaneous changes in reg and systolic arterial pressure to calculate regx. reg measurements were obtained from ten patients with acute brain injury. analog waveforms of reg and arm bioimpedance pulse waves were recorded with a bioimpedance amplifier. we used the icm+ program (prx) calcu bioimpedance pulse waves (regx) instead of icp and invasive arterial pressure. visualized by previously established waveform changes on reg. a change in mean regx greater than the previous recording's mean regx value was clinically significant as opposed to absolute mean regx . one patient with a right ica infarction clinically deteriorated from moving all extremities to extensor posturing on the right and flaccid paralysis on the left with significant delta mean regx. another with bilateral aca distribution ischemic infarctions worsened from flexor to extensor posturing with significant delta mean regx. lastly, a patient with ventriculoperitoneal shunt malfunction repair improved from gcs to with multiple significant delta mean regx values between recordings. our series demonstrated clinical significance of patient specific delta mean regx suggesting importance of presenting mean regx for detection of changes in intracranial compliance. like presenting blood pressure and relative changes in blood pressure rather than absolute changes in blood pressure or specific values, regx was shown significant in a similar manner. regx is a realistic means of future noninvasive neuromonitoring. dialysis is characterized by markedly increased rates of stroke and cerebral micro-vascular disease, though the mechanisms by which dialysis modalities impact cerebral hemodynamics have not been well studied. this case series compares intra-dialytic cerebral hemodynamics measured by transcranial doppler (tcd) in patients receiving intermittent hemodialysis (ihd) versus peritoneal dialysis (pd). ten outpatient end-stage renal disease (esrd) without stroke were identified. tcd mean flow velocity averaged. six patients administered hemodialysis were followed over minutes, with mean arterial d every minutes. there was no statistically significant difference between dialyses group and no significant change over time. to quantify volatility in patient measurements over time, we calculated the coefficient of variation -sum test. to test if there was a difference in volatility between dialyses groups, we used a wilcoxon rankgroup (p < . ). in this small case series, though cerebral hemodynamics are not significantly different among stable measures are more stable over time for patients on the peritoneal dialyses group. end-stage renal disease (esrd) patients with acute neurologic injury are at risk of altered cerebral hemodynamics during dialysis. here, we present transcranial doppler (tcd) images revealing marked intra-dialytic increased distal vascular resistance and compromised flow velocity in an esrd patient with acute traumatic brain injury. the patient underwent continuous tcd monitoring during hemodialysis to monitor intra-dialytic cerebral hemodynamics. a year-old man with esrd on chronic presented with headaches after a fall. ct head revealed mm right convexity acute subdural hematoma with - mm leftward midline shift and right parietal parenchymal contusion. on arrival to the neuro-icu, the patient was afebrile, hemodynamically stable, and fully oriented with no focal deficits. repeat ct head six hours from initial was stable. the patient was started on his outpatient prescription of dialysis (dialysate na meq/l, blood flow rate ml/min), run without heparin. within first hours of hemodialysis patient developed progressive rightsided headache, which evolved to vomiting, decreased in level of consciousness, and left-sided weakness. he intermittently opened eyes to stimulation but required persistent painful stimulation to answer orientation questions. he had no changes in mean arterial pressure during hemodialysis. his serum bun had decreased from to mg/dl, and his serum sodium remained unchanged. emergent ct head was stable from prior. intra-dialytic tcd waveforms revealed progressively increased distal resistance to flow, measured by pulsatility index (pi) at his bilateral middle cerebral arteries (mca), and compromised mca velocities. this change was dramatic on the right, the same side as his subdural hemorrhage and cerebral contusion. esrd patients with critical neurologic injury are at risk for altered cerebral hemodynamics during dialysis. tcd ultrasonography may be a practical bedside tool to screen for patients at particular risk, and guide medical decision-making regarding dialysis prescription for esrd patients in the neuro-icu. point of care ultrasound (pocus) differs from diagnostic ultrasound in being often performed by clinicians and focused to acquire only relevant images to answer a specific clinical question. most ultrasound modalities have differentiated clinical indications where pocus is appropriate: the use of echocardiography to rule out tamponade in shock is considered pocus while the assessment of diastolic dysfunction in heart failure deserves a diagnostic exam. neuroultrasound has been used in various clinical indications like vasospasm, intracranial stenosis, collateralization, and emboli monitoring. these studies are mostly performed by sonographers as diagnostic studies. with emerging interest in assessing pocus indications, we performed a systematic literature review to identify all clinical indications of neuroultrasound and used a delphi based review by three experts to differentiate clinical indications where neuroultrasound could have point-of-care uses. two authors (lmh, gb) performed a systematic review to identify all reported modalities and clinical indications of neuroultrasound (tcd, duplex, b-mode, carotid, ocular and temporal) in medline, embase, cochrane, and scopus databases. three experts (jgd, ct, as) were surveyed using the delphi method to review each clinical indication and modality on whether it was focused on diagnosis or management and whether the clinical indication was a valid pocus. differences in opinion were settled with a final face-to-face discussion to reach a consensus. the systematic review determined total clinical indications of point of care use of neuroultrasound individualized by disease and modality. in indications it was considered a diagnostic adjunct, in instances it was considered an aide in management, and in instances it was determined to aid in both diagnosis and management decisions. there are many point of care indications of neuroultrasound in neurocritical care. this consensus opinion can guide clinicians to clinical indications where point of care use can aide in bedside diagnosis and management. in a systematic review, we reported current literatures on neuromonitoring methods in left ventricular assist device(lvad) population. we searched five databases (pubmed, embase, cochrane library, web of science, scopus, clinicaltrials.gov) related to lvad and neurological monitoring methods from inception through january . of unique citations, studies ( participants) met the inclusion criteria. the median age was . (interquartile range . - . , . % male). study designs were retrospective observational studies (n= ) and prospective observational studies (n= ). neuromonitoring methods studies included transcranial dopplers(tcd) for emboli monitoring(n= ) or cerebral autoregulation monitoring (n= ), traditional neuroimaging (ct/mri) (n= ), cerebral oximetry(n= ), carotid ultrasound (n= ) and plasma vad, articles studied pulsatile- current evidence on neuromonitoring in lvad is limited and there is no consensus on the indication and effectiveness on use of any neuromonitoring methods. the publications have significant heterogeneity adequate power are warranted to develop an optimal neurological monitoring protocol and prevention strategy. midbrain compression secondary to cerebral edema or hemorrhage results in high mortality and morbidity. quantitative pupillometry holds promise as a bedside indicator of worsening anatomic tissue shifts. because pupil reactivity relies on an intact neural network through the diencephalon and brainstem, compression can lead to changes in pupil size and reactivity. we studied markers of compression and pupillometry within hours of head ct in patients with anterior ischemic stroke (ais) or supratentorial intraparenchymal hemorrhage (iph) causing mass effect. we reviewed scans from patients with unilateral injury from ais (> / of mca territory) or iph (> ml). we assessed midline (mls) and pineal gland shift (pgs), as well as novel measurements of midbrain compression including interpeduncular shift (ips) and the ipsilateral and contralateral cerebral peduncle hemi-distances to the interpeduncular cistern (icphd, ccphd). multilevel modeling was used to analyze radiographic measurements with quantitative pupil metrics including pupil reactivity (dnpi) and size (dsize) differences between eyes. pupil reactivity and size differences were significantly associated with radiographic markers of midbrain noninvasive indicators of brainstem compression. evaluation of optic nerve sheath diameter (onsd) has been widely examined as both a correlate of intracranial pressure (icp), and a potential predictor of outcome after neurological injury. recent studies have evaluated sonographic measurement of onsd, yet clinical limitations to this approach persist. evaluation of onsd measurements via routine brain computed tomography (ct) imaging has been less studied, but offers potential for detection of increased icp in the absence of invasive monitoring. previous studies have employed a cross-sectional approach to onsd measurements via ct scan, primarily among patients with traumatic brain injury (tbi). however, no studies have evaluated serial correlations between ct onsd measurements and icp to evaluate strength of correlations during hospitalization, and across diagnosis types. the purpose of this study was to investigate correlations between onsd via serial ct imaging and icp among adult patients with neurological injury. retrospective cohort study of all adult patients admitted with acute neurological injury requiring icp monitoring and critical care admission. n= . diagnosis type included tbi ( %), aneurysmal subarachnoid hemorrhage ( %), intracranial hemorrhage ( %), cranial mass ( %), and other ( %). there was a strong, positive correlation between right/left onsd across all time points (r= . - , p< . ), suggesting a consistent bilateral response. correlations were strongest between initial inpatient ct scan onsd readings and icp (r= . , p< . ), but decreased over time. patients with increased icp across all diagnosis types experienced higher onsd values upon presentation to the emergency department (ed) and on serial ct scans throughout hospitalization (range . mm- . mm, p< . ). urements as a potential indicator of increased icp in the absence of invasive monitoring. serial ct brain imaging is often performed to evaluate for intracranial changes during hospitalization, and measurement of onsd during this imaging can contribute to decisions regarding more invasive monitoring. monitoring of burst-suppression-pattern (bsp) in electroencephalography (eeg) is relevant to control barbiturate-induced coma. currently, the assessment of bsp is based on continuous observation of the eeg with manual counting of bursts per minute (bpm) by experts, which is prone to inter-rater variability. we evaluated the reliability of a new algorithm for automatic bsp-detection compared to manual assessment in two thiopental-induced burst-suppressed patients. a bipolar -channel eeg-montage was recorded. the montage was bandpass filtered into typical eeg rhythms and segmented into secs -moonen metric, a distance matrix between all epochs in the first hour of data from patient us to cluster this matrix into clusters: burst, suppression and artifact. we labelled the rest of the (test) data from patient and patient by training support vector machine classifier from the labels produced by clustering. the eeg was scored by a neurologist to get ground truth bpm ranges (min, max for intervals of minutes to hour) for both patients. the algorithm provided estimated ranges of bpm for these intervals. the pilot data shows a high correlation of automatic burst counts compared to the manual counting. we found a significant pearson correlation (patient : . , p< . , patient : . , p< . ) and linear regression coefficient (patient : . , p< . , patient : . , p< . ) between estimated and ground truth bpm ranges. the automatic detection of the bursts provides an objective and fast assessment of bsp. the algorithm showed a slightly lower sensitivity due to the missing detection of very short or low bursts. we are ation. ventilated neurocritically ill patients is unknown and explored in this study. a retrospective cohort study was performed on patients admitted to the neurocritical care service between / / and / / , hospital-wide o shut down for maintenance and a switch to olerated with lowest being % owest spo of > % and spo < % amongst the patients in the pre and post-o shutdown groups. -tolerated. with the risk of hyperoxia and its potential negative effects on neuronal injury, a subset of neurocritically whole body hypothermia has been used as a treatment for patients with severe traumatic brain injury (tbi) since many years. invasive brain temperature monitoring is the most commonly practiced for target temperature management in these patients; however, complications are common due to the invasive nature of the procedure. the objective of the current investigation was to evaluate the association between brain temperatures obtained using a non-invasive sensor (accucor) and an intracranial pressure/temperature (icp) catheter during selective brain cooling in patients with tbi. aluated during a selective brain cooling over hours using both a parenchymal icp catheter (raumedic -pt) and the accucor sensor, with a catheter positioned in the nasopharynx. mean temperature values for each participant were obtained along the cooling intervention. outlier values derived from the accucor sensor were detected and removed prior to comparison. the variation in brain temperatures was calculated by mean temperature differences obtained using both measuring devices for each participant. mean brain temperature values were very similar between devices: . °c ( . °c- . °c) for the icp catheter and . °c ( . °c- . °c) for the accucor sensor (p-value: . , % ci: - . to . ). the median temperature difference between the devices was . ºc (minimum: - . °c, maximum: . °c, p-value: . ). our results suggest that there were no differences between brain temperature measurements conducted using the icp catheter and the non-invasive accucor sensor. this conclusion highlights the precision of non-invasive temperature monitoring, a safe alternative to the current invasive practice. monitoring procedures. sepsis-associated encephalopathy (sae) is a multifactorial syndrome, characterized as diffuse brain dysfunction that occurs secondary to infection in the body without overt central nervous system infection. the prognosis for sae is associated with the degree of cerebral damage. we investigated the relationship between the wavelet coherence of cerebral oxyhemoglobin (oxyhb) among different channels and outcomes in patients with sae. consecutive patients with sae were included. moreover, we included normal controls (n= ) for comparison. the cerebral oxyhb data were collected using functional near-infrared spectroscopy (nirsit, obelab inc.). the coherence between sections of prefrontal oxyhb oscillations in five frequency intervals (i, . - hz; ii, . - . hz; iii, . - . hz; iv, . - . hz; and v, . - . hz) were analyzed using wavelet coherence. in addition, we analyzed the coherence of electroencephalography (eeg) signal in three frequency intervals (delta, - hz; theta, - hz; and alpha, - hz). we evaluated the outcomes using glasgow coma scale (gcs) cores at discharge. the patients were categorized into three groups of normal control, good outcome (gcs - ), and poor outcome among the included sae patients (mean age, . years; and male, . %), patients ( . %) had a good outcome. in the poor outcome group, phase coherence was significantly lower compared to good outcome and the normal groups, especially for the myogenic frequency interval iii ( . ± . vs. . ± . vs. . ± . , p < . , respectively). however, the phase coherence of eeg signal was similar in two groups. our results demonstrated that the lower phase coherence of oxyhb in the myogenic signal, which originated from the vascular smooth muscle cells in the brain, was related to the poor outcome in sae patients. this suggests that evaluating cerebral dysfunction using wavelet coherence of oxyhb could be a useful outcome predictor following sae. external ventricular drain (evd) placement is a common procedure in the neurointensive care unit and intracranial hemorrhage (ich) is a recognized complication. in this study we sought to determine the factors associated with ich development after evd placement. retrospective study performed at a tertiary hospital. we identified all patients in whom an evd was placed over a month period. electronic chart review was done to obtain basic demographics, past medical history, use of antiplatelets/anticoagulants, type of catheter placed and presence of intracranial hypertension (ih). computed tomographies were reviewed to identify evd-associated ich. ichs were classified into symptomatic (gcs decline > points, intubation, outcome of death, or new focal continuous variables were analyzed with a proportion of the means test. the sample was comprised of subjects, had evd-associated ich. the median age was years. there was no significant difference in race or gender between patients with ich and those without ich. age, catheter type, history or inpatient use of anti-thrombotics, recent surgery, tpa use, heparin use, history of hypertension, hospital outcome, prior stroke, symptomatic hemorrhages, and icp spikes were analyzed, but only age ( . hemorrhage and . non-hemorrhage, p = . ), history of antithrombotic use ( / hemorrhage and / non-hemorrhage, p = . ) and icp spikes ( / hemorrhage and / non-hemorrhage, p = . ) were significantly associated with ich occurrence. three significant factors were associated with tract hemorrhages; age, history of anti-thrombotic use, and icp spikes. two of these factors have been previously supported by prior studies however, no prior study has correlated icp spikes to evd hemorrhages. additional studies may further validate the association between icp spikes and evd-related tract hemorrhages. targeted temperature management(ttm) aimed at helping to improve neurological outcomes associated with ischemic stroke have been studied continuously. however, it is not well known whether the parameters in ttm initiation, induction, maintenance will affect neurologic prognosis. we restrospectively reviewed medical records of the patients with large hemispheric infarction(lhi) who underwent ttm at snubh neurological intensive care unit from . . . to . . . onset to ttm initiation, induction period, ttm maintenance duration were investigated and dichotomized. neurologic prognosis was determined by the month death and modified rankin scale(mrs). a total of patients were included in the study. longer onset to ttm initiation(> hours) was associated with less month death. shorter ttm induction period(<= hours) was associated with less death rate, more fair outcome(mrs - ). ttm maintenance duration(within days or more) was not statistically correlated with neurologic prognosis. shorter ttm induction period may reduce death in lhi through maximizing icp control effect. the high mortality rate in patients with shorter onset to ttm initiation is likely to be related to the severity of initial symptom(mean nihss vs ). non-pulsatile continuous blood flow can cause endothelial dysfunction and small vasculature injury. the impact of non-physiologic blood flow on cerebral autoregulatory function and brain injury has not been extensively studied. we report a case of posterior reversible encephalopathy syndrome (pres) in a patient supported by a continuous flow pump, venoarterial extracorporeal membrane oxygenation (ecmo) for acute cardiogenic shock secondary to iatrogenic ventricular septal defect (vsd). a year-old male with hypertrophic cardiomyopathy was admitted for elective septal myectomy with an ascending aorta and hemi-arch replacement. the surgery was complicated by an iatrogenic vsd requiring urgent va-ecmo cannulation for cardiogenic shock. on day , ct brain achieved for poor neurological examination revealed extensive bilateral parietal, occipital and cerebellar hypodense lesions consistent with the typical imaging features of pres. a repeat ct brain on day depicted further extension of brain injury to the bilateral frontal lobes. due to worsening neurologic status, the decision was made to place an intracranial pressure monitor and lower the ecmo flow to return to a pulsatile flow state. the patient was closely monitored for improvement with paco levels, serial ct scans, and neurologic examinations. repeat ct scans on pod and depicted improvement in the bilateral cytotoxic edema with paco levels improving to - mmhg at a reduced ecmo flow rate of . - . l/min. his neurologic examination also improved with spontaneous movements noted in all four extremities. although neurologically cleared for heparin loading, he remained too hemodynamically unstable for open surgical repair and his surrogate decision makers decided to withdraw life-sustaining therapy. our case report illustrates the limited knowledge on the consequences of ecmo's impact on cerebral dynamic cerebrovascular autoregulatory changes in real-time that occur with patients with continuous flow pumps. hospital-onset unresponsiveness (hou) may occur in patients hospitalized for non-neurological conditions; while hou tends to be a transient systemic event, it may also indicate underlying neurological problems. quantitative pupillometry provides npi (neurological pupillary index), a quantitative measurement of pupillary light reflexes that have been traditionally assessed via subjective visual impression. we determined the clinical usefulness of npi in predicting the outcomes of patients who have experienced hou. hou was defined as a newly developed altered mental status and cases coded as "unresponsive" in the acdu (alert, confused, drowsy, and unresponsive) scale. we analyzed the demographics, radiological findings, etiology of hou, npi, in-hospital mortality, and -month modified rankin scale (mrs) scores. a total of cases in patients were analyzed, out of which cases ( %) had been assessed with quantitative pupillometry. cerebral herniation syndrome (chs) was found in ( %) cases; higher npi was associated with decreased risk for chs (odds ratio, . ; % confidence interval [ci], . - . ; p= . ), and no other factors were associated with the risk of chs. a total of ( %) cases showed in-hospital mortality. after controlling for clinical covariates and the presence of chs, lower npi was independently associated with increased risk for in-hospital mortality (odds ratio, . ; % ci, . - . ; p= . ). at a cutoff value of . , the specificity and sensitivity of npi for predicting in-hospital mortality were % and %, respectively. multivariate analysis showed an independent association between lower npi and unfavorable clinical outcomes (common odds ratio, . ; % ci, . - . ; p= . ). npi, a quantitative index of pupillary light reflex, was significantly associated with the risk of cerebral herniation and in-hospital mortality in non-neurological patients with hou. measuring pupillary light reflexes through quantitative pupillometry may be useful when responding to hou cases. target temperature management (ttm) improves survival and neurologic outcome and is recommended for cardiac arrest (ca) survivors by international guidelines. shivering is both an anticipated consequence and a major adverse effect of ttm. the bedside shivering assessment scale (bsas) is a simple, validated four-point scale that enables repeated quantification of shivering at the bedside. in this study, we examine the association between time to return of spontaneous circulation (ttrosc) and shivering (defined as bsas > ). data on post-cardiac arrest patients treated with ttm were collected from apache outcome database and medical records. baseline characteristics included age, apache iii scores, ttrosc (minutes), time to target temperature (ttt, minutes), and bsas > (percentage of hours bsas > /total number of hours bsas was done). outcome was survival to hospital discharge with good neurologic outcome. group and group included patients with ttrosc below or above the median respectively. all patients received continuous infusions of fentanyl and sedatives (propofol, midazolam, and/or dexmedetomidine) as per our institution's protocol. compared to group (n = ), group (n = ) had similar age ( ± vs ± , p = . ), similar apache iii scores ( ± vs ± , p = . ), longer ttrosc ( ± vs ± , p = . ), similar ttt ( ± vs ± , p = . ), more shivering ( . % vs . %, p = . ), and similar survival with good neurologic outcome ( % vs %, p = . ) respectively. ttrosc was strongly positively correlated with shivering (pearson correlation coefficient, r = . ). in comatose survivors of cardiac arrest who received ttm, longer ttrosc (indirect measure of brain injury) was associated with more shivering. these findings should be further investigated in prospective studies. pupillometry assessment of the pupillary light reflex (plr) is gradually replacing manual plr assessment. this new technology has led to a recent increase in clinical research and subsequent need to validate those results. mcnett et al. recently investigated the association between intracranial pressure (icp) and serial pupillometer values and found that pupillometry readings are different significantly in the setting of increased icp. this is a replication of the mcnett study in a larger multicenter cohort to explore these findings. data from the establishing normative data for pupillometer assessments in neuroscience intensive care (end-panic) registry include over , patients with a neurological condition. subjects with documented icp readings provided , observations (daily mean icp values) which were included in this analysis. statistical analysis (sas v . ) included descriptive statistics and to examine the differences . subject mean age was years, % were female and . % were caucasian. student t-test analysis was used to explore for differences. excepting latency and right eye npi, lower plr values were associated with higher icp (compared to low or normal icp) for all mean pupillometer/plr variables for both left and right eyes (t range [- . to . ]; p-value range [< . to . ]). the findings confirm and extend those of mcnett. patients with increased icp tend to have lower pupillometer readings. automated pupillometer is a non-invasive method that provides prediction of the icp trends which can help neurocritical care professionals in assessing patients with neurological conditions. encephalopathy is a common complication in cirrhotic patients. clinical manifestations are diverse, but few data are available on pupillary abnormalities in such patients. the aim of this study was to evaluate whether automated pupillometry could detect pupillary dysfunction in this patients' population. prospective ongoing study including the assessment of the pupillary changes to light stimulation using automated pupillometry (neurooptics, irvine, usa) in adult cirrhotic patients after icu admission. the degree of encephalopathy was scored by the glasgow coma score (gcs). severity of cirrhosis was assessed by the child-pugh and meld scores. severity of liver encephalopathy was assessed according to standard criteria. different biological variables, including ammonium (nh ), was measured to pupillary assessment. the median values of pupillometry-derived variables were collected for both eyes. -pugh and nh levels were found with any of the pupillometry-derived variables. no differences in pupillometry-derived variables were observed across different degree of liver encephalopathy. automated pupillometry did not show correlations between pupillary abnormalities and the severity of critically ill patients with liver cirrhosis. prognostication in comatose survivors of cardiac arrest (ca) remains challenging. the purpose of this study was to determine if early quantitative analysis of resting eeg can improve prediction of commandfollowing by post-ca day . we prospectively enrolled patients admitted after ca. clinical care was performed according to our institutional protocol, which includes continuous eeg monitoring. -minute resting eeg epochs were clipped daily; clips were excluded if seizures or other confounders were present. epochs from post-ca days - were preprocessed for artifact reduction, then analyzed for three quantitative metrics: power spectral density, permutation entropy, and coherence. we created a predictive model using partial least squares regression analysis to distinguish eeg data as from patients who would or would not recover command-following by post-ca day . cross-validation of results was accomplished with a -times random assignment of % of data as training set and % as testing set. eeg clips were analyzed from patients ( . % female, age . +/- . years, pre-morbid mrs . +/- . and cpc . +/- . ). cardiac arrests occurred out-of-hospital in %, witnessed in . %, and had bystander cpr in . %. mean time to rosc was +/- minutes, . % had a shockable initial ekg rhythm, and . % of patients received therapeutic hypothermia. prior to day , . % regained consciousness and . % had withdrawal of care. using eeg data alone, predictive ability (expressed as average area under the receiver operating characteristics curve) yielded auc . +/comparison, the same model was constructed using clinical features (absence of pupil and corneal reflexes by day ) or laboratory testing (peak nse level). the model combining clinical, laboratory, plus eeg data yielded auc . +/- . , an improvement vs clinical features (auc . +/- . , p< . ) or nse levels (auc . +/- . , p< . ) alone. quantitative eeg analysis may provide adjunctive prognostic information regarding short-term recovery of consciousness. international guideline recommended pupillary light reflex (plr) and/or cortical response (n ) to short-latency somatosensory evoked potentials (sseps) at hours after return to spontaneous circulation as the only strong predictors of unfavorable outcome in comatose patients after cardiac arrest. the aim of this study was to compare this algorithm with a multimodal approach including other prognostic tools. post hoc analysis of an international multicenter (n= ; n= patients) prognostic study on automated pupillometry in comatose post-ca patients. the primary study endpoint was the accuracy of npi in predicting -month unfavorable neurological outcome (uo), defined as cerebral performance category (cpc) of - (severe disability, unresponsive wakefulness or death). patients with findings on plr, sseps, npi and eeg were included; the highest nse was also recorded, whenever available. an npi < on day , a discontinuous eeg background or clinical myoclonus over the first days, bilaterally absence of n calculated as: false positive / favorable outcome. we included patients; ( %) of those had uo. using the approach of guidelines, unfavorable outcome at day was observed in / patients with absent plr and / with absent n ; / ( %) patients with uo were identified. using the multimodal approach, uo was identified in / patients with npi < , in / patients with discontinuous eeg, in / patients with myoclonus and this study suggests that a multimodal approach, including npi, eeg, sseps and nse, could identify a after physicians introduced the idea to declare death based on loss of brain functionality, many countries incorporated brain death into their legal criteria for death. we sought to learn about the global legal perspective on brain death declaration (bdd). we collected legal documents about declaration of death around the world by searching national legislative databases and google. we utilized google translate to convert all documents into english then searched for references to criteria for bdd. in cases where there was conflicting information, we consulted local experts. we located legal documents on death declaration for countries, of which included a reference to brain death. legally stipulated criteria for bdd were identified for / countries. with respect to prerequisites for bdd legal stipulations existed in: / countries on confounders to exclude, / countries on an observation period before bdd, / countries on the minimum temperature for bdd and / countries on the minimum blood pressure for bdd. an assessment for coma was legally required in / countries. the fact that spinal reflexes do not preclude bdd was included in the legal criteria for bdd in / countries. a broad reference to an assessment for brainstem areflexia was legally mandated in / countries. the legal criteria included specific reflexes to test in / countries (pupillary / , corneal / , oculocephalic / , oculovestibular / , gag / , cough / , and other / ). every country legally required an assessment for the inability to breathe spontaneously, but only / described apnea testing in detail. the number of clinical exams required for legal bdd ranged from - . ancillary testing was legally required in / countries. the legally stipulated criteria for bdd differ around the world. standardizing the global legal perspective on bdd would help prevent ) variability in practice and ) false bdds. up to % of patients monitored with pupillometry during therapeutic temperature management (ttm) after cardiac arrest will have sluggish (sl) or non-reactive (nr) pupils. the neuroimaging findings and injury patterns of these patients have not been reported. adult patients treated with ttm after cardiac arrest with available pupillometry data from the neuroptics npi- were studied. discharge outcome was classified as poor (po) if the cerebral performance category score was - , and as good if - . pupil size, percent constriction, and constriction velocity were determined throughout ttm using data from the worst eye at each assessment. the neurological pupil index (npi) was scored from (nr) to (brisk), with values < considered sl. computed tomography (ct) and magnetic resonance (mr) neuroimaging was reviewed by a neuroradiologist blinded to pupillometry and outcome data. poor outcomes occurred in / ( %) patients with nr pupils during ttm, / ( %) patients with sl pupils, and / ( %) with normal (nl) pupil reactivity. pupil size did not predict outcome, but pupillometry data during ttm predicted poor outcome with auc . - . . when nonreactive pupils were first detected, / ( %) were < mm. % of patients had ct imaging, and % had mr imaging a median of (iqr - ) hours after recovery of spontaneous circulation. cerebral edema or herniation were identified in / ( %) nr vs / ( %) sl and / nl patients (p< . ). midbrain injury identified by t sequences was identified in / ( %) nr/sl patients versus / ( %) nl patients (p= . ). midbrain abnormalities were identified more often in patients with nr/sl pupils than edema/herniation ( % vs %, p= . ). a minority of patients with sluggish or non-reactive pupils after cardiac arrest have evidence of cerebral edema or herniation. midbrain injury is a more common mechanism to explain this common neurologic deficit. cardiac arrest (ca) survivors are often comatose and their arousal recovery is dependent on the extent of hypoxic-ischemic injury (hii). long-term neurologic outcomes are variable, difficult to predict, and biased by withdrawal of life-sustaining therapy. somatosensory evoked potentials (ssep) remain the gold standard for predicting arousal potential, but is not broadly available. we hypothesized that early hi-resolution mri may help assess arousal recovery potential as predicted by electrophysiologic outcome. comatose survivors of cardiac arrest admitted to an icu between june and january who underwent ssep and mri were retrospectively identified. d-hii burden in predefined regions. semi-automated region-of-interest (roi) tools in mipav were used to draw borders on dwi around the upper brainstem including the ascending reticular activating system (aras) to assess voxel intensity and derive hii volumes. our outcome of interest was ssep findings classified in two prognostic categories: indeterminate (bilaterally present n s or unilateral presence of n s) and poor prognosis (bilaterally absent n s). we used paired t-tests to compare presence of signal abnormality and rois between patients with sseps predicting poor outcome or indeterminate prognosis. consecutive ca survivors (mean age of . , % female) were included. no significant differences were noted in baseline characteristics between groups though time to rosc was noted to be vs mins for indeterminate and poor outcomes (p = . extent did not predict ssep status. no significant difference was noted in the voxel intensities on adc in the midbrain or pontine tegmentum. quantitative mri measures of hii extent may be superior in predicting arousal potential in comatose survivors of ca compared with manual rating. a quantitative image analysis pipeline is being developed for measuring aras lesion burden and predicting electrophysiologic based outcomes in ca. despite promising preclinical results, the application of intra arrest therapeutic hypothermia (iath) during cardiopulmonary resuscitation have produced controversial results in clinical trials. the aim of this review was to analyze the effects of such therapy on relevant outcomes in patients suffering from out-of-hospital cardiac arrest (ca). the following databases have been searched up to th may for human trials: pubmed (from ), embase (from ), cinahl (from ), the cochrane library (from ) and ovid/medline (from ). the search strategy will use the following terms: "arrest" or "cardiac arrest" or "heart arrest" and "intra arrest" or "during cpr" or "intra cpr" and "hypothermia" or "therapeutic hypothermia" or "cooling". references from identified studies and relevant review articles have also been searched for additional eligible citations. the search has been limited to english publications and has been conducted in accordance with the international liaison committee on resuscitation (ilcor) process of evidence evaluation. a total of six human studies (n= ; treated with iath) including four randomized controlled trial (loe ), one retrospective and one prospective controlled study (loe ) were identified. two studies used trans-nasal evaporative cooling and others intravenous cold fluids. overall rate of return of spontaneous circulation was similar between iath patients and controls ( / ) when compared to control group. no differences were found in the subgroup of shockable vs non-shockable rhythms. different effects on outcomes were observed according to the method used to induce iath when compared to controls. iath was not associated with improved outcomes when compared to standard of care. however, the method used to induce iath may potentially influence the beneficial effects of such intervention. amantadine may improve functional recovery in the subacute state following brain injury. we aimed to characterize eeg signatures in patients with acute brain injury (abi) receiving amantadine that did and those that did not recover consciousness. we studied a consecutive series of patients with acute brain injury patients who were treated with amantadine as a neurostimulant between september and december . all patients were initially comatose and underwent eeg prior to and after the initiation of amantadine. the ability to follow commands was assessed daily based on prior published methodology (claassen et al, annneurol ). eeg features that were assessed included sleep stages, posterior dominant rhythm (pdr), and power spectral density plots. we applied a multivariate regression model using generalized estimating equations (gee) to identify eeg features correlated with recovery of command following. eegs were analyzed by a board certified neurophysiologists. -free eeg clips), patients ( %) recovered consciousness during hospitalization. ich was the most common etiology in ( %) patients, followed by sah in ( %) patients. on average amantadine was given for +/- days. patients ( %) had seizures, only patients ( %) after starting amantadine. in our gee model, age (p= . ), sleep structures (p= . ), pdr (p= . ), and cumulative dose of amantadine (p= . ) were all associated with recovery of command following. spectral features corresponding to higher levels of anterior forebrain corticothalamic integrity correlated with higher levels of consciousness in % of recorded patients after days of amantadine use. the best spectral pattern per patient was seen . days on average prior to recovery of consciousness. eeg may provide a biomarker that indicates subsequent recovery of consciousness in unconscious patients with an acute brain injury that are treated with amantadine. depletion of cerebral glucose (i.e., cerebral glucopenia) occurs commonly and is associated with poor outcome in traumatic brain injury and subarachnoid hemorrhage. however, the incidence of cerebral glucopenia after diffuse hypoxic-ischemic brain injury (hibi) is unknown. we characterized the burden of cerebral glucopenia after hibi and its association with markers of physiological distress and outcome. we retrospectively analyzed cerebral microdialysis data from a cohort of patients with hibi. patients survived sudden cardiac arrest and patient had severe hypoxia after polysubstance overdose. hourly values of cerebral glucose, lactate, pyruvate, and glycerol as well as continuous intracranial pressure (icp), arterial blood pressure (abp) and interstitial brain oxygen (pbto ) were recorded. associations between average glucose/patient-day versus average lactate:pyruvate ratio, glycerol, icp, pbto , and abp were analyzed using linear regression. burden of glucopenia (defined % time with glucose < . mmol/l) was analyzed by patient-day. the relationship between glucopenia burden and discharge outcome was analyzed using the wilcoxon rank sum test. lower cerebral glucose was associated with higher cerebral glycerol (p= . ), higher lpr (p= . ), higher icp (p< . ), and lower pbto (p= . ) levels. there was no association between abp and cerebral glucose (p = . ). glucopenia burden increased progressively over time and peaked by postinjury day . / patients had good outcome (defined as return of consciousness prior to discharge). there was no association between outcome and cerebral glucopenia burden (p = . ). cerebral glucopenia is common after hibi and associates with markers of cellular distress. the burden of cerebral glucopenia progressively increases over several days and appears to peak more than week after injury. although there was no association between outcome and glucopenia burden, the number of patients in this study with good outcome was low. the utility of cerebral glucose monitoring after hibi merits further study. international guideline recommends using bilaterally absence of pupillary light reflex (plr) and/or bilaterally absence of the cortical response (n ) to short-latency somatosensory evoked potentials (sseps) at hours after return to spontaneous circulation to predict unfavorable outcome in comatose patients after cardiac arrest. the aim of this study was to compare this algorithm with a multimodal approach including other prognostic tools. retrospective study of adult (> years) cardiac arrest patients admitted from january to march and who underwent multimodal monitoring. we collected demographic characteristics and cardiac arrest data, together with sseps, the presence of burst-suppression on early eeg, a neurological pupillary index on the automated pupillometry < at after arrest and a neuron-specific enolase (nse) -month unfavorable neurological outcome (uo) with cerebral we included patients; ( %) of those had uo. using the approach of guidelines, unfavorable outcome at day was observed in / patients with absent plr, in / with absent n and / with combined absent pupillary light reflex and n ; / ( %) patients with uo were identified. using the multimodal approach, uo was identified in / patients with npi < and / patients with bs on eeg. among the others, uo was associated with absent n in / patients and with high nse values in / patients. this approach identified / ( %) patients with unfavorable outcome. the area under curve to predict uo for the approach of guidelines was . , which increased to . with the multimodal approach. this study suggests the a multimodal approach, including npi and bs on eeg, sseps and nse, has a higher predictive value for uo than recommended predictive tools. there is a high prevalence of seizures following cardiac arrest (ca), but not well studied among survivors with good neurological recovery. we describe the prevalence of clinical and electrographic seizures, anti-epileptic use, and eeg characteristics of ca survivors with good neurological outcomes. adults with return of spontaneous circulation (rosc) after in-hospital or out-of-hospital ca between / - / were eligible. a consecutive sample of survivors with included. prevalence of seizures and antiepileptic drugs (aed) use within -months after discharge were collected using a questionnaire administered via in-person or phone. a board-certified clinical neurophysiologist reviewed the eeg. of patients surviving to discharge, ( %) with -months follow-up were analyzed. average age was ± years, ( %) were women, ( %) patients had witnessed arrest, ( %) received defibrillation, with an average rosc duration of ± minutes, and a median cpc of at discharge. there were no clinical seizures reported during hospitalization. of available ( %) patients with raw eeg (median duration of days), only ( %) patients had electrographic seizures, ( . %) had continuous background as their best eeg pattern, ( %) with discontinuous background, ( %) with epileptiform discharges, and ( %) patients had burst suppression pattern that recovered later to a normal eeg pattern. none of the patients had any malignant eeg patterns, ( %) exhibited reactivity to a verbal or tactile stimulation and ( %) had the presence of sleep structures and posterior dominant rhythms. surprisingly, ( %) patients were discharged on an aed. clinical seizures and aed use were reported in / ( %) at -months follow up. both short and long-term seizure burden are very low among the cardiac arrest survivors with good neurological recovery. underlying factors related to high utilization of aed before discharge warrants further investigation. objective: early neuro-prognostication in the intensive care unit pediatric patients is essential to enable effective care planning, triaging level of care, and family support. in coma, the reliability of biomarkers such as electroencephalogram (eeg), anatomical neuroimaging to determine potential for consciousness and future functional capacity are less established in children. herein we present two case studies highlighting resting state functional mri (rs-fmri) as a clinically new means defining real-time brain function in the pediatric critically ill population. rs-fmri measures spontaneous low-frequency fluctuations in the blood oxygen dependent (bold) signal to investigate the networks of the brain. a standardized acquisition of data on a tesla mri under light tool melodic. whole brain networks determined by independent component analysis with false discovery rate at p< . to detect major brain networks. cases describe two critically ill children. one, with severe brain injury related to acute necrotic encephalopathy, and the other with diabetic ketoacidosis induced cerebral edema and uncal herniation. both had slow eeg background with sleep features approximately a week after presentation and were comatose by exam on the day of rs-fmri. rs-fmri detected normal brain function in the long-range fronto-parietal network, intact language-area networks, and default mode network. atypical networks were detected in brainstem and deep grey in both children. by hospital discharge, both children were awake and communicative with spontaneous movements. case one remain with tracheostomy with intermittent ventilation, case two had residual left hemiparesis, vision and language intact, mild cognitive deficits. in the cases reviewed, rs-mri may offer an objective measure of functional brain capacity and potential for meaningful recovery with preservation of language and long range connectivity networks in critically ill pediatric patients. provision of positive end-expiratory pressure (peep) through a conventional ventilator during apnea testing for brain death determination removes the need for additional equipment such as a peep valve, allows for use of high peep during apnea in patients with severe hypoxic respiratory failure and facilitates detection of respiratory effort on flow scalars. the advent of ventilators that permit deactivation of the apnea backup setting has made such testing possible. our goal was to examine the feasibility of peep use with conventional mechanical ventilation during apnea testing, with a focus on premature termination and inadvertent external triggering. performed without disconnection from the ventilator (dräger evita® infinity® v ), with deactivation of the apnea backup. this was a convenience sample based on availability of appropriately trained -support and peep - cmh o. apnea was confirmed by absence of chest rise and respiratory effort on the flow scalar. adequacy of respiratory stimulus was established by a co > mmhg and -point co rise from baseline. endpoints included early termination of the apnea test prior to minutes because of patient instability, any oxygen desaturation below % and inadvertent external triggering. inadvertent external triggering required repeat of apnea testing. ten patients underwent apnea testing while connected to the ventilator. apnea testing for at least minutes was successful in all patients. apnea was confirmed in all cases. no patient suffered oxygen desaturation below % or other instability. there was one instance of inadvertent external triggering caused by jostling of tubing, necessitating repeat testing. apnea testing with provision of peep through a conventional ventilator to improve tolerance is feasible. inadvertent external triggering is uncommon but may occur. despite well-defined aan guidelines on brain death declaration, there is marked variability in its practice nationally. this highlights the need for targeted brain death education initiatives. communication with surrogates or families about a brain death diagnosis and its implications is integral to brain death declaration, yet this has not been studied in a simulation setting. we developed a brain death simulation curriculum at our institution addressing knowledge and surrogate communication skill development. as part of this curriculum, multi-disciplinary critical care fellows completed a pre-curriculum multiple choice (mc) knowledge test and survey (likert - scale) evaluating comfort and confidence. a mandatory one-hour neurocritical care attending-led didactic regarding guidelines and technical aspects of brain death examination was conducted. subsequently, each fellow performed an observed brain death examination (simman g mannequin) with feedback followed by a standardized family scenario with delivery of a brain death -simulation survey, mc questions, and provided feedback. statistical analyses used -tail wilcoxon signed rank test (p<. ). thirteen critical care fellows participated (neurology[ ], anesthesia[ ], trauma[ ], pulmonary[ ]). only one fellow had previous formal brain death training with the majority [ %, (n= )] only participating in - brain death declarations. there was significant improvement across all measures: self-rated knowledge ( . to . , pre-simulation to post-simulation, p= . ), knowledge relative to peers ( % to %, p= . ), confidence ( . to . , p= . ) and comfort ( . to , p= . ) with performing a brain death exam, and comfort with family discussion ( . to . , p= . ). test scores improved from % to % after simulation (p= . ). all fellows found the curriculum beneficial (with all aspects wellreceived). critical care fellows may lack experience with brain death declaration. didactics coupled with simulation-based education can improve objective knowledge and comfort with brain death declaration and surrogate communication. there is a growing disparity between availability and demand for neurologic expertise, particularly in smaller community hospitals. telemedicine has helped to bridge this disparity with respect to cerebrovascular disease and is used increasingly to deliver other types of neurologic expertise to patients. while the nihss is widely used in telestroke, other formalized neurologic exams have not been well studied. we seek to determine whether the components of a brain death exam can be reliably performed via telepresence. patients suspected of meeting brain death criteria were enrolled from july to may . standard bedside neurologic exam (bne) performed by the attending neurointensivist in accordance with our institutional protocol was compared with the telepresence neurologic exam (tne) performed by a study neurointensivist blinded to the findings of the bne and a trained bedside assistant. we analyzed the agreement between examiners regarding findings of coma, corneal reflex, pupillary light reflex, oculovestibular reflex, oculocephalic reflex, cough, gag, motor response, and apnea. we enrolled patients over months. proximate causes were intracerebral hemorrhage ( / ), anoxic brain injury, ( / ), and cerebral infarction ( / ). all examination components performed in the bne could be completed by tne. in cases, neither examiner could assess all exam components. in cases spinal cord injury precluded oculocephalic testing. in case refractory hypoxia precluded apnea testing. bne and tne agreed in % of testable components. in cases testing pupillary light reflex was reported as difficult in the tne but not the bne. all telepresence examiners reported high confidence that the exam findings were consistent with brain death. preliminary findings from our pilot study suggest that the use telepresence for brain death examination introduction traumatic brain injury (tbi) is often followed by the loss of con increases each day following the injury, but the contents of consciousness, also known as qualia, do not uniformly return. while there is some information about brain regions supporting arousal, less is known about circuits encoding contents of consciousness. some evidence supports a role for the thalamus in consciousness, but it is controversial whether it supports arousal, or has a more nuanced role in consciousness. to address this question, we combined intracranial recordings in patients recovering consciousness with neuroimaging of thalamocortical circuits. electrophysiology we recorded electrocorticography (ecog) from prefrontal cortex and anterior cingulate cortex, as well as scalp electroencephalography (eeg) from a standard - montage, during singleand parietal cortex based on coherence between the evoked responses in these regions when acc was stimulated. radiology. regions of structural damage were extracted from the post-tbi mri and diffusion tensor imaging (dti) radiographs. tractography using dsi studio™ was performed with seed regions placed in the bilateral mediodorsal nucleus of the thalamus. we found that in patients with injury isolated to the cortex and/or white matter, the cortico-cortical functional connectivity across frontoparietal networks was preserved, and these patients recovered consciousness. however, a patient with thalamic injury failed to recover consciousness, despite an increased level of arousal following injury. the functional connectivity across cortical regions was drastically lower following thalamic injury, even when the cortical damage was minimal. we propose that integration and communication of information across frontoparietal networks, which is required for contents of consciousness, is dependent on thalamic input. thus future efforts have to be focused on restoring this input. brain herniation is a deadly event that requires rapid administration of hyperosmotic agents (hoas) such as . % nacl. a recent retrospective study showed that intraosseous (io) cannulation provides a safe route for rapid administration of hoas compared to central venous catheters (cvc) and peripheral intravenous catheters (piv). prospective study to measure the time-to-treatment for . % nacl or mannitol via io, cvc, or piv. a data collection form ("brain code narrator") was created by nurses and providers to prospectively collect clinical data, hemodynamic measures, and time-to-treatment and administration route for hoas during brain codes. in addition, demographics, diagnosis, serum sodium (na+) and complete blood cell count, as well as immediate and delayed complications, and outcomes were collected. brain code narrator was used to collect data for patients: males with median (iqr) age ( - ) years. diagnosis included intracerebral hemorrhage (n= ), subarachnoid hemorrhage (n= ), and other (n= ). all patients were intubated. most patients were co-treated with induced hyperventilation. . %nacl ( cc) via cvc and io route and mannitol ( gm) via piv were administered during , , and events with median time-to-treatments of ( , ), ( , ) and ( , ) minutes, respectively (p value < . for all comparisons). no adverse events, such as hypotension or tissue injury were noted. preliminary data suggest that during brain herniation, administration of . % nacl via io or cvc is more rapid than iv mannitol. io cannulation for . % nacl may be an alternate route of administration of hoas during brian code. additional data will be provided regarding herniation reversal and long-term hematologic abnormalities. stress hyperglycemia is common in the critically ill and is associated with poor neurological outcomes in cardiac arrest patients. it is unknown whether glycemic dysregulation have different prevalence according to cardiac arrest etiology. we hypothesized that overdose-related cardiac arrest (odca) patients are more vulnerable to hypoglycemic events given the circumstances of arrest. we retrospectively studied cardiac arrest patients treated at two urban hospitals from the multimodal outcome characterization in comatose cardiac arrest (mocha) registry from - . we examined glucose dysregulation (hypoglycemia blood glucose [bg]< mg/dl, hyperglycemia bg> mg/dl) within first h from arrest in odca and non-odca cohorts. statistical analyses included paired/unpaired t-tests, chi-al dysfunction was defined by scores of gos- of the patients, ( . %) were odca. there were no differences in bmi, gender, ethnicity, or therapeutic hypothermia (th) treatment across cohorts, but odca patients were younger ( ± vs ± year-old; p< . ), had lower prevalence of diabetes ( . vs . %; p= . ) and lower hemoglobin a c ( . vs . %; p= . ). mean bg reduction from - h to - h in odca patients was significantly smaller ( . ± . vs . ± . mg/dl; p= . ) despite no difference in mean peak bg. bg nadirs were lower in odca patients ( . ± . vs . ± . mg/dl; p= . ). patients developed glycemic dysregulation: ( %) odca vs ( %) non-odca; odca patients were nearly two times more likely to develop hypoglycemia (rr . [ . - . ]; p= . ) but had no increased risk of hyperglycemia (rr . [ . - . ]). among patients with glycemic dysregulation, odca was associated with higher risk of in-hospital death or neurological dysfunction (or . [ . - . ]; p= . ). despite exhibiting blunted bg reductions to hyperglycemic treatment, odca patients were more susceptible to hypoglycemia in the first h postmanagement strategies should account for cardiac arrest etiology. sedation and neuromuscular blockade (nmb) in patients undergoing targeted temperature management (ttm) after cardiac arrest (ca) are recommended for patient discomfort and management of shivering. this study assessed the association between nmb use and neurological outcome in comatose survivors of ca who received ttm. data on post-cardiac arrest patients treated with ttm were collected from apache outcome database and medical records. ttm of °c or °c is chosen based on critical care physician's discretion. baseline characteristics included age, apache iii scores, time to return of spontaneous circulation (ttrosc, minutes), time to target temperature (ttt, minutes), and shockable rhythm (sr, %). outcome was survival with good neurologic outcome. compared to the no nmb group (n = ), the prn nmb group (n = ) and continuous nmb group (n = ) had similar age ( ± and ± vs ± , p = . , . ),similar apache iii scores ( ± and ± vs ± , p = . , . ), comparable ttrosc ( ± and ± vs ± , p = . , . ), longer ttt ( ± and ± vs ± , p = . , . ), comparable percentage of sr ( % and % vs %, p = . , . ), and similar proportion of patients with tt of vs ( % and vs %, p = . , . ) respectively. survival with good neurologic outcome was achieved in % in no nmb group vs % in prn nmb group (p = . ) and % in continuous nmb group (p = . ) in the present study, in comatose survivors of cardiac arrest who received ttm, use of nmb had no effect on neurologic outcome. the apnea test is an essential examination for the determination of brain death. however, hypotension, hypoxemia, and other complications during the apnea test can affect the stability of brain-dead patients, as well as organ function for recipients. therefore, it is necessary to establish standard guidelines for apnea testing. the modified apnea test (mat) comprises delivery of % oxygen through the endotracheal tube connected to manual resuscitator (ambu® bag) with the positive end-expiratory pressure (peep) valve after disconnection of -nine instances of the conventional apnea test (cat) were performed in brain-dead patients; instances of the mat were performed in brain-dead patients. the mean duration of the apnea test was . ± . minutes in the cat group and . ± . minutes in the mat group. there were no significant changes in paco , pao , or ph between the cat and mat groups (p = . , . , and . , respectively). in overweight patients (body mass index prevented dramatic reductions in pao and sao (p < . for both). in the patients who had hypoxic brain injury due to hanging, differences in pao and sao in the mat group were significantly smaller than in the cat group (p < . ). although mat, which was invented to maintain peep, was not efficient for all brain-dead patients, it could be helpful in selected patient groups, such as overweight patients or those who had hypoxic injury due to hanging. clinicians should consider this reliable short-term apnea test. coma is a serious complication that currently has no good biological markers. the hypothalamus plays an important function in consciousness circuity. orexin a/b, a neuropeptide produced in the hypothalamus has an excitatory effect on multiple target areas in the brain. previous orexin studies ry (tbi), stroke and comatose states. the goals of our study: ( ) the utility of orexin as a marker of coma recovery, ( ) the correlation between orexin and recovery at and days, ( ) correlation of orexin and glasgow coma score/score (gcs) over time, a prospective, irb approved study with a target n= with a diagnosis of coma due to stroke, including hemorrhagic, and tbi, treated in the neuro critical care unit at stony brook university ho collected from an external ventricular drain (evd) and corresponding blood serum samples on days , , and . there was no modification to the clinical treatment of individual patients. dictive of whether patients recovered consciousness vs deteriorated. logistic regression showed the relative risk of recovery vs. deterioration: , ( %ci - . ± . , . ± . , respective p-values= . e- , . epredictive of initial coma severity (gcs), with a correlation coefficient, r = . . correlation between - . , - . ). dictive of poor overall not appear as significant as the baseline level in predicting recovery. there has been limited research over the past decade on how race impacts survival from cardiac arrest. it has been suggested that black patients are more likely to have unsuccessful resuscitation and lower rates of survival to discharge, however, it is unclear if this difference is secondary to hospital factors or patient specific factors. more research is needed on racial disparities in post-arrest outcomes at urban medical centers. multimodal outcome characterization in comatose cardiac arrest (mocha) is an irb-approved multicenter observational study. this study sample consists of consecutive cardiac arrest patients treated at two urban hospitals from - . the sample includes both patients who experienced in-hospital and out-of-hospital cardiac arrest. the outcome of interest was in-hospital mortality. associations between race and mortality were evaluated by chi-square and relative risk (rr) with % confidence interval. we included white ( %) and black patients ( % were all found to be at no increased risk for in-hospital mortality relative to other gender and race combinations. there was no difference in location of cardiac arrest (i.e., inhospital vs. out-of- the lack of racial differences in mortality could possibly be explained by the similar rate of out-ofhospital arrests, similar initial non-perfusing rhythms, lower socioeconomic status of all patients, and strong focus of the participating hospitals on addressing racial disparities in the healthcare system. hyperglycemia is associated with poor clinical outcomes in critically ill patients, such as post-cardiac arrest (ca) patients. post-ca prognostication studies have studied clinical examinations, electrophysiology, biochemical changes, and/or neuroimaging, but studies regarding patient blood glucose levels are mostly limited to mortality outcomes. new analysis of glucose trends is needed to guide ca prognostication in order to determine favorable outcomes regarding neurologic functioning. this study was conducted using the irb-approved multimodal outcome characterization in comatose cardiac arrest (mocha) registry. the sample included ca patients admitted to a university-affiliated urban hospital from - . case selection was determined by availability of serial glucose measurements over the first hours post-ca and outcome scores at hospital discharge. poor functional outcome was defined as modified rankin scale (mrs) - or glasgow outcome scale extended (gose) - . statistical analysis included chi-square tests, and prognostic value was calculated by sensitivity. there was no significant difference in outcome regarding age, sex, race, or ethnicity. the study sample consisted of % diabetic patients, with no significant difference in outcome. patients with glucose levels > mg/dl at least once during the first hours post-ca were associated with poor functional outc there appears to be a correlation between glucose > mg/dl within the first hours and poor functional outcome. however, it is still difficult to reliably predict poor vs. good functional outcome due glucose management are needed to better understand this relationship. post-cardiac arrest organ injury is associated with high mortality rate after icu admission. despite improvement in the post-cardiac arrest care, temporal changes in patients' severity, intensity of care and neurological outcome remain poorly defined. the aim of this study is to describe how epidemiology of cardiac arrest characteristics, therapies and outcome have changes over years. retrospective study including adult (> years) cardiac arrest patients admitted from january to march after ca to a university hospital. we collected demographic characteristics and cardiac arrest data, together with main therapies and monitoring during icu and hospital mortality. a total of patients (median age [ - ] years; male gender %) were included over the study period. time to rosc was significantly longer in period i and iv when compared to others (p< . ). icu length of stay and lactate levels on admission were also significantly higher in the period iv than others. there was a progressive and significant increase of out-of-hospital ca, non-cardiac origin of arrest and non-shockable initial rhythm from period i to period iv. also, there was a significant increase in the number of patients developing acute kidney injury and hypoxic hepatitis over time, from period i to period iv. despite a more frequent use of coronary angiography and multimodal neurological monitoring, hospital mortality increased (from period i, % to period iv, % -p< decreased (period i, % to period iv, % -p= . ) over time. in this study, severity of anoxic injury and the incidence of post-cardiac arrest organ dysfunction increased over time. this was associated with a higher proportion of patients with poor outcome. pressure reactivity index (prx) based optimal cerebral perfusion pressure(cppopt) is associated with outcome after traumatic brain injury, but is not explored after cardiac arrest. we examined post-arrest patients who underwent invasive intracranial monitoring to explore characteristics of prx and cpp, and whether these were useful predictors of survival. we included all comatose cardiac arrest patients without primary neurological pathology that underwent invasive intracranial monitoring between - at our institution. cpp, mean arterial pressure(map), prx, cppopt, and deltacpp (cpp-cppopt) were calculated. systemic and brain physiologic measures were compared across the primary outcome of survival. in this pilot study we demonstrated the feasibility of acquiring cpp, prx, and cppopt for post-cardiac arrest patients. in this sample, none of the systemic and brain physiologic measures were associated with survival but the approach is limited by the bias towards poor outcomes in patients receiving monitors. interestingly, cppopt obtained from invasive intracranial monitoring generally ranged within physiologic norms. deltacpp for the single patient with good outcome was positive and small, consistent optimizing cerebral perfusion after cardiac arrest improves outcome are warranted. prognostication after cardiac arrest is challenge because of many confounding factors during hypothermia, severity of the brain injury is a key determinant of whether maximal resources, such as the use of extracorporeal membrane oxygenation (ecmo), mechanical circulatory support, or even coronary artery bypass grafting, are advisable or appropriate. therefore, early and accurate prognostication is essential for decision of therapeutic plan including maxima intensive modalities. in this study, we focused not only the prognosis estimation using mri but also initial ct-based prognosis estimation where features captured by modern deep learning (dl) technique were commonly used. we selected total cardiac arrest patients having initial ct at er, and brain mri after hours from cardiac arrest. diffusion weighted image (dwi, b = ), and apparent diffusion coefficient (adc) images calculated. cerebral performance category (cpc) scores were used as the main outcomes of survivors after cardiac arrest. both experienced neurologist and emergency medicine tried to predict the devised two cascaded deep convolutional neural networks (deep cnns). even fully experienced neurologist and emergency physician could not predict the cpc score exactly with the initial ct scan only and even additional diffusion mri (accuracy : %- % with initial ct only - % with additional diffusion mri). by using dl technique, among subjects of train set, subjects had the correct prognosis score ( . % accuracy) and among subjects of test set, subjects had the correct prognosis score ( . % accuracy) with initial ct scans only. with additional diffusion mri, . % accuracy and % accuracy. in visually equivocal initial ct scans, dl was more related to quantification than visual assessment. dl is superior and very useful for accurate prognostication especially with visually equivocal initial ct scan. cardiac arrest (ca) is associated with a high risk of dying and of neurologic impairment in survivors. target temperature management (ttm) improves survival and neurologic outcome and is recommended by international guidelines. this study assessed the association between the initial acute physiology and chronic health evaluation (apache) iii score and neurological outcome in comatose survivors of cardiac arrest who received targeted temperature management (ttm). data on post-cardiac arrest patients treated with ttm were collected from apache outcome database and medical records. ttm of °c or °c is chosen based on critical care physician's discretion. baseline characteristics included age, gender, apache iii scores, time to return of spontaneous circulation (ttrosc, minutes), time to target temperature (ttt, minutes), and shockable rhythm (sr, %). outcome included hospital mortality, and good neurologic outcome (defined as discharge to home or rehab). compared to the bad outcome group (n = ), the good outcome group (n = ) had similar age ( in comatose survivors of cardiac arrest who received targeted temperature management, the apache iii score calculated in the immediate post-cardiac arrest period was a poor predictor of neurological outcome. brain dead patients are victims of trauma, entering the health care system through emergency department (ed).in the ed, these patients are received with injuries and de-arranged physiological conditions that depends on time sensitive treatment and have the potential for improvement with proper management. our study tries to find out the predictors at admission that contributes to brain death (bd) so that their timely intervention can prevent bd a retrospective analysis of the data related to severity of injuries, physiological parameters and laboratory investigation including ct scan of the head at the time of ed admission of each patients were assessed once they were diagnosed brain death. logistic regression analysis was employed to determine the independent factor. p value of < . was considered significant. results brain dead patients records at the time of admission were analysed. on univariate analysis we found glasgow coma scale (gcs) < , blunt trauma chest (btc),skeletal injury, intraventricular hemorrhage (ivh),skull fracture,subarachnoid hemorrhage (sah),midline shift (mls),mean blood pressure (mbp)< mmhg,use of ionotropes, hemoglobin (hb)< mg/dl,international normalization ratio(inr)> . ,albumin< mg/dl,sodium level (na)> meq/dl,urea > mg/dl significantly related to bd.on further multivariate analysis ,we found gcs< (or- . ), btc (or- . ), ivh (or- . ), mls (or- . ), mbp < mmhg (or- . ), inr> . (or- . ), albumin < mg/dl (or- . ) and na level > meq/dl(or- . ) at the time of admission are strongly associated with bd. our study tried to find the predictors at the time of admission which may contribute to bd. addressing them may prevent patient from becoming brain dead. biomedical technology in critical care is advancing at a rapid rate, offering the potential to substantially improve performance through improved efficiency and productivity. recent evidence suggests that visual assessment of pupillary size and reactivity has limited interrater reliability and accuracy, hence, we examined the introduction and implementation of an automated pupillometer in an academic neurological icu. we evaluated clinicians' perceptions about the added utility of the pupillometer to the standard visual pupillary exam. -minute bedside education and demonstration of the pupillometer by a 'superuser', we conducted usability testing at the bedside. participants completed the end-user testing methodology, where they completed specified tasks designed to test the pupillometer's features and later completed a questionnaire regarding their ease of use and interpretation of results, comfort and confidence using the pupillometer, and their behavioral intention to use the pupillometer if adopted into the clinical environment to date, participants have completed questionnaires. participants were allowed repeat enrollment in the study. the participant's professional designations include registered nurses, residents and fellows and the majority have practised in the icu for to years. most of the participants are somewhat comfortable ( / ) performing the traditional visual pupillary exam and somewhat confident ( / ) with the results obtained from this exam. twenty-one, out of responses, were very comfortable in using the pupillometer, / were somewhat comfortable, and / were neutral. if this technology is introduced into icu, the majority ( / ) will use this device to conduct pupillary exams, and / would consider changing management based on the pupillometer results. this study outlines a strategy to evaluate usability and implementation of a newly adopted technology into the critical care environment. improved implementation methods and evaluation of implementation processes are necessary for successful adoption of new technology in acute care settings. propofol infusion syndrome (pris) is a rare complication of propofol infusion. it is characterized by metabolic acidosis, rhabdomyolysis, acute renal failure, hyperlipidemia, and rapid cardiac failure. risk factors for developing pris are: propofol infusion > hours, dosing > mg/kg/hr, critical illness, malnutrition, and use of vasopressors. we present a case of pris that developed after propofol infusion was turned off. a year old woman with medically intractable epilepsy and developmental delay, presented with generalized tonic clonic status epilepticus. she was refractory to benzodiazepines, so she was intubated and started on a propofol infusion. at mcg/kg/min of propofol, she was still having generalized clonic tonic seizures. she was transferred to our neurological icu for continuous eeg monitoring. propofol infusion was increased to mcg/kg/min ( mg/kg/hr) to control her seizures. she remained seizure free for hours. propofol was weaned over hours because she became hypotensive and required norepinephrine. when the propofol was turned off, cpk was , lactate was . , and creatinine was . . she received propofol for hours. twelve hours after propofol was stopped, she developed a metabolic acidosis, lactate increased to . , creatinine increased to . , urine output decreased, and cpk increased to > , . she then developed bradycardia with wide complex qrs, which progressed to asystole. she could not be resuscitated and died. our patient developed pris after propofol infusion was off for hours. she had many risk factors for developing pris, including high dose of propofol, critical illness, malnutrition, and use of vasopressors. pris can occur after propofol infusion has been stopped, and should be monitored for after the infusion has been discontinued in patients that are at increased risk. subdural hemorrhage (sdh) is a common cause of morbidity. we sought to study the impact of antithrombotic drugs on nontraumatic sdh. we retrospectively reviewed medical records of , patients admitted at massachusetts general hospital for sdh during to based on a research patient data registry. there were patients without history of head trauma included in the analysis. baseline demographic and clinical characteristic data were collected. the outcomes including gcs, modified rankin scale (mrs), sdh size, sdh expansion, surgical evacuation, mortality rates, length of stay (los), bleeding and thromboembolic complications were compared between two groups. multivariate logistic regression was performed to analyze association between poor outcome (mrs - ) and all potential predictors (age, diabetes, conditional variable regression method was used because of relatively small sample size to avoid overfitting the model. among patients included, ( . %) were on antithrombotic agents, either antiplatelets or anticoagulants, at presentation and ( . %) were not. anticoagulant and antiplatelet agents constitute . % and . % of nontraumatic sdh, respectively. all antithrombotic agents were discontinued on admission. nontraumatic sdh patients who were on antithrombotic agents had longer los ( . ± . , p= . ), higher rate of sdh expansion (or . ; %ci . - . ; p= . ), higher rate of disability at discharge (mrs - ) compared to no antithrombotic group (or . ; %ci . - . ; p< . ). on multivariate logistic regression analysis, antithombotic group had higher rate of poor outcome than no antithrombotic group (or . ; %ci . - . %; p= . ). use of antithrombotic agents prior to admission in nontraumatic sdh patients correlates with longer los, higher sdh expansion and increased disability at discharge. maintaining goal sodium levels in the neurocritical care population can be challenging. historically, at our institution, the supplementation of enteral sodium occurred by addition of table salt to tube feeding formulas by our dietary team. to make this therapy easier to standardize, monitor, and titrate, a new process was developed. continuous % hypertonic sodium chloride solutions are now administered enterally via feeding tubes. this also allows for the charting of the medication and immediate dose titrations. this pre-post analysis includes patients admitted six months prior to the implementation of the new enteral sodium process compared to patients admitted within one year after the new process change. demographic variables, as well as the indication for sodium goals, initial sodium levels, sodium level for -hours post-addition of enteral sodium supplementations, concomitant use of intravenous hypertonic saline, and achievability of goal sodium levels were collected. descriptive analytics were performed to compare groups. a total of patients were included in the analysis: in the pre-implementation group and in the post-implementation group. the most common indication for goal sodium levels in both groups was traumatic brain injury with head bleed; patients ( %) in the pre-implementation group and ( %) in the post-implementation group. ability to maintain serum sodium concentrations (defined as the ability to maintain goal sodium without the need for intravenous hypertonic saline for > h) within goal in the pre-implementation group was successful in % of patients (n= ) compared with % (n= ) in the post-implementation group. the use of continuous enteral % hypertonic sodium chloride solutions to target and maintain goal sodium levels provided similar efficacy compared to the addition of table salt to tube feeding formulas and is safer and easier to monitor and titrate. coagulation factor xa (recombinant), inactivated-xa inhibitor associated life--factor prothrombin complex concentrate (pcc) was utilized off- retrospective, single center, cohort study including adult intracranial hemorrhage patients who received discharge between efficacy (defined by international society on thrombosis and haemostasis criteria), thrombotic events, icu and hospital length of stay, and mortality. andexxa, coagulation factor xa (recombinant), inactivated-zhzo is indicated for patients treated with rivaroxaban and apixaban, when reversal of anticoagulation is needed due to life-threatening or indication. there is no available literature supporting the use of this drug in acute neurosurgical emergencies. we present our experience of patients treated with andexxa who required acute neurosurgical interventions as a life saving measure. patients were identified from may , to may , using an electronic database report identifying those who received andexxa and subsequent chart review at a single center quaternary care academic medical facility. factor xa inhibitor and time of dosing. patient and both had an external ventricular drain placed while in the emergency room. patient suffered from a cerebral hemorrhage with hydrocephalus while patient was found to have a primary ventricular hemorrhage with hydrocephalus. both were treated with four factor prothrombin complex concentrate (pcc) at an outside hospital. there were no bleeding complications during the procedures. two patients had a craniotomy performed. patient was diagnosed with an acute subdural hemorrhage with worsening midline shift despite receiving pcc at the outside hospital. patient four had an acute-chronic subdural hemorrhage with midline shift but did not receive pcc. in both craniotomy cases, there were no bleeding complications. andexxa was used in four patients taking apixaban or rivaroxaban undergoing lifesaving neurosurgical procedures despite no the utilization of acute extracranial and intracranial stents for the treatment of cerebrovascular pathology is increasing. the optimal antiplatelet agent and dose in this population and the utility of platelet function testing is unclear. all patients from january to april who were hospitalized and received ticagrelor to maintain intracranial or carotid stent patency in which platelet function testing (verifynow) was utilized to guide dosing were collected. relevant demographic, clinical, platelet reactivity unit (pru), and ticagrelor administration data was collected and qualitative assessment of pru results was performed. data was collected on patients and the maintenance doses utilized were , , (most frequent) or mg bid and loading doses of mg or mg. a total of patients' doses were titrated in order to achieve the goal pru range ( - ). among patients given a dose of mg % had a pru in the optimal range ( - ) as compared to % among patients given a dose of mg. twice as many patients given a dose of mg as compared to mg ( % vs %) had a pru between - . among the patients whose dose was titrated the average pru prior to dose escalation was , the average pru subsequent to dose escalation was , and the average pru prior to dose decrease was and the range in % of cases and was between - in % of cases. the utilization of platelet function testing to guide dose titration of ticagrelor to a desired pru range is feasible. a major limitation of this study is the lack of patient outcomes related to thrombosis or bleeding. rivaroxaban. the efficacy and safety of andexanet alfa have been evaluated in the annexa- study, which excluded patients receiving prothrombin complex concentrate (pcc) within the days preceding enrollment. however, there have been limited reports of patients receiving both pcc and andexanet alfa for oral factor xa inhibitor-associated major bleeding, without adverse effect. while thrombotic events were observed in % of annexa- patients, potential for additive risk when combining andexanet alfa and pcc is undefined. we describe a patient who received pcc followed by andexanet alfa for an apixaban-associated intracerebral hemorrhage, who subsequently suffered devastating embolic strokes. de-identified patient data were retrospectively collected from the electronic medical record a -year-old male presented with acute left-sided hemiplegia caused by a large right-sided temporal lobe intracerebral hemorrhage. the patient had a history of atrial fibrillation, for which he was anticoagulated on apixaban. the patient initially received intravenous (iv) pcc units/kg for prevention of hematoma expansion. the following day, minimally expanded hemorrhage was observed on repeat imaging concurrent with a measured apixaban level of ng/ml (reference range - ng/ml). as a result, high dose andexanet alfa was administered as an mg iv bolus, followed by an iv infusion of mg/minute for minutes. over the next several days, the patient's neurologic exam supratentorial strokes, likely embolic in origin. unfortunately, the patient did not survive hospitalization. the combination of pcc and andexanet alfa may carry with it substantial thrombotic risk, and cannot be routinely recommended. targeted temperature management (ttm) is used for neurological protection in patients with neurological injury but shivering during ttm can reduce therapeutic effect by increasing oxygen consumption and metabolic rate. cisatracurium used to prevent shivering has a shorter half-life than vecuronium and is not affected by liver and renal function. the objective of this study was to compare the efficacy and safety between two neuromuscular blockers in order to determine the benefit of cisatracurium. we reviewed medical records of adult neurological intensive care unit (ncu) patients who received st, to may st, . the efficacy between the two groups was confirmed by the presence of shivering and the recovery time of motor function. safety was determined by the incidence of bradycardia and hypotension, the duration of antibiotic use and the mortality rate after discontinuation of the neuromuscular blocker in ncu. recovery time of motor function was assessed using 'motor power' and 'glasgow coma scale (gcs)'. a total of patients were included in the study: patients in cisatracurium group and patients in vecuronium group. the incidence of shivering was . % and . % (p = . ) in vecuronium and cisatracurium, respectively. the median recovery time of motor function was . [ . - . ], . [ . - . ] hours (p < . ) based on the motor power score, . [ . - . ] hours and . [ . - . ] hours (p < . ) based on the motor response score of gcs, respectively. the safety was not significantly different between the two groups. recovery time of motor function was significantly shorter in the cisatracurium group than in the vecuronium group and there was no significant difference in the others. this study identified the benefits of cisatracurium in ncu under ttm. amantadine and modafinil are neurostimulants that may improve or accelerate cognitive and functional recovery after a stroke. this systematic review describes amantadine and modafinil administration patterns post-stroke, evaluates their impact on cognitive and functional outcomes, and identifies the incidence of adverse drug effects. an investigator-initiated medline search identified all full-text english-language publications describing the administration of amantadine or modafinil post-stroke from inception through october , . -stroke); intervention (amantadine or modafinil treatment); comparison (not required); outcomes (cognitive or functional recovery). amantadine and modafinil administration practices, cognitive and functional outcomes, and incidence of adverse drug effects were collected according to the preferred reporting items for systematic reviews and meta-analysis protocols (prisma-p) approach. quantitative analysis was not performed due to heterogeneity in the measures of clinical effectiveness. initially, , publications were identified. eight amantadine ( patients) and modafinil ( patients) publications were included. only ( %) amantadine patients and ( %) modafinil patients received treatment during an acute hospitalization. time from stroke to amantadine initiation was ( , . ) days and the initial dose was ( - ) mg/day. time from stroke to modafinil initiation was ( , ) days and the initial dose was ( - ) mg/day. under-responsiveness was the most common indication for neurostimulants (n= / publications; %). thirty-eight unique measures of clinical effectiveness were reported. a positive response in at least one measure of clinical effectiveness was reported in % and % of amantadine and modafinil publications, respectively. visual hallucinations (amantadine) and excitability/agitation (modafinil) were the most common adverse effects. amantadine and modafinil may improve or accelerate cognitive and functional recovery post-stroke, but higher quality data are needed to confirm this conclusion, especially in the acute care setting. levetiracetam is an antiseizure medication that is used in neurocritical care (ncc) patients to prevent or treat seizures. behavioral adverse events (ade) are reported to occur in approximately % of patients taking levetiracetam; however, the incidence of these ades in ncc patients are unknown and may be exacerbated due to their unique cns pathology. the purpose of this study is to identify the incidence of levetiracetam-associated behavioral (lab) ades in ncc patients. adult ncc patients receiving levetiracetam, admitted between november , and october , , and diagnosed with tbi, sah or ich, or cerebral infarction were included in this study. criteria for determination of lab ades included the following: ) diagnosis codes for delirium, agitation, irritability, hostility, violent behavior, insomnia, anxiety, or depression during this hospital admit; ) administration of an antipsychotic; ) positive cam-icu; and/or ) physical restraints. day of lab ade onset was determined by the start date of the antipsychotic or a positive cam-icu. there were patients included in this study; % males, median admit gcs was . the most common neurological injuries were ich ( %) and tbi ( %). lab ades were identified in ( %) patients. these were identified by diagnosis codes in % of patients, with delirium, depression, and agitation being most common; % received an antipsychotic, % had a positive cam-icu, % had restraints ordered, and % had more than one determining factor. lab ades were reported a median of (range - ) days after levetiracetam initiation. patients with tbi had the highest reported incidence of lab ades ( %). almost half ( %) of ncc patients that received levetiracetam experienced a behavioral ade, which was of levetiracetam use in ncc patients. the recommend the use of units/kg of four--pcc) or rting lower dosing strategies of apcc. in , a fixed, lowimplemented at our institution. the objective of this study was to evaluate the efficacy and safety of fixed, low-dose apcc this single-center, retrospective chart review included adult ich patients who received apcc for oral tcome was achievement of ich hemostasis. hemostasis was defined as no progression of hematoma on head ct within hours post-apcc. safety outcomes included in-hospital mortality and incidence of thromboembolic event (vte) within days post-apcc administration or up to the time of discharge, whichever came first. -four patients receiving apcc for reversal of factor xa inhibitor associated ich ( traumatic and spontaneous) were included for analysis. median age was years; % of patients had a past medical history of atrial fibrillation and % were anticoagulated with apixaban. median apcc dose was units ( - units), with a median weight-based dose of units/kg ( - units/kg). hemostasis was achieved in % of all patients with ich ( % in patients with traumatic ich, and % of patients with spontaneous ich). mortality rate was % and vte incidence was %. of hemostasis in the majority of patients and a low incidence of vte. ally ill patients, yet the optimal monitoring method is unknown. the purpose of this study was to describe the correlation between aptt and anti-xa levels in patients receiving prophylactic sq- a retrospective chart review of patients admitted years were included if they received sq--xa level drawn within hours of each other. aptt and anti-xa levels were then compared to determine correlation and descriptive analyses were performed. correlation was defined as normal aptt levels ( . - . seconds) paired with undetectable anti-xa levels (< . iu/ml), sub-therapeutic aptt ( . - . seconds) with sub-therapeutic anti-xa ( . - . seconds), therapeutic aptt ( - seconds) with therapeutic anti-xa ( . - . iu/ml), and supra-therapeutic aptt (> seconds) with supra-therapeutic anti-xa (> . iu/ml) levels. a total of patients and paired levels were analyzed. the median time between paired aptt and anti-xa levels drawn was . hours, and . % ( / ) of levels were drawn within hour of each other. anti-xa levels were drawn at a median of . hours after the sqpaired levels correlated, while . % ( / ) of levels drawn within hour of each other correlated. a spearman's correlation coefficient of . (p= . ) was found between aptt and anti-xa levels drawn within hour of each other. a sub-therapeutic aptt with undetectable anti-xa was demonstrated in . % of levels drawn within hour of each other. the sqanti-xa levels. there was no significant correlation between aptt and anti-xa levels in patients who received sq--sqh monitoring method in the neurocritically ill population. the utilization of acute extracranial and intracranial stents for the treatment of cerebrovascular pathology is increasing. the optimal intravenous antiplatelet agent for short-term bridging of patients who are unable to tolerate or do not respond adequately to oral antiplatelet agents is unclear. cangrelor offers potential advantages over glycoprotein iib/iiia inhibitors because response can be readily measured using platelet function testing (verifynow) and it has superior pharmacokinetics including a rapid on-set of effect and rapid clearance. patients with intracranial or carotid artery stents who were administered cangrelor for bridging purposes when oral antiplatelet agents were not feasible were assessed. relevant demographic, clinical and procedural data as well as cangrelor dosing and platelet function testing data were collected. patients had carotid artery stents. the indications for bridging were acute gi bleeding, inability to tolerate oral medications due to severe nausea/vomiting and two patients had an inadequate response to initial oral ticagrelor dosing based on platelet function testing. the dose of cangrelor utilized for all patients was . mcg/kg/min and all patients were on a cangrelor infusion for less than hours. platelet function testing (verifynow) was utilized to ensure adequate platelet inhibition and all patients demonstrated adequate inhibition on the prescribed dose. no stent thrombosis or bleeding was observed. cangrelor is a reasonable option when patients with intracranial or carotid stents necessitate an intravenous antiplatelet for bridging when oral antiplatelet medications are not feasible. current guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult intensive care unit (icu) patients recommend a multimodal analgesia-first strategy to minimize opioid and sedative requirements and encourage early mobilization. the purpose of this study was to evaluate the success of a stepwise multidisciplinary implementation of an analgesiafirst sedation pathway followed by introduction of an early mobility protocol in a neuroscience icu (nsicu). we retrospectively evaluated mechanically ventilated adult nsicu patients admitted to a single-center academic medical center. three-month time periods were evaluated at baseline (phase i), after implementation of the sedation pathway (phase ii), and after implementation of the early mobility protocol (phase iii). total of patients were evaluated: phase i (n= ), phase ii (n= ), and phase iii (n= ). we observed a progressive decrease in propofol use during each phase (i, ii and iii) (median . mg/day versus . mg/day versus . mg/day, respectively; p= . between phase i and iii) and increased dexmedetomidine utilization ( % versus % versus . % of patients, respectively; p< . ). opioidanalgesia requirements during mechanical ventilation were similar between groups. we observed a quicker time from admission to pt evaluation between phase ii and phase iii (median [iqr] of days [ ] [ ] [ ] [ ] [ ] [ ] versus days [ - ], respectively; p< . ). rehabilitation therapy was provided in . %, %, and . % of patients while admitted to the icu in phase i, ii, and iii, respectively (p= . ) and increased number of pt sessions provided per patient (median of [ - ], [ - ], and [ - ] sessions/patient during each phase, respectively). no adverse events related to early mobility were observed. interdisciplinary coordination and communication is necessary for effective unit-based practice changes as education alone is insufficient. a multidisciplinary approach to goal-directed therapy targeting pain management and light sedation increased opportunity for early mobility. the use of opioids in the neuroscience intensive care unit offset the balance of analgesia and reliability in performing neurological exam. in lieu of the current opioid crisis, we describe our center experience about the use of ketamine as an alternative medication with opioid sparing/lowering effect. retrospective chart review of patients admitted to nsicu with severe brain injury between november to april were performed. patients were separated into two groups of twenty by randomization and matching, each receiving either ketamine or propofol infusion. data collected includes age, gender, diagnosis, comorbidities, duration of ketamine, propofol and morphine equivalent (me) opioid dose. statistical descriptive analysis and independent samples t-test analytical analysis were performed to determine the difference of opioid use between two groups using spss software. the range of ketamine used over the mean period of . (range - ) days was - mcg/kg/min, while that of propofol over the mean period of . (range - ) days was - mcg/kg/min. / ( %) and / ( %) patients in the ketamine and propofol group required opioids respectively. the cumulative and mean morphine equivalent (me) dose for the ketamine group was . mg and . mg respectively, while on propofol, it was . mg and . mg. results of independent t-test analysis showed a significant p-value of . , indicating significant opioid dose reduction with ketamine. it is essential to recognize the effectiveness of ketamine as an opioid sparing/lowering agent with potential analgesic-sedative medication without significant side effects. introduction different indications. however, serious complications such as i -current pulmonary embolism in patients with a contraindication to unknown. this information would be needed to determine if opportunities for improvement exists. with approval from the local investigational review board (irb), during the period of - were identified from the interventional radiology department. only identified patient data was manually extracted via chart review to determine patient characteristics and a total of patients met inclusion criteria. . % were male. the most common neurocritical care diagnosis were intracranial hemorrhage( %), ischemic stroke ( %), central nervous system (cns) neoplasm ( %) and cns trauma ( %). . % of patients had at least venous thromboembolism (vte) was the most common indication ( %) followed by vte with contraindication for ac ( %), primary adjunctive treatment ( %) adjunctive prophylaxis ( %) and secondary adjunctive treatment ( %). in this single center study, to anticoagulation. andexanet alfa was approved in may for reversal of life-threatening hemorrhages for patients on anticoagulation with apixaban and rivaroxaban. since its approval the reversal of direct oral anticoagulant (doac) associated intracranial hemorrhages (ich) has been controversial. the objective of this study was to describe real world utilization of andexanet alfa at a large academic health system. we retrospectively reviewed patients who received andexanet alfa for an ich. patients were included if they received andexanet alfa from its time of approval to formulary through april , . baseline demographics, anticoagulation and reversal information was collected. a neurointensivist reviewed all imaging. intracerebral hematoma expansion was defined as > % increase in hematoma volume. subdural (sd) and subarachnoid hemorrhage (sah) expansion was defined as > % increase in maximal hematoma diameter. thirteen patients received andexanet alfa for ich. nine patients had an intracerebral hematoma, patient had an isolated intraventricular hemorrhage, patients had sd, and patient had a sah. the median age was (iqr - ) and % of patients were male. six patients were receiving a doac for stroke prevention, and a majority of patients ( %) were taking apixaban. the median glasgow coma scale was (iqr - ), and for patients with intracerebral hematomas the median ich score was (iqr - ). there was follow-up imaging available for patients, and patient had hematoma expansion. one patient died and another had interval surgery prior to repeat imaging. no patients had in hospital thromboembolic events up to days. of the patients, % of patients would have met exclusion criteria from the anexxa- trial. in this small sample of patients who received andexanet alfa for ich it appears hemostatic efficacy was achieved in a majority of patients with no thromboembolic events; however, larger trials are needed. lacosamide is a monotherapy or adjunctive therapy used for treatment of partial onset seizure that enhances slow inactivation of sodium channels. uncommonly reported adverse effects include pr interval prolongation, bradycardia, atrioventricular block, and ventricular tachyarrhythmias. an year-old male with history of atrial fibrillation, hypertension and aortic valve replacement on warfarin presented with an acute subdural hematoma after feeling lightheaded and falling. the patient reported having multiple recent syncopal episodes. he received prothrombin complex concentrate and vitamin k for warfarin reversal with an initial inr of . . he was started on levetiracetam and home medications of metoprolol and diltiazem were continued. the next evening, he had focal seizures, was given lorazepam and transferred back to the icu. he received lacosamide mg iv loading dose, and within minutes had a second episode of asystole. his blood pressure remained stable and he did not lose a pulse. he was given atropine x doses with no response therefore transcutaneous pacing was initiated. several minutes later, he became hypotensive and was started on isoproterenol and epinephrine infusions. ekg showed complete heart block. cardiology was consulted and placed a transvenous pacer. vasopressors were eventually weaned off however neuro exam remained poor. about a week later, family made the decision to transition to comfort measures and the patient passed away. lacosamide is an anticonvulsant primarily used for partial complex seizures. only a few cases of third degree atrioventricular block have been reported in the literature. this case of extreme atrioventricular bock with a lacosamide loading dose is not common, but a drug-drug interaction with metoprolol and diltiazem was suspected. prescribing lacosamide with beta-blockers or concomitant medications that prolong the pr interval should be done cautiously due to increased risk of atrioventricular block. tissue plasminogen activator (tpa) is currently the preferred agent for treatment of acute ischemic stroke. in about % of cases, patients will develop life threatening intracranial hemorrhage. currently the aha/asa guidelines and ncs guidelines recommend reversal of intravenous tpa with cryoprecipitate and platelet infusion. both society recommendations are based off low quality evidence and are given weak recommendations.theoretically, the mechanism of action of tranexamic acid (txa) makes it an appealing agent for reversal of tpa ; txa competitively inhibits activation of plasmin countering the mechanism of action of tpa. the purpose of this case report is to report and support usage of txa for reversal of thrombolysis with tpa. this is a patient case report in which an extensive review of the patient chart was conducted to provide an accurate history of events. extensive literature review was compiled to reflect current therapy guidelines and the off-label use of txa for reversal of tpa. year-old male presented to a tertiary care medical center with signs and symptoms of ischemic stroke symptomatic cerebellar hemorrhage. the delay in obtaining cryoprecipitate and platelet transfusion led the medical team to discuss alternative agents for the reversal of tpa. reversal with txa was discussed based on the medication's mechanism of action. txa mg/kg ( mg) was prepared at bedside and administered over minutes. repeat head ct showed no further progression of hemorrhage and there was an improvement in the patient's neurologic condition was noted hemorrhagic transformation following thrombolysis for ischemic stroke is a life threatening emergency. txa is an appealing option for reversal of tpa as it directly counters the mechanism of tpa and can be easily and quickly accessed. this case reports further strengthens and supports its usage. drug level monitoring is essential to optimize valproic acid (vpa) efficacy and minimize toxicity. total serum vpa levels of - mcg/ml are recommended, though free drug is more precisely responsible for vpa's pharmacologic effect. the interpretation of total vpa levels is complicated by the drug's complex protein binding characteristics. the use of free serum vpa levels has garnered interest, though the therapeutic range is not well defined. little is known about the relationship between free vpa levels and toxicity. we present a novel and unambiguous case of hepatotoxicity associated with elevated free vpa levels. de-identified patient data were retrospectively collected from the electronic medical record a -year-old male with a past medical history of refractory epilepsy was hospitalized for generalized tonic-clonic seizures. his prior home antiepileptic drugs (aeds) included carbamazepine and the vpa precursor divalproex. the patient's total and free vpa levels upon admission were . mcg/ml and . mcg/ml (laboratory reference range normal. the patient's home divalproex er dose was increased from mg twice daily to vpa suspension mg twice daily for his low total vpa level. on hospital day (hd) , the patient had a therapeutic total vpa level of . mcg/ml, but an elevated free vpa level of . mcg/ml in the setting concurrent with a free vpa level of . mcg/ml. the patient's vpa was then transitioned to alternative aeds due to hepatotoxicity concerns. the patient's clinical status later improved, and he was discharged probability scale implicated vpa as the probable cause of hepatotoxicity in this patient. measurement of free vpa levels helps guide dosing decisions and may reduce drug-related toxicity. limited case reports of osmotic demyelination syndrome (ods) treated with intravenous immunoglobulin (ivig) with or without plasma exchange (pe) are published, demonstrating variable neurologic recovery. the combination of ivig and pe led to complete neurologic recovery of our ods patient. electronic chart review to collect data for this case report. -year-old male presented with asymptomatic serum sodium of meq/l in the setting of intractable vomiting and decreased oral intake secondary to small bowel obstruction. his sodium was overcorrected by meq/l within first hours. he subsequently developed altered mental status with lethargy and became unresponsive on day with flaccid quadriparesis and minimal motor response to noxious stimuli. mri of brain revealed osmotic demyelination of central pons and bilateral basal ganglia. ivig was initiated on the day when ods was confirmed on mri. his serum sodium normalized. after day course of ivig g/kg, he could intermittently track with eyes but did not recover motor function. plasma exchange was initiated days after ivig. after sessions of pe, he started to move his right upper extremity antigravity and was attempting to verbalize. after sessions of pe, he moved all extremities antigravity, could talk although he had staccato speech and was able to ambulate with assistance. after sessions of pe, he was ambulating independently; his motor strength was +/ throughout. he was cognitively intact. at one month follow up in the clinic, he was neurologically completely intact, except for minimal upper extremity intention tremor. ivig with plasma exchange led to the remarkable neurologic recovery of a patient with ods. a randomized control trial comparing ivig monotherapy versus pe monotherapy versus the combination of ivig and pe is warranted to better clarify the appropriate treatment protocol in ods patients. digoxin is a commonly used drug in the treatment of heart failure patients but with no intrathecal indication. we describe a rare case of accidental intrathecal administration of digoxin during an elective caesarian section that lead to severe neurological deficits. a -year-old hispanic female underwent elective caesarian section with separate attempts at regional spinal anesthesia with bupivacaine due to failure of achieving adequate anesthesia with the first injection. risk management discovered that patient had erroneously received digoxin as the initial injection, confirmed by therapeutic serum levels of digoxin. two hours after delivering a healthy child, the patient's mental status deteriorated and she became unresponsive. she had three witnessed generalized tonic-clonic seizures and was emergently intubated for airway protection and received keppra. twenty-four hours in, patient remained comatose, continuous electroencephalogram revealed no seizures, magnetic resonance imaging (mri) brain showed diffuse, patchy hyperintensities involving bilateral frontotemporal lobes and basal ganglia. mri spine showed extensive cervical and thoracic cord edema. cerebrospinal fluid analysis showed white blood cells and protein count of . she received solumedrol milligram intravenous for doses followed by -day course of intravenous immunoglobulin (ivig). eleven days in, she was extubated. at discharge, she had intact upper extremity strength, intact speech, with no sensation or motor response below t level. mri showed mild thoracic cord edema. at day follow up, she had intact mental status and minimal improvement in motor strength and sensation below t . this is an extremely sad case of severe neurological deficits resulting from a grave medical error. there are only previously reported cases of intrathecal administration of digoxin in literature but the mri findings, duration of symptoms and neurological deficits were far more severe in our patient. neither cases reported use of high dose steroids or ivig either. neurological complications following organ transplantation can be a result of a myriad of infectious, toxic-metabolic, vascular and iatrogenic causes. given the wide range of possibilities, accurate diagnosis can be challenging. we present a case of acute hyperammonemia complicating renal transplantation. a -year-old female with a remote left mca stroke was evaluated for progressively worsening lethargy that started approximately a week after she had undergone deceased donor renal transplantation. her immunosuppression comprised induction with alemtuzumab plus methylprednisolone with long-term mycophenolate mofetil plus tacrolimus, and antibiotic coverage included valganciclovir, trimethoprimsulfamethoxazole and fluconazole. progressive deterioration in the level of consciousness progressing to coma with absent cough, gag reflex, sluggish pupils and no motor response resulted in the patient being intubated. neurological examination did not reveal any focal deficits besides her pre-existing right hemiparesis. pertinent investigations included an mri brain that showed no acute changes, eeg suggestive of triphasic waves and serial lumbar punctures showing elevated pressures in the - cm h o range. level of umol/l. in addition to appropriate pharmacotherapy and dietary protein restriction, the patient underwent continuous venoher mentation to baseline. additional investigations done to determine the etiology of the hyperammonemia showed the patient to be infected with ureaplasma urealyticum which was treated successfully with doxycycline and moxifloxacin. to our knowledge, this is the first report of ureaplasma urealyticum infection resulting in hyperammonemia fo management of hyperammonemia. in the absence of hepatic impairment, alternate etiologies of hyperammonemia should be sought. acute hyperammonemia requires prompt evaluation and treatment to reduce the mortality and morbidity associated with it. prevalence, characteristics, and outcomes related to ventilator associated events (vae) in neurocritically ill patients is unknown, and explored in this study. a retrospective study was conducted to examine prevalence, factors, and outcomes of patients with vae admitted to the neurocritical care service at harborview medical center between january , and december , . chi-square test, analysis of variance was used to compare patients by vae status. amongst neurocritically ill patients, vaes occurred in ( . %) patients. most common vae was ventilator associated condition, vac, ( . %), followed by infection related vac (ivac), ( . %), and possible ventilator associated pneumonia (pvap), ( . %). most common trigger for vae was an increase in positive end-expiratory pressure (peep). age (median [iqr ], male sex ( %), and bmi ( . %) were comparable across groups with and without vaes. patients with vae experienced higher intracranial pressures than those without vae( . mmhg vs. mmhg, p < . ). compared to patients without any vae, patients with any vae spent longer time on mechanical ventilation ( . vs. . days, p < . ), and in the intensive care unit ( . vs. days, p < . ). mortality ( . % vs. . %), median hospital length of stay ( . vs days) and discharge to home ( . % vs. . %) were similar across both groups. ventilator associated events are prevalent amongst the neurocritically ill. they are commonly triggered by changes in peep, and are associated with intracranial hypertension, increase length of mechanical ventilation and intensive care unit stay but may not affect mor associated with vae in subgroups of neurocritically ill patients and their impact on clinical outcomes warrants further examination. synthetic cannabinoids (sc) are a heterogeneous group of compounds initially developed to study the endogenous cannabinoid system. most sc interact with cb and cb receptors with much higher affinity -tetrahydrocannabinol. the popularity of sc is increasing in adolescents and young adults because of the ability to produce a marijuana-like high without being detected on routine drug screens. we hereby present a case of sc related status epilepticus, hypoxic respiratory failure, severe acute kidney injury (aki) and cerebral edema with fatal outcome. -year-old man with suspected sc adulteration of cbd oil presented with headache and status epilepticus. labs showed leukocytosis, triple acidosis, and tetrahydrocannabinol in urine. ct head showed diffuse cerebral edema with sulcal subarachnoid hemorrhage. intracranial pressure was elevated to - mmhg. hospital course was complicated by severe and refractory metabolic acidosis into hospitalization patient suffered cardiac arrest from pulseless ventricular tachycardia secondary to severe acidosis and metabolic derangements. after multiple attempts of resuscitation, care was withdrawn, and patient passed away. in this case, severe refractory metabolic acidosis proved to be fatal. this case highlights the many challenges in managing a critically ill patient with cerebral edema and renal failure with medically refractory metabolic acidosis. sc are undetectable on routine drug screens and exposure is difficult to establish. sc can lead to multi-organ failure and death that may result from cardiovascular events, respiratory depression, pulmonary complications, and aki. a high clinical suspicion is warranted in atrisk patients. exposure to sc may lead to cardiovascular, cerebral and renal complications that respond poorly to devise appropriate therapeutic strategies in managing such patients. benzodiazepines are the standard medication class for treating alcohol withdrawal symptoms (aws). in acute brain injury benzodiazepines may worsen delirium and its central nervous system (cns) depressant effects may decrease level of consciousness and make the neurological-exam unreliable. barbiturates have similar actions to benzodiazepines on gaba receptors and cause less cns depression. we present our center's experience with the use of phenobarbital in patients with aws and acute brain injury. retrospective chart review of twenty patients admitted in neuroscience intensive care unit(nsicu)with acute brain injury and aws was done. treatment protocol consisted of mg/kg ideal body weight(ibw) of phenobarbital loading dose divided into three intramuscular doses three hours apart, followed by a tapering daily oral maintenance dose for total of seven days. alcohol withdrawal symptoms were assessed using the ciwa score for severity. serum phenobarbital levels were drawn five hours after the third intramuscular dose. liver function tests were performed before loading dose and daily for -times the upper limit of normal triggered protocol discontinuation. none of the patients developed alcohol withdrawal seizures, one patient developed severe transaminitis. loading doses of phenobarbital did not cause hypotension. systemic toxicity was absent and phenobarbital serum levels drawn after the loading doses ranged between . - . mcg/ml (normal range - mcg/ml). patients decreased their ciwa score after the loading doses of phenobarbital suggesting improvement of withdrawal symptoms and there was decreased use of adjunctive medications (benzodiazepines) for management of aws. nine patients required adjunctive benzodiazepines and received mg or less of lorazepam. phenobarbital for management of aws was associated with minimal adverse effects and did not lead to systemic toxicity. phenobarbital can be used in patients with acute brain injury without exacerbating delirium and can decrease the need for adjunctive benzodiazepines. aneurysmal subarachnoid hemorrhage (asah) has a case fatality rate of up to % in patient that rebleed. cerebral arterial vasospasm (vsp) after asah is a leading reason for death and disability. nicardipine is used to treat hypertension and angina, and has been investigate for a potential use in the treatment of vsp after asah. intraventricular nicardine was used for treatment of severe asah after traditional methods failed (ie. ir, hypervolemia, permissive hypertension and intravenous inotropes). mg of nicardipine was mixed with preservative free saline by pharmacy to total ml in volume. ml of cerebral spinal flu drawn from the patient external ventricular device (evd). then the nicardipine solution was instilled and the evd was clamped for minutes. patient had transcranial dopplers (tcds) prior to injection and hours after injection and reopening of the evd. patient's vasospam temporized and neuro exam returned to pre spasm baseline. patient survived vasospam window and was transferred to long term care facility. in neuroscience icu (nsicu) maintaining balance between performing reliable neurological exam with adequate analgesia without causing significant sedation is challenging. ketamine has significant neuroprotective and anti-seizure properties. in spite of these unique neuro-friendly pharmacological profile, it's role in nsicu unit is not well defined. we describe our experience about the use of ketamine in neuro-critical care unit. retrospective chart review of patients admitted to nsicu in whom ketamine was used as first line agent for sedation and analgesia in intubated patients with varied brain injury from january to april was performed. safety parameters collected includes blood pressure changes, intracranial pressure changes, heart rate, arrhythmias, excess secretions and apneic spells. pco was monitored and hypercarbia was avoided. effectiveness was measured by requirement of additional sedation-analgesic medications while receiving ketamine. twenty patients with varied brain injury who were on ketamine infusion as first line agent were selected. mean age was . years (range - years) and patients were male. admitting diagnosis was hemorrhagic stroke ( %), ischemic stroke ( %), seizures ( %), carotid stenosis ( %) and tumor mass ( %). mean duration of ketamine infusion was . days (range - days) and dose range was - mcg/kg/min. no icp elevation was noted among the patients where the icp was monitored. none of the patients had uncontrollable elevated blood pressures nor major fluctuation in heart rate or respiratory rate requiring discontinuation of ketamine. ( %) patients had increased secretions without respiratory compromise. opioid use decreased significantly moreover additional sedation was not required while on ketamine infusion. ketamine is a safe and effective sedative-analgesic in neuro-critical care patients while at the same time allow for a reliable neurological examination to perform while on sedation. more research is warranted before it could be considered as the standard of care. oromandibular dystonia (omd) is a movement disorder characterized by involuntary, sustained muscle contractions of varying severity resulting in sustained spasms of craniopharyngeal muscles affecting the jaws, tongue, face, and pharynx that can lead to abnormal jaw opening or closing or tongue protrusion. these disorders are often treated with botulinum for improvement of symptoms. there is minimal literature related to omd treated for botulinum in the neurocritically ill patient population. we conducted a retrospective electronic medical record review from - of all brain-injured patients admitted to our neurocritical care unit who were diagnosed with omd and received botulinum toxin injections. etiology and location of brain injury along with clinical characteristics including resolution of symptoms were recorded. over a -year period, we injected patients with botulinum type a injection ( mouse units or m.u.) into bilateral masseter muscles for severe omd causing tongue biting/maceration and difficulty with oral care, and refractory to antispasmodics and muscle relaxant medications. among the patients, patients were sah, patient with ich/ivh, patient with bilateral brain injury after post pituitary neurosurgical procedure and patient with diffuse bilateral ischemic stroke related to sickle cell disease. all patients tolerated the procedure with no immediate complications. all patients had gradual improvement of omd albeit variable and only out of patients required a nd treatment. in this small series, injection of botulinum toxin for severe omd from brain injury causing tongue injury appears to be safe, tolerable, and efficacious in reducing enteral antispasmodics/muscle relaxants. no short-term or long-term adverse effects were noted and it helped nursing with oral care over time. larger randomized controlled trials should be performed to evaluate the effectiveness and safety of treatment with botulinum in the critically ill neurologic population. the neurosurgical intensive care unit (nsicu), a level trauma center in san antonio, cares for neuro critical patients. the use of central access catheters is essential for hypertonic fluid administration, vasoactive medications, and general critical care. in this unique population the risk of developing deep vein thrombosis (dvt) is higher compared to other patients due to reasons related to neurological injuries. the objective of this research was to determine the incidence and prevalence of dvt between the use of peripherally-inserted central catheters (picc) versus central venous catheters (cvc) in the nsicu. we prospectively evaluated consecutive patients with a cvc or picc in the nsicu from to . data was collected, by a team of apps on: surveillance vs non-surveillance ultrasounds, blood stream infections (clabsi), indwelling time, complications, and icu length of stay. a total of piccs were placed for catheter days, patients were diagnosed with a dvt related to the catheter, rate of . per catheter days. a total of cvcs were placed for catheter days, patients were diagnosed with a dvt related to the cvc, rate of . per catheter days. a total of dvts were diagnosed, one symptomatic patient and remaining dvts were identified during surveillance ultrasound. two complications were encountered during insertion of a cvc and picc which included development of hematoma on insertion of each catheter. the average length of stay for patients with a picc line was . days. the average length of stay for patients with cvc was days. the nsicu surveillance ultrasounds identified more dvts with the use of picc lines versus cvc warranted if surveillance ultrasounds should be routinely performed for nsicu patients. mortality with acute respiratory distress syndrome (ards) is as high as % in patients with subarachnoid hemorrhage (sah). many of the therapeutic modalities of ards carry potential deleterious effects on icp. we are presenting a challenging case of severe ards and sah. single case report. -year-old male who developed a sudden severe headache. emergent workup revealed a large cerebellar hemorrhage, sah with ivh and hydrocephalus secondary to a ruptured arteriovenous malformation (avm). emergent suboccipital decompressive craniectomy followed by external ventricular drain (evd) placement were performed and transferred to our facility for further aggressive care. hospital course was complicated by severe pseudomonas pneumonia with progression to severe ventilation strategies, sedation, paralysis and inhaled nitric oxide (ino) failed to correct hypoxia. on hospital day (hd) he continued to show refractory hypoxia and was placed on roto-prone® bed. continuous intracranial pressure (icp) monitoring was utilized with evd open at cmh o. prone positioning was attempted for hours daily. hypercarbia during prone positioning lead to elevated icp patient showed improvement of hypoxia, with termination of prone positioning and subsequent weaning of paralytics and sedation. he started following commands and was discharged to a long term care facility after avm embolization, placement of a tracheostomy, feeding tube and ventriculoperitoneal shunt. our patient made remarkable recovery from ards in the settings of obstructive hydrocephalus and sah. strict icp monitoring, ongoing ventilator adjustment and careful utilization of kinetic maneuvers for ards, including prone positioning, contributed. proning may be a consideration in patients with sah, obstructive hydrocephalus and ards with ongoing icp monitoring and ventilator adjustment, but larger scale studies are needed to explore its potential. paroxysmal sympathetic hyperactivity (psh) has been associated with worse outcomes following traumatic brain injury, possibly representing both a marker of injury severity and a source of secondary injury. prior studies suggest that psh is under-recognized and its treatment often delayed. the identification of admission risk factors for psh may facilitate earlier recognition, treatment, and targeted prevention. adults with severe tbi admitted to a neurotrauma icu for at least hours and hospitalized for at least days between january and december were retrospectively identified. consecutive psh-tbi patients (n= ) were identified via review of medication administration records as having been treated with propranolol and/or bromocriptine for at least hours. control-tbi patients (n= ) were matched to the psh-tbi cohort for age ( +/- years) and gcs (median ( , ) ). admission head cts were scored using marshall and rotterdam criteria. independent-samples t-tests, chi-squared, and multivariate analyses of variance were performed. age-matched cohorts did not differ by sex, race, bmi, trauma type, trauma mechanism, iss, or triss. icu admission vital signs differed between groups with psh-tbi demonstrating a higher hr (p= . ) and a trend towards higher sbp (p= . ), but no difference in core body temperature. neuroradiographic features associated with psh included significantly higher rotterdam ct score (p= . ), presence of ivh/sah (p= . ), basal cistern compression (p= . ), and trends toward higher marshall ct score (p= . ), presence of epidural hematoma (p= . ), and ct dai (p= . ). a multivariate analysis adjusting for admission gcs and sbp identified rotterdam score (p= . ), presence of ct dai (p= . ), and icu admission hr (p= . ) as independent predictors of psh. admission ct findings along with hr may help predict subsequent development of psh requiring treatment. early identification, treatment, and prevention of psh may mitigate its negative impact on tbi outcomes. hyperchloremia in patients receiving chloride-containing solutions can contribute to metabolic acidosis and acute kidney injury (aki), and has been associated with increased inpatient mortality, length of stay and aki in patients with spontaneous intracranial hemorrhage. whether hyperchloremia is a risk factor for mortality in patients with traumatic brain injury (tbi) is unknown. the purpose of this study is to determine if patients that develop moderate hyperchloremia while receiving continuous hypertonic saline (hts) have a higher risk of inpatient mortality. this was a retrospective chart review of patients admitted between january and september . included patients were over years old, admitted to the trauma service with a diagnosis of tbi, and received continuous % hts for at least hours for the management of cerebral edema. exclusion criteria were baseline end stage renal disease or hemodialysis, transition to comfort measures within hours or inconsistent documentation. the primary objective was inpatient mortality. secondary objectives were aki, hospital and intensive care unit (icu) length of stay. after tbi, mortality was higher in patients who experienced hyperchloremia, while aki and length of stay were similar. although randomized controlled trials (rcts) did not prove benefits of hypothermia for severe traumatic brain injury (tbi), brain ct images have not been evaluated in detail in these studies. we aimed to explore the prognostic value of brain ct findings in bhypo study. bhypo study was a multicenter rct to investigate the effect of therapeutic hypothermia in patients with severe tbi. the protocol included collection of brain ct data on admission and around day . using the ct database, we evaluated following findings: presence of intracranial lesion (acute subdural hematoma: asdh, acute epidural hematoma, cerebral contusion, subarachnoid hemorrhage: sah, or intraventricular hemorrhage: ivh), basal cistern compression, lesion laterality, marshall ct classification, and rotterdam ct score. hematoma thickness and midline shift were also measured. unfavorable outcomes were defined gos of to by glasgow outcome scale (gos) assessed at months. ct data were obtained from patients on admission and patients around day . there were no differences in ct findings between hypothermia group and fever control group. in the initial ct, univariate analysis showed that odds ratio (or) and % confidence interval (ci) for unfavorable outcomes were: shift > hematoma thickness ( . , . - . : p= . ), sah ( . , . - . , p= . ), sah or ivh ( . , . - . , p= . ), absent cistern ( . , . - . ; p= . ), and midline shift > mm ( . , . - . , p= . ). rotterdam score was significantly higher in patients with unfavorable outcome ( . vs. . , p< . ). regarding the day ct, bilateral lesion ( . , . - . , p< . ) and sah or ivh ( . , . - . , p= . ) were significant. no patients with absent cistern survived. patients were appropriately assigned in bhypo study in terms of ct findings. shift > thickness, sah, absent cistern, and rotterdam score were powerful prognosticator in severe tbi patients undergoing targeted temperature management. cerebral edema (ce) following traumatic brain injury (tbi) causes secondary injury and increased mortality. yet, conventional measurements of ce on head computed tomography (ct) inadequately accounts for ce. serial volumetrics may facilitate estimation of total brain volume. the objective of this study was to measure the reliability of this technique and identify a threshold for brain volume (bv) change which could be indicative of ce. a subset of patients (n = ) with intracranial hemorrhage on admission ct were identified from a prospectively enrolled cohort of subjects with trauma sufficient to warrant icu admission. using medical image processing, analysis, and visualization (mipav), two independent raters calculated bv on admission and follow-up head ct scans by measuring the volume of the intracranial vault and the absolute difference (ml^ ) and percent difference between the bv values of the two scans were calculated. intraclass correlation (icc) and pearson's correlations were calculated, and significance set at . . the overall reliability of bv measurements between raters was excellent (initial scan icc . volumetric analysis to estimate bv appears to be a reliable technique across serial head ct scans. bv changes of more than . % may represent a clinically significant threshold and should be further investigated. beneficial effects of therapeutic hypothermia in adults with traumatic brain injuries are controversial. we wanted to study the effect of therapeutic hypothermia (th) on outcomes after severe traumatic brain injury (tbi) in real practice using the nationwide inpatient sample in the united states. the nationwide inpatient sample was used to obtain data on all adults who had been discharged from to with a primary diagnosis of tbi who required mechanical ventilation, intracranial pressure monitoring, or craniotomy/craniectomy. the patients with th were assigned to the th group, and the rest were assigned to the control group. the primary outcome was in-hospital mortality, and the secondary outcomes included mean the length of stay, non-routine hospital discharge, mean hospital charges. only patients ( . %) out of a total of , underwent th. th group was younger ( . versus . years, p <. ),had a lower proportion of females ( . % versus . %, p= . ) and a higher rate of in-hopsital complication of deep venous thrombosis ( . % versus . % p = . ). when controlling for age, gender, comorbidities, in-hospital complications, hospital characteristics and disease severity, th was associated with an increased rate of in-hospital mortality (odds ratio, . ; % confidence interval, . - . ), longer mean length of stay ( . vs. . days; p< . ), and greater mean total hospital cost ($ , vs. $ , ; p< . ). there was no difference between the two groups in terms of non-routine discharge (odds ratio, . ; % confidence interval, . - . ), therapeutic hypothermia was associated with poorer outcomes in patients with severe tbi. our findings disfavor therapeutic hypothermia in severe tbi in routine clinical practice. it warrants further investigation in a prospective, randomized study. a rising incidence of subdural hematomas (sdh) has been attributed in part to increased use of anticoagulants and antiplatelets. anticoagulants also worsen the severity and prognosis of sdhs, but the impact of antiplatelets on prognosis is unclear. we hypothesized that antiplatelets would not affect sdh severity or outcome, while anticoagulants would be associated with more severe features and a worse functional outcome. we systematically identified and collected data on patients presenting with a new diagnosis of sdh in at a level i trauma center. we examined common markers of sdh severity in three cohorts of patients: those not on any antithrombotics, those on antiplatelets alone, and those on anticoagulants. categorical data was compared with chi-squared tests, and continuous data was compared with mann-whitney u tests. multivariable logistic regression was used to assess the impact of antiplatelet use on functional outcome at discharge, with a poor functional outcome defined as a score of - on the modified rankin scale. we identified patients with a new sdh during : ( . %) did not take antithrombotics, ( %) took antiplatelets, and ( . %) took anticoagulants. antiplatelets were not associated with increased sdh volume, thickness, or midline shift; anticoagulants were associated with increased volume (p< . ), thickness (p< . ), and a trend towards increased midline shift (p= . ). antiplatelets were associated with a better admission score on the glasgow coma scale (p< . ). when adjusted for age and gender, antiplatelets did not affect functional outcome (or . , p . , % ci . - . ), while anticoagulants were associated with poorer functional outcome (or . , p . , % ci . - . ). despite its known association with overall sdh incidence, premorbid antiplatelet use was not associated with sdh severity or a worse functional outcome at a level trauma center. the common data elements therapeutic intensity level (cde-til) score, quantifies the intensity of nursing and medical care aimed at preventing intracranial hypertension for patients with severe traumatic brain injury. we validated the cde til in our neurotrauma intensive care unit (nticu) and found the cde-til to be highly reflective of perceived and measured therapeutic burden but noted that the scale had a ceiling effect. specifically when icp was - mmhg and higher, the cde-til did not capture the escalating burden. in an attempt to eliminate that ceiling effect and to incorporate current h til (p-til). under a quality assurance approved protocol, retrospective chart review was performed on adult patients with severe tbi. the til score was derived using both the cde-til and the p-til for each hour nursing shift for the first full days of admission. the relationship between the cde-til and p-til and the icp were investigated. reliability testing of the p-til, including interrater reliability, and validation of the p-til are ongoing. the p-til and the cde-til are highly correlated (r= . ) and the relationship between the scores and the maximum icp are similar at icp less than mmhg. at higher icps however, the slope of p-til increases to . compared to the cde-til slope of . and illustrates a . times stronger correlation between the intensity of care level as measured by p-til and icp. the p-til has greater sensitivity for quantifying the intensity of therapy aimed at controlling icps, most significantly for patients with the highest icps, icps - mmhg and above, making it an ideal scoring system for communicating current nursing and medical needs of individual tbi patients as well as potentially predicting post-intensive care or post-discharge needs. patients are frequently brought into neurologic intensive care units in cervical spine immobilization after sustaining ground level falls or after being "found down." currently there is no consensus regarding cervical spine clearance in these patients as they are unable to participate in neurologic examination. after normal ct scans, mri scans are frequently employed to evaluate for ligamentous injury and radiographic signs of cervical instability. we conducted a retrospective chart review of patients who were admitted to the neurologic intensive care unit between and in cervical collars after ground level falls or after being found down (presumed ground level falls). patients were included in the study if they were obtunded on admission (gcs< ) with neurologic exams consistent with their cranial pathology. all patients underwent a high definition ct cervical spine or cta of the neck and were cleared if there was no radiographic evidence of fracture or instability. between - , eight patients were admitted to the neurologic intensive care unit that met inclusion criteria. average age at presentation was . years. cranial pathology on presentation included intraparenchymal hemorrhage, ischemic stroke, and subdural hemorrhage. all patients underwent a high definition ct cervical spine or cta neck which showed degenerative changes without fractures, subluxations or other evidence of instability such as increased atlantodental interval, or prevertebral soft tissue swelling. average follow up was . days range ( - ). there were no cases of cleared patients that suffered secondary neurologic injury or symptoms of cervical instability during the follow up period. our study illustrates that obtunded patients after ground level falls can safely be cleared of cervical spine precautions after a high definition ct cervical spine fails to demonstrate fractures, subluxations, or other evidence of cervical instability. this protocol limits the costs associated with mri scans and the risks associated with cervical immobilization. the elderly comprise the highest incidence of traumatic brain injury (tbi) hospitalizations and death, yet most tbi studies neglect the geriatric population. previous studies suggest women have better outcomes after tbi but are inconclusive. we examined differences in outcomes between sexes after tbi in the geriatric population. this is an observational study of patients and older admitted with tbi to a level trauma center. clinical variables including medical history, severity of injury (gcs> , gcs - , and gcs< ), mechanism of injury, and ct findings were collected. good clinical outcomes were defined as a gose > and measured at discharge and months. the chianalysis were used where appropriate. subjects were included in the analysis. ( %) women and ( %) men. average age was . (sd . ) with no significant differences between sexes. ( %) were mild, ( %) moderate, and ( %) severe. the most common etiologies were mechanical fall ( %), motor vehicle accident ( %), and syncopal fall ( . %). no differences in severity of injury or mechanism of injury were found. on admission ct, men had more contusions ( %v %;p= . ) and skull fractures( %v %;p, . ) compared to women. older age, and history of atrial fibrillation or congestive heart failure were associated with increased incidence of death. men were more likely to have in-hospital mortality ( %v %; p< . ). in multivariable logistic regression analysis controlling for other factors associated with mortality, men were significantly more likely to have in-hospital death (or- ;p= . ). at months, men were still found to have higher mortality (or- . ;p< . ). however, there were no significant differences in good outcomes between sexes at discharge ( %v %; p= . ) or months ( %v %;p= ). men have significantly higher mortality rates compared to women in the geriatric tbi population. differences are needed. partial brain tissue oxygen tension (pbto ) can be regulated by the fraction of inspired oxygen and the level of oxygen carrying capacity. we performed a systematic review of the literature using pbto directed treatment with red blood cell transfusion (rbct) to analyze clinical and physiological outcomes as well as adverse events following rbct. we performed a systematic review following the prisma guidelines and pre-registered with the prospero database. the following terms were used: [(brain tissue oxygen or brain tissue hypoxia or pbo ) and treatment] or [(brain tissue oxygen) or red blood cell transfusion) or pbo ) or traumatic brain injury) and red blood cell transfusion]. inclusion criteria were studies in which pbto was measured before and after rbct. the tool used for qualitative scoring was the grade score. risk of bias was assessed via rti and robins-i. a total of articles were screened of which four articles were included in the final analysis. the intervention performed was to administer to units of rbc depending on the hemoglobin level and the threshold set in each study. the clinical outcome was not described in any of the studies. there was an increase in pbto in all the studies, but it was primarily significant when pretransfusion pbto was less than mmhg. the grade certainty rating for the included articles was low to moderate. our review shows that a significant increase in pbto is primarily seen when pre-transfusion pbto is less than mmhg. clinical outcome and adverse events were not described in any of the included studies. in view of the known adverse effects of rbct in critically ill patients and the limited available literature we found, transfusion should only be reserved as a later tier measure for pbto correction, and possibly only when pbto is less than mmhg. withdrawal of life-sustaining therapy (wlst) is associated with % of deaths after severe traumatic brain injury (tbi). wlst frequently occurs within the first days of hospitalization, when prognosis is most uncertain. while patient factors play a role in the decision, institutional practice patterns and physician perception of prognosis also contribute, as demonstrated in canadian studies. we hypothesized that the rate and timing of wlst among patients with severe tbi vary across the united states. we conducted a retrospective cohort study of patients with severe tbi admitted in to us trauma centers included in the trauma quality improvement program. severe, isolated tbi was defined by diagnosis code and glasgow coma scale (gcs) score < . patients under , with severe non-head injuries, or with advanced directives were excluded. centers were grouped by us census region (northeast, midwest, west, south). multiple logistic regression for wlst was performed with region, patient demographics, gcs motor score, pupillary reactivity, and midline shift as covariates. regression -hospital mortality. variability may reflect inconsistent institutional practice patterns, regional cultural differences, and the difficulty of prognostication. more reliable and standardized prognostic assessments are needed in this population. introduction: pre-injury use of antiplatelet agents may increase hemorrhage size and hematoma expansion after traumatic brain injury (tbi). however, empiric platelet transfusions may result in significant morbidity and unnecessary expense and may not be justified. we sought to determine whether a thromboelastography (teg) platelet-mapping (pm) algorithm could safely reduce platelet transfusion without clinically relevant hematoma expansion. methods: a prospective standardized teg pm-based treatment algorithm was instituted to guide reversal of antiplatelet medications in tbi patients. the algorithm established reversal thresholds for arachadonic acid inhibition (aa-inhibition > %) and adenosine diphosphate inhibition (adp-inhibition > %). consecutive tbi patients were enrolled and compared to a historical cohort. hematoma volume was calculated by itk-snap. conclusions: a teg-guided antiplatelet reversal algorithm may significantly reduce platelet transfusions without clinically significant hemorrhage expansion. increasing partial oxygen arterial tension is one method to increase the partial brain tissue oxygen (pbto ). however the effects of hyperoxia on clinical outcomes and adverse effects remain elusive. to investigate the effects of normobaric and hyperbaric hyperoxia on pbto in patients with tbi, we performed a literature review following the prisma guidelines and pre-registered with the prospero database. the following search terms were applied: [(brain tissue oxygen or brain tissue hypoxia or pbo ) and treatment] or [(brain tissue oxygen) or brain tissue hypoxia) or pbo ) or traumatic brain injury) and hyperoxia]. prospective trials and observational cohort studies were included in this review. two reviewers assessed the risk of bias of each study using the rti item bank. a total of articles were screened, of which articles were included. only one study investigated the effects of combined hyperbaric/normobaric hyperoxia and another used hyperbaric as a separate intervention; the majority of studies were of normobaric hyperoxia. overall, an increase in pbto was observed with both normobaric and hyperbaric. clinical outcome was mostly missing; one study showed an absolute reduction in mortality and improvement in favorable outcome using glasgow outcome score at months. adverse events were also only scarcely reported; studies showed that hyperoxia did not induce cerebral toxicity by using markers of oxidative stress, and one study showed no evidence of pulmonary oxygen toxicity in either the hyperbaric or normobaric hyperoxia groups. normobaric and hyperbaric hyperoxia consistently induced an increase in pbto . improvement in clinical outcome was reported in some studies but did not reach statistical significance except in one. adverse events were not adequately investigated. larger prospective studies are required to investigate the clinical outcome effects of hyperoxia, its adverse consequences, and its role in the tiered approach towards brain tissue dysoxia. early prognostication, either from clinical and/or radiological information, is an important aspect in the settings of neurocritical care with limited resources. we sought to determine the values of two radiological scoring systems in predicting the outcome of traumatic brain injury (tbi) patients, which are marshall and rotterdam ct scores in indonesia. therefore, a physician can make a better priority to provide high-yield care to all tbi patients. a retrospective cohort was conducted in a national referral hospital from july to december . all tbi patients admitted to the emergency department (ed) and had an initial ct scan were included in this study. their classification of tbi and initial ct scan were reviewed and all patients were followed to see whether the patient died or alive until discharge from the hospital (in-hospital mortality). statistical analyses were conducted to find the predictive values (sensitivity, specificity, cut-off point, relative risk) of both scoring systems. of tbi patients admitted to ed, there were patients had an initial ct scan. most of them were categorized as mild tbi ( . %), then moderate ( . %) and severe tbi ( . %). in-hospital mortality was . %. with cut-off point in marshall and rotterdam ct scores, their sensitivity ( . % vs. . %, respectively) and specificity ( . % vs. . %, respectively) were similar. same things also found in their relative risks, which are . ( % ci . - . ) and . ( % ci . - . ). both marshall and rotterdam ct scores have significant values in predicting the outcome of tbi patients, thus it should be implemented in daily emergency practice to assist a physician in making further clinical decisions. midline shift (mls) in brain is a critical condition. if not diagnosed timely, it could lead to a devastating outcome. computed tomography (ct) scan is the gold standard technique to diagnose mls in neurosurgical patients. the aim of our study was to find out association between transcranial sonography [tcs] and ct scan in assessing midline shift in patients with tbi. in this prospective ongoing study, adult patients ages - years, of either gender, with tbi were included. demographic details were noted. all patients underwent ct scan, followed by tcs. mls on tcs was determined using standard technique. we noted the mls on ct scan and time window between ct scan and tcs was also measured. consciousness was assessed using glasgow coma scale (gcs) and gcs -pupil [gcs-p] scales. descriptive data are given as mean (sd) or number. spearman's correlation test was used to detect relationship between gcs and mls assessed by ct scan and tcs, and also gcs-p. the value of p< . was considered significant. a total of neurosurgical patients were studied. male to female ratio was : . the age was [ . ] years with weight of . [ . ] kg. ten patients had gcs< . the mean value of mls measured by tcs - . , p = . ). the correlation between tcs and ct scan with gcs was in significan respectively. however the value of gcs- in patients with tbi, mls can be successfully assessed using bedside, non-invasive and non-radioactive monitor tcs when compared to a ct scan. there is a good correlation between gcs and gcs -p. early post-tbi seizures are reported to occur within hours and between days - following tbi in . % and . % patients, respectively. early seizure prophylaxis with phenytoin in severe tbi patients is drugs with better safety profile have emerged as potential alternatives. the objective was to describe seizure prophylaxis practices in critically ill tbi patients. we conducted a retrospective observational study of adult trauma icus. we included consecutive adult icu patients with moderate and severe tbi admitted between jan and dec . data were collected using standardized forms. our primary outcome was the incidence of seizure prophylaxis use. we included patients with a moderate ( %) or severe ( %) tbi. the majority were men ( . %) with mean age of . (sd . ) an ( %) and mva ( %). a total of % required invasive icp monitoring. a total of patients ( %) received early seizure prophylaxis, % for moderate and % for severe tbi. phenytoin, levetiracetam or their combination were used in ( %), ( %) and ( %) of cases, respectively. twelve patients ( %) were previously treated for pre-existing epilepsy. a total of ( %) patients experienced a seizure ( at the trauma scene, in er, in icu and on the ward). among the severe tbi patients in icu for days or more, anticonvulsants were continued for the recommended days in % of cases. early seizure prophylaxis is inconsistently used in severe tbi patients in canada. phenytoin still remains the agent most used. despite the current recommendations, % with severe tbi did not receive prophylaxis and % for a shorter period than days. raised icp persistently in severe tbi patients may be detrimental. however, chest physical therapy (cpt) is equally necessary for preventing secondary factors influencing the risk in these patients. this study was intended to observe the impact of short-term rise in icp with manual cpt in severe tbi patients on outcome along with hemodynamics. this was a prospective, observational trial on adult patients, of either sex, aged - years, with severe tbi, on mechanical ventilatory support with continuous icp monitoring, and receiving cpt on regular basis, included in this study. the cpt was applied for minutes' duration and repeated after an interval of hours in between for a total sessions in a day. the measurement measured intracranial pressure, cerebral perfusion pressure, heart rate, mean arterial pressure (from start of the intervention until min after the intervention at min interval each), and gcs after each session of cpt along with final outcome/gos at the time of discharge and months. the rise in median intracranial pressure of . (- . , . ) and median cerebral perfusion pressure of . (- , . ) was significantly higher during intervention and after intervention phase. in contrast, a median heart rate rise of . ( . , . ) and mean arterial pressure rise of . ( . , . ) were comparable. however, in patients with high baseline icp (> mmhg), poor outcome was noted in terms of low gose ( , ), and higher mortality ( . %) at hospital discharge or months after injury. significant increase in icp in severe tbi patients post cpt for minutes at a time (total minutes each day) was not tolerable in this cohort. moreover, we observed significantly low gose in patients with sustained intracranial hypertension. the effect of manual technique of cpt on final (long-term) neurological outcomes remain inconclusive but with favorable respiratory outcome. survivors of moderate and severe traumatic brain injury (mstbi) require substantial care, much of which is provided by friends and family. we sought to describe the experience and unmet needs of survivors and their informal caregivers follow mstbi, particularly related to care transitions. this study was conducted in two intensive care units (icus) at a level trauma center. we conducted qualitative, semi-structured interviews with both patients and informal caregivers of mstbi survivors at hours, one month, three months, and six months post injury. informal caregivers were defined as friends or family who planned to provide care for the patient. patients were years or older with an mstbi, and not expected to imminently die of their injuries. eighteen patient-caregiver dyads were enrolled. one patient died within hours. at hours, caregivers were interviewed; at one-month caregivers were interviewed; at three months caregivers and one survivor were interviewed; and, at six months caregivers and seven survivors were interviewed. three themes were identified in the qualitative analysis of caregiver interviews: caregiver burden, caregiver health related quality of life, and caregiver need for information and support. experiences varied depending on time since injury, discharge disposition, functional neurologic outcome, caregiver access to resources, and likely multiple other additional factors. interviews with survivors were not insightful secondary to post-traumatic amnesia. this study provides new information about the experience of informal caregivers during the six months after their friend or family member survived an mstbi. caregivers reported that needs evolved over time. at three to months, few moderate to severe tbi patients were well enough to be interviewed, and information obtained by survivors was not insightful. interventions to promote caregiving may be a substantial opportunity to improve patient and caregiver-centered outcomes following tbi. vasospasm following traumatic brain injury (tbi) has a high incidence and a detrimental effect on the neurological prognosis. yet, it remains a neglected, poorly understood phenomenon and there are no guidelines for its management. herein we present a case of severe vasospasm following tbi that caused secondary delayed cerebral ischemia (dci). we further appraised the current literature aiming at identifying predictors of vasospasm in tbi. a y/o white woman presented to the hospital after a mechanical fall resulting in mild tbi with associated subarachnoid hemorrhage (sah). glasgow coma scale (gcs) at presentation was , with no neurological deficits. a non-contrast ct head revealed diffuse bilateral fronto, parietal and temporal sah without evidence of aneurysm or vascular malformations on ct angiogram (cta). toxicology screens were negative. at hours from tbi patient developed acute severe headache. a repeated cta showed right internal carotid artery (ica) and middle cerebral artery (mca) vasospasm with no ischemia identified on mri brain. patient was started on nimodipine. on day- patient developed acute left side hemiparesis and neglect with neuroimaging evidence of a complete right mca infarct. hemodynamic augmentation therapy was initiated with partial improvement of deficits. patient subsequently developed hemorrhagic conversion of the right mca infarct. on day- neuroimaging revealed resolution of vasospasm. patient had residual left side neglect and anosognosia. in line with prior literature our patient developed vasospasm in the large intracranial vessels, at hours from the tbi and earlier than in aneurysmal sah. however, differently from previous reports, gcs at presentation was > , age was > and despite vasospasm developing later than hours it was not associated with good outcome. eded to identify accurate predictors of vasospasm following tbi with secondary dci that could improve detection and management of this detrimental phenomenon. therapeutic hypothermia and/or cooling therapy has been hypothesized to have benefits in patients with traumatic brain injury (tbi). several systematic reviews (sr) are being performed to address this question, but their results are inconsistent. the objective of this study was to assess the methodological quality of sr that included randomized clinical trials (rcts) that assessed the effects of therapeutic hypothermia and/or cooling therapy in patients with tbi. a critical appraisal study was performed in order to assess any sr that fulfilled the inclusion criteria. an unrestricted search of the literature was carried out in march at four major electronic databases (medline, embase, lilacs and cochrane library). two independent reviewers selected the studies, extracted the data and appraised the methodological quality of the included sr using the amstar- (a measurement tool to assess systematic reviews) tool. an overall assessment of the confidence in the results was performed using the checklist available in amstar- website (https://amstar.ca/amstar_checklist.php). the confidence of the results may be graded as high, moderate, low or critically low. this grading is based on the adequacy of the sr to the domains of the amstar- . the search strategy retrieved references. after the selection process, sr were included. the sr were published between - and included to rcts. the overall confidence in the results from included sr was graded as critically low in . %, low in . %, moderate in %, high in . %. a high number of sr addressing similar clinical questions were published in a short period of time. the methodological quality was adequate in only few sr. clinical practice guidelines should considered this result when choosing the evidence synthesis to recommend for practice. neurogenic pulmonary edema (npe) is a clinical syndrome characterized by acute onset after central nervous system injury. the aim of this study was to investigate the clinical features of npe in patients with subarachnoid hemorrhage (sah). the authors retrospectively analyzed a total of patients with sah who were treated at our hospital from april to september . of these patients, were included in this study after the application of predefined exclusion criteria. patient demographics, aneurysm size and location, clinical characteristics, and patient outcomes were reviewed and compared between an npe and a non-npe group. sixteen patients ( . %) presented with npe at admission. among them, patients ( . %) recovered from npe immediately, and ventilatory support was withdrawn within days from onset. a univariate analysis showed that patients with npe were of younger age (p= . ), had a higher rate of vertebral (p= . ), and lower systolic blood pressure on admission (p= . revealed significant differences in the frequency of vertebral artery dissection (odds ratio (or) . , % ci . -- . , p= . ) between the groups with and without npe. no significant group differences were found in other factors, including heart rate, neurologic outcomes at discharge. vertebral art factors for npe. however, neurologic outcomes at discharge did not differ between groups, suggesting that poor outcome due to npe could be reduced by appropriate diagnosis and treatment. antibiotic-impregnated catheters (aic) are recommended for the prevention of ventriculostomy-related infections (vri). other antibiotic prophylaxis strategies following external ventricular drain (evd) placement vary widely by institution. the role of systemic antibiotics for this indication remains controversial. we retrospectively reviewed the charts of all patients having an evd placed between january , and december , . after excluding patients who died or were discharged within hours of evd placement or had an evd placed due to suspected meningitis, patients were categorized into the periprocedural (p) or no periprocedural (np) antibiotics group. patients were determined to have a vri if catheter and up to days after catheter removal. mann-whitney u test was used to analyze descriptive data and baseline demographics. chi-squared models were used to analyze the incidence of infection. included in the no periprocedural antibiotics group (age [ - ] years; % male) and were included in the periprocedural antibiotics group (age [ - ] years; % male). the most frequent indications for evd were subarachnoid hemorrhage (sah) [np: n= ( %), p: n= ( ), p< . ], intracranial hemorrhage (ich) [np: n= ( %), p: n= ( %), p= . ), and other, which included colloid cysts and tumors [np: n= ( . %), p: n= ( %), p< . ]. there were infections in the no periprocedural antibiotics group compared to in the periprocedural antibiotics group (p= . ). the most common pathogen was coagulase-negative staphylococci (n= , %). the use of periprocedural systemic antibiotic prophylaxis did not significantly reduce the incidence of vri. periprocedural systemic antibiotics may not be necessary in the setting of antibiotic impregnated catheters to reduce the incidence of infection. cerebral artery vasospasm is a rare complication of craniopharyngioma resection but can have life altering consequences including delayed cerebral ischemia if not quickly recognized and managed appropriately. we present a case of craniopharyngioma resection in a year old male complicated by refractory vasospasm and its management with intraventricular nicardipine. data regarding the operative management, time course, vasospasm and management was accessed retrospectively after patient discharge. a year old male with recurrence of a craniopharyngioma presented with left eye vision loss and was admitted to the neurosciences intensive care unit after transsphenoidal resection. intraoperatively, the tumor was noted to be adhered to the posterior communicating artery and the left anterior cerebral artery. dense invasion into the hypothalamus was noted. this portion was carefully resected to avoid progressive lethargy. computed tomography angiography revealed new mild narrowing of the left anterior and middle cerebral arteries and bilateral posterior cerebral arteries consistent with vasospasm. the patient was treated with a vasospasm bundle including nimodipine, euvolemia, and blood pressure augmentation. over the next twenty days, the patient continued to have a variable amount of vasospasm despite aggressive medical and intra-arterial management. on post-operative day . nicardipine was then infused into the evd once a day for days, resulting in rapid and sustained improvement in vasospasm. the mechanism of vasospasm following skull base tumor resection is unknown. presence of blood in the operative bed, direct surgical injury to the blood vessels, hypothalamic dysfunction and the release of inflammatory chemicals have all been proposed. treatment remains similar to treatment used in sah, utilizing nimodipine, euvolemia, blood pressure augmentation and intra-arterial verapamil. this case demonstrates the effectiveness of intraventricular infusion of nicardipine on refractory vasospasm. to present a rare case of bilateral internal carotid artery (ica) aneurysms presenting as trigeminal neuralgia (tn), with good outcome post surgical treatment. a -year-old woman presented with disabling tn for year, exclusively affecting the right maxillary and mandibular divisions. symptoms did not abate with trial of adequate doses of gabapentin, duloxetine, oxcarbazepine and indomethacin. thin-cut magnetic resonance imaging (mri) brain with and without contrast showed rare contact with wide-necked aneurysms of bilateral petrous-cavernous icas producing prominent mass effect on bilateral adjacent trigeminal nerves. carotid arteriogram redemonstrated ica aneurysms with left measuring . mm x . mm and right measuring . mm x hours post procedure, tn had completely resolved. patient was started on aspirin mg and clopidogrel mg daily and is being tentatively planned for intervention on left aneurysm. on her month follow-up appointment with neurology, she reports no recurrence of tn. in cases of aneurysmal causes of tn, presence of bilateral aneurysms causing mass effect on the trigeminal nerve at its root is a rare occurrence and needs high clinical suspicion. due to the high risk of rupture associated with giant and symptomatic aneurysms, treatment should be expedited and aggressive in order to not only address symptomatic tn but also to avoid the risk of aneurysm rupture in the future. surgical clipping and endovascular coiling with or without stenting has demonstrated remarkable symptom relief in reviewed literature for other types of intracranial aneurysm. moyamoya disease is a chronic cerebrovascular disease characterized by spontaneous and progressive stenosis or occlusion of the internal carotid artery and its branches. revascularization procedures have been shown to improve cerebral hemodynamics and decrease the risk of strokes, but several postoperative complications are known to occur. we present a case with a fairly rare complication with characteristic radiological findings after surgery. a -year-old girl with moyamoya disease underwent left superficial temporal artery (sta)-to-middle cerebral artery (mca) anastomosis with encephalo-duro-myo-synangiosis (edms), and did right sta-mca anastomosis and edms one year after the initial surgery. the procedures were uneventful and the occlusion time was minutes. she recovered from the anesthesia without neurological deficit, and mri on postoperative day (pod) demonstrated no ischemic lesions and patent bypass, although swelling of the temporal muscle attached to the brain surface was noted. on postoperative day , she experienced a transient neurological event (left hemiparesis). magnetic resonance imaging revealed large cortical and subcortical hyperintense lesions in the middle cerebral artery territory on diffusion-weighted imaging and apparent diffusion coefficient imaging. subsequently, the radiographic findings improved within several days with resolution of the symptoms. revascularization surgery for improving a patient's hemodynamics can prevent the development of strokes, but is known to be associated with perioperative cerebral infarction and cerebral hyperperfusion causing transient neurological deterioration, delayed intracerebral hemorrhage, and vasogenic edema.this case is a reminder that hemodynamic complications can develop subacutely in patients who have undergone successful revascularization for moyamoya disease. the radiological features and mechanisms of this rare condition associated with revascularization surgery for moyamoya disease are discussed. vasospasm with delayed cerebral ischemia is a rare but known complication of endoscopic transsphenoidal resection of pituitary adenoma. this complication has rarely been reported in cases of -arterial treatment have been favorable in some cases. electronic medical record review. the patient is a year old male who underwent subtotal resection of pituitary adenoma via an open right fronto-temporal approach. eight days post-resection he developed progressive headache and leftsided weakness which acutely worsened the following day. his nihss on presentation was , consistent with right mca syndrome. ct brain showed mass effect in the right frontal lobe with . mm midline shift. cta showed sluggish flow through right m branch suggestive of vasospasm. he was taken to cerebral angiogram post-op day and received right ica intra-arterial verapamil and right ica and mca angioplasty. he was started on nimodipine following the procedure. his exam improved significantly over the course of - days. he was discharged home on verapamil mg q hours. at three month follow-up his nihss was and his modified rankin scale was . in the case we present, the patient received intra-arterial treatment with verapamil and angioplasty - days after onset of symptoms. despite delayed presentation the patient ultimately achieved a favorable functional status. vasospasm and stroke post-pituitary tumor resection are complications of which patients should be adequately informed, especially when considering the possibility of good functional outcome with intraof this potentially debilitating and life-threatening complication and attention should be paid to utilizing techniques for early detection of vasospasm. neuromonitoring is an essential part of the management of neurocritical patients. many icus in developing countries manage their patients without monitoring icp. intensivists play a vital role in clinical judgments to manage their patients. raised icp are handled either by medical management or surgical procedures like decompressive craniotomy. the study aimed to see the outcome of patients with raised icp and compare medical vs surgical management in these patients without monitoring icp. a retrospective observational study was conducted among patients admitted from january to december in the icu of dhaka medical college hospital, bangladesh. patients who had etiologies of brain code, clinical presentations and or radiological findings consistent with raised icp were included. patents were grouped into neurosurgical and medical management groups. length of icu stays and mortality were observed. student's t-test and chi-square tests were used to see the statistical significance. total of patients was selected. mean age was . ± . years, and . % were male. traumatic brain injury was the most common cause of raised icp ( . %) among selected patients. . % of patients were managed medically, and neurosurgical procedures managed . % of patients. length of icu stay was higher in neurosurgical patients compared to medical management group ( . ± . vs . ± . ; p= . , non-significant). mortality was higher in neurosurgical patients compared to medical management group ( . % vs . %; p= . , non-significant). mortality was also higher in traumatic brain injury patients who underwent neurosurgery compared to medical management ( . % vs %; p= . , non-significant). neurosurgical management didn't show a better outcome in patients with raised icp when monitoring was unavailable in a resource-limited icu. chronic kidney disease (ckd) independently increases the risk of stroke and burden of ischemic small vessel disease (svd). effects of ckd on intracranial hemodynamics remain poorly defined. this study compared svd and a transcranial doppler (tcd)-based marker of intracranial vascular resistance (pulsatility index, pi) in post-stroke patients with and without ckd. within three months of a stroke. anterior and posterior circulation pi (aca, mca, and pca) significantly correlated with mri lesion volume in all patients. ckd strongly correlated with higher distal resistance (median ckd aca pi . in patients with recent stroke, mri svd volume is significantly associated with anterior and posterior circulation pi. significantly higher svd lesion burdens and anterior circulation pis were observed in patients with ckd. ckd is an independent determinant of increased intracranial vascular resistance in both anterior and posterior cerebral circulations. atrial fibrillation is associated with an increased risk of stroke and systemic embolism. we investigated the prevalence of coexisting subdiaphragmatic visceral infarction (sdvi) in patients with acute ischemic stroke due to atrial fibrillation and also evaluated independent factors of acute sdvi. we enrolled a consecutive series of acute ischemic stroke subjects with atrial fibrillation between mra or cta were excluded. all subjects were prospectively examined using abdominal mr imaging at . t and transthoracic echocardiography (tte) within days of onset. a multivariable logistic regression analysis with predefined variable (age and sex) and the potential confounders that were associated with sdvi i the mean age was . ± . years ( % males). onset-to-abdominal image time was . ± . days. among patients, acute coexisting sdvi ( renal and splenic infarctions and superior mesenteric artery occlusion) were found in patients with acute ischemic stroke and atrial fibrillation. twelve patients had a chronic sdvi; renal and splenic infarctions. no hepatic and bladder infarction was shown. severe significantly associated with the coexistence of acute sdvi and acute ischemic stroke attributed to atrial fibrillation in the logistic regression model. (adjusted or, . ; % ci, . - . ; p = . ). there was a significant relationship between the presence of acute sdvi and severe left atrial remodeling in acute ischemic stroke patients attributed to atrial fibrillation. based on these results, we suggest that abdominal mr imaging for evaluating coexisting acute sdvi should be considered in patients with acute ischemic stroke due to atrial fibrillation, especially with left atrial enlargement on tte. patients with large hemispheric infarction are likely to accumulate chloride due to commonly used hypertonic saline for lowering elevated intracranial pressure. however, the effect of chloride burden on clinical outcomes in these patients is not well studied. this study aims to investigate the impact of maximum serum chloride concentration during admission on in-hospital mortality in critically ill patients with large hemispheric infarction. we conducted a retrospective observational study of patients with large hemispheric infarction who were admitted to the neurocritical care unit, between march and june . patients were excluded if they had baseline creatinine clearance less than ml/min, required neurocritical care for less than hours. multivariable logistic regression models were used to evaluate the association of maximum serum chloride concentration during admission with in-hospital mortality. of eligible patients, ( . %) were died in hospital. compared to patients who survive to hospital discharge, those who died in hospital had higher maximum serum chloride level during admission ( . ± . vs . ± . , p< . ). each mmol/l increase in maximum serum chloride concentration was associated with increased risk of in-hospital mortality with an odds ratio of . ( % ci, . - . , p< . ). after adjusting for confounders including acute physiology, age, chronic health evaluation ii (apache ii) score, baseline serum glucose, base deficit, use of mannitol, hypertonic saline, therapeutic hypothermia, and incidence of acute kidney injury, maximum serum chloride level remained an independent risk factor associated with in-hospital mortality (adjusted odds ratio for every mmol/l increment, . ; % ci, . - . , p= . ). higher maximum serum chloride concentration was associated with higher in-hospital mortality in critically ill patients with large hemispheric infarction. these results suggest serum chloride level should be monitored as high chloride burden may cause poor outcomes on those populations. patients with acute ischemic stroke caused by large vessel occlusion may receive both ct-angiogram (cta) and digital subtraction angiogram in the process of evaluation and management of restoring perfusion. neither aha/asa stroke/imaging guidelines address indications for transcranial doppler (tcd) and/or carotid duplex ultrasonography (cus) in early stroke evaluation and most patients do not receive additional cerebrovascular imaging after reperfusion. we investigated the clinical utility of performing tcd/cus after reperfusion in guiding post-acute care stroke management. we reviewed inpatient ischemic strokes admitted to a comprehensive stroke center in . of these had tcd/cus done and had cta done prior to tcd. of these underwent either tissue plasminogen activator or thrombectomy for reperfusion. these cases were reviewed by two experts (kh, qv), who were blinded to each other, to determine if tcd/cus provided any added value after cta affecting patient management. a nominal group process was performed, using a third blinded expert (as) in case of disagreements to reach consensus. the reviewers reported cases where tcd/cus provided incremental value for management. value added by tcd/cus, as noted by experts, included detection of residual/recurrent mobile thrombus requiring anticoagulation, confirmation of reperfusion in a symptomatic patient, distinguishing between carotid stenosis and occlusion by showing string sign on carotid ultrasound, confirming hemodynamic significance of angiographic stenosis helping triage the need for stenting/endarterectomy, and new information on chronicity of carotid stenosis based on collateral flow patterns hence deferring further intervention. our experience shows a significant added value of performing tcd/cus in more than % of stroke cases in our review. the incremental information provided by ultrasound-guided further evaluation and management decisions in most of these patients. axons of the wallerian degeneration slow (wlds) mutant mice survive weeks after traumatic and ischemic nerve injuries. prior characterization of the mutant wlds protein showed that it is a fusion gene product between the non-functional, truncated n amino acids of ube b and full functional sequence of nuclear nmnat , a rate-limiting enzyme in nad+ synthesis. however, the molecular mechanisms by which the mutant wlds protein protects axons from stroke injuries remain unclear. we sought to understand how wlds is able to robustly protect axons from ischemic injuries, and in doing so possibly identify novel therapeutic targets to attenuate axonal loss in stroke. we first sought to understand the temporal and spatial requirements of wlds activity in protecting axons from ischemic injuries. to achieve this, we developed a novel tool to conditionally regulate the expression of wlds protein by modulating its post-translational protein stability. using this powerful technique, we asked how conditionally "turning on" or "turning off" wlds activity affects axonal survival following ischemic insults. moreover, as the only known function of wlds is in catalyzing nad+ synthesis, we designed a high-throughput pharmacological screen for nad+ analogs to evaluate whether the nad+ synthetic pathway mediates wlds axon protection. we found that conditional expression of wlds protein within - hrs after stroke injuries was necessary and sufficient to confer axonal survival, whereas turning off wlds activity post-injury abolished axon protection. this indicates that wlds activity is a local event in the axon, and exerts axonal protection within a critical time window even after the injury has occured. we further observed that exogenous addition of nad+, but not its precursors or immediate metabolites, was sufficient to confer axonal protection, while attenuating nad+ levels abolished wlds axon protection. this suggests that nad+ is a molecular mediator of wlds axon protection in stroke. we showed that wlds activity is a local axonal event, and uncovered a critical window of - hrs poststroke injury in which the course of axon degeneration can be halted or even reversed in mammalian neurons. moreover, we showed that this process is mediated by rising nad+ levels in axonal compartments through a novel nad+ dependent cell signaling cascade. these findings provide powerful insight into the molecular bases of wlds activity, and uncover new therapeutic targets to delay and potentially even reverse axon degeneration in stroke. unruptured intracranial aneurysm (uia) are incidentally found on the computed tomography (ct) or magnetic resonance angiography in about % of patients. because of the risk of intracranial hemorrhage (ich), the presence of uia is contraindication to intravenous thrombolysis for acute stroke. as noncontrast ct (ncct) is mostly used for thrombolytic therapy and uia is difficult to diagnose using a ncct, uia may be found after thrombolysis. among the patients with acute ischemic stroke treated with intravenous thrombolysis for consecutive years in one stroke center, patients diagnosed with uia by ct angiography immediately after thrombolysis, were enrolled. characteristics of uia and clinical outcomes such as ich and modified rankin scale (mrs) score at discharge were analyzed. among patients treated with intravenous thrombolysis, ( . %) patients were diagnosed with uia. ally relevant artery and patients an aneurysm less than mm in diameter. the median value of the initial national institutes of health stroke scale score was (range - ). the median mrs score at discharge was (range - ). there was no patient who had ich or aneurysm rupture during admission. intravenous thrombolysis could be safe and necessary to the patients with hyperacute ischemic stroke and incidental uia. recent studies suggest that variations in the constitution of the gut microbiome contribute to atherosclerotic burden and cardiovascular disease. while many gastrointestinal (gi) diseases are known to cause disruption of the normal gut microbiome in humans, the clinical impact of gi diseases on subsequent vascular disease remains unknown. we conducted an exploratory analysis evaluating the relationship between gi disease and ischemic stroke or acute myocardial infarction (mi). we performed a retrospective cohort study using claims between - from a nationally composite of ischemic stroke or acute mi. stroke and mi were assessed separately as secondary outcomes. in an exploratory manner, we evaluated the association of each gi disorder in the icd- -cm classification with our outcomes. we then categorized individual gi disorders by anatomic location, disease chronicity, and disease mechanism. we used cox proportional hazards models to examine associations with adjustment for demographics and established vascular risk factors. since this was an exploratory, hypothesis-generating study, we report only notable positive associations. among approximately , , beneficiaries, the following gi disorders were associated with an increased risk of subsequent ischemic stroke: gastric ulcer (hr, . , % ci, . - . ), duodenal ulcer ( . , . - . ), gastritis and duodenitis ( . ; . - . ), disorders of function of stomach ( . , . - . ), other disorders of stomach and duodenum ( . ; . - . ), gastrointestinal mucositis ( . ; . - . ), unspecified noninfectious gastroenteritis and colitis ( . ; . - . ) and gastrointestinal hemorrhage ( . ; . - . ). the following categories of gi disorders were associated with an increased risk of ischemic stroke: stomach disorders ( . ; . - . ), stomach and small intestine disorders ( . ; . - . ), ulcerative disorders ( . ; . - . ) and chronic gi disorders ( . ; . - . ). gi disorders were not associated with an increased risk of mi, and some demonstrated a reduced risk. several gi disorders were associated with an increased risk of ischemic stroke, but none were associated with an increased risk of mi to evaluate the relationship between serum neutrophil-to-lymphocyte ratio (nlr) levels and early neurological deterioration (end) in ischemic stroke patients with large-artery atherosclerosis (laa). we evaluated consecutive ischemic stroke patients due to laa between january and december within the first hours of admission. the nlr was calculated by dividing the absolute neutrophil counts by the absolute lymphocyte counts. among the included patients (n = ; male, . %; mean age, years), . % (n = ) had end events. in multivariate analysis, serum nlr level was independently associated with end (adjusted odds ratio, . ; % confidence interval [ . to . ], p = . ). visit time from symptoms onset, and insitu thrombosis and artery-to-artery embolization mechanisms were also found to be significant factors for end events. in the analyses regarding the relationship between serum nlr values and burden of vascular lesions, nlr levels were positively correlated with both the degree of stenotic lesions (p for trend = . ) and numbers of vessel stenosis (p for trend = . ) in a dose-response manner. we also compared the difference of serum nlr levels according to the stroke mechanisms from underlying vascular lesions. then, hypoperfusion and in-situ thrombosis mechanisms showed higher levels of nlr. however, only in-situ thrombosis mechanism had higher nlr values among the end groups compared to non-end groups (p = . ). serum nlr levels were associated with end events in ischemic stroke patients with laa mechanism. since nlr was also closely correlated with the relevant vascular lesions, our results indicated clues for underlying mechanisms of end events. transcranial doppler (tcd) can detect emboli in numerous cerebrovascular settings. although previous studies have suggested that microembolic signals (mes) may predict recurrent stroke, the practical significance of such findings remains unclear. this uncertainty has deterred the widespread use of embolic monitoring among clinicians. in a retrospective fashion, we investigated the real-world applicability of tcd by examining whether the presence of mes portends worsened clinical outcomes. we reviewed the charts of all ischemic stroke patients (n = ) who underwent mes monitoring from january to december . of the stroke subtypes reviewed, % were atheroembolic, % were cardioembolic, % were lacunar, % were dissection, % were hypercoagulable, % were cryptogenic, and % were due to other causes. +/- mes were detected in % of patients. mes were detected at an average of . +/- . db (with a detection threshold > . db). recurrent stroke was seen in % of patients (monitored over . +/- . days). patients with mes were more likely to have recurrent stroke ( % vs. %, p < . ), undergo a revascularization procedure ( % vs. %, p = . ), have a longer length of stay ( vs. days, p = . ), and have a discharge mrs - ( % vs. %, p < . ) compared to those without mes. multivariable logistic regression analysis showed that mes was an independent predictor of recurrent stroke (or . , % ci . - . ) and of poor discharge mrs - (or . , % ci . - . ) despite controlling for antithrombotic treatments and stroke subtypes. in the largest series of patients who underwent embolic monitoring with tcd, mes predicted ischemic stroke recurrence leading to worsened disability and prolonged hospital stays. given that mes can provide important prognostic information, tcd with embolic monitoring may be clinically useful in the workup of ischemic stroke. expanded patient eligibility for mechanical thrombectomy (mer) of acute ischemic stroke (ais) has resulted in a proportional increase of patients who require emergency angioplasty and/or stenting (eas) to achieve recanalization. post-stenting antiplatelet medication management continues to remain a challenge due to lack of immediate effect and rapid reversibility ideal for patients at high risk of stent thrombosis and hemorrhagic complications, especially after intravenous alteplase (tpa). cangrelor is an immediate-acting intravenous p y receptor inhibitor with rapid clearance and restoration of normal platelet within one hour of infusion termination. we describe our preliminary experience with administration of cangrelor in ais patients undergoing mer and requiring eas as rescue therapy. ten patients with ais who received cangrelor after mer were identified. median admission national tpa prior to mer. cangrelor drip was started immediately prior to eas. median duration of cangrelor drip was hours. dual antiplatelet was given a median time of hours before discontinuation of cangrelor. seven patients had repeat imaging at months confirming durable vessel patency and no restenosis. none of the patients experienced clinical deterioration, symptomatic intracranial hemorrhage, or recurrent strokes during the hospital stay. one patient underwent surgical decompression but did not develop any hemorrhagic complications. median mrs at discharge was , and median nihss at discharge was . in our case series, cangrelor was observed to be a safe alternative to oral antiplatelet drugs in the immediate perioperative period among ais patients who underwent mer and required eas, , including patients who received tpa and at high risk for malignant cerebral edema or hemorrhagic transformation who may require emergency surgical decompression. the response of the neonatal brain to hypoxic ischemic injury (hi) is developmentally specific therefore therapies for brain hi cannot be standardized across the ages. while arginases (arg; isoforms arg- /arg- ) are enzymes actively studied for their neuroprotective/neuroregenerative effects in various neurological conditions, in neonatal hi the arg effect remains unknown. to test the hypothesis that arg changes with neurodevelopment and after hi we exposed mice c bl/ (wild-type) to hypoxia-ischemia on postnatal day , as follows: permanent coagulation of left common carotid artery to induce ischemia, a h recovery period and exposure to % oxygen/balance nitrogen at °c for min to induce hypoxia. animals were perfused at h, h, h, h and day with % paraformaldehyde, brains were post-fixed, sectioned on a cryostat ( um) and examined histologically with cresyl violet stain to assess the degree of damage and arg spatiotemporal localization via immunohistochemistry. arg expression was measured by western blot and arg activity spectrophotometrically. arg expression and activity increase during development, however this increase is suppressed by hi. arg- expression increases on day after hi which corresponds to our findings of arg- accumulation at the penumbra site. cortical arg activity remains suppressed after hi, compared to that in the hippocampus, where it increases. spatiotemporally, arg- localizes into myeloid cells in cns. arg- expression increases in microglia as early as h after injury and remains elevated for a prolonged time. arg- is localized in pyramidal neurons of the indusium griseum, fasciola cinerea, neocortex and hippocampus (ca , ca ). arg- -expressing cells are damaged by hi, however they do not undergo spatial changes. microglial arg- strongly responds to hi and may play role in neuroinflammation and neuroprotection, while argand therapeutic potential of the arg-pathway in neonatal hi. sisco: helping stroke patients with thermasuit cooling trial is a phase study in ischemic stroke with rapid induction of hypothermia to within one hour. this patient had induction followed by early malignant edema requiring decompressive hemicraniectomy while c. this is the first report of hemicraniectomy in a therapeutically hypothermic patient. results y/o woman presenting with a left mca syndrome. initial imaging demonstrated left m occlusion. she received iv tissue plasminogen activator (tpa) followed by thrombectomy with tici recanalization within practice guidelines. she was enrolled in sisco trial. she was sedated with propofol, fentanyl, and versed for induction, reaching target temperature of degrees within minutes. she remained on sedation for shivering and temperature was maintained at degrees with the artic sun. imaging hours after stroke demonstrated completed infarct with edema, midline shift, and lateral ventricle effacement. hypertonic saline was initiated, and she underwent emergent decompressive hemicraniectomy. balancing the risk of worsening edema and coagulopathy caused by mild hypothermia, rewarming was initiated at . degrees c per hour. at the time of procedure patient was at . . a successful hemicraniectomy was performed without complications. six months demonstrated improvement with the patient returning home with modified rankin , and cranioplasty performed without complications. during sisco, an emergency decompressive hemicraniectomy for malignant mca syndrome was performed for a cooled patient without complication or increased bleeding. while therapeutic hypothermia has not shown an outcome benefit in previous clinical trials, these trials have had limitations rapidly reaching targeted temperature. this may have blunted the therapeutic effect. using thermasuit, patients are able to reach target temperature significantly faster. additional clinical trials are needed to determine if the therapeutic window for targeted temperature management in ischemic stroke patients improves outcome. iv rt-pa guidelines exclude therapeutically anticoagulated or thrombocytopenic patients. these exclusion criteria may limit thrombolytic therapy to patients who might benefit. the objective of this study is to determine if iv rt-pa is safe and whether it increases neurocritical care resource utilization in this patient population. retrospective analysis of iv rt-pa treated patients receiving oral anticoagulation (warfarin (inr > . )), novel oral anticoagulant (noac), therapeutic heparin, low-molecular weight heparin (lmwh), or with thrombocytopenia (platelets < k). patients were treated using smart criteria (consent obtained for off label rtafter treatment. increased neurocritical care resource utilization was defined as transfer from a primary to comprehensive stroke center solely for additional monitoring after off-label iv rt-pa use. patients were identified. patients received therapeutic warfarin and one had coagulopathy (unclear etiology); mean inr= . (range . - ). received therapeutic iv heparin, full dose ( mg/kg bid) lmwh, and therapeutic noacs. had thrombocytopenia (mean platelet count k). received intra-arterial (ia) rt-pa, and thrombectomy. there were sich ( . %); for all sichs there were mitigating factors that contributed (undiagnosed malignancy, adjunctive ia rt-pa, incorrect time of onset). two developed hematoma at the catheter site with no clinical effect. patient was transferred for the sole purpose of monitoring post off-label iv rt-pa. these data suggest that iv rt-pa can be safely administered in therapeutically anticoagulated and thrombocytopenic patients, and sich rates were similar to the ninds cohort. the use of iv rt-pa in these patients may increase eligibility for acute stroke therapy, particularly where ia therapy is unavailable. -pa in such patients does not appear to increase neurocritical care resource utilization though further study with a larger population is warranted. although proteinuria has been reported as a predictor of neurological deterioration, poor functional outcome and in-hospital mortality after ischemic stroke, scarce study investigated the relationship between proteinuria and the malignant middle cerebral artery infarction (mmcai). this study aimed to determine whether proteinuria is associated with the development of mmcai. patients with infarction in middle cerebral artery territory were reviewed. on admission, all patients underwent brain computed tomography (ct), the assessment of national institutes of health stroke scale (nihss) and alberta stroke program early ct score (aspects), and laboratory surveys, including urine analysis by using urine dipstick. patients with known intracranial lesions or possible urinary tract infection were excluded. patients with proteinuria were defined if urine dipstick demonstrates reading of + to +, while others were defined as patients without proteinuria. chronic kidney disease (ckd) was defined if either proteinuria or estimated glome identified. mmcai was determined if a progressive conscious disturbance or signs of uncal herniation were recorded with a midline shift > mm on a follow-up brain ct. we screened patients, and -five ( . %) patients developed mmcai, and ( . %) patients had proteinuria. patients with mmcai had a significant higher score of nihss, lower aspects, less likely being dyslipidemia, and more likely having ckd and proteinuria than patients without mmcai did. after adjustment for age, sex, dyslipidemia and aspects, patients with proteinuria (or= . , %ci= . - . , p= . ) and ckd (or = . , %ci = . - . , p= . ) had a signifi ml/min/ . m did not. in conclusion, proteinuria is associated with the development of mmcai. we suggest that proteinuria may be considered as a clinical predictor for the development of mmcai. although tpa has been shown to improve outcome in ischemic stroke across various etiologies, tpa is contraindicated in stroke secondary to septic emboli due to a significantly higher risk of bleeding. the goal of this study is to determine the safety and short-term outcomes of acute ischemic stroke patients who underwent mechanical thrombectomy due to septic emboli from infective endocarditis (ie). in this multi-center retrospective case series, we reached out to thrombectomy centers known to our principal investigator. we have so far collected data from hospitals across the us to look at outcomes after thrombectomy in patients who had an ischemic stroke from infective endocarditis. centers reviewed their database and did not have eligible cases. to date, we have collected a total of cases ( % male; average age ; % had a known history of ivdu). in % the valve implicated was bioprosthetic. % of the occlusions were m , with the remaining being the carotid terminus ( %) and m ( %). microbiology revealed that % were caused by streptococcus, % staphylococcus, % enterococcus, and % were polymicrobial. the average nihss on presentation was . . % had received tpa prior to the thrombectomy (of those, / were known to have ie). the average best nihss after thrombectomy was . (averaged across cases, the other case expired from new cardiomyopathy and multi-organ failure). % had hemorrhagic transformation (of those, / were tpa recipients). thrombectomy may be a safer and promising option in patients with ischemic stroke secondary to infective endocarditis. more data is required to compare the outcome of patients who received thrombectomy alone versus tpa followed by thrombectomy, and data collection is ongoing. therapeutic hypothermia may be an effective therapeutic measure for malignant cerebral infarction alternative to or in combination with decompressive craniectomy. the neuroimaging marker that suggests the favorable clinical course during therapeutic hypothermia is needed to predict the outcome and/or determine best and earliest timing to rewarm the patients. we included cases who received therapeutic hypothermia for malignant middle cerebral infarction in seoul national university bundang hospital between july and may . we measured hounsfield unit of ischemic core in serial computed tomography scans in each patient. the nadir of hounsfield unit of each patient was calculated. the difference of the nadir by the early clinical outcome (the survival at discharge) was analyzed. the mean age was . ± . and the male comprised . % (n= ). three patients underwent early decompressive craniectomy plus therapeutic hypothermia and patients received only therapeutic hypothermia. the mean target temperature was . ± . . a total of patients ( . %) survived at discharge. a total of computed tomography scans were analyzed (about scans per patient). the mean of the nadir hounsfield unit of each patient was . ± . in the deceased patients and . ± . in the survived patients, and the difference was statistically significant (p-value = . ) the nadir of hounsfield unit in the ischemic core was lower in the survived group than the deceased group in malignant ischemic stroke patients who received therapeutic hypothermia. the change in hounsfield unit in serial computed tomography scan may be used to estimate clinical course and optimal timing of rewarming or rescue craniectomy after therapeutic hypothermia. the volumetric analysis using semi-automated planimetry is currently being performed to elucidate this association further. mhz pulsed-wave transcranial doppler (tcd) increases the exposure of an intracranial thrombus to tenecteplase (tnk-tpa) and facilitates early reperfusion. the aim of the present study is to ascertain if tcd along with tnk-tpa could improve functional outcome in patients treated with tnk-tpa after acute ischemic stroke (ais). this is a single center, prospective, interventional study. patients with ais with national institutes of -tpa bolus) within hours of symptom onset, were randomly allocated ( : ) to either mhz pulsed-wave ultrasound for min. (sonothrombolysis)-intervention group or only tnk-tpa group. ultrasound was delivered using a mark head frame, immediately after the bolus of tnk-tpa. the primary outcome was improvement in the modified rankin scale score at days and . the secondary end points were the occurrence of symptomatic intracerebral haemorrhages and death. between january and march , patients were randomly allocated to the sonothrombolysis group and patients received only tnk-tpa. at the end of days, the sonothrombolysis group achieved mrs - in / ( . %) compared to / ( . %) in the tnk-tpa group. the p-value is . . the result is significant at p < . . the rate of sich and mortality were . % in each group. sonothrombolysis of patients treated with tnk-tpa for ais was feasible and safe, with some clinical benefits at days. the recanalization rates and outcome are better than studies done with alteplase. there was no increase in sich or mortality. tnk-tpa should be the preferred drug for thrombolysis in ais. the study should be carried out in multiple centers to see if the results of the present study can be validated. acute ischemic stroke is the second leading cause of death, especially if the patient did not receive the appropriate treatment geared towards a timely recanalization of the occluded vessels, including intravenous tissue plasminogen activator (iv t-pa) or endovascular thrombectomy. little emphasis is given to the augmentation of collateral flow to offset the deleterious effect of ischemia or lessen the progression of the penumbral tissue into infarction. we present our initial experience with such vasoaugmentation strategy in patients with acute ischemic strokes. we present o university. our series included patients with acute ischemic strokes. we excluded patients with a large vessel occlusion. all other patients were included regardless of whether they received iv-tpa or not. all patients had a ct angiogram including collateral imaging and ct perfusion study at baseline. after explaining to the patients or their next-of-kin, we started the patients on a standardized protocol of milrinone ( mcg/kg bolus followed by . mcg/kg/minute). outcome assessment was comparing the initial mrs and that of the mrs at discharge. chi square contingency analysis was used with a set level of significance of p < . . out of the patients, had good collaterals and had poor collaterals. one of those poor collaterals patient had good cross flow from pcom to the affected hemisphere, but still demonstrated poor collateral score. in our cohort, ( %) achieved good neurological outcome of mrs of or below with patients ( %) achieving a discharge mrs of . conclusions collaterals and small infarction core. the presence of cross flow wasn't helpful. the symptomatology of delayed cerebral ischemia (dci) after aneurysmal subarachnoid hemorrhage (asah) is variable and often challenging to detect, particularly in patients with poor-grade asah. we report severe symmetric quadriparesis as a previously unreported symptom of dci. a -yearwas significant for intact brainstem reflexes and withdrawal in extremities. initial treatments included aminocaproic acid and external ventricular drain insertion, followed by intra-aortic balloon pump placement for stress-induced cardiomyopathy. she subsequently underwent coiling of a ruptured left anterior choroidal artery aneurysm. on post-bleed day , she was noted to have new onset of decreased tone and minimal complex posturing to noxious stimulation in all extremities and severe inattention. transcranial doppler and digital subtraction angiography revealed moderate left greater than right middle cerebral artery and bilateral anterior cerebral artery vasospasm and she received balloon angioplasty and intra-arterial nicardipine twice. post intervention, her quadriparesis moderately improved but she continued to have decreased tone and delayed movement initiation. on post-bleed day , brain mri demonstrated infarcts in bilateral medial frontal lobes, bilateral basal ganglia & subinsular cortices. on day of discharge, she was able to spontaneously raise her left arm and legs, but only minimally moved her right arm to noxious stimulation. this case report adds severe symmetric quadriparesis to the myriad of possible clinical symptoms of dci after asah. awareness of this uncommon clinical presentation could lead to timely detection and management of delayed cerebral ischemia after asah and improved clinical outcomes. brain mri to determine infarct size is common in acute stroke management. many patients cannot undergo mri imaging due to instability, or imaging contraindications. a common ct head finding postthrombectomy is contrast extravasation, thought to be secondary to "leakage" of the blood brain barrier due to ischemia. we hypothesized that extravasation volume on post-thrombectomy ct scan correlates with final infarct size. using ct head as a proxy for final infarct size may help guide clinical decision making when mri scan is not possible. we retrospectively examined a prospectively collected, irb approved stroke code database from / / to / / . inclusion criteria included: anterior strokes that underwent thrombectomy, ct scan within hours of thrombectomy with contrast extravasation, a mri within days of the thrombectomy. demographics, diagnosis, imaging findings were extracted via chart review. we used the alberta stroke program early ct score (aspect) score, to approximate the area of contrast extravasation (ct) and area of dwi hyper intensity (mri). each region of extravasation on ct head was deducted from a score of , resulting in the "estimated infarct size (eis)". each region of mri dwi was was calculated. we demonstrated usefulness of aspect scoring for comparing infarct volume between ct extravasation and final dwi infarct size. post-thrombectomy contrast extravasation consistently underestimated final mri infarct volume by %. this relationship, if validated, may be useful to approximate mri stroke volume. dizziness is a vaguely-defined complaint involving the subjective experience of lightheadedness, disequilibrium, and room-spinning sensation. it is a frequently encountered problem in office visits and in the acute care setting, with approximately . million presentations to the emergency department annually. the differential diagnosis is broad, ranging from benign and of peripheral origin, to timesensitive and potentially fatal of central origin, including ischemic or hemorrhagic stroke and ms. it is estimated - % of patients with dizziness receive stroke diagnoses . despite the low percentage, diagnosis of posterior stroke is the one most feared to be missed by clinicians. we hope to establish a clinical scoring system for timely triage of presentation with dizziness. we retrospectively reviewed charts of patients admitted at hahnemann university hospital between and , following irb approved protocol. charts were chosen with primary inpatient admitting diagnosis: cerebral infarction due to thrombosis of basilar artery, dizziness and giddiness, and cerebral infarction due to embolism of post cerebral artery for a total of charts. patient charts were reviewed to identify predisposing factors, data points for each patient. of patients reviewed, were found to have infarctions involving the posterior circulation, . % diagnostic yield for stroke. we collected a total of data points to understand the disease process. predisposing factors identified were chronic kidney disease, diabetes, hypertension, and hyperlipidemia. surprisingly, previous stroke was not found to predispose to posterior fossa strokes. common exam findings on presentation were hemiparesis and hemisensory loss. statistical analysis is currently in process we discuss our results in the context of previous efforts aimed at developing clinical predictors for posterior fossa stroke in patients presenting with dizziness. high hir (hypoperfusion intensity ratio) is known to correlate with core size, infarct growth and worse clinical outcomes. traditionally larger infarcts have been associated with higher rates of malignant cerebral edema and need for decompressive hemicraniectomy. patients with high hir and malignant profile (tmax > s greater than % of penumbra) are associated with increased risk of malignant cerebral edema. as part of an ongoing study, we retrospectively identified all ais patients with lvo who underwent ctp imaging between january to june in our healthcare system within hours from symptom imaging studies (ct or mri) were analyzed. hir was dichotomized based on proportion of greater and less than . into malignant vs favorable profile and correlation for development of malignant cerebral edema and need for hemicraniectomy was analyzed using chi-square test of proportion for nominal variables and wilcoxon ranked sum tests for the (skewed) continuous and ordinal variables. a total of patients with lvo were identified with a median age of (iqr - ), nihss of . patients with high hir suggestive of a malignant profile (n= ), regardless of reperfusion, were associated with increased risk of malignant cerebral edema compared to those with a favorable profile (n= ) (p< . ). patients with malignant hir developed malignant cerebral edema compared to patients with favorable hir (rr= . , or= . ). patient with malignant hir underwent decompressive hemicraniectomy compared to none with favorable hir. higher hir and malignant profile, regardless of reperfusion, is associated with times increased relative risk of development of malignant cerebral edema. these patients benefit from close monitoring and aggressive care for malignant cerebral edema including osmolar therapy and potential surgical intervention. we present the case of a patient with basilar artery dissection with thrombus, who underwent successful mechanical thrombectomy with stenting and was ambulatory at discharge. patient is an -year-old female with past medical history of ehler's danlos disease who presented with left sided weakness after being found down by her family. nihss on arrival was (left sided weakness / ), bp / , glucose . her cta showed a basilar angiography was notable for a basilar dissection with reocclusion, which was treated with enterprise stent placement with tici reperfusion. mri post intervention revealed right pontine infarct, punctate infarcts in cerebellum. her exam at discharge was notable for improvement in her left sided strength, at / . she was subsequently discharged to inpatient rehabilitation. mechanical thrombectomy and stenting of the basilar artery remains a largely experimental procedure, with few guidelines and little data on outcomes. we present a case of a patient with a basilar dissection who at discharge was ambulatory and near baseline. blood viscosity (bv) is the intrinsic resistance of blood to flow and characterizes blood stickiness. several clinical and epidemiologic studies demonstrated an association between bv and the occurrence of major thromboembolic events. though bv appears significantly higher in cases of lacunar or cardioembolic strokes, relationships with demographic and laboratory findings during the acute stage of ischemic stroke are unknown. we investigated the relationship between baseline characteristics and bv within hours of symptom onset in patients with acute ischemic stroke. we enrolled patients aged years or older with documented histories of ischemic stroke or transient ischemic attack within hours of symptom onset. a scanning capillary-tube viscometer (sctv) (hemovister, pharmode inc., seoul, korea) was used to assess the whole blood viscosity (wbv). the mean age was . ± . years and . % were female. of patients, . % had a history of hypertension; %, diabetes; . %, hypercholesterolemia; . %, coronary artery disease; and %, stroke. additionally, . % were current smokers. sixty-one ( . %) patients were taking antithrombotics regularly. multiple linear regression analysis revealed that hematocrit was positively related with increased bv and prior antithrombotic use was related with decreased bv. hematocritadjusted partial correlation demonstrated that prior antithrombotic use was significantly associated with decreased bv. prior antithrombotic use is significantly associated with decreased blood viscosity within hours of symptom onset in patients with acute ischemic stroke. our findings indicate that antithrombotic medications prevent stroke by inhibiting platelet function and by changing the hemorheological profile. ischemic stroke accounts for % of stroke and is the second cause of death in brazil. the decision regarding thrombolytic treatment depends on clinical history, physical examination, and imaging. one challenge is the exclusion of situations called stroke mimics (sm). a total of patients admitted to the stroke unit were prospectively analyzed. they received a full clinical and laboratory evaluation for the diagnosis of stroke and aiming to rule out the sm possibility. the study looked up for stroke etiology, demographical and epidemiological data, stroke-specific scales, sis, the occurrence of seizures and blood pressure lower than mmhg at admission as variables of interest. the prevalence of sm and the use of thrombolytic therapy in this situation was concordant with medical literature. the risk associated with anticoagulation in acute ischemic stroke (ais) is uncertain. anticoagulation is generally not indicated for early secondary stroke prevention, but may be considered in certain conditions. we assessed the use of a weight-based institution-specific heparin nomogram in ais patients. -new haven hospital who received anticoagulation with a continuous heparin infusion in the setting of ais over a -month period. anticoagulation was initiated with an initial infusion rate of units/kg/hr without bolus, with subsequent increases in the infusion rate by unit/kg/hr, based on aptts obtained every six hours until two subsequent aptts were within goal range. we collected indication for anticoagulation, dose at therapeutic aptt, time to target aptt duration of anticoagulation, transition to oral anticoagulant therapy, cerebrovascular/cardiovascular events and major and minor bleeding complications. patients were included in analysis, % of which were male, with a mean age of ± years and an average weight of . ± . kg. indications for ac were: intracardiac thrombus ( %), (sub)occlusive intra-arterial thrombus ( %), arterial dissection ( %), thromboembolic events and hypercoagulability ( %). the median time between diagnosis of stroke and initiation of anticoagulation was hrs mins. the time to goal aptt was ± . hours with a mean infusion rate of units/kg/hr at time of goal aptt. % of patients were transitioned to an oral anticoagulant and % of patients experienced a cerebrovascular event while on heparin infusion. our institution-specific heparin nomogram provides a safe anticoagulation strategy in ais, but with a longer time to reach therapeutic goal aptt range compared to previously published data. a more aggressive titration strategy with consideration of a higher infusion start rate may facilitate reaching the target aptt within a shorter time frame. vertebral artery dissection (vad) is one of the most common identifiable causes of ischemic stroke in young age patients forming intramural hematoma. vad may occur spontaneously or secondarily to trauma, infection, or underlying arteriopathy. we report cases of spontaneous bilateral vad presenting with lateral medullary infarction a -year-old woman transferred to the emergency room with vertigo. days ago, she felt severe headache on the left temporal area. on neurologic examination, ptosis, facial hypesthesia, dysmetria on the left side were noted, and dysarthria, dysphagia, right beating nystagmus were noted also. she had no past medical history and no familial history of stroke or cephalo-cervical trauma. brain mri depicted acute infarction in left lateral medulla and dissecting aneurysm of right va and near occlusion of left va on carotid enhanced mra. disease was normal. she was treated with warfarin. a -year-old man visited to the emergency room with headache on the right occiput. on neurologic examination, ptosis, miosis, facial hypesthesia, dysmetria on the left side and hemibody hypesthesia on the right side were noted. he had no trauma history or risk factors for stroke except hypertension. brain mri depicted acute infarction in right lateral medulla and dissecting aneurysm in the bilateral vertebral arteries on carotid enhanced mra. laboratory tests showed no abnormal findings. all results were normal for young age stroke evaluation. he was treated with warfarin. although unilateral or bilateral vad due to trauma or underlying medical conditions has been reported, spontaneous bilateral vad is rare. it can present with lateral medullary syndrome or nonspecific symptoms such as headache only. physicians should include vad in the differential diagnosis for patients presenting with brainstem neurologic abnormality or headache, especially young patients. cerebrovascular complications (cvcs) occur in - % of patients with infective endocarditis (ie) and manifest as ischemic stroke, meningitis or cerebritis with % occurring during first weeks of treatment. ct or mri brain can diagnose cvcs but are insensitive early on, precluded in critically ill patients and only demonstrate the sequelae. transcranial doppler (tcd) can identify high-intensity transient signals (hits) associated with cerebral microembolization and may have a role in detecting emboli and preventing cvcs in ie. retrospective chart review and literature review. we found patients with strokes caused by ie at our institution from / to / . tcds were obtained on patients, abnormal for cerebrovascular abnormalities. only patients had minute emboli monitoring performed of which one revealed hits. though mri studies have shown microemboli in % of ie patients (duval ann intern med ), we only found studies using hits on tcds as indicators of stroke risk in ie. in a prospective study of patients with left-sided ie, cvcs occurred in % of patients with hits on tcds versus % of patients who did not (p= . ) ( lepur scand j infect dis ). two studies investigated and patients with cardiac sources of embolism and documented occurrence of hits in % and % of subjects, respectively, with highest prevalence of hits in patients with ie (sliwka stroke , georgiadis stroke . detection of hits using tcd emboli monitoring has a potential to be an important tool for identifying cases of ie at highest risk for cvcs, especially in the early stages of antimicrobial therapy. this can aid further research into preventative interventions beyond antibiotics like earlier valvular surgery or vacuum assisted vegetation extraction. therapeutic hypothermia is considered as an effective therapy to reduce cerebral edema and intracranial pressure for malignant middle cerebral artery infarction, which can be used as a life-saving treatment alternative to or combined with decompressive craniectomy. however, malignant hemispheric infarction involving whole anterior, middle and posterior cerebral artery territory has been regarded as untreatable by any measures. a -year-old man who had had right ventriculoperitoneal shunt for hydrocephalus since several years ago presented with global aphasia and right hemiplegia in may . the brain magnetic resonance imaging showed large acute infarction involving whole left hemisphere including anterior, middle and posterior cerebral arterial territory by occlusion of distal internal carotid artery. as his family refused decompressive hemicraniectomy, therapeutic hypothermia using surface-cooling method (arctic sun® ) was initiated with a target temperature of . . the maximal midline shift on brain ct was approximately mm, five days after stroke onset, which led to foramen of monro obstruction and hydrocephalus in the lateral ventricle of the opposite side. since the hydrocephalus was controlled by draining of the cerebrospinal fluid into the ventriculoperitoneal shunt, the right hemisphere was saved and brain edema combined with midline shift gradually improved. the patient finally survived and was discharged. this case may be the first that therapeutic hypothermia successfully treated large hemispheric infarction involving cerebral arteries without decompressive craniectomy. since the mass effect in our case was much larger than that of malignant middle cerebral infarction, we extended the duration of therapeutic hypothermia ( . ) to days, which prevented herniation syndrome. another interesting point is that we could manage contralateral hydrocephalus caused by extensive midline shift, heralding a fatal clinical course in malignant ischemic stroke, using the preexisting ventriculoperitoneal shunt. current aha / asa stroke guidelines list arteriovenous malformation (avm) as a contraindication for intravenous alteplase (iv tpa) in ischemic stroke. while the associated risk of spontaneous intracerebral hemorrhage varies across the differing types of intracranial vasculature malformations, very little data or case reports exist regarding the risk of hemorrhage with intravenous thrombolytics for ischemic stroke in patients with vascular malformations. a -year-old male with history of cirrhosis and known atrial fibrillation (not on anticoagulation) presented with acute onset left facial droop and left hemiplegia, nihss . onset of symptoms were within the . hour window for iv tpa. a ct head demonstrated an aspects score of . iv tpa was thus initiated. cta of the head and neck revealed a right middle cerebral artery occlusion. additionally, there was a subtle tortuosity of blood vessels within the dural surface of the right temporal lobe, suggestive of possible avm. given the stroke severity, tpa was continued and successful recanalization was completed by thrombectomy of the right m occlusion by aspiration, with confirmation of a dural based avm. the patient did well, with no complications from tpa or thrombectomy and was discharged home with an nihss . the decision to administer iv tpa in patients with symptoms of acute ischemic stroke is determined by last known well time and a non-contrasted ct. vessel imaging should not delay administration of iv tpa as incidental findings may arise which may cloud the use of iv tpa in patients who otherwise may benefit from therapy. this case provides further insight that iv tpa in those with intracranial vascular malformations may be given safely with minimally increased risk. the prevalence of stroke mimics (sm) can reach % of presumable stroke, according to some authors. its presentation can predict the diagnosis of sm with a sensitivity and specificity of % and %, respectively. this study aimed to comparatively evaluate these data in a population hospitalized in a stroke unit. the study prospectively analyzed a total of patients admitted according to the suspicion of sm, the definitive diagnosis, etiology, demographic and epidemiological data, specific scales for stroke including features and its sensitivity and specificity in a specific population. a cross-sectional analysis comprised ( . % female) patients, median age . years ( - ). the median nihss was ( -- in . % of patients. twenty-four patients ( . %) presented with initial suspicion of sm, which was confirmed in ( . %). after univariate analysis on were statistically significant (p = . and p = . , respectively). the multivariate logistic regression showed that the absence of facial paralysis (or= . , p= . , % ci= . - . ), seizure convulsion on admission (or= . , p= . , % ci= . - . ) and blood pressure at admission lower than mmhg (or= . , p= . , % ci= . specificity of . % and . % respectively, with an area under the curve of . (se= . , % ci= . -conclusions sensitivity and specificity, probably secondary to selection bias. these data are inferior to the literature but better adapted to this study population. information collected from chart review and direct patient care. a year-presented with pre-syncope, abdominal pain, and malaise. he was febrile and tachycardic, and subsequently admitted for sepsis. shortly thereafter, he experienced transient diaphoresis, expressive aphasia and right-sided weakness. mri brain showed punctate ischemic cerebellar infarcts. there was high suspicion for embolic phenomena from sepsis or he acutely decompensated to complete non-responsiveness during the echocardiogram. ct brain showed diffuse air emboli in cerebral vasculature and subarachnoid air. he was placed in the left lateral decubitus position and managed with high concentration oxygen. additionally, his antimicrobials were broadened to include fungal coverage. thoracic ct revealed free air in the mediastinum between the candidate for surgical repair of his left atrium due to hemodynamic instability. instead, he underwent urgent endoscopic esophageal stent placement. he then developed a stemi, also thought to be due to air embolus, and went into cardiac arrest with return of spontaneous circulation achieved. the following day, he developed renal failure and coded again. autopsy, in addition to massive cerebral edema and cardiac ischemia, demonstrated strep oralis bacteremia, bilateral adrenal infarcts and acute tubular necrosis. is crucial for the ability to coordinate aggressive care. open surgical repair of the left atrium and esophagus offers the best chance of survival, but its use may be limited by severe sepsis and hemodynamic instability. the efficacy of mechanical thrombectomy (mt) for acute ischemic stroke (ais) due to large vessel occlusion (lvo) is well established in the anterior circulation (ac). ais from lvo in the posterior circulation (pc) differs from the ac in myriad ways, including presentation and resistance to hypoxia. we aim to characterize the differences in risk factors and outcomes of mt for ac vs pc stroke. demographic data was collected for cases of ais undergoing mt from january to january with follow-up imaging and documented functional status at discharge. operative reports were reviewed for procedural data including stroke onset to groin puncture time, number of passes of the stent retriever, and onset to recanalization time. radiology reports of postprocedural non-contrast ct images of the head were assessed. during the study period there were eligible patients ( ac and pc). atrial fibrillation ( . % and . %, p= . ) and hyperlipidemia ( . % and . %, p= . ) were more common in ac strokes while family history of stroke was more common in pc strokes ( . % and . %, p= . ). mortality erence in procedural factors or hemorrhagic complications. ac stroke but not pc stroke. our data shows that pc stroke has a higher mortality rate than ac stroke after mt with no difference in procedural factors or hemorrhagic complications. the higher mortality rate in patients with pc stroke is likely inherent to severe disability from basilar artery occlusion rather than recanalization therapy. the data also support worse functional outcome in ac strokes with increasing age and number of passes. calcinosis is a dysregulation of vascular calcium deposition characterized by small vessel calcification and secondary fibrosis. the effect of systemic calcinosis on mineralization within the central nervous system is underreported and poorly understood. a -year old man presented to icu for possible hemorrhagic transformation of a recent left mca stroke. his medical history was notable for atrial fibrillation, end-stage renal disease, calciphylaxis on warfarin, and parathyroidectomy. his post-stroke hospital course was notable for mildly elevated serum phosphorus. the patient started apixaban two weeks post-stroke as anticoagulation for atrial fibrillation, and underwent a routine ct head one day later. the scan showed extensive high-density signal along the cortex of the recently infarcted left mca territory, initially misinterpreted as hemorrhagic transformation. the signal measured at - hounsfield units, higher than expected for acute blood. a dual-energy calcium overlap map post-processing revealed the high-density material was consistent with acute mineralization, possibly potentiated by the patient's previous calciphylaxis. this case illustrates accelerated mineralization as a mimic of acute hemorrhagic transformation. dual-energy ct is useful for differentiating hemorrhagic transformation from mineralization, and may play a special role in patients with renal disease or history of calciphylaxis. this case illustrates accelerated mineralization as a mimic of acute hemorrhagic transformation of stroke in a patient with esrd and history of calciphylaxis. dual-energy ct can differentiate between intraparenchymal hemorrhage and calcification with high accuracy using material decomposition. this imaging technique may have an especial benefit in patients with renal disease or disordered mineralization. accelerated mineralization post-stroke may worsen cerebral vessel compliance and risk of future stroke, and merits further investigation. systemic inflammatory response syndrome (sirs) without infection is a surrogate of a systemic immune response and has been related with poor outcome in several vascular diseases. we investigated associations of sirs with long-term functional outcome and contributing factors after intracerebral hemorrhage (ich). we analyzed consecutive spontaneous ich-patients from our prospective cohort-study ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . sirs was defined according to standard criteria: i.e. two or more of the following parameters during hospitalization: body-temperature < °c or > °c, respiratory-rate > per minute, heart-rate > per consisted of the modified rankin-scale(mrs) at three and twelve months investigated by adjusted ordinal shift-analyses. bias and confounding were addressed by propensity score matching and multivariable regression models. of patients with ich . % (n= ) developed sirs during hospitalization. sirs-patients showed more severe ich compared to without; i.e. larger ich-volumes ( . cm³, iqr( . - . ) versus . cm³, iqr( . - . );p< . ), increased intraventricular hemorrhage ( . %,n= / versus . %,n= / ;p< . ), and poorer neurological admission status (nihss , iqr( - ) versus , iqr( - );p< . ). ich severity-adjusted analyses revealed an independent association of sirs with poorer functional outcome after three (or . , % ci( . - . );p= . ) and twelve months (or . , %ci( . - . );p= . ). increased ich-volumes on follow-up-imaging (or . , %ci( . - . );p= . ) and prior liver dysfunction (or . , %ci( . - . );p= . ) were associated with sirs. in ich patients we identified sirs to be predictive of poorer long-term functional outcome over the entire range of mrs-estimates. clinically relevant associations with sirs were documented for prior liver dysfunction and hematoma enlargement. acute major bleeding secondary to trauma is a significant complication of anticoagulated patients. in -threatening in the absence of a specific reversal agent. annexa- was a prospective, single-arm, open-label study evaluating the efficacy and safety of -primary efficacy endpoints were percent change from baseline in antiefficacy over the first hours after treatment, as determined by an independent adjudication committee. safety outcomes (including thrombotic events and death) were evaluated over days. among patients enrolled in the study, ( . %) had a bleed associated with trauma ( intracranial [ich] , non-ich). mean age was . years. eighty-three patients took apixaban, rivaroxaban, enoxaparin, and edoxaban. of the ich patients, ( . %) had bleeding in multiple compartments. the mean hematoma volume in the trauma patients with single-compartment intraparenchymal bleeding was . cc. among efficacy-evaluable ich patients, of ( . %) had excellent or good hemostatic efficacy. the percent reduction in anti-ich patients taking apixaban and rivaroxaban, respectively. the -day rates of thrombotic events and mortality were of ( . %) and of ( . %), respectively. conclusions high rate of excellent or good hemostatic efficacy, with a relatively low occurrence of thrombotic events. these results are comparable to what was observed for annexa- patients with spontaneous bleeding events, and suggest that andexanet alfa could be a safe and effective treatment in the traumatic population. -factor prothrombin complex concentrates -related ich. adult patients ( years or older) admitted to yale--related ich who evaluated at approximately hours after the baseline ct scan. secondary outcomes included mortality and modified rankin score (mrs) at hospital discharge. chi-square test and multivariable logistic regression analysis were used for unadjusted and adjusted analyses, respectively. twenty--related ich were included in the s patients received aa). majority of the patients were anticoagulated for atrial fibrillation (n= , %). group (unadju patients ( %) in aa group (unadjusted p= . ). there was no difference in mrs at discharge, patients - compared to patients ( %) in aa group (unadjusted p= . ). multivariable analyses adjusted for age, sex, race, and baseline mrs confirmed the absence of these associations (all p> . ). in our limited sample size, there was no significant difference in the degree of hemostasis achieved, allvalidate these results are warranted. symptomatic intracranial hemorrhage (sich) following mechanical thrombectomy (mt) for acute ischemic stroke (ais) due to large vessel occlusion (lvo) is a rare but devastating complication. however, it is difficult to differentiate sich from contrast extravasation on early post-procedural computed tomography (ct). we aim to evaluate the rate of sich and whether the presence of hyperdensities (hd) on post-procedural ct predicts functional outcome after mt. demographic data was collected for cases of ais undergoing mt from january to january with available follow-up imaging and documented functional status at discharge. operative reports were reviewed for procedural data and radiology reports of ct head performed immediately, and - hours post-mt were assessed. of the patients studied, ( . %, / ) had hd on immediate postoperative ct and ( . %, / ) were contrast extravasation (ce) due to resolution of hd on ct at patients developed new hd on follow-up ct, resulting in a total of patients ( . %) having ich and ( . %) having sich. in subgroup analysis, cardiac comorbidities were more common in ce patients than ich patients ( . % and . %, p= . ) with no mortality or outcome differences. diabetes mellitus (dm) was more common in sich patients than those with ce and asymptomatic ich ( . % and . %, p= . ). the mortality rate of sich patients was higher ( % vs . %) and the survivors had worse discharge nihss than pat difference in procedural factors or preference for circulation between any groups. our data show that presence of hd on immediate postoperative head ct does not predict mortality and is not related to circulation or procedural factors. sich is more common in patients with dm and associated with higher mortality rate and poor functional outcome. consecutive patients admitted to the health system with tsd -pcc between may and april were analyzed. baseline demographics and outcomes were abstracted through -up ct. tsdh volume was calculated using the abc/ method. descriptive statistics were used to analyze the -pcc and its association with outcomes. -pcc for tsdh were analyzed. the median age was [ to ], -pcc was . units/kg. patients with he had a median dose of . units/kg ( . to . ) versus . units/kg ( . to . ) for patients without he. he was seen in % of patients (rivaroxaban in , apixaban in ). among patients with he, % of patients died or went to a skilled nursing facility vs % in those without he. discharge to home or acute rehab was lower in those with he ( %) versus those without he ( %) doac use was associated with higher rates of hematoma expansion and worse outcomes in patients -pcc. treatments for the reversal of doac related tsdh should be investigated intracerebral hemorrhage (ich) is associated with peripheral immune dysfunction and infection. we aim to evaluate peripheral immune responses to ich and associations with infection and ich outcome. consecutive spontaneous ich patients admitted to a tertiary center ( / - / ) were included. patients with secondary ich and transition to comfort measures within hours were excluded. ich score, discharge modified rankin score (mrs), antibiotics use, acute clinical infections including pneumonia, bacteremia, and urinary tract infection were systematically adjudicated using modified pantheris criteria. peripheral immune dysfunction was characterized by lymphopenia and lower lymphocyte to neutrophil ratio (lnr). continuous variables were compared using student's t or wilcoxon test; univariate associations assessed using pearson's or spearman's correlation depending on distribution. ordinal logistic regression used to evaluate independent effect of lnr on discharge mrs. (jmp pro . ). cohort had mean age years, % female, median ich score [iqr - ] and median discharge mrs of . thirty-nine patients had suspected clinical infection treated with antibiotics, where only met modified pantheris criteria for infection. lower %lymphocyte (p< . ) and lnr (p< . ) on post-ich days - were associated with worse discharge mrs and higher ich scores (p's < . ). lower mean lnr on post-ich days higher mean lnr on post-ich days - (p< . ). lnr on post-ich day is independently associated with mrs (p= . ) after adjusting for ich score and sex. acute post-ich lymphopenia and reduced lnr are associated with ich score, infection and worse discharge outcome. lnr emerged as independent predictor of ich outcomes in preliminary analysis. determine how acute lymphopenia mediates ich infection risk and outcome. prolonged length of stay (los) in the intensive care unit (icu) is associated with significant medical complications and higher costs in patients with spontaneous intracerebral hemorrhage (ich). aim of this study is to assess predictors of prolonged icu los in ich. we conducted a retrospective analysis of ich patients admitted to our institution over a seven-year period. demographics, clinical data, and laboratory studies at presentation were recorded. initial ct scans were reviewed to determine location, hematoma volume, and presence of intraventricular extension. surgical interventions, insertion of an external ventricular drain (evd), and medical complications, including infections and deep vein thrombosis/pulmonary embolism (dvt/pe) were reviewed. los was calculated based on the number of midnights spent in the icu. patients spending less than -hours in the icu were excluded. ichs were analyzed. the mean age was . ± . years and . % were females. prolonged los, defined by using the point of change and cumulative sum methodology analysis after normalization of the sample, was found to be > days. intubation at presentation (p< . ), presence of ivh (p< . ), insertion of evd (p< . ), surgical evacuation (p< . ), chest infections (p< . . ) and dvt/pe (p< . ) were associated with prolonged los, while location of the hemorrhage, hematoma volume, and ich score at presentation were found not to be significant. this is a preliminary analysis to identify predictors of prolonged icu-los in intracranial hemorrhage. chest infections and dvt/pe were associated with prolonged los. surgical intervention, intubation at presentation, and insertion of evd were also independent predictors. these findings suggest that early evd weaning or shunt placement, and potentially early tracheostomy could help in decreasing the icu-los in patients with ich. diffusion weighted imaging (dwi) lesions are found in nearly % of patients with acute spontaneous intracerebral hemorrhage (sich). however, the timing of dwi lesions after sich ictus remains unknown. the purpose of this study is to estimate the timing of new dwi lesions after acute primary sich. by establishing a time frame, potential pathophysiologic mechanisms for dwi lesions can be elucidated. between september , and january , , patients were enrolled in a prospective study examining dwi lesions in acute primary sich. enrolled subjects received a research brain mri after admission blinded to the clinical teams. during the same admission, select patients received a separate brain mri as part of clinical care. subjects with scans were identified from the study cohort, and their imaging evaluated for dwi lesions. when compared to the first mri scan, the presence of a new dwi lesion on the second mri scan was defined as a new dwi event. a kaplan-meier analysis was performed to estimate the time to a new dwi event from the first mri scan. among enrolled subjects, ( . %) had two brain mris. mean age was . years, % were male, and . % were african american. the median ich score was (iqr ). median time from sich onset to first mri was . days (iqr . ). median time from first mri to a new dwi event was . days ( % ci, . to . ). median time between the first and second mri was . days (iqr . ). our data suggest that new dwi lesions occur days after sich ictus. therefore, acute interventions during the first hours after sich admission may not be associated with dwi is needed to elucidate potential mechanisms associated with dwi lesions in sich. intracranial hemorrhage (ich) is a common complication in children on ventricular assist device (vad) support, though bleed severity is highly variable. this study examined factors associated with ich requiring neurosurgical intervention in this at-risk population. children aged month- years old admitted between - with a diagnosis of intraparenchymal hemorrhage (iph) or subdural hemorrhage (sdh) while on vad support were identified retrospectively from an institutional database using icd- and icd- codes, after obtaining irb approval. patients requiring neurosurgical intervention (ns+) were compared with those who did not (ns-) using manniables). in total, children met inclusion criteria. of those, / ( . %) required neurosurgical intervention bleeds occurred in patients ( / ns+, / ns-). ns+ patients were older at bleed (mean . ± . years vs . ± . years, p = . ). all ns+ patients were taking warfarin, versus / ns-patients (p= . ); none of the ns+ patients had supratherapeutic inr. number of antiplatelet agents did not differ between groups ( . ± . ns-vs . ± . ns+, p = . ). patients received a median of ct scans (iqr - ) with no significant difference between surgical and nonsurgical groups (p = . ). among our cohort, older children and those on warfarin were more likely to require neurosurgical neurosurgical treatment, though results should be interpreted cautiously given small numbers. patients received multiple ct scans, though only a minority ultimately required neurosurgical intervention. unnecessary ct scans in this population. elevated intracranial pressure (icp), usually monitored by invasive icp-measurements, is associated with mortality in intracerebral hemorrhage (ich). the non-invasive evaluation of pupillary function using automated pupillometry is increasingly used in critical-care settings. the association of various pupillary parameters assessed by automated pupillometry with icp is unestablished, specifically the sensitivity and specificity during icp-elevation and the performance of sympathetic versus parasympathetic parameters. we enrolled ich patients admitted to our neurocritical-care unit who received invasive icpmeasurement by an external-ventricular-drain (evd). we monitored parameters of pupillary reactivity [i.e. light-reflex latency (lat; s), constriction and re-dilation velocities (cv, dv; mm/s), and percentage change of apertures (per-change; %)] using a portable pupilometer (neuroptics®) as well as corresponding icp values up to every minutes for the duration of hospital stay. receiver operating characteristic (roc) analysis was performed to investigate associations between changes in pupillary reactivity and elevated icp. sensitivity and specificity of sympathetic and parasympathetic pupillary parameters were analyzed to evaluate associations between pupillary reactivity and icp-elevation in patients ( women, mean age . ± . years), without icp-elevation and no midline shift upon neuroimaging, assessments were compared to assessments in patients ( women, . ± . years) during icp-levels > mmhg and corresponding midline shift. roc-analyses revealed a significant negative association of all assessed pupillary parameters with icp-elevation. best discriminative thresholds for icp-elevation were: cv< . mm/s, per-change< %, lat< . s, and dv< . mm/s. the highest sensitivity and specificity (i.e. . % and . %; p< . ) for an association with concomitant icp-levels > mmhg were found for a combination of the parasympathetic parameters cv< . mm/s and per-change< %. our data suggest an association between non-invasively detected changes in pupillary reactivity and elevated icp. parameters of parasympathetic pupillary modulation seem most reliable to indicate icpelevation. spontaneous ich (sich) remains a deadly complication from the use of direct oral anticoagulants -pcc for the reversal of doac -pcc in the prevention of hematoma expansion (he) in doac associated sich across a large health system. consecutive patients who were admit -pcc between may and april were analyzed. baseline demographics and outcomes were abstracted through retrospective chart review. he was defined as volume> % or > . ml between baseline and follow-up ct. sich volume was calculated using the abc/ method and ivh score. descriptive statistics were used -pcc and its association with outcomes. -pcc for sich. the median age was ( - ), % were caucasian and --pcc dose of . units/kg ( . - . ) compared to . units/kg ( . to . ) with he. he was seen in % of patients (rivaroxaban in , apixaban in ). among patients with he, % of patients died or went to a skilled nursing facility vs % in those without he. discharge to home or acute rehab was similar in both groups while rates of mortality and discharge disposition were similar between those with and without he, -pcc. treatments for the reversal of doac related sich should be investigated further. elderly patients with mild traumatic brain injury (mtbi) are frequently admitted to an intensive care unit (icu), which is potentially both harmful and unnecessary. however, little exists to inform early decision making to determine appropriate utilization of icu care. here we sought to elucidate factors available upon admission to identify geriatric patients who could safely be monitored in a non-icu setting. adults + years admitted with isolated mtbi, defined as positive radiologic study and glasgow coma scale (gcs) - , between january -december were identified. primary outcomes were ernight stay, no surgery, no intubation, and discharged home) and glasgow outcome scale (gos). positive outcome was defined as gos - and a total of patients met criteria. of these, underwent emergent neurosurgical intervention., leaving for analysis. most presented with gcs ( . %) and were admitted to icu ( . %). nearly point decrease in gcs during hospital stay. upon discharge, . % were classified gos - . predictors . ), and no home use of anticoagulant/antiplatelet medication (p = . ). presence/type of a single intracranial hemorrhage (ich) was not significantly associated with outcome, but presence of bilateral or multiple lesions independently predicted poor outcome (p = . ). overtriage of patients to an icu is costly, resource intensive, and avoidable. here, we suggest a conservative framework to assist the determination of which patients can be safely observed in non-icu population who present with mtbi. perihematomal edema (phe) is a known predictor of outcome after intraparenchymal hemorrhage (iph), but factors contributing to edema formation are incompletely understood. tissue water uptake measured using hounsfield unit density on ct scan has emerged as a predictor of edema in ischemic stroke. the aim of this study was to examine this association in iph, where the theoretical driver for edema volume is not anoxic cellular injury, but rather exposure of tissue to blood. women's hospital were prospectively enrolled between september and march . phe and hematoma were identified on ct scans performed at admission and an average of . +/- . hours later. hematoma volume, hematoma surface area and phe volume were measured. net water uptake (nwu) was calculated as the percent change in phe hounsfield unit density compared to normal contralateral hemisphere. associations between variables were examined with pearson correlations and regression analyses. hematoma volume and surface area at admission were significantly associated with phe volume on the admission scan (r = . , p < . and r = . , p < . respectively) and at the follow-up time-point (r = . , p < . and r = . , p < . respectively). there was no association between nwu and phe volume at either time-point (r = . , p = . and r = - . , p = . respectively). in multivariable analysis, hematoma volume at admission remained an independent predictor of phe volume on the follow- these results suggest that, unlike in ischemic stroke, phe volume is not related to water content. rather, hematom may suggests new avenues to predict edema formation. the risk of hematoma expansion (he) in patients with recent intracranial hemorrhage (ich) receiving therapeutic anticoagulation (ac) is not known. we aim to characterize complication rates and factors associated with he in these patients. we performed a retrospective cohort study of adult patients at harborview medical center between - , who presented with ich and were therapeutically anticoagulated within weeks after the ich for a venous thromboembolic event (vte). we excluded patients with ich due to hemorrhagic conversion of ischemic stroke, venous sinus thrombosis, or an aneurysm consequently secured. we assessed the rate of he, defined as either radiographically proven expansion requiring cessation of ac, or death due to he. t-tests and chi-squared tests were used to analyze factors associated with he. - ), % were female. we identified % sdh, % iph, and % multicompartment ichs, % due to trauma, % hypertensive, and % other etiologies. anticoagulation was initiated an average of . +/- . days after ich. overall, % developed he, one third of whom died. most patients ( %) experienced no complications, % developed minor extracranial bleeding events with ac subsequently resumed. patients with he were older ( vs. ), had higher gcs ( vs. . ), lower hematoma volume ( % vs. % > cc), larger maximal sdh diameter ( . vs . mm), anticoagulated earlier ( vs. days), and lower maximal ptt ( vs. ), although trends were not statistically significant. there was a marginally significant association between he and the presence of hydrocephalus (p< . ). while ac in patients with acute ich can be safely tolerated, there is a substantial proportion demonstrating he. our analysis was limited by the sample size. larger studies are needed to identify clinical and radiographic features associated with complications. intracerebral hemorrhage (ich) is a disease that is associated with high morbidity and mortality. we examined our center's experience with surgery for ich and clinical outcomes. we prospectively enrolled patients with spontaneous ich from to . patients were divided into two groups based on whether they received surgical or conservative management. surgical interventions included hemicraniectomy and/or hematoma evacuation. multivariable regression analysis was conducted to compare the clinical outcomes after adjusting for potential confounders. adjusted odds ratio (aor) or adjusted mean difference (amd) were reported. we included patients, ( %) had surgery and ( %) did not. of the surgical group, ( %) had hematoma evacuation, ( %) had hemicraniectomy, and ( %) had both. clinical characteristics were comparable in both groups. in the surgical group, nihss and glucose were higher and creatinine was lower compared with the nonoperative group. through multivariable analysis, we identified independent predictors of surgery in ich patients including baseline hematoma volume (aor . , % ci . - . ; p= . ) and enlargement with (aor . , % ci . increase in hematoma volume, there was a % increase in the odds of having surgical intervention. was less likely to have a favorable discharge disposition to home or inpatient rehabilitation ( % vs. %; p= . ). surgery was independently associated with longer icu length of stay (amd . , % ci . ,- . ; p= . ) and hospital length of stay (amd . , % ci . - . ; p= . ) after controlling for potential confounders. in our patient population, baseline hematoma volume and expansion were independent predictors for surgery in ich patients. after controlling for other variables, surgery did not impact ich outcomes and was associated with prolonged icu and hospital length of stay. moyamoya disease (mmd), an intracranial vasculopathy characterized by internal carotid artery hypoplasia, often presents with intracerebral hemorrhage (ich) presumably due to rupture of fragile collateral vessels. although mmd-related ich is generally managed similarly to spontaneous ich, we present a case in which standard management strategies may have led to an unprecedented catastrophic outcome. case report. a previously healthy -year-old female presented to the emergency department with right-sided weakness, dysarthria, and headache. she was intubated for airway protection. a head computed tomography (ct) demonstrated a large left basal ganglia ich. ct angiogram revealed diffuse narrowing of the entire anterior circulation with robust posterior communicating arteries. brain magnetic resonance imaging (mri) revealed prominent collateral vessels and sulcal hyperintensities ("ivy sign") consistent with mmd. given these findings, systolic blood pressure was kept under mmhg for the first hours. the following day, the patient's mental status gradually worsened. workup including repeat head ct, infectious and metabolic panels, as well as electroencephalogram (eeg) were unrevealing except for a decreased end-tidal carbon dioxide (co ). two days after presentation, the patient acutely developed fixed and dilated pupils. eeg concomitantly revealed slowing and attenuation of the background. repeat ct head showed new diffuse cerebral edema with tonsillar herniation. despite hyperosmolar therapy, paralytics, pentobarbital, and cerebrospinal fluid diversion, no improvement was noted. unfortunately, brain mri revealed multifocal brainstem infarcts with superimposed duret hemorrhages. herein, we report diffuse cerebral edema as a complication of mmd-related ich. we hypothesize that disruptions of delicate cerebral autoregulatory mechanisms led to extensive hypoxic-ischemic injury. in the setting of ich, aggressive blood pressure management coupled with relative hypocapnia may have likely caused vasoconstriction of poorly compliant arteries leading to worsened cerebral blood flow and ischemia. therefore, because of its complex pathophysiology, traditional blood pressure and co targets should be revisited in mmd-related ich. it is unknown whether admission systolic blood pressure (sbp) differs among etiologies of intracerebral hemorrhage (ich). such differences may have implications for blood pressure -lowering strategies after ich. we compared admission sbp across ich etiologies among patients in the cornell acute stroke academic registry (caesar), which has enrolled all adults with non-traumatic ich at cornell from through . trained analysts prospectively collected demographics, comorbidities, and admission sbp, defined as the first recorded value in the emergency department or upon transfer from another hospital. ich etiology was adjudicated by a panel of board-certified neurologists using the smash-u criteria. we used anova to compare mean admission sbp among ich etiologies. after verification of model assumptions, multiple linear regression was used to adjust for age, sex, race, and glasgow coma scale (gcs) score. among ich patients in caesar, admission sbp varied significantly across ich etiologies, ranging from mm hg in those with structural vascular lesions to mm hg in those with hypertensive ich (p < . ). the overall difference in admission sbp across etiologies remained significant after adjustment for age, sex, race, and gcs score (p < . by the wald test). the mean admission sbp in hypertensive ich cases was mm hg ( % ci, - mm hg) higher than in ich cases of all other etiologies combined. among patients with a history of hypertension, the mean admission sbp was mm hg ( % ci, - mm hg) higher in hypertensive ich than in ich cases of all other etiologies combined. in a single-center ich registry, admission sbp varied significantly among different ich etiologies. our results suggest that admission sbp is associated with ich etiology rather than simply representing a physiological reaction to the ich itself. incidence of clinical seizures after intracerebral hemorrhage (ich) has been reported to range from . % to %, with the majority occurring at or near onset. in the present study, we investigate incidence of clinical seizures in ich subjects during hospitalization and evaluate whether clinical seizures are associated with poor clinical outcomes at discharge. a retrospective review of consecutive patients with ich admitted to the baylor st. luke's medical center between january and december was conducted. demographics, admission gcs, admission nihss, admission mrs, incidence of clinical seizures and clinical outcome at discharge were recorded. associations between the presence or absence of seizures and clinical outcome, measured by the glasgow outcome scale (gos), were investigated using a multivariate logistic regression model. patients with ich were included. clinical seizures were identified in subjects ( . %), presenting in a median time of . days post-admission (iqr ). outcome was significantly worse for subjects who experienced a seizure compared to subjects who remained seizure-free, poor outcome (gos< ) was found on . % and . % respectively (or . , ]; p= . ). this increased risk was significant after controlling for gender, ethnicity, admission gcs, admission nihss, admission mrs higher in the seizure group compared to the seizure-free group, . % vs . % respectively (or . , % ci [ . - . ]; p= . ) after adjusting for mortality and severe vegetative state (gos , ) there was no statistical significant difference between both groups (p= . ). our study shows a significant association between clinical seizures and poor clinical outcome at hospital discharge after controlling for admission status and other type of complications; however, the presence of clinical seizures did not influence in-hospital rates of mortality. despite the well-established use of the national institutes of health stroke scale (nihss) score as a severity scale for ischemic stroke patients, it is still unclear which score is best for intracerebral hemorrhage (ich) patients. while some studies have looked at nihss and glasgow coma scale (gcs) as a predictor of mortality and -month mrs, there is a dearth in the literature looking at how they affect longer functional outcomes. in this study, we look at and compare how initial nihss and gcs predict month functional outcomes in ich patients. one-hundred patients who underwent minimally invasive ich evacuation, a standardized patient population, from december to october were retrospectively reviewed. we looked at nihss and gcs as a predictor of functional outcome at -months, defined as modified rankin scale (mrs) - . multivariate regression models were constructed using clinical and statistical inferences to predict mrs. these variables were also correlated with -month mrs in multivariate analyses. of patients, . % (n= ) were female and the average age was . (sd= . ). on admission, the median nihss was . (iqr . - . ) and the median gcs was . (iqr . - . ). multivariate logistical analyses showed that higher nihss predicts worse -month mrs, however gcs does not (p= . and . , respectively). correlation analysis with mrs at -months reveals that for every . point increase in nihss, mrs increased by . in this cohort, the admission nihss predicts -month mrs in ich patients while controlling for significant covariates, while gcs does not appear to. despite its simplicity and generalizability, the gcs lacks critical ich elements that the nihss includes. the usefulness of the nihss as a predictor of ich outcomes has been questioned, since ich patients often have depressed consciousness on presentation, however we demonstrate its utility as a predictor of -month functional outcomes. among patients with intracerebral hemorrhage (ich), it is unclear whether red blood cell (rbc) transfusions impact outcomes. we investigated the association between rbc transfusions and inhospital mortality in patients with ich. we performed a retrospective analysis using the national inpatient sample (nis) database. we used standard diagnosis codes to identify non-traumatic ich hospitalizations from through . our exposure was rbc transfusions during the ich hospitalization and the outcome was hospital mortality. we performed multivariable logistic regression to estimate the association between rbc transfusion and outcomes after adjusting for demographics, charlson comorbidity index (cci), and hospital characteristics. however, given the absence of ich severity and physiologic variable data within nis, we performed additional analyses in a separate, single-center ich cohort, adjusting for admission ich and apache-ii scores. of , non-traumatic ich hospitalizations in the nis, , ( %) patients received rbc transfusions. patients receiving rbc transfusions had more comorbidities than those not receiving rbc transfusions (cci > : % vs %). rbc transfusion was associated with increased odds of hospital mortality (adjusted or . ; % ci . - . ). in a separate cohort of primary ich patients, ( %) patients received rbc transfusions during their hospitalization. rbc transfusion was not associated with hospital mortality after adjusting for ich and apache-ii scores (adjusted or . ; % ci: . - . ). rbc transfusion was associated with increased odds of hospital mortality after ich. however, underlying medical comorbidities, acute physiologic derangements, and ich severity may account for some of these ns on outcomes after ich. deep venous thrombosis (dvt) is a common cause of morbidity and mortality in patients admitted to the neuro-intensive care unit (nicu). the aim of this work is to assess the incidence of dvt in patients diagnosed with intracerebral hemorrhage (ich) and study its demographic characteristics. a retrospective chart review of consecutive patients with ich admitted to the baylor st. luke's medical center between january and december was conducted. subject demographics, admission status, incidence of dvt, hospital length of stay (hlos), intensive care unit length of stay (icu-los) and clinical outcome at discharge were recorded. data was analyzed to assess the prevalence dvt in this period. patients with ich were included. dvt was identified in subjects ( . %). median time to dvt from diagnosis was h (iqr ) after the initial symptoms of ich. the mean age of patients with dvt was . (sd . ) and subjects ( . %) were female. . % subjects were of caucasian ethnicity, . % african-american, . % hispanic, . %asian and . % were from other ethnicities. median hlos was days (iqr . ) and icu-los was days (iqr . ). moreover, . % of patients who presented a hospital-acquired dvt had a poor clinical outcome at discharge (gos< ). ich patients admitted to the nic large prospective trials are needed to understand the baseline characteristics of patients at risk of dvt as well as the utility of surveillance and different prophylaxis methods. studies have demonstrated an association between high average systolic blood pressure (sbp), and increased sbp variability with worse clinical outcomes in non-traumatic intracerebral hemorrhage (ich). nevertheless, the optimal blood pressure target remains elusive. we aim at introducing an alternative approach to assess blood pressure in the acute phase of ich, by using the metric of sbp dose, and showing that it provides a more robust association with clinical outcome. we retrospectively evaluated ichs admitted to our institution over a seven-year period. initial ct scans were analyzed to confirm the presence of intraparenchymal blood. blood pressure was recorded at presentation and hourly for the first -hours. mean sbp (msbp) in the first -hours was calculated; sbp dose (dsbp) was calculated via the trapezoidal method from area under the curve (auc), and divided in three groups: no dsbp (no time spent above mmhg), moderate dsbp (auc spent above mmhg), and high dsbp (auc above mmhg). discharge dispositions were used as surrogates of clinical outcome. poor outcome included death, hospice, and long term acute care hospital. -one patients ( . %) had poor outcome. of the patients in the no dsbp group none suffered poor outcome; % of the patients in the moderate dsbp group, and % of patients in the high dsbp group suffered poor mean sbp in predicting patient outcomes (p< . ). high dsbp in the first -hours was associated with worse clinical outcomes, and was a better predictor compared to msbp. blood pressure dose is a promising novel metric that deserves further study in the management of ich. despite lack of ich-specific therapies that improve outcome, current guidelines recommend treatment of ich at tertiary care centers. as such, ich comprises a large proportion of inter-hospital transfers (ihts) to comprehensive stroke centers (cscs) despite studies suggesting lack of mortality benefit and low csc resource utilization. the subset of patients who derive the most benefit from a csc is unclear. here, we create a triage model to identify ich patients who can safely avoid transfer to a csc. a retrospective cohort of patients with spontaneous ich transferred to our csc was used to develop our triage model. patients with early discharge from the neuro-icu without use of any csc resource during hospitalization were identified as low risk, non-utilizers (lr--nu were identified and used to develop a triage model which minimized the likelihood of release of patients requiring csc resource. this model was tested in a replication cohort for accuracy. the development and replication cohorts comprised and patients respectively of whom ( %) and ( %) were lr-nu. initial gcs and baseline ich volume were associated with lr-nu in multivariate analysis. presence of ivh and infra-tentorial location of ich were also included. initial gcs > , ich volume < ml, absence of ivh, and supratentorial location had an auc, specificity, sensitivity, ppv, and npv of . , . %, . %, . %, and . % respectively for identifying lr-nu. in the development cohort and patient in the replication cohort had a neurosurgical intervention. however mostly these were for non-emergent avm interventions. spontaneous ich patients with initial gcs > , ich volume < ml, no ivh, and supratentorial location might safely avoid iht to a csc. validation in a prospective, multicenter cohort is warranted. metastatic cardiac myxomas have many neurologic complications, including intracerebral hemorrhage. cardiac myxomas are rare intracardiac tumors. though most myxomas are benign, the risk of malignant spread to the central nervous system (cns) is well known. we describe a case of multiple recurrent intracerebral hemorrhages (ich) occurring in the setting of a recently treated cardiac myxoma. a -year old woman with a history of resected left atrial myxoma presented with a one-day history of left ear paresthesias. computed tomography (ct) of the head was performed and demonstrated ichs within the right frontal and parietal lobes and left cerebellar hemisphere. she had presented to an outside hospital several weeks earlier with similar symptoms with imaging demonstrating similar definitive evidence of malignancy or infection. conventional angiography was negative for vasculitis. brain biopsy showed no evidence of amyloidosis or glioma. at our institution, magnetic resonance imaging (mri) of the brain with double inversion recovery also revealed no evidence of vasculitis; however, the study was concerning for multiple cavernous malformations. underwent genetic testing. no mutations associated with familial cerebral cavernous malformations syndromes were identified. several months later, she returned to the hospital with recurrent symptoms. head ct and mri re-demonstrated multiple cavernous malformations with surrounding vasogenic edema, which were mildly increased compared with prior studies. given progression of her mri findings, concern for metastatic cardiac myxoma was raised. considering that - % of patients with cardiac myxoma will have some form of neurologic complication, all should receive a comprehensive neurologic evaluation. diagnosis is made with neuroimaging and brain biopsy. primary treatment of cardiac myxoma includes surgical resection. when cns lesions are present, chemotherapy or stereotactic radiosurgery should be considered. an association between spontaneous hyperventilation, severity of disease at presentation, and poor clinical outcomes has been reported in patients with subarachnoid hemorrhage (sah). we evaluated the relationship between early breathing changes and outcomes in patients with intracerebral hemorrhage (ich). consecutive patients with spontaneous ich were enrolled in an observational cohort study conducted between and at a comprehensive stroke center. patient characteristics and functional outcome at discharge were prospectively recorded. arterial blood gas (abg) measurements and mechanical ventilation settings in the first hours of admission were retrospectively collected, when available. hyperventilation was defined as pco < mmhg concurrent with ph > . in spontaneously breathing patients, excluding mechanically ventilated patients not overbreathing the set rate of a control mode. we assessed for an association between early breathing changes, hemorrhage severity and hospital outcomes by univariate and adjusted analyses. early abg data were available for of patients. patients with abg data had more severe hemorrhages than those without (median ich score versus , p< . ). hyperventilation occurred in ( %) of cases. there was no univariate association between hyperventilation and ich score, admission gcs score or initial hematoma volume. lower initial pco was associated with greater risk of in-hospital death (or . per mmhg, %ci [ . , . ], p= . ) after adjustment for ich score, pneumonia and mechanical ventilation requirements. spontaneous hyperventilation is less common after ich than sah ( % vs %, respectively) and not associated with initial disease severity. the association between lower pco and in-hospital mortality after ich, independent of neurologic severity and comorbid respiratory complications, is consistent with findings of greater delayed ischemia and worse outcomes in spontaneously hyperventilating sah patients. these associations may be mediated by a potentially modifiable underlying mechanism such as acute shifts in cerebral hemodynamics due to pco changes. ich or sah patients often undergo interhospital transfers to tertiary centers. acute clinical deterioration diversion is often implemented via external ventricular drains (evd's). the safety and efficacy of leaving the evds clamped or open during inter-hospital transfer is not known. we aimed to implement a pilot during inter-hospital transport for hemorrhagic stroke patient. under the neuroemergencies management and transfers (nemat) program, department of neurosurgery at mount sinai health system, we implemented this protocol in october, . patients with ich or sah requiring evd placement prior to inter-transfer to a specialized center for ich or sah within our health system were enrolled. recommendations for icp management, for post-evd drainage h and cm or lower for ich were included. evd was clamped for transportation and a dose g/kg of mannitol was given just prior to transportation. icp precautions were maintained throughout transportation. ( male, female_ patients who underwent inter-hospital transfers for ich (n= ) and sah (n= ) after placement of evds for raised icp at the transferring hospital were included. all patients required endotracheal intubation for transfer. / patients had an icp less than mmhg on arrival at the receiving hospital. conclusion: protocolized care for ich and sah patients with evds and icp management during interhospital transfers for patients is safe and feasible. such a protocol could an help facilitate potentially rapid and safe life saving inter-hospital transfers for hemorrhagic stroke patients with evds in large urban health system to to hospitals with specialized definitive neurosurgical and neurocritical care. intracerebral hemorrhage (ich) during pregnancy is abound with diagnostic and therapeutic dilemmas and contributes to pregnancy-related mortality. we present a pregnant patient with ich due to moyamoya disease to highlight these issues. case report. a -year-old -week pregnant asian woman presented after developing an acute onset headache followed by loss of consciousness. in the emergency department, she was comatose with bilateral pinpoint pupils and required intubation for airway protection. initial ct head showed predominantly intraventricular hemorrhage (ivh) that emanated from the left thalamus. ct angiogram revealed highgrade stenosis of the left m segment with moyamoya collateralizations. due to hydrocephalus, an external ventricular drain (evd) was placed. the patient required admission to the neurocritical care unit for further monitoring of exam and vitals. continuous fetal monitoring, and ultimately, successful csection on day of hospitalization was performed through collaboration with the obstetrics and gynecology (ob/gyn) team. cerebral angiogram confirmed the diagnosis of unilateral moyamoya disease as the cause of the patient's ivh. the patient was discharged initially to acute rehab and then home with minor cognitive deficits. the work-up and management of ich in pregnant patients can be challenging. moyamoya disease is a non-atherosclerotic cerebral vasculopathy that can be included in the differential diagnosis for ich in pregnant woman. the most common presentation of moyamoya disease in adults is ich, and it's mainly due to the rupture of dilated and fragile vessels in the basal ganglia, and rupture of saccular aneurysms within the moyamoya collaterals. pregnancy might increase the risk of ischemic or hemorrhagic stroke in women with moyamoya, but available data is controversial. cooperation between the neurocritical care and ob/gyn teams can assist in determining the risks and benefits of medications, imaging, and the need and timing for delivery, thus assuring optimal outcomes for the patient and infant. spontaneous intracerebral hemorrhage (ich) is severely disabling, and survivors often require extensive rehabilitation to maximize recovery. recovery for survivors discharged from index hospitalization is variable and incompletely explained by discharge functional capacity. we assessed whether discharge disposition was independently associated with long term recovery potential. patients with acute ich hospitalized at a tertiary care comprehensive stroke center between and were enrolled in a prospective, observational study that recorded demographics, standard severity s was measured by the modified rankin scale (mrs) at discharge and three months. discharge disposition were ordinalized by activity engagement level from highest to lowest as follows: home, ; acute inpatient rehabilitation (air), ; skilled nursing facili ; and long-term acute care hospital (ltach), . ordinal regression was used to assess the prognostic association between discharge disposition and three month functional status by mrs, adjusting for the ich score and mrs at discharge. among patients enrolled, survived and had complete in-hospital data for analysis, and three outcomes at three months (mrs - ; . % and . % respectively), with most either bedbound or dead ( . % and . % respectively). poor outcomes were less common among patients discharged to air ( . %) or home ( . %). the adjusted model found that a better discharge disposition was associated with more favorable three month mrs (odds ratio . , % ci [ . , . ], p= . ). discharge disposition captures prognostically important characteristics in patients with intracerebral hemorrhage beyond traditional case severity and functional status measures. outcomes are poor for a large majority of patients unable to return home or qualify for acute rehabilitation. whether the prognostic characteristics requiring nursing facility care are modifiable by increasing rehabilitation services in those care environments is not known. as a reversal agent for uncontrolled or life-threatening bleeding for patients taking apixaban and rivaroxaban. approval was based on the results of interim analysis of the ongoing annexa- multicenter, prospective, open-label clinical trial. our institution began using the drug in august . we report our clinical experience. we conducted a retrospective observational study of patients admitted to stanford medical center from -associated intracranial hemorrhage. -associated ich. the mean age was (+/- ). patients were male. the mean glasgow coma scale score was . hemorrhage types included intraparenchymal hemorrhage ( patients), subarachnoid hemorrhage ( patients), and subdural hemorrhage ( patients). hemorrhage was associated with head trauma in patients ( %). ten patients ( %) had "excellent" or "good" hemostasis defined by the annexa- criteria. three patients ( %) developed deep venous thrombosis. no patients developed pulmonary embolism or myocardial infarction. -day mortality was % ( patients). we describe a case series of patients who received andexanet alfa for intracerebral hemorrhage at a large medical center. the incidence of intracerebral hemorrhage (ich) is . per , person years. nontraumatic spontaneous ich is usually seen in setting of uncontrolled hypertension or cerebral amyloid angiopathy and commonly occurs in basal ganglia, cerebral cortex, brainstem or cerebellum. spontaneous ich in corpus callosum with intraventricular hemorrhage (ivh) is very rarely seen and reported. we present an unusual case of corpus callosum hemorrhage with ivh associated with a reversible cerebral vasoconstriction pattern (rcvs) on cerebral angiography. the demographic information and clinical reports were obtained from electronic medical records retrospectively. select neuroimaging was obtained from neuroradiology department. year old caucasian male with a past medical history of chronic obstructive pulmonary disease, essential hypertension, and prior ischemic stroke with residual right hemiparesis presented in unresponsive state when he was discovered on bathroom floor. neurological examination on admission showed no verbal response, eyes open, with reactive pupils, and withdrawal to pain in left arm and leg. blood pressure on admission was / mmhg. computer tomography (ct) of head showed large ich in rostrum, genu and trunk of corpus callosum with intraventricular extension and hydrocephalus. he was intubated for respiratory distress and external ventricular drain (evd) was placed. he was also treated with intraventricular alteplase mg injection for total of doses, hours apart. blood pressure was controlled with nicardipine infusion initially, a up ct head showed resolution of ivh over the next several days, however, no significant clinical improvement was seen. patient remained abulic and akinetic. cerebral angiography performed showed right pericallosal artery beading pattern consistent with rcvs. after transition to comfort care, the patient expired on the th day of hospitalization. spontaneous non-traumatic corpus callosum ichs are rare, and while other causes have been reported, this particular etiology is likely due to rcvs. intracerebral hemorrhage (ich) is a leading cause of disability and mortality. infections are a common complication observed in ich and might be associated with worse outcomes. we aim to evaluate the association between infections and clinical outcomes at hospital discharge. a retrospective chart review of consecutive patients with ich admitted to the baylor st. luke's medical center between january and december was conducted. subject demographics, admission status, rates of infections including; pneumonia, urinary tract infection (uti), bacteremia and clinical outcome at discharge were recorded. associations between the presence or absence of infections and clinical outcome, measured by the glasgow outcome scale (gos), were investigated using a multivariate logistic regression model. patients with ich were included. infections occurred in subjects ( . %). uti was the most common infection ( . %) followed by pneumonia ( . %) and bacteremia ( . %). clinical outcome was significantly worse for subjects who experienced any type of infection during hospitalization, compared to non-infected subjects, poor outcome (gos < ) was found on . % and . % respectively (p= . ). this increased risk was significant after controlling for gender, ethnicity, ermore, an unfavorable discharge disposition -infected group, . % and . % respectively (p= . ). our study shows a significant association between infections and poor clinical outcomes at hospital intracerebral hemorrhage (ich) is a subtype of stroke associated with a high morbidity and mortality. low serum calcium levels have been previously associated with larger hematoma volumes, hematoma expansion and worse outcomes; however, the pathophysiological mechanisms are still not well understood. a confounding effect among serum calcium and magnesium levels has been previously considered. in the present study, we investigate whether hypocalcemia is associated with poor clinical outcomes controlling for serum magnesium levels. a retrospective chart review of consecutive patients with ich admitted to the baylor st. luke's medical center between january and december was conducted. serum calcium and magnesium levels were measured during hospitalization, hypocalcemia and hypomagnesemia were defined as serum levels below . mg/dl and . m/dl respectively. associations between serum calcium level and clinical outcome, measured by the glasgow outcome scale (gos), were investigated using a multivariate logistic regression model. patients with ich were included. hypocalcemia was identified in subjects ( . %). clinical outcome was significantly worse in the hypocalcemic group compared to the normocalcemic group, poor outcome (gos < ) was found in . % and . % respectively (p= . ). this increased risk was significant after controlling for gender, ethnicity, serum magnesium levels, admission gcs, admission death) was also higher in the hypocalcemic group compared to the normocalcemic group, . % and . % respectively (p= . ). our study shows a significant association between hypocalcemia and a poor clinical outcome after association. treatment of patients with intracerebral hemorrhage (ich) typically requires advanced care at a tertiary medical center. many patients present initially to regional or local emergency departments and require interfacility transportation to a referral center. mission hospital (mh) is a community-based nonacademic -bed tertiary care facility with comprehensive stroke center certification. we serve as the referral center for affiliated mission health hospitals and regional non-affiliated hospitals across counties. these hospitals are distributed throughout a mountainous and rural area with challenging terrain for transportation and limited resources for critical care transport. here, we aim to describe the current transfer paradigm and consistency of care provided during interfacility transport of ich patients prior to implementation of a dedicated ich regional interfacility transfer protocol. retrospective review of the electronic medical record was performed to identify all patients in calendar year admitted to mh with a principal diagnosis of nontraumatic ich who initially presented to another facility prior to transfer to mh. data, including demographics, transport service type, and transport sequential blood pressures, were collected. blood pressures during transport were analyzed to determine whether blood pressure exceeded our guidelines. patients with ich transferred to our referral center were identified. / ( . %) were transported via critical care transport, and / ( . %) were transported by local ems using general adult transport protocols. / ( . %) had uncontrolled hypertension as defined by or more bp readings above our guidelines. of these, / ( . %) were transported via critical care transport and / were transported via local ems. transport records were incomplete in / ( . %). elevated blood pressures during transport of ich patients are common. rural health systems are challenged by lack of critical care transport capabilities. we are currently implementing a dedicated protocol for interfacility transport care of ich patients. infratentorial intracerebral hemorrhage (ich) is associated with worse prognosis than supratentorial ich; however, infratentorial ich is often excluded or underrepresented in major studies of ich. we sought to evaluate the natural history of infratentorial ich stratified by brainstem or cerebellar location using a prospective observational study inclusive of all spontaneous ich presenting to our institution. using a prospective, single center cohort of patients with spontaneous ich between - , we conducted a descriptive analysis of baseline demographics, severity of injury scores, and long-term functional outcomes of infratentorial ich stratified by cerebellar or brainstem location. infratentorial ich occurred in ( %) of patients in our ich cohort. cerebellar ich occurred in ( %) and brainstem ich occurred in ( %). compared to cerebellar ich, brainstem ich had significantly worse severity of injury scores, including: admission glasgow coma scale (p < . ), ich score (p = . ), and national institute of health stroke scale (nihss) (p = . ). modified rankin scale (mrs) scores at months were significantly better in patients with cerebellar ich compared to brainstem ich (median [ . - . ] versus median [ . - . ], p = . ). patients with cerebellar ich were more likely to be discharged home or to acute rehabilitation (or . , % ci . - . ) but there was no difference in in-hospital mortality (or . , % ci . - . ) or cause of death (p = . ). patients with cerebellar ich who were alive at months had smaller hemorrhages and lower severity of injury on admission. patients with cerebellar ich have less severe symptoms at presentation and more favorable functional outcomes compared to patients with brainstem ich. it has been known that patients with intracerebral hemorrhage (ich) have a higher rate of acute renal tality. the factors such as medications for blood pressure control, blood pressure (bp) variations and use of contrast for imaging without history of previous kidney disease. we analyzed the records from hospitalized patients in the icu from to in a single academic center with primary diagnosis of ich and renal failure. a total of were analyzed, patients ( . %) were reported to ( . %) patients did not meet the criteria for renal risk, injury or failure and ( . %) did not have enough data for the study. antihypertensive therapy used within the first hours of admission was a combination of acei, arbs and b-blockers. patients showed a wide variability in blood pressure (max-min within a day) which could not be and use of iodinated contrast, since ct without contrast was the imaging study of choice in all patients. our observations did not show an association in between bp variability, type of antihypertensive therapy or use of iodinated contrast within the first hrs of admission to acute renal failure in ich patients either with or without history of renal disease. a larger study may be required to support this statement. milrinone, a phosphodiesterase inhibitor, has limited data as salvage therapy for cerebral vasospasm (cvs) secondary to aneurysmal subarachnoid hemorrhage (asah). to date, no study has compared patients treated with intravenous milrinone to a control group receiving standard treatment, primarily hemodynamic augmentation. we compared cvs duration in milrinone-treated patients to a control group, and evaluated additional safety and efficacy outcomes. this was a retrospective, single center, case control study. adult patients admitted to spectrum health or inclusion. the primary outcome was duration of cvs recorded on daily transcranial doppler exams. secondary outcomes assessed efficacy and safety. efficacy endpoints included, but were not limited to: incidence of ischemic stroke, interventions to treat cvs, icu/hospital length of stay (los), and in-hospital mortality. safety endpoints included vasopressor/inotrope requirements and incidence of arrhythmias. -treated and control patients. milrinone use was associated with a longer duration of cvs (p = . ), increased use of intraventricular medications for cvs (p= . ), greater vasopressor requirements (p = . ), and longer vasopressor duration (p= . ). there was no difference in arrhythmias or in-hospital mortality. icu los in milrinone versus control groups was . vs. . days (p= . ) and hospital los was . vs. days, respectively (p = . ). there were ischemic strokes in the milrinone group versus in the control group (p= . ). intravenous milrinone was associated with a longer duration of cvs in asah patients, greater vasopressor requirements, and trended towards a higher incidence of ischemic stroke, though not statistically significant. prospective, randomized, controlled trials are needed to further define the risks and benefits of milrinone therapy in asah patients. aneurysmal subarachnoid hemorrhage (asah) patients sustain several physiologic changes, including a rupture. mri is potentially useful for prognostication in asah but has not been well-studied in this patient population. we present our preliminary experience with multimodal mri in the acute period after asah. we hypothesized that changes in nodes of network critical to consciousness differ between patients with good and poor outcomes. thirty-four asah patients and healthy volunteers underwent multimodal mri at t. mri t images were segmented, and aslconsciousness (i.e., salience network, central executive network, default mode network). wilcoxon rankto test odds of modified rankin scale (mrs) - at months. asah patients had a mean age (±sd) of . ± . years, and controls were . ± . years (p< . ). prefrontal cortex - and - ). r age-matched studies with more subjects and additional mri sequences are needed to better determine mri's potential utility in asah prognostication. aneurysmal subarachnoid hemorrhage (sah) classically presents with the "worst headache of the patient's life" which can be very debilitating and persist for weeks. headache is often refractory to standard treatment, including opiates. pain is thought to be derived from meningeal irritation in the subarachnoid space. the sensory fibers in the anterior meninges are innervated by branches from the ophthalmic division of the trigeminal nerve, which is closely associated with the sphenopalatine ganglion (spg). spg blockade with local anesthetic, first described in , has used as a treatment for various types of headache disorder but has not been described in sah-associated headache. treatment approach is either transnasal or transcutaneous injection. this case series describes five patients who received spg blockade for intractable sah-associated headache. patients with acute aneurysmal sah in the neurocritical care unit were offered adjunct spg blockade for headache refractory to standard treatment. patients rated pain on a - numerical scale, both before and minutes after the procedure, which included either transnasal administration of ropivacaine using the tx device (tian medical) or transcutaneous administration of ropivacaine with decadron. ess score on admission (range - )); two ( %) received transnasal blockade and three ( %) received transcutaneous blockade. median pre-treatment pain score was (range their pain within minutes; the fifth reported % reduction of pain. transcutanous spg blockade resulted in complete pain relief in all patients. the effects were transient, and pain typically returned within hours. there were no complications associated with the procedure. repetitive spg blockade is a safe and effective adjunct treatment for sah-associated headache. a larger clinical trial is planned. tranexamic acid is recommended in the first hours after subarachnoid haemorrhage (sah) and before aneurysm treatment to reduce rebleeding. in brazil, patients are frequently submitted to delayed aneurysm occlusion after sah (> hours from ictus). the objective of this study was to evaluate the effects of tranexamic acid on hospital complications and outcome of patients with sah. all consecutive patients admitted with sah between and at a reference center were included. data were collected prospectively during the hospital stay. all sah patients within hours of ictus were considered eligible for tranexamic acid (ta) up to aneurysm occlusion. we analysed groups: no ta, low dose ta and high dose ta. the primary endpoint was mortality at hospital discharge. other outcomes included hospital complications such as rebleeding, delayed cerebral ischemia and adverse events such as deep venous thrombosis dvt) and pulmonary embolism (pe). one hundred forty five patients were included in the study. approximately half ( , %) received ta, with ( %) receiving low dose and ( %) high dose. at baseline, the high-dose ta group had more -dose group ( % vs %). patients in the low-dose group had lower rebleeding rates ( . %; p= . ) than the no-ta and high-dose ta groups. mortality was lower for the no-ta and low-dose ta groups as compared to the high-dose ta patients. moreover, patients that did not receive ta had longer icu and hospital lengths of stay. dvt/pe rates were very low in our cohort and not different between groups. our study showed that patients that received low dose of tranexamic acid had lower rates of rebleeding as compared to those that received no ta and high-dose ta. mortality was also lower in this group when compared to patients that received high-dose ta. aneurysmal subarachnoid hemorrhage (asah) carries high mortality and morbidity. symptomatic vasospasm is an important complication of asah. about thirty percent of patients with severe vasospasm do not respond to conventional management and will go on to develop delayed ischemic strokes. medical management in these patients are limited and require endovascular therapy with intraarterial vasodilators and angioplasty. milrinone has vasodilator properties and inotropic activity which has been used by intravenous and intraarterial routes for symptomatic vasospasm. in this study, we tested the safety and feasibility of intraventricular milrinone (ivm) in patients with severe vasospasm administered through the external ventricular drain (evd). a retrospective review of medical records of patients with subarachnoid hemorrhage who received ivm between - . ivm was given at a dose of . mg in ml sterile saline every hours through an evd that was subsequently clamped for h. patients received ivm for refractory vasospasm. among those, patients had ruptured asah and one patient had ruptured internal carotid artery pseudoaneurysm secondary to pituitary macroadenoma resection. the mean ivm doses were (range - doses). only one patient ( . %) developed ventriculitis days after ivm. there were no elevations of intracranial pressures with intraventricular administration of ivm. in patients with refractory vasospasm from aneurysmal subarachnoid hemorrhage, intraventricular milrinone administration seemed to be relatively safe. prospective trials are needed to further determine the safety and efficacy. rupture of cerebral aneurysm is the most common cause of subarachnoid hemorrhage (sah). hypertension is a particularly important risk factor for growing and rupture of cerebral aneurysm. in clinical practice, the non-adherence to anti-hypertensive medications is the most important cause of uncontrolled blood pressure. the aim of this study is to evaluate the effect of non-adherence to antihypertensive medications on the long-term prognosis of patients with hypertension and ruptured cerebral aneurysm based on the nationwide health claims database in korea. this study is retrospective cohort study using the national health insurance service-national sample cohort (nhis-nsc) in korea. we included non-traumatic sah patients (icd- ; i ) with hypertension who underwent endovascular coil embolization or surgical clipping for ruptured aneurysm. the primary outcome is defined as composites of recurrent stroke, myocardial infarction, all-cause death. adherence to anti-hypertensive medications is measured by calculating the proportion of days covered (pdc) based on the prescription records, which is treated as a time-dependent variable. we performed multivariate time-dependent cox regression analysis with adjustments for sex, age, diabetes mellitus, treatment morality (coil embolization or surgical clipping), and household income. -nsc, we found patients who received coil embolization or surgical clipping for aneurysmal sah. among them, patients with hypertension were included for analysis. during the . years of mean follow-up period, there were patients who had primary outcome. in the multivariate cox regression, poor adherence to antiindependently associated with increased risk of primary outcome (adjusted hr . , % ci . - . , p-value= . ). in this cohort study with real-world data, poor adherence to anti-hypertensive medications is a strong risk factor for worse prognosis in the hypertensive patients who underwent treatments for ruptured aneurysm. there is need for greater attention to adherence to anti-hypertensive medications in the high-risk patients. tcd is routinely used in aneurysmal subarachnoid hemorrhage (sah) for vasospasm surveillance. the value of tcd monitoring in non-aneurysmal sah (nasah) is unclear. in this study we sought to determine the clinical utility of performing tcd monitoring in a cohort of patients with nasah. retrospective case series study performed at a comprehensive stroke center in a university hospital. patients with sah in whom an aneurysm or other vascular lesion was not identified were extracted from a prospective database covering a year period. patients with nasah were categorized into perimesencephalic and diffuse sah based on the ct appearance. baseline demographics and clinical variables were obtained from the database. tcd results were obtained from a tcd database and conventional criteria were used to diagnose sonographic spasm. categorical variables were compared a total of nasah patients were identified; perimesencephalic and diffuse. spasm was identified in / ( %) perimesencephalic nasah patients and / ( %) diffuse nasah patients (p= . ). no differences were observed between groups in age (p= . ), discharge disposition (p= . ), median her score (p= . ) when comparing patients with spasm to those without spasm. similarly the median number of tcds (p= . ) did not differ among patients with and without spasm. the location of nasah did not influence the diagnosis of spasm (p= . ). sonographic spasm occurs in % of nasah patients but no specific clinical variable appears to influence its occurrence. the clinical significance of such finding needs further validation. complications following aneurysmal subarachnoid hemorrhage (asah) may be associated with early fluid status. this study aims to assess the relation of fluid balance and intravascular volume to outcomes including acute kidney injury (aki), delayed cerebral ischemia (dci), and vasospasm (vsp) in asah. consecutive asah patients were retrospectively collected including patient demographics and admission characteristics. intravascular volume on admission was measured by ivc ultrasound. daily fluid balance in the first days of admission were recorded along with changes in bun and cr. outcomes including dci and vsp were collected. spaghetti plots were used to illustrate trajectory patterns. a linear mixed effect model was used the test the trajectory of slopes. an interaction term between time and patient condition was used to test the slope difference between patient conditions. of patients underwent ivc ultrasound assessment of intravascular volume. patients were hypovolemic on admission with ivc collapsibility index > % or distensibility index > %. ivc slopes were found to be different by patient m balance decreased by - . ± ml/hr (p= . ) while it increased . ± . ml/hr (p= . ) in those - . ± . /hr (p= . ) while it increased . ± . /hr (p= . ) in those without dci (interaction p= . ). - . ± . /hr (p< . ) in those without vsp (interaction p< . ). patient hemodynamics on admission as determined by ivc ultrasound does not correlate with development of aki. however, fluid balance in the first days of admission may be associated with outcomes in asah. early prediction of delayed cerebral ischemia (dci) will improve management of subarachnoid hemorrhage (sah) patients. we used mass spectroscopy (ms) to undertake an unbiased interrogation of plasma proteins associated with dci. this is an observational prospective single-center study of patients admitted to a tertiary care center. serum samples from patients were obtained within hours post-admission. we performed analysis in cohorts separately at different times. the first cohort was a retrospective cohort of matched subjects ( no-dci vs dci). the second cohort consisted of matched subjects ( no-dci and dci). in both cohorts subjects were matched across dci status for age, sex and modified fisher scale. we performed t-tests across dci groups in both cohorts to identify proteins with a difference in concentrations between dci groups. we selected proteins with a p-value of < . for difference across dci in both cohorts as potential candidates. and proteins were identified in cohort- and cohort- respectively. we identified potential candidates in cohort- , and potential candidates in cohort- . six proteins were identified in both cohort- and cohort- (p-value cohort- and p-value cohort- ): complement factor h (p= . and p= . ); complement factor i (p= . and p= . ), antithrombin-iii (p= . and p= . ), histidinerich glycoprotein (hrg) (p= . and p= . ), fetuin-b (p= . and p= . ), and hemopexin (p= . and p= . ). all plasma protein levels were lower in the dci group. in our unbiased approach to identifying biomarkers of dci we identified potential candidates. the compliment cascade and antithrombin-iii has previously been identified as important in the pathophysiology of sah. of interest, we also identified hemopexin (part of the cd -heme-hemopexin scavenging system) and hrg which is associated with cerebral vessel contraction as potential -b has not been previously reported in sah. confirmatory testing needs to be performed to validate our findings. glycemic gap (gg), determined by the difference between glucose and the hba c-derived average glucose (adag), predicts poor outcomes in various clinical settings. our main objective was to evaluate various admission factors and outcomes in relation to gg. we retrospectively reviewed prospectively collected data on adult patients with aneurysmal subarachnoid hemorrhage. admission glycemic gap (agg) was defined as adag ( . ×hba c- . ) subtracted from admission glucose (ag). poor composite outcome was defined as death, tracheostomy, gastrostomy, and/or discharge to a nursing facility. spearman method was used for correlation. generalized linear model was used to test the difference in gg between patient categories. mixed effects model was used to test the difference in trajectory slopes in gg. area under the curve (auc) for roc curve was used to estimate prediction accuracy. sas . was used for all data analyses. the overall mean agg was . ± . mg/dl. agg was significantly correlated with ag (r= . , p< . ), gcs (r= - . , p< . ), lactic acid (r= . , p< . ), and procalcitonin (r= . , p< . ) on admission, but not with hba c (r= . , p= . ). there was a nonsignificant trend of higher agg in those with delayed cerebral ischemia ( . ± . vs. . ± . , p= . ). patients with poor composite outcome had both higher ag ( . ± . vs. . ± . , p= . ) and agg ( . ± . vs. . ± . , p< . ), but the difference in agg was more profound. trajectory slope in the first hours for gg did not differ in patients with poor vs. good composite outcome (- . ± . / hr vs. - . ± . / hr, p= . ), nor did it differ for pointof-care glucose testing (- . ± . / hr vs. - . ± . / hr, p= . ). agg had significantly better prediction accuracy than ag in predicting poor composite outcome (auc: . ± . vs. . ± . , p= . ). admission glycemic gap served as a better predictor of poor outcome than admission glucose. additionally, agg was correlated with ag, lactic acid, and procalcitonin, and inversely correlated with gcs. the use of standardized management protocols (smps) has been shown to improve patient outcomes for multiple neurocritical diseases. however, whether smps improve outcomes after subarachnoid hemorrhage (sah) is currently unknown. we aimed to study the effect of smps on -month mortality and neurologic outcomes following sah. a systematic review of randomized control trials (rcts) and observational studies was performed by searching multiple indexing databases from their inception through january . studies were limited -traumatic sah reporting mortality, neurologic outcomes, and delayed cerebral ischemia (dci). data on patient and smp characteristics, outcomes, and methodologic quality was extracted into a data collection form. methodologic quality of observational studies was assessed using the newcastle ottawa scale (nos). a total of , studies were identified; were assessed in full and met the criteria for inclusion. two studies were rcts and were observational. smps were divided into four broad domains: management of acute sah, early brain injury, dci, and general neurocritical care. the most common smp design was control of dci, with studies targeting this domain. overall, studies were of low quality; most described single-centre case series with small patient sizes. observational studies scored between and on the -point nos. dci and neurologic outcomes were defined inconsistently in the literature, leading to significant challenges in their interpretation. given the substantial hetereogeneity in reporting practices between studies, a meta-analysis could not be performed. the effect of smps on sah remains unknown due to major limitations in study design and quality. notable deficiencies relate to heterogeneous definitions of dci and inconsistent application of standardized neurologic assessment scales. our study highlights the need for rigorous rcts to determine whether the use of a protocol impacts outcomes in critically ill patients with sah. elevated serum chloride has been associated with increased inflammatory markers, worsened systemic hypotension, and renal injury. little is known regarding the effects of hyperchloremia on neurological outcomes after subarachnoid hemorrhage (sah). we reviewed prospectively collected data on adult patients who were admitted for spontaneous sah from to . chloride values were examined on days - . hyperchloremia was defined as serum chloride of meq/l or greater. the primary outcome was delayed cerebral ischemia (dci). secondary outcomes included hospital mortality and month modified rankin scores (mrs). chi-square test and two sample t-test were employed to assess dci and month mr analyze hospital mortality. sah patients were included in the analysis, ( %) developed dci and ( %) did not. patients with dci had higher rates of hyperchloremia on day ( % vs. %, p= . ), day ( % vs. %, p= . ), and day ( % vs. %, p< . ) than patients without dci. after controlling for age, hunt and . , p= . ) and day (or . , p= . ) were associated with higher likelihood of experiencing dci. good functional outcome (mrs - ) was seen in of patients ( %) at months. rates of hyperchloremia were significantly lower in the good outcome group at all time points. after multivariate analysis, hyperchloremia on day (or . , p= . ), day (or . , p< . ), day (or . , p= . , and day (or . , p< . ) were independently associated with decreased odds of good functional outcome at months. early hyperchloremia was associated with dci and worse functional outcomes from sah. the impact of chloride load and fluid management strategy on sah outcomes warrants further investigation. headache is the most common complaint of patients presenting with aneurysmal subarachnoid an efficacious adjuvant therapy in the management of sah-induced headache. we performed a retrospective chart review of patients treated for sah in the neurocritical care unit at a eceived steroids. dexamethasone ( mg every hours) is typically administered for - days in patients with headache refractory to acetaminophen and oxycodone. nursing documented numeric ( - ) pain scores were collected every two hours. we used paired t-tests to compare mean, maximum, and minimum daily pain scores on the day before and during steroid administration. we used multivariate analysis to assess for factors associated with steroid responsiveness, defined as an improvement of or more points in mean daily pain score. there were steroid treatment periods among patients ( % female, mean age ± . , median hunt--two ( %) were classified as steroid responsive. mean daily pain scores decreased by . points (p = . ) during steroid administration. responders reported higher pre-treatment pain scores ( . vs . , p = . ) and demonstrated greater decrease in mean pain scores ( . vs -. points, p < . ). there was no decrease in mean pain scores during the two days following therapy. in multivariate analysis, there was a weak signal that patients who underwent surgical clipping were more likely to have steroid responsive headaches (or . , . no other demographic or clinical characteristics were associated with steroid responsiveness. a subset of patients with sah induced headache may have a favorable, transient response to steroids. tterns and influence on opioid requirements. cerebral vessel vasospasm (cvv) is a feared complication following aneurysmal subarachnoid hemorrhage (asah). there has been an association between cvv and delayed cerebral ischemia which accounts for a great deal of morbidity and mortality following asah. though the majority of patients with cvv respond to blood pressure augmentation, many patients go on to develop delayed ischemic neurologic deficits despite aggressive therapy. there is some suggestion in the literature that intraventricular milrinone (ivm) may be useful in the treatment of cvv. retrospective case series of patients with asah that were treated with one or more doses of . mg index (pi) and frequency of intraventricular milrinone dosing was collected. all patients were treated at cleveland clinic in the neurologic intensive care unit between and . paired t-test analysis was patients in our cohort were dosed with ivm between and times. there were no significant differences territory. there was also no effect of ivm on cvv over time. there were no direct complications secondary to ivm in these patients. based on our results, ivm was non-therapeutic for the treatment of cvv in patients with asah. our data be conducted to evaluate the safety and efficacy of this treatment. our retrospective analysis suggests that the use of intraventricular milrinone may be non-therapeutic for the treatment of cvv. clinical and research tool for riskelement by the national institute of neurological disorders and stroke sah working group. there are few data assessing the we distributed a survey to a convenience sample of attending physicians that care for patients with questions regarding the definitions of the scale components (thin vs. thick, intraventricular blood vs no to determine the overall inter-ing. thirty-three respondents ( % neurocritical care fellowship trained, % ucns certified in neurocritical care, . % neurologists, median years (iqr - ) in practice, treating median of patients (iqr - ) with sah annually from institutions) completed the survey. twenty-three ( . %) reported r measurement of thin vs. thick blood, and . % correctly identified that blood in any ventricle is scored - . ) for the ct scans, which is considered poor agreement. agr regarding the definitions of the score components. the national institute of neurological disorders and stroke sah common data elements may require further clarification in order to standardize research in cerebral vasospasm leading to delayed cerebral ischemia (dci) is one of the most significant factors impacting functional outcome following subarachnoid hemorrhage (sah). although vasospasm is prevalent in this population, treatment options are limited. in recent years, several published case series have reported a positive effect of intrathecal (it) nicardipine for the treatment of vasospasm. we now report a single center one year retrospective cohort experience with intrathecal (it) nicardipine for the treatment of cerebral vasospasm following sah. all patients discharged in with a diagnosis of non-traumatic sah, either aneurysmal or idiopathic, were included in the analysis. demographics, risk factors, clinical course, radiological dci and functional outcome were analyzed. during , patients were admitted with aneurysmal (n= ) or idiopathic (n= ) sah. the mean age was . ± . and . % were women. low grade hemorrhage (h&h - ) was found in . %, medium (h&h ) in . % and high grade (h&h - ) in . %. cerebral vasospasm was diagnosed in . % of the patients, and it nicardipine was used in % of these patients (n= ). only . % of the patients required angiography to treat vasospasm. tcd data was available for patients who received it nicardipine. treatment reduced mean velocities in all arteries within one day (reduction of . - . %, p< . ). this effect remained through the treatment, until the vasospasm resolved. one patient suffered from bacterial ventriculitis. the overall rate of radiological dci, as found in a blinded post treatment assessment of patients' imaging, was . %. in this cohort, . % had a favorable functional it nicardipine is a safe and potentially effective treatment for cerebral vasospasm and prevention of the subsequent ischemic changes. we are currently expanding the analysis to prior years, however, future prospective controlled trials are still needed to evaluate the safety and efficacy of this treatment. patients remain at high-risk for vasospasm, delayed cerebral ischemia (dci), and hydrocephalus after diversion is often necessary in ma additional benefit over standard management by facilitating intracranial blood clearance and decreasing rate of vasospasm and dci, albeit with a possible increased risk of shunt dependency in historical studies. in this study, we assessed safety outcomes among patients who underwent this procedure. retrospective review of outcomes in pa cisternal drain placement at a single institution. between drain placement. the median hunt-hess score was , but the study population skewed towards large drain dwell duration was . days. radiographic vasospasm occurred in all but one patient ( . %) and developed meningitis/ventriculitis, none fatal. the mean length of stay in the icu was . days. sixteen patients ( . %) were discharged home, twenty-one to acute rehab ( . %), one to subacute rehab ( . %), and two died ( %). among survivors, shunt-dependency occurred in / ( . %), compared to the . %- . % range reported in prior literature. in the study population, cisternal drains appear to be safe as measured against historical cohorts, with comparable or lower shunt-dependency rates. this suggests the viability of further prospective studies to determine the appropriate population for and role of cisternal drainage in the management of asah. estimates of seizure onset after aneurysmal subarachnoid hemorrhage (asah) vary widely, reported rates range from % to %. moreover, seizures increase mortality and disability in patients with asah regardless of common asah complications such as: rebleeding, delayed cerebral injury and vasospasm. we sought to establish the frequency of seizures in asah patients, along with their impact over prognosis, during hospitalization and upon discharge. a retrospective review of consecutive patients with asah admitted to the baylor st. luke's medical center between january and december was conducted. subject demographics, admission gcs, admission mrs, incidence of clinical seizures and clinical outcome at discharge were recorded. associations between the presence or absence of clinical seizures and outcome, measured by the glasgow outcome scale (gos), were investigated using a multivariate logistic regression model. patients with asah were included. clinical seizures were identified in subjects ( . %). outcome was significantly worse for subjects who experienced a clinical seizure compared to subjects who remained seizure-free during hospitalization, poor outcome (gos< ) was found on . % and % respectively (or . , ]; p= . ) this increased risk was significant after controlling hospice, death) was more common for the seizure group compared to the seizure-free group, . % vs . % respectively, however this difference did not reach significance (or . , ]; p= . ) our results showed a low frequency of clinical seizures ( . %) after asah, when compared to other series that have identified an increased incidence of seizures through multimodal approaches. as indexed by gos, along with a non-significant trend towards an unfavorable discharge disposition, among patients with seizures. vasospasm and delayed cerebral ischemia (dci) account for % of the morbidity and mortality after aneurysmal subarachnoid hemorrhage (asah). perfusion ct has been shown to be useful in identifying vasospasm, but this technique is less sensitive to microvascular perfusion changes. mr perfusion (mrp) has been increasingly used in the acute ischemic stroke population and avoids ionizing radiation. we hypothesized mrp may predict the presence of vasospasm by providing measures of impaired cerebral perfusion. we performed a retrospective cohort study with consecutive asah patients between december and august . patients who underwent mrp for concern of dci followed by digital subtraction angiography (dsa) within hours were included. quantitative volumetric analysis was performed at several thresholds of cerebral for the presence of a tmax> lesion. exact wilcoxon rank sums test was used to compare perfusion volumes between patients treated endovascularly versus not treated for vasospasm. we identified patients with a total of mri studies meeting inclusion criteria ( patients treated, patients not treated). no tmax> s hypoperfusion lesion was identified in the untreated group, while / ( %) of the treated patients had at least some delay of tmax> s (p= . ). performance of mrp to detect vasospasm was sensitivity . ( %ci . - . ), specificity . ( %ci . - . ), ppv . ( . - . ), npv . ( %ci . requiring treatment for vasospasm. significant perfusion delay by tmax > s is present in patients requiring endovascular vasospasm treatment after asah. these results suggest that mrp may be a useful tool for patient triage for vasospasm therapy, and further studies are indicated for comparison to other screening methods for vasospasm. recent studies have suggested inflammation and immune dysregulation are important pathophysiology in aneurysmal subarachnoid hemorrhage (asah), and neutrophil to lymphocyte ratio (nlr) was considered as significant clinical predictor of unfavorable outcome including delayed cerebral ischemia (dci). we analyzed nlr of asah patients during ttm, and proposed that the changes in nlr may reflect therapeutic effect of ttm in asah. this retrospective single-center study included asah patients from november , to may , , among which patients underwent ttm after surgical procedures, and other patients didn't undergo ttm. target temperatures were . °c to °c and the durations of ttm were to days. we reviewed the changes of nrl of each patient during ttm and identified whether they had dci, and analyzed in-hospital outcome and -month outcome as measured by the modified rankin scale (mrs). there was no statistically significant difference of overall outcome between ttm group and non-ttm group, but ttm group showed slightly lower rate of dci and better functional outcomes. among the patients, patient who developed dci had higher nlr, and the decreasing rate of nlr was higher in ttm group than non-ttm group. higher decreasing rate of nlr in asah patients while undergo ttm may show the therapeutic effect of ttm. monitoring the trend of nlr value may be helpful in predicting the prognosis of asah patient and estimate the efficacy of ttm for individual patient. eventually, nlr may play important role in deciding practice strategy while treating ttm in asah patients. hydrocephalus is generally regarded as a progressive or static process, but there are few reported cases of transient obstruction of the ventricular system. here, the authors present a rare case of spontaneous symptomatic obstructive hydrocephalus that self-resolved. additionally, a brief review of the literature is performed. records of the patient presented were reviewed in a retrospective manner for all relevant information. pubmed was then searched for all relevant articles. here, we discuss the case of a gentleman in his late 's who presented with worsening confusion and lethargy in the setting of spontaneous subarachnoid and intraventricular hemorrhage. pre-hospital medication includes a daily fish oil supplement; he takes no anticoagulation or antiplatelet agents. approximately one year prior to admission, he experienced an episode of spontaneous left temporal intracerebral hemorrhage. this was attributed to amyloid angiopathy, as evidenced by multiple microbleeds observed on susceptibility weighted imaging at that time. the patient's neurocognitive status steadily declined admission, and he eventually became obtunded. in the process of transferring the patient to the intensive care unit for intubation and external ventricular drain placement, he suddenly became more awake and interactive. the patient's clinical symptoms completely resolved within - hours. no surgical intervention was undertaken. repeat head ct demonstrated that blood products seen in the third ventricle on previous imaging had now migrated into the fourth ventricle. lateral ventricular size had decreased from the prior scan. the following morning, his family members commented that the patient was back to his baseline. transient episodes of obstructive hydrocephalus have rarely been reported in the literature, and are generally associated with an inciting event such as trauma or hemorrhagic stroke. it is possible that there is a higher incidence of transient hydrocephalus, but medical/surgical interventions are performed before the condition is permitted to resolve on its own. raised intracranial pressure (icp) can be a dire consequence of extensive neurologic injury. medical management of elevated icp using intermittent doses of . % hypertonic saline (hts) and/or mannitol is relatively safe and effective for treating refractory intracranial hypertension. at our institution, prior to escalating to sedation and paralysis, hts and mannitol are scheduled. in this study, we aim to describe our experience with scheduled . % hts. methods doses of . % hts during acute admission were included in our retrospective evaluation. only patients who received scheduled . % for anticipated or acute elevated icp in the setting of high-grade subarachnoid hemorrhage (sah) were included. the primary outcome was to characterize efficacy of sustained icp control, by measuring frequency of icp > mmhg and need for escalation of icp management. safety outcomes included incidence of hypernatremia (sodium > meq) and metabolic acidosis. seven out of ( %) patients who received intermittent scheduled doses of . % hts were in the setting of highwere greater than mmhg and no patients required escalation of icp management for the duration of therapy. the median number of doses and duration of . % hts therapy were doses and days (iqr . than meq and patients ( %) developed metabolic acidosis in the setting of hyperchloremia. administration of scheduled intermittent . % hts in the setting of high-grade sah is relatively safe and achieves sustained icp control without need for escalation of icp management. comparative studies of scheduled intermittent . % hts vs alternative medical therapies for icp management are warranted. use of contrast-enhanced computed tomography (ct) studies to evaluate neurological disorders have increased due to its non-invasiveness, fast image acquisition, easy accessibility, and minimal complications. one such procedure is ct myelogram that delineates the extent of spinal stenosis and helps in neurosurgical planning. however, it can result in intracranial migration of contrast medium leading to contrast-induced-encephalopathy (cie). we report cases mimicking as subarachnoid hemorrhage after ct myelogram who subsequently developed cie. case : a -year-old man with chronic low back pain (clbp) was evaluated for confusion, headache due to "intracranial bleed". ct showed diffuse cerebral edema and hyperdensity in the subarachnoid space. external ventricular drain (evd) was placed for suspected post-sah hydrocephalus. however, ct and ct angiogram did not show any cerebrovascular malformation. the patient developed severe encephalopathy and left hemiparesis. repeat ct head showed worsening cerebral edema and hours prior to presentation. severe cerebral edema and left hemiparesis necessitated the use of dexamethasone with improvement in clinical symptoms and examination returning to near baseline. case : a -year-old man with clbp was admitted for "sah" and associated cerebral edema with hydrocephalus. the initial presentation was confusion, double vision, and headache. ct showed diffuse cerebral edema with sulcal effacement, loss of basal cisterns and dilated lateral ventricles. ct and ct angiogram did not show a days prior to presentation. evd placed for hydrocephalus was quickly weaned off the improvement of ventriculomegaly. the patient was discharged with complete resolution of symptoms. cie should be suspected in patients with encephalopathy after ct myelogram. non-contrast ct head is to be interpreted in conjunction with clinical history to avoid unnecessary procedures that might further worsen cie. seizures and ictal-interictal continuum (iic) activity may impact recovery from acute brain injury (abi). empiric antiepileptic drug (aed) intensification for electrophysiologic activity of uncertain significance is challenging to evaluate given structural neurologic deficits, variable pharmacodynamics, and potential sedative effects. we analyzed the eeg and electronic medical records to identify electrographic biomarkers predicting clinical response to aed therapy. we ascertained patients undergoing continuous electroencephalography (ceeg) during admission for abi from a prospective big data repository of clinical data including regularly sampled glasgow coma scale (gcs) scores and med -specific spectral power (alpha - hz, theta - hz, and delta . - hz) and graph theoretical metrics of eeg functional connectivity were compared at time intervals before and after aed therapy. patients met inclusion criteria. , aed doses were administered (mean . +/- . unique aeds per patient). initiating the first aed was followed by a . -point average improvement in gcs (p= . x - ); initiating a second or third aed yielded no significant change, and adding a fourth, fifth, or sixth aed was followed by a . -point worsening in gcs (p= . ). improvement in gcs hours after aed administration was heralded by decline in eeg delta power and rise in network density in the hour following treatment. decline in gcs was heralded by an early rise in delta power and decline in network density. patients with the highest tertile of eeg improvement (greatest combination of rising eeg density and declining delta power) had a consistently improving gcs trajectory in the hours following medication administration, whereas those in the lowest tertile had a consistently worsening gcs trajectory. empirically intensifying aed treatment for disorders of consciousness after abi has diminishing benefit after the initial agent. quantitative eeg biomarkers of early treatment response appears to robustly predict clinical response following aed treatment. new-onset refractory status epilepticus (norse) describes patients with no seizure history who develop refractory status epilepticus (se). the majority progress to super refractory status epilepticus (se). we present a single-center case series of super refractory norse patients to highlight unique features of this group. retrospective chart review was performed to identify adults (age> ) admitted to the columbia university neurological icu from / - / who required continuous midazolam infusions for treatment of super refractory norse. outcome was defined as modified rankin score (mrs) at hospital discharge. descriptive statistics were performed using microsoft excel. of the cases, %(n= ) had a prodrome prior to seizures (infectious, psychiatric or both). patient age was bimodally distributed with %(n= ) less than years old and %(n= ) over . the most common comorbidity was an underlying autoimmune/rheumatologic condition ( %,n= ), though most patients had no pre-existing conditions ( %,n= ). the average stess score was (standard deviation . ). the majority ( %,n= ) remained cryptogenic despite extensive testing. etiologies were identified in %(n= ) - with nmda encephalitis and two with cns infections. immunomodulatory treatment included steroids in %(n= , started on average days from seizure onset, range - ), intravenous immunoglobulin in %(n= , day , range - ) and plasmapheresis in %(n= , day , range - ). the average icu and hospital stays were (range - ) and (range - ) days, respectively. on discharge, %(n= ) had a good outcome (mrs - ), %(n= ) had fair outcome (mrs - ), %(n= ) had poor outcome (mrs - ) and %(n= ) died. compared to prior studies of all norse patients, our cohort with super refractory se were younger, had more frequent prodrome, longer icu and hospital stays and fewer identified autoimmune/paraneoplastic antibodies. the mortality rate was similar to prior studies, but among survivors, super refractory patients were less likely to have a good or fair outcome. we aimed to assess the management of refractory status epilepticus (rse) in developing (ding) and developed (dev) economies, as the management of this condition is resource intense and poorly standardized. investigators from continents collected a large cohort study of rse patients treated between / - / . case-report-forms were finalized at the annual ncs meeting. rse was defined as se that failed to respond to a benzodiazepine and at least one non-anesthetic antiepileptic agent, and was managed with midazolam (mdz) or propofol(pro). the united nations world-economic-situation-prospect was used to identify sites as being from dev or ding economies. four from dev ( patients) economies were included. patients from dev economies were slightly sicker (stess score . ± . vs. . ± . , p< . ). management of patients from dev economies more frequently involved prolonged eeg monitoring (continuous % vs. %, p< . ) but mdz ( . ± . vs. . ± . mg/kg/h) and pro ( ± vs. ± mcg/kg/min, p< . ) doses were higher in ding economies. breakthrough seizures were more common in ding ( % vs. %, or . , p= . ), but no difference in vasopressor use ( % vs. %; n.s.) or withdrawal seizures ( % vs. % n.s.) was seen. hospital ( ± vs. ± days, p< . ) and icu stays ( ± vs. ± days, p< . ) were longer for patients in ding economies. modified rankin scale at discharge was associated with higher stess scores (p= . ) but did not differ between ding and dev economies. direct comparisons between rse patients managed in ding and dev economies are challenging as the baseline level of illness differed but this dataset provides unique insights into differences in utilization of technology (i.e., eeg monitoring), medications (duration and dosage of anesthetics), and length of stay in different health care systems. larger follow-up studies need to explore matched cohorts and explore differences between private-public hospital settings. unlike most anesthetics ketamine acts as an nmda antagonist. we examine the efficacy of intravenous ketamine in the treatment of rse in a large series. retrospective case series of status epilepticus patients admitted between and who underwent treatment with ketamine, patients underwent multimodality monitoring (mmm). we compared patients with complete seizure cessation after ketamine with those without using chi-square and sample t-test. mean age was +/- years old, % of patients were female. seizure burden was decreased by % within hours of starting ketamine in patients ( %), with complete cessation in ( %). average rate of ketamine infusion was . +/- . mg/kg/h, with duration of . +/- . days. average dose of midazolam was +/- . mg/kg/h. ketamine was started on average +/- day after midazolam. patients without complete seizure control after initiation of ketamine ( / patients) were more commonly cardiac arrest patients % vs % (p=. ), and had lower stess score +/- vs +/- (p=. ). all other characteristics were not statistically significant between the two groups including; age, gender, ketamine infusion dosages and duration, apache score, and midazolam infusion dosages. patients ( %) were weaned off pressors after initiating ketamine infusion. when compared the mmm values h before and after ketamine initiation, intracranial pressure values ( +/- vs +/- ), cerebral perfusion pressures ( +/- vs +/- ), cerebral blood flow ( +/- vs +/- ), and lactate/pyruvate ratio ( +/- vs +/- ) were relatively stable. pbo values increased from +/- . to +/- . in our cohort ketamine infusion had a meaningful decreased in seizure burden in rse. our preliminary data also suggests that ketamine infusion didn't affect the intracranial pressure. continuous eeg (ceeg) is widely used to detect seizures (sz) in patients with acute brain injury. however, studies examining sz and epileptiform abnormalities (ea) using ceeg in acute ischemic stroke (ais) are limited. therefore, we aimed to describe the prevalence of electrographic patterns (sz and ea) in ais and its association with outcomes at discharge. retrospective chart review identified patients with ais who underwent ceeg between / and / . demographics, comorbidities and other relevant clinical factors including nih stroke scale (nihss) and treatment interventions were abstracted. ceeg closest to admission (median days) was reviewed for background, sz and ea (lateralized and periodic discharges (lpds and gpds) lateralized rhythmic delta activity (lrda) and sporadic epileptiform discharges (seds). computed tomography or magnetic resonance imaging of brain closest to the time of ceeg was analyzed for midline shift, hemorrhagic transformation (ht) and cortical involvement. outcomes measures were mortality and functional outcome in modified rankin scale (mrs) ( - good and > poor outcome) at discharge. of the patients, had sz and had ea ( . % lpd, . % lrda, . % gpds and . % seds). those with cortical involvement had higher rate of ea and sz compared to those with subcortical stroke ( . % vs . %, p= . ). no difference was found in sz and ea prevalence with regards to age, sex, nihss, midline shift or ht. overall mortality was . %. absence of posterior dominant rhythm (pdr) was associated with increased mortality ( . % when pdr absent vs . % when present, p= . ). sz and ea did not affect mortality or mrs at discharge. despite high frequency of ea ( %), the risk of sz in ais was low at . % and their presence did not impact functional outcome or mortality. however, eeg background with absence of pdr was associated with increased mortality. nonconvulsive seizures (ncs) are a common complication in patients admitted to neuroscience intensive care units and are associated with worse outcomes. ncs can only be diagnosed with continuous eeg (ceeg) monitoring. intermittent conventional ceeg review by neurophysiologists typically occurs - times a day, therefore patients may be seizing for extended periods of time before the seizure is detected. our study aims to evaluate the accuracy of a quantitative eeg (qeeg) trend, the automated seizure detector (asd) in detecting patients' first seizure, which could aid in rapid detection of ncs. this retrospective study includes review of ceeg and qeeg data from adult patients admitted to a single institution neuro icu who developed ncs on ceeg monitoring. independent conventional ceeg review without qeeg by two board-certified neurophysiologists determined the first seizure occurrence for each patient (gold standard). this was compared to the seizure detection sensitivity of the p asd (persyst, inc., prescott az), an algorithm with no user-adjustable settings. recordings from ncs patients were used. mean age was . years and % was female. seizures had variable durations and spatial extents. the sensitivity of p asd was . % ( % ci . - . ) and specificity was . % ( % ci . - . ). mean false alarm rate was . /hour (sd . ) in the time elapsed from the start of ceeg recording until first seizure occurrence. overall, p asd accurately detected the first seizure in % of patients, disregarding false positives. overall, median time to clinical seizure detection was . hours (iqr . hours). this analysis shows that the persyst p asd may have clinically useful sensitivity and specificity in critically ill patients admitted to a neuroscience icu. in conjunction with a low false alarm rate, incorporation of qeeg asd may lead to a reduction in time for seizure recognition. the incidence of early seizures (es) in traumatic brain injury (tbi) ranges between - %. however, the incidence of es after a non-severe tbi (nstbi) with traumatic hemorrhage (th) is unknown. moreover, the data about seizure prophylaxis (sp) in this population remains inconclusive. we aim to determine the incidence of es in nstbi and the efficacy of sp. we respectively reviewed all adult patients with nstbi with evidene of a th on presentation from to . patients with history of epilepsy or receiving antiepileptic drugs (aed) were excluded. we collected demographic data, the type, severity and mechanism of injury; the need for neurosurgical intervention (nsi); es; and sp use. a total of patients met our inclusion criteria, . % had mild tbi; mean age of . years (sd . ); . % males; and . % had subdural hematoma (sdh). same level fall was the most common ( . %) patients had an es in the sp group ( clinical) vs of ( . %) in the non-prophylaxis group (all clinical) (p = . ). levitiracetam as sp was used in . %. patients with combined sdh and traumatic subarachnoid hemorrhage or with multicompartment hemorrhage were more likely to have es than sdh alone (p = . and . , respectively). nsi was not a predictor for es in our cohort. the incidence of es in nstbi patients in our cohort falls within the previously reported ragne. however, it appears to be higher compared to reported rates for mild tbi. es were more likely in the sp group, which might indicate a clinical selection bias. prospective studies are required to further determine the predictors of es and the effect of sp on outcomes in nstbi patients. patients with psychogenic non-epileptic attacks (pnea) sometimes receive aggressive treatment leading to intubation. this study aimed to identify patient characteristics that can help differentiate pnea from true status epilepticus (se). we retrospectively identified patients with pnea and se who were intubated and underwent continuous had acute brain injury or progressive brain disease as a cause of status epilepticus were excluded. we compared clinical features, treatments and outcome between patients who were intubated for pnea and those who were intubated for se. of , patients who underwent ceeg monitoring, we identified and patients intubated for pnea and se, respectively. compared with patients intubated for se, intubated pnea patients were more likely to ( ) be < years of age ( % vs %, p< . ), ( ) be female ( % vs %, p< . ), ( ) be white ( % vs %, p< . ), ( ) have a history of a psychiatric disorder ( % vs %, p< . ), ( ) have no history of an intracranial abnormality ( % vs %, p< . ), and ( ) have a maximum systolic blood pressure < mm hg ( % vs %, p< . ). patients with - of these risk factors had a % ( / ) likelihood of having pnea, those with - had a % ( / ) chance of having pnea, and those with - had an % ( / ) chance of having pnea. sensitivity for pnea among those with - risk factors was % and specificity was %. pnea in patients presenting with emergent convulsive symptoms can be predicted with a high degree of certainty based on the presence of specific demographic, past medical, and physiologic risk factors. care should be taken to avoid over-sedation and unnecessary intubation in this at-risk patient population. a recent systematic review indicates that the mortality of status epilepticus (se) is about . % with a non significant downward trend in recent years. mortality has not changed much despite aggressive management. this study investigates trends and predictors of in-hospital mortality due to status epilepticus at national level in united states. we performed a cross-sectional analysis using the nationwide inpatient sample (nis), - , of us adult hospitalizations with status epilepticus. annual rate of in-hospital mortality was calculated using nis weighting. we identified our status epilepticus patient subset from using codes (dx = . ) from the international classification of diseases, th edition. potential factors associated with in-hospital mortality were assessed using logistic regression. of , hospitalized patients with status epilepticus, , ( . %) died during the index hospitalization. across - , . % of se patients died; with a downward but not statistically significant trend in-hospital mortality from . % ( ) to . % ( ) (p = . ). se patients with inhospital mortality were more likely to be women, older, and with a higher proportion of medical comorbidities, in-hospital complications and extreme loss of function as per all patients refined diagnosis al failure, apr drg severity, mechanical ventilation, tracheostomy, sepsis, pulmonary embolism, acute kidney injury and respiratory insufficiency. mortality due to se was lower than previously reported. mortality has had a non-significant downward trend in the years studied. age, female gender, medical complications and poor baseline functional status are important predictors. availability of aggressive treatment has not modified significantly mortality which requires further study. pregabalin (pgb) is an approved adjunctive treatment for focal epilepsy in adults. pgb lacks drug-drug interactions, has a favorable safety profile and can be rapidly titrated-attractive characteristics for its use in the neurocritically ill. however, data remain limited regarding its use in the icu setting. we are sharing our experience with pgb in neurocritically ill patients with refractory seizures. charts of eight adult patients admitted received pgb were reviewed retrospectively. demographics, antiseizure drug (asd) regimen, and h of eeg data pre-and post-pgb were analyzed descriptively. the cohort comprised eight patients ( females) with mean age of . years. mean icu stay was . days. three patients underwent a neurosurgical procedure related to their primary admission diagnosis, an asd prior to first seizure captured on eeg. prior to pgb, patients had failed on average ( - ) other asds trials. pgb was dosed - mg/day in - divided doses, following a load of - mg. pgb lead to a significant reduction on hourly median seizure burden: . to seizure/h and . to . min/h. pgb led to complete seizure cessation in patients within h and in out of within h of administration. pgb allowed for de-escalation of asd regimen in out of patients. pgb was well tolerated with the exception of mild sedation in patients, which did not warrant further intervention/neurodiagnostics. in this critically ill cohort with refractory seizures, pgb successfully aborted seizures in % of patients. include prospective pregabalin treatment protocols. to describe the first known reported case of utilization of electroconvulsive therapy (ect) to treat super refractory status epilepticus (srse) in pregnancy. we present the case of a year old caucasian female at weeks gestation with pmh focal and generalized seizures who was treated for srse successfully with ect after failed pharmacological treatment. the most likely etiology of srse was sudden cessation of medications upon pregnancy. eeg showed types of seizure activity: rhythmic theta waves over right temporal region with evolution and independent generalized seizures. treatment included use of approximately antiepileptics including , propofol, pentobarbital, magnesium, ketamine, topiramate and valproic acid over the course of days in addition to modifying epilepticus remained super refractory with appearance of mixture of sharp waves on weaning off sedation. she underwent ect with right unilateral electrode placement on day with remarkable improvement in eeg pattern and resolution of srse with single session. patient was back to baseline level of awareness at the time of discharge. on follow up in clinic, she had significant improvement in seizure control with normal fetal development and delivery. treatment of status epilepticus in pregnancy is challenging given the unknown effect of prolonged sedation or hypothermia on fetal development. alternative treatments like ect, vns, dbs, ketogenic diet and hypothermia are sporadically used. use of ect is not considered first or even second line treatment in srse, despite its safe profile, especially in pregnancy. this case adds to the available literature on the success of ect for treatment of srse and puts emphasis on the need for a clinical trial regarding use of ect in srse. the importance of neurocritical care (ncc) has been recognized. but no dedicated educational system for it exists in japan. we have established version of an educational ncc hands-on seminar. this study investigated its effects. this study was a prospective, before-after study using questionnaires and examinations. it was a full-day version . the learning concept was to identify the various methods for maintaining cerebral oxygen balance to prevent secondary brain injury. participants attended five skill sessions: intracranial pressure monitoring, trans-cranial color flow image, targeted temperature management, neuro examination, and eeg, and four scenario sessions: post-cardiac arrest syndrome, subarachnoid hemorrhage, traumatic brain injury, and non-traumatic acute weakness. they had examinations before and after the seminar. the primary outcome was the improvement on examination scores after the seminar. secondary outcomes were the degrees of satisfaction with it and confidence of participants in ncc. we evaluated the improvement of the outcome using wilcoxon signed rank test. a p-value of . or less was considered as significant. thirty-nine physicians and one nurse participated in the seminar. we excluded ( . %) participants because their answers were incomplete. we had ( . %) physicians who are in emergency or intensive care medicine, and ( . %) other professionals. their median age group was in their s (iqr: - ) with median intensive care medicine experience of years (iqr: . - . ). the percentage of correct answers, scores in the examination, improved significantly from (iqr: . - . ) to (iqr: . - . ) after the seminar (p< . ). eighteen ( . %) participants were satisfied with it, and the number of professionals who could not feel ncc-confident decreased from ( %) before the seminar to after its completion (p< . ). our seminar successfully improved the physicians' knowledge of ncc, and gave them more confidence in ncc. glutamic acid decarboxylase (gad) is the rate-limiting enzyme to convert glutamate to gammaaminobutyric acid (gaba). autoantibodies targeted against gad have been implicated in a number of syndromes with neurologic manifestations including stiff-person syndrome, cerebellar ataxia, limbic encephalitis, and epilepsy. we highlight an atypical presentation of this rare disorder with several unique features to the neurological intensive care unit. -year-old woman with pmh of dm, remote left insular ischemic stroke, and recent right leg dystonia presented after being found down with rightward eye gaze deviation, gtc shaking, and urinary incontinence. she required midazolam, lorazepam, loading doses of levetiracetam and fosphenytoin, and propofol infusion to achieve clinical seizure control. despite these interventions, eeg showed ncse with left temporal seizures and anterior midline epileptiform discharges. propofol was titrated to burst suppression. she had several other active medical problems including kidney injury, transaminitis, and myoclonus. seizures and myoclonus were greatly improved after the addition of clonazepam; however, she remained encephalopathic. pertinent diagnostic results included ferritin , ng/ml, ldh , units/l, il- r u/ml, b -micr and serum gad ab titer nmol/l. mri brain showed prominent superior frontal lobe cortical edema. bone marrow biopsy demonstrated good cellularity without malignancy. skin biopsies on three random samples were positive for perivascular dermatitis with telangiectasia. she was started on high dose steroids with subsequent progressive mental status improvement. anti-gad ab associated vasculitis is an exceedingly rare occurrence whose diagnosis previously involved brain biopsy. this case is unique given her acute presentation with refractory status epilepticus, systemic involvement, and diagnosis on skin biopsy. while management has involved immunotherapy, specific treatment guidelines do not exist. given her marked response to clonazepam and corticosteroids, we advocate for early initiation of gabaergic medications such as benzodiazepines and use of immunotherapy. epileptic seizures are a serious complication in patients with subdural hemorrhage (sdh), resulting in increased mortality rates. the incidence of new onset seizures in these patients is unclear. we examined the incidence for new onset seizures and status epilepticus (se) in sdh patients. we examined patients diagnosed with sdh and epilepsy between september to december . we included patients with new onset seizures and extracted those who had seizures after sdh evacuation. clinical and radiographic characteristics, and outcomes of those patients were described. we screened patients diagnosed with sdh, traumatic or non-traumatic. underwent a surgical intervention and ( %) patients had a seizure during their hospital stay. among those who had a seizure, patients had prior history of epilepsy, and had a new onset seizure. although sdh patients with history of epilepsy showed higher incidences of seizures than those with no history (p= . ), sdh patients with history of epilepsy mostly did not evolve into se and those who had no history of epilepsy usually did. there was no significant difference in patients developing se when compared to those without se between the sdh thickness, midline shift, temporal lobe involvement or age of blood (acute or chronic). seizure occurrence in patients with sdh is commonly new onset; however, they are infrequent. in addition, sdh patients with no history of epilepsy have a higher tendency to develop se as opposed to patients with history of epilepsy. larger multicenter cohort studies need to be done for evaluation of these findings. sequoia hospital in redwood city, ca implemented the ceribell rapid response eeg system in to expand its access to eeg for in-patient usage. previously, the hospital had no access to after-hours eeg and the majority of their eegs happened in the icu. this quality improvement project was initiated to understand how access to rapid eeg impacted clinical care and financial metrics across at sequoia hospital. data was analyzed for all patients who received either conventional or ceribell eeg from january , including the department where eeg was conducted, time of day of eeg was ordered, time when eeg began, and clinical diagnosis based on the eeg. data was also captured on patient transfer due to lack of eeg. % of eegs were ordered after hours after the introduction of ceribell, compared to nearly no eegs done after hours before ceribell. % of patients with ceribell eegs were diagnosed with seizures. in , of ceribell eegs, eegs occurred in the in-patient unit or ed. in % of patients with a high suspicion of seizure, seizures were ruled out as a result of reading the ceribell eeg. the introduction of ceribell eegs has greatly expanded access to eegs at sequoia hospital. before ceribell was introduced, eegs mostly occurred in the icu and nearly all happened during regular hours. after ceribell was introduced, eeg was also heavily utilized in the ed and the in-patient unit and gave sequoia eeg access during after hours. as a result of this expanded access and earlier application of eegs, patients have been treated more appropriately. tranexamic acid (txa) is an intravenous antifibrinolytic agent that is used routinely for elective surgery. we report a case of inadvertent intrathecal injection of txa resulting in refractory status epilepticus. case report. a -year-old healthy female admitted for bilateral total knee replacement was inadvertently administered mg of txa intrathecally instead of bupivacaine. soon after administration, she intubated, administered levetiracetam, started on a propofol infusion, and transferred to the neurointensive care unit (nicu). she developed persistent spontaneous and stimulus induced generalized myoclonus refractory to propofol. midazolam infusion was added. nchct and cta demonstrated pneumocephalus, but no acute arterial or venous thrombosis or stroke. veeg revealed generalized nonconvulsive seizures occurring once per minute, not correlating with spinal myoclonus . propofol and midazolam infusions were increased to mcg/kg/min and . mg/kg/hr, respectively, to achieve burst suppression, and valproic acid was added. over the following week, the drips were adjusted to suppress seizure activity. by hospital day , she was weaned off all infusions without recurrence of seizures. by hospital day , she was on levetiracetam monotherapy. she was discharged to rehab after a -day hospital course, and was discharged home days after initial presentation. residual deficits at the time of discharge included mild cognitive impairment and gait instability. she remains seizure-free since hospital day on levetiracetam mg bid. we report a case of refractory status epilepticus and spinal myoclonus after accidental intrathecal txa administration. with aggressive management, the patient survived with mild residual deficits. the mechanism by which txa causes status epilepticus and spinal myoclonus is hypothesized to be related to its inhibitory effects on gaba and glycine receptors, respectively. ictal bradycardia (ib) is a serious complication of temporal lobe epilepsy. if left untreated, ib can cause serious injuries related to syncope, complete heart block and death. management of this phenomenon is controversial: should you treat the seizures or the arrhythmia? we describe the management of a patient who presented with multiple syncopal episodes and found to have symptomatic bradycardia in the setting of temporal lobe seizures. a -year-old male with a recently resected brainstem cavernoma presented with episodes of 'spacing out', face tingling and transient periods of amnesia. he was started on topamax and lamictal. several months later, he began having multiple syncopal events (upwards of a day) that eventually brought him the hospital for evaluation. he was found to be bradycardic with a heartrate in the thirties and had sinus pauses lasting up to ten seconds requiring atropine, an isoproterenol infusion and transcutaneous (tc) pacing. he was also found to have another cavernoma in the right temporal lobe. eeg revealed epileptic activity within the right anterior temporal lobe with correlation to his tc pacing and ib events. lamictal was replaced with keppra and the seizure activity was controlled. he had a pacemaker implanted, after which he did not have any further episodes of syncope and no further seizure activity. the cavernoma was resected a few months later, and he did well postoperatively. ib is an uncommon, but serious, complication of temporal lobe epilepsy. the temporal insula plays a role in the parasympathetic activity of the heart which can cause ib. it may be beneficial for patients who present with symptoms characteristic of temporal lobe seizures or repeated falls/drop attacks to have a full cardiac work up to rule out ib in order to determine if a pacemaker is warranted. the ceeg has had rapid growth within neurological monitoring within the icu, however its still disparate resource in the icus of latin america. is important to know the real situation in colombia about the accessibility to ceeg monitoring. an anonimus survey of questions was conducted from october to april . it was answered by intensivists from latin america, europe, asia and usa. (n= ) considering the accessibility to the ceeg, the ceeg clinical indications and the ceeg monitoring extends (hours) in the icu, we can conclude that colombia is aligned with other countries in the world. in the icus of colombia less than half of the intensivists make decisions in ¨real time¨ with the ceeg and have access to the qeeg modality. the most common cause for non-presciption of ceeg was scarce resources (equipment and human resorces support from a neurology service). cefepime is a fourth-generation cephalosporin with broad-spectrum coverage used to treat infections in critically ill patients. neurotoxic effects have been associated with cefepime, including myoclonus, reduced consciousness, and seizures. we report a case of a patient receiving cefepime who developed non-fluent aphasia and non-convulsive status epilepticus (ncse). two seizure drug trials (levetiracetam and fosphenytoin) failed before marked clinical and electrographic improvement with clobazam. other than cessation of the offending agent, there is little known about the management of cephalosporin associated non-convulsive status epilepticus. data was collected from our institution's health record. a -year-old female with a history of diabetes, chronic kidney disease, recent coronary artery bypass grafting, and mitral valve repair presented with pseudomonas aeruginosa cellulitis of the sternotomy site. on day six of cefepime therapy she developed non-fluent aphasia. mri brain and toxic-metabolic work-up was unrevealing. eeg was consistent with non-convulsive status epilepticus. she failed to respond to standard levetiracetam or fosphenytoin therapy. lorazepam was given with marked improvement in her eeg. clobazam was subsequently started resulting in marked improvement in the patient's language and sustained resolution of ictal pattern on eeg. epileptogenic effects of ß lactam antibiotics are thought to be due to competitive antagonism of the gabaa receptor. beside the recommendation of withholding offending agents when safe to do so, there is no guidance in the literature regarding the appropriate antiepileptic drug choices for the treatment of cephalosporin associated ncse. in this case, clobazam, a benzodiazepine, was an effective treatment. given the theorized mechanism gaba antagonism of cefepime, it is possible that benzodiazepines may ch is needed regarding the optimal seizure control for various etiologies of ncse. when treating seizures and ncse, consideration should be given to the possible mechanism of action of the suspected offending agent. hashimoto encephalopathy is a rare disease. clinical manifestations include abnormal behavior or psychosis, seizures, encephalopathy. pathophysiology is not completely known but it has been associated with autoimmune thyroiditis. we report a case of hashimoto encephalopathy with status epilepticus which responded well to steroids and relapsed following steroid taper. -year-old previously healthy woman was admitted with encephalopathy, new-onset seizures, and delusional behavior for past - weeks. mri brain was unremarkable. eeg showed status epilepticus with right fronto-central origin. she was treated with multiple antiepileptic medications including evaluation for infections, autoimmune and paraneoplastic etiologies revealed elevated thyroid peroxidase, antithyroglubulin and mildly elevated gad antibodies. whole body ct showed no malignancy. she was diagnosed with hashimoto encephopathy. she was treated with iv steroids and ivig. her clinical improvement correlated with decrease in thyroglobulin antibody levels from . to . and thyroid peroxidase antibody levels from . to . . she was discharged on oral steroids and admitted again in few weeks with a relapse of behavioral issues and seizures following steroid taper. she was treated with high dose iv steroids, this time followed by rituximab with significant improvement. she was discharged again on oral steroids with very slow taper and close follow up. our patient had hashimoto encephalopathy and had relapse following taper of steroids. hashimoto encephalopathy is rare condition and is often under-diagnosed. anti-thyroglobulin and thyroid peroxidase antibodies should be checked in patients where no other etiology of new onset status epilepticus is identified. along with seizure management, they should be treated with immunomodulators. closer follow up is needed while tapering the steroids as relapse can occur with behavioral issues and seizures and they may benefit from steroid sparing long term immunomodulatory treatment. non-convulsive seizures (ncszs) and non-convulsive status epilepticus (ncse) are common in critically ill patients. both are associated with neurophysiological disturbances, and even mortality if untreated in a timely manner. [ ]continuous electroencephalogram (ceeg) monitoring has been proven to be effective in diagnosing ncszs and ncses, and assessing the efficacy of treatment thus it is a vital investigation. [ ] we conducted a national survey on the availability of ceeg monitoring within neuro critical care units (nccu) in the uk. to ensure accuracy the consultant in charge or st - covering the nccu was contacted by telephone and asked a serious of questions regarding their use of ceeg and reporting. hospitals were identified as having either stand alone or mixed nccu. responses were obtained from of the units contacted. only % of nccus were able to perform ceeg monitoring from am- pm this dropped to % at night. in % of nccus the itu consultant did not feel confident to analayse the ceeg and make treatment decisions based upon in. the inability of % of nccu to perform ceeg is very concerning, as a single eeg may miss episodes of status, and also makes treatment to achieve burst suppression very difficult. in addition, there appears to be a training gap in ability of icu doctors ability to interpret ceeg. commissioning standards may need to be modified to encourage take of this vital monitoring technique. in addition systems such as possibly setting up a central remote analysis site for all ceeg data for england might improve time to diagnosis and treatment whilst still remaining economically. traumatic brain injury (tbi) is the leading cause of disability in children. neuroimaging is essential for the acute evaluation of moderate-severe tbi, although its prognostic utility is unclear. magnetic resonance imaging (mri) allows for detailed characterization of diffuse axonal injury (dai), the hallmark pathology described in non-penetrating tbi. higher dai grade in adults correlates with worse outcome, but this association has not been rigorously tested in children. we hypothesize that acute rotterdam score and dai grade predict short-term functional outcome in children with acute tbi. patients admitted to stanford children's hospital for acute tbi were identified via retrospective chart review based on icd and icd codes for tbi. inclusion criteria were age > mo and < yrs with blunt, closed head trauma and mri brain obtained during hospitalization. exclusion criteria included history of epilepsy, prior tbi, developmental delay, and penetrating or non-accidental trauma. the first head ct and brain mri obtained during hospitalization were used for analysis of rotterdam score and dai grade, respectively. discharge destination (home versus facility) was used as a marker of short-term functional outcome. multiple logistic regression analysis on cohort of children revealed that lower gcs and ventriculostomy were independent predictors for discharge to acute rehabilitation (or . and , respectively) versus discharge home. neuroimaging analysis revealed that more severe dai significantly correlated with discharge to a rehabilitation facility (p= . ), while rotterdam ct score did not correlate with discharge destination (p= . ). our study demonstrates that higher dai grade is associated with worse short-term outcome in pediatric patients understand the short-and long-term prognostic value of acute neuroimaging in pediatric tbi. , niteroi, brazil zika virus has been associated with several neurological complications. we aim to present three cases of zika associated subacute encephalitis, all requiring intensive care. all patients derived from the rio-zikv-gbs study cohort. all were diagnosed with mac-elisa and pcr for case : -year-old man admitted with lower extremities weakness and urinary retention, preceded by -capsular area, extending to the corona radiata and cerebellar peduncles. he was treated with a -day cycle of intravenous immunoglobulin (ivig). he was discharged one year later due to protracted weaning from mechanical ventilation. case : -year-old man admitted with lower extremities weakness, dysphagia, and dysphonia. days before he presented with and middle cerebellar peduncles, extending to pyramidal tracts. he was treated with ivig. he was discharged after acute treatment and, one year later, presented only with ataxic gait. case : year-old woman admitted with disorientation and behavioral impairment. a week before she presented with % mononuclear) with mild protein elevation. mri revealed hyperintense -t levels. she was also treated with ivig. a year later her neurological exam returned to baseline. all patients had similar clinical presentation, starting with atypical measles syndrome, later evolving to a subacute encephalitis. all showed similar radiological findings, resembling the ones observed with japanese encephalitis, another flavivirus. this new entity is likely a result of zikv-mediated autoimmune activation and it is a challenge for neurocritical care units worldwide. there are two described forms of necrotizing encephalopathy: multifocal necrotizing leukoencephalopathy (mnl) and acute necrotizing encephalopathy (ane). mnl is characterized by multiple microscopic foci of white matter necrosis and is sporadic with predilection for the pons in patients with sepsis or immunosuppression. ane is characterized by multiple foci of grey and white matter disease and is either sporadic or familial; it is typically triggered by febrile viral illness in children without evidence of cerebral infection. a case report with review of the clinical, laboratory, radiographic, and pathologic data. a -year-old woman with post-traumatic epilepsy was admitted with acute encephalopathy and respiratory failure secondary to h n and strepotococcal pneumonia. she developed refractory hypoxemia requiring proning and eventually veno-veno extra corporeal membrane oxygenation. her neurological exam declined with no response to painful stimuli and absent corneal reflexes. continuous restricted diffusion lesions of the cerebral white matter, splenium of the corpus callosum, brainstem, cerebellar peduncles, and deep cerebellum. she died after transition to comfort care and autopsy was pursued by family. neuropathologic evaluation revealed microscopic acute and subacute necrotizing lesions throughout the white matter of the cerebrum, pons, and cervical spinal cord. there were similar lesions throughout the thalamus with sparing of other gray matter structures. there was no significant lymphocytic inflammation or meningoencephalitis. this presentation is consistent with mnl, yet the thalamic involvement is more characteristic of ane. however, ane is rare in adults and typically affects both the grey and white matter. our case affected mostly white matter with microscopic lesions in the grey matter of the thalamus. this case is unique in that it has features of both known necrotizing leukoencephalopathies without clear classification. pharmacotherapy after traumatic brain injury (tbi) aims to prevent secondary insults by optimizing brain homeostasis. to better understand the relationships between medication infusions and cerebral dynamics, we investigated their associations with cerebral compliance (cc), autoregulation (ca) and heart-rate variability (hrv). a retrospective analysis of severe tbi patients admitted to the pediatric icu who underwent brain multimodal monitoring was performed. ca, cc and hrv were estimated by using different parameters: ca by using the pressure reactivity index -a pearson correlation coefficient; cc by using the rap indexa correlation between icp and pulse amplitude; hrv by heart-rate root mean square of successive differences. analysis of variance was used to investigate cerebral dynamics differences during narcotic/sedation (dexmedetomidine, fentanyl, propofol), barbiturate (pentobarbital), vasoactive (epinephrine, milrinone, nicardipine, norepinephrine, phenylephrine) and paralytic (vecuronium, rocuronium) medication infusions. children were identified ( female; ages - years). ca values were significantly higher (i.e. larger positive values) in patients who received vasoactive infusions than those who did not (epinephrine ( . ± . ), norephinephrine ( . ± . )). cc values were much larger (closer to ) in patients who received barbiturate and paralytic infusions compared to those who received narcotic/sedation infusions (pentobarbital ( . ± . ), vecuronium/rocuronium ( . ± . ), fentanyl ( . ± . ), dexmedetomidine ( . ± . ), propofol ( . ± . )). hrv displayed significantly larger values in patients who received narcotic/sedation infusions compared to those who received barbiturate infusions (propofol ( . ± . ), dexmedetomidine ( . ± . ), pentobarbital ( . ± . )). these results suggest vasoactive infusions (epinephrine and norepinephrine) are associated with impaired ca, narcotic/sedation infusions (dexmedetomidine and propofol) are associated with improved cc and greater hrv, and barbiturate infusions (pentobarbital) are associated with impaired cc and less hrv after severe tbi. prospective analysis is needed to validate these associations and investigate whether these medications may be contributors or epiphenomena of altered cerebral dynamics. sleep wake disturbances (swd) after pediatric traumatic brain injury (tbi) requiring critical care admission are poorly quantified, but may have important implications for patient recovery. we conducted a systematic review to quantify swd after pediatric tbi requiring critical care, identify interventions for swd, and determine the association between swd and other post-intensive care syndrome (pics) morbidities after tbi. injury requiring neurocritical care published after and reporting a sleep or fatigue outcome. studies focused on concussion or mild tbi without differentiation of intracranial injury requiring critical care hospitalization were excluded. risk of bias was assessed for included studies. a meta-analysis was not performed due to heterogeneity of included studies. search results yielded articles. abstract review yielded articles, and studies were included in the final analysis ( observational, case reports). we found children with tbi had significantly more swd when compared to controls. studies reported over one third of tbi patients have swd, some persisting for years after injury, but often failed to delineate phenotypes of sleep problems. most studies used subjective measures with questionnaires or interview. seven studies used a validated sleep questionnaire. three studies with total patients presented objective data on swd using actigraphy (n= ), polysomnography (n= ), and electroencephalography (n= ). outside of one case report, no studies evaluated interventions for swd following pediatric tbi. swd in children surviving tbi were associated with pics morbidities including reduced quality of life, behavioral problems, and neurocognitive impairment. heterogeneity and risk of bias among studies was high. research is needed to quantify swd, including identifying phenotypes and utilizing objective measures of sleep. evaluation of pharmacological, psychological, and behavioral interventions for swd is warranted given associations between swd and pics. current guidelines for pediatric severe traumatic brain injury (tbi) recommend maintenance of mean intracranial pressure (icp) under mmhg. increasing evidence has suggested that icp waveform characteristics may be important in understanding the impact of pressure on cerebral physiology. our study objective is to investigate strength of association of brain tissue oxygenation with icp waveform characteristics. retrospective analysis was performed on pediatric patients with tbi who underwent multimodality monitoring including measurements of pbto and icp between january , and january , . data were limited to relatively normal values of pbto between and mmhg and icp values between and mmhg. univariate linear regression was performed to assess strength of association between pbto and icp waveform characteristics including, mean icp values, icp pulse amplitude (amp), and minimum and maximum values of the icp waveforms. patients were identified ( female, ages - years [mean . ; interquartile range . - . ]). pbto was negatively associated with all icp characteristics following analysis. the correlation coefficient (r) was stronger with respect to the relationship of pbto to amp (r = - . ) as compared to mean icp (r = - . ), maximal icp (r = - . ) and minimal icp (r = - . ). p-values were < . for all measurements. these data provide preliminary evidence that icp pulse amplitude is associated with pbto . these findings suggest that icp waveform amplitude should receive greater scrutiny in understanding the impact that icp has on pbto after pediatric severe tbi though further research is necessary to confirm this finding. sarcoidosis is a systemic disease characterized by formation of noncaseating granulomas. in - % of cases, sarcoid infiltrates the central nervous system causing a myriad of clinical symptoms and imaging findings. although rare, neurosarcoidosis commonly involves the brainstem, hypothalamic-pituitary axis, leptomeninges, and spinal cord, causing symptoms such as cranial neuropathies, hypopituitarism, aseptic meningitis, and seizures. based on the review of literature, neurogenic shock as a complication of neurosarcoidosis has not been previously reported. a retrospective chart review was performed on the patient's medical records to obtain laboratory results, imaging studies, and treatment modalities. we demonstrate a case of neurosarcoidosis that initially presented with neurogenic shock, seizure-like activities, and anterograde amnesia. a -year-old african american man with neurogenic shock and seizure-like activities was transferred to our neurointensive care unit. initial workup revealed panhypopituitarism, including hypothyroidism and central diabetes insipidus. mri of neuro-axis was significant for diffuse parenchymal and leptomeningeal enhancing lesions of unclear etiology, including the hypothalamic-pituitary axis, bilateral mesial temporal lobes, and cervical spinal cord. he was intubated for airway protection and treated with dopamine infusion for hypotension and bradycardia thought to be a manifestation of neurogenic shock from his extensive cervical spinal cord lesion. despite significant cervical cord involvement, he remained with good strength throughout. he was extubated after a short course of high dose steroids and stabilization of electrolytes and endocrine function however was found to have anterograde amnesia -pet revealed hypermetabolic lymphadenopathy throughout the neck, chest, abdomen, and pelvis without cardiac involvement. he subsequently underwent lymph node biopsy which revealed noncaseating granulomas. neurosarcoidosis is an infiltrative disease process with varied clinical and imaging presentations. although neurogenic shock is classically seen as a complication from spinal cord injuries above the t segment, neurosarcoidosis affecting the cervical spinal cord can also present with neurogenic shock. the primary goal of traumatic brain injury (tbi) management is the prevention of secondary injury achieved by invasive intracranial pressure (icp) monitoring. near infrared spectroscopy (nirs) is a continuous, noninvasive surrogate measure of cerebral blood flow and oxygenation making it a potentially useful adjunct in the management of tbi. we aimed to determine the association between regional oximetry (rso ) and icp in pediatric tbi. the association between rso and icp was estimated retrospectively in pediatric patients with severe tbi. digital record using univariate dynamic structural equations modeling with a % credible interval ( % ci) for the standardized regression coefficients (src). of study patients had documented events. the association between rso and icp varied between patients and event type. no events triggered by changes in rso occurred. a significant positive (src= . , % ci= . - . ; src= . , % ci= . - . respectively). a negative r this was not significant (src=- . , % ci=- . - . ). during times without intracranial hypertension, changes in icp were positively associated with changes in rso , which may be related to changes in cerebral blood flow. our results also suggest that cerebral desaturation may be seen during periods of intracranial hypertension. our data supports the utility of nirs as an adjunct to understanding changes in icp, however further research is needed to determine if these findings are clinically relevant. rapidly progressive (< hours) primary angiitis of the central nervous system (pacns) has rarely been reported in the literature. most cases have resulted in death. here, we describe the neurocritical care course of a patient with rapidly progressive pacns who survives with a good outcome. data was collected prospectively through direct patient care and chart review. a -year-old previously healthy male presented to an emergency room in acute coma. initial head ct showed diffuse cerebral edema and a left thalamic intracerebral hemorrhage. non-contrast brain mri c perivascular enhancement suggestive of cerebral vasculitis. an external ventricular drain was placed for intracranial pressure monitoring and cerebrospinal fluid sampling, which showed a neutrophilic pleocytosis (wbc= , % pmn). brain biopsy on hospital day (hd) # was consistent with a diagnosis of necrotizing pacns. rheumatologic evaluation was negative for systemic inflammatory disease. therapy included methylprednisolone, plasma exchange, and cyclophosphamide. his hospital course was complicated by ventilator-associated pneumonia, thrombocytopenia, cerebral salt-wasting, and malignant intracranial hypertension which was treated with hypertonic therapy, barbiturate coma, and hyperintensities and resolution of perivascular enhancement. he required tracheostomy and percutaneous gastrostomy and was discharged to a ventilator facility on hd # . on discharge, he was awake and texting on his cell phone. at -month follow-up, his modified rankin score was . our case demonstrates that rapid diagnosis, early immunosuppressant therapy, and aggressive neurocritical support in collected on the optimal therapy of the patients with rapidly progressive pacns. , detroit, mi, united states cerebral amyloid angiopathy (caa)-related inflammation, or cerebral amyloid angiitis is an uncommon disease that presents with acute symptoms secondary to a solitary area of vasogenic edema. this series examines patients presenting with acute neurological symptoms and imaging out of proportion to their exam, suggesting this is a common trend in this diagnosis. cases were collected through epic review, using slicer/dicer to select patients with both snomed diagnoses of caa and cns vasculitis, and snomed diagnosis of caa concurrently treated with prednisone - . cases: ( ) year old female with prior diagnosis of caa presents with transient worsening of right arm dexterity and word-finding difficulty. ( ) year old female presented with loss of vision in the right eye lasting for hours ( ) year old female presents with two days of word-finding difficulty and confusion, using her car remote for her television ( ) year old male presenting after being unable to find words and acting out for two days ( ) year old male with prior diagnosis of caa presents with one day of confusion and nonsensical speech.( ) year old male with history of bilateral occipital hemorrhages of cryptogenic etiology presents with two days of new onset dizziness and left hemianopsia. in each case, patient was identified to have a focal area of vasogenic edema on mri that was significant and alarming in comparison to the patient's presenting symptoms. swi mri showed numerous microbleeds elsewhere to the vasogenic edema consistent with caa. considered differentials included herpes encephalitis, melas, cadasil, and cns vasculitis due to lupus, however all patients exhibited a neurological exam less severe than expected of differentials mentioned prior. all patients were administered an oral steroid regimen with taper for an average of weeks and their symptoms resolved on follow up. use of cranial ultrasound (cus) in pediatrics has been limited to neonates or infants and transcranial doppler (tcd) for stroke risk in children with sickle cell disease. we describe a clinical case showing the utility of performing cus/tcds to assess for new intracranial process in a pediatric patient where head ct was difficult to obtain due to high frequ assessment of waveforms on tcd can be a useful bedside tool in assessing progression of cerebral edema in pediatric patients unable to get a head ct. -month child with acute respiratory distress syndrome required veno-venous ecmo and therapeutic anticoagulation complicated by intracranial hemorrhage with intraventricular extension, mm leftwards midline shift, and hydrocephalus. heparin was reversed and evd was placed. since heparin sedation/paralysis. osmotic therapy was guided by elevated icp. days later, the ability to monitor icps became unreliable due to intermittent evd dra repositioning was deferred because of bleeding risk and lack of clarity whether device malfunction or unsafe because of waveforms with robust arterial diastolic flow and venous flow signifying that icp was lower than plaining unreliability of and repeat head ct showed no gross change. cus and tcd can be a useful tool to screen for high icp using midline shift and spectral waveform analysis in pediatric patients where ct may be contraindicated or challenging to obtain. the structure of intensive care has evolved as the field of medicine has created needs for specialized care. large pediatric hospitals frequently have separated cardiac icu from general pediatric icus, however further subdivision is rare, which differs from adult institutions that often have surgical and neuro icus. this subdivision capitalizes on concentration of expertise and collaboration across providers to improve patient outcomes. texas children's hospital recently opened a new pediatric icu tower and subdivided the picu into six specialty units: surgical, neurology/neurosurgery, pulmonary, hematology/oncology, medical and transitional (for patients with complex needs). we sought to retrospectively review similar patients fitting predefined neuro icu criteria both pre and post move to determine if patient outcome measures were different after cohorting patients. we conducted a retrospective review of neuro icu patients before and after our specialty icu model by comparing june-august to june-august . patients were identified using local data from virtual pediatric systems (vps, llc) and outcomes collected from the electronic medical record utilizing automated data query. primary analysis included patient demographics and outcomes including icu length of stay (los), mortality, prism- and pim- risk of mortality scores. early subgroup analysis included patients with icp monitoring devices in both cohort groups. and patients were in the pre and post cohort group respectively, of which had icp monitors in each group. median time to icp measurement was (iqr - ) and minutes (iqr - ) respectively in pre and post groups (p = . ). icu los, mortality, prism- and pim- were not statistically different. we have developed an algorithm to capture the neuro icu population for future study. preliminary investigations will hopefully confirm patients benefit from this model after programmatic maturity is achieved. west nile virus (wnv) is a mosquito transmitted arbovirus that is endemic in the united states. only % with acute infection develop fevers, and only less than % develop neuroinvasive disease. although the presentation of acute flaccid paralysis is not uncommon, it is extremely rare to visualize the destruction radiographically. here we highlight a case of aggressive neuroinvasive disease with radiographic changes. results y/o caucasian male with arthritis on methotrexate and tofacitinib presented with encephalopathy and generalized weakness. initial evaluation included mri and lumbar puncture. initial mri did not demonstrate etiology of symptoms. lumbar puncture was consistent with viral meningitis (wbc , rbc , glucose and protein ). patient was started on broad spectrum coverage. there was no growth on bacterial or fungal cultures. pcr biofire was negative for acute viruses. weakness progressed, and required intubation for neuromuscular respiratory failure. diagnostic evaluation was repeated days later. repeat mri demonstrated changes on dwi and t weighted imaging, following the motor addition to continued acyclovir, plasma exchange was initiated for an attempt at treatment. the patient's mental status improved, and he refused further treatments including tracheostomy. he was extubated and comfort care was provided given his continued neuromuscular respiratory failure. this case demonstrates severe neuroinvasive west nile encephalitis and flaccid paralysis with radiographic findings. being immunocompromised and age increase his risk for rare presentation of aggressive disease. evidence regarding adequate caloric requirements of critically ill patients with acute brain injuries is suggesting potential risk of caloric debt in neurocritically ill patients. the primary objective of this study was to determine whether guideline recommended weight-based dosing provides adequate caloric requirements compared to indirect calorimetry (ic) measurements in this population. this was a single center, retrospective, observational case-crossover study that included adults admitted within days from admission. we compared resting energy expenditure (ree) determined via ic to the lower (bmi< kg/m : kcal/kg and bmi - kg/m : kcal/kg) and higher (bmi< kg/m : kcal/kg and bmi - kg/m : kcal/kg) actual body weight-based dosing guideline recommendations. we hypothesized that guideline recommended lower-weight based nutrition will not match the caloric demand of patients with acute brain injuries. a total of metabolic studies were performed in patients ( % ich, % non-traumatic sah, % ischemic stroke, % tbi, % status epilepticus, % other etiologies). the mean age was + years, mean weighed + kg with a bmi of + kg/m , and had mean baseline gcs of + . on average ic was obtained on day of admission. lower weight-based recommended nutrition did not provide adequate caloric needs as measured by ic adjusted for obesity ( ± vs ± kcal/day, p< . ). however, higher weight-based recommendation matched the caloric demand as measured by ic ( ± vs ± , p= . ) . in this preliminary analysis, higher weight-based dosing for nutrition matched the caloric demand of critically ill patients with acute brain injury. our results need to be confirmed in future larger prospective studies. central venous catheter (cvc) insertion is common in neurocritically ill patents. standard practice is to obtain a chest radiograph (cxr) to evaluate for the presence of complications, such as pneumothorax (ptx) and catheter misplacement. point-of-care ultrasound (us) has been suggested as an alternative methodology to assess for these complications by using a flush test. patients admitted to our neuro icu between / / - / / who required cvc placement were the subject of this quality improvement analysis. cvc's were placed in the internal jugular (ij) or subclavian (sc) vein followed immediately by lung us to assess for ptx. then, apical or subcostal four-chamber view of agitated saline injected through the distal port of the cvc (ie. flush test) was performed to assess for proper placement. we observed the time delay between start of agitated saline instillation and visualization of contrast in the right atrium and ventricle. this was then interpreted as appropriate (contrast present in </= cardiac cycles) or not. twelve patients were included in this analysis. no patients had a ptx on us or cxr. one patient had a misplaced catheter detected by an abnormal flush test after subclavian cvc insertion using the landmark technique. this was further confirmed by us visualization of the cvc terminating in the ipsilateral ij vein. after immediate removal and reinsertion, followed by an appropriate flush test, cxr then confirmed accurate placement. ultrasound evaluation of cvc complications took < minutes in all cases while it took an average of minutes for the cxr to be avai a potential savings of $ . for each cvc inserted by avoiding the cost of a cxr. in conclusion, we demonstrated us post cvc placement to be an accurate, fast, and potentially less expensive method of confirming cvc placement compared to cxr. major professional critical care societies recommend shared decision-making using decision aids (das) to reduce surrogate decisions incongruent with patient values and preferences and decisional conflict. no das currently exist for any decisions in the neurologic intensive care unit (neuroicu), including goalsof-care decisions. using multilevel input from stakeholders, we recently developed a goals-of-care da for critically-ill traumatic brain injury (tbi) patients that meets international da standards. we aimed to adapt this da to intracerebral hemorrhage (ich) and hemispheric acute ischemic stroke (ais) to widen its applicability and fulfill the shared decision-making needs of surrogate decision-makers of stroke patients. we adapted the existing goals-of-care da by replacing the tbi prognostication model with diseasespecific outcome models as recommended by da quality-standards. we selected the validated month ich-model and -month hemicraniectomy trial outcome data for ais because they include validated long-term outcome assessments. next, we performed acceptability and usability testing of both das using validated scales in family members recruited from two academic neuroicu waiting rooms. we successfully modified the das and created new icon-arrays to optimize the display of predicted outcome probabilities and uncertainties, as has been shown in risk communication studies. twenty family members from two centers participated in acceptability and usability testing. median usage time was ± minutes. usability was very good (mean system-usability-scale-score = / ). % of amount, balance and comprehensibility. we developed three goals-of-care das for surrogates of critically ill tbi, ich and ais patients that include disease specific icon-arrays to communicate outcome probabilities meeting international da standards. das is ongoing, in preparation for a future multicenter comparativeeffectiveness trial. our rigorous development process following international da standards may serve as a template for other neuroicu das. neurocritical care patients receiving rate-based enteral nutrition (rben) consistently received less than their full prescription of enteral nutrition (en) volume due to interruptions in feeding. rate-based en does not allow the nurse to increase the rate after interruptions leaving patients at risk for underfeeding (kim et al. , yeh & peev, . low caloric intake over time is associated with a) immunosuppression, b) impaired wound healing, c) muscle wasting, d) increased hospital and intensive care unit (icu) lengths of stay, e) increased costs, and f) increased mortality (barker et al. , elke et increase the likelihood of adult neurocritical care patients receiving the predetermined goal of % or more of the prescribed volume of enteral nutrition over the course of the nccu length of stay through the use of a volume-based en (vben) protocol which allows the rn to increase the tube feeding rate after interruptions occur. a retrospective pre and postimplementation chart review was conducted on patients aged or greater and less than years with a neurological-related injury or disease process who received en for three or more days during their nccu stay. despite no significant differences in characteristics or gastrointestinal complications between the groups, there was a significant increase in the percentage of prescribed en volume delivered over the course of nccu stay of . percentage points in the vben group (m = . , sd = . ) as compared to the rben group (m = . , sd = . ), t( , n = ) = . , p << . , two tailed, unequal variances. vben can be safely implemented in the neurocritical care population and is associated with significant improvement in en volume delivery. pain, agitation, delirium, and machine support in the icu. a--intensive care syndrome (pics), manifest as psychological and physical debilitation that persists beyond discharge. a-neurocritically ill patients is not known. practices aligned with individual elements of the apopulation were deemed beneficial for patients within this cohort. we asked the question, does the implementation of the a- systematic training on a--professional teams was implemented. baseline data, total bundle compliance, and individual element compliance were measured and analyzed using an approach adopted from the published sccm icu liberation campaign. mortality, ventilator hours, delirium, length of stay (los), and cost were compared to baseline against the third month post education to evaluate the impact of a- preliminary analysis suggests that increased compliance with a-whether wholly or in part, resulted in improved value of care, as evidenced by a decrease in mortality from % to %, as well as a reduction in total icu los adjusted by acuity from . days to . days. this translated into a reduction in cost. as additional experience (and data) become available, further analysis is planned to evaluate the impact of a- early results from a systematic implementation of aand pertinent to improving patient outcomes and value of care. many neurologic diseases are incurable, and patients are faced with prognostic uncertainty, progressive decline and early mortality. as a result, acgme requires training in serious illness communication for all neurology residents; however, only % of programs offer formal education. to address this gap at our institution, we created a training program for neurology residents to improve their skills, attitudes, and behaviors regarding serious illness conversations we designed and implemented a -hour training program utilizing the serious illness conversation guide (ariandnelabs.org). the training program is comprised of a didactic session, a simulated patient experience and debriefing. residents were asked to have a goals of care (goc) conversation with family members (actors) of a patient with catastrophic stroke. a faculty facilitator observed each interaction, allowing residents to self-assess, obtain feedback from the actors and peers and then practice specific components of the conversation. residents filled out a survey both prior to and following the simulation and the faculty filled out an evaluation for each of the residents. led out a pre-survey. the majority ( / ) felt that the residency did not adequately prepare them to have goc discussions though more than % of residents reported feeling comfortable and confident performing these discussions. despite this confidence, the observing faculty found / residents require direct supervision and are not ready to have these conversations independently. the residents struggled with conveying prognosis, maintaining silence, and dealing with strong emotions. all residents reported the training was a helpful, rewarding experience and improved their overall abilities to discuss goc, address prognosis, and explore end-oflife issues. this small pilot study demonstrates an innovative model to improve residents' communication skills surrounding effective goc discussions even when they report increased confidence and independence in these difficult conversations. studies of patient outcomes in mechanically ventilated icu patients have discovered associations among sedative drugs, patient characteristics (demographics and illness), burst suppression (brain inactivation), and mortality. however, association does not imply causation. it remains unclear ( ) whether unintentional burst suppression has a causal effect on mortality, ( ) the degree to which drugs directly impact mortality, and ( ) whether drugs impact mortality indirectly by causing burst suppression. patient characteristics are a possible source of confounding. we estimated causal effects of unintentional burst suppression, critical illness severity and the anesthetic sedation on in-hospital mortality in mechanically ventilated icu adult patients. this was a longitudinal study with an observational cohort of adult icu patients. eeg recordings were obtained for each patient and reviewed by clinical neurophysiologists per institutional protocol to determine the presence of burst suppression in each epoch ( - hour segment). the causal effects were estimated using causal statistical inference (pearl's do-calculus). to assess the robustness of our results towards unmeasured confounding, we performed sensitivity analysis using the e-value. % confidence intervals were created using bootstrapping. on average, increased drug exposure causes a % increase in mortality ( % bootstrapped confidence interval -. , . ) and a % increase in burst suppression incidence (. , . ). burst suppression mediates % of the impact of drug exposure on mortality and is associated with a % increase in mortality (. , . ). increased severity of illness causes a % increase in mortality (. , . ), and a % increase in burst suppression burden, measured by the percent of epochs during which patients experienced burst suppression (-. , . ). unintentional burst suppression contributes substantially to in-hospital mortality. however, unintentional burst suppression appears to be affected more by patient characteristics such as severe critical illness than by high exposure to sedative drugs. infectious endocarditis (ie) is a growing health concern, with increasing incidence in the context of the opioid epidemic. we described a large case series of patients with ie at an urban, academic safety-net hospital. clinical data on patients with diagnosis of ie were entered into an endocarditis work group single-center registry. the mission of the multidisciplinary group is to optimize clinical care, especially as it pertains to cardiac surgical management. we reviewed demographic information, history of prior cardiac valve replacement, intravenous drug use (ivdu), blood culture results, and diagnostic studies (ie echocardiogram, brain ct/mr imaging, and conventional angiography). between november and may , consecutive patients (mean . years; aged - years; % male) with ie were admitted to our center. patients had a history of ivdu in % of cases. unique microbes were isolated, most commonly staphylococcus species ( mssa, mrsa, other). polymicrobial infection occurred in patients. on echocardiogram, vegetations were seen on tricuspid ( ), mitral ( ), aortic ( ), and pulmonic ( ) valves. patients had multi-valve involvement. patients underwent brain ct or mri demonstrating-cerebral infarctions ( ), subarachnoid hemorrhage (sah) ( ), intracerebral hemorrhage (ich) ( ), brain abscesses ( ), and mycotic intracranial aneurysms ( ). neurologic complications occurred most frequently in the setting of mitral valve disease ( infarcts, sah, ich) and in those with staphylococcus ( ) and polymicrobial infection ( ). tricuspid valve vegetations were associated with cerebral infarcts and ich. despite frequent association with ivdu, left-sided cardiac valve vegetations were common. mitral valve involvement, staphylococcus species and polymicrobial infections were associated with increased risk for neurologic complications. neurologic complications also occurred in patients with right-sided valvular disease, suggesting a need for increased surveillance in this population. acute neurological conditions such as traumatic brain injury (tbi), cerebrovascular accident (cva), and hypoxic-anoxic injury (hai) can significantly impact a patient's functional status, and life expectancy. older adults may have poorer outcomes, especially those with premorbid conditions. studies have shown a preference for less aggressive care if patients and/or families anticipate a shorter life expectancy, or poor outcome. as such, early delivery of prognostic information and discussion of goals of care (goc) can be crucial for patients prior to transfer to a tertiary care facility. this is a retrospective cohort study of patients aged and older with cva, hai, or tbi who died within hours of charts were reviewed to assess documentation of pre-transfer goc discussions, code status change after transfer, prevalence of palliative care consultation, and other utilization markers. patients met inclusion criteria with . % being male and . % female with median age . . the majority of patients were transferred from an emergency department ( . %). only . % of patients had documented goc discussions prior to transfer. only . % patients of patients underwent surgical intervention. after transfer, . % of patients downgraded their scope of treatment to comfort measures prior to death, with this being even higher in those and older ( . %). palliative care consultation took place in only . % of patients after transfer. while transfer to a tertiary medical center is sometimes necessary, only . % of patients had documented goc discussions and the majority ( . %) downgraded their scope of treatment to comfort measures after transfer suggesting a potential opportunity for earlier goc discussion and possible avoidable hospital transfers. these findings can inform the design of future interventions to improve communication and decision-making regarding goals of care in patients with high mortality neurological conditions. a neurological emergency response team (nert) was implemented at a dedicated neuroscience hospital in an academic medical center in anticipation of higher patient volumes with the extended treatment window for acute ischemic stroke. goals of the nert are to ensure safe and effective care transition into the acute care setting and a standardize approach to neurological emergency. a dedicated clinical team examined the current structure for safe & effective patient triage, monitoring and transition from the interventional neuroradiology (inr) suite to the neurocritical care unit. clinical nurses with over three years' experience in neurocritical care were vetted, trained & scheduled to provide / continuous coverage. after patients were triaged via telemedicine technology, the nert nurse was alerted via automatic text message system and prepared to receive the patient via ambulance to the inr suite. during the assembly of the inr team, the nert nurse assessed and monitored the patient and initiated diagnostic testing. upon completion of intervention, the nert initiated transfer of care to the neurocritical care unit. stroke volume and door to treatment times were evaluated pre-and post-intervention. in , ischemic stroke patients were admitted through the inr suite, with being treated with endovascular intervention. in , ischemic stroke patients were admitted, with patients being treated with endovascular intervention. since the implementation of the nert, average median arrival time to skin puncture for intervention decreased by seven minutes with a % increase patient volume. a dedicated neurological emergency response team is an effective model to support the increase in patient volume for evaluation of acute ischemic stroke intervention. this approach demonstrates the potential for efficient, safe and timely triage, intervention and care transition to the neuro icu for stroke patients. arctic ground squirrels (ags) endure harsh winter environments through hibernation. curiously, ags are resistant to stroke and other ischemic injuries independent of season or metabolic state. the details of physiologic and cell autonomous genetic adaptations underlying this metabolic resilience is largely unknown. the resilient metabolic and mitochondrial phenotype of ags neural cells was examined in vitro after exposing cells to hypoxia, hypothermia, or mitochondrial toxins and assaying for cell survival, mitochondrial morphology, and oxygen consumption rate. a cdna library prepared from ags cells and nucleofected into mouse neural cells exposed to metabolic stressors was used to perform a functional genetic screen. a bio-informatics pipeline identified screened candidates with key amino acid substitutions that may have evolved to optimize stress response function. newly described dcas base editors capable of substituting c->t (and g->a) were used to systematically mutate and explore the role of identified proteins in mediating the ags optimized adaptive stress response. we found that ags neural cells exhibit marked resistance to all metabolic stressors. this is associated with enhanced mitochondrial function and improved morphology. the functional genetic screen identified a network of evolutionarily-conserved ags transcripts imparting cytoprotection. use of dcas base editors on candidates suggested by the bio-informatics pipeline, confirmed the coordinated role of specific components of the oxidative phosphorylation (oxphos) and endoplasmic reticulum (er) stress response systems in imparting mitochondrial and neuroprotection in our in vitro model. we gained key functional insights into how specific amino acid substitutions in the machinery of the oxphos and er stress responses systems alter mitochondrial function to impart cytoprotection to metabolic insults. this detailed dissection of the ags optimized adaptive stress response pathway will serve as an template for the development of new neuroprotective treatments. acute ascending weakness with respiratory failure is a frequent syndrome encountered in the neurocritical care unit (nccu), often related to demyelinating or infectious etiology. however, here we describe a case of acute ascending weakness with encephalopathy, respiratory failure and autonomic instability that was related to confirmed endocrinological etiology. prospectively collected data was retrospectively extracted from the electronic health record in a patient known to our nccu team. a -year-old male with medical history of childhood meningitis was transferred to the nccu after initially presenting to an outside emergency department (ed) with a chief complaint of bilateral lower extremity weakness progressing to paraplegia over hours. six hours into his course in the ed, he developed bilateral upper extremity paresis and respiratory distress. physical exam in this ed was additionally notable for areflexia and a sensory level at t . he was intubated, initiated on ivig and methylprednisolone, and airlifted to our institution. upon arrival, telemetry showed frequent supraventricular tachycardias refractory to standard treatment. labs (including cerebrospinal fluid) were notable only for serum potassium < . meq/l, thyroid stimulating hormone < . uiu/ml, t . uiu/ml ( . -- . ). he was diagnosed with thyrotoxic periodic paralysis. at endocrinology's urging, the patient was given propranolol mg iv every minutes for doses, propylthiouracil and hydrocortisone. in the hours following propranolol, his potassium improved, his paralysis and encephalopathy resolved, and he was ultimately extubated without difficulty < hours after admission. review of symptoms performed after improvement revealed recent symptoms consistent with hyperthyroidism. intensivists should remain aware of the differential diagnoses that can manifest with motor weakness and respiratory failure. in this patient, severely elevated thyroid hormone led to thyrotoxicosis and subsequent profound hypokalemia. acquiring a thorough history and reviewing laboratory abnormalities remain paramount for timely diagnosis. the objective of the study is to determine the prevalence of disability among icu survivors one year after admission, and factors influencing functional outcome. we conducted a population based cohort study in the icus of the mayo clinic, rochester, mn. we enrolled consecutive patients from the mayo clinic study of aging (mcsa) and then admitted to medical or surgical adult icus at mayo clinic, rochester between january , , and december , . patients admitted to the neuroscience icu were excluded. we collected their demographic and clinical variables, length of icu stay, functional and cognitive status (before and after icu admission), comorbidities (components of charlson score), and apache were retrieved from the electronic medical records using multidisciplinary epidemiology and translational research in intensive care (metric) data mart. one-year functional outcome was categorized using the modified ranking scale (mrs) with scores to representing good functional outcome. cases were included and ( . %) patients were alive one year after icu admission. of them, patients had one-year follow-up functional assessment and ( . %) of them had good functional outcome. on multivariable analysis, poor one-year functional outcome (death or disability) was more common among women, older patients, baseline cognitive impairment (mild cognitive impairment or dementia), higher charlson scores, and longer icu stay (all p< . ). after excluding deceased patients, these associations remained unchanged. in addition, ( . %) of patients who had post-icu cognitive evaluation, experienced cognitive decline after the icu admission. approximately two-thirds of survivors maintained or regained good functional status one year after icu hospitalization. older age, female sex, greater comorbidities, abnormal baseline cognition, and longer icu stay were associated with poor functional recovery. shared decision-making using decision aids (da) is recommended by major professional critical care societies for surrogate decision-making in the icu to reduce decisions incongruent with patient values and preferences and decisional conflict. we converted a paper-based goals-of-care da in critically-ill tbi patients to a digital da. we applied eye-tracking-technology in a single-masked randomized study to understand the effects of and optimize the da navigation design to facilitate information processing. we created two digital das: ( )unmodified conversion of the paper-da with horizontal, top-justified static navigation (control) vs. ( )vertical, left-justified navigation with page subsections and page completion checkmarks (experimental), which encourages users to view pages in order. sixteen healthy participants were randomly assigned to the two groups (n= /group, masked to da assignment) and navigated through the das. using t-tests, we compared user disorientation and usability using validated scales, and eye movements (fixation and saccades) recorded with eye-tracking-technology. impact of navigation on usability was assessed with linear regression, adjusting for disorientation(system-usability-score= b + b *disorientation). disorientation was significantly less in the experimental da (mean . vs. . ;p= . ;smaller values indicating increased disorientation) with no difference in usability (mean system-usability-scale scores vs. ;p= . ;scores> indicating good usability[range - ]). regression analysis revealed a significant association between disorientation and usability (p= . ), with disorientation explaining % of the variation in system-usability-scale scores (adjusted r = . ). eye-tracking measurements revealed longer average fixation per page in the experimental da (mean . s vs. . s;p= . ) and a higher ratio of information processing to search per page (fixation-duration over total duration of both fixations and saccades on a page; mean . vs. . ;p= . ). eye-tracking-technology suggested that the experimental navigation design significantly improved the navigation experience resulting in less disorientation and participants spending less time searching and more time processing the information. while there was no difference in subjective usability, we found a significant association between improved navigability and higher usability. high-fidelity simulation has become an important mode of learning in medical education. currently, there is little data regarding the impact of simulation-based learning in neurocritical care training. in may , we presented a poster at the american academy of neurology annual meeting introducing a comprehensive simulation-based curriculum for neurocritical care training at uc san diego (ucsd). in this poster, we aim to present additional preliminary findings regarding trainee comfort levels, interest, and areas of improvement. this is a single-group pre-post study involving current residents of the ucsd department of neurology. simulation sessions consist of interactive, faculty-led, and checklist-based clinical scenarios (ischemic stroke, intracranial hemorrhage, status epilepticus, spinal cord emergencies) followed by debriefing sessions. collected data assesses for self-perceived comfort/confidence levels, future interest, and checklist item completion. between january and july , pgy - neurology residents participated in various simulation sessions on ischemic stroke, intracranial hemorrhage, and status epilepticus. prior to the session, . % of all trainees reported no more than somewhat comfortable in treating neurological emergencies despite having received some type of neurological emergency training through didactic lectures. rtable in treating the specific simulation case in observation of each simulation session pinpointed specific areas of improvement amongst trainees on an individual basis (i.e. time to intubation after benzodiazepine administration in refractory status). preliminary results suggest that simulation-based learning is valuable and applicable in the neurocritical care training process, allowing trainees to feel more comfortable in managing acute neurological deterioration and faculty to directly observe trainee skill in a controlled setting. through this project, we hope to highlight the need for simulation-based education in neurocritical care training by providing evaluative information and generalizable curricular examples. chimeric antigen receptor (car) t cell therapy for refractory/relapsed hematologic malignancy often causes severe neurologic side effects ranging from encephalopathy and aphasia to fulminant cerebral edema and death. the cause of neurotoxicity is poorly understood. we sought to develop a score based on clinical and laboratory parameters to predict which patients would develop cart-associated neurotoxicity. all patients undergoing cart therapy at brigham and women's hospital for relapsed/refractory hematologic malignancy were prospectively studied. patients were assessed daily during their admission for cytokine release syndrome (crs) and neurotoxicity. vital signs, laboratory data, and medication administration records were extracted from the medical record. logistic regression was used to determine which clinical and laboratory features were significant predictors of developing neurotoxicity. patients were included. experienced crs and experienced neurotoxicity. early (within days after cart infusion) fever and elevated serum c-reactive protein (crp), timing of crs onset, crs grade, and treatment with tocilizumab were all significant predictors of neurotoxicity. using roc curves, optimal discriminators were defined and used to derive a score to predict neurotoxicity. one point was assigned for fever, serum crp > . mg/dl, and each dose of tocilizumab administrated, zero to four points for crs grade, and zero to three points for day of crs onset. this score ranged from to for our cohort and had an auc of %; a score >= predicted neurotoxicity with a sensitivity of % and a specificity of %. bootstrap analysis was used to demonstrate robustness. we used regression analysis to develop a score that can prospectively predict which patients are most likely to suffer from neurotoxicity related to cart therapy. this score can be used for triaging and resource allocation during the care of the patients after treatment with cart therapy. when brain herniation is impending, every minute matters; so the efficient and expedient procurement of all components required for external ventricular device (evd) placement is vital to neurological preservation. the neurosurgical residents at the university of rochester medical center often struggled to assemble the appropriate supplies for an evd placement in a timely manner when patients were not yet admitted to the neuro intensive care unit (neuro icu). additionally it was difficult to track equipment use and supply costs. in response, the neuro icu's quality improvement (qi) team designed an evd "go bag" in an effort to improve delays in care, patient experience, and avoidable costs. the multidisciplinary neuro icu qi team collaborated to design a portable bag that contained all equipment necessary for evd placement. two neurosurgery residents performed time trails, in real emergency situations, by measuring the time from decision to place an evd in emergency department (ed) critical care bay, to collecting the equipment from the neuro icu and return to the bedside in the ed. times were compared with and without using the evd "go bag". the evd "go bag" decreased the time to placement of an evd by up to minutes when compared to the traditional method of retrieving all evd equipment from the neuro icu stockroom. time reduction was due to the speed of gathering supplied and the ability for the neuro icu staff to bring the evd "go bag" to the patient's bedside. the evd "go bag" allowed for better tracking of monetary costs and equipment, allowing for appropriate billing and stocking of supplies. a system was developed where the bag was checked and restocked daily by the critical care equipment technicians and the neuro icu charge nurse despite a growing number of prognostication models in neurologic emergencies, prognostic uncertainty remains inevitable and plays a central role during goals-of-care decision-making for incapacitated critically ill patients. we aimed to examine surrogate decision-makers' communication needs and physicians' strategies for communication of prognostic uncertainty during family meetings for critically ill traumatic brain injury (citbi) patients. we qualitatively analyzed semi-structured interviews of surrogates of citbi patients from two level- u.s. trauma-centers and tbi expert physicians from u.s. trauma-centers. open-ended questions about prognostic uncertainty were asked. interview transcripts were analyzed with the investigatortriangulated-inductive-framework-approach in nvivo-software. prognostic uncertainty was identified as the most difficult aspect of decision-making for surrogates by physicians and surrogates alike, although most surrogates had some pre-existing expectation or understanding of it. % of physicians observed that uncertainty is distressing for families, with % employing specific measures to limit uncertainty. over half of physicians described explaining the concept of uncertainty so surrogates understand that physicians can estimate the odds but not predict the future. physicians typically conveyed prognosis using a range of outcomes, and conveying certainty only for prognostic extremes. surrogates found uncertainty around prognosis was lessened when physicians explained all possible treatment options, with support from clinical data. roughly half noted that too much certainty in providing a prognosis, without a range of possible outcomes, led to distrust in the information provided by the physician, increasing decisional conflict. the vast majority of physicians admitted statistical uncertainty in deriving prognosis, particularly for patients with tbi, and cited mistrust of prognostic models when deriving long-term prognosis. most physicians felt that uncertainty around prognosis led to increased incidence of tracheostomy and feeding tube placement. these results provide foundational knowledge for physician-family communication, by identifying important gaps between surrogates' communication needs and physicians' practices about prognostic uncertainty. the rapid rise in social media utilization among both patients and healthcare providers has moved a considerable portion of conversation around health and disease to the digital space. today, roughly nine-in-ten american adults use the internet, with % of internet users participating in social media. the power and reach of social media platforms makes it imperative for clinicians to be aware of the trends in the public narrative around common disease processes. in this study, we analyzed the last . years of postings ("tweets") from a popular social media platform, twitter, to characterize themes and trends in the digital conversation around stroke, the leading cause of long term disability in the us. tweets under the hashtag #stroke, published from january st to april th , were extracted through symplur signals, llc. a total of , #stroke tweets were qualitatively coded and sentiment analysis was performed after selection for relevance among all homographs. accounts owned by stroke-related advocacy groups were found to be the most prolific contributors of #stroke postings, with content mostly around primary stroke prevention (risks and signs). among the most popular associated hashtags, over half of the tweets focused on comorbidities and the challenges of the stroke recovery process (top trending words included #aphasia, #lockedin, #survivor, #depression). our preliminary analysis describes trends in themes and stakeholder participation in the current #stroke online conversation. it also exposes important gaps in the public discourse beyond the setting of academic and research online communities, namely around existence of therapeutic treatments, availability of resources for patients and families navigating the recovery process, and possibility of successful recovery and long term outcomes. such knowledge around the digital stroke narrative may provide valuable context to intensivists and stroke clinicians interacting with patients and families affected by stroke. the field of autoimmune neurology, specifically the autoimmune encephalitides, has expanded since the early 's. increasingly newer antibodies to various parts of the nervous system are being identified in discovered in patients with meningoencephalomyelitis, or some spectrum of these three singular entities. data was reviewed from electronic medical records for this case report. a previously healthy year-old male initially developed a case of aseptic meningitis, progressing to encephalitis and then extensive longitudinal myelitis leading to profound paresis and respiratory failure. an extensive workup was performed, including evaluation for rare infectious and ominant leukocytosis ( /μl and /μl) and elevated protein (> mg/dl). he was treated empirically with antibiotics which were discontinued after negative results and cultures. after therapy with high dose iv steroids he had minimal improvement and pl had improvement in his symptoms. he was started high dose prednisone with plans to slowly taper after return with positive anti- in review of the literature our patient had several characteristics consistent with others who were also antipsychiatric symptoms. many reports state steroids lead to remission and improvement, however in this case our patient did not have substantial recovery until after the initiation of plex. at this time it is hether these antibodies instead represent a marker of other underlying disease from cytotoxic t cell damage to astrocytes. the united council for neurologic subspecialties (ucns) accredits neurocritical care (ncc) subspecialty fellowships and certifies neurointensivists. in , the american board of medical specialties (abms) approved the application for ncc subspecialty certification by american board of psychiatry and neurology (abpn) and the accreditation council for graduate medical education (agme) approved ncc fellowship training in . previous studies have shown significant heterogeneity in ncc fellowship training and procedural competencies and that many programs do not have the necessary resources for a transition to acgme accreditation. in , an online survey of abpn neurology diplomates was utilized to estimate the number of neurologists practicing ncc, their ncc fellowship training experiences, whether their institutions required certification in ncc, their scope of practice, and their interest in pursuing abpn certification in ncc. survey respondents indicated that they practiced ncc. based upon ucns and other data, this is estimated to be at least % of all neurologists practicing ncc. % of ucns-certified ncc respondents identified the primary scope of their practice as academic involving a fellowship program, and % of non-ucns-certified ncc responders identified themselves as private practitioners. nearly % of fellowship trained ncc respondents obtained ucns certification. % of ucns-certified ncc respondents reported that their institutions required ucns certification, whereas % of non-ucnscertified ncc respondents reported no institutional requirements for certification. over % of respondents thought ncc training was relevant to their current clinical practice. most respondents indicated that they planned to take the abpn ncc examination, and > % of respondents reported that abpn certification would most benefit them by improving their colleagues' perceptions about the quality of certification. ncc training and certification is valued by most neurologists practicing ncc, and most believe that abpn ncc certification will advance the recognition of the field of ncc. cerebral edema is a severe complication of acetaminophen-induced acute liver failure (apapprimary objective was to describe the characteristics of patients with cerebral edema in the setting of apap- this analysis is part of a large, retrospective observational study inclusive of apap-year period from a regional transplant center. we used standardized data collection tools and trained defined cerebral edema based on the interpretation of this ct by a blinded radiologist. we performed univariate analysis based on the presence of cerebral edema. of a total of patients, had data on ct brain imaging. the mean age was . ± . years, and patients ( . %) were female. of patients with neuroimaging, ( . %) had evidence of cerebral edema. patients with cerebral edema had higher average ammonia levels on day of hospital admission ( , % ci - vs. , % ci - mcg/dl). patients with cerebral edema also had significantly higher meld scores by -hours ( . , % ci . - . vs. . , % ci . - . ). this significant difference persisted for subsequent hospital days. thirteen patients ( . %) with cerebral edema received intracranial pressure monitoring. mortality within -days was . % (n= ) if cerebral edema was present vs. . % if absent (n= ). the odds of death within -days, if cerebral edema was present, was . ( % ci . - . ). one patient with cerebral edema died awaiting transplant, and received liver transplant. in this study, cerebral edema was present in % of patients hospitalized for apapwith higher mortality. elevated intracranial pressure and cerebral edema are leading predictors of poor outcomes and mortality in patients with head trauma, intracranial hemorrhages, or acute ischemic strokes. while hypertonic saline (hts) is the mainstay of treatment, recent trials in critically ill populations have demonstrated a reduction in kidney related adverse events with the use of balanced crystalloid groups when compared to . % sodium chloride (nacl). the purpose of this study is to assess adverse kidney outcomes and risk of in-hospital mortality associated with hts in a neurocritical care population. a retrospective cohort study was conducted at a large academic medical center on adult patients in the neurosciences icu who received % nacl and/or . % nacl from july , to july , . the primary endpoint was major adverse kidney events (make- ), defined as at least one component of the composite: in-hospital mortality, receipt of new renal-replacement therapy, or persistent renal ays. baseline characteristics, indication for hts, pertinent lab values including changes in serum electrolyte concentrations, total hts volume and associated sodium and chloride milliequivalents, and patient outcomes were collected. statistical analysis was performed using spss software. in the chloride increase > mmol/l group, patients ( . %) experienced the primary outcome of make- , patients ( . %) experienced in-hospital mortality and patients ( . %) experienced aki primary outcome of make- , and patients ( . %) experienced in-hospital mortality (p= . ). the primary outcome occurred more often in the chloride increase > mmol/l group and in-hospital mortality accounted for the majority of the outcome in both groups. this was not statistically significant due to the sample size and unbalanced comparator groups. social media has been shown to be a valuable tool to improve knowledge, attitudes, and skills. it has been theorized that the success of medical education through social media can be contributed to increased learner engagement, real-time feedback, and enhanced collaboration. we hypothesize that social media is underutilized in critical care medicine in comparison to other specialty fields of medicine and surgery. a list of medical specialties as hashtags were run through "hashtagify" software. this software crossreferences up to , data points on instagram and twitter and assigns a "popularity score" for certain topics. the phrase "critical care" was cross-referenced through a database of medical news run by doximity over a month in comparison to other topic tags. in total, articles concerning the topic "critical care" were posted on doximity news over days. in comparison, there were articles posted under "cardiology," under "internal medicine," and under "emergency medicine." with respect to hashtag utilization on social media, critical care was under-represented, with a popularity score of . this was in comparison to other specialties such as neurology ( ), dermatology ( ), emergency medicine ( ), and ophthalmology ( ). within the critical care hashtag, the major influencers were those representing critical care nursing. despite the large amount of news pertaining to critical care on professionally-curated forums such as doximity, there is significant under-representation in social media. within the hashtag, "critical care," the major influencers represented critical care nursing suggesting that critical care physicians are even further underrepresented. this is in line with previous research suggesting the underrepresentation of medical doctors in social media. given that social media has been shown to be a valuable tool in enhancing medical education, we believe that a greater effort should be made to engage critical care physicians on social media outlets. there is a call for increased diversity in national and international annual meeting participation in terms of attendance, committee participation, leadership, awards and speakers. the neurocritical care society annual meeting(ncs-am) speaker qualifications are not specified in the bylaws. the speakership patterns of the ncs-am have not been examined. we described the speakership patterns in ncs across a -year time span ( ) ( ) ( ) and delineated the trends of united states-neurocritical-care-fellowship- longitudinal cohort study. the ncs-am conference program, a readily available online document, for the years - , were reviewed by the study authors. speakers were identified from the conference program. our primary outcome was the trend of speaker characteristics across the -year time span. our secondary outcome was to determine speakership trends among united states-neurocritical-care-fellowshipinstitution of employment at the time of the meeting. a total of speakers were included in this study, of which % were male. majority of the speakers were us-based( %), mid-to late-career ( %) and were physicians ( %). the speakers were ± years from fellowship. in -years, there was an increased trend towards international, non-physician and early-career speakers' trained from johns hopkins university (jhu) ( , %), massachusetts general hospital (mgh) ( , %) and cornell/columbia university ( , %); while the most common sites of employment at the time of the meeting were jhu ( , %), mgh ( , %) and university of pittsburgh medical center ( , %). this is the first study to evaluate speakership trends across a -year period of the ncs-am. diversity has ble institutional bias are unclear and deserves to be studied further to better define speaker selection in the ncs annual meeting. these data may also be utilized to explore opportunities for collaboration and diversity in future ncs-ams. urinary tract infections (utis) are the fourth most common type of healthcare-associated infection, primarily caused by instrumentation of the urinary tract. there is a %- % increased risk of patients acquiring a catheter-associated urinary tract infection (cauti) for each day an indwelling urinary catheter (iuc) remains in place. in critically ill patients, iuc placement is often required for precise urine output measurement. subarachnoid hemorrhage (sah) patients often require iuc's during the cerebral vasospasm period (i.e. post-bleed day, pbd - ) to maintain euvolemia. this places sah patients at increased risk for developing a cauti. in our local neurosciences intensive care unit (nsicu), an infection control team observed higher cauti rates as compared to the hospital and national average necessitating changing our urinary catheter utilization policy. we report change in practice pattern with implementation of new unit policy the intermittent catheterization (ic) algorithm includes clinician review of the patient's total intake and output and current clinical status. retrospective chart review of cauti incidence (rate per catheter days) and device utilization ratio (no. urinary catheter days/ no. patient days) months before and after implementation of the new policy. time periods were compared using appropriate statistical tests pre-and post-intervention the ic algorithm was implemented to reduce iuc utilization rate with aim to reduce cauti rates. the time periods studied were may to april (pre-intervention period) and may to april (post-intervention period). cauti rates decreased from . ± . during the former time-period to . ± . during the latter time period (p= . ). similarly, device utilization ratio decreased from . ± . to . ± . (p< . ). in addition, use of female and male external catheter devices were encouraged leading to increased utilization systemic team based implementation of policies can result in adoption of positive practices and reduce hospital acquired infectious complications. managing neurological emergencies, particularly overnight, is very challenging for neurology trainees at the beginning of their residency. preparation is key to ensure residents have the skills, confidence, and knowledge to manage acute scenarios. we developed a one-week immersive bootcamp to educate new neurology residents about neurological emergencies prior to the start of the academic year. the bootcamp includes the fourteen emergency neurological life support (enls) modules designed by the neurocritical care society, thirteen faculty-created didactics, nine case-based discussions, and four resident-created simulations. the bootcamp teaches residents about the management of acute ischemic stroke, acute non-traumatic weakness, anoxic brain injury, coma and brain death, intracranial hemorrhage, intracranial hypertension, meningitis, neuromuscular emergencies, status epilepticus, spinal cord emergencies, subarachnoid hemorrhage and traumatic brain injury. residents are also taught about communication with families during and after neurologic emergencies in a didactic session on breaking bad news. it is important for all neurology residents to be adept at managing neurological emergencies. however, having these skills is particularly important for residents in a military program, as residents in the military may ultimately be deployed overseas or stationed at facilities with minimal support, responsible for handling all neurological emergencies, regardless of their sub-specialty. enls training and didactics teach residents about the fundamentals of neurological emergencies. case-based discussions provide residents to act out the way they would utilize this knowledge in a risk-free environment that is translatable to acute clinical situations. the combination of enls training, didactics, case-based discussions and simulations into a one-week immersive bootcamp early in residency should, therefore, provide a solid knowledge base about management of neurological emergencies for incoming neurology residents and allow them to consolidate that knowledge leading to safe and effective management of neurological emergencies. trends and predictors of in-hospital mortality for status epilepticus: national inpatient sample study head or heart: ictal bradycardia and temporal lobe epilepsy julia bevilacqua higher dai grade correlates with worse short term outcome in pediatric traumatic brain injury anna janas; scott hamilton; zachary threlkeld; max wintermark post-intensive care syndrome amongst families of icu patients, including post-traumatic stress disorder (ptsd), is highly prevalent after patient discharge but understudied. the psychological model of "attachment theory" describes how people respond when being separated from loved ones; various "attachment styles" have been associated with the development of ptsd in other settings. adults can be "secure" (comfortable depending on others and being alone) or "insecure." the hypothesis of this exploratory study was that insecure family members of neuro icu patients would be more likely to report ptsd six months after patient hospitalization compared to secure family members. eligible participants were family members of neuro icu patients at a single center who already had attachment styles (secure vs. insecure) defined via a standard survey, the relationship questionnaire, during an earlier study in . over - , these subjects were asked by mail to complete the impact of events scale-revised (ies-r) six months following discharge or patient death. participants were considered to have ptsd if ies- / returned a completed ies-r ( . %). ( . %) of these subjects reported a secure attachment style vs. out of ( . %) insecure respondents (p= . ). this small study did not show a significant difference in rates of post-discharge ptsd amongst neuro icu family members with secure vs. insecure attachment styles, however was only powered to discover a large difference between groups and the rate of ptsd in our population was markedly lower than sible association in larger cohorts with an overall higher prevalence of post-discharge ptsd would be insightful. key: cord- -fidpskcs authors: meersseman, wouter title: invasive aspergillosis in the intensive care unit: beyond the typical haematological patient date: - - journal: aspergillosis: from diagnosis to prevention doi: . / - - - - _ sha: doc_id: cord_uid: fidpskcs data about incidence of invasive aspergillosis in intensive care units (icu) are scarce and variable. incidences ranging from to % have been reported, which might reflect different autopsy policies amongst centres. recent studies have shown that many patients with invasive aspergillosis do not have a haematological diagnosis. instead, conditions such as chronic obstructive pulmonary disease and liver failure became recognized as important risk factors. the diagnosis remains difficult in these patients, since diagnostic tests have not been widely validated outside the haematological boundaries. mechanical ventilation precludes the interpretation of clinical signs and radiological diagnosis is clouded by underlying lung pathology. respiratory cultures lack sensitivity and specificity. at the moment, diagnosis is best made by testing for galactomannan in bronchoalveolar fluid samples (sensitivity and specificity of > %). testing galactomannan in sera has limited sensitivity for the non-neutropenic. modern diagnostic tests such as pcr and beta-glucan have never been validated in an icu population. due mostly to major delays in the diagnosis, mortality exceeds %. although our therapeutic armamentarium against invasive aspergillosis has improved in recent years, data concerning safety and efficacy of new antifungal agents in the icu setting are lacking. autopsy studies show the emergence of aspergillus as a major pathogen, as well as the expansion of the spectrum of patients at risk for ia. in a non-selected patient population, the prevalence of invasive fungal infections in an academic hospital rose from . to . % over a -year period, largely due to an increase in aspergillus infections [ ] . however, estimates about the incidence of ia in critically ill patients are sparse and variable. for various reasons, figures about the true incidence are difficult to generate. first, in case of a positive culture for aspergillus species, discriminating between colonisation and infection remains challenging. second, very few institutions perform post-mortem examinations routinely, while in most cases, this is the only way for proving the definite nature of the diagnosis. third, characteristic radiological signs of ia are usually absent in the non-neutropenic icu patient. finally, to date, the diagnostic utility of recently available non-culture based microbiological tools, including the detection of fungal antigens and the detection of aspergillus-specific dna through polymerase chain reaction (pcr) techniques, has not been properly validated in the non-haematology icu population. in addition, typical icu patients such as those with chronic obstructive pulmonary disease (copd) or liver disorders were not considered amongst hosts at high risk for ia in the recently updated eortc/msg guidelines [ ] . a summary of available studies in icu patients is listed in table [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in a medical icu, we have observed high incidences of ia in two separate retrospective autopsy-controlled studies. in the largest one, of ( . %) hospitalised patients had microbiological or histopathological evidence of aspergillosis during their icu stay, including cases ( %) without underlying haematological malignancy. the observed mortality of % was much higher than the predicted mortality as per saps ii score ( %) [ ] . an earlier study looked for unsuspected causes of death in the same medical icu and showed that, out of autopsies, there were cases of ia, of which were missed pre-mortem [ ] . during a -year period, cornillet et al. found a mean number of patients per year diagnosed with ia; approximately half of them were in the icu [ ] . these inter-centre differences can be explained by differences in underlying patient characteristics, case mix and different autopsy policies. in a recent study published by our group [ ] , patients with fever new lung infiltrates were screened for ia using galactomannan testing in bronchoalveolar (bal) fluid. from a total of , patients admitted to the icu, patients fulfilled the entrance criteria and were evaluated. most patients had non-haematological diseases ( %), including liver cirrhosis ( %), copd ( %) and other systemic conditions ( %). the incidence of proven ia in this population was surprisingly high at . %, which might have been associated with the high frequency of autopsy ( % of fatalities), as well as the use of a sensitive diagnostic tool (more comments about galactomannan testing are presented below). as this was a single-centre study, the presence of an outbreak is also a possibility. who is at risk for developing ia in the icu? over the past two decades, ia has emerged as a life threatening fungal infection in patients with haematological diseases. although many of these infected patients will eventually be admitted to the icu for advanced supportive care, it seems that ia has also gained a foothold in less severely compromised icu patients [ ] . so, can a threshold of immunosuppression needed for the development of ia be defined? we grouped the risk factors for ia in the icu are into categories (high, intermediate, low) ( table ) . various factors adversely affect the defence systems of previously healthy individuals, including the prolonged use of antibiotics, the use of central venous catheters and/or mechanical ventilation. although these factors are present in most icu patients, many of them do not develop ia. one of the intriguing hypotheses for immunosuppression in the apparently immunocompetent patient with multiple organ dysfunctions is related to the biphasic response to sepsis. the initial hyperinflammatory phase is followed by relative immunoparalysis [ ] . this latter process is characterized by neutrophil deactivation and may put the patient at risk for developing opportunistic infections such as ia. further epidemiological study is warranted to better delineate this phase of immunoparalysis. more detail on the interactions between aspergillus and the immune system are presented in the chapter by dr romani. patients in the icu (medical and surgical) are often treated with steroids. recent work concluded that the mortality is reduced if septic shock patients with adrenal dysfunction receive hydrocortisone for a -day period [ ] . in vitro, however, pharmacological concentrations of hydrocortisone accelerate the growth of aspergillus spp. [ ] . clearly, high steroid intake diminishes both lines of cellular defence against ia (macrophages and neutrophils). palmer reported that the threshold steroid level varies according to the type of patients and emphasized that underlying lung disease is a risk factor for ia even at low doses [ ] . further study is needed to investigate whether the day course of hydrocortisone at -mg/day in patients with septic shock puts them at risk for ia, knowing that recognition of fungal infection may be delayed, since the anti-inflammatory properties of steroids blunt the signs of infection. two at-risk groups not included in the eortc/msg definitions stand out for ia, copd and cirrhosis patients. patients with copd are an increasingly recognized group of patients at risk for developing ia and in some institutions outnumber cases in "classic" patients. bulpa et al. analyzed a group of copd patients with proven or probable ia requiring icu admission. all patients were on steroid treatment. the outcome was invariably poor [ ] . this is in accordance with the report of rello et al., who describes another copd patients with ia and universally fatal outcome [ ] . guinea et al. from madrid recently presented results from a large series of ia cases in association with copd (n = ) [ ] . steroids were identified as a risk factor in % of patients, with % of patients having received total doses of > mg. most cases of ia in copd patients had only lung involvement, but patients also had probable brain involvement. data from the same group also revealed that copd became the leading underlying disease associated with ia ( . % of cases), far more frequent than classical conditions such as haematological malignancies ( . %) [ ] . hepatic failure is generally not recognized as a risk factor for ia. a literature review revealed that of previously reported cases of ia in seemingly immunocompetent hosts were associated with liver disease [ ] . our study revealed fatal cases of ia [ ] . patients with cirrhosis have depressed phagocytosis, which may increase their risk for severe infections. it is expected that new risk categories of ia will come up as new immunosuppressive agents are made available such as alemtuzumab and etanercept (tnf-α blocker) [ ] . there are numerous sources of aspergillus species for patients in the icu [ , ] . it is believed that the primary ecological niche is decomposing material. however, aerosolised spores may become a potential source of infection through improperly cleaned ventilation systems, water systems or even computer consoles. the use of high efficiency particulate air (hepa) filtration reduces the risk of ia but does not reduce it to zero, probably partly because patients may be colonised before admission to the icu, partly because of breaks in airflow. pittet described two patients who developed fatal ia in the icu. in retrospect, high concentrations of airborne aspergillus spores could be found, closely related to air filter change in the icu [ ] . besides the airborne route, contaminated water has been implicated as a source of infection [ ] . a study of ventilators as a source of infection has not been undertaken. of note, the development of ia is depends on an interplay between the inoculating dose, the ability of the host to resist infection (which also depends on the lung architecture) and the virulence of the infecting organism. the concept that increasing fungal burden due to specific icu treatments for other diseases than ia (e.g. steroids for septic shock) parallels the progression from subclinical to clinical aspergillosis, needs to be explored with more sensitive markers (e.g. pcr). pcr in respiratory secretions as a modality for surveillance is an interesting topic for research. generally speaking, there are types of pulmonary interactions between aspergillus species and humans. the most frequent interaction is colonisation of the airways. this can be present in patients with defective mucociliary clearance and structural changes in the bronchial wall. these changes are present in almost every mechanically ventilated patient, making them particularly susceptible to colonisation. ia will not develop in these patients unless a critical level of immunodeficiency has been reached. the second type of interaction is allergic in nature and is beyond the scope of this review (these are discussed in other chapter in this book). the most relevant form of interaction for icu physicians is the invasive disease that develops in persons with impaired immunity. the aggressive angioinvasive form is frequently encountered in neutropenic patients, whereas cavitating infiltrates are observed most frequently in patients on steroids, patients with copd, cirrhosis, and solid organ transplant recipients. other more rare presentations include endocarditis, wound infections, mediastinitis (post-cardiac surgery), infection of vascular grafts, and osteomyelitis. these are occasionally a problem in immunocompromised patients and may occur as outbreaks. infection of the central nervous system is frequently an ominous sign and may arise from haematogenous seeding (in which the lung is the most common primary site) or spread from the sinuses or following neurosurgery. the pathogenesis of ia in steroid-immunosuppressed patients differs greatly from that in neutropenic patients. data demonstrate that the pathological lesions are often widespread and that death is related to a high fungal burden in neutropenic animals, while the pathogenesis in non-neutropenic, steroid-treated animals is driven by an adverse inflammatory host response, frequently confined to the lungs, with a low fungal burden in the lung parenchyma and other organs [ , ] . the reader is referred to the chapter by drs ben-ami and kontoyiannis for more detail on the pathogenesis of ia. clinical signs are usually non-specific and do not necessarily differ from other causes of nosocomial pneumonia. in addition, critically ill patients with prolonged stays in the icu often develop pulmonary infiltrates, atelectasis and/or acute respiratory distress syndrome (ards), whereas patients with prior lung disease (e.g. copd) may present with pre-existing cavities on conventional chest radiographs (fig. ) . fig. chest x-ray from a copd patient on steroids, admitted to the icu because of an exacerbation with respiratory failure. patchy, hazy infiltrates with predominantly a peripheral localisation and a right sided pleural effusion were seen. bal culture was positive for haemophilus influenzae and negative for fungi. serum galactomannan was negative but showed a value of . ng/ml in the bal fluid. despite treatment with caspofungin (patient was in renal failure), he died and autopsy showed invasive aspergillosis, confined to the lungs making a timely diagnosis of ia in the icu population is probably even more challenging than establishing an early diagnosis in patients with haematological disease, basically because the index of suspicion is lower since most patients do not belong to one of the well-established risk groups. moreover, the diagnostic tools were mainly developed in haematological patients. in general, the diagnosis is based on a combination of compatible clinical findings, radiological abnormalities, and microbiological confirmation or on the histological proof of tissue invasion by the fungus. table gives an overview of the available diagnostic tools. over the past few years, lung computed tomography (ct) scan has become one of the most important tools for the diagnosis of ia [ ] . virtually diagnostic signs for angioinvasive pulmonary mycosis -not only due to aspergillosis but occasionally also due to zygomycosis as well as other vascular conditions -include single or multiple small nodules with a "halo" sign. it should be recognized that the utility of this sign has been evaluated almost exclusively in neutropenic patients. in other groups, including icu patients, similar ct-findings are frequently absent and, if present, are far less specific [ ] . many icu patients have non-specific interfering radiological abnormalities due to atelectasis, or ards (figs. , , and ) . a positive respiratory specimen by culture or by direct microscopic examination is present in only half of the patients with ia. the predictive value of a positive culture depends largely on the immunocompromised status of the patient and ranges from to %. given the ubiquitous nature of aspergillus spores, differentiating colonisation from infection remains problematic. two studies have examined the significance of isolation of aspergillus spp. in icu patients and confirmed the poor positive predictive values [ , ] . therefore, surveillance cultures in the icu will add little to the diagnosis of ia. serological techniques based on the detection of circulating fungal cell wall components such as galactomannan (gm) or β-d-glucan and detection of circulating fungal dna by pcr techniques hold promise in patients with haematological malignancy but limited data exist with the use of these tests in diagnosis of ia in the icu [ ] . although very useful in the haematological patient [ ] , serum gm is not a sensitive marker for ia in the non-neutropenic individual, as demonstrated in lung and liver transplant recipients [ , ] . viable fungi could endure in the lung tissue (with encapsulation by an inflammatory process), while circulating markers remain undetectable because of clearance by circulating neutrophils. bal fluid could be a better specimen for gm detection as recently was demonstrated in a prospective study performed in a medical icu in a tertiary referral hospital [ ] . this is reinforced by the data with the solid organ transplant population [ ] [ ] [ ] . on the other hand, gm testing in bal fluid samples seems very promising for the diagnosis of ia in non-neutropenic patients [ , ] . results from a single icu showed that test sensitivity and specificity were and %, respectively using a cut-off of . for bal testing. in contrast, the sensitivity of serum gm was % only. a bit of caution, however, is required with this, since the best cut-off for gm testing in bal [ ] . accordingly, many studies have shown that testing gm in bal fluid samples result in higher optical densities than testing sera [ , ] . in a study with non-immunocompromised patients, all cases of ia were associated with gm optical densities of ≥ . in the bal [ ] . a higher cut-off value for bal has also been suggested by other authors, in comparison to sera [ , ] . false-positive results have been observed when bal is tested for gm in patients colonised with aspergillus species, particularly lung transplant recipients [ ] (dr. pasqualotto, unpublished data). although attractive, other modern diagnostic tests have not been systematically evaluated for the diagnosis of ia in icu patients. the use of β-d-glucan detection in icu is hampered by false-positive readings (use of albumin, wound gauze, hemodialysis and bacterial infections) [ ] . galactomannan gives less falsepositive results, although the presence of β-lactam antibiotics such as piperacillintazobactam may pose also a problem [ ] . the impact of piperacillin-tazobactam is probably reduced if gm is tested in the bal fluid instead of sera, since the epithelial fig. chest x-ray and ct scan from a patient on high dose steroids because of graft-versus-host disease months after haematological stem cell transplantation for acute myeloid leukaemia. chest x-ray reveals a right-sided pleural effusion and adjacent lung infiltrate. ct scan confirms a right sided complicated parapneumonic effusion, a mass filled partially with air between the th and th rib (with partial destruction of the bone) and a wedge-shaped infiltrate on the left side. in the culture specimen of the pleural fluid grew aspergillus fumigatus. findings are compatible with a bronchopleural fistula, secondary to rupture of a cavitating infiltrate and adjacent bone destruction fig. chest x-ray and ct scan months post kidney transplantion for end stage diabetes. bilateral lower lobe cavities with adjacent pleural effusion on the right side are seen. transbronchial biopsy revealed aspergillus fumigatus. serum and bal galactomannan was . and . ng/ml, respectively. despite antifungal treatment, patient died of proven aspergillus endocarditis of the tricuspid valve lining fluid concentration of piperacillin is about half of the serum steady state concentrations [ ] . thus far, no prospective data on pcr detection are available in icu patients, and the usefulness of combining different diagnostic test in these patients is also unknown. antifungals for the treatment of ia in the icu treatment options for ia are reviewed in the chapter by dr marr. in summary, amphotericin b deoxycholate was the mainstay for the treatment of ia for a long time. however, this formulation is infamous for the occurrence of serious side effects (e.g., nephrotoxicity, hypokalemia, and infusion-related reactions). these events often result in the use of suboptimal dosing regimens. recently voriconazole, a derivative of fluconazole, has become the new standard of care for treating ia [ ] . caspofungin, micafungin, and anidulafungin belong to a new class of antifungal drugs, the echinocandins, which act by inhibiting the synthesis of ß-( , )-d-glucan in the fungal cell wall. echinocandins display activity against aspergillus species, as demonstrated in several salvage studies, but convincing first-line data are still lacking. however, most patients recruited in these first-and second-line treatment studies suffered from an underlying haematological disorder or were transplant recipients. patients with baseline characteristics that are commonly seen in icu patients have usually been excluded from these studies, including those with liver function abnormalities, coagulation disorders, or renal dysfunction, and patients in need of advanced cardiovascular or pulmonary support including mechanical ventilation. therefore, data on antifungal treatment in the icu remain anecdotal. in addition, many aspects of antifungal therapy that are relevant to the icu population have not been sufficiently addressed in clinical studies, including the pharmacokinetic profile of antifungals in patients with underlying renal, hepatic and/or cardiac dysfunction; the dose-response relationship; and the best route of administration (oral, enteral, or parenteral). for instance, a recent study showed found nasogastric/gastric administration of voriconazole to be an independent predictor for undetectable voriconazole serum concentrations [ ] . other important questions that should be better addressed include the monitoring of drug-related toxicities, and especially drug interactions with frequently used "icu-drugs". in an era of increased availability of new immunosuppressive drugs and better intensive care with prolonged survival, we can expect a continuing rise in the incidence of ia. its occurrence in icu usually entails a poor prognosis despite major recent improvements in the diagnosis and treatment of ia in patients with haematological diseases. multicenter studies are warranted to explore the exact incidence of ia in the icu and to better delineate the difference between hospital-acquired, icu-acquired and community-acquired aspergillosis. evaluating the value of galactomannan, β-d-glucan and pcr in non-neutropenic critically ill patients in different sample types (and especially in respiratory samples) is urgently needed as well as a better delineation of the patient population at risk for ia in the broad group of critically ill patients. finally, antifungal pharmacokinetics and pharmacodynamics and interactions with other drugs need to be explored more thoroughly. meanwhile, all new diagnostic techniques and therapeutic measures must be validated against post-mortem findings, since only proven cases offer the most valuable information. trends in the postmortem epidemiology of invasive fungal infections at a university hospital revised definitions of invasive fungal disease from the european organization for research and treatment of cancer/invasive fungal infections cooperative group and the comparison of premortem clinical diagnoses in critically iii patients and subsequent autopsy findings invasive aspergillosis in critically ill patients without malignancy post mortem examination in the intensive care unit: still useful? duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock clinical relevance of aspergillus isolation from respiratory tract samples in critically ill patients a -year study of severe hospital-acquired pneumonia requiring icu admission comparison of epidemiological, clinical, and biological features of invasive aspergillosis in neutropenic and nonneutropenic patients: a -year survey galactomannan in bronchoalveolar lavage fluid: a tool for diagnosing aspergillosis in intensive care unit patients immunoparalysis as a cause for invasive aspergillosis? effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock glucocorticoids and invasive fungal infections corticosteroid treatment as a risk factor for invasive aspergillosis in patients with lung disease chronic obstructive pulmonary disease patients with invasive pulmonary aspergillosis: benefits of intensive care? invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease: report of eight cases and review invasive pulmonary aspergillosis (ipa) in patients with copd: a description of th interscience conference on antimicrobial agents and chemotherapy chronic obstructive pulmonary disease (copd) is currently the most common predisposing condition to invasive aspergillosis invasive aspergillosis in a "healthy" patient infectious complications associated with alemtuzumab use for lymphoproliferative disorders aspergillus wound infection following laparostomy post-operative aspergillosis unusual cause of lethal pulmonary aspergillosis in patients with chronic obstructive pulmonary disease nosocomial aspergillosis is waterborne differences in patterns of infection and inflammation for corticosteroid treatment and chemotherapy in experimental invasive pulmonary aspergillosis invasive fungal infections in patients with hematologic malignancies in a tertiary care cancer center: an autopsy study over a -year period imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign isolation of aspergillus spp. from the respiratory tract in critically ill patients: risk factors, clinical presentation and outcome diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis prospective assessment of platelia aspergillus galactomannan antigen for the diagnosis of invasive aspergillosis in lung transplant recipients efficacy of galactomannan antigen in the platelia aspergillus enzyme immunoassay for diagnosis of invasive aspergillosis in liver transplant recipients bronchoalveolar lavage galactomannan in diagnosis of invasive pulmonary aspergillosis among solid-organ transplant recipients performance characteristics of the platelia aspergillus enzyme immunoassay for detection of aspergillus galactomannan antigen in bronchoalveolar lavage fluid use of bronchoalveolar lavage to detect galactomannan for diagnosis of pulmonary aspergillosis among nonimmunocompromised hosts a bad bug takes on a new role as a cause of ventilator-associated pneumonia pathogenesis of aspergillus fumigatus and the kinetics of galactomannan in an in vitro model of early invasive pulmonary aspergillosis: implications for antifungal therapy aspergillus galactomannan testing in patients with long-term neutropenia: implications for clinical management serum glucan levels are not specific for presence of fungal infections in intensive care unit patients false positive test for aspergillus antigenemia related to concomitant administration of piperacillin and tazobactam steady-state plasma and intrapulmonary concentrations of piperacillin/tazobactam g/ . g administered to critically ill patients with severe nosocomial pneumonia voriconazole versus amphotericin b for primary therapy of invasive aspergillosis clinical risk factors for undetectable voriconazole (v) serum concentrations voriconazole level,risk factors improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery the impact of culture isolation of aspergillus species: a hospital-based survey of aspergillosis workload due to aspergillus fumigatus and significance of the organism in the microbiology laboratory of a general hospital a systematic literature review on the diagnosis of invasive aspergillosis using polymerase chain reaction (pcr) from bronchoalveolar lavage clinical samples key: cord- -zpf xjqi authors: walter, james m. title: thrombocytopenia in the intensive care unit date: - - journal: evidence-based critical care doi: . / - - - - _ sha: doc_id: cord_uid: zpf xjqi the evaluation and management of thrombocytopenia is a daily challenge for clinicians in the intensive care unit (icu). thrombocytopenia is incredibly common, present in upwards of % of icu patients. additionally, thrombocytopenia in the critically ill is rarely caused by a single etiology. several causes of thrombocytopenia in the icu including heparin-induced thrombocytopenia (hit) and thrombotic thrombocytopenic purpura demand urgent recognition and intervention. this chapter provides a general overview of thrombocytopenia in the icu and highlights important diagnostic and management considerations for some of the most common etiologies. point during their icu stay [ , , , ] . in general, icu patients who develop thrombocytopenia are sicker than patients with normal platelet counts, with higher illness severity scores, more need for vasoactive infusions, and more organ dysfunction [ , ] . the presence of thrombocytopenia in the critically ill has consistently been associated with poor outcomes. in a multicenter review of over critically ill patients, patients with severe thrombocytopenia (defined as a platelet count < × cells/l) had an adjusted hazard ratio for hospital mortality of . ( % ci, . - . ) compared to patients with normal platelet counts [ ] . the association between thrombocytopenia and mortality has been identified in multiple studies [ , , , ] . regardless of the absolute value, a fall in platelet count by > % from a patient's admission level identifies patients who may be up to times more likely to die during their hospital stay [ , ] . patients whose platelet count fails to recover during their icu course represent a particularly high risk group [ , ] . the presence and severity of thrombocytopenia is included in several validated severity scores including the multiple organ dysfunction score and the sepsis-related organ failure assessment [ , ] . the evaluation of thrombocytopenia in the icu is challenging as thrombocytopenia is both a common problem and rarely due to a single etiology. in a study of over icu patients with either absolute (platelet count < × cells/l) or relative (decrease in platelet count > %) thrombocytopenia who underwent extensive evaluation including bone marrow aspiration, % had or more identifiable etiologies for their thrombocytopenia [ ] . as such, a structured approach to the evaluation and management of thrombocytopenia is essential. a comprehensive review of the myriad causes of thrombocytopenia is beyond the scope of this review. what follows is a simplified approach to the critically ill patient with newonset thrombocytopenia (fig. . ). step : confirm true thrombocytopenia pseudothrombocytopenia occasionally, a low reported platelet count does not represent true thrombocytopenia. exposure to ethylenediaminetetraacetic acid (edta) in blood collection tubes induces a conformational change in the platelet surface protein glycoprotein iib/iiia [ ] . patients may develop igm autoantibodies to these newly exposed giib/iiia epitopes which causes in vitro platelet clumping. large platelet aggregates are not recognized by automated counters, leading to a falsely low reported platelet count. the identification of platelet clumps on a peripheral blood smear and re-drawing blood using heparin or citrate containing collection tubes can help confirm the diagnosis. step : is the patient bleeding? there is a consensus that patients with clinically significant bleeding should be transfused to a platelet count of > × • if platelet clumps seen on smear, repeat blood draw in non-edta collection tube • platelet goal > x cells/l in non-cns bleeding [ , , ] the transfusion threshold should be increased to × cells/l in patients with intracranial bleeding [ ] . thrombotic microangiopathy (tma) is a pathologic term used to describe microvascular thrombosis in the arterioles and capillaries [ ] . the key clinical manifestations of tmas are microangiopathic hemolytic anemia (maha) and thrombocytopenia. tmas are a diverse group of disorders that can be classified broadly as primary (thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, drug-mediated, etc.) or secondary to a systemic disorder (disseminated intravascular coagulation, severe hypertension, hemolysis with elevated liver enzymes and low platelets during pregnancy, etc.) [ ] . while diseases like thrombotic thrombocytopenic purpura (ttp) are uncommon, their prompt recognition is critical as delayed or missed diagnosis can lead to significant patient harm. ttp and disseminated intravascular coagulation (dic) will be reviewed here as examples of primary and secondary tmas respectively. ttp is characterized by a functional deficiency in a vwf cleaving protein termed, "an acronym for a disintegrin and metalloprotease with thrombospondin- -like-domains" (adamts ) [ ] . with a functional deficiency of adamts , large vwf multimers accumulate, triggering platelet adhesion, activation, and the formation of platelet rich microthrombi [ ] . ttp is a rare disease with an incidence of cases per million in the united states [ ] . roughly % of cases of ttp are acquired, caused by the production of igg autoantibodies against adamts [ ] . antibody production can be idiopathic (≅ % of cases) or driven by a variety of conditions including malignancy, human immunodeficiency virus infection, pregnancy, autoimmune disease, medications, and following organ transplantation [ ] . ttp has historically been associated with a clinical pentad of maha, thrombocytopenia, neurologic symptoms, renal impairment, and fever. in the modern era, this constellation of symptoms is rarely seen [ ] . while maha and thrombocytopenia are universally present, upwards of % of patients will be afebrile and % will have either normal mental status or renal function [ ] . presenting symptoms are often non-specific and include nausea and abdominal pain [ ] . initial laboratory testing in patients with suspected ttp should confirm the presence of hemolysis (e.g., an elevated lactate dehydrogenase level, low haptoglobin, elevated indirect bilirubin, and elevated reticulocyte index). in contrast to dic, coagulation parameters are typically normal. a peripheral blood smear should be reviewed to identify fragmented red blood cells called schistocytes -one of the histologic hallmarks of tma ( fig. . ) . renal and cardiac biomarkers should be obtained to screen for organ dysfunction. the role of adamts assays is debated [ , ] . a severely low level (< %) confirms the diagnosis of ttp. however, it is imperative that the decision to initiate therapy is made urgently on the basis of an initial clinical and laboratory evaluation without waiting for adamts activity levels to result [ ] . ttp was previously viewed as an almost universally fatal diagnosis. however, with the rapid initiation of plasma exchange, survival rates now approach % [ , ] . plasma exchange should be continued until platelet counts are > × cells/l for days [ ] . steroids and rituximab may have a role in the treatment of refractory and recurrent disease [ ] . dic is defined by the international society on thrombosis and haemostasis (isth) as "an acquired syndrome characterized by the intravascular activation of coagulation with a loss of localization arising from different causes. it can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction." [ ] the pathobiology of dic is complex and is driven by dysregulated coagulation and fibrinolysis pathways. a central component of dic is excessive tissue factor (tf) expression and thrombin generation. depending on the clinical scenario, this can be caused by the release of inflammatory cytokines including il- and il- , increased tf expression on mononuclear cells, injury to vascular endothelial cells, and exposure to pro-coagulant molecules (e.g. amniotic fluid) [ ] . activated platelets contribute to excessive thrombin generation and the formation of microvascular clots. concurrently, fragmented red blood cells (schistocytes) are identified by * the major anticoagulant systems (antithrombin, the protein c system, and tf pathway inhibitor) are dampened due to impaired synthesis and increased degradation of the relevant factors [ ] . finally, intrinsic fibrinolysis is impaired in part due to elevated levels of plasminogen activator inhibitor . the propagation of microvascular thrombi leads to organ ischemia and dysfunction-one of the clinical hallmarks of dic. [ ] by far, the most common underlying cause of dic is sepsis. depending on the patient population and definition used, - % of patients with sepsis develop dic [ , , ] . in cases series, sepsis is identified as a risk factor for dic in over % of patients [ ] . other important causes of dic include trauma, obstetric emergencies, malignancies, and liver failure among many others [ ] . dic is consistently identified as a risk factor for increased mortality both in patients with sepsis and in critically ill patients more broadly [ , , ] . the diagnosis of dic should be suspected in any critically ill patient with thrombocytopenia, abnormal coagulation parameters (e.g., a prolonged prothrombin and partial thromboplastin times), maha, and laboratory evidence of fibrinolysis (e.g., an elevated d-dimer and reduced fibrinogen) [ ] . while catastrophic hemorrhage is uncommon, most patients have evidence of bleeding, often at sites of intravenous access [ ] . diagnostic criteria developed by the isth are available to aid diagnosis (table . ) [ ] . in a prospective validation study, a score > had a sensitivity of % and specificity of % for the diagnosis of dic [ ] . a score should be calculated daily both to accurately confirm the diagnosis and to aid prognostication [ ] . the foundation of dic management is treatment of the underlying disorder. there is limited data to guide the administration of blood products in dic. in general, guidelines agree that platelets, fresh-frozen plasma, and a source of fibrinogen should be given to patients who are actively bleeding or those undergoing invasive procedures [ ] . a platelet count > × cells/l, prothrombin (pt) and partial thromboplastin time (aptt) < . times normal, and a fibrinogen level > . g/l are typical targets [ ] . recommendations for the use of heparin vary across guidelines [ ] . in general, heparin is reserved for patients with clinical evidence of thrombosis. a host of targeted interventions aimed at augmenting the major anticoagulant pathways have failed to show benefit in large randomized trials including recombinant tf pathway inhibitors and anti-thrombin iii [ , ] . early studies of activated protein c (apc) in patients with sepsis showed promise, especially in the subset of patients with dic [ , ] . however, the recent prowess-shock trial, which included over patients with septic shock, did not identify any benefit to the use of apc [ ] . a careful review of a patient's medication list is an essential step in the evaluation of thrombocytopenia in the icu. indeed, medications may contribute to over % of new onset thrombocytopenia in the critically ill [ ] . well over drugs have been linked to the development of thrombocytopenia [ ] . a list of notable drugs known to cause thrombocytopenia is provided in table . . drug-induced thrombocytopenia can be grouped into two major categories: drug-induced non-immune adapted from toh [ ] . a score of > is compatible with dic, scoring should be repeated daily. a score < is suggestive of non-overt dic, scoring should be repeated in the next - days data adapted from mitta [ ] , reese [ ] , and the university of oklahoma web resource https://ouhsc.edu/platelets/ditp.html thrombocytopenia and drug-induced immune thrombocytopenia [ ] . drug-induced non-immune thrombocytopenia is far more common and is characterized by dose-dependent suppression of bone marrow platelet production. representative medications include linezolid, chemotherapeutics, and immunosuppressive agents like azathioprine [ ] . drug-induced immune thrombocytopenia occurs through a variety of mechanisms. rarely, medications may induce autoantibodies that destroy host platelets in the absence of the drug. examples include gold salts and procainamide [ ] . more commonly, a drug will induce the production of antibodies that bind to an epitope on a platelet glycoprotein in the presence of the medication. many antibiotics including aztreonam, piperacillin, sulfonamides, and vancomycin likely act through this mechanism [ ] . heparin-induced thrombocytopenia (hit) is a particularly important example and is reviewed in detail below. finally, antiplatelet agents such as eptifibatide used in the treatment of acute coronary syndrome facilitate antibody-mediated destruction of platelets through their binding of glycoprotein iib/iiia [ ] . drug-induced immune-mediated thrombocytopenia typically occurs - days after exposure to the causative medication. thrombocytopenia is often severe with platelet counts falling to < x cells/l. mucocutaneous bleeding and systemic symptoms may be present [ ] . the diagnosis requires a high index of suspicion given the lag between when a drug is started and the subsequent fall in platelet count. identifying drug-dependent platelet reactive antibodies helps confirm the diagnosis; however, testing is time consuming and available at a limited number of centers. treatment is focused on the identification and removal of the causative medication. when the offending drug is removed, platelets typically begin to improve in - days. the role of steroids and intravenous immunoglobulin in the treatment of refractory drug-induced immune thrombocytopenia is controversial [ ] . a helpful website, https://ouhsc.edu/platelets/ditp.html, includes a curated list of all drugs associated with drugdependent platelet-reactive antibodies identified by the bloodcenter of wisconsin dating back to . hit is caused by the production of host igg antibodies against platelet factor (pf )-heparin complexes. the fc domain of these immune complexes binds to the platelet fcγ riia receptor causing platelet aggregation, platelet activation, and eventual thrombin formation [ ] . thrombocytopenia is caused by intravascular platelet consumption. while a diagnosis of hit is frequently considered for thrombocytopenic patients in the icu, it is relatively uncommon. for patients in the medical icu, the incidence may be as low as . % [ ] . the biggest risk factors for hit include the use of unfractionated heparin and cardiac surgery. in these settings, the incidence increases up to % [ ] . hit is unique among the common causes of thrombocytopenia in the critically ill in that it is characterized by thrombosis rather than bleeding. over % of patients with hit develop thrombosis, most commonly in the deep veins of the extremities and pulmonary arteries [ , ] . hit can also cause arterial thrombosis, thrombosis in unusual venous structures (e.g. mesenteric vessels), and myocardial infarction [ ] . hit should be suspected when platelet counts fall by at least % - days after the initiation of heparin therapy [ ] . an important caveat to this pattern is patients who have been previously exposed to heparin. host igg against pf heparin complexes can remain active for up to days. during this window, heparin re-exposure can produce a rapid drop in platelet count within hours [ ] . up to % of cases of hit may present in this manner [ ] . thrombocytopenia in hit is generally less severe than other causes of thrombocytopenia in the icu with levels rarely falling below × cells/l. [ ] up to % of patients exposed to heparin produce igg antibodies against pf -heparin complexes while only a small minority develop hit [ ] . given the costs associated with laboratory testing for hit and the potential risk of transitioning to a non-heparin anticoagulant agent, the diagnosis of hit should only be pursued in patients with an intermediate to high pre-test probability of having the disease [ ] . the most widely used pre-test probability assessment tool for hit is the ts score (table . ) [ ] . a score < is associated with a negative predictive value for hit of > % and obviates the need for further testing [ ] . patients with a score ≥ should undergo step-wise serologic testing. the initial serologic test for patients with an intermediate to high pre-test probability of hit is an enzyme-linked immunoassay (elisa) to detect hit antibodies. these assays are widely available and result in a matter of hours. igg-specific elisas have a sensitivity of % and specificity of % for the diagnosis of hit [ ] . results are typically reported quantitatively as an optical density (od). the higher the od threshold used to identify a positive test, the more likely a positive elisa will predict a positive functional assay. the commonly used od cutoff of . has a sensitivity of > % for hit [ ] . patients with a positive elisa should undergo confirmatory testing with a functional assay -typically a serotonin release assay (sra). a sra evaluates for in vitro activation of platelets in the presence of patient serum and heparin. a positive sra has a specificity of nearly % for the diagnosis of hit [ ] . the cornerstone of management for patients with either an intermediate to high pre-test probability of hit or a confirmed diagnosis is transition to a non-heparin anticoagulant. options include direct thrombin inhibitors (e.g., lepirudin, argatroban, and bivalrudin) and factor xa inhibitors (e.g., danaparoid and fondaparinux) [ ] . there is currently insufficient evidence to support the use of direct oral anticoagulant agents in this setting [ ] . warfarin is contraindicated in patients with hit until the platelet counts rises above x cells/l as warfarin reduces protein c levels and may exacerbate thrombus formation [ ] . platelet transfusions should be avoided if possible and are only recommended for patients who are actively bleeding or those undergoing an invasive procedure associated with a high risk of bleeding [ ] . sepsis is one of the most common causes of thrombocytopenia in the icu and may contribute to a low platelet count in up to % of casas [ ] . the incidence of thrombocytopenia in patients with sepsis varies by illness severity. in a multicenter prospective evaluation of patients with severe sepsis, thrombocytopenia was present in . % of patients [ ] . in patients with septic shock, the incidence of thrombocytopenia approaches % [ , ] . thrombocytopenia has consistently been associated with increased mortality in septic patients [ , , ] . multiple mechanisms cause thrombocytopenia during sepsis. decreased bone marrow production, hemophagocytosis, platelet consumption in microvascular beds, sequestration, and hemodilution may all contribute to varying degrees [ ] . septic patients are at high risk for dic which can further lower platelet counts. additionally, many medications routinely administered to septic patients including antibiotics are associated with thrombocytopenia. based on very low-quality evidence, the surviving sepsis campaign recommends prophylactic platelet transfusions in septic patients with a platelet count < × cells/l and × cells/l for patients at high risk of bleeding. a platelet count > × cells/l is recommended for patients who are actively bleeding or undergoing invasive procedures [ ] . dilutional thrombocytopenia is a well-recognized complication of massive transfusion. the incidence of severe thrombocytopenia (defined as a platelet count < × cells/l) may be as high as % when patients require more than red blood cell containing products [ ] . prompt damage control and transfusion of blood products in a balanced ratio ( : : of red blood cells:plasma:platelets) are important preventative strategies [ ] . step : evaluate support devices support devices used in critically ill patients may lower platelet counts through mechanical shearing. veno-venous extracorporeal membrane oxygenation (vv-ecmo) is increasingly utilized in the management of severe acute respiratory distress syndrome (ards). in a retrospective study of patients placed on vv-ecmo for respiratory failure, % developed thrombocytopenia [ ] . severity of illness and the platelet count at the time of cannulation were the strongest predictors of developing thrombocytopenia. in a large randomized trial of ecmo for severe ards, % of patients randomized to ecmo developed adapted from lo [ ] . a score ≤ suggests a low pre-test probability for hit, a score - an intermediate probability, and a score > a high probability severe thrombocytopenia (defined as a platelet count < × cells/l) vs % in the control arm [ ] . for patients placed on an intra-aortic balloon pump, roughly % will develop thrombocytopenia [ , ] . despite the high incidence of thrombocytopenia in critically ill patients, there is a paucity of data to guide when prophylactic platelet transfusion is indicated. indeed, a recent systematic review did not identify a single high-quality study that investigated the impact of prophylactic platelet transfusions on bleeding rates in critically ill patients [ ] . recommendations on prophylactic platelet transfusions in critically ill patients are largely extrapolated from studies in patients with hematologic malignancies. in a landmark trial of platelet transfusion thresholds in patients with acute myeloid leukemia undergoing induction chemotherapy, a transfusion threshold of × cells/l did not increase the risk of major bleeding and reduced the need for platelet transfusions by . % compared to a threshold of × cells/l. [ ] a recent cochrane review supports the conclusion that a restrictive platelet transfusion threshold is safe in patients with hematologic malignancies [ ] . guidelines by the american society of clinical oncology recommend a prophylactic platelet transfusion threshold of × cells/l in patients with malignancy [ ] . it is unclear, however, if data from patients with malignancies can be reliably generalized to the heterogeneous group of patients cared for in the icu [ ] . some have advocated for an approach which reserves platelet transfusions for critically ill patients with clinical evidence of bleeding (regardless of the actual platelet count) [ ] . however, there is insufficient data to support the safety or efficacy of this practice. there is equally limited evidence to guide the platelet count needed to limit bleeding complications during bedside procedures commonly performed in the icu. the american association of blood banks recommends a platelet threshold of × cells/l for patients undergoing central line insertion and × cells/l for patients undergoing lumbar puncture although both are weak recommendations supported by low-quality evidence [ ] . a recent cochrane review of platelet thresholds for patients undergoing central line insertion was unable to draw any conclusions given the complete lack of data on the subject [ ] . there is mounting evidence that thoracentesis can be safely performed by an experienced operator in thrombocytopenic patients without prophylactic platelet transfusions [ ] . platelet biology and functions: new concepts and clinical perspectives beyond thrombosis: the versatile platelet in critical illness platelets and the immune continuum coagulopathy in critically ill patients: part : platelet disorders thrombocytopenic disorders in critically ill patients time course of platelet counts in critically ill patients thrombocytopenia in medical-surgical critically ill patients: prevalence, incidence, and risk factors thrombocytopenia in critically ill patients receiving thromboprophylaxis: frequency, risk factors, and outcomes the frequency and clinical significance of thrombocytopenia complicating critical illness: a systematic review thrombocytopenia in the intensive care unit thrombocytopenia in patients in the medical intensive care unit: bleeding prevalence, transfusion requirements, and outcome thrombocytopenia and prognosis in intensive care platelet count decline: an early prognostic marker in critically ill patients with prolonged icu stays blunted rise in platelet count in critically ill patients is associated with worse outcome the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome epidemiology and outcome of thrombocytopenic patients in the intensive care unit: results of a prospective multicenter study pseudothrombocytopenia due to platelet clumping: a case report and brief review of the literature bleeding and coagulopathies in critical care guidelines for the use of platelet transfusions evidence-based platelet transfusion guidelines consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies syndromes of thrombotic microangiopathy thrombotic thrombocytopenic purpura thrombotic thrombocytopenic purpura the incidence of thrombotic thrombocytopenic purpurahemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe adamts- deficiency epidemiology and pathophysiology of adulthood-onset thrombotic microangiopathy with severe adamts deficiency (thrombotic thrombocytopenic purpura): a cross-sectional analysis of the french national registry for thrombotic microangiopathy thrombotic thrombocytopenic purpura: diagnostic criteria, clinical features, and long-term outcomes from through guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. canadian apheresis study group towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation disseminated intravascular coagulation disseminated intravascular coagulation epidemiology of disseminated intravascular coagulation in sepsis and validation of scoring systems disseminated intravascular coagulation in sepsis trends in the incidence and outcomes of disseminated intravascular coagulation in critically ill patients ( - ): a population-based study the scoring system of the scientific and standardisation committee on disseminated intravascular coagulation of the international society on thrombosis and haemostasis: a -year overview thrombocytopenia in the icu: disseminated intravascular coagulation and thrombotic microangiopathies-what intensivists need to know prospective validation of the international society of thrombosis and haemostasis scoring system for disseminated intravascular coagulation what's new in the diagnostic criteria of disseminated intravascular coagulation? diagnosis and treatment of disseminated intravascular coagulation (dic) according to four dic guidelines efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial caring for the critically ill patient. high-dose antithrombin iii in severe sepsis: a randomized controlled trial efficacy and safety of recombinant human activated protein c for severe sepsis treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation drotrecogin alfa (activated) in adults with septic shock identifying drugs that cause acute thrombocytopenia: an analysis using distinct methods how i evaluate and treat thrombocytopenia in the intensive care unit patient drug-induced thrombocytopenia in critically ill patients drug-induced immune thrombocytopenia drug-induced thrombocytopenia: update of clinical and laboratory data heparin-induced thrombocytopenia heparininduced thrombocytopenia in the critically ill patient treatment and prevention of heparin-induced thrombocytopenia: antithrombotic therapy and prevention of thrombosis, th ed: american college of chest physicians evidence-based clinical practice guidelines temporal aspects of heparin-induced thrombocytopenia impact of the patient population on the risk for heparininduced thrombocytopenia argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial evaluation of pretest clinical score ( t's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings predictive value of the ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis evaluating thrombocytopenia during heparin therapy a prospective, observational registry of patients with severe sepsis: the canadian sepsis treatment and response registry thrombocytopenia is associated with a dysregulated host response in critically ill sepsis patients is thrombocytopenia an early prognostic marker in septic shock? sepsisassociated thrombocytopenia surviving sepsis campaign: international guidelines for management of sepsis and septic shock: complications of massive transfusion damage control resuscitation thrombocytopenia and extracorporeal membrane oxygenation in adults with acute respiratory failure: a cohort study extracorporeal membrane oxygenation for severe acute respiratory distress syndrome thrombocytopenia in patients treated with heparin, combination antiplatelet therapy, and intra-aortic balloon pump counterpulsation clinical implications of thrombocytopenia among patients undergoing intra-aortic balloon pump counterpulsation in the coronary care unit platelet transfusions for critically ill patients with thrombocytopenia the threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia gruppo italiano malattie ematologiche maligne dell'adulto comparison of different platelet count thresholds to guide administration of prophylactic platelet transfusion for preventing bleeding in people with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation platelet transfusion for patients with cancer: american society of clinical oncology clinical practice guideline update fresh frozen plasma and platelet transfusion for nonbleeding patients in the intensive care unit: benefit or harm? platelet transfusion: a clinical practice guideline from the aabb comparison of different platelet transfusion thresholds prior to insertion of central lines in patients with thrombocytopenia complications of thoracentesis: incidence, risk factors, and strategies for prevention key: cord- -sizuef v authors: nan title: ectes abstracts date: - - journal: eur j trauma emerg surg doi: . /s - - -y sha: doc_id: cord_uid: sizuef v nan the gertality-score: a feasible and adequate tool to predict mortality in geriatric trauma patients introduction: a large number of prediction models and subsequent outcome scores for trauma mortality have been developed over the last decades. however, feasible scoring systems for the severely injured geriatric patient are lacking. the aim of this study was to develop a new mortality prediction model for severily injured geriatric patients. materials and methods: the german trauma registry was utilized and all geriatric individuals (c years) admitted between and with an iss [ ] c were included. patient and trauma characteristics, diagnostics, therapy and outcome data were gathered. the specific odds of all variables for mortality were calculated. relevant variables were added to the novel gertality-scoring system. subsequently, this score as a sole predictor for mortality was compared with the geriatric trauma outcome score , iss, patient's age and max ais. results: a total of . trauma patients with a mean age of years were included. based on the univariable analysis, the following five variables were included in the gertality-score: age c years, pbrc-transfusion requirements from admission to ward, asa-score c , gcs b , ais c . the values of a given parameter are added to reach the total gertality-score (range - points). the auc found in the novel gertality-score was . , whereas the geriatric trauma outcome score had an auc of . . conclusions: the novel gertality-score is a simple and feasible scoring system that enables an adequate prediction of the probability of mortality in severely injured geriatric patients by using only five specific parameters. references: . champion hr, et al. the major trauma outcome study: establishing national norms for trauma care. j trauma. ; : - . . zhao fz, et al. estimating geriatric mortality after injury using age, injury severity, and performance of a transfusion: the geriatric trauma outcome score. j palliat med. ; ( ) : - . the longer the better! 'extending thawed plasma shelf life to days' introduction: major bleeding is one of the most common causes of death after severe polytrauma. one of the most recent interventions that aims for bleeding control is resuscitative balloon occlusion of the aorta (reboa). this study aims to compare macro-and microcirculatory changes of intraabdominal organs and the lower extremity during the use of reboa. materials and methods: six pigs were anesthesized and received a median laparotomy. the reboa catheter (reliant balloon, medtronic) was inserted via the inguinal artery and occluded in zones , and . the occlusion of the reboa was vizualized with fluoroscopy. the balloon was inflated for min per zone. during this time the local microcirculation was measured with oxygen to see (o c, lea). between each zone the balloon was deflated for min. blood pressure was measured at the carotis artery and the femoral artery. results: baseline values of microcirculation differ significantly among organs. the flow rate is significantly higher in intraabdominal organs (colon . a.u., stomach . a.u.) compared to the extremity ( . a.u., p \ . ). blood pressure measured at the carotic artery increased significantly after inflation of the balloon (p \ . ). this increase depends on the zone of inflation (increase of ? mmhg in zone compared to baseline). the increase of blood pressure after inflation in zone is comparable to the baseline value. the colon is most sensitive to changes of microcirculation whereas the stomach and the extremity are most robust. conclusions: reboa is a new device to control for massive bleeding. different organ systems react differently to the same occlusion of the aorta. the systemic blood pressure does not mirror the local microcirculation of the abdominal organs. during emergency resuscitation with reboa these changes should be kept in mind. none of the authors have any conflicts of interests to declare. investigation of coagulopathies and its relevance with mortality and transfusion rates using thromboelastography in trauma patients introduction: fibrinolysis shutdown after injury is a common and lethal coagulopathic phenotype. patients with polytrauma, especially those with brain hemorrhage, require delayed initiation of prophylactic or therapeutic anticoagulation despite a measurable hypercoagulable state. to understand and modulate the post-trauma coagulation milieu, we assess patients with daily thromboelastography(teg). we hypothesized that persistently high clot strength and low dissolution is associated with thrombotic adverse outcomes in severely injured patients. materials and methods: adult patients with blunt or penetrating injuries admitted to the icu of a level i urban trauma center from jan-jul were included. adverse outcomes were defined as death, ventilator-free-days (vfd) = , acute lung injury (ali), acute kidney injury (aki), and venous thromboembolic events (vte). we assessed trends of clot dissolution (fibrinolysis, ly %) and strength (maximum amplitude, ma) in the first icu days using linear mixed models to account for repeated measures and missing observations. ly % was box-cox power-transformed to approximate normality. significance for pairwise comparisons at each time was adjusted by false-discovery-rate. results: patients: median age -years, % female, iss (iqr - ), % blunt mechanism, median icu days . overall, % developed one or more of the following; %vfd = , %ali, %aki, %vte, %death. ly was persistently lower in patients with adverse outcomes compared to those without (interaction time*adverse_outcomes p = . ), with fdr-adjusted significant differences at icu days and (fig ) . conversely, ma did not differ significantly by adverse outcome status(interaction time*complications p = . , fig ) . conclusions: low clot dissolution, not clot strength, is associated with adverse outcomes in severely injured trauma patients. additional work is underway for earlier identification of sd phenotypes and strategies to mitigate impaired fibrinolysis. introduction: angioembolization (ae) is can be both diagnostic and therapeutic in management of a hemodynamically unstable trauma patient. however, patients who would benefit from ae typically require emergent surgery for their injuries. the critical decision of transferring a patient to the operating room versus the interventional radiology suite can be bypassed with the advent of intra-operative angioembolization (ioae) . while the ability to perform such an intervention was previously limited by the availability of costly rooms termed raptor (resuscitation with angiography, percutaneous techniques and open repair) suites, it has been suggested that using c-arm digital subtraction angiography (dsa) is a comparable alternative. this case series aims to establish the feasibility and safety of ioae. materials and methods: we conducted a retrospective anlaysis of all trauma patients at our level trauma centre who underwent ioae with a concomitant surgical intervention from january to april . results: a total of patients ( . % male, . ± . years, . % blunt) underwent ioae using the c-arm dsa. all but one patient underwent exploratory laparotomy, . % of which underwent an additional surgical procedure (ex. exploratory thoracotomy, orthopaedic). either gelfoam ( . %), coils ( . %), or a combination of both ( . %) were used for embolization. internal iliac embolization was performed in . % of cases ( . % bilateral) and five patients ( . %) required hepatic embolization. ae was successful in all but one case, inferior vena cava filters were placed in . % of cases, and . % of patients required a second ae. the -day mortality was . %. conclusions: our results suggest ioae is a feasible and safe management option in severe trauma patients with the advantage of concurrent operative intervention and ongoing active resuscitation with good success in hemorrhage control. introduction: partial resuscitative endovascular balloon occlusion of the aorta (reboa) is a new concept of aortic occlusion to reduce the ischemic injuries below the occlusion level. it is, however, difficult to determine when the occlusion is partial in a clinical setting. end-tidal carbon dioxide (etco ) is a product of aerobic metabolism and its production is reduced during ischemia and anaerobic metabolism. the aim of this study was to investigate if etco is a good predictor of the degree of aortic occlusion during normovolemia and hemorrhagic shock in a porcine model. methods: nine pigs, - kg, were anesthetized and surgically prepared. then, gradual zone aortic occlusion by %, % and % was induced, during first normovolemia and then controlled hemorrhagic grade iv shock. hemodynamic/respiratory variables, blood gases, aortic/mesenteric blood flow, blood pressure of common femoral artery and etco were measured continuously. oxygen consumption and carbon dioxide production were calculated for each timepoint for correlation measurement to different methods for partial occlusion determination. background: acute appendicitis is one of the most common surgical emergencies worldwide. the aim of this meta-analysis of randomized controlled trials was to compare the safety and efficacy of antibiotic treatment versus appendicectomy as the primary treatment for patients diagnosed to have acute appendicitis. methods: a systematic online search was conducted using the following databases: pubmed, scopus, cochrane database, the virtual health library, clinical trials.gov and science direct. only randomized controlled trials (rcts) that compared antibiotics treatment (a) versus surgical treatment (s) as primary treatment of appendicitis were included. results: eight rcts with . patients were included: in the antibiotics group and in appendicectomy group. higher rate of treatment success was noted in appendicectomy group . % versus only . % in the antibiotics group (p \ . ) (fig. ). follow up period for recurrence was one year in all studies and the recurrence at year was reported in . % ( / ) of patients treated with antibiotics and . % ( / ) of them underwent appendicectomy. moreover, rate of overall were . % in a group and . % in s group (odd ratio . [ . - . ], ci %, p-value: . ) (fig. ) . a longer length of hospital stay was reported among antibiotics group ( . ± . in a group versus . ± . in s group, p . ). conclusions: appendicectomy has significantly higher efficacy rate but higher complications rate when compared to antibiotics treatment. most of the studies included in this meta-analysis conveyed a high risk of bias, hence more well-designed rcts are recommended. introduction: post-operative adhesions are associated with increased risk of morbidity and mortality. up to date no effective measures has been introduced to decrease intra-abdominal adhesions following laparotomy. oxiplex-ap gel has been used in extra-abdominal surgical procedures to prevent adhesions. in the current study oxiplex-ap was tested in a mural animal model to investigate its efficacy in reducing post-surgical intra-abdominal adhesions. materials and methods: forty rats subjected to laparotomy were randomly divided into groups of . a serosa injury was made on the small intestine and three different treatments were applied: simple suture, simple suture ? oxiplexap, and oxiplex-ap only; the last group received no treatment of the injury before closure of the abdomen. all animals were kept alive for days, and a second laparotomy was done to measure the intra-abdominal adhesion by the nair classification. results: at second look laparotomy a significant difference in adhesion was noticed between the simple sutures and simple suture ? oxiplex-ap were the latter had developed less adhesions. there was also a trend towards less adhesion development between the simple sutures and oxiplex-ap only group, with less adhesions in the latter. conclusions: the use of oxiplex-ap was associated with decrease adhesion formation in the current animal model particularly without suturing. further investigations into these findings are needed. introduction: emergency abdominal surgery is known to result in high morbidity and mortality. furthermore, evidence suggests that unplanned admissions to the intensive care unit (icu) are associated with higher in-hospital mortality than those patients with planned icu admissions . the aim of the study was to describe the patient population who required an unplanned admission to icu following emergency laparotomy at the royal melbourne hospital. materials and methods: a single-centre retrospective observational study was performed using prospectively collected data between and . patients who underwent an emergency laparotomy and experienced an unplanned icu admission were included. patients who underwent a trauma laparotomy were excluded from the study. results: emergency laparotomies were performed. of these, ( . %) required an unplanned admission to icu. fourty-two patients ( %) were female, and patients ( %) were aged years and above. sixty-three ( %) were admitted due to single organ dysfunction (clavien-dindo iva). the median time to icu admission was days in patients classified to have experienced clavien-dindo iva, while it was days in patients who experience multi-organ dysfunction (clavien-dindo ivb). thirty-seven patients ( %) were admitted to icu due to complications classified as cardiopulmonary. conclusions: recognising that emergency laparotomy is a high risk procedure, with the elderly patients accounting for the majority of unplanned icu admissions, it is imperative to utilise risk stratification methods to guide optimal peri-operative management. this should result in improved utilisation of critical care resources and overall patient outcomes. introduction: the way of reconstruction following intestinal resection in the emergency settings is still controversial. the question which is better between hand-sewn and stapled anastomosis in trauma and emergency surgery occasionally arises; however, there have been few reports comparing these methods. materials and methods: a record-based retrospective study was performed to compare hand-sewn with functional end-to-end anastomoses in trauma and emergency operations from october to october in one of the largest trauma and emergency centers in japan. the patients who had intestinal resection with functional endto-end or hand-sewn anastomosis in an emergency surgery were included. the patients who had covering ileostomy or colostomy, or who underwent surgery as an elective operation were excluded. the primary outcome is the rate of complication associated with anastomosis. the statistical analyses were performed using a chi introduction: injuries are the fourth leading cause of death in europe. laparotomy is the standard treatment for penetrating abdominal wounds. because of the morbidity and the high rate of negative laparotomies, the nonoperative treatment is effectively developing. the aim of this study is to analyze the complications and the quality of life of the patients after laparotomy for this kind of wounds. materials and methods: a retrospective cohort of patients was studied between and at the laveran military teaching hospital in marseille. one hundred and eighty-six trunk gunshot or stab wound were recorded, including abdominal wounds. thirtyfour patients were managed by laparotomy and included in this study. the patients and their referring general practitioners were contacted to complete missing data and the sf- quality of life score. results: among the patients included, the average age was years and most of them were men. the indication for laparotomy was mainly based on the hemodynamic instability, then according to the results of the computed tomography in case of suspicion of specific lesions: bowel injuries, major vascular injury, mesenteric or mesocolic vascular injury, diaphragmatic injury and intraperitoneal bladder rupture. only laparotomies were negatives. eleven complications after laparotomy were found ( , %), including early (within the days) and late. no complication was found after negative or non-therapeutic laparotomies. the quality of life of the patients after one year is similar to those of the general population. conclusions: the most common indication for laparotomy for abdominal penetrating trauma is hemodynamic instability. the rate of laparotomy complications for penetrating abdominal trauma is similar to those of scheduled surgeries. the quality of life after this care remains unchanged. these results may insist on the fact that the ''gold standard'' treatment for penetrating abdominal injury remains the laparotomy objectives: splenic artery embolization (sae), a routinely used adjunct in the non-operative management (nom) of splenic injuries(si), was widely adopted in trauma about two decades ago. we examined complications that occurred with this modality at a level trauma center over a recent -year period and compared this to the prior years. methods: patients who had sae for si between - were identified. sae complications were noted. splenic abscess, splenic infarction and contrast-induced renal insufficiency were considered major complications. coil migration, fever and pleural effusions were regarded ''minor'' complications. the results were compared with data from a prior study examining similar indices at the same trauma center between and . fishers exact test was used for comparison. results: there were patients admitted with si in the recent period, of which ( %) underwent immediate splenectomy. sae was performed in ( . %) of the patients who underwent nom. of these sae patients, % had a contrast blush and . % were either aast grade or . five sae patients ( . %) had splenectomy for continued bleeding. the overall complication rate was . %. major complications occurred in patients ( . %) and minor in patients ( . %). embolization location in the splenic artery was proximal in . %, distal in . % and in both in . %. there was no association between complications and coil location by logistic regression. differences between the two periods shown in table . conclusion: sae continues to be a useful adjunct in nom of si and has seen increased utilization. complications continue to occur,although fewer minor complications were noted in the second period. no association between embolization location and complications was noted in the recent period. judicious utilization of sae is imperative given the complications that continue to be noted from this procedure. the effect of the time spent in the emergency department on the mortality rates and cause of death in patients who underwent emergent laparotomy introduction: the purpose of this study was to a) examine the effect of the time spent in the emergency department (ed) on hypotensive patients in need of emergent laparotomy and b) to determine the mortality rates and cause of death in these patients. materials and methods: between - , patients were included ( men and women, mean age . years) who underwent laparotomy less or equal to min from ed admission. of the patients, (group ) had a systolic blood pressure (sbp) greater than mmhg and had a sbp less or equal to mmhg. all patients had abdominal injuries with an injury scale score (iss) between and . the in-hospital mortality represented the primary outcome, while secondary outcomes included cause of death and time to death. results: in this study both groups spent a median of min in the ed, but the time from the ed to the operating theatre was shorter in the group ( min versus min). in total, the mortality rate was %, but in the group the mortality was %. the sbp on arrival in the ed was strongly associated with the risk of death. furthermore, we observed significant positive correlation between the probability of death and the time spent in the ed, with an increase of probability of death equal to . % per minute spent in the ed. in both groups the hemorrhage was the commonest cause of death ( %). the results of this study indicate that, in patients with abdominal injuries requiring emergent laparotomy, the probability of death is proportional to both extent of hypotension and the length of time spent in the ed. especially, in patients who were presented with a sbp inferior of equal of mmhg, this probability increased as much as % for each min. despite many advances in trauma surgery, half of hypotensive patients are going to die in the first h. introduction: injury to the pancreas may lead to significant morbidity and mortality. we studied the prevalence of pancreatic endocrine and exocrine functions and evaluated the morphological regenerations in pancreas following partial pancreatectomy. materials and methods: patients with pancreatic trauma were recruited ambispectively from january to december . endocrine functions were assessed at the time of admission and at months follow up with g oral glucose tolerance test (ogtt), serum insulin and c-peptide levels, hba c estimation and exocrine functions were assessed with faecal elastase test. pancreatic volumetry was done with imaging studies at -and -months post discharge. results: twenty patients were studied with a median age of years at the time of injury. all the patients were normoglycemic on admission; only one patient who underwent pancreatic resection developed diabetes mellitus requiring insulin on follow up. patients ( %) were found to have prediabetes by american diabetes association (ada) criteria. patients ( %) had pancreatic exocrine insufficiency. pancreatic volume increment, from mean pancreatic volume of . cm to . cm , was noted in partial pancreatectomy patients. conclusions: overt endocrine and exocrine insufficiency is rare in pancreatic trauma patients. but subsets of patients are biochemically predicted to have higher risks of endocrine dysfunction and exocrine insufficiency. hence, while dealing with pancreatic trauma patients, one should remember the possible metabolic disorders associated and the need for specific investigations. pancreatic volume increment is a new finding which opens up more opportunities for further research. hospital de santo espírito da ilha terceira, general surgery, angra do heroísmo, portugal, hospital de santo espírito da ilha terceira, orthopedics and traumatology, angra do heroísmo, portugal introduction: rope bullfights are traditional events in the azores islands, where a bull is set on the streets, arrested by a rope on its neck. around events happen every year and it is already part of the island's touristic attractions. inevitably, every year, people get injured either from direct trauma with the bull or from falls when trying to escape from the animal. the aim of this study was to characterize the type of injuries that occur in these bullfighting events, as to their incidence, mechanism of injury, anatomical affected area and severity. materials and methods: we prospectively registered all cases of injured people who suffered any type of trauma during rope bullfights and received emergency therapy in the local hospital, between and . results: patients recured to the emergency department, . % female, with mean age of . years. regarding the mechanism of injury, . % occured due to direct trauma to the animal while in the remaining . % resulted from falls during escape or handling of the rope. the most commonly affected anatomical areas were the limbs ( . %) followed by the head and neck ( . %) and thorax ( . %). in , % of the cases, patients suffered from multiple traumas. in . % of the cases the treatments performed were wound care, wound closure and/or symptomatic therapy. in total, patiens were hospitalized, patients required interventions in the operating room ( closed fracture reductions and exploratory laparotomy with splenectomy) and patients were hemodynamically unstable upon admission (hypovolemic shock due to splenic fracture and cet). conclusions: the rare articles published describe the mechanisms of injury associated with bullfights in spanish centers and injuries resulting from wild cow accidents in indian cities. this is the first local descriptive study on the prevalence of traumatic injuries associated to this specific type of rope bullfights. introduction: the two-stage splenic rupture is seldom, its risk is unpredictable and a precise diagnosis of a ct and/or mri imaging unexpectable or unexcludable. generally, and due to our experience and current literature a two-stage rupture occurs within one week after trauma. though dramatic courses after two or three weeks are known. therefore, it is suggested to perform a prophylactic angioembolization in (still) hemodynamically stable patients. materials and methods: a retrospective study in a level-one trauma centre of switzerland did analyse all patients that underwent a prophylactic angioembolisation after an explicit diagnose by ct and/or mri of a splenic parenchymal lesion after trauma between and . further inclusion criteria were hemodynamical stability (sys rr [ mmhg) and missing indication for immediate laparotomy. results: patients ( f, m) with an average age of ± years underwent preemptive angioembolisation after traumatic lesions of the spleen. the ais abdomen was in and in patients. besides a splenic injury patients did also have a kidney injury. the overall iss was ± points. patients suffered additional thoracic or head trauma. in patients the angioembolisation was performed on admission, in on the st, in at the nd and respectively in the rd and th day of. in case an uncomplicated selective embolization of a main duct of the splenic artery was performed. in patients the trouble-free proximal embolization of the splenic artery was done. the average stay was ± . days. no deaths or complications seen due to angioembolisation or splenic rupture. there were no complications or operative introduction: traumatic abdominal wall hernias (tawhs) are uncommon, and the optimal management is debated. tawhs most often result from blunt trauma and are associated with severe intraabdominal injuries. our institutional protocol mandates primary repair only if the patient undergoes laparotomy for other reasons and is without mesh. since , primary repair of lumbar hernias included bone anchors when indicated. we wanted to describe the tawh patients treated operatively during initial hospitalization focusing on injury mechanism, diagnosis, associated injuries, operative techniques, early complications and outcomes. materials and methods: we performed a retrospective, descriptive cohort-analysis of data from the institutional trauma registry from - . all operatively managed tawhs were identified based on ais codes, ncsp codes and relevant key words. results: of the identified patients, ( %) were women. median age was years (range - ). median iss was and patients had iss [ . injury mechanism was blunt except for one explosion. patients ( %) had been in a mvc, and of these ( %) had seat belt injuries. of these patients had a disruption of the muscle from the iliac crest, and one had a hernia through a fractured iliac wing. bicycle falls and fall from height had hernias in the anterior abdominal wall. two meshes were placed, with no known complications. bone anchors (twinfix Ò , mm) were used in patients. no recurring hernias were identified in the patients with routine follow-up ( - months) . conclusions: surgery for tawh is uncommon in our institution. tawh is often associated with severe torso injuries and primary repair is only done when laparotomy for other reasons is indicated. primary suture of the muscle, including use of bone anchors seems to be adequate treatment, as we have identified no recurrences. a longterm follow-up study is warranted for operated and non-operated patients with tawh. a comparison of sub-specialty operative adolescent patient outcomes in adult and pediatric trauma centers introduction: adolescent trauma victims may be treated at either an adult (atc) or pediatric trauma center (ptc). these centers have different resources, surgeon training and overnight in-house coverage. it is not known how outcomes compare with regards to the very small subset of patients that actually undergo a surgical trauma intervention. we hypothesized that presentation to a ptc would yield increased mortality when subspecialty intervention was required and that this would be most pronounced at night when in-house attending coverage is absent at all state ptcs. materials and methods: a review of the pennsylvania trauma outcome study (ptos) database was performed to capture patients aged - who underwent any non-orthopedic trauma surgery. cohorts were created for cranial, thoracic, abdominal or vascular surgery from - . trauma centers were divided as adult level (atc ), adult level (atc ) or pediatric (ptc). groups were created based on time of arrival with am- pm being dayshift and : pm- am being night shift. age, race, mechanism of injury, vital signs, gcs, iss, los and mortality were evaluated. ancova was utilized to control for iss variation. spss was used for all analyses. results: patients met initial criteria. atc s saw more minority patients and more males than other center types. atc s saw an overall older cohort ( . years vs . years in atc and . years in ptc, p \ . ). despite this age difference, presenting systolic blood pressure was lowest at the atc s ( . mmhg vs . mmhg at atc and . mmhg at ptc, p \ . ). iss and triss and overall mortality were not different and this included when grouped by day or night shift. of note, trauma thoracotomy was more likely to be performed at night in adult centers. hospital length of stay was significantly lower for atc ( . days vs . in atc vs and . in ptc). conclusions: adult and pediatric trauma centers see different patients. operative trauma cases are surprisingly low at our state's ptcs and trauma thoracotomy was more likely to be performed at night in atcs than ptcs. broader study is needed to uncover differences in operative care and outcomes. treatment of dislocation of the patella as a result of sports injuries in children. forecast and consequences in adulthood k. furmanova , o. loskutov , a. naumenko medinua clinic and lab, ortopedics, dnepr, ukraine introduction: dislocations of the patella with a rupture of the medial patellofemoral ligament (mpfl) account for - % of acute injuries of the knee joint [ , ] . inadequate therapeutic tactics of these injuries in childhood and youth, as a result of sports injuries, are fraught with complications in the form of the instability of the knee joint, residual deformities and contractures in patients in adulthood [ , ] . materials and methods: in the period from to cases of rupture of mpfl among children aged - years who were involved in sports were observed. the examination included conducting a clinical examination, axial radiography with flexion of the joint at angles of °and °, mri of the knee joint. results: in . % ( cases) the integrity of the mpfl(with a reduced number of sutures) was restored using a yamamoto suture, and in cases ( . %), the autoplasty of the mpfl was performed. excellent medium-term ( years) clinical and functional results according to the ikdc scale were noted in . % of cases, good in . %, satisfactory in . %. in patients ( . %) there was a relapse of dislocation after performing an mpfl suture during the first year after surgery mainly due to noncompliance with the recommendations. conclusions: injury to the knee joint with the patella dislocation in childhood and adolescence, associated with a sports injury is an indication for surgical treatment in order to adequately restore the integrity of the mpfl and prevent disabling complications. our yamamoto suture technique is more optimal for treating young patients with instability of the patella and is recommended for widespread use in pediatric orthopedists due to its undeniable clinical advantages. osteotomy with a defect cm placed cm below tibial plateau. types of fixation have been simulated: plate fixation of only a medial pillar, plate fixation of only a lateral pillar, plate fixation of both pillars, and locking intramedullary nailing. results: in case of plate fixation of only a medial pillar, the injury to an interosseal membrane causes an expressed valgus deformation at axial loading, leading to a reasonable ( . mpa) overload of the fixator in the osteotomy area. the use of a lateral plate leads to excessive loading on an external pillar, while the medial pillar remains unsupported. this causes overloads of the fixator in the osteotomy area ( . mpa). the double plate fixation is typical of the lowest extent of bone fragments displacements ( . mm) . this is a super-rigid type of osteosynthesis, able to cause a stress-shielding syndrome in the adjacent bone. it has been estimated that the method of im nailing is an optimal fixation method, with minimum loading of the fixator ( . mpa) and the best distribution of changed elastic strains in the bone-implant system. conclusions: the mathematical simulation demonstrates that fixation by a medial plate is possible only if support functions of the ligament system and interosseal membrane remained intact. if an injury is a high-energy one, nailing is preferable. introduction: treatment of large bone defects is one of the great challenges in contemporary orthopedic and traumatic surgery. grafts are necessary to support bone healing. a well-established allograft is demineralized bone matrix (dbm) prepared from donated human bone. a recent development is a new fibrous demineralized bone matrix (f-dbm) with a high surface-to-volume ratio. in this study we examine toxicity of an innovative dbm fibers preparation. materials and methods: f-dbm was transplanted to a mm, platestabilized, femoral critical-size-bone-defect of mm in sprague-dawley (sd)-rats (n = ). healthy animals were used as control. after months histology, hematological analyses as well as serum biochemistry was performed. were measured as indicators of free radical exposure. there were no significant differences between the control group and animals receiving f-dbm. hematology as well as biochemistry did not differ between operated animals and control. histologically no evidence of damage to liver and kidney and a good bone healing could be observed in most cases. conclusions: taken together, these results provide evidence for no systemic toxicity of the bone allograft. i have received no significant financial interest, consultancy or other relationship with products, manufacturer(s) of products or providers of services or financial support related to this abstract. • i hereby confirm that my abstract is based on previously unpublished data and that i own the rights to the written summaries of research or observations presented in the abstract, or that i have obtained permission for the acknowledged sources for other excerpts taken from copyrighted works. • in submitting an abstract i hereby agree that the copyright of my abstract is transferred to the european society of trauma and emergency surgery. • i hereby confirm that i will present my abstract at the congress in case it is accepted. sponsor: german institute for cell and tissue replacement (dizg, gemeinnützige gmbh), berlin, germany. intramedullary nailing through suprapatellar approach in distal tibia fractures: a retrospective study evaluating clinical and radiographic results d. bustamante recuenco , a. gómez , j. m. pardo garcía , e. garcía , p. castillón , p. caba doussoux hospital de octubre, madrid, spain, madrid, spain, hospital mutua terrasa, orthopaedics, barcelona, spain introduction: distal tibia fractures (dtf) can be operated either by intramedullary nailing (imn) or by orif with plates. the current literature shows a higher rate of malalignment and consolidation delay with imn when compared to plates. in these studies, an infrapatellar approach for the imn is performed. recent studies show a better alignment in dtf treated with imn by suprapatellar approach, though functional and biological outcomes have not been analyzed yet. our goal is to assess the clinical and radiographic results of the treatment of dtf with imn using a suprapatellar approach. materials and methods: a two-center retrospective study was performed, collecting the cases with dtf treated with suprapatellar imn from / to / . results: a total of patients were obtained, with a mean age of . years. the average follow-up was months. % of the fractures were ao type a, presenting the remaining % intra-articular involvement. patients presented complications, corresponding in of them to superficial infections. as for clinical results, complete mobility in the knee and ankle was obtained in almost all cases. at the radiographic level, a total of % ( ) of distal malalignment cases were detected, defined as more than °deviation from normal axis in the coronal and sagittal planes. most of the fractures consolidated in a period of - months. there were cases of delayed consolidation, from which developed pseudoarthrosis. conclusions: intramedullary nailing through a suprapatellar approach for dtf offers good clinical and radiographic results, with low rates of malalignment and lack of consolidation. more studies are required to compare the results obtained with other fixation methods for these fractures. reference: avilucea fr, triantafillou k, whiting ps, perez ea, mir hr. suprapatellar intramedullary nail technique lowers rate of malalignment of distal tibia fractures. j orthop trauma. ; ( ) : - . the clinical consequences of follow-up radiographs in ankle fractures are unclear and indications for these radiographs are seldom well-defined. routine radiographic imaging in the follow up of patients with an ankle fracture adds to treatment costs, although retrospective studies dispute its usefulness. the aim of this study was to assess if a protocol with a reduced number of routine radiographs would lead to cost savings, without compromising clinical outcomes. materials and methods: a multicentre randomized controlled trial was conducted. patients were randomly assigned in a : ratio to usual-care (consisting of routine radiography at one, two, six and twelve weeks) or reduced-imaging (radiographs only obtained for a clinical indication at six and twelve weeks). functional outcome was assessed using the omas and aaos ankle questionnaires, quality of life was measured with eq- d- l and sf- questionnaires. other outcome measures included complications, pain, the number of radiographs, health perception and self-perceived recovery. costs were measured with self-reported questionnaires results: the study group consisted of participants, of which ( %) received operative treatment. patients in the reduced-imaging group received median radiographs, whilst patients in the usual care group received median radiographs (p \ . ). omas, aaos scores, quality of life, pain, health perception and self-perceived recovery did not differ between groups. we observed complications in the reduced imaging group. this did not differ significantly from the usual care group ( complications p = . ). a significant reduction in radiographic imaging costs was observed (-€ per patient, % ci - to - ). overall costs per patient were comparable ( [ % ci - to ]). conclusions: implementation of a reduced imaging protocol in the follow up of ankle fractures leads to cost savings and more importantly does not lead to worse functional outcomes. results after percutaneous and arthroscopically assisted osteosynthesis of calcaneal fractures w. grün , m. molund , f. nilsen , a. stødle oslo university hospital, orthopaedic department, ullevål, oslo, norway, Østfold hospital, orthopaedic department, grålum, norway introduction: operative treatment of calcaneal fractures using the extensile lateral approach is associated with high rates of soft tissue complications. during the last years there has been a trend towards less invasive fixation methods. percutaneous and arthroscopically assisted calcaneal osteosynthesis (paco) combines the advantages of good visualization of the posterior facet of the subtalar joint with a minimally invasive approach. materials and methods: we conducted a clinical and radiographic follow-up of patients with calcaneal fractures treated by paco with a minimum follow-up of year. there were sanders ii and sanders iii fractures. the mean follow-up period was . months (sd . ). our primary outcome was the american orthopaedic foot and ankle society (aofas) ankle-hindfoot score. secondary outcomes were the calcaneus fracture scoring system (cfss), the manchester-oxford foot questionaire (moxfq), the visual analog scale (vas) for pain and the incidence of complications. radiographs were obtained to evaluate the reduction of the fractures as well as the presence of subtalar osteoarthritis. results: the median aofas score was (range, - ), the cfss score ( - ), the moxfq score . ( - . ). the vas pain score was ( - . ) at rest and . ( - . ) during activity. the böhler angle improved from mean . degrees (sd . ) preoperatively to . degrees ( . ) postoperatively. however, the follow-up radiographs showed subsidence of the fractures and a böhler angle of . degrees ( . ). % of the operated feet showed signs of posttraumatic subtalar osteoarthritis. there were no wound healing complications. two patients were reoperated with screw removal due to prominent screws. conclusions: our results suggest that paco gives good clinical results and a reduced risk of complications in selected calcaneal fractures. prospective longterm studies will be necessary to better evaluate the potential advantages and limitations of paco. with the nascent state of microsurgical services in the region the application of negative pressure wound therapy (npwt) has proven to be very helpful. an improvised npwt has made it locally available to patients. this report aims to show how this has improved the management of open fractures of the lower limb in a resource restricted setting. materials and methods: a -month review of cases of lower limb open fractures managed at a regional trauma centre in nigeria was done. the type of wounds were classified based on region and need for soft tissue coverage. results: a total of cases were reviewed approximately % of these case were gustilo and anderson type iii. of these had npwt as part of their management. some of the benefits of observed were; reduced frequency of wound dressings, and shorter time to optimize wound for closure. conclusions: the locally improvised npwt has proven to be an affordable and cost-effective tool in the management of open lower limb fractures. it remains an invaluable alternative of care in the absence of microsurgical skills and patented device with are far from reach owing to financial constraints. references: . hussain a, singh k, singh m. cost effectiveness of vacuum assisted closure and its modifications: a review. isrn plast surg. ; : - . . isiguzo c, ogbonnaya i, uduezue a. modification of negative pressure wound therapy in the economically constrained region: a preliminary report. vol. , nigerian j plast surg. joytal printing press; . p. - . . mba u, nevo a. challenges of limb salvage in a resource limited environment: case report and review of literature. niger j plast surg. ; ( ): . . novak a, wasim sk, palmer j. the evidence-based principles of negative pressure wound therapy in trauma and orthopedics. open orthop j. ; : - . introduction: lower extremity vascular trauma may result in limb loss or mortality. this study examined outcomes of lower extremity vascular trauma (levt) and potential associations to amputation/mortality. materials and methods: a retrospective cohort study of patients (n = ; limbs) with levt between and in a single trauma center. only patients requiring a vascular procedure were included. data were extracted from the swedish vascular registry (swedvasc) and the swedish trauma registry (swetrau). results: mean age ± years; men % ( / ); trauma mechanism % ( / ) blunt and % ( / ) penetrating. % of patients underwent preoperative cta; % of patients ( / ) were transferred to hybrid operating room. arterial injury was present in / limbs ( %) and venous injury in / limbs ( %). the most frequently injured artery was popliteal artery ( / ; %) followed by superficial femoral artery ( / ; %). most common vascular operative procedure was arterial bypass/interposition graft ( / ; %). a vascular shunt was used in % of cases ( / ). fasciotomy was performed in % ( / ) of limbs. four patients were lost to follow-up after less than five days. there were eleven limbs ( / ; %) amputated within -day postoperative follow-up. all amputations were caused by blunt trauma. % ( / ) of arterial injuries below-the-knee led to amputation. thirty-day mortality rate was . % ( / ) . univariate analysis showed that fractures (p \ . ), soft tissue injury (p \ . ), multiple injuries (p = . ), and blunt mechanism (p \ . ) were associated with amputation and mortality after levt. conclusions: this study showed that amputations after levt are caused by blunt trauma. also levt combined with fractures, soft tissue injury, or multiple injuries increased the risk of amputation and mortality. multi-center study enabling multivariate analysis to adjust for potential confounding factors is imperative to confirm these findings. incidence, treatment and financial burden of tibial plateau fractures in belgium between and describe the incidence, evolution in management and financial burden of tpf in belgium between and . we compare national data with data from uz leuven (uzl), the largest university hospital in belgium. materials and methods: this study includes all tpf treated in belgium between and . we identified . tpf, of which fractures were treated in uzl. despcriptive statistics were used to analyze the data. results: the annual incidence increased from . to . / , /y. an increase in number was true for both operatively treated patients (otp) and non-operatively treated patients (notp), but was more pronounced in the latter ( % vs. % increase). the rate of surgery (ros) decreased from . % to . %. the mean ros for uzl was . %. the total financial burden in belgium increased with %, mainly driven by increasing costs in otp. hospitalisation rates for notp decreased from % to %, as day hospital admission occured more commonly. the mean hospitalisation cost was € , for otp and € , for notp. costs for uzl inpatients were € , and € , . nursing days accounted for % of the cost in otp and % in notp. the mean los was . days for otp and . days for notp. uzl patients had a mean los of . and . days. conclusions: tpf are associated with increasing hospital related healthcare costs. as nursing days determine the majority of the financial burden, measures should be taken to avoid prolonged los. introduction: rotational malalignment (rm) is a common postoperative complication after intramedullary (im) nailing of tibial shaft fractures. computed tomography (ct) is commonly used for detection of malrotation, however reliability is frequently questioned. the purpose of this study is to evaluate the intra-and inter-observer reliability of low-dose protocolled bilateral postoperative ct-assessment of rotational malalignment after im nailing of tibial shaft fractures. materials and methods: a total of patients were prospectively included with tibial shaft fractures that were treated with imn in a level-i trauma center. all patients underwent postoperative bilateral low-dose ct-assessment (effective dose of . - . mgy) as per hospital protocol. four observers performed the validated reproducible measurements of tibial torsion in degrees, based on standardized techniques. the intra-class coefficient (icc) was calculated to evaluate intra-and inter-observer reliability. the intra-and inter-observer reliability was categorized according to landis and koch. results: intra-observer reliability for quantification of rotational malalignment on postoperative ct after imn of tibial shaft fractures was excellent with . ( % ci = . - . ). the overall inter-observer reliability was . ( % ci = . - . ), also excellent according landis and koch. discussion and conclusion: first, bilateral postoperative low-dosesimilar radiation exposure as plain chest radiographs-ct assessment of tibial rotational alignment is a reliable diagnostic imaging modality to assess rotational malalignment in patients following imn of tibial shaft fractures and it allows for early revision surgery. second, it may contribute to our understanding of the incidence, predictors, and clinical relevance of postoperative tibial rotational malalignment in patients treated with imn for a tibial shaft fracture, and facilitates future studies on this topic. the trauma emergency laparotomy audit (tela) t. collaborators , m. marsden , p. vulliamy , r. carden , o. najiuba , n. tai , r. davenport tela collaboration, natric, n/a, united kingdom, queen mary university of london, centre for trauma science, london, united kingdom introduction: mortality for shocked trauma patients undergoing emergency laparotomy remains unchanged for years. the tela study aimed to describe the contemporary peri-operative management and patient outcome following abdominal injury. materials and methods: a prospective multicentre observational study of all patients undergoing emergency abdominal surgery within h of injury was performed in the uk and ireland for six months from the st january . shock was defined as the receipt of blood transfusion, with clinical or biochemical evidence of hypoperfusion. results: the study included patients from hospitals, of whom ( %) were shocked and received a median of units red blood cells. shocked patients were more likely to have a blunt mechanism of injury ( % vs %, p \ . ) and had a % mortality ( / ). half of these deaths occurred in the operating room (or). patients that died were more severely injured (injury severity score (iqr - ) vs (iqr - ), p = . ) and had a greater degree of shock at hospital arrival (base deficit . (iqr . - . ) vs . ( . - . ) , p \ . ). processes of care were equivalent or better among non-survivors, with a higher proportion of patients that died undergoing laparotomy within min of arrival in the emergency department ( % vs %, p = . ) and a lower proportion receiving crystalloid in the or ( % vs %, p \ . ). however, delays to achieving definitive haemorrhage control and delivering balanced blood transfusion ratios were observed among both survivors and non-survivors. conclusions: damage control resuscitation principles are followed most closely in patients that die. despite better processes of care, in shocked patients died in this study justifying the continued search for novel therapeutic approaches. pre-operative temporary haemorrhage control and pharmacological mitigation of the effects of shock may be productive avenues of research to improve patient outcomes. introduction: tranexamic acid (txa) has been shown to reduce mortality in bleeding trauma patients, with greater effect if administered early. normally administered intravenously, txa can also be administered intramuscularly, which could be advantageous in low resource and military settings. intramuscular use has only been tested in healthy patients, and it is likely that shock will reduce intramuscular uptake. materials and methods: in a prospective experimental study norwegian landrace pigs ( - kg) utilised in a surgical course in haemostatic emergency surgery were subjected to various abdominal and thoracic trauma. after h of surgery the pigs were injected with mg/kg txa either intravenously or intramuscularly. blood samples were drawn at , , , , , , and min. the samples were centrifuged and analysed with liquid chromatography-mass spectrometry (lc-ms/ms). results: preliminary results from animals in the intramuscular and animals in the intravenous group. mean plasma concentration with sd of txa as a function of time is shown in figure . plasma concentration in the intramuscular group was near ug/ml min after administration, and rose above ug/ml after min. conclusions: plasma concentrations reported to inhibit fibrinolysis in vitro is - . ug/ml ( , ) . if this extrapolates to the clinical situation intramuscular administration would yield plasma levels within the lower end of therapeutic range after min. in ongoing haemorrhagic shock plasma concentrations of txa after intramuscular administration were considerably lower than after intravenous administration, but within therapeutic range . introduction: fallowing laparoscopic cholecystectomy(lc), patients suffer from postoperative pain, especially in the abdomen. intraperitoneal local anesthesia (ipla) reduces pain after laparoscopic cholecystectomy(lc). acute cholecystitis(ac)-associated inflammation, increased gallbladder wall thickness, dissection difficulties, and a longer operative time are several reasons for assuming a benefit in pain scores in urgent lc with ipla application. the aim was to determine the postoperative analgesic efficacy of high-volume lowdose intraperitoneal bupivacaine in urgent lc. materials and methods: fifty-seven patients, american society of anesthesiologists(asa) physical status i or ii were randomly assigned to receive either normal saline(group a) or intraperitoneal bupivacaine(group b) at the beginning or at the end of the surgery in urgent lc. the primary outcome was the scores of postoperative pain by visual analogue scale score (vas) after surgery. results: postoperative vas scores at st and th hours were significantly lower in group b than group a (p \ . ). postoperative vrs scores at st, th and th hours were significantly lower in group b than group a (p \ . , p: . , p: . ). anelgesic use was significantly higher in group a at st postoperative hour than group b (p \ . ). shoulder pain was significantly lower in group b than in group a (p \ . ). patient satisfaction was significantly higher in group b than in group a (p \ . ). conclusions: high-volume low-concentration intraperitoneal bupivacaine instillation resulted in better postoperative pain control along with reduced incidence of shoulder pain and analgesic consumption in comparison to control group in urgent lc. introduction: in-hospital resuscitative thoracotomy is an established procedure for patients with penetrating cardiac injuries. the survival rate is dismal in patients with cardiac arrest prior to admission. prehospital resuscitative thoracotomy (prt) was introduced by the london hems with the highest published survival rate of %. we aimed to identify the number of patients who could potentially benefit from prt in our major trauma center catchment area. materials and methods: data from to were collected from the institutional trauma registry and electronic records. we included patients [ years, with penetrating cardiac injury, or penetrating chest trauma and cardiac arrest, or penetrating chest trauma and sbp \ mmhg. commonly used criteria for prt are tamponade with cardiac arrest lasting \ min at the time of ambulance arrival and with [ min remaining transportation time to hospital. results: cardiac injury was found in of included patients. of these , arrived at the hospital with signs of life and survived. of the patients who died had tamponade. criteria for prt were not met in of patients with tamponade. two patients could have been eligible for prt. one patient was found in oslo with cardiac arrest lasting min. the patient had multiple stab wounds to the chest and had several perforations of the right atrium, not technically manageable in a prehospital setting. the second patient was injured outside our primary catchment area and arrested with prehospital personnel present. prt was performed and the tamponade relieved, but compression of the aorta was necessary. the patient was declared dead shortly after hospital admission. conclusions: in years in a population of . million, two patients met london hems criteria for prt. prt was performed in one patient who was declared dead shortly after hospital admission while one patient suffered from injuries which are unmanageable in a prehospital setting. isolated tissue injury leads to fibrinolytic shutdown, tpa resistance and alterations in clot structure in a porcine model introduction: trauma-induced coagulopathy includes a spectrum of hypo-to hypercoagulable phenotypes with differing levels of fibrinolysis and tpa sensitivity. fibrinolysis shutdown is associated with increased late mortality and shown in small animal studies to be driven by tissue injury. utilizing a novel method of clot structure analysis, we hypothesize that isolated tissue injury provokes fibrinolysis shutdown, tpa resistance and is associated with altered clot structure resulting in enhanced clot stability. materials and methods: all male pigs (n = ) underwent anesthesia, intubation, femoral artery cannulation and mini-laparotomy. tissue injury (n = ), was inflicted with bilateral chest wall muscular cutdowns and bilateral femoral fractures using a captive bolt pistol. mean arterial pressure was maintained at [ mmhg. timed blood samples analyzed using tpa challenged and citrated native teg to evaluate tpa resistance and fibrinolytic shutdown respectively. after mm punch biopsy induced splenic injury, clot was collected, washed, and chemically fractioned by strong cation exchange chromatography. tandem mass spectrometry and bioinformatic analysis were used to evaluate clot structure and factor xiiia cross-linking patterns and covalently associated proteins. results: tissue injury pigs showed increased tpa resistance (change tpa-teg ly : - . % vs - . % p = . ) and a trend of fibrinolytic shutdown evidenced by teg compared to control (fig. ) . splenic clot structure analysis demonstrated altered clot structure (fig. ) and identified elevated levels of protease inhibitors such as alpha macroglobulin and alpha antiplasmin at h post tissue injury compared to baseline. conclusions: in a porcine model, isolated tissue injury provokes fibrinolysis shutdown and tpa resistance resulting in altered clot structure with an increased incorporation of anti-protease proteins resulting in enhanced clot stability. there is a high incidence of rotational malalignment after intramedullary nailing of tibial shaft fractures: a prospective cohort series of patients n. j. bleeker amsterdam medical centre, flinders university, department of orthopedics and trauma surgery, amserdam, netherlands introduction: intramedullary nailing (imn) is the treatment of choice for most tibial shaft fractures due to its minimalistic surgical approach, superior fracture healing, and rapid recovery. however, an iatrogenic pitfall is rotational malalignment (rm). the aim of this prospective cohort study was to determine the incidence of rm and to evaluate the efficacy of protocolled bilateral postoperative computed tomography (ct) assessment of rotational tibial alignment. materials and methods: between and we prospectively included patients ( male ( %)), with a mean age of years, with a unilateral tibial shaft fracture. as per hospital protocol, patients underwent a routine low-dose bilateral postoperative ct to assess rm. forty-two patients ( %) suffered open injuries; ( %) were involved in a multi-trauma sustaining more than one injury. according to the ao/ota classification, there were simple ( %), wedge ( %), and complex fractures ( %). fracture location within the tibial shaft varied with six patients ( %) being within the proximal third, ( %) middle third, and ( %) distal third. there were segmental ( %) fractures that involved more than one third of the tibia. results: fifty-five patients ( %) had post-reduction rm including patients ( %) between °- °, seven patients ( %) with a rm between °- °, and two patients ( %) with a rm greater than °w hen compared to the uninjured side. of the patients with rm, the tibia was externally malrotated in patients ( %). three patients ( % of cohort or % of those with rm) underwent revision surgery to correct the rm as detected on ct scan. conclusions: this study reveals a high incidence of rm following tibial nails ( %) with a surprisingly low revision rate ( % of those with rm). a subsequent study should aim to assess clinical relevance of rm in terms of functional outcome and gait analysis. for now ctrotational-profiling provides a platform for early recognition and correction of rm secondary to tibial imn. level of evidence: therapeutic level ii -prospective cohort study. materials and methods: the tarn database was analysed retrospectively to quantify the number of trauma team activations, patients with major trauma (mt), causes of injury, and subspecialty-specific trauma procedures. crude and risk-adjusted mortality rates, observed to expected (o/e) mortality ratio, and risk-adjusted rates of survival from mt were also calculated. results: the number of trauma team activations has risen by a factor of . the predominant injury mechanism that resulted in mt was a fall from less than m. there has been a fivefold increase in the overall number of trauma surgical procedures. orthopaedic surgeons have performed % of trauma procedures, followed by neurosurgeons, oral and maxillofacial surgeons, and visceral trauma surgeons. the rate of trauma laparotomies per consultant fluctuated between . and . per month. a fall from less than m, road traffic accident and a fall from more than m were the three leading causes of death from mt. the overall o/e mortality ratio was . . conclusions: aintree trauma profile has significantly changed since . this change highlights the potential need for a review of how mt services are offered at aintree to reduce the o/e mortality ratio. this may be achieved through more co-ordinated provision of trauma care, prevention, audit and research programmes. the role of visceral trauma surgery should be reconsidered within the context of the surgical patients' needs and demands, and fundamental requirements of the profession. inter-hospital variation in surgical intensity for trauma admissions: a multicenter cohort study l. moore , m. p. patton , i. farhat , p. a. tardif , c. gonthier , a. belcaid , f. lauzier , a. turgeon , j. clément université laval, social and preventive medicine, québec, canada, chu de québec-université-laval, québec, canada, introduction: guidelines for trauma patients are increasingly moving away from surgical management towards less invasive procedures but there is a knowledge gap on how these recommendations are influencing practice. we aimed to assess inter-hospital variation in surgical intensity for trauma patients and identify determinants of surgical intensity. materials and methods: we conducted a retrospective multicenter cohort study based on the trauma centers of an inclusive canadian provincial trauma system. we included adults admitted for major trauma between and . analyses were stratified for orthopedic (n = , ), neurological (n = , ) and thoracoabdominal surgery (n = ). surgical intensity was quantified with the number of surgical procedures during the first h. inter-hospital variation was assessed with the intra-class correlation coefficient (icc) from multilevel poisson regression models. relative risks (rr) were generated to identify determinants. results: moderate inter-hospital variation was observed for orthopedic surgery (icc = . %, % confidence interval [ci]: . - . ) whereas variation was low for thoracoabdominal surgery (icc = . %, % ci: . - . ) and neurosurgery (icc = . %, % ci: . - . ). level iv centers had similar surgical intensity for thoracoabdominal injuries (rr: . , % ci: . - . ) but lower intensity for orthopedic injuries (rr = . , % ci: . - . ) than level i/ii centers. during the study period, we observed a decrease in intensity for neurosurgery (rr for (rr for - versus . , % ci: . - . ) and thoracoabdominal surgery (rr = . , % ci: . - . ). conclusions: the observed inter-hospital variation in risk-adjusted surgical intensity suggests that there may be opportunities for quality improvement in surgical care for injury admissions. a better understanding of how surgical intensity influences clinical outcomes is needed to inform quality improvement activities. pre-hospital injury diagnosis a. easthope , m. marsden , g. grier barts and the london medical school, london, united kingdom, royal london hospital, centre for trauma science, london, united kingdom introduction: accurate pre-hospital diagnosis of a patient's injuries may improve care by facilitating effective intervention at the scene and reducing time to definitive treatment in hospital . we sought to assess the diagnostic accuracy of injuries by london's air ambulance (laa) clinicians and identify conditions in which clinical accuracy may deteriorate. materials and methods: a retrospective review was undertaken of all patients conveyed to the royal london hospital by laa from october for six-months. pre-hospital injury scores, coded using the abbreviated injury score (ais) were compared to hospital discharge ais. patient outcomes were evaluated in the case of underscored injuries. results: during the study period patients were seen and met eligibility. mean clinical sensitivity and specificity was % and % respectively. chest injury identification was most sensitive ( %) and pelvic injury least sensitive ( %). the relative risk (rr) of underscored injuries to the chest, abdomen and pelvis increased with decreasing glasgow coma scale (gcs) peaking at . (iqr . - . ). the average accuracy of injury identification was % with a negative predictive value of %. no overt patient morbidity resulted from a missed, or under-scored injury. all missed injuries were subsequently identified in the emergency department. conclusions: the pre-hospital diagnosis of injuries has reasonable sensitivity and excellent specificity. accurate pelvic injury diagnosis is more challenging than chest or abdomen. with decreasing gcs, the risk of missing injuries increases. clinicians should be aware of the potential for error when treating trauma patients with impaired conscious levels. comorbidities, injury severity and complications predict mortality in severe thoracic trauma: a retrospective analysis from the norwegian national trauma registry of epidemiology, clinical factors and risk factors for mortality of patients with thoracic injuries. materials and methods: adult patients treated for severe thoracic trauma (injury severity ais c ), between and at haukeland university hospital were included. data were extracted from ( ) the haukeland university hospital local trauma registry, and ( ) the norwegian trauma registry. additional data on comorbidities and complications was collected from patient records. the factors age, gender, comorbidities [charlson comorbidity index (cci)], anticoagulant use, injury severity [revised trauma score (rts)], [injury severity score (iss)] and complications [clavien-dindo scale (cds)] were analyzed for being predictive of in-hospital mortality. multivariate logistic regression analyses with backward selection methods were used. results: data of patients were analyzed, of which ( %) patients died. median iss was in the non-survivors (iqr , ) and (iqr , ) in survivors (p = . ). data of patients were used in the risk factor for mortality analysis. two or more comorbidities measured by cci (or: . , p = . ), injury severity measured with the rts (or: . , p = \ . ), and grade c complications on the cds (or: . , p = . ) were significant predictors for mortality. conclusions: severe comorbidities significantly decreased the chances of survival after thoracic trauma. injury severity was also found to be a significant predictor of mortality. physiological injury severity, measured by rts, appeared to be a stronger predictor of mortality than iss after thoracic trauma. finally, severe complications led to considerably higher risk of mortality following thoracic trauma. the psychosocial impact of e-bike accidents and changing values of older patients in the netherlands, a qualitative study s. berben , l. vloet , e. c. t. tan , m. edwards , , a. brants , , , g. olthuis , , , , a. oerlemans , , , , f. haverkamp , , introduction: the mechanical impact of e-bike accidents, increasingly used by older persons, has shown to be higher compared to regular bike accidents. however, the psychological impact of e-bike accidents in older trauma patients, their experiences in emergency and follow-up care, and the possible change in values and beliefs in response to the accident is still unknown. materials and methods: we used a qualitative design and included older patients ( ? years) with a variety of (severe) injuries, who were admitted to the emergency department after an e-bike accident (n = ) and their relatives (n = ). they were interviewed within one month (t ) and after three months (t ) of the date of accident. interviews were transcribed verbatim and analyzed via a thematic analysis approach using an ethical perspective. results: many patients required (in)formal care after hospital discharge. in general patients were satisfied with the provided emergency surgical care, although some patients reported limited and insufficient information on rehabilitation and homecare support. the analysis yielded impaired physical condition, anxiety, increased vulnerability and dependency of care givers as psychosocial impact. freedom impairment, shifting relational autonomy, and confrontation with vulnerability and mortality were reported changes in values. central values as mobility and freedom, vitality and health, social participation and recreation were put under pressure and needed to be negotiated again after the accident in order to decide whether to use the e-bike again. conclusions: follow-up information of surgeons and emergency physicians after initial hospital care for older trauma patients with an e-bike accident shows room for improvement, with more specific consideration for the psychological impact of trauma and changes in values after e-bike accidents. eur j trauma emerg surg. . https://doi.org/ . /s - - - . traumatic subaxial cervical fractures: functional prognostic factors and survival analysis introduction: the main goal of this study is to identify the risk factors for poor functional outcomes and to analyze the overall survival (os) and complications rate in patients with traumatic cervical spinal cord injury (sci) and subaxial cervical fracture (sacf) treated with open surgical fixation. materials and methods: the authors retrospectively reviewed sixtyfive consecutive patients from one single center with traumatic unstable sacf and associated sci treated surgically between and . we exclude cervical fractures with concomitant severe head injury, brachial plexus injury, lumbar plexus injury, superior or inferior limb fractures and patients who were lost during the followup period. statistical analysis using a chi square test, student's t-test and logist regression were used to identify factors associated with poor functional outcomes after surgical treatment. os analyses were performed using kaplan-meier curves. results: the -year survival rate was . %. four patients died in the first days after surgery and , % need a reoperation. the median time from injury to surgery was . days. the complication rate was %, being respiratory failure the most common one. preoperatively, % had an asia \ c. about % of the patients with asia between a-d had improve one or more asia grades. logistic regression analysis show that older age, sacf above c , asia \ c pre-surgery and long time from injury to surgery were related with poor prognosis. the os rate was higher in patients with neurological improvement, without signs of neurogenic shock at presentation and in sacf bellow c . conclusions: our results suggest that sacf should be treated as soon as possible in order to improve the os rates and functional outcomes. older patients, lower asia at presentation and sacf above c are related with worst functional outcomes. introduction: compression fractures of multilevel vertebral bodies are common in children. due to segmental plasticity, several adjacent vertebral bodies are compressed to a lesser degree at each body. plain ap and lateral x-ray is the first diagnostic examination in the emergency department (ed), but a proper diagnosis is often delayed or missed. materials and methods: this is a retrospective, monocentric study in children falling on their back who showed up at the orthopedic ed, between december and september . nine children ( f, m) with an average age of . years were included. trauma occurred playing games and doing sports in all cases. all children were subjected to x-ray, followed by mri scans for doubtful findings on the plain x-ray or persistent mild pain (t , t , t -stir sequences). results: cuneiform vertebral fracture or vertebral body height reduction was diagnosed with x-ray in five vertebrae while mri showed fractures in vertebrae including compression and edema of adjacent vertebrae in the t -stir sequence. therefore only . % vertebral fractures have been detected by plain x-ray. the injured vertebral bodies were so distributed: t n = , t n = , t n = , t n = , t n = , t n = , t n = , t n = , t n = , t n = , l n = , l n = , s n = , s n = . the most involved spine section was between t and t with fractures. conclusions: vertebral fractures are not always related to hyperflexion or forward hinging mechanism. mri showed vertebral compression fractures and the t -stir sequence showed edema as post-traumatic evidence that had not been detected by x-ray. in absence of a radiologically visible lesion, the persistence of pain should be investigated by performing mri scans. the middle thoracic spine level appeared to be the most involved one in pediatric vertebral fractures. introduction: occipitocervical fixation (ocf) is an effective surgical method to treat various craniovertebral junction (cvj) pathologies. a rigid fixation achieved from ocf displaces other techniques of cvj stabilization unfortunately during procedure deep and wide wound is performed. aim of this study is to share our experience in ocf and lately performed percutaneous ocfs with intraoperative ct guided navigation system. materials and methods: of patients who underwent ocf were performed percutaneously. o-arm ct scans were used to illustrate and measure radiologic parameters. screws were implanted in c lateral masses ( ) , isthmus of c ( ) and c pedicles ( ) and assessed according gertzbein robbins (gr) in modification of bredow classification from a to e. results: a total screws were implanted, of them was performed in open surgery and percutaneously. outcome in gr classification for screws implanted in open surgery was: a ( , %), b ( , %), c ( , %), d ( , %) and e ( , %) while in percutaneous: a ( , %) and b ( , %) . in open surgery one screw was revised. conclusions: percutaneous occipitocervical fusion seems to be a good option to achieve desirable effect in cervical pedicle screws implantation. during procedure whole nuchal muscles are preserved. ct guided surgery and microscope view are necessary to perform percutaneous ocf. introduction: studies have found higher risk of traumatic deaths in rural areas in norway combined with a paradoxically decreased prevalence of severe, non-fatal injuries ( ) . this study investigates the risk of fatal and non-fatal injuries among all adults in norway in the period - . materials and methods: all traumatic injuries and deaths among persons with residential address in norway from - were included. data was collected from the norwegian patient registry and the norwegian national cause of death registry. all cases were stratified according to six groups of centrality based on statistics norway's classification of centrality . mortality-and injury rates was calculated per , inhabitants per year. results: the mortality rate differed significantly according to the levels of centrality (p \ . ). the mortality rate in the most urban group ( ) was . and in the most rural group ( ) . . the lowest mortality rate was found in centrality group ( . ). there was an increased risk of death between centrality group and group with a relative risk of . (ci: . - . , p \ . ). the most common cause of death was transport injuries, self harm, fall injury and other external causes. the highest urban-rural gradient was seen in transport injuries with a relative risk of . (ci . - . , p \ . ) comparing group to group . group had the lowest risk of nonfatal injuries ( ) and group the highest ( ). the risk of nonfatal injuries increased with higher grade of rurality, comparing group and revealed a relative risk . (ki . - . , p \ . ). conclusions: the more rural the higher risk of traumatic deaths and non-fatal injuries. transport injuries had the highest urban-rural gradient. references: . bakke hk, hansen is, bendixen ab, morild i, lilleng pk, wisborg t. fatal injury as a function of rurality-a tale of introduction: virtual fracture clinics (vfcs) are an alternative to conventional fracture clinics for management of musculoskeletal injuries. they have been shown to be a safe and effective model for upper and lower limb injuries. there is limited data to support their use for specialist thoracolumbar fracture follow-up. materials and methods: lean methodology including process mapping was applied to identify a safe virtual alternative for the pathway. first cycle analysis of consecutive referrals to a traditional specialist thoracolumbar fracture clinic. second cycle analysis of consecutive referrals six months after introduction of a vfc. results: mean time to first outpatient review in first cycle was days. referrals led to booked outpatient appointments and were missed ( % non-attendance). % of referrals had or more scheduled appointments. / were ao type a - and all of these received non-operative treatment. / were ao type a or b and of these received non-operative treatment. patient received operative stabilisation (ao type b). process mapping identified two pathways-virtual review with advice letter and physiotherapy referral (outcome a-ao type a - ) or face to face review (outcome b-ao type a or b). mean time to outpatient review in second cycle was days. / received outcome a. / ( %) made a telephone call for advice and only / ( %) asked for a face to face appointment. / received outcome b and all were discharged after one visit. patients in cycle required operative stabilisation. statistically significant reduction in number of scheduled face-to-face reviews ( versus ; p \ . ) and mean time to first review ( days versus days; p \ . ). conclusion: virtual thoracolumbar fracture clinics are a safe and clinically effective alternative to traditional fracture clinic models. lean methodology can be uses to extend virtual clinic pathways to specialist trauma clinics. treatment prognosis of cases of fragility fracture of pelvis m. yoshida fujita health universityhospital, emergency, aichi, japan introduction: the number of cases of fragility fracture of pelvis in the elderly has been increasing in recent years, but there are still not enough reports of surgical treatment as a treatment method, but there is still no certainty how to treat. so we investigated prognosis of cases of fragility fracture of pelvis. materials and methods: subjects were fragility fracture of pelvis treated at a single center from april to april , males, females, average age ± . years. only cases that had ct scan were included. we examined rommens classification, the presence of injury, presence of hip implants, functional prognosis, and -year mortality. results: the breakdown of rommens classification is type ia cases, ib cases, iia cases, iib cases, iic cases there were cases of iiia, cases of iiic, case of iva, cases of ivb, and cases of ivc. surgical treatment was indicated in cases ( . %) (iic case, iiia cases, ivb cases, ivc cases) there were cases ( . %) with no injury mechanism and cases ( %) with hip implants. cases ( %) were able to follow up for more than year including telephone surveys, and . % of them did not recover to functional level before injury. the one-year mortality rate was . %. conclusions: in the cases studied here, cases ( . %) were indicated for surgery. the prognosis and mortality rate are almost the same as those reported overseas, and as with proximal femoral fractures, there is a possibility that it may be greatly involved in adl decline in the elderly. we think that further study is needed in the future. conclusions: patients with a femoral neck fracture who received a hip hemiarthroplasty and used anticoagulation had no significant longer delay to surgery and had a higher mean loss of hemoglobin points. as a clinical consequence of this, more packed cells were supplemented. also more postoperative hematomas were found in the population with anticoagulation. no differences were found in mortality rates at -days and one year. results: on all eight patients the easy-approach was applied without adverse events. in four cases the plate osteosynthesis was done completely endoscopically with excellent results for the patients regarding pain relief and scar development. in the remaining four cases the endoscopic stabilization was not performed for the following reasons: in the first overall case primarily only the endoscopic approach was planned. in the fourth overall case, ventilation showed high end-expiratory co -levels after endoscopic situs preparation, so we converted to the open plating. in the fifth overall case, the easyapproach was applied to evacuate a retrosymphyseal hematoma in a patient with a stable pubic rami fracture. in the eighth overall case, the anterior pelvic ring injury was a bilateral multifragmentary pubic rami fracture in combination with a disruption of the symphysis. after endoscopic situs preparation with clipping of the corona mortis vessel, reduction of the displaced symphysis could not be done endoscopically. conclusions: we demonstrated that the endoscopic plate osteosynthesis of the anterior pelvic ring is feasible with existing standard laparoscopic instruments. the evaluation of the easy-approach in the clinical setting is going on, while the development of suitable reduction tools is one major goal of future studies. introduction: retrograde intramedullary pubic ramus screw fixation is less invasive method and biomechanically stable compared to the plate fixation. the purpose of this study is to examine the feasibility of screw insertion using computed tomography (ct). materials and methods: we analyzed sixty ct data ( cases in male and female each). by using ct analyzing software, the virtual column with . mm diameter was inserted so that we analyzed the feasibility of the screw insertion. and the intramedullary diameter of the pubic ramus at the parasymphyseal area, base, and acetabulum were measured. results: the virtual . mm diameter screws could be inserted in % ( / ) in male and . % ( / ) in female. the cause that screws insertion was impossible was penetration to the hip joint in all cases. the screw inserting point was . mm and . mm from the medial border of the pubic symphysis and . mm and . mm from the upper border of the pubic symphysis in male and female respectively (p [ . ). the intramedullary diameter of pubic ramus was . mm, . mm and . mm at parasymphyseal area, . mm, . mm and . mm at the base of pubis, and . mm. . mm and . mm at the acetabulum in male, female who had the screw corridor and female who didn't have the screw corridor respectively. the diameter of the pubic ramus of the female who didn't have the screw corridor was significantly small compared to male and pubic ramus in three measuring points (p \ . ). , % of the screws were revised. there were no neurovascular or urologic complications. radiographic nonunion was observed in % with a minimum follow-up of months, this correlated with a peri-implant infection (p . ), operation [ months after trauma (p . ) and non-significantly with implant loosening (p . ). there was no correlation of nonunion with patient's age, the fracture mechanism or a non-excellent reduction. in total, . % of the patients were re-operated, in . % a re-osteosynthesis was conducted. conclusions: retrograde trans-pubic screws show good clinical results with lower or similar complication rates compared to alternative methods as plate fixation or external fixator. fracture union did not depend on fracture mechanism or age. hence, this minimal-invasive method is especially attractive in elderly patients with an ffp. because it is an internal fixation of the superior pubic ramus with relative stability, an anatomic open reduction is not necessary to achieve fracture union. the need for extraperitonal pelvic packing -finally confirmed to be vanishing? introduction: the presence of cerebral venous thrombosis (cvt) is increasingly recognized in traumatic brain injury (tbi), but its complication rate and effect on outcome remains undetermined. in this study, we characterize the complications and outcome-effect of cvt in tbi patients. materials and methods: in a retrospective, case-control study of patients included in the oslo university hospital trauma registry and radiology registry from - , we identified patients with cvt (cases) and without cvt (controls). groups were matched regarding abbreviated injury severity (ais) head region score - . cases were identified by ais or icd-code for cvt and a ct/mr venography confirmed to be positive for cvt, whereas controls had no ais or icd-code for cvt and a ct/mr venography confirmed to be negative for cvt. risk of mortality was assessed using multivariate logistic regression adjusting for initial gcs, iss and rotterdam score. results are also reported for subgroups according to cvt location ( fig. introduction: the aims of this prospective cohort study were (i) to identify trajectories of recovery in patients with mild traumatic brain injury (mtbi) during the first two years after trauma and (ii) assess patients and injury characteristics for these trajectories. materials and methods: all adult trauma patients with mtbi (aisseverity or and an injury severity score \ ) who were admitted to a hospital in a region of the netherlands from august to november were asked to complete questionnaires. the questionnaires could be completed at week, and , , , and months and included the euroqol- -d for health status, including a cognition dimension, the hospital anxiety depression scale (hads-d and hads-a for symptoms of depression and anxiety respectively) and the impact of event scale (ies) (for post-traumatic stress symptoms). latent class trajectory analysis was used to determine trajectories of recovery in latentgold . , patient and injury characteristics of the classes were assessed in ibm spss . . results: a total of patients ( % of total) completed at least one follow-up questionnaire. the number of classes (trajectories) ranged from for cognition to for depression. poor recovery classes of cognition and health status consisted of mostly females, patients with low education, higher age, longer length of stay at the hospital and frail patients. the class with full recovery consisted of young patients, with most recovery occurring during the first six months after injury. patients who reported poor health status before injury scored significantly lower health status after injury and showed no recovery over time. conclusions: different recovery patterns were present in patients with mild traumatic brain injury. especially frail elderly patients who reported poor health status before injury have poor outcome up to months after injury. post-concussive symptoms in children and adolescents with traumatic brain injury: a center-tbi study introduction: acute respiratory is associated with high morbidity and mortality. in addition, its etiologies are heterogeneous and the outcome depends on the underlying cause. the aim of the present study is to analyze, whether the mortality of posttraumatic ards is affected ( ) over time, ( ) attributable to geographic distribution, ( ) related to the used definition and ( ) introduction: many factors of trauma care have changed in the last decades. this review investigated the effect of these changes on overall and cause-specific mortality in polytrauma patients admitted to the intensive care unit (icu). moreover, changes in trauma mechanism over time and differences between continents were analyzed. materials and methods: a systematic review of literature on overall mortality in polytrauma patients admitted to the icu was conducted. overall and cause-specific mortality rates were extracted as well as the trauma mechanism of each patient. linear regression on changes in overall and cause-specific mortality rates was performed. results: thirty studies, which reported mortality rates for , observed patients, were included and showed a decrease of . % in overall mortality per year ( fig. ). brain-related death has become more common over the years, whereas multiple organ dysfunction syndrome (mods), acute respiratory distress syndrome and sepsis became less prevalent (fig. ) . mods was the most common cause of death in north america and brain-related death was the most common in asia, south america and europe (fig. a) . penetrating trauma was most often reported in north and south america and asia (fig. b) . conclusions: overall mortality in polytrauma patients admitted to the icu has been decreasing as a result of the improvements in trauma care. a shift from mods to brain-related death could be observed. more research on preventative measures for the latter is required to ensure a further decline in mortality. moreover, we have shown geographical differences in cause-specific mortality, which may provide learning possibilities between similar trauma centers resulting in improvement of trauma care introduction: aim of the current study was to assess an association between trauma patient volume of the intensive care unit and inhospital mortality. materials and methods: from data of the japan trauma databank, this retrospective cohort study selected adult (c y) trauma patients hospitalized in the intensive care unit with the injury severity score of c . after applying a multiple imputation on all the study variables, a logistic regression generalized estimating equation after adjustment for age, sex, mechanism of trauma, and the injury severity score as covariates and hospitals as a cluster assessed an association between quartile of patient volume in intensive care unit and hospital mortality. introduction: quality and content of early fracture hematoma (fh) dictate the healing process in long bone fractures. different reaming protocols for intramedullary nailing (imn) are available. however, the impact of reaming strategies on immune cell characteristics of early fracture hematoma is unclear. we hypothesized that the application of reaming irrigation and aspiration (ria) techniques optimizes cellular content of fracture hematoma. materials and methods: twenty-four pigs underwent standardized femur fracturing. then, animals were exposed to different protocols of imn. group a underwent no reaming prior to imn. group b was treated with conventional reaming plus imn and group c composed of animals treated with ria and subsequent nailing. fracture hematoma was collected h after reaming. fh-immune cells were isolated and studied by flowcytometry. cell viability was tested by annexin-v-labelling. neutrophil activation was determined by mac- /cd bcell surface expression levels, whereas fcyriii/cd -receptor expression was utilized to investigate neutrophil maturation. results: all animals survived the observation period. propertions of white blood cell subtypes in fh did not differ between conditions. however, the percentage of viable fracture hematoma immune cells was significantly higher in the ria-group, compared with conventional reaming (respectively mean . % vs. . %, p = . ). additionally, both neutrophil cd -expression (- %) and cd bexpression (- %) were significantly lower in those animals treated with ria compared with the conventional reaming condition. conclusions: this experimental study reveals that reamed irrigationaspiration (ria) prior to imn is associated with increased immune cell viability and less neutrophil senescence/activation in early fracture hematoma. this underlines the important role of imn in optimizing local cellular immune homeostasis during the formationphase of early fracture hematoma. introduction: the study and determination of the traumatic pattern in bicyclists-delivery employees. the recording of personal protective equipment and evaluation of the selection criteria of their self protection. materials and methods: a total of patients ( men and woman) with mean age of . years ( - years) were included over a study period from january to march . twenty-one patients admitted to the hospital with a total of injuries treated operatively, whereas injuries were treated conservatively. we recorded and evaluated the use of adequate personal protective equipment of these delivery employees. results: the mean hospitalization time was . days ( - days) . a total of thoracic injuries, traumatic brain injuries, spine injuries, lower extremity injuries and upper extremity injuries were recorded. surgical treatment concerned patients with upper extremities and patients with lower extremities injuries and the anatomic regions involved were the distal radius ( ), pelvic ring injury ( ), femoral fractures ( ), tibial plateau fractures ( ), patella fractures ( ), diaphyseal tibial fractures ( ), and ankle fractures ( ) . conclusions: the lack of an adequate personal protective equipment due to their low financial status in combination with the absence of driving professional education among workers in this category of delivery employees results in lower extremity injuries with the majority requiring hospitalization and surgery. further investigation is needed, as well as constant training and setting right criteria for the pursuit of such employment. results: a total of nine rct's ( patients) and the sixteen observational studies ( patients) were included. the pooled nonunion rate did not differ significantly between both treatment groups (risk difference: %; or . , % ci . - . ). more patients treated with nailing required re-intervention (risk difference: %; or . , % ci . - . ) with shoulder impingement being the most predominant indication. more patients treated with pate fixation developed radial nerve palsy compared to nailing (or . , % ci . - . ). notably the absolute risk difference is small ( %) and during follow-up the palsy resolved spontaneously in the majority of patients. nailing lead to a faster time to union (mean difference: . week, % ci . - . ), lower infection rate (risk difference: %, or . , % ci . - . ) and shorter operation duration (mean difference: min, % ci . - . ). functional scores were comparable in both groups (standardised mean difference: - . , % ci - . to . ). there was no difference between effect estimates form observational studies and rct's. conclusion: there appears to be no difference between plate fixation and nailing for humeral shaft fractures with regard to non-union rate and functional outcome. patients treated with plate fixation have a higher risk for infection and radial nerve palsy, but lower risk for reintervention. the absolute differences, however, are small. nailing does differ significantly from plate fixation in terms of shorter operation duration and time to union. the pooled estimates from randomised clinical trials did not differ significantly from estimates obtained from observational studies. post-traumatic complications are more often after medial clavicle injuries compared to lateral clavicle injuries introduction: medial clavicle injuries (mci) are widely unexplored, especially in contrast to lateral clavicle injuries (lci). current research concerning mci assumes a higher severity of mci, e.g. concerning concomitant injuries. our aim is to evaluate by big data analysis if these rare injuries would also lead to a higher number of post-traumatic complications. materials and methods: we focused on the mci subgroup consisting of medial clavicle fracture and sternoclavicular joint dislocation. the lateral clavicle fracture and the acromioclavicular joint dislocation were summarized to the subgroup of lci. the midshaft clavicle fracture was analyzed for comparison. the data are based on icd- codes of all german hospitals as provided by the german federal statistical office. anonymized patient data from to were evaluated. the retrospective analysis addresses the fracture healing in dislocation, delayed union and non-union. results: the proportion of all patients suffering from complications was . %, which were attributed to one of the three post-traumatic complications. each complication rate for the single injury and the single complication was rather low with a maximum of %. mci were more likely to be affected by post-traumatic complications than lci with a ratio of . to . times (p \ . ). the midshaft clavicle fracture was similarly frequently affected by complications with . % of all complications as the mci ( . %). the lci accounted for the smallest proportion at . %. conclusions: we proved that mci are more often associated with post-traumatic complications than injuries of the other parts of the clavicle. this is another hint that mci appear to be more complex than lci. this could be due to a missing standard procedure and the higher number of concomitant injuries in mci. further representative clinical studies are required since miscoding is a frequent issue in research concerning clavicle injuries, especially in a big data analysis. quantification of trauma center accessibility using gis-based technology introduction: there is no generally accepted methodology to asses trauma system access and optimal geographical trauma center distribution. the goal of this study is to determine the influence of trauma center(tc) distribution during high and low traffic density using geographical-information-system(gis)-technology. methods: using arcgis-pro, we calculated differences in transport time (tt) and population coverage in seven scenarios with , , or tcs during rush [r]-and low traffic [l] hours in a densely-populated region with tcs in the netherlands (fig. ) . results: in the seven scenarios, the population that could reach the nearest tc within (\) min, varied between - % ( fig. ) in the three-tc-scenario, roughly % of the population could reach the nearest tc \ min in [r] and [l] . the hypothetical scenarios with two geographically well-spread tcs showed similar results as the current three-tc-scenario. in the one-tc-scenarios, the population reaching the nearest tc \ min decreased by - % in both [r] and [l] compared to the three-tc-scenario. in the three-tcscenario the average tt increased with about . min to almost min in [r] , in comparison to min during [l] (fig. ) . similar results were seen in the scenarios with two geographically well-spread tcs. in the one-tc-scenarios and the geographically close two-tcscenario the average tt increased by - min [l] and - min [r] in comparison to the three-tc-scenario. conclusion: this study shows that a gis-model for trauma center access offers a quantifiable and objective method to evaluate trauma system configuration in areas with different geography and demography. applying this technology to one of the most densely populated areas in the netherlands shows that the transport time from accident to trauma center would remain acceptable if the current situation with three trauma centers would be changed to a scenario with two geographically well-spread centers. classifying posttraumatic stress disorder courses in physical trauma patients: an observational prospective cohort study introduction: the aim was to identify different courses of posttraumatic stress disorder (ptsd) in physical trauma patients. then, to examine whether these classes could be characterized by sociodemographic, clinical, psychological, and personality outcomes. methods: patients completed the impact of event scale-revised (ies-r), m.i.n.i.-plus after inclusion, , , , and months after injury to examine different courses. the hospital anxiety and depression scale, neo-five factor inventory, state-trait anxiety inventory-trait, and the whoqol-bref were completed after inclusion only. latent class analysis, chi square tests, and anova were performed to analyze the aims. results: in total, patients were included. the mean age was . (sd = . ) and % were male patients. the ies-r (see figure ) and the m.i.n.i-plus had five classes ( : moderately, : little bit, : worse, : none, : quite a bit of ptsd symptoms). patients in class are diagnosed with ptsd (cut-off score c ). on both questionnaires, patients (proportion & %) in class or , scored higher on anxiety, depressive symptoms, neuroticism, and trait anxiety compared to the other classes over months after trauma. lower scores on all domains, except for social domain on the ies-r, were found compared to the other classes (ies-r; physical domain: class vs. (mean ± sd): . ± . vs. . ± . , p-value = \ . ). psychological and personality outcomes were significantly different on all courses. also, patients in class or were younger compared to the other classes (ies-r; class vs. : . ± . vs. . ± . , p-value = \ . ). no medical outcomes for ptsd were found. conclusions: about % suffer from ptsd symptoms months after trauma. different courses were defined by sociodemographic, psychological, and personality characteristics. professionals can, short after trauma, recognize patients at risk for ptsd when they focus on these characteristics. then, an intervention can be offered. six meter, the criterion for severe adult trauma to falls from heights in cdc field triage needs to be lowered introduction: trauma is one of major public health care issue which is costly to society. differences vary from region to region, but blunt trauma accounts for a large part of the total trauma, and the rates of the falls from heights among the blunt trauma is getting higher. it is serious that falls from heights is often accompanied by severe multiple trauma. therefore, authors studied the relationship between the height of the fall/other related factors and outcomes including hospital stay/mortality. materials and methods: retrospective cohort study of the adult falls-from-heights patients visited a regional trauma center for years (from . . to . . ). results: of total patients, the number of d.o.a patients were . the height from falls of the deceased patients was statistically significantly higher than that of the survived patients. ( . ± . m vs. . ± . , p \ . ) the auc of the roc curve of the height from fall to mortality was . . (figure) the sensitivity of . m was . % and . m was . %, respectively. the traumatic brain injury, pelvis fracture, visceral organ injury, age, and the height from fall were statistically significant risk factors in multivariate analysis for mortality (p = \ . , . , , , . , and . respectively). conclusions: the height from the fall is closely related with mortality. we think the current height for the severe fall injury in cdc field triage for trauma is high and needs to be lower to . introduction: operative management of severe trauma is a team effort, requiring excellent communication skills. surgeons, anesthesiologists and nurses need to coordinate effectively in order to ensure an excellent clinical outcome. the definitive surgical trauma care (dstc), definitive anesthesia trauma care (datc) and definitive perioperative nurses trauma care (dpntc) courses provide an excellent opportunity to train efficient teamwork. we aimed to study the impact of the joint dstc-datc-dpntc courses in candidates' perceptions and skills in perioperative communication. materials and methods: study population of candidates ( surgeons, anesthesiologists and nurses) participating in a joint dstc-datc-dpntc course in coimbra, portugal. median age of years (range - ). female gender in ( %) of cases. all participants attended joint lectures, case discussions and surgical skills session, emphasizing intraoperative communication. postcourse survey on several aspects of peri-operative communication, with responses on a likert scale. participants were also asked which aspects of intraoperative communication they valued the most. statistical analysis with spps, . (wilcoxon signed rank test, significance with p-value \ . ). results: all participants responded to the survey. results displayed an increase in the self-assessed importance of team briefing and intraoperative communication, particularly routine periodic communication, rather than only at critical moments (p \ . ). postoperative team debriefing was also valued as highly relevant. closed-loop and direct, by-name communication were highly rated (p \ . ). self-reported communication skills improved significantly during the course (p \ . ). conclusions: joint training in the dstc-datc-dpntc courses provides a unique opportunity to improve candidates' self-awareness and skills in intraoperative communication. a public health approach to knife related trauma in liverpool: a geospatial study r. shellien , n. misra , , j. germain , m. whitfield aintree university hospital, emergency general surgery and trauma unit, liverpool, united kingdom, liverpool john moores university, public health institute, liverpool, united kingdom introduction: liverpool is a city that has undergone recent rapic socioeconomic change. despite reductions in overall deprivation, incidents of stabbings have increased by % in the last years. this study will describe the trend in knife crime, drawing on governmental data and policies to conclude the reasons behind the trend. materials and methods: a retrospective cohort study of patients presenting to north-west ambulance service (nwas) with a penetrating injury in liverpool between and . data collected included patient demographics, geography and timing of incidents and correlation to datasets of multiple indices of deprivation and knife crime prevention outreach education programmes. results: incidents of stabbings have increased by % between and . victims were more likely to be males ( %) between the ages of and ( %). the peak rate was between : - : ( . %) and trough between : - : ( . %). there is a spike in incidents of stabbings of - year olds from : to : , correlating with school closure. there appears to be statistically poor correlation between deprivation of lower super output areas and stabbings (r = . , . and . for , and respectively). however, when the data is split into larger areas, middle super output areas (msoas), deprivation appears to be a further risk factor. this study has identified certain geographical areas as high risk. conclusions: this study allows for targeted public health interventions at populations most at risk of knife trauma, including geographical mapping of high-risk areas, so that interventions can be distributed appropriately. references: ministry of housing, communities and local government ( government ( , government ( , introduction: trauma teams treat complex patients with injuries posing significant resuscitative and management challenges. effective teamwork is essential to optimise patient outcomes and improve survival, with failure contributing to adverse events [ ] . the role of multidisciplinary (mdt) trauma training has been demonstrated by the military operational surgical training course (most) [ ] . it is imperative that civilian trauma training adopts similar methodology to optimise team work. materials and methods: the three-day multidisciplinary trauma course comprised cadaveric-based skills teaching supplemented by lectures and real-life scenario discussion. delegates were senior surgical and anaesthetic registrars and consultants, alongside trauma team leaders (ttl), scrub staff and operating department practitioners (odp). pre-and post-course questionnaires assessed perceptions of multidisciplinary trauma simulation and confidence in specialty specific skills. results: all delegates reported mdt simulation clarified each role, including their own, in the trauma team. post-course, scrub staff and odps felt confident gaining intraosseous access (p \ . ), surgical delegates had improved confidence performing all skills (p \ . ), with anaesthetists and ttls more confident in haemorrhage control and performing resuscitative thoracotomy (p \ . ). conclusions: mdt trauma training improves team understanding of role and effectively teaches skills. mdt courses with experienced faculty are one way of improving mdt trauma team function. further careful evaluation is required to assess performance of trauma teams in real scenarios. introduction: despite a dramatic rise in youth knife crime, the factors associated with it remain underexplored, especially in the critical pre-college years, which hinders effective counter-knife carrying interventions. the current research is the first to addresses this deficit. materials and methods: british male school students (mean age = . , sd = . ) coming from four different schools completed a short -min survey. they indicated their standing on a number of dimensions (school-adapted and shortened-scale-based predictors) derived from theories of violence, developmental psychology and related research (i.e. violence acceptance, need for respect, belief in self-defence, belief in a just world, narcissism, psychopathy, impulsivity, sensation seeking, and need for closure). results: for perceived knife harmfulness (i.e., the knife's assumed value in inflicting injury and death)-the total variance explained by the model was . %, r = . ; f( , ) = . . the only statistically significant predictors were: right-wing authoritariamism (b = . , p = . ) and need for respect (b = . , p = . ). the other factors were not statistically significant. for the perceived value of knife defence (i.e., its assumed defensive worth in violent confrontations) -the total variance explained by the model was . %, r = . ; f( , ) = . , pviolence acceptance (b = . , p = . ), followed by need for closure (b = . , p = . ), narcissism (b = . , p = . ) and psychopathy (b = . , p = . ). conclusions: this study provides evidence for future knife-carrying prevention interventions, such as talks in schools or social media videos, to focus more on how to increase self-esteem, stimulate empathy for and better understanding of other people, and approach problems from multiple (rather than just two) perspectives, emphasizing the ultimate superiority of the human intellect over brute force. introduction: the physician's response unit (pru) is a novel service that operates from the royal gwent hospital's emergency department (ed), in newport, south wales. it involves an emergency medicine consultant and a paramedic responding to calls in a rapid response vehicle. their aim is to treat and, hopefully, discharge patients at the scene, reducing ed admissions. the pru can also refer patients on to other departments, e.g. the medical assessment unit, allowing patients to bypass the ed. methods: the author spent six weeks out in the pru and in the ed to observe and speak to patients. to assess whether ed admissions were reduced, the dispositions of patients seen by the pru were recorded on a daily log sheet. the service users' satisfaction with the pru was evaluated using simple questionnaires. this included both patients and paramedics, who can request the pru for support with a patient. results: the pru saw patients during the project's timeframe. % (n = ) of these patients were discharged at scene, while % (n = ) were sent to the ed. % (n = ) of patients asked described the care they received from the pru as equal to or better than care they have received previously. % (n = ) of patients rated their overall satisfaction with the pru as / . conclusions: the pru is very well received by both patients and paramedics and has been shown to reduce the number of patients attending the ed. this system excellently implements the principles of prudent healthcare introduction: in germany reducing alcohol related harms in youth is still a priority, because adolescents and young adults still have the highest accident risk in road traffic. therefore, the p.a.r.t.y.-project aim to increase awareness of alcohol and risk-related issues. the purpose of this study was to analyse the risk behaviour of adolescents before and after a prevention project in two different hospitals in germany. materials and methods: during a one-day prevention project, young people within the age of to years got an overview of the route an accident victim go through from the ambulance until the rehabilitation. before and after the prevention day, a structured written survey was completed by the adolescents. results: students participated in the p.a.r.t.y. program between and . the gender distribution of the participating students were balanced. the average age of the adolescent was years. according to the program, the risk assessment and risk behaviour improved through the project significantly (\ . ). the evaluation of the students' satisfaction was rated as good. the majority of students prefer to repeat the project day after years. conclusions: the prevention program shows that the program increase for short-term the awareness for risk related trauma in youth. nevertheless, long-term studies are necessary to receive data regarding the long-lasting effect. references: the present study is funded by the ministry for energy, infrastructure and digitization of the country mecklenburg-vorpommern, germany. development of a claims-based risk adjustment model for trauma introduction: duodenal injury is rare. the diagnosis requires a high index of suspicion which might result in delayed treatment. there is limited data on the delayed diagnosis group, especially high grade duodenal injuries. the purpose of this study is to determine the characteristics and outcomes of delayed high grade duodenal injuries. materials and methods: charts of all patients from - who had history of small bowel injuries are reviewed. the inclusion criteria were age between - years old, diagnosis with duodenal injuries at least grade with delayed operation at least h after injuries. baseline characteristics and postoperative outcomes were recorded. results: of the small bowel injuries, ( %) were duodenal injuries. the overall mortality was %. delayed diagnosis more than h with at least grade of duodenal injuries were cases. the overall in-hospital mortality rate of the delayed group was . % ( / ) who had concomittent hemorrhagic shock and low initial systolic blood pressure. cases ( . %) were diagnosed within h and had better outcomes without leakage. they could step diet within days and had shorter length of hospital stay (mean = days). patients ( . %) presented with delayed diagnosis more than h (the maximum was h after injuries). all these patients had anastomosis leakage and need reoperation. they had initial low level of serum albumin (mean . mg/dl), high white blood cell count, low serum bicarbonate and presented with preoperative acute kidney injury. conclusions: delayed diagnosis and surgical treatment of high grade duodenal injuries lead to poor outcome. low initial blood pressure associated with mortality and delayed treatment more than h had higher morbidity. references: gary sa, frederick am, charles sc, et al. delayed diagnosis of blunt duodenal injury: an avoidable complication. acs meeting. ; ( ) : - . routine follow-up imaging has no advantage in the non-operative management of blunt splenic injury in adult patients modality. the aim of this study was to investigate the incidence and time to failure of nom as well as to evaluate the relevance of follow-up imaging. materials and methods: all adult patients with bsi admitted to our level i trauma center, including two associated hospitals, between / / and / / were retrospectively analyzed. demographic data, injury severity score, splenic injury grade, modality, results and consequences of follow-up imaging were retrospectively analyzed. results: a total of patients with a mean age of . ± . years ( - years) met inclusion criteria. patients ( . %) underwent immediate intervention. patients ( . %) were treated by nom. failure of nom occurred in patients ( . %). failure was significantly associated with active bleeding (or . , % ci . , . , p = . ) , and liver cirrhosis (or , % ci . , . , p = . ) . patients ( . %) in the nom-group received followup imaging by ultrasound (us, n = ) or computed tomography (ct, n = ). in cases, routine imaging examinations were conducted ( us and ct scans) without prior clinical deterioration. ( . %) of these imaging results revealed no new significant findings. every failure of nom was detected following clinical deterioration. conclusions: to our knowledge this study includes the largest monocentric patient cohort undergoing ultrasound as first-line followup imaging modality in the nom setting of bsi in adult patients. the results indicate that a routine follow-up imaging, regardless of the modality, has no therapeutic advantage. indication for radiological follow-up should be based on clinical findings. if indicated, a ct scan should be used as preferred imaging modality. the association between bmi and mortality of renal injuries in adult trauma patients introduction: the role of body mass index (bmi) on solid organ injuries remains debatable. while some studies have shown no association between bmi and hepatic or splenic injuries, others have reported that severe hepatic injuries were more common in pediatric patients with bmi [ . the aim of this study is to examine the association of bmi and mortality, as well as any significant differences between operative vs. non-operative management. materials and methods: this was a retrospective study using the american college of surgeons-trauma quality improvement program database to identify all adult patients (ages to \ ) with traumatic renal injuries. the primary analysis showed a different pattern of mortality between patients with bmi \ and those with bmi c kg/m . then, the study population was divided into patients with bmi \ and those with bmi c kg/m . multivariable logistic regression was conducted to assess any association of mortality with age, gender, bmi, and injury severity score (iss). results: adult trauma patients were identified. a greater proportion of males ( . %) and females ( . %) had bmi \ kg/m (p = . ). the average age of patients with bmi \ kg/m was . (sd = . ) years which was significantly younger than that in patients with bmi c kg/m , . (sd = . ) years (p = . ). patients with bmi \ kg/m were found to have a significantly higher mortality rate of . % vs. . % in patients with bmi c kg/m (p = . ). however, there was no significant difference in type of operative or nonoperative management between patients with bmi \ vs. bmi c kg/m . after multivariable logistic regression, mortality was associated with age, bmi and iss. no effect modification of sex was observed in the relationship of mortality and bmi. conclusions: adult patients with renal injuries and bmi \ kg/m have significantly higher rates of mortality compared with adult patients with renal injuries and bmi c kg/m . introduction: trauma is an ever-evolving surgical discipline. trauma remains a major source of global mortality. the operative and non-operative options for trauma patients has steadily increased. the development of trauma protocols, advancement in transport to trauma centres and radiological techniques has seen a shift in trauma surgery caseload. observing and understanding this shift from operative management to an increasing non-operative management of trauma cases will better prepare the acute medical team in this setting. materials and methods: prospective trauma registry data was collected and analysed retrospectively. patients presenting to a tertiary referral hospital between jan to dec with an injury severity score of [ were reviewed. patients who were transferred to another facility for management were excluded. the demographic data and surgical outcome data were collected and analysed. trend analysis of the operative cases performed for each specialty. results: major trauma patients presented to the john hunter hospital between january to dec . there was a non-statistically significant increase in the number of presentations ( pt in vs in , p = . ). there was a decreasing rate of operations performed for trauma patients ( % in vs % in , p \ . ). there was an increasing rate of orthopaedic surgery cases and operative time compared to other specialties ( in vs in , p \ . ). general surgical major trauma operating cases noted a significant decline over the study time ( in vs in , p \ . ). conclusions: there is a sizeable shift in the caseload of different surgical specialties in regard to major trauma patients over the course of years from to . orthopaedics has seen a significant increase in operative caseload and surgical time required to adequately manage major trauma presentations. the workload and experience of general surgical teams will likely be affected by these changes. the distribution of resources needs to be reflected in the changing work demands of each surgical subspecialty. traumatic internal hernia with delayed small bowel strangulation after pelvic ring injury hospitalization, follow up abdomen ct checked. there was no other specific change than increased thigh hematoma. eight days after hospitalization, ct was re-examined due to abdominal pain with abdominal distraction. an ct showed peritonitis with pneumoperitoneum and small amount of ascites. small bowel herniation through right pubic bone fracture site with ischemic change also noted. diagnosis: diagnosis was traumatic pelvic hernia with delayed small bowel strangulation. therapy and progressions: an emergency operation was performed. ileal loop was hernitated and perforation was found. emphysematouns change and fluid collection was exsited at perineal area and left high. after small bowel loop segmental resection, wound vac was applied at thigh area. comments: traumatic pelvic hernia is rare. diagnosis is challenging in the acute setting and often delayed due to lack of awareness. when diagnosed, efforts should be made to look for other serious injuries as traumatic pelvic hernia usually associated with concomitant intraabdominal injuries. the optimal management of traumatic hernia should be individualised based on the mechanism and severity of injury, presence of concomitant injuries, size of defect, and presence of incarceration. delayed treatment may read to fatal outcomes. careful inspection of the patient is important. references: vincent k, cheah sd. traumatic abdominal wall hernia-a case of handlebar hernia. med j malaysia. ; ( ): - . angio-embolization in pediatric trauma patients with blunt splenic injury: a systematicreview t. nijdam , r. spijkerman , l. hesselink , t. hardcastle , l. leenen , f. hietbrink umc utrecht, traumasurgery, utrecht, netherlands, inkosi albert luthuli central hospital, trauma, durban, south africa introduction: non-operative management (nom) for children with blunt splenic injury (bsi) is nowadays a commonly used treatment in pediatric trauma departments. in adult trauma departments the addition of splenic angio-embolization (sae) is suggested to decrease the failure rate of nom in high grade splenic injuries. however, the use of sae in pediatric trauma departments is very uncommon and it is unknown if sae is of additional value in pediatric trauma patients. therefore, the aim was to analyze the available literature on sae in pediatric trauma patients with bsi. materials and methods: a literature search was performed to find eligible studies that analyzed sae in pediatric patients with bsi. the primary outcome was failure of treatment in these patients. secondary outcomes were the success rate of sae, length of stay and mortality. the relative risk (rr) was calculated to compare primary outcome between study groups. results: in total studies were identified through the search, a total of studies matched our inclusion criteria and were selected for this review. studies included a total of . pediatric patients, of whom underwent sae. patient age ranged from &lt; year to years, mean age was . years. both injury severity score and spleen injury grade were higher in the sae group compared to the nom group. failure rate of sae was %. no spleen related morality was observed in the sae group. conclusions: the literature suggests that sae might be of added value in a very selective group of pediatric trauma patients with high grade splenic injures. however, since limited evidence is available concerning the use of sae in pediatric trauma patients with bsi, no firm conclusions can be drawn about safety and effectiveness. introduction: the management algorithms for trauma have changed with the development of specialised trauma centres. the aim of this study was to review the management and outcomes of patients with traumatic small bowel (sb) and colonic injuries. material and methods: patients treated for sb and colonic injuries between - at aintree university hospital (liverpool) were identified using the prospective trauma audit and research network database. the management and outcomes of the patients included were analysed. results: patients sustained sb and colonic injuries. there were ( . %) sb injuries and ( . %) colonic injuries ( patients had a sb and colonic injury). patients ( . %) of injuries were due to knife stabbing wounds, ( . %) patients were due to gunshot wounds, and ( . %) patients were due to road traffic accidents/ blunt blows. damage control surgery was performed in ( . %) patients. colonic injuries included ( . %) haematomas and ( . %) perforations. a resection and stoma (rs) procedure was performed in patients ( . %), primary repair (pr) in patients ( . %) and resection with anastomosis (ra) in patients ( . %). sb injuries included ( . %) haematomas and ( . %) perforations. pr was performed in ( . %) cases and ra in ( . %) cases. the overall complication rate after sb and colonic injury was % ( patients) with a significant complication rate ( patients, p value = . ) for patients undergoing rs in colonic trauma. the -day mortality rate was . % ( patient). conclusions: pr in sb and colonic injuries appears safe. in our dataset, rs appeared to have a higher complication rate. our study highlights that such injuries are uncommon with a high complication rate. surgeons need to provide individualised treatment. introduction: nowadays, patients with high grade bsi are preferably treated using spleen preserving treatments (spt). it is assumed that patients with low grade bsi treated with spt have a good splenic function after recovery. however, there is no consensus on splenic function after high grade bsi. in several institutions, asplenic/hyposplenic infection prevention protocol will be executed in all patients who had spt after high grade bsi, where other institutions evaluate splenic function first. scintigraphy is believed to be the best flow/activity test to approximate splenic functionality. the aim of the study was to analyze whether spleen injury grade is associated with diminished splenic function. secondarily, we aimed to evaluate whether splenic function testing is necessary in pediatric patients after bsi. material and methods: a retrospective study was performed from january to january . in our institution patients with bsi grade iv of v are assumed hyposplenic and will receive a splenic function test. we included all patients with a minimum follow-up test period of days. all tests were analyzed by the radiology specialist. for each patient we furthermore collected clinical data, including the date of trauma, gender, age, mechanism of injury, ais of splenic injury and iss. results: patients consisted of male and female, with a median (iqr) age of . ( . - . ) . median iss was . ( - . ) and the median spleen ais was ( ) ( ) . nom was used in patients, sae in five patients and two patients were treated with surgical mesh technique. the median follow-up time of all performed tests was ( - ) days. a total of patients ( %) had a grade iv or v splenic injury. scintigraphy was utilized to test most patients. a total of out of patients had an adequate splenic function, including all sae patients. conclusions: even high grade splenic injuries show adequate splenic function in the follow-up of pediatric trauma patients after bsi. therefore routine diagnostic follow-up by scintigraphy is not necessary in this specific patient group. evaluation of abdominal injuries treated at stavanger university hospital: occurrence, severity and mortality j. w. larsen , k. søreide , , j. a. søreide , , k. tjosevik , k. material and methods: retrospective evaluation of data recorded prospectively in the hospital's trauma registry between january and december . patients with abbreviated injury scale (ais) code for abdominal injury were included. descriptive analyzes are presented for demographic data, injury type, mechanism, and severity, as well as -days mortality. results: a total of patients with abdominal injuries were included ( . % of all trauma patients). % where men. median age was . the injury mechanism was blunt in %. transport accidents were the most frequent cause of injury ( %). median iss was , and median niss . overall -days mortality was . %, with a median trauma injury severity score (triss) of , . multiple abdominal injuries were recorded in % of the patients. % had associated injuries in other body regions, most frequently in the thoracic region ( . %). solid organ injury occurred in % of the patients, with liver injury ( %), splenic injury ( %), and kidney injury ( %) encountered most frequently. an ais score c was found in % of liver injuries, % of splenic injuries, and in % of patients with kidney injuries. hollow viscus injuries were found in % of the patients. injuries to the small intestine ( %) and colon ( %) were most frequent. abdominal vessel injuries were encountered in %, and % of these had an ais score c . conclusions: abdominal injuries are dominated by solid organ injuries following blunt injury mechanism and are often associated with concomitant thoracic injury. patients who dies within days from admission are characterized by a low probability of survival shown by triss. pancreatic trauma management in a third level centre a. gonzález-costa , r. gracia-roman , s. montmany-vioque , a. campos-serra , r. lobato-gil , c. zerpa-martin , f. j. garcía-borobia , p. rebasa-cladera , s. navarro-soto management. the aim of the study is to review the management and describe the most frequent complications of pancreatic trauma in our centre. material and methods: observational study with prospective collection of data, from march to march . inclusion criteria: trauma patients older than admitted to the emergency department who were admitted to icu or died before admission. demographic data has been collected, also vital signs, iss, mechanism of action, mortality, complications, and lesions. results: between and , polytraumatic patients were registered. only had pancreatic trauma ( . %). the male: female ratio was : ; with an average age of . years (sd . ) . mean iss of . (sd . ), mean ais of . (sd . ) and mortality of . % ( patients). the most frequent pancreatic lesion was at the head of the pancreas ( patients; . %), followed by body-tail ( patients; . %) and two patients with full section ( . %). . % of patients were treated with non-operative management. five patients required urgent surgery ( %), requiring corporocaudal pancreatectomy in cases and drainage in patients. an embolization of a gastroduodenal artery aneurysm was performed in patient. respiratory complications were the most frequent. patients developed a pancreatic fistula ( . %), although in surgical patients this complication was much higher ( % in our series). one of them required puestow pancreaticojejunostomy and patient developed necrotizing pancreatitis ( . %). conclusions: pancreatic trauma is very uncommon. its management can be difficult, depending on the degree of injury (aast), with a high rate of complications. therefore, combined management and monitoring by the surgery and intensive care team will be very important. introduction: the aim of this retrospective study was to evaluate and compare the clinical outcomes of conservative versus surgical treatment in a series of patients with liver injury. material and methods: between - , there were included patients. according the treatment chosen, the patients were subdivided in two groups. non-operative management was considered in hemodynamically stable patients. the failure of conservative treatment was defined as need to resort to operative management after a period of strict monitoring when the reason was related to the liver or associated injuries or need for late angioembolization. all hemodynamically unstable patients were subjected surgical treatment. results: conservative treatment was selected for patients and only in of them was failed due to associated delayed bleeding and small bowel injury. patients underwent emergent surgery which included packing, lobectomy and splenectomy. operative findings revealed grade iii liver injuries in % and grade iv in %. pneumonia, sepsis and ards were the most frequently associated complications. the overall mortality rate was . %. in patients of conservative group, non-surgical treatment failed with surgery being required. the mortality in the group of patients who underwent emergent laparotomy on admission was of patients. conclusions: conservative treatment of blunt traumatic hepatic injuries is applicable in patients presenting hemodynamic stability with mild hepatic injuries and it could be successful even in high graded injuries with low morbidity and mortality. surgical treatment is indicated in grade v injuries. nevertheless, failure of conservative treatment does not necessarily lead to an increase in the incidence of complications or mortality. with the trend towards more conservative management strategies, surgeons' exposure to laparotomies for blunt injuries in rtas has decreased. the aim of this study was to examine surgeons' exposure to laparotomies following blunt trauma which remains important to maintain low patient morbidity and mortality rates. material and methods: data was collected for adult patients admitted to mater dei hospital (malta) following rtas with ctproven intrabdominal injuries between january and january . results: patients ( ( . %) males vs. ( . %) female (p value \ . ), mean age = . years) were included in the study. patients ( . %) were car occupants whilst patients ( . %) were pedestrians. ( . %) patients had single intraabdominal organ injury, whilst ( . %) had multiple intraabdominal organ injuries. the -day mortality rate was . % ( patients). liver injuries occurred in ( . %) patients, splenic injuries occurred in ( . %) patients, kidney injuries in ( . %) patients and other organs were injured in ( . %) patients. conservative management was followed in ( . %) patients, angioembolisation was utilised in ( . %) patients and operative management was performed in ( . %) patients during the -year period. this resulted in trauma laparotomies following rtas per year. conclusions: only a minority of patients require operative management after rtas. surgeons in small countries have limited exposure to complex rta's. in view of the low exposure to emergency laparotomies following rtas, changes to our local training programme was done. trauma courses, lectures and fellowships in eu have been implemented to maintain surgical skills to an optimal level. references: european commission, annual accident report. european commission, directorate general for transport june . case history: a year old female presented to the accident and emergency department h post colonoscopy with complaints of left sided abdominal pain. this colonoscopy was requested under a -week wait for a history of chronic diarrhoea. this was a complete and uneventful examination ath the time, with random colonic and ileal biopsies taken. she attended a ? e with left sided abdominal pain increasing in severity. clinical findings: she was found to have an exquisitely tender abdomen, experienced more in the left upper quadrant. she was clinically shocked with a marked hypotension and tachycardia. investigation/results: a ct of her abdomen and pelvis showed free fluid within the abdomen and pelvis, with active bleeding and large haematoma adjacent to the spleen. the grade of splenic injury however was not commented upon by the reporting radiologist. interventional radiological embolism was considered but unfeasible as patient not stable haemodynamically. diagnosis: she was diagnosed with a splenic injury post-colonoscopy, with internal bleeding and haemodynamic instability. therapy and progressions: she underwent an emergency splenectomy overnight and was transferred to the intensive care unit for postoperative care. she recovered well, was stepped down to ward level care and was discharged with post splenectomy protocols, including all necessary vaccinations. comments: splenic rupture post-colonoscopy is a very rare event, with less than cases reported worldwide since . however, it still should be considered as a cause of a ? e presentation in patients with upper abdominal pain and haemodynamic instability after recent colonoscopy. we wanted to present this rare case to the international audience of estes congress to raise awareness of this rare complication. clinical findings: hemorrhagic shock and consciousness disorder were observed. her abdomen was distended, and she was intubated in the emergency room. investigation/results: ct revealed massive intra-abdominal bleeding. diagnosis: massive intra-abdominal bleeding due to hepatic laceration. therapy and progression: damage control surgery (dcs) and transcatheter arterial embolization (tae) were performed. she was transported to a hybrid operating room. she experienced cardiac arrest before operation. cardiopulmonary resuscitation was immediately initiated, resulting in the return of spontaneous circulation. laparotomy with perihepatic packing (php) was performed, but she experienced two more episodes of cardiac arrest during operation. then, tae was performed for right hepatic artery extravasation. after physiological function restoration, including rewarming, coagulopathy correction and hemodynamic stabilization in the intensive care unit. she gradually became hemodynamically stable. however, incomplete hemostasis was obtained at second-look laparotomy h later. because of bleeding, we repeated php. we performed cholecystectomy and abdominal closure after confirming complete hemostasis ( h post-accident). she was discharged ambulatory without neurological deficit (day ). comments: prognosis of traumatic cardiac arrest is generally poor, and survival without considerable neurological deficit is very rare. we reported a surviving patient with severe hepatic laceration. sharing of strategies and tactics, such as blood transfusion, tae, trauma team approach to surgery, early decision of dcs improves outcome of patients with severe abdominal trauma. references: resuscitation. ; : - . introduction: the spleen is the most commonly injured organ after blunt trauma. non operative treatment (nom) of splenic injuries has gained wide acceptance. transcatheter embolization of the splenic artery is considered a useful adjunct in aast lesions c without active bleeding. we report a retrospective review of all patients admitted to a level trauma center with blunt splenic injury from to and compare their treatment and outcome with a previous series from to , when angioembolization was performed only in case of contrast blush at ct scan. patients and results: from to june , patients with blunt splenic injuries were admitted to the ed of a level university hospital in milan, italy. men to female ratio was : ,the mean age . ± years (range - ), and the iss ± . (range - ). eight patients ( . %) underwent emergent splenectomy due to hemodynamic instability. of the stable patients treated with nom, those with aast lesions c (n = ) were submitted also to angiography and to embolization of the spleen ( %), either proximally ( ) or distally ( ). two nom failed, and the patients were submitted to splenectomy or distal embolization. the median hospital stay was . ± . days. the total spleen salvage rate was %. no associated abdominal injuries were missed in the nom group. in the previous series of patients (mean age . ± . years, range - , #:$ = : , iss ± , range - ), underwent emergency splenectomy ( %), and ( %) were treated conservatively, with only embolization ( , %) in case of aast c at ct scan. failure of nom were , and the spleen salvage rate . %. liver injury following multiple cardiopulmonary resuscitations case history: this is a case of a year old woman who presented to the emergency department (ed) due to worsening dyspnea complicated by two lengthy cardiac arrests. after the first resuscitation and return to spontaneous circulation (rosc), echocardiography was done and showed severely dilated right ventricle with strain, suggestive of massive pulmonary embolism, for which rtpa was given. arrest occurred again, and post rosc, heparin was started and the patient was transferred to the icu. extracorporeal membrane oxygenation (ecmo) was initiated but complicated by severe hemodynamic instability and a third cardiac arrest, so cardiopulmonary resuscitation (cpr) was performed till rosc and massive transfusion protocol was started for suspected intraperitoneal bleeding. clinical findings: after ecmo cannulation, abdominal distention was noted with a severe drop in hemoglobin and an increased intraabdominal pressure ( mmhg). abdominal bedside ultrasound showed significant amount of dense free fluid. the decision for an urgent exploratory laparotomy was made and the patient was taken to the operating room. therapy and progressions: deep liver laceration over the right hepatic dome with rupture of the capsule and an estimated hemoperitoneum of l were found intra-op. controlling the bleeding was difficult due to the laceration site and the patients coagulopathic status, so packing was done and the patient was transferred to icu for correction of the coagulopathy and re-evaluation in h. the liver was unpacked after h, bleeding sites were cauterized and sutured and the liver was wrapped with a mesh with an attempt for a tamponade effect. the patient's stay in icu was complicated with kidney injury requiring chronic dialysis but otherwise recovered well. comments: liver injury is a rare but serious complication after cpr that should be considered in case of persistent hemodynamic instability along with bedside findings. this case is intriguing due to the right sided liver injury with no overlying rib fractures. blunt renal trauma after electrical injury: a series of curious events. a. nixon , e. falidas , d. davris , a. botou , g. sofos chalkida general hospital, department of surgery, chalkida, greece case history: a yr old patient was referred to the emergency department (ed) of our hospital from a primary health center after sustaining an electrical injury ( v ac). the patient experienced loss of consciousness (loc) and promptly fell to the ground in a supine position. the patient arrived approximately h after the incident. clinical findings: vital signs: bp: / mmhg, hr: bpm. the patient's major complaint was left flank and abdominal pain. no obvious thermal injuries were observed or any other signs of external trauma. a left abdominal mass developed which was evident on physical examination. in addition, examination of urine revealed gross hematuria. investigation/results: ekg monitoring documented sinus tachycardia without evidence of cardiac arrhythmias. fast indicated the presence of a massive retroperitoneal hematoma. the fast exam indicated the left kidney as the probable source of hemorrhage. the initial hematocrit (hct) from the primary health facility was % while results from the ed recorded a hct of %. diagnosis: grade v renal trauma. therapy and progressions: a massive transfusion protocol was initiated. the patient underwent an emergency laparotomy and a left nephrectomy was performed. subsequent imaging did not reveal other injures. comments: the history of electrical injury could have misdirected investigation efforts towards cardiogenic shock. this case suggests that even in the absence of a high energy impact, sustained hemodynamic instability should always be attributed to hemorrhagic shock until disproven. in addition, the management of grade v renal trauma in blunt injury remains a controversial topic, however we believe that in cases of class iv shock, surgical management is imperative. case history: y.o. female with a history of chagas' disease of years duration and esophageal involvement in the last few months. she's admitted for a first endoscopic balloon dilatation due to dysphagia, which is performed according to protocol, and a tear of the mucosa layer is observed during it. clinical findings: she's stable for the first h but with continuous thoracic pain of moderate intensity according to the gi specialist. on the second day there's a general worsening of the patient's condition, with dyspnea, fever, desaturation and tachycardia. results and diagnosis: she develops leukopenia and elevations of acute phase reactants, and a ct scan reports a distal esophageal perforation with free extravasation of contrast in the mediastinum and bilateral pleural effusions. therapy and progressions: emergency surgery is performed through a midline supraumbilical laparotomy which shows peritonitis around the epigastric area. after opening the hiatus, a very long transmural esophageal tear with devitalized tissues and severe contamination are observed. a trans-hiatal esophagectomy was decided and, given the hemodynamic stability, a gastroplasty is performed and brought up to the neck without anastomosis, along with a terminal cervical esophagostomy and feeding jejunostomy. the patient did well in the postop period. we were able to do the esophagogastric anastomosis in the neck days later, during the same admission. comments: the surgical technique in esophageal perforation depends mainly on the time elapsed since the perforation, and on the condition of the patient. esophagectomy is sometimes unavoidable, and a gastroplasty can be brought up to the neck at the same time in selected cases, with reconstruction of the upper gi tract during the same admission. introduction: the spleen is one of the most frequently injured abdominal organ. the anatomy of the lesion defines the degree according to aast, ranging from grade i to v in increasing complexity. the diagnosis of splenic trauma may be difficult, as % of patients may show no signs or symptoms at primary survey. the approach involves two main strategies: conservative or surgical. the strategy should take into account four aspects: hemodynamic status, anatomy of the lesion, associated injuries and organizational structures of the evaluation site. this study aims to evaluate the type of approach performed on different degrees of splenic trauma during years in a portuguese trauma center. material and methods: we conducted a retrospective study including all patients diagnosed with splenic trauma during a period of seven years. by consulting the patient's clinical files we evaluated and compared: demographic data, trauma kinetics, degree of splenic injury and the approach taken as well as morbidity and mortality. results: of the patients studied, most were male with blunt trauma. in patients the inicial approach was surgery and in the option was conservative treatment. in grade iii or iv lesions conservative treatment failed in % of patients. patients in whom the surgical approach was first chosen had predominantly grade iv lesions, with total splenectomy being the preferred approach. in grade iii lesions, the option was mainly conservative surgery of the spleen. conclusions: the initial approach of splenic trauma results essentially of the experience of emergency teams and support structures for surveillance and intervention (intervention radiology and -h operating room availability). the attempt to try conservative strategy is increasing over time. introduction: for decades, helicopter emergency medical services (hems) contribute greatly to prehospital trauma patient's care by performing advanced medical interventions on scene. unnecessary dispatches, resulting in cancellations, cause these vital resources to be temporarily unavailable. these cancellations contribute to overtriage and provide additional costs to society. an earlier study showed a cancellation rate of % in our trauma region. however, little empirical knowledge exists about reasons for cancellations for different mechanisms of injury (moi) and type of dispatch. this study aims to examine the current cancellation rate in our trauma region over a -year period. additionally, insights in cancellation reasons for different moi and type of dispatch are evaluated. methods: a retrospective study was performed, using data derived from the hems database of trauma region north west netherlands, between april st and april st . information regarding patient's characteristics, date and time of day, moi, type of dispatch, and cancellation reason were compared. results: in total, , patients were included. hems was cancelled in . % of dispatches. the majority of dispatches ( . %) were cancelled because the patient was physiologic-and neurologically stable. dispatches simultaneously activated with ems were cancelled . % of times, compared to . % when hems assistance was additionally requested by ems on scene. no differences were found between dayand night-time dispatches. trauma related dispatches were cancelled more frequently compared to non-trauma related dispatches. conclusions: this study found a considerable-and increased cancellation rate compared to previous research. an explanation for this finding could be better adherence to dispatch protocols. furthermore, a great variety in cancellation rates was found among different moi's. therefore, continuous critical evaluation of hems triage is important and dispatch criteria should be adjusted if necessary. case history: two separate cases of high speed road traffic collision. the first is years old female without significant past medical history. the second is years old male who had short extremitis due to history of spastic quadriplegic cerebral palsy alongside congenital kyphosis and postural scoliosis. clinical findings: on examination the first patient was hemodynamically stable with soft abdomen and bruising over the left pelvic area. the second patient had left side neck and right side chest bruises; furthermore, he was tachycardic with normal blood pressure, but he was generally pale, getting clammy and significantly sweaty. investigation/results: fast scan for both patients showed free fluid in the abdomen and ct scan was uncertain of the source in the first patient. in the second, a large mesenteric haematoma was evident on ct with contrast extravasation with corresponding significant drop in hemoglobin and raised lactate levels. diagnosis: case : hemodynamically stable blunt abdominal trauma. case : hemodynamically unstable blunt abdominal trauma. therapy and progressions: the first patient was managed conservatively initially but worsened overnight with a drop in haemoglobin and increase in lactate mandating emergency laparotomy. hemoperitoneum and cm of ischaemic bowel with tear in the mesentery was found. she had an uneventful recovery after resection and primary anastomosis. the second patient underwent immediate emergency laparotomy. there was evidence of hemoperitoneum ( l) and similar mesenteric tear with ischemia involving cm of the terminal ileum. resection with end to end anastomosis was done. patient was then transferred to itu; however, he developed chest infection which prolonged hospital stay. comments: hemodynamic instability is a major factor in mandating urgent exploratory laparotomy in bat and bucket-handle injury is not uncommon following road traffic accidents. introduction: incisional hernias are one of the most common complications post-abdominal surgery, affecting between - % of patients undergoing a laparotomy. a number of risk factors are associated with their development such as age, bmi, type of surgery and co-morbidities. these risk factors also affect their levels of recurrence which is why the technique undertaken to repair these is of such interest. the primary purpose of this meta-analysis was to examine which repair technique is associated with the lowest level of recurrence whilst a secondary aim was to examine whether the frequency of common complications was dependent on the type of repair utilised. material and methods: this systematic review and meta-analysis was conducted by both co-authors. the following information sources were utilised; cochrane/embase/google scholar/pubmed/scopus. in relation to the eligibility criteria-papers that were published from onwards and in the english language were included with any length of follow-up. study selection was as per the inclusion/exclusion criteria below and only cohort studies/rcts/systematic reviews/ meta-analyses and case control studies were included. inclusion criteria: abdominal incisional hernias, all types of repairmesh/open/laparoscopic/sutured repair/primary repair etc. in terms of the exclusion criteria-any hernia repair that was not incisional was excluded. results and conclusions: in terms of the primary question posed by this repair, meta-analysis shows that there is a significant difference between open vs laparoscopic technique and recurrence rates in relation to the primary question posed by this paper whilst the use of mesh impacts negatively on post-operative wound infection rates. this invites an interesting debate on the merits of each technique whilst demonstrating the need for a multicentre randomised controlled trial. laparoscopic approach in penetrating abdominal trauma: case study and review of the literature b. vieira , v. taranu , a. silva , d. galvão , a. soares hospital de santo espírito da ilha terceira, general surgery, angra do heroísmo, portugal introduction: laparoscopy(ls) has greatly improved surgical outcomes in many elective abdominal procedures. the use of ls in acute care is becoming widely accepted. however, a number of safety issues have limited its application in abdominal trauma. notwithstanding with the reports and studies of the past decade proving its safety and accuracy, ls is slowly replacing the need for exploratory laparotomies. case report: a yo male sustained with penetrating stab wound on the left flank. he was hemodynamically stable. ct confirmed intraperitoneal positioning of the knife, without free fluid or air nor any evidence of organ injury. an exploratory ls was performed and confirmed the intraperitoneal positioning of the knife. abdominal exploration revealed a jejunal transfixating lesion about m from treiz's angle that was manually closed. the patient maintained a favorable po evolution and was discharged on the thpo day. discussion/conclusion: a number of concerns have limited the use of ls in abdominal penetrating trauma. initially, it resulted in high rates of missed injury, mainly of the small bowel, generating considerable criticism. the development of systematic abdominal explorations in ls, as described by choi and kawahara, resulted in a rate of missed injuries close to zero. moreover, direct visualization using ls has shown superior specificity and sensitivity in identifying peritoneal penetration, hollow viscus injuries and diaphragmatic lesions when compared to ct. in the case reported here, ct didn't show any image suspected of perfuration such as free air or fluid, and yet ls showed a small bowell injury. besides its advantages as a diagnostic tool avoiding negative laparotomies in more than % of the cases, thanks to evolving techniques and improved practice, it may also be therapeutic and allow safe definitive treatment for many types of injuries as described here. method: this is a monocentric retrospective study from a database entered prospectively. all patients admitted to the university hospital in nice with splenic trauma between / / and / / were included. the primary endpoint was performing splenectomy as a failure of a nom. results: patients were included in our study. the majority of splenic lesions were severe grades, that is to say greater than . in total, splenectomies were performed urgently, i.e. % of patients; angio-embolizations were performed, i.e. % of patients with a success rate greater than %; . % of patients who had not anterior angio-embolization required secondary splenectomy; . % of the patients who had anterior angio-embolization required secondary splenectomy. in the patient group with successful angio-embolization, the mean age was years vs . years in the nom failure group (p = . ). a decrease in hemoglobin between admission and h after admission was found in the nom failure group compared with the successful embolization group (p = . ). conclusion: hemoglobin monitoring in the hours following admission of a patient with splenic trauma may be an important factor in the surveillance of hemodynamically stable patients. prospective studies could confirm these results. missed ureteric injuries in gunshot injuries of the abdomen: how to avoid? introduction: traumatic ureteral injuries are uncommon. penetrating rather than blunt trauma is the most common cause of ureteral injuries. the aim of this study is to make a strategy to avoid missing ureteric injuries in gunshot injuries of the abdomen. material and methods: patients were operated in our hospital in years period. all patients were managed according to atls guidelines. for stable patients, full radiological work up was done, while hemodynamically unstable patients were shifted to or immediately for laparotomy and exploration. all patients demographic and clinical data were recorded these include :patient age, sex, mechanism of injury, hemodynamic state on arrival to the rr, anatomical site of gunshot injury, associated injuries, ureteric injuries detected early or late, early repair, delayed presentation and morbidly associated with delayed discovery. results: ureteric injuries were found in patients out of patients who underwent laparotomy for gunshot injuries had ureteric injury in an incidence of . %. ureteric injuries were missed in the first laparotomy in patients. associated injuries of other abdominal viscera include; colon injuries affecting ascending and descending colon in all the patients. conclusions: ct and pyelogram are the modalities of choice in stable patient but in unstable patients the early recognition of ureteric injuries depends on high index of suspicion leading to surgical exploration of the ureter along its course. case history: we present a case of a year old man, who was injured by his agricultural machine in the abdomen. clinical findings: he was transferred in the emergency department and he was hemodynamically stable. he had several traumas in his abdominal wall. from the largest one, in the left iliac fossa, omentum, transverse colon and loops of the small intestine were protruded out of the abdominal wall. the small bowel was ischemic and ruptured. investigation/results: computed tomography investigation, revealed small amounts of liquid and air in the abdominal cavity. diagnosis: the patient was immediately operated. the destroyed loop of the small bowel was resected with the use of a stapler and the field was washout. then with a midline incision the abdomen was opened. there were no other injuries inside the abdomen cavity. there was an extensive injury with a creation of a large gap in the anterolateral abdominal wall. it was impossible to identify the left rectus abdominis muscle as also the lateral muscles (external and internal oblique and transversus abdominis). therapy and progressions: a side to side entero-enteric anastomosis was created and a meticulous observation and washout of the abdomen were performed. for the closure of the abdominal wall a double-sided mesh from polypropylene coated with silicone on one side ( cm) was placed and the operation was completed. all the other wounds of the abdominal wall were closed with loop nylon stitches no . a closed suction drain was placed above the mesh. the patient had a very good postoperative course. he was dismissed from the hospital after days in a very good condition. comments: the usage of mesh was very useful for the reconstruction of the abdominal wall. there is no conflict of interest. strategy shift from damage control surgery to primary radical surgery improve the outcome of blunt hepatic injury involving inferior vena cava introduction: the diagnosis of abdominal trauma is a real challenge even for surgeons experienced in trauma. clinical findings are usually unreliable, and abdominal examination is made up of various factors. diagnostic tools that help the attending physician make critical decisions, such as the need for laparotomy or conservative treatment, are mandatory if we propose a favorable outcome. material and methods: the study was performed in the clinic i surgery, the county clinical emergency hospital craiova, between - and analyzed a number of abdominal traumas hospitalized, investigated and treated in the clinic. the methods of paraclinical diagnosis are evaluated comparatively, the study analyzing the evolution and the tendencies during the studied period, from , to . results: the study allowed an evaluation of the diagnosis and treatment methods compared to the data in the literature. conclusions: thus ct scan remains the standard criterion for detecting solid organic lesions. in addition, a ct scan of the abdomen may reveal other associated lesions. fast ultrasound is an important and valuable alternative for diagnosing abdominal trauma, especially for patients who are hemodynamically unstable and cannot be mobilized. there is a tendency in the treatment of abdominal trauma, as evidenced by the literature data on the use of conservative versus surgical treatment for a larger number of cases introduction: antiplatelet agents and anticoagulant drugs are widely used in prevention of cardiovascular incidents, which poses a challenge in surgical emergencies. the drafting of a multidisciplinary protocol for the treatment of pharmacological induced coagulopathy in patients who require urgent surgery standardizes management and increases patients' perioperative safety. material and methods: aims of the study were to describe the results from the protocol implementation. a retrospective study was conducted by examining reports of every patient presenting pharmacological induced coagulopathy and undergoing emergent surgery, recorded in our center from to inclusive. different algorithms used were explained and data such as need of transfusion, reintervention rate and perioperative complications were analyzed. results: data from patients were analyzed, median age of , ( %) men. patients ( %) used anticoagulant drugs. fresh frozen plasma transfusion and/or prothrombin complex concentrates were used according to the guideline. ( %) patients used antiplatelet agents. % of them underwent a delayed h surgery directly. tirofiban therapy was established in patients on dual therapy due to medium-high risk of cardiovascular event. regarding surgical approach, ( %) were laparoscopic, ( %) open and conversion occurred in ( %) cases, but only of them due to intraoperative hemorrhagic complication. only cases of postoperative hemorrhagic complications led up to reintervention and only one isolated case of thrombotic complication was reported. finally, ( %) mortality cases were reported, but none was caused by hemorrhagic nor thrombotic complications. conclusions: establishment of a guideline on management of pharmacological induced coagulopathy in emergent surgery is crucial in all surgical emergency units and has proven to be effective and safe. introduction: digestive haemorrhage is a frequent pathology. most of the episodes are self-limited, but in some cases massive haemorrhage occurs, leading to a % mortality rate. severe problems occurs when endoscopic treatment is not effective, requiring emergent surgery with poor prognosis. the aim of this study is to evaluate the implementation of interventional radiology techniques on short-term results. methods: a retrospective descriptive study was performed reviewing patients who underwent radiological embolization after failure of endoscopic conventional treatment between - in our hospital. a total of patients were included. results: patients were male. cases were from lower gi track and were from the upper gi with a similar death rate between them, with a higher rebleeding rate in upper gi ( . % vs . %). % of the arteriographies did not show any bleeding site, of them developed a new bleeding episode. overall patients who undergo embolization, urgent surgery was avoided in of the patients diagnosed as upper gi haemorrhage and in of the patients diagnosed as lower gi haemorrhage. patients died, those death occurred later on the recovery of the acute bleeding episode and embolization, all of them related to patients comorbidities. conclusions: arterial embolization has become an important tool in order to treat massive haemorrhages of the gastrointestinal tract. it seems to decrease the mortality and morbidity rate, but some complications can be associated such as rebleeding or bowel ischaemia. massive transfusion protocol with early administration of platelet and fresh-frozen plasma along with packed red cells in the initial phase of resuscitation is associated with improved outcomes introduction: massive transfusion (mt) in a ratio of : : (prbc:platelet:ffp) is the standard of care in hemorrhaging trauma patients. the aim of our study was to compare the outcomes of patients who receive near balanced resuscitation (nbr) compared to unbalanced resuscitation (ubr) during the initial phase of resuscitation. material and methods: we performed a -year analysis of the acs-tqip. all adult patients (age [ ) who received mt (defined as transfusion of prbc c units in -h) were included. patients were stratified into two groups: nbr defined as prbc:platelets:ffp in : [ . : [ . and ubr ( : \ . : \ . ) in the first h of resuscitation. primary outcome measure was mortality. secondary outcome measures were complications, and hospital length of stay. propensity matching was performed to match the two groups. results: a total of , patients received mt. mean age was ± years, median iss was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . overall h mortality was . %. only % patients received nbr while % received ubr in the first -h. using propensity score matching, patients were matched for demographics, ed vitals, iss, ais and injury parameters. patients who received nbr in the early resuscitation phase had lower mortality ( % vs. %, p = . ), lower overall complications ( % vs. %, p = . ), with no difference in hospital length of stay ( days vs. days, p = . ) compared to the ubr group. conclusions: only one-third of patient receiving massive transfusion receive prbc, ffp and platelet in a ratio closer to : : in the initial -h and they have lower mortality and complications compared to patients with unbalanced resuscitation. material and methods: the goal is to assess mtp strategies in level- trauma centres in the netherlands and compare these with each other and (inter) national guidelines. a trauma surgeon or anaesthesiologist involved in compiling the mtp in each level- trauma centre in the netherlands and dutch ministry of defence was approached to share their mtp and comment on their protocol in a survey or oral follow-up interview. results: all eleven level- trauma centres responded. content of the packages and transfusion ratio (red blood cells/plasma/platelets) was : : , : : , : : , : : , : : , : : , : : and : : . tranexamic acid was used in all centres and an additional dose was administered in eight centres. fibrinogen was given directly (n = ), with persistent bleeding (n = ), based on clauss fibrinogen (n = ) or rotem Ò (n = ). standard coagulation monitoring are used in all centres, but most hospitals use also rotational thromboelastometry (rotem Ò ) (n = ), thromboelastography (teg Ò ) (n = ) or both (n = ). all centres used additional medication for patients using anticoagulants, but its use was ambiguous. conclusions: mtps in dutch level trauma centres differs from (inter) national guidelines in transfusion ratio and additional medication, which could be explained by misinterpretation of the : : ratio, changes in components and following an outdated dutch national guideline. whether these differences in mtps actually leads to different patient outcomes will follow from data that is currently being collected. this study is sponsored by the dutch ministry of defence. anastomotic bleeding after colorectal surgery: incidence, management and complications introduction: postoperative anastomotic bleeding (pab) is a frequent minor complication ( - %) that usually resolves by a conservative approach. hemodynamic instability and anemization may develop requiring urgent management. the aim of our study is to describe pab and its treatment. material and methods: observational retrospective cohort study of patients with pab collected between july and september . pab was defined as an episode of lower gi bleeding after colorectal surgery with at least one anastomosis. characteristics of patients, surgery, length of hospital stay, morbidity and mortality, and management of pab were reviewed. results: a total of ( . %) patients with pab was collected. median age was of years (iqr - ), with a median estimated asa grade of . the most common procedure was a right hemicolectomy ( %), followed by sigmoidectomy ( %). % of surgeries were laparoscopic. only cases were converted to an open approach. % of patients had the first episode of pab during the first h after surgery, while % after the third postoperative day. pab was treated conservatively in % of the cases. the remaining % required urgent endoscopic management identifying the bleeding through the anastomosis line, using clips in patients and hemospray in patient to control it. no complications were recorded after endoscopic treatment. just case required surgical reintervention. a total of ( %) patients required blood transfusion with a median of (iqr - . ) units. length of hospital stay was . days. no mortality related to pab was registered. conclusions: pab is a mild complication after colorectal surgery. most of the patients respond to conservative management. urgent endoscopic treatment seems to be effective and safe to control pab even during the first postoperative day. introduction: hemorrhagic shock and associated reperfusion injuries are davastating situations during the treatment of polytrauma patients. the aim of this study was to analyze and compare alterations of the local circulatory changes of various body regions during hemorrhagic shock and after fluid resuscitation. material and methods: this study was conducted on male pigs. they suffered a standardized polytrauma including femoral fracture, blunt thoracic trauma and liver laceration. further, the suffered a hemorrhagic shock for h (aimed map mmhg). fluid resuscitation with three times drawn blood volume after hemorrhagic shock. retrograde nailing for femoral fracture and chest tube in case of pneumothorax liver packing. measuring circulation at liver, colon, stomach, and extremity. results: inclusion of animals. local circulation at the extremity decreased significantly compared to baseline values during hemorrhagic shock ( . a.u. versus . a.u., p \ . ). after resuscitation the flow rate at the extremity was comparable to baseline values. the stomach was least sensitive to hemorrhagic shock, whereas the oxygen delivery rate at the colon decreased during shock phase and remained decreased during fluid resuscitation (p \ . ). conclusions: different body regions react differently to hemorrhagic shock. the colon appears to be most vulnerable to changes based on hemorrhage. the delayed improvement of circulation in liver, colon, and extremities may represent a trigger for systemic hyperinflammation and subsequent sirs and sepsis. none of the authors have any conflicts of interest to declare. massive transfusion in penetrating trauma: the search for a specific prediction system introduction: prediction systems of massive transfusion (mt) were developed from cohorts with a small proportion of penetrating trauma. some of them required laboratory tests. we aimed to evaluate abc score and to identify independent predictors of mt in a cohort of torso penetrating trauma (tpt) material and methods: adults with tpt, managed in a level-i trauma center, who received one or more packed red blood cells (prbc), were included. variables obtained during the evaluation in the trauma bay were registered prospectively. the ability to predict mt was evaluated with simple, multiple logistic regressions and roc curves. results: we included patients; . % were male, and . % received fire-arm wounds. twenty-one ( %) received mt. mt patients were intubated more frequently in the pre-hospital, had lower sbp, higher hr, lower gcs, and received more frequently vasopressors (p \ . ) when compared with the no-mt patients. trauma mechanism, number or localization of the wounds, and positive fast could not discriminate mt (p [ . ). hypotension, tachycardia, and alteration of the glasgow coma scale or its motor response behaved as independent predictors of mt. models created with these variables showed better discriminative ability than abc score, with adequate goodness to fit. conclusions: prediction models of mt, based on heart rate, systolic blood pressure, and neurologic alteration outperformed abc score in a tpt cohort. introduction: rectus sheath hematoma presents with abdominal pain and anterior abdominal wall mass. it can be followed conservatively and rarely causes mortality ( ) . in this study we aimed to review rectus sheath hematoma cases consulted to our department and to present our management. material and methods: the data of patients admitted with rectus sheath hematoma between and was collected using hospital database. treatment modalities, demographic data and complications were reviewed retrospectively. results: all the cases presented with abdominal pain and/or with a palpable abdominal mass. . % of the patients (n = ) were receiving anticoagulant therapy at the time of admission. the mean inr value was . . patients were followed up with es&ffp transfusion and conservative treatment. patients not eligible for conservative care underwent inferior epigastric artery embolization and hematomas in patients were evacuated via a percutaneous drainage catheter. patient went through laparotomy for an infected hematoma and one patient underwent laparotomy plus packing. the patient who had laparotomy plus packing died due to intraabdominal hematoma and sepsis. conclusions: rectus sheath heamatoma is a rare cause of acute abdominal pain. the patients diagnosed early and have suitable indications can be treated conservatively ( ) . rectus sheath hematoma should be considered in the differential when a patient with a history of anticoagulant drug use presents with acute abdominal pain in order to prevent unnecessary surgery and complications. introduction: an early delivery of blood products when massive transfusion protocols (mtp) are triggered is mandatory to improve trauma patients survival. scores predicting massive transfusion (mt) have already been described ( ) . the aim of our study is to compare scores for predicting mt and identify the best trigger for mtp. material and methods: multicentric retrospective study from the trauma registry of the spanish surgeons' association. severe trauma patients (injury severity score [iss] c ), admitted to different level trauma centers, from january to september were included. demographic and clinical information was recorded, and predictive scores for mt were assessed. results: patients were included. medium age was . ± . years, ( . %) were male. median iss was (iqr ). in % of the patients a mt (defined as c units of packed rbc) was necessary, while a mtp was triggered in . %. surgery was performed in . %. the overall mortality was of . %. predictive scores for mt were compared: gap (glasgow coma scale, age, systolic blood pressure), shock index (si), assessment of blood consumption (abc) and mabc (modified abc). auroc for gap was . ± . , si . ± . , abc . ± . and mabc . ± . , showing differences between gap (the worst score) and the others, p \ . . no differences were found between si, ab and mabc. best cut-off points were calculated. si c . better predicts mt with a sensitivity %, specificity . %, positive and negative predictive values . % and %. conclusions: si, abc and mabc are all good scores for predicting mt in our population. appealing by its simplicity, we recommend si as the best trigger for mtp. protocols should be standardized to improve the accuracy of mtp activation for trauma patients. introduction: the prevalence of knife-related offences is rising in the uk. successful management of trauma patients requires the co-ordinated response of specialist services, including transfusion. we aimed to assess the impact of knife-crime on transfusion support within a uk adult major trauma centre (mtc). material and methods: retrospective review of patients admitted to a uk mtc following knife injuries resulting from interpersonal violence during a three-year period (may -april ). source material included electronic patient records, tarn database and massive transfusion protocol (mtp) logbook. patient characteristics, resource utilisation including transfusion, mtp activation and outcome were collated. results: patients were identified, ( %) were male. median age was years. ( %) were under the age of . patients ( %) presented with circulatory compromise (sbp \ ). patients ( %) had attended our hospital previously for violencerelated trauma. % arrived at hospital between h to h. ( %) required one or more surgical procedures. median length of stay was days. patients ( %) received blood transfusion. median units transfused were prbc, ffp, platelets (atd). mean component use was pbrc (range - ), . ffp ( - ), platelets . ( - ), cryoprecipitate . ( - ). annual mtp activations increased from to during the study period (total ). stabbings accounted for . % of these ( patients), of which ( %) were transfused. conclusions: knife crime presents a burden to blood transfusion, accounting for a quarter of mtp activations. patients typically present out of hours with implications for service planning and delivery. patient profile together with repeat healthcare attendance and surgery requiring transfusion has implications for red cell allo-immunisation. we recommend timely baseline blood grouping and triage to optimise the safe use of rhd positive cellular components. introduction: spontaneous intramural small bowel hematoma is a very rare complication of anticoagulant therapy. nowadays, the prevalence is increasing due to the widespread use of computerized tomography and the increasing number of patients receiving anticoagulant therapy. material and methods: patients admitted to our center between january and june and treated with the diagnosis of intramural hematoma were retrospectively evaluated. results: the median age of the patients was years ( - ) and ( %) were male. at the time of appeal, warfarin intoxication was present in cases ( %) and the median inr was . ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . one patient had known factor deficiency. diagnosis was made by computerized tomography in all cases. one intramural hematoma was localized in the duodenum ( . %), nine in the jejunum ( %), and five in the ileum ( . %) six patients ( %) had ileus findings. all patients underwent fresh frozen plasma replacement due to high inr levels and bleeding. median tdp transfusion was units ( - ). only patients ( %) required erythrocyte suspension replacement. all cases were followed up conservatively and there was no need for intensive care. the median hospital stay was ( - ) days. conclusions: due to the limited number of studies in the literature with a large number of cases, retrospective evaluation of singlecenter cases may be helpful. spontaneous intramural small bowel hematoma should be considered in the elderly population under warfarin therapy who present with abdominal pain, especially if inr values are above therapeutic limits spontaneous regression is seen in the majority of cases. non operative management and correction of coagulopathy with fresh frozen plasma replacement is the preferred approach. references: abbas ma, et al. spontaneous intramural small-bowel hematoma: clinical presentation and long-term outcome. arch surg. ; ( ) : - . pre-hospital decision-making: identifying the challenges assessing and managing traumatic haemorrhage and coagulopathy m. marsden , r. bagga , k. gillies , r. lyon , s. kellett , r. davenport , n. tai expert pre-hospital clinicians in making decisions about the diagnosis and treatment of patients with major haemorrhage and suspected tic. methods: semi-structured interviews were conducted with senior pre-hospital consultants from london's air ambulance and air ambulance kent, surrey and sussex. interviews probed clinicians on how they make decisions relating to the pre-hospital assessment of major haemorrhage and tic and subsequent blood product transfusion. the interviews were analysed using descriptive thematic analysis. results: all clinicians agreed that identifying and treating major haemorrhage was vital. half of the clinicians reported making no conscious assessment for tic and six reported tic should be managed in a hospital setting. four broad themes were identified: collation of information, weighing utility of different approaches, influence of experience and evaluation of unknowns. collating information from multiple sources drove clinical decision-making. decisions on blood product transfusion were made after weighing potential benefits (e.g. improve microvascular perfusion) against harms. clinical experience was reported as key to nuance clinical assessment, detect subtle signs and identify patterns. uncertainty complicated clinical decision-making in two domains; incomplete knowledge of a patient's injury and uncertainty of best clinical practice. conclusion: the pre-hospital identification and treatment of major haemorrhage was recognised as challenging and fundamental. necessity of pre-hospital tic diagnosis and treatment divided opinion. identifying these four themes allows for a greater understanding of the factors involved in making these decisions and will guide the creation of more accurate decision support tools to aid pre-hospital clinicians. nothing to declare. introduction: massive transfusion (mt) is defined as the administration of c packed red blood cells (prbc) in h. alternative definitions have been proposed; however, there is little understanding about the discriminative ability of different mt definitions with regards to mortality and multiorgan failure (mof). we aim to assess and compare the discriminative ability of different definitions of mt concerning mortality and mof. material and methods: we included patients who arrived to the emergency department and required trauma team activation at a level i trauma center in the city of cali, colombia between - . demographics and trauma characteristics were evaluated. the following mt definitions were measured: units of blood products in h (t ), u prbc in (t - ), u prbc in h (t - ), prbc in h (t - ), the combination of t - and t (t-combi), prbc in h (t - ), prbc in h (t - ) and units of prbcs in min. the operative characteristics were calculated for each definition. mof was defined as a sofa score of c points. results: we included subjects, . % male. trauma mechanism was penetrating in . %. the median and interquartile range (iqr) of age was years iqr ( - ) and of iss ( - ). lesions were located in the torso in . % of patients, and . % had a positive abc score. a total of ( %) received at least unit of prbc. tables and presents the operative characteristics of definitions of mt with respect to mortality and mof, respectively. conclusions: although all definitions showed an association with higher odds with the outcomes of interest, none of them showed an accurate diagnostic capacity regarding mof and mortality. thus, we advise caution when relying on the classical definition of mt ([ rbc units in h) to guide the flow of care of severely injured patients. trauma and coagulation: trends in coagulation factors in the severely injured trauma patient introduction: trauma-induced coagulopathy (tic), affects about - % of the major trauma patients. in the past, tic was considered as a consequence of the coagulation factors' dilution after a highvolume colloid administration. today tic is seen as a phenomenon that can arise after trauma; the first event is the c-protein activation by the tissue damage and hypoperfusion, resulting in the subversion of the hemostatic process. material and methods: the patients of the pilot study ''trauma and coagulation'' run in irccs san raffaele scientific institute have been reviewed and analyzed using a suite of experimental coagulation factors including rotem parameters, activated protein c (apc), thrombomodulin, endothelial protein c receptor, thrombin-antithrombin complex (tat), plasminogen activator inhibitor (pai- ), seselectin, interleukin- (il- ), interleukin- (il- ), d-dimer (xdp), antithrombin iii (atiii), and prothrombin fragment f ? (f ? ). new patients have been enrolled to validate the results of the pilot study. results: there is a statistically significative correlation between clinical scores of severity of trauma and risk of massive transfusion (iss, abc and tash) and some of the experimental coagulation factors analyzed. case history: to evaluate the role of negative pressure wound-care systems applied to the pleural cavity in case of severe acute empyemas and frail patients not amenable to conventional surgery. clinical findings: we report the case of a yrs old male critically ill patient suffering from complications of cardiac surgeries who developed a severe right empyema with broncho-pleural fistula through the site of a previous pulmonary hernia. investigation/results: we review the actual indications of negative pressure therapy in thoracic surgical emergencies especially in septic patients unfit for surgery. in our case the repeated application of negative pressure with dedicated dressings through the initial thoracotomy was the chosen damage control approach because of the sepsis and poor conditions. diagnosis, therapy and progressions: air leaks were later found to originate from a subsegmentary branch of middle lobe bronchus. subsequent video-assisted debridement procedures followed by negative pressure therapy managed to ( ) control the infection, ( ) reduce the thoracotomy incision into a thoracoscopic access and ( ) heal the pleural cavity, restoring eventually better general conditions of the patient. the closure of the bronchial fistula required further procedures after the acute phase when sepsis was overcome. comments: negative pressure systems can be applied to the pleural cavity with many advantages in selected critically ill patients. they allow to contain, treat and resolve infections both of chest wall and pleural cavity in case of severe empyemas reducing also wound pain and eliminating the need of chest drains. air leaks may also be managed by negative pressure therapy with adequate indications and particular attention to its settings. references: sziklavari z. mini-open vacuum-assisted closure therapy with instillation for debilitated and septic patients with pleural empyema. eur j cardiothorac surg. . flail chest: the renaissance of rib osteosynthesis c. leite , a. oliveira , a. lemos , b. barbosa , c. casimiro centro hospitalar tondela-viseu, general surgery, viseu, portugal case history: we present the clinical case of a male patient of years old. injury mechanism: fall from his own height over the right hemithorax. clinical findings: rib fractures with flail chest and significant displacement of bone edges. symptoms: intense thoracic pain. diagnosis: rib fractures with flail chest. therapy and progressions: multimodal analgesia. on the th day, he presented a tension pneumothorax. after adequate intercostal drainage, the pneumothorax relapsed. on the th day, he underwent a right posterolateral thoracotomy, open reduction and internal fixation of ribs with plates and screws and intercostal drainage. evolution: he received respiratory kinesiotherapy and was discharged on the th pos op day. follow-up at st and th months, without functional impairment and with preservation of quality of life. comments: rib fracture is the most common injury in the setting of thoracic trauma and is associated with a higher morbimortality. in the last years, positive pressure mechanical ventilation was the first line treatment of respiratory insufficiency caused by rib fractures. however, severe complications associated with prolonged mechanical ventilation, have elicited the rising implementation of open rib reduction and internal fixation techniques. the most consensual indications are: flail chest with fracture of at least ribs, significant displacement of bone edges or uncontrolled pain. rib osteosynthesis is a simple method but requires clinical experience in thoracic approaches and handling of specific instruments and material. its implementation in non-ventilated patients reduces the need for mechanical ventilation, pain, length of stay and allows preservation of quality of life. yokohama city university medical center, advanced critical care and emergency center, yokohama, japan, saiseikai yokohama-shi nanbu hospital, department of surgery, yokohama, japan, yokohama city university, department of general surgery, yokohama, japan, yokohama city university, department of emergency medicine, yokohama, japan introduction: although americans and europeans report emergency room thoracotomy (ert) is of value in penetrating trauma patients, most of ert is performed for blunt trauma in japan. after the establishment of the local government-directed major trauma center in the city of yokohama, the unexpected trauma survivor rate increased in the single center study. we report our experience in ert and surveyed the effect of the establishment. material and methods: patient characteristics (backgrounds, mechanism of injury, indication for ert, anatomic injuries, interventions and survival) of those who underwent emergency thoracotomy compliant with the guideline of western trauma association, between october and september were analyzed. results: fifty-eight patients ( males) underwent emergency thoracotomy. median age was . ( - ) years. fifty-seven were performed for blunt trauma ( %) and only for penetrating injuries. twenty-three patients presented with cardiac arrest on arrival, while thirty-five had deep and refractory hypotension. overall, survival rate improved from ( / ) to % ( / ) (p = . ) after the establishment of the trauma center. of patients presenting with cardiac arrest, only one survived. conclusions: the establishment of major trauma center seemed to affect the survival rate of the patient edt was performed. introduction: more than % of polytrauma events involve chest injuries. one third of these patients sustain thoracic instability due to serial rib fractures. thanks to numerous innovations in implant development several approaches currently exist for surgical rib stabilization (srs). however, no consensus exists regarding patient selection for srs to date. material and methods: retrospective single center cohort analysis in trauma patients. serial rib fracture was defined as three consecutive ribs confirmed by chest ct. cohort includes patients that were treated conservatively and patients that underwent srs by plate osteosynthesis. demographic patient data, trauma mechanism, injury pattern, injury severity score (iss), glasgow coma scale (gcs) and hospital course were analyzed. two matched pair analyses stratified for iss ( pairs) and gcs ( pairs) were performed to minimize selection bias. results: the majority of patients was male ( %) and aged ± years. serial rib fractures were located left/right/bilateral in %/ %/ % of cases. other thoracic bone injury included sternum ( %), scapula ( %) and clavicula ( %). visceral injury consisted of pneumothorax ( %), lung contusion ( %) and diaphragmatic rupture ( %). average iss was ± . . overall hospital stay was . and icu stay . days. in hospital mortality was %. srs did not improve hospital course or postoperative complications in the complete study cohort. however, patients undergoing srs had significantly reduced gcs ( . ± . vs . ± , ; p = . ). matched pair analysis stratified for gcs showed a reduced need for blood substitution and shorter icu stays ( vs days; p = . ) including shorter respirator time ( vs h; p = . ) and reduced in hospital mortality ( vs %). conclusions: patients with serial rib fractures and simultaneous severe cerebral injury benefit from surgical rib stabilization. tracheal and bilateral recurrent laryngeal nerve disruption injury secondary to accidental strangulation by dupatta case history: year old female brought to trauma emergency with a/h/o accidental strangulation injury with dhupatta at farm field while working with thresher machine after h of injury. patient had severe dyspnoea, dysphagia, paining neck clinical findings: primary survey revealed threatened airway with extensive surgical emphysema, rr- /min, spo - % on high flow oxygen mask, hemodynamically stable, and had no neurological deficits. patient was immediately intubated, however ventilation could not be maintained and surgical emphysema worsened hence immediate tracheostomy was established. investigation/results: computed tomography (ct) head and ct angiography of neck with venous phase study of neck and chest with ct esophagogram revealed complete disruption of cricotracheal junction with extensive cervical and upper thoracic surgical emphysema and no other injuries. diagnosis: disruption of trachea from cricoid cartilage with crushed trachea with loss of approximately cm, cricoid and thyroid cartilage fracture, complete avulsion of bilateral recurrent laryngeal nerves and serosal tear of esophagus. therapy and progressions: neck exploration with debridement of tracheal margins and anastomosis between trachea and cricoid cartilage with repair of cricoid, laryngeal cartilage and esophageal serosal repair was performed. comments: post-operatively patient underwent fibreoptic bronchoscopy and revealed paramedian location of vocal cords. at present patient is with tracheostomy tube in situ undergoing speech therapy and is able to generate comprehensible sounds. further laryngeal framework surgery is being planned. introduction: emergency resuscitative thoracotomy (ert) is a lifesaving procedure in selected patients and it is often considered a controversial ''last chance'' method of resuscitation. objectives of ert are to resolve pericardial tamponade, to repair heart injuries, to perform an open cardiac massage, to cross-clamp the aorta to redistribute blood flow to the myocardium and brain, to control intrathoracic bleeding and air embolism in the bronchial venous system. outcome mostly in blunt trauma is believed to be poor. material and methods: we retrospective reviewed patients c years who underwent ert at san camillo-forlanini hospital (rome, italy) between january and september with traumatic arrest for blunt or penetrating injuries. results: of ert, ( . %) were for blunt trauma, ( . %) were for penetrating trauma. . % of patients were male. the collectively reported overall survival was % (n = ). when including erts designated as done in the emergency department for blunt mechanism, only patient survived ( . %). survival after erts for penetrating trauma was % ( of ). conclusions: our experience suggests that ert is a technique that should be utilized for patients with critical penetrating injuries. the reported outcome after ert in european civilian trauma populations is favorable with an overall survival of %. multicenter, prospective, observational data are needed to validate the modern role of ert in blunt or penetrating trauma. references: narvestad jk, et al. emergency resuscitative thoracotomy performed in european civilian trauma patients with blunt or penetrating injuries: a systematic review. eur j trauma emerg surg. ; ( ) case history: an -year-old male driving a car collided with a wall at a speed of km/h and was brought to a hospital near the scene. he was diagnosed with right multiple rib fractures and hemopneumothorax, and transferred to our emergency center for definitive care. clinical findings: the patient's consciousness was clear and his heart rate, blood pressure, respiratory rate, and o saturation (room air) on arrival were /min, / mmhg, /min, and %, respectively. subcutaneous emphysema was identified on the right side of his chest and his right breathing sound decreased on auscultation. there was no tenderness and rebound on abdominal examination. investigation/results: an enhanced whole-body computed tomography scan revealed a small disruption on the right diaphragm behind the sternum and free air in the abdomen. diagnosis: the diagnosis was right traumatic diaphragmatic injury, sternum fracture, and right multiple rib fractures with pneumohemothorax. there was free air in the abdomen but without evidence of perforation of the digestive tract as there was no finding of peritonitis on physical examination. thus, pneumoperitoneum from the thorax was strongly suspected. therapy and progressions: laparoscopic observation revealed a . cm-length of disruption on the diaphragm in the right sternocostal triangle. this was covered with falciform ligament using extracorporeal knot tying method because there was little seam allowance in front of the disruption on the sternum side, and direct suture was not possible. prognosis was good following surgery, and the chest drain was removed on postoperative day and the patient was discharged on postoperative day . comments: laparoscopic repair of the diaphragm using extracorporeal knot tying method is often used for retrosternal (morgagni) hernias. however, the method was also useful in this case because the diaphragmatic injury occurred in the sternocostal triangle. rib fractures associated with pneumo-and/or hemothorax; does everyone need a chest tube? v. snartland , p. a. naess , c. gaarder , m. hestnes , p. majak , , faculty of medicine, university of oslo, oslo, norway, oslo university hospital, department of traumatology, oslo, norway, oslo university hospital, trauma registry, oslo, norway, oslo university hospital, department of cardiothoracic surgery, oslo, norway introduction: pneumo-and/or hemothorax are often seen in trauma patients with rib fractures (rfs). standard treatment for pneumothorax (ptx), hemothorax (htx) and hemopneumothorax (hptx) is tube thoracostomy (tt). however, a non-operative approach can be applied in selected patients. we wanted to assess our practice in patients with rib fractures and associated ptx, htx or hptx. material and methods: all adult patients (c years) with rf, admitted by a trauma team at oslo university hospital in were identified retrospectively and those with associated ptx, htx or hptx were then included in the study. patients who underwent tt prior to arrival and those who died were excluded. spss v was used for statistical analysis. results: of the patients with rfs, a total of patients had ptx, htx or hptx. fifty-one percent ( / ) of these patients were treated with tt and % ( / ) of the patients underwent tt within h after arrival. the presence of opacification (p \ . ), chest wall deformity (p \ . ) and pneumothorax size (p \ . ) were significantly higher on chest x-ray in the tt group compared to the nonoperative group. intubation at arrival was also significantly more common in patients treated with tt (p \ . ). there was no difference in the presence of subcutaneous emphysema between the groups. the tt group was sicker than the non-operative group (had a significantly lower systolic blood pressure, a lower gcs and a higher lactate on arrival). oxygen saturation, heart rate, respiratory rate, ph and hemoglobin did not differ significantly between the groups. conclusions: in trauma patients with rf concurrent ptx, htx or hptx should be suspected. in our study only half of these patients were treated with tt, and % of tubes were inserted within h after admission. size of the ptx, radiological presence of opacification and deformity of the chest wall should be addressed when choosing treatment strategy. introduction: emergency department thoracotomy (edt) is a potentially life-saving surgical procedure performed in the emergency department (ed) in patients presenting with cardiac arrest following penetrating thoracic trauma. however, it is not clear if all surgeons are prepared or motivated to perform this procedure. furthermore, not all institutions are equipped, either in terms of logistics or team training, to perform edt. our purpose was to perform a pilot study in a cohort of polish surgeons of various specializations, in order to ascertain who would and who would not (and why) perform edt in their departments. material and methods: study population of surgeons ( specialists, residents) from various hospitals in poland, mean age: - years, . % men, . % women. study respondents were asked to fill in a questionnaire on the indications and motivation to perform edt in their clinical practice. results: most respondents (n = , %) correctly recognized the indications to perform edt. however, only ( %) declared they would perform it. the reasons for not performing edt were: lack of team training ( . %); lack of equipment ( %); lack of motivation among ed personnel ( . %); the ed is not prepared ( . %); the respondent is not prepared ( %). only participants ( . %) declared that their institutions had the edt protocol. conclusions: this survey demonstrates that, although most surgeons agree on the indications for edt, the level of preparedness in its execution is lacking. the main reasons are the lack of team training, the lack of equipment and the lack of motivation among ed personnel. other relevant reasons were the lack of preparation of either a surgeon or a department. these results demonstrate that improvements in institutional logistics as well as in team and individual training can translate into improved care. we strongly advise the performance of a pan-european survey on edt to address other unrecognized issues. mediastinum widening: how to manage it? a. gonzález-costa , r. gracia-roman , s. montmany-vioque , m. s. santos-espi , r. lobato-gil , m. pascua-solé , a. campos-serra , a. luna-aufroy , p. rebasa-cladera , s. navarro-soto parc tauli hospital universitari, trauma and emergency general surgery department, sabadell, spain, parc tauli hospital universitari, esofagogastric general surgery department, sabadell, spain, parc tauli hospital universitari, angiology and vascular surgery, sabadell, spain case history: a -year old male was admitted to our emergency department as a polytrauma code, because of a gunshot wound in the neck. clinical findings: his airway was compromised with expansive cervical hematoma. intubation was difficult. he was hemodynamically unstable with cervical bleeding, in which manual compression was applied. results: chest x-ray showed mediastinal widening without pneumo or hemothorax. diagnosis: urgent sternotomy while maintaining manual compression on the cervical bleeding, followed by left antero-lateral cervicotomy. injuries: section of left jugular vein and left carotid artery, lesions of unnamed vein. free cervical chylous fluid. left pleura and pericardium were opened without identifying major injuries. therapy and progressions: jugular vein was repaired with continuous suture and carotid artery with patch sutured. unnamed vein was sectioned between ligatures. thoracic duct was ligated. after surgery, ct scan showed cervical and mediastinal hematomas without signs of active bleeding, and correct permeability of the vessels, with no cranial lesions. the patient was admitted to the intensive care unit. tracheostomy was performed. fibrobronchoscopy, fibrogastroscopy and esophagogastricoduodenal discarded airway and esophageal lesions. he presented the following complications: • small mediastinal collection • right diaphragmatic paralysis. • paralysis of vi left cranial nerve (mononeuritis of vascular origin). the patient was discharged on the th postoperative day. comments: in this kind of trauma is essential the airway management with intubation when necessary. it is important that mediastinal widening visualized in the chest x-ray in a traumatic patient, should be an indication of surgery. in our case, it was essential to start it with sternotomy while maintaining manual neck compression, and in a second time, perform the cervical approach since that prevented the patient from suffering a greater blood loss. background: clavicular fracture is very common in childhood. otherwise, the medial third of the clavicle is the less affected. the current report describes a new pattern of clavicular injury, in which a medial third clavicular fracture and posterior sternoclavicular joint (scj) dislocation occur together in a skeletally immature patient. clinical findings: an -year-old boy sustained a direct impact to his left shoulder resulting from the fall of a sofa. at admission, he complained of severe pain in the clavicular and shoulder associated with functional limb impotence. physical examination revealed deformity of the proximal third clavicle, with swelling and tenderness to palpation along the medial left clavicle. no signs of skin pression or neurovascular impairment were found. the anteroposterior radiograph of the left clavicle showed a fracture of the proximal third shaft and an asymmetry of the scj. computed tomography confirmed the association of a greenstick fracture of the proximal third clavicular shaft, accompanied by a mild posterior scj dislocation. therapy and progressions: the left limb was immobilized with a sling during weeks, after which physical therapy was initiated to improve range of motion using active and gentle active-assisted exercises. at the months medical consultation, he presented asymptomatic, with good bone healing, full range of motion of the shoulder and absence of relevant aesthetic deformity. comments: in the immature skeleton, scj dislocation and epiphyseal fracture of the proximal clavicle are very rare entities due to the multiple strong ligaments that stabilize the scj. trauma in the proximal third of the clavicle typically results in fractures in the region of the physis and only more rarely culminate in dislocations of the scj. these injuries warrant a high index of suspicion, and early ct scanning is recommended. although treatment may be conservative, in situations of major displacement, surgery should be considered. use of rib fracture scoring systems in a uk major trauma unit: a retrospective audit and lessons learnt introduction: rib fractures are detected in % of trauma patients [ ] . significant morbidity and admission to intensive care units (itu) is common [ ] . rib fracture scores do not have strong validity as a predictor, but are a useful screening tool to identify patients at higher risk, of morbidity. the aim of this study was to audit the use of rib fixation scores in a single major trauma centre. material and methods: a retrospective audit of trauma patients with rib fractures presenting to a single major trauma centre over a -year period subsequently admitted to itu was performed. demographics, length of itu stay, rib fracture score (rfs) and ribscore were recorded and comparisons made between patients who had surgical rib fixation and those who did not. results: patients with traumatic rib fractures were admitted to itu over -year, of whom had rib fixation. mean age of patients undergoing surgery was compared to in the non-surgical cohort. average rfs was higher in the surgical cohort ( vs ; p = \ . ), as was average ribscore ( vs ; p = \ . ). incidence of flail segment was higher in surgical cohort ( % vs %; p = \ . ), as was number of rib fractures ( vs ; p = \ . ) and incidence of st rib fracture ( % vs %, p = \ . ). rib fractures treated surgically had a longer itu stay ( . days vs . ; p = \ . ). conclusions: surgical rib fixation patients were older and had longer itu stay. higher rib fracture scores correlated with need for surgical intervention. this highlights the need for careful patient selection for rib fixation, as they appear to fall in a more vulnerable patient demographic. there is a need for a score combining ribscore and rfs, ensuring the nature of fractures and presence of flail segments are interpreted in the context of patient age, to ensure this vulnerable patient group undergoes surgical fixation only when necessary. jichi medical university, shimotsuke tochigi, japan case history: an -year-old female individual hurt her back while walking during a hospital rehabilitation program after experiencing a brain stroke. her hemoglobin level gradually decreased to . g/dl on the th day after injury. a non-enhanced abdominal ct scan revealed a burst fracture of the lumbar spine. the patient was brought to our emergency center for a thorough examination. clinical findings: her vital signs on arrival were gcs: e v m , hr: , bp: / , rr: , and bt: . . her back presented a severe kyphotic spine. the palpebral conjunctiva was anemic and there were no injuries on her surface. no abnormalities were detected upon auscultation of the thorax and no tenderness and rebound was detected upon physical examination of the patient's abdomen. investigation/results: hemoglobin level was . g/dl and lactate . mmol/l on arrival. an enhanced chest and abdominal ct scan revealed a burst fracture of the th lumbar spine, a large hematoma around it, and a pseudoaneurysm of the lumbar artery. diagnosis: a pseudoaneurysm of the lumbar artery and a burst fracture of the th lumbar spine was diagnosed. therapy and progressions: the angioembolization of the lumbar artery was abandoned because the distance between the abdominal aorta and the aneurysm was \ mm. endovascular aneurysm repair (evar) was finally performed. after the successful completion of the surgery, the patient was discharged on the th day after evar. comments: slight injury caused the fracture of the lumbar spine, possibly yielding pseudoaneurysm of the lumbar artery. such pseudoaneurysms are rare and employing evar for its treatment is equally rare. blunt lumbar artery injury may be a differential diagnosis for the elderly patients who present burst spine fractures with extreme anemia or shock, even if it results from a minimal injury. case history: a year old co-driver was hit by another car on her side. air rescue found the patient with gcs and right tension pneumothorax. oral intubation, decompression with chest tube and transportation to the nearest level one trauma center was undertaken. clinical findings/investigation/results: on presentation in the emergency room the patient was hemodynamically instable with free fluid in efast-sonography and a haemoglobin of . g/dl. she was immediately taken to the operation room where laparotomy was performed. liver rupture and right diaphragm rupture was found. diagnosis: right hilar bronchial disruption. therapy and progressions: despite packing of the liver the patient remained instable. due to continuous bleeding from diaphragm rupture side right anterolateral thoracotomy was performed. bronchial disruption close to the hilus was detected leading to total pneumonectomy. after surgery the patient recovered under intensive care. six weeks after initial trauma the patient presented with ileus. a gastric tube was placed without complications. chest x-ray was performed showing intrathoracal displacement of the gastric tube. in an emergency operation the insufficient bronchus trunk was covered with an intercostal muscle flap. comments: this case shows the rare necessity of total pneumonectomy after blunt chest trauma and its typical complication with insufficiency of the bronchial trunk. after total pneumonectomy surgery covering the bronchial trunk should be performed as soon as possible to prevent insufficiency. in these patients gastric tubes should only be placed under endoscopic vision. because of the high complication rate total pneumonectomy should only be performed as a last resort procedure in the context of damage-control surgery. introduction: multiple rib fractures continue to be a challenging problem as the associated pain leads to a compromise in respiration. proper analgesia is required for physiotherapy, and to prevent development of respiratory failure. ultrasound-guided serratus plane block (spb) has recently been described as a regional anesthetic technique to provide analgesia to a hemithorax by blocking the lateral branches of the intercostal nerves. material and methods: from sept we applied the serratus plane block for pain control in patients with multiple rib fractures. we administered . - . % bupivacaine solution with easypump for - days, the infusion rate was ml/h. after admission we measured pulmonary function of patients and recorded the forced vital capacity (fvc). we repeated the test after the catheter insertion on the - - days. in our control group ( patients introduction: rib fractures are the most frequent injury after blunt thoracic trauma. it is very important to choose the most appropriate interventions to minimize or prevent complications. but who will benefit most of those interventions remains a challenge. material and methods: a retrospective study with a prospective data collection from march to december . there have been included all traumatic patients older than years old, that were admitted to the icu or who were died before the admission and had a plain chest radiograph (cxr) and thoracic or thoraco-abdominal scan (ct scan) in the first h. demographic data has been collected, vital signs, iss, mechanism of action, need of ventilation or intubation, lesions, complications, cause of death. a total of cxr were reevaluated by one general surgeon (one of the authors) and one radiologist, who were blinded to the results of the subsequent chest ct scan, the written radiology report and the patient's outcome. rib fractures, pneumothorax, hemothorax, pulmonary contusion, laceration and atelectasis were described. results: attending to the number of fractures, the kappa between the radiologist, the surgeon and the ct report is very low: surgeon-ct k = . , radiologist-ct k = . , and radiologist-surgeon k = . . both radiologist and surgeon under-diagnosed rib fractures. we tried to predict respiratory failure and pneumonia using the number of fractures, and scores (chest trauma score, ribscore and rib fracture score). results are shown on the table. conclusions: plain radiography seems not to be a good diagnostic method for rib fractures. both radiologists and surgeons under-diagnosed rib fractures. scores based on radiography seem un-useful given that this under-diagnoses rib fractures; but with a precision of % by the surgeon evaluating cxr and using a score like rfs perhaps it is enough to decide which patients require a ct scan or more specific treatment in the icu. surgical experience of traumatic diaphragm injury in a single regional trauma center for years introduction: this study is a retrospective review of the experience with the management of traumatic diaphragm injury in our trauma center from to . material and methods: we identified a total of patients with the traumatic diaphragm injury coded from the institutional trauma registry. we reviewed the radiographic finding of radiologists and the electronic medical record (emr). results: the mean of injury severity score (iss) was . ± . . except for case, the plain chest x-ray was evaluated in the patients before surgery, only patients were revealed positive finding for diaphragm injury (n = / , %). the computed tomography (ct) was performed for patients, the positive finding was . % (n = / ). according to the clinician impression before surgery, the diagnosis for diaphragm injury was showed . % (n = / ). approaches were laparotomy in patients ( . %), thoracotomy in ( . %), thoracoscopy in ( . %), laparoscopy in ( . %), open conversion after thoracoscopic or laparoscopic exploration in ( . %), median sternotomy in ( . %). the occurrence of herniation was ( . %). the mean of the calculated rupture size in the operation field was . ± . cm. in our study, the herniated peritoneal organ was observed in more than cm size rupture of the diaphragm. patients were performed surgical management of diaphragm rupture after h. conclusions: without herniation of organs, the radiologic evaluation was difficult to detect diaphragm injury. and, detect of diaphragm injury with herniation of organ, the injury of the diaphragm was predicted a larger than cm. case history and clinical findings: a -year-old man presented to the emergency room with a single self-inflicted left chest gunshot wound at the level of nd rib. on arrival patient was conscious, with systolic blood pressure mmhg and heart rate bpm. extremities were pale, cold. jugular veins distended. investigation/results: fast scan was negative. chest radiograph revealed a metal foreign body with the size of mm at the projection of heart. a ct scan of chest and abdomen demonstrated bullet inside the dorsal wall of the left ventricle and blood in pericardium and left pleural cavity (figs. , ) . therapy and progression: patient was taken to the operation room for median sternotomy. due to severe deterioration of patient's condition, ml of blood was aspirated from the pericardium prior to sternotomy. during subsequent pericardiotomy ml of blood was evacuated. main pulmonary artery wall gunshot injury was detected above the pulmonary valve. the wound was sutured, after which the hemodynamics stabilized. cardiac surgeon was consulted about the air gun bullet inside the myocardium. it was decided that removal of the bullet is not indicated. the patient was observed in the icu for the next h, later transferred to the thoracic surgery ward. the postoperative course was uneventful. an echocardiogram demonstrated a perforation of the anterior leaflet of mitral valve with a mild to moderate regurgitation, otherwise no abnormalities. patient was discharged on day . patient has been followed up on an annual basis for the last years. patient's exercise tolerance and cardiac function according to repeated echocardiography remains unchanged with no evidence of dyskinesia or other abnormalities. bullet is retained in the same location (fig. ) . comments: this case illustrates a successful management of usually lethal injury of main pulmonary artery and reflects that retained myocardial foreign body does not necessarily cause any complications. profile of penetrating chest injuries in hostile environment: a three year study introduction: penetrating chest injuries are one of the leading causes of death and major morbidity in operations involving high energy weapon systems. this study aimed at assess the profile of penetrating chest injuries suffered during armed combat operations in a hostile environment over a three year period. material and methods: a retrospective and prospective, non-randomized study designed to assess the profile of chest injuries in armed combat operations over years. all patients with penetrating chest injuries were included in the study. results: there were trauma cases out of which patients suffered penetrating chest injuries. the age range of patients was - years and all were male. a total of casualties were brought dead ( . %). there were lung injuries and two diaphragmatic injuries. thoracotomy was required in patients ( . %) and intercostal chest drainage (icd) in patients ( . %). average blood loss was ml and duration of hospital stay ranged from to days. conclusions: ballistic injuries to the chest are frequently fatal due to injuries to the heart, major vessels and tracheobronchial tree. prompt and efficient pre hospital treatment, expedient evacuation to a surgical facility and swift management by critical care specialists and surgeons can be instrumental in reducing mortality and morbidity. the cornerstone of management is bedside intercostal chest drain insertion as a formal thoracotomy is seldom needed. penetrating chest injuries can be managed by general surgeons with training in thoracotomy and repair of intra-thoracic structures does the number of a-or low symptomatic but intervention requiring complications justify regularly chest x-ray controls after less than rib fractures? c. deininger , , f. wichlas , , s. deininger , v. hofmann , university hospital of salzburg, orthopedics and traumatology, salzburg, austria, universitätsklinikum salzburg, klinik für orthopädie und traumatologie, salzburg, austria, universitätsklinikum salzburg, universitätsklinik für urologie und andrologie, salzburg, austria introduction: fractures of less than ribs may still cause delayed complications ( ) . the aim of this retrospective study is to determine whether standardized control imaging in a-or low symptomatic patients reveals a significant number of intervention requiring complications and therefor should be recommended. material and methods: all patients with less than rib fractures presenting in our emergency department after any trauma mechanism in the study period of years ( - ) and available for follow up were included retrospectively in the study. results: we included patients in this study, ( . %) of which were male, female ( . %), with a median age of . ± . years. in patients ( . %) rib was affected, in patients ( . %) , the fractured ribs being true ribs ( - ) in cases ( . %), false ribs ( - ) in cases ( . %) and both in cases ( . %). the affected thorax half was the left side in cases ( . %), the right side in cases ( . %) and both thorax halves in cases ( . %). the trauma mechanisms were falls at home, traffic accidents, sporting accidents, work accidents, fighting related and minor trauma in ( . %), ( . %), ( . %), ( . %), ( . %) and ( . %) cases, respectively. the median follow up time was ± days. patients ( . %) required delayed intervention: case of hemopneumothorax and cases of pneumothorax all treated with chest tube. conclusions: planned chest x-ray controls seem not to be necessary. symptom triggered reappearance for patients after rib fractures in hospitals seems to be sufficient and more economical compared to regularly re-imaging ( ) is computed tomography a first line modality in stable blunt chest trauma elderly patients? a. becker , , y. berlin , , d. hershko , emek medical center, department of surgery a, afula, israel, technion-israel institute of technology, haifa, israel, emek medical center, surgery, afula, israel introduction: adult older, patients aged [ years, represent up to - % of all trauma patients admitted to the trauma centers. chest trauma in older patients have been recognized to strongly influence mortality. the estimated of % mortality and pneumonia rate for these patients was observed ( , ) . based on low diagnostic accuracy of cxr, interpretation difficulties due to aging chest wall deformities, we hypothesized that ct chest should be the first imaging modality in stable elderly blunt chest trauma patients. patients and methods a retrospective analysis of all blunt trauma admissions at emek medical center between - years was performed in order to identify patients with blunt chest trauma. only stable trauma patients with abbreviated injury score (ais). results: among patients that met inclusion criteria, there were ( %) patients aged - years old and ( %) patients aged c . in the first group of patients ( - ), had ct chest on arrival. in the second group of patients (aged c ), there were ( . %) patients with missed injuries. in this group, patients who had ct chest on arrival, of ( . %) patients had missed injuries. eleven of ( %) patients who had no ct chest on arrival, diagnosed with missed injuries (p- . ). readmission rate in the first group of patients ( - ) was of ( %) who had ct chest on arrival, and of ( %) who had cxr on arrival only (p- . ). in the second group (c ), readmission rate was of ( . %) patients with ct chest on arrival, and of who had cxr on arrival only ( %) (p- . ). conclusions: based on our study result we conclude that ct chest should be a first imaging tool in stable elderly patients with blunt chest trauma. no disclosures. efficacy and safety of small-bored tube thoracotomy for chest trauma: large-bored chest tubes will no longer be needed introduction: tube thoracostomy drainage is an important treatment for traumatic pneumothorax and hemothorax. traditionally, largebored chest tubes have been recommended for successful drainage and prevention for clogging by clots. however, there is little evidence that large-bored tubes are more effective than smaller ones. in consideration of invasiveness, in our emergency room (er), we use fr chest tube for all trauma patients when chest thoracotomy is indicated. the aim of our study is to investigate the efficacy and safety of small-bored tubes for chest trauma patients. material and methods: we conducted a retrospective observational study. we included the adult patients ([ years old) who had undergone tube thoracostomy with fr chest tubes for chest trauma during the years from october to september in our er. the patients with cardiopulmonary arrest on contact or on arrival were excluded. we evaluated tube-size related complications defined as obstruction and worsening of pneumothorax/hemothorax due to ineffective drainage. results: there were eligible patients, % were male, mean age was . and the average injury severity score was . (± . ). sixty-six tube thoracostomies were performed by emergency physicians and were performed by thoracic surgeons. the average duration of tube placement was . days (± . ). there were not any tube-size related complications nor any patients who required additional tube insertion. case history, clinical findings: different stable hemodynamic cases with thoracoabdominal penetrating trauma and negative fast evaluation were enrolled in study. subsequent hemo/pneumothorax was managed initially by tube thoracostomy. investigation/results: hence laparoscopic investigation is an effective method for evaluation of diaphragmatic injuries in thoracoabdominal penetrating trauma, patients underwent diagnostic laparoscopy. in case , classic approach was done by open technique mm port insertion in sub umbilical. two mm ports inserted in lower abdomen at the level of midclavicular line. then mm port was added in subxiphoid area and by introducing zero-degree camera through it a better exposure was obtained. in case , mm sub umbilical port, mm port in subxiphoid and another mm working port at the level of umbilicus and right midclavicular line were applied. a -degree camera used. exposure, working space and exploration maneuvers were much easier to perform in compare with case . in case , port placement was identical to case but zerodegree camera was used. due to poor exposure, subxiphoid port was replaced by a mm one and used for camera insertion, then an acceptable exposure was obtained. in case , port placement of case was used by using -degree camera which resulted in a great exposure. diagnosis, therapy, progressions: patients tolerated the operation well and underwent appropriate management according to their intra operation findings; post-op courses passed without any complications. comments: in patients with suspicious diaphragmatic injury and according to available facilities in our centers, in unilateral injuries we suggest that a mm port in subxiphoid area can be used instead of contralateral midclavicular mm port. in bilateral injuries, if enough exposure doesn't achieve, a mm port in subxiphoid can be added. in absence of degree cameras, mm port use in subxiphoid can give surgeons better exposure. hemodynamic instability in patients with extremity injuries: motor vehicle accidents and shot wounds vs. explosions a. mahamid , i. ashkenazi hillel yaffe medical center, hadera, israel introduction: we previously reported that hemorrhagic instability (hs) was a complication of extremity injuries in as many as of of patients treated in one medical center following explosions. the objective of this study was to evaluate whether the prevalence of hs in patients with other high energetic injuries such as motor vehicle accidents and shot wounds (mva/sw) is different or not. material and methods: victims following mva/sw with extremity injuries and hs treated in one medical center during were identified with the aid of the national trauma registry and the center's blood bank. hs was defined as tachycardia (pulse [ /min) and/or hypotension (systolic pressure \ mmhg) in need of blood transfusions to reverse instability. patients in whom hs could be attributed to injuries other than the extremity injury were excluded. these were compared to patients treated following bomb explosions ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) conclusions: the proportion of patients in need of blood transfusion is much higher in patients whose extremity injury was caused by an explosion. the relative risk for hs is almost times higher in these patients. new technologies in soft tissue wound management limit reconstruction complexity and enhance recovery introduction: large soft tissue losses are associated with infection, increased morbidity and mortality, increased costs and poor outcome functionality. the purpose of this study was to evaluate the efficacy of a combination treatment of combined topclosure Ò tension relief system (trs) and administration of regulated oxygen and antibiotic irrigation negative pressure-assisted wound therapy (roi-npt) in the treatment of patients suffering from significant soft tissue loss. patients with open abdomen, large infected wounds, and extensive soft tissue loss treated with trs and roi-npt. results: full wound closure was achieved in [ patients treated without skin grafts or flaps. primary failure was successfully followed with secondary closure with the same system. the trs system allowed early postoperative physiotherapy with good to excellent functional results. limitations and complications will be discussed. . trs is a novel device for stretching, and securing wound closure, applying stress relaxation and mechanical creep for primary closure of large skin defects that otherwise would have required closure by skin grafts, flaps or tissue expanders. . irrigation may accelerate the evacuation of infectious material from the wound and may provide a novel method for antibiotic administration. . supplemental oxygen to the wound reverses reduced o levels in the wound's atmosphere inherent to the conventional negative pressure-assisted wound therapy restricting vacuum use in anaerobic contamination. moris topaz is the inventor and patent holder of the topclosure Ò and vcarea Ò . attendees' perceptions about tourniquet safety use aboard, easiness of application, and preference among four devices tested assessed. material and methods: the descriptive study design assessed employing a post-seminar survey, participants' perceptions of tourniquet safety use, application easiness, and preference among the four devices tested (cat, sam-xt, swat-t, and rats). the first two variables measured on a one-to-ten scale (being ten the easiest or safest, and one the least easy or least safe), while preference was measured by frequency count, with only one device to select as the preferred. frequencies and percentages for categorical variables and averages calculated and compared using the anova test (p \ . ). results: a total of sailors, ( %) females, and ( %) males, aged between and , participated in the workshop and completed the survey. the mean for the perception of safety regarding onboard usage was . . as for application easiness, cat and sam-xt ranked equally high ( . ), followed by swat ( . ) and rats ( . ), and the only statistical difference found was for rats (p \ . ). cat was reported as preferred by participants ( %), followed by sam-xt ( %), swat-t ( %), and rats ( %). conclusions: jse crewmembers (non-medical personnel) considered safe the use of tourniquets on board. of the four devices assessed, cat and sam-xt were regarded as equally easy to use and rats the least of all. cat was reported as preferred by almost three out of every four respondents. introduction: surge capacity is the ability to manage the increased influx of critically ill or injured patients during suddenly onset crisis, like a mass-casualty incident (mci) or disaster. during such an event all ordinary resources are activated and used in a systematic, structured and planned way. there are, however, situations where conventional healthcare means are insufficient and additional resources must be summoned. this study investigates the possibility of using community resources such as primary health care centers, nonmedical professionals and non-standardized facilities together with educational initiatives to increase surge capacity in a flexible manner. purpose: to investigate the possibility of an increased and flexible surge capacity during a crisis, disaster or mass casualty incident (mci) by examining the main components of surge capacity (sc) (staff, stuff, structure, and system) in the västragötaland region of sweden. method: this thesis uses a mixed methods research approach with an explanatory sequential design. a literature search was performed by using standard search engines utilizing relevant keywords, questionnaires and semistructured interviews were used for data collection from primary health care centers, dental and veterinary clinics, schools, hotels and sports facilities to determine capabilities, barriers, limitations and interest to be included in a flexible surge capacity system. results: preliminary findings indicate that there is interest, capacity and capability in the investigated municipalities to partake in a fscplan: primary healthcare centers can be toned up with drills and exercises, civilians can be educated in advanced first aid procedures (immediate responders) and focused leadership (scene management), schools, hotels and sports facilities can be prepared with advanced first aids kits and be used as alternative care facilities. these alternatives together represent the concept of flexible surge capacity. conclusion: flexible surge capacity can be a possible approach to create extra resources in disaster situations, mci's, or whenever supporting infrastructure is not intact. new educational initiatives, drills and exercises, laymen empowerment and organizational and legal changes might be needed to realize a flexible surge capacity. introduction: a hospital may need partial or total evacuation because of internal or external incidents, such as in natural disasters and or armed conflicts. an evacuation aims either to transport a large number of patients to other medical facilities or to prepare enough space to receive a large number of victims. despite many publications and reports on successful and unsuccessful evacuations, and lessons learned, there is still no standardized guide for such an evacuation, and many hospitals lack the proper preparedness. we aimed to analyze the preparedness of hospitals for a total evacuation by looking into some key parameters necessary for a successful performance. material and methods: a literature search was performed by using the standard search motors in the related fields, and by using relevant keywords. eleven questions were sent to representatives from euand non-eu countries. results: our findings indicate that there is neither a full preparedness nor a standard guideline for evacuation within the eu or other non-eu countries included in this study. some countries did not respond to our questions due to the lack of relevant guidelines, instructions, or time. conclusions: hospitals are exposed to internal and external incidents and require an adequate evacuation plan. there is a need for a multinational collaboration, specifically within the eu, to establish a standardized evacuation plan. references: nero c, Ö rtenwall p, khorram-manesh a. hospital evacuation; planning, assessment, performance and evaluation. j acute dis. ; ( ): - . introduction: the importance of and the need for medical management during any armed conflict is a fact. many medical achievements have been accomplished due to wars and armed conflicts. the world is, however, divided into countries with and without related military healthcare services. there is a need for joint structure with the civilian in the former, while in the latter the civilian healthcare is responsible for offering services to the military. this study aims to identify the needs of military healthcare system and military medicine as an independent specialty. material and methods: a literature search was performed by using the standard search motors in the related fields, and by using relevant keywords. relevant professionals were asked about the pros and cons of having established military healthcare. the data was collected and analyzed. results: although our findings indicate a need for military medicine/ healthcare as a professional specialty, the organizational divisions between military and civilian healthcare systems seems to be changing. the current security issues worldwide, the pattern of injuries and resource scarcity indicates a need for improved collaboration and maybe a fusion between these entities. conclusions: new security threats, modern technology, the pattern of medical injuries, and the lack of adequate surge capacity may indicate a very close collaboration between military and civilian healthcare systems. such a close collaboration may develop to fusion and a total defense healthcare system that can act both in peace and during conflicts. references: ringel js. the elasticity of demand for health care. a review of the literature and its application to the military health system. https://apps.dtic.mil/docs/citations/ada khorram-manesh, a. facilitators and constrainers of civilian-military collaboration: the swedish perspectives. eur j trauma emerg surg. . https://doi.org/ . /s - - - . alternative methods of mandibular comminuted fracture fixation in severe maxillofacial injured patients introduction: severe maxillofacial injuries refer to significant facial trauma with communitive bony fractures and soft tissue loss. they result in violent trauma as firearm injuries (wartimes injuries, terrorist attack, suicide attempt) and high velocity motor vehicle accidents. the initial management consist of fighting hemorrhage, fighting asphyxia, wounds debridement and suture, and fractures stabilization, especially mandibular fracture stabilization. our study aims to share thoughts on the alternative methods of comminuted mandibular fracture fixation within the context: kind of injury, multitrauma patients, mass-casualty situation, precarious situation or hostile environment. material and methods: based on our experience (clinical cases), on senior surgeons questioning and on medical literature data, we sought to identify, to evaluate and to compare the different available methods to stabilize comminuted mandibular fractures in severe facial injured patients. results: open reduction and stable internal fixation (using macro plate), external pin fixation and closed reduction with maxillomandibular fixation are the methods of treatment which are the most classically used and described. however, some methods using kirschner wires are reported: in cross extrafocal pinning ( fig. ) , external fixation and handmade splints. all these methods differ in their complexity of use, in their availability, and in their possibilities to treat one kind of mandibular fracture or another. conclusions: the stabilization method of comminuted mandibular fracture will be choose depending on material availability, on surgeon's abilities, on the time available (mass-casualty situation) and on the patient's overall condition. even if stabilization methods using wires are less commonly used, they appear to us to be useful in the initial management of the severe maxillofacial injured patient with comminuted mandibular fracture, especially in austere conditions. causes of combat casualties' death at medical treatment facilities (mtf) in modern conflicts: russian experience i. samokhvalov , v. badalov , k. golovko , t. suprun , v. chupriaev material and methods: data including mechanism of injury, physiologic and laboratory variables, staged surgical treatment and cause of death were obtained from the combat trauma registry of the kirov military medical academy war surgery department. the combat trauma registry includes russian wounded in military conflicts over the past decades, of them ( . %) dead of wounds (dow) at the mtf. results: . % of the total dow number died at the role ii field medical units, . % died at the forward military role iii hospitals, and . % died at the role iv hospitals. the causes of dow patients delivered to the mtf were nonsurvivable traumatic brain wound ( . %), life-threatening consequences of injuries-mainly massive blood loss due to external and internal bleeding and acute respiratory failure ( . %), as well as the late septic complications ( . %). terms of death depended on the cause of dow. so for nonsurvivable traumatic brain injuries, they amounted to . ± . days, for lifethreatening consequences of wounds- . ± . days, and in the development of complications- . ± . days. conclusions: there is a high mortality rate among the combat casualties delivered to mtf in modern asymmetric warfare ( . %). moreover, half of these patients ( . %) die at role ii field medical units mostly from nonsurvivable injuries and from acute irreversible blood loss that occurred at the prehospital stage. the main cause of hospital combat mortality is severe septic complications of combat trauma. in consideration of the present counterterrorism practices, prevention and initial treatment for primary blast injury by shock waves constitute a particularly urgent subject because blast injuries and gunshot wounds account for the majority of terrorism deaths. in japan, due to strict ethical standards in animal experiments, there is no appropriate animal model of blast injury. we established an original small animal model of blast injury using a laser-induced shock wave at the national defense medical college (ndmc). however, since the experiments were conducted using only small animals, such as mice and rats, it was necessary to establish a medium-sized animal model aimed to test the applicability in human patients in the long term. correspondingly, we established a blast tube, which was authorized globally as a shock wave-generating device that causes blast injury based on air pressure differences, in the ndmc research institute using the budget of advanced research on military medicine of japan in . this allowed us to conduct scientific studies on blast injury using mediumsized animals. in this presentation, we will introduce the structure and function of the blast tube installed in the ndmc and present some of the results of our research thus far. this research is financially unfortunately, even if hospital and their staff are an essential key for successful response to mcis, the plan are seldom well-known and, above all, exercises are quite neglected at local and national levels. due to mci rarity, simulation exercises are the only way to achieve proficiency in mci response. therefore, we tested an original mci training system (macsim Ò ) adapted to the pemaf of a large university hospital in milan (italy). material and methods: the original mci training format called macsim-pemaf (emergency plan for massive influx of casualties)was developed for the italian society for trauma and emergency surgery (sicut) in . it uses macsim Ò , a simulation tool scientifically validated for training and assessment of healthcare professionals in mci management. between and the course was held for the emergency department staff of a single university hospital of milan (italy) (foundation cà granda-ospedale maggiore policlinico). macsim Ò was used to reproduce the hospital resources, with different mci scenarios. during the simulation the participants had the opportunity to test the local pemaf, in adjunct to their knowledge and skills. course effectiveness was evaluated by a pre-and post-course self-assessment questionnaire. results: macsim-pemaf was tested in seven courses, for a total of participants. pre-and post-test questionnaires showed a significant improvement in hospital staff self-perception of knowledge and skills in mci management. on a - scale, the improvement value was from . ± . to . ± . (p \ . ). conclusions: macsim-pemaf is a useful tool to test single hospital pemaf. it is versatile enough to adapt to specific realties, mimicking different traumatic scenarios. participants, acting in their usual professional roles, can increase their self-perception to be able to respond to a mci with in-hospital resources. introduction: emt are field health facilities, specifically structured to operate in case of disaster, where local healthcare resources are insufficient. there are types of emt. ''emt regione piemonte'' is the first italian emt to be certificated by who. it's a type , meaning that more than triage and stabilization of emergency cases it's provided with an icu, a / working operation room, a test lab, radiological and ultrasound devices. it can admit up to inpatients. cyclone idai made landfall on / / in the district of dondo in mozambique. it brought torrential rains and strong winds and had heavy impacts on the city of beira and surrounding areas resulting in loss of communication and access. in addition important damage and destruction to shelter, settlements, health and wash facilities occurred. on / italian government approved the aid mission, from march st to th three italian military aircraft transported the medical staff and the boxes containing the hospital to maputo and then in beira. on / , the hospital began working, treating an average of patients and performing - surgeries per day, involving mozambican staff who immediately well integrated with the italian colleagues. results: days of activities. surgeries ( orthopaedic, general surgery, gynaecology, plastic surgery). . % of the cases related to cyclone. mean tiss: ( - ). mean age ( - ) females, males. types of anaesthesia: % locoregional, % general, % analgosedation. conclusions: our first experience in a mass casualties' scenario showed how important is to refresh team skills through periodic drills. the leadership is of paramount importance to keep the team united and to support collaboration with other nations' teams and with the local population. adaptability and open-mindedness are fundamental. emts do not arrive in loco immediately so that longer periods of mission and integration with local medical staffs should be programmed. introduction: in utrecht, the netherlands, a worldwide unique major incident hospital is continuously standby to receive multiple victims during mass casualty events. each year, different types of mass casualty events are simulated with a varying number of victims, to train command and control under extreme circumstances. in utrecht, on march th , a terrorist opened gunshot fire in crowded public transport. the aim of the study is to compare our experiences in simulation versus reality. material and methods: an internal evaluation was performed by questionnaires completed by participants and an external evaluation was performed by interviews. results: all five victims were brought to the major incident hospital, of whom two were dead on arrival, one died seven days after due to multiple organ failure and two survived after multiple surgical procedures. all victims arrived within min after the major incident hospital was activated. a sufficient number of medical staff was alarmed for these five victims, however, since the event occurred during office hours, at least a double amount of staff showed up. among some medical staff on commanding key positions fear arose about their own safety and of relatives outside the hospital. this was exaggerated by incomplete and incorrect provided information from the scene. although medical care of the victims was not affected at all, occasionally the anxiety negatively influenced the command and control structure. conclusions: the combination of anxiety and a surplus of awaiting and benevolent curious medical staff resulted in occasional insufficient performance of the existing command and control structure, despite proper training. however, simulation of fear in a training is very difficult. nowadays, with the increasing threat of terror attacks, one should be aware of the influence of fear and anxiety on personnel, even with low numbers of victims. ethic and law issues during mass casualties management operations in foreign countries introduction: mass casualties incidents occur even more frequently during the last years globally. international help in order to manage them, when needed and asked, has to take into consideration special aspects of ethics and local law status in order to successfully fulfill its expectation. purpose: to demonstrate the ethic and law issues that arise during mass casualties management operations in foreign countries. material and method: literature review from recent management operations in syria, iran and sub saharan africa. results: during such operations a lot of ethical and law issues arise. the knowledge of ethics and laws in the country that these take place is essential and critical for the successful result of them. special care must be taken for the management of women, children and dead people. traditions and religion status of the local populations also must be taken into consideration and actions must take place in accordance to respect of the local authorities and social conditions. conclusions: mass casualties management operations in foreign countries is a challenging mission. ethic and law issues arise and must be taken into consideration for the success of the mission. western surgical experience is one thing, but surgical practice in countries in conflict zones is another. the pathologies are different, the thermal conditions are often difficult and the follow-up of the patients is fundamentally modified. humanitarian surgery is becoming more professional and most organizations are setting up a training program for new surgeons embarking on the humanitarian adventure. international committee of the red cross (icrc) has implemented an onboarding-surgeon experience, before to become a fully icrc surgeon. i hereby present my personal onboarding experience in south sudan: how to learn a new type of surgery, how to come with an helicopter to collect patients in the bush and then, how much you learn about yourself. conflict of interest: i only represent my own experience and i do not represent icrc. surgical clinical reasoning during the war in the period between and , i was the head of operating rooms and icu at the clinic for orthopedic surgery and traumatology, in sarajevo. working in the operating room whose walls are shaking because of the sniping and shelling was not remembered by any other generation of surgeons. there were around traumatized citizens of sarajevo. thousands of injured, dying patients were seeking for help from a small number of surgeons. the duty of a surgeon working in the war conditions, without water, electricity, medicines, or heat, is not easy at all, and there were a lot of difficult situations. for example, one day, operated children were again wounded by direct shelling on the walls of pediatric department of our clinic. after we re-operated the children, we also operated the injured nurses. th may, , th february, , and th august, were the most painful experiences in the surgical treatment of disaster in the center of sarajevo, with a large number of massively traumatized patients. while you were helping one casualty, others were pulling our arms or legs. while you were helping one patient, others were dying in the cramp of pain. during the war, a series of traumatic events happened. above many thousands of them, i admitted a -year-old girl, severely injured, with traumatic lower leg amputation of the leg, and severe injuries of the thigh, pelvis, and neck. we operated on her through the night. during the surgery, she received whole blood transfusions. following the surgery, she was stabilized on pediatric department of our clinic. one day, i saw her mother brought her a gift, immensely valuable in those days, a small canister of pure water. in the , one girl approached me, and asked me if i remembered her. i remembered the canister of pure water. she was happy to show me how she can walk now, and told me she lives in canada and works as a university assistant. i was more than happy to see her walk proudly, as she was leaving. she injury pattern of earthquake in athens, greece: the panic-effect introduction: earthquakes are devastating events. greece is known to be in the first place of seismicity in europe and sixth worldwide. lately, a . richter earthquake shook the greek capital, and fortunately no substantial construction damage was sustained. the aim of the study is to evaluate the classification and severity of all injuries, as well as the type of orthopedic surgical procedures performed, in addition to the role that panic plays on the occurrence of these kind of trauma material and methods: prospective case-series study, conducted in the emergency department of our hospital after the july th, earthquake. the study included patients treated by our department, who sustained injuries in their attempt to run away from the scene. age range was from to years old (mean . y.o), were female and were male. results: a total of injuries reviewed. upper extremities were involved in of all cases, lower extremities in and one patient suffered minor head trauma. four patients required hospitalization and all of them underwent surgical treatment. open reduction and internal fixation performed in patients ( calcaneus fracture and olecranon fracture), patient underwent intramedullary nail fixation (tibial shaft fracture) and external fixation was applied to another (distal tibia fracture). six patients were conclusions: panic is an independent contributing factor in natural disaster associated trauma. prior education, preparedness and combined team effort are clearly needed, in order to reduce the incidence of these injuries. regardless of age, panic may result in various types of fractures, even in cases there are no substantial construction damages after an earthquake. digital and analogue record system for mass casualty incidences at sea: results, reliability and validity introduction: mistriage may have serious consequences for patients in mass causality incidences (mci) at sea. therefore, an exercise was conducted to compare the reliability and validity of an analogue and tablet based recording system for triage of sample patients. material and methods: volunteers were asked to triage with the start-algorithm (black, red, yellow and green) patients in a given time using an analogue and tablet based system. triage score distribution and agreement between the two triage methods and a predefined standard were reported. the present study assessed the triage results as well as the reliability through cronbachs alpha and kappa. for testing of validity and internal consistency, the sensitivity, specificity and predictive value was measured. results: forty-eight participants completed a total of triages. while the number of triaged patients in the given time was significantly higher with the analogue system compared to the digital system (p-value . , t-test), the validity measured with the cronbachs alpha and unweighted cohens kappa was higher with the digital system. for each triage category, higher values were gained with the digital system. the sensitivity, specificity and predictive value for the digital system was higher than for the analogue system. conclusions: this study gives reliable and valid results comparing a digital versus an analogue triage system for a mci at sea. significant differences could be found for the number of triages and the number of under triage. the results of the study show that the used digital system has a slightly higher reliability and validity than the analogue triage system. references: the present work is part of the project improved emergency treatment and organization in the event of a mass casualty of casualties at sea (venomas), planned within the framework of the research network ''kompetenz und organisation für den massenanfall von patienten in der seeschifffahrt'' (kompass) and funded by the federal ministry of education and research (grant number: n ). predicting outcome for extremity wounds in pediatric casualties of war introduction: during the early s, the international committee of the red cross (icrc) implemented the red cross wound classification (rcwc) for penetrating wounds. wound grades of , and describe the amount of kinetic energy transferred to the tissue (low, high and massive, respectively). currently, this classification system mostly serves as a descriptive tool, but it is hypothesized it could also support clinical decision making. the aim of this study is to assess whether the wound grade of a pediatric patient's extremity wound correlates with patient outcomes. material and methods: this study included pediatric patients (age \ years), who have been treated by the icrc for conflictrelated extremity injuries between and . the correlation of the following variables with the wound grade were analyzed: number of surgeries required, length of stay, and in-hospital mortality. results: the study cohort consisted of pediatric patients. the higher the wound grade, the more surgeries were performed per patient (p \ . ), with a mean of surgeries per patient if they had a wound grading of . there were no significant differences in mortality rates between any of the wound grades, which were . % ( / ), . % ( / ) and . % ( / ) for wound grade , and respectively. pediatric patients with wound grade were hospitalized for the longest period (mean . days), followed by wound grade (mean . days) and wound grade (mean . days; all with p \ . ). conclusions: the wound grade of pediatric patients' extremity wounds appears to correlate with some patient outcomes, but not with mortality. grading of extremity wounds according to the rcws could support clinical decision making in pediatric patients. introduction: during the last few decades, french armed forces have regularly deployed in asymmetric conflicts. surgical support for casualties of these conflicts occurs in nato role and medical treatment facilities (mtf); definitive surgical care occurs in france following a strategic medical evacuation. the aim of this study was to describe the combat injury profile of these soldiers who presented with either non-exclusively orthopedic and/or non-exclusively brain injuries. material and methods: this descriptive study is a retrospective analysis of the surgical management of french casualties performed in role or mtf in afghanistan, mali, niger, djibouti and the central african republic between january and december . results: one hundred patients were included. forty had fragment wounds. the most severe lesions were of the head, neck or thorax. the average injury severity score (iss) was . (ic % . - ). damage control procedures were performed. thirty patients died with a mean iss of (ic % - ); deaths were considered as preventable deaths. the most frequent surgical procedures in the mtf were digestive (n = ) and thoracic surgery (n = ). thirty patients needed second-look surgery in france; eleven had severe complications. no patient died following medical evacuation to france. conclusions: results from this study indicate that the mortality following non-exclusively brain or orthopedic injuries remains high in modern asymmetric conflicts. introduction: telemedicine has been applied to disasters and extreme environments for more than years, however, despite the many lessons learned so far, telemedicine is still not a common part of the immediate disaster response. for this reason, a review of the literature was conducted to investigate whether telemedicine technology can be used to address medical and non-medical needs in extreme environments. material and methods: this systematic review included studies published in the period - , originating from literature search bases medline, scopus, cinahl and pubmed. the case of neemo project were studied so to evaluate the diagnostical and surgical care of the patients regarding the emergency response in a remote and constricted area, with limited human medical resources and using the telecommunications and telerobotic technologies. results: the majority of the included studies have highlighted the importance of telemedicine interventions in extreme environments, stressing that it is a viable solution to health care provision. in addition, it has been found that telemedicinal technology provides the possibility of virtual collaboration between healthcare professionals with various specializations. projects neemo , , engaged to eliminate the challenges of telesurgery. conclusions: future studies such as large multicentre randomized trials will have to be conducted that will lead to safe conclusions on the usefulness and efficiency of telemedicine applications in extreme environments. introduction: tourniquets are a critical tool in the immediate response to life-threatening extremity hemorrhage. the optimal tourniquet type and effectiveness of non-commercial devices is unclear, and the aim of this study. material and methods: this prospective observational cadaverbased study was performed using a perfused cadaver model with a standardized superficial femoral artery injury bleeding at ml/ min. five devices were tested: cat (combat application tourniquet), rats (rapid application tourniquet system), swat-t (stretch, wrap, and tuck tourniquet), a triangle bandage and a stick and a leather belt. volunteer medical students with no prior clinical tourniquet experience participated. each student underwent a practical hands-on demonstration of each of the tourniquets, prior to the test. using a random number generator, they then placed all tourniquets in random order. outcomes measures included time to hemostasis, total time to secure devices, estimated blood loss (ebl) and difficulty rating. a one-way anova repeated measures was used to compare efficacy between the tourniquets in achieving the outcomes. results: participants' mean age was ± . years and ( %) were male. all participants were able to stop the bleeding with of the tourniquets. with the rats there was a % failure rate. among the five types of tourniquets, time to hemostasis and ebl were not statistically significantly different (p [ . ). the swat-t required the longest time to be secured ( . ± . ), while the belt was the fastest ( . ± . ; p \ . ). conclusions: all five tourniquets, including the non-commercial devices, were effective in achieving hemostasis. a standard leather belt was the fastest to place and able to stop the bleeding. however, it required continuous pressure to maintain hemostasis. nevertheless, in an emergency setting where commercial devices are not available, improvised tourniquets may be an affective lifesaving bridge to definitive care. hospital preparedness for mass gathering events and mass casualty incidents in matera, european capital of culture for introduction: mass casualty incidents (mci) may occur during mass gathering events (mge). lack of preparedness of health system increases mortality. education and training are crucial. hospital mci plans are mandatory in italy, but they are poorly known. on , matera was declared italian host of european capital of culture for : the local hospital decided to revise the hospital plan for massive influx of injured (pemaf) and to start a program to train the staff. material and methods: the pemaf was reviewed through simulations that involved all the staff. a partnership with mrmi-italia (italian chapter of the international association medical response to major incident and disaster-mrmi&d) leaded to the support of experts and to the organization of residential courses based on the macsim Ò (mass casualty simulation) simulation tool. educational capacity of the residential events was tested through a self-assessment tool. results: alert, coordination and command sequences were defined. all the available resources were recorded and the functional areas identified. the communication network was improved. documentation and registration system was prepared. standard operational procedures (action cards) were created for the key positions. residential educational events of macsim-pemaf were organized. the educational capacity was tested through self-evaluation: knowledge of participants resulted improved. conclusions: mge are a great opportunity for the hosting community but they also represent an increased risk of mci. preparedness is mandatory for health system. the format macsim-pemaf seems to be adequate to review the existing plans and transfer skills to attendants. introduction: the cruise industry is facing a constantly growth of infectious diseases. some of them are reaching the extent of mass casualty incidences (mci), which are overwhelming the capacity of the local rescue system. our aim was to improve the ability to act in a mci due to an infectious emergency regarding the situation at sea/in the port. hamburg, as one of the largest ports in europe, was chosen for analysis. material and methods: the collaborative project ''adaptive resilience management in the port'' (armihn) is funded by the german federal ministry of education and research. scenarios due to an infectiological emergency were developed together with the university central department of occupational medicine and maritime medicine and the hamburg port health center in hamburg, germany. these scenarios were specified with all key stakeholders in the port. the organizational structure of the current emergency management was analyzed and a new concept was developed. results: for the ship and the port, emergency strategies dealing with mass casualties of injured persons are available. nevertheless, current concepts regarding this special situation of an infectiological mci were missing. we developed a new concept, which based on the models concerning mass casualties of injured persons. for this purpose, emergency surgeons can be recommended as experts regarding coping with a major emergency and for developing adaptive training concepts. conclusions: new operational concepts coping with mci of infectious patients were developed. in a second step, an emergency plan and a training concept for relevant stakeholders in the port will be developed. these will be evaluated in a full exercise in the port of hamburg and tested for their suitability. the results will be transferred to comparable infrastructures to cope with a major case incident with infected people in the port area. emergency surgeons should be involved in these steps due to their expertise. the work was funded by the german federal ministry of education and research ( n ). no further significant relationships. war surgery training, the use of swine model in military simulation center introduction: due to the international instability, our forces are deployed in many place and our military surgeons have to deal with ballistics trauma and improvised explosive devices related trauma. in order to be well prepared and effective in these isolated situation, the val de grace school (our military health service academy) provide a years course to train the young surgeon. this year surgical courses ended with war trauma surgery simulation on a swine model. material and methods: this use of the swine alive model is incorporated in the cesimco (military surgical simulation center) and also use for the training of our fully registered surgical team. this laboratory responds to all civilian authorizations and ethical considerations as enacted by european rules (felasa). results: the aim of this presentation is to show the different procedures and the teaching provided in this structure to improve surgical skills in war condition. all procedures are approved by the ministry in charge of the animal experimentation and respond to the animal welfare regulation. the number of swine used in these teaching is reduced to the minimum. we think that this animal model and its use in military forward surgical facilities, is the end point of the years military surgical course provided by the val de grace school. conclusions: this model is actually the most reliable and ethically acceptable teaching procedure we've found. during these teaching the students have to deal with open trauma and hemorrhagic lesions in damage control situation. we try to follow the different type of war related lesions observed in french military in order to stick to the reality of the field. this teaching is now mandatory before being deployed as a military surgeon on field. case history: -year-old male, previously healthy, admitted to the er due to shotgun injury to the right hip. during transport, the bleeding open wound was covered, two iv catheters were introduced, and saline and painkillers were administered. on admission, the patient was conscious, eupneic and normotensive, with a gcs score of . clinical findings: after the primary survey and exclusion of cranial, thoracic and abdominal lesions, the limb injury was addressed, showing a cm oval-shaped wound. the right leg was shortened and externally rotated. pulses were present but the patient referred calf and foot hypoesthesia. investigation/results: x-rays showed a comminuted pertrochanteric fracture and the presence of metallic foreign bodies. diagnosis: open right pertrochanteric fracture. therapy and progressions: initially, the wound was covered, and iv antibiotics and supportive therapy were given. in the or, irrigation, surgical debridement, and foreign body removal were performed, followed by orif with one dall-miles cable and a cephalomedullary femoral long nail. after surgery, the patient maintained lower limb hypoesthesia and had plantar flexion and foot dorsiflexion grade motor deficit. during follow-up, soft tissues recovered uneventfully and bone healing successfully occurred. full weight-bearing was tolerated at weeks post-op but the neurological deficits persisted despite physiatric treatment. electromyography confirmed severe partial lesion of the sciatic nerve. comments: generally, clean wound, fracture stability, restoration of circulation and skin closure of neurovascular structures are a priority and should be a reason for delayed nerve repair. introduction: despite mass casualty incidents (mci) are becoming a common concern, particularly regarding the care of paediatric victims, pure paediatric trauma centres (ptc) are still rare in europe. the purpose of this study is to assess the capacity of the hospitals in the metropolitan area of milan in case of mci involving the paediatric population, with focus on the pre-impact planning phase. material and methods: relevant literature and existing guidelines were reviewed by the representatives of four referral centres for the management of either trauma or paediatric patients. minimum standard requirements of care of paediatric trauma and consequently the maximal surge capacities for each hospital were defined based on the severity of injuries and personnel/equipment availability. results: overall, the four hospitals are able to treat patients with the highest priority (t ), to patients with intermediate priority (t ), and patients with deferrable priority (t ). severely injured patients \ years old should be preferentially transported to the hospitals with paediatric expertise, whereas patients between to years of age can be managed in multi-speciality structures. conclusions: in case of mci it is not always possible to rely on the availability of a ptc. hospitals with paediatric trauma care expertise can work in synergy with ptcs, or offer an alternative if there is no ptc, and should therefore be included in disaster plans for mci involving paediatric victims. case history: we present a case of a -year-old male with a proximal radius and ulna gunshot fracture associated with a complete lesion of the brachial artery, which was urgently repaired by grafting in his native country. a partial proximal radius excision was also performed. three months later, after soft tissue recovery, the ulna fracture was fixed with a dcp plate plus iliac crest bone graft. at months follow up x-rays showed hardware loosening, so the plate was removed and an external fixator was implanted. in this situation the patient attended to our clinic months after the initial injury. clinical findings: findings included proximal pin purulence, an elbow varus deformity and a limited joint motion: flexion °, extension °, supination/pronation °. investigation/results: x-rays and ct scan showed proximal ulna pseudoarthrosis. diagnosis: proximal ulna pseudoarthrosis after a gunshot fracture. therapy and progressions: a two-stage procedure was performed. initially we performed a wide debridement and external fixator removal. an ulna nail combined with gentamicin and vancomycin pmma spacer was implanted. s. aureus was identified in intraoperative cultures. in a second stage, year after, the nail and spacer were removed and a vascularized fibula graft with saphenous loop was implanted and fixed with a va-lcp plate. the central band of the interosseous membrane was repaired with a prosthetic device. currently, the patient presents full flexion range, hyperextension of °, active pronation of °and supination of °. x-rays show graft consolidation. comments: gunshot fractures are complicated lesions with significant soft tissue damage and high risk of vascular and nervous injury. a thorough study and initial systematic approach is mandatory in order to avoid later complications. introduction: the purpose of our study was to independently analyze pediatric trauma data, especially that of preschool-aged children, including demographics, injury patterns, the associated mechanism of injury, and outcomes, at a single institution in korea to gain a better understanding of current trends in non-regional trauma centers. material and methods: we conducted a retrospective review of preschool-aged children with trauma, who presented to the emergency department a single center between march and december . results: overall, there were pediatric patients who experienced trauma admitted during this study period. the frequency of admissions was similarly high in all seasons except winter. falls were the most common mechanism of injury at all ages, except , , and years of age, according to comparative analysis by age and mechanism. the most common place of trauma at - years of age was at home, and outside the home at the age of years or older. the most common injury region was to an extremity ( . %). mean injury severity score was ± . , and the mean hospital stay was . ± . days. conclusions: although mortality from trauma is low in pediatric patients, we must continue to improve treatment outcomes for children. it is unlikely for a hospital to have a pediatric trauma specialist, such as a pediatric orthopedic surgeon or plastic surgeon, due to manpower constraints. in order to further improve the outcome of treatment with insufficient resources, it is necessary to recognize agespecific characteristics. question: the new safety situation in europe and the lessons learnt civilian events of damage show that hospitals have to be prepared for mass casualties. the shift of the operational mode to ''emergency medicine'' have to be planed and practiced. the reporting tool for this is the hospital action plan (hap) that every hospital should have. the efficiency of the existing plan is already proven in different largescale exercises. in germany the legislator obligates the hospitals to enable there staff to properly perform the different tasks of the hap. in addition, the have to develop and evaluate proper training and exercises. goal of this study was to establish along the hap of a level one trauma center an modular mass casualty training (manv ) that would help to analyze the tasks to face and to deepen the existing structures of communication. method: we set a scenario with casualties and evolved the different shifting phases of the trauma center (alarming-, mobilization-, constitution phase). setting the concept of training outside the regular service period we took in account that there will be a lack of resources and material. we did not exercise in a large-scale but trained in small groups modular. we also did a screen adaption of the hap of the trauma center to have a mind set for the staff and a starting point to the scenario. to teach our operative procedure we simulated our '' columns concept'' (medical, personal and infrastructure) to the staff. specific to the different task groups (medical doctors, technicians, nurses) we exercised and the different sectors (er, triage, or, command etc.) and the necessary shifts of the different hospital sectors when a mass casualty occurs. before and after we did a query of the staff to see how much impact the modular exercise would have on the hap-knowledge of our staff. results: we were able to simulate realistically an identical mass casualty scenario to different staff groups of our hospital. knowledge about the hap increased significant from to % after the trainings. % of the staff see a clear improvement of information about the hap. also, the specific shifting-phases and the enrolment of the plan to move in an ''emergency medicine mode'' understand % better. % of the staff fell now a much better preparedness than before. % think that through modular exercises and small group training the communication in between working groups improved. conclusion: we could manage to improve a significant increase of knowledge about the hap in our staff. all the small group modular training in the different sector can be easily but together in large-scale exercise and other teams like police, military or fire-department can easily be added. introduction: dstc course focusses on surgical skills for trauma care. it is designed to teach surgical techniques for the definitive treatment of severe trauma. currently, it has evolved into an international trauma team course. our objective was to assess faculty members' opinion regarding course content, educational methods, and incorporation of non-technical skills. material and methods: a descriptive study was designed using an anonymous online survey issued from may to august , . senior international faculties' opinion from countries assessed. the survey inquired views of courses content, duration, adequacy of hands-on practice, need for updates, and usefulness of incorporating non-technical skills to the course. results: from the surveys issued, were ( %) answered. the course content was valued as very satisfactory by %; % were very satisfied or satisfied with courses educational method. % considered the time devoted to lectures, case discussions, and skills lab very adequate or adequate. course duration ( days) was valued suitably by % of responders. the inclusion of non-technical skills was considered as very important by %, important %, of some importance %, of little importance by %, and unimportant by %. this result reflects the insufficient sense of significance, among some, of the importance of trauma team dynamics. course content updates were seen as convenient by % of the surveyed population, suggesting them at least every - years. conclusions: dstc international faculty response to the online survey tool was inadequate, receiving % of the targeted study population. of the assessed faculty, most were satisfied with course content, duration, and educational methods. the surveyed population lacked a uniform perception of the importance of incorporating nontechnical skills. introduction: dstc is an iatsic course emphasizing on teaching surgical skills for trauma care. in many countries, it is an essential course focused on the ''second hour'' beyond atls and teamwork. initially centered on the surgeon, it currently seems to be adopting a trauma team training (ttt) model, incorporating the anesthetist to the program (ds-datc). our objective was to review this changing trend in three countries: spain, portugal, and brazil. material and methods: a descriptive study was designed by faculty from the three countries examining course records and analyzing its evolution during the last five years. number and types of courses delivered in each country from to reported, and the proportion of dstc to ds-datc scrutinized. frequencies and percentages calculated for categorical variables and the proportion of course types also determined. results: during the -year studied period, dstc courses were issued: ( %) in spain, ( %) in brazil, and ( %) in portugal. a total of ( %) ds-datc courses in the three countries, and the percentage of total delivered in each country was as follows; spain ( %), portugal ( %) and brazil ( %). overall ds-datc to dstc ratio was : , detailed as follows: portugal : , spain : , and introduction: thailand is a disaster-prone country with a high dependency on tourism. it has been affected by both natural and manmade emergencies. the thai emergency healthcare system consists of emergency physicians working at hospitals and prehospital levels, emphasizing their essential role in emergency management of any incident. we aimed to investigate the thai emergency physicians' level of preparedness by using tabletop simulation exercises and three different scenarios. material and methods: using the lc (three level collaboration) method, two training sessions were arranged for over thai emergency physicians, who were divided into three groups of prehospital, hospital, and incident command staff. three scenarios of a terror attack and explosion, riot and shooting, and high building fire were discussed in the groups. results: our findings indicate that the initial shortcomings in command and control, communication, coordination, and the ability of situation assessment increased in all groups step by step and after each scenario. new perspectives and innovative measures were presented by participants, which improved the whole management on the final day. conclusions: tabletop simulation exercises increase the ability, knowledge, and attitude of thai emergency physicians in managing major incidents in strategic, tactical, and operative managerial levels, and should be included in their professional curriculum. introduction: non-operative management of traumatic injuries has led to decreased surgical exposure for trauma trainees [ ] . while simulation using cadavers may improve exposure to damage control techniques, tissue handling realism is variable depending on embalmment and perfusion techniques [ ] . objective: to evaluate the feasibility of perfused thiel cadaver use for trauma surgery simulation. material and methods: thiel cadavers were cannulated in the ascending aorta and right atrium to create a left-to-right perfusion system. a magnetic pump was used to achieve a pulsatile flow with a gelatin-based solution, aiming for a flow of l/min. peripheral circulation was improved with arteriovenous fistulas (carotid-jugular, femoro-femoral and brachio-brachial). a left common iliac vein injury was performed laparoscopically through the sigmoid mesentery. the surgical trainee was blinded to the initial injury and assisted by a staff surgeon. results: a trauma laparotomy was performed. the small bowel was eviscerated and all four quadrants were packed with gauze. a left, expanding zone iii hematoma was detected. the left sigmoid colon was mobilized to achieve proximal control of the left iliac vessels. the left common iliac vein was actively bleeding and ligated according to damage control principles. the left ureter was uninjured. the sigmoid mesentery was closed, without active bleeding. the remaining of the abdominal cavity was explored without other injuries. time from laparotomy to closure was min. tissue handling and circulation dynamics were highly realistic due to thiel embalmment and pulsatile perfusion. conclusions: pulse-perfused thiel cadavers represent a realistic simulation option for surgical trainees. widespread implementation may provide accurate simulation for lifesaving procedures rarely performed in an era of non-operative management of traumatic injury. a new concept of intra-operative performance monitoring and self-assessment in hepato-pancreato-biliary surgery and other surgical specialties s. kharchenko , , m. yanovsky colmar civil hospital, university of strasbourg, department of general surgery, colmar, france, hepato-biliary institute henri bismuth, paris, france, interceg, kharkiv, ukraine introduction: currently, the majority of learning curve studies for surgical interventions associated with simple chronometric estimation in a whole: from incision to closure. a selective approach for step-bystep time fixation of all hpb interventions (hepatectomy, others) or other surgical specialties can bring a new vision of correlation between intra-operative timing and the clinical outcome. material and methods: every operation can be divided into step items so standardized worldwide, for example, planned or urgent laparoscopic cholecystectomy e.g. incision to port placement, exposure, dissection to cholangiography, cholangiography, extraction, closure. results: the prototype named chronoi of infrastructure for automated monitoring (simulator of time tracking activities, web-service for request processing, database and knowledge base collection subsystems, learning curve representative and analytics software) is designed and to be implemented. individual self-assessment is available in a real-time fashion. the learning curve changes are shown per procedure. up to our knowledge, we can firstly in the world describe the surgeons, incl. in hpb, as speedy, standard or nonstandard depending on the surgeon's ''individual speed'' in operative performance. it's to be documented in their e-logbooks according to the current fellowship standards or practice re-certification. conclusion: the intra-operative monitoring and worldwide standardization give a new vision of the surgical practice in hpb surgery meaning an introduction of monitoring-based clinical outcomes (timing with morbi-mortality or other). only new trials will approve the role of the presented concept in hpb surgery as well as in general, emergency and trauma. introduction: the management of patients victims of war weapons and collective emergencies represents a major public health issue in france, but also abroad. terrorist events in recent years on the national territory have highlighted the need for training the population and caregivers in the management of these injuries. because of his experiment in the domain, the french military medical service (fmms) was requested to cooperate with the french prehospital teams in order to improve knowledge and teaching in this area. today, a continuing medical education, easily available and free access is needed in this area. material and methods: development of video podcasts (infographics) of a few minutes on the theme of management of patients victims of war weapons and collective emergencies. the working group ensures the production and quality of educational messages. production is provided by the communication establishment of defense. the broadcast is displayed on the channel you tube of the fmms. results: the title of the traum'cast podcast is the contraction of trauma and podcast. twelve episodes are scheduled on a -weeks rhythm. the podcast program is as follows: conclusion: fmms knowledge and experiment in managing patients victims of war weapons is unique. teaching can take various forms, theoretical, practical, academic, or through publications. traum'cast is a major innovation in the dissemination of this knowledge and each episode focuses on a specific skill. traum'cast will highlight the applicability of military medicine concepts in a civilian environment. traum'cast will be translated in an english version. project was supported by grants of french ministry of defense (innovation department). splenectomy in current surgical practice: a tricky and elusive procedure for the surgical resident? introduction: splenic rupture and oncologic resections are the most common indications for splenectomy, but technical expertise is progressively being taken over by non-operative and more conservative approaches. material and methods: retrospective review of all total splenectomies performed between february and january at an italian academic hospital, assessing demographics, diagnosis, operating surgeon, surgical approach, complication rate, postoperative critical care admission, and -day mortality. results: over years, consecutive splenectomies were performed by different surgeons, of whom surgical trainees, with unplanned (i.e. emergency/iatrogenic injury) and planned (i.e. benign/malignant disorders) procedures and an average of . and . procedures per year respectively. over the study period, only surgeons performed at least procedures and only performed at least procedures. laparoscopy was performed in . % of cases, predominantly during planned procedures, with an overall . % conversion rate mostly related to technical difficulties (i.e. spleen dimension, difficult vascular visualization). overall major postoperative complication rate (clavien-dindo c ) was . %, slightly higher in emergency procedures although not significantly different ( . % vs. . %, p = . ). reintervention rate was . %, due to hemorrhage in more than half of cases. overall -day mortality rate was . %, with elective -day mortality rate of . % (p = . ). conclusions: splenectomy may be required ever more rarely but potential risks are not irrelevant. competence for surgical trainees should be achieved elsewhere (e.g. simulated/cadaveric training case history: an year old femal patient underwent changing of the components of the tha because of aseptic loosening. due to circumstances the surgeon decided to implant a cemented femoral component. the procedure was without any significant abnormalities. the first postoperative radiograph was planned after recovery-as usual. the x-ray imaging showed a misplaced femoral component. therefore a ct-scan was performed additionally and the malposition of the cemented femoral component was confirmed. the patient had to undergo another surgery-removing of the cemented femoral component and implantation of a new well placed one. therapy and progressions: after prompt resuscitation, an emergency laparotomy was performed and an anastomotic leak was found, requiring re-do ileo-ileal anastomosis. postoperative course was complicated by intra-abdominal collection treated by antibiotics alone (clavien-dindo grade ). the patient was discharged on th pod. at pathological report, segmental absence of intestinal musculature (saim) was diagnosed. the revision of past specimens confirmed the same finding. comments: usually recognized in neonates/premature infants, saim is generally an incidental finding in adults [ ] , often undiagnosed and more frequently described in the colon [ ] . in such scenario, main differential diagnosis is ischemia. etiology is unclear and can be classified as either primary/congenital or secondary. the former is characterized by acute onset of symptoms, whereas in the latter a longer history of intestinal symptoms is usually present [ , ] . most authors agree upon a congenital pathogenesis. generally, saim is associated with hollow viscus perforation and treated with surgical resection. contrary to our experience, no recurrence of intestinal perforation has been reported [ ] virgen del rocío university hospital, general surgery, seville, spain, hospital regional de málaga, general surgery, málaga, spain, hospital de estella, general surgery, navarra, spain, hospital gregorio marañón, general surgery, madrid, spain, complejo hospitalario de jaen, general surgery, jaen, spain introduction: specific training in the management of trauma patients is essential for surgeons. training through courses in this area (atls, dstc, musec) directly impacts the care of these patients. the aim of this study is to know the specific training in trauma care of spanish surgeons. materials and methods: a national survey has been sent to all member surgeons of the spanish surgeons association. it has evaluated their degree of participation in emergency surgery acute care, and therefore the possibility of attending trauma patients, their participation in the initial care at their hospital, as well as their specific training in this area. results: the survey has been completed by surgeons from spanish regions, and most surgeons who responded were from catalonia and andalusia. ( . %) of those surveyed take calls for the ed. only ( . %) report having a hospital registry of trauma patients. . % of surgeons answer that in their hospital the general surgeon is not involved in the initial care of trauma patients. . % have taken the atls course, . % the dstc course, and . % the musec course (or another course on e-fast). despite this, . % consider the atls course should be mandatory during residency, and . % of those surveyed consider trauma care in their hospital as very bad or deficient. conclusions: according to this survey, specific training in trauma care is still deficient in spain and with many aspects that can be improved. only % of those surveyed have received specific training in definitive surgical management of severe trauma. despite this, a large percentage of surgeons take calls for the ed routinely, and face the challenge of managing these patients. exploring team leaders' decision-making challenges in civilian and military complex trauma introduction: in the nordic countries professionals may work in both civilian and military trauma care. timely and effective decisionmaking in complex trauma is essential in improving survival benefits. the mindset and management priorities differ among medical professionals, and correlate with different experience levels. trauma leaders are usually senior surgeons with extensive experience and well-developed decision-making skills. simulation training has been shown to be effective in practicing decision-making. the aim of this study is to explore the team leaders' decision-making challenges in complex trauma care and structure them with the activity theory framework (at). material and methods: video recordings at a trauma center in johannesburg and live observations of complex trauma training in gothenburg focusing on team leaders' decision-making challenges were analyzed and systemized using the at. results: the team leaders' activities were mapped onto the main elements of at ( fig. ) whereby the decision making challenges were classified into six categories (table ) . conclusions: the at framework may benefit and inform the design of educational interventions by structuring key issues of complex activities. introduction: trauma is one of the main causes of mortality worldwide and prevention stands out as one of the main ways to modify its incidence. a prime example of such initiatives is the prevent alcohol and risk-related trauma in youth program (p.a.r.t.y.). it aims to raise awareness of the population most at risk for trauma, young people from to years. the study objective was to evaluate the program impact on students' knowledge and behavior. material and methods: a quantitative, uncontrolled intervention cohort study was conducted through the responses of the p.a.r.t.y. in and . data collection occurred through the application of a questionnaire to participating and non-participating students of public schools in the city of campinas, after a few months of participation in the program. results: among answers, . % were male, . % between and years, and . % program participants. time between participation and answers was . (± . ) months. regarding the first conducts when facing traffic trauma, . % of those who participated chose the correct answer, against . % of those who did not. about the first care while the service does not arrive, . % of the first group answered correctly, compared to . % of the second. concerning about the service that should be called in the event of a trauma, . % of participants would call correctly against . % of non-participants. in questions related to traffic laws, . % of participants opted for the correct answer as to what should be done in the face of a running over, against . % of non-participants. conclusions: students who had participated in the program had a higher rate of correct answers, a few months after the event, compared with students who did not attend. thus, it is concluded that there is a impact over the time caused by it. introduction: currently, intraosseous (io) devices are necessary for the resuscitation of severe trauma patients. however, opportunities to learn io device insertion are limited for residents. the aim of this study was to conduct a simulation of io device insertion for residents and to evaluate its effectiveness. material and methods: in this simulation, residents inserted io needles into the sternum of pigs under general anesthesia with the instructor's guidance. comprehension tests and questionnaires about satisfaction level and self-efficacy were conducted before and after the simulation. the objective evaluation was the io access success rate, and the subjective evaluation was obtained from points on comprehension tests and questionnaires. results: thirty-six residents participated in this study. just one resident had successfully obtained io access clinically. success rate of establishing io access in the simulation was %. the rate of test completion was % and that of questionnaire with survey response was %. the comprehension test results improved from . ± . to . ± . (mean ± standard deviation, p = . ) out of points. the questionnaires concerning satisfaction level changed from . ± . to ± . (p \ . ) out of points. the questions specifically concerning self-efficacy dramatically increased from . ± . to . ± . (p \ . ) out of points after the simulation. conclusions: the simulation in this study improved the knowledge, satisfaction level, and self-efficacy of the residents for io access. the success rate of confirmation of io access in this study was %. this experience may positively affect their clinical performance in trauma care. case history: case . a -year-old white man presented to the ed complaining of intense abdominal pain and vomiting. he referred at least two previous episodes with associated fever which resolved spontaneously. case . a years old white man consulted at the ed for intense abdominal pain, nausea, anorexia and constipation for the last h. none history of abdominal surgery were registered. clinical findings: in both cases, the abdomen was distended without bowel sounds. investigation/results: case . abdomen xr: distended small bowel loops localized at the right side. ct scan: an encapsulated cluster of dilated small bowel loops into the ascending mesocolon. case . ct scan: an encapsulated nonrotated small bowel in the right side of transverse mesocolon and mesenteric vascular pedicle displaced. diagnosis: intestinal obstruction secondary right paraduodenal hernia therapy and progressions: emergency midline laparotomy that evidenced a rpdh which was reduced before closing the mesentery defect. the postoperative was uneventful. comments: paraduodenal hernias are a type of internal hernia and a rare cause of intestinal obstruction accounting for about . % of all hernias. right paraduodenal hernias are far less common than left ones. symptoms of paraduodenal hernias are nonspecific. preoperative diagnosis of pdh by imaging techniques is difficult. contrastenhanced ct scan is highly recommended as the most specific method of diagnosis for pdh. with the increased use and improved enhancement of ct scans, paraduodenal hernias currently can be diagnosed preoperatively. this advancement in diagnostics coupled with increasing experience and facility of general surgeons in using laparoscopic techniques has led to the initiation of laparoscopic repair of internal hernias. case history: a -year-old female patient who goes to the emergency department due to vomiting and abdominal pain. since the accident, the patient reported post-prandial discomfort and gastroesophageal reflux, as well as self-limited abdominal cramps. clinical findings: soft, depressible abdomen. bowel sounds on left hemithorax. investigation/results: cxr: right hemidiaphragm elevation. lab test: leukocytosis. thorax and abdomen ct: right anterior diaphragmatic hernia and passive atelectasis secondary to ascent of dilated small intestine and colon. diagnosis: intestinal obstruction secondary post trauma diaphragmatic hernia. therapy and progressions: emergency laparotomy due to symptoms compatible with intestinal obstruction secondary to incarcerated diaphragmatic hernia. it is right diaphragmatic chronic rupture chronic with omental incarceration, antrum, small bowel and ascending colon with reversible signs of suffering. chelotomy and content reduction, herniorrhaphy with loose spots with non-absorbable material are performed. endothoracic drainage is left removed at h. the postoperative course is uncomplicated. comments: trauma events should be considered in the diagnostic process to avoid delayed treatment. case history/clinical findings: we present a -year-old male patient with a history of large pelvic mass in the rectum-prostate space under study, since months. he were admitted into the emergency unit, days after the mass biopsy, with fever up to °c and rectorrhagia. the patient rapidly developed septic shock with hemodynamic instability and elevation of acute phase reactants. abdominal ct was performed: pelvic mass of . . cm, of heterogeneous content, with areas of blood density. we decided doing an emergency surgical exploration of this mass as the only suspected origin of infection. investigation/results: in the surgical exploration the mass was protruding on the anterior rectum wall. the mass was drainaged with an output of ml of purulent material mixed with clots and necrotic tissue. foley no. probe was placed inside the cavity. in the postoperative period, the patient showed significant hematochezia, so he was reoperated performing hemostasis and rectal tamponade. it was effective and a new foley catheter was replaced at h. when the purulent drain gave way, the catheter was removed and the patient evolved favorably. diagnosis: cytology analysis: mesenchymal type lesion, morphologically and immunophenotypically compatible with gist (gastrointestinal stromal tumor). ihq profile: cd , dog , c-kit positive. therapy and progressions/comments: the complications of gist are usually acute abdomen due to peritonitis secondary to perforation or hemorrhage. however, the formation of intratumoral abscesses is very inusual, although is described in the literature. emergency surgery is often necessary due to the significant affectation of the general condition of the patient and the difficulty of the diagnosis. fournier's gangrene (fg) is a surgical emergency defined by an obliterating endarteritis of the subcutaneous tissue arteries of infectious etiology, with progressive necrotizing fasciitis of the perineal, abdominal, thoracic or lower limbs, which can lead to multiorgan failure. a years old woman was admitted in our er presenting with a week worsening vulvar pain. clinical exam showed vulvar and mons venus erythema, without lesions, bp was / mmhg and she had a fever of . °c. blood work showed leukocytosis ( . /ll), neutrophilia ( . /ll) and crp of mg/ l. past medical history of obesity, right thp and total thyroidectomy. vulvar cellulitis was the initial diagnosis and empirical atb was implemented. on d , due to an evolution into septic shock and spread of an emphysematous inflammatory process to the right thigh and buttock, the diagnosis of fg was made. during emergent surgery we observed extensive fascial and tissue necrosis from the asis and suprapubic region to the proximal third of the right thigh and perineum. extensive necrosectomy, drainage of purulent exudate and transversostomy were performed. empirical second-line broad-spectrum atb was started. she underwent new necrosectomies and surgical debridements on po days and and needed icu stay for days. daily dressing changes were performed with povidone iodine and later with octenidine. microbiology sample showed polymicrobial infection with gram positive and negative organisms as well as anaerobes, thus confirming the diagnosis of fg type i of vulvar origin. after surgical and hd stabilization, the patient underwent plastic reconstructive surgery, with local flaps and partial skin graft. the postoperative period was uneventful and the outcome was great. introduction: appendicitis is not uncommon in the elderly but may often be mis-diagnosed [ ] . the aim of this study was to explore the specific traits and treatments of this group in a swedish context to better understand where to optimize the management. material and methods: all acute appendectomies registered in the southern general hospital registry between january and june constituted the cohort (n = ). patients were stratified into two groups; c and \ years of age. significances were computed with pearsons chi and anova. results: the older group made up % of the study population (n = ). the elderly population was female to a larger extent (or . , p \ . ), triaged higher in the emergency department (p \ . ) and had higher asa classifications (p \ . ). the elderly were also perceived as sicker at the time of decision for surgery, expressed as having higher priorities for surgery (p \ . ). no significant difference between the groups in time from arrival to decision for surgery was found, nor for the time from arrival to surgery. there was a higher rate of perforations in the elderly group ( . % vs . %, p \ . ), twice the length of hospital stay (p \ . ) but no significant differences in complication rates ( . vs . %, p = . ). twenty-eight day mortality rate was % in the younger group and . % in the older group (p \ . ). conclusions: this study shows that an elderly group of appendicitis patients are more frail and more acutely sick when presenting to the hospital. in spite of higher priority for surgery, the elderly experience longer hospitalization and higher mortality rate, but not more complications. the findings are consistent with antecedent research. introduction: existing evidence points towards the notion that patients undergoing emergency surgery receive a poorer consenting quality when compared to their elective counterparts. with , cholecystectomies in england a year, cholecystectomy is one of the most frequently performed procedures both in the emergency and elective settings. however, to date, no studies have explored the relationship between consenting quality and the setting of cholecystectomy. we aimed to measure the quality of informed consent (ic) for patients who underwent emergency vs elective cholecystectomy. material and methods: the final review included the analysis of ic forms completed between - . percentage proportions were calculated to demonstrate the degree of completeness of consenting against a total of components of information. binary regression was utilised for subgroup analysis. results: patients undergoing emergency surgery were more likely than elective patients to be warned of severe perioperative complications such as cardiac disorders ( . % vs . %, p = . ), fluid collection ( . % vs . %, p = . ), and infected bile spillage ( . % vs . %, p = . ). elective patients were more likely to be counselled about the risk of less serious side effects of cholecystectomy such as diarrhoea ( . % vs . %, p = . ). patients in asa - group were more likely to be counselled about the occurrence of pulmonary embolism. interestingly, patients were more likely to receive a patient information leaflet if they were females and under . conclusions: the results of this study demonstrate multiple inconsistencies in the level of disclosed information to patients undergoing cholecystectomy. the results suggest that the consenting physicians make assumptions regarding the information that the patient would like to receive based on patient demographics and clinical factors, highlighting the need for more consistent consenting procedures. acute calculous cholecystitis and the timing of cholecystectomy: advocating early surgery i. moutsos , r. lunevicius liverpool university hospitals nhs foundation trust, general surgery, liverpool, united kingdom introduction: cholecystectomy cures acute calculous cholecystitis (acc) in nearly all patients and, according to nice, augis, tokyo and wses guidelines, should be conducted at the earliest opportunity, within days of the diagnosis. the present audit aimed to measure whether the care of patients with acc meets the standards of best practice and to assess whether early cholecystectomy was a more beneficial and safer intervention as compared to delayed cholecystectomy. material and methods: a ''snapshot'' sample of patients operated on between / and / with an index admission diagnosis of acc was reviewed. the selected patients were divided into three subgroups according to the timing of their surgery: - (early), - , and[ days. the other measures used in this audit were the rates of conversion to open surgery, subtotal cholecystectomy (stc), perioperative complication-specific morbidity, secondary interventions, and admission to intensive therapy unit (itu). results: nine patients ( %) underwent early cholecystectomy-laparoscopic (n = ) or primary open (n = ); of the other patients-delayed laparoscopic cholecystectomy. the rates of stc were similar in both subgroups- . % ( / ) vs . % ( / ). delayed cholecystectomy was related to five side effects: higher rates of postoperative collections (three patients, . %), external bile leak (one patient, . %), ercp ( . %), emergency re-operations (two patients, . %), and admission to itu ( . %). they all occurred in the delayed [ weeks surgery subgroup of patients. conclusions: although no significant associations were found when comparing early to delayed cholecystectomy, this analysis shows that postoperative morbidity, the rates of secondary interventions and admissions to itu were higher when surgery was delayed. this audit advocates that early cholecystectomy should become a standard of practice as per national and international guidelines. esophagopericardial fistula following primary repair for chronic esophageal ulceration presenting with pericardial tamponade: a case report and outline of management and treatment case history: a -year-old man with chronic esophageal ulcerations presented with substernal pain, fever, and shortness of breath. a radiograph revealed a right pleural effusion and pneumomediastinum consistent with an esophageal perforation (fig. ). he underwent a right thoracotomy, primary esophageal repair with intercostal muscle flap buttress, and gastrojejunostomy feeding access. a post-procedural gastrograffin study demonstrated an anastomotic leak (fig. ) . a right thoracostomy drain was placed for diversion. the patient was discharged home and returned days later. clinical findings: he presented with substernal pain, hypotension, and fatigue. thoracic computed-tomography (ct) revealed a pneumopericardium and an esophagopericardial fistula (epf) manifesting as pericardial tamponade (fig. ) . diagnosis: epf. therapy and progressions: the patient underwent a subxiphoid pericardial window and mediastinal drain placement for decompression. an esophagogastroduodenoscopy revealed an exposed right atrium, thus precluding esophageal stenting. sepsis and antibioticassociated clostridium difficile colitis complicated his post-operative course. once resolved, the patient underwent a partial esophageal resection, epf ligation, and esophagogastrostomy. the postoperative gastrograffin study did not demonstrate an anastomotic stricture or leak. the patient tolerated a regular diet and was discharged home. comments: esophagopericardial fistula is a rare clinical entity most often caused by benign disease. prompt diagnosis and treatmentpericardial decompression and fistula ligation-is critical. due to wide use of proton pump inhibitors and development of interventional radiology (ir), causative reasons are changing. introduction: secondary peritonitis yields high morbidity and mortality rates. besides rapid source control, adequate antimicrobial therapy is essential to improve outcomes. thus initial empiric therapy has to take suspected germ spectrum as well as possible resistance rates into account. microbial selection and resistances may pose problems during prolonged administration of antibiotics. however, a possible negative effect of multi-resistant germs on mortality has not yet been clarified. the choice of a suitable antibiotic and the relevance of its efficacy on isolated germs as well as the relationship between germ spectrum and clinical condition of the patients need to be clarified. material and methods: intraabdominal swabs from consecutive patients from to requiring intensive care due to secondary peritonitis were evaluated retrospectively. patient characteristics and outcomes, germ spectrum and resistance rates were collected. changes over the course of therapy and development of resistance as well as influences on the clinical course were analyzed. introduction: complicated intra-abdominal infections (c-iai) represent challenging diseases with high mortality rates. depending on different selection criteria and therapy strategies the reported mortality rates vary between . and %. usually a distinction between community (cap) and hospital acquired peritonitis (hap) is made. hap can further be classified as postoperative peritonitis (pop) or non-postoperative peritonitis (hap-non-pop). we conducted a retrospective analysis of patients with c-iai requiring intensive care therapy. material and methods: all patients with c-iai requiring surgery and intensive care treated at the danube hospital in vienna from to were retrospectively analyzed. a total of patients where included into the study and grouped as cap, hap-non-pop or pop. for each group comorbidity and patient characteristics, source and cause of infection, hospital and icu stay, apache ii, saps ii and sofa-scores, mortality and outcome were calculated and compared to each other, using fisher exact test or mann-whitney-u-test. results: a total of c-iai were treated, consisting of . % cap, . % hap-non-pop and % pop. concerning the patient characteristics and comorbidities no significant differences were seen between the groups, except for malignant diseases which were significantly higher in pop. the postoperative (source control) apache ii and saps ii values did not differ between cap and pop (apache ii mean: cap . , pop . ) whereas both were significantly higher in hap-non-pop (apache ii mean: . ). mortality rates were not significantly different in cap and pop ( . % vs. . %): however, hap-non-pop was complicated by a nearly doubled death rate ( . %). conclusions: although patients with pop are described to have a higher mortality in the literature, this could not be shown in our study. postoperative survival was comparable between cap and pop patients. hap-non-pop demonstrated a significantly higher mortality. acute appendicitis and acute diverticulitis presenting concurrently treated surgically and conservatively clinical findings: on examination the abdomen was soft but there was tenderness and guarding in the right iliac fossa and suprapubic region. her observations were stable on admission and she was afebrile. investigation/results: laboratory tests demonstrated a wcc . ( /l) and crp of . (mg/l). urinalysis was normal. a ct of the abdomen and pelvis with intravenous contrast demonstrated acute appendicitis with non-perforated sigmoid diverticulitis (fig. , fig. ). diagnosis: concurrent acute appendicitis and non-perforated sigmoid diverticulitis. therapy and progressions: the patient underwent a laparoscopic appendicectomy. intraoperative findings included a retrocaecal inflamed appendix and diverticulitis in the pelvis which was not disturbed. there was no pus in the pelvis. she recovered well postoperatively and was discharged home to complete one week of oral antibiotics the following day. the histology demonstrated acute appendicitis. comments: there are very few reports in the literature of concurrent appendicitis and sigmoid diverticulitis despite these two pathologies being amongst the most common presentations of abdominal pain. this case demonstrates the value of cross sectional imaging, ct imaging is a helpful diagnostic tool and is highly sensitive and specific for both diverticulitis and appendicitis.the challenge in this case is balancing the two differing managements of these two conditions. most cases of diverticulitis are managed conservatively with dietary modification and antibiotics. operative management is only usually considered if there are associated complications such as intraabdominal perforation. this is in contrast to appendicitis where the standard treatment is to undergo surgery. references millions of people die from major trauma annually. - % of these deaths are due to exsanguination, with nearly half dying prior to hospital arrival. when properly managed, these deaths are preventable. this paper summarizes data relating to the extent of hemorrhage as a cause of mortality in the traumatic arena. an overview of the pathophysiological steps occurring during massive bleeding and their clinical implication is presented. a variety of treatment options, both historical and current, is then discussed, including vascular occlusion methods and hemostatic dressings, along with their limitations and complications. finally, woundclot, a new hemostatic gauze, is introduced, which not only requires no compression when it is applied, but allows the first responder to rapidly and effectively treat more than one casualty within seconds. additionally, it is adaptable to a wide array of clinical applications, both traumatic and surgical, including situations where vascular occlusion methods are not practical or are contraindicated. i am the clinical research administrator for core scientific creations treating acute colonic diverticulitis with extraluminal pericolic air; a multi-centre retrospective cohort study background: since the emergence of acute care surgery as an entity encompassing trauma and emergency general surgery there have been several studies evaluating patient outcomes noting a higher unexpected survivorship and expedited operative times, shorter hospital stays, and fewer complications for patients undergoing procedures such as appendectomy; however, these superior outcomes have not been demonstrated across the array of emergency surgical cases. the aim of this investigation is to determine whether patients operated on by acute care surgeons in a trauma center benefit from the trauma model of in-house availability, earlier availability of surgical care, and care dictated by evidence-based protocol. we examined our health care system's data to determine if trauma centers were to able to provide more timely care with improved outcomes, by focusing on truly emergent general surgery cases. this was examined by identifying and quantitatively comparing time to operative intervention, need for re-operation, hospital length of stay, duration of stay spent in intensive care unit, and patient disposition at time of discharge. methods: this is a retrospective cohort study. patients presenting with emergency general surgery conditions (incarcerated hernia, perforated viscus, sbo, necrotizing soft tissue infection) who underwent surgery within h of presentation were selected. outcomes were compared between patients presenting to our two trauma centers versus our two non-trauma centers. n = results: at this time we are nearing the finalization of our data interpretation. we are examining mean time to operation, los, icu los, need for re-operation, and disposition at discharge. discussion: although our data analysis is not complete we feel that the results of our data will shed valuable and needed light onto the care delivered to emergency general surgery patients by surgeons in this increasingly complex population. anastomosis leakage after hartmann removal, with conservative treatment at the beginning but after, bad evolution, a surgery was performed with colostomy and vac system. patient. after h, he develop a compartmental syndrome and a vac system was applied. investigation/results: patient. after the first change the distance between the two layers was cm and botulinum toxin was applied. pat. the distance between the two layers of abdomen was cm and botulinum toxin was applied. patient. the distance between the two layers was cms and toxin was applied. unfortunately, he suffered from a hepatorenal syndrome and died. diagnosis: open abdomen with distance between the two layers: cm, and cm. therapy and progressions: we have added botulism toxin with doses of units in each side of abdominal wall. patient. three changes after, the abdomen wall was closed. months later, the abdominal wall is ok. patient. a reduction of % was got. comments: the use of open abdomen in patients suffer from septic shock or after an abdominal compartment syndrome often poses a challenge in the abdomen closure. we have developed a protocol, dividing our patients according to the distance between the two layers in two group: more than cm or cm or less. in the first group ([ ), we present our first cases in our protocol. conclusions: botulinum toxin can make easier abdomen closure when the distance between the two layers is more than cms incidentally discovered splenic peliosis in a patient with no comorbidity clinical findings: a -year-old man with no comorbidities visited our emergency medical center based on a complaint of chest pain. the chest and abdomen radiographs, electrocardiogram, and cardiac markers showed no abnormalities; therefore, he was discharged from the hospital. two months later, he returned to our hospital with abdominal pain and distension. he was hemodynamically stable, and there were little tenderness and rebound tenderness on his abdomen, although he complained a slight abdomen discomfort investigation/results: no abnormalities were found on the laboratory examinations, including complete blood cell count, cardiac markers, and coagulation profile. an abdomen computed tomography revealed multiple hemorrhagic cysts on spleen with moderate amount of hemoperitoneum. diagnosis: ruptured splenic peliosis with hemoperitoneum. therapy and progressions: laparoscopic splenectomy was done because recurrent rupture of hemorrhagic cysts was strongly anticipated. on histologic examination, the blood-filled cysts were welldemarcated, distributed in red pulp congestion. no vascular-endothelial cells were observed, and normal lining cells were disappeared in the wall. comments: a peliosis is a rare disorder characterized by widespread, blood-filled cystic cavities within the parenchymatous organs. the liver is the most commonly involved organ, and an isolated splenic peliosis is extremely uncommon. patients are often asymptomatic; therefore, early recognition and withdrawal of offending agents is crucial. in cases with the rupture of surface lesions, which can occur spontaneously or by the minor trauma, prompt surgical management is necessarily required. splenectomy offers the advantage of a definite histological diagnosis with the complete elimination of the risk of recurrent hemorrhage. introduction: despite an evident success and advantages of endoscopic surgery, the discussion on reasonability of endoscopic surgeries in children with acute appendicitis is still going on. purpose: to assess the effectiveness of laparoscopic techniques for treating appendicular peritonitis in children. material and methods: children with appendicular peritonitis were operated in our hospital ( ) ( ) ( ) . they aged - years ( ± . ); . % of boys, . % of girls. appendicular peritonitis was registered in . % cases of acute appendicitis. three ports were used for the approach: appendectomy was performed by the ligature technique with roder loop. results: laparoscopic surgery is indicated in all forms of appendicular peritonitis, except appendicular abscess stage , and total abscessing peritonitis. in appendicular abscess stage , we perform a puncture and drainage under ultrasound control. - months later appendectomy is made. total abscessing peritonitis is an indication for laparotomy. laparoscopic surgery in patients with peritonitis has the following stages: diagnostic laparoscopy; sanation of the abdominal cavity by the aspiration of purulent exudate; ligature appendectomy; in diffuse and combined peritonitis a pelvic aspiration drainage is made. in appendicular abscess stage , we additionally put the aspiration drainage in the cavity of destructed abscess. conclusions: laparoscopic technique applied for surgeries in children with acute appendicitis has considerably improved outcomes introduction: nighttime emergency surgery is associated with increased postoperative morbidity and mortality [ ] , and delayed appendectomy due to acute appendicitis is not linked to a higher rate of postoperative complications (pc) [ ] . the aim of this study was to determine whether appendectomy on-call (oc) was associated with higher risk of pc. ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . two patients underwent major thigh amputation. negative pressure wound therapy and hyperbaric oxygen therapy were used in and patients, respectively. three patients died (mortality rate = %). conclusions: the mortality and major amputation rates ( % and %, respectively) were lower than those reported previously. in this study, even when patients had multiple organ failure or septic shock, major amputation was not always needed because of effective communication between the infection control team and intensive care specialists, resulting in radical debridement without amputation. material and methods: a systematic search in pubmed/medline, embase, cinahl and central was performed. the primary outcomes were mortality and amputation. these outcomes were related to the following time related variables ( ) time from onset symptoms to presentation; ( ) time from onset symptoms to surgery; ( ) time from presentation to surgery; ( ) duration of the initial surgical procedure. for the meta-analysis, effects were estimated using random-effects meta-analysis models. results: a total of studies ( patients) were included for qualitative analysis, of which patients died ( . %). a total of studies ( nsti patients) were included for the different quantitative analyses performed. mortality was significantly lower for patients with surgery within h after presentation compared to when treatment was delayed more than h (or . ; % ci . - . ). surgical treatment within h resulted in a % mortality rate compared to % when surgical treatment was delayed more than h. also, surgery within h reduced the mortality compared to surgery after h from presentation (or . ; % ci . - . ). patient delay (time from onset of symptoms to presentation or surgery) did not significantly affect the mortality in this study. none of the time related variables assessed reduced the amputation rate. conclusions: average mortality rates reported remained constant (around %) over the past years (fig. ) . surgical debridement as soon as possible lowers the mortality rate for nsti with almost %. thus, a sense of urgency is essential in the treatment of nsti. altemeiers procedure in an emergency setting case history: three patients with irreducible incarcerated rectal prolapsed were referred to our department for treatment. all patients were female and their age was , and years old. all patients suffered from severe co-morbidities. clinical findings: all patients presented with incarcerated rectal prolapse. in one patient there was macroscopic evidence of mucosal necrosis, whereas the other two patients had evidence of ischemia. the former patient was febrile whereas the latter did not exhibit signs or symptoms indicative of sepsis. investigation/results: blood panels demonstrated leukocytosis and elevated levels of c-reactive protein (crp) in all patients. apart from routine imaging upon admission (e.g. chest radiography), no other imaging modalities were performed. diagnosis: irreducible incarcerated rectal prolapse. therapy and progressions: initially manual reduction of the prolapsed was attempted without success. all patients were evaluated as high risk surgical candidates. altemeier's procedure was selected as a safer alternative to an abdominal approach. all patients were successfully discharged after resumption of bowel function. comments: incarcerated rectal prolapse is a rare clinical condition. initial management involves manual reduction of the prolapse. when this is not feasible, urgent surgical management is mandatory. in patients with severe co-morbidities, altemeir's procedure is a safe and effective treatment when performed by an experienced practitioner. introduction: treatment options for sigmoid volvulus are decided by its severity. uncomplicated cases are usually treated by endoscopic detorsion followed by elective surgery and complicated cases or cases can't be detorsioned are treated with emergency surgery. in this study we aim to review a single center experience in long term management of sigmoid volvulus cases. material and methods: data of the sigmoid volvulus cases between - were collected using hospital database. files of patients were reviewed for treatment modalities, demographic info and complications. patients were dropped from the study due to inadequate long term follow-up. results: were men and were women. mean age was , . endoscopic detorsion was attempted in cases. success rate was % (n = ). of these patients were followed up with elective surgery. patients with complicated cases and unsuccessful detorsion patients were managed by emergency surgery. hartman procedures, anterior resections, left hemicolectomies, subtotal colectomy and transverse loop colostomies were done. a stoma was created in cases. patients had their stoma created in the primary surgery and an additional of stomas were created due to anastomosis leakage. mortality rate in the first days was % (n = ) in patients with a stoma (n = ). asa and charlson co-morbidity scores were exceptionally high in the mortality group. in the remaining patient group, stoma closure rate was . %. conclusions: endoscopic detorsion is a powerful and highly successful management option in uncomplicated cases when done by an experienced staff. emergency surgery shouldn't be delayed in complicated cases or after unsuccessful detorsion attempts. introduction: esophageal perforation has high mortality rates when not treated aggressively. treatment options are conservative approach, endoscopic intervention and surgery. purpose of this study is to review cases of esophageal perforation in a single center and to evaluate types of diagnosis and treatment options. material and methods: using hospital database we collected data of patients diagnosed with esophageal perforation between - . we reviewed treatment modalities, demographic data and complications. patient was removed from the study due to insufficient long term data. results: were female and were male. average age was . . average time between the onset of symptoms and admission was . days. the most common etiology was iatrogenic (n = ) followed by consumption of corrosive substances in patients, spontaneous perforation in patients, esophageal tumour in patients and foreign body ingestion in patients. patients were treated surgically, patients were treated with endoscopic stenting and patient was treated with surgery following stenting. patients were managed conservatively with antibiotherapy. average time in intensive care was . days and average hospital stay was . days. mortality was seen in patients treated with surgery and patients treated with stents. conclusions: esophageal perforations are mainly iatrogenic but also can be caused by multiple reasons. especially in cases developed after endoscopy, rapid intervention can be a significant factor that can decrease both mortality and morbidity rates. introduction: spontaneous rupture of liver tumors (rlt) is a rare but potentially life-threatening condition. damage control techniques, namely perihepatic packing (php), is a resource for the most physiologically compromised patients, with more stable patients undergoing transarterial embolization (tae) or immediate resection. decision algorithm depends on patient status, available resources and liver function. the authors present their center experience in managing rlt and propose a management algorithm. material and methods: eighteen consecutive patients who underwent surgery for rlt in our department (january -october ). inclusion criteria: spontaneous rupture and evidence of intraperitoneal bleeding. fourteen patients were male. mean age of . years ( - ). thirteen patients ( %) presented in hemorrhagic shock. mean tumor size was . cm ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . most frequent pathological diagnosis were: hepatocellular carcinoma in cases ( %); adenoma in three cases ( %); metastases in two cases ( %); liver sarcoma in one case ( . %). median of seven units transfused by patient ( - ). statistical analyses with spss tm version . results: six patients ( %) needed immediate surgery (php in three and resection in three). five ( %) underwent urgent ([ h and \ h) and seven ( %) delayed ([ h) resection. hepatectomy was performed on all (fifteen minor and two major) but one patient php only. eight patients ( %) underwent tae prior to resection, two of them ( %) between php and hepatectomy. median length of stay days . major morbidity in three patients ( %); mortality in three patients ( %). number of transfused units associated with increased risk of complications (p = . ). conclusions: rupture of liver tumors is a severe complication. although hepatic resection, with or without preoperative tae, should be considered gold standard, damage control techniques such as php are the only option for physiologically compromised patients (fig. ) . seasonal variability of cellulitis: a five year retrospective cohort study introduction: it is commonly purported that the incidence of cellulitis is highly seasonal but there is little empirical evidence supporting this assertion. this year retrospective cohort study set out to identify whether there is a statistically significant relationship between an increase in temperature and incidences of cellulitis. as a corollary to this proposition, length of hospital stay for cellulitis was examined in relation to the level of inflammatory markers upon admission and micro-organism identified on culture. material and methods: this is a year retrospective single centre cohort study of all patients admitted with cellulitis to tallaght university hospital from to inclusive. the patient cohort was identified via the use of a prospectively managed database of all surgical admissions and corroborated via examination of clinical chart records. dates of admission were correlated with the average temperature of dublin as provided by the meteorological office of ireland. site of infection, inflammatory markers and the prevalent micro-organism were also identified whilst the length of admission was extrapolated from hipe (hospital inpatient enquiry) records. results: there were admissions for cellulitis with cases of necrotising fasciitis. there was a statistically significant (p \ . ) relationship between temperature and cellulitis with admission peaking in late summer/autumn. age correlated significantly with readmission. furthermore, the level of crp had a statistically significant prognostic value as an independent predictor for the length of hospital stay with a high level resulting in a prolonged admission. conclusions: there is a statistically significant relationship between a rise in temperature and the incidence of cellulitis. furthermore age is an independent risk factor for re-admission with same whilst inflammatory markers at time of admission can be used as a prognostic marker for length of stay. case history | clinical findings: a -year-old female patient, with history of type ii diabetes, high blood pressure and major depressive syndrome, was admitted in the emergency room department complaining of abdominal pain. based on the patient's history and physical examination, a presumptive diagnosis of renal colic was initially made. however, after days, the patient showed signs of fever, aggravated abdominal pain and vomiting. investigation/results | diagnosis | therapy and progressions: a ct scan showed the presence of a radiopaque foreign body near the duodenum, the presence of air bubbles outside the intestinal lumen and an hepatic abscess. we agreed to perform a laparoscopy, drainage of hepatic abscess and fish bone removal after successfully identification. after days, the laboratory findings showed persistent leukocytosis and raised cpr, which led to a second ct scan with maintenance of the hepatic abscess. the decision was to perform a percutaneous drainage. after the second drainage, the patient had an uneventful recovery. comments: foreign body ingestion into the gastrointestinal (gi) tract is rare and typically accidental in adults. most ingested foreign bodies pass through the gastrointestinal tract without the need for any intervention. gi perforation is rare and can occur at any site. surgical intervention is required in less than % of the cases. fish bones are the most commonly ingested objects. preoperative diagnosis, when possible, is made with ct scan, identifying a linear high-density structure. high level of suspicion is of paramount importance. in cases of delayed diagnosis, perforation may lead to intraperitoneal abscess formation. reports of hepatic abscess secondary to fish bone perforation has been limited to isolated case reports in the literature. case history: description of two cases of appendicular goblet cell carcinoid tumors, which debuted as acute appendicitis. patient a was a -year-old woman with a -h evolution of classic symptoms of acute appendicitis. patient b was a -year-old female that consulted for chronic abdominal pain in rlq that recently increased pain intensity and fever. clinical findings: patient a had pain and defense in rlq without a fever. patient b had a chronic painful fluctuating mass in rlq, with fever over °c. investigation/results: patient's a lab test showed leukocytosis and us findings of acute appendicitis. the patient's b ctscan showed an intra-abdominal abscess fistulized to the abdominal wall, along with formation of a phlegmonous mass related to appendicular plastron. diagnosis: the anatomopathological reports for both patients were informed as appendicular goblet cell carcinoid tumor. therapy and progressions: both underwent laparoscopic exploration. after appendicectomy in patient a, when the diagnosis of gcct was made, the case was discussed at our mdt meeting and a right hemicolectomy was indicated and performed shortly after. in the patient b a right hemicolectomy was performed in the initial surgery due to the magnitude of tissue involvement. currently, both are receiving chemotherapy with xelox without signs of recurrence or tumor spread on follow up. comments: the gcc is a rare entity of appendicular tumors with a less favorable prognosis than the appendicular pure neuroendocrine tumors. it behaves like a low-grade adenocarcinoma and often presents as disseminated disease. therefore, sometimes surgical treatment with appendicectomy is not enough, needing the right hemicolectomy to avoid recurrence. this is recommended for tumors [ cm, pt or t and higher grade histology. introduction: among the post-pancreatoduodenectomy complications post pancreatoduodenectomy hemorrhage (pph) is the least common complication, but severe form may be life-threatening without an urgent treatment. late pph are more likely due to a complex physio-pathological pathway secondary to different etiologies. the understanding of the etiology and such a pathway could therefore be of great interest to guide the treatment of potential lifethreatening late severe pph. results: during the aforementioned period patients underwent pd, of whom ( . %) developed pph. early pph was reported in one patient ( . %) with severe bleeding from the gastric stapler line. late pph were reported in of these patients ( . %). the most common causes were bleeding from a vascular pseudoaneurysm reported in patients of which, one had mild and had severe hemorrhage and bleeding from gastro-enteric anastomosis marginal ulcer in patients, all with mild hemorrhage. no etiology was fond in patients with mild hemorrhage. a significant association was found between the severity of late hemorrhage and the vascular pseudoaneurysm as a cause of bleeding (p \ . ). all pseudoaneurysm bleeding occurred in cases complicated by a postoperative pancreatic fistula (popf) with a significant statistical association (p \ . ). conclusions: the most common cause of pph was bleeding from a vascular pseudoaneurysm, most of them were severe bleeding with late presentation and all were associated with a popf. in these cases, early detection by cta is mandatory, allowing an urgent treatment by angiography of such a bleeding vascular complication following pd. ventral hernia in hostile situation introduction: there is no consensus about the benefit or harm derived from adding a mesh hernioplasty at the same time as an urgent intraperitoneal surgery for another cause. the use of a prosthesis in contaminated fields is controversial, but suture repair has a high risk of recurrence. the main objective has been to analyze the impact of the simultaneous repair of uncomplicated midline hernias at the same time as emergency surgery for another cause, in relation to the presentation of complications, the surgical site infection rate (isq) and recurrences. material and methods: retrospective, observational study of all urgently operated patients (surgery open and laparoscopic) in the period between - who underwent a simultaneous midline primary ventral hernioplasty. the background, circumstances of the surgery and postoperative complications during the first month and long term through the basis of prospective data of emergency surgery and complications of our surgery department. results: a total of patients ( female) met the inclusion criteria with a mean age of . years (sd = . ), average bmi of . kg/ m (sd = . ). the most frequently performed interventions were: appendectomy ( . %); cholecystectomy ( . %); and lysis of adhesions ( . %). the . % of all interventions were performed by laparoscopic approach. they presented associated peritonitis in . % of the cases. the . % of patients presented some complication, in . % surgical site infection ( . % organ space). during the followup three recurrences were detected ( . %), no patient has presented chronic infection related to the use of prostheses. conclusions: in our series the simultaneous performance of hernia repair of the midline in the context of emergency surgery for another cause has been safe and not associated with long-term complications and low recurrence rate. the open abdomen: our experience introduction: ''open abdomen'' refers to a solution in which the abdominal content is left deliberately exposed under a temporary cover for a variable amount of time. since this method has been used more and more for the treatment of severe intra-abdominal infections. starting from the s the concept has been also applied in trauma surgery. material and methods: between / we have treated patients with this technique. in cases the etiology was traumatic, in the remaining cases the abdominal pathology was inflammatory. in the last years we also started to use it in some cases of treatment of surgical complications. the techniques we used were different and changed during the time. at the beginning of the experience we've completed drainages of the abdominal cavity according to mickulizt, laparostomies with mesh, bogota bags. these techniques have been abandoned since the negative pressure therapy came out. we started with the barker vacuum pack ( cases), followed by the vac (vacuum assisted closure) and ab thera kci Ò ( patients) systems and in the last three years we used the cnp suprasorb Ò of lohmann and raucher ( patients case history: year old lady presented at the a&e with few days history of constipation, faeculent vomiting, abdominal distension and pain in the lower abdomen. she had hysterectomy many years ago through a lower midline incision. her urgent ct scan of the abdomen and pelvis confirmed an incarcerated right obturator hernia containing a small bowel loop causing bowel obstruction. clinical findings: elderly, frail patient with mild tachycardia, distended abdomen and lower abdominal tenderness with guarding in the left iliac fossa. per rectal examination was unremarkable. investigation/results: inflammatory markers were raised, lactate, liver and kidney function was in normal limits with only mild hypokalaemia and hyponatraemia. ct abdomen and pelvis confirmed small bowel obstruction at the mid ileal level due to right obturator hernia. diagnosis: incarcerated right obturator hernia causing small bowel obstruction. therapy and progressions: patient was taken to the operating theatre for urgent laparotomy. dilated small bowel loops and incarcerated right obturator hernia was found with proximal ileal loop in it. after blunt stretching and dilatation of the obturator foramen, the involved ileal loop was reduced. it was deemed viable, therefore no bowel resection was required. the defect at the right obturator foramen was closed with suture. post-operatively the patient was transferred to the intensive care unit for further management. comments: obturator hernias are a rare type of pelvic hernias. their real incidence is unknown but it is thought to be less than % of all hernias worldwide and due to its non-specific symptoms and late diagnosis, they require bowel resectional surgery in nearly % of the cases. howship-romberg sign is helpful in diagnosing such a hernia, but the ultimate diagnostic choice is ct scanning which is the only way to find this condition early and avoid bowel ischaemia. case history: a -year-old woman without previous medical history presented to the emergency department with abdominal pain and dysphagia associated with nausea, vomiting and absolute constipation. during previous months, she reported having ingested hair. clinical findings: abdominal examination revealed a distended abdomen with rebound tenderness and tinkly bowel sounds. investigation/results: ct-scan showed a distended stomach with a mussel-shaped, heterogeneous and non-enhancing mass. an esophagogastroduodenoscopy revealed hair inside the lower esophagus and the stomach. diagnosis: high intestinal obstruction due to a gastric trichobezoar. therapy and progressions: the patient underwent laparotomy, gastrotomy and trichobezoar removal (fig. ) . the postoperative period was uneventful and she was discharged home on the th pod with a psychiatric evaluation scheduled. comments: bezoars are rare conditions consisting of compacted material that is unable to pass through the gastrointestinal tract. this condition usually involves the stomach; rarely, it can extend into the small bowel and even the colon, giving the so-called rapunzel syndrome. bezoars could be composed by vegetable material (phytobezoars), hair (trichobezoars), drugs (pharmacobezoars), or other materials. , a trichobezoar is the result of trichotillomania, trichophagia or other psychiatric disorders. always consider bezoars in differential diagnosis. introduction: the effectiveness of different step-up approaches is increasingly evaluated but results are controversial. we assessed the results of a standardized step-up approach protocol in the treatment of acute severe necrotizing pancreatitis, with a special focus on patient stratification to obtain an early identification of those deserving a more aggressive strategy. matherials and methods: this is a retrospective analysis of patients with acute severe pancreatitis over a period of years. the variables taken into account were: etiology and severity of the disease, sepsis, organ failure, hemodynamic stability, treatment, los, morbidity, mortality. since , patients with infected necrosis underwent a standardized step-up approach: percutaneous drainage only; percutaneous and endoscopic procedure; surgery. the results were compared with the standard care delivered from to . results: among patients, ( . %) were identified as affected by severe necrotizing disease. overall mortality was . %. the initial management was non operativein all patients. mortality in the step-up group was % ( / ) vs % ( / ) in the standard care group. conclusion: a standardized step-up approach protocol offers better results than standard care in the management of acute severe necrotizing pancreatitis. however, a better stratification of patients. introduction:the appendix stump closure in complicated appendicitis has been widely practiced in different ways such as metal clip, hem-o-lok clip, endoloop and endostapler. the treatment of complicated appendicitis with necrosis and perforation of the appendix base is controversial. we aimed evaluate the efficacy of laparoscopic partial caecum resection with endostapler in complicated appendicitis with necrosis and base perforation. material and methods:from january to october , we evaluated consecutive patients who underwent a laparoscopic partial caecum resection in complicated appendicitis with necrosis and perforation of the appendix base. partial caecum resection was performed with the endostapler to close the appendix base at ileocaecal junction. results:the laparoscopic partial caecum resection with endostapler was used in % . of the cases. the mean operative time was . ± . min. there were necrosis of appendix base in , perforation of appendix base and diffuse peritonitis in , perforation of the appendix base and localized peritonitis in of the patients. the wound and intra-abdominal infection rates were . % and . %, respectively. there were no operative complications and the conversion rate was . %. the average length of hospital stay was . ± . days. there was no leakage on the stapler line. conclusions:the laparoscopic partial caecum resection with endostapler in complicated appendicitis with necrosis and perforation of the appendix base, is a safe and effective technique. introduction: the term ''''volvulus'''' comes from the latin ''''volvere''''meaning twist. if left unattended, sigmoid volvulus can compromise the blood supply of the involved segment,leading to ischemia,gangrene,perforation and death. the mainstay of sigmoid volvulus management has been through proctoscopic or colonoscopic decompression when feasible, followed by surgery either during the same admission or electively. the aim of our study is to identify patients which can benefit of immediate surgical approach and prognostic factors associated with failure of conservative/endoscopic treatment. materials and methods: charts of patients admitted for sigmoid volvulus to our institute were retrospectively analysed. we revised ct scan images and laboratory tests of all the patients to identify risk factors for conservative treatment failure. results: patients underwent surgical procedures; in cases after a failure of an initial conservative approach; patients were managed with endoscopic approach only. elective surgery was performed in patients. case history: we report a -year-old male case presenting left hand middle finger pain after pressured paint gun shot in volar proximal phalanx clinical findings: on physical examination swelling and tenderness on the volar side of the hand was observed (fig. ) investigation/results: pain was remarkably more intense with passive finger extension. distal nerurovascular status was unscathed. there was no fracture reported on radiography. leukocytosis and acute phase reactants rise was observed on laboratory examination diagnosis: after physical, radiological and laboratory examination the diagnosis of acute flexor tenosynovitis was made. therapy and progressions: open debridement and irrigation following bruner incisions on middle finger was undertaken within h of injury. paint impregned in tissues could be observed in subcutaneous tissue, palmar fascia and flexor tendon sheath. paint affected tissues samples were analysed in microbiology laboratory (fig , ) after checking nerurovascular indemnity, g drainage was left in deep tissues and skin suture was performed with - monofilament non absorbable suture. the patient followed days intravenous antibiotical therapy followed by weeks oral treatment. he attended physiotherapy program postoperatively, reporting no functional disability or wound complications after weeks. comments: chemical flexor tenosynovitis is an important emergency which must be correctly diagnosed and treated due to quick progression and potential morbidity if not treated effectively ( ) in our experience, case was managed by open debridement and irrigation but different treatments can be followed depending of patientsclinical situation, such as iv antibiotics with serial examinations or percutaneous drainage. it should also be noted that australia does not have a specific subspecialty in emergency surgery. the acute surgical unit at the tch was set up in in order to provide a dedicated acute unit to service the ever increasing demand acute surgery. previous model was that the acute surgical service was integrated into the elective work. additional beds were provided to the unit including the positions of a dedicated director and chief nurse. the achievement of the unit has been the decreased time to theatre, less after-hours operating, standardised treatment approaches, and dedicated emergency surgery medical staff. the difficulties have included clinician engagement, competing resources with elective surgery, emergency surgical presentations increasing by - % each year, and the unit''s beds being used for non-acute patients as the hospital approaches regular %. the acute surgical unit has evolved into a specialised acute care that enables rapid assessment and treatment of patients with staff dedicated with skills in this area. treating pyogenic liver abscesses secondary to diverticulitis in a patient using immunosuppressants for crohns disease by performing a sigmoid colectomy introduction: pyogenic liver abscess (pla) formation due to microbial contamination of the liver parenchyma is often seen secondary to intra-abdominal infections. pla formation due to crohn''s disease (cd) is a rare complication and not well-documented in current literature. as symptoms often mimic a cd exacerbation, diagnosis is often delayed and severe disease may develop. optimal treatment for this group of patients remains debatable. case presentation: a -year-old man was admitted to the hospital with a -week history of overall malaise, fever and night sweats. patient''s history solely stated a -year treatment of cd that was stable over the past period with infliximab and azathioprine. investigations and treatment: biochemical analysis revealed a c-reactive protein of mg/l and a white blood cell count of . /l. an abdominal ct scan showed multiple abscesses in the right lobe of the liver and a thickening of the wall in the transition of the descendent colon to sigmoid. the patient''s immunosuppressants were paused, intravenous antibiotics were administered and a percutaneous drainage of the biggest pla was performed. however, the clinical condition of the patient did not improve. colonoscopy and pet-ct scan did not reveal any other sites of infections. as patient remained septic and previous imaging revealed mild diverticulitis rather than active cd, an emergency hartmann''s procedure was performed. hereafter, the patient recovered rapidly and the plas resolved completely. conclusion: diverticulitis of the sigmoid colon should be considered as causative pathology in patients presenting with multiple pyogenic liver abscesses and a history of crohn''s disease that is in full remission with immunosuppression. when the abscesses exceed cm in size and are multilocular, resection of the inflamed colon can be a treatment option of value. clinical findings: epigastric pain and recent episode of hematemesis. pain at deep palpation of the epigastrium, no signs of peritoneal irritation investigation/results: abdominal x-ray and ct showing a large right sided strangulated paraesophageal peh, with pneumatosis of the gastric wall diagnosis: right sided strangulated peh therapy and progressions: emergent laparotomy. peh reduced, ischemic portion of the stomach recovering viability. closure of diaphragmatic defect with non-absorbable suture, reinforcement of lower esophageal sphincter with round ligament (ligamentum teres hepatis) and anterior partial fundoplication (dor). postoperative course uneventful, patient discharged on th pod. comments: peh are mediastinal displacements of abdominal organs, most often the stomach, associated with laxity or a hole in the phrenoesophageal membrane, large enough to allow the gastric fundus to herniate. because the stomach is attached to the gastroesophageal junction, it tends to rotate around its axis leading to organoaxial volvulus. occurrence and size increases with age. peh account for - % of all diaphragmatic hernias. in patients without prohibitive operative risk, they should be surgically corrected, avoiding the risk of acute and potentially life-threatening complications when emergent surgical repair is required. the risk of developing these complications is less than %/yr and associated mortality rate is approximately %. case history: patient was a previously healthy -year-old female with an unremarkable past medical history, non-smoker with a high body mass index (bmi [ ). she first presented to a level medical facility with acute left upper leg pain and swelling. one week prior to this she had a progressive cough, swinging fever, and malaise. clinical findings: patient was transferred to our hospital haemodynamically unstable, acidotic, hypoxemic and delusional. tachypnea and oliguria were present. she continued to deteriorate clinically with pyrexia (t , oc), resistant shock, and toxaemia. on examination her left leg was found to be paresthetic below the femoral-inguinal fold. investigation/results: abg samples showed lactic acidosis with a ph of . and lactate of . mmol/l. hypoxia and hypocapnea were present.her biochemical profile showed acute kidney injury (aki) with raised creatinine kinase (cpk) and serum creatinine (cr) . . chest x-ray illustrated bilateral lung infiltrations (ards image). diagnosis: patient was urgently referred to a ct scan of the left femur with i.v. contrast for suspected necrotising fasciitis. ct findings highlighted a deep muscular femoral abscess with multiple regional fluid collections and necrotizing inflammation from the femur diaphysis to the patella. therapy and progressions: the patient was immediately transferred to or for emergency surgical exploration and debridement. almost the entire anterior compartment of the femur was necrotic and hence an extensive excision of the dead tissues and packing with npwt was performed. comments: severe snm can cause marked systemic toxic effects, namely, the streptococcal toxic shock syndrome (stss). stss secondary to snm is a life-threatening host response to gas superantigens with a mortality rate as high as %. clinical findings: patient had a diffusedlty tender abdomen and had not passed flatus proceeding his admission to the a ? e department and was vomiting. investigation/results: ct abdomen showed small bowel dilatation with abrupt cut-off point proximal to the icv diagnosis: a diagnosis of small bowel obstruction was made based on the clinical and ct findings. therapy and progressions: patient was taken to theatre for laparoscopy ? -proceed and a 'slipped' bowel lopp was noted within the peritoneal flap that had been created a week prior during the original hernia repair. the 'v lock'' suture line was found to be loose which is thought to have led to this complication. the bowel loop was reduced, deemed viable and an internal hernia repair was performed. post-operative period was unremarkable and the patient was discharged day posy-operatively. comments: during lap tapp hernia repair, there are currently at least options avaiable for peritoneal flap closure; (sutures, tackers and glue.) suregons prefernce prevails over the chosen approach. when sutures are chosen, most surgeons prefer the self-locking v-lock stitch. by adopting this technique, meticulous periotneal closure is impoartan, as loose suturing of the peritoneum can lead to post operative complications of internal herniation and small bowel obstruction, as described in this case. a multi-centre prospective study would be welcomed, to compare efficacy and safety of all types of peritoneal closure devices. introduction: peer review assessment of medical treatment has been shown to be a robust way of improving quality of care in trauma in our institution and globally. in we introduced regular morbidity and mortality meetings at the department of gastrointestinal surgery. severe complications (revised accordion classification [ ) after surgery were identified on a weekly basis, evaluated and data included in a local quality registry with the aim of revealing suboptimal surgical quality and continuously improving our results. material and methods: retrospective analysis of collected data from the described quality registry. all adult patients who had undergone gastrointestinal surgery in were assessed. results: of surgical procedures performed, % were emergency procedures. a total of % ( / ) experienced a severe complication after surgery and % ( / ) required reoperation. in the group of upper gastrointestinal surgery [n = ( %)] % were emergency procedures. anastomotic leak (al) was identified in % ( / ) undergoing thoraco-laparoscopic esophagectomy and in % ( / patients) after gastrectomy. of laparoscopic cholecystectomies, % were emergency procedures with % ( / ) reoperation. of hernia repairs, % required reoperation. in the group of lower gastrointestinal surgery [n = ( %)] % were emergency procedures. al was diagnosed in % of colonic resections and % of patients after rectal resection. in emergency colorectal resections(n = ) there were no al. of appendectomies, patients ( %) required reoperation. the most frequent cause of reoperation was revision of stoma ( ), followed by reoperation for al ( ), abscess ( ), and wound dehiscence ( ). patients died after surgery of which were emergency surgical patients. conclusions: systematic assessment of all severe complications helps reveal surgical procedures which can be improved but also to identify surgical procedures with low complications rates. plans are being developed to improve the quality of the identified procedures. all surgical departments should have regular and thorough assessment of their activity. acute surgical patients operated by emergency surgeons has less risk of post-operative complications and mortality d. gumaa east kent hospitals university nhs foundation trust, general surgery, ashford, united kingdom introduction: in england and wales, we perform over , emergency laparotomy every year. days mortality rate is around - %. in our study we are trying to demonstrate if have dedicated emergency surgery service will make a difference in the outcome of emergency laparotomy. material and methods: retrospective study on prospectively collected data from nela database done in a large district general hospital. all patients over years old who underwent emergency laparotomy for acute surgical condition between november and january were included in the study. mortality and post-operative complications were the primary outcomes. results: total of patients were included in the study, operations were performed by emergency surgeons (es). days mortality rate was %, while it was . % for the none emergency surgeons group (nes) post-operative complications were . % compared to % for patients operated by nes. there was shorter itu stay with average of . days, while the itu stay for the other group was . days, but the es group had higher chance of unplanned return to theatre. . % of the patients went back to theatre compared to % of the other group. reasons of unplanned return to theatre was mainly post-operative collection or wound dehiscence. conclusions: emergency surgeons has better outcomes when they perform emergency laparotomy, may be because they perform higher number of laparotomy compared to their peers. emergency surgery has been a growing subspeciality recently, and with no doubts having surgical emergency units has improved the patient's care around uk. the advantage of g over g of prophylactic cefazolin in surgical site infections in trauma surgery below the knee introduction: the rate of surgical site infections(ssi) after foot/ankle surgery remains high, despite the implementation of antibiotic prophylaxis ( ) . recently guidelines suggest a single dose of g instead of g of cefazolin for implant surgery, this decision is largely based on pharmacokinetic studies ( ) . however, the clinical effect of this higher dose has never been investigated in this region. this retrospective cohort study therefore investigated the effect of g compared to g of prophylactic cefazolin on the incidence of ssis in foot/ankle surgery. material and methods: all patients undergoing trauma-related surgery of the foot, ankle or lower leg between september and march were included. primary outcome was the incidence of a ssi. ssis were compared between patients receiving g and g of cefazolin as surgical prophylaxis. results: a total of patients received g and patients received g of cefazolin. the groups did not differ in gender, age, weight, co-morbidities or intoxications. the overall number of ssis was ( . %) in the g group and ( . %) in the g group. corrected for the confounders ''age'', ''smoking'' and ''blood loss'' this was not statistically significant (p = . ). conclusions: even though the decrease in ssi rate from . to . % was found not to be statistically significant, it might be clinically relevant considering the reduction in morbidity, mortality and healthcare costs. research linking pharmacokinetic and clinical results of prophylactic cefazolin is needed to establish whether or not the current recommendations and guidelines are sufficient for preventing ssis in foot/ankle surgery. introduction:right-sided colonic diverticulitis (rd) is much rarer than left-sided (ld) and subsequently, controversies concerning the most appropriate treatment remain unsolved. our experience let us believe that mild rd can benefit from an outpatient management. material and methods: we performed a single center retrospective comparative study in which we included all our diverticulitis patients that were treated as inpatient in our unit. we divided in two groups:rd and ld group. the ld group was created by randomization from a prospective ld patients database. results: we included rd and ld patients treated in our unit from july to july . median age was . in rd and . in ld, with a . % of females in rd vs . % in ld. asa classification was significantly lower in rd (asai: . % vs %, asaii: . % vs , , asaiii: vs . %, asaiv: vs . % p = . ). the presence of neumoperitoneum in ct scan was significantly higher in ld . % vs . % p = . ) surgery was performed in . % of the left-sided diverticulitis compared to of the rd group (p = . ). antibiotics of third line (imipenem and meropenem) were only required for ld ( vs . % p = . ). length of hospital stay was significantly shorter (p = . ) in rd ( . ± . ) than in ld group ( . ± , ) conclusions: in our series, patients with right diverticulitis had fewer perforations in the ct scan, they required lower spectrum antibiotics and did not required any surgical treatment with a shorter length of hospital stay. we consider that mild right diverticulitis could benefit from an outpatient treatment with oral antibiotic following similar recommendations to those followed for mild ld patients. when surgery should not be immediate, a night of hospitalization in a specialized environment is performed and surgery deferred overnight. in some selected patients, a return home is possible with a scheduled emergency surgery the next day. the pa.r.c.o.ur protocol is set up in the surgical emergencies of the university hospital of lille after a suitable medical treatment and enlightened information. this retrospective study assesses whether this deferred surgical management allows a return home on the day of the operation. methods: between / / and / / , records of patients operated for an abscess, appendicitis, cholecystitis or symptomatic inguinal hernia were reviewed. patients who did not have criteria for immediate surgical management (peritonitis, occlusion, sepsis, cellulitis, intravenous treatment need) agreed to return to their home for an os the next day. results: / % interventions were performed in os and allowed a return home at day , within a median time of h [iqr - ]. conclusions: the pa.r.c.o.ur protocol makes it possible to reserve the availability of the entire technical platform (operating rooms and beds) to the most serious pathologies with a failure rate of %. the medico-economic benefits, the efficiency in the management of the beds and the satisfaction of the patient and medical staff of this protocol must be evaluated prospectively. a years old woman was admitted in our er presenting with a h sharp epigastric and ruq pain, fever, nausea and vomiting, hd stable. the patient had a past medical history of tachyarrhythmia, open-angle glaucoma and lower limb venous insufficiency. her past surgical history included an hysterectomy and bilateral salpingooophorectomy, appendectomy and left inguinal hernioplasty. during clinical examination, signs of peritoneal irritation were present. ct scan revealed a small pneumoperitoneum in the luq and multiple small and large bowel diverticula, without free peritoneal fluid. blood work showed mild leukocytosis and neutrophilia. we performed an urgent exploratory laparoscopy in which dozens of small intestine diverticula were found, increasing proximally in number. one of them, cm distally from the treitzs angle, showed signs of perforation, with a small abscess and surrounding fibrin. the affected bowel was externalized through a cm laparotomy for segmental resection and a manual double-layer terminoterminal jejunojejunostomy was performed. in the perforated jejunal diverticulum, a mm cod fishbone was identified as the cause of the perforation. the histopathological examination of the extracted cm tissue sample, found several diverticular structures of the muscular wall, one of which with a mm perforation and a granulocytic infiltrate with serosa involvement. complicated cases of small bowel diverticulosis are best managed by segmental resection surgery. despite being quite rare, every surgeon should be aware of such acute abdomen presentation. asymptomatic cases benefit from a watch-and-wait approach. case history: a -year-old female consulted to the emergency department for a h epigastric pain. it was accompanied by nausea without vomiting. clinical findings: the patient was hemodynamically normal and the abdomen was soft with minimal distention. investigation/results: x-rays showed large gastric dilation. the abdominal ct scan showed mesenteric axial gastric volvulus with minimal free fluid. suddenly, the patient presented diffuse abdominal pain with diaphoresis, mucocutaneous pallor, hypotension and tachycardia. diagnosis: a gastric volvulus with gastric ischemia was suspected. broad-spectrum antibiotic therapy and resuscitation measures were started. emergency surgery was indicated. therapy and progressions: a decompressive gastrostomy, gastric reduction and devolvulation, transverse colon resection due to ischemia and splenectomy were performed. after h, she required total gastrectomy and right hemicolectomy due to ischemia secondary to severe septic shock associated with disseminated intravascular coagulation. comments: the gastric volvulus is an uncommon entity, being the mesenteric-axial type so rare. there are very few cases described whose manifestation is accompanied by hypovolemic shock secondary to splenic laceration, which occurred due to the great gastric distention. early diagnosis is the key to start treatment as quickly as possible, due to high mortality the main mechanism of death is usually vascular involvement, perforation and multiorgan failure. results: we analyzed , pediatric ogis, and . % of pediatric cases occurred in the - age group, . % in - , . % in - , and . % in - . the average age of the cohort was . years and . % of cases occurred in boys. racial distribution revealed . % of cases in caucasians, . % in african americans, and . % in hispanics. most ( . %) cases were documented in the southern united states. of our , cases, . % underwent vitrectomy, . % underwent enucleation, and . % developed endophthalmitis. the rate of endophthalmitis development after ogi was highest ( . %) in the asian/pacific islander group. the average length of stay for the entire cohort was . days, and the average cost per day was $ , . . table contains a breakdown of our statistics. conclusions: as documented in the nis, ogi occurs more commonly in boys than in girls at a ratio of approximately : . the rates of vitrectomy and enucleation are higher in boys. we noted a higher of rate of enucleation in asian/pacific islanders and african americans. the plurality of ogis occur in the - age group; this age group also has the highest relative rate of enucleation. with respect to location, ogis occurring in the western united states had the highest average cost per day of inpatient stay. autologous tissue from intramedullary channel parietes for femur nonunions management introduction: a reamer-irrigator-aspirator (ria) method is deeply reliable for getting high volumes of bone graft/mscs. high rates of successful outcomes have been reported after the use of ria bone fragments to cure non-unions. material and methods: being supported by histomorphological examination of the material acquired while drilling intramedullary channels of patients with femur nonunions ( -hypertrophic, oligotrophic), we have discovered that nevertheless, expressions of the dystrophy and necrosis in bone tissue and marrow in pseudoarthrosis areas depend on time since fracture occurrence, the microscopic study of the material cm above and below a fracture line has demonstrated ordinary structures of bone tissue and marrow in all cases. introduction: this study aimed to evaluate the outcomes of ankle fractures with posterior malleolus fragments (pmfs) involving \ % of the articular surface treated with or without screw fixation. material and methods: among patients with ankle fractures and pmfs who underwent surgery between march and february , with type pmfs involving \ % of the articular surface were included. of these patients, underwent screw fixation for pmfs and lateral and/or medial malleolar fracture fixation (group a) and underwent internal fixation for malleolar fractures without screw fixation for pmfs (group b). ankle joint alignment and fracture healing were measured using plain radiography and computed tomography (ct). clinical outcomes were determined using the american academy of orthopaedic surgeons foot and ankle questionnaire, short form- , and american orthopaedic foot & ankle society scale. results: nonunion was not noted in either group. however, we detected union with a step-off of mm or more in cases from group b. with regard to ankle joint alignment, case in group a and cases in group b showed mild asymmetry of the medial and lateral clear spaces on ct at months. clinical outcomes at and months after surgery were better in group a than in group b. conclusions: screw fixation of pmfs was effective for fracture healing and maintaining ankle alignment. additionally, it improved short-term clinical outcomes, which we believe was due to stabilization of ankle fractures with pmfs involving\ % of the articular surface. references: level ii, prospective comparative study. how accurate can gaps and step-offs be determined in acetabular fracture treatment? introduction: the assessment of gaps and steps in acetabular fractures is challenging. studies evaluating the value of various imaging techniques to enable accurate quantification of acetabular fracture displacement are limited. this study aimed to assess the inter-and intraobserver variability of gap and step-off measurements using pelvic radiographs, intraoperative fluoroscopy and computed tomography (ct). material and methods: sixty patients, surgically treated for acetabular fractures, were included. five observers measured the gap and step-off on all the pre-and postoperative pelvic radiographs and ct scans. intraoperative fluoroscopy images were reassessed to determine the presence of gaps and/or step-offs. the inter-and intraobserver variability were calculated for the measurements using pelvic radiographs or ct scans. kappa was calculated for the intraoperative fluoroscopy assessment. results: for the preoperative displacement, the intraclass correlation coefficient (icc) was . (gap and step-off) using pelvic radiographs, and . (gap) and . (step-off) using ct scans. for the postoperative displacement the icc was . (gap) and . (step-off) using pelvic radiographs and . (gap) and . (step-off) using ct scans. the average kappa for the intraoperative gap and/or step-off assessment using fluoroscopy was . (- . to ) both for the inter-and intraobserver assessment. conclusions: there is little agreement between the observers regarding the measurements of the preoperative displacement, the presence of gaps and step-offs intraoperatively and the measurements of the postoperative displacement. a possible explanation for this is that the acetabulum has a three-dimensional spherical shape with multiple fracture lines and fragments going in different directions. single radiographic or ct-based gap or step-off measurements do not seem to be representative for the fracture characteristics, therefore the use of d measurements should be considered. introduction: long-term intake of glucocorticoids leads to pathologic changes in bone and cartilage tissues. material and methods: to understand how to prevent the occurrence of the pathology, we studied the use of vitamin d, vitamin e and a combination thereof on the background of the intake of prednisolone, . mg/ g of body weight. the experiment involved male rats of wistar linear breed. the animals were months old and weighted . ± . g. the experiment included series of animals, rats in each, namely: the first group-intact animals; the rest of the animals received prednisolone, . mg/ g of body weight. the rats of the third series received additionally iu of vitamin d . the animals from the fourth group also received . iu ( . mg) of vitamin e. results: long-term administration of prednisolone to the experimental animals has caused significant structural and functional disorders in their bone and cartilage tissues. they can be construed as simulated glucocorticoid-induced osteochondropathy. the combination of the vitamins d and e has demonstrated its ability to promote restoration of histomorphologic features of bone and articular cartilage in proximal femur epiphysis and epiphyseal cartilage of proximal femur epimetaphysis in animals with simulated glucocorticoid-induced osteochondropathy. the combination of the vitamins d and e has demonstrated a better effect on the background of the glucocorticoid-induced osteochondropathy, compared to the vitamin d alone. conclusions: preventive administration of the vitamins d and e while treatment with prednisolone leads to avoidance of the majority of pathologic changes, resulting otherwise from glucocorticoid-induced osteochondropathy. konyang university hospital, orthopaedic, deajeon, south korea introduction: the purpose of this study was to evaluate clinical, radiological and functional outcomes of patients had osteochondral autograft harvested from the ipsilateral femoral head for a femoral head defect after posterior hip fracture dislocation material and methods: this study was approved by irb at our institution. a retrospective chart review of a prospectively performed operation was performed at two university hospital between march , , and june , . all fracture was classified by the ao/ota classification. we included the patients had minimum months of follow up periods. ten displaced head fractures were addressed through posterior surgical dislocation and two patients had no posterior dislocation was operated using smith-peterson approach. an osteochondral graft was harvested from inferior non-weight bearing articular surface and grafted to osteochondral defect. all patients were full weight bearing by months results: we had femoral head fracture dislocation. patients were excluded due to lost to follow up. twelve of with type i/ii pipkin fracture dislocation with the articular defect and reduced within h of injury was identified for review. the patients were followed up for a mean of . months. there was no osteonecrosis. decreased joint space was identified in two patients. all fractures achieved union. the mean harris hip score of last follow up was . ( - ) one patient who operated using the smith-peterson approach had femoral nerve palsy. conclusions: the clinical and radiological results after treatment of femoral head fracture dislocation with articular defect by osteochondral autograft harvested from its own non-weight bearing articular surface show good outcomes. hospital universitario fundacion jimenez diaz, madrid, spain, hospital universitario de octubre, madrid, spain, hospital universitario la paz, madrid, spain introduction: preoperative computerized tomography scan provides important information about ankle fractures associating posterior malleolus, helping us distinguishing fractures affecting distal tibiofibular joint. the aim of our paper is to describe our series of patients suffering an ankle fracture with posterior malleolus involvement. methods: fifty-two consecutive patients, with ankle fracture involving posterior malleolus were evaluated prospectively. all of them were assed with a preoperative ct scan, demographic data, fracture mechanism, surgical approaches, posterior malleolus size measured classification and treatments were analyzed. results: most frequent posterior malleolus pattern according to bartonicek classification was type ii, twenty-two patients ( . %). an alternative surgical approach was performed in thirty-three patients ( %) as a consequence of information provided by ct scan. no statistical differences were observed when measuring posterior malleolus in conventional x-rays or ct scan. analysis of variance showed a p value less than . when comparing pm size and haraguchi and bartonicek classifications. discussion and conclusion: ct scan is required to perform an adequate preoperative study of ankle fractures involving posterior malleolus, using this information to provide a better outcome to our patients. effect of atorvastatin and losartan on gene expression and cell count in a rat model of posttraumatic joint contracture of the knee-a blinded and randomized animal study introduction: myofibroblasts have been associated with increased posttraumatic joint contracture, which has a massive impact on articular function. atorvastatin and losartan have shown to reduce the proliferation of cardiac, hepatic and pulmonary myofibroblasts. the aim of this study was to evaluate the effect of atorvastatin and losartan on gene expression, cell count and collagen deposition in the posterior joint capsule , and weeks after trauma in a rat model of posttraumatic joint contracture of the knee. material and methods: posterior capsular injury and kirschner-wire immobilization of the knee were performed in sprague-dawley rats. atorvastatin, losartan, or placebo was administered daily orally. the rats were sacrificed at either (n = ), (n = ) or (n = ) weeks after initial surgery. rats euthanized at week had their k-wire removed at week , followed by a remobilization period of another weeks. the results were evaluated via qpcr and immunohistochemistry. results: losartan reduced the number of myofibroblasts in comparison to the control at week and , whereas atorvastatin lowered myofibroblasts only at week (p \ . ). atorvastatin reduced the collagen deposition at week , whereas losartan had no effect on collagen deposition. losartan decreased gene expression of connective tissue growth factor (ctgf) at week and of tgf-b at week . clinical findings: positive anterior drawer test, grade iii valgus instability, and a palpable gap below the patella were assessed. no neurovascular alterations were found and ankle-brachial index scored [ . . investigation/results: initial immobilization with a splint was performed. radiographs showed a high patella with no other lesions. mri revealed a complete rupture of the patellar tendon and a complex multiligamentous injury with complete anterior cruciate ligament (acl) tear, avulsion of distal medial colateral ligament (mcl), and a complex rupture of both meniscus. diagnosis: knee dislocation with patellar tendon rupture. therapy and progressions: definitive treatment was performed days after the initial lesion, with arthroscopic resection of the posterior horn of the external meniscus and reconstruction of the acl with posterior tibial tendon allograft, as well as open repair of the patellar tendon and the internal meniscus, with subsequent mcl distal reinsertion. immediate partial weight-bearing with an extension orthosis was allowed. the patient is currently progressing with rehabilitation. comments: knee dislocation is a rare injury, and most cases are due to highenergy trauma. concomitant rupture of the patellar tendon is very unusual, and most cases are described in the context of open injuries. surgery is mandatory in order to restore full stability of the knee, with either one intervention or a staged surgery, including repair of the collateral ligaments and the patellar tendon followed by arthroscopic reconstruction of the cruciate ligaments. postoperative management consists on early rom restoration and weight-bearing as tolerated. introduction: apophyseal anterior inferior iliac spine (aiis) fractures are rare injuries. they most commonly occur in athletes in adolescence period. because the ossification of pelvis is not completed, apophyses are the weakest part of musculo-tendinous unit during this period, thus avulsion fractures are more frequent than muscle ruptures. aiis avulsions are the result of sudden and forceful contraction of rectus femoris muscle concentrically or eccentrically. material and methods: we report a clinical case of a aiis avulsion fracture in a young male football player, after being misdiagnosed as muscle strain. results: our patient was treated with conservative treatment including bed rest, analgesia, using crutches and toe-touch weight bearing, progressing to full weight bearing as tolerated and nonsteroidal anti-inflammatory drugs. at follow-up, he showed relief from his pain and mechanical symptoms and regained full range of motion and returned to his previous levels of activity. conclusions: diagnosis requires careful attention to the physical examination and imaging. in this case, the fracture was managed successfully with a conservative approach. good results and return to previous levels of activity can be achieved with conservative treatment. when misdiagnosed as a simple strain, the late diagnosis may cause chronic pain with decreased sportive performance in the future. therefore, a carefully taken anamnesis and physical examination with comparative anterior-posterior pelvic x-rays are needed not to miss avulsions in adolescents; also in some instances, more advanced scanning methods must be considered. introduction: the problem of meniscus damage in children is due to unsatisfactory treatment results, which is associated with the frequent execution of meniscectomies. amount of unjustified meniscectomies and the incidence of osteoarthritis can be reduced if menisci are repaired. material and methods: during the period january -august children with injuries of the meniscus were treated in morozov children's clinical hospital. children underwent meniscus repair by suturing using three techniques: ''all inside'', ''inside out'' and ''outside to inside''. meniscus suture decision was made taking into account the assessment of the severity of the damage. the period from the moment of injury wasn't taken into account. the technique of meniscus suture was determined depending on the location and type of damage. we met children with damage to the discoid meniscus who underwent partial resection and meniscus suture. children underwent a meniscectomy due to severe traumatic and degenerative changes. children had mri of the knee after months and x-ray after months. results: children achieved a satisfactory functional result; operated children are at the rehabilitation stage. we faced a complication-limitation of flexion in the knee joint in child. in all children on the control mri, the absence of synovitis, the safety of the reconstructed meniscus contour and the decrease in the intensity of the hyperechoic signal in the gap zone in dynamics are determined. conclusions: the introduction of a technique for repair meniscus integrity in the daily practice of an arthroscopist makes it possible to reduce the number of meniscectomies, which will reduce the number of unsatisfactory treatment results for this pathology and prevent the development of early osteoarthritis of these, children revealed a fracture-dislocation of the patella. in children, a tangential fracture of the lateral condyle of the femur was noted. in children, the dislocation was repeated. we met children with bilateral damage. all children with complete damage to the medial patellofemoral ligament, fracture-dislocation of the patella and dysplastic dislocation were performed tendon plastic using the quadriceps femoris tendon. the technique includes: transplanting a graft quadriceps tendon graft without cutting off the patella. next, the transplant is subfascial carried out in the medial direction and is fixed with a bio-integrated screw in the femur. results: the rehabilitation period was months. % of children have a satisfactory result (there is a limitation of flexion in the knee joint to °). % have an excellent clinical result: the full range of motion in the knee joint, the absence of pain and a return to sports. none of the operated children had relapses of dislocation. conclusions: it is recommended to consider the technique of tendon plasty of the medial patellofemoral ligament using the quadriceps femoris tendon as a method of choosing the treatment for patellar dislocation in children. case history: a -year-old boy who was injured while playing baseball. he was playing as a catcher and was bumped into the runner, therefore his ankle got twisted. he was immediately taken to the hospital. clinical findings: x-ray the distal tibial epiphyseal growth plate was irregular. although the ankle joint was not dislocated. in the ct, the proximal fibular fragment was caught behind the posterior edge of epiphysis of the distal tibia and was trapped there. investigation/results: the patient must be operated in order to repair the ankle. but the reduction of the entrapped distal tibia epiphysis was not easy without open. diagnosis: we diagnosed with bosworth like fracture. therapy and progressions: reduction was not easy, however we performed it by the pulling the fibula towards to outside, pulling out the curled anterior tibiofibular ligament, and then pushing into the tibia. we performed screw fixation after reduction of distal tibial epiphysis. furthermore, we fixed the fibula with plate. we made him to do range of motion exercise and toe touch gait from next day, and full weight bearing from weeks. we removed the implant months after the surgery. he did well subsequently, and at years after injury, he had normal function of the ankle, and normal x-ray. and he has returned to sports without pain. introduction: judo is the most popular martial art in the world and the first martial art recognized since as an olympic sport. worldwide, the international judo federation has registered countries with about million judo practitioners. like martial arts, judo mainly involves grip and throwing techniques. the competition rules in judo have been subject to constant adjustment and optimization in recent years. injuries prevalence is an important factor in the contact martial arts. material and methods: a prospective cohort study of all registered international athletes ( ) at three different european judo contests in germany were accomplished with the aim to investigate the injury rate as well as the pattern of injury. the age of the athletes ranged between and years. injury incidence rates were calculated per athlete-exposures (iirae) and per min of exposure (iirme). independent variables were sex and weight division. subgroups were compared by calculating the injury incidence rate ratio. results: severe injuries by judo tournaments are rare. the most frequently injured regions were the hand and head. the fights of the main block are riskier than the finals. the incidence of injury in heavyweight division differed with lightweight competitors. the risk of injury for female and male competitors differed slightly. conclusions: further studies are needed to determine a judo specific injury patterns and factors especially in the pre-competitional phase. investigation of prevention-strategies like the adaptation of competition rules etc. makes sense. does garden''s classification of femoral neck fracture match between orthopedic specialist and clinical resident? t. inoue , s. inoue , t. muraoka prefectural miyazaki hospital, orthopedics, miyazaki, japan introduction: garden''s classification is the most popular classification of femoral neck fractures. femoral neck fracture should be operated^ h; however poor agreement make waiting time longer because it takes more time to prepare implants and biological clean room. we investigate the agreement of the garden''s classification (non-displacement type or displacement type) between clinical resident and orthopedic specialist. material and methods: the examiner are a clinical resident ( nd year) and an orthopedic specialist ( th year). the subjects were cases of femoral neck fractures treated at our hospital between january and december . first, the examiners classified them into a non-displacement type and a displacement type (test ). second, the examiners studied the literature about unclassifiable type. third, the examiners classified cases month later once more (test ). finally, we compared the first test with the second test using the agreement (the number of matched patients/total) and kappa coefficient. results: the test showed that the agreement and kappa coefficient were . % and . . the test showed agreement was . %, . . the intra-observer agreement of clinical resident was . % and kappa coefficient was . . the orthopedic specialist was . %, and kappa coefficient was . . at test , cases did not match. cases of those were unclassifiable type, which were valgus type with medial fracture line. with slight displacement, agreement will get lower; some doctors consider it displacement type. conclusions: unclassifiable type makes us confused. it makes agreement better to discuss about unclassifiable type. introduction: the aim of this retrospective study was to describe the profile of missed hand and foot fractures in multitrauma patients and to elucidate risk factors for the delayed diagnosis. material and methods: from to , there were included patients. missed fractures were defined as fractures, which were not diagnosed during primary and secondary survey. patients were assessed for age, sex, glasgow coma scale, injury severity score, and length of stay in hospital (los). timing of hand or foot diagnosis related to admission date (measured in days) was noted. results: overall, . % of patients had a delayed diagnosis of hand fracture, . % ha a delayed diagnosis of foot fracture. the mean gcs for patients with delayed diagnosis was , whereas patients with diagnosis the day of admission had and mean gcs of (p \ . ). patients with delayed diagnosis had a mean iss of . versus . for those diagnosed the day of admission (p \ . ). furthermore, patients with delayed diagnosis had a mean los of . days, whereas those diagnosed at the time of admission had a mean los of days (p \ . ). concerning delayed diagnosis hand fractures, metacarpal and phalangeal fractures were the most common injuries overall ( . % and . %, respectively). concerning delayed diagnosis foot fractures, metatarsal fractures ( cases) and calcaneus fractures were the most common injuries overall, followed by talus fractures and toe fractures. conclusions: this study revealed that with a decreased gcs and increase in iss, polytrauma patients are increasingly at risk for delayed diagnosis of hand and foot fractures with a concomitantly increased los. as a delayed diagnosis has significant impact on the final functional outcome, correct and careful primary, secondary and tertiary survey is essential. introduction: the aim of this study was a) to determine the methods of hemorrhage control currently being used in clinical practice and b) to analyze pelvic fracture mortality rates before and after initiation of a multidisciplinary pelvic fracture protocol. material and method: between and , we included trauma patients with pelvic fractures (group ). a similar retrospective examination was performed on a number of trauma patients without pelvic fractures (control group). there were collected injury severity score (iss), the highest abbreviated injury scale (ais) score in each anatomic region and methods of pelvic hemorrhage control. there were also recorded hospital lengths of stay (los) and in-hospital mortality. results: the average follow-up was -months. the average iss in group and group was respectively . and . . in both groups the commonest mechanism of injury was motor vehicle crash ( . %). in group , angioembolization and external fixator placement were the commonest used method of hemorrhage control. patients underwent diagnostic angiography with contrast extravasation noted in patients. patients with pelvic fracture had a mean hospital los of . days. the overall in-hospital mortality rate of patients with pelvic fractures was . %, while in group the overall in-hospital mortality was . %. age, shock, severe head injury and increasing iss, are all significantly associated with mortality in the pelvic fracture group. conclusions: the findings from this study demonstrate no clear relationship between the choice of hemorrhage control intervention used and the patient's clinical status. in healthier patients with unstable pelvic fractures, the mortality rate was similar to that of patients with stable fracture patterns. introduction: various percutaneous screw placement for pelvic and acetabulum fractures is often difficult because of complex anatomical morphology, however, it becomes very beneficial to set enough fixation stability if we can insert the long screws. d-ct navigation system for the screw placement is beneficial for precise screw insertion. we investigated the accuracy of screws with d-ct navigation. material and methods: our retrospective case series were assessed by the accuracy of screws with d-ct navigation for pelvic and acetabulum fractures. twenty-six patients who sustained pelvic fractures and thirteen patients who sustained acetabular fractures were included in this study and . mm cortical screws or . mm cannulated screws were inserted with d-ct navigation. we investigated the number of screws and screw positions which is measured by postoperative ct scan and classified by smith criteria. results: we inserted tits (transiliac-transsacral) screws and is (iliosacral) screws for pelvic fractures. of screws ( . %) were placed in correct position (grade or ). screw for s lesion was placed in incorrect position. meanwhile we inserted antegrade pubic screw, anterior column screws, posterior column screws and infra-acetabular screws. of screws ( . %) were placed in correct position (grade or ). screws were in incorrect position and they were all cortical screws. and there was no complication related to screw insertion. conclusions: our study highlights that d-ct navigation system reduced the malposition rate of screw insertion for pelvic and acetabular fractures. however, we sometimes had difficulty in inserting tits screw for s lesion and cortical screw for acetabular fractures. we assumed that this was caused by narrowness of s corridor and flexibility of drill or inserting cortical screws in wrong position manually. we should pay much more attention even using d-ct navigation. is operative therapy still warranted for dislocated acetabular fractures in elderly patients? introduction: the incidence of acetabular fractures in elderly patients is increasing. there is no consensus about the right treatment for the impaired elderly patient with an acetabular fracture. the aim of study was to investigate acetabular fractures in the elderly patient and the risk of a secondary tha. material and methods: a retrospective study was performed from till in the radboudumc nijmegen. all patients with an acetabular fracture were reviewed. they were divided into two groups, younger than and or older. ct scans were used for classification according to letournel and for the quality of the reduction according to matta. there was a follow-up of minimal years. results: in total, patients attended at the radboudumc with an acetabular fracture, of which were years or older. in the younger group, patients received surgery and elderly patients. according to matta, an anatomical reduction was achieved in % of the young patients and % of the elderly patients. imperfect reduction was achieved in % of the younger patients and % of the elderly patients. thirteen percent of younger group and % of the older group needed a tha based due to the posttraumatic arthritis, the younger group after months and the older group after months on average. one younger patient with anatomical reduction needed a tha, none of the elderly patients. twenty-three percent of the younger patients and % of the elderly patients, all with a poor reduction, needed a tha. age, the complexity of the fracture and the quality of the reduction were important factors leading to a secondary total hip arthroplasty. conclusions: elderly patients are two times more likely to need a secondary total hip arthroplasty. after an anatomical reduction, the risk is very low, even in the elderly. surgery for dislocated acetabular fractures is a good option when there is a possibility for a good reduction. references: letournel e. matta jm. introduction: in japan, as a definition of basicervical fractures of the proximal femur, a fracture line is placed into and out of the joint capsule of the hip joint. however, in fact there are various fracture types.we classified these fracture types based on treatment methods and reported on these results. material and methods: cases of proximal femoral fractures treated in our hospital from january to december . basicervical fractures occurred in cases ( . %). all cases diagnosed with x-ray and d-ct, and observed for months or more after surgery. results: there are two types of basicervical fractures: the fracture line exists around the just inside of the intertrochanteric part: normal type(n type); cases ( . %), and fracture line exists subcapital at ventral side, the coronal plane in the center of the neck and the trochanteric fossa at the dorsal part: coronal shear type(c type); cases ( . %).c type was further classified by treatment method depending on existence of posterolateral fragment and anterior wall fracture. c type without comminution ( part:c- type) was cases ( . %). with posterolateral fragment ( part:c- type) was cases ( . %), with posterolateral fragment and anterior wall fragment ( part:c- type) was cases ( . %).n type and c- type were treated by sliding hip screw (shs) with anti-rotation screw. c- type: shs with trochanteric stabilizing plate, c- type because of the bony contact area is very small: hemi-arthroplasty with calcar replacement was performed. cut out occurred in cases of c- type and case of c- type, but others obtained union.. one case of c- type occurred peri-prosthetic fracture intraoperatively. conclusions: we classified cases of basicervical fractures, and according to its classification, treatment method was decided and good clinical results were obtained. strategies aimed at preventing chronic opioid use after trauma: a scoping review c. cô té , m. berube université laval, faculty of nursing, québec city, canada, chu de quebec research center, université laval, trauma, emergency, critical care medicine, québec city, canada introduction: a high incidence of chronic opioid use (up to %) has been documented after trauma. solutions are urgently needed considering the importance of this public health issue. we aim to identify strategies to prevent chronic opioid use in the trauma population and to assess their level of evidence. material and methods: we initiated a scoping review of literature to identify research articles and guidelines on preventive strategies. several databases and websites of trauma were searched. strategies were classified according to their types and targeted trauma populations. the level of evidence was summarized according to an adaptation of oxford center for evidence-based medicine classifications and strategies effectiveness. results: close to items have been screened until now from which studies - and one guideline were found eligible. two studies - combined education with mandatory limit of opioid prescriptions (level iii) in the orthopaedic trauma population and the other study used tailored physical training after whiplash injury (level i). findings showed reduction of opioid use or complete weaning at and weeks after trauma, however the effect was not maintained beyond weeks. guidelines on orthopaedic trauma made the following recommendations: prescribe the lowest effective dose for the shortest period (strong, high-quality evidence), avoid long-acting opioids in the acute setting (strong, moderate-quality evidence), and prescribe precisely (avoiding ranges of dose and duration) (strong, low-quality evidence). conclusions: chronic opioid use is an important issue in trauma patients. findings highlighted the need for more research to reduce the burden associated with chronic opioid use in this population. references material and methods: we analyzed clinical cases: men- and women- , mean age years. trauma circumstances: habitual trauma- cases, traffic accident- , precipitation- , sport- , aggression- . for cohort analize schatzker classification was used: especially type i was meet in cases, ii- , iii- , iv- , v- , vi- ; close, open. for paraclinic examination were used x-ray and ct. surgical management consisted of: close reduction, internal fixation- cases ( -percutaneus canulated screws arthroscopic assisted, -external fixator), open reduction, internal fixation- cases. bone graft was done in cases. results: postoperative follow up was performed at , , , weeks. patients were evaluated according to the lysholm knee scoring scale, obtaining an average score of points. bone healing was achieved in a period of between to weeks. postoperative complication developed in cases. results were depending on the stability of osteosynthesis, precocity, rightness of functional reeducation and patient compliance. conclusions: favorable functional results and less complication were met in cases of individual approach of surgical management, a good choice of implants and minimally invasive surgical techniques. fractures of the shoulder processes-a case report case history, clinical findings and diagnosis: -year-old male, low-speed motorcycle crash with subsequent polytrauma. he presented with right shoulder pain, swelling and pain to the touch. articular ct revealed a type i fracture of the coracoid base, type iii acromion fracture and scapular body fracture without displacement. results, therapy and progressions: he was submitted to surgical treatment days later. a superior ''sabercut'' approach with open reduction and osteosynthesis of the coracoid process was performed with a cancellous screw and washer and fixation of the acromion with k-wires and tension band wire. fracture of the scapular body followed a conservative treatment. immediate postoperative period was uneventful and he presented with favourable evolution in the subsequent -week, -week and -month follow-up. at present time, at -month follow-up, maintained anatomical reduction in radiological control, complete arm abduction and no limitation with efforts. comments: conservative treatment is generally indicated for all shoulder body fractures without displacement. fractures of the coracoid or acromion with [ cm displacement are described as an indication for surgical treatment. fractures of the acromium without displacement may follow conservative treatment with sling immobilization. surgical fixation can be achieved with screws, plate and screws or tension band wire. although controversial, surgical treatment for coracoid fractures is preferred, especially in active young patients with open reduction and fixation with screws or, if necessary, with plate and screws. the treatment applied in the present case, all approaches described in the literature as being effective and with good results, is in agreement with the options described in the literature and constitutes a corroborative example of its efficient results. case history: a -year-old male, hand worker, attended to our emergency department after a traffic accident complaining about pain and swelling in his left wrist. initial radiographs revealed an isolated dorsal dislocation of the lunate that went unnoticed. two and a half months later he was referred to our clinic. clinical findings: findings included dorsal wrist deformity and pain. he presented a decreased passive wrist flexion and extension range of motion, with normal finger tendinous function. investigation/results: plain x-rays showed persistence of the lunate dorsal dislocation without any associated injuries. diagnosis: chronic isolated dorsal dislocation of the lunate therapy and progressions: open reduction was performed using a dorsal approach. the scapholunate, lunotriquetal and scaphocapitate spaces were stabilized with a compression screw and kirschner wires respectively. the patient persisted with pain and functional limitation after the surgery, showing an insufficient reduction of the scapholunate space on the x-ray. nine months after the initial surgery, he developed a purulent fistula on the ulnar edge of the carpus. after it was resolved, a total wrist arthrodesis was performed using the mannerfelt technique. at the months follow up, he was clinically stable, consolidation of the arthrodesis was documented and he had returned to his previous normal activities. comments: isolated dorsal dislocation of the lunate is a rare lesion. the delay in the diagnosis of carpal dislocations is frequent. this compromises the final outcome of reconstructive techniques and the risk of residual instability, hence increasing the risk of chronic pain associated with posttraumatic osteoarthritis. in the case of chronic lesions, treatment with palliative techniques such as proximal carpectomy or joint arthrodesis should be taken into consideration. references: siddiqui n., sarkar s. isolated dorsal dislocation of the lunate. open orthop j. ; : - is ultrasound-guided regional anesthesia safer than landmark technique? one-hospital experience introduction: according to the literature the application of ultrasound (us) in performing regional anesthesia had a significant impact on patient safety by increasing the success rate [ ] . in a donated ultrasound device became available in the institute of emergency medicine, chisinau, republic of moldova. due to lack of equipment both us guided and landmark techniques have been performed. the aim of this study was to analyze the two methods of performing regional anesthesia, in order to estimate the potentials benefits of of us guided techniques (succes rate and doses). results: the bivariate analysis showed that, out of anesthetics in lmg, a number of were reported as unsuccessful, compared with a number of in usg. the v test with corrections for continuity did not determine significance (test value . , df = , p = . , effect size = . ), rr being . ( % ci . - . ). linear regression for dose (lidocaine) modeling, in patients included in the research, showed a decrease of the dose by mg in lmg, the confidence interval being quite wide ( % ci -. , -. ). that is, the actual decrease is within the limits of and mg. conclusions: the tendency towards higher failure rate in successfully performing an us guided regional anesthesia and relative ''uncertain'' decreasing of dosage are in contradiction with the international statistical data. this in turn evidenced probable deficiencies in the training of the practitioners in field of ultrasound guided techniques in our country. the prospective research to confirme/infirme these results and estimate the complication rate follows. references: . barrington mj, uda y. did ultrasound fulfill the promise of safety in regional anesthesia? current opinion in anaesthesiology ; ( ) results: average age years old ( - ).all were active labour patient. the most frequent mechanism was high energy trauma (traffic accident), of who presented gustilo grade iiib open fractures operated in the country of origin. most frequent pattern of fracture was -c. ( cases) and -c. ( cases). initial conservative treatment was performed in of the cases. one persistent pseudoartrhosis with osteosynthesis material failure. in every case, preoperative ct and early surgical intervention were carried. in cases, an additional procedure was associated at the radioulnar distal joint. in all cases consolidation occurred. one patient required reintervention for persistent pseudoarthrosis. average consolidation time months ( ) ( ) ( ) ( ) ( ) ( ) ( ) .average follow-up of months ( - ). average active joint balance: flexion °( °- °), extension °( °- °), pronation °( °- °), supination °( °- °). average dash . ( - . ).force reduction greater than % compared to contralateral in of the cases. radiological parameters:radial height . mm ( - ),radial inclination °( - °),volar angulation . °( . °- °), ulnar variance . mm ( ) ( ) ( ) ( ) ( ) . conclusions: malunion of the distal radius is an uncommon and severe complication with increasing incidence that requires early and personalized surgical treatment to achieve the correction of the deformity, preserving mobility acquiring consolidation with acceptable functional results case history: isolated ulnar translocation of the carpus is unusual. when the translation occurs without injury of the radius, ulna or carpal bones are often misdiagnosed. early diagnosis is key, to avoid further complications such as redislocation of the carpus ( ). clinical findings: in our case a young male patient suffered a high energy motorcycle accident. he had no a b c d problem investigation/results: the ulnar translation of the left carpus was evident but comparison x-rays were taken on both wrist for further evaluation. the distance between the line, drawn through the axis of the radius and the center of the capitate bone was measured bilaterally. the results were . mm vs . mm. diagnosis: isolated, open ulnar translocation of the radiocarpal joint, dumontier type i, was diagnosed. treatment: the primary treatment was debridement, reposition and fixation with ex fix. after the wound healing on th days we made reconstruction. volar approach was used, we re-reponate the carpus and fixated the position with two mm smooth kirschner wires. the radioscaphocapitate and long radiolunate and radioscaphoid ligaments were reattached to the volar margins of radius using mitek mini anchors. we put the ex fix and left the bended wires percutaneously. after weeks the ex fix and the k wires were remove. wrist motion exercises were initiated under supervision of physiotherapist. comments: after weeks the wrist was in good alignment, the flexion-extension were - , the deviations were - °. the radiographic signs of this injury are unusual and often misdiagnosed. it can be useful to compare with contralateral x-rays. the radiolunate and radioscaphocapitate ligaments is considered crucial in prevention of ulnar translation. in our opinion the radiolunate arthrodesis can be reserved for failed ligament repairs. introduction: within the orthopaedic paediatric population, there is a distinct paucity of literature in regard to post-operative paediatric analgesic regimes. supracondylar humeral fractures account for % of all paediatric limb fractures and there has been a marked divergence in recent literature concerning the most appropriate choice of analgesia for this cohort with recent studies recommending the routine inclusion of an opioid agent post-operatively on prescription. opioids have deleterious side effects pertinent to paediatrics. in our institution, patients'' only receive a prescription for acetaminophen and nsaids upon discharge. our study assessed postoperative analgesic satisfaction rates in all paediatric patients who underwent crpp for supracondylar humeral fractures in our institution from january to december . material and methods: this is a retrospective multi-surgeon case series of all paediatric patients who underwent crpp from january to december . patient data was extrapolated from theatre records and clinical charts. for each patient, all analgesic agents given were identified, the dosage, route and frequency of administration in addition to the length of their hospital stay and time from injury to operation. following discharge, patients'' guardians were contacted retrospectively and a questionnaire was administered which ascertained the efficacy and duration of analgesia used by the patient postoperatively. results: fifty patients were identified for inclusion within the study who met the inclusion and exclusion criteria. there was a % satisfaction rating amongst the responders with the analgesic regime recommended-acetaminophen & nsaids. conclusions: in stark contrast to papers which we discuss throughout our paper, our study conclusively demonstrates that opioid prescriptions are not required upon discharge for supracondylar fractures within a paediatric population case history: a -year old man suffered an isolated injury of his right hand in a motorcycle accident. clinical findings: the patient presented with a swollen hand, a subtotal amputation of the middle finger at the level of the middle phalanx and lacerations to the other fingers (fig. ) . investigation/results: after excluding injuries to other body regions, radiographs and a ct of the hand were performed (fig. ) . diagnosis: closed fracture dislocation of cmc joints from ii. to v. finger, comminuted fracture of the middle phalanx of the middle finger, closed fracture of the proximal phalanx of the middle finger, other lacerations to the iv. and the v. finger. therapy and progressions: urgent open reduction and internal fixation (orif) with k wires of the cmc joints. exploration of the middle finger reviled heavy contamination and comminution of the phalanx, with injury to one neurovascular bundle. a phalangectomy with acute finger shortening was performed with creation of a new ip articulation (distal to proximal phalanx) (fig. , ) . progression after the surgery was uneventful. there was no sign of infection. the shortened finger was sufficiently perfused and the patient reported a sense of touch. k wires were removed after weeks and physical therapy was started. the patient has limited rom in his neo ip joint with minimal pain (vas - ) (fig. ) . comments: middle phalangectomy of the hand was described in the literature only in two papers which report treatment of chronical or congenital diseases. the authors propose this method as an alternative to amputation in selected trauma cases. results: patients ( m, f, mean age y) with fractures were included. kidney-tpl, lung-tpl, liver-tpl, heart-tpl, kidney/pancreas-tpl. all patients got treated with at least two immunosuppressive drugs. cause of accident: . % sports/leisure, % work/household, . % traffic accidents, % without trauma. the operation was performed under perioperative long-term antibiosis, often with a combination of two or three drugs. patients were hospitalized for an average duration of . days and were also examined by the particular organ specialists. osteosynthesis: in % primary operative fracture treatment, in % two-step procedure. plates distal radius and ulna [healing period (h) conclusions: the fracture healing was possible but significantly delayed. the wound healing took longer. the immunosuppressive therapy may be responsible for these problems. the rehabilitation of movement and weight bearing has to be adapted to the slowed fracture healing. introduction: the prevalence of fragility fractures of the pelvis (ffp) increases, including in up to % a lesion of the posterior pelvic ring. an operative therapy is indicated in cases of prolonged or immobilizing pain or in a displaced dorsal fracture. methods: patients suffering an ffp treated with a minimal-invasive trans-sacral bar through s from to were included. the patients or their relatives were contacted to ask about mortality, the present mobility and place of residence. % of all patients still alive could be included in follow-up. results: females and males with a mean age of . ± . years ( - ) were included. concomitant stabilization of the anterior pelvic ring was performed in %. . % underwent an operative revision ( % evacuation of hematoma, % peri-implant infection, % hardware removal-combinations possible). the trans-sacral bar was removed in one case due to malpositioning. the length of stay was ± days. at discharge, % were mobile on the ward, % in their room, % for transfer to sitting position and % were bedridden. % were discharged to their home, % in geriatric rehabilitation unit, the remaining to other rehabilitation or to a nursing home. during follow-up, mortality was %, one patient died during hospital stay. the patients died in average ± weeks after discharge. after a follow-up of ± weeks, % lived at their home, thereof one-third with assistance. % needed a walking aid, % were mobile without walking aid, % were bedridden or only mobile to sitting position. conclusion: the trans-sacral bar in s is a valuable minimal-invasive stabilization method to recover mobility in elderly with an ffp. a relatively long in-hospital stay could be explained by the initial trial of conservative treatment and due to intra-and inter-departmental cogeriatric services. the high mortality and need for assistance reflects this geriatric, multi-morbid patient collective. case history: a -years-old woman was admitted in the emergency room after being run over by a bus. clinical findings: at the emergency room, she was conscient and hemodynamic stable. head, thoracic or abdominal trauma were excluded. the patient presented with an open wound in left popliteal area with massive bleeding with exposure of gastrocnemius and soleus muscles and achilles tendon investigation: radiologic images didn't show any fracture. a limb angiography showed complete perfusion of the leg, without any lesion on major arteries. diagnosis: open aquilles tendon avulsion through the popliteal fossa therapy and progressions: the patient was taken to the operating room. we approach the popliteal area and found a small laceration of popliteal vein, which was sutured with prolene / . then, we reference the achilles tendon, and tunneled the posterior face of the leg, and passed the tendon through the tunnel. a distal approach, above the insertion of achilles tendon was done, and two suture anchors preloaded with sutures were inserted in the medial and lateral sides of the calcaneal tuberosity, then we did an krackow suture. we also did a fasciectomy on the lateral side of the leg, to prevent compartmental syndrome. the patient was put in a posterior cast with of flexion for weeks. the immediate post-operative time was in an intermedia unit care, to control possible multiorgan failure. in days, she was discharged to orthopedics nursery. due to the degloving of subcutaneous tissue, she evolved with some blisters which made her stay inpatient about weeks. after some time, she developed some areas of skin necrosis, which needed some intervention by plastic surgery with skin graft. now, she has skin completely healed, some loss of strength in the leg, with loss of plantarflexion, and is under prolonged rehabilitation program. therapy and progressions: she was rushed into the or and submitted to external fixation of the humerus and bones of the forearm, debridement, and primary closure of the forearm and hand. successive dressings and debridement was maintained and, at th postoperatory day(po) the external fixator of the left humerus was removed and a nailing was performed as well as an osteosynthesis of the clavicle fracture with anatomical plate. at thpo the external fixator of the forearm bones was removed and an open reduction and internal fixation of the radius with lcp plate and closed reduction and internal fixation of the ulna with an anterograde ten nail was performed. at thpo, she underwent an autologous skin graft of the forearm and hand wounds. good clinical evolution of the wounds and fractures, all of which evolved to consolidation, although m fracture malunion was verified as well as deficit of thumb abduction and extension of rd- th fingers. uefi of / . comments: the approach of polytrauma patients should be sequential, according to the atls protocol, preserving life, limb and function. treatment of these lesions is complex and, if poorly managed, can be associated with high morbidity, as most patients combine severe and contaminated lesions, extensive skin loss, open fractures, postoperative infection. a sequential approach is required, which involves injury assessment, infection prevention, soft tissue treatment and fracture stabilization. introduction: pelvic fractures, though rare ( - %), are often associated with high mortality ( - %). the factual outcomes in polytrauma patients with the additional burden of pelvic fractures are unknown. the purpose of this study is to provide an in-depth analysis of pelvic fractures in seriously injured patients. material and methods: this is a retrospective analysis of prospectively maintained trauma registry from to . we included all trauma patients with iss c . group i, which had an additional burden of pelvic fractures, was compared with group ii, consisted of patients without pelvic fractures. a double-adjustment propensity score match (psm) analysis was utilized to minimize confounding and unbiased estimation of the impact of pelvic fractures. . ± . , asmd = . ).patients in group i had higher number of genitourinary surgery (p = . ), exploratory laparotomy (p = . ). therequirement of angio-embolization was similar in between two groups (p = . ). while there were no difference in mortality (or . , % ci . - . , p = . ), group i had higher odds of severe sepsis (or . % ci . - . , p = . ) and ventilator-associated pneumonia (or . , % ci . - . , p = . ) conclusions: pelvic fractures in polytrauma patients did not translate into higher mortality. however, there was an increased risk of sepsis and vap. evidence-based management at tertiary care specialized centers can further enhance the outcomes. investigation/results: ap pelvis x-ray reveals a complex left proximal femur fracture with neck and trochanteric extension. a ct-scan was obtained and showed a complex fracture pattern with subcapital and trochanteric extension. blood analysis showed a hemoglobin of . g/dl. diagnosis: therapy and progressions: at admission, patient refused erythrocytes'' concentrate transfusion and was hospitalized for pain control and hemodynamic stabilization. despite alternative measures such as intravenous iron supplementation and erythropoietin, hemoglobin values remained lower than . g/dl, thus preventing any surgical procedure. at day , patient finally decided to accept packed red blood cells and was then transfused. at day and with a hemoglobin of . g/dl, the patient was finally submitted to a total hip arthroplasty with an uncemented revision femoral stem. at day , the patient initiated the rehabilitation protocol with hospital discharge at day with a hemoglobin of . g/dl. comments: proximal femur fractures arise as one of the major problems of present traumatology. comorbidities frequently prevent surgical treatment within the golden hour (first h) and thus limiting the postoperative results. in this particular case, a timely surgical approach would have made it possible to try a more conservative procedure with femoral osteosynthesis. the surgical delayed due to low hemoglobin values limited the surgical options and forced a more aggressive procedure. routine versus on demand removal of the syndesmotic screw; a multicenter randomized controlled trial on functional outcome introduction: syndesmotic injuries are common, being present in approximately - % of surgically treated ankle fractures . one of the most commonly used ways of fixation is the syndesmotic screw (ss). traditionally, this screw is removed after - weeks as it is thought to hamper ankle function and cause pain. however, a recent study showed that implant removal does not always result in improvement of functional outcome . with the relatively high complication rate of implant removal in mind, retaining sss could be beneficial. we therefore aimed to investigate the effect of retaining the ss on functional outcome. material and methods: in this multicenter rct, patients were randomized between routine and on demand removal (upon patients request). the primary outcome was functional outcome at months after ss placement, measured by the olerud-molander score (omas) with a non-inferiority limit of points ( % power, a = . ). secondary outcomes include quality of life, range of motion, complications and costs of ss removal. results: a total of patients were randomized, of which for routine removal and for on demand removal. the mean age was years old and % was male. follow up of all participants will be completed in march . results of the primary outcome analysis are therefore not yet available, but will be at the conference. conclusions: if on demand removal of the ss is non-inferior to routine removal in terms of functional outcome, this will offer a strong argument to adopt this as standard practice of care. this means that patients will not have to undergo a secondary procedure, resulting in fewer complications and subsequent lower costs. introduction: treatment options for pertrochanteric fractures of the hip are extra-or intramedullary fixation. the aim of this study is to identify risk factors for the development of complications: varus deformity, neck shortening, revision and cut-out. material and methods: retrospective cohort study in which radiographs of patients with pertrochanteric fractures, treated at the uz brussel between and , were reviewed. fracture type, type of the device, cut-out and revision where noted. measurements for the centrum-collum-diaphyseal angle (ccd) of the two hips, impaction, tip apex distance (tad), parker''s ratio were realized. statistical analyzes were made with logistic and multiple linear regression analyzes. results: patients were included. bmi (p = , ), type of osteosynthesis (p = , ), dhs ? plate (p = , ), short nail (p = , ) and the tad (p = , ) are independent risk factors for the development of varus deformity after consolidation. for impaction are bmi (p = , ), short nail (p = , ), long nail (p = , ) and fracture type a (p = , ) independent risk factors. we identified a marginal statistical significant risk factor for cut-out: tad (p = , ). conclusions: , % of the patients had varus deformity after consolidation. the risk of varus deformity rises with a higher bmi and a higher tad. the risk for this complication was higher when using a nail. neck impaction was shown more together with a high bmi and less in fracture type a and with the use of a short or long nail. in the prevention of cut-out, it is important to keep the tad low. case history: -year old female with previous distal femoral plating ( years ago) and ipsilateral proximal femoral nailing ( months ago) presented with a diaphyseal femur fracture. clinical findings: extremity was swollen, painful, neurocirculatory intact, no shortening or external rotation was seen. she was unable to lift her leg. scars showed no sign of infection. investigation: x-ray revealed a spiral fracture including distal pfna locking screw, unhealed proximal femur fracture without loss of reduction, protruding pfna blade and a healed distal femoral fracture. diagnosis: peri-implant fracture classification proposed by the singapore group presented a discrepancy between nail type subtype b and plate type subtype. by simplification, we disregarded the distal (healed) fracture to choose the first option. therapy: firstly, the distal femoral plate was removed as the preoperative simplification dictated. secondly, pfna distal locking screw was removed and the pfna blade shortened. after open reduction cerclage wires were applied. a long lcp plate was initially fixed through the plate and pfna locking hole, adjusted in line, fixed proximally with screws through a locking attachment plate and cerclage, distally locking screws were used. comments: distal femoral callus prevented the use of a long nail. as the proximal fracture was not yet healed, we avoided full implant removal. as the pfna was unstable, fixation through the plate and pfna distal locking hole enabled implant coupling to strengthen the construct. the plate covered the entire bone to bridge the possible loci minori left by the plate removal and minimize stress risers. background: we have been reported the usefulness of intra-medullary antibiotics perfusion (imap) and intra-soft tissue antibiotics perfusion (isap) for suppressing open fracture and bone infection. imap and isap was a method of antibiotics delivery with the continuous administration of high-dose aminoglycosides. however, the best dose was not obviously. the purpose of this study was to evaluate translation of aminoglycosides from imap or isap. as follows: males and females, average age was . years old, intramedullary nails and plates. one dialysis patient was including. we measured concentration of gentamicin from imap, isap and in blood, outflow. results: average administration concentration of all cases was . lg/ml. average blood concentration of all cases was lg/ml and outflow concentration were . lg/ml. average blood and outflow concentration of each dosage were shown as follows: lg/ ml: . lg/ml, lg/ml, lg/ml: . lg/ml, . lg/ml, lg/ml: . lg/ml, lg/ml, lg/ml: . lg/ml, . lg/ml. in dialysis patient case, lg/ml administration lead concentration of blood as . lg/ml, outflow as lg/ml. side effect were not observed. discussion: local antibiotic administration using imap and isap showed increasing blood concentration depend on administration dose. under lg/ml administration dose showed safe blood concentration(\ lg/ml). on the other hand, lg/ml administration dose achieve trough concentrations over - times of minimum inhibitory concentration. furthermore, we need to pay attention for administration dose in dialysis patient case. conclusion: lg/ml administration dose achieved safe and effective local concentration. introduction: distal radius fractures and supracondylar humerus fractures are two of the most common fractures seen in children. most can be treated with non-operative treatment but a small number require operative reduction and surgical stabilisation, often with percutaneous kirschner wires. this study aims to identify whether an early review is required before planned removal of the wires. materials and methods: retrospective review of paediatric patients undergoing surgical reduction and stabilisation with percutaneous kirschner wires for upper limb injuries. data collected over threemonth period (june-august ). number and type of outpatient reviews, imaging episodes and clinical interventions recorded. results: consecutive patients with mean age years (range - ). distal radius fractures and supracondylar humerus fractures. patients transferred to another unit. / patients received a week check and then a second review where the wires were removed. mean time to first outpatient review . days (sd . ). at initial appointment all patients had a change of cast and a satisfactory radiograph. mean time to second outpatient review was . days (sd . ). at the second appointment / patients had the wires and cast removed and subsequent satisfactory radiograph. / required a further period of casting. / had a third appointment. / required formal physiotherapy after cast removal. there was one transient anterior interosseous nerve palsy after supracondylar fracture stabilisation. clinical union of the fracture and good functional outcome was seen in all cases. conclusion: the initial outpatient review at - weeks allows a lighter weight cast to be applied but in this series the radiograph taken after the cast was changed did not alter management. our findings support a cast change alone at weeks and then clinician review with radiographs at the time of wire removal. introduction: the aim of this study was to describe surgical technique, report on patient-based functional outcomes and complications following open reduction and internal fixation in patients with scapular fractures. methods: the study comprised patients who were treated with open reduction and internal fixation (orif) of a scapular fractures between september and july . surgical indications were as follows: medial/lateral displacement greater than mm; shortening greater than mm; angular deformity greater than °; intraarticular step-off greater than mm and double shoulder suspensory injuries (including fracture of clavicle, coracoid or acromion with displacement greater than mm). all patients underwent x-ray examination (true ap, y scapular view) and computed tomography (ct) scans. fractures were classified according to the revised (ao/ota) classification system. functional outcome were measured using the constant-murley score. results: seven patients had glenoid fossa fracture, six patients had scapular body fracture and one patient had acromion process fracture. all glenoid fossa and scapular body fractures were exposed via the judet approach. eleven of patients were reviewed with constant-murley score at the final follow-up examination, three patients were lost for follow-up. the mean follow-up after injury was months ( - months). we found in four patients infraspinatus muscle hypotrophy. mean constant-murley score was . (± . ) for injured arm and . (± . ) for uninjured arm. mean score between injured and uninjured arm was . (± . ) which is excellent functional outcome according to grading the constant-murley score. conclusions: open reduction and internal fixation of displaced scapular fractures is a safe and effective treatment option that results in reliable union rate and good to excellent functional outcome. introduction: the aim of this study was to evaluate clinical and radiological results of intramedullary radius and ulna nails in treatment of adult forearm fractures. methods: the retrospective study included patients who were treated with intramedullary nailing of forearm fractures between january and september . the medical records and radiographic images of all patients, taken preoperatively and postoperatively, were reviewed. fractures were classified according to the ao/ota classification system by reviewing the radiographs. we analayzed time to union, union rate, clinical outcome and complications. results: primary intramedullary osteosynthesis were performed in patients with forearm diaphyseal fractures. the average time to union was months (range, - months) in primary osteosynthesis cohort. secondary intramedullary osteosynthesis were performed in four patients following removal of plates and screws due to pseudoarthrosis. the average time to union was months (range, - months) in secondary osteosynthesis cohort. overall union rate was , % in forearms with fractures or pseudoarthrosis of the radius, ulna, or both bones, which were treated with intramedullary nail with compression screw. overall complications were one nonunion, one postoperative rupture of the extensor pollicis longus tendon and one postoperative transitory radial nerve palsy. conclusions: intramedullary nailing of adult forearm fractures is a safe and effective treatment option that results in reliable union rate and good to excellent clinical outcome. key words: forearm fractures, intramedullary nailing, biological fixation, union rate results: transverse or short oblique fractures of the middle third of the humeral shaft were treated using a retrograde approach. spiral fractures of the middle third of the humeral shaft were treated through the antegrade approach. comminuted fractures of the proximal third of the humeral shaft were treated mostly through the antegrade approach. comminuted fractures of the distal third of the humeral shaft were usually treated using the retrograde approach. whenever possible, we prefer retrograde insertion because the approach through the shoulder joint is avoided. reduction with retrograde nailingnis easier because upper arm was placed on the radiolucent operating table extension. interlocking screw insertion by freehand techique is also easier to perform because there is no danger of radial nerve injury. nonunion was found in eight patients ( , %). there were five patients ( , %) with postoperative transitory radial nerve palsy that fully recovered within months. conclusions: the choice of approach to the medullary canal depends on the fracture type and the fracture site. therefore, antegrade nailing should be performed for proximal third humeral shaft fractures and complex middle third humeral shaft fractures, while retrograde nailing should be perforemd for distal third humeral shaft fractures and simple transvese or short oblique middle third humeral shaft fractures. keywords: humeral shaft fractures, intramedullary nailing, radial nerve palsy, nonunion the diaphyseal aseptic tibial nonunions after failed previous treatment options managed with the reamed intramedullary locking nail i. kostic , m. m. mitkovic clinical center nis, university hospital, orthopaedics and traumatology, nis, serbia, university of nis, serbia, orthopaedics and traumatology, nis, serbia introduction: in this article, we present our approach to the surgical treatment of noninfected tibial shaft nonunions. material and methods: between and , patients with aseptic diaphyseal tibial nonunion was treated by reamed intramedullary nailing and were retrospectively reviewed. all patients, preoperatively, were evaluated for the signs of the infection, by the same protocol. results: the time that elapsed from injury to intramedullary nailing ranged from to months (mean months).open intramedullary nailing was unavoidable in cases ( , %), while closed nailing was performed in patients ( , %). all patients were followed up in average period of years postoperative (range - years), and ( , %) patients achieved a solid union within the first months. conclusions: in conclusion, a reamed intramedullary nail provides optimal conditions for stable fixation, good rotational control, adequate alignment, early weight-bearing and a high union rate of tibial non-unions. percutaneous figure of suture as a novel technique for treating closed tendinous mallet injuries following failed splinting therapy. t. eltantawy , a. yousif , k. maheshwari , a. hartpinto bedford hospital, plastic surgery, bedford, united kingdom introduction: mallet injuries are common injuries affecting the hand. majority of them are managed using conservative method, however a small percentage of patients that do not do well on conservative treatment need an operative intervention. we wish to evaluate the efficacy of percutaneous figure of suture as a new technique for treating closed tendinous mallet injuries resistant to splinting therapy, as a minimally invasive treatment option. material and methods: we present a case series of patients who had persistence of more than degree extensor lag, despite splinting minimally for weeks. all of these were treated with a percutaneous figure of suture placed across the dorsum of dipj, which provided splinting for further weeks. this technique provides fixation for the dipj in hyperextension position by going through the periosteum on both sides and was done under local anaesthesia. results: the mean age of our patients was years, with a single digit involved in all patients. all the five cases had nearly fully straight dipj with less than °extensor lag following weeks of percutaneous stitch placement. there was no further recurrence with mobilisation or overlying skin necrosis. conclusions: percutaneous figure of suturing technique can be an effective, minimally invasive and safe technique to treat closed tendinous mallet injuries not responding well for conservative splinting. introduction: osteosynthesis of pertrochanteric fractures (pf) is a frequently performed procedure in orthopaedic trauma care. dynamization of the osteosynthesis during fracture healing can lead to dynamization of the lag screw. which can cause debilitating complaints. a spontaneous femoral neck fracture (sfnf) after implant removal was seen in patients over a month period. based on these cases we evaluate the different aspects of the pathophysiological and mechanical mechanisms of lag screw dynamization, complaints and complications in pf healing. material and methods: pubmed search on incidence of chronic pain, gait impairment associated with dynamization of osteosynthesis, risk factors for dynamization and complications after implant removal. based on research data preventive recommendations are suggested. results: literature describes complaints as reduced mobility, gait impairment and chronic pain in association with lag screw dynamization. an important risk factor is the ao-classification of pf, a type fractures are significantly associated with more dynamization and the onset of trochanteric pain and gait disturbances. partial implant removal can reduce complaints in the majority of symptomatic patients, and induce symptoms in % of asymptomatic patients. literature study shows a sfnf after lag screw removal with an incidence of %, affecting mostly vulnerable elderly patient resulting in a high mortality rate. risk factors associated with an increased risk of this complication are pre-existing systemic osteoporosis, stress-shielding, pre-loading of the implant. most importantly the removal itself, a sfnf with the implant in situ is very uncommon. conclusions: the clinical indications for implant removal in healed pf are not well established, and should be restricted to specific cases. after removal, partial weight bearing and good patient counselling is extremely important. replacement with shorter lag screw should be considered. metal osteosynthesis of pathological bone fractures with metastatic lesion of plates with a spray on their surface of hydroxyapatite and % silver v. protsenko , a. abudayeh , v. chornyi , y. solonitsyn institute of traumatology and orthopedics of nams of ukraine, onco-orthopedics, kiev, ukraine, bogomolets national medical university, kiev, ukraine introduction: surgical intervention in the case of pathological bone fracture against the background of metastatic lesion involves performing osteosynthesis. for more effective integration of the metal plate with the bone, a material based on bioactive glass was sprayed on their surface. bioactive glass-based material is an osteoinductive and osteoconductive biomaterial that integrates quickly with bone, forms a bone-ceramic complex, and is transformed into bone over time. material and methods: metal osteosynthesis of pathological bone fractures with metastatic lesion of plates with spraying on their surface of hydroxyapatite and % silver was performed in patients. the functional result of the operated limb was calculated on the msts scale. evaluation of pain was performed on the scale of r.g. watkins. the quality of life of patients was evaluated using the eortc qlq-c system. the evaluation of the integration of the plate with the bone was performed by radiological examination and by osteoscintigraphy. results: postoperative complications were found in ( , %) patient, recurrence of metastatic tumor was noted in ( , %) patients. the functional result of the operated limb after metal osteosynthesis was , %. the degree of pain decreased from , % to , %. the quality of life of patients after metal osteosynthesis improved from to points. x-ray examination revealed the formation of callus within a shorter timeframe, as evidenced by the more intense accumulation of radioisotope during osteoscintigraphy. introduction:the aim of this study was to evaluate the results in patients who had heal intertrochanteric fracture but did not receive adequate mobilization and rehabilitation support. material and methods:sixty patients over years old age were included in our study. the rehabilitation emphasized pain relief, muscle strength, range of motion, endurance, balance challenges, and proprioceptive enhancement for all patients. it started postoperative first day and was delivered twice a day by the physical therapist until discharge. patients were discharged on average . days ( - days) after surgery. the mobilization of patients was evaluated with the parker and palmer mobility scoring system, the clinical evaluation was performed with the haris hip scoring and daily living activities were evaluated with the barthel life index before and at the end of the fracture. results: female male patients were included in our study. the mean age was , ( - ) years and the mean follow-up period was , ( - ) months. patients had a type, patients had a type intertrochanteric femur fracture. in the last follow-up, all patients had fracture union. patients' mobility, daily life activity and clinical evaluations were found to be statistically significantly worse in the last control than before surgery. conclusions:the success of the surgical treatment and the union of the fracture after fixation are not sufficient for the successful mobility,daily life activity,and clinical results.the success in the functional results are significantly related with the ambulatory ability.although early mobilization and rehabilitation support are important in intertrochanteric femur fractures after surgery,the continuity of mabilization and rehabilitation support after hospital discharge is more important.the rehabilitation which administered by the patient''s ralations after hospital discharge is not sufficient.therefore,the importance of home-based rehabilitation is increased. the prognostic value of the hip screw position in trochanteric fractures i. gárgyán , î csonka , t. ecseri university of szeged, department of traumatology, szeged, hungary introduction: in our study, we analyzed one of the hungarian population's most frequent injuries, the hip fracture, focusing mainly on the lateral femoral neck and the pertrochanteric fractures. according to the classification of the swiss association for ostheosynthesis (ao), we focused on -a and -a fractures, the incidence of which increases by ageing. material and methods: between and , we analyzed the data of patients. all of the fractures were stabilized with intramedullary nails. patients received stryker gamma Ò , whereas patients' fractures were solved with synthesis pfna Ò nail. in all cases, closed reduction method was used with fluoroscopy on an extension table. the surgeries were done in general or epidural anesthesia and performed by traumatology residents or specialists using standard lateral exploration. data were collected using gepacs software and statistical analysis was done with ms excel. results: cut-out occurred in cases ( , %): out of that ( . %) were left sided and were ( , %) right sided. ( . %) patients were treated with gamma nail, and in ( , %) cases pfna nail was used. the average tad-index was mm. conclusions: according to recommendations of the tad-index value, when using dynamic hip screw, it should be mm or lower. the average index value was mm which was equal in the complicated and non-complicated groups. our study shows that the cutout is independent from the tad-index value, thus this recommendation cannot be applied for intramedullary nails. oita university hospital, acute trauma, emergency, and critical care center, yufu, japan, oita university, orthopaedic surgery, yufu-city, oita, japan introduction: dome impaction fragments (difs) in acetabular fractures are typically accompanied with anterior column fragments and recognized as the gull sign on plain radiographs. meanwhile there are some difs which do not fit into typical difs. the aims of this study were to define atypical dif and describe tips for diagnosis and intraoperative visualization. material and methods: this study was a retrospective case review. we defined atypical difs as the fragments which were independent of anterior column fragments and did not show the gull sign on plain radiographs. from jan to july , there were patients of acetabular fractures, and patients ( . %) had difs. among them, patients ( . %) were identified as the cases with atypical difs. all of them were male. the ages were from to . results: the atypical difs were not obvious on x-rays (fig. ) . all three atypical difs were located at posteromedial weight bearing zones of the acetabulum. case and were displaced in accordance with posterior column fragments, and were visualized clearly on the sagittal view of ct images (fig. ) . case was impacted posteriorly into a posterior part of the ilium as a free fragment, and well visualized on ct sagittal and coronal views. anterior intrapelvic approach was chosen in all patients to treat atypical difs. the iliac oblique view was useful to visualize the atypical difs intraoperatively in case and . in both cases, the reverse gull sign appeared after reduction of posterior column fragments (fig. ) . in case , the inlet view was useful to visualized the atypical dif intraoperatively.the fragments were reduced and fixed with supra-acetabular screws (fig. ) . results: we found prospective two to years after acetabular osteosynthesis , % complications. avn of the femoral head was present in , % of the hips reduced within h and , % of the hips reduced more than h after the injury [p = , ; = , ; or = ( % ci = , - , ) ]. post-traumatic oa of the hip we found in , % (fig. ) infections we found in , % ( deep, superficial), iatrogenic nerve palsy in ( , %), traumatic nerve palsy in , % ( ), dvt in , % ( ) , and ho in , % ( ) cases. in one case ( , %) revision surgery was done. conclusions: acetabular fractures are followed with complications. some complications depend on surgery, meanwhile others cannot be affected on (type of fracture, impaction of acetabulum, injury of the femoral head, dislocation of femoral head). good knowledge of acetabular anatomy, surgical technique, experienced surgical team, early surgery, anatomical reduction and stable orif, early mobilization, can significantly influence excellent/good functional outcomes and reduce possibility for complications. introduction: reduction is one of the important factors in surgical treatment of femoral trochanteric fractures. in this study, postoperative reduction status was examined and the relationship between this reduction status and unsatisfactory cases was investigated. material and methods: cases of femoral trochanteric fractures over years treated with pfna-ii were investigated. postoperative reduction status was evaluated in ap and lateral view of x-ray and ct. anatomical reduction means medial or anterior cortex is reduced anatomically (abbreviation am and aa). intramedullary reduction means medial or anterior cortex of proximal fragment is inside the shaft (im, ia). extramedullary reduction is medial or anterior cortex of proximal fragment is overlapped to cortex of shaft (em, ea). unsatisfactory cases were ununited cases until months and excessive sliding cases over mm. reduction status of these cases was evaluated. results: postoperative status was classified with combination of medial and anterior reduction status. so there are nine groups and number of each group are as follows; im-ia: case, im-aa: cases, im-ea: case, am-ia: cases, am-aa: case, am-ea: cases, em-ia: cases, em-aa: cases, em-ea: cases. non-united cases until months were cases. reduction status of non-united cases were; im-ia: cases, im-ea: cases, am-ia: cases, am-aa: cases, em-ia: cases, em-aa: cases. there was no case in extramedullary reduction of anterior cortex. excessive sliding of blade over mm was cases. there was also no case of extramedullary reduction of anterior cortex in these cases ( cases were cut out). conclusions: our results show there are no ununited cases and excessive sliding cases in extramedullary reduction of anterior cortex. this means extramedullary reduction of anterior cortex is important to reduce unsatisfactory results in surgical treatment of femoral trochanteric fractures. male injured open lateral condyle fracture of femur by to be bitten by a pig. after months from initial debridement, i confirmed the size of bone defect was cm( ) cm in depth. the same size of bone was harvested from iliac crest and transplanted in the bone defect area of lateral condyle of the femur. after months from bone transplantation, i confirmed bone union and two . mm diameter osteochondral grafts and . mm diameter osteochondral graft were transplanted for the chondral defect lesion. case ; seventy year old male injured open lateral condyle fracture of femur by traffic accident. after months from first debridement, i confirmed the bone defect (size cm( ) cm in depth) and the same size of bone was harvested from iliac crest and transplanted in the bone defect area. and simultaneously two mm diameter osteochondral grafts were transplanted for the chondral defect lesion. case ; year old male injured open lateral condyle fracture of femur by traffic accident. i confirmed the size of bone defect was cm( ) cm in depth. the same size of bone was harvested from iliac crest and transplanted in the bone defect area of lateral condyle of the femur. after month from bone transplantation, he had undergone autologous chondrocyte implantation. investigation/results: at last follow-up, average flexion angle of knee was degrees. in all cases, lysholm knee scoring scale was good. diagnosis: large traumatic osteochondral defect of the weightbearing articular surface of the knee comments: treatment of large traumatic osteochondral defect of the weight-bearing articular surface of the knee is a difficult condition to treat. combination of bone transplantation and osteochondral autograft transfer or autologous chondrocyte implantation is useful strategy for the injury. references: tegner y., lysholm j., clin orthop relat res., , - , pr treatment of double tension band wiring method with ai wiring system for transcondylar distal humeral fractures m. uchino hakujikai memorial general hospital, orthopaedic surgery, tokyo, japan introduction: as ai wiring system is united the pin with the cable due to compressed sleeve, the pin is never deviated. we review the treatment of transcondylar distal humeral fractures with ai wiring system in geriatric patients. patients and methods: were identified as receiving this surgery. all patients were female and their mean age was years. they were assessed union rate, range of motion for elbow joint, postoperative complication and functional outcome for japanese orthopedic score. results: union rate was %. the mean arch of motion was °at latest follow-up. the complications were detected cases which were temporary ulnar palsy for cases and hardware failure for case. the average of functional outcome was points ( / ). conclusion: tension band wiring of transcondylar distal humeral fractures with ai wiring system provides stable fixation for osteoporotic bone and tiny fragment. introduction: the purpose of this study was a comparative evaluation of the complications related to the treatment of trochanteric fractures using -screw proximal femoral nail (pfn) versus proximal femoral anti-rotational blade nail (pfna). material and methods: a retrospective review was conducted between march and march . the study included patients treated surgically for trochanteric fractures. the mean age was , ± , ( - ) years. patients were treated by pfn ( patients, , %) or by pfna ( patients, , %). implant related complications were the primary objectives. infection and revision surgery were also recorded. results: complications were observed in ( . %) patients in pfn group and ( , %) patients in pfna group (p = . ). screw backout (n = ) and cut-out (n = ) occurred in , % patients treated with pfn. in the pfna group, cut-out occurred in , % (n = ) of cases. infection (n = ) represented , % in pfna patients and , % (n = ) in pfn group. there were no statistically significant differences in both groups considering implant-related complications (p = , ) and infections (p = . ). revision surgery was performed in ( , %) patients. soft tissue problems are more likely in fractures due to high energy impact than low energy type fractures. high energy type present with horizontal fractures of tibia and fibula (i.e. on the same level), whereas in low energy type tibia fractures they present with spiral or oblique fracture patterns often associated with concomitant fractures of the posterior rim of the distal tibia (i.e. volkmann's triangle). posterior malleolus fractures occur regularly but are often missed and seen only on ct scans obtained either for preoperative planning or to verify postoperative rotation. in literature these mostly undisplaced fractures are treated with screw fixation mostly from anterior. but is this really necessary? material and methods: we retrospectively analysed consecutive tibia shaft fractures operatively treated over the past years at our regional hospital analysing the fracture pattern. results: out of patients with tibia shaft fractures patients presented with a posterior rim fracture of the tibia. no routine stabilisation of the volkmann fragment was performed, in all cases the posterior rim fragments healed uneventful. angles of °and above seem to present themselves with a concomitant fracture of the posterior malleolus. they are mostly undisplaced and the trauma mechanisms is low energy and torsion. none out of the patients had known osteoporosis. conclusions: low energy and torsion-type tibia fractures with an angle of [ °seem to have an accompanying undisplaced fracture of the posterior malleolus. these fractures are usually undisplaced and do not need to be addressed. as a consequence there seems to be no need to actively rule them out with ct scans prior to surgery. concomitant ankle fractures including posterior rim fractures should be addressed like isolated ankle fractures. the dangers of bouncing: a prospecive cohort study of injuries associated with trampolines and bouncy castles over a month period in a paediatric population. introduction: within the orthopaedic paediatric population, there is an increasing incidence of presentation of fractures associated with both trampolines & bouncy castles. whilst this phenomenon has been depicted frequently within the media in recent years given the dramatic upsurge in trampoline and bouncy castle usage, there have been few studies documenting either the incidence of fractures associated with either. materials and methods: this was a prospective cohort study conducted within our institution over a month period june to august inclusive . all paediatric patients who sustain a fracture and present to the national childrens'' hospital are referred to the orthopaedic department either whilst as an inpatient or as an outpatient depending on the assessment of the severity of injury. a standardised mixed questionnaire was given to all parents''/guardians which recorded the type of injury, type of trampoline/bouncy castle, inherent awareness of safety precautions governing the usage of either and application of same was recorded. the type of fracture was corroborated via examination of x-ray in addition to the recording of any complications via examination of clinical chart records. results: there were patients who sustained a fracture directly related to the usage of either a trampoline or bouncy castle for which the majority required operative intervention. there was wide variability in the nature of injuries recorded; supracondylar/radial fractures were the most common whilst more complex injuries such as an open fracture of the femur was rarer. conclusions: awareness and application of necessary safety precautions was low ( %) amongst parents'' supervising parents''/guardians highlighting the need for greater public awareness of same. furthermore, the incidence of severe injury relating to usage of trampolines/bouncy castles is not uncommon highlighting the high risk activity that trampolining is. introduction: conventional plate fixation (pf) of distal fibular fractures in elderly patients is associated with a high risk of wound and implant related complications. intramedullary fixation (imf) using a fibular nail is a minimally invasive alternative to pf that provides superior biomechanical strength and allows immediate full weight-bearing postoperatively. aim: to compare the postoperative complications of minimally invasive intramedullary nail fixation to conventional pf for lauge-hansen supination external rotation type fractures in patients aged years or older treated in a single geriatric trauma unit in the netherlands. methods: a retrospective cohort study was performed including unstable ankle fractures in patients aged years or older treated with either imf or pf between january to january . the primary outcome measure was the total number of wound related complications. results: a total number of patients were included with a mean age of . years (range to ). the imf-cohort (n = ) had a significantly higher mean age ( . versus . years, p = . ) and charlson co-morbidity index ( . versus . , p = . ) compared to the pf-cohort (n = ). the total number of postoperative complications was lower after imf ( %) compared to pf ( %), although this relative difference was not statistically significant (p = . ). all complications observed in the imf-cohort were wound related but demanded no debridement or implant removal. wound related complications did not differ significantly from pf ( % versus %, p = . ). no implant related complications, hospital-acquired complications or mortality were observed after imf. conclusion: despite the higher mean age and co-morbidity status of patients treated with a minimally invasive intramedullary nail, the total number of postoperative complications was lower after imf compared to pf. this technique might be a promising alternative in a selected group of patients. the authors declare that they have no commercial associations that might pose a conflict of interest. no funding or other compensation was received for the research, authorship or publication of this article. gustilo type ii and gustilo type iii fractures. the treatment protocol was external fixation at admission and definitive osteosynthesis with plate at ± days. a single approach to the tibia was performed in patients, and a combined anterior and posterior approach was used in . the incidence of complications was %: cases of poor soft tissue evolution, of which were infections. patients evolved to nonunion. osteoarthritis appeared in % of patients ( . % grade ), and only one patient needed arthrodesis. . % had a valgus ldta (\ °) and . % a varus deformity ([ °). we found a significant relationship between the history of open fracture and the development of complications (p \ . ). we found no relationship between the incidence of complications and the approach. conclusions: tibia ao c fractures have a high percentage of complications and evolve to well-tolerated osteoarthritis. open fracture seems to significantly influence the poor postoperative outcomes of these patients. clinical findings: a -year-old male, who suffers a closed chest trauma with pneumothorax, right pulmonary contusion and poor pneumoperitoneum. also a grade iiia open fracture of the right femur, with a cm bone defect. investigation/results: upon arrival at the hospital, he needs orotracheal intubation, as well as blood transfusion with red blood cell concentrates. external fixator is placed on the right femur. diagnosis: a iiia grade diaphyseal open fracture of the right femur with cm bone defect, bearing external fixator with one broken proximal pin and positive culture for s maltophila in the distal pin. therapy and progressions: antibiotic treatment and medical optimization are performed, cemented intramedullary nailing (t -stryker) with antibiotic (vancomycin-tobramycin), as well as cement spacer with antibiotic (masquelet's first stage) in the defect area. in second time, withdrawal of spacer and contribution of ria autograft of contralateral femur and allograft respecting membrane. the patient begins the protected weight bearing with two crutches immediately, without using them months after the surgery. bone consolidation without pain or limitation after year. comments: the induced membrane technique is a simple and effective technique for the reconstruction of segmental bone defects and can be used as a first time technique together with the initial stabilization, leaving the defect ready for graft delivery in the second time. introduction: carpal metacarpal dislocation is a rare entity that accounts for less than % of all carpal injuries. dorsal dislocations are the most common and occur most frequently after violent trauma in young individuals and are easily overlooked and may lead to longterm sequelae. material and methods: we present the case of a carpal metacarpal dislocation from d to d . male, years old, no relevant personal history. brought to the emergency service after a motorcycle accident with projection. he had a symphysis pubis diastasis, a distal radius fracture on the right wrist and a fracture of the left forearm bones. no other apparent injuries associated. at week , he presented edema and dorsal deformity of the left hand associated with limited finger movements. neurovascular assessment was normal. the radiological evaluation showed a carpal metacarpal dislocation from m to m . it was an unstable reduction so open reduction was performed, with debridement of fibrous material, until exposure of the articular surfaces, and reduction and fixation with k wires of the three metacarpals (from d to d ). similarly, m was stabilized with a k-wire due to clinical instability observed intraoperatively. results: it is necessary to reduce and stabilize these lesions to avoid vasculonervous compression and skin distress. open reduction is indicated in irreducible cases allowing debridement and excision or os of small osteochondral fragments and fixation of associated fractures. conclusions: combined dislocation of multiple metacarpals is a rare lesion that compromises the functional prognosis of the hand in the absence of adequate treatment. instability and post traumatic arthrosis are among the sequelae of this lesion. identify the lesion to allow the appropriate treatment usually leads to good results. case history: -year-old suffered direct trauma to his right hand after falling off his bicycle. clinical findings: on physical examination showed edema and bruising from the base of the thumb and thenar eminence, tenderness over the cmc joint and functional disability speacialy in pincer grasp. no neurovascular injuries investigation/results: the x-ray revealed a comminuted fracture of the base of the thumb metacarpal. diagnosis: we identifed a rolando fracture. therapy and progressions: on the day after the trauma, he was submited to open reduction and osteosinthesis with lateral-palmar plate and screws, through radiopalmar aproach of the thumb base. intra operatively no dorsal fragments werefound to be left undisplaced. two months after surgery, the patient went back to the hospital for sudden pain and inability to extend the thumb. clinically with rupture of the long extensor of the thumb. on the x-ray, the fracture was aligned. the latero-lateral tenorrhaphy with kessler suture was preformed and intraoperatively a bony spicule was identified in the proximal stump of the tendon, which was removed. months after the initial trauma, the patient has a consolidated neck and no limitation of the mobility of the thumb. comments: rollando fracture is relatively rare in adolescents. the aim of treatment should be exact reduction usually with open technics. the main complications are stifness and early arthrosis. there are also records of conflicts with the plates and even rupture of the extensor tendon, so the radiopalmar placement of the plate was chosen. nevertheless, the rupture occurred due to conflict with an unidentified bone fragment during surgery causing an unexpected complication in this case. the immobilization necessary after tenorrhaphy could have caused joint stiffness, but in this case the teenager fully recovered after physical therapy case history: periprosthetic and periimplant femoral fractures are an increasingly frequent pathology. in many cases they are a challenge with limited or too aggressive therapeutic options. it is important to investigate new approaches that increase the arsenal of the orthopedic surgeon. the recently described mipo (minimally invasive plate osteosynthesis) approach for the medial aspect of the femur may seem like a dangerous procedure because of the anatomical structures that run along the medial aspect of the thigh, but it is a viable and useful option in selected cases. clinical findings: we present the case of a -year-old patient with a total hip replacement who presented a first periprosthetic vancouver b fracture of the femur that was treated with a lateral blocked plate. subsequently the patient presented a second supracondylar femur fracture below the first plate (vancouver c). investigation/results: after thinking over the possible therapeutic options, we decided to treat our patient by means of the medial femoral mipo approach with a long medially placed blocked plate, managing to stabilize the fracture and superimpose the plate on the previous implants without the necessity of removing the previous lateral plate. diagnosis: periprosthetic and periimplant supracondylar left femoral fracture. therapy and progressions: we used the surgical technique of the medial femoral mipo approach as described by apivatthakakul . comments: we consider that the medial femoral mipo approach is a useful therapeutic tool to consider. it seems a safe and low-invasive option for the resolution of cases in which the lateral mipo approach is not a feasible option. references: c. jiamton y t. apivatthakakul, « the safety and feasibility of minimally invasive plate osteosynthesis (mipo) on the medial side of the femur: a cadaveric injection study » , injury, vol. , n.o , pp. » , injury, vol. , n.o , pp. - » , injury, vol. , n.o , pp. , nov. . posterior knee dislocation with neurovascular injury associated-a case report case history, investigation and diagnosis: a -year-old male was brought in after h following a heavy straw bale fall. he presented with a posterior knee dislocation that had already been reduced and an open wound in the popliteal fossa. the limb was flushed and pale on the extremity, with absence of the pedis and posterior tibial pulses. stability tests revealed unstable knee in all axes. an anterior shoulder dislocation was diagnosed and reduced. therapy and progressions: an emergent surgery was performed, involving a transarticular external knee fixation and a femoro-popliteal bypass above the knee (angiogram revealed a stop sign at the level of the interarticular popliteal artery). he developed circulatory shock and was admitted to the intensive care unit. on the stpostoperative day(po) was diagnosed a compartment syndrome that was treated with fasciotomies. these incisions showed a slow but progressive evolution, that required vacuum dressings and underwent autologous skin graft on the thpo day. the external fixator was removed on the stpo day and rehabilitation was started. on a -month follow-up, the patient had a good evolution of the wounds, but a knee with valgus and anteroposterior laxity and severe complete peroneal, tibial and sural neurological injury, confirmed with electromyography, and neuropathic pain. introduction: isolated iliac wing fractures represent only a small part of all pelvic fractures. these fractures are associated with severe injuries, but are considered benign. the literature lack information about the function and quality of life of these patients. our objective was to evaluate the long-term effects of isolated iliac wing fractures. material and methods: patients with pelvic fractures treated at oslo university hospital, ullevaal, in the time period - , were extracted from the local fracture registry. patients were registered in this period. a search was also made in the hospital''s administrative electronic database for patients registered with diagnose code s . in icd- in the same period. patients were identified. in total, patients had an isolated iliac wing fracture, and these were invited to a follow-up examination, including proms (eq- d- l and majeed score), clinical examination, and pelvic x-ray. results: nine patients agreed to participate in the study, median years after the fracture (range - ). all of them were injured from high energy trauma, with mean niss , (range - ) . four of the fractures were open, and seven of the patients had associated injuries. five were treated with internal fixation. the mean eq- d vas was (range - ). five patients reported pain, one of them related to the pelvic fracture. the mean majeed score was (range - ). seven patients had sensory deficit in the lateral thigh. one patient had difference in range of motion between the two hips. the x-rays showed healed fractures in all the patients. eight of them showed ectopic ossification. conclusions: our study confirms previous studies that isolated iliac wing fractures are results of high energy trauma with severe associated injuries. however, the majority of this group of patients seem to have a good general state of health, which is in accordance with the general assumption of the injury as a benign one. fenton's syndrome-a case report of a common underdiagnosed entity case history: a right handed -year-old male, construction worker, was admitted in our emergency department, after a meters fall. the authors report a case of fenton's syndrome in a politrauma scenarium. clinical findings: both right elbow and left wrist were painful, swollen and with a remarkable restriction of the range of motion (rom). patient also reported lower back pain. no neurovascular injuries were detected. investigation/results: x-ray and ct scan confirmed a fracture of a lumbar vertebra, fracture of the right olecranon and, on is left wrist, a carpal fracture-luxation mayfield of both scaphoid and capitate associated with rotation of the last one proximal pole-fenton''s syndrome. diagnosis: this syndrome is an atypical presentation of perilunate fracture dislocation and, therefore, difficult to diagnose. few reports were found in literature. after an open reduction of the fractures, a definitive fixation with headless herbert screws was achieved. percutaneous kw and immobilization of the wrist were performed to further stabilization of the lunotriquetral joint. weeks later consolidation was noted. a decrease of °in extension and flexion were detected when compared with the contralateral wrist. grip strength test was similar on both hands. osteosynthesis of the right olecranon was also realized. comments: a careful neurovascular assessment is important. although it is rare, injuries of median nerve were already reported associated to this complex fractures. open reduction and osteosynthesis are necessary due to the great instability and the risk of nonunion and osteonecrosis of the rotated proximal segment. introduction: intramedullary nailing has been popularly applied for the femoral shaft fractures. the current study aimed to analyze the femur geometry for development of implant design with dimensional skeletonization. material and methods: we acquired computed tomography (ct) images of both femur reviewed in a single center from to . the total participants were enrolled and they were divided into subgroups according to age (decades) and gender. each subgroup included persons, respectively. these images are used to produce d samplings. with the skeletonization, we obtained the geometry parameter; ( ) femur shaft length from the tip of the greater trochanter to the bicondylar line, ( ) the minimum diameter of the medullary canal and its location, ( ) anteroposterior (ap) diameter and lateral diameter of the entire femur, ( ) radius of curvature (roc) of the femur (bowing). we compared all parameters according to sex and age. results: the average age of the participants were . years (range - years) and the number of each gender was exactly same. the femur length was . ± . mm (range, . - . mm) and the femur shaft length was . ± . mm (range . - . mm), both of them were longer in male (p = . , \ . ). the minimum diameter of the medullary canal was . ± . mm (range . - . mm). the roc was . ± . mm (range . - . mm) . the rate of the minimum diameter less than mm and mm was . % and . %, respectively. the rate of roc with less than mm and mm was . % and . %, respectively. conclusions: this geometry analysis showed that there are mismatch problem between the current nail and the medullary canal in . % and the roc of the femur was smaller than that of the current nail systems ( - mm). the result indicates potential mismatch problem in clinical cases and the problem can be resolved with newly designed nail system. the study was funded by national reserach foundation of korea (nrf- r d a b ). safe zone of the infracacetabular screw: virtual mapping of three-dimensional hemipelvises for quantitative anatomic analysis introduction: an infra-acetabular screw can provide increased stability in fixating acetabular fracture. we conducted this study to define the incidence of the safe corridor for infra-acetabular screw and to determine the correlation between the safe corridor and other demographic factors such as age, sex and height. material & methods: pelvis computed tomography (ct) of participants was extracted with evenly age-and sex-allotted. virtual three-dimensional ( d) model was generated. a search was performed to find the maximum-with corridor connecting two points. the entry and exit point was displaced in the template. the maximum diameter of each corridor was measured in automatic procedure. a minimum mm corridor diameter, sate corridor, was defined as a cutoff for placing a . mm cortical screw in clinical setting. all data were presented as mean and range or mean and standard deviation. two-sample t test and regression analysis were used to compare difference between groups based on sex, age, and height. results: among hemipelvis, hemipelves ( . %) satisfied a minimum safe corridor diameter of mm. when divided into a subgroup by the patient's gender, the incidence of the safe corridor of a male group was statistically higher than a female group ( . % vs . %), with the mean corridor diameter of . mm ( % ci, . ) and . mm ( % ci, . ), respectively (p \ . ). in correlation analysis, only the height showed a positive correlation with the diameter of the safe corridor of a total population (r = . ; p \ . ). conclusions: the study provided the safe corridor was found in % of male and % of female, and the taller had the higher incidence of the safe corridor. the patient''s height was correlated with the corridor diameter of the infra-acetabular screw, whereas the patient''s age did not correlate with the corridor diameter. introduction: femoral neck fractures in middle-aged and older patients represent one of the most common orthopedic conditions. osteosynthesis, as a primary treatment option for femoral neck fractures has shown to have successful outcomes. however, this is not the case for old fractures. the purpose of this study was to evaluate the outcomes of treatment of femoral neck fractures in which cementless total hip arthroplasty was indicated. the aim of our study was to analyze the prosthetic failure, i.e., the reasons for unsuccessful outcome, in order to suggest the indications for primary osteosynthesis which could guide the femoral neck fracture management. material and methods: a total of patients were analyzed in this study, with femoral neck fracture treated with osteosynthesis. reviewing the radiological findings, as well as the course of the treatment, we set up the criteria, on the basis of which we could advice the immediate implantation of total hip prosthesis for the femoral neck fracture. results: old fractures, varus deformity of the femoral head and neck, dislocation, as well as the comminuted fractures, are all factors affecting the surgical outcomes of osteosynthesis. additionally, medical and technical equipment of medical institution, personnel competence, and minutious surgical technique affect the treatment outcomes. introduction:proximal ulnar fractures are usually osteosynthesized by means of angle stable plate osteosynthesis. despite good functional results of this procedure, complications such as high access morbidity and disruptive osteosynthesis material with a high rate of material removal are described. the aim of our study was the development of a new locking nail and test setup for comparison with a plate osteosynthesis on artificial bones. material and methods: in our biomechanical laboratory, a jupiter b fracture of the proximal ulna was standardized on sawbones and stabilized by means of the newly developed nail or anglestable posterior plate osteosynthesis. a servopneumatic testing machine, the specimens were flexed under a cyclic load ( - n) in the physiological range of movement of the elbow from °to °.the maximum elastic deformation of the specimens and the loosening of the implants were evaluated after test cycles. results: the primary stability of the constructs at the anterior cortical bone after nail osteosynthesis was significantly greater ( . ± . mm) than in the angle-stable plate osteosynthesis ( . ± . mm, p \ . ).after passing through the test cycles, both implants showed a low loosening rate. in the area of the anterior cortex, the locking nail showed a significantly lower rate of loosening (nail . ± . mm, plate . ± . mm, p \ . ). at the dorsal cortex, there were no differences between plate and nail in both series of measurements. conclusions: intramedullary implants provide biomechanical benefits in fracture stabilization. good biomechanical results have already been shown in the literature after nailing olecranon fractures . nevertheless, due to the complex anatomy and the resulting difficult implantation technique, ulnar nails could not prevail in practice. the presented nail allows a safe stability with simple surgical technique. introduction: adequate treatment of tibial plateau fractures is crucial to minimize patient disability, development of posttraumatic arthritis and subsequent need for a total knee arthroplasty (tka). however, due to the complexity of the fracture, adequate reduction cannot always be achieved which could result in the early conversion to a tka. in this study we introduce a quantitative d fracture assessment method and investigate whether it could help to identify patients that are at risk of conversion to a tka. material and methods: we retrospectively included patients, who were treated for a tibial plateau fracture between and . patients developed severe posttraumatic arthritis and underwent conversion to a tka. from all patients, d models were created using the pre-operative ct-scans. for each patient, the d gap area between the fracture lines, representing an innovative combined gap and step-off measurement in d, was determined in order to quantify the displacement (figure ). roc curve analysis was performed to determine a critical cut-off value for the d gap area. kaplan-meier survival curves were created to assess the association between d fracture anatomy and risk on a tka at follow up. results: a critical cut-off value of mm was found to give highest combined sensitivity and specificity for d gap area and the risk of tka at follow-up. kaplan-meier survival curves showed . % knee survival (no tka) at year follow up in the group with a gap area of \ mm , whereas in the group with a gap area of c mm a knee survival of . % was found. at year follow up knee survival was . % and . %, respectively, for the two groups (\ mm and c mm ). conclusions: we developed an innovative method to quantify the amount of displacement in d. pre-operative d fracture assessment could be used as an addition to the current fracture classification methods to help identify patients who have a high risk on conversion to tka at follow-up. introduction: soft tissue sarcomas (sts) in the anterior compartment of the thigh are frequent. the extent of quadriceps resection is controversial. the aim of the present study is to communicate our results in complete quadricectomies due to high-grade sts. material and methods: we present sts, in stage iiib of the ajcc, with a mean craniocaudal diameter of cm ( - ). there were women and men, with a mean age of years ( - ). six were undifferentiated pleomorphic sarcomas, myxofibrosarcoma and clear cell sarcoma. in every case, total quadricectomy was performed with wide margins. posterior reconstruction with local muscle transfers was performed, expect for the younger patient, who received a vascularized contralateral vastus lateralis transplant. in all cases, complementary radiotherapy was indicated, and in patients adjuvant chemotherapy. results: three patients required friedrich due to necrosis of the edges of the surgical wound. one patient died months after the intervention as a result of multiple metastasis, and two due to medical complications after week and months, respectively. the average follow-up time for the rest was months , with no local recurrence. as for functional outcomes, mean msts score was ( - ), with deficit of active knee extension in most of them. the functional result of the patient with the vascularized muscle transplantation was excellent. all of them were satisfied with the results of the treatment. conclusions: quadricectomy provides good functional and acceptable cancer results, although it is not exempt from complications in frail patients. vascularized muscle transplantation, though complex, can improve functional results, especially in younger patients. introduction: operative treatment is a valuable option in displaced proximal and/or middle one-third diaphyseal humeral fractures. although plate osteosynthesis is preferred to intramedullary nailing, surgery can be complicated by radial nerve palsy. a helical plate could avoid this high-impact complication. to date there is however a lack of published evidence in literature, although recent asian case reports show promising results. material and methods: we retrospectively reviewed patients who were treated with open reduction and internal fixation with a helical plate consecutively from october until august at az groeninge, kortrijk. a deltopectoral approach was used in combination with a distal anterolateral incision, whether or not in continuity. a self-molded long philos plate was used in the first patients, while in our last patients the a.l.p.s plate (zimmer Ò ) was used. standard radiographs were obtained pre-and postoperatively. we retrospectively searched for complications, e.g. radial nerve palsy, infection and/or loosening. in autumn , patients were reassessed. patient''s general health status was evaluated using the eq- d- l score. constant-murley scores and dash scores were used for evaluating shoulder function and disability measures consecutively. results: all humeral fractures consolidated at months. there were no radial nerve palsies due to surgery. one plate was removed after year due to a late infection. with a minimum follow up of year, the mean dash score was ( - ) and the mean constant-murley score was ( - ). the dash score was inversely proportional with the constant-murley score and patient''s general health status. conclusion: a helical plate avoids neurological complications with similar healing rates and good to excellent shoulder function at year follow up in the treatment for proximal and/or middle one-third diaphyseal humeral fractures. the use of antibiotic-impregnated cancellous bone grafts in onestage surgery for chronic orthopaedic infection: preliminary clinical results k. dendoncker , g. putzeys , az groeninge, tissue bank, kortrijk, belgium, az groeninge, orthopaedic center, kortrijk, belgium introduction: the use of cancellous bone allografts is an established technique in reconstructive orthopaedic surgery. unfortunately, its use is generally avoided in the presence of a local infection. antibiotic impregnated cancellous bone grafts has shown its effectiveness as an local antibiotic delivery system [ ] [ ] [ ] . in this clinical study, we report our first personal experience with the use of vancomycin-impregnated cancellous bone grafts in one-stage surgery for periprosthetic joint infections (pji) and fracture-related infections (fri). material and methods: between december and march nine patients were treated during a one-stage surgery with vancomycinimpregnated cancellous bone grafts, containing g vancomycin per cc bone. regular clinical, laboratory and radiographic follow-ups were performed for at least months after surgery. results: the procedures included revision of pjis (hip and humerus) and fris (tibia, femur and clavicula). one tibia required further revision because of recurrent infection and one hip has an uncertain infection state, however the remaining patients stayed free from infection during a follow-up of at least months. interestingly, in one patient the vancomycin concentration could be determined in the drainage fluid from the wound. radiographic examination revealed no signs of osteolysis or loosening, good incorporation of the bone graft and progressive consolidation. conclusions: within the limits of the study, the use of vancomycinimpregnated cancellous bone grafts in one-stage surgery to treat pji and fri yielded positive outcomes in terms of clinical, laboratory and radiographic follow-up. this technique might offer new treatment strategies in often devastating injuries. references: . putzeys g., et al. orthopaedic proceedings. ; -b:supp_ , - . with the modified arthroscopic approach (group b). the prospective follow-up included the lysholm score, the subjective questionnaire of the ikdc score and the specifically extended oak score for clinical evaluation. the rolimeter Ò was used to test the translational mobility of the knee joint. the statistical significance level was set at %. results: the follow-up was . ± . months and . ± . months postoperatively in group a and b, respectively. the subjective scores were tested. group a and b achieved a mean lysholm score of . ± . and . ± . points respectively. in the subjective ikdc assessment, group a achieved . ± . points and group b . ± . points. the clinical oak score was . ± . points in group a and . ± . points in group b. the following values could be recorded for the stability of the posterior cruciate ligament: the side difference in the rear drawer test was . ± , mm in group a and . ± . mm in group b. in the reversed lachman test, a difference of . ± . mm and . ± . mm was measured in group a and b, respectively. all values mentioned were comparable between the two evaluated groups. conclusions: the results of the two surgical techniques were comparable. therefore the arthroscopic approach is the preferred method in our institute. simple correction technique of femoral malrotation after pfn-a osteosynthesis of trochanteric fracture k. pavotbawan , p. stillhard , c. sommer kantonsspital graubünden, department of trauma surgery, chur, switzerland introduction: malrotation after intramedullary nailing in femoral shaft fractures are well known. but malrotation after nailing of trochanteric fractures is an underestimated problem. during surgery the axial alignment can easily be evaluated by fluoroscopy in both planes. but the torsional alignment is difficult to assess especially with the patient placed on the traction table. in literature a malrotation after pfna is described in up to % of the cases. a revision with replacement of the blade, especially in patients with poor bone quality, may result in a reduced stability. to our knowledge there is no publication till to date to give a treatment pathway for this problem. we developed a rather easy technique to derotate a malrotated femur after pfna fixation. material and methods: the basic idea is to leave the usually well placed blade insitu in the femoral head, just rotating the distal main fragment around the nail. therefore, a small u-shaped osteotomy with a chisel is performed in the femoral cortex just anterior of the entry site of the blade. the length (l) of this osteotomy can be calculated, following the formula: l = d x p x a/ (d = diameter of femur, a = angle of malrotation). then the distal locking bolt is removed, the leg derotated and finally locked again. the procedure is controlled by two schanz''screws separately inserted in both main fragments angulated to each other in the angle ''a''. results: since patients were detected with a clinically relevant femoral malrotation. all patients had an internal malrotation from to degrees confirmed and measured by ct scan. all of them were successfully revised in the above described technique - days after initial fixation. conclusions: first, we believe that malrotation after trochanteric fracture fixation is an underestimated problem. and second our method is a simple salvage procedure for malrotated trochanteric fractures after pfna, leaving the blade in situ in the femoral head. optimal intramedullary nailing for trochanteric fractures: the importance of distal locking screw and reduction position t. waki , t. yano , k. ito , s. matsushima akashi medical center, orthopaedic surgery, akashi, japan introduction: distal locking issue for trochanteric fractures is still controversial. therefore, the purpose of this study was to investigate the complications between distal unlocked group and distal locked group. further, the relationships were evaluated between these complications rates and their reduction positions after operation. material and methods: operations were performed for trochanteric fracture (ao a ?a ) from to . of these, patients with f/u periods [ month were . gamma im nailing system (stryker) was used for all patients. patients (unlocked group) from to operated without distal locking screw. patients (locked group) from to operated with distal locking screw. we retrospectively analyzed those patients who suffered complications such as delayed healing and postoperative periimplant fractures and cut-out of the lag screw. further, in lateral view of their radiographs, we evaluated the position of the proximal fragment compared with distal fragment. the reduction positions were divided into groups: anterior (subtype-a), neutral (subtype-n), and posterior (subtype-p). results: in unlocked group, complication was shown in patients (complication group). delayed healing was shown in / ( . %) in unlocked group and / ( . %) in locked group. peri-implant fracture was shown in / ( . %) in unlocked group and / ( %) in locked group. cut-out of the lag screw was shown in / ( . %) in unlocked group and / ( . %) in locked group. in complication group, subtype-p was more than non-complication group. conclusion: in the current study, higher number of complications was seen in the distal unlocked group. and, our study showed the reduction position might be associated with post-operative complications. we concluded that nailing without distal locking screw might be dangerous and subtype-p should be avoided. introduction: heterotopic ossification (ho) after acetabular fracture surgery has been one of the common complications and often limits function with the range of motion severely. surgical resection is challenging and only effective treatment for established ho. we herein report four cases who underwent surgical resection and mobilization for ho after acetabular fractures surgery. material and methods: four cases with severe ho after acetabular fracture surgery were included in this study. the mean age at operation was years old, and all patients were males. in judet-letournel classification, there were three cases classified as posterior wall fracture, and one case as transverse and posterior wall fracture. two of four cases were combined with posterior dislocation of the hip. in all cases, the first operation was performed using with the kocher-langenbeck (kl) approach. results: surgical resection of ho was performed using with the kl approach at . months (range - months) after the first operation. the median operating time and intraoperative bleeding were respectively . h and ml. intraoperative d navigation was used in one case. as postoperative complications, one case developed sciatic nerve palsy and another case sustained the iatrogenic femoral neck fracture. all cases have no recurrence with a follow-up of . years after the surgical resection. conclusions: surgical resection is the only treatment for symptomatic ho. but that requires preoperative planning and must be performed carefully because the extent of resection is still controversial and that may develop severe complications such as nerve palsy and iatrogenic fractures. by using navigation, we can determine the extent of resection easily and operated safely. case history: -year-old male, previously healthy, turned to the hospital after a motorbike crash, resulting in high energy direct trauma of the right wrist. clinical findings: upon admission, cranial, thoracic, abdominal and other traumatic injuries were excluded. the patient presented with pain, swelling and visible deformity of the right wrist and hand, hypoesthesia of the th finger, and no perfusion deficits. investigation/results: x-rays showed volar perilunate carpal dislocation with associated comminuted scaphoid fracture, radial styloid avulsion, and metacarpal phalangeal dislocation of the th digit. under sedation, closed reduction of the metacarpal phalangeal joint was accomplished, and reduction of the carpal dislocation was attempted unsuccessfully. the wrist was temporarily immobilized in a cast and taken to the or. diagnosis: transcaphoid-transradial-styloid-perilunate volar dislocation therapy and progressions: surgical treatment comprised loose bodies removal, reduction of the perilunate dislocation, orif of the scaphoid using a herbert screw, and stabilization of the carpal rows using two percutaneous kirschner wires. after surgery, a thumb spica cast was applied. post-operatively, neurovascular status was normal. at weeks, x-rays showed signs of bone healing, the cast and k wires were removed, and physical therapy was initiated. at months, scaphoid fracture consolidation was achieved. the patient remained with a mild deficit in wrist extension but reported no pain nor important limitation in daily living activities. comments: perilunate injuries with displacement or dislocation usually require surgery. persistent instability is a described complication, often progressing to secondary post-traumatic arthritis of the wrist and carpus, termed scapholunate advanced collapse. introduction: this study was conducted to study the patient characteristics, classification, treatment, complications and functional outcome of operatively treated displaced intra-articular calcaneal fractures (diacf) in a level trauma center in the netherlands material and methods: patients with an diacf, classified as sanders c and operatively treated with percutaneous screw fixation (psf) or open reduction and internal fixation (orif) between january and december were identified. pre-and postoperative radiological assessment was performed. functional outcome, range of motion and change in footwear were evaluated with the use of the american orthopaedic foot & ankle society (aofas) score and the maryland footscore. general health and patient satisfaction was assessed using the short form- (sf- ) and the visual analogue scale results: in total, patients with an operatively treated diacf were identified. patient with diacf completed the questionnaires. there were males and females, mean age at trauma was years. average follow up was years. were classified as sanders type , and as respectively type and . were joint depression and were tongue-type fractures. there were no differences in sanders classification between the group treated with orif and psf. for orif and psf there were ( - %), ( - %) and ( - %) for respectively sanders type , and fractures. mean aofas, mfs, sf- and vas was ( - ), ( - ), ( - ) and ( - ) for respectively orif and psf. mean pre-and post-bohler angle was ( - ) and ( - ) for respectively psf and orif. underwent an ankle arthrodesis. surgical site infection and deep infection occurred in ( , - %) and ( , - %) in respectively psf and orif conclusions: long-term comparison shows no significant differences between orif and psf in treatment of sanders fracture type, bohler angle reduction, on functional outcome or complication rates introduction: the prevalence of hand injury in the pediatric population is attributed to their curiosity, limited fear of pain and diminuted motor coordination. the seymour fracture, which was first reported by seymour in , represents a transverse extra-articular open fracture of the distal phalanges associated with nail bed injuries. the fracture includes salter-harris type i and ii fractures as well as juxta-epiphyseal injuries. material and methods: the aim of this report is to present a case of a seymour fracture in a young boy and describe the injury mechanism associated with misuse of the newly emerging vehicle, the hoverboard. results: our patient was treated promptly and provided with appropriate management following the standard of care in our hospital for such injuries: disimpaction and repair of the nail bed, reduction of the fracture, and k-wire fixation across the distal interphalangeal joint. the patient was discharged with a volar slab and was prescribed an oral antibiotic. the patient recovered well with no major deficits. conclusions: the timely recognition and management of seymour fractures is crucial. the surgical treatment has good results however, conservative management can be an option in some specific cases. antibiotics are always required. we report a case of a fracture pattern resulting from the improper use of an hoverboard. although improper use was a factor, design fault also plays a role in causing the injury. hoverboards are a new transport technology that has been introduced in recent years. because of the number of injuries that have resulted from hoverboards, they should be used in the most controlled way possible to prevent any unnecessary injuries. case history: we report the case of a years old male from bangladesh, with months of progressively increasing pain, limited range of motion and swelling on his left knee, with kg of weight loss and inguinal lymph nodes. clinical findings: knee radiography and mri of the knee demonstrated a voluminous soft tissue mass surrounding the distal femur with intraarticular and posterior extension. a toracic-abdominal-pelvic ct showed supra and infradiaphragmatic lymph nodes. c-reactive protein level was , mg/dl. investigation/results: the clinical picture suggested a lymphoproliferative syndrome. a biopsy was performed, revealing cm of purulent material. synovial fluid had leucocytes/ul, % of polymorphonuclear cells, % of mononuclear cells and undetectable glucose. acid-alcohol resistant bacilli test and pcr test for mycobacterium tuberculosis were positive. diagnosis: mycobacterium tuberculosis knee arthritis therapy and progressions: the patient was treated with polytherapy consisting on rifampin, isoniazid, pyrazinamide and ethambutol. months later, the patient reports no pain, and tumor size has decreased. comments: mycobacterium tuberculosis infection is not a common disease in developed countries. however, the incidence in europe is increasing due to immigration. even though the lung is the most affected organ, osteoarticular tuberculosis represents around % of extra-pulmonary cases. tuberculosis simulates several diseases. because of non-specific symptoms and radiological signs, it can be difficult to diagnose. in a patient with chronic knee pain and limited range of motion, tuberculosis infection should be kept in mind, among other differential diagnoses, such as fibromatosis, pigmented villonodular synovitis or soft tissue sarcomas. clinical findings: the patient presented with a valgus deformity of the knee, the medial femoral condyle protuding on the medial side of the knee. neurovascular status was intact. investigation/results: xray revealed lateral dislocation of the knee. mri revealed mcl, pcl and acl rupture. diagnosis: knee dislocation (kd) grade iii (schenck). therapy and progressions: the patient underwent emergent closed reduction. neurovascular status was intact after resuction. due to important oedema and blisters, the lower limb was immobilized with a brace to allow for skin surveillance. after weeks, the brace was replaced by a long leg cast for more weeks. after months, the patient maintained residual pain, rom - / and minor instability. comments: kd are unusual injuries, associated with high energy trauma, therefore they often result in disruption of at least major ligaments and associated injuries, from soft tissue to vascular structures. emergent reduction is mandatory, and definitive treatment can be conservative, or early/late surgical repair/reconstruction of the ruptured ligaments. there is a lack of large prospective clinical studies comparing the different types of treatment. even so, data tend to associate early surgical treatment with better functional outcomes, though there is no statistic evidence supporting its improvement of the range of motion or stability. long term complications most frequently include residual pain, instability or rigidity. rarely the knee returns to its pre-injured state, independently of the treatment used. references: dwyer, t., et al. ( ) . outcomes of treatment of multiple ligament knee injuries. the journal of knee surgery, ( ), - . advising a reduction after a fracture of the distal radius, reliability with and without use of expert based criteria introduction: distal radius fractures (drf) are common, however many aspects of its management remain subject of debate . this study assessed the interobserver reliability of surgeons concerning the recommendation for a reduction and the improvement of expert based criteria for reduction. material and methods: we sent out surveys to members of the science of variation group. the first survey divided participants in groups, each rated - radiographs of drf. resulting in rated fractures by participants. each observer indicated whether they would advise a reduction or not. the second survey randomized participants ( surgeons) to either receive or not receive criteria for reduction and participants indicated if they would recommend reduction. results: the reliability for advising a reduction was poor, kappa . ( % ci . - . ). multivariable linear regression analyses indicated that each additional degree of dorsal angulation increased the change of recommending a reduction by % (beta . , % ci . - . p \ . ). criteria for reduction did not increase interobserver reliability for recommending reduction (no criteria kappa . % ci . - . vs. criteria . % ci . - . ). the likelihood of recommending a reduction was higher in the group using the criteria ( . vs . , p = . ). conclusions: poor interobserver reliability is associated with greater practice variation. dorsal angulation is the main drive for recommending a reduction. the liberal use of the criteria in combination with a specific focus on dorsal angulation leads in our opinion to less variation in treatment recommendation for distal radius fractures. this is something future study could assess for distal radius fractures in actual practice introduction: the number of pertrochanteric hip fractures increases proportionally to the increase in life expectancy. currently, the most used treatment in these fractures is the antegrade nailing. suffering a second fracture in the same femur around an antegrade nail is an uncommon complication, but it has a great impact on the patient. the aim of this study is to describe the type of perinail femoral fractures observed in our center, the treatment performed and the medium-term results. material and methods: between and , patients presented a perinail femoral fracture. were women and one was male, with an average age of . initial fractures were classified according to the ao classification: were a , were a and were a . of them were synthesized by short pfn-a (synthes), with short pfn (synthes) and with gamma (stryker). the average time since osteosynthesis of the proximal femur fracture and the perinail fracture was . years ( month- years). results: of the peri-implant fractures occurred at the level of the nail tip or the distal locking screw. the remaining fractures occurred in the distal femur. these supracondylar fractures and of the fractures at the level of the nail tip were synthesized with a va condylar plate (synthes), overlapped with the nail. in the rest of the fractures around the tip of the nail, the short nail was removed and replaced by a long pfn-a nail. one of the patients died in the immediate postoperative period. two patients died during the first year. in the rest of the patients, a complete consolidation of the fracture was observed, and their previous baseline situation was recovered. conclusions: peri-implant femur fracture is a rare but very severe condition, which requires good surgical planning, and is not without complications. gamagori city hospital, department of orthopedics, gamagori, japan, nagoya daini redcross hospital, department of orthopedics, nagoya, japan introduction: hip fracture is a leading worldwide health problem for the elderly. a missed diagnosis of hip fracture on radiography leads to a dismal prognosis. the application of a computer-aided diagnosis (cad) system using artificial intelligence (ai) to detect hip fracture can potentially improve the accuracy and efficiency of hip fracture diagnosis. material and methods: cad system using ai was trained using cases, plain frontal pelvic radiographs (pxrs) between and from each institution. the accuracy, sensitivity, falsenegative rate, and area under the receiver operating characteristic curve (auc) were evaluated on independent pxrs. the authors mixed resnext as classification algorithm and ssd as object detection algorithm to train cad system. results: the algorithm achieved an accuracy of . %, a sensitivity of . %, a false-negative rate of %, and an auc of . for identifying hip fractures. the visualization algorithm showed an accuracy of . % for lesion identification. conclusions: our cad system using ai not only detected hip fractures on pxrs with a low false-negative rate but also had high accuracy for localizing fracture lesions. the cad system using ai might be an efficient and economical model to help clinicians make a diagnosis without interrupting the current clinical pathway. medical faculty university of nis, orthopaedic surgery, nis, serbia, clinical center nis, orthopaedic and traumatology clinic, nis, serbia, orthopaedic word of medical center, cuprija, serbia introduction: bone reconstruction and limb lengthening usually refers to application of ilizarov or other ring external fixation devi-ces . we present here series of posttraumatic reconstruction and limb lengthening, by the use of new concept of d unilateral external fixation device. material and methods: as a clinical material, we present series of patients with different posttraumatic deformities ( ) and limbs discrepancy ( ) as a result of severe traffic accidents and wars. all patients have been treated by specially designed unilateral d external fixation system. that system is not bulky and it is more comfortable in comparison to ring fixators. procedure is relatively simple, so patients handle the device by themselves. during biomechanical testing, it was found that stability of this device is similar to ring systems. the last version of the device includes computer program and two sensors. results: all deformity corrections have been achieved successfully. sliding graft procedure has successfully been performed in all patients with bone defect reconstruction from to cm. in one patient with complex deformity and shortening, correction couldn''t be achieved during one procedure, so additional operations, by the use of the same system have been performed and correction completed. superficial pin tract infection rate was . % and we didn''t have deep infection. there were no other complications including dvt, joint stiffness, neurovascular injuries. conclusion: unilateral external fixation device with balanced d stability provides the same success of bone reconstruction and limb lengthening as ring fixators, but it is more comfortable and more easy for handling. references: treatment principles in bone reconstruction and limb lengthening of the lower extremity. olesen uk, nygaard t, kold sv, hede a. ugeskr laeger. nov ; ( ) at this moment author has licence agreement with the producer of external fixation devices. all patients were classified into the isolated hip fracture and the concomitant fracture. we analyzed these patients'' characteristics such as age, gender, bone mineral density (bmd), body mass index (bmi), korean version of mini-mental state examination (mmse-k), injury mechanism, and length of hospital stay. results: the most common site of upper extremity fracture was distal radius fracture of patients ( . %), followed by proximal humeral fracture of ( . %). concomitant fractures occurred on the same side in patients ( . %). the mean age of patients with a concomitant fracture was younger than that of patients with an isolated hip fracture (p \ . ). mean preinjury mmse-k was . in isolated hip fracture and . in concomitant fracture patients (p \ . ). mean length of hospital stay was statistically significant different between two groups (p \ . ). according to fracture site of hip, there was no statistically different prevalence of upper extremity fracture in femoral intertrochanteric fracture compared to the neck fracture. conclusions: we found a . % prevalence of concomitant hip and upper extremity fractures. it was found that the younger the age with preserved cognitive ability in elderly patients with a hip fracture, the higher the prevalence of upper extremity fracture. in addition, it is important to keep in mind that patients with a concomitant fracture have a longer hospital stay and difficulty in rehabilitation. on the other hand, the amount of bleeding was ml in group e and ml in group l, and there was no significant difference between the two groups. poor cases on postoperative images were % in group e and % in group l, and the joa hip score was . (groupe) and . (group l). in clinical results is significantly improved in group l. conclusions: the treatment results improved significantly in group l. as the number of experienced cases increased from these results, the reduction accuracy and treatment results improved, so experience was considered important for improving the treatment results of acetabular fractures. the additional value of the weight-bearing and gravity stress radiograph in determining stability of isolated type b ankle fractures introduction: the goal of the current study is to investigate whether the weight-bearing and gravity stress radiographs have additional value in determining stability in isolated type b fibular fractures. this in order to make the important distinction between fractures that need surgical treatment and fractures that can be safely treated conservatively. material and methods: patients with an isolated type b ankle fracture, without medial or posterior fracture, and a medial clear space (mcs) \ mm on the regular mortise radiograph were included. in the emergency room, a gravity radiograph was performed (in accordance with out protocol). within week, an additional mri scan was made. at this moment, in patients a weight-bearing radiograph was performed too. the mcs measurements of these regular mortise, gravity and weight-bearing radiograph were compared with the mri findings. the mri scan was set as reference standard to detect injury of the deltoid ligament in order to determine (in)stability. results: mean mcs on mortise radiograph was . mm (range . - . ); in ( . %) patients the mcs was [ mm and in patients ( . %) the superior clear space (scs) was [ mcs ? mm. in ( . %) patients, the scs [ mcs ? mm. on the gravity stress radiograph, . % of the patients had a mcs [ mm. the weight-bearing radiograph showed a mcs [ mm in ( . %) patients. in ( . %) patients, the mri showed a complete rupture of the deltoid ligament. in ( . %) patients a partial rupture was seen. patients ( . %) received surgical treatment. in all conservatively treated patients, no secondary dislocation occurred and there was no need for postponed surgical treatment. conclusions: the gravity stress view has a tendency to overestimate the mcs. thus, potentially too many stable fractures are incorrectly diagnosed instable and receive unnecessarily surgical treatment (with additional costs and risks). the weight-bearing radiograph, on the contrary, does not overrate the medial injury and can safely be used in the decision making process of treating conservatively and weightbearing (for example by using a brace) introduction: the purpose of this study was to identify the effect of the intravenous iron supplementation on demand of perioperative blood transfusion and post-operative hemoglobin recovery in geriatric hip fractures. material and methods: a retrospective cohort study was performed on patients who underwent surgery with proximal femoral nail for hip fracture and age years old or older between jan and may in a single center. the participants were divided into groups according to preoperative intravenous iron supplementation (iron isomaltoside, monofer Ò , pharmacosmos, holbaek, denmark); group (n = ) with monofer mg before surgery and group (n = ) without monofer. transfusion was preformed when the hgb was less than mg/dl). primary endpoint was incidence of perioperative transfusion. secondary endpoints were various hemoglobin (hgb) levels. results: the average age of the participants were . years old, and average body mass index (bmi) was . . demographic data including age, sex, bmi, comorbidity (charlson comorbidity index) of each group showed no difference. the complications from intravenous iron administration were not occurred. the preoperative hgb was . mg/dl (group . ± . vs, group . ± . , p = . ). the hgb at the postoperative day was . mg/dl (group . ± . vs group . ± . , p = . ). the average hgb at the postoperative month was . mg/dl (group . ± . vs group . ± . , p = . ). transfusion rate was . % ( / ) and the rate showed no difference between groups ( . % vs . %, p = . . the recovery of hgb between postoperative month and preoperative state showed statistically difference (group . vs group -. , p = . ), and iron supplementation group had more recovery. conclusions: intravenous iron supplement before the hip fracture surgery in elderly helped to recover hgb at postoperative month. comminuted subtrochanteric femur fractures-our experiences introduction: subtrochanteric femoral fractures account for approximately % of all the hip fractures and their treatment represents a challenge because of the short proximal fragment and highenergy forces. material and methods: a total of patients with subtrochanteric, highly comminuted fractures, were included in this study, with age range from to years. the mechanism of injury in all patients was high-energy trauma. in each case we applied a long gamma nail (limma lto) without focus opening. results: in all patients, good clinical and radiologic results were accomplished, in addition to early weight-bearing, without shortening of the legs, or consequences on the state of the hip and morbidity in general. conclusions: although the comminuted subtrochanteric femur fractures represent a challenge for the orthopedic surgeons, osteosynthesis using long gamma nail without the focus opening provides outstanding results. introduction: this study analyzed the association between the postoperative reduced position obtained on using short femoral nails (sfns) and the amount of sliding after fixation in unstable trochanteric fractures. material and methods: this retrospective study included patients with unstable trochanteric fractures with posterolateral support deficiency who underwent osteosynthesis with sfns and were followedup for months or longer. the study included men and women with a mean age of . years at the time of fracture. closed or open reduction was performed to achieve anatomical to medial type position on frontal view and anatomical to extramedullary type position on lateral view, followed by fixation with sfns. immediately and extramedullary type in patients immediately after surgery. three months after surgery, the reduced position worsened from the anatomical to intramedullary type in patients. according to the reduced positions at months after surgery, the mean amount of sliding was . mm in patients with intramedullary type, . mm in those with anatomical type, and . mm in those with extramedullary type. the amount was larger in those with intramedullary type than in those with anatomical and extramedullary types. moreover, excessive sliding was observed in patient with intramedullary type. conclusions:to prevent excessive sliding by ensuring anteromedial bony support in unstable trochanteric fractures with posterolateral support deficiency, open reduction should be aggressively performed to overcorrect to the extramedullary type when reduction performed on a traction table results in either anatomical or intramedullary type positioning. in this paper, we report patient previously studied for osteomyelitis caused by high-energy missile trauma, in . that study involved a total of patients with osteomyelits, divided into two groups, according to the treatment protocol applied. the group included patients treated using classic surgical methods, including debridement, curretage, forage, perfusion drainage and sequestration. the group included patients treated using recommended surgical methods and used pmma antibiotic beads. years after, we tried to contact all of the patients, for the purpose of follow-up. however, only patient was available for analysis. among patients we followed-up, were treated using recommended surgical protocol, while the remaining patients were treated using classic surgical methods. we present the patients' general status, as well as the local surgical status and radiographic analysis, years after. we obtained long-term results of both treatment protocols applied. from the group , patients developed chronic recurrent osteomyelitis, while only one patient from the group developed such condition. introduction: the aim of this study was to evaluate the treatment results using anterior subcutaneous internal fixation(infix) for the pelvic fractures and to consider an improvement strategy for the complications. material and methods: from to , pelvic fractures were enrolled. there were two males and females. the average age was years. there were fragility fractures and five high energy fractures. our operative procedure was as below: the connection between screws and rod was just above the fascia of the sartorius muscle. the connection bar was pre-bended before the operation using the initial axial ct scan. we assessed bone union, additional fixation, the distance between the femoral artery and connection rod (dar), the distance of protruded bar lateral to the connection (dpb), and complications. results: bone union achieved in out of cases. there was one nonunion and three early deaths because of medical complications. seventeen out of cases required additional posterior fixations. the average dar was . ( . - . mm) , and the dpb was . ( - ) mm. thirteen out of cases ( . %) had complications. there were seven lateral femoral cutaneous nerve (lfcn) symptoms ( required implant removal (ir)), two infections ( required ir), one hematoma (ir), one irritation (ir), one heterotopic ossification, one loosening (re-operation). there were no femoral vessels and nerve-related symptoms. to release lfcn and surrounding soft tissues decreased the nerve symptoms. conclusions: to connect the screws, and the rod just above the sartorius fascia could avoid major vessels and nerve complications, and also irritations. although this study found a high complication rate of infix, to release the lfcn and around soft tissue could decrease the complications. introduction: several studies have reported that posterior or anterior tilt increases the risk of reoperation in undisplaced femoral neck fractures (garden i/ii) after internal fixation performed using nonangular stable devices such as pins and multiple screws. however, to the best of our knowledge, there is limited research involving angular stable devices. the present study aimed to investigate the clinical outcomes in undisplaced femoral neck fractures after internal fixation using angular stable devices. material and methods: this retrospective study included patients (mean age, . [range, - ] years) who underwent internal fixation using angular stable devices between january and january . undisplaced femoral neck fractures with garden alignment index (gai) b °(posterior tilt angle c °) or gai b °( anterior tilt angle c °) were included (posterior: , anterior: ) in this study. patients were followed up for at least months (mean, . months). we analyzed the preoperative and last-followed gai on lateral radiographs, non-union, and late segmental collapse (lsc). results: among the patients, non-union was identified in ( . %) and lsc was observed in ( . %). the mean preoperative gai was . °(range, °- °), and the mean last-followed gai was . °( °- °). the overall complication (non-union and lsc) rate was . % ( / patients). among patients with gai c °, lsc occurred in ( . %). conclusions: in undisplaced femoral neck fractures, preoperative posterior c °is a risk factor for postoperative complications even when internal fixation is performed using angular stable devices; thus, primary arthroplasty may be considered. case history: the patient is a -year-old female who had undergone lumpectomy at the age of when she was diagnosed with breast cancer. she had antiresorptive drug therapy for bone metastasis, since years after the lumpectomy. she fell down from standing height and was diagnosed as right femoral subtrochanteric fracture. her femur was fixed with short femoral nail. she complained left hip pain at age .she complained left hip pain from july . clinical findings: she could walk with crutch.rom of left hip was normal. investigation/results: breast surgeon took mri and there was metastasis in the proximal part of femur. he thought the cause of pain was this metastasis. however, there was fracture line at the height of lesser trochanter when she visited our department. diagnosis: atypical fracture was strongly suspected, however, fracture line was little higher as normal atypical fracture. therapy and progressions: osteosynthesis with long femoral nail was performed months after first visit to our department because of increasing pain. pathological findings were metastasis and fracture. after surgery, radiation to femur was performed. she can walk without pain by crutch and fracture line is almost disappeared on months after surgery. comments: atypical femoral fractures (affs) are recently observed as a complication of antiresorptive drugs for bone metastasis. however, there were metastasis and atypical fracture in this case. introduction: in the present study we aim to evaluate the articular surface reduction quality by means of postoperative computer tomography (ct), in complex tibial plateau fractures, treated with an illizarov frame. materials and methods: this retrospective case series covers the period from - to - . forty-four patients with a mean age of years (range - years), with a complex intrarticular proximal tibia fracture were included. fracture types iii to vi according to schatzker's classification were included. the majority were closed injuries, apart from cases (a gustilo anderson type a and a type ). all patients were placed on a fracture table. a mini-open reduction of the articular surface was followed by application of a knee spanning illizarov frame. post-operatively all patients were subject to ct of the injured knee. outcomes were measured using the american knee society score. results: mean outpatient follow up was of at least months (range of - months). mean time for fracture consolidation . weeks (ranging from to weeks). according to the degree of postoperative articular surface depression patients were grouped as follows: had under mm, had - mm and over mm of depression. those with less than . mm of collapse had % chances of an excellent result according to akss. on the contrary, those with more than . mm of articular surface collapse had % chances for low scores and functional results. the achievement of a mechanical axis within °of the contralateral limb was positively correlated with good functional results but did not have a correlation with the akss. conclusions: complex tibial plateau fractures may be treated successfully with mini open reduction and the application of an illizarov frame. post-operative ct denotes the exact degree of displacement of the articular surface, which is prognostic regarding outcome. postoperative x-rays may be misleading, since they can underestimate articular surface collapse. introduction: a new trauma center building was constructed in march , and the process from the trauma bay to the operation room is faster. we hypothesized that this process improved the survival rate of trauma patients in need of trauma laparotomy. material and methods: the new trauma center separates the trauma bay from the emergency room, and the trauma team exam patients initially. it also has a separate operation room that is always available for emergency surgery. therefore, the decision to perform laparotomy and time to operation has been shortened. from january to december , trauma patients who underwent emergency laparotomy were included. those younger than years, who had delayed operation, underwent surgical observation, delayed admission by patient, or underwent angiography first were excluded. patients were dichotomized to the before-trauma-center (bc) and after-traumacenter (ac) groups, and their characteristics and clinical outcomes were compared. results: of patients, were included in the bc group and were included in the ac group. the times from admission to operation introduction: acute care is a growing worldwide burden with increasing visits to the emergency department (ed). the acute care system in the netherlands is almost overloaded and costs are increasing. almost % of ed visits have surgical disease. there is no nationwide acute care surgery (acs) model implemented yet, and resources and infrastructure are organized differently in almost every hospital. this study provides an overview of the existing systems nationwide, and basis for a national uniform model. material and methods: an online survey was distributed through the dutch surgical society and sent to all dutch hospitals. after sending a reminder, the survey was closed and results were analyzed. results: thirty-two hospitals ( %) participated in the survey. in % a surgeon (trauma, vascular or gastro-intestinal) was assigned as consultant and responsible for ed admissions, emergencies in-house, and in some cases also emergency surgeries. % of hospitals have an ed observation unit (edou). a dedicated emergency surgery operating room (esor) is available in % ( / available in %), and used efficiently in % primarily due to the following challenges: elective surgery scheduled at esor ( %), necessary stop of esor when elective programs are delayed ( %). in hospitals without an esor, the emergency surgeries are scheduled in between elective surgeries resulting in extending programs into the evening. finally, % of respondents was familiar with acs, with % being positive about exploring options of implementing such a model in our country, and % of the respondents opts for more focus on acs in surgical residency. conclusions: in the netherlands the organization of acute care varies. the main common bottleneck is the logistics around the or. implementation of a dedicated esor and unconditional availability / of this or seem to be the most important factors for optimal efficiency. although there needs to be more focus on acs in general, implementing a uniform model nationwide seems challenging at this moment. trauma team activations (tta) at an european trauma center: cases analyzed s. saar , , e. lipping , h. vospert , r. volmer , h. k. laas , j. lepp , k. g. isand , p. talving , north estonia medical centre, division of acute care surgery, tallinn, estonia, university of tartu, tartu, estonia, north estonia medical centre, tallinn, estonia introduction: the north estonia medical centre (nemc) is the largest trauma center in estonia with evolving capabilities. however, studies scrutinizing trauma team activations (tta) are currently lacking. thus, we initiated an investigation to document tta profile and outcomes. material and methods: all tta patients admitted to the nemc between / and / were retrospectively identified. data collected included demographics, injury severity score (iss), management, hospital length of stay (hlos), and in-hospital outcomes. primary outcome was -day mortality. results: overall, patients were included. mean age was . ± . years and . % were male. penetrating and blunt trauma accounted for . % and . % of the cases, respectively. non-ground level falls were the predominant mechanism of injury constituting . % of the admissions. mean iss was . ± . and . % of the patients were severely injured (iss [ ). blood alcohol level (bal) was positive at . %. a total of . % of the patients had an emergent operation. mean hlos was . ± . days.overall -day mortality and mortality of severely injured patients was . % and . %, respectively. conclusions: the current investigation documents comparable outcomes with established european trauma facilities [ , ] . blunt injury patterns predominate, however, high penetrating trauma incidence for european settings was noted. high rate of positive bal in tta patients warrants national preventive measures. introduction: the acute care surgery (acs) model was initially developed as a dedicated service for the provision of high quality / non-trauma emergency surgical care. after implementation in the united states (us), the model has been adopted in several variations around the world.in this systemic review we investigated which components are essential for a potential uniform acs model, by giving an overview of the current available acs models worldwide and their state of implementation. material and methods: a literature search ( - ) was conducted using pubmed, medline, embase, cochrane library and web of science databases following the prisma guidelines. all relevant data of acs models were extracted from included articles. results: sixty-five articles describing acs models in different countries were included in this review. the majority consist of a dedicated surgical service, providing non-trauma emergency surgical coverage, with daytime on-site attending coverage by an attending surgeon who is cleared from elective duties, and / in-house resident coverage. emergency department coverage and access to an acute care operating room varied widely across countries. critical care is fully embedded in the original us model as part of the acute care chain (acc), while in most other countries it is still a separate unit. while in most european countries acs is not a recognised specialty yet, there is a tendency towards more structured acute care, with training and separation from elective practice. conclusions: acs is gradually implemented worldwide. however, large national and international heterogeneity exists in the structure and components of the model. critical care is still a separate unit and specialty in most systems while it is essential to be part of the acc in order to provide the best peri-operative care of the physiologically deranged patient. universal acceptance of one global acs model seems challenging, however a global consensus on essential components would benefit any healthcare system. introduction: the recent financial crisis in greece is coped mainly with reformations towards cost effectiveness and rationality in the management of public expenses. the goal of the study is to evaluate the cost and time effectiveness in the management of the surgical patients admitted in emergency department (ed). methods: for a period of h/day in consecutive days, surgical cases presented in the ed of a tertiary university hospital of athens were followed. inclusion criteria were need for laboratory tests or imaging examinations or an immediate resuscitative intervention. data recorded regarding demographics, vitals, critical time points, disease and management. physician related data and cost of examinations were also collected. case severity was calculated by early warning score [ ] . results: she average waiting time for each patient was min and the average total time until final decision was : h. blood tests costs reached an average of , € per case and imaging an average of , €. the striking finding was that only one out of patients was of medium clinical risk, while all the others were of low. thus, substantial symptoms and clinical findings were lacking and as the ''tertiary care'' character of the hospital was mandating conclusive diagnosis, exams were ordered. this approach absorbs time and funds putting at risk the very few severe cases which are the target population for the magnitude of the facility. the current study indicates that the use of a tertiary hospital as a primary health care center by the public, is disorganizing the system, and increase the cost in time, funds, and preventable morbidity and mortality. a pre-hospital triage and management of the low severity cases system is pending to be established in our environment and becomes top priority in an era of prolonged financial crash. for years, surgical emergencies in ecuador have been managed without significant standardization. scarce numbers of specialists, lack of a constant presence of full-time teaching faculty versed in emergency surgery and lack of continuity with surgical trainees led to variability in clinical and surgical decision-making. to address these issues, the regional hospital vicente corral moscoso (hvcm) adapted and implemented a model of ''trauma and acute care surgery'' (tacs) to the reality of cuenca, ecuador. a cohort study was carried out, comparing trauma and acute care surgery patients exposed to the ''traditional care model'' before the implementation of the tacs model. variables assessed included: surgical wait times, number of hospital visits, number of surgical interventions, number of surgeries performed per surgeon and inhospital mortality. higher mortality was found in the traditional care model (rr of . , p b . ) compared to the tacs model. we observed a statistically significant decrease in surgical wait time ( . - . h for emergency general surgery, . - . h for trauma, p b . ). lengthof-stay decreased in trauma patients ( - days p b . ). the total number of surgical interventions increased ( , . - , . , p b . ) ; by extension, the total number of surgeries performed per surgeon also increased ( . - . , p b . ) . the implementation of tacs model in a typical resource-restrained, tertiary care hospital in latin america had a positive impact by decreasing surgical waiting time in trauma and emergency surgery patients, and length-of-stay in trauma patients. we also noted a statistically significant decrease in mortality. while cost could not be objectively evaluated with the available data, savings to the overall system and patients can be inferred by decreased mortality, length-ofstay and surgical wait times. to our knowledge, this is the first implementation of an tacs model that has been described in latin america. introduction: traumatic injuries constitute one of our major public health challenges. the most effective means to reduce the impact trauma has on individuals and society is primary injury prevention, reducing the incidence of traumatic events, which relies on detailed knowledge of risk factors. the aim of this study is to facilitate targeted injury prevention through improved data collection and analysis on impairing substances as risk factors for traumatic injuries. material and methods: idart is a national prospective observational study including analyses of the toxicological profile of all patients c year of age admitted via trauma team activation to any norwegian trauma hospital (n ) during a month study period. residual blood from routinely drawn blood samples at trauma admission is analyzed for alcohol, illegal and psychoactive drugs. toxicological data will be linked to clinical data from the national trauma registry. results: the study period started march st, , and during the first months patients were included from trauma hospitals. more than % of the included patients tested positive for psychoactive substances according to preliminary data. data on the prevalence of different psychoactive substances disaggregated by mechanism of injury, demography and geography from the month study period will be presented. conclusions: the idart study will provide a detailed descriptive analysis on the prevalence of alcohol, illicit and medicinal drug use among all patients admitted to a norwegian hospital with suspected severe injury. subgroup analyses will include prevalence of alcohol and other substances in subgroups analyses on patient and injury characteristics and geographical variations. analyses will aim to identify high risk groups according age, gender, circumstances of the injury, geographical location and type of psychoactive substance. the dutch nationwide trauma registry: the value of capturing all acute trauma admissions m. driessen , l. sturms , l. leenen lnaz/umcu, trauma surgery, nijmegen, netherlands introduction: twenty years ago the dutch government decided to reform the trauma care system and designated level regional trauma centers (rtcs). these centers, in collaboration with ambulance services and regional hospitals, have managed to set up regionalized inclusive trauma systems. moreover, they set up the dutch national trauma registry (dntr) as a quality evaluation and epidemiology resource. in this resource all acute hospital admissions were included, in order to measure the hospital and prehospital processes and outcomes. in the current study we demonstrate its current status and compare it with national trauma registries from the uk and germany. material and methods: the dntr includes all injured patients treated at the ed of % of all hospitals in the netherlands within h after the trauma followed by direct admission, transfer to another hospital or death at the ed. a representative descriptive analysis of extracted data from is demonstrated. results: between and a total of , trauma cases have been registered in the dntr. hospital participation has increased from % up to %. in alone, a total of . patient were included, % concerned males, the median age was years. % of all admissions had an iss c , of which % was treated at a rtc. from this cohort, in comparison, only % and % of the dntr patients met tr-dgu or tarn inclusion criteria. particularly children, elderly and patients admitted at non rtcs are not captured in the tr-dgu or tarn. also, part of iss c and fatal cases do not meet tr-dgu or tarn inclusion criteria. conclusions: the dntr has evolved into a comprehensive wellstructured nationwide population-based trauma register, with an annual number of , cases being entered in the database the dtr has grown to be one of the largest trauma databases in europe. the registry enables studies on the injury burden and quality and efficiency of the entire trauma care system encompassing all traumareceiving hospitals. introduction: trauma mortality is not distributed evenly. rural areas have higher incidence rates of trauma mortality than urban areas. the rural northern part of the nordic countries have common challenges with sparsely populated areas, long distances, and an arctic climate. the aim of this study was to compare the cause and rate of fatal injuries in the northernmost area of the nordic countries over a fiveyear period. material and methods: in this retrospective cohort we used the cause of death registries and collated all deaths from to with an external cause of death (icd- , v -y , except y - and t - ). the study area was the three northernmost counties in norway, the four northernmost counties in finland and sweden and the whole of iceland. we used % confidence intervals (ci ) to test for differences between the countries. results: there were deaths in the study area during the -year period. low energy (le) trauma constituted % and high energy (he) trauma % of deaths. northern finland had the highest incidence for both high energy trauma and low energy trauma. iceland had the lowest incidence for high-, and low energy trauma. iceland had the lowest prehospital share of deaths at % and the lowest incidence of injuries occurring in a rural location. the incidence rates for he trauma death was , / . /year in northern finland, , / . /year in iceland, , / . /year in northern norway and , / . /year in northern sweden. conclusions: there were significant and unexpected differences in the epidemiology of trauma death between the countries. the differences suggest that a comparison of the trauma care systems and preventive strategies in the countries is required. the diurnal and seasonal relationships of pedestrian injuries secondary to motor vehicles in young people introduction: there remains a significant morbidity and mortality in young pedestrians that are hit by motor vehicles, even in the era of pedestrian crossings and speed limits. the aim of this study was to compare incidence and injury severity of motor vehicle-related pedestrian trauma according to time of day and season in a young population. we hypothesised that injuries in young people would be more prevalent during dusk and dawn and during autumn and winter. material and methods: data was reviewed from patients in the - year old age group in the trauma audit and research network (tarn) national database, who had been involved as a pedestrian in a motor vehicle accident between and . the incidence of injuries, their severity (using the injury severity score [iss]), hospital transfer time and mortality were analysed according to the hours of daylight, darkness and seasons. results: . % of injuries occurred during time of darkness post sunset, while . % occurred during daylight. the incidence of injuries in motor vehicle accidents, in absolute terms, was highest during - , with a second peak at - . the greatest injury rate (number of injuries/hour) occurred during - and - with respective rates of . and . injuries scoring an iss over occurred . % at - and a further . % until . mortality was greatest during - involving out of the total deaths. autumn was the predominant season and lead to . % of injuries, with a further . % in winter. this demonstrated a clear difference to . % and . % in spring and summer. conclusions: we have identified a relationship between reduced daylight and the frequency and severity of pedestrian trauma in young people suggesting that reduced visibility may play a significant role which could be addressed through a targeted public health approach to implement change. enhancing cost effectiveness in a system in crisis: a , patient study a. tsolakidis , c. christou , p. smyrnis , a. prionas , a. tooulias , g. tsoulfas , v. n. papadopoulos aristotle university of thessaloniki, st department of surgery, papageorgiou general hospital, thessaloniki, thessaloniki, greece introduction: to date, there is no national trauma database in greece. the goal of our study is to record and evaluate trauma management at our university hospital as well as to measure the associated healthcare cost, while laying out the foundations for a national database. material and methods: retrospective study of trauma patients (n = , ) between and . demographic information, injury patterns and severity, outcomes and cost were recorded. results: the proportion of patients that were transferred to the hospital by the national emergency medical services was , %, whereas ( %) of our trauma patients did not meet the us trauma field triage algorithm criteria. over-triage of trauma patients to our facility ranged from . to . %, depending on the criteria used. ( . %) of our patients received operative management and % ( ) of them had postoperative complications. an iss [ was seen in ( %) of our patients and their mortality was , %. the overall non-salary cost for trauma management was . . euros. the cost resulting from the observed over-triage ranged from . to . . euros. furthermore ( . %) of our patients underwent at least one ct scan that did not show any significant traumatic lesion. the cost of hospitalization of these patients was . euros. conclusions: the prehospital triage of trauma patients in the greek national health system is ineffective, with significant over triaging, leading to excessive costs. appropriate use of criteria for diagnostic procedures and algorithms may lead to a, much-needed, reduction of these costs. introduction: in japan, there are emergency and critical care centers nationwide (one center for approximately every , people), and a system is in place to accept local critically ill patients h a day, irrespective of whether their conditions are intrinsic or extrinsic. however, manpower and medical care systems differ depending on the emergency and critical care center, and the establishment of a system for consolidating severe trauma patients has been particularly problematic. material and methods: this study examined cases where the patient had some sign of life when encountered by ambulance teams of the cases of traffic accident deaths that occurred in chiba prefecture between and . thirteen emergency and critical care center representatives in chiba prefecture met to verify each case based on data from the police, fire department, and medical institutions. the cases were classified into ( ) preventable trauma death (ptd) cases, ( ) suspected ptd cases, and ( ) non-life-saving cases; the problems (causes of ptd) in each case were examined. result: there were cases ( %) of ptd and suspected ptd. sixty-eight of these cases were transported to emergency and critical care centers. the most common cause of death was bleeding, accounting for cases and the locations where the problems that caused ptd occurred were outside of the hospital (n = ) and in the hospital (n = ). the problems that occurred in the hospital (including duplications) include circulatory management (n = , %), the treatment plan (n = , %), delay of lifesaving surgery (n = , %), and delay of diagnosis (n = , %). most of these occurred in the initial emergency care room. conclusion: this study clarified that ptd still occurs in relation to bleeding control in the current trauma care system in chiba prefecture. it is vital to establish a national ''trauma center'' and to thoroughly consolidate trauma cases to eradicate ptd. analysis of the impact of the implementation of a trauma team in a trauma center from an upper-middle-income country introduction: trauma teams (tt) improve the care process and the outcomes. a multidisciplinary tt was conformed in september to achieve a rapid response by specialists in emergency medicine, trauma surgery, diagnostic imaging services, and blood bank in a level i trauma university hospital in southwestern colombia. objective: to evaluate the impact of a tt implementation in terms of times of attention and mortality. material and methods: retrospective study. all the patients with the highest level of tt activation treated in the months after the tt implementation were included. the subjects triaged to the trauma center in the months pre tt were taken as controls. four hundred sixty-four patients were included, before the implementation of the tt (btt) and after (att). demographic data, trauma characteristics, times to tomography, and trauma surgery and mortality were recorded. the analysis was made on stata , Ò . categorical variables were described as quantities and proportionscontinuous variables as mean and standard deviation or median and interquartile range (iqr). categorical variables were compared by chi or fisher's test. continuous variables with student's t or wilcoxon-mann-withney. a multiple logistic regression model was created to evaluate the impact on mortality if being treated att, adjusted by age, trauma severity, and physiologic response on admission. results: the time from admission to the ct scan was min (iqr - ) in the btt group and min (iqr - ) in the att group, p &lt; . . the time to trauma surgery was min (iqr - ) in the btt group and min iqr - ) in the att group, p &lt; . . mortality in the btt group was . % and . % in the att group. adjusted or was . ( . - . ) p = . conclusions: the implementation of a multidisciplinary trauma team associated with a reduction of the times to tomography and surgery and with a decrease in mortality risk. no prediction of an unfavourable outcome after surgical treatment of chronic subdural hematoma patients using machine-learning l. riemann , a. younsi , c. habel , j. fischer , a. unterberg , k. zweckberger university hospital heidelberg, neurosurgery, heidelberg, germany introduction: chronic subdural hematomas (csdh) are expected to become the most frequent neurosurgical disease by the year . although often perceived as a ''benign'' condition, considerable rates of mortality and poor outcome have been reported. we therefore evaluated factors associated with an unfavorable outcome after surgical treatment of csdh patients by developing a predictive model using machine-learning. material and methods: consecutive patients treated for csdh with surgical evacuation between and at a single institution were retrospectively analyzed. potential demographical, clinical, imaging and laboratory predictors were assessed and a decision-tree predicting unfavorable outcome (gos - ) was subsequently developed using the classification and regression tree (cart) algorithm. out-of-sample model performance was evaluated using repeated cross-validation (fivefold with repetitions). results: eligible patients were analyzed. median age was (iqr - ) years and % were males. mortality rate was . % and rate of unfavorable outcome was . %. the developed decision-tree to predict unfavorable outcome had splits and included the following clinical variables (in descending order of calculated importance): gcs, comorbidities, hb, and age. after cross-validation, the following model performance metrics were obtained: a model accuracy of . ( . - . ), sensitivity of . ( . - . ), and specificity of . ( . - . ). conclusions: gcs, comorbidities, hb, and age were identified as the most important clinical predictors for an unfavorable outcome in csdh patients after surgery. the developed model was simple and still displayed a high accuracy and very high specificity, the sensitivity was however rather low. our results might help clinicians to better assess the prognosis in patients with csdh. introduction: in most developing countries access to tertiary care neurosurgical setup is uncommon. majority trauma including neurotrauma & medical conditions requiring emergency neurosurgical interventions present to a general surgeon. this study is an attempt to highlight the importance of emergency neurosurgery as a skill amongst general surgeons & also focus on the challenges in managing such cases in austere environments material and methods: this study was a retrospective analysis of progressively collected data of trauma patients with a specific focus on head injuries & emergency neurosurgical interventions for both traumatic & non traumatic indications in a level trauma centre in a semi urban area over a period of years from august to september results: a total of patients of trauma were analysed out of which were head injuries. road traffic accidents accounted for nearly % of head injuries. atypical trauma especially in rural setup e.g. train collision, animal related causes were also seen. males accounted for majority (m:f = . : ). mean age was yrs. patients had imaging findings suggestive of severe head injury. acute sdh was the commonest post traumatic finding and mca territory infarct in non traumatic group. patients underwent emergency neurosurgical intervention with a survival of %. factors associated with poor outcome were delayed presentation (p \ . ), sdh with diffuse axonal injury. alcohol consumption was a significant factor. conclusions: emergency neurosurgery is an essential skill for general surgeons. performing such cases in a low resource environment in absence of modern day facilities for imaging, icp monitoring & powered equipment presents a significant challenge. general surgeons should be able to perform operative interventions with basic handheld instruments. operative management whenever indicated should be done & helps improve outcomes. head trauma in polytraumatized patient. analysis of risk factors and neurological prognosis b. castro , , , m. morote gonzález , , , l. cebolla , , , a. sada , , , l. seisdedos , , , , , j. gil , c. rey valcárcel , , f. j. turégano fuentes , , c. tristan , c. ruiz moreno hgugm, surgery, madrid, spain, hospital, madrid, spain, hospital, madrid, spain, hospitall, madrid, spain, hospital, madrid, spain, hospital, madrid, spain, hospital, madrid, sri lanka introduction: severe trauma is one of the most frequent causes of death and disability and traumatic brain injury (tbi) in polytrauma is the main cause of death and disability in survivors. the aim of this study is to analyze mortality associated to tbi in the last years, prognostic factors associated with it and neurological outcomes in survivors with tbi. methods: retrospective observational study that includes risk factors and functional neurologic evaluation in polytrauma patients attended in gregorio marañon hospital between - . inclusion criteria were severe trauma patients (iss c ) with a tbi and abnormal ct of the head. we analyzed mortality trend in two periods : - and - , and neurological evolution and outcome at discharge with functional scores (ramkin scale and gos) in the second one. results: from to , severe trauma patients were admitted, ( , %) with brain or central nervous system injuries visible on head ct. median age was ' ; . % were men. the global mortality of the cohort has been , %, . % of them for neurological causes. ischemic heart disease, anticoagulation, abnormal pupils or eye opening, the need for surgery, shock, gos, iss, niss, cranial ais are significant associated with higher mortality (p \ , ).the mortality rate due to neurological causes decreases in the second period from , to , %, this descent being statistically significant (p = , ). between and , % patients died from cnsi, and , % of tbi survivors had a vegetative status at discharge, , % had major disability, and , % had a good neurological recovery. conclusions: mortality due to tbi decreased in the last years, but this improvement after tbi was at the expense of a high rate of vegetative status and great disability, showing the need for continuous research in this area. introduction: severe traumatic brain injury (tbi) constitutes one of the most frequent causes of intensive care unit admissions and is a major cause of death and disability among young people. decompressive craniectomy (dc) is a life-saving measure used to relieve intracranial pressure (icp). this procedure is related with low mortality rates and poor functional outcomes. the aim of this study is to analyze the survival rates and prognostic factors related with functional outcomes after dc for severe tbi. material and methods: retrospective, single center study of patients with severe tbi in whom a dc was performed between the years and . demographic features, clinical parameters, radiological findings and clinical outcomes were included in the study. for the statistical analysis we used anova, chi-square, kaplan meyer, cox regression and logistic regression. a p value of less than . was considered to indicate statistical significance. results: the mean initial glasgow coma scale was , ± , and the mean initial motor response (imr) was , ± , . the mean icp after dc was , ± , . the -day survival after dc was %. twenty percent of the patients improve ate least point in the glasgow outcome scale (gos) between and months after surgery. twelve patients improve from unfavorable gos to favorable gos. at -month follow-up, % of the patients has gos [ . younger age, high irm a post-operative icp were the factors significantly associated with a higher chance of outcome improvement. conclusions: dc is useful for the management of refractory intracranial hypertension related to severe tbi, and in selected patients is associated with good functional outcomes. introduction: antiplatelets and anticoagulation, commonly referred to as antithrombotic therapy, are frequently used in patients c years. the use of antiplatelets and anticoagulation are associated with increased incidence of intracranial bleeding ( , ) . there are two research questions addressed in this study: ( ) does preinjury antithrombotic therapy affect survival in elderly patients with tbi? ( ) are direct oral anticoagulants (doacs) associated with better survival than vitamin k antagonists (vka) in tbi patients on anticoagulation? materials andmethods: retrospective cohort study based on data extracted from the oslo tbi registry. included in the study are tbi patients c years admitted to ouh with cerebral-ct showing signs of acute trauma (hemorrhage, fracture, vascular injury) in the time period - . the impact of age, comorbidity, antithrombotic medication and antithrombotic reversal protocol for survival will be explored. results: the patient inclusion is ongoing. preliminary data will be presented at the st ectes in april . the estimated number of tbi patients c years with cerebral-ct showing signs of acute trauma in the study period is * . in this patients group, the expected preinjury use of antiplatelet and anticoagulation medication is * % and * %, respectively. conclusions: the knowledge regarding impact of preinjury antithrombotic therapy on survival in elderly tbi patients is clinically relevant, and may improve patient management in the acute phase of injury. references: introduction: traumatic acute subdural hematoma (asdh), especially the large ones in need of surgical evacuation, is associated with high mortality. contemporary population-based series of surgically treated asdh are sparse. the two main aims of this single-center study from oslo university hospital (ous) were to estimate incidence of surgery for asdh in the population of helse sør-Øst, and estimate in-hospital and -month survival of these patients. treatment of tbi at ous adheres to the brain trauma foundation guidelines, with icp controlled therapy and evacuation of asdh when gcs \ and hematoma volume c cm or midline shift c mm or hematoma width [ mm. the goals of tbi treatment for adults have been to maintain icp \ mmhg and cerebral perfusion pressure (cpp) c mmhg. methods: from . . all patients with traumatic brain injury (tbi) with positive head ct, admitted to ous, living in helse sør-Øst ( . million inhabitants) and having a norwegian social security number, have been included in our approved tbi-quality register. included in the present study are all patients with asdh undergoing evacuation of the hematoma within days of trauma. the following data were extracted from the register; demographic variables, date of injury and trauma mechanism, severity of head injury according to hiss grade, rotterdam ct score, surgical procedures, multitrauma, glasgow outcome scale at discharge and date of death. results: asdh patients were operated in the -year period - , % males, mean age was years ( - ), the most frequent trauma mechanism was falls ( %), % were under influence of ethanol, % had severe tbi and % had multitrauma. the incidence of surgically treated asdh in helse sør-Øst was / . /year. in-hospital and -month mortality was . % and %, respectively. conclusion: the presented data for incidence and mortality will be compared with earlier reports. age-related difference in impacts of coagulopathy in patients with isolated traumatic brain injury: an observational cohort study w. takayama , a. endo , y. otomo tokyo medical and dental university hospital of medicine, trauma and acute critical care, tokyo, japan background: age and trauma-induced coagulopathy (tic) have been reported to be the predictors of poor outcome following traumatic brain injury (tbi). whether the impact of brain injury induced coagulopathy on outcomes have age related differently is unknown. objectives: we evaluated the age-related difference in the impact of tic on outcomes in patients with isolated tbi. methods: a retrospective observational study was conducted in two tertiary emergency critical care medical centers in japan from to . the patients with isolated tbi [head abbreviated injury scale (ais) c , and other ais \ ] were included. we evaluated the impact of coagulopathy (international normalized ratio c . , and/or platelet count \ /l, and/or fibrinogen b mg/dl) on the outcomes [glasgow outcome scale-extended (gos-e) scores, inhospital mortality and ventilation free days (vfd)] in both group using univariate and multivariate models. furthermore, we visualized the impact of coagulopathy on gos-e according to age, by using a generalized additive model. results: of the patients studied, they were divided based on their age: non-elderly group (n = , - years) and elderly group (n = , age c years). although, in the multivariate model, age and coagulopathy were significantly associated with lower gos-e, in-hospital mortality and shorter vfd in the non-elderly group, significant impact of coagulopathy was not observed for all the outcomes in the elderly group. the correlation between coagulopathy and lower gos-e decreased with age after round years old. conclusions: in patients with isolated tbi, impact of coagulopathy on functional and survival outcomes was lower in geriatric patients. no difference in mortality between isolated tbi and polytrauma with tbi: it is all about the brain introduction: despite improvements in trauma and critical care mortality caused by traumatic brain injury (tbi) remains high. [ ] as polytrauma is naturally associated with increased mortality, this study compared mortality rates in isolated tbi (itbi) patients and polytrauma patients with tbi admitted to icu. material and methods: a -year retrospective cohort study included both consecutive trauma patients with itbi with ais head c (ais of other body regions b ) and polytrauma patients with ais head c admitted to a level-i trauma center icu. patients \ years of age, injury caused by asphyxiation, drowning, burns and transfers from and to other hospitals were excluded. patient demographics, shock and resuscitation parameters, denver multiple organ failure scores and acute respiratory distress syndrome (ards) data were collected. [ ] data is shown as medians with interquartile ranges. p-values \ . were statistically significant. results: a total of patients were included. the median age was ( - ) years, ( %) patients were male, median iss was ( - ). seventy-nine ( %) of all patients died. polytrauma patients developed more often ards ( % vs % p = . ) but had similar mods rates ( % vs % p = . ). polytrauma patients stayed longer on the ventilator ( vs. days p b . ), longer in icu ( vs. days p b . ) and longer in hospital ( vs. days p b . ). there was no distinction in in-hospital mortality of itbi and polytrauma patients ( % vs. % p = . ). tbi contributed to all deaths in itbi patients and all but three deaths ( %) in polytrauma patients. conclusions: tbi was the main cause of death in both groups. there was no difference in mortality rates between polytrauma patients with tbi and itbi patients, even though polytrauma patients were more severely injured. references: [ ] dewan mc et al. estimating the global incidence of traumatic brain injury. j neurosurg. ; ( ): - . no significant relationships or conflict of interests. how modeling the brain ventricles could help brain trauma understanding ( ). in pathological cases as in hydrocephalus, or in brain trauma, it is likely that each patient's ventricle structure has an impact on the way they behave. for instance, a shock wave may turn out differently according to the ventricle's shape. this can explain why for a same shock, the clinical translation is not the same. the aim of the study is to implement a finite element model of the cranio-cerebral system and to analyse the impact of a trauma simulation. material and methods: this is amonocentricretrospective study from . the database contains ct scans of healthy patients. we used itk-snap software to segment the ventricles and matlab to implement the model. results: the mean volume of the total ventricles is ml (sd = ). the median is ml (table ) .to identify the correlation between the parameters acquired we performed a pearson test. we found multiple significant correlations and one of the most relevant one is between the ventricular volume and the width of the third ventricle ( table ). showing that the total ventricular volume is statistically correlated to the width of the third ventricle is clinically interesting. we could potentially simplify our analysis of the ventricular system in head trauma by measuring less coordinates and yet come up to an accurate prognosis. the ventricle volumes are used as neuroimaging marker of brain changes in health and brain trauma. to our knowledge, it is the first time they are studied in vivo on ct-scan. this study and the existing correlations are relevant for the configuration of the finite element model on going. it can surely help the comprehension of the interaction between the structural parts of the cranio-cerebral system during brain trauma. (excitatory-glutamate, and inhibitory-c-aminobutyric acid, gaba), is crucial for the normal cerebral functioning. gaba concentrations vary in different cerebral zones [ ] responsible for different cerebral tasks. in this study, [gaba] is measured in the posterior cingulate cortex (pcc) of children with acute mtbi. material and methods: acute mtbi patients (\ h since injury, . ± . y.o) and healthy controls ( . ± . y.o). mri scanner philips achieva t was used. standard mri protocol for tbi revealed no pathological lesions in brain of any subject. magnetic resonance spectroscopy (mega-press [ ] ) was applied to obtain gaba signal without macromolecules. spectroscopy voxel is demonstrated on fig. . intensities of gaba, glutamate ? glutamine, creatine and water signals were calculated in gannet program [ ] . absolute concentrations were calculated. mann-whitney was used to reveal the statistical significance of between-group differences. results: typical gaba spectrum processing in gannet is demonstrated on fig. . no changes in glx were found. the values of [gaba] in pcc are demonstrated on fig. : the increase in gaba is not statistically significant. conclusions: this is the first study of [gaba] in pcc of children with acute mtbi. the result of current work disagrees with our previous study, where gaba was increased (p \ . ) in the anterior cingulate cortex of children with mtbi [ ] . this indicates to a necessity of further data collecting in order to reveal any [gaba] alterations in various cerebral loci. this would help to identify the causes of an inhibition/excitation imbalance and to predict possible dysfunctions of cns following mtbi. results: tnaa and naag concentrations along with stable naa concentration were found to be reduced in patient group. reduced asp and elevated mi concentrations were also found. the main finding of the study is that tnaa signal reduction in wm after mild traumatic brain injury is associated with the drop of the naag concentration rather than of naa one, as it was thought previously. this highlights the importance of separation of these signals at least for wm studies to avoid misinterpretations of the results. naag plays an important role in its selective activation of the mglur receptors, thus providing neuroprotective and neuroreparative function immediately after mtbi. it might have potential for the development of new therapy strategy for patients with injuries of various severity. introduction: traumatic brain injury (tbi) is globally recognized as a major health and socioeconomic issue. however, reported numbers vary and often represent subgroups. the number of hospital-admitted tbi has an important impact on hospital resources. thus, the monitoring of hospitalized tbi patients is needed. in , oslo neurosurgical tbi registry was established and includes patients admitted to oslo university hospital (ouh) with traumatic intracranial injury identified by neuroimaging. the aim is to introduce the registry; describe the patient group and volume. material and methods: descriptive study from oslo neurosurgical tbi registry. results: patients from south-east region were included in - (population million). mean age was years (sd ), % were males. most frequent cause of injury was falls ( %), increasing with age. % was influenced by alcohol at time of injury. preinjury antithrombotic therapy was common ( %). most of the patients had multiple pathologies on ct caput, e.g. simultaneous cranial fracture, sdh, tsah and brain contusion (four most frequent). accompanying injuries were found in %. % was transported to ouh directly form accident scene. % was classified as severe tbi upon arrival ouh, % was intubated, and trauma team was activated in %. median annual and monthly numbers of cases were (range - ) and (range - ), respectively. no clear change in case load between years and months, except a slight decline in march. admission rate peaked during the weekend. patients were continuously admitted throughout day and night, [ % between : and : . conclusions: patients included in the registry were older than those included in previous tbi studies. the numbers of cases admitted were stable across the months and years. however, the majority of patients were admitted during weekends and nights; thus handled by duty staff. relationship between brain-body temperature difference and neurologic outcomes in patients with severe head trauma introduction: brain is one of the most vulnerable organ to temperature. the association between core body temperature(ct) and neurologic outcomes in patients with post-cardiac arrest, severe head trauma and stroke has been reported. there were few reports comparing brain temperature(bt) with ct and peripheral temperature(pt). we investigated the association of differences among bt, ct and pt with neurologic outcomes in patients with severe head trauma. material and methods: we retrospectively reviewed data for patients with severe head trauma who underwent monitoring intracranial cerebral pressure(icp), bt, ct and pt simultaneously between january and december . results: we evaluated patients with a median age of years (range - years). glasgow outcome scale(gos) at discharge were as follows: good recovery(gr) , severely disabled(sd) , vegetative state(vs) , death(d) . table showed the average values of icp, cerebral perfusion pressure(cpp), bt, ct, pt, differences between each temperature (bt-ct, ct-pt, bt-pt) and gos in each patients. there was remarkable difference between bt and ct in the dead patient, whereas less differences were found in the other alive patients. we found greater difference between bt/ct and pt in the vs patients than gr patients. conclusions: greater differences between bt/ct and pt can be related to poorer neurologic outcomes introduction: minor head traumas are difficult to assess even with guidelines, hence head cts are often requested. as head cts are increasingly accessible, the demand on the radiology department often exceeds its capacity. there has been an increase in head cts at the oslo emergency department (oed), norway. the scandinavian guidelines for initial management of head injuries in adults (sg) is standard practice in the oed when assessing patients with head trauma.the aim of this study is to assess the number of patients with traumatic brain injury, evaluate guideline compliance and false negative initial reports by junior radiologists. material and methods: a consecutive cohort of patients from jan-june who received a head ct at oed due to minor head trauma was assessed. data was gathered from the ct request form, radiology report and ct images. the data points analyzed were: type of trauma, gcs, anticoagulants, loss of consciousness, nausea and vomiting, positive traumatic ct findings, and number of head cts within a year period. results: intracranial bleeds were reported in ( %) patients, ( . %) required neurosurgical intervention. skull fractures were reported in ( . %) patients, however no intracranial bleeds were present. it was impossible to assess guideline compliance because % of the referrals lacked adequate clinical information. ten bleeds were missed, however no further action was needed. % received more than head cts in years conclusions: head injury guidelines can improve clinical practice and reduce unnecessary ct scans; thus minimizing radiation exposure. based on the low number of positive findings, we hypothesize that sg compliance can be improved at oed. compliance was not assessable for nearly half of the patients, due to vital clinical factors missing. implementation of a standardized ct referral form based on the sg and educating junior ed doctors may decrease the number of unnecessary head cts. introduction: to date, there is no ideal allograft that provides local antibiotic release. along with this, existing fillers are expensive material, which complicates their application in practice. all this leads to the need to look for new ways to solve this problem. material and methods: gentamicin was used as an antibacterial drug because of its wide spectrum of action and thermal stability. for the study, staphylococcus aureus attc was used as a microbial strain. the antibiotic release from the studied materials was determined by equilibrium dialysis over the entire observation period. gentamicin antibiotic concentration was determined by hplc. results: an allograft impregnated with an antibiotic, prepared according to the marburg system in the area of the subcortical part of the bone, suppresses the staphylococcus aureus attc strain twice as much as perossal. when comparing bone allografts impregnated in various ways, the longest release time showed a perforated allograft.a bone graft impregnated with an antibiotic by incubation showed a % longer release time compared to perossal granules (p \ . ).when in vitro incubation of the antibiotic gentamicin with the drug ''perossal'', the dissociation rate is more than % in the first two days. when the antibiotic gentamicin with a bone allograft is incubated in vitro on the second day, dissociation into the extracellular space makes up more than % of the drug from the previously bound (p \ . ), which also indicates a longer release time from the bone allograft. conclusions: in vitro, a bone allograft impregnated with an antibiotic is able to reversibly bind the antibiotic gentamicin and gradually release it over a period of days. the use of a bone allograft impregnated with an antibiotic suppresses the growth zones of staphylococcus aureus strains. references: rudenko a., impregnation of the bone allograft: comparison of heads coloring. european journal of trauma and emergency surgery (suppl) p. acute appendicitis and pregnancy: from incidence to modern management: literature review and proposal for consensus estes experts guidelines a. l. bubuianu , a. mihailescu , g. pokusevski tameside general hospital, general/emergency surgery, ashtonunder-lyne, united kingdom introduction: acute abdominal pathology during pregnancy has historically been a challenging decision for the emergency surgeon, that had to deal with patients at same time. acute appendicitis has probably the highest prevalence of all. early involvement of the gynaecological team was considered paramount and the ongoing debate laparoscopic versus open intervention, has been more recently challenged by case reports where antibiotics alone have been a successful strategy. material and methods: literature review has been conducted by the investigating team, using the following search algorithm: reviewers screened pubmed portal to conduct a thorough search of the most important medical databases, cochrane's library, medline and embase. case reports and low quality case series have been excluded from the literature review. results: there is currently no general consensus in regards to operative strategy in acute appendicitis during pregnancy, but most authors described safety of laparoscopic intervention in the first trimesters and favoured open approach in a mother closer to term. the antibiotic treatment alone can only be considered in presumed early appendicitis, where there are no features of pending perforation, presence of phlebolith or established peritonitis and should be done under the close monitoring of experienced general surgeons. conclusions: an expert consensus is required in first instance, (set of questions submitted to audience at end of presentation for their expert opinion) regarding optimal treatment strategy in acute appendicitis during pregnancy, followed by a multicenter prospective randomised control trial, which we are hopeful to engage with help of numerous european hospitals where estes members activate. introduction: deep tissue pressure injuries (dtpi) are complex and difficult to treat. the higher prevalence is observed in paraplegic and elderly populations. primary closure of large, stage- dtpis is rarely feasible and flap closure is customarily applied. presented is a technique using tension relief system (trs; topclosureÒ tension relief system) and regulated oxygen and irrigation negative pressure wound therapy (roi-npt; vcareaÒ) to facilitate simple primary wound closure of dtpis. methods: large, stage- dtpis were closed by a limited surgical procedure entailing conservative debridement, en-bloc primary wound closure based on the application of trs and roi-npt. results: details of the closure of consecutive large dtpis in patients is presented. immediate primary closure was achieved in cases, while three others were closed over - days. surgery time ranged between . and h and hospitalization between and days. following a median follow-up of months (range - months), all wounds healed with one late recurrence. post-operative wound infection observed in one patient was successfully treated with systemic antibiotics. minor skin damage inflicted by the tension sutures at the anchoring sites healed spontaneously. gradual return to partial loading of the operated area was enabled within - weeks and full weight-bearing was achieved within - weeks. introduction: chronic pain is a disabling condition affecting - % of trauma patients. considering the burden of chronic pain, interest in interventions to prevent this disorder after trauma has grown. a descriptive review of literature was undertaken to assess the evidence on these interventions. material and methods: medline, cinahl and cochrane library databases were searched to identify interventional studies published up to august . websites of injury, critical care and pain organizations were also consulted to retrieve relevant guidelines. the literature search used combinations of medical subject headings and keyword under the themes of pain, trauma, surgery and preventive interventions. results: many knowledge syntheses relevant to the population of trauma published between and were found. low to moderate level of evidence was reported for pharmacological interventions such as the administration of ketamine, neuropathic pain medication and multimodal analgesia. local or regional nerve block in the presence of factures was associated with a high level of evidence. very low to low evidence was described for nonpharmacological interventions including cryotherapy and early mobilization. finally, psychological interventions were associated with a low to moderate level of evidence and multimodal pain management interventions (pharmacological and non-pharmacological) with a high level of evidence. conclusions: research is still needed to define the role of interventions to prevent chronic pain in trauma patients. thus far, multimodal pain management interventions involving multidisciplinary team management appear to be the most promising. implementing such interventions could reduce the negative consequences associated with chronic pain. introduction: chronic use of opioids has been documented % of trauma patients. accordingly, the tapering opioids prescription program in trauma (topp-trauma) was developed. the aim of this study was to assess the feasibility of topp-trauma and explore the efficacy of topp-trauma in reducing opioid use. material and methods: a -arm pilot rct was conducted in patients presenting a high risk for chronic opioid use. we aimed to recruit participants to receive either topp-trauma or an educational pamphlet. topp-trauma comprised educational and counseling sessions. the feasibility assessment of topp-trauma was based on the ability to provide its components. the morphine equivalent dose (med) per day as well as pain intensity and pain interference with activities were measured at and weeks following discharge. results: preliminary findings based on data collected in participants showed that counseling sessions were most frequently needed to completely taper opioids. sessions attendance reached %. nearly % of eligible patients accepted to participate and an attrition rate of % was found. even though the experimental group consumed a higher med h prior to hospital discharge compared to the control group ( . vs . ), its med/day intake was lower at weeks ( . vs . ) and weeks ( vs . ). these self-reported data were validated by the total med delivered by participants'' pharmacy at both time points ( . vs . at weeks; . vs . at weeks). minimal mean score differences were observed in both groups with regard to pain intensity and interference with activities. conclusions: data collected until now provided evidence on the feasibility of topp-trauma and on the program potential efficacy. challenges that will require to be addressed in future rct include the acceptance to take part in the study and participants' drop out. introduction: head preserving surgical treatment for ao-type b fractures with little to no dislocation consists of three canullated screws or a dynamic hip screw (dhs). there is a new alternative: the femoral neck system (fns). the fns has some advantages over dhs. the anti-rotation screw provides extra rotational stability because of the diverging design. furthermore, the incision is smaller in fns and only one locking screw is necessary for plate fixation. we present the first results of this new surgical fixation of femoral neck fractures with fns. material and methods: during the period of november until october , all patients with femoral neck fractures treated with fns, were included in this prospective single center cohort study. patient characteristics, fracture classification (ao, garden, pauwel), perioperative parameters and postoperative complications were registered. patients were allowed to mobilize based on the principle of permissive weightbearing. follow up was planned after weeks and weeks. primary outcome measure was cut-out rate within months. results: twenty-four patients with a femoral neck fracture (ao-type b) were surgically treated with fns. median age was , (range - ). median operation time was mins (range - ). mean duration of in hospital stay was days (range - days). twentytwo ( , %) patients completed the regular follow up of weeks. one patient ( %) had a reoperation due to a cut-out. during follow up one patient developed a wound-infection ( %) which was treated with intravenous antibiotics conclusions: femoral neck system as surgical treatment for femoral neck fractures shows promising first results. low cut-out rate, limited operation time, low mortality and short duration of in-hospital stay make this device a possible alternative for dhs of canullated screws. definitive conclusions should be made after studying long term results in larger cohorts. references: none. new personalized approach to enteroatmospheric fistulas using d bioprinting device introduction: enteroatmospheric fistula is a challenge for surgeons. it presents a great clinical variability. this diversity means that, despite having tried multiple devices and techniques to achieve local control of the intestinal effluvium over the rest of the wound, there is currently no technique that can solve this problem in all patients. d printing is a novel therapy that allows the customization of the devices according to the needs of each patient. the aim of this study is to describe the technique of manufacturing a custom device designed by bioscanner imaging and manufactured using a d printer for use in the management of enteroatmospheric fistula. we describe our initial results. materials and methods: we present four patients with enteroatmospheric fistula. the intestinal segment involved, the dimensions of the wound, the intestinal debit and the size of the exposed intestinal surface are substantially. all require an average of - daily cures by the nurse. after obtaining images of each fistula with a bioscanner, a personalized device was designed and made by a d printer. the polycaprolactone device was placed including inside the fistulous orifices and surrounding it with npwt in order to accelerate the healing of the wound to ostomize the fistula or achieve its definitive closure. results: four devices with different designs have been manufactured. the wound remained isolated from the intestinal contents after placement, favouring the granulation of the surrounding tissue with npwt and thus avoiding contamination of the wound. the system remained without leaks for an average of h, reducing the need for daily cures, improving patient comfort and avoiding complications. conclusions: the use of a manufacturing model using d bioprosthesis printing in order to create a personalized device that fits the characteristics of the patient's wound is feasible and offers promising results in the management of enteroatmospheric fistulas. new approaches in bone tissue engineering: innovative scaffold design for principle unlimited size bone substitutes introduction: in bone tissue engineering (bte), autologous boneregenerative cells are combined with a scaffold for large bone defect treatment. microporous, polylactic acid scaffolds showed good healing results in bone defects in small animals. transfer to large animal models, however, is challenging and not easily achieved simply by upscaling the design. increasing diffusion distances has a negative impact on cell survival and nutrition supply. this can lead to cell death and ultimately implant failure.this approach focuses on scaffold architectures, that meet all the requirements for a modern bone substitute. biological-functional, porous subunits in a loadbearing, compression-resistant frame structure characterise the innovative design. an open, macro-and microporous internal architecture provides optimal conditions for oxygen and nutrient supply in the inner areas of the implant by diffusion. material and methods: during the design process, prototypes (temple (figure a) , grid (figure b) , onion (figure c)) were dprinted (fused filament fabrication) using polylactic acid (pla). -after incubation with saos- (sarcoma osteogenic) cells for days (measurements on days , , and ), cell morphology, distribution and survival (fluorescence microscopy, ldh-based cytotoxicity assay), metabolic activity (mtt test) and osteogenic gene expression were determined. results: all designs not only showed cell colonization, but cells also sustained their ability to differentiate (already after days) and to divide. the open, hierarchical-structured design, with its innovative porous structure, provides a good basis for cell settlement and proliferation. the modular design allows easy upscaling and offers potential solutions to previous limitations scaffold developement in bone tissue engineering. references: the value of d reconstructions in determining post-operative reduction in acetabular fractures: a pilot study introduction: in patients with acetabular fractures, the reconstructed three-dimensional ( d) model of the contralateral acetabulum could be used as a mirrored template for the anatomic configuration of the affected joint. this has not been validated. material and methods: computer tomography (ct)-scans of twenty patients with unaffected acetabula were used. the symmetry of the generated d models was evaluated through; ( ) mirroring of the acetabulum; ( ) initial rough matching; ( ) automatic optimisation of the matching via surface-based matching; ( ) calculation of distances between surfaces by evaluating the euclidean (straight-line) error distance between the closest points between left and right. the percentages of surface-points of the left and right acetabulum with a distance smaller than . , . , . and . mm were calculated and evaluated, in relation to matta's criteria, for acetabular fracture reductions. the analysis was performed using the mirrored left acetabulum matched onto the right original structure (left mirrored to right original; ''lm ro'') and the right mirrored to left original (rm lo). to determine the inter-observer agreement the procedure was repeated by a second assessor for the first ten patients. results: patients had a mean ± sd age of . ± . years, % was male. the mean distance deviation was less than . mm in all comparisons. the calculated distances in . % of the surface points of the left and right acetabulum were below the tolerance threshold of . mm, based on matta's anatomical reduction critera (table ). absolute differences between assessors were\ . mm per patient with an overall moderate agreement of %. conclusions: d reconstructed models of healthy left and right acetabula are highly similar and could potentially be used as mirrored duplicates. the next step will be to investigate these results in patients with reduced acetabular fractures. : matta, j. ( ).j bone joint sur am. : - pr minimally invasive plate osteosynthesis technique for distal humeral fracture: a cadaveric study v. hofmann , c. deininger , t. freude , f. wichlas university hospital salzburg, orthopedics and traumatology, salzburg, austria introduction: in our study we want to evaluate the feasibility of minimally invasive plate osteosynthesis (mipo) technique for distal humeral fracture using anatomically precontoured double plate osteosynthesis. material and methods: eight elbows from four thiel fixed cadavers were included. on unfractued cadavers we tested the minimally invasive approach with two separate incisions, one at the lateral and one at the medial epicondylus. the preformed plates were inserted directly into the bone on sides and fixed with percutaneous screws. then we created an ao type a and c fracture. the reduction was performed under x-ray control and stabilized with k-wires. then we also inserted the plates in mipo technique. in the case of an intraarticular fracture, an olecranon osteotomy was additional performed in a minimal invasive way to control the distal humeral joint surface. after finishing reduction and fixation the approach were extended to control the fracture alignement, position of the plates and to expose the ulnar nerve. results: the plate position was satisfactory and we could not detect any major soft tissue damage or ulnar nerve injury by using the minimally invasive plate osteosynthesis technique. in the extraarticular fractures, reduction was achieved with k-wires and was acceptable in all cases. the intra-articular fractures were controlled by an additional olecranon osteotomy using the mipo technique with a good view on the joint surface of the distal humerus. conclusions: the findings of the present study show that mipo technique in distal humerus fracture is feasible and save especially for ao type a fractures. in ao type c fractures the olecranon osteotomy provided enough visibility to evaluate the distal humeral joint surface. the surgical technique is demanding, and care must be taken not to injure the ulnar nerve. never the less it is an effective surgical treatment method and an alternative option to open techniques. correlation between pelvic incidence and acetabular orientation in anteversion and inclination-an analysis based on a d statistical model of the pelvic ring introduction: the pelvic ring is a complex bony structure with a central role for the human''s mobility building the connecting part between the upper body and the lower extremities. pelvic incidence and acetabular orientation are two important parameters used in the description of pelvic anatomy and are of central importance for understanding the biomechanical interaction of spine, pelvis and hip joints. the objective of the study was the analysis of a potential correlation between pelvic incidence and acetabular orientation. material and methods: a d statistical model of the pelvic ring consisting of individual ct scans of european adults without bony pathologies was used to analyse pelvic incidence and acetabular orientation in anteversion and inclination. an additional analysis on the correlation between those parameters was performed using the software spss. results: a slight positive correlation between pelvic incidence and acetabular anteversion could be shown (r = . ; p = . ) as well as a strong positive correlation between anteversion and inclination (r = . ; p \ . ). pelvic incidence and acetabular inclination showed none statistically significant correlation (r = . ; p = . ). conclusions: the results of the study might contribute to a better understanding of the biomechanical interaction between the axial skeleton and the lower extremities and deliver valuable information concerning preoperative planning in orthopaedic and trauma surgery of the lumbar spine, the pelvis and the hip joints like for example reconstructive surgery after trauma, operative treatment of congenital or acquired deformities or total joint arthroplasty. references: boulay et al., ''pelvic incidence: a predictive factor for three-dimensional acetabular orientation-a preliminarystudy. '' anat res int. ; : . doi: . / . epub . introduction: the majority of distal clavicle fractures (dcfs) are displaced fractures and are prone to delayed-or non-union. there are several options for surgical reconstruction, open reduction and fixation or hook plate, but in patients with a comminuted or small fracture they are known to have a high complication and failure rate, and secondary surgery for removal is often necessary. we hypothesize that resection of the distal fracture fragment and subsequent stabilization with the lockdown device, is an alternative for selected patients with dcfs. methods: eleven patients with a comminuted dcf were treated with a lockdown device. data on pain and range of motion were documented and the constant shoulder score (css), oxford shoulder score (oss) and nottingham clavicle score (ncs) were assessed at one year follow-up. results: eight patients underwent surgery within weeks, compared to patients where the surgery was delayed ([ weeks) due to persisting pain and delayed-union. none of the patients had postoperative complications. in months after treatment, patients were complaint-free. one patient had hardware removal due to pain at the site of the screw head. four patients were assessed after one year follow-up. the mean pain score was . . the mean flexion , °, abduction , °, exorotation °and extension °. the css had a mean of . , oss . and the ncs a mean of . conclusions: all patients had a good short-term clinical outcome and hardware complications did not occur. we are the first to describe the use of the lockdown device in dcfs. this device is not dependent on fracture healing and secondary surgery is not necessary, therefore it can be an alternative in the treatment of dcfs. a larger series and longer follow-up is necessary to confirm this conclusion. in this ongoing study, the remainder seven patients will be included and presented at the estes. moore type i tibial head fractures are one of the most challenging fractures to treat. material and methods: we performed the following approaches on eight thiel fixed cadavers: the anterolateral (with an osteotomy of the tuberculum gerdyi, a subcapital fibula-osteotomy and an osteotomy of the tuberositas tibia), the medial approach (with submeniscal arthrotomy and a dissection of the medial collateral ligament) and the posterior approach with a submeniscal athrotomy. the reachable borders of the articular joint surface have been marked by a k-wire. the visual joint surface has also been radiographically documented by inserting k-wires into the tibia head. finally the results have been photo documented on the exarticulated joints. results: the reachable areas of the articular surface have been defined and documented. the combination of the subcapital fibulaosteotomy and the submeniscal arthrotomy showed the most increase in accessibility to the articular surface in the dorsal part. an additional osteotomy of the tuberculum gerdyi increased the vision on the entire lateral and anterior articular surface. the submeniscal arthrotomy, at the medial approach, has not a good view on the surface. the posterior approach showed only a limited view on the lateral and medial articular surface at the dorsal part. none of the surgical approaches sufficiently visualizes the intercondylar region. conclusions: a fracture-specific approach strategy is critical for the preoperative planning of complex tibia-head fractures. subcapital fibula osteotomy is the most efficient surgical approach to reach the posterior and lateral articular surface. for the anterior articular surface, the best overview was achieved by an osteotomy of the tuberculum gerdyi. it was not possible to see and control the intercondylar region with any approach. introduction: osteosarcoma (os) is the most common bone carcinoma in humans. at the time of the first diagnosis are already in about % metastases present. the current treatment strategies include above all radical surgical resection and chemotherapy. in the search for alternative therapy methods. treatment with cold atmospheric plasma (cap) shows promising prospects. at the cellular level, this leads to various cellular mechanisms and finally to induction of anticancerogenic effects such as growth inhibition, apoptosis, and changes in the cell-cell interactions. the impact of cap on the integrity of the cell membrane of os cells, however, is unknown. material and methods: suspended cells from two human osteosarcoma cell lines (u -os, mnng) were treated for s, s, and s with cap. cell proliferation was determined after h, , , , and h using casy cell counter. dye loss assay was performed by using fluorescein diacetate (fda). this was followed by indirect treatment with cap for s. in the cell-free supernatant was determined by tecan multireader the dye emission. flow cytometry assay was used after cap treatments and incubation with fda. the mean fda fluorescence intensity of individual cells in the flow cytometer was measured. results: cell kinetics showed significant inhibition of cell proliferation in both cell lines after cap treatment. the assays for determination of the dye level showed a significantly increased membrane permeability of both cell lines after cap treatment. the significant effect on the membrane integrity correlated with treatment duration. conclusions: this confirms a modulating influence of cap on the functionality of the cell membrane and may support the anti-proliferative effect of the cap treatment. thus, cap is a promising therapy option, especially for chemotherapy-resistant entities introduction: osteosarcoma (os) is the most common bone cancer in humans. standard therapy includes radical surgical resection and chemotherapy, but due to strong toxic effects, new treatment options are urgently needed. currently, there is a discussion about expanding the oncological therapy spectrum and treat with cold atmospheric plasma (cap). it is a reactive ionized gas rich in radicals, photons, and electromagnetic rays. its biological effects are primarily mediated by reactive oxygen and nitrogen species (rons). due to its low temperature, cap is suited for medical applications. in vitro studies have shown the antitumoral effect of cap also for pancreatic cancer, melanoma, ovarian, breast, and colon cancer. material and methods: human os cell lines u -os and mnng/ hos were used. proliferation assay. the growth of cap-treated cells was examined using a casy cell counter. caspase / assay. following cap treatment, the activities of caspase- and caspase- were measured using a specific substrate peptide coupled with a fluorescent dye (cellevent tm ). single-cell gel electrophoresis comet assay. dna damage after cap treatment was identified using alkaline microgel electrophoresis. dna migration was measured using comet score software. the percentage of tail dna was used to indicate the relative fluorescence intensity of the head and tail. tunel assay. after cap treatment tunel analysis was performed. results: the results revealed that the cap treatment of os cell lines leads to significant inhibition of cell growth. subsequently, the activation of caspases and the induction of apoptotic dna fragmentation was demonstrated. the treatment of os cells with cap leads to an induction of apoptosis and a reduction of cell growth. introduction: extra peritoneal packing (epp) is a quick and highly effective method to control pelvic hemorrhage. we hypothesized that this procedure may be as safely and efficiently performed in the emergency room (er) as in the operating room (or). methods: retrospective study of patients who underwent epp in the er or or in two trauma centers in israel between - . material and methods: retrospective study of patients who underwent epp in the er or or in two trauma centers in israel between - . results: patients were included in our study, in the er-epp group and in the or-epp group. the mean injury severity score (iss) was . ± . . following epp, hemodynamic stability was successfully achieved in of patients ( . %). a raise in the mean arterial pressure (map) with a median of mmhg (mean . ± . , p = . ) was documented. all patients who did not achieve hemodynamic stability after epp had multiple sources of bleeding or fatal head injury and eventually succumbed. the overall mortality rate was . % ( / ) with no difference between the or and er-epp groups. patients who underwent epp in the er showed higher change in map (p = . ). no differences were found between er and or epp in the amount of transfused blood products, surgical site infections and length of stay in the hospital. however, patients who underwent er epp were more prone to develop deep vein thrombosis (dvt): % ( / ) vs % ( / ) in er and or-epp groups respectively (p = . ). conclusions: epp is equally effective when performed in the er or or with similar surgical site infection rates but higher incidence of dvt. level of evidence: retrospective cohort study, level iv. introduction: application of supraacetabular schanz screws is usually performed under image intensifier guidance. the aim of this study was to perform it without imaging, with the hypothesis that, respecting anatomical landmarks, pre-and intraoperative fluoroscopy can be avoided. material and methods: insertion of the supra-acetabular schanz screws was performed in human adult cadavers. with cadavers placed in supine position, the anterior superior iliac spine (asis) was palpated. starting from this landmark, cm were measured in a distal and cm in the medial direction. at this point, a cm long oblique skin incision was performed. through this approach, mm schanz screws were drilled bilaterally into the supra-acetabular corridor with an angulation of °to distal as well as °to medial. combined obturator oblique-outlet views (cooo) were taken bilaterally to prove the screw position. six of the specimens underwent a d-ctscan. images were evaluated concerning correct screw positioning. skin and subcutaneous tissues were removed in the ilioinguinal region and possible lesions to the lateral femoral cutaneous nerve (lfcn) or to the joint capsule were evaluated. results: during radiographic evaluation of the cooo-scans ( specimens) and the d-scans ( specimens), the schanz screws were placed inside the supra-acetabular corridor in all specimens ( / ). during dissections, no intracapsular screw placements or lfcn lesions were found. conclusions: using our technique, all schanz screws could be sufficiently inserted without intraprocedural x-ray imaging. references: . karaharju, e. and p. slätis, external fixation of double vertical pelvic fractures with a trapezoid compression frame. inhury, . : p. - . . mears, d. and f. fu, external fixation in pelvic fractures. orthop clin north am, . : p. - . . mears, d. and f. fu, modern concepts of external skeletal fixation of the pelvis. clin orthop, . : p. - . pr epidemiology of self-inflicted major trauma r. stoner , n. misra , l. mason aintree university hospital, liverpool, united kingdom introduction: in the united kingdom, severely injured patients are taken directly to a major trauma centre (mtc). whilst deliberate self harm (dsh) is a known mechanism for this, there is limited prior research. - % of major trauma is thought to be self inflicted , . our aim was to describe the epidemiology of presentation to our mtc resulting from dsh. material and methods: retrospective review of patient records in our mtc for adult trauma team activations between / / and / / . data was collected on patient demographics, location type, injury severity score (iss), mechanism of injury and mortality. results: episodes of dsh made up . % of all trauma cases, involving patients; . % re-attended. z-scores show no change in incidence over time, but significant variability month by month, with / months [ sd from mean. mean patient age years (range - ). . % were male. . % came from residential location and . % from prison. most common mechanism was penetrating trauma ( . %). in-hospital mortality was % ( . % in males vs . % in females, chi p = . ). conclusions: this is the largest review of self inflicted trauma cases in a uk mtc, with a similar incidence to prior studies. there was no observed correlation with season or trend over time. mortality was higher in male patients, in keeping with national statistics on suicide, whilst dsh in females was linked to less severe injury; severity is related to mechanism of injury. injury from self stabbing/cutting was most common in patients from residential locations, whilst hanging was more common in prisoners. this study identifies preventable risk factors for major self inflicted injury. introduction: the distribution of trauma deaths was classically described following a trimodal pattern. during the last decade improvements in trauma care as damage control resuscitation (dcr) have minimized resuscitation injury. we hypothesized that the implementation of dcr in severely injured trauma patients is associated with less mortality and modifies mortality pattern. material and methods: we performed a -year ( - ) retrospective cohort analysis of all severely injured trauma patients (niss c ) who underwent surgery at our level trauma center. since , dcr was implemented including damage control surgery, minimizing crystalloids and increasing the use of blood products. our patients were stratified into two phases: pre-dcr ( - ( ) and post-dcr ( . results: a total of patients were identified. there were patients ( . %) in the pre-dcr group and patients ( . %) in the post-dcr group. mean age ( . vs . , non significant (ns)), mechanism of injury (blunt trauma: . % vs . %, ns) and shock on admission ( . % vs . %, ns) were similar between groups. there is a significant reduction in the rate of overall mortality ( . % vs . %, p \ . ). while early deaths from traumatic brain injury ( . % vs . %, ns) and hemorrhage ( . % vs . %, ns) are alike, mortality secondary to multisystem organ failure (msof) is lessened ( . vs . %, p \ . ). conclusions: dcr has helped in reducing overall mortality and mortality due to msof in our severely injured trauma patients. introduction: the mangled extremity severity score (mess) was constructed as an objective quantification criterion for limb trauma. a mess of or greater than was proposed as a cut-off point for primary limb amputation. opinions concerning the predictive value of the mess vary broadly in the literature. the aim of this study was to evaluate the applicability of the mess in a contemporary civilian central european cohort. material and methods: all patients treated for extremity injuries with arterial reconstruction at two centres between january and december were assessed. the mangled extremity severity score (mess) and the amputation rate were determined. results: seventy-one patients met the inclusion criteria and could be evaluated for trauma mechanism and injury patterns. the mean mess was ). seventy-three percent of all patients ( / ) had a mess b and % ( / ) of c . eight patients ( %) underwent secondary amputation. patients with a mess c showed a higher, but statistically not significant secondary amputation rate ( . %; / ) than those with a mess b ( . %; / ; p = . ). the area under the roc curve was . (ci . ; . ). conclusions: based on these results, the mess seems to be an inappropriate predictor for amputation in civilian settings in central europe possibly due to therapeutic advances in the treatment of orthopaedic, vascular, neurologic and soft tissue traumas. introduction: in polytrauma victims the acute respiratory distress syndrome (ards) is a major cause of morbidity and mortality. it presents a complex pathophysiology that is characterized by pulmonary activated coagulation and reduced fibrinolysis. due to the fact that the pulmonary endothelium is considered a key modulator of ards and that tpa in plasma is predominantly synthesized and secreted by vascular endothelial cells, we hypothesized that the time courses of serum tissue-type plasminogen activator (tpa) and its main inhibitor, the plasminogen activator inhibitor type- (pai- ), might indicate a clinical approach to preventing ards in polytrauma victims. material and methods: twenty-eight consecutive polytraumatized patients with concomitant thoracic trauma, age c years, iss c , who were directly admitted to our level i trauma center, were evaluated. blood samples were taken initially and on day , , , , , , and during hospitalization. luminex multi-analyte-technology was used for analysis of tpa and pai- antigen levels. results: both levels were particularly high at admission. although they significantly declined within three and seven days, respectively, they remained elevated throughout three weeks. throughout this observation period mean tpa antigen levels were higher in polytrauma victims suffering ards than in those without ards, whereas mean pai- levels were higher in polytrauma victims sustaining pneumonia than in those without pneumonia. noteworthy, in each patient, who developed ards, the tpa antigen level raised up to the onset of the syndrome and declined afterwards. conclusions: the development of ards has to be expected in a polytrauma victims if the tpa antigen level continues to rise after admission. potentially, in patients with a low risk of excessive bleeding the onset of the syndrome might be prevented by the timely administration of recombinant profibrinolytic proteins. motocross is a dangerous business: small bowell perforation case report case history: a year-old male, previously healthy, was admitted to the ed after being involved in a motorcross accident. he suffered blunt abdominal trauma. clinical findings: at admission, patient presented pale but haemodinamically stable. physical examination was unremarkable except for an evident abdominal wall hematoma and abdominal guarding over the left quadrants. investigation/results: abdominal ultrasound showed an intestinal loop with decreased peristalsis with a small amount of liquid adjacent (fig ) . due to the patient's haemodynamic stability, ct scan was performed (fig . ) which showed liquid in the left flank and iliac fossa, but without an identifiable intrabdominal lesion. diagnosis: the patient was admitted to the operating theatre with acute abdomen. therapy and progressions: intraoperatively fecal peritonitis was evident from a cm-hole on the antimesenteric border of the jejunum, the enterotomy was closed and profuse lavage was done; the abdominal wall closed without drainage. the patient went through an empirical antibiotic cycle. liquids per os were started on the first postoperative day and the patient progressed without issues. he was discharged at the th postoperative day. the remaining follow-up was uneventful. comments: small bowel perforation after blunt abdominal trauma is rare. sbmi has a high morbidity and mortality that increase with delayed diagnosis; however, clinical and radiographic signs of perforation are often absent, like in the case presented. ct is considered the gold-standard. in our specific situation, the small bowel perforation did not produce any pneumoperitoneum in a young patient with very good physiologic status that kept him hemodynamically stable. the prognosis of pelvic injury is closely related to the severity of vascular injury rather than the complexity of bony fracture y. wu , c. hsieh , c. fu chang gung memorial hospital, trauma and emergency surgery department, taoyuan city, taiwan introduction: pelvic injuries are among the most dangerous and deadly trauma. although complex pelvic fractures are often associated with vascular injuries, it is still unclear regarding the impact of the severity of vascular injury to the outcome of patients. we hypothesized that, in addition to the complexity of bony fracture, the severity of pelvic vascular injury plays a more decisive role to the patients'' outcome. material and methods:medical records of patients with pelvic fracture in a single trauma center between jan and dec were retrospectively reviewed. those who had an abbreviated injury scale (ais) c other than pelvis were excluded. based on ct results, the type of pelvic fracture was classified according to young-burgess classification, and the severity of vascular injury were recorded as minor (fracture with or without hematoma) or severe (hematoma with contrast pooling or extravasation). the patient demographics, clinical parameters, and outcome measures were compared between the groups. results: among the patients, severe vascular injury were noted in patients. patients with severe vascular injuries had significantly increased amount of red blood cell transfusion (rbct) ( . vs. . units, p = . ), longer icu stay (is) ( . vs. . days, p = . ) and total hospital stay (hs) ( . vs. . days, p = . ) compared to minor vascular injuries. on the other hand, those with complicated pelvic fracture (lc type ii/iii, apc type ii/iii, vs and combined type) had similar amount of rbct and is compared to that of simple pelvic fracture (lc type i, apc type i) except a longer hs ( . vs. . days, p = . ). conclusions: our results indicated that the severity of vascular injury is more closely correlated to the outcome of patients with pelvic fractures than the type of bony fracture does. in addition to the type of bony fracture, the grade of vascular injury should be considered as an important part of pelvic injury classification. associated abdominal injuries do not influence reduction quality in operatively treated pelvic fractures-a multicenter cohort study from the german pelvic registry results: . patients with pelvic injuries were treated during this period. . % had a concomitant abdominal trauma. the mean age was . ± . years. comparing the two groups, patients with a combination of pelvic and abdominal trauma were significantly younger ( . ± . vs. . ± . years; p \ . ). both, complication rates ( . % vs. . %; p \ . ) and mortality ( . % vs. . %;p \ . ) were significantly higher. in the subgroup of acetabular fractures, the time until definitive surgery of the pelvis was significantly longer in the group with the combined injury ( . ± . vs. . ± . days; p \ . ) . the grade of successful anatomic reduction did not differ between the two groups. conclusions: patients with a pelvic injury have a concomitant abdominal trauma in about % of the cases. the clinical course is significantly prolonged in patients with a combined injury, with increased rates of morbidity and mortality. however, the quality of the postoperative results is not influenced by a concomitant abdominal injury. a. martins rangel , r. pozzi , j. alfredo cavalcante padilha , s. sardinha , f. eduardo silva , d. teixeira rangel heat, trauma center, são gonçalo, brazil f.f.c., male, years old, was admitted to the trauma center about h after a stabbing wound in the neck. upon examination the patient was mechanically ventilated and hemodynamically stable, with an exposed sectioned trachea, which had a tracheostomy tube applied. the penetrating injury itself was mostly allocated in zone ii. he had a ct angiography and was referred to the or for surgical treatment. the cervicotomy found that both the external and internal right jugular veins had been injured alongside the sternocleidomastoid, sternohyoid and homohyoid muscles, the thyroid cartilage, just above the vocal cords, which had exposed the anterior larynx and the epiglottis the right anterior jugular vein and smaller tributaries of the right internal jugular vein, were ligated; a tracheostomy was performed and the thyroid cartilage and anterior laryngopharyngeal wall were reconstructed with the epiglottis implantation, sternoid, homohyoid and sternocleidomastoid muscle sutures, after which the platysma was closed but not the skin, left to secondary healing. patient was extubated within h, discharged from icu on the fifth postoperative day. thickened oral diet was introduced on the th day, and by the th day he was discharged without the tracheostomy tube, with a normal diet. comments: the cervical region is an area susceptible to serious injury due to the presence of vital structures, with massive hemorrhage, airway obstruction, cervical spine injuries and cerebral ischemia as the leading causes of death. initial management of penetrating injuries follows the principles of trauma care with airway control initially. references: bhatt nr-penetrating neck injury from a screwdriver: can the no zone approach be applied to zone i injuries? bmj yan wang-penetrating neck trauma caused by a rebar-a case report. medicine ( ) introduction: annually, approximately , people decease as a result of a fall in the netherlands, according to the statistics netherlands. the aim of this study is to evaluate the demographic parameters, fall characteristics and resulting injury patterns of this group in the region of amsterdam. methods: all patients deceased as a result of injury due to a fall in the period july st until july st in the region of amsterdam were included. data were collected from the database (formatus) of the department of forensic medicine (public health service amsterdam). results: during the study period , patients deceased after a fall. the mean age was years ( - years) and % was male. a psychiatric disease was diagnosed or suspected in % of the population of which cognitive impairment, including dementia, was encountered in most of the cases ( %). the majority of the falls happened at home ( %) or at nursing facilities. a minority ( . %) was work related. over % of the falls was from standing position, . % was not from standing position of which . % regarded falls from stairs, the majority was male. multitrauma patients accounted for . % of the population. from the remaining , patients, . % sustained one or more injuries to the pelvis or extremities. central nervous system (cns) injuries were described in . % of the patients. mortality was in . % of the cases due to primary cns injury, . % was due to complications of which clinical deterioration ( . %) and infection ( . %) were the most common. conclusions: in the region of amsterdam the majority of deaths due to a fall regards the geriatric population. fall from standing position and mortality due to complications, mainly clinical deterioration, accounted for the majority of deaths. intervention to prevent falls and thereby complications need more awareness to reduce mortality. results from a multidisciplinary blunt splenic injury protocol introduction: the majority of splenic injuries are currently managed non-operatively. failure of non-operative management includes grade iv or v splenic injury or vascular abnormalities that are suitable for embolization. the primary indication for operative management of blunt splenic injury is hemodynamic instability. in our center, the last twenty splenic injuries, admitted during two years, were not managed according to published guidelines. ten patients ( %) underwent splenectomy, being unstable only of them ( % of the whole sample). material and methods: staff from anesthesiology, interventional radiology and trauma surgery came up with a joint protocol. grade iii splenic injury non-operatively management, including fluid responsiveness (achieving shock index (ht/bp) below . after a bolus of colloids) and, focus placed only on hemodynamic stability instead of on vascular abnormalities are our principal modifications regarding already published protocols. results: seventeen patients with blunt spleen trauma were admitted after starting up our protocol. six ( grade iii, grade ii and grade i) splenic injuries were successfully managed non-operatively. prophylatic embolization was performed in five patients: were grade iv spleen trauma and were grade iii spleen trauma with vascular abnormalities. one grade iii splenic trauma was embolized due to a pseudoaneurysm detected in ct scan performed h post injury. five grade v spleen trauma required urgent surgery. of them presented with shock index [ . . conclusions: our multidisciplinary protocol has helped in improving outcomes in blunt splenic injuries. we have achieved an almost full compliance to our protocol. case history: -year old male experienced severe blunt trauma after a bus accident. clinical findings: he is found alert (gcs = ), hemodynamically stable and with a patent airway. he presented catastrophic lower left limb where tourniquet was applied. gram of tranexamic acid (txa) and ml of crystalloids were administered. he was intubated in the site of injury and transfered to our center, being always hemodynamically stable. on hospital admission he was normotensive (bp = / mmhg, sinus rithm ppm), shock index \ . . he suffered uneventfully amputation of the limb with no need for blood products transfusion. his past medical history was only pertinent for hypertension. investigation/results: following urgent damage control surgery, ct scan was performed where acute bilateral pulmonary embolism was diagnosed. diagnosis: asymptomatic acute bilateral pulmonary embolism therapy and progressions: during icu stay, the patient kept hemodynamically stable. endotracheal tube is removed one day later and he is successfully transfered to the ward three days later. comments: hypercoagulability can occur after severe tissue injury, that is likely related to tissue factor exposure and impaired endothelial release of tissue plasminogen activator (tpa). in contrast, when shock and hypoperfusion occur, activation of the protein c pathway and endothelial tpa release induce a shift from a procoagulant to a hypocoagulable and hyperfibrinolytic state with a high risk of bleeding. it can be inferred that a patient presenting with severe tissue injury without shock is at high risk of perioperative thrombosis and txa might not be administered. ( ) . it signifies high energy force, representative of severe overall trauma. study reported mortality of blunt pelvic trauma to reach . - % ( ) . injury severity score (iss), hypotension, head injury, posterior fracture & haemorrhage have been implicated ( ) . however, there is a paucity of data in developing countries. this study identifies the problem burden, management outcomes and factors predicting mortality. material and methods: patients had pelvic trauma, retrospectively from jan to dec and prospectively from may to april . patients was included after excluding less than years and coagulation disorder results: majority were males ( . %),with a mean age of . . mechanism was rti ( . %) followed by fall from height ( %), railway accidents ( . %). mean iss & rts was . and . respectively. associated injury were long bone fractures ( . %), chest injuries ( . %).head injury ( . %). lateral compression ( . %), was the most common followed by anteroposterior compression ( %) & combined ( . %).majority underwent operative intervention ( . %) for pelvis or associated injury. the mortality rate was . % secondary to haemorrhagic shock ( . %) and sepsis ( . %). the factors were male gender, age, iss, rts, head injury, unstable pelvis. however, no association with haemoglobin, long bone fracture, and massive transfusion protocol was found conclusions: our study showed a mortality of . % which is comparing with previous study introduction: the number of patients admitted to oslo university hospital (ouh) due to bicycle trauma is increasing. we aimed to identify possible predictors of serious and fatal bicycle injury. material and methods: the ouh trauma registry was searched for patients treated for bicycle trauma between and . data extraction included putative predictors of serious and fatal injuries, defined as iss c and death within days, respectively. univariate analyses were performed and reported as odds ratios (or). p \ . was regarded as statistically significant. results: bicyclists were admitted, % were males, median age was years (range - ). injury mechanisms were single bicycle crash in %, collision with a motorized vehicle in %, bicycle vs. bicycle in % and others in %. serious injuries were seen in % and . % died. predictors for serious and fatal bicycle trauma are presented in figure . conclusions: we identified age c , high comorbidity and loss of consciousness (gcs b ) as predictors for both serious and fatal injury after bicycle trauma. single bicycle crash was the most common cause of serious bicycle injury in our trauma center. diagnosis, investigation and results: all case reports represent polytrauma patients with clinical worsening and admission to the icu, with subsequent development of acute respiratory distress syndrome (ards) refractory to primary measures. therapy and progressions: different mechanisms led to the development of ards in the different cases. on a primary approach, standard measures such as curarization, recruitment maneuvers, prone positioning and peep increase were applied whenever possible. an absence of improvement led to an almost inevitable need of extracorporeal membrane oxygenation (ecmo) rescue therapy. all patients responded positively to this treatment without major complications and were eventually discharged from the icu. comments: ards is a major cause of respiratory failure in polytrauma patients. among the many therapeutic options, ecmo emerges as a powerful tool as rescue therapy in respiratory failure refractory to all other measures, being the present case reports corroborative examples of its efficiency. introduction: nowadays when cities are improving fast and significantly, including transportation system, even more we encounter with high energy trauma . still the most vulnerable on the roads are pedestrians. material and methods: the analysis of the data collected prospectively from january to october was performed including the mechanism and diagnosis of polytrauma, patient demographics and the main outcomes. results: in total, patients were assessed according to the polytrauma protocol. the median age of the cohort was years (iqr - ), male patients, . % vs. . % females, p = . . the most frequent mechanism was a pedestrian struck by a vehicle in . % cases, and falling from a height of over m in . %. of those patients who had musculoskeletal injuries, in . % the trauma mechanism was a fall from a height and in . % pedestrians were struck by a vehicle, . % of patients who fell from a height and . % of those struck by a vehicle suffered visceral injuries. the most common cause of neurotrauma was a fall from a height in . %, and pedestrians involved in car accidents in . %. from the whole cohort, patients were not saved, resulting in a . % mortality rate. most patients ( ) who died had iss [ . the mortality reached . % among pedestrians struck by a vehicle and . % among patients who fell from a height of over m. conclusions: the most common mechanism in the cohort was a pedestrian struck by a vehicle, followed by falling from a height, with a predominant involvement of male patients. similarly, the most frequent cause of musculoskeletal injuries and visceral injuries was falling from a height and pedestrians struck by a vehicle, demonstrating an important direction for polytrauma prevention. introduction: recent reviews of uk trauma data show altering demographics. patients are increasingly older and sustain lower energy injuries, with falls \ m being the most common ( ) . material and methods: data collected over years in a major trauma centre was used to calculate injury specific admission rates, case fatality rates and injury specific mortality attribution. data on patient age, footwear, lighting, alcohol intoxication and previous admissions were collected in falls \ m resulting in mortality. results: patients sustaining falls \ m represented % of admissions and % of mortalities. all falls represented % of admissions and % of mortalities. case fatality of falls of \ m and [ m was . % and . %. all fall case fatality was . %. this was significantly higher than the case fatality of stabbings ( . %) and rtas ( . %). in falls \ m causing fatality, mean patient age was . years. % of patients aged - were under the influence of alcohol when falling, with % aged - , but only % patients aged - . % aged - who died when falling were wearing slippers. this increased to % in those aged - , and % aged - . % of falls occurred under daylight/full light. % of patients aged - who died after falling had been admitted to hospital within the last year, although this increased to % in those aged - , and % aged - . conclusions: falls were the most common cause for hospital admission, had the highest case fatality of injury mechanisms and caused the most patient mortality. alcohol intoxication was associated with falls in younger patients who died after falling, but this was less common in older patients. wearing slippers was less common in the young but significantly associated with fatal falls in older patients. these results offer a range of therapeutic targets when developing fall prevention strategies. introduction: the treatment of splenic lesions is determined by the hemodynamic situation, the degree of injury and the presence of bleeding. arterial embolization has expanded the indications of the conservative treatment. retrospective observational study on splenic traumatism and its therapeutic options. material and methods: a total of patients with splenic injury have been treated at our centre between and . patients were hemodynamically stable: were embolized and received a conservative treatment. patients were hemodynamically unstable: had a good response to the resuscitation treatment so they were embolized, but there was one patient who deceased because of other causes. from these patients, patients received splenectomy. results: the main objective of this study is to review the management of the trauma patient with splenic injury. of the total of patients with splenic trauma, average iss of , underwent splenic embolization, underwent urgent splenectomy and were treated with conservative treatment. the embolized, were hemodynamic unstable at arrival but responded to the fluid therapy, had a splenic lesion grade iv, a grade iii, grade ii and another a grade i. the success rate of embolization was % in the embolized patients. patient died, only one of them in the embolization group and was not related to the splenic trauma nor embolization, were in the urgent splenectomy group due to severity of trauma, died before receiving any treatment and in the conservative treatment group due to other complications. conclusions: patients who respond to volume or are hemodinamically with high-grade lesions, arterial embolization would be less aggressive treatment options with excellent results. haukeland university hospital, surgical unit/ regional traumacenter, bergen, norway, norwegian university of science and technology, trondheim, norway, haukeland university hospital, physical and rehabilitation medicine, bergen, norway, university of bergen, bergen, norway, st olavs hospital, physical and rehabilitation medicine, trondheim, norway introduction: during the past decades acute trauma care has improved through the development of highly specialized trauma centres and teams. since patients are considerable young when being affected, trauma may lead to life-long physical, cognitive and emotional constraints interfering with an independent self-determined life ( , ) . in , a revised national plan for the treatment of trauma patients in norway was published ( ) . the plan emphasizes the importance of rehabilitation and the need for early interdisciplinary rehabilitation. this study will examine in which extent patients receive rehabilitation in early phase after trauma as recommended in the norwegian national plan. in addition we will examine what follow-up patients receive after trauma, quality of life, functional level and use of health care and next-of kin resources. material and methods: patients admitted to regional trauma center in mid-or western norway in with niss c are recruited to participate. data will be collected from national trauma register, the norwegian patient register, the municipal patient and user register, data from statistics norway, the electronic patient record (epj) and the patient/relatives questionnaire. discussion: the results will be useful in the preparation of patient courses that comply with strong recommendations in the national trauma plan, ensuring equal treatment and raising awarness about rehabilitation for trauma patients. introduction: diaphragmatic lesions involve wounds and rupture of the diaphragm, through penetrating wounds or thoraco-abdominal trauma. their incidence is - %. the diagnosis may be late, despite the technical advances made by medical imaging. the choice of surgical approach and technique is still controversial. mortality is usually related to the associated injuries. the present paper analyzes the incidence of diaphragmatic lesions that occur in thoraco-abdominal trauma, their epidemiology, diagnosis and treatment. material and methods: we performed a retrospective study over a -year period ( - ) , in the surgical units of the emergency county hospital of braila, including all patients diagnosed with diaphragmatic lesions. results: during the study period, patients had thoracic-abdominal trauma. there were cases of blunt trauma and thoracic-abdominal trauma. our study involved cases of diaphragmatic injuries ( . %), by road accident and by white weapon. the sex ratio was : . the average age was years. chest radiography was a contributory preoperative diagnosis in cases. the diaphragmatic wound was on the left side in cases, and its average size was cm. the surgical procedure involved the reduction in the abdomen of the herniated viscera and the monoplane suture of the diaphragm by nonabsorbable ''x'' points in all cases. chest aspiration was the rule. there was only one death in a complex polytrauma case. case history: we report the one case which performed tae, angioplasty, thoracotomy, laparotomy and preperitoneal pelvic packing (ppp) in the hybrid emergency room (h-er). the patient was male in the s, who was riding on his motorcycle and fell from a m height. clinical findings: he was in shock state. diagnosis: we scanned cect and diagnosed subdural hematoma, traumatic subarachnoid hematoma, lt hemopneumothorax, lung contusion, multiple costal bone fracture, intercostal artery injury, splenic injury (gradeiii), pelvic bone fracture. therapy: we inserted the drainage tube to the hemopneumothorax and did the tae for the pelvic bone fracture and splenic injury. after tae, he was in still shock state. the bleeding volume from the lt drainage tube increased, so trauma surgeons did the emergency thoracotomy and thoracic endovascular aortic repair (tevar) for intercostal artery injury. we suspected he also had abdominal compartment syndrome due to recanalization of tae, and they performed the emergency laparotomy and did ppp for the pelvic bone fracture. comments: we install an ivr-ct system in our trauma resuscitation room in october . we named it h-er, as it enables us to do all examinations (sonography, ct and fluoroscopy) and treatments (ir, operation) required for trauma in a single room. we have to perform prompt diagnosis and treatment, especially in cases of severe polytrauma cases. a retrospective study proved that the h-er had shortened the time of ct initiation and emergency procedure and that lead to improve mortality ). h-er is a novel trauma resuscitation room to do all treatments required in the only one room for severe traumatic patients introduction: according to the previous advanced trauma life support (atls) guidance, the early assessment of trauma patients with haemorrhage were classified upon the vital signs. recently, national trauma registry analyses suggested to extend the assessment criteria with the base deficit (bd), referring to the metabolic status. our objective was to investigate the relevance of bd and to explore new prognostic factors in the early assessment of the severely injured. material and methods: our study included patients registered between . . and . . on our emergency ward for whom the trauma team was activated. they were grouped into severity groups (i-iv) according to either the vital signs (classical) or the extended criteria with bd. the data were extracted from medical documentations of the early phase of treatment. as primary outcome, we compared the -h mortality rate of the patient groups. we studied the need for massive transfusion and intensive care unit care as secondary outcomes. results: according to the classical assessment, % of the patients were assigned to group i (lowest risk for haemorrhagic shock) and % to group ii. the remaining % were grouped into groups iii and iv (higher risk). with taking bd into consideration, % were reassigned to a higher risk group; however, this change affected only groups i and ii. the -h mortality changed only in group i ( . % vs . %; p = . ). bd did not affect the need for massive transfusion. in groups i and ii, . % of the patients, in groups iii-iv % needed intensive care unit treatment. conclusions: bd is an effective prognostic factor in the early assessment of trauma patients. however, compared to the vital signbased evaluation, it provides extra informaton only in less severe cases. according to our findings, it may help to assess the need for the administration of blood products. grants: nkfi k ; ginop- . . - - - ; efop- . . - - - . complejo hospitalario de jaén, servicio de cirugía general y del aparato digestivo, jaén, spain, complejo hospitalario de jaén, servicio de anestesiología y reanimación, jaén, spain case history: years old male, with history of hypertension and dyslipidemia, suffered a backhoe accident and was admitted in a regional hospital. on initial assesment he presented contusion and two laceration wounds in left chest and in lumbar region. body ct informed subcutaneous emphysema and left rib fractures from th to th, left hemidiaphragm edema, laminar left pneumothorax and contusive lung. posterior lumbar hematoma and no intra-abdominal free fluid. laceration wounds were partially sutured, with drainages through the wounds clinical findings: he was transferred to our emergency department, presenting dyspnea, tachycardia, sweating, painful luq and left hemithorax worsening with breathing investigation/results: reviewed by our radiologist, tc images showed herniation of abdominal organs into the chest diagnosis: traumatic hernia in left costophrenic recess. multiple rib fractures therapy and progressions: the hernia contents (left colonic flexure and omentum) were reduced and defect closed with primary repair in emergency surgery. rib fractures treated by osteosynthesis.on th pod left renal artery dissection and renal infarction were evidence in a new ct. comments: diaphragmatic injuries are caused by blunt or penetrating thoraco-abdominal trauma. potentially life-threatening due to the herniation of abdominal organs and severe associated lesions. clinical suspicion is important as prompt diagnosis and treatment are necessary for good outcomes. in our case, the initial clinical assessment was incorrect and the transfer put the patient in danger as an emergency surgery should have been performed before transfer. this enhances the importance of a correct initial management of polytrauma patients. introduction: the fractures of the calcaneus account for about - % of all fractures of the human skeleton. the majority of these fractures ( %) are intra-articular and surgical intervention is a widely accepted way of treatment material and methods: the aim of this study was to evaluate the results of open reduction and internal fixation for di-afc.in a period of years ( - ) patients ( patients with bilateral fractures) with age range from to years old, were treated surgically using the lateral extensile approach. follow-up was - years. the results were evaluated based on x-ray parameters (calcaneal morphology, bohler''s and gissane''s angles), active range of motion, footwear problems and time needed to return to work. the sf- health survey was used for outcome assessment. results: fracture mean healing time was , weeks. the outcome was excellent in cases, good in cases and poor in cases. the complications were malposition of fixation in patients, superficial wound slough in patients, reflex sympathetic dystrophy in patients, deep infection in patients who were treated with antibiotics and metalwork removal following union of the fracture. one patient resulted in metal breakage with consequent pseudarthrosis. finally one patient developed chronic osteomyelitis and is under treatment. the treatment with open reduction and internal fixation for di-afc is indicated, provided that the restoration of calcaneal shape, alignment and height is achieved. long term functional results with mild pain, few alterations in activities of daily living or work, and essentially no footwear problems, can be expected from a properly performed open reduction and internal fixation. extraperitoneal rectal injury in emodinamically unstable patient treated after dcs with external traction applied in an endorectal balloon r. somigli hospital, general and emergency surgery, pistoia, italy case history: a -year-old man was crushed between two vehicles while he was working. he arrived in er hemodynamically unstable, so he underwent to emergency surgery. clinical findings: at rectal examination there was evidence of almost complete antero-lateral anorectal laceration. at abdominal examination there was evidence of anorectal full-thickness laceration and urethra full laceration. investigation/results: no diagnostic was required in preop because of patient instabilty. diagnosis: pelvic fracture with hemodynamic instability, severe rectal injury and complete prostatic urethra transection. therapy and progressions: el, lateral colostomy, pelvic paking, cistostomy and hip external binder. damage control surgery was performed. on pod second look was carried out and an almost complete extraperitoneal rectal injury was found during pelvic depaking. properitoneum was drained and a baloon probe was introduced in the rectum to allow the proximal rectal flap to advance to the distal rectum. stomal washes were performed with no rectal leak and rectal baloon traction mantained for days. radiological and endoscopic check haven't shown any leak and a good mucosal reconstruction. mri no sphincteral anatonical defects. waiting for emg before stoma reversal. comments: the optimal managment for extraperitoneal rectal injuries remains controversial. an approach with lateral colostomy and conservative treatment of rectal lacerations with rectal trac-tion baloon, could represent a safe treatment alternative in those cases with sphincter preservation, with a lower risk of complication. exploring differences between iss and niss scores for -day mortality in adult and elderly trauma patients in a norwegian national trauma cohort m. introduction: injury severity score (iss) and new injury severity score (niss) with a threshold over is commonly used to define severe injury and to define the study population in trauma registrybased studies for both adult and elderly trauma patients ( ) . for elderly patients (c years) this might be unreasonably high and might lead to exclusion of significantly injured elderly with increased risk of mortality. the aim of this study was to assess whether there were significant differences in -days mortality between adults and elderly trauma patients for different frequently used iss and niss thresholds material and methods: the norwegian trauma registry was interrogated to identify all adult (c years) trauma patients included in the registry from january through december . data were dichotomized to age groups ''adult'' and ''elderly'' ( - and c respectively) with -days mortality as primary endpoint. mortality rates were assessed for iss and niss thresholds of [ , [ and [ . we applied descriptive statistics and chi-squared test for comparisons. results: patients with available information about age, -days mortality and iss and niss scores were included in the analysis, of which patients were - years old and patients were c years. adult and elderly patients died, giving overall mortality rates of . % and . % respectively. for iss and niss [ there was a significantly higher -days mortality in elderly trauma patients ( . % and . % respectively) than adult patients ( . and . % respectively) (p \ , ), as for all other iss and niss thresholds tested. conclusions: this study demonstrates that elderly trauma patients has a significantly higher mortality risk than adult trauma patients at all iss or niss-thresholds analysed. this group has a significant mortality even at iss and niss above . introduction: the trauma tertiary survey (tts) is a widely accepted tool in the prevention of missed injury. existing literature on its effectiveness focusses on multitrauma patients. this study investigates the yield of the tertiary survey in trauma who are admitted for tts, without having any significant injury. material and methods: a single center retrospective cohort study was performed in a level ii trauma center. trauma patients without any clinically significant injury at the primary and secondary survey were included. the primary outcome was missed injury found during tts (type ). secondary outcomes were missed injury found after tts but during admission (type ), mortality and hospital length of stay [ days. results: from included patients, patients ( . %) had a type missed injury. alcohol consumption was associated with an increased risk for type missed injuries (odds ratio = . , % ci: . - . ) . a type missed injury was only found once, it concerned the only case of trauma related mortility. out of nonoperated patients, ( . %) were admitted for more than two days. these patients were significantly older ( vs. years, p \ . ) and had a higher asa classification, - vs. - ( . % vs. . %, p \ . ). conclusions: tts showed missed injuries in only . % of trauma patients who had no clinical significant injury found during primary and secondary survey. high costs of admission, together with a low yield found for this study's population the cost benefit of hospitalizing these patients is for discussion. future research should therefore focus on the identification of predictors of a positive tertiary survey. references: . advanced trauma life supportÒ student course manual. . keijzers, et al., the effect of tertiary surveys on missed injuries in trauma: a systematic review. . enderson et al., the tertiary trauma survey: a prospective study of missed injury. the -h rule in the emergency department and its association with surgical mortality in one public hospital in israel: retrospective study i. ashkenazi hillel yaffe medical center, hadera, israel introduction: in order to improve patient treatment the -h rule in the emergency department (ed) was introduced in many countries as well as in israel. within four h, patients attending the ed must be seen, treated, and a decision must be reached whether these patients are to be admitted or discharged. though a popular performancebased measure, whether the -h rule in ed is associated with a decrease in mortality is controversial. the primary objective of this study was to evaluate the association between time in the ed and surgical mortality in one public hospital in israel. material and methods: included in this retrospective study were patients admitted to the ed of hymc during . patients dying on the first day were excluded. . results: included in this study were , patients. of these, , ( . %) patients were hospitalized and the rest were discharged. overall, patients died. general surgery accounted for , patients of which died ( . % of hospital deaths; . % of all surgical patients; . % of patients hospitalized in general surgery). internal medicine together with general surgery and orthopedic surgery accounted for . %, . % and . % of the mortalities observed in patients with decisions made within - h, in patients with decisions made beyond h and in all the patients respectively. forty-five patients with decisions made within h died compared to with decisions made beyond h. these represent . % and . % of all surgical patients in the ed (whether hospitalized or discharged) and . % and . % of those hospitalized. conclusions: general surgery is the second largest contributor to hospital morality. in both absolute terms and relative terms, mortality was not increased by delays in decisions made beyond h. the adoption of this performance-based measure should be questioned. introduction: trauma is an important cause of mortality [ , ] . researchers are looking for optimal death/survival predictive models in trauma population. one way is to validate traumatic scores for different medical systems [ ] . the aim of our study was to validate the new injury severy score (niss) in severe trauma ( introduction: the international classification of diseases-based injury severity score (iciss) has been proposed as a reliable tool to measure trauma system performance especially in countries where a trauma registry has not been yet established. the purpose of this study is to assess the predictive capability for in-hospital mortality of iciss with international and adjusted survival risk ratios (srrs) in greek trauma population. material and methods: this single center, retrospective cohort study was conducted in a greek tertiary care hospital between january to december . the trauma population was defined as hospitalized patients with a principal hospital discharge diagnosis in the range icd- s -t . duplicated injury icd codes, readmissions, transfer to another hospital and missing data were excluded. the primary outcome was in-hospital mortality. adjusted srrs was calculated from patients with multiple injuries and the following two iciss scores were evaluated: multiplicative-injury (iciss) and singleworst-injury (swi). the models were assessed in terms of their discrimination, measured by receiver operating curve (roc) analysis and calibration measured using calibration curves. results: a total of patients were included in the study. median age was ± years and mortality rate was , %. based on international srrs, the area under the curve was , ( % ci . - . ) for iciss-multiplicative and , ( % ci . - . ) for iciss-worst injury. both modes had statistically significant better performance with adjusted greek srrs (aur = , % ci . - . and aur = , % ci . - . , respectively). conclusions: this analysis has demonstrated the validity iciss model for in-hospital mortality prediction in greek trauma population. further research is warranted to confirm the performance of iciss using a sufficiently sized sample to define national srrs. introduction: the occurrence of intra-abdominal abscesses is the most serious post-operative infective complication after appendectomy. a significant amount of research has been conducted in an attempt to identify those patients at greatest risk. pct is initially described as an early, sensitive and specific marker for sepsis associated with bacterial infection. we hypothesize that pct could serve as a predictor of the development of intraabdominal abscess and postoperative infective complication material and methods: the present study is a prospective, single centre, observational cohort study involving patients undergoing emergency appendectomy. all patients admitted to the acute care surgery ward for appendicitis were screened for study eligibility. pct poc samples will be obtained preoperatively (t ) and post procedure (t ) at h (t ), h (t ), and days (t ) post procedure. the primary objective of this study was to assess the diagnostic accuracy of point-of-care testing for pct in identifying post appendectomy abscess. the secondary objective was to determine the diagnostic accuracy in identifying any infective complication conclusions: we expect the incidence of abscess and infective complication to be increased in the pct elevated group compared with the control group. previous investigations indicate the overall morbidity related to infective complication is approximately - % of patient undergoing laparoscopic appendectomy. our pilot study revealed that the incidence could be as high as % in patients with prolonged elevated pct levels. introduction: hand trauma is a common cause for attendance to the accident and emergency (a&e), accounting for nearly - % of all patients . it is essential that accurate treatment and management is done as the implications of mismanagement are long term, which may lead to disability, loss of work and income, livelihood, and even psychological issues . the presence of a specialised hand surgeon is essential for management of these injuries , but in the a&e setting it is not always possible to have such specialised care and there is a need for an efficient triage system. materials and methods: we did an audit in our department and found a delay in the referral of patients from a&e to our trauma clinic, which was quite expected due to a high patient inflow. we devised a trauma pathway for the a&e, known as the d-system which outlines for them till what day from trauma is a particular hand patient safe to be sent to the hand clinic or who needs an urgent referral to a higher trauma centre, based on urgency of need of intervention. the pathway is in the form of a simple flowchart, which is easy to understand even for junior members of the team. we intend to do another audit after implementation of the pathway to assess change in practice. conclusion: it is essential to have simplified pathways for non-specialist areas in order to streamline treatment and offer the best care, in the limited availability of resources, especially at smaller hospitals. our aim is to develop one such system and assess it's effective in delivering better care. introduction: a quantitative method for measuring trauma severity has many potential applications. the intent of this study was to evaluate the accuracy of the mgap score and its components in prediction of in-hospital mortality versus the accuracy of the revised trauma score rts at a trauma center. material and methods: this study included patients with trauma. data regarding age, mechanism of injury, systolic blood pressure, glasgow coma score and respiratory rate were collected at trauma center of alberto torres hospital. mgap and rts scores were calculated, and their accuracy to predict survival/death outcome. results the study included patients, ranging in age from to years, % male. from the total sample, patients who suffered from penetrating trauma and patients who suffered from blunt trauma were observed. in the comparison of the scores, rts and mgap, there was no significant superiority in any of them for predicting the outcome -which in our study was hospital discharge or death -even when compared by trauma mechanism. the gcs proved to be a very sensitive criterion in both scores, especially in patients with traumatic brain injury, totaling patients in our statistical analysis, of which , % had a negative outcome. rts was slightly superior than mgap in patients classified by the score as high chance of mortality, with % versus % of assertiveness. conclusions: up to the moment, there is no evidence to support the superiority of one of the analyzed scores as a predictor of mortality in the patients evaluated. although the rts score is more widely used in trauma centers, the application of the mgap score is more feasible in pre or in-hospital care of polytrauma patients, since it does not use respiratory rate in its parameters. validation of d-dimer for screening for venous thromboembolism in pelvic and lower extremity trauma patients t. uehara , , t. noda , t. yumoto , n. kobayashi , a. nakao , t. ozaki okayama university, emergency healthcare and disaster medicine, okayama, japan, okayama university, orthopaedic surgery, okayama, japan, okayama university, musculoskeletal traumatology, okayama, japan, okayama university, emergency and critical care medicine, okayama, japan, okayama saidaiji hospital, okayama, japan introduction: venous thromboembolism (vte) is a life-threatening complication after major trauma patients. we previously reported that the patients with higher injury severity score (iss) and lower extremity trauma had high risk for vte. additionally, high d-dimer levels (cut-off d-dimer value, . lg/ml) on day were useful for screening for vte in major trauma patients. we validated d-dimer levels for vte screening for patients with pelvic and lower extremity trauma. material and methods: a retrospective study was undertaken between april and august at the okayama university hospital. patients with pelvic or lower extremity trauma were included (median iss, ). we collected following data; age, sex, iss, the number of operation times, value of d-dimer in screening, incidence of vte and use of anticoagulants. results: eleven patients showed high d-dimer levels in screening, furthermore, six patients were diagnosed vte using contrast-enhanced computed tomography. symptomatic pulmonary embolism was not occurred. patients with vte had undergone orthopaedic surgeries two or more times. fourteen patients received therapeutically or prophylactic anticoagulation therapies. conclusions: measurements of d-dimer levels after pelvic or lower extremity trauma patients were useful for screening of incidence of vte. direct oral anticoagulants were convenient for treatment to vte. trauma patients often needed several times of surgeries, heparin was also useful in perioperative period. introduction: early assessment of the clinical status of severely injured patients is crucial for guiding surgical treatment. several scales are available to differentiate between risk categories. we compared four established scoring systems in regard to their predictive abilities for early versus late in-hospital complications. methods: database from a level i trauma center. the following four scales were tested: the clinical grading scale (cgs; covers acidosis, shock, coagulation, and soft tissue injuries), the modified clinical grading scale (mcgs), the polytrauma grading score (ptgs), and the early appropriate care protocol (eac; covers acid-base changes). admission values were selected from each scale and the following endpoints were compared: mortality, pneumonia, sepsis, death from hemorrhagic shock, and multiple organ failure. results: in total, severely injured patients were included (mean age, . ± years; mean iss, . ± . points; incidence of pneumonia, . %; incidence of sepsis, . %; death from hem. shock, . %; death from multiple organ failure (mof), . %; mortality rate, . %). istinct differences in the prediction of complications, including mortality, for these scores (or ranging from . to . ). the ptgs demonstrated the highest predictive value for any late complication (or = . ), sepsis (or = . , p = . ), or pneumonia (or = . , p = . ). the eac demonstrated good prediction for hemorrhage-induced early mortality (or = . , p \ . ), but did not predict late complications (sepsis, or = . and p = . ; pneumonia, or = . and p = . ) cgs and mcgs are not comparable and should not be used interchangeably (krippendorff a = . ). conclusion: our data show that prediction of complications is more precise after using values that covers different physiological systems (coagulation, hemorrhage, acid-base changes, and soft tissue damage) when compared with using values of only one physiological system (e.g., acidosis). none of the authors have any conflicts of interest to declare. mortality rate related to trauma mechanisms in trauma center at alberto torres hospital from january to july r. p. pereira , r. adriana martins , j. a. c. padilha , f. e. silva , , d. rangel alberto torres hospital, trauma center, são gonçalo, brazil, federal university of rio de janeiro, niterói, brazil introduction: to demonstrate the healthcare services of the trauma center of rio de janeiro based on epidemiological data and on the specificity of the type of initial care delivered to multiple trauma patients, comparing the mortality rate at the second peak of death with the worldwide literature. materials/methods: retrospective study extracted from ''ct heat'' database. polytraumatized patients of both sexes were included and the mortality rate was calculated taking into account the second peak of death from trauma, gender, age and primary mechanisms of injury. discussion: the data collected show % mortality in the second peak, with firearm projectiles ( %) followed by traffic accident and fall as the primary causes of death. conclusion: because of the structural and health care profile of this trauma center, it was possible to reach the desirable mortality rate according to the worldwide literature (less than %). introduction: trauma patients are sometimes in critical condition upon arrival and need aggressive treatments to survive. despite all efforts many end up dying. it seems necessary to try to identify those patients with a very high risk of death to avoid futile treatments. the aim of our study was to develop a simple clinical tool to predict mortality in trauma patients that can be easily calculated in the ed. material and methods: we analyzed data from all trauma patients arriving at a spanish trauma hospital from june to june . patient demographics, physiologic trauma scores, vital signs, and glasgow coma scale (gcs) were recorded. our primary outcome was mortality. logistic regression analysis (lra) was performed using three variables (age, shock index (si), and gcs) to determine the appropriate weights for predicting mortality. using them, we constructed a simple score to calculate mortality. results: patients were studied. the mortality rate was . %. our score was constructed using weights derived from lra for age [ y ( points), si [ ( points) , and gcs conclusions: our score is easy and quick to calculate and could be a useful tool to predict mortality using early available parameters upon arrival in the ed. acknowledging the ethics involved in this topic, this score could sort out patients with a very high risk of death and in whom aggressive therapeutic measures could be limited early or withdrawn in agreement with family members references: haider a, et al ( ) ( ) ( ) states the average cost for an a&e attendance and non-elective inpatient stay is £ and £ , respectively highlighting the importance for schemes to reduce hospital admissions. assess impact of ambulatory care, surgical emergency assessment unit (seau) and ''emergency surgeon of the week'' (esw) on hospital admissions for surgical referrals (gp/ a&e). material and methods: retrospective analysis of prospectively collected data of hospital admissions from the patient centre database before and after implementation of seau (in november ) and esw (in november ), including the units'' activities. emergency general surgeon followed : (monday-thursday, - ) rota based at seau. results: since ( months), seau has reviewed (new ; follow ups ) patients. surgical admissions (sa) pre and post implementation seau were * and */month respectively, a drop by %. esw helped a further drop by another % to */month. % of new referrals were admitted and overall % of all patients reviewed were admitted. juniors (st /st ) and seniors (st - /staff grades/consultants) admitted % and % of the referrals respectively. uss and ct were performed in dedicated seau slots. % attending seau were likely to recommend the unit to friends or relatives. conclusions: in the face of unprecedented demand for hospital beds (more so in the winter), ''emergency surgeon of the week'' based at seau could be the answer to relieving the capacity, financial pressures and providing high quality safe patient care for our already strained nhs. surgical emergencies, an educational and medico-economic challenge introduction: surgical emergencies are a frequent reason for consultation in the emergency department and are responsible for significant morbidity and mortality. our study aims to present the number of patients admitted for a surgical emergency in a french level trauma-center and the volume of patients operated in emergency depending on the different specialties. method: we conducted a retrospective, single-center study of the hospital emergency department (uas) of the university hospital center of nice between january and december . we studied the volume represented by surgical emergencies according to the different specialties. results: the emergency department welcomed , patients, of which , surgical emergencies patients accounted for % of the total activity; patients were operated on urgently, which represents % of all surgical procedures in our hospital. conclusion: surgical emergencies are an important part of the activity of our hospitals. an academic definition is difficult to achieve. a regional organization is needed for the management and optimal care of these patients. the creation of regional centers, as for the trauma centers, seems indispensable, especially for the most serious patients, allowing both a better medico-economic and educational management of surgical emergencies. introduction: every new admission to the icu prompts a handover from the referring department to the icu staff. this step in the patient pathway provides an opportunity for information to be lost and for patient care to be compromised. mortality rates in intensive care have fallen over the last years, however, % of patients admitted to an icu will die during their admission ( ) . communication errors contribute to approximately two-thirds of notable clinical incidents; over half of these are related to a handover ( ) . nice have concluded that structured handovers can result in reduced mortality, reduced length of hospital stay and improvements in senior clinical staff and nurse satisfaction ( ) . material and methods: a checklist was created to review to score the handover. this was created with doctors and nurses and is relevant for handovers between all staff members. information was gathered prospectively by directly observing handovers on the icu. results: there is a notable discrepancy in the quality of handovers of new patients. this is true of handovers between doctors, nurses and a combination of the two. % (n = ) of patients weren't handed over to a doctor. the most commonly missed pieces of information were details of the patient's weight ( %, n = ), their height ( %, n = ), whether the patient has previously been admitted to an icu ( %, n = ) and whether the patient has any allergies ( %, n = ). conclusions: the handover of new patients to the icu is often unstructured and important information is missed. this can be said for all staff members and grades, and for handovers from all hospital departments. introduction: bowel resection for acute mesenteric ischaemia (ami) in elderly is associated with significant morbidity and mortality, and increasing age and frailty are associated with increased risk. this study aims to assess the short-term outcomes for elderly patients undergoing surgery for ami, and to assess the accuracy of surgical risk calculators in this population, to determine their utility in preoperative discussions. introduction: intertrochanteric femoral fracture of the super-elderly is often difficult to treat because good surgery does not always lead to good functional prognosis. we investigated the factors affecting the functional prognosis in patients with intertrochanteric fracture over years old. material and methods: cases of intertrochanteric fracture over years old who had undergone surgical treatment at our hospital between december and september were examined. nine men and women, age at injury ranged from to years, with a median of years. the average postoperative follow-up period was . months. for these cases, the mobility was classified into independent walking, assisted walking (cane, walker), wheelchair, bedridden, and the transition of pre-and postoperative mobility was analyzed. the significance test was performed using the mann-whitney u test, and p \ . was considered significant. results: by fracture type, when jensen classifications i and ii were stable, iii, iv, and v were unstable, mobility of unstable type was significantly reduced (p = . ). when the waiting period for surgery is divided by the median of days, there was no difference in mobility reduction between groups of less than days and groups of more than days (p = . ). although there was no significant difference in the presence or absence of preoperative rehabilitation intervention (p = . ), there was a tendency for less decline in mobility when preoperative rehabilitation intervention was performed. conclusions: in the treatment of this fracture, early surgical treatment after injury is recommended, but in the case of very elderly people, waiting is often required due to existing diseases and poor general condition . this study suggests the importance of preoperative rehabilitation intervention during the waiting period for surgery to prevent disuse disorders. references: . kelly-pettersson et al. waiting time to surgery is correlated with an increased risk of serious adverse events during hospital stay in patients with hip-fracture: a cohort study international journal of nursing studies ( ) - . older patients with traumatic shock exhibited lower pulse pressure compared with younger patients; an analysis of nationwide trauma data base in japan introduction: the study purpose was to assess the effect of age on the relationship between pulse pressure (pp) and systolic blood pressure (sbp) in patients with traumatic shock. material and methods: in this retrospective cohort study using nationwide trauma data base in japan from april to may , trauma patients years of age and older with sbp \ mmhg were selected. patients with severe traumatic brain injury (the abbreviated injury scale on head [ ) and cardiac arrest (hr = and sbp \ mmhg) were excluded. linear regression analysis assessed association between pp and sbp interacted by age group dichotomized as \ or c years old. results: during the study period, patients were included. the linear regression analysis indicated the significant association between pp and sbp in overall population (ec, estimated coefficient = . %ci [ . , . ], p \ . ). association between pp and sbp was significantly interacted by the age group (ec = . %ci [ . , . ] introduction: high rates of trauma in south africa (sa) predominantly affect the youth, yet the geriatric population is not exempt. in addition to inherent challenges of age, elderly trauma patients are further compromised by resource constraints. we aimed to assess injuries and outcomes in elderly patients admitted to a tertiary trauma unit in sa. material and methods: a retrospective record review was done of all patients years and older, admitted to the trauma unit over an -month period. injury severity score (iss), mechanism of injury (moi), in-hospital complications and length of hospital stay were documented. results: patients (mean age: years; % female) were included with mean iss of . the most frequent mois included nontraumatic falls ( %), falls from height ( %), motor-vehicle collisions ( %), pedestrian vehicle collisions ( %), and blunt injuries ( %, % intentionally inflicted). eighty patients ( %) experienced at least one in-hospital complication. the mortality rate was %. the mean length of hospital stay was days. conclusions: despite the known vulnerablities of the elderly, the mortality rate and isss of this cohort were relativley low. however, when compared to first world literature, intentionally inflicted injuries and certain preventable mois (e.g. fall from height and pedestrian vehicle collisions) were common, [ ] [ ] introduction: the majority of new colorectal cancer is diagnosed in people [ years, yet the elderly are less likely to undergo curative surgery. chronological age is poorly correlated with post-operative outcomes and is not an acceptable measure of risk. conversely, frailty is a strong predictor of poor outcomes following surgery and presents an opportunity for patient optimisation. the aim of this systematic review is to assess the available evidence between frailty and outcomes in patients of all ages undergoing surgical resections for colorectal cancer. material and methods: pubmed was searched for articles reporting outcomes for patients deemed frail undergoing elective or emergency colorectal cancer resection up until august . the primary outcome was mortality ( and day). secondary outcomes; length of stay, readmission, reoperation & post-operative complications. results: studies identified, studies were deemed eligible for inclusion. study types, frailty assessments & outcomes measured were variable. despite this heterogeneity, categorisation of ''frailty'' was associated with higher rates of post-operative mortality, complications, readmission, and length of stay. conclusions: based on current evidence, frailty is a strong predictor of poor clinical outcomes in patients undergoing surgery for colorectal cancer. standardisation of frailty assessment and measure of outcomes is needed for more robust analysis. accurate risk stratification of patients will allow us to make informed treatment decisions and identify patients who may benefit from prehabilitation and intensive tailored post-operative care. introduction: pneumatosis intestinalis (pi) and hepatic portal venous gas (hpvg) are two radiological findings associated with a broad range of medical conditions. pi can be primary ( % of cases),usually with a benign course, or secondary ( % of cases),which results from obstructive or ischemic gastrointestinal diseases. only a minority of pi is associated to free abdominal air. in literature there is no consensus on radiological and biochemical markers of favourable outcome nor on treatment options-medical or surgical. we tried to identify prognostic markers in a series admitted to a single university hospital. material and methods: the medical records of patients with pi and/or hpvg admitted to ospedale maggiore policlinico (milan, italy) in the period - were collected the ct scan were reviewed by a single radiologist. results: mean age was . ± years ( - ). pi was primary in , % of the patients (n = ), and secondary in , % (n = ). at ct, pi was associated to portal gas in patients ( %) ( dead, alive) and to free air in patients ( %) ( dead, alive). linear or rounded gas collections were equally distributed in primary and secondary pi. the colon was involved in patients ( %), followed by the small intestine in ( , %),and the stomach (n = ). in patients serum lactate was [ , and died. leucocytosis (wbc [ , /mm ) was present in patients ( alive).four patients had peritonitis and abdominal tenderness. laparotomy was performed in primary (alive) and secondary pi ( deaths).in two patients it was diagnostic; in and associated to right or left colectomy, in to ileal resection and in to other procedures.surgery was judged futile in patients; all died a few hours after emergency department access. conclusions: we could not found any relationship between clinical, biochemical and radiological findings and outcome of pi. mesenteric and portal gas is a ominous finding, but did not reach significant value. successful transcatheter arterial embolization for a giant pseudoaneurysm of gluteal muscle due to ground level fall in elderly woman with direct oral anticoagulants t. kadoya , r. nakama , k. arakawa , t. ogura , k. kase saiseikai utsunomiya hospital, department of emergency medicine and critical care medicine, utsunomiya, japan, saiseikai utsunomiya hospital, department of radiology, utsunomiya, japan case history: a 's year-old woman using apixaban fell on the ground and was transferred to previous hospital. magnetic resonance imaging was taken and she was diagnosed as gluteal hematoma. she was treated conservatively but hemoglobin (hb) level was gradually decreased. although she was administered red blood cell as needed, anemia progressed. contrast-enhanced ct showed expanding hematoma of gluteal muscle. she transferred our hospital for advanced treatment including surgery on th day on hospital. clinical findings: vital signs were stable on arrival at our hospital. extensive subcutaneous hematoma was found in the right thigh and gluteal lesion. investigation/results: laboratory test showed that hb . g/dl and normal coagulation status. contrast-enhanced ct showed a giant pseudoaneurysm inside the gluteal muscle. therapy and progressions: angiography showed a giant aneurysm of peripheral branch of internal iliac artery. we performed transcatheter arterial embolization (tae) for it by gelatin sponge. after tae, there was no complication and progressive anemia was stopped. she was transferred to another hospital for rehabilitation six days after tae. comments: increase use of direct oral anticoagulants in elderly people could induce severe hemorrhagic trauma by minimal mechanism. tae is minimal invasive and safety procedure for such trauma case. introduction: the number of elderly people will increase during the next few decades. more importantly, the number of people aged or above are projected to increase % in developed countries. in spain, people over age were . % of the population in , and this will increase to . % in . that has implications in the health services and in the management of trauma patients. material and methods: we did a retrospective cohort analysis of trauma patients c y.o. admitted to our level i trauma center during the time-period of - . demographic data, icu care, and mortality were assessed. results: trauma patients c y.o. were admitted during that period. this is a % increase compared with the number of patients admitted during the previous decade ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . mean age was . ± . years, and median new injury severity score (niss) was (interquartile range to ). % were male. the mechanism of injury was % falls, and % pedestrian runovers. patients were admitted to icu, with median niss of and mortality rate of %. among severely injured trauma patients (niss c ) the hospital mortality rate of those c years was %, much higher than in the age group of - years ( %), with a significant difference (p \ . ). no differences mortality rates between - years and youngers with the same niss. conclusions: the geriatric trauma patient population is on the rise worldwide. this should be taken into account in our trauma centres in order to be able to adapt and try to improve trauma care in these patients. introduction: frailty is a geriatric syndrome which has been considered as a risk factor in the elderly, increasing adverse events in terms of global health, as hospitalization, increase of falls, need of institutionalization, and mortality. the aim of this study is to evaluate relationship between frailty, and the presence of major complications in the postoperative course of patients older than years undergoing emergency surgery. material and methods: prospective, longitudinal, cohort study, using four different scales of frailty as a predictor of risk for short-term adverse events, for patients during the postoperative course of emergency surgery (may -september ). the sample is categorized according to four frailty scales (clinical frailty scale, frail score, trst and share-fi) . we analyze the variables regarding diagnoses, clinical examination at admission, surgical procedures, and postoperative outcomes during the first days. clavien-dindo classification was used in order to graduate the severity of complications. results: patients were included with a mean age of , years (sd , ) . , % of the simple are women. frailty prevalence ranges, according to the frailty scales, from , % to %. median hospital stay was days ( iqr , ) . all four frailty scales show statistical differences to predict major complication in our simple. trst and frail scales show the strongest measure of association (or , and , , respectively). the frail phenotype, is also related to an increased of mortality, and frail scale is the frailty scale with largest or (or = , ).only frail show association with longer hospital stay ([ days), and reoperation rate. conclusions: frailty represents a predictive marker of major complications and mortality, for patients older than years undergoing emergency surgery. frail score, shows the strongest relationship with mortality and complications. introduction: age has been identified as a predictor of trauma mortality [ ] and it is known that even low energy trauma may cause severe injuries in the elderly [ ] . the aim of this study was to explore how the elderly trauma patients, and the care thereof, differ from the younger ones in a swedish context. material and methods: the swedish trauma registry (swetrau) was used. consecutive recorded trauma cases that presented at one level ii trauma hospital during december -august were included (n = ). patients were stratified into groups; those c and those results: in the c years group, sex distribution was more even (female . vs . %, p \ . ), physical status according to pretrauma asa classification was higher (mean . vs . , p \ . ) and the trauma mechanism was predominantly low-energy (falls from no height) as opposed to the conclusions: the trauma among elderly swedish patients are more often of low energy compared to the younger population. in spite of this, the elderly are more severely injured, require more surgical interventions, and their short term mortality is increased -fold. measures aimed at prevention of low energy trauma of the elderly are therefore much needed. introduction: there are intramedullary or extramedullary methods in internal fixation od trochanteric fractures. seldynamisalbe internal fixator with two sliding screws (sif), as an extramedullary method, and gamma nail (gn), as an intramedullary method, are in routine trochanteric fractures treatment at our institution for last two decades. material and methods: health related quality of life and hip function were assesed at least two years after surgery, in the series of patients with a surgically treated ao a or a fracture type. there were two groups of patients: group treated by sif and group treated by gn. examination had been performed using sf- test, with its physical component score (pcs) and mental component score (mcs), and harris hip score (hhs) tests. results: in sif group, mean pcs was , , mean mcs was , and mean hhs was , . in gn group mean pcs was , , mean mcs was , and mean hhs was , . there was no significant difference regarding all these parameters between the groups of patients (p [ , ). there was correlation between all evaluated parameters, both in groups of patients particularly and in all patients (p \ , we identified undertriage in , % ( / ). falls from own height ( - m) was found in patients with iss [ , / ( %) of them was found to have been undertiaged (p . ). we found an association between gcs \ and undertriage (p = . ). % ( / ) falls between - m and % ( / ) of these without trauma team. falls between - m , % ( / ) without trauma team. all with fall [ m had trauma team. mortality was % ( / ), no association between height of fall and mortality (p . ). undertriage was not associated with increased mortality (p = , ). median age in mortality group was years versus years in surviving group (p \ . ). in univariate analysis there was association between prehospital bp \ (p . ), gcs \ (p \ , ), iss (p \ . ), prehospital rr [ , rts \ (p \ . ) asa score [ (p \ . ) and mortality. conclusions: we found significant undertriage in the geriatric trauma population with fall injuries. gcs \ and low energy falls was associated with undertriage but not with mortality. laparoscopic direct repair of an incarcerated spigelian hernia c. bergamini , v. iacopini , r. de vincenti , a. bottari , g. alemanno , p. prosperi aou-careggi, emergency surgery, firenze, italy spigelian hernia occurs through a defect in the anterior abdominal wall adjacent to the semilunar line. it is in itself very rare and more over it is difficult to diagnose clinically. it has been estimated that it constitutes . % of abdominal wall hernias. the majority of patients present with symptomatic incarceration of preperitoneal fat or intraabdominal viscera. radiographic studies are beneficial in confirming the diagnosis. the high rate of incarceration with or without strangulation mandates operative repair once the diagnosis is confirmed. the spigelian hernia has been repaired by both conventional and laparoscopic approach. laparoscopic management of spigelian hernia is well established. most of the authors have managed it by transperitoneal approach either by a direct repair or by placing the mesh in intraperitoneal position or raising the peritoneal flap and placing the mesh in extraperitoneal space. there have also been case reports of management of spigelian hernia by total extraperitoneal approach. we present the case of an obese eighty-four y.o patient. complaining for a sudden onset abdominal pain in the right low quadrant, mimicking an appendicitis. the ct scan demonstrated a typical picture of a spigelian hernia containing an intestinal loop. the loop showed classical signs of parietal wall ischemia. the video describes the surgical laparoscopic approach of this case which was able to confirm the diagnosis e to reduce the loop into the abdomen. the loop initially appeared diffusely ischemic, but after the intra-abdominal reduction some signs of vitality started to be noticed. however, they were incomplete; thus the loop was resected. the hernia defect was successively repaired in a direct way because of the small caliber (\ cm of diameter) and the possible contamination coming from the intestinal resection. post-operative course was particularly benign and the patient was discharged on the seventh post-operative day in good health. introduction: trauma audit & research network (tarn) data shows older persons falling from standing height and sustaining significant injury has become the commonest trauma presentation in england and wales . we aimed to assess whether frailty predicts poor outcomes in the elderly. material and methods: retrospective database review of tarn eligible patients [ years old admitted in a week period with documented rockwood clinical frailty score . age, injury severity score (iss), length of stay (los) and mortality were noted. the inhospital mortality group was sub-analysed. logistic regression was performed (stata v ), odds ratios and % ci reported. results: older age was associated with higher cfs in the patients studied. increasing cfs was associated with increased overall mortality (cfs - vs cfs - or . ; % ci . - . ), decreased likelihood of pre-hospital trauma alert and increased length of stay (cfs - stayed days more than cfs - ). all deaths had cfs [ and head or chest injury. adjusting for age and cfs those with chest injury were . times more likely to die (or . %ci . - . ). mortality in those with rib fracture was times higher in cfs - vs cfs - (or . %ci . - . ). conclusions: increasing age and cfs (especially - ) are associated with poor outcomes in elderly trauma, thus cfs is a useful prognostic tool in severely injured elderly patients. chest injuries are a major cause of mortality in this group, especially with increasing frailty. major trauma centres must develop practice management guidelines to appropriately manage these patients. introduction: major trauma causes activation of the complement system, which plays a key role in development of systemic inflammatory response syndrome and multiple organ failure. complement is known to be activated early after trauma , but the relationship between outcome and the extent of complement activation during the first critical hours after injury is unknown. we hypothesized that complement activation in the first hours after trauma displays a highly dynamic pattern which is associated with outcome. material and methods: complement activation was assessed by plasma terminal c b- complement complex (tcc) using elisa in a prospective cohort of trauma patients. samples were obtained at admission, after , , and h, and daily in the intensive care unit. the extent of complement activation was assessed as area under the concentration curves - h after injury (tcc-auc - ). the relative contribution of complement activation, base excess (be) and new injury severity score (niss) to outcome was analyzed by multivariable analyses. results: niss and be were associated with tcc-auc - in bivariate analyses (spearmans rho (p) was respectively , (p = . ) and - . (p = . )). in multivariable analyses, niss and initial tcc alone predicted % of the variability in ventilatorfree days (vfds), whereas initial tcc and tcc-auc - predicted %. tcc auc - alone contributed with % to the model. tcc-auc - was also significantly higher in patients deceased at day ( . ; . - . (median; quartiles) vs. . ; . - . , p = . introduction: massive transfusion protocols [mtp] have been widely adopted for the care of bleeding trauma patients but their actual effectiveness is unclear. this study aims to conduct an updated meta-analysis to evaluate the effect of implementing an mtp on the mortality of trauma patients. material and methods: medline, pubmed, google scholar and cochrane library databases were systematically searched for relevant articles published from january , to july , using a combination of key words and additional manual searching of reference lists. three reviewers independently screened the articles for potential inclusion. eligible articles were original articles in english, included trauma patients and compared mortality outcomes before and after institutional implementation of a mtp. primary outcomes were h and overall mortality. results: nineteen studies met inclusion criteria, analyzing outcomes from , trauma patients. there was a wide range of outcome and process indicators utilized by the different authors. mtps significantly reduced over-all mortality, pre-mtp- . % and post-mtp . % [or . ( . - . )] for trauma patients. -h mortality was not significantly reduced [or . ( . - . )]. conclusions: the institution of an mtp has a significant over-all mortality reduction for trauma patients. we encourage that researchers use standard nomenclature and indicators, provide more details regarding protocols and patient populations and incorporate advances in the management of bleeding trauma patients in all future mtp studies. introduction: when resuscitating patients with hemorrhagic shock following trauma, fluid volume restriction and permissive hypotension prior to bleeding control are emphasized with good outcomes for penetrating trauma patients. however, evidence that these concepts apply well to the management of blunt trauma is lacking. this study aimed to assess the impact of vasopressor use in patients with blunt trauma in severe hemorrhagic shock. material and methods: in this single-center retrospective study, we reviewed records of blunt trauma patients with hemorrhagic shock and included patients with a probability of survival \ . . patient's characteristics, examinations, severity and administrated therapies were compared between survivors and non-survivors. data are described with median ( - % interquartile range) or number. results: thirty patients were included and median injury severity score in survivors vs non-survivors was ( - ) vs ( - ) (p = . ), with no significant difference in probability of survival. despite no significant difference in injury severity, non-survivors were administered vasopressors significantly earlier after admission and at significantly higher doses. total blood transfusion amount administered within h after admission was significantly higher in survivors ( [ conclusions: vasopressor administration and high-dose use for hemorrhagic shock following severe blunt trauma are significantly associated with increased mortality. although the transfused volume of blood products tends to be increased, early termination of vasopressor should be considered. all authors have no significant relationships with regard to this study. early amplitudes of citrated functional fibrinogen in thromboelastography to predict massive transfusion introduction: this study aims to evaluate the role of early amplitudes of the thromboelastography measure of citrated functional fibrinogen (cff) to predict massive transfusion (mtx) defined as transfusion of c of any blood products within an hour of arrival to a major trauma centre. material and methods: trauma patients c years requiring activation of the major haemorrhage protocol with teg performed on a tegÒ s hemostasis analyser were eligible for inclusion. exclusion criteria were arrival [ h after injury, pregnancy, bleeding disorder or anticoagulant use. patient demographics and transfusion requirements were obtained from medical notes. teg manager was accessed to extract amplitudes at min (a ), min (a ) introduction: hyperfibrinolysis, remains a significant characteristic of acute traumatic coagulopathy induced mortality. s a , a cell surface protein, when shed creats an occult hyperfibrinolytic subtype. annexin a (a ), a multicompartment protein that co-localizes with s a and contains a tissue plasminogen activator (tpa) binding site has been shown to enhance tpa activity -fold and thus behaves as marker of hyperfibrinolysis. we hypothesize that increased concentrations of a in blood will enhance tpa fibrinolysis. material and methods: blood was collected from ( ) healthy volunteers. recombinant a in concentrations , , , , , lg/ ml was added blood and then combined with tpa ng/ml. samples were assessed using thromboelastography (teg). blood samples were collected from trauma activations from -current at a single, urban, level- trauma center. samples were assessed using a combination of rapid, citrated native and tpa challenge teg. a levels were established via proteomic analysis. results: a - (lg/ml) significantly increased tpa mediated ly % vs tpa alone (a ? tpa [ - ] median . % vs tpa . % p \ . ). a without tpa had no significant effect on ly % and was similar to the lysis of control (a lg/ml . % vs control . % p = . ). a - (lg/ml) significantly increased r time from control and tpa alone (control normalized to vs a median . -fold increase in minutes p \ . and tpa . -fold decrease vs a median . -fold increase p \ . ). rapid teg for patient vs patient in our ongoing study was . % vs . % and . % and . % respectively on tpa challenge teg. proteomic analysis of a relative activity found a . -fold a activity in patient compared to patient . conclusions: exogenous cell free a significantly increases tpa mediated fibrinolysis measured by teg. preliminary data from our ongoing trauma study evaluating a levels and hyperfibrinolysis coincide with our in vitro study. introduction: massive transfusion protocol can be activated to mobilize the blood products resource in a timely and effective manner. blood products, however, are still wasted or overused. we aimed to study what proportion of patients who met the abc criteria for massive transfusion received or more units packed rbc (prbc). material and methods: a retrospective study all level i trauma patients admitted with arrival systolic blood pressure of or less (july to may ) was recruited. transfusion was complied with stts. all clinical and laboratory findings, and management procedures were populated from the data registry. results: of admitted trauma patients met the inclusion criteria. of patients who where admitted with hypotension, of patients ( . %), who met the abc criteria for receiving or more prbc were stabilized with or units. in other words, stts enabled us to save units of prbc. arrival data, i.e. blood pressure (cut of point: mmhg and p value: . ), shock index (cut of point: . and p value: . ) and pulse rate (cut of point: beat/min and p value: . ) were significantly different in patients prescribed or more units prbc. after initial resuscitation, blood pressure (cut of point: mmhg and p value: . shock index cut of point: . and p value: . ), pulse rate(cut of poinan beat/min and p value: . ) presence of pelvic fracture, positive fast,and base deficit [ were significantly different in the group received or more units prbc. conclusions: massive transfusion protocol with abc criteria may lead to wasted or overused blood products.consideration of dcr continuation strategy complied with stts along with the findings of this study has resulted in a refined protocol characterized by more effective and efficient blood product resource allocation. references: -chang r, holcomb jb. optimal fluid therapy for traumatic hemorrhagic shock. critical care clinics. jan ; ( ) case history: we present the clinical case of a female patient of years old who had been taking aspirin. mechanism of injury: a fall from her own height, resulting in head trauma. clinical findings: dysphonia and stridor, having underwent an immediate orotracheal intubation. investigation/results: she had a head ct done that was normal; and a cervical column and neck ct that showed a large retropharyngeal hematoma, without an associated vertebrae fracture. diagnosis: large retropharyngeal hematoma. therapy and progressions: she was admitted to the intensive care unit for mechanical ventilation. on nd day, she underwent a surgical tracheostomy. on th day, underwent weaning from mechanical ventilation. on h day, was transferred to the ent ward, had the tracheostomy tube removed and was discharged from hospital. comments: a hematoma in this potential space may constitute an immediately life threatening emergency due to airway compromise. in , thomas et al found only cases described in the literature since . the most common cause is the blunt cervical trauma (in % of the cases). other causes are the cervical hyperextension injury, cervical vertebrae fracture, cough, sneeze, strain, blunt head trauma, swallow a foreign body, retropharyngeal infection, carotid artery aneurism, internal jugular vein puncture, metastatic disease, coagulopathy, anticoagulants, etc. in the setting of trauma, the mechanism of injury generally permits explaining the presenting injuries. in this case, the clinical severity expressed by the patient seemed to be disproportional to the resultant injury. however, the presence of haemorrhage contributing factors associated with the existence of fascial spaces in the neck, should warn us of the possibility of formation of deep cervical hematomas that may cause an occult airway obstruction. case history: a -year-old male with a personal history of consumption of alcohol, cannabis, smoked cocaine and heroin. he was found in decubitus position and in a situation of cardiac arrest. the last time he was seen in his baseline situation was h before. after performing cpr and administration of naloxone and flumacenyl, sinus rhythm was achieved. clinical findings: h after admission, increased tension was observed in left leg, thigh and gluteal region. absence dorsalis pedis, tibialis posterior and popliteal pulse was observed in a doppler examination. investigation/results: intracompartmental pressure measurement revealed a result of mmhg in the deep posterior compartment and mmhg in the superficial (diastolic bp mmhg). at admission k levels were . meq/l, creatinine . mg/dl and ck u/l. diagnosis: opioid-related compartment syndrome. therapy and progressions: urgent fasciotomies of the leg and thigh were performed h after diagnosis with a posteromedial and anterolateral approach in the first case and with a lateral approach in the latter. herniation and signs of poor viability in all the compartments were observed. after the surgery, he persisted with anuria and a ck peak of , u/ l, which was next normalized. debridements were performedfor the next days. subsequently, after the isolation of p. stutzeri and mucor in the wound and the absence of signs of vitality, a supracondylar amputation was performed. after, hemodynamic status improved. weeks after the amputation it was possible to withdraw hemodialysis, which he had required since admission. comments: opioid misuse is a topic of growing interest. recent works have reported a worse prognosis in the case of opioid-related compartment syndrome. a high level of suspicion is necessary to make a prompt diagnose in these patients. introduction: the pelvic binder is a mechanical device designed to compress instable pelvic ring fractures and minimize dead space in order to limit blood loss. it is generally recommended to apply a pelvic binder if an unstable injury is suspected and the patient presents with a ''c-problem''. the effectiveness remains questionable though. material and methods: a total of trauma patients between and were retrospectively evaluated regarding instable pelvic injury. patients were admitted with a pelvic binder applied. the correct application was evaluated using ct scout. four groups were generated: group with correct pelvic binder application, group with incorrect placement, group with no pelvic binder at time of admission, group with pelvic binder applied in er. total outcome was determined based upon iss, age, preclinical time, time to ct, shock index, hemoglobin at admission, survival rate, administration of blood products as well as total hospital and icu days. results: % of all pelvic binders were applied incorrectly. patients ( %) suffered an instable pelvic fracture. patient survival was not influenced by the preclinical application of a pelvic binder ( % group vs. , % group , p = , ). no significant statistical difference was found for total icu days , vs. , , p = , ; total hospital days , vs. , , p = , ; rbc transfusion , vs. , , p = , ; iss , vs. , , p = , . conclusions: the correct application of a pelvic binder seems to pose problems preclinically. while the need to minimize blood loss is crucial, our collective did not benefit from this device. additionally, survival rates of the patients that suffered an instable pelvic fracture were unaffected. the iss remains the strongest predictor of total patient survival in pelvic trauma. trauma resuscitation times in a level trauma center in the netherlands: a prospective overview introduction: in trauma, time is considered to be an important factor influencing patient's outcome. in the first hour after injury, appropriate care has the greatest effect on trauma patient's survival. previous research showed that measuring in-hospital trauma resuscitation times, contributes to insights and improvement of the resuscitation process. however, despite developments of atls guidelines, no recent empirical knowledge regarding resuscitation times exists. the aim of this study is to examine in-hospital trauma resuscitation times in a level trauma center in the netherlands. material and methods: a prospective study was performed in level trauma center amsterdam umc location vumc, between may and august . trauma patients, aged c , presented during daytime at the trauma resuscitation room were included. information regarding patient's characteristics, trauma-and injury type, handover duration, duration till start of diagnostics and intervention, total resuscitation time, patient's disposition and survival were compared. results: in total, patients were analyzed. motorized traffic accident ( %) and blunt injury ( %) were the most common mechanism-and injury types. median prehospital to in-hospital handover time was . min (iqr . ) . median duration till start of diagnostics and intervention were . (iqr . ) and . min (iqr . ) respectively. median total resuscitation time showed to be . min (iqr . background: terrorist attacks and civilian mass casualty events are frequent, and some countries have implemented tourniquets for uncontrollable extremity bleeding in civilian settings. we summarized current knowledge on the use of pre-hospital tourniquets in civilian settings to assess whether their use increases the survival rate in civilian patients with life-threatening hemorrhages from the extremities. methods: using the preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines, we searched medline (ovid), embase (ovid), cochrane library, and epistemonikos in january . all types of studies that examined the topic in a pre-hospital setting published after january , , were included. the protocol was registered in prospero (crd ). results: among screened records, studies were identified as relevant. due to a lack of relevant civilian studies, military studies were also included. the studies were highly heterogeneous, with low quality of evidence. most studies reported increased survival in the tourniquet group, but few had relevant comparators, and the survival benefit was difficult to estimate. most studies reported a reduced need for blood transfusion, with few and mainly transient adverse effects from tourniquet use. conclusion: the data suggest that the use of commercial tourniquets in a civilian setting to control life-threatening extremity hemorrhage is probably associated with improved survival, reduced need for blood transfusion, and few and transient adverse effects. the effect of venous infusion by emergency medical service personnel on the prognosis of severe traffic accident patients: a nation-wide study in japan y. katayama , t. kitamura , , t. hirose , y. nakagawa , t. shimazu osaka university graduate school of medicine, department of traumatology and acute critical medicine, suita, japan, osaka university graduate school of medicine, environmental and population science, suita, japan introduction: in japan, the law of paramedic was revised in , and it became possible for paramedic in japan to secure an infusion route before cardiac arrest for severe patients. however, the effect of this treatment on the prognosis of severe trauma patients has not been assessed. we assessed this effect on the prognosis of severe traffic accident patients with using population-based ambulance record and nation-wide hospital-based trauma registry in japan. material and methods: this study was a retrospective observational study and the study periods was years between january to december . we linked the nation-wide hospital based trauma registry (jtdb) and the population-based ambulance record in japan in case. in this study, we included the traffic accident patients with iss score more than and excluded cardiopulmonary arrest patients on the arrival of ems on the scene and missing data cases. the main outcome was cardiopulmonary arrest on hospital arrival. mcnemar's test and conditional logistic regression analysis were used to assess the association between the securing a infusion route by ems personnel and the primary outcome after one-to-one propensity score matching for securing a infusion route or not. results: traffic accident patients were eligible for analysis and patients were dripped by ems personnel. after one-to-one propensity score matching, the proportion of cardiopulmonary arrest on hospital arrival were . % ( / ) in patients dripped by ems personnel and . % ( / ) in patients not dripped by ems personnel, respectively (p = . ). the adjusted odds ratio for securing a infusion route was . [ % confidence interval; . - . , p = . ]. conclusions: in this study, there was no association between the securing a infusion route and outcome of traffic accident patients. the association between trauma patient characteristics and adverse laboratory values: which patient characteristics are most predictive? introduction: in more than countries worldwide, laboratory testing is protocol driven since when it was included in the practice guideline of the advanced trauma life support course (atls). however, it is not clear yet which patient characteristics are associated with unfortunate laboratory values. the aim was to create an overview of the characteristics that were associated with adverse laboratory values. material and methods: this cohort study was performed at amsterdam umc, location amc (level trauma center), including patients during a period of years. data concerning age, gender, asa scores, injury severity scores (iss), glasgow coma scores (gcs), mechanism of injury, type of injury (blunt or penetrating) and the presence of helicopter emergency medical services (hems) were obtained. the hematology panel included hemoglobin, hematocrit, mcv, leucocyte and thrombocyte values. the coagulation panel included inr, pt, aptt, fibrinogen and d-dimer values. other panels include arterial blood gas, kidney and liver panels. the association between trauma patient characteristics and laboratory values were determined by using binary and multinomial logistic regression. results: a total of patients were included, consisting of predominantly men ( %) with a mean age of years old. an increase in age and iss was correlated with abnormal laboratory values (p = . ). additionally, male gender, iss [ , blunt trauma and the absence of hems was associated with a deviation in laboratory values (p \ . ). other patient characteristics did not show a significant correlation with adverse laboratory values. case history: a -year-old man presented with a classic case of pituitary apoplexy with a history of headache, nausea and vomiting. clinical findings: he was found to have a sellar and suprasellar mass with internal cystic and hemorrhagic component consistent with a pituitary macroadenoma. investigation/results: he underwent transsphenoidal sugery for a pituitary macroadenoma. because the tumor was invaded to left cavernous sinus, we left small portion of the tumor. eighth day after surgery, he underwent gamma-knife surgery (gks) for residual tumor. after two weeks, he complained of left ptosis. we considered the rd nerve palsy to be a post-radiation reaction at first. after months, the symptoms had been continuous and mri showed increased size of cystic lesion involving left cavernous sinus. diagnosis: ct angiogram demonstrated a saccular aneurysm at left distal ica. endovascular coil embolization was performed. therapy and progressions: after months of the intervention, the rd nerve palsy was partly improving. comments: our case report emphasizes the necessity of cerebrovascular imaging before surgery for pa. mr angiography/ct angiography is not currently obligatory in patients with pituitary adenoma, but in cases with the symptoms of displacement of the neuro-vascular structures it can be of great value. even in patients without such presentations, it may be helpful to evaluate the vascular involvement. case history: a -year-old boy during the preparation for a fishing session was pierced to the left orbitary region by a high-speed spearfishing steel. clinical findings: upon arrival the patient was conscious and responsive with a gcs of , he followed commands appropriately and there were no motor of sensory deficits. investigation/results: plain skull radiographs showed the spear crossing the skull from the left orbit to the posterior part of the parietal bone. diagnosis: the patient was immediately intubated to prevent involuntary movement of the foreign body. ct scan showed the fracture of the left orbitary roof where a centimetres long metallic object crosses the cerebral parenchyma of the left hemisphere and perforates the left parietal skull. therapy and progressions: under direct visualization via transorbital approach the foreign body was removed together with bone fragments, hemostasis was done and orbitary roof repaired. serial cranial ct scan showed progressive reduction of frontal and parietal hematoma. the movement of the eye improved after a few days, normalizing with the regression of periorbital edema. upon discharge at th postoperative day the patient had a gcs score of , no motor deficit and minimal visual loss. comments: penetrating injury of the skull and brain are relatively uncommon events, representing about , % of all head injuries. orbital roof is relatively thinner part of the skull that can provide easy access to projectile objects, which can penetrate into cranial cavity and damaging the brain parenchyma. the principles of treatment are removal of bone fragments and foreign body, control of persistent bleeding and intracranial hypertension, prevention of infection though debridement of all contaminated and necrotic tissue and at the same time preservation of as much nervous tissue as possible. multitraumapatients whith severe head injury (ais ‡ ) are more quickly carried out ct scan on than a patient without severe head injury v. giil-jensen , k. andersen , t. k. helle haukeland univercity hospital, sugical department, bergen, norway, haukeland univercity hospital, ambulance service, bergen, norway introduction: trauma patients who are prone to severe head injuries during trauma may profit from obtaining a rapid clarification of the injury magnitude when using ct examination. in the case of a delayed ct examination, the consequence of the head injury could be more extensive. in this study, we wanted to see if those with severe head injury (ais c ) received a faster ct survey than those who had no severe head injury. material and methods: retrospective registry study of severely injured patients (iss [ ) which had been hospitalized as a trauma patient at haukeland university hospital in the period - . in the study, we have excluded all patients entered as multitrauma but who have iss \ and all patients who have not defined ct time. it turns out that over half of the patients lacked the registration of accurate time for the ct survey in the national trauma register. the number is still considered large enough to find a result. results: patients were received as multitraumatic at haukeland university hospital during the period. of these, was severely injured. of these, patients had severe head injuries and they again had head injuries as the only serious injury (ais c ). median time from arrival receipt to start ct, for this group was min. in the control group that was severely injured but without severe head injury is the same time min. there was patients in the control group. conclusions: for the patients in this study who had severe injuries (n: ), the median time from the arrival in the emergency department to the ct starts was min shorter for severe head injuries than for the group without severe head injuries. introduction: the patients with severe traumatic brain injury (stbi) who needs surgical intervention often experience acute traumatic coagulopathy (atc). earlier transfusion with high blood product ratios (plasma, platelets, and red blood cells via : : ratio) is recommended for severely injured patients. however, recommended blood product ratio for stbi is still controversial. material and methods: we retrospectively reviewed successive adult stbi who underwent surgical treatment in our hospital between january and december . we have transfused plasma aggressively to maintain blood fibrinogen above - mg/dl. we evaluated the total amount of transfusion and mortality. we exclude cases administered fibrinogen concentrate. results: patients were enrolled. the amount of transfusion for h is rbc . units, ffp . units, pc . units . stbi with severe other trauma needs higher ratio of plasma. discussion: tissue injury of stbi causes severe coagulopathy and : : transfusion was thought to be insufficient for stbi in order to maintain fibrinogen. we agressively transfused plasma but we achieved fibrinogen value above only in % of stbi with severe other trauma. agressive plasma transfusion had limitation for hyperfibrinolysis so we expect other product, for example fibrinogen concentrate. introduction: traumatic brain injury (tbi) remains a leading cause of hospital admission and mortality amongst trauma patients. intracranial hemorrhage (ich) can occur with tbi and presents a severe complication. low complication tolerance in developed countries and uncertainty on actual risk cause excessive diagnostics and hospitalization, considered unnecessary and expensive. methods: tbi cases indicated for cranial computer tomography (ct) according to international guidelines, at our level i trauma center between - were retrospectively included. multivariate logistic regression was performed for ich, progression and mortality predictors. results: tbi patients (m: . ; age at trauma: . ± . ), were included. ct was performed in . %, skull fracture diagnosed in . %, ich in . %, ich progression in . %. in patients \ a, chronic alcohol consumption (p = . ) and neurocranial fracture (p \ . ) were significant ich risk factors in a multivariate analysis. in patients between - a, chronic alcohol consumption (p \ . ) and skull fracture (p \ . ) revealed as significant ich predictors. in patients [ a, age (p = . ), anticoagulation (p = . ) and neurocranial fracture (p \ . ) were significant risk factors for ich, age (p = . ) was an independent risk factor for mortality. late onset ich only occurred in cases with at least of factors: age [ , anticoagulation, neurocranial fracture. overall hospitalization might have been reduced by . % via low risk cases. conclusions: triggered by decreasing error tolerance, international guidelines for mild tbi focus on safety maximization. repeated ct in initially ich negative cases should only be considered in high risk patients. non-ich cases aged \ years do not gain safety from observation or hospitalization. recommendations from our data might, without impact on patient safety, reduce costs by unnecessary hospitalization and diagnostics. references: to be added by the authors. evaluation of low-value clinical practices in acute trauma care: a multi-center retrospective study l. moore , k. soltana , j. clément , a. turgeon , î mercier , r. krouchev , p. a. tardif , s. bouderba , a. belcaid université laval, social and preventive medicine, québec, canada, chu de québec-université-laval, québec, canada, université-laval, québec, canada, introduction: low-value clinical practices have been identified as one of the most important areas of excess healthcare spending and are associated with adverse health outcomes. the objectives of this study were to estimate the frequency low-value practices in injury care and assess inter-hospital variations. material and methods: we identified low-value clinical practices from internationally recognized clinical guidelines. we conducted a population-based retrospective cohort study using data from an inclusive canadian trauma system ( - ) to calculate frequencies and assessed inter-hospital variations with intra-class correlation coefficients (icc). results: we identified low-value practices of which could be measured and validated using trauma registry data. the three lowvalue clinical practices with the highest absolute and relative frequencies were pelvic x-rays in hemodynamically stable patients with a negative physical exam for pelvic injury ( . %), head ct in adults with minor head injury who were negative on a validated clinical decision rule ( . %) and chest x-ray in hemodynamically stable patients with a normal physical exam ( . %). we observed high inter-hospital variation for surgical management of penetrating zone ii neck injury without hard signs (icc = %), and moderate variation for head ct in adults with minor head injury who were negative on a validated clinical decision rule (icc = . %). conclusions: we have developed and validated algorithms to evaluate nine potentially low-value clinical practices using trauma registry data. highest frequencies were observed for imaging in the emergency department and the highest inter-hospital variation was observed for inappropriate surgical management. these data can be used to advance the agenda on low-value care for injury admissions. dysfunction of functional connectivity between default mode network and cerebellar structures in patients with mtbi in acute stage. rsfmri and dti study introduction: mild traumatic brain injury (mtbi) occupies one of the first places in children injuries. among all brain networks at the resting state, the default mode network (dmn) is the most widely studied network. the aim of this study is to examine functional connectivity in normal-appearing cortex in acute period of mtbi using rsfmri. material and methods: mr negative participants were studied in age from to years (mean age- . years). group of patients consisted of children with mild traumatic brain injury in acute stage. age-matched healthy volunteers comprised control group. all studies were performed at phillips achieva . t mri scanner using -channel head coil. fmri data were processed using functional connectivity toolbox conn. seed-based analysis was performed in order to reveal disturbances in functional connectivity. statistical processing was performed using statistica . results: dti analysis didn't show any changes in values of apparent diffusion coefficient (adc) and fractional anisotropy (fa) between two groups (see fig. ). no statistically significant differences in correlation strength between dmn parts were observed in two groups (see fig. ). intergroup seed-based analysis revealed statistically significant (p \ , ) difference in neural correlations between dmn parts and vermis (cerebellum structural part): positive link in control group and negative link in group of patients. conclusions: one of the most common symptoms of mtbi is dizziness as a result of impaired movements coordination. vermis as an essential cerebellum part plays an important role in the vestibuloocular system which is involved in the learning of basic motor skills in the brain. vermis aids in the synchronization of eye and motor functions in order for the visual field and the motor skills to function together.our results show that mtbi appears to be a possible reason of connectivity malfunction in normal-appearing vermis. references: predictors of developing post-traumatic endophthalmitis introduction: h magnetic resonance spectroscopy ( h mrs) allows to study structural and metabolic brain disorders in various pathological conditions in vivo. non-invasive method determines its advantage for use in children in serious condition with acute cerebral injuries. this determined the purpose of the study: to identify criteria of irreversible brain damage based on the h mr spectra analysis in comatose children with acute traumatic brain injury (tbi) or anoxia. material and methods: patients ( months- years) were examined in the acute period of severe cerebral injury (gcs score - ): six were in acute and subacute period of severe tbi, one patient was examined on the seventh day after drowning, and one-a day after acute cerebral blood flow (hemorrhage). all patients died in - days after the study. control group included healthy children aged from to years. single voxel h mrs and d h mrs was performed on t scanner. h spectroscopic voxel (te/tr = / ms, voi = cm , nsa = ) was oriented on mri intact areas: cortex of frontal, parietal and occipital lobes (fig. ) , thalamic nuclei (fig. ) , cerebellum, brainstem (fig. ) . for d h mrs a spin-echo point-resolved spectroscopy (press) sequence was used (te/tr = / ms) with the spectroscopic voi of cm on frontal lobes. results: in all spectra lactate (lac) signal, dominating all other signals, was detected. n-acetylaspartate (naa) was reduced by % and creatine/phosphocreatine (cr)-by %. conclusions: h mrs is a non-invasive prognostic method in patients with acute cerebral brain damage in coma. the cause of patients' death is the shift of cerebral glucose metabolism to an anaerobic type, as evidenced by the accumulation of lac. disturbance of energy metabolism causes a decrease of cr and a decrease in the neuronal marker naa. the combination of these patterns in acute cerebral injury, regardless of etiology indicates irreversible brain tissue damage. introduction: scalds and contact burns are the most common burn injuries both in children and adults. data are conflicting regarding which type of burns are more severe. we compared scalds, contact, and flame/fire burns at our burn center to determine which type were more likely to result in full thickness injuries and prolonged length of stay (los). material and methods: we conducted a structured retrospective medical record review of all patient admissions to a regional burn unit over a -year period between and . data included demographic, clinical, and specific burn characteristics. the association between patient predictor variables and outcomes (full thickness burns, los) was explored using chi-square and stepwise logistic regression. results: there were , patients with either scald (n = , %), fire/flame (n = , %) or contact burns (n = , %). burn depth was not available for cases ( %). mean (sd) age was ( ), % were male. mean (sd) total body surface area (tbsa) was ( )%. % of burns contained areas of full thickness injury. patients with scalds were younger than those with contact or fire burns ( ± vs. ± vs. ± years respectively, p \ . ). the percentage of burns that were full thickness by etiology were contacts ( %), fire/flame ( %) and scalds ( %); p \ . . after adjusting for age, location, and tbsa, scalds were less likely to result in full thickness injuries than contact burns (odds ratio . , %%ci, . - . ). adjusting for multiple testing, univariate analysis (as well as the multivariate analysis) showed no difference in % rd degree burns between fire and contact burns, but scalds were significantly lower than each of those. los for scalds ( ± ) and contact burns ( ± ) was significantly shorter than for fire/flame ( ± days, p \ . ). conclusions: while less common, contact and flame burns were more likely to result in full thickness injuries than scalds. references: epidemiology, treatment, costs, and long-term outcomes of patients with fireworks-related injuries (rocket); a multicenter prospective observational case series introduction: the aim of this study is to provide detailed information about the patient and injury characteristics, medical and societal costs, and clinical and functional outcome in patients with injuries resulting from fireworks. material and methods: a multicenter, prospective, observational case series performed in the southwest netherlands trauma region, which reflects % of the netherlands and includes a level i trauma center, a burn center, and an eye hospital. all patients with any injury from consumer fireworks, treated at a dutch hospital between december , and january , , were eligible for inclusion. exclusion criteria were unknown contact information or insufficient understanding of dutch or english language. the primary outcome measure was injury characteristics. secondary outcome measures included treatment, direct medical and indirect societal costs, and clinical and functional outcome until one year after trauma. results: out of patients agreed to participate in this study. the majority was male (n = ; %), % were children \ years, and % were bystanders. injuries were located to the upper extremity or eyes and were mostly burns (n = ; %) of partial thickness (n = ; %). fifteen ( %) patients were admitted and ( %) patients needed surgery. the mean total costs per patient were € , ( % ci € , to € , ). patient-reported quality of life and functional outcome was not significantly different during follow-up compared with pre-trauma. conclusion: the most common injuries afflicted by consumer fireworks were burns, mostly located to the upper extremity, and eye injuries. fireworks can result in severe injuries, for which ( %) patients needed hospital admission and ( %) patients needed surgical treatment. although some injuries resulted in permanent disability, year after trauma it in general did not have major or longlasting impact on patients'' self-reported quality of life or functional abilities. persistent inflammation, immunosuppression and catabolism syndrome after polytrauma: a rare syndrome with major consequences. l. hesselink , r. spijkerman , r. hoepelman , l. koenderman , l. leenen , f. hietbrink umc utrecht, trauma surgery, utrecht, netherlands, wilhelmina children's hospital, center for translational immunology, utrecht, netherlands introduction: more severely injured patients survive the critical first phase after trauma nowadays. a substantial portion of these patients require long-term critical care support and suffer from recurrent infections. this clinical condition fits in a syndrome referred to as ''persistent inflammation, immunosuppression and catabolism syndrome'' (pics). the aim of this study was to investigate the incidence of pics and clinical outcomes of trauma patients with pics in a level one trauma center. material and methods: all trauma patients c years admitted to the intensive care unit (icu) for c days between and , were included. patients with isolated neurological injuries were excluded. pics patients were identified by icu stay c days, c infectious complications and increased catabolism. infectious complications included infections during hospitalization and readmissions due to an infection. increased catabolism was defined as weight loss [ %, a body mass index. results: of the , polytrauma patients, patients had an icu stay c days. after exclusion of patients with isolated neurological injuries, patients were included. of these patients, developed pics. pics patients sustained infectious complications on average (compared to in the non-pics group, p \ . ) and . % of the pics patients developed sepsis. also, pics patients had a longer hospital stay (mean of days versus days, p \ . ) and sustained more surgical procedures (mean of versus per patient, p \ . ). infectious readmissions occurred until years after the initial trauma. conclusions: patients who develop pics experience long-term inflammatory complications that lead to frequent readmissions and surgical procedures. therefore, despite its low incidence, this clinical condition forms a burden on patients and a substantial financial burden on society. hyperbilirubinemia as a risk factor of the trauma icu patient introduction: hyperbilirubinemia is common in the intensive care unit (icu). hyperbilirubinemia has been considered as a risk factor of the icu patient. hyperbilirubinemia can have various causes. the hyperbilirubinemia has never been studied for the trauma icu patient. the aim of this study is to elucidate the incidence and effects of the hyperbilirubinemia for the trauma icu patient. material and methods: retrospective review of the trauma icu patients from . . to . . . initial bilirubin serum level, h bilirubin level, day bilirubin level, highest bilirubin level, overall morbidity and mortality and other clinical variables were identified and evaluated. the patients who have highest bilirubin level c . mg/dl were defined as hyperbilirubinemia group. results: a total patients were enrolled in this study. hyperbilirubinemia above serum bilirubin c . mg/dl were appeared in patients. the mortality of the hyperbilirubinemia group was higher than the other group ( . % vs . %, p = . ). the icu stay of the hyperbilirubinemia group was longer than the other group ( . day vs . day, p = . ). the hyperbilirubinemia group had more incidences of pneumonia, acute kidney injury, and sepsis than the other group ( . % vs %, p = . / . % vs . %, p = . / % vs %, p \ . ). conclusions: the hyperbilirubinemia is a risk factor of the trauma icu. if the hyperbilirubinemia is appeared, the cause of the hyperbilirubinemia should be evaluated and make an effort to correct hyperbilirubinemia for the each cause of the hyperbilirubinemia. case history: we present the clinical case of a male patient of years old. injury mechanism: a firework burst on his right forearm. clinical findings: injury: a large area of carbonization of the muscles of the flexor compartment. signs and symptoms: intense pain in the hand and forearm with local oedema and tension. diagnosis: deep burn of the forearm. therapy and progressions: surgical debridement and fasciotomy of this compartment; followed by deferred and progressive primary closure by means of rubber bands that were tightened as the oedema diminuished-shoelace technique. evolution: discharged from hospital on the th pos op day; follow-up at rd and th month without functional impairment, with a good healing evolution. comments: deep burns that reach the subfascial planes of the limbs, increase the pressure in the muscular compartments, and may progress to a compartment syndrome. there is no specific cutoff value of pressure for this diagnosis; consequently, the final decision to proceed with a fasciotomy relies on the clinical experience. surgical debridement and fasciotomy may result in large wounds, sometimes difficult to close. grafts and flaps result in another wounds and carry a risk of pain, infection, scar shrinking and necrosis. the diagnosis of a limb compartment syndrome is almost always a clinical one and requires a high index of suspicion so as to the fasciotomy is done in time. the shoelace technique is a simple, reproducible and cost-effective method of deferred closure of a large wound, preserving functionality and resulting in a good final cosmesis. references: johnson ls et al, management of extremity fasciotomy sites prospective randomized evaluation of two techniques, am j surg. . the use of propranolol in the management of acute thermal burn injury: evaluation of the effect of fixed dosages in african patients c. jac-okereke , i. onah , esut teaching hospital, surgery, enugu, nigeria, national orthopaedic hospital, enugu, nigeria introduction: propranolol has been shown to improve outcomes in burn patients. its effects are achieved at doses that reduce the heart rate by - %. africans have a different propranolol pharmacogenetic profile as compared to other races. there is paucity of literary works on the use of propranolol in africans with burns. in our study, we explored the effectiveness of fixed dosages of propranolol in nigerian patients. material and methods: this was a prospective comparative study of adult burn patients; two test groups received propranolol mg/day and mg/day respectively. the average daily pulse rate prior to and after the administration of propranolol were compared. results: patients in the control group had no effective reduction in their pulse rate. patients who received propranolol at a dose of mg/day had a reduction c %. no adverse events were observed. conclusion: it is important to establish the effective dosage of propranolol in burn patients of african-descent and explore its potential benefits in their treatment. although we cannot draw strong case history: the authors present in their paper three cases of blunt abdominal injury caused by seat belt in car accident. in the first two cases there was no diagnostic problem thanks to clear clinical finding. in the third case there was no clinical correlation and even repeated auxiliary examinations did not indicate the need for surgical intervention of the abdominal cavity. clinical findings: case no. -male y. old, haemodynamic stability, thoracic an abdominal pain, fast positivity, on ct free fluid in abdominal cavity, small spleen laceration, positivity of peritoneal symptomatology. case no. -male y. old, haemodynamic stability, bilateral hypogastric pain without peritoneal symptomatology, fast with small perihepatic fluid, on ct fluido-pneumoperitoneum. case no. -female y. old, haemodynamic stability, thoracic pain, massive oedema on the right side of the neck and supraclavicular area, without abdominal symptomatology. fast with small subhepatal fluid collection- mm, ct scan with large neck haematoma and fracture of st rib, apical pneumothorax- mm. intraabdominal only subhepatal fluid stripe- mm, suspected of small hepatic laceration. after days the clinical status rapidly changed, during h peritoneal symptomatology occured. on control ct scan fluido-pneumoperitoneum was detected. investigation/results: all patients underwent surgical procedure diagnosis: bowel mesenteric injury therapy and progressions: the first patient underwent ileo-caecal and hartmann resection, by the second patient was small intestine and col. sigmoideum resection needed, and the last one underwent ileal resection and npwt. comments: despite the current diagnostic methods blunt abdominal injuries, unlike the penetrating ones, can present a certain diagnostic problem especially when they are accompanied by other serious conditions such as manifest chest injuries. introduction: patients with hypertension and peritonitis must undergo a laparotomy. in isolated parenchymal lesions of the liver, the spleen or kidneys interventional or conservative approaches are more frequently used. to miss a hollow viscus organ lesion, that would need an operative procedure, is a constant fear. it is the aim of this study to identify significant predictors of the simultaneous presence of a hollow viscus lesion in patients with parenchymal organ lesions. material and methods: data of over ' inpatients of a levelone-trauma centre between and were analysed. only hemodynamically stable patients with a splenic-, liver-, or kidney injury (independent of grade) after blunt abdominal trauma were included. significant predictors were detected in bi-and multivariant analysis. results: of the patients with an average age of ± years % (n = ) had a splenic-, % (n = ) a liver-and % (n = ) a kidney rupture. the total iss was ± points. in patients ( %) a hollow viscus injury could be found (stomach n = , small bowl n = , colon n = , rectum n = ). injuries of the thorax ( %), the extremities ( %), the head ( %), the vertebra column ( %) and the pelvis ( %) were diagnosed as concomitant injuries. due to multivariant analysis neither age, gender, heart frequency at admission, gcs, base excess, the coagulation parameters, the hemoglobin value nor the separate injury regions could be identified to be predictive factors for the presence of a hollow viscus lesion. conclusions: clinical parameters taken at admission are not useful to predict hollow viscus injuries. the ct-scan is currently seen to be the best possible imaging modality, but it can be false negative, especially within the first min after trauma. repetitive clinical examination is necessary. in doubt a diagnostic laparoscopy or even laparotomy has to be performed. introduction: a heavy abdominal trauma is associated with a high morbidity and mortality. it is the aim of this study to show injury patterns in the abdomen and concomitant injuries in polytraumatized patients as well as to identify risk factors of the decease. material and methods: data of over ' inpatients of a level-one trauma centre between and were retrospectively analysed. only patients with a relevant abdominal trauma (ais abdomen c ) were included. the ais score was determined either with a contrast enhanced computed tomography or intraoperatively. significant risk factors were detected in bi-and multivariate analysis. results: patients with an averaga age of ± years were included. % (n = ) had an ais abdomen of , % (n = ) of and % (n = ) of . the overall iss was ± points. the mechanism of injury was mainly blunt ( %). a splenic rupture was present in % (n = ), a liver rupture in % (n = ) and a kidney rupture in % (n = ). hollow viscus injuries were present in % (small bowl n = , colon n = , stomach n = , rectum n = , bladder n = ). concomitant injuries were determined in % of the patients. of these % were diagnosed a thoracic injury, % injuries at the extremities, % head injuries. % spinal injuries and % pelvic injuries. the mortality was % (n = ). a liver rupture (p = . , or . ), pelvic injuries (p = . , or . ), age (p = . , or . ), hypotension (systolic blood pressure \ mmhg) (p = . , or . ) and a low gcs at admission (p \ . , or . ) were determined to be significant risk factors. conclusions: in our trauma department life threatening abdominal traumata are treated about every days. lethal abdominal injuries were mostly associated with serious liver ruptures or pelvic injuries. due to our experience we recommend the use of an early ct-scan as thereby the injury severity can be fast and precisely assessed. case history: a yo female was tranferred to our icu on day of a severe acute necrotizing alchoolic pancreatitis with mof. crrt with cytosorb was immediately started. on day after onset (dao ) an acs with a new organ failure (lung) showed up. open abdomen (oa) and tac with mesh-mediated/npwt got a temporary improvement. clinical findings: on dao (oa ), reopening of the mesh entailed a sudden fascial retraction of cm. a new larger mesh was positioned. on dao (oa ) the fascial defect measured both on ct slices and in or was cm. provision of a longterm oa was done. therapy and progressions: a new fascial traction device (fas-ciotensÒ, germany) was positioned on dao (oa ), with a continuous traction weight of - kg. revision was scheduled any - days, according to clinical needs, including combined anterior and retroperitoneal necrosectomy. progressive traction allowed to get a cm fascial gap under traction on dao (oa ). anterior cst was thus performed and fascia primarily closed. completion of necrosectomy was done through the bilateral lumbar incisions and npwt. comments: early fascial closure is a goal in oa. mesh-mediated traction/npwt is the most effective strategy, but primary fascial closure is sometimes impossible. the duration of oa is a key point. fasciotensÒ allowed to overcome the failure of mesh-mediated option and avoided fascia retraction in a longterm oa. it was quickly managed by the nurse staff, allowed a easier access to the abdomen and a proper positioning of the protective film. its effectiveness in this demanding case makes it an interesting option for shortening fascial closure in septic oa too. background: small bowel obstruction (sbo) caused by intra-abdominal adhesions is one of the main surgical emergencies. in most of the time, adhesions are created by previous abdominal surgeries. without any severity signs, the medical treatment is first proposed to avoid superfluous surgery. we noticed that the failure of medical treatment is frequently seen in patients previously operated of appendicectomy. the purpose of this study is to determine the eventual relation between a previous appendicectomy and failure of medical treatment in sbo. methods: we conducted a retrospective data collection using a diagnostic code for bowel obstruction in patients who have consulted in emergency from . . to . . at the salengro university hospital in lille. using the administrative database, patients were identified. we excluded all children, patients with wrong diagnosis and those whose outcome was not known. finally, patients with sbo on intra-abdominal adhesions confirmed on ct-scan were reviewed. the patients were separated in two groups. the group (g ) included patients who required surgical management during hospitalization ( patients) and group (g ) patients with successful medical treatment ( patients). we compared the rate of previous appendectomy in these two groups using a pearson's chi-squared test. in a second step, we tried to find out if there were others factor associated with failure of medical management. results: there was significant difference between the two groups with a higher rate of appendectomy in the surgical management group g (p = . ). this difference was even more pronounced if appendectomy was the only surgical history. in the subgroup analysis of patients with previous appendicectomy, the laparoscopic approach or laparotomy didn't influence the outcome of the management of the sbo. conclusion: this study shows the difference between the two groups of sbo, with more surgery sanction in the group of patients previously operated of appendicectomy. perhaps because this surgery involves the very distal part of the small bowel and decrease the efficiency of a proximal nasogastric aspiration. these results should not change the initial management of sbo by medical treatment in absence of severity signs. however, knowing this data, we have to consider that a history of appendicectomy is a risk factor of failure of medical treatment in this situation. introduction: diaphragmatic injuries are a rare consequence of closed thoraco-abdominal trauma that could be difficult to detect due to paucity of clinical signs and frequent erroneous interpretation of radiological images. the overall incidence of diaphragmatic injury is , - , % in blunt trauma. if the injury is not recognized it could lead to considerable risk of late morbidity and mortality. this study reviews our years experience in the management of this patients. material and methods: a retrospective review of trauma registry of our tertiary referral centre was performed. preoperative, intraoperative and postoperative data were analysed to assess determinants of mortality, morbidity and effect of therapeutic delay by univariate analysis models. penetrating injuries were excluded from the study. results: over years patients with diaphragmatic injury due to blunt trauma were identified: had a simple laceration of the diaphragm without hernia, had acute and chronic diaphragmatic hernia. the mean patient age was years (range -- years). overall mortality was %. the site of injury was the left diaphragm in cases, the right diaphragm in cases and bilateral in case.the hernia content was stomach ( ), colon ( ), spleen ( ), liver ( ), omentum ( ) and multiorgan ( ). all acute patients were managed with primary suture repair via laparotomy except for two patients that required additional thoracotomy; chronic patients were treated laparoscopically in cases ( , %), in which a synthetic or a biosynthetic mesh was used to reinforce the suture. higher morbidity and mortality was seen in multiple associated injuries, head injuries associated, right diaprhagm injury, age [ years and treatment delay [ h. conclusions: delayed treatment of diaphragmatic injuries could be dramatic: it is importnat not to misinterpreter the radiological findings and to reassess the patient mantaining a high level of suspicion of these injuries. trauma opposing vector forces resulting in distal avulsion of internal oblique muscle: a case report p. spada , p. fransvea , g. altieri , m. di grezia , v. cozza , g. pepe , a. la greca , g. sganga fondazione policlinico universitario agostino gemelli irccs, catholic university of rome, division of emergency surgery, roma, italy case history: abdominal muscle injuries after blunt trauma are rare but increasingly recognized. here we report a case of blunt trauma resulting in a complete disinsertion of the distal part of the internal oblique muscle. case report: y.o. male, was involved in a roll over motor vehicle accident. primary survey was carried out according to atlsÒ approach with good response. he had a seatbelt sign. according to the dynamic of the trauma he underwent a ct. diagnosis: a ce-mdct revealed complete disinsertion of the oblique muscles of the left abdomen from their iliac insertion, with herniation of adipose tissue and hematoma of the soft tissues without active blushing. no other traumatic injuries were identified. therapy progressions: a conservative treatment of the hematoma of the left abdominal wall was adopted. the patients was then ischarged from hospital after days. no late complications were observed. comments: the overall incidence in all traumatic admission is . - . %. a deep knowledge of vector force involved in trauma and their influence in the specific anatomical changes of the abdominal wall muscle can lead to suspicious of this rare injuries even if no other lesion are detected. in our opinion this trauma case is useful in reminding us to look for it because the radiologist or a no well experienced trauma surgeon may miss it fondazione policlinico universitario agostino gemelli irccs, catholic university of rome, division of emergency surgery, roma, italy introduction: the best and correct management of patients with open abdomen (oa) is nowadays still unclear. our algorithm consists of using an intra abdominal negative pressure wound therapy device plus an early medial mesh mediated fascia traction (''step by step'' procedure). the aim of this study was to asses outcomes of this algorithm technique based on patient conditions and open abdomen technique performed. materials and methods: we performed a retrospective analysis of patients treated with open abdomen technique from / / to the / / . variables taken into account were: initial diagnosis, open abdomen technique used, number of surgical interventions, abdominal wall closure technique, length of stay in the icu, inhospital morbidity and mortality rates. we collected also data on the post-operative development of incisional hernias and entero-atmospheric fistula. results: / of open abdomen were done after trauma. in the remaining cases open abdomen was done for non-traumatic disease. patients have been treated following our algorithm (with negative pressure wound therapy abthera device and step by step approach with medial mesh mediated fascia traction). in this group fascial retraction was significant lower and definitive direct abdominal wall closure rate was statistically higher. conclusion: an early fascia traction mediated with a mesh lead to an earlier fascia closure with a lower need of mesh positioning for definitive closure; the rate of post incisional hernia is similar among the two groups references: case history: a year old male presented in the er with malaise, fatigue and loss of appetite. he was recently hospitalised due to a peritonsillar abscess and during investigations he was first-diagnosed with non-hodgkin lymphoma. his medical and surgical history were otherwise unremarkable. clinical findings: on admission the patient was febrile and tachycardic (hr bpm) but remained hemodynamically stable (bp: / mmhg). clinical examination revealed abdominal distention and rebound tenderness in the right abdomen. investigation/results: blood tests were significant for leukocytosis (wbc: . /ll-neut: %), acute kidney injury (urea: mg/dl, cr: . mg/dl), elevated crp ( mg/l) and ldh ( iu/l), hyponatremia (na: mmol/l) and hypoalbuminemia. chest and abdominal x-rays were non-diagnostic, while abdominal ultrasound showed increased air presence along the medial line. investigations concluded with an abdominal ct scan that revealed pneumoperitoneum, small bowel distention and multiple enlarged mesenteric lymph nodes. diagnosis: the patient was transferred to the or for an explorative laparotomy. he was diagnosed with ileo-cecal intussusception causing bowel ischemia and perforation at the ileocecal valve. enlarged lymph nodes were observed along the mesentery. therapy and progressions: the affected ileus and colon were removed and a subtotal colectomy with end ileostomy was performed. the pathology report confirmed infiltration of the dissected bowel and lymph nodes by lymphoma cells. the patient continued treatment in the icu. he was discharged on the th postoperative day. comments: intussusception is rare in adults and, contrary to children, is highly associated with malignancies. resection without reduction has been advocated-wherever possible-in order to ensure better oncological outcomes. introduction: emergency surgeries are oftenly related to contaminated/infected fields, where the implantation of non reabsorbable meshes for reconstruction of the abdominal wall may not be recomendable. we aim to evaluate the results of polyvinylidenfluoride (pvdf) meshes used for complicated ventral hernia in the acute setting material and methods: retrospective analysis of patients with vh undergoing emergency surgery on which a pvdf mesh was required, in a third level hospital (november -september ). we analyzed early and late postoperative complications and -year recurrence rates. association between grade of contamination, mesh placement and infectious complications and recurrences was investigated using binary and multiple regression. results: we collected patients with a mean age of '' years, mean bmi of '' kg/m and mean cedar index of '' . '' % of patients had a grade - ventral hernia according to rosen''s index. concomitant procedures included al least one organ resection in '' % of surgeries and previous contamined mesh explantation in '' %. a pvdf mesh was placed using an intraperitoneal onlay mesh (ipom) technique in '' % of cases and an interposition location in '' %. readmission rate was '' %, one-month recurrence '' % and recurrence after a year '' %. overall mortality rate was . %. risk of recurrence was related with patients with a rosen score over (p \ . ) and also with postoperative ssi (p = . ). higher recurrence rates were not found regarding the pdvf meshes placement. postoperative seroma and hematoma rates were '' % and '' %. enteroatmospheric fistula rate was '' %. conclusions: pvdf prosthesis seems to be an useful material for complicated ventral hernia repair, specially in the acute setting, showing similar recurrence and infectious complication (fistula, chronic mesh infection, surgical site infection) rates with regard to different prosthesis used in the literature. operative vs non-operative management in liver trauma patients in a uk major trauma centre conclusions: the airs can predict the histologic severity and the intra operative findings in patients with a high clinical suspicion of aa. airs could be useful to reduce negative appendectomy and predict the postoperative stay to evaluate the deformity progression in spine injuries (dorsal, dorsolumbar, lumbar) managed by internal fixation. introduction: there continues to be controversy surrounding the management of thoracolumbar burst fractures. numerous methods of fixation have been described for this injury, but to our knowledge, spinal fusion has always been part of the stabilising procedure, whether this involves an anterior or a posterior approach. material and methods: patients with spinal injury (dorsal, dorsolumbar, lumbar) were included. all patients had dorsal, dorsolumbar, lumbar spine injuries managed with posterior short segment pedicle screw fixation and were followed up for at least one year after surgery. preoperative, post operative and follow up lateral radiographs were examined for cobb''s angle, anterior wedge compression angle and upper and lower adjacent intervertebral disc heights anteriorly, middle and posteriorly. results: at final follow up, the mean improvement in cobb''s angle post operatively was . °. the mean loss of correction of cobb''s angle was . °with sd of . °compared to post operative. the mean improvement in anterior wedge compression angle was . °post operatively. the mean loss of reduction in anterior wedge compression angle was . °with sd of . °. the increase in cobb''s angle was statically significant (r = . , p = . ) with the loss of reduction of anterior wedge compression angle at follow up and loss in intervetebral disc height at upper intervetebral disc anteriorly only(r = . , p = . ). the mean period at which sitting and standing was initiated was . months and . months respectively and mean periods for which brace was used was . months. conclusions: pedicle screw fixation is good but related to loss in reduction of anterior wedge compression angle and decrease in upper intervertebral disc height anteriorly. references: p. l. sanderson:short segment fixation of thoracolumbar burst fractures without fusion. introduction: with the newly implemented ao upper cervical spine classification system a modern, pragmatic system has been established. to what extent the simplification is helpful or whether an adjustment of the new ao classification may be discussed, forms the question of this work. material and methods: retrospective analysis of upper cervical spine injuries with ct/mri diagnostics presented to trauma surgeons with several years' experience to do classification and suggest treatment. results: the classification according to the known systems showed a relatively good agreement in the exact classification and therapy. the classification according to the new ao upper cervical spine was simple and consistent but revealed different treatment recommendations for two subtypes (iii type a and iii type b). conclusions: the new ao upper cervical spine classification system leads to a simplification. uncertainties remain with the most frequent fractures on the upper cervical spine, the c fractures. these will be managed under iii type a. however, just these injuries require completely different treatment concepts. further adaptation is required for type iii b because there uncertainties regarding the therapy also remain. case history: a -year-old woman, on treatment with acenocoumarol due to atrial fibrillation, and interatrial communication, suffered a compression fracture of the vertebrae l to l after a lowenergy trauma. due to poor pain control, she underwent a percutaneous transpedicular kyphoplasty, with no intraoperative complications. clinical findings: during the immediate postoperative period, she developed dysarthria and claudication of barré in her right upper limb. investigation/results: an angio-ct scan was performed, showing endovascular material in the left middle cerebral artery (mca) and within the lungs, compatible with cement emboli. mri showed cortico-subcortical ischemic areas in mca territory. cement-embolism stroke after percutaneous kyphoplasty therapy and progressions: conservative treatment was chosen due to the high number of emboli and the favorable evolution of the patient, with resolution of the neurologic symptoms in h without sequelae. days later, she suffered a transient ischemic attack, with no changes in the ct-scan compared to the previous images, which also solved with no residual deficits. one month after this episode, the patient died due to a spontaneous cerebellar hemorrhage related to acenocoumarol overdose. comments: kyphoplasty is a safe technique performed to treat vertebral compression fractures in elderly patients, with good clinical results and a low complication rate. its main complications are related to the leakage of cement from the vertebral body, usually well tolerated. other complications are exceptional, such as cerebral strokes, cardiac perforation, or death. the present case, although infrequent, shows us the need to assess the risk-benefit balance when operating fragile patients, as life-threatening complications may happen in these procedures. references: . marden fa, putman cm. cement-embolic stroke associated with vertebroplasty. ajnr am j neuroradiol. nov; ( ): - . survival rate and application number of total hip arthroplasty in patients with femoral neck fracture: an analysis of clinical studies and national arthroplasty registers g. hauer , a. heri , s. klim , p. puchwein , a. leithner , p. sadoghi medical university of graz, department of orthopaedics and trauma, graz, austria introduction: total hip arthroplasty (tha) is an increasingly popular treatment option for fractured neck of femur (nof) [ , ] . the aim of this study was to systematically review all literature on primary tha after fractured nof to calculate an overall revision rate. furthermore, we wanted to compare primary tha implantations after fractured nof between different countries in terms of tha number per inhabitant. material and methods: all clinical studies on tha for femoral neck fractures between and were reviewed and evaluated with a special interest on revision rate. revision rate was calculated as ''revision per component years'' [ ] . tha registers were compared between different countries with respect to the number of primary implantations per inhabitant. results: twenty-two studies showed a mean revision rate of . % after ten years. we identified eight arthroplasty registers that revealed an annual average incidence of tha for fractured nof of . per , inhabitants (table ) . conclusions: we found similar annual numbers of thas for fractured nof per inhabitant across countries. revision rates in clinical studies are higher compared to registry data [ , , ] . the results of this analysis can be used to rank present and future national tha numbers within an international context. early clinical predictors of pneumonia in patients with acute spinal cord injury without bone injury: a retrospective study t. sakamoto , s. kanezaki , n. notani oita university, oita, japan introduction: pneumonia is still significant complication that associates with mortality and duration of hospitalization in patient with acute spinal cord injury without bone injury (sciwobi). the purpose of this retrospective study is to clarify early clinical predictors of pneumonia in patients with sciwobi. material and methods: we reviewed the medical records of patients with sciwobi who admitted between january and november . spearman's rank-correlation coefficient was used to test the relationship between each parameter. multiple logistic regression analysis was performed to determine the factors that influenced pneumonic morbidity. results: a total of patients with acute sciwobi, who were evaluated for neurological impairment within h after injury, were reviewed. pneumonia occurred in patients ( %), seven patients injured at c and four at c . according to spearman's rank method, asia motor score, beginning period of nutrition, ventilator use, neurological level of injury (nli) ] c , low prognostic nutritional index (pni) were correlated with onset of pneumonia. logistic regression found ventilator use to be most predictive of pneumonia (odds ratio [or] = . , % confidence interval [ci] . - ), followed by nli ] c (or . , % ci . - . ), beginning period of nutrition (or . , % ci . - . ), pni (or . , % ci . - . ). conclusions: in addition nli, low pni increases the risk of pneumonia. we consider that improving nutritional status, especially early initiation of enteral nutrition, decrease the incidence of pneumonia. bicycle-related cervical spine fractures e. helseth , j. ramm-pettersen , s. f. eng , i. naess , m. mejlaender-evjensvold , h. linnerud oslo university hospital, neurosurgery, oslo, norway introduction: the incidence of traumatic cervical spine fractures (cs-fx) in the norwegian population is / , /year, and % of these injuries are bicycle-related ( , ) . materials and methods: prospective cohort study of all bicyclerelated cs-fx in the south-east norwegian population ( . million) in the time period - . the data were retrieved from our quality control database for traumatic cs-fx in south-east norway. in the database all cs-fx patients (c (occipital condyle) to c /th ) are prospectively registered. results: during the four-year study period patients with bicyclerelated cs-fx were registered, ( %) were males, and mean age was years (range - ). the cs-fx was located in the upper cervical segment (c -c ) in ( %) patients, lower cervical segment (c -th ) in ( %), and at both segments in ( %). the most common fx subtype was c -fx. spinal cord injury secondary to cs-fx was registered in patients ( %). fracture stabilization was achieved with open surgery in ( %), external immobilization with a stiff collar alone in ( %,) and without treatment in ( %). conclusions: severe bicycle-related cervical spine injuries are not uncommon. the increasing political desire to move commuting from motorized vehicles to bicycles warrants a heightened focus on road safety. introduction: the need for cervical immobilization is predicted by the atls, the standard of care in trauma since , because cervical trauma is a important cause of disability. however, its discontinuation was linked to x-rays, a fact that has been changed thanks to the development of two algorithms that assess the severity of cervical trauma: the canadian c-spine rule (ccr) and the national emergency x-radigraphy utilization study (nexus). material and methods: this study aims to compare the reduction values in the number of ct scans required after the application of both algorithms in a level- trauma center and to verify the degree of adherence of residents in the use of each. cohort study with randomized application by residents of the algorithms in all patients suffering from blunt trauma with cervical collars who were admitted from august to october . the conducts had their frequencies analyzed to obtain an inference about the efficacy of each method in the abstention of x-rays and case resolution, in addition to verifying if the indicated conduct was followed by the resident, inferring on the confidence in the algorithm. results: cases were evaluated during this period, of which were by the ccr algorithm and by the nexus. the indication rate for ccr imaging was . % and nexus was . %, showing no statistical difference between them (p = , ; ci = %). in the evaluation of the effective conduct, which evaluated the reliability of the algorithm, there was no disagreement between them (p [ , ; ci = %). conclusions: neither method demonstrated superiority to the other in reducing the indication of imaging exams and its uses had equal adherence by resident physicians. panacek case history: a year old lady presented with severe neck pain following a fall and cervical hyper-extension injury. she had previously undergone anterior cervical discectomy and fusion at c / with placement of artificial interbody bone graft. postoperatively, the patient reported an excellent clinical outcome and later imaging confirmed interbody fusion. clinical findings: on examination, the patient was neurologically intact but reported severe mid-cervical neck pain with reduced range of movement. investigation/results: imaging included ct and mri of the whole spine diagnosis: imaging revealed an unstable hyper-extension injury of the cervical spine. a fracture extended through the caudal end of the fused graft-vertebral interface at c / with disruption of the posterior elements. therapy and progressions: given the severity of the injury surgery was recommended. the patient underwent uneventful c -t posterior instrumentation and fusion with excellent outcome (follow up two years). comments: this is the first report of a cervical spine fracture through the site of an anterior cervical discectomy and fusion. it is hypothesised that the fused cervical segment resulted in increased stress at the fused caudal graft-vertebral interface during hyper-extension, this combined with reduced tensile strength at the graft-vertebral interface resulted in this unusual transverse fracture pattern. the clinician should be aware that patients presenting with cervical spine trauma in the context of previous cervical spine surgery are prone to greater mechanical forces. there should be a high index of suspicion for serious injury prompting thorough assessment and investigation. pr s -screw-fixation: computer aided study prevent unguided missile r. krassnig , w. pichler , e. viertler , a. schwarz , r. wildburger , g. hohenberger auva rehabilitation clinic tobelbad, tobelbad, austria, boldin und pichler og, graz, austria, medical university graz, graz, austria, auva unfallkrankenhaus, graz, austria, medical university graz, orthopaedics and trauma, graz, austria introduction: transiliosacral screw fixation of unstable dorsal pelvic ring fractures is not much present neither in literature nor in practice. in cause of the complex anatomy and the varying narrow safe bony corridors its a demanding procedure. limited information is available on optimal placement and the geometry of safe zones for screw insertion in the pelvis. material and methods: d-reconstructions of consecutive ct scans of polytraumatic injured patients ( female, male) were the basis to insert two virtual cad bolts (representing screws) into the first two sacral segments as performing during screw fixation. results: in s the narrowest point was reached after a mean of . mm respectively . mm, depending on the selected way of measurement. for s the mean distance to the tricky constriction area amounted to . mm, respectively . mm. the average height in s measured . mm and the average width . mm. according, the average height for s was . mm and the average width . mm. the measurement results didn't show a significant difference between male and female pelvis bones for any distance of interest. conclusions: an optimal screw position is very important, because in the areas of bony narrowing are the exit points of the sacral nerves, which exit through the foramina anteriorly and posteriorly. damage to this nerve structures can cause severe long-term consequences such as numbness or paralysis. knowledge of predefined distances may aid in preoperative planning, decrease operative and radiation times and may prevent unguided missiles. clinical findings: there were absent breath sounds on the right side of the thorax, ultrasound showed an extensive pleural effusion. a chest tube was inserted and l of bloody-milky fluid was drained. investigation/results: ct scan showed fractured c -c and th -th vertebral bodies, fractured lateral osteophytes of th - and probable injury of the thoracic duct at th - level. pleural effusion analysis showed raised cholesterol and triglyceride levels. diagnosis: traumatic chylothorax; fractures th -th , th -th , c -c therapy and progressions: patient was kept on ventilatory support for days. primarily she was treated with total parenteral nutrition followed by no fat and hypolipidemic diet. the chest tube was removed after days. she was discharged in stable condition the following day. at the month check-up she was stable and eupnoic. comments: traumatic chylothorax caused by blunt chest trauma is extremely rare. there are hypotheses that injuries to the thoracic duct are caused by hyperextension of the spine or by increased thoracic/ abdominal pressure (seat-belt injuries). in our case, chylothorax probably resulted from fractured lateral osteophytes. patients are usually successfully treated with pleural drainage and total parenteral nutrition. if there is no improvement after weeks or if drainage exceeds . l/day or l/day for more than days, thoracic duct ligation should be considered. conservative treatment resulting in t-l or lumbar kyphosis can worsen the quality of life of the patient whereas traditional open surgery may be an overtreatment in some cases, considering blood loss, possible complications, hospital stay and delayed functional recovery. in this setting, a good option can be a percutaneous minimally invasive surgery. the advantages of percutaneous pedicle screw fixation are: preservation of posterior musculature, less blood loss, shorter operative time, lower infection risk, less postoperative pain, shorter hospital stay and easier implant removal after bone union. limitations such as inability to achieve direct spinal canal decompression can be dealed by combination with open techniques. the objective of this study was to report the results of ppsf on these fractures and the technical problems we had to overcome. methods: patients are included, treated with percutaneous transpedicular fixation and stabilization with minimally invasive technique from december to october . patients were males, females; average age was , years (range from to ). in all cases, system pathfinder-nxt (zimmer) was used. results: most of the patients presented an early post-operative mobilization with amelioration concerning pain and a low complication rate. limitations in mobilization were mainly due to coexistent injuries, polytrauma or non-reversible neurological deficit. conclusion: ppsf is a reliable and safe procedure which does not replace the open technique but adds to treatment options by restoring a good sagittal alignment similar to those reported for open surgery. removal of hard material is advocated after fracture healing to preserve the lumbar spinal mobility and avoid zygapophyseal joint osteoarthritis. critical surgery within the first hour of presentation: is it a feasible intervention for better trauma care outcomes in low and middle income countries? introduction: in low and middle-income countries (lmic) golden hour care concept is almost nonexistence due to resource constraints. in this study, we analyzed one novel concept of critical surgery within the first hour of admission as a possible intervention which could be applied in the existing scenario in these countries without much resource requirement. material and methods: a retrospective analysis of a prospectively maintained data registry under a project named titco (towards improved trauma care outcome) was done. registry data from a level - trauma centre in india were analyzed from october to september . all patients who admitted and underwent critical surgical interventions within the first hour of presentation were analyzed. these patients were divided into two groups depending upon primary presentation or referred from another facility. statistical analysis was done between these two groups to compare the outcome. results: sixty-one ( . %) patients were directly admitted from the site of the incident whereas forty-five ( . %) were transferred from other hospitals for surgical needs. the median time from injury to presentation for primary patients was min with interquartile range (iqr) of . in the referred patient median time gap between the injury to our center (not referring center) was min with iqr of . this difference was statistically significant. major outcome indicators in the form of median icu and total stay, as well as mortality, were not significantly different conclusions: proposed concept might be a useful hospital-based intervention in existing trauma system in lmic to improve the outcome of injured patients along with improving prehospital services. oslo university hospital, ullevål, orthopedic department, oslo, norway, extrastiftelsen, oslo, norway introduction: it is well-known that physical activity is good for us. although the skeletal muscle is the main organ which is directly affected, exercise affects the whole body. the mechanisms responsible for these beneficial effects are gradually becoming known to us through extensive research. this might make it easier for physicians to prescribe exercise as a therapy equally and even more beneficial than drugs regarding effect and risk profile. the aim of this thesis was to review the current literature on the molecular mechanisms of exercise-induced health benefits. material and methods: a search in medline and embase resulted in articles. they were sorted by title and abstract, then by reading the full text. relevant articles from the reference-lists were included. sources were found outside of the search. results: when we exercise, the skeletal muscle is subjected to several mechanical and chemical stimuli, which in turn activate a set of kinases and phosphatases. these are molecules that regulate transcription-factors and co-activators, and this leads to adaption of the muscle-cells. i addition, the muscle secretes a number of proteins called myokines, which conduct the effect of exercise to other organs and tissues. some lead to increased cerebral neuroplasticity, hypertrophy and angiogenesis (bdnf, vegf and igf- ). several interleukins have also been identified as myokines, and they mediate an anti-inflammatory effect which is favorable in the prevention and management of conditions like atherosclerosis and type diabetes. lastly, we found that exercise leads to epigenetic changes, altering the genetic expression in several types of tissues. some studies suggest that the epigenome is affected by exercise even before we are born, giving babies born to physically active mothers a favorable epigenetic expression. conclusions: we should use this knowledge to support the implementation of physical activity in treatment and preventive health care. impact on undertriage and mortality after changing from a twotiered to one-tiered trauma team activation protocol costs. prognostic factors may assist in identifying high cost groups with potentially modifiable factors for targeted preventive interventions, hence reducing costs and increase rtw rates. evaluation of long-term follow-up and consequences of gunshot and stab wounds in a french civilian population introduction: the data concerning long-temr follow-up of patients and consequences of gunshot wound (gsw) and stab wound (sw) are almost inexistent in the literature. in finland, a study showed that % of patients with trunk wounds died secondarily from alcohol-related or violent problems [ ] , highlighting the secondary importance of long-term care for these patients. the main objective of our study was to analyze the hospital and posthospital follow-up of patients with gsw or sw and to evaluate late complications and the consequences of these traumas. material and methods: from january to january , patients were hospitalized for gsw or sw management in laveran military hospital. hospital data were collected via informatic patient file and post-hospital data via a telephone questionnaire with the general physician (gp). results: median hospital follow-up was days . seventy-six patients had a follow-up visit with their gp ( %). median follow-up was mois . twenty-four patients were totally lost to follow-up ( . %). global follow-up identified patients with longterm consequences ( . %), psychiatrics and organics. seventeen cases of recurrence were found ( . %). high iss, age, gsw and gp identified in patient medical file were significantly linked to long-term consequences occurrence. conclusion: this study showed a high number of long-term consequences occurrence among patients with gsw or sw. however, the extra-hospital follow-up seems insufficient. it is therefore imperative to strengthen the compliance and adherence to the care network of these patients. awareness and involvement of medical, paramedical teams and gp role seems essential to screening and management of these consequences. introduction: focused assessment with sonography for trauma(-fast) is an effective tool for assessments of severely injured patients, especially in the settings of helicopter emergency medical service(hems) because of limited devices and time. the objective of this study is to investigate accuracy of trauma ultrasound in helicopter emergency service compared with enhanced ct scan. material and methods: we investigated the trauma patients in years which was demonstrated fast and delivered to the advanced critical care center in gifu university by hems. accuracy of the fast was determined by comparison to the presence of injury, primarily determined by computed tomography, and to required interventions. results: patients were included in this criteria. there were and patients in which we found fluids in thoracic or abdominal cavity by enhanced ct scans and ultrasounds in hems, respectively. sensitivity and specificity, positive predictive value, negative predictive value, accuracy were . , . , . , . , . . if we limited the data for abdominal fluids, each data were . , . , . , . , . . in the patients of negative fast with positive ct, no patient died due to hemorrhage in thoracic or abdominal cavity. conclusions: it has been reported that sensitivity of fast in hems was lower compared with in er. in the settings of prehospital trauma care, advantages of portable ultrasound could be limited because of peculiar environments. and also, the thoracic or abdominal fluids could increase with time by organ injuries and it causes fast negative in acute phases.in this series, we could not find cases which has possibility of death because of negative fast and might influence the treatment. repeated fast or careful assessment of patients based on the other findings could be beneficial. references: the sensitivity of fast in hems was low and demonstrating fast for several times could be effective to detect the thoracic or abdominal hemorrhage. pre-hospital trauma care in switzerland and germany: do they speak the same language? los angeles county ? usc medical center, department of surgery, divison of acute care surgery and surgical critical care, los angeles, united states introduction: field amputation can be life-saving for entrapped patients requiring surgical extrication. under these austere conditions, the procedure must be performed as rapidly as possible with limited equipment, often in a confined space, while minimizing provider risk. the aim of this study was to determine the optimal saw for a field amputation. material and methods: this was a prospective cadaver-based study. four saws (gigli, hand pruning, electric oscillating and reciprocating) were tested in human cadavers. each saw was used to transect four separate long bones (humerus, ulna/radius, femur and tibia/fibula). the time required for each saw to cut through the bone, the number of attempts, slippage, quality of proximal bone cut and extent of body fluid splatter as well as the physical space required by each device during the amputation were recorded. univariate analysis (fisher's exact and kruskal-wallis or mann-whitney u-test) was used to compare the outcomes between the different saws. results: the fastest saw was the reciprocating followed by oscillating ( . [ . - . ] sec vs . [ . - . ] sec, p = . ). the number of attempts required to amputate ( . [ . - . ] , p = . ) and the amount of slippage ( . [ . - . ], p = . ) were highest with the pruning saw. the reciprocating saw had the worst proximal bone cut quality ( % poor, p = . ) and the largest blood splatter ( . [ - ] , p = . ). the physical space required to perform an amputation ranged from cm with the oscillating to cm with the reciprocating saw. overall, the oscillating saw outperformed the others in number of attempts, slippage and quality of bone cut and physical space requirements, and was the second fastest ( table ) . conclusions: the speed, precision, safety, space required, as well as the highly adjustable blade in the oscillating saw make it ideal for a field amputation. a gigli saw is an excellent backup for when electrical tools cannot be used or fail. impact of air medical transport on the survival of major trauma patients in thailand e. surakarn , w. siriwanitchaphan bangkok hospital headquarters, bangkok trauma center, bangkok, thailand introduction: air medical transport is an alternative mode of interfacility transfer for injured patients who required a higher level of trauma care in thailand. this study assessed the impact of air medical transport on the survival of major trauma patients transferred from local hospitals to a tertiary care hospital. material and methods: trauma registry of - was reviewed. major trauma patients transferred by air ambulance were identified. injury severity score (iss), predicted mortality and actual survival to hospital discharge were studied and compared between two subgroups, the seriously injured patients (iss - ) and the severely injured patients (iss [ ) . the predicted mortality was calculated from the probability of survival (ps) of trauma and injury severity score (triss). results: there were major trauma patients (iss [ ) transferred by air ambulance in five years period. patients were severely injured (median iss = ), and patients were seriously injured (median iss = ). the range of flight time was - min. the overall survival rate was . %. the predicted mortality in the severely injured group was cases ( . %), but the actual mortality was nine ( . %), . % lower than predicted mortality. the predicted mortality in the seriously injured group was one case ( . %), while the actual number was two ( . %). the eleven deaths in this study were eight cases of severe traumatic brain injury(tbi) patients, two cases of massive bleeding with subsequent multi-organ failure and one drowning. conclusions: air medical transport significantly improved the survival of severely injured patients who need higher level of trauma care. severe tbi and the presence of multi-organ failure associated with unfavorable outcomes. however, a detailed analysis of the trends and epidemiology of rtis affecting the most vulnerable children in qatar, under years of age, has not been conducted. this study's primary objective of is to describe the epidemiology of rtis and deaths in young pediatric patients in qatar. material and methods: data, for all young pediatric [under years] victims of rti''s and rti deaths from january , , through december , , from the trauma registry of the hamad trauma center [htc], the national level trauma referral center of qatar, was analyzed. this data was correlated and compared with data from the hamad general hospital mortuary and vital statistics data from the qatar ministry of development planning and statistics, the vital statistics annual bulletin, for the years - . results: the htc attended to patients, under years, with severe rtis and in-hospital rti deaths were reported during the study period. males made up . % of the injured and % of fatalities.the average age of the injured was years and for fatalities was it was . years. the rti incidence rate per , for both sexes, under years, has been unchanged ( in and in ) . the road mortality rate, per , , has decreased significantly, from . in to . in . since , the proportion of pre-hospital deaths has been increasing, - %, and the in-hospital death rates has been reduced to %. conclusions: rapid improvements in pre and in-hospital post-crash care in qatar have resulted in marked reductions in in-hospital deaths for young children with rtis. the emergence of pre-hospital road deaths of under ''s must be made a priority for road safety in qatar. the implementation of proven prevention programsshould be fast tracked in order to directly address this issue. introduction: despite improving survival of patients in prehospital traumatic cardiac arrest (tca), initiation and/or discontinuation of resuscitation of tca patients remains a subject of debate among prehospital emergency medical service providers. the aim of this study was to identify factors that influence decision making by prehospital emergency medical service providers during resuscitation of patients with tca. methods: twenty-five semi-structured interviews were conducted with experienced ambulance nurses, hems nurses and hems physicians individually, followed by a focus group discussion. participants had to be currently active in prehospital medicine in the netherlands. interviews were encoded for analysis using atlas.ti. using qualitative analysis, different themes around decision making in tca were identified. results: the causes of bleeding were grouped into several categories.the most frequent cause with cases in a row is attributed to diverticular bleeding,other causes of bleeding were angiodysplasia,post polypectomy bleeding,gist tumor,rectal ulcers and inflammatory disease.no case presented mortal or serious complications,secondary to the procedure. only cases presented a mild complication: focal mucosal ischemia of the embolized intestinal segment that was resolved with conservative treatment.lesions in charge of bleeding in those cases in which the angiographic treatment failed,were:ulcer in cases,a case of bleeding after endoscopic polypectomy, a case of diverticular bleeding and bleeding secondary to a coagulation disorder.among these patients, the definitive treatment was the following: -a second angiographic treatment was effective in the case of bleeding due to coagulation disorder. -a case of self-limited bleeding. -surgical treatment was the definitive treatment in both cases of bleeding in the context of and patient with bleeding after polypectomy. we have not observed a significant relationship neither the type of lesion or its location with the probability of failure of the angiographic treatment. nor do we observe a significant relationship between the type of material used for embolization and the risk of treatment failure. comments: our data show that angioembolization is an effective and safe technique to treatment lgi bleeding. references: clin endosc . endoscopic therapy for acute diverticular bleeding introduction: the use of resuscitative endovascular balloon occlusion of the aorta (reboa) as adjunct for temporary hemorrhage control in patients with major torso hemorrhage is increasing. specifications and characteristics of available aortic occlusion balloons (aob) are diverse. in order to minimize the risk of failure and complications it is important to choose a device that fits the requirements per medical situation. the aim of this study is to provide guidance in the choice of an aob in a specific situation. material and methods: aob were assessed for characteristics and different properties of each are outlined. the bending stiffness was measured with a three-point bending device. results: although all aob tested are small caliber devices ranging from (er-reboa tm ) to french (codaÒ ), some need large bore access sheaths up to french (fogarty Ò and lemaitre tm ) or even insertion via surgical cut-down (equalizer tm ). the bending stiffness of the aob varied from . n/mm (± . sd) with the codaÒ to . n/mm (± . sd) with the russian prototype. guidewire-free devices are generally stiffer than over-thewire catheters. the tokai rescue balloon tm showed kinking of the shaft at low bending pressures. the er-reboa tm , fogarty Ò , lemaitre tm , reboa balloon Ò , and rescue balloon tm are the only catheters with external length marks to assist blind positioning. the only aob using a non-compliant balloon is the reboa balloon Ò . conclusions: specifications of available aob are diverse. in resource-limited settings, reboa should be performed with a rather stiff device that can be placed without wire and fluoroscopy, such as the er-reboa tm , fogarty Ò , and lemaitre tm . of these aob, the er-reboa tm is the only catheter compatible with a small french sheath. use of non-compliant balloons without real-time fluoroscopy is not advised given the potential risk of aortic rupture. when fluoroscopy is available, a guidewire can be considered. case history: year old male patient presenting with an initially uncomplicated pertrochanteric fracture, treated by an intramedullary nailing system (figs. and ) . days after the operation and mobilization without any adverse events the patient was readmitted. clinical findings: massive swelling, hematoma and pain. investigation/results: sudden fall of hb values down to , g/dl, ct scans showed the lesser trochanter located directly to the deeper femoral artery after mobilization (fig. ) . diagnosis: perforation of the deep femoral artery and several veins by the dislocated lesser trochanter therapy and progressions: blood transfusion, intraoperative cardiopulmonary resuscitation, several revision surgeries to stop the bleeding by oversewing the deep femoral artery and ligation of the veins, removal of the lesser trochanter fragment (fig. ) . admission to intensive care unit. subsequent plastic coverage. comments: according to literature, bleeding complications and injuries of the deep femoral artery can occur even several days after an initially uncomplicated pertrochanteric hip fracture. besides acute life-threatening bleeding, false aneurysm can occur ( ) ( ) ( ) . even if those late complications are very rare, the consequence for the patient can be devastating. these rare cases show the clear obligation to a thorough follow up treatment and regularly dressing changes. investigation/results: arterial colour doppler of the popliteal artery showed hypoechoeic contents and narrowed lumen. biphasic flow was seen in both popliteal and posterior tibial arteries. diagnosis: popliteal artery injury with delayed repair therapy and progressions: two incision and four compartment fasciotomy was done under regional block the next day which revealed a non contractile posterior compartment. superficial and deep muscles of the posterior compartment had doubtful viability. left distal sfa to infragenicular popliteal artery bypass graft was placed on day post injury. blood flow was established upto the ankle and foot, confirmed on check angio. however, foot drop of the patient persisted. after appearance of a healthy granulation tissue at the wound site ( days), a split thickness skin graft was placed to give coverage with % uptake of the graft. comments: blunt popliteal artery injury has been reported to result in amputation rates of nearly - %.the importance of a detailed vascular examination of a blunt trauma patient is emphasized as a limb can be salvaged if timely intervention is done. in this case even with an unfavourable mess score. case history: a healthy -year-old male, with no history of interest, suffers a high-energy trauma as a water bottle rushes over his left knee. clinical findings: go to the emergency room with pain and functional impotence in the left knee, with its anatomical deformity. knee x-ray pa and l are performed and the distal pulses that are present are taken. ankle-brachial index [ . . closed reduction is performed in emergencies under sedation and control x-ray is requested, aiming at correct reduction. it was decided to keep under observation for - h before discharge from hospital to schedule regulated ligament reconstruction surgery after studying with mri. therapy and progressions: at h of evolution after the accident and after having reduced the dislocation, the patient who has the leg with a temperature equal to the contralateral is reassessed, however, there is no palpable dorsal pedis pulse or posterior tibial palpation in the affected leg. it is decided to urgently request an angiotc and it is objective thrombosis of popliteal artery. vascular surgeon is contacted and emergency surgery is decided. a by-pass is performed with vena safena. diagnosis: traumatic knee dislocation and popliteal artery injury comments: in the st century, complementary tests in diagnosis are becoming increasingly important. however, in this case we want to management of aseptic tibial nonunion anastasios g. c. reamed interlocking intramedullary nailing for the treatment of tibial diaphyseal fractures and aseptic nonunions. can we expect an optimum result? results of a systematic approach to exchange nailing for the treatment of aseptic tibial nonunion management of tibial non-union using reamed interlocking intramedullary nailing the radiographic union scale in tibial (rust) fractures: reliability of the outcome measure at an independent centre pelvic trauma: wses classification and guidelines damage control orthopaedics in unstable pelvic ring injuries references: beuran, m. trauma scores: a review of the literature glasgow coma scale, age, and arterial pressure (mgap): a new simple prehospital triage score to predict mortality in trauma patients. critical care medicine. champion hr. a revision of the trauma score proximal femoral nail antirotation versus gamma nail for intramedullary nailing of unstable trochanteric fractures. a randomised comparative study results of the femur fractures treated with the new selfdynamisable internal fixator (sif) dhs helical blade for elderly patients with osteoporotic femoral intertrochanteric fractures the hypermetabolic response to burn injury and interventions to modify this response racial differences in propranolol enantiomer kinetics following simultaneous i.v. and oral administration propranolol dosing practices in adult burn patients the hypermetabolic response to burn injury and modulation of this response: an overview. wound heal south africa management strategies and outcome of blunt traumatic abdominal wall defects: a single centre experience blunt traumatic abdominal wall hernias: a surgeon's dilemma blunt traumatic abdominal wall hernias: associated injuries and optimal timing and method of repair traumatic abdominal wall herniation: case series review and discussion trauma patients with open abdomen: do they differ from others? a single center experience h. fagertun , a. seternes department of circulation and medical imaging, trondheim, norway introduction: treatment with open abdomen is demanding for patients, staff and hospital. a multidisciplinary approach is mandatory. the aim of this study was to compare trauma patients with open abdomen (oa) and patients treated with oa for other reasons, regarding outcome and resources spent. material and methods: retrospective study of patients treated with oa in a tertiary hospital in norway. ten were trauma patients vacuum-assisted wound closure and mesh-mediated fascial traction for open abdomen therapy-a systematic review prospective study examining clinical outcomes associated with a negative pressure wound therapy system and barker's vacuum packing technique thoracic-abdominal trauma with diaphragm lesions n. vlad , i. streanga , a. morar , i st. spiridon'' hospital iasi. we have analyzed clinical data, trauma mechanism, pathology of the lesion, time trauma-diagnostic, associated lesions, treatment, and follow-up. results: there have been patients ( men, women), mean age . location of diaphragmatic tears has been on the left hemidiaphragm ( cases), on the right hemidiaphragm ( cases), or bilateral ( cases). the trauma mechanism has been blunt ( cases) or penetrant ( cases). all patients had associated visceral lesions and had been operated right diaphragmatic injury and lacerated liver during a penetrating abdominal trauma: case report and brief literaturereview traumatic diaphrag-matic ruptures: clinical presentation, diagnosis and surgicalapproach in adults traumatic rupture of the diaphragm: experiencewith patients % ( / ) were aast grade or . in the total group, median age was years, . % were male and . % were blunt injuries. median iss in the nom group was and in the om group. median iss for those with grade or injury was . . % ( / ) underwent nom, compared to . % ( / ) of those with aast grade or . for each mmhg increase in systolic blood pressure, patients with grade or injury were % less likely to have an operation (or . , p = . ) and for each beat increase in heart rate intra-operative grade i was revealed in patients ( , %), grade ii in ( , %), grade iii in ( , %) grade iv in ( , %) and grade v in ( , %). histologic finding of catarral appendicitis was found in ( , %) patients, ( %) had phlegmonous appendicitis and ( , %) had gangrenous appendicitis. the airs difference was statistically significant with histological findings quality of publications regarding the outcome of revision rate after arthroplasty swedish hip arthroplasty register annual report joon yung lee: risk factors for failure of nonoperative treatment for unilateral cervical facet fractures in , patients were included in the trauma registry. median iss was and patients had an iss [ . of these patients / ( %) were undertriaged with a mortality of / ( %). the total mortality in was , % ( / ). i , median age was years for the patients with no tta vs years for those patients who did receive a tta (p \ . ) prognostic factors for medical and productivity costs, and return to work after trauma: a prospective cohort study l results: a total of trauma patients ( % of total study population) responded to at least one follow-up questionnaire. mean medical costs per patient (€ , ) and mean productivity costs per patient (€ , ) varied widely. prognostic factors for high medical costs were higher age, female gender, spine injury, lower extremity injury, severe head injury, high injury severity, comorbidities, and pre-injury health status. productivity costs were highest in males, and in patients with spinal cord injury, high injury severity, longer length of stay at the hospital and patients admitted to the icu. prognostic factors for rtw were high educational level, male gender, low injury severity swiss and german (pre-)hospital systems, distribution and organisation of trauma centres differ from each other [ , ]. it is unclear if outcome in trauma patients differs as well. therefore, this study aims to determine differences in characteristics, therapy and outcome of trauma patients between both german-speaking countries. material and methods: the traumaregister dguÒ (tr-dgu) was between - and - were included if they required icu care or died. trauma pattern trauma care in germany trauma systems in europe practical assessment of different saw types for field amputation: a cadaver-based test study these themes were: factual information (e.g., electrocardiography rhythm)educational programs and future guidelines. references: rosemurgy as, prehospital traumatic cardiac arrest: the cost of futility blunt vertebral vascular injury in trauma patients: atlsÒ recommendations and review of current evidence treatment-relater outcomes fron blunt cerebrovascular injuries. importance of routine follow-up arteriography provided the catheters used for this study. no other support was provided diagnosis: the probe had perforated the ivc wall. therapy and progressions: open repair was performed through a xifopubic laparotomy and the cattel-braasch maneuver to expose the ivc (fig. ). a retroperitoneal hematoma was observed anteriorly to the infrarenal ivc, without active bleeding. the ivc was dissected out sufficiently to permit proximal and distal vascular control (fig. ), the probe was then removed and the laceration on the infrarenal ivc closed with a running suture. the postoperative course was uneventful. comments: to our knowledge this is the first reported case of symptomatic ivc laceration by an ice probe during ca. references: enriquez a. use of intracardiac echocardiography in interventional cardiology complications of catheter ablation for atrial fibrilla iatrogenic percutaneous vascular injuries: clinical, presentation, imaging, and management vascular complications during catheter ablation of cardiac arrhythmias: a comparison between vascular ultrasound guided access and conventional vascular access false aneurysm of the profunda artery resulting from intertrochanteric fracture. a case report profunda femoris arterial laceration secondary to intertrochanteric hip fracture fragments. a case report with major thoraco-abdominal vascular injuries (aorta, inferior vena cava and main branches). data on demographic, clinical status and imaging was recorded. descriptive and kaplan meir survival analysis was performed. results: patients were included. median age was years (iqr - ), ( . %) were male. aorta was the most frequently damaged vessel ( , %) the median iss was (iqr - )interventional procedure. overall mortality was %, with % of deaths during the first hour, . % in the first h and . % afterwards. median survival was days (ic - ). we compared survival curves in periods abdominal vascular trauma. trauma surg acute care open history: popliteal artery injuries are frequently seen with fractures, dislocations, or penetrating injuries. a thirty one year old pathologies. references: natsuhara, k.m. et al, what is the frequency of vascular injury after knee dislocation knee dislocation and vascular injury: -year experience at a uk major trauma centre and vascular hub can vascular injury be appropriately assessed with physical examination after knee dislocation? introduction: this retrospective cohort study investigated the prevalence of and risk factors for preoperative venous thromboembolism (vte) in patients with a hip fracture and a delay of [ h from injury to surgery. material and methods: this observational study included patients with a hip fracture surgically treated at university hospital. patients underwent indirect multidetector computed tomographic (mdct) venography for preoperative vte detection after admission. overall vte risk and median time from injury to ct scan were calculated. age, sex, fracture type, time from injury to ct scan, body mass index, preinjury mobility score, previous anticoagulation treatment, previous hospitalization for vte, varicose veins, and medical comorbidities were considered potential risk factors. results: the prevalence of preoperative vte was . % ( of patients). the mean time from injury to ct scan was . days. the delay from the time of injury to ct scan averaged . days for patients who developed preoperative vte, compared with . days for patients who had not developed vte. in the adjusted models, female sex, subtrochanteric fracture, pulmonary disease, cancer, previous hospitalization for vte, and varicose veins were risk factors for vte. the final multivariate logistic regression analysis introduction: vertebral compression fractures constitute a large percentage of traumatic injuries of spine. the initial management plays an important role in the final outcomes. the present study aims to study the profile of vertebral injuries in rural & semi urban population & to analyse the role of level two hospitals in initial management of vertebral injuries. material and methods: this study was a retrospective analysis of progressively collected data of patients presenting with vertebral injuries in a level two hospital catering to semi urban & rural population in india. the initial presentation along with the age & sex profile was noted. etiological factors leading to compression fractures were noted. any neurological deficit either at the time of admission or transfer to a tertiary care neurocentre was noted as per asia scale. initial management was carried out in accordance with the atls guidelines. results: a total of out patients admitted with complaints of back pain were diagnosed to have compression fractures of the spine. the mean age was . years. male: female ratio was approx : . the lumbo sacral spine region was the most comply affected region. two patients were incidentally detected to have vertebral fractures as a result of metastatic malignancy. a due note was made regarding patients who had deteriorated during the transfer in terms of neurological deficit & evidence of spinal shock. conclusions: road traffic accidents contribute a significant portion of vertebral trauma . smaller hospitals & general surgeons have an important role to play in terms of initial stabilisation of such patients particularly the ones presenting with neurogenic shock. a good initial management has sigificant bearing on outcomes. analysis of risk factors for tracheostomy in cervical spinal cord injury without bone injury n. notani , s. kanezaki , t. sakamoto , h. tsumura oita university, orthopaedic surgery, yuhu, oita, japan introduction: there are many cases that require tracheostomy in the acute phase of cervical spinal cord injury, and various risk factors have been reported so far. however, there has been no report on cervical spinal cord injury without bone injury. the aim of this study is to evaluate risk factors for tracheostomy in patients with cervical spinal cord injury without bone injury. material and methods: we conducted a retrospective observational study. patients who were treated for cervical spinal cord injury without bone injury in our hospital were divided into groups: tracheostomy (tc) group and no tracheostomy (no tc) group. we compared variables, including age, sex, asia impairment scale (ais), neurological level of injury (nli), injury severity score (iss), vital signs, blood gas analysis, tracheal intubation, chest complication, smoking history between two groups. results: there were patients in tc group, and patients in no tc group. on univariate analysis, there were significant differences in age, ais a, tracheal intubation, nli ] c . on multivariate analysis, nli ] c was an independent predictor of tracheostomy. conclusions: in this study, we demonstrated that nli ] tc could be useful to predict tracheostomy in patients with cervical spinal cord injury without bone injury. case history: many fractures of the articular processes of the cervical spine are associated with displacement and instability, approximately % of all traumatic cervical spine injuries involve isolated fracture of the articular processes non-displaced or minimally displaced. [ ] this case demonstrates a isolated facet fracture of the cervical spine with c radiculapathy treated with minimally invasive spine surgery techniques clinical findings: a -year-old male was admitted to the neurosurgery department due to severe neck pain (vas / ). the pain radiating to the right upper extermity along dermatome c . neck and trunk rotation worsened the pain. investigation/results: furthermore, physical examination revealed hyperaesthesia in the right index finger without muscle weakness. ailments suddenly appeared weeks earlier after getting up in the morning. imaging demonstrated isolated, unilateral fracture of the right superior articular process of c diagnosis: imaging demonstrated isolated, unilateral fracture of the right superior articular process of c therapy and progressions: the patient was treated by microsurgical c decompression and fusion of c - under navigation guidance. intraoperative ct scans were performed to evaluate sufficient bone removal.after the surgery, the neck and upper extremity pain subsided. the patient had returned to his usual job and sport activities. comments: this case illustrates the value of the navigation and intraoperative ct in the evaluation of bony decompression, anatomy and location of implants. navigation minimized iatrogenic injury resulting in reducing postoperative complications like chronic pain, kyphotic deformity and muscular atrophy.introduction: resuscitative endovascular balloon occlusion of aorta (reboa) is a technique initially developed in the military for trauma patients injured in combat . recently, there has been much debate on its role in civilian trauma cases in controlling non-compressible torso haemorrhage (ncth) . this review aims to provide an update on current literature on the outcomes and concerns of this procedure. material and methods: a systematic literature search according to prisma guidelines was performed over the period of january to august across embase, medline and cochrane databases. patient characteristics, mechanism and severity of injury, survival rates and post-reboa complications between survivors and non-survivors were compared. results: a total of studies were included in this review. % and % of the reboa cases were penetrative and blunt cases respectively. the survival rates ranged from to % across the studies. systolic blood pressure (sbp) was significantly elevated post-procedure, from . to . mmhg in the survivor group (p \ . ) and . to . mmhg in the non-survivor group (p = . ). the injury severity score (iss) was lower in the survivor group ( . vs . ; p \ . ) whereas their glasgow coma scale (gcs) was higher ( . vs . ; p = . ). the survivors also had a shorter duration of aortic occlusion ( . vs . min; p = . ). common complications noted following the procedure include renal injury, lower limb ischaemia and thrombosis. conclusions: pre-reboa sbp, iss, gcs and duration of aortic occlusion were found to be associated with survival. complications directly due to the procedure were difficult to ascertain. a prospective study in a multiple trauma centre is needed for further evaluation of the indications, feasibility and complications involved in reboa. references: introduction: traumatic vertebral artery injury (vai) is a wellknown complication of cervical spine injury and often causes posterior circulation stroke. we report preventive effect of acute phase endovascular intervention for traumatic vai. material and methods: all patients with cervical spine injury were surveyed with post-contrast computed tomography for vai. when vai was diagnosed, the affected vertebral artery (va) was occluded with endovascular intervention before spine reduction and fixation. brain ischemic lesion was evaluated before and after the treatment. results: forty-one patients with vai associated with cervical spine injury underwent endovascular intervention. the affected va was occluded with endovascular coils before cervical spine reduction and fixation in patients, and after treatment in one patient. va stenting was done for another two. six presented new brain infarctions after spine surgery. of these, two had endovascular intervention after spine reduction. out of patients who had endovascular embolization before spine reduction, four had newly developed infarctions after spine surgery, of which two were symptomatic. there were no complications related to the endovascular procedure. conclusions: in conclusion, endovascular embolization for traumatic vai before spine reduction and fixation was found to be effective to prevent symptomatic brain infarction. introduction: the use of drug coating balloons (dcb) in primary or secondary angioplasty for peripheral vascular disease is a new tendency. the use of paclitaxel decelerates the growth and hyperplasia of neo-intima tissue which can cause re-stenosis and total occlusion in the spot of pta is a very promising technique in long lasting results of balloon ptas. purpose: to demonstrate our experience and results of the technique of dcb pta with the use of drag coating balloons. material and method: in the period between march and september , patients with sfa lessions were treated with pta with dcb for acute limb ischemia. were males and females. mean age was , y.o (± . ). patients were examined pro operationally and immediate post operationally in abi difference and their post operational follow up included measurement of abi and u/s triplex scan on the st, rd, th and th month(where chronically available) after pta. results: the mean immediate post operative increase of abi was , (± , ). were chronically available the increase of abi remained to , in the months follow up, , in the months and , in the th month follow up while patency of the artery treated remained in all patients. of the patients suffered from acute complications during or short after the pta ( with peripheral embolization and with retroperitoneal hematoma) which were treated immediately and left no consequences. conclusions: the use of dcb for pta in acute ischemia is a quite new, promising technique for maintaining patency of treated arteries for long time post operative period. the medium time results from its use in our clinic seem to be satisfactory. jichi medical university hospital, tochigi, japancase history: a -year-old male hit his neck hard against the fence. thereafter, he experienced difficulty in breathing and severe neck pain. he was brought to the emergency center by ambulance. clinical findings: his vital signs on arrival were gcs: e v m , hr: , bp: / , rr: , spo : ( lo ). significant neck edema and tracheal deviation were noted. inspiratory stridor was not heard with no signs of retracted breathing or subcutaneous emphysema. investigation/results: an enhanced ct scan of the neck revealed tracheal deviation and compression with ruptures of the left thyroid lobe. a large hematoma and arterial extravasation from a branch of the inferior thyroid artery were noted. diagnosis: rupture of the left thyroid lobe and injury around the distal portion of the left inferior thyroid artery. therapy and progressions: after securing the airway by intubation, angiography of the neck was performed; extravasation from a branch of the left inferior thyroid artery was suspected. angioembolization was continued for hemostasis using gelatin sponge. neck edema improved in the intensive care unit. following extubation on the hospital day , the patient was discharged on the th day with no complication. comments: thyroid injury due to blunt neck trauma is rare and surgical intervention such as hemithyroidectomy is generally prescribed. the patient''s condition, in this case, improved by angioembolization without any invasive surgical procedures. catheter procedure may, thus, be effective for hemostasis on thyroid injury after the confirmation of airway placement. introduction: the indication for resuscitative endovascular balloon occlusion of the aorta (reboa) is hemodynamically unstable patients in life-threatening hemorrhage below diaphragm. it was unclear that the difference of indications for reboa affects mortality in trauma.material and methods: this study used data from the japan trauma data bank (jtdb) ( - ), a nationwide trauma registry, to describe the epidemiology of reboa. adult trauma patients used reboa were included. patients were excluded if they had cardiac arrest at the scene or dead on arrival, or had an unsurvivable injury of any region of the body as defined by the abbreviated injury scale. patients were classified by whether patients had indications for reboa. the indications for reboa were defined by indications for hemostasis to intraabdominal, retroperitoneal, pelvic or extremity hemorrhage. the indications were decided by the delphi method with the cooperation of experts in trauma for this study. the contraindications were defined by brain injury needed intervention and hemorrhage above diaphragm. the logistic regression was used to assess the mortality after adjustment for injury severity score. as a sensitivity analysis, a generalized linear mixed model with random effects of a facility was performed. results: of , patients registered in the jtdb, patients underwent reboa. had indications for reboa and underwent reboa without indications. the physiological variables were similar, but the consciousness was worse in the no-indications group. injury severity of brain and chest were higher in the no-indications group. the indications group had . % and the no-indications group had . % contraindications for reboa. the mortality was similar ( . % versus . %, or . , %ci . - . ). a sensitivity analysis showed the same result as the primary analysis (or . , %ci . - . ). introduction: most incident first responders have a primary nonmedical role, but are frequently the only professionals initially at the scene. early hemorrhage control via advanced techniques such as resuscitative endovascular balloon occlusion of the aorta (reboa) can save lives. training first responders these techniques has therefore the potential to improve outcomes. this study evaluates the ability to train quick response team fire fighters (qrt-ff) to gain percutaneous femoral artery access and place a reboa catheter, using a comprehensive theoretical and practical training program. material and methods: six qrt-ff participated in the training. sof medics from a previous training served as control group. a formalized training curriculum included basic anatomy and endovascular materials for percutaneous access and reboa catheter placement. key skills were: ( ) preparation of an endovascular toolkit, ( ) achieving vascular access in the model and ( ) placement and positioning of the reboa catheter. results: qrt-ff had significantly better baseline knowledge of surgical anatomy (p = . ) compared to medics. they also scored significantly better on using endovascular materials (p = . ), performing the procedure without unnecessary attempts (p = . ) and overall technical skills (p = . ). the median time from start to reboa inflation was : min for qrt-ff and : min for medics. procedure times improved in all qrt-ff and of the medics in a second attempt of gaining vascular access and reboa placement. conclusions: our comprehensive theoretical and practical training program proves suitable for percutaneous femoral access and reboa placement training of qrt-ff without prior ultrasound or endovascular experience. repetition reduces procedure times. training in the use of advanced hemorrhage control techniques such as reboa, as a secondary occupational task, has the potential to improve outcomes for severely bleeding casualties in out-of-hospital settings. prytime medical tm devices, inc. provided the reboa access task trainer (ratt) and the catheters used for this study. no other support was provided.the authors declare that there are no conflicts of interest that could inappropriately influence (bias) their work. introduction: angioembolization (ae) has become an important component in the management of bleeding from severe pelvic fractures. timely availablity of ae is required for both, level and trauma centers. the aim of this study was to assess the utilization of this procedure in level and trauma centers and effect on oucomes. material and methods: retrospective, -year ( - ) study using the the american college of surgeons tqip database, including adult patients with isolated severe pelvic facture (ais [ ] [ ] [ ] . patients who underwent laparotomy or preperitoneal packing within h from admission were excluded, operative management for bleeding control between and h was considered as failure. univariate analysis was used to compare patients in level vs centers, multivariate regression analysis was performed to determine factors predictive for mortality and overall complications.results: patients ( in level ; in level centers) met the criteria for inclusion. overall, ( . %) underwent ae, with a trend toward higher ae rate in level centers ( . % vs . %, p = . ). no significant differences were observed in timing and failure rate of ae between the levels. particulary in the ae subgroup there was a significantly lower blood product utilization in the first h in level i centers (prbc . vs . units, p = . ; plasma . vs . units, p = . ). mortality and overall complication rates were similar. table the level of trauma center was not a predictive factor for mortality (or . , p = . ) and overall complications (or . , p = . ). conclusions: in isolated severe pelvic fractures, there was a trend toward higher ae rate and significantly lower utilization of blood products in level centers. there were no significant differences in mortality or complications. the ae subgroup in level centers had a higher blood products use without outcome benefit, suggesting more restrictive transfusion policy may be considered. portal vein thrombosis after distal splenopancreatectomy: successful recanalization using fogarty balloon catheter case history: intraoperative lesion of smv during distal splenopancreatectomy is repaired using peritoneal patch harvested from anterior abdominal wall clinical findings: postoperative increase in serum lactate and d-dimer without signs of peritonitis prompts bedside doppler us showing no blood flood within portal vein (pv) investigation/results: ct angiography is performed suspecting acute mesenteric ischemia, but no abnormal bowel enhancement/ thickness is seen despite complete pv thrombosis. anticoagulation with unfractioned heparin is started, but clinical conditions deteriorate diagnosis: at reintervention, bowel is viable, so the surgeon performs fogarty balloon catheter thrombectomy successfully reestablishing blood flow within pv. no intestinal resection is required therapy and progressions: pv patency is regularly evaluated with us. anticoagulation with low molecular weight heparin is prosecuted for months and then suspended since no recurrence is recorded meanwhile comments: pv thrombosis is uncommon but can follow injury to portal venous axis during surgery. anticoagulation with heparin should be started as soon as the diagnosis is made and maintained for at least - months postoperatively to prevent recurrence. patients with persisting/worsening symptoms - h after initiation of anticoagulation, or those with peritonitis who are poor surgical candidates may be considered for interventional radiological treatment. otherwise, surgical intervention is required and may encompass resection of necrotic bowel. thrombectomy and/or balloon dilation/vascular stent placement may be helpful in recently developed pv thrombosis since risk of recurrence seems to be decreased references: acute mesenteric ischemia: guidelines of the world society of emergency surgery (world j emerg surg ); mesenteric venous thrombosis (j clin exp hepatol ); contemporary management of acute mesenteric ischemia in the endovascular era (vasc endovascular surg ) key: cord- -z wpjr d authors: stephens, r. scott; wiener, charles m.; rubinson, lewis title: bioterrorism and the intensive care unit date: - - journal: clinical critical care medicine doi: . /b - - - - . -x sha: doc_id: cord_uid: z wpjr d nan • no country is fully prepared to avert illness when large portions of the population are covertly exposed to a serious bioweapons agent; a moderate or large-scale intentional release of a serious pathogen will likely cause lifethreatening illness in a large portion of exposed people. • intensivists will play a key role in the medical response to a bioterrorism event due to the clinical conditions caused by serious bioweapons pathogens, such as severe sepsis, septic shock, hypoxemic respiratory failure, and ventilatory failure. • compared with conventional disasters, bioterrorist attacks may not be readily recognized; thus, accurate clinical diagnoses and management on the basis of clinical suspicion are critical not only for appropriate care of individual patients but also for instituting an epidemiological investigation. • victims of a bioterrorist attack who require intensive care unit-level care may be more contagious than those who are less sick. • health care workers, accustomed to putting the welfare of patients ahead of their own in emergency situations, must be prepared for the proper use of personal protective equipment and trained in specific plans for the response to an infective or bioterrorism event. tive prophylactic countermeasures exist, a large portion of exposed people will likely develop life-threatening illness. although intensivists working in developed countries generally have little experience treating specific illnesses caused by serious bioweapon pathogens, these diseases result in clinical conditions that commonly require treatment in intensive care units (icus) (e.g., severe sepsis and septic shock, hypoxemic respiratory failure, and ventilatory failure). therefore, intensivists will play a key role in the medical response to a bioterrorism event. usual critical care practices will likely require modification for any event resulting in more than a few critically ill victims, and critical care specialists should participate in planning for such situations. capabilities to provide medical care, especially critical care, services to large numbers of contagious patients are very limited in most countries. local hospitals will be expected to care for seriously ill victims of a bioterrorist (bt) attack, and the ability to care for large numbers of critically ill patients will likely be a major determinant of the medical impact of such events. although the current risk of a large-scale bt event is uncertain, a number of groups throughout the world during past decades have deliberately exposed civilians to biologic agents. fortunately, none of these prior events produced a large number of casualties because of the nonlethal nature of the pathogens released (e.g., salmonella typhimurium in oregon in ), the lack of technical expertise to successfully disseminate lethal pathogens (aum shinrikyo in japan in ), or relatively limited exposure (the anthrax cases of in the united states). these limited exposures should not result in predictions of the numbers of potential casualties being reduced; rather, they simply reveal that an increasing number of groups throughout the world are willing to use biologic agents. the scope and effect of prior events could have been much greater if a contagious agent were used or if a lethal pathogen were widely disseminated. despite the increased attention to biodefense, the risk of subsequent bt events may paradoxically be increasing. rapid advancements in science are making synthetic and novel biologic agents more accessible and technologies to disseminate agents may no longer be restricted to only a few nations. to reduce the medical effect of a bt event, the major determinants of morbidity and mortality must be understood ( fig. . ). the number of deaths from a bt event depends in part on the lethality and infectivity of the released agent, in addition to how effectively and widespread it is delivered. many biologic agents could theoretically be used as weapons, but some are an intentional release of a biologic agent within a civilian population, exposing hundreds or thousands of people to a serious pathogen, is increasingly recognized as a plausible terrorism event. unlike most mass casualty incidents, releases of bioweapons agents may be covert, thus providing additional security and public health challenges to the medical response beyond the generic burden of scores of casualties. an optimal medical response to a bioweapon attack will require all or most of the following: early diagnosis, rapid case finding, large-scale distribution of countermeasures for postexposure prophylaxis or early treatment, immediate isolation of contagious victims, and enhanced capacity for providing medical care to seriously and critically ill victims. no country is fully prepared to avert illness when thousands of people are covertly exposed to a serious bioweapons agent. hence, after a moderate or large-scale intentional release of a serious pathogen, even one for which effec-more lethal, more available, and more easily disseminated (table . ). the agent's characteristics alone will not, however, determine the overall impact of the bt event. population characteristics (i.e., vulnerabilities) will also affect the impact of a bt event ( fig. . ). many agencies, professions, and community members must be involved in preparing and responding to a bt event. to optimally respond, hospital and public health cooperation, planning, and preparedness need to occur before the disaster. the integration and coordination of all these responders is very important, and detailed operational descriptions are beyond the scope of this chapter (see box . ). instead, this chapter is intended to be an introduction to the medical response issues for a bt event, specifically the critical care medical response. the centers for disease control and prevention (cdc) has compiled a list of potential agents of bioterrorism and divided these into three categories, a-c (see table . ). category a agents are those believed to pose the greatest threat in terms of potential lethality, ability for widespread dissemination, ability for subsequent human-to-human transmission, and disruptive impact on the community and the public health system. these agents include variola major (smallpox), bacillus anthracis (anthrax), yersinia pestis (plague), clostridium botulinum (botulism), francisella tularensis (tularemia), and viral hemorrhagic fevers (vhfs). this section provides a brief summary of the pathogenesis and diagnosis of each category a agent and also reviews current recommendations for treatment. bacillus anthracis is acquired from contact with infected animals or animal products and causes three forms of disease: cutaneous, inhalational, and gastrointestinal. approximately cases of cutaneous anthrax occur annually worldwide. inhalational anthrax has not occurred naturally within the united states since ; any case must therefore be considered a possible sentinel case of a bioterrorist event. gastrointestinal anthrax is uncommon in developed countries and is not discussed here. cutaneous and inhalational anthrax are the forms expected following an aerosol release of spores, with the latter being the most lethal. a estimate by the u.s. congressional office of technology assessment predicted that an aerosolized release of kg of "weaponized" anthrax over a populated city would cause , to million deaths, similar to the mortality of a thermonuclear detonation. inhalational anthrax results from spore particles to mm in diameter entering the alveolar spaces and being transported by macrophages to mediastinal lymph nodes. after an incubation period that ranges from days to www.acponline.org/bioterro www.upmc-biosecurity.org www.shea-online.org www.cdc.gov weeks (median of days during the cases and up to days after the release of spores in sverdlovsk in ), germination occurs, with the vegetative bacilli producing two toxinslethal toxin and edema toxin. initial symptoms of inhalational anthrax are nonspecific: fevers, chills, drenching sweats, nonproductive cough, dyspnea, nausea, vomiting, and fatigue. hemorrhagic thoracic lymphadenitis and mediastinitis develop, and hemorrhagic pleural effusions with compressive atelactasis are common. hemorrhagic meningitis may also occur. patients may rapidly develop hemodynamic collapse, which typically has been refractory to treatment if it develops prior to antimicrobial administration. diagnosis is predicated on a high index of suspicion. in the attacks, all patients with inhalational anthrax had an abnormal chest radiograph or thoracic computed tomography scan. mediastinal widening due to lymphadenopathy and large bilateral pleural effusions were the most common features (figs. . and . ). these findings in the setting of a previously healthy patient with the abrupt development of sepsis should raise suspicion of anthrax infection. sputum gram stain and culture are rarely positive. blood cultures may yield a diagnosis but require hours to days to grow the organism. as in many infections, blood cultures lose diagnostic utility if obtained after antibiotic administration. hemorrhagic meningitis was common ( % of patients) during the sverdlovsk incident but was only confirmed in of patients in . patients suffering from inhalational anthrax are likely to require icu care but do not require respiratory isolation. antibiotics must be started as soon as possible without waiting for diagnostic confirmation. treatment recommendations are summarized in table . . for adults, combination antimicrobial therapy with intravenous ciprofloxacin and one or two other agents is recommended. given the potential for meningitis, agents with good central nervous system penetration, such as rifampin, penicillin, or chloramphenicol, are recommended. clindamycin has been administered for the theoretical benefit of reducing toxin production by the vegetative bacilli, although this has been done in too few instances to critically evaluate its effectiveness. a change to oral therapy is acceptable once the patient is stable. therapy should continue for days. the concomitant use of an anthrax vaccine in a modified dosing regimen (three doses within the first month) may be limited by availability. there is anecdotal evidence that drainage of pleural effusions carries some benefit. whether the benefit is simply reduction of pleural fluid volume to improve oxygenation or actually helps to reduce toxin burden remains uncertain. during the outbreak, pleural drainage was accomplished via serial thoracenteses and tube thoracostomy. optimal management may require tube thoracostomy due to the hemorrhagic nature of the fluid. historically, inhalational anthrax had a mortality rate of approximately %. in the attacks, modern critical care interventions and use of multiple antimicrobial agents reduced mortality to %. cutaneous anthrax results after the inoculation of skin with anthrax spores. these patients are unlikely to require icu-level care if they are treated promptly. two exceptions are the possibilities of airway compromise due to a neck lesion with resulting edema or postoperative management of a compartment syndrome. local edema is the first feature of the condition, with the subsequent appearance of a macule or papule that rapidly ulcerates and develops into a painless black eschar ( fig. . ). systemic disease, including lymphadenopathy and lymphangitis, can follow. in the absence of antibiotic therapy, mortality has been reported to be as high as %; death is rare if adequate treatment is instituted. between and the early s, y. pestis, the causative agent of plague, swept through europe, eventually killing to million people-one-third of the population. plague continues to occur naturally as an insect-borne illness, infecting approxi-bioterrorism and the intensive care unit mately people annually worldwide. in the united states, most cases occur in the rural states of the southwest. plague occurs in three forms: bubonic, septicemic, and pneumonic. naturally occurring bubonic plague occurs when infected fleas bite a human and typically results in enlarged lymph nodes (bubo) and severe sepsis. a smaller percentage of patients may develop sepsis without bubo formation, and this is termed primary septicemic plague. rarely, patients with bubonic or septicemic plague develop pneumonia, and this is termed secondary pneumonic plague. patients with pneumonic plague can transmit disease through respiratory droplets. those who contract pneumonic plague from person-to-person transmission are considered to have primary pneumonic plague and do not develop buboes. both primary and secondary pneumonic plague are transmissible from person to person. the intentional release of aerosolized plague would result in primary pneumonic plague, a condition that is rare in naturally occurring plague. world health organization (who) estimates from predict that kg of y. pestis released over an urban area with million inhabitants would cause pneumonic plague in , , with , fatalities. exposure is followed to days later by fever, dyspnea, and cough with bloody, watery, or purulent sputum. gastrointestinal symptoms also occur. cervical buboes are rare. pneumonia progresses rapidly with unilateral or bilateral infiltrates or consolidation. severe sepsis and septic shock develop with leukocytosis, multisystem organ failure, and disseminated intravascular coagulation. in the absence of therapy, irreversible shock and death occur to days after exposure. a bioterrorist attack with aerosolized plague would likely present as an outbreak of severe pneumonia and sepsis. diagnosis depends on standard microbiologic studies, with confirmatory tests available only at select laboratories. hence, unless epidemiologic clues alert health care workers that these patients do not have community-acquired pneumonia, the first group of patients will likely be cared for with the hospital's usual infection control policies for this condition. unless droplet precautions are commonly used and strictly adhered to, a number of health care workers and addi- tional patients may be exposed to plague early in the outbreak. therapeutic recommendations for pneumonic plague appear in table . . streptomycin and gentamicin are the first-line agents. doxycycline, ciprofloxacin, and chloramphenicol are alternative choices. in the event of a mass casualty situation, or for postexposure prophylaxis, doxycycline or ciprofloxacin are the preferred agents for adults. francisella tularensis is an extremely infectious pathogen; exposure to as few as organisms can cause tularemia. naturally occurring throughout north america, europe, and asia, tularemia is transmitted to humans via arthropod bites, contact with small mammals or contaminated food, and inhalation. tularemia can take many clinical forms (box . ). disease manifestations depend on virulence, dose, and site of infection. the disease can begin in the skin, starting as a papule and resulting in an ulcer, and also involve regional lymph nodes (ulceroglandular). if contaminated water is ingested or contaminated droplets are inhaled, pharyngeal ulcers with cervical lymphadenitis can occur (oropharyngeal). the eyes can be the initial portal of entry leading to chemosis and lymphadenitis (oculoglandular). sometimes, lymphadenitis may occur without ulceration (glandular). inhalational tularemia may also occur naturally due to aerosolization of contaminated materials. this clinical scenario is the most likely after an intentional release, since aerosol release would be the most likely method of dissemination. who estimated that kg of aerosolized f. tularensis in a city of million would affect , people and cause , deaths. after an incubation period of to days, abrupt fever develops, accompanied by influenza-like symptoms (headache, chills, rigors, myalgias, coryza, and pharyngitis). bronchiolitis, pleuropneumonitis, and hilar lymphadenitis would be expected, although inhalational tularemia can often present as a systemic disease without respiratory features. progressive weakness, fever, chills, malaise, and anorexia rapidly incapacitate victims. hematogenous spread can lead to pleuropneumonia, sepsis, and meningitis. sepsis due to tularemia may manifest as severe sepsis or septic shock. mortality without antibiotic therapy can be as high as % to % for pneumonic and septic tularemia. current antimicrobial therapy results in a mortality rate of less than %. rapid diagnostic testing for tularemia is not widely available. the constellation of atypical pneumonia, pleuritis, and hilar lymphadenopathy in association with the previously described symptoms should raise suspicion for tularemia. in the wake of a bioterrorist attack, until a number of patients present, initial diagnosis may be delayed. most diagnoses are made serologically with a fourfold rise between acute and convalescent antibody titers. antibodies are slow to develop: titers will usually be negative at week, positive at weeks, and peak in to weeks. laboratories need to be specifically notified if tularemia is suspected, both to improve diagnostic accuracy and to protect laboratory workers. polymerase chain reaction (pcr) and antigen detection are rapid and available at reference laboratories in the united states through the laboratory response network. if the reference lab is alerted when specimens are sent, an answer can be given within hours. treatment recommendations for tularemia are presented in table . . in the event of a contained casualty situation, streptomycin is the preferred drug, with gentamicin as a first-line alternate. doxycycline, chloramphenicol, and ciprofloxacin are acceptable alternates. for mass casualties and for postexposure prophylaxis, oral doxycycline and ciprofloxacin are the recommended agents. treatment with aminoglycosides or fluoroquinolones should last days; tetracyclines and chloramphenicol require a -day course. botulinum toxin, produced by the bacteria c. botulinum and a few other clostridium species, is the most potent known neurotoxin. botulinum toxin inactivates proteins necessary for the release of acetylcholine into the neuromuscular junction. the toxin could be disseminated as an aerosolized agent or as a food contaminant. fewer than naturally occurring cases of botulism occur annually in the united states. the use of botulinum toxin by terrorists would result in inhalational botulism or foodborne botulism, depending on the mode of dispersal. the neurologic signs are identical regardless of whether the toxin enters the body via the lungs or the digestive tract. intestinal botulism may be preceded by gastrointestinal complaints. symptoms appear approximately to hours after exposure. botulism presents as an acute, symmetric, descending flaccid paralysis. there is no associated fever, and the bulbar musculature is always affected first. presenting complaints and findings are related to cranial nerve palsies and include diplopia, dysarthria, dysphonia, and dysphagia. hypotonia and generalized weakness ensue. loss of airway protection may necessitate intubation, and respiratory muscle paralysis may require mechanical ventilation. the course is variable and may require months of mechanical ventilation. during small outbreaks with sufficient medical resources, serial measurement of vital capacity can help identify patients with respiratory muscle weakness. elevation of paco is a late finding, and positive pressure ventilation should be instituted prior to frank ventilatory failure. notably, cognitive function is not affected; patients are completely awake and alert. a fever should raise suspicion of secondary infection or an alternative diagnosis. the diagnosis of botulinum intoxication is clinical and is classically described as the triad of symmetric cranial neuropathies with descending paralysis, clear sensorium, and lack of fever. other diagnoses to consider are listed in box . . in developed nations, the occurrence of a number of temporally related cases of acute paralysis points to botulinum intoxication. the edrophonium or "tensilon" test may be transiently positive in botulism, although it still may be helpful in distinguishing it from myasthenia gravis. csf is generally normal in botulism. an electromyogram demonstrating an incremental glandular ulceroglandular oculoglandular oropharyngeal pneumonic septic response with repetitive stimulation at hz may suggest botulism when the conduction velocity and sensory nerves are normal. culture of stool or gastric contents (for foodborne exposure) may yield clostridium. confirmation usually requires the mouse bioassay (mice are exposed to samples and those given polyvalent and specific antitoxin survive) but takes several days. samples for the mouse bioassay must be collected prior to the patient's receiving antitoxin. a clinician who suspects botulism must immediately notify local public health authorities to aid with epidemiologic and diagnostic investigations. most laboratory testing cannot be performed at hospitals. laboratories must be notified of suspicion regarding botulism, since samples can be potentially harmful to laboratory personnel. specific therapy consists of treatment with equine antitoxin (see table . ), which will not reverse extant paralysis but may prevent progression. it must therefore be administered as early as possible. in mass casualty situations, when the antitoxin supply may be limited, patients with weakness but not yet requiring mechanical ventilation may be the most appropriate for antitoxin therapy. supportive therapy is essential, with a specific focus on mechanical ventilation and efforts to prevent complicating events (e.g., ventilator-associated pneumonia, venous thromboembolism, and decubitus ulcers). nonventilated patients should be placed in the reverse trendelenberg position at to degrees to optimize respiratory muscle function and minimize the possibility of aspiration aminoglycosides and clindamycin should be avoided because of the potential for exacerbating the neuromuscular blockade. mortality for foodborne botulism averages %. the last naturally occurring case of smallpox was identified in , and the last case (due to a laboratory accident) was in . despite worldwide eradication, smallpox continues to concern biodefense experts due to uncertainties about available stocks of the virus. despite the mortality rate of smallpox ( %) being considerably lower than those of other bioweapons agents, its potential for harm is still very high because those who survive may be severely deformed or blinded and no proven specific therapy exists once exposed people become symptomatic. in addition, with cessation of worldwide vaccination, entire populations and especially younger persons are susceptible to infection. the agent of smallpox, the variola virus, belongs to the orthopoxvirus family. these viruses are quite stable in the environment, and hence an aerosol may be widely dispersed. any case of smallpox would be an emergency and must be considered to be the result of a deliberate act. the typical incubation period for smallpox is to days, with an average of to days for the majority of patients. initial symptoms include fever, rigors, backache, and headache. vomiting and delirium may develop in this prodromal phase. two or days later, a nonspecific erythematous rash begins. the rash first appears in the mouth and throat, with red spots appearing on the buccal and pharyngeal surfaces. the usual dictum is that a person is not contagious until the rash begins. in most patients, the macular lesions become papular followed by vesicles. the lesions then become pustular, which umbilicate and are deeply seated in the dermis. the crops of lesions appear at the same time and are all at the same stage on the affected part of the body (fig. . ). they usually begin and are more concentrated on the face and limbs rather than the trunk. this is in contrast to primary varicella, in which lesions on any given part of the body are in different stages of development (some macular, some vesicular, and some crusting) and in which the rash begins on the trunk and moves outward. after to days, scabs form at the sites of the pustules. in survivors, these become depressed depigmented scars. smallpox lesions also occur on the palms and soles, which rarely occurs with chickenpox. the previous description is seen in more than % of smallpox cases, but there are less common forms of smallpox as well. hemorrhagic smallpox is uniformly fatal (it tends to affect pregnant women more frequently), and it typically has a shorter incubation period and does not lead to the classic rash. instead, death follows development of a hemorrhagic rash. in the malignant or flat form of smallpox, the disease begins classically but does not progress to pustules. instead, the rash is confluent and may desquamate. also, variola minor is a less severe form of smallpox. suspicion of smallpox must initially be based on clinical findings; the possibility of this disease must be considered in any patient displaying fever and a characteristic centrifugal and uniform rash. definitive diagnosis requires specialized diagnostic techniques. electron microscopy can determine whether the virus is an orthopox, and confirmatory pcr techniques require primers specific to variola. laboratory confirmation will likely be required for the sentinel cases of an outbreak. after initial cases are confirmed, additional case identification can be based on clinically consistent criteria. miller-fisher variant of guillan-barré syndrome myasthenia gravis tick paralysis atropine poisoning paralytic shellfish/puffer fish poisoning if an exposure to smallpox is suspected but the patient is asymptomatic, administration of the vaccinia virus within a few days from exposure can prevent or greatly diminish the severity of the illness. once the disease develops, however, specific therapeutic options are limited (see table . ). there is evidence that cidofovir may have activity against the variola virus, although the evidence is based on alternative orthopox disease models and in vitro assays. supportive care for critically ill patients may limit mortality, but since the last case occurred more than years ago, it is uncertain what effect modern critical care will have on outcomes. mortality is expected to be approximately %, with far greater rates of disfigurement or disability. secondary transmission is most likely to occur through close contact with symptomatic patients (e.g., droplet and contact transmission), although fomite and airborne transmission have been documented. patients with a cough may be more likely to transmit droplet nuclei (i.e., airborne transmission), and those with atypical disease courses (e.g., hemorrhagic and malignant) may be more difficult to identify, so unprotected exposure of health care workers may be more likely. the viral hemorrhagic fevers believed to be possible agents of bt are listed in box . . the filoviruses and arenaviruses are transmissible from person to person. although the limited information available suggests that transmission is primarily via infected body fluids, mucosal transmission has been documented in experimental animals and airborne or droplet transmission has been suggested in several outbreaks. clinical manifestations will vary with the particular virus. in general, the vhfs have an incubation period ranging from to days (commonly, - days). initial symptoms are nonspecific and may last up to week. fever, malaise, headache, myal-gias, arthralgias, nausea, and gastrointestinal complaints are prominent. a rash may be present. on exam, patients are typically febrile, relatively bradycardic, hypotensive, and tachypnic. as the disease progresses, hemorrhagic manifestations, such as petechiae, mucosal bleeding, hematuria, hematemesis, and melena, may appear. eventually, disseminated intravascular coagulation, multiorgan system failure, and shock may develop. mortality rates vary greatly, but in the case of ebola virus they may be as high as %. confirmatory diagnosis of vhfs must be made at specialized laboratories. the diagnosis must be suspected in any patient presenting with acute fever, severe illness, and hemorrhagic manifestations. any patient who presents with a vhf who does not have a travel, contact, or exposure history consistent with the known natural occurrence of these illnesses must be considered as the possible victim of a bt attack. unfortunately, vhfs have a high lethality and supportive therapy is the only treatment (see table . ). there is evidence that ribavirin may have some effect against arenaviridae and bunyaviridae. no therapies have been shown to be effective against the filoviruses or flaviviruses. additionally, there is no recommended agent or vaccine for postexposure prophylaxis to any of the vhfs. many of the operational functions for the response to bioterrorism events are similar to those for other disasters (intentional or natural), such as requiring coordination and communication among a number of government agencies, professions, citizens, and community stakeholders for the response. however, bioterrorism events pose specific challenges for the medical response that may be serious enough that if not addressed may shut down hospitals and leave many victims without adequate options for health care (table . ). recognizing that a conventional disaster has occurred is usually immediate, and these events are limited both geographically and temporally. casualties have traumatic injuries, and a large portion of the survivors are taken to the nearest health care facility. within hours to a few days, the number of expected casualties is usually known. immediate death rates may be high, especially with structural collapse, but typically only a small bioterrorism and the intensive care unit fraction of survivors are critically ill (injury severity score > ). enclosed space explosions may lead to higher proportions of survivors with critical injuries, but the absolute number of critically ill patients is usually less than . after the initial chaotic response period, medical staff and equipment are usually not in short supply. if local hospitals are overwhelmed, additional staff and resources can be transported to the disaster area, or patients can be evacuated to unaffected areas. the recovery plans for the affected health care facilities are usually initiated within the same day or a few days following a conventional disaster. unlike conventional disasters, a release of a bioweapons agent may go undetected. in such situations, exposed people would present for medical care after the incubation period has passed. since people travel extensively in developed countries, and most incubation periods are days to weeks, patients are likely to present to a number of hospitals rather than to the facility located closest to the release. having patients distributed to a number of hospitals may lead to delayed recognition that a bt event has occurred. in addition, most diseases resulting from serious bioweapons agents initially cause symptoms and signs that are commonly seen every day in hospital emergency departments and outpatient clinics. there may be no pathognomonic signs that a bioterrorist event occurred in the sentinel patients initially presenting with respiratory failure or hemodynamic collapse. no diagnostic tests are available to help clinicians rapidly diagnose most diseases, so a bt event may go unnoticed until scores of ill victims arrive at hospitals. the presentation of multiple previously healthy patients with unusual and severe symptoms should prompt suspicion. because of the specialized diagnostic techniques required for these organisms, and the biosafety precautions that are frequently beyond the capabilities of most hospital-based clinical laboratories, confirmatory diagnostic testing for the category a agents in the united states is handled at laboratories of the national laboratory response network, which includes local and state labs as well as federal facilities, such as the u.s. army medical research institute of infectious diseases and the cdc. there will necessarily be a delay in final diagnosis because samples for confirmatory testing must be sent to off-site laboratories. this increases the importance of accurate clinical diagnoses and proceeding with management on the basis of clinical suspicion. prompt diagnosis is critical not only for appropriate care of individual patients but also for instituting an epidemiological investigation. the community or nationwide response hinges on the results of this rapid investigation. once the source, agent, and location of a bt attack have been deduced, other clinicians can be notified, resources can be mobilized, and the at-risk population can receive postexposure prophylaxis. the difficulties of recognizing initial exposures to a bt attack have profound implications for hospital functionality, particularly if the pathogen is contagious. health care workers (hcws) and other patients without adequate infection control protections may be exposed to contagious patients. during an outbreak of severe acute respiratory syndrome (sars), unprotected exposure of hcws and hospitalized patients to patients with sars was thought to be the major risk to a hospital remaining open. most victims of serious bioweapons attacks (e.g., anthrax, plague, smallpox, botulism toxin, tularemia, and vhfs) will develop illness that is rapidly progressive (ultimately requiring mechanical ventilation, hemodynamic support, or other aggressive therapeutic interventions) if they do not receive early medical intervention or if no disease-specific medical countermeasures exist. these critically ill patients will also likely require extended critical care for survival. few hospitals can provide even usual critical care services for an additional critically ill bt victims, especially if the pathogen is contagious. in the aftermath of a bt event, it may be very difficult to ascertain the extent of the exposure. incubation periods have a range, so the first cases may simply represent the tails of the gaussian distribution, and many more patients may require care in the following days. some ill patients may go unrecognized as cases, and patients may arrive at hospitals in a larger geographical area than is typical after a conventional disaster. the initially affected area may be quickly overwhelmed because of shortages of critical care resources. the unaffected regions may choose to wait to offer help until the size of the event becomes better delineated so that they do not send staff and resources away until they are certain they were unaffected. furthermore, if the pathogen is contagious, resources in affected areas may be more rapidly overwhelmed and unaffected regions may be even less likely to provide help. bt attacks resulting in a disproportion of critically ill victims to available icu beds are plausible. if such an event occurred today, many critically ill patients would have to forgo potentially life-sustaining critical care interventions. hospitals can plan to give traditional standards of critical care to the few who are fortunate to arrive early during the event, or they can modify critical care so that more patients have access to some of the most important critical care interventions (e.g., mechanical ventilation). methods to decide who should get critical care (e.g., triage algorithms), what critical care interventions should be provided, who should provide critical care, and where critical care should be provided need to be addressed before a bt event. through such planning, hospitals may "gracefully degrade" services rather than ceasing to function when overwhelmed. all efforts must be made to provide disease-specific therapies to victims of bioterrorism. unfortunately, not all of the serious bioweapons agents have effective treatments, and for those with treatments there is concern about development of antimicrobialresistant strains. systems must be in place for testing new treatments during an outbreak so that effective treatments can be rapidly communicated to other clinicians and ineffective or harmful treatments can be rapidly withdrawn. methodological issues, ethical concerns, skeleton protocol development, and information technology systems capable of making data rapidly available for analysis should all be developed and made functional before a disaster. patients seriously ill due to a bioweapons agent, regardless of whether a specific therapy exists, will likely require extensive supportive care, including interventions traditionally provided in icus. for small-scale events with few critically ill patients, traditional icu care will likely be provided. for larger events, deci- sions regarding which supportive care practices to continue and which to forgo will depend on the number of patients relative to the available resources. supportive care that is deemed most important can be better maintained if advanced planning and preparedness are undertaken. icu physicians should alert their hospitals to the potential need for rapid acquisition of additional mechanical ventilators, noninvasive respiratory aids, oxygen, palliative medications, and specialized staff in the event of a bt attack. perhaps the most critical aspect of caring for victims of a biologic attack or an emerging infective disease in an icu is the prevention of secondary transmission. in the sars outbreak of , % of cases in canada resulted from in-hospital exposure. in taiwan, the percentage of hospital-acquired cases was %. these data include other patients in the hospital who contracted the disease as well as health care workers who suffered occupational exposures. category a biologic agents that are transmissible from person to person are listed in box . . effective infection control measures are paramount in preventing the spread of disease through the hospital and, by extension, into the community. infection control is particularly important in the icu, in which a "perfect storm" for the rapid spread of an infection exists. victims of a bioterrorist attack who require icu-level care may be more contagious than those who are less sick due to higher levels of viremia or bacteremia. invasive procedures with their attendant risks of splashing or aerosolization of blood, respiratory secretions, or other bodily fluids are more commonly performed on critically ill patients. staff members in an icu are often called on to rapidly complete a number of tasks in stressful conditions, a situation conducive to errors in infection-control practices. since critically ill patients require a high level of frequent care, cumulative exposure to staff may be higher than in other areas of the hospital. finally, other patients in the icu are immunocompromised by virtue of their own critical illnesses, notwithstanding the disproportionate number of icu patients who are immunosuppressed secondary to organ transplantation, oncologic conditions, or infection with the human immunodeficiency virus (hiv). one of the mainstays of management of a chemical incident is rapid and effective decontamination of victims. decontamination serves both to limit the total dose of chemical agent received by the victims and to protect health care workers from remnant chemicals on patient skin or clothing. patients will not present for medical care after release of a biologic agent until the incubation period passes. decontamination is not necessary for these patients, since they are not likely to be grossly conta-minated at the time of presentation. for an overt attack, if the patient is grossly contaminated and there is concern about secondary aerosolization, it becomes reasonable to decontaminate the patient. since t mycotoxin can be transdermally absorbed, decontamination of patients grossly contaminated with this agent is also warranted. if possible, symptomatic victims of a communicable bioterrorism agent should be placed in a private room to prevent exposure to other patients. in the case of smallpox or a viral hemorrhagic fever, rooms should be under negative pressure and equipped with high-efficiency particulate air (hepa) filtration. the exhaust air from these rooms should be expelled directly to the outside, and the ventilation system should not be shared with other areas of the hospital. documented cases of smallpox transmission have occurred through ventilation systems. although the number of airborne infection isolation (aii) rooms in most hospitals is few, there are engineering modifications to increase modified aii capacity during an outbreak. planning for these modifications before an event is critical. assuming a large outbreak of disease, patients should be grouped together not only with respect to location but also with respect to nursing staff, physicians, and equipment. if no diagnostic test exists, care must be taken to minimize exposure of uninfected patients with similar signs or symptoms who may be inadvertently housed in the same location. although friends and family undoubtedly bring much comfort and support to critically ill patients, in the face of an infectious disease they become both potential victims and potential vectors. visitors of victims of bioterrorism with contagious agents, or victims of an emerging infectious disease, must be kept to an absolute minimum. they must be instructed and supervised in the use of proper protective equipment and notified that they must seek treatment immediately if they develop symptoms. in extreme circumstances, it may be necessary to completely preclude friends and family from visiting patients. health care providers are accustomed to putting the welfare of the patient ahead of their own; patient care, particularly in emergency situations, is often carried out without adequate protective equipment. this cannot be allowed in the case of extremely contagious agents, even in an emergency or "code" situation. a health care provider who has contact with a patient without suitable protective gear risks not only his or her own health but also the health of other patients, coworkers, visitors, and their own families. individual patient care issues must be secondary to adequate infection control practices, lest an epidemic of smallpox, sars, plague, or viral hemorrhagic fever spread unchecked. the cdc has developed categories of precaution that are to be applied to patients with potentially communicable diseases (box . ). these categories have been described at length elsewhere but are summarized in the following sections, along with their applicability to the category a biological agents. standard precautions should be applied to all patients and include measures designed to prevent transmission of blood- smallpox viral hemorrhagic fevers pneumonic plague cutaneous anthrax borne illnesses such as hiv and hepatitis b/c. most interactions with patients do not require any protective equipment, but gloves, gown, and face shield should be used for any activity that could potentially result in an exposure to blood or bodily fluids. of the category a agents, anthrax, tularemia, and botulinum toxin require only standard precautions because these diseases are not transmissible from person to person. cutaneous anthrax should perhaps be treated with contact precautions because transmission has been suggested following contact with the lesions of this type of anthrax. contact precautions are applicable to diseases that can be spread by touching the patient directly or indirectly by coming into contact with contaminated objects. common examples include scabies, herpes, clostridium difficile, and methicillin-resistant staphylococcus aureus. contact precautions must be used, if applicable, during all patient interactions, regardless of whether body fluid contact is expected. protective equipment consists of gloves and gown, and a face shield is mandatory if splashing or spraying of body fluids is possible. patients with smallpox and vhfs must be placed in contact precautions. patient care equipment must also be dedicated to these patients and not used on patients not suffering from these diseases. droplet precautions apply to diseases that are transmissible by large-particle droplets, defined as those greater than mm. due to the size of the droplets, transmission is highest over short distances (< m) and does not occur through ventilation systems. necessary equipment includes a face shield or surgical mask with eye protection, gown, and gloves. pneumonic plague requires droplet precautions. airborne precautions are required for diseases that are spread via droplet nuclei, which are less than mm. tuberculosis is the most familiar of airborne infectious agents, but of the category a agents, both smallpox and vhfs fit into this category. droplet nuclei may travel through ventilation systems, underscoring the importance of placing patients with these diseases in negativepressure rooms with hepa filters and exhaust of air to the outside. required equipment includes gown, gloves, and adequate respiratory protection. either an n respirator (specifications are described elsewhere) with eye protection or a powered air purifying respirator (papr) is acceptable. a misconception exists that once a patient is intubated and mechanically ventilated, both large droplets and droplet nuclei are no longer expelled into the air. this is true only if the ven-tilator expiratory circuit is fitted with a filter that meets hepa guidelines. unfortunately, many of the filters and heat/moisture exchanging filters commonly used do not meet hepa criteria. this poses dangers to health care personnel, visitors, and other patients not only for bioterrorist agents but also for tuberculosis, sars, and other emerging infections. hospitals would be well advised to stockpile hepa-grade filters for ventilator expiratory circuits. correct hand washing is an essential component of hospital infection control in all circumstances. this is perhaps even more true in the circumstances of an outbreak of an emerging infectious disease or possible agent of bioterrorism. hands must be washed after each patient contact even when protective gloves are used because a surprisingly high percentage of protective gloves contain microscopic holes, and holes may develop during the activities of routine patient care. failure to thoroughly wash hands following patient contact places other patients and health care workers at risk. there has been an increase in the use of waterless alcohol rubs in icus rather than soap and water. although these gels are generally effective against bacteria and viruses, they have been shown to be ineffective against bacterial spores such as anthrax. soap and water, antimicrobial or not, are effective at removing anthrax spores from hands. accordingly, we recommend the use of antimicrobial soap and water for the washing of hands after patient contact. complete recommendations for postexposure prophylaxis are given in table . . in the case of anthrax and tularemia, postexposure prophylaxis with vaccination has not been proven effective. there is no need for prophylactic antibiotic therapy for health care workers unless they were potentially exposed in the initial attack. vaccination does not confer protection against pneumonic plague. health care workers caring for patients with pneumonic plague should, however, receive prophylaxis with days of oral doxycycline. if symptoms such as fever develop, they should be aggressively treated with parenteral antibiotics. health care workers caring for patients with smallpox should be vaccinated as soon as possible because vaccination within days of exposure can prevent or limit the severity of subsequent illness. immediate isolation must follow the development of fever after exposure to smallpox. no postexposure prophylaxis exists for vhfs. although decontamination of victims of a biological attack is rarely necessary, the rooms in which they are treated can become contaminated with infectious organisms, particularly if sprays of bodily fluids or respiratory aerosols are produced. virions of smallpox, in particular, can persist in linens for extended periods of time; documented cases exist in which laundry workers contracted smallpox from handling contaminated bedding and clothing. the causal agents of vhfs may also be transmitted via contaminated linens. commercial hospital disinfectants and household bleach at a : dilution are effective at eliminating surface contamination with anthrax, smallpox, ebola and marburg viruses, tularemia, and plague. linens from infected patients should be incinerated, autoclaved, or the bodies of deceased patients with smallpox, plague, or vhfs continue to pose an infectious risk. autopsies or postmortem examinations should be avoided if possible. the bodies of victims of smallpox should be cremated. people who have died of a vhf should preferably be cremated, although prompt burial without embalmment is a secondary option. proper use of personal protective equipment is essential in order to protect staff from infectious disease. the equipment required depends on the particular disease, as described previously. effort must be made to ensure that adequate supplies of equipment exist, and requirements will likely be far greater than expected. calculations estimating the amount of equipment necessary for one nurse caring for four patients with a communicable disease are striking and sobering. during an -hour shift, one nurse would likely require sets of personal protective equipment: pairs of gloves; gowns; surgical masks, n masks, or papr hoods; and face shields. providing for the needs of physicians, respiratory therapists, and other ancillary personnel increases this equipment need markedly. beyond the availability of adequate stocks of equipment, health care workers must be adequately trained in their uses. n respirators require fit testing annually. the equipment must be used as designed, including donning and removing it correctly. removing equipment in the proper order is particularly important: the gloves must be removed first to avoid contamination of the face or clothing when removing the gown, mask, and eye shield. unfortunately, this correct sequence is not widely appreciated by health care workers. given the complexity of caring for victims of a bt attack or an emerging infectious disease, early planning for such an incident must be carried out at the institutional and icu levels. how will a hospital, or an icu, care for a potentially massive influx of patients with communicable disease or specific requirements? plans will differ in their specifics depending on each hospital and each icu's architecture and capabilities. general principles include the following: patients should be grouped according to infection, not necessarily by need. these patients should then be isolated from the remaining hospital population and staff. dedicated physicians, nurses, ancillary personnel, and equipment should be used so as to prevent exposure to other patients and keep the numbers of exposed health care workers to a minimum. the scale of a bioterrorist attack could potentially be enormous. as described previously, many of the category a agents could produce the same lethality as a nuclear explosion. the number of casualties could rapidly overwhelm any one hospital or even all of the hospitals in a community. staff safety must be paramount; if staff members believe themselves to be at risk, large numbers of nurses, physicians, and others may not show up to work, crippling or even forcing the closure of a hospital. although all risk cannot be avoided, all possible provisions must be made. all staff members must be trained in the proper use of personal protective equipment. beyond that, training should be provided in specific plans for the response to an infective or bt incident. physicians and nurses in particular should be educated with regard to possible agents of bt and presented with disease-specific issues. contingency plans must be made in advance for postexposure prophylaxis, either with antibiotics or vaccinations, as indicated. given the critical and limited time windows to initiate effective prophylaxis, plans for distribution of medication or vaccine must be thought through in advance and not made in an ad hoc manner. a large-scale bioterrorist incident could rapidly exhaust the resources of individual hospitals or even whole communities in a number of respects. the demand for personal protective equipment will be enormous. beyond that, there will be a need for pharmaceuticals of all types. antibiotics will be essential, but so will medications regularly employed in the icu setting: vasopressors, sedatives, narcotics, and others. mechanical ventilators may be at a premium for patients with acute respiratory distress syndrome, pneumonia, or ventilatory failure secondary to botulism. although in the united states, and likely in other countries, the federal government has assembled stockpiles of antibiotics, smallpox vaccine, and mechanical ventilators, it will take time for these to be deployed, and they may not contain all essentials. the prospect of bioterrorism is not an abstract one. it has been attempted before, and it will certainly be attempted again. that it has not happened is not reason for complacency. adequate response to a bioterrorist incident is possible, but it requires careful and thoughtful preparation. also, the preparation is hardly specific to the potential agents of bioterrorism. the principles of providing safe and effective care to victims of a bt incident are wholly applicable to the management of patients suffering from naturally acquired emerging infectious diseases. the age of bioterrorism is also that of sars, coronavirus, avian influenza, ebola virus, and, significantly, global travel. the potential for patients to present acutely ill with rare, unknown, and infectious diseases, whether naturally acquired or unleashed by criminals, has never been higher. planning and preparation are essential. botulinum toxin as a biological weapon. medical and public health management hemorrhagic fever viruses as biological weapons. medical and public health management tularemia as a biological weapon. medical and public health management the challenge of hospital infection control during a response to bioterrorist attacks smallpox as a biological weapon. medical and public health management plague as a biological weapon. medical and public health management updated recommendations for management key: cord- -u ngkpc authors: andersen, bjørg marit title: intensive patient treatment date: - - journal: prevention and control of infections in hospitals doi: . / - - - - _ sha: doc_id: cord_uid: u ngkpc intensive care units (icus) are treating hospital’s poorest patients that need medical assistance during the most extreme period of their life. intensive patients are treated with extensive invasive procedures, which may cause a risk of hospital infections in – % of the cases. more than half of these infections can be prevented. the patients are often admitted directly from outside the hospital or from abroad with trauma after accidents, serious heart and lung conditions, sepsis and other life-threatening diseases. infection or carrier state of microbes is often unknown on arrival and poses a risk of transmission to other patients, personnel and the environment. patients that are transferred between different healthcare levels and institutions with unknown infection may be a particular risk for other patients. in spite of the serious state of the patients, many icus have few resources and are overcrowded and understaffed, with a lack of competent personnel. icu should have a large enough area and be designed, furnished and staffed for a good, safe and effective infection control. the following chapter is focused on practical measures to reduce the incidence of infections among icu patients. all patients treated in intensive care units (icus) and personnel working in the intensive care units. the hospital's management should provide resources and written guidelines regarding infection control work, proper patient/care ratio, sufficient patient areas, isolation capacity and documented competence. the departmental management should provide competent personnel that follow guidelines. in circumstances that expose patients to increased infection risk, this is reported to the director immediately. the staff follows routines. expertise and practice in intensive medicine must be documented. it should be reported to the management if exposed to or infected by resistant or special microbes, for example, in work at other departments/countries. the patient and relatives/visitors should be informed about the department's routines, hand hygiene and good personal hygiene and cleanliness. intensive care unit (icu) should have a large enough area and furnished for a good, safe and effective infection protection [ ] . the state of infection or carrier state is often unknown on arrival and poses a risk of infection to other patients, personnel and the environment [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . patients transferred between healthcare levels and healthcare networks may spread infections [ ] [ ] [ ] [ ] [ ] . note! comprehensive responsibility! there must be one responsible department/ unit manager who has total responsibility for patients, personnel and the environment-in terms of infection control and patient protection. fragmentary leadership means that no one has direct responsibility for the patient's security and prevention of infection. . hygienic standard should correspond to an operation department-to reduce the number of infections, the use of antibacterial agents and resistance development. employees should carry out a good personal hygiene (see personal hygiene and regimes for isolation, chap. and - ). . separate patient rooms are recommended. this is due to the many direct openings into sterile tissues, via respirator, intravascular catheters, urinary tract catheter, surgical site and other wounds. all intensive patients should be protected against infections from other patients, personnel and the environment [ , ] . when sharing a room with a fellow patient, the distance between the patients must be - m from bed edge to bed side, and no one must have infections. . medical technical equipment associated with every intensive bed take a lot of space in the room, generates dust, particles and heat and are easily contaminated with skin particles and bacteria. written cleaning procedures must be available for all equipment. . the burden of bacteria, particles and other organic materials from the use of respirators, cough/suctions and particles from opening single-use equipment needs good room ventilation, preferably more than ten air exchanges/hour and control of bacterial numbers in the air, < cfu/m . the air should enter the ceiling level and be filtered by % effective filter with particle diameter max μm. exhaust air is extracted approximately cm above floor level (opposite side). avoid turbulence, shaking of clothes, abrupt removal of bandages, etc. that increase the amount of bacteria in the air [ ] . . hand hygiene is routinely enjoined for all personnel. proper use of hand disinfectants and gloves is important. non-sterile gloves often have a rich growth of environmental flora and do not protect the patient. jewellery, piercing and wristwatches are not allowed since this collects microbes and inhibits personal hygiene/hand hygiene. patient and visitor's hand hygiene routines will usually be the same in the hospital [ ] . . coats and outerwear are taken off outside the unit. . glove box for each patient, set date, and throw the box when the treatment ends. . water control. avoid splashes and aerosols from the sinks that are often colonized with gram-negative rods, and check the water for legionella and other gram-negative bacteria (see legionella and water control) [ , , ] . (a) cooling systems, water coolers and large water reservoirs are linked to the outbreak of legionella and resistant gram-negative rod bacteria [ ] . use sterile water for intensive care patients for oral hygiene. (b) biofilm formation in water systems, on surfaces, etc. is increasing. preventative measures are good such as daily cleaning with soap and water and disinfecting with chlorine or peracetic acid [ ] [ ] [ ] . biofilm can be resistant to chlorine [ ] . . clean work uniform; change every day or more often if necessary. (a) separate gown for each patient-long arms and cuffs. the gown is changed for each shift or more frequently if contaminated. (b) cap/surgical mask and visor are used by work with respiratory tract (respirator), intravascular catheter, surgical wound, drain, urinary tract catheter. . cleanliness and order to reduce biological burden in the environment and to reduce the risk to the patient. good daily cleaning removes possible pathogenic flora fairly quickly. good cleaning depends on good space and order. large amounts of skin waste, hair and microbes are released continuously from people in the room-and fall down as grey "dust" on all surfaces after the floating state in the air-and carry invisible amounts of bacteria. in addition, there may be huge amounts of particle release from all disposable devices that are opened. (a) all patient rooms, service rooms, guard rooms, wardrobes, etc. must be cleaned at least once a day with soap and water. (b) the washbasin is washed and disinfected daily [ ] . disinfect mobile phones, glasses, etc. and all other equipment before being brought into the icu. note! persons who perform room cleaning should not work with patients at the same time. this is to avoid cross infection. . medical technical equipment must be cleaned outside daily, when the treatment is completed and when it is going to enter or leave the department. it must also be cleaned inside after infection and after certain periods of use or after each use. all equipment is stored clean and dry, preferably with a clean chapel, on a separate clean storage. . sterile equipment is stored clean and dry on a separate storage for sterile equipment with requirements of low bacterial numbers in the air. . respiratory treatment: see separate chapters. . intravascular treatment: see separate chapters [ ] [ ] [ ] [ ] [ ] . there is estimated at least two competent intensive care nurses per patient. the icu patient is monitored continuously-in place-at the bed (not via ward room) on a -h basis. small changes in the patient can lead to a dramatic worsening of the condition if not detected early enough. understaffing leads to less competent personnel and temporary workers, increased stress in the work situation, reduced hand hygiene and lack of infection control [ ] . this increases the risk of serious nosocomial infection and fatal outcome. understaffing and overcrowding will also expose personnel and visitors to increased risk of infection [ ] . the icu should be large enough to cover demographic needs, operational activity and specialty in the coverage area [ , , ] . the department should be functional with ample space for each patient, necessary number of isolates, good ventilation, service rooms and storage space. the department must be prepared for good infection control, hand hygiene and a thorough cleaning system [ , , ]. patient groups vary according to type of intensive care unit: surgically intensive, medical intensive, child intensive or a blend of patient categories. • in germany, nosocomial infections were detected in . % of icu patients, and after discharge, the rate increased to . % [ ] . without follow-up afterwards, % of icu-associated infections were not recorded [ ] . • in belgium, there were icu patients examined in [ ] . nosocomial pneumonia and ventilator-associated pneumonia (vap) starting in the icu were / and / patient days, respectively, and icu-associated blood infections were . / patient days. during the period - , icu-associated infections increased, while infections related to equipment (respirator, catheter) were reduced [ ] . in , at least % of adult icu patients had nosocomial infections [ ] . • later studies showed that more than % of icu patients had infections like vap and catheter-associated infections [ ] . among , patients with more than days of stay in icus in european countries from to , it was estimated that % of the vap cases and % of bloodstream infections could be prevented [ ] . • intensive studies in the united states show that - % of catheter-associated blood and urinary tract infections can be prevented and % of cases of vap and postoperative wound infections [ ] . • the american network study ( ) of catheter-associated intravascular and urinary tract infections, vap and postoperative wound infections showed that these four infection categories caused , hospital infections per year, and it was found at least , pathogenic microbes in these patients [ ] . nearly % of the microbes were multidrug-resistant organisms (mdro) like mrsa, vre, esbl and cre isolates [ ] . • in , ca. general intensive beds were registered at hospital icus in norway (five million inhabitants) [ ] . in it was about , icu treatments and approximately , days of intensive care in norway are distributed between local hospitals . %; central hospitals, . %; and regional hospitals, . % [ ] . • more than half of the patients were on respiratory treatment, average stay in the icu was days, and . % were discharged from hospital, while % died on the icu and . % on other wards [ ] . • there is a calculated need for about icu beds per , inhabitants [ ] . calculated from today's approximately intensive beds, this amounts to . / , . • in , the prevalence of hospital infections in the norwegian icus was % in surgical icu/postoperative ward ( beds) and . % in medical icu/ward of monitoring ( beds) [ ] . about the same results were recorded in [ ] . • hospital infections and mortality are high in norwegian icus, especially in surgical icus. since postoperative beds are included in the number registered for intensive, the real number of hospital infections is probably much higher. the costs are uncertain but probably amounts to at least , nkr per day for regular intensive care. the presence of resistant microbes in norwegian icus is unknown but probably an increasing problem. • there are still too few icu beds in norway-maybe only half of what is needed-and this can lead to unnecessary disease and death [ ] . every th ( %) icu patient died on intensive or afterwards on ward in [ ] . the risk of death in icu is therefore very high. • many entry ports through skin/mucous membranes (trauma, surgical procedure, respirator, etc.). • flat bed rest over time. • reduced immunity to infections, impaired general condition. • many procedures and a lot of handling of the patient. • much instrumentation. • acute care procedures. • h- blockers with gastric colonization of gram-negative bacteria from the gut. • aspiration of stomach contents. • short distance between patients-high patient density and overcrowded. • many patients in the same room, open care-"dormitory" [ , , ] . • mixing of potentially infected patients with non-infected patients. • lack of isolates/single rooms and cross infection [ ] [ ] [ ] ] . • poor cleaning, lack of hygiene measures and lack of follow-up of hygiene guidelines [ , ] . • environmental contamination [ , ] . -contaminated water [ , ] . -biofilm formation with microbe growth in water, on surfaces and equipment [ , ] . -contaminated textiles. -contaminated/unsterile equipment and liquids [ ] . -contaminated patient room [ ] . • large consumption of antibacterial agents. -the use of multi-dose vials instead of single-dose. • large nursing load on few nurses, patient/nurse ratio-understaffing [ ] . -short-term employed and a high personnel turnover [ ] . -lack of knowledge, experience and use of written routines, large number of part-time workers and many "leaders" in the system. • number of days in hospital > days; transferral of the patient between several departments and undergone at least one invasive procedure. • transport between departments and hospitals [ ] . • airborne-droplet-borne infection: - [ ] [ ] [ ] . see separate chapter. • aerosol from contaminated nebulizer and other respiratory equipment. • aerosol/re-aerosol from change of bed linen, making the bed and other activities [ ] . • tracheal suction/coughing. • oral hygiene-lack of [ ] . • intravascular treatment, haemodialysis, peritoneal dialysis, etc. [ ] [ ] [ ] [ ] [ ] ] . • drainages and urinary tract catheters. • prolonged use of antibiotics and increasing bacterial resistance [ , ] . • personnel with infection/carrier state-without knowing-"cloud" personnel [ ] . • lack of tuberculosis control. the greatest risk of infection is the number of days in the icu and respiratory treatment (see separate chapter concerning vap). the icu patients have often complicating infections that lead to increased use of broad-spectrum antibacterial agents, which in turn often lead to resistant microbes. the patients' microbes become environmental, robust microbes that may be transmitted to the lungs, blood or wounds of room-mates. the accumulation of robust environmental microbes and bacterial-bearing dust (gram-negative rods, staphylococci and fungi), over time, is a great risk that may be removed only by good daily cleaning and environmental control. occasionally, patients bring serious infections or infectious agents to the hospital and the icu; multi-drug resistant organisms (mdro) such as mrsa, vre, esbl, ehec (entero-haemorrhagic e. coli, may be esbl at the same time), cre (carbapenemase-producing/resistant enterobacteriaceae). a number of others are introduced periodically in the department like norovirus and influenzae. the most common infections in icus are caused by s. aureus, e. coli, enterobacter, pseudomonas, klebsiella, serratia, acinetobacter, stenotrophomonas, burkholderia cepacia, enterococcus, clostridium difficile, coagulase-negative staphylococci and candida. during the stay in the icu, the early infections are often with "common" bacteria like staphylococci, and the later infections after longer stay in the icu are caused by more resistant bacteria like pseudomonas and fungi. in sweden, an increased incidence of invasive haemophilus influenzae, nontype b, has been reported, with more than one third being treated at the icu for septic shock [ ] . group a streptococci (gas) are epidemic in a number of countries and constitute an important intensive treatment and infection problem. in england, there was registered , gas cases in -the highest number of the past years of scarlet fever [ ] . healthcare professionals can become carriers of gas, and the infection can spread through air [ , , ] . bacteria that are transmitted via direct inhalation, swirling of dust or aerosols are gas, staphylococci, mrsa, meningococci, pneumococci, pertussis bacteria, diphtheria bacteria, ehec, acinetobacter legionella, pseudomonas, clostridium difficile (spores), mycobacterium tuberculosis and other mycobacteria, nocardia and a variety of other bacteria [ , [ ] [ ] [ ] [ ] [ ] . virus that is nosocomial through the air is respiratory virus (rsv, influenza, parainfluenza, rhinovirus, corona-, adeno-, entero-, parecho-, metapneumovirus), varicella-zoster virus, rubella, morbilli, norovirus, sapovirus, etc. [ ] . spores of fungi from aspergillus and similar fungus types are liberated easily into the air and causes severe systemic infections in immunosuppressed patients [ ] . antibiotic resistance has increased dramatically over the past years, and a large proportion of these occur in icu departments with severe infectious disease [ ] [ ] [ ] [ ] [ ] . new types of resistance appear as cre (carbapenem resistant), enterobacteriaceae: xdr (extensive drug resistance), acinetobacter species; and totally resistant (ndm- and colistin resistant) gram-negative rods, extremely to totally resistant tuberculosis bacteria, and others that can cause fatal nosocomial progress, also in almost immune-competent patients [ ] [ ] [ ] [ ] . these patients are often associated with icu, respiratory treatment, pulmonary disease, antibiotic use and a high bacterial burden in the environment [ ] . a specific "clad b" (xdr) strain of a. baumannii is-in the united states-a recent cause of fatal outcome of nosocomial infection in six patients: it is a highly resistant and dangerous (hypervirulent) strain [ ] . another multiresistant a. baumannii caused nosocomial infections in more than patients, of which five died in germany [ ] . in a study from brazil, the consumption of piperacillin-tazobactam, fluoroquinolones and cephalosporins increased at the hospital [ ] . at the icu, multi-resistance was detected in more than % of the cases, with increasing meropenem-resistant klebsiella and acinetobacter species. a significant correlation was detected between the proportion of multiresistant bacteria and the consumption of cephalosporins and fluoroquinolones [ ] . among hospitalized patients in germany, . % were colonized with fluoroquinolone-resistant e. coli (fqrec), and this was linked to poor clinical outcomes and high mortality [ ] . stay in hospital, cancer diagnosis and the use of first-generation cephalosporin or cefepime treatment increased the incidence of new colonization with fqrec [ ] . isolation, good hygienic measures and a better antibiotic policy reduce the spread of infection. fluoroquinolone resistance is an increasing problem since these drugs are used extensively both inside and outside hospitals [ ] . multiresistant bacteria may increase when using antibiotics in food and beverage production. an alarming occurrence of carbapenemase-producing gram-negative bacteria has been detected in food, for example, in canada [ ] . also in norway there are significant problems with resistant bacteria and other unfortunate agents in some food products [ ] . resistant microbes in the health system will migrate between health levels, such as either silent colonization or with infection symptoms, "the top of the iceberg". the real problem (the entire iceberg) is only detected by general screening and mapping of the patients [ ] [ ] [ ] [ ] . international studies show insufficient knowledge about how to use the testing of resistance against antibiotics, also shown in a norwegian study [ , ] . today, active screening of faeces/rectum samples (cre, esbl, vre, (mrsa)) may be used in combination with c. difficile detection [ ] . this has proven cost effective in icu departments with problems with a. baumannii [ ] . chlorhexidine "bathing" of icu patients to reduce infections is discussed, both for adults and children [ ] . this measure is probably not so successful concerning the development of resistance as long as it is done so little for general hygiene and infection control in icus. in norway, there is increasing resistance development and outbreaks of resistant microbes such as mrsa, vre and esbl in hospitals, especially in recent years, but is still thought to be a "limited problem" [ ]. many icus around the world, including norway, have until recently appeared like large dormitories, with mix of patient categories, no isolates and a strong understaffing in old and run-down areas. the outmost sever ill patients have often had the poorest treatment offer in the icu of the hospitals. "bad design, bad practices, bad bugs" is the starting point for a number of serious infection outbreaks in icus [ ] . • space around the patient is needed for different intensive equipment, nursing staff and family. each patient should have a separate room (approximately m patient) to be protected against infection/noise/stress from the environment and other patients. recent studies indicate that patients in separate icu rooms will have fewer hospital infections and thus a lower risk of fatal outcome [ , ] . • isolates. twenty-five percent of the bed capacity at intensive should be isolates with negative air pressure ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . the size should be at least m /isolate which includes patient room, sluice and disinfection room/toilet/shower. • service room. the unit must have service rooms/store rooms adapted to the number of intensive beds. the service rooms should be store room for single-use equipment ( m ), medicine room ( m ), disinfection room (needed, crosscontamination danger, m ), textile room (needed, danger of cross-contamination, m ) for technical equipment (respirator, infusion pumps, surveillance equipment, racks, etc., - m ), shower room for patients ( m ) and waste disposal room (large amounts of waste, m ). • entrance control. a separate sluice for entrance to the icu with wardrobes with washbasins and disinfectants. note: washbasins/sinks/shower rooms. a number of studies have documented bacterial aerosols around the sink/washbasin/shower room. a french multicentre study of washbasins in icus showed that one of three washbasins was contaminated with multiresistant esbl gram-negative bacteria [ ] . it was recommended that washbasins should only be used for hand washing and disinfected with chlorine agents daily [ ] . washbasins, with a small fall height from opening to bottom, should therefore be placed at least m from the patient to avoid aerosols. intensive care unit design and environmental factors in the acquisition of infection how many nosocomial infections are associated with cross-transmission? a prospective cohort study in a surgical intensive care unit an outbreak of acinetobacter baumannii: the importance of cross-transmission nosokomial infection with resistant enterobacter cloacae spread of methicillin-resistant staphylococcus aureus in a neonatal intensive unit associated with understaffing, overcrowding and mixing of patients environmental contamination by multidrug-resistant acinetobacter baumannii in an intensive care unit evaluation of bed-related airborne and surface methicillin-resistant staphylococcus aureus contamination tap water colonization with pseudomonas aeruginosa in a surgical intensive care unit (icu) and relation to pseudomonas infections of icu patients an outbreak of multidrug-resistant pseudomonas aeruginosa associated with increased risk of patient death in an intensive care unit intensive patient treatment. in: handbook for hygiene and infection control for hospitals. oslo: ullevål university hospital prevention of infections in intensive patient care. in: handbook for hygiene and infection control for hospitals. oslo: ullevål university hospital carbapenem-resistant enterobacteriaceae, long-term acute care hospitals, and our distortions of reality admission surveillance for carbapenemase-producing enterobacteriaceae at a long-term acute care hospital extensive dissemination of extended sprectrum beta-lactamase-producing enterobacteriaceae in a dutch nursing home association between hospitalacquired infections and patient transfers spread of hospital-acquired infections: a comparison of healthcare networks infection prevention and control in the intensive care unit: open versus closed models of care patient's hand hygiene at home predicts their hygiene practices in hospital contaminated sinks in intensive care units: an underestimated source of extended-spectrum beta-lactamase-producing enterobacteriaceae in the patient environments outbreak of stenotrophomonas maltophilia on an intensive care unit intensive care unit environmental surfaces are contaminated by multidrug resistant bacteria in biofilms: combined results of conventional culture, pyrosequencing, scanning electron microscopy, and confocal laser microscopy prospective study of arterial and central venous catheter colonization and arterial and central venous catheter-related bacteremia in intensive care units infections caused by percutaneous intravascular devices guidelines for the prevention of intravascular catheter-related infections prospective study of peripheral arterial catheter infection and comparison with concurrently centralized central venous catheters central venous catheter infections at a county hospital in sweden: a prospective analysis of colonization, incidence of infection and risk factors surveillance of nosocomial infections in icus: is postdischarge surveillance indispensable? infections acquired in intensive care units: results of national surveillance in belgium, - belgian national prevalence survey for hospital-acquired infections preventional proportion of severe infections acquired in intensive care units. case-mix adjusted estimations from patient-based surveillance data estimating the proportion of healthcare-associated infections that are reasonably preventable and the related mortality and costs antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the national healthcare safety network at the centers of disease control and prevention intensive medicine in norway annual report for . kvåle r. haukeland university hospital intensive capacity'. follow-up of pre-project for health care organization structure and task allocation in helse Øst prevalence of health-related infections in hospitals an outbreak of infections caused by non-typable haemophilus influenzae in an extended care facility outbreak of burkholderia cepacia in the adult intensive care unit traced to contaminated indigo-carmine dye risk of acquiring multidrug-resistant gram-negative bacilli from previous room occupants in the icu impact of a travelling of intensive surveillance and intervention targeting ventilated patients in the reduction of ventilator-associated pneumonia and its cost-effectiveness ventilator-associated pneumonia in a multi-hospital system: differences in microbiology by location targeted antibiotic management of ventilator-associated pneumonia oral decontamination for prevention of pneumonia in mechanically ventilated adults: systematic review and meta-analysis chlorhexidine-based antiseptic solutions versus alcoholbased povidone-iodine for central venous catheter care increasing resistance to vancomycin and other glycopeptides in staphylococcus aureus cloud" health-care workers invasive disease caused by haemophilus influenzae in sweden - ; evidence of increasing incidence and clinical burden of non-type b strains the surgical team as a source of postoperative wound infection caused by streptococcus pyogenes intraoperative patient-to-healthcare-worker transmission of invasive group a streptococcal infection medical and microbiological problems arising from airborne infection in hospitals aerial dispersal of methicillin-resistant staphylococcus aureus in hospital rooms by infected and colonised patients possible role of aerosol transmission in a hospital outbreak of influenza cephalosporin and fluoroquinolone combinations are highly associated with ctx-m beta-lactamase-producing escherichia coli : a case-control study in a french teaching hospital resistance surveillance studies: a multifaceted problem -the fluoroquinolone example impact of antibiotic use during hospitalization on the development of gastrointestinal colonization with escherichia coli with reduced fluoroquinolone susceptibility carbapenemase-producing organisms in food enterococci and vancomycin resistance prevalence and risk factors for acquisition of carbapenem-resistant enterobacteriaceae in the setting of endemicity rising rates of carbapenem-resistant enterobacteriaceae in community hospitals. a mixed-methods review of epidemiology and microbiology practices in a network of community hospitals in the south-eastern united states a fatal outbreak of an emerging clone of extensively drug-resistant acinetobacter baumannii with enhanced virulence acinetobacter -germany: fatal, nosocomial, multidrug-resistance impact of hospital-wide infection rate, invasive procedures use and antimicrobial consumption on bacterial resistance inside an intensive care unit food borne infection is a neglected problem clinicians' knowledge, attitudes, and practices regarding infections with multidrug-resistant gram-negative bacilli in intensive care units a multi-drug resistant, methicillin-susceptible strain of staphylococcus aureus from a neonatal intensive care unit in oslo active surveillance for carbapenem resistant enterobacteriaceae using stool specimens submitted for testing for clostridium difficile economic value of acinetobacter baumannii screening in the intensive care unit does chlorhexidine bathing in adult intensive care units reduce blood culture contamination? a pragmatic cluster-randomized trial bad design, bad practices, bad bugs: frustration in controlling an outbreak of elizabethkingia meningoseptica in intensive care units single rooms may help to prevent nosocomial blood stream infection and cross-transmission of methicillin-resistant staphylococcus aureus in intensive care units infection acquisition following intensive care unit room privatization key: cord- -cqmqwl i authors: fidalgo, pedro; bagshaw, sean m. title: chronic kidney disease in the intensive care unit date: - - journal: management of chronic kidney disease doi: . / - - - - _ sha: doc_id: cord_uid: cqmqwl i the incidence and prevalence of chronic kidney disease (ckd) and end-stage renal disease are increasing, and these patients have a higher risk of developing critical illness and being admitted to the intensive care unit (icu) compared to the general population. the higher prevalence of comorbid disease puts this population at higher risk for worse short- and long-term outcomes following icu admission compared to the general population, although short-term mortality seems to be determined largely by the acute illness severity rather than ckd status per se. the pathophysiologic changes accompanying ckd present unique challenges to the management of acute critical illness most notably volume and metabolic homeostasis and drug dosing adjustment. ckd is an important risk factor for the development of acute kidney injury (aki) complicating critical illness and can predispose to further accelerated decline in kidney function among icu survivors. renal replacement therapy (rrt) support is frequently used in icu settings, and continuous renal replacement therapy modality remains the most commonly used among critically ill patients. • ckd patients have a high prevalence of comorbid disease compared to non-ckd patients; however, ckd patients have reasonable short-term outcomes following icu admission compared to non-ckd patients. • the most common diagnoses contributing to icu admission in ckd patients are sepsis and septic shock and decompensated cardiovascular disease. • aki is a common complication of critical illness, most often precipitated by sepsis, and remains a strong negative modifier of short-and long-term survival. • ckd is an important and independent nonmodifiable risk factor for development of aki and long-term accelerated loss of kidney function among ckd survivor of critical illness. • while numerous factors influence the decision to start renal replacement therapy, the most common initial modality prescribed after icu admission worldwide remains continuous renal replacement therapy, particularly for hemodynamically unstable patients, and this may be associated with higher likelihood of recovery of renal function and dialysis independence. esrd, have a several-fold higher risk of developing critical illness. when considering these features, coupled with rising prevalence rates, the demand for intensive care unit (icu) support for ckd patients is expected to increase. this will likely present challenges for clinicians working in resource-limited settings regarding decisionmaking for icu support for ckd patients. there is limited data available on the prevalence of ckd among all critically ill patients supported in icu settings, and most studies have focused on the subset of dialysis-dependent patients with esrd [ ] . available data would suggest the proportion of patients admitted to icu with esrd ranges between and %. the reported variability in esrd admissions across studies is likely accounted for by differences in practice patterns, availability of icu resources, patient case-mix, and study design. esrd patients have consistently been shown to have an estimated - fold higher annual likelihood of admission to icu when compared with the non-esrd general population. esrd patients admitted to icu have several notable differences in baseline characteristics when compared with non-esrd patients. esrd patients are generally younger, have more comorbid disease, more likely medical (i.e., nonoperative admissions), and have higher illness severity scores compared with non-esrd patients. however, these observations may be susceptible to selection bias. available epidemiologic surveys of esrd patients admitted to icu are limited by not accounting for those patients referred and refused icu admission. the most common precipitants of critical illness prompting icu admission among esrd patients are sepsis/septic shock and decompensated cardiovascular disease including cardiogenic shock, myocardial ischemia/infarction, arrhythmic complications, and heart failure/pulmonary edema. cardiac arrest and cardiopulmonary resuscitation (cpr) are more common events occurring among esrd patients compared with non-esrd prior to icu admission. this may relate to several factors including a higher prevalence of comorbid cardiovascular disease and diminished cardiopulmonary reserve, a higher incidence of primarily arrhythmic complications, and the unique pathophysiologic stress of dialysis (i.e., rapid fluid-/electrolyte-related shifts). surprisingly, the early mortality for critically ill esrd patients is lower than for those with acute kidney injury (aki), suggesting that the prognosis is driven largely by acute illness severity rather than baseline comorbidities. however, esrd patients have consistently higher shortterm mortality rates ( - %) when compared to non-aki critically ill patients and an ageand sex-matched general population. factors that have been shown to be associated with icu mortality in esrd patients are older age, higher illness severity score (i.e., apache ii or saps ii), burden of nonrenal organ dysfunction/failure, medical or nonsurgical admission type, and provision and duration of life-sustaining technologies (i.e., mechanical ventilation, vasopressor therapy). studies reporting long-term survival among esrd patients show a trend for an increased mortality rate within the first months after icu discharge, with a relatively stable but increased risk for mortality thereafter. at years after icu admission, survival is generally poor. observational studies estimate only / of esrd patients admitted to icu were still alive. although long-term mortality in esrd patients is several times higher when compared to the general population, the presence of esrd does not appear to independently predict long-term mortality, suggesting short-term prognosis is more related to the acute illness severity rather than ckd and dialysis dependence. it has been increasingly recognized that ckd influences the risk of developing aki and that aki per se contributes to ckd progression and incidence of esrd. around % of patients who survive an episode of aki requiring rrt show significant loss of glomerular filtration rate (gfr) resulting in dialysis dependence after hospital discharge in approximately % of patients. the most important risk factor for incident esrd and dialysis dependence among survivors of critical illness is prior ckd. this would suggest continued surveillance of kidney function among survivors of critical illness is vital. data on changes to functional status and health-related quality of life (hrql) for esrd patients surviving an episode of critical illness are currently lacking. however, in non-esrd critically ill patients surviving critical illness, in particular for those with severe aki requiring acute rrt, long-term reductions in hrql and impaired functional status are common. these data coupled with the reduced hrql for esrd patients imply this may be a significant issue for survivors of critical illness. ckd, in particular esrd patients, consume more health resources in association with admission to icu compared with non-ckd patients. these patients have longer durations of icu stay, longer duration of hospitalization, and higher rates of short-term rehospitalization. moreover, these patients often remain chronically ill following icu discharge due to issues related to cardiovascular comorbidity, malnutrition, and deconditioning. these likely reflect diminished physiologic reserve and increased vulnerability to further adverse events. icu prognostication using icu-specific illness severity or organ failure scores (i.e., apahce ii, saps iii, sofa) can be challenging among patients with esrd. most scoring systems have not been specifically validated for esrd patients, and their performance routinely overestimates the risk of death [ ] . this may contribute to the perceived lack of benefit of icu support for ckd/esrd patients referred for icu support. the pathological changes accompanying ckd, although frequently not clinically evident until later stages of kidney disease, can present unique challenges for ckd patients presenting with critical illness. details of some of the unique challenges in the acute management of ckd patients in the icu are detailed in table . . there is a paucity of data with respect to the specificity of the management of ckd patients in the icu especially in the early stages of the disease. ckd patients should receive the same standard of care as the general population while accounting for some of the unique challenges that patients with ckd/esrd may pose to icu management. the general principles for support and management of critically ill patient in the icu focus on advanced hemodynamic and physiologic monitoring and multimodal organ support to guide restoration of tissue perfusion and oxygen delivery (table . ). the majority of patients have intravascular placement of arterial catheter for continuous blood pressure monitoring, due either to the presence of hemodynamic instability or to monitoring resuscitation (i.e., fluid therapy or titration of vasoactive therapy) or need for frequent blood sampling. arterial catheters display systolic, diastolic, and mean arterial pressure readings along with a continuous waveform. analysis of the pressure waveform may provide useful information regarding a patient's clinical status. variability on pulse contours is related to the elasticity, amplification, and distortion of smaller peripheral arterioles. ckd patients with significant peripheral vascular disease and/or arteriolar calcification may have reduced vessel elasticity (i.e., arterial stiffness) and exacerbated amplification that results in relative increases in systolic pressure and low diastolic pressure with rapid diastolic runoff (i.e., widened pulse pressure). esrd patients with a fistula or graft will have accelerated diastolic runoff and as a consequence lower diastolic and mean arterial pressure. in addition, given the prevalence of comorbid conditions in ckd such as cardiac valvular disease, ventricular hypertrophy (lvh), or pulmonary hypertension, arterial catheters may have misleading instantaneous accuracy, though likely have preserved trending [ ] . additional static hemodynamic measures, such as central venous pressure (cvp) and pulmonary artery occlusion pressure (paop), have focused on providing an estimate of left ventricular preload to guide fluid resuscitation. the challenge with these fixed pressure-derived measures is their lack of predictability to determine whether a patient will positively response to a fluid challenge (i.e., show improvement in cardiac output and performance associated with a fluid bolus). these measures are confounded by alterations in ventricular wall compliance (i.e., lvh in esrd). both cvp and paop lack precision in individual patients and should not be used in isolation to guide resuscitation. this may contribute to excessive and inappropriate fluid prescription. the central venous oxygenation (scvo ) is generally accepted surrogate for the venous oxygen saturation (s v o ) and reflects the adequacy of global cardiac output and oxygen delivery. functional dynamic metrics that utilize the observed variability in left ventricular filling neurologic examination, csf examination, brain radiology (ct, mri, angiography), eeg, brain damage-specific biomarkers (neuronspecific enolase, s β, myelin basic protein), invasive icp monitoring, cerebral microdialysis sedation, antiepileptic therapy, intracranial hypertension management, intraventricular drain abbreviations: co carbon dioxide, cpap continuous positive airway pressure, bipap bilevel positive airway pressure, ngal neutrophil-associated lipocalin, kim- kidney injury molecule- , il- interleukin- , fabp fatty acid binding protein, mars molecular adsorbent circulation system, nag n-acetyl-β-d-glucosaminidase, crrt continuous renal replacement therapy, sled sustained low-efficiency dialysis, irrt intermittent renal replacement therapy, icp intracranial pressure mechanical ventilation is a core life-sustaining technology that largely defined the modern practice of critical care. most critically ill patients require mechanical ventilation, whether for lung-specific indications (i.e., acute lung injury), systemic indications (i.e., shock), or postoperative support. a summary of the most common modes of mechanical ventilation provided in the context of critical illness is shown in pulse pressure variation (ppv): defined as the maximum pulse pressure minus the minimum pulse pressure, divided by the average of these two pressures over a mechanically delivered breath. ppv is based on the premise of pulsus paradoxus, the changes in arterial pressure during inspiration and expiration. ppv is not a true measure of preload or volume status, but an indicator of the position of the frank-starling relationship curve between stroke volume and preload to predict fluid responsiveness: stroke volume variation (svv): defined as the percentage of change between the maximum and minimum stroke volumes over a certain interval. similar to ppv, svv is not a true measure of volume status or preload but rather an assessment of response to fluid resuscitation: abbreviations: vcv volume-controlled ventilation, pcv pressure-controlled ventilation, psv pressure support ventilation, simv synchronized intermittent mandatory ventilation, vt tidal volume, peep positive end-expiratory pressure, vili ventilator-induced lung injury, ti inspiratory time utilization of mechanical ventilation for critically ill patients in recent years. these patients are generally burdened with a high prevalence of comorbid disease, in particular ckd, representing up to one quarter of all mechanically ventilated patients. kidney disease, both acute and chronic, can present unique challenges with respect to respiratory physiology, lung-kidney interaction, and mechanical ventilation support [ ] . first, ckd/ esrd patients often have high prevalence of comorbid respiratory illness such as restrictive or obstructive defects, pleural disease, pulmonary calcification, sleep apnea, or dialysis-associated hypoxemia. patients receiving pd have chronically elevated intra-abdominal pressure and diminished functional residual capacity. these factors predispose to limited pulmonary reserve. second, ckd/esrd patients often have diminished cardiac reserve and all have compromised capacity to excrete solute and water. acute cardiac events and/or fluid accumulation (i.e., noncompliance with diet, inappropriate dry weight prescription, missed dialysis) can predispose to acute cardiorenal syndrome and pulmonary edema. third, the development of acute injury to the kidney can induce a systemic inflammatory response with distant pathophysiologic effects in the lung (i.e., alterations in alveolar permeability and aquaporin expression). fourth, the positive pressure applied during mechanical ventilation acts to increase intrathoracic, intrapleural, and intra-abdominal pressures both during inspiration and for the duration of the respiratory cycle (i.e., peep) with the aim to improve and maintain adequate gas exchange. this can stimulate an array of hemodynamic, neural, and hormonal responses that can negatively impact kidney perfusion and further inhibit excretory function. this is observed as immediate and reversible declines in urine output and fluid retention, contributing to worsening fluid accumulation. finally, mechanical ventilation may provoke ventilator-induced lung injury (vili) leading to an exacerbating cascade of systemic inflammation that may have distant injurious effects on the kidney [ ] . data have also shown the development of aki may delay weaning from mechanical ventilation [ ] . this is likely multifactorial and related to greater difficulties with volume and acid-base homeostasis in aki. by extension, ckd/esrd patients are similarly likely to encounter prolonged weaning from mechanical ventilation. the most severe form of respiratory failure is acute respiratory distress syndrome (ards), defined as rapid-onset ( week) respiratory symptoms and hypoxemia associated with bilateral opacities resulting in respiratory failure not fully explained by cardiac failure or fluid overload. the incidence of milder forms of ards is . / , person-years while more severe ards occurs at a rate of . / , personyears. the most common predisposing factor is pulmonary and non-pulmonary sepsis. the mortality remains significant, in the range of - %, and long-term morbidity among survivors remains severely burdensome. the development of aki or worsening kidney function in the setting of ards is common, occurring in excess of %, and has an important modifying impact on increasing mortality risk ( - %) [ ] . it is believed part of the attributable mortality in ards has been related to the development of secondary harm associated with the mechanical ventilator (i.e., vili). accordingly, a number of "lung protective" strategies for improving outcome in ards have been evaluated (table . ). the advent of open lung low tidal volume ventilation to prevent alveolar overdistension, cyclic collapse, and barotrauma may be associated with iatrogenic alveolar hypoventilation and hypercarbic respiratory acidosis. this may be poorly tolerated in patients with aki or ckd/esrd with loss of renal compensation and inability to buffer the accumulated co . these patients are likely to require early initiation of rrt to mitigate severe acidemia and excessive fluid accumulation. patients with ckd/esrd are more susceptible to fluid and metabolic complications due to impaired fluid, electrolyte, and acid-base homeostasis. early short-term use of continuous nmb (< h) in severe ards may improve gas exchange and reduce vili recent level i evidence found lower -day and hospital mortality associated with a strategy of early short-term continuous infusion of nmb in severe ards and no increase in the rate of icu-acquired weakness daily sedation interruption a strategy of daily interruption or minimal sedation has been advocated to reduce duration of ventilation, duration of icu stay, and the incidence of delirium these patients did not necessarily have ards. recent level i evidence did not show evidence of reduced duration of ventilation or delirium associated with daily sedation interruption among ventilated patients receiving a sedation protocol conservative versus liberal fluid therapy strategy the rationale for a conservative fluid management strategy is based on the premise of minimizing nonessential fluid and active removal of excess fluid once physiologic stability was achieved recent level i evidence found that a conservative fluid strategy, compared with a liberal fluid strategy, resulted in a nonsignificant reduction in mortality and significant shorter durations of mechanical ventilation, icu stay, and trends for lower utilization of rrt. these findings were similar for the subgroup with aki prone positioning ards is often a heterogeneous syndrome with worse air space consolidation in basal (dependent) lung segments. the rationale for prone positioning is to improve v/q matching and reduce vili by having patients in prone position for - h per day prior trials have found prone positioning improves oxygenation; and recent level i evidence found a strategy of early prone positioning was associated with improved survival at and days. prone positioning should be protocolized the rationale for inhaled vasodilators, by reducing pvr and improving v/q matching in ards, can improve oxygenation meta-analyses of small randomized trials have found no improvement in mortality with inhaled vasodilators for ards; however, it was associated with transient improvements in oxygenation and increased risk of aki. inhaled vasodilators are a reasonable salvage therapy for refractory hypoxemia highfrequency oscillatory ventilation (hfov) the premise for hfov is to utilize subanatomical tidal volumes, high mean airway pressures, and high respiratory rates to maintain open lung ventilation, minimize the risk of vili, and allow lungs injury to recover recent level i evidence found early utilization of hfov, compared with standard lung protective ventilation, was associated with increased in-hospital mortality, greater use of sedation, neuromuscular blockade, and vasoactive therapy. hfov should be reserved for salvage therapy in those with refractory hypoxemia extracorporeal membrane oxygenation (ecmo) candidates should have potentially reversible respiratory failure, severe hypoxemia (murray score > . ), ideally venovenous circuit via dual-lumen catheter, early referral to experienced centers ecmo has generally been reserved as salvage therapy for adult patients; however, recent level i evidence from randomized trials and observational data during the ph n pandemic found reasonable survival fluid therapy is perhaps the most common intervention received by critically ill patients. the key concept for dosing fluid therapy in critically ill patients is to actively address ongoing losses coupled with constant reassessment of need for further hemodynamic support. while the optimal endpoints for fluid therapy during resuscitation remain controversial, increasing evidence suggests that resuscitation needs to be individualized and that the integration of functional hemodynamic measures to guide fluid responsiveness are superior to static measures of volume status. fluid therapy also represents a central cornerstone for the prevention and/or the management of aki. of the numerous strategies evaluated to date for prevention of aki, only fluid therapy has been shown to be consistently effective. importantly, however, there is no evidence that fluid therapy will reverse aki once established. reduced urine output is common and often precedes overt aki; however, it lacks specificity. oliguria in the absence of clear hypovolemia or fluid responsiveness is not necessarily an indication for a fluid challenge. the distinction is important. in the context of hypovolemia and/or reduced arterial filling, fluid therapy would appear appropriate. however, there is no evidence to support a fluid challenge in the resuscitated patient with oliguric aki. while such a fluid challenge may be intended to promote diuresis, dilute tubular toxins, and attenuate tubular obstruction from casts, there is no data to suggest it attenuates the severity of aki or improves clinical outcome. instead, the liberal use of fluid therapy in these circumstances may exacerbate fluid overload and lead to harm. fluid accumulation can also mask the presence and severity of aki by increasing the total body water and hemodiluting creatinine. recent evidence suggests that classifying aki after correcting creatinine concentration for the volume of fluid administered improves the ability to classify aki and predict mortality. unnecessary fluid accumulation and overload are associated with clear increases in morbidity, including worsening aki and delayed renal recovery, and mortality, in particular in patients with compromised kidney function across a range of clinical settings [ ] . diuretic therapy should be reserved for mitigating fluid overload in responsive patients rather than for preventing aki or promoting recovery of kidney function. in patients whose fluid balance cannot be managed adequately with conservative fluid administration or diuretic therapy, rrt should be considered. in addition, the routine practice of providing "maintenance" of unmeasured fluid deficits such as "third space losses" for the majority of critically ill patients is questionable, in particular for those with ckd/ esrd, and often contributes unnecessary fluid accumulation. in addition, the types of fluid administrated are increasingly recognized as having dosedependent qualitative toxic effects. colloids are commonly used for acute resuscitation in critically ill patients. synthetic colloids, such as hydroxyethyl starch (hes), have appeal for resuscitation fluids based on the premise that they attenuate the inflammatory response, mitigate endothelial barrier dysfunction, improve microcirculatory flow, and contribute to more rapid hemodynamic stabilization; however, accumulated data have now suggested use of these fluids in critical illness is associated with dosedependent risk for severe aki requiring rrt, bleeding complications, and death (box . ). in addition, these solutions are prohibitively more numerous high-quality randomized trials in adults have no clear evidence of benefit for these therapies abbreviations: aki acute kidney injury, ards acute respiratory distress syndrome, ecmo extracorporeal membrane oxygenation, hfov high-frequency oscillatory ventilation, ino inhaled nitric oxide, nmb neuromuscular blockade, pvr pulmonary vascular resistance, rm recruitment maneuvers, vili ventilator-induced lung injury expensive when compared with crystalloids. albumin is routinely used for resuscitation in liver failure patients with spontaneous bacterial peritonitis for prevention of hepatorenal syndrome and limited clinical data suggest albumin may improve outcome in severe sepsis. resuscitation with high chloride concentration solutions (i.e., . % saline -strong ion difference: meq/l) can directly contribute to iatrogenic hyperchloremic metabolic acidosis. the physiologic stress with large volume resuscitation of chloride-rich solutions may be less tolerated in ckd patients. recent data have compared resuscitation with saline ( . %) to balanced crystalloid solutions (i.e., ringer's lactate, plasma-lyte). preferential use of these balanced solutions with a lower "chloride load" that more closely mimic the chloride content and strong ion difference of plasma has been associated with fewer metabolic complications (i.e., metabolic acidosis, hyperkalemia, hypernatremia), reduced blood product utilization, reduced aki, and need for rrt and cost savings [ ] (box . ) . there is uncertain benefit for supplemental intravenous bicarbonate therapy for treatment of metabolic acidosis. bicarbonate is commonly used in critical illness when confronted by severe metabolic acidosis (i.e., ph < . ); however, its use is guided by limited clinical evidence. bicarbonate supplementation intended to treat loss of bicarbonate from the buffer pool (i.e., renal tubular acidosis) would appear logical; however, its use to treat acidosis due to elevated lactate has been associated with increased mortality. bicarbonate administration ( - meq/kg) can transiently increase serum ph and serum bicarbonate; however, it may precipitate untoward adverse effects including worsening intracellular acidosis, extracellular accumulation of co , chloride is the predominant strong anion capable of modifying serum ph. increases in serum chloride concentration ( . % saline administration) will reduce sid and contribute to metabolic acidosis with normal anion gap. accumulation of organic acids (i.e., lactate, keto acids) will increase other strong anions and induce metabolic acidosis by lowering sid with a normal serum chloride concentration and elevated anion gap. and hypocalcemia. the current surviving sepsis guidelines do not recommend use of bicarbonate for serum ph > . in patients with lactic acidosis associated with severe sepsis. when bicarbonate is administered, consideration should be given for a slow infusion, allowance for adequate co removal, and correction of hypocalcemia along with reversal of the underlying contributing factor for the acidosis. malnutrition is an important contributor to increased morbidity and mortality in critical illness. critically ill patients, in particular those with premorbid comorbid disease such as ckd and those with acute organ dysfunction such as aki, can often present nutritionally at risk or overtly malnourished at the time of admission. critical illness is a physiologic state characterized by widespread system inflammation, metabolic derangement, and catabolism. in these circumstances, critically ill patients, in particular those already malnourished, may be unable to adequately absorb or utilize nutrients. this may be further compounded by added clearance of nutrients during rrt. the goal in critical illness is to provide sufficient nutritional support as to maintain homeostatic and metabolic needs without precipitating complications. importantly, determination of the optimal caloric intake for critically ill patients ideally should involve the interdisciplinary contributions of a dietician. dieticians can assist with ensuring optimal nutritional prescription for critically ill patients with aki or ckd/eskd as their course and therapies evolve (i.e., resolving organ dysfunction, recovering kidney function, transition from continuous to intermittent rrt). early nutritional support in critical illness will not be significantly modified by the presence of ckd; however, in patients with advanced ckd or esrd not supported with rrt, specialized enteric formulas are available that are more caloric dense ( kcal/ml), low in electrolytes (i.e., k + , po − , mg + ), and fluid restricted. the intent of these specialized formulations is to pro-vide adequate nutritional support while mitigating the development of metabolic complications or unnecessary fluid accumulation in patients with reduced gfr. in patients with aki, one of the few interventions proven to improve renal recovery is delivery of adequate nutritional support, and therefore, more recent guidelines discourage protein restriction in critically ill patients with aki and supplement protein further in patients receiving rrt [ ] . the preferred method for delivery of nutritional support is by the enteric route. this should be started early after icu admission (within - h). the rationale for prioritizing enteric delivery of nutrition (en) is based on the premise that it will preserve gut mucosal integrity, reduce bacterial and endotoxin translocation, and reduce the risk of gastrointestinal bleeding. however, critical illness, coupled with baseline susceptibilities (i.e., diabetes mellitus), may be associated with enteric feeding intolerance from gut dysmotility (i.e., medications, electrolyte disorders, comorbid disease) and suboptimal absorption (i.e., gut wall edema). two recent trials in critically ill patients have shown no incremental outcome benefit for a strategy of "trophic" feeds (i.e., - ml/h) during the first few days of critical illness. likewise, high-quality evidence to support a strategy of intentional "permissive hypofeeding" (target - % total caloric intake) is currently lacking and cannot be recommended. measures to improve the success of enteric nutritional support include use of prokinetic agents (i.e., dose-adjusted metoclopramide, domperidone), advancement of small bowel feeding tubes, elevation of the head of the bed (~ - °), and not using specified gastric residual thresholds that often result in suboptimal delivery of targeted feeds. if there remains intolerance to en and failure to meet nutritional targets with en, or there are other medical or surgical reasons to avoid en, current evidence would suggest starting total parenteral nutrition (tpn) after a period of several days. the optimal amount of protein supplementation in aki is unknown. current practice guideline recommendations are to avoid protein restriction in critically ill patients if the intent is to prevent worsening azotemia with the goal of preventing or delaying the initiation of rrt. indeed, patients with aki are often catabolic and require protein supplementation, in particular to account for the added clearance of amino acids while receiving rrt. there is insufficient data to suggest the use of routine micronutrient supplementation [ ] . in fact, there is an increased risk of mortality associated with the use of glutamine in patients with multiorgan failure. the acute stress of critical illness coupled with nutritional support can often precipitate stress-induced hyperglycemia. the avoidance of significant hyperglycemia, hypoglycemia, and variation in glycemic control is associated with improved outcomes. however, recent trials have suggested that tight glycemic control (tgc) with intensive insulin therapy (iit) (bg . - . mmol/l) may be associated with increased risk for hypoglycemia and worse outcome. accordingly, current practice guidelines recommend a more pragmatic and less intensive strategy targeting glycemic control between . and . mmol/l ( - mg/dl) (box . ). sepsis is an important precipitant of critical illness and commonly prompts acute hospitalization and admission to icu. data from the usrds suggest infection is the leading cause of death among patients with esrd. ckd patients may be more susceptible to development of infectious complications and sepsis for a number of reasons including: • presence and repeated access to indwelling central venous catheters (cvc) and arteriovenous fistulas (avp) for dialysis access • acquired immunodeficiency related to primary etiology of kidney disease • immune dysregulation related to retention of uremic toxins (i.e., defective host responses in phagocytic cells, lymphocytes, and antigen processing, dysbiosis of gut microflora) • repeated episodes of systemic inflammation related to altered gut permeability and bacterial/endotoxin translocation during dialysis this risk is further modified by additional factors such as comorbid disease (i.e., peripheral vascular disease and diabetes mellitus, smoking) and frequent interaction with health-care services (i.e., colonization with antimicrobial-resistant the utilization of indwelling access catheters is a significant source of bloodstream infection and sepsis in ckd/esrd patients, is directly related to the duration of usage, is most commonly caused by gram-positive organism (coagulase-negative staphylococcus, staphylococcus aureus), and is associated with considerably higher risk of morbidity and mortality. the risk is two-to threefold higher for nontunneled (most commonly inserted in the icu) compared with tunneled catheters. for esrd patients receiving dialysis via tunneled catheters, the risk of bloodstream infection, infectionrelated hospitalization, and infection-related death is further two-to threefold higher than for those receiving hemodialysis via arteriovenous fistulas or grafts. important morbidity from temporary catheters arises from the risk of development of metastatic foci of infection from highly virulent bacteria, such as staphylococcus aureus, and includes endocarditis, septic arthritis, osteoarthritis, and epidural abscess. the most common sources of non-dialysisrelated infections among ckd/esrd patients are: • upper and lower respiratory tract infections (i.e., community and/or hospital-acquired) • genitourinary infections (i.e., pyocystis, pyelonephritis, perinephric infection) • cellulitis/osteomyelitis • gastrointestinal infections (i.e., clostridium difficile, cholangitis, hepatitis, gastroenteritis, diverticulitis, cholangitis) • central nervous systems infections (i.e., mucormycosis) pneumonia is a common contributor to morbidity and mortality in ckd/esrd patients. the risk of developing pneumonia is - times higher among ckd/esrd patients compared with matched population with normal kidney function and is associated with a higher likelihood of icu admission and - times the total duration of hospitalization. the prevalence of asymptomatic pyuria among ckd/eskd patients with residual urine production is common ( - %) but of undeter-mined significance, and the diagnosis of genitourinary infection mandates the presence of a positive culture result. indeed, genitourinary infections may be the most common source of nosocomial infection occurring in hospitalized ckd/esrd patients due primarily to urinary catheterization. these sources of infection may predispose to bloodstream infection in susceptible ckd/esrd patients and necessitate icu referral for resuscitation and hemodynamic support. in anuric esrd patients, urinary catheterization except for diagnostic indications should be avoided. cellulitis is a common precipitant of infection in ckd/esrd patients often predisposed by poor peripheral circulation (i.e., diabetes mellitus, peripheral vascular disease) coupled with extravascular peripheral edema or infection introduced through repeated puncture of the native vascular access. by extension, suboptimally treated cellulitis may result in osteomyelitis of adjacent bony structures. severe cellulitis may present with bloodstream infection in susceptible ckd/esrd patients and prompt icu admission. the incidence of common gastrointestinal infections in ckd/esrd patients is similar to the general population; however, their physiologic reserve to withstand these infections may be severely blunted and further predispose to added morbidity. the exceptions include susceptibility to infectious hepatitis (hepatitis b and c virus), peritonitis among patients receiving peritoneal dialysis, and clostridium difficile colitis due to frequent antimicrobial exposure and interaction with health services. sepsis is defined as the presence of infection together with systemic manifestations of inflammation. severe sepsis is defined as sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion, and septic shock is defined as severe sepsis plus hypotension not reversed with fluid resuscitation [ ] . the diagnostic criteria for sepsis and sepsis-related organ dysfunction are shown in box . . it is important to recognize that many of these criteria may be modified due to ckd/esrd and its treatment alone (i.e., dialysis-induced endotoxemia or hypotension) or due to concomitant comorbid disease (i.e., reduced cardiac reserve due to cardiorenal syndrome, autonomic dysfunction due to diabetes mellitus), drug therapy (i.e., β-blockers, coumadin), or not being applicable (i.e., serum creatinine elevation or oliguria in anuric eskd). the general principles and initial management of sepsis in ckd/esrd patients are similar to the acute resuscitation of patients with suspected sepsis and aki without kidney disease (boxes . and . ). early "bundled" resuscitation coupled with prompt broad-spectrum antimicrobial therapy and source control should be established in accordance with clinical practice guidelines [ ] . if there is suspicion that the source of sepsis is a vascular access catheter, this should be promptly removed once further central venous access has been confirmed. acute kidney injury (aki) is a common complication encountered in hospitalized patients, particularly in the setting of critical illness, occurring in up to two-thirds of patients [ ] . recently, the kdigo clinical practice guidelines for acute kidney injury published updated consensus criteria for the diagnosis and staging of aki [ ] (table . ). these criteria do not currently integrate evolving novel diagnostic biomarkers specific for kidney damage (i.e., ngal, kim- , il- , l-fabp). yet, these novel biomarkers show significant promise to improve the capacity for early diagnosis, prognostication, and informed decision-making in aki by helping to better discriminate etiology of loss of kidney function (i.e., aki vs. ckd), risk of worsening aki and need for rrt, and longterm risk of ckd. development of aki portends a worse clinical prognosis in critically ill patients and predicts such adverse outcomes as need for renal replacement therapy (rrt), prolonged icu and hospital stay, and increased mortality risk [ ] . importantly, for the ckd patients developing acute-on-chronic aki, the risk of worsened ckd and accelerated decline in function toward esrd is increased several fold. more severe forms of aki are also associated with gradient increases in the risk of death and/or non-recovery of kidney function and dialysis dependence [ ] . infection (confirmed or suspected) plus some of the following criteria: general variables fever (> . °c) or hypothermia (< . °c) heart rate > /min or more than standard deviations above normal for age tachypnea altered mental status significant edema or positive fluid balance (> ml/kg over h) hyperglycemia (blood glucose > . mmol/l) in the absence of dm leukocytosis (wbc > , /μl) or leukopenia (wbc < , /μl) or > % immature forms plasma c-reactive protein more than standard deviations above the normal value plasma procalcitonin more than standard deviations above the normal value aki is a syndrome with a spectrum of contributing factors. the risk factors for development of aki are often multidimensional and are related to synergy between premorbid susceptibility (i.e., older age, ckd, diabetes mellitus, hypertension, liver disease) and factors contributing to critical illness (i.e., sepsis, shock states, diagnostic procedures involving contrast media, major surgery) [ , ] . the diagnostic evaluation of aki should box . to be completed within h • measure serum lactate. • obtain blood cultures prior to administration of antimicrobials. • administer broad-spectrum antimicrobials. • administer ml/kg crystalloid for hypotension or lactate ≥ mmol/l. to be completed within h • administer vasopressors (for hypotension not responsive to initial fluid resuscitation) to maintain a mean arterial pressure (map) ≥ mmhg. central venous oxygenation (scvo ) and resuscitate to target cvp ≥ cmh o and scvo ≥ %. • remeasure serum lactate if initial value was elevated and resuscitate to target normalization. antimicrobial therapy and source control • aim to administer broad-spectrum "effective" intravenous antimicrobial therapy within the first h of recognition of sepsis. each h delay in administration of appropriate antimicrobials during the first h is associated with an % decrease in survival. • initial short-term ( - days) administration of empiric combination antimicrobial therapy should be undertaken for severe sepsis/ septic shock or difficult-to-treat sources of infection or suspicion of multidrug-resistant organisms. • evaluation for a specific anatomical diagnosis of infection should be undertaken for consideration for emergent (within - h) source control measures (i.e., surgical for septic arthritis, catheter removal for bloodstream infection, chest thoracostomy tube insertion for empyema). delay to source control when present is also associated with significant decrease in survival. source: reproduced with kind permission from springer science and business media: dellinger et al. [ ] box . . relevant clinical practice guidelines integrate routine biochemistry, urinalysis and imaging where indicated to rule out immediately reversible etiologies (i.e., post-obstructive) or those requiring specialized interventions (i.e., vasculitis). an understanding of the pathophysiology of aki is important to provide appropriate management for these patients. our current understanding of the pathophysiologic mechanisms contributing to aki remains incomplete; however, contrary to the conventional view, recent data argue against ischemia-reperfusion as the predominant pathophysiologic mechanism contributing to aki. the causal role of alternations in renal blood flow, microcirculation, and endothelial function, immune cell infiltration and activation, immunemediated toxic injury and apoptosis, and inflammatory mediator-induced organ cross talk is only beginning to be better understood. the general strategies for prevention and management of aki are similar for those with and without ckd [ ] (table . ). specific interventions for prevention and treatment of established aki are few and most have focused on preventing development of contrast-induced aki in susceptible patients such as those with ckd. several specific examples of mitigating risk of developing aki or its complications are outlined in table . [ , ] . renal replacement therapy (rrt) is a vital, life-sustaining, and organ support technology applied in approximately - % of all critically ill patients and in approximately % of those with more severe forms of aki [ ] . however, rrt also increases the complexity and health resource use for critically ill patients, and recent data have suggested its utilization may be associated with higher risk of death and dialysis dependence among survivors. these data highlight the existing uncertainty regarding many aspects of the decision to initiate and process of delivery of rrt to critically ill patients. current guidelines recommend the utilization of an uncuffed, non-tunneled dialysis catheter for acute rrt in the icu. the position of these acute catheters should avoid insertion in the subclavian vessels to mitigate the risk of long-term complications such as stenosis/thrombosis. existing tunneled dialysis catheters may be used if already in situ; however, use of fistulas or grafts in acute critical care settings, in particular for crrt, should be avoided. the optimal time to start rrt in critically ill patients with aki and/or ckd is currently unknown. there is general consensus that rrt should be urgently initiated in the presence of life-threatening complications related to aki such as severe electrolyte abnormalities (i.e., hyperkalemia), acid-base disturbances (i.e., academia), and fluid balance (i.e., pulmonary edema); however, outside of these indications, the optimal time to start is uncertain [ ] (table . ). it is likely more important to evaluate the broad clinical context of critically ill patients' admission diagnosis, illness severity, non-kidney organ dysfunction, the probability of worsening aki or non-recovery, and additional conditions that may be modified by rrt (i.e., fluid accumulation) rather than reliance on absolute thresholds in conventional biochemical markers such as creatinine or urea. early initiation of rrt in patients with aki or advanced ckd has the intuitive appeal of avoiding lifethreatening aki complications while ensuring the adequate delivery of essential medications (i.e., antimicrobials) and nutrition and transfusion support without concern for excessive fluid accumulation. recent systematic reviews have supported this concept, suggesting earlier rrt initiation may improve survival; however, studies included in these analyses were highly susceptible to bias [ , ] . the choice of ideal rrt modality for critically ill patients has long been debated. systematic reviews have not shown a clear survival advantage monitor daily fluid intake/output and daily/cumulative fluid balance, recognizing there is some "ebb and flow" to fluid balance in critical illness monitor for/avoid complications of overt kidney failure monitor aki and ckd patients for serious complications such as hyperkalemia, acidemia, fluid overload, and drug toxicities and appropriately plan for rrt maintain glycemic control glycemic control has been associated with reduced incidence of aki and lower utilization of rrt. the balance of evidence now recommends maintaining glycemic control with a target blood glucose (bg) of . - . mmol/l ( - mg/dl) rather than using intensive insulin therapy (iit) to maintain tight glycemic control, with bg of . - . mmol/l ( - mg/dl), due to the increased risk of hypoglycemia a there should be early use of invasive/functional hemodynamic monitoring (i.e., arterial catheter, central venous pressure, echocardiography, pulmonary artery catheter, or methods to measure stroke volume or pulse pressure variation) for one modality, continuous rrt (crrt), slow low-efficiency dialysis (sled), or intermittent rrt (irrt), over another in critically ill patients with aki [ ] (table . ) . ideally, the modality chosen should suit the patient's acute physiology and therapeutic objectives while avoiding treatment-related complications. crrt is the preferred modality in hemodynamically unstable patients and those with acute brain injury or fulminant hepatic failure and at risk for intracranial hypertension and cerebral edema [ ] . crrt has also been shown superior for maintaining fluid homeostasis and mitigating fluid overload. a recent systematic review suggested that initial therapy with crrt in critically ill patients is associated with lower rates of dialysis dependence among survivors when compared with irrt [ ] . these data may imply crrt may be the preferred initial modality for surviving critically ill patients at increased risk for incident or worsening ckd (i.e., those with baseline ckd). the optimal mode of crrt to improve outcome remains uncertain. the purported advantages to hemofiltration (cvvh) compared with hemodialysis (cvvhd) are the improved convective clearance of middle molecular weight solutes such as inflammatory and toxic mediators. recent data have suggested equivalent outcomes in terms of survival and recovery of kidney function; however, cvvh may be associated with short filter lifespan compared with cvvhd [ ] . the optimal time to transition from crrt to either sled or irrt is currently unknown; however, it pragmatically will coincide with physiologic stabilization and following weaning from vasoactive support. the utilization of peritoneal dialysis in critical illness may be impractical and result in insufficient solute clearance in catabolic patients and inadequate fluid removal. these factors may have contributed to the observation of higher mortality for critically ill patients treated with acei and arb lead to reduction in glomerular blood flow, which has beneficial effects for kidney survival in chronic kidney disease patients but may lead to worsening kidney function in patients with aki peritoneal dialysis compared with those treated with hemodialysis. determination of the optimal dose intensity for small solute clearance for critically ill patients with aki has long been a clinical priority. early randomized trials clearly favored a more intensive strategy; however, recent high-quality data have not shown a benefit with this approach. two multicenter randomized trials, the department of veterans affairs/national institutes of health (va/nih) acute renal failure trial network (atn) study and the randomized evaluation of normal versus augmented level (renal) replacement therapy study, found no incremental benefit in critically ill patients with aki from a more intensive (high-dose) rrt compared with a less intensive rrt strategy [ , ] . the more intensive strategy did not decrease mortality, accelerate recovery of kidney function, or alter the rate of nonrenal organ failure. importantly, these findings do not imply that the dose of rrt is not important, but rather, the evidence would these indications in critical illness may occur separately from patients with either life-threatening complications of aki or advanced aki and rather can be viewed as a platform for organ support to prevent complications and facilitate treatment volume homeostasis fluid accumulation is worse in aki and is associated with worse outcome. rrt may represent part of a strategy to mitigate excessive fluid accumulation nutritional support rrt can better enable the delivery of full nutritional support (i.e., enteral or parenteral) without the concern for excessive fluid accumulation acid-base/electrolyte homeostasis rrt may represent part of a strategy to enable "permissive hypercapnia" in icu patients with severe ards and aki/ckd or mitigate adverse effects from anticipated electrolyte disorders (i.e., tumor lysis syndrome) immunomodulation rrt may represent a strategy for modulating and restoring immune function in sepsis and associated severe inflammatory states. studies are ongoing drug delivery rrt can better enable the delivery of essential drugs (i.e., antimicrobials) without the concern for excessive fluid accumulation in general, rrt should be discontinued when it is no longer indicated due to either sufficient residual or recovering kidney function or a change in the overall goals of care of the patient. the best predictor for successful weaning from rrt for critically ill patients is the volume of spontaneous urine production in h. those capable of producing ≥ - ml urine per day have a higher likelihood of short-term recovery and dialysis independence. there is no evidence to suggest improved or accelerated recovery and dialysis independence with early forced diuresis with furosemide. drug pharmacokinetics in critical illness and aki is significantly modified due to alterations in drug bioavailability, reduced protein binding, increased volume of distribution, altered biotransformation, and reduced intrinsic clearance and elimination. appropriate drug dosing is further complicated by a number of factors, including baseline comorbid disease of patients (i.e., ckd), need for multiple drugs that potentially interact with vital functions, lower thresholds for toxicity, evolving illness severity and organ dysfunction (i.e., changes in gfr), and superimposed extracorporeal drug removal (table . ). in general, there are several pragmatic steps to help guide drug dosing in critically ill patients with aki and those receiving rrt [ ] . first, the literature should be reviewed for existing data on drug dose guidance for a specific drug [ ] . second, for drugs with primary renal elimination, a bedside estimate of baseline gfr and a dynamic assessment of total creatinine clearance, if applicable, should be undertaken, assuming there is no significant secretion or reabsorption. in particular, consideration should be given to patients receiving rrt who have recovering or residual renal function. third, particularly for drugs with a narrow therapeutic index and risk of toxicity, therapeutic drug monitoring when possible should be undertaken (i.e., phenytoin, vancomycin, aminoglycosides). fourth, several drug classes may be administered based on their observed clinical response, such as with sedatives, analgesics, or vasoactive medications. however, selected drugs have potentially toxic metabolites that can accumulate in patients with reduced kidney function. as examples, the elimination of α -hydroxymidazolam (main metabolite of midazolam) and glucuronide metabolites of morphine are principally eliminated by the kidneys and thus may accumulate in aki/ckd. finally, given the complexity, there is a recognized need for a dedicated icu pharmacist among the interdisciplinary icu team, particularly for patients with ckd or aki. the prevalence of ckd and esrd is increasing. these patients are burdened by high comorbid disease, are more likely to interact with critical care services, and have worse short-term and long-term outcomes compared with non-ckd patients. short-term mortality is predominantly driven by acuity of illness rather than ckd status per se, and ckd status should likely not preclude critical care support. the pathophysiologic changes associated with ckd/eskd and development of superimposed aki can present unique challenges for clinicians in the icu management of these patients. only drug within intravascular compartment available for ec clearance extracorporeal therapy dose intensity higher dose intensity, such as prescription of hvhf, will increase ec clearance; clearance impacted if large discrepancy between prescribed and delivered dose bfr higher blood flow rate will deliver more drug to filter, only important at either very low or high blood flow or large discrepancy between prescribed and delivered dose mode (convention vs. dialysis) ec clearance dependent on total effluent flow rate and/or dialysate flow rate replacement fluid prefilter replacement fluid administration will result in hemodilution and lower ec clearance filter membrane sieving/diffusion coefficient important, whereas surface area has limited impact on ec clearance organ recovery residual or recovery kidney function can greatly increase overall clearance during extracorporeal therapy before you finish: practice pearls for the clinician • ckd and specially esrd status alone should not exclude consideration for admission in the icu. • prognostic score results should be carefully considered since they routinely overestimate mortality in esrd patients. • the principles of management of sepsis should be applied to ckd, fluid overload being an obvious caveat. • fluid therapy should be considered a drug therapy and dosed accordingly. • long-term kidney function monitoring is mandatory after an aki episode. • consider initiation of rrt ahead of absolute indications. crrt is the preferred option for the hemodynamically unstable patient. • avoid nephrotoxic drugs for patients with ckd and/or at risk for aki. • adjust drug regimens to kidney function, except for the loading dose of antibiotics. chronic kidney disease: kidney disease: improving global outcomes (kdigo) chronic kidney disease working group. kdigo clinical practice guideline for the evaluation and management of chronic kidney disease surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock european society of intensive care medicine. consensus statement of the esicm task force on colloid volume therapy in critically ill patients nutritional support: critical care nutrition -canadian clinical practice guidelines patients with end-stage renal disease admitted to the intensive care unit: systematic review hemodynamic monitoring in the critically ill: spanning the range of kidney function mechanical ventilation and the kidney updates in the management of acute lung injury: a focus on the overlap between aki and ards fluid balance and acute kidney injury chloride-restrictive fluid administration and incidence of acute kidney injury-reply consensus statement of the esicm task force on colloid volume therapy in critically ill patients espen guidelines on parenteral nutrition: adult renal failure surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: kidney disease: improving global outcomes (kdigo) chronic kidney disease work group. kdigo clinical practice guideline for the evaluation and management of chronic kidney disease kidney disease: improving global outcomes (kdigo) acute kidney injury work group. kdigo clinical practice guideline for acute kidney injury acute kidney injury acute renal failure in critically ill patients: a multinational, multicenter study chronic dialysis and death among survivors of acute kidney injury requiring dialysis prevention of acute kidney injury and protection of renal function in the intensive care unit. expert opinion of the working group for nephrology, esicm a comparison of early versus late initiation of renal replacement therapy in critically ill patients with acute kidney injury: a systematic review and meta-analysis timing of renal replacement therapy initiation in acute renal failure: a metaanalysis continuous versus intermittent renal replacement therapy for critically ill patients with acute kidney injury: a meta-analysis choice of renal replacement therapy modality and dialysis dependence after acute kidney injury: a systematic review and meta-analysis hemofiltration compared to hemodialysis for acute kidney injury: systematic review and meta-analysis intensity of continuous renal-replacement therapy in critically ill patients intensity of renal support in critically ill patients with acute kidney injury drug dosing consideration in patients with acute and chronic kidney disease-a clinical update from kidney disease: improving global outcomes (kdigo) antimicrobial dosing concepts and recommendations for critically ill adult patients receiving continuous renal replacement therapy or intermittent hemodialysis key: cord- -lleti n authors: kassutto, stacey m.; kayser, joshua b. title: care of the surgical icu patient with chronic obstructive pulmonary disease and pulmonary hypertension date: - - journal: principles of adult surgical critical care doi: . / - - - - _ sha: doc_id: cord_uid: lleti n chronic obstructive pulmonary disease (copd) is a progressive chronic disease characterized by airflow limitation that is frequently progressive and associated with respiratory impairment. as the fourth leading cause of death in the united states and europe, copd results in a substantial and ever increasing economic and social burden [ ]. acute exacerbations of chronic obstructive pulmonary disease (aecopd) are frequently encountered in the intensive care unit (icu). although there is no standardized definition, aecopd are characterized by a significant change in patient symptoms from baseline accompanied by overall increased airway resistance [ ]. these exacerbations carry a significant risk to patients, with % in-hospital mortality and -year and -year all-cause mortality rates of % and %, respectively, in patients with hypercapnic exacerbations [ ]. other studies note in-hospital mortality rates as high as % with worse outcomes associated with older age, severity of respiratory and non-respiratory organ dysfunction, and hospital length of stay [ ]. given that patients transferred to the icu with aecopd are at high risk for complications and adverse outcomes, early diagnosis and management are critical to improve patient outcomes and survival in this population. aecopd are the result of increased airway resistance as a consequence of inflammation and/or increased airway secretions. data suggests that - % of aecopd are due to respiratory infections, with greater than % being due to bacterial pathogens. the most commonly isolated organisms include haemophilus influenza, streptococcus pneumonia, moraxella catarrhalis, and pseudomonas aeruginosa. gram-negative rods are isolated less frequently but are more common in patients with advanced disease and more severe exacerbations as well as those with diabetes. patients may be chronically colonized with bacteria in the respiratory tract, but it is unclear whether asymptomatic colonization leads to exacerbations caused by the same bacterial strains or predisposes to new bacterial growth. atypical bacteria such as mycoplasma pneumonia may be responsible for up to % of exacerbations [ , ] . viral infections are estimated to cause - % of exacerbations. however, many patients with documented bacterial infections report a viral prodrome, making the true prevalence of viral illness difficult to estimate. estimates indicate that rhinovirus ( - %) , influenza ( - %), parainfluenza ( - %), and respiratory syncytial virus ( - %) are among the most common viral pathogens in aecopd. adenovirus, human metapneumovirus, and coronavirus are also potential but less common culprits. in many cases the exact precipitant of an exacerbation may never be identified [ , [ ] [ ] [ ] . prior need for mechanical ventilation. patients with severe exacerbations presenting to the icu will often have signs of increased work of breathing including accessory muscle use, paradoxical chest or abdominal wall movements, cyanosis, altered mental status, and hemodynamic instability [ ] . a focused cardiopulmonary exam is recommended with close attention to work of breathing including use of accessory respiratory muscles, ability to speak in complete sentences, degree of air movement and adventitious lung sounds on auscultation, evidence of volume overload including jugular venous distension (jvd) and peripheral edema, presence of cardiac arrhythmias, and cyanosis. the patient's mental status and hemodynamic stability should also be assessed. the severity of aecopd varies greatly. mild exacerbations may be managed as an outpatient whereas others with the most severe presentations will require close monitoring in the icu setting. table . summarizes indications for icu admission. the bap- is a novel scoring system developed to risk stratify the need for mechanical intubation and mortality rate of hospitalized patients with aecopd (see table . ). although useful as a risk stratification tool, the decision to admit a patient to the icu should be based on individual patient presentation and treatment center capabilities. the assessment is based on the presence of any of the following, with increased scores portending a worse prognosis [ ] : the initial evaluation of a patient with suspected aecopd admitted to the icu should be focused on assessing severity of illness, need for possible ventilatory support, and exclusion of other possible causes for respiratory distress. for all patients admitted to the icu with suspected aecopd, we recommend the following diagnostic elements [ ] : • continuous pulse oximetry • arterial blood gas (abg) • chest radiograph • electrocardiogram • basic metabolic panel (bmp) • complete blood count (cbc) • sputum culture (consider induced sputum sample for patients with minimal sputum production) this initial workup may be useful in differentiating copd from other cardiac and pulmonary causes of respiratory failure. important differential diagnoses in patients with severe dyspnea and/or impending respiratory failure include congestive heart failure, acute coronary syndrome, pulmonary embolism, cardiac arrhythmia, pneumothorax, pleural effusion, acute infectious processes such as bacterial or viral pneumonia, and exacerbations of other underlying pulmonary conditions such as interstitial lung disease. these conditions may coexist with or precipitate aecopd. thus, it is important to pursue a thorough diagnostic workup in tandem with ongoing therapeutic interventions. additional diagnostic measures including chest computerized tomography (ct), echocardiography, cardiac biomarkers, brain naturetic peptide (bnp), and respiratory viral molecular testing should be considered in the appropriate clinical setting. spirometry during an acute exacerbation is not recommended as it is likely to be both difficult for the patient to perform and provide an inaccurate assessment of lung function. systemic glucocorticoids are considered a cornerstone of therapy in aecopd, particularly in patients ill enough to warrant icu admission. although the optimal formulation, duration, and dosage of treatment remains unclear, studies have shown that systemic steroids accelerate improvement in airflow, gas exchange, and symptoms in addition to reducing the rate of treatment failure [ ] . a trial by niewoehner [ ] note: indications will vary by institution and ability to do noninvasive ventilation outside of the icu and colleagues demonstrated that there was no benefit of weeks of steroid treatment compared to weeks [ ] . although some studies in patients with aecopd suggest that a -day regimen of mg of prednisone may be superior to days, no trials have clearly defined the optimal regimen for patients with severe exacerbations requiring icu admission [ ] . in general, we recommend intravenous steroid administration with . - . mg/kg methylprednisolone every h for h with tapering to twice daily and then daily over the course of - days as tolerated for patients with severe exacerbations admitted to the icu. in general, the duration of treatment should not exceed days. oral steroids are likely equivalent to intravenous formulations if the patient can take pills by mouth. careful monitoring for side effects including alterations in cognition, hyperglycemia, insomnia, fluid retention, and peptic ulcer formation is essential; routine h receptor antagonist or proton pump inhibitor prescription should accompany steroid therapy in those admitted to the icu [ ] . there are no controlled trials documenting efficacy of these agents. however, in general, combination short-acting inhaled beta- agonists (albuterol) with or without shortacting anticholinergics (ipratropium) every - h are recommended for the treatment of aecopd [ , ] . there is no evidence to support combination therapy, although albuterol and ipratropium are frequently used concurrently, particularly in patients requiring icu admission [ ] . for nonintubated patients admitted to the icu, we recommend these medications be administered in nebulized form as inhaler use is difficult for patients with significant respiratory distress. metered-dose inhalers should be used for patients requiring mechanical ventilation. as there is no evidence to support the addition of methylxanthines during an exacerbation, routine use is not recommended [ , ] . given that the majority of aecopd are thought to be due to bacterial infections, the empiric administration of antibiotics in patients with copd exacerbations has been frequently studied [ ] . antibiotic use during copd exacerbations reduces treatment failures, need for mechanical ventilation, risk for readmission, as well as mortality when administered in the inpatient setting [ ] [ ] [ ] . a study by anthonisen et al. showed that patients with increases in sputum production or changes in sputum color experienced a greater benefit from antibiotics [ ] . in addition, a study of patients with aecopd requiring mechanical ventilation showed that administration of a fluoroquinolone reduced mortality and the need for additional antibiotics when compared to placebo [ ] . therefore, antibiotics are recommended for patients admitted to the icu, particularly those requiring mechanical ventilation [ , ] . in uncomplicated patients, a beta-lactam, macrolide, or tetracycline antibiotic may be used [ ] . for most icu patients, we recommend a respiratory fluoroquinolone, third-or fourth-generation cephalosporin, or piperacillin/tazobactam. coverage for atypical bacteria with a macrolide or fluoroquinolone is also recommended if the patient lives in the community. broader coverage for nosocomial pathogens is recommended for patients residing in health-care settings and those who have had recent or repetitive contact with the hospital environment or therapeutic courses of antimicrobial agents. combination therapy is often necessary [ , , ] . see table . for antibiotic recommendations. in general, a total duration of days of antibiotics is usually appropriate. coverage may be tailored based on sputum culture results and sensitivities. there is no data to support the routine use of pharmacologic adjuncts or bronchoscopic mucus clearance techniques, although efforts to clear secretions via pulmonary toiletry and chest physiotherapy (e.g., percussion and postural drainage) are reasonable [ ] . oxygen supplementation is frequently necessary in aecopd. in order to maintain adequate cellular oxygenation while avoiding hypercapnia, careful monitoring and avoidance of over-supplementation is prudent. the goal is to maintain a pao > mmhg or spo of - %. values significantly above this provide little added benefit while potentially promoting co retention in this at-risk population. abgs should be checked frequently to identify any potential interval worsening of respiratory acidosis; vbgs may be a reasonable alternative to abg analysis when the focus of inquiry is ph-pco balance as opposed to oxygenation [ ] . many patients with aecopd will require respiratory support beyond supplemental oxygen. although endotracheal intubation may be required in severe cases, noninvasive positive-pressure ventilation (nppv) is a first choice treatment for patients with hypercapnic respiratory failure in severe aecopd and when there are no contraindications to noninvasive ventilation (see table . ). patients with clinical signs of respiratory muscle fatigue and/or increased work of breathing should also be considered for early nppv initiation. the success rate of nppv in randomized controlled trials of patients with severe aecopd has been documented as - %, with improvements in acute respiratory acidosis, tachypnea, work of breathing, and decreases in ventilatorassociated events [ , ] . previous studies demonstrated that the use of nppv was associated with a reduction in the overall need for endotracheal intubation, lower cost, reduced icu length of stay, and decreased overall icu mortality for patients placed on nppv [ , ] . nppv may not be efficacious in all patients with aecopd. in particular, patients with glasgow coma scale score < , acute physiology and chronic health evaluation (apache) score ≥ , respiratory rate ≥ , and admission ph < . have a failure rate of that exceeds %. close monitoring while on nppv is necessary and rapid clinical improvement is expected if nppv is likely to be of benefit. studies have shown that if the ph after h of nppv remains < . , there is a high likelihood of failure ( - %), and endotracheal intubation should be considered. conversely, if the ph and/or the paco improve within the first few hours of nppv, there is a significant probability of success [ ] . therefore, frequent monitoring with abgs and serial clinical exams is critically important. when interpreting abgs, the acuity of any respiratory acidosis should be considered given that many patients with copd have underlying chronic hypoxemia and/or hypercapnia. prior abgs or serum bicarbonate measurements during previous periods of stability may be useful for comparison. in addition, consideration of other coexisting acute or chronic conditions that might impact on acid-base balance (e.g., acute kidney injury or chronic kidney disease stage iii or greater) is also important to successful abg interpretation and clinical application. although nppv can rescue many from respiratory failure, invasive mechanical ventilation may be necessary in patients with particularly severe exacerbations. intubation should be considered in patients with nppv failure or contraindication, severe acidosis and hypercapnia (ph < . and/or pco > mmhg), life-threatening hypoxia, or tachypnea with impending evidence of acute respiratory failure [ ] . table . summarizes indications for invasive mechanical ventilation. in general, assist-control volume-cycled ventilation is recommended for patients with severe obstructive lung disease. this allows for careful control of minute ventilation, tidal volume, inspiratory flow rate, and expiratory flow time given the predisposition for this patient population to experience dynamic hyperinflation and ventilator-induced lung injury. specific recommendations for ventilator parameters are summarized in table . . it should be noted that no specific trials have been performed to determine optimal ventilator settings in patients with aecopd. it is likely that every patient will respond differently depending on the severity of underlying lung disease, existence and severity of other comorbidities, and degree of ventilator synchrony. careful titration and adjustment of ventilator settings at the bedside is often necessary given the dynamic nature of respiratory failure in this patient population. consultation with a pulmonologist with specific expertise in copd management may be necessary in select, severe cases in which ventilator management is a challenge. adjustments should not be made solely on the basis of gas exchange from abg results, rather in conjunction with close monitoring of the clinical exam including patient-ventilator synchrony, work of breathing, and hemodynamic parameters. sedation and analgesia are also important to successful ventilator management. auto-peep is an important consideration in patients with severe obstructive lung disease. positive end-expiratory pressure (peep) is the pressure in the alveolus at the end of exhalation. in patients with copd, increased airway resistance may result in incomplete deflation of the lungs prior to initiation of the next breath, causing the intra-alveolar volume and therefore pressure to remain elevated above that which is desired. this dynamic hyperinflation creates auto-peep (in contrast to the intentional application of extrinsic peep via mechanical ventilation). the presence of auto-peep is important as it can increase the work of breathing, trigger patient-ventilator dyssynchrony, and worsen gas exchange. auto-peep may result in misinterpretation of clinical data such as central venous or pulmonary arterial catheter measurements and lead to unnecessary treatments such as higher doses of sedative medications [ ] . auto-peep may also provoke hemodynamic compromise by increasing intrathoracic pressure that results in decreases in right and left ventricular preload, ultimately leading to arterial hypotension. misdiagnosis of the etiology of shock in this setting may lead to unnecessary fluid and vasopressor administration; failure to recognize and correct auto-peep may result in hemodynamic collapse and death. for this reason, any mechanically ventilated patient with copd and new onset hypotension should be assessed for the presence minute ventilation requirements will vary by patient, and settings for tidal volume and respiratory rate will need to be considered on an individual basis. high respiratory rates may provoke a shortened expiratory phase and lead to air trapping, auto-peep, and hemodynamic compromise of auto-peep. if hemodynamic compromise from auto-peep is present, disconnection from the ventilator circuit for - seconds should facilitate a release of air from the patient's pulmonary tree and improve hemodynamics. auto-peep can be monitored on the ventilator through the use of the end-expiratory hold maneuver (although accurate measurements require that the patient have no active respiratory effort) [ ] . auto-peep may also be identified by monitoring the flow-time trace where the exhilatory trace fails to return to baseline prior to the start of the next breath. significant auto-peep may be treated by careful ventilator management aimed at increasing the expiratory time to allow adequate emptying of the lungs. maneuvers include increasing the inspiratory flow rate and decreasing the respiratory rate or tidal volume. other methods for minimizing auto-peep include reduction of spontaneous ventilatory demand through the administration of sedation, analgesia, and occasionally paralytics. similarly, reducing flow resistance with larger bore endotracheal tubes, frequent suctioning, and bronchodilator administration may also reduce auto-peep by reducing resistance to gas flow. expiratory flow limitation can also be counterbalanced with the application of applied (external) peep to match the intrinsic (auto) peep [ ] . patients with severe underlying copd and exacerbations with resultant respiratory failure may experience difficulty weaning from the ventilator. goals of care discussions regarding tracheostomy, possible chronic mechanical ventilation needs, and advanced care planning may be necessary; palliative care consultation may be invaluable in this process. in general, patients with failure to progress in weaning toward possible extubation by the end of the second week of mechanical ventilation should be considered for tracheostomy as prolonged endotracheal intubation can result in upper airway injury. in patients with advanced copd, weaning from mechanical ventilation may require several weeks. strategies for ventilator weaning vary but typically consist of steadily increasing time on pressure support trials admixed with periods of assist-control volume-cycled ventilation for rest. the weaning process may be augmented by tracheostomy placement given the ability to perform tracheostomy collar trials with intermittent ventilator support rather than proceeding directly to extubation and independent ventilation. tracheostomy is also generally more comfortable for patients, thereby reducing sedation and analgesia needs that may accelerate weaning. nppv may also be an important salvage mode of ventilation for patients who initially fail extubation and only require intermittent ventilatory support. clinical decision-making regarding tracheostomy versus palliative extubation should be based on individual patient and family preferences. prognostication in this patient population is often challenging and complex but early involvement of palliative care consultants, where available, is recommended. an episode of respiratory failure should prompt discussions of patient care goals and values for both short-and long-term advanced care planning. when appropriate, formal hospice referrals should be considered. in all cases, sufficient treatment of dyspnea and pain should be provided. pulmonary hypertension (ph) refers to a complex group of clinical conditions defined by abnormal elevation of blood pressure in the pulmonary circulation. it is further defined as a mean pulmonary arterial pressure (mpap) of ≥ mmhg at rest on right heart catheterization (rhc) [ ] . typically ph is discussed in the context of true pulmonary arterial hypertension (pah) resulting from pressure elevations in the pulmonary arterial system or pulmonary venous hypertension (pvh) occurring secondary to pressure elevations in the pulmonary venous and capillary systems. pvh is typically seen in the setting of elevated pulmonary artery occlusion pressures (paop) resulting from volume overload in left ventricular (lv) failure. this distinction becomes important in understanding the pathophysiology of the disease and in treatment decisions. the world symposium on pulmonary hypertension updated its classification in to incorporate five groups of disorders (table . ) [ ] . the diagnostic evaluation and treatment of ph in the clinically stable patient is a separate topic and will not be addressed here. rather, the focus of this discussion will be on the pathophysiology, diagnostic evaluation, and treatment of ph and resulting right ventricular failure (rvf) as this is most commonly observed in the intensive care unit (icu) setting. pulmonary hypertension results from increases in pulmonary vascular resistance (pvr) present in both acute and chronic ph. rising pulmonary pressures create increases in afterload that are difficult for the rv to overcome. the right heart attempts to compensate for rising pressures by dilating acutely and hypertrophying chronically. however, these compensatory mechanisms are maladaptive, and the resulting volume overload that ensues as cardiac output declines ultimately leads to rvf. as the rv fails, stroke volume and cardiac output drop further, leading to cardiogenic shock. in the icu setting, rvf is typically acute but occasionally may be due to worsening of underlying chronic ph [ , ] . additional elements that may contribute to impaired cardiac function include compromised filling of the right coronary arteries due to elevated right-sided wall tension leading to myocardial ischemia, tricuspid valvular insufficiency, and bowing of the interventricular septum which impinges on lv diastolic filling (enlargement of the right heart due to increased pressure and volume displaces the interventricular septum toward the lv). because the heart functions in a fixed space within the pericardium, this displacement of the interventricular septum impedes lv filling, causing a further decrease in systemic stroke volume and cardiac output. this may result in hypotension and ultimately hemodynamic collapse [ , ] . in general the outcome for patients with ph admitted to the hospital with rv failure is poor, with an estimated mortality of - % for those requiring icu admission [ , ] . the majority of patients admitted to the icu with ph will have disease that is a result of underlying critical illness rather than preexisting ph. although not impossible, it is uncommon to diagnose de novo ph as the primary reason for icu admission except in the setting of acute pulmonary embolism. many triggering factors causing or aggravating rv failure include infection, anemia, injury, surgery, pregnancy, medical therapy nonadherence, pulmonary embolism, and arrhythmia. however, it is frequently the case that the exact trigger for decompensation is never identified. identification of an infection in this patient population at any time during the icu stay generally portends a poor prognosis [ , ] . acute rvf typically clinically presents with systemic congestion and/or low cardiac output. this usually manifests as chest pain, dyspnea, lightheadedness, syncope, altered mental status, cool extremities, and acute kidney injury. on exam, the jugular venous pressure will most often be elevated. other overt signs of volume overload include hepatomegaly, peripheral edema, ascites, and crackles on pulmonary auscultation. cardiac exam may reveal a rv heave, a tricuspid regurgitant murmur, an accentuated p , and/or an s or s gallop. in the icu, patients may present in extremis with tachycardia, tachypnea, hypoxia, hypotension, and shock as a result of inadequate cardiac output and elevated filling pressures [ , ] . the initial diagnostic workup of any patient admitted to the icu with known underlying ph with suspected decompensation or a possible new diagnosis of undifferentiated rvf should include the following: • infectious workup including chest radiograph and cultures of the blood, urine, and sputum when clinically indicated • basic laboratory evaluation including complete blood count (cbc) and comprehensive metabolic panel (cmp) to assess renal and hepatic function ongoing monitoring of end-organ perfusion including renal, hepatic, and neurological function is necessary. in addition, acute pulmonary embolism should be excluded in any patient with decompensated or acute rvf [ ] . in general, noninvasive testing and assessment of cardiac function are preferred prior to rhc. therefore, transthoracic echocardiography (tte) remains the cornerstone of the diagnostic evaluation in patients with suspected ph. assessment of both the pulmonary arterial systolic pressure (pasp) and rv structure and function is an important parameter in this evaluation. right atrial enlargement, pericardial effusion, low tricuspid annular plane systolic excursion (tapse), and septal displacement are poor prognostic indicators. in general, patients with an estimated pasp > mmhg or a peak tr jet velocity ≥ m/s are likely to have ph confirmed by rhc. however, rhc is the gold standard for confirming diagnosis of ph. invasive hemodynamic monitoring remains key to the ongoing evaluation and therapeutic management of these patients [ ] . in patients with confirmed or suspected ph and/or rv failure, a thoughtful, systematic, and multidisciplinary approach to medical management should be pursued. early consultation with an expert in pulmonary hypertension is advised as patients are often misdiagnosed and referred late for consideration of advanced therapies. consultation with ph experts may also be necessary to discern ph and rv failure from other causes of clinical decompensation. collaboration between local medical centers and ph specialty centers to facilitate referral and patient transfer when necessary is advised [ ] . careful monitoring of cardiac, renal, neurologic, and hepatic function is essential in the care of the patient with ph and/or rv failure. urine output, laboratory data (liver function tests, serum creatinine, lactate, troponin), and hemodynamic parameters obtained either from a central venous catheter (e.g., central venous pressure (cvp) and central venous saturation (scvo )) or pa catheter (right atrial pressure, cardiac index, mean pa pressure, pvr and mixed venous saturation (svo )) are useful in making management decisions. given their complexity, the use of rhc and ongoing invasive hemodynamic monitoring is recommended for patients with evidence of rv failure requiring icu admission, particularly in the setting of vasoactive agent titration [ ] . in general, management of acute rvf and severe ph in the critically ill patient focuses on optimization of rv preload, afterload, and contractility while also carefully controlling oxygenation, ventilation, and cardiac rhythm. the search for potentially reversible causes of decompensation is critical. if a specific cause of rv failure is identified, management should include consideration of one of the directed therapies listed in table . . consideration of acute pe is important in this population; however, its specific management will not be discussed here. careful attention to and evaluation of fluid status are critical in the management of ph. assessment based on clinical exam, cvp, and invasive hemodynamic monitoring with rhc may aid in accurate determination of volume status and fluid management. occasionally patients may be hypovolemic and require fluid administration. however, even in the case of suspected sepsis, overly judicious administration of fluids may have detrimental hemodynamic effects in patients with compromised rv function. thus, cautious administration is advised. a reasonable fluid challenge for a patient with acute rv dysfunction or acute ph is ml of a normotonic fluid over - min, with a general goal cvp target of - mmhg [ , , ] . more often than not, patients with rvf will be hypervolemic and require administration of intravenous (iv) diuretics or acute hemofiltration for volume removal. iv loop diuretics, potentially in the form of a continuous infusion to avoid abrupt swings in filling pressures, are preferred. extracorporeal fluid removal via ultrafiltration may be necessary in the presence of the cardiorenal syndrome and diuretic resistance. however, either of these generally portends a poor prognosis [ ] . afterload reduction with the use of pulmonary vasodilators remains an important consideration in severe ph and rv failure. however, systemic pah-specific therapies are discouraged in patients with ph of unknown etiology. pulmonary vasodilators may be considered in cases where immediate reduction of pvr is necessary [ ] . both iv medications with selective effects on the pulmonary vasculature and inhaled agents delivered directly to the lungs are available for this purpose. see table . for a summary of available vasodilatory medications for pah in the icu setting. oral agents including pde- inhibitors and endothelin receptor antagonists (eras) are typically not appropriate for use in the acute icu setting (except in selected treatmentnaïve pah patients who have been stabilized with iv prostanoids) and thus will not be covered in this chapter. it is important to note that treatment with pah-specific drugs has only been associated with improved outcomes in outpatients with chronic pah. given that few critically ill patients with ph and or rv failure will have underlying pah, many of these pah-specific drugs may not be warranted. in addition, no studies have demonstrated clinical superiority of one agent [ , , ] . one should also recall that systemic acidosis results in pulmonary arterial vasoconstriction. therefore, abrogation of acidosis may be a useful therapeutic goal using either augmented minute ventilation or intravenous fluids that influence ph such as those constructed entirely of, or supplemented with, sodium bicarbonate or sodium acetate (especially when nahco is in short supply). a variety of vasoactive drugs may be used in patients with rv failure and critical illness including vasodilators, inotropes, and/or vasopressors. the goal of therapy is to maintain end-organ perfusion through reduction in pvr without compromising systemic mean arterial pressure and increasing cardiac output. the selection of specific therapies or combinations thereof should be tailored to each patient, taking into account their hemodynamic, respiratory, and volume status. patients requiring initiation and titration of these therapies should have a pulmonary artery (pa) catheter placed for ongoing management optimization; while other hemodynamic monitoring techniques are available, none directly measure pa pressures. a combination of overstretching, derangements in cellular metabolism, and insufficient oxygen delivery lead to decreased rv contractility in the setting of critical illness. dobutamine, dopamine, and milrinone are the agents most commonly used for inotropic support in this patient population. see table . for a summary of the hemodynamic effects of commonly used vasoactive drugs. there is debate as to the first-line agent for inotropic support, but in general, dobutamine is preferred over dopamine for acute inotropic support in unstable patients in the icu, especially since dopamine is strongly pro-arrhythmogenic at higher doses. milrinone is also often strongly considered, particularly in patients with biventricular failure. however, caution should be exercised given the vasodilatory properties of both agents (dobutamine and milrinone) and their potential to provoke systemic hypotension. in some cases, concomitant administration of a vasopressor may be necessary to maintain systemic precapillary arteriolar sphincter tone, mean arterial pressure, and cardiac output. adequate systemic blood pressure is necessary to maintain coronary perfusion and cardiac function, and thus vasopressors may be a necessary first-line or adjunct therapy [ ] . as with inotropic support, careful selection of the most appropriate vasopressor will vary depending on the clinical scenario. the increased risk of tachyarrhythmias with all vasoactive agents is an important consideration given the potential hemodynamic impact on myocardial oxygen consumption, coronary artery flow demand, and rv filling time. the presence of atrioventricular synchrony is critical for optimal rv filling and maintenance of cardiac output. the presence of atrial arrhythmias (e.g., atrial fibrillation, atrial flutter, and supraventricular tachycardia) and electrical conduction delays (e.g., complete heart block) is associated with worse outcomes given that the rv is highly dependent on atrial contraction to maintain adequate filling. rate control alone is not typically sufficient and rhythm control is recommended. electrical cardioversion for tachyarrhythmias and atrioventricular (av) pacing for bradyarrhythmias are the first-line treatments for unstable patients. amiodarone is the recommended first-line medication for most tachyarrhythmias due to its lower risk of hypotension and comparatively fewer negative inotropic effects. the use of beta-blockers and calcium channel blockers is generally avoided given that both classes of agents may impair rv contractility as well as av nodal conduction [ , ] . hypoxemia and hypercapnia place additional strain on the heart by inducing hypoxic vasoconstriction with resultant increases in pvr and rv afterload. therefore, maintenance of normoxia (peripheral o saturation > %) and normocapnia (paco of - mmhg) is recommended. any other impedance to adequate oxygen delivery to the tissues should be corrected, including anemia if present (goal hgb > g/dl) [ , ] . in the setting of respiratory decline, every effort should be made to avoid invasive mechanical ventilation if possible. the risk for systemic hypotension and hemodynamic collapse during intubation as a result of sedative administration is significant. ongoing ventilator support with positive-pressure ventilation may also have untoward effects as the positive pressure increases intrathoracic pressure and may result in decreased venous return and hypotension. therefore, noninvasive ventilation should be considered prior to intubation if the patient's clinical condition is stable enough for a trial. however, if intubation is necessary, etomidate is the preferred drug for induction of general anesthesia given its minimal effect of cardiac contractility and vascular tone. one should recognize that controversy exists regarding the effects of etomidate on later adrenal function, and alternative agents should be considered dictated by provider training and agent availability. preemptive administration of vasopressors and or inotropes prior to intubation to offset the commonly induced hypotension should also be considered [ , ] . in select patients with medically refractory ph and/or rvf, advanced therapies including mechanical circulatory support and bilateral lung transplantation may be considered. right ventricular assist devices may be used as a bridge to durable mechanical support or as a bridge to recovery. they have been successfully used in the treatment of rv failure due to myocardial infarction, cardiopulmonary bypass, left ventricular assist device implantation, and cardiac transplant [ ] . extracorporeal membrane oxygenation (ecmo) has been used successfully to treat rv failure due to massive pe, chronic thromboembolic pulmonary hypertension (cteph), and pah as a bridge to endarterectomy or lung transplantation. typically venoarterial (va) ecmo is utilized to unload the rv while maintaining systemic oxygenation. in patients with pah, it may also be used to support the rv during initiation of pulmonary vasodilator therapy. however, complications including hemorrhage, infection, anemia, thrombocytopenia, thromboembolism, and neurologic sequelae are possible [ ] . percutaneous interventions such as balloon atrioseptostomy (bas) may be used as either a bridge to lung transplantation or as palliative therapy. the procedure works by creating an atrial level right-to-left shunt that bypasses the obstructed pulmonary circulation, allowing for improved lv filling, systemic oxygenation, and blood flow. however, its use as an emergent rescue therapy is not recommended given the high risk for fatal complications in patients with markedly elevated rv filling pressures and/or low oxygen saturations [ , ] . lung and or heart-lung transplantation is an important treatment option for patients with progressive ph, particularly in the presence of rv failure. bilateral lung transplantation may be considered in select cases with dual heart-lung transplant reserved for selected patients with severe irreversible ph and concomitant severe cardiac disease. indications and contraindications for transplant will not be reviewed herein as its consideration is complex and uncommon in the typical icu setting [ , ] . patients with end-stage rvf who are refractory to medical therapy and not candidates for advanced therapies have a poor prognosis and are unlikely to survive cardiac arrest. therefore, in patients with ph and rv dysfunction, early conversations regarding patient preferences and goals of care are essential, particularly in the icu setting. recommendations for limiting life-sustaining therapies may be appropriate. palliative care and hospice should be considered in the correct setting. patients with pulmonary hypertension have significantly elevated morbidity and mortality associated with surgery and anesthesia, in large part due to fluid shifts, mechanical ventilation, and inflammatory mediator release that results in the setting of surgical interventions [ , ] . both cardiac and noncardiac surgical patients with ph have higher incidences of postoperative congestive heart failure, hemodynamic instability, sepsis, respiratory failure, and in-hospital death. given the associated risks, nonemergent surgeries should generally be avoided in the setting of ph-induced rv failure [ ] [ ] [ ] . standards for the diagnosis and treatment of patients with copd: a summary of the ats/ers position paper copd exacerbations: ( ) aetiology outcomes following acute exacerbations of severe chronic obstructive lung disease. the support investigators (study to understand prognoses and preferences for outcomes and risks of treatments) hospital and -year survival of patients admitted to intensive care units with acute exacerbations of chronic obstructive pulmonary disease infection in the pathogenesis and course of chronic obstructive pulmonary disease prevalence of viral infection detected by pcr and rt-pcr in patients with acute exacerbation of copd: a systematic review pathophysiology of acute exacerbations of chronic obstructive pulmonary disease global strategy for the diagnosis, management and prevention of copd, global initiative for chronic obstructive lung disease (gold) global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease: gold executive summary validation of a novel risk score for severity of illness in acute exacerbations of copd clinical practice: acute exacerbations of chronic obstructive pulmonary disease effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the reduce randomized clinical trial acute respiratory failure due to chronic obstructive pulmonary disease exacerbations of chronic obstructive pulmonary disease contemporary management of acute exacerbations of copd: a systematic review and meta-analysis antibiotic therapy and treatment failure in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease association between antibiotic treatment and outcomes in patients hospitalized with acute exacerbation of copd treated with systemic steroids antibiotic therapy in exacerbations of chronic obstructive pulmonary disease once daily ofloxacin in chronic obstructive pulmonary disease exacerbation requiring mechanical ventilation: a randomized placebo-controlled trial non-invasive ventilation in acute respiratory failure noninvasive positive pressure ventilation in the setting of severe acute exacerbations of chronic obstructive pulmonary disease: more effective and less expensive does noninvasive positive pressure ventilation improve outcome in acute hypoxemic respiratory failure? a systematic review a chart of failure risk for noninvasive ventilation in patients with copd exacerbation auto-positive endexpiratory pressure: mechanisms and treatment management of pulmonary arterial hypertension updated classification of pulmonary hypertension management of acute right heart failure in the intensive care unit management of acute right heart failure in the intensive care unit prognostic factors and outcomes of patients with pulmonary hypertension admitted to the intensive care unit prognostic factors of acute heart failure in patients with pulmonary arterial hypertension intensive care unit management of patients with severe pulmonary hypertension and right heart failure pulmonary hypertension in the intensive care unit a comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension management of severe pulmonary arterial hypertension pulmonary hypertension and major surgery pulmonary hypertension: an important predictor of outcomes in patients undergoing noncardiac surgery severe pulmonary hypertension complicated postoperative outcome of non-cardiac surgery perioperative risk and management of patients with pulmonary hypertension key: cord- -k whepc authors: chan, kai man; gomersall, charles d title: pneumonia date: - - journal: oh's intensive care manual doi: . /b - - - - . - sha: doc_id: cord_uid: k whepc nan • pneumonia can be caused by over organisms. • the relationship between specific clinical features and aetiological organism is insufficiently strong to allow a clinical diagnosis of the causative organism. • early administration of appropriate antibiotics is important. the net result is that the differential diagnosis is wide and treatment should be started before the aetiological agent is known. the differential diagnosis and the likely causative organisms can be narrowed by using epidemiological clues, the most important of which are whether the pneumonia is community-acquired or healthcare-associated and whether the patient is immunocompromised. note that the flora and antibiotic resistance patterns vary from country to country, hospital to hospital and even icu to icu within a hospital and this must be taken into account. evidence-based guidelines have been issued by the british thoracic society, the infectious diseases society of america (idsa) and american thoracic society (ats) and the european respiratory society. links to these and other pneumonia-related guidelines can be found at the following 'link page': http://www. aic.cuhk.edu.hk/web /pneumonia% guidelines.htm. an acute infection of the pulmonary parenchyma that is associated with at least some symptoms of acute infection, accompanied by an acute infiltrate on a chest radiograph (cxr), or auscultatory findings consistent with pneumonia (e.g. altered breath sounds, localised crackles) in a patient not hospitalised or residing in a long-term care facility for ≥ days prior to the onset of symptoms. the overall incidence is - per inhabitants per year, with - % requiring hospital admission. overall, % of patients are admitted to icu. the overall mortality of hospitalised patient is approximately %. pneumonia produces both systemic and respiratory manifestations. common clinical findings include fever, sweats, rigors, cough, sputum production, pleuritic chest pain, dyspnoea, tachypnoea, pleural rub and inspiratory crackles. classic signs of consolidation occur in less than % of cases. multi-organ dysfunction or failure may occur depending on the type and severity of pneumonia. the diagnosis of pneumonia may be more difficult in the elderly. although the vast majority of elderly patients with pneumonia have respiratory symptoms and signs, over % may also have non-respiratory symptoms and over a third may have no systemic signs of infection. investigations should not delay administration of antibiotics as delays are associated with an increase in mortality. important investigations include: pneumonia . urinary legionella antigen. this test is specific (> %). in patients with severe legionnaires disease sensitivity is - % for l. pneumophilia serogroup (the most commonly reported cause of legionella infection). thus a positive result is virtually single or predominant organism on a gram stain of a fresh sample or a heavy growth on culture of purulent sputum is likely to be the organism responsible. the finding of many polymorphonuclear cells (pmn) with no bacteria in a patient who has not already received antibiotics can reliably exclude infection by most ordinary bacterial pathogens. specimens should be obtained by deep cough and be grossly purulent. ideally the specimen should be obtained before treatment with antimicrobials, if this does not delay administration of antibiotics, and be transported to the laboratory immediately for prompt processing to minimise the chance of missing fastidious organisms (e.g. strep. pneumoniae). acceptable specimens (in patients with normal or raised white blood cell counts) should contain > pmn per low-power field (lpf) and < - squamous epithelial cells (sec)/lpf or > pmn per sec. these criteria should not be used for mycobacteria and legionella infection. certain organisms are virtually always pathogens when recovered from respiratory secretions (box . ). patients with risk factors for tuberculosis (tb) (box . ), and particularly those with cough for more than a month, other common symptoms of tb and suggestive radiographic changes, should have sputum examined for acid-fast bacilli. sputum cannot be processed for culture for anaerobes owing to contamination by the endogenous anaerobic flora of the upper respiratory tract. in addition to the factors listed in table . , foul-smelling sputum, lung abscess and empyema should raise suspicion of anaerobic infection. . aspiration of pleural fluid for gram stain, culture, ph and leucocyte count -all patients with a pleural effusion > cm thick on a lateral decubitus chest x-ray. contamination and colonisation. pcr assays are more sensitive than culture for mycoplasma and chlamydia species and at least as sensitive for legionella. pcr assays also detect legionella strains other than serogroup . the bts guidelines recommend pcr of lower respiratory tract sample or, if unavailable, throat swab for the diagnosis of mycoplasma pneumonia. pcr for chlamydophilia should be performed when invasive respiratory samples were collected from patients with severe community-acquired pneumonia. the role of pcr in diagnosing pcp is mainly limited to non-hiv patients, in whom conventional microscopy and staining of induced sputum and bal have a lower sensitivity than in hiv patients. management general supportive measures intravenous fluids may be required to correct dehydration and provide maintenance fluid. a general approach should be made to organ support with an emphasis on correcting hypoxia. increased mortality among those who do not receive empirical antibiotics that cover the infecting pathogen(s) is well documented. each unit should have its own regimens tailored to the local flora and antibiotic resistance patterns. in the absence of such regimens the regimen outlined in figure other investigations should be considered in patients with risk factors for infection with unusual organisms. bronchoalveolar lavage may be useful in immunocompromised patients, those who fail to respond to antibiotics, or those in whom sputum samples cannot be obtained. molecular diagnosis (e.g. pcr-based methods) has the advantages of quick results (within hours), enhanced sensitivity, independence from organism viability and hence previous antibiotics, and theoretical possibility for determination of antimicrobial susceptibility. of note, it is important to test for genes specific for the organism in question and the sampling site remains important. pcr is most useful when per formed on specimens from a normally sterile site. for example, pcr for pneumococcus is positive in % of blood samples from adult patients with confirmed or probable pneumococcal pneumonia, whereas blood cultures are positive in only %. for respiratory specimens under most circumstances, interpretation remains problematic due to low specificity related to floral should be modified in the light of risk factors (see table . ). quinolones may be less appropriate in areas with a high prevalence of tb as their use may mask concurrent tb infection. appropriate antimicrobial therapy should be administered within hour of diagnosis. , there is controversy regarding the appropriate change to empirical therapy based on microbiological findings. , changing to narrower-spectrum antimicrobial cover may result in inadequate treatment of the - % of patients with polymicrobial infection. increasing evidence demonstrates improved outcome with combination antimicrobial as compared with monotherapy, particularly in severely ill patients with bacteraemic pneumococcal pneumonia. odds ratio of death was . to for monotherapy as compared with combination therapy. benefits were seen only in combination therapy with macrolide as part of the regimen, but not in combination with fluroquinolone regimen. for the treatment of drug-resistant strep. pneumoniae (drsp) the regimens in figure . are probably suitable for isolates with a penicillin mic < mg/l. if the mic is ≥ mg/l an antipneumococcal fluoroquinolone, vancomycin, teicoplanin or linezolid should be given. no clinical trial has specifically addressed this issue. courses as short as days may be sufficient. idsa/ ats guidelines recommend stopping after a minimum of days if the patient is afebrile for - hours and organ dysfunction has largely resolved. short courses may be suboptimal for patients with bacteraemic s. aureus pneumonia, meningitis or endocarditis complicating pneumonia or infection with less common organisms (e.g. burkholderia pseudomallei or fungi) or pseudomonas aeruginosa. procalcitonin may be useful to guide antibiotic therapy, but not all studies have demonstrated a benefit. this can be assessed subjectively (a response is usually seen within - days of starting therapy) or objectively on the basis of respiratory symptoms, fever, oxygenation, wbc count, bacteriology, cxr changes, c-reactive protein reduction and procalcitonin reduction of - % from peak value. the average time to defervescence varies with organism, severity and patient age ( days in elderly patients, . days in young patients with pneumococcal pneumonia, - days in bacteraemic patients with pneumococcal pneumonia, - days in patients with m. pneumoniae pneumonia and days in patients with legionella pneumonia). both blood and sputum cultures are usually negative within - hours of treatment although p. aeruginosa and m. pneumoniae may persist in the sputum despite effective therapy. cxr changes lag behind clinical changes with the speed of change depending on the organism, the age of the patient and the presence or absence of comorbid illnesses. the cxr of most young or middle-aged patients with bacteraemic pneumococcal pneumonia is clear by weeks, but resolution is slower in elderly patients and patients with underlying illness, extensive pneumonia on presentation or legionella pneumophilia pneumonia. if the patient fails to respond consider the following questions: • has the patient got pneumonia? • are there host factors that explain the failure (e.g. obstruction of bronchus by a foreign body or tumour, inadequate host response)? • has a complication developed (e.g. empyema, superinfection, bronchiolitis obliterans organising pneumonia, metastatic abscess)? • is the right drug being given in an adequate dose by the right route? • is the organism resistant to the drug being given? • are there other organisms? • is the fever a drug fever? useful investigations include computerised tomography (ct) of the chest, thoracocentesis, bronchoalveolar lavage (table . ) and transbronchial or open-lung biopsy. scoring systems have been developed to predict adverse outcome and icu admission including pneumonia severity index (psi), curb- , crb- , modified ats major and minor criteria, scap prediction rule, smart-cop, rea-icu index and cap-piro. although they may help identify the sicker patients they should not be used as a sole determinant of icu admission as local admission criteria will be affected by local facilities, both in and outside icu. it should be noted that none of the criteria has been prospectively demonstrated to avoid late transfers or lower mortality. influenza pneumonia may present with severe respiratory failure and multi-organ failure. however the pattern of organ failure appears to vary between strains with h n being associated with a much higher mortality and a higher incidence of multi-organ failure than pandemic h n , which itself presented differently to seasonal influenza. in particular, trophism for lower respiratory tract, a higher rate of icu admission and a higher rate of extrapulmonary complications were observed. early initiation of oseltamivir is recommended for critically ill patients although there is no direct evidence of outcome benefit. glucocorticoids do not appear to be useful and may prolong viral replication. bacterial superinfection should be considered, with grampositive cocci being most frequently isolated. failure and cancer) can cause infiltrates on a chest x-ray. identification of the organism responsible is even more difficult than in patients with community-acquired pneumonia owing to the high incidence of oropharyngeal colonisation by gram-negative bacteria. blood cultures are positive in only about % of cases of nosocomial pneumonia. ventilator-associated pneumonia (vap) is nosocomial pneumonia arising > - hours after intubation. reported incidence of vap is between and % for those receiving mechanical ventilation for more than hours. it is associated with a higher incidence of multi-drug-resistant organisms. nosocomial pneumonia is thought to result from microaspiration of bacteria colonising the upper respiratory tract. other routes of infection include macroaspiration although there are data demonstrating that surgical masks are as effective as n (ffp ) masks in preventing transmission of seasonal influenza in non-icu settings it is important to note that the capacity for airborne transmission (and hence the need for n masks) is dependent on the exact characteristics of the organism and the frequency of aerosol-generating procedures so these data should not be extrapolated to other influenza viruses and icu settings. nosocomial pneumonia occurs in . - % of hospital patients, with a higher incidence in certain groups (e.g. postoperative patients and patients in icu). diagnosis may be difficult: the clinical features of pneumonia are non-specific and many non-infectious conditions (e.g. atelectasis, pulmonary embolus, aspiration, heart table . procedure for obtaining microbiological samples using bronchoscopy and protected specimen brushing and/or bronchoalveolar lavage , infection control in patients suspected of having a disease that is transmitted by the airborne route (e.g. tuberculosis): • the risk of transmission should be carefully weighed against the benefits of bronchoscopy, which may generate large numbers of airborne particles • perform bronchoscopy in a negative-pressure isolation room • consider the use of a muscle relaxant in ventilated patients, to prevent coughing • staff should wear personal protective equipment, which should include a fit-tested negative-pressure respirator (n , ffp or above) as a minimum; use of a powered air-purifying respirator should be considered suction through the endotracheal tube should be performed before bronchoscopy avoid suction or injection through the working channel of the bronchoscope perform protected specimen brushing before bronchoalveolar lavage management is based on the finding that early treatment with antimicrobials that cover all likely pathogens results in a reduction in morbidity and mortality. the initial selection of antimicrobials is made on the basis of epidemiological clues ( fig. . , table . ). antimicrobials should be administered within hour of diagnosis. the results of microbiological investigations are used to narrow antimicrobial cover later. treatment should be reassessed after - days or sooner if the patient deteriorates ( fig. . ). an outline of management based on an invasive approach is given in figure . . current ats guidelines recommend days' treatment provided the aetiological agent is not p. aeruginosa or other non-lactose fermenter and the patient has a good clinical response with resolution of clinical features of infection. the outcome of patients who receive appropriate initial empirical therapy for ventilator-associated pneumonia for days is similar to those who receive treatment for days. of gastric contents, inhaled aerosols, haematogenous spread, spread from pleural space and direct inoculation from icu personnel. diagnosis is based on time of onset (> hours after admission to a healthcare facility ), cxr changes (new or progressive infiltrates) and either clinical features and simple laboratory investigations or the results of quantitative microbiology. using a clinical approach, pneumonia is diagnosed by the finding of a new infiltrate or a change in an infiltrate on chest radiograph and growth of pathogenic organisms from sputum plus one of the following: white-blood-cell (wbc) count greater than × l /l, core temperature ≥ . °c, sputum gram stain with scores of more than two on a scale of four of polymorphonuclear leucocytes and bacteria. these are broadly similar to those required in community-acquired pneumonia: • chest x-ray: although studies using a histological diagnosis as the gold standard have demonstrated that pneumonia may be present despite a normal cxr, most definitions of nosocomial pneumonia require the presence of new persistent infiltrates on a cxr. • respiratory secretions: considerable controversy surrounds the issue of whether invasive bronchoscopic sampling (table . ) of respiratory secretions is necessary. whether invasive sampling is employed or tracheal aspirates are used, empirical broad-spectrum antibiotics should be started while results are awaited. the results of microbiological analysis of respiratory secretions are used to either stop antibiotics or narrow the spectrum. although the use of an invasive strategy is associated with a higher likelihood of modification of initial antimicrobials, the effect on important clinical outcome such as mortality, antibiotic-free days, and organ dysfunction is variable. although tracheal aspirates may predominantly reflect the organisms colonising the upper airway, they may be useful in indicating which organisms are not responsible for the pneumonia, thus allowing the antimicrobial cover to be narrowed. the use of dual therapy is not well supported by evidence but it does reduce the probability that the pathogen is resistant to the drugs being given. if an extended spectrum β-lactamase-producing strain or an acinetobacter sp. is suspected a carbapenem should be given. if legionella pneumophilia is suspected use a quinolone. risk factors for mrsa infection in areas with a high incidence of mrsa include diabetes mellitus, head trauma, coma and renal failure. or with enlarged cervical nodes or other manifestations of extrapulmonary disease. clinical disease is seldom found in asymptomatic individuals, even those with strongly positive tuberculin test (heaf grade iii or iv). the outlook for patients with tuberculosis who require icu admission is poor. in one retrospective study the in-hospital mortality for all patients with tuberculosis requiring icu admission was % but in those with acute respiratory failure it rose to %. the presentation and management of tb in hiv-positive patients are different (see below). identification of mycobacteria multiple , sputum samples should be collected, preferably on different days, for microscopy for acid-fast bacilli and culture. if sputum is not available bronchial washings taken at bronchoscopy and gastric lavage or aspirate samples should be obtained. gastric aspirates need to be neutralised immediately on collection. bronchoscopy and transbronchial biopsy may be useful in patients with suspected tb but negative sputum smear. pleural biopsy is often helpful and mediastinoscopy is occasionally needed in patients with mediastinal lymphadenopathy. part of any biopsy specimen should always be sent for culture. nucleic acid amplification tests on sputum have sensitivity similar to culture in . % on the th day of icu in a recent study using a multicentre high-quality database and incorporating novel statistical methodology to control evolution of severity of illness. several guidelines for prevention of ventilatorassociated pneumonia and hospital-acquired pneumonia have been published. [ ] [ ] [ ] [ ] [ ] interventions can be divided into general infection control measures and specific measures. general measures include alcoholbased hand disinfection, hospital education programme on infection control, the use of microbiological surveillance and a programme to reduce antibiotic prescription. the major specific recommendations are summarised in table . . there is no evidence that 'bundles' of recommendations are more effective than the sum of the individual components. the main risk factors are listed in box . . typical clinical features include fever, sweating, weight loss, lassitude, anorexia, cough productive of mucoid or purulent sputum, haemoptysis, chest wall pain, dyspnoea, localised wheeze and apical crackles. patients may also present with unresolved pneumonia, pleural effusions, spontaneous pneumothorax and hoarseness , no effect on vap, mainly for staff safety . chlorhexidine oral decontamination , , . sedation vacation and weaning protocol , . judicious use of stress ulcer prophylaxis mortality reduction demonstrated when topical antimicrobials combined with short-course systemic antibiotics, bsac recommended sdd in patients expected to require mechanical ventilation for > hours, etf discourage routine use due to concern of emergence of resistant organisms not yet reviewed by guidelines . high-volume low-pressure ultrathin membrane endotracheal tube cuff with ssd . ultrathin membrane cuff with tapered shape and ssd . low-volume low-pressure endotracheal tube cuff with ssd . balloon device for biofilm removal . saline instillation before tracheal suctioning hme = heat moist exchanger; ssd = subglottic secretion drainage. smear-negative patients with pulmonary tuberculosis but have the advantage of a much more rapid result. there is, however, a significant false-negative rate. a normal cxr almost excludes tb (except in hiv-infected patients) but endobronchial lesions may not be apparent and early apical lesions can be missed. common appearances include patchy/nodular shadowing in the upper zones (often bilateral), cavitation, calcification, hilar or mediastinal lymphadenopathy (may cause segmental or lobar collapse), pleural effusion, tuberculomas (dense round or oval shadows) and diffuse fine nodular shadowing throughout the lung fields in miliary tb. inactivity of disease cannot be inferred from the cxr alone. this requires three negative sputum samples and failure of any lesion seen on cxr to progress. cxr appearances in hiv-positive fit-tested negative-pressure respirator (n , ffp or higher). use of a powered air-purifying respirator should be considered when bronchoscopy is being performed. detailed infection control advice can be obtained via the 'link page' (http://www.aic.cuhk. edu.hk/web /pneumonia% guidelines.htm.). the lungs are amongst the most frequent target organs for infectious complications in the immunocompromised. the incidence of pneumonia is highest amongst patients with haematological malignancies, bone marrow transplant (bmt) recipients and patients with aids. the speed of progression of pneumonia, the cxr changes ( table . ) and the type of immune defect provide clues to the aetiology. bacterial pneumonias progress rapidly ( - days) whereas fungal and protozoal pneumonias are less fulminant (several days to a week or more). viral pneumonias are usually not fulminant, but on occasions may develop quite rapidly. bronchoscopy is a major component of the investigation of these patients. empirical management based on cxr appearances is outlined in table . . early noninvasive ventilation may improve outcome amongst immunocompromised patients with fever and bilateral infiltrates. pneumocystis jiroveci pneumonia (pcp) the incidence of this common opportunistic infection has fallen substantially in patients with aids who are receiving prophylaxis and effective antiretroviral therapy, with most cases occurring in patients who are not receiving hiv care or among patients with advanced immunosuppression. the onset is usually insidious with dry cough, dyspnoea and fever on a background of fatigue and weight loss. crackles in the chest are rare. approximately % of patients have a concurrent cause for respiratory failure (e.g. kaposi sarcoma, tb, bacterial pneumonia). useful investigations are: . cxr: classical appearance is diffuse bilateral perihilar interstitial shadowing, but in the early stages this is very subtle and easily missed. the initial cxr is normal in %. in a further % the changes are atypical with focal consolidation or coarse patchy shadowing. none of the changes are specific for pcp and may be seen in other lung diseases associated with aids. pleural effusions, hilar or mediastinal lymphadenopathy are unusual in pcp but common in mycobacterial infection or kaposi's sarcoma or lymphoma. induced sputum: in this technique the patient inhales nebulised hypertonic saline from an ultrasonic nebuliser. this provokes bronchorrhoea and the patient patients with tb differ from those in non-hiv-infected patients. the decision to initiate anti-tb treatment should be based on level of clinical suspicion, results of afb smear and sometimes mycobacterial culture. if the initial clinical suspicion is strong and the patient is seriously ill attributable to possible tb, treatment should be initiated promptly, sometimes before the result of afb smear. subsequent positivity of afb smear or nucleic acid amplification test provides support to the continuation of treatment. combination chemotherapy consisting of four drugs is necessary for maximal efficacy. treatment is divided into initial phase and continuation phase. the most commonly used initial regimen consists of weeks of rifampicin mg daily ( mg for patients < kg), isoniazid mg daily, pyrazinamide g daily ( . g for patients < kg) and ethambutol mg/kg daily as initial phase treatment. ethambutol should be used only in patients who have reasonable visual acuity and who are able to appreciate and report visual disturbances. this mandates careful consideration in patients who require heavy sedation. visual acuity and colour perception must be assessed (if ethambutol is to be used) and liver and renal function checked before treatment is started. steroids are recommended for children with endobronchial disease and, possibly, for patients with tuberculous pleural effusions. pyridoxine mg daily should be given to prevent isoniazid-induced neuropathy to those at increased risk (e.g. patients with diabetes mellitus, chronic renal failure or malnutrition or alcoholic or hiv-positive patients). negative afb smear should not delay initial treatment if clinical suspicion remains high. supporting features included chronic cough, weight loss, characteristic chest x-ray findings, emigration from a high-incidence country, no other immediate diagnosis, and positive tuberculin test. patients admitted to an icu with infectious tb or suspected of having active pulmonary tb should be managed in an isolation room with special ventilation characteristics, including negative pressure. patients should be considered infectious if they are coughing or undergoing cough-inducing procedures or if they have positive afb smears and they are not on or have just started chemotherapy, or have a poor clinical or bacteriological response to chemotherapy. , patients with non-drug-resistant tb should be non-infectious after weeks of treatment which includes rifampicin and isoniazid. as tb spreads through aerosols it is probably appropriate to isolate patients who are intubated even if only their bronchial washings are smear-positive. staff caring for patients who are smear-positive should wear personal protective equipment including a and/or diuretics (patients often fluid-overloaded). approximately % of patients with hiv-related pcp who require mechanical ventilation survive to hospital discharge. initiation of antiretroviral therapy in patients presenting with hiv-related pcp is controversial. the centers for disease control and prevention (cdc) recommend against doing so in the acute phase, but recent data suggest that the outcome may be improved by initiation within the first days of icu admission. this is the most common cause of acute respiratory failure in hiv-positive patients. bacterial pneumonia is more common in hiv-infected patients than in the general population and tends to be more severe. strep. pneumoniae, h. influenza, pseudomonas aeruginosa and s. aureus are the commonest organisms. nocardia and gram negatives should also be considered. atypical pathogens (e.g. legionella) are rare. response to appropriate antibiotics is usually good but may require protracted courses of antibiotics because of high tendency to relapse. patients with severe immunodeficiency (cd + t lymphocyte count < /µl) and a history of pseudomonas infection or bronchiectasis or neutropenia should receive antibiotics that cover p. aeruginosa as well as other gram negatives. the possibility of concurrent pcp or tuberculosis should be excluded. tb may be the initial presentation of aids, particularly in sub-saharan africa. the pattern of tb in hiv patients coughs up material containing cysts and trophozoites. the technique is time-consuming and requires meticulous technique and is less sensitive than bronchoscopy but less invasive. the possibility of concurrent tuberculosis should be considered and steps taken to minimise the risk of spread of infection. the diagnosis in over % of cases. specimens should be sent for cytology. transbronchial biopsy is not necessary in most cases. pcr using bronchial lavage specimens may be useful in non-hiv patients with suspected pcp. antipneumocystis treatment should be started as soon as the diagnosis is suspected. treatment of choice is trimethoprim plus sulfamethoxazole (co-trimoxazole) mg/kg/day + mg/kg/day for weeks plus prednisolone mg orally twice daily for days followed by mg twice daily for days and then mg per day until the end of pcp treatment. side-effects of co-trimoxazole are common in hiv patients (nausea, vomiting, skin rash, myelotoxicity). the dose should be reduced by % if the wbc count falls. patients who are intolerant of co-trimoxazole should be treated with: • pentamidine mg/kg/day i.v. or • primaquine with clindamycin or • trimetrexate with leucovorin (±oral dapsone). response to treatment is usually excellent, with a response time of - days. if the patient deteriorates or fails to improve: consider (re-)bronchoscopy (is the diagnosis correct?), treat co-pathogens and consider a short course of high-dose i.v. methylprednisolone fungi are rare but important causes of pneumonia. they can be divided into two main groups based on the immune response required to combat infection with these organisms. histoplasma, blastomycosis, coccidioidomycosis, paracoccidioidomycosis and cryptococcus require specific cell-mediated immunity for their control and thus, in contrast to infections that are controlled by phagocytic activity, the diseases caused by these organisms can occur in otherwise healthy individuals although they cause much more severe illness in patients with impaired cell-mediated immunity (e.g. patients infected with hiv and organ transplant recipients). with the exception of cryptococcus these organisms are rarely seen outside north america. aspergillus and mucor spores are killed by non-immune phagocytes and as a result these fungi rarely result in clinical illness in patients with normal neutrophil numbers and function. this is effectively a combination of the two types of fungal infection in which impaired cell-mediated immunity predisposes to mucosal overgrowth with candida but impaired phagocytic function or numbers is usually required before deep invasion of tissues occurs. primary candida pneumonia (i.e. isolated lung infection) is uncommon , and more commonly pulmonary lesions are only one manifestation of disseminated candidiasis. even more common is benign colonisation of the airway with candida. in most reported cases of primary candida pneumonia amphotericin b has been used. in disseminated candidiasis treatment should be directed to treatment of disseminated disease rather than candida pneumonia per se. this is a highly lethal condition in the immunocompromised despite treatment and therefore investigation and treatment should be prompt and aggressive. it is associated with exposure to construction work. definitive diagnosis requires both histological evidence of acute-angle branching, septated non-pigmented hyphae measuring - µm in width, and cultures yielding aspergillus species from biopsy specimens of involved organs. recovery of aspergillus species from respiratory secretions in immunocompromised, but not immunocompetent, patients may indicate invasive disease with a positive predictive value as high as depends on the degree of immunosuppression. in patients with cd + t lymphocytes > cells/µl the clinical presentation is similar to tb in non-hiv-infected patients, although extrapulmonary disease is more common. in patients with cd + t lymphocytes < cells/µl extrapulmonary disease (pleuritis, pericarditis, meningitis) is common. severely immunocompromised patients (cd + t lymphocytes < cells/µl) may present with severe systemic disease with high fever, rapid progression and systemic sepsis. in these patients lower and middle lobe disease is more common, miliary disease is common and cavitation is less common. sputum smears and culture may be positive even with a normal cxr. response to treatment is usually rapid. management of tb in hiv is complex owing to numerous drug interactions; consultation with an expert in treatment of hiv-related tb should be strongly considered. complex interactions occur between rifamycins (e.g. rifampicin and rifabutin) and protease inhibitors and nonnucleoside reverse transcriptase inhibitors used to treat patients infected with hiv. the choice of rifampicin or rifabutin depends on a number of factors including the unique and synergistic adverse effects for each individual combination of rifampicin and anti-hiv drugs, and consultation with a physician with experience in treating both tb and hiv is advised. idsarecommended dosage adjustment for patients receiving antiretrovirals and rifabutin can be obtained via the 'link page' (http://www.aic.cuhk.edu.hk/web / pneumonia% guidelines.htm.). the optimal time for initiating antiretroviral therapy in patients with tb is controversial. early therapy may decrease hiv disease progression but may be associated with a high incidence of adverse effects and an immune reconstitution reaction. cmv pneumonitis , risk of infection is highest following allogeneic stem cell transplantation, followed by lung transplantation, pancreas transplantation and then liver, heart and renal transplantation and advanced aids. if both the recipient and the donor are seronegative then the risk of both infection and disease are negligible. if the recipient is seropositive the risk of infection is approximately % but the risk of disease is only %, regardless of the serostatus of the donor. however if the recipient is seronegative and the donor is seropositive the risk of disease is %. if steroid pulses and antilymphocyte globulin are given for treatment of acute rejection the risk of developing disease is markedly increased. infection may be the result of primary infection or reactivation of latent infection. it is clinically important, but often difficult to distinguish between cmv infection and cmv disease and a definitive diagnosis can be made only histologically. detection of cmv-pp antigen in peripheral wbc and detection of cmv dna or rna in the blood by quantitative polymerase chain needle aspiration or, if there is debris within the fluid, drainage using an intercostal drain. the diagnosis is confirmed by aspiration of pus. the mainstay of treatment is drainage either by intercostal drain or by surgical intervention. patients who present before the pus is loculated and a fibrinous peel has formed on the lung can usually be treated by simple drainage. the combination with intrapleural fibrinolysis may be beneficial. optimal surgical management, which consists of decortication (open or thoracoscopic), is indicated if the empyema is more advanced or if simple drainage fails. this is a major procedure and many patients with cardiac or chronic respiratory disease will not tolerate it. alternatives for these patients are instillation of thrombolytics into the pleural space or thoracostomy. antibiotics have only an adjunctive role. broad-spectrum antibiotic regimens with anaerobic cover should be used until the results of microbiological analysis of the aspirated pus are available. all tables and figures are reproduced from icu web (www.aic.cuhk.edu.hk/web ) with permission of the authors. - % in patients with leukaemia or bone marrow transplant recipients. bronchoalveolar lavage with smear, culture and antigen detection has excellent specificity and reasonably good positive predictive value for invasive aspergillosis in immunocompromised patients. although radiological features may give a clue to the diagnosis they are not sufficiently specific to be diagnostic. in acutely ill immunocompromised patients intravenous therapy should be initiated if there is suggestive evidence of invasive aspergillosis while further investigations to confirm or refute the diagnosis are carried out. first-line therapy is voriconazole. echinocandins and amphotericin are alternatives. this may be an uncomplicated effusion that resolves with appropriate treatment of the underlying pneumonia or a complicated effusion that develops into an empyema unless drained. complicated effusions tend to develop - days after initial fluid formation. they are characterised by increasing pleural fluid volume, continued fever and pleural fluid of low ph (< . ) that contains a large number of neutrophils and may reveal organisms on gram staining or culture. an outline of management is given in figure . . collection of pus in the pleural space. follows infection of the structures surrounding the pleural space, including subdiaphragmatic structures, and chest trauma, or may be associated with malignancy. anaerobic bacteria, usually streptococci or gram-negative rods, are responsible for % of cases. the diagnosis is usually simple. the patient is usually septic and may have a productive cough and chest pain. the chest x-ray may show features suggestive of a pleural effusion and underlying consolidation but may also show an abscess cavity with a fluid level, in which case ct scanning will be required to distinguish between an abscess and an empyema. ultrasound can be useful to confirm the presence of fluid in the pleural space and to determine whether it can be drained by guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare associated pneumonia infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults pneumonia guidelines committee of the bts standards of care committee. british thoracic society guidelines for the management of community acquired pneumonia in adults: update management of communityacquired pneumonia in adults cdc, and infectious diseases society of america. treatment of tuberculosis the standardization of bronchoscopic techniques for ventilator-associated pneumonia new issues and controversies in the prevention of ventilator-associated pneumonia guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare associated pneumonia infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults pneumonia guidelines committee of the bts standards of care committee. british thoracic society guidelines for the management of community acquired pneumonia in adults: update guidelines for the management of adult lower respiratory tract infections update in community-acquired and nosocomial pneumonia value of intensive diagnostic microbiological investigation in low-and high-risk patients with community-acquired pneumonia nucleic acid amplification tests for the diagnosis of pneumonia interpreting assays for the detection of streptococcus pneumonia severity of pneumococcal pneumonia associated with genomic bacterial load polymerase chain reaction for diagnosing pneumocystis pneumonia in non-hiv immunocompromised patients with pulmonary infiltrates early mortality in patients with community-acquired pneumonia: causes and risk factors surviving sepsis campaign guidelines for management of severe sepsis and septic shock antibiotics for bacteremic pneumonia: improved outcomes with macrolides but not fluoroquinolones high-dose, short-course levofloxacin for community-acquired pneumonia: a new treatment paradigm an esicm systematic review and meta-analysis of procalcitonin-guided antibiotic therapy algorithms in adult critically ill patients management of communityacquired pneumonia in adults avian influenza (h n ): implications for intensive care clinical characteristics and -day outcomes for influenza a (h n ) complications and outcomes of pandemic influenza a (h n ) virus infection in hospitalized adults: how do they differ from those in seasonal influenza? corticosteroid treatment in critically ill patients with pandemic influenza a/h n infection analytic strategy using propensity scores bacterial coinfections in lung tissue specimens from fatal cases of pandemic influenza a (h n ) -united states clinical and economic consequences of ventilator-associated pneumonia: a systematic review invasive approaches to the diagnosis of ventilator-associated pneumonia: a meta-analysis ventilator-associated pneumonia and mortality: a systematic review of observational studies attributable mortality of ventilator-associated pneumonia. a reappraisal using causal analysis guidelines for preventing health-careassociated pneumonia . recommendations of cdc and the healthcare infection control practices advisory committee shea/idsa practice recommendation. strategies to prevent ventilator-associated pneumonia in acute care hospitals guidelines for the management of hospital-acquired pneumonia in the uk: report of the working party on hospital-acquired pneumonia of the british society for antimicrobial chemotherapy vap guidelines committee and the canadian critical care trials group. comprehensive evidencebased clinical practice guidelines for ventilatorassociated pneumonia: prevention defining, treating and preventing hospital acquired pneumonia: european perspective active tuberculosis in the medical intensive care unit: a -year retrospective analysis national collaborating centre for chronic conditions. tuberculosis. clinical diagnosis and management of tuberculosis and measures for its prevention and control management of tuberculosis in the united states cdc, and infectious diseases society of america. treatment of tuberculosis guidelines for preventing the transmission of mycobacterium tuberculosis in health-care settings noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure treating opportunistic infections among hiv-infected adults and adolescents: recommendations from cdc, the national institutes of health, and the hiv medicine association/infectious diseases society of america improvements in outcomes of acute respiratory failure for patients with human immunodeficiency virusrelated pneumocystis carinii pneumonia centers for disease control. updated guidelines for the use of rifabutin or rifampicin for the treatment and prevention of tuberculosis among hiv-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors the lung in the immunocompromised patient management of cytomegalovirus infection and disease after solid-organ transplantation area under the viraemia curve versus absolute viral load: utility for predicting symptomatic cytomegalovirus infections in kidney transplant patients cytomegalovirus infection in organ-transplant recipients: diagnostic value of pp antigen test, qualitative polymerase chain reaction (pcr) and quantitative taqman pcr guidelines for treatment of candidiasis practice guidelines for diseases caused by aspergillus voriconazole versus amphotericin b for primary therapy of invasive aspergillosis the pleural cavity the standardization of bronchoscopic techniques for ventilator-associated pneumonia new issues and controversies in the prevention of ventilator-associated pneumonia key: cord- -hqj yxe authors: renew, j. ross; ratzlaff, robert; hernandez-torres, vivian; brull, sorin j.; prielipp, richard c. title: neuromuscular blockade management in the critically ill patient date: - - journal: j intensive care doi: . /s - - - sha: doc_id: cord_uid: hqj yxe neuromuscular blocking agents (nmbas) can be an effective modality to address challenges that arise daily in the intensive care unit (icu). these medications are often used to optimize mechanical ventilation, facilitate endotracheal intubation, stop overt shivering during therapeutic hypothermia following cardiac arrest, and may have a role in the management of life-threatening conditions such as elevated intracranial pressure and status asthmaticus (when deep sedation fails or is not tolerated). however, current nmba use has decreased during the last decade due to concerns of potential adverse effects such as venous thrombosis, patient awareness during paralysis, development of critical illness myopathy, autonomic interactions, and even residual paralysis following cessation of nmba use. it is therefore essential for clinicians to be familiar with evidence-based practices regarding appropriate nmba use in order to select appropriate indications for their use and avoid complications. we believe that selecting the right nmba, administering concomitant sedation and analgesic therapy, and using appropriate monitoring techniques mitigate these risks for critically ill patients. therefore, we review the indications of nmba use in the critical care setting and discuss the most appropriate use of nmbas in the intensive care setting based on their structure, mechanism of action, side effects, and recognized clinical indications. lastly, we highlight the available pharmacologic antagonists, strategies for sedation, newer neuromuscular monitoring techniques, and potential complications related to the use of nmbas in the icu setting. the introduction of neuromuscular blocking agents to the icu provides intensivists a unique capability in the management of critically ill patients. as with any therapy, however, the use of nmbas has inherent risks, particularly when providers are unfamiliar with the nuances of selecting the appropriate agent, monitoring the depth of neuromuscular blockade, and ensuring adequate skeletal muscle recovery once nmba therapy has ceased. optimal neuromuscular blockade management has challenged clinicians for decades, despite the frequent use of nmbas in clinical practice [ ] . complications associated with the nmba use can be particularly concerning in the critical care setting, as intensivists typically administer nmbas to critically ill patients with multi-organ system derangements for long periods of time resulting in greater accumulation of nmb drug and drug metabolites. the impact of such "off-label" use of nmbas in the icu is still being investigated. the society of critical care medicine (sccm) developed guidelines addressing optimal practice based on the available evidence to address these concerns [ ] [ ] [ ] . while guidelines can help clinicians navigate many clinical scenarios, these recommendations are often limited by the lack of well-designed prospective trials. ultimately, a thorough understanding of neuromuscular blockade management can equip clinicians to deal with scenarios that fall outside of the scope of medical specialty guidelines. this review provides up-to-date evidence to aid clinicians in selecting the right scenarios for establishing neuromuscular blockade in the icu as well as choosing the optimal agent for such scenarios. additionally, we will review methods to determine the level of neuromuscular blockade, the use of nmba antagonists, and the optimal methods to confirm an adequate neuromuscular recovery and avoid prolonged residual weakness in this vulnerable patient population. in , a task force comprising members from the society of critical care medicine (sccm) proposed updated and comprehensive recommendations for the use of neuromuscular blocking agents in the critically ill patient (table ) [ ] . the authors expanded upon previous recommendations from [ ] while utilizing the grading of recommendations assessment, development, and evaluation (grade) system [ ] to comment on the quality-of-evidence for each recommendation. these recommendations can be utilized in a variety of critical care settings that require neuromuscular blockade; however, these guidelines are limited by the relative paucity of definitive literature investigating neuromuscular blockade in the unique critically ill patient population. endotracheal intubation in the icu is a more challenging endeavor than in the controlled environment of the operating room (or), and the risk of a "failed intubation" is several-fold greater in the icu [ ] . unlike the or where the primary objective of tracheal intubation is to secure the airway after induction of anesthesia, the procedural objective in the icu is to secure the airway as a life-saving intervention in a patient with current or impending respiratory failure [ ] . endotracheal intubation in the critical care setting is associated with significant complications such as severe hypotension, hypoxemia, and even cardiac arrest [ ] [ ] [ ] . such complications can occur up to % of the time [ ] . moreover, when managing the difficult airway, the intensivist rarely has the option to awaken the patient during the scenario of "failed intubation" as suggested by the american society of anesthesiologists' (asa) difficult airway algorithm [ ] . nonetheless, the use of nmbas is an important adjunct to facilitate tracheal intubation as these drugs can create better conditions during laryngoscopy [ ] . in addition, the nmba use can significantly decrease airway trauma associated with this procedure and facilitate securing the airway in fewer attempts [ ] . succinylcholine and rocuronium are the two agents typically utilized when the neuromuscular blockade is desired to rapidly facilitate tracheal intubation. while succinylcholine provides rapid and reliable neuromuscular blockade, higher doses of rocuronium ( . mg/kg or × the effective dose that decreases the twitch by % from baseline [ed ]) can have a similar mean onset time (although a slightly wider range of onset times), a characteristic that makes this agent suitable for rapid sequence induction and intubation (rsii) [ ] . higher doses of rocuronium result in a much longer duration of action than succinylcholine, increasing concerns about its use in the patient with a difficult airway. however, high-dose rocuronium can be antagonized with sugammadex (at a dose of mg/ kg) after min in the "can't intubate/can't ventilate" scenario [ ] . this pharmacologic reversal, however, does not ensure the avoidance of dangerous periods of hypoxia (or hypoventilation due to opioid or sedative drugs co-administered), and rapid, appropriate airway management targeted at establishing airway patency remains paramount [ ] . management of the airway of icu patients presents multiple and varied challenges, as it is one of the most commonly performed procedures in this setting. the identification of the difficult airway is paramount, and its incidence may be over % [ ] . serious adverse events from attempted tracheal intubation performed in the icu patients occur in up to % of cases [ ] . in order to identify patients at risk of difficult intubation, some investigators have recommended development of simple scores that can be applied at bedside. one such scale, the macocha score, consists of a total of points (see table ), and combines patient, patient pathology, and operator factors to differentiate between difficult and nondifficult intubation patients in the icu [ ] . patient factors included are mallampati score of iii or iv, the presence of obstructive sleep apnea, reduced mobility of the cervical spine, and limited mouth opening. patient pathology factors were severe hypoxia and coma, while the operator factor was the presence of a nonanesthesiologist for airway management. the scale for identification of risk factors for difficult airway/intubation in critically ill patients by nonanesthesiologist trainees was further refined and validated in a prospective, observational single-center study [ ] . despite the availability of indicators of difficult airway in icu patients, however, a recent french survey found that % of intubating operators were still not fully proficient in the technique, with . % of them having had no intubation training, or only basic training, such as lectures or observation [ ] . this survey also reported that although video laryngoscopy is available in most of the french icus, its use was reserved for management of the difficult airway patients [ ] . remarkably, the vast majority ( %) of intensivists had placed less than a total of laryngeal mask airways, and half had performed less than intubations using fiberoptic bronchoscopy, despite the fact that a majority ( %) of clinicians expressed a desire to participate in high fidelity mannequin simulations [ ] . a spanish national survey reported that of the icus that responded, three quarters had no tracheal intubation or no difficult airway protocols [ ] . the authors thus called for the implementation of changes in the icu that include prospective identification of experts in management of the difficult airway and the development of specific guidelines for management of the icu patient with difficult airway [ ] . in japan, difficult airway management carts are largely unavailable in the icu, and capnography to confirm correct tracheal tube placement is used in only slightly over half of the patients [ ] . in the uk, . % of icu patients were judged to have an increased risk of airway complications, but only % of them had a plan in place for management of the difficult airway [ ] . in australia and new zealand, only a small minority of icus identify patients with "critical airways," and only % have specific protocols for care of these high-risk patients [ ] . the icu patient with a difficult airway poses a significant challenge not only when the airway needs to be secured; the same precautions and potential for adverse events remain at the time of tracheal extubation. the royal college of anaesthetists' th national audit project (nap ) has reinforced the importance of optimal airway management in the icu environment, has underscored the need for appropriate guidelines and strategies for the safe extubation of the trachea in patients with a potentially difficult airway, and has proposed key anesthetic principles for safe airway management (table ) [ ] . in the icu, nmbas are also commonly used for the facilitation of mechanical ventilation. the current sccm clinical practice guidelines [ ] suggest that an nmba be administered by continuous intravenous infusion early in the course of acute lung injury for patients with a partial pressure of oxygen to fraction of inspired oxygen (pao /fio ) ratio less than (weak recommendation with moderate quality of evidence). indeed, patients with acute respiratory distress syndrome (ards) are unlikely to oxygenate or ventilate optimally with sedation/analgesia regimens alone. gainnier et al. conducted a multicenter, prospective controlled randomized trial and found that the use of nmbas during a -h period in ards patients was associated with a sustained improvement in oxygenation [ ] . in the acurasys trial, pappazian et al. found that in patients with severe ards, early administration of cisatracurium continuously for h improved the adjusted -day survival, decreased the risk of barotrauma, and increased the time off the ventilator without increasing muscle weakness [ ] . however, more recent results from the reevaluation of systemic early neuromuscular blockade (rose) trial failed to show reductions in mortality when nmbas were administered in moderate-severe ards [ ] . while cisatracurium has been shown to possess anti-inflammatory properties in animal models [ ] , its clinically relevant benefit likely involves avoidance of ventilator dyssynchrony and improvements in lung compliance [ ] . the results of three recent meta-analyses have all demonstrated that nmba administration in ards patients is associated with reduced barotrauma and improved oxygenation; however, the impact on mortality remains unclear [ ] [ ] [ ] . thus, the nmba use in ards must be individualized and may be utilized as a part of an institutional-based protocol. the neuromuscular blockade has been used in patients with status asthmaticus. however, this specific application's use has decreased over concerns of severe weakness and critical care myopathy [ ] [ ] [ ] . indeed, the current sccm clinical practice guidelines [ ] suggest against the routine administration of an nmba to patients with status asthmaticus (weak recommendation with very low quality of evidence). interestingly, more recent investigations have suggested that replacing neuromuscular blockade with continuous deep sedation regimens did not change the incidence of muscle weakness in this group of patients, suggesting that prolonged immobilization and inactivity are key clinical contributors to this complication rather than solely due to the administration of nmbas [ ] . in patients with an acute brain injury, a mass occupying lesion or subsequent intracranial edema, increases in cerebral perfusion can cause a deleterious increase in intracranial pressure (icp). however, the current sccm clinical practice guidelines [ ] could not recommend whether nmbas were beneficial or harmful when used in patients with acute brain injury and raised icp (insufficient evidence). neuromuscular blockade may be useful in the short-term without negatively impacting hemodynamic parameters such as icp, cerebral perfusion pressure (cpp), and blood pressure [ ] . furthermore, the avoidance of coughing, straining, and ventilator dyssynchrony during periods of the neuromuscular blockade can avoid significant increases in icp and worsening of cerebral edema [ , ] . the benefits of nmbas are limited to endpoints such as reducing oxygen consumption as well as carbon dioxide production, although this practice has not been shown to improve overall outcomes and may increase the icu length of stay, risk of pneumonia, and overall costs [ ] . as in ards, the early use of nmbas in sepsis may reduce in-hospital mortality [ , ] . current guidelines from the surviving sepsis campaign [ ] list the administration of nmbas as a weak recommendation and suggest that their use may have some benefits if used within h in those adult patients with sepsis-induced ards. in patients who suffer an out of hospital cardiac arrest, the use of therapeutic hypothermia plays an important role in survival to discharge [ ] . however, the current sccm clinical practice guidelines [ ] make no recommendation on the routine use of nmbas for such patients (insufficient evidence). a complication from hypothermia is shivering, which leads to the deleterious consequences of increased metabolic rate and icp, heat production, inflammation, and decreased brain tissue oxygen levels [ ] . the american heart association guidelines recommend short-acting nmbas in conjunction with appropriate use of analgesia and sedation to alleviate shivering in this setting [ , ] . indeed, the sccm guidelines also suggest that nmbas be used to manage overt shivering during therapeutic hypothermia (weak recommendation, very low quality of evidence). the only neuromuscular blockade patient management recommendation that was rated as "strong" by the sccm panel of experts was the use of lubricating drops or gel along with eyelid closure for patients receiving continuous infusions of nmbas [ ] . additionally, targeting glucose levels less than mg/dl ( mm) and the implementation of a physiotherapy regimen during table key anesthetic principles for airway management strategies in icu patients . oxygenation, not intubation, is the priority at all times including during tracheal extubation. . airway equipment should be purchased with the least experienced potential user in mind, and not the most experienced (i.e., ideally, devices should be intuitive and user-friendly, requiring a short training period). . devices should have sufficient evidence from reliable research to support their clinical role. . rescue devices should have a close to % success rate to ensure the minimal number of steps when securing the airway. a device with a high success rate in routine use may have a lower success rate when used as a rescue maneuver, especially when the difficult airway is unexpected. urgency and operator's anxiety of impending patient morbidity or mortality is likely to hinder the success of any device. . devices should be trialed over an adequate period of time (several weeks or months in most cases, and a sufficient number of times, preferably more than ) to ensure that they are used for a variety of airway problems and by an adequate cross-section of staff. . to be successful, extubation should be planned in a similar manner to intubation. to be more specific, extubation techniques should be tailored to the type of expected airway difficulties. preparation for reintubation should be part of the extubation management plan with a clear indication of when an intervention is or is not working and when to seek alternative methods. . technical and non-technical training in all clinical environments must follow the implementation of new airway management and oxygenation devices. periods of neuromuscular blockade also represent "weak" recommendations. the sccm recommendations are not mandates, and the authors clearly state that therapy should be guided by the patient's condition, clinician experience, and equipment available in the icu [ ] . clinical care providers must maintain an understanding of clinical pharmacology in order to weigh the clinical benefits versus the associated risks when deciding when nmbas may suit the needs of their specific patient. nmbas cause skeletal muscle relaxation by blocking the transmission of impulses at the neuromuscular junction (nmj) [ ] . these agents are classified by their mechanism of action and chemical structure. based on their methods for establishing neuromuscular blockade, there are two types: depolarizing and non-depolarizing nmbas. the group of nondepolarizing nmbas is further subdivided according to their structure into benzylisoquinolinium (curare, atracurium, cisatracurium, mivacurium) and aminosteroidal compounds (rocuronium, vecuronium, pancuronium). selecting a specific nmba in the critically ill patient depends on the indication, patient's comorbidities (liver or renal failure), and interactions with other drugs that may enhance or prolong their action, as well as physiological changes and risk factors that may affect the pharmacokinetics of nmbas such as age-related changes [ ] , hypothermia [ ] [ ] [ ] , sepsis [ ] [ ] [ ] , and metabolic or electrolyte disturbances (table ) [ ] . atracurium is an intermediate-acting nmba that is metabolized through nonspecific plasma esterase-mediated hydrolysis as well as hofmann elimination reaction in which the compound is degraded based on body ph and temperature [ ] . this breakdown is nonenzymatic and occurs independent of hepatic and renal function, making this agent an attractive option in the intensive care unit in patients with renal and/or hepatic dysfunction. the hofmann elimination reaction produces laudanosine, a compound that has been shown to cause seizurelike activity in high doses but only in animal models [ ] ; in fact, this complication has never been reported in humans at clinically relevant doses [ ] . intubating doses of atracurium ( . mg/kg or × ed ) can cause clinically relevant histamine release, producing tachycardia, hypotension, and skin flushing [ ] . cisatracurium is the cis-cis isomer of atracurium, a feature that increases its potency four-fold, without the associated histamine release; therefore, a smaller dose is required for tracheal intubation ( . mg/kg or × ed ). this intermediate-acting agent is also metabolized through organ-independent mechanisms via the hofmann elimination reaction, making this benzylisoquinolinium drug one of the most commonly utilized nmbas in critically ill patients who require neuromuscular blockade [ , , ] . sottile and colleagues performed a large observational study in patients with ards and found that when compared with vecuronium, cisatracurium was associated with increased ventilator-free days and overall icu days but was not associated with a difference in mortality [ ] , suggesting cisatracurium is the preferred neuromuscular blocking agent for patients at risk for, or with, ards. unlike cisatracurium and atracurium, mivacurium is a short-acting nondepolarizing nmba. mivacurium was developed in the s and has recently been reintroduced to the us market [ ] . antagonism of mivacurium-induced neuromuscular blockade with anticholinesterase inhibitors can shorten the duration of blockade, although paradoxical prolongation of blockade has been reported, necessitating the need for confirmation of recovery using objective monitoring [ ] . spontaneous recovery from mivacurium occurs via butyrylcholinesterase degradation within - min after administration of an intubating dose ( . mg/kg or × ed ); patients deficient in this enzyme can have prolonged effects [ ] . rocuronium is an intermediate-acting nmba and is the only nondepolarizing drug that is currently utilized in a rapid sequence induction and intubation. a dose of . mg/kg ( × ed ) produces a similar average onset time to that of succinylcholine, although individual patient responses can vary [ ] . rocuronium administration is not associated with histamine release, and it has a little impact on hemodynamics. it is predominantly cleared through the biliary route, although a small portion is renally excreted and clearance can be slowed in patients with severe renal impairment [ ] . metabolism of rocuronium produces an active metabolite, -desacetyl-rocuronium, which has % of the neuromuscular blocking potency of the parent compound [ ] . allergic reactions may be a concern with the use of rocuronium as the frequency of such events is higher than with other nondepolarizing nmba and similar to that of succinylcholine [ ] . vecuronium, like rocuronium, is an intermediateacting nmba with a very stable hemodynamic profile. unlike rocuronium, higher doses do not result in significantly shorter time to onset, precluding the use of vecuronium in a rapid sequence induction and intubation. patients with hepatic or renal impairment can experience prolonged effects from vecuronium. furthermore, vecuronium is metabolized to -desacetyl-vecuronium, a compound with significant neuromuscular blocking activity [ ] . although vecuronium is not associated with hemodynamic perturbations, its active metabolites and association with icu-acquired weakness warrant caution in the critical care setting. pancuronium is a long-acting aminosteroidal nmba that can have prolonged effects in patients with organ dysfunction [ , ] . this agent causes direct sympathomimetic stimulation and antagonizes cardiac muscarinic receptors [ ] , often resulting in tachycardia. pancuronium is metabolized to three metabolites, with -oh pancuronium being the most clinically relevant: it has % of the neuromuscular blocking potency of the parent compound [ ] , contributing to the accumulation and prolonged duration of action with repeated pancuronium administration. therefore, the use of pancuronium in the critical care setting is discouraged. as the only depolarizing nmba available, succinylcholine produces neuromuscular blockade by competing with acetylcholine (ach) at the postsynaptic nicotinic receptors. following the administration, succinylcholine produces a reliably rapid blockade and can be used to facilitate rapid sequence induction and tracheal intubation. its use is associated with skeletal muscle fasciculations after administration, and waiting at least s after the cessation of fasciculations should provide optimal blockade for endotracheal intubation [ , ] . succinylcholine is a known trigger for malignant hyperthermia and causes a transient increase in plasma potassium levels by . - . meq/l [ , ] . this hyperkalemic response can be exaggerated in patients with upregulated extrajunctional nicotinic acetylcholine receptors (nachrs). the proliferation of such receptors occurs in patients with prolonged immobility, acute burns, stroke with paralysis, spinal cord injury, demyelinating disorders, and even sepsis [ ] . this feature is of particular concern in the critically ill patient as the duration of icu stay has been correlated with the risk of hyperkalemia (potassium ≥ . meq/l) [ ] . therefore, clinicians must be aware of recent serum potassium concentration and relevant patient history regarding neuromuscular pathology prior to administration of succinylcholine in the icu. in the perioperative setting, pharmacologic antagonism of neuromuscular blockade is routinely used to restore baseline function and reduce the risk of postoperative residual paralysis [ ] . current trends in icu management most often allow for spontaneous recovery, and pharmacologic reversal is uncommon. nonetheless, intensivists should be familiar with the antagonists for this potentially harmful class of medications in order to restore neuromuscular function in patients. neostigmine and edrophonium antagonize the action of nmbas by preventing the action of the enzyme acetylcholinesterase. this enzyme breaks down ach in the neuromuscular junction, and its inhibition results in the accumulation of ach that competes with nmba for binding sites on postsynaptic receptors. neostigmine should not be utilized to reverse moderate levels of neuromuscular blockade (train-of-four count < - ) but should be reserved for situations with the train-of-four count > (table ). median recovery time is approximately min, although significant variability exists among patients and clinical scenarios [ ] . because the increase in ach also affects muscarinic receptors, an antimuscarinic drug such as glycopyrrolate is typically co-administered to avoid side effects such as significant bradycardia and bronchoconstriction [ ] . rocuronium and vecuronium can be antagonized with sugammadex, a gamma-cyclodextrin compound that encapsulates and binds these nmbas. this encapsulation process occurs in the plasma, creating a concentration gradient that facilitates the transfer of aminosteroidal nmba from the neuromuscular junction back into the circulation. the tightly bound, inactive sugammadexaminosteroidal complex is then excreted in the urine [ ] . sugammadex has the unique ability to reverse deep or profound levels of neuromuscular blockade and restore neuromuscular function faster than spontaneous recovery from succinylcholine [ ] , although this rescue technique should not supplant prudent airway management [ ] . it is not approved for use in patients with a creatinine clearance < ml.min - ; however, several studies have reported its use in patients with a significant renal disease without complications [ ] [ ] [ ] . in addition, the nmba-sugammadex complex can be removed via standard dialysis techniques [ ] . concern exists over hypersensitivity reactions following sugammadex administration [ ] ; however, the overall incidence of such events remains low and rarely impacts routine clinical care [ ] . while not currently widely used in the critical care setting, its use may expand as new evidence emerges describing its use as a rescue therapy for residual blockade [ ] and its role in reducing the incidence of reintubation [ ] and promoting enhanced recovery protocols in the icu [ ] . in an effort to reduce the incidence of residual weakness and recurrence of neuromuscular blockade, we recommend dosing sugammadex based on actual body weight (rather than ideal body weight) and utilizing neuromuscular monitoring to confirm adequate recovery prior to extubating the patient's trachea. titrating appropriate levels of neuromuscular blockade may be essential to avoid prolonged paralysis in the icu [ ] . while the use of continuous nmba infusions rather than intermittent boluses was reported to minimize the risk of prolonged paralysis [ ] , current guidelines also suggest that the use of a peripheral nerve stimulator (pns) can be a useful tool, when combined with other clinical assessment, to determine adequate neuromuscular blockade. indeed, a pns is utilized by a majority of institutions to guide neuromuscular blockade in the critical care setting [ ] . while expert opinion has driven such implementation [ , ] , a large randomized, prospective study demonstrated that utilizing a pns reduced the incidence of prolonged muscle recovery and the overall amount of nmba administered [ ] . furthermore, the use of a pns has been shown to achieve overall cost savings, primarily through less drug being needed to maintain the desired level of paralysis [ ] . an international panel of experts recently recommended at least the use of a pns whenever neuromuscular blockade is utilized, although quantitative monitors are the only means of reliably confirming recovery [ ] . several obstacles and limitations exist when utilizing a pns. significant inter-observer variability can exist when using a pns as the providers may visually or tactilely evaluate the response to train-of-four stimulation [ ] . different muscle groups will have different sensitivity to nmba administration, leaving the site of monitoring particularly important when determining the level of blockade (fig. ) [ ] . the detection of fade, a feature that signifies some degree of the residual blockade and incomplete restoration of baseline function, is challenging even for the experienced anesthesiologist who evaluates multiple train-of-four stimulations daily [ ] . such challenges are magnified in the icu setting, as providers may have little or infrequent experience with using a pns. additionally, patients with significant perspiration and tissue edema in the icu can present obstacles to performing adequate neurostimulation. while not common practice, handheld quantitative (objective) monitoring technology is expanding and improving. the use of these devices is increasing in the perioperative arena, and their application to guide administration of nmbas and confirm recovery from neuromuscular blockade perioperatively has recently been recommended by a panel of experts [ ] . quantitative monitoring carries a distinct advantage over the use of a pns in that it objectively measures and calculates the train-of-four count and ratio, rather than relying on visual or tactile assessment by clinicians. transitioning from subjective evaluation to precisely measuring the level of blockade with quantitative monitoring represents a significant improvement in neuromuscular blockade management in the critical care setting and reduces inter-observer variability. additionally, quantitative monitors are the only reliable means to confirm adequate recovery from neuromuscular blockade prior to tracheal extubation, a clinical prerequisite that is vital in the vulnerable icu patient population. regardless of whether reversal agents are utilized or if clinicians rely on the nmbas' pharmacokinetics to recover spontaneously, adequate recovery must be documented to avoid complications of residual paralysis such as oropharyngeal dysfunction and critical respiratory events [ , ] . quantitative monitors can be categorized based on the mechanism by which the train-of-four count and/or ratio are measured [ ] . acceleromyography (amg) is the most commonly utilized quantitative monitor and relies on newton's second law that states force is proportional to acceleration. by measuring the acceleration of the monitored muscle group, amg devices can calculate the train-of-four ratio and confirm adequate recovery from neuromuscular blockade. kinemyography (kmg) measures the degree of bending of a sensor strip positioned between the thumb and index finger after neurostimulation. both kmg and amg require the muscle group being monitored to move freely without restriction as they utilize integrated piezoelectric motion sensors to quantify the response to neurostimulation. electromyography (emg) does not require freely moving muscle groups, as it measures the electrical response of the muscle upon neurostimulation. this response is proportional to the force of contraction, without requiring an actual contraction. because of this characteristic, emg may be suitable for confirming recovery for the neuromuscular blockade in the critical care setting that commonly utilizes limb restraints (and in clinical settings in which the use of amg-or kmg-based monitors is limited). similar to using a pns, emg-and amg-based quantitative monitors can also be utilized to monitor other muscle groups (facial, foot) if the hand is unavailable (figs. , , and ). a comprehensive review of sedation strategies in the icu is beyond the scope of this review. nonetheless, vigilance is warranted in maintaining adequate sedation when nmbas are utilized in order to avoid unintended patient awareness and recall. clinicians must recognize markers of inadequate sedation such as tachycardia, hypertension, diaphoresis, and ventilator dyssynchrony. while the use of processed electroencephalography (eeg) has been shown to decrease the risk of intraoperative awareness in high-risk surgical patients [ ] , current guidelines make no recommendations regarding the use of such technology in the critical care setting when nmbas are administered [ ] . however, we recognize that the utilization of processed eeg monitors at the bedside of icu patients receiving nmba infusions is becoming more common. the use of nmbas in the icu setting risks numerous complications. most notably, neuromuscular blockade results in prolonged patient immobility that can lead to the development of acquired weakness, myopathy, pressure ulcers, nerve injuries, and risk of deep venous thrombosis (dvt) [ ] . because the critically ill patient has an increased risk of dvt in their lower extremities compared with other hospitalized patients, special attention should be given to this potentially preventable complication [ , ] . boddi et al. found in their multivariate analysis that nmbas were the strongest independent predictor for dvt incidence in the icu [ ] . special care and consideration should be given to patients who receive nmbas with regard to optimizing dvt prevention. multiple studies have shown that there is a correlation between icu-acquired weakness (icuaw) and neuromuscular blockade [ , , ] ; however, there is a lack of well-designed clinical trials confirming this relationship [ ] . icuaw represents a heterogeneous term that has been used to describe varying conditions such as critical illness polyneuropathy (cip), critical illness myopathy (cim), and critical illness neuromyopathy (cinm), a diagnosis that is based on electrophysiologic testing. the etiology of such states is often multifactorial, and the reported outcomes are also heterogeneous. a recent meta-analysis suggested a modest association between nmba use and icuaw [ ] ; however, the studies that were included with a strong association have a high risk of bias, and the studies with the lowest risk of bias that performed multivariable adjustment suggested a small, but not significant association. nevertheless, the authors' sensitivity analysis showed an increased risk of cip in septic shock patients exposed to nmbas, and consistent with previous studies [ , ] , the association may be proportional to the severity of the sepsis; therefore, the authors recommended to be cautious and fig. the acceleromyography-based tofscan device (drager technologies, canada) measuring the response to neurostimulation of the adductor pollicis muscle target early use. association between the icuaw and nmba use remains controversial. well-designed trials should be performed to determine if the use of nmbas is an independent cause of icuaw. unintended (or accidental) awareness and recall are also a major concern during the use of nmbas [ , ] . in patient interviews, feelings of dying, being tied down, and fear were expressed with the concomitant use of nmbas. though the exact regimen of sedation and analgesia was not known in these patients, this complication reinforces the importance of providing proper sedation and not only relying on a single monitor, such as processed electroencephalography (peeg). rather, clinicians must assimilate multiple markers of sedation such as unexplained tachycardia and hypertension, ventilator dyssynchrony, and tearing to avoid this complication. once patients' tracheas are extubated, the most feared complication is hypoxemia and the subsequent need for reintubation. nmbas have been known to cause adverse pulmonary outcomes [ ] such as decreased inspiratory flow [ ] , residual paralysis [ ] , and impaired airway protective reflexes [ ] . such clinical features place patients at increased risk of upper airway obstruction, pneumonia, and reintubation. identification of patients who may be at risk for adverse respiratory events was highlighted by stewart and colleagues in [ ] . these investigators found that > % of patients in the fig. a the electromyography-based tetragraph device (senzime ab, uppsala, sweden) measuring the response to neurostimulation of the adductor pollicis muscle. b the electromyography-based tetragraph device (senzime ab, uppsala, sweden) measuring the response to neurostimulation of the flexor hallucis brevis muscle post-anesthesia care unit had residual neuromuscular blockade, and this risk was increased with older age, abdominal surgery, and surgery duration greater than min [ ] . patients with obstructive sleep apnea (osa) who receive nmbas may also be at higher risk for postoperative respiratory complications compared to patients who do not have osa [ ] . while this risk stratification has not been applied to the icu setting, such clinical predictors may prove useful and applicable in critically ill patients. additionally, the use of a "leak test" has been proposed to identify patients at risk for postextubation stridor that can result from laryngeal edema [ ] . while the incidence of this complication has been found to be as high as % [ ] , a recent prospective, multicenter trial found it to be less than % [ ] . interestingly, these authors propose that the increasing use of neuromuscular blockers at the time of endotracheal intubation may be a contributing factor to this decline [ ] . regardless, vigilance is warranted following extubation as post-extubation stridor is a significant predictor of prolonged mechanical ventilation and prolonged icu length of stay [ , ] . while the administration of nmbas can prove to be a life-saving therapy in select critically ill patients, these medications have unique inherent risks as well. however, by understanding the pharmacology, dosing, drug interactions, side effects, and monitoring techniques, clinicians can safely maximize the benefits. as there are few prospective studies that support improved long-term outcomes for patients in the icu, the administration of nmbas should be limited to facilitating endotracheal intubation, prevention of shivering following therapeutic hypothermia, and avoiding increases in intracranial pressure in patients at risk associated with coughing or ventilator dysynchrony. moreover, residual weakness following the use of nmbas in the icu is a particular concern, given this vulnerable population. this complication may occur more frequently in the icu, given the abundance of patients with significant organ dysfunction and delayed drug (nmba) elimination. we recommend continuous vigilance when nmbas are used in critically ill patients, selecting the most appropriate nmba for each individual clinical scenario, evidence-based protocols that ensure adequate sedation and analgesia, appropriate equipment for assessing the degree of neuromuscular blockade, and aggressive physical therapy regimens during periods of reduced mobility. such a multifaceted approach can improve patient safety when nmbas are utilized in the icu and reduce associated complications. ach: acetylcholine; amg: acceleromyography; ards: acute respiratory distress syndrome; asa: american society of anesthesiologists; cim: critical illness myopathy; cinm: critical illness neuromyopathy; cip: critical illness polyneuropathy; dvt: deep venous thrombosis; ed : effective dose that decreases the twitch by % from baseline; eeg: electroencephalography; emg: electromyography; grade: grading of recommendations assessment, development, and evaluation; icp: intracranial pressure; icu: intensive care unit; icuaw: intensive care unit-acquired weakness; kmg: kinemyography; nachr: nicotinic acetylcholine receptors; nap : th national audit project; nmba: neuromuscular blocking agent; nmj: neuromuscular junction; or: operating room; osa: obstructive sleep apnea; pao /fio : partial pressure of oxygen to fraction of inspired oxygen; peeg: processed electroencephalography; pns: peripheral nerve stimulator; rsii: rapid sequence induction and intubation; sccm: society of critical care medicine for all aspects of the work. sjb revised the manuscript critically for intellectual content, approved the final version of the manuscript, and agrees to be accountable for all aspects of the work. rcp revised the manuscript critically for intellectual content, approved the final version of the manuscript, and agrees to be accountable for all aspects of the work. authors' information jrr is a cardiac anesthesiologist who conducts research involving neuromuscular blockade and its management. rr is an intensivist who investigates methods to improve safety in the critical care setting. vht is a research fellow working with jrr and sjb on neuromuscular blockade research projects. sjb is an international expert and author of a consensus statement recommending appropriate neuromuscular monitoring in the perioperative setting. rcp is an intensivist, anesthesiologist, and international expert on neuromuscular blockade management. availability of data and materials not applicable ethics approval and consent to participate not applicable the patient provided written informed consent to reuse images presented in figs. , , and . jrr has completed industry-sponsored research with funds to the employer with merck, inc. rr has no conflicts of interest. vh-t has no conflicts of interest. rcp is on the speakers bureau for merck co., inc., and a consultant for residual neuromuscular block: lessons unlearned. part i: definitions, incidence, and adverse physiologic effects of residual neuromuscular block task force of the american college of critical care medicine of the society of critical care m, the american society of health-system pharmacists acocp. sedation, analgesia, and neuromuscular blockade of the critically ill adult: revised clinical practice guidelines for clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient: update-executive summary clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient grading quality of evidence and strength of recommendations difficult intubation in obese patients: incidence, risk factors, and complications in the operating theatre and in intensive care units endotracheal intubation in the icu comparison of tracheal intubation conditions in operating room and intensive care unit: a prospective, observational study tracheal intubation in the critically ill: a multi-centre national study of practice and complications clinical practice and risk factors for immediate complications of endotracheal intubation in the intensive care unit: a prospective, multiple-center study practice guidelines for management of the difficult airway: an updated report by the american society of anesthesiologists task force on management of the difficult airway avoidance versus use of neuromuscular blocking agents for improving conditions during tracheal intubation or direct laryngoscopy in adults and adolescents neuromuscular blocking agent administration for emergent tracheal intubation is associated with decreased prevalence of procedure-related complications rocuronium versus succinylcholine for rapid sequence induction intubation sugammadex, a selective reversal medication for preventing postoperative residual neuromuscular blockade the myth of rescue reversal in "can't intubate, can't ventilate" scenarios early identification of patients at risk for difficult intubation in the intensive care unit: development and validation of the macocha score in a multicenter cohort study nationwide survey on training and device utilization during tracheal intubation in french intensive care units the macocha score is feasible to predict intubation failure of nonanesthesiologist intensive care unit trainees french national survey on difficult intubation in intensive care units national survey on airway and difficult airway management in intensive care units difficult airway management resources and capnography use in japanese intensive care units: a nationwide cross-sectional study survey of airway management strategies and experience of non-consultant doctors in intensive care units in the uk strategies to prevent airway complications: a survey of adult intensive care units in australia and new zealand tracheal extubation of the adult intensive care patient with a predicted difficult airway -a narrative review effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome neuromuscular blockers in early acute respiratory distress syndrome early neuromuscular blockade in the acute respiratory distress syndrome neuromuscular blocking agent cisatracurium attenuates lung injury by inhibition of nicotinic acetylcholine receptor-alpha neuromuscular blockade in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials validation of neuromuscular blocking agent use in acute respiratory distress syndrome: a meta-analysis of randomized trials neuromuscular blockers in the acute respiratory distress syndrome: a meta-analysis medical and ventilatory management of status asthmaticus severe weakness complicating status asthmaticus despite minimal duration of neuromuscular paralysis myopathy following mechanical ventilation for acute severe asthma: the role of muscle relaxants and corticosteroids effects of cisatracurium on cerebral and cardiovascular hemodynamics in patients with severe brain injury early, routine paralysis for intracranial pressure control in severe head injury: is it necessary? treatment with neuromuscular blocking agents and the risk of in-hospital mortality among mechanically ventilated patients with severe sepsis clinical study of early use of neuromuscular blocking agents in patients with severe sepsis and acute respiratory distress syndrome surviving sepsis campaign: international guidelines for management of sepsis and septic shock hypothermia for neuroprotection in adults after cardiopulmonary resuscitation neuromuscular blockade in the st century management of the critically ill patient american heart association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care advances in neurobiology of the neuromuscular junction: implications for the anesthesiologist temperature-dependent pharmacokinetics and pharmacodynamics of vecuronium effects of hypothermic cardiopulmonary bypass on the pharmacodynamics and pharmacokinetics of rocuronium the influence of hypothermia (surface cooling) on the time-course of action and on the pharmacokinetics of rocuronium in humans sepsis attenuates the intensity of the neuromuscular blocking effect of dtubocurarine and the antagonistic actions of neostigmine and edrophonium accompanying depression of muscle contractility of the diaphragm acute late sepsis attenuates effects of a nondepolarizing neuromuscular blocker, rocuronium, by facilitation of endplate potential and enhancement of membrane excitability in vitro sepsis decreases the activity of acetylcholinesterase by reducing its expression at the neuromuscular junction introduction to drug pharmacokinetics in the critically ill patient biodegradable neuromuscular blocking agents. . stereochemical studies on atracurium and related polyalkylene di-esters cardiovascular and neurological effects of laudanosine. studies in mice and rats, and in conscious and anaesthetized dogs use of cisatracurium in critical care: a review of the literature histaminerelease haemodynamic changes produced by rocuronium, vecuronium, mivacurium, atracurium and tubocurarine current practices in sedation and analgesia for mechanically ventilated critically ill patients: a prospective multicenter patient-based study perceived versus actual sedation practices in adult intensive care unit patients receiving mechanical ventilation an observational study of the efficacy of cisatracurium compared with vecuronium in patients with or at risk for acute respiratory distress syndrome the clinical neuromuscular pharmacology of mivacurium chloride (bw b u). a short-acting nondepolarizing ester neuromuscular blocking drug reversal of mivacurium-induced neuromuscular blockade with a cholinesterase inhibitor: a systematic review neuromuscular blocking drugs and their antagonists in patients with organ disease pharmacokinetics and pharmacodynamics of rocuronium in patients with and without renal failure groupe d'etudes des reactions anaphylactoides p. anaphylaxis during anesthesia in france: an -year national survey the pharmacodynamics and pharmacokinetics of the metabolite -desacetylvecuronium (org ) and its parent compound, vecuronium, in human volunteers pancuronium pharmacokinetics in patients with liver cirrhosis dose-related tachycardia induced by pancuronium during balanced anaesthesia with and without droperidol the comparative potency and pharmacokinetics of pancuronium and its metabolites in anesthetized man fasciculation caused by suxamethonium and other cholinergic agents temporal correlation of succinylcholineinduced fasciculations to loss of twitch response at different stimulating frequencies biochemical changes following suxamethonium. serum myoglobin, potassium and creatinine kinase changes before commencement of surgery fasciculations, myalgia and biochemical changes following succinylcholine with atracurium and lidocaine pretreatment challenges and advances in intubation: rapid sequence intubation the limits of succinylcholine for critically ill patients residual neuromuscular block: lessons unlearned. part ii: methods to reduce the risk of residual weakness tactile assessment for the reversibility of rocuronium-induced neuromuscular blockade during propofol or sevoflurane anesthesia reversal of neuromuscular blockade sugammadex: a novel selective relaxant binding agent reversal of profound neuromuscular block by sugammadex administered three minutes after rocuronium: a comparison with spontaneous recovery from succinylcholine efficacy and safety of sugammadex in the reversal of deep neuromuscular blockade induced by rocuronium in patients with end-stage renal disease: a comparative prospective clinical trial multicentre, parallel-group, comparative trial evaluating the efficacy and safety of sugammadex in patients with end-stage renal failure or normal renal function shortterm safety and effectiveness of sugammadex for surgical patients with endstage renal disease: a two-centre retrospective study dialysability of sugammadex and its complex with rocuronium in intensive care patients with severe renal impairment sugammadex and rocuroniuminduced anaphylaxis comparison of incidence of anaphylaxis between sugammadex and neostigmine: a retrospective multicentre observational study sugammadex as rescue therapy for residual neuromuscular blockade in the intensive care unit neostigmine versus sugammadex for reversal of neuromuscular blockade and effects on reintubation for respiratory failure or newly initiated noninvasive ventilation: an interrupted time series design sugammadex--a short review and clinical recommendations for the cardiac anesthesiologist acquired neuromuscular disorders in the intensive care unit paralysis in the critically ill: intermittent bolus pancuronium compared with continuous infusion a national survey of critical care nurses' practices related to administration of neuromuscular blocking agents national practice with assessment and monitoring of neuromuscular blockade neuromuscular blockade in the intensive care unit a prospective, randomized, controlled evaluation of peripheral nerve stimulation versus standard clinical dosing of neuromuscular blocking agents in critically ill patients retrospective pharmacoeconomic evaluation of dosing vecuronium by peripheral nerve stimulation versus standard clinical assessment in critically ill patients consensus statement on perioperative use of neuromuscular monitoring the interpretation of train-of-four monitoring in intensive care: what about the muscle site and the current intensity? tactile and visual evaluation of the response to train-of-four nerve stimulation incidence of complications in the post-anesthesia care unit and associated healthcare utilization in patients undergoing non-cardiac surgery requiring neuromuscular blockade - : a single center study pharyngeal function and breathing pattern during partial neuromuscular block in the elderly: effects on airway protection neuromuscular monitoring in the perioperative period bispectral index for improving anaesthetic delivery and postoperative recovery reduction in deep vein thrombosis incidence in intensive care after a clinician education program deep vein thrombosis and its prevention in critically ill adults complication profiles of adult asthmatics requiring paralysis during mechanical ventilation critical illness myopathy and neuropathy neuromuscular blockade and skeletal muscle weakness in critically ill patients: time to rethink the evidence? neuromuscular blocking agents and neuromuscular dysfunction acquired in critical illness: a systematic review and meta-analysis a fresh look at paralytics in the critically ill: real promise and real concern critical illness polyneuropathy: risk factors and clinical consequences. a cohort study in septic patients patients' recollections of therapeutic paralysis in the intensive care unit th national audit project (nap ) on accidental awareness during general anaesthesia: summary of main findings and risk factors residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit dosedependent association between intermediate-acting neuromuscularblocking agents and postoperative respiratory complications residual paralysis at the time of tracheal extubation the impact of residual neuromuscular blockade, oversedation, and hypothermia on adverse respiratory events in a postanesthetic care unit: a prospective study of prevalence, predictors, and outcomes postoperative complications with neuromuscular blocking drugs and/or reversal agents in obstructive sleep apnea patients: a systematic review independent effects of etiology of failure and time to reintubation on outcome for patients failing extubation postextubation laryngeal edema in adults. risk factor evaluation and prevention by hydrocortisone cuff leak test for the diagnosis of post-extubation stridor: a multicenter evaluation study re-intubation increases the risk of nosocomial pneumonia in patients needing mechanical ventilation effect of failed extubation on the outcome of mechanical ventilation publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations adherence to national and international regulations not applicable authors' contributions jrr contributed to the conception of the manuscript, revised it critically for intellectual content, approved the final version of the manuscript, and agrees to be accountable for all aspects of the work. rr contributed to the conception of the manuscript, revised the manuscript critically for intellectual content, approved the final version of the manuscript, and agrees to be accountable for all aspects of the work. vht contributed to the conception of the manuscript, revised the manuscript critically for intellectual content, approved the final version of the manuscript, and agrees to be accountable fig. the electromyography-based twitchview device (blink device company, seattle, wa) key: cord- -amet wx authors: park, caroline; clark, damon title: care of the patient with liver failure requiring transplantation date: - - journal: surgical critical care therapy doi: . / - - - - _ sha: doc_id: cord_uid: amet wx patients undergo liver transplantation to address chronic liver failure, acute fulminant liver failure, or primary liver cancer. depending on acuity, patients with decompensated chronic or acute fulminant liver failure generally require preoperative intensive care unit admission to manage organ dysfunction. those with chronic liver failure are allocated an organ based on waiting list position determined by their local organ procurement organization (opo). this position is dependent upon blood type and model for end- stage liver disease (meld) score. these patients thus are critically ill and require preoperative icu monitoring and care. patients with hepatocellular carcinoma (hcc) who require liver transplantation are given a meld exception and rarely require preoperative icu care. the patient’s ability to undergo liver transplant in the setting of hcc is determined by the milan criteria or the university of california, san francisco (ucsf) criteria. patients undergo liver transplantation to address chronic liver failure, acute fulminant liver failure, or primary liver cancer. depending on acuity, patients with decompensated chronic or acute fulminant liver failure generally require preoperative intensive care unit (icu) admission to manage organ dysfunction. those with chronic liver failure are allocated an organ based on waiting list position determined by their local organ procurement organization (opo). this position is dependent upon blood type and model for end-stage liver disease (meld) score. meld is determined by a weighting of serum bilirubin, creatinine, and international normalization ratio (inr). those with a high meld score have a greater risk of mortality and thus are given priority to transplantation. patients with a meld score of have a % chance of death within months. this is particularly important given the transplantation is typically performed on those with high meld scores in large urban areas such as ours in the greater los angeles area. these patients thus are critically ill and require preoperative icu monitoring and care. patients with hepatocellular carcinoma (hcc) who require liver transplantation are given a meld exception and rarely require preoperative icu care. the patient's ability to undergo liver transplant in the setting of hcc is determined by the milan criteria or the university of california, san francisco (ucsf) criteria. hcc patients with a single tumor < cm, up to three tumors < cm, absence of macroscopic vascular invasion, and absence of extrahepatic spread may undergo liver transplantation based on the milan criteria. altered level of consciousness is common in patients with decompensated cirrhosis. this is a result of portosystemic shunting and hepatocellular dysfunction/toxin production that results in hepatic encephalopathy. most severe or accelerated changes in the level of consciousness are the result of a precipitating event such as a significant upper gastrointestinal bleed and resultant uremia or a new infection. encephalopathy can be exacerbated by the administration of medications such as benzodiazepines that are generally avoided in the routine treatment of this patient population. those with low-grade encephalopathy, manifested by mild confusion and tremors, are administered agents such as lactulose to decrease ammonia absorption by acidifying bowel content and increase transit of the bowel contents. rifaximin is also commonly used to diminish the presence of urease and protease-splitting bacteria. it is important to remember to discontinue lactulose therapy in advance of anticipated liver transplantation to avoid intraoperative diarrhea and possible bowel distention. systemic and splanchnic arteriolar vasodilation is a wellknown physiologic derangement in patients with end-stage liver disease. as a result, these patients have hyperdynamic and low systemic vascular resistance cardiac profiles and often require vasopressor therapy-whether oral (e.g., midodrine) or intravenous (e.g., norepinephrine)-to maintain adequate mean arterial pressures (map) of > mmhg. it is important to consider that hypotension may be multifactorial, resulting from active hemorrhage, infection, and/or systemic inflammatory response (sirs). further, cardiac contractile function may be impaired in patients with longstanding cirrhosis or in those with associated ischemic cardiac disease. routine use of beta blockade as prophylaxis in those with varices may also cause hypotension. if hemor-rhage and sirs response have been addressed and ruled out, refractory hypotension could be a result of adrenal insufficiency; this is a common pathophysiology in end-stage liver disease patients. there is little additional role for invasive cardiac monitoring in cirrhotic patients for the diagnosis and treatment of shock over echocardiography and other noninvasive means. in general, the treatment of shock does not depart much from that in other patients. patients should be approached similarly with crystalloid resuscitation and early goal-directed therapy; there is little evidence that albumin should be the resuscitative fluid of choice. monitoring base deficit and lactate is as prognostic and useful to guide resuscitative efforts in patients with decompensated liver disease as it is for the general icu population. patients with advanced liver disease may have other associated pulmonary disorders, including hepatic hydrothorax, emphysema from alpha- -antitrypsin deficiency, hepatopulmonary syndrome (hps), and portopulmonary hypertension (pph). hydrothorax is typically the result of tense abdominal ascites and should be addressed by paracentesis, thoracentesis, and total body volume management. draining of pulmonary effusions should be limited to those with impending respiratory failure due to the risk of infection and hemorrhage associated with invasive procedures and re-accumulation. definitive treatment of pulmonary effusions is with liver transplantation. hps is caused by intrapulmonary shunting and does not result in right heart failure. patients with hps will classically experience positional hypoxia. pph on the other hand results from pulmonary vascular vasoconstriction and can ultimately lead to thrombosis and fibrosis. in contrast to hps, right heart failure is typical in pph. it is important to distinguish between hps and pph. in general, liver transplantation is curative of the former and, until recently, was contraindicated in the latter. however, the introduction of many new agents and classes of agents to treat pulmonary hypertension may render liver transplantation possible in centers of excellence with careful pre-and intraoperative monitoring. although noninvasive monitoring is helpful and new modalities are being developed, the most expeditious and accurate modality to differentiate between hps and pph is right heart catheterization. hps, pph, and chf can all cause elevated pulmonary artery pressures. however, pulmonary artery wedge pressure (pawp) is low in hps and pph (and elevated in chf). pulmonary vascular resistance (pvr) is normal to decreased in hps but elevated in pph. thus, cardiac output is elevated in hps and normal to decreased in pph. one of the major causes of aki in patients with advanced cirrhosis and ascites is the phenomenon of hepatorenal syndrome (hrs) or acute renal failure without other etiology. there are two subtypes of hrs, types i and ii. the first type generally progresses with a rapid decrease in renal function and is characterized with doubling in serum creatinine within that period of time. it may be precipitated by spontaneous bacterial peritonitis, gastroenteritis with high-volume diarrhea, volume loss from gastrointestinal bleed, or largevolume paracentesis without appropriate volume repletion. type i hrs can be fatal and often leads to multi-system organ failure. type ii hrs demonstrates a more indolent course of renal failure, often precipitated by ascites refractory to diuretic treatment [ ] . hrs develops due to splanchnic circulation vasodilation, intravascular hypovolemia, and renal vasoconstriction and is most often a diagnosis of exclusion after investigating for other causes of renal failure. the treatment approach includes strict intake and output monitoring, serum creatinine monitoring, and following changes from baseline or within the past h. if the patient develops oliguria with elevated serum creatinine greater than % from a reference value or baseline serum creatinine level, suspect aki. multiple diagnostic variable are used to diagnose hrs in patients with cirrhosis ( fig. . ). these patients may require combined liver and renal transplant and/or intraoperative renal replacement therapy to assist with volume status, correcting acidosis, and electrolyte abnormalities. the mainstay of treatment for hrs is liver transplantation, after which a majority of patients demonstrate a return to adequate renal function. consideration should be given to a combined liver/kidney transplantation in those who have required dialysis for greater than months, although this time period is controversial. a variety of approaches can be used to increase intravascular volume and map including albumin and vasopressors (norepinephrine, terlipressin). intermittent paracentesis may be necessary to manage third spacing of fluids in hepatorenal syndrome prior to liver transplant [ , ] . type hrs requires multiple therapeutic strategies and therapies; please refer to fig. . for a detailed algorithm. the presence of infection in a cirrhotic patient quadruples mortality and worsens liver function. those with chronic liver failure are functionally immunosuppressed and are often colonized with multiresistant organisms. the most common infection in these patients is spontaneous bacterial peritonitis. strict attention should be paid to removing unnecessary catheters and avoiding intubation/mechanical ventilation, when possible. patients require prophylactic antibiotics for spontaneous bacterial peritonitis after a variceal bleed; however, there is little need for general broadspectrum antimicrobial therapy. patients with fulminant liver failure receive a meld exemption in listing-the appropriateness of transplantation may be determined by king's criteria (table . ). in general, patients experience toxic necrosis of the liver on a baseline of normal function, most commonly due to intentional or inadvertent ingestion of large doses of acetaminophen. thus, the abnormalities noted are lactic acidosis, marked elevation of inr, and high-grade encephalopathy. ascites and hepatorenal syndrome are often not present given the acuity of presentation. creatinine, however, is often elevated due to atn. if time of ingestion is known, and within h, n-acetylcysteine should be administered to prevent further toxicity in acute liver failure patients. if the patient fails medical management with progression of liver failure, liver transplantation will be required. the most significant risk of mortality to a patient with fulminant liver failure is that of cerebral edema and subsequent death from cerebral hernia-tion. intracranial monitoring remains controversial given severe coagulopathy, thrombocytopenia, and risk of infection. serum sodium of - meq/l should be maintained with hypertonic saline to decrease the amount of cerebral edema. if renal dialysis is required, a continuous mode is preferred to avoid rapid fluid shifts that may exacerbate cerebral edema. patients having undergone liver transplantation will require postoperative intensive care unit (icu) admission. close communication and coordination of care between the surgeons, anesthesiologists, intensivists, and nursing staff are essential to the management of the patient in this setting. liver transplantation typically entails a lengthy surgical procedure requiring significant amounts of blood product transfusion and risk of postoperative respiratory insufficiency. preoperatively, many of these patients have neurologic, cardiopulmonary, and renal dysfunction requiring fentanyl, a narcotic, is the first-line agent for the treatment of pain and agitation given its rapid onset and short duration of action in postoperative transplant patient. those who require additional sedation for agitation not controlled with narcotic analgesia benefit from the use of dexmedetomidine over benzodiazepines given a decreased risk of iatrogenic delirium and decreased length of mechanical ventilation [ ] . dexmedetomidine is an alpha- adrenoreceptor agonist and should be used in caution with patients with hypotension and baseline bradycardia as it can exacerbate both conditions. with the use of spontaneous awakening trials (sats), richmond agitation and sedation score (rass), and confusion assessment method for the icu (cam-icu), patients have decreased episodes of delirium, duration of mechanical ventilation, and icu and hospital length of stay [ ] . in this particular population, however, sustained delirium and encephalopathy may be the result of poor functioning of liver transplant graft, infection, intracranial hemorrhage or cerebral ischemia, seizures, and/or immunosuppressant toxicity. there should be a low threshold to pursue diagnostic ct scan of head, cultures including cerebral spinal fluid, and electroencephalography (eeg) in the posttransplant patient with change in mental status. encephalopathy due to cerebral edema associated with fulminant liver failure and elevated ammonia levels in patients with end-stage liver disease should be corrected with an adequately functioning liver transplant graft. if an intracranial monitor was placed preoperatively, it should be maintained until the inr is corrected and the liver is functioning well. in the past decade, early recovery after surgery or "fasttrack" programs have been implemented in a variety of disciplines, including hepatobiliary and colorectal patients after elective surgery with no worsening of postoperative outcomes and improvement in patient satisfaction. liver transplant patients may be eligible for fast-track extubation immediately postoperative in the operating room and upon arrival to the icu. patients that successfully undergo fasttrack extubation have been shown to benefit from decreased rates of re-intubation and tracheostomy along with improved survival [ ] . patients that are likely not candidates for fasttrack extubation include those with preoperative acute liver failure, re-transplantation, child's c cirrhosis, and intraoperative red blood cell transfusion > units [ ] . patients that require continued mechanical ventilation upon arrival to the icu should be placed on ventilator settings of tidal volume ml/kg and fio < . [ ] . patients who may exhibit transfusion-related lung injury after receiving a significant amount of blood products require ventilation strategies similar to patients with acute respiratory distress syndrome (ards); in this case, target tidal volumes of ml/kg with supplemental oxygen and positive endexpiratory pressure (peep) [ ] . infections of the lower respiratory tract require broad-spectrum antibiotics and antifungals until species and sensitivities are established. the liver transplant patients who remain hemodynamically stable and require minimal mechanical ventilation settings with resolved encephalopathy should undergo daily spontaneous breathing trials (sbt) and subsequent evaluation for possible extubation to reduce the duration of mechanical ventilation and icu length of stay [ ] . early mobilization and aggressive chest physiotherapy are performed to prevent complications of atelectasis and inadequate ventilation. centers may opt to monitor patients intraoperatively with pulmonary artery catheters and/or transesophageal echocardiography. once stable and resuscitated, patients should be liberated from these devices. steroids are routinely administered as a part of early immunosuppression regimen after liver transplant and may require a prolonged course in treating hypotension secondary to adrenal insufficiency. liver transplantation patients remain at risk for postoperative hemorrhage due to thrombocytopenia, fibrinolysis, and deficiency of coagulation factors. abnormal coagulation tests and platelet count are not good predictors of bleeding; thus aggressive correction of these coagulopathies should be avoided. therapy should also include practical measures as avoiding hypothermia and persistent acidosis. aggressive correction of coagulopathy and thrombocytopenia may also put patients at higher risk of hepatic artery, portal vein, and deep vein thrombosis. typical target ranges include hemoglobin of g/dl and platelet count > × ^ /l [ ] . thromboelastography (teg) may be useful in dictating guided blood product resuscitation in the post-liver transplant patients to decrease blood loss and transfusion requirements [ ] . liver transplant patients with hemorrhage that are undergoing appropriate blood product resuscitation and become hemodynamically unstable or develop abdominal compartment syndrome should return immediately to the operating room. patients with advanced cirrhosis are often malnourished and as such are at higher risk for infections, worsening encephalopathy, and decompensation. though these patients may appear grossly overweight, their usual or dry weight is often masked by massive ascites and edema secondary to hypoalbuminemia. the american and european society for clinical nutrition and metabolism and the european society for clinical nutrition and metabolism (aspen [ ] and espen [ ] , respectively) have compiled an extensive set of guidelines, both of which provide a subset of consensus statements for patients with hepatic failure. the primary goals of nutrition for patients with hepatic failure include ( ) identifying and assessing patients at risk for undernutrition, ( ) calculating nutritional needs and incorporating adequate protein and high-calorie formulas, and ( ) considering dobhoff placement if encephalopathy precludes voluntary enteral nutrition or short-term parenteral nutrition if unable to provide enteral feeds secondary to ileus or malabsorption. dry or usual weight may be difficult to ascertain given the chronicity of liver disease, thus complicating calculations for caloric needs. poor oral intake may be a result of underlying encephalopathy, gastroparesis, and overall decreased gastrointestinal motility. in prior years, protein restriction was emphasized to mitigate the effects on worsening hepatic encephalopathy. however, given the already reduced lean muscle mass of this vulnerable patient population, proteinrestricted diets can worsen hepatic failure. recommended protein intake is . - . g/kg/day, with a total energy intake of - kcal/kg/day. dobhoff placement is recommended if the patient is unable to meet his/her caloric needs per os; percutaneous endoscopic gastrostomy or open gastrostomy tube is otherwise not recommended given an increased risk of complications [ ] . post-liver transplant acute kidney injury (aki) is a frequent event with reports of up to % of patients developing aki [ ] . factors such as increased child-pugh score, preexisting diabetes, and large number of intraoperative transfusions increase the risk of aki in the post-liver transplant. the development of post-liver transplant aki leads to prolonged icu and hospital length of stay, increased mortality, and decreased duration of liver graft function [ ] . in patients that develop aki post-liver transplantation, treatment includes the prevention of hypotension and decreased use of unnecessary blood products. the use of renal replacement therapy is reserved for patients that develop significant volume overload, uremia, and electrolyte abnormalities. the most effective treatment of postoperative liver transplant aki is prevention. preventive strategies include delayed initiation of calcineurin inhibitors, avoiding nephrotoxic agents such as iv contrast, and ensuring adequate control of hyperglycemia [ ] . the most common cause of morbidity and mortality after liver transplantation is infection, accounting for % of the deaths after liver transplantation [ ] . prolonged and complicated operations, multiple catheter insertions, immunosuppression, and large quantities of fresh frozen plasma can all increase the risk of infectious complications [ ] . diagnosis of infections in this patient population may be difficult due to the lack of signs and symptoms such as fever, chills, cellulitis, and leukocytosis due to an immunosuppressed status. early postoperative infections in liver transplant patients are typically bacterial and related to the donor's status (previous infections from advanced cirrhosis), the surgical procedure itself, prolonged use of invasive catheters, and duration of mechanical ventilation. perioperative antibiotics are typically broad spectrum and may include third-generation cephalosporins. early removal of invasive catheters, early mobility, pulmonary toilet, vigilant monitoring of patient's surgical wounds and drains, and early discharge from the icu may decrease these infectious complications. liver transplant patients are at risk of developing opportunistic infections given the initial burst of immunosuppression with high-dose steroid therapy and, as such, should be initiated on prophylactic trimethoprimsulfamethoxazole (tmp-smx) to prevent pneumocystis carinii pneumonia and ganciclovir to prevent cytomegalovirus infection. besides surgical and coagulopathic bleeding, other postoperative complications can occur; these include postoperative hepatic artery thrombosis ( %) or portal vein thrombosis (< %) [ ] . the resulting lack of blood flow and developing ischemia and necrosis from hepatic artery thrombosis present with signs and symptoms similar to fulminant liver failure patients with elevated liver serum tests, coagulopathy, and severe metabolic acidosis. doppler ultrasound of the hepatic artery and portal vein is routinely employed within the first - h after liver transplant to diagnose possible vascular complications prior to the development of ischemia and necrosis of the liver transplant graft. these patients are at high risk for continued ischemia and necrosis of the graft with the need for urgent relisting and re-transplantation. compared to patients with hepatic artery thrombosis, those with portal vein thrombosis do not present with such critical signs and symptoms as a rapid rise in liver function tests and disruption in synthetic function. although portal vein thrombosis leads to elevation in liver serum tests, signs and symptoms are less dramatic and may consist of mesenteric venous congestion, gastrointestinal hemorrhage, and the development of ascites. although these patients may require retransplantation, they can typically be managed with thrombectomy, shunt, or revision of the portal vein anastomosis. biliary duct complications, which include anastomosis stricture or leak, affect - % of liver transplant patients and are often delayed diagnoses [ ] . thrombosis of the liver transplant hepatic artery can also lead to nonanastomotic stricture [ ] . biliary duct complications can be evaluated with ultrasound of the liver transplant graft looking for biloma and biliary duct dilation. similarly, internal to external drains placed during the liver transplantation may show biliary drainage during the first several postoperative days. elevated serum liver tests specifically bilirubin will elevate or fail to appropriately decrease after liver transplant, and the patients may develop signs and symptoms of infection. magnetic resonance cholangiopancreatography (mrcp) may be used as a noninvasive diagnostic modality to look for biliary anastomosis complications. endoscopic retrograde cholangiopancreatogram (ercp) can be used for the diagnosis of biliary anastomosis leak and stricture, in addition to possible treatment with sphincterotomy and/or biliary stent [ ] . endoscopic treatment is often preferred over percutaneous management of biliary leaks and stricture. treatment options include endoscopic dilation and stenting and have excellent success rates approaching % [ ] . surgical revision of the biliary anastomosis due to stricture or leak may be required in - % of patients [ , ] . the use of broad-spectrum antibiotics for treatment or prophylaxis is recommended due to the high risk of cholangitis and intra-abdominal sepsis [ ] . - % of patients with biliary stricture will have to undergo re-transplantation due to chronic biliary cirrhosis due to obstruction even with adequate treatment [ , ] . primary graft nonfunction and hyperacute rejection can occur in the immediate or acute postoperative setting. primary graft nonfunction occurs in - % of orthotopic liver transplants and typically presents similar to fulminant liver failure with significant metabolic acidosis, elevated liver enzymes, coagulopathy, and lack of bile production [ , ] . intraoperative hemodynamic instability, reperfusion injury of the liver transplant graft, marginal livers, and advanced age of donors and recipient are factors that may lead to primary graft nonfunction. once diagnosed, the only treatment indicated is for relisting and liver re-transplantation. development of hyperacute rejection (har) after liver transplant is a rare complication that may develop intraoperatively or in the immediate postoperative period, which is antibody-mediated and due to abo crossmatch incompatibility. patients with har typically present with progressive encephalopathy and weakness, elevated bilirubin, severe coagulopathy, thrombocytopenia, metabolic acidosis, and shock. diagnosis is confirmed with doppler ultrasound that displays portal vein thrombosis and absence of biliary duct stricture. along with critical care supportive therapy, patients can be managed with plasma exchange for antibody removal and intravenous immunoglobulin [ ] . overall, patients that develop har will need immediate relisting and re-transplantation. acute cellular rejection after liver transplant may occur within the first - weeks, and the patients are often out of the icu and no longer critically ill. patients with acute cellular rejection typically are not critically ill and may present with fever, weakness, and elevated liver function tests. prior to treating the patients for acute cellular rejection, one must rule out all possible acute infections that could account for the signs and symptoms given that the treatment of acute cellular rejection requires immunosuppression with pulse-dose glucocorticoids and adjustment of other immunosuppression medications. glucocorticoids are the first-line therapy for the prevention and treatment of acute cellular rejection. common glucocorticoids used for liver transplant include prednisone, hydrocortisone, and methylprednisolone with the first dose given while in surgery. intravenous hydrocortisone is typically administered in the immediate postoperative period until the patient is taking enteral nutrition and can transition to oral prednisone. most patients will undergo a glucocorticoid taper and either transitioned off of glucocorticoids or to a low maintenance dose, typically over a -month to -year period [ ] . glucocorticoids have a significant number of side effects including poor wound healing, increased infection risks, hyperglycemia, and hypertension; these patients may need judicious adjustment of insulin sliding scale for hyperglycemia. glucocorticoid-free immunosuppression is possible and may be of benefit in patients with cirrhosis due to hepatitis c virus. [ , ] calcineurin inhibitors (cni), including cyclosporine and tacrolimus, are used to prevent and treat acute rejection and liver transplant graft loss. both provide immunosuppression by inhibiting interleukin- and interferon-gamma production and require monitoring of blood levels to reach appropriate therapeutic levels. potential side effects including altered mental status, seizures, neuropathy, renal failure, electrolyte abnormalities, and others should be monitored for and treated appropriately. tacrolimus is currently the cni of choice and has demonstrated superiority in preventing acute rejection and graft loss with decreased mortality [ , ] . posterior reversible encephalopathy syndrome (pres) is a rare syndrome and side effect of cni that is diagnosed with clinical exam and ct or mri. patients with pres most commonly present with seizures but may also have symptoms such as headache, delirium, and visual changes. head ct or mri typically demonstrates vasogenic edema of the parietal or occipital lobes; however mri may be more sensitive in diagnosing pres. treatment of pres most often involves discontinuing the offending cni and supportive care. mycophenolate mofetil (mmf, cellcept) is an antimetabolite that inhibits purine and pyrimidine synthesis with the active by-product of mycophenolic acid (mpa). mpa ultimately inhibits the proliferation of t lymphocytes for immunosuppression. mmf is typically used long term to reduce the dose or replace glucocorticoids. as such, the use of mmf will avoid common cni side effects, such as nephrotoxicity and neurotoxicity, though it can cause other side effects, including abdominal pain, nausea, vomiting, anorexia, diarrhea, and bone marrow suppression. mmf as a monotherapy after the acute phase of liver transplant has shown similar results to glucocorticoids and cni for prevention of chronic rejection and mortality [ , ] . mammalian target of rapamycin (mtor) inhibitors (everolimus and sirolimus) inhibit the proliferation of lymphocytes. the use of mtor inhibitors allows for immunosuppression while avoiding renal dysfunction and has shown potential benefit in patients undergoing liver transplant for hcv. common complications of dyslipidemia and oral ulcers are typically easy to manage. hepatorenal syndrome pathogenesis of hepatorenal syndrome: implications for therapy systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome management of the critically ill patient with cirrhosis: a multidisciplinary perspective improved analgesia, sedation and delirium protocol associated with decreased duration of delirium and mechanical ventilation dexmedetomidine vs. midazolam or propofol for sedation during prolonged ventilation fast tracking in liver transplanatation: which patient benefits from this approach? a trial of intraoperative low-tidal-volume ventilation in abdominal surgery the acute respiratory distress syndrome network. ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome protocolized versus non-protocolized weaning for reducing the duration of mechanical ventilation in critically ill adult patients immediate postoperative management and complications on the intensive care unit methods to decrease blood loss and transfusion requirements for liver transplantation guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of critical care medicine (sccm) and american society for parenteral and enteral nutrition espen guidelines on enteral nutrition liver disease acute kidney injury following orthotopic liver transplantation: incidence, risk factors and effects on patient and graft outcomes causes of death in autopsied liver transplantation patients risk factors for cytomegalovirus and severe bacterial infections following liver transplantation: a prospective multivariate time-dependent analysis management of biliary complications after liver transplantation biliary complications after liver transplantation: the role of endoscopy efficacy of endoscopic and percutaneous treatments for biliary complications after cadaveric and living donor liver transplantation anastomotic biliary strictures after liver transplantation: causes and consequences nonanastomotic biliary strictures after liver transplantation, part : management, outcome and risk factors for disease progression improving the diagnostic criteria for primary liver graft nonfunction in adults utilizing standard and transportable laboratory parameters: an outcome-based analysis influence of steroids on hcv recurrence after liver transplantation: a prospective study a randomized, multicenter study comparing steroid free immunosuppression and standard immunosuppression for liver transplant recipients with chronic hepatitis c randomized, multicenter trial comparing tacrolimus plus mycophenolate mofetil to tacrolimus plus steroids in hepatitis c virus-positive recipients of living donor liver transplantation randomized controlled trial of tacrolimus versus microemulsified cyclosporine (tmc) in liver transplantation: poststudy surveillance to years cyclosporin versus tacrolimus for liver transplanted patients corticosteroid-free strategies in liver transplantation four-year follow-up of mycophenolate mofetil for graft rescue in liver allograft recipients key: cord- - xzc uc authors: nan title: esicm wednesday sessions october date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: xzc uc nan power spectrums for vt and eadi are shown in fig. (ps and nava) for a typical patient. the enlarged section highlights how changes in eadi are highly synchronized with nava ventilation, but less so for ps. table ) and complications of mechanical ventilation ( table ) did not differ significantly between the two studied groups. introduction. high tidal volumes in mechanically ventilated patients with ards lead to baro/bio-trauma and increase mortality. also, it was recently shown that ventilation with high tidal volumes is a risk factor for ''acquired ards'' in a medical population. objective. we evaluated the impact of high tidal volumes after cardiac surgery. method. we analysed the prospectively recorded data of , consecutive patients who underwent cardiac surgery from to . we predefined groups of patients based on the tidal volume delivered immediately after surgery: ( ) low: - . , ( ) ''traditional'': - . , ( ) high: above ml/kg of predicted body weight (pbw). we assessed the risk factors for organ dysfunction (prolonged mechanical ventilation, hypoxemia, hemodynamic failure and renal failure) by univariate and multivariate analysis, including the initial tidal volume in the models. mean tidal volume/actual weight and tidal volume/pbw was . ± . and . ± . in men (p \ . ), . ± . and . ± . in women (p \ . ). patients ( %) were ventilated with low tidal volumes, , ( . %) with ''traditional'' tv and ( . %) with high tv. the mean body mass index in the groups was . ± . , . ± . and . ± . respectively (p \ . ). with increasing bmi, the tidal volume/ actual weight decreased while the tidal volume/pbw increased (figure) . the percentage of women was . , . and . % respectively for low, ''traditional'' and high tv (p \ . ). high tidal volumes were associated with prolonged intubation ([ h) ( . vs. conclusion. traditional and very high tidal volumes are associated with prolonged mechanical ventilation and organ dysfunction after cardiac surgery and use of high tidal volumes is an independent risk factor. ''prophylactic'' protective ventilatory strategy should be provided in this population with inflammatory state at risk to develop ventilator induced pulmonary edema. women and patients with high bmi are more at risk to be ventilated with injurious tidal volumes. introduction. evidence shows that clinicians' non-technical skills (behavioural and cognitive skills) have a significant impact on teamworking, patient safety, efficiency of care provided and potentially patient outcomes ( ) . such skills are key for cardiac arrest teams (cats), which are multi-professional (anaesthetists, physicians and nurses) and normally function under high pressure. to date, most tools to assess nontechnical skills in healthcare have focused on surgery ( ) and anaesthesia ( ) . no validated, robust tools are currently available for assessing non-technical skills in cats. objectives. to develop and validate an observational skill-based clinical assessment tool for resuscitation (oscar). this should be psychometrically robust for use in both training and assessment contexts. methods. oscar was based on a well-validated tool for surgery (otas) ( ) and was developed in phases. six behaviours were included in the assessment: communication, cooperation, coordination, monitoring, leadership and decision-making. observable behavioural exemplars were derived for each one of these behaviours across the three cat subteams-anaesthetists, physicians and nurses (phase ). quantitative expert consensus methodology was employed to assess content and face validity and observability of the exemplars (phase ). two clinician observers used oscar to blindly rate eight cats performance in a series of simulated cardiac arrests. psychometric analyses of these ratings were used to determine observable behaviour applicability, internal consistency, and inter-rater reliability (phase ). . of oscar behaviours demonstrated high internal consistency (cronbach a = . - . ). psychometric analyses dictated removal of three behavioural exemplars (two in anaesthetic group; one in physician group) to significantly improve internal consistency. inter-rater reliability was also high (inter-observer pearson r = . - . , all p \ . ). inter-observer reliability analyses revealed a learning curve between the two observers, with significant reduction in scoring discrepancies from the first to the eighth observed resuscitations. conclusions. oscar is a psychometrically robust (reliable, content-and face-valid) tool for the assessment of teamworking skills in cardiac arrest events. the tool is feasible to use and can be employed for both training and assessment purposes. introduction. different educational methodologies are used to teach basic skills in emergency medicine. high-fidelity patient simulation offers an ideal venue for presentation of critical events that can be managed by medical students without risk to a patient. therefore full scale simulation training could be superior to paper case based seminary rounds to achieve these specific educational objectives. objectives. the aim was to compare simulation to a standard education measured by multiple choice questionnaire. after written informed consent and approval of the institutional research ethics board fifth year medical students were included in the survey. they took part in the compulsory emergency medicine curriculum of charité universitätsmedizin berlin. the students completed a basic multiple question tests on day including questions concerning the topic of ''acute coronary syndrome'' (acs). on day for the topic ''acs'' half the group was assigned a min session simulation training while half the group was assigned a min session paper case training. on day groups were reversed and the topic ''aic'' was taught in either simulation training or paper case seminary round. the test of day was repeated after each training sessions. results of the tests were evaluated using spss(tm) . the mann whitney u test was used to show any significant differences in reaching educational objectives in the test (a \ . was considered significant). there was an even distribution of men and women among the two groups. the test results showed no significant difference between the two groups on day . on day two for the topic ''acs'' the group with simulation training achieved significantly better test results. for the topic ''acs'' on day there was no difference while students received further training in acs not using a high fidelity simulator. the results were not linked to specific teachers. introduction. rapid sequence induction (rsi) involves loss of spontaneous breathing and mandates airway control. steps to reduce adverse incidents include adherence to minimum monitoring standards, appropriate drug selection, access to difficult airway equipment and presence of skilled anaesthetists. there is substantial evidence that appropriate monitoring reduces risk by detecting the consequences of errors, and by giving early warning of patient deterioration. objectives. to assess conduct of emergency anaesthesia (monitoring and drugs) for critically ill patients not in an operating theatre (or) administered by intensive care doctors. methods. prospective analysis of rsi for critically ill patients in a uk nhs acute hospital over month. or based practice was excluded. reason for anaesthesia, location, drugs administered, monitoring modalities, adverse events and access to airway equipment were recorded. results. data from patient episodes were collected: predominantly in the emergency department ( %) and intensive care unit ( %) for respiratory failure ( %), reduced consciousness ( %) and to facilitate investigations ( %) . the most common induction agent was propofol ( %); thiopentone ( %) and etomidate ( %) were less frequently used. suxamethonium ( %) was preferred for initial neuromuscular blockade. during induction most doctors used pulse oximetry, electrocardiography and blood pressure monitoring. only % used capnography. no doctor used minimum monitoring to association of anaesthetists of great britain and ireland (aagbi) standards. rescue airway equipment immediately available is shown in fig. . complications occurred in cases (fig. ) . patients that had a hypotensive episode during induction all had thiopentone or propofol used as induction agents. % of patients had a period of desaturation, and % required more than one attempt for successful intubation. in cases with complications, rescue airway equipment was unavailable in[ and % did not achieve uk minimum monitoring standards. conclusions. shortcomings during emergency anaesthesia were recorded including monitoring, access to rescue airways and physiological disturbance. procedural guidelines and training are to be developed for emergency anaesthesia; access to capnography and alternative airway equipment will be assured. these issues are unlikely to be unique to our trust and assessment of practice is recommended. introduction. critical care echocardiography (cce) is performed and interpreted by the intensivist at the bedside to establish diagnoses and guide the management of patients with circulatory or respiratory failure in the icu. competence in basic and advanced cce has been recently defined [ ] , but no curriculum to reach the required cognitive and technical skills has yet been elaborated. objectives. to assess the efficacy of a limited, tailored training program for noncardiologist residents without experience in ultrasound to reach competence in basic cce. methods. six noncardiologist residents (anaesthesiology: n = , pneumology: n = ) without previous experience in ultrasound participated to the study during two -month periods. the curriculum consisted in h of didactics, h of interactive clinical cases and h of tutored hands-on. color doppler mapping was excluded from the training. after completion of the training program, all eligible patients underwent subsequently a transthoracic echocardiography (tte) performed in random order by a recently trained resident and an experienced intensivist with expertise in cce who was used as a reference. in each patient, the resident and the experienced intensivist answered binary ''rule in, rule out'' clinical questions covered by basic cce [ ] : global left ventricular (lv) size and systolic function (eye-ball evaluation of ejection fraction), homogeneous or heterogeneous lv contraction pattern, global right ventricular (rv) size and systolic function, identification of pericardial fluid and tamponade, and assessment of both the size and respiratory variations of the ivc. in case of undetermined interpretation, the corresponding clinical question was considered not addressed. the agreement between responses to clinical questions provided by the two investigators who independently interpreted the tte study at bedside was used as an indicator of effectiveness of the tested curriculum. proportion of graduates to work within a ''critical care'' setting. the level of support available to trainees may vary with local resources but risk management and national guidelines stipulate that close supervision is provided to junior doctors in high stake decisions and procedures until deemed competent at the relevant tasks . furthermore, substantial ongoing reduction in working hours places further limitations on training; both majors can impact adversely on junior doctors service output and experience. a modified delphi method was used years ago to design a task focused single-day course on the theoretical basis of critical care and provide lab-based training in delphi identified high risk procedures and interventions . objectives. assess the impact of the course on the following: trainee confidence and the start of the ''novice'' critical care post trainee performance in comparison to peers perceived educational benefit from their training post compared to peers methods. junior doctors attending the course were enrolled in the study and matched for graduation year and medical school to junior doctors who did not attend similar training prior to commencing their post. data was collected through anonymous standardized forms on the day of the course, first day of the job, end of week , week and months into the post. trainee confidence and self perceived competence were assessed on a ten point scale. in addition, trainees were requested to maintain a log of interventions: -ultrasound guided central venous catheter insertion, -arterial catheter insertion, -ventilation problem solving. candidates attending the course demonstrated greater confidence at multiple points within their post as well as higher performance, satisfaction and educational value scores. conclusions. critical care trainees benefit from a task focused orientation to the fundamentals of critical care before commencing first post in this setting. . enrolled patients in each group. no differences in age and gender. incidence of vap-study group . % compared to control group . % p value . . vap per , hospital days: control- . % compared to study- . % p value . ; average days in icu control- . compared to study- . , p value . ; average ventilated days, control- . compared to . , p value . ; average antibiotic use in days control- . compared to study- . , p value . . introduction. nosocomial infections are the most common in-hospital complications with high morbidity and mortality. educating healthcare professionals is an important prevention measure. objective. to analyze the impact of a nurse consultant team on nosocomial infections prevention in the icu, the improvement in prevention knowledge of the nurse staff, and its impact in the application of the prevention measures in the daily practice. methodology: the nurse referent team was constituted by nurses. the study subjects were all the staff icu nurses and all the patients admitted during pre and post-intervention phases. the study was conducted in our medical-surgical icu ( beds) in phases: pre-interventional ( / / - / / ) observational. record of the accomplishment of cdc recommended variables about mechanical ventilation associated pneumonia (vap) and catheter related bloodstream infection (cr-bsi) prevention measures. interventional ( / / - / / ) eight educational meetings with the nurses staff groups to teach the most important aspects of the nosocomial infections prevention. before and after lectures every nurses answered an anonymous questionnaire about their knowledge in those subjects. a poster with the most important reminders was place in every icu patient room. post-interventional ( / / - / / ) observational. new record of the same cdc pre-interventional variables. we compared the accomplishment of these variables before and after the interventional phase as well as the number of correct questionnaire answers. statistics were made with spss software. results. during the interventional phase % of the staff nurses attended the educational meetings. the number of correct answers increased significantly after the conference ( . vs. . % p \ . ). regarding to the daily practice, we observed a significant increase in the accomplishment in most of the variables (see table below), while in of them no improve was observed and in the improvement was not statistically significant. during the study period we observed a decrease in the incidence of vap ( . - . episodes/ , mv days) and cr-bsi ( . introduction. glucose variability has been found to be associated with mortality in critically ill patients, independent of mean glucose concentration [ ] . objectives. the aim of this analysis was to assess the impact of real time continuous glucose monitoring (cgm) on glucose variability in critically ill patients receiving intensive insulin therapy (iit). methods. this is the post-hoc analysis of a prospective, randomized, controlled trial [ ] . data of patients admitted to the icu either receiving iit according to a real time cgm system (guardian Ò , medtronic, northridge, ca, usa) (n = ) or according to an algorithm (n = ) with selective arterial blood glucose measurements (simultaneously blinded cgm) for h were analysed. insulin infusion rates were guided according to the same algorithm in both groups. mean glucose and standard deviation, as a marker of glucose variability, were calculated for the first h (glumean , glusd ) and for the whole study period (glu sd ). statistical comparison of parameters between study groups and between icu survivors (n = ) and non-survivors (n = ) was performed using student's t test. results. the variability of sensor glucose during the entire study period was comparable between the real time cgm group and controls ( . ± . vs. introduction. in the gastrointestinal tract, the gut flora which comprises several hundred grams of bacteria is crucially involved in host homeostasis through their metabolic, trophic, and protective activities. however, the immediate changes in the gut flora in critical illness following severe insults are unknown. objectives. to investigate the changes in the gut flora at an early phase of severe insult in critically ill patients. methods. fifteen patients who experienced a sudden and severe insult including trauma, out-of hospital cardiac arrest, and cerebral vascular disease were studied, along with healthy volunteers as the control group. two fecal samples were acquired from the subjects by swabs of the rectum within h after admission to the emergency room (day ). samples were serially collected from patients on day , , , , , and . samples were collected from control subjects. results. total bacterial counts, especially various obligate anaerobes and total lactobacillus, significantly decreased in comparison to those of the control subjects on day . in addition, on day , the total organic acid levels of the patients were significantly lower than those of the control subjects; particularly acetic acid, propionic acid, and butyric acid. the levels of these acids remained low throughout the days period of study. the total bacterial counts did not recover to normal levels during the day study period. obligate anaerobe counts of the patients did not improve until day . total lactobacillus counts were low on day and increased gradually thereafter, but did not attain the levels found in controls. the counts of pathogens (enterococcus and pseudomonas) increased during the study period. conclusions. gut flora in critically ill patients can change drastically immediately after a severe insult, and may not recover for up to days. at the same time, the number of harmful bacteria can increase. total bacteria . ( . - . ) . ( . - . ) . obligate anaerobes clostridium cocades group . ( . - . ) . ( . - . ) . clostridium leptam subgroup . ( . - . ) . ( . - . ) . bacteroides fragilis group . ( . - . ) . ( . - . ) . bifidobacterium . ( . - . ) . (\ . - . ) . atopobium cluster . ( . - . ) . (\ . - . ) . results. mean serum (oh)d level was . ± . ng/ml. by current definitions the majority of patients ( . %) were vitamin d deficient (\ ng/ml) and . % were vitamin d insufficient (c and \ ng/dl). normal (oh)d levels ([ ng/ml) were present in . %. table provides information on clinical and laboratory findings in the three (oh)d groups. both lower (oh)d tertiles were associated with increased hospital mortality after adjustment for age, sex and saps ii. for patients both (oh)d and pth levels were available. adjusting the cox regression analysis also for pth and dialysis status increased the hr for hospital mortality to . ( . - . ) and . ( . and . ) for the two lower (oh)d tertiles. in addition tertiles of pth and serum calcium levels suggested higher mortality rates for patients in the highest pth (p = . ) and those in the lowest calcium tertile (p = . ). our results demonstrate that independent of baseline saps ii, age and sex, critically ill patients with low (oh)d levels seem to be at increased risk for hospital mortality. whether a rapid correction of vitamin d status may be beneficial in the icu setting remains to be further explored in randomized controlled trials. • the autonomic storm after brain death must be early diagnosed and treated with a standardized protocol including hormone therapy introduction. the use of filling pressures of the right atrium and left atrium is normal in the monitoring of critically ill patients undergoing mechanical ventilation. this monitoring is done through an invasive catheter placed in the superior vena cava and pulmonary artery, which is not free of complications. the ability to make measurements of these parameters in a non invasive way, makes the echocardiography an useful and essential tool when monitoring critically ill patients objectives. we focus the study on validate the reliability of noninvasive measurements by echocardiography and invasive measurement catheters of filling pressures methods. we conducted a prospective observational study relating the filling pressures, between central venous pressure (cvp) with the diameter of the inferior vena cava and left atrial pressures with the values of the ratio e/e . the filling pressure variables were only discriminated as high or low. low values were accepted when invasive measurement of cvp was \ and \ mmhg in the lap; and by echocardiography when the diameter of the ivc was\ mm and the ratio e/e \ . high values were accepted when the measurement of cvp was higher than and mmhg in lap and in echocardiography when the diameter of the ivc [ mm and the ratio e/e [ . we collected data from patients in the immediate postoperative period, under mechanical ventilation (vt - ml/kg, fio %, peep ), sinus rhythm, good cardiac function and without postoperative drug support. all of them had a central venous line and right atrium catheter as habitual monitoring of postoperative cardiac patients. we performed an echocardiography when the patient presented hypotension, with low values of cvp and lap, and we repeated the measurements after the infusion of the habitual fluid protocol ( ml hes % in - min). the data we record were: diameter of ivc and ratio e/e by echo and cvp and lap values by invasive catheters. rd esicm annual congress -barcelona, spain - - october s introduction. an attenuated cardio-hemodynamic response to dobutamine is associated with a poor outcome in established human sepsis [ , ] . establishing a sensitive method to identify early cardiac dysfunction in both experimental and human sepsis would be a useful tool to explore timesensitive mechanisms further. objectives. to assess myocardial responsiveness to dobutamine in early sepsis. methods. all procedures were in accordance with uk home office laboratory animal legislation. under isoflurane anaesthesia, male adult wistar rats underwent left common carotid and right internal jugular venous cannulation for blood sampling/continuous bp monitoring and fluid administration respectively. rats received either . ml caecal slurry (sepsis; n = ) or . ml saline (sham; n = ) ip, before fluid resuscitation ( . % saline ml/kg/h) and conscious monitoring was commenced. after h, rats were re-anaesthetized with isoflurane and transthoracic echocardiography was performed. stroke volume was optimised with saline boluses prior to an incremental dobutamine infusion ( . - mcg/kg/ min). data are presented as mean (sd); analyzed with -way anova and post-hoc tukey test. results. figure summarizes hemodynamic changes after sepsis, fluid resuscitation and dobutamine infusion. baseline parameters were similar after echocardiography-guided fluid resuscitation, with contractility and stroke volume restored in septic rats to sham values. septic rats demonstrated an enhanced chronotropic response to dobutamine compared to sham (p \ . ). both peak velocity and cardiac output were attenuated by c % in sepsis (p \ . ). in sepsis, baseline map was higher but neither sham nor septic maps were affected by dobutamine infusion. conclusions. dobutamine stress echocardiography is a sensitive, reproducible, dynamic physiological probe that reveals early cardiac dysfunction in septic rats with apparently similar baseline cardiovascular physiology. introduction. the evaluation of right ventricular (rv) function is clinically useful in patients with acute respiratory distress syndrome (ards) because the presence of rv failure has large prognosis implications. the purpose of the current study was to compare right ventricular myocardial strain imaging parameters with conventional echocardiographic indices evaluating right ventricular function during ards. objectives. we hypothesized that peak systolic strain would be more sensitive than conventional echocardiographic parameters in detecting subclinical right ventricular systolic dysfunction in patients with ards. methods. in total, patients with ards and with normal right ventricle function assessed by two dimensional echocardiography and age matched subjects under mechanical ventilation without heart or pulmonary disease were included in the present study. conventional echocardiography parameters for rv function assessment like rv fractional area change (rvfa) or the tricuspid annular plane systolic excursion (tapse) were measured and compared to tissue doppler imaging parameters with strain value obtained from the right ventricle free wall. . strain values were reduced in the rv free wall of the patients with ards compared with the control group ( . % ± . vs. . % ± . p = . ) moreover no significant difference was observed in conventional two dimensional parameters evaluating rv systolic function between these two groups of patients. in patients with ards a significant relationship was shown between peak systolic strain at basal free wall and arterial carbon dioxide tension (rho = - . p = . ) and with the end inspiratory pressure (rho = - . p = . ). conclusions. during the ards, doppler tissue imaging parameters can determine rv dysfunction that is complementary to conventional echocardiographic indices and is correlated with respiratory parameters. on doppler tissue imaging, patients with ards exhibit abnormal rv systolic function even in patients with normal rv function assessed with conventional echocardiographic parameters. objectives. studying the effect of olv on rv outflow impedance during inspiration and expiration using transesophageal echo-doppler in a trial to differentiate the rv consequence of increasing lung volume from those secondary to increasing airway pressure during mechanical ventilation. methods. thirty stable patients on mechanical ventilation because of different causes were enrolled prospectively in this single center, cross sectional clinical study. each patient was firstly subjected to conventional ventilation (cv) with volume controlled ventilation, followed by open lung concept (olc) ventilation by switching to pressure controlled mode, then recruitment maneuver applied until pao /fio [ torr. hemodynamic (mean arterial pressure ''map'', central venous pressure ''cvp'' and heart rate ''hr'') and respiratory (total and intrinsic peep, peak, plateau and mean airway pressure and total and dynamic lung compliance) measurements were recorded before, min after a steady state of cv and min after a steady state of olc ventilation. also, transesophageal echo doppler was performed at end of inspiration and end of expiration to calculate the mean acceleration (ac mean ), as a marker of the rv outflow impedance, min after a steady state of cv and min after a steady state of olc ventilation. results. during inspiration, ac mean was significantly lower during cv compared to olc ventilation (p value . ). inspiration didn't cause a significant decrease in acmean compared with expiration during olv (p value. ) but did do so during cv. in comparison to baseline and cv, olc ventilation was associated with a statistically significant higher cvp (p value . for both), higher total quasi-static lung compliance (p value . for both) and dynamic lung compliance (p value . for both). moreover, pao /fio ratio of olv was significantly higher than in baseline and cv (p value . for both). conclusions. olc ventilation does not change rv afterload during inspiration and expiration as rv afterload appears primarily mediated through the tidal volume. moreover, olc ventilation provide a more stable hemodynamic condition and better oxygenation and lung dynamics. introduction. among indices provided by the analysis of aortic blood flow through esophageal doppler, mean acceleration (acc) is supposed to reflect the left ventricular (lv) systolic function, but this has been poorly validated. in particular, acc could be influenced by loading conditions of the lv. objectives. to test whether acc actually behaves as an indicator of lv systolic function by testing if . it increased with inotropic stimulation, . it was not altered by fluid loading, . it correlated with the echographic lv ejection fraction (lvef) and it reliably tracked the changes in lvef during therapeutic intervention. in patients with cute circulatory failure (sapsii ± , age ± years, receiving norepinephrine), we administered either a volume expansion ( ml saline over min in patients) or dobutamine ( lg/kg/min in patients). we simultaneously measured acc (cardioq, deltex medical) and lvef at baseline and after therapeutic intervention. results. volume expansion significantly altered neither lvef (from ± to ± %) nor acc (from . ± . to . ± . cm/s ) while dobutamine infusion significantly increased lvef by ± % and acc by ± %. considering the acc/lvef pairs of measurements, an acc \ . cm/s predicted a lvef b % with a sensitivity of % ( % ci [ - %]) and a specificity of % ( % ci [ - %]). the changes in lvef and in acc during fluid and dobutamine administration were significantly correlated (r = . , p \ . ). conclusions. acc fulfilled the criteria required from a clinical indicator of lv global systolic function. a given value of acc allowed detecting a low lvef with a modest accuracy. by contrast, the treatment-induced relative changes in acc were reliable for tracking the treatment-induced relative changes in lvef. objectives. to compare the relationship between systolic or diastolic dysfunction at icu admission and the incidence of cardiologic complications and mortality at sixth months. methods. prospective study of forty consecutive patients diagnosed of acute myocardial infarction (ami) ( nstemi, stemi) who were admitted in the icu of university hospital puerto real (cadiz, spain) from st may to th september . studied variables: age, gender, type of ami (nstemi, stemi), left ventricular ejection fraction (lvef) by biplanar simpson's rule, diastolic function (ratio e/e of the mitral annulus included), incidence of cardiac complications (acute pulmonary oedema, atrial fibrillation with hemodynamic instability and cardiogenic shock) and mortality at sixth month. echocardiographic studies were performed with a ge vivid pro(r) by an intensivist who had performed up to doppler studies in critical patients. all studies were remeasured by a second observer in an echocardiographic workstation with no statistical difference in measured velocities. patients were classified according to their lvef in (a) preserved ([ %), (b) mildly depressed ( - %), (c) moderately depressed ( - %) and (d) severely depressed (\ %); and according to their e/e ratio in (a) normal e/e ratio (\ ) and (b) elevated e/e ratio (c ). the results were statistically analysed with chi-square test and odds ratio calculus. results. diastolic dysfunction measured with e/e ratio was associated with high incidence of cardiac complications (chi test cl % p \ . , or ). systolic dysfunction measured by lvef was also associated with more complications but with less strength of statistical association (chi test cl % p \ . , or . ). there were no significative statistical difference between lvef and e/e ratio in mortality at sixth month. conclusions. in our study, diastolic and systolic dysfunctions in patients with ami at icu admission were associated with high incidence of cardiac complications, with more strength of statistical association in patients with diastolic dysfunction. the small sample volume didn't allow us obtaining significative statistical differences in mortality at sixth months. a new method has been developed to assess global end-diastolic volume (gedv) and extravascular lung water (evlw) from a transpulmonary thermodilution curve. our goal was to compare this new method to the established method currently in clinical use, over a wide range up to extreme pathophysiological conditions. objectives and methods. anesthetized and mechanically ventilated pigs ( - kg) were instrumented with a central venous catheter and a right ( f pulsiocath, pulsion, munich, germany) and a left ( f volumeview, edwards lifesciences, irvine, ca) thermodilution femoral arterial catheter. the right femoral catheter was connected to a picco monitor (pulsion) and used to measure cop, gedvp and evlwp using the old method based on the equation: gedv = cop (mtt -dst). the left femoral catheter was connected to the new ev monitor (edwards) and used to measure coe, gedve and evlwe using the new method based on the equation: gedve = f (s /s ) coe mtt, where s and s are respectively the maximum up-and down-slopes of the dilution curve, respectively. measurements were done during inotropic stimulation (dobu), during hemmorhage (hypo), during fluid overload (hyper), and after inducing oleic acid-acute lung injury (ali). overall, cop and coe ranged from . to . and from . to . l/min, respectively. cop and coe were closely correlated (r = . ), mean bias (± sd) was . ± . l/min and %error was %. gedvp and gedve ranged from to , and from to , ml. gedvp and gedve were closely correlated (r = . ), mean bias was - ± ml and %error was %. evlwp and evlwe ranged from to , and from to , ml. evlwp and evlwe were closely correlated (r = . ), mean bias was - ± ml and %error was %. parameters over the study period are presented in the table (*p \ . intervention vs. base or hyper). introduction. fluid resuscitation is a major therapy in icu. various mechanisms are involved in the regulation of the microcirculation and the macrocirculation. objectives. the goal of this study is to assess the sublingual microcirculatory changes in response to fluid challenge in preload-responsive and non preload-responsive patients. after approval by our local institutional review board, patients in surgical icu have been included in an observational study. each patient was monitored by an arterial catheter and an oesophageal doppler. the decision of fluid infusion was taken by the physician in charge of the patient. preload-responsive patients were defined by variations in cardiac index (ci) c %. sublingual microcirculation videos were obtained using the orthogonal polarized spectral (ops) imaging technology. functional capillary density (fcd, cm cm - ) and microcirculatory flow index (mfi) were collected. the macrocirculatory and microcirculatory measurements were obtained before, during and after the infusion of ml of saline. five sublingual sites were recorded before and after the fluid resuscitation. the ventilator settings and sedative and vasoactive drugs infusion rates were kept constant throughout the procedure. results. patients were admitted in icu for acute brain trauma (n = ), hemorrhagic shock (n = ), septic shock (n = ), acute brain hemorrhage (n = ) and acute pancreatitis (n = ). the average age of the patient was ± . the mean values of ci and mean arterial pressure (map) before the fluid therapy were respectively . ± . l/min/m and ± mmhg. nine patients responded to fluid infusion (ci c %.). about the microcirculation, there was no significant difference between responders (r) and non-responders (nr) concerning the variations of mfi ( . introduction. passive leg raising (plr) was shown to discriminate hemodynamically unstable patients who will benefit from subsequent fluid administration or not. concerned by the possibility of harmful hypotension starting the plr maneuver from a °semirecumbent position, in a previous study, we found that raising patients' legs from a supine position, we were not able to predict fluid responsiveness in a heterogeneous cohort of medical intensive care unit (icu) patients. objectives. to investigate whether starting plr maneuver from a °semirecumbent position would better predict volume responsiveness without harmful hypotension in spontaneously breathing critically ill medical icu patients. methods. fluid responsiveness was tested in consecutive patients ( sepsis, respiratory failure, heart failure, others) with a mean arterial pressure (map) \ mmhg and/or a cardiac index (ci) \ . l/min/m . heart rate (hr), mean arterial pressure (map), global end-diastolic volume index (gedvi), cardiac index (ci) and stroke volume index (svi) were recorded using the picco method. patients were stable in a semirecumbent ( °) position when first measurements were taken (baseline ). for the plr maneuver, patient's bed was tilt to have the lower limbs raised to a °angle while the patient's trunk was then in a supine position. changes after min were recorded. the patient was then brought into a supine position, and heamodynamic measurements were recorded when stable (baseline ). thereafter, ml of . % nacl were administered over min. positive predictive values (ppv) and negative predictive values (npv) of the plr maneuver were calculated using a cut-off value of % increase for ci and svi and % increase for map. results. patients' median age was ( - ) years and their saps score ( - ). all patients received vasopressors and/or inotropes. baseline hemodynamics and changes after plr and fluid challenge are shown in table . results are given as median (range); n/a = not available, *p \ . versus baseline. ppv and npv for ci were and %, for svi and % and for map and %, respectively. conclusions. in our hands, plr was not useful identifying fluid responders in this heterogenous population of severely ill medical icu patients, the starting semirecumbent position being associated with a potentially harmful decrease in map. however, it was helpful to detect patients who will not benefit (or even suffer harm) from further fluid administration. recently, some studies suggested that an impaired diastolic function is a predictive factor of mortality in patient with shock. it is not already known whether fluid infusion could improve diastolic function. objectives. the aim of the study was to determine the impact of rapid fluid infusion on diastolic function. after acceptance by the local ethic committee, icu patients were prospectively included. volume expansion (ve) by ml of saline was performed by the intensivist in charge. transthoracic doppler echocardiography was performed before and after fluid infusion. stroke volume (sv), early diastolic transmitral velocity (e), early diastolic mitral annular velocity (ea) and e/ea ratio (reflect of lv filling pressure) were studied. patients were divided in groups according to their sv' increase: responders (r) (those who increased their sv by at least %) and non-responders (nr). wilcoxon rank sum test was performed to compare data before and after ve. data are presented in median (iqr) results. fifty-three ( %) patients were r and ( %) were nr. in the overall population, ea increased significantly with ve [from . ( . ) to . ( . ) cm/s, p = . ]. in the r group ea increased significantly [from . ( . ) to . ( . ) cm/s, p = . ] and e/ea did not change significantly [from . ( . ) to . ( . ), p = . ]. however in the nr group, ea did not change significantly [from ( ) to . ( . ) cm/s, p = . ] while e/ea increased significantly [from . ( . ) to . ( . ) cm/s, p = . ]. conclusions. according to these results, adequate fluid infusion seemed to enhance lv relaxation without increasing lv filling pressure while inadequate fluid infusion did not affect relaxation but increased lv filling pressure. objectives. the aim of our study is to compare the rapid variation of co measured by vigileo-flotrac Ò with doppler-echocardiography which is considered as a reference method. during the first hours of hospitalisation, we studied mechanically ventilated patients receiving norepinephrine who underwent arterial pressure monitoring via a radial artery catheter. the flotrac Ò pressure sensor and the vigileo Ò monitor were connected to the arterial line. at each fluid expansion or norepinephrine dose modification a transthoracic doppler-echocardiography was performed and co was calculated. variations for co measured by each method were compared. results are presented as median (iqr). linear regression and the bland-altman method were used for statistical analysis. methods. for the in vitro experiments blood of healthy donors was incubated (in the ratio : ) with one of the following solutions: ringer solution, ringer-lactate solution, modified gelatin (gelofusin); hydroxyethyl starch (hes) / . . after incubation, the following parameters of erythrocyte aggregation were measured: t and t -characteristic times of spontaneous erythrocyte aggregation; b-hydrodynamic strength of aggregates; i . -index of strength of the largest aggregates at shear rate . s - . rbc deformability at various shear stresses was determined by ektacytometry. in vivo study on patients with trauma treated randomly with either only crystalloids (group ; n = ), or crystalloids + hes / . (group ; n = ) or crystalloids + gelofusin (group ; n = ) over days, the same parameters as in vitro study were determined at day - . twenty healthy men and women were included as controls. for statistical analysis the statistical package spss version . was used. statistical significance was considered at p \ . . in vitro study in the final analysis effects of different colloids on rbc aggregation and deformability were considered as increasing impact (:), decreasing impact (;) and no impact (-) ( table ) . in vivo study significant microrheological disturbances were detected at day after admission. deformability index was lower in patients compared with controls ( . ± . vs. . ± . ; p = . ). simultaneously, the patients showed erythrocytes hyperaggregation compared with control (;t , ;t ; :i . , :b). in the first group (crystalloids) described violations persisted throughout the study time. in group (crystalloids + hes), the deformability was higher than in the st group, from days till the end of the study, attaining the normal range, and also higher than in the third group (crystalloids + gelofusin). in the third group, deformability index was not significantly different from group . according aggregatometrical data in the first group hyperaggregation syndrome remained the entire period of observation. hes adding (group ) decelerated aggregate formation (:t , :t ; ;i . ). in contrast, modified gelatin adding enhanced erythrocyte aggregation (;t :i . , :b). conclusions. crystalloid solutions are not able to improve microrheological parameters. hes / . increases rbc's deformability and reduced rbc's aggregability. gelofusin increases erythrocyte aggregation and no effect on deformability. introduction. trauma patients often require norepinephrine (ne) infusion and fluid challenge to keep normal blood pressure values. the reliability of dynamic predictors of fluid responsiveness during vasopressors therapy is under debate. we investigated the impact of norepinephrine (ne) infusion changes on pulse pressure variation (ppv) assessed with the mostcare system (vytech health, laboratoires pharmaceutiques vygon, ecouen, france) in intensive care unit patients. this device is a pulse contour method that provides cardiac output and fluid responsiveness variables and does not need any kind of calibration or preloaded data. methods. trauma patients ( female, male, mean age ± ) admitted to a -bed university hospital medico-surgical icu were prospectively enrolled. inclusion criteria were: mechanically ventilated patients (tidal volume [ ml/kg and constant respiratory rate); invasive arterial blood pressure monitoring; ne infusion. ppv values were recorded continuously during three different haemodynamic states: at baseline (t ), min after a . lg/kg/min ne increase (t ), min after a further . lg/kg/min ne increase (t ), min following the reduction of ne to t dosage (t ) and min after setting ne to baseline value (t ). during the study neither fluid challenge nor other vasoactive/inotropic drug changes were done. anova test was applied. results. see data in table . at t ne mean dosage was . lg/kg/min (range . - . lg/kg/min). the mean ppv was: at t . ± . %, at t . ± . %, at t . ± . %, at t . ± . %, at t . ± . % (p \ . ). conclusions. our findings demonstrated that ppv was significantly affected by changes in ne: the higher the ne dosage the lower the ppv. changes in arterial tone due to ne infusion can impair ppv reliability in assessing fluid responsiveness in trauma patients. introduction. in mechanically ventilated patients respiratory variation in the arterial pulse pressure (dpp) is a reliable predictor of fluid responsiveness . respiratory variation of pulse oximetry plethysmographic waveforms correlate to dpp and can be calculated automatically in real time (heart-lung index [hli Ò ] from hamilton medical). this prospective study evaluates the relationship between dpp and hli Ò to predict fluid responsiveness. mechanically ventilated patients were investigated; all connected to an hamilton g ventilator and ventilated in adaptive support ventilation (asv), paralyzed and none had severe cardiac dysrhythmia. were eligible for fluid expansion. dpp, hli Ò (obtained from a finger probe pulse oxymeter integrated to the ventilator) and cardiac index (ci from transthoracic echo-doppler), were obtained before and after fluid expansion ( ml/kg of hea over min). ci-responders were defined by % increase from baseline. results. out of the patients were ci-responders and had significantly higher hli Ò before volume expansion ( % ± vs. % ± , p \ . ). before fluid expansion hli Ò was correlated with dpp (r = . , p \ . , fig. ). hli and dpp were significantly correlated with change in ic induced by fluid expansion (r = . and r = . , respectively). objectives. the primary end point of this study was to evaluate the rvd of the ivc in icu patients with spontaneous breathing. methods. icu patient with spontaneous breathing and signs of hypoperfusion (oliguria, mottles, serum lactate level [ mmol/l) were eligible after the approval of the local ethics committee. we excluded patients with acute heart failure with pulmonary edema, moribund and arrhythmic patients. the trans thoracic echocardiographic (tte) evaluation was done by confirmed intensivists (level [ in echocardiography). the aortic diameter measured at the lv outflow chamber and the tvi were measured. the vena cava inferior diameters at inspiration and at expiration were measured on the sub costal view. the rvd of the ivc was defined as the (maximal ivc diameter -minimal ivc diameter)/maximal ivc diameter. these measures were realized at t , before fluid challenge, and after a fluid challenge of ml of hes % ( . / ) over min (t ). patients with an increase of tvi of more than % were considered as responders to the fluid challenge. the measures of tvi and of the rvd of the ivc were validated by an experimented intensivist and echographist (level ) after blinding the patient' name and of the times of measurement. roc curves were constructed, and the cut off was determined as the closest point of the roc curve to the ideal point (sensibility = specificity = ). the values are expressed as median and extremes. objectives. our objective was to test whether non invasive assessment by trans thoracic echocardiography of sub aortic velocity time index (vti) variation after a low volume of fluid infusion ( ml of hydroxy ethyl starch, hes) can predict fluid responsiveness. methods. sub aortic vti was measured by transthoracic echocardiography before fluid infusion (baseline) in sedated patients with acute circulatory failure and low tidal volume mechanical ventilation in whom volume expansion was planned. then, vti was recorded after ml of fluid infusion over min, and after an additional infusion of ml of hes over min. we measured the variation of vti after ml of fluid (dvti ) for each patient. receiver operating characteristic (roc) curves were generated for dvti in all patients. when available, roc curves were also generated for pulse pressure variation (ppv) and central venous pressure (cvp). , volumes (gedvi) and variabilities (svv, ppv) have been suggested to predict volume responsiveness (vr). the final classification of a patient as ''volume responsive'' is usually made by a volume challenge (vc) with an infusion of a pre-defined amount of fluid over a certain time. among many variations of vcs, the infusion of ml crystalloid over min is one of the most established. despite superior predictive capabilities of svv, ppv and gedi compared to cvp and pawp in a number of studies, they fail to predict vr in a substantial number of patients. furthermore, the use of these parameters is limited due to femoral access of the cvc (gedi; cvp) or the absence of controlled ventilation and/or sinus rhythm (svv, ppv). repeated ''exploratory'' vcs with ml/kg might result in volume overload in some patients. objectives. therefore, we investigated the usefulness of a ''small vc'' with . ml/kg crystalloid over min compared to a standard vc with ml/kg over min. in patients equipped with picco hemodynamic monitoring we performed a min vc with ml/kg of crystalloid. during the vc transpulmonary thermodilution (td) was performed at , and min to obtain td-derived ci (ci td ). additionally pulse contour ci (ci pc ) was recorded in intervals of min. introduction. the prevalence of obesity, defined as a body mass index (bmi) c kg/ m , reaches epidemic proportions. it is not only a risk factor for health problems, but also exacerbates illness progression. consequently, the number of obese patients on the intensive care unit (icu) has increased enormously. caring for obese patients can be quite challenging due to the weight and size of this person. the extent of and specific problems associated to the care of obese icu patients are unknown. the aim of this study is to identify and quantify problems nurses face in caring for obese patients on the icu. this study was performed on the icu at the radboud university nijmegen medical centre and contained two parts. in the first part a selection was made of obese patients admitted between and ; these patients were matched with normal weight patients (bmi . - . kg/m ). patients were matched on gender, age, length of icu stay and apache-ii score. all patient files were screened for the presence and intensity of problems in caring for these patients. in the second part nurses were asked in a survey to share their experiences in caring for obese patients. they were asked about the nature, frequency and intensity of the problems they faced. in total, problems were identified in the screened patient files. seventy-two problems ( . %) occurred in care for obese patients and ( . %) in care for normal weight patients. in both groups, most of the problems were related to activities of daily living (adl) such as (re)positioning in bed, transfers and personal care. surprisingly, the intensity of the problems was similar in both groups. most of the problems were moderate (hardly to solve by one person) or severe (only to solve with two persons or special equipment). moderate problems occurred in . % of normal weight patients and in . % of obese patients; severe problems . and . %, respectively. this result was also confirmed by the survey. the nurses qualified most of the problems they were asked about as moderate or severe, and the frequency of the experienced problems was much higher. from the files it appeared that in . % of the obese patients nurses had adl problems. strikingly, in the survey nurses reported that they frequently ( . %) or even always ( . %) experienced adl problems in obese patients. nurses reported and experienced more problems in daily care for obese icu patients compared to normal weight icu patients. although the intensity of the problems with obese patients did not differ from normal weight patients, the frequency in which they occur was much higher. differences between reported problems and the survey suggest an underestimation of problems that can be solved by performing a prospective study. nevertheless, based on these results, and taking into account that obesity will increase in the future, we recommend anticipating to the needs of the nurses whenever possible. introduction. worldwide the number of obese patients (bmi [ ) is increasing rapidly ( ); this also includes patients admitted to the intensive care units (icu). this raises special demands on the staff, the surroundings and the equipment ( ) . often the obese patient is not mobilised according to the clinical standard this causes complications to breathing, circulation and skin etc. furthermore the length of stay in the icu increases and the mortality rises. objectives. the aim of this study therefore was to make clinical guidelines and recommendations for mobilisation of the obese icu patient based on evidence. this will increase the knowledge and importance of mobilisation between staff and on longer term improves the daily average number of mobilisations performed with these patients. a secondary aim is that increased knowledge on this topic will improve the interdisciplinary work between the different professions based on the same overall aim. a systematic review of the literature concerning mobilisation of the obese icu patients was made in the year - . the study is still work in progress analysing the literature to make guidelines and recommendations based on evidence. furthermore evidencebased education of special trained staff in mobilisation has been conducted in january/ february to improve their knowledge of the impacts mobilisation has on the respiration, circulation and skincare etc. the education was planned to aiming at a interdisciplinary audience. results. the preliminary results shows that it is more difficult to care for and mobilise the obese icu patient, because there is lack of space, non-availability of the correct equipment, too few available staff members and a significant negative attitudes among the staff towards the obese patient. recommendations are made within airway, breathing, circulation, nutrition, pain, equipment and patient experience according to the procedure of mobilisation of the obese icu patient. the recommendation was implemented in the already performed education and resulted in a changed attitude among the participant and improved the status of mobilisation in the daily prioritization. this knowledge was obtained in the evaluationinterview conducted approximately one month after the seminar. conclusions. according to the literature mobilisation of the obese icu patient needs special attention towards a safe clinical practise based on evidence with focus on both the patient and the staff. special attention towards this group of patient is created by performing evidence based research resulting in clinical guidelines that has to be implemented through theoretical and practical education on an interdisciplinary level. nurses are constantly exposed to the pain and suffering of those in their care . the primary aim of this study was to investigate the risk of secondary traumatic stress/compassion fatigue (sts/cf-the trauma suffered by the helping professional) and burnout (bo-emotional exhaustion, depersonalization, and reduced sense of personal accomplishment), and the potential for compassion satisfaction (cs-the fulfillment from helping others and positive collegial relationships) among nurses working in icu. an additional goal was to test the relationship of these three constructs to each other. ( ) . the use of closed suction circuits has been suggested beneficial as a prophylactic measure ( ) . objectives. the aim of this study was to compare the incidence of vap and the occurrence of desaturation during suction using either oss or css. we also investigated contamination of the closed suction circuit and the occurrence of adverse events. methods. css were a new product in our clinic. all staff underwent a user course supervised by the manufacturer of the closed circuit. after this, data were collected during four periods in , month css followed by months oss which was repeated twice. during the summer period css were used without any data collection and then followed by two periods of css and oss. all mechanical ventilated patients were consecutively included. a culture of deep endotracheal aspirate and a blind microbiology brush was taken in association with the intubation, after h and every monday. after changing css and in case of extubation, the tip of the catheter was sent for culture. demographic data were retrieved from the hospital database. data were analyzed with descriptive methods. results. the incidences of vap were higher in the css group (table ) . both suction systems showed almost no desaturation during and after suctioning. positive cultures were obtained in % of all the retrieved css catheters. the microbiological flora resembled the species found in the airway cultures. there were no inter patient contamination and neither did the bronchoscopy frequency differ between oss and css patients. in the css group six adverse events were seen; three tube occlusion and three incidences with secretion clogging. conclusions. the use of a css did not prevent vap, in our study. there were no benefit with css other than maybe to protect the staff and our finding of positive culture in % of the cases is in line with earlier studies. objectives. the aim of this study was to determine which intensive care patients the nurses defined as 'difficult' and their experiences in coping with such patients. the study was carried out as a qualitative design with voluntary nurses employed in five intensive care units of a research and training hospital. the data were collected using demographic characteristics form and a semi-structured interview form. interviews with nurses were made individually and face to face. the data were evaluated by using colaizzi's phenomenological data analysis method. as a result of data analysis into two categories and two themes were identified. the categories were ( ) difficult patient definition of the nurses, ( ) the effect of difficult patients on their care, and ( ) how the nurses are affected and cope with difficult patients. the nurses listed their reasons for defining some persons as difficult as difficult physical care of the patients, and the difficulty in communicating due to dementia, agitation, alzheimer's disease or the patient's personal characteristics. the nurses said that they found taking care of patients they found difficult physically and psychologically demanding. they used methods such as finding out the patient's problem and taking appropriate measures, increasing communication with the patient and providing explanations, trying to obtain spiritual satisfaction and transferring the patient's care to another nurse when communication problems were impossible to overcome. intensive care nurses have difficulty in caring for and communicating with some intensive care patients due to the characteristics of the disease, physical/psychological factors and personal characteristics. we found that nurses continued the care of these ''difficult'' patients by focusing on solving their problems, transferring the care to another nurse when necessary or by trying to obtain spiritual satisfaction. methods. teams of three delirium experts visited ten icu's in the the netherlands in which the cam-icu was incorporated in daily practice, twice. these teams consisted of two consultants in either psychiatry, clinical geriatrics or neurology, and either a research-physician (mmjve) or a research-nurse (mvdb). based on cognitive testing, inspection of the files and dsm-iv criteria for delirium, the teams classified patients as awake and not delirious, or delirious or comatose. this classification served as gold standard to which the cam-icu as performed by the bed-side nurses was compared. a simple table was used to calculate the sensitivity and specificity. results. delirium experts performed assessments. ( %) of these patients were assessable for delirium, ( %) patients were excluded because the level of consciousness was too low, and ( %) patients were non-assessable due to other reasons. overall, we found a sensitivity of % ( % ci - %) and a specificity of % ( % ci - %). the strengths of this study include the large numbers, the multicentre design, the extensive evaluations by teams of various delirium experts and the independent assessments of delirium experts and bed-side nurses. a limitations is the time interval between the expert assessment and the administration of the cam-icu (mean min; standard deviation min). there were striking differences in implementation strategies of the cam-icu between the centres. tables , . rd esicm annual congress -barcelona, spain - - october s introduction. presence of expiratory ineffective efforts in mechanically ventilated patients is a common problem associated with increased duration of mechanical ventilation, length of stay and also a higher cost and mortality. nowadays, identification and categorization of expiratory asynchronies can only be done at the bedside with the continuous observation of the ventilator interface. nurses must be skilled to understand non appropriate situations of anomalous patient-ventilator interactions. objectives. we tested the hypothesis that after specific training nurses would acquire enough skills to detect expiratory efforts as intensive care expert physicians would do. training phase: nurses were provided with selected bibliography on patient ventilator interaction and afterwards trained by intensivists with expertise on mechanical ventilation ( h/day during days) on airway pressure, flow and volume waveforms identification and eye interpretation of early and late ineffective expiratory efforts during expiration. validation phase: airflow and airway pressure waveforms were obtained from different icu mechanically ventilated patients using and acquisition and processing biomedical signal software (better care Ò ). one thousand and seven breaths were randomly selected from a total of , , breaths. subsequently, selected breaths were blindly analyzed by trained nurses and intensivists to identify ineffective expiratory efforts. introduction. several publications indicate that manual hyperinflation is a widely used measure in the icu, but more important is the fact that there is no uniformity in the implementation of this measure. this is also on my ward. in literature there are a number of reasons given to start manual hyperinflation: abolish mucus retension, improve oxygenation and removal of atelectasis. the positive effects are improved compliance, improved oxygenation and a decrease in the number of vap's (ventilator associated pneumonia). the negative effects are a decrease in cardiac output due to high peak pressures, an increased risk of baro-/volutrauma and the risk of giving too much tidal volumes. the risk of barotrauma increase with pressures above cmh o. other side effects include the development of a pneumothorax and increased icp (intra cranial pressure). objectives. creating more awareness of the procedure with lower peak pressures as a result. methods. through literature review, clinical courses and the introduction of a pressure gauge achieve greater uniformity and awareness of the procedure. we used a flow analyzer of imt medical, a laptop with flowlab software version . . and an artificial lung to demonstrate how much pressure and volume is generated during manual hyperinflation. conclusions. compliance with bts guidelines could be improved. unsurprisingly co-morbidities were frequent, but did not seem to affect outcome. use of a pneumonia severity assessment tool was sub-optimal, however mean curb- score didn't correlate with that recommended to prompt critical care assessment. apart from functional status, we are unable currently to identify any factors in this age group which can be used to guide critical care admission decision making. conclusions. in our study the incidence of complicated pneumonia was / , patients admitted in picu. in necrotizing pneumonias the blood cultures were more positive than in non-necrotizing patients. although the surgical approach in necrotizing pneumonia is controversial, it resulted in a insignificantly lower mortality rate, comparing with non-necrotizing pneumonias. background. community-acquired pneumonia (cap) of mixed etiology has frequently been described in the literature, but its clinical significance remains unknown. the aim of this study was to describe the prevalence, clinical characteristics, and outcome of severe cap of mixed etiology in icu patients. a -year prospective study was conducted on consecutive patients with severe cap admitted to icu in whom an extensive microbiological investigation was performed. results. patients were included. a single pathogen was detected in ( . %) cases, while two or more pathogens in ( . %) cases. the most frequent pathogens' combinations were those of two bacteria ( . %) and bacterium plus virus ( . %). compared with patients with monomicrobial pneumonia, patients with mixed pneumonia were older, had higher severity score (psi) and were more likely to have previous chronic pulmonary disease (see table below). moreover, mixed cap patients showed similar clinical and analytical data at admission but increases in the frequency of respiratory distress and in length of stay and a trend to higher orotracheal intubation and mortality rates. a mixed etiology was detected in % of cases with cap requiring icu hospitalization and was associated with older age and increased severity. despite similar radiological features (n of involved lobes, pleural effusion) at admission, cap with mixed etiology showed a trend to worse clinical course and outcomes than monomicrobial pneumonia. objectives. to assess the incidence and aetiology of pneumonia in a mixed medicalsurgical icu, in order to develop local epidemiologically guided protocols to reduce antibiotic resistance selection in patients with pneumonia. methods. retrospective observational study on prospectively collected data in a mixed medical-surgical icu of a secondary care italian hospital. at our institution, epidemiological data on infections and data on antibiotic use are recorded since ; in a new electronic recording of icu infections was introduced. type of infection, germ characteristics, clinician diagnosis and antibiotic use were prospectively collected in an electronic database and retrospectively reviewed. antibiotic exposure index was calculated as each antibiotic total amount administered divided by its defined daily dose times total days of admission. between and a total of patients were admitted to our icu. pneumonia was the commonest infectious disease at admission ( cases, % of patients), and the commonest infectious complication during icu stay ( new occurrences, % of total pneumonia patients). table shows major epidemiological findings in the study population. the incidence of acquired pneumonia was remarkable: . cases every , days of mechanical ventilation. the most frequent isolated organisms were s. aureus ( patients) and p. aeruginosa ( patients). methicillin-resistant s. aureus (mrsa) accounted for % of pneumonia caused by s. aureus, and its prevalence matched closely the exposure index to vancomycin. such a high incidence of mrsa is consistent with other records in mediterranean countries. carbapenem-resistant p. aeruginosa was somewhat less of a problem ( % of pneumonia by p. aeruginosa), and was not apparently associated with antibiotic exposure, at least within the unit. conclusions. in our retrospective observational study we found a high incidence of pneumonia at our institution, as well as a high percentage of mrsa, the latter with strong relationship with exposure to vancomycin. new protocols for infection containment and antibiotic usage are urgently needed. introduction. community-acquired pneumonia (cap) carries a high morbidity and mortality. a major problem is the insufficient monitoring of cap by standard chest radiography, as the evaluation depends highly on the observer and the extent of pulmonary infiltration cannot be assessed properly ( ). objectives. the aim of our study was to compare the process of inflammation in cap measured by alveolar nitric oxide (no)-analysis ( ) in exhaled breath and the extent of the inflammatory infiltration by electrical impedance tomography (eit) ( ) in spontaneously breathing patients. after approval of the local ethic committee and obtained written informed consent patients with cap were included in the study. all patients showed an acute pulmonary infiltration in chest x-ray, pulmonary symptoms (coughing, shortness of breath), positive findings in auscultation, leukocytosis, elevated crp and a pneumonia severity index c . no analyses (analyser cld sp, eco medics, dürnten, switzerland) were performed at t (up to h after admission), t ( days after admission) and t ( days after admission. eit measurements (eit evaluation kit, dräger medical, lübeck, germany) were performed at t and t and inhomogeneity of ventilation was assessed by offline analysis. all measurements were made at beside in sitting position. data were compared by t test and regression analysis. results. there was no significant correlation between the alveolar no concentration and the extent of inhomogeneity of the local infiltration measured by eit. also during the study the time course of the inhomogeneity index was not correlated with change in exhaled no. the right/left distribution of the pulmonary infiltration in the chest x-ray and the eit measurement showed a positive correlation (p \ . ; r = . ). conclusions. pulmonary regional infiltration in cap measured by eit can not predict the actual alveolar process of inflammation in the lung. nevertheless the monitoring devices give additional information to better evaluate the time course of inflammation and the dimension of the respiratory dysfunction in diseased lung. organizing pneumonia (op) presenting as acute respiratory failure (arf) is a relatively rare disease, and was only previously specifically reported in small series [ , ] , with mortality up to %. these studies were performed before the publication of international consensus classification of idiopathic interstitial pneumonias in [ ] . objectives. to compare clinical features and prognosis of patients with op with those of patients presenting diffuse alveolar damage (dad), during arf. design: retrospective monocentric study in a university hospital conducted during an yr-period. to determine predictors of niv failure in patients who were intubated for respiratory failure and extubated directly to niv. methods. this is a retrospective analysis of prospectively collected data from january to dec . patients with respiratory failure were mechanically ventilated in a university hospital's medical intensive care unit (icu) and subsequently extubated to niv. physiological and biochemical parameters, using arterial blood gas measurements, were collected at the end of the spontaneous breathing trial and h after the application of niv. failure of niv was defined as respiratory failure requiring re-intubation within h. out of patients, . % were successfully extubated to niv. success rates were . % in patients with chronic obstructive pulmonary disease (copd) and . % in other patients (p = . ). patients who failed niv were more tachypnoeic, acidaemic and hypercapnic pre-niv, and more tachycardic, hypotensive, acidaemic, hypercapnic and hypoxaemic post-niv (p all. ). on logistic regression analysis, three physiologic parameters predicted niv failure: pre-niv respiratory rate (or . , % ci . - . per breaths increase), post-niv heart rate (or . , % ci . - . per beats increase) and post-niv systolic blood pressure (or . , % ci . - . per mmhg decrease). conclusions. physiologic parameters, including the respiratory rate pre-niv, and heart rate and systolic blood pressure post-niv, independently predict niv failure post-extubation. these parameters should be taken into account in the decision to extubate directly to niv. introduction. discontinuation of mechanical ventilation in critically ill patients is a challenging task and involves a careful weighting of the benefits of early extubation and the risks of premature spontaneous breathing trial (sbt). only a few studies have explored indices derived from both heart rate and breathing pattern variability analysis for the estimation of weaning readiness. objectives. to investigate heart rate (hr) and respiratory rate (rr) complexity in patients with weaning failure or success, using both linear and nonlinear techniques from signal processing theory. methods. forty-two surgical patients were enrolled in the study. there were who passed and who failed a weaning trial. signals were analyzed for min during two phases: despite of passing the protocol the decision to extubate was postponed in some patients. to gain insight on the physicians reasons for continuing mechanical ventilation after passing the wean screen protocol. a wean screen protocol was introduced at a mixed medical (neuro-)surgical icu of a teaching hospital in december to april . ventilation practitioners assessed ventilated patients and recorded the physicians reasons for continuing mechanical ventilation despite of passing the wean screen protocol. . patients were ventilated in this period. daily screens were performed, screens were successful. only passed wean screens resulted in extubation. the rate of extubation was %. % screens did not lead to liberation from mechanical ventilation. the extubation rate does not correspond with the findings of the abc trial with an extubation rate of %. table shows the physicians' reasons to continuing mechanical ventilation. it should be noted that all patients with an unsafe airway were patients with a glasgow coma scale (gcs) of b [intracerebral haemorrhage ( %), cerebral infections ( %), post-cpr encephalopathy ( %) and severe brain injury ( %)]. we accomplished a reduction in the use of sedatives (- % midazolam and - % propofol) and morphine (- %) ( table ). the amount of time spend on ventilators decreased, albeit not significantly (p = . ). this was probably due to the vap-ventilatorbundle (introduced last year), the heterogeneity of our cohort and the already short mv-duration. . non-invasive ventilation (niv) has been utilized in selected patients with hypoxemic arf to avert endotracheal intubation, which is related to life-threatening complications. niv has been also proposed to facilitate weaning and extubation in patients with hypercapnic arf. so far, no controlled randomized study has investigated the potential role of niv in weaning patients with hypoxemic arf. objectives. we designed this pilot study to assess safety and feasibility of niv to wean hypoxemic arf patients. twenty mechanically ventilated patients with hypoxemic arf were randomized to receive early extubation followed by niv application via helmet (helmet group) or conventional weaning through the endotracheal tube (tube group). primary outcomes were the duration of invasive mechanical ventilation and the adherence to the study protocol. secondary outcomes were protocol failure (i.e. need for re-intubation), icu and hospital mortality, rate of tracheotomy, duration of continuous intravenous sedation, weaning time, and septic complications. table . weaning through helmet by niv application following early extubation was safe and feasible. overall the adherence to the study design was %. in addition, in the helmet group, there was a significant reduction in the rate of tracheotomy and a trend toward a lower rate of protocol failure, and fewer days on invasive ventilation. there was no difference with respect to days of continuous sedation, icu and hospital mortality, weaning time and septic complications. ( ) . delirium is a common occurence on the icu and is associated with increased length of stay (los) and poor outcomes ( ) . objectives. we developed a combined daily sedation hold, delirium management, and weaning (sdw) protocol and implemented this to reduce icu los and improve outcomes. methods. a sdw protocol was implemented in . we prospectively audited all patients from january to march . delirium was measured using the icdsc. data was analysed using graphpad statistical software. results. consecutive patients were analysed. the incidence of delirium was % ( pts). of these, % ( ) had risk factors for delirium. there was no difference in onset of delirium between sexes, age, type of admission, or severity of illness. however, in patients with delirium, duration of mechanical ventilation (mv) and icu los were significantly longer and there was a trend towards increased hospital los ( conclusions. measuring the linear dependence of variables through time by k and ø may be used to determine non-linear behavior between the variables of the emmv. non-linear behavior during weaning perhaps indicates the dependency of, either the resistance or compliance of the respiratory system, on the ventilatory support (i.e. pi). accordingly, k and ø, estimated at the frequency interval form to (h) - , can provide information concerning to the dynamics of the respiratory system that can be used as a complement to determine the suitability of the mv withdrawal. objectives. to study the potential superiority of aprv on cmv in a subgroup of patients with severe ards. methods. retrospective observational study on patients severe ards who were admitted between july and january to mafraq hospital icu in uae. the diagnosis of ards was based on presence of bilateral infiltrates in cxr and p/f ratio of less than in absence of evidence of elevated left atrial pressure. all patients were managed according to ardsnet guidelines using low tidal volume cmv and iv steroids. criteria for transition to airway pressure release ventilation (aprv) included failure to wean down fio below % after h, hemodynamic instability due to high peep, and failure to maintain plateau airway pressure below cmh o. initial settings of aprv were ph , pl , th , and tl . with titration of fio as required keeping pao more than mmhg. we compared the outcome of cmv and aprv groups with special concern to the duration of mechanical ventilation, requirement for tracheostomy, and survival to icu discharge. twenty four male and females were included in the study with a mean age of years (± ). fourteen out of them fulfilled the criteria and were shifted to aprv within h of initiating mechanical ventilation. ten out of ( %) patients in the aprv arm survived to icu discharge versus out of ( %) patients in cmv group (p . ). survivors in aprv group spent significantly shorter periods of mechanical ventilation compared to survivors in cmv group ( . vs. . days p . ). while out of ( %) survivors in cmv required tracheostomy for prolonged intubation or recurrent lavage, only out of ( %) survivors in aprv group required tracheostomy tube placement (p . ). we concluded that aprv can be effectively used as rescue measure of ventilation in patients with severe ards. although our study does not show any mortality benefit of using aprv over cmv, there was a shorter ventilation days and icu stay using aprv. we strongly recommend further studies to investigate the probability of using aprv as initial mode of ventilation in this subset of patients. weaning from mechanical ventilation is a common daily procedure when caring for critically ill patients, and a lifesaving practice on which nurses are taking an increasing role with the introduction of nurse-led protocols. the literature supports that nurse-led protocols facilitate weaning and increase nurses' input in decision-making. on the other hand, decision-making is a complex function affected by the nature of the task, the decision environment and the characteristics of the decision maker. although the cognitive process of clinical decision-making has been investigated with many different methodologies, little is known about the decision environment and its impact on decisions' during the weaning process. objectives. this paper aims to address one of the factors of the clinical environment and its impact on the decisions when discontinuing mechanical ventilation. methods. this paper is part of a large comparative ethnographic study looking at nurses' input during the weaning process of mechanically ventilated patients. participant observation of critical care nurses took place in an -bedded icu in greece and an -bedded icu in scotland for months each to examine nurses' involvement in the decisions made. in-depth semi-structured interviews with the nurses followed focusing on how nurses perceived their participation in the decisions made. data from field notes and interview transcripts were analysed thematically using the qualitative data analysis software nvivo, version . inter-personal and inter-professional relationships were considered revealing influences of nurses' input in decision-making. clinicians' personality played a significant role in their involvement in decisions, whereas trust and appreciation, the sense of support and the sense of accountability were also considerable dynamics of inter-professional relationships and predisposed decision-making. clinical decision-making is a multi-dynamic process specifically in complex clinical long-term situations such as weaning. aspects of the decision environment, such as the interprofessional relationships should be acknowledged when introducing methods to enhance nurses' role in teamwork and collaborative decision-making in order to improve the weaning process of ventilated patients and their outcome. objectives. the objective of our study was to analyze the temporal trends and outcomes of two cohorts of patients ventilated with psv and pav+. a cohort of consecutive patients who were ventilated with pav+ and another cohort of consecutive patients who were ventilated with psv were compared. all patients had the same inclusion criteria (gas exchange, ventilatory mechanics, peep level, resolution/stabilization of the cause leading to invasive mv and appropriate level of consciousness). both modes were adjusted to predefined clinical criteria (psv to reach a respiratory rate about bpm and pav+ to reach a physiological inspiratory effort introduction. presence of expiratory asynchronies (ea) (ineffective efforts, cough and continued contraction of inspiratory muscles) is a common problem associated with increased duration of mechanical ventilation, longer stay, higher costs and increased mortality. because of the lack of systems that automatically detect and report ea, their identification is currently done by examining ventilator interface at the bedside or by applying dedicated algorithms in investigational conditions. validate the accuracy of linear mathematical algorithms to automatically detect ea built in a new computerized system that grabs and process data from different bedside icu monitors and mechanical ventilators. observational and prospective study in a general icu of beds. two beds were equipped with a software (better care Ò ), a technological platform responsible for data acquisition and synchronization, processing, storing-as non static and processable dicom objects-and also for integrating all this data with health information systems. by using the better care Ò platform, a total of , , breaths from consecutive adult patients were collected with at least h of mechanical ventilation. algorithm # : the ea algorithm consisted in a mathematical analysis of the airflow and airway pressure waveform variations during expiration not followed by a mechanical breath. algorithm # : designed to select , breaths out of the total number. this algorithm sorted and classified the breaths by the percentage of deviation from the expected expiratory curve. the result was , breaths covering most of the shapes the expiratory curve could have. five expert attendant physicians independently analyzed the , selected breaths and classified them as ea or not. the ea algorithm processed the same , selected breaths and assigned a percentage to each one, according to the variation in the shape and direction of the expiratory airflow and airway pressure curves. the expert criterion against the ea algorithm scores was used to construct a logistic regression model. we calculated sensitivity, specificity, positive predictive value and negative predictive value. the predictive performance of ea algorithm was evaluated using roc curves. optimal sensitivity and specificity were achieved by setting the cut-off point at a ea algorithm score of %. a variation in the shape and direction of the expiratory airflow and airway pressure curves [ % compared to the theoretical curve identified an ea with a sensitivity of . %, specificity of . %, a positive predictive power of . % and a negative predictive power of . %. introduction. near-infrared spectroscopy (nirs) in combination with a vascular occlusion test (vot) has been proposed to assess and identify metabolic and microcirculatory alterations during sepsis and shock in critically ill patients. however, to automatize repeated measurements at the bedside, this technique can potentially cause discomfort to the patient. vascular arterial occlusion performed in the finger may be a more attractive method to execute repeated measurements at the bedside because of more tolerability from the patient. we have previously showed in healthy volunteers that nirs can be used on finger to assess the sto response to vot and that min was an adequate occlusion time to provide the best curve fit for nirs dynamic variables . objectives. we aimed to investigate whether sto response to vot obtained from the finger could predict conventional sto response measurements obtained from the thenar of critically ill patients. parameters of sto response were measured with an inspectra spectrometer model (hutchinson technology inc.) equipped with a -mm or a -mm probe. the mm probe was placed over the thenar eminence and the -mm probe was place over the ventral face of the middle finger. we performed in each patient a series of two vascular occlusion tests (vot): one on the finger ( min) followed by one on the arm ( min). the measurements were obtained within h of intensive care admission and every h thereafter until day . vot-derived sto traces were analyzed for baseline, ischemic (rdecsto , %/min) and reperfusion (rincsto , %/s) parameters. we performed paired of nirs measurements in critically ill patients (age ± ; m/ f). although sto did not differ significantly between thenar and finger ( % ± vs. % ± ; p = . ), rincsto and rdecsto were statistically lower in the finger ( . %/s ± . vs. . %/s ± . , p = . ; . %/min ± . vs. %/min ± . ; p = . ). we performed bivariate linear model with correlated errors in which sto outcomes on thenar and on finger were treated as responses. the correlation was significant for sto and rincsto , but not for rdecsto (table ) . furthermore, mixed model analysis showed that thenar-sto as dependent variable could be significantly predicted by finger-sto parameters with estimation coefficient (± se) of . ± . (p = . ), . ± . (p = . ) and . ± . (p = . ) for sto , rincsto and rdecsto , respectively. correlation of sto response: finger vs. thenar a prospective randomized clinical trial performed in icu's of an university and teaching hospital during a . year period, involving septic and non-septic patients, randomized (after stratification) to hemodynamic monitoring, by picco tm or pac with both techniques allowing cardiac output and central/mixed venous o saturation monitoring. methods. hemodynamic management was guided by extravascular lung water index (evlwi) and global end-diastolic volume index (gedvi) in the picco tm group and by the pulmonary capillary wedge pressure (pcwp) in the pac group for consecutive days. primary outcome measures were ventilator-free days (vfd), for which the study was powered, and lengths of stay in icu and hospital. secondary measures were the course of cardiorespiratory parameters, fluid and vasopressor requirements, lactate levels, organ functions and mortality. in the study period, septic and non-septic patients were included. patients received a picco tm and a pac catheter. monitoring arms were comparable at baseline, although sepsis differed from non-sepsis in hemodynamics and severity of lung injury. premorbidity was greater in non-septic patients. the fluid infusions and balances did not differ between monitoring arms, except at t = h when the picco tm group had a more positive balance (p = . ). cardiac index and central venous o saturation increased more in the course of time in the picco tm than in the pac group. the decrease in norepinephrine requirements strongly tended to favor the picco tm group (p = . ). the course of lactate levels and organ failure did not differ between monitoring arms. vfd did not differ among monitoring arms. picco tm monitoring was associated with relatively fewer mechanical ventilation and icu days in sepsis but more in non-sepsis (after day ). the changes in respiratory parameters, sofa and number of catheter-related complications did not differ among the arms of the study. overall, patients ( %) died in the picco tm group before day and ( %) in the pac group (p = . ). conclusion. hemodynamic management guided by picco tm monitoring is safe and results in better tissue oxygenation than guidance by pac, without inducing pulmonary overhydration, in septic and non-septic, critically ill patients. this was associated with fewer mechanical ventilation and icu days in patients with sepsis but more days in patients with non-sepsis (after day ), partly attributable to greater cardiovascular premorbidity in the latter. the major primary and secondary endpoints, vfd and mortality, were not affected. introduction. non-invasive evaluation of endothelial function may be easily accomplished by ultrasound assessment of flow-mediated vasodilation (fmd) of the brachial artery, but this technique has not been fully explored in septic patients. objectives. this prospective study aims to investigate the role o fmd analysis on intra hospital prognosis of patients with severe sepsis and septic shock. adult patients admitted to the intensive care unit with a diagnosis of severe sepsis or septic shock (\ h of duration) were consecutively included. fmd of the brachial artery was measured upon admission and after and h using a high-frequency linear transducer ( . - mhz) according to internationally accepted protocols. a group of apparently health subjects paired for gender and age was used as controls for fmd analysis. patients were followed up to discharge or death. we studied adult patients mean age ± years, females, % on vasopressors with sepsis predominantly of abdominal or respiratory etiology ( %). apache ii risk score was ± and intra hospital mortality rate was %. fmd was similar in patients with or without use of vasopressors at baseline (p = . ). fmd in septic patients was significantly lower than in health controls ( . ± vs. ± %; p \ . ). we observed that survivors depicted a gradual improvement on endothelial function, so that h after sepsis onset fmd was significantly lower in nonsurvivors (- . ± vs. . ± %; p \ . ; time-group interaction p value = . ). conclusions. brachial fmd is altered in septic patients with hemodynamic instability and its improvement may be an early marker of favorable prognosis. introduction. change in pulse pressure variation (dpp) and respiratory variation of the pulse oxymetry plethysmogram (pop) may predict the hemodynamic effect of peep in mechanically ventilated patients [ , ] . reported comparisons [ , ] between pop variations (popv) and co or dpp are based on selection of - consecutive breaths (dpp b) during a ''stable'' period of pop. recently, a fully automatic ventilation mode (intellivent Ò , hamilton medical, switzerland) that incorporates an automatic and continuous popv calculation (hli Ò ) using a dedicated algorithm has been developed. the present study was designed to compare dpp b, dpp calculated with the algorithm as hli Ò (dppalg) and hli Ò. . . sedated icu patients ventilated with hamilton medical s ventilator (with integrated pulse oxymetry (po)) were included (age = ± years, saps ii = ± , no arrhythmia, norepinephrine: . ± . mg/h in patients, map = ± mmhg, vt = . ± . ml/kg). waveforms of po from a finger sensor and of blood pressure from a radial catheter were recorded for - h. from the waveforms, breath by breath (using respiratory flow signal), without pre-selection of stable periods and using known formula [ ] dpp b (averaging breaths without any filtering), dppalg and hli Ò were automatically obtained (matlab Ò ). dpp b was compared to dppalg ( pairs) using mann-whitney t test. pairs of hli Ò and dppalg values (see fig. below) were compared using linear regression and bland-altman method. a dppalg threshold value of % was used to generate hli Ò roc curves. results. dpp b and dppalg were significantly correlated (r = . , p \ . ), but standard deviation of dpp b were higher than the standard deviation of dppalg ( . ± . vs. . ± . %, p \ . ). dppalg and hli Ò were correlated (r = . , p \ . ), mean difference was ± %. hli Ò above % predicted dppalg above % with a sensitivity of % and specificity of % (roc: . ). conclusions. dpp b should be interpreted with caution due to the high variance of this index. in real conditions and during long time monitoring dppalg and hli Ò are in acceptable agreement and hli Ò may help estimating continuously the hemodynamic effects of ventilation. introduction. transthoracic echocardiography (tte) is supposed not to be useful in ventilated patients (pt). echocardiography is usually performed transesophageally in ventilated pt and is thought to be independent of the examiner's skills. we want to demonstrate that tte in ventilated pt could be learned even by medical students with reasonable results and that tte could add useful informations for interpretation of the hemodynamic status. objectives. in a prospective observational study consecutive patients (pt) were enrolled in a -bed medical intensive care unit of a university hospital. inclusion criteria was septic shock according to actual guidelines. transthoracic echocardiography (acuson cv , siemens, germany) was performed by a medical student in each subject on day , day and survival was reported on day . tte-examination was reduced to an apical -chamber view for interpretation of left ventricular global function and calculation of left ventricular ejection fraction (ef) with the simpson method and to a subcostal view in order to examine the diameter of the inferior caval vein (ivc) and to rule out pericardial effusion. each examination was digitally recorded and was interpreted by an experienced cardiologist. every single pt was mechanically ventilated. cardiac output (co) was measured with the transpulmonary thermodilutional technique (picco-catheter, pulsion, germany). the insertion of the picco-catheter took place due to an individual physician's decision. crp was measured as an parameter of inflammation. results. pt, mean age years ± . , male ( %), pt with known coronary artery disease ( %), pt with known dilated cardiomyopathy ( %). mean apache ii-score . ± . . pt died within days ( %). picco-catheter was inserted in pt ( %). tte could be successfully performed in pt ( %). the following values are expressed as mean values ± sd, student's t test, p \ . denotes statistic significance. ef on day . % ± . , ef on day . % ± . , p = . . ivc on day . mm ± . , ivc on day . mm ± . , p = ns. co on day . l/min ± . , co on day . l/min ± . , p = . . crp on day . mg/dl ± . , crp on day . mg/dl±, p\ . . pericardial effusion in no pt. in older pt coronary artery disease is common and ef is at the start of septic shock severely diminished. ef decreased slightly in the early course of septic shock, may be as an expression of septic cardiomyopathy. the ivc diameter did not change and may not be useful as a predictor of preload in ventilated pt. co decreased over time as the hyperdynamic circulation in septic shock is getting normalised. tte adds useful hemodynamic information and should be performed in each ventilated pt. tte could be performed in almost each ventilated pt and is easily learned even by medical students. ( , ) , which can often be caused by anaemia. in current guidelines the transfusion trigger is haemoglobin (hb) \ g/dl, but there is no recommendation for scvo ( ). objectives. the aim of this retrospective study was to evaluate the change in scvo before and after transfusion and to reveal whether co -gap reflects it. methods. over a month period hb, scvo , co -gap and o -extraction ratio (o er) were recorded before and after transfusion. data are presented as median [interquartile range], for statistical analysis wilcoxon, mann-whitney tests and pearson correlation were used as appropriate. results. out of transfusion events the scvo was measured in cases. after transfusion hb increased significantly: . [ . - . ]- . [ . - . ] g/dl, p \ . . the median scvo was %, therefore two groups were created: ''low'' (scvo \ %, n = ); ''high'' (scvo c %; n = ). hb increased significantly in both groups (p \ . ), but scvo conclusions. in the high-group the low hb levels did not cause oxygen debt, as after transfusion hb increased significantly but scvo did not, and o er and co -gap were within the normal range. our results give further support that not only the hb level should serve as a transfusion trigger, but measures of oxygen debt such as scvo and co -gap should also be considered, hence unnecessary transfusions could be avoided. introduction. intellivent Ò is a fully closed loop ventilation designed to keep the patient within target ranges of etco and spo . the system includes an automatic adjustment of peep and fio following the ardsnetwork tables [ ] . if required peep is changed by cmh o every min with a maximal possible value set by the user or depending on an automatic and continuous calculation of the respiratory variations of the plethysmogram from an integrated pulse oxymeter (hli Ò ), i.e. the higher the hli Ò the lower the maximal peep allowed by the system. the present study was designed to estimate whether changes in peep are reflected in hli Ò changes. in sedated icu patients ventilated for min in fully closed loop ventilation with intellivent Ò (hamilton medical s ventilator), episodes of significant changes in peep (c cmh o) were selected and hli Ò values within min before and after peep changes were collected. statistics were done using sigmastats with p \ . as significant. results. changes in peep and in hli Ò are shown in the table ± cmh o ± cmh o ± % ± % p \ . the correlation between change in peep and change in hli Ò is shown on the fig. . conclusions. based on these preliminary data changes in peep are reflected hli Ò changes and may help estimating continuously the hemodynamic effects of ventilation. objectives. we have tested a axis accelerometer sensor for detection of regional left ventricular ischemia. in pigs a -axis accelerometer was sutured to the left ventricular (lv) apical region in left descending coronary artery (lad) supply area accelerometer x-axis measured longitudinal-, y-axis circumferential-and z-axis radial epicardial motions. epicardial displacements were calculated from the acceleration signals and systolic displacements within ms after peak r on ecg was measured. lad was occluded for s to induce regional lv dysfunction. myocardial circumferential strain (shortening) measured by echocardiography in the lv apical anterior region was used to confirm ischemia. the ecg st-segment in lead ii was also monitored. data are presented as mean ± se. early systolic displacement at baseline was ± mm, ± mm and ± in circumferential, longitudinal and radial directions, respectively. lad occlusion induced akinesia in circumferential ( ± mm, p \ . ) and radial ( ± mm, p = . ) directions, whereas longitudinal displacement changed less to ± mm (p = . ). ischemia was confirmed by echocardiography strain, showing lengthening in systole (p \ . ). no significant changes were observer in the ecg st-segment during coronary occlusion (p = . ). introduction. there is increasing evidence to suggest perioperative complications are predictive of long term survival and that reducing them may improve survival rates . goal directed therapy has been shown to reduce mortality and morbidity perioperatively, with those unable to increase oxygen delivery perioperatively having demonstrably worse outcomes. the advent of non invasive tissue oxygenation monitors using near infrared spectroscopy has allowed further study of oxygen flux during goal directed therapy. objectives. to observe changes in tissue oxygenation during an h oxygen delivery targeted post surgical optimisation program and provide long term mortality followup of a surgical cohort of high risk patients. methods. patients undergoing high risk surgery and postoperative optimisation (targeting of oxygen delivery index of [ ml/min/m ) on the tensive care unit at a london teaching hospital were enrolled. each patient underwent a protocolised haemodynamic optimisation protocol as per our standard unit policy for h with consecutive recordings of tissue oxygenation at the thenar eminence using an inspectra monitor. additional variables relating to global and tissue perfusion were measured concurrently. patients were followed up for survival status at . years using routinely available information held within our hospital records. in hospital mortality was . % (n = ), whilst at . years this had increased to % (n = ). there was no significant difference between apii scores ( ) versus . ( ), age . ± . versus . ± . or operation type for survivors and non-survivors at . years respectively. significant differences between groups were found however for admission and mid optimisation protocol ( h) hr and sto (see table there were no significant differences in measured variables for day mortality. conclusions. there appears to be a statistical and clinical difference in hr and tissue oxygenation between the long term survivors of high risk surgery who undergo monitored postoperative goal directed optimisation. introduction. bronchoscopic bronchoalveolar lavage (b-bal) is today the gold standard for sampling of inflammatory markers in the distal airways. nonbronchoscopic bronchoalveolar lavage (n-bal) by ordinary suction catheter has been investigated as a more easily accessible method for alveolar sampling in the setting of acute respiratory distress syndrome (ards). the results, however, were disappointing, probably due to more proximal sampling by the n-bal. to investigate wether n-bal by a catheter with physical properties similar to those of the bronchoscope is comparable to b-bal. methods. b-bal and n-bal by cook's airway exchange catheter was performed with ml normal saline on opposite sides min apart at nine different occasions on anesthetized and intubated pigs. the volume of the recovered lavage was noted, after which the fluid was analyzed for albumin, total cell count, viability and differential cell count. statistical analysis was performed using wilcoxon's rank-sum test. results. n-bal yielded significantly higher albumin content than b-bal ( . ± . vs. . ± . mg/l, p = . ). in all other measurements there were no significant differences between n-bal and b-bal (recovered volume . objectives. we hypothesized that collagen synthesis and degradation are disturbed in acute respiratory failure. in the finnali-study we defined acute respiratory failure as need of noninvasive and/or invasive ventilatory support for more than h ( ). after informed consent we collected blood samples for serum procollagen propeptides i and iii (pinp, piiinp) and ictp levels at study admission, day , and . patients with all four blood samples were included in this substudy. multiple organ dysfunction (mod) was defined as two or more individual organ sofa scores of - at any day during the first week. results. the study population comprised of finnali patients ( ). the mean (sd, range) age was years ( , - ) and the majority were male %. on admission the mean sapsii score was ( , - ). patients ( %) developed mod during the first days. over time piiinp/pinp-ratio first increased and then decreased to baseline by day while pinp/ictp-ratio decreased and then decreased to baseline by day (p \ . and p = . , respectively) ( fig. ). there were no statistical differences in the ratios between patients with or without mod. conclusions. we found that in patients with acute respiratory failure the balance of collagen synthesis was towards degradation of type i collagen and production of collagen type iii. ± ng/ml in the ards group, and significantly higher than the . ± . ng/ml in the ali (not ards) group. the difference in hmgb values in the early stage between the group that died up to the by th day and the surviving group was not significant, but the hmgb values were significantly higher in the group that died until the th day and th day than in the survival group. it was concluded that differences in hmgb values in the early stage after the onset of ali (not ards)/ards are useful as outcome determining factors after days of onset. an inverse correlation was observed between the hmgb values and lung oxygenation, suggesting the possibility that hmbg is involved in the development of respiratory failure. s. shibata , g. takahashi , n. shioya , s. endo akita city hospital, anesthesiology, akita, japan, iwate medical university, emergency medicine, morioka, japan, iwate medical university, critical care medicine, morioka, japan sivelestat sodium hydrate (sivelestat) is a selective polymorphonuclear leukocyte elastase (pmn-e) inhibitor and has also been shown to be effective for pulmonary disorders associated with sirs in clinical patients. blood levels of inflammatory cytokines have been shown to be decreased in patients treated with sivelestat. however, since patients with sirs have already received other drugs, it remains indefinite whether or not sivelestat might suppress the production of cytokines. moreover, it is difficult to clarify any cells releasing cytokines. in the experiment using cells isolated from the blood, intercellular mutual actions and cytokine networks were blocked and the experiment failed to faithfully reproduce the in-vivo condition. objectives. the possibility of sivelestat suppressing the production of cytokines from granulocytes and monocytes was assessed by intracellular cytokine staining using the whole blood culture method and flow cytometry to faithfully reproduce the in-vivo condition. methods. blood samples were collected from healthy volunteers. a vehicle (control group), lipopolysaccharide (lps; lps group), or lps + sivelestat (sivelestat group) was added to the whole blood, followed by the addition of a protein transport inhibitor in each group. after incubation, they were subjected to staining of the cytokines retained in the cells by the addition of an anti-interleukin (il- ) or anti-tumor necrosis factor a (tnf-a) antibody and analysis by flow cytometry. the data were analyzed by the kolmogorov-smirnov test. values obtained [d/s(n)] result from the comparison of the fluorescence histograms of each sample with a control one. addition of sivelestat at low concentrations ( and lg/ml) significantly (p \ . ) suppressed the production of il- from granulocytes induced by a low concentration ( ng/ml) of lps. on the other hand, the granulocytic production of tnf-a induced by a high concentration of lps ( ng/ml) was significantly (p \ . ) suppressed by treatment with sivelestat at high concentrations ( and lg/ml). with regard to the monocytic production of tnf-a and il- induced by lps, there was no significant suppression of either tnf-a or il- production by sivelestat. conclusions. sivelestat, a neutrophil elastase inhibitor, suppressed granulocytic production of il- and tnf-a, suggesting the potential usefulness of sivelestat for the treatment of various morbid conditions involving il- and tnf-a in their onset. introduction. coagulation, fibrinolysis and extravascular fibrin deposition are the hallmarks of the pathogenesis of acute lung injury (ali). pai- has a central role in antagonizing fibrinolysis by decreasing the plasminogen turnover to plasmin. pai- has been suggested as a clinical severity marker of ali. in previous studies it was associated with higher mortality and morbidity in the critically ill. upar is a cell surface receptor activating the serine protease upa. increased expression of upar is found in various stages, including inflammation, tissue remodelling and malignancies, indicating poor prognosis. pai- antagonizes the proteolytic activities of upa and plasmin. objectives. we sought to evaluate the prognostic value of supar and pai- for -day mortality of patients with acute respiratory failure (arf). the finnali-study patients needed invasive or non-invasive ventilation for more than h ( ). blood samples were collected from patients at baseline and on day after baseline. healthy volunteers were also analyzed. sera were frozen at - °c until analyses. concentrations of supar and pai- in blood serum were measured by enzyme linked immunosorbent assay (elisa). data are presented as median (iqr). the prognostic value of supar and pai- for -day mortality was determined with roc analysis. in the critically ill, supar and pai- were . ( . - . ) ng/ml and . introduction. acute lung injury is a common disease in intensive care, associated to various septic or inflammatory diseases. inflammation is part of the defense mechanisms of innate immunity, occurring after tissue injury. objectives. the aim of the project was to decipher the transcriptional changes occurring after the onset of an inflammatory injury by intravenous injection of oleic acid. experimental study of the lung transcriptome after oleic acid injection. thirtysix c bl/ j mice, aged of weeks, were sacrificed at h, h , h, h, h and h after physiological serum or oleic acid injection ( ll) in the caudal vein. left and right lung were separated for mrna extraction and pathological examination. labelled cdna were hybridized on cdna nylon microarray (tagc, marseilles, france) and raw data were extracted from scanned images with bzscan software. raw data were normalized with the quantile method, and supervised analysis was conducted with significance analysis of microarray algorithm within the r statistical suite and bioconductor libraries. after the administration of oleic acid, the mice were tachypneic and prostrated. all survived during the first hours. the pathological analysis of lung tissue revealed an early inflitration of the lung tissue by polynuclear cells, as well as a pulmonary edema. these alterations were not observed after h. the time course analysis of transcriptional lung data identified a thousand genes which expression is modulated after injury. hierarchical clustering identified major groups of genes. the first one ( genes) is composed of genes transiently up-regulated between h and h after oleic acid injection. th second group ( genes) is composed of genes expressed between h and h. the third group ( genes) is composed of genes expressed at the later time points ( h- h). the functional annotation linked these signatures with keywords related to pro-inflammatory response, vascular endothelium modification and lipid metabolism, respectively. rt-pcr analysis of pro-(tnf, il ) and anti-inflammatory (il , il ) markers related the pro-inflammatory phase to the earlier time points ( h- h ) and the anti-inflammatory phase to the late points (after h). conclusions. oleic acid injection in mice induced a transient acute lung injury. this is confirmed by clinical, pathological and transcriptional modifications. the modulation of gene expression after the oleic acid injection revealed an early pro-inflammatory response, followed by an anti-inflammatory response and lipid metabolism modificiations. this model could now be used to describe the specific modulation occuring during pulmonary infection and critical injuries like acute respiratory distress syndrome. introduction. ventilator associated lung injury (vali) is influenced by tidal volumes, airway pressure and cyclic opening of alveoli during mechanical ventilation. preserved spontaneous breathing during partial ventilatory support may be protective, but it is not known whether the transpulmonary pressure generated by spontaneous breathing has the same effect on vali as if generated by the ventilator. to determine whether hemodynamics, respirtory function and vali are influenced by the amount of support provided by pressure support ventilation. after approval from the institutional animal care committee, acute lung injury was induced in anesthetized sd rats by acid aspiration. ten animals each were then ventilated with positive end-expiratory pressure cmh o in pressure control (pc), pressureregulated assist control (ac) or pressure support mode with % (ps ), % (ps ) or % (ps ) pressure support of initial distending pressure needed to maintain tidal volume. pc animals were paralyzed. after h animals were killed and vali determined. results. there were no differences in baseline characteristics. acute lung injury was characterized by a decrease of the p/f ratio from ± to ± mmhg and of the dynamic compliance from . ± . to . ± . ml/cmh o. conclusions. compared to controlled ventilation, preserved spontaneous breathing activity improved hemodynamic stability, respiratory function and lung edema clearance. the reduction in pressure support did not lead to reduced tidal volume, but transpulmonary pressure was preserved by muscular activity of the chest wall. no difference was observed between full or % of pressure support, but further reduction in pressure support resulted in increased wet-dry ratio. objectives. we studied the effects of metabolic acidosis on enzymatic and non-enzymatic no-production in hypoxic and hyperoxic lung regions in a pig model. eighteen healthy anesthetized pigs were separately ventilated with hypoxic gas to the left lower lobe (lll) and hyperoxic gas to the rest of the lung. six pigs received hcl infusion (hcl group), six pigs received n w -nitro-l-arginine methyl ester (l-name) and hcl (l-name + hcl group) and six pigs received buffered ringer's solution (control group). no concentration in exhaled air (eno), no synthase (nos) activity in lung tissue, and regional pulmonary blood flow were measured. results. metabolic acidosis, induced by infusion of hcl, decreased the relative perfusion to the hypoxic lll (q lll /q t ) from (± ) to (± )% in the hcl group (p \ . ), and from (± ) to (± )% in the l-name + hcl group (p \ . ), without any measurable significant changes in eno from hypoxic or hyperoxic lung regions there were no significant differences between the hcl and control groups for ca + -dependent or ca + -independent nos activity in hypoxic or hyperoxic lung regions. metabolic acidosis augmented the hypoxic pulmonary vasoconstriction, without any changes in pulmonary enzymatic or non-enzymatic no-production. when acidosis was induced during ongoing nos-blockade, the perfusion of hypoxic lung regions was almost abolished, indicating acidosis-induced pulmonary vasoconstriction was not no dependent. assessing and monitoring biomarkers in acute lung injury (ali) may improve knowledge of its pathogenesis, early recognition, and management and predict remote organ injury and multiple organ failure. objectives. early consents for research are difficult to obtain in patients with or at risk of ali because of the emotional burden of the severity and sudden onset of the disease. however, study samples may be obtained from left-over clinical blood draws, which are readily available if processed adequately. the aim of this study was to compare fresh and ''waste'' blood samples prospectively in a series of consecutive critically ill patients. the hypothesis is that ''waste'' blood samples if appropriately processed provides accurate and reliable results comparable to the gold-standard, which is immediate collection and processing of fresh blood samples. prospective study comparing biomarkers of epithelial injury (srage) and inflammation ( different cytokines/chemokines) in critically ill patients measured on fresh blood or waste blood, kept at degrees celsius for h. an automated system performed a daily screening of adults in the icu with an increased risk for ali (lung injury prediction score, lips) within h of admission and/or on recognition of the diagnosis of ali, using the american-european consensus conference criteria. risks factors for ali include pneumonia, sepsis, pancreatitis, shock, aspiration, high risk surgery and high risk trauma. irb approved the protocol and written consent was obtained from patients or their surrogates. statistical measurements were performed using the bland-altman analysis for correlation between fresh and waste blood sample data. between may and december , patients were enrolled. one patient was excluded due to lack of sample. samples were obtained either at one time point (n = ) or two, on consecutive days (n = ). female/male patient ratio was / . seven of the patients had ali. twenty two patients had risk for ali with a median lips score of (iqr . - . ). sepsis was the most common risk factor, present in patients. in-hospital mortality was % ( / ). the bland-altman plot (mean bias ± se, limits of agreement) showed good correlation for il- ra (- ± . pg/ml, - . to . pg/ml), il- ( . ± . pg/ml, - to . pg/ml), il- (- . ± . pg/ml, - . to . pg/ml), il- (p ) (- . ± . pg/ml, - . to . pg/ml), mcp- (- . ± pg/ml, - . to . pg/ml) and srage (- ± pg/ ml, - to pg/ml) between fresh blood and ''waste'' blood samples. in patients with ali, properly stored blood, drawn for clinical purposes, can be processed within h for research purposes. however, the stability of each biomarker of interest needs to be individually validated before using stored blood introduction. pulmonary surfactant inactivation following acute lung injury might promote alveolar derecruitment and reduce the airspace available for ventilation, making the lung more prone to ventilation-induced lung injury (vili). our aim was to test the potential for a protective effect of exogenous surfactant treatment in a model of acid aspiration and vili. methods. male c /bl mice were anesthetized, mechanically ventilated (vt ml/ kg; rr /min; peep ± . cmh o; fio . ) and immediately subjected to intrabronchial (right) instillation of . ml/kg hcl . m. mechanical ventilation went on for min. min after the acid instillation, mice were treated with exogenous surfactant ( mg of phospholipids/ml) given as bolus of ml/kg in the right bronchus (surf group). we measured oxygenation, lung compliance (measured every min throughout the experiment), macrophage inflammatory protein (mip) in broncho-alveolar lavage (bal) fluid. . pao at the end of the experiment was significantly higher in the surf than in control group ( ± vs. ± mmhg, p \ . ). although surfactant bolus caused a reduction in lung compliance measured and min after treatment, in the surf group compliance restored to ± % of the post injury level, while it decreased in control group to ± % (p \ . ). there were no differences between groups in the dosage of mip- in bal neither in right or left lung. conclusions. exogenous surfactant treatment improved lung function in a murine model of two hit lung injury. grant acknowledgment. introduction. ventilator induced lung injury significantly contributes to the mortality in patients with acute respiratory distress syndrome, the most severe form of acute lung injury. understanding the molecular basis for response to cyclic stretch and its derangement during high volume ventilation is of high priority. objectives. to identify specific molecular regulators involved in the development of ventilator induced lung injury. we undertook a comparative examination of cis-regulatory sequences involved in the coordinated expression of cyclic stretch responsive genes using microarray analysis. analysis of stretched vs. non-stretched cells identified significant enrichment for genes containing binding sites for the transcription factor atf (activating transcription factor ). to determine the role of atf in vivo, we compared the response of atf gene deficient mice to wild type litter mates in an in vivo model of ventilator induced lung injury. results. atf deficiency results in increased sensitivity to mechanical ventilation alone or in conjunction with inhaled lipopolysaccharide ( mg/kg) as determined by assessment of lung and bronchoalveolar lavage cell infiltration and pro-inflammatory mediator release, pulmonary edema and indices of tissue injury. the expression of genes containing an atf cis-regulatory region was significantly altered in gene deficient animals. atf protein expression and nuclear translocation is increased after mechanical ventilation. conclusions. atf deficiency confers increased sensitivity to mechanical ventilation alone or in combination with inhaled endotoxin. in our model, atf acts to ''counterbalance'' cyclic stretch and high volume-induced inflammation, limiting its potential to cause additional lung injury and consequently protecting animals from injurious cyclic stretch. objectives. our aim was to evaluate the role of the alveolar macrophages in a murine model of ali, by selective depletion of this type of cells from the air space achieved by clodronate administration. mice were treated (it) with ll of clodronate (clo)-or pbs (pbs)-liposomes. after h mice were anesthetized and ventilated (vt - ml/kg, rr min - , fio . ); in order to induce lung injury ml/kg of hcl ( . m) or air bolus (sham group) was instilled in the right bronchus. mice were ventilated for min, and extubated after awakening. h after injury, animals were sacrificed and broncho-alveolar lavage (bal) and blood gas analysis (fio = . ) were performed. . h after lung injury animals with alveolar macrophages depletion, showed a better oxygenation versus pbs-treated group. however, recruitment of neutrophils in bal was not statistically different between clo_hcl and pbs_hcl group. results. high levels of oc were found in patients treated by mg of ot bid. oc levels ranged from , to , ng/ml in these patients. concentrations of oc were five-to tenfold higher than concentrations reported in healthy volunteers. lesser levels were found in patients treated by mg of ot bid. nevertheless, the patient with the moderate renal failure seemed to accumulate oc (levels ranged from to ng/ml) whereas concentrations reported in the patient with a normal renal clearance were below ( - ng/ml). conclusions. ecmo seemed not to have any influence on oc concentrations while renal insufficiency seemed to be the parameter leading to oc accumulation. as ic was very low and reached even with usual dosage, increasing ot dose to mg bid appeared to be unnecessary. objectives. aim of our study was to evaluate the effect of nursing care on patients undergoing venous-venous ecmo for acute respiratory distress syndrome (ards). methods. we recorded physiological and ecmo parameters (heart rate, arterial blood pressure, mixed venous saturation (svo ), arterial oxygen saturation (spo ), body temperature and extracorporeal blood flow (bf)) before and during daily nursing in patients undergoing vv-ecmo for several days (each patient was followed on average for . days, cases in total). arterial blood gases were also collected before and after nursing care. daily nursing was performed following defined steps (sponge bath, oral hygiene, change position of endotracheal tube, elevation with scooping stretcher for sheets replacement and back hygiene, dressing replacement) in agreement with a standard protocol in use in our department. (expressed as mean ± standard deviation). all patients were affected by ards h n -related. patients were sedated with propofol ( ± mg/h) or midazolam ( . ± . mg/h) plus an opioid drug (fentanyl ± mcg/h or remifentanil . ± . mcg/kg/min or sufentanil . ± . mcg/kg/min). ramsey score before nursing was . ± . . in cases patients were paralysed. in table we summarized the adverse events observed during nursing care, divided into hypertensive or tachycardic episodes, blood oxygen desaturation, reduction in svo or reduction in bf. forty-nine sedative bolus were administered during nursing (mean request for each patient: . ± . ), always after an episode of hypertension or tachycardia (most frequently during elevation with scooping stretcher and changing position of endotracheal tube). although in cases preventive bolus of sedation were administered before nursing, in of those cases ( %), additional bolus were required. we found an inverse correlation between bf and the increase in heart rate, drop in arterial saturation and svo . despite active warming, we observed a drop of . ± . °c (p \ . ) in body temperature. nursing care may have a significant impact on physiologic parameters of patients during vv-ecmo. tachycardia, hypertension and reduction in oxygenation were commonly recorded and were not prevented by pre-nursing bolus of sedation but were attenuated in patients with higher bf. introduction. prone position has been used in cases of ards with refractory hypoxemia but some physiological effects are still unknown. prone position could increase intraabdominal pressure (iap) and could lead to acute renal failure (arf). acute kidney injury in icu is associated with increased mortality. objectives. the aim of this study was to determine whether prone position could increase intraabdominal pressure and possibly promote arf. we studied all adult ards patients who were ventilated using the protective strategy defined by ards network criteria and who needed prone position to improve oxygenation. we collected respiratory data (ventilator parameters and gas exchange) and hemodynamic variables (heart rate, systolic, diastolic and mean arterial pressure). iap was measured using the abdo-pressure tm bladder transducer following world society of acute compartment syndrome recommendations. abdominal perfusion pressure was calculated as mean arterial pressure minus iap. main renal parameters were: filtration gradient (fg), creatinine clearance, fractional excretion of sodium (fena) and urea (feurea). patients were classified according to rifle score after each manoeuvre. all data were recorded in prone and in supine position at least once per day. results. the study included patients ( male) admitted to a medical-surgical icu over a one-year period. their mean age was . ± . and length of icu stay was ± days. all patients had primary ards and had received nephrotoxics. icu mortality reached %. we recorded at least manoeuvres per patient (a, b, c). prone positioning improved pafio ratio from . ± to ± (p = . ). iap showed a small increase from . ± . to . ± . mmhg (a; p = . ), from . ± . to . ± . mmhg (b; p = . ) and from . ± . to . ± . mmhg (c; p = . ). there were no statistically significant changes in hemodynamic parameters or abdominal perfusion pressure. renal function parameters (fg, creatinine clearance, fena and feurea) showed no modification after each prone positioning. in contrast, when patients were classified according to rifle score, we observed a trend towards worsening, though this was not statistically significant. conclusions. prone positioning improved arterial oxygenation in primary ards patients and was associated with an increase in iap. however, creatinine clearance and glomerular filtration remained unchanged. percutaneous extracorporeal life support system (p-ecls) including ecmo becomes widely used in medical and surgical emergent situation, such as refractory cardiogenic shock, cardiac arrest and acute respiratory failure. patients requires highly specialized intensive care and monitoring system. we reviewed our ecls experience and tried to analyze the clinical outcomes, factors for survival and frequently faced problems during management for improving weaning and survival rate (medical vs. surgical patients). introduction. in spite of the huge efforts spent over the last years, conventional treatment of acute hypoxemic respiratory failure (ahrf) is often inadequate and alternative procedures must be instituted. icus skillful in extracorporeal membrane oxygenation (ecmo), as recently shown [ ] , may improve survival of these patients. since we developed a treatment algorithm for ahrf which encomprises: ( ) low flow venous-venous ecmo (lf-ecmo) consisting in a relatively low initial blood flow (bf, - . l/min) to maximize extracorporeal co removal while providing partial oxygenation (if needed, bf can be increased up to . - l/min to keep arterial po above mmhg); ( ) femoral-femoral percutaneous cannulation with - fr cannulas to allow free movements of the neck and increase patient's tolerance; ( ) early institution of spontaneous assisted ventilation (sb) and weaning from sedation and mechanical ventilation (mv) while on ecmo. objectives. to review our last years lf-ecmo activity. methods. study period was january - . lf-ecmo entry criteria were: potentially reversible acute hypoxemic respiratory failure, lis c , no evidence of intracranial bleeding and no absolute contra-indications to heparinization. ecmo was performed with different type of heparin coated hollow-fiber artificial lungs. . we treated patients (mean ± sd, ± . years old, % males, bmi ± , sofa . ± , oi ± ). % of these patients were placed on ecmo at other hospitals and transported to our icu by a dedicated ecmo team. ventilation days before ecmo were ± (range - ). before ecmo vt/kg was ± . and rr was ± : after ecmo beginning vt/kg was unchanged while rr decreased to ± (p\ . ). ecmo was set at bf . ± l/min, gf . ± . l/min, fio . ± . introduction. ventilating patients with acute lung injury (ali) in supine position potentially leads to an impaired pulmonary gas exchange. prone position (pp) is an attractive means to improve ventilation-perfusion (v/q) ratio [ , ] but has several contraindications and showed no improvement in survival so far [ ] . another therapeutical option is an upright position, which is easy to perform and has theoretical advantages over pp: the upward shift of the abdominal compartment is less pronounced, thus increasing thoracoabdominal compliance [ ] . however, to date regimes of an upright position did not tilt patients more than ° [ ] . objectives. we hypothesised that a °standing position (sp) during mechanical ventilation may improve respiratory function. furthermore, we aimed to determine the feasibility of a sp for h during mechanical ventilation. we studied adult patients, receiving mechanical ventilation for more than h in the intensive care unit of an university hospital. after recording baseline data, patients were placed in a °sp with the body entirely straight. further data sets were recorded during h in sp, and after patients position was readjusted to supine position. functional residual capacity (frc) increased immediately after reaching sp (p \ . ) and remained elevated after repositioning to supine position. pao /fio ratio and compliance decreased initially during sp, but increased (p \ . ) after patients were retransferred to supine position. haemodynamic variables remained stable under a moderate increase of doses of catecholamines during the study period. conclusions. changes in respiratory function during sp are probably explained by a downward shift of the diaphragm due to gravitational forces leading to an increased frc but not altering v/q ratio as demonstrated by the pao /fio ratio. after reaching the initial supine position the opening of the lung proved by the elevated frc is the predominant effect now associated with an increase in oxygenation as reflected by the pao /fio ratio due to an optimised v/q ratio. our results are confirmed in a subgroup analysis for patients meeting ali criteria. ventilating patients in sp may be a new therapeutical approach to improve respiratory function in patients with ali. ( ) . there are several clinical trials investigating the efficacy of the free radical scavenger n-acetylcysteine (nac) in ards, but its advantage remains uncertain. objectives. critically appraise and summarize all randomized clinical trials involving intravenous nac administration in adult patients suffering from ards. we included trials involving participants with ards according to the american-european consensus conference criteria ( ) regardless of the underlying cause, and where one of the groups was treated with intravenous n-acetylcysteine in bolus intravenous doses or as continuous infusion, or combination of the two, and the other group was given placebo or standard treatment. conclusions. the main finding of this meta-analysis is that intravenous nac is ineffective in reducing mortality, length of stay or duration of mechanical ventilation in ards. we also found that late administration of nac may be associated with adverse outcome. the mechanism of this potentially deleterious effect remains unclear, but dosing and timing of nac appear to be critical issues. objective. to evaluate if extubation during ecls is harmful or beneficial. a -year-old woman was admitted to our intensive care unit (icu) after removal of a left ventricular assist device. this device was implanted as bridge to recovery for postpartum cardiomyopathy and ventricular function seemed to have recovered sufficiently. however, shortly after icu admittance she developed massive left and right ventricular failure. therefore a centrally cannulated veno-arterial ecls (maquet permanent life support) was implanted as a bridge to transplant. four days later she was extubated while on full ecls support, in order to reduce the risk of ventilator associated pneumonia. while on ecls, the patient was mobilized, practiced with an ergometer and chatted with her family. three days later the patient underwent cardiac transplantation. the postoperative period was characterized by temporary pulmonary failure, due to the combination of lung edema and atelectasis. eventually she made a full recovery. discussion. ecls provides a valuable means as bridge to transplantation, bridge to bridge or bridge to recovery. with the increasing use of ecls for circulatory failure, debate about the necessity of mechanical ventilation during this treatment ensues. ecls is usually applied under deep sedation and controlled mechanical ventilation. discontinuation of sedation possibly prevents intensive care acquired weakness. extubation during ecls may provide better pulmonary perfusion due to negative intra-thoracic pressure. furthermore, the awake and extubated patient is able to mobilize and exercise which may reduce the risk of atelectasis and ventilator associated pneumonia. our patient however developed pulmonary edema and atelectasis after discontinuation of ecls. the edema was probably a consequence of reperfusion injury, due to severely decreased pulmonary flow while on ecls. an absent ventilatory drive while on ecls may have led to hypoventilation while the patient was extubated, resulting in atelectasis. an extensive medline search resulted in one other case report describing an extubated patient on ecls. intermittent non-invasive positive pressure ventilation was used to prevent atelectasis, but the patient developed pneumonia after days of ecls. our patient was successfully extubated while on ecls. however, we conclude that there is insufficient evidence to recommend or oppose extubation of patients on ecls for circulatory failure. severe ards and refractory hypoxemia were defined with a pao / fraction of inspired oxygen (fio ) ratio of b , or uncompensated hypercapnea with a ph of \ . despite receiving optimal conventional treatment. the ecmo can be used as a rescue treatment in these case. objectives. evaluation of severe ards treated with extracorporeal oxygenation (ecmo). all these ards were due to bacterial pneumonia or h n influenza. over the last year (december -january ), the recourse to extracorporeal oxygenation (ecmo) was used in ten patients with severe ards and severe hypoxemia. two groups were defined: bacterial pneumonia with ards (bp group, n = ), and h n influenza with ards (h n group, n = ). all ecmos were implanted at the bedside to facilitate intra-hospital or inter-hospital transfer, because of severe hypoxemia or hemodynamic instability making impossible patient mobilization before ecmo. results. data sets of patients of consecutive patients treated with ecmo were complete and included into analyses. we had no clinical or radiological evidence for thrombosis or clotting within ecmo-circuit with a target-ptt of s. one patient with systemic aspergillosis died because of intracranial hemorrhage. one ecmo circuit had to be replaced due to insufficient oxygenator function after days. further data are presented in tables and . conclusions. in this retrospective analysis of patients who underwent ecmotreatment, ac with low-dose heparin (target-ptt of s) was safe and without any observation of macroscopic thrombosis or clotting within the circuit. transfusion requirements and intracranial hemorrhage were low as compared with previous reports [ , ] . therefore our data suggest that it is possible and safe using ecmo-therapy with low-dose heparin. introduction. in response to h n pandemy, italy and lombardy created a national and a regional icu network, respectively, for treatment of ards patients. our hospital policlinico san matteo of pavia participated with a team for inter-hospital ecmo implantation and subsequent patient transport. objectives. description of the pavia ecmo team and activity analysis. methods. our team is composed by a cardiac surgeon, two intensivists, a perfusionist, an icu nurse, two emergency rescue technicians and a driver. all necessary aids for implantation and intensive care are ranged in three trolleys and three transport bags. equipments are firmly mounted on a two-level steel bridge connected to a spinal board. a portable ultrasonograph is also available. the ecmo team was alerted by the national call center. each mission used two ambulances, and in one case the ambulances were embarked on a hercules c j. from october to december , four patients were implanted and transported, three suffering from h n influenza (including a -kg body weight patient) and one from acute mitral valve rupture. all patients, already mechanically ventilated with maximal support, had veno-venous ecmo implanted by femoro-femoral percutaneous cannulation. the median mission duration was of . h (range - h). all patients were transported to our icu, where the median ecmo duration was of days (range - days). no major managing issue occurred during the ecmo missions, and patient hospital survival was of %. a multispecialist team with good knowledge of ecmo can provide an effective support in severe respiratory failure, with ecmo implantation in peripheral hospitals and subsequent patient transport, thus realizing a fast and safe continuum between phone call activation and admittance to the reference center. introduction. when patients with sever respiratory failure are treated with v-v ecmo the right heart sometimes fails. this is a serious complication with a high mortality. in our unit these patients have been converted to v-a ecmo, although it is not fully agreed upon in the ecmo community due to previously depressing results. objectives. to evaluate the results of conversion to v-a from v-v ecmo in case of right heart failure. retrospective analyses of all patients with severe respiratory failure, treated between and at the karolinska ecmo centre. patients who were converted to v-a ecmo due to right ventricular failure were evaluated. a total of patients ( adults, peadiatric, neonatal) were treated on v-v ecmo for severe respiratory failure. of them ( adults, peadiatric, neonatal) needed conversion to v-a ecmo due to right ventricular heart failure demonstrated clinically by multiorgan failure and verified by echo cardiography. the survival after conversion to v-a ecmo was / ( %) in the adult age group, / ( %) in the peadiatric age group and / ( %) among the neonates. conclusions. given the high risk of fatality if not treated, conversion to v-a from v-v ecmo should be considered when the right ventricle fails. patients on v-v ecmo with right ventricle heart failure have very bad prognosis. it is concluded from the present results that conversion to v-a ecmo can save some of these patients. cardiac surgery and regional hemodynamics: objectives. to test whether tapse and right ventricular systolic (sm) and diastolic (em and am) tissue doppler imaging velocities are related with pulmonary artery systolic pressure (pasp) and length of the weaning process in mechanically ventilated patients with acute heart failure (ahf). methods. rv fractional area change (rvfac), left ventricular ejection fraction (lvef), pasp, tapse, sm, em, am rv tdi velocities, early diastolic mitral e wave and e maximal tdi velocities of the mitral annulus at the lateral wall were obtained at admission by doppler echocardiography in a cohort of patients with ahf, presented with pulmonary oedema, who required positive-pressure ventilation for more than h in the intensive care unit (icu). echo-derived measures were compared between patients with and without pulmonary hypertension, whereas their association with duration of mechanical ventilation and length of the weaning process was tested with multivariate linear and logistic regression analysis. and increased e/e ratio ( . ± . vs. . ± . , p \ . ) compared with subjects with normal pasp (n = ). these variables were negatively associated with duration of mechanical ventilation (r = . , beta slope = - . for tapse, r = . , beta = - . for sm, r = . , beta = - . for em/am, p \ . ) and were proven to successfully discriminate patients with (n = ) and without (n = ) prolonged weaning ([ days of weaning after the first spontaneous breathing trial failure, p \ . for all comparisons). conclusions. we suggest that in critically ill patients with ahf presented with pulmonary oedema, low tapse and rv tdi velocities upon admission are associated with pulmonary hypertension and prolonged length of the weaning process. objectives. the aim of the study was to study changes in cerebral blood flow (cbf), as determined by tcd, during the early postoperative course of cvs and to correlate such changes with post-operative nc. we studied patients undergoing extracorporeal circulation cvs (coronary by-pass, valve replacement or both) between march and march . cbf was assessed by measuring bilateral mca flow velocities by tcd before and , and h after cvs. changes c % between consecutive tcd results were considered significant. demographic and clinical variables, co morbidities, euroscore, sofa, type and duration of surgery and type and severity of nc were also recorded. patients were assigned to groups according to cbf changes from baseline: a) changes b %; b) cbf increases c %, c) cbf decreases c %. nc were classified as major (stroke, tia and coma) and minor (delirium, encephalopathy, transient cognitive impairment). we used descriptive statistics and inference by v , anova and pearson's correlation. of the patients, were excluded ( early post-operative death and due to technical difficulties or incomplete tcd recordings). of evaluable patients, ( %) had no cbf changes (group a), ( %) had increases c % (group b) and ( %) had decreases c % after cvs (group c). a positive correlation was found between cbf changes and duration of circulatory arrest (p \ . ), maximum sofa score (p \ . ), respiratory dysfunction (p \ . ) and duration of mechanical ventilation (p \ . ). neurological complications occurred in patients ( %), of which ( %) were major and were minor ( % introduction. the sole monitoring of macrohemodynamic variables is not always sufficient in the early detection of tissue hypoperfusion, especially in cardiac surgical patients that frequently present with microcirculatory derangements. near infrared spectroscopy (nirs) is an easily applicable non invasive technique that has been used to provide an estimate of tissue oxygenation at the bed side. objective. the aim of our study was to evaluate the effect on outcome of guiding hemodynamic therapy and specifically inotrope titration in cardiac surgical patients postoperatively with nirs. methods. patients operated on with cardiopulmonary bypass were assigned, after stratified randomization (gender, euroscore-cutoff of ), to an intervention (ig) and a control group (cg). postoperatively, following cardiac intensive care (cicu) admission, after initial resuscitation according to cicu protocol, sto (%) was measured in patients of the ig in muscle sites: thenar, masseter and deltoid. if it was less than % in / sites, dobutamine was administered in incremental doses ( . lg/kg/min), with the sto (%) measured every half hour. the interventional period began upon cicu admission and lasted for h, after which both groups were treated according to cicu protocol. primary outcome measured was the oxygen consumption rate at the end of the h intervention period as assessed with nirs vascular occlusion technique. . patients were included in the study ( in the intervention group and in the control group). the groups did not differ statistically significantly regarding age, euroscore, and macrohemodynamic variables postoperatively (with the exception of cvp). microcirculatory parameters upon admission to the cicu also did not differ, excluding masseter sto (%). the oxygen consumption rate and the reperfusion rate increased in the h study period in both groups, without differing statistically significantly between the groups at any time point (cg oxygen consumption rate . ± . upon cicu admission and . ± . h later, ig . ± . and . ± . respectively) (cg reperfusion rate ± upon cicu admission and ± h later and ig ± and ± respectively). as far as outcome parameters were concerned, the groups did not differ statistically significantly in the total hours and total dose of vasopressors ± inotropes received, in the hours of mechanical ventilation, in the duration of cicu or hospital stay, and in sofa scores the days following the operation. conclusion. nirs guided titration of inotropes did not lead to a greater improvement in the microcirculation h postoperatively, or to a better outcome. the limited power of the study prevents definite conclusions on the role of nirs in hemodynamic therapy in cardiac surgery patients. objectives. to estimate the prevalence of pulmonary embolism among mv patients in icu and its association to deep vein thrombosis (dvt). in a monocentric prospective observational study, we included all the patients requiring mechanical ventilation with no previously diagnosed pe, who underwent a thoracoabdominal ct contrast scanner for any medical reason. we used a modified protocol for pe diagnosis with a -multidetector row ct scan read by two independent radiologists. the association with a dvt was explored by performing venous compression ultrasound of four limbs. objectives. the aim of this animal study was to evaluate the effect of intraabdominal hypertension on left ventricular diastolic function. after approval by an institutional animal care committee, rabbits were anesthetised before mechanical ventilation. an intraperitoneal infusion of . % glycine solution was used to increase intraabdominal pressure to mmhg. the right common carotid artery was catheterised in the neck in order to introduce a millar mikro-tip catheter (millar instruments inc., houston, usa) into the left ventricle. heart rate, arterial pressure, central venous pressure, oesophageal pressure and intraabdominal pressure were measured. the s time constant of relaxation which is considered as best index of relaxation was calculated using the derivative method ( ). all haemodynamic measurements were registered at baseline and after inducing intraabdominal hypertension. data are presented as mean (iqr) and were compared using a wilcoxon rank sum test. results. heart rate (from ± to ± beat/min, p = . ), mean arterial pressure (from ± to ± mmhg, p = . ) and dp/dt max (from , ± to , ± mmhg/s, p = . ) were not significantly modified by intraabdominal hypertension. however, the s time constant of relaxation increased significantly (from ± to ± ms; p = . ). conclusions. in this animal model, intraabdominal hypertension impairs left ventricular relaxation. these changes in the condition of the microcirculation have been related to the degree of organ dysfunction and thus patient outcome ie hospital length of stay. near infrared spectroscopy (nirs) is an easily applicable non invasive technique that has been used to provide an estimate of tissue oxygenation at the bed side. objectives. the aim of our observational study was to examine whether impaired tissue oxygenation as assessed with nirs immediately postoperatively correlates with hospital length of stay. patients undergoing a planned cardiac surgical procedure on cpb were included in the study. patients' thenar tissue oxygenation (sto %) was assessed with nirs postoperatively in the cardiac intensive care unit (cicu). results. patients undergoing cardiac surgery on cpb ( male/ female) (age: ± years, euroscore: . ± ; mean ± sd) were enrolled in the study. patients length of stay was . ( - ); median(range). the haemodynamic parameters of our patients upon admission to the cicu were: map ± mmhg, cvp ± mmhg, pcwp ± mmhg, mpap ± mmhg, ci . ± . l/min/m , svr ± dyne x s/ cm , pvr ± dyne x s/cm , hr ± bpm, hb . ± . g/dl, lactate . ± . mg/dl; (all variables expressed as mean ± sd). upon admission to the cicu all patients were mechanical ventilated, under vasopressor ± inotrope support and their central temperature was . ± . ; mean ± sd. the thenar sto % was ± ; mean ± sd. thenar sto % correlated statistically significantly with hospital length of stay (r = . , p = . ). discussion. tissue oxygenation as assessed with nirs reflects the balance between regional oxygen delivery in relation to oxygen utilization. an elevated sto in the presence of normal macrohemodynamics may reflect impaired oxygen consumption and thus an impaired microcirculation. conclusion. patients with impaired tissue oxygenation immediately postoperatively have a longer hospital length of stay. further studies are needed to confirm these results and to investigate the potential benefit from incorporating this information regarding tissue oxygenation in the treatment algorithm. objectives. the goal of this study was to compare two different sedative agents for implantation of crt-ds related to incidence of adverse events and patient's satisfaction. methods. the study included forty-two, asa iii-iv patients, undergoing transvenous implantation of crt-ds under local infiltrative anesthesia with to ml of % lidocaine. intraoperative sedation was established with intermittent boluses of midazolam ( - mg) to achieve desirable level of sedation. before the induction of ventricular fibrillation in order to test the defibrillator function of the crt-d device, patients received an additional bolus of either propofol ( . - . mg kg - , p group, n = ) or etomidate ( . - . mg . kg - , e group, n = ) targeting bis values in the range - . the incidence of apnea, hypotension, nausea, myoclonus, pain at injection site, allergic reactions as well as patient's satisfaction with anesthesia described as feel of well being were registered and compared between groups. results. in subjects ( %) no complications were recorded. myoclonus was registered in patients from e group ( %) and in none from p group (p \ . ). no patients receiving etomidate reported pain at injection site compared to patients ( %) receiving propofol (p \ . ). there was no significant difference in incidence of apnea between two groups ( vs. %, p = . ). two patients in p group ( %) and in e group ( . %) became hypotensive after delivering the hypnotic agent (p = . ). also, there was no statistically significant difference between groups considering the frequency of nausea ( % vs. %, p = . ). all the patients whom propofol had been delivered ( %) reported feel of well being and only four of them filed the same after etomidate ( %) (p \ . ). no allergic reactions and major adverse events were registered. conclusions. implantation of crt-ds and its testing can be successfully performed with administration of both propofol and etomidate as a safe procedure with low per operative morbidity and shorter complication rates. still, treating with propofol tends to be more satisfactory for the patients. introduction. ultra-short-acting b selective adrenergic antagonists are now widely used to control tachycardia and tachyarrhythmia perioperatively. among them, landiolol, a new ultra-short-acting b -blocker, has been reported to exert a more potent negative chronotropic effect with little effect on blood pressure than esmolol ( ). however, detailed mechanisms underlying different cardiovascular actions are still unknown. objectives. in this study we evaluated direct effects of landiolol on cardiac performance and single cell electrophysiology in comparison to those of esmolol. methods. the present study composed of two parts. the first part of the study used isolated guinea-pig hearts which were perfused in the langendorff mode at constant flow with oxygenated tyrode solution at °c. the coronary perfusion pressure (cpp) was continuously monitored throughout the experiment, and intrinsic heart rate (hr) and isovolumetric left ventricular contraction were measured with a thin saline-filled balloon inserted into the left ventricle. the second part of the study was to measure action potentials and ionic currents in ventricular myocytes isolated enzymatically from guinea-pig hearts. comparison of data was conducted by repeated-measure anova with post hoc test (bonferroni's correction). conclusions. esmolol had a more potent negative inotropic effect than landiolol. this effect is, at least in part, derived from shortening of apd. in addition, increase of the coronary resistance would facilitate the negative chronotropic action of esmolol in vivo. conclusions. nma moderates hpv in the conscious spontaneously breathing beagle, but not to the same degree as acz. as compared to acz, the additional methyl-group in nma may impair its capability in vivo to act on a non-ca acz-sensitive cellular receptor or channel or that both, ca-dependent and ca-independent actions of acz yield a greater effect. introduction. tee with bubble test is considered as the ''gold standard'' method to detect a pfo with right to left shunt. tcd is a non-invasive method which has been shown to be as accurate as tee for pfo detection. we conducted a multicenter trial to estimate the prevalence of pfo, the influence of the size of the heart chambers on the prevalence of pfo and the accuracy of tcd as a non invasive method for pfo detection in mechanically ventilated icu patients. one hundred icu patients ( m and f) under mechanical ventilation who needed a tee study for hemodynamic assessment were included in the study. in each patient, the presence of a pfo was detected by tee and tcd. three bubble tests with agitated haemacel Ò were performed by each method, with tee probe at and rotation and with tcd the gate of pulse wave doppler (pwd) at the m segment of the middle cerebral artery (mca). patients without temporal acoustic window to perform tcd were excluded from the study. the size of pfo was classified as grade i, ii and iii according to the number of microbubbles passing from the right to the left atrium and the number of hits (high intensity transient signals) detected with pwd in the mca (grade i: \ microbubbles or hits, grage ii: [ and \ and grade iii: more than microbubbles or hits). for each patient included in the study we measured and correlated the presence of pfo with the tidal volume (v t ), the plateau pressure (p plat ), the compliance of the respiratory system (c rs ) and the size of the right (rv) and left (lv) ventricle. results. mean p a o /fio was (min , max ), mean c rs was ml/cmh o (min , max ), mean v t was ml (min , max ) and mean p plat was cmh o (min , max ). the prevalence of pfo detected with tee was % and with tcd %. there was no pfo detected with tee and missed by tcd. tcd was more sensitive than tee in detecting pfo of grade i ( with tee, with tcd) and ii ( with tee, with tcd), while for grade iii the two techniques had equal sensitivity ( with tee, with tcd). no correlation was found between p plat , c rs , v t and the presence of pfo. on the contrary, a strong correlation was found between rv dilatation and the presence of pfo (p \ . ). conclusions. the prevalence of pfo detected by tcd is very high in mechanically ventilated icu patients and this may have important clinical implications. tcd is more sensitive than tee in detecting a small pfo. the presence of rv dilatation increases the prevalence of pfo. objectives. the aim of our study was to identify in mechanically ventilated patients for ali/ards the prevalence of pfo and to evaluate the factors that may influence the prevalence of pfo. methods. two groups of mv patients, one with ali/ards and one without respiratory failure (rf), were enrolled in the study. all patients underwent a tee study for hemodynamic assessment. in each patient three consecutive bubble tests with agitated haemacel Ò were performed at and rotation of the tee probe. the bubble test was performed through a central line in the inferior or superior vena cava (ivc, svc). a pfo was diagnosed by the presence of microbubbles in the left atrium within five cardiac cycles following the injection. furthermore, in ali/ards patients in whom a pfo was not detected at baseline mv, three consecutive bubble tests during recruitment maneuver at cmh o for s were performed. the compliance of the respiratory system (c rs ), blood gas exchange and the ventilatory settings (p plat , v t ) were recorded in both groups. o, respectively. the presence of rv dilatation was a strong predictor for the fo opening (p \ . ); on the contrary, no statistical significant difference was found between the site of injection (svc vs. ivc), the c rs , v t , and p plat and the presence or absence of a pfo. a high prevalence of pfo was found in ali/ards patients. rv dilatation seems to be the reason of this high prevalence. rv dilation may be due to the lower c rs and higher p plat of the ards patients. introduction. the clinical evaluation of arterial tone is mainly based on the calculation of total systemic vascular resistance (tsvr). however, given the pulsatile nature of arterial flow, this parameter provides an inadequate assessment of vascular tone. another approach proposed would take account of changes in pulse pressure and blood flow, relationship known as arterial elastance (ea). so, for a given stroke volume, the blood pressure generated in the circulatory system will depend on ea ( ). to assess the ability of the dynamic arterial elastance (ea dyn ), defined as the relationship between pulse pressure variation (ppv) and stroke volume variation (vvs), to predict the hemodynamic response in mean arterial pressure (map) to a increase in stroke volume (sv) in hypotensive preload-dependent patients with acute circulatory failure. we performed a prospective clinical study in a -bed multidisciplinary intensive care unit, including patients with controlled mechanical ventilation and monitored with the vigileo Ò monitor, for whom the decision to give fluids was taken due to the presence of circulatory, including arterial hypotension (map b mmhg or systolic arterial pressure \ mmhg), and preserved preload-responsiveness condition, defined as svv c %. dynamic arterial elastance (vpp/vvs ratio), arterial pulse pressure to sv ratio, map/sv ratio, tsvr and map were compared to predict a map increase c % after volume expansion (map-responders). results. at baseline, only ea dyn was significantly different between map-responders and nonresponders. ve-induced increase in map was strongly correlated with baseline ea dyn (r = . , p \ . ) and changes in ea dyn after ve (r = . ; p \ . ). the only predictor of map increase was ea dyn (auc . ± . ; % c.i.: . - ). a baseline ea dyn value [ . predicted an increase c % in map after fluid administration with a sensitivity of . % ( % c.i.: . - . %) and a specificity of % ( % c.i.: - %). conclusions. dynamic assessment of arterial elastance by pvv to svv ratio during controlled mechanical ventilation could be used to predict mean arterial pressure increase after volume loading in hypotensive preload-dependent patients. severe sepsis is one of the major reasons for intensive care unit (icu) admission and leading causes of mortality. some of these score systems have been customized for patients such as apache ii, apache iii, sasp ii and mods. this study is to assess the validity of mortality prediction systems in severe septic patients. objectives. the aim of this study was to compare and evaluate four severity scoring systems in intensive care unit (icu), including apache ii, apache iii, sasp ii and mods in severe septic patient. methods. fifty-six severe septic patients were divided into two groups. one was survival group and the other was non-survival group. besides general data, the continuous surveillance of apache ii, apache iii, sasp ii and mods were recorded by st, rd and th day. results. compared with survival group, mods was significant difference in non-survival group only in st day ( . ± . vs. . ± . , p \ . ) but apache ii, apache iii and sasp ii were significant difference through st, rd and th day(p \ . ). in seven-day comparison, p value of apache iii in non-survival group was the minimum (p = . ) and p value of mods was the maximum (p = . ). in optimal survival evaluation, it seemed that apache iii was the best (apache iii [ apache ii = saspii [ mods). conclusions. in order to evaluate the critical condition and prognosis of severe septic patients, apache iii was the best and apache ii and sasp ii were followed and mods was the worst. objectives. to assess compliance with the cem standards for management of severe sepsis across three ed sites in the west midlands. methods. data was collected retrospectively over months. patients presenting to the ed within this period were assessed for likelihood of severe sepsis by the diagnostic code given to each patient upon leaving the ed. data was analysed using a scanned copy of the ed clerking. patients' notes were assessed for sirs criteria and signs of new infection. if these criteria were met, and organ dysfunction was present, they were included in the audit. results. patients with severe sepsis were identified. of these % were documented as septic by ed staff. the cem standards of care were received in % of patients with a documented diagnosis of severe sepsis in the ed, and % of patients overall. % of patients received the 'treatment' aspects of care: oxygen, iv antibiotics (with blood culture) and iv fluids. % of severely septic patients had no documented consideration of icu referral. conclusions. early recognition of severe sepsis in the ed led to greater performance in meeting the cem standards. although % of patients received observations and % received the treatment interventions, we performed poorly in meeting the remaining cem standards. the trust has developed a severe sepsis proforma which incorporates the cem standards to accurately record the completion of each intervention. a sepsis course for staff has been launched trust wide, and a formal referral process to icu for all severely septic patients is being implemented. objectives. to observe association of body temperature (bt) and antipyretic use with mortality in the critically-ill. a prospective multi-national, multi-center observational study. consecutive patients whose icu stay were expected to be more than h were recruited from centers in japan and centers in korea. patient's bt was prospectively recorded every h until patient's death, discharge from the icu or up to days. information including patient's clinical characteristics at admission, presence of infection, and use of steroids, extracorporeal circuit, and antipyretics were recorded. ( ). while blood culture results take time, treatment for bloodstream infection should be provided swiftly, usually before results are available ( ) . prior treatment with antimicrobials increases the chances of false negative results. haste, poor technique and alteration in commensal flora may increase the chances of falsely identifying pathogens. objectives. we have investigated the utility of blood culture tests in our general critical care unit over year in terms of results yielded and actions prompted. methods. the indication for blood culture was clinician's discretion. all critical care sourced blood cultures for the period oct to sept were reviewed from the microbiology laboratory database. blood culture specimens were collected in bact/alert Ò bottles (biomerieux, durham, nc, usa ). notes review was made of the positive blood culture episodes to determine actions after the results were known. consideration was given to the source of the blood sample: clean stab versus from an intravascular device. categoric data was analysed using the chi-squared test and p value of . was accepted as significant. objectives. we hypothesized that in the emergency department of our hospital many patients with sepsis are not recognized as such. methods. in a retrospective design, patients of an age of years and older who were admitted to the emergency department during a period of months between january-april and diagnosed as having an infection were included. the diagnose infection was made on admission by the emergency department nurse. the included patients were either classified as having sepsis or not having sepsis, according to the sirs criteria. conclusions. h n infection was associated with significant morbidity and mortality. it occurred mainly in young pts with co-morbidities and was associated with severe hypoxemia, a trigger for prolonged mechanical ventilation and frequent use of lung rescue therapies. a significant delay in hospital admission and start of antiviral therapy should also be noted. admission to administration time difference between cycles was . h, with a mean reduction of . h between clinician assessment and prescription time in cycle two. we identified delays against the standard after both cycles of the audit. we demonstrated that the method of prescription should be taken into consideration when prescribing antibiotics in patients with suspected sepsis. there are a multitude of factors that could contribute to a reduction in the clinician assessment to prescription time, which may be investigated in further audits. conclusions. despite high levels of resistance among psa and ab from these icus, cfr for most carbapenem dosing regimens were above the reported susceptibility. doripenem provided greater cfr than meropenem, which was superior to imipenem against these isolates. while higher doses combined with prolonged infusions significantly improved cfr against psa, alternative therapeutic strategies will be required to address these highly resistant ab. grant acknowledgment. the passport study is supported by a grant from janssen-ortho-mcneil. introduction. drug interactions are common, and the effects of these interactions can range from innocuous to deadly. critically ill patients often receive a variety of potent drugs, including antimicrobials, making this population extremely susceptible to drug-drug interactions. therefore, physicians must be familiar not only with the antimicrobial drugs capable of producing adverse drug events, but also their potential drug-drug interactions. there are scarce data about the incidence of these types of drug interactions and the how frequently it might cause adverse events. objectives. the purpose of this study is to evaluate the incidence of potential drug interactions involving antimicrobials and the possibility to cause adverse events. the clinical pharmacist has prospectively analyzed icu prescriptions between january and december with the purpose to identify potential drug-drug interactions involving antimicrobials. the screening was done with the relief from a software (epocrates rx Ò drug reference). the interactions detected were classified in eight groups according to the affected system (neurological, cardiovascular, gastrointestinal, renal, endocrine, hematological, musculoskeletal and others) and through the type of interaction (pharmacokinetic, pharmacodynamic and others). we have identified the most common potential effects, the medications involved and have observed the incidence of adverse drug events. results. the icu admitted patients during the study period. we have analyzed physician orders with prescribed items. we have identified antimicrobial drug interactions ( different interactions) which compound % of the total drug interactions (n = ). the cardiovascular system and the pharmacokinetic interaction were the most potentially affected ( %; %). the most common medications involved were: fluconazole ( %), clarithromycin ( %), levofloxacin ( %); linezolid ( %). the clinical pharmacist has made an intervention regarding medication safety in % (n = ) and the acceptance rate by the medical icu staff was %. we have not been able to identify any adverse drug event caused by drug interaction even with our active search and the spontaneous reports. however, sub notification must be taken into consideration. conclusions. clinicians should be aware of potential drug-drug interactions when making therapy selections for critically ill patients. antimicrobial drugs are susceptible to interact with other drugs, which may increase the risk of adverse drug events. the clinical pharmacist interventions may improve clinical outcomes by optimizing medication use, monitoring potentially preventable adverse drug events and promoting information about this important issue to the icu multi-professional team. introduction. cefazolin is one of the most frequently administered antimicrobial agent for prophylaxis in ''clean'' surgery. its broad spectrum against gram + micro-organisms and its pharmacological characteristics make it an easy-to-use choice to prevent infections caused by staphylococcus aureus and coagulase-negative stapylococci. objectives. the aim of this study is the evaluation of the plasma concentrations of cefazolin administered as a prophylactic antimicrobial agent during cardiac surgery with cpb. adequate cefazolin plasma levels can maintain a tissue concentration high enough to prevent the risk of developing post-operative infections. after obtaining ethical committee approval and personal written consent, two groups of patients were enrolled in this prospective study. the first group, patients, received cefazolin, g, - min before skin incision and g adjunctive dose after h. then, three g doses were administered every h. in the second group of patients the adjunctive g cefazolin dose was given at the beginning of the cpb. blood samples were collected immediately before the first dose and every hour for the whole time of surgery, and, only in the second group, after surgery, at th, th and th hour. plasma cefazolin concentration was determined with a biological radial diffusion assay. results. plasma cefazolin was constantly higher than the mic of the most involved micro-organisms (according to clsi). in the first group, cefazolin concentration suddenly decreased after starting cpb. the g adjunctive dose immediately restored it. the earlier administration of this dose in the second group prevented this sudden fall. plasma cefazolin was maintained at effective inhibitory levels for the whole time of surgery in all patients ([ mcg/ml). during the postoperative period cefazolin decreased slowly, but inhibitory plasma levels were always maintained. the rate of cefazolin clearance was found equal to the creatinine clearance in all patients. perioperative plasma cefazolin concentration conclusions. the administration of cefazolin g every h can guarantee effective inhibitory plasma concentrations during surgery and during the first h after surgery. cpb causes a sudden fall in cefazolin plasma levels. this can be avoided administering an adjunctive g dose immediately before starting cpb. objectives. vancomycin dose regimen was adjusted based on trough plasma levels in burn patients that were distributed according to the extension total burn surface area (tbsa); also pharmacokinetics changes were compared. methods. twenty seven adult burn patients of both sexes, requiring antimicrobial therapy with vancomycin for the control of sepsis were investigated. pharmacotherapeutic follow up was performed in a serial of periods ( observations) for all patients investigated by collection of blood samples, ml each from the venous catheter as follows: st blood sample collection, h after the beginning of drug h infusion and a nd sample blood collection at the trough, immediately before the next dose. if necessary, additional sample blood collections were performed based on the laboratorial data for patients any time, for dose adjustment purpose and optimization of drug therapy. vancomycin plasma concentrations were determined by highperformance liquid chromatography. plasma curve decay was plotted, and pharmacokinetics was analyzed by one-compartment open model against the reference data reported. results. burn patients receiving the empiric dose regimen showed trough plasma level lower than the minimum effective concentration, consequently dose adjustment was required. vancomycin adjusted dose regimen showed statistical significance differences according to tbsa (p \ . ) as follows for daily dose normalized to body weight and expressed by mean ± sd: . ± . mg/kg/day were required for patients with tbsa below %, . ± . mg/kg/day for tbsa - % and . ± . mg/kg/day were required for tbsa above %. relevant changes on pharmacokinetics were observed by drug plasma clearance increased according the increase of tbsa (p \ . ), while the apparent volume of distribution and also the biological half-life remained unchanged. additionally, a weak correlation was observed between vancomycin plasma clearance and creatinine clearance (r = . ; p = . ), probably due to the contribution of the extra-renal clearance on total drug elimination. on the basis of data obtained in the present study and to prevent therapeutic failure and also to reduce the risk of bacterial resistance, dose adjustment in burn patients is recommendable based on vancomycin plasma monitoring and also on the extension of total burn surface area. introduction. the importance of early antibiotic therapy has been recently demonstrated. regarding a rapidly increasing number of obese patients, appropriate drug dosage in these patients is an important challenge of critical care since it has been shown that not only early start of antibiotics but also correct target concentrations decrease mortality. vancomycin is administered according to body weight (bw). nevertheless, little is known about the percentage of obese patients achieving pre-defined target serum levels within h after initiation of vancomycin therapy compared to patients with normal bw. objectives. therefore, it was the aim of our study to analyze the appropriateness of serum vancomycin levels in patients with a bw between and kg. vancomycin is almost entirely excreted by the glomerulus and may be responsible for nephrotoxicity [ ] . however, there is a lack of definitive evidence linking concentrations to either outcome or toxicity [ ] . few reports exist comparing intermittent dosing and continuous infusion. ingram [ ] suggested that whilst associated with a slower deterioration in renal function, there was no difference in the prevalence of nephrotoxicity. similarly, hutschala [ ] demonstrated worsening creatinine in patients following cardiac surgery with both intermittent and continuous infusion but infusion tended to be less nephrotoxic despite receiving higher doses. we wish also to report our experiences with vancomycin infusion in critically ill cardiac patients. methods. we examined retrospective data from , patients treated with vancomycin. we perform adjusted and un-adjusted analysis using sofa on the day of starting vancomycin and total dose received. to assess the differences in either an initial pulmonary or non pulmonary presentation. methods. prospective, observational, multi-center study conducted in intensive care (icu). we reviewed demographic and clinical data for all pandemic h n influenza a infections reported in the esicm h n registry. results. patients were screened from the registry. patients with completed data entry for pulmonary and non pulmonary with outcomes were identified and analysed. all patients had either suspected, probable or confirmed pandemic h n influenza a infection and were being cared for in an icu. % of the patients were male with a median age of (iqr - ) years. the admission mean saps score was ± and the apache ii score was ± . % of the patients subsequently received non invasive ventilation and % received invasive mechanical ventilation. the icu mortality rate was %. the hospital mortality was %. % of patients presented with a pulmonary presentation. % of these were admitted with ards and/or bacterial pneumonia and % with an acute bronchospastic exacerbation. % of patients were admitted to the icu with a non pulmonary presentation. the main reasons for admission in these patients were: cardiovascular instability ( %), altered level of consciousness ( %), renal failure ( %) and acute coronary syndromes ( %). patients with a pulmonary presentation were older, had a increased history of asthma or copd and were more likely to be ventilated. they had a higher mortality rate in the icu. non pulmonary presentations were more likely to suffer from chronic renal impairment. a total of episodes of pandemic influenza a (h n )v infections in critical care setting were analyzed: with bacterial pneumonia ( males and females) and with wheezing or viral pneumonia ( males and females). the mean age was (± ) years in patients with bacterial pneumonia and (± ) in patients viral pneumonia. the mean apache ii score was (± ) and (± ), with a corresponding probability of death of (± )% and (± )%. comorbidities were common, but without significant differences between the two groups (only exceptions pregnancy-more prevalent in patients without bacterial pneumonia-and dialysis dependence-more prevalent in patients with bacterial pneumonia). at icu admission shock and acute renal failure were more common in patients with bacterial pneumonia. in patients without pneumonia; severe hypoxia and ards did not presented significant differences between groups. aims. evaluation if an isocaloric beginning of artificial nutrition in critically ill medical patients is associated with increased nutritional related side effects compared to a hypocaloric start. methods. critically ill medical patients with an expected need for artificial nutrition of [ days were included into this prospective, randomized clinical study. artificial nutrition was started either isocalorically right from the beginning (group a; n = ) or hypocalorically ( % of the energy demands) followed by a stepwise increase over the next days (day : %); day : %) (group b; n = ). nutrition related side-effects were defined as the occurrence of hyperglycemia, hyperlactatemia, hypertriacylglycerolemia, upper digestive intolerance, cholestasis, or diarrhea as well as disturbances of serum electrolytes and were assessed on a daily basis. patients were randomized to receive either an artificial nutrition started isocalorically (group a) or hypocalorically followed by a stepwise increase (group b). of the patients, patients completed the study (group a: n = ; group b: n = ). the calculated, cumulative energy requirements of patients of group a and b were , ± , and , ± , kcal, respectively (p = ns). patients of group a received ± % and patients of group b ± % of the calculated energy requirements (p \ . ). the incidence of nutritional related side effects was not different comparing both groups, except for hypophosphatemia, which was more pronounced in group a. additionally, exogenous phosphate needs were higher in patients of group a. the number of interruptions of the artificial nutrition did not differ between groups. conclusions. an isocaloric start of artificial nutrition provided more energy during the first days of their icu stay than a hypocaloric beginning. there was no difference in the number of interruptions and in the incidence of nutritional related side effects, except hypophosphatemia suggesting the presence of refeeding syndrome. in studies carried on to demonstrate positive effects of glutamine (gln) that has innumerable biological features, the main point of discussion isn't whether gln has positive effects in sepsis but rather the effect difference between different administration routes. only enteral (en.) or parenteral (pn.) administration was analyzed in this respect and no studies on combined administration were performed. the primary endpoint in this study was to analyze the effects of administration of en. and pn. gln together or separately on intestinal mucosa + immune system in the experimental sepsis model. for this purpose villus atrophy, bacterial growth in blood and tissue, levels of blood gln, tnfa and il were examined. the secondary endpoint was to evaluate the different administration models in terms of cost. wistar, adult female rats were used. they were fed standard. sepsis was developed in groups (all rats) by injection of intraperitoneal(ip.) ml ( cfu/ml) e. coli. grup c (n = ):en./pn. isotonic saline ( ml/day; ml/d); grup e (en., n = ):en. gln ( . g kg - day - ) + pn. saline ( ml/d); grup p (pn., n = ):pn. gln ( . g kg - day - gln) + en. saline ( ml/d); group ep (en. ± pn., n = ):pn. gln ( . g kg - day - ) ala-gln = . g kg - day - gln) + en. gln ( . g kg - day - ); were administered. feeding of rats began h (h) after administration of ip e. coli. blood gln (with spectrophotometer), tnfa and il concentrations(with elisa) were examined at the start (baseline levels) and at - h after the experiment started. samples of tissue from mesenteric lymph node, liver, lung, blood and small intestine were collected. ala-gln = . g kg. . rates of reproduction of the strain administered were found lower for group ep than group c (p \ . ). rates of villus atrophy in ileum of group ep, p and e were lower than group c (p \ . ).plasma gln levels were found lower in groups ep and p at h, and higher at h than other groups (p \ . ). when plasma gln levels at h were compared with their baseline levels, significant increases were detected in groups ep and p and significant decreases were detected in groups c and e (p \ . ). serum tnfa and il levels were found lower for groups ep and p at and h when compared between groups (p \ . ). when serum tnfa and il levels at h were compared with their baseline levels, more distinctive increases were detected in groups c and e than other groups (p \ . ). significant positive correlation was determined between tnfa and il levels at h (p \ . ) and h (p \ . ). cost of simultaneous administration of en. and pn. gln was higher than en. administration but close to pn. administration at these doses. methods. medline and embase were searched. hand citation review of retrieved guidelines and systematic reviews was undertaken and academic and industry experts were contacted. only methodologically sound randomised controlled trials (rcts) were eligible for inclusion in the primary analysis. the primary analysis was conducted on clinically meaningful patient oriented outcomes, which included mortality, functional status and quality of life. secondary analyses considered vomiting/regurgitation, pneumonia, bacteremia, sepsis and multiple organ dysfunction syndrome. meta-analysis was conducted using the peto analytic method, which is known to minimize bias in the presence of sparse events. the impact of heterogeneity was assessed using the i metric. results. , unique abstracts were identified, resulting in the retrieval of papers for detailed eligibility review. four rcts were identified to be on topic however one rct reported excessive loss to follow-up such that an intention to treat analysis could not be conducted. analysis based on the three methodologically sound rcts demonstrated the provision of early en was associated with a significant reduction in mortality (or = . , % confidence interval . to . , i = ). no other outcomes could be pooled. sensitivity analysis including all four on-topic rcts (or = . , p = . , i = ), and a simulation analysis conducted using a different analytical method. (or exact = . , % ci . to . ), confirmed the presence of a mortality reduction. conclusions. although the detection of a statistically significant reduction in mortality is promising, overall trial size was small. the results of this meta-analysis should be confirmed by the conduct of a large multi-center trial. reference(s). results. the mean ibp was . ± . and mean igp was . ± . . correlation between the ibp and igp was significant however moderate (r = . ). analysis according to bland and altman showed a bias and precision of . and . mmhg respectively, however the limits of agreement (la) were large and ranged from - . to . mmhg. the median grv proto was ml ( - , ) and median grv classic was also ml ( - , ). correlation between the methods was excellent (r = . ). analysis according to bland and altman showed a bias and precision of - . and . ml respectively and the limits of agreement (la) ranged from - to mmhg. the median drainage time and return times were min ( . - ) and . min ( - ) for grv proto compared to min ( . - ) and min ( - ) for grv classic. a preliminary cost effectiveness analysis shows that the price of measuring grv with the classic method ranges from . € to . € per day, depending on the grv size. price of measuring grv with the gastro pv system is independent of grv size and is estimated at . € per day. the gastro pv system if priced at . € could become cost effective at grv of cc and more. conclusions. the interim results of an ongoing multicentre pilot study show that the gastro pv is a good alternative to the standard method for measuring grv. because the nurse can perform other tasks during drainage and return of the grv, and the fact that the system remains closed during measurement, this could be a major step forward in standardisation of grv measurement. furthermore it allows screening for intra-abdominal hypertension via igp estimation. acknowledgment. the gastro pv devices were provided by holtech medical, free of charge. introduction. the importance of early enteral feeding of the critically ill patient has been well documented. it is the more physiological approach, which is associated with lower rates of infectious complications. early enteral nutrition within h is recommended by the espen guidelines on enteral nutrition. a recent meta-analysis revealed that mortality and the incidence of pneumonia were significantly reduced in patients with enteral nutrition within h. parenteral nutrition may be associated with higher mortality. objectives. evaluation of a new technique for the placement of postpyloric feeding tubes by intensive care physicians. methods. prospective cohort study in critically ill patients subjected to transnasal endoscopy and intubation of the pylorus. attending intensive care physicians were trained in the handling of the new endoscope for transnasal gastroenteroscopy for days. a jejunal feeding tube was advanced via the instrument channel and the correct position assessed by contrast radiography. primary outcome measure was successful postpyloric placement of the tube. secondary outcome measures were time needed for the placement, complications like bleeding and formation of loops and the score of the placement difficulty graded from (easy) to (difficult). data are given as mean values and standard deviation. out of attempted jejunal tube placements, tubes ( %) were placed correctly in the jejunum. the duration of the procedure was ± min. the difficulty of the tube placement was judged as follows: grade : patients, grade : patients, grade : patients, grade : patients. in cases, the tube position was incorrect, and in another cases, the procedure had to be aborted. only in one patient, bleeding occurred that required no further treatment. conclusions. fast and reliable transnasal insertion of postpyloric feeding tubes can be accomplished by trained intensive care physicians at the bedside using the presented procedure. this new technique may facilitate early initiation of enteral feeding in intensive care patients. grant acknowledgment. the authors acknowledge the support of pentax, hamburg, germany, who provided the endoscope used in the study and of fresenius kabi, bad homburg, germany who provided the feeding tubes. a well-nourished condition before prolonged endotoxemia results in a better ability to adapt to endotoxin-induced metabolic deterioration of arginine-nitric oxide metabolism than does reduced caloric intake before endotoxemia ( ). the role of individual organs in the arginine-citrulline metabolism during malnutrition and sepsis is unknown and may be key to direct future interventions. to study the effects of reduced caloric intake and endotoxemia on the citrulline-arginine metabolism in the gut-liver-kidney axis. organ arginine-nitric oxide metabolism was measured by using a primedconstant stable-isotope infusion of [ n ]arginine and [ c- h ]citrulline during conditions; a -day reduced caloric intake feed regimen (starv; n = ), normal control feed regimen (co; n = ), endotoxemia alone (ce) and reduced caloric intake and endotoxemia (re) in. catheters for blood sampling were placed in the abdominal aorta, which, in combination with the catheters in the portal, hepatic and renal veins, served for metabolic measurements across the portal-drained viscera, liver and the kidneys, respectively. results. interestingly, re animals had similar citrulline appearance from the gut ( ± nmol/kg/min) compared to control and animals during ce, but higher in endotoxemia alone ( ± , p \ . ). this was related to a significantly higher no production from the gut in the re group ( , ± vs. ± , p \ . ). in the kidney arginine appearance from citrulline decreased significantly during re compared the control animals ( ± vs. ± nmol/kg/min, p \ . ). in contrast, the liver disposed more arginine in the re group compared to the other conditions, while no production was not higher. conclusions. despite reduced caloric intake prior to endotoxemia, the gut remains capable of increasing release of citrulline, although the capability of the kidney for the de novo production of arginine is severely compromised. metabolic control of the citrullinearginine metabolism in the gut-liver-kidney axis should focus on increasing de novo arginine production from citrulline. objectives. the aim of this study was to measure duodeno-caecal transit times of enteral feed in this patient group using a scintigraphic technique. a prospective observational study was performed in mechanically ventilated critically ill patients ( m, age ± yr, bmi ± kg/m , icu admission day ± , apache ii on study ± ; mean ± sd) and healthy subjects ( m, age ± year, bmi ± kg/m ). after a h fast a ml enteral feed (ensure kcal/min), labelled with mbq m tc-sulphur colloid, was infused into the distal duodenum over min. dynamic anterior scintigraphic images were recorded in min frames for min and the time of first appearance of activity in the caecum was recorded by two blinded operators (kj, ar). data were assessed using mann whitney u test and are presented as median (iqr). introduction. erythromycin, a macrolide antibiotic is widely used as a prokinetic agent in intensive care unit (icu) despite the lack of data supporting its prolonged effectiveness in enteral nutrition (en) intolerant critically ill patients. to evaluate impact on clinical outcome of erythromycin prescription as prokinetic agent in icu. all patients consecutively admitted from january through december mechanically ventilated for more than days and receiving en were included in an observational cohort study. en intolerance was defined clinically as a -hourly gastric residual volume (grv) c ml or vomiting. successful en was defined as a grv\ ml with a feeding rate c ml/h. erythromycin prescription was left to practician appreciation. objectives. this study aims at evaluating the relationship between diarrhoea and en in icu patients. methods. during month, the days with and without diarrhoea (c liquid stools/day) and the characteristics of nutritional support of all patients staying in our icu were recorded. patients staying \ h or presenting an intestinal stomy were excluded. we compared, between days with and without diarrhoea, total energy coverage and energy coverage by en as % of needs, en energy intake and en volume for each patient. needs were estimated as - kcal/kg body weight for women and men, respectively. the relationship between antibiotics, laxative treatment and diarrhoea was also analysed. results are presented as mean ± sd. comparisons were made by mann-whitney test. the risk of diarrhoea with en was calculated by odds ratio and confidence intervals (ci). the study included days of hospitalisation of patients ( ± years, bmi ± kg/m , sofa score at admission ± ). en was present in days of diarrhoea and days without diarrhoea. determining the small bowel function is of great concern in icu patients, because a malfunctioning small bowel may predispose to malnutrition and may increase the risk of sirs. a recently developed test, the citrulline generation test (cgt), measures the enterocytes' capability to convert glutamine into citrulline. the production of citrulline exclusively takes place in functioning enterocytes, therefore this conversion represents small bowel function. objectives. we aimed to define the cgt reference values in 'stable' icu-patients to assess small bowel function. secondly, we wanted to compare four different cgt methods; enteral and iv administration of dipeptiven and measurement of citrulline in both arterial and venous samples. we performed the cgt on stable icu-patients, defined as having respiratory failure but not dependent on vasopressors. they had a normal renal function and were able to tolerate enteral nutrition. a h fast was followed by administration of g of glutamine-alanine (dipeptiven Ò ) either intravenously or enterally, randomly determined. the next day the same test was performed by using the other route. after each administration of dipeptiven, citrulline levels, both arterial and venous, were measured at fixed time points using reverse-phase high performance liquid chromatography (hplc). results. nine females and males were admitted to the icu with either a medical ( ) or a surgical ( ) diagnosis. they had a mean (± sd) age and bmi of . ± years and . ± , kg/m respectively. their median apache ii score was . (iqr = . - . ). on the day the cgt was performed their median sofa score was . (iqr = . - . early post-pyloric feeding has been shown to improve clinical outcomes [ ] . commonly used methods for placing a nasojejunal tube (njt) are blind, endoscopic or fluoroscopic placement. the later two methods are relatively invasive, expensive and can cause delay to feeding, whereas blind placement is often unsuccessful. electromagnetic sensor guided njt insertion is a bedside technique able to confirm successful placement without the need for abdominal x-ray. the system incorporates a liquid crystal display and a receiver unit. the receiver is placed over the patient's xiphoid process and picks up the signal from an electromagnetic transmitter located at the tip of the feeding tube. the screen provides a visual aid to enable the operators to trace the route of the tube tip and identify its' location according to anatomical markers. objectives. we were interested to determine the suitability of electromagnetic sensor guided njt insertion especially in relation to success rate and procedure time. methods. fifty patients were referred for electromagnetic njt insertion on units at the leeds teaching hospitals. insertion time was measured from oesophageal visualisation until post-pyloric placement. various positional manoeuvres were employed along with administration of sedatives, prokinetics and air insufflation when applicable. all insertions were carried out by experienced investigators. all njt insertions were confirmed by abdominal x-ray. data collection included patient demographics, hospitalisation and procedural information. results. forty male and female patients, mean age (range - years), bmi mean ( - ), had attempted electromagnetic njt placement. patients had been hospitalised for a median of days ( - ). indication for njt insertion was either large aspirate and/or reflux ( %). seventy six percent of patients had an artificial airway and % of patients were receiving sedation. forty six percent of patients received metoclopramide and % air insufflation. thirty six percent of patients were moved into either left or right lateral position. successful post-pyloric placement was achieved in % of patients confirmed by additional abdominal x-ray. procedural time varied from to min (mean ). two of the placement failures were due to patient intolerance. conclusions. bedside electromagnetic guided njt placement technique is an acceptable method of placing post pyloric feeding tubes with a high success rate. gastrointestinal failure (gif) score has been suggested ( ). the gif score defines gi failure as the occurrence of feeding intolerance (fi) and intra-abdominal hypertension (iah) simultaneously. to compare the outcome of patients with primary vs. secondary gif. methods. all consecutive, mechanically ventilated (mv) patients treated for at least h during january to december in two icus were studied. gif was defined as gif score equal or above points according to the gif score ( ). points = fi and iah simultaneously; points = abdominal compartment syndrome (acs). fi was defined as the need to stop enteral feeding for any clinical reason (vomiting, high gastric residuals, bowel distension etc). iah was defined as mean intra-abdominal pressure (iap) c mmhg on any day. acs was defined as iap [ mmhg with the new onset organ failure. when gif developed in a patient with primary pathology in abdomino-pelvic region it was classified as primary gif, when occurred without previous pathology in abdomino-pelvic region it was taken as secondary. objectives. in this study the biochemical quality and prion safety of the pharmaceutically licensed plasma octaplaslg Ò was evaluated. the prion reduction factor achieved by western blot was confirmed by animal studies. eighteen consecutive batches of octaplaslg Ò (octapharma ppgmbh, vienna, austria) were tested on global coagulation parameters, fibrinogen levels, activities of coagulation factors and protease inhibitors, activation markers, as well as von willebrand factor multimers. in parallel studies, plasma pool was spiked with exogenous spike material, derived from brains of hamsters infected with hamster-adapted scrapie k, and a down-scale of the octaplaslg Ò manufacturing process was performed. the prp sc reduction factor for the resin was investigated in both western blot and hamster bioassay studies. a reduction factor of c . log prp sc was found for this process step by western blotting. the outcome of the hamster bioassay confirmed that the high level of removal prp sc seen during octaplaslg Ò manufacturing was equivalent to a removal of infectivity ( . log ). in octa-plaslg Ò , a parallel reduction of the s/d virus inactivation step led to significantly higher activities of plasmin inhibitor. our studies demonstrated that the same amounts of prp sc and prion infectivity bind rapidly and with a very high affinity to the chromatography resin. octaplaslg Ò has the same clinical safety and efficacy profile compared to that demonstrated by octaplas Ò over the last years, except for the increased safety margin in terms of prion disease transmission and the possible effect of a significantly increased plasmin inhibitor activity. uniplas Ò is a second generation solvent/detergent (s/d) treated, coagulation active plasma for infusion produced with an implemented prion removal step. it was developed as an alternative to the blood group specific s/d plasma products, octaplaslg Ò and octaplas Ò , in order to obtain an universally applicable (i.e. blood group independent) plasma that can be used without taking into account the blood group of the recipient. due to an initially controlled, optimal mixing of plasma of different blood groups prior to s/d treatment, in uniplas Ò , the blood group specific antibodies (anti-a and anti-b of both igm and igg type) are neutralised and/or removed by free a and/or b substances and red blood cells (rbcs) to a clinical acceptable level with very limited or no complement activation. objectives. in this study an extensive biochemical characterisation of the first uniplas Ò validation batches was performed. methods. three batches of uniplas Ò were produced by octapharmappgmbh (vienna) under production conditions in [ ] [ ] . uniplas Ò batches were tested on all important coagulation factors, protease inhibitors, activation markers, adamts and factor h levels, as well as von willebrand factor multimers. in addition, anti-a and anti-b titres of igm-and igg-type were investigated. finally, complement activation products, as well as key components of the complement system, were measured. results. in uniplas Ò batches, all coagulation factor activities were higher than . iu/ml and all protease inhibitor activities, including protein s and plasmin inhibitor, were higher than . iu/ml. uniplas Ò contained standardised levels of adamts and factor h, within the normal ranges for single-donor freshfrozen plasma. there was no activation of fvii obtained during manufacturing, thrombin-antithrombin (tat)-complex, prothrombin fragments (f + ) and d-dimer levels were within the normal ranges. anti-a and anti-b titres were within the uniplas Ò specification, i.e. anti-a igm and anti-b igm\ : as well as anti-a igg and anti-b igg \ : , respectively. uniplas Ò did not contain an increased amount of immune complexes and the manufacturing of uniplas Ò associated with more complement activation than the one seen for octaplaslg Ò . conclusions. the present study confirmed that uniplas Ò displays the same high quality and clinical efficacy as the s/d treated blood group specific plasma octaplaslg Ò , but with the additional advantage in being a blood group independent universally applicable plasma. most pts received more fluids than calculated by parkland formula ( ± . ml/kg %tbsa). interestingly, nonsurvivors received less ( . ± . vs. . ± . ml/kg %tbsa). gastric decompression, ascites drainage and the implementation of a stool protocol with rectal enemas ( interventions in pts) was able to remove . ± . l of body fluids and this was related to a significant decrease in iap and cvp and an improvement in oxygenation and urine output ( conclusions. pris is a difficult condition to diagnose and routine monitoring of the adverse effects of high-dose propofol remains sub-optimal. hypothermia has been reported to alter propofol pharmacokinetics and we propose that active cooling may increase the risk of developing pris. this may be particularly relevant in patients with tbi who are on high doses of propofol to control icp in addition to concomitantly administered catecholamines to maintain cerebral perfusion pressure. we recommend that further research is required in this area in view of the increasing use of induced hypothermia in icu. objectives. to compare differences in fluid resuscitation based on direct or indirect admissions to the london burns unit. methods. admissions to the burns unit with [ % burned surface area (%bsa) were identified over years. were excluded from analysis due to palliation or death within the first h. sets of notes were randomly selected for analysis of fluid balance in the first h period of fluid resuscitation after the burn injury. results. mean (sd) time from burn injury to arrival at the burns unit was lower for patients transferred direct to the burns hospital rather than via another hospital ( . ± . vs. . ± . min p = . ). mean (sd) error in burn size estimation was lower for patients initially treated by burns specialists versus non-burns specialists ( ± . vs. . ± . %, p = . ). all patients were resuscitated according to the parkland formula calculated at one of , or ml/kg/%bsa. the mean (sd) actual fluid volume differed from the target by . % (± . %); the lower the calculated fluid target, the greater the error between actual and planned resuscitation volumes; there was no difference in accuracy of fluid resuscitation at h between patients initially managed by burns specialists versus non-burns specialists ( . ± . vs. . ± . % respectively, p = . ). conclusions. burned patients transferred directly to specialist burns care receive a faster and more accurate assessment of their burn injury. despite this, we found no difference in fluid targeting errors at h, though this may reflect corrective fluid management on arrival at the specialist centre. echocardiography is an useful and minimally invasive tool that allows to know the heart filling pressures, also it has proven highly accurate in predicting the response to volume in critically ill patients. we try to determinate the response to fluid infusion by static variables as cvp or lap, comparing with the variation of ivc. methods. an observational prospective study with patients undergoing coronary cardiac surgery ( patients were excluded by a no presenting a good echo views), in the postoperative period under mechanical ventilation (vt ml/kg, fio %, peep ). we performed an echocardiography if the patient presented hypotension, just before the habitual fluid load protocol were started ( ml hes % in - min). we collected data before and after the infusion, and determine the responsiveness to volume if the cardiac output increased more than %. data in the report included invasive cvp and lap, and echo measures, ratio e/e', diameter and variations of inferior vena cava (ivc) and variations of stroke volume by echocardiography (Ølvot x vti lvot) and with vigileoÒ system. . the correlation between low values of cvp/lap and volume response was poor, the relationship between cvp below mmhg with increased cardiac output had a correlation (pearson correlation - . ) with a significance ( -tailed) . , and the relationship between lap \ mmhg and an increase in cardiac output had a correlation (pearson correlation . ) with a significance of ( -tailed) . . the measurement of the variation of the inferior vena cava, led us to calculated a cutoff point more sensitive to determine which patients were responders to volume. through the roc curves (sensitivity/specificity), with the area under the curve of . % (se = . %) and with a confidence interval of % (p significance of . ), resulted in a % variations of ivc with a sensibility of % and specificity of % (younden's index of . %). the same calculation, based on kraemer's quality indices (qi) gave us a % of variation in ivc, with a w = . specificity rather than sensitivity (qi . ), and with a w = . sensitivity rather than specificity (qi . ) objectives. to ascertain whether postoperative hypothermia is linked to high or low risk surgical patients. we conducted a prospective systematic analysis looking at the incidence of postoperative hypothermia in adults who underwent general anaesthesia. children age \ , pregnant women and patients undergoing regional anaesthesia were excluded from the survey. to identify the current level of doctors' knowledge on perioperative fluid management. methods. the survey was conducted at george eliot hospital, nuneaton, uk in may . questionnaires consisting of ten multiple-choice questions on basic sciences and clinical scenarios were devised by a consultant anaesthetist. these were personally distributed to doctors of all grades working in anaesthetics and the surgical specialties. doctors were asked to complete the questionnaire within min. of the questionnaires distributed, were completed. results. the mean questionnaire score varied between specialties from % in the anaesthetics department to % for doctors in surgical specialties. the mean score of registrars and fy doctors in surgical specialties was found to be and % respectively. the overall mean score was %. of all doctors surveyed, the daily maintenance water requirement was known by only %, % knew the daily maintenance sodium requirement and % knew that of potassium. the electrolyte contents of . % sodium chloride and hartmann's solution was answered correctly by % and % respectively. there is a significant deficiency in doctors' knowledge on perioperative fluid management. more emphasis on optimal perioperative fluid management is required in undergraduate and postgraduate training. increased awareness of the british consensus guidelines on intravenous fluid therapy for adult surgical patients would aid training. based on this survey, a regional online survey of junior doctors is planned to further identify gaps in perioperative fluid management training. optimal fluid management could also help to reduce prolonged hospital stay which can result from fluid-related complications. objectives. to evaluate dynamic echocardiographic parameters as predictors of volume responsiveness in surgical patients. methods. patients were included in the study after laparotomy surgery performed on the same day ( breathing spontaneously and mechanically ventilated in volume controlled mode with tidal volume of ml/kg). a fluid challenge was performed in spontaneously breathing patients by passive leg raising and infusing saline ( ml/kg). echocardiographic analysis of respiratory changes of inferior vena cava diameter (ddivc) and aortic blood flow (dabf) was performed in all patients. a threshold of % for ddivc was used for classifying patients as volume responders or non-responders. age, sex, gender, bmi, cvp, iap, map, left ventricular ejection fraction, left ventricular systolic and diastolic area, and stroke volume in all patients, as well as itbvi, ci, ppv and svv in patients were measured. a positive correlation with ddivc was established for itbvi (r = . , p = . ), iap (r = . , p = . ) and ef (r = . , p = . ). a positive correlation with dabf was not established for any variable measured. patients ( %) were classified as volume responders and ( %) as non-responders. responders had overall higher iap than non-responders ( . ± . mmhg vs. . ± . mmhg respectively, p = . ). respiratory changes of ivc diameter showed positive correlation with itbvi. so, conclusions about itbvi could be indirectly made from ddivc values in patients who are not being invasively monitored. ppv and svv did not show positive correlation with itbvi. surprisingly, we confirmed a positive correlation between ddivc and iap. we detected patients with high iap, while all the volume responders had overall higher iap. although further investigations are needed to establish how longer duration of high iap may influence ddivc, it seems that ddivc is a good parameter of volume responsiveness during first h after laparotomy surgery. unlike from other studies, we could not establish a positive correlation between dabf and any variable measured. these studies were performed in hypovolemic septic patients, so this could be the reason for such different results. more studies are needed in a larger set of patients undergoing laparotomy surgery to evaluate dabf. introduction. fluid optimization after major cardiac surgery was shown to improve patients postoperative outcome significantly. several hemodynamic parameters were proposed for the guidance of therapy but never compared in a head to head trial. objectives. in this prospective randomized trial patients scheduled for elective cardiac surgery underwent early goal directed fluid therapy guided either by stroke volume variation (svv) or by oxygen delivery index (do i). we hypothesized that while svv is easier to obtain it will not be inferior to do i in outcome parameters. methods. following ethics committee approval and signing of a written informed consent, patients were randomized in two groups to undergo either fluid optimization guided by do i or svv in the first postoperative hours in the icu following elective cardiac surgery (cabg). following a standardized egt protocol the parameters were collected by using hemodynamic monitoring based on a pulse contour analysis and a transpulmonary lithium dilution (lidco plus, lidco,uk). we compared amount and type of volume infused, need and amount of inotropic or vasopressor substances, time spent on ventilator, los in the icu and postoperative complications. statistics were evaluated by using a t test for unpaired samples. table . compared to the do i group fluid optimization using svv showed reduced ventilator times (p = . ) and less complications (p = . ) in the first days after surgery. no differences between the groups were detected concerning the type and amount of volume infused, need for inotropes or vasopressors or the los in hospital conclusions. while svv is less invasive, cheaper and easier to be obtained than do outcome was at least not inferior and even showed improvements in postoperative cardiac surgery patients. rd esicm annual congress -barcelona, spain - - october s introduction. over the years, there have been concerns over incompatibility of transfused blood with various intravenous fluids during blood transfusion, especially related to increased levels of haemolysis. it is often impractical, particularly in an emergency situation, to flush through a giving set with a so-called ''safe'' fluid prior to and after delivering blood. we wanted to investigate whether this is actually necessary and whether the usual fluids used in the perioperative period really do cause any demonstrable alteration in the composition of transfused blood. objectives. the purpose of this study was to expose packed red cells to a variety of different intravenous fluids commonly used during the perioperative period and to measure a number of parameters in the blood following their contact with each different fluid, including a blood film to examine for clumping of cells or haemolysis. a unit of a positive blood was passed through blood giving sets which were primed with various intravenous fluids. after adequate mixing of blood with fluids, samples were collected for full blood count, urea and electrolytes and blood films. one millilitre of mixed blood was taken in each bottle at a time. the intravenous fluids used in this study were normal saline, hartmann's solution, % dextrose, % dextrose, starch and gelatin. there was no significant rise in blood parameters suggestive of haemolysis. the potassium and ldh levels were not significantly different with various fluids. the haemoglobin and haematocrit levels were also comparable to one another. there was no demonstrable changes in blood parameters suggestive of haemolysis, nor were there any change in electrolyte values. this suggests that all of the fluids investigated during this study would be suitable to be used via the same giving set before and after the transfusion of pack red cells. objectives. to assess the compliance with the national guidelines in avoiding inadvertent peri-operative hypothermia in an acute district general hospital in england. we prospectively studied our local practice on maintaining normothermia in consecutive adult surgical patients { men, mean age . years, patients with asa grade ( . %), emergency surgical patients ( . %), patients with significant cardiac disease . %}. we used a questionnaire that was filled pre-operatively by anesthetic nurses, intra-operatively by anesthesiologists, and post-operatively by recovery nurses. patients were recruited from the following surgical subspecialties: general surgery ( %), gynecology ( %), trauma ( %), breast surgery ( %) and orthopedics ( %). day surgery patients were excluded. peri-operative hypothermia was defined as temperature \ °c as per the nice guidelines. results. less than half of our patients ( . %, n = ) had their temperature measured preoperatively, on whom incidence of hypothermia was . % (n = ). only one of these patients was warmed prior to induction. patients requiring emergency surgery and those with asa grade had increased incidence of preoperative hypothermia ( . % and . % respectively, p \ . ). based on nice guidelines, patients needed intraoperative forced air warming but only ( . %) patients received it. intraoperative temperature measurement was made on patients, of whom . % (n = ) were hypothermic. incidence of intraoperative hypothermia was high in surgical procedures lasting longer than min (p \ . ) but was not affected by the use of regional anesthetic techniques. patients had their temperature measured on arrival to recovery of whom ( . %) were hypothermic. patients ( . %) had their temperature measured every min (nice recommendation) and the mean time interval for temperature measurement in recovery was min. patients were still hypothermic on leaving recovery. conclusions. majority of our surgical patients did not receive adequate perioperative care on maintaining normothermia. consequently, the incidence of hypothermia was significant pre-, intra-and post-operatively. we are currently analyzing the data to investigate the effect of hypothermia on duration of recovery stay, length of hospitalization and mortality in our patients. we completed a double-blind randomized trial in patients undergoing cardiac surgery in which we compared fluid resuscitation with a hydroxyethyl starch (hes, % mw pentastarch) and saline. use of hes resulted in markedly less use of catecholamines the morning after surgery. an underlying design principle was that assessment of cardiac index (ci) is essential for a proper fluid protocol. in this analysis we examine that supposition. all subjects had pulmonary artery catheters. patients were consented preoperatively, but randomized post operatively to receive up to blinded ml boluses for predefined hemodynamic targets; ci \ . l/min/m , blood pressure (bp) set by admitting team, cvp \ mmhg, or urine output \ ml/h. hemodynamic measurements were made before and after each bolus. after the study boluses, only saline was used. results. patients received fluids, hes and saline. there were study boluses, hes and saline. of these, boluses ( %) could not be assessed for this hemodynamic analysis (but were still used for the primary outcome) because of protocol violation or missing data. of the rest, ( %) of boluses were given for a low ci; in bp and cvp were also low so that ci was the only trigger in %. a low bp was a trigger in ( %). low cvp was the trigger in ( %). only hes and saline patients required the maximum allowed blinded boluses. at the th bolus, low ci was the trigger for ( %) of hes but ( %) of saline patients. there were that could be evaluated for hemodynamic response based on four possible outcomes of cvp and ci. objectives. the aim of our study was to evaluate the predictive value of cvp with regard to gedi, and to correlate these parameters to cardiac index (ci). conclusions. volume depletion according to gedi was found in more than half the patients. the predictive values of cvp with regard to volume depletion were low gedi and its changes significantly correlated to ci and its changes, which was not observed for cvp. therefore, gedi appears to be more appropriate for volume management during mayor liver resections. introduction. regional anticoagulation with citrate is an effective and established anticoagulation strategy during crrt in critically ill patients, especially in surgical patients with a high risk of bleeding and in case of a heparin-induced thrombocytopenia ( ). however, citrate crrt could be associated with major metabolic derangements such as metabolic alkalosis, hypocalcemia, hypernatremia and citrate toxicity. objectives. the aim of our study was to investigate efficacy, safety and metabolic stability during citrate crrt in critically ill patients with acute kidney injury. methods. the retrospective study was performed in a mixed surgical and trauma icu in a university hospital. patient charts were reviewed for demographic data, the period and dosage of citrate crrt and metabolic parameters. reasons of admission, comorbidities and severity of illness were also evaluated. citrate crrt was performed using commercially available equipment and fluid solutions (multifiltrate Ò with integrated ci-ca Ò -system; fresenius medical care; germany). to maintain stable metabolic and haemodynamic conditions we used an internal standard protocol for citrate crrt. statistical analysis was performed using descriptive methods (mean, median and standard deviation) and a mann-whitney u test where appropriate. p \ . was regarded as statistically significant. conclusions. although minor metabolic imbalances were observed, none led to a termination of citrate crrt and all of them could be managed by adjustments of blood flow and dialysate rates according to a preset protocol. our findings suggest citrate crrt to be a safe and effective strategy for crrt even in patients with hepatic dysfunction. nevertheless, metabolic parameters need to be monitored regularly to avoid severe metabolic derangements. introduction. the liver is central to ammonia metabolism, being the main site of urea cycle enzyme pathways. in acute liver failure (alf) and decompensated chronic liver disease (cld) ammonia dysmetabolism results in hyperammonaemia, thought to be of central importance in the pathogenesis of hepatic encephalopathy and, in alf cerebral oedema [ ] . continuous renal replacement therapy (crrt), commonly used in critically ill patients may be an effective method of clearing ammonia. little is known of the efficacy such techniques have on ammonia clearance. objectives. to quantify the clearance of ammonia using an aquarius haemofilter (ahf) using different renal replacement doses and techniques. methods. patients with a circulating ammonia level[ lmol/l due to commence crrt were enrolled. the ahf was programmed to run in either pre-or post-dilution modes at a blood flow rate of ms/min using a . or . m filter depending on the crrt ultrafiltration (uf) dose, which included , or ml/kg/h (adjusted for ideal body weight). ml of blood and effluent fluid were collected, on ice into lithium/heparin and serum separation tubes, from pre and post filter access points and effluent tubing to calculate urea and ammonia clearance using the cordoba formula [ ] . delta whole body ammonia clearance was determined by measuring arterial ammonia at and min. ammonia measurements were performed using a pocketchem Ò blood ammonia bedside testing machine. results. patients ( alf and cld) were recruited (mean age years, sd ( ), with mean arterial ammonia lmol/l, sd ( ). min whole-body ammonia clearance was - lmol/l, p = . , paired t test). ammonia and urea clearance were correlated (r = . , p = . ); uf rate correlated negatively with filtrate ammonia (r = - . , p = . ) and positively with ammonia clearance (r = . , p = . ). filter ammonia clearance was not dependent on filter size for the standard blood flow rate. pre or post dilution modes did not affect ammonia clearance (p = . , student's t test). a constant filter size and blood flow rate achieved ammonia clearance of ml/min/m for ml/kg/h, ml/min/ m for ml/kg/h and ml/min/m for ml/kg/h (p = . , one way anova). conclusions. ml/kg/h based on ideal body weight appears to be the optimum dose of crrt for ammonia clearance when using a blood flow rate ml/min and a . m filter. filter and delta whole body ammonia clearance may be increased further using the combination of a higher dose ( ml/kg/h) with a larger filter size and higher blood flow rates. introduction. malnutrition is common in intensive care following the catabolic state induced by critical illness. patients who progress from enteral nutrition back to oral feeding are usually in an energy deficit. espen guidelines recommend increasing calorie delivery during the recovery period to cover this anabolic phase. oral nutritional supplements (ons) are widely used to facilitate calorie delivery within the hospital setting however the effectiveness of this strategy is dependent on patient compliance with the products. compliance among the elderly ward-based population has been considered ( ) however that of intensive care patients has not been reported. to evaluate compliance to ons in a mixed medical and surgical adult intensive care unit (icu) in a district general hospital. prospective observational study was conducted over a month period with data compiled from fluid chart analysis and discussions with nursing staff. all adult icu patients prescribed, or offered without prescription, an ons were included until the point they were discharged to the ward. the supplements studied, resource Ò energy, . fibre, fruit and dessert (nestlé nutrition), were selected based on their availability within the trust. patients were offered a choice of flavour. results. data was collected and analysed for patient days. a total of supplements were prescribed. of the prescribed supplements, . % were offered to patients and . % consumed. % were offered the same at nursing discretion based on clinical need and . % were consumed. resource Ò energy was the most frequently prescribed and offered product ( . and . % respectively). most common flavours selected by patients were strawberry and vanilla. resource . fibre was better tolerated ( . %) than resource energy, resource fruit and resource dessert ( . , . and . % respectively). across all products the best tolerated flavours were apricot, chocolate and coffee ( %). the highest calorie supplement, resource Ò . fibre, resulted in the best compliance in both tested flavours. compliance with ons demonstrated here is higher than previous studies ( ) partly attributable to one-on-one nursing of icu patients enabling active encouragement with feeding. nursing staff discretion had better uptake than routine prescription of ons. however, difficulties with ons still remain. interestingly in our study the highest calorie density supplement was tolerated the best and thus giving the most benefit to the patient. despite the difficulties associated with ons uptake we would recommend its regular use on icu with a drive towards the highest calorie supplements being offered. introduction. cirrhosis is a chronic disease and the patient's quality of life is affected in a negative way due to the problems like ascites, jaundice, nutrition deficiency, fatigue, activity intolerance, itching, pain, insomnia, anxiety, hopelessness, work loss and depression. objectives. the aim of this study is to examine the changes in patient's lives that diagnosed with cirrhosis of the liver disease owing to the symptoms they experienced. methods. this research is a qualitative study that has been carried out with inpatients diagnosed with liver cirrhosis in the gastroenterology clinic of a teaching and research hospital. average age of patients was (ranging - ). descriptive characteristics form and semi-structured interview form were used in the data collection. interviews with patients have been performed individually and face to face. the data were evaluated by using colaizzi's phenomenological data analysis method. as a result of the data analysis, three categories and six themes were identified. categories include: (i) problems of symptoms related to the physical limitations (ii) psychosocial issues. patients suffer mostly from fatigue and malaise ( patients), while those in the later stages suffer from, additionally, physical ailments caused by acid. inability to sleep due to anxiety and increase in tendency to sleep in advanced stages have been identified after being diagnosed. the majority of patients were identified to have undergone an anxiety besides having a fatal disease due to concern for the future, being forced to quit the job and being affected by the experiences of the patients in advanced stages. it also has been discovered that the patients had experienced social isolation because of fatigue and weakness in particular. as the result of this study it has been determined that patients with cirrhosis have mainly problems of fatigue, weakness, sleep disorders, anxiety and associated problems. rd esicm annual congress -barcelona, spain - - october s [ ] . while in patients with acute liver failure, elevation of arterial ammonia levels has been linked to cerebral complications and increased mortality, the role of arterial ammonia in hh patients is unknown. our study aims at evaluating arterial ammonia levels in patients with hh. furthermore, we wanted to elucidate the potential consequences of high ammonia levels in these patients. arterial ammonia levels were measured and documented in hh patients without liver cirrhosis who were admitted to the medical icu. icu mortality and overall day-survival were documented. cox regression was performed to describe the impact of ammonia levels on mortality. mann-whitney test was used for comparison of metric variables. results. overall median arterial peak ammonia level in our patients was lmol/l ( . - . lmol/l), whereas median arterial peak ammonia value was significantly higher in icu non-survivors compared to survivors ( ( - . ) vs. . ( . - . ); p \ . ). saps ii and sofa score were significantly higher in icu non-survivors (p \ . and p \ . , respectively). cox regression revealed that arterial peak ammonia levels were significantly associated with higher -day-mortality (p \ . ), even after adjustment for saps ii. median arterial peak ammonia levels in patients with verified brain edema were significantly higher than in patients without ( . lmol/l ( - . lmol/l) vs. . lmol/l ( . - . lmol/l); p \ . ) after exclusion of patients following cardiopulmonary resuscitation with consecutive hypoxic brain damage. our results suggest that increased levels of ammonia are associated with high mortality and can lead to brain edema in patients with hh. % of patients had a diagnosis of sepsis and % of patients were admitted under the neurosurgical team, the latter of which may have contributed to the relatively low anticoagulant use of %. systemic heparinisation was the sole anticoagulant used, but compliance with local protocols was poor with % of appts below the therapeutic range and % of infusions commenced at the wrong rate. % of filter changes were due to clotting and mean filter life was h. despite this, dose delivery was acceptable, with % of prescribed dose delivered. conclusions. as previously reported , our demographic data confirm the relatively poor outcome of patients needing crrt. we have identified areas where care for these patients could be optimised and endeavour to do this locally via improved protocol design and an ongoing educational programme. many of the components of crrt could be incorporated into care bundles, but certain aspects of treatment remain controversial which may be a barrier to their adoption. given the high numbers of neurosurgical patients in our unit, consideration should be given to the use of regional anticoagulation such as citrate. introduction and objectives. accurate prognostic indicators of patient survival in an intensive care unit (icu) help guide clinical decision making. factors known to portend poor prognosis in acutely ill cirrhotics in icu include the need for mechanical ventilation, development of shock, renal failure and sequential increase in the number of failing organs. while serum lactate is now an established marker of survival and/or the need for transplantation in fulminant liver failure, its impact on critically ill cirrhotics is less well known. methods. we retrospectively studied consecutive acutely ill cirrhotics admitted to the icu between and at the royal free hospital, a tertiary referral centre in liver diseases and transplantation. data were collected on demographic variables, aetiology of liver disease, liverspecific prognostic scores [child-turcotte-pugh (ctp), model for end-stage liver disease (meld), united kingdom model for end-stage liver disease (ukeld)], and acute illness scores [acute physiological score and chronic health evaluation (apache ii), sequential organ failure assessment score (sofa) ]. in addition, serum lactate levels at , and h were also recorded. multivariable logistic regression analysis was performed, and the discrimination ability of each of the above-mentioned scoring models in predicting icu and hospital survival of these patients was evaluated using the area under the receiver operating characteristic (roc) curve. conclusions. one third of lt recipients present a documented bacterial infection within year after surgery. we found a high prevalence of ciprofloxacin resistance and a low incidence of s.aureus witch was often resistant to methicillin. non fermentative gram negative bacilli represent % of the pathogens and should be taken in account for treatment of the most severe patients. extracorporeal liver support therapy is in its infancy but is valued as a detoxification treatment option for patients with cirrhosis who have rapid worsening of their liver function. we report the use of prometheus Ò , a new extracorporeal liver support system allowing the removal of protein bound and water soluble toxins by fractionated plasma separation and absorption (fpsa) in a patient with wilson's disease (wd) who developed rapid worsening of their liver function. a -year-old female patient, diagnosed with wd since the age of , was initially treated in an irregular pattern with penicillamine. therapy was discontinued. now, years later, she developed acute decompensated liver failure with hepatic encephalopathy with a meld . liver transplantation (lt) was the treatment option for this patient. but, in this case, the rapid and adverse evolution of the liver failure with renal failure and the unknown waiting time for a emergency liver donor in our country led us to use the extracorporeal liver support therapy. after h min of therapy we reduced the amount of bilirrubin for less than a half, we increase the urinary output and next day the patient went to liver transplant, stable, with a renal function improved. conclusions. acute liver failure due to wd is most of the time fatal without emergency lt. this case report highlights discontinuation of chelants treatment in a patient with wd. as the patient progressed to decompensated liver cirrhosis with encephalopathy, lt was the only treatment option but while we don't get a donnor, we can use, for a short period of time, an extracorporeal liver support therapy as a very useful bridge. results from two studies presented at the recent easl congress have shown that treatment with extracorporeal devices may not confer a survival advantage for severe liver failure patients, despite positive dialysis effects. however, results among a small sub-group of patients show promise like severely ill patients with hepatorenal syndrome type or a meld score over . ( ) . metoclopramide is used to stimulate the upper gi tract and seems to have no effect on colonic motility. objectives. the aim of this in vitro study was to compare the prokinetic potency of those substances. a tissue bath with guinea pig colonic segments fixed on a polyacrylic tray allows the evaluation of the transit time (tt), the time necessary for a wooden pellet to perambulate. a decrease of the tt reflects stimulation, and an increase inhibition of peristalsis. after stable peristalsis activity the effect of increasing concentrations of prucalopride, neostigmine or metoclopramide on tt were evaluated. dose response curves were constructed, two way anova (sigma stat) was used for statistics, p values b . were considered to be significant. effect of prucalopride and neostigmine on motility results. prucalopride stimulates normal peristalsis in vitro only in the highest tested concentration of lm (p \ . ). neostigmine's prokinetic effect was limited to a small concentrations range ( . lm, p \ . ), the concentration of . lm had a moderate, but not statistically significant prokinetic effect and the highest tested concentration ( lm) lead to a complete block of peristalsis (fig. ) . metoclopramide, as expected, was devoid of any effect on colonic motility. conclusions. this experimental setting is a reliable method to evaluate the effect of different substances on colonic motility in vitro. prucalopride's prokinetic activity is concentrations dependent and limited. neostigmine is well known to improve colonic motility, but it seems imperative that the drug's effective dose range be use-higher concentrations have inhibitory effect on peristalsis. objectives. robotic radical prostatectomy involves extreme changes in patient position and often associated with a longer operative time than other commonly performed laparoscopic procedures. this review discusses the anesthetic considerations in robotic radical prostatectomy while analyzing potential risk factors related to pulmonary complications. we retrospectively reviewed the medical records of all the patients who had undergone robotic radical prostatectomy at our institution. among the total patients of , aged to years, patients were capable of spontaneous respiration at the end of surgery (group i) whereas patients needed assist ventilation (group ii). the demographic characteristics, coexisting diseases, anesthesia and operation time, anesthetic agents, the amounts of blood loss, infused fluid and transfused blood products were compared between the groups. results. the mean age of the patients was . ± . years. the mean operation times were . ± . min (range, - min). age, body mass index (bmi) and asa status did not differ significantly between the two groups, whereas operation time, the amount of blood loss and the incidence of transfusion were significantly higher in the group ii. although patients with subcutaneous emphysema and atelectasis needed prolonged ventilator care for h, the incidence of atelectasis and subcutaneous emphysema was similar between the groups. conclusions. prolonged laparoscopic surgery in a steep trendelenburg position has a high possibility of postoperative respiratory insufficiency and the possible contributing factor is a long operation time. objectives. we examined the frequency of postoperative cough reflex and its effect on postoperative clinical outcome retrospectively. we examined the patients who admitted into the icu after the esophagectomy with lymphadenectomy during the period from september, , to february, . in addition to usual criteria for extubation we removed their tracheal tube if the cough reflex was identified when one milliliter of half saline was distilled into their trachea. if the cough reflex was absent until days after the operation the patient underwent tracheostomy and after that they weaned from the ventilator. results. there were patients (f/m / ), and their mean age was . ± . . cough reflex were confirmed by seventh postoperative day in patients ( %) but residual patients underwent tracheostomy because of absence of cough reflex ( introduction. the technique of laparoscopic cholecystectomy carried with carbon dioxide pneumoperitoneum may lead to adverse events in mechanical, hemodynamic and respiratory systems as a consequence of physiopathological changes such as increased intraabdominal pressure. _ it may cause hypoxemia, hypercapnia, hemodynamic instability and impairment of oxygenation. decreased functional residual capacity, ventilation/perfusion imbalance and sympathetic stimulation effects of co that is absorbed from peritoneum are basic problems. in perioperative period, application of mechanical ventilation and anesthesia should be reviewed because of these physiopathological mechanisms. in this study, we aimed to investigate the effects of cmh o peep application on etco , minute ventilation and arterial oxygenation during laparoscopic cholecystectomy operations. for this reason, the study included total patients and they were randomly divided into two groups. same anesthetic protocol was applied in both groups. for general anesthesia induction; mg/kg dose of fentanyl, mg/kg dose of propofol were administered. following this procedure endotracheal intubation was applied with . mg/kg dose of cisatracurium. patients received % o -% n o (mixture with equal amounts) with . - . mac end-tidal sevoflurane for anesthesia maintenance. before co insufflation, respiratory parameters were recorded on the respiratory apparatus adjusting etco - mmhg, respiration rate /min., inspiration/expiration rate : , vt: - ml/kg. patients were ventilated by volume controlled mechanical ventilation. heart beats, mean arterial blood pressure and peripheric o saturation (spo ), etco , minute ventilation(v) and peak airway pressure(p _ ip) values of all patients were recorded just before insufflation (t ). after recording, cmh o peep was applied to the first group (group ). peep wasn't applied to the nd group (group ). these parameters were repeated in periods such as (t ) and (t ) minutes after insufflation, preexsufflation (t ) and postexsufflation (t ) in both groups. before insufflation, respiration rate ( /min) and etco ( - mmhg) values were adjusted as planned in both groups and minute ventilation was also adjusted. at the same time, total insufflated amount of co for distending abdomen was recorded. arterial blood gas analyses were made just before induction (while patients were breathing normal room air, t ), min after induction (t ) and just before the end of the operation (t ). in our study, we found that minute ventilation to stabilize etco - mmhg was significantly increased in group in which peep was not applied (p \ . ). none enhancement was needed in minute ventilation in group and arterial oxygenation was significantly increased in group (p \ . ). aside from the cholesterol lowering effects of statins, as a class of drugs they have been shown to exert anti-inflammatory effects and have the potential to be therapeutic in neuroinflammatory disorders . we tested the hypothesis that atorvastatin improves memory retrieval post unilateral nephrectomy in a murine model. methods. c /bl mice were randomly allocated into groups (n = - /group): control plus placebo, control plus atorvastatin, nephrectomy plus placebo and nephrectomy plus atorvastatin. animals were given either a placebo ( . ml normal saline) or lg in . ml normal saline of atorvastatin by gavage once a day for days. on day all animals underwent fear conditioning training using a conditional stimulus of a db tone and an unconditional stimulus of a . ma electric shock. on day the surgical animals underwent unilateral nephrectomy, whilst the control animals received no surgery. at post-surgical day all animals were tested for hippocampal dependent memory retrieval using the fear conditioning paradigm, with freezing response to the db tone as a marker of memory retrieval. all animals were then terminated. results. surgery evoked a reduction in hippocampal dependent memory retrieval in the nephrectomy plus placebo group as measured by % freezing time (mean ± sd: ± ) when compared to the control plus placebo group ( ± ; p \ . ); a situation mimicking pocd. this change was obviated in the nephrectomy plus atorvastatin group ( ± ; p [ . vs. control plus placebo). conclusions. our data suggested that atorvastatin has the potential to improve postoperative cognitive performance in a murine model of pocd. the proven safety of the drug along with its already widespread use and cost effectiveness would permit rapid instigation of a human randomized controlled trial to explore efficacy in the clinical setting. a. puxty , r. docking glasgow royal infirmary, department of anasethetics, glasgow, uk hypotension in the post-operative period is common but guidelines recommend its prevention/treatment [ ] . epidurals are common practice following major surgery in many institutions and can prevent pulmonary complications [ ] but have also been associated with falls in blood pressure when compared to other analgesic techniques [ ] . fluids therapy is a common intervention for hypotension but fluid overload has been associated with worse outcomes in surgical patients [ ] . we decided to audit the incidence and management of hypotension in the surgical high dependency unit of a large tertiary referral hospital. to determine the incidence and management of hypotension in the surgical high dependency unit in pancreatic, upper gi and lower gi patients. we prospectively looked at patients who underwent major upper gi, lower gi or pancreatic surgery involving epidural analgesia. the first h of care from onset of anaesthesia was closely looked at with regards to fluid management, epidural management and actions taken on episodes of hypotension or severe hypotension (defined as systolic blood pressure of \ and \ respectively). each episode of hypotension was looked at to determine the actions taken at that point. of the patients looked at, were major pancreatic, lower gi and upper gi patients. ( %) had at least one episode of hypotension, with ( %) having at least one episode of severe hypotension. mean fluid in during the first h was ml, with a mean fluid balance of ml. there was no difference between the doses of epidural local anaesthetic in h between the hypotensive and non hypotensive groups (p = . ). management of hypotensive episodes was variable, but the most common intervention at episode one was fluid bolus ( %) and discontinuation of epidural was most common at episode two ( %). use of vasopressors for hypotension was very low with only two infusions being started altogether. conclusions. hypotension is very common in our high dependency unit. fluid balance in our patients was far more positive that we had expected. management of hypotension was variable. we plan to institute a protocol for hypotension and fluid administration to determine if improvements can be made. objectives. to identify predictive factors associated with the need for relaparotomy in patients with ssp. adult ssp patients undergoing laparotomy between and included within a single-center peritonitis registry (perit) were collected. patients subjected to relaparotomy were studied. we excluded patients with severe peritonitis secondary to appendicitis. apache ii and sofa score at icu admission after the initial laparotomy were recorded. variables with a p value. in a bivariate analysis were included in a multivariate logistic regression for further analysis of predictors for need for re-laparotomy. results. two-hundred forty-seven patients were obtained from perit registry. a total of patients with spp were included in the analysis. eighty seven patients ( %) required relaparotomy. median number of re-laparotomies was . most spp were associated to colon (n = , . %), small intestine (n = , . %) and biliary tract (n = , . %) perforations. cultures were positive in . % of first laparotomy: gram negative bacteria were isolated in . %, gram positive bacteria in . % and fungi in . %. hospital mortality was % (n = ). multivariate analysis is described in the table . conclusions. in obese patients scheduled for surgery, the previous use of cpap has not shown an improvement in blood gas parameters. the use of cpap in the hours before and immediately after surgery has not been associated with better postoperative oxygenation. combined icu-surgery dpt. action in these cases seem to contribute to better patient outcomes. objectives. we set out to quantify the intensive care workload and changes to that workload over the first years following the transfer of a specialist bariatric service to our hospital. a prospectively collected bariatric surgical database was cross-referenced to the itu database (ward-watcher) to identify admissions to the -bedded critical care unit of all patients who had undergone any bariatric procedure. for each patient identified; demographics, reason for admission, level of support, length of stay and outcome were recorded. data were grouped into -month periods for trend analysis. research in emergency situations and especially in resuscitation field raises important ethical and regulatory issues. the globalization of the resuscitation science through multicentric trials for example highlights the need for a more consistent approach to regulatory aspects to enable the science to grow while protecting human rights. objectives. the purpose of this analysis is to compare the different regulations approaches in emergency research in north america (canada, usa) and in europe (european directive, france). conclusions. this analysis emphasizes the lack of international standardization of regulatory measures and ethical decisions. however some countries like the us seem to advance in the democratic process by mandating additional regulatory measures (community consultation, public disclosure to the communities) prior to initiation of clinical investigation; nonetheless, there is little evidence of their effectiveness. many challenges are raised. firstly, the variability in regulations, and consequently in local board's assessments, is problematic, pleading for international regulations. secondly, the current heterogeneous ethical review process and demanding unsubstantiated regulatory measures poses a risk to all when it is not evidence based and it is applied inconsistently between countries, within a country and worse at the level of each individual hospital review board. it puts the investigator at risk for unnecessary criticism and the community at risk as it is unknown if we truly consult or inform our target communities about waiver of consent research through our current ethical and regulatory processes. globalization and evaluation of the ethical and regulatory processes are urgently needed; regulatory community has to work towards a standardized evidence-based process upon which to base regulatory decisions. introduction. in research outside the intensive care field it is known that a high score for the psychological factor ''perceived hopelessness'' experienced by healthy individuals increases risk of death several fold. objectives. the aim of this study was to examine if the score of the psychological factor ''perceived hopelessness'' may predict long term mortality (mean or high perceived hopelessness score) when assessed post icu care in former icu patients. methods. prospective, multicenter study in three mixed icu's in sweden. questionnaires, including the -item hopelessness scale, demographic data and previous illnesses, were sent months after discharge to all former adult icu patients who thereafter were followed for another years. a reference group of individuals from the uptake area of the hospitals served as controls. results. ( %) patients returned the questionnaires. the icu patients reported significantly higher mean scores in perceived hopelessness score compared with the general population, . (sd . ) compared with . (sd . ) (p \ . ), and % (n = ) of the icu patients perceived a mean or high hopelessness score compared with % of the general population (p \ . ). the icu patients who died during the follow-up period reported a significantly higher perceived hopelessness score (n = ) . (sd . ) (p \ . ) as compared with those who survived up to years after discharge (n = ) . (sd . ). in a logistic regression model the long term mortality for the icu group was found to be affected by: pre-existing disease [odds ratio (or): . ], age (or: . ) and perceived hopelessness score (or: . ). the new and interesting finding of this study is that icu patients score higher on ''perceived hopelessness'' than a control population and this increase is predictive for the post icu mortality. furthermore, the size of this effect is significant and only exceeded by pre-existing disease and age. we performed a retrospective observational study to evaluate what proportion of met calls was associated with lomt issues. to estimate the proportion of met reviews involving patients with a not-forresuscitation (nfr) order and the timing of met calls in relation to admission and death or discharge from hospital. to compare the patient characteristics and outcome for met calls associated or not associated with lomt issues. we obtained hospital research ethics committee approval. we performed a retrospective observational study involving five-year (august -april ) in a single tertiary australian hospital. we obtained information on demographics, on the met review and hospital outcome. lomt included nfr orders, not for met orders and palliative care plans. results. we analysed met reviews in patients. table and fig. summarize major findings for overall population and the two subgroups of patients with or without lomt. patients with lomt care plan were older, more likely to have medical diagnoses, were reviewed later during their hospital stay and closer to their hospital discharge or death. fewer lomt patients were admitted to icu. hospital length of stay was shorter, mortality in lomt care patients was double that of non-lomt patients. however, more % of patients with lomt were discharged alive from the hospital. conclusions. more than one third of met activations deal with lomt issues. although the mortality of these patients is high, a large proportion survives to hospital discharge. evaluation of the patient experience in intensive care (icu) frequently depends on reports from surrogates such as relatives. there is a concern regarding the validity of the surrogate opinion which might not represent the values of the incapacitated patient and treatment decisions therefore maybe biased [ ] . others have found that there is a strong preference within a population for utilizing relatives as surrogate decision-makers in the event of admission to icu and this attitude is not influenced by ethnicity, religion or education level [ ] . objectives. the objective was to measure the ability of the relative to answer on behalf of the patient. a further wish was to determine the validity of their surrogate responses. a retrospective study, which surveyed relatives of patients who had died within a critical care service during a -year period ( , ) . the item questionnaire allowed for the collection of quantitative and qualitative data with respect for each item to overcome the limitations of the quantitative format which may not be sensitive to all the issues which can surround the provision of end-of-life care [ ] . for items, relatives were asked specifically to grade their capacity to represent the patient. results. quantitative data from the items designed to test the relatives' perception of their ability to act as surrogates indicates that relatives considered they could respond to these items for % (average) of instances. when the relative did answer on the patient's behalf, the level of concordance between the surrogate (relative) and the patient's perceived opinion was % suggesting that when the relative is willing to act as surrogate the response is likely to have validity. (table ) . results from the qualitative data indicates that the low ( %) level of willingness to answer these questionnaire items reflected a reluctance to answer on behalf of a sedated or ventilated patient, rather than an inherent inability to represent the patient. conclusions. the response rate to the items vindicates concerns regarding the ability of relatives to represent the patient in icu settings and supports a need for further study. where the relative is willing to act as surrogate, concordance does exist. qualitative data clarified quantitative results and was instrumental in promoting a better understanding of the concerns of relatives who have a family member admitted to icu. . the majority of patients that died in icu were provided some kind of therapy restriction. an important conflict strains between clinical practise, bioethical principle and jurisdiction laws; the solution of this conflict is more and more urgent. therapy restriction has also important economical aspects since the number and cost of available treatments constantly increase. our survey studied therapy restriction procedures in hungary for the first time. in we performed a survey with questionnaire among intensive care physicians. questionnaires were sent out electronically to registered members of the hungarian society of anaesthesiology and intensive care. respecting anonymity we have statistically evaluated replies ( %) with t test and anova. we grouped intensive care physicians based on gender, years spent in work, religion and type of department they were working, and we compared data from these groups. intensive care physicians generally make their decisions alone, based on the patient's long-term life prospects and physical status ( . / points). they are slightly influenced by the opinion of the patient ( . ), the relatives ( . ) and other medical personnel ( . ). if the physician sees any chance of recovery but the patient or relative requests treatment restriction then . % of physicians that completed the forms would continue therapy against the will of the patient or relative. only . % would accept the patient's/relative's opinion and autonomy in such a case and would stop therapy. in fact . % of physicians would make their decisions without considering or even against the opinion of patient if they think therapy is useless. if there is no chance of recovery despite medical treatment % of physicians stop the treatment, . % would continue it without informing the patient or the relatives, . % informs the relatives but continues useless treatment irrespective of the will of the patient or relative. having analyzed the groups we found two significant differences. in case of useless treatment physicians working in university hospitals more often choose treatment restriction without informing relatives (p \ . ) then those working in non-university hospitals. physicians who declare themselves as atheist rather choose the continuation of treatment without informing relatives (p = . ). conclusions. the hungarian practise of end of life decisions among intensive care specialists is paternalistic, physicians make their decisions alone, do not consider the requests of the patient or relatives. our goal is to strengthen patient autonomy and to support their opinion by training icu physicians. on the other hand it is inevitable to define what useless medical treatment exactly is and to introduce this category in medical ethics and also in jurisdiction practise. objectives. to determine the frequency and processes of eol care at our centre. between october and december , / ( %) patients staying in the icu for more than day, underwent some form of eol care in the icu. icu staff notified investigators whenever an eol decision was made. we recorded demographic details, documentation of the eol care process in the case notes, and interviewed icu staff to determine the eol care processes involved. results. patients ( %) were male, ( %) were females. mean age was . ± years. icu stay was . ± . days, admission apache ii score was . ± . which increased to . ± . on the day of eol care decision. % patients had metastatic cancer. reasons for initiating eol care were refractory acute illness in %, advanced cancer in %, brain death in %, and lack of finances in %. eol discussions were initiated by the family in %, and by the icu medical team in % patients. families wanted to take the patient home to die. the icu consultant was involved in all discussions with the family, the primary consultants in % and primary team residents in %. nurses were involved in only patients. agreement on eolc was reached after discussion in %, discussions in %, and discussions in % of cases. documentation of the eol care process was not done in % cases. withholding of life support (wh) was practised in / patients ( %) and withdrawal of life support (wd) in %. intubation was withheld in . % patients, cardiopulmonary resuscitation in %, inotropes in % and dialysis in %. regarding wd, only / patients were extubated and the ventilator withdrawn in another / patients. inotropes were withdrawn in patients ( %). reduction of fio . without discontinuing mechanical ventilation was the commonest mode of wd, in patients ( %). all patients received morphine infusions during lols/wols. family members were present by the bedside in % cases. conclusions. wh is preferred over wd. documentation of the eol process does not occur in a significant proportion of cases. nurses are rarely involved in the eol care decision making process. legal issues may be barriers to good eolc in our icu, and perhaps in india. objectives. to know the point of view of the staff is essential to understand their beliefs, attitudes and decisions. brazilian private general icu with beds. the following items were analyzed: profile of the interviewed; their opinion about end of life questions: fear of death, fear of experience pain before death, the best place to die, advanced directives, decision-making process, therapeutic withhold of mechanical ventilation, nutrition, fluid management, antibiotics, vasoactives drugs, sedation and analgesia in patients which death is imminent and irreversible. results. about . % of our icu team answered the research (n = ). the mean age is . years (sd . ), . % of female, . % married, . % protestants and . % catholics and icu professional experience of . years (sd . ). using a visual analog scale ( , no fear to , the worst fear possible) the team pointed . as their fear of death; the fear of suffering pain before death was . . for . % of the responders, the best way to die would be with their lovely ones, no matter if at home or at hospital. only . % would prefer to die an icu. the majority of the team ( . %) would share the eol decision-making process with the family instead only by the medical staff ( . %). about . % would leave an advanced directive with their therapeutic preferences like do not resuscitation orders. the icu team agreed on the withdrawal of vasoactives drugs ( . %), antibiotics ( . %), nutrition ( . %) and mechanical ventilation ( . %) in patients out of treatment. our results showed the staff vision about their own death and their opinion about the end-of-life care issues. in developing country as brazil there is a still gap between everyday practice and the current legislation. fortunately, the debate about eol issues has increased in last years. the end-of-life discussions and decisions should begin by respect to points of view of all involved: patients, family, medical staffs with a legal support of the society's beliefs and expectations. prospective observational study conducted in greek multidisciplinary icus. we studied all consecutive icu patients who died, excluding those who stayed in the icu \ h or were diagnosed with brain death. patients comprised the study population [mean age ± (sd) years, mean apache ii score on admission ± ]. results. of patients studied, % received full support including unsuccessful cardiopulmonary resuscitation (cpr). % died after withholding of cpr, % after withholding of other treatment modalities besides cpr, and % after withdrawal of treatment. patients in whom therapy was limited had a longer hospital (p = . ) and icu (p \ . ) stay, a lower admission gcs score (p \ . ), a higher apache ii score h prior to death (p \ . ), and were more likely to be admitted with a neurological diagnosis (p \ . ). patients who received full support were more likely to be admitted with either a cardiovascular (p = . ) or trauma diagnosis (p = . ), and to be surgical rather than medical (p = . ). the most important factors affecting the physician's decision to provide full support were reversibility of illness and prognostic uncertainty; the physician's religious beliefs and legal concerns had minimal impact. the main factors guiding the decision to limit therapy were unresponsiveness to treatment already provided, prognosis of underlying chronic disease, and prognosis of acute disorder; old age was not a determinant, while economic cost and lack of icu beds seem to play no role. relatives' participation in decision-making occurred in % of cases and was more frequent when a decision to provide full support was made (p \ . ). the principal reason for not discussing end-of-life dilemmas with relatives was the fact that the family was thought not to understand ( %) advance directives were rare ( %). icus. however, in a large majority of cases, it involves the withholding of cpr only. withholding of other therapies besides cpr and withdrawal of support are infrequent. physician has a dominant role in decision-making. objectives. the primary objective of this study is to determine the prevalence of inappropriate or non-beneficial care in icu patients as perceived by their icu healthcare providers, as well as the reasons for this perception. second, we want to determine which factors are associated with the perception of inappropriate care. a descriptive survey design is used. a single-day cross-sectional evaluation of perceptions of inappropriate care among , icu healthcare providers in icu centres in european countries will take place on may th . questionnaires will be administered to icu healthcare providers (nurses, head nurses, junior and senior icu physicians) providing bedside care to adult icu patients on that particular day. in this study, inappropriate care is defined as a patient care situation that is similar to one or more of seven scenarios. these scenarios were created based on the literature and a multidisciplinary conference attended by experts in intensive care, geriatrics, and palliative care. . the cross-sectional study will take place on may th . preliminary results will be given at the esicm conference. we have designed a one-day cross-sectional study to record inappropriate or non-beneficial care in european icu's. results will be available for the esicm conference. grant since the introduction of the mental capacity act in the uk in , the impact within research in the intensive care environment has not been elucidated. since many of the patients are incapacitated and therefore unable to consent, it is now stipulated by the ethics committee that the researcher must make reasonable attempts to identify a consultee, failing this, nominate a person unrelated to the research project to be consulted. in order to comply with the mental capacity act, retrospective consent must be obtained, once the patient regains capacity. objectives. the aim of the study was to highlight the difficulties in obtaining retrospective consent, evaluate the methods used and demonstrate the adaptations made to increase retrospective consents. methods. this explorative analysis investigated the process of obtaining consent in patients enrolled in an observational study on critically ill patients. consent was obtained on admission if the patient had capacity. assent from the patient's next of kin or a legal professional representative was obtained before enrolment in patients who lacked capacity. after discharge from icu, a member of the research team re-visited these patients to explain their involvement in the research, its purpose, procedures, implications and any further participation required by the subject. at this point, the patient could consent or withdraw from the study. if the patient decided to withdraw from the study, all data collected and samples stored were destroyed. the researcher visited the patient for a minimum of two visits; firstly to explain the study; secondly to establish if the patient has retained the information and to gain retrospective consent. results. patients were recruited within the time period of which ( . %) died. in ( . %), consent was obtained on admission as the patients had capacity, ( . %) were discharged prior to obtaining retrospective consent, ( %) lacked capacity on the researcher's visits, and patient ( . %) withdrew from the study. patients ( . %) were successfully consented retrospectively. overall, the researchers performed visits to obtain from the patients for whom retrospective consent was required. conclusions. the process of recruiting patients who lack capacity within the intensive care unit is challenging and time consuming. stipulations set by the ethics committee to seek retrospective consent once the patient has regained capacity, has a major impact on research staff time and finances. detailed recommendations as well as guidelines how to assess capacity in the post-icu patient and how the assessment of capacity has to be applied to intensive care research are needed to fully comply with ethical and legal requirements. objectives. we wanted to know if patients expressed to surrogate decision makers, after icu discharge, specific resuscitation directives, and we have investigated any factors related to the patients and their illness or care process that might be associated with this. we reviewed patients admitted in the icu between december and may . a random sample of survivor patients has been defined. seven patients were excluded ( for language barrier, died, were no more reachable). fifty three patients took part in semistructured interview at - month post icu discharge. the questionnaire discussed in detail the aspects of advance directives. patients had also completed a quality of life questionnaire (euroqol d), and we calculated the eq- d visual analog scale. we reviewed medical records in icu data base: age, gender, length of stay, saps ii, bmi, length of ventilator support and central venous catheterization as well as prescription of transfusion, hemodialysis or adrenergic agonist. multivariate logistic regression was practiced to investigate any factor associated to expression of specific resuscitation directives after icu discharge. after icu discharge, % of interviewed survivors expressed specific resuscitation directives to an appropriate identified surrogate (written ''living will'' or oral statement). eq- d visual analog scale was ± . on multivariate regression analysis, only one studied variable was significantly associated to the post-icu expression of specific resuscitation directives: age (odds ratio = . , z = - . , p = . ). conclusions. after icu discharge, a majority of our patients expressed to surrogate decision makers specific resuscitation directives, especially the younger patients. our findings suggest that surviving to icu is an opportunity to specify oral or written directive, and both may help to illuminate future decision making from the patient's perspective. objectives. to explore the issues around eolc provision for cancer patients in a critical care unit through family, professional and patient experiences. to explore how a diagnosis of cancer impacts upon eolc provision for critically ill patients. a heideggerian phenomenological interview approach was undertaken, in order to gain personal experiences. families of those patients who died after decisions to forgo lifesustaining treatment (dflsts) were interviewed. patients who were seriously critically ill (apache ii [ or had received cpr) who experienced critical care were also interviewed, since patients' views about eolc provision are very rarely explored. doctors and nurses also contribute their vision for, and experiences of, eolc in a cancer critical care unit. thirty seven participants were interviewed. tensions between treating families versus treating patients impacted on timeliness of eolc. achieving a good death was possible through caring activities that made best use of technology to prevent prolonged dying. decision-making and eolc could be difficult to separate out which, in turn, affects prospects for eolc. three main themes included: dual prognostication; the meaning of decision-making; and care practices at eol: choreographing a good death. these themes outlined the essence of moving along a continuum toward patients' deaths and the impact that had on opportunities for care and a good death. conclusions. cancer affected the trajectory in unexpected ways. the trajectory could be very quick, especially in unexpected death and some newly diagnosed cancers. even in the face of a life-limiting and serious disease like cancer, death could be unexpected. the rapidity of trajectory related to cancer diagnosis, prognosis, withdrawal and patient demise significantly impacted on the potential for, and timing of, eolc. a sentiment of moving on from historical practices around critical care for cancer patients, and related poor prognoses, was overwhelmingly agreed on but important caveats in cancer prognostication remains. conclusions. these data suggest that oscillation settings of and hz provided more optimal pef/pif ratio ([ . ). our data also suggests that airway clearance using hfcwo may facilitate improved gas exchange in mechanically ventilated patients. further study is required to confirm these results grant acknowledgment. partial funding support in the form of devices was provided by hill-rom inc. a. esquinas , m. folgado , j. serrano hospital morales meseguer, intensive care unit, murcia, spain, hospital virgen de la concha, zamora, spain, hospital reina sofia córdoba, intensive care unit, cordoba, spain objectives: we hypothesized that the use of intrapulmonary percussive ventilation (ipv) could effect hypercapnia/acidosis and airway secretions control during treatment with noninvasive mechanical ventilation (nippv) in exacerbations of copd associated with bronchial secretions. prospective multicenter study. the study was performed in the medical icu of spanish university hospitals members of the spanish ipv working group. we enrolled copd exacerbation patients with secretions and the need for nippv in icu. criteria of exacerbations of copd are: a respiratory frequency c /min, a pao [ mmhg and ph b . . we define two ipv strategies as complementary treatment during nippv to evaluate the effects of ipv. strategy group i: nippv at first line and combination of ipv in early periods without nippv in spontaneous breathing and ph c . . strategy group ii: first line of ipv with mouthpiece/face mask and oxygenation previous to the application of nimv with ph \ . . in both groups daily sessions ipv were applied by for min/ day by mouthpiece or face mask during stay in icu. nippv was applied with bipap ventilator (respironics) and face mask with bipap mode. cardiopulmonary monitoring, clinical and arterial blood gases were evaluated. therapy was considered as successful when patients did not need nippv support and clinical and arterial blood gases returned to baseline. results. patients with copd exacerbation were admitted in icu for nimv, age ± years, male ( %) were excluded for severe hypoxemia (pao :fio b ) associated with pneumonia ( / ) and cardiac insufficiency ( / ). fifty patients were enrolled in the study. -up tilt-table rehabilitation better than sitting in a chair for ventilated adults in intensive care in terms of improving lung function? j. manners , a. thomas , s. boot , g. mandersloot barts and the london school of medicine and dentistry, london, uk physiotherapy intervention is a fundamental part of the patient stay in an intensive care unit (icu) and treatment is often aimed at maintaining/improving respiratory function. physiotherapists use the upright posture to elicit these improvements and sitting in a chair and standing with a tilt-table are commonly used interventions. to date there are no published reports comparing the efficacy of these interventions in ventilated subjects. • to compare the effects of these two positioning techniques employed with icu patients. • to measure changes in respiratory rate, tidal volume and minute volume during these positioning interventions. • to measure functional residual capacity during positioning interventions. • to measure the change in metabolic demand during positioning interventions. methods. convenience sampling of ventilated subjects meeting the inclusion criteria was employed. subjects acted as their own controls undergoing sitting in a trauma chair and standing on a tilt table at degrees in random order on the same day. respiratory rate (rr), tidal volume (v t ), ventilation (v e ) and oxygen consumption (vo ) were measured at minute intervals during baseline and intervention for min. functional residual capacity (frc) was measured once at rest and following each intervention. measurements were recorded using the ''e-covx'' module for the ''ge carestation ventilator''. results. subjects were recruited. no adverse events occurred during interventions. significant increases from baseline rr (p \ . ), v e (p \ . ) and vo (p = . ) occurred during the tilt table intervention. there was an increase in frc during tilting of . l which failed to reach significance. significant increases from baseline rr (p \ . ), vo (p = . ) and a decrease in v t (p = . ) occurred with the chair intervention. conclusions. these interventions are safe in a critical care population. increased muscular activity associated with upright interventions elicited expected elevations in vo . the tilt-table produced an increase in v e driven by an increased rr at the expense of v t . v e was not elevated during chair sitting despite an increased vo and was accompanied by an unexpected decrease in v t. introduction. uk guidelines about rehabilitation after critical illness highlight the need for outcome measures to determine patient progress and efficacy of treatment [ ] . there is no consensus about the most appropriate measures of patient function. the austoms [ ] tool was designed by therapists in australia to measure activity and function across nine scales assessing structural and functional difficulties and ability to perform activities. scales are split into four domains (impairment, activity limitation, participation restriction and distress/wellbeing) and scored from to with . intervals allowed. acceptable inter-rater variation is defined as an absolute difference of . . austoms has not been appraised in patients recovering from critical illness. objectives. to prospectively determine the inter-rater reliability of the austoms physiotherapy scales in adult patients who had undergone cardiothoracic surgery and required critical care admission for over days. methods. the therapy (physiotherapy and occupational therapy) team underwent a h teaching session using the austoms handbook prior to commencing the trial. austoms was then used over eight consecutive weeks during the weekly therapy goal setting meeting. each week a patient was selected to be scored using the most appropriate functional scales. the clinical history was presented to the team by the therapist leading the patient's care. therapists were then asked to independently score patients across the four domains for each scale. reasons underlying differences in scores were explored by group discussion. the difference between the th and th centiles of the initial scores was calculated for each domain as a measure of inter-rater variability. results. - therapists were present at each meeting. respiratory function and musculoskeletal movement related function were the most common scales used. the mean difference between th and th centiles was greater than . (± . ) for all domains. none of the scales/domains showed consistent inter-rater reliability over the week period. overall the activity limitation domains of each scale showed the least inter-rater variance of scores. clinical experience of therapist did not appear to influence scores. conclusions. the austoms outcome measure showed poor inter-rater reliability when evaluated over an week period on our intensive care unit. further work is ongoing to evaluate the ability of austoms to reveal changes over time when scored by therapists. introduction. uk guidelines on the rehabilitation of patients after critical illness highlight the importance of establishing and reviewing individualised rehabilitation goals for all patients that are at risk of developing physical and non-physical morbidity [ ] . our institution's practice is to create objective goals that are smart-specific, measurable, achievable, realistic and timed [ ] . objectives. the aim of this audit was to prospectively collect data regarding the setting of rehabilitation goals in a group of patients admitted to a cardiothoracic intensive care unit. methods. all consecutive patients admitted under the intensive care team in november were included. data regarding the timings of initial physiotherapy assessment, goal setting, and concomitant sedation were collected using a structured questionnaire completed by the treating physiotherapist. results. patients were admitted under the critical care team. patients were assessed by a physiotherapist within h of admission. of these , had smart goals set within a median of days of initial assessment (range - days). there was a correlation between level of consciousness and the number of days taken to set goals. patients who were fully conscious or drowsy on initial contact (n = ) had a smart goal set in a median of days. by contrast patients who were sedated/paralysed on initial assessment (n = ) had goals set in a median of days. initial goal setting did not include other therapists or the family. goals fell in to categories, range of movement, hoisting out to chair for periods of time, sitting on the edge of the bed, transferring out to the chair by standing and mobility goals-i.e. walking set distances. the maximal interval between reviews of the patients' goals was days. most patients had smart goals defined and regularly reviewed. however, despite physiotherapy assessment within h of admission, there was often a delay in setting these objective goals. the need for continuous sedation acted as a barrier to explicit setting of goals. the results emphasised the need to improve patient and family/carer involvement with initial goal setting in order to be compliant with uk standards. objectives. investigation of ems effects on muscle strength and exploration of issues in relation to handgrip dynamometry in icu patients. one hundred seventy two consecutive patients with apache ii score c , were randomly assigned to the ems (n = , age: ± years, apache ii: ± ) or the control (n = , age: ± years, apache ii: ± ) group. ems sessions applied daily in muscles of both lower extremities. the strength evaluation of various muscle groups of the upper and lower extremities was made clinically upon awakening with the mrc scale, ranging from to (normal strength) for each group. the same scale was also employed in the diagnosis of cipnm (mrc \ / ). a subgroup of these patients also performed handgrip dynamometry. results. fifty seven patients (ems: , control: ) were finally evaluated. ems patients scored higher than controls (p b . ) in wrist flexion, knee extension, ankle dorsiflexion and right side hip extension, while they tended to perform higher in all other muscle groups (p: . - . ) ( table ) . grant acknowledgment. this project has been co-financed by e.u. and the greek ministry of development. background. secretion removal is major aim of respiratory physiotherapy in intensive care. manual hyperinflation provides a tidal volume to the lungs that is greater than baseline. it is effective in secretion clearance and is frequently used [ , ] . there is a limited evidence that addressed the effects of combining rib-cage compression and suctioning on oxygenation, ventilation, and airway-secretion removal in mechanically ventilated patients [ ] . objectives. the aim of this study was to investigate the effects of manual hyperinflation administered in combination with expiratory rib-cage compression on lung compliance, gas exchange, and secretion clearance in mechanically ventilated patients. methods. twenty-two intubated, mechanically ventilated, and hemodynamically stable patients were studied. the patients received manual hyperinflation, with or without expiratory rib-cage compression, with a minimum -h interval between the two interventions. manual hyperinflation with or without expiratory rib-cage compression was performed for min before endotracheal suctioning. respiratory mechanics and hemodynamic variables were measured min before (baseline) and then and min after the interventions. arterial blood gases were determined min before (baseline) and min after the interventions. secretion clearance was measured as sputum weight. the two measurements were obtained on the same day. results. no significant differences were observed in gas exchange and secretion clearance between the two interventions (p [ . ). in each case, static lung compliance and tidal volume improved significantly at min post-intervention (p \ . ), whereas at min postintervention, only static lung compliance had improved significantly above baseline (p \ . ). our results suggest that the addition of expiratory rib-cage compression to manual hyperinflation does not improve lung compliance, gas exchange, or secretion clearance in mechanically ventilated critically ill patients. recently, there has been an interest in mobilization of acutely ill patients who are in an intensive care unit (icu). in the literature, the major safety issues while mobilizing critically ill patients has been outlined. cardiac reserve [(cr) (% of age predicted maximal heart rate)] and respiratory reserve [(rr), ratio of partial pressure of oxygen in arterial blood to the inspired fraction of oxygen (pao /fio )] are the important factors that can affect the ability to tolerate the mobilization. patient who has rr more than and cr lower than % is considered to have sufficient reserve to tolerate mobilization [ , ] . objectives. the aim of this study was to compare the effects of mobilization on respiratory and hemodynamic parameters in patients with sufficient and insufficient respiratory and/or cardiac reserve. mobilization events are divided into two groups (sufficient, insufficient) according to the pre-mobilization cr (sufficient, \ %; unsufficient, [ %) and rr (sufficient, [ ; insufficient, \ ). heart rate (hr), systolic/diastolic/mean arterial blood pressure (sbp, dbp, mabp), respiratory rate (rsr) and percutaneous oxygen saturation (spo ) were recorded from the monitor. respiratory and hemodynamic parameters were collected just prior to the mobilization, just after the completion of the mobilization when the patient had been returned the supine position and min of the recovery period and compared between the groups. a total of abdominal surgery patients ( male, female) received mobilization treatments in icu. the mean age was . years, mean body mass index (bmi) was . kg/m , mean apache ii score was . and mean icu stay was . days. mobilization events included ( %) sitting on the edge of the bed, ( %) standing, ( %) walking to chair and sitting in the chair. % ( ) of mobilization events had insufficient rr and % ( ) of mobilization events had sufficient rr. . % ( ) of mobilization events had insufficient cr and . % ( ) of mobilization events had sufficient cr. all respiratory and hemodynamic parameters were found similar in sufficient rr and insufficient rr group at all stages of the mobilizations (p [ . ). spo was higher, while hr and rsr was lower at all stages in sufficient cr group compared to insufficient cr group (p \ . ). resting hr and cr may affect the safety of mobilization, for this reason it is important to consider respiratory and hemodynamic parameters prior to and while mobilizing the icu patients. introduction. obesity is a chronic disease and a major health problem. obesity in critically ill patients is associated with a prolonged duration of mechanical ventilation and intensive care unit (icu) length of stay [ ] . objectives. the aim of this study was to investigate the effects of mobilization on respiratory and hemodynamic parameters in the critically ill obese patients. [ . kg/m )] were included as soon as their cardiorespiratory stability allowed mobilization protocol. mobilization was defined as sitting in the bed, sitting on the edge of the bed, standing, walking to chair and sitting in the chair. heart rate (hr), systolic/diastolic/mean arterial blood pressure (sbp/dbp/mabp), respiratory rate (rr) and percutaneous oxygen saturation (spo ) were recorded from the monitor. respiratory and hemodynamic parameters were collected just prior to the mobilization (supine position), just after the completion of the mobilization when the patient had been returned the supine position and min of the recovery period. all parameters were compared with initial values. the ratio of partial pressure of oxygen in arterial blood to the inspired fraction of oxygen (pao /fio ) was calculated from the arterial blood gas samples before and after the mobilization. introduction. the use of respiratory therapy for patients with a variety of lung disease is a standard in medical care [ ] , including in the intensive care unit (icu) setting [ ] . in this context, it is widely accepted the routine use of physical therapy in several situations in the intensive care, such as the care of critically ill patients not requiring ventilatory support, assistance during the postoperative recovery and the assistance to critically ill patients requiring ventilatory support [ ] . at present definitive recommendations cannot be made regarding the use of respiratory physiotherapy for decreasing relevant clinical outcomes in critical ill patients requiring mechanical ventilation. objectives. this study aimed to determine the impact of providing chest physiotherapy on the duration of mechanical ventilation, intensive care length of stay, intensive care and hospital mortality in mechanically ventilated patients. single-centre, randomized, controlled trial in a university hospital general intensive care unit (icu). were included in the study patients aged more than years, admitted to the icu needing mechanical ventilation for longer than h. physiotherapists provide group intervention (p) with the intensity and frequency of therapy they felt appropriate based on their assessment of the likely treatment benefit. control patients (group c) only received suctioning, decubitus care and general mobilization. results. primary outcomes were icu and hospital mortality regardless of the cause of death. secondary outcomes were length of icu and hospital stay, length of mechanical ventilation, weaning and extubation failure. patients in the p group more frequently achieved parameters to start weaning, but there were no significant differences between p and c groups on weaning and extubation failure, length of mechanical ventilation and length of icu stay. there was fewer hospital, but not icu, mortality in the p group. conclusions. we demonstrated that respiratory physiotherapy decrease hospital mortality and suggest that this effect was, in part, secondary to the effect of the intervention on weaning from mechanical ventilation. introduction. critical illness can cause diverse cerebral dysfunctions ranging from unconsciousness to minor cognitive impairments (mci). severe cerebral dysfunction, as delirium, is known to affect outcome after critical illness but it is uncertain whether minor impairments affect mortality or morbidity [ ] . objectives. the primary aim of this study was to estimate the incidence of mci in a group of general icu survivors immediately after icu stay and three and months after discharge. secondary we wanted to explore if type of cerebral dysfunction after icu discharge affected mortality and morbidity. methods. patients admitted to our general icu were included prospectively. we included patients. / ( %) were delerious and / ( %) were not delerious but had mmse \ after icu stay. of the patients with mmse c , were possible to classify as having mci or not. / ( %, % ci: - %) were found to have a mci after icu discharge. on and months these numbers were respectively: % ( % ci: - %) and % ( % ci: - to %) there was an increased risk of both death and being institutionalised at both and months regarding delirious patients and patients with mmse \ compared to patients with mmse [ . no such differences were found regarding patients with or without mci. (tables and ) . conclusions. the incidence of mci after critical illness is high on discharge but drops on and months after. severe cognitive impairments affect mortality and morbidity, but minor cognitive impairments do not. objectives. this study analyzes mid-term survival and risk factors associated with survival of patients undergoing cardiac surgery in son dureta hospital. methods. patients were consecutively operated from november to december . patients who were discharged alive from hospital were followed until december . we did kaplan-meier survival analysis and logistic regression study of variables associated with mid term mortality. results. in-hospital mortality was . % ( % ci: . - . %). information was available on , ( %) of , patients who survived until hospital discharge. at the end of the follow-up period, observed mortality was . % (ci %: . - . %). survival probability at , and years of follow-up was , and %, respectively. the mean time of follow-up was . years (range . - . ). patients c years showed a lower survival rate than patients \ years of age (log rank \ . ). age c years, history of severe ventricular dysfunction (ef \ %), diabetes mellitus, preoperative anemia and hospital stay were independently associated with mid-term mortality. conclusions. mid-term survival of patients alive after hospital discharge was very satisfactory. mid-term mortality varied according to age and several preoperative chronic diseases. a closed-ended questionnaire was developed by the nurse congress commission of the société de réanimation de langue française (srlf). an invitation to complete it online was sent by email to caregivers registered on the srlf push-list. results were analyzed by icu or by respondent. results. caregivers working in icus completed the questionnaire ( % were nurses, % were doctors, % were nurse's aides, % worked in adult icus and % in pediatric icus). % of adult icus (n = ) had unrestricted policy but % had a visiting time of less than h per day. at the opposite, % of pediatric icus (n = ) had unrestricted policies. % of the respondents working in icus with a visiting time \ h per day considered very useful or essential to enlarge visiting periods but % of them considered this enlargement as unhelpful. at the opposite, % of the respondents working in icus with unrestricted policy found very useful or essential to reduce visiting periods. % of caregivers working in icus with unrestricted policy but only % of caregivers working in other icus thought that an unrestricted policy was able to improve often or systematically the relations with families. moreover, only % of caregivers working in icus with unrestricted policy but % of caregivers working in other icus thought that an unrestricted policy disturbs the organization of care. % of respondents found very useful or essential to give information in a dedicated room whereas it was often or systematically done in only % of icus. identically, % of respondents found very useful or essential to give information to proxies with the patient's nurse whereas it was often or systematically done in only % of icus. some cares were often or systematically programmed for family participation in % of pediatric icus but in only . % of adult icus. indeed, proxies often or systematically participated in nursing in % of pediatric icus but never in adult icus. at the opposite, proxies often or systematically participated in tracheal aspirations in only % of pediatric icus and in . % of adult icus. conclusions. more than half of respondent's adult icus are closed but caregivers working in icus with unrestricted policy perceive it favorably. some improvements are also expected by caregivers on the use of dedicated rooms for information and on the participation of nurses in meetings with families. finally, participation of families to care is not a practice of french adult icu caregivers. methods. included: patients with dysfunction of two or more organs in the first h, admitted and discharged from icu during . excluded: neurocritical and politrauma patients. contact year following discharge; questions were asked concerning symptoms related to a period in intensive care that presented following discharge and which were not present prior to admission. in the case that the patient was not contacted, the next of kin was asked. results. patients included. general characteristics during admission to icu: % male; age . ± . years; sofa* ± . ; apache** ii . ± . ; apache** iv ± . ; length of stay in icu: . ± . days; . % were on invasive mechanical ventilation and . % on non-invasive mechanical ventilation. data collection was carried out over ± . months, on average months (range: - months). . % ( patients) had died at the time of contact. the person contacted was the patient in . % of the cases, the spouse in . % and immediate family (patient's parent/child/sibling) in . % of the cases. . % had difficulty sleeping following discharge from icu with an average time since discharge of . ± . months; . % suffered feelings of sadness and difficulty in finding enjoyment which had persisted for . ± . months; . % had experienced difficulty in concentrating over an average of . ± . months; . % had suffered some form of memory loss after discharge over an average period of . ± . months; . % presented with asthenia over an average of . ± . months; . % had arthromyalgia over a period of . ± . months; . % had experienced changes in appetite over an average of . ± months; . % had changes in intestinal habit over an average of . ± months; of which . % had diarrhoea, . % constipation, and . % both symptoms; . % presented with headache over a period of . ± . months; . % had tremors, that had not previously been present, over an average of ± . months; . % had experienced reduced vision, over an average period of . ± . months; . % presented with speech/ language problems, over an average period of . ± . months; . % exhibited newly presenting changes in micturition, over ± . months. another less frequently occurring symptom was loss of hearing ( . %). conclusions. severely ill patients that are admitted to icu frequently present with ''residual'' symptomatology following discharge, most notably arthromyalgia and asthenia. many of these conditions persist for months. intensive care unit (icu) readmission rates range from to %, in spite of initial recovery from critical illness. previous researches report that the revised acute physiology and chronic healthy evaluation (apache ii) score at either admission or discharge is an important predictor for readmission after icu discharge. however, there are a few papers concerning the association of discharge apache ii score with readmission after discharge from surgical intensive care unit. objective. we compared the ability of the discharge apache ii score with that of the admission apache ii score in predicting readmission, especially early readmission within h, after discharge from icu. conclusion. this study showed that both discharge apache ii score and admission apache ii score are useful predictors for readmission after icu discharge, but discharge apache ii score is only independent factor in predicting early readmission within h after icu discharge. introduction. health related quality of life (hrqol) is decreased in former icu patients. in research outside the intensive care field it is well known that the psychosocial factors, coping strategies and perceived hopelessness affect hrqol. however, the influence of coping and hopelessness on hrqol after intensive care is unknown. objective. the aim of this study was to examine how coping strategies and perceived hopelessness among former icu patients compares to corresponding in a reference group. we also evaluated the effect of coping and hopelessness and icu related factors on hrqol. methods. prospective, multicenter study in three mixed icu's in sweden. patient demographics, length of stay, apache ii score, reason for admission and time on ventilator were collected for all adult patients. questionnaires, including the coping instrument pearling-schooler mastery scale (pms), the -item hopelessness scale, sf- , demographic data and previous illnesses were sent months after discharge from hospital to the patients. the reference group (n = , ) was a random selection of persons from the same catchment area as the study patients. . ( %) icu-patients, - years, returned the questionnaires. the patients reported significantly lower mean scores in coping . (sd . , p \ . ) and higher perceived hopelessness . conclusions. this study indicates that coping strategies and perceived hopelessness are important for the hrqol of previous icu patients. however, the magnitude of these effects are smaller than that of pre-existing diseases. introduction. mortality on a medical intensive care unit (icu) is estimated to occur in about % of patients. its association with age, severity of illness and comorbidities is well established. for other diseases like coronary artery disease it has been shown that pre-existing depression is a risk factor for worse outcome. the role of depression regarding the outcome of icu patients has not been investigated so far. we studied the association between pre-existing depression and mortality in medical icu patients and present preliminary data of this ongoing study. objectives. assessment of a possible association between mortality of icu patients and prevalent depressive mood at time of icu admission. the primary endpoint was -day mortality. methods. prospective cohort study. all patients admitted to a medical -bed icu in a university hospital, older than years, were eligible. postoperative patients and patients who had an expected length of stay below h (survey) were excluded. patients whose cognitive function allowed appropriate comprehension and response answered the hospital anxiety and depression scale (had). prevalent depressive mood at admission was defined by a score c in the depression dimension. all other patients were assessed by observer rating by next-ofkin. in this case the hammond scale, a validated instrument for observer rating of depressive mood (cut-off c ), and a modified version of the had for observer rating (cut-off c ) were used. in addition apache ii, saps ii, sofa, age, sex, comorbidities, reason for admission, length of icu stay and ventilator days were recorded. . by now patients had complete follow up data. of these patients ( %) were classified to have depressive mood at icu admission. in total patients had died by day ( %). the -day mortality was % ( / ) in patients with depressive mood and % ( / ) in patients without (p = . ). patients with and without depressive mood did not differ with respect to age, sex, apache ii, saps ii or sofa score at admission. multiple logistic regression analysis with -day mortality as the dependent variable revealed that prevalent depressive mood at the time of icu admission was an independent risk factor for mortality (table ) . conclusions. pre-existing depressive mood is an independent risk factor for mortality in medical icu patients. introduction. some classical post-icu discharge predictors of death are described, such as age, severity of disease and level of nursing care [ ] . besides these factors, some laboratorial data at icu discharge are potential predictors of post-icu death. objectives. the aim of this study was to investigate whether standard base excess (sbe), ph, lactate, hemoglobin level, creatinine, platelets, leukocytes and albumin at the icu discharge as well as the % decrease on c-reactive protein concentrations (crp [ %) from the day pre-icu discharge to the day of icu discharge may be useful predictors of in-hospital outcome. patients discharged from the icu after at least h of stay were retrieved from our prospective collected data base. a multivariate analysis was performed using a backward-lr binary logistic model taking in-hospital death as a dependent variable and the cited data as independent variables. results. patients were retrieved. the average age was ± years old, mean apache ii score was ± , and the main causes of admission were septic syndromes and respiratory failure. the in-hospital mortality after icu discharge was %. the icu length of stay was ± days. at the time of icu discharge ph was . ± . , sbe was - . ± . mmol/l, lactate was . ± . mmol/l, hemoglobin . ± . , creatinine was . ± . g/dl, albumin was . ± . g/dl, platelets was , ± , /mm , leukocytes was , ± , cells/mm and the number of patients who lowered crp at least % were ( % conclusions. this study demonstrated that sbe, lactate, hemoglobin and albumin concentrations on the day of icu discharge are independent predictors of in-hospital mortality. moreover, the reduction on crp levels above % in the last h of icu stay is a strong predictor of better in-hospital clinical outcome. we suggest that these variables together with the clinical judgment may be taken into account on the icu discharge decision process. readmissions to the intensive care unit (icu) are usually associated with increased morbidity and mortality, and they may evidence the quality of patients' care. the risk for icu readmission varies across studies, and is generally analyzed just before icu discharge, leading to deviation of icu team and patients' daily goals. early prediction may improve the care for patients in risk for icu readmission, and help developing mechanisms for its prevention. objectives. to analyse risk factors for readmission in intensive care unit looking at the first h data after unit admission. methods. the first intensive care unit admission of patients was analyzed from january to december in a medical-surgical unit. readmission to the unit was considered those during the same hospital stay or within months after intensive care unit discharge. deaths during the first admission were excluded. demographic data, acute illness and comorbidity prognostic scores, and use of mechanical ventilation were submitted to uni and multivariate analysis for readmission. numeric variables were expressed as median or percentage. conclusions. age, medical admission, sofa score and respiratory-and/or sepsisrelated admission are early associated with increased icu readmission risk. objectives. the aim of this study was to examine patient perceived hrqol in former icu patients that die in the period from month up to years after discharge from intensive care unit and the hospital. methods. prospective, multicenter study in three mixed icu's in sweden. questionnaires, including hrqol (sf- ), demographic data and previous illnesses, were sent out six, , and months after discharge to all former adult icu patients. data for this study were only collected among those dying before the months post-icu follow-up. of the patients who returned the questionnaires ( . %) died, ( . %) between and months, ( . %) between and months, and ( . %) between and months. the most frequent admission diagnoses were respiratory problems n = ( . %) and gastrointestinal diseases n = ( . %). examining hrqol in the former icu patients the following observations were made: (see fig. ). a pronounced and quantitatively large decrease in hrqol is seen for the surviving patients with pre-existing disease as compare to the previously healthy survivors. although already at a very low value further decreases in hrqol for the patients dying before years post icu is significantly less as compared to the icu patients with pre-existing disease that survives. the decrease is mainly in physical function, role physical function and role emotional function (marked in the figure). conclusions. yes, health related quality of life is extensively affected, mainly in the dimensions physical function, role physical function and role emotional function. importantly, in these two affected physical dimensions a shorter time to death increases such a decrease. the finding further stresses the importance of pre-existing diseases for the final hrqol outcome of former icu patients. introduction. despite initial recovery from critical illness requiring icu admission, many patients remain at risk of subsequent deterioration and death [ ] . recent studies have shown readmission rates ranging between and % [ ] ; this population had mortality rates six times higher and were eleven times more likely to die in hospital [ ] . . to calculate the readmission rate in our mixed icu unit over a months period . to identify risk factors associated with readmission into the icu . to study the outcomes of these readmissions methods. a retrospective observational study, data was collected from an icu computer database (metavision) and analysed manually results. the total number of admissions in this period was , average patient age was ± with . % being males. readmissions constituted . % of the total admissions with . % of those readmitted within h of their initial discharge. % of the initial discharges from the unit were made out of hours i.e. unplanned, presumably due to heavy demand on beds. readmissions were particularly associated with patients discharged to surgical wards . % and the hepatobiliary hdu . %, the latter might reflect the proportion of that particular patients population received. . % of the readmissions required to stay h or less in icu. the overall mortality of the patients requiring more than one admission in this months period was . %. there is an urgent need for expanding icu services in our hospital, i.e. extra beds, staff, outreach teams, etc in addition to investing in nursing capacity building especially in surgical wards. we agree with others studies that compared with the general population, icu survivors report lower hrqol. moreover, a relationship between several factors like sepsis, renal failure, sofa (first and second day score), critical illness polyneuropathy, mechanical ventilation, sedation time, previous psychiatric history and blood products transfusions were found in our study population. conclusions. according to our data, subclavian vein was the most common insertion site used, especially as nd and rd placement and was related with the lower incidence of becteremia episodes. although the risk of placing a cvc for inflection complications is against the risk for mechanical complications, we have to improve our cvc policy, preferring the subclavian or the jugular site of insertion, in order to minimize the infection risk for a nontunneled cvc. objectives. objectives for this study were to determinate the frequency and the risk factors associated with bos. secondarily, we searched several variables as civil status, age, sex, work seniority as potential risk factors. inclusion criteria were to work in critical care unit (ccu) the hospital clínico universidad de chile (hcuch). this unit included subunits: intensive care unit (icu), middle care unit (mcu). the mbi Ò instrument was applied between april to july of . all staff of ccu were asked to response the instrument. as previously reported, bos was defined with high ee, high dp and low pa. risk of bos was anything of the three dimensions positive for bos. we gave information on specifics objectives and the schedule of a future intervention programme. for analysis, comparisons were made based on student t test, chi-square test with yates corrections or fisher exact test as corresponded. for all tests we used confidence interval % with p \ . . a total of mbi Ò tests that included all sub-units in ccu. this is a % of all personal working in the ccu. bos was found in . % of cases. women ( %), unmarried ( %), with an average of age . years old. ( - years old) and with a work seniority younger than years ( %). ee is high ( . %), for nurse and paramedical personals. dp was . and . % to middle level, for nurse and medical doctor, and low pa in % for paramedical personal, with longer work seniority (more than years). risk factors were female gender, unmarried status, childless, middle aged ( - years old) and recent start in the job (stay younger than years). introduction. burnout is a prolonged response to chronic emotional and interpersonal stressors on the job, and is defined by three dimensions: exhaustion, cynism (depersonalization), and inefficacy. icu physicians are exposed to several stress factors and are particularly predisposed to this syndrome. to describe the prevalence of burnout syndrome among intensivists and its relation to their quality of life. methods. an epidemiological cross-sectional survey conducted to evaluate all adult icu physicians in salvador, ba (brazil), from october to december . the quality of life and burnout syndrome were evaluated respectively by the whoqol-bref instrument and the maslach burnout inventory (mbi). burnout was classified into low, moderate and high levels for the three studied dimensions, according the mbi classification, and it was defined by the presence of a high level in at least one dimension. the quality of life was evaluated in four domains: physical, psychological, social relationships and environment, graduated from to , with higher scores denoting higher quality-of-life. [ ] ) has been successfully used to measure nursing workload on an intensive care unit over a -h period. in contrast to intensive care, the nursing care workload on mc is not evenly spread over a twenty four period, but tends to vary between shifts. objectives. the aims of this pilot study were ( ) to assess the fitness of nas as an accurate reflection of nursing workload on an mc unit. ( ) to determine the nursing work load, per patient, per h shift. prior to the commencement of the study all thirty one nurses taking part received instruction in the content and registration of nas. at the end of each h shift, each nurse retrospectively scored their patient(s) using nas. this consists of a check list containing twenty three items giving a possible score between and , where equates to . full time equivalent (fte) intensive care nurse. the nas were entered in to a database and the average scores, per patient, per shift were calculated. three hundred patients were retrospectively scored over a -month period in october and november . not all patients were scored on all three shifts as some patients had been transferred out of the unit before shift end. in addition any incorrectly completed forms were discarded and excluded from the study. methods. this multicenter pilot study included doctors working at (pediatric) intensive care units (icu). subjects were randomly assigned to two groups: one was first tested during day, then during night, while the other was tested in reverse order. the d test of attention [ ] was used to assess attentional performance. total performance (tn-f) score, standardized for age and level of education, was used to express attentional performance. subjective, -to- scores were gathered in two questionnaires. results. figure displays standardized total performance scores of doctors. measured attentional performance showed high intra-and interpersonal variability and did not differ between both shifts (p [ . ). in contrast, doctors expected alertness to be decreased ( . ± . and . ± . (mean ± sd) on subjective -to- scale during day and night shifts, respectively; p \ . ) and the chance of making errors to increase (from . ± . to . ± . (mean ± sd); p \ . ) during night shifts. conclusions. physicians working at icu are aware of the risk of making errors during night shifts. however, we showed that doctors perform equally during night and daytime when confronted with a short-time challenging task. consequently, a discrepancy between measured attentional performance and expected alertness was observed. these results suggest nocturnal alertness might be comparable to daytime during short-lasting tasks that elicit a high level of stress and motivation (e.g. testing, medical emergency). further research is needed to elucidate if longlasting (routine) tasks reflect decreased sustained attention and contribute to medical errors. we studied physicians, the majority of whom were male ( %). mean age and time since graduation were . and years, respectively. high levels of emotional exhaustion, depersonalization, and reduced personal accomplishment were found in . , . , and . %, respectively. prevalence of burnout syndrome, defined as a high score in at least one dimension, was . %, while prevalence was . % for all three dimensions. in conclusion, burnout syndrome was common in this sample of icu physicians. aims. our goal was to assess the physician's opinion about potential competencies of a triage nurse. a representative cross sectional study design was applied with self-fill-in questionnaire about physician's attitude related to skills of triage nurses. the questionnaires were distributed between september and november in (out of ) eds. in this survey physicians' questionnaires were processed. chi-square and student-t test was used for comparison of variables. p values less than . were considered statistically significant. results. . % of physician would support the special training of triage nurse. . % of physician suggests that the nurses use the patient's physical examination regularly in eds. the full time (ft) emergency physician significantly would reduce the basic competencies of nursing (e.g. dressing, feeding of patient, p = . , and p \ . , respectively) than parttime (pt) emergency physicians. significantly greater part of the ft physician would widen the competency of triage nurses in the field of physical examination of nervous system (p \ . ) and cardiovascular system (p = . ) than the pt physician. conclusion. hungarian emergency physician would widen the competency of triage nurse, but only half of physician would like to that nurses apply physical patient examination in practice. the full time physician would give more competencies for triage nurse than part time ones, but the final field of competency will be depended on other factors. healthcare-associated infections (hcai) are estimated to affect . million people worldwide, causing longer hospital stay, increasing hospital costs and excess mortality [ ] . hand hygiene represents the single most effective way to prevent healthcareassociated infections. compliance with hand hygiene amongst healthcare workers (hcw) has been demonstrated to be quite low at % [ ] . to quantify the degree of compliance to hand hygiene norms in the icu and to assess the short term success of strategies to improve hand hygiene compliance. setting. bedded medical-surgical icu in a tertiary care centre. design. prospective observational. method. unobtrusive observer (single person). observed over sessions of h. the compliance was calculated as :number of times the staff performed hand hygiene/number of hand hygiene opportunities. the number of hand hygiene opportunities was based on the who tools [ ] : before touching a patient, before clean/aseptic procedures, after body fluid exposure risk, after touching a patient and after touching patient surroundings. introduction. icu delirium represents a form of brain dysfunction that in many cohorts has been diagnosed in - % of patients receiving mechanical ventilation. delirium is a common but complex clinical syndrome characterized by disturbed consciousness, cognitive function or perception, which has an acute onset and fluctuating course and is associated with poor outcomes. and yet, it can be diagnosed and treated. in the uk, reporting of delirium is generally considered to be poor. in light of updated nice guidelines on delirium due out this year, specialist clinical assessment will soon become gold standard as a means of diagnosing and reducing the prevalence of this condition in the icu setting. nice recommends that cam-icu (confusion assessment method) be used by healthcare professionals who are trained and competent in the diagnosis of delirium. on our -bed unit, we are currently implementing cam-icu assessments to be performed twice daily (at the commencement of each nursing shift) as well as rass (richmond agitation and sedation scale) scoring on an hourly basis for all patients. objectives. to implement training of all our icu nursing staff in the use of cam-icu and rass scoring. to periodically validate and reinforce earlier training, so as to improve assessment and reporting of delirium. methods. our 'delirium group' comprising both nursing and medical staff, taught cam-icu and rass to staff members using multimedia presentations in small groups and/or individual teaching sessions over weeks. scoringofcam-icu andrasswassubsequentlyauditedon occasions post training. discrepancies were discussed and post-audit retraining provided where necessary. results. the following audit and validation data were generated on our unit as documented in table . no statistical analysis was undertaken. we anticipate focusing on the challenges encountered and strategies used in managing this change in our icu practice. methods. the factors causing resistance to change based on multisource data. qualitative technical methods were used: brainstorming and focal groups. the data collection elaboration was created by the collaboration of icu nurse, quality department nurse and external reviewers. finally, the main factors were classified in different categories. each category was scored by to according to gravity and prevention possibility. finally, priority was given to more serious and easier prevention problems. results. the most serious problems for icu professional was the historical factors. the easier solution problems were ''the lack of information'' and all evaluators were agree with it. we arranged the factors in order to the next classification (tables and ). discussion. all investigators were agreed with the low importance of problems with payments and low prevention probability of low organisational flexibility, so they were agreed on not to work about them. the icu professionals were more pessimistic and have lower confidence in prevention possibilities but they showed more confidence about the capacity to learn new skills. they weren't worried about resistance to do experimental things. probably, historic factors play an important role in this pessimistic attitude. on the other side, quality and safety experts have more experience in prevention programs and they put all their trust in its. after doing the analysis, we chose the ''lack of information problem'' to plan prevention activities. we consider it is a serious and real problem but at the same time, easy of prevent. conclusions. the implementation of the patient safety program in the icu means a real cultural change. the priority analysis could help to plan strategies in order to avoid the program failure. objectives. we concerned about whether medical personnel could recognize management of the cuff of artificial airway or not. we asked to doctors and nurses working in intensive care unit of konyang university hospital, daejeon, republic of korea. we asked questions with contents of questionnaire that was composed of methods of set initially, maintenance and appropriate pressure of cuff. results. of medical personnel replied to us. most of them had worked in intensive care unit, so they had placed of artificial airway. . % of them used manometer to adjust the cuff. we could find that nurses had more cognition compared to doctors for it ( vs. %). only . % of doctors described pressure of the cuff in medical record. of medical personnel replied that they knew the appropriate range of cuff pressure. % ( / ) of them replied that the range of cuff pressure was kept with - mmhg and % ( / ) was - mmhg. % of nurses in the icu knew that range of cuff pressure was - mmhg. most of them knew complications of high and low pressure of the cuff. . % of medical personnel monitored the cuff balloon during receiving mechanical ventilation and they used manometer to adjust it. % of nurses knew that the cuff should be adjusted continuously, but % of doctors did. interval measuring the cuff pressure was % of once a day, % of three times a day, % of more than four times a day conclusions. most of the medical personnel knew to keep appropriate cuff balloon to prevent various complications of artificial airway. they had insufficient cognition about maintaining the cuff balloon and appropriate level of cuff pressure. that was more prominent in doctors than nurses interhospital transfer is occasionally required as a consequence of limited therapeutic options or because of a need for a higher intensity of medical care that cannot be given in rural intensive care units. along with the potential benefit for the to be transferred patient, transport may also lead to hemodynamic and pulmonary deterioration. in order to minimize additional risk of interhospital transport of critically ill patients, a mobile intensive care unit with a specialized retrieval team was established in our university hospital-based intensive care unit. from march , transport of the critically ill patients in our adherence region are performed by micu. objectives. in this prospective audit adverse events and patient stability during micu transfers were assessed and compared to our previous data on transfers performed by standard ambulance [ ] . results. interhospital transfers over a -month period were evaluated. systolic blood pressure, glucose and haemoglobin were significantly different at arrival compared to departure, although never significant values for major deterioration were reached. an increase of total number of variables beyond threshold at arrival was found in % of patients, percent exhibited a decrease of one or more variables beyond threshold and thirty percent showed an equal number of trespassed thresholds. there was no correlation between the patients status at arrival and the duration of transfer or severity of disease. icu mortality was %. compared to standard ambulance transfers of icu patients performed in , there were far less adverse events: . vs. %, which in the current study were merely caused by technical (and not medical) problems. although mean apache ii score was significantly higher, patients transferred by micu showed less deterioration in pulmonary parameters during transfer than patients transferred by standard ambulance. conclusion. transfer by micu imposes less risk to critically ill patients compared to transfer performed by standard ambulance and has therefore resulted in an improvement of quality of interhospital transport of icu patients. introduction. previous studies in adult intensive care units (icus) reported rates of pre-mortem to post-mortem discrepancies ranging between and % depending on the population studied. and, most of them were retrospective studies, which included small number of patients. to compare clinical and pathological diagnoses and to determine the types of errors in a large and multidisciplinary icu-patient population. we conducted a prospective study of all consecutive autopsies performed on patients who died in the icu of the hospital universitario de getafe, madrid, spain, between january and december . the diagnostic errors were classified in two categories: class i errors that were major misdiagnoses with direct impact on therapy, and class ii diagnostic errors which comprised major unexpected findings that probably would not have changed therapy. conclusions. this study found significant discrepancies between clinical diagnoses before death and post-mortem findings. this reinforces the importance of the post-mortem examination in detecting otherwise unexpected diagnoses and improving the quality of care of critically ill patients. introduction. unplanned extubation is associated to a high risk of reintubation end correlates with increased risk of nosocomial pneumonia. on the other hand, reintubation significantly increases morbidity and mortality in critical ill patients, increasing the incidence of ventilator associated pneumonia (vap) rate and makes the airway management risky. objectives. the aim of our study was to test the rate of unplanned extubation as well as the reintubation rate in our icu, in order to evaluate the efficiency of our airway and weaning time protocols. methods. during a nearly year's period, patients admitted to the icu, mean age: . years, mean apache ii score: . , mean los: . days, with predicted and actual mortality: . and . % respectively. from these, were intubated and included retrospectively in our study. patients were extubated, while the others either underwent bedside percutaneous tracheostomy or died. we concerned that the number of days of mechanical ventilation were about equal to the number of days of intubation. reintubation was defined as the need to reintubate during the first h after extubation. we recorded four episodes of unplanned extubation. three of them caused by malfunction of the tube due to secretions and airway obstruction and one of them was undesired extubation caused by the patient himself. the total number of days of intubation was , , mean ± sd: . ± . , min: , max: days. therefore the rate of unplanned extubation was . %, while the standard limit is below %. the total number of reintubations was , while the total number of scheduled extubations was . therefore, the reintubation rate was . %, while the standard limit is below %. conclusions.the recorded rate of unplanned extubation was low in our icu patients, below the acceptable limit, assuming that our sedation and airway management policy is effective. on the other hand, the recorded rate of reintubation was high in our study, above the acceptable limit. although a low rate of reintubation might indicate excessively long mechanical ventilation times, this did not recorded to our study. nevertheless, our data suggest that we have to improve further our weaning time protocols, making the extubation procedure safer, and avoiding risk factors for vap. . pvs such as inappropriate enrollment of patients with a contraindication to the study treatment may lead to excess harm in the active intervention group [ ] and failure to deliver the study intervention according to the study protocol may underestimate true treatment efficacy [ ] . full reporting of pvs may aid in the interpretation of rct results however there are no published reviews on this topic [ ] . objectives. to determine reporting rates for key types of pvs and to investigate study characteristics that may be related to reporting. publications were excluded because they were subgroup or economic analyses of a previously published rct [ ] , not a rct [ ] , not published in the target journal [ ] , systematic reviews [ ] , or other reason [ ] . median trial size was participants (range: to , ). / ( %) of rcts were single centre, / ( %) were industry funded and / ( %) reported negative findings. overall / ( %) of rcts reported some form of pv, these included: / ( %) patient compliance; / ( %) discontinuation of study intervention due to safety; / ( %) study intervention-related researcher error; / ( %) inappropriate enrollment and; / ( %) technical errors in randomisation. multi-centre rcts may be more likely to report study intervention-related researcher errors ( % of multi-centre trials vs. % of single centre trials, p = . ). academic trials were less likely to report discontinuation of study intervention due to patient safety ( % of academic trials vs. % of industry trials, p = . ) and were less likely to report technical errors in randomization ( % of academic trials vs. % of industry trials, p = . ). conclusions. multi-centre trials are accepted to be organizationally complex. on-site education may be required to reduce errors in study intervention delivery attributable to the research team. it is possible the apparent excess harm attributable to industry trials is a reporting artifact however, if it is real, it must be addressed. additional research is required to investigate patient safety-related pvs and technical randomization errors, which may be lower in academic trials. to determine the occurrence of harmless incidents and ae related to physician's competences in icus, disclosing their potential risk factors. conclusions. this prospective study was essential to identify the proportion of our icu admissions affected by md-inc and md-ae, disclosing their nature. our md-ae rates, affecting more than % of admissions, were higher than those described in prior general studies, including not only icus. among the detected md-ae, hypoglycemic episodes not related to insulin administration predominated, indicating important deficiencies regarding nutritional support. severity on admission and length of stay were important risk factors for the occurrence of at least one md-ae. a systematic measurement and analysis of unintended events (ue) have been recommended for patient safety and improvement of quality of care in critically ill patients. however, a spontaneous reporting system may be inefficacious in intensive care unit (icu) because of a poor data collection, particularly by physicians staff. objectives. the aim of this study was to evaluate the reliability of a staff spontaneous event report by comparison with events collected by an external observer in a surgical intensive care unit (icu). to facilitate the reporting and the analysis, we identified a series of events with a serial number and a colour code related to their for each of the following macro-phases: icu bed booking, admission procedures, patient stay, discharge and emergency procedures. a specific structured form including ue's code and colour, date and hour of the event and type of patient has been prepared and proposed to staff -week for each month after a proper phase of education. the report was voluntary and anonymous and the data collected during the morning shift from september to december have been compared to those collected from an external observer. in the studied period, healthcare staff reported ues: % collected by nurses, % occurred during the morning shifts and % were classified as moderate or severe. the rate of ue in the morning shift was ues per patient days. the external observer identified events in morning shifts with an incidence of ues per patient days. the violation of isolation rules for patient with multi-drug resistant bacteria infection both by icu staff and surgical consultant was the ue observed more frequently by the staff ( %) and by the external observer ( %). conclusions. the above data indicated that: . in our icu the incidence of ue is very high, particularly for compliance to isolation of infected patients and . the spontaneous reporting system under-estimated largely the real incidence of ues. introduction. importance of renal assessing in intensive care unit (icu) patients is unquestionable for a correct drug dosing, fluid requirements or decisions for renal replacement therapies. serum creatinine (sc) is a very common biochemical parameter in clinical practice for assessment of renal function. many equations have been designed to estimate creatinine clearance based on sc, but their capacities for providing a correct estimate of glomerular filtration rate (gfr) are suboptimal. this is even worse in critically ill patients due to malnutrition and/or immobilization. in clinical practice, despite its limitations, h-urine creatinine clearance (crcl h ) is used as a reference method to determine gfr. data show that cystatin-c could be promising as an endogenous filtration marker in icu settings. objectives. to assess in a medical icu population whether the arnal-dade formula of cystatin-c clearance (cc) developed from serum cystatin-c (scc) shows better predictive performance of gfr than sc-based formulae, as regards to patients' renal function: crcl h c ml/min . m or crcl h \ ml/min . m . results. all formulae showed notable bias from the reference method. interestingly, all equations based on sc-values clearly overestimated crcl h (cg: . %; mdrd: . %; fv-mdrd: . %), whereas cc showed underestimation of these crcl h (cc: - . %). in the crcl h c ml/min . m group (n c = ; patients), cc showed the best correlation indexes (cc-crcl h ; r = . , r = . ), the second most biased (- . %) and the worst precision ( . %). in this group, mdrd was the least biased (- . %) and the most precise ( . %). in the crcl h \ ml/min . m group (n \ = ; patients), cc was the worst correlated with crcl h (r = . , r = . ), in contrast to mdrd (r = . , r = . ). in terms of precision, mdrd showed again better results than cc: . % vs. . %, respectively. conclusions. in our icu population, cc did not demonstrate a clear improvement on the remainder sc-based formulae in either of the two groups according to crcl h . however, in a patient with high mdrd values and suspicion of low gfr, cc could be useful as guidance before obtaining the definitive confirmation by crcl h . introduction. there are well established and robust techniques for measuring and categorizing renal function in people with chronic kidney disease (ckd). a number of rapid bedside estimates of renal function have been devised incorporating routine daily measurements, such as serum creatinine, in combination with demographic data (e.g. cockroft-gault, the mdrd series). the addition of serum cystatin c measurements to some equations may also improve accuracy of estimation. the current and accepted categorical classification of acute kidney injury (aki: akin/rifle) has been useful epidemiologically but does not provide a continuously variable measure of severity of aki which would be valuable for both clinical management and research. objectives. previously published abstracts have suggested a role for egfr in describing renal function in the critically ill but a more comprehensive analysis was needed. methods. ( male) (mean age range - ) critically ill patients with aki were recruited. a h creatinine clearance ( crcl) (previously validated as a measure of renal function in critically ill patients) was measured and simultaneous blood sampling was done for creatinine, urea, albumin and cystatin c. various equations used to estimate gfr were compared to crcl with regression and bland-altman analysis. all patients had a crcl of\ ml min per . m introduction. epithelial-mesenchymal transition (emt), a key process in tissue development and repair, has also been identified as a major mechanism in fibrogenesis. the cytokine tgfb has been shown to induce transformation of epithelial cells into matrixforming and smooth muscle actin (sma)-expressing myofibroblast (mf) via emt. the other prerequisite is an injury-induced loss of intercellular contact, including adherens junctions (ajs). the classical experimental method to induce aj disruption is the uncoupling of e-cadherin-mediated contacts by low calcium medium (lcm). this concept has been termed as the two-hit model of emt ( ). b-catenin, a scaffold protein of the aj, released by cell contact injury, can act as a transcription factor and has been shown to facilitate emt. however, the mechanism whereby cell contact injury promotes emt is not understood. our recent studies have shown that smad , one of the main signal transducers of the tgfb pathway is a strong inhibitor of epithelial sma expression, by interfering with myocardinrelated transcription factor (mrtf) [ ] . the latter is the main driver of the sma promoter, through it association with serum response factor (srf). intriguingly, b-catenin can bind to smad . to clarify the mechanisms whereby aj injury promotes sma expression. methods. ajs were manipulated in kidney tubular cells, either by sirna-mediated downregulation of e-cadherin, b-catenin or through chemical uncoupling of ajs by lcm. protein expression was detected by western blotting and immunofluorescence microscopy, proteinprotein interactions were monitored by co-immunoprecipitation, and the activity of the sma promoter was determined by luciferase reporter assays. knockdown of e-cadherin promoted b-catenin translocation to the nucleus and induced a threefold rise in the tgfb-triggered sma expression. conversely, silencing of b-catenin strongly suppressed the two-hit (tgfb + lcm)-induced activation of the sma promoter, and inhibited sma protein and mrna expression by %. the same stimuli induced strong association of b-catenin with smad . transfection of cells with a b-catenin expression vector dose-dependently prevented the inhibitory action of smad on the mrtfinduced activation of sma promoter. moreover the active (myogenic) mrtf-srf complex was restored, as b-catenin preempted smad 's inhibitory effect on the complex. these studies define a novel mechanism whereby epithelial injury activates the myogenic program, a central process in organ fibrosis. our results imply that b-catenin, liberated from the injured ajs, facilitates the activation of the myogenic program by preventing or mitigating the inhibitory action of smad on mrtf. these hitherto unknown interactions among smad , b-catenin and mrtf represent novel targets to lessen fibrogenesis. introduction. in intensive care unit (icu) patients, kidney function is monitored by the creatinine clearance (crcl). it can be measured by two methods. urinary crcl (ucrcl) is directly measured, using the urinary and serum creatinine. but commonly crcl is estimated from serum creatinine (scr) alone, as estimated glomerular filtration rate (egfr); using equations validated in chronic kidney diseases. there is paucity of literature on validation and comparison of these methods in icu (hoste) . objectives. we compared -h timed ucrcl and egfr in the newly admitted critically ill. we also sought to ascertain the incidence of high crcl and the agreement between methods in this subgroup. conclusion. the use of rifle criteria gives a high incidence of aki in the icu setting. in this unselected population of critically ill pts, cysc seems to be superior to cre in predicting pts who will develop aki and will need rrt during their hospitalization in the icu. early identification of high risk patients may allow potentially beneficial therapies to be initiated early in the disease process, before irreversible injury occurs. introduction. the contrast-induced nephropathy (cin) is consider to be the most frecuence reason of acute renal failure in hospitalized patients. they are defined by a fixed increase ( . mg/dl) o a % rise serum creatinine level after to be exposed h to the contrast. the main complications are kidney and cardiac problems and this will lead to longer hospitalization and increased mortality. objectives. to compare cin occurrence after a injecting a iso-osmolar contrast (ioc, idixanol) or a low-osmolar contrast (loc, iohexol) to a group of patients submitted to coronary angiography, with o without percutaneous coronary intervention (pci). to establish unrelated cin markers and to evaluate the efficiency of the kidney protection protocol used in our hospital. conclusions. the loc was associated to a greater number of cin than ioc. patients who developed cin were significantly longer hospitalized. the use of point giving system that includes cin's predictors like dm, hematocrit \ %, ami, and treatment with diuretics helps us to classify cin risk and use a correct kidney protection protocol. introduction. the incidence of acute renal failure in the intensive care unit (icu) is around % of cases and is related to increase in mortality in patients who required dialysis as far as %. early detection of acute kidney injury (aki), after damage is not on set could be crucial to develop therapeutic strategies to modify the course of injury. blood and urinary concentrations of ngal are early biomarkers of aki ; to date, little information exists regarding ngal usefulness in critically ill patients. objectives. to analyze: . the capacity of urine ngal (ungal) to predict akievaluated by rifle score-in critically ill patients and, . the ungal values in patients with sirs, sepsis or septic shock. methods. ngal was measured in urine sample by an automatic analyzer device (architect ci Ò ; abbott diagnostics) at admission and h later in patients admitted to a general icu. patients were classified both by rifle score at admission and and h later and by ungal concentrations at admission. to the later classification, the cut-point for aki prediction was obtained by roc curve analysis. ungal values at admission were compared in patients with sirs, severe sepsis or septic shock. clinicians were blinded to ngal results. the study included consecutively-admitted patients ( female) with mean age . ± . years, and length of icu stay of . ± days. fifty-four sirs, severe sepsis and septic shock. thirteen patients developed rifle f score, of them at icu admission; extracorporeal renal therapies were required in cases. when patients were classified according to their rifle score at h of admission, ungal values at admission were: ( - ) ng/ml in patients with rifle , ( - ) ng/ml in with rifle r, ( - ) ng/ml in with rifle i and ( - ) ng/ml in with rifle f (p = . ). five patients were excluded, three died before h with ungal ( - , ) ng/ml and two were discharged before h with ungal ( - ) ng/ml. the area under roc curve of ungal at admission for aki prediction was . ( % confidence interval . - . , p \ . ), with an optimal cutoff value of ng/ml with % sensitivity and % specificity. forty-seven patients have ungal b ng/ml. ungal concentrations at admission were ( - ) ng/ml in patients with sirs, ( - ) ng/ml in patients with severe sepsis and ( - ) ng/ml in patients with septic shock (p = . ). conclusions. urine ngal concentrations measured at icu admission appeared as a useful predictor of aki in critically ill patients; in addition, ungal concentrations showed an increasing pattern from sirs to severe sepsis and septic shock. rd esicm annual congress -barcelona, spain - - october s introduction. two previous studies using the rifle criteria in intensive care patients have found the incidence of acute kidney injury (aki) to be and %. however, these studies used calculated basal value of creatinine in a considerable proportion of their patients, which is a possible source of error. objectives. the aim of this study was to investigate the incidence and severity of acute kidney injury in intensive care patients using true baseline creatinine values. objectives. the aim of this study was to define the status of hcy and b vitamins at admission and days of icu stay in critically ill patients, and to evaluate its relationship between them. a prospective study was done on critically ill consecutive patients with inclusion criteria: c years old, sirs and apache ii [ . hcy, b and folic plasma levels were measured by enzymoimmunoassay and enzymatic method. for b , b and b in erythrocyte. permission was obtained from an institutional ethical committee and written informed consent was asked. results. at and days of icu stay and % of patients were b deficient, respectively. and % were b deficient on both times, respectively. folic levels show significant differences between and days of icu stay. we found association between b vitamin and hcy at admission and days. no differences were found between and days hcy values. introduction. cytochrome p a (cyp a), the most abundantly expressed cytochrome p enzymes in liver, are responsible for the metabolism of over % of drugs used across several therapeutic classes. in adults, cyp a is represented primarily by the major isoform, cyp a , and a polymorphically expressed isoform, cyp a . individuals with at least one wild-type cyp a * allele synthesise functionally active enzyme while homozygotes for the * allele are functional non-expressers of the enzyme. the presence of functional cyp a increases the hepatic metabolism of cyp a substrates such as tacrolimus. ckd is known to reduce the hepatic metabolism of drugs via the cyp a enzyme system and we have shown, recently, that aki has a similar effect and that the length of time with aki is the most important variable. we hypothesise that expression of functional cyp a may reduce the impact of aki on hepatic drug metabolism as has been shown to be the case for drug interactions with the imidazole antifungals. methods. ( male) (mean age range - ) critically ill patients with no aki and varying degrees of severity of aki were recruited. midazolam concentration was measured h after intravenous administration as a probe-drug for hepatic cyp a / enzyme activity (t [midazolam] ). this is a validated method for testing cyp a activity in critically ill patients. patients were excluded if they were on any known cyp a / inhibitors. results. two patients with severe aki had unexpectedly high t [midazolam] . figure demonstrates the following: without a cyp a * allele, the rate of midazolam metabolism increased with duration of aki (r = . ; p \ . ) (solid line). patients who had at least one * allele (dashed line) were protected from the inhibitory effect that aki has on hepatic drug metabolism (significant difference between the correlation lines p = . ). if the two major outliers are removed (dotted grey line) from the * /* group (r = . ; p \ . ), the correlation lines remain statistically different (p = . ). conclusions. the presence of an allele which codes for functional cyp a protects critically ill patients from the inhibitory effect of aki on the hepatic metabolism of midazolam. thyroxine replacement therapy has become commonplace in the management of organ donors to reverse hemodynamic instability and homeostasis, yet the pharmacokinetics of thyroxine are unknown in this patient population [ , ] . since t is only available in oral form, we studied the pharmacokinetics of oral versus intravenous t to determine if oral administration is suitable. objectives. ( ) to study the pharmacokinetics of oral versus iv t therapy; ( ) to determine if oral thryoxine therapy is suitable. with ethics approval and signed consent from the substitute decision maker, patients who were determined to be neurologically dead and consented for organ donation, were randomized to receive either an oral or intravenous dose of t ( mcg/kg). all patients received an oral and iv preparation; one of which was a placebo. this study was also double blinded and randomization occurred in blocks of - . free serum levels of t and t were measured hourly until the time of organ procurement. the area under the curves (auc) were determined and compared using. results. there were patients ( males) in the oral versus patients ( males) in the iv group, with an average age of ± vs. ± , respectively. there was no significant difference at baseline or h between groups for hemodynamic variables, free t , free t or tsh levels. the only exception was map where it was higher at baseline in the oral group and there was a significant increase at h in the iv but not the oral group ( - vs. - in the oral). the auc for t was greater for the iv group ( pmol/l/ h) compared to the oral group ( pmol/l/ h). there was no statistically significant difference in any of the levels from to h between the oral and iv groups. oral bioavailability of t was %. conclusions. administration of iv t resulted in a slightly greater auc compared to oral administration. however, oral bioavailability of t in our population was very high, at %. t is currently the recommended thyroid replacement in neurologically dead organ donors. however, intravenous t is unavailable in many jurisdictions. iv t has been used as a substitute. our study shows that in this select population, oral bioavailability is high suggesting that oral t may be a reasonable alternative. further work is needed to determine whether there was a difference in the number and rate of organ retrieval in the oral versus intravenous groups. introduction. specific characteristics of metabolic derangements occurring in critical illness is domination of developing catabolic state particularly in acute necrotizing pancreatitis. as a result, we faced such a problem as developing a clinically apparent protein-calorie deficiency which is resistant to standard nutritional support. the treatment of acute necrotizing pancreatitis in chronic abuse patients is difficult to handle for the clinician and should include sufficient energoplastic supply. objectives. in our research we aimed to assess the efficacy of adding of ornithineaspartate complex in carbohydrate metabolism in chronic abuse patients with acute necrotizing pancreatitis. methods. comparable chronic abuse patients with acute necrotizing pancreatitis (control group n = , mean age . ± . ; ornithine group n = , mean age . ± . ) received early parenteral nutrition from the moment of admission to hospital with universal system ''three-in-one''. ornithine group also received ornithine-aspartate complex by parenteral administration ( g/day). on the second day the patients were admitted parenteral nutrition and tube feeding h/day. the volume of parenteral nutrition was gradually decreasing. biochemical and metabolic endpoints were measured at baseline and on th day (nitrogen balance, amino acids spectrum, plasma whole protein, transferring concentrations, glucose and insulin levels) at the clinical laboratory in all patients metabolic disturbances with protein status and carbohydrate metabolism shifts were revealed. dynamic of the whole protein, albumin/protein ratio and nitrous balance in both group showed similar tendency of metabolic improvement. dynamic of essential and nonessential amino acids concentration remained normal showing adequate energoplastic supply in both groups. glutamine concentration in ornithine group remained stable and even increased by the th day of nutritional support, while in control group glutamine concentration was decreasing, and by the th day of nutritional support it was below normal values. in ornithine group higher levels of endogenous insulin at normal values of glucose and faster fisher index improvement were detected. conclusions. administration ornithine-aspartate complex in therapy of acute necrotizing pancreatitis in chronic abuse patients, probably, may influence on disease outcome. in ornithine group duration of delirium tremens causes was ± days versus control group ( ± days). restoration of metabolic activities confirms adequate nutritional support in both groups but ornithine-aspartate complex adding provides faster improvement of protein and carbohydrate metabolism. objectives. this study was designed to evaluate the nutrition indexes including serum prealbumin level as prognostic indicators of patient recovery in critically ill patients with comparing severity scoring systems. we selected patients over years old, supplied with total parenteral nutrition (tpn) for more than days in surgical intensive care unit, ajou university hospital, suwon, korea. the serum prealbumin, albumin levels and total lymphocyte count were measured at the first, rd, , , , th days of nutrition support care by tpn. we checked apache (acute physiology and chronic health evaluation) ii score, saps (simplified acute physiology score), mods (multiple organ dysfunction score) and sofa (sequential organ failure assessment) score of patients. results. there were male patients and female patients with mean age . years. the mean day of sicu staying was . days. we compared two groups; survivor group (n = ) and non-survivor group (n = ). there were significant statistical differences in icu staying days (p = . ), apache ii score (p \ . ), saps (p \ . ), mods (p = . ) and sofa score (p = . ) between two groups. however, serum prealbumin level (p = . ), albumin level (p = . ) and total lymphocyte level (p = . ) did not showed significant difference between two groups. receiver operating characteristic curve showed low accuracy of serum prealbumin level as a prognostic factor (area = . ). prealbumin level showed correlation with albumin (r = . ), however did not show correlation with apache ii (r = - . ), saps (r = - . ), sofa (r = - . ) and mods (r = - . ). conclusions. nutrition indexes including prealbumin did not correlated with clinical outcome of critically ill patients. introduction. physical function is impaired following critical illness [ ] . anaemia is a common complication of critical illness and has the potential to influence physical function [ ] . it is not known whether anaemia affects the physical components of quality of life, the ability to carry out the activities of daily living (aodl) or the actual physical function of patients during recovery from critical illness. to determine the physical quality of life, ability to perform activities of daily living and actual physical function in a cohort of icu survivors dichotomised on the presence of anaemia at months following icu discharge. one other organ failure were recruited from a general icu population. patients with a preexisting haematological condition were excluded. baseline and characteristics of icu stay were recorded. the patients were assessed with the sf- quality of life questionnaire (pcs), the frenchay activities index (fai) of aodl recalled for pre-morbid status and at and months, and the min walk test ( mwt) for actual physical function at and months following discharge from icu. organotopic measures of haemaglobin, creatinine, serum c-reactive protein and albumin concentration were also recorded. the results were dichotomised on the presence of anaemia at months for statistical analysis. baseline characteristics were compared with student's t test. a way anova was performed on the pcs and fai score as well as comparisons with t test between each time-point. the distance walked as part of the mwt was compared with mann-whitney u test. patients who remained anaemic at months were older, had a longer icu stay and had a greater requirement for inotropes during their icu stay. the pcs score of quality of life and the fai score was significantly impaired in both groups during follow up, but there was no effect of anaemia. the results of the t tests showed that there was a significant difference between the groups at months for pcs but not for fai scores. the distances walked were severely impaired compared to the normal population ( and m at and months for anaemic group and and m for non-anaemic) in both groups was not significantly different between the two groups. the non-anaemic group did increase the distance walked significantly from to months. there was no difference between albumin, crp and creatinine concentrations between the groups. methods. this experiment was divided into two procedures. the first procedure is to choose two kinds of cell strains, including jurkat cell strain (comes from leukemia) and ccrf-cem cell strain (comes from acute lymphocyte leukemia).we cultivate this two kinds of cell strains to mature stage, then inoculate every kind of cell strain into four culture dishes, two culture dishes was stimulated by lg/ml lipopolysaccharide(study group), and the other two culture dishes serve as blank control(not stimulated by lg/ml lipopolysaccharide). eight hours later, we extracted the microrna in each culture dish. the second procedure is to use the technique of gene microarray to analysis the difference expressions of microrna. in the context of a high altitude expedition human subjects can safely be submitted to prolonged hypoxia and the resulting changes in mitochondrial function can be explored in a controlled fashion. the effect of hypoxia on immune cells-key players in the pathophysiology of sepsis-is of particular interest. to measure mitochondrial function of monocytes during prolonged hypobaric hypoxia. methods. serial blood samples were collected and oxygen saturation was measured in twelve climbers before and throughout a high altitude climbing expedition to pik lenin ( , m). measurements were performed at m (baseline) and at the altitudes of , m (day ), m (day ) and , m (day ) above sea level. pure monocytes were isolated by the use of an antibody-antigen mediated immunomagnetic cell isolation procedure and lysed for determination of activities of mitochondrial enzymes cytochrome c oxidase and citrate synthase. repeated measurements anova followed by least significant difference (lsd) post hoc test were used to compare results on different altitudes. mean oxygen saturation was ± % on , m, and decreased to ± % on , m and ± % on , m (p = . ). we observed an increase in citrate synthase activity on all altitudes compared to baseline levels (p = . ). compared to the baseline, prolonged hypobaric hypoxia induced an increase in the mitochondrial respiratory chain enzyme cytochrome c oxidase enzymatic activity only at , m (p = . ). normalization of cytochrome c oxidase enzymatic activity by citrate synthase activity (relative enzymatic activity) yielded a decrease in relative cytochrome c oxidase enzymatic activity during hypoxia on , and , m (fig. ) . expressing cytochrome c oxidase enzymatic activities as a ratio to citrate synthase is intended to act as a safeguard for potential differences in mitochondrial enrichment. conclusions. the data demonstrates that prolonged hypobaric hypoxia leads to a decrease in relative cytochrome c oxidase activity. this is due to an increase in citrate synthase activity as a marker enzyme for the mitochondrial matrix representing mass and/or number of mitochondria which is not counterbalanced by a corresponding increase of cytochrome c oxidase activity. results. glycocalyx degradation was increased in the lps-treated animals ( . lm, p \ . ) compared to controls. intracellular tissue no concentrations were two-to threefold higher in the lps-treated mice compared to controls (liver, kidney, heart, gut). the number of infiltrating mpo-positive cells increased significantly during endotoxemia. levels of both plasma arg and cit were significantly lower in lps-challenged mice than in controls, whereas plasma ornithine levels were significantly higher. conclusions. in this new developed murine sepsis model, the prolonged infusion of lps resulted in increased glycocalyx degradation and associate endothelial leakage. the enhanced no levels correlated with decreased plasma levels of arg and cit. our murine model with prolonged infusion appears applicable as a model for the human clinical situation, enabling adequate investigation of the influences of the arg-no metabolism on endothelial dysfunction in sepsis. critical illness polyneuromyopathy is a muscular weakness occurring in intensive care unit. one of the major risk factor is sepsis. an early decrease in membrane excitability was described [ ] but corresponding mechanisms are imperfectly known. tnfa is released in the first time of sepsis and could be involved in the physiopathology. objectives. the aim of our study was to investigate tnfa effects on muscular voltage gated sodium channels (nav) in an in vitro model. early effects of tnfa on nav were analysed by macro-patch clamp on muscular fibers isolated from rat peroneus longus. measurements were performed on control fibers and after addition of tnfa at concentrations ranging from . to ng.ml - . the effects of chelerythrine, a specific inhibitor of protein-kinase c (pkc), were also tested. experimentations were realised in a laboratory with permission of experimental research on animals and under the supervision of an authorized person (no - ). tnfa produced a concentration-dependant inhibition of nav currents (fig. ) . maximal inhibition ( % of control current) was observed with concentrations from ng ml - and above. this decrease was fast: % of maximum inhibition was observed in less than min. moreover, chelerythrine inhibited tnfa action on nav. conclusions. in our experimental model, tnfa induce a rapid and concentration dependant decrease of muscular nav currents like observed in chronic sepsis [ ] . as this effect is too quick to be a transcriptional one, and as it is blocked by chelerythrine, it can be assumed that tnfa action is mediated by a nav phosphorylation secondary to pkc activation. in conclusion we evidenced that tnfa reduce muscle excitability in the early stages of sepsis. further studies are needed to obtain a precise description of tnfa mechanisms. may also contribute to cell signaling and regulation of the immune response. nad(p)h oxidase in leukocytes and the vascular wall is a major regulated source of o . we hypothesized that mice deficient in the p phox (ko) component of nad(p)h oxidase would have less pulmonary inflammation than wild type (wt). we treated wt or ko mice with iv saline or lps and assessed lung injury by: . wet-dry-weight ratio; . leak of evans blue (eb) labeled albumin; and . histological score for edema. we used myeloperoxidase activity to indicate neutrophil (pmn) accumulation in lungs, and measured accumulation of macrophages and neutrophils in bronchial alveolar lavage (bal). apoptosis was assessed by tunnel staining. we also expression of icam- , an adhesion molecule, and nitric oxide synthase (nos) enzymes, enos and inos (western and northern analysis) as well as nitrotyrosine formation. results. lung injury was increased in both groups. surprisingly there was greater eb leak in ko than wt at h and a greater edema score at and h. pmn and macrophage accumulation in bal were the same in both groups at h but greater in ko mice at h. myeloperoxidase activity was similar at h post lps in ko and wt indicating that similar accumulation of pmn in the lungs. apoptosis was increased in both groups at h, but resolved in wt at h and persisted in ko. nitrotyrosine was increased in both groups but appeared higher in ko. expression of enos and inos increased in both groups but was greater in ko than wt. conclusions. in contrast to our prediction, lung injury was greater in p phox ko mice which indicates that this complex is not essential for lung injury. however, the injury was more severe and prolonged in ko mice indicating that o may regulate the inflammatory response. introduction. septic shock remains the main cause of mortality in the icu, thus a persistent challenge. recently, dna and mrna analysis by microchip and gene expression by real time pcr highlighted proteins s a , s a and their complex, known as the calgranulins, as potential key prognostic markers for this disease: those two proteins, whose expression seems to be restrained to phagocytes cells are newly recognized components in sepsis-induced inflammation. moreover, they were shown to be at significantly higher concentrations in the plasma of septic shock patients that were going to die. in the contrary, those who were to survive saw their plasmatic concentration decrease, all severity scores in between the population being the same. objectives. the aim of this study was to determine the repartition of these proteins in immune cells, their intracellular variation, at baseline and after cell activation and finally to understand the relation between their intracellular and extracellular expression. we used an in vitro model close to the immuno-inflammatory aggression that is septic shock. we stimulated in vitro for , and h whole blood from healthy volunteers using agonists found in the inflammatory storm that is septic shock (lps, fmlp, gmcsf, ifng). we also induced death cell, either using an apoptotic agonist, or by necrosis technics. we then analysed the intracellular variation of the calgranulins using flow cytometry technics. the extracellular quantification was made using elisa methods. all the statistic analysis were made using a mann-whitney test. we showed in this work for the first time that the intracellular repartition of the calgranulins is different depending on the type of cell: the complexe is the main form in the monocyte cytoplasma, whereas s a is the main intracellular form of the pmn. this repartition remains after cell activation. we also checked the absence of calgranulins in lymphocytes. after cell activation we showed that intracellular s a , s a and s a a increased, but at different levels depending on the cell and the agonist used. extracellular s a also raised after cell stimulation, but the concentration found were very low compare to those found in the plasma of septic shock patients. conclusions. together, these results suggest a different regulation depending on the form of the protein and of the cell and thus of proper distinct function of each monomer and of the complex. in the limits of our model the increased concentrations found in the plasma of patients with a septic shock can't be explained by immune cell activation. objectives. although there is no specific antidote for these potent toxins, drugs like penicillin g and silibinin have been used with conflicting evidence. we successfully managed two patients with mushroom poisoning by using silibinin and nac. methods. two members of a family, a mother years old, and her son years old were admitted to our icu h after the ingestion of wild mushrooms. they presented with abdominal cramps, vomiting, profuse diarrhea ([ /day), myalgias, confusion and agitation. the clinical examination showed severe dehydration, tachycardia, oliguria with grade i-ii hepatic encephalopathy. laboratory exams revealed elevation of liver enzymes sgpt: / u/l, sgot: / u/l. coagulation parameters were as following: prothrombin time . / . , factor v \ %/ %, factor vii \ / %. high ammonia levels were noted, reaching and ng/dl, respectively. metabolic acidosis was also present with mild renal dysfunction. the ultrasound performed in both patients showed hepatosplenomegaly. aggressive fluid and electrolyte replacement started upon admission. silibinin was given at a dose of mg/kg/day intravenously, in four divided doses, for three consecutive days, while nac was given as a continuous infusion at a dose of mg/kg for the first hour, mg/kg for the next h, and thereafter mg/kg/day for the following four days. hepatic encephalopathy, mild jaundice and renal dysfunction resolved within h, and liver function tests returned to normal within days. the patients recovered fully and were discharged to a medical ward. recent experimental and clinical studies have shown a strong protective and antioxidant effect against hepatic cell injury in amanita toxicity by the administration of nac and silibinin, either as monotherapy or as a combination therapy. although further clinical research is required to confirm their efficacy in reducing mortality and transplantation rate, nac has been used in our icu in hepatic dysfunction of different etiologies with promising results. we have recently shown that in patients with lactic acidosis due to metformin intoxication (serum drug level = ± lg/ml; therapeutic level is b lg/ml) systemic oxygen consumption (vo ) can be abnormally low despite a preserved global oxygen delivery (do ) ( ). the study, however, suffered from being retrospective. objectives. to prospectively clarify whether metformin primarily impairs vo . methods. eight sedated, paralyzed and mechanically ventilated pigs received a continuous i.v. infusion of metformin, at a rate of . g/h. the amount of metformin administered to each animal ranged from and g. the experiment always finished h after the initiation of drug infusion. use of sedative and neuromuscular blocking drugs, as well as ventilatory setting, were always kept constant. serum metformin concentration was measured at the end of the experiment, using high performance liquid chromatography (hplc). arterial ph, lactatemia, vo (indirect calorimetry) and do (computed from cardiac output measured by pulmonary artery thermodilution) were recorded hourly. data are presented as mean ± sd. statistical testing was performed using the one-way repeated measure anova and the linear regression analysis. metformin infusion produced toxic serum drug levels ( ± lg/ml; n = ). arterial ph drop from . ± . (prior to infusion) to . ± . (end of the experiment) (n = ; p \ . ) and lactatemia rose from ± to ± mmol/l (n = , p \ . ). vo progressively decreased (from ± to ± ml/min; n = , p \ . ) while do did not significantly change over time (from ± to ± ml/min; n = , p = . ). the decrease in vo was proportional to the dose of metformin administered (r . ; n = , p = . ) and to the serum drug level reached by the end of the experiment (r . ; n = , p = . ). conclusions. lactic acidosis develops during metformin intoxication in the presence of a diminished vo but in the absence of any clear evidence of inadequate do . this finding suggests that impaired oxygen utilization, rather than availability, may have a role in the pathogenesis of metformin-induced lactic acidosis. : min) . death was consequent to multiorgan failure, anoxic encephalopathy or capillary leak syndrome if ecls was performed under cardiac massage. four patients presented with documented brain death, allowing organ donation in cases. among these patients, the heart of one flecainide-poisoned patient was successfully transplanted, after normalization of ecg and myocardial function as well as toxicant elimination under ecls. prognostic factors in ecls-treated poisoned patients were as follows: qrs enlargement on admission (p = . ), saps ii score on admission (p = . ), ecls performance under massage (p = . ), arterial ph (p \ . ), lactate concentration ( . [ . - . ] versus . mmol/l [ . - . ], p = . ), as well as red cell (p = . ), fresh plasma (p = . ), and platelet (p = . ) transfusions within the first h. conclusions. to our knowledge, this is the larger series of ecls-treated poisoned patients ever reported. ecls appears to be an efficient salvage technique in case of refractory toxic cardiac failure or arrest, with a % survival rate. our series clearly demonstrate that toxic refractory cardiac failure remains the best indication with a % survival rate. objectives. aim of the study was to investigate the incidence of infections in patients treated with hypothermia while receiving sdd. in this retrospective case control study patients treated with prolonged hypothermia (cases) were identified and patients with severe brain injury were included (controls). propensity score matching was performed to correct for differences in baseline characteristics and clinical parameters. primary outcome was the incidence of infection. the secondary endpoints were the micro-organisms isolated from surveillance cultures and during infection. the demographic and clinical data indicated that the cases and controls were well matched. the length of stay in the icu and duration of mechanical ventilation were comparable between the groups. the overall risk of infection during icu stay was % in the hypothermia groups versus . % in the normothermia group (p = . ). pneumonia was diagnosed in . % of patients in both groups (p = . ). the incidence of meningitis, wound infection, bacteremia, and urinary tract infection was low and comparable between the groups. staphylococcus aureus was most frequently identified as the causative infectious microorganism in both the hypothermia ( . %) and normothermia ( . %) group (p = . ), followed by coagulase negative staphylococci ( . % in the hypothermia and . % in the normothermia patients, p = . ) gram-negative bacteria were isolated from the surveillance cultures in . % of patients treated with hypothermia and . % of patients in the control group (p = . ). colonization of the rectum with gram-negative bacteria was significantly more frequent in patients treated with hypothermia compared with normothermia ( . vs. . % respectively, p = . ). in contrast, colonization of the upper gastrointestinal tract and sputum was comparable between the groups with an incidence of . % in the hypothermia patients versus . % in the normothermia patients (p = . ). use of sdd mitigates the increased risk of infection in patients treated with hypothermia. based on the surveillance cultures, it seems that oropharyngeal decontamination is the most effective part of the sdd regimen in the prevention of pneumonia. introduction. prognostic scores specific for critical patients were developed in order to predict mortality based on physiologic and laboratorial variables. on the other hand, specific scores for burn patients are calculated taking into consideration inhalation injury, age and total burned surface area (tbsa), among others. however, scores utilized in general icu have not been evaluated in burn patients. objectives. therefore, the aim of the present work was to validate apache ii, saps as well as initial sofa in a population of patients with massive burn. these scores were compared to some specific burn patient scores, including absi (abbreviated burn severity index) and estimates of the probability of death. retrospective study employing data collected prospectively from may to february ( months) at an icu specialized in burn patients at a teaching hospital which is considered a reference centre in trauma care. all patients admitted during this period were included. one hundred and fifty-four consecutive patients were studied (male: %; female: %), with averaged age of . ± . years and a hospital stay of . ± . days. mortality rate of our sample was . %. incidence of inhalation injury was % and total burn surface area (tbsa) was the following: . % of patients had % or less; . % had - % of tbsa whereas . % showed % or more. area under curve of receiver operating characteristic (roc) of evaluated indexes is displayed on table . computerized head tomography is routinely performed as a diagnostic tool after the occurrence of neurologic deterioration in the icu adult patients. however, the ct findings in this setting are rarely reported. we hypothesized that the analysis of a series of cranial cts would help to understand the neurologic conditions of the critically ill patients and improve their management. objectives. to analyze, over a three-month period, the head ct scans performed in the adult icu in the albert einstein hospital in são paulo, brazil. methods. all cranial cts performed in the icu patients during the studied period were analyzed by two radiologists from the albert einstein hospital staff from may st to august st, , according to a pre-established protocol: . presence of acute cerebral ischemia; . presence of previous cerebral ischemia; . presence of acute cerebral hemorrhage; . presence of cerebral edema; . cerebral aneurisms; . cerebral tumors and . normal cerebral tomography. we studied ct scans from ( . %) males and ( . %) females, mean age . ± . years. the head ct findings were the following: ( ) presence of acute cerebral ischemia = ( . %); ( ) presence of previous cerebral ischemia = ( . %); ( ) presence of acute cerebral hemorrhage = ( . %); ( ) presence of cerebral edema = ( . %); ( ) cerebral aneurisms = ( . %); ( ) cerebral tumors = ( . %) and ( ) c years c , abc (assessment blood consumption) cp: c and ets (emergency transfusion score) cp: c , c years c . these scales handle the following combinations of variables for calculation: age, sex, type of admission, mechanism, blood pressure, focussed assessment for the sonography of trauma, hemoglobin, orthopedic or pelvic trauma, heart rate. mt was defined as the transfusion of units or more of packed red blood cells in the first h. we study the sensitivity (s), specificity (sp), positive and negative predictive value (ppv, npv), likelihood ratios positive and negative (lhr+ , lhr-) and area under the receiver operating characteristic curve (auroc) of different scales for the predictive power of tm validated in the literature. patients were available for analysis ( . % men, iss ± , blunt trauma . % objectives. we measured patient-reported outcome following surgical management with dc using a quality of life instrument. methods. survivors discharged between and months after severe tat were contacted after obtaining approval by our institutional irb. we excluded patients with neurotrauma. we applied self-response version euroqol questionnaire (eq- d) and visual analog scale (eq-vas: (worst health)- (best health). euroqol it is based on a descriptive system that defines health in terms of dimensions: mobility, self-care, usualactivities, pain/discomfort and anxiety/depression. each dimension has levels of response: no problems (level ), some problems (level ) severe problems (level ). results. thirty four patients were contacted. mean ± sd age was . ± . yrs, male were . % and penetrating trauma occurred in . %. mean ± sd in severity scores were: ati . ± . , iss . ± . and apache ii ± . the median time from discharge was months (iqr - months). the eq- d dimensions in which the largest proportion of patients reported severe problems were usual-activities (work, study) and pain/discomfort . % and . % respectively as shown in the conclusions. survivors of severe trauma and dc, reported acceptable quality of life with minimal limitations with social functioning. a prospective study should assess quality of life in these patients from hospital discharge and systematically over time. introduction. brain tumors surgery is one of the main causes of admittance to the nicu. it is important to know the risk factors associated to hospital mortality of patients admitted to nicu due to this reason. to identify perioperative factors associated to higher hospital mortality in a series of patients admitted to nicu immediately after a bt elective resection. methods. data of patients operated for bt elective resection and consecutively admitted to nicu at imss umae bajío were prospectively obtained. nicu bt database includes perioperative items. we divided the series in two groups: surviving and deceased patients. then, we analyzed the perioperative behavior differences between both groups. either student's t test or chi-square test was used, as it corresponded, for the analysis of differences observed between both groups. values of p lower than . were considered significant. results. the hospital mortality observed in this series of patients was . % ( / ). data of the nine variables showing significant differences between surviving and deceased patients groups are shown in table . even if hypoxic brain injury has been reported as the strongest factor affecting the poor outcome of near-drowning patients, little has been known about prognostic factors affecting the outcomes of those patients receiving mechanical ventilation. to define prognostic factors affecting the outcomes of patients mechanically ventilated after near-drowning. , white blood cell counts (or, . ; % ci, . - . ; p = . ), serum creatinine (or, . ; % ci, . - . ; p = . ), and serum lactic acid (or, . ; % ci, . - . , p = . ) were associated with favorable outcomes, respectively. however, only higher body temperature as a clinical parameter and the level of serum lactic acid as a laboratory parameter were significant predictors of favorable outcomes in multivariate analyses; the or were . ( % ci, . - . ; p = . ) and . ( % ci, . - . ; p = . ), respectively. conclusions. initial body temperature and the level of serum lactic acid were two most important clinical and laboratory prognostic factor in nearly drowned patients. the outcomes were not affected by the degree of initial hypoxemia. to determine the use of automated external defibrillators (aed) and manual defibrillators deployed in the various hospital wards (unmonitored areas) in a university hospital. a prospective study was performed according to utstein style of all cardiac arrests occurred in the hospital during the first months after the implantation of a new protocol of care for hospital cardiac arrest. because of this plan automated external defibrillators were located for hospital wards and common service areas (radiology areas, outpatients, …) where one would expect a lower incidence of cardiac arrests, according to the risk map elaborated previously. in areas of greatest risk manual defibrillators previously existed. all resuscitation attempts in these areas were analyzed, excluding the emergency department because of a separate protocol against the rest of the hospital. special attention was given to the use of aeds by wards staff before the arrival of resuscitation team. also a comprehensive volunteer training program was designed, but it began after the analyzed period was finished. results. during the first months we collected a total of pcr in hospital wards and public areas, with a median age of years and predominantly male ( patients). the most common origin was respiratory ( patients) followed by cardiac ( patients). the most frequent rhythm detected was non-shockable ( patients), only in was shockable and unknown in . before the resuscitation team arrival only two patients had been manually defibrillated and were never used the new aeds. conclusions. the aeds provided in the hospital were completely useless in the first months after placement, probably due to the lack of a comprehensive training plan associated to the population goal. methods. descriptive longitudinal study. patients were studied by encephalic death, as potential donors of organs, alerted to the network of regional transplant (cdtot), by units of intensive care, for months, in barranquilla's city. it was applied qualifying each of the variables in agreement to the vital opposing signs and biochemical tests brought in this moment. . . % of the subjects were male; the average of age was . years (±sd: . ). the values of blood sugar, sodium, osmolaridad, tonicidad, po , fc, pam, and glasgow, determined a score of , qualification that there had patient with encephalic death with the scale mbcm, as a test of certainty of the scale to diagnose encephalic death in total absence of reflections of stem. conclusions. there is recommended the application of mbcm's scale to every neurological patient by diagnosis of encephalic death in proof of certainty, in absence of others. by the high specificity of the already demonstrated scale there is recommended that scores lower than they should restate the qualification. a score of is an encephalic death in absence of reflections of stem. grant acknowledgment. clínica general del norte-cdtot introduction. prospective analysis of tracheostomies performed in patients admitted to a neurotrauma icu, the reasons for its implementation, and intraoperative complications in the first week. methods. all patients admitted to the icu of neurotrauma, which underwent a tracheostomy after admission. data were collected: affiliation, cause of admission, average stay, cause for realization of tracheostomy, tracheostomy time delay from its indication, place of performance of the procedure (icu or operating room), perioperative complications (event at transfer to operating room or during surgery: hypoxia, hypotension, arrhythmia, bleeding, premature extubation, false cannulation, cardiac arrest, pneumothorax or death), and postoperative complications in the first week (bleeding, difficulty in changing cannula, stomal infection, pneumothorax, death). introduction. the s- b protein is a brain-specific protein release from astroglial cells into the circulation after traumatic brain injury (tbi). researches indicate that the s- b serum level could be a useful indicator of tbi severity, however there is not evidence enough about the role of s- b in nonsevere head trauma. the hypothesis that s- b is a useful screening tool to detect brain injury in patients with a normal level of consciousness after a head trauma was tested. a total of patients with the diagnosis of mild tbi without decrease of consciousness (according to the gcs) with at least one neurological symptom or finding like amnesia, headache, dizziness, convulsion and vomits, were prospectively included. we recorded the clinical data on admission and a blood sample before h after tbi, for s- b inmunoluminescence analysis. a routine cranial computed tomography scan (ct) was obtained within h after the injury (categorized in normal or pathological). the diagnostic properties of s- b serum levels. lg/l, for prediction of intracranial lesions revealed by ct were tested with receiver operating characteristic (roc) analysis. seventy of the patients ( . %) were men, with a mean (sd) age of . ( . ) years (range, - years). a total of patients ( . %) had intracranial lesions. serum s- b levels were significantly higher in patients with intracranial lesions than in the remaining patients. the average value of the protein in patients without intracranial lesion was . lg/l with a ci % ( . - . lg/l), and in those with pathological findings in ct was . lg/l with a ci % ( . - . lg/l). significant differences were found between levels of s b protein and the presence of pathological findings in the ct (p = . ) (fig. ) . the roc curve analysis showed that s b protein is a useful tool to discriminate the presence of intracranial injury in ct (auc, . , % ci, . - . , p \ . ). s b analyses with a cut-off level of . lg/l showed a sensitivity % but a specificity . %. we evaluated different cut off values and in our series, the best cut off of the s b protein is at . lg/l with a sensitivity of % and specificity %. (fig. ) conclusion. determination of serum protein s- b is a useful biochemical indicator of brain damage in head trauma. our results show that an increase in the cut-off point of s- b to . lg/l increases its accuracy in the prediction of the existence of macroscopical lesions. key words. protein s- b, brain injury, minor head trauma, cranial computed tomography. critically ill patients with systemic inflammatory response syndrome frequently suffer muscle weakness due to critical illness myopathy (cim) and polyneuropathy (cip). several in vitro studies have shown that the cause of muscle weakness is a loss of membrane excitability accompanied by membrane depolarization [ ] . objectives. we investigated membrane polarization and excitability parameters in muscle and motor nerve in vivo within the first week after intensive care unit (icu) admission. methods. the study was approved by our local ethics committee. patients with sofa scores c on consecutive days underwent nerve conduction studies including direct muscle stimulation to categorize patients as icu-control, cim-(dmcmap \ mv) and/or cippatients (reduced snap amplitude) within the first days after icu admission. to assess excitability parameters we recorded stimulus-response behaviour, threshold electrotonus, current-threshold relationship and recovery cycle from abductor pollicis brevis muscle following stimulation of the median nerve [ ] . data are shown as median and %/ % percentile. conclusions. we describe for the first time that critically ill patients in general show muscle-and nerve membrane depolarization, whereas patients later suffering from muscle weakness due to cim or cim/cip feature additionally reduced membrane excitability. this suggests that membrane depolarization in critically ill patients is caused by energy failure leading to dysfunction of the na-k pump, the motor of membrane repolarisation-whereas reduced membrane excitability in cim or cim/cip needs an additional dysfunction of voltage gated sodium channels for example occurring in the presence of endotoxins [ ] . in intensive care patients with central nervous system (cns) disease, the systemic inflammatory response syndrome (sirs) criteria are often unreliable as a basis for identifying the inflammatory process. even with the presence of some infection they could be signs of the diencephalons-catabolic syndrome. diencephalons-catabolic syndrome like sirs constitutes of hyperthermia over °c, tachypnea of over per minute, tachycardia, and arterial hypertension. thus, sirs symptoms may occur after antibacterial treatment even if there is no infection or inflammation. we suggest a more precise method which could help to avoid the excessive antibacterial therapy and to control it in patients with cns disease-a procalcitonin test. objectives. reduce the use of wide specter antibiotics makes the control over antibacterial therapy in patients with cns diseases more precise; reduce the number of complications related to unnecessarily long antibacterial treatment. after obtaining the informed concern, in our investigation we included patients with different neurological disorders, who had recently transferred neurosurgical operations. all of them demonstrated sirs symptoms on different postoperative terms. when sirs symptoms occurred, we checked the level of procalcitonin in the patient's serum by a semi quantitative method on a disposable brahms pct-q system. the procalcitonin level was determined against a color scale. procalcitonin level over . ng/ml ( patients) considered a sign of infection and in such cases we prescribed antibacterial treatment , mg of selenase for - days. if the test result was negative ( patients) we repeated it in h and in cases with the same results, no antibacterial treatment was administered even if there were sirs symptoms. if pct-q test was negative patients were sedated (fentanyl . - . lg/kg/h and clonidine . - . lg/kg/h) to achieve autonomic stability and attenuate clinical manifestation of sirs. we had not observed any cases of sepsis in both groups of patients. by mince of pct, we had managed to reduce the quantity of wide specter antibiotics, used in neurosurgical patients for . %. conclusions. procalcitonin test in neurosurgical clinic let us determine the necessity of antibacterial treatment reduce the use of wide specter antibiotics, medical costs and prevent the forming of polyresistant infection. l. combe , r. appleton , c. gilhooly , j. kinsella university of glasgow, department of anaesthesia and critical care, glasgow, uk intensive care unit-acquired weakness (icuaw) is increasingly recognised as a common complication of critical illness with potentially prolonged debilitating sequelae. the estimated incidence is % in patients with sepsis, multi-organ failure or prolonged mechanical ventilation [ ] and suggested risk factors include: the systemic inflammatory response syndrome (sirs), sepsis, higher severity of illness, hyperglycaemia, renal replacement therapy and parenteral nutrition. objectives. the aims of this study were to determine the incidence, risk factors and outcomes for patients diagnosed with icuaw in glasgow royal infirmary's (gri) icu. the study was undertaken in two parts, firstly as a case-control study [matched for age (within years), sex and admission apache ii score (within points)] and secondly by comparing identified cases of icuaw to a -month cross-sectional sample ( / / - / / , patients) of gri's icu patients. data for both parts of the study was obtained from two electronic databases, wardwatcher and carevue. carevue was searched to identify patients with icuaw and wardwatcher was used to identify the controls. data collected included: patient and illness characteristics, severity of illness scoring, organ support and treatments provided, laboratory results and outcomes. minitab software was used for statistical analysis. conclusions. the incidence of icuaw was very low, we hypothesise this to be explained by the absence of systematic evaluation of patients for icuaw. the risk factors and outcomes for icuaw were consistent with some of the published literature. prospective study is now planned to systematically evaluate this condition. with increasing age, comorbidity, and socioeconomic deprivation being associated with higher risk pregnancies, there comes a potential higher risk of complications. neurological and neurosurgical complications, which can be particularly devastating during the peripartum period, include those due to medical conditions of pregnancy (hypertensive disease, sepsis, thromboembolic disease, hypoxic-ischaemic brain injury), iatrogenic complications secondary to anaesthetic or obstetric interventions, incidental illness or injury (pharmacological alterations, trauma, tumour), and deliberate self-harm and violence. objectives. to ascertain the frequency of neurocritical care admissions in the west of scotland, the nature of the admission diagnoses, the impact they have on our service (length of stay), and maternal and foetal outcome. methods. using the scottish intensive care society audit group wardwatcher patient database, female patients aged - years old who were admitted to the neurocritical care unit were identified (january -december ). we manually reviewed the electronic admission note for each of these women in order to gain diagnoses; a targeted case note analysis ensued. within the month study period there were a total of admissions to neurocritical care, of whom fulfilled the age and gender criteria; admissions ( . % of total) were for neurological complications in the peripartum period. the age range was to years (median years). three women ( %) were intrapartum ( - weeks gestation) at the time of their admission, and three were postpartum ( day- months). half of admissions were due to incidental illness or injury, a third to pregnancyrelated medical complications, and one case was iatrogenic in nature. length of stay in icu was to days (median . days). one patient sustained a residual facial nerve weakness and deafness. conclusions. this survey provided insight into the incidence and nature of pregnancyrelated pathology requiring acute referral to a regional neurosciences centre. as highlighted in other surveys, there may be many more peripartum patients with neurological complications who are cared for in general critical care units, and do not require admission to a tertiary referral centre [ ] . further work is underway to ascertain the true numbers of neurological complications of pregnancy countrywide. our approach represents a paradigm for the continuing audit of pregnancy-related critical care resource use in scotland. introduction. hypertonic saline has an osmotic effect on the brain because of its high tonicity and ability to effectively remain outside the blood-brain barrier. there may be a minimal benefit in restoring cerebral blood flow, which is thought to be mitigated through local effects of hypertonic saline on cerebral microvasculature. most comparisons with mannitol suggest almost equal efficacy in reducing icp but not compared their effects on eeg. objectives. we aimed to compare the effects of % mannitol, % or % hypertonic saline on hemodynamic parameters, intracranial pressure and electroencephalography in experimental head trauma. bilateral craniotomy were carried out in the parietal region and head trauma was applied for all rabbits. the rabbits were randomly divided into four groups. in group i rabbits were only observed. in group ii: % mannitol, in group iii: % hypertonic saline and in group iv: % hypertonic saline was administered intravenously to achieve similar osmolar load. electroencephalography, mean arterial pressure, heart rate, intracranial pressure were recorded before trauma and and min after trauma. results. increased intracranial pressure was significantly decreased by mannitol, and % hypertonic saline solutions at the end of study (p \ . ). but intracranial pressure values of mannitol and % hypertonic saline groups were lower than the other groups (p \ . ). the electroencephalography scores decreased after trauma in all groups (p \ . ). at end of the study, and % hypertonic saline groups had similar electroencephalography scores with pretrauma scores (p [ . ). the mean arterial pressure and heart rates increased after trauma in all groups (p \ . ). mean arterial pressure values were found lower only in mannitol group at end of the study (p \ . ). our study showed that when used in intracranial hypertension treatment, % hypertonic saline solution is as effective as mannitol, and preserves hemodynamic parameters, and normalizes traumatic electroencephalography abnormalities better than mannitol. objectives. to identify the causes of new onset seizures in patient admitted in medical icu. methods. all the patient admitted in icu and who had new onset seizures were evaluated. the patients were evaluated for metabolic profile. imaging (ct/mri) was done whenever needed. patients with preexisting seizure history were excluded from study. . ( males, females) patients, who had first seizure during hospitalization in icu were included. patients had generalised and one had focal seizures. patients had metabolic abnormalities. ( . %) had evidence of hepatic encephalopathy. ( . %) had only hepatic encephalopathy while rest had associated uremia, hyponatraemia, hypophosphatemia and hypomagnesemia. out of patients, who had renal failure, had evidence of uremia while rest had associated hyponatraemia or hypophosphatemia. only one patient had evidence of hypocalcemia. imaging was done in patients. ( %) had abnormal ct scan results. ( . %) had intracranial hemorrhage, ( . %) had infarct, ( . %) had brain metastasis, had evidence of hydrocephalus and one each had evidence of extradural hemorrhage and tuberculoma. csf analysis was done in ( . %) patients. ( . %) had evidence of tuberculosis and ( . %) had evidence of pyogenic infection. to study the role of various investigations and ct in evaluating these patients. all patients admitted with new onset seizures within h prior to presentation were included. all the patients were questioned and an attempt was made to assign an electroclinical syndrome to seizure. patients were evaluated for metabolic profile, neuroimaging. csf examination was done in those who had persistently altered mental status, infectious symptoms and fever. results. patients were admitted ( . % of total patients who came to emergency) with history of new onset seizures. . % patients were diagnosed to have acute symptomatic seizures and were placed in ilae category . and three patients were placed in ilae category of remote symptomatic seizures. the cause of seizures was established in ( . %) patients and remained unestablished in ( . %) patients. ( . %) patients were diagnosed to have neurocysticercosis. other important causes were acute infarct, uremia, hyponatremia, hypernatremia, viral encephalitis, post partum eclampsia, pyogenic and tubercular meningitis. alcohol withdrawal seizures were seen in . % patients. metabolic derangements were seen in ( . %) patients. computed tomography was done in patients and % had abnormal findings. mri was done in patients and had abnormalities. conclusions. neurocysticercosis was found to be most common cause of seizure activity in our part of country. though metabolic derangement can cause significant proportion of new onset seizure patients routine imaging of brain should be performed in patients with new onset seizures. work environment and organisational issues: - subjective and objective research into the working conditions and their effect on the health and safety of people working in icu, focusing mainly on the natural factors of temperature, humidity, ventilation, lighting and noise (part ) n. karachalios , e.c. katsilaki , d. sfyras general hospital of lamia, icu, lamia, greece the aim of the project is the subjective and objective investigation of the conditions of work and the relation repercussions on the health and safety of people working in the icu, focusing mainly on the natural factors that are likely to cause the sick building syndrome. for this purpose a protocol of research in two phases has been planned. the first included objective measurements, with the use of suitable equipment, of the natural factors of temperature, humidity, ventilation, lighting and noise. the second phase included the subjective estimation of the working people about their own health and conditions of their work, in the particular area of the hospital with the use of substantiated anonymous questionnaire. after the subjective and objective study and analysis of questionnaires and measurements of natural factors, we found that the medium temperature of the icu was °c. the mean relative humidity of the icu was % (highest . % and lowest . %). the mean ventilation rate of the icu was m /h (highest . and lowest \ . m /h). the mean sound pressure was . db (highest and lowest . db). the average lighting was . lux ( lux lowest and lux highest). the objective data seem to keep pace with the subjective opinions of the working people, as they were impressed in the questionnaires of subjective estimate. the objective data were compared with the subjective. the results of the research were also compared with data from the existing bibliography and current legislation, leading to a line of conclusions. ( ) insufficient and bad quality ventilation. ( ) the existing temperature of the environment contributes to the appearance of sick building syndrome. ( ) the working environment is noisy. ( ) the environment of work has problematic or insufficient lighting. ( ) the icu under study is a building area which can be characterized as ''sick'' if immediate action is not taken. background. up to % of critical care nurses test positive for (symptoms of) post traumatic stress disorder (ptsd) [ , , ] . it is assumed that these symptoms are caused by professional involvement in life-threatening events [ ] . in a sample of intensive care nurses, we investigated which work related incidents were perceived as most distressing. method. in interviews, nurses ( % female) were asked to memorize and tell about their most traumatic work related event. all interviews were recorded. after verbatim transcription, the 'most critical events' were extracted and categorized bij two independent psychologists. . none of the nurses reported major life-threatening events such as trauma-related injuries, massive bleeding or seeing patients die as their 'most critical incident'. conclusion. not the major life-threatening events but relatively 'normal work related events' under unusual circumstances are mentioned as most critical by nurses. in contrast to major life-threatening events, these 'normal events' are usually underestimated by colleagues, and thus potentially compromise peer-support. a care bundle refers to evidence based interventions and information grouped together to improve outcomes and consistency of provided care [ , ] . at the icus charge nurses and intensivists as shift leaders are responsible for daily management of unit activities. several immediately made decisions by shift leaders are made under time pressure and high information load with inadequate information. though we have evidence of structure and process based factors such as material and human resources, admission and discharge decisions or bed utilization, the support for information transfer and integration is poor in organizational decision-making concerning these factors. objectives. to identify immediate information needs of charge nurses and intensivists during the management of daily activities at the icu and evaluate how necessary this information is for their decision-making. from september to november , all charge nurses (n = ) and intensivists (n = ) of university affiliated icus providing comprehensive care in finland were surveyed with an on-line questionnaire using statements. the questionnaire was developed based on our previous observation study and statements of our survey regarded information needs related to the icu care activities. a rating scale from to (completely unnecessary-absolutely necessary) was used to assess the necessity of the information. for each statement, a response with mean or over was regarded as necessary information for immediate decisions. results. the response rate was . % (charge nurses . %, intensivists . %). the working experience varied from to years (mean . , sd . ). over % of respondents worked as a shift leader once a week or more often. statements of were valued as a necessary (mean [ or more) for immediate decision-making. absolutely necessary information (mean [ or more) for immediate decision-making were assessed related to the statements. these statements concerned isolations, mechanical ventilation, admissions and discharges, special treatments, patient's condition, and scheduled dates or times for surgery or other procedures. conclusions. both icu charge nurses and intensivists identified several information needs that are crucial for immediate decision-making during the whole icu care process. information needs of the shift leaders differed and they were strongly connected to the needs of one's professional requirements. an integrated overview and summarization of immediately needed information-a care bundle for organizational decision-making-at the icus is highly needed for icu shift leaders. the common interests of both professionals, charge nurses and intensivists, should be emphasized when new technology-based systems are developed. background. the nursing shortage is an international problem that is expected to worsen in the coming years. studies show that one of the main reasons nurses leave the profession is their dissatisfaction with their work environment. structural empowerment and nurse-physician collaboration are two elements of the nurses' work environment that are potentially related to one another according to kanter's theory ( ) . in addition, a nurse's clinical specialization has been found to influence perceptions related to these two concepts. to examine the level of perceived structural empowerment, the perceptions of nurse-physician collaboration and the relationship between these two variables, among intensive care unit (icu) nurses and general ward nurses in israel, and to compare the groups. a descriptive, correlational, comparative study design was used on a sample of icu nurses and nurses from internal medicine and general surgery wards in a large university hospital in israel (response rate %). a three section, self administered questionnaire was used to measure the study variables: the condition of work effectiveness scale-ii (cweq-ii), the collaboration with medical staff scale (cmss) and demographic-professional background. results: perceived structural empowerment was found to be moderate (m = . , sd = . , range = - ). nurses tended to agree that there was nurse-physician collaboration (m = . , sd = . , range = - , = strongly disagree, = strongly agree). a correlation was found between structural empowerment and the nurse-physician collaboration (r = . , p \ . ). a significant difference was found between icu nurses and general ward nurses on their perceptions of nurse-physician collaboration (t ( ) = - . , p \ . ; general wards: m = . , icu: m = . ). no significant differences were found between nurse specialization on perceived level of structural empowerment. conclusion. nurses in this study tended to agree that there was nurse-physician collaboration on their unit/ward. nurses who perceived themselves as having a higher level of structural empowerment, felt that there was a higher level of nurse-physician collaboration. general ward nurses had more positive perceptions about nurse-physician collaboration on their ward as compared to icu nurses. no difference was found between the two groups on the level of structural empowerment. recommendation. the findings of this study can be used as the basis for the design of interventions, aimed at enhancing structural empowerment and nurse-physician collaboration, in order to improve nurses' work environment, as one of strategy to decrease the nursing shortage. further study of additional hospitals in the country is also recommended. teams have expanded and in some hospitals h cover has been instituted. researchers are questioning the validity of outreach services and its impact on patient outcomes. as cco has been viewed as the panacea to all problems, data collection and analysis is fundamental in proving its financial and clinical benefits. objectives. this comparative study aims to evaluate retrospective data from month in and month in . data does not encapsulate patient outcomes; it will compare frequency of referrals and interventions. this data provides an indication to the extent cco has participated in the care of the acutely ill over a given time period. methods. data was collected from the d medicus database collating intervention data. analysis occurred using key interventions using excel software conclusions. whilst the validity of services has been questioned, the data itself indicates that more patients are referred and frequency of interventions has increased. various system changes occurred during this time period such as a change of mews trigger scores, the advent of h cco and courses such as alert and survive sepsis were introduced into the basic training of staff. it must be noted that the intention in the uk for cco was a service that empowered staff through education to undertake this care themselves; therefore the increase in interventions could indicate that the educational approach hasn't made progress. although the study compares interventions, an increase in the type of interventions was also noted such as ward based cco supervised cpap and establishing a picc line service. therefore this highlights the changing application of interventions. further analysis is required to look at the appropriate skills required for the delivery of safe care to the acutely ill in the ward environment. whilst ward staff are increasingly under resourced, both in skills and manpower, cco do provide the skills, knowledge and time to meet the shortfall in safe timely care. introduction. working as a critical care nurse involves situations where teamwork is essential and rapid, effective communication is of importance [ ] . the education to become a specialist icu nurse gives skills and knowledge to manage patients who are critically ill with rapidly changing conditions [ ] . experimental research is one way of contributing to the acquisition of such knowledge. to describe how icu nurses may contribute and perform in the experimental research process, an environment usually unfamiliar to them. we describe our experiences with regard to clinical contribution and our subjective evaluation of involvement in animal experimental research. method. three icu nurses in a swedish hospital were asked to participate in a research project investigating myocardial metabolism in porcine models of shock. the tasks were anaesthesia and pain management, assisting with catheter insertion and haemodynamic monitoring the pigs during the process results. although the situation was new, the nursing role and function in the team were at once similar and different to the daily work situation in the icu. one major skill learnt was the rigour of experimental measurements and sources of error, which is sometimes neglected in clinical care. being able to observe changes due to shock in a controlled setting, we improved our ability to critically 'think ahead' in anticipation of clinical deterioration [ ] . our first-hand experiences at the animal experimental laboratory allayed many anxieties and misconceptions with this type of research. conclusions. the critical care environment demands skills such as the ability to accurately define and change priorities rapidly, good communication and teamwork [ ] . we believe that the experimental research setting is one way of enhancing this ability. in these units patients condition may change rapidly and they may need close inspection as well as emergency response. early warning scoring (ews) system may make early recognition of and response to bad condition possible by observation based on systematic parameters. ews was developed as a simple scoring system to be used at ward level utilizing routine observations taken by nursing staff. ews is based on five physiological parameters; systolic blood pressure, pulse rate, respiratory rate, temperature and avpu score (alert; reacts to voice; reacts to pain; unresponsive). objectives. the aim of this study was to evaluate ews among patients admitted to pacu. methods. ews parameters were recorded four times from patients after their admission to pacu. the first record was taken during the first admission to pacu (ews ), the second (ews ) after min, the third after (ews ) and the fourth record after min. the correlation between variables like differences of four ews, patients age, the asa score, duration of operation were statistically examined. early treatment and recognition of sepsis is a stated aim of the surviving sepsis campaign [ ] but in busy clinical environments the delivery of antibiotics and fluids can often be delayed. we describe the implementation of an audit proforma, based on the survivesepsis.org [ ] resuscitation bundle, as a tool to deliver six aspects of management within h of recognition sepsis. . improve the early recognition and treatment of sepsis in acute medical patients. . provide a sustainable change in the management of septic patients . improve mortality and length of hospital stay methods. the proforma consist of six treatment management steps, based on the survivesepsis.org ''septic six'': oxygen, blood cultures, antibiotics, lactate, iv fluids, strict fluid management. it is triggered by patients satisfying two or more of the systemic inflammatory response syndrome criteria. all management steps should be implemented within h of the trigger time stated on the form. the forms are collected and analysed every month and the results are displayed for staff working on the medical admissions unit and accident and emergency. a total of forms have been collected, % diagnosed with severe sepsis. the progress on all six parameters is shown below. over the initial seven month period we have demonstrated a sustained improvement in the rapid delivery of all six of the management parameters. introduction. the early goal-directed resuscitation has been shown to improve survival in patients presenting with septic shock. a recent systematic review demonstrated the inability of central venous pressure (cvp) to predict the hemodynamic response to fluids infusion, and it should not be used to make clinical decisions regarding fluid management in critical patients. the clinical implication of this fact in septic shock is not well-known. objectives. the aim of this study is to determine if the resuscitation with fluids guided by cvp has clinical implications in patients with septic shock. post-hoc analysis of a patients' cohort with septic shock admitted in the medical intensive care unit since june to june . all of them were treated on basis of a bundle for severe sepsis management. chi-square analysis was used to compare categorical data. continuous data were compared using student's t test. we used multiple logistic regression model to assess the association between the independent variable and mortality, after adjustment for possible confusing factors (we considered variable to be confounding if the estimate of the coefficient changed by more than %). eighty-five patients were studied. % were male. their average age was ± and % had previous chronic diseases. severity scores: apache ii ± , sofa ± and % of patients had multiorganic dysfunction. infectious focus was respiratory in %. cvp mean was ± mmhg, scvo ± % and the mean amount of fluids provided was ± cc. % of patients needed mechanical ventilation. hospital-stay middle was days ( - ) and days in icu conclusions. in our patients' cohort with septic shock treated under the basis of the early goal-directed resuscitation, the volume of fluids infused was associated independently with mortality. a lower fluid administration in the resuscitation probably could be caused by the early reach of a high central venous pressure. blinding of study interventions is necessary to prevent bias in randomized controlled trials (rct). since normal saline and % albumin are packaged in bags and bottles, respectively and they have different color and texture, a blinding procedure is necessary to ensure the fluids appear identical for comparative rcts. objectives. to describe the blinding procedure and evaluate sterility and stability involved in the transfer and storage of study fluids in the precise pilot rct. a standard operating procedure for concealment, meeting pharmacy guidelines and good manufacturing practices was developed by the manufacturing pharmacist at the coordinating centre and used by all participating sites. fluids were transferred with aseptic technique into identical ml bottles under a sterile hood by the pharmacy or transfusion medicine technician then covered with an opaque wrapping. average time to transfer of study fluids from their original packaging was recorded to understand labor involved with creating each study fluid package. yellow intravenous tubing was manufactured to also conceal the fluid color. six blinded bottles of normal saline and % albumin from the participating centers were stored at room temperature for at least months. cultures of the fluids using blood culture media and/or endotoxin levels (measured by commercial assay) were obtained to document sterility of the study fluids. protein electrophoresis was used to assess albumin stability. results. transfer of the study fluids was the responsibility of the research pharmacist/ technician and blood bank at and sites, respectively. average time to transfer containers of normal saline and % albumin into bottles was ± and ± min, respectively. sterility (culture negative and/or endotoxin undetectable) of study fluids was confirmed from all bottles of normal saline and albumin that underwent testing. protein electrophoresis of albumin samples showed a single band suggesting no degradation of albumin during transfer and storage. conclusions. the standardized blinding procedure developed for transfer of study fluids in this pilot rct confirmed sterility and stability of our study fluids for months. these data are important when considering the length of allowable storage time for these study fluids. due to the resources and time involved with the transfer of these fluids for individual sites, this transfer method needs to be incorporated into budgeting and may not be feasible in the context of a large rct. grant acknowledgment. the precise pilot rct was funded by a grant from canadian blood services. covidien, singapore, singapore, yong loo lin school of medicine, national university of singapore, biostatistics unit, singapore, singapore introduction. the surviving sepsis campaign recommends a -h resuscitation bundle and a -h management bundle to improve outcomes in severe sepsis. compliance with and relevance of these recommendations to asian intensive care units (icus) are unknown. objectives. the primary objective of the present study was to assess the compliance of asian icus and hospitals to these bundles. the secondary objectives were to evaluate the impact of compliance on mortality, and the organisational characteristics of asian hospitals which are associated with higher compliance. methods. this was a prospective observational study of patients with severe sepsis who were admitted to the participating icus in july . we recorded the organisational characteristics of participating centres, the patients' baseline characteristics, and the achievement of targets within the resuscitation and management bundles. results. sixteen countries and icus participated, enrolling patients. hospital mortality was . %. achievement rates for the bundle targets were: lactate measurement, . %; blood cultures, . %; broad-spectrum antibiotics, . %; fluids ± vasopressors, . %; central venous pressure, . %; central or mixed venous oxygen saturation, . %; low-dose steroids, . %; drotrecogin alfa, . %; glucose control, . %; lung-protective ventilation, . %. compliance rates for the entire resuscitation and management bundles were . and . % respectively. on logistic regression analysis, achievement of the targets for blood cultures, antibiotics, and central venous pressure independently predicted decreased mortality. high-income countries, university hospitals, icus with an accredited fellowship programme, and surgical icus were more likely to be compliant to the resuscitation bundle. conclusions. compliance to the resuscitation and management bundles is generally poor across asia. given the resource limitations in asia, the most appropriate strategy to improve outcomes in severe sepsis may be to concentrate on ensuring early administration of antibiotics after blood cultures, and appropriate fluid therapy. cerebral oxygen desaturation predicts cognitive decline and longer hospital stay after cardiac surgery monitoring brain oxygen saturation during coronary bypass surgery: a randomized, prospective study the work is supported by departmental sources. clinical features and prognosis of organizing pneumonia pre-senting as acute respiratory failure in icu reference(s). . webster nr. ventilation in the prone position prone position in acute respiratory distress syndrome effect of prone positioning on the survival of patients with acute respiratory failure acute effects of upright position on gas exchange in patients with acute respiratory distress syndrome this study was funded by arjo international ag, florenzstrasse d metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports longterm propofol infusion and cardiac failure in adult head-injured patients mild hypothermia alters propofol pharmacokinetics and increases the duration of action of atracurium intermittent haemodialysis versus crrt for arf in the intensive care unit dialysis dose in acute kidney injury: no time for therapeutic nihilism cirrhotics admitted to icu, and when added to the liver-specific scores of meld or ukeld, improves their respective predictive value intensive care, london, uk, royal free hospital epidural anesthesia, hypotension and changes in intravascular volume intraoperative fluid restriction improves outcome after major elective gastrointestinal surgery surrogate designation: can we trust our relatives? does chest physical therapy work? physiotherapy in intensive care: towards an evidence-based practice fisioterapia no paciente sob ventilação mecânica this research was supported by grants from the following brazilian funding agencies/programs: cnpq, capes, fapesc and unesc readmission to surgical intensive care increases severity-adjusted patient mortality physiological scoring systems and audit predicting death and readmission after intensive care discharge a case-control study of patients readmitted to the intensive care unit severity of illness and risk of readmission to intensive care: a meta-analysis a comparison of admission and worst -h acute physiology and chronic health evaluation ii scores in predicting hospital mortality: a retrospective cohort study learning from the past to inform the future-a survey of consultant nurses in emergency care assessing emergency nursing competence post-traumatic stress among swedish ambulance personel levels of mental health problems among uk emergency ambulance workers partial and full ptsd in brazilian ambulance workers: prevalence and impact on health and on quality of life ambulance personnel and critical incidents impact of accident and emergency work on mental health and emotional well being artemis health institute, director, critical care, pulmonology and sleep medicine, gurgaon, india, artemis health institute, nursing, gurgaon, india reference(s) the australian incident monitoring study in intensive care: aims-icu. the development and evaluation of an incident reporting system in intensive care adverse events in critical ill patients ministry of health and social policy communication: a key factor in the patient safety? anemia of the critically ill: acute anemia of chronic disease impact of allogenic packed red blood cell transfusion on nosocomial infection rates in the critically ill patient high dose recombinant human erythropoietin stimulates reticulocyte production in patients with multiple organ dysfunction syndrome: the journal of trauma: injury, infection and critical ca to the staff of the critical care department, faculty of medicine injury severity and quality of life: whose perspective is important? quality of life and persisting symptoms in intensive care unit survivors: implications for care after discharge variations in health-related quality of life in critical patients funded in part by fogarty international center nih grant no. d tw - and clinical research institute-fundacion valle del lili glasgow coma score, use of mechanical ventilation and vasoactive agents, and the occurrence of severe sepsis (according to bone's criteria- ). the causes of admission were divided as: ischemic stroke, hemorrhagic stroke, subarachnoid hemorrhage, status epilepticus, traumatic brain injury, elective neurosurgeries, and miscellanea. the foci of infection, microbiological data and bacteremia were analyzed from septic patients. numeric data were expressed as median and interquartiles, while categorical data were calculated as percentage. univariate and multivariate (logistic regression) analysis was carried out to point factors associated with hospital mortality. results. we included patients, with median age years (iq range - ) and % were male %) patients, while it occurred during icu stay on ( %) patients. hospital mortality was associated with age, the admission cause (higher for hemorrhagic stroke, traumatic brain injury and status epilepticus), apache ii score, glasgow coma score and severe sepsis on the univariate analysis cnpq perioperative factors associated to higher mortality in patients admitted to the neurological intensive care unit (nicu) immediately after brain tumor (bt) resection saldívar umae (high-specialty medical unit no ) el bajío, imss and nicu, hraeb (high-specialty regional hospital of el bajío) anaesthesiology and intensiv care medizin anaesthesiology and intensive care unit charité universitätsmedizin-berlin, department for anesthesiology and intensive care medicine after approval of the local ethics committee, the pdr icg was measured within h post injury (day ) using the non-invasive limon system (pulsion medical systems of pdr icg to supranormal values higher sofa scores were indirectly associated with lower pdr icg values, particularly for sofa scores[ . when patients were grouped by icu length of stay (\ , c days, corresponding to the mean icu los of the german trauma registry), logistic regression analysis identified pdr icg consumables were provided by pulsion medical systems influence of apoe polymorphism on cognitive and behavioural outcome in moderate and severe traumatic brain injury genetic variation of the apoe promoter and outcome after head injury effects of apolipoprotein e genotype on outcome after ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage the association between apoe « , age and outcome after head injury: a prospective cohort study decreased cerebrospinal fluid apolipoprotein e after subarachnoid hemorrhage correlation with injury severity and clinical outcome « association of ventilation rates and co concentrations with health and other responses in commercial and industrial buildings « sensitivity to noise, personality hardiness, and noise-induced stress in critical care nurses recommended lighting level for offices » the chartered institution of « sick building syndrome, sensation of dryness and thermal comfort in relation to room temperature in an office building: need for individual control of temperature silent misery: most severe critical incidents post traumatic stress disorder in the emergency room: exploration of a cognitive model trauma exposure and post-traumatic stress disorder in intensive care unit personnel increased prevalence of post-traumatic stress disorder symptoms in critical care nurses drivers of quality in health services: different worldviews of clinicians and policy managers revealed systems thinking, system dynamics the fifth discipline: the art and practice of the learning organisation the development of system dynamics as a methodology for system description and qualitative analysis finnish funding agency for technology and innovation nursing activities score tradução para o português e validação de um instrumento de medida de carga de trabalho de enfermagem em unidads de terapia intensiva: nursing activities score (nas) nursing activities score in the intensive care unit: analysis of the related factors the self-perceived health between medical-surgical and crit-ical care nurses in hungary deutsch , i. boncz , a. sebestyen , a. olah university of pecs faculty of health sciences a longitudinal study design was used to explore the self perceived health of inhospital nurses in acute care settings (surgery, casualty, internal medicine, intensive, coronary care, emergency room) in two hungarian factors predicting team climate, and its relationship with quality of care in general practice nurse working conditions, organizational climate, and intent to leave in icus: an instrumental variable approach critical care nurses' work environments: a baseline status report quality of practice in an intensive care unit (icu): a mini-ethnographic case study vasps/intv ). medicinska fakulteten, lunds universitet critical thinking and clinical decision making in critical care nursing assessing and developing critical-thinking skills in the intensive care unit gulhane military medical academy, haydarpasa training hospital, istanbul, turkey, gulhane military medical academy technology as a catalyst to transforming nursing care devices and desire: gender, technology and american nursing surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock division of pulmonary and critical care medicine, seoul, republic of korea, peking union medical college hospital, department of critical care medicine mai hospital, intensive care department, hanoi, viet nam, king saud bin abdulaziz university for health sciences, king abdulaziz medical city, intensive care department dr soetomo general hospital, department of intensive care republic of china, ripas hospital, intensive care unit surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock the surviving sepsis campaign: results of an international guideline-based performance improvement program targeting severe sepsis great differences in compli-ance with surviving sepsis campaign bundles surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock delayed diagnosis is associated with increased morbidity, mortality and cost in the icu. as the mortality rate of severe sepsis remains unacceptably high, a group of international expert developed guidelines in , termed the surviving sepsis campaign (ssc). the ssc group has introduced the ''sepsis care bundles surviving sepsis campaign guidelines for severe sepsis and septic shock implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality improving outcomes for severe sepsis and septic shock: tools for early identification of at-risk patients and treatment protocol implementation observational, prospective follow-up. patients who were admitted into the intensive care unit in university hospital complex a coruña (chuac) during the months of hospital mortality was surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock early goal-directed therapy in the treatment of severe sepsis and septic shock associated with decreased mortality translating research to clinical practice: a -year experience with implementing early goal-directed therapy for septic shock in the emergency department improvement in process of care and outcome after a multicenter severe sepsis educational program in spain duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock delta co (pvco -paco ) as a prognostic factor in septic shock septic shock using the new device inspectra : relation to macro-and microhemodynamic and outcome c. luengo , , f. vallée , c. damoisel , m. resche-rigon among the techniques assessing microperfusion, near infrared spectroscopy (nirs) gained interest. more than baseline sto values, the reperfusion slope after a vascular occlusion test (vot) nirs parameters, especially the reperfusion slope scvo or svo ); metabolic (ph, base excess and lactate) parameters were collected. microperfusion data consisted in: nirs (baseline sto , occlusion and reperfusion slopes (%/s), automated software); skin laser doppler microflow (baseline flow (tpu), peak flow (tpu) and slope during reperfusion (tpu/s), measured during and after a min vot. survivors (s) and non-survivors ] differed between s and ns at day . macro-hemodynamic and metabolic data did not differ between s and ns plan quadriennal ea svo does not predict fluid responsiveness in critically ill septic patients supported by msm research grant: replacement of and support to some vital organs years) were studied. apache ii and sofa score at study entry were (range: - ) and (range: - ) respectively. the septic syndrome was due to sepsis (n = ), severe sepsis (n = ) or septic shock (n = ). sites of infection included the lung reference(s). . ungerstedt u: microdialysis: principles and applications for studies in animals and man the pathophysiology and treatment of sepsis management of sepsis surviving sepsis campaign guidelines for management of severe sepsis and septic shock relation between muscle na + k + atpase activity and raised lactate concentrations in septic shock: a prospective study long-term continuous glucose monitoring with microdialysis in ambulatory insulin-dependent diabetic patients whether it is worth to correct acidemia by infusion of alkaline solutions is a matter of discussion. there are a number of evidences against the use of alkalinization therapy with respect to the benefits of reversing ph and the side effects of sodium bicarbonate infusion [ ]. nonetheless, as recently shown by means of an on line survey, % of critical care physicians administer base to patients with lactic acidosis mmol/l), animals were randomized to min of: a) sustained lactic acid infusion, a + b) sustained infusion + sodium bicarbonate, o) transient infusion, b) transient infusion + sodium bicarbonate. in the transient infusion (group o and b), at randomization lactic acid was replaced with normal saline. acid-base status and lactate levels were measured over time. in a number of animals phosphofructokinase (pfk) enzyme's activity was also measured. results. following lactic acid infusion blood lactate rose unnecessary use of alkali perturb acid-base status and lactate metabolism potentially overcoming metabolic adaptive strategies. reference(s). . boyd jh, walley kr. is there a role for sodium bicarbonatein treting lactic acidosis from shock? use of base in the treatment of acute severe organic acidosis by nephrologists and critical care physicians: results of an online survey strong ions gap (sig) quantifies unmeasured blood anions and it is calculated by the difference between strong cations and strong anions (all of them, dissociated in blood plasma) retrospective, observational study of all patients with septic shock as defined by the american-european consensus, admitted to the icu from arterial blood gases, albumin, lactate and electrolytes were obtained at admittance and h later; apache and sofa score, central venous saturation and lactate comparison of acid base models for prediction of hospital mortality following trauma forty-five sepsis patients [median age, (iqr, - ) years; admission saps ii, ( - ) pts; severest multiple organ dysfunction syndrome score interaction of vasopressin infusion, corticosteroid treatment, and mortality of septic shock comparing two different arginine vasopressin doses in advanced vasodilatory shock: a randomized, controlled, open-label trial lambert university of leicester, division of anaesthesia, leicester, uk blood samples were taken: at induction of anaesthesia, at and - h post-cpb. neutrophils were isolated, mrna extracted, dna cleaned and reverse transcribed supported by a grant from the association of anaesthetists of great britain and ireland, and the british journal of anaesthesia/royal college of anaesthetists secretoneurin (sn), a neuropeptide, is specifically expressed in endocrine elevated nucleosome levels in systemic inflammation and sepsis extracellular histones are major mediators of death in sepsis rd esicm asymmetric and symmetric dimethylarginines (adma, sdma) are protein-breakdown markers; both compete with arginine for cellular transport and are excreted in urine. moreover adma, sdma, their ratio (marker of adma catabolism), arginine, interleukin- (il- ), tumor-necrosis-factor-a (tnf-a), c-reactive-protein(crp) on day , , , , and at discharge in consecutive severely-septic patients were measured sdma were higher than normal, adma/sdma ratio was halved, arginine was low. adma was related to total sofa and arginine, inversely related to il- and crp; sdma was related to saps ii, sofa, blood urea, creatinine, arginine. adma/sdma ratio was inversely in non-survivors, creatinine, il- , tnf-a, crp and adma were stable, sdma increased, adma/sdma ratio remained low figure: time course of adma and sdma blood levels (mean ± standard error) during icu stay and the last icu day protein-hmgb- levels as predictors of outcome in patients with sepsis and septic shock hmgb as a predictor of organ dysfunction and outcome in patients with severe sepsis early low dcs counts may be correlated to disease severity and could predict fatal outcome. however, little is known about dc number in other shock than septic. objectives. to evaluate and compare the circulating dcs number in patients with severe sepsis, septic or cardiogenic shock. methods. in a prospective multicentric study ( icu), consecutive immunocompetent patients with severe sepsis (ss), septic shock, cardiogenic shock were included. peripheral blood dc counts, measured by flow cytometry, were evaluated and compared between the three populations at admission and h later. correlation to disease severity evaluated by clinical scores and day mortality was studied. results. patients were included (age ± years, male, sofa d . ± . , saps ii ± ): septic shock, severe sepsis and cardiogenic shock. mortality at d was respectively , and %. patients presented a sepsis associated to cardiogenic shock. at baseline and at day , a dramatic diminution in the numbers of total dcs either myeloid (mdcs) or plasmacytoid (pdcs), was observed in sepsis (severe sepsis or septic shock) compared to cardiogenic shock patients. no difference was seen between severe sepsis and septic shock patients (fig. ). we did not observe any correlation between the number of total dcs at admission or at day and severity of illness scores dc reduced number is a valuable marker of severe sepsis in shock and is not affected by hemodynamic changes. it could not be used as a prognostic marker in severe septic patients. preliminary results from a prospective study assessing the relationship between standard laboratory coagulation and global tests of clot-formation using thromboelastography in patients with fulminant hepatic failure v the routine use of international normalized ratio (inr) to establish the coagulation status in patients with fulminant hepatic failure (fhf) may be misleading. anecdotally, fhf patients, despite a significantly deranged inr, may display a normal or even hypercoagulable state, as recently shown, albeit in an extracorporeal setting, with frequently clotted circuits, despite raised pt we prospectively studied coagulation, demographic, survival and outcome measures of fhf patients (defined by de-novo liver failure, coagulopathy-inr [ . , and encephalopathy) admitted to the royal free hospital liver and/or intensive care unit(s) (icu), a tertiary referral centre in liver diseases and transplantation we present the standard clotting tests and teg results from (of a required ) patients currently enrolled, demonstrating variable degrees of encephalopathy and coagulopathy effect of norepinephrine on cardiac output and preload in septic shock patients apparent heterogeneity in splanchnic vascular response to norepinephrine during sepsis aggressive use of high-dose norepinephrine in the treatment of septic shock norepinephrine requirement is not an independent variable to predict outcome in severe septic shock patients aim. the aim of this study was to measure the level of ptsd among hungarian ambulance workers, and explore factors which can influence it.sample and methods. hungarian ambulance workers were involved to this crosssectional study ( ambulance drivers, ambulance nurses, and ambulance team leaders: medical doctors and ambulance officers). self filling questionnaire were used for data collection, including briere's trauma symptom checklist, and socio-demographic questions. chi square test, independent t test and variance analysis were used for comparison of variables.results. the average ptsd-points of ambulance workers was . there was significant association between level of ptsd and gender: women's average , men's average ptsd-points (p = . ). there were no correlations between level of ptsd and type of settlement, location of ambulance station and level of education. those who would need psychological support (p = . ), and those who had psychologically traumatic experiences in the last years have significantly higher ptsd-points (p = . ).conclusions. hungarian ambulance workers are exposed with many effects which can lead ptsd. professional psychological support is needed in order to cope with ptsd successfully.the results were presented and discussed in our weekly meeting on patient safety and healthcare for all icu personnel. by the end of this year all the recommendations will be implemented in our icu.conclusions. we improved the safety and quality of in hospital transportation of icu patients by performing a prospective risk analysis. bow-tie is a good instrument to identify health care risks. to determine the incidence of phrenic neuropathy associated with the catheterization of internal jugular and subclavian veins, without ultrasound support, in patients admitted to an icu. a prospective study was performed by following patients admitted in the icu between october and may . a normal neurography of both right and left phrenic nerves at the moment of their admission was the main inclusion criteria. after this baseline study, a new neurography was repeated weekly (chen and resman method, sinergy medelec), during their stay and at the moment of being discharge from icu. simultaneously, all vascular subclavian and internal jugular vein catheterization were registered. a final neurography and a fluoroscopy study were performed after being discharged from hospital. results. patients were included and two hundred and ten neurographies of both right and left phrenic nerves were performed. patients did not receive any vascular punctures in the cervical region during the follow up period, acting as control group. patients underwent a total of vascular catheterization, in subclavian vein ( . %) and in internal jugular vein ( . %). a phrenic neuropathy was diagnosed in patients. this represented an incidence of % ( / ) of phrenic neuropathy per patient and % ( / ) related to subclavian and internal jugular vein catheterization. in relation to patients without phrenic nerve injury who underwent subclavian and internal jugular vein catheterization, patients affected of phrenic neuropathy had longer mechanical ventilation time ( ± days vs. ± , p = . ) and longer average stay time in icu ( . ± days vs. ± , p = . ), although these differences have not statistical significance. we did not find significantly differences related to age ( ± vs. ± , p = . ) and apache ii index ( ± . vs. . ± . , p = . ) between both groups (wilcoxon two-sample test). we performed a control neurography of case patients after being discharged from hospital. we checked the cmap phrenic nerve reappearance after weeks and months of being diagnosed its neuropathy, respectively. conclusions. we found an incidence of phrenic neuropathy of % per patient and % related to subclavian and internal jugular vein catheterization, during the follow-up period. the time of reappearance of phrenic cmaps after being detected its neuropathy points to a neuroapraxia or partial axonotmesis as pathogenic type of injury.discussion. phrenic neuropathy has to be considered in cases of difficult weaning of unclear etiology. the catheterization of subclavian and internal jugular veins should be recommended employing ultrasound support. p. merino , m.c. martin-delgado , j. alvarez , i. gutiérrez-cía , Á . alonso-ovies , syrec hospital can misses, icu, ibiza, spain, isde, Á rea de salud, madrid, spain, hospital de fuenlabrada, icu, madrid, spain, hospital clínico universitario, icu, zaragoza, spain introduction. syrec project aims to improve icu patient safety. the project includes an epidemiological study. we present the main results.objectives. to estimate the near miss (nm) and adverse events (ae) rate in spanish intensive care units (icus). we study the incidence and nature. finally, we classify and analyze its severity.methods. multicenter prospective observational cohort study. inclusion criteria: patients admitted to the participant icus during the -h observation period. during this period, nm and ae detected and reported inside and outside icu were included. only outside icus were considered when its were the reason for admission. we evaluate the kind of incident, severity and preventability. data collection studied under the distribution of frequencies.results. , patients were included. , incidents were reported in patients, were nm and ae. risk: the median risk of nm was % versus ae %. . incidents per patient admitted. incidence rate: the incident rate median was . per patients per hour icu stay, the nm of . per patients per hour icu stay and that of ae, . per patients time of stay in icu. the % of the incidents reported have been nm and % ae. this incidents causing temporary damage in the . % of occasions and in the . % permanent damage, compromised the patient's life or contributed to death. classification of incidents (table ) . conclusions. our study shows a high individual risk. our icus services present a highrisk environment. therefore we have to go into the developement of epidemiological studies depth, in order to create further strategies supporting patient safety. restore cardiovascular performance in severe lactic acidotic rats a. kimmoun , n. sennoun , n. ducrocq , b. levy , inserm u , groupe choc, vandoeuvre-lès-nancy, france, chu nancy brabois, intensive care unit, vandoeuvre-lès-nancy, france introduction. lactic acidosis during shock is responsible for myocardial failure, vascular hyporesponsiveness and a decrease in sensitivity to vasopressor agents. sodium bicarbonate is a proposed treatment to correct acidosis, although with deleterious cardiovascular effects. indeed, hypocalcemia and hypercapnia, both powerful myocardial depressants, are the main side effects of the administration of this therapy [ ] . objectives. already studied in experimental models of isolated lactic acidosis, the cardiovascular effects of sodium bicarbonate administration have never been explored after correction for hypocalcemia and hypercapnia. methods. we therefore compared, in a rat model of severe lactic acidosis (ph \ . , hyperlactatemia[ mmol/l) induced by a state of controlled hemorrhagic shock, the cardiovascular effects of: ( ) standard resuscitation plus administration of sodium bicarbonate with correction for calcemia and paco (''adapt'' group, n = ); ( ) standard resuscitation plus administration of sodium bicarbonate without correction for paco and calcium (''nonadpat'' group, n = );( ) standard resuscitation; (''stand'' group, n = ); ( ) standard resuscitation plus calcium administration (''calc'' group, n = ). evaluation at steady and shock state, min and min was focused in vivo on arterial gas and myocardial contractility (emax) by conductance catheter. ex vivo vasoreactivity was tested on mesenteric arteries ( lm) by myography. sodium intakes were equivalent between groups. results. our model displayed a profound acidosis from . to . ± . (p = . ) and hyperlactatemia from . ± . to . ± . mmol/l (p \ . ). emax decreased from . ± . to . ± . mmhg/ll p = . . in the adapt group, at min, ph was normalized at . ± . (p = . ). furthermore, emax was enhanced at ± % (p \ . ) (stand: ± %, nonadapt: ± %, calc: ± %). the cumulative dose of infused norepinephrine was significantly lower in the adapt group ± lg/kg compared to other groups (stand: ± lg/kg, nonadapt: ± lg/kg, calc: ± lg/kg, p = . ). ex vivo mesenteric vasoreactivity in the adapt group was normalized (graph ).mesenteric vasoreactivity to phenylephrine conclusions. in severe lactic acidosis, infusion of sodium bicarbonate after correction of its side effects improves myocardial function and vasoreactivity. [ ] . the prevalence and significance of -hydroxyvitamin d deficiency in the intensive care unit have not been fully determined. a recent study of an unselected group of itu patients [ ] has suggested low itu admission -hydroxyvitamin d levels are common. objectives/hypotheses to be tested. royal free hospital intensive care unit patients exhibit low circulating levels of -hydroxyvitamin d. circulating levels of -hydroxyvitamin d decrease further during the course of hospital admission. admission circulating levels of -hydroxyvitamin d affect itu morbidity and mortality methods. all itu admissions were assessed within h of presentation and patients who were deemed to have the potential to require admission for at least week were included. demographic and clinical data were obtained in a prospective manner. results were recorded from samples obtained at admission, days and days. standard itu nutrition protocols were used. no interventions were performed. results. clinical and outcome data were obtained for patients. no significant differences between apache , saps or apache scores for survivor and non-survivor groups at either itu or hospital discharge were noted. further patients await complete data analysis. % ( of for whom results were available) achieved an adequate ([ nmol/l) circulating hydroxyvitamin d level. patients ( . %) demonstrated levels within the insufficient range ( - nmol/l). patients ( . %) did not have any detectable -hydroxyvitamin d. the remaining patients ( . %) were either in the deficient ( . %, - nmol/l) or severely deficient ( . %, - nmol/l) ranges. admission -hydroxyvitamin d levels in survivors and non-survivors were compared at itu and hospital discharge. no significant differences between the four groups (p [ . , anova) were observed, indicating that in this data set, admission -hydroxyvitamin d levels do not appear to alter or determine clinical course. mean -hydroxyvitamin d levels were compared at admission, day and at day . no significant differences between the three groups (p [ . , anova) were identified. no significant differences between the mean -hydroxyvitamin d levels of the survivors and non-survivors at day or day were apparent (small numbers). admission [ , ] and patients undergoing surgical procedures [ ] . patients with neurological illness can receive significant quantities of ns, chosen primarily for its iso-osmolar properties. objectives. ns is commonly used as maintenance and resuscitation fluid by the anaesthetist, and as intravascular flushes by the radiologist during prolonged interventional neuroradiological (inr) procedures. this pilot feasibility study aimed to ascertain the effect of ns infusion on acid-base measurements in patients undergoing inr procedures under propofol-remifentanil anaesthesia. methods. we collated routine electrolyte, albumin and acid-base data of patients who underwent coil/glue embolisations of intracranial aneurysms and vascular malformations, both before and after the procedure. base excess (be) was partitioned into the effects of sodium chloride difference (na-cl), albumin, lactate and unmeasured anions (uma), using the stewart-fencl-story approach [ ] . all values are reported as medians (ranges objectives. to investigate the erythropoietic response to hight dose of a weekly schedule of recombinant human erythropoietin (rhuepo) in critically ill anaemic septic patients. a total of patients admitted to the intensive care unite (icu) were enrolled in this study, patients were randomized to receive either rhuepo or not, patient did to form the rhuepo group, did not to form the control group.results. the epo treated group of patients showed significant increase in reticulocyte count compared with baseline p \ . , as well as with the control group p \ . . the epo treated group exhibited also a significant increases in hb concentration compared with baseline p \ . as well as the control group . . all patients in the control group received rbc blood transfusion %, while only . % of the epo group did. the epo treated group showed significant decreases in their apache ii score during the study period compared with baseline p \ . as well as with the control group p \ . . the epo treated group showed no significant difference in their sofa score compared with baseline p \ . , however the control group exhibited continuous and significant increase in their sofa score throughout the study period compared with their baseline p \ . , there was no significant difference in the final outcome recovery, mortality or morbidity p . , p \ . respectively.conclusions. the administration of rhuepo to critically ill anaemic septic patients is effective in raising their reticulocytic counts, hb concentrations and in reducing the total number of units of rbcs they require. in addition there was a trend toward better in hospital clinical course, increased recovery and decreased mortality in the rhuepo group.conclusions. anaemia is common following critical illness but does not appear to affect the physical aspects of recovery during medium term rehabilitation. this may be due to an overwhelming degree of symptom burden from other complications of critical illness impairing physical function to such a degree that the effects of anaemia are negligible in the medium term. although decreases in number and function has mainly been described in skeletal muscle, also other organs seem to be affected and it has been hypothesized that mitochondrial dysfunction might be involved in the development of organ failure. to study the effect of plasma of patients with septic shock on mitochondrial function in vitro to potentially later on identify a central factor affecting mitochondria in all tissues during sepsis and leading to multiple organ failure.methods. after sacrificing - week old sprague-dawley rats, mitochondria from soleus muscle were isolated through homogenization and a series of centrifugations. mitochondrial function was assessed by measuring of oxygen consumption, using an oxygraph containing a clarke-electrode, after addition of adp. before these measurements, mitochondria were incubated with plasma from septic patients or healthy volunteers, respectively, for min. in our second series, the mitochondria were incubated with different concentrations of il- , tnf-a or buffer. respiration rates were measured in the presence of adp (state ; a measure for the oxidative capacity to produce atp) and without the presence of adp (state ; a measure for the amount of uncoupling). respiratory control ratio (rcr; a measure for the respiratory efficiency of the mitochondria) was calculated by dividing state by state activity. all measurements were related to citrate synthase activity to compensate for the amount of mitochondria. statistical differences between the groups were analyzed using a student's t test.results. adp dependent (state ) respiration was % higher and rcr % higher in the mitochondria incubated with plasma from the septic patients compared to those incubated with plasma from healthy volunteers (table) . there were no significant differences between the groups incubated with preservation buffer or the different cytokines (table) . introduction. microvascular fluid loss from the intravascular to the interstitial space generates tissue edema and is one of the major challenges in emergency and intensive care medicine. isolation of interstitial fluid (if) from skin makes it possible to study the microcirculation and proteins in this environment both during normal as well as pathophysiological conditions such as acute inflammation.objectives. by studying bio-markers from proteomic analysis by mass spectrometry in an inflammation model, we wanted to find proteomes that could be important in explaining inflammation. we have applied a recently described centrifugation method in a porcine model and compared it with implanted wicks. in nine anesthesized piglets we compared the methods and evaluated the if, by overhydrating the pigs with ml of acetated ringer's solution for h, and thereafter continuously supplemented for h according to fluid losses. if was isolated from implanted dry wicks, wet wicks and by centrifugation of excised skin. the methods were evaluated by the ability to reflect overhydration and to show the expected composition of plasma proteins in if by use of hplc. the if was also processed further with mass spectrometry to find possible tissue degradation or inflammation due to overhydration. statistics: by spss v . and graphpad instat (version . ). significance level: p = . . colloid osmotic pressure in if was significantly lowered after overhydration for all the tree methods. wet wicks p = . , dry wicks p = . , skin samples p = . . hplc of if collected with centrifugation after overhydration, identified peaks representing molecules smaller than albumin. mass spectrometry of the same if identified several proteins associated with inflammation: alpha- -antichymotrypsin and lumican, the latter a protein identified as a modulator of inflammation. we have introduced a new centrifugation method for isolation of if from the skin of pigs. by further analysis of if isolated by centrifugation we were able to distinguish proteins found only in the if of the pigs overhydrated with ringer's acetate. these proteins could be associated with an inflammatory condition in the skin caused by massive overhydration, again causing tissue degradation. identification and validation of proteomic biomarkers can be a useful tool in future treatment of inflammation in general, and in sepsis in special. objectives. to define the pattern of change in metabolites by mrs in experimental sepsis. male sd rats (weight - g) underwent cecal ligation and puncture or sham procedure (n = per group), and h after surgery were euthanized. pulmonary tissue was extracted for magic angle mrs (hr-mas) and processing by the r metabonomic package. a supervised statistical analysis of main components (mc) was performed on the processed spectra.results. the mc analysis discriminated both group (septic and nonseptic) indicating a different metabolite profile. in addition, the analysis of mc loading revealed displacement positions in the discrimination between groups with a variation in the signal intensity of %.conclusions. metabolomic analysis of pulmonary tissue by mrs is a potentially useful technique for the detection of biomarkers in sepsis.grant acknowledgment. introduction. cd + cd + neutrophils are a key subset of phagocytes associated with severe bacterial sepsis [ ] . their characteristics, and potential neuro-immunomodulation, have not been explored in humans neutrophils exposed to septic plasma from icu patients. to assess the effect of adrenergic/cholinergic neurotransmitter molecules on human neutrophil adhesion and activation markers following exposure to human septic plasma. with irb approval, neutrophils were isolated from healthy volunteers (ficoll density gradient separation) and incubated for h with either plasma from healthy volunteers or septic patients plus pathophysiological concentrations of epinephrine (e), norepinephrine (ne) or acetylcholine (ach) and nicotine (nic) to assess potential parasympathetic-related neuro-immunomodulation. flow cytometry (dako cyan) measured expression on neutrophils of cd , cd , cd antibody markers and viability. median values are shown; analyzed by anova.results. neutrophils were unaffected by ne, e, ach or nic after incubation with plasma from healthy volunteers. after incubation with septic plasma, marked neutrophil activation occurred (p = . ). however, nic reduced cd + cd + activation (* fig. a ) by % (median ( - %; th- th centiles); p = . ). nic also attenuated cd expression, suggesting reduced neutrophil adhesion (* fig. b) . neutrophil viability was similar across drug and plasma treatments. conclusions. these preliminary data suggest that nicotine attenuates both the activation and adhesion of human neutrophils exposed to human septic plasma, but does not affect viability. objectives. the aim of this study was to evaluate the potential impact of lag between sepsis initiation and start of treatment on mitochondrial respiration. methods. animals [ . ± . kg] were randomized (n = /group) to a control group (group i) and three groups resuscitated at (group ii), (group iii), and (group iv) hours, respectively, after fecal peritonitis induction. fecal peritonitis was induced with instillation of . g/kg of autologous feces via intra-peritoneal drain. resuscitation was performed according to the ssc and esicm sepsis guidelines for h. respiration of permeabilized skeletal muscle fibers and their isolated mitochondria was assessed at baseline and after , , , and h, when applicable, or before death occurred, if earlier. at the end of the experiment, also isolated brain, hepatic and myocardial mitochondrial respiration was measured using high resolution respirometry (oxygraph- k, oroboros instruments, innsbruck, austria). results. mortality ( %, each) and organ dysfunction was highest in groups iii and iv. in these two groups, different pattern of changes of skeletal muscle mitochondrial complex i-dependent respiratory control ratio (rcr) were observed (table ) . no significant differences between groups were observed for complex i-and ii-dependent rcr values of hepatic, myocardial and brain mitochondrial respiration (fig. ). there were no significant differences between the groups for any of the complexes in permeabilized skeletal muscle fibers mitochondrial respiration (data not shown). conclusions. despite the high mortality observed in groups resuscitated at later time points after induction of sepsis, end organ mitochondrial function assessed using physiological substrates was preserved. despite significant changes in skeletal muscle mitochondrial respiration efficiency in the two groups with the highest mortality, our findings do not support the view that mitochondrial dysfunction plays a major role in the pathogenesis of multiorgan dysfunction in experimental sepsis. grant acknowledgment. swiss national fund, nr: - ; stiftung für die forschung in anästhesiologie und intensivmedizin. adipose tissue is an endocrine organ which produces signalling proteins involved in inflammation and glucose homeostasis [ ] . one of these proteins, adiponectin, promotes glucose utilisation and fatty acid oxidation and thus improves insulin sensitivity via its two receptors, adipor and adipor [ ] . adiponectin expression has been shown to be reduced in type ii diabetes, obesity and endotoxaemia [ , ] . adiponectin also exhibits antiinflammatory properties [ ] . in this study, we have examined whether adiponectin and its receptor gene expression changes in murine adipocytes stimulated by lps. methods. t --l adipocytes were grown in culture media (dmem with % fetal calf serum) until confluent. pre adipocytes were differentiated with the addition of mg/ml insulin, mm dexamethasone and mm ibmx. media was changed every h. cells were treated on day with ng/ml, or mcg/ml lps (escherichia coli, sigma-aldrich). cells were harvested at and h. mrna levels were determined by rt pcr in a . ll reaction volume consisting of . ng of reverse transcribed cdna mixed with optimal concentrations of primers and probe and qpcr tm core kit (eurogentec, uk) in -well plates on a mx p detector. results. cell response to lps was confirmed using il as a reference gene. expression of adiponectin mrna was significantly reduced in cells treated with lg/ml lps harvested at h ( . fold p = . ). there were no changes in cells treated with lower concentrations of lps. there were no changes at h. r gene expression was significantly reduced following treatment with ng/ml lps at h ( . fold p = . ), but treatment with higher concentrations did not change expression. there were no changes at h. r expression levels were significantly reduced at h in the and the mcg/ml groups ( . fold p = . and fold p = . ) respectively. there were no changes at h. discussion. our results add to the evidence that changes occur in the adiponectin system during inflammation. in this model, we observed rapid reduction (at h) in adiponectin at high dose lps, r at low dose lps and r at medium and high doses. there were no changes in expression levels at h. this suggests that a rapid change in the adiponectin system may occur in response to lps but this change is not maintained at h. in a previous study, our group has shown reduced adiponectin gene expression in adipose tissue depots in lps induced endotoxaemia [ ] . it is interesting that different concentrations of lps induce different changes within the adiponectin system. further studies are needed to elucidate whether reductions in both adiponectin and its receptor may contribute to the inflammatory changes and hyperglycaemia commonly observed during sepsis including all co poisoned patients treated with hyperbaric oxygen. following parameters were seized: age, sex, date of admission, sofa, the source of the intoxication, the gravity co score, the initial clinical examination (realized by first aid), biology, the rate of hbco, the murray score and the rate of complication. results. patients were included in the study. the sex ratio was %, the mean age was ± years and the global mortality was , %. among the patients % were poisoned by smoke (s group), % by pure co (c group) and % by exhaust fumes. more than % of the exhaust fumes victims were suicide origin. this characteristic is associated with neurological impairment induce by ingested drugs. then, their neurological status is impossible to link to the co poisoning. we have therefore decided to exclude this group. the sofa score was higher in the s group compared with the c group ( . - . ; p \ . ). a co score equal to was present in versus % respectively in s versus c group (p \ . ). in the under group of patients having a co score at , % ( / ) of co poisoned patients versus . % ( / ) of smoke poisoned patients were ventilated (p \ . ). these patients were intubated either during transport or in the intensive care and none of them received hydroxycobalamine during the first aid (before intubation). the laboratory data showed in the s group a higher lactates level ( . vs. . mmol/l; p = . ) and lower initial pao /f i o ratio ( vs. ; p = . ). nine percent of the s group present a murray score at versus % for c group (p \ . ). pneumonia, shock and death were significantly more frequent in the s group (respectively . vs. . %, p \ . ; . vs. . %, p \ . ; and . vs. . %, p \ . )conclusions. as expected the smoke poisoned group has a higher mortality than pure co group (mortality % vs. overall mortality . %). at equivalent co gravity score, mortality and complications are always more frequent in the smoke poisoned group. the smoke poisoned group has a high risk of degradation. those patients require specific monitoring and support and probably early administration of hydroxycobalamine. hypothesis. at administration and maintaining higher plasma levels of at can reduce the need for inotropes in burn shock patients. we performed a retrospective cohort study of burn shock patients admitted to a single tertiary care center over years period. patients were eligible for inclusion if they were received fluid resuscitation with ringer's solution and colloid according to clinical guidelines. data were abstracted including demographic, burn injury characteristics, resuscitation fluid volume, the type of colloid and the average of plasma at levels within h after burn injury. administration of fresh frozen plasma and/or recombinant human at was defined as at administration. the decisions of at administration and inotropic support (dopamine or dobutamine) were made by the attending intensivists. primary outcome measure was the need for inotropes within h after burn injury. cox regression model was used to estimate the risk reduction by at administration and average of at levels. [ ] . argon, another member of the noble gas family has been reported previously to have a neuroprotective property [ ] . the aim of this study was to investigate whether it attenuates neuronal injury in a rat model of neonatal asphyxia. methods. seven-day-old postnatal sd rats underwent right common carotid artery ligation and then recover with their dim for h. thereafter, they were exposed to % o balanced with nitrogen for min. after h, they were treated with % argon or % nitrogen (positive control group) for min. the cohort pups without intervention served as naïve control. they were perfused days later and their brains were sectioned and stained with . % cresyl violet. microphotographs were taken from ca area of the hippocampus near - . bregma relative to adult brain at magnification. healthy cells were counted in a blind manner and their mean value was used for data analysis. results. the thickness of healthy layers in the right ca area of the positive control group was remarkably reduced compared with other groups (fig. ). quantitative analysis revealed that argon treatment significantly increased healthy cell numbers in the right ca area of hippocampus from . ± . in the positive controls to . ± . (p \ . ) (fig. ). grant acknowledgment. this study was supported by a grant from action medical research, uk. objectives. our objective was to study the mechanisms of death following high-dose citalopram administration in rats. experimental study in sprague dawley rats with intraperitoneal (ip) citalopram administration; determination of the median lethal dose (mld)using the dixon and bruce upand-down method; clinical descriptive study of citalopram-induced features and measurement of alterations in respiratory pattern (arterial blood gases and plethysmography) and biological parameters including blood lactate (scout Ò , ekf diagnostic), plasma and platelet serotonin concentrations (high-liquid performance chromatography-fluorometry); determination of the preventive activity on seizures and death of diazepam, cyproheptadine, and propranolol pretreatments with the determination of their minimal effective dose; comparisons using anova for repeated measurements followed by bonferroni post-test.results. citalopram ip-mld was determined as mg/kg in rats. seizures were significantly increased in rats receiving and % of citalopram mld versus controls (p \ . and p \ . , respectively), while death rate was only significantly increased in rats treated with % of citalopram mld (p \ . ). significant decrease in body temperature was observed after min in rats treated with doses[ % mld in comparison to controls (p \ . ). occurrence of serotonin behavioural syndrome was comparable in all groups. citalopram administration did not result in significant hypoxemia, hypercapnia, and lactate elevation, thus not supporting the hypothesis of the occurence of any significant deleterious cardiovascular effect in citalopraminduced toxicity. however, a significant moderate increase in the inspiratory time (p \ . ) accompanied with an expiratory braking was observed. a significant decrease in platelet serotonin and increase in plasma serotonin concentrations were measured (p \ . ). pre-treatment with diazepam ( . mg/kg) and cyproheptadine ( . mg/kg) of rats receiving a lethal citalopram dose prevented seizures and death, while propranolol was ineffective.conclusions. citalopram respiratory toxicity remains mild, while deaths result from seizures probably related to serotonin toxicity. our observations may be helpful to better understand and manage human citalopram poisonings. objectives. to define the population pharmacokinetics (pk) of phenytoin in the critically ill, in addition to risk factors for sub-therapeutic dosing.methods. free and total ptn concentrations were measured in serum by means of high performance liquid chromatography following microfiltration, two to three times in the first h after a loading dose. population pk modelling, including intra and interindividual variability, were determined using nonmem (r) . in the netherlands the use of diazepam is advised as first line treatment although evidence is not established and mainly provided through case-reports [ ] . to compare the effect of diazepam on mortality in (hydroxy) chloroquine intoxication to standard therapy. we performed an extensive medline search ( -april ) with a manual reference search of identified papers. (hydroxy) chloroquine intoxication studies and case reports in english, dutch or french were evaluated. patients older than years with severe intoxications, based on measured concentrations or life-threatening symptoms, were included. pooled relative risk (rr) for mortality with corresponding % confidence interval (ci) were calculated by means of a fisher exact test. our results were compared with two retrospective and one prospective study.results. there were case reports identified from which case reports met our inclusion criteria. thirteen patients received diazepam of whom two died, compared to twelve patients who did not get diazepam of whom one died. statistical analysis demonstrated that treatment with diazepam was not associated with a lower mortality rate (rr: . ci . - . ; p = . ).although pooling of case reports is debatable, these results were comparable to the retrospective and prospective studies that didn't show any benefit from diazepam in chloroquine intoxication [ , , ] . the positive effect of diazepam may have been underestimated, due to the fact that it has been given only as rescue therapy.conclusions. based on our analysis there is a lack of evidence concerning any antidotal effect of diazepam. good supportive treatment is pivotal. if the clinical manifestations of (hydroxy) chloroquine intoxications require sedation or treatment of seizures, diazepam is a good choice based on its pharmacological profile. a prospective study which compares diazepam to sedativa with similar pharmacokinetic and dynamic profile is required to prove that diazepam has any antidotal effect. introduction. brain is one of the first organs affected in sepsis and evaluation of brain function is difficult since patients are under sedation. it has been shown that mitochondrial dysfunction may play a significant role in the pathogenesis of septic encephalopathy. here we investigated inflammatory and metabolic parameters in a model of polymicrobial sepsis in mouse. methods. sepsis was induced by intraperitoneal injection of feces. animal received imipenem h after the procedure. control animals received intraperitoneal saline and imipenem after h. blood cytokines and serum lactate were measured. the animals were sacrificed by cervical dislocation. brain slices of mcm were used to measure oxygen consumption and glucose uptake.results. interleukin , mip a and interleukin b significantly raised in the first h after sepsis induction (p = . ; p = . ; p = . respectively). in h only mip a was significant higher (p = . ). lactate was elevated and h after sepsis induction (p \ . and p \ . respectively). oxygen consumption increased after h of sepsis and drops under control values h after the induction of sepsis. glucose uptake, measured by the nbdg fluorescence, was higher after h (p = . ) and h after sepsis induction.conclusion. in a murine model of abdominal sepsis, inflammatory markers, lactate production, and brain glucose uptake increased and were parallel to alterations in the mitochondrial oxygen metabolism. introduction. the royal bournemouth hospital has one of the highest out-of-hospital cardiac arrest admission rates in the uk. in , following ilcor/aha guidelines [ ] , a cooling protocol was developed for patients with return of spontaneous circulation after advanced life support for ventricular fibrillation or pulseless ventricular tachycardia. in preparation for potential new ilcor/aha guidelines in , the prospective database of outcomes for these patients was analysed.objectives. to evaluate the outcomes of therapeutic hypothermia for patients with return of spontaneous circulation following cardiac arrest. outcome data from our prospective registry of cooled patients are summarised.results. sixty-three patients were cooled in years (median age years; mode ; range - years). % survived to itu discharge and % to hospital discharge. % of these were discharged home ( % to a rehabilitation hospital before home and one patient to a long term care facility). ninety-five percent of survivors were alive at months and % alive at year with seven status results still pending. median itu length of stay was . days (range - ). six patients required temporary percutaneous tracheostomies for airway protection and weaning from ventilation. median duration from itu to hospital discharge was days (range - ).conclusions. this series is large by comparison to other uk centres. survival to hospital discharge, at months and year were better than other published results. although neurological outcomes were not formally assessed, we believe that the capacity to discharge home is a desirable patient outcome and represents the beneficial neurological effect of our cooling protocol. selection bias will have undoubtedly affected our results. however the age of our patients was higher than in published trials and in other reports is considered an adverse outcome predictor. our data would not support restricting induced hypothermia on the basis of age alone. we consider the itu and hospital lengths of stay required to discharge these patients to be long. these data were not reported in original trials. discharges may obviously be delayed for non-clinical reasons. this aside, neurological recovery progresses for months after cardiac arrest and discharge home may still prove possible if time is allowed. however, post-itu resource implications should be considered when introducing a cooling protocol. introduction. acute ischaemic stroke (ais) is the third largest cause of mortality and the leading cause of chronic disability in the industrialized world. in some parts of europe and the united states - % of patients with ais may be admitted to a neurological intensive care unit (icu) for supportive therapy with - % receiving mechanical ventilation [ , ] . there are currently no agreed uk criteria for the admission of ais patients to critical care.objectives. to review the incidence and outcome of ais in our tertiary icu over the last five years. november and november . ais was classified as thrombo-occlusive or embolic. subarachnoid haemorrhage and primary intracerebral haemorrhage were excluded. demographic and outcome data were recorded and compared against a mean value of all icu admissions.results. ais comprised . % of icu admissions during the study period. demographic data is presented in table as mean ± standard deviation or median (interquartile range) as appropriate. in % ( / ) of hospital ais admissions were admitted to icu. patients had surgical procedures including decompressive craniectomies. % of survivors had a discharge gcs of / . mortality for unselected medical admissions over the study period was %. there are differences of significance in the mortality according to the age, classified by age groups with an age cut off of years (\ years . vs. c years %, p \ . ). apart from the gcs, the rest of the variables analyzed in the ich score are not of significance; supra and infratentorial, presence of intraventricular blood neither on the divided volume over or under cc although, in the latter, a p \ . can be observed and if we only analyze the supraventricular, it comes out as significant. other analyzed data are the time of the surgery, which is not significant, the need for mechanical ventilation, which is ( . vs. . %, p \ . ), and the days of ventilation with a mortality clearly higher on those patients with\ days of ventilation ( %) and on those of shorter stay (lesser then days %).conclusions. let be remarked that the samples have been taken from patients admitted in the intensive care unit, losing a possible sample of less serious patients, and with a higher level of consciousness, what might explain why supra or infratentorial location and the volume don't come out as forecasting factors, since its likely that there are many small infratentorial outside the intensive care unit. we highlight also that the high mortality in the first few days can be caused by those patients who are admitted as donors, developing an encephalic death in the first days, conditioning also the data regarding the mortality on fewer days with ventilation. the finish up, we have to point out the fact that the presence of previous hypertension during the treatment might be a bad forecasting factor that should be deeper studied. to determine whether a delay exists between the time of diagnosis of intracranial haemorrhage and the time of reversal of anticoagulation, in patients presenting within our region. following approval by all audit and haematology departments a month retrospective analysis was performed. we reviewed consecutive patients who received reversal of anticoagulation with pcc and vitamin k having presenting with intracranial haemorrhage whilst on warfarin. time of diagnosis was obtained from the time of scan and time of pcc issue was obtained from the blood bank database. case note analysis was performed to obtain further information.results. patients were identified, in the neurosurgical centre and in peripheral hospitals. the median time from scan to issue of pcc was min. patients were reversed within min and patients waited longer than min to have pcc issued. no adverse thromboembolic events were encountered.conclusions. avoidable delay exists between ich diagnosis and pcc issue. pcc could be stored in the emergency department and a stat dose administered immediately after diagnosis facilitating rapid correction of inr. repeat audit will be required to assess safety and efficacy. objectives. the aim of this study was to compare the functional ability and muscle strength between these two groups of patients. twenty-nine patients were evaluated (m: , f: ) (age: ± years).the diagnosis of critical illness polyneuromyopathy was based on muscle strength measurement according to the medical research council (mrc) of muscle strength methodology. nine patients were diagnosed with critical illness polyneuromyopathy during their icu stay (mrc \ / ).the patients were evaluated with mrc and hand-grip dynamometry (hgd) every days until their discharge from the hospital. the fim scale (functional independence measure) was used to evaluate the functional ability ( - ).the first evaluation was done at the discharge from the hospital and the second one ± months afterwards.results. the patients who developed critical illness polyneuromyopathy had statistically significantly lower mrc ( ± vs. ± , p \ . ) and hgd at icu discharge (left ± kg vs. ± , and right ± kg vs. ± , p \ . ) compared to those who did not. the muscle strength as assessed with the mrc days after icu discharge had statistically significantly lower ( ± vs. ± , p \ . ), just as the second hgd evaluation (left ± kg vs. ± and right ± vs. ± kg, p \ . ).compared to those who did not develop critical illness polyneuromyopathy, the patients who did, had statistically lower fim values during their discharge from the hospital ( ± vs. ± , p \ . )and months afterwards ( ± vs ± , p \ . ).conclusions. the patients who developed critical illness polyneuromyopathy had significantly inferior muscle strength at their discharge from the icu. these patients also had lower functional ability. this functional ability remained defected even months after their discharge from the hospital. these initial findings are suggestive that the appearance of critical illness polyneuromyopathy affects the patients mobility after their discharge either from the icu or from the hospital and persists for several months after icu discharge. further studies are needed to evaluate the effect of this impairment on the quality of life of these patients and also to evaluate therapeutic tools for critical illness polyneuromyopathy. introduction. this poster presents a qualitative system dynamics (sd) analysis of the factors which influence the care of acutely unwell ward patients in new zealand. this systems thinking approach is commonly used in organisational research and offers a way to make sense of complex relationships between variables. this approach has previously been used in health care to demonstrate differences in mental models between policy makers and clinicians (cavana et al., ) . since the factors which influence the care of acutely unwell ward patients are complex and multi faceted the qualitative sd method becomes an ideal analytic approach (e.g. see wolstenholme and coyle, ; senge, ; vennix, ; or maani and cavana, ) .objectives. the aim of this study was to examine the factors which influence the care of acutely unwell ward patients from an organisational perspective. key objectives were to determine the enablers and barriers to care from a nursing, medical and managerial (at ward and executive level) perspective.methods. using a multiple case study approach in four wards in two new zealand hospitals, focus groups and one to one interviews were conducted with key stakeholders identified as nurses, doctors and managers. initial coding of the data generated themes. these themes were then clustered to provide variables which were mapped to generate separate causal loop diagrams (clds) for each of the stakeholder groups to provide the basis for analysis. the clds were compared for characteristics and world views. preliminary results demonstrate a difference between clinical and managerial staff in characteristics and world view regarding the factors which affect the care of acutely unwell ward patients.conclusions. the qualitative sd approach has offered a novel and helpful way to make some sense of the complexity associated with caring for acutely unwell ward patients. organizational responses that may improve care delivery to these patients should be based on frank and open discussions between staff at all levels to ensure a shared mental model as the basis for change. objectives. the aim of the study is to explain the nursing in the technologicallyadvanced intensive care units. in this phenomenologically-designed study, a face-to-face in-depth interview was performed with nurses, who were experienced for - years in the intensive care unit of cardiovascular surgery clinics. during the interviews, a semi-structured form was used. data were analysed using colaizzi's method of data analysis. the study was approved by the ethics committee of the institution.results. according to the nurses, nursing in technologically-advanced environment has three stages. these stages constituted three themes of the study: technology shock (first stage), understanding the technology-supported care (second stage), competency in technological environment (last stage). in the first stage, the nurses focus on themselves and technology; perceive the environment as frightening and complex. in the second stage, nurses gain control on technology, feel themselves safe and recognize their responsibility. in the last stage, the nurses experience anxiety related to their accountability. this anxiety may be motivating but also may be wearisome.conclusions. the nurses passes through three stages in a technologically-advanced environment. helping nurses to pass through these three stages appropriately will increase the contribution of technology to the patient care, more utilization of technology by nurses and more job satisfaction. unexpectedly, the compliance rate with the recommendations was significantly better over night. although the number of nurses is constant in the h, the number of doctors is lower and less differentiated in the night shift. in an attempt to find an explanation for these findings we looked at the patient flow and time span until the first medical observation in the different time periods and we found that over night admissions (between : a.m. and : a.m.) corresponded only to % of all admissions and were seen sooner, which might explain our findings. a. objectives. the purpose of the study was to assess whether the completion of the sepsis resuscitation bundle within the first h after icu admission, but beyond the specific time limit of the various bundle interventions, is related to an improvement in survival in patients with severe sepsis/septic shock. this was a single-center prospective observational study of patients admitted to the medical-surgical icu of an urban tertiary care teaching hospital with severe sepsis/septic shock. patients were recruited from june to november . we assessed the compliance with the different tasks included in the -h resuscitation bundle. furthermore, we ascertained within the first h after icu admission the compliance with those tasks not carried out within their specific time limits; we have called this variable ''bundle improvement at the icu''. results were stratified by the number of tasks of the bundle completed before admission at the icu, and the lag time between the beginning of severe sepsis and admission to the icu. these late completed tasks at the icu were related to hospital mortality by a cox regression model. objectives. the aims of this study were to assess the compliance rate with h bundle as defined in the surviving the sepsis campaign guidelines in patients diagnosed with sepsis regardless of severity and whether compliance affects the rate of mortality and/or hospital stay. we conducted a prospective observational study. we randomly recruited adult patients from acute admissions unit and intensive care in an acute district general hospital in england who met the diagnostic criteria for sepsis. for each patient, compliance with sepsis care bundle was obtained from medical notes. the following components of the h sepsis bundle were assessed: obtaining blood cultures, initiating antibiotic therapy, measuring serum lactate and in the event of septic shock administration of fluid therapy. conclusions. long and unacceptable delays in admission to iccu were identified despite evidence of significant organ dysfunction in many of these patients. with all bundle elements being met for only patient it is apparent that evidence based endpoints aimed at reducing mortality from severe sepsis are not being met despite all the bundle elements being practically deliverable. poor compliance with taking blood cultures prior to antibiotic administration and lack of scvo measurement are areas requiring particular attention. further work is recommended to identify potential contributing factors to non-compliance. introduction. international guidelines recommend that cardiac output measurement is required in addition to arterial pressure monitoring in patients with persistent shock after initial therapy [ ] . nevertheless, these recommendations are not supported by any comparison of arterial pressure and cardiac output for monitoring the effects of the most current treatments like fluid therapy. objectives. to evaluate in which extent monitoring the haemodynamic effects of a standardized fluid challenge with the sole arterial pressure could help for detecting the fluidinduced changes in cardiac index (ci). in critically ill patients with acute circulatory failure deemed at receiving a -ml saline infusion over min, we measured the systolic (sap), diastolic (dap), mean (map) and pulse (pp) arterial pressure and transpulmonary thermodilution ci before and after volume expansion.results. volume expansion significantly increased ci, sap, dap, map and pp by ± %, ± %, ± %, ± % and ± %, respectively. the fluid-induced changes in pp, sap and map were significantly correlated with the fluid-induced changes in ci (r = . , . and . , respectively). the changes (in %) in pp were significantly related to the changes (in %) in stroke volume for all quartiles but with different coefficients of correlation: r = . for the st quartile ( - years), r = . for the nd quartile conclusions. pp and sap were the best arterial pressure values for detecting the fluidinduced changes in ci. using the sole pp for assessing fluid responsiveness led to a non negligible proportion of false negative cases. this supports the recommendation that when a precise monitoring of fluid resuscitation is required, like in refractory shock, a direct assessment of cardiac output is required. objectives. aim of our study is to show that it is possible to reduce high catecholamines in previous improper volume resuscitated patients by forced volume resuscitation combined with active dose reduction and generate the hypothesis of an avoidable catecholamine induced circulation injury. introduction. the sialic acid content of the red blood cell (rbc) membrane decreases early in sepsis [ ] , and this alters the rbc shape and metabolism [ ] . an increased ratio of the rbc proteins band /alpha spectrin was observed in a mouse model of septic shock, suggesting a possible alteration of the rbc membrane integral/peripheral proteins ratio [ ] . as there are interspecies differences in membrane composition, these observations need confirmation in humans. we studied rbcs from patients with (n = ) and without (n = ) sepsis at icu admission and on day in the septic patients. exclusion criteria were recent rbc transfusion, hematologic diseases, cirrhosis and diabetes mellitus. procedures included screening for rbc membrane protein alterations by cryohemolysis test and separation of the rbc membrane and skeletal proteins by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate [ ] . comparison between groups was made by the student's t test or the mann-whitney test. a p value . was considered as statistically significant.results. the hemogram, including reticulocyte count was similar in septic and non-septic patients at icu admission. no significant difference was observed for cryohemolysis test results and the amount of the rbc proteins (table ) . objectives. our purpose was to compare a new method (patrol fr - ) with the reference method (randox tm ) during cbp. patients scheduled for coronary artery bypass (cb) and aortic valve replacement (avr) under cbp were enrolled after written informed consent in this protocol approved by local ethics committee. anesthesia protocol was standardized with systematic use of tranexamic acid. three blood samples were harvested: t = induction; t = min. after cross aorta clamping; t = h after induction. the patrol method was performed after serum exposition to a photosensibilizer agent then to a laser irradiation leading to the formation of free radicals. oxidation by those free radicals of a fluorometric sensor allowed an indirect measure of tas. this measurement in arbitrary unit (au) corresponded to area under curve compared to a control value from a pool serum. a value higher than indicated a lower capacity for the given serum to neutralize free radicals whereas a lower value indicated a higher capacity. the same sample allowed tas determination (lmol/l) with randox tm method. results were expressed as absolute numbers, mean ± sd. tas were compared with anova test; p \ . was significant.results. the seven patients ( male, female; ± years old) enrolled underwent cardiac surgery ( cb and avr) without any problem. there was no variation in tas determination with the randox tm method: t : . ± . ; t : . ± . ; t : . ± . lmol/l. conversely a two fold significant increase was measured during cpb with the patrol method: ti: . ± . ; t : . ± . *; t : . ± . au. *p \ . versus t .conclusions. oxidative stress due to overwhelming release of reactive nitrogen/oxygen species (rn/os) is held largely responsible for sepsis-induced organ failure and mortality [ ] . up-front and/or ongoing distortion of the pro-oxidant/anti-oxidant balance is likely to play an important role in this situation and in ischemia-reperfusion. therefore the patrol test which appeared to be more sensible than the randox tm method could a good tool in these cases and for evaluation of new anti-oxidant treatments in critical care medicine. these results have to be confirmed in a larger population. introduction. sepsis is the leading cause of death in critically ill patients. despite attempts to improve standardized strategies in resuscitation and treatment of sepsis, the morbidity and mortality remain unacceptably high. early diagnosis and stratification of the severity of sepsis is the key to start timely the appropriate treatment. sepsis is the systemic inflammatory response syndrome to infection; it can lead to hypoperfusion and organ dysfunction and at the cellular level to aerobic mitochondrial dysfunction. lactate is the product of anaerobic metabolism and thus may serve as a prognostic factor in this subset of patients.objectives. the authors propose to test the association of the first serum lactate at hospital admission with shock and icu mortality in patients with community-acquired severe sepsis. during the study period , patients were admitted in the unit, of those ( %) had severe community-acquired severe sepsis (cass). crude icu mortality rate among cass was %. considering the model previously described in methods and when the variables were adjusted only gender, age, saps ii, severity of sepsis and serum lactate were retained in the final model for icu mortality and saps ii nad serum lactate for shock (see table ). a first blood lactate level was independently associated with shock and icu mortality in patients community-acquired severe sepsis admitted in intensive care. objectives. the objective of this study was to test whether svo can predict fluid responsiveness in these patients. we studied patients who were monitored with a pulmonary artery catheter for severe sepsis and septic shock. hemodynamic measurements were obtained before (baseline values) and after a fluid challenge with colloids or crystalloids. responders were defined as those with a[ % increase in cardiac index (ci). no additional interventions were performed during the test. student's t test and linear correlation were used for the statistical analysis.results. mean patient age was ± years and the mean sofa score ± . mean arterial pressure was ± mmhg, cardiac index . ± . l/min/m , pulmonary artery balloon-occluded pressure ± mmhg, and heart rate ± bpm. thirty-four patients ( %) responded to the fluid challenge. responders and non-responders had similar baseline svo ( ± vs. ± %, p = . ). baseline svo was[ % in responders ( %) and in non-responders ( %). there was no correlation between changes in ci (%dci) and the baseline svo (fig. ) . sepsis is a disorder of microcirculation [ , ] . although the pathogenesis of microvascular dysfunction in sepsis is extremely complex, neutrophil activation and their interaction with endothelial cells are considered central features of sepsis-induced microcirculatory alterations. to our knowledge, however, no study evaluated the microvascular pattern of septic patients with chemotherapy-induced severe leukocytes depletion.objectives. to assess early microcirculatory response to sepsis in patients with and without drug-induced neutropenia.methods. demographic and hemodynamic variables together with sublingual microcirculation recording (ops-sdf videomicroscopy) were collected in four groups of subjects: septic shock (ss, n = ), septic shock in neutropenic patients (nss, n = ), neutropenia without inflammation (neutr, n = ) and healthy controls (crtl, n = ). except for controls, all measurements were repeated after complete resolution of septic shock and/or neutropenia (tp ). collected video-files were processed using appropriate software tool and semi-quantitatively evaluated (functional capillary density, fcd (cm/cm ); mean flow index, mfi [ ] ) [ ] . conclusions. microvascular derangements in sepsis did not differ between non-neutropenic and neutropenic patients. surprisingly, neutropenia per se without measurable systemic inflammation was also associated with alterations of the sublingual microcirculation. although we cannot exclude the role of residual neutrophils, our data could indicate that leukocytes are not the only and exclusive modulators of septic microvascular dysfunction. in addition, the role and mechanisms of microvascular changes associated with chemotherapyinduced neutropenia warrants further investigation. multiple organ failure is a leading cause of death in critically ill patients. improvements in outcome will most rely on our capacity to measure rapidly accessible biomarkers.objectives. to investigate if the time sequence of reactive oxygen metabolites (roms) production with sofa score could be prognostic for outcome. the study included critically ill patients (from september to december ) who had roms measured (hydroperoxides) during icu stay, when the diagnostic criteria for sepsis (observed n = ), severe sepsis (observed n = ) and septic shock (observed n = ) were present, - days and weeks after the diagnosis (samples n = ); on the same days, the sofa score was calculated. the plasma roms values were assayed by a diacron-italia kit, applied to an automatic instrument (olimpus au ). statistical analysis was performed used mann-whitney test and the linear regression analysis. the roms values and sofa score were inversely correlated (r = . for sepsis; r = . for severe sepsis; r = . for septic shock). the droms (the difference between the first and the last measurement of roms levels in each individual patient) was significantly different between survivors and non-survivors. clinical characteristics of the patients are presented in table . values are presented as median and interquartile rangers. a p value . was considered as statistically significant.conclusions. the plasma roms values decreased when the critically conditions rapidly evolved towards organ failures with higher sofa. to explore: (a) stress neuropeptides (acth, cortisol, prolactin, neuropeptide y (npy) and substance p (sp)) in critically ill subjects and controls, (b) potential association between levels of stress neuropeptides, disease severity and pain. a prospective correlational study, with repeated measurements and cross-sectional comparisons. fifty-three critically ill patients with diverse primary diagnoses and -age and gender-matched healthy controls were studied for days. serum neuropeptides were quantified by elisa (npy, sp) and chemiluminescence immunoassays (acth, cortisol, prolactin). pain levels were assessed by payen and puntillo scales. clinical severity was quantified by multiorgan failure scoring system (mof) and the multiple organ dysfunction score (mods). results. we observed: (a) statistically significant differences between critically ill and control subjects in regard with cortisol (p \ . ), npy (p \ . ) and sp (p \ . ) levels throughout the study. specifically, cortisol levels were higher and npy and sp levels were lower in patients compared to controls, (b) significant bivariate associations between stress neuropeptides (p \ . ), (c) statistically significant associations between acth and pain intensity levels assessed by payen (r = . , p = . ) and puntillo (r = . , p = . ) scales. there was also a constant but not statistically significant (p = . ) trend for lower sp levels in patients receiving opioids than in controls. moreover, npy levels were significantly lower in patients receiving analgesia (p = . ), (d) lower acth and cortisol levels in survivors (p \ . ) (e) at the day of least severity, a significant association between sp levels and mof was observed (r = . , p \ . ).conclusions. (a) despite the fact that npy and sp are stress neuropeptides, their levels appear to be decreased in mods patients. it is worth-exploring whether critical illness may be a state of suppressed activity of some neuropeptides, (b) the observed association between stress neuropeptide levels and survival in critical illness needs to be explore further, (c) bedside measurement of selected neuropeptides in the future may provide an estimation of pain in uncommunicative patients.hence, the study of stress neuropeptides may provide new insight for the management of the critically ill. objectives. the objective of this study was to compare septic and non-septic inflammatory process in critically ill patients with respect to paraoxonase activity, lipid profile and lipid peroxidation markers. methods. analyzed were serum paraoxonase activity, lipid profile, oxidized low density lipoproteins and conjugated dienes in critically patients with sepsis n = ), age/sex/ap-acheii matched critically ill controls with non-septic sirs (n = ) and age/sex matched outpatient controls without inflammation (n = ).results. the activity of pon was lower in septic patients ( . ± . u/ml) as well as in patients with non-septic sirs ( . ± . u/ml) compared to healthy controls ( ± . u/ml). the decrease in paraoxonase activity, high density lipoprotein cholesterol and apolipoprotein a- concentrations was closely followed by the counter increase of serum amyloid a in both groups of patients. there was no difference in paraoxonase activity between septic and non-septic critically ill patients. the concentration oxidized low density lipoproteins and conjugated dienes as markers of lipid peroxidation, were raised in both septic and non-septic sirs critically ill patients as compared with healthy controls. however there was no difference between both critically ill patient groups.conclusions. the decreased activity of paraoxonase in negative correlation with lipid peroxidation markers offers a potentially useful nonspecific marker of inflammation in critically ill patients.grant acknowledgment. objectives. in the present study, we studied the short-term and direct effects of ivig with sepsis.methods. patients was investigated. following the administration of g of ivig for h, we took blood samples immediately following ivig treatment and at h after ivig treatment. blood samples taken at h and just prior to ivig administration were used as controls. while there was no difference between h before and just prior to ivig treatment, statistically significant decreases were observed in the levels of il- after the administration of ivig. no significant changes were observed in the levels of tumor necrosis factor-a and high mobility group box- .changes in serum tnfa, il- , hmgb we confirmed the results of previous animal studies. while we reported that the administration of ivig directly reduces the levels of il- in patients with sepsis, a further prospective study of the ant-cytokine effects following ivig treatment will be conducted in the near future. objectives. to investigate the levels of nucleosome in septic patients and to determine whether nucleosome could serve as a biomarker for sepsis. sixty-four consecutive patients who were newly admitted in surgical intensive care unit at two university hospitals were enrolled in this study. whole blood samples were drawn within h of admission and on the third, fifth and seventh days. a last blood sample was drawn after recovery at icu discharge in survivors or at imminent death in the cases of non-survivors. plasma levels of nucleosome as well as cytokines il- and il- were detected by means of enzyme linked immunosorbent assay. . fifty patients were diagnosed as sepsis and the other fourteen patients were classified as controls. plasma levels of nucleosome were significantly higher in septic patients than in controls (two-way anova, p \ . ), while the levels of il- and il- were comparable between septic patients and controls. the septic patients presented the highest levels of nucleosome on the admission day, which was significantly different from the admission levels of nucleosome in controls ( . ± . vs. . ± . , p \ . ). the plasma levels of nucleosome between survivors and nonsurvivors showed no statistical significance.conclusions. plasma levels of nucleosome may serve as a valuable biomarker for sepsis.introduction. high mobility group box protein (hmgb- ) is a cytokine that can mediate inflammatory response in different conditions included rheumatoid arthritis, infections, sepsis and septic shock. hmgb- released by activated macrophages/monocytes acts as a late mediator of sepsis. studies have shown that serum hmgb- concentrations were elevated in patients with severe sepsis.objectives. in the present study, we evaluated the role of the hmgb- levels at the time of admission at the intensive care unit (icu) as predictor of outcome in patients with sepsis and septic shock.methods. forty-four patients admitted to the icu with sepsis and septic shock was recruited. serum samples were obtained at the time of admission for the determination of hmgb- levels. the results were correlated with the origin of sepsis, severity, organ dysfunction, requirements of mechanical ventilation and vasoactives, days at the icu, comorbidities and mortality at the icu and days after admission. twenty-six patients were male ( . vs. . %). septic shock was present in patients ( . %). the mortality rate at the icu was . % (n = ) and . % (n = ) at day th. hmgb- levels were . ng/ml ± . ( . - . ng/ml). hmgb- levels were significantly higher in non-survivors at the icu than in survivors ( . ng/ml ± . vs. . ± . , p \ . ). higher levels of hmgb- in serum at the admission were correlated with a higher mortality rate in the icu (p \ . ) but not at day th (p = . ). these levels were not correlated with days at the icu, requirements of vasoactives, mechanical ventilation, and apache score.conclusions. the determination of hmgb- levels at admission at the icu in patients with sepsis and septic shock is a good predictor of worse outcome and lethality.introduction. recent experimental and clinical data ( , ) support the hypothesis that costimulatory molecules, such as cd , play an essential role in the innate immune response during sepsis. expression of cd on the surface of monocytes could represent an important pathway in the modulation of the production of several key inflammatory mediators.objectives. to investigate whether the expression of cd molecule on the surface of plasma monocytes differs among the various stages of sepsis. a total of participants ( icu patients with sepsis, icu patients with septic shock and healthy controls) were included in the study (male patients . %, mean age . ± . years). inclusion criteria: icu patients on mechanical ventilation with first episode of sepsis or septic shock during current hospitalization. exclusion criteria: immunosuppression, neoplasia, autoimmune disease, cardiovascular disease. age, gender and comorbid conditions were recorded. a blood sample for quantification of cd expression was obtained at the time of enrollment (day ), and on the fifth day after the onset of sepsis; measurement was made on the same day. cd expression on the surface of plasma monocytes (on days and ) was assessed by flow cytometric analysis. statistical analysis: kruskal-wallis test to identify difference of cd expression among the groups was performed. post-hoc analysis was made by mann-whitney u test between independent groups, using bonferroni correction for multiple comparisons. roc curve analysis was used to determine the accuracy of cd in identifying patients with sepsis or septic shock. patients with sepsis had significantly higher levels of cd (day ) compared with healthy controls subjects ( . ± . vs. . ± . , p b . ). on the contrary, patients with septic shock did not show any significant difference compared with controls. a roc curve analysis for cd (day ) (auc = . , p b . ), revealed that a cut-off value of . could predict patients with sepsis with a sensitivity of % and a specificity of %.conclusions. upregulation of cd expression may reflect a protective phenomenon during sepsis. on the contrary, low cd expression could represent impaired immune function associated with more severe disease. in order to increase the cardiac output in the septic shock patients, according to surviving sepsis campaign team, norepinephrine (ne) or dopamine administration was recommended. the both agents increase the sympathetic tone which antagonize against parasympathetic activity used for gastrointestinal motility (involved gastric emptying). then, it is raised a question whether ne delayed the gastric emptying or not.objectives. this study was aimed to evaluate the gastric emptying in the septic shock patients with norepinephrine. a prospective observational study involved adult septic shock patients, who received ne continuously in icu sardjito general hospital (yogyakarta, indonesia). patients with any head pathologies (trauma, surgical procedures for tumor or bleeding), any gastrointestinal or abdominal pathologies (diarrhea, trauma, surgical procedures for cancer, peritonitis, ileus etc.), and administrations of metochlopramide or alinamin were excluded. nutrition fluids ( ml) was given passively via nasogastric tube, then after min the tube was aspirated. the volumes of aspirates were recorded in % as a gastric residue. once measurement was done with time randomly for every patient. at the measurement time were recorded the dose of ne and the vital signs.results. the gastric residues were . ± . % ( patients), . ± . % ( patients) and . ± . % ( patients) for the doses of ne of . , . and . lg/kg b.w./ min respectively. at the ne doses of . , . and . lg/kg b.w./min, all of the gastric residues were zero ( patients). the correlation between the ne doses and the gastric rescues was statistically significant (p: . ). the mean arterial pressures (map) were . ± . mmhg (ranges from to mmhg. there was no significantly correlation between map and the gastric residues.conclusions. the gastric emptying in the septic shock patients was not disturbed by administration of ne. introduction. anemia is a frequently encountered problem on the intensive care unit. several factor lead to anemia, among which are traumatic blood loss and the drawing of blood for routine laboratory tests. it's not known how this may affect innate immunity. hepcidin is a central regulator of iron homeostasis. it is induced in response to iron and inflammation and reduced in response to anemia and hypoxia. the suppression of hepcidin leads to the internalization and degradation of the iron exporter ferroportin on intestinal cells and macrophages, leading to the uptake of iron from the gut and the release of iron from the macrophages from the reticulo-endothelial system (res). these cells are central to the innate immune response and the altered iron status of these cells due to suppression of hepcidin may affect the inflammatory response of these cells. we tested the hypothesis that phlebotomy in human volunteers would lead to a suppression of the innate immune response. this abstract provides data of a pilot study carried out in subjects. to investigate the effect of phlebotomy on the innate immune response of whole blood in human volunteers.methods. three volunteers were subjected to the letting of ml of blood by phlebotomy. blood for the determination of hemoglobin and iron parameters, leucocyte count and differential, and hepcidin- was drawn at day , and after phlebotomy. further whole blood stimulation was carried out at each time point by adding . ml heparin anticoagulated whole blood to a prepared tube containing endotoxin, pam cis or rpmi as a control. final concentrations of lps and p c were ng/ml and lg/ml respectively. these tubes were incubated at °c for h and centrifuged for min at , g. the supernatant was frozen at - until the measurement of tnf-alfa and il- by elisa. cytokine production was corrected for the number of monocytes present. data are expressed as mean ± sem. hemoglobine decreased from . ± . mmol/l at baseline to . ± at day . it returned to normal at day . there were no apparent changes in serum iron levels. there was however a clear decrease in serum ferritin levels from ± at baseline to ? at day . leucocyte count and differentiation did not show any significant changes. hepcidin was clearly suppressed from to day after phlebotomy (from ± to ± ). tnf-alfa production dropped from to ng/ monocytes at day . il- production dropped from to ng/ monocytes. hepcidin levels correlated well with cytokine production (r . for tnf-alfa, r . for il- ).conclusions. phlebotomy leads to suppression of the innate immune response in whole blood. this could be a result of the intracellular decrease of iron in immune cells due to the systemic suppression of hepcidin. these findings are relevant to critical care patients that are subject to the repeated drawing of blood while their immune system is often compromised. introduction. hypothermia and hyperthermia occur in many pathological states presenting to the emergency department. both these processes are known to significantly impair coagulation pathways but as yet there is little evidence to show what affect they have on the evolving clot structure. previous studies have attempted to determine the effect of temperature on whole blood coagulation using techniques such as thromboelastometry (teg) but its ability to provide meaningful outcomes in terms of clot quality and structure remains elusive. recent studies have highlighted the potential of a new technique, gel point (gp) and fractal dimension (d f ), as a functional biomarker in haemostasis. to explore both the changes in coagulation pathways and their associated effect on clot structure and quality based on the new biomarkers, gp and df. following full ethical approval, healthy whole blood samples were obtained from individuals and tested at temperatures of °c (n - ), °c (n - ), °c (n - ), °c (n - ), °c (n - ). an oscillatory shear technique [ ] using an ar-g instrument (ta instruments) was applied to each sample. the gp, which indicates the formation of the fibrin network, was obtained for each sample using the chambon-winter gel point criterion [ ] . this method provides the basis from which d f can be determined [ ] to interpret the structural properties of the clot network. the results were compared with the standard teg analysis. firstly, results showed a significant progressive change in the clot structure by this new biomarker across the whole temperature range ( - °c). secondly, it also highlighted a significant and meaningful correlation between coagulation pathway change (time to gp, tgp) and the eventual clot outcome (fractal dimension). the tgp of the incipient clot was prolonged and the corresponding d f decreased with reduced temperature values. although, the changes in the coagulation pathway of the teg (r time) and the rheometer (tgp) correlated, the new biomarker, d f , provided additional structural data on the fibrin network formed and highlighted the relationship between coagulation pathway changes and the eventual fibrin clot structure.conclusions. in this study, we describe and quantify for the first time how temperature affects the coagulation pathways and how this impacts on the fibrin clot network, morphology and strength by using the new biomarkers, gp and d f . the potential of these new biomarkers in determining the effects of temperature change in critical illness and injury needs to be evaluated clinically. key: cord- -cvb v v authors: dahlberg, jørgen; eriksen, camilla; robertsen, annette; beitland, sigrid title: barriers and challenges in the process of including critically ill patients in clinical studies date: - - journal: scand j trauma resusc emerg med doi: . /s - - -x sha: doc_id: cord_uid: cvb v v background: clinical research in severely ill or injured patients is required to improve healthcare but may be challenging to perform in practice. the aim of this study was to analyse barriers and challenges in the process of including critically ill patients in clinical studies. methods: data from critically ill patients considered for inclusion in an observational study of venous thromboembolism in norway were analysed. this included quantitative and qualitative information from the screening log, consent forms and research notes. results: among eligible critically ill patients, ( %) were omitted from the study due to challenges and barriers in the inclusion process. reasons for omission were categorised as practical in ( %), medical in ( %), and legal or ethical in ( %) of the patients. among included patients, ( %) consents were from patients and ( %) from their next of kin. several challenges were described herein; these included whether patients were competent to give consent, and which next of kin that should represent the patient. furthermore, some included patients were unable to recall what they have consented, and some appeared unable to separate research from treatment. conclusions: barriers and challenges in the inclusion process led to the omission of near three out of four eligible patients. this analysis provided information about where the problem resides and may be solved. the majority of challenges among included patients were related to issues of autonomy and validity of consent. trial registration: clinicaltrials.gov (nct ). clinical studies in severely ill or injured patients are essential to improve healthcare. there are, however, several barriers and challenges in actually including critically ill patients in clinical studies. such obstacles may cause eligible patients fulfilling inclusion and exclusion criteria to be omitted from a study for various reasons. among the included patients, there may be difficulties in retrieving valid consent for study participation. a next of kin consent is often provided in cases when patients are incompetent to give consent. previous studies have identified obstacles when performing research in critically ill patients at intensive care units (icu) related to challenges in the recruitment process [ ] [ ] [ ] [ ] . some studies have described practical, ethical or legal challenges in obtaining informed consent [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . other studies have debated that such patients have compromised autonomy and reduced capacity to decide [ ] [ ] [ ] [ ] [ ] . there is an ongoing debate on how to protect the patients in such research, and how to obtain a next of kin consent [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the legislation and clinical practice vary across the world, and a prior pubmed search did not disclose any resent scandinavian research covering the overall barriers and challenges in the process of including critically ill patients in clinical studies. the purpose of this study was to identify practical, medical, legal or ethical barriers and challenges in the process of including critically ill patients in the norwegian intensive care unit dalteparin effect (norides) study. the primary aim was to identify and quantify barriers and challenges among eligible patients considered for inclusion and among included patients. a secondary aim was to report qualitative data on study investigators experiences during the inclusion process. the norides study was a prospective, observational study of consecutive adult icu patients admitted to oslo university hospital in norway between december , , and march , . the aim was to investigate the effect of thromboprophylaxis with dalteparin in critically ill patients with and without acute kidney injury (aki) treated with renal replacement therapy. patients included in the norides study received standard treatment with additional doppler ultrasound screening of veins to detect venous thromboembolism (vte), and additional blood samples drawn from intravascular catheters for coagulation analyses. the main results of the norides study describing the occurrence, risk factors and outcome of vte is published [ ] , and additional results of coagulation tests are pending. in the norides study, informed consent for participation was obtained from the patients or their next of kin in cases when patients were incompetent to give consent. when consent was provided from next of kin, patients were later informed wherever possible that they were included and had the right to withdraw from the study. data from all patients considered for inclusion in the norides study were included in this study; a detailed description of the study population is provided elsewhere [ ] . data were collected from the screening log, consent forms and research notes from study investigators in the norides study. quantitative data were collected on the number of patients omitted from the norides study, although they fulfilled the inclusion criteria and the reasons for such omission. we also collected data on the number of consents obtained from the patients or next of kin, and the number of oral and written consents. qualitative data on the study investigators experiences were collected. notations were analysed and categorised in order to identify challenges and barriers experienced during the inclusion process and while collecting data from the patients. in the norides study, patients were eligible according to the inclusion and exclusion criteria predefined in the study protocol. five of these were later excluded as predetermined because they were dispatched from the icu within h. among eligible patients, ( %) were omitted from the study due to challenges and barriers in the inclusion process (fig. ) . the reasons for omission were categorised as practical in ( %), medical in ( %), and legal or ethical in ( %) of the patients, respectively (fig. ) . practical reasons for omission were lack of capacity to include, previous inclusions, communication barriers and too many patients without aki already included. medical issues causing omission from the study were low or high patient weight, plasmapheresis treatment and hygienic reasons. legal or ethical reasons for omission were psychiatric conditions and end-of-life care (detailed description is presented in table ). informed consent was provided for all patients included in the norides study. among these consents, ( %) were from patients, and ( %) were from their next of kin. of the consents from patients, ( %) were oral, and ( %) written (fig. ). in cases with oral consents, study investigator ensured a signature from a witness who was not part of the study. several patients disclosed that they did not recognise their signature on the consent form directly after having signed. in cases, a valid consent could not be obtained from the patient, and consent was therefore obtained from their next of kin. among these patients, were on mechanical ventilation during their icu stay, and remained on mechanical ventilation during the whole icu stay. ten of these patients died at the icu, and six were transferred to another icu department. the study investigators experienced several factors affecting the inclusion process (fig. ). they described that it was especially challenging to determine whether their severely ill patients were autonomous and competent to give consent. it appeared difficult to assess whether the patient actually "understood" what the information entailed due to their physical condition, treatment and mental state. even though patients appeared to understand, appreciate, provide reasoning and express a choice, they still experienced that some of these patients were unable to recall being part of a study. even though the information had been transferred thoroughly during inclusion, many patients did not remember that they had consented. when study investigators discovered this, they later sent a copy of study information and consent along with the patient at discharge from the icu. some patients were also unable to separate treatment from research, and when study investigator performed doppler ultrasound of veins, some patients thought this procedure was part of their hospital treatment. another challenge reported by study investigators was difficulties in engaging next of kin. one challenge was the process of identifying which next of kin that should represent the patient, and how to solve any discrepancies in cases where several persons were involved as next of kin. in the norides study, this was solved by obtaining consent from several next of kin in some cases. another difficulty was to meet the next of kin, as they were often present at the hospital at evenings or weekends when study personnel were absent. because of this, some consents from next of kin initially was obtained during telephone consultation, with later personal meeting and written consent. study investigators felt that it was problematic to mix their roles as treating physician and researcher for the same patients. they noted concerns that some patients may have consented to participation to keep the goodwill of the doctor. they also noted that it was difficult to assess autonomy and valid consents as many of the patient appeared to have reduced, but not necessarily absent, ability to understand. this study revealed that near three out of four eligible patients fulfilling predefined inclusion, and exclusion criteria were omitted from the study due to barriers and challenges in the inclusion process. such loss of participants in a study represents a possible source of attrition bias that alters the participants in a study [ ] . because omitted patients are not a random sample of eligible patients, this may affect study outcomes. the reasons for omissions in the present study were most often practical, followed by legal or ethical, and medical. the study revealed that some challenges might be avoided with better planning of the study or more resources available for study investigators, whereas other problems may be considered unavoidable. many factors do clinical research in critically ill patients challenging. the number of critically ill patients is limited, and patients are often acutely admitted outside working hours. the patients represent a heterogeneous group with variable baseline characteristics and acute organ dysfunctions. because they have reduced body functions and require intensive treatment, the risk of study participation is high. in order to limit variability in the case-mix study and ensure the safety of patients, study investigators often use narrow inclusion criteria and broad exclusion criteria compared to researchers in safer elective settings. lack of capacity to include (n = ) patients admitted to the icu in periods where there were no study investigators available to include or adequately follow up patients were omitted, for instance, during holiday periods. patients already included in the study who were readmitted to the icu were omitted to avoid double inclusion. communication barriers (n = ) foreign language patients or next of kin where consent could not be acquired due to communication barriers in spoken and/or written communication were omitted. too many without acute kidney injury already included (n = ) the protocol for the norides study required two evenly distributed patient groups with and without acute kidney injury, some patients without acute kidney injury were omitted to achieve even numbers in the groups. low or high patient weight (n = ) patient weights were considered important for some of the outcomes of the study, patients below kg or above kg were therefore omitted as low or high patient weight were not exclusion criteria in the study protocol. lasmapheresis treatment (n = ) plasmapheresis treatment was considered important for some of the outcomes of the study; patients treated with plasmapheresis were therefore omitted from the study as it was not an exclusion criterion in the study protocol. the study involved an investigation with a doppler ultrasound apparatus that could potentially transfer infectious diseases from one study participant to another; some patients were omitted to ensure infection prevention and control. psychiatric conditions (n = ) patients admitted to the icu following suicide attempts were omitted as it was not an exclusion criterion in the study protocol. however, the study personal considered that inclusion could add potential strain for the participants. end-of-life care (n = ) study personal omitted patients who were not expected to survive at admission or had treatment withdrawal during icu stay. both circumstances were not exclusion criteria in the study protocol. however, the study personal considered that inclusion could add potential strain to the patients or next of kin. results are presented as numbers (n); icu intensive care unit, norides study norwegian intensive care unit dalteparin effect study dahlberg et al. scandinavian journal of trauma, resuscitation and emergency medicine ( ) : as observed in the present study, researchers studying critically ill patients often end up with a relatively small proportion of admitted patients fulfilling eligibility criteria. many patients in our study were omitted for reasons not necessarily specific to critically ill patients. these reasons may, however, have a more significant impact on this specific group of patients. for instance, since critically ill patients and their next of kin often are in a crisis, study investigators asking for consent should be able to understand the situation and act appropriately. under these circumstances, obtaining consent should be performed by a person familiar with this setting. another example may be hygienic considerations because critically ill patients are at high risk to become infected, hygiene will usually be prioritised higher than in most other clinical settings. other reasons herein may be more numerous and specific for critically ill patients, such as ethical considerations in end-of-life care. the practical reasons to omit patients from the present study could, to some extent, have been avoided. an issue that could be handled by extending the list of exclusion criteria in the study protocol was previous inclusion. lack of capacity is here a significant contributor to omitting patients. under ideal circumstances, this could be reduced with more resources available aiming at having available staff capable of obtaining informed consent h a day, seven days a week or (if feasible) extending the timeframe of inclusion. the communication barrier could, to some extent, have been reduced by providing interpreter services, but this is often problematic with critically ill patients in an icu setting. an alternative might be to add non-native speakers to the exclusion criteria in the study protocol. the challenge with too many without aki already included seems unavoidable, unless researchers are willing to change the population of interest in the study or amending the inclusion system to in-roll in two groups. all the medical reasons to omit patients in this study could have been identified as exclusion criteria in the initial protocol. however, with the complexity and heterogeneity of critical care patients, it may be challenging to identify all relevant exclusion criteria during the planning of a study, and several issues may be identified first after inclusion of patients has started. the legal or ethical reasons to omit patients were pointed out as the most challenging by the study investigators. the reasoning for both the psychiatric and end-of-life care omission was the intent to lessen the burden for the patients and next of kin. this is a questionable assumption since participation could be conceived as a meaningful contribution to science for these patients [ ] [ ] [ ] . in our study, no patients were omitted because they were unable to consent or that researchers were unable to determine consent competence. challenges in obtaining consent were identified primarily as a problem regarding how to obtain valid consent for patients enrolled. the challenges herein were, therefore, questions regarding whether the patient still obtained personal autonomy by being competent to consent or not, alternatively by whom and how consent should be obtained from next of kin. a general principle when obtaining patient consent is that the patient must be competent to give consent. this is often interpreted as a requirement for the patient to be able to understand, appreciate, reason and express a choice with regards to a specific question [ , ] . although some useful tools are developed to aid in these assessments, they only provide general guidelines that must be interpreted in a clinical setting [ ] [ ] [ ] [ ] . the ability of critically ill patients to understand may vary depending on several fluctuating factors such as medication, tiredness and severity of illness, and the assessment of decision-making capacity may be challenging [ , ] . there is norwegian and international legislation regulating informed consent from the patient or next of kin in clinical research [ ] [ ] [ ] [ ] . the current norwegian legislation requires that the patient "clearly do not understand what the consent entails" in order to conclude on the lack of competence [ ] . the assessment and decision on whether the patient is competent falls on the person responsible for obtaining the consent. under this rule, the patient shall be treated as competent to consent if it is probable that the patient understands. in our study, the researchers made their assessments of patients' autonomy at the time of inclusion to the best of their ability. however, it remains unclear whether many of the enrolled patients had decision-making capacity at the time they consented. the fact that many were unable to recall having consented to be part of a study should probably be separated from consent competence [ ] . several options may be available to ensure that patients know that they have consented. one solution is to repeat the information several times to the patient; another is to provide information to their next of kin. a third possibility is to send written material about the study to the patients, for instance at discharge from the icu or by postal mail after discharge. our study revealed that % of patient consents were oral, even though study investigators tried to obtain written consent whenever possible. under norwegian law, oral consent is considered as binding as written consent [ ] . this may differ from other countries where specific requirements to written consent can pose a significant potential barrier on including critically ill patients in clinical studies. since the burden of proof is more challenging in oral compared to written consent, it might be good practice to ensure a witness when obtaining oral consent. our observation that many patients did not recognise their signature was probably because severe disease affected their handwriting capabilities or perception of the signature. less than half of the consents were directly from patients. the cause of this observation is for a large part due to the severity of illness in critically ill patients, which reduces their ability to be autonomous. critically ill patients are especially challenging compared to other patient groups since they often have reduced or fluctuating consciousness, severe illness and high mortality rates [ , ] . it is probable that these factors were present in our study, since many of the study participants were on ventilator treatment, and some died during icu stay. the organisation of hospital treatment is also an explaining factor, as several patients were transferred from the university hospital to a local hospital before regaining consciousness and thereby, competence to give consent. when the patients lack the competence to consent, representative consent may be obtained through the closest next of kin if researchers have approval for such practice [ ] . as observed in our study, next of kin consents may also be challenging, even though this is partly regulated by law [ ] . an obstacle is to decide which person that should be considered closest next of kin. this should be the person mentioned by the patient as their next of kin. if no such information is available, it should be the person who lives with the patient in a relationship resembling a marriage or partnership. if there is no such person, it should be the closest relative in the order of inheritance. an unsolved difficulty is how to handle disagreements in the question of consent between equally qualified representatives such as between parents or children. the regulations on appointing representation for patients without competence to consent may again differ significantly from other countries, thus providing this to be a variable barrier depending on the local jurisdiction. clinicians and researchers should be aware that there might be a discrepancy between patients and surrogate opinion about treatment and research [ , [ ] [ ] [ ] . an independent person who is neither part of the treating personnel nor engaged in the study may solve the challenges with patients and next of kin consent. in cases where researchers have approval for the use of such consent, this may prevent the misinterpretation of research being treatment, and add a third-party assessment. such a person should seek the preferences of the patient and aim to conclude according to the probable wish of the patient. the identified challenges in including critically ill patients in clinical studies raise concerns regarding how to ensure respect for the autonomy of patients [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . regarding this, researchers have to work within the local legal framework and practice shared decision-making. they also have an ethical obligation to act in the interest of the patient, and this may include several issues not covered by the legal requirements. researchers should intend to optimise the decision-making capacity of patients; this entails to provide practical support and have adequate timing of the question of study participation. rules of informed consent are similar in observational and interventional studies and independent of the risk of study participation. even though the legislation is similar, some argue that researchers have an ethical obligation to consider the risk profile of a study when obtaining consent and be especially cautious in high-risk studies [ ] . in line with this, the mix of roles as researchers and clinicians for the same patients should be avoided whenever possible, because researchers have an interest in having patients included. however, such a separation of the roles may be difficult in clinical practice due to the lack of trained personal available, especially at small hospitals. the described barriers and challenges in including critically ill patients in clinical research may have negative effects, including fewer study participants and thereby reduced statistical power. the main concern may be that omitted patients are not a random sample of eligible patients; this might affect study results because study participants are not representative of the population of interest. there may also be positive effects of omitting patients, for study quality, it may be necessary to avoid double inclusion and exclude patients with conditions that interfere with study outcomes. for patients, it is beneficial that they are protected against infectious diseases and having to consent under certain conditions as language barriers or end-of-life settings. such omissions should, however, be properly described when reporting study results to ensure transparency. this study has many limitations; including the single centre location, observational design and relatively low number of patients. our findings could have been broadened by including data from other studies on critically ill patients as the challenges and barriers expectedly may vary depending on the specific study. we also refer to norwegian laws and research, and it is clear that legislation and practice vary across the world. there is, therefore, a vast number of studies published touching on one or several of the challenges or barriers described by us pointing to other results. strength of the study is that we included all challenges and barriers in the process of including critically ill patients in clinical studies. the study also provides qualitative data on the study investigators experiences during the inclusion process. it is important to have data from scandinavian patients since they are previously not much described and might differ from other places. we observed that barriers and challenges in the process of including critically ill patients in research led to omissions of the majority of eligible patients from the study. this might be important information for clinicians and researchers, because such attrition bias may affect study outcomes. we further categorised these obstacles as practical, medical, legal or ethical, and discuss to which extent such obstacles are avoidable. the study revealed that most critically ill patients at icu were unable to provide written, informed consent for study participation. among patients who gave consent, we observed that the question of preserved autonomy and competence to consent was challenging. even though patients appeared to be competent under the given rules, some were still unable to recall what they had consented, and some appeared unable to separate research from treatment. the use of next of kin as surrogate decision-makers provides additional challenges. further studies on challenges and barriers in critical care research should be conducted in order to map out these important questions. supplementary information accompanies this paper at https://doi.org/ . /s - - -x. additional file . additional information. abbreviations aki: acute kidney injury; icu: intensive care unit; norides: norwegian intensive care unit dalteparin effect study; vte: venous thromboembolism research in emergency and critical care settings: debates, obstacles and solutions research recruitment practices and critically ill patients. a multicenter, cross-sectional study (the consent study) exploring obstacles to critical care trials in the uk: a qualitative investigation intensive care unit research and informed consent: still a conundrum ethics research in critically ill patients informed consent for procedures in the intensive care unit: ethical and practical considerations ethical considerations in consenting critically ill patients for bedside clinical care and research ethical challenges involved in obtaining consent for research from patients hospitalized in the intensive care unit informed consent in clinical care: practical considerations in the effort to achieve ethical goals how to protect incompetent clinical research subjects involved in critical care or emergency settings intensive care unit research ethics and trials on unconscious patients protecting participants of clinical trials conducted in the intensive care unit ethical issues of recruitment and enrollment of critically ill and injured patients for research compromised autonomy and the seriously ill patient can the patient decide? evaluating patient capacity in practice informed consent during the clinical emergency of acute myocardial infarction (hero- consent substudy): a prospective observational study informed consent in clinical trials in critical care: experience from the pac-man study an ethical analysis of proxy and waiver of consent in critical care research european legislation impedes critical care research and fails to protect patients' rights confronting the ethical challenges to informed consent in emergency medicine research inability to obtain deferred consent due to early death in emergency research: effect on validity of clinical trial results research without informed patient consent in incompetent patients the 'consent to research' paradigm in critical care: challenges and potential solutions enhancing the informed consent process for critical care research: strategies from a thromboprophylaxis trial the experience of surrogate decision makers on being approached for consent for patient participation in research a multicenter study icu research: the impact of invasiveness on informed consent obtaining surrogate consent for a minimal-risk research study in the intensive care unit setting who should consent for research in adult intensive care? preferences of patients and their relatives: a pilot study venous thromboembolism in the critically ill: a prospective observational study of occurrence, risk factors and outcome reporting of consent rates in critical care studies: room for improvement feasibility of conducting prospective observational research on critically ill, dying patients in the intensive care unit ethical challenges in conducting research on dying patients and those at high risk of dying strategies for enhancing family participation in research in the icu: findings from a qualitative study clinical practice. assessment of patients' competence to consent to treatment bioethics for clinicians: . capacity cmaj sunnybrook & women's college health sciences centre does this patient have medical decision-making capacity? the norwegian health research act article , lov- - - - , § hforsknl the norwegian patients´rights act article - , lov- - - - , § - pbrl doing research on the ethics of doing research the norwegian health research act article , lov- - - - , § hforsknl the norwegian patients´rights act article - , lov- - - - , § - pbrl surrogate and patient discrepancy regarding consent for critical care research family understanding of seriously-ill patient preferences for family involvement in healthcare decision making barriers and facilitators to initiating and completing time-limited trials in critical care publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable.authors' contributions jd, ar and sb contributed to the conception and study design, acquisition of approvals, analysis and interpretation of data, drafting and revising the manuscript. ce contributed to the analysis and interpretation of the data and critically revised the manuscript. all authors read and approved the final manuscript. the authors declare that they have no competing interests. ( ) : key: cord- -gzqd g k authors: vitug, sarah; ravi, vikas; thangathurai, duraiyah title: sedation with ketamine and fentanyl combination improves patient outcomes in intensive care units date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: gzqd g k psychological manifestations such as depression and suicidal ideation are commonly caused by poorly controlled pain, anxiety, and sleep deprivation in intensive care unit (icu) patients. we are concerned that previous analgesic and sedative techniques administered as single-medication approaches are outdated and inadequate. it is imperative that icu practitioners are knowledgeable in multimodal approaches to pain and sedation in high acuity settings. we have shown that appropriate combinations of ketamine and fentanyl are effective, and if further supplementation is needed, we utilize additional pharmacological agents in low doses and regional techniques that ultimately lower the overall opioid consumption. we acknowledge that a variety of medication supplementations tailored to the patient’s clinical needs and nature of surgery improves a patient’s outcome in icu and overall quality of life. pain, anxiety, and sleep deprivation are commonly experienced by intensive care unit (icu) patients. often, these issues may result in psychological manifestations such as severe depression, demoralization, hopelessness, delirium, psychosis, delusions, ptsd, and, occasionally, suicidal ideations. in these scenarios, patients lose the will to live, as severe hopelessness and learned helplessness may cloud decision-making which may result in patient request for termination of care. the neuroendocrine stress responses often associated with noxious conditions can produce deleterious hemodynamic, metabolic, nutritional, and immunologic changes. prevention or timely treatment of symptoms can reduce the need for large doses of sedatives. however, irritation by the endotracheal tube may result in coughing and fighting the ventilator, which necessitates large doses of sedatives. this further complicates the management of patients on ventilatory support. asynchrony between spontaneous ventilatory efforts and machine-delivered breaths predisposes to pulmonary barotrauma, interferes with alveolar gas exchange, and increases the work of breathing [ ] . inappropriate hyperventilation is a common occurrence and may lead to hypocapnia, respiratory alkalosis, and hemodynamic disturbances. for these reasons, sedation is mandated, which also provides amnesia. neuromuscular paralysis may be used to decrease patient resistance to ventilatory support; however, side effects such as prolonged muscle weakness and myopathic changes are associated with these drugs. earlier sedation practices relied primarily on intermittent intravenous narcotics such as morphine sulfate, meperidine, or methadone [ ] . benzodiazepines such as diazepam, lorazepam, and midazolam, and barbiturates such as phenobarbital and pentobarbital were given when amnesia or hypnosis was required. these drugs are known to cause addiction, potentially leading to increased tolerance and functional changes within the brain. long-acting sedatives and narcotics often cause respiratory and circulatory depression, which may prolong the stay on respirators. opioid sedatives can also decrease gastrointestinal function and increase the risk of aspiration pneumonia, by slowing motility and prolonging ileus. for the last years, we have adopted a multimodal approach for pain and sedation, such as ketamine and fentanyl combinations for many of our postoperative icu patients. of note, the majority of our patient population have undergone major oncologic surgeries at the norris cancer institute/usc. a multimodal approach minimizes the requirement of individual medications and their potential side effects. in patients who are resistant to sedation, we add medication in addition to ketamine and fentanyl, such as low-dose propofol, midazolam, or dexmedetomidine [ ] . if analgesic requirement is high, we supplement with iv infusions of acetaminophen. ketamine, in particular, has many beneficial effects such as hemodynamic stability, bronchodilation, and minimal respiratory depression. ketamine also has many powerful analgesic and amnesic properties [ ] . ketamine is used in acute and resistant-depressive states, which is common in the icu [ ] . although the rate of hallucinations and nightmares is less than %, these psychotomimetic reactions are attenuated when ketamine is combined with a benzodiazepine or opioid. a concomitant infusion of an opioid or ketamine augments the sedation, provides analgesia, and reduces drug requirements. adding fentanyl to ketamine as an appropriate combination can provide excellent analgesia and reduce further sedative or analgesic requirements. we have been using a ketamine and fentanyl combination in surgical oncology icu for over years with excellent results, including early extubation, early return of gastrointestinal function, fewer hemodynamic/ respiratory complications, minimal psychological issues including depression and psychosis, shorter icu stays, and overall decreased morbidity and mortality. the purpose of our multimodal approach to pain and sedation in the postoperative icu setting is to improve the quality of care for our patients by minimizing undesired effects associated with analgesic agents. in standard practice, ketamine is commonly used in larger doses for induction and anesthesia maintenance. intraoperatively, higher doses of ketamine are associated with hypertension, tachycardia, and arrhythmias. postoperatively, hallucinations and psychotic states are occasionally associated with ketamine. ketamine use may result in medication-related psychotic states in patients with a history of psychoses such as schizophrenia or similar disorders, substance abuse/withdrawal, or medication-induced or metabolic-related causes. thus, we take extra precautions in patients with relevant psychiatric or medical histories. we found that by using sub-anesthetic doses of ketamine in combination with either low-dose fentanyl or midazolam, the incidence of psychotic symptoms is minimized. occasionally, we supplement ketamine with low-dose dexmedetomidine infusion or quetiapine (seroquel) in those who develop persistent psychotic symptoms. we acknowledge that even lowdose ketamine and supplementary analgesic/sedative agents can precipitate unwanted medication-induced psychotic symptoms and other side effects; thus, continued close monitoring of postoperative icu patients under this multimodal regimen is advised. authors' contributions all authors dutifully fulfill the following criteria: -substantial contributions to the conception or design of the work or the acquisition, analysis, or interpretation of data for the work -drafting the work or revising it critically for important intellectual content -final approval of the version to be published -agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved sedating patients in intensive care units analgesia and sedation in intensive care early sedation with dexmedetomidine in critically ill patients ketamine by continuous infusion for sedation in the pediatric intensive care unit ketamine and depression publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. sn compr conflict of interest the authors declare that they have no conflict of interest. key: cord- -nsrs dmc authors: waldeck, frederike; boroli, filippo; suh, noémie; wendel garcia, pedro david; flury, domenica; notter, julia; iten, anne; kaiser, laurent; schrenzel, jacques; boggian, katia; maggiorini, marco; pugin, jérôme; kleger, gian-reto; albrich, werner christian title: influenza-associated aspergillosis in critically-ill patients—a retrospective bicentric cohort study date: - - journal: eur j clin microbiol infect dis doi: . /s - - - sha: doc_id: cord_uid: nsrs dmc influenza was recently reported as a risk factor for invasive aspergillosis (ia). we aimed to describe prognostic factors for influenza-associated ia (iaa) and poor outcome and mortality in critically ill patients in switzerland. all adults with confirmed influenza admitted to the icu at two swiss tertiary care centres during the / influenza season were retrospectively evaluated. iaa was defined by clinical, mycological and radiological criteria: a positive galactomannan in bronchoalveolar lavage or histopathological or cultural evidence in respiratory specimens of aspergillus spp., any radiological infiltrate and a compatible clinical presentation. poor outcome was defined as a composite of in-hospital mortality, icu length of stay (los), invasive ventilation for > days or extracorporeal membrane oxygenation. of patients with influenza in the icu, ( %) were diagnosed with iaa. all patients with iaa had poor outcome compared to ( %) patients without iaa (p < . ). median icu-los and mortality were vs. days (p < . ) and / ( %) vs. / ( %; p = . ) in patients with vs. without iaa, respectively. patients with iaa had significantly longer durations of antibiotic therapy, vasoactive support and mechanical ventilation. aspergillus was the most common respiratory co-pathogen ( / , %) followed by classical bacterial co-pathogens. iaa was not associated with classical risk factors. aspergillus is a common superinfection in critically ill influenza patients associated with poor outcome and longer duration of organ supportive therapies. given the absence of classical risk factors for aspergillosis, greater awareness is necessary, particularly in those requiring organ supportive therapies. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. influenza infection has been recently defined as a risk factor of invasive aspergillosis [ , ] . influenza can cause severe pneumonia and acute respiratory distress syndrome (ards) [ , , ] . respiratory bacterial superinfection of influenza represents a common complication with high mortality [ , , , , ] . bacterial pathogens superinfecting influenza pneumonia have changed over time probably as a function of both different hosts and influenza strains. these include haemophilus influenzae, streptococcus pyogenes, staphylococcus aureus and streptococcus pneumoniae [ ] . s. pneumoniae was the most common pathogen in the pandemic [ ] and s. aureus emerged as another frequent co-pathogen during the / h n pandemic [ , ] . high prevalence of pseudomonas aeruginosa superinfection has been reported in intensive care unit (icu) patients [ , ] . superinfection with aspergillus spp. has been increasingly described since the electronic supplementary material the online version of this article (https://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. / influenza pandemic [ , , , ] associated with even higher mortality ( - %) [ , , , , ] . iaa is independent of influenza type (a or b [ , ] ) and also affects immunocompetent hosts. between - % of influenza patients in the icu [ , , ] , less frequently in north america ( . %) [ ] and % of immunocompromised influenza patients have been reported to have iaa [ ] . predictors of iaa, poor outcome and mortality in influenza patients in the icu remain unknown. since no data on iaa was available from switzerland, we retrospectively analysed all patients with severe influenza infection needing treatment in two large swiss icus during the / influenza season with regard to predictors of iaa, mortality and poor outcome. in this retrospective cohort study, sixteen icus of tertiary hospitals in switzerland were asked if they had observed cases of iaa and severe influenza and routinely looked for iaa based on clinical suspicion with galactomannan and fungal cultures in bal; only two of them met the criteria (cantonal hospital of st. gallen and university hospital of geneva). all adults (≥ years) with confirmed influenza infection during the / influenza season (december -april ) admitted to the icu for ≥ h of those centres were included. patients whose influenza diagnosis occurred after the discharge from the icu were excluded. influenza infection was diagnosed by polymerase chain reaction (pcr) from nasopharyngeal swab, sputum or bronchoalveolar lavage (bal). patients were identified from the icu databases, infectious diseases and hospital epidemiology databases in order to improve identification of patients and reduce reporting bias. the study was approved by the local ethics committees (ekos - ). there was no funding. the primary aim was to identify predictors of iaa in critically ill patients with influenza infection. secondary aims were to detect predictors of mortality and poor outcome of severe influenza infection. poor outcome was defined as a composite of icu length of stay (los) ≥ days, need of extracorporeal membrane oxygenation (ecmo), invasive ventilation for ≥ days or in-hospital death. ards was diagnosed according to the berlin criteria [ , ] . a. definitions iaa was defined by clinical, radiological and mycological criteria according to the modified criteria of iaa by schauwvlieghe et al. and blot et al. (supplementary table ) [ , ] . records of all iaa patients were reviewed and consensus was achieved by investigators from both centres whether criteria of iaa were fulfilled. the platelia assay "aspergillus ag" (biorad) was used to detect gm. respiratory superinfection was defined as (i) detection of clinically relevant bacterial or fungal pathogen in respiratory specimens or positive blood cultures that was treated with antibiotics or antifungals, respectively, (ii) a positive pneumococcal urinary antigen, pneumocystis jirovecii antigen in bal or positive gm in serum or bal ( table in the appendix). other superinfection included all respiratory superinfections, bacteraemia, catheter-associated infections and clostridioides difficile colitis. organ supportive therapies were defined as need of renal replacement therapy, vasoactive support, invasive mechanical ventilation and ecmo. continuous variables were assessed by t tests or mann-whitney u tests as appropriate. for categorical values, comparison was done by fisher's exact test. missing data were not imputed. a two-sided p value < . was considered as statistically significant. given the small number of each outcome, only the univariate but not the multivariable analyses are reported. data analysis was performed with sas (version . , sas institute inc., cary, nc, usa) and r core team ( , r foundation for statistical computing, vienna, austria). of patients identified from the databases, were excluded ( patients per centre) and were included and analysed. median follow-up time was days. nine patients had iaa ( %). there were no statistically significant differences in baseline characteristics between patients with and without iaa ( table in the appendix). immunosuppressive diseases were uncommon in both groups. during hospitalization, corticosteroids were initiated in half of all influenza patients ( % vs. % in iaa and non-iaa, p = . ). / ( . %) patients with influenza a had iaa and / ( %) with influenza b (p = . ). duration of influenza symptoms before diagnosis of influenza was significantly longer in those with iaa (median duration days (interquartile range (iqr) - ) vs. days (iqr - ) in non-iaa, p = . ), whereas there was no difference in duration of symptoms until hospitalization (median duration days (iqr - ) in iaa and days (iqr - ) in non-iaa, p = . ). iaa symptoms started after a median of days after icu admission. iaa was diagnosed after a median of days after icu admission and days after first symptoms of influenza (iqr - and - days respectively). gm was measured in % of all patients ( % in iaa and % in non-iaa, p < . ). gm was positive in of ( . %) patients in non-iaa and of ( %) samples with iaa (p < . ). all patients with positive gm had antibiotics prior to gm testing, as had of ( . %) patients with a negative gm (p = . ). two patients with iaa and negative gm had therapy with voriconazole started on the same day as gm testing was performed. it cannot be excluded that treatment was started before bal was performed which could have caused in a false-negative test result. eight of patients with iaa had radiologic infiltrates and nodules. there were no positive cultures of aspergillus spp. in non-iaa patients but growth of aspergillus spp. in ( %) patients with iaa, mainly aspergillus fumigatus ( of patients). organ supportive therapies and complications were more frequent in iaa patients than in non-iaa patients ( table in the appendix). median duration of antibiotic treatment ( vs. . days), invasive mechanical ventilation ( vs. days), vasoactive support ( vs. days), hospital-los ( vs. days) and icu-los ( vs. days) were significantly extended in iaa compared with non-iaa patients (fig. ) . the length of stay in the icu was significantly elevated in iaa patients (fig. ) . treatment with antivirals (oseltamivir with or without zanamivir) was initiated in all patients with iaa and % of non-iaa patients (p = . ). mold-active antifungal treatment was initiated in patients ( patients each with iaa and non-iaa because of presumed iaa during hospitalisation). median duration of antifungal treatment was days (iqr . - . ) in iaa. antifungal treatment was stopped when diagnostics were negative in those without iaa. corticosteroids were used during hospitalisation in . % of patients ( % in iaa vs. . % in non-iaa, p = . ) and before influenza diagnosis in of of patients with iaa and in of of patients without iaa ( % vs. %, p = . ). all patients with iaa had poor outcome compared with % of non-iaa patients (p < . ). iaa patients had more bacterial or fungal (other than due to aspergillus spp.) respiratory superinfections ( % vs. %, p = . ). other infectious complications were catheter-related bloodstream infections and oropharyngeal and oesophageal candidiasis. aspergillus (n = ) was the most frequent respiratory co-pathogen in influenza patients. other common pathogens were s. aureus, s. pneumoniae, s. pyogenes and gramnegative bacteria (fig. ) . invasive mechanical ventilation, vasoactive support, ecmo, any complication, respiratory and any superinfection were significantly associated with mortality and poor prognosis ( table in the appendix). our study has several main findings. iaa is a severe and relatively frequent complication affecting % of patients with influenza treated in two swiss icus. aspergillus represented the most frequent respiratory co-infection of influenza in this cohort. patients with influenza were most commonly superinfected with aspergillus spp. despite lacking classical risk factors of invasive aspergillosis. in our study, all patients with iaa had poor outcome and needed more frequently and longer organ supportive therapies such as invasive mechanical ventilation, renal support and vasopressors. further risk factors for poor outcome were respiratory superinfections. iaa patients in our study did not have classical risk factors for aspergillosis such as underlying immunosuppressive disease, hematologic malignancies, solid organ or haematopoietic stem cell transplantation or immunosuppressive medications before hospitalisation. instead, severe influenza infection was frequently their unique risk factor. the occurrence of iaa independent of classical risk factors of invasive aspergillosis has been previously reported [ , , , ] . one study showed higher mortality in immunosuppressed patients with iaa in comparison to immunocompetent patients [ ] . reported risk factors for iaa are male sex and corticosteroid therapy prior to the influenza infection [ , ] . the latter might explain the relatively high number of patients with obstructive lung diseases [ ] . we identified the need for prolonged organ supportive therapies in the icu as a predictor for iaa. the length of icu was significantly elevated. because of small sample size, a competitive risk analysis was not performed. since iaa can occur in the absence of underlying diseases, requirement of vasoactive therapy, rapidly deteriorating respiratory failure and progressive multiple organ failure might be useful alerts for icu physicians of iaa in severely ill patients with influenza. surprisingly, in our cohort, aspergillus was identified as the most common respiratory superinfecting pathogen in influenza infection. aspergillus was seen in % of all respiratory copathogens in our analysis in contrast to . - . % of positive cultures from respiratory specimen reported in the literature [ , ] . bacterial pathogens are more frequently reported as influenza co-pathogens than aspergillus [ , ] . bacterial coinfections in influenza showed increasing trends over the last years (from . % in to % in ) while aspergillus isolation from culture was relatively stable at~ % in a study of spanish icus [ ] . bacterial respiratory superinfection was even more common in our analysis ( %). concurrently, s. aureus and s. pneumoniae were frequently observed in our analysis as were gram-negative bacteria including p. aeruginosa. respiratory co-infections were significantly associated with duration of antibiotic use, organ supportive theraphies and los in patients with iaa (light green) and without iaa (dark green). boxplots show th and th percentile with horizontal bar indicating median and whiskers the th and th percentile. outliers are shown with dots. *only vv-ecmo-treated patients were analysed for duration of ecmo. niaa = patients without influenza-associated invasive aspergillosis, iaa = patients with influenza-associated aspergillosis, ecmo = extracorporcal membrane oxygenation, los -lenght of stay, icu -intensive care unit, vent -ventilation kaplan-meier curve on the probability and lenght of icu stay in iaa (light green) and non-iaa patients (dark green). probability to stay on the icu is shown on x-axis, days after admission to icu are shown on y-axis. iaa = influenza-associated aspergillosis, niaa = patients with influenza without aspergillosis fig. kaplan meier curve on the probability of icu stay in iaa and non-iaa patients mortality in our univariate analysis. association of co-infection with s. aureus, p. aeruginosa or aspergillus spp. with mortality has been described [ ] . therefore, influenza patients at risk for respiratory superinfection need to be identified and early diagnostics and treatment need to be implemented. the increasing reports of iaa could be due to greater awareness and lower threshold for more and more sensitive diagnostics or indeed an increasing prevalence of this fungal disease. iaa was first reported in [ ] but only received attention of a wider audience in the last decade after the influenza h n pandemic [ , , , ]. an influencing factor could be the wide use of corticosteroids [ ] and neuraminidase inhibitors for influenza infections in the icu. in our analysis, many influenza patients received corticosteroids during hospitalization ( . %) with a non-significant difference between patients with or without iaa, despite data showing increased mortality of influenza pneumonia with corticosteroid use [ , ] . corticosteroid use has been associated with aspergillosis independently of influenza infection [ , , , ] and corticosteroid use prior to influenza infection has been associated with iaa [ , ] . furthermore, experimental in vitro studies and studies in mice indicate that neuraminidase inhibition decreases immune response by impaired cytokine production in response to aspergillus spp. this effect is also seen with corticosteroid and neuraminidase treatment [ ] . this implies that therapy of influenza with neuraminidase inhibitors and corticosteroids might increase susceptibility and predispose to mold infection in influenza. we hypothesize that a greater use of neuraminidase inhibitors since the influenza pandemic could have contributed to the emergence of iaa. alternatively, as recently reported in a retrospective cohort study from alberta, canada, from to , different influenza seasons may be associated with varying rates of iaa. in their study, schwartz et al. identified a considerably higher rate in the most recent / season [ ] . gm values in bal in our study were slightly lower than in previous reports ( - % [ , , ] or even % among patients with underlying respiratory diseases [ ] ), which may have been in part due to the possibility that patients with negative bal gm might have received voriconazole prior to diagnostic testing. interestingly, two patients, who met our criteria for iaa, were not or only briefly treated with antifungal therapy. both patients survived. we cannot definitely exclude colonisation with aspergillus because no histological examination was done. elevated gm, long duration of invasive ventilation ( and days) and icu los ( and days) argue in favour of iaa in these two patients. these two patients could have had a less severe form of iaa. importantly, of patients had cultural evidence of aspergillus spp., arguing against false-positive gm results. iaa is a relatively new field of research with few clinical studies and no prospective data. because iaa patients do not fulfil eortc criteria for invasive fungal disease [ ] new diagnostic criteria were proposed [ , , ] . these criteria do not allow for graduation of classification as with eortc criteria (possible, probable, confirmed ia), have not been evaluated prospectively and diagnosis of iaa remains difficult. furthermore, optimal treatment duration remains a matter of debate. iaa likely represents a heterogeneous entity and a benign course of disease could be possible although previous studies suggest otherwise with reported mortality of - %, and % in taiwan [ , , , , ] . mortality in our cohort was in concordance with previous reports in non-immunocompromised patients ( %) [ ] . our study has a few limitations. firstly, it is limited by the retrospective design. we cannot rule out that cases of aspergillosis have been missed but the rarity of positive gm tests or growth of aspergillus in cultures in the non-iaa group and the poor outcome in iaa which would lead to diagnostic work-up suggest otherwise. however, the true incidence of iaa might have been even higher. secondly, two patients without iaa did not fulfil mycological iaa criteria but received long antifungal therapy for presumed iaa during hospitalisation and had extended los on the icu. therefore, differences concerning outcomes might have been underestimated between groups. furthermore, the generalisability is limited by small sample size. however, respiratory co-pathogens in influenza. pathogens were isolated from bal or blood cultures. *other gram-negative pathogens include escherichia coli, morganella morganii, haemophilus influenzae and proteus mirabilis ( isolate each) fig. number of isolated pathogens in patients with influenza patients' characteristics and mortality are concordant with previous studies on iaa. finally, owing to the retrospective design, it was not always possible to distinguish whether a complication was predisposing to iaa or a complication of iaa. of note, both hospitals are the only major tertiary care centres in their area. since all patients who fulfilled the listed criteria were included in the study, we consider recruitment bias unlikely. in conclusion, iaa represents an underappreciated complication of influenza infection with severe morbidity and mortality in swiss icus. only out of swiss icus participated in the study because screening and diagnosis of iaa were rarely done which is evidence for the poor awareness of this disease. while bacterial superinfection was frequent in influenza patients in the icu, aspergillus was even more common. the need for organ support therapy might serve as a predictor of iaa. because of frequency and severity of disease, greater awareness of iaa is needed and lower thresholds for diagnostic testing (gm, bacterial and fungal cultures from bal) and treatment should be implemented in the icu, especially in patients requiring organ support therapies. a multicentre study including all university hospitals in switzerland and two tertiary care centres is on its way to confirm our study outcome and raise awareness of this severe entity. prospective studies are urgently needed to evaluate proposed diagnostic criteria, characterize clinical outcomes, identify patients at risk of iaa and define optimal antiviral and antifungal treatment and duration. authors' contributions w.f. and a. w.c. had the idea and initiated the study and wrote the protocol. w. f., b. f., s. n., w. g. p. d., a. w. c., m. m. and s. j. managed the study and collected the data. w. f., k. g. r. and a. w. c. were responsible for and performed the statistical analysis. w. f., b. f., i. a., b. k., k. g. r., a. w. c., k. l. and j. p. interpreted the data. w. f., k. g. r. and a. w. c. drafted the manuscript. all authors amended and commented on the final manuscript. conflict of interest the authors declare that they have no conflict of interest. y years, iqr interquartile range, copd chronic obstructive pulmonary disease, iaa influenza-associated aspergillosis, non-iaa influenza infection without aspergillosis, gm galactomannan, bal bronchoalveolar lavage, ta tracheal aspirate saps ii simplified acute physiology score, estimates mortality in icu patients [ ] . neutropenia is neutrophil count ≤ . g/l and lymphopenia is lymphocyte count ≤ g/l *any immunosuppressive condition included solid organ or haematologic stem cell transplantation, haematologic malignancy or any immunosuppressive drugs including corticosteroids before diagnosis of influenza **total of patients with gm measured ( cases had gm measured in bal (cut-off, optical density (od) ≥ . ) and serum (cut-off, od ≥ . [ ] ) ***total of patients ( cases had gm measured in bal and serum) pulmonary aspergillosis following post-influenzal bronchopneumonia treated with antibiotics isolation of aspergillus in three h n influenza patients: flu and aspergillus acute respiratory distress syndrome: the berlin definition definitions, mechanisms, relevant outcomes, and clinical trial coordination a clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients fulminant invasive pulmonary aspergillosis in immunocompetent patients-a two-case report invasive aspergillosis associated with severe influenza infections revised definitions of invasive fungal disease from the european organization for research and treatment of cancer/invasive fungal infections cooperative group and the national institute of allergy and infectious diseases mycoses study group (eortc/msg) consensus group a new simplified acute physiology score (saps ii) based on a european/north american multicenter study invasive aspergillosis complicating pandemic influenza a (h n ) infection in severely immunocompromised patients higher mortality of severe influenza patients with probable aspergillosis than those with and without other coinfections let's add invasive aspergillosis to the list of influenza complications invasive aspergillosis after pandemic (h n ) glucocorticoids and invasive fungal infections increased incidence of co-infection in critically ill patients with influenza use of early corticosteroid therapy on icu admission in patients affected by severe pandemic (h n )v influenza a infection the acute respiratory distress syndrome the co-pathogenesis of influenza viruses with bacteria in the lung invasive aspergillosis in the intensive care unit corticosteroid treatment in critically ill patients with severe influenza pneumonia: a propensity score matching study risk assessment and prognostic factors for mould-related diseases in immunocompromised patients corticosteroid treatment as a risk factor for invasive aspergillosis in patients with lung disease novel tests for diagnosis of invasive aspergillosis in patients with underlying respiratory diseases critical illness from pandemic influenza a virus and bacterial coinfection in the united states invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study high rates of influenza-associated invasive pulmonary aspergillosis may not be universal: a retrospective cohort study from alberta, canada invasive pulmonary aspergillosis and influenza coinfection in immunocompetent hosts: case reports and review of the literature autopsy series of cases dying before and during the influenza pandemic peak pandemic influenza a (h n ) pathogenesis of influenza-induced acute respiratory distress syndrome inhibition of host neuraminidase increases susceptibility to invasive pulmonary aspergillosis invasive pulmonary aspergillosis complicating severe influenza: epidemiology, diagnosis and treatment. curr o p i n i n f e c t d i s the acute respiratory distress syndrome invasive pulmonary aspergillosis is a frequent complication of critically ill h n patients: a retrospective study do corticosteroids reduce the mortality of influenza a (h n ) infection? a meta-analysis publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -mip mkef authors: jo, sungyang; chang, jun young; jeong, suyeon; jeong, soo; jeon, sang-beom title: newly developed stroke in patients admitted to non-neurological intensive care units date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: mip mkef background: little is known about newly developed stroke in patients admitted to the intensive care unit (icu). objective: this study aimed to investigate characteristics and outcomes of newly developed stroke in patients admitted to the non-neurological intensive care units (icu-onset stroke, ios). methods: a consecutive series of adult patients who were admitted to the non-neurological icu were included in this study. we compared neurological profiles, risk factors, and mortality rates between patients with ios and those without ios. results: of , patients admitted to the icu for non-neurological illness, ( . %) developed stroke (ischemic, n = ; hemorrhagic, n = ). the most common neurological presentation was altered mental status (n = ), followed by hemiparesis (n = ), and seizures (n = ). the most common etiology of ios was cardioembolism ( % [ / ]) for ischemic ios and coagulopathy ( % [ / ]) for hemorrhagic ios. in multivariable analysis, the acute physiology and chronic health evaluation ii (apache ii) score (adjusted odds ratio [aor] = . , % ci = . − . , p < . ), prothrombin time (aor = . , % ci = . − . , p = . ), cardiovascular surgery (aor = . , % ci = . − . , p < . ), mechanical ventilation (aor = . , % ci = . − . , p < . ), and extracorporeal membrane oxygenation (aor = . , % ci = . − . , p < . ) were related to the development of ios. stroke was associated with increased -month mortality after hospital discharge (aor, . ; % ci, . – . ; p < . ), after adjustment for apache ii and comorbidities. conclusions: patients who developed ios had characteristics of initial critical illness and managements performed in the icu as well as neurological presentations. the occurrence of ios was related to high morbidity and mortality. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. in conjunction with high incidence, in-hospital stroke showed lower rates in reperfusion therapy and greater risk of mortality compared with community-onset stroke [ ] [ ] [ ] . patients admitted to intensive care unit (icu) have distinct features such as unstable vital signs, coagulopathies, inflammation, as well as multiple comorbidities, and they often receive invasive procedures or surgical treatments. thus, there may be high risks of stroke as well as delays in the diagnosis of stroke during admission to the icu, leading to suboptimal management of critically ill patients [ , ] . early detection of acute stroke is imperative for saving viable brain tissues and recovery of neurologic deficits [ ] . time saving measures are being implemented at every step from symptom recognition, imaging studies, and treatments. however, early detection of stroke symptoms in icu-onset stroke (ios) is challenging, not only due to comorbidities, but also due to immobilization, medical equipment, and use of sedative agents [ , ] . accordingly, there are substantial barriers to the conduct of neuroimaging studies to reveal ios in the context of general critical care. comprehensive studies regarding ios are lacking, which limit the development of strategies for the prevention, early detection, and proper managements of ios. here, we aimed to investigate the neurological and radiological profiles, risk factors, and clinical outcomes of ios. furthermore, we aimed to investigate differences of such characteristics between ischemic and hemorrhagic strokes. this study was performed at asan medical center, a bed tertiary hospital in seoul, republic of korea. for this study, medical records of a consecutive series of icu patients between november st, and march st, were retrospectively evaluated. we included patients who ( ) were years of age or older, ( ) were admitted to clinical departments other than neurology and neurosurgery, and ( ) did not have acute stroke before icu admission. this study was approved by the institutional review board of asan medical center, and the need for written informed consent was waived because of the retrospective design of the study. according to the routine practice of our icus, neurological evaluations, including the glasgow coma scale, a pupillary size, light reflexes, and muscle strength (the medical research council scale), were performed and documented by nurses every − h. when nurses detected abnormal neurological findings during their routine evaluations, they notified such findings to treating doctors perform computed tomography (ct) or magnetic resonance imaging (mri) scans of the brain. we reviewed electronic medical records for patients' baseline characteristics, laboratory findings, and acute physiology and chronic health evaluation ii (apache ii) score at the time of admission to the icus [ ] . we investigated whether the patients underwent surgery (cardiovascular vs. non-cardiovascular surgery) and invasive cardiovascular interventions before the occurrence of stroke. moreover, we assessed the application of life-support modalities such as inotropic agents, mechanical ventilation, continuous renal replacement therapy, or extracorporeal membrane oxygenation (ecmo). systemic inflammatory response syndrome (sirs) was defined in accordance with international guidelines [ ] . we defined ios if ( ) ct and/or mri scans of the brain were performed during icu admission and ( ) ct and/ or mri images revealed findings compatible with acute infarcts, intracerebral hemorrhage (ich), or subarachnoid hemorrhage (sah). we dichotomized ios into ischemic ios (infarcts) and hemorrhagic ios (ich and sah). for patients with a diagnosis of ios, we categorized their symptoms (or signs) into categories such as altered mental status, seizures, pupillary changes (size and light reflexes), hemiparesis, and others. time domains such as last-knownnormal time, first-found-abnormal time, and time to initial neuroimaging studies were also reviewed. clinical outcomes included length of icu stay, length of hospital stay, mortality before icu discharge, mortality before hospital discharge, mortality at days after hospital discharge, and mortality at days from icu admission. we evaluated for the presence of vascular stenosis (> % reduction of vascular diameter) or occlusion, if the patient underwent cerebral angiography. the subtypes of ischemic ios were determined according to the classification of the trial of org , in acute stroke treatment (toast) [ ] . for patients with ich, we measured the ich score as well as the lesion location and volume [ ] . we categorized the etiologies of ich into hypertension, cerebral amyloid angiopathy, coagulopathy, medication (antiplatelet agents or anticoagulants), and unknown cause groups [ ] . for patients with sah, we reviewed ct brain scans to identify the presence of ruptured aneurysms and assessed sah severity using the modified fisher scale. neuroimaging studies (ct, mri, and angiographic studies) were reviewed jointly by two investigators and a third investigator was consulted in case of disagreements. treatment modalities for ischemic ios included antiplatelet agents, anticoagulants, intravenous thrombolysis, intraarterial thrombectomy, and neurosurgery, and those for hemorrhagic ios were categorized into either neurosurgical or medical treatments. we compared baseline demographics, comorbidities, apache ii score, the presence of sirs, laboratory findings, and treatment modalities between patients with ios and those without ios using χ tests, t tests, and kruskal-wallis tests, as appropriate. variables with a p value of < . by univariate analysis were included as candidate variables in multivariable analysis. backward stepwise selection was conducted to find factors associated with ios in multivariable logistic regression models. we further performed all analyses using a forward selection procedure to confirm the final model. we also compared the aforementioned variables between patients with ischemic ios and those with hemorrhagic ios. a cox proportional hazards model was used to assess the hazard ratios of -day mortality from icu admission according to the presence of stroke, with adjustments for demographics, comorbidities, and apache ii scores. kaplan-meier survival curves were also plotted for mortality of patients with ios and patients without ios. additionally, we evaluated the association between stroke and mortality, with adjustments for demographics, comorbidities, and apache ii scores using multivariate logistic regression. all statistical analyses were performed using r, version . . (r foundation for statistical computing, vienna. austria) and spss version . (ibm corp., armonk, ny, usa). a total of , patients were admitted to adult icus during the study period. of these, we excluded patients younger than years of age (n = ), those who were admitted to neurological and neurosurgical departments (n = ), and patients diagnosed with acute stroke before admission to the icu (n = ). thus, we finally included , patients. the median age of included patients was . years (iqr, . − . years) and , ( . %) patients were male. table shows baseline characteristics of the finally included , patients. altered mental status (n = ) was the most common neurological manifestation of ios (the reason to conduct neuroimaging studies), followed by hemiparesis (n = ), seizures (n = ), pupillary changes (n = ), and aphasia (n = ). comatose state ( . % vs. . %; p < . ) and pupillary changes ( . % vs. . %; p < . ) were more common in patients with hemorrhagic ios than those with ischemic ios, while aphasia ( . % vs. %; p < . ) and hemiparesis ( . % vs. . %; p < . ) were more common in patients with ischemic ios than those with hemorrhagic ios. (table i the main reasons for delays in stroke recognition included the use of sedative agents following surgery (n = ) or mechanical ventilation (n = ), presumed metabolic encephalopathy (n = ), and missed findings of neurological deficits during routine hourly evaluations (n = ) (as described for patients who had such a time interval beyond the median time of . h). patients with altered mental status as an initial stroke manifestation had time delays to the stroke recognition than patients without altered mental status (p = . ), while patients with seizure as an initial stroke manifestation had shorter time intervals for the stroke recognition than patients without seizure (p = . ). the main reasons for delays in neuroimaging study included unstable vital signs (n = ), the application of ecmo (n = ), poor cooperation of patients (n = ), and unknown reasons (n = ) (as described for patients who had a time interval beyond the median time of . h). patients with hemiparesis or pupillary changes as a stroke manifestation had shorter time intervals for neuroimaging studies than patients without those symptoms (p = . and . , respectively) ( table ) . radiological findings and presumed etiologies of ischemic ios and hemorrhagic ios are shown in table . of the patients with ischemic ios, cardioembolism ( . %) was the most common etiology of ischemic ios, followed by undetermined etiology ( . %), other determined etiology ( . %), large-artery disease ( . %), and small-vessel disease ( . %). other determined etiologies included cancer-related stroke (n = ), cerebral air embolism (n = ), and arterial dissection (n = ), and meningitis-related stroke (n = ). of the patients with ich, the most common etiology of ich was coagulopathy (n = ), and the presumed causes of such coagulopathy were liver disease (n = ), sepsis (n = ), and hematologic malignancy (n = ). among patients with sah, modified fisher scale was in patients and in patient, and only patient had a ruptured aneurysm. in the univariable analysis, risk factors associated with ios were older age, apache ii score, sirs, cardiovascular surgery, non-cardiovascular surgery, use of mechanical ventilation, continuous renal replacement therapy, and use of ecmo. the following laboratory findings were also associated with ios: hemoglobin level, platelet count, and prothrombin time (p < . for all variables of the patients with ischemic ios, antithrombotic agents (antiplatelet agents and anticoagulants) were given to patients. antithrombotic agents were not given to patients due to thrombocytopenia (n = ), hemoptysis (n = ), large infarct size (n = ), and for uncertain reasons (n = ). the reperfusion therapy rate for ios was . % ( / ; intravenous thrombolysis, n = ; intraarterial thrombectomy, n = ) in our study population. intravenous thrombolysis (infusion of alteplase) was attempted in patients. the reasons not to perform intravenous thrombolysis in the remaining patients were as follows: neuroimaging studies were performed beyond . h from the last-known-normal time (n = ), patients underwent recent major surgery (n = ), had large hemispheric infarct (n = ), prolonged activated partial thromboplastin time (n = ), mild neurological deficits (n = ), delays in decision-making (n = ), and uncertain reasons (n = ). of patients with large-artery occlusion, intraarterial thrombectomy was performed in patients. of the remaining patients, intraarterial thrombectomy was not attempted due to reasons such as the patients having absence of diffusion-perfusion mismatch (n = ), recent aortic surgeries (n = ), rapidly resolving neurological symptoms (n = ), unstable vital signs (n = ), or for uncertain reasons (n = ). two patients received decompressive craniectomy for large hemispheric infarcts. of the patients with hemorrhagic ios, ( . %) underwent surgical treatments including decompressive hemicraniectomy (n = ), decompressive hemicraniectomy with hematoma evacuation (n = ), and bilateral frontotemporal decompressive craniectomy (n = ). the length of icu stay was longer in patients with ios compared with those without ios (median days, . [iqr, (fig. ) . in the multivariable logistic regression analysis, patients with ios had higher mortality before icu discharge (aor, . ; % ci, . − . ; p = . ), before hospital discharge (aor, . ; % ci, . − . ; p < . ), and at days after hospital discharge (aor, . ; % ci, . - . ; p < . ) than patients without ios, after adjustments for apache ii score and comorbidities. the cox proportional hazard model showed that patients with ios had a hazard ratio of . in terms of mortality at days after hospital admission ( % ci, . - . ; p = . ) after adjusting for apache ii score and comorbidities (fig. ) . this is one of the largest studies reported to date on the rate of newly developed stroke during icu care in patients with non-neurological disease. we found the incidence of ios among adult patients admitted to icu with non-neurological critical illnesses was . % ( / , ). the proportions of patients with ischemic and hemorrhagic ios were % and %, respectively. cardiovascular surgery was associated with ischemic ios, and prothrombin time prolongation was associated with hemorrhagic ios; higher apache ii scores, mechanical ventilator and ecmo were associated with both ischemic and hemorrhagic ios. patients with ios had high mortality rates before hospital discharge ( %) and at days after hospital discharge ( %), which were approximately twice as high as the mortality rates of patients without ios. furthermore, the occurrence of ios was independently associated with . -fold increased risk of mortality at days from hospital discharge. the incidence of ios was higher than expected. during a median . days of their icu admission, . of patients developed ios, which was much more common compared with general population in korea (stroke incidence, per , person-years) [ ] . moreover, risk factors for ios in the current study were very different from well-known risk factors for community-onset stroke: critical conditions (e.g., apache ii score, cardiovascular surgery, mechanical ventilation, and ecmo), but not the premorbid conditions (e.g., old age, hypertension, diabetes mellitus, and atrial fibrillation), were related to ios. cardiovascular surgery was also a risk factor for in-hospital stroke [ ] . prothrombin time prolongation, which suggests increased bleeding tendency, was associated with hemorrhagic ios. this is in line with the most common etiology of ich; coagulopathy from sepsis, liver failure, and hematologic malignancy. we also found that the application of mechanical ventilation and ecmo was related to both ischemic and hemorrhagic ios. positive pressure ventilation may provoke thromboembolism by inducing hypercoagulable state, opening unrecognized patent foramen ovale, and new-onset atrial fibrillation [ ] [ ] [ ] [ ] [ ] . in addition, weaning from mechanical ventilation may induce hemodynamic changes and cardiac failure [ ] . exposure of blood to the ecmo circuit may result in the formation and embolization of thrombi. ecmo may also lead to platelet dysfunction and coagulopathy, and the use of anticoagulants may contribute to the occurrence of ich [ ] . these conditions might invoke or trigger both ischemic and hemorrhagic ioss in vulnerable patients who were admitted to the icu. the current study showed that neurological manifestations may differ between ischemic and hemorrhagic ios. aphasia and hemiparesis were more common in patients with ischemic ios than in patients with hemorrhagic ios, while altered mental status and pupillary changes were more common in patients with hemorrhagic ios than in patients with ischemic ios. the diagnosis of stroke based on clinical findings is important in ios, because there are high risks in transporting patients to the outside of the icu for neuroimaging studies [ , ] . it is important to recognize altered mental status as a potential clinical presentation of ios. the recognition of stroke is probably the first step to perform urgent brain and vascular imaging and allow rapid treatments. in patients admitted to the icu, however, altered mental status related to sedative agents are likely difficult to be differentiated from altered mental status as the presenting symptom of ios. the most common reason for delays in stroke recognition in our patients was the use of sedative agents following surgery and mechanical ventilation. unfortunately, altered mental status was also the most common neurological manifestation of ios. thus, delays in symptom recognition were substantial in our patients with altered mental status. to reduce delays in the stroke recognition for patients requiring sedative agents, targeting light sedation, interrupting sedative agents daily, and administering sedative agents with short contextsensitive half-time may be helpful [ , ] . patients with hemiparesis and pupillary changes had significantly shorter time intervals from the recognition of stroke symptoms to the performance of neuroimaging studies. such differences of time intervals according to neurological symptoms may be in part due to the physician's confidence of the occurrence of ios, otherwise, coexisting medical conditions such as unstable vital signs and applications of medical equipment could have interfered with the performance of neuroimaging studies. time delays in diagnosing stroke may contribute to low rates of reperfusion therapy, which may result in worse outcomes. reperfusion therapy was performed in only . % in patients with ischemic ios (intravenous thrombolysis, . %; intraarterial thrombectomy, . %), which is much lower than the reperfusion therapy rate in our previous study of emergency room treatment of community-onset stroke (intravenous thrombolysis and/or intraarterial thrombectomy, . %; intravenous thrombolysis, . %; intraarterial thrombectomy, . %) as well as that in korean nation-wide statistics for patients with community-onset stroke (intravenous thrombolysis, . %; and intraarterial thrombectomy, . %) [ , ] . notably, in % ( / ) of patients with ischemic ios, the reason to not conduct intravenous thrombolysis was delays in identifying stroke beyond . h from the last-known-normal time. these patients could have received thrombolytic therapy if their strokes were detected earlier, and such therapy could have improved their outcomes. these findings suggest that special attention is necessary to expedite assessments and therapies for patients with ios. the mortality rate at any stage from icu discharge to days after discharge was significantly higher in patients with ios than those without ios. we evaluated increased risk of mortality by stroke both at days after hospital discharge and days after admission, because stroke onset time was wide-ranging. the mortality rate at days after hospital discharge in patients with ios was %, which is approximately three times higher compared with mortality rate in patients without ios ( %) and mortality rate in patients with community-onset stroke ( %) [ ] . it is uncertain whether the high mortality rate of patients with ios resulted from ios per se or if the high rate resulted from an underlying medical illness or an interaction between an underlying illness and ios. however, the occurrence of ios was associated with mortality, even after adjustments for apache ii scores and comorbid conditions. these findings underline the importance of early detection and proper management of stroke in patients admitted to the icu with non-neurological critical illness. as most patients with ios are taken care of by general physicians and intensivists who do not specialized in stroke management, the activation of stroke code and specialized teams may be needed for patients with stroke symptoms [ ] . our study has limitations. first, this is a single-center retrospective study; thus, our findings should be interpreted cautiously for patients in other centers. second, the incidence of ios might be underestimated in our study. we defined stroke according to the findings on ct and/or mri images of the brain, but only % of icu patients underwent such neuroimaging studies, so patients who developed stroke but did not undergo neuroimaging studies, due to very unstable vital signs and early death soon after admission to the icu, may not have been identified as having ios. moreover, among patients who underwent brain scans for this study, as many as . % underwent ct scans without mri. it is possible that ct scans could have missed acute infarcts, because the sensitivity of ct for detecting acute infarct is lower than mri (diffusion-weighted imaging). third, neurological outcomes as evaluated with validated scales, such as the modified rankin scale, were not available for this retrospective study. the mortality and length of stay at icu and at hospital may be insufficient to evaluate clinical outcomes of stroke victims. patients with initially severe illness, cardiovascular surgery, prothrombin time prolongation, and application of mechanical ventilation and ecmo had high risks for developing acute stroke during their admission to the icu. substantial time delays ensued in the evaluation and management of ios. ios was associated with increased morbidity and mortality. these results call for strategies for prevention, early detection, and proper managements for ios. author contributions sj, jyc, and s-bj contributed to the concept and design of the study. sj, jyc, sj, sj, s-bj contributed to the acquisition and analysis of the data. sj and s-bj contributed to drafting the text, which was reviewed and revised by all co-authors. data availability all deidentified data that support the findings of this study are available upon reasonable request to the corresponding author from other researchers if ethical approval is granted. the authors have no conflicts of interest to declare. ethical standards this study was approved by the institutional review board of asan medical center. ethics approval and consent to participate this study was approved by the institutional review board of asan medical center, and the need for written informed consent was waived because of the retrospective design of the study. comparison of the characteristics for in-hospital and outof-hospital ischaemic strokes characteristics of in-hospital onset ischemic stroke -hospital stroke in a statewide stroke registry care and outcomes of patients with in-hospital stroke stroke in critically ill patients mr clean, a multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke in the netherlands: study protocol for a randomized controlled trial -hospital stroke critical care for patients with massive ischemic stroke efficacy of the apache ii score at icu discharge in predicting post-icu mortality and icu readmission in critically ill surgical patients surviving sepsis campaign: international guidelines for management of sepsis and septic shock classification of subtype of acute ischemic stroke. definitions for use in a multicenter clinical trial. toast trial of org in acute stroke treatment the ich score: a simple, reliable grading scale for intracerebral hemorrhage new ischemic lesions coexisting with acute intracerebral hemorrhage executive summary of stroke statistics in korea : a report from the epidemiology research council of the korean stroke society ventilator-induced coagulopathy in experimental streptococcus pneumoniae pneumonia a case of shunting postoperative patent foramen ovale under mechanical ventilation controlled by different ventilator settings transient increase in intrathoracic pressure as a contributing factor to cardioembolic stroke atrial fibrillation among medicare beneficiaries hospitalized with sepsis: incidence and risk factors pulmonary embolism in the mechanically-ventilated critically ill patient: is it different? weaning the cardiac patient from mechanical ventilation documenting the invisible in stroke-like symptoms during extracorporeal membrane oxygenation high-risk intrahospital transport of critically ill patients: safety and outcome of the necessary "road trip recommendations for the intra-hospital transport of critically ill patients clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the icu management of pain and agitation for patients in the intensive care unit multidisciplinary approach to decrease in-hospital delay for stroke thrombolysis neurological emergencies in patients hospitalized with non-neurological illness hemorrhagic transformation within hours of a cerebral infarct: relationships with early clinical deterioration and -month outcome in the european cooperative acute stroke study i (ecass i) cohort key: cord- -yn z authors: abe, toshikazu; yamakawa, kazuma; ogura, hiroshi; kushimoto, shigeki; saitoh, daizoh; fujishima, seitaro; otomo, yasuhiro; kotani, joji; umemura, yutaka; sakamoto, yuichiro; sasaki, junichi; shiino, yasukazu; takeyama, naoshi; tarui, takehiko; shiraishi, shin-ichiro; tsuruta, ryosuke; nakada, taka-aki; hifumi, toru; hagiwara, akiyoshi; ueyama, masashi; yamashita, norio; masuno, tomohiko; ikeda, hiroto; komori, akira; iriyama, hiroki; gando, satoshi title: epidemiology of sepsis and septic shock in intensive care units between sepsis- and sepsis- populations: sepsis prognostication in intensive care unit and emergency room (spice-icu) date: - - journal: j intensive care doi: . /s - - - sha: doc_id: cord_uid: yn z background: diagnosing sepsis remains difficult because it is not a single disease but a syndrome with various pathogen- and host factor-associated symptoms. sepsis- was established to improve risk stratification among patients with infection based on organ failures, but it has been still controversial compared with previous definitions. therefore, we aimed to describe characteristics of patients who met sepsis- (severe sepsis) and sepsis- definitions. methods: this was a multicenter, prospective cohort study conducted by intensive care units (icus) in japan. adult patients (≥ years) with newly suspected infection from december to may were included. those without infection at final diagnosis were excluded. patient’s characteristics and outcomes were described according to whether they met each definition or not. results: in total, patients with suspected infection were admitted to icus during the study, of whom ( . %) met the sepsis- definition and ( . %) met the sepsis- definition. the two groups comprised different individuals, and ( . %) patients met both definitions. in-hospital mortality of study population was . %. in-hospital mortality among patients with sepsis- and sepsis- patients was comparable ( . % and . %, respectively). patients exclusively identified with sepsis- or sepsis- had a lower mortality ( . % vs. . %, respectively). no patients died if they did not meet any definitions. patients who met sepsis- shock definition had higher in-hospital mortality than those who met sepsis- shock definition. conclusions: most patients with infection admitted to icu meet sepsis- and sepsis- criteria. however, in-hospital mortality did not occur if patients did not meet any criteria. better criteria might be developed by better selection and combination of elements in both definitions. trial registration: umin sepsis is an aberrant or dysregulated host response resulting in organ dysfunctions and is different from infection [ ] . it is not a single disease but a syndrome exhibiting with various symptoms caused by pathogens and host factors. sepsis should be immediately recognized because it is the primary cause of death from infection, especially if not diagnosed and treated promptly. sepsis- has high sensitivity [ ] but captures mild infection and not infectious diseases. sepsis- was established to improve risk stratification among patients with a suspected infection focusing on organ failures [ ] . when considering previous studies about the diagnosis and taxonomy of sepsis to date [ , , ] , nearly all of them just defined sepsis as cases of high mortality due to infectious diseases. sepsis studies may be controversial because they were unable to differentiate an aberrant or dysregulated host response itself from infection. the definitions of sepsis- and sepsis- have still been inadequate to accurately capture sepsis. therefore, both definitions may have misclassified patients with sepsis as patients with infectious diseases. although the true nature of sepsis remains to be identified, we should clearly know what the definitions of sepsis- and sepsis- indicate because different definitions could change its epidemiology to identify the clinical care, future research, and healthcare planning. such information would facilitate the definition criteria of the next sepsis. therefore, this study aimed to describe characteristics of patients who met sepsis- and sepsis- definitions. this multicenter, prospective cohort study was conducted in an intensive care unit (icu) subset of the japanese association for acute medicine sepsis prognostication in intensive care unit and emergency room (jaam spice-icu), including icus in japan from december to may . adult patients (≥ years) with newly suspected infection were included. suspected infection was defined by the administration of any kind of antibiotic, and thereby a culture of body fluids or imaging should be conducted to identify the infectious pathogen. all patients were admitted to the icus in study hospitals. exclusion criteria included patients who were not transferred from other hospitals and those without infection at the final diagnosis. data were extracted from the spice database, compiled by spice investigators. collected variables included relevant patient information, such as demographics, comorbidities, degree of clinical frailty, vital signs, and site of infection. in-hospital mortality was identified as the primary outcome. secondary outcomes were ventilator-free days (vfd), intensive care unit-free days (icu-free days), length of hospital stay (los), and condition at discharge. data collection was conducted as part of the clinical routine workup. spice site investigators recorded all data throughout the patient's hospital stays. if case of missing data, the spice committee requested a reconfirmation of data extraction from spice investigators. sepsis- was defined as having a suspected site of infection, ≥ systemic inflammatory response syndrome criteria (sirs) [ ] and ≥ organ dysfunction criteria [ ] . severe sepsis was actually defied as sepsis- according to the sepsis- definition [ ] . sepsis- was defined as having a suspected site of infection and organ dysfunction (an acute change in the total sequential organ failure assessment (sofa) score of ≥ points consequent to the infection) [ ] . regarding shock, sepsis- and sepsis- shocks were defined according to the sepsis- [ ] and sepsis- definitions, respectively [ ] (supplemental file ). frailty was defined according to the clinical frailty scale (cfs), an easy and intuitive determinable categorization tool based on simple visual descriptions [ ] . patients' status for cfs before hospital admission was obtained from patients themselves or their relatives. infection sites at final diagnosis included the lung, intraabdominal, urinary tract, soft tissue, central nervous system (cns), osteoarticular, endocardium, wound, catheter-related, implant device-related, others, or unidentified infections. the diagnosis of the infection site was recorded at discharge. acute physiology and chronic health evaluation ii (apache ii) score was calculated at the initial examination instead of the worst data within h. if apache ii score was missing, zero was used instead of missing data. sofa score was calculated similarly as the apache ii score. vfd was defined as the number of days within the first days postadmission that the patient can breathe without a ventilator. the vfd of patients who died during the study period was set as zero. icu-free days were calculated similarly with vfd. status at discharge was categorized as home, transfer to another facility (including longterm care and nursing homes), or death. patients with infection in icus were compared according to whether they met sepsis- or sepsis- definition. patients were divided into five groups: sepsis- ; sepsis- ; sepsis- and sepsis- ; sepsis- and no sepsis- ; no sepsis- and sepsis- ; and no sepsis- and no sepsis- . descriptive statistics included proportions for categorical variables, and medians (interquartile range [iqr]) of continuous variables were calculated because not all variables were normally distributed. a few missing data was considered missing randomly. no assumptions were made on these data. all statistical analyses were performed using the stata software version . (statacorp, tx, usa). a total of patients with suspected infection admitted to icus during the study period were included in this study. among them, ( . %) patients had sepsis- , and ( . %) had sepsis- ; most patients were overlapped; however, patients with sepsis- and sepsis- were different individuals. a total of ( . %) met both definitions, and exclusively met the sepsis- (only baseline sofa for sepsis- glasgow coma scale ( - ) ( - ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( - sepsis- ), and exclusively met the sepsis- (only sepsis- ) definition. a total of patients did not meet either of the definitions (fig. ) . majority of patients were admitted to the icus directly from the emergency departments (eds) ( . %). a total of ( . %) patients were positive for sirs, and ( . %) were positive for qsofa. a total of ( . %) patients met the sepsis- shock criteria, and ( . %) met the sepsis- shock criteria. table shows characteristics of patients with infection in icus according to sepsis definitions. the distributions of baseline characteristics such as age, sex, and comorbidities were comparable between sepsis- and sepsis- . the baseline sofa score for the sepsis- only group was (iqr, - ) although the baseline sofa for other groups was or . lactate and blood culture positivity were lower if they did not meet the definitions. the sofa score was lower if they did not meet any definitions. the trend in pathogens and antibiotics according to sepsis definitions was also nonspecific; however, blood culture positivity was lower if patients did not meet any definitions (sepsis- or sepsis- ), and carbapenem was more frequently used in patients who met any definitions (table ) . in-hospital mortality of study population was . %. in-hospital mortality among patients with sepsis- and sepsis- patients was comparable ( . % and . %, respectively) ( table ). patients exclusively identified by sepsis- or sepsis- had a lower mortality ( . % vs. . %, respectively). no patients died if they did not meet any definitions. patients who met sepsis- shock criteria had higher in-hospital mortality than those who met sepsis- shock criteria. characteristics and in-hospital mortality were compared according to sepsis- and sepsis- definitions in this prospective observational cohort of icu patients. almost all patients presenting to icu with infection fulfill both definitions, but what each definition identified is different. however, in-hospital mortality was zero if patients did not meet any definitions. better criteria might be developed by better selection and combination of elements in both definitions. nearly all patients admitted to icu with suspected infection fulfill both definitions in our study as well as in previous studies [ , ] . in a retrospective cohort study of icus in england, with similar setting as in our study, sepsis- and sepsis- definitions identified similar populations ( % overlapped), which is consistent with that of our study ( % overlapped). actually, % of patients overlapped if sepsis- definition was evaluated in sepsis- (severe sepsis) population in our cohort. their severity scores, such as the sofa, were derived from an estimation such as a receipt of organ support and could have been over-or underestimated in the study [ ] . another study also virtually calculated the sofa score, even though it is one of the most important elements in sepsis- definition [ ] . previous studies reported some variations of epidemiology by data sources, data acquisition timing, and interpretation of organ failure criteria in sepsis criteria [ , , ] . our prospective study was designed to compare sepsis- and sepsis- among patients with suspected infection and directly confirmed results of previous studies [ , ] . however, these minor variations in the precise interpretation of definitions may have not affect characteristic and mortality differences, especially in the icu setting [ ] . patients exclusively identified with sepsis- or sepsis- had different characteristics when compared to patients with both sepsis- and sepsis- . although a total of % patients were diagnosed with sepsis- using qsofa, only % of patients with sepsis- (−)/sepsis- (+) were diagnosed with sepsis- using qsofa. patients exclusively identified with sepsis- or sepsis- presumably included those who have clinically unmeasured features such as vague symptoms [ ] . patients who meet only one definition may need more attention because their symptoms were not prominent. since sepsis- captures high level of inflammation, a patient with sepsis- would still need further attention; however, a negative sepsis- does not meet the current definition of sepsis. in-hospital mortality differed by approximately four times between the sepsis- (+)/sepsis- (−) group and the sepsis- (−)/sepsis- (+) group ( % vs. %). although the number of patients was small, judging by one definition alone may cause misclassification of poor outcome patients who may be identified by the other definition. however, since they were actually in the icu, the physician did not misclassify the patients. this highlights the limitations of both the definitions. since sepsis- does not include an increased acute sofa score from the baseline, any chronic organ failure may possibly be regarded as an acute organ failure. sofa score was not identified even though sepsis- was defined based on this score, except for chronic organ failures. in our cohort, ( %) patients had "not available" (na) sepsis- baseline sofa, which was indicated as zero according to the sepsis- definition, although all data of chronic organ failures were tried to obtain. therefore, a number of patients with unknown chronic organ failures at baseline should have been included in those with acute organ failure in any definitions. either way, the sepsis- definition has become more clinically objectively understandable than the sepsis- definition. moreover, the sepsis- definition was originally easier to evaluate than the sepsis- definition. excluding sirs as the starting point for sepsis- did not affect the incidence as majority of patients with organ failures also tend to have sirs. the sepsis- shock was associated with a higher risk of death than sepsis- [ ] , because the sepsis- shock requires the presence of elevated serum lactate levels in addition to fluidresistant hypotension [ ] . the problem of sepsis diagnosis has been a little arbitrary, with differences in epidemiology. the sepsis- definition may be advantageous because it may increase the comparability of sepsis incidence and related mortality among studies by possibly reducing the subjective interpretation [ ] . a consistent diagnosis of sepsis and septic shock between institutions should be considered not only for research purposes but also for quality measurement. generally, severity scores such as sofa were better used for clinical research and quality measurement rather than risk assessment. therefore, the definition of sepsis has undoubtedly dramatically advanced the research due to enhanced medical research efficiency when agreed disease and outcome definitions are used. however, definitions are still insufficient and have not been used beyond as tools of research and quality measurement. when a patient was admitted to icu due to an infection, his or her mortality rate was approximately % in this cohort. this will make little contribution even if new criteria are used because % is one of the highest mortality in icu diseases. the advancement of sepsis definitions may lead to the concept that similar conditions were caused by infections, despite the different backgrounds and triggers. however, risk stratifications and predictions should be investigated in detail in the future. for example, the upgrade or downgrade type of sepsis should be assessed based on the immune response, a subgroup for site of infection, or a phenotype of treatment responsiveness. "one size fits all approach" has reached its limits. this study has several limitations. first, organ failure data before the icu admission were missing in some patients, which was also noticed in the original sepsis- study [ ] . second, regarding to apache ii score, data at initial diagnosis were used instead of the worst data within h of icu admission because of availability. this may have led to underestimation of the severity of patient conditions. third, missing data were indicated as zero in the apache ii and sofa scores, if some elements were missing. this would have been used to identify any underestimation of the variance of patient's severity. however, effects of missing data should be small because missing data of elements were few. a majority of the patients who were admitted to the icu with suspected infection met sepsis- and sepsis- definitions. in-hospital mortality was indicated as zero if patients did not meet any sepsis definitions. supplementary information accompanies this paper at https://doi.org/ . /s - - - . the third international consensus definitions for sepsis and septic shock (sepsis- ) classification of sepsis, severe sepsis and septic shock: the impact of minor variations in data capture and definition of sirs criteria sis international sepsis definitions conference of critical care medicine consensus conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis the surviving sepsis campaign: results of an international guidelinebased performance improvement program targeting severe sepsis surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: clinical frailty scale (cfs) reliably stratifies octogenarians in german icus: a multicentre prospective cohort study robustness of sepsis- criteria in critically ill patients epidemiology of sepsis and septic shock in critical care units: comparison between sepsis- and sepsis- populations using a national critical care database severe sepsis cohorts derived from claims-based strategies appear to be biased toward a more severely ill patient population variation in identifying sepsis and organ dysfunction using administrative versus electronic clinical data and impact on hospital outcome comparisons presenting symptoms independently predict mortality in septic shock: importance of a previously unmeasured confounder the influence of a change in septic shock definitions on intensive care epidemiology and outcome: comparison of sepsis- and sepsis- definitions sepsis definitions task f, et al. developing a new definition and assessing new clinical criteria for septic shock: for the third international consensus definitions for sepsis and septic shock (sepsis- ) publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank the jaam spice study group for the contribution to this study. we would like to thank enago (https://www.enago.jp) for english language editing. this work was supported by jsps kakenhi grant number jp k .notation of prior abstract publication/presentation we will present this research at rd annual congress european society of intensive care medicine (esicm) . authors' contributions ta contributed to the acquisition of data, conceived of and designed this study, interpreted the data, drafted the manuscript, and revised the manuscript for important intellectual content. ky contributed to the acquisition of data, conducted data cleaning, interpreted the data, and revised the manuscript for important intellectual content. all of the authors contributed to the acquisition of data, and reviewed, discussed, and approved the final manuscript. this study was supported by the japanese association for acute medicine ( - ). the datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. the study protocol was reviewed and approved by the research ethics committee of all participating institutions at the japanese association for acute medicine (jaam) spice study group. given the retrospective and anonymized nature of this study in the routine care, the ethics committees waived the need for informed consent from the study participants. the institutional review board of hokkaido university, a leading institution in spice, approved this study (approval no. - ). competing interests all authors declare that they have no competing interests. key: cord- -m n r authors: sole-violan, j; sologuren, i; betancor, e; zhang, s; pérez, c; herrera-ramos, e; martínez-saavedra, m; lópez-rodríguez, m; pestano, j; ruiz-hernández, j; ferrer, j; rodríguez de castro, f; casanova, j; rodríguez-gallego, c title: lethal influenza virus a h n infection in two relatives with autosomal dominant gata- deficiency date: - - journal: crit care doi: . /cc sha: doc_id: cord_uid: m n r nan introduction acute myocardial depression in septic shock is common [ ] . myocardial depression is mediated by circulating depressant substances, which until now have been incompletely characterized [ ] . the aim of our study was to observe the eff ects of tnfα on the model of perfused rat heart. methods after profound anesthesia with pentothal, the wistar rats were killed by exsanguination. after sternotomy, the heart was taken and connected to the langendorf column. the apex of the heart was hooked to a strength sensor. biopac student laboratory software was used to record and analyse heart contractions. contractions were recorded every minutes during periods of minutes. control measurements were fi rst recorded. we measured four parameters: heart rate, contraction force, speeds of contraction and relaxation for control, during tnfα ( ng/ml) exposure and after removal of tnfα. we express the variations of parameters as percentage of the control ± sem. a paired t test was used to compare heart rate, contraction amplitude, speeds of contraction and relaxation with tnfα and control measurements and after removal of tnfα. results eight rat hearts wistar (weight = ± g) were studied. see table . heart rate ± * ± introduction traditional whole blood experiments suggest that sepsis causes abnormal red blood cell (rbc) deformability. to investigate this at the cellular level, we employed a novel biophysical method to observe individual rbc membrane mechanics in patients with septic shock. methods we collected blood samples from patients with septic shock until either death or day of admission. thermal fl uctuations of individual rbcs were recorded allowing a complete analysis of rbc shape variation over time. mean elasticity of the cell membrane was then quantifi ed for each sample collected. we recruited nine patients with septic shock. table shows mean rbc thermal fl uctuation and sofa scores. conclusion rbc thermal fl uctuation analysis allows variations in rbc elasticity during sepsis to be quantifi ed at a cellular level. we could not identify any specifi c trend between sepsis severity and erythrocyte elasticity. cells demonstrated both increases and decreases in fl uctuation independent of sofa score. this is contrary to current evidence that suggests rbc deformability is reduced during sepsis. reference introduction whole blood experiments suggest that cardiopulmonary bypass (cpb) causes red blood cell (rbc) trauma and changes in deformability that may contribute to postoperative microcirculatory introduction neutrophil gelatinase-associated lipocalin (ngal)/ lipocalin , known as a sensitive biomarker of acute kidney injury, prevents bacterial iron uptake, resulting in the inhibition of its overgrowth [ ] . we previously demonstrated that this protein was discharged into gut lumen from crypt cells in septic conditions, and inhibited the growth of escherichia coli [ ] . however, it remains unclear which pathway is associated with the upregulation of ngal. we therefore designed the present study to reveal whether the patternrecognition receptor of bacteria, the toll-like receptor (tlr) family, plays a pivotal role for ngal secretion from gut crypt cells. methods with our institutional approval, the ileum and colon of male c bl/ j mice ( to weeks) were everted and washed by ca + and mg + free pbs buff er fi ve times. tissues were incubated with ca + and mg + free pbs containing mm edta for hour to isolate crypt cells of gut. the cell suspension was fi ltered through a cell strainer ( μm) twice, and deposited the crypt cells by centrifugation at ×g. the isolated crypt cells were resuspended in pbs and stained with . % amido black for labeling paneth cells. the × crypt cells were resuspended in ml hbss containing . % fetal bovine serum and % penicillin-streptomycin. the crypt cells were incubated at °c with or without tlr ligands: lipopolysaccharide (tlr ligand, μg/ml) and cpg-dna (tlr ligand, μg/ml). after a -hour incubation period, the crypt cells were deposited and eluted mrna to measure the expression of both ngal and tlr mrna using real-time pcr. results more than to % of collected cells were stained by amido black. lps signifi cantly upregulated the expression of ngal and tlr mrna in ileum and colon crypt cells (p < . ). although the cpg-dna did not upregulate ngal and tlr mrna in ileum crypt cells, the apparent expression of ngal and tlr mrna was found in colon crypt cells (p < . ). conclusion bacterial stimulation of tlr and tlr pathways plays a pivotal role in the expression of ngal mrna in gut, suggesting that ngal, derived from gut crypt cells, could contribute to the regulation of the intraluminal microfl ora in the critically ill. references introduction most individuals infected with the pandemic h n infl uenza a virus (iav) (h n pdm) experienced uncomplicated fl u. however, in a small subset of patients the infection rapidly progressed to primary viral pneumonia (pvp) and a minority of them developed ards. inherited and acquired variability in host immune responses may infl uence susceptibility and outcome of iav infection. however, the molecular nature of such human factors remains largely elusive. methods we report three adult relatives with the autosomal dominant gata- defi ciency. p and his son p had a history of myelodysplastic syndrome and a few episodes of mild respiratory infections. they developed pvp by h n pdm which rapidly evolved to ards. they died at the age of and , respectively. results patients were heterozygous for a novel r l mutation in gata . like other patients with gata- defi ciency, the three relatives had absence of peripheral nk and b cells and monocytopenia. however a high number of plasma cells, which were found to be pauciclonal, were observed in peripheral blood from p during h n pdm infection. p and p had normal levels of immunoglobulins and igg antibodies against common viruses. microneutralization test showed that p produced normal titers of neutralizing antibodies against h n pdm and against the previous annual h n strain. our results suggest that a few clones of long-living memory b cells against iav expanded in p ; and that these cells produced cross-reactive antibodies against h n pdm, similar to those recently described. during the fl u episode p had a strong increase of ifnγ-producing t cells and of ifnγ production. the th -related chemokines cxcl and cxcl , as well as ifnγ, mcp- and il- , were strongly elevated in serum from p and p in the course of h n pdm infection. conclusion gata- defi ciency is the fi rst described mendelian inborn error of immunity underlying severe iav infection. primary immunodefi ciencies predisposing to severe iav infections may debut, even in adults without a history of previous severe infections. the massive ifnγ-mediated cytokine storm may explain the fatal course of h n pdm infection in our patients. introduction adenosine exerts anti-infl ammatory and tissue protective eff ects during systemic infl ammation. while the anti-infl ammatory properties may induce immunoparalysis and impede bacterial clearance, the tissue protective eff ects might limit organ damage. the eff ects of a common loss-of-function variant of the adenosine monophosphate deaminase gene (ampd ), which is associated with increased adenosine formation, in patients with sepsis are unknown. methods in a prospective cohort, genetic-association study, the eff ects of the presence of the ampd gene on immune function, multiorgan dysfunction and mortality in septic patients was studied. pneumosepsis patients (n = ) and controls without infection (n = ) were enrolled. results in pneumosepsis patients and controls, a similar prevalence of the c>t (rs ) mutation in the ampd gene was found. univariate logistic regression analysis showed a tendency of increased mortality in patients with the ct genotype, compared with patients with the cc genotype (or . ; % ci . to . ). moreover, carriers of the ct genotype tended to suff er more from multiorgan dysfunction, or . ( . to . ) and . ( . to . ), for ct and tt, respectively (p = . ). in septic carriers of the ct genotype, the ex vivo production of tnfα by lps-stimulated monocytes was attenuated (p = . ), introduction hypogammaglobulinemia has been frequently found in adult patients with severe sepsis and septic shock. furthermore, it seems that at least a low serum level of igm is correlated with higher mortality in sepsis. the mechanisms of hypogammaglobulinemia in septic shock have not yet been explained. it has been hypothesized that outfl ow of immunoglobulins into the extravascular space due to increased capillary permeability could reduce immunoglobulin serum concentrations. angiopoietin- , which directly disrupts the endothelial barrier, is markedly elevated in sepsis and other infl ammatory states and its serum level has been correlated with microvascular leakage, end-organ dysfunction and death in sepsis. methods in the prospective, noninterventional study, we assessed the correlation between the capillary leakage marker angiopoetin- and serum levels of igg and igm in patients with community-acquired severe sepsis or septic shock on admission. blood samples were obtained during the fi rst hours after admission to hospital. results mean age of patients ( females) was years. median apache ii and sofa scores at admission were and , respectively. the mortality rate was %. thirty-four percent of all patients had level of igg < mg/dl. the median concentration of angiopoietin- in the hypo-igg group was , pg/ml, which was not statistically diff erent (mann-whitney; p > . ) than in the rest of patients with normal levels of igg ( , pg/ml). the concentration of igm < mg/dl was found in only four patients ( %) and all died. pearson's correlation test showed that the correlation between the concentrations of angiopoietin- and igg (correlation coeffi cient . ) or igm (correlation coeffi cient . ), respectively, were not statistically signifi cant (p < . ). conclusion at present the hypothesis that increased microvascular leakage is responsible for hypogammaglobulinemia in septic patients could not be accepted. studies on larger number of patients are needed. in addition, it is necessary to further explore other possible mechanisms, such as increased catabolism and consumption of antibodies or inadequate synthesis of immunoglobulins, which could also be responsible for hypogammaglobulinemia in sepsis. introduction septic encephalopathy is a frequent complication in severe sepsis but its pathogenesis and mechanisms are not fully understood. oxygen supply and utilization are critical for organ function, especially for the brain, a tissue extremely dependent on oxygen and glucose. disturbances in oxygen utilization are common in sepsis and a number of mitochondrial dysfunctions have been described in diff erent tissues in septic animals as well as in septic patients. our group described mitochondrial dysfunctions in the brain during experimental sepsis. methods experimental sepsis was induced by endotoxemia (lps mg/ kg i.p.) in sprague-dawley rats and by polymicrobial fecal peritonitis in swiss mice. brain glucose uptake was observed in vivo in endotoxemic rats using positron emission tomography with [ f]fl uorodeoxyglucose and autoradiography with -deoxy- c-glucose. results mice with polymicrobial sepsis present hypoglycemia, hyperlactatemia and long-term cognitive impairment. we observed a rapid increase in the uptake of fl uorescent glucose analog -deoxy- -(( -nitro- , , -benzoxadiazol- -yl)amino)-d-glucose in brain slices from septic mice in vitro. a similar increase in brain glucose uptake was observed in vivo in endotoxemic rats. remarkably, the increase in glucose uptake started hours after lps injection, earlier than other organs. the brains of mice with experimental sepsis presented neuroinfl ammation, mitochondrial dysfunctions and oxidative stress, but mitochondria isolated from septic brains generated less ros in vitro in the fi rst hours. this led us to investigate the role of nadph oxidase, an enzyme induced during innate immune response, as a potential source of reactive oxygen species in experimental sepsis. inhibiting nadph oxidase with apocynin acutely after sepsis prevented cognitive impairment in mice. our data indicate that a bioenergetic imbalance and oxidative stress is associated with the pathophysiology of septic encephalopathy. we are observing a new metabolic phenotype in the brain during sepsis, characterized by a rapid increase in glucose uptake and mitochondrial dysfunctions that may be secondary to infl ammation and hypoxia. introduction pathophysiology of brain dysfunction associated with sepsis is still poorly understood. potential mechanisms involve oxidative stress, neuroinfl ammation and blood-brain barrier alterations. our purpose was to study the metabolic alterations and markers of mitochondrial dysfunction in a clinically relevant model of septic shock. methods twelve anesthetized (midazolam/fentanyl/pancuronium), invasively monitored, and mechanically ventilated pigs were allocated to a sham procedure (n = ) or sepsis (n = ), in which peritonitis was induced by intra-abdominal injection of autologous feces. animals were studied until spontaneous death or for a maximum of hours. in addition to global hemodynamic and laboratory assessment, intracranial pressure and cerebral microdialysis were assessed at baseline, , , and hours after sepsis induction. after death, brains were removed and brain homogenates were studied to assess markers of mitochondrial dysfunction. introduction identifying a group of patients at high risk of developing infectious complications is the fi rst step in the introduction of eff ective pre-emptive therapies in specifi c patient groups. quantifying cytokine gene expression also furthers our understanding of trauma-induced immunosuppression. our group has already demonstrated that a predictive immunological signature derived from mrna expression in elective thoracic surgical patients accurately predicts pneumonia risk [ ] . methods in total, ventilated polytrauma patients were recruited. mrna was extracted from paxgene tubes collected within hours of the initial insult, at and hours. t-helper cell subtype specifi c cytokines and transcription factors mrna was quantifi ed using qpcr. ten healthy controls served as a comparator. results the median injury severity score (iss) was . time bloods demonstrated a reduction in tnfα † , il- § , il- ‡ , rorγt* and t bet § , and an increase in il- * and il- † mrna levels in comparison with the control group (*p < . , † p < . to . , ‡ p < . to . , § p < . to . ). there was a positive correlation between iss and il- ‡ whilst both il- § introduction measurement of biomarkers is a potential approach to early assessment and prediction of mortality in septic patients. the purpose of this study was to ascertain the prognostic value of proadrenomedullin (padm), measured in all patients admitted to the icu of our hospital with a diagnosis of severe sepsis or septic shock during year. methods a cohort study of patients > years with severe sepsis according to the surviving sepsis campaign, in an icu of a university hospital. demographic, clinical parameters and padm, c-reactive protein and procalcitonin were studied during year. descriptive and comparative statistical analysis was performed using the statistical software packages statistica stat soft inc . and medcalc . . . . results we analyzed consecutive episodes of severe sepsis ( %) or septic shock ( %) in the icu. the median age of the patients was introduction sepsis results from complex interactions between infecting microorganisms and host responses, often leading to multiple organ failures and death. over the years, its treatment has been standardized in early goal-oriented therapies, which may benefi t from circulating biomarkers for early risk stratifi cation. we aimed to evaluate the prognostic value of presepsin (scd -st), a novel marker of bacterial infection. methods we performed a nested case-control study from the randomized controlled albumin italian outcome sepsis (albios) trial, enrolling patients with severe sepsis or septic shock from icus in italy. fifty survivors and nonsurvivors at icu discharge were selected, matched for age, sex, center and time of enrollment after inclusion criteria were present. edta-plasma samples were collected at days , and after enrolment for presepsin (immunechemiluminescence assay pathfast presepsin, url pg/ml, cv %; mitsubishi chemicals) and procalcitonin assay (pct, elecsys brahms cobas® pct, url . ng/ml, cv . %; roche diagnostics). results clinical characteristics were similar between the two groups, except for a worse sofa score at day in decedents. presepsin at day was signifi cantly higher in decedents ( , ( , to , ) pg/ ml, median (q to q )) than in survivors ( , ( to , ) pg/ml, p = . ), while pct did not diff er ( . ( . to . ) vs. . ( . to . ) ng/ml, p = . ). presepsin decreased over time in survivors, but remained elevated in decedents ( ( to , ) vs. , ( , to , ) pg/ml at day , p = . for time-survival interaction); pct decreased similarly in the two groups (p = . ). patients with early elevated presepsin had worse sofa score, higher number of mofs, hemodynamic instability (lower mean arterial pressure at baseline and after hours), and mortality rate at days ( % vs. %, logrank p < . ). the association between presepsin and outcome was more marked in patients with late enrollment ( to hours), and in septic shock. early presepsin had better prognostic accuracy than pct (auroc . vs. . , p = . ), and improved discrimination over sofa score, especially in septic shock. conclusion early presepsin measurements may provide important prognostic information in patients with severe sepsis or septic shock, and may be of crucial importance for early risk stratifi cation. introduction infections are a major complication during the postoperative period after heart transplantation (ht). in our hospital, nosocomial pneumonia is the most frequent infection in this period. the objective of this study is to determine the epidemiological and microbiological characteristics of this disease in our centre. methods a descriptive retrospective study of all medical records of ht performed in a single institution from to followed until june . clinical and microbiological variables were considered. centre for diseases control (cdc) criteria were used to defi ne nosocomial infections. invasive aspergillosis was considered if there were criteria for probable aspergillosis according to idsa criteria. results in hts there were infectious episodes in patients ( . %). eighty-fi ve patients ( . %) died during hospitalization. infection is the second cause of mortality during the postoperative period ( . % of dead patients). the most common locations of infections were pneumonia (n = , . % of infection episodes), bloodstream (n = , . %), urinary tract (n = , . %), surgical site (n = , . %) and intraabdominal infections (n = , . %). patients with pneumonia were treated according to knowledge in a specifi c moment, thus diff erent antibiotics were used. the duration of antibiotic therapy was ± . days. in nine episodes of pneumonia according to the cdc no germ was isolated in the cultures. six of the episodes were polymicrobial infections. the most frequent microbes isolated were e. coli (n = , . % of pneumonia cases), a. fumigatus (n = , . %), s. aureus (n = , . %), p. aeruginosa (n = , . %), p. mirabilis, k. pneumoniae, e. cloacae, e. faecalis, c. glabrata, and s. marcescens (one case each, . %). pneumonia was suspected but not confi rmed in patients. despite this, antibiotic treatment was maintained for a media of . ± . days: wide-spectrum treatments and targeted therapy after knowing the antibiogram. the length of icu stay was . ± . ( to ) days, of hospital stay was . ± . ( to ) days and of mechanical ventilation was . ± . ( to ) days. the mortality of patients with pneumonia was . %. conclusion nosocomial pneumonia is the most frequent infection in our series. despite when infection was not confi rmed, antibiotic therapy was maintained in suspect cases. we found a high incidence of aspergillosis. limitations because of wide duration of this study should be considered. that numbers of cvc, intubation and surgery, the use of muscle relaxant and steroid were independent risk factors for developing vap. ventilator days and icu length of stay were longer in the vap group ( vs. and vs. days, respectively). lastly, the hospital mortality rate was signifi cantly higher in the vap group ( % vs. %, p = . ). conclusion the incidence of vap was . % in the sicu of siriraj hospital, which was comparable with previous reports. bundles of care to prevent vap should include weaning from a ventilator. muscle relaxant and steroid should be administered according to strong indication. meticulous care of the airway should be implemented as protocol in order to prevent complications that can result in the development of vap. reference introduction this is a -year prospective study to determine the incidence, source and etiology of hospital-acquired bloodstream infection (habsi) in the indian context. the resistance pattern was also reviewed. methods a single-centre prospective study in a -bed icu. habsi was defi ned according to current cdc guidelines. hcap, catheterassociated uti (cauti) and skin-related infections causing bsi was also defi ned according to recent guidelines and analysed. results out of positive samples, samples (n = ) were habsi. the microbiological analysis showed % were gram-negative, % were candida and % were gram-positive. the commonest isolate was klebsiella and mrsa was commonest in gram-positive. the source of habsi showed crbsi was the commonest cause at %, which correlates with international data. ventilator-associated pneumonia and cauti caused . % bsi respectively. the resistance pattern among gram-negative bacteria showed multidrug-resistant (mdr) and extreme drug-resistant (xdr) isolates were highest. see tables and . introduction catheter-related bloodstream infection (crbsi) is a complication of central venous catheters (cvcs) with an attributable morbidity, mortality and cost [ ] . we examined patient risk factors for crbsi in an adult parenteral nutrition (pn) population. the study was carried out in a -bed tertiary-referral teaching hospital over a -year study period ( to ). all inpatients referred for pn via cvcs were included. prospectively collected data were recorded in a specifi c pn record. the crbsi audit group met quarterly to review all sepsis episodes, assigning a diagnostic category (crbsi or non-crbsi). patient risk factors for development of crbsi were examined using a logistic regression model to take account of the dichotomous nature of the outcome. odds ratios from a model incorporating demographic and clinical data were tested for statistical signifi cance. introduction many patients develop infections following operations. decreased immune competence has been demonstrated in acute neurological conditions. a strong cytokine-mediated antiinfl ammatory response was observed in stroke patients at infection, although infection due to the decreased proinfl ammatory mediators can be expected as well. to investigate this question the following experiment was performed. methods twenty-two urinary bladder cancer patients with radical cystectomy and lymphadenectomy were studied. blood samples were taken on day (before) and days , , , and after operation as well as on days , , and during follow-up. tnfα, soluble tnfα receptor i and il- levels in sera were determined by hs elisa and/or elisa. plasma acth and cortisol values were measured by ria kits. results from patients, eight deep wound and urine infections were found in days and six urine and wound infections in days after surgery, all survived. all patients were bacterially contaminated, as wound samples taken at the end of operation demonstrated. on day the circulating tnfα values were lower in infected patients. tnf started to increase from day to day , never reaching values of the uneventful healing group. soluble tnf receptor i, il- , acth, and cortisol concentrations did not demonstrate any diff erence on day but from day started to increase transiently, reaching higher levels in septic patients. conclusion a low proinfl ammatory response is a key facilitating factor for the development of infection. measuring serum tnfα levels before and after operations can thus predict the outcome. evaluation during days in may including direct observation of hand hygiene compliance by control nurses and hand cultures of healthcare workers (hcw). based on the who guidelines on hand hygiene in health care [ ] , cleaning of hands with alcohol-based hand rubs (sterillium) was prescribed before touching a patient and before aseptic procedures, after body fl uid exposure risk and after touching a patient and touching his/her surroundings. promotion of the hand hygiene program consisted of lectures and web-based self-learning, posters located near points of care and verbal reminders by control nurses. new observations of hand hygiene by control nurses during days and hand cultures of healthcare providers were performed in september . consumption of alcohol-based hand rub (product volume use per patient-days) was used as a surrogate marker of hand hygiene over time. the diff erence in hand hygiene compliance during the two periods was examined using a chi-squared test. diff erences in hand cultures were examined using a student's t test. time trends in the consumption of alcohol-based hand rub were examined using linear correlation. p < . was considered statistically signifi cant. the study was approved by the institutional ethics review board. results during the survey, in may opportunities to observe hand hygiene were presented and in september. overall compliance improved from . % ( / ) to % ( / ), χ = . (p < . ). in may, hcw had a mean of . ± . colony-forming units (cfu) on their hands compared with . ± . cfu on the hands of hcw in september (p = . ). we also observed an initial increased use of alcohol-based hand rubs from ml per patient-day in may to a maximum ml per patient-day in june, but a decline to ml per patient-day in september, pearson correlation coeffi cient = . (p = . ). conclusion implementation of a new hand hygiene program at our icu resulted in improved hand hygiene compliance and less cfu on the hands of hcw. there was no signifi cant increased use of alcohol-based hand rubs over time. the results indicate that constant awareness is vital for success. reference introduction icu-acquired infection is directly related to hospital mortality. hand hygiene is an eff ective, low-cost intervention that can prevent the spread of bacterial pathogens, including multidrugresistant organisms. historical compliance with hand hygiene guidelines by physicians, nurses and other care providers is poor. methods present expectations by the infection control committee are to 'pump in, pump out' of every room, using % isopropyl alcohol. we performed , observations of hand hygiene in the surgical icu from march through october , and intervened to change behavior by providing monthly feedback to specifi c provider groups and services. we made use of the unit coordinator to measure compliance of all individuals in the icu. results overall compliance by physicians was . %, for nonphysicians was . %. feedback to physicians, individually and by service, dramatically increased hand hygiene compliance, defi ned as both on entry and exit from the patient room, over the study period. see figure . conclusion physician behavior is responsive to monthly feedback that is specifi c to the individual or surgical service. use of the unit coordinator was very eff ective at gathering a very large sample size in a short period of time. introduction the benefi ts of universal glove and gowning (bugg) study is a cluster-randomized trial to evaluate the use of wearing gloves and gowns for all patient contact in the icu. the primary outcome is vre and mrsa acquisitions; secondary outcomes include frequency of healthcare worker visits, infection rates, hand hygiene compliance and adverse events. methods we enrolled icus in states. icus collected nasal and perianal swabs on all patients at admission and discharge/transfer. after a -month baseline period, units were randomized to the intervention arm and required to wear gloves and gowns for all patient contact. an intervention toolkit was created based on site feedback and compliance reports. swab collection compliance was fed back and discussed during site conference calls on a weekly basis. site coordinators monitored compliance with gloves and gowns, hand hygiene and frequency of hcw visits and reviewed patient charts for adverse events. results during the -month study period, , swabs were collected. after the baseline period, we were able to achieve and maintain swab compliance rates between and %. monthly discharge compliance increased by % by the beginning of the intervention period ( figure ). observers found % compliance with universal glove and gowning over , -minute observation periods ( figure ). ninety charts at each site were reviewed for adverse events. conclusion over a diverse group of us hospitals, we achieved high compliance with surveillance cultures and implementing universal gloving and gowning was achieved quickly with high compliance. introduction sepsis accounts for a very high mortality. the surviving sepsis campaign recommends a fi rst hours resuscitative bundle to improve patient outcome. despite this, the bundle is poorly performed because of several organizational and cultural barriers. in recognition of this, we guess that an educational and organizational intervention out of the icus could impact on septic patient outcome. in order to test our hypothesis we carried out, in hospitals, a pre-intervention survey of the human and organizational resources (hor) available in the management of septic patients. the aim is to seek any barrier potentially aff ecting correct guidelines implementation. methods thirty-nine medical wards (mw) and emergency departments (ed) were enrolled. every unit was asked to fi ll in a pre-agreed hor checklist focused on the main requirements suggested by the guidelines. results analysing the human resources available, we see that the bedto-doctor ratio signifi cantly (p < . ) increases from the day to the night shift: from to beds per doctor on the mw (median). otherwise, the ed staff remains roughly the same: from . to . doctors on duty (median). the analysis of the organizational tools (table ) points out a low percentage of hospitals having: a diagnostic and therapeutic protocol for sepsis management ( . %), some hospital empirical antibiotic therapy guidelines ( %) and an infective source eradication protocol ( . %). moreover, just % of hospitals involve an infectious diseases expert in every case of severe sepsis or septic shock. conclusion we guess that the poor availability of hor showed by the hospitals could have a role in the guidelines implementation and in the patient's outcome. only a comparison between these results and data collected from a clinical checklist, focused on sepsis bundle compliance, and from a patient's outcome summary could confi rm our hypothesis. this is the aim for our next part of the study. reference introduction the incidence of patients carrying esbl-positive bacteria in our icu ( in admissions in ) was not considered problematic. however, routine cultures had identifi ed esbl-negative patients who had become colonized with esbl strains during their icu stay. self-disinfecting siphons, preventing bacterial growth by antibacterial coating and intermittent heating, and biofi lm formation by electromechanical vibration, were placed in all sinks in the icu. the aim of the present study was to evaluate the eff ect of this intervention. methods an intervention study in a -bed icu. the intervention involved placement of self-disinfecting siphons (biorec). all patients with an expected icu stay of days or more between january and december were studied. samples of throat, sputum and rectum were taken at admission and twice weekly, and cultured for esbls. between june and october , sinks in patient rooms were cultured regularly for esbls. after the intervention in april , multiple repeat cultures were taken. whenever the species and antibiogram of bacteria cultured from patients and sinks matched, they were typed by aflp. results before intervention multiple esbl-forming strains were found in sinks of all patient rooms. eighteen patients who were esbl-negative on icu admission became colonized with diff erent esbl strains, that were present in sinks of their admission rooms ( figure ). four contaminations were proven by aflp-tying. one patient died of esblpositive e. cloacae pneumonia. after intervention all sinks were negative for esbl strains. no further patients became esbl colonized during the icu stay. conclusion wastewater sinks were the likely source of esbl colonization for icu patients. after placing self-disinfecting siphons introduction the present study investigated the eff ects of a single dose of intraperitoneal (i.p.) igg and iggam administration on various behavioral alterations in a cecal ligation perforation (clp)-induced sepsis model in rats. methods female wistar albino rats ( to g) were divided into fi ve groups (n = ): a naive control group, a sham operated group receiving conventional antibiotic treatment, a clp group receiving clp procedure and conventional antibiotic treatment, and igg and iggam groups which were also applied g/kg, i.p. igg and igam therapy minutes after the clp procedure. ten, and days after the surgery, animals underwent three behavioral tasks: an open fi eld test to evaluate the locomotor activity, an elevated plus maze test to measure the level of anxiety, and a forced swim test to assess the possible depressive state. the results acquired from these tests were used to estimate the eff ect of immunoglobulin therapy on behavioral changes in clp-induced sepsis in rats. in the open fi eld test, the clp group showed a signifi cant decrease in total squares passed on days and . similarly, total numbers of rearing and grooming were dramatically decreased in the clp group in comparison with control and sham groups (p < . ). in the elevated plus maze test, the number of entries to open arms decreased in the clp group. in the forced swim test, there was a tendency for increase in immobility time in the clp group, although the data were statistically insignifi cant. all of these values which were indicating the importance of behavioral alterations were improved on day . immunoglobulin therapy prevented the occurrence of these behavioral changes. especially, animals in the iggam group conserved the values quite near to those of the control group in measured parameters. conclusion sepsis, even though it has been treated with conventional antibiotics, caused a negative eff ect on behavioral parameters. in this study, igg and iggam treated animals in the presence of clp did not show these behavioral changes. therefore our results suggest that a single dose of i.p. igg and iggam treatment, which was applied immediately after the sepsis procedure, prevents behavioral defects observed following sepsis. introduction thrombomodulin is an endothelial cell cofactor and glycoprotein for thrombin-catalyzed activation of protein c. a recombinant human soluble thrombomodulin (rhstm) has been recently developed, and this new agent has a unique amino-terminal structure exhibiting anti-infl ammatory activity including sequestraction and cleavage of high-mobility group box (hmgb- ). methods in this study, patients with septic disseminated intravascular coagulation (dic) were treated with rhstm, which is recomodulin® inj. (asahi kasei pharma co., tokyo, japan). patients with septic dic were treated with to u/kg/day. results there were signifi cant results for improvement of apache ii score and dic diagnostic criteria score for critically ill patients after treatment using rhstm (p < . ). improvement for platelet count and d-dimer level were also observed in this study (p < . ). activation of antithrombin (at) also was signifi cantly increased after treatment (p < . ). hospital mortality was . % in this study. conclusion the rhstm might be one of most important endogenous regulators of coagulation, acting as the major inhibitor of thrombin as well as at iii. this new agent may play an important role in treatment for septic dic. introduction antithrombin iii (at iii) has been known to contribute to anti-infl ammatory response as well as its anticoagulation. our previous introduction sepsis and septic shock are complex infl ammatory syndromes. multiple cellular activation processes are involved, and many humoral cascades are triggered. presumably, endothelial cells play a pivotal rule in the pathogenesis of sepsis, not only because they may infl uence the infl ammatory cascade but also because, upon interaction with excessive amounts of infl ammatory mediators, the function of these cells may become impaired. it is likely that a general dysfunction of the endothelium is a key event in the pathogenesis of sepsis [ ] . hmg-coa-reductase inhibitors have been shown to exhibit pronounced immunomodulatory eff ects independent of lipid lowering. most of these benefi cial eff ects of statins appear to involve restoring or improving endothelial function [ ] . we hypothesize that statins can improve endothelial dysfunction in septic patients. methods a double-blinded, placebo-controlled, randomized trial was undertaken. we enrolled adult patients within hours of severe sepsis or septic shock diagnosis and randomized them to placebo or atorvastatin mg/day for a short term. endothelial dysfunction was assessed measuring plasmatic levels of il- , et- , vcam- by elisa and measuring fl ow-mediated vasodilatation of the brachial artery at basal, and hours after randomization. results we studied patients, in the placebo group (mean age ± years, . % male; apache ii risk score . ± . ) and in the statin group (mean age . ± years, . % male; apache ii risk score ± . ). the baseline characteristics of the placebo group were similar to statin patients as well as the mean length of stay in the icu ( . ± . and . ± days, respectively) and the time on vasopressors ( . ± . and ± . hours, respectively). no signifi cant diff erence was observed on the temporal variation of biomarker levels (il- , vcam- , et- ) between treatment and control groups. the intrahospital mortality rate was % in the statin group and % in the placebo group (p = . ). introduction a novel sorbent hemoadsorption device for cytokine removal (cytosorbents, usa) was developed and successfully tested in animal models of sepsis. the experience in the clinical setting is still limited to case reports. in this fi rst clinical trial, we tested the hypothesis that treatment with sorbent hemoadsorption could safely and eff ectively reduce cytokines in septic patients with acute lung injury (ali). methods ventilated patients fulfi lling the criteria for severe sepsis and ali were enrolled in this multicenter randomized, controlled, openlabel study comparing standard of care with or without hemoperfusion treatment. primary endpoints were safety and il- reduction. treated patients underwent hemoperfusion at fl ow rates of ~ to ml/ minute for hours per day for consecutive days. the overall mean reduction in individual plasma cytokines for the control and treatment groups during the treatment period was calculated using a generalized linear model. results forty-three patients ( treated, control) completed the study and were further analyzed. incidence of organ dysfunction at enrollment (treatment vs. control) was: septic shock ( % vs. %, p = . ), acute respiratory distress syndrome ( % vs. %, p = . ), and renal failure ( % vs. %, p = . ). during treatments no serious device-related adverse events occurred. on average, there were no changes in hematology and other blood parameters except for a modest reduction in platelet count (< %) and albumin (< %) with treatment. hemoperfusion decreased il- blood concentration signifi cantly (- . %, p = . ), with similar reductions of mcp- (- . %, p = . ), il- ra (- . %, p = . ), and il- (- . %, p = . ). the -day mortality ( % vs. % control, p = . ) and day mortality ( % vs. % control, p = . ) did not diff er signifi cantly between the two studied groups. conclusion in this fi rst clinical study of a novel sorbent hemoadsorption device in patients with severe sepsis and ali, the device appeared to be safe and decreased the blood concentration of several cytokines. further research is needed to study the eff ect of the device on the clinical outcome of septic patients. response; and the changes of endotoxin and proinfl ammatory molecules. methods forty septic/septic shock patients with renal failure were enrolled in the study. all patients had preoperative endotoxin > . level/units (eaa spectral d) and were submitted to high-volume hemodiafi ltration ( ml/kg/hour, prismafl ex; gambro) with a new treated heparin-coated membrane (oxiris; gambro). at t (pretreatment) and t ( hours) the main clinical and biochemical data were evaluated. all data are expressed as mean ± sd. one-way anova test with bonferroni correction was used to evaluate the data changes. p < . was considered signifi cant. results table presents the main results of this study. conclusion in septic/septic shock patients with renal failure, crrt with a new treated heparin-coated membrane (oxiris; gambro) is clinically feasible, and has a positive eff ect on renal function and hemodynamics. an adsorbing eff ect on proinfl ammatory mediators may have a role in these results. these data and the trend toward a decrease of endotoxin during the treatment warrant further investigation. reference introduction endotoxin, a component of the outer membrane of gramnegative bacteria, is considered an important factor in pathogenesis of septic shock [ ] . the aim of our study was to determine whether endotoxin elimination treatment added to the standard treatment would improve organ function in patients with septic shock. methods adult patients with septic shock who required renal replacement therapy (rrt), with a confi rmed endotoxemia, and suspected gram-negative infection were consecutively added to the study within the fi rst hours after diagnosis. all patients received full standard treatment for septic shock. endotoxin elimination was performed using the membrane oxiris (gambro, sweden), a medical device for continued rrt with the unique feature of endotoxin adsorbtion. an endotoxin activity assay was used to monitor endotoxin elimination therapy at baseline (t ), hours (t ), hours (t ), hours (t ), hours (t ), and hours (t ). our key indicators were the improvement in hemodynamics and organ function, and decrease of endotoxin activity (ea) in blood. continuous variables are presented as mean values with standard deviations. results high ea level at baseline ( . ± . endotoxin activity units (eau)) signifi cantly decreased during rrt with oxiris membrane to . ± . (t ), . ± . (t ), . ± . (t ), . ± . (t ), . ± . (t ) eau (p < . ). map increased from baseline ± to ± , ± , ± , ± , ± mmhg (p < . ), and the mean norepinephrine use decreased from . ± . to . ± . , . ± . , . ± . , . ± . , . μg/kg/minute (p < . ) at t , t , t , t , t , t , respectively. the sofa score had decreased from ± to ± , ± , ± points (p < . ), and the procalcitonin level declined from ± to ± , ± , ± ± ng/ml (p < . ) at t , t , t , t . conclusion rrt with oxiris membrane resulted in the eff ective elimination of endotoxins from the blood. the therapy was associated with an increase in blood pressure, a reduction of vasopressor requirements, and an improvement of organ function. the application of the endotoxin activity assay was useful for bedside monitoring of endotoxemia in icu patients. introduction severe sepsis and septic shock remain the most serious problem of critical care medicine with a mortality rate of to % [ ] . several studies have demonstrated positive eff ects of selective adsorption of lps on blood pressure, pao /fio ratio, endotoxin removal and mortality [ , ] . the purpose of the study was to evaluate the effi ciency of using the selective adsorption of lps, toraymyxin -pmx-f (toray, japan) and alteco® lps adsorber (alteco medical ab, sweden), in the complex treatment of patients with severe sepsis. methods forty-six patients with gram-negative sepsis in the postoperative period were enrolled into the study. toraymyxin -pmx-f was used in the pmx-f group (n = ), while alteco lps adsorption was used in the alteco lps group (n = ). the clinical characteristics are listed in table . the sofa score, pao /fio , procalcitonin (pct), c-reactive protein (crp), endotoxin activity assay (eaa) was noted before, and hours after the selective adsorption of lps. results at hours after pmx-f, signifi cantly decreased pct from . ( . ; . ) to . ( . ; . ) ng/ml, p = . , decreased crp from ( ; ) to ( ; ) mg/l, p = . and sofa score from . ( , ; . ) to . ( , ; . ), p = . . at hours after alteco lps, signifi cantly decreased pct from . ( . ; . ) to . ( . ; . ) ng/ml. the -day mortality rate was . % (n = ) in the pmx-f group and . % (n = ) in the alteco lps group. introduction corticosteroid (cs) therapy in sepsis remains controversial and was fi rst introduced in sepsis management for its antiinfl ammatory property. cs has found a role in septic shock amelioration with inconsistent outcomes. the surviving sepsis campaign (ssc) includes cs as a level c recommendation in septic shock [ ] . adapting and practicing ssc guidelines vary between critical care units. accordingly, a survey was conducted to elucidate the usage of cs for septic shock by uk critical care physicians (ccps). methods following approval by the uk intensive care society (ics), the survey was publicised on the ics website and its newsletter. results a total of intensivists responded to this online survey. seventy-four ( . %) ccps prescribed cs only if the septic shock is poorly responsive to fl uid resuscitation and vasopressor therapy. six ( . %) initiated cs at the same time as vasopressor therapy. none initiated cs for patients with severe sepsis. no cs other than hydrocortisone is being used. the most commonly used intravenous regimen is mg hourly ( %) followed by mg hourly ( %). only % of ccps would prescribe it by infusion. less commonly used regimens were mg hourly ( %) and mg hourly ( %). only % would consider adding fl udrocortisone. prior to initiating cs, % of ccps would perform a short synacthen test, while % would not. the majority ( %) of ccps would stop cs after resolution of shock state or when vasopressor infusion is terminated whilst % after a fi xed duration. withdrawal of cs also diff ered, in that % tapered/weaned steroids, % stopped it abruptly and % of ccps would base their cs cessation pattern on the clinical context. only % of ccps believe that cs is benefi cial whereas % were unsure of the benefi ts in septic shock. only ( %) responders indicated that their critical care unit had a written protocol for cs in septic shock. conclusion the perceptions, usage and cessation of cs in septic shock vary but do appear to have shifted in the last decade. a uk survey in identifi ed that only % of icus used cs for septic shock and over % perform a short synacthen test [ ] . it appears that many intensivists are using cs for septic shock, despite confl icting outcome data. we all strive to practice evidence-based medicine but until we have a robust, reliable and methodical randomised control trial that attempts to resolve the cs debate, practice will remain diverse on this subject, as refl ected by our survey. references introduction from december to december , patients in scotland presented with confi rmed anthrax infection manifested by soft tissue disease related to heroin injection. these cases represent the fi rst known outbreak of a recently recognized form of anthrax, termed injectional anthrax, which appears to be associated with a high mortality rate ( % in confi rmed cases from the uk outbreak). while epidemiologic data from this outbreak have been published, no report has systematically described fi ndings in patients at presentation or compared these fi ndings in nonsurvivors and survivors. methods to better describe injectional anthrax, we developed a questionnaire and sent it to clinicians who had cared for confi rmed cases during the outbreak. completed questionnaires describing patients, nonsurvivors and survivors, were returned. results in preliminary analysis of categorical data, a signifi cantly (fisher exact test) greater proportion of patients with compared with without the following fi ndings did not survive; history of alcohol use (p = . ); the presence of lethargy (p = . ), confusion (p = . ), nausea (p = . ), abdominal pain (p = . ), or the need for vasopressors (p = . ), oxygen, mechanical ventilation, or steroids (all p = . ) at presentation; and excessive bleeding at surgery (p = . ). initial analysis of continuous data demonstrated that, compared with survivors at presentation, nonsurvivors had signifi cantly (one-way anova) increased respiratory rate, percent neutrophils on complete blood count, hemoglobin, inr, c-reactive protein, and bilirubin and signifi cantly decreased temperature, systolic blood pressure, platelets, sodium, albumin, calcium (corrected for albumin), base excess and bicarbonate (all p ≤ . ). conclusion the implications of the apparent diff erences noted between nonsurvivors and survivors in this survey of cases from the fi rst known outbreak of injectional anthrax require further study. however, these diff erences might inform the design of research during future outbreaks or of methods to identify patients most in need of anthrax-specifi c therapies such as toxin-directed antibodies. introduction based on the results of our previous studies [ ] we have identifi ed clinical risk factors for the emergence of gr(+) infections in our icu and we have developed a new algorithm for combating them. the choice of the particular antibiotic drug is guided by additional risk factors for severity of illness and data on the infectious focus. the response to therapy and its duration are also stated. the aim of the current study was to evaluate the effi cacy and safety of this preemptive approach. methods a randomized prospective controlled trial was carried out from september to september . patients were submitted to block randomization and stratifi ed on the basis of their initial saps ii exp score. antibiotic therapy was started on the day of inclusion in the treatment group and only with proven gr(+) pathogen in the control group. initial data were gathered on demographics, diagnosis, proven risk factors for sepsis-related mortality, severity of infl ammatory response, ventilator-associated pneumonia and organ dysfunction. dynamics of sirs, cpis and sofa scores, subsequent infectious isolates, ventilator-free days, length of icu stay and outcome were followed for each patient. results a total of patients were enrolled. no statistically signifi cant diff erences in their basal characteristics were found. the subsequent score values, length of icu stay and the number of ventilator-free days were also comparable between groups. the majority of gr(+) pathogens were isolated between and days of inclusion. no diff erences were found regarding the concomitant gr(-) fl ora and the related antibiotic therapy. the new organ dysfunction severity was similar in both groups (p = . ). the in-hospital mortality was . % in the treatment group versus . % in the control group (p = . ). signifi cant diff erences between the kaplan-meier estimates of survival were also not found (log-rank test p = . ). no major adverse reactions were observed. conclusion the implementation of this new policy failed to reduce the degree of organ dysfunction severity and was not associated with signifi cant survival benefi t. moreover, even though it did not reach statistical signifi cance, a second peak of gr(+) isolates was observed as a possible complication of the preemptive therapy. whether this approach could lead to vancomycin mic creep or there could still be a niche for it later in the course of treatment and/or in nontrauma patients remains to be further explored. reference introduction acinetobacter baumannii (a. baum) is a leading cause of septicemia of patients hospitalized in the icu with high mortality rates. the aim of our study is to investigate the risk factors associated with a. baum bacteremia and its mortality rates. introduction the french military hospital at the kaboul international airport (kaia) base provides surgical care for international force and afghan national army soldiers, and also local patients. the development of multiresistant bacteria (mrb) nosocomial infections has raised a major problem complicating the care of combat casualties [ ] . the aim of this study is to assess the prevalence of mrb carriage on admission to the icu in this combat support hospital. methods we used a prospective observation study on patients admitted to the french military icu in kaia over months (july to september ). all hospitalized patients were assessed for the presence of colonization with mrb: nasal and rectal swabs were performed to identify, respectively, methicillin-resistant staphylococcus aureus (mrsa) and extended-spectrum β-lactamases bacteria (esblb). the following data were recorded for each patient on admission: demographic characteristics, bacteriological results, length of stay, type of previous hospitalization. results sixty-three patients were admitted. the mean length of stay (mls) was ± days, and the mean age was ± ( patients < years). patients were hospitalized for combat-related trauma ( %), noncombat-related trauma, medical pathologies ( %), and postoperative care ( %). they were afghans ( %) or westerners ( %). swabs were not realized for eight patients. forty-three percent revealed an esblb colonization: escherichia coli ( patients), klebsiella pneumoniae (one patient), acinetobacter baumanii (one patient). no patients were colonized with mrsa. ten patients ( %) were directly admitted to the icu, ( %) had been hospitalized before admission, ( %) were transferred after resuscitative and stabilization care in a level unit. for the two last categories, the mls (for previous hospitalization) was respectively ± days and ± hours. among patients transferred after care in a level unit, mls was no diff erent between colonized and noncolonized patients: ± versus ± hours (p = . , mann-whitney test). conclusion in this study, prevalence of colonization with esblb at admission is very high, suggesting a high prevalence of mdr colonization in the local population in afghanistan. it remains important to intensify the prevention policy against mrb cross-transmission in the deployed icu. critical care , volume suppl http://ccforum.com/supplements/ /s introduction the aim of this study is to describe the clinical and epidemiological profi le of icu patients receiving tigecycline (tgc) and to evaluate the potential benefi ts of tgc higher doses. methods all patients admitted to our icu between june and may who received tgc were evaluated. cases were excluded when infections were not microbiologically confi rmed. results over the study period, patients fulfi lled the inclusion criteria: in the sd group ( mg every hours) and in the hd group ( mg every hours). the sd group and the hd group were not signifi cantly diff erent in terms of age, severity of disease, duration of tgc therapy, rate of concomitant other active antibiotic use and of inadequate empirical antimicrobial therapy (iiat) (p = ns). mdr a. baumannii and k. pneumoniae were the main pathogens isolated. the percentage of germs other than a. baumannii and k. pneumoniae was higher in the sd tgc group (p < . ). otherwise infections due to less susceptible germs (tgc mic value ≥ μg/ml) were mainly treated with tgc higher doses (p < . ). no signifi cant diff erences were found in terms of icu mortality (p = . ). the rate of abnormal laboratory measures during tgc treatment was similar between the two groups (p = ns). no patients required tgc discontinuation or dose reduction because of suspected adverse events. in the vap subpopulation ( patients: received sd and hd), the clinical cure rate and microbiological eradication percentage were higher when tgc was used at higher doses ( . % vs. . %; p = . and . % vs. . %; p = . ). table shows multivariate analysis of clinical cure predictors in the vap subgroup. conclusion in critically ill patients, hd tgc use seems to be safe and, combined with other active antibiotics, may increase the rate of mdr germ vap clinical success. iiat and the severity degree of patients' clinical condition still remain major determinants of vap treatment failure. reference introduction amikacin inhale (nktr- , bay - ) is a drugdevice combination in clinical development for adjunctive treatment of intubated and mechanically ventilated patients with gram-negative pneumonia. the product uses a proprietary vibrating mesh nebulizer system (pdds clinical) with amikacin sulfate formulated for inhalation ( . ml of mg/ml amikacin solution) for a -day twice-daily course of therapy. it is designed for use with two delivery systems: one system for intubated patients (on-vent; figure ), and a second handheld (hh) system for patients who are extubated before completing the course of therapy ( figure ). we investigated in vitro the amikacin lung dose delivered by pdds clinical. methods an estimated lung dose (eld) for on-vent setting was measured in vitro after collecting aerosolized amikacin from a fi lter at the end of an endotracheal tube during ventilation. the eld for the hh device was calculated from the fi ne particle fraction (fpf < μm) postmouthpiece, multiplied by the in vitro delivered dose post-mouthpiece. fpf < μm refl ects lung deposition observed during phase clinical trials [ ] . eighty-one nebulizers with volume median diameter (vmd) introduction recent studies demonstrate that a loading dose of mg/kg (total body weight) of amikacin in septic patients is required to reach a suffi cient peak concentration. this study examines parameters infl uencing the relation between amikacin dose and peak concentration. methods in this retrospective study we looked at patients ( peak levels) between and . multivariate linear regression analysis was done for several parameters: administered dose calculated with total body weight, ideal body weight, adjusted body weight, type of intensive care patient, bmi, daily fl uid balance, sofa score and apache score, and patient characteristics were analyzed. results a linear correlation between dose and amikacin peak level was confi rmed (figure ) . a total . % of all amikacin administrations did not result in a therapeutic peak level. the multivariate linear regression analysis showed the best linear correlation with adjusted body weight and sofa score. the comparison of variables between four patient groups, based on the deviation between measured peak level and predicted peak level (according the linear correlation), showed new variables that may infl uence peak level. conclusion this confi rms that low doses (< mg/kg) of amikacin in intensive care patients seldom result in a therapeutic peak level. the proposed loading dose of mg/kg is good for reaching a therapeutic level, although . % remains subtherapeutic. due to the linear correlation, more therapeutic levels may be reached with higher doses ( to mg/kg). new variables need further investigation to explain the high variability in achieved peak level. introduction antibiotic-associated diarrhoea (aad) occurs in as many as % of patients receiving antibiotics, often leading to increased morbidity, prolonged in-hospital stay and additional healthcare resource utilisation. age, antibiotics and prolonged postoperative ward and icu stay have been suggested to be independent risk factors. in such patient populations, probiotics may be used to prevent antibioticassociated diarrhoea, yet they are not routinely recommended as a component of perioperative care. the aim of this study was to model the long-term costs associated with aad and to assess the eff ectiveness of probiotics as a preventive strategy. we developed a simulation model to determine clinical costs and outcomes attributable to aad. to assess the cost-eff ectiveness of probiotics, as part of a perioperative regime, we constructed a decision critical care , volume suppl http://ccforum.com/supplements/ /s s tree. the model observes long-term costs and outcomes of probiotics as compared with conventional therapy, from a societal perspective. input parameters, extracted from meta-analysis, clinical trials and national databases, include incidence numbers, costs and qualityadjusted health states for the remaining life (qalys). outcomes assessed were overall costs attributable to add and the cost-eff ectiveness of probiotics, described as costs/qaly. our results indicate an estimated incremental lifetime cost of £ , . per add patient, largely driven by increased icu length of stay and readmission rates. the addition of probiotics to the standard perioperative regime is associated with a small survival benefi t of . months, yet a cost reduction of £ . /add patient. the main cost was increased duration of icu stay and readmissions, which contribute to % of total expenses. conclusion aad is associated with a signifi cant increase in costs from a societal perspective. the provision of probiotics can achieve substantial cost savings and can be recommended as a cost-eff ective regime in the perioperative setting. preventing add off ers a potentially signifi cant reduction of in-hospital costs and resource expenditures. introduction novel treatment strategies for invasive candidiasis (ic) are constantly emerging. nevertheless, diffi culties in diagnosis pose a challenge on their reliability, effi cacy and safety. we have previously developed and approbated in our icu an algorithm for empirical antimycotic therapy, combining the most signifi cant risk factors for ic with three major clinical criteria for persistent nonbacterial sepsis [ ] . on the other hand, preemptive therapy, based on identifi cation of mycotic antigens and/or anti-mycotic antibodies in serum, is regarded as more reliable, even though it is known for its low sensitivity. the aim of the current study was to compare and evaluate the possible outcome benefi t of our protocol implementation versus detection of galactomanan in patient's serum as a trigger for antimycotic treatment initiation. methods a randomized prospective controlled trial was carried out from september to september . after the implication of the inclusion and exclusion criteria, patients were submitted to block randomization and stratifi ed on the basis of their initial saps ii exp score. antimycotic therapy was started on the day of inclusion in the control group and only with positive galactomanan serum test in the preemptive therapy group. initial data were gathered on demographics, proven risk factors for ic-related mortality, severity of infl ammatory response and organ dysfunction. dynamics of sirs and sofa values, candida colonization index, ventilator-free days, length of icu stay and outcome were followed for each patient. results a total of patients were enrolled. no statistically signifi cant diff erences in their basal characteristics were found. the subsequent sirs and sofa scores showed fi rm dynamics in the control group, although the new organ dysfunction severity was insignifi cantly lower. the length of icu stay and the number of ventilator-free days were comparable. the in-hospital mortality was . % in the preemptive therapy group versus . % in the control group (p = . ). a total of seven adverse reactions were observed among treated patients, yet not associated with higher mortality risk. conclusion the choice of empirical versus preemptive therapy led to earlier and more stable reduction in the degree of organ dysfunction severity. it showed to be at least not inferior if not equal; in terms of survival benefi t and expediency of treatment. moreover, galactomanan detection fails to guide the choice of the individual antimycotic, based on the expected candida spp. reference introduction invasive candidemia is a major cause of increased mortality among icu patients. antifungal agents like liposomale amphotericin b and azoles could not accomplish the claim to be fi rst choice in the treatment of invasive fungal infection (ifi) because of side eff ects and eff ectiveness. especially, cardiothoracic surgery patients as a group of high-risk patients are in a focus for new strategies and agents. a new class of antimycotic agents, the echinocandins, with a low profi le of side eff ects, low interactive potential and high eff ectiveness in the treatment of candidemia, is a powerful option in the treatment of ifi. we report our single-center experience with a modifi ed clinical treatment approach based on clinical score of leon and using echinocandins as fi rst-line therapy for proven and suspected fungal infection. methods from may to october , , patients were treated on our cardiothoracic icu. we evaluated cardiothoracic postoperative patients with proven or suspected ifi or prophylaxis ( figure ). the records were evaluated for cardiothoracic procedures, microbiological and yeast date, cardiothoracic surgery score (casus), icu and clinical data. mean age was . years with % male patients. most patients had combined cabg and valve procedure (n = ), other groups were htx and ltx (n = ), assist therapy (n = ), tavi (n = ) and other procedures. mean predicted mortality using the logarithmic casus score at the onset of ifi was %. c. albicans was isolated in %, c. glabrata in %. length of antifungal treatment using micafungin in cases was ± days. eradication of yeast was successful in % but mortality of all patients remains high at . % but was lower than predicted in the casus score. mortality was not yeast related. conclusion our described treatment approach shows encouraging results for the treatment of ifi especially in high-risk cardiothoracic patients. with fungi [ ] . the relationship between colonization and invasive fungal infection (ifi) in severely ill icu patients with a vad support is not described. this study analyzes the incidence and outcome of fungal infection and colonization in vad patients in bridge to transplantation or in destination therapy. methods we conducted a retrospective review of all vad implantations in our surgical icu between and . the incidence of fungal colonization, antifungal prophylaxis, bacterial sepsis and the mortality of ifi versus no ifi patients were compared. results in the study period, patients with severe heart failure or cardiogenic shock were selected for a vad implantation (nine in destination therapy). the overall mortality rate was % during mechanical assistance. confi rmed (n = ) and highly suspected (n = ) ifi occurred during the icu stay in % of patients who were treated with echinocandins, voriconazole and/or liposomal amphotericin b. the isolated fungi were: six candida albicans, two parapsilosis, one glabrata and one invasive pulmonary aspergillosis. antifungal prophylaxis with fl uconazole was administered to % of patients at mean for days mainly in the more recent implantations. in the no ifi population, % (n = ) had a systemic or vad bacterial sepsis with a mortality rate about %. the mortality without any sepsis was reduced to %. fungal colonization was signifi cantly more present ( % vs. %) before ifi in vad patients. the mortality rate was dramatically higher with ifi ( % vs. %) in accordance with the literature [ ] . see table . conclusion in our center, we observed a high incidence of ifi in icu patients with vad that was associated with a mortality rate of %. screening of fungal colonization appears to be very important during the icu stay for vad patients. trials are needed for investigating the use, the drug choice and the timing of antifungal prophylaxis for such high-risk patients. reference introduction echinocandins are recommended fi rst-line treatment for candidaemia [ ] . a cost-eff ectiveness model developed from a uk perspective examined costs and outcomes of antifungal treatment for candidaemia and other forms of invasive candidiasis based on european clinical guidelines [ ] . methods costs and treatment outcomes with the echinocandin anidula fungin were compared with caspofungin, micafungin, fl uconazole, voriconazole and amphotericin b. the model included non-neutropenic patients aged ≥ years with confi rmed candidaemia/ another form of invasive candidiasis receiving intravenous fi rst-line treatment [ ] . patients were categorised as a clinical success or failure (patients with persistent/breakthrough infection); frequency data for each outcome were taken from a mixed-treatment comparison [ ] . successfully treated patients switched to oral therapy. clinical failures switched to a diff erent antifungal class. it was assumed that second-line treatment duration was equivalent to that of fi rst-line treatment and only two lines of therapy were required to treat infection. other inputs were all-cause -week mortality, cost of treatment-related adverse events (aes) and other medical resource use costs. life-years were calculated using a published model [ ] . antifungal agent-related aes were taken from the product label/literature. resource use was derived from the literature and discussion with clinical experts. drug acquisition/ administration costs were taken from standard uk costing sources. results first-line anidulafungin for treatment of candidaemia was cost-eff ective per life-year gained versus fl uconazole (incremental cost-eff ectiveness ratio £ ). anidulafungin was cost saving versus caspofungin and micafungin in terms of life-years gained due to lower icu costs and a higher rate of survival combined with a higher probability of clinical success. conclusion anidulafungin was cost-eff ective compared with fl uconazole for treatment of candidaemia and was cost saving versus other echinocandins in the uk. european guidelines recommend echinocandins as fi rst-line treatments for candidaemia [ ] ; this model indicates that anidulafungin marries clinical eff ectiveness and cost-eff ectiveness. introduction invasive fungal infections (ifi) aff ect % of icu patients and are increasing in incidence. ifis are associated with a poor prognosis, which is further complicated by diffi culties in identifi cation of fungal organisms by traditional culture methods and the emergence of candida species resistant to triazole therapy [ , ] . this study aimed to assess the prevalence of ifis, the organisms responsible and outcomes of patients aff ected. the majority of patients ( %) were treated with echinocandins, whilst of the nine patients who were initially treated with fl ucanazole, six ( %) required therapy escalation to an echinocandin. the results of our study are consistent with other published data, in that whilst ifi prevalence is low, they are associated with increased morbidity in critically ill patients. this study has led to a change in hospital policy regarding antifungal use in the icu, with echinocandins being fi rst-line in the pre-emptive treatment of ifi. we keenly await the results of the fire study, which will provide important insights to identifi cation of patients at risk of ifis and optimal drug therapy. introduction the aim of this study was to compare self-reported beliefs with actual clinical practice of oxygen therapy in the icu. hyperoxia is frequently encountered in ventilated patients and prolonged exposure has repeatedly been shown to induce lung injury and (systemic) toxicity. methods an online questionnaire for icu clinicians was conducted to investigate beliefs and motives regarding oxygen therapy for critically ill patients. furthermore, arterial blood gas (abg) samples and corresponding ventilator settings were retrieved to retrospectively assess objective oxygenation between april and march in the icus of three teaching hospitals in the netherlands. results analyzable questionnaire responses were received from icu physicians and nurses. the majority of respondents believed that oxygen-induced lung injury is a concern, although barotrauma and volutrauma are generally considered to impose a greater risk in mechanical ventilation. frequently allowed minimal saturation ranges in the questionnaire were to % and to kpa ( figure ). selfreported fio adjustment in hypothetical patient cases with variable saturation levels was moderately impacted by the underlying clinical condition. to study actual clinical practice, a total of , abg samples with corresponding ventilator settings, covering , patient admissions, were retrieved. analysis showed a median (iqr) pao of . kpa ( . to . ), median fio was . ( . to . ), median peep was ( to ). a total . % of all pao registries were higher than previously suggested oxygenation goals ( . to . kpa) [ ] . in . % of cases with pao higher than the target range, neither fio nor peep levels had been lowered when the next abg sample was taken. conclusion most clinicians acknowledge the detrimental eff ects of prolonged exposure to hyperoxia in the icu and report a low tolerance for high saturation levels. however, the self-reported intention for conservative oxygen therapy is not consistently expressed in our objective data of actual clinical practice and a large proportion of patients was exposed to high and potentially toxic oxygen levels. introduction during mechanical ventilation, oxygenation can be infl uenced by adjusting fio and positive end-expiratory pressure (peep). there have been recommendations for how the fio and peep should be set [ ] . however, in a recent audit we found that the compliance of doctors of these recommendations is very low [ ] . conclusion implementing an fpi ≤ -based algorithm signifi cantly reduced the fio and increased the peep applied in mechanically ventilated within the fi rst hours. whether this has any impact on earlier weaning due to reaching the weaning criteria of fio sooner, and as a result shortening the duration of mechanical ventilation, has to be investigated in the future. references system) were applied with the humidifi er to optimize humidication. typeb was used in three patients and typev in four patients. the fl ow was started at l/minute. this fl ow rate was titrated upwards to a maximum of l/minute ( , , , , , l/minute) and the agfr was measured. intratracheal pressure tracing was done over minute. airway pressure measurement was repeated and the maximal expiratory pressure was measured in mmhg. the agfr in the respiratory circuit was almost same in typeb, but there was obvious decrease in the agfr in typev ( . ± . , . ± . , . ± . , . ± . , . ± . , . ± . l/minute at assumed fl ow, , , , , , l/minute, respectively). hfnc signifi cantly increased maximal expiratory pressure in both groups, . ± . , . ± . , . ± . , . ± . mmhg for typev and . ± . , . ± . , . ± . , . ± . mmhg (maximum mmhg) for typeb, when agfr was set at , , , l/minute. higher agfrs were found to result in larger increase in maximum expiratory pressure. the data indicate that hfnc are associated with an increase in intratracheal expiratory pressure. because it was diffi cult to determine end-expiratory pressure, we chose maximal expiratory pressure for a substitute. the reason why agfr in typev was lower than assumed fl ow may be the resistance generated by nc. the larger increase in expiratory pressure in our study than previously reported may be due to the eff ect of high respiratory resistance of japanese who have relatively small airway structure compared with western people. conclusion hfnc are eff ective in providing higher expiratory pressure. it is important to know the fl ow rate is lower than expected when the venturi type is used. results a weaning-induced pulmonary edema was diagnosed in instances (paop signifi cantly increased from . ± . to . ± . in these cases). evlwi, bnp, plasma protein and hemoglobin concentrations signifi cantly increased in these instances ( . ± . %, . ± . %, . ± . % and . ± . %, respectively) while they did not signifi cantly changed in cases without weaning-induced pulmonary edema. the increase of evlwi ≥ . % (+ . ml/kg), an increase in bnp ≥ . % (+ pg/ml), an increase in plasma protein concentration ≥ % and in hemoglobin concentration ≥ % exhibited good areas under the roc curves to predict weaning-induced pulmonary edema ( . ± . , . ± . , . ± . and . ± . , respectively). these areas under the roc curves were not statistically diff erent. the baseline values of evlwi, bnp, plasma protein and hemoglobin concentrations did not predict weaning-induced pulmonary edema. conclusion the increases in evlwi, in plasma protein and hemoglobin concentration and in bnp are valuable alternatives to the pulmonary artery catheter for diagnosing weaning-induced pulmonary edema. the primary aim of this study is to assess the impact of pressure support ventilation (psv) on the rate of pneumothorax and mortality in critically ill patients with lung injury. the secondary aim is to evaluate pressure-volume (p-v) relationships. spontaneous modes of ventilation have been associated with lower rates of atelectasis, less muscle atrophy, better airfl ow distribution and importantly lower sedation requirements, which relates to lower mortality. accordingly, we hypothesized that the use of psv in patients with moderate/severe lung injury would have rates of pneumothorax and mortality within the standard of care. we further hypothesized that given its spontaneous nature, set pressures (peep and ps) but not tidal volume (vt) would be related to airway pressures. methods all adult patients admitted to two surgical/medical icus subjected to invasive mechanical ventilation (mv) were enrolled. patients were stratifi ed by lung injury score (lis) in two groups: < . (lisl); ≥ . (lish). exclusion criteria included pneumothorax on admission, use of other ventilatory strategies, and inability to trigger ventilation. patients were ventilated with psv, and treated only with pro re nata haldol, morphine and clozapine. airway pressures and conclusion we demonstrate that psv in minimally sedated patients with severe lung injury is safe as it is associated with low incidence of barotrauma, atelectasis and mortality, and with ppl and duration of mv within standard of care. we also demonstrate in psv that p-v relationships may diff er and that in this setting higher vt may not be deleterious. introduction the aim of this study is to compare two ventilation strategies, the ardsnet protocol and open lung management, using computer control for hours. the standard therapy for patients with ards does typically apply a mechanical ventilator to support breathing. the cost of therapy is high and it requires much attention from physicians to adjust the proper ventilation settings in a timely manner. a closed-loop ventilation concept has therefore been developed and tested with two induced ards pigs. methods the hardware system is composed of a ventilator (servo ), a spectrophotometry (cevox), a capnography device (co smo+), an electrical impedance tomography device (goe mf ii) and a patient monitor (sirecust). the software is developed with labview . . with approval from the ethical committee, two kg pigs were exposed to surfactant depletion with a warm saline washout to induce ards (pao / fio < mmhg). one pig model was ventilated with an automatic ardsnet protocol and another was automatically ventilated with open lung management. blood gas analysis (bga) was carried out every half an hour. results artifi cial ventilation using the auto ardsnet protocol successfully stabilized oxygenation, minimized plateau pressure (< cmh o), and controlled the ph value for acidosis and alkalosis management. on the other hand, auto open lung management off ers a distinctive result of ventilation. a signifi cant improvement of oxygenation and lung compliance was observed within a few breaths after the recruitment maneuvers. both subjects were ventilated at the same tidal volume of ml/kg and the comparative results of automatic ventilation settings and bga are provided in table for every hours. conclusion the auto open lung management concept gave much better gas exchange than the auto ardsnet protocol. these preliminary results showed a necessity to evaluate the two diff erent ventilation strategies. therefore, further experiments with pig models will be implemented in the near future to obtain results with statistical signifi cance and to ensure the safety of automation in a mechanical ventilation system. intellivent-asv has been developed to provide fully closed loop mechanical ventilation using a ventilation controller keeping etco and spo within expert-based ranges. ventilation of ards patients focuses on delivering adequate oxygenation and allowing elimination of co while protecting the lung. the objectives were to compare intellivent-asv with conventional ventilation on safety and effi cacy, and to compare the number of manual adjustments between the two ventilatory modalities. methods a randomized, controlled study including all consecutive patients receiving mechanical ventilation for at least hours. patients were randomly ventilated either with intellivent-asv or conventional ventilation, with a s (hamilton, bonaduz, switzerland). parameters were adjusted by the clinician in charge of the patient. ventilatory and oxygenation parameters were recorded cycle by cycle during hours and blood gases were performed every hours. results twenty-four patients with ards were included, female, male, median age ( to ) years, apache ii score ( to ), pao /fio at inclusion ( to ). eleven were ventilated in the conventional group and in the intellivent-asv group. the study was stopped for one patient from the intellivent-asv group because of a pneumothorax not caused by ventilation. the delivered vt was slightly higher during intellivent-asv ( . ( . to . ) vs. . ( . to . ) ml/kg, p = . ). the time spent by the various parameters in the suboptimal zone (safety) is the same for the two ventilation modes. the time spent in the optimal zone (effi cacy) is the same for the two ventilation modes, introduction ventilator-induced lung injury (vili) is a well-known side eff ect of mechanical ventilation. the pressures and volumes needed to induce vili in healthy animals are far greater than pressure and volumes applied in clinical practice [ ] . a possible explanation may be the presence of local pressure multipliers (stress raisers). methods we retrospectively analyzed ct scans of patients with ards and ct scans of healthy subjects. a homogeneous lung would have the same gas/tissue ratio in all its regions. if a lung region expands less than the neighbour regions these will be more strained to vicariate the non/less expanding region. we measured the stress raisers by computing the ratio between the gas fraction of the region of interest and the neighbouring regions: if the infl ation would be the same (homogeneity), the ratio will be equal to one; if the infl ation of the surrounding regions would be greater than the region of interest (that is, more strained), the ratio between the two will be greater than one and was taken as a measure of stress raiser. we considered pathological stress raisers as the regions showing infl ation ratio greater than the th percentile of the control group ( . ) and defi ned as the extent of the stress raisers the fraction of lung volume above this threshold. the extent of stress raisers increased with the severity of ards ( ± , ± , ± % of lung parenchyma in mild, moderate and severe ards, p < . ). the extent of stress raisers correlated with the dead space fraction (r = . , p < . ), with the fraction of poorly aerated tissue (r = . , p < . ) and also has a negative correlation with the fraction of well infl ated tissue (r = . , p < . ). the response to peep, passing from to cmh o is minimal (average decrease of stress raiser extent ± %) and inter-individual variability is great (in patients, stress raisers increased passing from peep to peep ). stress raisers turn out to be greater in nonsurvivor patients than in survivor patients ( ± vs. ± % of lung volume, p = . ). the art strategy did not increase the risk of barotrauma (relative risk (rr) = . , % ci = . to . ) in the fi rst days after randomization or the need to initiate or increase vasopressors or mean arterial pressure < mmhg (rr = . , % ci = . to . , p = . ) hour after randomization. however, the art strategy increased the risk for severe acidosis (ph < . ) hour after randomization (rr = . , % ci = . to . , p = . ). conclusion art is feasible. the incidence of adverse events was similar between groups except for severe acidosis hour after randomization. hence we adjusted the study protocol, increasing the respiratory rate (from to /minute) during msarm. introduction cardiac surgical procedures are associated with a high incidence of postoperative complications, increasing costs and mortality. the purpose of this study is to evaluate prospectively the impact of two protective mechanical ventilation strategies, both using low-tidal volume ventilation ( ml/kg/ibw) after cardiac surgery. conclusion the reliability of pressure measurements and also of compliance estimation via the tested catheters is high. only in two catheters was the fi lling volume a critical point for a precise measurement of pressure or for estimation of compliance. immediately after unpacking, adhesion of the balloon material might prevent reliable pressure measurement, therefore before the fi rst measurement overfi lling of the balloon and retention of the excess gas seems strongly recommended. introduction low tidal volume (vt) ventilation in intensive care patients without lung injury attenuates the systemic infl ammatory response [ ] . the contribution of the specifi c organ infl ammatory responses to the systemic picture remains to be elucidated. we investigated the eff ect of low vt ventilation compared with medium high vt on hepatic, splanchnic and cerebral cytokine responses in an experimental large animal postoperative sepsis model. methods twenty pigs, group protective ventilation (pv), were ventilated with low vt ( ml/kg) and peep cmh o while pigs, group control (c), were ventilated with a vt of ml/kg and peep cmh o. catheters were introduced into an artery, the jugular bulb, the hepatic vein and the portal vein. laparotomy for hours simulated a surgical procedure after which baseline ensued and a continuous endotoxin infusion was started at . μg/kg/hour for hours. diff erences were analyzed with anova for repeated measures. results tnfα levels were higher in the hepatic vein than in the artery, the jugular bulb and the portal vein. il- levels were higher in the artery and the jugular bulb compared with the portal and hepatic veins. il- levels were higher in the portal vein compared with the jugular bulb and hepatic vein. the organ-specifi c il- concentrations were all higher than the arterial concentration. comparison between the ventilation groups showed that tnfα, il- and il- in the hepatic vein were higher in group c compared with group pv at the end of the experiment. peak concentrations of tnfα and il- in the portal vein were higher in group c compared with group pv. in this experiment tnfα was mainly generated in the liver while the results point to signifi cant nonhepatic il- and il- production. ventilation with low vt and medium-high peep attenuated hepatic and splanchnic cytokine production compared with mediumhigh vt and lower peep. reference introduction airway pressure release ventilation (aprv) allows spontaneous breathing throughout the ventilation cycle. it increases venous return and cardiac index, which will signifi cantly improve organ perfusion. this is important in septic shock patients to prevent extrathoracic organ system failure secondary to poor perfusion. benefi ts of aprv with cardiovascular changes are noticed in patients with acute lung injury and acute respiratory distress syndrome. it is not well established whether applying aprv will improve the survival outcome for septic shock patients. the primary outcome is whether the use of aprv in septic shock patients restores hemodynamic stability earlier than the cmv mode. the secondary hypothesis is whether the use of aprv in septic shock patients improves their survival in the icu. methods after institutional review board approval, we retrospectively analyzed the clinical data of septic shock patients who received ventilator support between january and december at a tertiary care hospital. the cox proportional hazards model was used in adjusting potential confounding factors. the nonparametric wilcoxon rank sum test was used to assess signifi cant outcome diff erences between groups. time to event/survival data will be analyzed using kaplan-meier methods. these analyses were accomplished using sas, version . . results among the patients, were excluded as per the exclusion criteria: incomplete data (n = ), do not resuscitate (n = ), icu readmission (n = ) and head injury (n = ). finally, patients were included, from these received cmv and received aprv. at the beginning of the study, there were no diff erences between the groups in relation to hemodynamic parameters. reversal of shock achieved in less than hours was statistically signifi cant between the groups (aprv, n = ( %) and cmv, n = ( %), p = . ). the proportion of patients recovering from septic shock after initiation of ventilator therapy was higher in aprv than the cmv group ( % vs. %, respectively, p < . ). the mortality rate was signifi cantly higher in cmv (n = , %) as compared with aprv (n = , %) (p = . ). conclusion the use of aprv in septic shock patients restores hemodynamic stability earlier than the cmv mode. there was a signifi cant improvement in icu survival using aprv over cmv. early initiation of aprv in ventilated septic shock patients was associated with a decrease in icu mortality. obese patients are at risk of developing atelectasis and acute respiratory distress syndrome (ards) [ ] . the prone position (pp) may reduce atelectasis, and improves oxygenation and outcome in severe hypoxemic patients in ards [ ] , but little is known about its eff ect in obese ards patients. introduction protective mechanical ventilation (mv) in ards is based on reduced stretch of pulmonary tissue, sometimes resulting in severe hypoventilation that can be avoided when using high respiratory rate. high-frequency positive-pressure ventilation (hfppv) has not been fully explored, especially when associated with other strategies aiming to avoid hypercapnia. methods we induced ards in eight pigs by lung lavage with saline plus hours of injurious mv with low peep and high driving pressure (dp). we then performed a recruitment maneuver (rm) followed by peep titration using the amount of alveolar collapse in electrical impedance tomography (eit). then stabilization during hours with tidal volume (vt) at ml/kg, respiratory rate (rr) breaths/minute and peep selected with the peep-fio table (arma study), which was kept constant during two steps of hfppv with a rr : one without an inspiratory pause (hfppv- ), and one with a pause of % of inspiratory time (hfppv- w/p %). in another hfppv step, we used peep titrated with eit after rm (hfppv- w/rm). during each hfppv step, vt was set to reach a paco of ± mmhg. distribution of regional ventilation was analyzed using eit. equilibrium was considered if paco was stable (< % of variation) for > minutes. results hfppv allowed reduction in paco levels: ( , ) versus ( , ), ( , ), ( , ) mmhg, besides using lower vt: . ( . , . ), . ( . , . ), . ( . , . ) and . ( . , . ) ml/kg during stabilization, hfppv- , hfppv- w/p % and hfppv- w/rm, respectively. it had no signifi cant diff erent results comparing hfppv- with and without an inspiratory pause. hfppv- w/rm allowed a better alveolar homogenization and improvement in oxygenation, shunt, dead space and dp compared with the other steps. see table . conclusion hfppv with a conventional mechanical ventilator is able to maintain stable paco in clinically acceptable values, allowing reductions in vt. hfppv- w/rm and peep titration using eit allowed further physiologic benefi ts in a severe ards model. high-frequency percussive ventilation (hfpv) is a rescue technique for most severe acute lung injury/acute respiratory distress syndrome (ards) patients [ ] , especially with smoke inhalation or respiratory burns [ ] . this study aimed at characterizing hfpv as delivered by percussionnaire vdr ® and at evaluating how hypobarism interferes with hfpv, in order to assess its usability at altitude. methods using a mechanical test lung mimicking ards (compliance ml/cmh o) with two resistance levels ( and cmh o/l/second) and ventilated with vdr ® in a hypobaric chamber, ascents/descents between and , and then and , ft were performed. adjustable vdr ® parameters were modifi ed one at a time at each altitude. besides these parameters (cross-measured with standalone hardware), oxygen consumption of the respirator and three calculated parameters were studied: low-frequency tidal volume (vt, integrated from instantaneous fl ows measured with a fleisch pneumotachograph), end-inspiratory (pmei) and end-expiratory (pmee) mean pressures. pmei and pmee in hfpv refl ect plateau pressure and positive end-expiratory pressure in conventional ventilation. the correction of altitude-induced off set with the modifi cation of working pressure was also tested. results data displayed by vdr ® overestimated pulmonary pressures by more than %, but were reliable for other parameters. during ascent, an off set appeared for all respiratory parameters: vt increased by % and pmei by % between and , ft. during descent, the off set was reversely directed with a % decrease in vt and a % decrease in pmee between , and ft. modifying working pressure adequately corrected pmei and pmee, but not vt. in all cases, manually correcting vdr ® parameters to their ft level also corrected these off sets. multivariate analysis further established that, adjusting for other parameters, vt, pmei and pmee did practically not depend on altitude. oxygen consumption of the respirator was high, l/minute at ft, and stable with altitude. it was reduced with percussive rate and with fio . conclusion hfpv can be safely used at altitude, provided that vdr ®displayed parameters are used to manually adjust settings in order to avoid exposing patients to volutrauma or barotrauma during ascent, and to major hypoventilation and alveolar collapse during descent. the high oxygen consumption is currently the main limit to its use for longrange aeromedical evacuations. the application of peep is commonly used in acute respiratory distress syndrome (ards) and has been shown to improve oxygenation. to identify patients that most benefi t from the application of peep, the discrimination of recruiters and nonrecruiters has been postulated by gattinoni and colleagues [ ] . recently, dellamonica and colleagues [ ] presented a method to predict alveolar recruitment. we hypothesised that the amount of recruitable volume allows the discrimination between ards patients and patients with healthy lungs (hl). methods we recalculated the recruited volume (rv) in patients with ards [ ] according to the method proposed by dellamonica and colleagues during an incremental peep manoeuvre (peep increased until the plateau pressure reached cmh o). rv was calculated as the change in end-expiratory lung volume minus total respiratory system compliance times the peep change (rv = Δeelv -ctot×Δpeep). for comparison, patients with hl undergoing elective surgery in general anaesthesia were measured using the same protocol. results both ards and hl patients exhibited typical p-v curves and stepwise recruitment ( figure ). by raising peep from to cmh o, ards patients recruited ± ml (mean ± sd) and hl patients ± ml. there was a strong correlation (r = . ) of the total rv with the end-inspiratory volume at a plateau pressure of cmh o in both groups; that is, recruitment was found to the same extent in both groups ( figure ). conclusion the relative contribution of rv to lung volume gain is similar in ards and in patients with healthy lungs. our results question the relevance of recruitability as defi ned by dellamonica and colleagues as a typical phenomenon of ards, but support the baby lung concept, as the recruited volume was closely related to the size of the lung. introduction venovenous extracorporeal membrane oxygenation (vv-ecmo) for respiratory failure in the icu is used in a variety of clinical situations and has been demonstrated to signifi cantly improve survival without disability in adult respiratory distress syndrome [ ] . ecmo has been presented as a risk factor for bloodstream infection although recently published data do not support this view or the use of antibiotic prophylaxis [ ] . we aimed to examine vv-ecmo as a risk factor for nosocomial bloodstream infection. a larger study is needed to confi rm such fi ndings and to assess the need for specifi c intervention, namely routine antibiotic prophylaxis. introduction aptt is a common tool for anticoagulation monitor ing during extracorporeal membrane oxygenation (ecmo). thromboelasto graphy (teg) is another available option in this setting. methods a prospective observational study on consecutive patients during venovenous ecmo. anticoagulation was provided critical care , volume suppl http://ccforum.com/supplements/ /s s with unfractioned heparin titrated to an aptt ratio target of . to . kaolin-activated teg (k-teg) was contemporarily measured but did not guide heparin infusion. baseline k-teg reaction time (r) > minutes is accepted for anticoagulation but when it exceeds minutes anticoagulation may be too great [ ] . results mean ecmo duration was ± days. a total of k-tegs were collected. comparison between aptt and k-teg r is reported in table . four patients ( %) had hemorrhagic complications. neither aptt nor k-teg r were signifi cantly diff erent in patients with hemorrhagic events compared with patients without hemorrhagic events but the latter received a signifi cantly lower total heparin dose (p = . ). conclusion anticoagulation was excessive in more than one-half of the samples according to teg monitoring, while negligible based on aptt. reference introduction the usefulness of extracorporeal membrane oxygenation (ecmo) is being rediscovered in the wake of the pandemic of h n infl uenza. however, it has been reported that patients who received ecmo often developed virus-associated hemophagocytic syndrome (vahs), compared with those without ecmo support. although there is ample evidence that extensive cytokine activation is a key factor in vahs, ecmo itself could be a potential trigger to exacerbate the pathology by amplifying cytokine activation. in this study, we investigated whether mediators such as cytokines may be produced by ecmo. methods patients with severe respiratory failure who were placed on ecmo were enrolled between june and july . this study was approved by the ethics committee. blood specimens were drawn from the blood circuit at the inlet of the centrifugal pump (before) and outlet of the hollow fi ber oxygenator (after) at a frequency of three to four times per day. blood il- β, il- , il- , il- , il- , il- , il- , il- , il- (p ), il- , il- , g-csf, gm-csf, ifnγ, mcp- , mip- β, and tnfα were measured globally using a multiplex cytokine bead array system (bio-plex; bio-rad, tokyo, japan). hmgb was measured using an elisa kit (shino-test, tokyo, japan). results two patients with interstitial pneumonia were studied. the ecmo system consisted of a rotafl ow centrifugal pump (maquet japan, tokyo, japan), a biocube tnc coating (nipro, osaka, japan), and a percutaneous cardiopulmonary support system (capiox ebs; terumo, tokyo, japan). the blood fl ow rate was . ± . l/minute. a total of blood sets were collected. in most cases, blood levels of il- β, il- , il- , il- , il- (p ), il- , il- , gm-csf, ifnγ, and tnfα were below the detection limit and did not increase during ecmo. the other mediators were detected at the inlet (before), but no signifi cant increase was observed at the outlet (after) (hmgb , p = . ; il- , p = . ; il- , p = introduction during severe exacerbation of chronic obstructive pulmonary disease (copd) tachypnea, as a consequence of respiratory acidosis, and airfl ow limitation, due to small airway obstruction, lead to lung hyperinfl ation, respiratory distress and gas exchange impairment. invasive mechanical ventilation could worsen lung hyperinfl ation and produce a vicious circle. we investigated whether increasing extracorporeal carbon dioxide removal (ecco cl) could reduce the respiratory rate (rr), so prolonging time for lung emptying and allowing resolution of hyperinfl ation. methods six patients with copd exacerbation with respiratory acidosis (paco ± mmhg, ph . ± . ) and tachypnea (rr ± ) despite maximal non-invasive ventilation underwent venovenous extracorporeal membrane oxygenation (vv-ecmo). all patients were awake and spontaneously breathing an adequate air-oxygen mixture to correct hypoxemia (pao ± mmhg). while keeping the blood fl ow stable ( . ± . l/minute), we changed the gas fl ow of the artifi cial lung to modify the extracorporeal co clearance as a percentage of total patient co production (% ecco cl/total vco ) and we observed the variations of rr. we recorded rr at three levels of gas fl ow in each patient ( figure ) . in all patients rr decreased with the increase of extracorporeal co removal and a negative correlation was found between rr and ecco cl/total vco (r = . , p < . ). in all patients we were able to obtain a reduction of rr below ( ± vs. ± , rr at low gas fl ow vs. rr at maximal gas fl ow, p < . ). the selected maximal gas fl ow was variable between diff erent patients ( . ± l/minute), corresponding to diff erent levels of ecco cl/total vco ( ± %, range to %) and rr response ( ± , range to ). conclusion in patients with copd exacerbation, who failed noninvasive ventilation, vv-ecmo allows one to maintain spontaneous breathing. titration of extracorporeal co removal leads to control rr. this approach could interrupt the vicious circle of dynamic hyperinfl ation and allow the defl ation of lung parenchyma. table presents the main results. the co removal by membrane oxygenator ranged from to ml/minute. all patients survived to the treatment and / were weaned from the ventilator at the end of ecco removal. only one oxygenator was used for every patient without clotting of the circuit or any major bleeding problem. we have previously shown, in an ex vivo porcine model, that lung elastance calculated as the peep change divided by lung volume increase (Δpeep/Δeelv) is closely correlated to conventionally measured lung elastance using oesophageal pressure [ ] . in this study we hypothesize that the successive change in lung volume during a peep-step manoeuvre could be predicted from Δpeep and lung elastance as Δpeep/el. the objective of the study was to validate this hypothesis in patients with acute respiratory failure (arf). methods thirteen patients with arf were studied during an incremental peep trial, - - - - cmh o. Δeelv was determined as the change in expiratory tidal volume following each peep step. conventional calculation of lung elastance was obtained from tidal variation in airway pressure minus tidal variation in oesophageal pressure divided by tidal volume. position of the oesophageal catheter was verifi ed according to baydur [ ] . the measured change in end-expiratory lung volume during the peep-step manoeuvre using spirometry was compared with the end-expiratory lung volume change calculated from el and stepwise changes in peep as Δpeep/el. results there was a close correlation between the measured build-up of end-expiratory lung volume during a peep-step manoeuvre and Δpeep/el where el was conventionally determined using oesophageal pressure measurements (see figure ). conclusion esophageal pressure measurements are diffi cult to perform [ ] and rarely used in routine clinical practice. our fi ndings indicate that a change in peep together with measurements of the resulting change in end-expiratory volume by spirometry in the ventilator could be used to determine lung elastance separately, the relation between lung and chest wall elastance as well as the transpulmonary pressure. references introduction long-term use of mechanical ventilators may lead to ventilator-induced diaphragmatic dysfunction (vidd) and increase the duration of weaning from mv [ ] . it was hypothesized that stimulating the diaphragm during mv may prevent vidd and may lead to early weaning [ ] . in this study, the feasibility of generating coordinated contraction of both diaphragms was investigated using a novel transvenous diaphragmatic pacing system. methods two juvenile pigs were anesthetized with propofol ( to μg/kg/minute) and ventilated (vent) with an assist control mode mv (nellcor puritan bennett ). using fl uoroscopy, a novel multipolar neurostimulation catheter (inspirx rl picc ; respithera, bloomington, mn, usa) was threaded into the left internal jugular vein and advanced to the junction of right atrium and the superior vena cava using a modifi ed seldinger technique. the successful capture of the right and left phrenic nerves was confi rmed by fl uoroscopic visualization. peak airway pressures (pawp) and blood gases were determined after minutes mv (mv), mv and stimulation applied together (mv+stim) and stimulation only (stim). no animal-ventilator dyssynchrony during stimulation (mv+stim) was noted while peak airway pressures were reduced. during stim there was no discernible paradoxical movement of the diaphragm. in addition, pco and po confi rmed that adequate ventilation and oxygenation can be provided by the system, while pawp could be reduced (table ) . introduction retrospective studies suggest that cardiac troponin levels are often elevated in patients with acute exacerbation of chronic obstructive pulmonary disease (aecopd) indicating a poor survival. novel high-sensitivity cardiac troponin (hs-ctnt) assays have better analytical precision than standard troponin (ctnt) assays. we elaborated a prospective cohort study to investigate the prognostic value of this novel biomarker in patients with aecopd. methods fifty-six patients (mean age years, % male) with the fi nal diagnosis of aecopd were enrolled. those who were diagnosed with acute coronary syndromes were excluded. we measured cardiac troponin t with a standard fourth-generation assay and a highsensitivity assay. clinical, electrocardiographic and echocardiographic data were collected at admission and the primary prognostic endpoint was death during days of follow-up. introduction british thoracic society guidelines on communityacquired pneumonia (cap) advocate icu referral for patients with curb score of and . a recently developed scoring system, smart-cop, designed to identify patients at need of intensive respiratory or vasopressor support (irvs), has been validated in a variety of settings. it predicts the need for icu admission (defi ned as need for irvs) with greater accuracy than curb , but is not used routinely in our uk institution. methods we retrospectively analysed critical care admissions of patients with a diagnosis of cap in a uk district general hospital -icnarc-coded diagnoses of pneumonia (bacterial, viral, no organisms isolated) over a -month period (august to january ). we ascertained the curb and smart-cop scores on referral to the icu and matched them in relation to the need for irvs, length of inotropic and ventilatory support and icu length of stay. results our search revealed potential matches. five patients were excluded (not cap) and the notes for seven patients were not available for analysis. we analysed the notes of patients matching our criteria. in this small sample, there was a strong association between increasing smart-cop score and the need for irvs (correlation coeffi cient r = . ). there was also a strong correlation with longer inotropic support (r = . ) and longer ventilatory support (r = . ) with increasing smart-cop scores but a weaker correlation with length of icu stay (r = . ). moreover, none of the patients admitted to the icu had curb score higher than at the time of icu referral. conclusion in our small sample, higher smart-cop score was associated with increased likelihood of irvs. this suggests that a further study with a larger sample size should be performed to investigate whether smart-cop is an improvement on curb in predicting the need for irvs in uk intensive care patients. introduction streptococcal pneumonia remains the most common cause of community-acquired pneumonia (cap), bacterial meningitis and bacteremia. severe pneumonia caused by streptococcal pneumonia frequently exists in the emergency room or icu. we performed this study to evaluate the eff ect of steroid therapy for severe streptococcal pneumonia patients with mechanical ventilation retrospectively. methods we enrolled adults of streptococcal pneumonia patients who required mechanical ventilation. seven of patients (s group) were administered with steroid (hydrocortisone to mg/day), and the remaining six patients received no steroid therapy (ns group). as the conventional therapies, mechanical ventilation was commenced when a patient's pao /fio showed less than or they clinically complained of being short of breath. all patients received appropriate fl uid therapies, vasoactive agents and blood transfusion according to the protocol of early goal-directed therapy in the surviving sepsis campaign guidelines , and also were treated with antibiotics, immunoglobulins ( g/day for days) and sivelestat sodium hydrate ( . mg/kg/day for days). the apache scores in the s group and ns group were ± and ± , sequential organ failure assessment scores were ± and ± , respectively. these scores showed no signifi cant diff erence between the groups. procalcitonin (pct) in the s and ns groups was . ± . and . ± . ng/ml, respectively, and there was no signifi cant diff erence between the groups. pct declined signifi cantly in both groups. pao /fio of the ns group was signifi cantly higher than the s group on icu admission and days after admission, but no signifi cant diff erence on days after icu admission. il- of the ns group declined signifi cantly after icu admission, and the s group also tended to decline. conclusion steroid therapy for severe streptococcal pneumonia patients with mechanical ventilation may have a potential to maintain oxygenation of the lung, but no signifi cant eff ects on changes of infl ammatory markers (il- , crp). introduction electrical impedance tomography (eit) is a non-invasive and nonradiating imaging technique, which can be used to visualize ventilation distribution of the lungs and could distinguish between the dependent (dorsal) and nondependent (ventral) parts. methods the aim of this study was to observe ventilation distribution between dependent and nondependent lung regions, for the individual patient, during three diff erent levels of support during pressure support (ps) and neurally adjusted ventilatory assist (nava) ventilation. ten mechanically ventilated patients in the icu were included. the ratio for dependent/nondependent distribution of ventilation is signifi cantly higher at lower support levels compared with higher support levels in both ps and nava. however, during nava there was signifi cantly less impedance loss between the diff erent levels of assist compared with ps. tidal volumes decreased when decreasing assist levels during ps whereas not during nava ventilation. the electrical activity of the diaphragm decreased in both ps and nava with higher levels of assist. three patients showed an increase in dependent tidal impedance variation (tiv) after lowering the assist level from to cmh o. this increase in tiv did not occur during nava ventilation. conclusion there is more ventilation in the dependent part of the lung, compared with the nondependent part, at lower levels of assist. this could indicate that at higher support levels the contribution of the diaphragm is reduced. during nava ventilation, there is an autoregulation in which the patient is adjusting his tidal ventilation to maintain homogeneous ventilation distribution. in status asthmaticus. our purpose was to analyze bipap use and outcomes for children with status asthmaticus and obesity in our ped. methods patients placed on bipap in the ped for status asthmaticus from january to august were included in the analysis. subjects were divided into moderate and severe exacerbations and then further subdivided into the following growth curve-based weight subgroups: < percentile, to percentile and > percentile. subjects received standard asthma therapies in addition to bipap. data were obtained at the bedside by the respiratory therapist or collected retrospectively by study investigators. data were stored and analyzed using a redcap database. results three hundred and fi fty-nine subjects were analyzed. table shows the time on bipap per visit. children whose weight was > percentile revealed trends towards longer treatment times on bipap compared with the other two groups. we explored the feasibility, reliability and physiological signifi cance of diaphragm thickening on ultrasound. methods five healthy subjects participated. we monitored inspiratory fl ow, volume, esophageal and gastric pressures, and diaphragm electrical activity (by esophageal and surface electromyography) while subjects performed a series of inspiratory maneuvers: tidal breathing, threshold-loaded breathing, a muller maneuver, and inspiration to various lung volumes above functional residual capacity. at the end of each inspiratory eff ort, subjects were instructed to close the glottis and relax the respiratory muscles (so as to maintain lung volume while eliminating diaphragm activation). sonographic images of diaphragm thickening during these maneuvers were obtained using m-mode with a mhz linear array probe placed in the right ninth, th, or th intercostal space between the middle and anterior axillary lines. results diaphragm thickening in the zone of apposition was readily visualized by ultrasound in all fi ve subjects. mean end-expiratory diaphragm thickness was . mm (sd = . mm). during tidal breathing, the diaphragm thickened by a mean of % (sd = %). the bland-altman coeffi cient of reproducibility was . mm; approximately % of measurement variability arose from caliper positioning on the ultrasound machine; diaphragm thickness measurements changed as the probe was placed in diff erent intercostal interspaces. diaphragm inspiratory thickening increased signifi cantly with increasing inspiratory eff ort but also varied with lung volume independent of eff ort. at inspiratory volumes below % of inspiratory capacity, lung volume change contributed minimally to diaphragm thickening. conclusion visualizing diaphragm thickening in the zone of apposition by ultrasound provides a feasible non-invasive technique for monitoring diaphragm activation in healthy subjects. diaphragm thickening primarily refl ects muscular eff ort rather than altered muscle conformation induced by changes in lung volume, especially at lower inspiratory volumes. the theoretical advantages of monitoring the electrical activity of the diaphragm (eadi) and neural triggering of support breaths (nava-maquet) have not yet been shown to translate into signifi cant clinical benefi t [ ] . here we assess the eff ect of eadi monitoring, in patients at risk of prolonged weaning, on outcomes. introduction emergency endotracheal intubation results in accidental oesophageal intubation in up to % of patients often with disastrous consequences. we have previously published a highly specifi c and sensitive novel method to detect endotracheal intubation based on diff erences in ventilation pressure waveforms in the oesophagus and in the trachea in patients with healthy lungs [ ] . a detection algorithm, based on diff erences in compliance/elasticity between the lung and the oesophagus, generated a d-value indicating tracheal intubation if d > . and oesophageal intubation if d < . . the aim of the current study was to validate the algorithm in patients with lung disease. methods after obtaining institutional approval, intubated and ventilated icu patients were included. inclusion criteria were controlled mechanical ventilation and at least mild to moderate lung injury according to a murray lung injury score > . . a connecting piece was placed between the endotracheal tube and the ventilation bag. this piece comprised a thin air-fi lled catheter inserted through the tube lumen at cm from the distal end, and a second catheter located at the proximal end of the tube. we performed three consecutive manual bag ventilations while recording the pressure curves through both catheters. for each ventilation, a d-value was calculated. results mean age (sd) of the patients was ( ) years, % were male. the mean (sd) murray score was . ( . ). pathologies included pulmonary oedema, pneumonia, atelectasis and traumatic lung injury. all d-values are represented in figure . the median (iqr, range) d-value was ( to , . to , ). our algorithm therefore confi rmed a high sensitivity to detect correct endotracheal intubation also in patients with lung disease. under the hypothesis that oesophageal compliance does not increase signifi cantly in patients with lung disease, the specifi city of our algorithm will not be aff ected. the aim was to compare two novel endotracheal tubes (ett), mallinckrodt taperguard (tg, tapered polyvinyl chloride (pvc) cuff ) and kimvent microcuff (mc, cylindrical polyurethrane cuff ), with conventional portex (pt, globular pvc cuff ) in leakages across cuff s (microaspiration) under simulated clinical situations. it has been shown that globular pvc cuff s protect poorly against leakages due to microchannels formed from infolding of redundant cuff material [ ] . we hypothesized that tg and mc better prevent microaspiration, which is a major mechanism of ventilator-associated pneumonia (vap the most common cause of ventilator-associated pneumonia (vap) is aspiration of oral secretion through the endotracheal tube (et). subglottic suction drainage (ssd) has been recommended as a safety measure against aspiration due to its high eff ectiveness. currently, two types of cuff shape -spindle and tapered -are predominant in high-volume, low-pressure (hvlp) ets with ssd. however, the shape most suitable for preventing dripping onto the subglottis has not been determined. the purpose of this study was to determine whether an et with tapered-type cuff can reduce the incidence of vap. methods after approval from the appropriate ethics committee, we conducted a single-institutional prospective randomized clinical trial on the eff ectiveness of using an et with a diff erent cuff type. introduction national audit project (nap ) highlighted the need to improve airway management in icus and key recommendations were the continuous use of end-tidal carbon dioxide (etco ) monitoring, pre-intubation checklists and diffi cult airway trolleys [ ] . this complete cycle audit aimed to quantify the current state of airway management on our icu and the eff ectiveness of implementing the nap recommendations. methods data collection was carried out prospectively for both phases and included documentation of intubation, use of etco and the incidence of serious adverse events (saes). the contents of the intubation boxes were compared against the diffi cult airway society (das) guidelines [ ] . the re-audit was carried out months following the introduction of a pre-intubation checklist, a documentation sticker, a diffi cult airway trolley and standardization of the basic bedside airway boxes with a checklist of contents. a training program in airway management for all icu staff was also introduced. micro-ct scan (skyscan ; bruker, belgium) was performed using a resolution of μm. axial sections of the cm above the cuff were reconstructed, and the volume of secretions was assessed by a density criterion. microbiological cultures of the ett lavage fl uid were then obtained. patient's demographics and clinical data were recorded. in a diff erent set of bench experiments, we injected ml water-based polymer into new etts of diff erent sizes. we measured resistance to airfl ow before and after using an ett cleaning device (airway medix closed suction system; biovo technologies, tel aviv, israel). we also obtained resistance values of intact etts as controls. the studied etts remained in place for a median of days (iqr range to ). the amount of secretions assessed by ct scan was . ± . ml (range . to . ml). secretion volumes were not related to patient severity at admission (saps , p/f ratio) or days of intubation; an inverse correlation with patient's age was present (p = . , r = . ). bacterial growth was present in / ( %) ett fl uids cultures and candida spp. showed an elevated prevalence ( / , %). in the bench tests, the cleaning device reduced resistance to airfl ow (diff erence before and after cleaning . ( % ci = . to . ) cmh o/l/second, p = . ). after cleaning, resistance resulted higher than intact etts, although with a clinically negligible diff erence (diff erence . ( % ci = . to . cmh o/l/second), p = . ). conclusion micro-ct scan is a feasible and promising technique to assess secretions volume in etts after extubation. the use of an ett cleaning device decreases resistance to airfl ow in bench tests; the eff ectiveness of such a device in the clinical setting could be properly assessed by post-extubation ct scan. [ , ] . the objective was to develop and validate a simplifi ed score for identifying patients with di in the icu and to report related complications. methods data collected in a prospective multicenter-study from , consecutive intubations from icus were used to develop a simplifi ed score of di, which was then validated externally in consecutive intubation procedures from other icus and internally by bootstrap on , iterations. in multivariate analysis, the main predictors of di (incidence = . %) were related to the patient (mallampati score iii or iv, obstructive sleep apnea syndrome, reduced mobility of cervical spine, limited mouth opening), to pathology (severe hypoxia, coma) and to the operator (non-anesthesiologist). from the β-parameter, a sevenitem simplifi ed score (macocha score; introduction in mechanically ventilated neonates the fl ow-dependent resistance of the endotracheal tube (ett) causes a noticeable pressure diff erence between airway and tracheal pressure [ ] . this may potentially lead to retardation of the passive driven expiration and dynamic lung infl ation consecutively but more importantly increases . the aim of this study was to evaluate the correlation between nt-probnp and cce and the potential usefulness of such variables during the weaning process from mv. methods twenty-two long-term (> hours) mechanically ventilated patients capable of performing a weaning trial of spontaneous breathing (sbt) were enrolled in the study. inclusion criteria were: age > years and equipment with a standard arterial catheter line. exclusion criteria were: neuromuscular disease, tracheotomy, renal failure, and traumatic brain injury. during the weaning process, nt-probnp plasma levels, cce, and standard hemodynamic and ventilatory data were collected minutes before extubation (t ), hours (t ) and hours later (t ). after removal of tracheal tube, patients with a history of heart failure received continuous positive airway pressure (cpap group). patients with normal cardiac function were maintained with spontaneous breathing (sb group). results sixty-six paired nt-probnp and cce values were obtained. patients in the sb group and in the cpap group were and , respectively. in both groups there was a trend towards an increase in nt-probnp values after extubation, an opposite trend was observed regarding cce values (p < . ). nt-probnp levels showed an increase after extubation (t , t ) compared with t ; conversely, cce showed an inverse trend. overall, a negative correlation was found between nt-probnp and cce values (r = - . , p < . ). signifi cant inverse correlations were found between nt-probnp and cce at t , t , and t (r = - . , - . and - . respectively; p < . ). the overall correlation between nt-probnp and cce was - . in the sb group and - . in the cpap group. standard hemodynamic and ventilatory data did not show signifi cant changes during the study. conclusion nt-probnp correlated well with cce. the latter seems to be an additional attractive index of cardiovascular state that, in association with nt-probnp changes, may provide information about cardiac function on a beat-by-beat basis during weaning process from mv. comparison of outcomes between early and late tracheostomy for critically ill patients k suzuki , s kusunoki , t yamanoue , k tanigawa introduction tracheostomy is one of the more commonly performed procedures in critically ill patients requiring long-term mechanical ventilation. however, the optimal timing or method of performing tracheostomies in this population remains to be established. in the present study, we compared outcomes of early and late tracheostomy in critically adult patients with diff erent clinical conditions. methods all patients needing tracheostomy in the critical care medical center of hiroshima prefectural hospital from january to december were surveyed. patients with tracheostomy who were not indicated for mechanical ventilation were excluded from the subjects. early tracheostomy (et) was defi ned as < days after tracheal intubation and late tracheostomy (lt) was defi ned as ≥ days after intubation. we compared patient characteristics, type of tracheostomy procedure, length of weaning from ventilator and outcomes between the groups. data are shown as the mean ± sd, with unpaired t test and mann-whitney u test used for statistical analyses. statistical signifi cance was accepted at p < . . results one hundred patients were surveyed. the et and lt groups included and patients, respectively. tracheostomy was performed using a percutaneous procedure in patients (et: , lt: ) and a surgical procedure in patients (et: , lt: ). sixty-two patients (et: , lt: ) survived to discharge and patients died in the icu (et: , lt: ). fifty-six patients (et: , lt: ) were weaned from ventilator support and tracheostomy cannula was removed in patients (et: , lt: ). there were no signifi cant diff erences in type of tracheostomy procedure, period from tracheostomy until icu and hospital discharge, rate of patients who could be weaned from ventilator and removed tracheostomy cannula, and icu and hospital mortality between the groups. the length of mechanical ventilation and the time to removal of tracheostomy cannula were signifi cantly shorter in the et group ( ± vs. ± and ± vs. ± days, respectively). conclusion in this retrospective study, early tracheostomy reduced the length of weaning after tracheostomy and the time to removal of tracheostomy cannula, while there were no diff erences in the length of icu stay and patient outcome. in critically ill adult patients who require mechanical ventilation, a tracheostomy performed at an earlier stage may shorten the duration of artifi cial ventilation. a further randomized clinical trial is essential to determine the eff ectiveness and safety of early tracheostomy. reference s variability in the course of blood vessels in the pre-tracheal area. a % risk of clinically relevant bleeding was recently reported for patients undergoing pdt [ ] . we conducted a systematic review of reports evaluating clinical outcomes following use of ultrasound scanning (us) for pdt. methods two investigators performed a search of the literature using the following databases: central, embase, medline and scopus. the following eligibility criteria were used: population including adults > years managed in the icu; use of ultrasound to guide decisionmaking pre-pdt or guide pdt performance; report of clinically relevant outcome measures. nonrandomised controlled trials were classifi ed according to cochrane non-randomised study methods group criteria [ ] and evaluated for risk of bias. results an initial search identifi ed , reports, of which studies met eligibility criteria: eight case series, one randomised controlled trial (rct) and one prospective cohort study, incorporating patients. two studies specifi cally reported data on patients with obesity (n = patients) and one study reported data for a group of patients with spinal cord fi xation (n = ). us was used to guide decision to perform pdt or surgical tracheostomy in fi ve studies, with decision to perform surgical tracheostomy ranging from to % of cases. us was used to guide insertion point in seven studies, and used real-time in four studies. times to perform us-guided pdt were reported in four studies (ranging from to minutes). no studies compared time taken with or without us. data on complications of procedure were reported in nine studies. minor bleeding was reported for eight cases ( . % overall). prolonged bleeding was reported in two cases ( . %). there were no episodes of catastrophic bleeding among cases. high risk of bias was identifi ed in fi ve studies in terms of patient selection. an intervention protocol was not defi ned in three reports. no attempt was made at blinding any aspect of the studies. conclusion use of us guidance could theoretically help minimise risk of haemorrhagic complications during pdt and perhaps reduce time taken to perform pdt. however, there is currently inadequate evidence from controlled cohort studies or rcts to suggest that routine use for pdt in selected or unselected groups improves clinically relevant outcome measure. introduction failed airway situations are potentially catastrophic events and require a correct approach with appropriate tools. recently, ventrain has been presented as a manual device for emergency ventilation through a small-bore cannula, which can provide expiratory assistance by applying the venturi eff ect. methods we used the simularti human patient simulator to evaluate ventrain. initially, we studied the eff ectiveness and security in ventilating and oxygenating the patient. in a second phase, the ventrain performance was compared with what is considered to be the present gold standard (quicktrach ii, portex mini-trach ii seldinger kit, melker emergency cricothyrotomy catheter set). seven anesthesiologists performed an emergency transcricoid ventilation with each device in the same setting. results ventrain provided an average tidal volume of ml and an average minute volume of . l in the considered situation, with a modifi cation of pao from to mmhg and of paco from . to . mmhg. in the second phase, the time needed to obtain an eff ective oxygenation with ventrain was found to be shorter than other devices (median diff erence; vs. minitrach - seconds; vs. melker - seconds; vs. quicktrach - seconds) ( figure ); the ability to remove co resulted bigger (average diff erence: vs. minitrach - . ; vs. melker - . ; vs. quicktrach - . ) ( figure ) and moreover the users judged it more favorably. conclusion in this manikin study, ventrain seemed to be able to appropriately oxygenate and ventilate a patient in a cicv situation. when compared with the best available choices, it has shown not to be inferior. introduction eff ective delivery of aerosolized bronchodilators for patients with asthma is crucial for adequate therapy in critical care and emergent settings. often administered with pressure-metered dose inhalers (pmdis), bronchodilator delivery depends on the correct patient technique during administration [ ] and the ability to measure treatment response, which are diffi cult to monitor at the point of care and particularly so in resource-poor settings where standard inhospital monitoring is unavailable [ ] . methods a point-of-care device for airfl ow measurement during bronchodilator delivery was designed and tested for use in resourcelimited settings. the handheld device was constructed from a clinical aerosol delivery tube with a bidirectional sensor for pressure diff erential detection about the aerosol element ( figure ). the custom low-cost introduction protocol-based care of the tracheostomised patient is important, as adverse events confer a high rate of mortality. little is known regarding the existence of formal evidence-based guidelines on tracheostomy care. the aim of this study was to perform a systematic review for evidence-based guidelines on adult tracheostomy care. methods a systematic search of pubmed, medline, guideline clearinghouses, centres of evidence-based practice, and professional societies' guidelines relating to care of adult patients with a tracheostomy was performed by two reviewers. in addition, a google search of publicly available tracheostomy care guidelines was performed. search terms: (tracheostom* or tracheotom*) and (protocol* or guideline* or standard* or management or consensus or algorithm*). filters: english language, human, from january to date, adult patients. guideline appraisal criteria: the quality of guidelines retrieved was assessed using the appraisal of guidelines research and evaluation ii (agree ii) instrument [ ] . the search results are summarised in table . a total of guidelines were identifi ed. five were found to satisfy the agree ii criteria and only three related to the entire spectrum of tracheostomy management. the majority was informal and was not published or evidence based. conclusion five evidence-based guidelines on adult tracheostomy management were identifi ed. this may represent a paucity of evidence on the subject, suggesting that further clinical trials on the topic are needed to contribute to the evidence base. this also highlights the need for international consensus on the topic, to reduce duplication of eff orts, standardise practice, and improve outcomes. [ ] concluded that the majority of airway-related signifi cant complications in icus resulted from displaced or blocked tracheostomies and recommended together with the intensive care society and the national tracheostomy safety project that each icu in the uk should have an emergency airway management plan and guidelines [ ] . the aim of this survey was to establish whether such guidelines exist and are familiar to those working within the icus of the east of england (eoe), their ease of availability in an emergency and the degree of emergency tracheostomy training within the region. methods data collection was via a telephone survey of icus in the eoe training region during july with one senior icu nurse and one icu trainee questioned per hospital. questions related to the existence and accessibility of guidelines for tracheostomy emergencies, and to the respondent's degree of emergency tracheostomy training and their perceived availability of formal training. results all icus questioned perform and manage tracheostomies. of respondents, knew of guidelines covering all of the emergencies described above and their location. four respondents thought that these guidelines were accessible in an emergency setting, one-half of which were on computer systems requiring a login and search function. with regards to emergency management, respondents felt competent in a tracheostomy emergency; almost exclusively through experience and in-house teaching. no respondents were aware of any formal emergency tracheostomy management courses. conclusion despite national guidance within the uk this survey highlights that implementation and awareness of emergency tracheostomy guidelines in icus in the eoe region is poor, and when present they are not readily accessible in an emergency. emergency training has largely been informal and the availability of formal training courses has not been recognised. in order to improve patient safety there is a need to ensure that emergency tracheostomy management including guidelines, equipment and formalised tracheostomy emergency training are adopted and embraced universally. references introduction a fatal incident related to a blocked tracheostomy tube prompted a review in our trust. to provide safe tracheostomy care, changes in staffi ng, education and operational policies were recommended. training of potential fi rst responders to tracheostomy or laryngectomy emergencies remains outstanding. we aim to quantify the training defi cit. tracheostomies are common in critical care but these patients require ongoing management of an artifi cial airway on discharge to the ward and even the community. in our critical care unit cared for tracheostomy patients, of which were transferred to the wards. the th national audit project highlighted complications including hypoxic brain injury and death [ ] and the national patient safety agency recognised a number of avoidable aspects [ ] . existing guidelines for management of these patients including emergencies are not widely known. methods an anonymous online survey was sent to all trainees who may respond to a tracheostomy emergency in our organisation. trainees in anaesthesia/critical care, general medicine, general surgery, ent, thoracics and a&e were approached. all completed forms were included. we achieved a response rate of % ( / ). respondents comprised: % anaesthesia/critical care, % medicine and % surgery. over one-half ( / ) had managed tracheostomy/laryngectomy emergencies, with % ( / ) of these incidents occurring on the wards and one in an outpatient clinic. only % ( / ) had received any formal training on management of a blocked/misplaced tracheostomy tube and only % ( / ) were aware of any guidelines. one-third of responders lacked confi dence in management of these emergencies and % felt they would benefi t from formal training including simulation. conclusion the population of patients with exteriorised tracheas is increasing and represents a high-risk group. management of airway emergencies in these patients is not part of standard life-support courses. according to our trainees, these scenarios are relatively common and a signifi cant proportion of fi rst responders are poorly equipped to deal with them. our trust will be including specifi c training on the emergency management of neck breathers as part of in-house resuscitation training. we would contend that national resuscitation courses should consider doing the same. introduction usually percutaneous tracheostomy is accomplished via the tracheal tube. some severe complications during percutaneous dilatational tracheostomy (pdt) may be related to poor visualization of tracheal structures. the alternative implies extubation and reinsertion of a laryngeal mask (lma). an accidental extubation as well as an injuring of the vocal cords (because of the infl ated cuff during dislocation) appears impossible in this method. subjectively, the bronchoscopic view obtained via a lma seems to be better than that obtained with an endotracheal tube (et) [ , ] . methods in this prospective observational study, the bedside pdt was performed using the ciaglia blue dolphin method in critically ill patients. the patient's tracheal tube was exchanged for a lma fastrach™ before undertaking pdt. the insertion of the lma, the quality of ventilation, the blood gas values, the view of the tracheal puncture site, and the view of the balloon dilatation were rated as follows: very good ( ), good ( ), barely acceptable ( ), poor ( ), and very poor ( ) . results pdts with lma were successful in . % of the patients (n = ). the ratings were or in % of cases with regards to ventilation and to blood gas analysis, in . % for identifi cation of relevant structures and tracheal puncture site, and in . % for the view inside the trachea during pdt. a rating of was assigned to one patient requiring tracheal reintubation for inadequate ventilation. there were no damages to the bronchoscope or reports of gastric aspiration. conclusion the blue dolphin pdt using a lma showed defi nite advantages regarding inspection of dilation process. this method improves visualization of the trachea and larynx during a video-assisted procedure and prevents the diffi culties associated with the use of an et such as cuff puncture, tube transection by the needle, accidental extubation, and bronchoscope lesions. the lma results as an eff ective and successful ventilatory device during pdt. this may be especially relevant in cases of diffi cult patient anatomy where improved structural visualization optimizes operating conditions. the intensivist performing pdt should be scrupulous when deciding which method to use. in our icu the blue dolphin pdt with lma has become the procedure of choice. introduction acute cor pulmonale (acp) is associated with increased mortality in patients ventilated for acute respiratory distress syndrome (ards). interventional lung assist (ila) allows a lung-protective ventilatory strategy, whilst allowing co removal, but requires adequate right ventricular (rv) function. rv restriction (including presystolic pulmonary a wave) [ ] is not routinely assessed in ards. methods a prospective analysis of retrospectively collected data in patients with echo during ila was performed. data included epidemiologic and ventilatory factors, lv/rv function, evidence of rv restriction and pulmonary hemodynamics. data are shown as mean ± sd/median (interquartile range). results thirty-two patients ( ± years), male ( %), sofa score . ± . were included. pulmonary hypertension (pht) was %, and hospital mortality %. mortality was not associated with age, days on ila, length of icu stay, inotropic support, nitric oxide or level of ventilatory support, but was associated with pressor requirement (p = . ), a worse pao :fio ratio ( . ( . to . ) vs. . ( . to . ), p = . ) and higher pulmonary artery pressures ( . mmhg ( to ) vs. . ( . to . ), p = . ). no echo features of acp were found, with no signifi cant diff erence between rv systolic function, pulmonary acceleration time and pulmonary velocity time integral between survivors and nonsurvivors. the incidence of rv restriction was high ( %), and independent of pht, rv systolic function and level of respiratory support, but correlated with co levels (restrictive . kpa ( . to . ) vs. . ( . to . ), p = . ). see figure . conclusion typical echo features of acp were not seen in this study, possibly because of the protective ventilatory strategies allowed by use of ila. the incidence of rv restriction may refl ect more subtle abnormalities of rv function. further studies are required to elucidate rv pathophysiology in critically ill adult patients with ards. reference introduction global left ventricular electromechanical dyssynchrony (glvd) is uncoordinated lv contraction that reduces the extent of intrinsic energy transfer from the myocardium to the circulation leading to a reduction in peak lv pressure rise, prolonged total isovolumic time (t-ivt) and fall in stroke volume [ ] . this potentially important parameter is not routinely assessed in critically ill cardiothoracic patients. methods a prospective analysis of retrospectively collected data in cardiothoracic icu patients who underwent echocardiography was performed. in addition to epidemiological factors, echo data included comprehensive assessment of lv/rv systolic and diastolic function including doppler analysis of isovolumic contraction/ relaxation, ejection time (et) and fi lling time (ft). t-ivt was calculated as ( -(total et + total ft)) and the tei index as (ict + irt) / et. t-ivt > second/minute and tei index > . were used to defi ne glvd [ ] . data are shown as mean ± sd/median (interquartile range). results a total of patients ( . ± . years), male ( %), apache ii score ( . ± . ) were included. the prevalence of glvd was high ( / , %) and associated with signifi cantly increased mortality, . % vs. % (p = . ). there was no diff erence in requirement for cardiorespiratory support between the two populations, but there were signifi cant diff erences (no glvd vs. glvd) in requirement for , p = . ), mitral regurgitation ( . % vs. . %, p = . ), or any other measures of lv systolic or diastolic function between the two groups. there was good correlation between the two methods used to assess dyssynchrony (lv t-ivt:lv tei index correlation coeffi cient = . , p < . ). conclusion glvd that limits cardiac output is common in the cardiothoracic icu, and signifi cantly related to mortality. when diagnosed, the underlying cause should be sought and treatment instigated to minimize the t-ivt (pacing optimization/revascularization/ inotrope titration/volaemia optimization). references introduction correction of coagulopathy before central venous catheter (cvc) insertion is a common practice; however, when ultrasound guidance is used this is controversial as mechanical complications are rare. studies in oncology patients suggest that cvc placement without prior correction of coagulopathy is safe but no studies are available for critically ill patients and guidelines do not give recommendations [ , ] . we do not routinely correct coagulopathy, even if severe, when ultrasound guidance is used and the purpose of this retrospective study was to evaluate the safety of this practice. methods data for all ultrasound-guided interventions, including complications, are prospectively collected in our department for audit purposes; in this study we involved only cvc insertions in the icu between february and november . electronic medical and laboratory records and paper-based nursing charts were retrospectively studied for all interventions, specifi cally looking for blood results, coagulation abnormalities and intervention-related complications. in the study period, ultrasound guidance was employed for a total of central line insertions in icu patients. coagulopathy was detected in cases at the time of cvc placement ( . %). on the day of cvc insertion, coagulation abnormalities were corrected in cases ( . %); out of patients with severe coagulopathy ( . %) and out of patients with coagulopathy of moderate severity ( . %) had no correction at all. correction was started only after cvc insertion for reasons unrelated to cvc placement in a further eight and two patients with severe and less severe coagulopathy ( . % and . %), respectively. no bleeding complications were observed. conclusion in patients undergoing cvc insertion in our icu, coagulopathy is common. we observed uncomplicated cvc placement in all patients with severe uncorrected coagulopathy and in a further patients with coagulopathy of moderate severity. when combined with other studies, our data suggest that ultrasound-guided cvc placement without routine correction of coagulation abnormalities may be safe in the icu. introduction early bleeding from the exit site after cvc or picc placement is a very common event that causes diffi culties in the patient's care and logistical problems. in our experience, the rate of signifi cant local bleeding after placement of piccs without reverse tapering may be as high as % at hour and % at hours, while the rate of bleeding after placement of a large-bore dialysis catheter is above % at hour. methods the aim of this pilot study was to verify the effi cacy of a cyanoacrylate glue in reducing the risk of early bleeding at the exit site after cvc or picc placement. we studied a group of adult patients consecutively undergoing placement of polyurethane cvcs or piccs without reverse tapering in a non-intensive ward of our hospital. all lines were inserted according to the same protocol, which included % chlorhexidine antisepsis, maximal sterile barriers, ultrasound guidance, ekg guidance and securement with sutureless device. two minutes after placement of the glue, the exit site was covered with a temporary gauze dressing, which was replaced by transparent membrane at hours. all patients were assessed at hour and at hours. results in consecutive patients ( piccs, dialysis catheters and nine cvcs), there was no signifi cant local bleeding at hour or at hours after catheter placement. no local adverse reaction occurred. no damage to the polyurethane of the catheters was detected. conclusion glue is an inexpensive and highly eff ective tool for avoiding the risk of early bleeding of the exit site after catheter placement. we also suggest that in the next future the glue might prove to have benefi cial collateral eff ects on the risk of extraluminal contamination (by reducing the entrance of bacteria in the space between the catheter and the skin), as well as on the risk of dislocation (by increasing the stability of the catheter inside the skin breach). introduction about years ago the use of chest radiographs as the golden standard to ensure correct positioning of central venous catheters (cvc) was questioned. the frequent use of cvcs was also challenged. we decided to retrospectively evaluate our routines in a large surgical unit in a swedish university hospital. methods all x-rays were centrally registered. chest x-ray performed in our unit is almost entirely used to confi rm cvc positioning. the certofi x cvc set for the seldinger technique in combination with certodyn -universaladapter (b braun, germany) is now used as the routine equipment and the right jugular vein is our standard approach. in the total number of x-rays performed in patients at our unit was , , which corresponds to the approximate number of inserted cvcs at that time, since a confi rmatory x-ray was routine. x-rays were rarely performed on other indications in our unit. x-ray costs were at that time approximately € , (~€ /each). the year after, , chest x-rays were performed, refl ecting both the use of intracardiac confi rmation of correct cvc position and also a reduced use of cvcs. this trend has continued over time. in approximately cvcs were inserted at our unit. x-rays were performed in about % of these cases. the cost for a chest x-ray is today ~€ , meaning that x-ray costs were approximately € , . we have not experienced any medical problems when intracardiac ecg was used for positioning confi rmation. on the contrary, aspiration of venous blood without apparent p-waves in a patient with sinus rhythm may suggest improper placement of the cvc; for example, the right brachial vein. conclusion if we had continued to use cvcs at the same frequency as we did years ago, and used x-ray confi rmation in practically all cases, we would have paid approximately € , annually. reduced use of cvcs, in combination with intracardiac confi rmation of cvc positioning, has not only allowed us to reduce costs associated with cvc insertion by more than € , , corresponding to a reduction rate of more than %, but also decreased the patient's exposure to x-ray irradiation. introduction in cases of arrhythmia, the beat-to-beat variation of arterial pressure (ap) may impair the accuracy of automated cuff measurements. indeed, this oscillometric device relies on the detection of arterial wall oscillations. our aim was to determine, in icu patients, whether brachial cuff measurements are really less reliable during arrhythmia than during regular rhythm. methods patients with arrhythmia and carrying an intra-arterial catheter were prospectively and consecutively included in this multicenter study. after each arrhythmic inclusion, a regular rhythm patient was included. a second inclusion was possible in case of change in the cardiac rhythm. three pairs of invasive and brachial cuff (philips® mp monitor) measurements of mean arterial pressure (map) were respectively averaged. some patients underwent a second set of measurements, after a cardiovascular intervention (passive leg raising, volume expansion, initiation of/increase in catecholamine infusion) allowing the assessment of map changes. introduction signifi cant changes in haemodynamics occur after brain stem death (bsd) and there is evidence that yield of transplantable organs may be decreased in donors who remain preload responsive prior to donation [ ] , suggesting that optimisation of the cardiac output (co) may be benefi cial in potential organ donors. we describe current uk practice with regard to co monitoring in this group. methods we reviewed a database of brain-stem-dead potential organ donors collected by specialist nurses in organ donation (sn-od) over a -month period ( april to october ) across multiple uk centres. the database contained data on donor management in the period from initial sn-od review to immediately prior to transfer to the operating theatre. we analysed data on co monitoring and vasopressor/inotrope use. where information was missing/not recorded in the dataset, the treatment referred to was interpreted as not given/not done. fifty-three patients ( . %) had evidence of co monitoring. lidco was the most popular method ( figure ). a total of ( %) patients received treatment with vasopressors and/or inotropes. co data were utilised in a variety of ways ( figure ). conclusion the majority of potential donors require vasopressors and/or inotropes post bsd, but it seems only a minority currently have their co monitored. there is variation in how co data are utilised to direct haemodynamic management. we welcome the development of standardised bundle-driven donor management. reference the indocyanine green plasma disappearance rate (icg-pdr) is a dynamic liver function test that can be non-invasively measured by pulse densitometry. icg-pdr is associated with mortality and other markers of outcome. due to predominant use of icg-pdr in the icu setting, the normal range is based on scarce data available outside the icu and given with to %/minute. methods to prospectively re-evaluate the normal range and to analyze the potential impact of biometric data on icg-pdr, we measured icg-pdr (i.v. injection of . mg/kg icg; limon, pulsion, munich, introduction mixed venous oxygen saturation (svo ) represents a well-recognized parameter of oxygen delivery (do )-consumption (vo ) mismatch and its use has been advocated in critically ill patients in order to guide hemodynamic resuscitation [ ] and oxygen delivery optimization. nevertheless, the pulmonary artery catheter (pac) is not readily available and its use is not devoid of risks. furthermore, its use has been decreasing in recent years in surgical and cardiac surgical patients as the benefi t of guiding therapy with this device is unclear [ ] [ ] [ ] . central venous oxygen saturation (scvo ) has been suggested as an alternative to svo monitoring due to its feasibility in several settings. unfortunately concerns arise from its capability to correlate with svo , the relationship being infl uenced by several factors, such as hemodynamic impairment and pathological process. hemodynamic instability and shock often complicate cardiac surgery, and the svo -scvo relationship has not been specifi cally investigated in this setting. the aim of this study is to compare svo and scvo values in patients with cardiogenic shock after cardiac surgery. methods a prospective observational study was designed and conducted. inclusion criteria were: patients who had underwent elective or urgent/emergent cardiac surgery, with cardiac index (ci) < . l/minute/m estimated by means of a pac, left ventricle ejection fraction (lvef) < %, lactate > mmol/l, age > years. a central venous catheter (cvc) and a pac were inserted for each patient before surgery in the same right internal jugular vein in accordance with standard procedure. proper position of the pac was confi rmed with pressure tracings and chest x-ray. mixed and central venous blood samples were collected from the distal ports of the pac and cvc respectively minutes after icu admission, and every hours for a total of three samples in a -hour period for each patient. all blood samples were analyzed by a co-oximeter (radiometer abl fl ex; radiometer, copenhagen, denmark). statistical analysis was performed by stats direct (ver. . . , cheshire, uk) and graphpad (vers. prism . ; san diego, ca, usa). all data were tested for normal distribution with the kolmogorov-smirnov test. statistical analysis was performed by linear regression analysis. the agreement between absolute values of scvo and svo were assessed by the mean bias and % limits of agreement (loa) ((mean bias ± . )×standard deviation) according to the method described by bland and altman [ ] . results a total of patients were enrolled. in out of cases all three blood samples were collected. in two patients only two blood samples were drawn as they exited the inclusion criteria. linear regression analysis between the two variables resulted in an r of . . bland-altman analysis ( figure ) for the pooled measurements of svo and scvo showed a mean bias and loa of . % (sd of bias . ) and - . to + . % respectively. conclusion scvo has been advocated as an attractive and simple indicator of do -vo mismatch [ ] . its role as a surrogate of the wellestablished svo has been investigated in several settings, and it has been purposed in the hemodynamic resuscitation of critically ill septic patients [ ] . nevertheless, the svo -scvo relationship can be infl uenced by several factors due to scvo dependency from global blood fl ow redistribution that can occur during hemodynamic impairments. it has been shown previously that in healthy people scvo values tend to underestimate svo values, due to the higher oxygen content from inferior vena cava [ ] . during circulatory shock, not homogeneous oxygen extraction and regional blood fl ow methods we assessed the benefi t these tee data provided in the assessment of fi ve domains: hypovolemia, right ventricular dysfunction, left ventricular dysfunction, sepsis, and valvular abnormality. bedside practitioners listed their diagnoses before and after seeing primary tee images perform by trained physicians. we used a to likert scale to assess diff erential diagnosis before and after the tee, comparing changes using a paired t test. results all requests for tee were to access hemodynamic instability. a total of patients were screened and nine were eligible, in which total tee studies were performed. there were no complications with tee and all patients tolerated the long-term placement of the probe well. of the fi ve diagnostic domains studied, right ventricular failure was the most commonly underdiagnosed contributor to the hemodynamic instability among patients prior to tee (p = . ) (figures and ). introduction echocardiography is increasingly utilized by inten sive care physicians in everyday practice. standardization of echocardiographic studies and reporting, quality assurance and medicolegal requirements necessitate establishment of a dedicated system within the critical care setting. we describe the process of setting up a critical care echocardiography (cce) laboratory based on our experience from three separate icus. methods a retrospective review and analysis of the process involved in establishment of echocardiography laboratories within icus. results creating a cce service involves a number of stages and takes several years to achieve. major components include staffi ng, equipment, quality control, study archiving and networking capability. for staffi ng the objective is to identify and recruit staff with adequate training and expertise in cce, providing / specialist cover in addition to supporting and training junior medical and nursing staff . there is further a need to acquire funding for high-quality ultrasound machines and related hardware as well as long-term dicom-based archiving and reporting systems. this should be based on projections of annual volumes of echo studies and corresponding digital storage. networking connectivity is highly desirable, including obligatory back-up solutions and site allocations. a business case incorporating all the above should precede any development as identifi able funding sources and administrative approval are essential. the implementation stage requires the presence of a project leader who can organize the trialing of scanners, archiving, reporting and research systems, ensure compatibility with existing hospital and cardiology networks, and who can assist in individualizing archiving and reporting software refl ecting institutional and icu specifi cs. coordination with the it department is very important. clear contractual vendor obligations for service, maintenance and future upgrades of hardware and software need to be specifi ed. training and credentialing of staff is best achieved within a systematic framework that includes ongoing competency review, education and qa programs. partnership with cardiology may benefi t both groups. major pitfalls are associated with poor initial training, lack of expertise and leadership, and bad vendor contracts. conclusion establishment of a cce laboratory requires careful planning, and allocation of adequate human and fi nancial resources. many potential problems can be identifi ed and prevented in advance. strong expert leadership plays an important role. introduction contrast-enhanced ultrasonography (ceus) is a dynamic digital ultrasound-based imaging technique, which allows quantifi cation of the microvascularisation up to the capillary vessels. as a novel method for assessment of tissue perfusion it is ideally designed for use in the icu. ceus is cost-eff ective and safe and can be repeatedly performed at the bedside without radiation and nephrotoxicity. critical care , volume suppl http://ccforum.com/supplements/ /s methods the frequency of ceus use in the multidisciplinary surgical icu was retrospectively evaluated for the period from september to september . furthermore, contributions of this novel method to the management of critically ill icu patients as well as its accuracy were assessed. results in total, ceus studies were performed in critically ill icu patients. the most frequent indications included: assessment of the liver perfusion, assessment of the pancreas and kidney perfusion after pancreas and kidney transplantation, assessment of the renal perfusion in acute kidney injury (aki), assessment of active bleeding and assessment of the bowel perfusion. in all studies, the correct diagnosis was achieved and the transport of critically ill patients to the radiology department for further diagnostic procedures as well as application of iodinated contrast agents was avoided. in cases signifi cant new fi ndings were detected. twelve of them were missed by conventional standard doppler ultrasound prior to ceus. in assessment of seven cases with aki, impaired or delayed perfusion and microcirculation of the kidney was observed in six patients. in three patients urgent surgical intervention was performed because of ceus results. in three cases active bleeding was excluded at the bedside due to absence of contrast agent extravasation into hematoma (thigh and perihepatic) or into abdominal cavity, without need for complementary ct imaging or angiography. in one case the regular perfusion of intestinal anastomosis was confi rmed with no need for surgical exploration. none of patients undergoing ceus manifested any adverse reactions or developed any complications associated with the imaging technique. conclusion contrast-enhanced ultrasonography clearly improves visualization of the perfusion in various tissues. it is very likely to be superior to standard doppler ultrasound, and is safe and well tolerated in critically ill patients. promising indications for the use of ceus in the icu may be the assessment of kidney microcirculation and assessment of liver perfusion in liver transplant and liver trauma patients. introduction even though invasive hemodynamic devices are usually used for assessment of septic shock victims, they cannot evaluate the heart function. lv dysfunction as well as right heart syndrome are not uncommon in sepsis and critical patients. intensive care ultrasound discloses these data and leads to appropriate treatment. methods the study was a prospective cross-sectional study. the measurement was performed within hours of icu admission. we excluded patients with history of copd and pulmonary hypertension from any diseases. only good-quality images acquired from subjects were included for analysis. the primary objective was to disclose how the hemodynamic changed in septic patients by icu-us. introduction thermodilution (td) is considered a gold standard for measurement of cardiac index (ci) in critically ill patients. the aim of this study is to compare intermittent bolus td ci with intermittent automatic calibration ci (autoci) and two continuous cis obtained by pulse contour analysis with picco (picci) and pulsiofl ex (pucci). methods interim results of an ongoing prospective multicentre study in patients. age . ± . , saps ii score . ± . and sofa score ± . . all patients underwent picco monitoring via a femoral line whilst a radial line was kept in place during four -hour time periods (in the fi rst two periods, the pulsiofl ex was connected to a radial line; in the last two it was connected to a femoral line). in the fi rst and third periods, the pulsiofl ex was calibrated with tdci, for the second and fourth periods pulsiofl ex was calibrated with autoci. simultaneous picci and pucci measurements were obtained every hours while simultaneous tdci and autoci were obtained every hours. we also looked at the eff ects of interventions. in total, cci and tdci values were obtained: paired picci and pucci; paired autoci-tdci measurements. tdci values ranged from . to . l/minute/m (mean . ± . ), autoci from . to . ( . ± . ), picci from . to . ( . ± . ) and pucci from . to . ( . ± ). pearson's correlation coeffi cient comparing mean pucci and picci values per patient had an r of . . comparison between autoci and tdci had an r of . . changes in autoci correlated well with changes in tdci (r = . , concordance coeffi cient = . ), as did changes in pucci versus changes in picci (r = . , cc = . %). changes in picci and pucci induced by an intervention correlated well with each other (r = . , cc = %). the percentage error (pe) obtained by bland and altman analysis and r for the diff erent comparisons are presented in table . the preliminary results indicate that in unstable critically ill patients, ci can be reliably monitored with pulsiofl ex technology via a femoral line. pulsiofl ex was also able to keep track of changes in ci. interim results of an ongoing study on the use of non-invasive hemodynamic monitoring with nexfi n in critically ill patients introduction perioperative goal-directed therapy (pgdt) can substantially improve the outcome of high-risk surgical patients [ ] . but the approach needs an initial investment and increases the staff workload. economic factors might participate in the weak adherence to the pgdt concept. some model studies support pgdt cost-eff ectiveness, but real economic data based on a recent clinical trial are lacking. we performed an economic analysis of hemodynamic optimization using the stroke volume variation trial [ ] in order to elucidate this issue. methods the hospital care invoices of all patients included in the trial were retrospectively extracted. due to the nature of the data we have adopted the healthcare payer's perspective. we performed a comparison of induced costs between the vigileo (n = ) and control (n = ) groups and constructed a cost tree using the study group and complications occurrence as distributive parameters. the incremental cost-eff ectiveness ratio per complication avoided was calculated and, fi nally, diff erent reimbursing categories were assessed as potential cost drivers. results a decreased rate ( vs. patients) and number of complications ( vs. ) were observed in the original trials vigileo group. the mean cost of intervened patient was lower (€ , ± , vs. € , ± , ; p = . ). according to the cost-tree analysis, patients with complications (n = ; %) consumed signifi cantly more resources (€ , ; %). a gain of € per avoided complications confi rms that the lower complications rate was the most important cost driver. both the clinical care for patients costs (€ vs. ; p = . ) and ward stay costs (€ vs. ; p = . ) were decreased by the intervention. on the contrary, the intervention increased anaesthesia costs (€ vs. ; p = . ). conclusion intraoperative fl uid optimization with the use of stroke volume variation and the vigileo/flotrac system showed not only a substantial improvement of morbidity, but was also associated with an economic benefi t. this observed benefi t highly exceed the increased monitoring costs in our trial. introduction hemodynamic monitoring is important in high-risk surgical patients in order to detect and correct circulatory instability, thereby improving outcome [ ] . the extravascular lung water index (evlwi) refl ects pulmonary edema [ ] . the new ev /volumeview (edwards lifesciences) can accurately measure evlwi corrected for the actual volume of lung parenchyma (evlwic). the aim of our study is to prove a stronger correlation between evlwic and pao /fio compared with evlwi in patients undergoing pulmonary resection. methods a prospective observational study. seven patients with lung cancer undergoing pulmonary resection were monitored using the ev plathform. evlwi was assessed by thermodilution at the following time points: after intubation (t ); during single-lung ventilation (t ); after lung resection (t ); after icu admission (t ); hours (t ) and hours after icu admission (t ). evlwic values were also collected at t and t . pao /fio was measured at the same time points. results no signifi cant correlation was found between evlwi and pao / fio (r = - . , p > . ), while a signifi cant correlation was seen between evlwic and pao /fio (r = - . , p = . ; figure ). conclusion despite the small sample size, this study shows that in patients undergoing pulmonary resection the evlwic is more strongly correlated to pao /fio than evlwi. therefore, the ev may be a valuable tool for more reliable hemodynamic monitoring in this subgroup of patients. references or extracardiac arteriopathy) were allocated to gdt or conventional hemodynamic therapy. we excluded patients with endocarditis, previous use of dobutamine, need for iabp, high dose of vasopressors and emergency surgery. the gdt protocol involved hemodynamic resuscitation aimed at a target of a cardiac index > l/minute/m through a three-step approach: fl uid therapy of ml lactated ringer's solution, dobutamine infusion up to a dose of μg/kg/minute, and red blood cell transfusion to reach a hematocrit level above %. results twenty patients from the gdt group were compared with control patients. both groups were comparable concerning baseline characteristics and severity scores, except for a higher prevalence of hypertension and heart failure in the gdt group. intraoperative data showed no diff erence regarding length of extracorporeal circulation, fl uid balance, transfusion or inotropic requirement. patients from the gdt group were given more fl uids within the fi rst hours as compared with the conventional group ( , ml vs. ml, p < . ). gdt patients showed a median icu stay of days ( % ci: to ) compared with days in control patients ( % ci: to ). moreover, hospital stay was less prolonged in gdt patients ( days vs. days, p = . methods sixteen patients were divided into two groups: one group was treated with a restrictive approach (≤ ml/kg/hour), and the other with a liberal approach (> ml/kg/hour). patients were randomly allocated using sealed envelopes. during the thoracic part of the surgical procedure, all patients received one-lung ventilation (olv). in the group treated with a restrictive volume approach, patients received fl uids at the rate of . ± . ml/kg/hour. pao /fio was ± after intubation and ± before extubation. in the group treated with a liberal volume approach, fl uids were replaced at . ± . ml/kg/hour. pao /fio was ± after intubation and ± before extubation. surgery combined with olv was found to signifi cantly aff ect the pao /fio value (anova, f , = . a, p = . , partial η = . ). the average pao /fio level was signifi cantly higher in the restrictive-replacement group than in the liberal-replacement group (anova, f , = . , p = . , partial η = . ). there was no interaction between the groups (anova, f , = . a, p = . , partial η = . ). mean length of stay in the icu was similar between the restrictive-replacement group ( . ± . days) and the liberalreplacement group ( . ± . days) (anova, f , = . a, p = . , partial η = . ). conclusion results from this small sample indicate that esophageal carcinoma surgery by itself had a detrimental eff ect on the pao /fio value, which restriction of perioperative volume did not signifi cantly aff ect. volume restriction also did not aff ect length of stay in the icu. we hypothesized that goal-directed therapy (gdt) is not associated with an increased risk of cardiac complications in high-risk, noncardiac surgical patients. patients with limited cardiopulmonary reserve are at risk of mortality and morbidity after major surgery [ ] . augmentation of the oxygen delivery index (do i) with a combination of intravenous fl uids and inotropes (gdt) has been shown to reduce the postoperative mortality and morbidity in high-risk patients [ ] . however, concerns regarding cardiac complications associated with fl uid challenges and inotropes used to augment cardiac output may deter clinicians from instituting early gdt in the very patients who are more likely to benefi t. methods systematic search of medline, embase and central databases for randomized controlled trials of gdt in high-risk surgical patients. studies including cardiac surgery, trauma, and pediatric surgery were excluded to minimize heterogeneity. we reviewed the rates of all cardiac complications, arrhythmias, acute myocardial ischemia, and acute pulmonary edema. meta-analyses were performed and forest plots drawn using revman software. data are presented as odd ratios (ors) ( % cis), and p values. and compared with those calculated with the echocardiographic standard formulation (stroke volume = cross-sectional area×velocity time integral; coecho = sv×heart rate). in every patient co was measured twice: at baseline (t ) and after volume loading ( ml lactate ringer solution) (t ). agreements between covig, comc, and coecho were evaluated by means of simple linear regression (r ) and bland-altman analysis. results twenty patients were enrolled in the study. values of r , bias and limit of agreement at t and t are summarized in table . co values ranged from . and . l/minute (echo), from . to . (vigileo) and from to . (mostcare); the pearson's and bland-altman methods showed poor agreement between coecho and covig, demonstrating a tendency to overestimation (see figure ). the percentage of error (pe) was . % at t and . % at t . on the contrary, mostcare measures showed good agreement with echocardiography (see table ) with a pe of . % at t and of % at t . conclusion vigileo did not prove to be a substitute to the reference system; pre-loaded data, necessary for vascular impedance estimation, may be one of the main limitations that made vigileo measurements less accurate than the mostcare ones. on the contrary, mostcare, an uncalibrated totally independent system, was shown to properly estimate the vascular impedance in these hemodynamically stable patients. further comparisons in unstable conditions are needed to confi rm our observations. references previous studies have found an association between severity of acute infl ammatory states and increased arterial stiff ness but it is not known whether non-invasive pulse waveform analysis could predict development of multiple organ failure in septic patients. the purpose of this study was to evaluate the photoplethysmographic brachial artery pulse wave transit time and augmentation index and their changes in response to induced forearm ischemia in septic icu patients and correlate these indices to the development of subsequent end organ damage. methods a prospective observational study in patients with sepsis within hours of admission. severity of sepsis was assessed with apache ii score (median . ) and sofa score (median . ). threeminute signal recording was done concurrently from the brachial artery at the elbow and the radial artery at the wrist with an originally designed photoplethysmograph at rest and after minutes of induced forearm ischemia. recordings were analyzed to obtain the pulse wave transit time and augmentation index at rest and seconds after induced ischemia. the sofa score was recalculated at hours post recording. results we studied consecutive general icu patients. there was a negative linear relationship between the pulse wave transit time (median . ms) at rest and increase in sofa score in hours (p = . , r = . ). the postischemic pulse wave transit time increased in all patients (median . ms) but no association was found between the proportion of increase and subsequent change in sofa. correlation between rest (median . ) and postischemic (median . ) augmentation index and -hour sofa scores was not statistically signifi cant (r = . , p = . ). conclusion this study indicates that in early sepsis pulse waveform characteristics could predict the risk of developing end organ failure. the pulse wave transit time is more robust than the augmentation index and could be easier to use in patients with poor perfusion. vascular reactivity indices do not seem to have predictive value in this context. reference in clinical practice, blood volumes (bv) are typically measured by thermodilution. recently, contrast-enhanced ultrasound (ceus) has been proposed as an alternative minimally invasive approach for bv assessment [ ] . this method measures bv using a single peripheral injection of a small bolus of ultrasound contrast agent (uca) detected by an ultrasound scanner. by measuring the acoustic backscatter, two indicator dilution curves (idcs) can be derived from two diff erent sites in the circulatory system. idc analysis permits deriving the mean transit time (mtt) the bolus takes to travel between the injection site and two measurement sites. assessment of the bv between these sites is obtained by multiplying the diff erence in mtt (Δmtt) by the blood fl ow. in this study, we compare diff erent volumes in an in vitro set-up by ceus with true set-up volumes and thermodilution acquired volumes. methods the in vitro set-up consisted of a centrifugal pump, a network of tubes with variable volumes, an electromagnetic fl owmeter to measure and adjust the generated fl ow, heating devices to maintain constant temperature ( °c), two thermistors for thermodilution measurement, an ultrasound transducer and a pressure stabilizer. a small bolus of uca diluted in cold saline ( mg sonovue® in ml saline at °c) was injected into the system. the cold uca passage through a fi rst and a second region of interest (roi) was measured simultaneously with the ultrasound transducer and the thermistors. the measurements were performed at diff erent fl ows and volumes. bvs were estimated using the two diff erent approaches, namely ceus and thermodilution. the idcs were processed and fi tted separately with a dedicated model to estimate the Δmtt of the cold uca bolus between the two rois and the two thermistors. all the measurements were repeated three times. results a linear relation between bvs estimated by the two techniques was observed with a correlation coeffi cient of . . the bias of ceus with respect to the true volumes was - . ml; the bias of thermodilution was . ml. the most prominent diff erences between the two techniques were observed in case of high volume and low fl ow, possibly due to diff erent transport kinetics between ucas and heat. the use of cardiac output monitoring has been shown to be benefi cial in the setting of perioperative medicine and critical illness [ , ] . more recently, its application in the setting of major trauma has been described [ ] . here, we describe our preliminary experience of embedding bioreactance fl ow monitoring within the major trauma primary survey of severely injured patients and the subsequent eff ect on patient management. methods institutional ethical approval was obtained. intubated major trauma patients were sequentially enrolled. exclusions included major thoracic burns and children. bioreactance fl ow monitoring (nicom; cheetah) was applied at the same time as ecg leads and the calibration step performed during handover from the prehospital team. time to availability of oxygen delivery data was recorded and trauma team members surveyed regarding for perceived benefi ts and concerns from this monitoring. the infl uence of fl ow monitoring on fl uid resuscitation, time to ct and defi nitive disposal (to or/icu) was measured and compared with a control population matched for injury severity score, age and sex. results cardiac index was available at mean . minutes (median minutes; sd . ), fl uid responsiveness at mean . minutes (median ; sd . ) and oxygen delivery calculation at mean . minutes (median ; sd . ). passive leg raise was not performed in % of patients due to concerns about pelvic or brain injury. volume of fl uid infused (mean vs. ml; p = . ), time to ct (mean . vs. . minutes; p = . ), and time to defi nitive disposal (mean . vs. . minute; p = . ) were all reduced in the fl ow monitored group, although not signifi cantly diff erent when compared with a matched control group (mann-whitney u rank sum). eighty-four percent of trauma team members surveyed felt the fl ow monitoring data to be useful, and only % felt it may impair clinical management. conclusion cardiac index, fl uid responsiveness and oxygen delivery data can be obtained inform a primary survey. rather than introducing delays, the use of fl ow monitoring was associated with a trend towards decreased time to imaging; less fl uid use pre-damage control point and reduced time to defi nitive disposal. further research is required to confi rm benefi ts and mechanism. references introduction pulse pressure variation (ppv) is a dynamic indicator of fl uid responsiveness, which is known to have a low sensibility and specifi city in patients ventilated in pressure support (ps) [ ] . we aim to investigate patient-ventilator asynchrony as a potential source of hemodynamic interference in ps. methods we performed a prospective study including ps ventilated patients who met inclusion criteria for fl uid depletion [ ] . patients who showed an asynchrony index (ai) exceeding % were included in the asynchrony group (ag). the remaining patients were included in the synchrony group (sg) [ ] . beat-to-beat hemodynamic variables were recorded through pram (mostcare; vytech health srl, padova, italy). ppv cutoff of % was used to identify fl uid responders/nonresponders. a fl uid challenge of ml normal saline was given in minutes. an increase of % of cardiac index after minutes indicated fl uid responsiveness. results so far, eights patients showed an ai > % while did not. overall sensitivity was . % versus % in sg; overall specifi city was . % versus . % in ag. overall cohen's k was . % versus . % in ag (see figure ). however, because none of the responders in the ag group was detected by ppv, statistical analysis was not feasible within this subgroup. the mini-fl uid challenge is a widely used strategy to manage fl uid loading in the icu and or. although it might be a rational strategy, data on the mini-fl uid challenge and its reliability are very limited. we investigated the value of changes in pulse contour cardiac output as a result of a mini-fl uid challenge of and ml to predict fl uid loading responsiveness. methods we measured the eff ects after the administration of , and ml bolus colloid infusions on co (modelfl ow (com) and lidco (coli)), cvp and map in patients on mechanical ventilation after elective cardiothoracic surgery. from the data we analysed the smallest volume that was predictive for the eff ects of ml on cardiac output. results coli and com increased after , and ml fl uid loading. best results are observed for changes in com after ml fl uid loading (area under the roc . , % ci between . and . ). a change in modelfl ow co of at least . % has a sensitivity of % and a specifi city of % after ml fl uid loading. sensitivity is % and specifi city % for a similar cutoff in co measured with the lidco device after ml fl uid loading. in our patient population, map and coli did not predict responsiveness with more accuracy than mathematical chance. see figure . conclusion changes in pulse contour co can be used in a mini-fl uid challenge to assess fl uid responsiveness in our postcardiac surgery patients. introduction fluid responsiveness is defi ned based on an arbitrary increase of cardiac output (co) or stroke volume (sv) of to %. we hypothesise that the variation of heart effi ciency (eh) and the slope (s) defi ned by the relative increase of co over the relative increase of mean fi lling pressure (pmsa) can be used as alternative defi nitions of fl uid responsiveness. introduction fluid overload is associated with poor outcome in the critically ill. thus, an accurate predictor of a positive haemodynamic response (increase in stroke volume) to fl uid challenge is vital. methods we studied the predictive value (positive response defi ned as change in stroke volume > % after ml/kg fl uid bolus) of a range of haemodynamic variables: static (cvp, active circulating volume, central blood volume, total end diastolic volume), dynamic (systolic pressure variation, stroke volume variation) and contactility (dp/dt), in a group of ventilated children (median weight kg). variables were measured using transpulmonary ultrasound dilution and pram (an arterial pulse contour method). we performed paired measurements (pre-fl uid and postfl uid challenge), with a sv response rate of %. overall predictive values were poor, but slightly better for static versus dynamic variables (table ) . when sv response was analysed as a continuous variable, the two predictive multivariable variables were change in tedvi and baseline dp/dt (r = . , both p < . ). conclusion the predictive ability for typical static and dynamic haemodynamic variables, when taken in isolation, is poor. however, improved prediction is seen when baseline contractility is taken into account. pressure (map)-guided fl uid therapy on microcirculatory perfusion in patients undergoing abdominal surgery. methods patients undergoing elective abdominal surgery were randomized into a ppv/ci-guided group (n = ) or a map-guided (n = ) group. ppv, ci and map were measured using the non-invasive fi nger arterial blood pressure measurement device ccnexfi n (edwards lifesciences bmeye, amsterdam, the netherlands). tidal volumes were ≥ ml/kg with peep ≥ mmhg. in both groups, map of mmhg was maintained. in the ppv/ci group, an intraoperative algorithm was used keeping the ppv under % and ci above . l/minute/ m using fl uid therapy and dobutamine and noradrenaline infusion, respectively. sublingual microvascular perfusion was measured after anesthesia induction, and every subsequent hour using sidestream dark-fi eld imaging (microscan; microvision medical, amsterdam, the netherlands). the perfused small vessel density (pvd) values were offl ine quantifi ed. the fi rst hour during surgery, the ppv/ci-guided group tended to receive more fl uids than the map-guided group ( , ± ml vs. ± ml; p = . ). at this time point, the pvd was slightly lower in the ppv/ci-guided group ( . ± . mm/mm ) when compared with the map-guided group ( . ± . mm/mm ; p = . ). in both groups the pvd remained stable during the fi rst hours of surgery. however, hours after the start of surgery, the pvd in the ppv/ci group restored and tended to be higher than in the map-guided group ( . ± . vs. . ± . mm/mm ; p = . ). after hour of surgery, the administered fl uid volume correlated inversely with pvd (r = - . , p = . ). conclusion goal-directed fl uid management resulted in a higher administered fl uid volume in the beginning of surgery, and this was associated with a slightly reduced microcirculatory perfusion when compared with map-guided fl uid management. microcirculatory perfusion tended to improve as surgery progressed in the goal-directed fl uid therapy group. our fi ndings suggest that goal-directed and mapguided fl uid management are associated with distinct patterns in fl uid resuscitation, which may be of consequence for microvascular perfusion. introduction previous studies demonstrate that loss of glycocalyx integrity is associated with impaired microvascular function. we investigated whether glycocalyx dimensions are reduced in patients undergoing cardiac surgery with or without cardiopulmonary bypass (cpb), and are paralleled by loss of microcirculatory perfusion using in vivo microcirculation measurements. methods patients undergoing on-pump surgery with nonpulsatile (n = ) or pulsatile (n = ) cpb or off -pump surgery (n = ) underwent sublingual sidestream dark-fi eld imaging at baseline, during coronary grafting and upon icu admission to assess perfused microvascular vessel density. glycocalyx integrity was evaluated using the glycocheck measurement software, and expressed as the perfused boundary region (pbr). an increase in pbr represents deeper penetration of erythrocytes into the glycocalyx, and is indicative for compromised glycocalyx thickness. introduction cold exposure can be adapted for exercise or therapeutic purposes, but its impact on microcirculation in healthy humans has not been well defi ned. we hypothesize that whole body cold stress may impair microcirculation. methods seven volunteers were recruited for the water immersion procedure. during the cooling protocol the volunteers every minutes of immersion were asked to step out from the bath and rest for minutes in a room environment and then return to the water bath for the next minutes of immersion. this head-out immersion procedure in bath water at °c continued until the rectal temperature was dropped to . °c or the time of minutes was terminated. maximum cold water immersion time was minutes. before, at the end of whole body cooling and hour after cooling was ended, systemic hemodynamics and direct in vivo observation of the sublingual microcirculation were obtained with sidestream dark-fi eld imaging. assessment of microcirculatory parameters of convective oxygen transport (microvascular fl ow index (mfi), proportion of perfused vessels (ppv)), and diff usion distance (perfused vessel density (pvd) and total vessel density (tvd)) was done using a semiquantitative method. results during cooling and hour after cooling was ended, a signifi cant increase in cardiac output (p = . and p = . ) was observed, but there were no changes in heart rate or mean arterial pressure in comparison with baseline variables. there were no signifi cant changes in ppv, mfi, pvd and tvd of small vessels in comparison with baseline variables during all observational time. conclusion defined cold exposure had no effect on the microcirculation. introduction vasodilation and increased skin blood fl ow (also sweating) are infl uential in heat dissipation during heat exposure and exercise. it is unclear how heat stress infl uences microcirculation. side dark-fi eld imaging visualizes the blood fl ow at the capillary level and helps to assess perfusion heterogeneity. clinical and experimental data show that the sublingual region is clinically relevant for detecting microcirculatory alterations and more represents central microcirculation than cutaneous perfusion. we hypothesize that whole body heat stress may increase capillary density. methods eight healthy men with no history of cold and/or heat injury were recruited to this study. passive body heating was performed by continuous immersion up to the waist in the water bath at °c and continued until rectal temperature reached . °c. before, at the end of whole body heating and hour after heating was ended, systemic hemodynamics and direct in vivo observation of the sublingual microcirculation were obtained with sidestream dark-fi eld imaging. assessment of microcirculatory parameters of convective oxygen transport (microvascular fl ow index (mfi), proportion of perfused vessels (ppv)), and diff usion distance (perfused vessel density (pvd) and total vessel density (tvd)) was done using a semiquantitative method. vessels were separated into large (mostly venules) and small (mostly capillaries) using a diameter cutoff value of μm. results whole body heating resulted in signifi cantly increased heart rate (p = . ) and cardiac output (p = . ) in comparison with baseline variables. one hour after heating was ended, the heart rate introduction serial measurements of lactate over time may be a better prognosticator than a single lactate concentration [ ] . early lactateguided therapy also reduces icu length of stay and icu and hospital mortality [ ] . this study aims to assess the prognostic value of the lactate clearance (lc) in the fi rst hours in surgical patients. methods in a prospective cohort during year, we followed consecutively enrolled patients admitted immediately postoperative to the surgical icu of hospital santa luzia, brasília, brazil. patients were assigned to two groups: lc > % and lc ≤ %. the primary outcome measure was mortality at and days. the secondary outcome included hospital and icu length of stay (los). results a total of patients were followed. in total, . % were male and % underwent elective surgery. the mean age was ± , apache ii score ± , saps ± . the mortality at days was . % (n = ) and the mortality at days was . % (n = ), respectively. hospital mortality was . % (n = ). sixty-one percent (n = ) of the patients had lc > % versus % (n = ) with lc ≤ %. those who had lc ≤ % were older ( ± vs. ± , p = . ) and had greater apache ii score ( ± vs. ± , p = . ) and saps ( ± vs. ± , p = . ). there was no diff erence in icu los ( ± vs. ± days, p = . ) and hospital los ( ± vs. ± days, p = . ). initial lactate levels were lower in the group with lc ≤ % ( . ± . vs. . ± . , p = . ); however, mean lactate was higher in hours ( . ± . vs. . ± . , p = . ). all of the patients who died in the fi rst days had lc ≤ % ( . %, n = , p = . ); this group also had a higher mortality at days ( . %, n = vs. . %, n = ; p = . ). the relative risk for mortality lc ≤ % in and days was . ( % ci: . to . ) and . ( % ci: . to . ), respectively. signifi cant diff erence was observed in the kaplan-meier survival curves for and days (p = . and . , respectively). the sensibility of lc ≤ % was % ( % ci: to %) for -day mortality and % ( % ci: to %) for -day mortality. the specifi city was % ( % ci: to %) for -day mortality and % ( % ci: to %) for -day mortality. conclusion despite initial lactate levels, lactate clearance ≤ % proved to be a good predictor of mortality in and days in surgical patients admitted in the postoperative period to the icu. references introduction the use of peripheral perfusion objective parameters to anticipate successful resuscitation in septic shock has been recently investigated [ ] . the mottling score, a perfusion parameter used for decades, has been proposed to correlate with septic shock survival [ ] , and was tested in this study as a clinical tool in predicting mortality. methods a prospective observational study was conducted, with patients consecutively admitted to a tertiary hospital icu in brasília, brazil. from july to may , all patients diagnosed with septic shock were enrolled. demographic data, diagnoses, shock origin and severity scores were recorded. after initial resuscitation, the score was registered in the fi rst days by the same observer, considering the score on the lower limb without an arterial catheter, or the worst between the lower limbs, and the worst in the days. exclusion criteria were terminal illness with no intervention decision and incomplete methods pigs ( to kg) were randomized into one of the groups: sham (n = ), hs (n = ), lr ( × volume bled; n = ) or terli ( mg bolus; n = ). hs induced to target map of mmhg was maintained for minutes. brain tissue oxygen pressure (pbto ), intracranial pressure (icp), cerebral perfusion pressure (cpp), haemodynamics and blood gas analyses were assessed prior to hs (baseline) up to minutes after treatment. tissue markers of brain oedema (aquaporin- (aqp ) and na-k-cl cotransporter- (nkcc )), apoptosis (pre-apoptotic protein (bax)) and oxidative stress (thiobarbituric acid reactive substances (tbars)) were also measured. results sham animals had no signifi cant changes in the variables assessed. hs resulted in a signifi cant decrease in cpp (mean varied from to mmhg), pbto (from . to . mmhg), icp (from to mmhg) and haemodynamics (map from to mmhg; ci from . to . l/minute/m ), and a signifi cant increase in blood lactate (from . to . mmol/l) and cerebral aqp (mean ± se; ± % of sham), nkcc ( ± % of sham), bax ( ± % of sham) and tbars. fluid resuscitation was followed by an increase in icp (from to mmhg) and a decrease in cpp (from to mmhg), with an increased expression of cerebral aqp ( ± % of sham), nkcc ( ± % of sham) and bax ( ± % of sham introduction shock induces mitochondrial damage, which can lead to tissue injury and infl ammation. resuscitative adjuncts to limit mitochondrial injury may be eff ective to reduce tissue injury and protect against the sequelae of hemorrhagic shock (hs). others and we have demonstrated the protective eff ects of inhaled carbon monoxide (co) or nebulized sodium nitrite (nano ) in models of hs. our aim was to test the hypothesis that co and nano protect against hemorrhagic shock-induced tissue injury/infl ammation by limiting mitochondrial damage and preventing bioenergetic failure. methods twenty anesthetized female yorkshire pigs were subjected to severe hemorrhage until unable to compensate or minutes, and were then resuscitated with volume/pressors. muscle and platelet samples were obtained at baseline (bl) and hours after resuscitation (endobs). animals were randomized to: standard of care (hsr, n = ); hsr+co (co; ppm× minutes, n = ); or hsr+nano (nano ; mg in pbs× minutes, n = ), and sham (n = ). co or nano were initiated ~ minutes before resuscitation. primary endpoints were changes in muscle and platelet mitochondrial respiration between bl and endobs, quantifi ed by muscle respiratory control ratio (rcr, traditional respirometry), and by the change in proton-leak respiration (plr) and mitochondrial reserve capacity in platelets. secondary endpoint was mortality at endobs. results skeletal muscle rcr decreased in the hsr group (p = . ) but not in sham. decrease in rcr was primarily due to decreased adpdependent respiration, without change in state respiration. hsr also resulted in platelet mitochondrial dysfunction as demonstrated by increased plr and decreased reserve capacity. this correlated with increased platelet activation (%cd p+ by fl ow cytometry) in hsr. co or nano treatment prevented these deleterious changes in both muscle and platelet mitochondrial respiration, as well as limited hsr-induced platelet activation. co treatment also improved reserve capacity compared with baseline. mortality was higher in hsr than in co or nano ( vs. and %, respectively). conclusion in severe hs, mitochondrial injury in platelets and muscle was limited by co or nano . although not powered for a secondary endpoint, mortality was double in hsr versus adjunctive therapies. this suggests that co and nano may protect mitochondrial function by maintaining atp-coupled respiration and reserve capacity, and that this may confer a survival advantage. however, further investigations are required. introduction norepinephrine has been widely used in septic shock. however, its eff ect remains controversial. we conduct a systematic review and meta-analysis to compare the eff ect between norepinephrine and other vasopressors. methods the pubmed, embase, and cochrane library databases from database inception until october were searched. we selected randomized controlled trials in adults with septic shock and compared norepinephrine with other vasopressors. the quality of each study included was assessed with jadad score. after assessing for heterogeneity of treatment eff ect across trials using the i statistic, we used a fi xed eff ect model (p ≥ . ) or random-eff ects model (p < . ) and expressed results as the risk ratio (rr) for dichotomous outcomes or the standardized mean diff erence (smd) for continuous data with % ci. results eighteen trials (n = , ) met inclusion criteria, which compared norepinephrine with fi ve diff erent vasopressors (dopamine, vasopressin, epinephrine, terlipressin and phenylephrine). the mean jadad score was . . overall, there was no diff erence in mortality in the comparisons between norepinephrine and vasopressin, epinephrine, terlipressin and phenylephrine (p > . , respectively). however, norepinephrine had a trend in decreasing mortality compared with dopamine (rr, . ; % ci, . to . ; p = . ). there were a decreased heart rate (hr) (smd, - . ; % ci, - . to - . ; p = . ), cardiac index (smd, - . ; % ci, - . to - . ; p = . ) and an increased systemic vascular resistance index (svri) (smd, . ; % ci, . to . ; p < . ) with the treatment of norepinephrine compared with dopamine. conclusion there is not suffi cient evidence to prove that norepinephrine is superior to vasopressin, epinephrine, terlipressin and phenylephrine in terms of mortality. however, norepinephrine is associated with a decreased hr, cardiac index and an increased svri, and appears to have a greater eff ect on decreasing mortality compared with dopamine. introduction vasoplegic syndrome is a common complication after cardiac surgery, with negative impact on patient outcomes and hospital costs. pathogenesis of vasodilatory phenomenon after cardiac surgery remains a matter of controversy. loss of vascular tone can be partly explained by the depletion of neurohypophyseal arginine vasopressin stores. vasopressin is commonly used as an adjunct to catecholamines to support blood pressure in refractory septic shock, but its eff ect on vasoplegic shock is unknown. we hypothesized that the use of vasopressin would be more eff ective on treatment of shock after cardiac surgery than norepinephrine, decreasing the composite endpoint of mortality and severe morbidity. methods in this prospective and randomized, double-blind trial, we assigned patients who had vasoplegic shock to receive either vasopressin ( . to . u/minute) or norepinephrine ( . to μg/ kg/minute) in addition to open-label vasopressors. all vasopressor infusions were titrated and tapered according to protocols to maintain a target blood pressure. the primary endpoint was major morbidity according to sts ( -day mortality, mechanical ventilation > hours, mediastinitis, surgical re-exploration, stroke, acute renal failure). secondary outcomes were time on mechanical ventilation, icu and hospital stay, new infection, the time to attainment of hemodynamic stability, occurrence of adverse events and safety. results a total of patients underwent randomization, were infused with the study drug ( patients received vasopressin, and norepinephrine), and were included in the analysis. patients who received vasopressin had a lower rate of morbidity ( . % vs. %, p = . ) as compared with the norepinephrine group. the -day mortality rate was . % in the norepinephrine group and . % in the vasopressin group (p = . ). there were no signifi cant diff erences in the overall rates of serious adverse events ( . % and . %, respectively; p = . ). results patients in the two groups were statistically comparable with respect to sex (p = . ) and age (p = . ). the causes of the syndrome of tako-tsubo were: subarachnoid hemorrhage (six patients) after coronary artery bypass graft (four patients), and polytrauma (two patients). all patients had low cardiac output. in the levosimendan group the ejection fraction at entrance was ± %, after hours ± %, and ± % after hours. in the control group the ejection fraction at entrance was ± %, after hours ± % and after hours ± %. comparing the two groups we reached statistical signifi cance, p = . . conclusion comparing the two groups, we noticed that both started from a low cardiac output. however, in the group who used the drug therapy based on levosimendan we saw a return of systolic function of the left ventricle to near-normal levels within hours, while in the control group there remains a dysfunction in systolic function. we have shown the drug therapy based on levosimendan contributes to improving the systolic function of the left ventricle compared with treatment with dobutamine despite the initial cardiac stunning. reference introduction in the critically ill, the incidence of raised cardiac troponin t (ctnt) levels is high. although the mechanisms of myocardial injury are not well understood, raised ctnt levels are associated with increased mortality. the aim of our study was to determine the incidence, prevalence and outcome of silent myocardial injury as determined by raised ctnt levels and concomitant ecg changes in critically ill patients admitted for noncardiac reasons. methods ecgs were taken and ctnt was measured daily during the fi rst week and on alternate days during the second week until discharge from the icu or death. after completion of the study, all ctnt levels and ecgs were analysed independently and patients were classifi ed into four groups: defi nite mi (ctnt ≥ ng/l and defi nite ecg changes of mi), possible mi (ctnt ≥ ng/l and ischaemic changes on ecg), troponin rise alone (ctnt ≥ ng/l with no ischaemic ecg changes), or normal. all medical notes were reviewed independently by two icu clinicians. results a total of patients were included in the analysis ( % female; mean age . (sd . ); mean apache ii score . ). in total, patients ( %) had at least one ctnt level ≥ ng/l during their stay in the icu. twenty patients ( %) fulfi lled criteria for a defi nite mi, of whom % were septic and % were on noradrenaline at the time (icu and hospital mortality: % and %, respectively). thirty-nine patients ( %) had a possible mi, of whom % were septic and on noradrenaline (icu and hospital mortality: % and %, respectively). sixty-two patients ( %) had a raised troponin without ecg, of whom % were septic and . % were on noradrenaline (icu and hospital mortality: % and %, respectively). twenty-three patients had normal ctnt results and serial ecgs, of whom % had sepsis. icu and hospital mortality was %. only % of defi nite mis and % of possible mis were recognised by the clinical teams at the time. conclusion eighty-four per cent of critically ill patients had a raised ctnt level at some stage during their stay in the icu. more than % of patients fulfi lled criteria for a possible or defi nite mi, of whom only % were recognised clinically. icu and hospital outcome were signifi cantly worse in patients with a ctnt rise. the proportion of patients with sepsis was similar between the patients with a defi nite, possible or no mi. the grace risk score for predicting death within months of hospital discharge was validated and can be used in patients with acs. it would be perfect in the future to include the grace risk score in the medical records of this type of patients. also it would be very interesting to validate this in a multicentric study. figure ). patients in group had more prolonged length of stay in the icu and in hospital than patients in group . after recovery from septic shock we notice a huge accumulated fl uid balance. a more positive fl uid balance was associated with a more prolonged length of stay in the icu and in the hospital. ugib patient needs an intervention or not. however, the intervention which the gbs mentions includes not only endoscopy but also blood transfusion. therefore, we cannot determine whether a ugib patient needs urgent endoscopy or just blood transfusion by gbs alone. we hypothesized that high lactate clearance (clac) would decrease the likelihood of sustained ugib. methods this is a retrospective study. ugib patients, who visited the emergency department (ed) of the national center for global health and medicine from april to march and received urgent endoscopy in the ed, were enrolled. we collected for each patient the gbs, the blood lactate value on arrival in the ed, the blood lactate value after bolus administration of to ml/kg ringer's acetate (initial fl uid therapy) and the report of urgent endoscopy. we classifi ed the severity of ugib according to gbs. a score ≤ was classifi ed as moderate, and a score ≥ was classifi ed as severe. clac was defi ned as the percentage decrease in blood lactate from the time of arrival in the ed to the time when an initial fl uid therapy was fi nished. clac < % was defi ned as low, and clac ≥ % was defi ned as high. whether a patient had sustained bleeding or not was determined based on the report of urgent endoscopy. the relationship between clac and sustained bleeding was examined by fisher's exact test, and p < . was considered statistically signifi cant. results seventy-nine patients were enrolled. fifty-one patients were with moderate ugib, and patients were with severe ugib. as indicated in tables and , there was a signifi cant relationship between clac and sustained bleeding in moderate ugib (p = . ). on the other hand, there was no signifi cant relationship between clac and sustained bleeding in severe ugib (p = . ). introduction the aim of our study was to assess the muscular glucose by microdialysis and its association with mortality in septic shock patients. we conducted a preliminary prospective study. we included septic shock patients hemodynamically optimized according to international recommendations. a microdialysis catheter was inserted in the femoral quadriceps. interstitial fl uid samples were collected every hours for days. the determination of muscular glucose was performed by the cma analyzer (cma/microdialysis ab, sweden). we also performed a dosage of concomitant blood glucose. the study population was divided into two groups according to hospital mortality. statistic analysis: mann-whitney test and chi-squared test: comparisons between groups. quantitative variables were expressed as mean ± standard deviation or median (interquartile range) as appropriate. results we included patients with septic shock. the mortality rate was %. demographics were comparable between groups except for age ( ± vs. ± , dead patients vs. survivors, respectively; p = . ). pneumonia was the major cause of septic shock ( patients). we analysed blood samples and muscular glucose samples. we found a positive association between muscular glucose, blood glucose and mortality. tissue glucose was signifi cantly higher among dead patients compared with survivors at the th hour. comparing all data, muscular glucose (p = . ) and blood glucose (p = . ) were signifi cantly higher in dead patients (table ) . conclusion our data suggest that muscular glucose assessed by microdialysis and blood glucose are associated with mortality in septic shock patients. therefore, muscular glucose may refl ect the metabolic alterations and microcirculatory dysfunction induced by septic shock. methods the audit had the trust audit committee's approval. the existing protocol was used as the benchmark. patients were studied prospectively to assess compliance with the local bowel protocol, incidence of constipation and relationship to weaning from respiratory support and feeding. all hdu and all mechanically ventilated icu patients who stayed on the ward for more than days were included, except for patients after bowel surgery and patients with encephalopathy. results among the hdu and icu patients audited in the royal liverpool university hospital, % and % respectively were constipated. laxatives were prescribed when patients had not opened their bowels for days in % hdu and % icu cases. taking into consideration that the median age, apache ii score and length of stay for constipated and nonconstipated patients were similar, the relationship to feeding and respiratory support were assessed. introduction it was noted on our unit that dislodgement of nasogastric tubes occurred commonly. this can lead to an increased risk of aspiration, interruptions in nutritional support, skin breakdown and radiographic exposure [ ] . it is recommended that the position of nasogastric tubes should be confi rmed by aspiration and ph testing, with radiographic confi rmation used only when this is not possible [ ] . methods we performed a retrospective review of chest x-ray (cxr) requests for the -month period june to august using the trust radiology information system. the proportion of cxr requests for confi rmation of position and patient demographics were measured with an estimation of the fi nancial cost performed. results there were patients admitted to the critical care area in the study period. in total, out of , ( . %) cxrs performed were for confi rmation of position. repeated x-rays were required in some patients (see table ); these patients were older and tended to have a longer length of stay. a mobile cxr costs £ in our trust, if one cxr is accepted per patient with a nasogastric tube; there was an excess of images with a cost of £ , in the -month period. conclusion an excess of cxrs were performed for confi rmation of nasogastric tube in our patient population. the recommended methods for position confi rmation were reinforced amongst medical staff . the high number of repeated imaging for some patients indicates that dislodgement of tubes was also a problem. we propose that nasogastric tubes should be bridled after fi rst dislodgement or at tracheostomy insertion to minimise dislodgement in the future. methods mechanically ventilated, not enterally fed icu patients (n = ) were recruited from an interdisciplinary icu. healthy, overnight-fasted volunteers (n = ) served as reference. a primed constant i.v. infusion of h-labeled phenylalanine (phe) and tyrosine was used to quantify whole-body protein metabolism. patients remained on parenteral nutrition (pn) as clinically indicated; controls received pn starting . hours before starting enteral feeding. intrinsically c-phe-labeled casein was infused for hours by nasogastric tube at . g protein/ hour, together with maltodextrin at . g/hour. protein breakdown, synthesis, net balance, and phe splanchnic extraction were calculated before and at the end of the enteral feeding period, using equations for steady-state whole-body protein kinetics. comparisons were made by wilcoxon matched pairs and mann-whitney u tests; values are reported as mean ± sd. results protein net balance was lower in patients than in the reference group at baseline (- . ± . vs. . ± . mg/kg bw/hour, p = . ), and after enteral feeding (- . ± . vs. . ± . mg/kg bw/hour, p = . ). recovery of labelled phe from enteral feeding into the systemic circulation was higher in the reference group as compared with patients ( . + . % vs. . + . %, p = . ). enteral feeding did not aff ect protein metabolism in the reference group. in patients, protein breakdown became slightly lower during enteral feeding ( . ± . vs. . ± . mg/kg bw/hour, p = . ) and protein net balance became slightly higher (- . ± . vs. - . ± . mg/kg bw/ hour, p = . ). conclusion intrinsically isotope-labelled casein can be used to quantify dietary contribution to protein metabolism in critically ill patients. hypocaloric enteral feeding marginally improved protein balance in these patients. the low recovery of enterally administered labelled amino acid underlines the need to quantify uptake from the gastrointestinal tract when protein turnover measurements are performed in critically ill patients on enteral nutrition. methods this small-scale study of ngt placements during a -week period collated data supplied by questionnaire by healthcare workers responsible for ngt placements. results analysis of adverse incident reports identifi ed no never events of misplaced ngts within the previous years. this audit revealed that the commonest type of ngt was a radio-opaque tube with stylet (corfl o) ( % of placements), with occasional use of the electromagnetic placement system (cortrak) ( % of placements). sizes ( %) and ( %) were most common. tube placement was confi rmed by: x-ray ( %); ph of aspirates ( %); electromagnetic tube placement (one patient). the time taken from decision to place ngt to use varied (range to minutes). little distinction was seen in the time taken to use and ngt confi rmed by aspirate alone ( minutes) or by x-ray ( minutes), although the shortest interval was seen in electromagnetic ngt placement ( minutes). the cost of ngts confi rmed by aspirate alone was low (approximately £ . ), higher with x-ray confi rmation/electromagnetic placement (approximately £ . ). conclusion despite the small dataset the results demonstrate a concerning delay in the application of enteral feeding and/or drug administration. whilst reassuring in the steps taken to avoid never events, this study demonstrates that there may be delays in time-critical administration of enteral medicine or optimal nutritional practices. this study reveals a signifi cant problem with aspirating gastric contents for ph testing, necessitating a large number of x-ray position confi rmations. even if the frequency and volume of gastric aspiration were greater, there is a belief that ph testing may not be suffi ciently accurate (since many factors alter patients' gastric ph). it is possible that new technologies such as electromagnetic ngt placement may allow faster/equally safe practices. further study including cost/benefi t analysis will be needed to confi rm this. reference . eighteen readings were from newly placed ng tubes and readings from old ng tubes. fiftythree per cent of routine ph readings were falsely high; that is, ph or above despite the ng tube being in the stomach (figure ). twentyeight per cent of newly placed ng tubes had falsely high ph readings ( figure ). conclusion in this population of icu patients, routine/daily checks of ng ph aspirate appear to be limited. this is almost certainly due to the use of continuous ng feed together with ppis. the usefulness of ph testing in newly placed ng tubes, however, appears more reliable. introduction sepsis is the most common cause of death in icus [ ] . destruction of intestinal barrier function and increased translocation of bacteria to systemic blood fl ow can lead to sepsis [ ] . probiotics may have benefi cial eff ects in improvement of critically ill patients by modulating intestinal barrier and reduction of infl ammation [ ] . the aim of this trial was to determine the eff ect of probiotic on infl ammatory biomarkers and mortality rate of sepsis in critically ill patients in the icu. methods this double-blind, randomized controlled trial was conducted on critically ill patients admitted to the icu. they were randomly assigned to receive placebo or probiotic for days. the apache score, sequential organ failure assessment (sofa) and systemic concentrations of il- , procalcitonin (pct) and protein c were measured before initiation of the study and on days and . also, day mortality was evaluated for each patient. results il- and pct levels decreased and protein c levels increased signifi cantly in probiotic group over the treatment period (p < . ). there was a signifi cant diff erence in il- , pct and protein c levels of the th day between two groups (p = . , . and < . , respectively). compared with controls, probiotic was eff ective in improving apache and sofa scores in days (p < . ). there was signifi cant diff erence between the probiotic and control group in the -day mortality rate ( % vs. % respectively, p = . ). conclusion probiotics reduce infl ammation and mortality rate in critically ill patients and might be considered as an adjunctive therapy to sepsis. introduction the aim of this study is to establish whether diff erent types of sepsis have an impact on selenium levels. selenium is an essential trace element involved in antioxidant and immunological reactions. selenium levels have been shown to be low in patients with systemic infl ammatory response syndrome and sepsis. selenium replacement has been recommended in patients with sepsis [ , ] . greater than days of supplementation may also help to prevent the development of new infections on icus [ ] . methods this is a prospective survey where selenium levels were collected from patients admitted with septic shock to a tertiary icu, for months from october to march . results selenium levels were measured in patients with septic shock. abdominal and chest sepsis were the main sources of infection. those with an abdominal source of sepsis had the lowest levels, as shown in table . all septic shock patients who had selenium levels taken within the fi rst days of admission had subnormal levels (< . mg/dt), and after days had levels within the normal range, as shown in figure . introduction glutamine regulates many biological functions in preserving the cell, acts as a key respiratory fuel and nitrogen donor for rapidly dividing cells, and modulates the expression of many genes associated with metabolism, cell defences and repair, and cytokine production. in severe thoracic trauma, glutamine supplementation is essential because the body consumes more than it produces and glutamine eff ects become dependent on its route of delivery. methods fifty-two patients to years old with surgery for severe thoracic trauma were assessed in two groups: group a received . to . g/kg/day i.v. glutamine + g enteral glutamine for days, supplementation to enteral nutrition; group b receive only i.v. glutamine supplementation to enteral nutrition . to . g/kg/day for days. weaning time, the duration of p.o. ileus, incidence and time to resolution of vap, glycemic level and the percentage decrease of crp at hours were assessed in both groups. results weaning time and the duration of p.o. ileus were signifi cantly lower in group a; although the incidence of vap is similar in both groups, the time of vap resolution is lower, the glycemic control is better in group a. the percentage of crp decrease is higher in group a. see figure . conclusion glutamine becomes an essential amino acid in severe thoracic trauma and when the patients are fed other than tpn (enteral, oral); although hard evidence is lacking, both administration routes may be effi cient as soon as possible. results total cholesterol (tc) and low-density lipoprotein-cholesterol (ldl-c) levels were less changed signifi cantly in the low ratio group ( ± vs. ± mg/dl, p = . for tc, ± vs. ± mg/dl, p = . for ldl-c) compared with the high ratio group in postoperative patients. other laboratory parameters and adverse events did not show statistically signifi cant diff erences between the groups. see table . introduction the optimal feeding of critically ill patients treated in the icu is controversial. present guidelines for protein feeding are based on weak evidence obtained with suboptimal methods. whole body protein kinetics is an attractive technique to assess optimal protein intake by measuring the eff ect of protein feeding strategies on protein synthesis rates, protein degradation rates and protein balance. here protein kinetics were measured in critically ill neurosurgical patients during hypocaloric and normocaloric parenteral nutrition. methods neurosurgical patients on mechanical ventilation (n = ) were studied. energy expenditure was measured with indirect calorimetry. after that, the patients were randomized to receiving hours of % of measured energy expenditure followed by hours of % or % before %. whole body protein kinetics were measured during the last half hour of the feeding periods using stable isotope-labeled phenylalanine as a tracer. during a continuous infusion of labeled phenylalanine and tyrosine, plasma samples were obtained and later analyzed for the content of the labeled amino acids using mass spectrometry. protein kinetics were calculated using standard steady-state kinetics. in addition, amino acid concentrations were analyzed by hplc. student's t test was used for statistical analyses. the patients received . ± . and . ± . g amino acids/ kg/day (p < . ) on the days with and % of measured energy expenditure respectively. energy expenditures were . ± . and . ± . kcal/kg/day (p = . ) on the and % days respectively. plasma amino acids concentrations were . ± . and . ± . mm (p = . ) on the days respectively. whole body protein synthesis was % lower when % of energy expenditure was given, . ± . versus . ± . mg/kg/hour (p = . ), whilst protein degradation was unaltered . ± . versus . ± . mg/kg/hour (p = . ). also protein oxidation was unaltered . ± . versus . ± . mg/kg/hour (p = . ). this resulted in a % higher whole body protein balance with the normocaloric nutrition, - . ± . versus - . ± . mg/kg/ hour (p = . ). conclusion the protein kinetics measurements and the protocol used were useful to assess the effi cacy of nutritional support in critically ill patients. in the critically ill neurosurgical patients treated in the icu, hypocaloric feeding was associated with a more negative protein balance, while the amino acid oxidation was not diff erent. controlled trial (epanic: clinicaltrials.gov: nct ) [ ] showed that withholding parenteral nutrition during the fi rst week of icu stay whereby tolerating substantial caloric defi cit (late pn) accelerated recovery and shortened weaning time as compared with early parenteral substitution for defi cient enteral feeding (early pn). we examined the impact of late pn, as compared with early pn, on incidence and recovery of icuaw. methods a preplanned subanalysis of adult patients included in the epanic trial. the study was performed between october and november and included those patients who required intensive care for ≥ days as well as a computer-generated, admission categorymatched, random sample of short-stay icu patients, the latter to correct for possible bias evoked by earlier icu discharge in one of the two study groups. assessors blinded for treatment allocation evaluated muscle strength clinically three times weekly from awakening onward and performed nerve conduction studies and electromyography (ncs and emg) weekly. the primary outcome was the incidence of icuaw, diagnosed clinically by the medical research council (mrc) sum score (< / ) [ ] at fi rst evaluation. secondary outcomes included icuaw at worst and last mrc evaluation, recovery from icuaw and incidence of abnormal fi ndings on ncs and emg. all analyses were performed on the total dataset and on a for-baseline characteristics propensity score-matched sample to correct for possible imbalances between the groups. [ ] . plasma total bilirubin was quantifi ed in all patients daily while in the icu. liver enzymes alt, ast, ggt and alp were quantifi ed twice weekly in all patients while in the icu. in a random predefi ned subset of patients, circulating bile salts were also quantifi ed with ms-hplc at baseline and on day , day and the last day in the icu (n = ). gallbladder sludge was evaluated by ultrasound on icu day by blinded assessors (n = ). results from day after randomization until the end of the -day intervention window, plasma bilirubin was higher in the late pn than in the early pn group (all p < . ). in the late pn group, as soon as pn was started on day , plasma bilirubin also fell and the two groups became comparable. maximum levels of ggt, alp and alt during the icu stay were higher in the early pn group (all p < . ). compared with baseline, the circulating glycine and taurine conjugated primary bile salts were elevated on day , day and last day of the icu stay (p < . for all). however, there was no diff erence between the two groups. more patients in the early pn than in the late pn group had gallbladder sludge on day ( % vs. %; p = . ). conclusion tolerating substantial caloric defi cit by withholding pn until day of critical illness increased circulating levels of bilirubin but reduced the occurrence of gallbladder sludge and lowered ggt, alp and alt levels. these results suggest that hyperbilirubinemia during critical illness dies not necessarily refl ect cholestasis and instead may be an adaptive response. additional analyses on a propensity scorematched patient population are ongoing. reference the duration of renal replacement therapy (rrt) [ ] . the impact of the intervention on early markers of catabolism has not been investigated. methods we studied the impact of early versus late pn on daily markers of catabolism in the icu in the total study population and in propensity score-matched subgroups of long-stay patients. in addition, we calculated the net incorporation rate of the extra amino acids supplied by early pn. results plasma urea, the urea/creatinine ratio and nitrogen excretion increased over time in the icu. early pn further increased these markers of catabolism, from the fi rst day of amino acid infusion onward, and only marginally improved the nitrogen balance. also in the group that received pn only after the fi rst week in the icu, ureagenesis was increased by infusing amino acids. over the fi rst weeks, approximately two-thirds of the extra amino acids supplied by early pn were net wasted in urea. the above fi ndings were confi rmed in propensity scorematched subgroups of long-stay patients. the higher urea levels with early pn, rather than the kidney function as such, may have driven the observed longer duration of rrt, as supported by multiple regression analysis. conclusion the extra amino acids supplied by early pn appeared ineffi cient to reverse the negative nitrogen balance, not because of insuffi cient amino acid delivery, but rather because of insuffi cient incorporation with, instead, increased degradation into urea. the substantial catabolism of the extra amino acids, leading to pronounced urea generation, may have prolonged the duration of rrt in the early pn group. introduction muscle weakness of critical illness is associated with prolonged dependency on ventilatory support and delayed rehabilitation. muscle wasting related to poor nutrition has long been considered a major determinant, whereas the importance of myofi ber integrity only recently emerged [ ] [ ] [ ] [ ] . we hypothesized that nutrient restriction early during illness aggravates atrophy while preserving myofi ber integrity by activating the crucial cellular quality control pathway autophagy. the latter could be important to preserve muscle function. methods critically ill patients (n = ) were randomized to early (early-pn) or late (late-pn) initiation of parenteral nutrition to complete failing enteral nutrition, while maintaining normoglycemia ( to mg/ dl) with insulin, in the epanic study [ ] . vastus lateralis biopsies were harvested after week and compared with matched controls (n = ). results as compared with controls, muscle from critically ill patients showed reduced myofi ber density, a shift to smaller (especially type i) myofi bers, lower myosin and actin mrna, upregulated mrna of the ubiquitin ligases muscle-ring-fi nger- and atrogin- , a small increase in the autophagosome formation marker lc -ii/lc -i, and increases in the autophagic substrates ubiquitin and p (all p ≤ . ). late-pn, resulting in a larger caloric defi cit than early-pn, had no substantial impact on atrophy markers. in contrast, late-pn increased lc -ii/lc -i (p = . ), which coincided with less accumulation of ubiquitinated proteins/aggregates (p = . ). fewer patients on late-pn developed muscle weakness as compared with early-pn ( % vs. %, p = . ). in multivariable analysis, a lower lc -ii/lc -i ratio (p = . ) and higher myofi ber density (p = . ) were independently associated with muscle weakness. conclusion early-pn did not counteract muscle atrophy whereas it suppressed autophagy and aggravated weakness. statistically, muscle weakness was not explained by atrophy or wasting but rather by impaired autophagy and preservation of muscle density. thus, tolerating nutrient restriction early during critical illness may preserve myofi ber integrity by activating autophagy. introduction closure of an acute hospitals emergency department (ed) has important ramifi cations for those centres expected to take up the resultant workload. the continued reconfi guration of emergency care is likely to produce an increasing number of these scenarios. little evidence is available to support planning of such initiatives and thus the implications are diffi cult to anticipate. this study aims to demonstrate one hospital's experience of the rationalisation of emergency care and its eff ect on workload. methods this retrospective study was conducted in a large teaching hospital. activity data were analysed for a -month period following the closure of a neighbouring ed. the results were subsequently compared against the year prior to closure. attendance, triage data, admission rates and waiting times were compared across the two periods, as were workload data for all grades of physician. the chisquared test was used to examine diff erences between groups. results in the period studied, the gross attendance fi gure increased by , ( . %), whilst the admission rate rose from to %. following closure of the neighbouring ed, the proportion of highacuity patients attending our institution increased dramatically, with the proportion of category one and two patients (manchester triage scale) increasing by . % (p = . ) and . % (p < . ), respectively. likewise, ambulance arrivals increased out of proportion to the total increase in attendances (p = . ). admissions from the ed to the icu increased by . %. consultants workloads now include % more category and patients (p = . ). conclusion reconfi guration of emergency care can have dramatic implications for existing services; these may not always be anticipated. rationalisation of ed's may result in a concentration of high-acuity patients accompanied by a downturn in the numbers of patients whose presentations are amenable to care delivered in other settings. this abrupt change in case mix requires a re-examination of existing workforces and their seniority. overcrowding estimation in the emergency department: is the simplest score the best? introduction emergency department (ed) overcrowding is a major international problem with a negative impact on both patient care and providers. among validated methods of measurement, emergency physicians have to choose between simple and complex scores [ , ] . the aim of the present study was to compare the complex national emergency department overcrowding scale (nedocs) with the simple occupancy rate (or) determination. we further evaluated the correlation between these scores and a qualitative assessment of crowding. methods the study was conducted in two academic hospitals and one county hospital in liège, chênée and verviers; each with an ed census of over , patient visits per year. samplings occurred over a -week period in january , with fi ve sampling times each day. results ed staff considered overcrowding as a major concern in the three eds. median or ranged from to , while the nedocs ranged from . to . . we found a signifi cant correlation between introduction it is evident that accident and emergency departments are overloaded with patients, which results in delays in healthcare provision [ ] . a large proportion of patients consist of patients with minor illness that can be seen by a healthcare provider in a primary care setting. the aim of the study was to determine the characteristics of patients using gp walk-in services, patients' satisfaction and the eff ect on emergency department (ed) services. methods the survey was conducted in sheffi eld and rotherham walk-in centres over weeks during september and october . a self-reported, validated questionnaire was used to conduct survey on the patients presenting at these centres. we estimated that a sample size of around patients from each centre was required to achieve statistically robust results. a post-visit, short questionnaire was also sent to those who agreed for the second questionnaire and provided contact details. ed data were also obtained from april to march , year before and year after the opening of the gp walk-in centre. data were entered and analysed in pasw statistics . ethical approval of the study was obtained from the nhs ethical review committee. results a total of , patients participated in the survey (rotherham ; sheffi eld ). the mean age of the participants was . years at sheffi eld and . years at rotherham. a higher proportion of users were female, around % at both centres. most of the patients rated high for convenience of the centre opening hours and location (above %, apart from the location of sheffi eld centre, which was rated high by around % of the research participants). overall % patients were satisfi ed with the service at rotherham centre and around % at the sheffi eld centre. based on the estimation of the monthly counts of patients attending ed and the gp walk-in centre, around % monthly reduction in minor attendances at ed was expected. however, ed routine data did not show any signifi cant reduction in minor attendances as a result of the opening of the gp walk-in centre. conclusion these walk-in centres have been shown to increase accessibility to healthcare service through longer opening hours and walk-in facility. although the eff ect on the reduction of patients' load at the ed is not visible as these centres cover a fraction of the population, the centre has a potential to divert patients from the ed. reference overcrowding in emergency departments (eds) is a widely known problem. it causes problems and delays in the ed and has a negative impact on patient safety [ ] . the aim of this study was to analyse whether a reform of emergency care can reduce patient fl ow into the ed. methods a substantial reform of emergency care took place in the province of kanta-häme in southern finland. three separate out-ofhours services in primary healthcare (phc) and one ed in the hospital were combined into one large ed in april . basic principles of the new ed were: the ed is only for those patients who are seriously ill or injured, and need immediate care; phc (healthcare centres) take care of acute ordinary illnesses and nonserious injuries during offi ce hours. to achieve these principles a regional fi ve-scale triage system was planned and implemented. the information plan was established. citizens were systematically informed about the principles of the new ed by mail, articles in the newspapers and interviews in the radio and television. the ed's internet pages were planned and established. the number of patient visits (hämeenlinna region) was analyzed years before and after establishing the new ed. results during the -year period before the establishment of the new ed the mean number of gp patient visits was , ± /month. during the -year period after the reform the number was diminished to , ± /month. this change was not associated with the increase of the patient visits taken care of by specialists and hospital residents. see figure . conclusion an extensive reform of the emergency services can notably reduce patient fl ow into the ed. reference abdominal pain in adolescent females has undergone recent changes with regards to its management under various specialities. the authors report a single-centre audit looking at the correct investigation and management of -year-old to -year-old girls with abdominal pain in the emergency department setting. methods a single-centre audit and retrospective analysis of patients took place using case notes and computerised records. documentation was analysed using statistical analysis and minimum standards were set and reviewed. results after exclusion criteria females between the ages of and presented to the paediatric emergency department in leicester with abdominal pain as the predominant admission symptom during a -month period. documentation of the gynaecological history was poor (menstrual history %, sexual history %, contraception %), as was the performance of basic investigations (urine dipsticks %, pregnancy test %). documentation was analysed with regard to discharge diagnosis. ultrasound investigation was performed on seven of the patients but only once admitted to various specialities. no ultrasound was undertaken upon admission. conclusion improvement in documentation of minimum standards for these patients is needed. a multidisciplinary care pathway could improve outcome. consideration should be given to whether early ultrasound investigation is appropriate and there is a further need for investigation as to whether this would improve longer term outcomes. introduction bipap utilization for the treatment of severe refractory status asthmaticus patients has become an accepted therapy but is not well described for moderate exacerbations. we sought to analyze outcomes from our bipap quality database for children presenting in status asthmaticus at varying levels of severity. methods ped status asthmaticus patients requiring bipap from january to august had a bedside interview and documentation of information at the time therapies were given. incomplete data were collected retrospectively. all data were stored and analyzed using a redcap database. subjects were stratifi ed into severity groups based on asthma score at the time of bipap placement. results there were subjects in the moderate severity group and in the severe group. table shows the groups were well matched and compares other pertinent data. children with severe presentations were placed on bipap sooner (p < . ) and remained on bipap longer (p < . ). the moderate group had a longer wait until bipap placement. tables and demonstrate higher initial bipap (ipap/epap) settings with increasing age and severity. figure trends initiation and termination asthma scores stratifi ed by severity at bipap we present a case series of toxicity due to a novel substance in the uk: eric- . novel drugs of abuse are becoming more common throughout the world, and they represent particular diffi culties in their acute management. a recent report from the european monitoring centre for drugs and drug addiction and europol has reported new psychoactive substances reported via its early warning system. methods this was a retrospective case-note review over a -month period. patients were included if their presentation was due to recent ingestion of eric- . physiological data, symptoms, outcome and destination of the patient from the emergency department were collected. postmortem toxicological analysis was obtained for one of the two patients who died. results forty-one attendances were identifi ed from patients. two patients died and fi ve were admitted to the icu. heart rate and temperature on arrival tended to be above normal (mean heart rate was bpm, with an sd of ; mean temperature was . °c with an sd of . ). in total, . % of attendances included agitation and . % choreiform movements. α-methyltryptamine and -/ -fl uoroephedrine were found in the blood of one of the patients who died. conclusion in this outbreak in the uk, eric- gave symptoms similar to other stimulants known as legal highs, including death. it may have been a novel substance, -/ -fl uoroephedrine. this underlines the need for prospective data collection and early national and international information sharing. introduction thallium is an odorless, tasteless, heavy metal that has been often used for intentional poisonings. in severe patients, thallium poisoning produces neuromuscular symptoms such as extreme pain and muscle weakness. methods five case reports. results all patients worked at a pharmaceutical factory. they joined a tea party held at their workplace at the end of april . the fi ve patients drank tea from a teapot someone had put thallium in. a few days later, they complained of femoral numbness and pain caused by pressure. about a week later, three of fi ve patients had profound hair loss. three weeks after the party, they came to our er. we thought that their symptoms might be caused by some chemicals. we searched the keywords: 'lower extremity pain' , 'hair loss' and 'poison' in the internet. as a result, thallium, mercury, lead, and so forth, were suspicious metals. in those metals, thallium was most likely because it was used in their factory. we immediately examined the blood concentration of several metals and ordered iron(iii)hexacyanoferrate(ii) that is known as the antidote for thallium poisoning. only thallium was positive in the blood metal concentration test. three patients consented to oral administration of an antidote. two patients rejected administration because their symptoms were mild and getting better. all symptoms of all patients gradually disappeared by august. we also followed up the course of blood concentration of thallium. the concentration in three patients who took the antidote was reduced more rapidly than the two patients who did not take it. conclusion all patients recovered without any sequelae. three patients' hair started to grow months from ingestion of thallium, and after half a year their hair was restored to their former state. we had diffi culty ordering iron(iii)hexacyanoferrate(ii) because this is also known as an antidote for cesium. on march a megathrust earthquake and tsunami hit japan and the giant tsunami gave rise to an accident at a nuclear power generation plant. because the rumor of radioactive substances including cesium might be spread was the talk in the city near the nuclear power plant, the authorities put the antidote under heavy supervision. we could also collect the data for the course of thallium concentration. thallium concentration of the patients who had an antidote was reduced more rapidly but these patients had a loose stool, thought to be a side eff ect of this antidote. reference . ± sd . . ± sd . drugs aff ects the central nervous and cardiovascular systems, resulting in severe arrhythmia and death. heart rate variability (hrv) analysis is a non-invasive assessment method that allows evaluation of the cardiac autonomic (sympathetic and parasympathetic) activity. the aim of this study was to evaluate hrv in children requiring icu stay due to tca poisoning. methods twenty children with isolated tca poisoning aged between and years who were hospitalized in the pediatric icu, between march and july , and healthy children as a control group were enrolled. clinical and electrocardiographic (ecg) fi ndings were noted in the tca poisoning group. in both groups, -hour time domain hrv analysis (sdnn, sdann, sdnni, rmsdd, nn , and pnn ) was performed. we also recorded frequency domain analysis results at the fi rst minutes and the last minutes of the -hour record (vlf, nlf, nhf, lf/hf ratio). the average level of tca in the study group was , ± and tca levels were positively correlated with the duration of qrs interval (p < . ). in time-domain nonspectral evaluation, sdnn (p < . ), sdnn (p < . ), rmsdd (p < . ), and pnn (p < . ) were found signifi cantly lower in the tca intoxication group compared with the control group, while nn (p < . ) was signifi cantly higher in value. the spectral analysis (frequency domain) of data recorded at fi rst minutes after intensive care admission showed that the values of the nlf (p < . ) and lf/hf ratio (p = . ) were signifi cantly higher in the tca intoxication group than the controls, while nhf (p = . ) values were signifi cantly lower. the frequency domain spectral analysis of data recorded at the last minutes showed a lower nhf (p = . ) in the tca intoxication group than the controls, and the lf/hf ratio was signifi cantly higher (p < . ) in the intoxication group. sdnn (p < . ), rmsdd (p < . ), sdnni (p < . ), and pnn (p < . ) levels were higher in patients with positive ecg fi ndings than those without positive ecg fi ndings. the lf/hf ratio was higher in seven children with seizures (p < . ). conclusion existing fi ndings give us an idea about hrv's value to determine arrhythmia and predict convulsion risk in tca poisonings. hrv can be used as a non-invasive method in determining the treatment and prognosis of tca poisoning. results hmmd receives an average of cases of stroke monthly, and thrombolysis did not occur before the implementation of the tm project, because of the lack of neurologists available to conduce the cases. after implementation of the tm program, six cases of ischemic stroke were thrombolyzed with alteplase; only one case ( %) progressed to death from septic shock, and one case ( %) presented symptomatic intracranial hemorrhage. conclusion thrombolysis in ischemic stroke reduces % the risk of disability and % the mortality rate. this procedure has been only feasible to be done in the community setting because of the implementation of the tm project, which permits the presence of a real time consultation with a specialized neurological team from a tertiary center. analyses, and then returned home. in total, . % of patients were hospitalized in a medical or surgical department, and . % in the short-term hospitalised unit of the emergency department (stay duration < hours). some . % of patients worsened and were oriented in the icu. a total . % of patients in a cardiac icu. in total, . % of patients had stay duration less than hours in the ed, . % < hours. forty percent of patients supported by fi remen and % supported by private ambulance left the hospital after a single medical consultation. conclusion nearly % of patients calling the french emergency medical dispatching centre are sent to hospital. those transportations are supported for two-thirds of cases by a private ambulance or fi remen ambulance. one out of two patients only receive a simple medical consultation in the ed, and go back home. this may concur to the defi ciency of using general medicine in town. they prefer using emergency services for free. only one patient out of four was hospitalized more than hours. introduction early onset eff ective care in the emergency department (ed) has been reported to have a great infl uence on the intensive care patients' morbidity and mortality [ ] . little is known about the infl uence of the reorganisation of the ed on patient intake to the icus. the aim of this study was to analyse monthly intake of patients from the ed to the cardiac care unit (ccu) and icu before and after the reform of emergency services. methods in kanta-häme central hospital, a new ed started on april . four older emergency rooms were combined into one bigger emergency department and an observation ward was introduced with continuous follow-up of vital signs. this study is a retrospective analysis of the patient intake to the ccu and icu year before and after the reorganisation. using as data the finnish intensive care quality consortium (intensium, finland) database and the cardiac database of the hospital, patient transfer from ed to the icu and ccu was collected and analysed. monthly pre/post comparisons were carried out statistically by a nonparametric wilcoxon signed-rank test. the total decrease in monthly patient infl ow from ed to the icu and ccu was . % (p = . ); that is, from the mean of . ± . to . ± . patients (figure ) < . ) . the result is longer overall hospitalization of patients having wi (p < . ) and a higher number of surgeries (p < . ). after the er, % of patients with wi were hospitalized in the icu ( % of them after surgery) but only % of patients involved in a ca ( % after surgery). as many patients with wi as involved in a ca ( %) were admitted to the ward ( % of patients with wi after surgery but only % of patients with injuries due to a ca). thirty-three per cent of patients involved in a ca returned home and one was transferred, whereas only three patients with wi returned home after being in the er, three patients were transferred and one died in the operating room. observed paediatric mortality in our medical treatment facility was . % ( children out of ): three children died of wi, three due to a ca and one of septic shock due to a medical cause. conclusion war injuries are more prone to cause polytrauma than ca. according to the pts, iss, niss, triss and ascot, children experiencing wi have higher severity scores and predicted mortality rate than others, stay longer in the hospital and have more surgeries. our research indicated that disaster medicine should be established systematically or it is necessary to compile a compendium of disaster medicine from a broad perspective or from a bird's-eye and long-term view. the japanese version was tentatively completed with volumes as of the fi nancial year , of which nearly three-quarters are written in japanese. although this worked partly during the aboveshown catastrophe in japan , several problems are left to be solved; that is, the insuffi cient operation system of the japan dmat or disaster medical assistant team that seemed to have caused a large number of preventable deaths. conclusion the large number of casualties during a major disaster is a global problem, even in the developed countries. when the role of the intensivist is reviewed, many roles were verifi ed to be important; that is, as a leader of a medical team or triage offi cer as well as a professional in the fi eld of specifi c intensive care. however, there are many problems to be solved in the fi elds of disaster medicine. in order to solve the diversifi cation or the various medical problems, it is necessary to compile or systematize a disaster medicine of the world version. the concept of the compendium and our process of trial are shown in relation to intensive care. there are distinct diff erences in the pathophysiology between medical cardiac arrests and tca. traumatic pathologies associated with an improved chance of successful resuscitation include hypoxia, tension pneumothorax and cardiac tamponade [ ] . the authors believe a separate algorithm is required for the management of out-of-hospital tca attended to by a highly trained physician and paramedic team. methods a suggested algorithm for tca was developed based on the greater sydney area helicopter emergency medical service's standard operating procedures and current available evidence. results an algorithm for the general management of tca can be seen in figure . in tca, priority should be given to catastrophic haemorrhage control (tourniquets, direct pressure, haemostatic agents, pelvic and long bone splintage) and volume resuscitation. simultaneous oxygena tion optimisation should occur with proactive exclusion of tension pneumothoraces with bilateral open thoracostomies. cardiac ultrasound (us) should be used to help exclude cardiac tamponade and assist in prognostication. the us presence of true cardiac standstill versus low pressure state/pseudo-pea, and an etco < . kpa carries a grave prognosis in tca. given the high incidence of hypovolaemia, hypoxia and obstructive shock prior to tca, the role of adrenaline and chest compressions are limited. figure shows a suggested algorithm for the management of penetrating tca requiring prehospital thoracotomy. conclusion the suggested algorithm is designed for a highly trained physician-led prehospital team and aims to maximise the number of neurologically intact survivors in out-of-hospital tca. little is known about the benefi t of physician winching in addition to a highly trained paramedic. we analysed the mission profi les and interventions performed during rescues involving the winching of a physician in the greater sydney area hems (gsa-hems). methods all winch missions involving a physician from august to january were identifi ed from the prospectively completed gsa-hems electronic database. a structured case-sheet review for a predetermined list of demographic data and physician-only interventions (poi) was conducted. we identified missions involving the winching of a physician, of which case sheets were available for analysis. the majority of patients were traumatically injured ( %) and male ( %) with a median age of years. seven patients were pronounced life extinct on the scene. a total of poi were performed on patients. administration of advanced analgesia was the most common poi making up . % of interventions. patients with abnormal rtsc scores were more likely to receive a poi when compared with those with normal rtsc (p = . ). the performance of poi had no effect on median scene times ( vs. minutes; p = . ). see tables and . conclusion our high poi rate of % coupled with long rescue times and the occasional severe injuries supports the argument for winching doctors. not doing so would deny a signifi cant proportion of patients time-critical interventions, advanced analgesia and procedural sedation. the aim was to assess the content and state of repair of equipment carried for transfer of critical care patients to other hospitals. by chance, several items of date-expired stock were identifi ed in the transfer kit whilst moving a patient to a tertiary centre. this raised the possibility of a more extensive problem with the equipment bags. due to the geographical location of our district general hospital we undertake around transfers of critical care patients to other hospitals per year ( % by air) and it is clearly important that our equipment is well maintained for these journeys. methods we maintain two identical sets of equipment (syringes, fl uid, airway management items, and so forth) and drug bags to take on transfers; one equipment and one drug bag taken on each trip. the contents of all four bags were checked and itemised. by careful consideration of the aims of the bags (to provide emergency equipment and drugs for managing one patient during an en-route emergency) a new inventory was devised. excess items were removed to lighten the bags and improve accessibility to the essential items. expired stock was removed. a daily checking procedure and tamper-proof seals on the bags were instigated and the bags were reassessed months later. results a total of . % of drug items and . % of equipment items had expired or would do so within days of the initial assessment. the combined weight of one equipment and one drug bag was reduced from to kg ( % reduction) by introducing the new inventory. at reassessment in november , only items of equipment ( . %) were expired or near to expiry and there were no expired drug items ( . % near to expiry). in total, . kg ( small items) of extraneous equipment had been added through over-restocking and was removed. conclusion these bags are designed for a clinician to manage a patient when an emergency arises during transfer of a critical care patient. by the introduction of simple measures, the risks posed by expired items or cluttered equipment bags have almost been eradicated. signifi cant weight savings have been made; this off ers improved ergonomics for staff and is also an important consideration for aeromedical operations. our department was surprised to discover the extent of decline of our equipment and it may be that other departments would fi nd themselves in a similar position. the anaesthetic registrars who routinely escort the transfer patients have a vested interest to maintain this equipment and this has secured their buy-in to the new checking procedure with clear results. conclusion prehospital hyperoxemia did not infl uence the functional neurological outcome. one of the reasons for this fi nding could be the short arrival time to the trauma center where repeated analyses of arterial blood gases were performed. therefore, correction of fraction of inspired oxygen according to the arterial blood gas analysis shortens the time of hyperoxemia, thus reducing neuronal brain damage. introduction severe burn patients are often noted to have subsequent neurocognitive problems. experimentally, we have found striking, prolonged elevations of infl ammatory markers in the brain (for example, il- ) even when the injury occurs in a remote anatomic location. this neuroinfl ammatory response can also be signifi cantly blunted by a single post-burn dose of estrogen. sonic hedgehog (shh), an important signaling protein found in the brain, controls and directs diff erentiation of neural stem cells, infl uencing brain regeneration and repair by generating new neurons throughout life. as estrogens not only blunt infl ammation but also exert an infl uence on a variety of stem cells, we hypothesized that β-estradiol (e ) might aff ect levels of shh in the post-burn rat brain. methods male rats (n = ) were assigned randomly into three groups: controls/no burn (n = ); burn/placebo (n = ); and burn/e (n = ). burned rats received a % ° tbsa dorsal burn, fl uid resuscitation and one dose of e or placebo ( . mg/kg intraperitoneally) minutes post burn. eight animals from each of the two burn groups (burn/placebo and burn/e ) were sacrifi ced at hours and at days, respectively (sham group at days only), with four each of the two burn groups sacrifi ced at days. brain tissue samples were analyzed by elisa for shh. results mean levels of shh levels were signifi cantly elevated within hours as much as days post injury in burned animals receiving the β-estradiol (> , pcg/mg) as compared with the placebotreated burned animals (< pg/mg) and controls (< pcg/mg). see figure . conclusion early, single-dose estrogen administration following severe burn injury signifi cantly elevated levels of shh in brain tissue. this fi nding may represent an extremely novel and important pathway for both neuroprotection and neuroregeneration in burn patients. introduction many proposed resuscitative therapies for cardiac arrest and trauma will require the earliest possible intervention and would occur under volatile circumstances, making true informed consent for clinical trials unfeasible. the purpose here was to report our experience using exception to informed consent during the inaugural pilot study of infusing estrogen for acute injury, the so-called rescue shock study. methods fifty patients were enrolled in rescue shock in which estrogen or placebo was infused as soon as possible in the emergency department for trauma patients with a low systolic blood pressure (< mmhg) at two level i trauma centers. they were all treated with a single-dose estrogen or placebo infusion within hours using exception from informed consent following us federal guidelines. results investigator-initiated exception from informed consent studies is feasible, with our fda ind approval obtained in days, irb approval in days, and irb approval in days. community consultation/notifi cation was successfully accomplished with no one opting out and / enrolled patients or their legal representatives were notifi ed of participation (one died unidentifi ed, two died with no known contact). the average number of days to verbal notifi cation of patients or advocates was . days (range to days) as the study team began notifi cation only after the patient or family was able to reasonably understand information about the study. no one decided against continued follow-up. overall, patients and their families were very enthusiastic about participation and the data safety monitoring board had no safety concerns after reviewing all study data. conclusion although delayed notice of participation occurs for many justifi able reasons, the use of exception from informed consent for novel, time-sensitive resuscitation studies is not only crucial, but can be feasible, and well accepted by patients, their advocates and communities at large. introduction patients with severe burn injury experience a rapid elevation in multiple circulating proinfl ammatory cytokines, with the levels correlating with both injury severity and outcome. in animal critical care , volume suppl http://ccforum.com/supplements/ /s s models, accumulations of these cytokines have been observed in remote organs, including the heart, brain and lungs. however, data are lacking regarding the long-term levels of cytokines in the heart following severe burn injury and also how infusion of parenteral estrogen, a powerful anti-infl ammatory agent, would aff ect these levels. using a rat model, we studied the eff ects of a full-thickness thirddegree burn on cardiac levels of il- and tnfα over days with and without β-estradiol infusion. methods a total of male rats were assigned randomly to one of three groups: ( ) conclusion following severe burn injury in an animal model, an early single dose of estrogen can decrease the prolonged let alone the early onset of cardiac infl ammation. based on these data, clinical studies of estrogen infusions should be seriously entertained as estrogen may not only be an inexpensive, simple adjunctive therapy in burn management, it may also obviate the need for many subsequent interventions altogether and even diminish mortality. conclusion the results of this study highlight the risk factors for the development of complications following blunt chest trauma. a risk stratifi cation tool has also been developed that could assist in the prediction of poor outcomes in this patient group. the next stage is to complete a prospective validation study. reference introduction we have reported the risk of chest drain insertion inferior to the diaphragm when using current international guidelines [ ] . another complication is damage to signifi cant peripheral nerves, such as the long thoracic nerve causing winging of the scapula [ ] . we assessed these risks using: the european trauma course method, a patient's handbreadth below their axilla just anterior to the midaxillary line; the british thoracic society safe triangle [ ] ; and the advanced trauma life support (atls) course guidance [ ] . methods we used the above guidelines to place markers (representing chest drains) in the thoracic wall of cadavers bilaterally ( sides), cm anterior to the midaxillary line. subsequent dissection identifi ed the course and termination of the long thoracic nerve, the site of lateral cutaneous branches of intercostal nerves, and their relation to the markers. the long thoracic nerve was found in the fi fth intercostal space in of cases, always in or posterior to the midaxillary line. contrary to the description in grays' anatomy ( th edition) it terminated before the inferior border of serratus anterior. most commonly it was found to end by branching in the fourth (right) or fi fth (left) intercostal space (range third to sixth). lateral cutaneous branches of intercostal nerves were found in the fi fth intercostal space in of cases. contrary to the description in last's anatomy ( th edition) they always passed anterior to the midaxillary line (and marker). conclusion placement cm anterior to the midaxillary line minimises risk to the long thoracic nerve and lateral cutaneous branches of intercostal nerves. we therefore conclude that not all areas of the british thoracic society safe triangle are indeed safe, and anteroposterior placement should follow the european trauma course and atls guidelines: just anterior to the midaxillary line (for example, cm). introduction whole body computed tomography (wbct) appears to be useful for the early detection of clinically occult injury, although its indications have been controversial. the purpose of this study was to develop a clinical prediction score to clarify the indications for blunt trauma patients with multiple injuries (mi) who require wbct. methods we conducted a retrospective study of patients with blunt trauma who underwent wbct at our emergency center between june and july . we chose the presence or absence of mi (injury severity score ≥ ) in need of surgical intervention as the outcome variable. we used bivariate analyses to identify variables potentially predicting the presentation of mi. the predictor variables were confi rmed by multivariate logistic regression analyses. we assigned a score based on the corresponding coeffi cients. results among the patients enrolled, were in the mi group. four predictors were found to be independently signifi cant by the logistic analysis: ( ) body surface wound ≥ regions, ( ) positive focused assessment with sonography for trauma, ( ) white blood cell count ≥ , /μl, and ( ) d-dimer ≥ μg/ml. score was assigned to predictor ( ), score was assigned to predictors ( ), ( ) and ( ). a prediction score was calculated for each patient by adding these scores. the area under the receiver operating characteristic curve was . . no patients with a score of or less had mi (figures and ) . conclusion in patients with a score of or , the presence of mi is less likely. these patients may not require wbct, and selective ct scans of body parts based on clinical presentation should be considered. (figure ) . the most common intervention as a result of the ultrasound was initiation of a pressor infusion ( . %), of which . % were ionotropes. additional therapies included blood transfusion ( . %), heparin ( . %), tpa ( . %), cardiac catheterization ( . %), and surgery ( . %). rosc was achieved in . % of patients; average time to rosc was minutes. a total . % of patients who underwent als were alive at hospital discharge and . % at year. conclusion focused cardiac ultrasound is a feasible adjunct to als resuscitation and may assist in the early identifi cation of reversible causes of cardiac arrest. care must be taken to ensure no interruptions to cardiac compressions are made by performance during pulse checks. further studies are needed to examine the outcomes associated with its integration into resuscitations. introduction in this case report, we describe a patient who presented with a cardiac arrest as a result of an obstructive shock, which progressed into cardiac arrest, caused by an acute para-esophageal gastric herniation. methods our patient, with a medical history of a laparoscopic repair of a symptomatic diaphragmatic hernia months prior, presented herself at the emergency department with pain in the upper abdomen and nausea. the physical examination, laboratory tests and x-ray of the thorax were normal and she was sent home. twenty-four hours later paramedics were summoned to our patient because of increased complaints. on arrival of the paramedics she had a normal electrocardiogram (ecg) and during the transfer from her bed to the stretcher she collapsed due to pulseless electric activity (pea), for which cardiopulmonary resuscitation was started. sinus rhythm and output was regained after several minutes and the patient was transported to the hospital. at arrival in the hospital, the x-ray of the thorax showed an intrathoracic stomach and a signifi cant mediastinal shift to the right. results after emergency laparotomy, which concerned correcting the gastric herniation and resection of an ischemic part of stomach, the patient remained hemodynamically stable. cardiac ischemia was ruled out based on ecg, laboratory fi ndings, cardiac ultrasound and cardiac computed tomography. the ultrasound in the emergency department did show a distended right ventricle and normal left function, which disappeared later (after repositioning the stomach), which is evidence for the mediastinal shift as a cause for the pea. conclusion we are the fi rst to describe a patient requiring cardiopulmonary resuscitation for progressive obstructive shock, due to an intrathoracic stomach. especially after a laparoscopic repair of a diaphragmatic hernia, this is a rare cause for shock and cardiac arrest, which requires a diff erent medical approach. is a key factor in improving survival from out-of-hospital cardiac arrest (ooh-ca). the alert algorithm, a simple and eff ective compression-only telephone cpr protocol, has the potential to help bystanders initiate cpr. this study evaluates the eff ectiveness of the implementation of this protocol in the liege dispatching centre. methods we designed a before-and-after study based on a -month retrospective assessment of the adult victims of ooh-ca in , before the implementation of the alert protocol in the liege dispatching centre, and the prospective evaluation of the same -month period in , immediately after the implementation of this protocol. data were extracted from ambulance, paramedical and medical intervention teams fi les, as well as the audio recordings of the dispatching centre. conclusion in ohca patients with unshockable initial rhythm, prehospital epinephrine administration signifi cantly increased the rate of survival at month after cardiac arrest. the best single predictor for favorable neurological outcomes at month following prehospital epinephrine administration after cardiac arrest was age (< years) followed by total dose of epinephrine ( mg) and then by call-response time (< minutes). [ ] . methods this was a single-center retrospective cohort study of patients who suff ered ohca and were transported to our hospital between april and march . we investigated the patients' characteristics, whether they met the tor criteria, and their outcome at the time of hospital discharge. results a total of patients (mean age, years), % of whom were male, were transported to our hospital after suff ering ohca. cardiopulmonary arrest was witnessed in cases ( %). the aha guidelines for cpr and ecc regarding the criteria for tor were applied in cases ( %), of whom ( %) were dead on arrival, and were successfully resuscitated and admitted. the outcomes for these patients were as follows: died in the hospital, two patients were discharged with a glasgow pittsburgh cerebral performance category (cpc) score of , and one patient was transferred to another hospital with a cpc score of . conclusion in our study, % of the patients who were transported to the hospital after ohca met the criteria for tor. outcomes for patients who met the tor criteria were signifi cantly worse than those who did not meet the criteria ( . % vs. . %, p < . ). in japan, eff orts are made to resuscitate almost all individuals who suff er ohca, but % of those patients die within a day. in light of the fact that even the medical cost for each of these patients who die within a day amounts to us$ , [ ] , the introduction of tor will have a particularly strong impact in japan. introduction detection and treatment of cardiopulmonary arrest and their antecedents may be less eff ective at night and weekend than weekdays because of hospital staffi ng and response factors [ ] . early detection and resuscitation of cardiopulmonary arrest are crucial for better clinical outcome. we conducted our study to evaluate event survival of in-hospital cardiopulmonary arrest after regular working hours in nonmonitored areas of a tertiary-care center. = ) , hypoxia (n = ), cardiac other (n = ), sepsis (n = ), arrhythmia (n = ) and pe (n = ). in two ihca patients more than one likely cause of arrest was reported and in cases no cause was identifi ed. the presenting rhythm was ventricular fi brillation (vf) in . % (n = ), pulseless electrical activity in . % (n = ) and asystole in . % (n = ). a total of . % (n = ) were thrombolysed and one ( . %) patient was referred for emergency pci. conclusion as previously reported [ ] , ihca was associated with a worse prognosis than ohca. the ohca survival rate was better than reported elsewhere [ ] . the percentage of ihca attributed to mi was low. only one ohca patient was referred for emergency pci. routine coronary angiography with ad hoc pci in vf ohca has been associated with increased survival [ ] . greater availability of pci post ohca could further improve mortality in patients with a primary cardiac pathology. further investigation should include management of noncardiogenic cardiac arrest. introduction mild therapeutic hypothermia (mth) is the most powerful therapy to improve survival and neurologic outcome after out-ofhospital cardiac arrest. such benefi t may also occur for unconscious patients after in-hospital cardiac arrest. the aim is to compare -year evolution of neurological outcomes of patients treated with mth after in-hospital versus out-of-hospital cardiac arrest. methods a prospective study of patients treated with mth after cardiac arrest in a community hospital in são paulo, brazil. after return of spontaneous circulation, unconscious survivors received mth using topical ice and cold saline infusions in order to achieve a to °c goal temperature, within hours of cardiac arrest, and maintained in the management of out-of-hospital cardiac arrest (ohca) is not clear cut [ ] . it has historically been used in patients with st elevation on post-resuscitation electrocardiogram (ecg) although this is a poor predictor of acute coronary occlusion after cardiac arrest [ ] . this study investigates the benefi t of pci regardless of post-resuscitation ecg. benefi t is widely claimed for therapeutic hypothermia, so cooling parameters were included. methods we analysed all consecutive adults admitted post ohca to a university hospital icu between january and december . patients received pci regardless of ecg changes. a cox proportional hazards model was used to determine the relationship between pci, cooling and survival to discharge. routinely collected data such as demographics and details of resuscitation (ohca utstein data) were also included. results survival to hospital discharge was % with % of survivors discharged to a neurological rehabilitation centre. multivariate analysis using a cox proportional hazards model showed pci to be an independent predictive factor of survival, unrelated to ecg (hazards ratio, . ; % ci, . to . ). cooling had no signifi cant impact on patient survival. see figure . conclusion in this small retrospective study primary pci appears to be an independent predictor of survival after ohca. this is consistent with other studies suggesting benefi t for primary pci regardless of the post-resuscitation ecg [ ] . cooling was not found to improve survival to discharge but further analysis is required to determine impact on neurological function. introduction sedation and therapeutic hypothermia (th) modify neurological examination and alter prognostic prediction of coma after cardiac arrest (ca). additional tools, such as eeg and evoked potentials, improve prediction of outcome in this setting, but are not widely available and require signifi cant implementation. methods using a new device for infrared pupillometry, we examined the value of quantitative pupillary light reactivity (plr) to predict outcome in comatose post-ca patients treated with th. twenty-four comatose ca patients treated with th ( °c, hours) were prospectively studied. the percentage variation in plr was measured during th ( hours from ca), using the neurolight algiscan® (idmed, marseille, france). for each patient, three consecutive measures were performed and the best value was retained for analysis. the relationship of plr with survival and neurological outcome (cpc scores) at months was analyzed, and the predictive value of plr was compared with that of standard clinical examination (motor response and brainstem refl exes) performed at hours from ca. results quantitative plr was strongly associated with survival (median left-eye plr % ( to %) variation in survivors vs. . % ( to . %) in nonsurvivors, p < . ) and -month neurological outcome ( % ( to %) in patients with cpc to vs. . % ( to . %) in those with cpc to , p < . ). comparable fi ndings were obtained using right-eye plr. a plr > % was % predictive of patient prognosis, with false-positive and false-negative rates of % for outcome. clinical examination was signifi cantly associated with outcome; however, motor response (mr) and brainstem refl exes (brs) yielded higher falsepositive and false-negative rates than plr (table ) . conclusion quantitative plr appears highly accurate and superior to standard neurological examination to predict outcome in patients with post-ca coma. further study is warranted to confi rm these promising fi ndings. acknowledgements supported by grants from the swiss national science foundation (fn _ ) and the european critical care research network (eccrn). figure . mv was associated with a signifi cant reduction of scto from baseline ( % ( to ) to % ( . to . ), p < . ). no signifi cant changes in scto were found after ih ( ( to ) vs. ( to . ), p = . ). conclusion moderate hv was associated with signifi cant reduction in cerebral saturation, whilst ih may be detrimental after ca and th, whilst increasing map to supranormal levels with vasopressors does not improve cerebral oxygenation. these data stress the importance of strict control of paco following ca and th to avoid secondary cerebral ischemic insults. introduction after cardiac arrest, microcirculatory reperfusion dis orders develop despite adequate cerebral perfusion pressure. increased blood viscosity strongly hampers the microcirculation, resulting in plugging of the capillary bed, arteriovenous shunting and diminished tissue perfusion. the aim of the present study was to assess blood viscosity in relation to cerebral blood fl ow in patients after cardiac arrest. methods we performed an observational study in comatose patients after cardiac arrest. patients were treated with hypothermia for hours. blood viscosity was measured ex vivo using a contraves ls viscometer. mean fl ow velocity in the middle cerebral artery (mfvmca) was measured by transcranial doppler (tcd) at the same time points. < . ) . there was a signifi cant association between viscosity and the mfvmca (p = . ). see figure . conclusion viscosity decreases in the fi rst days after cardiac arrest and is strongly associated with an increase in cerebral blood fl ow. since viscosity is a major determinant of cerebral blood fl ow, repeated measurements may guide therapy to help restore cerebral oxygenation after cardiac arrest. in preliminary data, we report that sr > might correlate with bad outcome and that combining nse and sr might improve the predictive value. also, low nse and good initial bis values correlate with preserved cerebral potential and should encourage the clinician. introduction accurate prediction of neurological outcome after cardiac arrest is desirable to prevent inappropriate withdrawal of lifesustaining therapy in patients who could have a good neurological outcome, and to limit active treatment in patients whose ultimate neurological outcomes are poor. established guidelines to predict neurological outcome after cardiac arrest were developed before the widespread use of therapeutic hypothermia. the american association of neurology guidelines [ ] currently recommend that absent or extensor motor scores on day post arrest are reliable indicators or poor neurological outcome with a false positive rate of to %. methods a review of existing literature was undertaken to examine whether the utility of motor scores to predict poor neurological outcome is infl uenced by the use of therapeutic hypothermia. results six studies were identifi ed [ ] [ ] [ ] [ ] [ ] [ ] that investigated the use of motor scores on day post cardiac arrest in patients who had received therapeutic hypothermia. false positive rates (defi ned as -specifi city) for predicting poor neurological outcome were calculable in fi ve of the six studies [ ] [ ] [ ] [ ] [ ] and were %, %, %, % and % respectively. in all studies the fpr for motor scores of extension or worse were signifi cantly higher than the % ( to % % cis) in the aan guidelines. conclusion motor scores at day post cardiac arrest of extension or worse do not reliably predict poor neurological outcome when therapeutic hypothermia has been used. clinical neurological fi ndings may not be valid predictors of poor neurological outcome after therapeutic hypothermia. introduction it has been reported that the young are much more resistant to transient cerebral ischemia than the adult. methods in the present study, we compared the chronological changes of calcium binding proteins (cbps) (calbindin k (cb-d k), calretinin (cr) and parvalbumin (pv)) immunoreactivities and levels in the hippocampal ca region of the young gerbil with those in the adult following minutes of transient cerebral ischemia induced by the occlusion of both the common carotid arteries. in the present study, we examined that about % of ca pyramidal cells in the adult gerbil hippocampus died at days post ischemia; however, in the young hippocampus, about % of them died at days post ischemia. we compared immunoreactivities and levels of cbps, such as cb-d k, cr and pv. the immunoreactivities and protein levels of all the cbps in the young sham were higher than those in the adult sham. in the adult, the immunoreactivities and protein levels of all the cbps were markedly decreased at days post ischemia; however, in the young, they were apparently maintained. at days post ischemia, they were decreased in the young; however, they were much higher than those in the adult. conclusion in brief, the immunoreactivities and levels of cbps were not decreased in the ischemic ca region of the young days after transient cerebral ischemia. this fi nding indicates that the longer maintenance of cbps may contribute to a less and more delayed neuronal death/ damage in the young. delay in reaching target temperature [ ] . we hypothesize that early and rapid induction of hypothermia will mitigate neuronal injury and improve survival in a swine model of tbi. methods twenty domestic cross-bred pigs ( to kg) were subjected to a atm ( ms) lateral fl uid percussion tbi. the brain temperature and icp were measured using camino®. serum biomarkers for neuronal injury -s- β, neuron-specifi c enolase, glial fi brillary acid protein (gfap), and neurofi laments heavy chain -were measured daily using enzyme-linked immunosorbent assay. twelve of the injured animals were rapidly cooled to °c within minutes of the injury using a transpulmonary hypothermia technique [ ] . hypothermia was maintained for hours. eight injured control animals were maintained at °c. in both groups, anesthesia (isofl urane %) was discontinued and the animals were weaned off the ventilator after hours. five days post injury, the surviving animals were euthanized and necropsied. the data were analyzed using a log-rank (mantel-cox) test, and anova. results ten of the hypothermia and four of the eight normothermia animals survived to the end of the -day study (χ = . , df = , p = . ). although the probability of type i error between survival curves was %, the study was clinically signifi cant and showed a clear trend toward improved survival with hypothermia. the intracranial pressures were signifi cantly (p < . ) lower in the hypothermia group. both interventions -that is, general anesthesia and hypothermiamitigated the rise of serum biomarkers following tbi. however, the suppression of biomarkers was sustained during the recovery period only in the hypothermia group. with the exception of the gfap levels, the curves of all biomarkers were signifi cantly diff erent between the groups. conclusion our preliminary fi ndings show early initiation, rapid induction, and prolonged maintenance ( hours) of cerebral hypothermia to lower intracranial pressure, blunt the rise in serum biomarkers, and improve survival following tbi. references introduction traumatic brain injury (tbi) is a contributing factor to approximately one-third of all injury-related deaths in the usa annually. updated statistical records for tbi in egypt are lacking. the current research is aiming to estimate the prevalence of tbi in egypt in order to develop a comprehensive tbi prevention program. methods a -year period (one calendar month every quarter of ) descriptive epidemiological study of moderate and severe tbi cases admitted to the emergency department, cairo main university hospital. the data collection sheet included personal data (age, sex and residency), incident-related data (cause, nature and time of injury) and both clinical and radiological fi ndings. introduction one of the most used prognostic models for traumatic brain injury is the impact-tbi model, which predicts -month mortality and unfavorable outcome. our aim was to study whether adding markers of coagulation improves the model's predictive power when accounting for extracranial injury. methods patients with a tbi admitted to a designated trauma center in / were screened retrospectively and included according to the impact study criteria. the predictive outcome was calculated for included patients using the full impact-tbi model. to assess coagulopathy and extracranial injury we used the prothrombin time percentage (pt), platelet count ( ), and injury severity score (iss introduction evidence suggest that endogenous lactate, produced by aerobic glycolysis, is an important substrate for neurons, particularly in conditions of increased energy demand. this study aimed to examine brain lactate metabolism in patients with severe traumatic brain injury (stbi). methods a prospective cohort of stbi patients monitored with cerebral microdialysis (cmd) and brain tissue oxygen (pbto ) was studied. brain lactate metabolism was assessed by quantifi cation of elevated cmd lactate samples (> mmol/l). these were matched to pyruvate and pbto , and dichotomized as hyperglycolytic (cmd pyruvate > μmol/l) versus nonhyperglycolytic or as hypoxic (pbto < mmhg) versus nonhypoxic. data were expressed as percentages per patient. global brain perfusion (categorized as oligemic, normal or hyperemic) was assessed with ct perfusion (ctp). results twenty-four patients (total , cmd samples) were studied. samples with elevated cmd lactate were frequently observed ( ± % sem of individual samples). brain lactate elevations were predominantly hyperglycolytic ( ± . %), whilst only ± . % of them were hypoxic. trends over time of both lactate patterns are shown in figure . on ctp (n = ; average hours from tbi) hyperglycolytic lactate was always associated with normal or hyperemic ctp, whilst hypoxic lactate was associated with oligemic ctp (table ) . our fi ndings suggest predominant nonischemic lactate release after tbi and identify, for the fi rst time, an association between cerebral hyperglycolytic lactate production and normal to supranormal brain perfusion. our data support the concept that lactate may be used as energy substrate by the injured human brain. in the prehospital setting, it is diffi cult to use the glasgow coma scale (gcs) to evaluate the consciousness state using in pediatric patients with severe trauma. the japan coma scale (jcs) is a consciousness scale used widely in japan and, with its four grades, is simpler and quicker to use than the gcs. this study examined whether our study identifi ed a moderate relation between peep and osnd and a weaker one between ppeak, pm and osnd. thus, in selected cases osnd could serve as a bedside marker of eff ect of airway pressure to icp. yet, larger studies are needed to come to a safer conclusion. reference introduction following primary neurological insult, initial manage ment of traumatic brain-injured (tbi) patients has a clearly defi ned pathway [ ] . however, after arrival at tertiary centers, further manage ment is not standardized. intracranial hypertension (ich), systemic hypotension, hypoxia, hyperpyrexia and hypocapnia have all been shown to independently increase mortality [ ] . despite numerous studies, there is currently no level evidence to support any specifi c management [ ] . our objective was to provide an overview of the current clinical management protocols in the uk. methods thirty-one icus managing patients with severe tbi were identifi ed from the rain (risk adjustment in neurocritical care) study, and a telephone survey was conducted. results a total % of units used a cerebral perfusion pressure protocol for the initial management, with % targeting pressures of to mmhg and % aimed for > mmhg. ninety-one percent of units monitored co routinely with % targeting co of . to kpa (figure ). regarding osmotherapy, mannitol was still the preferred agent, with % of units using it as fi rst line; % used hypertonic saline, while % of units used either depending on clinicians' preference. sixteen percent questioned were currently enrolled on the eurotherm hypothermia trial, while % never used hypothermia and one unit used prophylactic hypothermia routinely. the remaining % of units used hypothermia only to manage refractory ich. conclusion there is no clear consensus on the initial targets used. the surviving sepsis campaign showed that protocol-led care can reduce mortality [ ] . perhaps it is time for a similar approach to be adopted, with specialists coming to together to review the evidence and formulate guidelines that can then be tested. introduction traumatic brain injury (tbi) is a major cause of permanent disability and death in young patients. controversy exists regarding the optimal cerebral perfusion pressure (cpp) required in tbi management. a tool for monitoring autoregulation and determining an optimal cpp is the pressure reactivity index (prx), defi ned as a moving correlation coeffi cient between the mean arterial blood pressure (map) and intracranial pressure (icp) at a frequency of at least hz. this requirement of high frequency has constrained its use to a few academic centers. an association was shown between outcome and continuous optimal cpp based on hours of prx [ ] . we present a novel low-frequency autoregulation index (lax), based on correlations between icp and map at a standard minute-by-minute time resolution. methods a total of patients from the brain-it [ ] multicentre european database had registered outcome and icp and map for the fi rst icu hours. twenty-one tbi patients admitted to the university hospitals of leuven, belgium and tubingen, germany were continuously monitored using icm+ software (cambridge enterprise) allowing for continuous prx calculation. autoregulation indices versus cpp plots for prx and lax were computed to determine optimal cpp every minute during the fi rst icu hours [ ] . results on the brain-it database, lax resulted in an optimal cpp for % of the fi rst hours. table shows recommendations with respect to outcome. in the leuven-tübingen database, prx and lax resulted in % and % recommendations respectively. the average diff erence between methods was . mmhg. conclusion the diff erences in optimal cpps derived from prx and lax were not clinically signifi cant. lax allowed for recommendations to be computed for longer periods. signifi cantly better outcome (table ) was observed in patients for whom optimal cpp derived from lax was maintained. introduction pediatric patients with altered mental status (ams) present with poor histories resulting in delayed testing and potential poor outcomes. non-invasive detection for altered cerebral physiology related to tbi would improve resuscitation and outcome. cerebral rso (r c so ) studies demonstrate its utility in certain neurological emergencies. methods a retrospective analysis of r c so utility in ams. rcso data were collected every seconds for ams patients who had a head ct. patients with a negative head ct were compared with those with an abnormal head ct. roc analysis was performed to fi nd the auc for each summary statistic and performance characteristics. subgroup analysis was done to determine whether r c so predicted injury and location. results r c so readings across , , , and minutes were stable (figure ). r c so readings with one or both sides < % or a wide diff erence between l and r cerebrum was predictive of an abnormal ct scan. a mean diff erence of . was % sensitive for detecting a ct lesion with % specifi city, % ppv, and % npv; a mean diff erence of . was % specifi c for an abnormal head ct. lower mean r c so readings localized to the ct pathology side, and higher r c so readings trend toward the edh group. conclusion cerebral rcso monitoring can non-invasively detect altered cerebral physiology and pathology related to tbi as the cause for pediatric altered mental status. the utility of r c so monitoring has shown its potential for localizing and characterizing intracranial lesions among these altered children. further studies utilizing r c so monitoring as an adjunct tool in pediatric altered mental status evaluation and management are ongoing. introduction fever is a dangerous secondary insult for the injured brain [ ] . we investigated the cerebral and hemodynamic eff ects of intravenous (i.v.) paracetamol administration for the control of fever in neurointensive care unit (nicu) patients. methods the i.v. paracetamol ( g in minutes) was administered to nicu patients with a body temperature (temp.) > . °c. its eff ects on mean arterial pressure (map), heart rate (hr), intracranial pressure (icp), cerebral perfusion pressure (cpp), jugular venous oxygen saturation (sjvo ) and temp. were recorded at the start of paracetamol infusion (t ) and after (t ), (t ) and (t ) minutes. interventions for the maintenance of cpp > mmhg or icp < mmhg were recorded. (figure ). in fi ve cases norepinephrine infusion was started for cpp < mmhg. in another two cases, for the same reason, the norepinephrine dosage was augmented. the proportion of patients who had infusion of norepinephrine increased from . % at t to . % at t (p = . , chi-square for trends). conclusion use of i.v. paracetamol is eff ective in the maintenance of normothermia in acute brain-injured patients. however, adverse hemodynamic eff ects, which could represent a secondary insult for the injured brain, must be rapidly recognized and treated. reference introduction evaluating resource utilization is paramount in critically ill patients with traumatic brain injury (tbi), but little is known on readmissions after hospital discharge. we evaluated rates and determinants of unplanned readmission following tbi. methods we conducted a multicenter retrospective cohort study from april to march . data were obtained from a canadian provincial trauma system, based on mandatory contribution from trauma centres, and a hospital discharge database. patients aged ≥ years with tbi (icd- or icd- codes of - and s , respectively) were included. patients who died during the index hospitalization, who lived outside the province, who could not be linked with the hospital discharge database were excluded. we collected baseline and trauma characteristics, hospital admissions in the months preceding index admission, and readmissions in the following months. primary outcome was unplanned readmission days, months and months post discharge. we evaluated sociodemographic and clinical factors associated with readmissions using a logistic regression model. results among , adult patients with tbi identifi ed in the registry, , patients were included among which , had severe, , moderate and , mild traumatic brain injury. most patients were young (mean age: ± years) and had no comorbidity ( . %). overall, , patients ( . %) were readmitted within days, . % within months and . % within months. at days post discharge, ( . %) were readmitted for a complication. the median length of stay was days (q to q : to ). more than % of patients aged ≥ years with ≥ comorbidity or with ≥ admission prior to index hospitalisation were readmitted. the severity of the tbi was not an independent predictor of readmission. age, highest ais, number of comorbidities, number of admissions prior to index hospitalization, level of index trauma center and discharge destination were associated with readmissions on multivariate analysis. conclusion readmissions in the months following tbi are frequent, but were not found to be associated with the tbi severity. further studies evaluating reasons for readmission are warranted in order to develop strategies to prevent such events. introduction pituitary disorders following traumatic brain injury (tbi) are frequent, but their determinants are poorly understood. we performed a systematic review to assess the risk factors of tbiassociated pituitary disorders. methods we searched medline, embase, scopus, the cochrane library, biosis, and trip database, and references of narrative reviews for cohort, cross-sectional and case-control studies enrolling at least fi ve adults with tbi in whom ≥ pituitary axis was tested and one potential predictor reported. two independent investigators selected citations, extracted data and assessed the risk of bias. we pooled the data from all studies assessing a specifi c predictor, regardless of the pituitary axis being evaluated. when more than one pituitary axis was assessed, we used the data related to hypopituitarism or the data from the most defective axis. when a pituitary axis was evaluated several times, we used assessment farthest from the injury. a meta-analysis was performed using random eff ect models and i was used to evaluate heterogeneity. introduction prevention of secondary neurologic injuries is paramount for improved neurologic outcomes after traumatic brain injury (tbi). evidence suggests that although therapeutic hypothermia (th) lowers intracranial pressure and attenuates secondary cerebral insults after tbi [ ] , it also induces hypotension. brief episodes of mild hypotension in brain-injured patients can trigger secondary injuries, which have been associated with increased mortality in patients with tbi [ ] . vasopressin mitigates hypotension in septic shock and improves coronary perfusion in hypothermic cardiac arrest models [ ] . we hypothesized that a lowdose vasopressin infusion may reduce the cumulative epinephrine dose in hypothermic, brain-injured swine. methods six domestic cross-bred pigs were subjected to epinephrine infusion after general anesthesia, standardized tbi and transpulmonary hypothermia ( °c for hours). all animals received the same care, aiming for a mean arterial pressure > mmhg. at hour , animals received additional vasopressin infusion at . units/minute. we measured the cumulative epinephrine dose for each animal pre and post vasopressin infusion ( figure ) and performed a twosample wilcoxon rank-sum test, comparing the median cumulative epinephrine doses in the two groups. the median cumulative epinephrine dose in the animals that received the vasopressin infusion was mg with a th to th interquartile range (iqr) of to mg. the median cumulative epinephrine dose in the control group was , mg (iqr , to , mg). this was statistically signifi cant (p = . ), based on the wilcoxon rank-sum test. conclusion a low-dose infusion of vasopressin can signifi cantly reduce vasopressor requirements and improves hemodynamics in hypothermic, brain-injured swine. this hemodynamic stability may improve neurological outcomes. introduction severe traumatic brain injury (tbi) is a major cause of death and of severe neurologic sequelae. long-term functional outcome of tbi and its best timing of assessment are not well understood, and may be evaluated too prematurely in clinical studies because of resources required to do so without too much missing data. hence, we conducted a systematic review of studies in severe tbi patients to evaluate the long-term functional outcome. we hypothesized that functional impact measured by the glasgow outcome scale (gos), or the extended version (gose), may plateau after several months in patients with severe tbi. methods we performed a systematic review of randomized controlled trials and cohort studies (prospective and retrospective) in patients with severe tbi. we searched medline, embase, cochrane central, biosis, cinahl and trip database from their inception to december . references of included studies were searched for additional studies. two reviewers independently determined study eligibility and collected data. the primary outcome measure was the proportion of unfavourable functional outcome (gos to or gose to ) at to months, to months, to months and more than months after severe tbi. we calculated freeman tukey-type arcsine squareroot transformations and pooled data using random-eff ect models. heterogeneity was assessed with the i test and sensitivity analyses were based on a priori hypotheses. in total, , studies were assessed for eligibility; studies (n = , ) were included. in the studies using the gos, a poor functional outcome was observed in . % ( % ci = . to . %, i = %), . % ( % ci = . to . %, i = %), . % ( % ci = . to . %, i = %) and . % ( % ci = . to . %, i = %) of patients at to months, to months, to months and beyond months, respectively. in the studies using gose, a poor functional outcome was observed in . % of patients at to months ( % ci = . to . %, i = %) and . % at to months ( % ci = . to . %, i = %). heterogeneity was present in most analyses and was not entirely explained by the planned sensitivity analyses. conclusion considering that the incidence of patients with an unfavourable outcome remained constant at diff erent assessments, a follow-up of severe tbi patients longer than months does not provide incremental information. functional outcomes measured longer than months after the injury may not be warranted in clinical studies. introduction prevention of secondary brain injury is the cornerstone in the management of patients with severe traumatic brain injury (tbi) and raised intracranial pressure (icp). although a variety of monitoring methods are available, due to lack of strong evidence their use varies considerably [ ] . the objective of this survey was to provide an overview of the current practice in monitoring of patients with severe tbi in all neuro-icus across the uk. introduction pulmonary complications are frequently occurring medical complications after aneurysmal subarachnoid hemorrhage (asah) [ ] . early respiratory deterioration (erd) may be associated with delayed cerebral ischemia (dci) or outcome and would then be a potential target for therapeutic interventions. we investigated whether respiratory deterioration within the fi rst hours after admission predicted dci or poor outcome. methods we conducted a retrospective study in consecutively admitted patients with asah, admitted between october and october to the icu of a university hospital. erd was defi ned as increased need for ventilatory support the second or third day after admission (table ) . elective intubation for a surgical procedure was not included as erd. inclusion criteria were availability of detailed information on respiratory status and level of support, admission within hours after hemorrhage and age ≥ years. multivariable survival analysis was used to investigate associations of dci, death and glasgow outcome scale (gos) with erd adjusted for condition on admission, hijdra score, treatment of ruptured aneurysm and pulmonary comorbidity. gos was assessed at to months after the bleed. dci was defi ned as described recently [ ] . results mean age of the patients was . (± . ) and . % was female. a total . % of the patients developed dci. mortality was . %. forty percent of the patients were classifi ed as having erd. erd was not associated with dci (adjusted hr = . ; % ci = . to . ; p = . ). erd showed a trend towards an association with mortality (adjusted hr = . ; % ci = . to . ; p = . ; additionally adjusted for age, and rebleed). a clear association was found between absence of erd and functional outcome with ordinal logistic regression analysis ( . point increase in gos score at to months; % ci = . to . ; p = . ; additionally adjusted for age and rebleed). conclusion erd within hours after admission is associated with increased risk of poor functional outcome after asah, but not dci. further investigations are required to assess whether prevention of erd may improve outcome. introduction elevated intracranial pressure (icp) may have deleterious eff ects on cerebral metabolism and mortality after aneurysmal subarachnoid hemorrhage (sah) [ , ] , but its relevance has not yet been well explored. aims of this study are to track icp changes after sah, to identify clinical factors associated with it and to explore the relationship between icp and outcome. methods a total of consecutive sah patients with icp monitoring were enrolled. episodes of icp > mmhg for at least minutes and the mean icp value for every -hour interval were analyzed. the highest mean icp collected in every patient was identifi ed. icp values were analyzed in relation to clinical and ct fi ndings; -month outcome and icu mortality were also introduced in multivariable logistic models. results eighty-one percent of patients had at least one episode of elevated icp and % had a highest mean icp > mmhg. the number of patients with highest mean icp > mmhg or with episodes of hicp was maximum at day after sah and decreased only after day . neurological status, aneurysmal rebleeding, amount of blood on ct and ct ischemic lesion occurred within hours from sah were signifi cantly related to highest mean icp > mmhg in a multivariable model. patients with highest mean icp > mmhg showed signifi cantly higher mortality in icu. however, icp is not an independent predictor of months unfavorable outcome. conclusion elevated intracranial pressure is a common complication in the fi rst week after sah. it is associated with early brain injury severity and icu mortality. . we systematically reviewed their prevalence, aiming particularly at studies with low risk of bias. methods we searched embase, medline, the cochrane library, trip database, references of included studies and narrative reviews. we included cohort studies, cross-sectional studies and rcts published in any language that tested the integrity of ≥ pituitary axis in adults with asah. studies including more than % of non-aneurismal sah were excluded. studies were considered at low risk of bias if the authors defi ned inclusion/exclusion criteria, avoided voluntary sampling, and tested > % of included patients with proper detailed diagnostic criteria. studies testing all pituitary axes were considered as evaluating hypopituitarism, which was defi ned as the dysfunction of ≥ axis. we used a freeman tukey-type arcsine square-root transformation and pooled prevalences using the dersimonian-laird random-eff ect method. we determined the degree of heterogeneity with i values. results among , citations, we included studies ( , patients). patients were mostly female ( %) aged . ± . . sixteen studies reported the severity of asah, reported the procedure for securing the aneurysm and reported the location of aneurysm. overall, hypopituitarism was observed in . % of patients at shortterm (< months), . % at mid-term ( to months) and . % at long-term (> months) ( table ). there was an insuffi cient number of studies with low risk of bias to perform sensitivity analyses according to study quality. conclusion the exact prevalence of pituitary disorders following asah remains uncertain, mainly due to high heterogeneity and the small number of studies with low risk of bias. however, the prevalence seems to decrease during the recovery phase. the prevalence, risk factors and clinical signifi cance of pituitary disorders in asah will require further rigorous evaluation. is associated with a high morbidity and mortality. although uk anaesthesia guidelines advocate early coiling or clipping of the aneurysm within the fi rst hours of admission for all grades of asah, the optimal timing of treatment and whether this is linked with better neurological long-term outcome are a subject of debate [ ] . we aimed to investigate whether the timing of the occlusion of the aneurysm translates into better outcome. methods a retrospective analysis of prospective collected data in a tertiary neuroscience centre from january to september . all patients were managed according to the local guidelines for the management of asah. outcome was assessed at months using the extended glasgow outcome scale (gose) defi ning good recovery as a gose ≥ and poor outcome as gose ≤ . results a total of patients were included within the study period. three patients were not expected to survive the fi rst hours and were not included in the study. seventeen patients were classifi ed as good grade asah (wfns i to iii) and eight as poor grade (iv to v). twenty-two patients underwent successful coiling while the other three required clipping due to unsuccessful coiling. we did not fi nd any correlation between the timing of coiling/clipping and the -month gose (figure ) . a total % of the patients had a poor -month gose while % had a good long-term functional outcome. the overall mortality rate was %. conclusion overall mortality in patients with asah is low when aneurysm is treated early post rupture of aneurysm. we did not fi nd any correlation between the timing of occlusion of aneurysm and the -month functional outcome. patients underwent neuropsychological evaluation at early (< days, days) and delayed time points ( month, months). patients were tested for language, verbal fl uency, short-term and long-term memory, attention, executive functions, praxis, and neglect. impairments in activities of everyday life were assessed using the activities of daily living scale and the instrumental activities of daily living scale. the sf- was used to assess the quality of life at months. since complications of aneurysm treatment in addition to asah severity may signifi cantly aff ect cognitive status, patients were evaluated according to the world federation of neurological surgeons score after treatment (wfnspt). all wfnspt to patients completed neuropsychological tests at each time point. wfnspt and wfns patients were testable in % and % of the cases respectively at early time points. wfns patients were not testable at any time point. in all testable patients, cognitive functions were severely impaired at early time points. at months in wfns to a good recovery of language defi cits while only a partial recovery of attention, memory and executive functions were observed; at the same time point % of wfns patients became testable, but they had a worse recovery of all cognitive functions. at month after sah less than % of patients return to work, at months approximately %. despite a good recovery of everyday life activities at months, for all patients quality of life was lower than a normal population. conclusion cognitive dysfunction has diff erent time courses after asah: signifi cant defi cits in diff erent cognitive domains, worse quality of life and diffi culties in return to work persist in more than % of patients at months following sah. results pretreatment with mg/kg, but not mg/kg, of asa-da protected against ischemic neuronal death and damage, and its neuroprotective eff ect was much more pronounced than that of asa or da alone. in addition, treatment with mg/kg asa-da reduced the ischemia-induced activation of astrocytes and microglia. conclusion our fi ndings indicate that asa-da, a new synthetic drug, prevents against transient focal cerebral ischemia, which provides a resource for the development of its clinical application for stroke. introduction acute neurological injury is a leading cause of morbidity and mortality in children. global prevalence and regional disparities of etiology, interventions, and outcomes are unknown. the aim of this point-prevalence study was to measure the burden of pediatric neurological injury and to describe variations in interventions and outcomes in icus. methods one hundred and three icus on six continents enrolled subjects on specifi c days in a -year period. included subjects were between ages days and years who were diagnosed with acute traumatic brain injury, stroke, cardiac arrest, central nervous system infection or infl ammation, status epilepticus, spinal cord lesion, hydrocephalus, or brain mass. sites completed a secure web-based case report form that included subject and hospital demographics, details about the neurological disease, interventions, length of stay, and pediatric cerebral performance category (pcpc) score (good outcome = pcpc to ) and mortality at hospital discharge. results of , subjects screened, , ( %) met enrollment criteria. the mean number of subjects enrolled per site for each study day was . . most sites were dedicated pediatric icus with a mean number of icu beds (range to ). icus had resources to invasively monitor intracranial pressure ( %), continuous electroencephalography ( %), invasive and non-invasive brain tissue oxygenation ( % and %), and somatosensory evoked potentials ( %). there were on average icu faculty and six fellows per site, and nearly one-half reported a neurocritical care icu team. subjects were % male and % white, and % had normal pre-admission pcpc scores ( %). status epilepticus and cardiac arrest (both %) had the highest prevalence. sixty-one per cent of subjects were mechanically ventilated during icu admission. icu length of stay was a mean days (median days) and hospital los was a mean days (median days). survival at hospital discharge was % with % of subjects discharged home and % to inpatient rehabilitation. conclusion acute neurological disease is a signifi cant pediatric health issue. these data suggest a vital need for increased research and healthcare resources to assist in the challenge of improving outcomes for these children. the newly approved oral anticoagulant dabigatran has no eff ective antidote. we therefore suspected an overall increase in mortality in patients presenting to the emergency department (ed) with a bleeding complication on dabigatran compared with warfarin or aspirin. methods we conducted a post hoc analysis on a database of all patients admitted to a tertiary-care ed with any kind of bleeding or suspicion of one from march to august who were taking dabigatran, warfarin, or aspirin. the primary endpoint was long-term survival. patients were censored at death or at the end of the study period ( december ). we performed a cox proportional hazard model, controlled for age, to calculate the hazard ratio (hr) for dabigatran versus warfarin and one for warfarin versus aspirin. statistical signifi cance was set at α = . and results are presented with % ci. results in total, patients met the inclusion criteria with a mean follow-up period of year. the mean age was . years and . % were men. a total of deaths ( . %) were recorded within the follow-up period; eight ( %) for dabigatran compared with ( . %) for warfarin and ( . %) for aspirin. the mortality risk for patients on dabigatran was signifi cantly higher than for patients on warfarin: hr = . ( % ci: . to . ), p = . after controlling for age. aspirin had a lower (but not statistically signifi cant) mortality risk compared with warfarin; hr = . ( % ci: . to . ), p = . after controlling for age. the results showed higher overall mortality in patients who presented to the ed with a bleeding complication and were taking dabigatran compared with warfarin or aspirin. physicians should be aware of the potential higher mortality with dabigatran over warfarin when treating a bleeding patient. however, this was a singlecentre retrospective analysis with a small number of patients taking dabigatran (n = ), and further studies are needed to corroborate the results. introduction dose adjustments of low molecular weight heparin (lmwh) based on daily anti-xa measurement by chromogenic assay remain controversial in daily clinical practice. one of the major obstacles is the cost of such a test. an aff ordable and reliable bedside test could change practice to an individual tailored dosing of lmwh. the aim of our study was to evaluate whether a prophylactic dose regimen of mg enoxaparine in cardiac surgical patients increases the anti-xa activity to the level necessary for effi cient prevention of a thromboembolic event [ ] . secondarily we tested whether there was a reliable correlation between a bedside anti-xa measurement compared with a two-stage chromogenic assay at the laboratory [ ] . this was an open, single-centre, prospective, nonrandomized clinical trial at a university hospital. all patients that needed prophylactic dosing of enoxaparine after cardiac surgery were duly informed and after giving written consent we included patients with a mean euroscore of . . the demographic specifi cations, medical and surgical history of all patients were collected. anti-xa activity was measured at three diff erent points in time. we determined baseline, peak and trough anti-xa activity: preoperatively, and respectively hours after the third dose of enoxaparine and minutes before the fourth dose. each measurement was done with both techniques, the two-stage chromogenic assay at the laboratory (biophen®) and the bedside assay (hemochron® jr). results our dose regimen of enoxaparine achieved in one-half of the included patients a suffi cient anti-xa activity for prevention of thromboembolic events. one-half of the patients with insuffi cient anti-xa activity had a body mass index over kg/m . comparison of the bedside assay with the two-stage chromogenic assay by means of the pearson's correlation coeffi cient showed correlation of the two tests if no variables were taken into account. in the bland-altman analysis we could not confi rm this correlation. conclusion the bedside anti-xa activity assay with a hemochron device tends to show some correlation with the two-stage chromogenic assay, but insuffi cient to be used as an alternative, in this small but uniform patient population. use of a standard dosing protocol for enoxaparine administration is prone for underdosage in post-cardiac surgery patients and may increase postoperative morbidity. references introduction we hypothesized that higher doses of enoxaparin would improve thromboprophylaxis without increasing the risk of bleeding. critically ill patients are predisposed to venous thromboembolism, leading to increased risk of adverse outcome [ ] . peak anti-factor xa (anti-xa) levels of . to . iu/ml, hours post administration of enoxaparin, refl ect adequate thromboprophylaxis for medico-surgical patients. methods the sample population consisted of patients, randomized to receive subcutaneous (s.c.) enoxaparin: mg × (control group), versus mg × , mg × or mg/kg × (test groups) for a period of days. anti-xa activity was measured at baseline, and at , , and hours post administration on each day. patients did not diff er signifi cantly between groups. results on day of administration, doses of mg × and mg × yielded similar mean peak anti-xa of . iu/ml and . iu/ml respectively, while a dose of mg × resulted in subtherapeutic levels of anti-xa ( . iu/ml). patients receiving mg/kg enoxaparin achieved near-steady-state levels from day with mean peak anti-xa levels of . iu/ml. steady-state anti-xa was achieved for all doses of enoxaparin at day . at steady state, mean peak anti-xa levels of . iu/ ml and . iu/ml were achieved with doses of mg × and mg × respectively. this increased signifi cantly to . iu/ml and . iu/ml for doses of mg × and mg/kg enoxaparin respectively (p = . ) (figure ) . a dose of mg/kg enoxaparin yielded therapeutic anti-xa levels for over % of the study period. there were no adverse eff ects. introduction unfractionated heparin is preferred over lmwh in icu patients but lmwh is used more frequently in many european icus. thromboprophylaxis with standard doses of nadroparin and enoxaparin has been shown to result in signifi cantly lower anti-xa in icu patients when compared with medical patients [ , ] . methods icu patients (saps ± , mv, n = ; pressors n = ) received , iu (group , n = ) or , iu dalteparin s.c. (group , n = ). twenty-nine medical patients receiving , iu dalteparin served as controls (group ). results group had signifi cantly lower areas under the xa curve (auc) compared with groups and (table ) . diff erences were not signifi cant between groups and . peak anti-xa activities (c max -anti-xa) were delayed (t max -anti-xa) in group compared with groups and (table ) . conclusion in icu patients a s.c. dose of , iu dalteparin results in signifi cantly lower xa activities when compared with normal ward patients. a s.c. dose of , iu dalteparin in icu patients resulted in kinetics and peak anti-xa activities comparable with medical patients receiving , iu dalteparin. introduction anemia is very frequently encountered on the icu. increased hepcidin production is one of the cornerstones of the pathophysiology of anemia of infl ammation. the fi rst-in-class hepcidin antagonist nox-h , a pegylated anti-hepcidin l-rna oligonucleotide, is in development for targeted treatment of anemia of infl ammation. we investigated whether nox-h prevents the infl ammation-induced serum iron decrease during experimental human endotoxemia. methods a randomized, double-blind, placebo-controlled trial in healthy young men. at t = hours, ng/kg e. coli endotoxin was administered intravenously (i.v.), followed by . mg/kg nox-h or placebo i.v. at t = . hours. blood was drawn serially after endotoxin administration for measurements of infl ammatory parameters, cytokines, nox-h pharmacokinetics, total hepcidin- , and iron parameters. the diff erence of serum iron change from baseline at t = hours was defi ned as the primary endpoint. results endotoxin administration led to fl u-like symptoms. infl ammatory parameters (crp, body temperature, leucocytes, and plasma levels of tnfα, il- , il- , and il- ra) peaked markedly and similarly in both treatment groups. nox-h was well tolerated. plasma concentrations peaked at . ± . hours after the start of administration, after which they declined according to a two-compartment model, with a t / of . ± . hours. in the placebo group, serum iron increased from . ± . μg/l at baseline to a peak at t = hours, returned close to baseline at t = hours and decreased under the baseline concentration at t = hours, reaching its lowest point at t = hours. in the nox-h group, serum iron concentrations rose until t = hours and then slowly declined until t = hours. from to hours post lps, the serum iron concentrations in nox-h -treated subjects were signifi cantly higher than in placebo-treated subjects (p < . , ancova). conclusion experimental human endotoxemia induces a robust infl am matory response and a subsequent decrease in serum iron. treatment with nox-h had no eff ect on innate immunity, but eff ectively prevented the infl ammation-induced drop in serum iron concentrations. these fi ndings demonstrate the clinical potential of the anti-hepcidin drug nox-h for further development to treat patients with anemia of infl ammation. the association between haemoglobin concentrations and mortality has been studied in patients with various comorbidities [ , ] . this study aims to determine the association between haemoglobin levels on admission to intensive care and patient length of stay and mortality. methods a retrospective collection of data from patient admissions to a single fi ve-bed icu over a -year period identifi ed , patients between april and november . patients were split into groups according to haemoglobin concentration on admission. the data were analysed to determine whether there was any relationship between haemoglobin concentration at icu admission and any of our outcome measures (unit and hospital mortality, unit and hospital length of stay). results patients with haemoglobin concentrations ≤ g/dl and > . g/dl were used in mortality comparisons. patients with a haemo globin concentration ≤ g/dl had an increase in icu mortality compared with those with haemoglobin levels > g/dl (or = . , % ci = . to . , p < . ). a similar diff erence was seen with hospital mortality (≤ g/dl . % vs. > g/dl . %, p < . ). unit length of stay was signifi cantly longer in patients with admission hb ≤ g/ dl ( . days) compared with an admission hb > g/dl ( . days), p < . . hospital length of stay was also signifi cantly longer in patients with hb ≤ g/dl versus hb > g/dl ( . days vs. . days, p < . ). there was seen to be an inverse correlation between haemoglobin concentration and patient age (r = - . ; p < . ). conclusion haemoglobin concentrations ≤ g/dl on admission to the icu are associated with an increase in icu mortality, hospital mortality, unit length of stay and hospital length of stay when compared with patients admitted with haemoglobin concentrations > g/dl. introduction according to many authors, acute necrotizing pancreatitis (anp) still remains one of the diffi cult problems of abdominal surgery. the complexity of the pathogenesis of the disease, features of the pancreas pathomorphology, abdominal hypertension, and high mortality ( to %) necessitate a search for new ways to treat this disease. the study was conducted in patients with anp, who were divided into two groups according to type of analgesia: epidural or opioids. patients from the fi rst group (n = ) had epidural analgesia by ropivacaine to mg/hour during to days, and from the second group (n = ) opioid analgesia by trimeperidine mg three times a day during the same period. we monitored the level of septic and thrombohemorrhagic complications by clinical and instrumental data, during the month after treatment starting. the hemostatic system was evaluated using indicators of hemoviscoelastography (mednord- m analyzer). results it was found that all patients with anp initially have hypercoagulation and fi brinolysis inhibition. levels of hemostatic disorders correlate with the level of septic complications, treatment in the icu, and mortality. in the fi rst group we noted a deep vein thrombosis, two pneumonia, seven pseudopancreatic cysts and abscesses, two deaths and time of stay in the icu as . days. in the second group: three cases of deep vein thrombosis, four pneumonia, pseudopancreatic cysts and abscesses, two episodes of gastroduodenal bleeding, fi ve deaths and time of stay in the icu as . days. conclusion using epidural anesthesia in patients with anp reduced the number of septic complications on . %, and reduced the mortality rate from . % (second group) to . % (fi rst group). we think that violations of blood coagulation and microcirculation are the basis for ischemia, necrosis in tissues and septic complications. epidural analgesia is an eff ective method to decrease the level of septic and thrombohemorrhagic complications and mortality in anp patients. methods after ethics approval and informed consent, we studied the functional state of hemostasis in a group of healthy volunteers, who were not receiving drugs aff ecting coagulation, and patients with postphlebothrombotic syndrome (ppts). in the ppts patients we conducted baseline studies of coagulation state and daily monitoring of dynamic changes in the functional state of hemostasis, a comparative evaluation of performance low-frequency piezoelectric vibration hemoviscoelastography (lpvh) and platelet aggregation test (pat), standard coagulation tests (sct), and thromboelastogram (teg). we found that lpvh correlated with sct, pat and teg. however, our proposed method is more voluminous: indexes icc (the intensity of the contact phase of coagulation), t (the time for the contact phase of coagulation), and ao (initial rate of aggregation of blood) are consistent with pat; indexes icd (the intensity of coagulation drive), cta (a constant thrombin activity) and cp (the clot intensity of the polymerization) are consistent with sct and teg. in addition, the advantage of this method is to determine the intensity of fi brinolysiswith the indicator iris (the intensity of the retraction and clot lysis). conclusion lpvh allows one to make a total assessment of all parts of hemostasis: from initial viscosity and platelet aggregation to coagulation and lysis of clots, as well as their interaction. these fi gures are objective and informative, as evidenced by close correlation with the performance of traditional coagulation methods. prophylaxis in orthopedics or in cases of acute coronary syndromes. the main drawback of fond is that routine monitoring is not currently available. this could be a problem during the management of critical and surgical patients, especially in cases of old patients and renal failure. the aim of this study is to evaluate the ability of thromboelastography (teg) to determine the level of anticoagulation due to fond in a surgical population. we prospectively analyzed all patients to whom elective major orthopedic surgery was consecutively performed in a -month period. all the patients received fond . mg in the postoperative period according to accp guidelines. native and heparinase (hep) teg (haemoscope corporation, niles, il, usa) tests activated with kaolin were performed using whole blood citrated samples at four times: t , before fond administration; t , hours after administration; t , hours after administration (half-life); t , hours after administration. the following native and hep teg parameters were analyzed: reaction time (r), α angle, maximum amplitude (ma) and coagulation index (ci). these parameters were compared with levels of anti-xa. unvariate analysis and spearman's test were applied to our data. results eighteen patients were analyzed. ten patients met the inclusion criteria. the mean r value increased from t to t . the mean r parameter was in the normal range at any phase of the study and there was no signifi cant diff erences between the r mean value at the diff erent phases. the lowest value of r was at t , which coincides with plasmatic peak concentration of fond. this value did not correlate with anti-xa mean value at t , which showed the highest value at that time. there was signifi cant diff erence between the mean native and hep r value only at t (p < . ), native and hep α angle at t , ma and ma hep at t (p < . ) and ci and ci hep at t (p < . ). only the parameter ma had signifi cant variation over time (p < . ). conclusion r represents the time necessary to thrombin formation and in the presence of fond we hypothesized a prolonged r time. in our population, teg performed with citrated kaolin-activated whole blood was not able to detect prophylatic doses of fond in every phase. on the contrary, levels of anti-xa were able to reveal the exact pharmacokinetics of the drug. further studies including a large number of patients are necessary. introduction coagulopathy, particularly a trend toward hypercoagula bility and hypofi brinolysis, is common in critically ill patients and correlates with worse outcome. available laboratory coagulation tests to assess fi brinolysis are expensive and time demanding. we investigated whether a modifi ed thromboelastography with the plasminogen activator urokinase (ukif-teg) [ ] may be able to evaluate fi brinolysis in a population of critically ill patients. methods ukif-teg was performed as follows: fi rst urokinase was added to citrate blood to give fi nal concentrations of ui/ml, then thromboelastography (teg) analysis was started after kaolin activation and recalcifi cation with calcium chloride. basal teg (no addition of urokinase) was also performed. fibrinolysis was determined by the loss of clot strength after the maximal amplitude (ma), and recorded as ly (percentage lysis at minutes after ma) and as ly (percentage lysis at minutes after ma). results ukif-teg was performed on healthy volunteers and critically ill patients. ly was predicted by ly according to an exponential function, so we used ly as an indicator of clot lysis. basal teg showed increased coagulability and a trend toward less fi brinolysis in critically ill patients compared with healthy volunteers (reaction time . ± . minutes vs. . ± . minutes, p < . ; α-angle . ± . vs. . ± . , p < . ). this reduction of fi brinolysis was more evident at a urokinase concentration of ui/ml (figure ). conclusion ukif-teg could be a feasible point-of-care method to evaluate fi brinolysis in critically ill patients. methods we performed a randomized, double-blind study in patients who underwent cesarean section. patients were divided into two groups: the fi rst group (n = ) received preoperative ( minutes before operation) tranexamic acid mg/kg; the second group (n = ) received preoperative placebo. the condition of hemostasis was monitored by haemoviscoelastography. results all patients included in the study before surgery had moderate hypercoagulation and normal fi brinolysis: increasing the intensity of clot formation (icf) to . % compared with normal rates; the intensity of the retraction and clot lysis (ircl) was . ± . in both groups. at the start of the operation in patients (group ), icf decreased by . % (p < . ), and ircl decreased by . % (p < . ) compared with preoperatively. in group , there was icf decrease by . % (p < . ), and ircl increase by . % (p < . ) compared with preoperatively. at the end of the operation, the condition of hemostasis in both groups came almost to the same value -moderate hypocoagulation, depressed fi brinolysis. in both groups there were no thrombotic complications. intraoperative blood loss in the fi rst group was ± . and in the second was ± . . conclusion using of tranexamic acid before surgery signifi cantly reduces intraoperative blood loss by %, without thrombotic complications. introduction rotational thromboelastography (rotem) can detect dilutive and hypothermic eff ects on coagulation and evaluate corrective treatments. the aim of this in vitro study was to study whether fi brinogen concentrate alone or combined with factor xiii could reverse colloid-induced and crystalloid-induced coagulopathies in the presence and absence of hypothermia. methods citrated venous blood from healthy volunteers was diluted by % using / . hydroxyethyl starch or ringer's acetate. rotem was used to evaluate the eff ect of addition of either fi brinogen concentrate corresponding to g/ kg, or this fi brinogen dose combined with factor xiii equivalent to iu/kg. blood was analyzed at or °c with rotem extem and fibtem reagents. results a signifi cant dilutive response was shown in both groups: hypocoagulation was greater in the starch group. hypothermia lengthened the following: extem clotting time (ct), clot formation time and α angle; fibtem maximal clot formation (mcf). irrespective of temperature, fi brinogen overcorrected ringer's acetate's eff ects on all rotem parameters and partially reversed starch's eff ects on extem ct and fibtem mcf. fibtem demonstrated that factor xiii provided an additional procoagulative eff ect in the ringer's acetate group at both temperatures but not the starch group. the only extem parameter to be improved by addition of factor xiii was mcf at °c. conclusion rotem shows that fi brinogen concentrate can reverse dilutive coagulation defects induced by colloid and crystalloid at both and °c. some additional reversal was provided by factor xiii: higher doses of both fi brinogen and factor xiii may counteract starch's eff ects on clot structure. introduction natural colloid albumin induces a lesser degree of dilutional coagulopathy than synthetic colloids. fibrinogen concentrate has emerged as a promising strategy to treat coagulopathy, and factor xiii (fxiii) works synergistically with fi brinogen to correct coagulopathy following haemodilution with crystalloids. objectives were to examine the ability of fi brinogen and fxiii concentrates to reverse albumininduced dilutional coagulopathy. high and low concentrations of both fi brinogen and fxiii were used to reverse coagulopathy induced by : dilution in vitro with % albumin of blood samples from healthy volunteers, monitored by rotational thromboelastometry (rotem). results haemodilution with albumin signifi cantly attenuated extem maximum clot fi rmness (mcf), α angle (aa), clotting time (ct) and clot formation time (cft), and fibtem mcf (p < . ). following haemodilution, both doses of fi brinogen signifi cantly corrected all rotem parameters (p ≤ . ), except the lower dose did not correct aa. compared with the lower dose, the higher dose of fi brinogen signifi cantly improved fibtem mcf and extem mcf, aa and cft (p < . ). the lower dose of fxiii did not signifi cantly correct any of the rotem parameters, and the high dose only improved extem ct (p = . ). all combinations of high/low concentrations of fi brinogen/ fxiii signifi cantly improved all rotem parameters examined (p ≤ . ). fibrinogen concentration generally had a greater eff ect on each parameter than did fxiii concentration; the best correction of rotem parameters was achieved with high-dose fi brinogen concentrate and either low-dose or high-dose fxiii. conclusion fibrinogen concentrate successfully corrected initiation, propagation and clot fi rmness defi cits induced by haemodilution with albumin, and fxiii synergistically improved fi brin-based clot strength. results iocs was used in severe pphs and severe pph controls were managed without iocs. placenta accreta can be selected as the best indication for rbc restitution. in the , to , ml pph, allogeneic transfusion was decreased in the iocs group: . versus . % (p = . ); prbc: ( to ) versus ( to ) (p = . ). iocs spared blood bank prbc ( , ml); that is, . % of the total transfusion need. no amniotic fl uid embolism has been observed in the group with iocs whereas one case appeared in the control group without iocs. conclusion regarding the literature [ ] [ ] [ ] [ ] and our study, iocs could be used safely in pph during cs. a leukocyte fi lter for retransfusion has been recommended and rhesus isoimmunization must be precluded and monitored by repeated fetal rbc testing. bleeding with the use of a protamine infusion and an abolishment of heparin rebound [ ] . the aim of this study was to see whether the use of postoperative protamine infusions in our cardiac itu was associated with a reduction in heparin rebound and blood loss. methods data from cardiac surgery patients were retrospectively analysed. of these, had routine management with a bolus of protamine to correct the activated clotting time and then expectant management of subsequent bleeding, and had the same but also a protamine infusion of to mg/hour for between and hours postoperatively. blood loss was measured at , , and hours. in all, excessive bleeding was investigated using thromboelastography (teg). rebound heparinisation was determined by a ratio of r-times (heparinase/plain) < . . the mann-whitney u test and the chi-squared test were used to assess statistical signifi cance. results there was no signifi cant diff erence in blood loss between the two groups. blood loss at hour in the infusion and non-infusion group was and ml, respectively (p = . ); at hours: and ml (p = . ); at hours: and ml (p = . ); and at hours: and ml (p = . ). there was also no signifi cant diff erence in those getting heparin rebound with % in the infusion group and % in the non-infusion group (p = . ). conclusion unlike teoh and colleagues [ ] , we did not fi nd an advantage in using protamine infusions. that there were still cases of heparin rebound in the infusion group suggests that the infusion was not as eff ective as expected and/or the dose was inadequate. however, previous studies assessed heparin rebound using isolated clotting parameters [ , ] . here, we used teg. as teg measures the thrombodynamic properties of whole blood coagulation, perhaps it is a more reliable indicator of heparin activity? as a retrospective study, there are limitations; namely, the nonstandardised management of the patients and the potential bias in the anaesthetists' selection of patients for an infusion. this group may be inherently higher risk for bleeding. however, heparin rebound is common and protamine is a simple, relatively safe and low-cost intervention compared with transfusion and so further study is needed. introduction the purpose of this study was to evaluate whether a restrictive strategy of red blood cell (rbc) transfusion was superior to a liberal one for reducing mortality and severe clinical complications among patients undergoing major cancer surgery. methods the trial was designed as a phase iii, randomized, controlled, parallel-group, superiority trial. the inclusion criteria were adult patients with cancer who were undergoing major abdominal surgery requiring postoperative care in an icu. the patients were randomly allocated to treatment with either a liberal rbc transfusion strategy (transfusion when hemoglobin levels decreased below g/dl) or a restrictive rbc transfusion strategy (transfusion when hemoglobin levels decreased below g/dl). the primary outcome was a composite endpoint of death or severe complications. the patients were monitored for days. results a total of , patients were screened for eligibility and met the inclusion criteria. after exclusions for medical reasons or a lack of consent, patients were included in fi nal analysis, with allocated to the restrictive group and to the liberal group. the primary composite endpoint -all-cause mortality, cardiovascular complications, acute respiratory distress syndrome, acute kidney injury requiring renal replacement therapy, septic shock or reoperation at days -occurred in . % of the patients in the liberal strategy group and in . % in the restrictive group (p = . ). the liberal strategy group had a signifi cantly lower -day mortality rate as compared with the restrictive group ( . % ( % ci, . to . %) vs. . % ( % ci, . to . %), respectively, p = . ). the occurrence of cardiovascular complications was lower in the liberal group than in the restrictive group ( . % ( % ci, . to . %) vs. . % ( % ci, . to . %), respectively, p = . ). the restrictive strategy group had a higher day mortality rate as compared with the liberal group ( . % ( % ci, . to . %) vs. . % ( % ci, . to . %), respectively, p = . ). conclusion the liberal rbc transfusion strategy with a hemoglobin trigger of g/dl was associated with fewer major postoperative complications in patients undergoing major cancer surgery compared with the restrictive strategy. introduction red blood cell (rbc) transfusion is associated with morbidity and mortality in critically ill patients. congenital cardiac surgeries are associated with high rates of bleeding and consequently with high rates of allogeneic transfusion. we aimed to evaluate the association of transfusion with worse outcomes in children undergoing cardiac surgery. methods we performed a prospective cohort study of patients undergoing cardiac surgery for congenital heart disease. we recorded baseline characteristics, rachs- score, intraoperative data, transfusion requirement and severe postoperative complications as need for reoperation, acute kidney injury, arrhythmia, severe sepsis, septic shock, bleeding, stroke, and death during days. we performed univariate analysis using baseline, intraoperative and postoperative variables. selected variables (p < . ) were included in a forward stepwise multiple logistic regression model to identify predictive factors of a combined endpoint including -day mortality and severe complications. results one hundred and thirty-six patients ( . %) were exposed to rbc transfusion. in the intraoperative room, . % of patients received at least one rbc unit, and in the icu, . % of children were transfused. from all patients, ( . %) presented the combined endpoint. patients with complications had higher rachs- score, were younger ( months ( to ) vs. months ( to ), p < . ), had a lower weight ( kg ( to ) vs. kg ( to ), p < . ), a longer time of surgery ( minutes ( to ) vs. ( to ), p < . ), a longer duration of cardiopulmonary bypass ( minutes ( to ) vs. minutes ( to ), p = . ), a lower svo at the end of surgery ( % (iqr to ) vs. % ( to ), p < . ), a higher arterial lactate at the end of surgery ( . mmol/l ( . to . ) vs. . mmol/l ( to ), p = . ), a lower intraoperative hematocrit ( . ± . % vs. . ± % (p < . )) and a lower hematocrit at the end of surgery ( . ± . % vs. . ± . % (p < . )) as compared with patients without complications. patients with complications were more exposed to rbc transfusion in the intraoperative room ( % vs. %, p = . ) and in the icu ( % vs. . %, p = . ). in an adjusted model of logistic regression, rbc transfusion is an independent risk factor of combined endpoint (or . ( % ci, . to . ), p = . ). conclusion blood transfusion after pediatric cardiac surgery is a risk factor for worse outcome including -day mortality. avoiding blood transfusion must be a goal of best postoperative care. introduction we do not have enough criteria to make a judgment of the need for a massive transfusion (mt) in severe blunt traumatic patients. as a scoring system to predict the need for a mt, we usually use the assessment blood consumption score (abcs) and/or the trauma-associated severe hemorrhage score (tashs). however, for these scoring systems, the procedure is slightly complicated. the aim of this study was to establish a predictor of a mt using coagulation or fi brinolysis markers. methods a retrospective analysis of mt was conducted in patients with severe blunt traumatic injury, which was defi ned as injury severity score (iss) of or more admitted to the icu between june and december . blood samples were collected from patients immediately after arriving at our level i trauma center. we defi ned the patients who received more than unit packed red blood cells (prbcs) within the fi rst hours as a mt group and who received less than units prbcs as a non-mt group. after the demographic data, number of units of prbcs and the need for massive transfusions were recorded and analyzed in each groups, we compared data between two groups. results there were patients who met the inclusion criteria. fifty patients received blood transfusions ( . %; / ). there were patients in the mt group ( . %; / ) and in the non-mt group. the mt group was signifi cantly higher in the ratio of females (p < . ), iss (p < . ), pt-inr (p < . ), aptt (p < . ), abcs (p < . ) and tashs (p < . ) than in the on-mt group. on the other hand, the mt group was signifi cantly lower in ps (p < . ) and fi brinogen level (p < . ) than the non-mt group. in the receiver operating characteristics (roc) analysis, the area under the curve (auc) to distinguish a mt was the highest for tashs ( . , p < . ), followed by fi brinogen ( . , p < . ), and abcs ( . , p < . ). fibrinogen was only a predictor of a mt without a scoring system such as abcs and tashs, and the optimal cutoff value was mg/dl. conclusion we found that the level of fi brinogen was the most valuable predictor of a mt in the coagulation or fi brinolysis markers. it is certain that the level of fi brinogen at admission was not as useful as the tashs about predicting a mt in this study. whereas the scoring systems require the assessment of several factors, the measurement of fi brinogen is simple, easy and quick. we strongly suggest that the level of fi brinogen will be a useful predictor of a mt at in severe blunt traumatic patients. introduction red blood cell (rbc) transfusions are frequent in critically ill children. their benefi ts are clear in several situations. however, issues surrounding their safety have emerged in the past decades. it is important to identify the potential complications associated with rbc transfusions, in order to evaluate their risk-benefi t ratio better. methods a single-center prospective observational study of all children admitted to the pediatric intensive care unit (picu) over a -year period. the variables possibly related to rbc transfusions were identifi ed before the study was initiated, and their presence was assessed daily for each child. in transfused cases (tcs), a variable was considered as a possible outcome related to the transfusion only if it was observed after the fi rst transfusion. results during the study period, admissions were documented, of which were included in the study. among them, ( %) were transfused. when comparing tcs with nontransfused cases (ntcs), the odds ratio (or) of new or progressive multiple organ dysfunction syndrome (npmods) was . ( % ci = . to . , p < . ). this association remained statistically signifi cant in the multivariate analysis for children with admission prism score ≤ (or = . , % ci = . to . , p = . ). tcs were ventilated longer than ntcs ( . ± . days vs. . ± . days, p < . ). this diff erence was still signifi cant after adjustment using a cox model. moreover, we observed an adjusted dose-eff ect relationship between rbc transfusions and length of mechanical ventilation. the picu length of stay was signifi cantly increased for tcs ( . ± . days vs. . ± . days, p < . ), even after multivariate adjustment (hazard ratio of picu discharge for tcs: . , % ci = . to . , p < . ). we also observed an adjusted dose-eff ect relationship between rbc transfusions and picu length of stay. the paired analysis for comparison of pre-transfusion and posttransfusion values showed that the arterial partial pressure in oxygen was signifi cantly reduced after the fi rst transfusion (mean diff erence . mmhg, % ci = . to . , p < . ). the paired analysis also showed an increased proportion of renal replacement therapy, while the proportions of sepsis, severe sepsis and septic shock did not diff er. conclusion rbc transfusions were associated with prolonged mechanical ventilation and prolonged picu stay. the risk of npmods was increased in some transfused children. moreover, our study questions the ability of stored rbcs to improve oxygenation in critically ill children. these results should help to improve transfusion practice in the picu. introduction microcirculatory alterations during sepsis impair tissue oxygenation, which may be further worsened by anemia. blood transfusions proved not to restore o delivery during sepsis [ ] . the impact of storage lesions and/or leukocyte-derived mediators in red blood cell (rbc) units has not yet been clarifi ed [ ] . we compared the eff ects of leukoreduced (lr) versus nonlr packed rbcs on microcirculation and tissue oxygenation during sepsis. methods a prospective randomized study. twenty patients with either sepsis, severe sepsis or septic shock requiring rbc transfusion randomly received nonlr (group , n = ) or lr (group , n = ) fresh rbcs (< days old). before and hour after transfusion, microvascular density and fl ow were assessed with sidestream dark-fi eld imaging sublingually. thenar tissue o saturation (sto ) was measured using near-infrared spectroscopy and a vascular occlusion test was performed. results the de backer score (p = . ), total vessel density (p = . ), perfused vessel density (p = . ), proportion of perfused vessels (p = . ), and microvascular fl ow index (p = . , figure ) increased only in group . the sto upslope (figure ) during reperfusion increased in both groups (p < . ). in group the baseline sto and sto downslope during ischemia increased, probably refl ecting a lower o consumption. conclusion unlike nonlr rbcs, the transfusion of fresh lr rbcs seems to improve microvascular perfusion and might help to restore tissue oxygenation during sepsis. introduction obstetric haemorrhage remains a leading cause of maternal mortality and severe morbidity. cardiovascular and haemostatic physiology alters in pregnancy and massive transfusion protocols have been implemented for obstetric haemorrhage based on limited evidence. the objective of this study was to examine the pattern and rate of blood products used in massive transfusion for obstetric haemorrhage in a tertiary obstetric hospital. methods massive transfusion was defi ned as or more units of red blood cells within hours in accordance with the australian massive transfusion registry defi nition. following ethics approval, all cases fi lling this criterion were identifi ed in the hospital's birthing and blood bank systems. data were extracted from the medical histories and analysed using spss. p < . was considered statistically signifi cant. results twenty-eight women in three years ( to ) underwent a massive transfusion for obstetric haemorrhage, with nine receiving more than units of rbcs in hours. eleven ( %) were admitted to the icu and underwent a hysterectomy, of which six were admitted to the icu. the median estimated blood loss was , ml (iqr , to , ). median blood product delivery was rbc units (iqr to ); ffp units (iqr to ); platelets units (iqr to ) and cryoprecipitate units (iqr to ). one-half of the women received the fi rst four units of rbcs in less than minutes. other blood products were started a median of minutes, minutes and minutes after the rbc transfusion commenced, respectively. eight women had a fi brinogen level < . g/l on the initial coagulation test during the haemorrhage. the remaining women had a median fi brinogen level of . g/l (iqr . to . ). there was no diff erence in the transfusion of rbcs (p = . ), ffps (p = . ) and platelets (p = . ) in women who showed an initial low fi brinogen and those who did not, although there was a diff erence in the number of units of cryoprecipitate (p < . ). the median lowest hb during the haemorrhage was g/l (iqr to ) and median discharge hb was g/l (iqr to ). no blood product reaction was noted and there was one death. conclusion massive transfusion for obstetric haemorrhage involved rapid blood product administration with no consistent pattern in the ratio of products administered. introduction blood transfusions are associated with longer icu and hospital inpatient durations, and an increase in mortality [ ] . this study was undertaken to investigate whether the practice of packed red cell critical care , volume suppl http://ccforum.com/supplements/ /s s (prc) transfusions in the icu was in accordance with the best clinical evidence. a number of studies, most notably the tricc study [ ] , have shown that indications for icu blood transfusions are a haemoglobin (hb) level of < g/dl or evidence of acute haemorrhage [ ] . these criteria were therefore employed. methods this study prospectively examined episodes of prc unit transfusions over a -month period in the icu of a large level trauma centre and a tertiary cardiac unit. the number of prc units transfused in each episode was recorded by nurses, along with the proposed indication and concurrent hb level. the data were analysed to assess the number of transfusions administered contrary to the guidelines, along with the average hb level at which a prc unit was transfused and the average number of units administered per episode. results a total units of prc were transfused in the icu, over episodes during the -month period (excluding immediately postoperative transfusions). ninety-four units ( . %) administered in transfusion episodes ( . %) occurred contrary to the guidelines. in . % of these cases the recorded reason for transfusion was an apparently low hb level. the median (iqr (range)) hb level at which patients were transfused: within guidelines was . g/dl ( . to . ( . to . )); within guidelines, excluding cases of acute blood loss, was . g/dl ( . to . ( . to . )); and outside the guidelines was . g/dl ( . to . ( . to . )). one unit of prc was transfused in episodes ( . %), units of prc were transfused in episodes ( . %), and to units were transfused in episodes ( . %), with two-thirds of the latter due to acute haemorrhage. our results indicate a liberal transfusion threshold currently exists in the icu. patients are frequently receiving excessive prc transfusions for hb levels above the recommended concentration. in the -month study period, these were associated with a cost of approximately £ , . we recommend increased staff awareness of the guidelines to reduce the number of unnecessary transfusions. this would decrease exposure of icu patients to unnecessary risks of blood transfusion, reduce cost of treatment and help to preserve a valuable resource. introduction transfusion-related acute lung injury (trali) has a high incidence in critically ill and surgical patients and contributes to adverse outcome, while specifi c therapy is absent. recently it was demonstrated that complement activation plays a pivotal role in trali. we aimed to determine whether a c inhibitor is benefi cial in a two-hit mouse model of antibody-mediated trali. methods balb/c mice were primed with lipopolysaccharide (lps, from e. coli :b ) that was administered intraperitoneally in a dose of . mg/kg, after which trali was induced by injecting mhc-i antibody against h kd (igg a,k) at a dose of mg/kg. mice infused with pbs or lps served as controls. concomitantly, mice infused with the mhc-i antibody were treated with c inhibitor (cetor®; sanquin, amsterdam, the netherlands) in a dose of iu/kg intravenously. after infusion, mice were mechanically ventilated with a lung-protective pressurecontrolled mode for hours and then sacrifi ced, after which a bronchoalveolar lavage (bal) was done. statistics were analyzed by one-way anova, values expressed as mean and standard deviation. results injection of lps and mhc-i antibodies resulted in trali, indicated by increased levels of protein in the bal fl uid, wet/dry ratios and levels of kc, mip- and il- . c inhibitor cetor® signifi cantly reduced total protein in bal fl uid from ( ) to ( ) μg/ml (p < . ) and tended to reduce the wet/dry ratio from . ± . to . ± . (p = . ). cetor® also reduced balf levels of mip- from ( ) to ( ) pg/ml (p < . ). kc and il- levels were not aff ected. conclusion in a model of antibody-mediated trali, c inhibitor attenuated pulmonary infl ammation. c inhibition may be a potential benefi cial intervention in trali. introduction transfusion-related acute lung injury (trali) is a syndrome that presents as a sudden onset of respiratory distress hours after transfusion of blood products. the diagnosis is based on clinical and radiographic fi ndings. particularly at risk for trali are cardiac surgery patients. however, specifi c patient risk factors and data on outcome are largely unknown. the aim of this study was to investigate incidence, risk factors and outcome of trali in cardiac surgical patients on cardiopulmonary bypass. methods all thoracic surgery patients from a university hospital in the netherlands of years and older admitted to the icu from january until december were screened. included patients were observed during surgery and the fi rst hours on the icu for the onset of possible trali. the canadian consensus conference trali defi nition was used. two independent physicians blinded to the predictor variables scored the chest radiographs for the onset of bilateral interstitial abnormalities on k monitors. when interpretation diff ered, chest radiographs were reviewed by a third physician to achieve consensus. the european system for cardiac operative risk evaluation (euro score) and the american association of anesthesiology (asa) were scored before surgery. by calculating the acute physiology and chronic health evaluation (apache) ii and iv scores the severity of illness was determined on arrival in the icu. in total, , cardiac surgical patients were included. a total of ( . %) patients developed trali within hours following surgery. patients developing trali were older compared with patients not developing trali, mean age respectively and years (p = . ). furthermore, patients developing trali had higher apache ii, apache iv, euro and asa score (p = . , p = . , p = . and p = . introduction volume resuscitation is essential to restore normovolemia during hemorrhagic shock, burns and sepsis. however, synthetic colloids cause dilutional coagulopathy. the aims were to determine whether the natural colloid albumin induces a lesser degree of coagulopathy compared with synthetic colloids, and the comparative eff ectiveness of fi brinogen concentrate to reverse coagulopathy following dilution with these solutions. methods rotational thromboelastometry-based tests were used to examine coagulation parameters in samples from healthy volunteers, in undiluted blood and samples diluted : with saline, was seen for samples diluted with synthetic colloids (p < . ) but not albumin (p = . ). following addition of fi brinogen, fibtem mcf, extem mcf and extem aa were signifi cantly higher, and extem cft was signifi cantly shorter in samples diluted with albumin versus those treated with hes or dextran (p ≤ . ). conclusion hemodilution using albumin induced a lesser degree of coagulopathy compared with the synthetic colloids hes and dextran. in addition, albumin-induced coagulopathy was more eff ectively reversed following addition of fi brinogen concentrate compared with coagulopathy induced by synthetic colloids. comparative assessment of the diff erent fl uid modalities is hampered by a paucity of direct trials. we present a network meta-analysis for assessing the relative eff ectiveness of two fl uid treatments in sepsis when they have not been compared directly in a randomized trial but have each been compared with a common treatment. methods a systematic review of trials sepsis yielded trials for assessment in network meta-analysis. the indirect comparison between albumin, hes and crystalloid was conducted using bayesian methods for binomial likelihood, fi xed-eff ects network meta-analysis with a monte carlo gibbs sampling method. studies in septic patients with crystalloid as a reference treatment compared with any formulation of the colloid treatments albumin or hes were included, as were direct head-to-head trials between the two colloids. results odds ratios between the diff erent treatments were obtained ( figure ). ranking the interventions [ ] demonstrated that albumin ranked highest in lowering mortality at a . % probability compared with . % and . % for crystalloid and hes, respectively. conclusion albumin as a fl uid therapy in sepsis is associated with the lowest mortality of the three modalities studied. (sap), sv and co were recorded directly before the administration of any colloid (t ) and every minutes for the next hour (t to t ). kolmogorov-smirnov was used to test normal distribution of data and anova was used for the statistical analysis. p < . was considered statistically signifi cant. results demographic data and asa classifi cation did not diff er statistically signifi cant among the six groups of the study. co, sv, hr and sap did not show any statistically signifi cant evolution compared with their baseline value during the study period. moreover, there were no statistically signifi cant diff erences among the six study groups with regard to any of the recorded parameters. conclusion according to our results, volume replacement with the six colloids tested in our study did not result in any hemodynamic response. within comparison of these six colloids did not reveal any statistically signifi cant diff erence in any of the parameters recorded according to our protocol. the biochemical characteristics of infused fl uids may be important in regulating acid-base balance, by modifying plasmatic volume and strong ion diff erence. in vitro and animal studies [ , ] have shown that volume and strong ion diff erence of infused fl uids (sidin) as well as the arterial baseline bicarbonate concentration (hco -a) infl uence acid-base variations. our aim was to verify these changes in critically ill patients after surgery. methods an electronic-dedicated database was created to retrospectively collect volume, type of fl uids infused and plasmatic acidbase balance variations in postoperative icu patients from admission to : am of the day after. sidin was calculated as the average sid of all fl uids infused during the whole study period (crystalloids, colloids and blood products). arterial base excess variation (Δbea) was computed as the diff erence between values at : am on the day after and those at entry. we report data from all patients admitted in and ( patients). results nine patients not receiving intravenous infusions were excluded. the remaining population was divided into three groups according to sidin distribution (group , ± ; group , ± ; group , ± meq/l). we observed a progressive increment in Δbea between the groups ( . ± . vs. . ± . vs. . ± . mmol/l, p < . ). we further subdivided each group by the median value of baseline hco -a ( . ( . to . ) mmol/l) and we analyzed the Δbea: we observed a greater increase in patients with lower baseline hco -a (group , . ± . vs. . ± . , mmol/l, p < . ; group , . ± . vs. . ± . , mmol/l, p < . ; group , . ± . vs. . ± . mmol/l, p < . ), as compared with those with higher baseline levels. when the study population was divided into quartiles of the diff erence between sidin and hco -a, Δbea appeared to increase with the rise of such diff erence (p < . ). conclusion sidin aff ects the acid-base status per se and in relationship with hco -a. we verifi ed this hypothesis in critically ill patients, highlighting the importance of the diff erence between sidin and hco -a, which better describes and predicts the acid-base modifi cations to fl uid therapy. introduction fluid resuscitation should improve tissue oxygenation in hypovolemia, besides restoring macrohemodynamic stability [ ] . we evaluated the microvascular response to fl uid challenge with diff erent colloid solutions and its relation to macrohemodynamics. methods an observational study of patients receiving a fl uid challenge ( ml colloids in minutes) according to the attending physician's decision. before and after the infusion, sublingual microcirculation was evaluated with sidestream dark-fi eld imaging (microscan; microvision medical, amsterdam, the netherlands). microvascular fl ow and density were assessed for small vessels [ ] . the cardiac index (ci), intrathoracic blood volume index (itbvi) and extravascular lung water index (elwi) were measured in seven patients with picco (pulsion medical system, munich, germany). results ten patients (two sepsis, four trauma, three intracranial bleeding, one post surgery) received either saline-based hydroxyethyl starch (hes) / . (amidolite®; b.braunspa; n = ) or balanced hes / . (tetraspan®; b.braunspa; n = ). the ci (p = . ) and itbvi (p = . ) tended to increase, the evlwi did not change. microvascular fl ow and density improved in the whole sample. no correlation was found between macro-circulatory and micro-circulatory parameters. balanced hes led to a greater increase in capillary density than nacl hes (figure ). conclusion balanced hes may be more effi cacious than saline-based hes in recruiting the microcirculation, thereby improving tissue o delivery. introduction are safety guidelines being followed when administering procedural sedation in the emergency department? between november and november , the npsa received alerts of patients being given the wrong dose of midazolam for procedural sedation [ ] . in the fi rst years of midazolam use there were deaths, most related to procedural sedation [ ] . methods we searched through the controlled drugs book in resuscitation over a -month period and found a list of patients who had received midazolam or fentanyl. from this, we could make a search for the relevant a and e notes for these patients. from these notes, we looked for (see shorthand in table ): verbal consent documentation (consent), past medical history recorded (pmhx), safe initial dose of midazolam (midaz), pre-procedure monitoring (pre), post-procedure monitoring (post), and monitoring for hour before discharge ( hr). following introduction of a reminder in the controlled drugs book/ sedation room and staff education, the case notes were analysed over another -month period ( sets of notes) to assess practise against safety guidelines. results see table (key for shorthand in methods). conclusion the re-audit notices within the procedural sedation room and controlled drug book front cover served as a reminder of good practise. the visibility of this reminder (within the cd book) helped ensure better adherence to the audit standard. this reminder will now be kept within the cd book. introduction daily sedation interruption and protocol implementation have been recommended to reduce excessive sedation; however, their use has been inconsistent. we hypothesized that the use of an age, kidney and liver function adjusted sedation protocol would be associated with reduced doses and improved outcomes compared with a standard protocol. methods this was a prospective cohort study comparing months of a standard protocol (control group) with months of an adjusted protocol (intervention group). in the adjusted protocol, patients were divided into three categories: category (age < years, and normal kidney and liver function), category (age = to years, or moderate kidney or liver function impairment), and category (age > years, or severe kidney or liver function impairment). the upper limits of analgesics and sedatives doses were determined by age, and kidney and liver function, being lowest in category , and lower in category than category . all consecutive adults mechanically ventilated patients who required infusion of analgesics and/or sedatives for > hours were included in the study. we compared the main outcomes of both groups including average daily doses of analgesics and sedatives; average sedation-agitation scale (sas), pain and gcs scores; mechanical ventilation duration (mvd); sedation-related complications during icu stay; icu and hospital length of stay (los), and icu and hospital mortality. results two hundred and four patients were included in the study (control group = ; adjusted protocol group = ). there was no diff erence in baseline characteristics between the two groups. the adjusted protocol group, compared with the control group, received signifi cantly lower average daily doses of fentanyl ( , ± , μg vs. , ± , μg, p = . ), nonsignifi cant lower average daily doses of midazolam and dexmedetomidine, and a trend toward higher average daily doses of propofol. pain score was higher in the adjusted protocol group ( . ± . vs. . ± . , p < . ) with no diff erence in sas or gcs scores. sedation-related complications during icu stay were not diff erent between the two groups; however, agitation (sas = ) was less frequent in the adjusted protocol group ( % vs. %, p < . ). icu mortality was signifi cantly lower in the introduction the aim of this research was to provide clinically relevant evidence for y-site compatibility of drug infusion combinations used in the picu. pharmacists and clinicians regularly have to interpret limited published data, particularly when more than two drugs are y-sited. the risk of potential incompatibility must be balanced against that of additional line insertion. methods a full -factorial design (total combinations) was used to investigate chemical and physical compatibility of fi ve drugs (clonidine, morphine, ketamine, midazolam and furosemide). the drugs were studied at their highest commonly infused concentrations and exposed to three variations in environmental conditions (diluent: sodium chloride . % or glucose %; temperature or °c; and normal room lighting or blue light phototherapy). chemical stability was assessed using hplc; > % reduction in concentration indicated incompatibility. physical incompatibility was confi rmed by precipitation, ph or colour change. results environmental conditions had no eff ect on the drug mixtures. the precipitation observed in incompatible combinations was due to either a change in ph, or with ketamine the presence of benzethonium chloride. of possible drug combinations, were incompatible. a further three combinations were incompatible at extreme ph, or were of concern and so should be avoided. the incompatible formulations all contained furosemide. all combinations of the sedative agents studied were chemically and physically compatible. conclusion this work provides evidence for y-site compatibility of morphine, midazolam, clonidine and ketamine in any combination, which will potentially reduce the need for extra intravenous lines. furosemide is incompatible with any of these sedative drugs and must be infused via a separate line. these results will aid clinical decisionmaking and help satisfy the requirements of recent uk department of health legislation relating to the mixing of medicines. reference introduction in light of the interest in the relationship between glycemia control in critically ill subjects and outcome, we set up a study to investigate whether benzodiazepine, commonly used in anesthesia and icus, interferes with glucose metabolism and to explore the mechanism. methods a total of sedated and paralyzed sprague-dawley rats ( ± g) were investigated in four consecutive studies. ( ) to investigate the eff ects of diazepam on blood glucose, rats were randomly assigned to intraperitoneal anesthesia with tiopenthal mg/kg (dzp ), tiopenthal mg/kg + diazepam mg/kg (dpz ) or tiopenthal mg/kg + diazepam mg/kg (dzp ). blood levels of glucose (gem premier ; il) were measured at time intervals over hours. ( ) ten animals randomized to dzp or dzp underwent an intravenous glucose tolerance test with glucose bolus ( . g/kg). acute insulin response, the mean value of blood insulin (insulin elisa kit; millipore) from to minutes after glucose bolus, was measured as index of insulin secretion. ( ) a hyperinsulinemic euglycemic clamp obtained by a continuous intravenous infusion of insulin ( mui/ kg/minute) was run in animals randomized to dzp or dzp and the glucose infusion rate (gir, mg/kg/minute) was assessed [ ] . ( ) introduction we report our experience in the use of isofl urane for prolonged sedation in severe ards patients. prolonged sedation in the icu may be diffi cult because of tolerance, drug dependence and withdrawal, drug interactions and side eff ects. inhaled anesthetics have been proposed for sedation in ventilator-dependent icu patients. anaconda is a device that allows a safety and easy administration of inhaled anesthetics in the icu. methods from january to june , patients were sedated with isofl urane by means of the anaconda device. we consider administration of isofl urane as a washout period from common sedative drugs in patients with (at least one of ): high sedative drug dosage (propofol ≥ mg/hour or midazolam ≥ mg/hour) to reach the target richmond agitation sedation score (rass) or inadequate paralysis; two or more hypnotic drugs to reach the target rass (propofol, midazolam, hydroxyzine, haloperidol, diazepam, quetiapine); and hypertriglyceridemia. during isofl urane administration previous hypnotic drugs were interrupted. we retrospectively collected data before, during and after administration of isofl urane: hemodynamic parameters, renal and hepatic function, level of sedation (rass) and sedative drug dosage. all data are reported as mean ± standard deviation, otherwise as median (minimum to maximum). results mean age was ± years and saps ii was . ± ; patients were treated with ecmo for severe ards and four had a history of drug abuse; median icu length of stay was ( to ) days and they were ventilated for ( to ) days. due to severe critical illness, target rass was - for all patients, most of which were also paralysed. isofl urane was administered in nine patients because of a high level of common sedative drugs, in fi ve patients due to the use of two or more hypnotic drugs and in one patient because of hypertrigliceridemia. isofl urane administration lasted . ± . days. during isofl urane administration no alteration in renal function or hemodynamic instability was recorded. after the isofl urane washout period we observed a reduction in sedative drug dosage in patients while two patients were quickly weaned from mechanical ventilation and the target rass raised to . in two patients isofl urane was precautionarily interrupted because of concomitant alteration of liver function and suspected seizures respectively. conclusion inhaled anesthetics could be successfully used in the icu especially in case of an inadequate sedation plan; for example, in patients with a history of drug abuse or young severe ards patients that required deep sedation and paralysis for a long period. introduction pharmacological agents used to treat critically ill patients may alter mitochondrial function. the aim of the present study was to investigate whether fentanyl, a commonly used analgesic drug, interacts with hepatic mitochondrial function. methods the human hepatoma cell line hepg was exposed to fentanyl at . , or ng/ml for hour, or pretreated with naloxone (an opioid receptor antagonist) at ng/ml or -hydroxydecanoate ( -hd; a specifi c inhibitor of mitochondrial atp-sensitive k + (katp) channels) at μm for minutes, followed by incubation with fentanyl at ng/ml for an additional hour. the mitochondrial complex i-dependent, ii-dependent and iv-dependent oxygen consumption rates of the permeabilized cells were measured using a high-resolution oxygraph (oxygraph- k; oroboros instruments, innsbruck, austria). the respiratory electron transfer capacity of intact cells was evaluated using fccp (carbonyl cyanide p-trifl uoromethoxyphenylhydrazone) to obtain the maximum fl ux. results incubation of hepg cells with fentanyl ( hour, ng/ml) induced a reduction in complex ii-dependent and iv-dependent respiration ( figure ). cells pretreated with -hd before the addition of fentanyl exhibited no signifi cant changes in complex activities in comparison with controls. pretreatment with naloxone tended to abolish the fentanyl-induced mitochondrial dysfunction. treatment with fentanyl led to a reduction in cellular atp content ( . ± . in controls vs. . ± . μmol/mg cellular protein in stimulated cells; p = . ). we did not observe any diff erence in basal or fccp-uncoupled respiration rates of cells treated with fentanyl at ng/ml compared with controls (data not shown). conclusion fentanyl reduces cultured human hepatocyte mitochondrial respiration by a mechanism that is blocked by a katp channel antagonist. in contrast, antagonism with naloxone does not seem to completely abolish the eff ect of fentanyl. introduction endothelial dysfunction during endotoxemia is responsible for the functional breakdown of microvascular perfusion and microvessel permeability. the cholinergic anti-infl ammatory pathway (cap) is a neurophysiological mechanism that regulates the infl ammatory response by inhibiting proinfl ammatory cytokine synthesis, thereby preventing tissue damage. endotoxemia-induced microcirculatory dysfunction can be reduced by cholinergic cap activation. clonidine improves survival in experimental sepsis [ ] by reducing the sympathetic tone, resulting in the parasympatheticmediated cap activation. the aim of this study was to determine the eff ects of clonidine on microcirculatory alterations during endotoxemia. methods using fl uorescent intravital microscopy, we determined the venular wall shear rate, macromolecular effl ux and leukocyte adhesion in mesenteric postcapillary venules of male wistar rats. endotoxemia was induced over minutes by intravenous infusion of lipopolysaccharide (lps). control groups received an equivalent volume of saline. clonidine μg/kg was applied as i.v. bolus in treatment groups. animals received either (i) saline alone, (ii) clonidine minutes prior to saline administration, (iii) clonidine minutes prior to lps administration, (iv) clonidine minutes prior to lps administration, (v) clonidine minutes after lps administration or (vi) lps alone. results all lps groups (iii to vi) showed a signifi cantly reduced venular wall shear rate compared with the saline group after minutes. there were no signifi cant diff erences between the numbers of adhering leukocytes in the clonidine/lps groups (iii, iv, v) and the lps group after minutes. macromolecular effl ux signifi cantly increased in all groups over the time period of minutes. after minutes there was no diff erence between the lps group and the clonidine minutes prior to lps administration group (iv) whereas all other groups (i, ii, iii, v) showed a signifi cantly reduced macromolecular effl ux compared with the lps group. conclusion clonidine has no positive eff ect on microhemodynamic alterations and leukocyte-endothelial interaction during endotoxemia. the reduction of capillary leakage in clonidine-treated groups depends on the time interval relative to the initiation of endotoxemia. endothelial permeability and leukocyte activation are regulated by diff erent pathways when stimulated by clonidine during endotoxemia. we conclude that clonidine might have an important time-dependent anti-infl ammatory and protective eff ect on endothelial activation during infl ammation. introduction delivering analgesics via conjunctival application could provide rapid and convenient pain relief in disaster medicine. there are sporadic reports from the usa concerning inhalation administration of aerosol with various drugs producing a wide variety of eff ects from anxiolysis, sedation, and loss of aggressiveness to immobilisation. we attempted to determine in an animal experiment whether conjunctival administration of s+ketamine could produce signifi cant eff ect without side eff ects. methods after ethic committee approval, rabbits were administered conjunctival s+ketamine . mg/kg. measured parameters were spo , blood pressure (bp) and heart rate (hr) before administration and in -minute intervals and immobilisation time (loss of righting refl ex [ ] . we can speculate that the reason for stability of cardiorespiratory parameters was due to the sympathoadrenergic eff ect of ketamine or due to the method of administration. there were no signs of conjunctival irritation in any animal (s+ketamine is a preservative-free solution). conclusion conjunctival s+ketamine . mg/kg in rabbits produced rapid onset without changes in cardiorespiratory parameters and without signs of irritation of the eye. the results of our project warrant further research to increase the variety of drugs and methods of their administration for anxiolysis, sedation and analgesia in disaster medicine. introduction procedural sedation is used in the emergency department (ed) to facilitate short but painful interventions. many patients are suitable for discharge after completion. ideally, the agent used to achieve sedation should not have a prolonged eff ect, allowing safe discharge in the shortest time frame. we hypothesised that propofol, with its short onset and off set, may reduce length of stay (los) in comparison with traditional benzodiazepines. methods data from a prospective registry were analysed for the period august to january . patients who underwent procedural sedation and who were discharged from the ed were identifi ed. individuals were grouped as having received propofol, midazolam or a combination of the two. all were discharged when fully alert and able to eat and drink. demographic details and the type of procedure undertaken were extracted. anova was performed to identify diff erences in the length of stay between groups, in addition to descriptive analysis. results during the study period patients underwent procedural sedation and were discharged from the ed. the median age was years and % were male. the commonest procedure performed was shoulder reduction ( %). in the propofol group (n = ) the mean los was minutes compared with minutes in those receiving midazolam (n = ) and minutes in those receiving a combination (n = ), p = . . there was no diff erence in adverse events between groups. see figure . conclusion propofol is increasingly used in eds for procedural sedation due to its short duration of action. this study suggests that a shorter duration of action and faster recovery may result in a reduced los in the ed. the use of propofol for sedation in intensive care has been associated with the propofol infusion syndrome (pris) characterised by cardiac dysfunction, metabolic acidosis, renal failure, rhabdomyolysis and hyperlipidaemia. we prospectively monitor biochemical markers that we believe demonstrate early signs of this dangerous, often fatal syndrome. when this pre-pris state is identifi ed, propofol is withdrawn whilst the syndrome is still reversible. methods we prospectively audited our monitoring of these markers over a -month period in propofol-sedated patients: propofol infusion rate, creatine kinase (ck), triglycerides (tg), creatinine, lactate, ph and base defi cit. we defi ned the criteria for pre-pris as requiring a ck ≥ mmol/l that had doubled from its base level and a rise in tg ≥ . iu/l; both that followed a trend with propofol dose. conclusion we propose that a paired rise in ck and tg that can be attributed to propofol alone represents a pre-pris state that is at risk of developing into full pris. we noted this in % of our patients, all on modest doses of propofol. it is unclear what proportion of patients will develop the full syndrome as it is not ethically possible to continue propofol in this situation. we advocate daily monitoring of ck and tg to identify pre-pris so that propofol can be reduced or substituted to avoid the morbidity and mortality of the full syndrome. introduction until recently there were no guidelines for the reporting of adverse events (aes) during procedural sedation [ , ] . a consensus document released in by the world siva international sedation task force proposed a benchmark for defi ning aes [ ] . we analysed , cases of procedural sedation in the emergency department. methods the study is based on , patients who received procedural sedation with propofol in the emergency department between december and march . patients were selected and sedated to a strict protocol by ed consultant staff . we applied the ae tool by performing a search through patient records, discussion with consultants performing the sedation and consensus opinion. results from , cases we identifi ed sentinel (six of hypotension, fi ve cases of hypoxia), moderate, minor and three minimal risk adverse events. the study shows a % adverse event rate. this supports use of propofol sedation by emergency physicians but within the limits of a strict governance framework. our safety analysis using the world siva adverse events tool provides a reference point for further studies. introduction physical restraints are used to facilitate essential care and prevent secondary injuries. however, physical restraint may be regarded as humiliating. it may lead to local injury and increase the risk of delirium and post-traumatic stress syndrome. research on physical restraint is scarce. the aim of this study is to investigate the scope of physical restraint use. methods twenty-one icus ranging from local hospitals to academic centres were each visited twice and patients were included. we recorded characteristics of restrained patients, motives and awareness of nurses and physicians. results physical restraint was applied in ( %) patients, ranging from to % in diff erent hospitals. frequent motives for restraint use were 'possible threat to airway' ( %) and 'pulling lines/probes' ( %). restrained subjects more often had a positive cam-icu ( % vs. %, p < . ), could less frequently verbally communicate ( % vs. %, p < . ), and received more often antipsychotics ( % vs. %, p < . ), or benzodiazepines ( % vs. %, p = . ). the use of physical restraint was registered in the patient's fi les in % of cases. of the interviewed nurses, ( %) were familiar with a physical restraint protocol and ( %) used it in any situation. thirty percent of the interviewed physicians were aware of the physical restraint status of their patients. conclusion physical restraint is frequently used in dutch icus, but the frequency diff ers strongly between diff erent icus. attending physicians are often not aware of physical restraint use. introduction physical restraint (pr) use in critically ill patients has been associated with delirium, unplanned extubation, prolonged icu length of stay, and post-traumatic stress disorder. our objectives were to defi ne prevalence of pr use, and to examine patient, treatment, or institutional factors associated with their use in canadian icus. measures aimed at delirium prevention (psychohygiene and early mobilization) were carried only in a small minority or were not documented. to implement protocolled delirium care in the region at study, a multifaceted tailored implementation program is needed. introduction the objective of this study is to investigate the eff ect of intraoperative administration of dexamethasone versus placebo on the incidence of delirium in the fi rst four postoperative days after cardiac surgery. methods within the context of the large multicenter dexamethasone for cardiac surgery (decs) trial [ ] for which patients were randomized to mg/kg dexamethasone or placebo at induction of anesthesia, a monocenter substudy was conducted. the primary outcome of this study was the incidence of delirium in the fi rst four postoperative days. secondary outcomes were duration of delirium, use of restrictive measures and sedative, antipsychotic and analgesic requirements. delirium was assessed daily by trained research personnel, using the richmond agitation sedation scale and the confusion assessment method. medical, nursing and medication charts were evaluated for signs of delirium and use of prespecifi ed medication. analysis was by intention to treat. results of eligible patients, complete data on delirium could be collected in patients. the incidence of delirium was . % in the dexamethasone group and . % in the placebo group (odds ratio = . , % ci = . to . ). no signifi cant diff erence was found on the duration of delirium between the intervention (median = days, interquartile range to days) and placebo (median = days, interquartile range to days) group (p = . ). the use of restrictive measures and administration of sedatives, haloperidol, benzodiazepine and opiates were comparable between both groups. conclusion intraoperative injection of dexamethasone seems not to aff ect the incidence or duration of delirium in the fi rst days after cardiac surgery, suggesting this regimen is safe to use in the operative setting with respect to psychiatric adverse events. reference introduction the beliefs, knowledge and practices regarding icu delirium among icu professionals may vary. this may interfere with the implementation of the dutch icu delirium guideline. we aimed to get insight into potential barriers and facilitators for delirium guideline implementation that may help to fi nd an eff ective implementation strategy. methods an online survey was sent to healthcare professionals from the six participating icus. respondents included icu physicians, nurses and delirium experts (psychiatrists, neurologists, geriatricians, nurse experts). the survey consisted of statements on beliefs, knowledge and practices towards icu delirium. agreement with statements by more than % of respondents were regarded as facilitating items and agreement lower than % as barriers for implementing protocolled care. of the surveys distributed, were completed ( . %). the majority of respondents were icu nurses ( %). delirium was considered a major problem ( %) that requires adequate treatment ( %) and is underdiagnosed ( %). respondents considered that routine screening of delirium can improve prognosis ( %). however, only a minority ( %) answered that delirium is preventable. only % of the respondents had received any training about delirium in the previous years and % of them found training useful. the mean delirium knowledge score was . out of (sd = . ). when all groups were mutually compared, nurses scored lower than delirium experts (anova, p = . ). the respondents ( %; n = ) from three icus indicated that cam-icu assessment was department policy. however, % (n = ) of these respondents felt unfamiliar with cam-icu and only % (n = ) of them indicated that a positive cam-icu was used for treatment decisions. haloperidol was the fi rst-choice pharmacological treatment. only % of all respondents knew that a national icu delirium guideline existed, but in-depth knowledge was generally low. conclusion our survey showed that healthcare professionals considered delirium an important but underdiagnosed form of organ failure. in contrast, screening tools for delirium are scarcely used, knowledge can be improved and protocolled treatment based on positive screening is often lacking. these results suggest that the focus of implementation of icu delirium management should not be on motivational aspects, but on knowledge improvements, training in screening tools and implementation of treatment and prevention protocols. introduction delirium is an acute disturbance of consciousness and cognition. it is a common disorder in the icu and associated with impaired long-term outcome [ , ] . despite its frequency and impact, delirium is poorly recognized by icu physicians and nurses using delirium screening tools [ ] . a completely new approach to detect delirium is to use monitoring of physiological alterations. temperature variability, a measure for temperature regulation, could be an interesting parameter for monitoring of icu delirium, but this has never been investigated before. the aim of this study was to investigate whether temperature variability is aff ected during icu delirium. methods we included patients in whom days with delirium could be compared with days without delirium, based on the confusion assessment method for the icu and inspection of medical records. patients with conditions aff ecting thermal regulation, including infectious diseases, and those receiving therapies aff ecting body temperature were excluded. twenty-four icu patients were included after screening delirious icu patients. daily temperature variability was determined by computing the mean absolute second derivative of the temperature signal. per patient, temperature variability during delirious days was compared with nondelirium days using a wilcoxon signed-rank test. with a linear mixed model, diff erences between delirium and nondelirium days with regard to temperature variability were analysed adjusted for daily mean richmond agitation and sedation scale scores, daily maximum sequential organ failure assessment score, and within-patient correlation. results temperature variability was increased during delirium days compared with days without delirium (mean diff erence = - . , % ci = - . ; - . , p < . ). adjusting for confounders did not alter our fi ndings (adjusted mean diff erence = - . , % ci = - . ; - . , p < . ). conclusion temperature variability is increased during delirium in icu patients, which refl ects the encephalopathy that underlies delirium. opportunities for delirium monitoring using temperature variability should be further explored. particularly, in combination with electroencephalography it could provide the input for an objective tool to monitor delirium. in icu patients, little research has been performed on the relationship between delirium and long-term outcome, including health-related quality of life (hrqol), cognitive functioning and mortality. in addition, results seem to be inconsistent. furthermore, in studies that reported increased mortality in delirious patients, no proper adjustments were made for severity of illness during icu admission. this study was conducted to investigate the association introduction we aimed to clarify the diff erences between primary and secondary acute gi injury. methods a total of , consecutive adult patients were retrospectively studied during their fi rst week in the icu. pathology in the gi system or laparotomy defi ned the primary gi insult. if gi symptoms developed without primary gi insult it was considered secondary gi injury. absent bowel sounds (bs), vomiting/regurgitation, diarrhoea, bowel distension, gi bleeding, and high gastric residuals (grv > , ml/ hours) were recorded daily. results in total, , patients ( . % male), median age years (range to ), were studied. eighty-four per cent of them were ventilated, % received vasopressor/inotrope. median (iqr) apache ii score was ( to ) and sofa on the fi rst day was ( to ). a total . % had primary gi pathology. during the fi rst week % of patients had absent bs, % vomiting/regurgitation, % diarrhoea, % bowel distension, % high grv and % gi bleeding. all symptoms except diarrhoea occurred more often (< . ) in patients with primary gi insult. eighty-fi ve per cent of patients with primary gi insult versus % without developed at least one gi symptom. the incidence of gi symptoms was signifi cantly higher in nonsurvivors. icu mortality was lower in patients with primary than secondary gi injury ( . % vs. . %, p = . ). nonsurvivors without primary gi insult developed gi symptoms later (figure ). conclusion primary and secondary acute gi injury have diff erent incidence, dynamics and outcome. ventilation with relative risk of to % and with mortality of to % [ , ] . one of the promoting factors of vap is the increased ph of the gastric acid, which occurs when h -receptor antagonists (h ra) or proton pump inhibitors (ppi) are used for stress ulcer prophylaxis. the results of this pilot study suggest that there may be no diff erence in the incidence of vap and gi bleeding if stress ulcer prophylaxis is performed by h ra or ppi. as the latter is more expensive, its use as fi rst choice in critical care should be questioned. conclusion depending on resection size liver resection acutely increases portal venous pressure and induces neurohumoral activation resulting in compromised renal function and increased risk of developing aki. introduction severe acute pancreatitis (sap) requiring admission to an icu is associated with high mortality (hospital mortality reached %) and long lengths of stay [ ] . survival among patients with predicted sap at admission has been shown to correlate with the duration of organ failure (of) [ ] . the systemic determinant of severity in a new classifi cation of acute pancreatitis (ap) is also based on identifi cation of patients with transient or persistent of [ ] . methods the aim of the study was to retrospectively determine the predictors of early persistent of in icu patients with sap. the analysis involved patients. the median time interval between the onset of ap and admission was ( ; ) hours. the patients were divided into two groups: the fi rst group (n = ) had transient of and the second group (n = ) had persistent of. the ability of the apache ii score, total sofa score and number of organ/system failure to discriminate transient from persistent of was explored with receiver operating characteristic (roc) curves. results hospital mortality was signifi cantly higher in the second group as compared with the fi rst group ( % vs. %, p = . ); while infectious complications were % versus % (p = . ) and median lengths of icu stay were ( ; ) days for the second group and ( ; ) days for the fi rst group (p = . ). optimum cutoff levels (by roc curve analysis) were apache ii score ≥ (sensitivity . ; -specifi city . ), total sofa score ≥ (sensitivity . ; -specifi city . ), and failure ≥ organs/systems (sensitivity . ; -specifi city . ). see table . introduction the aim of this study was to evaluate the accuracy of thrombopoietin (tpo) plasma levels as a biomarker of clinical severity in patients with acute pancreatitis (ap). tpo is a humoral growth factor that stimulates megakaryocyte proliferation and diff erentiation [ ] . furthermore, it favors platelet aggregation and polymorphonuclear leukocyte activation [ ] . elevated plasmatic concentrations of tpo have been shown in patients with critical diseases, including acs, burn injury and sepsis [ ] . in particular, clinical severity is the major determinant of elevated tpo levels in patients with sepsis [ ] . ap is a relatively common disease whose diagnosis and treatment are often diffi cult, especially in the clinical setting of the emergency department (ed introduction renal ischemia-reperfusion injury (iri) is a common cause of acute kidney injury and occurs in various clinical conditions including shock and cardiovascular surgery. renal iri releases proinfl ammatory cytokines within the kidney. atrial natriuretic peptide (anp) has natriuretic, diuretic and anti-infl ammatory eff ects [ ] and plays an important role of regulating blood pressure and volume homeostasis. the hypothesis was that renal iri induces infl ammation not only in the kidney but also in remote organs such as the lung and heart and anp attenuates renal injury and infl ammation in the kidney, lung and heart. methods male sprague-dawley rats were anesthetized with pentobarbital. tracheostomy was performed and rats were ventilated at vt ml/kg with cmh o peep. the right carotid artery was catheterized for blood sampling and continuous blood pressure measurements. the right femoral vein was catheterized for infusion of saline or anp. rats were divided into three groups; iri group (n = ), left renal pedicle was clamped for minutes; iri+anp group (n = ), left renal pedicle was clamped for minutes, anp ( . μg/kg/minute, for hours minutes) was started minutes after clamp; and sham group (n = ), the shamoperated rats. hemodynamics, arterial blood gas, and plasma lactate levels were measured at baseline and at hour, hours and hours after declamp. the mrna expression of il- in the kidney, lung, and heart were measured. the kidney, lung and heart were immunostained to examine the localization of il- and nf-κb and assigned an expression score. the wet/dry ratio of the lung was also measured. results renal iri induced metabolic acidosis, pulmonary edema, mrna expression of il- in the kidney, lung and heart. renal iri increased immunohistochemical localization of il- in the proximal convoluted tubule of the left kidney and nf-κb in the bronchial epithelial cells of the lung. anp attenuated metabolic acidosis, pulmonary edema and expression of il- mrna in the kidney, heart, and lung. anp decreased immunohistochemical localization of il- in the left kidney and nf-κb in the lung. conclusion these fi ndings suggested that infl ammation within the kidney after renal iri was extended into the lung and heart. anp attenuated metabolic acidosis and infl ammation in the kidney, lung and heart in a rat model of renal iri. anp may attenuate organ crosstalk between the kidney, lung and heart. reference increase in urinary ngal in patients receiving bicarbonate infusion was observed compared with control (p = . ). the incidence of postoperative rrt was similar but hospital mortality was increased in patients treated with bicarbonate compared with chloride ( / ( . %) vs. / ( . %), or . ( . to . ), p = . ). see figure . conclusion on this basis of our fi ndings we do not recommend the use of perioperative infusions of sodium bicarbonate to reduce the incidence or severity of aki in this patient group. figure ). an excellent predictive value was found for ungal/uhepcidin ratio (auc . , figure ). this ratio combines an aki prediction marker (ngal) and a marker of protection from aki (hepcidin), potentiating their individual discriminatory values. contrarily, at icu admission, none of the plasma biomarkers was a good early aki predictor with auc-roc ≥ . . conclusion several urinary markers of acute tubular damage predict aki after cardiac surgery and the biologically plausible combination of ngal and hepcidin provides excellent aki prediction. introduction furosemide is one of the most employed diuretics in the icu for its ability to induce negative water balance. however, one common side eff ect is metabolic alkalosis [ ] . we aimed to describe the time course of urinary excretion and changes in plasmatic acid-base balance in response to the administration of furosemide. methods we connected the urinary catheter of icu patients to a quasi-continuous urine analyzer (kidney instant monitoring®), allowing measurement of ph (phu), sodium, chloride, potassium and ammonium concentrations (na+u, cl-u, k+u, nh +u) every minutes. the study period lasted hours after a single intravenous bolus of furosemide (time ). in patients receiving two or more administrations over a longer period ( ( to ) hours), according to clinical needs, we reviewed data on fl uid therapy, hemodynamics and acid-base balance from the beginning to the end of the observation. results ten minutes after furosemide administration, na+u and cl-u rose from ± to ± and from ± to ± meq/l respectively, while k+u fell from ± to ± meq/l (p < . for all electrolytes vs. time ) with a consequent increase in urinary anion gap (agu = na+u + cl-u -k+u). urinary output increased from ( to ) to ( to ) ml/ minutes (p < . ). after the fi rst hour cl-u remained higher than na+u, which progressively decreased, leading to a reduction in agu and phu over time. in parallel, a progressive increment in nh +u was observed. in patients receiving more than one administration we observed an increase in arterial base excess ( . ± . vs. . ± . mmol/l, p < . ) and plasmatic strong ion diff erence (sidpl) ( ( to ) vs. ( to ) meq/l, p = . ) during the study period. these changes were due to a decrease in plasmatic clconcentration ( . ± . vs. . ± . meq/l, p = . ). plasmatic sodium and potassium concentrations did not change. in these patients, considering the total amount of administered fl uids and urine, a negative water and chloride balance was observed (- ± ml and - ± meq, respectively). conclusion furosemide acts immediately after administration, causing a rise in urinary output, na+u and cl-u concentrations. loop-diureticinduced metabolic alkalosis may be due to an increased urinary chloride loss and the associated increase in sidpl. reference introduction given the signifi cant morbidity and mortality associated with acute kidney injury (aki), there is a need to fi nd factors to help aid decision-making regarding levels of therapeutic support. as a prognostic biomarker, the red cell distribution width (rdw) has attracted interest in the setting of critical care when added to existing scoring systems [ ] . by examining rdw in a previously studied aki cohort, we aimed to evaluate the utility of this routine blood test. methods a cohort of mixed critical care patients who received renal replacement therapy for aki had their demographic and biochemical data retrieved from electronic databases. outcomes were gathered for icu and hospital mortality. incomplete datasets were discarded, leading to complete sets. rdw data were taken from the fi rst sample after admission to the icu, as were all other biochemical values apart from pre-rrt creatinine and potassium. overall cohort characteristics were gathered, and two groups were created: those with a rdw value within normal range (≤ . %) and those with a greater than normal value (> . %). we then further subgrouped rdw to assess the correlation between rising levels and icu mortality. results a total . % of our cohort had a rdw greater than the normal laboratory range at time of icu admission. key baseline characteristics (age, apache ii score, length of stay, icu mortality) did not diff er signifi cantly between patients with normal and abnormal rdw. when subgroup analysis was performed, no statistically signifi cant correlation between rising rdw and icu mortality was found (spearman correlation = . , p = . ). conclusion in this cohort of critically ill patients with aki, rdw was not found to be a predictor of mortality. our results contradict those of recent studies [ , ] . however, both groups of rdw patients in our study suff ered a higher icu mortality than in other studies. to further explain these fi ndings, we intend to perform multivariate logistic regression analysis and assess the eff ect of social deprivation on rdw. introduction intra-abdominal hypertension (iah) is an independent predictor of renal impairment and mortality [ ] . organ dysfunction caused by the pressure eff ect of iah is well understood, but how this is modifi ed in the presence of bowel obstruction is unclear. the aim of this study was to determine how diff erent iah models cause renal dysfunction in a pig model. methods twenty-four pigs were divided into three groups; a control group (n = ), a pneumoperitoneum (pn) (n = ), and an intestinal occlusion (oc) model (n = ). iap was maintained for hours at mmhg during which time creatinine, urea, urine output, potassium, and glomerular fi ltration pressure (gfp) were measured. statistical analysis was performed using repeated-measures anova. results over the fi rst hours there was a statistically signifi cant diff erence between the control group and both iah models for conclusion as expected the iah models resulted in signifi cantly worse renal function after hours. this early renal dysfunction may be as a result of an early infl ammatory process that has been associated with the pathophysiology of acute kidney injury. potassium was signifi cantly elevated in the pn group as compared with the oc group. early changes in potassium levels with iah may be a marker of early renal dysfunction and the usefulness of other renal biomarkers, such as ngal, prompts further investigation. reference introduction oliguria is common in septic patients and is frequently therapeutically addressed with loop diuretics; that is, furosemide. diuretic treatment in shock and hypovolemia is not rational, but can be tried in oliguric patients with normovolemia or hypervolemia and without hypotension. in such patients it still does not always increase dieresis and can also be harmful. the resistive index is a measure of pulsatile blood fl ow that refl ects the resistance to blood fl ow caused by the microvascular bed distal to the site of measurement. it can refl ect functional status of the tissue distal to the point of measurement. we investigated whether measuring the renal resistive index (ri) could be helpful in determining which patients will respond to furosemide treatment. methods we included medical icu patients with sepsis and oliguria (urine output < ml/kg/hour) who were prescribed i.v. furose mide. patients with known chronic renal failure, hypovolemia (cvp < mmhg) or severe hypotension (map < mmhg) were excluded. resistive index ( − (end diastolic velocity / maximum systolic velocity)× ) was measured in at least three segmental arteries of both kidneys, the average of all measurements was reported as the result. repeated assessments were viewed as independent if separated by more than hours. furosemide was given intravenously in the dose of mg after ri measurement. positive response to furosemide was defi ned as doubling of hourly dieresis or achieving urine output > . ml/kg/hour after drug administration. we included patients with a total of measurements. in cases patients had positive response to furosemide. median ri in responders was . (range . to . ) and in nonresponders . (range . to . ); p = . . construction of receiver operating characteristic curve showed % sensitivity and % specifi city for the cutoff ri . . no other measured patient characteristic was found to be predictive of response to diuretic treatment. conclusion our results show that the ri could be used to guide diuretic treatment in nonhypovolemic, nonhypotensive septic patients. further studies are needed to confi rm those preliminary results. introduction as a proof of concept, the potential added value of chitinase -like (chi l ) as a more early and specifi c diagnostic parameter for acute kidney injury (aki) was investigated in adult icu patients that underwent elective cardiac surgery. . conclusion sdma appears to be an accurate and precise estimate of gfr and a more sensitive biomarker of renal dysfunction than scr. we predict sdma will perform better than scr as a biomarker of aki. this forms the basis of a future study. introduction growing evidence hints that bidirectional interaction between heart failure and kidney disease and renal insuffi ciency is a strong predictor of mortality as well as causally linked to the progression of heart failure. neutrophil gelatinase-associated lipocalin (ngal) is an early predictor of acute kidney injury (aki). we evaluated the impact of ngal on morbidity and mortality in patients with acute heart failure. methods seventy-six patients presenting with symptoms consistent with acute heart failure (median age years, % male) were enrolled. plasma ngal levels were measured by an elisa at admission and compared with the glomerular fi ltration rate (egfr) and b-natriuretic peptide (bnp) levels. the primary outcome was aki development defi ned by rifle criteria (fall in gfr > % or creatinine rise ≥ % from baseline, or a fall in urine output < . ml/kg/hour) and secondary outcomes were duration of hospital stay and in-hospital mortality. conclusion ngal is emerging as a promising biomarker of aki in the setting of acute heart failure and elevated ngal levels indicate a poor prognosis in this population regarding morbidity and mortality. introduction aki is a common occurrence in sick hospitalized patients, in particular those admitted to intensive care. published data suggest that to % of all critically ill patients develop severe aki and require initiation of renal replacement therapy (rrt) [ , ] . such patients have high mortality rates often exceeding % [ ] . we aimed to review the outcomes of patients admitted to the icu and required renal replacement therapy for aki. we examined whether aetiology of aki, comorbidity burden, hospital length of stay and treatment in icu had any signifi cant association with survival in the study cohort. methods during , patients were identifi ed to have received rrt with aki who were admitted to the icu at the royal wolverhampton hospitals nhs trust. computerised and paper-based case records were examined for these patients to collect the data. akin classifi cation was used to classify the severity of aki. conclusion individuals who develop dialysis-dependent aki in the icu setting in general terms either die or recover. sepsis is the most common association with death. the need for mechanical ventilation and inotropic therapy are both associated with increased incidence of death. introduction this study was to evaluate the effi ciency of the early start of intermittent substitutive renal therapy in patients with polytrauma complicated by multiple organ failure syndrome. methods forty-two patients with polytrauma complicated by multiple organ failure syndrome were included in the study. the age of the patients was from to years ( . ± . years average). all patients were divided into two equal groups. in the control group (cg) the criteria for the start of the substitutive renal therapy were: hyperkalemia ≥ mmol/l, plasma creatinine ≥ μmol/l, diuresis ≤ ml/hour. in the investigation group (ig) there were subtests to carry out the substitutive renal therapy, allowing one to start it in the earlier period of the multiple organ failure progression. these are increase of na + > mmol/l, osmolarity > mosm/l, elevation of the plasma toxicity according to the average molecule concentration ≥ . , diuresis decrease ≤ ml/hour. these were examined: lethality, quantity of the substitutive renal therapy procedures, mechanical lung ventilation duration (mlv), intensive care and hospital duration. the substitutive renal therapy was carried out by ak- -ultra apparatus (gambro, sweden). the statistical analysis was realized using statistica . and the mann-whitney u test. the average quantity of the substitutive renal therapy procedures in the cg was . ± . , in the ig it was ± . (p < . ). the recuperation of the renal excretory functions was on ± day in patients of the cg, and on ± . day in the ig, from the moment of substitutive renal therapy start (p < . ). lethality in the cg was % (nine patients), and in the ig it was % (six patients, p < . ). the duration of the mlv in the cg and ig was ± . days and ± . , respectively (p < . ). in the ig the duration of the icu was lower by %, hospitality duration was lower by % (p < . ). conclusion the effi ciency of the substitutive renal therapy depends directly on the hydroelectrolytic and metabolic changes and toxicosis degrees in the polytrauma complicated by multiple organ failure syndrome. the early start of the dialysis methods treatment allows one to achieve the earlier recuperation of the renal functions and to decrease the lethality level by %. can treatment with the molecular adsorbent recirculation system be the solution for type- introduction it has been suggested that fl uid balance is a biomarker in critically ill patients [ ] . there is a paucity of randomized trials examining the eff ect of daily fl uid balance on outcomes in patients on continuous renal replacement therapy (crrt). the renal trial did not fi nd mortality diff erence with higher crrt dose [ ] , but did not investigate the eff ect of daily fl uid balance on patient outcomes. a post hoc analysis suggested survival benefi t in patients with negative fl uid balance [ ] . in this study, we hypothesize that daily fl uid balance is an independent predictor of mortality in critically ill patients. we conducted a retrospective cohort study in eight icus of a tertiary academic center. we constructed a robust clustered linear regression model of daily fl uid balance and all-cause hospital mortality among critically ill patients receiving crrt. we adjusted the model for the charlson comorbidity score, the daily sofa scores in the fi rst week after initiation of crrt as well the type of icu. results after adjusting for the type of icu and the daily severity of illness, patients who died had on average ml higher daily fl uid balance compared with patients who survived (p < . , % ci = to , ml, figure ). severity of illness predicted daily fl uid accumulation; each additional point of the sofa score predicted an additional ml of extra daily fl uid (p = . ). balance and intradialytic hypotension with mortality and recovery of renal function. methods we conducted a retrospective cohort study among patients aged ≥ years who had rrt initiated and continued for ≥ days in a level or icu at two academic centres, and had fl uid balance data available. patients with end-stage kidney disease, within year of a renal transplant or who had rrt initiated to treat a toxic ingestion were excluded. we used multivariable logistic regression to determine the relationship between mean daily fl uid balance over the fi rst days following rrt initiation and the outcomes of mortality and rrt dependence in survivors. introduction acute kidney injury (aki) is a common complication of critical illness and sepsis [ ] . dosing of antibacterial agents in septic patients is complicated by altered pharmacokinetics due to both acute renal failure and critical illness [ ] . current dosing regimens for administration of gentamicin and vancomycin to septic patients with aki on continuous venovenous hemofi ltration (cvvh) at a fi ltration rate of ml/kg/hour are missing. methods seventeen septic patients with aki treated with vancomycin and seven patients with gentamicin on cvvh were included. in the vancomycin group, patients received the fi rst dose of . g intravenously followed by . g/ hours if not adjusted. in the gentamicin group, patients received a loading dose of mg followed by a maintenance dose every hours. the vancomycin maintenance dose was optimized to achieve auc - /mic ≥ (cmin > mg/l), gentamicin target was cmax/mic of to . maintenance doses were adjusted according to drug level simulation using a pharmacokinetic programme. the median vancomycin total clearance (cltot) was . and . ml/minute/kg on the fi rst and second day of the study. crrt clearance accounted for about to % of vancomycin cltot found in a population with normal renal function ( . ml/minute/kg). vancomycin serum concentrations after the fi rst dose were below the required target of mg/l as early as hours in patients. auc - / mic ≥ ratio was achieved in % of patients on the fi rst day. the median gentamicin cltot was . and . ml/minute/kg on the fi rst and second day of the study. crrt clearance accounted for about % of gentamicin cltot found in a population without renal impairment ( . ml/minute/kg). the target cmax/mic ratio was achieved in % of patients after the fi rst dose. conclusion cvvh at a fi ltration rate of ml/kg/hour leads to high removal of both antibiotics. due to rapid change in patient's clinical status it was impossible to predict a fi xed dosage regimen. we recommend administration of unreduced loading dose and: blood sampling as early as hours after fi rst vancomycin dose; blood sampling to minutes after gentamicin administration and before the next dose; and the maintenance dose should be based on druglevel monitoring. crrt. the aim was to evaluate the eff ects on electrolyte and acid-base status of a new rca-cvvh protocol using an mmol/l citrate solution combined with a phosphate-containing replacement fl uid, compared with a previously adopted rca-cvvh protocol combining a mmol/l citrate solution with a conventional replacement fl uid. methods until september , rca-cvvh was routinely performed in our centre with a mmol/l citrate solution and a postdilution replacement fl uid with bicarbonate (hco - , ca + . , mg + . , k + mmol/l) (protocol a). in cases of metabolic acidosis, not related to inappropriate citrate metabolism and persisting after optimization of rca-cvvh parameter setting, bicarbonate infusion was scheduled. starting from september , in order to optimize buff er balance and to reduce the need for phosphate supplementation, a new rca-cvvh protocol has been designed using an mmol/l citrate solution combined with a recently introduced phosphate-containing replacement fl uid with bicarbonate (hco - conclusion protocol b provided a buff er balance more positive than protocol a and allowed one to adequately control acid-base status without additional bicarbonate infusion and in the absence of alkalosis, despite the use of a standard bicarbonate concentration replacement solution. furthermore, the combination of a phosphate-containing replacement fl uid appeared eff ective to prevent hypophosphatemia. introduction the aim of this study was to establish the intraobserver and interobserver variation of ultrasonographic measurements of the rectus femoris muscle cross-section area (rf-csa). muscle wasting is frequent in the icu, aff ecting more than one-half of the patients with severe sepsis [ ] . muscle mass reduces rapidly, and to % is lost within the fi rst week [ ] . to monitor muscle mass, ultrasound has the benefi ts of being both readily available in the icu and non-invasive. ultrasonographic measurement of rf-csa has an almost perfect correlation with mri (mean interclass correlation (icc) = . ) [ ] and rf-csa is linearly related to maximum voluntary contraction strength in both healthy subjects and copd patients (r = . ) [ ] . methods the study had two purposes: to determine the intraobserver variation for rf-csa by one observer scanning healthy adult volunteers three times each at -day intervals; and to determine the interobserver variation for rf-csa by two observers each scanning adult icu patients on the same day. patients were in a supine position, legs in passive extension. the transducer was placed perpendicular to the long axis of the right thigh over the rf, two-thirds of the distance from the anterior superior iliac spine to the superior patellar border [ ] . rf-csa was calculated by planimetry. at each scan, three measurements were made. for intraobserver variation, the × scans were analyzed using the interclass correlation coeffi cient. for interobserver variation, the three measurements from each observer were averaged and compared using bland-altman statistics. results intraobserver variation: healthy adults, age . ± . years, weight . ± . kg, sex three male/ female. icc: . ( % ci: . to . ). interobserver variation: icu patients, age: ± . years, weight: . ± . kg, sex nine male/six female. bland-altman: bias: - . cm , % limits of agreement - . to . cm . conclusion ultrasonographic measurement of rf-csa is easily learned and quickly performed. it has a very low intraobserver and interobserver variation and can be recommended as a reliable method for monitoring muscle wasting in the icu. in artifi cially fed critically ill patients, adipose tissue reveals an increased number of small adipocytes and accumulation of m -type macrophages [ ] . we hypothesized that nutrient-independent factors of critical illness explain these fi ndings, and also that m macrophage accumulation during critical illness may not be limited to adipose tissue. methods we performed a randomized investigation in a septic mouse model of critical illness and a study of icu patient biopsies. in the critically ill mouse, we compared the eff ect of parenteral nutrition (n = ) with fasting (n = ) on body composition, adipocyte cell size, and macrophage accumulation in adipose tissue, liver and lung. fed healthy control mice (n = ) were studied for comparison. in vivo adipose tissue was harvested after week of illness from human patients (n = ) who participated in a rct on early parenteral nutrition versus tolerating nutrient restriction [ ] , adipose tissue morphology was characterized and compared with healthy controls (n = ). results irrespective of nutritional intake, critically ill mice lost body weight, total fat and fat-free mass. part of the fat loss was explained by reduced ectopic fat accumulation. adipocyte cell number and the adipogenic markers peroxisome proliferator-activated receptor γ and ccat/enhancer binding-protein β increased with illness, again irrespective of nutritional intake. macrophage accumulation with predominant m -phenotype was observed in adipose tissue, liver and lungs of critically ill mice, further accentuated by fasting in visceral tissues. macrophage m -markers correlated with chemoattractant factor expression in all studied tissues. in human subcutaneous adipose tissue biopsies of critically ill patients, increased adipogenic markers and m macrophage accumulation were present irrespective of nutritional intake. conclusion adipogenesis and accumulation of m -macrophages are hallmarks of critical illness, irrespective of nutritional management in humans and mice. critical illness evokes macrophage polarization to the m -state not only in adipose tissue but also in liver and lungs, which is further accentuated by fasting. introduction intravenous magnesium sulfate is commonly used in obstetric patients with pre-eclampsia. following a case of acute symptomatic hypocalcemia we retrospectively examined a cohort of patients to investigate the frequency of hypocalcemia. methods obstetric patients were identifi ed from the icu admissions database and divided into two groups -those treated with magnesium (for suspected pre-eclampsia) and those admitted for other obstetric indications (postpartum hemorrhage, infection, etc.). the baseline calcium values were compared, as well as the lowest and discharge values. albumin and magnesium values were also compared. all comparisons used student's t test. results data were collected on parturients admitted over years including ( %) who received magnesium and ( %) who did not. magnesium-treated women were younger (age: ± vs. ± years, p = . ). the baseline calcium concentrations were similar for the two groups ( . ± . vs. . ± . mmol/l, p = . ). patients receiving magnesium had signifi cantly higher magnesium concentrations ( . ± . vs. . ± . mmol/l, p < . ), and signifi cantly lower calcium concentrations during therapy ( . ± . vs. . ± . mmol/l, p < . ). at discharge, the calcium levels were closer (magnesium treated . ± . vs. untreated . ± . mmol/l, p = . ). the albumin concentrations did not diff er between the two groups (magnesium treated ± vs. nontreated ± g/l, p = . ). normal values: calcium . to . mmol/l, magnesium . to . mmol/l, albumin to g/l. conclusion magnesium therapy was associated with hypocalcemia. potential causative mechanisms include a renal excretion interaction and magnesium-induced suppression of parathyroid hormone secretion. physicians should be aware of the potential for symptomatic hypocalcemia during magnesium therapy. introduction disorders of sodium (na + ) and water homeostasis are common in hospitalised patients. hyponatremia in particular has been associated with worse hospital outcome and length of stay [ ] . we aimed to defi ne the incidence of hyponatremia (serum na + ≤ mmol/l) in our intensive care population and to determine whether it was associated with icu outcome or length of stay. methods demographics, apache ii score, outcome data and admission sodium were retrieved from the ward watcher system in the victoria infi rmary icu for , consecutive admissions from january to present. we divided patients into three groups depending on serum na + (≤ mmol/l, to mmol/l, ≥ mmol/l) and compared apache ii score, length of stay and icu outcome between patients with a low versus a normal serum na + . data were analysed using the chi-squared test, student's t test and the mann-whitney test where appropriate. results of the , patients studied, , had apache ii data and serum na + recorded and so were included for analysis. in total, patients ( . %) had a serum na + ≤ mmol/l and , patients ( . %) had a serum na + of to mmol/l. patients with a low na + had a higher mortality (or = . , % ci = . to . , p < . ), a higher apache ii score ( vs. , p < . ) and higher mean age ( years vs. years, p < . ) than patients with a normal serum na + . mean length of stay of patients with low serum na + was also longer ( . days vs. . days) although this was not statistically signifi cant (p = . ). conclusion in summary, hyponatremia is a useful index of severity of illness in our icu population. whether this is a direct adverse eff ect of low serum sodium levels, or if hyponatremia is simply a marker for 'sicker' patients, is not known. reference introduction the anion gap (ag) is used routinely in the assessment of metabolic acidosis, but can be misleading in patients with hypoalbuminemia and other disorders commonly encountered in intensive care. this approach to acid-base analysis relies on assessment of ph, pco , sodium, bicarbonate and chloride, and can lead to underestimation or overestimation of the true electrochemical status of a patient, as it does not include important ions such as lactate, calcium, magnesium, and albumin. the strong ion gap (sig) is an alternative to the ag and is based upon stewart's physical chemistry approach. however, the sig is cumbersome to calculate. as such, a number of shortcut equations have been developed in an eff ort to approximate the sig. we sought to compare three such equations, the kellum corrected anion gap (kellagc), the moviat equation, and ezsig, in an eff ort to evaluate precision and accuracy [ ] [ ] [ ] . methods we conducted a retrospective chart review of consecutive patients admitted to the icu of george washington university medical center from september to march . of the , patients screened, met inclusion criteria, which included availability of all laboratory components to calculate the sig, obtained within hour of each other. demographic data and serum values for ph, pco , albumin, lactate, sodium, potassium, chloride, bicarbonate, magnesium, phosphate, and calcium were collected. the ag, sig, kellagc, ezsig, and moviat equations were subsequently calculated and compared using pearson correlation and bland-altman analysis. results the mean sig was . ± . . mean values for kellagc, moviat, and ezsig were . ± . , . ± . , and . ± . , respectively. pearson correlation coeffi cients for kellagc, moviat, and ezsig when compared with the sig were r = . , p = . ; r = . , p = . ; and r = . , p = . , respectively. in bland-altman analysis, the mean bias for the test equations versus the sig were: kellagc ( . ), moviat (- . ), and ezsig ( . ). conclusion while all three equations correlated highly with the sig, the ezsig and moviat outperformed the kellagc in pearson and bland-altman analysis. the ezsig had a smaller bias than the moviat equation and a slightly better correlation ( . vs. . ). in the assessment of critically ill patients, ezsig is a candidate scanning equation for the measurement of the sig when all sig components are not available. university-affi liated teaching hospital in tunis. patients admitted within the fi rst hours post burn with greater than % total body surface area (tbsa) burned were enrolled in this study from january to june . exclusion criteria were pregnancy, history of adrenal insuffi ciency, or steroid therapy within months prior to burns. a short corticotrophin test ( μg) was performed, and cortisol levels were measured at baseline (cs t ) and minutes post test. adrenal insuffi ciency was defi ned by a response ≤ μg/dl. relative adrenal insuffi ciency was further defi ned by a baseline cortisol > μg/dl. results patients were assigned into two groups: g (rai, n = ) and g (absence ai, n = ). comparative study of the two groups shows the results presented in table . conclusion rai is common in severely burned patients during the acute phase, and is associated with shock. further prospective controlled studies will be necessary to establish risk factors of rai in severely burned patients and its impact on their prognosis. albumin-adjusted calcium concentration should not be used to identify hypocalcaemia in critical illness t steele , r introduction hypocalcaemia is common in critical illness and accurate assessment is crucial. small studies have shown that albumin-adjusted calcium (adjca) does not accurately predict the ionised calcium (ica) concentration in critically ill patients, yet adjca continues to be widely used [ ] . we investigated the reliability of using adjca to identify hypocalcaemia in a large, diverse population requiring intensive care. methods in a retrospective study of patients admitted to the icus of a tertiary care hospital between january and , ica and ph were extracted from routine blood gas results and total calcium, albumin and phosphate from routine biochemistry results. adjca was calculated using a formula derived from and validated on the local population [ ] . sensitivity, specifi city, positive and negative predictive values (ppv and npv) and area under the curve (auc) of adjca for predicting hypocalcaemia (ica < . mmol/l) were calculated. results in total, patients were included. the mean age was ± years, mean weight ± kg, apache ii score ± and most patients suff ered from pneumosepsis. on the fi rst day of intubation, total and free testosterone levels were extremely low in most patients and remained low during the fi rst week (figure ). β-estradiol levels were elevated on day and decreased during the fi rst week. lh and fsh levels were inappropriately low. all lipoprotein fractions and their apo-proteins were reduced as well as -oh-progesterone, dhea and dheas. in contrast, androstenedione (adione) levels were elevated. this suggests preferential and stimulated synthesis of androstenedione ( figure ). the high β-estradiol levels indicate that androstenedione is shunted into the estrogen pathway, a process that requires high aromatase activity. the high estradiol/total testosterone ratio supports this conclusion. conclusion hyperestrogenic hypotestosteronemia is a frequent fi nding in the acute phase of severe sepsis in male patients with respiratory failure. it is suggested to be caused by decreased androgen production and shunting of androgen to estrogen synthesis as a result of increased aromatase activity. the clinical relevance of gonadal hormone substitution needs further study. introduction melatonin could have a meaningful role in critically ill patients, because of its immunomodulatory, antioxidant and sleep regulation properties; it is reduced in critical illness. the purpose of this study is to describe the endogenous blood melatonin values in icu patients and their correlation with clinical parameters. methods seventy-three high-risk critically ill patients mechanically ventilated for > hours were enrolled. blood samples for melatonin assay were collected between the rd and the th day of the icu stay. melatonin was determined by radioimmunoassay and elisa. the peak and the area under the curve (auc) calculated for each patient were correlated with the clinical parameters using the regression for quantiles test. results endogenous melatonin was found lower in critically ill patients compared with healthy subjects (figure ) , although it showed a great individual variability and it generally maintained a night-time increase. in the univariate analysis the peak was found related to: blood creatinine (p = . ); patients in coma (p = . ); hospital mortality (p = . ). the auc was found related to: saps ii (p = . ); creatinine (p < . ); ast (p < . ); alt (p < . ); hospital mortality (p < . ). peak and auc were found higher in nonsurvivor patients. in accord with previous studies, the endogenous blood melatonin was found reduced in icu patients. the higher melatonin peak in renal failure may be due to an increased distribution volume; greater auc in patients with liver failure could be due to a less effi cient removal of the hormone from the systemic circulation. the fi nding of increased peak and auc in nonsurvivor patients could be due to a hormonal response increased by the body stress reaction, potentially similar to cortisol [ ], or to a higher production of a physiological antioxidant [ ] with a decreased ability to use it. introduction metformin intoxication inhibits mitochondrial complex i and oxygen consumption (vo ). succinate bypasses complex i by donating electrons to complex ii. the aim of this study was to clarify whether succinate ameliorates mitochondrial vo of metforminintoxicated human platelets. methods platelet-rich-plasma was incubated for hours with metformin at a fi nal concentration of mg/l (control), . mg/l (therapeutic dose) or mg/l (toxic dose). platelet vo was then measured with a clark-type electrode, in the presence of glutamate plus malate (complex i electron donors) (fi nal concentration: mmol/l for both) or succinate (complex ii electron donor) ( mmol/l), before and after adding cyanide ( mmol/l). mitochondrial (cyanide-sensitive) and extra-mitochondrial (cyanide-insensitive) vo were corrected for platelet count. the main results, from four preliminary experiments, are shown in figure . in the presence of glutamate plus malate, only platelets incubated with a high dose of metformin had a mitochondrial vo signifi cantly lower than controls. in the presence of succinate, mitochondrial vo of controls did not change signifi cantly whereas that of platelets incubated with metformin did. the eff ect of succinate tended to become larger as the dose of metformin was increased from up to mg/l ( . ± . vs. . ± . vs. . ± . nmol/minute* cells) (p = . ). even so, mitochondrial vo of platelets incubated with the highest dose of metformin did not return to the levels of controls. extra-mitochondrial vo was always the same. introduction metformin, widely used as an antidiabetic drug, activates the amp activated protein kinase, a key regulator of the metabolism providing protection under fuel defi ciency. chronic metformin therapy has been shown in long-term follow-up clinical studies to reduce cardiovascular mortality [ ] . in animal experiments, acute metformin pretreatment has been shown to reduce ischemia-reperfusion injury on cardiomyocytes [ ] . we want to evaluate whether outcomes are aff ected in coronary artery bypass grafting (cabg) surgery. introduction metformin, an oral hypoglycemic drug, belongs to the biguanide class and is now generally accepted as fi rst-line treatment in type diabetes mellitus, especially in overweight patients [ ] . in some predisposing conditions, the use of metformin may result in metforminassociated lactic acidosis (mala), a rare adverse event associated with a high mortality rate [ ] . the aim of this study is to assess risk factors and prognostic factors in patients with mala. [ ] . in our study, a higher plasma concentration of lactate represents the main negative prognostic factor, as pointed out by other studies [ ] . the prothrombin activity, which is considered to be a decisive prognostic factor in the study of peters and colleagues [ ] , was not impaired in patients with poor outcome. introduction stress hyperglycemia in the critically ill is a complex process in which insulin signaling is systematically hijacked to provide energy substrate for metabolic priorities such as cell healing or infection containment. fluctuating levels of plasma glucose are associated with increased mortality in the icu [ ] . we develop a multiscale mathematical model that can characterize the severity of stress hyperglycemia based on a fundamental understanding of the signaling molecules involved. methods insulin resistance following insult has been shown to be driven primarily by the immune response via the cytokine il- [ ] . we created a multiscale mathematical model that links circulating glucose and insulin concentration dynamics from the extended minimal model [ ] to a cellular insulin response model [ ] that captures insulinmediated glucose uptake in an insulin-responsive cell. results inhibitory dynamics driven by il- were incorporated into the cellular model to attenuate an insulin signaling intermediate (insulin receptor substrate ) according to the proposed biological mechanisms. the percentage reduction in glucose uptake as a function of il- concentration was fi t to data from patients who underwent elective abdominal surgery [ ] , shown in figure . the overall multiscale model captures decreased insulin signaling as a result of increased il- levels and the subsequent hyperglycemia that may ensue. introduction hyperglycemia is frequently encountered in critically ill patients, and associated with adverse outcome. improvement of glucose protocol adherence may be accomplished using electronic alerts. we confi gured a non-intrusive real-time electronic alert, called a glyc sniff er, as part of our intensive care information system (icis) that continuously evaluates the occurrence of persistent hyperglycemia and hypoglycemia. conclusion a real-time electronic persistent glycemia sniff er resulted in a signifi cantly higher proportion of normoglycemia, without increasing the variability. furthermore, hypoglycemic events occurred less frequently, and were resolved more timely. smart alerting is able to improve quality of care, while diminishing the problem of alert fatigue. introduction a recent study showed that hyperglycaemia (blood glucose ≥ . mmol/l) in nondiabetic patients hospitalised in a medical icu is associated with increased risk of diabetes [ ] . we investigated a large mixed icu population to confi rm these results. methods this study retrospectively included patients with negative history of diabetes admitted to icus during the year . we excluded patients receiving steroids, with newly diagnosed diabetes and those with end-stage disease. patients were followed-up years after index admission. diagnosis of diabetes within months from the index admission was presumed as revealing dm at inclusion, which excluded the patient. patients who were taking glucocorticoids during the followup period were excluded. diabetics were identifi ed from icd- documentation. propensity score for death (pdead) was computed from either sap (mimicii) or apache iii (hidenic) to assess the risk of death. hypoglycemia was defi ned as avg ≤ mg/dl. avg was computed as the area under the glucose curve throughout icu admission. mortality was examined within bins (each bin is categorized by a mg/dl increase in avg) and was compared between adjacent categories using a chi-square test. the same method was repeated among diabetics, nondiabetics, patients with lower (pdead greater than median) and higher (pdead lower than the presence of decubiti on admission to the icu is associated with longer hospitalizations even after adjusting for age, acuity, and organ supportive therapies. du on admission to icu provide a unique, unambiguous marker of increased resource utilization. introduction the aim was to analyze the prognosis of aids patients with organ dysfunctions at icu admission. methods a prospective cohort study, including all patients with hiv/ aids diagnosis, who were admitted to a specialized icu from november until may . patients with less than hours of icu stay were excluded. demographics and nutritional status were collected. the organ dysfunctions were classifi ed according to the sofa score, and categorized as absent ( sofa point), mild ( to points) and severe ( to points). we expressed numeric variables as median and interquartile interval ( % to %). we performed a multivariate analysis of possible variables associated with hospital mortality (p < . ), and we explored the -day, -day and -day survival of patients with and without independent risk factors. we included patients with hiv/aids admitted to the icu. median age was ( to ) years and % were male. severe malnutrition was common ( %). the cd cell count was ( to ) cells/mm and viral load was , ( to , ) copies/ml; % had at least one opportunistic infection; % had used antiretroviral therapy previous to icu admission. mechanical ventilation was used by % of patients and hospital mortality was %. total sofa score was ( to ) points. cardiovascular dysfunction was the most common on the fi rst day of stay ( %), followed by respiratory ( %), neurological ( %), renal ( %), hematological ( %) and hepatic ( %). cardiovascular and renal dysfunctions presented with higher rate of severe dysfunction ( % and %, respectively). rates of neurological (p = . ), renal (p = . ) and hematological (p = . ) dysfunctions were higher in nonsurvivors. age, cd cell count, malnutrition, and opportunistic infections were included in the multivariate analysis. neurological dysfunction was the independent risk factor for hospital mortality (odds . ( . to . )). the presence of neurological dysfunction was dichotomized: associated or not with primary neurological diagnosis; survival was lower in the patients with neurological dysfunction and without primary neurological diagnosis (log-rank test . in the -day and . in the -day analysis). sixty-day survival was similar in primary and secondary neurological dysfunction, but it remained lower than in patients without neurological impairment. conclusion neurological dysfunction was independently associated with hospital survival, mainly in those aids critically patients without primary neuropathy. results a total of charts were reviewed. in total, were categorized into a (n = ), b (n = ) or c (n = ). d (n = ) consisted mainly of patients with hematological malignancies (n = ) and patients with chemotherapy or immunosuppressive treatment (n = ). the groups diff ered in length of stay with a< b< c. during the fi rst days the sofa score was higher in a compared with c and in b compared with c. the duration of antibiotic therapy was longer in both b and c compared with a. there were no diff erences in -day mortality (a: / = %, b: / = %, c: / = %); however, the proportions of patients dying between days and were higher in b ( / = %) and c ( / = %) compared with a ( / = %). conclusion in this retrospective material it was possible to categorize . % of all patients as having primary, secondary or tertiary sepsis. the categories diff ered in clinical picture at presentation as well as in outcome. a prospective study is warranted to validate the results of this study. conclusion older people represent a growing proportion of the population although their representation in the critical care population remained constant in this -year study. these patients had a slightly higher median apache ii score and . % greater critical care mortality than the younger patients. the majority of survivors were able to go home; however, % died within months with signifi cant life expectancy curtailment, surviving on average only . months after discharge; this has not changed in the last years. those who survived this initial period ( %) had a much better outlook. this information may be vital to patients and physicians when discussing admission to critical care. reference methods potential risk factors for psychological problems were prospectively collected at icu discharge. two months after icu discharge icu survivors received the questionnaires post-traumatic stress symptom scale- (ptss- ) and hospital anxiety and depression scale (hads) to estimate the degree of post-traumatic stress, anxiety and depression. of the responders, % had adverse psychological outcome, defi ned as ptss- > and/or hads subscales ≥ . after analysis, six predictors with weighted risk scores were included in the screening instrument: major pre-existing disease, being a parent to children younger than years of age, previous psychological problems, in-icu agitation, being unemployed or sick-listed at icu admission and appearing depressed in the icu. each predictor corresponded to a given risk score. the total risk score, the sum of individual risk scores, was related to the probability for adverse psychological outcome in the individual patient. the predictive accuracy of the screening instrument, as assessed with area under the receiver operating curve, was . . when categorizing patients in three risk probability groups -low ( to %), moderate ( to %) and high ( to %) risk -the actual prevalence of adverse psychological outcome in respective groups was %, % and %. conclusion the preliminary screening instrument may aid icu clinicians in identifying patients at risk for adverse psychological outcome after critical illness. prior to wider clinical use, external validation is needed. the multiorgan dysfunction syndrome (mods) is a dynamic process involving simultaneously or consecutively two or more organ systems [ ] . the organ dysfunction's degree can be assessed by three severity scores (sofa [ ] , mods [ ] , lods [ ] ), but they have some limitations: they do not allow the evaluation of the clinical course of a patient, they are not reliable in populations diff erent from the reference one, and they do not support clinicians' decisions. because mods implies a systemic infl ammatory reaction leading to microcirculatory dysfunction, our hypothesis was that organ failures follow a predictable sequence of appearance. our aims were to verify the presence of more likely organ failure sequences and to assess an online method to predict the evolution of mods in a patient. the high mortality and morbidity rate of mods in icus can in fact be reduced only by a prompt and well-timed treatment [ ] . methods we selected patients consecutively admitted to the icu of sant'andrea hospital from january to june . the inclusion criteria were at least two organ systems with sofa ≥ , icu length of stay > hours. for each patient we calculated the sofa since the beginning of the inclusion criteria and daily for days. for the statistical analysis we used dynamic bayesian networks (dbns) [ ] . dbns were applied to model sofa changes in order to identify the most probable sequences of organs failures in a patient who experienced a fi rst known failure. we created a dbn for the analysis of mods studying the relations between organ failures at diff erent times. the dbn was made so that each organ failure is dependent on the previous one. we also considered a corrective factor to take account that not all patients completed the observation. using software (genie) we obtained the probabilities of the organ failure sequences. conclusion the use of dbns, although with our limited set of data, allowed us to identify the most likely organ dysfunction sequences associated with a fi rst known one. capability to predict these sequences in a patient makes dbns a promising prognostic tool for physicians in order to treat patients in a timely manner, or to test a treatment effi cacy. introduction assessing whether a critically ill patient should be admitted to an icu remains diffi cult and mortality amongst icu patients is high. to render intensive care with no prospect of success is an immense emotional burden for both patient and relatives, and a great socioeconomic burden for society as well. therefore, validated strategies that can help identify patients who will benefi t from intensive care are in demand. this study seeks to investigate whether preadmission quality of life can act as a predictor of mortality amongst patients admitted to the icu. methods all patients (> years) admitted to the icu for more than hours are included. in order to assess preadmission quality of life, the patient or close relatives complete the short-form (sf- ) within hours after icu admission. mortality is evaluated from icu admission until days hereafter. logistic regression and receiver operating characteristic analyses are employed to assess predictive value for mortality using fi ve models: introduction long-term compromise after traumatic injury is signifi cant; however, few modifi able factors that infl uence outcome have been identifi ed. the aim of this study was to identify acute and early post-acute predictors of long-term recovery amenable to change through intervention. methods adults (> years) admitted to the icu, princess alexandra hospital, australia following injury were prospectively followed. data were collected on demographics, pre-injury health, injury characteristics and acute care factors. psychosocial measures (selfeffi cacy (se), illness perception (ip), post-traumatic stress disorder (ptsd) symptoms and psychological distress) and health status (sf- ) were collected via questionnaire , , , and months post injury. outcomes of interest were the physical function (pf) and mental health (mh) subscales of the sf- . regression models were used to estimate predictors of physical function and mental health over a -year period. a subject-specifi c intercept in a mixed model was used to account for repeated data from participants over time. results participants (n = ) were young (median , iqr to years), predominantly male ( %) and spent on average days in the icu and weeks in hospital. response rates were over % at each follow-up, with responders similar to nonresponders except for being generally older. pf and mh scores improved over time, although the averages remained below the australian norms at months. predictors of pf included ip (β = - . , % ci = - . to - . , p < . ), se (β = . , % ci = . to . , p < . ), hospital length of stay (β = - . , % ci = - . to - . , p < . ), never having been married (β = . , % ci = . to . , p = . ), and having injury insurance (β = - . , % ci = - . to - . , p < . ). predictors of mh included ptsd symptoms (β = - . , % ci - . to - . , p < . ), psychological distress (β = - . , % ci = - . to - . , p < . ), se (β = . , % ci = . to . , p < . ), and unemployment (β = - . , % ci = - . to - . , p = . ). conclusion trauma icu patients experience compromised physical function and mental health months after injury. psychological distress, self-effi cacy and illness perception infl uence outcomes and are potentially amenable to change in response to interventions initiated during hospital stay. introduction swiss diagnosis related groups (swissdrg) have been eff ective since january . the infl uence of this new system on patients' discharge characteristics from a large icu is not known. with the introduction of the drg we expect patients to be discharged after a shorter length of stay on the icu and with higher severity of illness. methods the icu of the city hospital triemli in zurich has an interdisciplinary organization with surgical and internal medical patients, with a maximum occupancy of beds and a center function for the surrounding hospitals. in this ongoing prospective observational study, we collect and analyze the anonymized data of all patients discharged from our icu prior to and after the introduction of the swissdrg. the primary endpoint was the length of stay on the icu in hours. the secondary endpoints were the severity of illness of the patients at the time of discharge, detected by the scoring system saps ii as well as measured by the number of readmissions to the icu. initially all patients were analyzed and in a second step only patients within percentiles to were considered. we also analyzed the subgroups of patients referred internally, patients sent back to referring hospital and patients regionalized to a homebase hospital. the statistics have been done with spss and p < . was considered signifi cant. results we present the results of an -month period, months prior to and months after the introduction of the swissdrg. data of , and , patients were analyzed, respectively. when all patients were included, we found prior to and after the introduction of the drgs a comparable length of stay on the icu (mean ± sd of . ± . hours vs. . ± . hours), no diff erence in the severity of illness at discharge detected by the saps ii (mean ± sd of . ± . vs. . ± . ) and the number of readmissions ( vs. ). there was also no signifi cant diff erence when only percentiles to were included or when the three subgroups were analyzed. conclusion up to now, the introduction of the swissdrg has no infl uence on patients' discharge characteristics from a large icu. data assessment will continue and further data analysis has to be performed. there are only few data on the infl uence of drg on icu patients [ , ] . we expect that the introduction of the drg in switzerland will change the number of admissions from external hospitals to a large icu with a centre function and will infl uence the severity of disease of the admitted patients. the icu of the triemli city hospital in zurich has an interdisciplinary organisation with surgical and internal medical patients, with a maximum occupancy of beds and a centre function for the surrounding hospitals of the region. in this prospective ongoing observational study, we collect and analyse the anonymised data of all patients admitted to our icu from an external hospital during months prior to ( january to december ) and after ( january to december ) the introduction of the drg in switzerland. exclusion criteria are admissions by the emergency department, self-assignments into the hospital and internal relocations. the primary endpoint is the number of admissions from an external hospital to our icu. secondary endpoints are the severity of the disease of the admitted patients, detected by the scoring systems saps ii and apache ii as well as the length of stay in external hospitals before admission. the statistical analysis is descriptive. results we present the preliminary data for months (in each case january to october) before and after the introduction of the drg. we observed an increase of . % ( vs. patients) of admissions to our icu after the introduction of the drg. the severity of disease determined by the saps ii score is unchanged (mean . vs. . points, p = . ). the severity of disease determined by the apache ii score is signifi cantly lower ( . vs. points, p = . ). we also noted that after the introduction of the drg the patients were earlier transferred from an external hospital to our icu (mean time until transfer . vs. . hours), but this value was not signifi cant (p = . ). conclusion up to now the introduction of the drg in switzerland has had a complex infl uence on the number and the kind of patients (lwp, n = ); and patients whose waiting time was equal to or less than that period, short waiting period (swp, n = ). results in total, patients were included, of which belonged to the lwp group ( . %). for the entire cohort, the mean apache ii score was ± , the mean age was ± years, and patients were male ( . %). the lwp group did not show diff erence in the apache ii score ( ± vs. ± , p = . ), but was older ( ± vs. ± , p = . ). lwp also had a higher incidence of primary bloodstream infection ( . % vs. . %, p = . ) and catheter-associated urinary tract infection ( . % vs. . %, p = . ). lwp patients had higher mortality ( . % vs. . %, p = . ) and longer icu los ( ± vs. ± days, p = . ). relative risk for death in the lwp was . ( % ci: . to . ). conclusion despite showing no signifi cant diff erences on apache ii scores from the swp group, patients from the lwp group presented greater incidence of primary bloodstream infection, catheterassociated urinary tract infection, higher mortality outcomes and longer icu los. references intensivists are expected to have many roles during and after a major disaster/catastrophe; that is, triage, intensive care, education for people, and so forth. the roles of intensivists against special disaster or nuclear disaster are studied based on actual experiences. methods several disasters are studied. the fukushima daiichi nuclear plant explosion after the higashinihon earthquake was medically reviewed based on the total -day stay on-site in addition to several days around the site. the chernobyl incident was inspected years after the incident. other nuclear disasters are included. results many serious problems were revealed in the medical teams, which are as follows: inappropriate basic preparedness against large special disasters, including nuclear disaster; lack of appropriate education and training for medical teams against nuclear disasterthat is, most members of japan dmat or the disaster medical assistance team are still laypersons; incorrect standard/rules of japan dmat, which were excessively focused upon cure of the usual type of injury and planned short period or nearly hours, which should be abandoned; and insuffi cient consideration to the weak/vulnerable people or cwap, children, (pregnant) women, aged people, and the poor people/sicker patients. many of them died because of an insuffi cient emergency transportation system from their contaminated houses or hospital. conclusion in order to cope with the special disasters, such as nbc or nuclear, biological and chemical disaster, it is insuffi cient to take makeshift measures or use cheap tricks. working out the systematization of disaster medicine, based upon the academic viewpoints and philosophy/reliability, is essential to protect the people and the nation. variation in acute care burden and supply across diverse urban settings s murthy , s austin , h wunsch , nk adhikari , v karir , k rowan , st jacob , j salluh , f bozza , b du , y an , b lee , f wu , c oppong , r venkataraman , v velayutham , d angus the world bank has warned that the rapid growth of the world's urban population can only be accommodated safely if cities adequately develop key infrastructure, such as the provision of acute care resources. yet, even basic descriptive information on urban acute care supply and demand is extremely limited. we therefore conducted a pilot assessment across seven diverse urban settings across the world. we selected a convenience sample of seven large cities with varying geographical and socioeconomic characteristics: boston, paris, bogota, recife, liaocheng, chennai, and kumasi. to estimate acute care supply, we developed an instrument to collect data on acute and critical care infrastructure. we collected data from municipal authorities and local research collaborators. we expressed the burden of acute disease as the number of deaths due to acute illnesses, estimated from the global burden of disease study. results were expressed as acute care supply and acute deaths per , population and acute care supply per acute deaths. the supply of hospital beds varied from . / , population in kumasi to . / , in boston. icu beds with capacity for invasive mechanical ventilation and intensive nursing services ranged from . / , in kumasi to / , population in boston. the number of ambulances varied -fold between cities. the gap between cities widened when demand was estimated based on disease burden, with a -fold diff erence between cities in icu beds/acute deaths. in general, most of the data were unavailable from municipal authorities. conclusion the provision of acute care services, a key aspect of urban infrastructure, varied substantially across the seven diverse urban settings we studied. furthermore, the local municipal authorities generally appeared to have little knowledge of their acute care infrastructure, with implications for future planning and development. resources may not always be allocated by severity of illness, but by custom or habit, particularly if diff erent groups administer bed control and triage. specialty-specifi c diff erences may exist even when a single team controls triage. variability in resource utilization has important implications for cost-containment and triage. methods patients admitted to a single, closed medical/surgical icu with full-time intensivists and unifi ed triage control in a large, university-affi liated hospital were evaluated during to . patients who died in the icu were excluded. the day of discharge (d/c) and severity using apache iv and its related acute physiology score (aps) component were calculated daily for the fi rst days. trend was assessed across days by cuzick's test. results a total of surgical and medical patients met inclusion criteria. in total, . % of surgical and . % of medical patients had an icu los < ; p = . . admission severity was correlated with length of stay, p = . for both medical and surgical patients. medical patients are sicker on admission and d/c from the icu than surgical patients (p < . ) (figure ). conclusion icu utilization diff ered by patient type even with unifi ed triage control within a single unit. surgical patients were less severely ill on admission to and d/c from the icu. a signifi cant percentage of medical and surgical patients are d/c within day and may be more effi ciently served in a less resource-intensive environment. the reasons for the diff erences in icu utilization for surgical versus medical patients require clarifi cation and may have implications for both resource utilization and cost. introduction interest in safety and clinical outcomes of inpatients has been growing in japan, because the , lives campaign was introduced under the japanese patient safety act in . in this act, an introduction of the rapid response system (rrs) was one of the mainstreams to inpatients' care. however, many japanese healthcare providers cannot understand how to achieve the introduction of the rrs, because there are few who have knowledge of the system. therefore, we developed a new introductory training course for the rrs. the educational eff ectiveness was analyzed through the surveillance questionnaires after the course. methods the educational program includes a lecture series con cerning the outline and management methods, introduction of facilities that have already deployed, small group discussions, and teaching methods-of-training for the medical emergency team using a simulator. evaluation was made in the fi ve-point scale by participants ( physicians, nurses and eight other professions) throughout seven courses. the questionnaires are: a. understanding of rrs, b. knowledge acquisition about patient safety, c. expectation for decreasing the cardiopulmonary arrest by rrs, and d. expectation for decreasing the psychological burden by rrs. results seventy-three participants ( . %) answered the questionnaires. the numbers of participants who scored more than four points were as follows: a. was ( . %), b. was ( . %), c. was ( . %), and d. was ( . %), respectively. the majority of participants obtained the correct knowledge, and had a solid understanding for the rrs. it was evident that providing abundant material and didactic lectures traced from the introduction to management, and collecting and resolving the questions, promoted comprehension. however, there is a limitation of whether or not the participants introduce the rrs into their own institutions. it is essential to improve the course and continue to support the activities of the participants. conclusion our training course may promote the introduction and dissemination of the rrs in japan. introduction teaching of medical ethical issues including confi dentia lity and consent have long been a small part of the medical curriculum. these issues are more complex in an icu where patients may lack capacity. documents such as good medical practice , confi dentiality and the mental capacity act give guidance to medical professionals in these matters in the uk. methods a questionnaire was distributed amongst staff in four icus in south london. results were analysed according to level of experience and background (medical/nursing or allied health professional (ahp)). of questionnaires distributed, the response rate was % ( % doctors, % nurses and % ahp). staff with either less than year experience or greater than years experience had the greatest exposure to the mental capacity act and data protection act, suggesting a gap in knowledge in staff with intermediate experience. knowledge of the caldicott principles were unaff ected by experience, with many experienced respondents having 'no idea' . the majority of respondents (unaff ected by experience) felt that when giving information to relatives face to face, relatives should be kept fully informed. when giving information over the telephone, most doctors felt the response should be tailored to the knowledge of the person being spoken to whilst nurses were split between tailoring the response, giving full information, setting up a password system and not giving any information at all. most respondents felt date of birth and hospital number constituted 'patient identifi able information' . however, experienced staff did not appreciate the importance of unusual diagnosis and clinical photographs as also being able to identify patients. similarly, the majority knew that the patient themselves identifi ed the 'next of kin' but % (unaff ected by experience) felt this was decided by the family and felt the family could decide on resuscitation status. when consent is required for an elective procedure in a patient who lacks capacity, doctors tended to have a better understanding of the need to delay the procedure where possible than nurses, the majority of which felt this could be decided by the next of kin or two consultant doctors. most doctors felt that 'acting in the patient's best interests' would mean doing what would give the patient the best outcome rather than doing what the patient would have wanted (unaff ected by experience). the majority of staff , on answering this questionnaire, felt that they lacked suffi cient knowledge on the subject and most felt annual reminders would be useful. the icu is an environment where issues of consent, confi dentiality and disclosure of information occur daily. staff feel they lack knowledge in these areas that is unaff ected by their experience. we need to ensure that all staff have the necessary knowledge to deal with these situations. introduction alcohol-related hospital and icu admissions are known to have a huge impact on healthcare resources in the uk. excessive use of alcohol is independently associated with sepsis, septic shock and hospital mortality among icu patients. this study assesses the relationship between alcohol abuse and intensive care resource utilisation in a mixed medical, surgical and neurosurgical icu. methods a prospective survey of emergency alcohol-related admissions over a -year period was undertaken at a tertiary university adult general and neurosurgical icu. all patients were screened for acute and chronic alcohol abuse on admission. acute alcohol abuse was defi ned as being intoxicated with alcohol at the time of admission and chronic alcohol abuse was defi ned as chronic alcohol use exceeding recommended uk national guidelines on consumption. the amount of alcohol consumption was obtained, diagnosis on admission, icu and hospital mortality, length of stay, and total cost were recorded. all patients were screened for alcohol-related comorbidities. comparative retrospective data were obtained for the same time period for nonalcohol-related emergency icu admissions. data were analyzed using spss. results in total, . % of patients were admitted with a history of acute/chronic alcohol excess. sixty-seven per cent of alcoholrelated admissions were due to acute alcohol excess. neurosurgical patients admitted due to alcohol excess had higher itu mortality than nonalcohol-related neurosurgical patients: . % versus . % (p = . ), respectively. ninety-three per cent of alcohol-related neurosurgical admissions were caused by acute alcohol intoxication. the intensive care cost was signifi cantly higher for alcohol-related (£ , per patient) compared with nonalcohol-related neurosurgical admissions (£ , per patient). of the medical patients admitted, % of these admissions were due to acute alcohol excess. the cost of intensive care treatment was lower for alcohol-related medical admissions. conclusion this is one of the largest studies of alcohol-related admissions to critical care. our survey confi rms that alcohol-related admissions to the icu are commonplace; however, our frequency is signifi cantly less than previously reported. our study reveals interspecialty variations in demographic data, apache ii scores, mortality and cost of admission. neurosurgical alcohol-related admissions bear higher mortality and result in greater resource utilisation relative to nonalcohol-related neurosurgical admissions. alcohol continues to burden both our patients and critical care. during the fi rst three postoperative days, preoperative ahi > was associated with a prolonged weaning time, a reduced oxygenation index (arterial po /fio ), an impaired kidney function, an augmented infl ammatory response and an overall increased length of stay in the icu. the observed association of high preoperative ahi values with postoperative clinical characteristics remained statistically signifi cant throughout the fi rst three postoperative days. conclusion undiagnosed sdb is highly prevalent among cardiac surgical patients. clinical trajectories of individuals with severe sdb are described by a prolonged recovery of pulmonary function, delayed weaning and a pronounced infl ammatory response after surgery. screening for sdb might identify patients that are susceptible for a complicated postoperative course. introduction a literature review was performed to assess whether massage benefi ts patients postoperatively following coronary bypass grafts (cabg) and or valve replacement/repair. a case study on a patient who had suff ered a hypoxic brain post cardiac arrest was conducted. methods a review on medline and cochrane using search terms massage, cardiac and icu identifi ed nine research papers on the benefi ts of massage postoperatively for the aforementioned patient group. other papers were listed but unrelated to cardiac surgery. none of the nine papers identifi ed for this review were icu specifi c in the title but the icu was mentioned in the main text body. for the purpose of this review the selected papers are researching the eff ects of massage on physiological parameters, anxiety, pain, calm and perceived stress indicators in the cabg and/or valve repair/replacement. out of these nine papers, one is british ( ). five are american ( to ), two are brazilian ( ) and one is an indian paper ( ). all papers are randomised control trials (rcts). papers written prior to were excluded from this literature review. introduction vap has continued to be a major cause of morbidity and mortality in critically ill patients in thailand for decades. previous research found that the implementation of vap care bundles and the educational program can reduce vap incidence in the icu [ ] . in this research we aimed to observe the reduction of vap incidence after the implementation of vap care bundles to icu medical personnel. methods inclusion criteria: all adult surgical patients (> years old) who are on ventilatory support in the surgical icu at siriraj hospital. there are two groups, divided into pre-educational group (group i) and post-educational group (group ii) (n = /group). we also observed the adherence rate to vap care bundles according to the educational program. the pretest and post-test to determine the effi cacy of the educational program were done. the vap care bundles consisted of weaning according to weaning protocol, sedation vacation, headof-bed elevation, measurement of cuff pressures four times/day, % chlorhexidine use for mouth care and emptying of ventilator circuit condensate. results there were . and . episodes of vap per , ventilatordays in group i and group ii, respectively (p = . ). the incidence of vap was . % in group i and . % in group ii (p = . ). there was signifi cant reduction in the length of ventilatory support per person (group i = , group ii = (median), p = . , % ci = . to . ) and mortality rate (group i = . %, group ii = . %, p = . ). there was no signifi cant diff erence in loi, loh and atb cost. the pretest scores were . and . on average from medical personnel in group i and group ii, respectively (p = . ). the head-of-bed elevation adherence rate was improved after the educational program (group i = . %, group ii = . %, p = . ). but the adherence to other bundles was not improved. see tables and . introduction following our study of severe sepsis care across three centres [ ] , we aimed to introduce a rapid feedback mechanism into our rolling audit programme. whilst previous audits raised awareness of severe sepsis, only whole organisation performance was reported and no feedback was given to individual clinicians. it is recognised that such feedback loops can improve clinical practice [ ] . methods patients admitted to critical care ( beds, four units) with a primary admission diagnosis of infection were screened for severe sepsis. pre-icu care was then audited against the surviving sepsis guidelines [ ] . time zero is defi ned as when criteria for severe sepsis were fi rst met. an individualised traffi c-light report was then generated and emailed to the patient's consultant and other stakeholders involved in care (figure ). we aimed to report cases within days of critical care admission. a cumulative report is generated monthly to track organisation-wide performance. since november , cases of severe sepsis have been audited and reported back to clinicians. compliance with antibiotics in < hour has risen from to % and compliance with the pre-icu elements of the resuscitation bundle has risen from to % ( figure ). feedback from clinicians has been encouraging as our reports highlight both positive and negative examples of practice. conclusion individualised feedback on sepsis care has led to substantial improvements in guideline compliance. this concept could be translated to other time-dependent patient pathways. introduction when we talk about safety culture, we speak of being aware that things can go wrong. we must be able to recognize mistakes and learn from them, sharing that information fairly and impartially to try to prevent its recurrence. organizations such as the agency for healthcare research and quality (ahrq) have developed tools to help organizations measure their safety culture and there is little information about our country. methods a descriptive survey study. we sent the spanish version of the questionnaire on patient safety culture (ahrq) to the nursing staff of a polyvalent icu of beds in a tertiary hospital. the questionnaire was sent to nurses, receiving correctly answered surveys (response rate of . %). on a scale of to , . points was obtained to estimate the safety climate for staff respondents. the item best scored was teamwork in the unit ( . %). detected as a fortress, 'communication between nurses at shift changes' ( . % positive responses). the worst rating was obtained in the section on human resources, followed by management support in the fi eld of patient safety. conclusion the perception of safety culture in an icu by nursing staff is far from optimal levels. the team work dimension was identifi ed as the most valued by workers, with the transmission of information on shift changes the most valued item. methods to compare our number of admissions, related activity and case-mix indicators year before and after the geographical change was done. we analyzed our whole number of patients admitted to the icu. we used the chi-square test for categorical variables and one-way analysis of variance for quantitative data. minitab and statbas statistical programs were used. we plotted activity data using the barber-johnson diagram. results a total of , cases ( % males; mean age years) were admitted to our icu during the period ( year before and after the transfer). no diff erences between both groups were founded in demographic data, knaus score and nyha status. regarding their origin, we found more patients admitted from other hospital centers ( vs. %; p < . ). apache ii score increased from . to . % (p < . ) and a slight increase change in saps score was also found ( . to . ; p < . there are several defi nitions of level (l ) care, all refer to a group at risk of clinical deterioration on the ward [ ] [ ] [ ] . there is evidence that ward patients who become acutely unwell often receive suboptimal care [ ] . a regional study commissioned by norfolk, suff olk & cambridgeshire critical care network (nscccn) found that a majority of ward patients may be of l dependency and death rates appear to be correlated with l status. we aim to examine the relationship between the ward distribution of illness acuity, staffi ng and patient outcome. methods data were collected as part of nscccn's observational prevalence study in . ward surveys included acuity of illness, staffi ng levels and skill mix. secondary data were obtained from the patient administration system. emergency, oncology, paediatric and maternity units were excluded. results complete datasets were obtained from , patients in wards in our university hospital over two seasons. this constitutes . % of inpatients from those wards. the mean ward occupancy rate was % ( th to th percentile: % to %). at least one l acuity criterion was scored by ( %) patients, with % from geriatrics followed by orthopaedics ( %) and general surgery ( %). each ward had an average of eight qualifi ed nursing staff (range: to ) equating to an average staff :patient ratio (spr) of . . there was no correlation between ward occupancy and nursing staff (pearson correlation, corr: . ), nor between prevalence of l criteria and staffi ng (corr: . ). the admission rate to intensive care was noted to be higher if the patients were nursed in a ward with lower than average spr compared with higher spr ( . % vs. . %, p = . fisher's exact), but this was not statistically signifi cant. senior nursing (band ) staff were part of the skill mix on only nine of ward surveys. conclusion better outcome with improved spr may be unsurprising, although if proven conclusively would signifi cantly inform workforce planning. lack of correlation between staffi ng levels and occupancy or acuity is also interesting given that we know l criteria are associated with worse outcome. introduction prolonged shifts, workload, stress, and diff erent confl icts are associated with burnout, loss of psychological wellbeing, and probably with an inadequate sleep quality (isq). this relevant disturbance leads to deterioration of the work performance, may impair quality of care provided to patients and increases the incidence of serious adverse events. the objective was to determine the prevalence of isq and sleepiness among uruguayan icu workers, and to evaluate risk factors associated with isq. methods a survey was conducted in six uruguayan icus. the sleep quality was evaluated on the basis of the pittsburgh score (ps), and the sleepiness was identifi ed by the epworth scale. isq was defi ned as ps greater than points and sleepiness by an epworth scale higher than points. icu's, patient's, and clinician's characteristics were assessed for their association with the prevalence of isq. all variables with p < . in univariate analysis were included in a model of ordinal regression. p < . was considered statistically signifi cant. results the survey was completed by icu workers. the global prevalence of isq in icu was . %. isq was observed in % of physicians and % of nurses and nurses assistant (p < . ). sleep medication was used by . % of the icu team. univariate analysis showed that isq was signifi cantly associated with sex ( % vs. %, p = . in women and men, respectively), marital status ( % vs. %, p = . in single and couple workers, respectively), more than hours working in the last week ( % vs. %, p = . ) and less than sleeping hours ( % vs. %, p < . ). multivariable analysis demonstrated that a sleep duration less than hours was independently associated with isq (or = . ; % ci = . to . ; p < . ). furthermore, pathologic sleepiness was present in . % of icu workers. sleepiness was independently associated with use of sleep medication (or = . ; % ci = . to . ; p = . ). conclusion the prevalence of isq and sleepiness is very high among icu workers. those disturbances are independently associated with a sleep duration less than hours, and sleep medication use, respectively. these results highlights that strategies to decrease isq and sleepiness in icu clinicians are urgently needed to improve work performance, improve quality of care provided and prevent adverse events. introduction work-related stress is a potential problem among doctors and is associated with anxiety, depression, reduced job satisfaction, days off work, errors and near misses [ ] . to compare stress levels between diff erent groups of doctors and identify causes of stress, we conducted a survey at university hospital lewisham using the uk health and safety executive's management standards (hsems). hsems is a validated tool developed to identify work conditions that warrant interventions to reduce stress levels across organisations [ ] . methods we conducted an anonymous survey of doctors working in anaesthetics, intensive care, general medicine and accident and emergency (a&e) departments over weeks using the hsems question naire. we also surveyed awareness of the trust's stress management services and whether staff had a designated supervisor or mentor. results were analysed using the hsems analysis tool, which rates stressors with a score from to ( represents the lowest amount of stress). we compared the trust's results against hsems national standards. results seventy-two doctors completed the survey. lowest stress levels were found in doctors working in intensive care (n = , mean . , sd . ). this was followed by medicine (n = , mean . , sd . ), anaesthetics (n = , mean . , sd . ), and a&e (n = , mean . , sd . ), which had the highest stress levels. there was no signifi cant diff erence in stress levels between diff erent grades of doctors. when compared with hsems targets, staff relationships and peer support exceeded national standards. however, management of organisational change and demands at work need improvement. the majority of doctors ( %) had no idea what stress management services were provided by the trust. seventy-nine per cent of doctors had an allocated supervisor or mentor, % of those felt able to approach their supervisor. conclusion these survey results provide reassurance that stress levels in intensive care compare well, despite critically unwell patients and higher mortality rates. we identifi ed areas that need improvement within the trust and will present these results to all relevant departments. with the support of hospital management we will initiate hsems-validated measures to reduce stress. introduction although recent reports show an improvement in outcomes for pediatric hematology patients requiring intensive care [ , ] , respiratory failure remains one of the major risks of pediatric mortality. this study was conducted to assess our hypothesis that mortality associated with respiratory failure is higher than that for other organ failures in pediatric hematology patients admitted to our icu. methods a retrospective study analyzed children with hematological disorders admitted to our icu between april and june . all of the included children required emergency admission and invasive mechanical ventilation. those who did not need intubation, or required intubation only for therapeutic intervention and died within hours of icu admission were excluded. the survival group was defi ned as patients who were discharged from the icu, and the nonsurvival group was defi ned as those who died in the icu or within days after discharge from the icu. the pelod score and pim-ii were applied as morbidity scoring systems results twenty-seven patients, including males and nine females, with a median age of . years (range, . to . years) were analyzed. sixteen patients had leukemia, fi ve had hemophagocytic syndrome, six had solid tumors. the average predicted mortality rate was . % in pim-ii. the survival group included patients ( %) and the nonsurvival group included patients ( %). when the survival group was compared with the nonsurvival group, there were no signifi cant diff erences in the systolic blood pressure ( . ± . mmhg vs. . ± . mmhg; p = . ), the proportion of patients requiring continuous renal replacement therapy ( . % vs. . %; p = . ), and pelod score ( . ± . vs. . ± . ; p = . ). in the nonsurvival group, the pim-ii was higher than that in the survival group ( . ± . vs. . ± . ; p = . ); the pao /fio ( . ± . vs. . ± . ; p = . ) and oxygenation index ( . ± . vs. . ± . ; p = . ) were signifi cantly worse in the nonsurvival group than in the survival group. conclusion the data show that respiratory failure is more strongly associated with mortality than other organ failures in pediatric hematology patients requiring intensive care. these results also suggest that mechanical ventilation intervention in patients with respiratory failure must occur earlier to improve the outcomes for these patients. introduction critically ill patients with haematological malignancies (hm) have high hospital mortality [ ] . severity of illness scores may underestimate mortality in such patients [ ] . methods data collection was conducted at three hospitals from to . patients with any active hm condition were matched with two control patients at two hospitals and with one control at christie hospital. control patients had the same apache ii (within points) and admission diagnosis, but no hm. readmissions and planned surgical cases were excluded. results a total of patients with hm were compared with control patients. seventy-four admissions with hm were identifi ed at two hospitals, and each was matched with two control patients. eightynine admissions with hm from christie hospital were identifi ed. these were matched with controls. patients with hm spent signifi cantly longer in hospital before icu admission (table ) . unit and hospital mortality rates were not statistically diff erent between patients with hm and without hm ( table ) . conclusion unit mortality of critically ill patients with hm was similar to those without hm. hospital mortality in patients with hm was higher than those without hm, although not statistically signifi cant. severity of illness at presentation to critical care is the main determinant of outcome in patients with hm. group when requiring emergency admission to the icu in a tertiary cancer centre. methods a retrospective review of medical notes between and . results a total of patients were admitted, of whom had more than one admission. there were episodes in total. leukaemia n = ; lymphoma n = ; myeloma n = . we compared the characteristics of those who survived icu admission with those who failed to survive to discharge from icu. the two populations were similar (age vs. ; males % vs. %). those who survived had a lower apache ii score on admission ( vs. ; p < . ), lower mean organ failure scores ( vs. ; p < . ), lower requirements of inotropes ( % vs. %; p = . ), ventilation ( % vs. %; p = . ) and fi ltration ( % vs. %; p = . ). there was no diff erence in the prevalence of sepsis at the time of admission ( % vs. %). both groups included patients with prior bone marrow transplant ( % vs. %). of note, icu and -month survival were % and %, respectively. these values are lower than those reported in the literature to date. conclusion icu and -month mortalities were % and %, respectively. patients with haematological malignancy stand to benefi t from intensive care, and should be off ered admission based on clinical need. introduction many evidence-based interventions are not delivered to patients [ ] . this may not be due to a clinician's intentional decisions. the aim of this project was to compare the use of starch before and after removing it as an option from an e-prescribing template. methods our e-prescribing software enables users to prescribe intravenous fl uids from a series of menus. one of these is a template that has several fl uids available to use as a bolus when instructed by a clinician. we removed starch as an option from the template in april . starch could still be prescribed elsewhere on the prescribing system. data on the use of starch from november to november were analysed as the mean volume of starch infused per patient per month. the mean of each set of parameters was then compared using a student's t test. results the mean volume of starch per patient administered before and after electronic prescription options were altered was ml and ml, respectively (p = . ). see figure . conclusion despite clinicians intending to reduce the use of starch it was still regularly administered on our icu. the removal of a default prescribing option dramatically reduced the volume of starch used whilst not restricting the ability to make a conscious choice to prescribe it. adjusting default options has potential to infl uence clinical decisions and ensure more reliable, evidence-based care. introduction early detection of sepsis is important for a suffi cient treatment to reduce mortality. we hypothesized that using modifi ed systemic infl ammatory response syndrome criteria over hour using an electronic software program facilitates the clinical diagnosis of sepsis. methods after irb approval and informed consent we enrolled in this prospective, observational, single-center study , consecutive patients (age . ± . , female/male / ) admitted over a -month period to a surgical icu. a total of them met modifi ed systemic infl ammatory response criteria. patients were monitored by an electronic software program using live data from the laboratory and bedside monitors to detect modifi ed systemic infl ammatory response syndrome criteria persisting over hour. the physicians were blinded to the software program alerts that notifi ed in real time when modifi ed systemic infl ammatory response syndrome criteria were detected and persisted over hour, but did not provide treatment recommendations. results there was a total of modifi ed systemic infl ammatory response syndrome criteria alerts. seventy-four were confi rmed as true sepsis cases by physicians. the overall incidence of sepsis was %. patients were categorized into length of stay < hours, to hours and > hours. the overall sensitivity of our system for detecting sepsis was % and the specifi city was %. the positive predictive value is % and the negative predictive value is %. conclusion real-time alerts using an automated, electronic monitoring of modifi ed systemic infl ammatory response syndrome criteria facilitate the clinical diagnosis of sepsis. beds. intentional rounds or proactive patient rounds were recognised by the royal college of physicians and the royal college of nursing [ ] as structured, evidence-based processes for nurses to carry out regular checks with individual patients at set intervals. the senior nursing team decided to adapt this initiative to the intensive care setting in order to address clinical challenges and provide guidance for shift leaders to focus on key elements of care. methods our intentional rounds, performed once per shift (twice daily), include two components. first, pressure area care -this component involves the shift leader checking whether key elements of pressure sore prevention have been performed. these include completion of the waterlow risk assessment tool [ ] , noting the frequency of repositioning, use of lateral positioning and pressure-relieving pads. second, renal replacement therapy rates -this element was identifi ed as an area for focus after we established that our haemofi ltration fl uid use per hour of therapy was twice that of a near identical clinical setting. this pattern continued even after adopting similar therapy guidelines. the shift leader was guided to check whether therapy rates had been adjusted in line with latest biochemical results. the incidence of pressure ulcers in the months since the initiative began has averaged . per month compared with . per month prior to commencement of intentional rounding. added to the rounding tool at the end of september , rrt rates in the preceding months averaged . ml/kg/hour over hours, an . % reduction from the previous average of . ml/kg/hour. if the pattern of rrt was to continue, this could equate to a cost saving of uk£ , per annum. conclusion the use of a modifi ed targeted intentional rounding tool by the nursing shift leader can help ensure that best practice guidelines are adhered to. this strategy can improve patient outcomes and provide potentially signifi cant fi scal benefi ts. references introduction handovers are often associated with poor communi cation. icu patients with multiple complex problems are ideal to study naturally occurring handovers. however, few studies have been conducted in the icu. methods we conducted questionnaires of physicians and nurses involved and observed handovers in real time of medical icu patients over month. we interviewed of physicians and nurses involved ( . %) and observed real-time handovers ( patients, . %) of patients. mean duration of handover was . (± . ) seconds, . % were face to face and . (± . ) distractions per handover were noted, person-to-person calling being the commonest mode of distraction ( . %). nurses received training during induction in signifi cantly higher numbers, covered allied specialties more and reviewed the patients early (all p < . ). perception of the relative importance of diff erent components of the handover varied signifi cantly between donors, recipients, physicians and nurses. both physicians and nurses seldom ( . %) reviewed the available electronic past medical records of the patient before handover, which in addition to training in handover and overall confi dence level in the management following handover are signifi cantly associated with better satisfaction in univariate analysis; only the confi dence level in patient management remained signifi cant after multivariate analysis. however, agreement between donor and recipient on overall satisfaction was poor (p > . ). nursing handovers were signifi cantly longer than physicians' ( . ± . vs. . ± . seconds, p < . ) but are also associated with higher distractions particularly during evening shifts. conclusion a higher percentage of nurses received handover training; nursing handovers are longer and more inclusive of other components of patient management; perceived importance of components of handover varies among healthcare professionals; distractions are common during handovers and associated with longer duration, by nurses and in the evening shifts; and higher confi dence level in patient's management following the handover is associated with better satisfaction. using telemedicine to provide acute burn and critical care consultation on pediatric and adult burn patients in lviv, ukraine, as well as in triage and transport of critically ill patients from lviv to a tertiary-care facility in the usa for further management. methods using a new telemedicine learning center established at city hospital # in lviv, ukraine, consultations regarding acutely injured burn victims occurred between physicians in ukraine and physicians at shriners hospital and massachusetts general hospital in boston. after the initial presentation, each patient was reviewed on a daily basis by physicians in boston. skype, an internet-based communication tool, was used in communication with the burn center in lviv. radiographic images were scanned and digitalized using an electronic scanner, and jpeg image compression was used to facilitate the transmission of radiographic images and patient charts. informed consent and hippa guidelines were followed in transmitting any patient-related information. results since we have provided consultation on patients in lviv, ukraine, ranging in age from months to years. each patient had an average of six consultations. we present two of these cases as examples of the capabilities of our telemedicine program. the fi rst case involved a -month-old female with % tbsa from scald injury, where telemedicine was instrumental in the primary assessment as well as to arrange a direct assessment from a nearby burn surgeon. the second case resulted from a house fi re with multiple casualties, where physicians in boston were able to utilize telemedicine to guide the initial resuscitation and airway management of three critically burned children, as well as to arrange for transport of one of the victims, an -year-old male with % tbsa, from ukraine to the usa for acute management. multiple diffi culties were overcome in implementing the system between the two countries including: time zone diff erences, language barrier, and diff erent approaches to patient care. conclusion we have established a telemedicine program linking physicians in boston, ma, usa with city hospital # in lviv, ukraine to improve care in pediatric and adult burn patients. our program has provided consultation on patients since , and it highlights the capabilities of telemedicine for acute consultation as well as triage and transport of critically ill patients to tertiary-care facilities. introduction during the last few years the frequency of end-oflife decisions (eold) signifi cantly increased in icus. the method of nurse involvement in making eold is diff erent worldwide [ , ] . the purpose of this study was to analyze opinions of nurses about therapy restriction. we have examined with a multicenter study the opinions of the medical stuff about end-of-life care in hungarian icus. methods we performed a questionnaire evaluation among physicians and nurses of icus about infl uencing factors of therapy restriction, the method of the decision-making process, and the frequency of diff erent eold. the questionnaire, containing questions, was delivered electronically to hungarian icus, and then we analyzed the responses anonymously. the retrieved answers ( physicians, nurses) were analysed using a nonparametric student's test. results a total % of the nurse responders work in university clinics, % in regional centrum, % in municipal hospital, % in other icus. the nurses found both human ( . / vs. . / ) and material ( . / vs. . / ) resources more restrictive factors during patient admission than physicians (p = . , p = . ). nurses working in municipal hospital were more strongly infl uenced by lack of material and human resources ( . / , . / ) than nurses working in university clinics ( . / , . / ), p = . , p = . . younger nurses (working between and years) were more interested in the patient's or surrogate's wishes than older nurses (working more than years). religion did not infl uence patient admission and forego therapy; however, religious nurses compared with atheists and nonpracticing believers preferred to prolong therapy against the patient's will (p = . ). nurses felt that physicians slightly involved them in the end-of-life decision-making process ( . / vs. . / p = . ). conclusion we found that the workplace, level of medical attendance, godliness, work experience, and position in medical staff strongly infl uenced making eold. while limitation of the therapy should be team work, nurses felt their opinions were hardly taken into consideration, although nurses seemed to be more realistic in the decision-making process. introduction more than one in fi ve people admitted to an icu will die there. research has highlighted concerns about support for patients and families and decision-making in this context [ , ] . here, we describe the development and evaluation of a tool to improve palliative care in a -bed general icu in a central london teaching hospital. methods medical research council guidance for complex interventions phase to i comprised literature review, theoretical modelling, observation and qualitative interviews and focus groups with staff and families exploring concerns and views of interventions identifi ed in the literature review. phase ii comprised intervention development, implementation and evaluation of tool feasibility and eff ects using staff survey, observation, audit of records and relative survey. results phase i: staff and family members were interviewed. the short time between decisions for treatment withdrawal and death, plus concerns for support management, communication and decision-making, highlighted a need to ensure excellent psychosocial assessment for all. phase ii: as part of integrated care guidelines, we developed the king's psychosocial assessment and care tool (k-pace). k-pace is used for all patients entering the icu, completed within hours of admission. it contains psychosocial assessment of the family and patient needs, and identifi es key individuals for contact. educational training was supported by k-pace and was implemented in two waves. post-implementation survey of icu staff found that most ( %) were aware of k-pace. eighty-two per cent of nurses but only % of doctors had completed the tool. in total, / ( %) family members responded to the survey (additionally three patients responded). there were high levels of satisfaction for symptom control and psychosocial care but concerns continued regarding explanation of treatment and care. conclusion k-pace is a feasible tool to improve the palliative care of patients and their families in the icu. further refi nement is needed and planned, with consideration of roll-out into the wider medical centre. be concerned involving the family's will. especially, stopping or withdrawing therapy is a quite diffi cult operation in japan because of legal issues. our hypothesis is that some diff erence exists in thoughts between physicians and nurses for terminal patients in the icu. the aim of this study is to know their real thoughts. methods a questionnaire survey was performed on physicians and nurses in our medico-surgical icu. the questionnaire consists of questions with fi ve optional answers related to the thoughts of participants about treatment of hopeless or brain death patients. concretely, the questions were; whether to withhold therapy or not, whether to accept to withdraw therapy or not and with family's will, whether to accept to immediately stop therapy and with family's will, whether to positively or not donate organs from a brain death patient, necessity of icu care for brain death patients, and feeling guilty and stress for stopping or withdrawing therapy. the optional answer has fi ve gradations from 'yes' to 'no' for all questions. the participants were asked to answer the questionnaire by expressing themselves without regarding legal issues or the consensus. it was guaranteed to be anonymous for them in the data analysis. the answers were compared between physicians and nurses. the mann-whitney u test was used for statistical analysis. p < . was considered statistically signifi cant. results there were in total participants (response rate . %) with physicians and nurses. withdrawing therapy was signifi cantly accepted in nurses than in physicians ( % vs. %, p = . ), when the family well understood. withholding therapy should not be operated for brain death patients for physicians ( %), while it seemed a diffi cult judgement for nurses ( %, p = . ). icu care for brain death patients is less necessary for physicians than nurses ( % vs. %, p = . ). there were no signifi cant diff erences in other questions between physician and nurses such as feeling guilty or stress for stopping or withdrawing therapy. conclusion some of end-of-life thoughts in the icu showed diff erences between physicians and nurses. introduction optimal patient evaluations of icu rehabilitation therapy remain unclear. methods one hundred icu patients with acute respiratory failure were randomized to receive early rehabilitation (er) or usual-care (uc). cohort (n = ) received er as one physical therapy (pt) session/day versus uc; cohort (n = ) received er as pt/day with the second session resistance training, versus uc. uc was without er. blood was drawn for cytokines through day . cohort underwent strength and physical functional assessments using the short physical performance battery (sppb), a valid and reliable measure of physical function consisting of walking speed, balance, and repeated chair stands. it is a well-studied composite measure in older persons, but has not been used in icu survivors. small changes of . to . points in the sppb have been shown to be clinically meaningful. conclusion in this pilot study, early icu rehabilitation was safe, and was associated with numerically although not statistically shorter hospital stay, greater strength and improved functional scores. particularly, the sppb demonstrated discriminatory ability in groups of icu survivors with low physical function. future early icu rehabilitation studies should consider icu survivor assessments using the sppb due to its ease, reproducibility and discriminatory ability following icu and hospital discharge. of the demographic variables such as sex, age, education, race and length of stay had an eff ect on perceived quality of care. conclusion the cqi 'r-icu' turned out to be a valid, reliable, sensitive and feasible instrument. large-scale implementation is recommended. actual incidence of global left ventricular hypokinesia in adult septic shock sepsis and the heart cardiovascular biomarkers in the icu plasma endothelin- levels in septic patients the role of endothelium and endogenous vasoactive substances in sepsis nicotinic acetylcholine receptor α subunit is an essential regulator of infl ammation cholinergic agonists inhibit hmgb release and improve survival in experimental sepsis thrombocytopenia in patients in the medical intensive care unit: bleeding prevalence, transfusion requirements, and outcome infl ammation, stress, and diabetes procalcitonin increase in early identifi cation of critically ill patients at high risk of mortality post-operative hypoalbuminaemia and procalcitonin elevation for prediction of outcome in cardiopulmonary bypass surgery enhanced oxygen delivery by perfl ubron emulsion during acute hemodilution iv perfl ubron emulsion versus autologous transfusion in severe normovolemic anemia: eff ects on left ventricular perfusion and function effi cacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar): a multicentre randomised controlled trial nosocomial infections in a cohort of extracorporeal life support patients the epidemiology and outcome of medical emergency team call patients treated with non invasive ventilation early prehospital use of non invasive ventilation improves acute respiratory failure in acute exacerbation of chronic obstructive pulmonary disease bts guidelines for the management of community acquired pneumonia in adults: update smart-cop: a tool for predicting the need for intensive respiratory or vasopressor support in community-acquired pneumonia the smart-cop score performs well for pneumonia risk stratifi cation in australia's tropical northern territory: a prospective cohort study application and comparison of scoring indices to predict outcomes in patients with healthcare associated pneumonia eff ects of continuous positive airway pressure in acute asthma noninvasive positive pressure ventilation in status asthmaticus eff ect of nasal continuous positive airway pressure on methacholine-induced bronchoconstriction the royal college of anaesthetists [www.rcoa.ac.uk/nap ] . diffi cult airway society equipment list cochrane handbook for systematic reviews of interventions. version . . . the cochrane collaboration proceedings book of th congress of the society of critical care medicine early goal-directed therapy in the treatment of severe sepsis and septic shock oxygen transport in cardiogenic and septic shock evidence based of the use of the pulmonary artery catheter: impact data and complications the eff ectiveness of right heart catheterization in the initial care of critically ill patients statistical methods for assessing agreement between two methods of clinical measurement use of central venous oxygen saturation to guide therapy comparison of central-venous to mixed-venous oxygen saturation during changes in oxygen supply/demand systematic review and meta-analysis on the use of preemptive hemodynamic intervention to improve postoperative outcomes in moderate and high-risk surgical patients intraoperative fl uid optimization using stroke volume variation in high risk surgical patients: results of prospective randomized study accidental catheter removal in critically ill patients: a prospective and observational study national patient safety agency: reducing harm caused by the misplacement of nasogastric feeding tubes. npsa/ /psa . nhs national patient safety agency: reducing the harm caused by misplaced nasogastric feeding tubes. npsa/psa ./psa . npsa epidemiology of severe sepsis in the usa: analysis of incidence, outcome, and associated costs of care post-injury multiple organ failure: the role of gut probiotics in the intensive care unit measures of crowding in the emergency department: a systematic review measuring and forecasting emergency department crowding in real time promoting global research excellence in severe sepsis (progress): lessons from an international sepsis registry interhospital transfer of critically ill patients: demographic and outcomes comparison with nontransferred intensive care unit patients outcomes of patients admitted to tertiary intensive care units after interhospital transfer: comparison with patients admitted from emergency departments outcome of critically ill patients undergoing interhospital transfer brain tissue oxygen monitoring and hyperoxic treatment in patients with traumatic brain injury association between early hyperoxia and worse outcomes after traumatic brain injury both hypoxemia and extreme hyperoxemia may be detrimental in patients with severe traumatic brain injury focused assessment with sonography in trauma (fast): should its role be reconsidered? it's higher than you think: chest drains and the th ics tube thoracostomy: complications and its management bts guidelines for the insertion of a chest drain american college of surgeons committee on trauma: advanced trauma life support for doctors, course manual. chicago: american college of surgeons american heart association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care heart rate response to hemodialysis-induced changes in potassium and calcium levels survival in cancer patients undergoing in-hospital cardiopulmonary resuscitation: a meta-analysis acute intrathoracic gastric herniation as a rare cause of cardiac arrest dw hoelen references . kern kb: optimal treatment of patients surviving out-of-hospital cardiac arrest immediate coronary angiography in survivors of outof-hospital cardiac arrest immediate percutaneous coronary intervention is associated with better survival after out-of-hospital cardiac arrest hypothermia for neuroprotection in adults after cardiopulmonary resuscitation investigation and early management of head injury. london: national collaborating centre for acute care updates in the management of intracranial pressure in traumatic brain injury guidelines for the management of severe traumatic brain injury bundled care for septic shock early prognosis in traumatic brain injury: from prophecies to predictions one-year extended glasgow outcome scale and hospital mortality predictors in patients with severe traumatic brain injury in brazil r turon , fr ferreira , d prado bioavailability of subcutaneous low-molecular-weight heparin to patients on vasopressors prophylactic anticoagulation with enoxaparin: is the subcoutaneous route appropriate in the critically ill? s -s . p massive blood transfusion for obstetric haemorrhage s simmons graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial the rule regulating ph changes during crystalloid infusion in vivo conditioning of acid-base equilibrium by crystalloid solutions: an experimental study on pigs mixing of medicines prior to administration in clinical practice: medical and non-medical prescribing procedural sedation goes utstein: the quebec guidelines barriers to propofol use in emergency medicine international sedation task force: adverse event reporting tool to standardize the reporting and tracking of adverse events during procedural sedation: a consensus document from the world siva international sedation task force mediators infl amm acute kidney injury in an infant after cardiopulmonary bypass predictive power of serum cistatin c red cell distribution width improves the simplifi ed acute physiology score for risk prediction in unselected critically ill patients red blood cell distribution width is an independent predictor of mortality in acute kidney injury patients treated with continuous renal replacement therapy incidence and prognosis of intraabdominal hypertension in a mixed population of critically ill patients: a multiplecenter epidemiological study eff ect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients acute renal failure in critically ill patients: a multinational, multicenter study impact of etiology of acute kidney injury on outcomes following liver transplantation: acute tubular necrosis versus hepatorenal syndrome cirrhotics admitted to intensive care unit: the impact of acute renal failure on mortality hyponatraemia as a risk factor for hospital mortality albumin-adjusted calcium is not suitable for diagnosis of hyper-and hypocalcemia in the critically ill derivation and internal validation of an equation for albumin-adjusted calcium conclusion succinate ameliorates (but does not return to normal) references . uk prospective diabetes study group p root cause analysis of hypoglycemic events in critically ill patients a mcdonald offi ce of national statistics population data sccm/esicm/accp/ats/sis international sepsis defi nitions conference the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome the logistic organ dysfunction system: a new way to assess organ dysfunction in the intensive care unit visualizing multiple organ failure: a method for analyzing temporal and dynamic relations between failing systems and interventions modelling gene expression data using dynamic bayesian networks disaster medicine compendium team japan critical care university of toronto, canada; intensive care national audit & research centre oswaldo cruz foundation, rio de janeiro, brazil; peking union medical college hospital standards for consultant staffi ng of intensive care units. ics & ibticm standards eff ectiveness of an educational program to reduce ventilatorassociated pneumonia in a tertiary care center in thailand: a -year study multi-departmental system analysis is needed for evaluation of severe sepsis care: a multi-centre study audit and feedback: eff ects on professional practice and health care outcomes surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock levels of critical care for adult patients acutely ill patients in hospital. nice guideline . nice an acute problem? ncepod hse management standards and stress-related work outcomes references . centre for maternal and child enquiries: saving mothers' lives: reviewing maternal deaths to make motherhood safer: - . the eighth report on confi dential enquiries into maternal deaths in the united kingdom % in non-infected patients, p = . ) and . % were under haart ( . % in patients admitted without infection, p = . ). mean cd count at admission: . ± . cells/mm (vs. . ± . , p = . ) ) and . % renal replacement ( . % in no septic patients, p = . ). mean icu and hospital los was ± . days (p = . ). icu mortality: . % ( % in nonseptic patients, p = . ) conclusion sepsis is a common reason for admission to the icu in hiv patients and is accompanied by high mortality. pneumonia is the most frequent source of infection. septic patients are less frequently under haart and have a worse inmune status (lower cd count and higher viral load). despite a higher apache ii, and a higher need for hemodynamic and respiratory support, there is no statistically signifi cant diff erence in icu and hospital mortality between septic and nonseptic patients p survival of critically ill patients with haematological malignancies compared with patients without haematological malignancy r pugh the outcome of haematological malignancy in scottish intensive care units intensive care unit admission in patients with haematological disease: incidence, outcome and prognostic factors intensive care management of patients with haematological malignancy comorbidity as a prognostic variable in multiple myeloma: comparative evaluation of common comorbidity scores and use of a novel mm-comorbidity score icu and -month outcome of oncology patients in the intensive care unit assessing the quality of interdisciplinary rounds in the intensive care unit uni-and interdisciplinary eff ects on round and handover content in intensive care units perspective: physician leadership in quality rcn: ward rounds in medicine. principles for best practice. london: royal college of physicians, royal college of nursing the importance of accurate risk assessment and appropriate intervention in tissue viability handover in the emergency department: defi ciencies and adverse eff ects communicating in the 'gray zone': perceptions about emergency physician hospitalist handoff s and patient safety a national survey of end-of-life care for critically ill patients nurse involvement in end-of-life decision making: the ethicus study p alternative to improve palliative care for all patients and families in critical care units: development and preliminary evaluation following mrc guidance of the king's psychosocial, assessment and care tool i higginson, c rumble half the families of icu patients experience inadequate communication with physicians confl icts between physicians' practices and patients' wishes improving the quality of end-of-life care in the pediatric intensive care unit: parents priorities and recommendations on speaking less and listening more during end-of-life conferences evaluating end of life in ten brazilian pediatric and adults intensive care units parents' perspectives on physician-parent communication near the time of a child's death in the pediatric intensive care unit ) and sepsis (p = . ) were signifi cantly diff erent between responders and nonresponders. responders had a lower mean gcs ( ± vs. ± ), lower amount of edema and were less likely to have had sepsis. in a multiple regression analysis, sepsis, edema, bmi and age explained % of the variance conclusion in patients with a better neurological condition, sepsis and/ or leg edema it was more diffi cult to obtain an adequate quadriceps contraction with nmes. nmes is safe to apply on the icu. references . dh and modernisation agency: the national outreach report. london: nhs modernisation agency pilot study of early rehabilitation strategies in acute respiratory failure d files physical rehabilitation following critical illness long term outcome from critical illness cg critical illness rehabilitation: guideline public health resource unit: critical appraisal skills programme. questions to help you make sense of qualitative research quality measurement at intensive care units: which indicators should we use? handboek cqi ontwikkeling: richtlijnen en voorschriften voor de ontwikkeling van een cqi meetinstrument using the commissioning for quality and innovation (cquin) payment framework -guidance on national goals for refi nement, scoring, and validation of the family satisfaction in the intensive care unit (fs-icu) survey our data showed no benefi t with the use of a potent statin acutely in patients with sepsis or septic shock with regards to improvement in endothelial function. references conclusion the use of the lps-selective adsorption (particularly pmx-f) in patients with severe sepsis leads to improvement of systemic infl ammation and organ dysfunction. references s on these data we will continue to the next phase of this project and test pfc in the prevention of ards alone, and in combination with hs. references conclusion pp seems safe in obese patients and may improve oxygenation more than in nonobese patients. obese patients could be a subgroup of ards patients who may benefi t most from pp. references long-term functional outcome in adults with severe tbi: a meta-analysis m asselin , y lachance , g lalonde introduction two previous classifi cations of acute kidney injury (aki) that are known as rifle criteria and akin criteria have shown that aki is associated with increased morbidity and mortality. diff erences in predicting ability for prognosis, however, have been reported. in , kidney disease improving global outcomes (kdigo) created the new aki criteria, combining rifle and akin criteria. however, such a combination might cause inconsistency among each defi nition in the criteria. we have investigated all of the defi nitions in the new kdigo criteria in detail. methods this is a retrospective historical cohort study including adult patients admitted to the icu (jikei university, tokyo, japan) between january and october . patients undergoing chronic dialysis were excluded. kdigo criteria were applied to all patients to diagnose aki. hospital mortality of patients with aki diagnosed by the defi nitions in the criteria was compared. results a total of , patients were evaluated. aki occurred in . % with standard defi nition of kdigo; . % with creatinine criteria alone; . % with urine output alone. by multivariable analysis, each aki stage was associated with hospital mortality: . %, odds ratio . , for stage ; . %, odds ratio . , for stage ; . %, odds ratio . , for stage . crude hospital mortality stratifi ed by the defi nitions showed increasing trends with stage progression. mortality of the three defi nitions in stage was from . % to . %. stage had two defi nitions and their mortality was . % and . %. stage had fi ve defi nitions and their mortality was from . % to . %. conclusion aki defi ned by the new kdigo criteria was associated with increased hospital mortality. in addition, defi nitions in the kdigo criteria seem to be appropriate because of clear relations between mortality and stage progression. introduction to evaluate whether urinary neutrophil gelatinaseassociated lipocalin (ungal) detects acute kidney injury (aki) earlier than the estimated glomerular fi ltration rate (egfr) in cardiac surgery patients. methods two-hundred and seventy-four adult patients undergoing cardiac surgery were consecutively included from february to december . exclusion criteria were absence of diuresis due to end-stage renal disease or chronic renal failure and a previous cardiac catheterism with i.v. contrast use the week before surgery. four serial blood and urine samples immediately before (pre) and after (post) surgery, and day ( d) and days ( d) after surgery were obtained. ungal was measured in an architect (abbott diagnostics). akin criteria were used to diagnose aki. the study was approved by the local ethics committee and all patients gave informed consent. delta ungal was defi ned as the diff erence between the pre and the posts concentrations. results one-hundred and eighty-one patients ( . %) were men; mean age was . ± . years. valve replacement was performed in , coronary artery bypass graft (cabg) in , valve surgery + cabg in , cardiac transplant in fi ve, aorta aneurism surgery in nine, and other procedures in eight patients. icu and hospital stays were . ± . and . ± . days, respectively. renal replacement therapy (rrt) was required in patients ( . %) within hours of icu stay and in patients ( . %) within weeks. mortality at days was . %. eighty-six patients ( . %) were diagnosed with aki within hours of surgery. area under the roc curve of post ungal for aki diagnosis was . ( . to . ) (p < . ) at an optimal cutoff value of μg/l, introduction acute renal failure (arf) is a common complication in patients admitted to the icu. sepsis is also a well-known risk factor for the development of arf. the combination of arf and severe sepsis was reported to carry a mortality up to % whereas the mortality of arf alone is to %. the aim of the study is to evaluate the role of renal perfusion scanning in detecting the prognosis and outcome of patients with acute renal failure due to sepsis. methods forty patients with acute renal failure due to sepsis, aged between and years, were enrolled in the study. they were monitored for their icu prognosis and outcome after doing renal perfusion scanning. all patients were subjected to routine icu and laboratory investigations including apache ii and sofa score. results thirty patients had normal renal scan and patients had abnormal renal scan. the mortality percentage was higher among abnormal renal scan cases (three out of , %) compared with cases with normal renal scan (seven out of , . %) with nonsignifi cant p value: . . the median length of stay/day in icu was longer among nonsurvivors than survivors . ± , . ± , p value: . (approaching signifi cance). apache ii score was higher in nonsurvivors than survivors . ± . , . ± . , p value: . . the percentage of mortality among cases that needed mechanical ventilation was higher (nine out of , . %) compared with mortality cases that did not need mechanical ventilation (one out of , . % with p value: . ). conclusion arf may exert an independent adverse eff ect on outcome in septic and septic shock patients. it is also a risk factor for mortality. tc- m dmsa scanning is useful for detecting renal dysfunction and help to predict the outcome and prognosis. reference introduction acute kidney injury (aki) complicates over % of icu admissions. episodes of aki are a major risk factor for development or progression of chronic kidney disease (ckd); however, methods of estimated glomerular fi ltration rate (egfr) may be poorly calibrated to survivors of critical illness who may have reduced muscle mass. we hypothesized that egfr may underestimate rates and severity of ckd in icu survivors. methods a retrospective observational study of renal function in all patients admitted to a london teaching hospital icu for ≥ days and surviving to hospital discharge in . we excluded cases with current or new diagnosis of end-stage renal disease or renal transplant. we assessed aki in icu by kdigo criteria and hospital discharge egfr by the ckd-epi equation. for comparison we assumed a normal gfr in a healthy individual as ml/minute/ . m at age decreasing by . per year over age . results we identifi ed patients, of whom had aki. median age was and % were male. median hospital discharge serum creatinine was μmol/l (range to ), median egfr was signifi cantly higher than predicted normal gfr for age at versus predicted (p < . , median diff erence ). in patients who had not had aki discharge the egfr was versus normal predicted (p < . , median diff erence ), suggesting that egfr could be overestimating true gfr in our population by at least a factor of . ( figure ). applying this correction factor to egfrs of patients who had recovered from aki resulted in % more diagnoses of ckd (egfr < ) at hospital discharge ( vs. ). conclusion egfr may overestimate renal function in survivors of critical illness confounding identifi cation of ckd in this at-risk population. prospective studies with measurement of actual gfr are required to assess the burden of ckd in survivors of critical illness. to analyze whether variables related to cardiopulmonary bypass (cpb) infl uence acute kidney injury (aki) occurrence and urinary neutrophil gelatinase-associated lipocalin (ungal) in cardiac surgery patients. methods a total of adult cardiac surgery patients were consecutively included from february to december . exclusion criteria were absence of diuresis due to end-stage renal disease or chronic renal failure and cardiac catheterism with i.v. contrast in the week before surgery. cpb, when performed, was used as standard cpb (scpb) or minicpb. we obtained four serial blood and urine samples, immediately before (pre) and after (post) surgery, and day ( d) and days ( d) after surgery. ungal was measured by architect (abbott diagnostics). akin criteria were used to diagnose aki. the study was approved by the local ethics committee and all patients gave informed consent. results one hundred and eighty-one patients ( . %) were men; mean age was . ± . years. icu and hospital stays were . ± . and . ± . days, respectively. twenty-eight-day mortality was . %. eighty-six patients ( . %) were diagnosed with aki within hours after surgery. in total, patients required cpb ( scpb, minicpb) and did not (no-cpb). seven no-cpb patients ( . %) developed aki and their median ungal post was ( . to . ) μg/l compared with . ( . to . introduction neutrophil gelatinase-associated lipocalin (ngal), measured early after cardiac surgery, has been demonstrated to predict postoperative acute kidney injury (aki). fluid overload potentially masks a subsequent acute renal function loss through dilution of serum creatinine and maintenance of urine output just above akidefi ning criteria. methods we investigated the early postoperative value of ngal versus that of simultaneously measured serum creatinine to predict subsequent fl uid overload. we studied adult cardiac surgery patients in the control arm of a rct (nct ). severe postoperative fl uid overload was defi ned as positive fl uid balance > % of preoperative body weight within hours after surgery. results severe postoperative fl uid overload was present in % of patients with a mean positive fl uid balance of . ± . l. at icu admission, urine ngal predicted severe fl uid overload (auc-roc . ( % ci = . to . )) ( figure ) and mortality (auc . ( . to . )). serum creatinine measured at the same time did not predict severe fl uid overload (auc . ( . to . )) or mortality (auc . ( . to . )). conclusion early ngal-guided adjustments to fl uid management may reduce organ edema after cardiac surgery. findings should be validated in larger cohorts. survivors of acute kidney injury requiring renal replacement therapy rarely receive follow-up: identifi cation of an unmet need cj kirwan, r taylor introduction acute kidney injury (aki) occurs in more than % of icu admissions, requiring renal replacement therapy (rrt) in around % of cases. there is now increasing evidence that aki is a risk factor for the development and progression of chronic kidney disease (ckd); however, when aki occurs as a complication of critical illness appropriate follow-up may be neglected. accordingly, we reviewed the follow-up of renal function in all patients who received rrt on our icu and survived to hospital discharge. methods a retrospective audit of patients who received rrt in a central london adult critical care unit during . results of patients admitted, received rrt with surviving to hospital discharge. we excluded patients who had end-stage renal disease, renal transplant or known glomerular disease. of the remaining aki patients, median age was (range: to ) and ( %) were male. median discharge creatinine was . μmol/l ( to ). forty-two ( %) were off ered follow-up, but in only six cases ( %) was this to nephrology services. twenty-eight attended follow-up (fi ve to nephrology) at a median time of weeks; however, creatinine was measured at in only and in six of these it had risen (by median . μmol/l). in addition, patients had creatinine measured to months post discharge and in eight it had risen (by median . μmol/l). conclusion follow-up of patients who received rrt for aki in the icu was poor and they were rarely referred to nephrologists. where renal function was measured after discharge, there was evidence of progressive renal dysfunction; however, renal function was often not assessed. we propose an algorithm for clinicians to guide follow-up. see figure . introduction hyperglycemia and hypoglycemia have been linked to worse outcomes in critically ill patients. while there is controversy as to the optimal tightness of glucose control in critically ill patients, there is agreement that an upper limit to safe glucose levels exists and that avoiding hypoglycemic episodes should be prioritized. our algorithm can assist clinicians in maintaining blood glucose ([gbl]) within a desired target range while avoiding hypoglycemia. methods our model predictive control (mpc) algorithm uses insulin and glucose as control inputs and a linearized model of glucoseinsulin-fatty acid interactions. to allow the controller model to learn from data, a moving horizon estimation (mhe) technique tailored the tissue sensitivity to insulin to individual responses. patient data ([gbl] measurements, insulin and nutritional infusion rates) were from the hidenic database at the university of pittsburgh medical center. [gbl] measurements, typically hourly, were interpolated to impute a measurement every minutes. the model captured patient [gbl] via nonlinear least squares by adjusting insulin sensitivity (si) and endogenous glucose production (egp ). the resulting virtual patient (vp) is used to evaluate the performance of the mpc-mhe algorithm. results mpc controller performance on one vp is shown in figure . across a population of vps, the average [gbl] under mpc is . mmol/l, the average minimum is . mmol/l, the population individual minimum is . mmol/l and the average absolute average residual error is . mmol/l from a . mmol/l target. with standard intervention, the vps have an average [gbl] of . mmol/l, an average minimum [gbl] of . mmol/l, and a population minimum [gbl] of . mmol/l. algorithm performance deteriorates signifi cantly if the imputed sampling time exceeds minutes, underlining the importance of dynamic variations in insulin sensitivity in this population. conclusion the mpc-mhe algorithm achieves targeted glucose control in response to changing patient dynamics and multiple measured disturbances for a pilot population of vps. furthermore, the mhe scheme updates patient parameters in real time in response to changing patient dynamics. introduction blood glucose (bg) control reduces morbidity and length of stay, and is standard practice in patients undergoing cardiac surgery [ ] . however, maintaining bg in the target range, while avoiding hypoglycemia, is challenging. continuous glucose monitoring (cgm) is a promising technology that may help address these challenges. we investigated the performance and safety of medtronic sentrino®, a newly developed cgm for critically ill adults, in the cardiac icu. methods adult patients with actual or planned cardiac icu admission at a single tertiary center were approached for participation and signed consent. other inclusion criteria were treatment with i.v. insulin (target bg < mg/dl) and life expectancy > hours. after initiation of i.v. insulin, sentrino® subcutaneous glucose sensors were inserted into patients' anterior thighs with planned study participation of to hours. reference bg was collected according to icu protocol, obtained from central venous catheter and analyzed with bedside blood gas analyzer (bga; i-stat®, abbott, usa). sensor glucose (sg) results were displayed, and its predictive alerts and alarms fully enabled. additional reference bgs were obtained during alarms and calibration. all treatment decisions were based on bga data, not on sg values. results a total of patients were enrolled; all successfully completed the study. mean age was years, % were women, % had diabetes. types of surgery were cabg ( %), valve replacement ( %), combined cabg and valve ( %) and cardiac transplant ( %). sg was displayed % of the time during the study, and paired bg-sg points were used for analysis. overall mean absolute relative diff erence (mard) was . %. no diff erences in cgm system accuracy were seen within subgroups of low versus high society of thoracic surgeons (sts) score (mard . % and . % for sts > % vs. ≤ %, respectively) or hemodynamic status (mard . % and . % for compromised vs. stable hemodynamics). consensus grid analysis showed > % of sg values within a/b zones, and % in d/e zones. no device or study-related adverse events were reported. in total, % and % of clinicians found sentrino® easy to use after one and two patients, respectively. conclusion the sentrino® cgm system demonstrated good analytic and clinically relevant accuracy, excellent reliability and safety in critically ill cardiac patients; and was easy to use and integrate in the cardiac icu. future studies are needed to determine whether cgm can improve bg control and reduce hypoglycemia in this patient group. introduction a large rct showed that tight glucose control (tgc), targeting age-adjusted normal fasting blood glucose levels with insulin infusion, decreased morbidity and mortality in critically children [ ] . however, the incidence of hypoglycemia increased substantially in the tgc group. we aimed to assess the eff ect of tgc on the three domains of blood glucose dynamics (hyperglycemia, hypoglycemia and blood glucose variability) and their independent association with mortality in the pediatric icu. methods this is a preplanned substudy of a published rct in one -bed pediatric icu. seven hundred patients (age to years), admitted to the picu between october and december , were randomized to either tgc ( to mg/dl in infants, to mg/dl in children) or to the usual care tolerating hyperglycemia up to mg/ dl (uc). patients with at least two arterial blood glucose measurements were included (uc n = ; tgc n = ). results mean blood glucose levels were lowered from ± mg/dl in the uc group to ± mg/dl (p < . ). the median number of samples per patient did not diff er between uc ( ( to )) and tgc ( ( to )). tgc lowered the hyperglycemic index, a marker of introduction hiv infection is a major public health problem in the world. the use of prophylaxis against opportunist infection and the introduction of haart in increased life expectancies. the therapeutic use of icu resources for hiv patients has been controversial, questioning the admission of these patients especially in advanced stages of the disease, given the poor prognosis. the aim of this study was to determine the experience of the past years in relation to the income of these patients in an icu. methods a retrospective case series consisting of patients with diagnosis of hiv infection (known or unknown) admitted between january and december . we collected demographic and epidemiological data, process of acquisition of the disease, infection status: known or unknown patient infected, whether or not receiving antiretroviral therapy and whether it was eff ective (undetectable viral load at the time of admission), apache ii, cause of admission, need for mechanical ventilation (mv), pathology related or unrelated to hiv infection and icu mortality. results during this period , patients were admitted to the icu, ( . %) hiv-positive. mean apache ii score . , median age years, % men and % spanish nationality. principal risk behavior: addiction drugs injection ( %). seventeen percent of patients did not know who was infected with hiv at the time of admission to the icu. fifty-three percent were not receiving haart. of the patients treated, % were receiving haart (eff ective in % of cases). sixty percent of the patients came from the emergency department of the hospital. main admission diagnoses: acute respiratory failure caused by infection (streptococcus pneumoniae and pneumocystis jirovecii), neurological disorders (coma for illicit drugs and psychotropic) and septic shock. seventy percent required mv. of patients whose hiv infection was not known, . % were admitted for related pathology. in patients of known infection, the pathology associated with hiv was %. average length of stay was days. icu mortality was %. most frequent causes of death: septic shock and multiple organ failure. conclusion depending on the patient and the cause of admission, icu admission may represent an excellent opportunity as a screening method to determine hiv status. given the greater effi cacy of haart at present, most patients with medical or surgical conditions unrelated to hiv infection will be eligible to join the icu. people with hiv can and should benefi t from using reasonable and individualized care in an icu. references conclusion neither immune status-related variables nor comorbidity or infection focus are mortality predictors. poor nutritional status, delayed icu admission, shock or renal failure increase the icu relative mortality risk. tachycardia, hypotension, hypercapnia, acidosis, and oliguria in the fi rst icu hours increase signifi cantly icu mortality. mechanical ventilation is not a mortality predictor. introduction patients with lung cancer commonly require the icu for a variety of acute illnesses related to the underlying malignancy, treatment, or comorbid conditions. icu admission of patients with nonresectable lung cancer has been criticized based on the high mortality rate in this population. however, recent advances in critical care may have changed this scenario. the aim of this study was to identify factors associated with hospital mortality in this group of patients. methods a retrospective study was conducted in consecutive medical and surgical patients with lung cancer admitted to a university hospital icu in são paulo, between and . a univariate analysis was performed to identify associated variables with hospital mortality. selected variables were included in the multivariate model. results from patients included in the study, were medical admissions ( . %) and were surgical admissions ( . %). four hundred and twenty ( %) patients had metastasis, patients ( %) required the icu because of respiratory failure and ( %) because of septic shock. the icu and hospital mortality rates were . % and %, respectively. in the univariate analysis, variables associated with hospital mortality were diagnosis of nonsmall-cell lung cancer, higher charlson morbidity index, medical admission, active neoplasm, vasopressor need at admission to and at hours of icu, acute renal failure at admission, non-invasive ventilation or mechanical ventilation need at admission to and at hours of icu and a higher admission arterial lactate. by multivariate analysis, risk factors of hospital mortality were diagnosis of nonsmall-cell lung cancer (or = . ; % ci, . to . , p < . ), medical admission (or = . ; % ci, . to . , p < . ), acute renal failure at admission (or = . ; % ci, . to . , p < . ), non-invasive ventilation at hours of icu (or = . ; % ci, . to . , p = . ) and mechanical ventilation at hours of icu (or = . ; % ci, . to . , p < . ). conclusion hospital survival in patients with lung cancer requiring icu admission was %. our results provide evidence that icu management may be appropriate in patients with nonresectable lung cancer and appoint risk factors for mortality, helping to better triage cancer patients who will benefi t from icu care. introduction because the prognosis of older patients with cancer may be poor compared with younger patients, it remains controversial whether they benefi t from icu treatment. the objective of this study was to identify factors associated with hospital mortality in older patients with cancer requiring the icu.methods a retrospective study was conducted in consecutive medical and surgical older patients with cancer admitted to a university hospital icu in são paulo, between and . univariate and multivariate analysis were performed to identify associated and independent factors related to hospital mortality. results from , patients with cancer requiring icu at the period, patients were years old or higher. most patients were male ( %), had solid neoplasm ( %), were from medical admission ( %) and % had metastatic disease. the mean age was years (± ). the icu and hospital mortality rates were % and %, respectively. in the univariate analysis, variables associated with hospital mortality were diagnosis of lung cancer, medical admission, active neoplasm, vasopressor need at hours of icu, acute renal failure at admission, mechanical ventilation need at admission to and at hours of icu and a higher admission arterial lactate. by multivariate analysis, risk factors of hospital mortality were diagnosis of lung cancer (or = . ; % ci, . to . , p < . ), medical admission (or = . ; % ci, . to . , p < . ), acute renal failure at admission (or = . ; % ci, . to . , p < . ), mechanical ventilation at hours of icu (or = . ; % ci, . to . , p < . ) and lactate levels at admission (or = . ; % ci, . to . , p < . ). conclusion hospital survival in older patients with cancer requiring icu admission is acceptable. our results provide evidence that icu management may be appropriate in older patients with cancer and appoint risk factors for mortality, helping to better triage cancer patients who will benefi t from icu care. introduction readmission to the icu within hours is an indicator of quality of intensive care and is associated with an increase in mortality. during the last years several groups have published data based on multivariate logistic regression analysis to describe characteristics of patients who needed readmission to the icu. older age, comorbid conditions and severity of illness (apache score) have been among the strongest predictors for readmission. in our icu most patients are in the groups formerly identifi ed as risk groups, which means that stratifi cation and prediction of readmission is diffi cult. because of the unusual high severity of acute and pre-existing illnesses we could not fi nd a data match on comparable patient groups. to investigate whether we could reduce our rate of readmission we therefore decided to perform a qualitative investigation to identify risk factors related to readmission. after identifi cation of the risk factors we will take actions to optimize care and perform ongoing control of the implemented actions to secure that they decreases the rate of readmission. methods retrospective data on patients readmitted to the icu within hours during an -month period (november to june ) were drawn from the critical information system (cis) at icu zit, bispebjerg hospital, denmark. zit is a multidisciplinary unit with beds and to admissions/year and a median saps ii score of . a group of consultants, junior doctors and nurses from the icu and the ward each read the patient fi les with focus on pattern recognition and suggested trigger points to focus on. data on trigger points were then drawn from the cis system and re-evaluated. finally, fi ve key points were identifi ed and serves as basis for future actions. results in a qualitative analysis, readmissions to the icu are related to the following fi ve key points -discharge outside day hours, lack of infection control, stay in icu < days, lung physiotherapy ordinated but not eff ectuated, and several minor organ dysfunctions (atrial fi brillation and acute kidney injury). age, diagnosis, saps ii score or ventilator treatment during intensive care was not diff erent in patients with successful discharge and patients readmitted in this group of patients. conclusion it is possible and suitable to identify key points for future eff orts in a given subgroup of patients using a systematic qualitative approach. conclusion the latest audit follows introduction of a referral system directly to the icu consultant and may account for the reduction in numbers of referrals attended by junior doctors. ed/medicine persist as the main source of referral to the icu. discussion with the referring team consultant may reduce inappropriate referrals. icu staffi ng should not be reduced. [ , ] . this study aims to evaluate the impact of the time elapsed from request until admission to the icu on mortality and icu length of stay (los). methods a retrospective cohort study performed on patients in the icu of hospital regional de samambaia over a period of years, from january to december . the patients were allocated into two groups: patients who waited longer than hours, long waiting period the management of emergency medical admissions has been a subject of recent clinical incidents. there was a high percentage of patients that were referred to the icu by staff in training, and % of referrals were made by junior doctors. consultant physicians had no knowledge of the case in % of referrals. methods a prospective study of cases of referrals and admissions to the icu was conducted at the glasgow victoria infi rmary hospital from to september . a questionnaire was produced relating to the referrals, admissions, seniority involvement, cause of referral, and time of patient review by the icu consultant after icu admission. they were distributed to specialist registrars and the icu consultants. all data were electronically recorded into an excel database. questionnaires that were not completely fi lled were further investigated using patient clinical notes and contact with medical staff . information that may identify a patient or clinician was removed from the questionnaire for confi dentiality purposes. results twenty-one complete questionnaires were collected. fiftyseven percent ( / ) of cases involved admission to the icu. nine percent of the cases involved contacting either a specialist registrar or icu consultant intensivist for assistance in practical procedures. of the patients admitted to the icu, % ( / ) were from medical wards, % were admitted from a&e. consultants were the most common professionals who referred patients to critical care ( %; / ). fourteen percent of cases ( / ) involved the referral of patients into icu by a junior doctor, but only one of the referrals was accepted by the icu intensivist. consultants referred or were aware of the referral in % ( / ) of cases. of admissions, % ( / ) were accepted by the icu consultant and the remaining by the specialist registrars. all accepted were acknowledged by the icu consultant. after admission all of the patients were reviewed by the icu consultant and the time of review after admission was on average hour minutes ( minutes to hours minutes). conclusion there is still an issue with junior doctors referring patients to the icu without the acknowledgement of consultant physicians, resulting in unnecessary admissions and decreased time that icu trainees spend in the icu. there are more appropriate icu admissions when there is involvement with seniority. contact with icu staff to perform practical procedures outside the icu and not about admissions should be explored further. reference introduction the requirements for the intensivist in handling medical technology are constantly growing. it appears necessary to acquire technological competences particularly within the fi elds of medical technology and physics. in the master's degree program 'masteronline physico-technical medicine' , such technical authority is conveyed. to cope with the intensive vocational situation of the physician, this study course follows the blended-learning concept; that is, it is conceived as an online study course with small portions of intermittent presence phases. within the fi rst year, technical basic skills such as 'measurement technique' , 'informatics' , and 'advanced physics' are covered. subsequently, two of various advanced courses in diff erent fi elds of medical technology ('technology in intensive care medicine' , 'technology in surgery' , 'technical cardiology' , 'radiology' , and other) are selected. methods in a survey, we evaluated the study course. therefore, a questionnaire was distributed among all students including the topics course contents, learning materials, time management, supervision, and overall impression. the students were asked to score their agreement to the statements 'content is well structured' , 'content extent is appropriate' and 'content is relevant for medical purposes' on a scale ranging from (fully disagree) to (fully agree). results the students participated actively in this study course with highest motivation and large commitment. the students' workload was in the targeted range of about hours/week. content structure was scored with . ± . , content extent with . ± . and medical relevance with . ± . . conclusion the blended-learning concept fulfi lls the requirements for occupation-accompanying continued medical education, since it off ers the possibility to study self-employed accessing text documents, lecture recordings, and electronic lectures and to convert in concentrated presence phases this knowledge into practical exercises. the fi rst-hour protocol determines the patient-specifi c resources for the start of an icu stay [ ] . staff resources are decided through triage. task charts direct the start of intensive care. our primary goal is to improve patient care. methods a triage method (red, yellow, green) is used to manage icu resources according to the severity of illness. for example, one doctor and one nurse would admit a stable (green) patient coming from the operating room for postoperative icu care. a patient in septic shock with multiple organ disorder (red), on the other hand, would be admitted by a team of two doctors and three nurses. each staff member has a task chart in a checking-list format. also, an admission chart is used to improve data collection. the use of the protocol started as a pilot study in early . simulation education for staff members started in august and has included video recordings and debriefi ng of each simulated icu admission. primary goal-directed therapy goals have been mean arterial pressure (map > mmhg), spo > %, timing of the laboratory tests, start of antibiotics, and blood glucose level to mmol/l. quality indicators have been followed from the data provided by the finnish intensive care consortium. questionnaires for the staff members have been used to evaluate opinions about the fi rsthour protocol. results according to the questionnaire replies, % (n = / ) of our nurses estimate that the fi rst-hour protocol has improved the starting process of our patients' intensive care. twenty percent (n = / ) of the nurses considered that the protocol has no eff ect, and none thought it to be adverse for patient care. corresponding numbers for our icu doctors were % (benefi cial n = / ), % (no eff ect n = / ) and % (adverse). furthermore, . % (n = / ) of the nurses replied that education of new nurse staff members has improved because of the fi rst-hour protocol. a total of . % (n = / ) thought there has been no eff ect, and none considered the protocol harmful for education. for icu doctors the protocol did not bring either clear educational advantages or disadvantages. the variable life-adjusted display curves (the finnish intensive care consortium) have shown improvement in our patient care after the implementation of the fi rst-hour protocol. however, we cannot determine whether it is a signifi cant factor in our intensive care results. conclusion the fi rst-hour protocol has helped us in resource management, start of the patients' intensive care and education of nursing staff . introduction demand for critical care services is increasing yet a comprehensive understanding of how critical care nurses -the largest group of icu direct care providers -impact outcomes remains unclear. the purpose of this study was to determine how critical care nurse education (hospital proportion of bachelor's prepared icu nurses) and icu work environment infl uenced -day mortality of mechanically ventilated older adults. methods a multi-state cross-sectional nurse survey was linked to hospital administrative data and medicare claims ( to ). the fi nal sample included , mechanically ventilated older adults in hospitals. logistic regression modeling was employed to jointly assess the relationship of critical care nurse education, work environment and staffi ng on -day mortality while adjusting for hospital and patient characteristics and accounting for clustering. results a % increase in the proportion of icu nurses with a bachelor's degree or higher was associated with % lower odds of death while controlling for patient and hospital characteristics. patients cared for in better work environments experienced % lower odds of riskadjusted death than those cared for in poorer icu work environments. conclusion patients cared for in hospitals with a greater proportion of bachelor's prepared icu nurses and in better icu work environments experienced signifi cantly lower odds of death. as the demand for critical care services increases, attention to the education level of icu nurses and icu work environment may be warranted to optimize currently available resources and potentially yield better outcomes. introduction information about big hospital geographical transfer is scarce in the medical literature. on february our hospital (in fact, a big university complex) was transferred from their previous location in the north-center of our city towards a new southern peripheral, geographical location. this transfer has been done without any changes in assisted population or nursing/medical staff . the only change was a slight increase in bed number ( to ). our aim is to analyze changes in activity indexes (length of stay, occupancy rate, and so forth) and case mix (origin, previous quality of life and nyha score, main diagnostic groups, severity scores, in-icu and in-hospital mortality). introduction south-east london (sel) presents unique challenges to healthcare providers due to its diverse demographic. the high levels of poverty, immigration and psychiatric illness impact delivery of obstetric care. these were identifi ed as risk factors for poor outcome in the latest cmace report [ ] . the intensive care national audit and research centre (icnarc) produced data on obstetric critical care admissions in [ ] . we reviewed the obstetric critical care admissions in three sel hospitals and compared this with the national average determined in the icnarc and cmace data. methods all critical care admissions in three high-risk obstetric units in sel ( august to july ) were screened for patients who were currently or recently pregnant. we compared local results with national data by icnarc and cmace. there were obstetric critical care admissions in the sel hospitals within the audited time frame. the mean age was . in icnarc data compared with . in sel. average apache ii scores were lower in sel compared with the icnarc data, but length of stay was greater in sel ( . days) compared with icnarc ( . days). haemorrhage was the most common reason for admission in sel, whilst sepsis was the leading cause of death according to the latest cmace report (figure ). conclusion data from national audits may guide protocol, but services must be tailored to local circumstances. sel has unique population characteristics and obstetric critical care admissions diff er signifi cantly from national statistics; in particular, haemorrhage is over-represented in our region. critical care services were generally required for a short period of time; during this period, routine postpartum care may be omitted as treatment priorities diff er. dedicated critical care services on the labour ward may be a way to combine postnatal care with transient high-dependency requirements. this may enhance patient experience and prove cost-eff ective. introduction adverse drug events (ades) are associated with a substantial increase in morbidity and mortality in any setting. because patients in icus were critically ill with complex diseases and varied organ dysfunction, the incidence of ades on such patients is much more crucial than the counterparts. we thus assessed the nature of ades and their infl uence in icus. methods we conducted a prospective cohort study at icus at three large tertiary-care hospitals in japan. trained research nurses reviewed all medical charts, incident reports and reconciliations from the pharmacy to identify suspected ades as well as the background of patients. ades are any injuries that result from the use of a drug. after suspected ades are collected by research nurses, physician reviewers independently evaluated them and classifi ed them as ades or rule violations. we used the validated methodology [ ] . results we included patients with , patient-days. the median age was years and the median length of stay was days. in total, patients ( %) had at least one ade during their stay in the icu. the median icu stay in patients who had ades was days while days in patients who had no ades (p < . ). the median length of the ade onset days since admission was days. regarding the mortality, patients ( %) were dead during their icu stay: deaths ( %) in patients who had ades and three of deaths were caused by an ade, and deaths ( %) in counterparts (p = . ). there were no signifi cant diff erences of patients' characteristics between patients with ades and without ades (table ) . conclusion ades were associated with longer stay and caused a part of death in icu ( %) although they did not increase the mortality. because the characteristics of patients were not associated with ades, early detection and intervention for ades could be important to improve the morbidity and reduce the death caused by ades in icus. introduction in hungary, despite the high level of social support, the number of organ recoveries from deceased donors has not changed signifi cantly. the donation activity shows a positive relationship with the level of education of staff in icus as well as with their attitude towards transplantation. the aim of this cross-sectional study is to estimate the attitude and knowledge of intensive care specialists and nurses as regard donation and transplantation. methods the self-completed questionnaire that consisted of items was completed at the congress of hungarian society of anesthesiology and intensive therapy in . besides the epidemiological data, the intensive care specialists (n = ) and nurses (n = ) were asked about donation activity, participation in an organ donation course, selfreported knowledge of joining eurotransplant, donor management, legislation, and transplantation. the data were analyzed by spss . . results a total of . % of physicians and . % of nurses attended an earlier organ donation course (p < . ). the average age of those who participated in training was signifi cantly higher among doctors (p < . ). fifty-nine percent of doctors and . % of nurses did not even want to participate in such training. donation activity was higher among staff who joined training (p < . ). independently from accepting the presumed consent legislation ( . %), % of physicians agreed with the hospital practice that requests the adult donor's relatives to consent to organ recovery. this standpoint did not depend on donation activity, participation in an organ donation course, opinion about legislation and the nature of staff . a total . % of participants consented to their organ retrieval after death. the staff who participated in an organ donation course had more knowledge regarding the law and ethics of donation (p < . ), donor management (p < . ), living and deceased donor transplantation (p < . ) and joining eurotransplant (p < . ). older professionals had more information about all fi elds (p < . ). nurses had less knowledge concerning donor management (p < . ), law and ethics (p < . ) and deceased donor transplantation (p < . ) than doctors. conclusion education about organ donation needs to be part of specialist training of intensive care staff , and refresher courses every fi fth year as well. the course should include knowledge regarding brain death, donor management and communication with family. this is the fi rst step to improve the number of transplantations. in the uk, three people die each day awaiting trans plantation, due to the unavailability of donor organs. traditionally, donor identifi cation has been restricted to the icu. however, following the uk organ donation taskforce report in [ ] , a number of emergency departments (eds) have been working with specialist nurses for organ donation (sn:od) to identify potential donors and approach their families for consent in the ed. we present our initial experience after the introduction of a sn:od to an irish teaching hospital's ed. methods we conducted a retrospective review of deaths in our ed during a -month period. for those who died in the ed, case notes were reviewed to identify those suitable for organ donation. referral and donation rates were compared in two cohorts, pre and post introduction of a sn:od. fisher's exact test was used to assess diff erences between groups. results ninety-one deaths occurred in the study period. following introduction of the sn:od, referrals increased from zero to eight. of the eight referred, three received consent and were transferred to the icu, two of whom became successful donors. the number of missed potential donors fell from six to one (p = . ). conclusion introduction of a sn:od and a clinical pathway has led to the identifi cation of previously missed potential organ donors in the ed. several patients have subsequently been admitted to critical care solely to facilitate organ donation. reference introduction admission to hospital overnight has been shown to increase mortality and decrease hospital length of stay [ ] . the objective of this study was to determine whether this relationship is valid in patients admitted to our icu, and whether length of stay was aff ected. methods a retrospective data collection identifi ed , patients admitted to a fi ve-bed icu from april to november . data regarding patient age, sex, apache ii score and icu admission date and time were collected along with the length of stay in the unit and hospital. defi nitions of day and night were set to local icu standards of : am to : pm. patients were then separated into two groups and analysed using analyse-it software for excel. results crude icu and hospital mortality rates in patients admitted during the day and overnight were examined. there was no signifi cant diff erence in unit mortality (day . % vs. night . %, or = . , % ci = . to . , p = . ) or hospital mortality (day . % vs. night . %, or = . , % ci = . to . , p = . ). the mean unit length of stay showed no diff erence in patients admitted during daytime compared with those admitted overnight ( . days vs. . days, p = . ). the mean hospital length of stay was decreased in patients admitted during daytime compared with patients admitted overnight ( . days vs. . days, p = . ). the average age of patients was less in those admitted out of hours (night . years vs. day . years, p = <. ). there was no signifi cant diff erence in apache ii scores of patients between the groups (day vs. night , p = . ). conclusion there is no signifi cant diff erence between the mortality of patients admitted overnight and patients admitted during the day to our unit. the hospital length of stay is increased in patients who are admitted overnight to intensive care; however, icu length of stay is not aff ected. adjustment for other confounders such as current bed occupancy and staffi ng ratios during the entire patient stay may help to understand the diff erences seen in the hospital length of stay. introduction interdisciplinary rounds (idrs) in the icu are increasingly recommended to support quality improvement and to reduce confl icts, but uncertainty exists about assessing the quality of idrs. we developed, tested, and applied a scoring instrument to assess the quality of idrs in icus. methods a literature search was performed to identify criteria for instruments about assessing team processes in the icu. then, videotaped patient presentations led by diff erent intensivists were analyzed by delphi rounds. appropriate and inappropriate behaviors were highlighted. the idr-assessment scale was developed and statistically tested. the inter-rater reliability was evaluated by rating nine randomly selected videotaped patient presentations by three raters. finally, the scale was applied to videotaped patient presentations during idrs in three icus for adults in two hospitals in groningen. results the idr-assessment scale had quality indicators, subdivided into two domains: patient plan of care, and process. the domain patient plan of care refl ects the technical performance from the initial identifi cation of a goal to the evaluative phase. the domain process refl ects the team processes that are important to ensure that the appropriate plan of care is agreed, understood, and executed as planned by all care providers. indicators were essential or supportive. the inter-rater reliability of nine videotaped patient presentations among three raters was satisfactory (κ = . ). the overall item score correlations between three raters were excellent (r = . to . ). internal consistency in videotaped patient presentations was acceptable (α = . ). application to idrs led by diff erent intensivists in three icus in two hospitals demonstrated that indicators could be unambiguously rated. the staff and management of all three icus that were rated had considered their idrs to be adequately performed, and they were surprised by these study results. conclusion this study showed that the quality of idrs can be reliably assessed for patient plan of care and process. the idr-assessment scale had satisfactory inter-rater reliability, excellent overall item score correlations, and acceptable internal consistency. our instrument may provide feedback for icu professionals and managers to develop adjustments in quality of care. testing the idr-assessment scale in other icus may be required to establish general applicability. the development of patient-centered care by interdisciplinary teams in the icu has focused attention on leadership behavior. the purpose of this intervention study was to measure the eff ect of leadership training on the quality of performed interdisciplinary rounds (idrs) in the icu.methods in this nonrandomized intervention study, participants included nine intensive care medicine fellow trainees (intervention group) and experienced intensivists (control group). participants in the intervention and control groups previously were untrained in leading idrs in the icus. after each participant led an idr that was videotaped, the fellow trainees participated in a -day leadership training, which was consistent with principles of adult learning and behavioral modeling. after training, each fellow trainee led another idr that was videotaped. quality of the performed idrs was measured by review of videotapes of the idrs lead by intensivists, including patient discussions subdivided into four icus, and assessment with the idr-assessment scale. results comparison of the intervention versus control groups shows that the intervention group has more yes scores on the idr-assessment scale than the control group. this diff erence was signifi cant in of the, in total, quality indicators. conclusion quality of leadership will be reliably trained and measured in the context of idrs in icus. training in a simulation environment, with real-life idr scenarios including confl icting situations, and workplacebased feedback in the preparation and feedback phases, appears to be eff ective to train leadership behaviour. results over a -month period, teleconsultations ( patients) were done. mean age was . years, . % was male and mean apache ii score was . . a total of . % originated from the icu and . % from the ed. main consultation diagnoses were sepsis ( . %); stroke ( . %); survival from cardiac arrest ( . %); trauma ( . %); and acute myocardial infarction ( . %). tm improved diagnosis in . % and infl uenced the clinical management in . % of the consultations. invasive procedures were indicated in . %. life-saving procedures were tm related in seven patients ( . %): stroke thrombolysis (n = ) and limb amputation (n = ). seven patients ( . %) were transferred and submitted to surgical procedures (heart surgery (n = ), neurosurgery (n = ) and liver transplantation (n = )). the majority of the patients remained at hmmd and were discharged. conclusion a tm program is feasible to be implemented in a community hospital. the major benefi t is expertise medical transfer from the tertiary hospital to the community setting, improving diagnosis and management of critical care patients, and avoiding routine transfer to a major urban center. introduction the purpose of our study was to assess the attitudes of slovenian intensivists towards end-of-life (eol) decision-making and to analyze the decision-making process in their clinical practice. methods a cross-sectional survey among slovenian intensivists and intensive care medicine residents from diff erent icus was performed using a questionnaire containing questions about views on eol decision-making. fisher's exact test and the fisher-freeman-halton test were applied to cross-tabulated data; signifi cance level was set at p ≤ . due to the large number of tested hypotheses. the response rate was . % ( questionnaires were returned out of distributed), which represented roughly the same percentage of all slovenian intensivists. termination of futile treatment was assessed as ethically acceptable (p < . ). the statement that there is no ethical distinction between withholding and withdrawing of treatment could not be confi rmed (the answers 'there is a diff erence' and 'undecided' were less frequent, but not statistically signifi cant; p = . ). a do-not-resuscitate order (dnr) was used more often than other withholding treatment limitations (p < . ). a dnr was used most frequently in internal medicine icus (p < . ; compared with paediatric and surgical icus). withdrawal of inotropes or antibiotics was used more often than withdrawal of mechanical ventilation or extubation ( . % vs. . %; p < . ). withdrawal of mechanical ventilation or extubation was more often used in the paediatric icus ( . %) as compared with the internal medicine icus ( . %) and the surgical icus ( %) (p < . ). over two-thirds ( . %) of intensivists were against termination of hydration, which would be more often used in the internal medicine icus (p < . ). thirty-one percent of intensivists used written dnr orders. conclusion termination of futile treatment was found to be ethically acceptable for slovenian intensivists, although they were not convinced that withholding and withdrawing of treatment were ethically equal. a dnr would be used most often. withdrawal of inotropes or antibiotics would be used more often than withdrawal of mechanical ventilation or extubation. termination of artifi cial hydration would be rarely used in practice. of consultant attendees from the uk, completed the survey ( %). for % of consultants there was no formal institutional protocol for withdrawal of futile therapy. when deciding to withdraw therapy, % of consultants routinely seek and document a second opinion. regarding donation after cardiac death (dcd), % of consultants were happy to delay withdrawal to facilitate successful donation, % have already done so in their practice and % routinely withdraw therapy in theatres rather than on the icu. even if it would impact on the care of other patients, % would delay withdrawal of therapy to facilitate dcd. for patients accepted for dcd, % think that some intensivists withdraw more aggressively (in essence, hasten death) in the hope of improving the likelihood of a successful organ donation and % have felt pressurised to withdraw therapy more quickly than their usual practice. furthermore, % experienced pressure to refer a patient for dcd when it they felt it was not appropriate. conclusion this survey confi rms variation in the practice and attitudes to withdrawal of futile therapy amongst uk consultant intensivists. formal protocols were frequently unavailable to guide withdrawal and second opinions were often not sought. nearly one-half of the intensivists delay withdrawal to facilitate donation, even if this may impact on the care of other patients. many intensivists have felt pressure to refer for donation when they feel this is inappropriate and there is a perception that some intensivists may withdraw care more aggressively in those who are accepted for dcd to improve the likelihood of a successful donation. this survey may help inform debate in this ethically challenging area. reference the research shows that the diffi culty of communi cation is a factor that impacts negatively on the grieving process. moreover, it stresses the importance for parents to rediscuss the moment of their child's death with health professionals. references methods a randomised controlled trial was undertaken in adult survivors of icu admission. they were allocated to receive an -week in-hospital supervised aerobic programme consisting of two cycle ergometry and one unsupervised session per week (exercise group) or no exercise (control group). primary outcomes were the anaerobic threshold (in ml o /kg mass/minute), physical function and mental health scores (sf- questionnaire), measured at weeks and . participants were then allocated to focus groups where the interpretation of experiences was compared with outcomes from the pix study. results fifty-nine patients were recruited to the study. the anaerobic threshold increased at week in the exercise group by a clinically and statistically signifi cant amount of ml o /kg mass/minute ( % ci, to ml/kg/minute). there was further improvement in fi tness levels in both groups by week (although no signifi cant diff erence between groups). no signifi cant diff erence in hrqol measures between groups was demonstrated; however, the exercise group did show an improvement in their mental health scores. the focus groups centred on feelings of isolation, abandonment, vulnerability, dependency and reduced physical activity post hospital discharge. many reported a lack of social inclusion as they did not have the energy or confi dence to venture outside. however, those in the exercise group felt that the rehabilitation programme was motivating, built up confi dence, improved fi tness, helped social interaction and gave them a sense of achievement.conclusion the -week exercise intervention resulted in statistically signifi cant improvements in fi tness at weeks while focus group participants highlighted the positive eff ects of the exercise intervention leading to enhanced energy levels, motivation and achievement. psychological benefi ts of the exercise programme are apparent from the focus group, emphasising the important link between physical and mental health. introduction survivors of critical illness often have a prolonged stay on the icu. these patients may suff er from icu-acquired weakness. it has been shown that reduction in muscle mass and muscle strength occurs early after admission to the icu. however, in the very early stage on the icu, patients are often sedated and not able to participate in any active mobilizations. therefore the use of neuromuscular electrical stimulation (nmes) is becoming a treatment of interest in the icu. the aim was to study the feasibility and safety of nmes in a surgical and medical icu of a large, tertiary referral university hospital. methods fifty patients with an expected prolonged stay on the icu of more days (judged on day ) with no trauma or neurological disease were included. they then received daily a nmes session (duo ; gymna, belgium) for minutes on the quadriceps bilaterally during their entire stay on the icu. the main outcome was the ability to produce a contraction of the quadriceps through nmes. the muscle contraction was quantifi ed on a -point scale: (no contraction palpable and visible) up to (contraction very well palpable and visible). patients were classifi ed as responders when an adequate muscle bulk was obtained in ≥ % of the sessions. the potential factors associated with the feasibility were: gender, age, body mass index (bmi), diagnosis of sepsis, barthel index prior to admission to the hospital, apache ii score, glasgow coma scale (gcs), fi ve questions for adequacy, stimulus intensity and leg edema. a multiple regression analysis was performed to identify the factors determining whether or not a contraction could be expected in a patient. safety of nmes was assessed through heart rate, blood pressure, oxygen saturation and respiratory rate. results in % of the patients we were able to achieve adequate muscle contractions in more than % of the sessions. gcs (p = . ), edemaintroduction trauma is the most common cause of morbidity in young people. it has a high social impact both because of the high cost of the acute treatments and because of the physical and psychological consequences that it may cause. a prospective, observational, singlecenter study on quality of life to months after trauma was carried out. the aim of the study is to evaluate life quality after trauma and to identify the most important needs of the patients, in order to improve the level of care after an icu stay and to implement a faster and more eff ective reintegration into the active and productive society. the aim was to analyse the outcomes and patient satisfaction of a recently implemented icu follow-up clinic. these clinics are national institute for clinical excellence recommended [ ] . methods a retrospective analysis of prospective collected data from january to december . the clinic is run monthly by an icu consultant and a critical care outreach sister. criteria to be invited to the clinic are mechanical ventilation ≥ days. patients fi lled an anonymous satisfaction survey after the clinic. results our attendance rate is % ( patients), which is similar to other series reported in the literature. those patients who attended the clinic required a longer length of mechanical ventilation ( . days vs. . ) and a longer length of stay in the icu ( . vs. ) and in hospital ( vs. ). we identifi ed a wide range of physical and nonphysical morbidities on these patients (figure ). we referred them to the appropriate specialities. patients were very satisfi ed with this new service ( figure ). this study aims to quantify the acute exercise response to early passive and active activities in order to inform exercise prescription when designing rehabilitation programmes for the critically ill. critical care survival is often associated with a poor functional outcome [ ] , with recent investigations presenting the case for early rehabilitation in order to optimise functional recovery [ ] . there, remains, however, a scarcity of research investigating the immediate response to exercise and subsequent exercise prescription, in the acute phase following critical illness. methods this study is a prospective randomised controlled trial with a repeated-measures crossover design. eligible participants, requiring mechanical ventilation for or more days, completed two exercise activities routinely used in early critical care rehabilitation, a passive chair transfer (pct) and active sitting on the edge of the bed (soeob). the oxygen consumption and cardiovascular parameters were measured to quantify and compare the exercise response between the two activities. introduction the aim of this study was to investigate the eff ect of a -week exercise programme on outcomes in post-icu patients. with improvements in intensive care medicine, increasing numbers of patients are surviving catastrophic illness [ ] . severe weakness is common in patients with prolonged critical illness and results in considerable morbidity, mortality and healthcare costs [ ] . the nice guidelines rehabilitation in critical care recommend follow-up for post-icu patients and that further research is needed in this fi eld [ ] . methods patients who have been discharged home from hospital following an icu stay of hours or more were recruited to the study. patients were only excluded if they were not considered safe for exercise. baseline measurements were completed prior to stratifi ed (age, gender, apache ii score) random allocation to either the exercise or control group. outcome measures included cardiopulmonary fi tness ( -minute walk test), balance (berg balance scale), grip strength (jamar grip dynamometer) and hospital anxiety and depression (had score). the exercise group completed a -week supervised exercise programme, twice a week for up to hour. in the seventh week, all patients repeated the baseline measurements. an unpaired student's t test was used to compare any diff erences between the control and exercise groups. results at baseline measurements, there were no statistical diff erences in age, gender, length of stays or apache ii scores between the two groups. results indicate that the exercise group (n = ) had signifi cantly greater improvements in cardiopulmonary fi tness (p < . ) and balance (p < . ) compared with the control group (n = ). greater improvements were also evident in anxiety, depression and grip strength in the exercise group, although not statistically signifi cant. conclusion this pilot study highlights that a -week supervised exercise programme can signifi cantly improve cardiopulmonary fi tness and balance in post-icu patients. further recruitment to the study and -month/ -year follow-up is needed. references introduction intensive care patients suff er psychological and physiological distress that may have debilitating and long-lasting eff ects [ ] [ ] [ ] . healthcare professionals are in a position to help avoid or alleviate this stress [ ] . to action this it is important to identify the main stressors from the patient's perspective. a systematic review was performed to provide a list of what patients consider stressors in intensive care. these were then ranked in order to provide an identifi cation tool that can be used to shape appropriate care. methods a systematic review was performed using medline, cinahl, psych info and academic search complete. grey literature was included and searches were not restricted to type of intensive care or country. criteria were used to fi lter those articles that identifi ed the patients' views of their stressor, not the patient experience. eligible articles were critiqued using the critical appraisal skills programme for qualitative studies [ ] and brought together using a narrative synthesis.all of the reviewed studies used a questionnaire as a means to identify what elements on the intensive care patients found stressful. a list of the top- stressors could then be expressed for each study and compared. from this information, a set of guidelines for best practice were devised. introduction this study describes the development and validation of the consumer quality index relatives in icus (cqi 'r-icu'), which aims to measure the satisfaction of relatives and to identify aspect of care that need improvement in the icu in a reliable and valid way.according to the quality standards of the dutch society of intensive care, every icu needs to record the satisfaction of relatives [ ] . at this moment there is insuffi cient insight into the quality of care off ered to relatives on the icu because an evidence-based dutch measurement instrument is missing. methods the cqi 'r-icu' has been developed based on a scientifi c and standardised method [ ] . a mixed design method is used, consisting of qualitative and quantitative survey studies. factor analyses are carried out to determine the underlying structure of the newly developed questionnaire. multiple regression analysis is used to explore the relationship between demographic variables and the perceived quality of care. results in six hospitals the cqi 'r-icu' is sent to relatives after receiving informed consent (n = ), . % of the respondents are the patient's partner. respondents seem to be most satisfi ed with the presence of a professional at fi rst entrance to the icu. the highest need for improvement scores relate to information about meals, parking and other disciplines (for example, social worker, spiritual worker or psychologist). factor analysis shows that quality of care is determined by four clusters of items: support, communication, general information and organisation. the reliability of the cqi 'r-icu' is suffi ciently high, only communication and support are signifi cant predictors of total quality judgement of relatives (adj. r = . ). in addition, there is a signifi cant diff erence in mean total quality judgement between the six hospitals as well as between the four wards within erasmus mc. none we are conducting a cluster randomized trial with two parallel arms to evaluate strategies to improve family satisfaction with the care that themselves and their critically ill relatives receive in the icus of nonacademic brazilian public hospitals. here we report the results of the baseline phase of this trial. methods in this baseline phase, we interviewed the family member most closely involved with the care of critically ill patients who stayed in the icu for at least hours. we applied a form with questions divided into four domains: overall icu experience, communication, decision-making, and questions related to end-of-life care for patients who died in the icu. each question scored from (very poor) to (excellent). the form was adapted from the family satisfaction with care in the icu (fs-icu ). as many questions assessed the quality of intensivist care or communication, the interview was applied by a psychologist or a nurse. results families of patients were interviewed. a total / ( . %) died in the icu. most respondents were satisfi ed with overall icu experience (mean ± sd score . ± . ). however, family satisfaction with communication ( . ± . ) and decision-making ( . ± . ) resulted in somewhat lower scores. most families of patients who died in the icu ( / ( . %)) considered that their relative's life was neither extended nor shortened unnecessarily. also, most of the families believed that their relative did not suff er or suff ered little in the icu ( / ( . %)) and felt supported by the healthcare team ( / ( . %)). conclusion most families were satisfi ed with the care themselves and their critically ill relatives received in the icu. also, most relatives of patients who died in the icu felt that end-of-life care was adequate. although we believe there is much room for improvement in communication, decision-making and support critically ill patients and their families, as their baseline satisfaction with patient care is quite high, it may be hard to demonstrate substantial improvement after interventions. key: cord- -mk t f authors: weeden, m.; bailey, m.; gabbe, b.; pilcher, d.; bellomo, r.; udy, a. title: functional outcomes in patients admitted to the intensive care unit with traumatic brain injury and exposed to hyperoxia: a retrospective multicentre cohort study date: - - journal: neurocrit care doi: . /s - - -y sha: doc_id: cord_uid: mk t f background: supplemental oxygen administration to critically ill patients is ubiquitous in the intensive care unit (icu). uncertainty persists as to whether hyperoxia is benign in patients with traumatic brain injury (tbi), particularly in regard to their long-term functional neurological outcomes. methods: we conducted a retrospective multicenter cohort study of invasively ventilated patients with tbi admitted to the icu. a database linkage between the australian and new zealand intensive care society adult patient database (anzics-apd) and the victorian state trauma registry (vstr) was utilized. the primary exposure variable was minimum acute physiology and chronic health evaluation (apache) iii p(a)o( ) in the first h of icu. we defined hypoxia as p(a)o( ) < mmhg, normoxia as – mmhg, and hyperoxia as ≥ mmhg. the primary outcome was a glasgow outcome scale-extended (gose) < at months while secondary outcomes included and months gose and mortality at each of these timepoints. additional sensitivity analyses were undertaken in the following subgroups: isolated head injury, patients with operative intervention, head injury severity, and p(a)o( ) either subcategorized by increments of mmhg or treated as a continuous variable. results: a total of patients met the inclusion criteria. the mean age was . years, . % were male and the mean acute physiology and chronic health evaluation (apache) iii score was . ( . ). patients experienced normoxia, and hyperoxia. the primary outcome occurred in ( . %) of patients overall with ( . %) from the normoxia group and ( . %) from the hyperoxia group—odds ratio . ( . – . ). no significant differences in outcomes between groups at , , and months were observed. sensitivity analyses did not identify subgroups that were adversely affected by exposure to hyperoxia. conclusions: no associations were observed between hyperoxia in icu during the first h and adverse neurological outcome at months in ventilated tbi patients. electronic supplementary material: the online version of this article ( . /s - - -y) contains supplementary material, which is available to authorized users. supplementation of oxygen in critically ill patients is ubiquitous [ ] [ ] [ ] . however, increasing recognition that hyperoxia may not be benign, has led to re-examination of liberal oxygen administration in this setting [ , ] . indeed, retrospective studies have raised concern about greater mortality with hyperoxia [ ] [ ] [ ] , albeit a recent large, multicenter randomized controlled trial (icu-rox) demonstrated no effect of liberal oxygen exposure on ventilator-free days or mortality in a mixed intensive care unit (icu) population [ ] . in traumatic brain injury (tbi) specifically, the impact of hyperoxia on patient-centered outcomes remains confused. a retrospective cohort study of patients with tbi from north america, found hyperoxia was associated with both increased mortality and a worse glasgow coma scale (gcs) score at hospital discharge [ ] . in contrast, others have shown no association between oxygen exposure and mortality [ , ] , including a large retrospective bi-national multicenter study of over , patients [ ] . clinical concern about the deleterious effects of hyperoxia persist however, because functional outcome may be more sensitive than crude mortality to any potential exposure related injury. currently, there is a paucity of data exploring the association between hyperoxia and functional outcome in tbi, an endpoint that has critical implications for patients, caregivers, and the community. in view of this knowledge gap, we designed a retrospective cohort study to explore the association between early hyperoxia (as measured by the partial arterial pressure of oxygen [p a o ]) and , , and months functional outcomes in ventilated tbi patients admitted to the icu. we hypothesized that early hyperoxia would be associated with a higher proportion of adverse functional outcomes. we undertook a retrospective multicenter observational cohort study of mechanically ventilated tbi patients admitted to icu in victoria, australia. this utilized linked data, from the australian and new zealand intensive care society (anzics) centre for outcome and resource evaluation (core) adult patient database (apd), and the victoria state trauma registry (vstr). the apd is a binational voluntary database containing records on over million icu admissions. de-identified data are entered on a quarterly basis, and are primarily used for quality assurance and benchmarking activities. icus at major tertiary trauma centers in australia and new zealand contribute data. the vstr receives data from health services in the australian state of victoria, capturing all major trauma patients from a population of approximately . million people, and aims to improve the delivery of trauma care by reducing preventable deaths and permanent disability from major trauma. the vstr includes the follow-up of major trauma patients who survive to hospital discharge and utilizes a dedicated call center, with trained staff to undertake the -month gose assessment [ , ] . individual patient records in the anzics-apd and vstr were linked for the period january , , through to december , . this was performed using a probabilistic merge using site, admission date, discharge date, age, gender, mortality status, and icu length of stay. all data included were de-identified. all patient records in the linked database were adult (age > years) non-transferred index trauma admissions to victorian hospitals for the study period. from this cohort, we then selected patients who had a primary apache iii-j code of head injury ± multitrauma. we excluded patients who were not mechanically ventilated, and those with missing icu p a o data. these criteria match that of our previous study concerning in-hospital mortality [ ] . data from the anzics-apd included: age, gender, date of admission, gcs, hospital and icu admission source, hospital and icu length of stay, discharge location, level of admitting hospital, apache ii and iii scores (as well as their predicted mortality), and the australian and new zealand risk of death (anzrod) (including the related component physiological data required for this model). all physiological data recorded in the anzics-apd represent the 'worst' values recorded in the first -h of icu admission. in the case of gcs, this is the lowest value recorded at the time of, or just prior to institution of sedation and/or neuromuscular blockade. data from the vstr included: initial ambulance gcs, injury severity scores (iss), and functional assessment at , , and months. the latter were undertaken using the glasgow outcome scale-extended (gose) [ ] . an adverse neurological outcome was defined as a gose < at months, and was used as the study's primary outcome. oxygen exposure in the first -h was determined using the 'worst' p a o values from the anzics-apd [ ] . for abgs where the patient is intubated and the fio values are ≥ . , the a-a gradient is used to determine the apache iii-j score. for abgs where the patient is not intubated, or for intubated patients with fio values < . , the p a o value is used to determine the apache iii-j score. for the purposes of analysis, we defined hypoxia as a p a o < mmhg, normoxia as - mmhg, and hyperoxia as ≥ mmhg. this is similar to our previous work concerning in-hospital mortality [ ] and is based on prior work by bellomo et al. [ ] . to provide greater granularity, we also considered six categories of p a o , e.g. < , - , - , - , - , and > mmhg, and additionally examined p a o as a continuous variable. the primary exposure variable of interest was p a o as defined above. the primary outcome was gose at months, with a value < being considered as unfavorable. this dichotomy is consistent with previous large tbi trials conducted in our region [ ] [ ] [ ] . group comparisons between those with and without an adverse outcome, were performed using chi square tests for equal proportion, analysis of variance for normally distributed data and kruskal-wallis tests otherwise, with results presented as counts (%), means (standard deviations) or medians [interquartile range (iqr)], respectively. gose at and months were similarly examined as secondary outcomes. to explore the relationship between oxygen exposure and outcome, hierarchical logistic regression models were used with patients nested within sites and sites treated as a random variable adjusting for patient severity and utilizing three categories of p a o : hypoxia, normoxia, and hyperoxia. patient severity was measured by anzrod [ ] with the oxygen component removed to avoid confounding with p a o . of note, this methodology includes treatment limitations on icu admission as a covariate. results are presented as odds ratios ( % ci) referenced against a normal range ( - ). additional sensitivity was performed using the six categories of p a o , as described above. subgroup analysis included those coded as having an isolated head injury, non-operative versus postoperative admissions, and on the basis of tbi severity (gcs < , - , and > ). based on the observed standard deviation in p a o of , this study has % power ( sided p value of . ) to detect a mmhg difference in p a o between patients with good and bad outcomes in the primary analysis. no imputation was made for missing data, and all proportions were reported on the basis of available data. sas version . (sas institute inc., cary, nc, usa) and stata ® version (statacorp llc, college station, tx usa) were employed for statistical analysis, with a p value < . deemed as statistically significant. no adjustment has been made for multiple comparisons. linking the anzics-apd and vstr for the period january to december yielded , patients. of these were identified as having head injury ± multitrauma based on apache iii-j diagnostic codes. patients not requiring intubation were excluded from this group, as were patients for whom p a o data was missing, leaving in the final dataset for analysis (fig. ) . the mean patient age was . ( . ) years, . % of patients were male, and the initial median ambulance gcs was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the mean apache iii score was . ( . ) and the mean iss was . ( . ) in keeping with a cohort of patients suffering 'major trauma' [ ] odds ratios ( % ci) for an adverse functional outcome at , , and months, based on p a o category (hypoxia, normoxia, or hyperoxia) are presented in fig. . sensitivity analyses for patients with an isolated head injury, who required operative care, and according to tbi severity (gcs < ; gcs - ; gcs > ) are presented in the supplementary material, along with the isolated mortality data for each analysis. hyperoxia was not associated with a greater likelihood of adverse functional outcomes overall, nor in any of the pre-defined subgroups. moreover, subgrouping p a o values by mmhg increments, did not result in identification of subgroups with an increased or of adverse functional neurological outcome or death. these data are presented in fig. . finally, as a further sensitivity analysis, we treated p a o as a continuous variable, and generated a locally weighted scatterplot smoothing (loess) of predicted risk of a gose < at months, versus worst p a o in the first h of icu admission (see supplementary material). when treated as a continuous variable (including splines), there was no evidence of a significant relationship between p a o and worse outcomes. in a large cohort of mechanically ventilated tbi patients, hyperoxia in the first h of icu admission was not associated with greater neurological morbidity at months. this finding was consistent regardless of tbi severity, the need for operative care, and whether or not the head injury was isolated, or part of multisystem trauma. these findings were consistent out to months of follow-up and persisted regardless of how p a o was subcategorized. our study is unique in its investigation of long-term functional outcomes in a large cohort of tbi patients. in regard to mortality, the three largest randomized controlled trials of liberal versus conservative oxygen exposure in general icu patients have shown mixed results. the hyperoxia intervention arm of the french hypers s study received an fio of . and was stopped early for safety after recruitment of patients, with strong mortality and morbidity signals for harm [ ] . the oxygen-icu trial enrolled patients from a single italian centre and compared target oxygen saturations of - % with > % [ ] . they observed statistically significant associations between hyperoxia and shock, liver failure, and new bacteraemia. icu-rox, the largest of these studies to date, with patients, found no difference between outcomes with a targeted spo of < % versus usual care. this study included only a small number of patients with tbi ( patients) [ ] limiting its comparability to our study's population. studies focused on tbi have, to date, had mixed results and varied in quality and setting. a retrospective registry study of patients in the us found an association between extreme hyperoxia on the initial hospital blood gas and mortality-however, this was only seen with a p a o above mmhg, not lower, limiting generalizability [ ] . they observed a similar association using discharge destination as a proxy for functional outcome status at discharge from hospital. these results primarily reflected pre-hospital care, rather than oxygen exposure in the icu. in contrast, a us prospective single-center cohort study of patients with tbi found no association between hyperoxia in the first h of icu and excess mortality [ ] . a small iranian randomized controlled trial of patients with severe tbi exposed patients to either % or % oxygen during the first h of their icu admission. they measured functional outcomes including the glasgow outcome score at months and reported significant improvements with higher fio exposure [ ] . however, given the small sample and large putative effect size, this result must be viewed cautiously. finally, a small finnish pilot randomized controlled trial of severe tbi patients did not show differences in biochemical markers of neurological injury when patients were treated with either an fio of . or . , providing mechanistic evidence that hyperoxia is not injurious to this population [ ] . in this study, no relationship was observed between hyperoxia in the first -h in icu, and greater adverse functional outcomes in mechanically ventilated tbi patients. given the lack of high-quality data to guide practice otherwise, our results imply that rigorous clinical avoidance of hyperoxia in tbi patients may not be necessary, and should reinforce clinical equipoise for future randomized controlled trials in this area. specifically, given our findings, and those of previous clinical trials [ , ] , it may be that optimization of cerebral oxygenation represents the most logical study intervention, as opposed to simply avoiding hyperoxia. the key strength of our study and it is unique contribution to the tbi literature is our examination of long-term neurological outcomes. functional neurological outcome after tbi may potentially be differentially and subtly more sensitive to exposure to hyperoxia in the hours following injury. studies focused on mortality may be insensitive to long-term neurological morbidity and disability, and as such, our work provides critically needed insights. linkage between the anzics-apd and vstr has also meant we have captured a large cohort of patients, managed within a standardized comprehensive state-wide trauma system, with relatively homogenous ventilation and/or oxygenation strategies. data were collected by trained staff for the purposes of audit and quality assurance, and for this reason, are unlikely to be subject to fig. adjusted or of gose < by p a o by mmhg increments relative to - mmhg group bias. moreover, use of centralized vstr follow-up has ensured consistency in applying the gose. finally, we have used statistically robust techniques, using validated markers of illness severity, to control for known confounders. as with any registry-based project, data were missing in some cases. importantly, our secondary analysis suggested no differential effect of hyperoxia according to tbi severity, and given that hyperoxia may arguably be more harmful with more severe brain injury, it is unlikely that excluding these patients has concealed any signal. in a similar fashion, follow-up at , , and months was not complete in all cases, albeit our cohort still represents one of the largest published to date regarding longer-term functional outcomes following tbi. as our data demonstrate, tbi patients typically have a lengthy stay in both the icu and hospital, and our ability to quantify oxygen exposure over this entire period is limited. although the hyperoxia group manifest very high p a o values during the first h in icu-their nominated p a o represents the minimum p a o in this period-we were unable to quantify this over any other time frame (either before icu admission or after -h). as such, our study does not examine the effect of prehospital and emergency department hyperoxia, which may be more prevalent. finally, we acknowledge that our cohort includes patients with varying degrees of multitrauma, and different subtypes of tbi (e.g., subdural hematoma versus diffuse axonal injury). albeit such heterogeneity may have weakened the signal overall, we did not observe any significant association between hyperoxia and adverse functional outcomes in isolated head injury, operative versus non-operative diagnosis, nor on the basis of tbi severity. in a large cohort study of tbi patients, managed in a comprehensive state-wide trauma system, we found no association between hyperoxia in the first -h of icu admission, and adverse long-term functional outcomes. this finding was consistent, regardless of need for surgery, presence of multitrauma, severity of head injury, or degree of hyperoxia. current oxygen management in mechanically ventilated patients: a prospective observational cohort study anzics clinical trials group and the george institute for global health. oxygenation targets, monitoring in the critically ill: a point prevalence study of clinical practice in australia and new zealand current oxygenation practice in ventilated patients-an observational cohort study harmful effects of early hyperoxaemia in patients admitted to general wards: an observational cohort study in south korea understanding the benefits and harms of oxygen therapy association between administered oxygen, arterial partial oxygen pressure and mortality in mechanically ventilated intensive care unit patients mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (iota): a systematic review and meta-analysis the association between supraphysiologic arterial oxygen levels and mortality in critically ill patients: a multi-centre observational cohort study conservative oxygen therapy during mechanical ventilation in the icu association between early hyperoxia and worse outcomes after traumatic brain injury hyperoxemia and long-term outcome after traumatic brain injury early exposure to hyperoxia and mortality in critically ill patients with severe traumatic injuries early hyperoxia in patients with traumatic brain injury admitted to intensive care in australia and new zealand: a retrospective multicenter cohort study inter-rater agreement on assessment of outcome within a trauma registry population-based capture of long-term functional and quality of life outcomes after major trauma: the experiences of the victorian state trauma registry structured interviews for the glasgow outcome scale and the extended glasgow outcome scale: guidelines for their use arterial hyperoxia and in-hospital mortality after resuscitation from cardiac arrest effect of early sustained prophylactic hypothermia on neurologic outcomes among patients with severe traumatic brain injury: the polar randomized clinical trial decompressive craniectomy in diffuse traumatic brain injury erythropoietin in traumatic brain injury (epo-tbi): a double-blind randomised controlled trial risk prediction of hospital mortality for adult patients admitted to australian and new zealand intensive care units: development and validation of the australian and new zealand risk of death model defining major trauma using the hyperoxia and hypertonic saline in patients with septic shock (hypers s): a two-bytwo factorial, multicentre, randomised, clinical trial effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit: the oxygen-icu randomized clinical trial both hypoxemia and extreme hyperoxemia may be detrimental in patients with severe traumatic brain injury effects of normobaric hyperoxia in traumatic brain injury: a randomized controlled clinical trial a pilot study of hyperoxemia on neurological injury, inflammation and oxidative stress outcomes of two trials of oxygen-saturation targets in preterm infants the victorian state trauma registry (vstr) is a department of health and human services, state government of victoria and transport accident commission funded project. the victorian state trauma outcome registry and monitoring (vstorm) group is thanked for the provision of vstr data. we would like to acknowledge the work done by each of the icus who contributed data to the anzics-apd: albury mw/au designed the study. bg/dp/mb had full access to the raw data. statistical analysis was performed by mb. mw/au drafted the initial manuscript. all authors critically revised the manuscript for important intellectual content and read and approved the final version. professor andrew udy gratefully acknowledges salary support from the national health and medical research council of australia (early career fellowship; gnt ). anzics core is funded by the state and territory health departments of australia and the new zealand ministry of health to monitor performance and provide benchmarking services to icus and health departments throughout both countries. the vstr is a department of health and human services, state government of victoria and transport accident commission funded project. the authors declare that they have no conflict of interest.ethical approval/informed consent access to the data was granted by the anzics core management committee and the vstr data custodians. ethics approval was obtained from the alfred health human research ethics committee (ref: / ), with a waiver of individual patient informed consent. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -f w fw q authors: nan title: abstracts presented at the neurocritical care society (ncs) th annual meeting date: - - journal: neurocrit care doi: . /s - - - sha: doc_id: cord_uid: f w fw q nan external ventricular drain (evd) management after subarachnoid hemorrhage (sah) is thought to influence patient outcomes and complications. evidence from single center randomized controlled trials suggest that an early clamp trial is safe and associated with shorter icu stay and fewer evd complications. however, a recent survey revealed that most neuro icu's across the us still adopt a gradual wean and continuously draining evd strategy. therefore, we sought to determine the optimal approach at our institution. we reviewed consecutive patients admitted to our institution from to with nontraumatic sah requiring an evd. in , our neurocritical care unit revised our internal evd management guideline from a gradual wean to an early clamp trial approach. we performed a retrospective multivariate analysis to compare outcomes before and after our guideline change. patients that were gradually weaned after institution of the new guideline were also included in the early clamp trial group. we observed a significant reduction in ventriculoperitoneal shunt (vps) rates after changing to an early clamp trial approach ( % early clamp vs % gradual wean, p= . , or= . on multivariateanalysis). there was no increase in delayed vps placement at months ( . % vs . %, p= . ). an early clamp trial approach was also associated with a shorter mean evd duration ( . vs . days, p< . ), shorter icu length of stay ( . vs . days, p= . ), shorter hospital length of stay ( . vs . days, p< . ), lower rates of non-functioning evd ( % vs %, p= . ), and fewer ventriculostomyassociated infections ( . % vs . %, p= . ). we found no difference in symptomatic vasospasm rates between the groups ( . % vs . %, p= . ). an early clamp trial approach is associated with fewer complications and shorter length of stay compared to a gradual evd wean. prospective multicenter studies are needed to provide further insight into the best strategy. autoimmune encephalitis refers to rare sometimes paraneoplastic conditions in which the immune system attacks the brain, leading to altered function. delayed diagnosis and treatment potentially leads to permanent neurological injury or death. the primary objective of this study was to analyze the admission and discharge modified rankin scale (mrs) assessments among patients diagnosed with autoimmune encephalitis, and to identify any effectiveness of immunosuppressive therapy on a subset of these patients. through retrospective chart review we identified patients that met currently accepted clinical and serological criterion for autoimmune encephalitis. clinical data was obtained on these cases and a modified rankin score mrs was assessed on both hospital admission and discharge or subsequent 'best clinical' visit. assessment of "improvement" from initial therapy was based on any decrease in mrs score and clinical neurological functional improvement in accordance with physician and patient affirmation by the time of discharge. seventy-seven patients met criterion for clinical or serological autoimmune encephalitis. of these patients, had cancer and did not have known cancer. fifty-seven ( %) patients underwent immunosuppressive therapy with corticosteroids, ivig, and/or plasma exchange and patients experienced a decrease in mrs score. improvement from initial treatment was %, %, %, and % for admitting mrs scores or through respectively. the p-values for improvement from initial immune therapy based on an mrs of , , or compared to an mrs of were . , . , and . respectively. immunosuppressive therapies for patients with an initial mrs score of , or may have a higher yield than for those with an mrs of . these therapies are generally reserved for those with an mrs of or greater. further study is needed to assess functional improvement in those with autoimmune mediated encephalitis treated with immunosuppressive therapies. many patient, family and hospital factors have been associated with obtaining consent for organ donation after brain death (bd). we evaluated potential factors that played a role in the consent rate in a large tertiary hospital over a period of . years. we evaluated all declarations in our hospital's bd registry between january and june regarding consent for donation. we cross-matched the hospital electronic medical records with the records of the local organ procurement organization to identify this population. patients were included in the registry ( . % african american) and were approached for donation. there was a . % consent rate for organ donation. there was no significant relationship between sex, admission diagnosis, icu (neuro vs. medical vs. surgical), physician specialty (neurology vs. other), time from event to bd declaration or religion and decision to donate. families were more likely to consent to donation if the patient was non-aa ( % vs % for aa, p< . ), was younger ( . vs . , p= . ), had a lower creatinine at the time of death ( . ± . vs . ± . mg/dl, p= . ), and had an apnea test completed ( % vs %, p= . ). in a logistic regression model, only aa race and pao independently predicted refusal of donation (odds, %ci, . , p< . and . , p= . , respectively) . although the majority of bd patients in this large series were aa, their families were times less likely to consent for organ donation than non-aa families. there is an urgent need to explore the reasons for low donation rates in this population. post-anoxic myoclonus is seen in up to % of patients who remain comatose, and historically was felt to be a poor prognostic sign. little distinction has been made in the literature between epileptic (cortical) vs subcortical myoclonus. from consecutive cardiac arrest patients that did not return to baseline (may -may ) we identified % (n= ) patients with clinical myoclonus. basic demographics and characteristics of their arrest were collected and eeg reports were reviewed. raw eeg including video was reviewed by two epilepsy-trained neurologists, whenever available. myoclonus was subcategorized into subcortical and cortical based on the presence of a preceding eeg correlate. jerk-locked eeg back-averaging was performed on two representative patients. the average age of patients with myoclonus was +/- years, and % (n= ) survived to discharge. cortical myoclonus was twice as likely as subcortical myoclonus ( % vs %, respectively). compared with patients without myoclonus, patients with myoclonus were more likely to have longer, more severe arrests. patients with subcortical myoclonus were at risk for electrographic seizures, although at a lower rate than those with cortical myoclonus ( % vs %, respectively). mortality rates did not differ between patients with cortical and subcortical myoclonus ( % vs %). patients with cortical myoclonus were more likely to be discharged in a vegetative state compared to those with subcortical myoclonus ( % vs %, respectively (or . ; %ci . - . ). amongst survivors, good functional outcome at discharge did not differ between cortical vs subcortical myoclonus ( vs %, respectively). jerk-locked eeg back-averaging was useful in distinguishing subcortical from cortical myoclonus. myoclonus is seen in every sixth patient with cardiac arrest. cortical and subcortical myoclonus cannot be distinguished using clinical criteria. both may have good outcomes when managed with targeted temperature management and an aggressive antiepileptic regimen. intoxication by central nervous system (cns) depressant drugs can lead to anoxic brain injury by cardiac or respiratory arrest. we tested the hypothesis whether intoxication by these drugs contributes to mortality in acute anoxic brain injury we utilized healthcare cost and utilization project databases (nationwide inpatient sample and kids' inpatient database) to obtain patients admitted with diagnosis of anoxic brain injury. patients with drug intoxication (opioid, alcohol, sedative/hypnotic drugs) were identified. regression analysis was used to assess relationship between drug intoxication status to in-hospital mortality. the regression model was adjusted for age, gender, chronic medical comorbidities, presence of cardiac arrest and hospital characteristics. we analyzed a total of , patients with anoxic brain injury out of which ( . %) had drug intoxication and % were reported to have cardiac arrest. median age was years and % patients were males. in-hospital mortality was %. among the survivors, % underwent feeding tube placement and % had tracheostomy. drug intoxication was a significant positive predictor of inhospital mortality with adjusted odds ratio . ( . - . ), p= . . cns depressant drug intoxication is associated with higher in-hospital mortality in patients with acute anoxic brain injury. cardiac arrest affects approximately , individuals every year and is the third most common cause of mortality in the us. currently, there is no way of reliably risk stratifying survivors of cardiac arrest. identifying early predictors of outcome is vital for triaging and clinical trial enrollment. we proposed to identify key clinical and laboratory parameters that can reliably predict long-term outcomes among comatose survivors of cardiac arrest. this was a retrospective chart review of comatose survivors of cardiac arrest. we gathered data regarding several clinical (age, pre-arrest mrs, gcs on admission, and hours, presence/absence of shock and respiratory failure) and laboratory parameters (troponins, lactate, creatinine, and alt at admission, and peak values within the first and hours) as well as characteristics of the cardiac arrest (duration, arrest rhythm, location, and bystander cpr). we used a dichotomized gos ( - vs - ) at months as the primary outcome. we performed univariate and multivariable analysis to identify predictors of poor outcome. a total of patients were enrolled. on univariate analysis, higher age, higher pre-arrest mrs, lower gcs at hours, non vf/vt arrest rhythm, in-hospital arrest location, absence of bystander cpr, and shock were statistically significant (p < . ) for poor outcome. in multivariable analysis, only higher prearrest mrs and lower gcs at hours were independent predictors of poor outcome; no bystander cpr demonstrated a trend for being an independent predictor. none of the early laboratory data achieved statistical significance for predicting poor outcome. we identified several clinical predictors of poor outcome in our small cohort of comatose survivors of cardiac arrest. the above variables need to be analyzed among a larger cohort that includes all survivors of cardiac arrest in order to develop an injury severity score that can help risk stratify cardiac arrest survivors. after cardiac arrest, somatosensory evoked potentials (sseps), eeg characteristics, and mri are routinely used to evaluate comatose patients. the relationship between structural hypoxic injury, absent cortical potentials and the generation of background reactivity or epileptogenic potentials is unclear. here we evaluate a consecutive series of patients with cardiac arrest that were studied with sseps and evaluate clinical, eeg, and mri measures to study the dissociation between hypoxia-induced thalamic disconnection and spontaneous cortical activity. in this retrospective cohort study, all comatose patients post-cardiac arrest who received sseps were identified and reports were reviewed. patients were found; one patient with a high cervical cord injury was excluded. we recorded presence of cortical (n ) and subcortical evoked responses (p ), whenever available. based on the closest available eeg (maximum days from ssep recording) we determined reactivity, background characteristics (diffuse suppression or burst-suppression versus all other backgrounds), and presence of generalized periodic discharges (gpds) or seizures. diffusion weighted or t flair abnormalities in the thalamus were evaluated based on available mris. chi-square and fisher's exact test were applied as applicable. of patients with ssep, ( %) had absent n s, and % of those (n= ) had absent p . eeg reactivity was possible, albeit less common, in patients with absent n s ( % vs %, p< . ), but none of the patients with absent p s had a reactive eeg. those with absent n s were more likely to have diffusely suppressed or burst-suppressed background ( % vs %, p= . ) and to have abnormal thalamic signal on mri ( % vs %, p= . ). gpds, stimulus-induced gpds, and seizures were equally common in those with and without n s. the integrity of the somatosensory thalamo-cortical pathway does not appear to be necessary for presence of reactivity or generation of periodic epileptiform discharges. all families of patients who have become brain dead (bd) should be offered the choice of donation. this does not always happen and the factors that lead to approaching them or not are not known. our objective was to evaluate which factors influence the donation coordinators (dc) working for an organ procurement organization approach families after brain death we evaluated all declarations in our hospital's bd registry between january and june regarding consent for donation and cross-matched the hospital electronic medical records with the records of the local organ procurement organization. in order to refine neurologic prognosis in cardiac arrest patients we sought to incorporate heart rate variability into a multimodal prediction model. heart rate variability has been shown in animal studies to be preserved in survivors of cardiac arrest. in our preliminary study, we retrospectively analyzed patients admitted to the university of virginia who had undergone a cooling protocol following cardiac arrest. analysis of heart rate variability for each patient was done in the frequency domain using the fast fourier spectral transform with spectral bands at . - . hz for high frequency (hf) and low frequency (lf) power within the frequency band . - . hz. the unit-less lf/hf ratio was considered a measure of balance between sympathetic and parasympathetic tone. over a -year period, a total of patients were cooled. patients ( %) had ceeg, ( %) had routine eegs and ( %) had sseps performed. numerous patients ( , % of all arrests or % of all eegs performed) had malignant patterns, defined as burst suppression, severe suppression, or generalized periodic discharges. of the sseps, had an absent n (none survived to discharge) and had an n that was present ( survived to discharge). patients with absent n s and malignant eegs had lower lf/hf ratios when compared to survivors with present n s ( . vs. . ). the trend towards parasympathetic dominance following a severe neurologic injury and loss of normal sympathetic tone in those patients with absent n s and malignant eegs and may serve as an additional marker of poor prognosis following cardiac arrest. physicians often struggle with the intricacies of brain death determination and communication about end-of-life care. in an effort to remedy this situation, we introduced an educational initiative at our medical school to improve student comprehension and comfort dealing with brain death. beginning in july , students at our medical school were required to attend a -minute brain death didactic and simulation session during their neurology clerkship. students completed a test immediately before and after participating in the initiative. of the students who participated in this educational initiative between july and june , ( %) consented to have their data used for research purposes. students correctly answered a median of % of questions (iqr - %) on the pretest and % of questions (iqr - %) on the posttest (p< . ). comfort with both performing a brain death evaluation and talking to a family about brain death improved significantly after this initiative ( % of students were comfortable performing a brain death evaluation before the initiative and % were comfortable doing so after the initiative, p< . ; % were comfortable talking to a family about brain death before the initiative and % were comfortable doing so after the initiative, p< . ). incorporation of simulation in undergraduate medical education is high-yield. at our medical school, knowledge about brain death and comfort performing a brain death exam or talking to a family about brain death was poor prior to development of this initiative, but awareness and comfort dealing with brain death improved significantly after this initiative. this initiative was clearly a success and can serve as a model for brain death education at other medical schools. early withdrawal of life support (ewls) is a major factor in deaths following hypoxic ischemic injury after cardiac arrest (ca) in patients receiving targeted temperature management (ttm). appropriate timing of prognostication, and subsequent withdrawal of life support is recommended in recent guidelines, but is not always followed in clinical practice. we describe the impact of ewls in a multicenter registry database. using data from the international cardiac arrest registry (intcar), we defined ewls as withdrawal in the first three days of hospitalization. among all patients treated with targeted temperature management, we developed a logistic regression model to predict ewls. we then performed a propensity score and evaluated the incidence of good outcome between deciles of risk for ewls. patients entered into intcar from - from different hospitals were included. mean age was (± ) years, mean cpr duration was (± ) minutes, ( %) had a shockable rhythm, and ( %) received bystander cpr. support was withdrawn in , with ( %) events classified as ewls. ( % of total cohort). among patients with support withdrawal, older age (p= . ), nonshockable rhythm (p= . ), increased ischemic time (p= . ), and shock on admission (p< . ) were associated with ewls. among propensity matched patients grouped into deciles of probability for ewls, survival with good functional outcome occurred in % ( th decile), % ( th), % ( th), % ( th), and % ( th decile). early withdrawal of life support after cardiac arrest occurs frequently, and is associated with age, duration of cpr, a non-shockable rhythm, and shock at the time of admission. a cohort of patients propensity-matched to those with ewls had - % survival with favorable neurologic outcomes. these data support that in most patients receiving ttm, conservative and delayed prognostication after cardiac arrest is appropriate. brain herniation (bh) is a deadly event that requires immediate central venous access for infusion of hyperosmotic agents, especially . % nacl. traditional venous catheters, whether peripheral or central, takes several minutes to place, and requires skill for successful placement, thus delaying critical treatment. intraosseous (io) cannulation has been shown, at least during cardiac arrest, to be a secure and rapid means of central vascular access that requires limited training. however, limited data exists on the use of io in bh for administering . %. the aim of study of this study is to measure changes in serum sodium and bh reversal after administering . % via io. retrospective chart review of patients with acute neurologic injury requiring . % and io placement due to a lack of central access. demographics, diagnosis, gcs, sodium (na+), and pupillary reactivity, and immediate and delayed complications were collected. results patients included: males, age range - yo. diagnosis include intracerebral hemorrhage ( n= ), extra-axial hematoma (n= ) and sah (n= ). gcs ranged to . all patients were intubated. most patients were co-treated with hyperventilation, nabicarb, mannitol, and propofol. io was placed in tibia ( ) or humerus ( ); all placed correctly on first attempt. comparing hr post- . % nacl treatment to pretreatment: na+ level increased in of ; gcs improvement in of ; and returned pupillary reactivity in of . no adverse events reported, such as shock, cardiac arrest, tissue or limb injury. preliminary data suggest that during bh, io cannulation results in safe and timely . % administration in patients with no central access. additional safety data is needed, particularly with regards to the potential for myonecrosis. however, if safe, io cannulation should replace central line placement as the initial route of central venous access during bh. the pupillary light reflex is associated with outcome after cardiac arrest as a dichotomous variable (present/absent) at various time points following resuscitation (rosc). infrared pupillometry provides quantitative measures including pupil diameter (pd), and neurological pupil index (npi) which ranges from (nonreactive) to (brisk) and reflects velocity and degree of pupil constriction in response to a standardized light stimulus. these measures may provide early prognostic information to guide therapy. comatose adult survivors of cardiac arrest treated with targeted temperature management were monitored with the neuroptics npi- pupillometer. outcomes were defined as good (go) if discharge cerebral performance category score was - , and poor (po) if - . data are presented as median (iqr). groups were compared using non-parametric statistical tests. fifty-one patients were enrolled; the median age was ( . - . ), and ( %) were male. initial rhythm was vt/vf in %, asystole in %, and pea in %. outcome was good in ( %) patients. the initial pd did not differ between outcome groups [ . ( - . ) po vs . ( - . ) go]. the initial npi was lower in poor outcome patients [ . ( . - ) vs . ( . - . ) go, p= . ] measured . ( . - . ) hours after rosc. npi dropped below in more poor outcome patients [ ( %) vs ( . %) go, p= . ], and to zero in ( %) poor vs ( %) good outcome patients (p= . ). receiver operator characteristic curves confirmed that initial npi predicted poor outcome better than pupil diameter (auc . vs . , p= . ). a low neurological pupil index predicted poor outcome - hours after resuscitation from cardiac arrest, and dropped to abnormal levels (< ) and to zero (reflecting a non-reactive pupil) more often in patients with poor outcomes. additional research is needed to define potential confounders, optimal timing, and thresholds for different levels of neurological risk with pupillometry. prediction of death in a timely manner after withdrawal of life support (wls) is essential during organ donation after cardiac death (dcd). we aimed to develop a modified version of the recently develop dcd-n score to improve the specificity of prediction and test it in a specific group of patients with catastrophic brain injuries referred for dcd. we analyzed prospectively collected data by our local organ procurement agency on all consecutive adults with severe neurological injury evaluated for dcd across centers in the usa from march to may . we analyzed three variables used in the dcd-n score (corneal reflex, cough reflex and oxygenation index) and substituted the fourth variable for vasopressor support. a total of patients, mean age (sd± ) years were included in the final analysis. anoxic brain injury was the most common cause of death ( %) followed by stroke ( %). in multivariate logistic regression analysis adjusted for age and cause of death, absent corneal reflex (or . , % ci . to . , p = . , points), absent cough reflex (or . , % ci . to . , p = . , point), vasopressor support at high doses (or . , % ci . to . , p < . , points) and o ind ci . to . , p = . , points) were associated with the likelihood of death within minutes of specificity % and auc . . the modified dcd-n score has a greater specificity in predicting death within minutes of wls and is developed specifically from a cohort of patients evaluated for dcd. future prospective studies are needed for further validation of this scoring system. significant number of the patients with anoxic brain injury have poor neurological recovery. this created a significant anxiety in families who often request early prognostication. this study was conducted to evaluate possible ultra-early prediction of good neurological recovery in patients undergoing hypothermic protocol for anoxic brain injury retrospective chart review of the patients with anoxic brain injury was conducted. all patient underwent standard evaluation and management in the early stages of icu care, including initiating of hypothermic protocol with intravenous cooling device. all patients underwent evaluations with eeg and ssep within first day after admission during hypothermia phase and mri brain after re-warming. total of charts were reviewed. patient had normal ssep and normal mri. all patients had good neurological recovery, except for one patient who died secondary to severe cardiac failure eeg did not have any predictive value for the good neurological outcome when it was done during hypothermic protocol. normal ssep may a reliable predictor for good neurological recovery. apnea test is the essential component to confirm brain death by stimulation of respiratory center in brainstem. guidelines recommend that apnea testing should meet the criteria of disconnection from mechanical ventilator, and oxygen supplying by catheter. however, during the apnea test under this technique, disconnection from ventilator may induce hypoxia due to abrupt decruitment of alveoli and pulmonary barotrauma such as pneumothorax. there are some studies that suggest continuous positive airway pressure can be effective for patients with hemodynamically instability and respiratory impairment. we suggest a novel method of apnea test by using ambu bag with positive end-expiratory pressure (peep) valve to avoid abrupt change of peep during the apnea test. apnea testing was performed by using ambu bag with peep valve to adult brain death patients. ambu bag was not bagging during the testing and just connected to endotracheal tube with l/min of % oxygen. peep valve was applied the same peep of previous mechanical ventilator. on the apnea testing, vital signs and ekg were monitored. arterial blood gas analysis were measured and minutes after disconnection from mechanical ventilator. there were no significant differences in mean pao between before and after apnea test ( ± and ± , p= . ). mean arterial blood pressure were ± mmhg and ± mmhg before and after the test, respectively. during the intervention and following observation, arrhythmia or pulmonary complications had not occurred. we suggest a novel method of apnea testing which is a simple and easy technique by using ambu bag with peep valve to minimize decruitment of alveoli. this method shows vital signs and respiratory oxygenation of the patients remained stable during the test. declaration of brain death based on clinical exam has been plagued with challenges. as a result, ancillary testing such as nuclear scintigraphy cerebral blood flow (cbf) studies have been recommended. we present a case in which the apnea test could not be completed due to hemodynamic instability and where the nuclear scintigraphy cbf study resulted in a false declaration of brain death. a y/o male was admitted with bilateral hearing loss and confusion. on day two, the patient developed blurred vision, and an mri confirmed bilateral cerebellar and pontine infarctions. by day four, he had developed diffuse cerebral edema in the cerebellum, brainstem, and bilateral occipital lobes, and we proceeded with the clinical exam for brain death. all cranial reflexes were absent; however the apnea exam could not be completed due to blood pressure instability. a nuclear scintigraphy cbf study revealed the complete absence of radiotracer activity, and the patient was pronounced dead. two hours later, the patient regained a gag reflex. on the following day, the clinical exam, with the exception of apnea testing, was again consistent with brain death. a cerebral angiogram was performed and demonstrated normal blood flow to the anterior circulation. the patient was ultimately pronounced dead on day eight after two separate complete clinical brain death exams, including apnea testing, were performed. cerebral angiography showed essentially normal blood flow where nuclear scintigraphy showed no blood flow. nuclear scintigraphy cbf studies are commonly recommended when apnea testing cannot be completed. given the dramatic differences in the results observed between these modalities, a reevaluation of this practice should be considered. patients' perceptions of recovery moderate outcomes, however studies exploring the specific cognitive, functional, and psychological domains associated with subjective perceptions of recovery at hospital discharge after cardiac arrest (ca) are lacking. this is a prospective, observational cohort of patients admitted to columbia university medical center after ca, and survived to hospital discharge between / - / . patients with sufficient mental status to perform a neuropsychological exam and a questionnaire at discharge were included. subjective perceptions of recovery were assessed via responses to the forced-choice dichotomized question, "do you feel that you have made a complete recovery from the arrest?"objective outcome measures of recovery included: repeatable battery for neuropsychological status (rbans), modified lawton physical self-maintenance scale (l-adl), barthel index (bi), cerebral performance category scale (cpc), center for epidemiological studies-depression scale (ces-d), and post traumatic stress disorder-checklist (ptsd-c). chi-square, wilcoxon-rank sum, and logistic regression were used to compare the respondents, and determine factors associated with subjective perceptions of recovery. patients were included with mean age of ± years; % were men and % were white. % responded not having made a complete recovery. no significant differences were found between respondents in terms of demographics, charlson comorbidity index, arrest-related variables, rbans, l-adl, bi, pre-or post-arrest cpc scores. those responding that they had not made a full recovery had higher rates of ptsd-c ( % vs %, p< . ), and depression ( % vs %, p= . ). moreover, everyone that screened for ptsd (n= ) reported not having made a complete recovery. patients with higher ptsd scores were more likely to report not having made a complete recovery (or . ; p< . ) after adjusting for age, gender and depression scores. presence of post traumatic stress disorder symptomatology at discharge, and not neurocognitive or functional status, is highly associated with post-cardiac arrest patients' subjective perceptions of recovery. early eeg background reactivity is a strong predictor of neurological recovery after hypoxic-ischemic brain injury despite hypothermia and sedation. unfortunately, expert interrater-agreement on visual scoring of eeg background reactivity ranges from - %. recent studies indicate that machine-learning approaches using quantitative eeg (qeeg) might yield equivalent or superior performance to current eeg reactivity assessment practices, however its ability to predict outcomes has not been tested. we hypothesized that a qeeg reactivity method can predict long-term functional outcome in hypoxic ischemic brain injury. we retrospectively reviewed clinical and eeg data of cardiac arrest patients managed with hypothermia at two university hospitals. eeg reactivity was tested daily using a structured exam consisting of auditory, tactile, and visual stimulation. our quantitative eeg method evaluated changes in eeg spectra, entropy, and frequency features during seconds before and after each stimulation-step ( qeeg features used). only the first eeg reactivity assessment for each subject was used in the final analysis. good outcome was defined as cerebral performance category of - at six months. a penalized multinomial logistic regression was utilized for feature selection and a random-forest classifier was employed in the training and validation sets. model performance evaluation metric was the area under roc curve (auc). outcome and eeg data was available for a total subjects, and cases were excluded due to presence of burst-suppression, periodic epileptiform discharges, or eeg artifact. forty-seven subjects were included in the final analysis. mean age was . (standard deviation . ) years and . % had good outcome. the combination of four features provided best outcome prediction performance with an auc of . (kolmogorov-smirnov test, skewness, two-group test, and renyi entropy). early qeeg reactivity is predictive of good outcome at six months. a quantitative approach to eeg reactivity analysis might facilitate accurate and individualized prognostication in hypoxic-ischemic brain injury. hypoxic-ischemic brain injury is the leading cause of morbidity and mortality following cardiac arrest, and the ability to predict neurologic recovery in comatose cardiac arrest survivors is limited. functional mri measures brain network connectivity and resting-state network connectivity can be measured in comatose patients. the default mode network (dmn) is one resting state network that has been correlated with consciousness. we hypothesized the degree of connectivity in the dmn and other resting-state networks would correlate with consciousness recovery in post-cardiac arrest coma. consecutive patients with hypoxic-ischemic coma were enrolled. functional mri was obtained on all patients on post-arrest day - on an inpatient tesla mri. the connectivity in multiple resting-state networks was analyzed using pearson's correlations between component maps for each subject and previously defined standard network maps. connectivity in the default mode network and in additional resting-state networks was correlated with outcome. good outcome was defined as consciousness recovery at any point in the acute hospitalization. patients were included in this study. the mean age was ± years ( - ) and were male. patients survived with good outcome. the primary arrest rhythm and the duration of cardiac arrest did not differ between groups (primary rhythm as vt/vf: % vs %, good vs poor, p= . ; cardiac arrest duration: . ± . minutes vs . ± . minutes, good vs poor, p= . ). patients with good outcome had significantly higher mean network connectivity ( . ± . vs . ± . , good vs poor, p= . ). dmn connectivity showed a trend towards significance ( . ± . vs . ± . , good vs poor, p= . ). in comatose patients following cardiac arrest higher fmri measured resting state connectivity correlated with consciousness recovery. functional connectivity may be developed as a prognostic biomarker. sedative and analgesic infusions and neuromuscular blockade agents (nmba) are commonly used for comfort, suppression of shivering, and reduction of metabolic activity during targeted temperature management (ttm) after cardiac arrest. the optimal sedation and analgesia regimens are unknown. we sought to describe variability in sedation and shivering management practices at us and european cardiac arrest receiving centers. international cardiac arrest registry (intcar) centers were surveyed regarding sedation protocols for ttm after cardiac arrest. the survey was administered via redcap with a response rate of %. ten united states and european centers completed the survey. shivering is measured at ( %) of centers and recorded at ( %) centers. ten centers use nmb to control shivering prophylactically, centers use nmb only if shivering occurs, and centers increase opioids or sedatives when shivering occurs, but do not use nmb. the most common sedative was propofol ( / centers), followed by midazolam ( / ) and the most common analgesic was fentanyl ( / ) followed by remifentanyl ( / ). , , and centers report having a sedation target of light, moderate, or deep respectively. a sedation scale is used at ( %) centers, targeted to patient comfort at ( %) centers. daily sedation lightening is protocolized when rewarming starts at ( %) centers, when normothermia is reached at ( %) and not specified in the remainder of groups. of patients who awaken, centers report that they expect this to occur at ( centers), ( centers) and ( centers) hours respectively. among cardiac arrest receiving centers internationally, there is significant variability in ttm sedation and shivering management strategy. our hospital policy allows an optional sbd (with an apnea and a cerebral blood flow test) or a dbd (with an apnea test). we have evaluated the adoption of and reason for performing a single brain death exam (sbd) vs two (dual) brain death exams (dbd) and their impact on organ function and consent for organ donation. we evaluated our hospital's bd registry between january and june regarding sbd or dbd. we also cross-matched our electronic medical records with the records of the local organ procurement organization. of bd declarations, ( %) were sbd and ( %) dbd. during the st five years, % of all bd exams were sbd and during the second %. patients with sbd were older ( . ± . for sbd vs . ± . years for dbd, p= . ), had a primary neurologic diagnosis ( % vs %, p< . ) and were admitted to the neuro-icu ( % vs %, p< . ). during the nd exam, . % patients were on equal or higher dose of pressors. sbd patients had lower k+, bun, creatinine and heart rate, but higher peak na+ and apnea pao (for all p< . ), although apnea ph and paco were similar. the time between injury to bd pronouncement was shorter in sbd by . hours. there was no difference in consent rate between sbd and dbd ( % vs %, p= . ). at our institution, bd declaration was more often done by dbd exams, although the primary diagnosis and the unit of admission influenced the decision. an increased adoption of sbd exams was noted after the aan bd guidelines, supporting sbd exam, were published. although the number of exams did not affect rate of consent for donation, surrogate markers indicated better function of organs after sbd, while dbd patients stayed in the icus over a day longer. there are no data supporting better numbers or function of organs in donors after brain death (bd), if there is a shorter waiting period (as expected with single brain death exam [sbd] ) from the time that bd is declared to the time the patient arrives at the operating room (or). our goal was to find if the number of brain death exams, either sbd or dual (dbd), had any impact on the number of organs recovered and transplanted we evaluated our hospital's bd registry between january and june regarding sbd or dbd and cross-matched our electronic medical records with the records of the local organ procurement organization out of bd declarations, led to consent, of which ( . %) after sbd and ( . %) after dbd. there was a trend for longer consent to or time for dbd ( . ± . hours vs . ± . for sbd, p= . ). there was no difference in the number of organs recovered or transplanted based on the number of exams ( . ± . vs . ± . organs/patient recovered and . ± . vs . ± . transplanted for sbd vs dbd, respectively, p> . ). there was a trend for more lungs to be transplanted after sbd exam ( % vs %, p= . ), but this was not found with kidneys, heart, liver, pancreas or intestines. in multiple logistic regression models, adjusting for variables pertinent to each individual organ function (for example, bun or creatinine level for kidneys, blood gases for lungs etc), the number of exams was not an independent predictor for successful transplantation conclusions sbd exam led to similar numbers of organs transplanted compared to dbd exam in this single center registry analysis. more rapid brain death declaration, as with sbd, is not a factor that influences organ transplantation the glasgow coma scale (gcs) is a standardized and commonly used way of assessing important aspects of neurological condition for critically ill patients. while it is a validated tool for prognostication, it is unclear whether serial measurements add value to this prognosis. we used a large set of serially collected gcs measurements to assess the impact of gcs score on the trajectory of neurological recovery as well as factors affecting score variance. gcs total and subscores ( , time points from , patients) recorded hourly by registered nurses in the neurosurgical intensive care unit (nsicu) between january, and may, were analyzed retrospectively. k-means clustering provided groups with similar progression characteristics during nsicu stay. k-means clustering provided groups with similar progression characteristics during nsicu stay. descriptive features for each cluster were binned into histograms and evaluated for similarity using and kruskal-wallis tests. linear correlations of the sub-scores were very high (eye-verbal: . , eye-motor: . , verbal-motor: . ), while compositional variance was low for aggregate scores. hour-to-hour variance in gcs correlates to significant nsicu activities such as nursing shift changes. among patients with similar minimum gcs scores during their stay, those that recovered were significantly less likely to have deteriorated in the hospital ( , p<< . ). for patients with a minimum gcs<= , those that arrived at their minimum score (i.e., did not deteriorate in nsicu) were . % more likely to recover than those who deteriorated in-hospital (kw, p<< . ) . patients that experienced recovery show significantly greater improvement as early as hours after their minimum score (kw, p<< . ). the gcs is unnecessarily complex for most nsicu patients and can be represented by fewer variables. serial gcs measurements do provide value for prognosis and may be able to distinguish patients with potential to recover early in their hospital course. stroke is a major cause of death and disability, and common admission to neurological intensive care units. preferences for cardiopulmonary resuscitation (cpr) are often discussed, but there is limited understanding of cpr outcomes among stroke patients. systematic review and meta-analysis of published literature from to among stroke patients undergoing in-hospital cpr. preferred reporting items for systematic reviews and meta-analysis, metaanalysis of observational studies in epidemiology, and utstein guidelines were used to construct standardized reporting templates. detailed searches of pubmed and cochrane libraries were supplemented with hand-searched bibliographies. primary data from studies meeting inclusion criteria at two levels were extracted, i) survival to hospital discharge after cpr, and stroke as a primary admitting diagnosis, and the less restrictive, ii) survival to hospital discharge after cpr with stroke listed as a comorbidity, were meta-analyzed to generate weighted, pooled estimates of survival to hospital discharge. of articles screened, there were articles ( %) that underwent full review. three articles met primary inclusion criteria, specifically identifying patients with stroke as a primary admitting diagnosis. twenty additional articles met secondary inclusion criteria, listing stroke as a comorbidity. there was an % ( % confidence interval (ci) . , . ) rate of survival to hospital discharge rate from a combined sample of patients that received in-hospital cpr. among the more heterogenous population of inpatients with stroke listed as a comorbidity, there was % ( % ci . , . ) rate of survival to hospital discharge. adherence to utstein reporting guidelines was poor, and neurological outcomes were measured in ( %) of studies. survival to hospital discharge among stroke patients is lower relative to general hospital populations. these preliminary findings highlight the need for improving the quality of evidence to inform patient and provider discussions of cpr among stroke patients. there is often a tendency to treat patients with traumatic brain injury (tbi) and a glasgow coma scale (gcs) score of on presentation less aggressively because of low expectations for a good outcome. based on the crash trial database, a prognosis calculator has been developed for the prediction of outcome in tbi patients. our aim was to investigate whether the crash calculator can be used for prognostication in patients with tbi and gcs of on presentation. we performed a retrospective review of patients with tbi and a gcs score of from / to / . the crash calculator has been validated to estimate mortality at days and death and severe disability at six months (glasgow outcome scale-gos - ). the calculator uses country of origin (usa in our dataset), age, gcs, pupils reactivity to light, presence of major extracranial injury, and findings on ct scan of brain (petechial hemorrhages, obliteration of the third ventricle or basal cisterns, subarachnoid bleeding, midline shift, and non-evacuated hematoma). the individual prognosis for mortality at days and unfavourable outcome at months was calculated and compared with the actual outcomes. a total of patients were included. a tend toward underestimation of the risk of mortality at days was found (estimated mortality was % compared to actual mortality of %; difference of %, p = . ). however, the estimation of outcome at months was accurate (estimated gos - was . % compared to actual of . %, p = . ). the crash prognosis calculator underestimated the risk of mortality, but accurately predicted unfavourable month outcome in patients with tbi and gcs of on presentation. pending larger studies to validate our findings, we believe that crash calculator can only support -not replace -clinical judgment. there are no nationally enforced standards regarding brain death. few data exist on how brain death is determined across the u.s. we used claims data from - from a nationally representative % sample of medicare defined as icd- -cm code . . the primary outcomes were evaluation by a neurologist or neurosurgeon, defined as a physician evaluation-and-management claim associated with the medicare provider specialty codes for neurology or neurosurgery, during the dates of the hospitalization. cpt codes were used to ascertain ancillary testing: brain radionuclide imaging, transcranial doppler ultrasound, or electroencephalography for brain death determination. exact binomial confidence intervals (cis) were used to report proportions. we identified patients with a brain death diagnosis. common associated neurological diagnoses were stroke ( patients; . %), cardiac arrest ( ; . %), and traumatic brain injury (tbi) ( ; . %). head ct or brain mri was performed in . %; this was true of . % of cases of stroke or tbi versus . % of cardiac arrests. neurologists were involved in the care of patients ( . %; % ci, . - . %). they were more commonly involved in the care of stroke ( . %) or cardiac arrest ( . %) than tbi ( . %) or other conditions ( . %). neurosurgeons were involved in cases ( . %; % ci, . - . %), mostly after tbi or stroke. two hundred patients ( . %; % ci, . - . %) were seen by a neurologist or neurosurgeon. twenty-nine patients ( . %; % ci, . - . %) underwent any ancillary testing. two hundred and nine patients ( . %; % ci, . - . %) were seen by a neurologist or neurosurgeon or underwent ancillary testing. in a nationally representative cohort of elderly patients, one-third of patients with a brain death diagnosis were not evaluated by a neurologist or neurosurgeon or by using ancillary tests. traumatic brain injury (tbi) is a major cause of death and disability in the us. recent advances in d illustration ( di) can precisely quantify intracranial pathology on computed tomography (ct). the current standard of measurement, abc/ , demonstrates variability in precision with bleed phenotype. the aim of this project is to assess accuracy automated di and compare it to standard abc/ measurements. baseline ct scans collected during the protectiii multicenter clinical trial (n= ) were retrospectively reviewed by a central neuroradiologist. subdural and epidural hematomas were identified (n ). the radiologist calculated abc/ score using osirix (mac) and radiant (pc) workstations. in a blinded fashion, research assistants concurrently generated di using the following methods: dicom data were resampled to . mm thickness slices and symmetrized using image analysis software (aquarius terarecon inc, ) . lesions were then compiled into single volumetric regions of interest ( d slicer v . , ) . hemorrhages were divided into two groups for analysis: group . volume of hemorrhage bland-altman analysis. this study was irb approved. there is a significant difference between the results of the di and abc/ methods. in group . the estimated relative bias between the two measurements (after transformation) is . (sd . ; pvalue . ; % ci . , . ). in group , the relative bias is - . , sd . , pvalue < . , % ci (- . , - . ). the di method calculates detailed surface area measurements in large and small volume hemorrhages, while abc/ averages cross-sectional area. the abc/ estimates vary by bleed phenotype and offer less topographical precision than di. this is particularly true in extra-axial hemorrhages, which are numerous studies have shown a significant association between hypotension and poor outcome in patients with head injuries. prior investigations have demonstrated that generation of negative intrathoracic pressure (itp) in ventilated patients with brain injury improves mean arterial pressure (map) and lowers intracranial pressure (icp). we hypothesized that augmentation of negative itp by breathing through an impedance threshold device (itd) with cmh o of inspiratory resistance would improve mean arterial pressure in a porcine model of intracranial hypertension. six spontaneously breathing female pigs ( . ± . kg), anesthetized with propofol, were subjected to focal brain injury through inflation of an french foley catheter placed in the epidural space. once a stable injury was obtained, baseline data were collected for minutes followed by minutes of itd use. results are reported as mean ± sd. the itp without the itd during inspiration was - . ± . mmhg, compared to - . ± . mmhg with the itd, p< . . following brain injury, map (mmhg) was significantly higher during itd use ( ± vs. ± ; p< . ). cerebral perfusion pressure (mmhg) was also significantly higher during itd use ( ± vs. ± ; p< . ). icp (mmhg) was not significantly different between groups ( . ± . vs. . ± . ; p= . ) although end tidal carbon dioxide levels (mmhg) were significantly higher during itd use ( ± vs. ± ; p< . ) presumably due to lower respiratory rates during itd use ( ± vs. ± ; p= . ). contralateral cerebral blood flow (ml/ gm/min) was similar between groups ( ± vs. ± ). in this porcine model of intracranial hypertension, spontaneous respirations through an itd significantly improved map and cpp. this approach could be utilized to prevent hypotensive episodes in the setting of brain injury. the impact of applying nanotechnology and biomedical engineering to improve the management of patients with spinal cord injuries (sci) is still not accurately described, nor understood. a systematic review of the literature was conducted, according to prisma criteria, to identify publications revolving around "sci+nanotechnology" and "sci+biomedical engineering" indexed on pubmed in the period - . furthermore, the database of clinicaltrials.gov was searched to highlight the stage of translation of this research into clinical practice through randomized clinical trials (rct). finally the uspto database was interrogated to identify the number of pertinent patents filed in northamerica in the same timeframe. the literature on bioengineering and nanotechnology contributions to sci is exponentially growing, with almost % of articles published between and . its quality and the interest of the scientific community are high, as confirmed by the average impact factor ( . ) and the average number of citations ( ) of articles published in the last two years. this field still represents a niche of sci research: the articles reviewed represent only . % of all articles on sci published in the same decade. this trend is confirmed on clinicaltrials.gov: out of rct on sci only few focus on the application of those technologies, furthermore out of articles spurring from the rct identified were published after , and % after . interestingly, with patents registered by the uspto, the interest in the commercial application of this research seems vivid. currently, the most promising areas of research are: nanofabrication/nanoscaffolding for structural repair, nanodrugs for regeneration, and design of neural interfaces for functional therapies. this review showed that both universities and independent research institutions (mostly from usa, china and european union) are driving this research race; the figures provided above suggest its potential to become a successful example of translational medicine. there are no neuroprotective and neuroregenerative treatments available for traumatic brain injury (tbi). clinical trials investigating potential treatments such as therapeutic hypothermia and progesterone have failed. pre-clinical studies indicate there may be a role of stem-cells in promoting neuroprotection/neuroregeneration in-vivo in animal models of tbi. we aim to provide a pre-clinical literature review into stem-cells as a potential therapeutic option in tbi-animal models. a literature search was conducted on pubmed and google scholar using the terms "traumatic brain injury", "stem-cell", "preclinical", and "animal studies". studies were included if there was an in-vivo animal model of tbi with either intravenous or intra-cortical stem-cell transplantation, along-with a control group, and investigated either motor or behavioral outcomes, or a combination. twenty-seven studies (n= animals) satisfied the criteria. / ( . %) animals were investigated for outcomes. studies harvested stem-cells from human-source, whereas harvested stem-cells from animal-source. bone-marrow stromal-cells (bmsc) were used in studies, neural stemcells (nsc) in , and miscellaneous in . / ( . %) animals received any stem-cell transplantation, whereas were controls. of animals receiving stem-cell transplantation ( ), ( . %) showed significantly better outcomes relative to control animals in each individual study, with exception of one study. amongst transplanted animals, functional outcomes did not differ significantly when grouped by stem-cell type (p= . ), transplantation route (p= . ), and source (p= . ). animals were followedup until week (n= studies), weeks (n= ), weeks (n= ), or > -weeks (n= ). this pre-clinical data demonstrates that stem-cell transplantation may have treatment potential in tbi as shown by improvement in functional outcome in as many as three-quarters of all animals that were treated with stem-cells. this data provides a foundation for the design of clinical translational studies. age of trauma patients including those with asdh is increasing as stated by national trauma registers. we were especially interested if age > years significantly influences outcome compared to younger patients and if other factors like initial gcs have an influence too. methods midline shift, if asdh was surgically removed, additional contusions, comorbidities and intake of anticoagulants. outcome was analyzed using the glasgow outcome scale (gos) at hospital discharge (gos ) and if possible months after discharge (gos ). uni-and multivariate analysis (cox regression model) was performed using the sigma stat softwar . . adverse outcome p= . . in addition, all patients > years with an initial gcs died whereas only % of younger patients with initial gcs died (p< . ). this was the only significant result in the multivariate analysis the monovariate analysis of our data showed a significantly higher risk for adverse outcome after asdh whe it should be considered if it is reasonable to transfer them from local hospitals to a specialized neurosurgical clinic, especially in times of limited resources. reported incidence of pulmonary edema in isolated head injury varies from - %. lung sonography is a potentially useful non invasive technique to detect extravascular lung water(evlw). this study aimed to identify the presence of evlw using lung ultrasound (b lines > per lung field) in chead injured patients admitted to icu . secondary objectives were to compare diagnostic accuracy and time to identification of evlw using chest x ray versus lung ultrasound. association of evlw with duration of mechanical ventilation (mv)and icu stay were observed after ethical clearance (iec no. int/iec/ / ), patients with head injury requiring mv and critical care were enrolled in the study. daily routine chest x ray and bedside lung ultrasound were done from the day of icu admission until the patient was on mechanical ventilator support. four inter costal spaces (ics) were scanned in semi recumbent position; third and sixth ics on either side of sternum till mid clavicular line. evlw was reprted as > b lines per lung field scan sonographically. details of mv and icu management were noted . evidence of evlw at the time of admission using sonography and cxr was recorded in and patients respectively. during icu stay . % patients showed evlw using lung usg (vs patients on cxr). mean delay in detection of evlw on cxr after detection on ultrasound was . ± . days. patients with low gcs, s. albumin, pao /fio ratio and greater apache ii and saps ii had significantly higher incidence of evlw. duration of weaning, mechanical ventilation and icu stay was significantly longer in patients with presence of evlw (p < . ) conclusions: lung ultrasound appears promising in detecting evlw earlier than chest x ray and may aid to minimize the duration of mechanical ventilation, weaning and icu stay . antiepileptic drugs (aeds) are recommended by guidelines for prophylaxis of early post-traumatic seizures (pts) associated with traumatic brain injury (tbi). there has been an increased use of both phenytoin and levetiracetam for this indication. the purpose of this study is to determine the incremental cost-effectiveness of phenytoin compared with levetiracetam for early pts prophylaxis in tbi patients. a cost-effectiveness study was conducted comparing phenytoin and levetiracetam for early pts prophylaxis during the days post-tbi. patients were included if they were years or older, received a study drug, and had a diagnosis of tbi. patients were excluded if they had a history of epilepsy, did not sustain a recent tbi, were initiated on both study drugs concurrently, or were switched to pentobarbital for elevated intracranial pressure. data was collected via retrospective chart review using electronic medical records and publically reported costs. effectiveness was measured as having a successful seizure prophylaxis regimen (sspr), which was defined as ) no clinical or electrographic seizure, ) no discontinuation of study aed, ) no cross-over of study aed to different aed, or ) no addition of aed during the days of therapy. the costs included costs of the study drugs, phenytoin level, and eeg. the data was used to calculate the primary endpoint, the incremental cost for the incremental change in sspr or the incremental cost effectiveness ratio (icer). the phenytoin regimen (n= ) cost $ . and had an sspr of . %. the levetiracetam regimen (n= ) cost $ . and had an sspr of . %. the icer was $ for each % increase in sspr with levetiracetam. the sspr of phenytoin and levetiracetam were similar. because patients who received phenytoin may differ from those who received levetiracetam, further analysis is needed prior to drawing any conclusions about the cost-effectiveness of levetiracetam relative to phenytoin. augmented renal clearance (arc) has been reported in up % of critically ill tbi patients and may impact therapeutic drug concentrations. improved predictors of arc are needed. serum cysc, a validated marker of glomerular filtration, has not been examined as a marker for arc in critically ill tbi patients. this pilot study tested the hypothesis that serum cysc concentrations are lower than reference values following tbi. adult tbi patients enrolled in the ukccts-unctracs prospective study of arc effects on drug clearance, were eligible. cysc serum concentrations (elisa -r & d cysc) were measured daily for up to days and compared to reference values. descriptive statistics and student t-test for continuous measures (patient vs. reference lower range cysc) were calculated. the first ten patients [ m/ f, mean age= . years ( - y/o), median gcs= (iqr - )] provided a total of serum cysc for analysis. each patient provided at least samples (range - ) for up to seven days. measured serum cysc concentrations were below the reference range in of samples. the overall mean cysc concentration was . + . mg/l vs expected mean of . + . . (ns) measured values fell below the lower reference range in patients ( m/ f) for the first study days (mean = . + . vs . + . p< . ). the mean difference between measured concentration and reference value was . + . mg/l. after days, four patients ( m/ f) remained below reference values with a mean difference of . + . mg/dl. preliminary results show cysc was not consistently below reference ranges in all tbi subjects. a subset of subjects showed significantly lower cysc within seven days of injury. the relationship between cysc and arc needs to be further examined as analysis continues. functional connectivity of the default mode network (dmn) is believed to be necessary for recovery of consciousness after coma. however, dmn connectivity has not been comprehensively studied in patients with acute severe tbi. we hypothesized that dmn connectivity in patients with acute severe tbi is associated with level of consciousness. we prospectively enrolled patients admitted to the intensive care unit for acute severe tbi and performed resting-state functional mri (rs-fmri) as soon as safely possible. dmn functional connectivity was assessed by rs-fmri analysis of the blood-oxygen level dependent (bold) signal using a seed-based approach. pearson's correlation coefficients were calculated between the mean bold time series within dmn nodes and all other regions in the brain. level of consciousness was assessed at the time of the scan using the coma recovery scale-revised (crs-r). two-sample t-tests were performed to identify brain regions with connectivity differences between conscious and unconscious subjects. we then tested for associations between level of consciousness and dmn connectivity within these regions. we enrolled patients ( male, mean+/-sd age +/- years) and matched controls ( male, age +/- years). rs-fmri was performed . +/- . days post-injury. at the time of rs-fmri, patients' levels of consciousness were coma (n= ), vegetative state (vs; n= ), minimally conscious state (mcs; n= ), and post-traumatic confusional state (ptcs; n= ). connectivity within the medial prefrontal cortex and posterior cingulate was selectively reduced in unconscious patients (coma and vs) compared to conscious patients (mcs and ptcs; false discovery rate-corrected p < . ). when these regions were further interrogated, connectivity correlated with crs-conclusions dmn functional connectivity correlates with level of consciousness after acute severe tbi. traumatic brain injury (tbi) is a substantial source of death, disability, and healthcare utilization. many older tbi patients present to community hospitals and are transferred to trauma centers for further care; however, little is known about the provision of care and patient outcomes at the final receiving hospital. we described trauma center care among geriatric transfer patients with tbi. we conducted a secondary analysis on a sub-cohort from a prospective multi-center study focusing on ambulance and emergency department (ed) care of injured older adults transported via ambulance. the current analysis focused on tbi patients transferred to the region's level i trauma center from another hospital. transfer paperwork from the originating hospital was reviewed and we conducted a detailed medical record abstraction, including computed tomography (ct) findings, procedures, length of stay (los), and ed disposition. data were collected on transfer patients. thirty had confirmed abnormalities on head ct ( . %). the mean age was years (range: - ), % female, and the most frequent mechanism of injury was falls ( %). average los was . days (range: - , median los . ), with patients staying one day or less. ct findings included subdural hematoma ( %), subarachnoid hemorrhage ( %), and intraparenchymal hemorrhage ( . %). five patients required neurosurgical intervention ( %), eight required icu admission ( %), two were discharged from the ed ( %), and two transitioned to inpatient hospice ( %). tbi is a frequent cause of transfers to trauma centers. in our sample, admission occurred in the majority of patients, but neurosurgical intervention was less common. however, for appropriately selected patients, strategies such as telemedicine may reduce transfers thus saving resources and improving continuity of care for patients and their families. this is an area in which future research is warranted. the prospects and timing of decannulation may affect surrogate decision making regarding tracheostomy for traumatic brain injury (tbi) patients, yet predictors of decannulation are unknown. methods tracheostomy admitted to an affiliated acute rehabilitation hospital between january and december . patients who had life-sustaining measures withdrawn were excluded. admission data, including injury characteristics and presence of lung injury on initial chest x-ray, and inpatient complications were compared. patients were followed throughout rehab and to the point of decannulation. patients lost to follow up were eliminated from analysis. time of decannulation was verified by inpatient physician notes. a cox proportional hazards model was created to determine factors associated with the time to decannulation and reported as hazard ratios (hr). there were tbi patients admitted to the icu during study period and ( % men, mean yearsold, median gcs ) underwent tracheostomy after ± days of intubation, of which were followed throughout rehabilitation. overall cannulation time was ( - ) days. ( %) patients had their trach removed prior to discharge from rehab after ( - ) days of cannulation. in a cox proportional model adjusting for sex, reintubation, aspiration pneumonitis, and presence of lung injury on admission chest x-ray; a higher hospital discharge gcs was associated with a shorter time to decannulation (hr, . ; % ci, . - . ; p =. ) while patients who required inpatient dialysis had a longer time to decannulation (hr: . ; % ci, . - . ; p = . ). the majority of tbi patients that require tracheostomy will be decannulated prior to discharge from rehab. longer durations of tracheostomy cannulatio hospital discharge and those that receive inpatient dialysis. goal directed therapy (gdt) is thought to be associated with outcome after traumatic brain injury (tbi). our team applied gdt to standardize care in patients with moderate to severe tbi, who were enrolled in a large multicenter clinical trial. physiologic goals were defined a priori in order to standardize care across sites participating in the protect iii trial. data were collected hourly for all randomized subjects (n= ). hours where gdt were not achieved were classified as "transgressions". these included: map . ; platelets mg/dl; and sbp mmhg. the proportion of hours spent in transgression was calculated for each parameter and grouped by quartile. poor outcome was defined via stratified dichotomy of the gos-e. data were adjudicated electronically and via expert review. for each parameter, the association between outcome and either ( ) occurrence of transgression or ( ) cumulative duration of transgression was estimated via logistic regression model, and backward selection was used to identify the physiologic parameters associated with outcome. subgroup analyses were performed in subjects with intracranial monitoring (ticp, n= ) . parameters significant at alpha . are reported. prolonged duration of transgression was associated with poor outcome when: glucose> mg/dl (p= . ); hgb mg/dl (p= . ) and inversely associated with map mg/dl (p= . ) or and was inversely associated with map< mmhg (p= . ). the protect iii clinical trial rigorously monitored compliance with gdt after tbi. multiple significant associations between physiologic transgressions and patient outcome were found. the data suggest that reducing physiologic transgressions is important to minimizing patient morbidity after tbi. the measurement and management of intracranial pressure (icp) is a key component in the care of severe head injury. extracranial ventricular drains (evd) have remained the standard due to the ability to lower icp with the drainage of cerebrospinal fluid (csf). placement of an evd is a more invasive procedure than intraparenchymal icp monitors (ipm) and it is unclear if the use of an evd improves outcomes. we hypothesized that early placement of an evd, in adult patients with severe head injury, would not affect outcomes. utilizing data from the citicoline brain injury treatment (cobrit) trial, a prospective multicenter study, we identified patients who met the inclusion criteria; ) placement of an icp monitoring device, ) glasgow coma score (gcs) less than , ) evd placement prior to arrival or within hours of arrival at the study institution. primary outcome was glasgow outcome score-extended (gose) at days post injury. secondary outcomes included neuropsychological evaluations at days post injury, mortality, and length of icu stay. logistic regression with forward-stepwise predictor adjustment and propensity score adjustment was performed to assess the independent association between evd placement and outcomes. patients who received an evd prior to or within hours of arrival at the study institution had worse gose at days ( . ± . vs . ± . , p= . ), higher in hospital mortality ( % vs %, p = . ), and did worse on out of neuropsychological measures at days. there was no difference in icu length of stay ( . ± . vs . ± . , p= . ). early placement of evds in severe adult head injury is independently associated with worse outcomes and higher in hospital mortality. goal directed therapy (gdt) is thought to be associated with outcome after traumatic brain injury (tbi). our team applied gdt to standardize care in patients with moderate to severe tbi, who were enrolled in a large multicenter clinical trial. physiologic goals were defined a priori in order to standardize care across sites participating in the protect iii trial. data were collected hourly for all randomized subjects (n= ). hours where gdt were not achieved were classified as "transgressions". these included: map . ; platelets mg/dl; and sbp mmhg. the proportion of hours spent in transgression was calculated for each parameter and grouped by quartile. data were adjudicated electronically and via expert review. for each parameter, the association between outcome and either ( ) occurrence of transgression or ( ) cumulative duration of transgression was estimated via logistic regression model, and backward selection was used to identify the physiologic parameters associated with mortality. subgroup analyses were performed in subjects with intracranial monitoring (ticp, n= ). parameters significant at alpha . are reported. mortality was . % and . % in the full and ticp cohorts. prolonged duration of transgression was associated with increased mortality for: hgb . (p mg/dl (p mg/dl (p= . ), and sbp . (p . (p= . ). covariates inversely related to mortality included single occurrence of map mmhg (p< . ). the protect iii clinical trial rigorously monitored compliance with gdt after tbi. multiple associations between physiologic transgressions and mortality were observed. the data suggest that maintaining physiologic measures within gdt guidelines may be important in preventing deaths. current outcome models in moderate-severe traumatic brain injury (mstbi) include only admission characteristics. yet, mstbi patients commonly have prolonged intensive-care-unit(icu)-stays with high risks to develop icu complications, lending to the hypothesis that these may be additionally associated with outcomes. the objective of this study was to examine the incidence rates of pre-specified medical and neurological icu complications, and their impact on post-traumatic in-hospital mortality and month functional outcomes. we analyzed mstbi patients consecutively enrolled in the prospective observational optimismstudy at a level- trauma center between / - / . poor outcome was defined as glasgow outcome scale - . multivariable logistic regression was employed to adjust for admission characteristics and icu-length-of-stay. the mean age was ± years, % were men, and median motor glasgow-coma-scale and injury-severity-scores were (iqr ; ) and (iqr ; ), respectively. the three most common medical and neurological icu complications were: hyperglycemia ( %), systemic inflammatory response syndrome ( %) and fever ( %); intracranial pressure crisis (icp; [ % of n= with icp-monitor]), brain edema requiring osmotherapy ( %), herniation ( %). multivariable models were adjusted for age, marshall-ct-classification, motor glasgow-coma-scale, pre-admission hypotension, icu-length-of-stay and injury-severity-score. after adjustment, in-hospital mortality was significantly associated with in-icu-cardiacarrest (or ; %ci . - . recent studies suggest benefits for early tracheostomy in patients with traumatic brain injury (tbi), yet data regarding who will require tracheostomy is lacking. ad lifesustaining measures withdrawn were excluded. admission and inpatient variables were compared. multivariable logistic regression analyses were used to assess admission and inpatient factors associated with receiving a tracheostomy and to develop models predictive of tracheostomy. there were patients ( % men, mean years-old, median gcs ) meeting study criteria with tracheostomy performed in ( %). admission predictors of tracheostomy included gcs, marshall score, injury mechanism, pao /fio ratio, and number of quadrants on chest x-ray with consolidation. inpatient factors associated with tracheostomy included the requirement for an external ventricular drain (evd), number of operations, pneumothorax, inpatient dialysis, aspiration, reintubation, and the presence of hospital acquired infections. multiple logistic regression analysis demonstrated that the development of hospital acquired infection (adjusted odds ratio [aor], . ; % confidence interval [ci], . - . ; p < . ), number of operations (aor, . ; % ci, . - . ; p < . ), pneumothorax (aor, . ; % ci, . - . ; p = . ), reintubation (aor, . ; % ci, . - . ; < . ), penetrating tbi (aor, . ; % ci, . - . ; p= . ) and placement of evd (aor, . ; % ci, . - . ; < . ) were independently associated with patients undergoing tracheostomy. a model of inpatient variables only was more strongly associated with tracheostomy than one with admission variables only (roc auc . vs. . , p< . ) and did not benefit from addition of admission variables (roc auc . vs . , p= . ). potentially modifiable inpatient factors have a stronger association with tracheostomy than do admission characteristics. existing traumatic brain injury (tbi) guidelines are designed primarily for the evaluation and management of tbi in tertiary care centers with advanced neuroscience capabilities. military special operations medical providers, however, are often required to treat and sustain patients in austere environments with limited resources for up to hours. tbi management guidelines directed specifically toward the care of these patients are needed. a review of recent operational experiences involving tbi and a survey of military special operations medics prompted a multidisciplinary expert panel to develop draft clinical practice guidelines/recommendations for prolonged field management of tbi. the panel conducted an in-depth review of literature on tbi and related topics and adapted existing and emerging therapies to address the unique challenges encountered in prolonged field care. tbi management while optimal management of pbto is not fully established. the objective of this -coeur arterial blood gas was drawn (icp, cpp, hemoglobin, temperature, pco and pao ). probes were localized in normal appearing white matter. we used a was calculated. a total of data sets were collected from patients (mean age . ± . , median gcs , mortality range from to ). mean pao for the group as a whole was mmhg (± ) and mean cpp was mmhg (± ). mean duration of pbto monitoring was . days (± . ). taking into account all determinants of pbto and using a protocolized approach to correct pbto , the mmhg for a few days. high pao values are possibly required due to the fact that oxygen delivery to the brain is rate-limited by diffusion and impaired by oedema or microvascular ischemia. it should be noted that pulse oximetry is not sensitive to detect pao below this level. traumatic brain injury (tbi) and stroke are extremely common causes of acute brain injury (abi), which cause long term disability and permanent neurological impairment. coma and stupor are common manifestations of abi, due to interruptions of the ascending reticular activating system (aras). neuro stimulants can improve functioning of the aras. despite decades of research there is a paucity of prospective high-level evidence utilizing neuro stimulants to help with earlier awakening from coma and stupor in abi. we reviewed the literature using the grade level of evidence (loe) methodology. we performed a preliminary literature search of the national library of medicine (nlm) using search terms abi and stimulants. within the literature we searched for timing of stimulant use among abi studies and included all forms of abi such as tbi, stroke, and anoxic injury. we retrieved total results, of which we excluded since they did not meet grade high loe criteria or were "n of " studies or aggregates. only high loe randomized studies or meta-analyses were found. among these various stimulants were investigated including methamphetamines such as methylphenidate and lisdexamfetamine, caffeine, armodafinil, galantamine, and amantadine. methylphenidate had randomized trials and a meta-analysis in subacute tbi but reported only attention as a main outcome. we were unable to draw broad-level recommendations about optimal timing, best stimulant, and patient centered outcomes from this data. there is insufficient data to recommend optimal stimulant, timing, and dosing among heterogeneous abi disease models. we propose conducting future homogenous abi neuro stimulant trials in for safety, tolerability, dose-finding, optimal timing, and outcomes based efficacy. neuro stimulants could play a role in earlier awakening and extubation in abi which could improve outcomes similar to sedation/vacation bundles in icu's currently if studied adequately. tbi remains the leading cause of death and disability in young adults in the us and europe. thus far, pharmacological and non-pharmacological intervention studies did not confirm benefits on functional outcomes. the inducible enzyme nitric oxide synthase (inos) is upregulated in response to brain injury, causing excessive production of no, a key driver of secondary injury after tbi. the antipterin vas is a structural analogue of the endogenous nos cofactor and a potent in-vivo selective inhibitor of inos. a randomized, placebo-controlled phase study examined dose levels of vas in patients with acute moderate or severe tbi. cerebral microdialysis showed pharmacologically relevant drug concentrations close to the injury and a tendency for vas to increase the arginine/citrulline ratio, an indirect marker of nos inhibition (stover et al., j neurotrauma ). vas conferred a significant benefit on the extended glasgow outcome scale interview (egos-i) at and months after injury. no changes in systemic blood pressure or partial brain oxygen pressure were noted. a recent pharmacokinetics and pharmacodynamics study further corroborated the selective inos inhibition by vas . the confirmatory nostra phase trial (eudract no. - - ; clinicaltrials.gov identifier nct ) was initiated in . adult patients with a nonrequiring intracranial pressure monitoring, are randomized : to vas or placebo, administered in addition to standard of care, as intravenous continuous infusion for hours, starting between and hours post tbi. the primary efficacy endpoint is egos-i at months post injury. additional endpoints include the daily therapy intensity level and tbi-specific quality of life measures. continuous safety monitoring is performed by an independent committee. nostra iii, the only ongoing registration study in acute moderate and severe tbi, is sponsored by vasopharm gmbh, and plans to recruit patients by q . a glasgow coma scale (gcs) score of on presentation in patients with traumatic brain injury (tbi) portends a poor prognosis. consequently, there is often a tendency to treat these patients less aggressively because of low expectations for a good outcome. we performed a retrospective review of patients with tbi and a gcs score of . demographics, apache iv scores , pupillary reactivity to light, intracranial pressure (icp), icp burden (the number of days with an icp spike > mm hg as a percentage of the total number of days monitored), and outcome (mortality and glasgow outcome scale-gos at months, with good outcome defined as gos of - ). patients were divided into groups: group (gos = - ) and group (gos = - ). a total of patients were included. the overall mortality rate was . %. at -month, patients ( . %) achieved a gos - . compared to group (n = ), group (n = ) had higher average apache iv score ( ± vs ± , p = . ), more patients with bilateral fixed pupils ( % vs %, p = . ), and higher icp burden ( ± vs ± , p = . ). gos score - was achieved in % of patients presenting with bilateral reactive pupils versus . % of patients presenting with bilateral fixed pupils (p = . ). . % of patients with tbi and a gcs of at presentation achieved a good outcome at months. apache iv scores, icp burden, and pupillary reactivity were significant predictors of outcome. we believe that patients with severe tbi who present with a gcs of should still be treated aggressively initially since a good outcome can be obtained in a significant proportion of patients. elevated circulating catecholamine levels are independently associated with functional outcome and mortality after isolated traumatic brain injury (tbi). we assessed the ability of peripheral catecholamine levels to improve the prognostic performance of the crash and impact-tbi models. prospective, observational, multicenter cohort study, conducted at three level trauma centers in canada and usa. epinephrine (epi) and norepinephrine (ne) concentrations were measured in the peripheral blood at admission (baseline), , and h after trauma. outcome was assessed at months and dichotomized into favorable [extended glasgow outcome scale (go -tbi models, which identified core prognostic markers of severe tbi. the baseline model (m ) included age, gcs and pupillary size/reactivity. the model (m ) included m + hypoxia, hypotension and marshall ct classification. model and included m + epi levels, and m + ne levels, respectively. the risk models performance was assessed by comparing receiver operating characteristic (roc) curves, and by the use of integrated discrimination improvement (idi) index. m had significantly higher roc and idi than the baseline model (m ), to predict mortality. m had a roc = . ( . - . , p = . ) and idi = . (p = . ). the prediction of mortality was not improved by including ne [m = roc = . ( . - . , p = . ) and idi = . (p= . )]. the integrated discrimination improvement index indicated the prediction of unfavourable outcome by the baseline model was improved by including epi (idi = . , p= . ), and ne (idi = . , p= . ) in the models. catecholamine levels improved risk models performance to predict mortality and unfavorable outcome after traumatic brain injury. following traumatic brain injury (tbi), depression is common and may influence recovery. small trials demonstrated that various drugs are beneficial in managing depression following tbi, but no large, definitive study has been conducted. we performed a meta-analysis to estimate the potential benefit of anti-depressant medications following tbi. multiple databases were searched using the terms "anti-depressant tbi," and "depression treatment tbi" to find prospective pharmacologic treatment studies of depression following tbi. studies were excluded if they did not measure depression as an outcome. effect sizes for anti-depressant medications in post-tbi patients were calculated for within-subjects designs that examined change from baseline after receiving medical treatment and treatment-placebo designs that examined the differences between anti-depressants and placebo groups. a random effects model was used for both analyses. of titles screened, studies were included, with total patients. medications evaluated included selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, and tricyclic antidepressants. pooled estimates showed significant reduction in depression scores for individuals after pharmacotherapy (mean change [mc] - . , % confidence interval [ci]: - . to - . ) and significant difference in reduction of depression scores between medications and placebo in the pooled estimate (standardized mean difference of four trials [smd] - . , % ci: - . to - . ); however only one of the four treatment-placebo studies found medications significantly reduce depression scores more than placebo. this meta-analysis found a significant benefit of pharmacotherapy for treatment of depression in patients with tbi. however, there was a high degree of bias and heterogeneity regarding tbi severity, time since injury, depression severity, and demographics. larger prospective studies on the impact of anti-depressants on post-tbi depression are warranted to better understand treatment effects and the relationship of post-tbi depression and outcome more broadly. pleural effusion (pe) has been reported in % of medical icu. there is little published data on the prevalence and clinical significance of pe in mechanically ventilated patients with traumatic brain injury. head injury patients admitted to icu for mechanical ventilation (mv) within - hours and gcs > were assessed for eligibility. presence of pe was assessed by serial cxr on daily basis and volume of effusion was estimated and recorded. in case there was no evidence of pe on cxr, a bedside sonography in semi recumbent position was done within h of icu admission. pleural fluid volume was estimated based on -point classifications on sonography. details of mechanical ventilation and icu management were recorded. successful weaning was defined as ability to breath spontaneously for h. primary aim was to observe prevalence of pe in mv head injured patients. as secondary measure; impact of pe on duration of mv, weaning and length of icu stay were compared. study enrolled patients. three baseline cxr showed pe. total of ( %) patients developed pe in icu. patients had evidence of pe on both cxr and usg. patients had only sonographic evidence of pe, which were not detected on cxr. significantly more minimal effusions were detected on sonography ( / , p= . ). duration of mechanical ventilation and duration of icu stay were significantly more in patients with pe. (p= . , mann whitney rank sum test) there was no significance difference in duration of weaning in patients with and without effusion ( . ± . , . ± . , p= . ). chest ultrasonography increased the detection rate of pleural fluid. patients with pe had longer duration of mechanical ventilation. early detection may be associated with shorter period of mechanical ventilation and icu stay spine surgery can trigger a systemic inflammatory response syndrome and lead to hypotension requiring vasopressors. as sepsis is a major differential diagnosis in the post-operative period, the objective of this study is to understand the prevalence of a true systemic infection in this setting. retrospective review of all consecutive adults with post-operative shock requiring vasopressors following spine surgery in an academic tertiary medical center. a total of patients, median age years (iqr - ), were included in the final analysis. comorbidities included a median bmi of (iqr - ), coronary artery disease ( %) and diabetes mellitus ( %). median estimated blood loss was cc (iqr to cc). circulatory volume was adequately replaced in a total of % patients within hours post-op. all patients received crystalloids, and an additional % received multiple (> ) units of prbcs transfusion. adequate urine output was confirmed in ( %) of the patients. the maximum median rate and duration of each vasopressor infusion was as follows: phenylephrine mcg/min (iqr - , n = ), hours (iqr - ), norepinephrine mcg/min (iqr - , n = ), hours (iqr - ), epinephrine mcg/min (iqr - , n = ), hours (iqr - ) and vasopressin . units/min, hours ( - , n = ). of the patients, ( %) met at least sirs criteria. infection was confirmed in a total of patients; positive respiratory or blood cultures in ( %) patients and positive urinalysis or urine culture in ( %). two patients ( %) were diagnosed with myocardial infarction. no patients had pulmonary embolism. our study suggests that the risk of infection and sepsis in patients with persistent shock following spine surgery is small but not negligible. larger multicenter studies are needed to confirm our findings and to identify the predictive factors. ischemic and hyperemic injuries may occur unnoticed after severe traumatic brain injury (tbi) and contribute to additional brain damage. maintaining an adequate cerebral perfusion is considered crucial in preventing such injuries, as deviations from autoregulation-guided optimal cerebral perfusion pressure (cppopt) are associated with greater mortality and disability. this makes reliable estimation of cppopt an interesting diagnostic and treatment tool for monitoring. cppopt is defined as the cerebral perfusion pressure (cpp) at which the pressure reactivity index (prx) is minimal. the leading method for estimating cppopt automatically, by aries et al. ( ) , fits a parabola to pairs of prx and cpp data. the method uses preset heuristics to reject the fit as unreliable, namely when the parabola is too "shallow" or does not cover a certain cpp range. as a result, the cppopt estimates could be generated only about - % of the time. moreover, the manually set heuristics potentially restrict the generality of the model. here, we propose an alternative method based on bayesian inference. treating prx at each time as a function of cpp corrupted by noise serves as a "forward model" that can be inverted to yield, for a given data set, a temporally evolving posterior probability distribution over cppopt. the mean of this distribution is a bayesian estimate of cppopt; we find that these estimates are generally consistent with those obtained from the classic method. importantly, the width of the distribution at a given time serves as a metric of uncertainty about cppopt estimation. we find that this uncertainty tends to be large at time points where the classic method with preset heuristics rejects the fitted parabola. our method makes manually setting rejection criteria unnecessary. bayesian estimation of cppopt holds promise as a tool for providing additional decision support in the care of individual tbi patients. quantitative parameters derived from continuous eeg (ceeg) have been useful to understand evolution of traumatic brain injury (tbi) and the impact on regional networks. these parameters are often interrogated at a global level rather than region-specific. the regional evaluation of quantitative eeg parameters may provide an objective assessment of regional network function, and be of predictive value for prognostication continuous eeg was performed in patients with tbi, and mri imaging was obtained during acute and chronic time points post injury (within days and months, respectively). the extended glasgow outcome scale (gose) assessed clinical recovery at months, with good recovery defined as gose score - and poor as gose score - . volumetric measurements of selected brain regions, both cortical and subcortical, were obtained at acute and chronic time points. quantitative parameters derived from ceeg, such as percent alpha variability (pav) and hemispheric symmetry, were calculated continuously and anatomically (frontal, temporal, occipital) through the acute hospitalization course. we hypothesized that persistent regional variation in alpha power post injury would lead to brain regionspecific atrophy and may predict outcome at months acute pav within the first hours post injury was poor in patients with poor outcome. in addition, patients with poor outcome had significantly more atrophy in the thalamus, hippocampus, and temporal and occipital lobes. asymmetry of the hemisphere pav values correlated with both brain atrophy and clinical outcome regional asymmetry of pav within the first hours post injury correlates with chronic brain atrophy and clinical outcome after tbi after moderate and severe traumatic brain injuries (tbis), individuals are often admitted to an intensive care unit (icu), and later require intensive rehabilitation. many neuro-icus engage therapists and physiatrists for rehabilitation and therapy during a patient's icu admission. however, the optimal timing, intensity, and components of rehabilitation needed while in the icu are not known and practice patterns are highly variable. the goal of this study is to describe the rehabilitation practices to identify whether there is consensus on best practices. an electronic survey asking participants to describe tbi rehabilitation practices in their icu was distributed via redcap through the neurocritical care society (ncs) and american congress of rehabilitation medicine (acrm) websites. potential respondents were first asked if they cared for patients with tbi in the icu, and if they answered "yes," they were invited to complete the survey. two email reminders were sent to each group for completion. after weeks, the data were extracted and analysis completed. there were respondents who reported that they cared for patients with tbi in the icu ( attending physicians, advanced care practitioners, therapists, nurses, fellows, and other). of these, % recommended early rehabilitative care. the most common reasons to wait for the initiation of physical therapy and occupational therapy were normalization of intracranial pressure (icp) ( % and % respectively) and hemodynamic stability ( % and % respectively). speech therapy was typically recommended after extubation ( %) and normalization of icp ( %). the majority of clinicians caring for patients with tbi in the icu support early rehabilitation efforts, typically after a patient is extubated, intracranial pressure has normalized and the patient is hemodynamically stable. prospective studies evaluating the merits of these self-reported rehabilitation initiation criteria are warranted. high-dose methylprednisolone (hdmp) has been studied as a potential therapeutic option for acute sci, with mixed results regarding efficacy and consistent suggestion of complications. we conducted a retrospective cohort study of acute sci patients extracted from the medical information mart for intensive care iii (mimic-iii) database to evaluate the hypothesis that steroid-related adverse drug events (ades) occur less often than in published clinical trials using hdmp. three groups of patients coded for acute sci were identified from mimic-iii from june to october : hdmp recipients per nascis ii/iii protocols (hdmp, n = ), patients who received some steroids but not per nascis ii/iii protocols (non-hdmp, n = ), and patients who did not receive steroids (no steroids, n = ) . demographics and data on complications of steroid therapy were extracted. one-way anova or student's t test were used to evaluate continuous variables; chi-squared or fisher's exact test were used for nominal or categorical variables. there were no differences in steroid-related ades between the three groups. there were higher average blood glucose readings in recipients of any steroids compared with the no steroids group, and more variation in blood glucose readings in hdmp recipients compared with the other two groups. there was a higher icu los and ventilator time in the hdmp group compared with the other two groups. compared with three other trials examining similar use of hdmp in acute sci, there were higher rates of pneumonias overall, though lower rates of urinary tract infections, skin & soft tissue infections, pressure ulcers, and superficial thromboemboli/thrombophlebitis. the results of this study are consistent with previous works related to the potential for harm regarding the use of hdmp or any steroids in acute sci. changes in selected adverse event profiles may be due to standardization of icu supportive care over time. cervical spinal immobilization and clearance protocols are important steps in the minimization of secondary spinal cord injury. patients with primary neurologic diseases are frequently found down and placed in rigid cervical collars despite sustaining minimal-to-no cervical injury. in these patients, neurologic dysfunction can complicate and delay cervical clearance. decreasing time spent in cervical spinal immobilization could improve patient care by allowing greater access to / range-of-motion of the neck, increasing patient comfort, and decreasing skin breakdown. through retrospective chart review over a -month period, we collected the following: the rationale behind each mri, any mri evidence of cervical instability, the result of any ct imaging, and the basic mechanism of any trauma. for patients that were simply found down, any evidence of trauma either by history or physical exam was recorded. during the study period, there were instances where an mri of the cervical spine was performed. of those mris, ( %), were performed for cervical spinal clearance. sixty-one ( %) of mris were ordered without any ct imaging first. of the patients with a normal ct, six ( . %) were found to have mri evidence of cervical instability. notably, of the patients who were found down, there was only one instance where the mri demonstrated instability. that patient had extensive facial injuries suggestive of an unwitnessed fall. in the patients that were found down with no history or evidence on physical exam of trauma, there was no mri instability. for patients that are found down without any history or evidence on physical exam of trauma, a ct of the cervical spine is likely sufficient for cervical spinal clearance. acute subdural hematoma (asdh) represents a major clinical entity in severe traumatic brain (stbi), approximately % are accompanied by various extents of asdh. stbi has been reported to cause cerebral circulatory disturbances at an acute stage and had the worst circulatory disturbance among stbi. in this study, we focused on the cerebral circulation of asdh, evaluated the absolute left-right difference between cerebral hemispheres and compared the cerebral circulation between the favorable outcome group and the unfavorable group. we retrospectively reviewed patients with asdh. they were admitted to our hospital from to . in these patients, we simultaneously performed xenon-computed tomography (xe-ct) and perfusion ct to evaluate the cerebral circulation on post-injury days - . we measured cbf using xe-ct and mean transit time using perfusion ct and calculated the cerebral blood volume (cbv). a significant absolute difference in cerebral circulation between the hemispheres among different types of tbi was observed in mtt. there was no significant difference in these parameters between left-right hemispheres with asdh among the favorable outcome group and unfavorable group. although there was no significant difference in age, gcs at the onset of treatment, cbf and cbv, there was significant difference only in mtt between the favorable outcome group and unfavorable group. the circulatory disturbance in patients with asdh occurs diffusely despite the focal injury. additionally, in unfavorable patients, the circulatory disturbance is worse than in favorable patients. because asdh suffered ischemia more than other types of stbi, we had to perform not only removal of the occupying lesions, but also neurointensive care, including whole-body management and hypothermia therapy for the ischemic brain after surgery. we have to adopt a treatment strategy appropriate to the pathophysiology of the different tbi types. kcentra is -factor prothrombin complex concentrate that is fda approved for reversal of warfarin. there is limited research describing the use of kcentra for coagulopathy in the setting of traumatic intracranial hemorrhage. here, we show the largest ever retrospective review for the use of kcentra in the setting of traumatic intracranial hemorrhage. retrospective chart review was performed from - for patients with intracranial hemorrhage who presented to the r adams cowley shock trauma center. patients who received kcentra were identified. basic clinical information was obtained including cardiac/stroke history, blood pressure, glasgow coma score, medication history, and categorization of hemorrhage. pre and post inr level was assessed. hemorrhagic expansion was assessed with ct scan up to up to hours. disposition and thromboembolic events were recorded. forty-four patients were identified as receiving kcentra in the setting of traumatic intracranial hemorrhage. pre and post kcentra dosing inr was found to be significantly different (p< . ) across the two groups assessed (warfarin and tbi/noac coagulopathy). seventeen patients ( . %) had hemorrhagic expansion as determined on ct scan. disposition (home vs rehab vs death) was found to have three significant variables: history of stroke, hemorrhagic expansion, and admission glasgow coma score. eight patients ( . %) were found to have thromboembolic events. here, we show the largest retrospective review describing the clinical use of kcentra for coagulopathy reversal in the setting of intracranial hemorrhage. overall, kcentra is shown to be a safe and effective drug for the reversal inr. importantly, our reported hemorrhagic rate of . % is lower than established rates reported in the literature for warfarin/coagulopathic patients with intracerebral hemorrhage ( - %). the prognostic importance of hemorrhagic expansion was highlighted in the disposition analysis which showed that zero patients were discharge home if there was recorded expansion. despite the impact of post-traumatic amnesia (pta) duration on long-term functional outcome after traumatic brain injury (tbi), radiologic predictors of pta duration are lacking. we hypothesized that the number of traumatic microbleeds (tmbs) detected by gradient recalled echo (gre) magnetic resonance imaging (mri) in neuroanatomic regions that mediate memory correlates more strongly with pta duration than does the number of global tmbs. using a prospective outcome database of patients treated for mild-to-severe tbi at an inpatient rehabilitation hospital, we retrospectively identified patients who underwent acute mri with gre. pta duration was determined by the galveston orientation and amnesia test, orientation log or chart review. a rater blinded to pta duration identified tmbs on the gre datasets globally and in neuroanatomic regions that mediate memory, including the hippocampus, fornix, corpus callosum, thalamus, and the temporal lobe. associations between global and regional tmbs (in the mentioned locations) and pta duration were tested using spearman rank correlation coefficients. the cohort was comprised of % ( hippocampus and corpus callosum tmbs are associated with pta duration, and thus may have greater utility for predicting functional outcomes than global tmb number. validation of these findings in larger prospective studies is indicated. using a large two-center cohort of penetrating traumatic brain injury (ptbi) patients, we previously developed the survival after acute civilian penetrating brain injuries (spin) score, a logistic regressionbased parsimonious risk stratification scale for estimating survival after civilian ptbi. the objective of the present study was to externally validate the spin-score. our multicenter validation cohort comprised ptbi patients retrospectively identified from three u.s. level- trauma center registries. the spin score variables (motor gcs [mgcs], sex, pupillary reactivity, self-inflicted ptbi, transfer status, injury severity score [iss] and inr) were collected from the trauma registries supplemented by chart review. using the spin-score multivariable logistic regression model from the original study, receiver-operating-characteristic area-under-the-curve (roc-auc) analysis and hosmer-lemeshow goodness-of-fit testing was performed. the mean age was ± years, and patients were predominantly male ( %), with % white and % black. in-hospital mortality was %, and -month mortality of discharge survivors was . in this multicenter external validation study, the full spin-model predicts in-hospital survival after ptbi with excellent discrimination and calibration. after removing inr from the model, discrimination remained excellent, but model calibration diminished. the full spin-score may provide important information to guide families and physicians after civilian ptbi. limited data has described alterations in vancomycin pharmacokinetic (pk) parameters in traumatic brain injury (tbi) patients that have resulted in sub-therapeutic concentrations. the primary objective of this study is to evaluate the pk parameters of vancomycin in tbi patients to determine if using the common clinical practice of capping creatinine clearance (crcl) to ml/min in determining dosing impacts achievement of therapeutic concentrations. this was a single-center, retrospective study of patients at least years of age with tbi who received vancomycin and one reported steady-state vancomycin serum level from april to december . predicted pk parameters based on population data using actual and capped creatinine clearance (crcl) at ml/min were compared with calculated pk parameters based on serum trough concentrations at steady state. the difference was assessed using a two-sample wilcoxon rank-sum test where p < . was considered statistically significant. when using actual crcl [median ml/min patients with tbi experienced crcl that were greater than predicted. based on the results of this study, actual crcl is more accurate at predicting vancomycin pk than the common practice of capping crcl at ml/min. therefore, actual crcl should be used when determining vancomycin dosing regimens in patients with tbi to achieve desired therapeutic concentrations. neurocritical care is traditionally provided within institutions in urban centers while access in rural communities has been limited. transport to urban centers is not always favorable for a variety of reasons including critical patient condition, family wishes, weather, and geography. our hypothesis is that tele-neurocritical (tele-ncc) can extend access to this service with meaningful impact on icu outcomes. a tele-ncc pilot study was initiated within intermountain healthcare. starting / / , the study included all ischemic stroke patients admitted to the icu of one primary stroke center in utah. tele-ncc consultations were provided by ncc physicians at our flagship hospital located three hundred miles from the spoke site. tele-ncc consultations occurred via an existing telehealth platform developed inhouse. primary outcomes for this pilot study were icu and hospital lengths of stay (los). secondary outcomes include stroke complication rates and results on a provider satisfaction questionnaire. to date, tele-ncc consultations have been performed with median hospital los = days (iqr . - . ) and icu los = . days (iqr - ). in the months prior to the pilot, there were admissions to the icu for ischemic stroke with median los = days (iqr . - . ) and icu los = . (iqr - . ). for this small sample size, the p-values for comparison of hospital and icu lengths of stay before and after tele-ncc are . and . respectively. tele-ncc care can have significant impact on icu outcomes by expanding access to critical support from neurocritical care specialists. tele-ncc expands access to not only consultation on critical neurological emergencies, but also on when to de-escalate from the icu or in end of life discussions with which general icu teams may not be comfortable. these impacts could be measured as important decreases in hospital and icu los. hospital readmissions increase health care costs, increase patient exposure to nosocomial disease, and imply patients were not stable for discharge. because readmissions are a target for hospitals and payers, several centers have developed predictive readmission scores in order to identify high-risk patients. we contend that these general readmission scores are not suitable for neurocritically ill patients and that specific predictive score must be developed to identify high-risk patients. we conducted a retrospective chart review of consecutive patients admitted to our neuroscience critical care unit. we recorded the readmission scores, reason for admission, length of stay,and if they were readmitted. we then compared the median readmission scores between the two groups. after removing patients without readmission scores or died at the end of the original admission,we analyzed the records of patients. patients were more likely to be readmitted if they were initially emergently hospitalized or had malignancy. readmitted patients had a longer original hospital length of stay. we found no difference median readmission score between those who were readmitted, and those who were not. most readmitted patients ( . %) had an original "low-risk" readmission score. we found that our center's score was poor in predicting readmission for neurocritical care patients and that several components of the score do not apply to our patient population. we propose that to accurately predict readmission,centers should create their own unique readmission scores for more homogeneous admission populations. clinical evaluation of the level of consciousness in non-communicative patients can be very challenging. in this study, we aimed to evaluate the nurses and nursing assistants' (nas) perception of the consciousness on patients suffering from disorder of consciousness (doc). through their activities, nurses and nas have an extended observation time of patient's behavior, and make repeated implicit assessments of patients' clinical state of consciousness. we hypothesized that even in the absence of a structured and explicit evaluation of consciousness (in contrast for instance with the coma recovery scale revised -crs-r), nursing expertise could be a valuable measure to improve assessment of state of consciousness in doc patients. this was a prospective observational single-center study. our primary objective was to correlate the nurses and na's assessment of doc-patients' consciousness quantified through an analogic visual scale (the "doc-feeling score") with the results of the standard methods (including crs-r, fmri, electrophysiology). the secondary objective was to identify elements which correlate with this assessment and/or with the expert's diagnosis (such as visual pursuit, patient's participation to nursing, motor responses to verbal command or adapted reactions to painful care). . linear regression reveals a good correlation between the "doc-feeling score" and the crs-r gold standard (r = . , p-value < . , figure ). global assessment of the level of consciousness by all the caregivers interacting with the patient using the "doc-feeling score" is reliable and can improve assessment of state of consciousness in doc patients. investigating causes of deterioration in neurological patients is important to anticipate these complications and improve outcomes. this is a prospective observational study performed at an academic tertiary care trauma, stroke and neurorehabilitation center. data was collected over a year from rapid response system activations (rrsa). in one year, our center had admissions. rrsa were performed on patients. most common admission diagnosis was ischemic stroke ( %). most common rrsa organ system involvement was respiratory system (n= , . %). the only predictors of death or new limitation of care in those patients who had rrsa were age ( years vs years, p < . ) and history of cancer ( %) vs ( %) p= . . . % (n= ) of rrsa happened during day shift and . % (n= ) during night shift. . % (n= ) of rrsa happened around shift change and were more likely to result in an unplanned icu admission. . % (n= ) of rrsa happened within hours of admission and were more likely to result in unplanned icu admissions. the most common reasons for in hospital decompensation in neurological inpatients are nonneurological. most common organ system involvement responsible for rrsa is respiratory system. the only predictors of death or new limitation of care were history of cancer and age and older. rrsa activations were more frequent during day shift. however, there was no different in the outcomes we evaluated between day and night shifts. rrsa happening around shift change wew more likely to result in unplanned icu admission. rrsa within hours of admission showed an increased risk of unplanned icu admission when compared to rrsa happening after hours of admission. neurocritical care is a growing field with an increasing number of dedicated neuroscience intensive care units. in this dynamic context, it is unclear which types of physicians provide neurocritical care across the united states. we performed a retrospective cohort study using claims data from a nationally representative % within analyzed critical care procedures . the primary outcome was physician specialty, defined by medicare provider specialty codes. in a sensitivity analysis, we excluded claims for services on the day of admission and claims associated with a diagnosis of cardiac arrest, since these activities may often occur outside of neuroscience intensive care units. we identified between and , neurologists were responsible for approximately one-quarter of neurocritical care services among a nationally representative cohort of elderly patients. critically-ill patients on mechanical ventilation (mv) cannot verbally communicate. research suggests several phenomena occur in patients during mv because of impaired communication including anxiety, loss of control, loneliness, and compromised interaction (schou and egerod, ) . for neurocritical care patients, this can be especially profound when coupled with cognitive and motor/sensory deficits. currently, the blom® speaking valve (sv) is the only approved product available that allows phonation in ventilator-dependent patients with tracheostomy. sv trials are known to facilitate vent-weaning. the current standard of care (passy-muir speaking valve, minute trials), is contra-indicated in patients who cannot tolerate cuff deflation. as such, the blom® sv was evaluated for clinical and quality efficacy. we retrospectively evaluated clinical outcomes associated with blom® sv on mv during a trial in a neuroicu of a large tertiary center between / / and / / . baseline demographics, diagnoses, physiologic, sedation, delirium, mobility and swallowing parameters, length of stay, ventilator modes and settings, ventilator days, work of breathing and presence of pneumonia were abstracted along with patient, family and interdisciplinary staff satisfaction survey results. patients were recommended for blom® tracheostomy. patients received sv trials. of the trials were performed, % ( ) were optimal/completed ( + minutes); % ( ) were suboptimal/completed trials ( - minutes); % ( ) unable to complete. satisfaction results from patients/families were positive compared to the interdisciplinary team survey results. remaining parameters currently in analysis with results pending, to be completed by end of august, . impaired communication during mv is suboptimal for neurocritical care patients. our clinical experiences with blom® sv showed positive and negative outcomes. positive benefits were enhanced patient/family engagement and family satisfaction. unanticipated obstacles included significant increase in patient fatigue during sv trials, often delaying ventilator weaning. further study is needed to determine efficacy in this population. patients with clinical signs of cerebral herniation require immediate intervention known as a "brain code". in our neurosciences critical care unit (nccu), a rapid response program is in place to ensure the safety of . % hypertonic saline's use (high risk medication) and to expedite its delivery to the bedside given the emergent need for this medication when ordered. our institution, however, is lacking a more holistic and structured approach to cerebral herniation syndrome that include components of tiers zero to three emergency neurological life support elevated icp or herniation protocol. the neurocritical care communication council consists of bedside staff nurses, nursing leadership, advanced practice providers (nurse practitioners and clinical nurse specialist), pharmacists, respiratory therapists and physicians. the council identified processes during neurological brain codes that could be improved as a result of using a bedside debriefing tool. the unit leadership council of the nccu reviewed literature on hospital debriefing tools and referenced this organizations current resuscitation debriefing tool. from these sources, a brain code debriefing form was constructed. a clinical tool was developed with the expectation of standardizing the brain code process in this nccu. the brain code debriefing form will be piloted to determine unit and system wide value. pre-and postimplementation data will be collected to discover areas of improvement for optimized patient care. through the development of this debriefing tool, it was ascertained that a clinical practice guideline for impending cerebral herniation would be beneficial to further guide and direct evidence-based care. thus, a preliminary algorithm for identification and emergency treatment is in process. the americas medical center is a -bed tertiary hospital complex, located in the city of rio de janeiro. the center was elected by the international and the brazilian olympic committees as the referral hospital for the olympic family (of), comprised of athletes and their crews, support and technical personnel, credentialed media and credentialed governmental representatives from the participating countries. the neurology and neurocritical care teams were selected to head a comprehensive program of acute emergency neurology, including a -bed neurocritical care unit (nicu), and - emergency neurology service. we hereby describe our experience during the olympic games in rio de janeiro, brazil results neurological assessments were conducted in patients from the of, of these involving athletes from countries. the most common reason among athletes were traumatic brain injuries (tbi), with politraumas (all involving cycling), mild tbi ( of boxing, of field hockey, of rowing and of cycling) and moderate tbi (cycling and water polo). three patients were admitted to the nicu: ischemic strokes and politraumas with tbi. motor vehicle accidents with associated tbi involving the of were surprisingly frequent, with assessments, none requiring admissions. finally, ct scans of head, ct scans of the cervical spine and mri scans ( brain and spine mri) were performed to assess the patients. of note, cases of seizures, functional deficits, multiple sclerosis flare and psychiatric complaints were observed affecting the of. not only that multiple sports-related injuries were observed, cases of diverse acute neurological issues were reported involving members of the of. olympic games are complex events mobilizing thousands of people, and a comprehensive and detailed plan for neurological emergencies is of extreme importance the term "handoff" has been defined as the "transfer and acceptance of responsibility for patient care that is achieved through effective communication, passing patient-specific information from one caregiver or team of caregivers to another to ensure the continuity and safety of the patient's care" (patterson and wears, ) . the joint commission reported that two-thirds of sentinel events occur at the time of patient handoff, which led to a national patient safety goal, requiring standardized process for handoffs (the joint commission on accreditation of healthcare organizations, ) . to support this npsg, a nccu specific handoff tool and timeout process were created to support the transition from or to nccu. nccu postoperative handoffs were identified as an area to enhance staff satisfaction and patient safety. baseline data to evaluate the frequency of neurosurgery report was performed in may . using a qualtrics survey in june , staff satisfaction with current ns or report was obtained from nccu rns, nps, and fellows evaluating whether they felt they received: accurate medical history, accurate information about performed procedure, sufficient handoff for patient care, specific patient goals, recent pharmacological intervention, anticipated concerns regarding diagnosis/procedure, estimated blood loss, blood/fluid intake, airway concerns, complications and overall satisfaction with handoff. a taskforce of rns, nps, neurointensivists, and neurosurgeons was established, ending with the creation of a handoff tool and timeout process. the new tool and process were initiated and two months later, a repeat survey was sent to evaluate staff satisfaction and perceived effectiveness of the new process and handoff tool. currently being tabulated at time of submission. using standardized, open communication techniques including handoff tools and a timeout throughout the perioperative period is crucial to positive outcomes and can improve perioperative care in the nccu patient and increase satisfaction and collaboration of all team member during or handoff. in the age of the healthcare reform and rising costs, it is important for strategic service lines to explore cost saving and care efficiency strategies. beginning in september , physician and administrative leadership within the duke neurosciences intensive care unit (neuroicu) began investigating per patient cost to explore opportunities to decrease direct cost to the neuroicu, cost to the patient, and reduce redundancy of care. with assistance from health system finance, the team assessed the following data points within each cost group and compared these values to that of our peers within the us news and world report top honor roll: · number of units · direct cost per unit · total direct cost our performance according to our peers in the following cost areas was: .pharmacy-ranked th out of .laboratories-ranked th out of .radiology-ranked th out of .cardiovascular-ranked th out of . based on these performance metrics, neuroscience administrative and medical leadership developed a project grid of prospective initiatives and identified the following for each cost area: ·stakeholder-led teams inclusive of providers, nursing, and administration ·duration or impact of each initiative: short, medium, or long ·activity phases based on duration the stakeholder-led groups would propose and validate projects based on scope and duration. at each group's meeting, members reviewed charge level financial data by activity code for the group's respective cost area to develop applicable initiatives. multiple initiatives are currently underway including those within the cost areas of pharmacy, laboratories, and radiology. included among these initiatives is a change in routine resistant organism screening and cervical spine clearance. other initiatives will be target intravenous anti-hypertensive treatment and laboratory frequency. the total cost savings from these initiatives can only be estimated at this point but will likely be in excess of $ , for the calendar year. it is uncertain whether dedicated neurocritical care units are associated with improved outcomes for critically ill neurologically injured patients in the era of collaborative protocol-driven care. we examined the association between dedicated neurocritical care units and mortality, and the effects of standardized management protocols for severe traumatic brain injury. we surveyed trauma medical directors from centers participating in the american college of surgeons trauma quality improvement program (tqip) to obtain information about icu structure and processes of care. survey data were then linked to the tqip registry, and random-intercept hierarchical multivariable modeling was used to evaluate the association between dedicated neurocritical care (ncc) units, the presence of standardized management protocols and mortality. we performed three sensitivity analyses reclassifying ncc units by restricting to closed units, under ucns director leadership, and exclusion of neurotrauma units. data was analyzed from , adult patients with isolated severe traumatic brain injury admitted to tqip centers between to . fifty icus were dedicated neurocritical care units, whereas were general icus. rates of standardized management protocols were similar comparing dedicated neurocritical care units and general icus. care in a dedicated neurocritical care unit was not associated with improved risk-adjusted in-hospital survival (or . ; ( % ci . - . ; p= . ). the results from the model were robust in our sensitivity analyses. the presence of a standardized management protocol for these patients was associated with lower risk-adjusted in-hospital mortality (or . ; % ci . - . ; p= . ). compared to dedicated ncc models, standardized management protocols for severe traumatic brain injured patients are low-cost process-targeted intervention strategies that may improve clinical outcomes. understanding the differences in processes of care within the context of icu structure is necessary to better understand mortality differences observed between centers, and may help in the design of future trials for severe tbi patients. complex multidisciplinary care of patients in the neurocritical care unit requires reliable and effective communication to minimize medical errors. we implemented a structured rounding process that incorporates ahrq-endorsed team strategies and tools to enhance performance and patient safety (team stepps) to improve interprofessional collaboration between team members. we convened a project team of physicians, advanced practice providers (apps), nurses, respiratory therapists, and pharmacists in a -bed nicu. we defined structured rounding processes and implemented team stepps strategies to promote closed-loop communication between team members during daily rounds. the assessment of interprofessional team collaboration scale (aitcs-ii) was administered to team members at baseline and months post-intervention. impact on overall team collaboration and subscale domains of team partnership, cooperation and coordination was assessed. the possible range of the overall collaboration score is to ; higher scores indicate better collaboration. the survey was completed by ( %) staff at baseline, and ( %) staff post-intervention. overall team collaboration scores improved significantly pre and post-intervention ( . ± vs . ± , p < . ), as did subdomain scores of team partnership ( . ± . vs . ± . , p < . ), collaboration ( . ± . vs . ± . ), and coordination ( . ± . vs . ± . ., p < . ). perceived shared understanding of patient daily goals between nurses and providers (physicians/apps) increased from % to % (chi-square . ; p < . ). % of staff reported that the intervention shortened or did not affect the duration of rounds. of those who reported longer duration of rounds, % responded that the intervention was worthwhile. interprofessional team collaboration can be enhanced by structured rounding and communication workflows. by promoting closed-loop communication during daily rounds, shared understanding of patient daily goals between team members is increased, and may optimize quality and safety of patient care. advanced practice providers (apps) are increasingly utilized to provide clinical care within neurocritical care units (nsicu) . despite the complex issues in this patient population, the specific educational and orientation needs of these providers have not been established. to meet the demands for rapidly and effectively training apps to provide advanced neurocritical care (ncc), a structured educational curriculum was developed and integrated within the standard orientation and on-boarding process for newly-hired app within our nsicu. this curriculum was designed with measurable learning goals, objective assessments of goal achievement, and opportunities for additional education and remediation at multiple steps within the program. the curriculum has three phases with distinct goals and assessments. phase i covers basic triage and resuscitation issues for the acutely-decompensating patient. phase ii covers general critical care principles in significantly greater depth. phase iii provides detailed experience and exposure to specific ncc issues. each phase incorporates relevant reading assignments with a tailored study guide, as well as a multiple-choice question post-test to demonstrate knowledge acquisition. phases ii and iii also include an oral exam incorporating hypothetical patient scenarios to allow the app to demonstrate comprehension and application of the goals for each phase. each phase lasts approximately to weeks with the expectation that the entire orientation curriculum will be completed within six months of employment. in addition to the educational curriculum, phases i and ii include working alongside a more senior app preceptor and providing bedside care for a progressively increasing number of patients. apps not meeting minimum established standards on any aspect of the curriculum are provided additional remediation and instruction by the preceptor and ncc faculty based on an individualized learning plan. a standardized educational curriculum provides a structured learning environment for new apps in the field of neurocritical care. reimbursement changes from the centers for medicare and medicaid services and value based purchasing systems have made quality improvement linked to clinical outcomes more crucial than ever. in one neuroscience icu, providers and nurses collaborate to address key infection parameters that impact patient outcomes. quality metric data in one neuroscience icu was collected over a period of fiscal years. outcome measures, consisting of glycemic and temperature control, and ventilator weaning strategies, were obtained after certain parameters were enforced over two years and then compared to the initial year. the urinary catheter utilization has decreased by over %, with catheter associated urinary tract infections decreased by % in years (p-value < . ). central line utilization decreased by %, with a % decrease in central line associated blood stream infections in years (p-value . ). new ventilator weaning strategies were put into place utilizing adaptive support ventilation mode, which decreased total ventilator days by days/year . successful weaning and extubations resulted in no recorded ventilator-associated pneumonia in the last years. this neuroscience icu maintains glucose below mg/dl more than % of the time. regarding temperature control data, a normothermia protocol was implemented that utilizes aggressive temperature control coupled with bromocriptine administration. as a result, % of patients had a temperature less than °c. all of the quality initiatives that have been implemented have improved the observed/expected mortality ratio by . %. this study shows that by optimizing infection control, temperature management, glycemic control and ventilation strategies, there is an overall positive impact on the patient's morbidity and mortality. as evidenced by these results, this institution is now a top performer when compared in a national clinical database. this presentation will share the pragmatic strategies to create a culture of quality improvement in any neurocritical care unit or patient care organization. health care records are not accessible universally at point of care delivery. in developing countries like thailand a large proportion of health care records are still paper based. patients may not able to convey relevant information about their own medical problems and medications during patient-physician encounters or in the event of emergency. our purpose was to create a simple platform for recording relevant basic healthcare information through a system that can be securely accessed even in countries like thailand. our vision is to improve healthcare communications and leverage social media in thailand and other developing countries, particularly for patients with lower levels of education or socioeconomic status. we created a cloud-based personal healthcare information platform 'meid' that uses a qr code scanned from wristbands and other products like stickers to access patient information. conventional methods require a treating team to request medical records from a patients' prior hospital visits including visits at different medical facilities. time lost during this process can potentially cause delay in treatment decisions. we also aim to improve health literacy in thailand. application name 'meidth' is available in both apple store and google play. we launched meid in thailand in april of . we have more than , active users and have sold more than wristbands. the meid thailand facebook page has received , likes. there are at least two patients that have already benefited from this product: one of these patients received intravenous tissue plasminogen and had a good outcome. timely access to his past medical history and medications via meid was a key in this case. our cloud based personal healthcare information platform using qr codes from wristbands and stickers can help increase health literacy, decrease times to appropriate treatment, improve patient safety and decrease healthcare costs. clinical pharmacists have become an integral part of multidisciplinary medical teams. expanding the role of pharmacists in the neurocritical care units has the potential to positively impact the quality of patient care and provide costs savings. this study examines these potential benefits at one neurocritical care unit. we reviewed patient medication profiles and had formal rounds with a pharmacist four times per week. for the purposes of this study, the focus was on minimization of a select number of high expense drugs. nine months of baseline data was compared to three months of post intervention data. interventions were performed at the time of rounding, which involved timely conversion to enteral formulas, changes to alternative medications or discontinuation of medications. we then performed a cost-benefit analysis to assess the net amount of money saved by reducing inappropriate pharmacy drug use following the interventions. average cost of nicardipine was $ , pre-intervention, compared to $ , post-intervention (pvalue . ). the cost of iv levetiracetam usage on average was $ , pre-intervention and $ , post-intervention (p-value . ), while the cost of iv dexmedetomidine was $ pre-intervention compared to $ post-intervention (p-value . ). average expense per month was reduced by approximately $ , per month compared to the average expense per month from the previous months (p-value . ). appropriate use of stress ulcer prophylaxis was also positively impacted; patient days/month on famotidine was reduced by approximately % from baseline, patient days (pre-intervention) vs days post-intervention. pharmacist interventions within a neurocritical care unit are known to be beneficial clinically for patients, however this study also shows that their interventions offer substantial cost benefits and should justify creating collaborations between pharmacists and neurointensivists. multi-disciplinary rounds have been shown to improve patient outcomes. the objective of this study is to observe the effect on patient care, team dynamic, and nursing satisfaction before and after the implementation of a nursing-led rounding model in the neurological icu. prior to the implementation of the nursing-led rounds quality initiative, nurses in the neurointensive care unit (nicu) were asked to answer a brief survey on basic demographics and perceptions of team dynamics and satisfaction in the nicu. a multidisciplinary systems-based rounding sheet inclusive of the abcdef bundle and previous nicu checklist was created and revised with extensive bedside and senior nursing educator input. while rounding, nurses presented and clinicians were to in real-time come up with an assessment and plan and relay these to the nurse and other team members. any questions, educational pearls or concerns by the clinician team or the bedside nurse were encouraged during these rounds. nurses completed a month post-implementation survey. of the full-time nicu nurses ( %) responded to both the pre-implementation and postimplementation surveys. a bimodal distribution of nursing experience was noted with % new nurses (< year) and % experienced nurses ( years+). more than half of the nurses ( %) reported doing both night and day shifts as opposed to being exclusive to only day or night. there was an increase in the nursing perceptions of participation during rounds as well as education during rounds. nurses felt significantly more involved with patient decision making and felt that they were able to give input into the patients care. the implementation of a nursing-led rounding structure may be beneficial to communication, education and overall patient care. as the project continues, we hope to further examine common icu objective measures as well as other subjective measures such as patient satisfaction scores and communication perceptions. with increased elective and non-elective volume, directing the flow of admissions has become essential to the efficient operation of inpatient strategic service lines. this is especially true in the neurosciences where widespread acute ischemic stroke intervention has placed an especially high demand on comprehensive stroke centers. as a result, an important collaboration was formed at duke between the health system, transfer center and neurosciences to create an algorithm-driven multi-hospital triage and pre-hospital care system called phast (pre-hospital acute services team). in this abstract, we present the formation and current state of this service. this effort was formally begun in the spring of with an initial focus on centralizing the admission process into the duke neurosciences intensive care unit (neuroicu) by an icu physician. after some initial success, it was clear that the service line would benefit from a more formalized process. as a result, a successful multidisciplinary collaboration with a core group of physicians and administrators was formed to develop algorithms and to overcome multiple administrative and legal hurdles. over a period of months, multiple algorithms were developed to systematize neuroscience admissions including acute ischemic stroke and vascular and non-vascular neuroscience emergencies. in an effort to decrease door-to-intervention times as well as effectively mitigate the impact of limited bed-space availability, this system now serves hospitals including with acute neurointerventional services and the rd with a burgeoning neurohospitalist program and incorporated rehabilitation services. in addition to systematizing the transfer and admission process, quality assurance, improvement, and educational processes are in a place. the current state of phast is that of a young but maturing and now essential service for duke neurosciences. extubation involves removal of an endotracheal tube (ett) and is a common intensive care unit (icu) procedure. extubation failure occurs in - % of icu patients and can be difficult to predict accurately. we hypothesized that a multivariate re-intubation scale calculation (risc) model could predict extubation failure better than a single variable like rapid shallow breathing index (rsbi). after irb approval, we conducted a retrospective review of data on mechanically ventilated icu patients above years of age who were not receiving mechanical ventilation through a tracheostomy tube from january , , through december , at mayo clinic rochester. various data points were gathered on these patients via electronic medical records search, and reintubations within hours of extubation were identified. univariate and multivariate logistic regression models were used to predict reintubation after extubation and construct a risc estimate. we included a total of patients which were randomly divided into a derivation set (n= ) and validation set (n= ). in the derivation set, patients had a mean age of ± years, and % were men. three hundred and ninety three extubation failures occurred within hours. predictors of extubation failure included underweight status, gcs score>= , mean airway pressure at minute= ml and total mechanical ventilation days>= in the final multivariable model. risc score was calculated using the validation set and ranged from to . logistic model result shows that, as risc increased by , the odds of having extubation failure was . fold higher (c-index= . ). roc analysis shows that the best cut off for risc was >= vs. < , which demonstrated a sensitivity of . , specificity of . and auc= . . the current risc model warrants further exploration in a prospective study to help critical care providers to decide when extubation can be done more safely. this report presents results of the nd nationwide survey concerning neurocritical care units (ncus) in china. this is an observational cross-sectional survey and close-ended self-reported questions were used. the questionnaire was sent to different provinces (autonomous regions and municipalities) across china from october st, to january st, . basic information, equipment and device information, and staffing and organization information were investigated. in total, questionnaires from ncus at hospitals in regions were received. most of the hospitals with ncus were large-scale (average hospital beds: ), teaching ( . %), and tertiary hospitals ( . %). the average number of ncu beds was , occupying . % of the total number of beds in their department. most of the equipment and devices ( / ) were available in over % of the ncus. however, some devices were centralized by hospital and operated with assistance from other departments. a total of full-time doctors and full-time nurses were employed at the ncus. a few of the ncus achieved a doctor-to-bed ratio of . : ( . %) and a nurse-to-bed ratio of : ( . %). and respiratory therapists, clinical dieticians, clinical pharmacists, and physiotherapists were present in . %, . %, . % and . % of the ncus. the number of ncus increased, the availability of ncu equipment became more sufficient, and the staffing of ncus improved. however, we should pay attention to the management of specialized ncu equipment, the shortage of ncu staff, and the need of ncu training. automated devices collecting quantitative measurements of pupil size and reactivity are increasingly used for critically ill patients with neurologic disease. however, there is limited data on the effect of ambient light conditions on pupil metrics. to address this issue, we we tested the range of pupil reactivity in healthy volunteers in both light and dark conditions. we measured quantitative pupil size and reactivity in seven healthy volunteers with the neuroptics- pupillometer in both bright and dark ambient lighting conditions. bright conditions were created by overhead led lighting in a room with ample natural light. dark conditions consisted of a windowless room with no overhead light source. the primary outcome was the neurologic pupil index (npi), a composite metric ranging from - in which > is considered normal. secondary outcomes included resting and constricted pupil size, change in pupil size, constriction velocity, dilation velocity and latency. results were analyzed with multi-level linear regression to account for both inter and intra-subject variability. seven subjects underwent ten pupil-readings in bright and dark conditions, yielding total measurements. mean resting pupil sizes were . v. [ . - . ], p< . ). all additional secondary outcomes except latency were also significantly different between conditions. we found that ambient light levels impact pupil parameters in healthy subjects. however, changes in npi are small and more consistent in varying lighting conditions than other metrics. further testing of patients with poor pupil reactivity is necessary to determine if ambient light conditions could influence clinical assessment in the critically ill. practitioners should standardize lighting conditions to maximize the reliability of their measurements. neural stem cells (nscs) are known to have anti-inflammatory effect in strokes in previous studies. however, the mechanism of anti-inflammatory effect in direct co-culture with nscs in hemorrhagic stroke remains unclear. the aim of this study was to investigate whether direct co-culture with nscs modulates hemolysate-induced inflammation in raw . cells. we stimulated raw . cells with hemolysate to induce hemorrhagic inflammation in vitro. hemolysate-activated raw . cells were co-cultured with hb .f directly for hours. following direct co-culture, the production of cycloxygenase- (cox- ), interleukin-signal regulated kinase (erk) were assessed by western blotting, and tumor necrosis factor (tnfevaluated by enzyme-linked immunosorbent assay (elisa). hemolysate generates an activation of inflammatory response in raw . cells. direct co-culture with hb .f significantly suppressed the phosphorylation of erk / in hemolysate-activated raw . cells. the expression of inflammatory mediators such as cox- , il-by direct co-culture with hb . f cell. in addition, the expression of cox- , il-attenuated by erk inhibitor (u ). our results demonstrated that direct co-culture with hb .f cells reduced the inflammatory responses in hemolysate-activated inflammation via suppressing erk / pathway. this suggests that nscs treatment can suppress the inflammatory response in hemorrhagic stroke. no pharmacological intervention improves outcomes after primary intracerebral hemorrhage (ich). we developed a novel therapeutic approach based on known biological function of endogenous apolipoprotein e (apoe). apoe is a key mediator of neuroinflammatory responses and modifies recovery from a variety of acute and chronic brain injuries. unfortunately, intact apoe holoprotein does not cross the blood brain barrier (bbb) and cannot be administered as a neurotherapeutic. we created apoemimetic peptides that cross the bbb and down-regulate neuroinflammatory responses in vitro and in vivo. cn- , our lead candidate, is a -amino acid apoe-mimetic peptide derived from apoe's receptorregion. cn- retains anti-inflammatory and neuroprotective effects of intact apoe, was well-tolerated in preclinical studies, readily crosses the bbb, and demonstrates excellent pharmacokinetic, safety, and tolerability profiles in phase studies. this is a multicenter, open-label phase a trial of cn- in patients with acute primary supratentorial ich. a total of participants between the ages and years across study centers, with a confirmed radiographic diagnosis of spontaneous, primary supratentorial ich. patients will be evaluated for eligibility within hours of symptom onset. eligible participants will receive cn- intravenously over --minute infusion every hours up to day maximum. participants will be monitored daily throughout the treatment phase and receive standard-of-care treatment for the duration of the study. primary: to assess safety of cn- administration in primary ich. secondary: to evaluate effects of cn- administration on --day mortality and functional outcomes. exploratory: to investigate feasibility of radiographic surrogates of clinical outcomes using perihematomal edema measurements on serial brain ct and mri, and investigate feasibility of serial biochemical markers of neuroinflammation as surrogate measure of perihematomal edema and clinical outcome. cn- represents a first-in-class agent now entering phase clinical trials in patients with acute ich. novel oral anticoagulant (noac) associated intracranial hemorrhage is a life-threatening condition for which activated prothrombin complex concentrate factor eight inhibitor bypassing activity (feiba) may be used for reversal. few studies report its use in spontaneous or traumatic intracranial hemorrhage. our institutional protocol is reversal with feiba units/kg and escalating doses as needed. the safety and efficacy of this protocol was assessed. we performed a retrospective review of adult patients presenting to a level trauma center between - with spontaneous or traumatic intracranial hemorrhage while on a noac . we evaluated the medication they presented on, indication for anticoagulation, location and size of the hemorrhage, presentation gcs, dosage of feiba recieved, change in size of hemorrhage on serial imaging as well as time between serial images, complications from reversal, and need for blood product transfusion. we identified patients with an acute intracranial hemorrhage while on noacs. patients underwent a baseline head ct documenting acute intracranial blood, were reversed with feiba ( u/kg), and underwent repeat imaging hours later per protocol. ten ( %, / ) patients had no increase in hematoma volume on repeat imaging. two underwent neurosurgical procedures (aneurysm coiling, sub-occipital craniectomy) without intra-operative bleeding complications. five ( % / ) patients had clinically insignificant increase in size of hemorrhage. of those, one underwent a subsequent neurosurgical procedure, which was already anticipated. two ( %, / ) patients had clinically significant hematoma enlargement. of those, one underwent urgent craniectomy (indicated based on initial presentation) and one required a ventriculostomy for hydrocephalus. two patients had no repeat imaging. adjusted dose feiba ( units/kg) may be an effective alternative to standard dose ( unit/kg) for reversal of noacs in acute intracranial hemorrhage. our experience showed clinically significant hematoma expansion in % of patients and no increase in unplanned neurosurgical procedures after reversal with feiba. here we sought to determine if there is an association between recanalization success and rate of hemorrhagic transformation amongst patients who have undergone intra-arterial thrombectomy for ischemic stroke secondary to anterior circulation large vessel occlusion (lvo), many treated at extended time from last seen well (lsw) after mri assessment. stroke patients with anterior circulation lvo treated with thrombectomy between april, to june, were studied. group-wise comparisons were made between patients with post thrombectomy hemorrhage (as confirmed by a single, blinded neuro-radiologist reviewer) and patients without hemorrhage. failed or incomplete recanalization was defined as mtici < b. symptomatic intracranial hemorrhage (sich) was defined as validated hemorrhagic conversion or parenchymal hematoma plus point decrease in nihsss. pertinent baseline characteristics were recorded and analyzed. sich was more prevalent amongst patients with tici< b recanalization (or . [ ci . - . ]). interestingly there was a low rate of sich amongst patients with tici= recanalization ( / [ . %]). although many patients were treated at advanced time lsw no excess rate of sich was observed. baseline characteristics including age, presentation nihss, and presentation aspects were similar among the two groups. rates of sich are low after successful mri seleted thrombectomy regardless ot time lsw. patients with poor recanalization show increased rates of sich in keeping with past literature. our data suggest that thrombectomy after mri selection may be safe and effective for patients at extended time lsw of tor patients with unknown lsw. cta spot sign is associated with hematoma growth, a common complication of intracerebral hemorrhage (ich) that portends worse outcomes. magnesium and calcium are cofactors in the clotting cascade and for platelet aggregation. we tested the hypothesis that magnesium and calcium levels are associated with the presence of the cta spot sign. patients with spontaneous ich presenting to northwestern memorial hospital were identified from a prospective observational registry. inclusion criteria included cta obtained within hours of symptoms onset and admission magnesium and calcium levels. cta spot sign (active contrast extravasation on ct angiography) was identified by a board-certified neurointensivist or neuroradiologist. variables suggesting association with spot sign at p< . were assessed for inclusion in a logistic regression model, and a parsimonious predictive model for ct spot sign was developed using backward stepwise variable selection. patients (age ± . years, % male, median ich score [iqr - ]) were included. seventeen ( . %) patients with cta spot sign were identified. admission magnesium was . +/- . and calcium was . +/- . . lower magnesium (or . , % ci . - . , p . ), lower calcium (or . , % ci . - . , p . ), and higher ich score (or . , % ci . - . , p . ) were independently associated with ct spot sign. magnesium and calcium level on admission are associated with the presence of a cta spot sign in patients with ich. magnesium and calcium supplementation may be attractive therapeutic targets for preventing harm from hematoma growth. cerebellar intraparenchymal hemorrhage (iph) is a rare and likely underreported complication of subdural hematoma (sdh) evacuation. we present two cases of post-operative iph and review the literature. case . an -year-old man underwent craniotomy for evacuation of a chronic right frontoparietal sdh. post-op ct showed pneumocephalus. the patient was extubated and clinically improved. three days post-operatively, he became lethargic and a ct brain revealed a cc right cerebellar iph. he was unable to safely swallow, declined a feeding tube and died under hospice care nine days later. case . a year-old man underwent craniotomy for evacuation for a left convexity sdh. routine post-op ct revealed an incidental left cerebellar iph. he returned to baseline one month later. only four such cases have been reported in the literature ( - ). two cases led to death within one week and two recovered, one with significant deficits. five more occurred following burr hole drainage of sdh and two others following drainage of subdural hygromas ( , - ). the incidence of cerebellar iph following supratentorial craniotomy has been reported in up to . % of cases with significant morbidity or mortality ( ). it occurs irrespective of age, pre-existing coagulopathy or arteriovenous malformations. size of insult and amount of csf loss do not correlate to iph, despite the fact that cerebral blood flow imaging shows over-drainage of cerebrospinal fluid (csf), causes intracranial hypotension and subsequent damage to dural veins ( , ). iph also occurs independently of operating room position, even though having the head turned is thought to compress venous drainage in the neck and cause congestion ( ). cerebellar vasculature may be more sensitive to changes in intracranial pressure, though why this does not lead to complications more routinely is not clear. cerebellar iph should be considered in cases of neurological decline after sdh evacuation. intracerebral hemorrhage (ich) location predicts outcome, but most studies have examined differences between deep, lobar, and infratentorial locations. this study aims to characterize specific deep ich locations in a diverse cohort. the ethnic/racial variations of intracerebral hemorrhage (erich) study is a multi-center, prospective, u.s.-based study. subjects with supratentorial deep ich, known ich volume, and three-month follow-up data were included. logistic regression was used to evaluate the association between location and poor outcome (mrs > ). receiver operating curve (roc) analysis was performed to identify ich volumes specific for poor outcome by location. thalamic, putaminal, and caudate ichs were included. median ich volume was largest in putamen ( ml), followed by thalamus ( ml) and caudate ( ml, p<. ). intraventricular hemorrhage (ivh) was most prevalent in caudate ( %), followed by thalamus ( %) and putamen ( %, p < . ). subjects with thalamic ich were older ( vs vs years, p < . ) and more likely hypertensive ( % vs % vs %, p= . ) than those with putaminal and caudate ich, respectively. compared to thalamic, putaminal ich had more ich expansion ( % vs %, p < . ) and surgery ( % vs % p = . ) but fewer external ventricular drains ( % vs %, p < . ). thalamic location predicted poor outcome (or . , % ci . - . ) at days after adjustment for age, sex, premorbid disability, ich volume, ich expansion, ivh, and admission gcs. roc analysis identified ml for thalamic and ml for putaminal ich without ivh as having % specificity for poor outcome. there are significant differences in characteristics and outcomes within deep ich. specificity estimates for the identified ich volume thresholds require external validation. these findings may have implications for prognostication and clinical trial design. racial differences in outcome after intracerebral hemorrhage (ich) among asians, native hawaiians and other pacific islanders (nhopi) have been inadequately studied since these racial groups have been historically aggregated into a single racial category. a multiracial prospective cohort study of ich patients was conducted from to at a tertiary center in honolulu, hi to assess racial disparities in come after ich. favorable outcome was defined as month modified rankin scale (mrs) score £ . patients with no available -month functional outcome, race other than asians and nhopi, and baseline mrs > were excluded. multivariable analyses using logistic regression were performed to assess the impact of race on favorable outcome after adjusting for the ich score, early do-not-resuscitate (dnr) order and dementia/cognitive impairment. a total of patients ( asians, nhopi) were studied. overall, ( . %) achieved favorable outcome at months. nhopi were younger than asians ( . ± . vs. . ± . years respectively, p< . ), and had higher prevalence of diabetes ( . % vs. . % respectively, p= . ), obesity ( . % vs. . respectively, p< . ), and lower prevalence of early dnr order ( . % vs. . % respectively, p= . ) and advance directive presence ( . % vs. . % respectively, p= . ). nhopi race was a predictor of favorable outcome in the unadjusted model (or . , % ci: . , . ) and after adjusting for the ich score (or . , % ci: . , . ) but not in the final model (or . , % ci: . , . ) . in the final model, the ich score remained as the only independent negative predictor of outcome (or . , % ci: . , . per point). nhopi are more likely to achieve favorable functional outcome after ich compared to asians even after controlling for ich severity. however, this association was attenuated after adjusting for dnr status and baseline cognitive factors. intracerebral hemorrhage (ich) patients often require continuous antihypertensive infusions. we sought to identify clinical and care process predictors of anti-hypertensive infusion duration, and tested whether infusion duration independently predicts intensive care unit length of stay (icu los) after adjusting for validated measures of ich illness severity. we identified spontaneous ich patients admitted / - / to a tertiary center, excluding those transitioned to comfort care within hours. we abstracted demographic and clinical variables from the medical record. we calculated the total duration each patient received continuous infusion of an antihypertensive medication. we categorized glasgow coma scale score as - ; - ; or < . two reviewers independently classified ich location and etiology. we determined univariate associations of clinical variables to anti-hypertensive infusion and performed regression analysis to determine the effect of continuous infusion on icu los. we identified spontaneous ich patients and excluded for early comfort care. in the remaining , mean age was [ - ] years, % were female, median ich score was [ - ], and % had lobar hemorrhages. continuous infusion included nicardipine, clevidipine, labetalol and diltiazem. a total of ( %) patients received anti-hypertensive infusions, mean hours. mean time to enteral antihypertensive administration medication was . hours, and mean icu length of stay was . days [ . - . ]. predictors of longer antihypertensive infusion duration were male gender (p= . ), non-lobar ich (p= . ), non-caucasian race (p< . ), younger age (p< . ), higher initial systolic (p= . ) and diastolic bp (p= . ), worse gcs category (p< . ), and longer time to first enteral medication (p< . ). anti-hypertensive infusion duration independently predicted icu los (p< . ) after adjusting for age, race, gcs category, time to enteral antihypertensives, and ich score. worse gcs category, younger age, non-lobar ich location, and race are significant independent predictors continuous iv antihypertensive infusion duration, which is significantly associated with longer icu stay. patients with sich have a high risk of vte. pharmacological prophylaxis such as unfractionated heparin(ufh) has been demonstrated to reduce vte. however, published datasets exclude patients with recent ich out of concern for hematoma enlargement. aha/asa guidelines recommend ufh - days after hematoma stabilization while the eso has no recommendations on timing of ufh. there are few data for patients who received ufh before hours. our institutional practice is to begin ufh following sich after hours of clinical and radiographic stability. we examine the impact of this practice on risk of hematoma expansion. we performed a retrospective cohort analysis of sich patients admitted in - to a single us university hospital. demographic and clinical characteristics were abstracted. ich was measured via d volumetrics for an admission ct, a hour follow-up, and a follow-up prior to discharge. percent hematoma growth between -hour ct and discharge ct was calculated. risk factors for expansion > %, including early heparin use, were analyzed via oneway t-test and chi-squared tests. results sich patients analyzed had a median ich score of (iqr - ) and median admission gcs of (iqr - ). %( / ) patients received early ufh. %( / ) suffered hematoma expansion > %. overall mean hematoma growth was higher with early ufh (ufh hr - %,p= . ). in multivariate analysis, ich score, gcs and initial hematoma size did not predict > % hematoma expansion. early vte prophylaxis at hours from sich had a statistically significant increase in hematoma size, but this increase is clinically insignificant. in this cohort, early ufh did not increase risk of significant hematoma expansion. further prospective trials are warranted, given the high risk of vte in this population. antiplatelet therapy at the time of spontaneous intracerebral hemorrhage (sich) may increase the risk of hemorrhage expansion and mortality. current guidelines recommend consideration of a single dose of desmopressin in sich associated with cyclooxygenase- inhibitors or adenosine diphosphate receptor inhibitors. this study sought to compare outcomes in patients that received desmopressin for antiplatelet reversal in the setting of sich to similar patients that did not receive desmopressin. this retrospective chart review of the electronic medical record included adult patients admitted for sich that were on antiplatelet agents at the time of diagnosis. patients that received desmopressin were compared to similar patients that did not receive desmopressin. exclusion criteria included traumatic brain injury, active coagulopathy and thrombocytopenia. the primary outcome was the incidence of hematoma expansion. additional outcomes included average increase in hematoma volume, in-hospital mortality and functional outcome at hospital discharge. overall, patients ( received desmopressin, did not receive desmopressin) were included for analysis. incidence of hematoma expansion was not different between groups ( % with desmopressin vs % without desmopressin, p= . ). average largest increase in hematoma volume on follow-up imaging from baseline was not different ( . ± . ml with desmopressin vs . ± . ml without desmopressin, p= . . in-hospital mortality was significantly higher in the desmopressin group ( % vs % without desmopressin, p= . ) as well as the incidence of a modified rankin score of - at discharge ( % vs % without desmopressin, p= . ). administration of desmopressin for antiplatelet reversal in sich does not appear to reduce the incidence of hematoma expansion. further studies assessing temporal relation of desmopressin administration and hematoma expansion are needed to confirm the results of this single-center retrospective study. clinical outcome after intracerebral hemorrhage (ich) remains poor. definitive phase- trials in ich have failed to demonstrate improved outcomes with intensive systolic blood pressure (bp) lowering.we sought to determine whether other bp parameters-diastolic bp, pulse pressure (pp), and mean arterial pressure (map)-showed an association with clinical outcome in ich. we retrospectively analyzed a prospective cohort of patients with spontaneous ich and documented demographic characteristics, stroke severity, and neuroimaging parameters. consecutive hourlybp recordings allowed for computation of systolic bp, diastolic bp, pp, and map. threshold bp values that transitioned patients from survival to death were determined from roc curves. using inhospital mortality as outcome, bp parameters were evaluated with multivariable logistic regression analysis. patients who died during hospitalization had higher mean pp compared to survivors ( . ± . mmhg vs. . ± . mmhg; p= . ). the following admission variables were associated with significantly higher in-hospital mortality (p < . ): poorer admission clinical condition, intraventricular hemorrhage, and increased admission normalized hematoma volume. roc analysis showed that mean pp dichotomized at . mmhg, provided a transition point that maximized sensitivity and specific for mortality. the association of this increased dichotomized pp with higher in-hospital mortality was maintained in multivariable logistic regression analysis (or . ; %ci . - . ; p < . ) adjusting for potential confounders. widened pp may be an independent predictor for higher mortality in ich. this association requires further study. a national confidential enquiry into patient outcome and death (ncepod) report concerning management of aneurysmal subarachnoid haemorrhages in the uk suggested up to half of patients received suboptimal consideration for organ donation. as demand for organs continues to increase, so does the need to pursue all potential sources of donor organs. subarachnoid haemorrhages have an estimated mortality of % and can potentially provide younger donor organs with less chronic pathology. this is a comprehensive picture of donation rates within a tertiary centre. retrospective data regarding all deceased patients on the neuro-intensive care unit during with aneurysmal subarachnoid haemorrhage as the cause of death was obtained from the nhs blood and transfusion team. the local audit committee provided ethical approval. data regarding organ donation was extracted and compared to national data, then analysed using fisher's exact test. referral rates were %. this is greater than the national average of . % (p= . ), yet only . % of referred patients proceeded to organ donation. consent was withheld in . % of potential donors. nationally . % of donors are lost due to non-consent (p= . ). . % of consented patients were unable to donate organs, similar to national figures (p= . ). referral rates within this centre are excellent; consent remains the main obstacle. consent rates can be improved using a long contact model where specialist nurses in organ donation establish relationships with relatives prior to any discussion of donation. the ideal discussion is a pre-planned collaboration involving a senior doctor and a specialist nurse. early brain stem testing may facilitate earlier acceptance of death by relatives whilst reducing the duration of the multi-systemic effects of the associated hyperresponsive cascade on donor organs. neurosurgeons should be encouraged to suggest organ donation when declining referrals. further work is needed to assess the barriers to instituting these measures and inspiring change. spontaneous brainstem hemorrhage has been historically associated with high mortality. however, updated data on the frequency and outcome of spontaneous brainstem hemorrhage is scarce vis-a-vis advances in neuro-critical care. the purpose of this study was to investigate the frequency and outcome of spontaneous brainstem hemorrhage. records of consecutive intracerebral hemorrhage (ich) patients presenting to an urban academic medical center from january though december were reviewed. cases with brainstem hematomas were isolated for analysis. data on demographics and outcomes were collected and analyzed. sub-group analysis was also done to look at outcomes based on location of hemorrhage in the brainstem. of consecutive spontaneous ich patients, ( . %) presented with brainstem hemorrhage; ( . %) were pontine, ( . %) mesencephalic, and ( . %) were located in both the pons and the midbrain. the average age was . years and ( . %) were men. median glasgow coma scale on presentation was . . thirty-day mortality rate was . %, with in-hospital deaths and deaths post discharge. two and patients were discharged home or a rehabilitation facility, respectively. in subgroup analysis, thirty-day mortality for midbrain, pons and combined pons/midbrain hemorrhage was %, % and %, respectively. spontaneous brainstem hemorrhage remains an uncommon but highly fatal clinical entity. more than one-half die within days. only a minority are discharged to rehabilitation or home. in sub-group analysis, location of brainstem hemorrhage was shown to influence outcome, with % mortality in case of combined pons/midbrain hemorrhage, and more than % mortality with pontine hemorrhage. midbrain hemorrhage was associated with good outcome with % survival. patients with intracerebral hemorrhage (ich) frequently present with hypertension. it is unclear whether this is due to preexisting hypertension (prhtn) causing the bleed, an effect of the bleed, or both. we retrospectively analyzed a single-institution cohort of ich patients presenting between and . data included home antihypertensive use; asbp; tte, and ekg and imaging results; and nicardipine administration. the primary objective was to assess the relationship between prhtn and asbp, while the secondary objectives were to assess the relationship between prhtn, imaging and acute antihypertensive requirements. ich patients met inclusion criteria. in our assessment for prhtn, we found that % of patients were on antihypertensives, % had lvh on ekg, and % had lvh on tte. there was a significant relationship between lvh on tte and lvh on ekg (p< . ), but not between home antihypertensive use and presence of lvh using either modality. asbp was higher for all patients with markers of phtn, but this was only significant for patients with lvh on tte ( mmhg, iqr - vs. mmhg, iqr - , p < . ) and patients with lvh on ekg ( mm hg, iqr - vs. mm hg, iqr - , p< . ). all patients with markers of prhtn were more likely to require nicardipine, but this was only significant for patients with lvh on tte ( % vs. %, p= . ) and patients with lvh on ekg ( % vs. %, p= . ). all patients with markers of prhtn were more likely to have deep bleeds (p= . for patients with lvh on ekg vs. those without lvh on ekg). there was no relationship between any markers of prhtn and the presence of a spot sign. in patients with ich, prhtn is related to higher asbp, deep bleed location, and increased acute antihypertensive requirements. all spontaneous intracerebral hemorrhage (sich) patients, including those with low severity are uniformly admitted to the intensive care unit (icu) at our institution. many may not benefit from this high-intensity observation and leave the icu within hours without experiencing any complications. identifying low-risk characteristics could aid in triaging such patients to stroke units instead. retrospective data collection of all sich patients admitted to our institution from june , -june , included ich score, need for surgical interventions, medical complications, and icu/hospital los. we analyzed variables predicting short (< hour) icu los among low severity (ls-ich) patients (defined as those with ich score - ). ( %) of sich patients had ich scores of - , of which just under half ( ) had icu los hr. they also spent significantly fewer days in hospital ( vs . , p< . ). we could not identify a clear ich score cutoff that was sensitive enough to predict short icu los. however, requirement for antihypertensive infusion and early clinical deterioration correlated strongly with longer icu los p< . . there appears to be a subset of mild ich patients (ich score - ) who do not require icu observation. a risk assessment score incorporating gcs and ich volume may be able to delineate this low-risk population who could instead be admitted to a stroke unit, with the potential for significant cost saving and hospital efficiency. obesity has been linked with relative longevity in several disease conditions. this relationship has been termed the "obesity paradox." in this study we sought to evaluate the impact of obesity on short-term outcomes in patients with intracerebral hemorrhage (ich). patients admitted with a diagnosis of ich were selected from the - nationwide inpatient sample (nis) database, using icd- codes. patients with ich were dichotomized based on the presence of obesity as a coexisting diagnosis based on icd- codes and diagnosis related groups. the primary outcome measure was in-hospital mortality. length of stay and total charges were also examined as resource utilization measures. of obesity is a major health care burden as evidenced by higher resources utilization. counterintuitively, obesity appears to be associated with lower in-hospital mortality in ich patients. one possible physiological basis for this could be that the higher ldl levels on presentation result in a lower likelihood of hematoma expansion. recent short-term outcome analysis indicates association of spontaneous intraventricular hemorrhage (ivh) related hydrocephalus with incontinence and gait dysfunction. we explore the association of hydrocephalus scores, intraventricular alteplase and clinical variables with these outcomes at long term follow up in survivors from the clear iii trial. clear iii, a randomized, multi-center, double-blinded, placebo-controlled trial was conducted to determine if pragmatically employed external ventricular drainage (evd) plus intraventricular alteplase improved outcome, in comparison to evd plus saline in patients with ivh causing obstructive hydrocephalus. we assessed hydrocephalus scores on survivors at diagnosis, days and . incontinence and dysmobility were defined using -month barthel index subscores (< for bladder and < for mobility, respectively). outcome measures were predictors of incontinence and gait dysmobility at year after ich. this prospective observational study analyzed consecutive ich-patients (n= ) treated at the neurological and neurosurgical departments of the university-hospital erlangen, germany over a month inclusion period ( / - / ). we analyzed the influence of patient characteristics, inhospital measures and functional status on treatment recommendations and on oac initiation during -month follow-up. clear treatment recommendations by attending stroke physicians seem necessary to ensure oac initiation after ich. oac showed beneficial associations; however data here suggests the presence of an indication bias introduced by treatment recommendations and outpatient care during follow-up. therefore, observed association with age and functional status might affect unadjusted analyses. although recently, non-vitamin k antagonist oral anticoagulants (noacs) therapy in patients with non valvular atrial fibrillation have half the incidence of intracerebral hemorrhage (ich) compared to warfarin. however, it would be still controversial subject that outcome of noac-associated ich (nich) might be worse or better than warfarin-associated ich (wich). in this study, we investigated clinical outcome and radiological finding of ich between two different anticoagulation treatments. retrospective review of medical records was performed for , patients who admitted with ich from to in seoul national university bundang hospital. clinical characteristics, functional outcome, location and volume of ich, and all-cause mortality within days were analyzed. among those patients, patients with wich and patients with nich were included. lesion location was common in supratentorial deep area ( . %, . %), lobar area ( . %, . %) and brainstem and cerebellum ( . %, . %) in the nich and wich group, respectively. no significant difference found in initial nihss ( . vs ), discharge nihss ( . vs ), mrs ( to ) at discharge ( . % vs . %), mrs ( to ) at discharge ( . % vs . ), mrs ( to ) at days ( . % vs . ) and mrs ( to ) at days ( . % vs . ) in nich and wich group. we did not find any difference between nich and wich for allcause mortality at discharge ( % vs %), days ( . % vs %), and year ( % vs %). median baseline ich volume was not significant difference in two groups ( . vs . ). in our study, functional outcome, mortality, and baseline ich volume were similar following nich and wich. because of low statistical power due to small sample size in our study, further studies with prospective larger patient cohorts will need to be conducted. novel oral anticoagulants (noac) are increasingly used as an alternative to vitamin-k antagonists (vka) such as warfarin for anticoagulation and have shown lower rates of intracranial hemorrhage in several randomized clinical trials. it has been suggested that noac-iphs might be particularly dangerous, yet the literature regarding hematoma characteristics and outcomes between noac-iphs and vka-iphs is inconclusive. given the lack of standardized reversal strategies and lack of information on outcomes following noac-associated iph, the aim of this meta-analysis was to compare ) mortality; ) hematoma volume, and ) risk of hematoma expansion in patients who developed an iph on noacs versus vka. a meta-analysis of the literature through december was conducted using pubmed, embase and cochrane databases in accordance with prisma guidelines. pooled risk ratios (rr) were calculated for mortality and hematoma expansion and pooled mean difference (md) was calculated for hematoma volume (ml) using random-effect (re) and fixed-effect (fe) models. noac-iph was not associated with increased mortality (re and fe: rr: . ; %-ci: . ; . , i = . %, p-heterogeneity= . ; studies) and hematoma expansion (re and fe: rr: . ; %-ci: . ; . , i = . %, p-heterogeneity= . ; studies) compared to vka-iph. the hematoma volume of noac-iph was smaller than vka-iph (re: md: - . ml; %-ci: - . ; - . , fe: md: - . ml; %-ci: - . ; - . ; studies), but with considerable heterogeneity that could not be alleviated (i = . %, p-heterogeneity . ). noac-iph was not associated with increased mortality or hematoma expansion compared to vka-iph and may be associated with a smaller hematoma volume. controversy exists regarding blood pressure (bp) reduction and perihematomal ischemia (phi). we investigated the association of acute bp reduction and presence of qualitative and quantitative phi in a large prospective cohort of intracerebral hemorrhage (ich). consecutive patients from the prospective nih funded dash study (> years, primary spontaneous ich) were included. phe volume was outlined on t /flair and ich volume on gre; these and adc were co-registered. tissue characteristics was defined as: ce = adc x - mm /sec. the association of clinical, radiographic factors and bp at baseline and hours with qualitative perihematomal and/or remote ischemia (i.e. dwi bright adc dark) and quantitative ce on adc were determined. patients ( % female) with mean age ± , and nihss (iqr , ) were included. mri time was . hours (iqr , ). % had lobar ich. ich volume was cc (iqr , ). % had perihematomal ( %) or remote ischemia ( %). % of patients had areas of perihematomal adc cc) was associated with higher absolute ( ± mm hg, p= . ) and relative ( % ± % vs % ± %, p= . ) map reduction, younger age (p= . ), h/o tia/stroke (p= . ) and larger ich volumes ( vs cc) (p< . ). in multivariate analysis, map reduction was not significantly associated with ce whereas ich volume was (p= . ). perihematomal and remote ischemia is frequently seen after ich, but the severity of phi is small and of unclear significance. bp reduction may be associated with phi but this was not an independent predictor. introduction: patients with left ventricular assist devices (lvads) receive anticoagulation and antiplatelet therapy to prevent pump thrombosis. consequently, neurological events including intracranial hemorrhage (ich) are one of the most feared causes of morbidity and mortality in these patients. there is little evidence to guide initiation of anticoagulation after such ich events. methods: this is a retrospective, single academic center analysis of lvad patients from - . the electronic medical record was reviewed after irb approval for the physiologic, laboratory, and radiographic data of these patients as well as survival or cause of death by days or by discharge. results: during the analysis, patients were reviewed, of which ( . %) had intracranial hemorrhage. one patient was excluded from analysis after care was transitioned to hospice, thus follow-up scans were not obtained. the remaining patients were receiving both aspirin ( - mg daily) and warfarin ( - mg daily) with an inr of . - . (mean= . ) at the time of ich. aspirin ( - mg daily) was resumed within - (mean= . ) days post ich. warfarin was resumed - (mean= . ) days post ich at - mg (mean= mg) with goal inr ( . - )-( - ) depending on device. there was death due to withdrawal of life support in setting of multiple comorbidities, though follow-up scan days post warfarin resumption revealed no evidence of rebleed. the remaining patients showed no evidence of rebleed on ct scans at months post warfarin resumption and were subsequently discharged to rehab facilities or home with modified rankin scores - (mean= . ). conclusion: in this review of lvad patients, about % suffered ich, and of those survivors aspirin was safely resumed within days and warfarin was safely resumed as early as days post-event. further studies are needed in order to establish safe practice guidelines and risk factors to prevent ich. intracerebral hemorrhage (ich) remains a devastating form of stroke, and perihematomal edema worsen outcomes after ich. recent studies have demonstrated the safety of minimally invasive surgery (mis) for hematoma removal, but the efficacy of mis in the treatment of ich is controversial. this study aimed to evaluate the effect of mis compared with medical treatment for basal ganglia ich. we retrospectively analyzed the clinical outcomes of prospectively collected data from two stroke centers. the treatment strategies of the two stroke centers for basal ganglia ich are different; one stroke center underwent mis and the other stroke center medically treated according to the current guidelines. we hypothesized that mis could reduce perihematomal edema and improve functional outcomes compared to medical treatment. primary outcome of this study was a modified rankin scale (mrs) at months after ich occurrence. a total of patients with basal ganglia ich were treated with different treatment strategies; patients underwent mis and patients received medical treatment. no statistically significant differences were found in age, sex, hematoma volume, and glasgow coma scale scores between the groups. a better functional recovery (mrs < ) at months was found in the medical treatment group than the mis group ( . % vs . %, p < . ). no significant differences were observed between groups in terms of mortality. our findings suggest that the best medical treatment improves functional recovery after basal ganglia ich compared to mis. these results are contrary to other studies of ich, and further randomized trials are required. perihematomal edema (phe) after intracerebral hemorrhage (ich) is thought to be predominantly vasogenic. the presence and extent of cytotoxic edema (ce) is controversial. we investigated phe diffusivity (phed) and factors associated with ce. consecutive patients from the prospective nih funded dash study (> years, primary spontaneous ich) were included. phe volume was outlined on t /flair and ich volume on gre; these and adc were co-registered. tissue characteristics was defined as: ce = adc x - mm /sec. clinical and radiographic factors associated with ce were determined. cytotoxic edema is detected in the perihematomal area, early after ich and is associated with younger age, larger ich and prior h/o tia/stroke. its clinical significance needs to be studied further. hemorrhagic stroke carries a high mortality rate and determining prognostic factors during initial presentation can aid redirecting intensive care unit (icu) management. we described the physiological profile and clinical outcomes of hemorrhagic stroke patients in a colombian icu. we retrospectively reviewed all hemorrhagic stroke patients admitted to our icu from - . clinical characteristics, outcomes, available laboratory values and hourly vital signs from the first hours in the icu were retrieved and analyzed. our primary stroke center admitted patients, ( %) were hemorrhagic. out of these, required icu management, representing % of the total icu admissions during this time frame. intracerebral hemorrhage (ich) was present in patients while subarachnoid hemorrhage (sah) was seen in . the latter had a median fisher score of . for all patients, the most common risk factors were hypertension ( . %), dyslipidemia ( . %) and smoking ( . %). icu mortality was . % ( . % with ich and . % with sah). mean sequential organ failure assessment (sofa) score was significantly greater in patients who died ( . vs. . , p< . ) and mean glasgow coma scale was significantly lower ( . vs. . , p< . ). vasopressors were required in patients ( . %), mechanical ventilation in ( . %), and half of the patients requiring either support therapy died. only patients ( . %) had fever in the first hours and all died. mean coefficient of variation for systolic, diastolic and mean blood pressure was significantly lower in patients who survived. mortality cases were more likely to have hypokalemia and hypomagnesemia than surviving patients ( . % vs. . % and . % vs. %, respectively). icu-admitted hemorrhagic stroke patients have a poor prognosis. sofa and gcs are accurate predictors of mortality. certain electrolyte disturbances, fever and a higher variation of blood pressure during the first hours were associated with a worse outcome. the association between worsening cerebral edema and unfavorable outcome in ich patients has been described in rcts. the objective of this analysis was to compare hospitalized spontaneous ich patients with and without perihematomal edema (phe) expansion and to evaluate relationships between hypertonic saline (hts) use, peak serum na, phe expansion, and short-term outcomes. we conducted a cross-sectional study of consecutive spontaneous ich patients admitted to a single center from / - / . head cts during the first week of admission, use of hts, and phe (using abc/ method) were evaluated. phe expansion of % or more was considered worsening edema. outcomes of interest included time to peak na, poor disposition (not home or inpatient rehabilitation), discharge mrs - , and in-hospital death. of ich patients, % experienced worsening phe. there was no difference in age, race, sex, arrival bp arrival, or vascular risk factors in patients with or without worsening phe. however, for each mm of midline shift (mls) present on initial head ct, odds of phe expansion was decreased by % (or . , %ci . - . , p= . ). mls on initial head ct was the best discriminator of phe expansion (auc . ( %ci . - . ). although hampered by small sample size, our data indicates that finding that ich patients with degree of mls on initial head ct is the best radiographic predictor of had lower odds of phe expansion. those without mls at presentation may be at risk of phe expansion, and counterintuitively may be those most in need of aggressive medical management. may suggest a role for intensive osmotherapy in patients with favorable imaging at presentation. intracerebral hemorrhage (ich) is a devastating stroke with high mortality rates. previous studies have shown a potential role of immune cells as a prognostication method. a high neutrophil to lymphocyte ratio was associated with poor outcomes after ich. we sought to determine whether absolute lymphocyte count(alc) at admission was predictive of outcomes in patients with ich. we performed a retrospective chart review of all patients admitted to our hospital with a diagnosis of ich from january to december .we collected baseline demographic characteristics, medical history, ich scores, differential leucocyte, platelet and total leucocyte(tlc) counts at admission. the functional outcomes after ich were measured using modified rankin scale (mrs) at discharge. mrs of and were considered poor outcomes. statistical analysis was done after grouping lab values into higher and lower groups with respect to the normal reference ranges a total of patients with ich were admitted to our center during the study period. patients were included in the study and the rest were excluded due to lack of differential leucocyte counts at admission. % ( of ) had poor outcomes. univariate analysis using fisher's exact test showed significant association between low alc levels ( . ) were also found to be significantly associated with worse outcomes (p = . , . , . , respectively). however, after multivariate analysis, only low absolute lymphocyte counts retained significant association (p = . ). intracerebral hemorrhage patients with low absolute lymphocyte counts at admission have a higher probability of poor outcomes at discharge. further studies are required to confirm our results. intraventricular hemorrhage (ivh) is a significant predictor of poor outcome after intracerebral hemorrhage (ich), and may differentially predict hydrocephalus and mortality among blacks vs. nonblacks. we aimed to confirm these findings in a separate cohort of spontaneous ich patients with severe ivh. the cleariii-ivh trial was a randomized, multi-center placebo controlled trial examining the effect of intraventricular alteplase versus saline, on outcomes in patients with spontaneous ivh. we retrospectively analyzed data on all patients, including self-reported race/ethnicity, medical comorbidities, presentation characteristics and functional outcomes. represented race/ethnic groups with > subjects per group were ( . %) white/non-hispanic (wnh), ( . %) white/hispanic (wh), ( . %) black/african american/non-hispanic (bnh), and ( . %) asian. bnh were significantly younger than rest of the cohort with median age [interquartile range] [ , ] years, had more hypertension( %, p= . ), and significantly higher rates of antihypertensive medication non-compliance ( . %, p= . ). wnh had more frequent coronary artery disease ( . %, p< . ), use of vitamin k antagonists ( . %, p= . ) and elevated inr on presentation ( . %, p= . ). bnh had significantly more frequent hydrocephalus on presentation ( . %, p= . ), and a higher rate of ventriculoperitoneal shunt placement ( %, p= . ). neither ich nor ivh volume at enrollment, nor ivh remaining at end of treatment differed significantly between race/ethnic groups. however, bnh patients were more likely to have greater than % ivh reduction, a recognized endpoint for better functional outcomes in cleariii ( . % vs. %-wh; . %-wnh; . %-asian; p= . ), and this difference persisted in those who received intraventricular alteplase (p= . ) and after adjustment for diagnostic ivh volume (p= . ). race/ethnicity was not an independent predictor of mortality or poor outcome at or days on multivariable logistic regression. although functional outcomes did not differ significantly among race/ethnic groups, differences in risk factors, hydrocephalus/shunting post ivh and response to thrombolytic therapy warrant further exploration. investigators from the randomized trial of unruptured brain arteriovenous malformations (avm) trial (aruba) reported in that interventions to obliterate unruptured avms resulted in greater morbidity and mortality compared to medical management. we investigated whether patterns of avm treatment changed after aruba's publication. we used inpatient and outpatient claims data from - from a nationally representative % sample of medicare beneficiaries. unruptured brain avms were identified using icd- -cm code . . the date of first avm diagnosis was coded as occurring before or on november , (online publication of aruba) versus after. outcomes were referral to a neurologist or neurosurgeon, and interventional treatment. interventional treatments were identified using cpt codes - , - , , , or - . the likelihood of outcomes after versus before aruba was compared using survival analysis with log-rank tests and cox proportional hazards models adjusted for age, sex, race, and the charlson comorbidity index. we censored patients at diagnosis of intracranial hemorrhage. we identified , patients with a mean . (± . ) years of follow-up after diagnosis of unruptured brain avm. diagnosis was most often by neurologists ( . %), neurosurgeons ( . %), and internal medicine specialists ( . %). after aruba publication, there were no changes in -year cumulative rates of referral to a neurosurgeon ( . % after, . % before; p = . ) or neurologist ( . % after, . % before; p = . ), but there was an increase in avm treatment ( . % after, . % before; p = . ). after adjustment for demographics and comorbidities, there was an increased likelihood of interventional management (hr . ; % ci, . - . ) after aruba's publication. in a nationally representative cohort of elderly patients, we found an increase in interventional avm management after publication of aruba. this is notable given that our data pertain to older patients who are generally seen as less suitable surgical candidates. elderly patients with severe intracerebral hemorrhage (ich) are often projected to have future functional dependence but unclear degree of cognitive recovery. surrogates for such patients frequently weigh multiple concerns when facing the difficult decision of whether to prolong life with tracheostomy and gastrostomy tube insertion versus pursue comfort care. we aimed to characterize distinct groups of surrogates in these situations, based solely on how they prioritize their concerns. subjects recruited from a probability-based us population sample completed an online best-worst survey that presented the above scenario and asked the respondent to prioritize concerns as the patient's surrogate. clusters were identified with latent class analysis after weighting data to match the us census demographic distribution. class solutions were replicated times from random starting seeds, with the solution chosen after factoring in akaike's information criterion. we identified distinct decisional groups among respondents (response rate = . %). all groups reported multiple concerns as important, but group ( . %) was more concerned than any other that the patient was too old to live with disability. group ( . %) focused on ensuring agreement among other family members. group ( . %) was concerned that the patient might suffer if tube feeding and iv fluids were stopped and that the prognosis could be incorrect. group ( . %) had numerous considerations that were comparably important but prioritized paying for long-term care. groups varied in whether they would actually request prolonging care for the patient (group = . %, g = . %, g = . %, g = . %, p< . ). in a multivariate model, religious affiliation and frequency of attending religious services were the only variables independently predicting group membership. we identified distinct profiles of decisional patterns for surrogates of severe ich patients with uncertain prognosis. these data will inform development of strategically tailored decision aids. cerebral venous sinus thrombosis (cvst) represents an important cause of both ischemic and hemorrhagic strokes in young people. while recent guidelines recommend management in a stroke unit, the impact of neurocritical care in this condition has not been studied. we aimed to assess whether the introduction of a neurocritical care program influenced clinical outcomes in cvst patients. we retrospectively reviewed electronic medical records of adult patients admitted to yale new haven hospital's neuroscience icu (nicu) between and with a diagnosis of cvst. demographics, vascular risk factors, comorbidities, length of stay and discharge modified rankin scale (mrs) were collected. patients were excluded for age hours of presentation. we compared two time periods, before (epoch , - ) and after (epoch , - ) the introduction of continuous staffing of cvst cases by neurointensivists in the nicu. univariable and multivariable logistic regression were utilized to model the odds of poor outcome (dichotomized mrs - vs - ). fifty-three patients with cvst met the inclusion criteria during the study period (mean age (+/- ) years, % female). patients were identified for epoch and patients for epoch . overall, patients ( %) had a good (mrs - ) outcome. for epochs and , good outcomes were observed in ( %) and ( %) patients, respectively (p= . ). in both univariable and multivariable regression analysis (adjusted for age and sex), admission during epoch was associated with a significantly reduced odds of a poor outcome (or . , ci . - . ; p = . ) and (or . , ci . - ; p= . ), respectively. in this small, single-center cohort of patients with cvst, most patients experienced a good outcome. the institution of continuous neurointensivist coverage was independently associated with better outcomes. further validation in prospective, multicenter cohort studies is needed. thrombelastography (teg) provides a dynamic assessment of clot formation, strength, and stability. we examined relationships between teg parameters and outcomes from intracerebral hemorrhage (ich). we prospectively enrolled patients with spontaneous ich between to . teg was performed at the time of admission. we divided patients into two groups based on the presence or absence of hematoma expansion (he). clinical characteristics, baseline teg values, and outcomes were compared between the two groups. multivariable regression analysis was conducted to compare the differences of teg components between the two groups after adjusting for potential confounding effects. we included patients, ( %) with he and ( %) without he. patients with he were more often male and had higher rates of aspirin use, lower incidence of intraventricular hemorrhage, and larger baseline hematoma volumes. after controlling for potential confounders, mean r time was independently associated with he ( . ± . vs. . ± . mi significantly higher risk of he with or . ( % ci: . , . ), p=< . . patients with hematoma expansion were more likely to have poor neurological outcome (mrs - ) at discharge ( % vs. %, p= . ) and had higher mortality rates ( % vs. %, p= . ). overall, patients ( %) died in the hospital. following multivariable analysis, patients who died had significantly lower mean delta ( . ± . vs. . ± . mins.; p= . ) and smaller angle ( . ± . vs. . ± . degrees; p= . ) than those who lived. hematoma expansion and mortality from ich are independently associated with slower clot formation on teg. baseline teg identifies significant coagulation disturbances which may predict poor outcome and represent potential targets for therapeutic intervention. intracerebral hemorrhage (ich) patients often present with acute hypertension requiring intravenous and enteral antihypertensive medications. we performed a cohort study to determine clinical predictors of time to enteral antihypertensive medication and its effect on icu length of stay (icu los). we identified consecutive spontaneous ich patients admitted from / to / to a tertiary center, and excluded those transitioned to comfort care (cmo) within hours of admission. we calculated time from hospital admission to first enteral (oral or feeding tube) antihypertensive. we abstracted demographic and clinical variables. two reviewers examined medical records and classified ich location and etiology. we determined univariate and adjusted associations of clinical variables to time to enteral antihypertensive medication and performed regression analysis to determine effect on icu los. we identified patients and excluded for early transition to cmo. endotracheal intubation (p= . ), higher ich score (p< . ), no outpatient antihypertensive use (p= . ), and non-lobar ich location (p= . ) predicted longer time to starting enteral antihypertensive in adjusted analysis. presenting systolic or diastolic bp, time of icu admission (day vs. night), sex, and race were not significant predictors of time to enteral antihypertensive. time to enteral anti-hypertensive is the strongest predictor of icu los (p< . ) after adjustment for age, gcs, ich score, sex, race, and duration of iv antihypertensive infusion. patients with higher ich scores, intubation, no prior antihypertensive use, and non-lobar ich are at risk for increased time to enteral antihypertensive administration. timely enteral antihypertensive administration is an important and potentially modifiable predictor of icu los in acute ich. overall mortality from intracerebral hemorrhage (ich) represents a combination mortality from a potentially fatal disease as well as practice variation around treatment withdrawal of care. early do-not-resuscitate (dnr) rates are independently associated with in-hospital mortality and may serve as a proxy for withholding aggressive care. the american heart association (aha) guidelines recommended that dnr orders should not be applied before hours out of a concern that less aggressive care would lead to a self-fulfilling prophecy and excess mortality. we performed a retrospective analysis of temporal trends among primary ich patients presenting to all nonfederal emergency departments in california from to using data from the office of statewide health planning and development (oshpd). demographic information, clinical covariates (such as mechanical ventilation, craniotomy), and early dnr status within hours were collected and analyzed using segmented regression to evaluate for differences in linear trends from - compared with - . over a use of early dnr orders for ich patients has steadily decreased over the last years, even after adjusting for age and disease severity. the pace of this downward trend did not significantly change around the time when recommendations on early dnr use for ich in aha guidelines were revised in . spontaneous intracerebral hemorrhage (ich) is a common form of stroke that often results in severe morbidity or death. for most ich, there are no proven therapies for acute management. evidence suggests minimally invasive surgical evacuation of ich may result in improved patient outcomes. the enrich clinical trial is designed to determine the efficacy and economic impact of early ich evacuation using minimally invasive, transulcal, parafascicular surgery (mips) compared to standard guideline-based management. in this abstract we present the trial design and rationale at the foundation of the enrich clinical trial. enrich is an adaptive, prospective, multi-center clinical trial designed to enroll up to patients with acute ich. patients are block-randomized based on hemorrhage location (lobar vs basal ganglia) : to mips or standard management. included patients are - years, gcs - , baseline mrs , presenting within hours from last known well and found to have a spontaneous, cta-negative, supratentorial ich ( - ml). primary efficacy will be determined by demonstrating significant improvement in the mean utility-weighted mrs at days after enrollment. economic effect of mips will be determined by quantifying the cost per quality-adjusted life-years gained at pre-determined time points. the rationale for early intervention is to interrupt the time-dependent ich related pathophysiology caused by mechanical pressures and the pro-inflammatory secondary cascade that leads to worsened cellular injury and edema formation. the planned enrichment strategy acknowledges that hemorrhages in varied locations may have a differential response to mips. study adaptation, in the form of enrichment, may occur if pre-determined futility rules are met for the primary outcome in either of the two locations. enrich is designed to establish the clinical and economic value of early mips in the treatment of ich. enrollment was initiated in december . early seizures (< days) after intracerebral hemorrhage (ich) may be associated with the presence and degree of perihematomal cytotoxic injury. we explored the association between perihematomal diffusivity (phd) and early seizures after ich. consecutive patients from the prospective nih funded dash study (> years, spontaneous ich) were included. all patients had multimodal mri within weeks. perihematomal edema (phe) volume was outlined on t /flair and ich volume on gre; these and adc were coregistered to analyze phd. eeg monitoring was performed for clinical suspicion of seizure. mean adc values of phe and the percentage of phe volume were compared between the seizure and no-seizure groups, with adc values as vasogenic edema. results ( %) of a total of patients had early seizures at a median of day post ich. mean adc in the phe region was higher in the seizure group (mean: +/- vs +/- , p= . ). ich, absolute, and relative phe volumes were not different between groups. the phe of the seizure group had a lower percentage of cytotoxic edema ( % vs %, p= . ) and a higher percentage of vasogenic edema ( % vs %, p was the most predictive of seizure with auc = . , though adc thresholds between - had largely similar auc's. phe volume of > % (of adc > ) identified patients with seizure with sensitivity of . , specificity of . , and remained significant in multivariable analysis. patients with early post-ich seizures have higher mean perihematomal adc and a larger percentage of vasogenic edema in the perihematomal region. vasogenic edema due to bbb breakdown and perihematomal inflammation rather than cytotoxic injury is associated with early post ich seizures. novel neuroprotective treatments hold the promise to improve patient outcomes by broadening time windows of intervention and reducing hypoperfusion and reperfusion injury in the era of mechanical thrombectomy for acute ischemic stroke. hibernating species, such as arctic ground squirrels (ags), demonstrate remarkable resilience to ischemic and reperfusion injuries. bioinformatic analyses of genomes of hibernating species reveals signatures of convergent evolution in genes regulating stability and formation of mitochondrial respirasomes. hypoxia pre-conditioning (hpc) also leads to improved survival upon subsequent exposure to hypoxia, and is associated with increased stabilization of respirasomes. the respirasome is a macromolecule consisting of oligomers of complex i, iii, and iv. cox a l is a key mediator of respirasome stability via interactions with complex i and iii. in this study, we explored the role of cox a l in mediating respirasome stabilization in ags neural stem and progenitor cells (nsc/npcs) as well as mouse nsc/npcs exposed to hpc. respirasome stability was assessed using blue native gel electrophoresis and mitochondrial metabolism assessed by measuring oxygen consumption in vitro (seahorse metabolic analyzer). exposure to mild hypoxia and induction of hif leads to stabilization of respirasomes, upregulation of hif, and modulation of mitochondrial metabolism. interestingly, overexpression of the ags isoform of cox a l, which has amino acid substitutions in residues mediating respirasome stability, recapitulates the effects of hypoxia on respirasome stability and mitochondrial metabolism without altering hif expression. targeting respirasome stability by modulating cox a l is a potentially novel neuroprotective target for treatment of ischemic injuries. testing of these hypotheses in pre-clinical models of stroke is on-going. acute stroke symptoms need timely diagnostics in order to ensure best outcomes. as a non-academic, community-based center located in rural western nc, where we are the regions only comprehensive stroke center, we developed a process to intake stroke patients quickly directly from ct to interventional radiology when applicable. a smooth transition reduces the quantity of time from imaging to interventional suite, ultimately reducing the time it takes to prepare to actively treat a patient. interventional radiology value stream mapping started in june . multidisciplinary team worked in multiple work groups to design and create "code ir stroke now". flow chart created to show multiple moving parts simultaneously, to streamline transition from er (sometimes this includes triage from the region also) to ir. an ir "ready" criteria was made, er and ir checklists, followed by post procedure debrief and treatment plans/order set to standardize care and documentation. first mock code ir was done / / , this was critiqued/perfected. "go live" date: / / . we continue process improvement today. in first three months, patients have gone through this process. average compliance for goal door to puncture < min went from . % to %. door to groin times reduced from minutes to minutes. our performance is minutes quicker than other comprehensive stroke centers ( m avg gwtg database). saved an average of million neurons per patient. total of million neurons saved on average since / / ! door to groin times can be reduced with streamline approach to care. multidisciplinary team approach, including house supervisors, anesthesia, switch-board in addition to the bedside staff and providers can make a smooth transition from the time a large vessel occlusion is identified to getting the patient to the interventional suite. activation of "code ir stroke now" page activates this team / . it is unknown whether antithrombotics for secondary stroke prevention in patients with acute ischemic stroke (ais) due to infective endocarditis (ie) reduce the rate of secondary ais or increase major bleeding. we conducted a multi-center, retrospective cohort study from - of patients with ais secondary to left-sided ie, separated into two groups (antithrombotic vs no antithrombotic). antithrombotics included antiplatelets and/or therapeutic anticoagulation. the primary outcome was a composite of recurrent ais and major bleeding. secondary outcomes included ais and major bleeding individually. a binary logistic regression model adjusted for age and native vs prosthetic valve involvement was used for outcome evaluation. the final analysis included patients ( antithrombotic vs no antithrombotic). median age was years and ( %) patients had prosthetic valve infections. infecting organisms were mostly methicillin sensitive s. aureus ( %) or streptococcus spp. ( %). valve repair/replacement occurred in ( %) patients. aspirin with or without another antithrombotic ( %) was the most common antithrombotic treatment. the primary outcome occurred in . % vs . % of patients with antithrombotics vs no antithrombotics, respectively (or . ; % ci . to . ). ais ( . % vs . %; or . ; % ci . to ) and major bleeding ( . % vs . %; or . ; % ci . to . ) were similar between groups. a subgroup analysis of aspirin monotherapy vs no antithrombotic yielded similar results for the primary outcome ( . % vs . %; or . ; % ci . to . ) and ais ( . % vs . %; or . ; % ci . to . ). major bleeding was increased, however ( . % vs . %; or . ; % ci . to . ; p= . ). antithrombotics after ais secondary to ie were not associated with a decrease in recurrent ais or an increase in major bleeding. aspirin monotherapy was associated with an increase in major bleeding without any reduction in ais. malignant hemispheric stroke (mhs) represents between - % of all hospitalized ischemic stroke in the united states. pooled analysis of european studies has demonstrated that decompressive hemicraniectomy (dchc) for mhs reduces mortality compared with conservative medical management and may also improve functional outcomes. these trials however, excluded patients with major medical comorbidities that might confound clinical outcomes. apache ii and sofa scores are validated icu scoring systems to help characterize disease severity and estimated hospital mortality. this study aims to evaluate apache ii and sofa scores in predicting outcomes for patients undergoing dchc for mhs. this is a single center retrospective analysis of patients who underwent early dchc for mhs between may through january at unc chapel hill. apache ii and sofa scores were calculated for the date of admission or date of first presentation to neurologic care. outcomes included mortality at discharge, mortality at day, and functional outcome at last follow up, up to one year. multivariate analysis included timing of surgery, age, laterality, presence of midline shift, hemorrhage or multiple territory infarction. we identified patients who met inclusion and exclusion criteria. the median age was ( to ), -nine percent of patients received surgery by hospital day . full statistical analysis is pending. our hypothesis is a positive correlation between icu severity scores and mortality. given apache ii and sofa scores capture the effects of acute and chronic disease that would affect patient recovery, we hope to provide a more comprehensive prognostication of outcomes following surgery to help guide physicians and family members of these patients in their decision-making process. we conducted this study to investigate the effects of decompressive craniectomy (dc) combined with hypothermia on mortality and neurological outcomes in patients with large hemispheric infarction. within hours of symptom onset, patients were randomized to one of the following three groups: dc group, dc plus head-surface cooling (dcsc) group and dc plus endovascular hypothermia (dceh) group. we combined the data of the dcsc and dceh group to dch group during analysis. the primary endpoints were mortality and modified rankin scale (mrs) score at months. there were patients in the dc group, patients in the dcsc group and patients in the dceh group. for all patients, the mortality at discharge and after months was . % ( / ) and . % ( / ), respectively. the dch group had lower mortality, but the difference was not statistically significant (at discharge, . % vs. . %, p= . ; months, . % vs. . %, p= . ). after months, patients survived, and . % of the surviving patients had good neurological outcomes (mrs score of - ). the dch group had better neurological outcomes, but this difference was also not statistically significant ( / , . % vs. / , . %; p= . ). the total number of patients experiencing complications in the dc group and the dch group was ( . %) and ( . %), respectively. treatment with hypothermia led to decreased mortality and improved neurological outcomes in lhi patients who received dc. a multi-center rct is needed to confirm these results. destiny ii investigated hemicraniectomy in patients -years and older for the treatment of malignant cerebral edema. we sought to describe the treatment effect of early hemicraniectomy in destiny ii, using number needed to treat to benefit (nntb) and benefit per hundred (bph) treated at and months. as an mrs of is generally undesirable, we also present nntb and bph excluding this outcome. for all possible dichotomizations of the mrs, net nntb was derived by taking the inverse of absolute risk difference, and net bph by multiplying absolute risk difference by . for benefits simultaneously across all disability transitions on the mrs, nntb, and bph, estimates were derived using joint outcome tables: ) algorithmic minimum and maximum and ) four independent experts. the expert data is presented as geometric mean. the algorithmic nntb was . (range . - . ) at -months and . ( . - . ) at -months, while bph was . ( - ) and . ( - ). the expert nntb was . ( . - . ) at -months and . ( . - . ) at -months, and the bph was . ( - ), and . ( - ) respectively. excluding mrs the algorithmic nntb was . (range - . ) at -months and . ( . - . ) at -months, while bph was ( - ) and . ( - ). the expert nntb was . ( . - . ) at -months, and . ( . - . ) at -months, and bph was . ( - ) and . ( - ) respectively. early systematic hemicraniectomy improves outcome (including mrs ) for every - patients treated. excluding patients with mrs , hemicraniectomy improves outcome for every . patients treated. the algorithmic range provides bounds to the data, while the expert geometric mean provides the most accurate point estimate. these data provide a powerful tool to describe the potential treatment outcomes to families during the first day following a malignant middle cerebral artery infarction. background cerebral bypass surgery is performed to restore, or revascularize blood flow to the brain. previous studies have not shown whether emergency surgical reperfusion therapy may be effective in acute ischemic stroke patients with large artery occlusion and hemodynamic deterioration. objective to evaluate the effect of emergency sta-mca bypass surgery on the outcome of hemodynamic compromised patients who had progressive or fluctuating stroke despite best medical treatments. we retrospectively reviewed the clinical and radiological data of consecutive patients treated by both emergency bypass surgery ( cases, . %) and elective bypass surgery ( cases, . %) due to large artery occlusion at a single center. the effect of surgical therapy was measured with the modified rankin scale (mrs) at months. clinical severity was evaluated by the national institutes of health stroke scale (nihss) between pre-and post-operative state. major perioperative complications were defined as any hemorrhagic stroke, myocardial infarction and death. results occlusive sites were the cervical internal carotid artery in ( . %) patients and the middle patients in emergency surgery group and ( . %) patients in elective surgery group. emergency bypass surgery improved nihss (preoperatively, [ - ] ; weeks postoperatively, [ - ]). major perioperative complications in days were happened in three patients ( . %) after emergency bypass surgery, and four patients ( . %) after elective bypass surgery. emergency revascularization surgery may be effective alternative treatment for acute ischemic stroke patients with hemodynamic deterioration refractory to maximal medical treatments without significant complications. larger randomized clinical study is needed to evaluate the effect of emergency revascularization surgery in acute hemodynamic deterioration. multiple studies have reported lower mortality rates in obese patients with various cardiovascular disorders, a phenomenon called as the 'obesity paradox'. such relationship has been largely unreported in patients with neurological pathologies especially stroke. this study reports the effect of obesity on prognosis in patients with ischemic stroke. analysis of national inpatient sample data ( - ) showed a total of , , patients discharged with primary diagnosis of is, icd- code .xx and .xx. patients with obesity were identified using agency of healthcare research and quality (ahrq) criteria. we used binary regression to compare inhospital mortality between obese and non-obese patients with ischemic stroke. from - , , , patients with ischemic stroke were identified of which . % were found to be obese. obese patients with ischemic stroke were more often younger, female, and african american as compared to caucasian. after risk adjustment for demographics, and baseline comorbidities, obese patients with ischemic stroke had lower observed in hospital mortality as compared with non-obese patients with ischemic stroke ( . % vs %, or: . ci= . - . p< . ). from an eleven year nationwide cohort of patients with ischemic strokes, we observed a significant protective effect of obesity and better prognosis including a lower mortality rate. more prospective studies are warranted to further analyze this counter-intuitive trend. very early mobilization of critical care patients improves outcome, length of stay, and patient satisfaction. data for efficacy of very early mobilization for stroke patients have been mixed, and there is limited outcomes data for patients mobilized within hours of receiving intravenous alteplase (iv tpa). the objective of this retrospective observational study was to determine if patients receiving iv tpa who were mobilized earlier were more likely to discharge home. medical records of ischemic stroke patients who received iv tpa between and at two urban facilities were reviewed for mobility protocol activities. patients who received endovascular treatment, were placed on comfort care day zero or one, mobilized after the first hours, and transferred out or left against medical advice were excluded. multinomial regression was used to determine if there were significant differences in patients' discharge status by time first mobilized, adjusting for stroke severity using the national institutes of health stroke scale (nihss), age and gender. of the patients included, . % (n= ) were female, mean age was . (± . ), and the median admit nihss was . [iqr: . , . ]. the median time first mobilized was . hours [iqr: . , . ], . % (n= ) of patients were discharged to home, . % (n= ), a skilled nursing facility (snf), . % (n= ), an inpatient rehab facility (irf), and . % (n= ) hospice or expired. there was suggestive, but inconclusive evidence for a relationship between time first mobilized and discharged to snf versus home (p=. ). for every one hour increase in time mobilized, patients were . ( % ci= . - . ) times more likely to be discharged to snf than home. this study reveals very early mobility is potentially efficacious after iv tpa. longer time to first mobility was associated with discharge to skilled nursing facility, although this was not statistically significant. medical management of cerebral edema after large volume stroke varies greatly across institutions. hypertonic saline has emerged as a common treatment strategy to attempt to reduce edema and theoretically prevent the need for decompressive hemicraniectomy. there is no established protocol for hypertonic saline administration and there have been concerns regarding safety. in a single-center, retrospective analysis we identified patients who received hypertonic saline for malignant edema after an ischemic stroke involving the entire hemisphere or diffuse middle cerebral artery (mca) territory. we compared patients who received continuous infusions of % or % hypertonic saline to those who received continuous infusions with boluses of . %. the primary endpoint was time to goal sodium ( ). secondary endpoints included the need for surgical decompression and adverse events. we included patients who received only continuous infusions of hypertonic saline and patients who received a combination of continuous infusions and bolus doses. we found no significant difference between number of patients who reached goal sodium ( vs respectively, p= . ) or time to goal sodium ( hours vs . hours, p= . ). there was a significant difference in the number of patients who underwent surgical decompression ( vs , p= . ). there was not a significant difference in the rate of acute kidney injury or development of acidosis between groups ( vs. , p= . ). both hypertonic strategies appear to be safe. bolus dosing, on review, was more often instituted during clinical deterioration, accounting for the higher rate of surgical intervention. we feel we can safely be more aggressive earlier in the clinical course to potentially avoid surgical decompression. furthermore, we may need to look more closely at our target sodium, evaluating whether it should be based on the patient's baseline sodium or a universal value. even though recanalization is strongly associated with improved functional outcomes and reduced mortality, clinical benefit from thrombolysis is reduced as stroke onset to treatment time increases. in the recent study, endovascular treatment(evt) has been demonstrated to improve functional outcome in patients with acute ischemic stroke (ais) within the time window of onset to or hours. however, beyond usual thrombolysis time window, early neurologic deterioration(end) related with proximal artery occlusion is not uncommon in ais. with this, we report ais case series treated with evt because of end related proximal artery occlusion. from january through march , all patients underwent iat for ais with anterior circulation stroke. among them, twenty-four patients underwent evt due to end. at admission, all twenty-four patients showed near to complete occlusion of a proximal artery and had diffusion-perfusion mismatch. mean age was . initial median initial national institutes of health stroke scale (nihss) was and nihss after end was . all patients had diffusion-perfusion mismatch over %. seven patients treated with iv-tpa before evt. good recanalization (tici b/ ) was achieved in . %. the hemorrhagic complication was seen in the follow-up computed tomography scan in of cases: three were hemorrhagic transformation, another was the subarachnoid hemorrhage. the thromboembolic mortality case. in our report, evt in ais with end achieved safe and successful recanalization. and successful recanalization was associated with good clinical outcome. we think evt could be a useful method in case of end in ais patients with proximal artery near to complete occlusion, even beyond usual to hours time window for evt. jugular bulb venous monitoring can provide information about cerebral hemodynamics and metabolism. we investigated the feasibility and clinical application of jugular bulb venous monitoring in acute ischemic stroke patients at neurocritical care unit. from march to june , we conducted jugular bulb venous monitoring in patients in a tertiary referral hospital. five patients were excluded; without ventilator care and other diseases than stroke. jugular venous catheters were placed in internal jugular vein by ultrasound-guided method. lactate, venous oxygen saturation (sjvo ), and arteriovenous oxygen saturation differnece (avdo ) were monitored every hours. metabolic derangement was defined when lactate level was more than . mmol/l. patients were divided according to presence of clinical deterioration. for long-term prognosis, modified rankin scale - at months were defined as poor outcome. twelve patients ( . %) showed metabolic derangement and they experienced more frequent clinical deteriorations compared to patients without metabolic derangement (n= , . % vs. n= , . %, p= . ). clinical deterioration was noted in patients, and lactate level was significantly higher in the presence of clinical deterioration group ( . ± . vs. . ± . mmol/l, p= . ). adjusting other potential variables (age, baseline stroke severity, sjvo , and avdo ), metabolic derangement was an independent factor associated with clinical deterioration (or . , % ci . - . , p= . ). meanwhile, poor outcome group (n= ) showed no difference on lactate level, but avdo were higher in poor outcome group ( . ± . v. . ± . , p= . ). avdo remained an independent factor for poor outcome after multivariable logistic regression analysis (or . , % ci . - . , p= . ). this study showed that lactate was associated with clinical deterioration during neurocritical care, whereas venous desaturation contributed to long-term prognosis. jugular bulb venous monitoring is a feasible tool in patients with acute ischemic stroke at neurocritical care unit. swift recognition of stroke symptoms, immediate access to testing and timely treatment plays a vital role in functional outcomes (middleton et al., ) . delays can postpone treatment and complicate recovery. delays at this facility included registration, order entry times, and imaging. pi included evaluating and eliminating interruptions, with a goal of reducing the time to treatment. process improvement (pi) utilized an evidence-based algorithm to improve performance metrics and treatment of acute strokes. setting was a suburban, ancc magnet recognized primary stroke center with beds in the ed that experiences , ed visits and , admissions per year. patients included in the acute stroke protocol presented with signs and symptoms of stroke and last known well within hours of symptom onset. participation included ed staff, and staff working in areas impacted by stroke care. code stroke was initiated for patients who fit the criteria. an overhead page was implemented notifying the team throughout the hospital. radiology would prioritize ct and call the ed as soon as ct was ready. in the meantime, ed team continued assessments. with ct resulted, the physician would determine whether the patient was eligible for tpa. the acute stroke protocol included a list of inclusion/exclusion criteria for tpa administration. other treatment requirements included reminders for frequency of vital signs, neuro checks and assessments. implementation began in may and the team began to see a significant decrease in ct times and better compliance of dysphagia screening and nih assessments. ct tat completed within minutes increased from % to %. nih stroke scale completion rose from % to %. compliance with completing dysphasia screening increased from % to %. results stem from a commitment to excellence from the entire team. pi continues to further improve care for stroke patients. induced hypertensive therapy (iht) has used to enhance cerebral perfusion pressure in subarachnoid hemorrhage and stroke, but there is no established indication for iht in ischemic stroke. we report the usage of iht in acute ischemic patients with hemodynamic instability caused by steno-occlusive disease of a main cerebral artery. we reviewed acute ischemic stroke patients with cerebral perfusion deficit due to intracranial and extracranial steno-occlusive disease. iht was applied for early neurological deterioration and maintained until hemodynamic instability was stabilized over hours or neurointervention including angioplasty and extracranial intracranial arterial bypass surgery were performed. patients were analyzed. territories of stroke were of anterior circulation of intracranial vessels, of posterior vessels, and of extracranial vessels. mean duration of ih therapy was . minutes. pre and post nihss score of ih therapy was . and . , respectively. patients ( . %) were showed improvement and patients ( %) were stabilized without further aggravation. patients revealed bradycardia. there was no fatal complication of therapy. patients were performed further treatment include bypass surgery, angioplasty, and stenting after ih therapy. at months follow up, patients showed good outcomes (modified rankin scale , , and ). iht may be safe and effective for the neurologic deterioration or progression of acute ischemic stroke with hemodynamic instability due to severe steno-occlusive disease of major cerebral artery. large randomized trials are needed to confirm this result. most patients with progressive stroke have a poor prognosis. the aim of our study was investigate the factors related with progressive neurologic deficit (pnd) in the patients receiving recanalization therapy for acute ischemic stroke. -month period, were enrolled. blood pressures (bps) at , , and hours after admission and bp variation (bpv) for the first hours were collected. variables associated with pnd were analyzed. among enrolled patients, patients showed pnd. the patients with pnd had higher systolic bps at , , and hours after admission and higher bpv than the others (p < . ). posterior circulation stroke was more prevalent in the patients with pnd (p < . ). in logistic regression analysis, pnd was independently associated with posterior circulation stroke [odds ratio (or) = . , p < . ] and systolic bp at hours after admission (or = . , p = . ). pnd may be associated with elevated systolic bp for the first hours after admission in the patients receiving recanalization therapy for acute ischemic stroke. telestroke has revolutionized stroke care delivery in the modern era. massachusetts general hospital (mgh) uses the most common model, the hub and spoke. the demonstration of superiority of endovascular therapy (et) with intravenous tpa over tpa alone for acute stroke patients with large vessel occlusions prompts a thorough assessment of telestroke's role in the delivery of et, particularly in terms of transferring patients to hubs capable of et. our primary objective was to examine associations between transfer time and clinical outcomes. patients were selected from the get with the guidelines-stroke registry who were transferred to mgh from jan to oct who had nihss> and last known well< h on mgh arrival (n= ). we excluded patients for whom we could not calculate the primary predictor, transfer time (defined as the mgh arrival time minus the telestroke consult answered time, n= ). several clinical outcomes were explored by linear and logistic regression to determine association with transfer time. of the patients in the study, ( %) were transferred by ambulance, ( %) by helicopter, and ( %) underwent et at mgh. median transfer time was min, and median aspects decrease was during transfer. longer transfer time was associated with decreased likelihood of undergoing et (p= . ). however, transfer time was not significantly associated with aspects decrease during transfer. for those patients undergoing et, transfer times bore no association to day mrs. this study identifies an association between longer transfer time and decreased likelihood of undergoing et. reasons are varied, and are not clearly related to imaging progression alone. only % of transferred patients underwent et. more efficient spoke triage and transfer may improve the ratio of patients treated with et. these data provide an important perspective during this period of stroke triage evolution. intra-arterial thrombectomy (iat) has been approved for acute treatment of ischemic strokes (is). with the advent of several new devices for iat, this procedure has become more widely utilized with better outcomes. we performed this analysis to evaluate trends and predictors of utilization of iat over an year period. analysis of nationwide inpatient sample data ( to ) showed a total of , patients discharged with a primary diagnosis of is, icd- code .xx, and .xx. iat was ascertained by icd- procedure code . . independent predictors of iat were studied using binary logistic regression. the predictors included in the model were age, sex, race, teaching status, and insurance type. results or . % of is patients received iat. mean age of patients receiving thrombolysis was . years. percentage of is patients receiving iat has consistently increased from . % in to % in . we also observed significant year to year decrease in mortality among patients receiving iat. in , . % of iat patients died as compared to . % in . using binary logistic regression, the statistically significant independent predictors of iat utilization were age (or= . , p= . ), female gender (or= . , p= . ), insurance type as compared to medicare (private insurance or= . p= . , and self-pay or= . p= . ). as compared to caucasians, african americans were less likely to receive treatment (or= . p= . ). also, a teaching hospital was found to be more likely to administer iat as compared to a non-teaching hospital (or = . , p= . ). is patients with younger age, female gender, private insurance and patients admitted to teaching hospitals are more likely and african americans are less likely to receive iat. this study showed that iat utilization has increased significantly since with a steep decline in the in-hospital mortality. this may point to improved iat devices and better patients' selection. telestroke plays an integral role in stroke care. nationally the most common model is the hub and spoke, which is used at our institution. understanding telestroke's role in the transfer of candidate patients for endovascular therapy (et) is critical to minimizing delays. our primary objective was to evaluate predictors of transfer delay. patients were selected from the get with the guidelines-stroke registry who were transferred to mgh from jan to oct with nihss> and last known well< h on mgh arrival (n= ). we excluded patients for whom we could not calculate transfer time (the mgh arrival time minus the telestroke consult answered time, n= ). ideal time was calculated using google maps incorporating date/time information for ground transfers and straight line distance at mph for helicopter transfers. ideal time was subtracted from actual time to calculate delay, accounting for distance, mode of transport, weather, and traffic. analysis of covariance was used to explore possible predictors of delay (night vs. day, weekend vs. weekday, tpa delivery at spoke). of the patients in the study, ( %) were transferred by ambulance, ( %) by helicopter, and underwent et. a significant proportion of the variation in delay was explained by the predictors (f= . , p< . ). nocturnal transfer ( - hrs) was associated with significantly longer delay ( . additional minutes relative to daytime transfers, p< . ). weekend vs. weekday transfer and tpa delivery at spoke hospital did not contribute significantly to model variance. our findings highlight the importance of refining protocol approaches. nocturnal transfers were associated with substantial delay relative to daytime transfers. in contrast, delivery of tpa was not associated with delays, underscoring the impact of effective protocols that are in place. metrics and protocols for transfer, especially at night, may have a positive impact on transfer times. the use of anticoagulant therapy in the acute stage of ischemic stroke is controversial. novel oral anticoagulant (noac) is effective in preventing recurrent embolism in patients with non-valvular atrial fibrillation (nvaf), but the risk of hemorrhagic transformation is the major concern for its early use in ischemic stroke. we aimed to study the use of noac in patients with acute ischemic stroke and nvaf. patients with acute ischemic stroke and nvaf, who were admitted to our acute stroke unit from to , were recruited in this single-centre cohort study. the timing of initiation of noac is at the discretion of the treating physician based on the stroke severity and infarct size. nvaf attributed to . % ( / ) of all ischemic stroke cases. the early recurrent embolism rates were . %, . % and . % at one week, two weeks and one month respectively. noacs were prescribed in patients. noacs were initiated within one week in patients ( . %). the median time to noac initiation were five days (iqr . - . ), nine days (iqr . - . ) and days (iqr . - . ) for patients with no/small-sized infarct, moderate-sized infarct, and large-sized infarct respectively. at one month, two patients had recurrent ischemic stroke despite treated with noac. only one patient, who had a large-sized infarct, developed symptomatic hemorrhagic transformation. early use of noac in ischemic stroke appears to be safe. further large prospective studies are required to evaluate the risk and benefit of noac use in acute ischemic stroke. osmotherapy (hypertonic saline or mannitol) is the mainstay of available therapy to counter cerebral edema that can develop after large hemispheric infarction. in a post-hoc analysis of the games-rp trial, we hypothesized that patients with large infarction, treated with intravenous glyburide, might require less osmotherapy than placebo treated patients. games-rp was a multi-center prospective, double blind, randomized, placebo controlled study which enrolled patients with large anterior circulation infarction. patients were randomized to iv glyburide administration (biib ; n= ) or placebo (n= ) with target time from symptom onset to drug infusion decompressive craniectomy (dc), or both. total bolus osmotherapy dosing was quantified by an "osmolar load" (volume in l * osmolarity in mosm/l). of the subjects, the percentage of patients who received bolus osmotherapy did not differ between the glyburide and placebo treated subjects ( % v. %; p= . ). there was no difference in mean total osmolar load received (mosm) or hours from drug bolus to osmotherapy administration. overall, subjects received osmotherapy. the baseline dwi lesion volume (ml) was significantly larger in the osmotherapy treated group ( . ± . v. . ± . ; p= . ). the presence of adjudicated malignant edema on imaging was more common in the osmotherapy group ( % v. %, p= . ), as was dc ( % v. %; p< . ). among patients with adjudicated clinical neurologic deterioration from edema, % (n= ) did not receive osmotherapy. treatment with iv glyburide was not associated with less osmotherapy, possibly due to a ceiling effect resulting from the large infarct volumes. however, osmotherapy use was associated with larger infarct volumes, malignant edema, and higher incidence of dc. use of osmotherapy did not always follow the appearance of clinical or radiographic malignant edema. acute ischemic stroke patients receiving intravenous alteplase (iv-tpa) are placed on bedrest for hours or longer due to provider fear of worsening stroke symptoms from decreased cerebral perfusion. this is based on medical uncertainty and lack of robust studies, despite american stroke association (asa) recommendations for mobilization when hemodynamically stable. this retrospective observational study evaluates very early mobility in acute ischemic stroke patients post iv-tpa while evaluating for change in nihss. medical records of ischemic stroke patients who received iv-tpa between and at two urban hospitals were reviewed for mobility protocol activities. patients who were given endovascular treatment, placed on comfort care on day zero or one, mobilized after the first hours, transferred out or left against medical advice were excluded from the analysis. multiple linear regression was used to determine if those patients mobilized earlier saw a greater change between nihss at admit and hours post iv-tpa administration, adjusting for age and gender. of the patients included in the final analysis, . % (n= ) were female, mean age was . the multiple linear regression results showed no significant relationship between change in nihss from admit to hours post iv-tpa and earlier mobilization, after adjusting for age and gender (ß= - . change in nihss points per hour; p= . ). this study reveals early mobility does not worsen stroke symptoms or severity based on nihss. this suggests that very early mobility of patients after iv-tpa is safe as recommended by asa. interhospital transfers to a stroke center following iv-tpa administration are increasingly common. however, no studies have evaluated icu needs in these transfer patients and such understanding may have a significant impact on resource utilization. the aim of this study is to compare the frequency, timing, and nature of icu-level needs in post-iv-tpa patients that were transferred versus those who present directly to the admitting hospital. retrospective chart review of consecutive, tpa-treated ischemic stroke patients admitted to the icu at a comprehensive stroke center servicing a large telestroke referral network from / to / was performed. we evaluated patient demographics, stroke characteristics, and icu needs between transfer and non-transfer patients before and after icu admission. results patients were admitted to the icu post-tpa. patients ( . %) were transferred from an outside hospital, of which patients had icu needs ( . %). this frequency of icu needs was no different when compared to the non-transfer patients ( / , . %, p = . ). similar icu needs were observed for each specific icu intervention between transfer and non-transfer patients (iv antihypertensive, vasopressor requirement, iv rate control, respiratory support, ia therapy, icp monitoring, hypertonic therapy, and neurosurgical intervention, all p > association with icu needs (or . in transfer patients, or . in non-transfer; both p < . ). transferring post-iv-tpa patients is not associated with increased icu needs. about one-half of post-tpa patients do not have icu needs, and these patients typically have milder stroke severity. our data supports the safety of transferring post-tpa patients, and to potentially monitor a subgroup of these patients in a non-icu setting. the ability to appropriately triage post-tpa patients may lead to more efficient and cost-effective stroke care. stroke patients requiring decompressive craniectomy remain at high risk of prolonged mechanical ventilation as well as ventilator associated pneumonia (vap). early tracheostomy placement may provide a reduction in the duration of mechanical ventilation however prediction of those who ultimately require a tracheostomy remains a clinical challenge. a preoperative assessment of tracheostomy dependence may help to guide decision making. the authors compare key outcome data after early versus late tracheostomy and develop a preoperative decision-making tool to predict postoperative tracheostomy dependence. a subsequent validation utilizing a decision tree analysis applied prospectively is ongoing and will be presented. we performed a retrospective analysis of prospectively collected registry data and developed a propensity weighted decision tree analysis to predict tracheostomy requirement utilizing factors present prior to surgical decompression. outcomes include probability functions for icu los, hospital los, and mortality based on data for early ( day) tracheostomy. a subsequent validation of the decision tree is being applied prospectively to evaluate its predictive value. a total of surgical decompressions were performed on patients with acute ischemic or spontaneous hemorrhagic stroke between - . forty eight patients ( . %) required a tracheostomy, whereas ( . %) developed vap, and ( %) survived hospitalization. mean icu and hospital los were . and . days respectively. utilizing gcs, sofa score and hydrocephalus presence, our decision tree analysis provided a % sensitivity and % specificity for tracheostomy prediction. early tracheostomy conferred significantly fewer ventilator days (p< . ) and shorter hospital los (p= . ) with similar vap and mortality rates between groups. early tracheostomy shortens duration of mechanical ventilation and length of stay following surgical decompression for stroke, however without a demonstrable impact in mortality or vap rates. a preoperative decision tree awards a practical tool that may provide insight to guide preoperative decision-making with patient families. patients suspected acute stroke are critical in time delay of endovascular or intravenous thrombolytic therapy. prehospital notification from emergency medical services (ems) may shorten the door to recanalization time. the 'brain saver', web-based prehospital notification system could reduce the time interval from symptom onset to recanalization. beginning in march , stroke team consisted of stroke specialized doctors, nurses and radiologists of multi departments received direct alarms via smart phone application from paramedics of ems about transport information of patients with suspected stroke. we compared baseline characteristics and prehospital/ in-hospital delay time in stroke patients treated with intravenous thrombolysis or endovascular treatment for months with and without ems use brain saver protocol. patients ( patients with protocol and patients without protocol) were enrolled in this program. the patients who used brain saver had shorter median onset-to-arrival times ( minutes versus minutes, p < . ) and in in-hospital delay time ( minutes versus minutes, p<. ). prehospital notification by brain saver was associated with shorter median door-to-imaging time ( minutes versus minutes, p<. ), door-to-needle time ( minutes versus minutes, p <. ), door to puncture time ( minutes versus minutes, p < . ) we found that prehospital notification was associated with faster door-to-imaging time, door-to-needle time and door-to-puncture time in patients presenting within hours of symptom onset. close collaboration between stroke team in hospitals and the ems system gives stroke suspected patients an in-time emergency care system. infection is a common complication in the acute phase after ischemic stroke. furthermore, malnutrition is associated with unfavorable outcome in patients with stroke. therefore, we investigated that premorbid undernutrition identified by objective and quantitative method, nutritional risk index (nri) was related to the risk of infection after ischemic stroke. a consecutive patients who were admitted within days after ischemic stroke onset between october and october were included. we assessed initial nutritional status using nri, and nri formula as follows: nri = ( . × serum albumin, g/dl) + { . × present weight (kg)/ideal body weight (kg)}. the patients were categorized into three groups on the basis of nri [no risk (nri > . ), moderate risk (nri . - . ), and severe risk (nri < . )]. we compared the clinical characteristics and nri according to the presence of infection. among the included patients (mean age, . years, male, . %), ( . %) patients experienced infection during hospitalization. the rate of pneumonia was . % (n= ), and the rate of urinary tract infection was . % (n= ) among total infection. the proportion of lower nri patients (moderate risk and severe risk) was significantly greater in the infection group ( . % vs. . % and . % vs. . %, p < . ). moreover, higher nri patients were less likely to be admitted to the intensive care unit ( . % vs. . % vs. . %, p = . ). a multivariate analysis revealed that lower nri groups had a higher risk of infection [odds ratio ( % confidence interval); moderate risk . ( . - . ); severe risk . ( . - . ), p for trend = . ]. our study demonstrated that the lower nris predicted infection complications and severe infections after ischemic stroke. this suggests that assessment of nutrition depletion could be a useful predictor and a modifiable risk factor for infection following stroke. cyp c plays a major role in the metabolism of the clop[idogrel. cyp c generates an active oxidized metabolite of clopidogrel that exerts antipl;atelet activity by inhibiting p y reeceptor. the major alleles of the cyp c gene are * , * , * and * and approximately % of caucasians and % of asians have one or more loss of function alleles in this study, patients with at least two * or * allels were classified as poor metabolizer(pm), those with one * or * allele were classified as intermediate metabolizer(im), and those without a * , * or * alleles were classified as extensive metabolizer. in addition. those with (* /* or * /* ) were classified as unknown metabolizer. stroke patients were enrolled for this trial. the mean age was years, and % were women. % had a history of hypertension, % of dm and % of dyslipidemia. of the participants, % were classifies as em, % as um, % as im, % as pm and % as unknown metabolizer. % had good genotype for clopidogrel metabolism and % had poor genotype. there were no significant diffirences in the demographic and clinical findings between the good and poor genotype groups the prevalence of cyp c polymorphisms is different according to the ethnicity. the racial difference in platelet function may lead to diffrerences in the treatment as well as new targets for antiplatelet therapy the social brain hypothesis is an evolutionary theory proposing that the number of contacts in a primate's social network is proportional to neocortical volume. we tested the hypothesis in a patient population with social network data before and after vascular events. we studied whether social network indices would decrease after stroke, but not after myocardial infarction (mi), as anticipated by the theory. we examined trajectories of the lubben social network scale score (range - , higher values indicating larger network) before and after vascular events in participants from the cardiovascular health study. we used a repeated measures design with linear mixed models to compare the change in social network score before and after events in persons with ischemic stroke and with mi. over a mean of . years of follow-up for stroke and . years for mi, we examined an average of social network scores for each participant. we controlled for socio-demographics, baseline cognitive function, and comorbidities. social network scores declined significantly after stroke (an additional - . points every year, % ci - . , - . , p= . ), but not after mi (- . , % ci - . , . , p= . ) compared to the baseline slope in fully adjusted models. social network score declined more steeply after stroke than after mi, even after adjusting for potential confounders. these findings support the social brain hypothesis but do not address mechanism. shrinkage of the social networks may be a specific target for interventions to optimize recovery in vascular diseases, particularly stroke. emergency neurological life support (enls) protocols are an essential component to assessment and management of patients within the first hours of the neurological emergency. with increasing focus on emergent endovascular treatment for large vessel occlusion (lvo) in acute ischemic stroke our institution incorporated stroke van assessment as part of the enls acute stroke initial assessment protocol. stroke van screening tool was taught to all nurses in the emergency department (ed) who triage stroke. all patients who presented to the ed with suspected stroke had a van assessment completed prior to ed physician evaluation and ct imaging. patients with weakness in addition to visual changes, aphasia, or neglect were considered van + and triaged immediately to ct angiogram head/neck with immediate notification to the neurointerventionalist. a sample of patients presenting to the ed as a stroke alert over an month time period were utilized. using the stroke van assessment tool was found to improve time to identification of lvo by reducing time from arrival to cta for van positive patients from minutes pre-intervention (n= ) to minutes post-intervention (n= ). this was a significant decrease in time to identification of patients presenting with lvo (p< . ), improving time to endovascular treatment. incorporating stroke van as part of the acute stroke assessment protocol improved identification of patients presenting with lvo, decreased time to cta imaging and improved time to endovascular treatment which is well documented with improved neurological prognosis. time is essential in neurological emergencies. the van assessment is quick and easy to perform, requires no scoring or calculations, and is the only lvo screening tool tested in the ed by ed nurse and physicians. we suggest incorporating stroke van to the enls acute stroke protocol as a way to improve identification of lvo and improve time to endovascular treatment. elevated blood pressure (bp) is known to be related to hemorrhagic transformation (ht) after ischemic stroke. however, the effect of bp variation on the ht remains unclear, especially in patients with successful recanalization after mechanical thrombectomy. therefore, we investigated the relationship between bp and ht after mechanical thrombectomy following ischemic stroke. a consecutive patients with acute ischemic stroke and successful recanalization (tici b or tici ) were included for the analysis between january and november . the information on bp was obtained over the first hours using various parameters including mean, maximum (max), minimum (cv), and successive variations (sv) for systolic, diastolic bp, and mean bp. we defined major ht as a parenchymal hematoma type (ph ). among the included patients (age, . ; and male, . %), patients ( . %) developed major ht over the first hours after successful recanalization. systolic bp max-min was significantly increased in patients with major ht compared to those without major ht ( . mmhg vs. . mmhg, p = . ) while other bp parameters were not. in addition, systolic bp max-min was significantly associated with symptomatic ht (n= , . %, p = . ). after adjusting for confounders, systolic bp max-min was independently associated with major ht (odds ratio, . ; % confidence interval, . - . ). our results demonstrated that absolute change of systemic bp over the first hours was associated with major and symptomatic ht after successful mechanical thrombectomy after acute ischemic stroke. this suggests that maintaining stable systolic bp is an important factor in possibly preventing major ht after successful recanalization. the benefits of intravenous tissue-plasminogen activator in acute ischemic stroke are highly timedependent. however, there are so many cross-departmental tasks to eligible patent that many stroke centers have difficulty achieving the guideline recommended -hour door-to-needle (dtn) time. we have developed web based visual task management system called "task calc. stroke" (tcs) by using information and communication technology. herein, we performed a trial installation and preliminary evaluation of tcs. the application software of tcs was designed to run on the google cloud platform. tcs alerts the relevant hospital staff to the patient's arrival condition and time, and displayed tasks to be performed and its treatment status by changing color in real time on networked wall-mounted smart devices in the several relevant departments. we started a trial installation of tcs during the daytime from august . we compared lead times before (august to july ) and after (august to july ) trial installation of tcs. trial installation of tcs in our hospital showed successful information sharing. a total of patients included (pre: , post: ) . after the installation, significant reductions occurred in the median time from door to complete blood count time [ . vs. . min, p < . ] and a trend toward a reduction from door to needle time [ . vs. . min, p = . ]. tcs may be useful tool to reduce the lead times of acute stroke patients. tcs is a new approach that has the potential to promote efficiency for acute stroke care. prior history of intracranial hemorrhage (ich) has been considered a contraindication to administration of intravenous recombinant tissue plasminogen activator in acute ischemic stroke, per the original activase fda label and aha/asa guidelines. however, limited data are available on the risks of lysis in patients with prior ich. we performed a cross-sectional study of adult patients who received thrombolysis, using administrative claims data on admissions to acute care hospitals in california between - . diagnosis codes were used to identify patients who received thrombolysis, and to ascertain ( ) a prior diagnosis of ich, including intraparenchymal hemorrhage (iph), subarachnoid hemorrhage (sah), subdural hematoma (sdh), or epidural hematoma (edh); and ( ) relevant comorbidities, including hypertension, smoking, diabetes, heart failure, atrial fibrillation, renal disease, malignancy, and demographic data. we used univariable and multivariable logistic regression to model the odds of in-hospital mortality as a function of prior ich, after adjusting for potential confounders. , patients received thrombolysis during the study period (mean age [sd ], female count , [ %]). of these, patients ( . %) had a documented diagnosis of prior ich on admission. inhospital mortality was % overall, . % for patients without prior ich, and . % for patients with prior ich. in multivariable analysis, all prior ich subtypes remained independently associated with in-hospital mortality, including iph (or . , ci . - . , p < e- ); sah (or . , ci . - . , p < e- ); and sdh (or . , ci . - . , p= . ). only patients had edh and testing was not possible. . % of patients who received thrombolysis during the study period had prior diagnosis of ich. prior ich was found to be significantly associated with in-hospital mortality regardless of ich subtype. we evaluated the association between early neurological improvement (eni) after ert and time spent from symptom onset to recanalization, according to the degree of collateral circulation measured using multiphase cta. patients with anterior circulation occlusion who underwent ert based on a non-contrast brain ct and multiphase cta were evaluated. collateral status was evaluated using a pial arterial filling score, which was developed into a six-point scale. eni was defined as equal to more than %, or as an -point decrement in nihss from baseline. neurological statuses at day and at day (or discharge) were determined by a certified neurologist using nihss. the collateral circulation degree measured by multiphase cta was inversely correlated with baseline stroke severity (p= . ). the proportion of eni at day was significantly lower in patients with poor collateral status (score ~ ) according to the time from symptom onset to recanalization ( - , . %; - , . %; > , . %; p= . ). however, the proportion was similar in patients with a good - , . %; - , . %; - , . %; > , . %; p= . , day or discharge; - , . %; - , . %; - , . %; > , . %; p= . ). collateral status was the best predictor for eni after ert. eni was achieved in only ( . %) patients with poor collateral status, and their time from symptom onset to recanalization was more than minutes. the time window for ert might differ according to baseline collateral status measured by multiphase cta. the current time window for ert within hours from symptom onset to groin puncture could be atrial fibrillation (af) is the most common cardiac arrhythmia among adults. despite of the proven advantage in primary and secondary stroke prevention in patients with af, antithrombotic therapy has been reported to be still underused in many countries. however, there is a little data about the incidence of af and any changing pattern of antithrombotic therapy among patients with af over the past decade in korea. data source for this study were obtained from the nationwide sample cohort comprising , , individuals ( % of entire population in korea) which were established by nationwide health insurance system. during a -year follow-up period, there was , developed af ( . %). the incidence of patients with af remained relatively constant during study period ( . % in vs . % in ). the proportion of patients with antithrombotic therapy increased from . % in to . % in significantly (p for trends < . ). however, the proportion of patients with antiplatelet agents was higher than with oral anticoagulation. af steadily increased over recent years in korea. however, only . % of af patients were receiving antithrombotic therapy. our study demonstrated that there was huge gap between the clinical practice and treatment guideline in antithrombotic medication for af patients in korea over the past decade. ohiohealth (oh) possesses one of the nation's largest neuroscience programs and is the leading volume provider of stroke care in ohio. oh is comprised of hospital-based sites, primary stroke centers, comprehensive stroke center, and a virtual health (vh) stroke network that serves hospitals throughout the state. in august , stroke services at ohiohealth were restructured to enable dedicated clinical time for vh providers, require expertise, training, and quality review participation for stroke responders, streamline activation algorithms to limit hand-offs, and eliminate identified barriers to vh consultation. a month interim analysis was planned to assess the impact of these changes (termed "stroke . "). comparative analyses were performed between the first months of stroke . and the similar time period of the year prior to restructuring. pre-defined metrics included consultation volume, vh response time, iv-tpa time to treatment, research enrollment volume, endovascular referral rate and time to treatment, ischemic stroke (is) observed : expected (o:e) mortality data, and patient retention rate at associate vh sites. during the first months of stroke . , encounters were seen (historical ) with a mean activation to vh log in of . minutes. both volume of patients treated with iv-tpa ( vs. , p< . ) and mean treatment times ( vs. minutes; p< . ) were significantly reduced. mean time to endovascular intervention was less during stroke . ( vs. minutes, p < . ). system-wide o: e mortality was reduced after restructuring ( . vs. . , p< . ), accounting for additional lives saved. acute stroke research enrollment doubled ( vs. ) during this same period. transfer rates to vh hub were unchanged ( vs. %, p = . ). strategic changes in staffing, expertise, vh structure, and access can have profound and positive changes on a well-functioning stroke system. strokes due to cns fungal infections (scfi) are often misdiagnosed. retrospective study of electronically-extracted records in patients with strokes & positive fungal studies, from cerebrospinal fluid (csf) or brain biopsy. other stroke etiologies were excluded. thirteen patients had scfi by a priori exclusion & inclusion criteria. nine were males. mean age was + years. symptoms were mild [nihss ( , . ) (median and iqr)]. focal deficits & headaches (both . %) were common. seventy-percent were immuno-compromised (medications, malignancy, transplant recipients). clinical course was indolent in . %. seventy-percent had poor outcome ( -ltac, -snf, -dead). ninety-two percent had csf pleocytosis (range: - ) while % had csf glucose less than mg/dl (range: - ). seventy-five percent had lymphocytic predominance. seven strokes were from yeasts ( -cryptococcus, -coccidiomycosis, -histoplasma, -candida) and from molds ( -zygomycetes, -aspergillus). sixty-two percent had posterior circulation involvement ( . % yeast vs % molds). there was lepto-meningeal enhancement in % of yeast vs. % of molds infections (p= . ). the basal ganglia (bg) was involved in % of intravenous-drug users (ivdu) vs. % of non-ivdu (p= . ). one had abnormal cns vessel imaging directly attributed to the ischemic lesions. in this series, patients were young, immunocompromised or ivdu. stroke sizes & clinical deficits were modest with no angiographic evidence of vasculitis. majority had csf pleocytosis & hypoglycorrhachia. posterior circulation involvement was typical. lepto-meningeal meningitis was only seen in yeast infections. the bg was spared in non-ivdu but common in ivdu. mechanism of stroke in yeast infections is probably from meningitis & secondary involvement of small perforating branches. mechanism in mold infections in immuno-competent ivdu is probably direct angio-invasiveness in small vessels of the bg. outcomes are poor in spite of therapy. scfi should be considered in selected cases of cryptogenic (recurrent or progressive) strokes with clinical, csf and mri features described. life-threatening bleeding requires prompt reversal of factor xa (fxa) inhibitors. their anticoagulant effects can be reversed with the antidote andexanet alfa. the efficacy of andexanet to reverse bleeding in an apixaban anticoagulated porcine trauma model was investigated. after ethical approval, male pigs (n= ) were given apixaban for days ( mg daily); the sham group (n= ) received placebo. standardized polytrauma by blunt liver injury and bilateral femur fractures were inflicted. minutes post-trauma, animals were randomized (n= per group) to a single andexanet bolus ( , mg), a bolus ( , mg) + infusion ( , mg over hours) regimen, or vehicle (control). blood loss (bl) and hemodynamics were monitored over hours or until death and analyzed by anova (mean±sem). apixaban anti-fxa levels were ± ng/ml with no differences between anticoagulated groups prior to injury. bl in the sham animals was ± ml minutes after injury (total bl ± ml at "x" hours; % survival). anticoagulation with apixaban significantly increased bl minutes after injury ( ± ml; p< . ). controls exhibited a total bl of , ± ml with % mortality (mean survival time = minutes). treatment with a bolus or bolus+infusion of andexanet was associated with a significant reduction in bl versus sham (p< . ) and % survival. two hours after injury, apixaban anti-fxa levels in bolus animals were ± ng/ml, whereas the bolus+infusion regimen resulted in levels of ± ng/ml (p< . ). hemodynamic parameters (e.g., cardiac output) and markers of shock (e.g., lactate) recovered to pre-trauma levels in andexanet-treated groups. clinically and macroscopically, no adverse events were observed. in this study, andexanet effectively and safely reversed apixaban anticoagulation and reduced bl induced by severe trauma under anticoagulation. the bolus alone had a similar impact on survival and bl as the bolus+infusion regimen in this lethal porcine model. current guidelines for management of pain, agitation, and delirium in mechanically ventilated patients in the intensive care unit (icu) recommend an analgesia-first approach to sedation management. however, these guidelines are derived from non-neurologic patient populations leaving uncertainty in their generalization to this population. the purpose of this study was to evaluate implementation of an analgesia-first sedation clinical pathway in the neuroscience icu. a single-center cohort study was performed within the neuroscience icu including patients mechanically ventilated for greater than hours over a time period of three months before and after clinical pathway implementation. providers were educated on the pathway with emphasis on frequent assessment of richmond agitation-sedation scales (rass), critical care pain observation tool (cpot), and confusion assessment method-icu (cam-icu) scores and systematic de-escalation of sedatives through adequate pain and delirium management. outcome measures included frequency and magnitude of rass, cpot, and cam-icu scores, analgesic and sedative medication prescription/administration per day of mechanical ventilation (mv). a total of patients met inclusion criteria ( pre-pathway and post-pathway). there was no statistically significant difference in the median frequency of rass ( . vs. . ) and cpot ( . vs. . ) assessments per day of mv or in median rass (- vs. - ) and cpot ( vs. ) scores. mean acetaminophen usage increased from . % to % (p< . ) post-pathway implementation. there was no statistically significant difference in mean opioid or propofol usage, however a trend toward increased morphine and decreased propofol usage was observed post-pathway. analgesia-first sedation pathway implementation trended towards increased opioid analgesic and decreased sedative use, however only increased acetaminophen usage was significant. this highlights challenges in changing unit-based practices and future directions include focus on the frequency and reliability of pain, agitation and delirium assessment. interdisciplinary coordination and communication remains necessary for effective unit-based practice changes. andexanet alfa (andexanet), a modified, recombinant human factor xa (fxa) molecule, binds and sequesters fxa inhibitors. in a phase study of apixaban, rivaroxaban, edoxaban, and enoxaparin in healthy volunteers, andexanet rapidly reversed pharmacodynamic markers of anticoagulation. here, the ability of andexanet to reverse the anticoagulant activity of betrixaban was investigated. in a randomized, double-blind, phase study in healthy subjects, andexanet (n= ) or placebo (n= ) was administered intravenously following mg po qd betrixaban to steady state ( days). in cohort (andexanet bolus only), subjects (n= ) received a -mg andexanet bolus hours after the last betrixaban dose (day ) or placebo (n= ). in cohort (andexanet bolus plus -hour infusion), subjects (n= ) received a mg andexanet bolus hours after the last betrixaban dose, followed by a -hour infusion of andexanet ( mg/min) or placebo (n= ). endpoints included safety and pharmacodynamic markers of anticoagulation reversal. following treatment with betrixaban in cohort , andexanet rapidly decreased anti-fxa activity from . ± . to . ± . ng/ml, while the anti-fxa levels following placebo were largely unchanged ( . ± . to . ± . ng/ml). unbound betrixaban plasma concentration decreased from . ± . to . ± . ng/ml with andexanet, but remained constant following placebo administration ( . ± . to . ± . ng/ml). similar results were observed in cohort following andexanet bolus ( minutes after bolus), and the effects were maintained during the -hour infusion of andexanet. for cohort , thrombin generation was restored in / ( %) and / ( . %) of andexanet-administered and placebo subjects, respectively. for cohort , thrombin generation was restored in / ( . %) of andexanet subjects versus / ( . %) of placebo subjects. andexanet was well tolerated; there were no thrombotic events or serious/severe adverse events. andexanet was well tolerated and rapidly reversed anticoagulation effects of betrixaban in healthy subjects. these and other studies indicate that andexanet could be a universal antidote for fxa inhibitors. andexanet alfa (anxa), a recombinant human fxa molecule, reverses the anticoagulant activity of fxa inhibitors. in studies of healthy volunteers, anxa showed dose-dependent reversal of direct and indirect fxa inhibitors in tissue factor (tf)-initiated thrombin generation (tg). we compared rivaroxabaninduced inhibition of tg initiated via the extrinsic pathway (tf) versus intrinsic pathway (non-tf). tf-initiated tg was measured using a calibrated automated thrombogram (cat) and ppp-reagent. non-tf-initiated tg was measured using cat and actin fs. anti-fxa activity was measured using an anti-fxa chromogenic assay. pooled plasma was spiked with rivaroxaban or rivaroxaban+anxa; tg, anti-fxa activity, and clot formation were measured. for low tf-initiated clot formation, thromboelastography profiles were measured. anxa alone had minimal effect on endogenous thrombin potential (etp). anxa fully reversed rivaroxaban-induced anticoagulation in the actin fs assay, independent of anxa-tfpi interaction. modulation of tf activity was assessed by correlating etp versus anti-fxa activity with rivaroxaban or rivaroxaban+anxa. rivaroxaban dose-dependently inhibited tf-initiated tg as anti-fxa activity increased. at similar anti-fxa levels, rivaroxaban+anxa had higher etp than rivaroxaban alone, but not in the actin fs assay. clot formation was studied in plasma using thromboelastography without rivaroxaban. anxa did not affect thromboelastography parameters, with/without recombinant tissue plasminogen activator (rtpa). when low tf initiated clot formation without rtpa, anxa reduced the thromboelastography-r parameter, but not maximum amplitude. the fibrin clot was lysed at low rtpa, resulting in well-segregated coagulation and fibrinolysis. with the optimal rtpa, fibrin clots formed at each tf concentration were compensated by the fibrinolytic activity of rtpa. without a fxa inhibitor, anxa had minimal effect on tf or actin fs-initiated tg with no direct effect on rtpa function. anxa dose-dependently and completely reversed rivaroxaban-induced inhibition of tg initiated by intrinsic or extrinsic pathways, but had different effects on etp due to the anxa-tfpi interaction. there is a growing body of evidence relating poor outcomes to off-hour management. studies investigating the effect of overnight extubation (oe) have produced mixed results, and limited data is available for brain-injured patients. there may also be tendency to limit oe due to decreased staffing levels at night. we sought to determine the safety of oe and risk factor profiles associated with extubation failure (ef) in this cohort. we conducted a retrospective review of mechanically ventilated patients admitted to a single-center in-house database. exclusion criteria included limitations in care, tracheostomy placement, selfextubation, and death prior to extubation. the primary outcome was ef defined as non-elective endotracheal intubation within hours. ef rates were compared between daytime ( am - : pm) and overnight ( pm - : am) extubation cohorts. in-hospital mortality served as a secondary outcome. amongst identified patients, ( . %) underwent daytime extubation (de) and ( . %) oe. ef was indifferent between de and oe ( . % and . % respectively; p= . ). however, multivariable adjustment for clinical severity indicators suggests higher ef for oe (or: . , ci: . - . ; p= . ). compared to de, oe was more likely performed in elective post-operative patients ( . % vs . %; p= . ) with lower apache-ii scores (median vs ; p= . ), and shorter durations of mv (median . vs . days; < . ). higher apache-ii score, longer duration of mv, and admission diagnoses of acute vascular injury or neuromuscular disease were associated with ef. there was no difference in mortality (p= . ). in our cohort, oe was not associated with increased ef or mortality. our results suggest that oe can be performed safely if standard extubation criteria are met in low-risk patients. these data provide a basis for subsequent more robust studies. case series have reported reversible left ventricular dysfunction, also known as stress cardiomyopathy or takotsubo cardiomyopathy, in the setting of acute neurological diseases such as subarachnoid hemorrhage. the nature of the association between various neurological diseases and takotsubo remains incompletely understood. we performed a cross-sectional study of all adults in the national inpatient sample, a nationally representative sample of u.s. hospitalizations, from - . our exposures of interest were primary diagnoses of acute neurological disease, defined by icd- -cm diagnosis codes. our outcome was a diagnosis of takotsubo cardiomyopathy. binary logistic regression models were used to examine the associations between our prespecified neurological diagnoses and takotsubo cardiomyopathy after adjustment for demographics. we identified , , adults with a primary acute neurological diagnosis and , , patients admitted to the hospital without a primary acute neurological diagnosis. among neurological diagnoses, subarachnoid hemorrhage (odds ratio [or], . ; %ci, , status epilepticus (or, . ; % ci, . - . ), transient global amnesia (or, . ; % ci, . - . ), and meningoencephalitis (or, . ; % ci, . - . ) were most strongly associated with takotsubo cardiomyopathy. weaker associations were present for ischemic stroke (or, . ; % ci, . - . ) and migraine headache (or, . ; % ci, . - . ). intracerebral hemorrhage and guillaine-barre syndrome were not significantly associated with takotsubo cardiomyopathy. in our multivariable model, female sex was significantly associated with takotsubo (or, . ; % ci, . - . ). we found associations with takotsubo cardiomyopathy for several acute neurological diseases besides subarachnoid hemorrhage. gram-negative meningoventriculitis (gnmv) causes significant morbidity and mortality. in addition to intravenous antibiotics, intra-thecal (it) or intraventricular (iv) antibiotics may be used to treat central nervous system (cns) gram-negative infections, including multi-drug resistant gnmv. there are limited studies on the effect of direct cns administration on cerebrospinal fluid (csf) cultures, csf routine parameters and other clinical outcomes. we conducted a retrospective chart review of all patients who received it or iv antibiotics for gnmv since . demographics, source of illness, severity of illness (sofa), intravenous and it/iv antibiotic choice and csf microbiological, drug level and routine analysis were collected. time to pathogen clearance from csf culture was also measured. there were inpatient encounters where iv/it antibiotics were given for gnmv during our study period, of which were cared for in a neurosciences intensive care unit. antibiotics utilized were: gentamicin ( ), colistimethate sodium ( ), amikacin ( ), and tobramycin ( ). the most common pathogens were p. aeruginosa ( ), k. pneumoniae ( ), enterobacter sp. ( ) and e. coli ( ). prior to dosing, median csf white blood cell (wbc) count, protein and glucose was /ul, mg/dl and mg/dl, respectively. it/iv antibiotics were dosed a median of times per patient and clearance of csf culture occurred in a median of days. there were significant changes in csf wbc (p< . ), protein (p<. ) and glucose (p<. ) between the first and last dose of iv/it antibiotics. twenty-five ( . %) patients survived to discharge, ( . %) were confirmed alive at months. patients who survived to discharge went to rehabilitation ( ), home ( ), long-term acute-care ( ) and skilled nursing facility ( ). it and iv antibiotics significantly improve csf wbc, protein and glucose profiles and clear csf cultures in patients with gnmv. it and iv administration may provide additional benefit to systemic therapy. gram-positive organisms are the most common cause of meningo-ventriculitis. systemic antimicrobial therapy may fail to achieve adequate cerebrospinal fluid (csf) concentrations, particularly against organisms with higher minimum inhibitory concentrations, such as mrsa and vre. direct intraventricular (iv) or intra-thecal (it) administration may be beneficial as they can facilitate high csf levels at the site of infection. there are limited studies on the effect of direct central nervous system (cns) administration of antibiotics on csf cultures, csf routine parameters and other clinical outcomes. we conducted a retrospective chart review of all patients who received it/iv antibiotics for grampositive meningo-ventriculitis since . demographics, source of illness, severity of illness (sofa), intravenous and it/iv antibiotic choice and csf microbiological, drug level and routine analysis were collected. time to pathogen clearance from csf culture was also measured. there were inpatient encounters where iv/it antibiotics were given for gram-positive meningoventriculitis during our study period, of which were cared for in a neurosciences intensive care unit. antibiotics utilized were: vancomycin ( ) and daptomycin ( ). the most common pathogens were staphylococcus sp. ( ), enterococcus sp ( ), and streptococcus sp ( ). prior to dosing, median csf white blood cell (wbc) count, protein and glucose was /ul, mg/dl and mg/dl, respectively. it/iv antibiotics were dosed a median of times per patient and clearance of csf culture occurred in a median of days. there were significant changes in csf wbc (p< . ), protein (p<. ) and glucose (p=. ) between the first and last dose of iv/it antibiotics. twenty-nine ( . %) patients survived to discharge, ( . %) were confirmed alive at months. it and iv antibiotics significantly improve csf wbc, protein and glucose profiles and clear csf cultures in patients with gram-positive meningo-ventriculitis. it and iv administration may provide additional benefit to systemic therapy. use of prothrombin complex concentrate (pcc) for urgent reversal of anticoagulant associated coagulopathy is increasing, and at the university of illinois hospital (uih), an anti-thrombotic reversal guideline was developed in may in order to assist licensed practitioners in choosing the appropriate reversal agent, optimal dosing, and improve timely administration pcc. the current study examined the safety and efficacy of pcc used for the urgent reversal of anticoagulant associated coagulopathy before and after the development of the anti-thrombotic reversal guideline. this was a retrospective chart review of adult patients who received pcc as the only hemostatic agent at the uih from jan to april . the primary endpoint was hemostasis and secondary endpoints included thromboembolic events and time to pcc administration. there were and patients who received pcc before and after the anti-thrombotic reversal guideline, respectively. frequent cause of coagulopathy was warfarin ( % and %, respectively), and frequent indication for pcc was acute intracranial hemorrhage ( % and %, respectively). -factor pcc was more frequently used before the guideline and -factor pcc was more frequently used after the guideline. in patients presenting with warfarin induced major bleeding, target inr < . was achieved in % and % of these patients before and after the guideline, respectively. clinical assessment of bleeding cessation from direct oral anticoagulant (doac) therapy was difficult to assess. thromboembolic event was observed in % and % of the patients, respectively. median time to pcc administration from its initial order was minutes and minutes, respectively. hemostasis was similarly observed in the warfarin group before and after the development of reversal guideline, but more thromboembolic events were observed before the reversal guideline. in order to further reduce the pcc administration time, a change in workflow has been made to administer pcc in timely manner. dexmedetomidine, a selective alpha- adrenoreceptor agonist inhibiting sympathetic neuronal activity, is a mild sedation agent. two recent case reports showed reduced norepinephrine (ne) requirement in septic shock with clonidine, a less selective alpha- agonist. increased vasopressor responsiveness (vr) was also observed with dexmedetomidine in cardiovascular surgical settings. sympatholytic effects of the alpha- agonists reverse vascular desensitization due to high levels of sympathetic activity in sepsis. depletion of intra-neuronal catecholamines with reserpine has shown to increase vr. in septic sheep infused with escherichia coli, clonidine reduced renal sympathetic tone and restored vr. additionally, alpha- agonists have shown to decrease pro-inflammatory cytokines and reduce mortality, improve capillary perfusion deficit, and lower arterial lactate in animal sepsis models. a prospective trial in human septic shock is in the pipeline. we report decreases in vasopressor requirement with initiation of dexmedetomidine in two patients with brain injury. a -year-old woman presented with a high-grade subarachnoid hemorrhage and concomitant reverse takatsubo cardiomyopathy. her clinical course was complicated by septic shock secondary to aspiration pneumonia at admission. when dexmedetomidine was started after hours of ne infusion, a steady decrease in ne dosage was observed until its discontinuation. increased vr was also observed in a year-old man being treated for new onset refractory status epilepticus. on hospital day , the patient continued to have stimulus-induced seizures on ketamine, midazolam and pentobarbital infusions and required ne to maintain an adequate mean arterial pressure. when dexmedetomidine was added, a decrease in ne infusion was observed within an hour and continued for six hours until the patient no longer required vasopressor therapy. these findings are consistent with aforementioned reports of restored vr by alpha- agonists in septic shock, and warrant further investigation of possible beneficial effects of attenuated hyperadrenergic state conferred by alpha- agonists in various neurocritical care settings. decreasing the amount of time a patient remains intubated has been shown to reduce multiple negative outcomes. by extubating these patients earlier, risk of infection, prolonged immobility, and delirium are reduced. in early , this nsicu was chosen to participate in the society of critical care medicine's icu liberation collaborative. the collaborative was focused on implementation of the abcdef bundle or icu liberation. the successful implementation of the bundle led to a decrease in the amount of time neurocritically ill patients were intubated. the bundle elements began to be rolled out in june (end of st quarter). included in the bundle's roll out was the creation of a respiratory clinical specialist role to help the interprofessional team with the respiratory components of the bundle. this role was a full time respiratory care practitioner who was dedicated to the nsicu and helped to ensure standards were being met. additionally, as a part of the bundle's implementation, a spontaneous awakening trial and spontaneous breathing trial algorithm was developed and initiated. this algorithm relied on interprofessional collaboration between nursing and respiratory therapy with communication to the provider and was rolled out in september (end of rd quarter). ventilator o/e for : st quarter- . , nd quarter- . , rd quarter- . , th quarter- . ventilator o/e for : st quarter- . , nd quarter- . the bulk of the research conducted that proved the benefits of the bundle elements has been completed in medical and/surgical patient populations. the neurocritical care patient population is very specialized and has several nuances that may impact the way the various elements need to be implemented. through this process, we have found that the techniques suggested within each element can positively impact the neurocritical care patient population. the cognitive reserve hypothesis refers to inter-individual differences in the ability of patients to cope with brain pathology. cognitive reserve can be measured by surrogate markers such as education and occupation and has shown to be an important predictor of outcomes in alzheimer disease, multiple sclerosis and traumatic brain injury. in this prospective longitudinal cohort study we determined whether cognitive reserve measured as number of years of education and employment status predicted -month functional outcome of ncc patients. demographic and clinical data, including number of years of education and occupational status, were collected. at three months after discharge, glasgow outcome scales (gos) were collected via telephone from patients or surrogate respondents. gos scores were categorized into 'good' or 'poor' outcome (gos - ). from march to july , / patients with -month follow-up data were included. mean age was ± years, ( %) were male, with stroke as the predominant admitting diagnosis.the two groups with good vs poor outcomes did not differ in age, gender or race in univariate analysis although employment status was statistically different in the two groups. in multivariate logistic regression neither employment nor education was a significant predictor of good vs poor outcome (p = . , p = . ). prognostication in neurocritical care patients is difficult. the effect of cognitive reserve needs to be studied further. our current sample size is small and as enrollment continues, we will determine the relationship between cognitive reserve and -month functional outcome. fever commonly occurs in patients with spontaneous intracerebral hemorrhage (sich). however, it is non-infectious in the majority of cases. blood cultures (bcx) are often obtained as part of a fever workup, yet their utility may be limited and false-positive results may potentially compromise patient care. we hypothesized blood cultures in the first hours would more likely be false-positive. we performed a retrospective chart review of patients admitted to a tertiary medical center with a diagnosis of spontaneous intracerebral hemorrhage. patients with secondary causes of ich as well as institution of comfort measures only were excluded. data obtained included demographics, clinical parameters of ich and blood culture results. blood culture results and charts were reviewed for adjudication of false-positive and true-positive cultures. of included patients with sich, patients ( %) had blood cultures obtained. cultures were positive, of which were classified as false-positive and as true positive. false positive results were more common in the first days ( vs. ), while true positive results were more common after the first hours ( vs. ) (p= . ). early blood cultures in patients with sich are more commonly non-infectious. in line with prior published data, our results demonstrate the high cost and limited yield for blood cultures within the first hours. predictive energy expenditure (pee) equations are commonly used in lieu of indirect calorimetry (ic) due to cost and limited resources; however, these equations may not be as accurate as ic in estimating resting energy expenditure (ree) in critically ill patients. the purpose of this study is to compare pee and measured energy expenditure (mee) in critically ill adults with acute brain injury. this was a retrospective review of adult patients admitted with acute brain injury between may st, and april st, who had ic performed. three predictive equations (pe), harris benedict (hbe), penn state university, and mifflin st jeor (msj), were used in comparison to ic results. subgroup analyses included a modified aspen weight-based equation, stratifying patients based on bmi and type of acute brain injury. patients met inclusion criteria. comparing the pee estimated by the three predictive equations to the mee from ic found no significant difference. high degrees of interpatient variability were discovered in each anova analysis, with standard deviations ranging from - %. despite no difference found among pee and mee, pearson's correlations indicated weak associations when hbe, penn state, and msj were individually compared to mee (r-values = . , . , and . , respectively). in patients with a bmi < kg/m , a significant difference was found (p-value= . ) with pee underestimating the ree. additionally, in aneurysmal subarachnoid hemorrhage a significant difference was observed between pee and mee( p-value= . ). the results of this study highlight the importance of using ic whenever feasible due to the interpatient variability of the ree of critically ill patients with acute brain injury. although predicative equations appear to have similar estimations as ic, interpatient variability warrants more accurate measurement with ic to optimize nutrition in patients with acute brain injury. introduction -factor prothrombin complex concentrate (pcc) should be administered as soon as possible for reversal of anticoagulation in the setting of life-threatening bleeding or urgent procedures. limited information is available on the safety, efficacy, and time to administration of pcc when administered at high infusion rates. on march , grady health system implemented a rapid pcc administration strategy while attempting to reduce times from order entry to administration as a quality improvement initiative. this irb-approved, retrospective evaluation includes pcc administrations days pre-and post-protocol implementation. after protocol implementation, pcc doses were prepared in up to four, -ml syringes, dependent on the ordered dose. each syringe was administered over minutes, not exceeding a rate of iu/minute. the primary objective of this study is to evaluate the safety of a rapid administration strategy for pcc. secondary objectives include turn-around times and effectiveness of inr reversal in patients previously on warfarin. results unique pcc administrations were identified: administrations in the pre-cohort and in the postimplementation cohort. most pcc administrations were in the setting of spontaneous or traumatic intracranial hemorrhage. there were no infusion-related adverse events documented with the exception of a possible pcc infiltration post-implementation which resolved with supportive care only. the median order entry to administration time was higher in the post-implementation group ( vs. minutes). administrations in the pre-cohort and administrations in the post-cohort were for warfarin reversal. a greater percent of patients previously on warfarin reversed to an inr < . in the post-cohort compared to the pre-cohort, . % vs . %, respectively. this retrospective evaluation suggests that rapid intravenous push administration of -factor pcc is safe and effective. time to administration was longer after implementation of rapid pcc administration and may have been due to operational limitations. icu readmission is defined as a return to the icu during the same hospital admission. there are multiple studies related to medical and general surgical recidivism, however there is limited data on icu readmissions following spine surgery. the aim of this study was to evaluate factors associated with icu readmissions following spine surgery. patients requiring icu admission following spine surgery from june to june were studied. variables included age, gender, icu and hospital disposition, icu and hospital length of stay, bmi, comorbidities, surgical location, number of previous surgeries and vertebra manipulated, estimated blood loss, post op blood transfusions, and cause of readmission. a : matched control group based on age, bmi and location of surgery was identified. thirty-two patients required readmission following spine surgery during the study period. there was a higher prevalence of preoperative atrial fibrillation in the readmission group ( % vs. %, p= . ). ebl ( vs ml, p= . ) and lowest maps ( vs . mmhg, p= . ) were not significantly different in the two groups. we found a higher mortality rate ( % vs %, p= . ), longer icu ( . vs . hours, p= . ) and hospital los ( . vs . days, p= . ) in the readmission group. respiratory distress ( %) was the most common reason for readmission followed by cardiovascular instability ( %). discharge rates to inpatient rehabilitation and nursing facilities were similar for both groups; however % of the control group went directly home as opposed to % of the readmission group. complex spine patients who experience icu recidivism have a longer hospital stay and incidence of death within years of their index procedure. they are less likely to be discharged home. preoperative a-fib correlates with increased incidence of readmission to icu post-operatively. further studies are needed looking at post operative fluid and pain management. to demonstrate the feasibility of exenatide infusion for hyperglycemia following acute brain injury. adult patients with acute brain injury and having two blood glucose concentrations > mg/dl and was administered within hours of admission and continued per protocol for a maximum duration of hours. the primary endpoint was feasibility (< % of subjects experiencing severe hypoglycemia (< - mg/dl). descriptive endpoints were also collected. data is presented as medians [interquartile range] or percentages. a total of eight patients received exenatide (age . years [ . , . ], . % male, . % caucasian, . % history of diabetes, a c . % [ . , . ]). admitting diagnoses were intracerebral hemorrhage (n= ), acute ischemic stroke (n= ), subarachnoid hemorrhage (n= ), and subdural hematoma (n= ). glascow coma score was . [ . , . ] and sequential organ failure assessment was . [ . , . ]. based upon predefined criteria, feasibility was met with % of subjects experiencing severe hypoglycemia, . % achieving the blood glucose goal, and % experiencing nausea requiring discontinuation. blood glucose was controlled during the -hour exenatide infusion ( intravenous exenatide infusion is feasible for the treatment of hyperglycemia following acute brain injury. extubation failure remains a common complication in critical care patients, and is associated with increased intensive care unit and hospital length of stays, hospital costs, morbidity and mortality. the most common cause of reintubation is laryngeal edema, often identified by the presence of a high pitched inspiratory whistling sound known as post-extubation stridor (pes). providers in the neurocritical care unit (nccu) at a large urban academic medical center noted higher than normal rates of pes. to reduce the rates of pes and reintubation without delaying extubation, a clinical pathway was created by an interdisciplinary team. the purpose of the pathway was to aid in the identification of patients expected to develop pes and guide prophylactic treatment. prior to project implementation, all providers in the nccu completed hands on training with practice in completing the pathway in the form of a checklist. during the week implementation phase, checklists were completed on all intubated patients daily during rounds. during the week trial, there were a total of ventilator days. there were completed checklists, yielding an . % compliance rate for utilization of the clinical pathway. of the patients who were extubated during the trial, had a checklist completed, generating . % compliance on the day of extubation. a chi-square analysis was performed to evaluate outcomes following all non-palliative extubations during the week pre-implementation (n = ) and post-implementation (n = ) periods. implementation of the pathway was associated with a statistically significant reduction in rates of pes ( , n = ) = . , p< . , reintubation ( , n = ) = . , p< . and reintubation due to pes, ( , n = ) = . , p< . . the clinical pathway implemented in our nccu was safe and effective in reducing rates of pes, reintubation and reintubation due to pes. agency for healthcare research and quality (ahrq) identified postoperative deep vein thrombosis (dvt) or pulmonary embolism (pe), also commonly referred to as venous thromboembolism (vte), as one of the complications acquired in the hospital and thus developed a mechanism to report its rate using administrative data. postoperative vte rate reduction became top priority for the university of illinois (uih) due to its high yearly rate, especially among patients in the neurosciences intensive care unit (nsicu). therefore, a quality improvement team in the nsicu implemented vte bundle and analyzed its effect on the vte rate. the vte bundle was initiated on all neurosurgery and neurology patients admitted to the nsicu since march . vte bundle included lower extremity doppler ultrasound within hours of admission, vte education provided to patient or family member within hours of admission, and daily surveillance on proper use of mechanical sleeves and the mechanical device, low-dose heparin initiation and maintenance therapy, and documentation of activity status. the nursing staff were encouraged to follow the early mobilization protocol. mean vte rate was . per cases approximately -year before and . per cases approximately -year after the implementation of vte bundle. the rate of compliance was high on all aspects of vte bundle, especially on correct placement of ipc sleeve > %; functioning ipc device > %; low-dose heparin > %; documentation of activity status > %. no adverse effects were noted (i.e., skin breakdown, major bleeding) during the study period. this was the first time in years at uih, the postoperative vte rate was reduced among nsicu patients based on the ahrq reports. the reduction may partly be attributed to the implementation of vte bundle; however further evaluation need to be performed to determine the effect size of vte bundle. increasing evidence suggests that large volume infusions of . % sodium chloride (nacl) for resuscitation are associated with hyperchloremic metabolic acidosis and renal vasoconstriction leading to an increased risk of acute kidney injury (aki). in patients with neurologic injury, hypertonic ( . % or %) nacl or sodium acetate (naacetate) may be required for therapeutic hypernatremia, treatment of cerebral salt wasting or elevated intracranial pressure. the primary aim of this study was to determine the incidence of aki in neurologically injured patients receiving intravenous hypertonic nacl and in those who were switched to hypertonic naacetate based on provider preference. this single-center, retrospective study compared patients that received only hypertonic nacl to patients that were switched to naacetate. data was collected to assess renal function, hyperchloremia, and metabolic acidosis. a total of patients were screened and of those were included. the patients who were switched from nacl to naacetate (n= ) had a greater incidence of aki ( % vs. %, p< . ) and hyperchloremia ( % vs. %, p = . ) compared to patients who received only nacl (n= ). the incidence of metabolic acidosis was increased but not statistically significant ( % vs. %, p = . ). on average, hypertonic nacl was switched to hypertonic naacetate on day of treatment with a mean chloride of . meq/l at the time of the switch. there was no statistical difference in the administration of nephrotoxic antibiotics, mannitol, vasopressors, or contrast dye between the two groups. the receiver operating characteristic (roc) analysis demonstrated that if a patient received greater than meq of chloride over days they were more likely to develop aki (sensitivity %, specificity %, p= . , auc . ). neurologically injured patients receiving hypertonic sodium therapy requiring a switch to hypertonic naacetate had an increased incidence of hyperchloremia and aki. in-hospital complications following acute neurological injury has been a topic of extensive research to help reduce the morbidity and mortality among the patients. however, the incidence and prevalence of in-hospital infections following an acute neurological injury at the national level has never been studied. the aim of our study is to determine the frequency and prevalence of in-hospital complications among different patient groups admitted following acute neurological injury. we identified patients with primary diagnosis of ischemic stroke (is), subarachnoid stroke (sah), intracerebral hemorrhage (ich), status epilepticus (se), meningitis, encephalitis and traumatic brain injury (tbi) from nationwide inpatient database ( - ) through using the respective icd- codes. common in-hospital complications among the above-mentioned diagnoses through using their respective icd- codes patients with primary diagnoses of is (n= ), sah (n= ), ich (n= ), se (n= ), meningitis (n= ), encephalitis (n= ), tbi (n= ) were identified. in-hospital events such as myocardial infarction (mi), sepsis, pneumonia, deep venous thrombosis (dvt), pulmonary embolism (pe), urinary tract infections (uti), and gi bleed were identified and compared among different patient groups. patients with se were noted to experience higher systemic complications, mi ( . %), sepsis ( . %), pneumonia ( . %), dvt ( . %), uti ( . %), gi bleed ( . %). patients admitted with meningitis had a higher incidence of sepsis ( . %), pneumonia ( . %), dvt ( . %), pe ( . %) and uti ( . %) compared to the other groups. uti was the most common in-hospital complication observed. based on our analysis, we report a higher incidence of urinary tract infections among all patients admitted following acute neurological injuries. patients with primary diagnosis of status epilepticus experienced more systemic complications compared to the other diagnoses. macroglossia is a phenomenon that has been documented in association with prolonged neurosurgical procedures, brainstem injury, phenobarbital administration, and venous/lymphatic congestion of the tongue. however, exact causation of this condition in the neurocritical care population remains unclear. patients with macroglossia face significant risk for airway compromise. no interdisciplinary patient safety and management protocol exists. patients admitted to two neuro icu's within a single health system between - were reviewed. twenty-five patients with macroglossia were identified. an interdisciplinary patient management protocol was created, instituting airway safety standards, oral care directives, and interventions to promote symptom resolution. early consultation to oral and maxillofacial surgery and consideration of early tracheostomy was recommended. seventeen patients ( %) were women. age ranged from - years. the majority ( / ) of patients were african american. primary diagnoses included status epilepticus ( / ) and stroke ( sah, ais, ich). nineteen patients received antiepileptic medications before diagnosis. average gcs at symptom onset was . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and at time of discharge was . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . median symptom onset was hospital day [ - ]. twenty patients ( %) required tracheostomy. nine ( %) experienced symptom resolution by hospital discharge. two patients received botulinum toxin injection; both experienced symptom resolution. lingual massage was performed in two patients; in both patients, tongue swelling resolved. tongue lacerations occurred in / patients ( %), although most were observed following macroglossia onset, ruling out trauma as an inciting event. chlorhexidine oral rinse was discontinued for all except five patients due to concern for angioedema. endotracheal tube was dislodged in two patients, complicating reintubation, although successful. no trend in pre-existing allergies or antibiotic regimen was apparent. macroglossia is a relatively uncommon but high-risk condition in the neuro icu that warrants further study. care of patients with macroglossia should be standardized in order to ensure airway safety. an interdisciplinary approach is recommended. one of the biggest challenges of magnetic resonance imaging (mri) examination is the acquisition of high-quality diagnostic images, as it requires the neurological intensive care unit (nicu) patients to keep still for a significant time. in situations with poor patient cooperation, unplanned sedation is inevitable, which can lead to complications such as desaturation and hypotension. we investigated the incidence and factors related to complicated mri examinations (mri-c) in patients admitted to the nicu. we designed a retrospective study to review the data of patients who had an attempt to undergo brain mri during stay in the nicu between july and august . the mri-c group was defined when a patient met one of following criteria: ) required sedation for mri examination due to irritability mmhg or required inotropic agents, ) developed cardiac or respiratory arrest. of patients, ( . %) developed mri-c. the most common cause of mri-c was unexpected irritability at the mri room. among patients with mri-c, ( . %) patients required unplanned sedation; , desaturation; , hypotension; none, cardiac or respiratory arrest. higher apache ii scores (p = . ) and lower gcs scores (p = . ) on admission and use of sedative agents during critical care in the nicu were associated with mri-c (p < . ). in addition, patients with mri-c had longer mri scan time than those without mri-c (p = . ). many of neuro-critically ill patients undergo unsafe mri scans. our findings suggest that severity of illness and use of sedative agents during management in the nicu were factors related to mri-c. introduction: fulminant hepatic encephalopathy (fhe) with diffuse cerebral edema has dismal prognosis if transplantation is not performed. novel therapeutic interventions may change this outcome. we reviewed all cases with fhe admitted to our hospital since . in , we developed a multidisciplinary management protocol, mandating transfer of patients entering grade from other icus to the neurosciences-icu (nicu) for intracranial pressure (icp) management. multiple interventions were utilized including coagulopathy reversal with factor vii and prothrombin complex concentrate (pcc, kcentra), icp device placement, osmotherapy, aggressive ammonia lowering regimen with lactulose and rifaximin, early renal replacement therapy, mild hypothermia for refractory icp, in conjunction with liver transplantation candidacy investigation. results: twenty-four patients ( women, mean age of all patients years) were admitted; seven were managed in the micu/sicu and in the nicu. the etiology of fhe was acetaminophen toxicity in % of patients. the model for end-stage liver disease (meld) admission scores and liver enzymes between the micu/sicu and the nicu were not different (mann-whitney test). although the nicu admission ammonia level was higher than the micu/sicu ( . vs . , p = . ), the lowest achieved ammonia was lower in the nicu ( . vs . , p = . , mann-whitney). patients received icp monitoring (all in the nicu plus in the sicu) and the highest icp recorded was mm hg. the preand post-coagulation reversal inr were . and . , p= . , wilcoxon test). seven patients in the nicu received hypothermic treatment. mortality in the micu/sicu was . % ( / ) and in the nicu . % ( / ), p = . (chi square test). conclusion: a multidisciplinary approach centered around anti-cerebral edema protocol-driven management based on novel interventions may improve the outcome of patients with fhe. catheter-associated urinary tract infections (cauti) are among the most common health-care associated infections (hcais), (gould, ) . neurological patients in the critical care setting are particularly at risk for cauti due to cognitive, motor, and sensory deficits. in the neuro intensive care unit, despite following recommended cauti reduction bundle guidelines, cauti rates continued to rise over the last five years with rates reaching . per catheter days. in january of , the unit implemented a cauti taskforce to perform a literature review of best practices and subsequent : peer training and education targeting cauti reduction. in an analysis of organisms causing the infections, e. coli and enterococcus bacteria accounted for more than % of cautis on the unit. the taskforce (comprised of staff nurses) focused on fecal management, proper cleaning technique, and proper indications of indwelling urinary catheter necessity. using training videos, indwelling urinary catheter care checklists, and real-time feedback on technique, the taskforce performed : training with bedside staff over four weeks. to ensure undivided attention, the taskforce worked in pairs enabling one trainer to teach and observe the staff member receiving training while the second trainer provided the necessary clinical duties for the trainee's patients. after implementation, the cauti rate decreased to . for january-march and . for april-june , lowering total cauti events to for fy compared to for fy . implementing a : training program focused on fecal management, cleaning techniques, and appropriately timed catheter removal can reduce cauti rates in the neuro critical care setting. brain aneurysms can be treated with coil embolization or flow-diverting devices. thromboembolism is a major complication of aneurysmal coil embolization, with an incidence as high as % . new flowdiverting devices have been designed to have a mesh with high coverage area and high flexibility to facilitate the redirection of blood flow. these features can induce blood stagnation and thrombosis. to reduce the risk of thrombosis, the common but unproven practice of dual antiplatelet therapy with aspirin and clopidogrel has been implemented from the cardiac literature. despite some favorable outcomes, clopidogrel, "non-responsiveness" has been reported to be present in as low as % to as high as % making this agent not optimal. this will leave practitioners with other oral p y alternatives such as prasugrel and ticagrelor that have not been studied widely in this setting. it is therefore likely that controversy exists among practitioners regarding the use of optimal antiplatelet agents in neurointerventional procedures. we hypothesized that practices in regards with the use of oral antiplatelets in neurointerventional procedures are likely heterogeneous and different from state to state. by using an electronic survey, we would like to identify different practices surrounding the use of oral anti-platelets in neuro-endovascular centers in the united states. an electronic survey will be distributed via the web using survey monkey (seattle, wa). the survey will be posted on the neuro-critical care society (ncs) web page. all practicing neuro icu or stroke physicians, pharmacists, physician assistants, or nurse practitioners are eligible to respond to this survey. this survey is approved by the johns hopkins hospital irb and the ncs research committee. centers have completed the survey at this point. the results will be analyzed after the closing date of survey ( / / ). to be completed myasthenia gravis (mg) crisis and guillain-barre syndrome (gbs) are immune mediated diseases that may require mechanical ventilation as part of their management if severe. comparative analysis of outcomes in terms of length of stay, disability, and mortality between these two disease entities at national level is not reported mechanically ventilated patients with primary diagnosis of guillain-barre syndrome and myasthenia gravis were identified from the nationwide in-patient sample (nis) database for the years to mechanically ventilated mg patients (n= , mean= +/- . years) were older compared to gbs patients (n= , mean= . +/- . years, p= . ). medical co-morbidities were significantly higher in mg patients (diabetes mellitus, congestive heart failure, coagulopathy, chronic lung disease and dyslipidemia) whereas significantly higher nicotine dependence and alcohol abuse were noted in gbs. significantly higher in hospital complications of pneumonia and urinary tract infection were noted in gbs. disease severity measured by apdrg severity index and rate of treatment with intravenous immunoglobulin and plasma exchange was comparable. length of stay ( . ± . days , p < . ); hospital charges ( $ . ± . vs . ± . p = . ) ; moderate to severe disability ( . % vs . % p < . ) were significantly higher for gbs patient compared to mg. inhospital mortality was comparable ( . % gbs vs . % mg, p = . ). in multivariate analysis after adjusting for confounders including treatment, myasthenia gravis patients had significantly less disability (or . ( % ci . - . ) and shorter length of stay (or . , % ci . - . ). mechanically ventilated gbs patients have higher in-hospital complications, length-of-stay, and disability compared to mg. this may reflect a delay in diagnosis of gbs at admission and poor response to immunotherapy in certain gbs variants. betrixaban is an inhibitor of factor xa (fxa) for prophylaxis of venous thromboembolism (vte) in at-risk patients hospitalized for acute medical illness. a phase trial (apex) compared extended-duration anticoagulation with betrixaban to enoxaparin in acute medically ill patients; the effect of patient characteristics on population pharmacokinetics and exposure-response relationships is analyzed here. patients received betrixaban ( - days; n= , ) or enoxaparin ( ± days; n= , ). the primary efficacy and safety endpoints were composite occurrence of vte events and incidence of major bleeding, respectively. betrixaban dose was mg po qd ( mg po qd for patients with severe renal insufficiency/requiring concomitant p-glycoprotein inhibitor). pharmacokinetic samples were collected - hours or - hours after the most recent dose of study medication. patient characteristics included age, sex, race, region, body weight, crcl category, and specific p-glycoprotein inhibitor. , pharmacokinetic samples were analyzed. at mg, the projected concentration was . ng/ml at hours post-dose and . ng/ml at hours post-dose, showing a stable daily concentration. coadministration of p-glycoprotein inhibitors on the day of sampling more than doubled betrixaban concentration to ~ ng/ml at hours post-dose. at mg, the projected concentration was . ng/ml at hours post-dose, indicating a greater-than-dose-proportional exposure relationship. patient age, sex, weight, crcl category, p-glycoprotein inhibitors, and region were significant covariates affecting betrixaban pharmacokinetics. the exposure-response relationship for the primary efficacy endpoint was not significant, but the relationship between betrixaban concentration and major/clinically relevant nonmajor bleeding was significant in multivariate testing (p= . ). the betrixaban pharmacokinetic profile exhibited stable serum concentrations with qd dosing. several covariates had a %- % effect on betrixaban concentration, but no effect on efficacy/safety. betrixaban dose should be adjusted to mg for patients taking amiodarone or clarithromycin, but not other p-glycoprotein inhibitors. andexanet alfa is being investigated for reversal of anticoagulation by factor xa (fxa) inhibitors. a pharmacokinetic/pharmacodynamics model, developed in healthy subjects, predicted the andexanet regimen required to reverse anticoagulation by fxa inhibitors. the current analysis validated the pharmacokinetic/pharmacodynamic model using interim data from the annexa- study in patients with acute major bleeding. in annexa- , an ongoing prospective, open-label study, bleeding anticoagulated patients received iv andexanet bolus ( or mg) followed by -minute infusion ( or mg/min). anti-fxa activity was measured before andexanet administration (baseline), at end of bolus (eob), at end of infusion, and at , , and hours after infusion. the relationship between baseline anti-fxa activity and reversal in healthy subjects was derived from the pharmacokinetic/pharmacodynamic model and used to predict percent reversal for patients with acute major bleeding. from the first interim analysis of annexa- , patients (apixaban, n= ; rivaroxaban, n= ) had plasma levels available for model qualification, although did not meet criteria for inclusion into safety and did not meet criteria for efficacy analysis. the mean observed percent reversal of anti-fxa activity for rivaroxaban and apixaban was well predicted by the healthy subject pharmacokinetic/pharmacodynamic model; the point estimates fell within the % confidence intervals of predicted values. the percent reversal at eob for rivaroxaban and apixaban were . [ . - . ] and . [ . - . ], compared with . and . predicted by the model. the predicted reversal closely fit the observed confidence intervals through the first hours for rivaroxaban and apixaban, and extended through all evaluated time points for rivaroxaban and slightly outside of post- -hour time points for apixaban, possibly due to higher baseline anti-fxa activity levels for apixaban. the pharmacokinetic/pharmacodynamic model in healthy subjects closely predicted the extent of reversal of anti-fxa activity for apixaban and rivaroxaban in patients with major bleeding. risk factors and methods to predict extubation failure are well established for patients in medical icus and surgical icus. literature on patients who fail extubations in neurological icus is limited. the intention of this study was to collect descriptive information from patients with neurological injuries who failed liberation from mechanical ventilation. retrospective review of all patients with acute neurological injury who were admitted to our neuro icu and who required reintubation within hours of discontinuation of mechanical ventilation between january -february . we identified patients intubated primarily due to neurological pathology who required reintubation within hours after initial extubation over a -year study period. the majority of reintubated patients (n= ; . %,) had a positive fluid balance prior to failed extubation. twenty-six of the reintubated patients had a concurrent underlying chronic cardiac and/or pulmonary disease. five patients were placed on noninvasive ventilation post extubation. low glascow coma scale and absence of basic brainstem functions (gag and cough reflexes) was only minimally predictive of extubation failure. most of our reintubated patients did not have significant supratentorial midline shift nor an insult to the posterior circulation or dominant hemisphere. in patients with primary brain injury who required reintubation, a positive fluid balance prior to extubation may confer a lower rate of successful extubation. lesion location and supratentorial midline shift may not be tightly associated with extubation success. overall, our reintubation rate is quite low. early tracheostomy may play a small but significant role in the low rate of reintubation. further studies may be useful in creating a scoring system to identify the likelihood of extubation success in patients with neurological injury. surgical prophylaxis guidelines for evd insertion recommend peri-procedural antibiotics rather than prolonged antibiotic administration for the duration of evd placement. several small studies have shown that prolonged systemic antibiotic use does not reduce the incidence of catheter related ventriculitis. prolonged use is also associated with a higher rate of multi-drug resistant (mdr) infections. this study aims to show that prolonged antibiotic administration following evd insertion is potentially harmful. this is a single center, retrospective, chart review. all patients admitted to our hospital who had an evd placed from january to march were identified. patients with preceding infections, incomplete data or uncertain infection diagnosis were excluded. sixty-nine patients were analyzed. documented variables included demographics, comorbidities, indications for evd, duration of antibiotic therapy, infections and organisms' sensitivities. eight patients ( %) did not receive any antibiotic therapy; the rest received cefazolin following evd insertion. infections occurred in of ( %) patients; of ( %) were mdr bacteria. ventriculitis occurred in ( %) patients, and of these were resistant to cefazolin (mdr). ventriculitis was not associated with the use or duration of antibiotic therapy. graphical analysis showed that the probability of any infection decreased during the first days of antibiotic prophylaxis. after days, the longer patients remained on prophylactic cefazolin, the higher the probability of infection (spearman rank correlati patients who received antibiotics for > days were . times as likely to develop mdr infections ( % ci, . to . ; p= . ). cefazolin may prevent infections for the first days after evd insertion. however, prolonged administration increased the risk of mdr bacterial infections. a randomized study comparing periprocedural ( hrs) antibiotic use is needed to resolve this controversy. each year more than , deaths are associated with urinary tract infections. eighty percent of all utis are associated with an indwelling catheter. neuroscience intensive care (neuro-icu) units have the highest rates of catheter associated urinary tract infections. catheter associated urinary tract infection (cauti) increases morbidity rates, length of stay, and costs among hospitalized patients. at an urban academic medical center, our neuro-icu had the highest cauti cases among our icus. the purpose of this project was to reduce our cauti cases by %. this quality improvement project used several strategies: ( ) formed a multidisciplinary cauti task force that included nurses, physicians, infection control, management and supply chain personnel; ( ) developed an action plan to update standard of practice by conducting a review of the literature and pilot testing new products; and, ( ) educated staff using huddles, a bedside guide, and email blasts with cauti facts starting in august . additionally, cauti prevention was discussed during patient handoffs among nurses and physicians. data were collected for all neuro-icu patients from fiscal year (fy) - . cauti cases are determined by utilizing cdc's national healthcare safety network. analysis included evaluation of trends across time. we reduced our number of cauti cases from in fy to in fy . as of the beginning of fy , we have not had a cauti for days. a comprehensive approach with a strong commitment by clinicians is critical for sustaining a reduction in cauti. we reduced our cases and exceeded our goal. our efforts to provide evidence-based care are ongoing as we continue to monitor the research and upcoming supplies aimed at making hospitalacquired cauti a never event. isophane insulin (nph) is a commonly prescribed basal insulin to manage hyperglycemia in critically ill patients on continuous tube feeding due to its intermediate duration of action. however, the incidence of hypoglycemia may be higher given the duration of nph can last between - hours and because of the potential for unexpected interruption in feeding. using scheduled regular insulin (ri) instead of nph may reduce this risk given its shorter duration of action. it may also improve glycemic control due to more frequent titration. this was a single-center, retrospective, observational, cohort study from december to may . patients on continuous tube feeding who were prescribed scheduled ri were compared to those prescribed nph. all patients continued to receive an insulin sliding scale. choice of agent was determined by the bedside team. the primary endpoint was incidence of hypoglycemia while secondary endpoint assessed efficacy. in our patient population, a higher incidence of hypoglycemia was seen in those that received nph. hypertonic saline bolus (hsb) is a proven intervention for neurological emergencies arising from cerebral edema and increased intracranial pressure. safety of hsb administered via central venous catheters is well established. however, infusion of hsb through peripheral intravenous access raises concern for complications related to caustic nature of the solution. we aim to assess the safety of peripherally administered boluses of hypertonic saline ( % sodium chloride) at a regional level trauma and comprehensive stroke center. we performed retrospective chart review of patients who received hsbs from january , to january , as part of a quality improvement project. we identified instances of hsb administration. the cases were individually reviewed for iv gauge, location of the iv, whether central access was present at the time of administration, documentation of iv removal, and volume of boluses. patients were excluded if there was concurrent central venous access catheter present at the time of hsb administration or unrelated death within hours after administration of hsb. adverse events were defined as line infiltration, erythema, or swelling at the site of hsb administration. charts were excluded from the study because of presumed administration of hsb through central venous access, not peripheral iv. two patients had adverse events ( . %). none of the patients progressed toward limb threatening complications. the majority of patients ( / ) did not experience erythema or infiltration of the iv. hsb administered through peripheral intravenous access does not pose significant risk of severe complications and may be safely used in emergency situations in the absence of central line access. routine screening of high risk asymptomatic trauma or surgical patients for venous thromboembolism(vte) is controversial. studies suggest against screening while others recognize that some patients at high risk may benefit. the purpose of this pilot study is to evaluate the outcome of routine screening in patients who underwent neuro-surgical interventions. all adult patients admitted to a neuro-intensive care unit with a primary diagnosis of brain injury requiring surgical interventions were included. data from april-june, were retrospectively collected on all subjects who had either spine or cranial surgery. data collected include: incidence of vte, number of times duplex ultrasonography and computed tomography of the chest was performed. on july st, prospective data collection began by screening for presence of deep vein thrombosis(dvt) on day , and from admission or surgery day. all patients received pharmacologic and mechanical vte prophylaxis within - hours post-operatively. a total of (pre-pilot, n= and post-pilot, n= ) subjects were included in the study. in the pre-pilot group, the ages ranged from - and most were male. majority, / ( %) had either craniotomy/craniectomy while / ( %) had spine surgery. about / ( %) were admitted with primary diagnosis of traumatic brain injury. of the subjects, had duplex screening for dvt and had screening for pulmonary embolism(pe). the incidence of vte was confirmed in / ( %); (dvt- % and pe- %). median hospital length of stay was (iqr - ) days. / ( %) were discharged home and / ( %) death rate was attributed to pe. in the post-pilot group, one incidence of pe was identified on day post surgery screening. the rest of the results are still pending. in this preliminary report, post surgical patients have a higher incidence of vte. routine screening might benefit to lower the incidence of mortality caused by pe. epsilon aminocaproic acid (eaca) is an antifibrinolytic agent that crosses the blood-brain barrier and has shown benefit in decreasing bleeding in patients acutely. its use in intracranial hemorrhage has uncertain benefit. we aimed to describe the administration and impact of eaca in a single-center neurosciences intensive care unit (neuroicu) over one year. we performed a single-center retrospective study of neuroicu patients undergoing intravenous eaca administration over a one-year time period. inclusion criteria included eaca administration over hours for a diagnosis of acute traumatic hematoma. the dose and duration of eaca infusion was collected. we additionally collected and compared pre-administration and post-administration prolonged thromboplastin time (ptt) hematology assays and neuroimaging. clinical outcomes were reviewed for survival at hospital discharge. over a -month period (april -may ), patients each received a -hour infusion of eaca. the most common indication for eaca was to prevent worsening of intracranial hemorrhage in patients in traumatic coma (gcs < ). % of patients underwent neurosurgical management. ptt assay values showed a significant difference before and after eaca administration. (ptt . +/-sd vs. . +/-sd; student's t test p< . , n= ). stability of the intracranial hematoma burden was evident following eaca in % of patients. % of patients who received eaca survived to discharge. patients receiving eaca showed a significant reduction in ptt assay values hours after completing their dose. ct neuroimaging demonstrated stable intracranial hemorrhage burden in most patients receiving eaca despite a high prevalence of acute operative neurosurgical management. however, only a modest number of patients receiving eaca survived to discharge. these results suggest that eaca may acutely reverse hematologic abnormalities and enable emergent neurosurgical management in patients with severe, acute traumatic hemorrhage, despite a limited role in affecting survival outcomes in these patients. prognostication is difficult for patients admitted to a neurocritical care unit (nccu). can serum biomarkers obtained as part of routine admission lab work help predict outcomes among patients in this prospective cohort study, the following biomarkers were measured at admission: c-reactive protein (crp), arterial lactate, neuron specific enolase (nse), lactate dehydrogenase (ldh), albumin, and brain natriuretic peptide (bnp). we collected information about demographics, comorbidities, hospital procedures and complications and -day mortality. we compared these serological biomarkers in patients who were alive versus those who had died at days. a total of patients were enrolled over months from june to september , of which whom ( . %) died within days of admission. there were no statistically significant differences in age or gender between the two groups. the -day mortality group had a higher mean charlson comorbidity index (cci) ( . vs . , p= . ) as well as mean nse ( . vs . ug/l, p= . ) and bnp levels ( . vs . pg/ml, p= . ). mean crp, lactate, and ldh were also higher in the -day mortality group ( . vs . mg/l, . vs . mmol/l, and . vs . u/l) while mean albumin was lower ( . vs . g/dl), although these differences were not statistically significant (p< . ). cci and serological biomarkers may have utility in predicting -day mortality among patients admitted to the nccu. as we continue enrollment, we plan to develop a predictive model for -day mortality on admission for patients admitted to the nccu using serological biomarkers, cci and admission characteristics. among hospitalized acutely ill medical patients, the risk for venous thromboembolism (vte) is high. the goal was to examine vte prophylaxis of at-risk patients and vte risk during hospitalization and in the outpatient continuum of care. acutely ill medical patients were identified from the marketscan commercial and medicare databases from / / to / / . inclusion criteria were hospitalization for heart failure, respiratory diseases, ischemic stroke, cancer, infectious diseases, and rheumatic diseases; months of continuous insurance coverage prior to (baseline period) and after (follow-up period) the index hospitalization. outcomes included the proportions of patients receiving inpatient and/or outpatient vte prophylaxis, and the risk for vte events. years, and . % were female. patients were hospitalized for infectious diseases ( . %), respiratory diseases ( . %), cancer ( . %), heart failure ( . %), ischemic stroke ( . %), and rheumatic diseases ( . %). mean hospital length of stay was . days. in total, . % (n= , ) of patients did not receive any vte prophylaxis, and . % (n= , ) received both inpatient and outpatient vte prophylaxis. during hospitalization, . % (n= , ) received vte prophylaxis (enoxaparin, . %; warfarin, . %; enoxaparin and warfarin, . %; a direct oral anticoagulant (doac), ~ %). following discharge, . % (n= , ) received outpatient vte prophylaxis (warfarin, . %; doac, . %; enoxaparin, . %; enoxaparin and warfarin, . %). among the entire study population, the vte event risk remained elevated up to - days after hospital admission. among hospitalized acutely ill medical patients, the risk for vte was present in both the inpatient and outpatient settings, with significant vte risk extending into the post-hospitalization period. only a small portion of at-risk patients ( . %) received vte prophylaxis in both the inpatient and outpatient continuum of care, suggesting an unmet medical need for vte prophylaxis in the post-hospitalization. brain edema is a good research target in various forms of neurologic injury. a real time measurement of brain edema is possible using thermal conductivity methods. however, this technique might be hard to apply in small rodents, which are commonly used as experimental brain edema models. we developed a new approach method for applying thermal conductivity methods in rodent brain edema model. a -week-old spraque-dawley rats were used for brain edema model. qflow probe was inserted through a suboccipital burr hole, located mm left from the midline, then was advanced anteriorly mm from the occipital bone margin until probe place assistance value indicates valid values (ranging from to . ). probe was fixated using adhesive glues and tagging suture. in vivo brain water content was continuously calculated using thermal conductivity values. for validation, calculated brain edema was compared with standard methods (dry/wet brain weight ratio) in water intoxication models (intraperitoneal injection of distilled water, % of body weight) and drying effect of mannitol was validated in streptokinase induced intracerebral hemorrhage (ich) models. calculated brain water content was . ± . % in thermal conductivity method and . ± . % using dry/wet weight ratio methods (p= . ). in water intoxication model, brain water content started to increase minutes after injection and reached up to . ± . % at hours post injection. on wet/dry weight method, edema was measured as . ± . % (p= . ). in ich model, brain water content started to drop minutes after administration of mannitol ( . mg/kg) and drifted back hours after injection of mannitol. thermal conductivity method in assessing brain edema is applicable in rodents using suboccipital approach through burr hole. this method may better reflect dynamic changes of brain edema. in patients with critical brain injury, alterations of brain physiology with dialysis initiation are poorly understood. from a consecutive series of brain-injured patients undergoing invasive multimodality monitoring between and , patients that underwent continuous veno-venous hemodialysis (cvvh-d) and patients that underwent intermittent hemodialysis (ihd) were identified. changes in mean arterial pressure (map), intracranial pressure (icp), and brain tissue oxygenation (pbto ), and microdialysis lactate-pyruvate ratio (lpr) were compared six hours prior to and twelve hours following dialysis initiation. high-resolution data was collected every seconds, with the exception of lpr collected hourly. data were normalized to patient maximum values, analyzed by fitted segmented regression, and checked for slope change-points by davies' test. values prior to dialysis initiation were averaged as a baseline for comparison. median values for patients undergoing cvvh-d were map +/- . , icp . +/- . , pbto . +/- . mmhg (n= ), and lpr . +/- . (n= ). normalized median values for patients undergoing ihd were map +/- . , icp +/- . . for the cvvh patient segmented regressions with normalized data, there was no change in map (slope . ) during the twelve hours. however, we found a change-point in icp at . hours (ci . - . , slope change . to . ) and pbto at . hours , slope change . to - . ). lpr increased through cvvh (slope . +/- . ). median values for patients undergoing ihd were map +/- . , icp +/- . . there was no identified change-points in map or icp in ihd patients, further parameters were limited by small sample size. initiation of cvvh in patients with neurologic multimodality monitoring showed change-points in icp and pbto in setting of stable map, with slight decrease in icp and pbto . initiation of hd in showed no change-points in icp. data on the cerebral effects of antihypertensive agents are limited but potentially important in patients requiring blood pressure reduction in neurological emergencies. our objective was to measure the effect of rapid-acting antihypertensive agents on cerebral blood flow (cbf) in patients with acute hypertension we conducted a prospective, quasi-experimental study of patients with a sbp > mmhg and planned rapid-acting antihypertensive treatment in the emergency department. patients < years or pregnant were excluded. non-invasive hemodynamic and transcranial doppler measurements of the middle cerebral artery mean flow velocity (mfv) were obtained prior to and post treatment. analysis included descriptive statistics and generalized linear modeling to test the effect of four categories of antihypertensive agents on mfv. categories included clonidine, iv labetalol, iv hydralazine and combination therapy. we enrolled patients ( % female) with a mean age of ± years. eight ( %) patients received clonidine, ( %) iv labetalol, ( %) iv hydralazine and ( %) combined therapy. the mean baseline sbp was ± mmhg and mfv ± cm/sec. the mean percentage fall in sbp by medication was: clonidine - ± %, labetalol - ± %, hydralazine - ± %, and combination - ± %. the overall change in mfv was - ± %, and by medication was: clonidine - % ( %ci - to - %), labetalol - % ( %ci - to - %), hydralazine + % ( %ci - to + %), and combination - % ( %ci - to - %). adjusting for baseline bp, hydralazine caused less change in mfv compared to other medications (difference between means + %, %ci - to + %, p= . ). in this study with modest bp reductions, rapid-acting antihypertensive medications had comparable effects on cerebral blood flow. these results hint that cerebral blood flow may be more stable with hydralazine administration, but further testing of hydralazine and infusions such as nicardipine is required. studies exploring correlations between non-invasive (oscillometric) blood pressure (nibp) and intraarterial blood pressure (abp) have excluded neurocritically ill patients with continuous infusion of vasoactive medications. compared to abp, nibp monitors generally tend to over-read at low values and under-read at high values. this study examines the relationship between simultaneously measured nibp and abp recordings in these patients. following informed consent, prospective observation of patients (n= ) admitted to a neurosciences icu, with simultaneous abp and nibp monitoring and continuous vasopressor (n= ) or antihypertensive (n= ) infusion. paired nibp/abp observations along with covariate and demographic data were abstracted via chart audit. analysis was performed using sas v . . , paired nibp/abp observations from subjects ( % male, % white, mean age years) receiving vasopressors (n= ) or antihypertensive agents (n= ). t-tests show significant difference between paired readings: ([sbp: m= vs mmhg respectively; p<. ], [dbp: m= vs mmhg respectively, p<. ], [map: m= vs m= mmhg respectively, p<. ]). the paired differences for specific medications were tabulated, with - % of the differences < mmhg, and - % of the values with < mmhg difference. bland-altman plots for map, sbp, and dbp demonstrate good intermethod agreement between paired measures (excluding outliers) and demonstrated marked nibp-abp sbp differences at higher blood pressures. pearson correlation coefficients for paired measurements show strong positive correlation for map (+ . ), sbp (+ . ), and dbp (+ . ). despite a statistically significant difference between nibp and abp readings for patients on vasoactive medications, there may be no clinical significance. the relatively positive and linear correlation between paired values guide providers towards not being forced to use one over the other. the final manuscript will aim to detail whether there is a clinical significance in particular vasoactive medications. pathological activity in continuous electroencephalogram (ceeg) data of icu patients is conventionally categorized into a small number of named rhythmic and periodic patterns. we aimed to develop a valid method to automatically discover a small number of homogeneous pattern clusters, to facilitate efficient interactive labeling by ceeg experts. we extracted time and frequency domain features from + hour ceeg recordings from different icu patients. after removing artifacts, we applied principal component analysis ( % variance retained), then separated the data into clusters (k-means). from each cluster we took random samples plus the most central one, rendering samples in total. three expert electroencephalographers independently categorized all samples into one of standard pattern categories (seizures, gpds, lpds, lrda, grda, burst suppression, other). we compared two methods for labeling clusters: ( ) "labor intensive labeling" (lil): assign the most frequent of expert-provided labels; ( ) "labor efficient labeling " (lel): assign the most frequent of the expert labels for the central sample. we compared interrater agreement (ira) among experts vs. between each expert and consensus labels using lil vs. lel. finally, we used laplacian eigenmaps (le) to visualize the data. this research suggests that large ceeg datasets can be automatically clustered into a small number of patterns described by standard icu eeg pattern labels. we demonstrated efficient cluster labeling by inspecting only the central-most representative of each cluster. furthermore, le visualizations support the hypothesis of an interictal-ictal continuum. real time measurement of cerebral oxyhemoglobin (oxyhb) and deoxyhemoglobin (deoxyhb) using near infrared spectroscopy (nirs) may help us better understand the status of cerebral oxygenation and possibly cerebral blood flow (cbf) in patients with acute brain injury. we developed multichannel functional nirs (fnirs) system and evaluated its role in patients with acute brain injury. a channel fnirs system (nirsittm) was used for measuring cerebral oxyhb and deoxyhb in patients with brain injury. measurement protocols were as follows; baseline measurement for minutes with activation stimuli (nipple pinching for seconds). patients groups were categorized as follows; ) global cerebral ischemia with profound cerebral injury (n= ), ) large ischemic stroke or decrease in cbf in the frontal lobe due to severe stenosis in the middle cerebral artery (mca) or internal carotid artery (ica) (n= ), ) high grade subarachnoid hemorrhage with a risk of vasospasm (n= ), control groups did not have either cerebral lesion or cbf abnormality (n= ). global ischemia with good functional outcome group had better oxyhb level (rso ) compared to those with poor outcome ( . % vs. . %, respectively, p = . ). patients with poor perfusion in the mca territory had low oxyhb level compared to mirror lead in the contralateral hemisphere. oxyhb level in patients with decreased vasomotor reactivity on diamox spect had improved after carotid stenting. three patients who underwent superficial temporal artery-middle cerebral artery bypass surgery had transient hyperperfusion syndrome. oxyhb and total hb were elevated in the affected area. patients with sah and vasospasm had blunted oscillation pattern of oxyhb compared to those without vasospasm. bedside multichannel measurement of oxyhb and deoxyhb using fnirs might be useful in understanding hemodynamic changes occurring in patients with acute brain damage at the real time. multimodality monitoring (mmm), brain tissue oxygenation (pbto ) and microdialysis (md) in sah may be important to the treatment of delayed cerebral ischemia (dci). our hypothesis was that concordance between pbto and md occurs in the tissue bed displaying angiographic vasospasm. this retrospective observational study includes patients with sah. the extent of angiographic vasospasm for each vessel was graded on angiography by the on call neuro-interventionalist and quantified as (no spasm) to (severe spasm). pbto and md probes were placed in the frontal lobe white matter. the severity of vasospasm was estimated by the weighted average of ( x aca + x mca + x ica) / . cases with score of or more were considered to have clinically relevant vasospasm. using a within-subjects design, epochs of baseline mmm were compared with during spasm using daily mean for pbto , lpr, glucose, icp and cpp. given the limited number of observations the simplifying assumption was made that the observations from all epochs are independent. the measurements from all patients were divided in the two groups with and without spasm and were compared using a twotailed non-paired student t-test. sixteen sets of baseline and vasospasm epochs were evaluated for pbto and for md. compared with baseline values, the average pbto was significantly lower ( . vs . mmhg, p= . ), lpr was non-significantly higher ( . vs . , p= . ), and glucose was similar ( . vs . mmol/l, p= . ) during vasospasm epochs. there was no difference in icp ( . vs . mmhg, p= . ). these differences were unaffected by induced hypertension, when cpp was augmented for treatment of dci ( . vs . mmhg, p= . ). mmm during angiographic vasospasm after sah suggests discordant changes in brain oxygenation and metabolism. these data suggests that dci may be related to metabolic factors other than tissue oxygenation. multimodal monitoring including brain tissue oxygenation (pbto ) is increasingly used for the management of acute tbi patients. the optimal management of pbto is not fully established. increasing fio is efficacious to correct pbto but may mask other oxygen delivery mechanisms which may be deficient. the objective of this study was to explore the clinical utility of a pbto /pao ratio to detect overtreatment by fio . retrospective cohort stud were collected simultaneously whenever an arterial blood gas was drawn (icp, cpp, hemoglobin, temperature, pco and pao ). causes of cerebral hypoxia (pbto < mmhg) were noted. pbto /pao ratio < . was considered abnormal and plotted over time for each patient individually. data sets were collected from patients (mean age . ± . , median gcs , mortality %). . % of the time and associated with a mean pao of mmhg. measures within the low pbto -low ratio category had significantly lower cpp ( vs mmhg), higher pao ( vs mmhg) than patients with normal pbto or normal ratio respectively. various causes of hypoxic pbto were reported when the ratio was abnormal: hypocapnia, low cpp, low cardiac index, long equilibration time... four patterns of evolution of the ratio over time were identified and associated with different mortality rate: . %, . %, . % and %. conclusions associated with increased pao and decreased cpp. this suggests clinicians often used fio to compensate for deficient cerebral oxygen delivery. indeed, various causes of hypoxia besides low pao were identified and corrected. pattern of temporal evolution of the ratio seems to correlate with mortality. pupillary light response (plr) evaluates cranial nerves ii, iii, and midbrain function. bedside quantitative infrared pupillometry provides reproducible assessment of the plr, reported as the neurological pupillary index (npi). increased intracranial pressure results in decreases in npi. intracranial hypotension (ih) can also cause brainstem distortion. we therefore hypothesized that similar changes in npi could be seen with ih. here, we describe sequential changes in npi in ih before and after treatment. we identified four patients monitored with pupillometry for clinical care during ih diagnosis and treatment. ih was diagnosed with a compatible history, exam, and characteristic neuroimaging findings. patients' npi at baseline, during symptomatic ih, and after treatment were compared using related samples friedman's two-way anova and wilcoxon signed ranks tests. two patients were male; causes of ih were csf leak following lumbar instrumentation (n= ) and basilar skull fracture (n= ). mean baseline npi was normal (defined as > ) and declined in one or both eyes concurrent with clinical deterioration in the - hours preceding definitive diagnosis. all patients underwent treatment for csf leak with epidural blood patch or fracture repair, with return of npi > within hours of treatment. the baseline, symptomatic and post treatment npi's differed significantly ( . ± . vs . ± . vs . ± . , mean +/-sd, pre-treatment vs nadir vs post-treatment, p= . ). both baseline and post treatment npi's differed from the npi nadir (p= . ) but there was no difference between baseline and post-treatment npi (p = . ). impairment of the plr, as measured by npi, occurred during symptomatic ih and resolved after treatment. because management of intracranial hyper-and hypotension differ markedly, our results emphasize the importance of evaluating the clinical context before attributing pupillary/npi changes to increased icp. automated pupillometry provides a non-invasive, bedside tool for monitoring progression and treatment of intracranial hypotension the correlation of optic nerve sheath diameter (onsd) as seen on ultrasonography (us) and directly measured intracranial pressure (icp) has been well described. nevertheless, differences in ethnicity and type of icp monitor used are obstacles to the interpretation. therefore, we investigated the direct correlation between onsd and ventricular icp and defined an optimal cut-off point for identifying increased icp (iicp) in korean adults with brain lesions. this prospective study included patients who required an external ventricular drainage (evd) catheter for icp control. iicp was defined as an opening pressure over mmhg. onsd was measured using a mhz us probe before the procedure. linear regression analysis and receiver operator characteristic (roc) curve were used to assess the association between onsd and icp. optimal cut-off value for identifying iicp was defined. a total of patients who underwent onsd measurement with simultaneous evd catheter placement were enrolled in this study. thirty-two patients ( . %) were found to have iicp. onsd in patients with iicp ( . ± . mm) was significantly higher than in those without iicp ( . ± . mm) (p . mm disclosed a sensitivity of . % and a specificity of . % for identifying iicp. onsd as seen on bedside us correlated well with directly measured icp in korean adults with brain lesions. the optimal cut-off point of onsd for detecting iicp was . mm. impaired cerebral autoregulation following neurological insult has been established as a strong predictor of clinical outcome. hypothermia may offer autoregulatory protection in these patients, although the effect of body temperature on autoregulatory status is unclear. retrospective analysis of data from an ongoing prospective study to evaluate multimodal monitoring using near infrared spectroscopy (nirs) for bedside measurement of autoregulation. ninety-one comatose patients (gcs < ) were continuously monitored for up to three days. nirs derived cerebral oximetry index (cox) was used as a marker of autoregulation. cox was calculated as a moving, linear correlation coefficient between regional cerebral oxygenation saturation and map. autoregulation improves as cox values approach , and is impaired as values approach . patients were grouped by trend in temperature seen over the monitoring period: no change (< oc temperature change, n= ), increase (n= ), decrease (n= ), increase followed by decrease (n= ), decrease followed by increase (n= ), and fluctuating (n= ). we performed multivariable logistic regression analysis to assess the association between temperature and outcomes. the association between hourly temperature and cox was assessed using mixed random effects models with random intercept. in patients showing a sustained increase or decrease in temperature, a linear relationship between temperature and cox was seen; for every oc increase or decrease in temperature, cox changed by . ± . (p< . ) and - . ± . (p= . ), respectively, after adjusting for pco , haemoglobin, map and temperature probe location. mean temperature changes over the monitoring period for these groups were . ± . oc and - . ± . oc, respectively. cox did not change significantly in other groups. there was no significant difference in mortality or poor outcome (mrs - ) at discharge and , , or months between patients in each group. in acute coma patients in the neurocritical care unit, increasing body temperature is associated with worsening cerebral autoregulation as measured by cox. the historical tradition of examining the pupillary light reflex (plr) required the examiner to score the size and reactivity of the pupil. a change in the plr from brisk to sluggish or fixed may be a marker of a pathological process and a need for intervention. the plr has been difficult to quantify and has poor inter-rater reliability. handheld pupillometry provides several novel measures, such as the neurological pupillary index™ (npi) and constriction velocity (cv) that may be more quantifiable than the plr. the purpose of this analysis is to examine the relationship between cv and npi in neurologically injured patients. the end-panic registry is a prospective registry of pupillometer values and variables associated with intracranial dynamics (e.g., icp). this analysis from adult (over years) patients from hospitals includes , pupillometer readings; left eye ( , ), and right eye ( , ). subjects had a mean age of . yrs and . % were male. the primary admission diagnosis included neoplasm ( ), ischemic stroke ( ), sah ( ), ich ( ), tbi ( ), and other ( ). the left eye mean/s.d. cv ( . / . ) npi ( . / . ) and size ( . / . ) were similar to the right eye cv ( . / . ) npi ( . / . ) and size ( . / . ); statistically significant difference related to large sample size. the correlation between left eye cv and npi (r = . , p< . ) was significantly improved after controlling for size (r = . , p< . ). the correlation between right eye cv and npi (r = . , p< . ) was significantly improved after controlling for size (r = . , p< . ). constriction velocity is highly dependent on size of the pupil. further studies need to be undertaken to determine the sensitivity and specificity of abnormal npi and cv in detecting pathological processes such as midline shift or rd nerve compression that effect pupillary reactivity. cerebral injury is increasingly described in adult recipients of extracorporeal membrane oxygenation (ecmo) therapy. we describe the association between regional brain tissue oxygenation (rso ) measured by near infrared spectroscopy (nirs), survival, and cerebral injury on neuroimaging. a single-center retrospective chart review was conducted of adult patients who underwent veno-arterial (va) ecmo from april to october . all patients had received nirs monitoring during ecmo therapy. baseline demographics, in-hospital complications, and mortality were recorded. desaturations of rso , defined as decline > % below baseline or absolute value < , were recorded and analyzed. desaturation burden was calculated by area under the curve analysis and measured by rso *seconds. eighteen va ecmo patients ( females) underwent nirs monitoring during the study period. eleven patients experienced desaturations, while did not. patients with desaturations tended to be younger ( . vs. . years old), more likely female ( vs. ), had lower ejection fraction ( . % vs. . %) and experienced liver dysfunction ( patients vs. ). patients with desaturations were more likely to have abnormalities on ct scan ( vs. ). eleven of the patients survived to discharge. survivors tended to be younger ( . vs. . years old) and had lower initial ecmo sweep ( . vs. . ). survivors had lower baseline rso values at the beginning of nirs monitoring (right - vs. , left - vs. ), fewer desaturation events ( vs. ), lower desaturation burden, and spent less overall time desaturating ( : vs. : hours). desaturation on nirs may be correlated with cerebral injury in the adult va ecmo population and may have utility in triggering clinical investigation or determining prognosis. further studies in larger patient populations are needed to determine its reliability and accuracy. pressure reactivity index (prx) is the most validated index to measure cerebrovascular reactivity in patients after traumatic brain injury. the aim of this study is to identify the natural history of cerebral autoregulation measured by prx in various forms of brain injury to monitor restoration or not of cerebral vasomotor reactivity in the acute phase. retrospective analysis of data from ongoing prospective study to evaluate multimodal monitoring using prx for the measurement of cerebral autoregulation at the bedside. thirty comatose patients (glasgow coma scal used as a marker of autoregulation. prx was calculated as a moving, linear correlation coefficient between icp and map. impaired cerebral autoregulation has been pre standard maximal medical therapy was implemented to treat elevated icp, cerebral edema, etc. patients with withdrawal of care in the first hours or brain death on neurological exam were excluded. thirty comatose patients from acute brain injuries ( intracerebral hemorrhage, tbi, aneurysmal subarachnoid hemorrhage, intraventricular hemorrhage, hypoxic ischemic encephalopathy) were studied. the average prx upon starting neuromonitoring using prx was . ± . (impaired), whereas the average prx at the end of day of neuromonitoring was ± . (restored). one third of the patients had icp crisis during monitoring. the average opening icp= . , average highest recorded icp= . . impaired cerebral autoregulation has been implicated as a predictor of clinical outcome. aggressive medical therapy instituted by the neurocritical care team (icp and cerebral edema management, blood pressure control, etc.) may result in restoration of cerebral vasomotor reactivity measured by prx by intensive care day - . restoration of cerebral vascular reactivity may be a necessary but not sufficient for favorable outcome. elevated intracranial pressure (icp) is an important cause of death following acute liver failure (alf). while invasive icp monitoring (iicpm) remains the gold standard, the presence of coagulopathy increases the risk of bleeding in alf. measurement of optic nerve sheath diameter (onsd) using optic nerve ultrasound (onus) may accurately detect elevated icp. our goal was to study the ability of onus to detect sustained intracranial hypertension following alf, and to predict death and therapeutic intensity level (til), a quantitative measure of the intensity of treatment required to control icp. consecutive patients with alf admitted to our institution in a -year period underwent onus. blinded measurement of onsd was performed from deidentified onus videos. patients underwent iicpm on the basis of an institutional protocol for selection of appropriate candidates, coagulopathy reversal and insertion of an intraparenchymal monitor. the til-basic for management of icp during the icu stay was recorded. the ability of highest onsd to predict concurrent icp> mmhg at the time of measurement, sustained icp elevation > mmhg at any time and til-basic> was assessed in patients who underwent iicpm, while prediction of death was assessed in all patients. receiver operating characteristic (roc) curves were constructed for the outcomes of interest. thirty-nine patients with alf were admitted during the study period, / ( %) underwent onus, / ( %) underwent iicpm and ( %) died. of patients who underwent iicpm, ( %) developed sustained icp elevation and ( %) had a til-basic> . the roc area under the curve (auc) of onsd for prediction of concurrent icp> mmhg was . ( % confidence-interval . - . , p= . for null hypothesis of auc= . ), sustained icp elevation at any time was . ( . - . ,p= . ), death was . ( . - . ,p= . ) and til> was . ( . - . ,p= . ). in patients with alf, onsd measurement performed poorly for detection of icp elevation, and was a poor predictor of til and death. limited literature exists regarding the neurochemical and physiologic events that occur as brain death develops. using intracranial multi-modality monitoring, we identify physiological changes that signal the onset of brain death. we measured intracranial pressure (icp), brain partial oxygen tension (pbto ), cerebral blood flow (cbf), and biochemical correlates of cerebral metabolism in patients with diffuse hypoxic ischemic brain injury after cardiac arrest during the development of brain death. monitoring probes were inserted into cerebral white matter through a burr hole using a ct compatible multi-lumen bolt. brain tissue energy-related metabolites (lactate, pyruvate, glutamate, glucose, glycerol) were measured using a bedside microdialysis analyzer. pbto and temperature were measured via a licox catheter. cerebral perfusion was measured with a hemedex bowman perfusion monitor. brain death was confirmed in accordance with institutional guidelines. a characteristic pattern of physiologic and neurochemical findings emerged as brain death occurred. absolute loss of cerebral autoregulation, with a near perfect correlation between icp and map was followed by equalization of map and icp resulting in progressive drop in cpp to zero, followed by a progressive decline in pbto that became unresponsive to a % fio challenge. cerebral perfusion decreased in tandem with pbto . lactate/pyruvate ratio (lpr), glutamate, and glycerol all increased precipitously, with lpr consistently > . brain temperature decreased despite maintenance of a normal core temperature. finally, intracranial compliance, while initially very low (evidenced by marked increase in the p component of the icp waveform), appeared to paradoxically re-normalize as the recording continued. continuous neuromonitoring reveals a characteristic pattern of cerebrovascular physiologic changes that accompany brain death. these changes are consistent with a progressive cessation of cerebral perfusion caused by diffuse cerebral edema. although not currently a part of the formal brain death determination process, such monitoring could be helpful to identify when brain death has truly occurred. automated devices that collect objective quantitative data on pupil size and reactivity are increasingly used for critically ill patients with neurologic disease. however, there is limited data on the normative range of pupillary reactivity in the critically ill, and the relationship between reactivity and traditional monitoring metrics. to determine pupil characteristics in this population, we prospectively collected quantitative pupillometry data in patients admitted to the neuro icu with an expected stay of at least hours. trained nursing staff measured pupillary reactivity with the neuroptics- pupillometer device every -hours. measurements included the neurologic pupil index, (npi) a composite metric ranging from - in which > is considered normal, resting and constricted pupil size, constriction velocity, dilation velocity and latency. these recordings were compared with averaged intracranial pressure (icp) and glasgow coma scale (gcs) assessments within the same hour. we used univariate and spearman's rank tests to explore associations between pupil characteristics and clinical variables, followed by multi-level linear regression to account for intra-and inter-subject variability. one-hundred patients underwent paired observations. fifty-five patients had at least one recorded episode of anisocoria, had low npis in more than % of recordings, and had normal pupil reactivity. average and minimum npi was correlated with average and minimum recorded hourly glasgow coma score (gcs) (p values < . ). increased asymmetry in both pupil size (p= . ) and dilation velocity (p= . ) was associated with increased intracranial pressure (icp). anisocoria was associated with hyperosmolar therapy (p= . ). the presence of low npis in more than % of total pupil measurements was associated with death at discharge (p= . ). the range of pupillary metrics varies among critically ill neurologic patients and correlates with gcs and icp. further study is needed to establish whether change in pupil metrics predict specific clinical events. near infrared spectroscopy (nirs) provides a non-invasive measurement of regional cerebral oxygen saturation (rso ) that may be able to detect seizure activity. in this study, we explored the hypothesis that rso is lower ipsilateral to seizures or epileptiform activity compared to the contralateral side in comatose patients. five patients ( men and women; mean age ) underwent continuous electroencephalography (ceeg) monitoring and nirs recording. ceeg data were classified as baseline, epileptiform activity or seizure, slowing, or burst suppression at hourly intervals over the course of the recoding period (mean duration . hours, range to hours). three patients had idiopathic status epilepticus, two had intracranial hemorrhage, and one had a temporal meningioma. the relationship between rso and epileptiform discharges was explored using scatterplots. the association was assessed using mixed random effects models with a random intercept. an independent within-subject residual structure was used. there were measurements with ceeg and nirs from patients. one patient was excluded as the nirs sensors were potentially reversed. epileptiform activity or seizures were observed in a median of % of the measurements (iqr - %). rso was significantly lower on the side ipsilateral to seizures - . , p < . ) after adjusting for map. all patients only had partial seizures with no generalization. partial seizures and/or epileptiform discharges were not associated with impaired autoregulation. we found a significant lower cerebral oxygen saturation ipsilateral to seizures and/or epileptiform activity. the association was observed in patients with various etiologies of coma, and with either convulsive and non-convulsive seizures. decreases of regional cerebral oxygen saturation at the bedside may alert the clinician of ipsilateral seizures. elevated intracranial pressure (icp) and cerebral edema are common causes of mortality in neurocritical-care patients. key monitoring techniques for icp-elevation include neuroimaging and invasive icp-measurement. examination of the pupils is routinely performed to determine disturbances within cerebral physiology but shows high inter-rater variability. portable infrared pupillometry is increasingly used for accurate measurements. the benefit of these technique remains to be established in patients with elevated icp. aim of this study was identify pupillary parameters associated with icpcrisis in neurocritical-care patients. we prospectively enrolled critically-ill patients (subarachnoid hemorrhage/intracerebral hemorrhage/stroke/bacterial meningitis) admitted to our neurointensive care unit( / - / ) who required placement of external ventricular drains. we recorded serial pupillometer readings [i.e. maximum/minimum apertures(mm), constriction/dilation velocities(mm/sec.), latency period(sec.)] and corresponding icp values every hours after admission. neurological pupil index(npi), an algorithm that compares above mentioned pupillary parameters to a normative model of pupil reaction to light, grades pupil-function on a scale of (nonreactive) to (normal). receiver operating characteristic(roc) curve analysis was performed to investigate associations between pupillary parameters and presence of icpcrisis(icp> mmhg). in our data suggest a relationship between non-invasively detected changes in npi, cv or mcv and icpcrisis. yet, clinical benefit of these parameters is subject to future studies. lung injury is frequently observed in patients with severe, acute brain injury. while these patients often require mechanical ventilation, a lung protective ventilation strategy has not been extensively studied. this may be due, in part, to concerns that elevated positive end-expiratory pressure (peep) could adversely affect intracranial pressure (icp) or cerebral perfusion pressure (cpp). we were interested in exploring this relationship as a first step towards understanding whether mechanical ventilation resulted in a transmission of pressure to the brain. ) and received both mechanical ventilation and icp monitoring were enrolled in this pilot study. an esophageal balloon was inserted to measure their transpulmonary pressure (ptp). fluid responsiveness was assessed prior to the intervention. subjects underwent a step-wise increase in peep (increments of five) from to cmh o. airway pressure, ptp and icp were measured at each peep interval. of the planned twenty, three patients have been enrolled to date. primary diagnoses included aneurysmal subarachnoid hemorrhage and intraparenchymal hemorrhage with a median gcs of . patients were ventilated using either volume control or pressure support ventilation; median fio was . . two patients were on vasopressors and the same two patients were determined to be fluid responsive. at baseline (peep ), mean icp, cpp, and ptp were mmhg, mmhg, and - . cmh o, respectively. when peep was increased to cmh o, the average change from baseline in icp and cpp was - . % and - . %, respectively. when increased to cmh o the change from baseline in icp and cpp was . % and . %. during the intervention icp did not exceed mmhg, nor did any patient experience hypotension. preliminary data suggests that intrathoracic pressure is not directly transmitted to the intracranial compartment. continued enrollment is needed to confirm these findings. neurocritical care after severe traumatic brain injury (stbi) is focused on detecting and preventing secondary brain injuries. in addition to intracranial pressure (icp), measures of brain tissue oxygen (pbto ), regional cerebral blood flow (rcbf), and electrocorticography (deeg) may provide critical clinical data. few studies have assessed the safety of such an approach and the reliability of data that is gathered. we describe here the placement, complications, and reliability of multimodality monitoring (mmm) data from a novel, single burr hole approach using a four-lumen bolt at our institution. we included consecutive adult stbi patients admitted to the neuroscience intensive care unit at the university of cincinnati from april to march who underwent mmm as part of standard clinical management per institutional protocol. data was obtained regarding device placement and complications. all data was visually inspected for errors and gaps in data. patients were included. the mean age was +/- and % were men. bolts were placed a median of . (iqr . - . ) hours from injury. no clinically significant complications occurred, although . % had minor complications (e.g. small tract hemorrhage or pneumocephalus). suboptimal placement of probes was noted in %. we monitored patients a median . (iqr . - . ) hours. icp data was the most reliable, with data available . % of the total monitoring time and only . % error time. pbto and deeg data were reliable for > % of total monitoring time with < % error time. rcbf provided data for % of total monitoring time and had . % error time. mmm in stbi may be carried out via a single burr hole without significant clinical complications and reliably yields continuous data to facilitate clinical decision making. this supports the feasibility of our approach as an alternative to icp monitoring alone. intracranial hemorrhage patients with non-compliant ventricles may have high intracranial pressure (icp) despite normal ventricle size. we aimed to assess the incidence of elevated icp among those with no radiographic evidence of intracranial hypertension. prospectively enrolled primary intracranial hemorrhage patients (sah, sdh and iph) admitted to two tertiary-care centers between / - / were retrospectively reviewed. among patients with external ventricular drainage (evd), admission head ct (hct) scans within h prior to evd placement were reviewed for evidence of elevated intracranial pressure (icp) including: ventricle size (bicaudate index, temporal horn size), basal cistern effacement, midline shift and global cerebral edema. when all of these features were absent, patients were classified as having normal-icp hct. the incidence of elevated icp (> mmhg) at the time of evd placement and during hospital stay were recorded. of intracranial hemorrhage patients enrolled, ( %) had evd. / ( %) had a normal-icp hct. of these, / ( %) had elevated opening pressure at the time of evd placement, and / ( %) had elevated icp during their hospital stay. among normal-icp hct patients with icp> mmhg, % had sah, and the median gcs and hunt-hess scores were (range - ) and (range - ). the positive and negative predictive values of normal-re % %, respectively (auc . , p= . ) the only radiographic feature that was associated with elevated icp was global cerebral edema (or . , % ci . - . , p< . ). approximately half of intracranial hemorrhage patients without radiographic features of elevated icp had icp> mmhg at the time of evd placement and additional patients had elevated icp during their hospital stay. radiographic findings should not be relied upon to exclude the possibility of elevated icp. the measurement of intracranial pressure (icp) is a cornerstone of intensive care management following severe traumatic brain injury (stbi). it has been only recently that the time integral of icp has been quantified in relation to outcome; the time integral of brain tissue oxygen (pbto ) has not been studied. we gathered time-locked intracranial monitoring data on s tbi patients at the university of cincinnati over years. clinical management of all patients followed national standards. raumedic pto probe was used to measure icp and pbto ; accuracy was verified by visual inspection with automated data cleaning. normalized data was mapped based on correlation with glasgow outcome scale scores at - months. we studied patients aged +/- years (mean+/-sd); % were male. initial post-resuscitation glasgow coma scale score was median (interquartile range: . - ). / underwent craniectomy prior to monitoring. among those with good (gos - ) and poor (gos - ) outcome, the average icp was . +/- . mmhg and . +/- . mmhg (p= . ); the average pbto was . +/- . mmhg and . +/- . mmhg (both n.s.). the correlation with outcome was dependent on both icp and time: an icp > mmhg for > minutes was associated with poor outcome, whereas an icp < mmhg was associated with poor outcome only after hours. in contrast, the pbto level, but not the duration, correlated with poor outcome in those without craniectomy at a pbto < mmhg, and particularly below mmhg. pbto burden was less reliable in those following craniectomy. we replicated the effects of icp/time in a cohort of patients with severe tbi, both with and without craniectomy and subsequently demonstrated the burden of brain tissue hypoxia in those without craniectomy. the time integral of multimodality monitoring data may provide more accurate measures of secondary insult burden with implications for clinical care and prognosis. neurologists who work in neurocritical care (ncc) as neurointensivists may have critical care (cc) charges rejected for payment unless they are classified per centers for medicare services (cms) taxonomy codes in their systems as critical care providers. the neurocritical care society and cms created a new ncc code a x to fix this issue. we polled the aan ccen section members for awareness of this problem. we conducted a six question google forms survey using the aan ccen synapse community website to assess knowledge of the ncc taxonomy code: we received anonymous responses by the time we closed the poll on / / . question (q ) and (answers, a ): are you a neurology or neurosurgery back grounded intensivist who does neurocritical care at your hospital? y/n (yes/no). a : % reported being neurologists. q : were you aware of the new cms neurocritical care taxonomy code a x ? y/n a : % were aware of the taxonomy code. q : are you aware why the ncc taxonomy code was created? y/n a : % of respondents were unaware why this code was created. q : what is your primary department for revenue collection? a : % reported neurology, % neurosurgery, % critical care, and % blend. q : are you aware that medicare can reject critical care charges ( and ) can be rejected unless you are listed as a cms 'critical care provider' or as a neurocritical care provider? a : % reported rejected charges at their centers. q : are you aware of rejection of critical care charges happening at your own institution due to this misclassification? y/n a : % of respondents reported rejected charges at their center. although limited in sample size, this survey revealed almost half of the respondents were unaware of the ncc code. we believe a larger study is warranted. arterial subdural hemorrhage (sdh) is a rare but potentially devastating neurologic entity. it has been associated with ruptured aneurysms. we report a case-series of five patients with arterial sdh and their outcomes. a retrospective chart review of our institute's vascular database was conducted using a pre-defined search strategy including the terms "aneurysm", "arterio-venous malformation", "subdural hemorrhage", and "dural arterio-venous fistula" (dural-avf). amongst patients in the database, five cases were identified with ages ranging from to (four females). four had sdh due to aneurysm (two internal-carotid, one middle-cerebral, and one posteriorcerebral artery; one had parieto-occipital dural av-fistula. no patient had preceding head-trauma or anticoagulation. of aneurysmal patients, one had no sah. on admission ct-head imaging, the mean-sdh size was . mm (sd . ; range . - mm), and mean midline-shift (mls) was . mm (sd . ; range - mm). the mean ratio between sdh-size and mls was . (sd . ). in a historic cohort of acute subdural hemorrhage of non-arterial etiology ; the mean size of sdh was . mm and the mean mls was . mm. ratio of mls: sdh size was . . in our series, three patients with aneurysms had decompressive-craniectomy, one had mini-craniotomy for sdh evacuation; the patient with dural-avf had coiling and mini-craniotomy for sdh evacuation. four patients had died during hospitalization, whereas patient with dural-avf recovered to baseline functional-status at -month follow-up. arterial sdh is a rare entity and may present without subarachnoid hemorrhage and any preceding head-trauma. the degree of midline-shift is usually out of proportion to sdh size. there should be a low threshold to obtain vessel imaging in cases of sdh with no clear trauma history. mls: sdh ratio may be a useful screening tool for possibility of arterial sdh especially in absence of trauma and may reflect rate of bleeding. neurostimulant medications (amantadine and modafinil) are sometimes prescribed after acute nontraumatic brain injury to facilitate wakening and rehabilitation participation; the safety and effectiveness of this practice is unknown. following a retrospective evaluation of our experiences, we characterized anticipated challenges to designing a prospective randomized trial of neurostimulant medications to promote rehabilitation participation after acute non-traumatic brain injury. retrospective chart review of patients over with subarachnoid hemorrhage (n= ), intracerebral hemorrhage (n= ) and ischemic stroke (n= ) who received neurostimulant medications over a period of months. data regarding clinical course and potential confounders to assessing response were collected. continuous data are reported as median and interquartile range. neurostimulant medications were initiated in patients at a median of ( - ) days after hospital admission, for hypersomnolence ( %), not following commands ( %), lack of eye opening ( %), and/or low gcs ( %). thirty-nine ( %) patients were receiving sedatives or opioids at the time of neurostimulant(s) initiation. twenty-two ( %) patients received newly prescribed sedatives or opioids after neurostimulant(s) initiation. potentially sedating antiepileptic medications were prescribed to ( %) of patients. twenty-two ( %) patients were intubated at the time of neurostimulant initiation confounding the gcs-v. potentially confounding clinical factors included hydrocephalus ( %), vasospasm ( %), and seizures ( %). twenty-eight ( %) of patients had temporary cerebrospinal fluid diversion in place at the time of neurostimulant initiation. initiation and titration of neurostimulant medications after acute non-traumatic brain injury was common, but timing and indications varied widely. confounders to assessing effectiveness included concomitant sedating medications, variable pathophysiology related to the type and location of the stroke, and clinical factors like seizures, vasospasm, and hydrocephalus. these confounders are likely to make prospective evaluation of neurostimulant medication effectiveness difficult in the period of initial therapy following acute non-traumatic brain injury. brain small vessel disease can cause cognitive impairment via ischemic or hemorrhagic mechanisms. current imaging modalities, specifically magnetic resonance imaging allow for easier detection of different intracranial pathological processes including cerebral microhemorrhages (cms). research demonstrated that the number and location of cms correlate with the type of cognitive impairment (memory, processing speed, executive function, and motor speed). a retrospective analysis of patients (age to ) seen at our neurology outpatient clinic from to who were identified by linguamatics software to have "microhemorrhage" in their radiology mri report. additional information included age, sex, cognitive examination, presence of cardiovascular risk factors, mri, and the number and location of cms. cognitive function was determined by mini mental state examination (mmse) score and diagnosis by a cognitive neurologist. patients were grouped by presence of cm or greater ( to ) and regression was used to determine a relationship with mmse and vascular risk factors. the number of microhemorrhages per patient were ( patients), ( patients), ( patients), ( patients), ( patients), ( patients) and ( patients). vascular risk factors included hypertension ( patients), diabetes mellitus ( patients) and smoking history ( patients). regression analyses indicated that the presence of more than cm correctly predicted mmse lower than at % (p= . ). age was the only factor that influences this finding and increased this prediction to %. this study provides novel evidence that the presence of multiple cms on brain images predicts the presence of cognitive impairment. this study raises the need for more investigations. point-of-care ultrasound is a valuable tool in critical care, allowing timely and frequent beside assessment of clinical questions. neurocritical care has long utilized transcranial doppler but is still early in the adoption of other critical care ultrasounds. this study looked at the comfort level and competency of the participants at the point-of-care ultrasound workshop at the neurocritical care society annual meeting. the workshop comprised of didactics and hands-on small group practice using live models. topics covered included ultrasound physics, lung, cardiac, optic nerve sheath ultrasounds, as well as case studies in neurocritical care. participants were asked to complete an anonymous pre-and postworkshop assessment on a volunteer basis. a total pre-workshop and post-workshop assessments were completed. the mean age of the participants was . ± . years. there were ( . %) attending physicians, ( . %) advance practice practitioners, ( . %) fellows, ( . %) residents, and ( . %) research scientist. participants had limited ultrasound experience prior to the workshop, with ( . %) reported none, ( . %) reported < year, and ( . %) reported to years. on a - scale on comfort using ultrasound with being very uncomfortable and being very comfortable, participants reported a median score of (iqr - ) pre-workshop with an improvement to (iqr - ) post-workshop. for matched pre-and post-tests, all participants had an improvement in their ultrasound knowledge. while the majority of the participants at this workshop had prior ultrasound experience, many are still uncomfortable with their ultrasound competency. the format of didactics and hands-on small group practice improved the comfort level as well as overall ultrasound knowledge of these participants. additional opportunities for point-of-care ultrasound training should be considered in neurocritical care fellowships and meetings. event related potentials (erps) allow assessment of cognitive processing in unconscious brain-injured patients. here we explored the diagnostic and prognostic value of erps obtained shortly after brain injury. we prospectively collected a comprehensive erp paradigm labeled "local global paradigm" from a consecutive series of unconscious patients with acute brain injury. this auditory paradigm allows the assessment of: ) cortical responses, ) unconscious cognitive processing, ) unconscious focusing of attention, and ) conscious processing of sounds. levels of consciousness assessed with the coma recovery scale-revised (crs-r) at the time of recording were correlated with the presence/absence of each erps component and functional connectivity/complexity measures. we tested the prognostic value of each measure for recovery of consciousness prior to discharge. we analyzed recordings from patients (median recordings per patients [iqr , ]). recordings were made [iqr . , . ] days after brain injury and all patients were unconscious at the time of the initial recording. underlying etiologies included ich(n= ), sah(n= ), tbi( ) and other (n= ). there were trends for higher crs-r scores in patients with preserved erp components. crs-r scores correlated with the functional connectivity indexed (rho= . ; p= . ) but not with complexity measures. five ( %) patients regained consciousness (within to days from brain injury). one of these patients had to be excluded due to poor quality recording. all the ( %) remaining patients had the three type of non-conscious responses preserved on at least one recording in comparison to only ( %) among patient who did not recover consciousness (fischer p-value = . ). similarly, connectivity was greater in patients who regained consciousness ( . vs . ; p= . ) but the complexity was similar. simple bedside erp responses indexing cognitive processing during the local global paradigm obtained shortly after brain injury correlate with the level of consciousness but, more importantly, the probability to recover consciousness. over a decade ago, the institute of medicine introduced family-centered care (fcc) as a vital aspect of quality health care by strongly recommending that family members of intensive care unit (icu) patients be actively involved in decision-making. while there are many resources to help icu staff conduct meetings and provide information to families, the latest society of critical care medicine guidelines for fcc recommend the implementation of communication and decision support tools for family members to use. electronic decision support tools such as my icu guide have been effective in pilot studies at allowing family members to customize information delivery and communicate their preferences to icu staff. we sought to integrate a decision support and communication tool for families into an electronic patient portal. we developed an electronic patient and family engagement checklist for the neurointensive care unit (nicu) using doctella (patient doctor technologies, sunnyvale, ca), an existing patient engagement application. checklist components included: identifying a spokesperson, developing an advance directive, understanding diagnosis and prognosis, access to helpful resources, and a family meeting guide and planner. we presented the checklist to our hospital's patient and family engagement steering committee for the icus and received useful feedback. the checklist will also be vetted by the hospital's patient and family advisory council. usability testing will also be conducted. a family engagement checklist using an electronic patient portal is a novel strategy to enhance communication in the nicu. further validation of the tool is needed. applying painful stimuli to brain injured patients is a time-honored practice assumed to provide valuable clinical information for diagnosis, prognosis, and potential guidance for therapeutic interventions. however, there is limited literature that has evaluated and discussed the benefits and potential adverse effects related to repeated painful stimulation during bedside neurological examinations. though providers intend to do no harm, the practice of repetitive painful stimulation can unintentionally damage patient's skin, muscle, and bone, as well as inflict emotional duress. in conjunction with basic ethical principles used to justify painful stimulation during patient examinations, we propose a revisiting of the practice of routine repetitive painful stimulation in neurologic bedside assessments. . discuss the current literature regarding the use of painful stimulation and its beneficial and damaging effects, . describe alternative strategies for neurologic assessments, . propose guidelines to optimize accurate neurologic assessments while avoiding unnecessary repeated painful stimulation, . propose the development of a graded methodology for delivering painful stimulation when necessary for neurologic assessments. a summary of the literature will be outlined and discussed focusing on the ethical considerations and justification for the use of painful stimulation in the neurologic patient and the perception of pain in coma and minimally unconscious patients, . alternative strategies will be presented to minimize bodily and emotional injury, . a proposed outline with a companion flow diagram "easing the pain guidelines" implemented in a tertiary care neurocritical care unit will be presented. there has been little attention paid to the burden of painful stimulation inflicted on patients in the neurocritical care unit. the guiding principle of nonmaleficence (do no harm) morally obligates clinicians to evaluate current practice standards using repetitive painful stimulation in routine neurologic assessments. implementing standardized guidelines will limit unintended harm to patients without compromising accurate neurologic assessments. plasmapheresis is utilized in anti-n-methyl-d-aspartate receptor (nmdar) encephalitis to remove autoantibodies. antiepileptic drugs (aed), such as valproate, are often used to control seizures which may complicate anti-nmdar encephalitis. it is important to prevent rapid reductions of aed levels to ensure proper seizure management in this setting. we obtained total and free (active drug, unbound to plasma proteins) valproate levels intermittently throughout two -day courses of daily plasmapheresis. during the first course, trough levels were obtained. during the second course, levels were obtained before, during, and after plasmapheresis. the patient was a year old female, weighing kg. albumin was . g/dl. her valproate regimen ranged from mg to mg every hours ( to mg/kg/day), given intravenously or enterally. prior to the first plasmapheresis, valproate dose was mg every hours, resulting in a total level of mcg/ml (reference range: - mcg/ml). free valproate was mcg/ml (reference range: - mcg/ml); free fraction was % (reference range: - %). four days later, prior to the th plasmapheresis, the total valproate level was . mcg/ml. two days after the th plasmapheresis the total level was unchanged at mcg/ml; free valproate was mcg/ml and free fraction was %. during the second course of plasmapheresis, valproate total levels, free levels, and free fractions were mcg/ml, mcg/ml, and % before, mcg/ml, mcg/ml, and % during (valproate dose given upon initiation of plasmapheresis), and mcg/ml, mcg/ml, and % after plasmapheresis, respectively. valproate serum levels were not markedly influenced by plasmapheresis. free valproate levels and the free fraction were highly elevated throughout the patient's hospital course, however. future studies should evaluate critically ill patients' clinical response and toxicity correlations as the free fraction of valproate appears to be elevated in this setting. the purpose of this study is to assess knowledge retention of emergency neurological life support (enls) after participation in the course via a prospective observational study. study subjects seeking enls certification consented for study participation (enls-vs) from the ncs website then took a closed-book, multiple-choice question pre-test within hours of enls course participation. after completion of the enls course, participants took the same closed-book, multiplechoice question test (post-test). these tests consisted of novel questions from material presented in the course. questions were not repeated from the enls certification exams. thirty participants enrolled in the study with completing both the pre-test and immediate post-test. all participants' scores improved on the post-test as compared to the pre-test. the mean percent correct on the pre-test was . % with a median of . % (range . - . %). of the participants who have completed both pre-and immediate post-test, the mean pre-test score was . % with a median of . % (range . %- . %). the mean post-test score was . % with a median of . % (range . %- . %). the improvement of scores was statistically significant on the post-test compared to the pre-test ( . % vs. . % %, p< . ). all participants in the emergency neurological life support course showed improved test scores immediately after participation in the standard enls course. this study will assess knowledge retention at -months following training, and is actively enrolling new participants. augmented renal clearance (arc, defined as a creatinine clearance of > ml/min) has been demonstrated in neurocritical care disease states such as traumatic brain injury, intracranial hemorrhage, and subarachnoid hemorrhage. arc may result in increased elimination of renallyeliminated medications, thereby reducing drug exposure with standard doses. the overall prevalence of arc is not well described. the purpose of this study was to estimate the overall prevalence of arc in a neurocritical care population. this was a retrospective cohort study of adults > years of age admitted to the intensive care unit on the neurosurgery service. demographic and pertinent laboratory data were collected for patients admitted from january , thru december , . an arctic score was calculated for each patient ( or greater suggests arc). parametric data was compared using one-sample student's t-test, nominal data was compared using fisher's exact test (alpha = . ). statistical analysis was conducted using ibm spss version . present in a total of . % of patients. a broad spectrum of neurocritical care diagnoses was present. the mean age in years was significantly lower in patients with arc [ . ( sd)] than without arc [ ( sd), p = . ], as was the serum creatinine [with arc . mg/dl ( . sd) vs without arc mg/dl ( . sd), p < . ]. mean hospital length of stay was greater in patients with arc than without [ . ( sd) vs . ( sd), p < . ]. arc occurs commonly in neurocritical care patients and likely merits proactive screening or direct measurement of creatinine clearance in select patients. pharmacokinetic studies of commonly used renally-eliminated medications may be needed to establish population parameters in the neurocritical care population. education surveys demonstrate gaps in resident neurocritical care education and training. we assessed junior residents' baseline knowledge of neurologic emergencies, procedural competency, knowledge of available resources, and the impact of pre-rotation orientations. junior residents (neurosurgery pgy s and neurology pgy s) who had not previously rotated in the neuroicu were surveyed. a three-part survey was administered: part i, knowledge of icu structure and personnel; part ii, procedural competency; part iii, comfort with common neurocritical care emergencies. the survey was comprised of selection responses. after the survey but prior to starting the rotation, each resident was oriented to the unit by a neuroicu attending and nursing director. this orientation reviewed rotation goals, icu structure, personnel and rounding expectations. a survey was repeated to evaluate the orientation. of residents who had not rotated in the icu, ( . %) responded. none of the residents understood their specific role within the icu team. % did not understand the role of the resource nurse and were unaware of where to find procedure equipment. % of residents were not comfortable placing an a-line; % were not comfortable performing a lumbar puncture. over half of respondents said they "didn't know and could not easily find" the indications for hemicraniectomy after malignant mca ischemia, the indications for icp monitoring, or the initial workup of autoimmune encephalitis. residents responded to post orientation surveys. % felt the orientation was helpful in explaining the roles of team members. % felt it was at least "somewhat helpful" in understanding the role of the resource nurse. % felt the orientation was "helpful" and % felt it was "somewhat helpful" in identifying the goals of the rotation. these baseline measures underscore the importance of structured interventions, both before and during the neuroicu rotation, to improve junior resident comfort and preparedness in managing neurologic emergencies. physician-staffed helicopter emergency medical services (hems) are a well-established component of prehospital care in japan. however, there has been no report on hems and neurocritical care patients. we studied characteristics of neurocritical care patients who were transported by hems. we retrospectively evaluated neurocritical care patients who were brought to our emergency and critical care medical center (eccmc) by hems between january, and march, . we excluded patients in whom the outcome was unknown, those who were transported to other hospitals or between facilities. of the most important role of hems is rapid transportation of a flight medical team to the scene to provide immediate, lifesaving medical treatment. we found that half of patients admitted to our hospital by hems were neurocritical care patients. as proposed in the enls of neurocritical care society, hems is considered useful to allow neuro-emergency patients to receive the best care in the first hour. optic nerve sheath diameter (onsd) measurement using ocular ultrasound has been shown to accurately detect elevated intracranial pressure (icp), but does require specialized training. variations in the optimal onsd threshold for detection of elevated icp in the literature limits clinical utility, and may reflect heterogeneity in manual measurement techniques. our objective was to develop, and validate against expert measurement, an image-analysis algorithm for onsd measurement to facilitate standardization and ease of use of this technique. consecutive patients with acute brain injury admitted to the neurointensive care unit underwent ocular ultrasound with a multipurpose point-of-care ultrasound machine. a -second video was recorded from each eye in the axial plane and downloaded in dicom format. the onsd measurement algorithm was as follows. an average of images was calculated using non-overlapped segments of the image sequence. a line integral was performed to estimate the border of the region of interest (roi), the globe. the roi orientation and globe point of the segmented region were established, then a point mm posterior to the globe point identified. the onsd was measured at this point. manual onsd measurement was performed separately from the dicom videos by an expert blinded to the algorithm measurement. an intraclass coefficient (icc) was calculated for absolute agreement between highest onsd measured by the algorithm and expert manual measurement. a total of patients with acute brain injury underwent ocular ultrasound. the icc for absolute agreement between algorithm (median . , interquartile range . - . ) and manual expert (median . , . - . ) highest onsd measurement was . ( % confidence interval . - . ). an algorithm for automated measurement of onsd was developed and demonstrated good inter-rater agreement with expert measurement, although further refinement is required. automated measurement may help standardize and simplify a promising noninvasive bedside tool for the detection of elevated icp. after transition to electronic health record (ehr), transition to inpatient hospice required a separate encounter to account for change in insurance payer in our neuroicu. this negatively affected completed transitions and hence patient-centered care. the focus of this quality improvement project was to define the new process, improve outcomes, and identify further opportunities. the quality improvement method "plan-do-study-act" was employed for this work within a -bed neuro-icu at a large academic medical center. we assessed the current state (not enabling transition to inpatient hospice) and the desired state (enrollment in hospice during inpatient stay). a new process was created using an ehr discharge navigator, coordinating all relevant stakeholder groups (patient/caregiver, nurse, pharmacist, bed control, physician,). in addition, standard methodology for unit-based education, in-service, just-in-time training, and booster education was employed to identify process, outcome, and improvement opportunities. after rollout of the new discharge navigator, % of all patient-facing staff successfully completed the inpatient hospice training. process improvements lead to increase in palliative care consults by % ( to annually) and inpatient hospice discharges up to % ( to annually). furthermore, there was a statistically significant improvement in the vizient mortality index r = . , f( , ) = . , p < . and length of stay index r = . , f( , ) = . , p < . within the study population and period. ability to transfer patients to inpatient hospice is often limited and complicated. this study shows how employing standard quality improvement as well as education and implementation methods can result in improved process and outcome measures with sustainable success. opportunities remain in further analyzing and optimizing 'time to palliative care consult', 'time to admission to hospice and withdrawal of artificial support'. arnp and pa's are a rapidly growing part of the critical care workforce. proper selection among a pool of app candidates for the job is necessary to ensure the "right fit" and optimize patient safety. conventional interview techniques may not be adequate when selecting critical care app's. we hypothesized that use of a simulation center could be used to help select app candidates based on their critical thinking skills in conjunction with contemporary interviewing skills. from to , we performed conventional interviews for app's to staff critical care and neurocritical care patients. in we changed to an interview process consisting of the conventional interaction with the interviewee followed by simulation. after narrowing down the initial candidate pool, each was taken to the simulation center where they participated in a simulation of a decompensating patient. proctors were able to view the simulation in a separate room and direct the simulation mannequin. during this time proctors were able to evaluate the interviewee's patient interaction, assessment and interventions. an evaluation tool was to grade app candidates for their decision making skills, communication and thought. from to , we screened candidates before selecting for interviews and finally of those for simulation. over this timeframe, our center hired app's. comparing the ratio of screen applicants to employment was . and ratio of interviewed to hired candidates was . . these ratios show the competitive process and potential use of simulation in selecting apps. compared to the time period of applicants prior to simulation to after, retention went from to %, and disciplinary action for practice deficiencies went from % to %. the use of simulation based interviews for critical care app's in our institution improved retention and decreased the number of disciplinary actions compared to conventional interview methods. the contraindications for lumbar puncture (lp) in the setting of cerebral mass effect remain debatable. limited retrospective data advocate its potential safety. yet, high-quality guidelines specifically addressing this topic are not available. specific patient populations (post-instrumentation & immunosuppressed) may benefit from csf studies. we reviewed consecutive patients who underwent lp and cerebral imaging a week before or after lp from - . all individuals with evidence of brain herniation, a component of midline shift, or mass effect were included. all subjects received a low volume lp ( - cc of csf). there were patients with radiological increased icp. midline shift (average = mm) was present in patients. we also observed herniation: uncal (n= ), subfalcine (n= ), and a combination of both (n= ) , ventricular effacement (n= ) and cisternal compression with partial occlusion: quadrigeminal cistern (n= ), cerebellar-pontine-angle cistern (n= ), ambient cistern (n= ), crural cistern (n= ), prepontine cistern (n= ), suprasellar cistern (n= ), basal cistern (n= ), suprachiasmatic cistern (n= ), cisterna magna (n= ), interpeduncular cistern (n= ), medullary cistern (n= ). all patients tolerated the lp without complications. most survived a week after the procedure (n= , %). notably, four individuals deteriorated for reasons unrelated to the lp and expired within a week because of withdrawal of care. as brain compliance cannot yet be accurately determined radiologically, we believe anatomical involvement should drive decision-making regarding lp safety. our data suggest that a low volume lp ( - cc) might be safe in individuals with subfalcine herniation, midline mass effect < mm at foramen of monro level, and partial cisternal effacement. we believe that while lps might be safer in patients with supratentorial mass effect, individuals with posterior fossa involvement may tolerate it as well. these promising findings need further verification in larger sample populations. the importance of neurocritical care has recently been recognized in japan. however, to date, there has been no neurocritical care training program. we developed the neurocritical care hands-on seminar as a proposed training module, and here we report the satisfaction of participants. we prepared a post-course questionnaire about participants' degree of satisfaction. the main concept of our seminar was "how to maintain cerebral oxygen demand and supply balance." beginning with a short lecture about this concept, participants joined four hands-on scenarios: post-cardiac arrest syndrome (pcas), subarachnoid hemorrhage (sah), traumatic brain injury (tbi), and states epilepticus (se). in the pcas scenario, participants learned how to trouble shoot regarding targeted temperature management, especially in regard to the management of shivering. in the sah scenario, they learned about perioperative management, including delayed cerebral ischemia. in the tbi scenario, starting with actual insertion of an intracranial pressure (icp) monitor in the simulator, they learned about icp management through a scenario-based simulation. in the se scenario, they learned about se management, with actual continuous electroencephalogram monitoring. this seminar was held twice in . most participants were middle-aged intensivists; % were in their twenties ( / ), . % were in their thirties ( / ), . % were in their forties ( / ), and . % were in their fifties ( / ). most of the participating physicians were specialists in emergency or intensive care medicine ( . %; / ); nurses ( . %; / ) and a clinical engineer ( . %: / ) also participated. most participants ( . %; / ) were satisfied with the seminar, and almost all ( . %; / ) improved their self-confidence in the ability to carry out clinical practice in neurocritical care. we received positive, satisfied reactions from the japanese intensivists who participated in our seminar. for further improvement, we need to collect objective data to assess the utility of our neurocritical care hands-on seminar. lumbar puncture in the presence of mass effect? ciro ramos-estebanez uhcmc, case western reserve university/neurology, cleveland, ohio, usa introduction ) we propose an international consortium that would prospectively confirm the safety of low volume lumbar puncture (lp) in the presence of mass effect in selected scenarios. ) welcome peers and advisors to join the effort. lp may be clinically necessary in the presence of cerebral mass effect. while empirical antibiotic therapy is generally successful, specific groups such as post-instrumentation patients and immunosuppressed individuals may benefit from cerebrospinal fluid (csf) studies. in the absence of high-quality clinical recommendations, uncontrolled retrospective literature suggests that a small volume lp ( - cc) might be without complications in specific situations. nevertheless, the ethical principle of non-maleficence and the liability risk prevent clinicians from performing lps. in this scenario, an extended length of stay, poor outcomes, or a higher cost of care are legitimate concerns. synthesize an external peer reviewed methodology to maintain rigour and transparency. . seek appraisal, approval and endorsement of national and international quality improvement committees. . generate and assimilate the most current clinical evidence through: a. systematic review and meta-analysis. b. prospective randomized controlled clinical trial. . construct a protocol to inform decision making amongst healthcare and non-healthcare personnel. . dissemination and implementation. . schedule updates and/or revision. centers across the globe (north america = , south america= , europe= , and asia= ) have agreed to establish an lp consortium so far. retrospective analyses suggest low-volume lp's relative safety in the presence of increased icp. thereby, an expert consortium trusted with prospective verification would potentially benefit specific patient populations. patient centered decision making in the nccu requires family members understanding of their loved one's preferences and values as well as the complexities of their medical condition and treatments. family-centered care (fcc) is essential so that family members are actively involved in decision-making. stakeholders have reported their preference to receive prognostic information in smaller packets and recapitulated in different venues including rounds, bedside and care conferences. we examine implementation of a multimodal communication strategy on clinician utilization, family engagement and satisfaction in the nccu. an interdisciplinary team convened to develop a plan implementing a multimodal communication strategy. pre-implementation survey of clinicians (mds, nps, rns, etc.) and patient families was completed to determine the level of family engagement already in place in the nccu. four interventions were implemented: family communication boards were installed in patient rooms; family engagement pamphlets developed; a script and schedule for family care rounds was developed; nursing and provider staff were educated on inviting families to participate in patient care team rounds. family involvement on patient care rounds and family conferences was compared before and after the implementation of the best practice initiatives. additionally, pre and post implementation patient satisfaction survey results were also compared to evaluate the project's success. pre-implementation data was collected from october -november . sixty-one clinician surveys and forty family surveys found that family more consistently participated on daily rounds. baseline and postimplementation surveys demonstrated families feeling supported during the decision-making process. the implementation of a multimodal communication framework to achieve consistent family engagement and communication has led to an appreciable change in utilization by clinicians. its use is supported by consistent positive family attitudes towards communication and availability of information in the nccu. neurocritical care society undertook initiatives to integrate social media in member engagement activities and initiated a twitter journal club (#ncstjc) in with the first journal club conducted in february . articles were chosen by a subgroup of the communications committee in consultation with dr. eelco wijdicks, chief editor, neurocritical care journal. these articles were chosen based on their overall importance and the interest bound to generate amongst the journal club attendees. the journal club occurs bimonthy over an hour and is unique in the participation of the authors. the journal club is registered with healthcare hashtag project. each article chosen for #ncstjc is made available free to download weeks before and after the scheduled date for the journal club courts springer. analytics data on usage on article discussed in #ncstjc was obtained from sean beppler, editor, clinical medicine. between feb and apr , sessions were held with data available from . the ncc articles discussed had higher than average altmetric scores (measuring social media activity). these articles represented % of all ncc articles discussed on twitter since feb but . % of all tweets. total usage (number of times an article html page is accessed, or a pdf is downloaded ) was , ( mean , n= ) representing . % usage of all neurocritical care articles, a total of citations and downloads ( mean ) . the upper bound of the audience as assessed by the publisher was total of , for all articles (mean , per article) twitter is becoming an emerging platform for dissemination of information in medical education and academic activities. while the exact impact of the initiative on member engagement or outreach in enhancing journal impact or citations is hard to determine, we saw trends in enhanced engagement. neurostimulant medications have been studied in patients with traumatic brain injury, but few studies describe their use in patients with acute non-traumatic brain injury. our objective was to describe neurostimulant medication prescribing patterns, clinical response, and potential adverse effects in this patient population. retrospective database review of patients with acute ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage who received amantadine or modafinil from december through june . neurostimulant selection, dosing regimen, and indication were recorded. patients were classified as responders if they met two of the following three criteria within days of neurostimulant initiation: ) increase in average daily gcs of greater than points, ) neurological improvement documented in provider progress notes, or ) increased participation in rehabilitation therapies documented in physical or occupational therapist progress notes. safety data included need for a new anxiolytic or sleep aid or seizure. continuous data are reported as median with interquartile range. eighty-eight patients received neurostimulants: intracerebral hemorrhage (n= ), ischemic stroke (n= ), subarachnoid hemorrhage (n= ). median age was ( - ) years and ( %) were male. amantadine (n= ), modafinil (n= ), or both (n= ) were initiated a median of ( - ) days after hospital admission. the median initial daily dose of amantadine and modafinil were mg and mg, respectively. reasons for initiation included somnolence ( %), not following commands ( %), lack of eye opening ( %), and low gcs ( %). forty ( %) patients were responders, occurring at a median of ( - ) days after neurostimulant initiation. twenty-three ( %) patients required new prescription of an anxiolytic or sleep aid. four ( %) patients developed seizure. neurostimulant medications may increase wakefulness and participation in rehabilitation therapies in patients with acute non-traumatic brain injury, with tolerable adverse effects. the role of neurostimulants in this population should be defined in prospective studies. difficulty in obtaining peripheral intravenous (piv) access often necessitates central venous access placement in many critically ill patients. central line placement exposes patients to potential complications such as pneumothorax, hemorrhage, catheter-related infection or deep venous thrombosis. ultrasound-guided piv placement has become common practice in emergency departments, but there is no systematic program to train and support routine use of ultrasound-guided piv access in icus. we have developed a systematic program to train and support icu nurses in becoming experts and clinical leaders in ultrasound-guided piv placement. we hypothesize that implementation of this program will increase nurse confidence and chances of successful piv placement subsequently decrease central line-related complications in -bed neurocritical care icus. we have developed a video didactic training program for the neurocritical care nursing staff. the program discusses use and maintenance of the ultrasound machine and guided-technique for piv placement including the short-and long-axis approaches. the training video is followed by a hands-on simulation session using mannequins. standardized-surveys are administered to nurses before training and then at and months post training. we are prospectively collecting data on nurse comfort level with ultrasound-guided piv placement, total iv attempts, patient central line associated bacteremia (clab) rates and total number of patient central line days. we will compare this data for months pre-and post program implementation. comparisons will be made using t-test and chi-square analyses or non-parametric equivalents depending on data distribution. central-line related complications are an important clinical problem in all icus. we have developed and implemented a systematic training program to support nursing-led ultrasound-guided piv placement. we will determine if this program reduces the overall number of central lines placed, duration of indwelling central lines, and clab rates in a neurocritical care, and subsequently expand to additional icus and beyond. ultrasound measurement of optic nerve sheath diameter (onsd) is a sensitive and specific non-invasive ultrasonographers. despite clinical applications in the icu, er and outpatient settings, neurology residents lack experience and training. the aim of our project was to provide neurology residents with foundational skills in ocular ultrasound and onsd measurement. we designed a two-part workshop for neurology residents covering ultrasound basics, measurement of onsd, and ultrasound appearance of papilledema. workshop was a minute lecture and demonstration followed by minutes of hands-on practice. two weeks later, workshop included additional minutes of practice to consolidate learning. the practical portions were facilitated by emergency medicine attendings and residents with experience in performing ocular ultrasounds. neurology residents tracked the number of practice ultrasounds performed. they also completed anonymous pre-and posttests to assess their knowledge of ocular ultrasound and their comfort level and likelihood to perform future procedures using a -point likert scale. prior to the workshop, the majority ( / ) of neurology trainees had never performed an ocular ultrasound. one ( / ) was able to answer two basic questions about the procedure correctly, which increased to % on the posttest (n= ). trainees performed an average of ultrasounds total during the workshops. resident self-assessment of comfort performing the procedure increased from a median of "very uncomfortable" to "moderately comfortable" on the -point likert scale (p= . ). resident likelihood to perform the procedure in the future increased from a median of "very unlikely" to "moderately likely" on the -point likert scale (p= . ). this session successfully increased basic knowledge, comfort, and likelihood to perform ocular ultrasound among neurology residents. future directions include follow-up to gauge magnitude of practice changes and accuracy of procedural skills. reaching patients by telephone is a common method of assessing functional outcome, cognitive function, and quality of life after hospital discharge. however, when patients do not answer the phone, missing data creates bias and warrants strategies to increase follow-up rates. we hypothesized that we would have less follow up with patients discharged to long-term care facilities and sought to examine other potential sources of lost data. between / and / , we identified all patients admitted to the university of cincinnati neuroscience intensive care unit (nsicu). we excluded those with recurrent admissions, boarders, and those admitted < hours or for uncomplicated post-op care. telephone follow-up was attempted for each patient. univariate analysis was used to identify associations with patients who did not answer the phone. critically-ill patients were included. average age was . +/- . and % were men. the average hospital length-of-stay was . +/- . days. major diagnoses were: ischemic stroke ( %), intracerebral hemorrhage ( %), traumatic brain injury ( %), seizures/status epilepticus ( %) and subarachnoid hemorrhage ( %). ( %) died in the hospital; ( %) died by follow-up. survivors were assessed . +/- . days following admission. calls were answered, were not. there were no associations between rate of answered calls and age, gender, race, hospital length-of-stay, diagnosis, or hospital disposition. there were no differences in between morning vs. afternoon calls. only the number of attempts differed: the probability of an answered call was % on the first attempt but declined to % by the third attempt (or . ; p< . ). our outcome assessment strategy captured data on % of neurocritically ill patients. those who answer the phone are most likely to answer with the first call; the probability of a patient answering after a second phone call may not justify resources needed to continue calling these patients. posterior reversible encephalopathy syndrome (pres) typically presents with vasogenic edema on neuroimaging. a subset of patient, however, can have "atypical findings" including restricted diffusion and intracranial hemorrhage. these atypical findings all suggest acute vascular injury, and may mark a distinct pathophysiological subtype of pres. however, it is unknown whether atypical imaging findings are associated with differences in precipitating factors or outcome. patients with evidence of restricted diffusion, frank hematoma, microhemorrhage, or subarachnoid hemorrhage were classified as having atypical imaging findings. the demographics, risk factors, clinical outcomes, and degree of vasogenic edema for patients with typical (n = ) vs atypical pres findings of vascular injury (n = ) were analyzed. patients with atypical pres had a longer hospital stay ( . vs . days; p = . ) and were less likely to be discharged home ( . % vs . %; p = . ). severity of vasogenic edema (graded using a standardized radiologic scale) was also higher in patients with atypical imaging findings (severe edema: . % vs . %; p = . ). restricted diffusion and hemorrhage are features of acute vascular injury that may mark a unique pathophysiological subtype of pres. pres patients with these atypical imaging features had longer hospital stays, greater degree of vasogenic edema, and were less likely to be discharged home. this may be due to the fact that bleeding and infarction lead to irreversible brain injury, prolonging hospital stay and contributing to overall disability. in , deaths occurred in the neuro-oncologic critical care unit (nccu). the impact of this event is significant for patients, families, and the staff that care for them. brain and spinal pathology can be incredibly debilitating causing a rapid and impromptu decline of the patient's status. in order to better support patients, family, and staff throughout the dying process, the nccu staff created formalized endof-life care interventions. these interventions include educational pieces and supportive approaches to aid all involved through the dying process. several interventions were created to help transition the family members during the dying process. these include the creation of: dnr-cc closet, homemade blankets, condolence cards, hygiene bags, educational packets, word clouds, and aromatherapies and massage items. once the patient's code status is changed to comfort care, a blanket is given to the patient. family members are provided with a bag of toiletries for those that remain at bedside. education on the dying process are given to family members. multidisciplinary resources are provided, such as religious support focused on patient/family beliefs, palliative care for symptom management, and dietary provision of light snacks to the family. education for the physicians, nurse practitioners, nurses, and patient care associates was provided for those who wished to attend to further understand this end of life care program. a item tool was created to collect before and after data on staff satisfaction and comfort with the end of life process. results from this process are currently in process. creating specific end-of-life care interventions for the nccu have enabled staff to better care for patients and families. through the creation of the interventions and utilization of the dnr-cc closet, this unit has been able to better provide comprehensive education and supportive pieces to patients and family members during such a difficult time. delirium is a neuropsychiatric syndrome, characterized by disturbance in awareness, with reduced ability to sustain attention, impaired cognition, perception, tends to fluctuate in severity during the day; in critical care is associated with longer stay and increase mortality. this study aimed to determine the incidence, prevalence, predictors, risk factors and outcomes of delirium in critically ill adult. a historical cohort study was conducted in adult patients hospitalized in a polyvalent icu from january until december . delirium was diagnosed using cam-icu. a bivariate and multivariable risk were analyzed and presented as odds ratio (or) and % confidence interval (ci). a total of patients were enroll. delirium developed in patients.the incidence was . %. three independent predictors for delirium were identified, sedation (or ( % ci, p < , ); alcohol dependence (or , ; %ci, p < , ) and glasgow coma scale < (or , ; % ci, p < , ). delirious patients had a significantly apache ii ( ( - ) vs ( - ), p < . ), higher sofa, ( ( - ) vs ( - ), p< . ) and higher saps iii ( ( - ) vs ( - ), p< . ). other risk factors were hyperlactatemia ( p< . ), and hypotension (map< mmhg),(p< . ). patients required prolonged mechanical ventilation, p< . ), and prolonged icu-hospital stay. the incidence of delirium in the period from january to december , was . % in a polyvalent intensive care unit. exposure to sedative medications, alcohol dependence, and decrease glasgow coma scale minor are independent predictors for the development of delirium. similarly, the icu stay was longer in the group that developed delirium; however, mortality was not affected by the presence of this condition. it has been previously reported that the course of hsv- in the cns is significantly more benign that hsv- , and that it rarely causes encephalitis or significant morbidity in immunocompetent adults. the aim of our study was to investigate the claim that hsv- cns infections are typically benign, and to assess for predictors of poor outcome in those patients who do suffer significant morbidity from hsv- cns infections. restrospective chart reviews were completed on patients with a positive hsv pcr at our institution from july until july . patients with a hsv pcr positive for hsv- were selected in our analysis. multiple clinical variables were evaluated in these patients and we assessed outcome in the patient population, dichotomizing outcome into two categories at the time of discharge: good outcome defined as home or inpatient rehabilitation versus those with poor outcome defined as death, hospice, or placement in a long term acute care facility. patients with hsv- positive pcrs were identified. their charts were evaluated for demographics, laboratory values (serum and csf), imaging results, and outcome. there were patients with poor outcomes. it was noted that they were all female, their mean age was . (vs . in the good outcome group) and two of the three were immunocompromised ( % vs % in the good outcome group). statistical analysis was performed however due to the small sample size no statistical significance was found. however, age, sex, clinical presentation consistent with encephalitis and immune status seemed to have a trend towards poor outcome in this pilot study. future study with larger sample size is warrented to further assess this trend, as hsv- may not be as benign as previously reported. there is a high prevalence of non-traumatic illness in patients presenting to emergency departments as trauma team activations (tta). we sought to determine the prevalence of neurologic emergencies within a population of patients receiving a tta. this was a retrospective review of prospectively-collected registry data capturing all ttas in a highvolume, urban, academic level i trauma center. records from june through june were reviewed to identify patients found to have a diagnosis of ischemic stroke, intracerebral hemorrhage (ich), subarachnoid hemorrhage (sah) or status epilepticus. further demographic, clinical, and outcomes data was then abstracted from the electronic medical record. a proportion of abstracted charts were reviewed by an independent reviewer to ensure data quality. there were , trauma activations in the registry during the study period. patients ( . %) were found to have a nontraumatic neurologic emergency and were included in the analysis. of these patients, there were ischemic stroke ( %), ich ( %), sah ( %), and status epilepticus ( %) patients. the mean age was , and patients ( %) were male. the mean gcs on presentation was . about half of these patients ( %) were intubated in the emergency department. all patients received a head ct scan. patients ( %) received intravenous thrombolysis. neurologic emergencies such as ischemic stroke, ich, sah or status epilepticus were common diagnoses in this population of trauma activation patients. clinicians caring for patients in these settings must maintain a high index of suspicion for non-traumatic illnesses, and act quickly to mobilize appropriate resources when a diagnosis is made to avoid delays in care. further research is needed to examine ways to improve both time to diagnosis and quality of care in this patient population. formalized communication strategies decrease post-traumatic stress disorder (ptsd) symptoms in caregivers in the intensive care unit (icu). in one study, only % of family meetings met all shared decision-making criteria. however, much of the research has focused on family meetings, ignoring less formalized communication. the decision maker (patient or caregiver) was interviewed for all patients admitted to the medical (micu), neurosciences (nsicu), surgical (sicu), and cardiothoracic icu (cticu) for greater than hours. subjects who stated significant decisions had been made were asked to report on aspects of shared decision making on a -point scale. they identified the lead provider, who was subsequently approached to complete the same questionnaire. overall, eligible decision makers were identified, ( %) in the micu, ( %) in the nsicu, ( %) in the sicu, and ( %) in the cticu. of these, ( %) were unable to be contacted, ( %) had insufficient english, and ( %) reported no decisions made, with ( %) enrolled. nineteen ( %) provider interviews were completed. topics most reported covered "well" or "thoroughly" by caregivers were assessment of understanding ( , %) and the nature of the decision ( , %), while those least covered were need for input from others ( , %) and the context of the decision ( , %). topics reported most covered by providers were the nature of the decision ( , %) and opinions about the treatment decision ( , %), while those least covered were patient's values and preferences ( , %) and their preferred role in decision making ( , %). eighteen ( %) caregivers and ( %) providers described all topics covered "well" or "thoroughly." these results demonstrate differences in perception of shared decision making by decision makers and providers. further qualitative investigation is underway to elucidate the nature of these inconsistencies. organ donation is a life-saving medical intervention. the effect of race, insurance and economic status on organ donation and recipients has not been studied at a national level. in our study, we analyzed nationwide in-patient (nis) database of years - to select donors and recipients. baseline demographics (i.e., age, gender, race), insurance status and socio-economic status was compared between two groups. we identified donors (n= ) and recipients (n= ) from - . recipients were significantly older (mean age ± sd, . ± . vs . ± . , p< . ). donors had higher ( . % vs . %, p< . ) proportion of women compared to recipients. both groups had a higher proportion of whites compared to other races ( % and . % respectively). insured patients were largely represented in both groups with private insurance predominating in donors ( %) and medicare in recipients ( . %). interestingly, self pay represented . % of donors but only . % of recipients. race, insurance and socioeconomic status seem to be evenly similarly represented in donors and recipients. interestingly self pay insurance has a higher distribution among donors than recipients. central line-associated bloodstream infections (clabsis) are a common health care associated infection accounting for , infections annually in the intensive care and acute care areas (cdc, ). according to the center for disease control, clabsis result in thousands of deaths yearly and upwards of billions of health care dollars spent on preventable hospital acquired infections. intensive care patients, especially the neurocritical care population, have an increased need for centrally placed catheters related to inadequacy of peripheral access, need for caustic iv medications, and fluid resuscitation. our neuroicu's goal was to decrease utilization and subsequently reduce number of clabsis. in february , we initiated a patient-centered quality improvement effort with this goal in mind. the neuroicu clinical nurse leaders conducted rounds daily to evaluate the necessity and management of central lines. the neurocritical care team and clinical nurse leaders collaborated in exploring alternatives if central lines were present. in addition to daily rounding, clabsi bundles based on cdc guidelines for clabsi prevention were initiated. our neuroicu developed checklist "buster cards" in september of , prompting staff to the bundle interventions. the intent of the cards was to enhance nurse to nurse dialogue of bundle elements. the cards were evaluated monthly for trends in care. from august -june , there was a % reduction in neuroicu utilization of central lines. in addition, the mean number of clabsis per month decreased from . to . . trending of unit buster cards did not show care variances during this time period. implementing daily clinical nurse leader rounds with enhanced team communication significantly reduced the neuroicu's utilization of central lines and thereby decreased the rate of clabsis. percutaneous dilatational tracheostomy (pdt) is one of the most commonly performed procedures on critically ill patients. many studies showed the safety and feasibility of pdt, but there is limited data of pdt in neurocritical care units. we have described our experience of pdt performed by neurointensivist. pdts were performed by neurointensivists at bedside using the griggs guide wire dilating forceps technique. to confirm a secure puncture site, pdt was done under fiberoptic bronchoscopic guidance. from september to may , procedural data were prospectively collected. the patients' demographic and clinical characteristics were retrospectively reviewed. we analyzed immediate complications of pdt as the primary outcome. pdts were performed for patients; the mean age was . years, ( . %) were male, and mean acute physiology and chronic health evaluation ii score was . ± . . overall, the procedural success rate was % and the mean procedural time was . ± . min. periprocedural complications occurred in patients; had minor bleeding and had tracheal ring fracture. there were no serious periprocedural complications of pdt. from our experience, pdt performed by neurointensivist was safe and feasible and was implemented without serious complications. the neurocritical care unit (nccu) is a fast paced setting with a multitude of providers and team members requiring optimal communication. it is also a high cost/high utilization environment, dictating the need for patients to be moved thru appropriate levels of care efficiently. all of this must be accomplished while providing support and opportunity for collaboration and decision making on the part of the patient/ family unit. there is great discussion in the case management world about the benefits of a unit based verses service based case management model. we looked at outcomes following the implementation of a unit based case manager in the nccu. a dedicated case manager (cm) was implemented in the nccu to maximize assessment, advocacy, communication, education, identification of resources, and facilitation of services. processes to support maximal contributions were created.interventions included use of a discharge planning worksheet, implementation of a morning huddle, and space for the case manager to be physically available on the unit. los of patients discharged from nccu decreased from . to . . alos for patients that passed thru the nccu during their hospitalization decreased from . days to . . there was a % increase in discharges from nccu from to . average time from admission to cm assessment decreased from hours to . hours. progress notes indicating intervention and/or communication of the plan increased from to . staff questionnaire indicated increased awareness of los and dc plan needs. in this midwestern, academic medical center, integrating a dedicated, unit based cm resulted in improved los, increased discharges and improved staff awareness of dc plans. high throughput genotyping technologies and large collaborative consortia have revolutionized the field of medical genetics. open data access is the final barrier to be overcome to capitalize fully on the opportunities currently available in stroke genetics research. the international stroke genetics consortium (isgc) has created the cerebrovascular disease knowledge portal (cdkp), a comprehensive web-based resource to explore and freely access genetic data related to cerebrovascular diseases. funded by the nih, the cdkp has been jointly developed by the isgc and the american heart association (aha) institute for precision cardiovascular medicine. the cdkp seeks to democratize access to genomic data and potentiate stroke genomics research by providing open access to genetic, phenotypic and imaging data on stroke. within the cdkp, data are aggregated, integrated, and harmonized according to a pre-specified standardized pipeline. any institution or investigator working with stroke genomic data is welcome to deposit their data or use available data. the cdkp houses two types of data, each meeting different regulatory and analytical needs: summary level data and individual level data. the cdkp offers three main features: ( ) a web-based graphical user interphase that allows the exploration of stroke genomics information through a wide menu of integrated tools for analysis and data visualization; ( ) a repository of full sets of genome-wide summary statistics produced by published landmark studies in the field, available with a single mouse click ; and ( ) a repository of individual level data, accessible through a secure cloud working space provided by the aha platform for precision medicine. the cdkp can be accessed at www.cerebrovascularportal.org. the cdkp advances the isgc's goal of liberal data sharing in stroke genomics and other areas of cardiovascular research that may benefit from genomic analyses. in the future, phenotypic datasets can be added to further enrich sharing of non-genetic data as well. hyperosmolar therapy using hypertonic saline is common in patients admitted to the neurocritical care unit (nccu) for the management of different type of cytogenic cerebral edema or increased intracranial pressure (icp). vancomycin is commonly prescribed in nccu as empiric antimicrobial therapy. the purpose of the study is to evaluate the effects of hypertonic saline therapy on the pharmacokinetic parameters of vancomycin in critically ill patients with generalized or compartmental icp. this was a retrospective, observational study of adult patient consecutively admitted in the nccu between february and february who received hypertonic saline ( % sodium chloride) and vancomycin dosing protocol managed by the pharmacist. patients with serum creatinine > . mg/dl were excluded from the study. the estimation of vancomycin trough levels was done by using published pharmacokinetic equations and then compared to the measured trough levels with the paired t test. the study protocol was approved by our institutional review board. of forty-four patients who met the inclusion criteria, twenty-one patients ( . %) were diagnosed with intracerebral hemorrhage, nine ( . %) ischemic stroke, seven ( . %) subarachnoid hemorrhage, four ( %) subdural hemorrhage, two with brain tumors, and one patient with chiari malformation. the mean dosing regimen was . ± . mg/kg every ( - ) h. the mean measured trough level was lower than the predicted trough level ( ± . vs. . ± . mcg/ml; p < . ). the mean serum sodium level was ± meq/l and the mean serum osmolality was ± mosm/kg. critically ill patients with cerebral edema or high icp who were treated with hypertonic saline achieved a subtherapeutic vancomycin level that may lead to lower through level and possibly poor clinical response. further research is warranted to evaluate the clinical response of vancomycin in this patient population. unnecessary telestroke activations are costly to emergency departments (ed), telestroke providers, and patients. therefore it is important that ed nurses are well trained to effectively recognize stroke symptoms, and decrease the rate of false-positive stroke code activations. the nursing-driven acute stroke care (nas-care) study aims to determine if implementing a standardized ed stroke program decreases door-to-needle times in emergency departments utilizing telemedicine. the nas-care intervention consists of ed nursing education including mock codes, nihss certification, and implementation of a standardized flow sheet. in this interim analysis from the first (of ) nas-care study hospitals, we examined ed admission and discharge diagnoses at each site for months of blinded baseline data collection ("control") and months after standardized training ("intervention"). false-positive encounters were defined as stroke code activations for which the patient diagnosis on leaving the ed was not stroke. although hospitals trended toward a reduction in false-positive stroke code activations after implementation of the standardized stroke education, mock stroke codes, and flow sheet, none of the values were statistically significant. further research is needed to determine whether intensive ed nursing education can improve telestroke resource utilization. pharmacist-driven intravenous (iv) to oral (po) conversion protocols result in greater compliance, improved cost-savings, and better patient outcomes related to length of stay, re-admission, and duration of intravenous therapy. this study aims to determine the cost-savings and patient impacts of such a conversion protocol for anti-epileptic drugs (aeds) including lacosamide, levetiracetam, phenytoin, and valproic acid. a retrospective, observational phase was conducted to determine usual practice patterns concerning conversion to oral therapy between / / and / / . the conversion protocol was approved in december and implemented in january . a second retrospective phase observed conversion practices beginning / / and ending / / . length of intravenous and oral therapy, date eligible for conversion, and date of conversion were recorded. hospital acquisition costs were utilized for medication expenditure calculations. this information was used to determine financial impact of the protocol and is presented as descriptive endpoints. adverse drug events were collected via an institutional incident reporting system. a total of encounters were identified, resulting in encounters in the pre-cohort and postcohort encounters. looking at the pre and post cohorts respectively, both cohorts had similar median lengths of stay ( days vs. days), -day readmission rates ( . % vs . %), and rates of conversion from oral back to intravenous therapy ( . % vs . %). the median length of intravenous therapy was days prior to protocol implementation and decreased to days in the post-cohort. the average cost per day of aed therapy was $ . in the pre-cohort but decreased to $ . in the post-cohort. median missed opportunity costs, defined as the cost savings if conversion occurred at the earliest possible date, also decreased between the cohorts from $ . to $ . . pharmacist involvement in aed conversion had a positive financial impact without compromising patient care. the national institute of neurological disorders and stroke (ninds) established the nih strokenet to facilitate the rapid initiation and efficient implementation of multi-center exploratory and confirmatory clinical trials focused on promising interventions in stroke prevention, treatment, and recovery. strokenet was initiated in the fall , and involves over hospitals across the us. the network is anchored by regional coordinating centers (rccs), along with the national coordinating center (ncc) at the university of cincinnati and national data management center (ndmc) at the medical university of south carolina, as well as active participation by the ninds. one of the primary goals of the strokenet is to serve as the primary infrastructure for conducting stroke clinical trials and pipeline for new potential treatments. to maximize the impact of nih strokenet, it is important for the larger community of stroke researchers and clinicians, including the neurocritical care specialists, to know its structure and the process and timeline by which stroke trials are developed and implemented. since the inception of the network, * proposal concepts have been submitted to the strokenet and are in different development stages. among those evaluated to obtain ninds permission to submit a grant application, have submitted and are in the process. every application has been prepared and submitted for peer review within months of the ninds permission. two* funded strokenet trials are now underway with brisk enrollment rates, and another is awaiting study initiation. (*as of abstract submission date) the nih strokenet has become a stable infrastructure and offers several distinct advantages to developing competitive clinical trial proposals, including scientific input from the strokenet working groups, comprehensive feasibility assessments (including site enthusiasm and patient availability), assistance with grant budgeting, and other requirements for grant submission that are likely to help refine and improve the application. the modified early warning score (mews) is a physiological scoring system, validated in adult medicalsought to determine the value of mews to identify clinical deterioration or occurrence of sepsis in neuroicu patients. we retrospectively reviewed all patients admitted to the neurological intermediate care unit (imc) or neuroicu of a large tertiary care center from / presentation/during admission. baseline characteristics, diagnoses, physiologic parameters, infections, treatment with antibiotics, neurological worsening and mortality were abstracted from the electronic medical record. outcomes were defined as escalation of care and discovery of a new infection or sepsis. of p were male. % were intubated, and in-hospital mortality was % (versus % for all admissions). ( %) were already treated with antibiotics for a known infec diagnosed in %. in reaction to the elevated mews score, antibiotics were added or broadened in %, and level of care was escalated in . % from imc to icu. in . %, there was neurological worsening, most frequently associated with increasing cerebral edema ( %) and midline shift/herniation ( %). the mews score is not a valuable screening tool in the neuroicu population. it preferentially was triggered in known high acuity patients with ongoing or present infections with no change of management in the majority of patients. while associated with high mortality, its ability to indicate new infections or sepsis was poor. in out of patients, the mews score was associated with neurological worsening known at that time of the score. other screening tools should be explored for early warning in the neuroicu. introduction: it is challenging to maintain neurosciences critical care nursing expertise in an environment of a rapidly expanding knowledge, changing evidence-based practices and technological advancements. to address the needs for neuroscience nursing expertise in a mixed critical care unit, our institution developed a core group of nurses, known as "neuro champions", who have additional training and expertise in neurocritical care. methods: nursing participation was voluntary and recruitment was via unit-wide announcements. the goal was to improve patient care by developing a core group of nurses who serve as resources and educators for all things neurosciences related. to develop content expertise, the nurses initially completed a set curriculum including: neuro anatomy and pathophysiology, cerebral hemodynamics and multimodal monitoring, pupillometry, eeg interpretation, temperature management, evds, and quality indicators. bi-monthly meetings continued ongoing education, with content including clinical case studies and review of processes and protocols. additionally, beds staffed by neuro champions were designated as critical neurological care unit ("cncu") beds to co-localize the highest acuity neurosciences patients. the neuro champions are responsible for educating and sharing neuro related practices with the entire icu nursing staff. results: as a result of the implementation of the neuro champion role, our icu has benefited from: ) dedicated co-localized beds for the highest acuity neuro patients; ) increased number of enls certified nurses; ) improved collaboration between the medical team and nurses; ) promoting care uniformity to maintain comprehensive stroke center certification; ) integration of multimodal monitoring advancements, all of which supports advances in patient care and research. conclusions: the neuro champion role has provided a platform for neurosciences-specific nursing expertise in a mixed critical care unit and has facilitated education dissemination to the entire staff via a core group of nurses. this expanded knowledge has improved the care of the neurologically critically ill patients. the rate of cerebrovascular complications in patients treated with extracorporeal membrane oxygenation (ecmo) is about %. transcranial doppler (tcd) can be used to noninvasively monitor cerebral blood flow velocities (cbfvs) in patients undergoing ecmo. the aim of this study is to describe tcd-cbfv patterns in patients undergoing venovenous (vv) and venoarterial (va) ecmo. a neuro-surveillance protocol among ecmo patients was initiated as part of a quality improvement project at our institution. daily neurological exam, daily tcd, brain-ct on days one and three and -hr continuous eeg were performed in all patients undergoing vv and va-ecmo. demographics, clinical and imaging data were collected for the duration of ecmo support. cbfvs, lindegaard ratios (lr), pulsatility index (pi) and resistance index (ri) on tcd were collected. total of patients were included in the study [ female ( %); caucasians ( %)]. mean age was years. ( %) patients received va-ecmo; ( %) vv-ecmo; ( . %) received both va and vv-ecmo. median days on ecmo was days. median number of tcd studies performed was (mean, . we observed an overall pattern of low-normal flow cbfvs and reduced pulsatility in patients on va-ecmo. nurse practitioner (np) and physician assistant (pa) roles continue to expand in the critical care setting. single and multisite studies have examined various aspects of app practice, but none have focused on role implementation within the neurologic critical care unit (nccu). the purpose of this study was to obtain foundational knowledge about how nccu apps are implementing the role nationally this was a voluntary, cross-sectional, descriptive study of nurse practitioners (np) and physician assistant (pa) practicing in the us. apps were invited to participate in this voluntary, item survey. distribution occurred initially through email inquiry via multidisciplinary, professional organization listservs (ncs, aacn, aann) followed by snowball effect circulation. enrollment occurred from march to june . data was collected in redcap and analyzed using spss with descriptive statistics for demographic, institutional, practice, role characteristics of the sample and for each survey data element app participants completed the survey: % np, % pa, % other. the majority of respondents were master's prepared ( . %) acute care trained, ( . %) and hospital employed ( . %). participants were either early in their career ( . % - years as app) or experienced ( . % > years). % work in a direct care role with % providing total care for their patients with an average daily caseload of . + . patients. % of providers believed - patients was a reasonable caseload for total care. in addition to the nccu, % of participants care for patients in step-down or emergency department ( %) with % routinely bilingl for their work. this study is the first to provide information regarding how ncc apps are implementing the role in the united states. this study provides benchmarking data which may guide future research with this population as well as serve as a template for evaluation of other app specialty roles. despite advances in treatment, the median survival for high grade gliomas (hgg) remains poor. there is a growing body of research showing that palliative care improves quality of life and survival in patients with advanced malignancies. we sought to examine our own practices in the neurologic intensive care unit (nicu) regarding palliative care consultation in this population. we hypothesized that the incidence of palliative care consultation is low and associated with a clarification of patient's wishes, measured by a change in code status. we conducted a retrospective cohort review of patients with previously diagnosed hgg admitted to the nicu from - with a length of stay (los) greater than hours. the primary outcome was the incidence of patients with an advanced directive or inpatient palliative care consult (pcc). secondary outcomes included intensive care unit los, change in code status and location of death. patients were identified with hgg. the mean age was . years ( - years), % were male, % were white. zero patients were admitted with an advanced directive on admission. pcc was obtained in patients ( %). pcc was associated with increased nicu stay ( hrs vs hrs p= . ), a change in code status to do not resuscitate ( % vs % p= . ), and an increased likelihood to not die in the hospital ( % vs % p= . ). at our large academic tertiary care facility intensivists underutilize palliative care services for hgg patients. patients with fatal brain tumors are not having end of life discussions prior to admission, indicating a need for early palliative care intervention. patients are six times more likely to change their code status and there is a trend towards dying outside of the hospital if they receive a palliative care consult. hypertonic saline (hts), a hyperosmolar solution, is typically administered using a central venous catheter (cvc) due to concerns of extravasation, but a cvc is rarely readily available. in emergent situations, intraosseous (io) access is used when peripheral intravenous access is not available. existing literature does not address the administration of hypertonic saline using io access for adult patients with brain injury. the administration of hts is often delayed due to the time taken to obtain a central venous access. insertion of an io needle is typically much faster than a cvc. we report the safety and tolerability of hts using io route. a prospective pilot study on the safety and tolerability of % hts via io is currently underway. data on local complications at the site of injection, pain during insertion and during infusion, and serial serum sodium levels were collected. additionally, we report a case of successful administration of . % hts using the io route. preliminary data demonstrated that % hts was well-tolerated, with no reports of severe pain, infections, extravasation, soft tissue injury or local infectious complications in our sample of patients with brain injury. indications for use of hypertonic saline included patients with cerebral edema and mass effect from intracerebral hemorrhage. an appropriate rise of serum sodium levels by approximately mmol/l/hr in was observed. in the case where ml of . % hts, no local complications were observed and serum sodium levels rose appropriately. administration of hts using io route appears to be safe and feasible. utilizing io access for urgent administration of hts may reduce the lag time to administration of the initial bolus, reduce the need for emergent placement or eliminate the placement of cvc in certain cases. optic nerve sheath diameter (onsd) measurement is an emerging bedside tool to assess intracranial pressure (icp) non-invasively in brain injury patients. multiple studies demonstrate onsd width from . mm to . mm correspond to an external ventricular device (evd)-measured icp > mmhg. we sought to create a low cost, -d constructed, re-usable osnd teaching model to train neurology, neurosurgery, and critical care advanced practice providers and physicians. we searched the national library of medicine using terms "optic nerve sheath diameter ultrasound" with combinations of "simulation" and "model." the literature was used in conjunction with a human non-contrast head ct head model to make an eye ball model which was then tested in our simulation center and compared to a live human model. we identified articles, of which were associated with models and two with simulation. one gelatin model was reported, upon which we based our initial design. we could not validate the visual findings of this model. however, following construction of multiple beta models, the design most representative of human eye anatomy was a globe made of ballistics gel with either a mm, mm or mm -d printed "optic nerve" attached to a platform composed of ballistics gel and psyllium powder with a hollowed out core for ultrasound gel the globe rests upon. this model was taught to learners at a continuing medical education event prior to teaching osnd on a live human model. a -d printed skull from ct head data is being created to incorporate this model. a simple -d ballistic onsd model allows learners to learn proper hand placement, basic landmarks, onsd measurement, and practice proper pressure on human eyes. this model can be replicated and utilized in a sustainable fashion given that the globe and platform are composed of ballistics gel. pressure measurements using pressure guide wires is an invaluable diagnostic tool in the management of many endovascular revascularization therapies. its role is well established in coronary artery disease management such as use of fractional flow reserve (ffr) as a standard diagnostic tool to determine need for stenting, angioplasty or bypass. renal fractional flow reserve remains an integral physiologic parameter used in endovascular revascularization therapy of renal artery stenosis. despite the wide spread use of pressure wires in endovascular therapies, its application in the management of cerebral venous diseases remains vastly unexplored. we sought to evaluate the safety and applicability of pressure guide wires in several cerebral venous diseases. patients undergoing diagnostic angiography for possible venous outflow obstruction had pressures measured by pressure guide wires (volcano verrata® or prestige primewire®) across the following vessels: superior sagittal sinus, torcula, right and left transverse sinus, right and left sigmoid sinus, and right and left internal jugular vein. venous pressures were also collected from patients undergoing venous thrombectomy, stenting, or an arteriovenous malformation embolization (avm). five patients who underwent diagnostic angiography for pseudotumor cerebri showed no major variability in their pressures across the cerebral venous architecture which was confirmed by lack of stenosis or thrombi on intravascular ultrasound (ivus). four patients had a pressure difference above which was suggestive of a stenosis and later confirmed by ivus. patients undergoing pressure measurements that had evidence of stenosis or thrombosis by ivus showed improvement in pressure gradients post stenting or thrombectomy. no variability in pressure gradients were noted in a patient that underwent avm embolization. pressure measurements using pressure guide wires can improve diagnostic accuracy and guide management of several diseases of the cerebral venous system. further studies are necessary to understand the applicability of this approach in the management of venous disease. monitoring metrics is imperative for quality assurance and ongoing improvement in a developing clinical unit. a new neurocritical care unit (nccu), specializing in the treatment of critically ill, neurologicallyinjured patients opened in july . this study examined quality metrics that correlate with the development and growth of a neurocritical care program. data from patients with principle diagnoses of ischemic stroke (isc), subarachnoid (sah) or intracerebral (ich) hemorrhage, seizure, or brain tumor, admitted to nccu in and were used in the analyses. quality metrics included overall and individual complication rates per , patient days of pneumonia, venous thromboembolism, pulmonary embolism, sepsis, septic shock, pulmonary edema, gastrointestinal bleeding, and catheter associated urinary tract infection, as well as hospital mortality and length of stay (los). chi-squared and mann-whitney tests and poisson regression were used to compare metrics between and . patient volumes increased by . % ( to ) from to . the overall complication rate declined significantly from . to . per , patient days (p= . ). the highest complication rate in and was pneumonia ( . and . per , patient days, respectively). the proportion of patients who expired decreased from . % (n= ) in to . % (n= ) in , though not significantly (p= . ). there were no significant differences in los among patients with isc, brain tumor or seizure. however, those with sah or ich had significantly shorter stays in (median [interquartile range] = . [ . , . ]) versus ( . [ . , . ]) (p= . ). data suggest that over the initial -year period, complication rates among patients in the nccu improved. los did increase for hemorrhage patients; however, this may be related to greater severity of illness in the patient population over time. further analyses will be conducted to account for severity and other factors. delirium is a frequently seen but underestimated problem in critical care settings. delirium screening is considered time consuming, which is one of the factors leading to under diagnosis. the cam-icu screening tool for delirium has been validated in medical and surgical icus. among neurological patients, it has been validated in stroke patients but not in general neurocritical care population. this study was designed to validate cam-icu flow sheet in neurointensive care unit. a prospective cohort study was conducted in a bed neurointensive care unit of a university hospital. patients meeting the inclusion criteria (all nicu patients) and exclusion criteria (comatosed, aphasic, psychotic, prior diagnosis of neurocognitive disease, persistently vegetative state, sedated) were screened for delirium by ( ) a nurse practitioner using confusion assessment method (cam-icu) and ( ) a physician reference rator using delirium screening criteria in diagnostic and statistical manual of mental disorders- . assessments were done daily monday through friday for the icu stay. paired assessments were done less than hours apart. the study enrolled patients ( male, female). daily assessments were done. mean age of the patients was . and mean sap score was . admitting diagnoses were ich ( ), sah ( ), ischemic stroke ( ), tumor ( ), spinal surgery( ), neurological infections( ), seizures( ),elective angiograms( ), hydrocephalus( ), transverse myelitis( ) and av dural fistula( ). using dsm- criteria, the reference rator identified delirium in out of ( %) patients during the icu stay. out of assessments were positive for delirium according to dsm- and according to cam-icu. cam-icu flow sheet had sensitivity of . % ( %ci . % - . %) and specificity of . % ( %ci . %- . %). cam-icu has high sensitivity and specificity for diagnosing delirium in critically ill neurological population. it is a valid tool for diagnosing delirium. a value stream mapping event (vsm) for general neurology inpatients, revealed multiple barriers related to videofluoroscopy swallow studies. there was a high volume of patients requiring instrumental swallow assessments, a limited number of radiology appointments, and transportation delays that were delaying feeding plans, discharge recommendations and goals of care discussions. an operations engineer involved in the vsm event started the process by collecting observational data regariing timing. after meeting with the chief operating officer, director of patient transport, director of radiology, speech pathology manager, neuro intensive care unit manager and the operations engineer, a pilot program was agreed upon. the results for the three week pilot program were successful, and resulted in a permanent change in procedure. the pilot data showed a decrease in test time by minutes, a decrease in transport delays by minutes, and a decrease in length of stay by . days. the number of patients waiting for the study dropped from . to . per week. by annualizing this data, the change has created new available bed days, additional patient encounters and an incremental annual contribution margin of $ , . with the appointment time consistent, the nurse is able to plan patient care around the study, and ensure the patient is prepared and not delayed for the study. it has also allowed, if deemed safe for the patient to swallow, medications to be changed from the intravenous route to the oral route earlier, and earlier determination of safe feeding and diet restrictions. we previously reported outcome for children with refractory and super-refractory status epilepticus in a cohort of patients. mortality was %. % of survivors required new tracheostomy and/or gastrostomy tubes. the majority of surviving patients experienced some degree of disability at discharge as determined by the pediatric cerebral performance category scale (pcpc). here, we aimed to identify patient factors in this cohort that were associated with a decline in functional neurologic outcome at discharge. retrospective chart review of children age - years who received pentobarbital infusion for status epilepticus in the pediatric intensive care unit of a large tertiary children's hospital from - . outcome was defined using pcpc at admission and discharge. potential factors associated with outcome were evaluated using fisher's exact test and wilcoxon rank sum test. children were included. pcpc score at admission (p= . ), etiology of status epilepticus (p= . ), new tracheostomy (p= . ), and new gastrostomy tube (p= . ) were all significantly associated with children were more likely to have normal baseline neurologic function and more likely to have febrile encephalitis, stroke/trauma, or hypoxic ischemic encephalopathy as the etiology of status epilepticus. duration of pentobarbital infusion (median = days vs. days) (p= . ) and duration of hospital admission (median = . months vs. . months) (p= . ) were both longer in patients who had an admission pcpc score, etiology of status epilepticus, new tracheostomy and gastrostomy tube as well as longer duration of pentobarbital infusion and longer hospital stay were significantly associated with a decline in functional neurologic outcome at hospital discharge in children with refractory and superrefractory status epilepticus. status epilepticus (se) is the most common pediatric neurological, and super-refractory se is a lifethreatening form of se that continues or recurs for more than hours despite multiple therapeutic interventions. this population-based study investigated pediatric se and srse admissions in germany. pediatric (age - years) admissions between - were identified in the arvato health analytics database. se, epilepsy, and febrile seizure cases were identified using a modification of a previouslypublished algorithm based on icd- diagnosis codes (g , g , and r ) and coding for ventilator and intensive care unit use. based on primary diagnosis, prior epilepsy status, and ventilation se was subclassified as non-refractory, refractory (rse), and super-refractory (srse). inpatient mortality, costs, length-of-stay (los), and discharge disposition were assessed overall and for rse and srse. the algorithm identified , seizure-related admissions and classified % as se, of which . % were rse and . % were srse. the rse frequency was highest among ages - . the incidence of cases classified as srse peaked among newborns (age< year), decreasing between ages - years. cases classified as se accounted for . % of total costs associated with seizure-related hospitalizations. srse exhibited the highest per case cost (mean € , ), amounting to . % of all se costs, and these costs correlated with the highest los (median . days). srse was associated with greater mortality ( . %) cases classified as srse accounted for . % of all pediatric seizure-related costs, despite representing only . % of admissions. srse was associated with the highest los and mortality rate. these results highlight the burden of illness associated with srse and suggest that optimization of srse management has the potential to improve outcomes and reduce costs. despite its more routine use and the recognition that mri provides superior detection of traumatic brain injuries, there has been little written about how mri might affect the acute management of trauma patients. we sought to describe mri findings in a cohort of children admitted to the picu with tbi and to extend comparisons between ct and mri in acute trauma. a secondary aim was to quantify in what ways mri findings influenced clinical management in this cohort. we retrospectively identified patients admitted to the picu with an acute head injury between september and may who underwent head mri within the first hrs. we compared mri with ct findings, using the nih common data elements definitions of injury type. we determined by chart review the indication for mri and if there was documentation that mri led to a change in management, defined as either an escalation or a de-escalation of care. seven patients had mri only, and mri identified additional lesions in of the patients who had first undergone head ct. of these, patients had new intra-parenchymal lesions, had new extra-axial lesions, and had both a new intra-parenchymal and a new extra-parenchymal lesion identified. the most frequent new lesions were contusions and traumatic or diffuse axonal injury. acute management was influenced by mri in a majority of patients, leading to an escalation of medical or surgical management in nearly one third and a de-escalation of care in half. early mri may have a beneficial role in the acute management of pediatric traumatic brain injury. mri frequently identified clinically important lesions not appreciated on ct, and findings influenced management decisions. future studies will assess whether early mri improves patient outcomes or provides cost/benefit by reducing length of stay. while adverse outcomes of decompressive hemicraniectomy (dh) including infection, disturbances of the csf compartment, and sunken flap syndrome are well documented, there is a dearth of literature assessing outcomes related to the timing of cranioplasty. while adverse outcomes of decompressive hemicraniectomy (dh) including infection, disturbances of the csf compartment, and sunken flap syndrome are well documented, there is a dearth of literature assessing outcomes related to the timing of cranioplasty. we identified patients who received dh, of whom underwent reconstructive cranioplasty at our institution. the post-cranioplasty complication rate was %, which was due in part to hemorrhage, infectious complications, or csf compartment disturbances. patients receiving early cranioplasty developed an increased rate of hemorrhagic complication ( % vs %; p = . ), increased median hospital length of stay (los) ( vs days; p = . ) and increased median icu los ( vs days; p = . ). of the patients who received dh surgery related to malignant cerebral edema from an acute ischemic stroke, total complication rates trended down for early compared to late cranioplasty surgery ( % vs %; p = . ). patients receiving dh surgery for any cause who underwent early reconstructive cranioplasty, experienced higher rates of hemorrhagic complications and increased hospital and icu los. however, among those patients receiving dh surgery for the specific indication of malignant cerebral edema from acute ischemic stroke, significant differences did not exist between the early and late cranioplasty groups. the total complication rates in these patients trended lower in the early group. another important and mainly unpublished finding is that a majority of dh patients are lost to surgical follow up and may therefore impact the complication rate of this not so benign surgery. postoperative antibiotics (pa) are often administered to patients after instrumented spinal surgery until all drains are removed to prevent surgical site infections (ssi). this practice is discouraged by numerous medical society guidelines, so our institutional neurosurgery quality improvement committee decided to discontinue use of pa for this population. we retrospectively reviewed data for patients who had instrumented spinal surgery at our institution for seven months before and after this policy change and compared the frequency of ssi and development of antibiotic related complications in patients who received pa to those who did not (non-pa). we identified pa patients and non-pa patients. discontinuation of pa did not result in an increase in frequency of ssi ( % of pa patients vs. . % of non-pa patients, p= . ). growth of resistant bacteria was not significantly reduced in the non-pa period in comparison to the pa period ( % vs. %, p= ). the cost of antibiotics for pa patients was $ , . , whereas the cost of antibiotics for the non-pa patients was $ . on a per patient basis, the cost associated with antibiotics and resistant infections was significantly greater for patients who received pa than for those who did not (median of $ . with iqr $ . -$ . vs. median of $ with iqr $ -$ ; p< . ). after discontinuing pa for patients who had instrumented spinal procedures, we did not observe an increase in the frequency of ssi. we did, however, note that there was a non-significant decrease in the frequency of growth of resistant organisms. these findings suggest that patients in this population do not need pa, and complications can be reduced if pa are withheld. the development of flow-diverting stents has allowed for new treatment options for giant vertebrobasilar aneurysms. however, the expertise required to perform these procedures safely and concerns about complications continue to limit their use. we sought to identify common complications of this treatment that can be anticipated by neurointensivists, to optimize management in the postoperative period. we retrospectively reviewed our hospital database of treated aneurysms to identify those with giant vertebrobasilar aneurysms. medical and neurological complications were recorded. six patients ( male, female) underwent treatment of giant vertebrobasilar aneurysms with pipeline embolization devices. five received adjunctive coiling. frequently reported pre-procedure symptoms were dysphagia (n= ), diplopia (n= ), dysarthria (n= ), facial weakness (n= ), hemiparesis (n= ), gaze palsy (n= ), and nystagmus (n= ). five patients ambulated normally. due to concerns about necessary procedures after stenting when on antiplatelet therapy, three patients received prophylactic ventriculoperitoneal shunts, two underwent gastrostomy, and two underwent tracheostomy. angiography confirmed successful aneurysm embolization in all patients. postoperatively, all patients developed new or worsened symptoms attributed to brainstem edema, including hemiparesis (n= ), facial weakness (n= ), dysphagia (n= ), diplopia (n= ), nystagmus (n= ), gaze palsy (n= ), and dysarthria (n= ). neurological symptoms were treated with steroids, with most symptoms subsiding by discharge. five patients had medical complications, including pneumonia (n= ), respiratory failure (n= ), gastrointestinal bleeding (n= ), arrhythmia (n= ), urinary tract infection (n= ), and myocardial infarction (n= ). two patients were re-intubated, three underwent gastrostomy, and one underwent tracheostomy. functional status at -months was available for five patients. three achieved modified rankin scale scores between - , one regressed to a , and one died. the treatment of giant vertebrobasilar aneurysms presents significant challenges. practitioners should anticipate temporary postoperative neurological worsening and various medical complications. prophylactic shunt placement, gastrostomy, and/or tracheostomy should be considered in patients anticipated to likely need these procedures after treatment. ventriculostomy-related infection (vri) remains a major complication of external ventricular drain (evd) placement. historically, prophylactic antimicrobials are utilized to decrease the incidence of vri after evd placement. recent guidelines for the insertion and management of evds recommend a single preoperative dose prior to evd insertion and urges against the use of duration antibiotic prophylaxis. prior to the publication of this guideline, we hypothesized that significant variations existed among institutions with respect to antibiotic prophylaxis practices in this setting. the purpose of this practice survey was to determine trends in antimicrobial prophylactic strategies utilized by various healthcare institutions for evd placement prior to publication of the neurocritical care society (ncs) evidence-based guidelines for the insertion and management of evds. a seven-question practice survey on antimicrobial prophylaxis for evd placement was distributed to active pharmacist members of the ncs by email and open for response from / / to / / . the following information was collected: antimicrobial prophylaxis regimen utilized, pharmacologic class, utilization of impregnated catheters, and institution guidance. survey results were analyzed for trends in antimicrobial prophylaxis in the setting of evd placement. respondents ( / , % response rate) from institutions completed a seven-question evd management survey. most institutions initiate a single dose of antibiotics prior to evd insertion ( / , %). periprocedural antimicrobial therapy is the most common prophylactic strategy utilized by respondents ( / , %). of respondents who do not continue antimicrobial prophylaxis for the duration of evd placement, % ( / ) utilize antimicrobial-impregnated catheters to reduce incidence of vri. the importance of antimicrobial prophylaxis to prevent infectious complications associated with evd placement is widely accepted. prophylactic strategies vary between institutions. periprocedural antimicrobial therapy is the most common prophylactic strategy utilized by survey respondents. antimicrobial-impregnated catheters are commonly utilized in institutions using periprocedural antimicrobial prophylaxis. the postoperative course seen in critically ill neurosurgical patients is known to vary depending on the timing of the surgical procedure. this study seeks to compare the clinical characteristics, complications, and outcomes between elective or urgent surgery patients admitted to the intensive care unit (icu). retrospective review of a two-year neurosurgical patients' cohort. the pre and postoperative conditions and outcomes were compared between elective (group a) and emergency (group b) surgery patients. a total of patients were evaluated, in group a and in group b. the most common diagnosis was intracranial tumor. the mean american society of anesthesiology (asa) score was significantly higher in group b than in group a ( . vs. . , p< . ). mean sequential organ failure assessment (sofa) score on admission was higher in group b ( . vs. . , p< . ). these patients were more likely to require mechanical ventilation (or . , p< . ) and vasopressors (or . , p< . ) . group b had a higher probability of rebleeding (or . , p< . ), intracranial hypertension (or . , p< . ), hydrocephalus (or . , p< . ), and reintervention (or . , p= . ). post-operative nausea and vomiting were less likely in group b ( . % vs. . % and vs. . %, respectively). mean hospital and icu los were shorter in group a than in group b ( . vs. . and . vs. . , p< . respectively). mortality rate during icu stay was higher in group b ( . % vs. . %; or . , p< . ). the preoperative glasgow coma scale (gcs) in patients who died, was below in only a minority of them ( . % in group b; % in group a). in this cohort of neurosurgical patients, emergency, compared to elective operations, were associated with higher post-operative complications and mortality rates. emergency surgery was associated with a higher severity of illness measured by the sofa and asa scores. intraprocedure rupture (ipr) is a rare but potentially serious complication of endovascular coiling of intracranial aneurysms. potential complications include hemorrhage, ischemic stroke, vasospasm and hydrocephalus which can lead to increased morbidity and mortality. the clinical course for these patients is not well studied and characterized. we performed a retrospective review of prospectively collected data for all unruptured aneurysms treated with endovascular coil embolization between july and march at a large universitybased hospital. out of cases of all unruptured aneurysms coil embolizations, ( . %) patients had ipr. we reviewed baseline data, procedure notes, clinical course, and outcomes at discharge and at , and months. among the ten patients, the location of the aneurysms included: basilar apex, internal carotid artery anterior communicating artery, posterior cerebral artery, and posterior communicating artery aneurysm. patients were monitored in the icu for variable lengths of time and daily transcranial doppler ultrasound detected no significant sonographic vasospasm. the large majority of the patients ( / ) were discharged to home at their baseline functional status assessed by modified rankin scale. one patient was discharged to inpatient rehabilitation for cognitive deficits from ipr of a basilar apex aneurysm. they were subsequently discharged home with supervision. there was a single mortality in a patient receiving retreatment of a proximal ica aneurysm with prior stenting and coil embolization who developed massive subarachnoid hemorrhage with diffuse intraventricular hemorrhage with external ventricular drain placement. the incidence of ipr is very low and potentially serious complications occur rarely in these patients. the location and factors associated with ipr are highly variable and without clear associations. outcomes of such complications are overall favorable. a short observation period in the hospital is likely warranted with a benign clinical course the most likely outcome. the standard treatment of cerebral venous-sinus thrombosis (cvst) is anticoagulation. however some patients clinically deteriorate secondary to mass-effect from infarct or intracerebral-hemorrhage (ich). the role of decompressive-craniectomy (dc) in this patient population is unknown. we elucidate the baseline characteristics of patients treated with dc, and report their outcomes. a retrospective chart review of our institutional database identified patients with cvst who were treated with dc. demographic and clinical data were collected. imaging variables collected from ct-head or mri-brain immediately before dc were intracerebral-hemorrhage volume (ich-v), combined volume of mass-effect from infarct/ich and peri-lesional edema (me-v), midline-shift at level of pinealgland (mds-p), midline-shift at cranial-most portion of corpus-callosum (mds-cc), and herniation-type. favorable outcome was defined as glasgow-outcomes scale of - upon last-known follow-up. a total of patients (females= ) treated with dc were identified with mean-age . (+/- . ), mean glasgow-coma scale (gcs) before surgery (+/- . ), mean-ich-v . ml (+/- . ), mean-me-v . ml (+/- . ), mean-mds-p . mm (+/- . ), and mean-mds-cc . mm (+/- . ). transverse-sinus was most commonly involved (n= ). / patients had any herniation, most commonly cingulate (n= ). meanchange in gcs from admission to before-surgery was - . (+/- . ). ten patients were anticoagulated before surgery. on last-known follow-up, / patients had a favorable outcome. four had died. on chisquare analysis, superior-sagittal sinus thrombosis was associated with unfavorable outcomes (p= . ), and mortality (p= . ). on univariate binary-logistic regression, there was a non-significant trend towards unfavorable outcomes (p= . ) and mortality (p= . ) with every-point decrease in mean-gcs before surgery. the predictive-value of other factors towards outcomes is unknown given limited sample-size. decompressive-craniectomy might improve outcomes even in patients with cvst who have developed coma, cerebral herniation, have failed treatment with anticoagulation, and have large-volume masslesions causing midline-shifts of > mm. a prospective multi-institutional observational-cohort would poster presentations better delineate outcomes in comparison to matched-patients who are not treated with decompressivecraniectomy. meningiomas are often benign and mostly asymptomatic, and the treatment approaches may include open surgical resection, radiosurgery, and/or watchful waiting. reported morbidity and mortality rates for elderly patients undergoing meningioma resection vary widely. we sought to investigate mortality rates for elderly patients undergoing craniotomy for meningioma resection using the nationwide inpatient sample (nis). the nis datasets from to were used to identify patient admissions for meningioma resection based on the icd- -cm code . . age categories were defined as years of age. primary outcomes were in-hospital mortality, poor outcomes (defined as death or discharge to a facility other than home), cost and length of hospitalization. a total of , patients were identified who underwent meningioma resection during - of which . % were elderly (> years). each of the primary outcomes was heavily influenced by the advancing age. in-hospital mortality was higher in the elderly as compared to the younger patients ( . % vs % p< . ), as was the rate of a poor outcome ( . % vs . %, p< . ). elderly patients also had a higher cost ($ vs $ , p= . ) and increased length of hospitalization ( . vs . days, p< . ). in our study, age > was strongly associated with adverse outcomes after meningioma resection. this increased risk should be taken into account when considering surgical intervention in this subgroup. based on this study, closer perioperative monitoring may be warranted in the elderly patient subgroup. treatment with anticoagulation improves outcomes in cerebral venous-sinus thrombosis (cvst). however patients who develop extensive infarcts and/or intracerebral-hemorrhage with mass-effect resulting in comatose-state are at risk of poor outcomes, and may benefit from decompressive craniectomy (dc). we evaluated the role of dc in the management of malignant cvst and its impact on outcomes. literature-search was conducted on pubmed and google-scholar using terms "craniectomy", and "cerebral venous-sinus thrombosis". we included studies that described any number of patients with cvst who underwent dc after clinical deterioration and reported their outcomes. a similar search strategy identified patients from our institute. outcomes were reported as modified-rankin scale (mrs) or glasgow-outcomes scale (gos) and were classified as favorable (mrs - ; gos - ), or unfavorable (mrs - ; gos - ). a total of patients (females= ; males= ; unknown= ) who underwent dc for malignant-cvst were identified from studies (n= ) and our institute (n= ). age and gcs (before-surgery) were only available from patients, with mean-age . (+/- . ) and mean-gcs . (+/- . ). patients ( . %) had favorable-outcomes, while patients ( . %) died. in the multi-variate binarylogistic regression-model, every point-drop in gcs decreased the odds of favorable-outcomes by . times (p< . ; %ci= . - . ), and survival by . -times (p= . ; %ci= . - . ). thrombosis in internal-jugular vein (ijv) (or= . ; %ci= . - . ; p= . ) and deep-cerebral veins (dcv) (or= . ; %ci= . - . ; p= . ) predicted unfavorable-outcomes. ijv-thrombosis (or= . ; %ci= . - . ; p= . ) and dcv-thrombosis (or= . ; %ci= . - . ; p= . ) also predicted mortality. interestingly, cortical-vein thrombosis was associated with lower odds of unfavorable outcomes (or= . ; %ci= . - . ; p= . ). data regarding anticoagulation and long-term follow-up were not uniformly available. for patients with malignant-cvst, craniectomy could potentially improve outcomes. factors such as gcs before-surgery and cvst location can help predict outcome following dc and aid the decision-making process. a multi-institutional observational cohort should be designed to prospectively evaluate predictors for, timing of, and outcomes after craniectomy in cvst. the external ventricular drain (evd) is commonly used in the neurocritical care unit to help monitor intracranial pressure (icp) with the added advantage of therapeutically treating elevated icp by diverting cerebrospinal fluid (csf). placement of an evd can be complicated by hemorrhage surrounding the catheter insertion tract, which in some cases may prove to be fatal. this retrospective study was designed to look at the rate of tract hemorrhages after evd placement that were performed at our institution as well as associated outcomes. we conducted a retrospective review of all patients who underwent evd placement during a year period using our institutional database. postinsertion computerized tomography (ct) scans of the head were analyzed independently by physicians to identifying tract hemorrhages. data on primary diagnosis, age, sex, length of icu stay and mortality were collected and analyzed. a total of patients were identified as having had an evd placed during their hospital course. patients were excluded as there were no images of evds present in their records. patients were analyzed, of which % were male. mean age was . years. % of patients had a diagnosis of subarachnoid hemorrhage, % with intraparenchymal hemorrhage and % with ischemic stroke. mortality was % among all evd patients. the rate of tract hemorrhages among all patients with evd images was %. asymptomatic tract hemorrhages occurred in patients ( . %) with patient ( . %) dying due to the tract hemorrhage itself. among patients with tract hemorrhages mortality was . %. the rate of tract hemorrhages was noted to be % with the majority being asymptomatic. there was no difference in mortality among patients with evds who developed tract hemorrhages compared to patients with no tract hemorrhages. verapamil is a phenylalkylamine calcium channel blocker that blocks the calcium ion influx through slow channels into conductile and contractile myocardial cells and vascular smooth muscle cells resulting in vascular relaxation and vasodilatation. symptomatic hypotension and/or extreme bradycardia/asystole are often seen with intravenous verapamil administration requiring pharmacologic treatment. in neuroendovascular field verapamil is mainly being used as a vasodilator agent. current lack of pharmacokinetic/pharmacodynamics data of intra-arterial verapamil often makes very challenging to neurointerventionalists during endovascular procedures. the purpose of this study is to observe acute hemodynamic effects of intra-arterial verapamil administration as well as the safety of higher dose of the medication during endovascular treatment. ten patients who underwent endovascular treatment for acute ischemic stroke were evaluated pre and post procedure with vital signs. the dosage of intra-arterial verapamil was documented and tabulated along with the pre and post heart rate and systolic blood pressure. the dose of intra-arterial verapamil varied from to mg in each internal carotid or vertebral artery, total dose per patient per procedure varied from . to . the average dose of intra-arterial verapamil administered was . ± . mg or . ± . mcg/kg that were infused over to minutes. at the baseline before administration of intra-arterial verapamil, the mean systolic blood pressure (sbp) was . ± . mm hg and the mean heart rate (hr) was . ± . bpm. after administration of intraarterial verapamil, sbp decreased by mean of . ± . mm hg but we observed no symptomatic hypotension requiring any pharmacologic treatment. hr changed only by mean of . ± . bpm post intra-arterial verapamil. we observed no acute significant changes in hemodynamic parameters with administration of verapamil in carotid or vertebral arteries. this may represent its safe use during neuro-endovascular therapy. growing evidence suggests inflammation is critical in epileptogenesis. endogenous brain apolipoprotein e protein (apoe) modulates neuroinflammatory responses to injury through downregulation of glial activation and secondary neuronal injury. we created a amino acid peptide (cn- ) mimicking the binding face of apoe. cn- downregulates the inflammatory response in vitro and in vivo and improved histologic and clinical outcomes across several injury models in mice. we hypothesized that downregulation of inflammation by administration of cn- will reduce the development of epilepsy after pilocarpine induced status epilepticus in mice. c bl/ mice were intraperitoneally injected with pilocarpine to induce status epilepticus. following induction of status, animals were randomized to receive two doses of cn- or vehicle at minutes and hours. status was terminated by injection of benzodiazepine at minutes. epidural eeg leads were surgically placed at weeks and continuous video-eeg (cveeg) monitoring was performed for several days in a row at - weeks post status to determine spontaneous seizure development and frequency. at - weeks following induction of status epilepticus, administration of . or . mg/kg cn- reduced the development of epilepsy by approximately % compared to vehicle treated animals. further, cn- treated animals that did develop seizures had significantly fewer seizures than vehicle mice. similar results were seen with daily doses of mg/kg starting at minutes. importantly, cn- is not an anticonvulsant as cveeg monitoring during status induction clearly demonstrated that seizures were not stopped or reduced by injection of cn- . these results are consistent with the hypothesis that inflammation plays an important role in the development of epilepsy after injury and demonstrates treatments that target inflammation, like cn- , can prevent and/or reduce the development of epilepsy. this represents the first therapy to prevent the development of epilepsy that has entered into clinical trials. to determine the speed of brain entrance of the antiepileptic drugs (aeds) brivaracetam (brv) and levetiracetam (lev) after single intravenous dosing in humans. brv and lev both bind to synaptic vesicle protein a (sv a), but brv has more rapid brain entry than lev in mice and monkeys [ ] . sv a can be quantified in the living human brain using pet imaging with [ c]ucb-j[ ]. pet scans (n= ) were performed with [ c]ucb-j administered by a bolus-infusion protocol in healthy volunteers (n= ). therapeutic dosages of brv ( mg, n= ; mg, n= ; or mg, n= ) or lev ( mg, n= ) were administered as -minute intravenous infusions minutes after the start of the first pet scan. tracer displacement half-times were determined by subtracting the radioligand clearance halftime from the radioligand displacement half-times estimated by exponential fitting of the post-aed drop in distribution volumes (vt). data were also analyzed using an advanced mathematical model that described the relationship between brain [ c]ucb-j pet data and time-varying aed plasma curves to directly estimate brain entrance (k ) of both aeds and [ c]ucb-j, free fraction of [ c]ucb-j in the brain, and vt values. the radioligand clearance half-time was minutes. tracer displacement half-times were . and . minutes for brv mg, and ± minutes for lev mg. lower brv doses had longer half-times, but values were misleading as they assumed % sv a occupancy. the advanced compartment model described well -dose scans. using the advanced model, the brv uptake rate (~ ul/min/cm ) was found to be at least -fold higher than that of lev (~ ul/min/cm ). the results demonstrate that brv enters the human brain faster than lev. the potential therapeutic benefit of this has yet to be determined. while intravenous anesthetic therapy (ivat) represents the gold-standard for treatment of refractory status epilepticus (rse), the optimal depth and duration of therapy is not known. the goal of this retrospective observational study was to describe the relationship between the depth of burst suppression and the ability to successfully wean ivat during rse treatment. fifty patients were identified with rse who underwent continuous electroencephalography. using persyst, the suppression ratio (sr) was calculated up to hours prior to weaning ivat. the type and duration of ivat was recorded, as well as complications. we compared these variables between successful and unsuccessful weans. the mean sr for all patients was . ± . %, with a mean treatment duration of . ± . hours. there was no difference in treatment duration between successful and unsuccessful weans(p= . ), but sr was significantly lower in successful weans ( . ± . % vs . ± . %, p= . ). the receiver operating curve (roc) for the sensitivity and specificity of the mean sr to predict a successful weaning attempt did not identify a threshold to predict weaning success. the use of pentobarbital was associated with a significantly higher sr when compared to midazolam ( . ± . % vs . ± . %, p < . ). patients failed ivat weaning a mean . ± . hours after initiating the ivat wean, which occurred after a mean decrease in the midazolam infusion rate of ± %. depth of sr was not associated with infection risk (p= . ), but was associated with the need for tracheostomy ( . ± . % versus . ± . %, p= . ). vasopressors were required in . % of patients while on ivat. unsuccessful weaning of ivat was associated with a higher depth of sr, which is likely a marker of disease severity. depth of sedation was not associated with increased risk of infection, but was associated with the need for tracheostomy. vasopressor requirements are common. the primary objective of this study was to determine the sensitivity and specificity of real-time neuro icu nurse interpretation of quantitative eeg (qeeg) trends in the identification of recurrent nonconvulsive electrographic seizures in adult patients admitted to the neuro icu. thirteen adult patients admitted to the neuro icu that had nonconvulsive seizures on continuous eeg (ceeg) monitoring were included in the study. neuro icu nurses consented for their participation and underwent a brief, standardized qeeg training session. a -hour qeeg panel (rhythmicity spectrogram, left/right and amplitude-integrated eeg, left/right) printout containing the marked sentinel seizure(s) was displayed next to the bedside ceeg/qeeg monitor. at one-hour intervals, the nurses logged the number of seizures seen in the past hour based on their qeeg interpretation for the duration of their shift. their answers were compared with the gold standard of neurophysiologist interpretation of seizure occurrence on raw eeg. a total of hours of qeeg data was reviewed for patients. average length of data collection was . hours. for the neuro icu nurses' ability to detect the presence of seizures on real-time qeeg the sensitivity was . % ( % ci, . - . %) and specificity was . % ( % ci, . - . %). the positive predictive value for seizure detection was . % ( % ci, . - . %) and the negative predictive value was . % ( % ci, . - . %). the false-positive rate was . /hr. a simplified panel of qeeg trends can be used by neuro icu nurses to screen for recurrent electrographic seizures in critically ill patients with a reasonable sensitivity, an excellent specificity and a very low false-positive rate. this may facilitate earlier identification of recurrent electrographic seizures by notifying the neurophysiologist who is not present in the icu and not able to perform real-time ceeg interpretation. nonconvulsive status epilepticus (ncse) is an indicator of poor outcomes in neurocritical care settings. however, because of unfamiliarity with continuous electroencephalography monitoring (ceeg), the diagnosis and treatment of ncse remains challenging, and its clinical impact and prognostic factors have not been sufficiently reported in japan. we performed ceeg for adult patients in our neurocritical care unit with coma or unexplained altered mental status from april to september . we reviewed all ceeg records according to the american clinical neurophysiology society's terminology ( version), and diagnosed patients with ncse when the ceeg revealed spatiotemporally evolving or fluctuating periodic or rhythmic discharges and after considering clinical information based on the modified salzburg consensus criteria. patients with ncse were aggressively treated with benzodiazepines, fosphenytoin, and levetiracetam. they were divided into a generalized convulsive status epilepticus (gcse) group and a non-gcse group. we compared mortality and outcomes between the two groups after months using fischer's exact test. outcomes were defined as poor when the glasgow outcome scale score was worse at the -month follow-up than at admission. we excluded cases undergoing supportive care or lacking of follow-up. of cases in the study, cases were diagnosed with ncse, including cases with accompanying gcse and cases without. mortality rates at the -month follow-up were significantly higher in the non-gcse group than the gcse group ( % vs. %, respectively; p = . ). the rate of poor outcomes was significantly higher in the non-gcse group than in the gcse group ( % vs. %, respectively; p = . ). this study suggests that the absence of gcse is associated with increased mortality and poor outcomes among ncse patients. limitations of this study include its retrospective design and small number of ncse patients. further studies are necessary to identify additional prognostic factors. super-refractory status epilepticus (srse) is a life-threatening condition in which status epilepticus recurs or continues for over hours despite first-, second-, and anesthetic third-line agent (tla) medications. no treatments are currently approved for srse. a randomized, double-blind, multi-center, placebo-controlled phase trial evaluated brexanolone (usan; formerly sage- injection), a synaptic and extrasynaptic gabaa receptor positive allosteric modulator as adjunctive therapy for srse (nct ; "status trial"). enrolled subjects underwent a qualifying tla wean after at least hours of seizure-or burstsuppression. srse subjects failing the qualifying wean were randomized : to a blinded infusion of brexanolone or placebo as adjunctive therapy following resumption of one or more tla infusions. subjects were administered the blinded infusion for days, during which attempts were made to wean off tla infusions. clinical standardization guidelines (csgs) facilitated standardization across sites by outlining eeg patterns for which tla weaning should be continued, paused, or discontinued. an on-call clinical standardization team provided real-time support. safety was assessed via adverse events, laboratory testing, vital signs, and ecg parameters. the primary endpoint was defined as successfully super-refractory status epilepticus (srse) is a life-threatening neurological condition characterized by status epilepticus persisting over hours despite treatment with first-, second-, and third-line agents (tlas) or upon the weaning of tlas. currently, there is no consensus around treatment protocols for srse. this study aims to describe srse treatment patterns and related outcomes in a us population. we retrospectively identified srse cases in cerner healthfacts®, a large, de-identified, us electronic health record database, using records from - . cases were classified as srse using a modified version of a previously published algorithm using icd- and procedure coding for status epilepticus ( . , . , . x, . , . , . , and . ) , ventilator support, pharmacotherapies. descriptive and univariate statistics were used to evaluate anesthetic treatment, anti-epileptic medications, and the association between glasgow coma score (gcs) and mortality. using our algorithm, srse cases ( patients) were classified. multiple tlas were received in % of cases, and in %, > concurrent tlas were received. the first post-admission tlas were propofol, lorazepam and midazolam, respectively, in %, % and % of cases. median anesthetic duration was . days. mortality was higher in - ( . vs. . days; p< . ). srse patients identified in our analysis underwent variable treatment patterns, reflecting lack of co days of tla treatment. nonconvulsive seizures (ncs) and nonconvulsive status epilepticus (ncse) occur in approximately % of neurologically critically ill patients. the most effective antiepileptic drug (aed) regimen to treat ncs and ncse is unknown. this study was designed to determine the efficacy of add-on clobazam, a unique , -benzodiazepine with favorable pharmacokinetic properties, in the treatment of ncs and ncse. a retrospective chart review was performed on adult patients who were admitted to the neurological intensive care unit between january , and june , , were diagnosed with ncs or ncse by continuous eeg monitoring and received clobazam as add-on therapy. the primary efficacy endpoint was defined as clobazam being the last aed added before ncs/ncse cessation, regardless of latency between dosing and ncs/ncse cessation. of the patients included in this study, ( %) had ncs vs. ( %) with ncse. the most common etiologies were autoimmune (n= ) and cns tumor (n= ), with patients ( %) having pre-existing epilepsy. clobazam was the last aed added before cessation of ncs/ncse in of ( %) subjects. clobazam was chosen as the rd to th line agent. clobazam was started at a median of days from the onset ncs/ncse (range - days). the median total daily dose of clobazam was mg (range - mg). this study suggests that clobazam may be effective at various time points in the treatment of ncs/nsce and may prevent the need for addition of intravenous anesthetic drugs to control seizures. however, a prospective study is warranted to determine efficacy and optimal dosing. continuous electroencephalography monitoring(ceegm) with international - system is essential for detect nonconvulsive status epilepticus (ncse). in japan, both ceegm systems and human resources are lacking, and few facilities are able to conduct such advanced monitoring. the ceegm headset, described in this report, is a novel and easy-to-use technology. we attempted to validate the novel ceegm headset by comparing it with a conventional, international - ceegm system (conventional ceegm). we completed this study at a single center, eight-bed neurocritical care unit, between january and june . the new, ceegm headset features eight electrodes (f, c, t, o), and is capable of simultaneously transmitting eeg data by bluetooth. patients with disturbed consciousness, of unknown etiology, underwent ceegm headset followed by conventional ceegm. we verified the concordance rate of the two systems for detecting eeg morphologies (e.g. periodic discharges, rhythmic delta activity, spikes and waves), and diagnosing ncse. eeg morphologies were appreciated according to "american clinical neurophysiology society's standardized critical care eeg terminology: version" and diagnosis of ncse were done according to modified salzburg consensus criteria. among this period, we enrolled thirty patients. three patients were excluded because of not satisfying protocol. final analyses included verified data from patients. the mean age was years old (range: - ), % were male, mean acute physiology and chronic health evaluation (apache) ii score was (range: - ), and mean full outline of unresponsiveness (four) score was (range: - ). we appreciated concordant eeg morphologies, and ncse, in % ( / ), and % ( / ) of patients, respectively. this easy novel ceegm headset may be useful in settings with limited resources or access to conventional ceegm technology. further study is needed to validate the actual diagnostic ability of this novel headset. the traditional approach to interpreting eeg requires physicians with formal training to visually assess the waveforms. this approach is less practical in critical settings when a trained eeg specialist is not readily available to diagnose subclinical seizures, such as non-convulsive status epilepticus, in patients with altered mental status. we have recently invented an algorithm for sonifying eeg, and in the current study, we explored whether individuals without eeg training can detect ongoing seizures by simply listening to one channel of sonified eeg. we sonified eeg samples ( -second long) that represented various conditions commonly seen in the icu ( seizures; lpd, gpd, or burst suppression, and normal or slowing). medical students and nurses were asked to indicate each audio sample as "seizure" or "non-seizure". we then compared their performance with that of eeg experts [epilepsy attendings with > years of experience (n= ) and epilepsy fellows (n= )] and some of the medical students (n= ) who also diagnosed the same eegs on visual display. non-experts listening to single-channel sonified eegs detected seizures with remarkable sensitivity (students: ± %; nurses: ± %) compared to experts or non-experts reviewing the same eegs on visual display (attendings: %; fellows: ± %; students: ± %). if the eegs contained seizures or seizure-like activity, non-experts listening to sonified eegs rated them as seizures with high specificity (students: ± %; nurses: ± %) compared to experts or non-experts viewing the eegs visually (attendings: ± %; fellows: ± %; students: ± %). our study confirms that individuals without eeg training can detect ongoing seizures or seizure-like rhythmic periodic activity by merely listening to short duration of sonified eeg. while sonification of eeg cannot replace the traditional approaches to eeg interpretation, it provides a meaningful triage tool for fast assessment of patients with suspected subclinical seizures. super-refractory status epilepticus (srse) is a life-threatening form of status epilepticus (se) that continues despite, or recurs after, hours of therapeutic interventions, including continuous intravenous anesthetic third-line agents (tlas). no therapies are approved for srse, leading to substantial variation in both management and determination of treatment response. for the phase trial of brexanolone as adjunctive therapy for srse involving up to international sites, we developed and implemented clinical standardization guidelines (csgs) for real-time support of tla administration, weaning, and outcome assessment under eeg neuromonitoring. a clinical standardization team (cst), including investigators and se experts, developed consensus csgs defining acceptable eeg patterns for continuation, termination, or pausing the weaning of tlas. csg implementation was facilitated by training and cst call centers staffed internationally by physicians with critical care eeg expertise. in cases of disagreement, the local site retained final decision-making authority. a "traffic light" system defined: )"green" tolerated eeg patterns (improving background, seizures within hours, discharges > hz, or discharges - . hz with evolution and no improvement over hours), and )"amber" eeg patterns not meeting the above, for which tla weaning should be paused while optimizing anti-epileptic medications and monitoring for transitions to green/red eeg patterns. the initial cst consultations yielded % csg compliance; % of eegs underwent cst review. few cst consultations lasted > minutes ( %); most lasted < minutes ( %). this phase trial demonstrates the feasibility of applying neuromonitoring csgs for tla weaning in srse patients, to ensure better consistency of clinical care and reliability of the primary outcome measure in clinical trials. csgs were well accepted by investigators and may serve as a framework for future clinical trials or clinical therapies in srse. severe brain trauma is a leading cause of death and disability worldwide. post-traumatic epilepsy (pte) is a chronic complication that occurs in up to % of cases (frey, ; najafi et al., ) . drugs and other interventions to prevent epileptogenesis would likely be most effective early after traumatic brain injury (tbi), but cannot be given indiscriminately. there is a critical need for tools that quantify those at high risk for pte. abnormal neural activity, in the form of ictal-interictal continuum abnormalities(iicas) are increased acute brain injuries, and appear to differentiate patients at risk for secondary brain injury (e.g. kim et al., ) . we hypothesized that iicas acutely following tbi may be a marker of posttraumatic epilepsy risk. we evaluated continuous eeg data from moderate to severe tbi patients who did and did not develop pte, (any seizure - months post-tbi; n= ). seizures < month post-tbi were classified as symptomatic, not pte. conventional - scalp electrode placement was used and eegs were reviewed by standard visual analysis, by the mgh neurophysiology service. daily eeg reports were scored for the presence of iicas and seizures. demographic data including gender, age, tbi severity and type of brain injury were recorded. univariate and multivariate regression analyses were performed to determine which iica and demographic features correlated with pte. gcs (p= . ) and tbi severity (p= . ) were significantly associated with pte, as expected. seizures (p= . ), epileptiform discharges (p= . ), generalized periodic discharges ( . ) and lateralized rhythmic delta activity (p= . ) independently predicted risk for post-traumatic epilepsy. epileptiform discharges, in particular, were more prevalent acutely post-tbi in pte patients. increased iica prevalence is significantly associated with pte and may be a predictive marker for identifying patients who may benefit from anti-epileptogenesis trials. rapidly obtaining eeg signals in the ed and icu for at-risk patients can enhance diagnosis accuracy and speed, while cutting down time until treatment. ceribell inc has developed a portable eeg data recorder and electrode headset with rapid setup (~ min) technology without any eeg technician required to overcome the inaccessibility of eeg in urgent situations when seizures are suspected. the purpose of this study is to evaluate the signal quality and performance of the ceribell system compared to a reputable clinical eeg system. we collected eeg samples in the laboratory and at stanford university medical center. laboratory collections on healthy volunteers included simultaneous collection of eeg using ceribell and nihon kohden systems, and a split-signal that recorded eeg to both data recorders from the same electrodes. in the icu, eeg was recorded with the ceribell system on patients and subsequently with the clinical eeg system. data was filtered and spectral densities, mean frequency (mf), spectral entropy (se), and % spectral edge frequency (sef ) were computed. in the split-signal test, the waveforms consistently appeared similar by visual inspection. the analysis of ceribell data revealed (mf = . hz, se= . , sef = . ) similar to the commercial system (mf = . hz, se = . , sef = . ). in the simultaneous test, the ceribell system produced (mf = . hz, se = . , sef = . ) similar to the commercial system (mf = . hz, se = . , sef = . ). in the clinical setting, the ceribell system showed spectral density distributions comparable with the commercial system. our results indicate that the signal quality of the ceribell system is similar to a commercially available eeg used widely in the clinical setting, while requiring less setup time and allowing more portability. status epilepticus (se) is a life-threatening condition characterized by prolonged seizures without regaining consciousness between seizure events. when se continues or recurs hours or more after treatment with third line anesthetic agents, it is considered super-refractory se (srse). there are few population-based studies on the descriptive epidemiology of srse at a national level. the objective was to estimate the incidence of srse in canada in - . we analyzed standardized national administrative record-level data covering all provinces across canada as provided by the canadian institute for health information. srse episodes were classified from two databases for acute care admissions (discharge abstract database) and emergency visits (national ambulatory care reporting system) over fiscal years ( / to / ). cases were identified as srse using a modification of a previously published algorithm using icd- -ca diagnostic codes for epilepsy (g ), status epilepticus (g ), or convulsions (r ) plus an intensive care unit stay of days or more with mechanical invasive ventilation. using our algorithm, from - , the mean annual number of cases classified as srse was , ( . / , persons per year). the annual incidence was higher in males ( . / , per year) than females ( . / , per year). the highest rates were in the age group - years: . and . per , per year for females and males, respectively. the mean age of srse patients was years (sd= years), with % males. the most common comorbidities for srse included metabolic disturbances ( %), sepsis ( %), toxic withdrawal state ( %), cardiovascular disease ( %), and head trauma ( %). in-hospital mortality for srse was %. this is the first study reporting estimates of srse incidence in canada. these results suggest that srse is associated with a substantial disease burden. interventions that improve patient outcomes and reduce mortality are required. new-onset refractory status epilepticus (norse) is a condition characterized by prolonged pharmacoresistant seizures in a previously healthy individual with no identifiable etiology during initial evaluation. typical magnetic resonance imaging (mri) findings include bilateral limbic and neocortical t -weighted hyperintense lesions. fluorodeoxyglucose (fdg)-positron emission tomography (pet) findings have not been previously reported. this study sought to describe fdg-pet and mri characteristics in patients with norse. methods patients were retrospectively identified amongst a database of autoimmune-mediated encephalitis from - , meeting diagnostic criteria for norse and having undergone mri and pet over the course of their illness. imaging findings were confirmed with a board-certified neuroradiologist. nine patients were autoantibody positive: three n-methyl-d-aspartic acid (nmda) receptor, two glutamic acid decarboxylase (gad), three voltage-gated potassium channel (vgkc)-complex with two having leucine-rich glioma-inactivated protein igg positivity, and one gamma-aminobutyric acid (gaba) b receptor. all patients had identifiable abnormalities on fdg-pet. hypometabolism was most common, with of patients having diffuse, bilateral, or unilateral frontal, parietal, or occipital cortical hypometabolism. nine patients also had bilateral ( ) or unilateral ( ) mesial temporal hypermetabolism. two patients had multifocal hypermetabolism with bilateral or unilateral frontal abnormalities in addition to mesial temporal findings. of the nine patients with fdg-pet hypermetabolism, concurrent mri scans failed to show corresponding t -weighted hyperintense lesions in the mesial temporal and medial frontal regions in two patients. fdg-pet findings in norse include bilateral or unilateral mesial temporal or mesial frontal hypermetabolism with diffuse, bilateral, or focal cortical hypometabolism. hypermetabolism may reflect regions predominantly involved in acute epileptogenesis. fdg-pet may improve sensitivity when compared to mri alone. while seizures are uncommon but reported in primary intraventricular hemorrhage (ivh), little evidence is available on the prevalence of hyperexcitable patterns on long term eeg monitoring. we sought to determine the prevalence of hyperexcitable patterns and seizures in patients with primary ivh who were extracted from a cohort consisting of patients with spontaneous intracerebral hemorrhage (sich) who underwent continuous electroencephalogram (ceeg) monitoring between january and december at yale-new haven hospital. indications for ceeg monitoring included fluctuation of or depressed mental status, abnormal movements and a limited clinical exam. we recorded demographics, radiologic hydrocephalus, duration of eeg recording and eeg findings. hyperexcitable patterns comprised generalized, bilateral independent or lateralized periodic discharges (pds), lateralized rhythmic delta activity (rda), brief potentially ictal rhythmic discharges (b(i)rds), and spike-and-wave discharges (sw). of adults with sich who had ceeg performed, patients had primary ivh. hydrocephalus was present in patients ( %). patients were monitored for a mean duration of . (± . ) hours. patients had hyperexcitable patterns and/or electrographic seizures ( %): electrographic seizures and co-existent hyperexcitable patterns were captured in of patients ( %) and hyperexcitable patterns without seizures in of patients ( %). hyperexcitable patterns included periodic discharges (pds) ( ) (generalized, lateralized and bilateral independent, with and without rhythmicity), rhythmic delta activity (rda) ( ) (both lateralized and generalized, with and without sharps), brief potentially ictal rhythmic discharges(b(i)rds) ( ) and spike-and-wave discharges (sw) ( ). there was no significant difference between patients with and without hydrocephalus and hyperexcitability or electrographic seizures (p= . ). both electrographic seizures and/or patterns of hyperexcitability on eeg are common in our selected cohort of primary ivh patients. this underscores the importance of continuous eeg monitoring in this patient population, since the detection of non-convulsive seizures may offer an opportunity for therapeutic intervention. patients with aneurysmal sah (asah) frequently have ictal-interictal continuum (iic) eeg patterns. while seizure burden can worsen outcomes, less is known about iic burden. we investigated the impact of iic burden and anti-epileptic drug (aed) treatment on asah outcomes. we included patients with asah undergoing continuous eeg (ceeg) from - . patients with nonaneurysmal sah or %, - %, - %, - %, < %. age gender, admission gcs, apache ii score, fisher and hunt and hess (hh) scores, aed dosing and discharge gos were ascertained by chart review. presence of iic patterns in asah independently predicts worse neurologic outcome, although maximum burden does not. although nearly half of these patients receive aed treatment, our data suggest that aed treatment may not influence outcome. prospective studies may further delineate the clinical risks and benefits of aed treatment. refractory status epilepticus (rse) is defined by failure to control epileptic activity after the administration of st and nd line antiepileptic agents. mortality associated with rse has been estimated to be around - % at hospital discharge. we conducted this study to analyze trends in the frequency and management of rse. we conducted a cross-consortium (uhc) database from to . this is a database from academic medical centers and their affiliated hospitals in the united states and consists of a sample of , , patients. data including age, sex, antiepileptics (aed) and length of stay was collected. total mean age was . years and females were . %. there was an increasing trend of using lorazepam as the first line aed ( . % in to . % in ) and a decreasing trend was noted of using midazolam as the first line aed ( . % in aed ( . % in to . % in . leviteracetam was the most common second line aed used throughout all years which was followed by propofol followed by phenytoin/fosphenytoin. mean length of hospital stay was . days. between to , the proportion of hospitalized patients in the united states diagnosed with rse has increased. lorazepam and leviteracetam have been the most common aeds used. mean length of hospital stay has not changed. status epilepticus is associated with high risk of multi-organ dysfunction. ketamine for the treatment of super refractory status epilepticus (srse) has the benefit of a different mechanism and lack of cardiac depression when compared with other anesthetic agents. this study evaluated the improvement in sequential organ failure assessment (sofa) score in patients treated with ketamine for srse. this is a retrospective study of patients with srse from to . the timing and dosage of anesthetic agents used in their treatment were abstracted. sofa scores at admission and for the first days after initiation of ketamine were calculated. the presence of shock prior to initiation of ketamine included septic shock and cardiogenic shock. outcomes including mortality, organ failure, and hospital associated infections (hais) were also recorded. a total of patients were treated with ketamine after failure of seizure control using other anesthetic agents. seventeen ( . %) had an improvement of their sofa score while ( . %) did not. the median sofa score on admission was (iqr - ) for those who had an improvement and (iqr - ) for those who did not (p= . ). cardiac arrest was the etiology of srse for ( . %) patients who improved vs. ( . %) patients who did not (p= . ). patients required to vasopressors for hemodynamic support, with less needed for those who had an improvement (p= . ). there was a higher rate of hais in patient who did not have an improvement of their sofa score (p= . ). there is a subset of patients treated with ketamine for srse who have an improvement in their sofa score, require less vasopressor support, and have a lower rate of hais. further studies are needed to better understand which patient population may most benefit from the use of ketamine for treatment of srse. the ceribell eeg system (ces) is a novel channel eeg device with instant sonification and visual display capability that can be set up quickly without an eeg technician. we hypothesized that by using ces, we can decrease time to eeg acquisition and improve diagnosis and treatment decisions in suspected nonconvulsive seizures (ncs). adult icu patients (gcs < ) who had continuous eeg (ceeg) as part of clinical care were enrolled. once ceeg was ordered, consent was obtained and ces was placed by the treating physician (n= ) who listened to the left/right hemisphere signals for seconds each. suspicion for seizure ( =low, =high) and decision to treat (yes/no/not sure) were rated pre-and post-sonification. three blinded epileptologists compared accuracy of sonification with visual ces eeg. outcomes were difference in time to eeg acquisition, change in suspicion for seizure and decision to treat, and ease of use ( =challenging; =easy). patients (mean age +/- , median gcs of (iqr - . ) were enrolled from : am to : pm. start of eeg acquisition was significantly faster for ces ( minutes (iqr - ) vs minutes (iqr - ) p< . ), median difference minutes (iqr - ). one patient had ncs during sonification and this was accurately identified and treated. low suspicion for seizure ( ) was more likely postsonification ( % vs %, p= . ). treatment decision changed in % after sonification, and this was in the correct direction % of the time. inappropriate decision to treat decreased from % to % (p= . ). negative predictive value was % ( % ci - %). ces was consistently rated easy to use. the ceribell eeg system is easy to use, speeds eeg acquisition, accurately identifies ncs, and enables appropriate treatment decisions. it has the potential to greatly enhance timely diagnosis and treatment of ncs in critically ill patients. the aim of the study was to understand the efficacy of ketamine in refractory status epilepticus and identify the underlying factors affecting the effectiveness of ketamine. moreover, we also studied the rate of complications in patients who underwent continuous midazolam ketamine dual therapy for treatment of refractory status epilepticus. this is retrospective cohort study evaluating the efficacy of ketamine in patient with refractory status epilepticus in total of patients admitted to university of maryland medical center in either neuro intensive care unit /micu during the last five years between ( - ). we established a standardized algorithm for managing refractory status epilepticus. electrographic and clinical control of seizures was classified into four groups: likely response, possible response, permanent response and no response reviewed by a team of epileptologist and neuro intensivist. the effective doses of ketamine to abort rse were studied. complications intensive care unit stay while on therapy were reviewed. of the patients, were male, were female. % of the patients had cardiac arrest as an etiology of seizures. median loading dose was . mg/kg, median maintenance dosage was mg/kg/hr. % of the patients had no response to ketamine. % were responsive to ketamine of which, patients had likely response to ketamine, patients had possible response. . % of the patients had permanent response to ketamine. % patients had hospital acquired infections, % patient had metabolic acidosis, % had ards. this is one of the largest single center study illustrating the efficacy of ketamine in aborting rse. further study should address the difference in incidence of complications in patients with usage of ketamine versus groups alternative therapies. this study also demonstrates the etiology of seizures and its influence on efficacy of ketamine in aborting rse. acute cardiopulmonary complications are frequently observed in convulsive status epilepticus but mechanism is poorly understood. complications include tachy-arrhythmias, myocardial ischemia, takotsubo cardiomyopathy and neurogenic pulmonary edema. herein, we mapped evolution of cardiac dysautonomia as function of sequential electrographic stages of se in four subjects admitted to icu. we hypothesize pathological co-activation of both arms of autonomic system contributes to cardiac complications. heart rate variability (hrv) is considered a proxy for ans tone on heart. we analyzed hrv in time and frequency domain, complexity measure (lempel ziv-lz) during se and mapped changes as function of stages of se as determined by scalp eeg. conventional scalp eeg recording and lead i-ekg (sampled at hz) were analyzed using kubios hrv software . . cardiac vagal index (cvi) and cardiac sympathetic index (csi) were calculated using geometric lorenz-plot method. parasympathetic activity is expressed in rmssd, pnn, cvi, and hf power four adults (range - ; m= ) were admitted to icu following convulsive se. ictal hrv changes initially reflected high sympathetic system activation (high csi) and reduced vagal tone (low hf, rmssd) as reported previously with convulsive seizure. earlier stages of se (stage i and ii) were marked by dual activation of the ans with sympathetic predominance (lower cvi/csi ratio). later stages of se (stage iv and v), demonstrated progressive increase in parasympathetic activity (hf power, rmssd, cvi, cvi/csi ratio). hf power and rmssd at stage v se was three times higher than during discrete seizure. lz complexity measure downtrended with the loss of fluctuations in late stages of se. in one subject se terminated with asystole this case series highlights dynamic changes in sympatho-vagal imbalances with progressive se. dual activation of sympatho-parasympathetic system and loss of complexity measures are associated with increased cardiac complications. therapies directed towards stabilization of cardiac dysautonomia might minimize complications super-refractory status epilepticus (srse) is a life-threatening neurological condition that is characterized by status epilepticus that persists for hours despite treatment with first-, second-, and third-line agents (tlas) or upon the weaning of tlas. srse is associated with limited treatment options, and high morbidity and mortality. this study aims to describe and quantify inpatient srse treatment and its associated outcomes in the us. srse cases were classified retrospectively using a modified version of a previously published algorithm applied to a large, de-identified, us electronic health record database (cerner health facts®) covering > hospitals ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . cases were classified utilizing icd- and procedure coding for status epilepticus ( . , . , . x, . , . , . and . ) , ventilator support or with los> days or missing age were excluded. univariate statistics were used to describe mortality, hospital los, icu los, and discharge disposition. our algorithm classified cases as srse ( patients). most cases ( %) were to large ( + beds) and/or teaching hospitals ( %). mean hospital los was . days, and icu los was . days. both los and icu los were significa average mortality rate was . %. mortality rates increased with number of tlas used ( - tla= . %; -rged home ( % with tracheostomy), while % (n= ) were discharged to another facility. treatment of srse requires acute, intensive management in the hospital setting. los and mortality rates were high and increased with increasing use of tlas. while good outcomes remain possible even after srse, additional interventions are needed that enable seizure control, liberation from anesthetic and ventilator management, and improved mortality. refractory status epilepticus (se) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. initially used in childhood epilepsies, ketogenic diet (kd) has also accumulated supporting evidence in the treatment of pediatric se. recently, the implementation of kd in adults with refractory and super-refractory se has been shown to be feasible and effective. we describe our recent experience with a new onset refractory status epilepticus (norse) patient and the unexpected challenge of achieving and maintaining a ketotic target. practical advice, a comprehensive review of offenders jeopardizing ketosis commonly used in the neurocritical care unit and alternatives is provided. a previously healthy -year-old woman was admitted with cryptogenic norse following a febrile illness with a course complicated by prolonged super-refractory se. a comprehensive work-up was notable only for mild cerebral spinal fluid (csf) pleocytosis, elevated non-specific inflammatory serum markers, and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (mri). repeat csf testing was normal and serial mris demonstrated resolution of edema and diffusion restriction with gradually progressive hippocampal and diffuse atrophy. she required an aggressive approach including high anesthetic infusion rates, anti-seizure drug trials (in various combinations), empiric partial bilateral oophorectomy, and immunosuppression. enteral ketogenic formula was started on hospital day , however, sustained beta-hydroxybutyrate levels > mmol/l were only achieved days later following a careful comprehensive adjustment of the care plan. notably, a significant response to kd was only achieved with beta-hydroxybutyrate levels > . mmol/l. there are hidden carbohydrates in commonly administered medications for se, antibiotics, and even electrolyte repletion formulations and solutions used for oral care -all challenging the use of kd in this setting. tailoring comprehensive care and being aware of possible complications of kd are important for the successful implementation and maintenance of ketosis. early seizures are estimated to occur in - % of patients with moderate to severe traumatic brain injury (tbi) (herman , vespa ). continuous eeg (ceeg) is essential for detection of nonconvulsive seizures (claassen ) the university of california davis protocol for tbi includes ceeg on a case by case basis, which we reviewed. a retrospective review of patients admitted to icu for tbi from / / - / / was performed for demographics, icu length of stay (los), and ceeg. patients with ceeg were assessed for demographics, tbi severity, gcs, ceeg indication and findings. patients were identified. twenty-one were monitored on eeg. median age was , % were female. indications for ceeg included seizure prior to admission (n= ), altered mental status (ams) (n= ), ams with paroxysmal events (n= ). seizures were recorded in patients. median duration of ceeg was . , . , and . hours among the groups. those with seizures prior to hospitalization were connected to ceeg earliest (median . hours) but had the longest median icu los ( . hours), followed by ams ( . and . hours) and ams with paroxysmal events ( . and . hours). median gcs was , , and respectively. median los for patients without seizures or interictal epileptiform activity (iea) was . hours, . for those with iea only, and . for those with seizures. median gcs was . , , and among the eeg groupings. our data suggests seizures prior to hospitalization, ceeg recorded seizures, and iea predict longer icu los. associated lower gcs likely indicates more severe injuries. tbi patients with ams may have delay to seizure detection and treatment. our rate of seizure detection is lower than expected. a more consistent protocol for ceeg will likely improve seizure detection. prospective studies are needed to determine if ceeg can predict and influence outcomes. status epilepticus is a serious neurologic emergency. although many studies have been published on incident status epilepticus, there are few data on the risk of recurrent status epilepticus. we performed a retrospective cohort study using administrative claims data to identify all patients hospitalized with status epilepticus in california, new york, and florida between - . our primary outcome was a recurrent hospitalization for status epilepticus. survival statistics were used to calculate the cumulative rate of recurrence at days, year, and years. in subgroup analyses, we compared rates of recurrence according to age, gender, race, and etiology (stroke, traumatic brain injury, acute and chronic central nervous system (cns) infections, brain tumors, dementia, autoimmune cns disease, or unspecified etiology). we identified , patients with status epilepticus. during a mean follow-up of . (± . ) years, , ( . %; % ci, . - . %) developed recurrent status epilepticus. the cumulative rate of recurrence was . % ( % ci, . - . %) at days, . % ( % ci, . - . %) at year, and . % ( % ci, . - . %) at years. the -year cumulative rate of recurrence was . % ( % ci, . - . %) in women versus . % ( % ci, . - . %) in men, . % ( % ci, . - . % ( % ci, . - . %) in patients < , and . % ( % ci, . - . %) in white patients versus . % ( % ci, . %- . %) in non-white patients. the -year cumulative rate of recurrence was highest for status epilepticus associated with autoimmune cns disease ( . %; % ci, . - . %) and chronic cns infection ( . %; % ci, . - . %). approximately in patients with status epilepticus experienced a recurrent episode within years. recurrence was most often seen in younger patients, non-white patients, and patients with underlying autoimmune cns disease or chronic cns infection. super-refractory status epilepticus (srse) is a rare, life-threatening form of status epilepticus (se) refractory to multiple therapies including anesthetic third-line agents (tlas). enrollment in a srse clinical trial is challenging because patients may present urgently before srse is confirmed or may dynamically improve before randomization. pivotal clinical trials in srse require patient selection criteria accurately identifying srse at randomization. in this phase trial of brexanolone as adjunctive therapy for confirmed srse, the enrollment scheme enabled operationally confirming srse prior to randomization during a qualifying wean (qw) under real-time eeg neuromonitoring. informed consent was obtained for all subjects ) admitted in se having failed first-and second-line therapies; ) transferred on tlas in seizure-or burst-suppression; or ) transferred without seizure-or burst-suppression or not receiving tlas. subjects were required to achieve seizure-or burst-suppression for hours through continuous administration of one or more tlas, followed by a post-enrollment qw of tlas. enrolled subjects failing the qw were randomized to concomitant brexanolone or placebo following reinstitution of one or more tlas. subjects not randomized after a successful qw underwent a -week follow-up. the qw protocol and criteria for qw failure were developed and implemented utilizing eeg neuromonitoring to confirm srse after enrollment using the definition of shorvon and colleagues. a qw was performed on over evaluable subjects across international sites to enable enrollment of patients with confirmed srse. subjects with a successful qws who were not randomized provided insight into outcomes associated with se and avoided the randomization of patients who did not meet srse criteria following enrollment. the use of neuromonitoring-guided diagnosis during a structured qw helped confirm srse, facilitating the enrollment of appropriate patients into this phase trial in a rare, critically ill, and dynamic srse patient population. autoantibodies to the kda isoform of gulutamic acid decarboxylase (gad ab), commonly found in t dm patients, have been associated with drug resistant epilepsy. ketosis prone diabetes is a heterogenous syndrome encompassing various forms of beta cell dysfunction culminating in diabetic ketoacidosis. rates of epilepsy in patients with ketosis prone diabetes are not known. we compared the prevalence of epilepsy in patients with ketosis prone diabetes in a multi-ethnic population with the prevalence of epilepsy in the type diabetes population as well as the general population in a metropolitan medical center. our study design is prospective review of retrospectively collected sera of patients admitted for diabetic ketoacidosis (defined as ph < . , bicarb < , with ketonemia or ketonuria) for the presence of gad ab. all these sera were assessed separately for autoantibody presence or absence at dr hampe's lab in washington, seattle. we also reviewed patients medical records for neurological diagnoses. this done in a blinded fashion by two separate reviewers. out of our patients with ketosis prone diabetes, . % also had epilepsy. this is higher than the published rate in type diabetics ( . %) and the general population in the surrounding area (< . %). antibody testing revealed % of patients with ketosis prone diabetes were gad ab positive with a rate of epilepsy of %. a two-tailed t test between the gad ab + group and gad ab -group showed no statistically significant difference in prevalence of epilepsy in these two groups. while prevalence of epilepsy is higher in the ketosis prone diabetes population than the general population of houston, the difference is not related to titers of gad ab, and must be due to some other unknown factor in these patients management of refractory status epilepticus commonly involves the induction of seizure-or burstsuppression using anesthetic agents. however, the duration and endpoints of these therapies are not well defined. specifically, weaning anesthetic agents is complicated by the emergence of eeg patterns on the ictal-interictal continuum (iic), which have uncertain significance, given that iic patterns may worsen cerebral metabolism and oxygenation, have a dissociation between scalp and depth eeg recordings, and indicate a late stage of status epilepticus itself. determining the significance of iic patterns in the unique context of anesthetic weaning is important to prevent the potential for unnecessarily prolonging anesthetic coma. we identified a series of patients who underwent over hours of burst-suppression therapy, multiple weaning attempts, and continued weaning despite the initial emergence of iic patterns. patients who experienced anoxic brain injury were excluded from the series. we report cases of patients who underwent successful weaning despite initial emergence of iic patterns. eeg patterns following anesthetic weaning (including lateralized periodic discharges approaching hz frequency and lateralized rhythmic delta activity) as well as terminal eeg patterns are described in detail. in these patients, continuing weaning of anesthetic agents despite the emergence of iic patterns did not result in relapse to status epilepticus. while the metabolic impact of these patterns on brain activity is uncertain, weaning strategies that treat iic as a surrogate of recurrent status epilepticus risk further prolonging anesthetic management and its known toxicity. we speculate that iic patterns are transitional and may have a context-specific association with status epilepticus relapse, with less risk conferred when these patterns are observed during the weaning of anesthetic agents after prolonged burst-suppression therapy. other electrographic features aside from this clinical context may discriminate the risk of status epilepticus relapse, such as eeg background activity. brivaracetam (brv) is approved as adjunctive therapy for focal (partialyears) with epilepsy. brv is available as oral tablets, oral solution, and an intravenous (iv) formulation. the formulations are interchangeable. this abstract reports the safety and tolerability of iv brv. during clinical development, participants received iv brv. we report pooled safety findings from participants receiving brv - mg doses. the therapeutic range of brv is - mg twice daily. in n , healthy volunteers received iv brv as a -minute infusion or mg/min bolus ( , , , or mg single doses; n= in all groups). in ep (nct ), healthy volunteers received iv brv mg as a single -minute bolus injection or oral tablets. in n (nct ), patients received days of brv oral tablets mg twice daily or placebo, and then . days of iv brv mg twice daily either as a -minute bolus or -minute infusion for nine doses in total. treatment-emergent adverse event (teae) data were pooled. data reported are for iv brv - mg (n= ). most frequent teaes were somnolence . %, dizziness . %, fatigue . %, headache . %, dysgeusia . %, euphoric mood . %, feeling drunk . %, and infusion-site pain . %. infusion-site pain was specific to administration route. most teaes were mild or moderate and occurred mostly in healthy volunteers. iv brv was well tolerated, with an ae profile consistent with oral administration except for routespecific injection-site aes, dysgeusia, euphoric mood and feeling drunk. the interpretation of these data was complicated by the difficulty of pooling disparate studies involving healthy volunteers and epilepsy patients with heterogeneous medical histories and concomitant antiepileptic drug use. further clinical trials or real-world experience are needed to understand potential clinical impact. ucb pharma funded refractory status epilepticus (rse) is a challenging condition that requires multiple antiepileptic drugs (aed) to treat. during rse, the brain is under excessive excitation, which results in an increase in glutamate receptors such as alpha-amino- -hydroxy- -methyl- -isoxazolepropionic acid (ampa) and nmethyl-daspartate (nmda).. perampanel (per), a novel, noncompetitive ampa-receptor antagonist, may have a role in the treatment of rse and there are positive results in different animal models with rse. we identified adults patients over a month period who were treated with per for different forms of rse. one was excluded as the etiology of rse was anoxic brain injury and care was transitioned to comfort only within hours of initiating per. three patients had a definite response to per, which we defined as resolution of ictal patterns on electroencephalogram (eeg) within hours of per without adding a new aed. one had a possible response with significant improvement in eeg findings; however, there was some eeg improvement predating the initiation of per. in observed several treatment factors that may have increased response to per. those who responded had it used earlier in the treatment cascade (sixth or seventh vs. ninth or tenthaed ), higher initial dose ( mg vs mg), and were escalated to maximum dosage within hours. they were also more likely be receiving continuous ketamine and midazolam, suggesting a possible synergy with per. there were no documented adverse effects in any patient prior to discharge. one patient did experience a decline in phenytoin levels, which could be related to per as there are reports of enzyme-inducing properties. we observed efficacy of per in several patients with focal and generalized rse without a significant adverse effect profile. further studies are needed to clarify the dosing, timing and appropriate indications in rse treatment. topiramate is a potent broad-spectrum anti-epileptic drug (aed) with several mechanisms of action including blockage of the inotropic glutamatergic ampa receptor, voltage-gated sodium channels, antagonism of non-nmda glutamate receptors and enhancement of gaba mediated chloride conductance. we hypothesize that topiramate is an effective adjunctive therapy in rse and srse due to multiple mechanisms of action. we performed a retrospective analysis of patients admitted to the intensive care unit with status epilepticus (se) at a tertiary referral center from - . we reviewed demographics, age, seizure type, etiology, prior aed/topiramate exposure, time to response to treatment, eeg reports and neuroimaging results. rse was defined as failure of benzodiazepine and another conventional second line aed to stop se. srse was defined as se that continues or recurs hours after being treated with an anesthetic agent. ( %) were male, ( %) had a history of seizures; mean age of patients with se was . years. of treated patients, ( %) had focal non-convulsive se (ncse), ( %) had myoclonic se, had myoclonic, followed by generalized ncse, ( %) had generalized ncse, and ( %) had focal and generalized nonconvulsive se, prior to administration of topiramate. ( %) patients were treated with aeds, ( %) patients with aeds prior to topiramate. electrographic seizures improved in ( %) patients after receiving topiramate. resolution of electrographic seizures occurred within hours in ( %) patients, hours in ( %) patients, hours in ( %) patients and hours in ( %) patients. our findings suggest that topiramate could be an effective adjunctive treatment in rse and srse. however, prospective studies, including larger number of patients are needed to confirm these findings. patients with refractory status epilepticus (se) require multiple antiepileptic drugs (aeds) to abort seizures, and often barbiturates. there is a paucity of data on how to wean aeds safely once seizures are controlled while minimizing medication side-effects or withdrawal symptoms. a retrospective review of patients admitted to mayo clinic in rochester, minnesota for se between and was performed. patient demographics, se type (focal versus generalized, convulsive, and refractoriness), seizure etiology, aeds in admission and at outpatient follow-up, aed side effects from use and withdrawal, and functional outcomes in terms of modified rankin scale were recorded. of ( . %) patients had refractory se, ( . %) patients had refractory non-convulsive status epilepticus (ncse), ( . %) patients had convulsive se, ( . %) patients had ncse, and ( . %) patients had epilepsia partialis continua. of the patients with outpatient follow-up (ranging to weeks following hospital discharge with . % patients following-up within one month), patients were on an aed regardless of etiology. patients were on a median of aed in both refractory and nonrefractory se at follow-up. ( . %) patients had withdrawal seizures after aeds were weaned ( had a prior stroke, traumatic brain injury, idiopathic, multifactorial). none of the patients completely weaned off a barbiturate had seizure recurrence at follow-up. -month mortality in refractory se was / ( . %) and / ( . %) in non-refractory cases. favorable functional outcome at follow-up was achieved in / ( . %) patients with refractory se versus / ( . %) in non-refractory se. we found a low rate of late seizure recurrence after weaning aeds in refractory and non-refractory se, particularly in the case of barbiturates. spreading depolarizations (sd) are strongly associated with secondary brain injury after aneurysmal subarachnoid hemorrhage (sah). however, studies to understand whether sds play a causal role in secondary injury are hindered by existing sd induction methods which are invasive, cumbersome, and cause primary tissue injury. we developed a method to study the role of sds after experimental sah using commercially available transgenic optogenetic mice which express channelrhodopsin (chr ) in cortical neurons. we used in vivo laser speckle and doppler flowmetry, intrinsic signal imaging, and local field potential (lfp) and extracellular potassium shifts to detect sds. we optogenetically induced sds with light through intact and unaltered skull in multiple regions without causing primary brain injury. we found regional differences in thresholds for optogenetically-induced sds (from lowest to highest threshold): ( ) whisker barrel, ( ) motor, ( ) sensory, and ( ) visual cortex. lower thresholds were associated with higher chr tissue expression. changes in lfp and increased extracellular potassium concentrations at the site of stimulation preceded precipitation of an sd. finally, we induced and detected sds in the setting of sah over several days through chronically implanted glass coverslips non-invasive optogenetic light stimulation can reliably induce sds in the setting of sah. longitudinal optogenetic induction of sds in chr transgenic mice is a potentially useful tool to study the role of sds in the pathogenesis of secondary brain injury after sah. aneurysmal subarachnoid hemorrhage is a devastating neurologic injury with significantly prolonged hospital courses and high morbidity and mortality. when aneurysms are detected, they often require securement either via surgical clipping or endovascular techniques. a subset of intracranial aneurysms, given location, poor surgical approach, and wide neck are amenable to flow diversion which promotes thrombosis through redirecting of blood flow within an aneurysm leading to slow obliteration. approximately % of treated aneurysms with flow diversion do not obliterate after months, but currently there is no validated way to predict treatment failure. computational models of blood flow of flow diverted aneurysms predict a significant difference in the hemodynamic energy loss across aneurysms between cases that resolve and those that do not. energy loss could be estimated clinically during angiography, however, this hypothesis needs to be validated experimentally because computer models often over estimate hemodynamic parameters, poorly predict flow through stents, and may not have the resolution to fully describe intra-aneurysmal blood flow. in this pilot study, four cases of giant fusiform intracranial aneurysms will be selected --two with resolution following flow diversion treatment, and two without resolution. models of each vessel geometry will be fabricated using additive manufacturing techniques. under fluoroscopy, within the model vessel, flow diverting stents will be placed within the aneurysm in the same configuration that was achieved clinically. model blood, containing tracer particles will be pumped through model aneurysms and using particle image velocimetry, energy loss will be calculating within model vessels following treatment. energy loss between aneurysms successfully and unsuccessfully treated with flow diversion will be compared experimentally. hemodynamic energy loss may be a clinically measurable value which could predict treatment failure after flow diversion. additive manufacturing techniques can be used to test patient specific hemodynamics to improve understanding of flow-diversion treatment success or failure. the national institute of neurological disorders and stroke (ninds) and the national library of medicine (nlm) initiated development of unruptured cerebral aneurysms and subarachnoid hemorrhage (sah)specific common data elements (cdes) in as part of a joint project to develop data standards for funded neuroscience clinical research. through the development of these data standards, the ninds and nlm sah joint cde initiative strives to improve sah data collection by increasing efficiency, improving data quality, reducing study start-up time, facilitating data sharing/meta-analyses and helping educate new clinical investigators. the sah cde working group (wg) consisted of international members with varied fields of sahrelated expertise and was divided into domains such as subject characteristics and assessments and exams. the wg developed a set of sah-specific cde recommendations by selecting among, refining and adding to existing field-tested data elements, especially established stroke cdes. wg cde recommendations were drafted into the nih cde repository. following an internal review of recommendations, the sah cdes were vetted during a public review on the ninds website for weeks and later posted on nlm and ninds websites. version . of the sah cdes was available on the ninds cde website in april . these new sah cdes and recommendations include those developed for unruptured intracranial aneurysms and long-term therapies. the website provides uniform names and structures for each data element, as well as guidance documents and template case report forms using the cdes. the ninds encourages the use of cdes by the clinical research community in order to standardize the collection of research data across studies. the ninds cdes are a continually evolving resource, requiring updates as research advancements indicate. these newly developed sah cdes will serve to be a valuable starting point for researchers and facilitate streamlining and sharing data. subarachnoid hemorrhage (sah) represents % of stroke admissions in the us. aneurysmal hemorrhage represents the most dangerous etiology, however - % of sah have negative digital subtraction angiography (dsa). there is variation in practice with regards to repeat diagnostic studies and timing of such studies. it is not uncommon to repeat dsa in - days of the initial assessments. this study aims to describe the costs associated with prolonged icu stay and repeat diagnostic studies this patient cohort. retrospective review of all patients admitted for spontaneous sah between january and april at our single institution. patients with at least one negative initial angiogram for suspected spontaneous sah were included. patients were categorized into diffuse patterns of sah and nondiffuse. cost estimates were based on standard costs as provided by our financial department and cdc estimates for costs of hospital acquired infections. one hundred fifty-four patients were identified with initial negative dsa. second angiograms were performed in % of patients, and potentially positive causal findings in / ( . %). icu los for angiogram negative diffuse sah and non-diffuse were . and . days respectively. other indications for icu stay included vasospasm ( . %), evd placement ( . %), and intubation ( %). the excess cost estimates per patient for angiogram negative diffuse and non-diffuse sah were $ , and $ , respectively. hospital acquired complications were an additional total $ , for the cohort. this is the first study to our knowledge attempting a cost analysis of the diagnosis and management of patients with angiogram negative sah. we had a high frequency of patients requiring icu admission for other indications, which should continue to dictate the level of care. however, there may be a cohort of lower risk patients in which de-escalation would not harm, and be of benefit in the reduction of morbidity and cost. purpose: to evaluate the feasibility and potential role of bedside optical coherence tomography (oct) as a diagnostic protocol in terson's syndrome (ts) in patients with acute subarachnoid hemorrhage (asah). background: % of sah patients become permanently legally blind. the average cost of lifetime support and unpaid taxes for each blind person is approximately $ , . ts presents as ocular bleeding commonly associated with asah. it can be diagnosed by fundoscopy, yet retinal haemorrhages, detachments and macular holes may be undetected. early ts identification is critical since untreated it may lead to legal blindness, limit rehabilitation and impair quality of life. pilot study: sah patients were screened for ts with dilated fundoscopy and then with oct. mood assessments (phq- , hds), quality of life measures (nih-promis) and subjective visual function scales (vfq- ) were performed. there was a . % (n= ) incidence of ts. dilated retinal fundoscopy significantly failed to detect ts (n= , . % missed cases). ivh was significantly more in ts ( . % vs. %). no participants experienced any complications from oct examinations. neither decreased quality of life visual scores nor a depressed mood correlated with objective oct pathological findings at weeks follow-up after discharge. there were no significant mood differences between ts cases and controls. oct is the gold-standard in retinal disease diagnosis. this pilot study showcases its bedside feasibility in asah. in our series, oct was a safe procedure that enhanced ts detection by decreasing false negative/ inconclusive fundoscopic examinations. it allows early diagnosis of macular holes and severe retinal detachments, which require acute surgical therapy to prevent legal blindness. besides, oct aids ruling out potential false positive visual deficits in individuals with a depressed mood at follow up. a comprehensive study is underway to understand the impact oct might exert on blindness prevention and quality of life. fever is common in patients with aneurysmal subarachnoid hemorrhage (asah), and blood cultures are commonly sent to diagnose etiology. several studies have shown a low incidence of positive blood cultures, but no studies have assessed blood cultures in patients with asah. we performed a retrospective analysis of patients admitted with asah between january to december . blood cultures were adjudicated as true positive (tp) or false positive (fp) based on speciation, time to positivity, number of cultures positive, and repeat culture results. tp patients were compared to all other patients. age, gender, hunt hess, modified fisher, aneurysm treatment, incidence of delayed cerebral ischemia (dci), length of stay (los), and neurological outcomes were analyzed. patients with asah were included. blood cultures were sent on ( %). sixteen were positive. eleven were adjudicated tp and fp. thus, . % ( / ) of patients had true bacteremia, and blood culture yield for true infection was . % ( / ). fp rate was . % ( / ). eight tps were gram negative ( %), and all contaminants were staphylococcus non-aureus. median post-bleed day for tp results was . only patients were tp within the first week of admission ( . %). tp patients had higher admission wfns (p=. ) and ivh score (p=. ), but age, gender, aneurysm treatment, and fisher score did not differ. tp patients had longer icu and hospital los and higher incidence of dci ( % vs %, p=. ). mortality did not differ in the two groups either. the yield of blood cultures in asah patients is low. even with a contamination rate under %, % of positive blood cultures are fp. future studies should evaluate factors to identify patients at higher risk of bacteremia to reduce costs and improve care. intra-arterial verapamil therapy reduces cerebral vasospasm after aneurysmal subarachnoid hemorrhage (sah). there is little literature that quantitatively describes its safety, required dosing, or efficacy. as a result, therapeutic outcomes need to be subjectively analyzed by experienced radiologists during the intervention and clinically correlated by cerebral perfusion pressure, intracranial pressures and transcranial dopplers. we present a novel imaging analysis to quantify cerebral perfusion in realtime and apply this technology to patients undergoing therapy for vasospasm. we developed software to evaluate changes in contrast flow dynamics for digital subtraction angiography (dsa) scans performed pre-and post-intra-arterial therapy for vasospasm. performing signal intensity curve deconvolution on a voxel by voxel basis provides quantitative d perfusion parameters including: time to peak, time to drain, area under the curve, root mean transit time, arrival time, tissue concentration, arterial input functions and cerebral blood flow at each voxel. after aligning perfusion studies, our software then displays and automatically creates regions of interests for changes in perfusion to visualize the effects of interventions. our software quantitatively measures perfusion from dsas and can normalize two dsas accounting for differences in volume and speed of contrast administration. two applications of this technology are demonstrated. the first subtracts perfusion from pre-and post intra-arterial interventions quantifying exact changes in perfusion at each voxel. the second compares two dsa studies of the same patient at different dates to contour the territories susceptible to delayed cerebral ischemia. we compare this analysis to mri imaging when applicable demonstrating ischemic changes aligning to the susceptible territories outlined by our analysis. dsa based perfusion is an effective study to quantify the need for and the precise effects of endovascular interventions. quantitative thresholds and analysis based on dsa perfusion may assist with real-time assessment of treatment efficacy for patients undergoing intra-arterial verapamil therapy. we aim to characterize the clinical predictors of ventriculoperitoneal shunt (vps) placement in aneurysmal subarachnoid hemorrhage (asah) patients. there has been no clear consensus as to effective measures of predicting vps placement in these patients. we reviewed the clinical data of patients with aneurysmal subarachnoid hemorrhage (asah) who were treated at our institution between - . we eliminated patients who died or had withdrawal of care during admission. we recorded patient demographics and clinical predictors including admission/discharge glasgow coma scale (gcs), hunt hess score, aneurysm size/location, modified fischer score, modified rankin scale (mrs), intracranial pressure (icp) values during evd clamp trial, and incidence of vasospasm requiring intra-arterial therapy. there were patients included in this study and % of patients required vps (n= / ). vps patients had significantly worse mrs functional scores at discharge ( . vs . ; p= . ), but this began to balance at year ( . vs . ; p= . ). aneurysms were significantly larger in vps patients ( . cm vs . cm; ci: . to . ; p= . ). a greater percentage of vps patients had posterior fossa aneurysms, but this was not found to be statistically significant ( % vs %; p= . ). vps patients had significantly lower gcs scores at admission ( . vs . ; p= . ), and discharge ( . vs . ; p= . ). there was no difference in modified fischer score (p= . ) or hunt hess (p= . ), but both variables were higher in the vps cohort. there was no difference in the frequency of vasospasm in the vps cohort (p= . ), or icp values (p= . ). patients presenting with large aneurysms and poor gcs scores had a significantly higher likelihood of requiring vps during admission. these patients had significantly poorer mrs scores at discharge but not at year. subarachnoid hemorrhage (sah) affects a young population and results in death or disability in the majority of those who experience it. this epidemiology is very different from other forms of stroke. consequently, patients with sah and their families may have different priorities for recovery. involving patient perspectives is encouraged in research and is often accomplished using patient-reported outcome measures (proms). however, whether proms reflect patient and family priorities is unclear given that (a) proms are often developed without their input; and (b) generic proms may not apply to specific conditions. we aimed to systematically review the sah literature that has: a) involved patient, family or caregivers in evaluating existing outcome measures, b) developed novel outcome measures by incorporating their perspectives (including co-development), or c) described outcomes important to patients, families, or caregivers. we searched embase and ovid medline from inception to december , . study eligibility and data extraction was performed independently and in duplicate. for each eligible citation, we abstracted the following: study population, design, type of patient involvement, and outcome measure(s), as applicable. we planned a qualitative summary of all included studies. our search yielded unique citations. only four articles have met our eligibility criteria. in each, patients (n= ) self-report impairments resulting from sah and their impact on their lives (aim c). none involve the evaluation of prom applicability. additionally, we found articles that, although they did not meet our a priori eligibility criteria, discuss collecting proms (n= ), using proms to predict health outcomes (n= ), and comparing prom applicability without patient perspectives (n= ) in sah populations. based on our findings, there is alack of patient, family, or caregiver involvement in selecting or identifying outcomes after sah with direct relevance to them. sah research may be overlooking outcomes that are important to patients. early brain injury (ebi) after aneurysmal subarachnoid hemorrhage (asah) is defined as brain injury occurring within hours of aneurysmal rupture. although ebi is the most significant predictor of outcomes after asah, its underlying pathophysiology is not well understood. we hypothesize that ebi after asah is associated with an increase in peripheral inflammation measured by cytokine expression levels and changes associations between cytokines. methods asah patients were enrolled into a prospective observational study and were assessed for markers of ebi: global cerebral edema (gce), subarachnoid hemorrhage early brain edema score (sebes), and huntassays to determine levels of pro-and anti-inflammatory cytokines. pairwise correlation coefficients between cytokines were represented as networks. cytokines levels and differences in correlation networks were compared between ebi groups. of the patients enrolled in t associated with high grade sebes. correlation network analysis suggests higher systematic inflammation conclusions ebi after sah is associated with increased levels of specific cytokines. peripheral levels of il , il and ession levels of individual cytokines may offer deeper insight into the underlying mechanisms related to ebi. few recent studies have evaluated health resource utilization and patient outcomes in aneurysmal subarachnoid hemorrhage (asah) in the united states. empirical evidence implicates asah as one of the highest cost diseases treated in the hospital. we identified asah patients to determine hospital charge, length of stay (los) and patient disposition associated with care in u.s. hospitals using claims data from the national inpatient sample (nis). patients within the international classification of disease, th revision (icd- ) diagnosis code were identified; a secondary analysis of the nis ( ) was conducted utilizing icd- clinical modification codes excluding patients with traumatic and non-aneurysmal sah. population size, patient outcome, average charge and average los were calculated using subgroups including: aneurysmal clipping or endovascular coiling (n= , ), aneurysmal clipping or coiling with external ventricular drain (evd) (n= , ), use of evd only (n= , ), other surgical procedures (n= ) and medically managed (n= , ). analyses were survey-weighted and adjusted for patient and hospital characteristics. in , asah resulted in an average per patient hospital charge of $ , , an average los of days, an average mortality of % and total, annual hospital charges of $ . billion. the highest average charge per patient ($ , ) and hospital los ( days) were attributed to clipped or coiled patients with evd, and highest mortality ( %) found in medically managed patients. these data support the conclusion that asah is a high cost illness managed in u.s. hospitals, and help raise awareness to the potential economic benefits resulting from developing safer, more effective therapies. additional analyses with updated datasets including lifetime burden of asah (e.g. physician fees, long term medical and care costs, hospital re-admission impact, quality of life, productivity loss, caregiver burden) should be explored to understand the full economic burden of asah and the potential cost effectiveness of new therapies. external ventricular drain (evd) placement is a mainstay of treatment for patients with aneurysmal subarachnoid hemorrhage with hydrocephalus or elevated intracranial pressures, but the optimal strategy for evd management is still unclear. the goal of this study was to compare the impact of evd clamping at three different levels on the duration of drain placement and the intensive care unit (icu) length of stay. we performed a retrospective analysis of patients admitted with aneurysmal subarachnoid hemorrhage to the neurological icu from december to january and included all patients who had an evd placed. patients who died were excluded from the study. patients were divided into three groups: patients whose evd was clamped at mmhg, patients whose evd was clamped at mmhg, and patients whose evd was clamped at mmhg. duration of drain placement in days and icu length of stay in days was compared among the groups using an analysis of variance (anova). outcomes were adjusted for presenting hunt-hess score, modified fisher grade, gender, and age. there were patients who had their evd clamped at mmhg, who had their evd clamped at mmhg, and who had their evd clamped at mmhg. there was no difference in duration of evd placement among the three groups (adjusted p-value . , unadjusted p-value . ) nor in icu length of stay (adjusted p-value . , unadjusted p-value . ). evd clamping at three different levels did not affect drain duration nor length of stay in icu. this study was limited by the small number of patients enrolled. further studies are need to clarify optimal strategies for evd management in the icu. headache is a presenting complaint in majority of patients with asah and is known to persist long after initial icu care. various medications have been used for control of headache with major emphasis on opiate use. history of a prescription for an opioid pain medication increases the risk for overdose and opioid use disorder. we looked at prevalence of opiate use at discharge and its associated factors. chart review of all patients admitted in a tertiary care center between jan and march was carried out. along with baseline demographic data, information about use of pain scores, csf diversion, use of opiates, average morphine equivalent doses, use of opiates at discharge and destination at discharge was collected. analysis was carried out using microsoft excel. the study was approved by hospital irb. patients were admitted with asah in above period ( % female, average age: yrs). ( % home, % snf) survived to discharge. among survivors, % required csf diversion for hydrocephalus. all people complained of pain on presentation and were prescribed opiates during hospital stay. average oral morphine equivalent doses used was mg per day. ( %) patients were prescribed opiates on discharge. alternative regimens included ( patients: tricyclic antidepressant (tca), opiate + tca, acetaminophen, dexamethasone, tca and opiates). most common prescribed form of opiate was oxycodone. there was no significant association between opiate use/morphine dosing and age, gender, final disposition and csf diversion, opiate prescription at discharge is common in patients with asah. no clinical characteristic seem to predict analgesic need at discharge. little data exists about better alternatives leading to variety of treatment approaches. further controlled trials are needed to decrease opiate use and prevent adverse effects delayed cerebral ischemia (dci) in sah has been associated with vasospasm-dependent and vasospasmindependent phenomena. for more than years isolated hemostasis disorders have been reported in these patients. the objective of this systematic review is to describe the natural history of hemostasis in sah. we systematically reviewed the medline, embase, cochrane and lilacs databases using controlled language and the prisma statement and included studies on spontaneous sah analyzing any hemostasis parameter. we screened titles, of which observational were included. evidence was evaluated following the strobe statement. no meta-analysis was attempted because of the methodological nature and heterogeneity of the studies. hemostasis is profoundly altered during the first hours after bleeding, with several alterations noted including a hypercoagulable state concomitant with increased fibrinolysis activation and reduced clot stability. direct and indirect coagulation markers show a trend towards normalization of hemostasis in the first to days. platelet count decreases with a nadir to days after bleeding and a recovery in the following weeks. a later nadir is associated with dci. platelet aggregability is consistently decreased in the first few days, regaining its normal function around the second week after bleeding. in addition, the persistence of these alterations or the presence of a second peak in pro-coagulatory activity is associated consistently with dci and worse functional outcomes. the hyperacute phase of sah is characterized by a profound activation in hemostasis with reduced clot stability, probably due to an increase in the fibrinolytic pathways. on the second day post-bleeding, a slow trend towards normalization takes place, except in patients evolving towards dci. further research on the pharmacologic manipulation of hemostasis in sah might be warranted to decrease dci and improve outcomes in this population. hypertonic saline(hts) is a treatment for sah-related cerebral edema, administered to improve cerebral perfusion and reduce brain injury. hts a supra-physiological chloride concentration that can contribute to acute kidney injury which can lead to a poor outcome. in a previously published single-center cohort of , l sah patients, . % developed acute kidney injury (aki). hyperchloremia, but not hypernatremia, was correlated with an increased risk to develop aki (o.r. . ). aki was correlated with increased mortality. a secondary analysis of the aforementioned sah patient cohort ( ) ( ) ( ) ( ) ( ) ( ) , was analyzed. trends of acute kidney injury were evaluated in relation to the burden of exposure to intravenous chloride, as well as serum levels of sodium and chloride. the proportion of patients developing aki with a maximal serum chloride concentration of (p , will be randomized into one of two treatment groups: standard hypertonic saline solution (nacl . %) versus a solution of nacl/na-acetate. we hypothesize that by reducing the iv chloride burden(baseline compared to post randomization exposure), the delta serum chloride level will decrease, and will subsequently reduce aki occurrence (acetate trial, clinicaltrials.gov nct ). aki is common in sah patient population, and associated with worse outcomes. serum chloride concentrations are a significant risk factor for the development of aki. a prospective randomized clinical trial now underway examining the relationship between the hypertonic solution composition and serum chloride concentration, and to the development of acute kidney injury in aneurysmal sah. spontaneous spinal subarachnoid hemorrhage (ssah) is a rare but serious condition that can lead to a variety of medical complications. literature to this point primarily includes isolated case reports, and none have looked at hyponatremia as a complication. patients were identified from the electronic medical record database at the mayo clinic in rochester, minnesota. the advanced cohort explorer tool was used, searching from january to december . inclusion criteria were spinal subarachnoid blood products due to hemorrhage into the spinal subarachnoid space not due to ( ) redistribution of blood from intracranial subarachnoid hemorrhage, ( ) trauma, ( ) medical procedures, or ) predominant hematomyelia who experienced symptoms and received treatment at our facility. eight patients (median age years, range - ) were identified as meeting the study criteria. five of these eight patients experienced hyponatremia during hospitalization with a median value of meq/l. all of these patients were treated with free water restriction and one patient briefly received . % sodium chloride solution; in all cases the hyponatremia improved after free water restriction. in all cases the hyponatremia improved with fluid restriction, and there was no documentation of increased urine output, suggesting that it was likely due to siadh. cord compression and hyponatremia were present together in two patients, and in these cases treatment of the hyponatremia was particularly useful to avoid worsening edema. to our knowledge this is the first compilation of cases of spontaneous ssah highlighting hyponatremia as a complication. there is significant morbidity and mortality associated with aneurysmal subarachnoid hemorrhage (sah) and only about % of patients survive and resume their previous lifestyle after - months. many randomized clinical trials (rcts) have been conducted yet no treatment definitively improves outcome from sah. outcome is strongly related to baseline factors, yet imbalances are common in early trials. we developed a technique to identify promising treatments at early phase using a pooled control arm model (ppredicts: kent, shah, mandava neurology ) that compares early studies at their own baselines. we applied this method to sah to develop a multi-dimensional model (ppredicts-sah). models for functional outcome and mortality (dependent variables) were developed based on baseline variables (eg: wfns grade - % and age) using methodology developed for ischemic stroke (mandava, kent, stroke ). the outcome model is a -dimensional surface bounded on either side by +/- . prediction interval surfaces. these prediction interval surfaces incorporate statistical variability to assess whether a treatment differs from expected outcome. treatment arms from rcts and single arm trials, of various treatments of sah were compared against the pooled controlled arm. the best model fit was for good outcome (modified rankin score - equivalents) based on % patients with wfns - and age (r = . ; p< . ). seven trials of known negative drug tirilazad were superimposed on the model and fall within the +/- . prediction interval surfaces confirming futility. three trials were neutral and within the prediction interval surfaces while case series using implanted prolonged release nicardipine and a low dose heparin study were above the +p= . surface showing promise. models were also developed for mortality (r = . , p=. ). outcome models based on percentage of high grade wfns and age were successfully developed. this approach may be useful to prioritize treatments worthy of further study. oral nimodipine is recommended to improve outcome in treatment of aneurysmal subarachnoid hemorrhage (asah). fda approved nimodipine liquid oral solution (nos) in to reduce complications associated with administering nimodipine capsules (nc) to patients with impaired swallow. experience with nos at our center has been complicated by increased liquid bowel movements (lbm) prompting unnecessary testing for infectious diarrhea and exposure to invasive fecal management devices. study approved by local qualtiy improvement review committee. data was collected prospectively in consecutive patients diagnosed with asah during intensive care unit (icu) course. formulations of nimodipine available were generic nc (heritage pharmaceutical) and nos (arbor pharmaceuticals). we examined total icu days exposed to nos, icu days with lbm, infectious diarrhea investigations, and fecal management device use. all statistical tests were performed using minitab. patients were studied from / / to / / ; patients exposed to nos for icu days, icu days with lbm, infectious diarrhea investigations, and required fecal management devices. patients exposed to nc for icu days, icu days with lbm (all cases were also received nos), no infectious diarrhea investigations, and no fecal management device requirements. odds ratio for lbm with exposure to nos was . ( % ci . to . , p < . ). the high incidence of lbm with nos resulted in more infectious diarrhea testing and fecal management device use. uncontrolled diarrhea may increase risk for dehydration and delayed cerebral ischemia, although this is not explored in the current study. nos can mitigate risks associated with needle aspiration of nc, however these issues coupled with higher cost may limit benefit of its use. possible solutions may include compounding nc into a liquid formulation by pharmacists or pharmacy technicians. possible safety and cost benefits require further investigation. headache (ha) management after subarachnoid hemorrhage (sah) is challenging and lacks standardization. we hypothesized that inadequate inpatient ha pain management leads to the development of chronic ha (cha) after sah. prospective, observational study of non-traumatic hunt and hess (hh) grades i-iii sah patients admitted from / to / . after informed consent we recorded demographics, clinical and radiographic features, analgesic and steroid doses, hospital course and inpatient pain scores using numeric rating scale (nrs, - ) before (nrs-pre) and after each analgesic administration over post-bleed days - . a phone survey administered - months after admission evaluated cha burden. inpatient ha control effectiveness was evaluated by percent pain resolution from initial pain score, using nrs-pre. the percentage of administrations yielding full pain resolution was compared between those with and without cha. chi-square and t-tests were used for statistical analyses. patients, % female, mean age . ± . years with hh grade i ( / ), ii ( / ), and iii ( / ) sah were enrolled with lost to follow-up. at follow-up, . % patients ( / ) reported daily ha, . % ( / ) occasional ha, and % ( / ) no ha. full pain resolution after analgesic administration was associated with less cha ( [ . %] vs. [ . %], p= . ). mean daily inpatient opioid dose (morphine equivalents) for patients with and without cha was . mg and . mg, respectively (p= . ). mean nrs-pre were . vs . for patients with vs without cha, respectively (p= . ). inpatient analgesia for sah-related ha is inadequate and may be associated with the development of chronic ha. patients with cha had higher mean inpatient pain score and fewer analgesic administrations resulting in complete pain resolution. inpatient opioid dose per day was higher in cha group, although not statistically significant. additional research is needed to characterize the relationship between inpatient headache management and chronic headache after sah. subarachnoid hemorrhage (sah) remains a significant cause of neurological morbidity and mortality with few interventions to prevent delayed cerebral ischemia. hypocapnia has been associated with worse outcomes in brain injury. sah patients may be particularly susceptible to hypocapnia induced vasoconstriction. this study aims to describe the incidence of iatrogenic and spontaneous hyperventilation in sah patients. a descriptive analysis was performed on a retrospective cohort of adult sah patients admitted to beth israel deaconess medical center icus between and with gcs < who were treated with mechanical ventilation and an extraventricular drain, and had at least one abg. patients on chronic ventilator support were excluded. the lowest paco per icu day was analyzed. patients were included with days with at least one documented paco . mean gcs on admission was . (sd . ). . % of patients survived to hospital discharge. . % of patients were exposed to severe hypocapnia (paco mmhg, those with severe hypocapnia had similar pao and pao /fio ratios, but mildly increased leukocytosis ( . vs . ). . % of paco s < mmhg occurred during spontaneous ventilation or over-breathing. prior studies have shown that hypocapnia causes decreased brain tissue perfusion and is associated with worse outcomes in sah patients. these recent data demonstrate that severe hypocapnia is common in patients with sah severe enough to warrant intubation, and is associated with both iatrogenic and spontaneous hyperventilation. hypocapnia is not primarily compensatory or hypoxia driven, as suggested by mean ph and pao . confirmation of this association and potential future interventions require further study. although delirium is associated with higher rates of hospital complications among critical care patients, limited data exist on risk factors for delirium in aneurysmal subarachnoid hemorrhage (sah). a previous study identified older age, high hunt hess grade, intraventricular hemorrhage (ivh), and hydrocephalus as risk factors for delirium. we sought to identify risk factors for delirium during admission after sah. retrospective review was performed of prospectively collected data for consecutive sah patients enrolled into the university of maryland recovery after cerebral hemorrhage (reach) study. baseline data and clinical complications during each admission, including delirium, were recorded. statistical analysis was performed using univariate and multivariate logistical regression. sah patients from july to january were reviewed. while age was not singly associated with delirium during icu admission, higher hunt hess grade, ivh, hydrocephalus, hospital-acquired infection, elevated troponin, and intubation were significantly associated with delirium on univariate analyses. upon stepwise multivariate logistic regression, ivh (or . , p= . ) and intubation (or . , p= . ) remained significantly associated with delirium. ivh and intubation predicts delirium during icu admission for sah. further analyses are needed to determine if the relationship between ivh and delirium is primarily explained by risk of hydrocephalus, risk of fever, medication exposure, or through independent mechanisms. stroke triage scales are very important in order to expedite acute evaluation, assure quick door to neuroimaging time and decrease door to needle time in patients with ischemic stroke eligible to intravenous thrombolysis. subarachnoid hemorrhage (sah) is associated with a high mortality in the acute phase due to a particular risk of early and devastating re-bleeding. therefore patients with sah also need urgent assessment. the performance of classic triage stroke scales in the identification of patients with sah was not previously evaluated. the objective of our work was to evaluate the performance of the los angeles prehospital stroke screen (lapss) in identifying patients with sah admitted to a tertiary hospital. we evaluated consecutive patients admitted to a tertiary hospital with sah from january to may . at hospital admission, lapss was applied by trained nurse personnel to all noncomatose patients with complaints suggestive of neurological disease. a total of with sah patients were evaluated (mean age . +/- . ), . % females). lapss was applied to patients. lapss was positive in only patients ( . %). patients with a positive lapss had higher nihss stroke score at admission ( , [ , ] versus , p< . ), lower glasgow coma scores ( [ , ] versus , p< . ) and a significant shorter door to neuroimaging time (p< . ). in patients with sah and mild symptoms, lapss was not a sensitive screening tool in our series. hospital and pre hospital services using lapss for triage of patients with stroke should be aware of this limitation and include in triage flowcharts specific questions evaluating sah specific symptoms. spontaneous subarachnoid hemorrhage (sah) is a neurological emergency, which despite current advances in management strategies and advent of institutional protocols, remains with significant rates of mortality due to poorly understood causes. our objectives were to characterize in-hospital mortality by evaluating the primary cause of death and externally validate the hair score, a clinical score that prognosticates mortality. in this retrospective cohort study, we reviewed all sah patients admitted to our neuro-icu between april , and march , . univariate and multivariate logistic regressions were performed to identify predictors of in-hospital mortality, our primary outcome. to validate the hair score, the model's predictors were hunt and hess score at treatment decision, age, intraventricular hemorrhage, and re-bleeding within hours. discrimination was assessed by visualizing the receiver-operating curve and calculating the area under the curve (auc). among sah patients with a median age of years (interquartile range, - ), . % females, inhospital mortality was . % (n= ). of those, ( . %) had a neurological cause for death or withdrawal of care and ( . %) had a cardiac death. median time from sah to death was days. the main causes of death were the primary effects of the initial hemorrhage, re-bleeding and refractory edema. factors significantly associated with in-hospital mortality in the multivariate analysis were age, hunt and hess score, and intra-cerebral hemorrhage. maximum lumen size was also a significant risk factor among aneurysmal sah patients. the hair score had a satisfactory discriminative ability, with an auc of . . our in-hospital mortality is lower than previous reports, attesting to the continuing improvement of our protocolized subarachnoid hemorrhage care. the major causes are the same as previous reports. the hair score showed good discrimination and could be a useful tool for predicting mortality. so far, scientific and therapeutic efforts mainly focused on the prevention of rebleeding and ischemic complications(dci) in patients with subarachnoid hemorrhage(sah). however, data regarding the impact of parenchymatous hemorrhage(ph) on longterm outcome in these patients is limited. all consecutive patients with atraumatic sah admitted to our hospital over a -year-period( - ) were retrospectively analyzed. extent of sah as well as presence, localization and volume of ph were evaluated. functional and health outcome were assessed after months using the modified rankin scale (unfavorable: - ) and the eq- d. propensity-score(ps)-matching was performed to minimize potential bias due to confounding variables between sah-patients with and without ph. of overall patients with atraumatic sah, ( . %) patients had ph on initial imaging. ph-patients had a worse clinical condition on admission (wfns: ph ( - ) vs. Øph ( - );p< . ) and a greater extent of sah (modified fisher: ph ( - ) vs. Øph ( - );p= . ). median ph-volume was . ( . - . )ml with largest volumes in patients with ruptured )ml). after successful ps-matching (parameters: age, wfns, modified fisher and graeb score) patients with ph had worse functional and health outcome after months compared to those without ph (mrs - : ph / ( . %) vs. Øph / ( . %);p= . ; eq- d: ph ( - ) vs. Øph ( - ); p< . ). in multivariate analysis presence of ph was the strongest independent predictor of unfavorable outcome after months followed by the occurrence of dci (risk-ratio( %ci): ph . ( . - . ); p< . ). parenchymatous hemorrhage is frequent and associated with functional and subjective impairments in patients with atraumatic sah. aneurysmal subarachnoid hemorrhage (asah) is associated with early and delayed brain injury. insulin growth factor (igf ) is a potent cellular growth-promoting factor with demonstrated independent neuroprotective actions in stroke and neurologic disease but has not been well characterized after asah. this study sought to examine the relationship between plasma igf levels and outcomes after asah. this cohort of asah patients was . years (sd . ) and female ( %) with a mean hh ( %), wfns ( %) and fisher ( %). initial and peak plasma igf concentrations were measured in plasma samples from a banked biorepository using a commercial sandwich solid-phase elisa kit. delayed neurological deterioration (dnd) and delayed cerebral ischemia (dci) were determined using radiologic and clinical information. igf levels were log transformed due to non-normality. anova, t-tests, pearson correlations and logistic regression analyses were completed using spss and sas. older age was significantly associated with lower initial and peak plasma igf levels (r=. , p<. ; r=. , p<. ). men had higher initial and peak plasma igf levels than women (p<. ; p=. ), and premenopausal women had higher initial and peak plasma igf levels than post-menopausal women (p=. ; p=. ). lower peak plasma igf levels were associated with increased clinical severity by wfns (p=. ) and fisher grade (p=. ) as well as the development of dnd (p=. ; p=. ). lower peak igf levels were associated with the presence of dci (p=. ). controlling for age and fisher grade, log peak plasma igf levels remained significantly associated with the presence of dnd (p=. ; or . ; ci: . -. ) and dci (p=. ; or . ; ci: . - . ). igf levels have not been well characterized after asah. these results suggest lower plasma igf are associated with clinical severity and outcomes after asah and provide impetus for future work to further examine these relationships. induced hypertension (ih) is the mainstay of medical management for delayed cerebral ischemia (dci) after subarachnoid hemorrhage. however, using vasopressors to raise systemic blood pressure well above normal levels may be associated with systemic and neurological complications, of which posterior reversible encephalopathy syndrome (pres) has been increasingly recognized. however, the frequency and risk factors for ih-induced pres have never been systemically evaluated we identified patients treated with ih from sah patients admitted over a three-year period. pres was diagnosed based on clinical suspicion (i.e. unexplained deterioration), confirmed by imaging. we conducted retrospective extraction of data on ih therapy, including baseline and highest target mean arterial pressure (map) and vasopressor dose/duration. we compared those with pres to ihtreated controls and also described the clinical features and sequelae of all pres cases. five sah patients were diagnosed with pres, with median time from initiation of vasopressors to diagnosis of . days (range - days). baseline map did not differ between pres and ih controls, but highest target map was greater ( vs. mm hg, p= . ). magnitude of ih was similarly greater ( vs. mm hg above baseline, p= . ). all cases presented with lethargy, three had new focal deficits, and one had a seizure. one died from cardiac complications but the other four patients had complete resolution with ih discontinuation, without infarction or residual disability. pres was diagnosed in % of patients undergoing ih therapy and was most likely when map was raised well above baseline to levels exceeding the traditional limits of autoregulation ( - mm hg). high clinical suspicion for this reversible disorder appears warranted when aggressive ih targets are maintained for several days or in the presence of unexplained neurological deterioration. other interventions may be preferable for refractory dci when moderate degrees of ih have been attempted. patients with aneurysmal subarachnoid hemorrhage (asah) may receive significant exposure to potentially harmful ionizing radiation exposure (phire) from diagnostic tests and therapeutic procedures during their initial hospitalization. we hypothesized that risk factors to detect excessive phire are present at the time of admission. following irb approval, all patients admitted to our institution with documented asah over a -year period were retrospectively evaluated for inclusion and exclusion criteria. patients were excluded if they died prior to discharge. all study data, including sah-specific and patient-specific risk factors, were obtained from the electronic medical record. the total effective dose of ionizing radiation (tedir) per patient was calculated from previously published radiation exposure data. phire was considered to have occurred if tedir was greater than msv, the annual phire limit for radiation workers. logistic regression models were then fit to the dataset to evaluate clinical variables that significantly the risk of phire in these patients. data were collected from patients ( . % of all asah patients evaluated). the mean tedir in these patients was . msv. forty-two ( . %) of patients met criteria for phire. in multivariate logistic regression modeling, male gender (or= . , ci= . - . ), posterior circulation aneurysms (or= . , ci= . - . ) and ventriculostomy (or= . , ci= . - . ) were significantly associated with an increased risk of phire. in this study, approximately % of asah patients received phire. male gender, posterior circulation aneurysms and ventriculostomy were significantly associated with increased risk of phire. these factors may serve as important predictors of patients who require additional or complex care necessitating repeated diagnostic or therapeutic procedures during their hospitalization. alternative diagnostic or therapeutic modalities should be considered for patients with these risk factors to limit the risk of phire. future research should also evaluate the effect of phire on neurologic outcomes in these patients. it remains unclear whether patients with unruptured intracranial aneurysms (ica) should be treated. vessel wall enhancement (vwe) in high-resolution magnetic resonance vessel wall imaging constitutes a promising marker of aneurysm instability in this population. to find risk factors for aneurysm instability, we sought to identify predictors of vwe in patients with unruptured icas. we conducted a retrospective analysis of prospectively collected data on patients with unruptured ica evaluated by a single provider. all patients were evaluated using a previously validated algorithm to ascertain vwe using high-resolution magnetic resonance vessel wall imaging. two different raters, blinded to the study data, categorized all observed aneurysms as vwe-positive or vwe-negative. kappa statistics were used to evaluate the reproducibility of this approach. univariable and multivariate logistic regression modelling was utilized to identify factors associated with vwe after adjusting for potential confounders. patients with unruptured ica were included in the analysis (mean age [sd ] , female sex [ %]). of these, ( %) were vwe-positive and ( %) were vwe-negative. inter-rater reliability for vwe ascertainment was excellent (kappa . , %ci . , . ). out of ( %) patients presenting with cranial nerve palsy were vwe-positive. in univariable analysis, age (p= . ), headache on presentation (p= . ), and size (p< . , per additional millimeter) were associated with vwe-positive status. in multivariable analysis, headache on presentation (p= . ) and size (p= . ) remained independently associated with vwe. cranial nerve palsy is an established clinical marker of aneurysm instability; consequently, our results confirm the role of vwe as a marker of aneurysm instability. headache on presentation and aneurysm size are independently associated with vwe; these risk factors for aneurysm instability could be used to select patients with unruptured icas that may benefit from vessel wall imaging. prognostication in subarachnoid hemorrhage (sah) patients presenting in coma is crucial for surgical decision making. indications for aggressive aneurysmal treatment are unlikely for those not demonstrating signs of neurological improvement chronologically or after ventricular drainage. early neurological evaluation is, however, challenging in critically ill sah patients requiring anesthesia and intubation for airway protection. in this single-center retrospective study, we applied continuous amplitude-integrated eeg (aeeg) monitoring using a subhairline montage for wfns grade v patients who did not undergo emergency aneurysm treatment. monitoring was initiated soon after admission to the icu. patterns of aeeg findings were classified according to rundgren, et al. as follows: flat (f); suppression-burst (sb); electrographic status epilepticus (ese); and continuous (c). based on the aeeg findings, indications for aneurysm treatment were reevaluated. outcome was assessed at six months using the glasgow outcome scale. twenty-three patients, men and women, aged . ± . years (mean ± sd), were eligible since december . all patients underwent prophylactic intravenous sedation. the population represented % of all grade v patients including those resuscitated after cardiac (n= ) or respiratory (n= ) arrest. the glasgow coma scale scores were (n= ), (n= ), and (n= ), respectively. aneurysms were located in the posterior fossa in patients ( %). aeeg monitoring was initiated . ± . hours median . , . - . hours after arrival. all patients showing early f (n= ) or sb patterns (n= ) died. one patient demonstrated ese remained in a persistent vegetative state. five out of patients with a c pattern underwent aneurysm treatment; clippings and coil embolization. moderate disability was attained in and severe disability in . two patients undergoing conservative therapy died. continuous aeeg provided useful prognostic information for identifying salvageable sah patients undergoing sedation in the early phase. delayed cerebral ischemia (dci) may result in focal neurological deficits and cerebral infarction after subarachnoid hemorrhage. while global cerebral blood flow (cbf) may be variably reduced, dci is more likely related to regional impairments in cbf below critical perfusion thresholds. we applied volumetric methods to assess the proportion of brain exhibiting hypoperfusion (pbh) in those with clinical dci and in the symptomatic hemisphere of those with focal deficits. methods patients with aneurysmal sah underwent o-pet and ct imaging during period of risk for dci (median days after sah, iqr - ). we measured pbh as proportion of voxels with cbf < ml/ g/min, after excluding regions of infarction/hematoma on ct. we compared pbh in patients with vs. without dci at time of pet and, in those with focal deficits, we compared hypoperfusion between affected and unaffected hemispheres. pbh was greater in the ( %) with dci compared to those without dci ( %, ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) p= . ) despite higher mean arterial pressure (map) and most being on active hemodynamic therapies. global cbf was also lower in those with dci ( . vs. . ml/ g/min, p= . ) but did not differ between those remaining symptomatic and those whose deficits had resolved. while mean hemispheric cbf was not lower in the affected hemispheres of with lateralizing deficits ( . vs. . ml/ g/min, p= . ), there was greater pbh in the symptomatic hemisphere ( % vs. %, p= . ). sah patients with dci have a greater proportion of brain with hypoperfusion despite active hemodynamic therapy and higher map. there was also larger proportion of the symptomatic hemisphere with hypoperfusion despite no asymmetry of hemispheric cbf. such measurements of hypoperfusion may better reflect the regional pathophysiology of dci than global averaged measures of cbf. further studies should determine whether burden of hypoperfusion correlates with tissue and patient outcomes. patients who survive aneurysmal subarachnoid hemorrhage (asah) are often burdened with lasting cognitive impairment due to a combination of sequelae including neuro-cardiac injury. the impact of neurocardiac injury after asah is poorly understood. this study sought to examine if neurocardiac injury detected by global longitudinal strain (gls) is associated with poor performance in neuropsychological np memory impairment after asah. we studied asah patients at months and at months (sahmii study r nr ) after hemorrhage. speckle tracking gls from apical views were assessed days - from bleed from transthoracic echocardiograms. neuropsychological (np) outcomes covering domains were completed at and months after hemorrhage by trained personnel. memory tests included controlled oral word association (cowa), wechsler memory scale (wms) and rey auditory (r-aud) and complex figure (reyc). anova and kruskal-wallis, pearson and spearman correlations and logistic regression were completed using spss and sas. there were ( %) patients with abnormal gls (defined as >- %) and ( %) in the and months groups respectively. gls groups had similar age, gender and fisher grade. abnormal gls was associated with higher hh at (p=. ) and (p=. ) months. abnormal gls was significantly associated with decreased performance in r-aud memory domains at months (p=. ) and months (p=. ) after asah and even when controlling for age and hh at months (p=. ). gls<- was associated with poor memory performance months after asah in cowa (p=. ) and the wms (p=. ) even after adjusting for age and hh, cowa (p=. ) and wms (. ). neuro-cardiac injury detected by gls was associated with decreased performance in memory domains of np function at and months after asah. while these relationships require further examination, neurocardiac injury may contribute to long term np impairment after asah. delayed cerebral infarction (dci) is a frequent complication following high-grade aneurysmal subarachnoid hemorrhage (asah). management of dci includes maintaining hypertension, which is challenging in heavily sedate patients. ketamine is a hemodynamically stable, analgesic sedative not studied in this population. we hypothesize that ketamine infusion (k), as compared to traditional sedatives (control), will safely improve the hemodynamic profile in high grade ventilated asah patients retrospective review of asah patients admitted / to / requiring mechanical delayed cerebral infarction (dci) is a frequent complication following high-grade aneurysmal subarachnoid hemorrhage (asah). management of dci includes maintaining hypertension, which is challenging in heavily sedate patients. ketamine is a hemodynamically stable, analgesic sedative not studied in this population. ventilation > hrs, and without dnr within hrs from admission. we assessed demographics, hemodynamics, pressor, dci at weeks, ventilator and icu los, and mortality. fisher exact, wilcoxon, and paired t-test applied. comparing k (n= ) vs control (n= ), median (q , q ) results for: age ( , ) vs ( , ); hunt and hess ( , ) vs. ( , ); mpm- day estimated mortality . % vs. . %; and gcs ( , ) vs ( , ) . ketamine initiated on day ( , ); icu los ( , ) vs. ( , ); and vent los ( , ) vs. ( , ) . mean (sd +/-) for hours before and after ketamine: map ( ) vs ( ), p . , except where noted. ketamine infusion, as a second line sedative, had no effect on mortality or icp, and improved map. however, there was a nonsignificant increase in dci as well as vent los, without a greater rate of tracheostomy. prospective studies are needed to study the effect on dci and long term outcomes. seizures are a well-known complication of aneurysmal subarachnoid hemorrhage(asah) and occur most commonly in the immediate post-hemorrhagic period. most commonly used antiepileptic drugs (aeds) for seizure prophylaxis in asah include phenytoin and levetiracetam. there is no reliable data available on the safety and efficacy of restricting aed prophylaxis only till the aneurysm is secured. we retrospectively chart reviewed patients admitted to our neurosciences intensive-care-unit with asah during the last two years. seizure incidence was studied in patients treated with phenytoin versus levetiracetam and in patients treated for to days versus those where aed was discontinued immediately after aneurysm was secured. in patients aed prophylaxis was discontinued immediately after the aneurysm was secured, and in patients it was continued for to days. of th phenytoin was used in patients and levetiracetam was used in patients. in patients receiving aed prophylaxis for to days, phenytoin was used in cases and levetiracetam was used in cases. none of these patients had seizures reported during hospitalization or at three month follow-up. stopping the aed prophylaxis immediately after aneurysm coiling is not associated with increased risk of seizures. seizures at presentation in patients with asah are not associated with development of epilepsy at months. both phenytoin and levetiracetam are well tolerated in patients with asah when limited to the immediate post-hemorrhagic period. the main preceding factor of delayed cerebral ischemia (dci) in asah is cerebral vasospasm (cvs). anticipating dci can have major impact on patient outcomes. studies have attempted to predict dci in patients with asah by using various imaging modalities that measure cvs, ranging from transcranial doppler ultrasonography, ctp, and mr perfusion. few compare these imaging modalities to the accepted gold standard of dsa. we propose that mri using asl imaging can be used as a sensitive and specific measure of cvs and can be used as a marker to identify patients with asah who are at risk for developing dci. to support our hypothesis, we compare asl results in patients with documented cvs on dsa who developed dci. patients in the academic years to with the diagnosis of asah were admitted to our nicu. the inclusion criteria for the patient population was the presence of asah confirmed by dsa, diagnosis of dci by a neurointensivist, mri with asl, and a repeated dsa during the hospitalization after dci was suspected. all patients underwent mra with asl on day in an attempt to capture the peak time of cvs. nine patients were included in this study. all cases with perfusion defects on asl sequences had confirmed cvs on dsa except for one. the outlier in our cohort developed dci with asymmetry on asl that was not demonstrated on dsa. to our knowledge, no studies have compared the specificity of asl with dsa in detecting cvs. this study highlights the utility of asl in detecting cvs in patients with asah. our limited data suggests asl can be utilized for detection of dci and cvs with greater confidence than the conventional modalities. we also suggest that asl approaches the utility of dsa in the detection of cvs. blood glucose dysregulation following aneurysmal subarachnoid hemorrhage is associated with serious complications and poor clinical outcome. an influence of hyperglycemia on the occurrence of delayed cerebral ischemia (dci) is assumed, nevertheless the exact mechanism remains unclear. the goal of the present study aims to investigate the influence of systemic blood glucose level on cerebral perfusion measured by dynamic perfusion computed tomography (pct) and outcome. daily serial blood glucose levels and pct data sets of patients treated at our neurointensive care unit after asah were retrospectively analyzed. serial pcts were performed between six hours and days after aneurysm repair. mean average of mean transit times (mtts) was calculated for each perfusion scan. the maximum mean transit time (maxmtt) and outcome assessed with glasgow outcome scale were correlated with defined blood glucose ranges as followed .) > mg/dl (hyperglycemia) .) - mg/dl (elevated glucose level) .) - mg/dl (strict glucose control) and < mg/dl (low glucose level). hyperglycemia (> mg/dl) was associated with prolonged maxmtt (p< . , rs = . ) and was linked to an increased risk of infarction (p < . ) whereas strict glucose control ( - mg/dl) correlated significantly negative with maxmtt (p < . , rs = -. ). strict glucose control was also associated with a lower occurrence of cerebral infarction and good outcome (p < . , rs = . ). in contrast, elevated blood glucose levels ( - mg/dl) and hyperglycemia showed a negative correlation with good outcome (p < . , rs = -. , rs = -. ). the present analysis supports for the first time the assumption that dysregulation of blood glucose balance influences cerebral perfusion and thus may contribute to the occurrence of dci and poor outcome. therefore careful monitoring and prompt treatment of blood glucose levels after asah should be highly valued to avoid cerebral perfusion deficits correlated with poor outcome. the aim of this study was to determine the correlation between transcranial doppler (tcd) velocities and angiographic vasospasm after subarachnoid hemorrhage (sah). methods patients with sah were evaluated with spencer technologies tcd power m mode from - days, following the sah. both the temporal windows were insonnated to determine flow velocities in the middle (mca) and anterior cerebral arteries (aca) and the suboccipital widow was used to determine flow velocities in the vertebral (va) and basilar arteries (ba). the middle cerebral artery/ipsilateral extracranial internal carotid artery velocity ratio (lindegaard ratio) was also correlated with vasospasm ct angiography and conventional cerebral angiography was used to confirm tcd findings suggestive of vasospasm. the sensitivity, specificity, likelihood ratios for positive and negative tcd results, positive there was males and females and with mean age . +- . years. % were aneurysmal sah. delayed ischemic neurological deficits (dind) developed in / patients ( . %). interobserver ue of cm/s were useful (likelihood ratio for negative result = . , likelihood ratio for positive result = . ). lindegaard ratios correlated well with vasospasm. tcd diagnosis of vasospasm was more often present in the mca, followed by aca and basilar arteries. tcd is a good non invasive method to detect vasospasm and predict the occurrence of dind. very high angiographic vasospasm. tcd is also useful to follow up patients with angiographically proved vasospasm. aneurysmal subarachnoid hemorrhage (asah) is a significant cause of morbidity and mortality. the mortality rate approaches %. nearly half of the survivors remain unable to care for themselves . dci occurs in % of these patients . when present, it doubles the risk of poor outcome. -several methods have been used to treat cerebral vasospasm and dci, which is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (sah). milrinone safe and, potentially, effective treatment of dci as reported in low level of evidence literature . however, the efficacy not compared in a randomized way to placebo. we will examine the effectiveness and safety of intra-venous injection of milrinone for the treatment of dci following aneurysmal sub-arachnoid haemorrhage. our intension is to study the outcome of using milrinone as an addition to current therapies such as hypertensive therapy are not effective enough, yet can not be replaced as it is standard of care. as intravenous milrinone was not yet shown to have an affect in dci in a randomized controlled trial. this pilot trial is a step towards that study. the study is a pilot trial of a randomized placebo-controlled double blind trial testing the potential beneficial effect of milrinone, a phosphodiesterase inhibitor, on clinical neurological outcome in patients with dci after aneurysmal subarachnoid hemorrhage. the study drug will be given along with the standard therapy when dci occurs. the administration of milrinone increases cerebral blood flow most likely as a result of cerebral vasodilation. as intravenous milrinone was not yet shown to have an affect in dci in a randomized controlled trial. this pilot trial is a step towards that study. milirinone promising treatment for delayed cerebral ischemia following aneurysmal sub-arachnoid haemorrhage .particulary by using standardized protocol as a finding suggestive of good prognosis fever in the neurocritical care population is very common and is strongly associated with increased mortality and poor outcome. fever is aggressively treated in the icu due to its deleterious effects. yet despite best efforts with standard antipyretic agents and even with aggressive cooling measures with endovascular cooling catheters some patients may still have refractory fevers. celecoxib, a cyclooxygenase- (cox- ) inhibitor, has been used as an adjunctive antipyretic agent. this is a retrospective analysis to evaluate the effectiveness of celecoxib in lowering temperatures in patients with refractory fevers. this is a retrospective chart review of patients admitted to a neurointensive care unit at a single institution with fevers (> . c) that do not respond to convention treatment with acetaminophen, endovascular cooling catheters and ibuprofen. patients with severe traumatic brain injury, subarachnoid hemorrhages and intracerebral hemorrhages were included. patient temperature recordings were obtained in the period of hours before and hours after administration to the first dose of celecoxib. the mean temperature of the before and after periods were compared and temperature difference was calculated. patient records were included. the average of the mean temperatures in the before periods and after periods were . c (+/-sem . ) and . c (+/-sem . respectively. there was a significant difference on mann-whitney-wilcoxon rank sum test (p< . ). one average there was a drop of . (+/-sem . ) degree celsius of the mean temperature after the start of treatment. in neurocritically ill patients with fevers that are refractory to conventional treatments adding celecoxib, a cox- inhibitor seems to be effective at lowering the core body temperature. further study is warranted to evaluate for adverse effects such as risk of cardiovascular events. achieving and maintaining normothermia (nt) after subarachnoid hemorrhage (sah) or intracerebral hemorrhage (ich) often requires temperature modulating devices (tmd). shivering is a common adverse effect of tmd's that can lead to further costs and complications. we evaluated a new esophageal tmd, the ensoetm (attune medical: chicago, il), to compare nt performance, shiver burden, and cost of shivering interventions with existing tmd's. patients with sah or ich and refractory fever were treated with the ensoetm. patient demographics, temperature data, shiver severity, and amount and costs of medication used for shiver management were prospectively collected. control patients who received other tmds were matched for age, gender, and body surface area (bsa) to ensoetm recipients and similar retrospective data was collected. all patients were mechanically-ventilated. fever burden was calculated as areas of curves of time spent above . or c. demographics, temperature data, and costs of ensoetm recipients were compared to recipients of other tmd's. eight ensoetm recipients and controls between october and november were analyzed. there were no differences between the two groups in demographics or patient characteristics. no difference was found in temperature at initiation (p = . ) and fever burden above °c (p = . ). ensoetm recipients showed a non-significant trend in taking longer to achieve nt than other tmd's (p = . ). ensoetm recipients required fewer shiver interventions than controls (p = . ). ensoetm recipients incurred fewer costs than controls per day (p = . ). the ensoetm achieved and maintained nt in sah and ich patients and was associated with less shivering and lower pharmaceutical costs than other tmd's. further studies in larger populations are needed to determine the ensoetm's efficacy in comparison to other tmd's. targeted temperature management is an important aspect of care in neurologically impaired patients. however, achieving optimum temperature for a specific patient can be challenging; a patient's size, body composition, metabolism, and hypothalamic function contribute to his or her response to a given temperature management modality. the purpose of this study is to evaluate patient response to esophageal temperature management when continuously applied for at least h. deidentified core temperature data for patients (a total of measurements) were obtained from three hospital sites where esophageal temperature management was used for at least h (range - h). indications for active temperature management included: cardiac arrest ( ), refractory fever ( ), subarachnoid hemorrhage ( ), intracranial hemorrhage ( ), and traumatic brain injury ( ). goal temperatures ranged from - °c and initial patient temperatures ranged from - °c. deviation from goal was calculated by subtracting target temperature from actual temperature for each measurement which allowed the calculation of the mean and standard deviation for each time point across all temperature management protocols. across time points, representing an average treatment time of . h, . % of mean deviations from goal were within ± °c and . % were within ± . °c. in interpreting these results, several limitations must be considered. this dataset reflects a wide range of temperature management protocols and clinical scenarios. for example, a larger than average deviation in measurements recorded in the - h period was related to rewarming in cardiac arrest patients who rewarmed slowly. also, the later time points were dominated by sah, ich, and refractory fever patients who often experience more pronounced fever spikes. this analysis indicates that esophageal temperature management is a feasible option for patients who require active temperature management for or more hours. the role of therapeutic temperature management (ttm) in neurocritical care is uncertain. one question that has been inadequately addressed is the diversity of practice across multiple neurocritical care units (nccu) throughout the world. a barrier to understanding this practice variance is a data collection method that would provide adequate understanding of how ttm is implemented in various nccus. the purpose of this pilot study is to test the efficacy of a data collection method that would provide unitlevel data on ttm practice. the design of this study was prospective, observational, and cross-sectional study using quality assurance methodology. the study received institutional review board approval. to reduce the risk of loss of confidentiality and promote privacy, individual patients were not consented. data on temperature management was collected each day for consecutive days. completed data was available for days. mean daily census of patients included the following mean number of patients with sah ( ), ich ( ), ischemic stroke ( ) and other ( ). of those, ttm was provided to at least one patient during of days ( . %). the most common ttm method (tylenol) was used on patient days; surface cooling was used on patient days. ttm was initiated for fever management ( patient days) and normothermia ( patient days). the most common associated complication was hypocalcemia ( ) and hypokalemia ( ). the data collection form was easily and quickly filled completed on a daily basis, but provides limited data. although the form captured a significant number of events surrounding the use of ttm, the primary limitation noted is the inability to link specific events (e.g., hypokalemia) to specific patients or diagnoses. this pilot study demonstrates the efficacy of data capture and provides insight towards refining a prospective observational study to describe ttm practice. brainstem tumors are exceedingly dangerous due to its proximity to the structures responsible for basic human survival in the neurocritical care setting. these lesions may cause autonomic dysregulation. we report on a rare case of a female with a past surgical history of ventriculoperitoneal shunt with a brainstem mass of müllerian type epithelial tissue. methods year old caucasian female presented to our hospital status-post fall after episodes of lightheadedness, as well as, episodes of decreased respirations in her sleep. mri showed a medullary contrast enhancing mass with calcifications measuring . x . x . cm and a small calcified lesion in the right lateral ventricle. suboccipital craniectomy for biopsy and decompression was performed. intraoperatively, the heart rate and blood pressure dropped transiently due to the mass being firmly adhered with calcification to the medulla. the neuropathologist diagnosed the tissue as mullerian type epithelium with estrogen receptors. post-operatively, our patient encountered several instances of cardiac pauses on monitoring that required the need for cardiology to place a permanent pacemaker. the above is a rare case of a calcified heterogeneously contrast enhancing brainstem mass that underwent neurosurgical biopsy. histopathology results indicated müllerian type epithelial tissue which is tissue that gives rise to female reproductive organs. the origin of a brainstem lesion from an embryologically gynecological site could be speculated to have traveled retrograde via the ventriculoperitoneal shunt catheter. patient required postoperative cardiac management and intervention with a pacemaker for encroachment or mechanical conflict of the mass onto the rostral ventrolateral medulla. oncology recommended pet ct scan and further consideration for tamoxifen chemotherapeutic regimen. this case is a reaffirmation of the importance of brain tumor location and tissue diagnosis for the purpose of adjuvant treatment of neurosurgical lesions in the neurocritical care setting. tranexamic acid (txa) has been used off label in cardiovascular and orthopedic surgery, as well as in trauma resuscitation. the use of txa has increased since the publication of crash- ( ) and matters ( ), demonstrating its efficacy in trauma patients to reduce bleeding. there remains concern about the thrombotic risk as well the reduction in the seizure threshold after txa administration. case description: we present a case of a -year-old female admitted to the surgical icu after a motor vehicle accident with multiple traumatic pelvic and extremity fractures and soft tissue injury. she subsequently developed extensive arterial and venous thromboses with bilateral acute ischemic strokes with superimposed posterior reversible encephalopathy syndrome after txa administration. a second case involved a -year-old female who had a fall from standing and given txa in the field by ems. shewas admitted to the neurocritical care unit with status epilepticus and suffered a complicated course with cardiogenic shock due to stress induced cardiomyopathy. discussion: the risk-benefit balance of txa administration is generally considered acceptable in severe bleeding. the cases presented here suggest the neurological risks of txa administration may be poorly understood and demonstrate the need for better patient selection and heightened awareness for early identification and management of complications given the possible severity of neurologic sequelae. conclusion: txa is an anti-plasmin drug that is increasingly used in the areas of trauma and postoperative bleeding. we aim to educate clinicians in the potential neurological complications that can arise with its use. cryptococcus neoformans is normally an opportunistic infection known to cause meningoencephalitis and can present with stroke like symptoms. in imaging, cns vasculitis can be identified, which can lead to cerebral infarcts. when involved, these cerebral vessels are small sized leading to lacunar infarcts. we present a case that involved a large vessel territory leading to patient mortality. initial treatment with glucocorticoids, though beneficial in other meningoencephalitidies, may actually be harmful in fungal cns infections. case: a year old male with a presents with weeks slurred speech and worsening headache. an enhancing lesion on brain mri in left temporal lobe was concerning for vasculitis. patient was treated with glucocorticoids, with a negative rheumatologic workup and discharged home. patient subsequently presented days later with worsening symptoms, with ct imaging showing completed infarcts. blood cultures were positive for cryptococcus neoformans; patient died due to diffuse right mca territory edema and brain herniation syndrome. discussion: it is important to consider cns infection even in immunocompetent patients who present with any of the following: fever, nuchal rigidity, mental status change, and headache. cns vasculitis in association with infection is caused by basilar meningeal exudates. these cause traversing vessels to become inflamed, leading to distal inflammation and subsequent thrombus and infarction. we present a right mca territory infarct , presumed to be based on the aforementioned vasculitic process. when acute infarcts are associated with opportunistic cns infections, they are usually not associated with large vessel infarction. we also examine the adjunctive use of glucocorticoid therapy for treatment of fungal cns infections. this is an infrequent case of cryptococcus neoformans causing a cns infection in an hiv-seronegative patient not on chronic immunosuppressive medications. this case presents a unique complication of cryptococcal infections, a cns vasculitis leading to infarction in a large vessel territory. we describe the baseline characteristics, continuous intravenous midazolam doses, seizure control, hospital course and outcomes in patients who received high dose continuous midazolam infusion for refractory status epilepticus in this retrospective case series study, we evaluated adult patients with refractory status epilepticus treated with high continuous intravenous midazolam doses in an academic neurocritical care unit between august and june . four patients were identified. the maximum midazolam dose for each patient was: withdrawal seizures (occurring within hours of discontinuation of continuous iv midazolam) occurred in patient b. "ultimate continuous iv midazolam failure" (patient requiring change to a different continuous intravenous antiepileptic drug despite maximum optimized dose) was not observed in any of the four patients. hospital complications occurred in patient a and b due to infections. hypotension related to continuous infusion midazolam occurred in patient a. three out of four patients discharged alive to a skilled nursing facility; after a goals of care discussion with the family, the fourth patient had withdrawal of care due to the severity of his brain injury. in this case series, we report the use of high dose continuous iv midazolam for treatment of refractory status epilepticus. there were no midazolam-related deaths. neurologic complications in infective endocarditis (ie) occur up to % and are independent predictors of mortality. infectious intracranial aneurysms known as "mycotic aneurysm" (ma) are rare constituting - %. hemorrhaging rate is %. mortality is % with rupture. ruptured ma poses significant management conundrum due to lack of available solid prospective data guiding the order (cardiac vs neurosurgical) or timing (early vs delayed) of surgery. a y/o male iv drug abuser presented with acute hypoxemic respiratory failure secondary to pneumonia and suspected meningitis. gsc intubated on iv antibiotic. hemodynamic instability prompted tee showing large aortic valve vegetation. blood cultures positive mssa fulfilled criteria for ie. tests showed kidneys infarctions. ct brain showed r mca territory infarct with sah.cta head revealed small ma along the distal r mca m branch confirmed with cerebral angiogram. acute heart failure and arrhythmia led discussion on cardiothoracic surgery for valve replacement. due to ruptured ma, decision to secure it was made prior to cardiac surgery. after failed endovascular intervention, patient underwent surgical clipping. post operative mri brain showed new infarcts suggesting recurrent embolization. due to risk of intracranial bleeding, cardiac surgery was postponed for at least weeks initially then to weeks. patient underwent avr after completed weeks of antimicrobial therapy with st jude mechanical valve and discharged on anticoagulation with a modified rankin scale of . this case reflects on how urgent surgical intervention should take place.safety period between neurological event and cardiac surgery is largely debated because of lack of controlled studies. there has been no consensus on how to approach those cases as paucity of robust evidence. given their rarity the best management modality remains unclear. this case stress the importance of multimodal therapy in achieving good outcome although the timing of surgery remains a matter of debate. we present a patient with vertebral cerebral artery embolism (cae) following blunt trauma. case presentation: a year-old male was admitted with a right vertebral artery dissection and occlusion with intraluminal air, widespread pneumocephalus, bilateral pneumothoraces, a pulmonary laceration, and multiple fractures including ribs, c transverse foramen (with normal alignment), and femur following a motor vehicle collision. his pupils were initially nonreactive, and he experienced one hour of witnessed generalized seizure activity on arrival despite aggressive treatment. management: midazolam infusion, levetiracetam, and fosphenytoin were initiated for seizure control. targeted temperature management to celsius was initiated on arrival out of concern for hypoxic brain injury. computed tomography at hours demonstrated resolution of vertebral and intracerebral air, diffuse edema, and diffuse loss of gray-white matter differentiation, thus a hypertonic saline infusion was initiated. the following day, an mri demonstrated diffusion restriction in the areas adjacent to the air, including c - and diffusely throughout bilateral cerebral hemispheres. prognosis was thought to be poor. however, the following day, the patient awoke. by day four he followed commands. he was discharged to skilled nursing on day . at three months he had only minimal residual right hip weakness. discussion: there are only three case reports of cae following blunt trauma, and only one involving the vertebral artery. air migrates to the arterial circulation due to a positive gradient from low central venous pressure or high airway pressure. pulmonary venous air then embolizes to cerebral vasculature. as little as ml of arterial air emboli can be fatal with the major cause of death being circulatory obstruction and arrest from air trapped in the right ventricular outflow tract. conclusion: this patient developed pneumocephalus and cae due to a pulmonary laceration. as the cerebral air reabsorbed, his seizures resolved and his exam improved. petrous ica aneurysms are extremely rare - and difficult to treat surgically, due to the inherent challenges of microsurgical access to the carotid canal of the petrous bone - . endovascular approaches may also prove challenging, typically as the consequence of therapeutically-unamenable morphology, but occasionally due to size considerations as well. a -year-old male presented with headache and vertigo for the past weeks. the patient was hivpositive with medication noncompliance and denied any history of trauma or head injury. head ct identified a . x . cm heterogeneous soft tissue density lesion in the right petrous bone. ct angiography revealed a . x . x . cm lobulated giant aneurysm of the right petrous ica. mri/mra was performed to rule out thrombosis and showed giant partially thrombosed right petrous ica aneurysm. the decision was made to treat using flow diversion. the patient underwent catheter angiography, confirming a giant x . cm right internal carotid artery petrous segment aneurysm. we proceeded with flow diversion pipeline endovascular device, placement of two pipeline endovascular devices (flex x and x ) successfully. final angiographic runs showed significant stasis within the aneurysm and demonstrated the flow-diverter construct was well placed both proximal and distal to the aneurysm neck with no sign of endovascular leak. the patient was discharged home well. we suggest that flow diversion is an ideal treatment for petrous ica aneurysms, specifically un-ruptured lesions of complex morphology. other options for treating petrous ica aneurysms challenging, not possible, less effective, and/or carry substantial risks. second, several of the disadvantages of pedocclusion of side vessel branches and preclusion of future coil embolization, do not apply to the petrous segment of the ica. lastly, use of ped in petrous ica aneurysms has proven effective in the vast majority of reports. the spot sign is a focus of enhancement within the hematoma on ct angiogram (cta) with unique characteristics. it has a spot-like appearance within the margin of a parenchymal hematoma without connection to an outside vessel. it should measure greater than . mm in diameter in at least one dimension. its contrast density (hounsfield units, hu) is at least double that of the background hematoma. finally, there should be no hyperdensity at the corresponding location on non-contrast ct. it is a strong predictor of hematoma expansion and poor prognosis in intra-parenchymal hemorrhage. the pathogenesis of spot sign remains unclear. some studies showed an association with faster rates of contrast leakage which indicates continued bleeding. a spot sign has not been reported with isolated intraventricular hemorrhage (ivh) before. a case report of a -year-old man with a past medical history of hypertension who got admitted to the er with acute encephalopathy and right-sided weakness. head ct-scan (hct) revealed isolated ivh. cta was notable for a spot sign. it measures . mm in diameter and hu in density (surrounding hematoma measures hu). it lies within the hematoma without connections to any adjacent vessel. a follow-up hct after four hours showed expansion of the ivh. although seems uncommon, looking for a spot sign in isolated ivh can also anticipate expansion of the hemorrhage. a further study is needed to validate this observation and calculate the prevalence of the spot sign in isolated ivh. west nile neuroinvasive disease may present with nonspecific physical exam and imaging findings. to our knowledge, this is the first report of wnnd involving the temporal lobe in adults with neuroimaging suggestive of limbic encephalitis. our patient presented in winter and developed autonomic instability and sensory deficits, which are all rare findings in wnnd. -year-old texan with dm presented with acute confusion and seizure in november. patient complained of headache, fever, diarrhea and lower extremity weakness after a fishing trip. patient was febrile with mosquito bites on his arms. neurological exam was significant for comatose state, absent brainstem and deep tendon reflexes, and flaccid paraparesis. he developed autonomic instability with labile blood pressures. lp revealed wbc/mm (monocyte predominance), rbc/mm , glucose mg/dl, elevated protein of mg/dl, and a positive west nile virus (wnv) igm antibody; gram stain, hcv pcr, and the paraneoplastic and autoimmune panels were negative. eeg showed severe diffuse brain slowing. mri brain had t flair and dwi changes in right hippocampus and posterior limb of internal capsule. emg described severe subacute sensorimotor axonal polyneuropathy without prolonged distal latencies and normal conduction velocities. he received days of ivig without improvement and was terminally extubated. our patient presented with both clinical entities of west nile: wn fever and wnnd (present in less than % of cases). our patient had axonal polyneuropathy with paralysis which is due to inflammatory changes in the white matter tracts affecting spinal sensory pathways. sympathetic ganglia involvement caused the autonomic instability, another very rare manifestation of wnnd. november presentation was due to warmer texas winter. recognize that west nile fever and west nile neuroinvasive disease may present together in winter. recognize that west nile neuroinvasive disease can present with rare temporal lobe neuroimaging, sensory involvement, and autonomic instability. intracerebral hemorrhage (ich) is a common pathology seen in the neurocritical care setting that can be associated with significant morbidity and mortality. the use of sympathomimetic agents containing phenylpropanolamine (ppa) have been associated with ich in the past which lead to the drugs' removal by the fda as an over the counter medication in . we report a case in which ppa was the etiology for a spontaneous ich in a patient who was taking an appetite suppressant. case report and review of the literature we report a case of a year old female with no prior medical history, who presented with sudden onset left sided hemiparesis and hemianesthesia found to be due to a right striatocapsular intraparenchymal hematoma. systolic blood pressures at presentation and throughout the hospital course were normal. extensive work up including multiple ct scans of the head, mri brain, ct angiography, mr angiography and digital subtraction angiography were performed with no evidence of any vessel abnormality. etiology of the ich was attributed to the use of ppa. in young patients with no known comorbidities, ppa use should be considered a primary etiology of ich when no intracranial vessel abnormality can be detected. seizures have been known to cause sudden death, but reports in the literature of only cardiopulmonary failure in cases of sudden unexpected death in epilepsy (sudep). we present the case of a patient who presented post-seizure and developed sudden progressive and fatal cerebral edema within hours after a second seizure. a year old female with a history of down syndrome and epilepsy presented to the emergency department after a prolonged convulsive seizure. she received doses of mg lorazepam and levatiracetam . mg/kg with cessation of seizure activity and return to baseline neurologic status within hours of the initial event. head ct showed lack of sulci throughout the cerebral hemispheres and basilar cistern effacement despite being at her baseline neurologic status. hours after presentation the patient had another seizure, vomited, was intubated and an additional mg/kg of levatiracetam given. hours after presentation, the patient was admitted to the neuroicu with absent brainstem reflexes and repeat head ct with worsened cerebral edema and tonsillar herniation. formal brain death testing was performed approximately hours after the patient's initial presentation. seizures are known to cause a hypermetabolic state in the brain. uncontrolled neuronal firing leads to hyperemia, failure of na+/k+ atp pump, increased levels of neuronal chloride, and inability for cells to maintain homeostasis. in this case, the patient's initial head ct showed cerebral edema, likely from prolonged seizure activity. once the second convulsive seizure occurred, a period of pre-intubation hypoxemia coupled with post-intubation hypotension allowed for progression of cerebral edema in an already compromised brain; similar to what is seen in post-cardiac arrest and traumatic brain injury. this case illustrates the importance of controlling for factors that can contribute to secondary brain injury in seizure patients. posterior reversible encephalopathy syndrome (pres) is a clinico-radiographic syndrome characterized by seizure, headache, encephalopathy and neuroimaging findings of symmetric white matter edema in the posterior cerebral hemispheres. cerebellar and brainstem involvement occurs rarely. here, we report a patient who presented with severe pres complicated by diffuse cerebellar edema and obstructive hydrocephalus requiring decompression with ventriculostomy placement. this is a case report from a tertiary medical center. a -year-old woman with a history of migraine presented to the emergency room with -day history of fever, right upper quadrant abdominal pain, nausea and vomiting. on day two of hospitalization, the patient developed worsening headache, dizziness and lethargy and her blood pressure was elevated to / mmhg. ct of the brain showed cerebellar edema and bilateral occipital lobes with effacement of the fourth ventricles and associated hydrocephalus involving the lateral and third ventricle. mri obtained post-operatively revealed t -weighted/flair diffuse hyperintensities in the parietal, occipital lobes and cerebellum. there was no mass lesion or restricted diffusion in diffusion weighted images (dwi) suggestive of acute infarction. cerebellar edema with compression of the fourth ventricles with hydrocephalus was slightly improved status post interval ventricular drain placement. ventriculostomy was weaned off over the course of seven days. follow up mri showed improvement of the hydrocephalus with decreased in t -weighted hyperintensities in posterior parietal and occipital lobes as well as within the cerebellum. severe cerebellar edema with obstructive hydrocephalus is an exceedingly rare complication of pres; however, prompt recognition and surgical decompression in addition to usual medical management is critical to achieve a favorable outcome. while obstructive hydrocephalus may be successfully treated with medical management and blood pressure reduction, this case emphasizes that clinical evidence of brain herniation should prompt immediate consideration for emergent ventriculostomy placement or surgical decompression to redirect cerebrospinal fluid and reduce intracranial pressure. one of the biggest uses of qeeg is the alpha delta ratio (adr). adr drops of % from baseline are associated with vasospasm (vsp/dind). we describe a case in which subtle qeeg adr change occurred in a poor grade sah patient over a number of days, making it challenging to detect an acute adr drop. this is a case report and literature review. this study also compared hemispheric adr values against the mca values by tcd, dsa, cta and clinical exam. a year old female with hunt hess iii, wfns iv, came in comatose with a ruptured ica aneurysm. over six days, she developed refractory vsp/dind. the patient's adr was gradually declining but their increased icp required propofol sedation, which itself lowers adr. re-analysis over multiple days had to be performed, and that re-analysis showed a gradual adr decline preceding the vsp/dind. when looking at our cases, we found a sensitivity and specificity of ( , %) when using the adr nadir compared to cta/dsa. recent publications have shown the adr method has less than ideal sensitivity and specificity of ( , %). qeeg adr is a useful multimodal monitoring parameter in neuroicu patients with relatively good baseline adr. however, its ability to detect vsp and dind in poor grade sah patients who have adr values that are already low (< . ) is challenging, particularly given the confounders in this population, such as eeg artifact which artificially raise adr values, and sedation (e.g., propofol) which suppress adr values. based on this information, we would suggest neuroicu centers carefully use continuous eeg monitoring for other indications such as nonconvulsive seizures, unless they have sophisticated bedside protocols about sedation vacation (baseline daily adr that is not) and eeg department resources (technicians who can fix eeg electrode artifacts). hypoxic-ischemic brain injury is a severe consequence of global cerebral hypoperfusion following cardiac arrest. brain ct findings may include diffuse sulcal effacement, loss of cisternal spaces, poor differentiation of grey/white matter, and decreased densities in the basal ganglia and watershed territories. the connection between aggressive resuscitation, as seen with in-hospital cardiac arrest, and cerebral edema is unclear. here we present the case of a hemodynamically unstable patient who developed transient reversible cerebral edema believed secondary to aggressive resuscitative efforts and pressor therapies. a year old female with a past medical history significant for diabetes and hypertension presented to the emergency department with headache and non-bilious vomiting. workup revealed isolated ventricular hemorrhage secondary to a ruptured left posterior inferior cerebellar artery (pica) aneurysm and cerebellar arteriovenous malformation, which underwent subsequent embolization. during her early hospital course she remained intubated due to pulmonary factors, but awake and alert with a non-focal neurologic examination. her course was subsequently complicated by a severe metabolic acidosis requiring several doses of bicarbonate boluses and continuous infusion, cvvhd, intravenous crystalloids, hydrocortisone and multiple pressors to maintain stability. over a hour period she received liters of volume while maintaining a mean arterial pressure above mm hg and o saturations above %, without requiring cpr. subsequent progressive encephalopathy developed, with a ct brain revealing diffuse sulcal effacement prompting hyperosmolar therapy. gradually her encephalopathy began to improve, with repeat imaging showing improvement of cerebral edema and return of grey/white matter differentiation. this case highlights a potential etiology of reversible cerebral edema that may confound early prognostication in patients with hemodynamic instability such as multi-organ failure and in-hospital cardiac arrest. further investigations are warranted. langerhans cell histiocytosis (lch) is a rare disease with an incidence of . - . cases per , children under years of age. frequency in adults is unknown. the hypothalamic-pituitary manifestations of lch (commonly diabetes insipidus) and hypernatremia are well known complications. here we present a case where a patient presented with poor mental status and the etiology remained unknown initially despite extensive testing. electronic medical record was reviewed regarding hospital course, sodium trends, and radiology images. this patient is a year old female with history of langerhans' cell histiocytosis with biopsy-confirmed suprasellar metastases (complicated by pan-hypopituitarism) who was transferred to our institution for hypernatremia and hydrocephalus. she had undergone two cycles of chemotherapy, most recently one week prior to presentation, and five rounds of radiation completed three months earlier. her presentation to the community hospital from a nursing facility was with unresponsiveness and she was intubated on arrival. her sodium was at that time; and had been three days prior. sodium was corrected from to over the course of four days with a drop from to within the first ten hours. her mental status improved to the point where she was awake and following commands; however still remained intubated. when she presented to our institution her sodium was and subsequently became unresponsive with a poor neurological exam limited to cranial nerve function only. she was evaluated with eeg monitoring and mri brain; however both were unrevealing for a cause. she had an external ventricular drain placed for concern for hydrocephalus that did not change her exam. one week later repeat mri brain revealed extrapontine myelinolysis. this case highlights the complications associated with intracranial lch and the need for repeat imaging in patients with rapid sodium correction to identify effects of osmotic demyelination. cangrelor is a rapid-acting, intravenous p y platelet receptor inhibitor with a plasma half-life of - minutes and full platelet recovery achieved within one hour after discontinuation. because it is rapidly reversible, cangrelor is commonly used to bridge patients with recent coronary stents to cabg surgery. oral p y inhibitors, such as clopidogrel, have a delayed onset and offset with platelet recovery occurring over - days, making their use challenging perioperatively or in the setting of an acute bleed. safety and efficacy data of cangrelor in noncoronary stents are lacking. we present two patients in whom cangrelor was used to maintain internal carotid artery (ica) stent patency acutely. both patients presented with an ischemic stroke secondary to acute occlusions of the left ica and left middle cerebral artery (mca) and were taken emergently to the neurointerventional suite for carotid artery stenting (cas) and mechanical embolectomy of the mca clot. heparin and eptifibatide were administered intraoperatively. post-procedure dynact demonstrated intracranial hemorrhage complications. dual antiplatelet therapy (dapt) with clopidogrel and aspirin, typically initiated following cas, was deferred given the difficulty of reversing their antiplatelet effect in hemorrhage expansion. instead, cangrelor was initiated to maintain carotid stent patency at . mcg/kg/min in one patient and . mcg/kg/min in the other patient and infused for . and hours, respectively. platelet reactivity was trended with the verifynow® assay and used to adjust cangrelor dosing. serial imaging was obtained to monitor hemorrhage expansion. one patient was transitioned to oral dapt and discharged while the other patient deteriorated neurologically from malignant cerebral edema and expired. cangrelor may be useful following cas complicated by intracranial hemorrhage when the need to maintain stent patency must be balanced with the risk of hemorrhage expansion. further research is warranted to determine its safety and efficacy in noncoronary stents. cerebral amyloid angiopathy (caa) although has been described in the literature, the different categories of this entity and its recognition and subsequent treatment are still elusive. it is important for neuro intensivists to recognize its variable presentation . we describe a single case report and perform a systemic review. caa depending on pathology can be categorized as inflammatory-caa where perivasculitis is seen on biopsy. this causes a non-destructive perivascular inflammatory infiltration and amyloid deposition pattern. on the other hand, amyloid beta related angitis (abra) results in a vasculitis and there is predominantly granulomatous angio-destructive inflammatory mediated disease affecting leptomeningeal and cortical vessels characterized by meningeal lymphocytosis and abundant amyloid-beta deposition within the vessel walls. caa on the other hand results in no inflammation of vessels but rather just deposition of amyloid deposition in the walls of vessels. we report a case of a year old man with an extensive cardiac history, who presented with syncope. initial computed tomography (ct) of head was negative. during admission, he acutely started having trouble answering questions including his name, and was unable to communicate his needs. repeat ct head showed hypodensity in left frontal region which was attributed to a stroke. he than developed complex partial seizures requiring intubation and seizure management. lumbar puncture showed mild pleocytosis. mri brain showed edematous changes of the left subcortical and deep white matter frontal lobe region which on repeat imaging subsequently worsened. biopsy was eventually performed which confirmed inflammatory cerebral amyloid angiopathy. he was treated with steroids and immunosuppression with gradual improvement. month follow up in clinic with continued improvement to independence. recognize the various subtypes of caa in their pathology, presentation and potential treatment. in acute emergency situations, intraosseous vascular access represents an alternative route of vascular access when peripheral vein insertion is difficult. we present the first documented case of intraosseous alteplase (tpa) administration in a patient with acute ischemic stroke symptoms. methods year old male with past medical history of hypertension, end stage renal disease, and diabetes mellitus presented to the hospital with sudden onset expressive aphasia and right sided numbness minutes prior to ed arrival. nihss was and code stroke was activated. patient blood pressure was / . ct head did not show any acute intracranial hemorrhage. it was decided to proceed with thrombolytic therapy. one peripheral venous access was obtained through which nicardipine drip was started to lower the blood pressure however second peripheral venous access was attempted multiple times but was unable to be obtained. tpa is more effective the faster it is administrated, and there was no known contraindications to administering tpa via intraosseous access (io). we report the first known case of successful and safe administration of fibrinolytic therapy through the intraosseous route in a patient with acute ischemic stroke symptoms. intraosseous access has been considered to be more invasive than intravenous (iv) and carries theoretical risk of bleeding however we were able to demonstrate tpa administration through io without any local or systemic complications. the bioavailability of alteplase through io access has not been studied however it is considered to be close to iv infusion in case of morphine and vasopressors. no studies negate or support the use of intraosseous access in stroke patients. contraindications are few and complications are uncommon. the findings of our case report suggest that intraosseous cannulation may be safely used for fibrinolysis in acute ischemic stroke patients with difficult peripheral venous access in in-hospital or out-of-hospital setting. tufts medical center, boston, massachusetts, usa we report a case of a pregnant patient with bilateral ovarian teratomas who presented with treatment refractory nmda receptor encephalitis despite removal of bilateral teratomas, successfully treated with rituximab. case report and discussion of treatment and outcome. year old weeks pregnant female with known ovarian cysts who presented with one week of confusion and subsequent status epilepticus. she was started on empiric treatment with ivig while undergoing workup. nmda receptor antibody was confirmed. left oophorectomy and right ovarian cystectomy were performed, both of which confirmed ovarian teratoma. she was given high dose steroids. her worsening condition prompted consideration of additional agents. plasma exchange and rituximab were initiated and then she was continued on rituximab alone. she improved dramatically over six weeks and delivered at full term via spontaneous vaginal delivery. at one year follow up, the child was healthy and meeting appropriate milestones. we report the use of rituximab for safe and successful treatment of nmda receptor encephalitis in a gravid female. neovascular glaucoma (nvg) is a known complication of carotid endarterectomy in patients with carotid stenosis. there are no previous reports of acute nvg refractory to medical treatment following carotid artery stenting (cas). we report a patient who needed surgical treatment for acute exacerbation of nvg following cas. a -year-old man with hypertension, diabetes, and hypercholesterolemia presented with recurrent transient weakness in his right hand. fifteen days before presentation, he had experienced acute loss of vision on the left side because of central retinal artery occlusion. magnetic resonance imaging of the brain was unremarkable. conventional angiography showed an occlusion of the left proximal internal carotid artery. ophthalmological evaluation before cas showed neovascularization of the iris and a normal intraocular pressure (iop) of mm hg in the left eye. cas was uneventful, but the following morning, the patient developed pain in the left eyeball with an iop of mm hg. anterior chamber paracentesis followed by intraocular injection of bevacizumab, panretinal photocoagulation, and medical treatment failed to reduce the iop below - mm hg. eighteen days following cas, an ahmed glaucoma valve was implanted in the left eye to treat the refractory nvg. iop decreased to mmhg and his ocular pain resolved completely post implantation. although nvg is a rare complication of cas, it should be suspected in patients who develop acute ocular pain following cas. nvg may respond to anterior chamber paracentesis, panretinal photocoagulation, and bevacizumab, but surgical treatment, such as implantation of an ahmed glaucoma valve, should be considered in cases with refractory nvg. background: cerebral amyloid angiopathy is a common cause of spontaneous lobar intracerebral hemorrhage. convexal subarachnoid hemorrhage can be a manifestation of cerebral amyloid angiopathy. whether focal amyloid burden predicts future hemorrhage is unclear. case: an -year-old man presented with transient left arm weakness and paresthesias in the setting of previous cognitive decline. mri showed a convexal subarachnoid hemorrhage of the right central sulcus, as well as susceptibility weighted imaging findings consistent with superficial siderosis. lumbar puncture revealed normal cell count with a mildly elevated protein. he had spontaneous resolution of his symptoms after several hours. one year later he presented with sudden onset confusion and imaging again showed a convexal subarachnoid hemorrhage over the posterior right frontal lobe. susceptibility weighted mri revealed hemosiderin over the right posterior frontal and anterior parietal lobes. an amyloid-pet, obtained one year prior to his first spell as a research participant, demonstrated asymmetric amyloid deposition in the right temporo-parietal region. years after his initial episode he presented again with confusion, headache, and decreased level of alertness. a ct scan demonstrated a right-sided temporo-parietal intracerebral hemorrhage in the area of asymmetric amyloid deposition on pet. his family opted for comfort measures only, and he was discharged to hospice. autopsy revealed severe amyloid angiopathy, as well as alzheimer disease, braak stage vi. discussion: this case illustrates the clinical course of a patient with amyloid angiopathy, including recurrent convexal subarachnoid hemorrhages, and superficial siderosis. of importance, the amyloid pet scan predicted the location of his intracerebral hemorrhage years later. the case of a -year-old man, presenting with a past medical history of migraine headaches, dipola, vertigo, with symptoms later progressing to lethargy and confusion for days. brain mri revealed a peripherally enhancing mass within the left thalamus with central restricted diffusion, which is consistent with a cerebral abscess. case report of congenital heart disease when discovered in adulthood is an interesting entity, especially when it is the source of brain abscesses. detailed history taking, physical examination and appropriate imaging can usually reveal the anomaly. the diagnosis of brain abscess should promote the clinician to consider right to left shunts as a possible predisposing condition for brain abscess management of acute cerebral embolism in patients with implanted ventricular assist devices (vads) is particularly challenging, since chronic anticoagulation often precludes the use of intravenous tissue plasminogen activator (iv-tpa). we describe a vad patient who suffered cerebral embolization, and was successfully treated with thrombectomy, emphasizing the nuances particular to this clinical scenario in the context of limited historical experience. a year-old man with heart failure (ejection fraction %) and heartware ii vad implantation about months prior, was found at the scene of a car accident with expressive aphasia, right homonymous hemianopia, extinction and right hemiplegia, with a national institutes of health stroke scale (nihss) score of . upon arrival, his ct was unremarkable, but cta revealed occlusion of the left middle cerebral artery (m segment). since his inr was . , he underwent emergent thrombectomy with the solitaire device, resulting in complete revascularization (tici = ) minutes from onset, with rapid deficit resolution (nihss = ). the procedural and clinical success was accompanied by lack of evidence of infarction in subsequent ct studies, and a modified rankin score of upon discharge. the removed thrombus displayed early organization, suggesting unexpected firmness, and underscoring the potential importance of mechanical removal rather than chemical lysis in vad patients. our case has attributes that set it apart from those previously reported: ) the use of a hybrid (i.e. retrieval plus aspiration) endovascular retrieval technique, ) the lack of concurrent use of thrombolytic drugs, and ) the rapid, sustained and optimal clinical improvement. the utilization of vads continues to grow, yet the literature regarding endovascular techniques for managing these types of patients remain scarce. however, the increasing availability of centers capable of delivering this type of treatment, suggests that thrombectomy should be strongly considered in vad patients with acute cerebral embolism. extreme cerebral oxygen changes has not been reported via monitoring of partial brain tissue oxygen levels. here we present an asah patient with brain tissue oxygen (pbto ) monitoring, who developed cerebral hypoxia due to cerebral vasospasm, then went on to develop cerebral hyperoxia with associated cerebral infarction. methods yo female with hh fg sah with initial gcs of t underwent coiling of a ruptured basilar tip aneurysm. a pbto monitor was inserted to guide therapy. this patient had multiple episodes of low pbto ( mmhg). this corresponded to infarction on follow up head ct and mri with preservation of local arterial vessels on mra, consistent with diagnosis of dci. in the present case, high pbto is more likely resulted from a combined effect of ) increased cbf from co-administration of ketamine at the time of milrinone infusion; ) decreased cerebral metabolic demands in already infarcted left frontal lobe, resulting in reduced oxygen uptake; ) accelerated reperfusion and thus hyperemia with milrinone. restoration of flow with milrinone may have been too late to reverse the prolonged period of vasospasm induced ischemia, resulting in perfusion of infarcted tissue, or luxury perfusion. clinicians utilizing pbto monitoring for dci management should be cautious of high pbto values, as it may herald cerebral infarction. further studies are needed to better elucidate the mechanism of reperfusion injury and potential treatments. patients with acute brain injury, especially those with intracranial hemorrhages are at a higher risk for hemorrhage while on therapeutic anticoagulation. unfractionated heparin (ufh) is frequently used as it is easily reversible and has a short half-life. activated partial thromboplastin time (aptt) is traditionally used to monitor its effect. several disadvantages with aptt monitoring include inability to reach therapeutic goal, over-or under-dosing and its associated complications. anti-xa level is reported to have better correlation with actual degree of anticoagulation using ufh. retrospective chart review of patients with acute brain injury who required initiation of early therapeutic anticoagulation and monitored with anti-xa level. case - year-old-man with intracerebral hemorrhage (ich) developed lower extremity deep vein thrombosis (dvt) and required therapeutic anticoagulation. patient became therapeutic within six hours of titrating infusion based of anti-xa levels and remained therapeutic. asymptomatic rectal bleeding associated with fecal management system was noted. case - year-old-man with cerebral venous sinus thrombosis presented required therapeutic anticoagulation. ufh infusion was initially monitored using aptt levels which had widely varied lab results, thus monitoring was switched to anti-xa levels which provided a more consistent therapeutic range. however, patient developed thrombocytopenia in the setting of inflammatory bowel disease. therefore, ufh infusion was changed to argatroban infusion. case - year-old-man with lower medullary acute ischemic stroke due vertebral artery dissection required therapeutic anticoagulation to prevent recurrence. patient became therapeutic within hours of titrating based of anti-xa levels. to monitor therapeutic anticoagulation, anti-xa level appears to achieve target anticoagulation level faster and without serial variation as compared to aptt. however, anti-xa level estimation is costlier as compared to aptt and not widely available. by restricting it to special populations like those with acute brain injury might justify its use and underscore cost-effectiveness. neurological admissions presenting to the icu benefit from a dedicated neurocritical care team but many community hospitals lack this subspecialty expertise. with an aging population and a neurointensivist shortage, more patients are transferred to designated neurocritical care units which increases healthcare spending and resource utilization. recognizing this obstacle, we describe the management of a patient in status epilepticus via our novel "eneuro-icu" consult program in which a 'sub-hub' of the northwell health tele-icu was set up at the only hospital out of in our health system that is staffed / by neurointensivists. a -year-old man with history of a left frontal meningioma presented with multiple seizures to a hospital within our healthcare system. he received mg of lorazepam and levetiracitam in the emergency department and was admitted to the icu for further monitoring. there he was witnessed to have recurrence of clinical activity concerning for ongoing seizure. levetiracitam was increased and phenytoin was added. neither immediate neurological consult nor continuous eeg was available, thus an "eneuro-icu" consult was obtained. in this model, the bedside provider contacts the tele-icu that facilitates a conference call with the neurointensivist. av technology was used to provide consultations and follow ups. the neurointensivist determined the patient was rapidly returning to baseline and recommended a head ct, lab studies and continuation of the anti-epileptic drugs. the eicu team monitored the patient overnight. by leveraging the infrastructure in place for management of critically ill patients remotely, an additional level of subspecialty care was offered in a timely manner and allowed the patient to remain at their local facility. based on the success of the initial program we are currently in the process of extending the virtual consult service to various community hospitals' eds/icus to improve outcomes for patients who would benefit from neurocritical care services. hypoglycemic encephalopathy is a potentially life-threatening manifestation of hypoglycemia, it is usually caused by metabolic change, hypoglycemic agents, and malignancy. here, we report a patient with hypoglycemic encephalopathy caused by sleeve gastrectomy a -year-old woman was admitted due to unconsciousness of acute onset. she showed normal corneal and vestibulo-ocular reflex but sluggish pupil light reflex and decerebrated posture by painful stimulation. she has taken severe medications for weight control including orthosiphon powder and hydrochlorothiazide after bariatric surgery. laboratory studies showed significantly low blood glucose level ( mg/dl) with normal liver enzyme and creatinine. there was no evidence of adrenal insufficiency. electroencephalography showed no epileptiform discharge. initial and follow-up brain magnetic resonance imaging revealed diffuse high signal intensity on white matter expanded to cortex, corpus callosum and posterior limb of the left internal capsule, suggesting hypoglycemic encephalopathy. in abdomen-pelvic ct, there is no mass lesion like carcinomas or insulinoma. the clinical diagnosis of hypoglycemic encephalopathy followed by sleeve gastrectomy was made by given history of bariatric surgery and the lack of evidence of hypoglycemic agent overdose, adrenal insufficiency, endogenous hyperinsulinism or malignancy. there are several hypotheses that sleeve gastrectomy can encourage hypertrophy of beta cells, hypersecretion of glucagon-like peptide, glucagon abnormality and increased insulin sensitivity, that may induce hypoglycemia. we suggest that clinicians should consider sleeve gastrectomy itself as a possible cause of profound hypoglycemia pulmonary embolism (pe) is a fatal complication in neurological conditions with plegic extremities. clinical presentations and supportive testing can be variable. we present a case of pe which presented with st segment elevations weeks after spontaneous intracerebral hemorrhage (sich). case report and review of the literature we present a case of a year old female with a history of a recent sich with resultant left hemiplegia who presented with a syncopal episode and chest pain. on physical examination, she was noted to be tachypneic and tachycardic with an unchanged neurological exam. pulmonary embolism can present with a variety of ekg abnormalities including st elevations after sich and the treating physician should be aware of these idiosyncrasies. anticoagulation should be cautiously initiated in such cases. infectious intracranial aneurysms (iia) are rare neurovascular lesions associated with infective endocarditis. we present a case of a large iia which developed within hours of a negative ct angiogram and ruptured despite weeks of appropriate antibiotic treatment. a year-old woman presented with fevers and malaise. her initial workup revealed an aortic valve mass and blood cultures grew out streptococcus. three days after intravenous penicillin therapy was initiated for bacterial endocarditis, she developed a new headache and right hemianopsia. a head ct demonstrated a left occipital lobe stroke with hemorrhagic transformation. further workup with ct angiography revealed a mm outpouching along of the distal branch of the left pca, consistent with an infectious intracranial aneurysm. on repeat imaging, this aneurysm demonstrated growth despite medical treatment, and required coil embolization/occlusion. aortic valve replacement was planned after weeks of antibiotic therapy because of continued severe aortic insufficiency and persistent valve vegetation. on the day of surgery, she developed acute word-finding difficulty followed by a rapid neurologic deterioration resulting in coma. a head ct demonstrated a new left frontal intraparenchymal and subarachnoid hemorrhage associated with the rupture of an mm x mm irregularly shaped aneurysm in the region of the left mca bifurcation, which had been absent on a prior surveillance ct angiography just hours prior. she underwent emergent coil embolization, extraventricular drain placement, and decompressive hemicraniectomy. despite these measures, her exam did not improve. she was transitioned to comfort measures and life-sustaining therapies were withdrawn. the development of iia can occur despite appropriate medical treatment. these aneurysms may rapidly expand and rupture within hours, as shown by our case. even with prior exonerating imaging, clinicians should have a high suspicion for iia development in all infective endocarditis patients. the corneomandibular reflex, also known as wartenburg reflex or von solder phenomenon, is a rare pathological reflex signifying severe supranuclear trigeminal injury. it presents as contralateral jaw deviation to corneal stimulation. etiologies include upper brainstem lesions, large hemispheric lesions with brainstem compression, as well as advanced amyotrophic lateral sclerosis and multiple sclerosis when corticobulbar pathways are affected. this clinical finding is useful in differentiating structural and metabolic causes of coma, as this examination finding would not be present in metabolic phenomena. a middle aged man presents with a hypertensive right thalamic hemorrhage and a four score of e m b r . the patient's cornea was stimulated with a cotton swab. the cornea was tested bilaterally to determine any lateralizing features. recording on video was performed with patient's family written consent as patient was comatose. upon stimulation of the patient's cornea a contralateral jaw jerk was appreciated. this was replicated contralaterally. this case describes a common patient with a rare physical examination finding. there is utility in recognizing this finding as it will aid in determination of the underlying cause of a comatose state. the corneomandibular reflex present at presentation rules out a metabolic cause. a structural cause was validated by imaging studies (shown). the reflex arc was researched and has been independently artistically rendered (shown), which demonstrates the pathway beginning with the afferent limb of the corneal stimulus (v ) which travels to the main trigeminal sensory nucleus via the trigeminal ganglion. severe supranuclear trigeminal lesions will inhibit inhibitory interneurons within the mesencephalic nucleus, leading to activation of the motor nucleus of the trigeminal nerve. this causes activation of the ipsilateral external pterygoid muscle which produces a contralateral jaw jerk. overall this patient fared poorly and expired several days after admission. pneumocephalus is when air enters and is contained inside the intracranial compartment. when intracranial pressure increases causing neurological decline, patients can experience nausea, vomiting, seizures, dizziness, and altered mental status. here we present three cases of postoperative pneumocephalus which resolved quickly with humidified oxygen delivery via high-flow nasal cannula. we follow the cases with a review of the mechanisms and pathophysiology of pneumocephalus and its treatment, as well as future directions in management. case series of patients with post-operative pneumocephalus who were treated with high-flow nasal cannula. case describes a -year-old woman who underwent hemicraniotomy for removal of meningiomas, with focal postoperative neurological signs and mm of midline shift on head ct due to pneumocephalus. case describes a -year-old woman who underwent right anterior temporal lobectomy for seizures, who developed postoperative focal prefrontal lobe signs and mount fuji sign on head ct. case describes a -year-old man with bilateral subdural hematomas, status post bilateral burr hole evacuation. he was excessively somnalent postoperatively with bilateral pneumocephalus. with high-flow nasal cannula, they all returned to clinical, and near radiographic baseline within , , and hours, respectively. recognizing the limitations of a small case series, we believe these cases support use of high-flow nasal cannula when treating patients with symptomatic pneumocephalus. thsee patients showed more rapid clinical and radiographic improvement after implementation of hfnc oxygen therapy than previously described using other methods. high-flow nasal cannula may help washout nitrogen from the lungs, allowing a downward gradient from the nitrogen in the intracranial air bubble out the lungs. in addition, high-flow nasal cannula is more comfortable for the patient, allowing for more consistent treatment. randomized studies are needed to confirm our findings. the neurotoxin produced by clostridium botulinum is the most lethal toxin known by weight. early recognition and treatment of botulism are crucial for full recovery. we present a case of progressive paralysis secondary to botulism toxemia following a gunshot wound (gsw). a -year-old man suffered a gsw to the right lower extremity. he was treated in the emergency department where the wound was irrigated and closed. some bullet fragments could not be retrieved due to close proximity to popliteal vessels and surrounding nerves. he returned ten days later with diplopia and nausea. he denied consumption of canned foods or illicit substances and had no preceding upper respiratory or gastrointestinal illnesses. on examination, he exhibited ptosis and symmetric bilateral motor weakness with diminished deep tendon reflexes. the gsw showed no signs of infection. progressive respiratory insufficiency resulted in intubation and mechanical ventilation. a lumbar puncture revealed normal opening pressures and cerebrospinal fluid analysis was unremarkable. titers for acetylcholine receptor and anti-muscle specific kinase antibodies were negative, as was a tensilon test. blood toxicology analysis showed no evidence of illicit substances or heavy metal poisoning. a high suspicion for wound botulism led to consultation with the regional poison center and cdc. blood and anaerobic wound samples were obtained for toxin bioassay and culture. empiric intravenous penicillin g therapy was started. equine heptavalent antitoxin (h-bat) was obtained and administered on hospital day . serum toxin bioassay tested positive for botulinum neurotoxin type a. the patient required a gastrostomy tube due to persistent dysphagia. after one month of hospitalization, he was discharged home and continues outpatient physical therapy. wound botulism from traumatic injury is exceedingly rare with only one to two cases reported annually. our case is the first reported incidence of wound botulism from a single gunshot wound. hyperammonemic cerebral edema (hce) with brain herniation carries a dismal prognosis historically despite aggressive treatment. however, we report a case where a patient with severe hce and herniation returned to her neurological baseline after aggressive medical management. a -year-old woman became acutely comatose with a blown left pupil and required intubation several days after admission for encephalopathy. head ct demonstrated diffuse cerebral edema with central and bilateral uncal herniation. profound hyperammonemia ( ug/dl) was implicated, though hepatic function was normal. her intracranial hypertension was ultimately controlled using hyperventilation, sedation, and osmotherapy, resulting normalization of her brainstem reflexes and improvement in her coma and imaging. continuous veno-venous hemodialysis (cvvhd) normalized her ammonia and encephalopathy that was initially refractory. multiple porto-hepatic shunts were identified on hepatic ct angiogram as the cause of her hyperammonemia, and were embolized. she was eventually weaned off cvvhd and extubated, without residual neurological deficits. our case demonstrates that, with contemporary management, clinical and radiographic reversal of hce and herniation is possible and prognosis is not uniformly poor. therefore, neurological prognostication in these patients should only be performed after assessing the clinical trajectory following cerebral resuscitation and ammonia reduction. furthermore, our case provides an example of how cvvhd can be used to reduce refractory hyperammonemia quickly until the cause of the hyperammonemia can be ascertained and addressed. finally, this is the first case reported of hce secondary to primary portosystemic shunt in absence of hepatic disorder; vascular imaging of the liver should be considered in the work-up of patients with hyperammonemia. a good neurological prognosis is possible for patients with hce and cerebral herniation with aggressive management that includes reduction of icp and ammonia. ccvhd is a useful adjunct to treat refractory hyperammonemia. a porto-systemic shunt should be considered as an etiology for hyperammonemia. cerebral venous sinus thrombosis (cvst) often presents with intracerebral hemorrhage and seizures. extensive involvement of the cerebral sinuses can lead to comatose state due to cerebral edema and associated intracranial hypertension. if not reversed with early therapeutic anticoagulation, then mechanical thrombectomy and decompressive hemicraniectomy (dhc) may be necessary as life-saving measures. however, etiological diagnosis of associated hypercoagulable state is needed for successful long-term treatment. case report of a patient presenting with cvst requiring anticoagulation, dhc and total colectomy (to treat underlying ulcerative colitis) as treatment with full anticoagulation was associated with lifethreatening hematochezia. twenty-five year old man with one week history of diarrhea presented with left sided weakness. imaging studies confirmed extensive cvst with minimal venous drainage through bilateral cavernous sinuses as well as right hemiparesis secondary to left post cingulate intracranial hemorrhage. patient subsequently developed loss of vision and became encephalopathic, despite initiation of anticoagulation with heparin. hence, mechanical thrombectomy was attempted but was unsuccessful. he also developed consumptive thrombocytopenia for which his anticoagulation was switched to argatroban. progressive neurologic deterioration necessitated dhc. his neurological examination progressively improved upon re-initiation of anticoagulation resulting in restoration of vision and resolution of left hemiparesis. later in the disease course, he developed symptomatic hematochezia associated with his primary disease, ulcerative colitis and required total colectomy. subsequently he was transitioned to oral anticoagulation and transferred to inpatient rehabilitation facility due to deconditioning from prolonged hospitalization. cvst can be life-threatening unless early treatment is initiated. appropriate and timely treatment including etiological diagnosis can lead to favorable patient outcomes. adverse effects of intrathecal non-ionic contrast during myelography are rare but can include seizures and encephalopathy. to our knowledge, cerebral edema has only been reported in the literature in two previous cases. we report a case of malignant cerebral edema following intrathecal administration of non-ionic contrast who developed seizure like activity with radiographic evidence on a head computerized tomography (ct) scan of acute diffuse cerebral edema. an year-old male underwent an elective spinal ct myelogram using mm of isovue m non-ionic contrast to evaluate chronic lumbar pain related to spinal stenosis. no complications were reported intra-procedurally and the patient was discharged home. the patient began to complain of progressive worsening headaches. the following morning he started complaining of nausea/vomiting, lost consciousness with posturing vs seizure like activity. a head ct revealed extensive brain edema and swelling with crowding of the brainstem and herniation ( fig. ). this patient was intubated and given an iv mannitol, . % hypertonic saline followed by an infusion of % hypertonic saline infusion. serial cts revealed complete resolution of his cerebral edema hours after admission ( fig. and ) . the patient's mental status improved, was extubated, and then was discharged home days after admission. while significant adverse effects of non-ionic contrast following spinal myelography are rare, the potential life threatening severity of these incidents warrants further patient education following this routine outpatient procedure. we recommend close neurological monitoring after intrathecal administration of contrast media. patients should be provided with detailed instructions about the potential side effects of non-ionic contrast and how to seek medical attention if symptoms of cerebral edema are noted post procedurally. a large acute traumatic subdural hematoma with brain compression and midline shift is typically considered a neurological emergency necessitation surgery. spontaneous resolution of a large subdural hematoma is considered a rare phenomenon with a few case reported in the literature. to our knowledge, we present the first case of spontaneous resolution of a traumatic acute subdural hematoma with brain compression and midline shift on dual antiplatelet therapy. a year-old patient initially presented after being found down and unresponsive in his home. the patient was on aspirin and clopidigrel. he was found to have altered mental status, wasn't following commands, and had a glascow come scale score of < . the patient's initial head ct revealed a large left acute subdural hematoma (sdh) measuring . cm in diameter. neurosurgery was consulted upon arrival for possible emergent evacuation. the patient's repeat head ct showed a decreased sdh to . cm in diameter. given the rapidly resolving sdh, surgery was postponed. another repeat head ct the following day revealed a decrease in size of the sdh to mm in diameter. several theories have been proposed for the rapid resolution of an acute sdh including csf leaking into the sdh through a tear in the arachnoid membrane with rapid reabsorption, redistribution of the hematoma in the subdural space, and acute fluctuations in icp driving the spontaneous resolution of the sdh. close neurological and repeat imaging may be helpful in managing these patients. as seen in our patient and others, a low density band in the subdural hematoma may indicate csf and be a predictor for spontaneous resolution of an acute sdh. the features of this atypical case offer points of discussion regarding the surgical or non-surgical approach of these patients. early post-hypoxic myoclonus -or myoclonic status epilepticus -develops within hours of the initial anoxic injury and is associated with poor outcomes per current aan practice guidelines. late posthypoxic myoclonus -or lance-adams syndrome -develops > hours after the anoxic injury, consciousness is regained, and is associated with relatively good outcomes. the patient is a yo man with a history of alcohol and cannabis use disorder, bipolar disorder, pnes who presented after attempted hanging for up to minutes. intial rhythm was pea; he had rounds of cpr, received mg epinephrine, and was intubated prior to rosc. myoclonic jerks were noted within hours post arrest. hypothermia protocol was initiated as gcs was t. ct head showed subtle loss of grey-white differentiation. eeg initially showed that his generalized myoclonic jerks correlated with cortical activity. he was started on versed gtt, keppra, vpa with improvement in the frequency of jerks. on post-arrest day , mri brain showed mild cerebellar edema. mri c-spine was negative for significant myelopathy, arguing against myoclonus as a spinal reflex. mentation gradually improved; on post-arrest day he opened his eyes to command. eeg evolved to show gpeds and sirpids and oxc and tpm were added. on post-arrest day a paralytic challenge resolved electrographic spikes, suggesting subcortical origin of myoclonus. he continued to improve cognitively, but despite clonazepam, vpa, home oxc he continues to have severe intention myoclonus. despite the presumed poor prognosis, the patient's family pursued aggressive measures and his mentation gradually improved. early post-hypoxic myoclonus carries a poor prognosis, however, in this case, the patient survived with a good cognitive outcome likely owing to his age and relatively few comorbidities. further studies are needed to differentiate early-onset lance-adams from myoclonic status since prognosis differs greatly. posterior reversible encephalopathy syndrome (pres) can occur from multiple etiologies and often presents with rapid-onset headache, altered consciousness, seizures and/or visual disturbances. vasogenic edema involving predominantly cerebral white matter is a key finding on imaging studies. although seizures are a frequent presenting symptom of pres, refractory status epilepticus (rse) requiring multiple antiepileptic medications is very rare. a case report of a patient presenting with pres and clinical course complicated with rse necessitating use of intravenous anesthesia, ketamine, and newly-available brivaracetam. -year-old woman with history of congestive heart failure, chronic iron deficiency anemia and uncontrolled hypertension was admitted for severe encephalopathy and convulsive status epilepticus (cse) for longer than minutes necessitating propofol and midazolam infusions. her admission systolic blood pressures were in the s, and mri brain revealed bilateral parieto-occipital t /flair hyperintensities consistent with pres. despite adequate control of hypertension following admission, patient remained encephalopathic and continuous electroencephalography (eeg) demonstrated nonconvulsive status epilepticus (ncse). the patient's ncse continued despite use of maintenance antiepileptics (fosphenytoin, lacosamide, levetiracetam) and high-dose infusions of midazolam and propofol. ketamine infusion was started to maximize nmda receptor blocking properties, and burstsuppression pattern on eeg was easily achieved with bolus infusions followed by continuous infusion. addition of brivaracetam was used to replace levetiracetam and allowed patient to remain seizure-free when iv anesthetics were weaned off. patient required prolonged hospitalization with gastrostomy tube placement and tracheostomy, which was later decannulated prior to patient's discharge to home with family. high index of suspicion is necessary to identify patients in ncse with prolonged encephalopathy that have pres. early use of ketamine along with a benzodiazepine may result in rapid achievement of burstsuppression to treat se. brivaracetam may be a useful agent to treat rse. diagnosis of diabetes insipidus(di) includes polyuria, hypernatremia and low urine specific gravity. we present two patients, receiving hyperosmolar therapy for intracranial hypertension (iht), in whom using low urine specific gravity to diagnose di lead to delayed treatment. this is a retrospective case series. criteria used to diagnose di at our institution include polyuria, sodium < mosm/kg and urine to plasma osmolality ratio < . case : -year-old male with subdural hematoma, iht on hyperosmolar therapy, developed polyuria. sodium rose from to meq/l. urine specific gravity was . excluding di. eventually, sodium rose to meq/l. specific gravity remained . but urine osmolality was mosm/kg and urine/plasma osmolality ratio was . , consistent with di. vasopressin was initiated, however the patient had already developed lactic acidosis and renal failure due to hypovolemia. case : -year-old female with intracerebral hemorrhage and iht on hyperosmolar therapy, developed polyuria. sodium rose to meq/l, specific gravity remained > . but urine osmolality was mosm/kg and urine/plasma osmolality ratio was . consistent with di. vasopressin was initiated. hyperosmolar therapy increases urine osmoles and raises urine specific gravity. this interferes with diagnosis of di which requires low urine specific gravity. while specific gravity measures the weight of particles, osmolality measures particles independent of their weight and thus accurately measures urine tonicity in the presence of heavy particles like mannitol. moreover, urine/plasma osmolality ratio is able to demonstrate relative hyposmolarity of urine when compared to serum assisting with diagnosis of di even when urine specific gravity is elevated. we conclude that urine specific gravity does not reliably detect di in patients receiving hyperosmolar therapy. urine osmolality and urine/plasma osmolality ratio may detect di earlier and prevent dehydration and kidney injury. these findings should be validated prospectively. endovascular intervention in the treatment of cvt(cerebral venous thrombosis) is an alternative strategy when cases deteriorate despite best medical management or develop refractory intracranialhypertension. we present a patient with cvt due to heparin-induced thrombocytopenia(hit), with intraparenchymal hemorrhage(iph) and refractory intracranial-hypertension, who was managed with systemic anticoagulation, continuous intra-sinus infusion of rtpa and mechanical thrombectomy(mt) resulting in excellent outcome. case report: a -year-old woman with left parafalcine meningioma s/p cyberknife was started on subcutaneous heparin for radiation necrosis days prior to admission. she presented to the hospital with new onset headaches and nausea. ct head showed increased edema with mid-line shift around the meningioma, for which steroids were started. within days her headaches worsened and repeat imaging demonstrated right temporal iph. emergent hematoma evacuation was performed. mri brain showed right cerebellar infarct and mra head showed extensive cavernous sinus thromboses, from right internal jugular vein and into sigmoid and transverse venous sinuses. she tested positive for hit and was switched to argatroban drip. patient however continued to deteriorate due to refractory intracranial-hypertension. intra-cavernous rtpa injection and mt was done but the thrombosis was noted to recur on repeat angiogram hrs later. an intra-sinus catheter was left in place for continuous infusion of rtpa at mg/hr. for hrs was done while argatroban drip was continued. the patient's intracranial pressure returned to normal. repeat venogram showed resolution of cvt. patient tolerated the therapies well, without any further hemorrhagic complications. modified rankin score at month follow-up was . this case features successful aggressive endovascular interventions including in-situ rtpa infusion, mt and concomitant systemic anticoagulation for cvt due to hit, complicated by intracranial hemorrhage and refractory intracranial hypertension. the paucity of high quality evidence related to safety, efficacy and modality of endovascular treatment lead to making therapeutic decision on individual basis. acute brain injury may be followed by encephalopathy marked by electroencephalographic features along the ictal-interictal continuum (iic). the use of perfusion imaging to co-localize radiographic features of known malignant eeg patterns may add an important context to guide treatment escalation or de-escalation. this is only the second report in which widely available ct or mr perfusion techniques were favored for this application over more cumbersome metabolic imaging such as pet. retrospective analysis was performed on records for patients admitted to a neurosciences icu, exhibiting encephalopathy, with eeg features on the iic, who underwent perfusion imaging. studies included ct perfusion, mr perfusion, arterial spin labeling, or spect. these studies were obtained for unrelated purposes. escalation or de-escalation of anti-convulsant and sedative medication, hospital course, and patient outcomes were extracted. perfusion imaging data was juxtaposed with eeg patterns along the iic, and patient outcomes are described in narrative form. seven cases were identified. four cases occurred in the context of intraparenchymal hemorrhage, of which one was secondary to meningioma resection. two cases occurred after treatment for subdural hematoma, and one case was related to ischemic stroke. anti-convulsant and sedative management was escalated or de-escalated relative to the presence or absence of radiographic co-localization of hyperperfusion in all but one case. emerging data indicates that some iic eeg patterns may merit aggressive treatment. metabolic signatures of secondary brain injury as measured by cerebro-oximetry or microdialysis have associated these patterns with unfavorable outcomes. we report case studies in which information gleaned from basic perfusion imaging may suffice to distinguish between benign iic patterns and those that should be regarded as near-ictal. the cases hint at novel ways to conceptualize treatment of encephalopathy following acute brain injury and suggest a dimensional shift in thinking towards electroperfusive status epilepticus. sudep has classically been a diagnosis of exclusion. recent studies have shown, however, that similar genes -and even genes within the same family -are associated with sudep and brugada. this suggests that perhaps the cardiac irritability of brugada syndrome exists on a spectrum with epileptic sudden death. a yo man with a history of presumed seizure disorder presented as a transfer from another hospital after being found to have anoxic brain injury following cardiac arrest. he had been shopping with his wife when he was thought to have one of his typical seizures. he was non-responsive for about minutes. on arrival ems found him pulseless. cpr was started en route and continued for minutes in the ed where he was defibrillated three times before achieving rosc. he completed the therapeutic hypothermia protocol. cardiac catheterization was clean. eeg showed diffuse slowing with no epileptiform discharges. imaging showed diffuse anoxic brain injury. after nearly two weeks without clinical improvement he was made comfort care. . of note, previous seizure workup failed to identify epileptiform activity. he was given an aed prescription which he never filled. further chart review showed that he had previously presented to the ed after a "seizure" episode which lasted minutes. his neuroexam was non-focal. ct head was negative. review of his ekg at that time showed type brugada syndrome pattern with an elevated jpoint and t-wave inversions in v and v . his sudden cardiac arrest is most likely a result of symptomatic brugada symptomatic brugada is important to identify early since deaths such as the one discussed above may be prevented by an implanted defibrillator. this case highlights the need for heightened awareness and more effective testing for brugada in the setting of seizure or pseudoseizure. patients with cerebral air embolism (cae) often exhibit more severe symptoms than those typically associated with the number of air emboli and size of infarcts on brain images. however, this discrepancy between symptoms and imaging findings has not been sufficiently explained. we report a case of cae in which disruption of the blood-brain barrier (bbb) and perfusion defects were identified via brain magnetic resonance imaging (mri). a -year old man with a lung mass was admitted to our hospital. percutaneous needle aspiration of the mass was performed in the left lower lobe of the lung. the patient developed sudden confusion and irritability after the procedure. during neurological examination, he could follow only simple commands and exhibited symptoms of left-sided weakness and neglect (medical research council grade ). noncontrast computed tomography (ct) of the brain revealed a few small air emboli in the right frontal subcortical area. multimodal mri of the brain was performed minutes after the onset of symptoms. t -weighted gradient-echo imaging revealed only a few small air emboli in the right frontal area, and diffusion-weighted imaging findings were unremarkable. in contrast, time-to-peak imaging revealed widely distributed perfusion defects in the right hemisphere, while contrast-enhanced t -weighted imaging revealed prominent leptomeningeal enhancement, suggestive of bbb disruption in the right hemisphere. magnetic resonance angiography revealed no steno-occlusive lesions. the patient was treated with % oxygen via a high-flow nasal cannula. his weakness subsided the next day, although his confusion persisted for days. follow-up mri performed five days after the onset of symptoms revealed resolution of the abnormal findings. our findings suggest that disruption of bbb and perfusion defects may develop in patients with cae. extensive impairments of the bbb and perfusion may explain the mismatch between severe neurological symptoms and small air emboli/infarcts. co-existence of cerebral salt wasting and diabetes insipidus is an extremely rare entity that has only been described in adult case series and a paediatric series. due to the complex nature of diagnosing this entity, mistreatment may ensue and lead to high morbidity and mortality rates. we report a case of a patient who was admitted to the neurosurgical intensive care unit after sustaining a subarachnoid haemorrhage secondary to a ruptured anterior communicating artery aneurysm. a -year old lady presented with sudden onset of severe headache and nausea. gcs was (e v m ) with no focal neurological deficits. she underwent endovascular coiling and embolisation of the aneurysm under general anaesthesia and had a left external ventricular drain inserted. in the immediate postoperative period, she was found to be polyuric, with the initial workup suggestive of diabetes insipidus. desmopressin was administered with initial good effect. however, her polyuria recurred and persisted despite desmopressin. the repeat workup revealed the presence of concomitant cerebral saltwasting. she was then treated with fludrocortisone and sodium chloride supplementation. careful monitoring of her serum sodium levels and overall fluid balance allowed close titration of the desmopressin, fludrocortisone and sodium chloride supplementation. she was eventually weaned off treatment and discharged well with normal sodium levels and with no neurological deficits. this case highlights the difficulty encountered in managing concomitant cerebral salt wasting and diabetes insipidus in critically ill neurosurgical patients and the need to for a high index of clinical suspicion, early intervention and close monitoring. levetiracetam is a commonly used antiepileptic drug (aed) used to treat epilepsy. this agent was approved by the fda in , is available in oral and intravenous formulations, and offers advantageous pharmacokinetics, minimal drug interactions, and a favorable side effect profile. the purpose of this case report is to describe a case of severe, asymptomatic rhabdomyolysis exacerbated by levetiracetam administration. the medical record was reviewed and data was collected to describe a case with a pertinent review of the literature. a -year-old african-american male with a history of hypertension presented to the emergency department following a tonic-clonic seizure. baseline labs were drawn and revealed a ck level of , iu/l, negative urine myoglobin and normal renal function. levetiracetam therapy was initiated and no further seizures were noted. the patient's ck continued to trend up throughout his stay despite aggressive fluid resuscitation with a positive myoglobin on hospital day . the ck reached a peak of , iu/l on hospital day . after a literature review and evaluation of his medication list, six casereports were identified linking elevated ck and rhabdomyolysis to levetiracetam administration. at that time levetiracetam was discontinued and the ck rapidly declined to , iu/l on hospital day . the patient never had muscle pain or kidney injury and was discharged on hospital day . this case-report describes rhabdomyolysis associated with levetiracetam administration with a naranjo probability scale score of indicating a probable adverse drug reaction. the adverse effects of generalized pain and neck pain are described in the package insert with an incidence of - %; however, it is not reported that ck levels were monitored. due to the frequent use of this aed and given the rare yet serious adverse effect of rhabdomyolysis, ck levels should be monitored upon initiation. acute toxic leukoencephalopathy (atl) is a potentially reversible disturbance to white matter caused by exposure to toxins. we report the first case of a patient with atl in the setting of a fentanyl overdose and reviewed the literature. a year-old man with a history of opiate abuse was found unconscious, last seen well nine hours prior. he was known to have purchased mg of fentanyl that day. he was intubated and briefly required blood pressure support. he was initially hypoglycemic and suffered fulminant liver damage, acute kidney injury, rhabdomyolysis, and stunned myocardium. comprehensive toxicology screen was positive for cannabis and fentanyl. mri of the brain showed pronounced bilateral restricted diffusion in the high frontoparietal subcortical white matter with radiographic stability five days later. he remained intubated and neurologic exam poor with fluctuating brainstem reflexes and posturing despite improvement in end-organ function. atl has been reported in a -month-old girl and an -year-old man with exposure to transdermal fentanyl, both of whom had favorable outcomes ( , ). one case has been reported following oral oxycodone ingestion ( ). of cases of atl secondary to inhaled heroin, % were fatal ( ). preferential white matter injury has been seen in cases of hypoxic ischemic encephalopathy (hie) ( , ). it was initially thought to be secondary to wallerian degeneration following grey matter damage, but post-mortem pathology has shown direct insult to axons ( ). atl has been reported in one case of hypoglycemic coma ( ) and one case of uremia ( ). it has never been reported in isolated hepatic encephalopathy, secondary to seizure, or with cannabis use alone. based on our review of the literature, the most likely causes of this patient's atl are fentanyl or hie. fentanyl should remain on the differential as a previously unreported cause of atl. autonomic dysregulation is a common complication of acute spinal cord injury (sci). subsequent hypotension may worsen central nervous system injury as well as neurologic and mortality outcomes. to help mitigate this occurrence, consensus guidelines recommend maintaining patients' mean arterial pressure (map) > mmhg within the first seven days based on evidence from limited clinical trials. limited data exists describing the use of midodrine, an alpha- agonist and the previously only available enteral vasopressor, for blood pressure (bp) augmentation in this setting. the use of midodrine is limited by cardiovascular side effects such as bradycardia. droxidopa, a novel enteral precursor of norepinephrine that works independently of the central nervous system, may serve a role in sustaining map in acute sci. we describe a novel case of droxidopa use in a -year old male who sustained a spinal cord contusion secondary to severe stenosis at the fourth cervical vertebrae following a ten-foot fall. droxidopa was used to facilitate vasopressor wean in the setting of neurogenic shock as a complication of acute spinal cord injury. to sustain adequate cns perfusion (map goal > - mmhg) and facilitate patient transfer to a lower level of care, droxidopa mg three times daily was initiated after five days of continuous infusion of intravenous norepinephrine. daily assessments of hemodynamic parameters were performed, including blood pressure, heart rate, map, and an electrocardiogram. successful wean of norepinephrine was achieved within hours of droxidopa initiation, with an average map sustained above mmhg. the patient was transferred to a lower level of care within hours of droxidopa initiation. no cardiovascular side effects were observed. droxidopa was well tolerated and facilitated transition from norepinephrine infusion to an enteral option. droxidopa may be a viable option in stable neurocritical care patients who require vasopressors to sustain adequate cns perfusion. traumatic brain injury is acute and sometimes rapidly aggravated during or after surgical treatment. imaging study is most important and computed tomography (ct) is the golden standard in tbi. however the patient should be transfer to ct room or relatively high cost mobile ct scanner may be used. ultrasound is not expensive and also does not produce radiation exposure. we studied the effectiveness and advantages of intra-operative ultrasound examination in traumatic brain injury patients intra-operative ultrasound was used after decompression of injured brain from june to april . the ultrasound device was the affiniti (philips ultrasound inc, usa) and . mhz transducer was used. the transducer was covered by thin transparent sterilized vinyl with ultrasonic gel with aseptic manner. to protect brain injury by the ultrasonic probe, a saline soaked gauze was applied on the cerebral cortex. the axial images were captured and then stored in pacs system promptly. ultrasound images were compared to postoperative ct scan. there were male and female patients were examined by ultrasound during there surgery. ipsilateral hemisphere, especially cortical layer was slightly distorted to identification. brain stem area was visible in most cases. contralateral hemisphere was seen in unilateral craniotomy and craniectomy cases. in bilateral craniectomy cases, both hemispheres were observed well. parenchymal hemorrhage was also identified and confirmed for removal using ultrasound. in severe brain swelling cases, arachnoid space was seen increased echogenicity. ultrasound image was compared to postoperative ct scan. intra-operative ultrasound is effective in real time inspection of brain during surgery and may helpful detect opposite or parenchymal hemorrhage before closure and leaving operation room. to describe a rare case of a varicella zoster virus (vzv) meningitis with progressive multiple cranial nerve deficits in the absence of cutaneous zoster rash. a young woman with idiopathic thrombocytopenic pupura on steroids presents with horizontal diplopia in the setting of seven days of intractable headache. she had no meningeal signs, fever, leukocytosis or cutaneous rash. within three days into hospitalization, she developed bilateral cn vi, cn iii, right cn v and right cn vii palsies in a progressive fashion. csf analysis revealed cell count of , /mm , a protein of mg/dl and glucose mg/dl. cytology, tuberculosis, bacterial and fungal cultures, ace and hiv testing were negative. vzv-dna was detected in csf in high titers vzv quant: . million. contrasted brain mri revealed mild diffuse leptomeningeal enhancement in the basilar region. she recovered almost all cranial nerve function within days of treatment with acyclovir and high dose steroids. a diagnosis of polyneuritis cranialis with zoster sine herpete (zsh) was made given pcr positive vzv-dna in csf. vzv reactivation with a wide array of neurological deficits can present without rash making diagnosis challenging. zsh should be in the differential for acute cranial nerve deficits as prompt treatment with acyclovir can lead to rapid recovery. stress-induced cardiomyopathy or neurogenic stunned myocardium is a well-documented cardiac complication following aneurysmal subarachnoid hemorrhage (sah). onset is usually immediate, within hours after aneurysm rupture, and is characterized by left ventricular dysfunction with pulmonary edema and elevation in cardiac biomarkers. this can often be mistaken for an acute myocardial infarction or ischemia. the pathogenesis appears to be the result of elevated catecholamine levels following injury leading to myocardial contraction band necrosis and cardiac dysfunction. this syndrome occurs more commonly in patients with severe or "high-grade" sah. we review a case of delayed cardiac dysfunction coinciding with the onset of vasospasm. a -year-old female presented with a h&h , mf sah. she appeared to have lost consciousness prior to arrival and was reporting worst headache of life. she had an evd placed upon arrival with opening pressure at . she underwent endovascular coiling of a ruptured aneurysm of her anterior communicating artery aneurysm. initial echocardiogram demonstrated normal wall motion with ef of %, and minimal troponin i elevation at . ng/ml. on post-bleed day the patient became more somnolent and developed chest pain with an ecg demonstrating st-elevation in all anterolateral leads concerning for acs. she was taken for cardiac catheterization where she had non-obstructive vessels with no vasospasm seen. her ef was reported at - % with apical ballooning present. her repeat echocardiogram also demonstrated a new apical akinesis with ef %, and troponin peaked to ng/ml. her tcds at the time were suggestive of vasospasm with bilateral lr > , but no focal deficit present. it appears that regardless of timeline, stress-induced cardiomyopathy or neurogenic stunned myocardium occurs after sympathetic or catecholamine surge and may occur after the onset of vasospasm in patients with aneurysmal sah. the rapid neurological assessment of critically ill patients with neurologic disease is paramount when determining a course of action. neuromuscular blockade is often used during critical care transport and in the emergency department. unfortunately, this can delay examination and assessment leading to unnecessary testing and procedures. historically, neuromuscular blockade reversal was accomplished using a combination of neostigmine and glycopyrrolate. however, this can lead to incomplete reversal and unwanted side effects from these medications. sugammadex is a cyclodextran injectable compound that has been fda approved in the united states since for rapid reversal of rocuronium induced neuromuscular blockade. sugammadex works by forming a complex with rocuronium and rendering it unable to bind to nicotinic cholinergic receptors at the neuromuscular junction. sugammadex can reverse neuromuscular blockade without the unwanted side effects of cholinesterase inhibitors. this is a case report of the successful use of sugammadex to reverse the effects of neuromuscular blockade in an intracerebral hemorrhage patient. a year old male with a history of atrial fibrillation and a supratherapeutic inr presented via aeromedical ambulance with a ml left frontal intracerebral hermorrhage causing a mm midline shift. he received a mg bolus of rocuronium prior to arrival and had a gcs of upon presenting to the neurosciences icu. a train-of-four revealed / twitches. he was given mg/kg of sugammadex with a return of / twitches within seconds. a more accurate neurological examination was then obtained demonstrating that his brainstem reflexes were intact, he could open his eyes spontaneously and reacted purposefully to painful stimulation. this allowed a non-operative course to be taken. sugammadex can reliably and quickly reverse neuromuscular blockade allowing for the immediate assessment of the neurocritical care patient. it is a useful tool with minimal side effects. piperacillin-tazobactam is commonly deployed as empiric antibiotic therapy. piperacillin-induced hematologic laboratory test abnormalities were rare in pre-marketing studies, and whether these alterations are of clinical significance has been studied little. aberrations in platelet function have not been implicated. in the present case, we discuss a patient presenting with hypertensive intracerebral hemorrhage (ich) who sustained two additional hemorrhages in distinct locations after routine removal of intracranial monitors and an external ventricular drain (evd). these significant bleeding events occurred exclusively during piperacillin-tazobactam therapy and were correlated with new abnormalities in the patient's platelet function assay (pfa) results. a -year old vietnamese male with hypertension presented for treatment of a left basal ganglia ich. epinephrine/collagen and adenosine diphosphate/collagen pfas at the time of evd and quad-lumen bolt placement were normal, and imaging showed no hemorrhage after placement. hospital course was complicated by aspiration pneumonia requiring empiric piperacillin-tazobactam administration. after removal of the quad-lumen bolt and evd on separate days, both follow-up ct scans showed new hematomas in the devices' tracts, with significant intraventricular hemorrhage. repeat pfas were abnormally prolonged, representing a distinct change from baseline. a trend toward normalization of pfas was observed after discontinuation of piperacillin-tazobactam with progression toward baseline thereafter. the present case is unique in that the significant bleeding that occurred was attributable to objectively confirmed platelet dysfunction rather than thrombocytopenia. other possible innate causes of bleeding were less likely as the patient demonstrated normal platelet count, von willebrand multimers, platelet morphology, and clotting factors. this is the first reported case of intracranial (periprocedural) hemorrhage potentially related to piperacillin-tazobactam; further research into this drug's impact upon qualitative platelet function is needed. the life-saving potential of extracorporeal membrane oxygenation (ecmo) has been well recognized since the s. modern advancements of research and technology have allowed ecmo to be accepted as a dependable intervention for patients with severe pulmonary or cardiac failure. however, with increased use, associated complications that detract from the benefit of ecmo are surfacing as well. this case report describes a case of diffuse intracerebral hemorrhage (ich) after prolonged ecmo resulting in cerebral edema, mass effect, and eventual brain herniation. the patient is a previously healthy year old female who presented with fever, chills, and myalgia. when evaluated at urgent care, she was noted to be hypoxic and was sent to an outside hospital where her monospot test was positive. upon arrival, the patient was placed on venovenous ecmo (vv-ecmo) due to severe hypoxia. she was also in acute renal failure requiring continuous renal replacement therapy (crrt). she had an episode of hypotension with bradycardia. subsequently, her pupils were noted to be fixed and dilated. a stat ct head then showed diffuse bilateral hemorrhages at the graywhite junction as well as diffuse edema. labs showed thrombocytopenia likely due to disseminated intravascular coagulation (dic). her exam was consistent with brain death. it has been estimated that up to % of patients who were placed on ecmo as a last resort for respiratory failure have neurological complications including ich. there is no stereotypical pattern of bleeding but diffuse hemorrhage has been seen, which is consistent with the pattern seen in our patient. notably, those with ich have significantly higher rates of mortality. thrombocytopenia, dic, and platelet dysfunction that develop as a result of ecmo are thought to play a role in the development of ich. to present a case report of syndrome of the trepheined (sot) and paradoxical herniation without craniectomy. sot is reported when a constellation of positional neurological symptoms arise following large craniectomy, resolving in a delayed fashion following cranioplasty. paradoxical herniation may occur in extreme cases.the pathophysiology is incompletely understood however proposed mechanisms include compression of underlying brain by the flaccid skin flap due to the gradient between atmospheric and intracranial pressure exacerbated by upright pressure, changes in cerebral blood flow, and csf fluid. a middle aged woman with a history of mood changes eight months preceding admission presents with worsening left hemiplegia over one week. mri revealed a x mm right frontal cystic mass. hyperosmolar therapy and steroids were initiated for midline shift and brainstem compression. her immediate post operative course after tumour excision was uncomplicated. on post-operative day two, she developed uncontrolled hypertension, worsening anisocoria, and decerebrate posturing requiring urgent intubation. head ct revealed uncal and subfalcine herniation despite a large resection cavity. an external ventricular drain was placed and removed due to lack of drainage. within hours of trendelenburg positioning, she improved both clinically and radiographically. she did not undergo an intraoperative csf reduction and no preadmission history (back pain, orthostatic headache, trauma) to support an occult csf leak. she had a recurrence of symptoms on post-operative day eight which also resolved upon lying flat for hours. she was ultimately discharged to acute rehab and tumor pathology returned as glioblastoma (who grade ). this novel case of sot in the absence of craniectomy demonstrates the complex and poorly understood consequences of slow growing massive tumors, csf dynamics and exertional force on static cns structures. this case also illustrates the benefits of a collaborative, multidisciplinary approach to patient care in the neuroicu. to present a lesser known leukoencephalopathy that occurs when patients overdose on inhaled heroin vapor 'chasing the dragon" is a method of inhaled heroin vapor that is different from smoking or snorting heroin. heroin powder is placed on aluminum foil, which is heated by placing a flame underneath. the white powder turns into a reddish-brown gelatinous substance that releases a thick, white smoke, which resembles a dragon's tail. the fumes are "chased" or inhaled through a straw or small tube. currently the us is facing a growing epidemic of heroin use making this leukoencephalopathy more pronounced. a -year-old female with history of drug abuse presented to the emergency department with altered mental status. the boyfriend informed staff that she likely smoked heroin. on arrival, she was drowsy but easily arousable. her brainstem reflexes were intact but she was grossly dysmetric. urine drug screen was positive for opiates only. initial ct of the brain demonstrated extensive loss of gray-white differentiation within the cerebellar hemispheres and bilateral lucency in the globus pallidus and developing hydrocephalus. patient was placed in the neurointensive care unit to monitor and was managed medically with hypertonic therapy to combat her cerebral edema. an mri was done which demonstrated a distinctive pattern of symmetrical white matter t hyperintensities in the cerebellum, hippocampus and internal capsule bilaterally characteristically known as "chasing the dragon" sign. the patient gradually improved with supportive treatment, but continued to have mild ataxia upon discharge. we present a case of leukoencephalopathy that was generally rare to see, but now that heroin use is now at a year high within the us, this phenomenon may become more prominent. heroin inhalation leukoencephalopathy should be suspected in all patients with a history of chasing the dragon when they present with neurological abnormalities. the use of intra-venous (iv) thrombolysis for the treatment of acute ischemic stroke is now the standard of care. this is typically followed by endovascular thrombectomy if patient is eligible does not improve . we present a rare acute ischemic posterior circulation stroke that had progression of the stroke despite receiving both intra-venous thrombolysis and endovascular thrombectomy. case report: a years old african-american gentleman with past history of obesity, sleep apnea and prostatic hyperplasia, presented with acute onset left hemiparesis, with limb ataxia, who then progressed to altered sensorium in the emergency room needing endotracheal intubation. his initial nihss was . he was given iv thrombolysis, with subsequent vascular imaging that showed a top of the basilar clot, that was removed via endovascular intervention. a sister and one of the aunts reported a history of 'clots' when asked about family history. despite initial improvement, the patient deteriorated clinically after about hours from symptom onset, and was found to have extension of stroke into the brainstem, with simultaneous acute loss of brainstem reflexes . the patient was started on palliative withdrawal of care by the family about days from the initial onset of symptoms. his thrombophilia work-up revealed later that he was homozygous for methylenetetrahydrofolate reductase (mthfr) gene mutation, c >t. this case with a poor outcome due to extension of the ischemic stroke despite receiving the standard of care therapy, highlights the need for considering the use of anticoagulation within hours postthrombolysis and thrombectomy in cases with underlying thrombophilia. the current guidelines do not support this aggressive approach. there is a dire need for randomized controlled trial about such cases to provide evidence based care to avoid a repetition of a similar poor outcome. barbiturate therapy has shown benefit in reducing intracranial pressure (icp) in patients who are refractory to other treatment modalities. however, severe adverse drug effects can accompany barbiturate use when used at the high doses required for icp management, such as hypotension, hepatic/renal dysfunction, and infection, among other deleterious consequences. dyskalemia has been reported infrequently in the literature with most of the cases involving patients on thiopental. there remains little guidance for management of this adverse effect. we present a case of severe dyskalemia induced by high-dose pentobarbital therapy and experience with management of this rare but life threatening effect. the patient was a -year-old male with traumatic brain injury and subdural hematomas complicated by refractory icp elevations. after hyperosmolar therapy, sedation, and csf drainage failed to control icp, and he was deemed to not be a candidate for surgical decompression, high-dose pentobarbital was started. after initiation of pentobarbital, his initial potassium of . mmol/l decreased to a nadir of . mmol/l over the next hours despite aggressive repletion with a total of meq of oral and intravenous potassium chloride. upon down-titration and discontinuation of pentobarbital, the serum potassium rapidly rebounded to . mmol/l with st-segment elevations on ekg. pentobarbital was restarted in an attempt to stabilize escalating icps and elevated serum potassium. subsequently a slow taper was utilized to mitigate dyskalemia during barbiturate discontinuation. dyskalemia associated with high-dose barbiturate therapy presents a significant dilemma to practitioners as both severe hypo-and hyperkalemia can be life threatening. published literature provides little guidance on how to safely manage patients who experience this adverse effect. patients receiving barbiturate therapy should have frequent potassium monitoring especially in the initiation and discontinuation phases. potassium repletion should be approached with caution, especially preceding discontinuation of barbiturate therapy. diffuse astrocytoma (formerly known as 'gliomatosis cerebri') may present with seizures or symptomatic raised intra-cranial pressure. this is typically followed by a few months of relatively stable phase (with treatment) and then possible subsequent development of glioblastoma multiforme. we present a rare case of a previously healthy caucasian lady who had new onset seizures, that showed glioblastoma multiforme already present on a background of diffuse astrocytoma. case report: a years old caucasian lady with no significant past medical history was admitted with new onset focal seizures with secondary generalization, needing intubation and propofol for airway protection. brain imaging showed left frontal ring-enhancing mass, with a smaller satellite lesion in the left insular cortex, on a background of diffuse infiltrative lesion involving left fronto-temporal lobe and a smaller area of right parafalcine frontal lobe. biopsy of the left frontal mass revealed it to be glioblastoma multiforme. this is a rare situation when a previously healthy patient presents with new onset seizures and already has glioblastoma multiforme on a background of diffuse astrocytoma (or 'gliomatosis cerebri'). her post operative imaging revealed disease progression with increase in the size of the left insular cortical lesion. she was discharged home with plan for radiotherapy and chemotherapy. diffuse astrocytoma with glioblastoma multiforme within can remain asymptomatic till late in the disease course. diffuse astrocytoma (or 'gliomatosis cerebri') is a rare disease and even more rare is to have this remain asymptomatic till the development of glioblastoma multiforme within. this particular case highlights the need for vigilance about such a possibility, as this aggressive brain tumor carries a grave prognosis, especially when it develops on background of a diffuse astrocytoma. subdural hygromas (sdg) are cerebral spinal fluid collections in the subdural space that may occur following trauma. decompressive craniotomy may increase the risk for acute sdg or other forms of external hydrocephalus along the surgical plane. while these are traditionally benign and resolve spontaneously, they may in rare cases cause clinical deterioration. we report three cases. cases and were alcoholic men aged and , respectively, who suffered severe traumatic brain injury (tbi) following falls while intoxicated. they had early clinical deterioration prompting emergent hemicraniectomy for left-sided sdh with midline shift (mls). case clinically worsened on postoperative day (pod) with posturing, decreased pupillary responses, and new-onset seizures. new bilateral, extensive subdural hygromas were noted, enlarging over serial ct scans up to -cm with progressive mass effect. uncal herniation and downward brainstem displacement occurred by pod despite external ventricular drainage. case deteriorated on pod with fluctuating exam and newonset seizures. imaging revealed new subgaleal fluid collection measuring . -cm and a contralateral sdg. on pod , hemicraniectomy was performed for new mls from enlarging fluid and hemorrhage in extradural component. both died shortly after withdrawal-of-care. case was a year-old man with dural arteriovenous fistula who presented with spontaneous left-sided sdh and underwent left hemicraniectomy. on pod , he had new-onset seizures and new bilateral sdg measuring . -cm on the left and . -cm on the right without mass effect. two days later; the right sdg grew to . -cm causing significant mass effect. he recovered after burr-hole evacuation and temporary subdural drain placement. sdg following sdh evacuation can have a malignant course, causing clinical deterioration without prompt recognition and csf diversion. all patients had large volume sdh and two were alcoholic; larger prospective cohorts are required to identify risk factors. seizures may be an early clinical sign. moyamoya disease is an intracranial vasculopathy that results in stenosis of bilateral internal carotid arteries with subsequent development of extensive collateralization. the diagnostic criteria for moyamoya disease are well established and generally accepted, yet reaching the diagnosis can be challenging in some cases. herein, we present an unusual case of progressive cerebral vasospasm triggered by pituitary apoplexy that led to a delay in the underlying diagnosis of moyamoya disease. case report. a -year-old female with hyperlipidemia presented to the emergency department with a bifrontal headache, right-sided weakness, and dysarthria. ct angiogram showed extensive multifocal narrowing of the bilateral supraclinoid icas, proximal aca/mcas, and posterior circulation. mri brain revealed a left insular stroke as well as a sellar mass with a central hemorrhagic component. mr perfusion demonstrated decreased perfusion in the right hemisphere. lumbar puncture and extensive vasculitic workup was unremarkable. endocrine studies were notable for elevated prolactin with low fsh and lh levels. despite protracted blood pressure augmentation strategies, the patient continued to experience progressive infarcts in the left mca/aca territory. repeat ct angiogram showed progression of vasculopathy, and transcranial doppler studies demonstrated worsening vasospasm of the right mca and left pca arteries. the patient received corticosteroids given concern for apoplexy, and was maintained on aspirin and verapamil. given the aggressive nature of her vasculopathy, the patient underwent conventional angiography two weeks later, which revealed bilateral suzuki grade iii moyamoya. following this diagnosis, she received bilateral sta-mca bypass surgeries. it is important to revisit the differential diagnosis of cerebral vasospasm when the clinical course does not conform to expectations. this case highlights moyamoya as the causative agent in progressive vasculopathy likely masqueraded by pituitary apoplexy and concomitant vasospasm. moyamoya is an important diagnosis to consider in patients with a fulminant vasculopathy refractory to traditional treatment of vasospasm. visualization of intracranial structures by ultrasound in adults is limited by the presence of skull, though ultrasound imaging can occur through temporal windows. point of care ultrasound allows assessment of midline shift, brainstem, and ventricles. doppler allows visualization of cerebral perfusion patterns. patients with a hemicraniectomy have better temporal windows available since a portion of their skull has been removed. in such patients, ultrasound can provide a non-invasive method to serially assess midline shift, intracranial hematomas, and focal ischemia at the bedside. we present images of a cranial ultrasound that shows remarkable anatomical details that correlate well with computed tomography (ct) head. a year-old male presented with right-sided weakness and confusion and was found to have a left parietal intraparenchymal hemorrhage with cerebral edema and left-to-right midline shift on ct head. increase in cerebral edema and expansion of the hematoma caused clinical neurological decline necessitating a left-sided hemicraniectomy with clot evacuation. a cranial ultrasound was performed two days after surgery to assess for progression of cerebral edema and intracranial hemorrhage. a transtemporal approach in axial plane was used to visualize intracranial structures through the craniectomy window. physiological structures like the falx cerebri, lateral ventricles, midbrain, mammillary bodies, choroid plexus, splenium of corpus callosum, thalami, and circle of willis were visualized with incredible anatomical detail. pathology such as intracranial hemorrhage, focal ischemic areas, vasogenic edema as well as encephalomalacia were identified with close correlation to the noncontrast head ct. the patient is currently recovering in the neurocritical care unit with supportive care. cranial ultrasound has potential applications in point of care assessment of intracranial pathology in neurocritical care patients. this application has promising use in directing therapy in patients who are otherwise unstable for transport or are unable to undergo neuroimaging secondary to positioning needed for management of cerebral edema. cerebral mucormycosis is a rare infection caused by fungi found in soil and decaying vegetation. the rhino-orbital-cerebral type is classically associated with aids, diabetes, malignancy and immunosuppression. we observed a series of young immunocompetent patients who presented with a fulminant form of isolated cerebral mucor associated with severe meningoencephalitis, parenchymal necrosis and symptomatic cerebral edema. six patients with histopathological diagnosis of cns mucormycosis admitted to the university of cincinnati neurocritical care unit between and are presented. patient ages ranged from - (median ). none had diabetes or hiv. drug use (intravenous and intranasal) was confirmed in patients. they presented with altered mental status ( ) and focal neurologic deficits ( ). four patients presented with fever and leukocytosis. mri revealed lesions in the basal ganglia ( ) or cerebellum ( ) which were characterized by t hyperintensities with patchy restriction and susceptibility signal. contrast enhancement was present in patients. mass effect ( ) and midline shift ( ) were prominent. mechanical ventilation was required in four patients. all but one patient received amphotericin b. three died from intractable intracranial pressure (icp). one patient eventually gained functional independence, one still requires high level of care, and one was lost to follow-up. csf analysis was negative for mucor in all cases. fulminant cerebral mucormycosis should be considered in every young patient presenting with rapid onset meningo-encephalitis and necrotized cerebral lesions, especially if located in the basal ganglia. history of ivdu should raise further suspicion. these patients should be monitored in intensive care settings as they can rapidly develop malignant cerebral edema and increased icp. antifungal therapy should be initiated upon presentation as it has been shown to improve morbidity and mortality. the incidence of acute ischemic stroke in the immediate post-partum period ranges between - % and is considered a serious cause of morbidity and mortality. pregnant or postpartum women are less likely to receive iv tissue plasminogen activator (tpa) primarily because of pregnancy, ongoing peripartum bleeding and/or recent delivery. the fda classifies tpa as a category c drug and current recommendations consider pregnancy a relative contraindication for receiving tpa. we present two cases of peripartum ischemic strokes with varying ischemic stroke time windows requiring aggressive revascularization therapy (endovascular and pharmacologic). a y g p presented to an outside hospital days post-partum with new onset of facial droop and left upper extremity weakness (nihss ). imaging showed right m cutoff and occlusion of several m branches. the patient was not a candidate for tpa given ongoing vaginal bleeding. the decision was made to proceed with mechanical thrombectomy when her exam worsened to nihss . the thrombectomy was successful with tici c reperfusion. she was discharged home days later with a nihss of zero. a y g p presented days post-partum with new onset of left facial droop and slurred speech (nihss ). imaging showed right m cutoff with reconstitution, but with significant associated penumbra. acute worsening of exam post tpa triggered a push for mechanical thrombectomy achieving a tici recanalization. post procedure the patient's only symptom was decreased sensation in left fingertips. at -day follow up the patient had returned to her baseline with a nihss of zero. endovascular and pharmacologic revascularization therapy should be considered on an individual basis in the peripartum population. current literature is limited to case reports /case series. larger multicenter trials are warranted and anticipated in the near future. while the optimal duration of burst suppression for status epilepticus (se) has not been established, burst suppression poses significant morbidity that may be dependent on the amount of time spent in burst suppression. herein, we report a case of se that resolved after ultra-short burst suppression. case report. a year-old female was admitted to the neuro-intensive care unit after experiencing several brief tonic-clonic seizures characterized by right-sided shaking and left-sided head turn. despite lorazepam and levetiracetam administration, the patient did not return to baseline and was transferred to our unit. on presentation, her workup revealed a leukocytosis and a glucose level > mg/dl. lumbar puncture showed a mild pleocytosis for which broad spectrum antibiotics were initiated. on initial examination, she was unresponsive and was not following commands. electroencephalogram (eeg) demonstrated frequent sharp and slow discharges in the right posterior quadrant with generalization (~ seizures/hour) with minimal improvement following levetiracetam and phenytoin administration. given the refractory nature of seizures, the patient was intubated and treated with general anesthetics. using propofol, burst suppression was achieved (consisting of - s bursts with intermixed suppressions) and was continued for < hours. following weaning, the patient had no further evidence of seizures, and eeg showed lateralized periodic discharges in the right occipital lobe. mri did not demonstrate an occipital focus, but did reveal cortical diffusion restriction in the bilateral posterior hemispheres. the patient was extubated the following morning, and was transferred to the neurology floor two days later. this case provides evidence that in certain situations, relatively brief periods of burst suppression in se can serve as a "reset switch", allowing for resolution of seizures while minimizing toxicities associated with prolonged burst suppression. further studies to determine which patients may benefit from ultrashort burst suppression are warranted. there are two systems of facial control, voluntary and emotional; these are independent up to the level of the facial nucleus. we described a case of a patient who presented with isolated emotional facial palsy after intracerebral hemorrhage (ich). retrospective review of a case admitted to the neurocritical care unit (nccu) of the johns hopkins hospital. a year-old woman with history of migraines who presented to the emergency room after a colleague noticed she was not moving the left lower side of her face when she smiled. head ct showed a large right frontal ich involving the medial frontal lobes and anterior thalami. on review of an old mri done, an underlying developmental venous anomaly with an associated cavernoma was seen. her exam was notable for a flattened emotional affect, no facial palsy when asked to activate on command, but a facial droop that occurred in the context of her smiling to jokes and other humor. her nccu course was complicated with significant brain edema requiring osmotherapy up to weeks out from the initial insult with self-limited episodes of brain herniation characterized by extensor posturing, dilated pupils, hypertension, hyperventilation and tachycardia. these were initially dismissed as sympathetic storming vs seizures as she will come out of those to her baseline (awake with mild left sided weakness) many times without therapy. she eventually required a hemicraniectomy two weeks after presentation. conclusions solated emotional facial palsy can be the presenting sign after ich when the hemorrhage involves the contralateral thalamus, of the striato-capsular region or the medial frontal lobes. in this case, transient icp elevations were leading to dilated pupils, tachycardia and hypertension -highlighting that heart rate changes can be variable with elevated icps and that in young patients, brain herniation episodes can be self-resolved with hyperventilation. yo female with no pmh developed fever, headache, and neck pain. she presented to outside hospital day after ct head was negative, patient was discharged. symptoms did not improve and she went to her pcp on day and was instructed to go to the ed. she presented to osh and underwent a lp that was indicative of viral meningitis with wbc cells/mm and protein mg/dl. patient admitted and treated with acyclovir. on day , she developed generalized body aches. on day , she was trying to stand with assistance and she became rigid. parents report a total of seizures and was intubated for airway protection. she underwent another lp on day with an opening pressure of cm h o. csf was sent for paraneoplastic panel. csf analyses and blood cultures were negative. evd placed for icp pressures of - cm h o. history obtained from mother and father who reported the patient had been hiking weeks prior. results mri brain showed meningeal enhancement scattered throughout the supratentorial and infratentorial brain and most compatible with inflammatory sequela of meningitis. patient continued on keppra, high dose steroids, antibiotic, antiviral, antifungal therapy until cultures resulted. additional treatments included ivig therapy followed by plasmapheresis, and finally rituximab. continued workup with brain biopsy showed demyelinating process and possible necrotizing encephalitis. mri four weeks after initial presentation showed white matter demyelination and deep gray nuclei lesions consistent with adem. four score of on admission improved to (e , m , b , r ) weeks after patient presented from osh. diagnosis of adem vs ms variant made based on the above data. case provides information for the clinician diagnosing and treating adem. potential for further studies with treatments described above and their effect on meaningful neurological outcomes. dengue is a flaviviruses transmitted via mosquitos and prevalent in south east asia. neurological complications are rare but can involve encephalitis, myelitis, neuromuscular dysfunction and neuroophthalmological problems. we describe an interesting case of dengue encephalomyelitis. retrospective review of a case admitted to the neurocritical care unit (nccu) of the johns hopkins hospital a year-old ship filipino captain with no significant past medical history but an extensive exposure to heavy metals, travel throughout the pacific, who presented with progressively worsening fevers, encephalopathy, urinary retention and tremors. he was transporting iron ore and other metals in a cargo ship from russia through south-east asia through to bermuda. while passing through the pacific, he began to experience malaise, myalgia, and fever. he was treated with amoxicillin but became worse, developing urinary retention, periods of confusion, and word finding difficulties. he was initially hospitalized in bermuda and then transferred to our hospital for further workup. given his rapid deterioration, he was initially in the nccu. his exam was notable for mild expressive aphasia, paratonias, right-sided weakness with hyper-reflexia, and a low amplitude tremor. his csf was notable for lymphocytic pleocytosis, elevated protein, low glucose. mri brain showed flair hyper-intensities in the frontal lobes, and diffusion restrictions in the bilateral basal ganglia and thalami. mri spine showed extensive flair hyper-intensity lesions. an extensive workup evaluated for heavy metal toxicities, autoimmune disorders and infectious workup. csf analysis came back positive for dengue igg and igm, leading to a diagnosis of acute dengue fever and encephalomyelitis. with supportive care in the nccu, he improved considerably over - weeks and was discharged home to the philippines. dengue encephalomyelitis is a rare infection but should be considered in patients living in endemic areas. treatment includes supportive care with fluid resuscitation, neurological monitoring and monitoring for hemorrhage. posterior reversible encephalopathy syndrome (pres) is known to cause altered mental status and leukoencephalopathy in the setting hypertensive emergency. we present a novel case of severely asymmetric pres due to a concurrent right transverse sinus dural arteriovenous fistula (davf). a year-old woman with hypertension, non-compliant on medication, had fatigue and weeks of intermittent left sided weakness when she presented to an outside hospital for evaluation. initially upon arrival her glascow coma scale (gcs) was . her mental status deteriorated over hours, eventually requiring intubation. her peak blood pressure was / . outside ct demonstrated scattered intracerebral hemorrhage (ich) and she was transferred for higher level of care. on admission her gcs was . review of her outside ct was remarkable for extreme right-sided white matter hypodensity, moderate left white matter hypodensity, and small scattered ich. workup including infectious, inflammatory, and neoplastic processes were excluded through serum, csf studies, and mri. conventional angiogram demonstrated a right transverse sinus davf with reflux into cortical veins, which was subsequently embolized. her white matter t -weighted hyperintensities improved on follow-up mri, and her gcs was at the time of discharge. our case highlights the possibility of asymmetric pres due to abnormal venous congestion due to the right-sided davf. venous hypertension likely caused the patient's intermittent left sided symptoms in the weeks prior to admission. few cases of unilateral or asymmetric pres have been reported following induced hypertension for treatment of subarachnoid hemorrhage or in the setting of vascular malformation. to our knowledge, this is the only case of severely asymmetric pres and preceding stroke like symptoms due to a davf. the most common pathology associated with an intraluminal carotid thrombus is underlying atherosclerosis. in rare cases it may be associated to thrombocytosis. currently there are no clear recommendations for the treatment of ischemic stroke associated with thrombocytosis. our case describes the use of plateletpheresis for the acute management of thrombocytosis complicated by an internal carotid artery thrombus resulting in a right mca stroke. a -year-old female with past medical history of menorrhagia who presented complaining of left face, arm and leg weakness with associated shortness of breath. upon arrival her nihss was and the initial head ct was unremarkable. laboratory results revealed a hemoglobin . mg/dl, hematocrit mg/dl, and platelet count of x /ml. she was not a candidate for thrombolytic therapy due to the time window. soon after admission she had acute worsening of symptoms with an nihss of . a cta of the head and neck showed acute ischemic infarction involving the right mca territory with non-occlusive intraluminal thrombus within the right carotid bulb. asa mg and heparin infusion were initiated promptly. after a thorough work-up for thrombocytosis, reactive thrombocytosis secondary to iron deficiency anemia was diagnosed. plateletpheresis as well as oral ferrous sulfate were started. after one plateletpheresis cycle the platelet count stabilized at x /ml. complete thrombus resolution was confirmed on follow-up cta on day of admission without need for surgical revascularization. the role for plateletpheresis is not well established in secondary thrombocytosis. in cases with extreme thrombocytosis immediate surgical thrombectomy may be contraindicated due to high risk of rethrombosis. urgent cytoreduction with correction of the putative mechanism for thromboyctosis should be undertaken for optimal management. plateletpheresis is safe and efficient in reducing the platelet count to decrease the risk of clot progression or further clot formations which could worsen patient outcome. hyperpyrexia is an elevated core body temperature secondary to an elevated hypothalamic set temperature. hyperthermia is an elevated core body temperature beyond the normal hypothalamic set temperature. intracranial hypotension can present with a wide variety of symptoms ranging from orthostatic headache up to coma. it has never been reported to present with fever, namely hyperpyrexia. a case report of a year old female patient with a history of depression, diabetes mellitus, hypertension, and angiogram negative subarachnoid hemorrhage status post ventriculo-peritoneal (vp) shunt placement six years ago who was complaining of worsening headaches and slurred speech for the past three months but acutely decompensated one morning. she suddenly became confused and agitated but became obtunded. initially, she was given haldol. she was found to be febrile (rectal temperature of . f). she was given dantrolene and bromocriptine for suspected malignant neuroleptic syndrome with no effect. creatine phospho-kinase was not elevated. she underwent infectious work up which later came negative. cooling measures like external cooling, peripheral iv cooling, tylenol and nsaids were also not helpful. fever responded to central intravascular cooling but encephalopathy did not. several expert attempts of lp and shunt tapping failed to obtain csf. brain imaging showed bilateral chronic symmetrical hygromas, diffuse pachy-meningeal thickening and enhancement, slit-like ventricles and slumping of the midbrain with closure of the mammillary pontine distance. following shunt setting adjustment, the encephalopathy markedly improved and the fever did not recur after stopping the cooling measures and antimicrobials. intracranial hypotension might present with hyperpyrexia, likely secondary to hypothalamic dysfunction. in our case, hyperpyrexia was reversible as the intracranial hypotension was emergently treated. nevertheless, spontaneous intracranial hypotension might be difficult to diagnose especially if it presented with non-classical symptoms like fever. complex emotions about critical illness can affect families in the icu. rightfully, we put focus on how they are impacted, but we also need to pay attention to how it can affect providers and our decision making. a poignant case from my training was a -year-old girl struggling with lupus. she had now developed lupus cerebritis and had massive intracranial hemorrhages. despite aggressive efforts to manage cerebral edema, she repeatedly herniated brain matter out of old craniotomy scars with incredible force. it was the most horrifying thing i've ever seen. other organs were also failing, with four consulting services working to salvage them unsuccessfully, prompting numerous procedures. this went on for a month. the therapies that we can offer have limits from a physiological standpoint which we must recognize and respect. we struggle with reconciling the interventions we feel compelled to implement versus what is realistic. i remembered the most valuable advice that i once received: "only do something to someone if it does the complexity of the neuro icu is amplified by the nature of intracranial catastrophes and poor recovery (in contrast to pure medical illness). providers cling to what is technically indicated while families cling to hope, but neither is enough and concurrently too much. we lose our autonomy to grieving families telling us to "do everything" losing sight of the bigger picture. we lose our autonomy to one another by pushing onwards, which can unintentionally push each other into the territory of doing more harm than good. something for them". all services began to share this view, thus slowly dialysis, steroids and immunosuppression stopped. eventually, her heart stopped. my experiences have reiterated a simple paradigm: to do no harm. through this, i can empower myself to take control of each situation by first taking control of myself. we report a case of an hiv positive patient who presented with cryptococcus gattii meningitis who then developed acute respiratory distress syndrome (ards) secondary to pneumocystis jirovecii pneumonia (pjp) that required ecmo support. ards in immunocompromised hiv positive patients is associated with extremely high mortality. ecmo can improve oxygenation in patients without increasing alveolar pressure and therefore avoid mechanical lung damage with ventilation. we present a patient with newly diagnosed aids with cryptococcus gattii meningitis and course complicated by pjp that progressed to severe acute respiratory distress syndrome (ards) for which veno-venous ecmo was initiated. patient is a year old male who presented to the emergency department with new onset seizures. lumbar puncture in the ed overflowed the manometer and demonstrated wbc , rbc , protein , glucose , positive yeast gram stain positive for yeast with pcr and ag positive. his cultures later grew out cryptoccoccus gattii. he was admitted to the nsicu and we placed a lumbar drain and an intraparenchymal ipc monitor that demonstrated elevated icps to the - mmh but improved with drainage. the day of admission he acutely desaturated and required emergent endotracheal intubation. chest x-ray demonstrated bilateral infiltrates. bal was positive for pj. five days following presentation and respiratory failure he was started on veno-venous ecmo. two days following initiation of pjp treatment with bactrim his chest x-rays and lung compliance began to improve. he remained on ecmo for a total of days before decannulation. he underwent induction chemotherapy for four weeks for meningitis. this case report demonstrates the use of ecmo in a complicated and critically ill patient with aids, pjp, and cryptoccous gattii meningitis. to our knowledge, few cases of ards secondary to pjp are reported and none are reported with concurrent cryptococcus gattii infection. sympathetic storming occurs during the acute care of patients following severe brain injury. cannabinoid cb receptors (cb r) mediate the effects of delta( )-tetrahydrocannabinol (thc), the psychoactive component in marijuana. expression of cb r is widespread in the central nervous system and includes the hypothalamus, which is thought to mediate the hypothermic inducing effects of cannabinoids. dronabinol is a synthetic analogue of thc we present a novel therapeutic use of cannabinoids in a case of super-refractory sympathetic storming following coccidioidal meningitis and extensive bilateral subcortical stroke a -year-old previously healthy man was transferred from an outside hospital for treatment of meningitis, vasculitis, and hydrocephalus requiring placement of a ventriculostomy. workup subsequently revealed coccidioidal meningitis. during hospitalization the patient had severe vasospasm, elevated intracranial pressure, diabetes insipidus, cerebral salt wasting, and severe sympathetic storming. intermittent storming episodes with high fever persisted for over weeks despite treatment with bromocriptine, dantrolene, tylenol, ibuprofen, phenobarbital, and sinemet. due to its mechanism of action, a trial of dronabinol mg divided twice daily was tried. the storming episodes ceased and within hours the average temperature decreased by about . degree centigrade. temperature over the next several days was better controlled with a substantial reduction in use of anti-pyretics, surface cooling measures, and other storming medications our case highlights a novel therapeutic use of cannabinoids in super-refractory sympathetic storming related to brain injury. dronabinol may be an alternative pharmacotherapy with unique mechanism of action in difficult to control sympathetic storming patients with poor grade subarachnoid hemorrhage(sah) commonly present with significant mental status changes that preclude reliance on neurologic exam for screening for neurologic deterioration. jugular venous oximetry monitoring has been suggested for use in guidance of hyperventilation therapy, barbiturate coma, and vasospasm monitoring. no studies are found in literature validating its use in sah. milrinone has been using for the treatment of vasospasm in sah in an established protocol in the montreal neurological hospital. this study was performed using multiple methods of monitoring, but not jugular bulb oximetry. we report one case with high grade subarachnoid hemorrhage complicated by vasospasm treated with milrinone using jugular bulb monitoring for dose titration. methods years old female presented with thunderclap headache and subsequently became comatose. noncontrast head computer tomography showed posterior fossa subarachnoid blood. she was intubated, external ventricular drain (evd) was placed and she was admitted to neurosurgical intensive care unit (nsicu). angiogram showed left posterior inferior cerebellar artery aneurysm and was successfully coiled. her hospital course was complicated by refractory symptomatic vasospasm. angiogram showed basilar artery vasospasm treated with intra-arterial verapamil. post procedure patient was not able to tolerate norepinephrine due to tachycardia and could not maintain hypertension on phenylephrine. milrinone was then started. jugular bulb catheter was place because the area at risk was not amenable to invasive multimodality monitoring. oximetry was monitored and her milrinone rate was titrated to goal of venous oximetry in the range of - %. on day , angiogram showed no more evidence of vasospasm. her exam was back to her prior poor baseline. subsequently, she was discharged to long term care facility. our case demonstrates the benefit of using jugular venous oximetry monitoring guidance for milrinone dose titration. further, it may be an effective tool is research studying treatments of cerebral vasospasm repetitive transcranial magnetic stimulation (rtms) is increasingly used in treatment of various conditions including depression, chronic pain, and movement disorders. the use of rtms for chronic management of medically refractory epilepsy has grown substantially in the last years. however, little literature exists on use of rtms for acute status epilepticus. the exact antiepileptic mechanism of rtms remains unclear, but may be secondary to inhibition of cortical excitability. we report promising response to rtms in a case of super-refractory focal status epilepticus. the study is a case report. a daily dose of pulses of hz rtms was applied to the left occipital lobe. treatment course was divided into periods of - consecutive days each for a total of days of treatment over days. a -year-old woman with recent hemiarthroplasty complicated by wound infection presented with acute unresponsiveness and right gaze deviation, evolving into fluctuating encephalopathy, word finding difficulty, and right hemineglect. eeg revealed persistent left posterior quadrant lateralized periodic discharges (lpds), at times evolving into electrographic seizures, and positron emission tomography demonstrated a co-localized hypermetabolic focus. mri revealed subtle bilateral occipital t hyperintensity without diffusion restriction, which later resolved; cerebrospinal fluid was noninflammatory. seizures continued despite treatment with multiple aeds, burst suppression, and empiric trial of high dose corticosteroids. the patient demonstrated abrupt electrographic and clinical improvement after rtms initiation. previously unseen brief periods of lpd resolution were observed within minutes after first tms session with further improvement in eeg background correlating with improvement in encephalopathy and clinical findings over subsequent days. given excellent safety profile, rtms may be useful transitional therapy in management of some cases of status epilepticus. durability of efficacy, patient selection, and optimal treatment schedules remain important unresolved questions. further study is required. central pontine myelinolysis (cpm) occurs due to rapid osmotic shifts causing demyelination in white matter, typically due to rapid correction of hyponatremia mostly in setting of alcoholism, malnutrition, and/or liver/renal dysfunction. sequelae may include cranial neuropathies, quadriparesis, seizures, and encephalopathy. no specific treatment exists; literature reports indicate favorable outcomes in only - % of patients. our patient is a year old male with hypertension, tobacco and alcohol abuse, admitted with severe aortic stenosis, complicated by alcohol withdrawal, pneumonia, and acute kidney injury. he was treated with benzodiazepines, broad spectrum antibiotics, and fluid resuscitation. on hospital day (hd) , he had to be intubated for airway protection due to acute confusion and quadriparesis. his blood work was notable for wide fluctuations in serum sodium, from on admission to on hd to on hd . otherwise, laboratory evaluation was remarkable only for mildly elevated ast and serum creatinine. mri brain days after symptom onset (hd ) showed dwi and flair hyperintensities around central pons bilaterally crossing midline. eeg showed severe generalized slowing. diagnosis of cpm was made and intravenous immunoglobulin (ivig) ( . g/kg/day for days) was initiated within days of symptom onset, on hd . after initiation of ivig, patient showed rapid improvement, first noted in the bilateral upper extremities. by hd i.e., days after initiation of ivig, he was able to be successfully extubated; and he had regained - / strength in all extremities. neuropsychology testing at month demonstrated intact cognition. we describe a case of rapid clinical improvement in cpm following treatment with ivig. in addition to ours, about similar cases have been reported, in which beneficial outcomes were demonstrated following prompt initiation of ivig. one proposed theory would be through reduction of myelinotoxic antibodies, thus promoting remyelination. few cases have reported central neuronal hyperventilation (cnh) secondary to infiltrative malignancy or autoimmune disease. the lesion is usually located at the pontine tegmentum and interrupts the fibers between the respiratory centers in the pons and those in the medulla. we report a case of a year old female with multiple comorbidities who was admitted to the neurocritical-care unit after intra-operative rupture of a mm distal basilar aneurysm while being electively coiled. an external ventricular drain (evd) was placed due to early signs of ventriculomegaly. the postoperative exam showed progressive encephalopathy, left > right hemiplegia progressive tachypnea (rate and depth) despite being on assisted mode ventilation leading to severe hypocapnia ( . mmhg) and compensatory renal acidosis (bicarbonate = . mmol/l) to maintain normal ph. attempt to sedate the patient led to severe metabolic acidosis. intraventricular nicardipine was started and the patient ventilator settings were changed to bi-level pressure control. transcranial doppler (tcd) showed markedly improved vasospasms. the patient respiratory rate and, to a lesser extent, the tidal volumes improved after several days. sedation was weaned off successfully. evd was successfully weaned off and removed. tcd and ct angiogram showed severed basilar artery vasospasm while mri done later showed bilateral tegmental midbrain ischemia. one case has reported acute central neuronal hyperventilation following left thalamic bleed while another reported chronic neuronal hyperventilation that was attributed to old bilateral lacunar thalamic strokes by exclusion. our case is the first to report central neuronal hyperventilation following aneurysmal subacrachnoid hemorrhage that got complicated by bilateral tegmental midbrain strokes. while respiratory centers are known to exist in the medulla and the pons, more recent articles have described networks that regulate breathing extending to the midbrain peri-acquiductal grey and possibly the thalami. our unique case supports this hypothesis. serotonergic and atypical antipsychotic drugs are often used in the critically ill in the treatment of posttraumatic depression and anxiety disorders. hyperactive delirium may mask serotonin syndrome, which carries high morbidity and mortality if left untreated. we describe a case of serotonin syndrome in a critically ill patient in the setting of surgical and neurocritical intensive care unit. a -year-old male with remote trauma presented with left upper abdominal pain. a ct-scan of abdomen showed left diaphragmatic hernia. he underwent left thoracotomy and repair of diaphragmatic hernia. his postoperative course was complicated by sepsis, ileus, and aspiration pneumonitis. he was started on sertraline and quetiapine for stress-induced anxiety disorder, depression and agitation. despite increasing doses of sertraline, patient became agitated, tremulous, and confused. physical examination included fever, tachycardia, hypertension, diaphoresis, dilated pupils, hyperactivity, and clonus. initially considered to be due to hyperactive delirium, these manifestations did not improve with haloperidol. neurocritical care was consulted. due to presence of hyperactivity, fever and clonus, serotonin syndrome was strongly suspected. sertraline and quetiapine was discontinued and cyproheptadine added. within -hours his symptoms improved and cyproheptadine was tapered over days. serotonin syndrome, a potentially life-threatening syndrome, is manifested by triad of mental status changes, neuromuscular and autonomic hyperactivity. a multitude of drug combinations can result in serotonin syndrome. serotonin syndrome is a diagnosis of exclusion, based on history and neurological examination in a patient taking serotonergic drug. ht- a receptors are most commonly incriminated along with high levels of norepinephrine.the keys to management include discontinuation of all serotonergic agents, supportive care, and cyproheptadine. cyproheptadine, a potent ht- a antagonist, is effective in ameliorating symptoms. a high suspicion for diagnosis is important for reducing morbidity and mortality associated with this neurologic syndrome in the critically ill. ruptured cerebral mycotic aneurysm as consequence of infective endocarditis (ie): a management qeeg adr in poor grade sah: is it really useful? recognize the various subtypes of cerebral amyloid angiopathy bilal butt baylor college of medicine -hour development of a giant infectious intracranial aneurysm: a case report catherine albin intra-operative ultrasound in traumatic brain injury patients namkyu you syndrome of the trepheined (sot) and paradoxical herniation without craniectomy elysia james spectrum health neurosciences -icu division stephen a. trevick , andrew naidech , leah tatebe patients were included. median age was years. % were female, % smokers, % hypertensive and % diabetic. % had a history of cad or mi and % had hyperlipidemia. in the multivariable analysis, the odds ratio for unfavorable outcome, defined as mrs score of - , was . ( %c.i: . - . ) and . ( %ci: . - . ) for the intermediate-grade(iii) and high-grade(iv and v) hh groups respectively, when compared to the low-grade(i and ii) hh group. age, hypertension and diabetes were found to be negatively associated with mrs, while hyperlipidemia was positively associated. gender, race, smoking and history of cad/mi were not significantly related to mrs. a positive trend for better mrs outcome was observed across years (p= . ). this trend was not related to hh grade on admission, (p= . for interaction between hh grade and year). hh scale on admission is associated with the mrs outcome upon discharge for patients with nontraumatic sah. models predicting the probability of a good mrs outcome could be created based on the hh grade on admission, age, hypertension, diabetes and hyperlipidemia status. the data suggest a trend toward improvement in medical and surgical care for this patient population across years. ciro poor-grade subarachnoid hemorrhage (sah) is associated with high mortality rates. although death rates have decreased in the last three decades, the exact mechanisms of demise are still to be determined in this patient population. a retrospective study of consecutive poor-grade sah patients (world federation of neurosurgical societies grades iv and v) aggressively treated in two academic high-volume centers, one in the netherlands (amc) and one in canada (smh). the primary outcome was in-hospital mortality. the main reasons of death were evaluated. a total of poor-grade sah patients were admitted between and , to amc and to smh. ( %) patients died, and ( %) of those patients died before having the culprit aneurysm treated. the median interval between hospital admission and death was three days (iqr - ).withdrawal of life support was the main reason of death in both centers (total of deaths - %), cardiopulmonary causes, aneurysm rebleeding, refractory intracranial hypertension, and other extracranial causes), represented less than %. extensive review of patients chart for all the data collection including literature search for similar cases if reported before. although rare, there are multiple case reports and series of nkh and clinical findings of hemichorea-hemiballism (hc-hb). there are few case reports of nkh with unilateral signal changes in the caudate and putamen. our patient presented with acute right basal ganglia ich. despite the typical imaging findings of nkh, work-up and management of ich took precedence over control of bg. mri findings were different in our patient given presence of positive gre and dwi/adc in areas other than t hyperintensity, which is known to be associated with nkh. we hypothesize an association between ischemia and hemosiderin deposition with hyperglycemia. the selective vulnerability of unilateral involvement of basal ganglia and caudate is unclear and needs more research. identification of neuroimaging findings in nkh in absence of focal neurological deficits (hc-hb) is important, especially for a first responder. early recognition can prevent icu admission, provide efficient patient care and allocation of resources. although most metabolic diseases affect basal ganglia bilaterally; nkh is associated with specific unilateral neuroimaging findings even in absence of movement disorders or focal neurological deficits. a year old male with a history of seizure disorder due to mesial temporal lobe sclerosis, presented with altered mental status after a lamotrigine overdose. he had consumed . gm of the drug. he was awake and alert at presentation. urine toxicology was negative. initial creatine kinase (ck) was iu/l and peaked at iu/l; his creatinine was . mg/dl. lamotrigine level went from mcg/ml to . mcg/ml after hours. four days after admission it was mcg/ml. a head ct at admission was negative. despite initial alertness, he developed profound encephalopathy with agitation and rigidity, requiring heavy sedation, induced paralysis, and intubation. this in turn lead to hemodynamic instability, which along with persistently elevated lamotrigine levels, prompted initiation of continuous veno-venous hemodia-filtration (cvvhdf) on hospital day . the lamotrigine level declined to . mcg/ml within hours, the encephalopathy and rigidity resolved, and he was extubated. to our knowledge, this is the first reported case of lamotrigine toxicity managed with cvvhdf. overdoses up to g have been reported and can even result in death. while cleared hepatically, the half-life of lamotrigine is approximately twice as long when patients have chronic renal failure. in a small series of patients with renal failure, approximately % of lamotrigine was reported to be removed by hemodialysis. we applied this principal to our patient. our experience suggests that augmenting drug clearance with dialysis may help reduce the time on mechanical ventilation, need for higher doses of sedatives, and improve time to discharge. cvvhdf should be considered a supplemental treatment option for lamotrigine toxicity. traumatic brain injury (tbi) complicated by percutaneous coronary intervention (pci) remains a significant clinical dilemma. dual anti-platelet therapy (dapt) is standard after pci, but may contribute to progression of tbi. novel antiplatelet drugs with ultra-short half-lives, such as the p y -adenosine receptor antagonist, cangrelor, may provide added clinical flexibility in avoiding tbi-associated hematoma progression, particularly in the absence of reversibility options. case report. we report a year-old female who presented to the ed after a syncopal episode with a fall down a flight of stairs. an ekg was obtained demonstrating inferior wall stemi. signs of head trauma included facial and scalp contusions, and bloody otorrhea. initial gcs was . a non-contrast head ct demonstrated tsah and contusions of bilateral frontal lobes and left temporal lobe, and a non-displaced fracture of the left temporal bone. neurosurgery, interventional cardiology and critical care were consulted. the patient developed signs of cardiogenic shock related to stemi and was taken emergently to cath lab. successful revascularization of proximal rca occlusion was achieved. heparin was given per protocol, and aspirin and cangrelor administered post-pci. cath lab was complicated by tonic-clonic seizures requiring intubation. repeat head ct demonstrated blossoming of bifrontal contusions, trace subdural hematoma development and increased tsah conspicuity. dapt infusion was continued, and subsequent imaging was stable, allowing transition to asa and clopidogrel. she survived with only minor disability. newer generation p y inhibitors can be administered intravenously with reliable platelet inhibition similar to older p y receptor inhibitors. with rapid reversibility upon discontinuation, their utilization should be considered any time pci complicates tbi. cerebral air embolism (cae) is a rare but potentially fatal entity with high morbidity and mortality, commonly seen secondary to iatrogenic causes like neurosurgical procedures, vascular surgeries, etc. as also deep sea diving. cae after esophagogastroduodenoscopy (egd) is extremely uncommon. we present a rare case of cae post egd resulting in diffuse cortical infarction. an year old man underwent an elective (egd) for esophageal stricture with biopsy and balloon dilatation. patient did not wake up after procedure. on initial exam, patient was comatose, glasgow coma scale t with decerebrate posturing. computed tomography (ct) revealed multiple foci of cerebral air embolism. ct angiogram of the brain was negative. diffusion weighted imaging and apparent diffusion coefficient imaging sequences in magnetic resonance imaging (mri) showed diffuse, global bi-hemispheric cortical infarction. ct chest showed pneumomediastinum. only cases of cae from egd have been reported in literature prior to this case. received hyperbaric oxygen therapy(hbo). patients had a documented patent foramen ovale (pfo) or some form of arteriovenous (av) shunt. presence of av shunts/ pfo, therapeutic endoscopic procedures providing vascular communication as well as providing pressure gradient are all factors facilitating air embolism associated with egd. hbo therapy has been shown to improve outcomes in cae patients, initiating therapy > hours after insult and early and significant ischemic changes seen on ct/ mri prior to starting therapy were strong predictors of poor outcomes. our patient did not have a documented echocardiogram with a shunt study prior to the egd. cae after egd causing global cerebral bi-hemispheric ischemia as seen in our case is extremely rare. hbo has been shown to improve outcomes. time to treatment > hours and early ct/ mri changes suggest poor outcomes. studies do not recommend benefit of screening for pfo or av shunts prior to every egd. key: cord- - ataw gy authors: masur, henry title: critically ill immunosuppressed host date: - - journal: critical care medicine doi: . /b - - . -x sha: doc_id: cord_uid: ataw gy nan as the population of patients with cancer, organ transplants, vasculitides, and human immunodefi ciency virus (hiv) infection has grown, intensivists are seeing more and more patients with altered immunity. these patients may come to the intensive care unit (icu) because of life-threatening opportunistic infections, or they may develop life-threatening infection while in the icu for an unrelated problem. intensivists must recognize how these patients differ from immunologically normal patients in terms of clinical presentation and management of these infections. this chapter emphasizes the important ways in which immunosuppressed patients differ from immunologically normal individuals in terms of infectious complications. clearly, however, immunosuppressed patients also develop complications from their underlying diseases and the drugs used to treat these underlying processes. these noninfectious complications are not the focus of this chapter but are reviewed in chapter . patients who are at increased risk for infectious complications because of a defi ciency in any of their host defense mechanisms are referred to as compromised hosts. patients in icus are almost universally compromised either by virtue of their underlying disease or by virtue of the invasive devices utilized to support and monitor them. patients are termed immunocompromised or immunosuppressed if their defect specifi cally involves immune response. often, patients who have defi cient infl ammatory response (e.g., neutropenia) are grouped into the category of immunocompromised or immunosuppressed, although technically they have a different category of defi cient host response. patients in icus are often immunosuppressed as a result of their underlying disease, therapy, or nutri-tional status. this chapter focuses specifi cally on patients who are immunocompromised or immunosuppressed. the microbial complications that any patient develops are determined by general, nonspecifi c barriers; innate immunity; acquired specifi c immunity; and environmental exposures. nonspecifi c barriers include anatomic barriers such as intact skin and mucous membranes; chemical barriers such as gastric acidity or urine ph; and fl ushing mechanisms such as urinary fl ow or mucociliary transport. organisms that breach these barriers encounter nonspecifi c and innate host factors termed the acute phase response. acute phase responses include trigger molecules and effector molecules. organisms also encounter acquired specifi c immune response systems including mononuclear phagocytes and antibodies. infections that occur may result from normal fl ora that colonize mucosal or cutaneous surfaces. infections may result from abnormal fl ora that have invaded or replaced normal fl ora because of environmental exposures, disrupted barriers, or selective pressure of antimicrobial agents. table - lists organisms that cause disease when specifi c anatomic defenses are disrupted in individuals with normal microbial fl ora. infections may also result from common defects in the infl ammatory or immunologic systems; examples are detailed in table - . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] infl ammatory and immunologic barriers can be disrupted by the primary disease process (e.g., tumor can invade the bone marrow, immunologic abnormalities associated with aplastic anemia or collagen vascular disease can destroy cells either in the bone marrow or the periphery). infl ammatory and immunologic mechanisms can also be disrupted by drugs. cytotoxic drugs, for instance, can reduce neutrophil number and function. certain monoclonal antibodies can destroy lymphocyte populations or interfere with cytokine attachment to receptor sites. some agents such as corticosteroids have multiple effects on neutrophils, lymphocytes, and soluble factors. infections may result from organisms that are usually not pathogenic, but become opportunistic because of poor host defense mechanisms. opportunistic infections are defi ned as those that occur with enhanced frequency or severity in a specifi c patient population compared with a normal patient population. pneumocystis jiroveci, for example, never causes disease in immunologically normal individuals but can cause frequent episodes of pneumonia in certain immunosuppressed patients. candida can cause mild mucosal disease in normal patients receiving antibacterial drugs but causes more frequent and more severe mucositis when patients have impaired cell-mediated immunity. recognition of which host defense mechanisms are disrupted enables the clinician to focus diagnostic, therapeutic, and prophylactic management and optimize patient outcome. for instance, if a patient presents with severe hypoxemia and diffuse pulmonary infi ltrates, a health care provider who recognizes a prior splenectomy as the major predisposition to infection would focus the diagnostic evaluation and the empiric therapy on streptococcus pneumoniae and haemophilus infl uenzae. by contrast, if the patient's major predisposition to infection were hiv infection with a cd + t lymphocyte count below cells/µl, the health care provider would focus on pneumocystis jiroveci and s. pneumoniae; if a cytomegalovirus (cmv)-negative patient's major predisposition were a recent allogeneic stem cell transplant from a cmv-positive donor, then cmv would be a prime consideration. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] immune competence should ideally be measurable by objective laboratory parameters. in fact, the risk for opportunistic infection in patients with hiv infection can be assessed by clinical laboratories with a high degree of accuracy by measuring the number of circulating cd + t lymphocytes. the susceptibility of cancer patients to opportunistic bacterial and candida infections can be assessed by measuring the number of circulating neutrophils. , , the predisposition of patients with certain congenital immunodefi ciencies can be assessed by measuring serum immunoglobulin levels. unfortunately, however, for a large number of immunodefi ciencies, no objective laboratory measures have been validated as predicting the risk of infection. moreover, laboratory measures must be interpreted in context. cd + t lymphocyte counts have great prognostic value in patients with hiv infection but not in most other patient populations; neutrophil counts are relevant in all patient populations, but low counts are associated with disrupted mucosal surfaces compared with those with intact mucosa. thus laboratory parameters must be interpreted in the context of the patient's underlying disease-risk is not always easily manageable by measuring one laboratory parameter. most importantly, most patients have multiple overlapping predispositions to infection. knowledge of the infectious complications associated with specifi c diseases, specifi c immune defects, and specifi c laboratory abnormalities is helpful for predicting and managing infectious complications. however, a specifi c diagnosis should be established in each patient: knowledge of the immune defect helps guide empiric therapy or helps determine therapy if a diagnostic procedure is not safe to perform. immunocompromised patients, by defi nition, are susceptible to a broader array of pathogens than immunocompetent patients. understanding the specifi c immune defect can be enormously helpful in understanding the likely location and source of infection. however, the immune defect must be assessed in the context of the specifi c disease: the clinical manifestations of hiv infection, for instance, are quite different from the clinical manifestations of patients with other diseases that alter cellmediated immunity such as lymphoma. the immune defect must also be interpreted with the understanding that predisposition to infection is usually multifactorial: in addition to neutropenia or lymphocyte depletion, patients often have impaired mucosal barriers, poor ciliary function, or breaches in their skin (i.e., from catheters) that can increase their risk of infection. effective management of opportunistic infections requires understanding of several basic tenets of care. . diseases may present with subtle symptoms and signs, and patients are predisposed to deteriorate precipitously. because immunocompromised patients may lack infl ammatory and/or immunologic mediators, the clinical manifestations of infections are often less prominent and less impressive than immunocompetent patients with similar complications. thus clinicians must recognize that even subtle changes in skin color, catheter site appearance, chest radiograph, or abdominal examination may warrant an aggressive diagnostic evaluation and early institution of broad-spectrum empiric therapy. although all icu patients demand prompt attention and vigorous diagnostic and therapeutic management, many types of immunosuppres-sion can be associated with especially precipitous clinical deterioration despite their innocuous presentation. . fever is not invariably present when patients are infected. although fever is not invariably present in any patient population with infection, immunosuppressed patients are notorious for developing infection in the absence of fever. thus infection must be considered as part of the differential diagnosis among patients with afebrile syndromes that might not appear to be infectious. conversely, patients with fever may not have infection: fever may be a manifestation of the underlying disease, an allergic response to a drug, or an underlying neoplastic or collagen vascular disease. . diagnostic evaluation needs to be prompt and defi nitive. as indicated earlier, patients with life-threatening infection may present with subtle symptoms and signs that progress rapidly: these early manifestations merit aggressive attempts to defi ne the anatomy of the lesion and the causative microbial pathogen. because the spectrum of potential pathogens includes a wide array of microorganisms (e.g., viruses, fungi, protozoa, or bacteria), clinicians must be certain that appropriate specimens are obtained and the appropriate microbiologic and histologic tests are ordered to identify common, as well as uncommon or unusual, pathogens. invasive diagnostic techniques such as bronchoalveolar lavage or tissue biopsies should be performed with less hesitancy than in immunologically normal patients. patients often have enhanced risk factors for invasive procedures, such as thrombocytopenia, coagulation factor defi ciencies, or compromised organ function. however, the benefi t of defi nitive diagnosis often outweighs these risks when the procedures are performed by experienced operators. . the threshold for initiating broad-spectrum empiric therapy should be low. because patients can deteriorate rapidly and because they are susceptible to such a wide array of microbial pathogens, clinicians should have little hesitation in instituting empiric antimicrobial therapy. this therapy must be directed at the full range of bacterial, fungal, viral, protozoal, and helminthic infections to which patients are predisposed. this therapy should be administered promptly, preferably within an hour of suspecting an infectious process. clinicians should initiate comprehensive regimens: antimicrobial agents can be discontinued or reduced when culture results and clinical events clarify the scenario. . foreign bodies and infectious foci should be addressed. patients may need careful imaging to be certain that they do not have an obstructed viscus or localized collection that should be drained. such imaging is appropriate even when signs or symptoms are unimpressive. similarly, patients often have multiple intravascular catheters that may need to be removed, as discussed in chapter . . consideration should be given to augmenting the immune or infl ammatory response. there may be opportunities to augment immunologic or infl ammatory responses by administering pharmacologic or biologic agents such as granulocyte colony-stimulating factor (g-csf) or intravenous immunoglobulin. [ ] [ ] [ ] [ ] eliminating immunosuppressive drugs or reducing the dose can also improve the patient's prognosis. . effi cacy and toxicity of therapy should be assessed serially. icu patients characteristically require attentive monitoring to assure the adequacy and safety of therapy. immunocompromised patients often have multiple prior and concurrent insults to their renal and hepatic function, and they often receive multiple drugs that can produce drug-drug interactions. thus monitoring the pharmacokinetics and assessing potential toxicities are especially important in these patient populations. moreover, because response to therapy may be less robust than in immunocompetent patients, antigen titers or pcr titers, as well as serial imaging studies, can be important to assure the adequacy of the management plan. therapy must often be continued longer than in immunologically normal patients. cytotoxic therapy-induced neutropenia is a major predisposition to infection. , counts below cells/mm (the total of polymorphonuclear neutrophils and bands) increase susceptibility to infection in a linear fashion (i.e., the lower the neutrophil count, the greater the degree of susceptibility). the absolute neutrophil count is not the only factor that determines susceptibility, however, because some patients with cyclic neutropenias, druginduced neutropenias, or hiv-induced neutropenias, for example, are not nearly as susceptible to infection as are cancer patients receiving cytotoxic therapy. other important contributors to susceptibility, in addition to the absolute neutrophil count, are the duration of neutropenia, the functional capability of neutrophils, the integrity of physical barriers such as the skin and gastrointestinal mucosa, the patient's microbiologic environment (endogenous and exogenous fl ora), and the status of other immune mechanisms. for example, a patient with vancomycin-induced neutropenia during therapy for a staphylococcal infection may not develop any complications if the neutropenia is brief and defense mechanisms are otherwise intact. a patient with hiv-induced neutropenia may have prolonged or even lifelong neutrophil counts below /µl yet suffer few serious bacterial complications. the presence of intact physical defense barriers is a major difference compared with cancer patients, whose skin and mucous membranes are disrupted by cytotoxic therapy in which the skin and gastrointestinal tracts are portals of entry for infections that are not controlled by diminished host immunologic or infl ammatory defenses. thus the patient with hiv infection is usually at a much lower risk for a bacterial infection than is a cancer patient, despite a comparable neutrophil count. in the s and s, aerobic gram-negative bacilli such as escherichia coli, klebsiella pneumoniae, and pseudomonas aeruginosa predominated as pathogens in neutropenic patients. anaerobic bacteria and aerobic gram-positive cocci were recognized less commonly. aerobic gram-negative bacillus infections were also associated with a poorer outcome than infections from gram-positive cocci. given the spectrum of pathogenic organisms that were seen in that era, combination therapy was usually advocated. , - a number of reasons were proposed to justify combination therapy: ( ) broad coverage of potential pathogens; ( ) prevention of emergence of resistance; and ( ) synergy. in general, these principles are reasonable concepts on which to base a preference for using combination therapeutic regimens. however, no study unequivocally demonstrated that combination therapy provided better outcomes than did monotherapy, assuming that both study arms contained drugs that had activity against the causative organism. in addition, predicting synergy proved diffi cult. in the s the spectrum of causative pathogens in neutropenic patients shifted from a predominance of gram-negative bacilli to a majority of gram-positive cocci including streptococci, staphylococci (including oxacillin-resistant staphylococcus aureus), and enterococci (including vancomycin-resistant enterocci). , , the development of potent broad-spectrum β-lactam and quinolone drugs in the s and s has provided single agents that can probably provide comparable outcomes to combination therapy when used empirically or specifi cally. in the current era the choice of single or combination regimens is based predominantly on the spectrum of organisms that needs to be covered rather than attempting a strategy of trying to obtain more potency through additive or synergistic combinations. , promptly initiating broad-spectrum antibacterial therapy for all cancer patients who are febrile and who are neutropenic (neutrophil count < /mm ) as a result of cytotoxic chemotherapy is standard practice. , , for febrile neutropenic patients who have no apparent source of infection, there is no evidence that the initial antibacterial regimen is any more effective if a broad-spectrum antibacterial regimen consisting of two or more drugs is used instead of a single broad-spectrum antibacterial drug. for stable "low-risk" patients outside the icu, an oral regimen is now considered a reasonable approach. , , such oral regimens would not be used for inpatients in most circumstances and would not be appropriate for high-risk or unstable patients. , antifungal and antiviral drugs are generally not used empirically when neutropenic patients are initially treated unless there is a specifi c reason to have a high suspicion for a fungal or viral process. historically, an infectious cause of fever has been found in about two thirds of febrile, neutropenic cancer patients. when a specifi c causative organism is identifi ed, antimicrobial therapy is modifi ed to include an agent or agents determined to be active by in vitro susceptibility tests and that penetrate to the site of the infection. combination therapy is advocated by some authorities for the specifi c (compared with empiric) therapy of either gram-positive or gram-negative bacteria, although, as noted earlier, there are little data for most pathogens that indicate that a combination regimen produces a better outcome than an appropriate single agent. therapy is generally not narrowed in terms of spectrum, however, because alteration of broad-spectrum coverage to focused therapy has been associated with more complications (e.g., "breakthrough bacteremias") unless the neutropenia resolves. whenever fever persists, therapy has generally been continued during the entire course of neutropenia because cessation of antimicrobial therapy has been associated with recurrent bacteremia resulting from the initial causative organism or a newly identifi ed pathogen. a -to -day course of antibacterial therapy is usually the minimum recommended if a causative infection is identifi ed. therapy is usually stopped promptly when the neutrophil count exceeds cells/µml if fever resolves and no source was ever identifi ed. empiric antibacterial therapy has been a successful strategy for reducing morbidity resulting from bacterial processes but has been associated with the emergence of fungal infections, as well as resistant bacterial pathogens. candida and aspergillus organisms, in particular, have become major causes of morbidity and mortality over the past decades. these fungal processes can be diffi cult to diagnose because they are not always associated with detectable fungemia. the emergence of fungi as important pathogens, especially in patients with prolonged neutropenia, has led to the recommendation that empiric antifungal therapy be added to neutropenic patients who do not have an identifi ed bacterial process and who do not defervesce within to days of empiric antibacterial therapy. , fluconazole or an amphotericin b compound (e.g., liposomal amphotericin b) are often used, although echinocandins or certain other azoles such as voriconazole are being used by some investigators and clinicians. [ ] [ ] [ ] [ ] as patients receive chemoprophylaxis with quinolones and/or azoles during periods of intense neutropenia or immunosuppression, breakthrough pathogens are more and more likely to be resistant to the prophylactic agents. , thus empiric regimens must be chosen with keen attention to the drugs that patients have received in the recent past, as well as pathogens they have previously been colonized or infected with. patients with fever and neutropenia require aggressive diagnostic efforts to identify the cause of fever so that the appropriate antimicrobial agent is used and appropriate procedures (e.g., surgical drainage, removal of foreign body such as a catheter) can be performed. regular physi-cal examination is necessary to identify sites that merit more focused investigation: with impaired infl ammatory response, fi ndings on examination may be subtle. knowledge of the specifi c immunologic defect is important so that when cultures of blood, sputum, urine, or other appropriate body fl uids or body sites are performed, special microbiologic approaches can be used to detect viruses, fungi, helminths, protozoa, and bacteria. imaging studies are also important because intra-abdominal, intrathoracic, intracerebral, or musculoskeletal processes can be clinically subtle and may not be associated with identifi able organisms in the bloodstream. a growing array of antigen, nucleic acid, and gene detection systems including polymerase chain reaction and microarray gene assays are being investigated to facilitate diagnosis. some antigen or nucleic acid detection systems for blood or other body fl uids can be useful for detecting cryptococcus, histoplasma, hepatitis b and c, hiv, mycobacteria, pneumococci, and legionella. some of these approaches, despite their promising initial reports, are not yet clinically practical because of their level of sensitivity, specifi city, or the cost or expertise required to perform them adequately. careful attention to antimicrobial susceptibility patterns is also important. patients are exposed to repeated courses of antimicrobial agents. patients come into contact with contaminated environments in a variety of health care settings. resistance is no longer an issue exclusively for aerobic gram-negative organisms but is a concern for anaerobes, gram-positive cocci, viruses, fungi, and protozoa. clinicians must recognize that pathogens may be resistant when they are acquired by the patient, or they may become resistant during therapy if there is an inducible resistance mechanism or drug concentrations are not adequate to inhibit or kill the organism. a broad-spectrum agent used as monotherapy for febrile, neutropenic patients should have activity against aerobic gram-positive cocci and aerobic gram-negative bacilli including p. aeruginosa. , , , potential drugs for this indication include certain cephalosporins (e.g., cefepime), carbapenems (e.g., imipenem or meropenem), and βlactam/β-lactamase combination agents (e.g., piperacillintazobactam). ceftazidime is an option chosen by some, but its poor activity against gram-positive cocci has caused some clinicians to use other agents. intensivists must recognize, however, that these monotherapy regimens may not be appropriate in an icu. patients in icus, by defi nition, are either unstable hemodynamically or have a potentially life-threatening process such as diffuse pneumonia or are "fragile" because of concurrent processes. thus combination regimens are preferred by many authorities in icu settings, even though no study clearly documents superior outcomes from such combination regimens. the decade that started in is an era when microbial resistance is becoming an increasingly important problem for many types of bacteria including aerobic grampositive cocci and anaerobes, as well as aerobic gramnegative bacilli. multiple drug empiric regimens are more likely than monotherapy regimens to include an agent with activity against the offending pathogen(s). thus in a situation in an icu when failure to use an active drug is more likely to be lethal than in other settings, and when enhanced potency is a logical goal, combination therapy is prudent as an initial management strategy. thus adding vancomycin or linezolid or daptomycin for better grampositive coverage, adding a quinolone for better gramnegative bacillus coverage, and adding metronidazole to cefepime would be prudent in this patient population pending results of initial diagnostic studies. of note, however, is that although this strategy is logical, no study has shown convincingly that such an approach improves outcome. a substantial number of febrile, neutropenic patients fail to improve in terms of fever or other manifestations. failure to improve may result from poor immune response, a need for drainage or necessity to remove foreign bodies, the use of drugs without activity against the causative organism, or a noninfectious process including drug allergy (i.e., fever resulting from a drug including an antimicrobial agent). the potential causative processes need to be aggressively reassessed on a regular basis by physical examination, history, cultures, and imaging techniques. most centers add antifungal therapy empirically at day or day of therapy if patients remain febrile. , , , , fluconazole, liposomal amphotericin b, caspofungin, or voriconazole may be used: in some situations fl uconazole would be less attractive either because the patient has received fl uconazole prophylaxis or because molds are suspected. , , the toxicity profi le of amphotericin b, even in its liposomal form, has led many clinicians to prefer voriconazole or one of the echinocandins (i.e., caspofungin, micafungin, or anidulafungin). , , after empiric antimicrobial therapy is initiated, the optimal duration of therapy is a complex issue that depends on the type and severity of the infectious process and the duration and severity of immunosuppression, especially the neutropenia. if a causative bacterium is identifi ed, a minimum of to days of therapy is generally advocated, with at least to days being administered after neutropenia has resolved. longer courses may be required in certain settings. the duration of antifungal therapy is a complex issue and depends on the specifi c mycosis, the location and extent of disease, and the patient's immune status. this is discussed in chapter . the use of combination therapy for fungal diseases remains controversial. , a common problem in febrile, neutropenic patients is managing indwelling intravascular lines. [ ] [ ] [ ] in general, these lines can be left in place initially if examination of the site reveals no indication of infection. blood cultures should be drawn through the catheter. although some experts advocate drawing a culture through each port of each catheter, obtaining this many blood cultures is often not feasible. if a patient is hemodynamically unstable and fails to respond promptly to fl uid administration, it is prudent to remove the line in case an infected catheter is the source of the sepsis. failure to remove the foreign body in this situation probably increases the likelihood of an unfavorable outcome. should blood cultures become positive and should the suspicion be high that the catheter is the source, antibacterial therapy may be successful in some settings (e.g., if the pathogen is a bacteria that is relatively sensitive to antibacterial therapy), thus avoiding the need to remove the catheter. situations suggesting that catheter removal is necessary include hemodynamic instability despite aggressive fl uid resuscitation, tunnel infection, or infections resulting from fungi or relatively antibiotic-resistant bacteria such as p. aeruginosa. a major determinant of prognosis is the immunologic status of the patient. prompt return of neutrophil number to normal improves the outcome. the use of g-csf or granulocyte-monocyte colony-stimulating factor (gm-csf), if not contraindicated by the underlying disease, can improve clinical status by hastening the return of neutrophil numbers and function. [ ] [ ] [ ] [ ] granulocyte transfusions have not been proved useful in most clinical settings because of the inability to administer a large number of cells with adequate frequency. the manipulation of immune response with cytokines, cytokine inhibitors, or immunoglobulins is the subject of considerable investigation: such interventions may reduce the duration of fever or the incidence of infections when used empirically, but in no setting have they been clearly shown to improve survival when administered after an infection has been documented. an algorithm for managing fever in neutropenic patients is provided in figure - . table - suggests modifi cations of standard empiric regimens in certain common clinical scenarios. given the experience with frequent and severe infectious complications in cancer patients with neutropenia, it has been logical to attempt to prevent infection. most microorganisms causing disease in this patient population arise from endogenous gastrointestinal, cutaneous, or respiratory fl ora. total protected environments probably reduce frequency of infection, but this approach is expensive and inconvenient. trying to prove a consistent benefi cial impact on survival has been diffi cult, and thus such isolation is rarely used anymore. some experts are enthusiastic about placing patients in positive pressure rooms so that pathogens do not enter via particles and droplets from outside the room. this type of isolation has not clearly improved outcome, however, and is not a standard of care. prophylactic bacterial therapy has also been controversial. systemic antibacterial prophylaxis and systemic antifungal prophylaxis have been shown in some studies to reduce the number of infections, but their lack of effect on patient survival, their cost, and their impact on the emergence of resistance have made many clinicians reluctant to use them. selective gastrointestinal decontamination has not consistently improved survival and thus is not recommended by most authorities in the united states. antipneumocystis prophylaxis is, in contrast, highly effective in susceptible populations. prophylaxis for cmv is highly effective in well-defi ned, high-risk patients (e.g., some recipients of organ transplants who are either sero-positive for cmv or who are seronegative but received a graft from a seropositive donor). , , strategies that reduce the period of immunologic susceptibility (e.g., reduce the duration of neutropenia), such as adding g-csf to a regimen or reducing the intensity of chemotherapeutic regimens, are promising. because so many patients are receiving highly active antiretroviral therapy (haart), opportunistic infections are not complicating the course of hiv infection to the same degree that they did in the s and early s. [ ] [ ] [ ] [ ] opportunistic infections continue to occur, however, in three groups of hiv-infected patients: ( ) those who are unaware of their hiv status until they develop a clinical syndrome; ( ) those who are unable or unwilling to receive appropriate therapy; and ( ) those who fail haart and opportunistic infection prophylaxis. although haart has dramatically reduced the incidence of opportunistic infections, a surprisingly large fraction of patients either never respond virologically and immunologically or lose their response within the fi rst to months of therapy. these patients, most of whom have dominant viral quasispecies that are highly resistant to currently licensed antiretroviral drugs, will likely experience immunologic decline over the next few years and will again become more susceptible to opportunistic infections. severe necrotizing mucositis or gingivitis add specifi c antianaerobic agent (e.g., metronidazole, meropenem, imipenem, or piperacillin-tazobactam) plus agent with activity against streptococci; consider acyclovir. ulcerative mucositis or gingivitis add acyclovir and anaerobic coverage. add fl uconazole or caspofungin; consider adding acyclovir. pneumonitis, diffuse or interstitial add trimethoprim-sulfamethoxazole and azithromycin or levofl oxacin or moxifl oxacin (plus broad-spectrum antibiotics if the patient is granulocytopenic). perianal tenderness include anaerobic agents such as metronidazole, imipenem, meropenem, or piperacillin-tazobactam. abdominal involvement add antianaerobic agent (e.g., metronidazole, meropenem, imipenem, or piperacillin-tazobactam). patients with hiv infection develop clinical disease as a result of three basic processes: the direct effect of hiv on specifi c organs (e.g., cardiomyopathy, enteropathy, dementia); immunologically mediated processes (e.g., glomerulonephritis, thrombocytopenia); or opportunistic infections and tumors that are enabled by hiv-induced immunosuppression. hiv appears to cause direct organ damage. , - this damage may be mediated by cytokines, lymphocytes, monocytes, or infl ammatory cells. cardiomyopathy, for example, can be a profound and lethal process that can lead to icu admission or complicate other processes. when patients present with or develop pulmonary manifestations such as shortness of breath or diffuse bilateral infi ltrates on chest radiograph, cardiogenic causes must be considered. hiv also causes a diffuse pneumonitis, profound encephalopathy, and a diffuse enteropathy. patients with compatible syndromes need a comprehensive evaluation to look for other specifi c opportunistic infections or tumors, especially those that can be specifi cally treated. in all of the hiv-caused syndromes, hiv as the etiology remains a diagnosis of exclusion. the institution of antiretroviral therapy appears to be benefi cial for patients with susceptible isolates, although data regarding such effects for these hiv-related entities are largely anecdotal. hiv-related thrombocytopenia and anemia appear to be immunologically mediated. , both can be severe: platelet counts below , /mm and hemoglobins below g/dl can be seen with the expected complications. these disorders are related to the development of antigenantibody complexes and may improve dramatically with the institution of antiretroviral therapy and a decline in viral load. for thrombocytopenia, intravenous immunoglobulin (or anti rhd antibody), corticosteroids, or splenectomy may also be useful. hemolytic anemia can also be severe: hemoglobin levels below g/dl can be seen. the most prominent manifestations of hiv continue to be the opportunistic infections and tumors that occur as a consequence of hiv-induced immunosuppression. the cd + t lymphocyte cell number is a useful marker for predicting the occurrence of opportunistic infections in patients with hiv infection. , this relationship of cd + t lymphocyte count to the occurrence of opportunistic infection continues to be as valid in the era of haart as it was before the licensing of the fi rst antiretroviral agent, zidovudine, in . [ ] [ ] [ ] figure - demonstrates the typical relationship of cd + t lymphocyte counts to the occurrence of opportunistic infections. knowledge of this relationship permits the focusing of diagnostic, therapeutic, and prophylactic management. for instance, if a patient with hiv infection and a cd + t lymphocyte count of cells/µl presents with diffuse pulmonary infi ltrates, the diagnostic evaluation and empiric antimicrobial regimen should focus on s. pneumoniae; h. infl uenzae; mycoplasma, legionella, and chlamydia organisms, as well as common community-acquired viruses. in contrast, if the same patient had a cd + t lymphocyte count of cells/µl, the evaluation and empiric regimen would focus on pneumocystosis and cmv, although the previously mentioned processes that occur at high cd + t lymphocyte counts can also occur at lower cd + t lymphocyte counts. keeping in mind that cd + t lymphocyte counts are useful predictors of susceptibility to infection is important, but they are not perfect. occasionally, patients will develop opportunistic infections at "uncharacteristically" high cd + t lymphocyte counts. for instance, % to % of cases of pneumocystosis occur at cd + t lymphocyte counts greater than cells/µl. clinical parameters can provide additional clues; for example, oral candidiasis, a previous opportunistic infection, a prior episode of pneumonia, or high viral load are independent risk factors for the occurrence of pneumocystis jiroveci carinii pneumonia (pcp), and logically for other infections as well. a frequent question is whether an hiv-infected patient's prior cd + t lymphocyte count nadir affects the likelihood of an opportunistic infection occurring if haart has stimulated a cd + t lymphocyte count rise. specifically, if a patient has a cd + t lymphocyte count of cells/µl while receiving haart and that patient's cd + t lymphocyte count was cells/µl before haart, is that patient at greater risk for developing an opportunistic infection than another patient whose current cd + t lymphocyte count is cells/µl but whose nadir before haart was cells/µl? the data suggest that these two patients have comparable risk (i.e., the current cd + t lymphocyte count is the most important predictor of risk and the earlier nadir has only minor infl uence on opportunistic infection susceptibility). in evaluating the differential diagnosis of infectious syndromes in patients with hiv (and in every other patient population as well), geography is an important part of the history. tuberculosis is always a concern because of the extraordinary susceptibility of hiv-infected patients for developing active disease. in many urban settings in the united states, each pulmonary evaluation should include smears and cultures for m. tuberculosis, both to diagnose the appropriate cause of the pulmonary dysfunction and to assist in determining what respiratory precautions are appropriate. in some areas of the country, such as the ohio river valley and indianapolis, histoplasmosis is as common as pneumocystosis in causing diffuse pulmonary infi ltrates. in the southwestern united states, coccidioidomycosis must be recognized as a cause of pulmonary infi ltrates. the clinical presentations of tuberculosis, histoplasmosis, coccidioidomycosis, and other processes such as cmv can be clinically indistinguishable from pcp. thus for patients with pulmonary infi ltrates in an icu, prolonged empiric therapy is discouraged in favor of vigorous efforts to establish a specifi c diagnosis. hiv-infected patients are admitted to icus for several major syndromes: respiratory insuffi ciency, cerebral dysfunction, septic shock, hepatic or renal failure, and drug toxicities. however, patients with hiv infection also come to icus for routine procedures and routine postoperative care. in those situations their management ordinarily requires no extraordinary measures, with two exceptions. first, the staff must be fully aware of how hiv is transmitted, the danger of injuries resulting from sharp objects, and the procedure for managing injuries involving sharp objects contaminated with blood or other biologic fl uids from infected or potentially infected patients. second, drug interactions involving drugs used during procedures and certain antiretroviral drugs can have important clinical consequences. , many of the protease inhibitors and the non-nucleoside reverse transcriptase inhibitors that are now the backbone of antiretroviral therapy can inhibit or enhance the metabolism of drugs that depend on the cytochrome p system. thus the half-lives of certain analgesics, sedatives, and hypnotics can be prolonged in hiv-infected patients who are taking ritonavir, for example. this pharmacokinetic effect is also relevant for a host of other therapeutic agents used in the icu and may affect their effi cacy or safety. clinicians need to be familiar with these interactions when selecting new therapies for procedures or for clinical entities. patients with hiv infection can develop severe pulmonary dysfunction because of common community-acquired pathogens such as s. pneumonia, legionella, mycoplasma, and chlamydia; adenovirus; infl uenza; or respiratory syncytium virus, as well as other opportunistic viruses and fungi. thus the diagnostic evaluation needs to be comprehensive, emphasizing direct smears of sputum or bronchoalveolar lavage. it is important to recognize that the clinical presentations produced by many causative agents can be similar. for instance, histoplasmosis, tuberculosis, and nonspecifi c interstitial pneumonitis can present identically to pcp. , , , , thus although empiric diagnosis and empiric therapy may be reasonable as initial approaches to some patients with hiv infection and mild pneumonitis, such an approach is usually not appropriate for patients in an icu. evaluation of induced sputum is the fi rst step in the diagnostic approach to pcp. sensitivity can be % to % at many hospitals (at some institutions the yield is considerably lower). specifi city should be % in an experienced laboratory. other pathogens, including mycobacteria, fungi, and routine bacteria, can be identifi ed in sputum as well. for intubated patients, respiratory secretions obtained by deep intratracheal suctioning are also likely to be useful, although they have not been as carefully studied as induced sputum. should the diagnosis not be established by evaluation of sputum or intratracheal secretions, bronchoscopy should be performed. bronchoalveolar lavage should diagnose almost % of cases of pcp, even if patients have received to days of empiric therapy. a diagnosis of pcp is established by visualizing one or more clusters of organisms. diagnostic criteria for other opportunistic infections are reviewed in chapters and . in patients with hiv, cmv merits special mention. culture of sputum or bronchoalveolar lavage does not provide useful information because patients with cd + t lymphocyte counts below cells/µl will predictably have cmv present in their secretion independent of whether or not pulmonary disease is present. a diagnosis of cmv pneumonia in this patient population is suggested by cytology and confi rmed by the presence of multiple inclusion bodies in lung tissue obtained by transbronchial or open lung biopsy. similarly, mycobacterium avium complex (mac) and hsv can often be found in respiratory secretions, but these organisms almost never cause pneumonia in patients with hiv infection. in other patient populations they can clearly cause pneumonia, but the dearth of cmv, mac, and hsv pneumonia in this patient population emphasizes the point that it is important to know from published literature what the clinical likelihood is for different microbial processes. fungal pneumonias other than pcp are generally diagnosed by direct microscopy or culture of respiratory secretions (sputum or lavage). candida organisms almost never cause pneumonia in patients with hiv infection. the frequency of cryptococcus, histoplasma, blastomyces, and coccidioides organisms as causes of pneumonia depends on the geographic exposure of the patient. among these mycoses, antigen detection techniques can be useful for fi nding cryptococcus and histoplasma organisms. mycobacteria frequently infect the respiratory tract of patients with hiv infection. as noted earlier, m. avium complex almost never causes pulmonary dysfunction in this patient population. when acid-fast bacilli are seen (as opposed to cultured) in respiratory secretions or tissue, m. tuberculosis is almost always the pathogen; m. kansasii and other mycobacteria less commonly cause disease. screening all patients with acid-fast bacillus smears is important for preventing transmission of tuberculosis and text continued on p. should be considered as part of a routine respiratory evaluation for patients with radiographic infi ltrates in most areas of the united states. therapy of opportunistic infections is summarized in table - . while awaiting a specifi c diagnosis, it is reasonable to initiate empiric therapy in patients ill enough to merit admission to an icu. for patients with a cd + t lymphocyte count greater than to cells/µl, azithromycin and ceftriaxone or azithromycin and ampicillin-sulbactam would be reasonable choices. for patients with cd + t lymphocyte counts below to cells/ µl, levofl oxacin or moxifl oxacin plus trimethoprimsulfamethoxazole or pentamidine plus levofl oxacin or moxifl oxacin would be potential regimens. if pcp is documented, trimethoprim-sulfamethoxazole is always the drug of choice in patients who can tolerate it. table - lists alternatives for sulfa-intolerant individuals. regardless of which specifi c antipneumocystis regimen is used, corticosteroid therapy is indicated for any patient who presents with an oxygen pressure (po ) below mm hg or an alveolar-arterial gradient higher than mm hg. [ ] [ ] [ ] [ ] patients with an initial po lower than mm hg are the subgroup with substantial mortality for whom corticosteroids have been shown to provide a survival benefi t. corticosteroids may provide more rapid and perhaps more complete resolution of pulmonary manifestations in patients who present with better pulmonary function, but survival in this population is so high that clinical trials have not been able to show survival benefi t. some experts are concerned that corticosteroid use will be associated with reactivation of latent infections such as cmv or tuberculosis. however, reactivation of life-threatening infections has not been associated with this corticosteroid regimen. how should a patient with aids-associated pcp be managed if there is no improvement, or if there is deterioration, after to days of therapy? the median time to improvement in clinical variables is to days; therefore, changes in therapy are probably not warranted before to days. at that point the accuracy of the diagnosis should be reassessed: consideration should be given to repeat bronchoscopy with transbronchial biopsy to determine if cmv, fungi, mycobacteria, or a nosocomial bacterial process is present. noninfectious processes such as congestive heart failure or tumor (e.g., kaposi's sarcoma) must also be considered. if pneumocystosis is the only causative process that can be identifi ed, corticosteroids should be added to the regimen if they have not been already. whether switching from one antipneumocystis agent to another or whether adding a second agent is helpful has not been determined by clinical trials. some human pneumocystosis isolates are resistant to sulfonamides, but such testing is available only in a few research centers. most clinicians add parenteral pentamidine to trimethoprim-sulfamethoxazole. parenteral trimetrexate or clindamycin-primaquine could be used as salvage regimens as well. patients who have not improved after to days of therapy with specifi c chemotherapy plus corticosteroids have an exceedingly poor prognosis. should patients with aids-related pcp be intubated and provided with mechanical ventilation? mortality for such patient populations was % to % in several series in the early s. [ ] [ ] [ ] [ ] since that era, supportive care has improved, and treatment modalities for concurrent infectious and noninfectious processes have become more effective. patient selection for ventilatory support is probably also improving. patients who have multiple active opportunistic infections, substantial weight loss, and no response to days of therapy have a worse prognosis than ambulating patients who develop respiratory failure the third day of therapy. thus decisions about icu support for patients with hiv infection and respiratory failure need to be individualized on the basis of a realistic assessment of prognosis, the availability of resources, and the preference of the individual patient. a frequent question for any hiv-infected patient in the icu is whether antiretroviral drugs should be continued or initiated during the critical or life-threatening illness. although there is no specifi c study of various strategies, most authorities discourage the use of antiretroviral drugs in the icu because of drug interactions and drug toxicities. in addition, the initiating haart can be associated with dramatic "immune reconstitution" syndromes that can complicate the process that brought the patient to the icu. [ ] [ ] [ ] finally, almost all antiretroviral drugs that are commercially available are oral: in most situations it is better to discontinue all antiretroviral drugs for a few days or weeks or months rather than risk poor absorption and suboptimal serum levels. the latter would enhance the emergence of drug-resistant hiv. an important cause of admitting hiv-infected patients into the icu is either seizures or altered mental status. either can result from infectious or neoplastic processes caused by meningeal disease or parenchymal involvement. the differential diagnosis of meningeal disease includes pneumococcal and staphylococcal meningitis, cryptococcal meningitis, tuberculous meningitis, and lymphomatous meningitis, as well as involvement from other endemic mycoses and common community-acquired viral and bacterial processes. , diffuse central nervous system parenchymal disease can be caused by hiv itself, by progressive multifocal leukoencephalopathy, and occasionally by herpes viruses such as cmv or herpes simplex virus. focal mass lesions may be caused by toxoplasmosis or lymphoma. less often, tuberculosis, fungi, conventional bacterial abscesses, nocardia, and other tumors are the cause of focal lesions. these lesions can be diffi cult to distinguish clinically and radiologically. the cd + t lymphocyte count can help narrow the differential diagnosis, but csf or brain tissue is usually necessary for defi nitive diagnosis. the routine therapies for many of these processes are outlined in table - . toxoplasmosis deserves particular mention because of its frequency. [ ] [ ] [ ] toxoplasmosis occurs mainly in patients with hiv infection who have cd + t lymphocyte counts below cells/µl, have a positive igg antibody titer against toxoplasma, and who have not been receiving trimethoprim-sulfamethoxazole or dapsone prophylaxis. patients present with altered cognition, focal motor or sensory defi cits, or seizures. lesions may be unifocal or multifocal. they usually enhance with contrast, but this is not invariably true. for patients who fi t the profi le for high risk of toxoplasmosis, and with a compatible presentation, it is reasonable to establish an empiric diagnosis and institute specifi c therapy with sulfadiazine plus pyrimethamine or, for patients unable to tolerate sulfa, clindamycin plus pyrimethamine. corticosteroids may be needed for patients with considerable intracerebral edema or elevated intracranial pressure. antiseizure medication is usually instituted only after a seizure has occurred rather than prophylactically. most patients improve clinically and radiologically within to days. if patients fail to improve, a stereotactic needle biopsy is appropriate, especially because the prevalence of lymphoma is increasing. organisms can be diffi cult to see in brain specimens obtained by this technique. patients with hiv infection develop hypotension resulting from the same types of disorders as with non-hiv infected individuals-sepsis from a primary infection or a wound or device (especially an intravascular access device), fl uid depletion from vomiting or diarrhea, and hemorrhage from a gastrointestinal lesion are examples of common causes. the evaluation of hypotension in a patient with hiv infection must take into account factors particular to this patient population: it is susceptible to opportunistic infections; it undergoes many procedures that can be associated with infectious complications; and it receives an array of drugs, some of which have cardiovascular effects. thus evaluating hypotension in this patient population requires a comprehensive and thorough approach. a differential diagnosis of the major causes is shown in table - . adrenal function always deserves special attention because several viral processes, fungal and mycobacterial diseases, hiv, and drugs can suppress the adrenal axis and either cause hypotension or exacerbate it. patients with hiv infection typically receive several antimicrobial agents to reduce the likelihood they will acquire opportunistic infections. primary prophylaxis is the term used to indicate strategies that reduce the likelihood of an initial episode of a disease process. secondary prophylaxis is the term used to indicate strategies that prevent recurrences or relapses. chronic suppressive therapy is identical to secondary prophylaxis: this refers to regimens that are continued after the initial therapeutic course to prevent relapses. all patients with hiv infection and cd + t lymphocyte counts below cells/µl typically receive antipneumocystis prophylaxis. trimethoprim-sulfamethoxazole is the regimen of choice. patients who actually take this drug have very few breakthroughs of pcp and receive considerable protection against toxoplasmosis and certain routine bacterial infections. alternative regimens include monthly dapsone, weekly dapsone-pyrimethamine, or daily aerosol pentamidine. prophylaxis against m. avium complex is recommended for patients with cd + t lymphocyte counts under cells/µl; clarithromycin and azithromycin are currently the drugs of choice. many clinicians also use fl uconazole or acyclovir prophylaxis to reduce the frequency of fungal and viral processes, respectively, although this is not recommended because of issues of cost, pill burden, and the emergence of resistant pathogens. isoniazid prophylaxis is important for any patient with a tuberculin skin test that shows more than mm of induration or a history of substantial recent exposure. transmission of tuberculosis from patients to other patients, from patients to staff, or from staff to patients is an urgent concern in icus. patients with hiv infection are extraordinarily susceptible to tuberculosis. thus an infected patient poses a substantial risk, especially when hospitalized for pneumonia or when undergoing procedures at high risk for producing aerosols such as intubation, bronchoscopy, sputum induction, or aerosol pentamidine treatment. identifying potentially infected patients early and placing them in appropriate isolation until their tuberculosis status is fully examined is important. in many centers, patients with syndromes compatible with pulmonary or upper airway tuberculosis are maintained in isolation at least until three specimens of respiratory secretions have been examined for tuberculosis. hiv-infected health care practitioners need to carefully assess their risk of acquiring tuberculosis by their exposure in the icu. transmission of hiv is an issue that requires attention in the icu. no evidence exists that hiv-infected health care professionals can infect patients, regardless of what procedure they perform, outside of two unusual events. hiv patients pose a risk to health care professionals, however. this risk can be substantially reduced by education, by strict monitoring for compliance with universal precautions, and by having proper equipment. almost all hiv transmission in an occupational setting occurs as a result of injuries involving sharp instruments (e.g., needles, scalpels). the risk of such injuries is about one case of hiv transmission per injuries, but the likelihood of transmission in an individual accident depends on the amount of viremia at the time of the accident (late-stage patients generally have more circulating virus than do early-stage patients) and the nature of the accident. most authorities recommend immediate prophylaxis if a signifi cant injury occurs involving an hiv-infected patient. considerable debate exists over the optimal choice of drugs and the optimal duration of therapy, but it is clear that initiating therapy within a period of hours rather than days is best. many authorities now advocate a haart regimen for any situation when the patient and health care provider determine that therapy is appropriate, and continue that for to weeks. increasingly, icus are caring for organ transplant recipients, either in the period immediately after the procedure or during a crisis that occurs days, weeks, months, or years after engraftment. managing each type of organ transplant recipient has unique features depending on whether bone marrow, kidney, heart, lungs, liver, or other organs are transplanted. , laboratory monitoring provides useful predictive information about the status of cellular immunity, humoral immunity, and neutrophil number and function. ultimately, however, clinical experience is necessary with each type of organ transplant and each immunosuppressive regimen to predict the most likely pathogens, when they most characteristically occur in relation to the transplant procedure, and what infl uence each immunosuppressive therapy has. an example of the temporal pattern of infectious complications after bone marrow transplantation is shown in figure - . although such fi gures are useful conceptually, however, the immunosuppressive regimens are changing rapidly, and such fi gures may be misleading when applied to current transplantation protocols. organ transplant recipients share a complex interaction between immunosuppression and infection. immunosuppression is usually necessary in allogeneic transplantation to permit graft survival. the more potent the immunosuppression, the more likely infection is to occur. strategies that use antimicrobial agents (drugs, vaccines, and other biologic products) aggressively may reduce the risk of and damage from infection in a manner that allows more potent immunosuppression and better graft survival. such approaches may include prophylactic antibacterial and antiretroviral treatment, as well as prompt empiric therapy for emerging febrile episodes. patients receiving hematopoietic stem cell transplantation (hsct) or solid organ transplants are often receiving antimicrobial prophylaxis. acyclovir for hsv, valacyclovir for cmv, fl uconazole for yeast, voriconazole for yeast and molds, trimethoprim-sulfamethoxazole for pcp, and quinolones for bacteria are used in various combinations at different transplant programs. these agents dictate which organisms will break through to cause disease, and what their antibiotic susceptibility patterns will be. several pathogens deserve special mention. cmv is one of the most prominent pathogens for solid organ and bone marrow transplant recipients. [ ] [ ] [ ] most disease is secondary (i.e., disease results from reactivation of a previously acquired, latent infection) in a seropositive organ recipient. in urban areas of the united states, % to % of the population is seropositive for cmv, and thus % to % of the transplant recipients will have latent infection that could potentially be reactivated. some cmv seronegative patients acquire primary infections from a cmvinfected organ or from cmv-infected blood or blood products. a few cmv seropositive individuals develop superimposed cmv disease from cmv acquired through a seropositive donor. laboratory monitoring of patients for evidence of cmv disease by using a dna amplifi cation assay, or surveillance of cmv antigen in buffy coat smears, is an important feature in efforts to reduce morbidity and mortality resulting from cmv. , [ ] [ ] [ ] [ ] [ ] intensivists need to understand how to interpret these assays in terms of starting empiric, pre-emptive, or defi nitive therapy. strategies to reduce the frequency of cmv disease with acyclovir, intravenous or oral ganciclovir (or oral valganciclovir), the investigational agent proganciclovir, or immune globulin are used by many programs. cmv disease can cause substantial morbidity and mortality including fever, hypotension, pneumonitis, hepatitis, glomerulitis, enteritis, and allograft injury. the availability of ganciclovir, foscarnet, and cidofovir has enabled these conditions to be treated successfully in many instances, although all three of these drugs are associated with substantial toxicity. whether immune globulin (either immune globulin or specifi c hyperimmune globulin) adds anything to the potency of therapeutic regimens is not clear, although these products are usually administered when they are available. pcp has been reported in recipients of most types of organ transplants. most organ transplant programs use pcp prophylaxis. , , trimethoprim-sulfamethoxazole is usually the prophylactic agent of choice because it is more effective than other agents, is well tolerated, and reduces the frequency of urinary tract infections and other potential complications (e.g., disease resulting from nocardia, s. pneumoniae, and haemophilus organisms). fungal infections have been common, but the causative pathogens are changing because of changes in prophylactic regimens. with the use of fl uconazole, candida albicans infections became less common. molds, especially aspergillus, became more important pathogens, as did fl uconazole-resistant candida. some programs are now using voriconazole prophylaxis. for such patients, mucormycosis and non-albicans candida are becoming more prominent causes of morbidity. thus clinicians must know what antifungal prophylaxis has been used in order to anticipate which complications will occur. mold infections can be diffi cult to diagnose: serum galactomannan assays can yield specifi c information, but the test has low sensitivity. mold infections almost never cause fungemia. thus diagnosis depends on cultures, which can be highly suggestive if obtained from sources such as bronchoalveolar lavage or biopsy. viral respiratory infections require particular mention because some are treatable and most are transmissible. community-acquired respiratory viruses such as adenoviruses, coronaviruses, or infl uenza can occur in immunocompetent or immunosuppressed patients. when respiratory infections occur in immunocompromised patients, health care professionals need to be certain that a transmissible virus is not the cause because of the potential to infect other patients, families, or hospital staff. of the respiratory infections, rsv deserves special attention in hsct patients. although rsv can, like other community-acquired viruses, cause disease in any patient population, it is especially lethal in solid organ, bone marrow, and stem cell transplants. thus rsv must be specifi cally sought in this patient population, as well as their visitors and health care providers, so that it does not spread to highly susceptible patients. similarly, when caring for immunosuppressed patients, attention to mycobacterium tuberculosis is important because this pathogen can also spread to other patients, families, and hospital staff. with more immigrants in the united states and more patients having travel exposure, m. tuberculosis needs to be considered in the differential diagnosis and specifi cally sought by gene probe, smear, or culture where appropriate. diagnosis and therapy of opportunistic infections and nosocomial infections should follow the guidelines given in chapters , , and . in choosing therapies, attention must be focused on the toxicities of antimicrobial agents and how they infl uence the outcome of the transplanted organ. in addition, drug interactions are important, especially with cyclosporine. drugs that alter hepatic metabolism, such as rifampin, rifabutin, and fl uconazole, can have substantial infl uence on cyclosporine levels and thus need to be used with careful pharmacologic attention. finally, clinicians must recognize that new immunosuppressive regimens and changing prophylactic regimens are changing the spectrum of infectious complications. as mentioned earlier, fungal infections are increasingly likely to be caused by species other than c. albicans: non-albicans candida, fusarium, and rhizopus are recognized with increasing frequency. similarly, prophylaxis with valganciclovir is reducing cmv disease and pushing disease that does occur later and later in relation to the transplant procedure. viruses such as hhv- and bk virus are causing disease. thus clinicians need to look for changing spectrum of pathogens, as well as changing manifestations if the morbidity and mortality caused by infection is to be managed optimally. ■ knowledge of a patient's specifi c defects in immunologic and infl ammatory response helps predict which opportunistic pathogens are most likely to occur. ■ icus are increasingly successful in enabling immunosuppressed patients to survive acute crises, especially if the defect in immunologic or infl ammatory function is reversible over time or by replacement therapy. ■ for neutropenic patients, gram-positive cocci are becoming more frequent than gram-negative bacilli as causes of life-threatening illness. ■ resistance to antimicrobial agents is becoming a major problem including bacteria (e.g., vancomycin-resistant enterococci and penicillin-resistant pneumococci), fungi (e.g., fl uconazole-resistant candida organisms), as well as pcp, and viruses (e.g., acyclovir-resistant herpes simplex and ganciclovir-resistant cmv). ■ in neutropenic patients, combination therapy should be considered when treating any life-threatening bacterial process. ■ a substantial fraction of hiv-infected patients with pcprelated respiratory failure can survive mechanical support and be discharged from the hospital. ■ adjunctive corticosteroid therapy is indicated for respiratory failure related to pcp. ■ tuberculosis is a concern in any immunologically abnormal individual with pulmonary disease but is a special concern in hiv-infected patients. tuberculosis in these cases often warrants respiratory isolation until appropriate specimens are evaluated for mycobacteria. ■ organ transplant recipients develop opportunistic infections at relatively predictable points depending on the type of transplantation and the specifi c immunosuppressive regimen used. innate (general or nonspecifi c) host defense mechanisms infections in solid organ transplant recipients infectious diseases associated with complement defi ciencies infection in organ-transplant recipients cd counts as predictors of opportunistic pneumonias in human immunodefi ciency virus (hiv) infection recent advances in the diagnosis and management of infection in the organ transplant recipient infections in recipients of hematopoietic stem cell transplantation bacteremia and fungemia in patients with neoplastic disease guidelines for the preventing opportunistic infections among hiv-infected persons- recommendations of the u.s. public health service and the infectious diseases society of america guidelines for the use of antimicrobial agents in neutropenic patients with cancer fever in immunocompromised patients use of intravenous immunoglobulin in human disease: a review of evidence by members of the primary immunodefi ciency committee of the american academy of allergy, asthma and immunology colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of randomized controlled trials neutropenia, neutrophil dysfunction, and bacterial infection in patients with human immunodefi ciency virus disease: the role of granulocyte colony-stimulating factor update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline monotherapy with meropenem versus combination therapy with ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer. the international antimicrobial therapy cooperative group of the european organization for research and treatment of cancer and the gruppo italiano malattie ematologiche maligne dell'adulto infection program a double-blind comparison of empirical oral and intravenous antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy monotherapy for fever and neutropenia in cancer patients: a randomized comparison of ceftazidime versus imipenem treatment of febrile neutropenia with cefepime monotherapy additional anti-gram-positive antibiotic treatment for febrile neutropenic cancer patients fever in the pediatric and young adult patient with cancer. a prospective study of episodes gram-positive infections and the use of vancomycin in episodes of fever and neutropenia ceftazidime monotherapy for empiric treatment of febrile neutropenic patients: a meta-analysis staphylococcus epidermidis: an increasing cause of infection in patients with granulocytopenia antibiotic synergism and response in gram-negative bacteremia in granulocytopenic cancer patients vancomycin-resistant enterococcal infections an evidence-based evaluation of important aspects of empirical antibiotic therapy in febrile neutropenic patients effi cacy of caspofungin against invasive candida or invasive aspergillus infections in neutropenic patients antifungal therapy in patients with fever and neutropeniamore rational and less empirical? caspofungin versus liposomal amphotericin b for empirical antifungal therapy in patients with persistent fever and neutropenia a randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin b versus amphotericin b lipid complex in the empirical treatment of febrile neutropenia. l amph/ablc collaborative study group levofl oxacin to prevent bacterial infection in patients with cancer and neutropenia guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. recommendations of cdc, the infectious disease society of america, and the american society of blood and marrow transplantation breakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants beta-lactam antibiotic therapy in febrile granulocytopenic patients. a randomized trial comparing cefoperazone plus piperacillin, ceftazidime plus piperacillin, and imipenem alone risk assessment and riskbased therapeutic strategies in febrile neutropenia randomized, double-blind clinical trial of amphotericin b colloidal dispersion vs. amphotericin b in the empirical treatment of fever and neutropenia voriconazole versus amphotericin b for primary therapy of invasive aspergillosis review of treatment of zygomycosis with posaconazole in a patient with acute myeloid leukemia intravenous and oral itraconazole versus intravenous amphotericin b deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy. a randomized, controlled trial anidulofungin: a new echinocandin with a novel profi le combination antifungal therapy for invasive aspergillosis treatment of solid organ transplant patients with invasive fungal infections: should a combination of antifungal drugs be used? prevention of intravascular catheter-related infections guidelines for the management of intravascular catheter-related infections guidelines for the prevention of intravascular catheter-related infections eortc guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapyinduced febrile neutropenia in adult patients with lymphomas and solid tumours return of granulocyte transfusions metaanalysis: the effi cacy of strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients intensive care of patients with hiv infection current issues in critical care of the human immunodefi ciency virus-infected patient declining morbidity and mortality among patients with advanced human immunodefi ciency virus infection. hiv outpatient study investigators critical care of immunocompromised patients: human immunodefi ciency virus neurologic manifestations of aids frequency of myocarditis, left ventricular dysfunction and ventricular tachycardia in the acquired immune defi ciency syndrome nonspecifi c interstitial pneumonitis: a common cause of pulmonary disease in the acquired immunodefi ciency syndrome small intestinal structure and function in patients infected with human immunodefi ciency virus (hiv): evidence for hiv-induced enteropathy thrombocytopenia in hiv infection human immunodefi ciency virus-associated autoimmune thrombocytopenic purpura: a review surveillance for aids-defi ning opportunistic illnesses prophylaxis against opportunistic infections in patients with human immunodefi ciency virus infection relations among cd lymphocyte count nadir, antiretroviral therapy, and hiv- disease progression: results from the eurosida study tuberculosis in patients with human immunodefi ciency virus infection disseminated histoplasmosis in the acquired immune defi ciency syndrome: clinical fi ndings, diagnosis and treatment, and review of the literature public health service guidelines for the management of occupational exposures to hiv and recommendations for postexposure prophylaxis interactions among drugs for hiv and opportunistic infections drug interactions in infectious diseases tuberculosis in patients with human immunodefi ciency virus infection. how often does it mimic pneumocystis carinii pneumonia? diagnosis of pneumocystis carinii pneumonia: improved detection in sputum with use of monoclonal antibodies the diagnosis of pneumocystis carinii pneumonia in patients with the acquired immunodefi ciency syndrome using subsegmental bronchoalveolar lavage lack of clinical utility of cytomegalovirus blood and urine cultures in patients with hiv infection national institute of health-university of california expert panel for corticosteroids as adjunctive therapy for pneumocystis pneumonia: consensus statement on the use of corticosteroids as adjunctive therapy for pneumocystis pneumonia in the acquired immunodefi ciency syndrome corticosteroids prevent early deterioration in patients with moderately severe pneumocystis carinii pneumonia and the acquired immunodefi ciency syndrome (aids) corticosteroids as adjunctive therapy for severe pneumocystis carinii pneumonia in the acquired immunodefi ciency syndrome. a double-blind, placebocontrolled trial a controlled trial of early adjunctive treatment with corticosteroids for pneumocystis carinii pneumonia in the acquired immunodefi ciency syndrome. california collaborative treatment group pneumocystis carinii pneumonia and respiratory failure in aids. improved outcomes and increased use of intensive care units critical care of patients with aids survival and prognostic factors in severe pneumocystis carinii pneumonia requiring mechanical ventilation survival following mechanical ventilation for pneumocystis carinii pneumonia in patients with the acquired immunodefi ciency syndrome: a different perspective incidence and risk factors for immune reconstitution infl ammatory syndrome in an ethnically diverse hiv type -infected cohort immune reconstitution syndrome in hiv: validating a case defi nition and identifying clinical predictors in persons initiating antiretroviral therapy incidence and risk factors for immune reconstitution infl ammatory syndrome during highly active antiretroviral therapy infections with cryptococcus neoformans in the acquired immunodefi ciency syndrome evaluation of the policy of empiric treatment of suspected toxoplasma encephalitis in patients with the acquired immunodefi ciency syndrome toxoplasmic encephalitis in patients with the acquired immunodefi ciency syndrome. members of the actg p/anrs study team toxoplasmic encephalitis in aids preemptive ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus antibody-positive renal transplant recipients. a randomized controlled trial prevention of fungal and hepatitis virus infections in liver transplantation antiviral drugs for cytomegalovirus in transplant recipients: advantages of preemptive therapy randomised trial of effi cacy and safety of oral ganciclovir in the prevention of cytomegalovirus disease in livertransplant recipients. the oral ganciclovir international transplantation study group whole blood real-time quantitative pcr for cytomegalovirus infection follow-up in transplant recipients prophylactic versus preemptive oral valganciclovir for the management of cytomegalovirus infection in adult renal transplant recipients benefi ts of cytomegalovirus prophylaxis in solid organ transplantation posttransplant microbiological surveillance should prophylaxis for pneumocystis carinii pneumonia in solid organ transplant recipients ever be discontinued? key: cord- -egoso w authors: sinha, vikas; jha, sushil g.; umesh, samanth talagauara; chaudhari, nirav p.; parmar, bhagirathsinh d.; patel, rashmin s. title: bedside tracheostomy: our experience in a tertiary care hospital date: - - journal: indian j otolaryngol head neck surg doi: . /s - - -w sha: doc_id: cord_uid: egoso w tracheostomy is the creation of a stoma at the surface of skin, which leads into trachea. in the critically ill patients, it is one of the most frequently done procedure especially in intensive care unit (icu) for those requiring prolonged mechanical ventilation. about % of all patients in icu need tracheostomy (esteban et al. in am j respir crit care med : – , ). historically it had a high complication rate and so many authors suggested that it should be done only in operating room (dayal and masri in laryngoscope : , ). a standardized procedure to reduce complications was described by jackson (laryngoscope : – , ). the aim of the study is to observe and analyze the outcome of bedside open tracheostomy, in relation to its safety, complications and simplicity. study consists of patients who underwent bedside tracheostomies in a tertiary care center from to in medical/surgical/paediatric icu’s. all the procedures followed a standard protocol. in all the surgeries, two e.n.t. surgeons were scrubbed and did the procedure, assisted by two icu nurses. one anesthetist who administered sedation and monitored the patient. if coagulation disturbances were present in elective case then they were corrected prior to the procedure. we all want the latest, safest, simplest and cheapest available technique in medical practice. bedside tracheostomy is one such procedure. it is better than tracheostomy in operating room for patients who need prolonged mechanical ventilation in icu as it eliminates the need of patient transport to or and its associated complications and also minimizing cost. training programs need to be provided to the assisting staff for better procedural outcome. tracheostomy is the creation of a stoma at the surface of skin, which leads into trachea. in the critically ill patients, it is one of the most frequently done procedure especially in intensive care unit (icu) for those requiring prolonged mechanical ventilation. about % of all patients in icu need tracheostomy [ ] . historically it had a high complication rate and so many authors suggested that it should be done only in operating room [ ] . a standardized procedure to reduce complications was described by jackson [ ] . in , sheldon [ ] introduced a newer method of percutaneous tracheostomy which had many techniques over the years [ ] . the technique described by ciaglia [ ] is being currently used most often. of late tracheostomies done bedside in icu's are proven to be safe [ ] . tracheostomy allows for patient mobilization, helps in feeding, physical and occupational therapy and decreases the need of sedation when compared to keeping patient intubated for prolonged duration. bedside tracheostomy is convenient and offers scheduling flexibility. it can be done without any coordination with operating room in normal business hours. also bedside tracheostomy obviates the transfer of critically ill patients to operating room [ ] . in a study massick et al. [ ] found excellent results in bedside tracheostomy and suggested that it reduces the patient charge and provides a more secure airway. the aim of this study is to highlight the advantages and disadvantages encountered during bedside tracheostomy. study consists of patients who underwent bedside tracheostomies in a tertiary care center from to in medical/surgical/paediatric icu's. all the procedures followed a standard protocol. in all the surgeries, two e.n.t. surgeons were scrubbed and did the procedure, assisted by icu nurses. anaesthetist who administered sedation and monitored the patient. if coagulation disturbances were present in elective case then they were corrected prior to the procedure. before starting the procedure, ventilator was changed to a set rate of at least and fio increased to %. intravenous sedation by midazolam and fentanil was given by anaesthetist on surgeon's request in un-cooperative and anxious patients. blood pressure, cardiac rhythm and arterial haemoglobin saturation were monitor by the anaesthetist continuously throughout the procedure. the neck was hyperextended with the help of a shoulder bag and head supported with a head ring (removed in patients needing more extension). aseptic surgical field was achieved by painting with betadine solution first followed by spirit. drapes were applied. local anaesthetic (lignocaine with adrenaline : , ) agent was injected into the neck soft tissues around the incision site to cause anaesthesia and to reduce bleeding. a vertical cm skin incision placed in the midline just above the suprasternal notch. skin and subcutaneous tissues divided up to the depth of strap muscles. strap muscles are separated vertically by blunt dissection. it is necessary at each step to palpate for the trachea and keep the surgical site clear of blood by repeated mopping. subsequently thyroid isthmus is seen which is retracted superiorly. then the tracheal rings can be palpated. trachea can be confirmed by presence of bubbles after introducing a half empty syringe in at and withdrawing it. next the tracheal incision is generally kept through the second to fourth tracheal rings. this is followed by dilating the tracheal opening with a tracheal dilator. after dilating the trachea, appropriate sized tracheostomy tube is introduced along with simultaneous withdrawing of endotracheal tube in intubated patients. following this tracheostomy tube is held in its position either by silk stay sutures or tying it with gauze piece. betadine gauze piece is kept below the tracheostomy tube to prevent skin necrosis below the tracheostomy tube. correct position of tube is confirmed by checking for movement of gauze piece placed in front of tube, maintaining of oxygen saturation, and lastly the presence of bilateral equal air entry. chest x-ray was taken the next day to confirm the correct tube placement and to look for pneumothorax if any. the study group had patients. it included males, females and children (\ years). maximum patients belonged to - years of age. among the various departments in which bedside tracheostomy (both elective and emergency) needed to be done, majority patients were in ent dept. ( %, n = ) followed by medical icu ( . %, n = ), then surgical icu ( %, n = ) and paediatric icu and burns ward. the most common cause for bedside tracheostomy was prolonged intubation ( %, n = ); this included road traffic accident with head injury, cardio vascular stroke, accidental fall down, organophosphate poisoning, guillan barre syndrome, chronic obstructive pulmonary disease, acute respiratory distress syndrome. other causes were cancer patients ( %, n = ) of larynx, buccal mucosa, tongue which sometimes needed a prophylactic pre-operative tracheostomy. few patients were of burns. paediatric causes ( %, n = ) were tetanus, diphtheria. the mean operative time was min (range - min). we faced many major and minor complications during tracheostomy. one of the most common was minor bleeding following either skin incision or after separating the strap muscles due to tissue disruption of the neck. this was managed with either tying the bleeder or using monopolar cautery (table ) . stromal infection within a month was very frequent and hence associated with significant morbidity. in this study the incidence of stromal infection was in % of patients, which is less than that in literature [ ] . low infection rate in our study was due to careful separation and not cutting of neck tissues. this happens due to unsterile instruments or procedure. once diagnosed we send the pus for culture and sensitivity followed by appropriate antibiotic therapy and regular sterile dressing. few patients had surgical emphysema. this is due to a large opening in the trachea more than the diameter of the tracheostomy tube or due to a large skin incision. its management is by manual removal of subcutaneous emphysema by pressure and reducing the length of skin incision by suturing. cardiac arrest was seen in three patients. these were patients with dyspnea for a long duration. there respiratory drive was co dependent. therefore, as soon as the tracheal incision was placed, co escaped and patient went into cardiac arrest. two of the three patients could be revived by cpcr, but one succumbed to death. the incidence of post cannulation stenosis was also low [ ] due to avoidance of tracheal ring resection. this is in line with larger studies, which have reviewed complications, including a meta-analysis of outcomes for surgical procedures [ , ] . simpson et al. [ ] stated that out of fear of transporting ill patients tracheostomies were less frequently used in the past. so it was preferred to do tracheostomies in operating room (or) instead of bedside due to better lighting, sterile and adequate instruments and support facilities [ ] . problems encountered in this are hazard of moving critically ill patients, [ ] the cost and inconvenient or schedules. but in a study by henrich it is shown that transportation is not a critical issue [ ] also in many hospitals the number of icu beds are limited [ , , ] and patients with ventilators are kept in regular wards [ , , ] . in addition, there is delay in performing tracheostomy in operating theatre due to less number of or and more elective and emergency procedures. this causes an overall lengthening the hospital stay of patients, delaying the weaning process [ , [ ] [ ] [ ] [ ] and patient's morbidity is increased [ , , ] . doing tracheostomy bedside is less time consuming. it is safe in icu patients. study by massick et al. concluded that bedside tracheostomy provides a secure airway at markedly reduced patient charges [ ] . but there are a few inherent difficulties performing a bedside tracheostomy like big sized icu beds; few having water beds and hence not a firm surface to do tracheostomy, causing discomfort to the operating surgeon, inadequately trained staff for assistance, inadequate lighting, unsterile and insufficient instruments. in a study by bowen et al. [ ] % (n = ) and in a study by gysin et al. [ ] the rate is % (n = ), in our study it is % (n = ) which is acceptable. in a study by upadhyay et al. [ ] major bleeding occurred in % (n = ) of patients, whereas in our study there were no patients with major bleeding. terra et al. [ ] had . % (n = ) of infections at stoma site, but we have had % (n = ) infections at stoma site. based on our study there are two crucial principles for best results in bedside tracheostomy. firstly, the team should be well versed with tracheostomy. many feel that tracheostomy is a simple procedure, but overconfidence and inexperience may lead to disastrous consequences. secondly, there should be a standardized procedure and team cooperation between operating surgeon, anaesthetist and staff nurse. adequate lighting and material should be there and everyone involved must be familiar with the steps of the surgical procedure. we all want the latest, safest, simplest and cheapest available technique in medical practice. bedside tracheostomy is one such procedure. it is better than tracheostomy in operating room for patients who need prolonged mechanical ventilation in icu as it eliminates the need of patient transport to or and its associated complications and also minimizing cost. training programs need to be provided to the assisting staff for better procedural outcome. how is mechanical ventilation employed in the intensive care unit? an international utilization review tracheostomy in intensive care setting a new method for tracheostomy review of percutaneous tracheostomy percutaneous tracheostomy: has its time arrived? percutaneous or surgical tracheostomy: a meta-analysis tracheotomy and the intensive care unit patient bedside tracheostomy in the intensive care unit: a prospective randomized trial comparing open surgical tracheostomy with endoscopically guided percutaneous dilational tracheostomy a prospective, randomised evaluation of early and late complications after either percutaneous or surgical tracheostomies the impact of percutaneous tracheostomy on intensive care unit practice and training elective bedside tracheostomy in the intensive care unit bedside tracheostomy in the intensive care unit mechanical ventilation of patients hospitalized in medical wards vs. the intensive care unitan observational, comparative study medical and economic implications of prolonged mechanical ventilation and expedited postacute care predictors of mortality of mechanically ventilated patients in internal medicine wards comparison of safety and cost of percutaneous versus surgical tracheostomy percutaneous versus surgical tracheostomy, a double-blind randomized trial elective bedside tracheostomy in the intensive care unit open bedside tracheostomy: routine procedure for patients under prolonged mechanical ventilation key: cord- -m c nv authors: wijdicks, eelco f. m. title: communicating neurocritical illness: the anatomy of misunderstanding date: - - journal: neurocrit care doi: . /s - - -x sha: doc_id: cord_uid: m c nv we talk, text, email all day. do we perceive things correctly? do we need to improve the way we communicate? it is a truism that providing insufficient information about a patient results in delays and errors in management. how can we best communicate urgent triage or urgent changes in the patient condition? there is no substitute for a face-to-face conversation but what would the receiving end want to know? one starting point for those practicing acute neurology and neurocritical care is a new mnemonic tell me (time course, essence, laboratory, life-sustaining interventions, management, expectation), which will assist physicians in standardizing their communication skills before they start a conversation or pick up a phone. these include knowing the time course (new and "out of the blue" or ongoing for some time); extracting the essentials (eliminating all irrelevancies); communicating what tests are known and pending (computerized tomography and laboratory); relaying how much critical support will be needed (secretion burden, intubation, vasopressors); knowing fully which emergency drugs have been administered (e.g., mannitol, antiepileptics, tranexamic acid), when transport is anticipated, and what can be expected in the following hours. perfect orchestration in communication may be too much to ask, but we neurointensivists strive to convey information accurately and completely. communication must be taught, learned, and practiced. this article provides guiding principles for a number of scenarios involving communication inside and outside the hospital. we write and read notes; then we talk, call, text and email about our patients [ ] [ ] [ ] [ ] . we can be reached instantaneously, but, in all sincerity, why are some messages unheeded? we all like to believe that we are getting the relevant information in a timely manner-but not necessarily. bear in mind that providers are interrupted constantly [ ] ; plans change and decisions multiply rapidly throughout the day. communication between healthcare workers involves communication of an incoming patient or outgoing patient with transfer in the hospital or out the hospital. handoffs (sign-outs) have been best studied and the importance of the handoff is bolstered by the observation that night interns reference the written or verbal sign-out in order to answer questions that arise during the night [ ] . at least one survey suggests that a "better" signout would lead to a reduction in adverse events [ ] . another survey study asked clinicians to identify for each patient whether they anticipated any nighttime events and what type of events they would expect. in handoffs of over patients, nighttime clinicians were interviewed immediately after the handoff, before they cared for patients. nighttime clinicians were only able to identify % of the daytime clinicians' diagnoses [ ] . these were clustered into five predefined domains (hemodynamic, respiratory, metabolic, neurologic, and hematologic). patients with changes in level of consciousness were less likely to have correctly identified diagnoses. in many instances, there was a fundamental misunderstanding of a patient's course. more seriously, communication errors may have contributed to underestimation of aspiration risk and cardiac arrhythmias [ ] . a communication loaded with irrelevancies, extraneous detail or self-contradictory information, and a lessthan-succinct summary clearly sets up a risk for missed vital information and misunderstanding. without a standardized handoff, the risk of not communicating potentially relevant information may leave the recipient healthcare provider in a state of confusion [ ] [ ] [ ] [ ] . in any case, improved provider perceptions of transfer workflow efficiency and patient safety may not be enough; communication must also include solutions for active medical problems and an outline of anticipatory guidance ("what if-what then" scenarios) in the event an acute change in clinical condition occurs. checklists improve communication [ , ] . incorporating the checklist into the electronic health record allows data to auto-populate and eliminates reliance on the provider's memory for specific details of, for instance, medication dosages or administration times. the remaining problem is the sustainability of checklists and whether they may eventually disappear or remain unfiled. checklists may not reduce intensive care unit (icu) readmissions or rapid response team calls [ ] . the rapid readmissions or so-called bounce backs remain difficult to predict, and communication failure is just one factor [ , ] . generally, inadequate communication leads to a diffused responsibility, and we will pay a price. in addition, physicians tend to overestimate the effectiveness of their communication. moreover, when retrospectively surveyed, there is significant disagreement on what is the most important piece of communicated information. crosscoverage demands solid communication. one important -month study at brigham and women's hospital showed that the risk of a preventable adverse medical event was more than twice as likely with coverage by a physician from another team [ ] . no currently existing tool, requirement, or system provides a standard system of communication. most recently, the emergency neurological life support (enls) lecture series [ ] provides communication tables with sample scenarios to use when transitioning care from prehospital to emergency department and to neurocritical care unit. in-hospital communication protocols have used the "situation-background-assessment-recommendation" (sbar) model, but it lacks specificity. use by nursing staff is inconsistent, and use by icu physicians is virtually non-existent. many derivatives of the sbar model have been used but with insufficient validation in most of them [ ] . in addition, there often is a lack of training on effective communication and how to avoid interruptions and distractions in a chaotic environment. most of the time, it appears there is inadequate amount of time for a successful communication. the perfect note in the medical record may tell it all, but there cannot be a substitute for a face-to-face conversation. once we have a detailed neurologic and physical examination, we should have a good sense of what we are up to and what might happen. i will explore the commonly encountered scenarios, communication style, and how to acquire the necessary skills. the goal is to help readers understand the great variety of responses to presented information. the information provided would help physician in all specialties and levels of training. this information may come from outside the hospital (out-in) or inside the hospital (in-in) or (in-out) when it relates to transfers to the floor or other institutions such as skilled nursing homes. the purpose here is to do far more than examine our foibles and to present a framework for adequate communication in the form of a mnemonic. without intentionally disparaging respected colleagues (and in full awareness that none of us are infallible), i offer a few examples (inspired by real events) to illustrate some of the issues at hand. i have added a more detailed description with each of these conversations to point out missed opportunities of communication. typically, the most error-prone situations are the triage and direct admissions to the neurosciences icu and the communications on management or transfer out of the icu. physician a: i have a patient here who is pretty much unresponsive after a fall and computerized tomography (ct) scan shows a hemorrhage. i want to send him over. neurointensivist: what more can you tell me? physician a: we are going to intubate him. neurointensivist: what does his examination show? physician a: glasgow coma scale (gcs) of . neurointensivist: can you tell me more? physician a: that is pretty much it. otherwise stable. the situation: the ct scan shows an acute subdural hematoma with shift. the brainstem reflexes are intact, but the pupil on the same side of the hemorrhage is wider. inr returns markedly elevated. best advice is osmotic diuretics and adequate reversal of anticoagulation with pcc and iv vitamin k and to call a neurosurgeon before he arrives. any neurointensivist will instinctively ask, "what is the matter with this patient?" and look for patterns even when our referring colleagues do not explain things clearly. we have trouble understanding those who do not seem to understand and unintentionally make use of imponderables and less-than-clear phrases (table ) . inarguably, communicating insufficient information about the patient can result in insufficient or inappropriate care before transport, such as in the example above. perfect orchestration in collaborative communication may be too much to ask, but the neurointensivist should continue to consider these three most pertinent questions: . is the patient deteriorating and, if so, from what? . is a neurosurgical (craniotomy) or neurocritical care intervention (osmotic agents) urgently needed? . is an endovascular procedure needed? physician a: i am covering the rapid response team and i have a patient on the ward who just had a seizure and needs to go to the neuro icu. calls from the rapid-response team are common reasons for intensive care admissions, and the rapid responder has (and should have) the upper hand. information is fragmented, and rapid transfer takes preference above detailed planning. some arriving patients look just fine; others are very unstable. regardless, their arrival often leads to some sort of surprise. we have an obligation to support our colleagues who take on rrt services, but we also hope for effective communication. patients should not be different than "advertised. " the neurointensivist: we are going to transfer a tbi patient to you because he does not need any more icu level of care, and we have a bed crunch. the floor consultant: anything more i need to know? the neurointensivist: he has been doing fine. we kept him longer because there were some secretion and blood-pressure issues. the floor consultant: do you think the nursing staff will be comfortable with taking care of him? the neurointensivist: i think so. the situation: this patient just recovered from a ventilator-associated pneumonia. moreover, there was an escalation of blood pressure medication and only h of significant reduction of secretion burden. six hours after transfer, the patient bounced back with difficulty clearing secretions and a blood pressure surge. how can we best communicate urgent admissions to and discharges from the neurosciences icu? ideally, correct information is provided, and no further questions are needed. any tool must be both useful to the sender (who knows what to focus on) and receiver (who knows what to ask) and should be user friendly to all levels of expertise. one reasonable start is the mnemonic tell me (fig. ) to assist physicians to standardize their communication. components of tell me include knowing table less than clear phrases and imponderables "altered" "not talking and moving only on the left side" "going in and out of consciousness" "pupils are now sluggish" "staring and not responding" "shakin' all over" "it is bad; i mean, really bad" "no responses anywhere" fig. mnemonic tell me the time course (new and unexpected or ongoing for some time), extracting essential information from irrelevancies, communicating which tests are pending (ct and laboratory), relaying how much crucial support will be needed (e.g., secretion burden, intubation), knowing which emergency drugs have been administered (e.g., mannitol, antiepileptics, tranexamic acid), certainly when transport is planned, what neurosurgical procedure or endovascular intervention can be anticipated, and planning for worst-case scenarios. with this information, the staff knows exactly what to expect and is well prepared to intervene quickly. additional guidance will also improve communication. here are suggestions. . reverse the order. try starting with your final diagnosis and then discuss how you arrived there. the listener's mind is better attuned to hearing the key findings first, followed by an abbreviated timeline. while a few options can be mentioned, a full differential diagnosis takes too long and should be considered later. . extract the essence. our cognitive processing ability is continuously challenged. vague descriptions (e.g., patients are unresponsive, seizing, trashing around) are not helpful. avoid digressions as well as unnecessarily complex, repetitive, and long-winded exposition. cut to the chase! most healthcare workers with a lot on their plates have very short attention spans and little time for festooned language. if detail in neurologic examination is provided, remember that symmetric reflexes are not essential information (unless the patient has guillain-barré syndrome), sensation findings are seldom urgent (unless there is a clear spinal cord level or discrepancy between modalities), and same with tone (unless the patient has a serotonin syndrome or exhibits dysautonomic storming). . avoid numbers that lack specifics. "this patient was found with a gcs of and nihss of ." unsurprisingly, the most simple scales are the most likely to persist in medical practice, which also implies that they are too simplistic to be informative or have domains with little clinical applicability. moreover, some scores may hide important information, and numbers are only useful with clinical trial statistics. scales and sum scores have inflicted serious harm on how we communicate the results of the neurologic examination and neuroimaging. "the ct scan shows no bleed" is not an appropriate description. instead, tell me what you looked for; for example, "the ct scan shows no hyperdense mca or hyperdense basilar sign, or the basal cisterns are open, the ventricles are normal in size, there is no contusion or traumatic subarachnoid hemorrhage, and there is no soft tissue hematoma. " . avoid language we cannot understand. some vagueness can easily slip in (table ) . we cannot expect superior knowledge of the neurologic examination and expert grasp of the meaning of clinical patterns mean from those less experienced in assessing acutely ill neurologic patients. but the sender of information should not attempt to compensate for lack of knowledge by guessing. likewise, the receiver should not berate the sender. most neurologic findings on examination require some deep thinking and time. . what do i need to know for the night? communication during shift changes is crucially important. neurocritical care is a sui generis specialty. one of the major paradoxes of neurocritical care is that the talkative, comfortable patient sitting in a chair after a ruptured cerebral aneurysm and in situ ventriculostomy is actually critically ill. critical illness is not defined by systemic criteria but by the high likelihood the patient may deteriorate quickly from consequences of the initial injury-the second wave of devastating neurologic injury, so to speak. summarize the examination and what it would look like when deterioration occurs (e.g., sleepiness, any confusion or agitation, new speech difficulties, new drift, not moving legs, cerebral vasospasm in the anterior cerebral artery). . which studies are repeated? which pending studies need review, and when are they expected? electronic devices can set up alerts from electronic medical records in some institutions, but we still need to know when to expect the study. what are the potential expectations? watch for new blossoming contusions, enlarging subdural hematoma, worsening hydrocephalus, to name a few. a good line of communication should establish what to expect. . what is the resident or fellow's threshold to call a consultant? not a minor issue in training hospitals. very few consultants routinely remain in the icu overnight, and night is covered by residents and fellows. with standard staffing, a historical paradigm in the unit is an intensivist present during the daytime and taking calls from home at night, returning to icu as deemed necessary. shift work may not be the best solution. in fact, avoidance of shift work is the most common reason for emergency medicine physicians to retire as they age [ ] . easy remote access to patient data has reduced the need to be onsite. my residents always ask me when i like to be called, and i share my three criteria: call me min before you get nervous, do not let me miss the excitement, and remember i am comparable to a operator who will answer the phone immediately day and night. i do not ask the residents if i should come in (they always answer with an emphatic no), but i return to the hospital if there is a potential benefit to the patient or family. i cannot promise anything less while on call. these directives have always been understood and worked very well. . call, text or email? it is a new world of information gathering. for the younger generation, speaking on the phone is a lower priority. but a few simple suggestions are worthwhile. we should not email if we can text. e-mails should not be time-sensitive or require a response within a few hours. texts are irrepressible but should be considered urgent; a breezy, inappropriate subject line such as "heads up" downplays the urgency. . is your "listener" actually listening? it takes a while to discern, but some behaviors clearly show that your listener is, indeed, not listening. learn to recognize perfunctory attention from someone who is preoccupied or focused on something else (such as checking a smart phone while speaking). behaviors include looking at the phone, an unfocused gaze, or mentioning another, imminent commitment (e.g., "sorry, i have to run to another meeting, " "i have to take this call. "). . do you become easily annoyed? can you avoid being dismissive or overwrought? do you recognize loss of resilience? as a cautionary note to all of us: burnout manifests itself first in communication and is recognizable by irritating and snarky remarks. dark sarcasm and compassion fatigue follow. it is eventually destructive and adversely affects care and professionalism. moral distress, incivility, and conflict among colleagues are important drivers of burnout. one european multinational landmark icu study found that personal animosity, mistrust, and communication gaps are the most common inter-professional, conflict-causing behaviors [ ] . communications with specialists with no neurologic background can be very successful but only if time is taken to discuss the presenting clinical picture in detail. it is a sad indictment of our profession that we have grown accustomed to disinformation, delayed information, or no information at all (and even no patient identity). however, most of us would strongly prefer it be otherwise, and it is something we need to address. to change a possible culture of using generalities, scores, scales and other inessentials, we need to engage many of our colleagues. we can expect a readiness to improve by all accounts, particularly if the outcome leads to more appropriate triage and better preparedness before the patient goes enroute. unquestionably, there is a need for research into how communication is used. we can consider using simulation centers, which might be ideal set-ups for communication scenarios; these could include scenarios with deliberately confusing or vague language to recreate the potential downstream consequences for management. a control group could make use of tell me (fig. ) or other simple mnemonics. these might be more helpful than checklists, which can be too time consuming and too specific. only with those data can communication be taught, learned, and practiced. ropper famously asked two crucial questions in how to determine if you have succeeded at neurology residency. he provocatively asked, "can you present a case to an intelligent colleague in min?" and "can you tell who is sick?" [ ] . many of us need to continue to hone our interpersonal communication skills, and the aforementioned fundamentals can help to change a culture of fragmented communication. it requires recognition of what is important (and what is not) and of how to avoid wasting time. however, as a whole, better communication means understanding what your listener wants or needs to hear. ideally, the communicator is logically succinct, and the listener asks answerable questions. every complex problem can be easily summarized in a few sentences with training. none. using texting for clinical communication in surgery: a survey of academic staff surgeons secure clinical texting: patient risk in high-acuity care email for clinical communication between healthcare professionals leading article: use of smartphones to pass on information about patients-what are the current issues? overnight crosscoverage on hospital medicine services: perceived workload based on patient census, pager volumes, and patient acuity assessment of internal medicine trainee sign-out quality and utilization habits attitudes about patient safety: a survey of physicians-in-training kajdacsy-balla amaral ac. handovers among staff intensivists: a study of information loss and clinical accuracy to anticipate events fumbled handoffs: one dropped ball after another residents' and attending physicians' handoffs: a systematic review of the literature standardized sign-out reduces intern perception of medical errors on the general internal medicine ward simple standardized patient handoff system that increases accuracy and completeness structured handoff checklists improve clinical measures in patients discharged from the neurointensive care unit standardized sign-out improves completeness and perceived accuracy of inpatient neurology handoffs preventing early bouncebacks to the neurointensive care unit: a retrospective analysis and quality improvement pilot a standardized checklist improves the transfer of stroke patients from the neurocritical care unit to hospital ward does housestaff discontinuity of care increase the risk for preventable adverse events? emergency neurological life support: fourth edition, updates in the approach to early management of a neurological emergency systematic review of handoff mnemonics literature factors associated with career longevity in residency-trained emergency physicians prevalence and factors of intensive care unit conflicts: the conflicus study how to determine if you have succeeded at neurology residency none. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -wo r zny authors: collins, curtis d; west, nina; sudekum, david m; hecht, jason p title: perspectives from the frontline: a pharmacy department’s response to the covid- pandemic date: - - journal: am j health syst pharm doi: . /ajhp/zxaa sha: doc_id: cord_uid: wo r zny purpose: the global coronavirus (covid- ) pandemic has created unprecedented strains on healthcare systems around the world. challenges surrounding an overwhelming influx of patients with covid- and changes in care dynamics prompt the need for care models and processes that optimize care in this medically complex patient population. the purpose of this report is to describe our institution’s strategy to deploy pharmacy resources and standardize pharmacy processes to optimize the management of patients with covid- . methods: this retrospective, descriptive report characterizes documented pharmacy interventions in the acute care of patients admitted for covid- during the period april to april , . patient monitoring, interprofessional communication, and intervention documentation by pharmacy staff was facilitated through the development of a covid- –specific care bundle integrated into the electronic medical record. results: a total of , pharmacist interventions were documented in patients who received a total of , medication days of therapy during the study period. the average number of interventions per patient was . the most common interventions were regimen simplification ( . %), timing and dosing adjustments ( . %), and antimicrobial therapy and covid- treatment adjustments ( . %). patients who were admitted to an intensive care unit care at any point during their hospital stay accounted for . % of all interventions documented. conclusion: a pharmacy department’s response to the covid- pandemic was optimized through standardized processes. pharmacists intervened to address a wide scope of medication-related issues, likely contributing to improved management of covid- patients. results of our analysis demonstrate the vital role pharmacists play as members of multidisciplinary teams during times of crisis. s ince the first case of severe acute respiratory syndrome coronavirus (sars-cov- ) infection was discovered in wuhan, china, in december , there has been an explosion of coronavirus disease (covid- ) cases, leading to significant strains on healthcare systems and workers around the world. hospitals have been forced to respond to a large influx of patients with covid- while adjusting to staffing and medical supply shortages, including shortages of personal protective equipment (ppe) and critical medications such as antimicrobials, sedatives, and paralytics. , the therapeutic management of patients with covid- also constitutes a unique challenge. patients can quickly decompensate, and unproven medical therapies are being used for treatment based on anecdotal or lowquality evidence. , many of these treatments also come with the potential for significant toxicity and a need for close monitoring, which requires the note pharmacy department's response to covid- pandemic leadership of the pharmacist as a key part of the multidisciplinary team. pharmacists are well positioned to be a source of critical information and support during this public health crisis. pharmacy services in critical care settings have been shown to reduce drug errors, adverse drug events (ades), morbidity and mortality rates, length of stay (los), and healthcare costs. [ ] [ ] [ ] [ ] [ ] pharmacists also play a role in minimizing safety risks and conserving ppe by optimizing medication regimens to reduce entry to and exit from patient rooms. managing and preventing drug shortages is a critical need during the covid- pandemic, and pharmacists are well suited to meet this challenge. , a pharmaceutical framework for the management of covid- has been suggested by clinicians from around the world. this framework emphasizes pharmacist involvement in evidencebased decision-making regarding medications, assisting clinicians in formulating and adjusting drug regimens of patients with covid- , providing close monitoring of medication safety and efficacy, and managing drug interactions. , , pharmacists have a history of responding similarly in previous outbreaks, such as the pandemic caused by influenza a virus subtype h n , and national organizations such as the american society of health-system pharmacists have issued guidance on the role of pharmacists in emergency preparedness. [ ] [ ] [ ] although these concepts are familiar and part of the day-to-day fabric of pharmacy activities, the fluidity and rapidity of the spread of covid- is unprecedented. developing and implementing processes and interventions targeting specific disease syndromes has been shown to be an effective way to improve prescribing in the management of other infectious diseases, because messages can be focused, reinforced, and sustainable. [ ] [ ] [ ] [ ] here we describe our experience and approach to management of patients with covid- in a time when our state and healthcare organization were among those hit particularly hard by the pandemic. utilizing aspects of the pharmaceutical framework for the management of covid- , our institution created a comprehensive care bundle within the electronic medical record (emr). decentralized clinical pharmacists were integrally involved in the care of patients with covid- and used this comprehensive care bundle to help optimize patient care. the aim of this descriptive report is to share our experiences by describing pharmacy services at our institution during the covid- pandemic. the primary objectives of this analysis are to describe strategies used to standardize pharmacy processes to optimize the management of patients with covid- and to quantify the volume and scope of pharmacist interventions during the peak of our pandemic response. secondary objectives include describing clinical and medication use characteristics of patients with covid- and analyzing documented interventions in patients receiving various medication therapies. workforce processes and bundle development. our hospital is a -bed community teaching hospital located in the state of michigan. it has a central distribution pharmacy model and uses the epic emr (epic systems corporation, verona, wi). clinical pharmacy services are provided by a team of clinical specialists ( . full-time equivalents), clinical pharmacists, and postgraduate year pharmacy residents. during the study time period, the number of confirmed covid- cases in the state of michigan rose from , to , , with the number of reported deaths climbing from to , . the first patient with covid- treated within our organization was admitted in mid-march . the number of admitted patients with confirmed or suspected covid- increased dramatically, with a proportionally greater increase in the intensive care unit (icu) population. elective procedures and surgeries were suspended. the icu capacity of beds was increased to beds in order to house primarily patients with covid- . a -bed overflow special pathogens unit, previously equipped for management of critical care patients during a disaster response, was opened. the overall hospital census was below normal, so the clinical pharmacy coverage model was adjusted with a goal of to icu patients per pharmacist and a maximum of patients (to include with covid- ) for pharmacists covering intermediate care and general care patients. the pharmacy resident rotation schedule was revised so that residents could be part of the care teams during the crisis and still meet the requirements of the residency program. pharmacists with previous critical care experience were oriented to covid- protocols to ensure adequate clinical coverage for a potential icu surge. the institutional and department of pharmacy leaderships made it a priority to respect social distancing guidance and to protect the workforce. the department implemented strategies to limit healthcare worker exposure, both for immediate safety reasons and also to protect the ability to call upon those workers later for necessary in-house work and/or to provide relief for on-site pharmacists as the pandemic evolved. therefore, as part of that overall • a pharmacy department's response to the covid- pandemic was optimized through standardized processes. • results of a retrospective descriptive analysis show the quantity and scope of interventions clinical pharmacists are making in the care of patients with covid- . • the results demonstrate the vital role pharmacists play as members of multidisciplinary teams during times of crisis. pharmacy personnel also led or supported organizational efforts in several ancillary ways. pharmacy personnel collaborated to proactively develop strategies to mitigate resource limitations using a well-established process. the first step was identification of all available medications used for the treatment and management of covid- (including sedatives, analgesics, paralytics, antimicrobials, continuous renal replacement therapy solutions, and immune modulators). we then worked with suppliers to obtain adequate stocks to meet the predicted pandemic surge. daily shortage updates were disseminated to the pharmacy and hospital staffs. the most challenging medication shortages involved neuromuscular blockers and intravenous (i.v.) sedatives. the availability of products fluctuated, requiring careful oversight by pharmacists. in order to reduce ppe use by the pharmacy staff, the department leadership adjusted workflow in the i.v. room, consolidated medication deliveries to nursing units, and increased stocks in automated dispensing cabinets (adcs) to reduce potential pharmacy technician exposure to sars-cov- . additionally, pharmacists adjusted medication orders and administration times during verification to help the nursing staff reduce trips into patient rooms. analysis of the rapidly evolving stream of primary literature pertaining to covid- in order to contribute to the development of organizational guidelines was also a vital component of our response. this area of activity included incorporation of resident and student learners to maximize the review and evaluation process. guidelines for covid- management included a suite of recommendations emphasizing that standard therapy is supportive care and that antimicrobial use is guided by institutional antimicrobial stewardship principles. additional recommendations included qtc monitoring (ie, cardiac monitoring of heart rate-corrected qt interval), and drugdrug interaction and laboratory monitoring targeted to covid- therapies. use of hydroxychloroquine was listed as a conditional "consider" recommendation, and we recommended avoidance of combined hydroxychloroquine and azithromycin therapy. all covid- antimicrobial therapies and consideration of interleukin- inhibitor use required infectious diseases staff approval. expanded access investigational new drug applications and clinical trial enrollment were also explored early in the pandemic response. this process was facilitated by redistribution of efforts by our oncology investigational research team and coordination between infectious diseases and pharmacy personnel and our investigational review board. during the latter half of the analysis, patient enrollment for an expanded-access trial of remdesivir (clinicaltrials.gov trial identifier, nct ) began. qualifying patients were also subsequently enrolled in an expanded-access trial of convalescent plasma therapy (trial identifier, nct ). in order to standardize processes, the clinical pharmacy team developed a covid- syndrome-specific intervention in the form of a standardized care bundle for management of patients with covid- . elements of the bundle ensured that all aspects of care were addressed daily: optimization of medication therapy, streamlining of regimens for nursing workflow efficiency, and management of drug shortages. the components of the bundle were built in an epic smartphrase, which was loaded into the pharmacy handoff tool as a template for documentation ( figure ). interventions were captured using the epic ivent tool (figure ). the process for bundle review and documentation was not a unique concept for the pharmacy staff at our organization, as we use this strategy to target other high-impact infectious disease syndromes and the process is incorporated into the daily pharmacy workflow. [ ] [ ] [ ] study design. a retrospective, descriptive analysis covering the period april through april , , was conducted. patients with covid- were identified through review of emr documentation. all patients during the study period with a documented pharmacy intervention and a positive sars-cov- test were included in the analysis. positive tests were confirmed through reversetranscriptase/polymerase chain reaction assay via nasopharyngeal swab. medication utilization data were unavailable for patients in our cohort, and these patients were excluded from medication utilization analyses. as patient admission may have occurred prior to the data collection period, total length of stay was calculated as the interval from admission to discharge or the end of the study period. concurrent disease states was determined through emr reporting. medications were grouped for analysis according to therapeutic category. covid- therapies were defined as hydroxychloroquine, tocilizumab, and remdesivir. antipseudomonal antimicrobials were defined as any antimicrobial with activity against pseudomonas aeruginosa. medication days of therapy (dot) was measured as the number of calendar days with any documented administration. all pharmacy documentation was reviewed by research team members. interventions were defined as any documentation of action by pharmacy personnel. intervention types were classified according to predefined categorization built via smartphrase into ivent documentation. research team members reviewed each intervention and categorically classified interventions based on written commentary by the clinical pharmacy team (if available). if commentary was unavailable, interventions were classified according to the designated category assigned by the pharmacist at the time of ivent documentation. data analysis was performed using microsoft excel (microsoft corporation, redmond, wa). the study was approved by the health system's institutional review board. clinical and demographic information on the patients identified for inclusion in the analysis is presented in table . thirty-nine percent received care at any point in their stay in a designated icu, and the average length of stay in the icu during the study period was . days. at the end of the study period . % of the patients remained admitted, . % had been discharged home, and . % had died. the patients received a total of , medication dot ( table ). the average number of dot per patientday was . , and patients received an average of . different medications. the most commonly received regimens included anticoagulation therapy included anticoagulation therapy ( . %), electrolyte supplementation ( . %), covid- -related treatment regimens ( . %), and antimicrobials ( . %). excluding covid- -related treatments (eg, hydroxychloroquine), the average duration of antimicrobial therapy in patients treated for suspected or confirmed infection was . days. antimicrobial use was generally directed towards community-acquired pathogens; however, % of patients received vancomycin and . % received antipseudomonal coverage at any point during the study period. the average durations of vancomycin or antipseudomonal coverage were . and . days, respectively. there were a total of ivent entries documenting , interventions throughout the study period ( table ). the average number of interventions per patient was , with an average of intervention per patientday. there were documented interventions involving all elements of the covid- monitoring bundle. the most common pharmacy interventions were regimen simplification ( . %), timing and dosing adjustments ( . %), antimicrobial and covid- treatment adjustments ( . %), and nonspecific interventions classified as other ( . %). documented interventions for patients receiving sedation with or without neuromuscular blockers and patients receiving antimicrobial therapy and/or other covid- treatments averaged . and . interventions per patient, respectively. seventy-five ( . %) patients received care in an icu at any point in their stay. this cohort of patients accounted for . % of documented interventions. the top interventions among icu patients were sedation and neuromuscular blockade ( . %), antimicrobials and covid- therapy ( . %), and timing and dosing adjustments ( . %). the top interventions for patients without an icu stay were regimen simplification ( . %), timing and dosing adjustments ( . %), and antimicrobials and covid- therapy ( . %). the study quantified the volume and scope of interventions by clinical pharmacists in the care of hospitalized patients with covid- at our institution. intervention data were reflective of work done by clinical pharmacists who were rounding at the bedside within the institution and those working remotely. we feel the use of standardized processes for patient monitoring in the form of a care bundle for patients with covid- was an effective method for directing the focus of the clinical pharmacy team as they managed complicated patients in a challenging envi ronment. this tool was also beneficial to our department and the care of our patients, as some staff members were reassigned and were caring for patient populations outside of their usual scope of practice. in addition, the care bundle streamlined and facilitated the pharmacist handoff process during alternating shifts and across multiple pharmacists. many pharmacy departments around the country will be faced with similar situations throughout the remainder of the covid- pandemic as well as when planning for future disaster responses. our descriptive analysis may help to guide allocation of pharmacy personnel in resourcelimited settings by showing the quantity of interventions made during our experience responding to a surge in covid- cases. the most common interventions during the study period were regimen simplification and adjustment of the timing or dosages of medications. our clinical pharmacy department placed an emphasis on minimizing the bedside exposure of other healthcare workers, so efforts were made to adjust regimens so that medications administration times were consolidated and to discontinue unnecessary medications as part the bundle of care. antimicrobial stewardship-related interventions closely followed simplification-and dosing/timing-related interventions, with each of those intervention categories accounting for approximately % of all documented interventions. our organization maintains a robust antimicrobial stewardship program complete with well-established guidelines and treatment recommendations. daily antimicrobial surveillance combined with prospective audit and feedback is a performance expectation for all clinical pharmacists. the influx of patients with covid- presented a unique opportunity to reinforce established principles as well as relay emerging and evolving covid- treatment recommendations in a hectic patient care environment. the high rate of antimicrobial-oriented interventions, results of review of documentation commentary, and relatively short durations of antimicrobial use (including vancomycin and antipseudomonal agents) suggest antimicrobial streamlining in areas such as avoidance of unneeded antimicrobial therapy and changing or escalating therapy when necessary. these practices were not dissimilar from routine antimicrobial stewardship efforts in our institution; however, the unfamiliar nature of the disease created unique opportunities to optimize antimicrobial therapy in a complex patient population. the most common interventions for patients who received care in an icu were related to sedation and/ or neuromuscular blockade. clinical pharmacists rounding in the icu were relied upon by the care teams to guide therapy, given the profound shortages of first-line sedatives and neuromuscular blockers. prevention of selfextubation in patients with covid- requiring mechanical ventilation was also a priority for clinical pharmacists within the icu, as evidenced by an average of . sedation interventions per patient. emergent intubations pose a significant risk of exposure for the providers performing the procedure due to a high likelihood of viral load in the airway. inadequate sedation is a significant risk factor for self-extubation, so vigilant monitoring and adjustment am j health-syst pharm | volume | number | september , note pharmacy department's response to covid- pandemic of therapy to maintain adequate sedation is essential. a significant limitation of our descriptive study was that patients were included in the analysis only if they had an intervention documented by a clinical pharmacist. patients who were positive for sars-cov- without a documented intervention were not captured by the emr reports used for data collection; this inherently biased the results for number of interventions per patient. however, the primary objective of the analysis was to quantify the type and scope of interventions, which we successfully did. it is also a limitation that we were unable to correlate interventions with clinical outcomes. however, previous studies have shown that prospective pharmacy involvement and interventions improve outcomes in critically ill patients and those with infectious diseases. a study by leguelinel-blache and colleagues found that bundled care services provided by icu pharmacists to , critically ill patients led to decreases in icu los and duration of mechanical ventilation of . days and . days, respectively, and decreased overall cost of care by € , . a scoping review by hammond and colleagues evaluated studies of cost avoidance resulting from common pharmacy interventions in critically ill patients. interventions were grouped into overarching sections: ade prevention, resource utilization, individualization of care, prophylaxis, hands-on care, and administrative tasks. although such an evaluation was beyond the scope of our analysis, it is likely that the interventions made for covid patients led to cost avoidance like that seen by hammond and colleagues. interventions evaluated in our analysis could also be grouped into these categories, as the scope of our work was not dissimilar from interventions normally made for critically ill patients. however, our experience caring for patients with covid- differed from normal practice because of the increased quantity of critically ill patients, reassignment of other healthcare practitioners to critical care units outside of their usual scope of practice, and the rapidity with which treatment strategies evolved. in contrast to usual practice, during the study period pharmacists dealt with widespread shortages of medications commonly used in critically ill patients. medical teams relied heavily on pharmacists to combat these unprecedented shortages by using therapeutic strategies they otherwise might have been unfamiliar with. for example, many critically ill patients were switched to sedation with ketamine or high-dose enteral opioids in the absence of more familiar agents like propofol and fentanyl. pharmacists also had an unusually heightened awareness of the need to conserve medications and ppe, which was likely reflected in the pattern of interventions reported. pharmacists also played an important role in patient care in the icu population due to the number of physicians, mid-level practitioners, and nurses reassigned to critical care units outside of their usual practice areas. in many cases the pharmacist was the only experienced icu clinician and took a lead role in formulating therapeutic plans. this situation was unique to the covid- pandemic response; under usual circumstances, critically ill patients are exclusively cared for by experienced icu providers. treatment strategies also evolved quickly with the release of new primary literature and guidelines during the onset of our health system's pandemic response. pharmacists took the lead in evaluating this literature and formulating treatment strategies that they disseminated to medical providers and the rest of the patient care team. this surge of evolving treatment strategies was our descriptive study was conducted at a single institution and captured pharmacy interventions during only weeks of what we hope proves to be the peak phase of the covid- pandemic at our institution. therefore, the study results may not be generalizable to all institutions, but the study provided a good framework for clinical pharmacy involvement in response to a pandemic. when developing and implementing the bundle, we educated clinical pharmacy staff on the bundle elements to standardize documentation of interventions. however, there were clinical pharmacists who documented interventions, so there was likely variability in reporting and categorization. our analysis did not assess the acceptance rate for each of the evaluated interventions or the exact details of all interventions made. pharmacists have a history of responding during times of need such as the h n influenza pandemic. pharmacists around the world cared for critically ill h n -infected patients as well as serving on the front lines to educate communities and administer vaccinations. a study by miller and colleagues showed an increase in the proportion of patients willing to receive the h n vaccine from . % to . % following intervention by student pharmacists. the value of pharmacists in response to a pandemic has also been highlighted by influential organizations like the american college of chest physicians, which has pointed out that "during a disaster or pandemic, serious medication errors are likely to increase . . . . pharmacists play an important role on interdisciplinary icu teams as medication safety experts. " pharmacists take an oath to "devote myself to a lifetime of service to others" and to "consider the welfare of humanity and relief of suffering my primary concerns. " pharmacists at our institution and around the world are fulfilling this oath during the covid- pandemic. results of our analysis show the quantity and scope of interventions clinical pharmacists are making in the care of patients with covid- . our institution is not unique. we are confident this analysis is representative of the impact pharmacists are having as they work tirelessly to improve the treatment and management of patients with covid- in healthcare systems and across the continuum of care around the world. a pharmacy department's response to the covid- pandemic was optimized through standardization of clinical monitoring and documentation processes. pharmacists intervened to address a wide scope of medication-related issues, likely contributing to improved management of patients with covid- . am j health-syst pharm | volume | number | september , extraordinary care and self-sacrifice provided during the pandemic response. dr. collins reports a consulting arrangement with ashp consulting. the other authors have declared no potential conflicts of interest. coronavirus -ncov: a brief perspective from the front line providing pharmacy services during the coronavirus pandemic us food & drug administration. fda drug shortages infectious diseases society of america guidelines on the treatment and management of patients with covid- surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ). intensive care med clinical and economic outcomes of involving pharmacists in the direct care of critically ill patients with infections pharmacist participation of physician rounds and adverse drug events in the intensive care unit clinical pharmacy services and hospital mortality rates evaluation of the role of the critical care pharmacist in identifying and avoiding or minimizing significant drug-drug interactions in medical intensive care patients impact on patient outcomes of pharmacist participation in multidisciplinary critical care teams: a systematic review and meta-analysis covid- : the uninvited guest in the intensive care unit (icu): implications for pharmacotherapy ashp guidelines on managing drug product shortages in hospitals and health systems antimicrobial stewardship efforts to manage a pentamadine shortage roles of the clinical pharmacist during the covid- pandemic hospital pharmacists' pharmaceutical care for hospitalized patients with covid- : recommendations and guidance from clinical experience. res social adm pharm ashp statement on the role of health-system pharmacists in emergency preparedness pharmacy intervention on antimicrobial management of critically ill patients defining roles for pharmacy personnel in disaster response and emergency preparedness implementing an antibiotic stewardship program: guidelines by the infectious diseases society of america and the society for healthcare epidemiology of america impact of an antimicrobial stewardship care bundle to improve the management of patients with suspected or confirmed urinary tract infection effect of an antimicrobial stewardship bundle for patients with clostridium difficile infection impact of an antimicrobial stewardship program comprehensive care bundle on management of candidemia us national library of medicine. expanded access to convalescent plasma for the treatment of patients with covid- precautions for intubating patients with covid- a retrospective analysis of determinants of self-extubation in a tertiary care intensive care unit impact of quality bundle enforcement by a critical care pharmacist on patient outcomes and costs scoping review of interventions associated with cost avoidance able to be performed in the intensive care unit and emergency department defining the pharmacist role in the pandemic outbreak of novel h n influenza surge capacity logistics: care of the critically ill and injured during pandemics and disasters: chest consensus statement american association of colleges of pharmacy house of delegates. oath of a pharmacist the authors acknowledge the immense contributions of the entire department of pharmacy staff at the study institution, not only their participation in the study through dutiful documentation of efforts but also their key: cord- -uhrkb p authors: koeze, jacqueline; van der horst, iwan c. c.; wiersema, renske; keus, frederik; dieperink, willem; cox, eline g. m.; zijlstra, jan g.; van meurs, matijs title: bundled care in acute kidney injury in critically ill patients, a before-after educational intervention study date: - - journal: bmc nephrol doi: . /s - - - sha: doc_id: cord_uid: uhrkb p background: acute kidney injury (aki) often occurs in critically ill patients. aki is associated with mortality and morbidity. interventions focusing on the reduction of aki are suggested by the kidney disease: improving global outcomes guideline. we hypothesized that these educational interventions would improve outcome in patients admitted to the intensive care unit (icu). methods: this was a pragmatic single-centre prospective observational before-after study design in an icu in a tertiary referral hospital. all consecutive patients admitted to the icu irrespective their illness were included. a ‘save the kidney’ (stk) bundle was encouraged via an educational intervention targeting health care providers. the educational stk bundle consisted of optimizing the fluid balance (based on urine output, serum lactate levels and/or central venous oxygen saturation), discontinuation of diuretics, maintaining a mean arterial pressure of at least mmhg with the potential use of vasopressors and critical evaluation of the indication and dose of nephrotoxic drugs. the primary outcome was the composite of mortality, renal replacement therapy (rrt), and progression of aki. secondary outcomes were the components of the composite outcome the severity of aki, icu length of stay and in-hospital mortality. main results: the primary outcome occurred in patients ( %) in the stk group versus patients ( %) in the usual care group, relative risk (rr) . , % confidence interval (ci) . – . , p < . . secondary outcomes were, icu mortality in . % versus . %, (rr . , % ci . – . , p = . ), rrt in . % versus . % (rr . , % ci . – . , p = . ), and aki progression in % versus % (rr . , % ci . – . , p = . ). conclusions: providing education to uniformly apply an aki care bundle, without measurement of the implementation in a non-selected icu population, targeted at prevention of aki progression was not beneficial. acute kidney injury (aki) occurs in to % of all critically ill patients [ , ] . the initial definition of aki was defined as an increase in serum creatinine and/or a reduction in urine output by bellomo et al. in , which was revised by mehta et al. in and once again in the current definition by kidney disease: improving global outcomes (kdigo) in [ ] [ ] [ ] . irrespective of the definition, the occurrence of aki is associated with increased mortality rates and also increased incidences of chronic kidney disease (ckd) after discharge [ , ] . the severity of aki is associated with increased intensive care unit (icu) and hospital mortality [ ] . despite the lack of evidence for benefit, guidelines directed to prevent aki recommend either volume resuscitation or volume restriction, promote and dismiss various types of fluids, pose blood pressure targets, and emphasize avoidance of nephrotoxic drugs [ ] . the recommendation of controlled fluid resuscitation is based on observations that both hypovolemia and hypervolemia can induce aki [ ] . the use of artificial colloids and (loop-) diuretics is dissuaded based on aggregated data from randomised trials and large cohort studies [ , ] . nephrotoxic drugs and drug dosing should be weighed carefully, especially in critically ill patients already at risk for aki [ ] . further, guidelines recommend targeting blood pressure at a mean arterial pressure (map) above - mmhg using vasopressors [ , ] . a bundled approach of care for the critically ill including these individual recommendations is suggested to preserve renal function [ ] . care bundles targeted at the treatment of sepsis and ventilator-associated pneumonias (vap) have improved outcomes in critically ill patients [ ] [ ] [ ] . bundles targeted at aki prevention have already been successfully tested in patients undergoing cardiac surgery and also in hospitalized patients, but not in a general critically ill population [ , ] . we therefore hypothesized that the implementation of education for bundled care targeted at prevention of aki progression and a reduction in aki severity, would improve patient outcome. a pragmatic single-centre prospective observational before-after study design was used. the study was performed in a tertiary referral hospital. the need for informed consent was waived by the institutional review board of our hospital (metc - ). the ethical board waived consent because the care bundle was implemented at a department level and changed overall daily practice. patients were treated according to usual care during the first period. after the first ('before') period of the study the educational intervention was introduced at a department level to all personnel between june th, and october th, . during the second period patients were treated according to the 'save the kidney' (stk)-bundle in addition to usual care. the duration of both study periods was estimated from admittance rates combined with sample size calculations. consecutive patients admitted to the icu were included irrespective their illness. both scheduled post-surgery patients needing postoperative icu observation and acutely admitted patients, both surgical and medical, were included. patients with known chronic kidney disease (defined by a serum creatinine greater than μmol/l, based on the definition used by the nationale intensive care evaluatie (nice)) and patients on chronic renal replacement therapy (rrt) were excluded from the analysis. if patients were readmitted to our icu within the study period only data of their first admission were included in the analysis. patients were splitted into two groups based on admission date, divided into two set periods of time. baseline data of all patients were recorded, including age, sex, body mass index (bmi), apache iv and admission category and type (medical or surgical; scheduled or emergency). in addition to age and severity of illness, the presence of known diabetes mellitus was recorded as it is a known risk factor for aki development. we recorded mortality (icu and hospital), the need for rrt, the occurrence and severity of aki and the length of icu stay. serum creatinine was recorded each day and urinary output was recorded hourly. the reference creatinine was based on the ideal serum creatinine, which was calculated assuming a clearance of ml/ min/ . m using the 'modification of diet in renal disease' (mdrd) formula. the incidence and severity of aki were assessed in each patient according to the kdigo definitions, using both serum and urine output criteria (supplementary figure ) . aki progression was defined as any progression (i.e. to , to , etc.) in aki stage during the first h of admission. the 'save the kidney' educational intervention bundle the stk bundle was encouraged in all patients ( table ). the stk bundle consisted of optimizing the fluid balance (based on urine output, serum lactate levels and/or central venous oxygen saturation), discontinuation of diuretics, maintaining a map of at least mmhg with the potential use of vasopressors and critical evaluation of the indication and dose of nephrotoxic drugs [ ] . discouraging artificial colloids was not part of the bundle, since colloids were already excluded in the past ( table ). avoidance of hyperglycaemia as is suggested by the kdigo guidelines was not part of the bundle, as we already used a computerised algorithm regulating serum glucose which was the same in both groups [ ] . close monitoring of serum creatinine, also suggested by the kdigo guidelines, was also the same in both groups. as mentioned before we measured serum creatinine daily and urine output hourly. the 'stk'-bundle was introduced using introductory lectures to all physicians and nurses, by the distribution of pocket cards, and emphasized during discussions on the wards. the specific interventions were left open for the treating physician to make the bundle more compliant with different personal preferences within the treating intensivist group. we did not assess compliance with the bundle. the primary outcome measure was a composite of serious adverse events (sae's) consisting of icu mortality, the need for rrt and/or the progression of aki. secondary outcomes were the three individual components of the composite primary outcome, including icu mortality, the need for rrt, and the progression of aki during the first h of icu stay. in-hospital mortality and icu length of stay were considered as well. a previous study in a comparable critically ill population observed a -day mortality of %, a cumulative incidence proportion of approximately % for rrt and the cumulative incidence proportion of % for aki [ ] . based on these data, we estimated a cumulative risk of % of one or more of the sae in the control group of our icu population. with a cumulative event rate of % in the control group, a relative risk reduction (rrr) of % of sae (which would imply a reduction of sae from to %, which was considered clinically relevant), a type i error of . , and a type ii error of . , we calculated that patients were needed in each group of the study (and patients in total). we anticipated a study period of months for each group. the proportions of aki were calculated based on data of the first h of icu admission. aki severity was calculated in all patients. dichotomous data were presented as percentages. continuous variables were reported as means (with standard deviations (sd)) or as medians (with interquartile ranges (iqr)) depending on normality. data were analysed using student t-tests, mann whitney u tests, or chi-square tests, when appropriate. as a sensitivity analysis, analysis were repeated in patients with and without diabetes mellitus. missing hourly urine output data were replaced based on averages using the first recorded value over the missing hours. urine output data were omitted from the analysis if all hourly urine output was missing. a total of patients were admitted between the start of the study january st, and study closure on march th, . the first period was from to - until - - and the second period was from to - until - - . a total of patients ( %) were included in the usual care group and patients ( %) were included in the stk group. (fig. a) . patients in both groups were similar regarding age, sex, bmi, severity of illness and the presence of known diabetes mellitus ( table ). more patients in the stk group were admitted for a medical reason and less patients were admitted after scheduled surgery ( table ) . patients in the stk group had a lower median cumulative fluid balance during the first days of icu admission. serum creatinine at admission was unavailable in patients ( . %) and in patients ( %) there was insufficient data to estimate the presence or absence of aki based on urine output criteria on admission. overall, the median available hours of urine output data calculated as a percentage of length of stay was % (iqr - %). serious adverse events defined as icu mortality, the need for rrt and/or the progression of aki was observed in patients ( %) in the stk group compared to patients ( %) in the usual care group (rr . , % confidence interval ci . - . , p < . ) ( table ) . the aki progression during the first h after icu admission was not different between the stk group and the usual care group (table and fig. b) . in the stk group patients ( . %) died during their icu admission compared to patients ( . %) in the usual care group (rr . , % confidence interval . - . , p = . ) ( table ) . rrt was used in patients ( . %) in the stk group versus patients ( . %) in the usual care group rrt (rr . , % confidence interval . - . , p = . ) ( table ) . based on serum creatinine and urine output criteria patients ( %) in the stk group developed aki progression versus patients ( %) in the usual care group (rr . , % confidence interval . - . , p = . ). aki progression based on the separate components serum creatinine and urine output is shown as supplementary material (supplementary data and supplementary table ). the sensitivity analysis showed that patients with diabetes mellitus did not show a difference in outcome (supplementary table ). based on serum creatinine and urine output aki severity differed in the stk group compared with the usual care group. in the stk group patients ( %) had stage aki and in the usual care group patients ( %). in the stk group patients ( %) had stage aki and in the usual care group patients ( %). in the stk group patients ( . %) had stage aki and in the usual care group ( . %) (p < . ) ( table ) . aki severity based on the separate components serum creatinine and urine output is shown in the supplementary table . median icu length of stay in the stk group was days [iqr - ] and in the usual care group also days [iqr - ] (p = . ) ( table ) . in the stk group patients ( %) died during their hospitalisation and in the usual care group patients ( %) (rr . , % confidence interval . - . , p = . ) ( table ). we used a pragmatic before-after design to test whether a bundled approach targeted at prevention of aki and a reduction of aki severity and aki progression, introduced at a department level impacts the outcome of critically ill patients. this study showed that implementation of an educational 'save the kidney bundle care in critically ill patients aiming at a reduction of aki had no beneficial effect on patient outcome when evaluated by a composite of icu mortality, the need for rrt and aki progression. these results are in contrast with the few studies that evaluated aki care bundles in hospitalized patients in general or in patients after cardiac surgery [ , ] . those studies showed either a reduction in aki incidence and aki severity in cardiac surgery patients or a reduction in aki incidence and a reduction in-hospital mortality. our study was not powered to detect significance in individual components of the primary endpoint. the primary outcome showed no benefit as a result of a higher aki incidence and contrary, a lower need for rrt in the stk group (table ). in our study icu mortality was higher in the stk group, albeit nonsignificant. therewith, the effects of the implemented bundle were contradictory, given the fact that need for rrt is associated with a higher mortality. our results are also in contrast with other bundles in critically ill patients such as the treatment bundle of the surviving sepsis campaign (ssc) to reduce mortality in patients with sepsis or the bundle to reduce incidence of ventilator associated pneumonia (vap) in mechanically ventilated critically ill patients [ , ] . it is important to note however that our study comprised an educational intervention of which affects are often difficult to assess. our study has several limitations. first, we did not record which patients had the bundle applied in their treatment. besides that, we did not record which part of the bundle was applied in which patients. it is possible that one of the suggested interventions of the bundle has detrimental effects on the composite primary outcome, while others may have positive effects. moreover, not all interventions were clearly described, but adjustments in antibiotic dose were based on renal clearance and accordingly appropriate drug dosing. this also holds for the optimization of the fluid balance, physicians and nurses were stimulated to critically evaluate the need for fluids. this was based on the formulation of the kdigo guidelines. second, we did not assess the full make endpoint, which was not published at the time. however, our primary endpoint was the composite of death, new renal replacement therapy, or persistent renal dysfunction which is recommended, as a patient-centered outcome for pragmatic trials involving aki. third, we did not analyse the compliance of the bundle and furthermore, the same bundle can be implemented differently by different clinicians. a recent study showed that using an interruptive aki alert therapeutically interventions in patients increased from . to . % of the patients [ ] . therefore, it is likely that the compliance of this study was not %. future research of our group and others on the effect of aki care bundles in critically ill patients need to address this issue. fourth, we did not correct for all previously reported comorbidities, hence, differences in illness severity between groups may have played a role in our findings. furthermore, we had insufficient urine output data to estimate aki incidence and severity based on urine criteria in nearly % of patients, with unequal amounts of missing data between the two groups. this might have led to underestimation of aki incidence in the usual care group since urine output is more sensitive in detecting aki than serum creatinine. this could have exaggerated the (negative) effect of the care bundle. last, we did not collect baseline creatinine but estimated renal function based on the assumption of a glomerular filtration rate of l/min/ . m . a strength of this study is the prospective study design with the inclusion of all patients, except for patients with ckd, which reflects real life daily practice and patient population. even though this resulted in relatively low median apache scores, aki incidence was still high and the kdigo guidelines suggest that the measures they advise may reduce aki incidence in general. no comparable studies have been performed in critically ill patients. we constructed an educational intervention regarding bundled elements of aki care as advised by international guidelines. each of the measures is supported by literature and guidelines suggest beneficial effects of bundled care. the results of our study show a contradictory effect. this may be caused by limitations of the current study or by chance, but it may also be the result of the bundle itself. the simultaneously taken measures rather than measures taken subsequently might induce harm. a possible cause is for example the reduced fluid resuscitation with possible adverse effects on outcome due torelativehypovolemia. also, the reductions in antibiotic dosing propagated by the bundle may have led to insufficient treatment of infections. this may support therapeutic drug monitoring (tdm) [ ] . in future research protocol adherence and effects of implementation need to be studied. although more patients in the control group developed stage aki compared to those in the stk intervention group, providing education to uniformly apply an aki care bundle, without measurement of the implementation in a non-selected icu population, targeted at prevention of aki progression was not beneficial. one-year mortality among danish intensive care patients with acute kidney injury: a cohort study incidence, risk factors and -day mortality of patients with acute kidney injury in finnish intensive care units: the finnaki study acute renal failure -definition, outcome measures, animal models, fluid therapy and information technology needs: the second international consensus conference of the acute dialysis quality initiative (adqi) group acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury kidney disease: improving global outcomes (kdigo) acute kidney injury work group. kdigo clinical practice guideline for acute kidney injury small acute increases in serum creatinine are associated with decreased long term survival in the critically ill the attributable mortality of acute kidney injury: a sequentially matched analysis* acute kidney injury in the intensive care unit according to rifle prevention of acute kidney injury and protection of renal function in the intensive care unit. expert opinion of the working group for nephrology, esicm hydroxyethyl starch / . - . versus crystalloid or albumin in patients with sepsis: systematic review with meta-analysis and trial sequential analysis high versus low blood-pressure target in patients with septic shock early goal-directed therapy in the treatment of severe sepsis and septic shock surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock reducing ventilator-associated pneumonia in intensive care: impact of implementing a care bundle prevention of cardiac surgeryassociated aki by implementing the kdigo guidelines in high risk patients identified by biomarkers: the prevaki randomized controlled trial impact of compliance with a care bundle on acute kidney injury outcomes: a prospective observational study design and implementation of grip: a computerized glucose control system at a surgical intensive care unit impact of real-time electronic alerting of acute kidney injury on therapeutic intervention and progression of rifle class clinical implications of antibiotic pharmacokinetic principles in the critically ill publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank igor van der weide for his support with the database. please contact the author for data requests.ethics approval and consent to participate informed consent was waived by the institutional review board of the university medical center groningen because the study had an observational design and all data were de-identified (metc - ). not applicable. on behalf of all authors, the corresponding author states that there is no conflict of interest. supplementary information accompanies this paper at https://doi.org/ . /s - - - .additional file : figure s . aki classification according to the kdigo guideline.additional file . supplementary data .additional file : table s .additional file : table s . key: cord- - taco authors: aboelnile, diaaeldin badr metwally kotb; elseidy, mohamed ismail abdelfattah; kenawey, yasir ahmed elbasiony mohamed; elsherif, ibrahim mohammed alsayed ahmed title: prediction of fluid responsiveness in mechanically ventilated patients in surgical intensive care unit by pleth variability index and inferior vena cava diameter date: - - journal: ain-shams j anesthesiol doi: . /s - - - sha: doc_id: cord_uid: taco background: patients may have signs of hypovolemia, but fluid administration is not always beneficial. we are in need of bedside devices and techniques, which can predict fluid responsiveness effectively and safely. this study is aiming to compare the effectiveness and reliability of the pleth variability index (pvi) and ivc distensibility index (divc) as predictors of fluid responsiveness by simultaneous recordings in all sedated mechanically ventilated patients in the surgical intensive care unit (icu). we used the passive leg raising test (plr) as a harmless reversible technique for fluid challenge, and patients were considered responders if the cardiac index (ci) measured by transthoracic echocardiography (tte) increased ≥ % after passive leg raising test (plr). results: this observational cross-sectional study was performed randomly on intubated ventilated sedated patients. compared with ci measured by transthoracic echocardiography, the divc provided . % sensitivity and % specificity at a threshold value of > . % for fluid responsiveness prediction and was statistically significant (p < . ), with an area under the curve (auc) of . ( . – . ), while pvi at a threshold value of > % provided . % sensitivity and . % specificity and was statistically significant (p < . ), with an auc of . ( . – . ). conclusion: pvi and divc are effective non-invasive bedside methods for the assessment of fluid responsiveness in icu for intubated ventilated sedated patients with sinus rhythm, but pvi has the advantage of being continuous, operator-independent, and more reliable than divc. perioperative prediction of fluid responsiveness has been a challenge for many years. it is known as the ability of the circulation to increase cardiac output (co) in response to volume expansion. accommodation of the large volume of venous return (vr) is done by stretching ventricles, which is known as cardiac preload. since preload is related to co, increased negativity of intrathoracic pressure (itp) during inspiration subsequently increases vr and subsequently co, and the reverse occurs during expiration (chu et al., ) . hemodynamic optimization by intravenous (iv) fluid administration is very important to correct any fluid deficits created by fasting, blood loss, and urinary excretion, or in septic and other critically ill patients to improve oxygen delivery and overall hemodynamic function. however, it may be ineffective or harmful to patients if no suitable monitoring methods are used. interstitial fluid accumulation by more volume expansion may worsen oxygen diffusion to the tissues and decrease myocardial compliance. therefore, it became essential to develop an approach for the evaluation of patients who are likely to get benefit from fluid administration (cumpstey et al., ) . methods for assessment of volume responsiveness depending on what and how surrogate is measuring can be classified into static and dynamic measures (jalil & cavallazzi, ) . swan and ganz developed in the pulmonary artery flow-directed catheter. it has the ability to measure the pulmonary artery occlusion pressure (paop), but due to its complications and the same limitations as central venous pressure (cvp) (chatterjee, ; marik & cavallazzi, ) , multiple studies found that it cannot be a good predictor of fluid responsiveness (marik & lemson, ) , as these static techniques cannot predict the effect on itp during inspiration and expiration (wise et al., ) . michard and others discovered that the interaction between the heart and lung during mechanical ventilation could be used for the prediction of fluid responsiveness (michard et al., ) . based on this idea, dynamic measurements such as pulse pressure variation (ppv) and stroke volume variation (svv) were used to predict fluid responsiveness in a more accurate way, especially in sedated mechanically ventilated patients, but due to being invasive and affected by multiple clinical factors (marik & lemson, ) , non-invasive bedside and continuous techniques became more popular (haas et al., ) . pleth variability index (pvi) is a dynamic variable, which has recently gained a lot of interest. by using the amplitude of the pulse oximeter waveform, it measures the respiratory variation continuously and automatically. therefore, it became an effective dynamic fluid response predictor in sedated mechanically ventilated patients with sinus rhythm by providing simple numeric value on the monitor screen (chu et al., ) . ultrasound calculation of inferior vena cava distensibility index (divc) in mechanically ventilated patients has been reported as a widely available and non-invasive measure for prediction of fluid responsiveness in multiple patient settings (de backer & fagnoul, ) . it can also be used with an ultrasound of the lungs and heart to give a comprehensive sonographic picture especially for critically ill patients in icu (evans et al., ) . we aim to compare the accuracy and reliability of the pvi and divc as predictors of fluid responsiveness by simultaneous recordings in mechanically ventilated sedated patients in our surgical icu. after approval of the ethical committee in the faculty of medicine, number fmasu m d / , this observational prospective study was conducted over patients for year from march to march . written informed consent was obtained from the patients' legal guardians after explaining the procedure and its potential complications. the inclusion criteria are age ≥ years, admission to the icu preoperative (in need of ventilation) or postoperative, and sedated on controlled mechanical ventilation with arterial and central venous catheters. the included patients were in need of iv fluid challenge for resuscitation based on the clinical characteristics (systolic arterial blood pressure (bp) < mmhg, or mean arterial pressure (map) < mmhg, or a fall of > mmhg from the baseline of map, or with signs of hypoperfusion as oliguria less than . ml/kg/h and arterial lactate > . mmol/l). the exclusion criteria are spontaneous breathing, poor cardiac echogenicity, cardiac arrhythmia, severe valvular heart disease or intracardiac shunt, impaired left ventricular function (ejection fraction < %), ascites, pregnancy, and any contraindication to fluid resuscitation, such as congestive heart failure, evidence of fluid overload, and renal dysfunction. all patients were fully assessed with general physical examination, and their baseline characteristics, including age, gender, height, weight, body mass index, body surface area, and acute physiology and chronic health evaluation score (apache) ii score (knaus et al., ) , were recorded. patients were sedated using iv titration of fentanyl starting with . mcg/kg and midazolam starting with . - mg to achieve a ramsay sedation score of - (ramsay et al., ) , before muscle relaxation with . mg/kg rocuronium iv. patients were mechanically ventilated (newport™ e ventilator; newport medical instrument, ca) in volume control mode with tidal volume = ml/kg of predicted body weight, inspiratory to expiratory ratio = : , and positive end-expiratory pressure = cm/h o, and end-tidal carbon dioxide was monitored and maintained between and mmhg by adjusting the respiratory rate. recorded measurements were heart rate (hr), map, cvp with a zero referenced to the middle axillary line, pvi, divc, and cardiac index (ci). at first, every patient was positioned semi-recumbent with an angle of °between the trunk and the bed plane to record the initial measurements. then, in the passive leg raising (plr) position, other measurements were recorded after min from leg elevation to °with the horizontal plane of the trunk. positioning was done by an automatic bed mechanism controlled by a remote controller. co was measured by the same operator using transthoracic echocardiography (tte) (acuson x ™ ultrasound system, premium edition, siemens healthcare, mountain view), as the product of stroke volume (sv) and heart rate (hr). sv is equal to the product of the aortic cross-sectional area, and the distance of a column of blood travels through it with each stroke, which is known as the velocity time integral (vti) (desai & garry, ) . the cross-sectional area of the aortic annulus was estimated from the diameter (d) of the annulus using the parasternal long-axis view of the left ventricle. from this view, d is the maximal distance between the hinge points of the anterior and posterior aortic cusps in early systole, and the cross-sectional area is equal to the product of square d by . divided by (desai & garry, ) . vti can be estimated by obtaining the apical fourchamber (a c) view, then tilting the ultrasound beams anteriorly to get the apical five-chamber (a c) view, where the proximal ascending aorta, aortic valve, and left ventricular outflow tract (lvot) come in the view (matta et al., ) . the pulse-wave (pw) doppler is positioned within °to the lvot, just in proximity to the aortic valve for the best flow estimation (miller & mandeville, ) . we calculated ci using co, bw, and height, and we defined patients as "volume responders" if they had a ≥ % increase in the ci after the plr test, and "non-responders" if they had no change or a change of < %. the pvi was automatically calculated and recorded using an adhesive oximeter probe (lncs adtx, masimo, irvine, ca) placed on the finger and wrapped with a black protector for minimizing light interference and then connected to a masimo radical- monitor (masimo corp., irvine, ca). the divc is the percentage of variation in the ivc diameter during inspiration vs expiration. which we measured by another single operator simultaneously, using the convex probe of ultrasound (mindray m , umt- /china) by the subcostal view approach using m-mode during the same respiratory cycle, then we calculated divc percentage by the following formula: the quantitative data were presented as mean, standard deviations, and ranges. also, qualitative variables were presented as number and percentages. the paired student t test was used to compare between hemodynamic data before and after plr. independent sample t test was used to compare between responders and non-responders for normally distributed parametric variables, while for the non-parametric data, we used the mann-whitney test. the receiver operating characteristic (roc) curves and area under the curve (auc; with % confidence intervals [cis]) of pvi, divc, and cvp were calculated and compared for the assessment of the ability of these methods to predict fluid responsiveness. the confidence interval was set to %, and the margin of error accepted was set to %. so, a p value < . was considered significant, a p value < . was considered as highly significant, and a p value > . was considered insignificant. the pass program is used, setting alpha error at % and power at %. the result from the previous study by pişkin and Öz (pişkin & Öz, ) showed that the auc for diagnostic accuracy for pvi was . , while for the diagnostic accuracy for ivc, the auc was . in the study done by long et al. (long et al., ) based on this, the needed sample is responders and nonresponders. after the exclusion of patients due to exclusion criteria, mainly poor echogenicity ( patients), the study was conducted on patients; we divided them into two groups ( responders and non-responders). there were no significant differences in patient demographics between the groups as shown in table . hemodynamic data presented in table show a significant difference after plr in the responders group (p < . ), while only hr showed a significant difference after plr in the non-responders group. the baseline map, cvp, and ci of the responders were significantly lower than the non-responders (p < . ); the baseline pvi and divc were significantly higher than responders (p < . ), while hr readings showed no significant difference (p > . ) between the baselines of the two groups. the difference between cvp, pvi, and divc regarding performance is presented in table . cvp at a threshold value ≤ mmhg had . % sensitivity and . % specificity, with auc = . ( . - . ), and was not significant (p = . ). divc had . % sensitivity and % specificity at a threshold value of > . % with auc = . ( . - . ) and was highly significant (p < . ). pvi had a . sensitivity and an . specificity at a threshold value of > % with auc = . ( . - . ) and was highly significant (p < . ). figure shows the roc curves of the three methods comparing their effectiveness in the prediction of fluid responsiveness. this observational cross-sectional study was done for year in the surgical icu. collected data from patients were analyzed for reaching the final results. we compared between pvi and divc regarding their reliability and effectiveness as simple non-invasive dynamic techniques in mechanically ventilated sedated patients with sinus rhythm. the best way to test the sensitivity of the heart to preload changes is to detect the change in co after a fluid bolus (pierrakos et al., ) . the usual fluid challenge has two concerns. first, one is that we should not use a procedure, which may entangle in itself harm and volume overload due to irreversibility (muller et al., ) . therefore, we used plr as a dependable test for the recognition of preload responsiveness (monnet et al., ) . the second concern is that we need to measure co directly, so we used tte as it is considered the gold standard dynamic technique in icu (desai & garry, ) , moreover, a meta-analysis in revealed that it could predict fluid responsiveness accurately by plr in icu (xiang et al., ) . patients in our study were defined as responders when their co increased by % or more after plr. the responders' fraction for plr in our work was . %. the deleterious effect of over fluid transfusion on different organs made a continuous need for new dynamic indicators for fluid management which are more preferable than unreliable static ones (sakr et al., ) . that was obvious in our study as cvp was a weak predictor for fluid responsiveness with best threshold value ≥ mmhg and auc of . ( . to . ). dynamic methods in fluid responsiveness identification are more accurate (theerawit et al., ; guérin et al., ) , but some of them require invasive procedures like arterial line insertion, and also, not all of them can provide continuous readings. minimally or noninvasive cardiac output monitors have the least prerequisites and can be used in a variety of critically ill patients for estimating co rapidly (jalil & cavallazzi, ) to values are expressed as mean ± sd ci cardiac index, cvp central venous pressure, divc caval index, hr heart rate, map mean arterial pressure, pvi pleth variability index, sd standard deviation *p < . vs baseline **p < . vs "responders" minimize the risk (scheer et al., ) to already ill patients. pvi differs from other invasive dynamic techniques in providing the physicians with a numerical value continuously, automatically, and non-invasively (sandroni et al., ) . in a study done by forget and others, they found that pvi-based goal-directed fluid therapy reduced the volume of infused fluids intraoperatively, so reduced lactate levels intraoperative and postoperative (forget et al., ) . it is suitable only for patients on mechanical ventilation (keller et al., ) , and it is not suitable for patients with open chest, irregular heart rhythm, rv failure, or high intra-abdominal pressure . different other factors can affect the accuracy of pvi as the anatomical region where we made our readings. the fingertips may be affected more than the cephalic region (desgranges et al., ) (forehead and earlobe); also, vasoactive drugs such as norepinephrine, perfusion problems, or hypothermia may affect the vasomotor tone and decrease peripheral perfusion (broch et al., ; yamaura et al., ; monnet et al., ) . our observational study included only patients on mechanical ventilation with the exclusion of any patient with factors affecting the heart-lung interaction or with vasoactive drug infusion, so our study results are not affected by these factors. on the other hand, we used fingertip measurements as an easier way to calculate pvi for fluid responsiveness identification. the roc analysis in our study revealed that the best pvi threshold value was more than %, with . % sensitivity, . % specificity, and auc ( % ci) for the roc curve of . ( . - . ). in a recent meta-analysis done by liu et al. which was including studies, they concluded that pvi has a good bedside reliability in icu especially with % sensitivity, % specificity, and auc of . ( . - . ) also its limited ability in the prediction of fluid responsiveness in general (liu et al, ) . however, chu et al.'s metaanalysis showed higher sensitivity of fluid responsiveness in operating theaters than icu but with the same specificity and nearly equal auc of . ( . - . ) in operating theater (or) and auc of . ( . - . ) in icu (chu et al., ) . this is in line with our results; also, our study was in a surgical icu using plr with the exclusion of any patient on vasoactive drugs, which was not met with the two included meta-analysis studies. lately, ultrasound became one of the most important devices in icu; it can be used as a bedside non-invasive method for the assessment of fluid responsiveness in daily icu practice (theerawit et al., ; orso et al., ) by divc using variation in the diameter of the ivc (barbier et al., ) . in a systematic review and meta-analysis done by long et al. (long et al., ) , they found that pooled results of divc in mechanically ventilated patients had auc of fig. the receiver-operating characteristic curves comparing the ability of cvp, divc, and pvi to predict fluid responsiveness. cvp, central venous pressure; divc, caval index; pvi, pleth variability index . with a sensitivity of % and a specificity of %, which is not in line with our results. in another recent systematic review and meta-analysis done by huang et al. (huang et al., ) , divc has better performance in mechanically ventilated shocked patients with a pooled auc of . ( % ci . - . ) with a specificity of % and a sensitivity of %, which is near to our study results with . % sensitivity and % specificity at a threshold value of > . % with auc = . ( . − . ). however, several studies showed poor performance of divc. a study included medical and surgical septic mechanically ventilated patients who had an auc of . and % ci . - . ) with % sensitivity and % specificity (charbonneau et al., ) . many factors can affect divc measurements and cause this difference between studies as respiratory compliance (lakhal et al., ) , difference in adjusted tidal volume, amount and type of infused fluids (barbier et al., ) , and factors affecting intra-abdominal pressure (bendjelid & romand, ; santa-teresa et al., ) . the results of our study showed that assessment of pvi and divc non-invasively were good predictors for fluid management and responsiveness prediction using plr technique in the surgical icu mechanically ventilated patients. our observational study has many limitations. the first one was in the accuracy of measuring co by vti using tte. it necessitates good echogenicity of the patients, so we excluded patients not fulfilling these criteria before data analysis. the second limitation was in the comparison between pvi and divc; it is difficult to equalize blood volume added to circulation to all patients after plr. however, the reversible plr technique was proven trustworthy for preload responder identification (monnet et al., ) with less harm to the candidate patient than irreversible transfusing of the same volume of crystalloid or colloid to all patients including the non-responders with no benefit. the third limitation was intra-abdominal pressure, as we did not measure it in our patients. however, we excluded all patients with any expected cause of increased intra-abdominal pressure like ascites, pregnancy, abdominal malignancy, distension, and acute abdomen. pvi and divc can be used in the assessment of fluid responsiveness of the intubated ventilated sedated patients with sinus rhythm in icu, and both methods are noninvasive and can be performed at the bedside, but pvi has the advantage of being continuous, operatorindependent, and more reliable than divc. respiratory changes in inferior vena cava diameter are helpful in predicting fluid responsiveness in ventilated septic patients accuracy of the pleth variability index to predict fluid responsiveness depends on the perfusion index using arterial pressure waveform analysis for the assessment of fluid responsiveness predicting preload responsiveness using simultaneous recordings of inferior and superior vena cavae diameters the swan-ganz catheters: past, present, and future: a viewpoint accuracy of pleth variability index to predict fluid responsiveness in mechanically ventilated patients: a systematic review and meta-analysis fluid management and its role in enhanced recovery intensive care ultrasound: vi. fluid responsiveness and shock assessment assessing dynamic fluid-responsiveness using transthoracic echocardiography in intensive care influence of the site of measurement on the ability of plethysmographic variability index to predict fluid responsiveness volume responsiveness in critically ill patients: use of sonography to guide management goal-directed fluid management based on the pulse oximeter-derived pleth variability index reduces lactate levels and improves fluid management monitoring volume and fluid responsiveness: from static to dynamic indicators prediction of volume responsiveness using pleth variability index in patients undergoing cardiac surgery after cardiopulmonary bypass value of variation index of inferior vena cava diameter in predicting fluid responsiveness in patients with circulatory shock receiving mechanical ventilation: a systematic review and meta-analysis predicting fluid responsiveness: a review of literature and a guide for the clinician ability of pleth variability index to detect hemodynamic changes induced by passive leg raising in spontaneously breathing volunteers apache ii: a severity of disease classification system respiratory pulse pressure variation fails to predict fluid responsiveness in acute respiratory distress syndrome reliability of pleth variability index in predicting preload responsiveness of mechanically ventilated patients under various conditions: a systematic review and meta-analysis paediatric research in emergency departments international collaborative (predict) ( ) does respiratory variation in inferior vena cava diameter predict fluid responsiveness: a systematic review and meta-analysis does the central venous pressure predict fluid responsiveness? an updated meta-analysis and a plea for some common sense fluid responsiveness: an evolution of our understanding pocus series: the use of velocity time integral in assessing cardiac output and fluid responsiveness relation between respiratory changes in arterial pulse pressure and fluid responsiveness in septic patients with acute circulatory failure predicting and measuring fluid responsiveness with echocardiography pleth variability index is a weak predictor of fluid responsiveness in patients receiving norepinephrine prediction of fluid responsiveness: an update an increase in aortic blood flow after an infusion of ml colloid over minute can predict fluid responsiveness: the mini-fluid challenge study accuracy of the caval index and the expiratory diameter of the inferior vena cava for the diagnosis of dehydration in elderly can changes in arterial pressure be used to detect changes in cardiac index during fluid challenge in patients with septic shock? accuracy of pleth variability index compared with inferior vena cava diameter to predict fluid responsiveness in mechanically ventilated patients controlled sedation with alphaxalone-alphadolone higher fluid balance increases the risk of death from sepsis: results from a large international audit accuracy of plethysmographic indices as predictors of fluid responsiveness in mechanically ventilated adults: a systematic review and meta-analysis incidence and prognosis of intra-abdominal hypertension in critically ill medical patients: a prospective epidemiological study clinical review: complications and risk factors of peripheral arterial catheters used for haemodynamic monitoring in anaesthesia and intensive care medicine inferior vena cava diameter variation compared with pulse pressure variation as predictors of fluid responsiveness in patients with sepsis strategies for intravenous fluid resuscitation in trauma patients diagnostic accuracy of transthoracic echocardiography to predict fluid responsiveness by passive leg raising in the critically ill: a meta-analysis evaluation of finger and forehead pulse oximeters during mild hypothermic cardiopulmonary bypass publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. authors' contributions db designed the study, revised the literature, performed the analysis, followed up the patients, measured the inferior vena cava distensibility index, and wrote the manuscript. mi designed the study, performed the analysis, and wrote and critically revised the manuscript. ya revised the literature, performed the analysis, and critically reviewed the manuscript. im revised the literature, followed up the patients, measured and calculated the cardiac index, collected the data, performed the analysis, and critically reviewed the manuscript. all authors approved the final version of the manuscript. none. the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. after approval of the ethical committee in the faculty of medicine, ain shams university, number fmasu m d / , this observational prospective study was conducted over patients for year from march to march . written informed consent was obtained from patients' legal guardians after explaining the procedure and its potential complications. not applicable. the authors declare that they have no competing interests.received: july accepted: september key: cord- -vk qnumx authors: freedberg, daniel e.; messina, megan; lynch, elissa; tess, monika; miracle, elizabeth; chong, david h.; wahab, romina; abrams, julian a.; wang, harris h.; munck, christian title: impact of fiber-based enteral nutrition on the gut microbiome of icu patients receiving broad-spectrum antibiotics: a randomized pilot trial date: - - journal: crit care explor doi: . /cce. sha: doc_id: cord_uid: vk qnumx objectives: dietary fiber increases the abundance of bacteria that metabolize fiber into short-chain fatty acids and confers resistance against gut colonization with multidrug-resistant bacteria. this pilot trial estimated the effect of fiber on gut short-chain fatty acid–producing bacteria in the icu. design: randomized, controlled, open label trial. setting: medical icu. patients: twenty icu adults receiving broad-spectrum iv antibiotics for sepsis. intervention: : randomization to enteral nutrition with mixed soy- and oat-derived fiber ( . g fiber/l) versus calorie- and micronutrient-identical enteral nutrition with g/l fiber. measurements: rectal swabs and whole stools were collected at baseline and on study days , , , and . the primary outcome was within-individual change in the cumulative relative abundance of short-chain fatty acid–producing taxa from baseline to day based on s sequencing of rectal swabs. the secondary outcome was day cumulative short-chain fatty acid levels based on mass spectrometry of whole stools. analyses were all intent to treat. main results: by day , the fiber group received a median of . g fiber cumulatively (interquartile range, . – . ) versus g fiber (interquartile range, – . ) in the no fiber group. the median within-individual change in short-chain fatty acid producer relative abundance from baseline to day was + % (interquartile range − to + , ) in the fiber group versus − % (interquartile range, − to + ) in the no fiber group (p = . ). whole stool short-chain fatty acid levels on day were a median of μg short-chain fatty acids/g stool (interquartile range, – , ) in the fiber group versus μg short-chain fatty acids/g stool (interquartile range, – , ) in the no fiber group (p = . ). conclusions: enteral fiber was associated with nonsignificant trends toward increased relative abundance of short-chain fatty acid–producing bacteria and increased short-chain fatty acid levels among icu patients receiving broad-spectrum iv antibiotics. larger studies should be undertaken and our results can be used for effect size estimates. u p to a third of icu patients have gastrointestinal colonization with multidrug-resistant organisms (mdros) such as vancomycin-resistant enterococcus or mdr gram-negative bacteria ( ) . once colonized, icu patients are at increased risk for subsequent infection with the same organisms ( ) ( ) ( ) ( ) . if gut colonization could be prevented, many high-mortality icu infections would be avoided. loss of commensal gut bacteria facilitates colonization with mdros. nonpathogenic colonic anaerobes compete with mdros for shared resources and in some cases directly antagonize them by producing antibacterial small molecules ( ) . among the commensal microbiota, the bacteria that ferment fiber into short-chain fatty acids (scfas) have drawn attention. in animal models, scfa-producing bacteria confer protection against mdro colonization ( , ) . administration of fiber, either by increasing the abundance of scfa producers or by raising scfa levels themselves, confers similar protective effects ( ) ( ) ( ) ( ) . fiber also may attenuate the damage caused by antibiotics on the commensal microbiota ( ) . fiber therefore appears to be a suitable therapy to test for the prevention of mdro gut colonization in the icu. yet the effects of fiber on the gastrointestinal microbiota of icu patients, and whether such effects can still be observed in the face of broadspectrum antibiotics, is unknown. this pilot study was designed to test the hypothesis that fiber-based enteral nutrition increases the levels of scfa-producing bacteria and scfa levels in icu patients receiving broad-spectrum iv antibiotics, with a goal of generating effect size estimates that could be used as the basis for future studies involving fiber. adults -years-old or more at the time of medical icu admission were eligible for the study if they were expected to receive or more days of enteral nutrition and had received a broad-spectrum iv antibiotic for sepsis within the previous hours. empiric antibiotics were accepted, and subjects were enrolled without a requirement for positive cultures. the following antibiotic classes were considered broad spectrum: β-lactam/β-lactamase inhibitor combinations, carbapenems, cephalosporins, fluoroquinolones, and clindamycin. patients were excluded if they lacked capacity and had no health surrogate, had surgery involving the intestinal lumen within days, or had limited treatment goals (i.e., do not resuscitate/do not intubate). this study was approved by the institutional review board of columbia university medical center and registered on clinicaltrials.gov (nct ). patients were randomized in blocks of four with : assignment to one of two forms of complete enteral nutrition. they received either mixed soy-and oat-derived enteral nutrition with . g fiber/l (brand name: promote . with fiber; abbott nutrition, chicago, il) or calorie-and micronutrient-identical nutrition with g/l fiber (brand name: promote . ). enteral nutrition higher in fiber is available but these formulas were selected because they are identical aside from fiber. the formula manufacturer, abbott nutrition, had no involvement in the study. after patients were randomized, icu teams were instructed to continue the assigned formula as long as possible, but not to withhold ad lib nutrition once patients were ready to transition to oral diets. enteral feeding rates were individualized based on estimated energy requirements using the mifflin-st. jeor equation and the penn state university b and equations, as recommended by the american society of parenteral and enteral nutrition ( ) . patients were assessed at baseline/day (i.e., before starting enteral nutrition) and subsequently on days , , , and . assessments continued until withdrawal from the study, hospital discharge, day , or death (whichever came first). at each study assessment, a deep flocked rectal swab (copan diagnostics, murrieta, ca) was collected with fecal soilage to verify sample adequacy. interval spontaneous stools were also collected because rectal swabs do not provide enough material to directly test scfa levels. swabs and stools were flash frozen at − °c immediately after collection. to ascertain the amount of fiber actually received, the hourly enteral nutrition infusion rate was multiplied by the fiber content of the formula after accounting for interruptions in the feeding. for patients taking food by mouth, the type of meals, number of meals, and percentage of meal consumption was recorded by the patient's nurse. nutritional values for each meal type were obtained from the department of nutrition, including fiber content, so that fiber intake could be calculated even among patients who had transitioned to an oral diet. the primary outcome was the within-individual change from baseline (preintervention) to day in the relative abundance of scfa-producing bacteria from rectal swabs. at the end of the study, rectal swabs were thawed and dna was batch extracted for sequencing of the v region of the s rrna gene (additional details in supplemental methods, supplemental digital content , http://links.lww.com/ccx/a ) ( ) . using this data, operational taxonomic units (otus) were classified as scfa-producing or non-scfa-producing based on the study by vital et al. ( ) , which identified taxa that account for % of colonic butyrate production. the relative abundance of these scfa-producing otus was summed within each patient and calculated as [(day − baseline)/baseline]. differences between study groups were assessed as an intent-to-treat wilcoxon rank-sum test. later study assessments were used to investigate durability of effect using similar methods. sequencing fastq data files are publicly available within the short read archive under bioproject prjna . the secondary outcome was scfa levels, measured from whole stool samples. because baseline stools were unavailable, scfa levels were determined from the stool sample closest to day rather than as change from baseline. at the end of the study, homogenized fecal samples were thawed and assessed using liquid chromatographymass spectrometry (supplemental methods, supplemental digital content , http://links.lww.com/ccx/a ). the concentrations of eight scfas including butyrate were summed within each sample to yield a single total scfa concentration in μg/g of stool. the clinical effects of fiber administration were assessed focusing on caloric intake, stool frequency, and stool consistency. stool frequency was measured by asking icu nurses at each study assessment to report the number of stools during the prior -hour period. stool consistency was measured on a -point likert scale analogous to the bristol stool scale ( = watery; = loose/mucousy; = loose with solid elements; = formed, soft; = formed, hard) ( ) . nutritional intake was measured as the proportion of goal calories consumed. adverse effects were assessed in two ways. first, daily medical progress notes were reviewed to ascertain untoward health events, which were graded in terms of severity and relatedness to the study intervention. second, because untoward health events are so common in the icu and because it is challenging to determine relatedness ( ) , three types of adverse events were prespecified that could be ascertained objectively: death, culture-proven infection, and electrolyte abnormalities. death was ascertained from the electronic medical record, which interfaces with the social security death index; culture-proven infection was operationalized as previously described ( ); and electrolyte abnormalities were recorded as the maximum and minimum values for serum potassium, sodium, calcium, and phosphate. all analyses were performed intent-to-treat, among the patients who provided baseline and day samples. primary analyses were conducted using the baseline and day data, with the later study assessments used to assess for durability of effects. categorical data were compared using fisher exact text and continuous data were compared using rank-sum tests. a power calculation was performed before the study was begun as a two-sample test of means. it was estimated that a sample size of patients per group would yield % power to detect a difference of . sd between groups. all testing was two-sided with alpha . considered statistically significant. from august to june , patients were enrolled all of whom had received either a third-generation cephalosporin, carbapenem, or β-lactam/β-lactamase combination antibiotics within the preceding hours (for antibiotics received and duration, see supplemental table , supplemental digital content , http://links.lww.com/ccx/a ). one patient was randomized to fiber with surrogate consent but self-extubated the next day and declined to continue the study. another was randomized to no fiber and died before day . this left patients who provided baseline and day samples and were analyzed. clinical characteristics were similar for the fiber and no fiber groups ( table ) . four patients crossed over, two in each group. two patients assigned to fiber had delays initiating of enteral nutrition and did not receive any within days of enrollment. two patients assigned to no fiber transitioned to oral diets more rapidly than anticipated and received small amounts of fiber before day . these four patients were analyzed based on their original study assignment (i.e., intent-to-treat). overall, the fiber group received a median of . g/d (iqr, . - . ; maximum, . ) fiber by day versus g/d (iqr, - . ) in the no fiber group (p < . ). by the day study assessment, there was no difference in observed fiber intake between study groups (fig. ) . within-individual change in scfa-producing bacteria from baseline to day was compared between study groups. there was a median + % (iqr − to + , ) in the fiber group versus − % (iqr, − to + ) in the no fiber group (p = . ) (fig. ) . this nonsignificant trend toward increased scfa producer relative abundance in the fiber group remained for subsequent study assessments. when scfa-producing otus were considered as individual data points (i.e., with a given patient contributing a data point for each otu), the difference in scfa producers seen with fiber became statistically significant (supplemental fig. the median day fecal scfa concentration was μg/g stool (iqr, - , ) in the fiber group versus μg/g stool (iqr, ) in the no fiber group (p = . ) (fig. ) . there were no significant differences between scfa levels during subsequent assessments, although the trend remained higher in the fiber group (supplemental fig. , supplemental digital content , http://links.lww.com/ccx/a ; legend, supplemental digital content , http://links.lww.com/ccx/a ). there were no differences in alpha diversity between study groups, with both groups declining in diversity as the study progressed (supplemental fig. , supplemental digital content , http:// links.lww.com/ccx/a ; legend, supplemental digital content , http://links.lww.com/ccx/a ). when sequencing data were assessed in a hypothesis-free manner, there were day declines in the non-scfa-producing otus classified as finegoldia genus (p = . ) and erysipelotrichaceae family (p = . ), comparing fiber versus no fiber. through day , a median of % (iqr, - %) of goal calories were provided in the fiber group versus % (iqr, - %) in the no fiber group (p = . ). there was a median of stools/d (iqr, . - . ) in the fiber group versus . stools/d (iqr, . - . ) in the no fiber group (p = . ). stool consistency was . (iqr, adverse effects were monitored through study day . there were no differences in the number or severity of untoward health events based on study group (supplemental table , supplemental digital content , http://links.lww.com/ccx/a ). there were also no differences in deaths (two fiber vs. four no fiber, p = . ), culture-proven infections (three fiber vs. three no fiber, p = . ), or electrolyte abnormalities (supplemental table , supplemental digital content , http://links.lww.com/ccx/a ). power calculations were performed to guide sample size calculations for future studies. the observed mean change between baseline and day in scfa producers was + % (sd = %) for fiber and − . % (sd = %) for no fiber. the fiber group had + . sd increase in scfa producers, whereas the study was powered to detect a . sd or greater change. assuming similar effect size and variance, future studies would require patients ( per group) to achieve % power. this pilot study of icu patients receiving antibiotics found that a median dose of g/d of mixed fiber given as enteral nutrition was associated with a % gain in putatively beneficial scfaproducing bacteria over a day time span, whereas patients who were not randomized to fiber had a % decline in the same bacteria. actual scfa levels paralleled the changes in scfa producers and were six-fold higher in the fiber group. despite these large differences, neither the scfa producer result nor the scfa level result was statistically significant. all observations were intent-totreat and there was a % rate of crossover, a common challenge for icu nutrition studies ( ) . this result provides a valuable effect size estimate for future studies. such studies will require - patients to be adequately powered to assess effects of fiber on scfa producers, although this will presumably depend on fiber amount and type. prior studies have tested prebiotic interventions in the icu. results of these studies are mixed and, because the interventions tested have been heterogenous, hard to interpret. o'keefe et al ( ) looked at scfa producer relative abundance and fecal scfa levels in response to supplementation with - g wheat dextrin/d in icu patients ( ) . with fiber, there was a dramatic increase in firmicutes and other scfa producers and substantial increases in scfa levels including a doubling of fecal butyrate concentrations. this result contrasts sharply with the decline in scfa producers and scfa levels usually observed in icu patients ( , ) . it also accords well with our own retrospective study of icu patients, which found that observed mixed fiber intake correlated well with scfa producer relative abundance during the hours after icu admission ( ) . in that study, patients in the highest tertile of fiber received had a two-to figure . actual amount of fiber received during the trial, stratified by study group. box-and-whisker plots depict the mean amount of fiber received for each study period (between baseline and day , between day and day , etc.), stratified by study group. patients were enrolled in the study if they were expected to receive enteral nutrition for a minimum of days. after days, as patients transitioned off enteral nutrition and onto oral diets, there was substantial crossover between study groups. based on original study assignment, there was a statistically significant difference in the actual amount of fiber received between enrollment and day (p < . ), but not at later study timepoints. these values were then compared between the two study groups as a wilcoxon rank-sum test. none of the differences between groups were statistically significant. three-fold increase in the relative abundance of scfa producers compared with patients in the lowest tertile of fiber received. other trials have had contradictory results. a study testing days of g/d inulin versus maltodextrin supplementation in icu adults initiating enteral nutrition found no difference in fecal abundance of faecalibacterium prausnitzii or bifidobacteria, or in fecal scfa levels ( ) . across these studies, differences in the type and amount of fiber, mode of delivery (supplementation vs. fibercontaining enteral nutrition), and outcome ascertainment could account for the differences in findings ( ) . in this study, there were trends toward clinical benefits associated with fiber, some of which reached statistical significance. with fiber, there was a % absolute increase in goal calories consumed through day (equivalent to an additional kcal/ patient/d), which was not statistically significant. also, with fiber there was firmer stool consistency and a decrease in stool frequency by about stool/patient-day. this last finding was significant despite the small study size and some crossover. improved stool consistency is not likely to impact survival in the icu but probably does impact patient comfort, hygiene, and nursing care. importantly, fiber did not cause diarrhea, bezoars/intestinal obstruction, or other adverse effects in the icu as has been suggested in the past ( ) . this study has strengths but also limitations. by randomizing patients to one of two forms of complete enteral nutrition that were calorie and micronutrient identical other than fiber, it allowed us to reasonably attribute any observed differences to fiber itself. on the other hand, the difference in actual fiber intake between study groups- g/d for days-was neither as high in dose nor as long in duration as we would have wished. indirect calorimetry was not performed to measure energy consumption, and we instead relied upon estimating equations ( ) . the fiber was integrated within enteral nutrition rather than supplementation with a specific fiber type (e.g., inulin, psyllium, wheat dextrin). this improves generalizability but might obscure biological effects that would only be seen with monosupplementation using a specific fiber type. we have initiated a follow-up trial testing up to g/d of inulin for days in the icu in part to address these limitations (nct ). last, the trial was small but rigorously prespecified the primary outcome and a supporting secondary outcome, and carefully assessed relevant clinical and adverse effects. in summary, this randomized icu pilot trial found that mixed fiber, given as part of enteral nutrition, was associated with nonsignificant increases in fecal scfa-producing bacteria and in fecal scfa levels. the study did not seek to investigate the clinical consequences of these microbiome changes. fiber improved stool consistency and was apparently safe up to a maximum of g/d. the results of this trial provide effect size estimates that can be the basis for future trials testing whether fiber, by increasing scfa producers and/or scfa levels, might confer benefit in the icu. supplemental digital content is available for this article. direct url citations appear in the html and pdf versions of this article on the journal's website (http://journals.lww.com/ccejournal). short-chain fatty acid (scfa) levels measured from whole stools on day , stratified by study group. baseline preintervention whole stools were not available so scfa levels were compared between study groups at day . the sum total of eight scfas was measured using an aliquot of homogenized stool: -methylbutyrate, acetate, butyrate, hexanoate, isobutyrate, isovalerate, propionate, and valerate. world health organization: antimicrobial resistance: global report on surveillance. who library cataloguing-in-publication data pathogen colonization of the gastrointestinal microbiome at intensive care unit admission and risk for subsequent death or infection associations between enteral colonization with gram-negative bacteria and intensive care unitacquired infections and colonization of the respiratory tract entry of bacteria into the urinary tracts of patients with inlying catheters the pathogenesis of catheter-related bloodstream infection with noncuffed short-term central venous catheters a gut commensal-produced metabolite mediates colonization resistance to salmonella infection bifidobacteria can protect from enteropathogenic infection through production of acetate depletion of butyrate-producing clostridia from the gut microbiota drives an aerobic luminal expansion of salmonella a dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility dietary supplementation with nonfermentable fiber alters the gut microbiota and confers protection in murine models of sepsis dietary cellulose supplementation modulates the immune response in a murine endotoxemia model dietary xanthan gum alters antibiotic efficacy against the murine gut microbiota and attenuates clostridioides difficile colonization recovery of the gut microbiota after antibiotics depends on host diet, community context, and environmental reservoirs nutrition support core curriculum: a case-based approach: the adult patient. silver spring, md, american society for parenteral and enteral nutrition the human microbiome project colonic butyrate-producing communities in humans: an overview using omics data stool form scale as a useful guide to intestinal transit time serious adverse events in academic critical care research the intensive care medicine research agenda in nutrition and metabolism effect of fiber supplementation on the microbiota in critically ill patients rapid and sustained long-term decrease of fecal short-chain fatty acids in critically ill patients with systemic inflammatory response syndrome rapid gastrointestinal loss of clostridial clusters iv and xiva in the icu associates with an expansion of gut pathogens relationship between dietary fiber intake and short-chain fatty acid-producing bacteria during critical illness: a prospective cohort study additional oligofructose/inulin does not increase faecal bifidobacteria in critically ill patients receiving enteral nutrition: a randomised controlled trial guide to designing, conducting, publishing and communicating results of clinical studies involving probiotic applications in human participants intestinal obstruction from cecal bezoar; a complication of fiber-containing tube feedings society of critical care medicine; american society for parenteral and enteral nutrition: guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of critical care medicine (sccm) and american society for parenteral and enteral nutrition for information regarding this article, e-mail: def @cumc.columbia.edu or cm @cumc.columbia.edu key: cord- -j mknuv authors: rahim, fawad; amin, said; noor, mohammad; bahadur, sher; gul, huma; mahmood, afsheen; usman, muhammad; khan, muhammad asif; ullah, raza; shahab, khalid title: mortality of patients with severe covid- in the intensive care unit: an observational study from a major covid- receiving hospital date: - - journal: nan doi: . /cureus. sha: doc_id: cord_uid: j mknuv objective to determine the mortality of patients with severe covid- in the intensive care unit (icu) in relation to age, gender, co-morbidities, ventilatory status, and length of stay (los). methods this was a cross-sectional study based on data retrieved for patients admitted to the icu of hayatabad medical complex, peshawar, pakistan, from april to august . study variables were age, gender, co-morbid conditions, ventilatory status, and length of stay (los). the data were analyzed using spss version (ibm corp., armonk, ny). the independent t-test and the chi-square test were used to compare the means and frequencies of variables. multivariate regression analysis was used to predict the likelihood of mortality. results the overall mortality was %. non-invasive ventilation (niv) was administered to . % of patients. mortality was higher for invasive mechanical ventilation (imv) ( . % vs . %, p< . ) and for over years ( . % vs . %, p= . ). mortality without co-morbidities was . %. comparative mortality rates for at least one co-morbidity ( . %), diabetes mellitus ( . %), hypertension ( %), diabetes mellitus and hypertension both ( . %), and chronic obstructive pulmonary disease ( %) were insignificant. the los for survivors was longer ( . ± . versus . ± . days, p= . ). the los < h was associated with higher mortality ( . % vs . %, p= . ). on multivariable regression, the likelihood of mortality was high for imv ( . , % ci . - . , p< . ) and elderly (> years) patients ( . , %ci . - . , p= . ). mortality decreased with los longer than h ( . , %ci . - . , p= . ). co-morbidities did not have any effect on mortality. conclusions age more than years and imv were independent risk factors for higher mortality. longer icu stay, specifically more than hours, was associated with lower mortality but los less than hours might not have a causal relationship with mortality. the odds of survival were not affected by co-morbidities. coronavirus disease (covid- ) started as atypical pneumonia in wuhan, china, in december and soon became a global pandemic [ ] . globally, there are , , confirmed cases as of september , , and , have succumbed to the disease [ ] . pakistan reported its first case on february , , and as of september , , there are , confirmed cases with a death tally of , [ ] . the clinical manifestations of covid- vary from asymptomatic seroconversion to mild upper respiratory tract infection, severe pneumonia, and multiorgan failure [ ] . the mortality of covid- pneumonia is higher than other viral pneumonia [ ] . after the outbreak, a large number of patients requiring respiratory support placed an unprecedented demand for intensive care services [ ] . this necessitated a rapid expansion of intensive care infrastructure, capacity building, and staffing in many countries [ ] . the data in terms of mortality, ventilatory support, comorbid conditions, and length of hospital stay is conflicting because different authors have reported the outcomes of a fraction of admitted patients and at variable durations since admission [ ] [ ] . multiple factors influence icu mortality in covid- . these include the severity of the illness itself, gender, ethnicity, age, comorbid conditions, blood type, mode of ventilatory support, in addition to the availability of trained staff in the icu [ ] . studies have reported nearly % mortality amongst patients on invasive mechanical ventilation (imv) during the peak of the pandemic [ ] . mortality among patients on imv was . %, %, %, %, . %, %, and %- % in new york [ ] , china [ ] , uk [ ] , spain [ ] , australia [ ] , and india [ ] , respectively. with time, the mortality in icus declined to around % [ ] . in the early days of the outbreak, there were no international guidelines for managing patients admitted to the icu, and the rationing of resources based on local policies in overwhelmed icus might have added to divergent data. it is likely that due to the pressure of the pandemic on icu services, there has been widespread use of other respiratory support (niv or high-flow nasal oxygen) outside icus, and, therefore, patients admitted to the icu were disproportionately sicker. fatality rates vary significantly by country, as the magnitude and velocity of surge fluctuated in different regions of the world on different time frames [ ] [ ] ] . moreover, the preparedness of the health services, the response of the community, and cultural and religious beliefs might have added to the outcome [ ] . pakistan is a developing country where one-third of the population is living below the poverty line (less than one dollar a day) [ ] . the health system is weak and already overstretched. covid- further added to this. there was a social stigma attached to a covid- diagnosis [ ] . patients would often hide epidemiological risk factors & even clinical features of the disease to avoid being diagnosed. many patients would not come early even with severe disease to the hospital and relatives would keep them at home till very late. moreover, the shortage of icu beds, ventilators, and trained staff was another worry, adding to the nightmare of the worst outcome for the patients of covid- in pakistan [ ] . there was no harmony in the vision and actions of different stakeholders and policymakers of the government to prevent the spread of the virus [ ] . amidst the pandemic and prevailing ground realities, the general perception of the medical community was that pakistan's overall mortality, in general, and icu mortality, in particular, will be strikingly different from the rest of the world [ ] . this necessitated determining the survival of covid- patients in relation to comorbid conditions and ventilatory support in our population. this cross-sectional study was carried out in a major covid- receiving tertiary care hospital in peshawar, pakistan. it is a -bedded hospital, caring for patients coming from all over the province. since there were no national or international guidelines for treating severely ill patients with covid- in the early days of the pandemic, a local criterion for admission to the icu was devised. while devising the criteria, the severity of the disease itself, the degree of hypoxia, hemodynamic stability, co-morbid conditions, and multiorgan involvement were considered. the study was approved by the institutional review board of khyber girls medical college/hayatabad medical complex, peshawar, pakistan. permission was obtained from the medical director. data were retrieved for patients admitted from april , , till august , . study variables were age, gender, comorbidities, ventilatory status, length of stay (los), and outcomes in terms of survival and death. ventilatory status was taken as the highest level of respiratory support received, either non-invasive ventilation (niv) (continuous positive airway pressure therapy (cpap) or bilevel positive airway pressure (bipap)) or imv. survival was defined as shifting from the icu to a general isolation ward when the patient improved clinically and did not need further icu care. the data were analyzed using spss version . the independent t-test and chi-square test were used to determine the statistical significance of differences in age, gender, comorbidities, ventilatory status, and los between survivors and non-survivors. the multivariable regression model was used to predict the likelihood of mortality for the above-mentioned variables. the mean age of the study population was . ± . years. out of the total of patients, ( %) were male. around two-thirds of patients ( . %) were under the age of years. one-hundred twenty-five ( . %) patients did not have any co-morbidity. the most common co-morbidities were diabetes mellitus (dm) and hypertension (htn) ( . % of patients had both dm and htn in addition to . % who were diabetic only). the mean los in icu was . ± . days, and ( . %) patients spent less than hours in the icu. demographic parameters are summarized in table . [ ] . the reasons for the difference in survival compared to the developed countries could be due to the better availability of trained and dedicated staff for icus, the timely preparedness of the health system for the pandemic, sufficient resources, and the late phase of the pandemic in their regions. moreover, in most of the above-mentioned studies, a significant number of patients were still receiving icu care when the studies were published while in this study the outcome of all the admitted patients has been reported. the mean age of patients admitted to the icu was . ± . years. this contrasts with studies reported from the usa [ ] , italy [ ] , and spain [ ] , where the mean age of patients ranged from to years. pakistan has only a . % population over the age of years [ ] . this might be the reason for the lower mean age of the patients in the present study. co-morbid conditions have been reported to contribute to the severity and worse outcomes in covid- . however, the distribution of comorbidities varies by region [ ] . in the present study, dm was the leading comorbid condition. in addition to . % of patients who had both dm and htn, . % had dm alone followed by copd ( %) and htn ( . %). in other studies, htn has been the most common co-morbid condition [ , , ] . the high proportion of dm in this study may be due to the high prevalence of type dm and pre-dm in pakistan ( . % and . %, respectively) [ ] . this varied co-morbid profile also warrants further studies to better understand the impact of individual patient risk factors. in the present study, % of patients did not have any co-morbid condition in contrast to that reported from italy [ ] and china [ ] , where % and . % of patients, respectively had at least one co-morbid condition. the reason for the difference might be the younger age of our study population. niv has been the mainstay of treatment ( . %) while . % were treated by imv. yu . this might be explained by the fact that these studies were conducted during the early days of the pandemic when recommendations about the most appropriate modality of ventilation were not clear, and imv was considered a more effective option. moreover, there was a fear that niv could generate an aerosol. it was quite late into the pandemic that niv was advocated as the preferred alternative, especially for patients without significant co-morbidities [ ] . a higher proportion of patients with dm only, htn only, dm and htn both, and copd did not survive. but, when compared to those without any co-morbidity, the difference in mortality for any of the co-morbid conditions is not significant. this contrasts with published literature, where the presence of these comorbidities increased the odds of mortality from covid- [ ] . however, a metanalysis (articles = , n= , ) by bajgain et al. concluded that the presence of one or more co-morbidity is not associated with a higher fatality rate [ ] . overall, the mortality was higher ( . %) for those on imv than those on niv ( . %). treatment with niv significantly increased the odds of survival ( . , ci . - . , p=< . ). this is consistent with the mortality rate observed by wang et al. and yang et al. in china [ ] [ ] . the high mortality with imv patients could be due to inadequate intensive care services and lack of enough experience with treating covid- related acute respiratory distress syndrome. moreover, late shifting to the icu at a stage where patients had developed multiorgan failure also added to the high mortality in this study. when compared to younger patients (age less than years), elderly patients had significantly higher mortality (or . , ci . - . , p= . ). higher mortality among the elderly has been consistently reported [ , ] . it is a punishment from god. the response of the government was also far from ideal. tactics of using the police, rangers, and army for a selective lockdown of infected neighborhoods, escorting infected patients to isolation centers, the presence of guards at the cases' residences, and repeated check on their family members at their homes regarding symptoms and test results, were tantamount to treating patients and their families like criminals. all these culminated in the social stigma attached to a covid- diagnosis [ ] . this led to the development of a reluctant attitude in the public to seek timely medical attention. the overall mortality in the present study was %. age more than years was an independent risk factor for higher mortality. mortality was high for patients on imv. the odds of mortality were not affected by dm, htn, dm and htn both, and copd. longer icu stay, specifically, more than hours, was associated with lower mortality but los less than hours might not be associated with higher mortality. to conduct the following study: "mortality of severe covid- patients in intensive care unit; an observational study from a major covid- receiving hospital" the institutional review board needs to be informed and approached for revision of approval shall any significant change(s) are made in the study design/protocol. animal subjects: all authors have confirmed that this study did not involve animal subjects or tissue. conflicts of interest: in compliance with the icmje uniform disclosure form, all authors declare the following: payment/services info: all authors have declared that no financial support was received from any organization for the submitted work. financial relationships: all authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. other relationships: all authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. clinical characteristics of coronavirus disease in china covid- ) dashboard outcomes from intensive care in patients with covid- : a systematic review and meta-analysis of observational studies practical recommendations for critical care and anesthesiology teams caring for novel coronavirus ( -ncov) patients. directives concrètes à l'intention des équipes de soins intensifs et d'anesthésiologie prenant soin de patients atteints du coronavirus -ncov preparing for covid- : early experience from an intensive care unit in singapore presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region factors associated with death in critically ill patients with coronavirus disease in the us clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study clinical course and outcomes of intensive care patients with covid- icnarc report on covid- in critical care. icnarc covid- study case mix program database sars-cov- in spanish intensive care units: early experience with -day survival in vitoria fewer covid- deaths in icu suggest hospital care improving: study cultural behaviour and health beliefs during covid- : grasp something as a remedy social and behavioural response to covid- estimation of the final size of the covid- epidemic in pakistan pakistan says no more lockdown despite surging cases new algorithm shows alarming number of covid- deaths in pakistan by characteristics and outcomes of critically ill patients with covid- in washington state baseline characteristics and outcomes of patients with covid- admitted to intensive care units in vancouver, canada: a case series risk factors for mortality and respiratory support in elderly patients hospitalized with covid- in korea diabetes prevalence survey of pakistan (dps-pak): prevalence of type diabetes mellitus and prediabetes using hba c: a population-based survey from pakistan patients with covid- in icus in wuhan, china: a cross-sectional study noninvasive versus invasive ventilation in covid- : one size does not fit all! impaired fasting glucose and diabetes are related to higher risks of complications and mortality among patients with coronavirus disease. front endocrinol (lausanne) prevalence of comorbidities among individuals with covid- : a rapid review of current literature we acknowledge the support of prof. khalid mehmood and prof. akhtar sherin for reviewing the manuscript. we also acknowledge the support of muhammad irfan (medical student) for his contribution to data entry. key: cord- - ncfyc authors: farasat, sadaf; dorsch, jennifer j.; pearce, alex k.; moore, alison a.; martin, jennifer l.; malhotra, atul; kamdar, biren b. title: sleep and delirium in older adults date: - - journal: curr sleep med rep doi: . /s - - -y sha: doc_id: cord_uid: ncfyc purpose of review: poor sleep and delirium are common in older patients but recognition and management are challenging, particularly in the intensive care unit (icu) setting. the purpose of this review is to highlight current research on these conditions, their inter-relationship, modes of measurement, and current approaches to management. recent findings: sleep deprivation and delirium are closely linked, with shared clinical characteristics, risk factors, and neurochemical abnormalities. acetylcholine and dopamine are important neurochemicals in the regulation of sleep and wakefulness and their dysregulation has been implicated in development of delirium. in the hospital setting, poor sleep and delirium are associated with adverse outcomes; non-pharmacological interventions are recommended, but tend to be resource intensive and hindered by a lack of reliable sleep measurement tools. delirium is easier to identify, with validated tools available in both icu and non-icu settings; however, an optimal treatment approach remains unclear. antipsychotics are used widely to prevent and treat delirium, although the efficacy data are equivocal. bundled non-pharmacologic approaches represent a promising framework for prevention and management. summary: poor sleep and delirium are common problems in older patients. while these phenomena appear linked, a causal relationship is not clearly established. at present, there are no established sleep-focused guidelines for preventing or treating delirium. novel interventions are needed that address poor sleep and delirium, particularly in older adults. over the past two decades, delirium, in particular in older adults (≥ years old) hospitalized in intensive care units (icus), has gained substantial attention as a common and major health problem. this attention has been driven, in part, by the rise in the older adult population, combined with an explosion in research highlighting numerous adverse consequences of delirium, including long-term cognitive, physical and mental health impairments, and early death. this knowledge has motivated efforts to better understand and to prevent delirium, highlighting poor sleep, and more specifically sleep/ wake disruption, as a common and potentially modifiable risk factor for delirium. interest is growing in the delirium-sleep/ wake relationship, in particular their shared characteristics and mechanisms, bidirectional effects, and impact on outcomes in older adults. this review aims to provide an in-depth overview on this topic, focusing specifically on ( ) delirium and ( ) poor sleep in older adults; ( ) the sleep-delirium connection; ( ) tools to evaluate delirium and sleep; and ( ) prevention and management of poor sleep and delirium. we conclude by highlighting areas for future research. delirium, an acute, severe neuropsychiatric syndrome characterized by waxing and waning levels of consciousness and periods of inattention and confusion, has gained attention over the past years as a major health problem. a sequela of illness, hospitalization, or post-surgical states, delirium complicates up to % of emergency department visits [ ] , % of hospitalizations [ ] , and % of intensive care unit stays among older adults [ ] . while predisposing factors such as advanced age, medical comorbidities, and baseline cognitive impairment can predispose patients to delirium, many modifiable precipitating factors also contribute to delirium, including uncontrolled pain, dehydration, and polypharmacy [ , ] . in hospitalized patients, delirium leads to prolonged length of stay, increased hospital costs [ ] , long-term cognitive impairments, prolonged institutionalization [ , ] , and early death [ , ] . delirium is also costly, accounting for up to $ billion in annual us health care expenditures [ ] . due to its short-and long-term consequences and costs, delirium has been identified as a research priority by the american geriatrics society (ags) and national institute on aging [ ] , and a quality-of-care predictor of survival in the assessing care of vulnerable elders study (acove) [ ] . while delirium is a multifactorial phenomenon, with several proposed pathophysiological mechanisms, mechanistic research has been slow in part due a lack of wellestablished animal models and an absence of easily obtainable biomarkers [ ] . among the neurological pathways hypothesized to precipitate delirium, one involves the prefrontal cortex, anterior cingulate, and basal ganglia, and another involves the parietal lobes, superior colliculus, and thalamic pulvinar nucleus [ ] . more recently, a functional network comprised of several interconnected brain structures has been implicated in delirium [ ] . disturbances in these pathways lead to decreased cholinergic activity and dopaminergic excess, contributing to delirium [ ] . the depressed cholinergic activity pathway is supported by the observation that anticholinergic medications precipitate delirium [ , ] , and dopaminergic excess based on the possible therapeutic effect on delirium of haloperidol, a potent dopamine antagonist [ ] . recently, the dopaminergic pathway has been a common target for pharmaceutical trials for delirium treatment and prevention [ ] . besides acetylcholine and dopamine, neurotransmitters serotonin, gamma-aminobutyric-acid (gaba), glutamate, histamine, and norepinephrine are also implicated in delirium, but their mechanisms are not well established [ , ] . a pro-inflammatory pathway may also contribute to delirium [ ] , particularly in acutely ill patients with higher levels of inflammatory biomarkers (e.g., cytokines) [ ]. theoretically, this pro-inflammatory state disrupts the bloodbrain barrier, leading to tissue edema, neurotransmitter imbalance, and apoptosis leading to cognitive dysfunction [ ] . oxidative stress, another potential mechanism behind delirium, occurs when chronic hypoperfusion leads to a mismatch between oxygen delivery and consumption, leading to a rise in non-oxidative metabolism and accumulation of reactive and potentially toxic oxygen and nitrogen species [ ] . accumulation of these products can damage cerebral tissue, contributing to cerebral dysfunction and manifesting as delirium [ ] . once delirious, patients can exhibit either hyperactive, hypoactive, or mixed motoric subtypes [ ] . in the icu, hypoactive delirium predominates, characterized by reduced psychomotor activity, lethargy, and augmented gaba and melatonin activity [ ] . in contrast, depressed gaba and melatonin often occur with hyperactive delirium, characterized by increased psychomotor activity, agitation, disruptive behavior, sleep-wake disruption, and hallucinations [ ] . patients with mixed delirium fluctuate between the hypoand hyperactive states. recent research suggests that the hypoactive subtype portends a poor prognosis compared to the hyperactive form [ ] . the majority of delirium occurs in older (≥ years old) hospitalized adults, affecting up to % [ ] and % [ ] of older non-icu and icu patients, respectively. delirium also commonly affects older patients in non-hospital nursing units and post-acute care facilities [ ] . advanced age is independently associated with delirium in the acute care setting [ ] , as dementia and mild cognitive impairment are often clinically unrecognized [ ] . while the mechanism for increased risk of delirium in older adults is unclear, age-related neurodegeneration and associated alterations in acetylcholine, catecholamine, and serotonin may play a role. as compared to their younger counterparts, older patients are at risk for worse delirium-associated outcomes [ ] . incident delirium predisposes patients to new and persistent cognitive deficits and can accelerate the development of dementia for those with pre-existing cognitive impairment [ ] . in older adults, hospital-associated delirium increases the risk of accidental disruption of life-sustaining therapy (e.g., selfextubation) and longer duration of mechanical ventilation and icu and hospital length of stay [ , , ] . decreased ability to perform activities of daily living and loss of functional independence is a common outcome of delirium lasting or more days [ ] . incident delirium also increases the risk of mental health impairments including posttraumatic stress and depression [ ] . as a consequence, delirium in older adults, and its associated cognitive, physical, mental health, and quality of life impairments, increases the risk of rehospitalization and early death [ , ] . the remainder of this review will focus on the relationship of poor sleep, sleep/wake disruption, and delirium in older adults. under normal circumstances, total sleep time declines until age years, plateauing at to h a night [ ] . however, with age, sleep becomes more fragmented, with a rise in n and n ("light") sleep and a corresponding decline in slow wave sleep (sws) and rapid eye movement (rem), stages considered vital for rest and repair [ ] . more n /n and less sws render older adults more susceptible to arousals and awakenings from noxious stimuli such as light, sound, and physical discomforts such as pain or urge to micturate. hence, up to % of older adults experience poor sleep quality [ ] . moreover, approximately % of older adults have clinically significant insomnia and % have sleep apnea syndromes [ ] , further contributing to sleep disruption [ ] . finally, older patients with dementia exhibit greater n sleep, altered n architecture, and decreased sws and rem compared to non-demented counterparts [ ] . for all hospitalized patients, sleep is generally poor quality, with sleep disorders, pain, anxiety, and acute illness representing predisposing factors, and hospital-and carerelated disruptions representing precipitating factors [ , ] . among modifiable disruptions, hospitalized patients have identified noise ( %), nursing interruptions ( %), uncomfortable beds ( %), bright lights ( %), and unfamiliar surroundings ( %) as common reasons for poor sleep in the hospital [ , ] . in older hospitalized adults, sleep quality is particularly poor, averaging . fewer hours than home [ ] . sleep quality is even worse in older patients hospitalized in icus, characterized by fragmentation, decreased or absent rem and sws, preponderance of n , and predominance during daytime hours [ , , ] . in the icu environment, frequent loud sounds, patient-care interactions, sleep-altering medications (i.e., sedative infusions), and mechanical ventilation contribute to disrupted sleep [ ] [ ] [ ] [ ] . while the mechanism is not understood, poor sleep quality during hospitalization has been associated with adverse outcomes in older adults [ ] . for example, poor hospital sleep quality is believed to hinder participation in self-care and rehabilitation activities during post-illness recovery [ ] , increasing older adults' risk of falls, functional impairment, institutionalization, and early death. though causal pathways remain elusive, sleep/wake disruption and delirium are believed to be tightly associated, with a bidirectional relationship that is accentuated with aging. parallel symptoms have been noted in both sleep-deprived and delirious states, including fluctuating periods of inattention, mental status, and cognitive dysfunction [ , ] . attention and memory impairment, two key features of delirium, are also common after partial and total sleep deprivation [ , ] . additionally, poor sleep and delirium share many common risk factors, such as uncontrolled pain, stress, prolonged immobility, and acute illness [ ] . among medications, benzodiazepines are independently associated with delirium and disrupt sleep architecture by suppressing sws and rem [ ] , with a dose-dependent effect [ ] . anticholinergic medications are also associated with delirium and rem suppression [ ] . despite overlapping factors, strong evidence regarding the association between poor sleep and delirium is lacking, particularly in hospitalized patients. conflicting findings have been found in critically ill patients; however, studies have been limited substantially by unmeasured confounders and challenges in accurate, large-scale measurement (see sleep and delirium measurement below) [ ] . perhaps the most compelling icu study in mechanically ventilated patients demonstrated a significant adjusted association between shorter versus longer rem duration, as measured using polysomnography, and incident delirium [ ] . several studies have evaluated the relationship between the pre-existing sleep disorders syndromes and postoperative delirium (pod). for example, two studies evaluating patients undergoing elective knee [ ] and/or hip replacement surgery [ ] showed that those with obstructive sleep apnea (osa), versus those without, were more likely to develop delirium. similarly, following cardiac surgery, sleep-disordered breathing has been associated with a -fold increase in delirium risk [ ] . these data were synthesized in a recent systematic review and meta-analysis involving studies, which suggested a pooled odds ratio of pod of . for patients with osa, and . for unspecified sleep disorders [ ] . while prior studies on pod were limited by lack of sleep measurement, a recent pilot study involving eeg recordings suggested an association of lower sleep time and higher sleep latency on postoperative day and higher prevalence and severity of pod [ ] . the underlying pod-sleep mechanism remains unclear and may involve factors such as hypoxia and stress. some have speculated that that severe osa may be associated with reduced cholinergic activity, a known delirium risk factor [ ] . although little mechanistic data exist on poor sleep precipitating delirium, several plausible pathways have been proposed. sleep deprivation involves various specific areas of the brain, many of which are involved in the pathogenesis of delirium. in healthy volunteers undergoing -h sleep deprivation and pet imaging, decreased cerebral metabolism was noted in the prefrontal cortex, thalamus, and posterior parietal cortex, key brain areas involved in delirium [ ] . another study involving eeg demonstrated involvement of the frontal and parietal cortical areas in sleep-deprived subjects [ ] . similarly, from a neurohormonal standpoint, imbalances seen in delirium have been observed during sleep deprivation, including those involving acetylcholine and dopamine [ ] . dopaminergic activity rises after periods of sleep deprivation and is similarly upregulated in delirium [ ] . aside from acetylcholine and dopamine, melatonin and its precursors and breakdown products have received considerable attention in the context of the sleep-delirium relationship. under normal circumstances, the amino acid tryptophan undergoes conversion to melatonin, and melatonin is subsequently released by the pineal gland in a circadian pattern. melatonin release is strongly influenced by sleep-wake rhythms and zeitgebers such as ambient light, feeding schedules and social interactions, and tightly intertwines with other vital circadian processes, including rest-activity rhythms and transcription of genes necessary for cell repair, regeneration, and death. in the hospital setting, circadian misalignment is common and is considered a predisposing factor for delirium. this theory is supported by several studies, including those linking lower tryptophan levels with incident delirium following cardiac surgery [ ] , and others demonstrating higher delirium incidence in patients with abolished circadian melatonin secretion [ , ] . studies evaluating urinary sulphatoxymelatonin ( -smt), a melatonin breakdown product, demonstrated lower -smt levels in patients with hyperactive delirium and higher levels in hypoactive delirium, suggesting a relationship of melatonin and circadian misalignment with motoric subtypes of delirium [ ] . feasible, large-scale modes of evaluation are vital for efforts aimed at better detecting, preventing, and treating poor sleep and delirium, and for future research focusing on the sleepdelirium relationship and associated outcomes. however, as delirium predominantly occurs in the inpatient setting, in particular the icu, measurement of both delirium and sleep is extremely complicated, hindered by logistical and confounding factors inherent to the busy hospital environment. the primary modes of measurement are summarized below and in tables and . the gold standard for measuring sleep in non-critically ill populations is polysomnography (psg), which involves electroencephalography, electrooculography, electromyography, respiratory, oxygen saturation, and electrocardiography. despite its utility, psg is costly, cumbersome, resource intensive, and prone to electrode dislodgement, particularly in hospitalized or critically ill patients [ ] . additionally, in critically ill patients, the presence of severe sleep fragmentation [ ] , daytime sleep [ , ] , and atypical eeg patterns [ ] makes psg vulnerable to misinterpretation using traditional scoring criteria. for example, sleep spindles, which characterize n sleep, commonly occur with administration of benzodiazepines, while delta wave activity (as seen in sws (n )) can be seen in the setting of encephalopathy (i.e., secondary to toxic-metabolic disturbances or hepatic dysfunction). hence, traditional sleep staging should be applied cautiously in icu patients. an icu-specific psg scoring algorithm has been proposed but has yet to gain widespread use [ , ] . electroencephalography (eeg) utilizes scalp electrodes to measure brain activity, without emg, eog, and other monitors, and is therefore less cumbersome than psg [ ] . in noncritically ill patients, eeg and psg are highly sensitive and specific for delineating wake versus sleep, with eeg lacking [ ] . in critically ill patients, eeg interpretation is especially challenging, due to marked sleep-wave fragmentation, artifact, and alteration of normal signals by common icu issues such as sedation and illness itself. eeg recordings have also been used to calculate an odds ratio product (orp), a continuous estimate of sleep depth validated in ambulatory and icu patients [ , ] . the orp ranges from (deeply asleep) to . (fully awake), with orp < . predicting sleep and > . predicting wakefulness [ ] . orp can help differentiate sleep and wake, and was used in a recent study to demonstrate that increased wakefulness and right-left hemisphere orp concordance can predict extubation success in mechanically ventilated patients [ ] . however, orp-based sleep stage determination in hospitalized patients is limited by substantial interrater variability, similar to eeg. in patients with delirium, eeg tends to demonstrate background slowing and increased spectral variability with periodic discharges such as triphasic waves and polymorphic delta activity [ ] . similar patterns can also be seen in nonconvulsive status epilepticus (ncse), a mimicker of delirium [ ] . actigraphy involves an accelerometer, usually housed in a wristwatch-type interface, to measure activity levels. computer algorithms are then applied to activity data to determine sleep and wake. in community-dwelling adults, actigraphy has been validated to measure sleep [ ] , but has been shown to overestimate sleep in mostly inactive critically ill patients [ , ] . however, given its minimal invasiveness, long battery life, and low cost, actigraphy has potential for large-scale, long-term sleep estimation in hospitalized patients [ , ] . however, similar to psg, hospital-and icu-specific interpretation algorithms are needed before actigraphy can be used widely in the inpatient setting. unlike objective modes of sleep evaluation, questionnaires, though subjective, are feasible to perform on a large scale. specifically, the richards-campbell sleep questionnaire (rcsq), a -item instrument evaluating sleep depth, latency, efficiency, quality, and number of awakenings, has been validated against psg in critically ill patients [ ] . while the rcsq has been used in several icu-based studies to evaluate sleep, and the impact of interventions to improve sleep [ , ] , it must be completed by an alert patient, thus limiting its utility in the context of delirium. bedside staff (i.e., nurses) can complete the rcsq on their patients' behalf, but have been shown to overestimate patient sleep quality [ ] ; hence, proxy completion should be performed with caution. other subjective methods of assessing sleep are available and include the verran/snyder-halpern sleep scale [ ] , leeds sleep evaluation questionnaire (lseq) [ ] , sleep in the intensive care unit questionnaire (sicuq) [ ] , and saint mary's hospital sleep questionnaires (smhsq) [ ] ( table ) . in the inpatient setting, delirium frequently goes unrecognized. validated delirium assessment tools are essential for prompt identification and management of delirium. the society for critical care medicine (sccm) pain, agitation, delirium, immobility and sleep disruption (padis) guidelines recommend routine screening for delirium in the icu setting [ ] . these guidelines recommend two delirium screening tools: confusion assessment method for the intensive care unit (cam-icu) [ ] and intensive care delirium screening checklist (icdsc) [ ] . both screening managing poor sleep in the hospital is challenging, particularly in older adults, but may help with delirium prevention. it is widely believed that any interventions to improve sleep should involve a multifaceted, interdisciplinary approach [ ] . in a recent systematic review of sleep-focused icu interventions to improve delirium, of studies reported statistically significant reductions in delirium incidence, while showed a reduction in delirium duration [ ] . both pharmacologic and non-pharmacologic interventions can be employed, with minimization of sleep-disrupting medications as an important cornerstone of treatment. non-pharmacologic interventions to improve sleep include environmental optimization and relaxation techniques. while non-pharmacologic strategies can be resource intensive and require rigorous implementation methods to maintain sustainability, they are generally safe, low cost, and have limited side effects. buy-in from hospital systems can be difficult, given inherent challenges in measuring improvements in sleep, and a lack of data on sleep interventions leading to improved outcomes. data are also mixed regarding specific nonpharmacologic sleep promoting interventions in non-icu hospitalized patients, as noted in a recent systematic review of studies. more specifically, in this systematic review, interventions involving relaxation techniques ( rcts) demonstrated a - % improvement in sleep quality, involving daytime bright light a - % improvement, and two involving a sleep hygiene intervention a - % improvement [ ] . however, of these studies had a medium to high risk of bias (e.g., were limited by sampling error or selection, detection, and/or performance bias). from an environmental standpoint, noise minimization has been shown to improve subjective sleep quality ratings and includes staff-wide behavioral modification, use of ear plugs with or without eye masks, white noise, and soundproof material [ ] . daytime mobility interventions may also help with delirium prevention and may also help promote nighttime sleep, though evidence is lacking to support this notion [ , ] . after non-pharmacological interventions are attempted, pharmacologic strategies to promote sleep can be considered. a key first step in this approach is the discontinuation of sleep-disrupting and/or deliriogenic medications. the american geriatric society beers criteria for inappropriate medications in older adults can help identify many of these medications [ ] (table ). in the area of delirium prevention, there is substantial interest in the role of antipsychotics; however, efficacy data are equivocal [ ] . more specifically, a recent rct examined the use of haloperidol for delirium prophylaxis showed no decrease in delirium incidence and no improvement in overall mortality [ ] . subsequently, another rct examining the effect of haloperidol or ziprasidone versus placebo on icu delirium found no difference in delirium-free days [ ] . while recent guidelines make no recommendation regarding antipsychotics for the prevention or treatment of delirium [ ] , these medications may be reasonable to administer in the setting of agitation with the risk of staff or patient harm. aside from antipsychotics, other pharmacologic strategies to improve both sleep and delirium are being investigated. specifically, a recent study evaluated low-dose nocturnal dexmedetomidine (an α- agonist with sedative, hypnotic and analgesic properties) in mostly mechanically ventilated icu patients had mixed results, with improvements in delirium incidence but no improvement in sleep quality [ ] . additionally, melatonin and melatonin receptor agonists are gaining attention, in part due to their favorable side-effect profile and role in re-entraining circadian rhythms [ ] . despite this attention, a cochrane review involving randomized trials and participants found insufficient evidence to conclude that melatonin improves the quality and quantity of sleep in patients hospitalized in icus [ ] . regardless of equivocal supporting evidence, pharmacologic strategies remain a compelling area of investigation. whether non-pharmacological only, or combined with pharmacological interventions, a multicomponent, bundled approach is recommended for sleep and delirium improvement [ , , ] . among recent interventions, the icufocused "abcdef" bundle (assess, prevent and manage pain; both spontaneous awakening and breathing trials; choice of analgesia and sedation; delirium assessment, prevention, and management; early mobility and exercise; family engagement/empowerment) has gained popularity and has been associated with reductions in delirium, ventilator days, and icu readmissions [ , ] . alternatively, the ecash (early implementation of comfort and analgesia using minimal sedation and humane care) concept, derived from the pain, agitation and delirium guidelines, is a new approach to improve outcomes of patients in icu [ ] . sleep promotion is one of many components embedded within these bundles, making them particularly attractive options for intervention efforts aimed at improving sleep and delirium in hospitalized older adults. implementing and sustaining such bundles is challenging and requires buy-in from staff and leadership, dedicated champions, an interdisciplinary team, and audit-and-feedback methods. ongoing investigations are needed to evaluate, refine, and reproduce these invention bundles. as evidence grows regarding the benefits of multicomponent interventions to improve sleep and delirium in inpatient settings, methods for intervention implementation into routine care will need to be studied. furthermore, mechanistic research on how poor sleep or sleep/wake disruption, particularly among older adults, may lead to delirium will increase the utility of sleep-related delirium prevention efforts. finally, larger studies are needed to evaluate the risks and potential benefits of medications and medication deprescribing in hospitalized older patients at risk for poor sleep and delirium. delirium in the nursing home patients seen in the emergency department in the clinic. delirium characteristics associated with delirium in older patients in a medical intensive care unit delirium: acute cognitive dysfunction in the critically ill delirium in the intensive care unit: a review costs associated with delirium in mechanically ventilated patients delirium and long-term cognitive impairment delirium in the icu and subsequent long-term disability among survivors of mechanical ventilation delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit incidence, risk factors and consequences of icu delirium one-year health care costs associated with delirium in the elderly population prospective cohort study estimating total -year healthcare costs of delirium in the usa ranging from of $ - billion the american geriatrics society/national institute on aging bedsideto-bench conference: research agenda on delirium in older adults acove quality indicators delirium pathophysiology: an updated hypothesis of the etiology of acute brain failure neurocognitive consequences of sleep deprivation brain network disintegration as a final common pathway for delirium: a systematic review and qualitative meta-analysis is there a final common neural pathway in delirium? focus on acetylcholine and dopamine medication profiles of patients with cognitive impairment and high anticholinergic burden cholinergic deficiency hypothesis in delirium: a synthesis of current evidence the neuropathogenesis of delirium. a need to focus our research haloperidol and ziprasidone for treatment of delirium in critical illness biomarkers associated with delirium in critically ill patients and their relation with long-term subjective cognitive dysfunction; indications for different pathways governing delirium in inflamed and noninflamed patients review on delirium pathophysiology and nonpharmacologic and pharmacologic management in critically ill patients impaired oxidative metabolism precipitates delirium: a study of icu patients delirium: acute confusional states recent systematic review and metaanalysis demonstrating that hypoactive delirium predominates in the icu and is more prevalent in patients with greater illness severity the relation between the clinical subtypes of delirium and the urinary level of -smt phenomenological subtypes of delirium in older persons: patterns, prevalence, and prognosis delirium in hospitalized older patients characteristics associated with delirium persistence among newly admitted post-acute facility patients a systematic review of risk factors for delirium in the icu risk factors for incident delirium among older people in acute hospital medical units: a systematic review and meta-analysis predicting outcome in older hospital patients with delirium: a systematic literature review delirium is a strong risk factor for dementia in the oldest-old: a population-based cohort study intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of non-ventilated patients delirium duration and mortality in lightly sedated, mechanically ventilated intensive care patients long-term mental health problems after delirium in the icu observational cohort study demonstrating that persistent delirium after admission to a post-acute care facility is an independent predictor of -year mortality premature death associated with delirium at -year follow-up meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: developing normative sleep values across the human lifespan sleep problems in the elderly sleep complaints among elderly persons: an epidemiologic study of three communities review of sleep and aging, including a discussion of insomnia and sleep disordered breathing in older adults estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis sound and light levels are similarly disruptive in icu and non-icu wards sleep disturbance: the patient care activities applied at the night shift in the intensive care unit sleep quality and factors influencing self-reported sleep duration and quality in the general internal medicine inpatient population quality and quantity of sleep and factors associated with sleep disturbance in hospitalized patients objective sleep duration and quality in hospitalized older adults: associations with blood pressure and mood quantity and quality of sleep in the surgical intensive care unit: are our patients sleeping? a description of night sleep patterns in the critical care unit contribution of the intensive care unit environment to sleep disruption in mechanically ventilated patients and healthy subjects patient perception of sleep quality and etiology of sleep disruption in the intensive care unit sleep disturbances in the critically ill patients: role of delirium and sedative agents assist-control ventilation vs. low levels of pressure support ventilation on sleep quality in intubated icu patients poor self-reported sleep quality predicts mortality within one year of inpatient post-acute rehabilitation among older adults sleep deprivation in critical illness: its role in physical and psychological recovery performing while sleepy: effects of experimentally-induced sleepiness. sleep, sleepiness and performance. human performance and cognition prefrontal neuropsychological effects of sleep deprivation in young adults-a model for healthy aging? the effects of total sleep deprivation on recognition memory processes: a study of event-related potential the microstructure of dual-task interaction. . sleep deprivation and the control of attention bench-to-bedside review: delirium in icu patients -importance of sleep deprivation sleep disruption in critically ill patientspharmacological considerations lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients sedative and analgesic medications: risk factors for delirium and sleep disturbances in the critically ill promoting sleep in critically ill patients obstructive sleep apnea and incidence of postoperative delirium after elective knee replacement in the nondemented elderly postoperative complications in patients with obstructive sleep apnea syndrome undergoing hip or knee replacement: a case-control study sleep-disordered breathing is a risk factor for delirium after cardiac surgery: a prospective cohort study a systematic review and meta-analysis examining the impact of sleep disturbance on postoperative delirium pilot prospective study of post-surgery sleep and eeg predictors of post-operative delirium neural basis of alertness and cognitive performance impairments during sleepiness. i. effects of h of sleep deprivation on waking human regional brain activity the impact of moderate sleep loss on neurophysiologic signals during working-memory task performance sleep disruption in the intensive care unit is delirium after cardiac surgery related to plasma amino acids and physical condition? abolished circadian rhythm of melatonin secretion in sedated and artificially ventilated intensive care patients postoperative delirium and melatonin levels in elderly patients feasibility study of unattended polysomnography in medical intensive care unit patients characterisation of sleep in intensive care using -hour polysomnography: an observational study abnormal sleep/wake cycles and the effect of environmental noise on sleep disruption in the intensive care unit atypical sleep in ventilated patients: empirical electroencephalography findings and the path toward revised icu sleep scoring criteria a new classification for sleep analysis in critically ill patients the feasibility and utility of continuous sleep monitoring in critically ill patients using a portable electroencephalography monitor comparison of a single-channel eeg sleep study to polysomnography prospective study of mechanically ventilated patients undergoing psg; those with higher odds ratio product (orp), suggesting more wakefulness odds ratio product of sleep eeg as a continuous measure of sleep state the eeg in metabolic encephalopathy and coma the role and validity of actigraphy in sleep medicine: an update actigraphy to evaluate sleep in the intensive care unit. a systematic review : . systematic review of studies that used actigraphy to evaluate activity in critically ill patients feasibility of continuous actigraphy in patients in a medical intensive care unit noise and light pollution in the hospital: a call for action measurement of sleep in critically ill patients the effect of a quality improvement intervention on perceived sleep quality and cognition in a medical icu the effect of a multicomponent multidisciplinary bundle of interventions on sleep and delirium in medical and surgical intensive care patients patient-nurse interrater reliability and agreement of the richards-campbell sleep questionnaire instrumentation to describe subjective sleep characteristics in healthy subjects factor analysis of a sleep evaluation questionnaire the st. mary's hospital sleep questionnaire: a study of reliability clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (cam-icu) intensive care delirium screening checklist: evaluation of a new screening tool the richmond agitation-sedation scale: validity and reliability in adult intensive care unit patients assessment scales for delirium: a review validation of the delirium rating scale-revised- : comparison with the delirium rating scale and the cognitive test for delirium the neecham confusion scale: construction, validation, and clinical testing the delirium observation screening scale: a screening instrument for delirium fast, systematic, and continuous delirium assessment in hospitalized patients: the nursing delirium screening scale bundling sleep promotion with delirium prevention: ready for prime time? the impact of interventions to improve sleep on delirium in the icu: a systematic review and research framework non-pharmacologic interventions to improve the sleep of hospitalized patients: a systematic review clinical review: the impact of noise on patients' sleep and the effectiveness of noise reduction strategies in intensive care units early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial the association of sleep quality, delirium, and sedation status with daily participation in physical therapy in the icu updated american geriatrics society (ags) beers criteria for potentially inappropriate medication use in older adults antipsychotics for the prevention and treatment of delirium effect of haloperidol on survival among critically ill adults with a high risk of delirium: the reduce randomized clinical trial low-dose nocturnal dexmedetomidine prevents icu delirium. a randomized, placebocontrolled trial melatonin for the promotion of sleep in adults in the intensive care unit caring for critically ill patients with the abcdef bundle: results of the icu liberation collaborative in over , adults improving hospital survival and reducing brain dysfunction at seven california community hospitals: implementing pad guidelines via the abcdef bundle in , patients comfort and patient-centred care without excessive sedation: the ecash concept sleep in the intensive care unit: strategies for improvement an approach to drug induced delirium in the elderly principles and practice of sleep medicine postoperative sleep disturbance: influences of opioids and pain in humans opioids, sleep architecture and sleepdisordered breathing sleep and delirium in icu patients: a review of mechanisms and manifestations risperidone versus haloperidol in psychotic patients with disturbing neuroleptic-induced extrapyramidal symptoms: a double-blind, multi-center trial effect of risperidone on sleep in schizophrenia: a comparison with haloperidol effects of common medications used for sleep disorders nih state of the science conference statement on manifestations and management of chronic insomnia in adults dynamics of eeg slow wave activity during physiological sleep and after administration of benzodiazepine hypnotics benzodiazepine use as a cause of cognitive impairment in elderly hospital inpatients effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the mends randomized controlled trial sleep circuitry and the hypnotic mechanism of gabaa drugs dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial early postoperative cognitive dysfunction and postoperative delirium after anaesthesia with various hypnotics: study protocol for a randomised controlled trial-the pinocchio trial eeg and semg monitoring during induction and maintenance of anesthesia with propofol randomised clinical trial of the effects of prolonged-release melatonin, temazepam and zolpidem on slow-wave activity during sleep in healthy people new perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation preventive effects of ramelteon on delirium: a randomized placebo-controlled trial melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial assessment of role of perioperative melatonin in prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -gdhz mr authors: li, xiaoran; ge, peilin; zhu, jocelyn; li, haifang; graham, james; singer, adam; richman, paul s.; duong, tim q. title: deep learning prediction of likelihood of icu admission and mortality in covid- patients using clinical variables date: - - journal: peerj doi: . /peerj. sha: doc_id: cord_uid: gdhz mr background: this study aimed to develop a deep-learning model and a risk-score system using clinical variables to predict intensive care unit (icu) admission and in-hospital mortality in covid- patients. methods: this retrospective study consisted of , persons-under-investigation for covid- between february and may . demographics, chronic comorbidities, vital signs, symptoms and laboratory tests at admission were collected. a deep neural network model and a risk-score system were constructed to predict icu admission and in-hospital mortality. prediction performance used the receiver operating characteristic area under the curve (auc). results: the top icu predictors were procalcitonin, lactate dehydrogenase, c-reactive protein, ferritin and oxygen saturation. the top mortality predictors were age, lactate dehydrogenase, procalcitonin, cardiac troponin, c-reactive protein and oxygen saturation. age and troponin were unique top predictors for mortality but not icu admission. the deep-learning model predicted icu admission and mortality with an auc of . ( % ci [ . – . ]) and . ( % ci [ . – . ]), respectively. the corresponding risk scores yielded an auc of . ( % ci [ . – . ]) and . ( % ci [ . – . ]), respectively. conclusions: deep learning and the resultant risk score have the potential to provide frontline physicians with quantitative tools to stratify patients more effectively in time-sensitive and resource-constrained circumstances. since the first reports of severe respiratory illness caused by coronavirus disease in wuhan, china in mid-december zhu et al., ) , over . million individuals have been infected, resulting in over , deaths this retrospective study was approved by institutional review board with exemption of informed consent and hipaa waiver (irb- - ; stony brook university hospital, stony brook, ny, usa). stony brook university hospital, the only academic hospital serving suffolk county, about miles east of new york city, was one of the hardest hit counties in the country at the time of this writing. the covid- persons under investigation (pui) registry consisted of , patients from february to may . only patients who were diagnosed by positive tests of real-time polymerase chain reaction (rt-pcr) for severe acute respiratory syndrome coronavirus (sars-cov- ) were included in the study. demographic information, chronic comorbidities, imaging findings, vital signs, symptoms, and laboratory tests at admission were collected. imaging findings were extracted from patient chart review, which included information provided by radiology report as part of standard of care. the primary outcome was icu admission versus general floor admission, and the secondary outcome was in-hospital mortality versus discharge. mortality outside of hospital after discharge was not obtained. figure shows the flowchart of patient selection. of the , confirmed covid- positive cases, all , hospitalized covid- positive patients were used in our analysis. seventy-seven ( ) patients were admitted to the icu directly and an additional patients were subsequently upgraded to an icu from a general floor. among these icu patients, were discharged alive, expired during the hospitalization and the other are still in the hospital at the time of this analysis. comparison was made to general admissions who did not receive icu care, among whom patients were discharged alive and expired during the hospitalization (none remained in the hospital). two patients were excluded from machine learning analysis for missing categorical variables. brain natriuretic peptide (bnp) was missing from > % of patients, thus they were excluded from machine learning analysis. for the rest of the laboratory variables, missing data (in < % of patients) was imputed with predictive mean modeling using the ranking of clinical variables of categorical or numerical values were made using the boruta, a statistical software (kursa & rudnicki, ) . boruta ranks feature importance using the random forest method. in this decision tree-based method, the quantitative measure of importance is the gini feature of importance, which counts the times that a feature is used to split a node of a decision tree, statistically weighted by the number of instances the node splits. in the dnn model, the top predictors were those that demonstrated statistical significance using built-in statistical methods within the boruta algorithm. a correlation coefficient > . from collinearity analysis was used to exclude correlated variables from machine learning analysis. note that none of the top features we used in the final analysis demonstrated strong correlation with other features. thus, no top features were removed as a result. a deep neural network (dnn) was constructed to predict icu admission and mortality using five fully connected dense layers . the top clinical predictors were input parameters, determined by testing subsets of these parameters, and icu admission and mortality were outcome parameters. the dnn model used five hidden layers with , , , , neurons respectively. we explored a few models using a range of number ( - ) of layers, and the -layer model yielded the optimal validation result. relu activation function for the hidden layers, the sigmoid activation function for the output layer, and the "he_normal" normalization scheme were applied. in the model training process, we used adam optimizer, mean squared error as the cost function, a default learning rate of . , and number of epochs of . the reported results yielded from the average of five consecutive runs. the dataset was randomly split into % training data and % testing data. icu admission and mortality results were categorized using a binary classification. to minimize overfitting, we employed -fold cross-validation, ranked and removed less important features using correlation analysis and based on statistical significance by boruta. we also employed regularization and stopped the training process at epochs. risk-score systems were constructed using the top independent clinical variables to predict icu admission and mortality. for risk score, the mixed generalized additive model was used to plot the probability of icu admission and mortality for each clinical variable wood & augustin ( ) . different cutoff points were evaluated where the chosen cutoff points yielded the optimal distribution (not skewed to high or low scores) of the risk score model. the corresponding numerical values of each top feature at probability of . for icu and . for mortality were found to be the optimal cutoff values for the risk score model. each of the top variables was assigned a weight of one point if the clinical measurement was above the probability cutoff. the risk score ranged from to for icu admission and - for mortality (which were chosen based on statistical significance, see "results"). statistical analysis was performed in spss v and in r (statistical analysis software . ). group comparisons of categorical variables in frequencies and percentages used the chi-square test or fisher exact test. group comparison of continuous variables in medians and interquartile ranges (iqr) used the mann-whitney u test. a p value < . was considered to be statistically significant. for performance evaluation, data were split % for training and % for testing. prediction performance was evaluated by calculating the area under the curve (auc) of the receiver operating characteristic (roc) curve, accuracy, sensitivity, specificity, precision, recall, negative predictive value (npv), positive predictive value (ppv) and f score (a harmonic mean of precision and recall). the average roc analysis was repeated with five runs. in risk score models, spss was used to cross-check statistical significance of the top features, in which all top features used in the final analysis of risk score model had a p < . . table summarizes the demographic characteristics, vital signs, comorbidities and laboratory data for the icu (n = ) and non-icu (n = ) group. the median age of the icu group was lower than that of the general admission group ( years (iqr: - ) vs. years (iqr: - ), p = . ). disproportionally more males were admitted to the icu ( . % vs. . %, p < . ). history of cancer was the only comorbidity that was significantly associated with icu admission (p = . ). all measured vital signs were significantly different between the icu group and the non-icu group. the icu group had higher heart rate, respiratory rate and temperature, but lower systolic blood pressure and oxygen saturation (p < . ). the icu group had higher alanine aminotransferase (alt), c-reactive protein (crp), d-dimer, ferritin, lactate dehydrogenase (ldh), white blood cells (wbc) and procalcitonin (p < . ) and lower lymphocyte counts (p < . ). cardiac troponin and bnp were not significantly different between groups (p > . ). the symptom of dyspnea was significantly associated with icu admission (p = . ). patients admitted to icu were more likely to present with abnormal chest x-ray (p < . ), and more likely to have bilateral chest x-ray abnormalities on presentation, compared to that of general admission group (p < . ). figure shows the ranking of the clinical variables associated with icu admission. the top five statistically significant predictors of icu admission were procalcitonin, ldh, crp, ferritin, and spo . a deep neural network predictive model for mortality was constructed using the top clinical variables and trained using the training dataset and tested on an independent testing dataset. the roc and confusion matrix of the testing dataset are shown in fig. . the performance of the dnn model yielded an auc = . ( % ci [ . - . ]), sensitivity = . , specificity = . and f score = . in predicting icu admission for the testing set (table ) . a risk score system was constructed (training data set) using the top five statistically significant clinical variables, with one point given for each variable meeting the following criteria: procalcitonin > . ng/ml, ldh > u/l and < , . u/l, crp > . mg/dl, ferritin > , ng/ml and < , . ng/ml and spo < . %. odds ratios of procalcitonin, ldh, crp, ferritin and spo for icu admission were . , . , . , . and . , respectively. figure shows the results for the testing data set using the risk score system. icu admission rate increased with increasing risk scores. clinical variables associated with mortality table summarizes the demographic data, vital signs, comorbidities and laboratory data for the non-survivors (n = ) and survivors (n = ) group. the median age of the non-survivor group was higher than that of the survivor group ( years (iqr: - ) vs. years (iqr: - ), p < . ). there was a disproportionally higher mortality rate in males ( . % vs. . %, p = . ). of the comorbidities, hypertension, coronary artery disease, heart failure, chronic obstructive pulmonary disease, smoking history and chronic kidney disease were significantly different between groups (p < . ). among vital signs, tachypnea and hypoxemia were significantly different between groups at presentation (p < . ). the expired cohort had higher bnp, crp, d-dimer, ferritin, ldh, wbc, procalcitonin and cardiac troponin but lower lymphocytes (p < . ). alt was not significantly different between groups. among the symptoms, cough, myalgia, nausea or vomiting, chest discomfort, fatigue, fever, loss of taste and headache were significantly different between groups (p < . ). there was no significant difference in x-ray findings between groups at presentation. the top six statistically significant predictors of mortality were age, ldh, procalcitonin, troponin, crp and spo (fig. ) . a deep neural network predictive model for mortality was constructed using the top clinical variables and trained using the training data set. the roc and confusion matrix are shown in fig. . the performance of the dnn model yielded an auc of . ( % ci [ . - . ]), sensitivity = . , specificity = . and f score = . for the testing dataset (table ). a risk score system was constructed (training data set) using the top six statistically significant clinical variables to predict mortality. the thresholds for the risk scores were: age > years, ldh > u/l, procalcitonin > . ng/ml, troponin > . ng/ml, crp > mg/dl and spo < %. odds ratios of age, ldh, procalcitonin, troponin, crp and spo for mortality were . , . , . , . , . and . , respectively. higher mortality rate was associated with higher risk scores for the testing set (fig. ) . the performance of the risk score yielded an auc of . ( % ci [ . - . ]) in predicting mortality for the testing set. mining a large cohort of covid- patients in the united states, deep-learning and resultant risk score models identified the top predictors of icu admission in covid- to be the admission levels of procalcitonin, ldh, crp, ferritin and spo ; the top predictors of mortality were age, ldh, procalcitonin, cardiac troponin, crp and spo . predictive models were developed using deep neural network of the top predictors, yielding an auc of . and . for predicting icu admission and mortality, respectively. the corresponding simplified risk scores yielded an auc of . and . , respectively. the association between these biomarkers and poor outcomes in covid- victims is biologically plausible: procalcitonin is elevated during bacterial infection, but less so during viral infection, suggesting that bacterial co-infection leads to worse outcome in covid- patients (assicot et al., ) . ldh reflects tissue damage ; zhu et al., ) , while crp is indicative of inflammation (gabay & kushner, ) . elevated ferritin is associated with acute respiratory distress syndrome (ards) (connelly et al., ) and may be a marker of aberrant iron metabolism that could render the lungs susceptible to oxidative damage (mumby et al., ) . ferritin may reflect hyperinflammation associated with a cytokine storm and multi-organ failure (mehta et al., ) . low spo indicates failure of the lungs to oxygenate blood effectively, leading to tissue hypoxia (connelly et al., ) . elevated cardiac troponin indicates cardiac injury . although these variables have been previously associated with covid- infection, most previous studies did not rank these clinical variables, or develop predictive models or risk scores to predict icu admission or mortality. not surprisingly, some of the same biomarkers in our study predicted both the need for icu admission and likelihood of mortality. however, age and admission troponin level were uniquely predictive of mortality, indicating older age and cardiac issues are associated with higher rate of mortality in covid- infection. it is notable that individual comorbidities did not rank high in predicting icu admission and mortality. specifically, a history of heart failure, copd, and coronary artery disease only ranked th, th and th respectively for predicting mortality. similarly, the patients' symptoms and vital signs (other than spo ) at the time of admission were not found to be the top predictors of poor outcome. although some comorbidities have been reported to be associated with critical illness and mortality, most previously studies did not rank their importance with respect to other laboratory variables. our predictive auc performance for icu admission was poorer than that for mortality. we speculate this might be due to variability in triage decision-making to send patients to icu among frontline clinicians. for both predictions, precision, ppv and f scores were comparatively low, which was not unexpected due to the imbalanced sample sizes between the two groups as well as small sample sizes. further studies are warranted. while a large number of studies have previously identified clinical variables associated with the severity of covid- infection, only a few studies have attempted to develop a predictive or risk score model to predict mortality and disease severity. jiang et al. ( ) used supervised learning (not deep learning) and found mildly elevated alanine aminotransferase, myalgias and hemoglobin at presentation to be predictive of severe ards of covid- with - % accuracy. this study had small, non-uniform, heterogeneous clinical variables, obtained from different hospitals . ji et al. ( ) used logistic regression to predict stable versus progressive covid- patients (n = ) based on whether their conditions worsened during hospitalization. they reported comorbidities, older age, lower lymphocyte and higher lactate dehydrogenase at presentation to be independent high-risk factors for covid- progression but did not develop a risk score. a nomogram of these four factors yielded a concordance index of . . yan et al. ( ) utilized supervised machine learning to predict critical covid- at admission using presence of x-ray abnormality, cancer history, age, neutrophil/ lymphocyte ratio, ldh, dyspnea, bilirubin, unconsciousness and number of comorbidities. they reported an auc of . . yuan et al. ( ) went one step further to predict mortality more than days in advance with > % accuracy across all cohorts. moreover, their kaplan-meier score shows that patients upon admission could clearly be differentiated into low, medium or high risk. they created a simple risk score system, and validated using multiple independent cohorts (yuan et al., ) . our approach used a deep-learning algorithm which is novel and has distinct advantages over logistic regression and supervised learning approach. deep learning is increasingly being used in medicine (deo, ; santos et al., ; tschandl et al., ) . in contrast to conventional analysis methods, which specify the relationships amongst data elements to outcomes, machine learning employs computer algorithms to identify relationships amongst different data elements to inform outcomes without the need to specify such relationships a priori. deep learning can outperform human experts in performing many tasks in medicine (killock, ) . in addition to approximating physician skills, deep learning can also detect novel relationships not readily apparent to human perception, especially in large, complex, and longitudinal datasets. disadvantages of deep learning methods are that it requires comparatively large sample size, there is a potential of overfitting, and the complex relations could make deep learning results difficult to interpret, amongst others. in addition, we devised a simplified practical risk score adds practical utility to these findings. although we ranked all variables and explicitly listed or top variables, we built the predictive model and risk score model using only the top five variables to simplify and increase translation potential in the clinical settings. the excellent prediction performances using a few clinical variables are encouraging. this study has several limitations in addition to those mentioned above. this is a retrospective study carried out in a single hospital. these findings need to be replicated in large and multi-institutional settings for generalizability. we only analyzed clinical variables at admission. longitudinal changes of these clinical variables need to be studied. as in all observational studies, other residual confounders may exist that were not accounted for in our analysis. future prospective studies validating our predictive models and scores are warranted. we implemented a deep-learning algorithm and a risk score model to predict the likelihood of icu admission and mortality in covid- patients. our predictive model and risk score model can be easily retrained with additional data, new local data, as well as additional clinical variables. this approach has the potential to provide frontline physicians with a simple and objective tool to stratify patients based on risks so that covid- patients can be triaged more effectively in time-sensitive, stressful and potentially resource-constrained environments. high serum procalcitonin concentrations in patients with sepsis and infection lymphocytopaenia is associated with severe sars-cov- disease: a systematic review and meta-analysis of clinical data imaging and clinical features of patients with novel coronavirus sars-cov- : a systematic review and meta-analysis feature selection may improve deep neural networks for the bioinformatics problems serum ferritin as a predictor of the acute respiratory distress syndrome machine learning in medicine acute-phase proteins and other systemic responses to inflammation clinical features of patients infected with novel coronavirus in prediction for progression risk in patients with covid- pneumonia: the call score towards an artificial intelligence framework for data-driven prediction of coronavirus clinical severity ai outperforms radiologists in mammographic screening diagnostic performance of ct and rt-pcr for covid- : a meta-analysis feature selection with the boruta package first-wave covid- transmissibility and severity in china outside hubei after control measures, and second-wave scenario planning: a modelling impact assessment hlh across speciality collaboration uk. . covid- : consider cytokine storm syndromes and immunosuppression lung heme oxygenase- is elevated in acute respiratory distress syndrome clinical, laboratory and imaging features of covid- : a systematic review and meta-analysis artificial intelligence, machine learning, computer-aided diagnosis, and radiomics: advances in imaging towards to precision medicine comparison of the accuracy of human readers versus machine-learning algorithms for pigmented skin lesion classification: an open, web-based, international, diagnostic study mice: multivariate imputation by chained equations in r gams with integrated model selection using penalized regression splines and applications to environmental modelling an interpretable mortality prediction model for covid- patients evaluation of covid- rt-qpcr test in multi-sample pools development and validation of a prognostic risk score system for covid- inpatients: a multi-center retrospective study in china. epub ahead of print china novel coronavirus i and research t. . a novel coronavirus from patients with pneumonia in china we thank all healthcare professionals for their hard work being at the front line of the pandemic. the authors received no funding for this work. the authors declare that they have no competing interests. xiaoran li conceived and designed the experiments, performed the experiments, analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the paper, and approved the final draft. peilin ge conceived and designed the experiments, performed the experiments, analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the paper, and approved the final draft. jocelyn zhu performed the experiments, analyzed the data, prepared figures and/or tables, and approved the final draft. haifang li performed the experiments, analyzed the data, authored or reviewed drafts of the paper, and approved the final draft. james graham performed the experiments, analyzed the data, prepared figures and/or tables, and approved the final draft. adam singer performed the experiments, analyzed the data, authored or reviewed drafts of the paper, and approved the final draft. paul s. richman performed the experiments, analyzed the data, authored or reviewed drafts of the paper, and approved the final draft. tim q. duong analyzed the data, authored or reviewed drafts of the paper, and approved the final draft. the following information was supplied relating to ethical approvals (i.e., approving body and any reference numbers):stony brook university irb approved this study (irb - ). the following information was supplied regarding data availability: raw data is available in the supplemental files. supplemental information for this article can be found online at http://dx.doi.org/ . / peerj. #supplemental-information. key: cord- - c gt t authors: segrelles-calvo, gonzalo; de granda-orive, josé ignacio; lópez-padilla, daniel; zamora garcía, enrique title: therapeutic limitation in elderly patients: reflections regarding covid () date: - - journal: arch bronconeumol doi: . /j.arbr. . . sha: doc_id: cord_uid: c gt t nan the sars-cov- pandemic has put the spanish health system to the test, revealing an imbalance between clinical needs and the availability of resources (structures, equipment, and professionals) that has had serious consequences on the outcomes of patients, their families and health professionals themselves. this situation requires complex decision-making based on the classic principles of bioethics, distributive justice, patient autonomy, beneficience and non-maleficience, to ensure the appropriate allocation of available resources in a scenario of shortfall. in our view, this distribution of resources must be based on maximizing benefits in the attempt to "save" the greatest number of patients who are more likely to survive. the document published by the spanish society of intensive care calls for performing triage on admission (a proposal we share) based on giving priority to patients with greater life expectancy (le), an estimate that is unavoidably probabilistic and difficult to quantify. according to this document, patients older than years of age with comorbidity will preferably receive non-invasive respiratory therapies (nirts), and those aged - years with no significant prior pathology would be candidates for invasive mechanical ventilation (imv). when patients are competing for the same resource, a clinician might decide to base their decision purely on age, as the highest mortality rate occurs in the older age groups (age group - years = . %, and older than years = . %). the older group includes individuals with more comorbidities and fragility; however, we should not make the mistake of considering them, per se, a group with less le in whom nirt or imv would be pointless because of the scant benefit. in clinical practice, making decisions based on the variables of age and comorbidity is not easy, due to the wide variety of comorbidities, many of which are not included in the most commonly used comorbidity indices, and their different impact on the patient's frailty if they are considered separately. joynt et al. analyzed reasons for ruling out icu admission and concluded that age, diagnosis, and disease severity were the main criteria for rejection. while it is true that the mortality of patients > years who are admitted to the icu is high, at around % per year, these figures depend, fundamentally, on comorbidity and frailty. [ ] [ ] [ ] [ ] [ ] these data highlight the need for a more complex assessment based on the frailty index (fi) which, in addition to comorbidities, takes into account the patient's functional status and presence of geriatric syndromes. in population-based studies, the prevalence of frailty varies between . % and . % and pre-frailty between . % and . %. prevalence by age group is % in > -year-olds and % in > year-olds and between % and % , in icu patients. in these cases, frailty was an age-independent prognostic factor associated with increased mortality during admission and the months after discharge. the studies consulted recommend the use of tools to detect frail patients after admission to the hospital. the fi was the most widely used, as it has a good capacity to distinguish subgroups of patients, and its use could be extrapolated to the covid- pandemic for the selection of frailer patients. our group is currently conducting a study that analyzes the impact of frailty on elderly patients admitted for respiratory failure who require non-invasive mechanical ventilation (nimv): the fragrancia study (study on the impact of frailty in older patients requiring nimv). an intermediate analysis of the results, not yet published, suggests that frailty in the elderly population is associated with higher early mortality (< days from admission) and mortality at year of follow-up ( frail patients vs. patients in the non-frail group, p = . ) ( table ) , and that the fi is able to differentiate these risk groups. we are aware that the fi is not the only answer to the prioritization problems we have experienced during the covid- pandemic, when resources were sometimes unavailable for even the youngest and healthiest of patients. in a recent editorial, published in the new england journal of medicine, the authors address the problem of having to choose between or more patients for the assignment of resources, such as icu admission. the need to weigh up multiple ethical values in order to prescribe different interventions and allocate limited resources can generate different benchmarks for the weight assigned to each value in a particular case. this real situation that arose during the covid- pandemic underlines the need to develop fair resource allocation procedures that include all the stakeholders involved in patient care, and the patient and family themselves, in order to develop prioritization criteria for decisionmaking in times of adversity, without transferring this burden to a single healthcare professional in a specific situation. at the present time, there are no valid criteria to deny icu admission to people with good life expectancy. the lessons learned from this pandemic underline the need for the health system to increase its resources to adapt to emergency situations. in adversity, respiratory medicine experts have demonstrated the value of our knowledge of nirt in critical and semi-critical patients and the importance of the development of respiratory intensive care units (ricu). the ricu plays a role not only in the treatment of the acute patient, but also in the weaning of icu patients, and helps free up beds. the ricu has eliminated any argument for the need to reserve icu beds "just in case". refusing a patient access to the icu in order to assign the place to another patient more likely to survive is justifiable in a pandemic, but even more so when the initial patient can be transferred to a ricu, where imv can be withdrawn and replaced by nirt under a level of monitoring and care that is superior to a conventional hospital ward. the development of joint care protocols with the collaboration of intensive care units, internal medicine, and emergency departments, together with respiratory medicine, is essential to maximize the management of available resources. pre-selecting patients with easy, intuitive tools, such as the fi, is indispensable for improving decision-making. among the many changes that will emerge after the covid- pandemic, we believe that one of the most relevant will surely be the expansion of ricus and the leadership of respiratory medicine in decision-making on borderline patients, such as the elderly, unifying selection criteria, clarifying the concept of frailty, and integrating its use into our clinical practice. los principios de la bioética y la inserción social de la práctica médica recomendaciones éticas para la toma de decisiones en la situación excepcional de crisis por pandemia covid- en las unidades de cuidados intensivos (semi-cyuc) situación de covid- en españa. basada en la notificación diaria de casos de covid- al ministerio de sanidad prospective evaluation of patients refused admission to an intensive care unit: triage, futility and outcome elderly patients and intensive care: systematic review and geriatrician's point of view is frailty a prognostic factor for critically ill elderly patients? the impact of frailty on intensive care unit outcomes: a systematic review and meta-analysis prevalence and impact of frailty on mortality in elderly icu patients: a prospective, multicenter, observational study association of frailty with short-term outcomes, organ support and resource use in critically ill patients global prevalence of physical frailty by fried's criteria in community-dwelling elderly with national population-based surveys fair allocation of scarce medical resources in the time of covid- key: cord- - fmse authors: maslov, sergei; goldenfeld, nigel title: window of opportunity for mitigation to prevent overflow of icu capacity in chicago by covid- date: - - journal: nan doi: nan sha: doc_id: cord_uid: fmse we estimate the growth in demand for icu beds in chicago during the emerging covid- epidemic, using state-of-the-art computer simulations calibrated for the sars-cov- virus. the questions we address are these: ( ) will the icu capacity in chicago be exceeded, and if so by how much? ( ) can strong mitigation strategies, such as lockdown or shelter in place order, prevent the overflow of capacity? ( ) when should such strategies be implemented? our answers are as follows: ( ) the icu capacity may be exceeded by a large amount, probably by a factor of ten. ( ) strong mitigation can avert this emergency situation potentially, but even that will not work if implemented too late. ( ) if the strong mitigation precedes april st, then the growth of covid- can be controlled and the icu capacity could be adequate. the earlier the strong mitigation is implemented, the greater the probability that it will be successful. after around april , any strong mitigation will not avert the emergency situation. in italy, the lockdown occurred too late and the number of deaths is still doubling every . days. it is difficult to be sure about the precise dates for this window of opportunity, due to the inherent uncertainties in computer simulation. but there is high confidence in the main conclusion that it exists and will soon be closed. our conclusion is that, being fully cognizant of the societal trade-offs, there is a rapidly closing window of opportunity to avert a worst-case scenario in chicago, but only with strong mitigation/lockdown implemented in the next week at the latest. if this window is missed, the epidemic will get worse and then strong mitigation/lockdown will be required after all, but it will be too late. we estimate the growth in demand for icu beds in chicago during the emerging covid- epidemic, using state-of-the-art computer simulations calibrated for the sars-cov- virus. the questions we address are these: ( ) will the icu capacity in chicago be exceeded, and if so by how much? ( ) can strong mitigation strategies, such as lockdown or shelter in place order, prevent the overflow of capacity? ( ) when should such strategies be implemented? our answers are as follows: ( ) the icu capacity may be exceeded by a large amount, probably by a factor of ten. ( ) strong mitigation can avert this emergency situation potentially, but even that will not work if implemented too late. ( ) if the strong mitigation precedes april st , then the growth of covid- can be controlled and the icu capacity could be adequate. the earlier the strong mitigation is implemented, the greater the probability that it will be successful. after around april , any strong mitigation will not avert the emergency situation. in italy, the lockdown occurred too late and the number of deaths is still doubling every . days. it is difficult to be sure about the precise dates for this window of opportunity, due to the inherent uncertainties in computer simulation. but there is high confidence in the main conclusion that it exists and will soon be closed. our conclusion is that, being fully cognizant of the societal trade-offs, there is a rapidly closing window of opportunity to avert a worst-case scenario in chicago, but only with strong mitigation/lockdown implemented in the next week at the latest. if this window is missed, the epidemic will get worse and then strong mitigation/lockdown will be required after all, but it will be too late. this document describes the results of computer simulations of a standard population level epidemiological model (seir-model) with seasonal affects and parameters calibrated to be appropriate for sars-cov- . the calculations are done by solving differential equations of the seir model [ ] , without spatial extension, demographic stochasticity or attention paid to smallworld and scale-free network effects, but these are potentially important and [ , ] could be readily added in the future [ ] [ ] [ ] [ ] [ ] . the model additionally has categories for severely sick people who are hospitalized, people in critical condition in need of icu rooms and ventilators, and a fatal category. the simulation uses severity assumptions as a function of individual age, informed by epidemiological and clinical observations in china [ ] ; no modifications have been to take into account national differences, such as number of smokers in the population etc. the model has been calibrated with the hospital data in the chicago area and is able to account for the rapid rise in covid- patients that we are starting to see (see figure ). here is how we performed calibration. the simulation needs a starting assumed number of cases, and we initially used the value . here is why. previously we had estimated that the chicago community cluster was infected individuals on march . the way we did that estimate was to work backwards from the number of icu confirmed covid- patients at a major chicago hospital ( confirmed, persons under investigation (puis) but % of those will turn out to be covid- positive). then we used the doubling time of . days which was true at that time, and used a % hospitalization rate for covid- patients, with a time interval between infection and hospitalization of . days. then we found that this cluster originated around february . however, we were not satisfied with this argument, because it predicted the first covid- confirmed case would be too late. to do this, we experimented with moving the starting time of the simulation with one infected individual, and found that this would work if the date of infection was february th . reassuringly, this date is roughly consistent with the working backwards calculation! we ran the simulations with this initial condition: one infection event on feb th . starting with this value, our simulations predicted that on march , between and people would be hospitalized, with patients in icu. at that time, the data available indicated at least icu patients (of which were a cluster at a single hospital) and at least non-critical hospitalized patients. we regarded this agreement as satisfactory within the uncertainties inherent in computer simulation at the population level with such small numbers of cases. now we need to comment about the r parameter used in the simulations. there is no real consensus on the right value for r at this stage in the infection, so we experimented to find a value that replicated the observed doubling time of about . - . days in illinois (figure ). we found that we could match the emergence of the infection in illinois with an r = . (annual average), latency = days, infectious period = days, seasonal forcing strength . and seasonal peak in january. this value is within the ranges reported in an extensive epidemiological study [ ] . we ran the simulation for a town with a population of . million, and with age structure appropriate for the us. this is supposed to represent chicago (not the chicago metropolitan area). we calibrated the model to match the observed epidemiological statistics. we found that the "patient zero" who started the local cluster was infected around feb . the parameters of the model were selected to reproduce the observed doubling time of . days for reported cases in illinois (figure ) . the model predicts a current situation of hospitalized non-critical patients, and patients in icu across chicago. from a sample of three large hospitals in chicago there are at least hospitalized noncritical patients and additional in icu. due to the inevitable uncertainties in computer modeling and the chance events that dictate early infections, we regard this agreement as satisfactory. the most important thing is that our simulations are calibrated to reproduce well the growth trend, so that we can predict the future course of the epidemic. we ran the simulation until september , and this was long enough to see the time course of the epidemic. the goal of our numerical experiments was to estimate the effect of strong mitigation scenarios on the peak number of severe cases (requiring hospitalization), peak number of critical cases (requiring hospitalization and special treatment) and total number of deaths. in particular, we wanted to observe the sensitivity of the outcomes to the time when strong mitigation was implemented, rather than the effects of different potential mitigations implemented at the same time [ ] . strong mitigation is defined in our calculation by reducing the transmission in such a way that the effective epidemiological parameter r drops below unity and stays there. if r < , it is a mathematical certainty that the infection will die out, and the smaller it is, the faster the die-out occurs. peak table . prediction of the number of icu beds needed in chicago, the date when this peak will be reached, the peak in the number of hospital beds required, and the total number of deaths by september , . the rows correspond to two scenarios: just-in-time and delayed mitigation scenarios described in the text. in figure and table , we show the results of simulating the effects of strong mitigation on the demand for icu beds in chicago. we ran two simulations with the parameter r = . , probably the least severe mitigation that one can do which is guaranteed to eventually end the covid- epidemic. in one simulation (the "late mitigation" scenario), shown by the red curve, the mitigation was fully implemented by april th . in the other, shown by the blue curve (the "just-in-time mitigation" scenario), the mitigation was fully implemented by april st . the implementation of the mitigations was assumed to ramp up gradually over a period of time, and the strong steps already taken in illinois are part of this mitigation and included in the calculation. further mitigations are no doubt possible, and strong mitigation would be the final additional step. the late mitigation scenario predicts that the number of icu beds needed as the epidemic progresses in chicago quickly exceeds the city's available beds ( , shown by the dashed horizontal line) and even the entire icu bed capacity of the city ( , not shown for reasons of clarity). the amount by which the available capacity is exceeded is by a factor of , and the amount by which the total capacity is exceeded is more than a factor of . in this scenario, the total number of deaths is estimated as . the just-in-time mitigation scenario predicts that at the peak of the epidemic, the demand for icu beds does not exceed the number of available beds, and is significantly below the city's total icu capacity. in this scenario, the "curve is flattened", and the epidemic dies out without a catastrophic impact on the city's ability to cope, and without icu beds having to be set aside from their regular functions, associated with surgery etc. in this scenario, the total number of deaths is estimated as . both scenarios involve strong mitigations, certainly stronger than current measures already implemented. both mitigations end the epidemic eventually, around august. but one causes along the way a catastrophic event for the healthcare system, with many potential deaths predicted, and one does not. we note that in both wuhan and italy, strong mitigation measures were taken such as lockdown, but they were taken too late and still resulted in thousands of lives lost, including those of healthcare professionals. as the epidemic develops along its inevitable exponential growth trajectory, it is equally inevitable that leadership will eventually be forced to implement lockdown. thus, if this is going to happen anyway, it should be taken as early as possible. our calculation shows that the just-in-time scenario accomplishes this and that the window for such a strong mitigation will soon be closed. of course, one cannot be sure that the dates and course of the epidemic are going to follow the precise predictions we have made. there are inevitable uncertainties in making predictions for such a powerful phenomenon as an epidemic. however, whether the outcomes predicted by our scenarios occur on exactly the dates given here, and with exactly the numbers provided here, they will occur as we have predicted. the window that we have predicted is rather short, perhaps two weeks at the longest. thus to be safe, the mitigation measures should be implemented as soon as possible, while they will be effective; at the same time, for humanitarian reasons, the societal implications of lockdown require appropriate arrangements to be made for the city's population, as has already done for the mitigation efforts to date. covid scenario simulator stochastic epidemic dynamics on extremely heterogeneous networks when individual behaviour matters: homogeneous and network models in epidemiology small world and scale free model of transmission of sars epidemic processes in complex networks. reviews of modern physics super-spreaders and the rate of transmission of the sars virus effect of small-world networks on epidemic propagation and intervention halting viruses in scale-free networks the novel coronavirus pneumonia emergency response epidemiology team, vital surveillances: the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- )-china, . china cdc weekly epidemiological benchmarks of the covid- outbreak control in china after wuhan's lockdown: a modelling study with an empirical approach impact of non -pharmaceutical interventions (npis) to reduce covid - mortality and healthcare demand this work would not have been possible without the generous assistance of many individuals who contributed their expertise, guidance and technical assistance. we used an outstanding simulation of the seir model of epidemics (covid- scenario explorer) with parameters and features appropriate for covid- , developed by ivan aksamentov, nicholas noll and richard neher at the university of basel, and used with their permission. this scenario explorer was customized for us by nicholas noll (university of california at santa barbara and university of basel) and zhiru liu (stanford university). we benefitted from numerous discussions with the following individuals: david ansell and bala hota at rush university medical center, chicago; mark johnson at carle hospital, urbana; alexei tkachenko at brookhaven national laboratory. key: cord- -hzy fuw authors: soltani, farhad; salari, amir; javaherforooshzadeh, fatemeh; nassajjian, nozar; kalantari, farahmand title: the effect of melatonin on reduction in the need for sedative agents and duration of mechanical ventilation in traumatic intracranial hemorrhage patients: a randomized controlled trial date: - - journal: eur j trauma emerg surg doi: . /s - - - sha: doc_id: cord_uid: hzy fuw purpose: this study aimed to determine the effect of exogenous melatonin on the number of sedative drugs and the duration of mechanical ventilation in traumatic intracranial hemorrhage patients in icu. methods: this double-blind randomized clinical trial study was conducted in the icu wards of golestan hospital, ahvaz, iran, from september to march . in this study, patients with intracerebral hemorrhage were selected by convenient sampling ( patients in each group) and were randomly assigned to two groups of melatonin and control. sedation and pain management package was applied to both groups. outcomes: amount of the sedative and opioid drug; mechanical ventilation time; icu staying time; glasgow coma score; hemodynamic parameters. results: there was no significant difference between them in terms of demographic characteristics. cumulative doses of morphine and mechanical ventilation time were significant in two groups. (p < . ) the mean length of icu staying was not significant. glasgow coma score on the th day was significant in two groups (p < . ). diastolic blood pressure was significant between groups (p < . ). conclusion: this study presented that morphine consumption and mechanical ventilation time were significantly lower in the melatonin group than in the control. also, rise in gcs in the melatonin group was faster in the melatonin group than in the control. the use of melatonin can be recommended for patients with ich in the icu for better outcomes. ich is most commonly caused by hypertension, arteriovenous malformations, or head trauma. traumatic intracerebral hemorrhage (tich) accounts for - % of strokes all inclusive. it is characterized by unfortunate results, with a high mortality rate of - % and the neurological outcomes of patients who survive are also very poor [ ] . on the other hand, evidence has shown that most patients who present with small ichs can survive with good medical care [ , ] . this suggests that suitable medical involvements may improve the outcome of these patients [ , ] . the available data have shown that the early start of neuroprotective management might defend susceptible neurons and improve outcomes in hemorrhagic stroke [ ] . melatonin (n-acetyl- -methoxytryptamine) is a neurohormone that has attracted a great deal of interest as a therapeutic option for various neurological diseases because of its low toxicity, antioxidative, antiapoptotic, and anti-inflammatory properties. also, it has some selective properties that are highly desired in the intensive care unit (ic) [ , ] . melatonin was found to reduce inflammatory pain, probably by blocking the production of no by inducible no synthase and the signaling pathways of no-cyclic gm. [ ] . melatonin is an effective free radical scavenger and an indirect antioxidant that has shown neuroprotective effects in both in vitro and in vivo ischemic-hypoxia models [ ] . decreased blood melatonin levels are associated with sepsis severity, delirium, and the severity of sleep alteration during critical illness. the purpose of this study is to assess the effect of exogenous melatonin on the reduction in the need for sedative agents and the duration of mechanical ventilation in tich patients in icu. this is a double-blind, randomized controlled study with a parallel assignment of patients and ratio : between two groups. the local ethics committee of ahvaz jundishapur university of medical sciences, ahvaz, iran, approved all of the procedures of this study (ir.ajums.rec. . ). the rct code of this study was: irct n . written informed consent was collected from the families of the patients. after patients' neurological conditions improved, there were exactly well versed in the study, and their written consent was got both for their previously-collected records and further randomized treatments. the study was conducted from september to may in patients admitted to the general icu of golestan hospital, ahwaz, iran. the inclusion criteria: age ≥ years, traumatic intracranial hemorrhage confirmed by computer tomography (ct) requiring surgery, initial gcs - , the average volume of ich - cc and expected length longer than days. exclusion criteria were: liver disease, renal insufficiency, pregnant women, patients with a brain tumor, and allergy to melatonin. the nurse to patient ratio was : during the morning, : during the evening and nightly, and intensivists were present in icu at all times. melatonin mg tablet (webber naturals® canada; prolonged-release tablets) or control (placebo capsules filled by cornstarch powder (beijing, china) was administered in the first h at : p.m. and continued for all the days of hospitalization in icu by ng tube. patients were followed daily. according to the local guidelines, sedation started with intravenous midazolam ( . mg/kg/h) and fentanyl ( µg/kg/h) that were discontinued as soon as possible. all tablets were directed by a nasogastric tube after shocking the tablet and mixing it with ml of water, followed by another ml to flush out the remainder. opiates (morphine sulfate or methadone if the patient was addicted) were administered according to verbal rating scale > (vrs: verbal rating scales include the following five-point sets of descriptors which facilitate pain evaluation and treatment: "none", "mild", "moderate", "severe", "very severe" [ ] or behavioral pain scale > ( bps, range - ,) [ ] and not as sedatives. validated scales for pain and sedation/agitation monitoring (vrs or bps) were used four times a day. each morning, nurses blinded to melatonin treatment prescribed the daily therapy. in the presence of deeper-thandesired sedation levels, the prescribed drugs were decreased/ withdrawn. conversely, according to clinical needs, an extra amount of drug was always allowed and recorded. therapeutic decisions were made by blinded icu physicians; neurological monitoring was performed by icu nurses, also blinded to the group assignment. primary outcome was the amount of the most used sedative drug (sum of all midazolam and fentanyl doses administered, methadone, and morphine sulfate during the melatonin/placebo treatment). secondary outcomes were mechanical ventilation time; icu staying time; glasgow coma scale (gsc); hemodynamic parameters. based on a predicted % reduction from the patient's baseline, our sample size estimation indicated that patients per group would give a power of . at an error . for detecting a % reduction in opioid consumption. mean and standard deviations in opioid consumption were derived from ismail et al. [ ] and thus the total sample size was a prospective set of patients. however, we increased our sample size to patients to accommodate any withdrawal or missing data points. treatment distribution was obtained through a computergenerated eight-patient block randomization procedure. after eligibility assessment at icu admission, each patient received a sealed brown envelope containing the random melatonin or placebo treatment. it was then opened just evening of the first icu day. two physicians, according to ethics committee requirements, were aware of treatment allocations after the group assignment and monitored for possible side effects, without participating in clinical decisions about sedative administration or study treatment interruption. the statistical analysis was performed using a standard spss software package (chicago, ‖il). data were expressed as mean values ± sd, percentages (%) and numbers (n). independent samples t test and paired-samples t test were used to analyze the parametric data, and discrete (categorical) variables were analyzed using the χ test, with p values < . considered statistically significant. during the study period from september to may of golestan hospital, ahwaz, iran, in patients admitted in the general icu, patients were eligible to participate in the trial. after initial screening, cases agreed to participate and their families provided informed consent. among them, patients did not satisfy inclusion criteria. finally, patients were enrolled in the study and were assigned into two groups of melatonin and placebo, patients in each group (fig. ) . there was no statistically significant difference between the two groups in terms of demographic characteristics (p > . ) ( table ). the rate of cumulative dose of prescribed fentanyl and midazolam administration during admission in icu was not statistically significant between the two groups. cumulative methadone administration was not significant between groups, but cumulative doses of morphine that were administered were significantly different between the groups (p = . ) ( table ). mechanical ventilation time was significant between groups ( ± days in the melatonin group vs. ± in the control, p = . ). the mean length of stay of the subjects in the icu was calculated and compared in the melatonin and the control groups ( . ± . days vs. . ± . days). the independent t test showed that the length of stay was not significant between groups (p = . ). gcs at the beginning of hospitalization in the icu ( st day) was not significant between the two groups, but gcs on the th day was . ± . in the melatonin group vs. . ± . in the control that was significant (p = . ) (fig. , table ). gcs changes on day compared to day in the melatonin group p < . . gcs changes on day compared to day in the control group p = . . gcs on the th day was . ± . in the melatonin group vs. . ± . in the control that was significant (p = . ). among the hemodynamic parameters, diastolic blood pressure was significant between groups ( . ± . in the melatonin group vs. . ± . (p < . ). other parameters (systolic blood pressure, pulse rate, and o saturation) were not different between groups (table ). this study was a double-blind randomized controlled trial that was considered to evaluate the effect of melatonin on the need for sedative agents and duration of mechanical ventilation after tich. melatonin is a neurohormone created from the amino acid, tryptophan, and is mainly secreted by the pineal gland into the circulation [ ] . the effectiveness of exogenous melatonin for the treatment of sleep disturbance [ ] , as antioxidant [ ] , antianxiety agent like benzodiazepine action has been established in many studies [ , , ] . furthermore, different from the conventional sedative agents, this hormone does not deteriorate nighttime hypoxemia or ventilator responses [ ] [ ] [ ] . besides, it has been shown that melatonin can treat and avoid icu delirium [ ] . all of the patients with hemorrhagic stroke and loss of consciousness need to be mechanically ventilated. although mechanical ventilation is often a life-giving treatment, its usage can result in unwanted side effects, including ventilator-associated lung injury, ventilator-associated pneumonia, sinusitis, gastrointestinal bleeding, and venous thromboembolism. [ , ] it has been well recognized that the optimal use of the sedating agent may influence the duration of mechanical ventilation. benzodiazepines and opiates are the most frequent drugs used for sedation and analgesia in the icu. both of these agents show some respiratory depressant effect, which can cause the duration of mechanical ventilation to be lengthy [ ] [ ] [ ] . melatonin is a neuroprotective agent with sedative, hypnotic, and analgesic properties and without any respiratory they determined that the lower plasma melatonin levels were linked with ineffective weaning [ ] . in dianatkhah et al.'s study, the duration of mechanical ventilation and length of icu stay were shorter in patients who received melatonin in comparison with the control group, but this difference was statistically not significant for the length of icu stay and marginally significant for the duration of mechanical ventilation (p = . ) [ ] . in our study, as shown in table , the duration of mechanical ventilation was shorter in patients given melatonin vs. the control group that was in line with the frisk, dessap, and dianatkhah studies. on the other hand, the mean length of stay of the subjects in the icu was not in line with dianatkhah's study. our study included patients. results showed that lower doses of fentanyl and midazolam were used in the melatonin group, although this difference was not significant between the two groups. also, the total dose of morphine sulfate in the melatonin group was significantly lower than the placebo. a study by mistraletti et al. showed that administration of melatonin as an adjuvant in the icu patients was associated with a reduction in the need for sedative agents, shortening the duration of mechanical ventilation, better neurological indicators, and cost reduction [ ] . according to the literature, melatonin can be administered as an adjuvant with hypnotic properties and it may have shortened the number of hypnotic drugs and related side effects, including respiratory depression and delirium, which are both risk factors of lengthy weaning off from ventilator. gcs is one of the determinants of neurological outcome in tich patients. many studies have shown the anti-inflammatory effect of melatonin that was similar to our results. concerning the unusually high antioxidant effect of melatonin, it has been postulated that the administration of melatonin may be protective against ventilator injury [ , ] . as shown in table , gcs was raised in the melatonin group in comparison with the control, which can be credited to the neuroprotective effect of melatonin. this finding was similar to that in osier and coworker [ ] . li s and coworker presented that the melatonin attenuates early brain injury after subarachnoid hemorrhage by the jak-stat signaling pathway. one of the results of their study was melatonin treatment dramatically decreased neurological score and alleviated brain edema at h after sah [ , ] . in our study, gcs score on the th day was better in the melatonin vs. placebo group significantly. this finding was comparable with li s's study. this study has some limitations. the first is that this study was a single-center with a guideline for sedative drugs that may be different from other icu. besides, trauma patients were compared with non-trauma patients. the third limitation was the lack of measurement of reactive oxygen species. the fourth limitation was we did not determine endogenous melatonin concentrations and circadian phase in our patients. finally, our last limitation is the lack of information about the severity of head trauma, such as ais and icp. these are recommended for evaluation in future studies. this study presented that morphine consumption and mechanical ventilation time were significantly lower in the melatonin group than the placebo group. also rise in gcs in the melatonin group was faster in the melatonin group than in the placebo. melatonin has sedative, analgesic, anticonvulsive, anti-inflammatory, and antioxidative properties that differentiate it as a new and an attractive drug in patients with mechanical ventilation. it is recommended to use melatonin for patients with ich in the icu for better tolerance of mechanical ventilation. the injury and therapy of reactive oxygen species in intracerebral hemorrhage looking at mitochondria molecular signatures of vascular injury are associated with early growth of intracerebral hemorrhage incidence and -year survival of intracerebral hemorrhage in a populationbased registry guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the american heart association/american stroke association emorragie cerebrali non traumatiche. emc-neurologia melatonin and ischemic stroke: mechanistic roles and action protective effect of melatonin upon neuropathology, striatal function, and memory ability after intracerebral hemorrhage in rats the antioxidant effects of melatonin after intracerebral hemorrhage in rats validity and reliability of the verbal numerical rating scale for children aged to years with acute pain translation, adaptation, and validation of the behavioral pain scale and the critical-care pain observational tools in taiwan melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia evaluating the potential effect of melatonin on the post-cardiac surgery sleep disorder efficacy of melatonin for sleep disturbance following traumatic brain injury: a randomised controlled trial antioxidant melatonin: potential functions in improving cerebral autoregulation after subarachnoid hemorrhage melatonin as an antioxidant for stroke neuroprotection melatonin as a treatment after traumatic brain injury: a systematic review and metaanalysis of the pre-clinical and clinical literature melatonin supplementation may improve the outcome of patients with hemorrhagic stroke in the intensive care unit melatonin in perioperative medicine: current perspective effect of melatonin on sleep quality of chronic obstructive pulmonary disease (copd) patients effectiveness of melatonin treatment on circadian rhythm disturbances in dementia. are there implications for delirium? a systematic review nursing strategies for effective weaning of the critically ill mechanically ventilated patient. criti care nurs clini patient safety: identifying and managing complications of mechanical ventilation. criti care nurs clini adverse events associated with sedatives, analgesics, and other drugs that provide patient comfort in the intensive care unit the association between sedation practices and duration of mechanical ventilation in intensive care comparison of effects of melatonin and gabapentin on post operative anxiety and pain in lumbar spine surgery: a randomized clinical trial melatonin supplementation may improve the outcome of patients with hemorrhagic stroke in the intensive care unit low melatonin excretion during mechanical ventilation in the intensive care unit delirium and circadian rhythm of melatonin during weaning from mechanical ventilation: an ancillary study of a weaning trial melatonin reduces the need for sedation in icu patients: a randomized controlled trial melatonin pharmacological blood levels increase total antioxidant capacity in critically ill patients melatonin: pharmacology, functions and therapeutic benefits melatonin as a therapy for traumatic brain injury: a review of published evidence melatonin attenuates early brain injury after subarachnoid hemorrhage by the jak-stat signaling pathway a comparative study of the amount of bleeding and hemodynamic changes between dexmedetomidine infusion and remifentanil infusion for controlled hypotensive anesthesia in lumbar discopathy surgery: a double-blind, randomized, clinical trial we sincerely thank the patients who cooperated with us in this project and supported the research team. we want to thank the clinical research development unit, golestan hospital, ahvaz jundishapur university of medical sciences, and ahvaz, iran, for their cooperation. key: cord- - xl isee authors: andrei, stefan; ghiaur, alexandra; brezeanu, lavinia; martac, cristina; nicolau, andreea; coriu, daniel; droc, gabriela title: successful treatment of pulmonary haemorrhage and acute respiratory distress syndrome caused by fulminant stenotrophomonas maltophilia respiratory infection in a patient with acute lymphoblastic leukaemia – case report date: - - journal: bmc infect dis doi: . /s - - - sha: doc_id: cord_uid: xl isee background: stenotrophomonas maltophilia-induced pulmonary haemorrhage is considered a fatal infection among haematological patients. the outcome can be explained by the patients’ immunity status and late diagnosis and treatment. case presentation: we present the rare case of successful outcome in a -year-old female who developed alveolar haemorrhage and acute respiratory distress syndrome days after a chemotherapy session for her acute lymphoblastic leukaemia, in the context of secondary bone marrow aplasia. stenotrophomonas maltophilia was isolated in sputum culture. the patient benefitted from early empirical treatment with colistin followed by trimethoprim/sulfamethoxazole, according to the antibiogram. despite a severe initial clinical presentation in need of mechanical ventilation, neuromuscular blocking agents infusion, and ventilation in prone position, the patient had a favourable outcome and was discharged from intensive care after days. conclusions: stenotrophomonas maltophilia severe pneumonia complicated with pulmonary haemorrhage is not always fatal in haematological patients. empirical treatment of multidrug-resistant stenotrophomonas maltophilia in an immunocompromised haematological patient presenting with hemoptysis should be taken into consideration. stenotrophomonas maltophilia is an anaerobic nonfermentative bacteria that does not cause infections in immunocompetent hosts, but might be fatal in patients with weakened immune system [ ] . several case reports and case series describing pulmonary haemorrhage caused by respiratory infection with stenotrophomonas maltophilia have been reported in adult patients with haematological diseases [ ] . severe pulmonary haemorrhage due to stenotrophomonas maltophiliahas also been reported in neonates [ ] . the literature presents a variety of cases in adults with allogeneic stem cell transplantation [ , ] or secondary to chemotherapy-induced pancytopenia, particularly myeloid leukaemia [ , ] . in all these cases, the mortality was very high; mori et al. reported no survival in one review of haematological adult cases [ ] . we report the case of successfully treated severe stenotrophomonas maltophilia respiratory infection complicated with pulmonary haemorrhage in a chemotherapyinduced pancytopenia patient diagnosed with acute lymphoblastic leukaemia. a -year-old female was diagnosed in december with philadelphia chromosome-positive acute lymphoblastic leukaemia. her past medical history was significant for hypertension and type diabetes mellitus for more than years. at the moment of diagnosis, the total white blood cell count was × /l (wbc) with peripheral blood smear showing % blasts, haemoglobin . g/dl, and × /l platelets count (plt). the bone marrow smears showed hypercellularity with more than % blast cells. the flow cytometry revealed % blast cells compatible with common b cell acute lymphoblastic leukaemia. the cytogenetic and fluorescence in situ hybridization analysis have identified the translocation t ( ; )(q ;q )(philadelphia chromosome). the molecular analysis was positive for bcr-abl fusion gene (p isoform), and the bcr-abl/abl ratio was . %. the patient received treatment according to graaph protocol with imatinib mg/ day. the patient achieved complete morphological remission after the induction, with a molecular response bcr-abl/abl ratio of . % is. the months follow-up assessment showed a deep molecular response (molecular analysis ratio bcr-abl/ abl: . % -mr . log is). the cytogenetic analysis ,xx [ ] was consistent with a complete cytogenetic response, and the bone marrow aspiration showed trilineage dysplasia. her treatment was continued with the same regimen. on day eight after consolidation therapy with cycle (methotrexate g/m at day , cytarabine mg/m bid at day and day ), a severe aplasia developed ( . × /l wbc, × /l absolute neutrophil count (anc), × /l plt), and she became febrile with a mild cough and a small area of right perihilar infiltration on chest x-rays ( fig. ) , despite prophylactic treatment with levofloxacin. sputum culture and peripheral blood cultures were performed, and the patient was started on empirical broad-spectrum antibiotics (piperacillin-tazobactam, amikacin) and fluconazole. over the next days, the respiratory status worsened, and the patient developed severe cough and hemoptysis, dyspnea and an increased in the oxygen demand. considering the worsening clinical status, the risk of multidrugresistant (mdr) germs infection, as well as severe bone marrow aplasia with multiple hospitalizations, the antibiotic treatment was escalated to meropenem, linezolid, amikacin, and fluconazole was switched to voriconazole. the patient received platelets and subcutaneous granulocyte colony-stimulating factor treatment. four days after the onset of fever ( days after chemotherapy), the patient was admitted to icu for type i respiratory failure and pulmonary haemorrhage. on icu admission, the patient was conscious and oriented, very dyspneic and tachypneic with a respiratory rate of /min, and a spo % on l per minute (lpm) o on facial mask, and bilateral auscultatory pulmonary crackles. the blood pressure was / mmhg, and the heart rate was beats per minute, sinus rhythm. there were no signs of peripheral hypoperfusion. the temperature was . o celsius. the arterial blood gases revealed a ph . , pao mmhg, paco mmhg, lactate . mmol/l. the antibiotic cover was broadened with the addition of colistin. after h on high flow nasal oxygen (fio , flow lpm) and in the absence of clinical improvement (persistent respiratory effort), mechanical ventilation ( ml/kg, positive end-expiratory pressure titrated at cm h o, plateau pressure cm h o), sedation, and continuous muscle paralysis were initiated. one-hour post intubation, the pao /fio ratio was to , on % o . the decision to initiate ventilation in prone position for h was made at this point, with poor respiratory responsiveness (pao /fio ratio ). the chest x-rays at this moment is shown in fig. . the acute respiratory distress syndrome (ards) diagnosis was established. within the next h in the icu (day after chemotherapy), the patient recovered from aplasia ( . × /l wbc, . × /l anc, × /l plt). the neuromuscular blockade was discontinued after h. the clinical state and blood results prior to icu admission are summarized in fig. . the sputum culture was positive for stenotrophomonas maltophilia (cultured on day after chemotherapy, days before the icu admission). therefore, the antibiotic treatment has been de-escalated to colistin ( . miu, bid, after initial bolus dose of miu) and trimethoprim/sulfamethoxazole ( mg/ mg, qid). after other days, the antibiogram showed a germ susceptible to trimethoprim/sulfamethoxazole (tmp/smx), intermediary susceptible to levofloxacin, and resistant to all beta-lactams and aminoglycosides (no determined mic available). the antibiotic treatment has been further de-escalated the next day to tmp/smx only for a total duration of days. unfortunately, the laboratory was logistically unable to test the susceptibility to colistin at this point. all blood cultures were reported negative during the hospital stay. the respiratory improvement allowed for a bronchoscopy with bronchoalveolar lavage, days after icu admission, which showed a non-haemorrhagic mucosa, and numerous blood clots. the cytologic examination was very rich in red blood cells with some macrophages, rare lymphocytes and neutrophils. respiratory cultures from the bronchoalveolar lavage were negative. the clinical course was marked by a failed extubation at day of icu, explained by icu-induced neuromyopathy and ventilator-associated pneumonia (vap) with mdr pseudomonas aeruginosa susceptible only to colistin (mic ), and resistant to carbapenems and other antibiotics. treatment with iv and nebulized colistin was introduced for a total duration of weeks. the respiratory status progressively improved, allowing the successful extubation on day in icu. the chest x-rays post extubation is shown in fig. . the patient was transferred to the haematology ward after days of icu stay and days after chemotherapy. the patient was discharged home soon after, on family request, and her clinical condition and respiratory function were excellent at months follow up. we reported a case of severe acute respiratory distress syndrome (ards) with alveolar haemorrhage and a good response to treatment. to our knowledge, this is the first reported case of pulmonary haemorrhage and ards caused by a fulminant stenotrophomonas maltophilia respiratory infection in eastern europe, and it seems to be a rare case of positive outcome in a patient with haematological malignancy. the patients diagnosed with acute leukaemia have a high risk of infection with opportunistic pathogens. the pulmonary haemorrhage caused by stenotrophomonas maltophilia is a rare condition with a poor outcome. several reports have shown the presence of predisposing factors like severe thrombocytopenia, severe and prolonged neutropenia, the previous use of quinolones, corticosteroids, and immunosuppressive therapy [ , , ] . our patient had grade iv thrombocytopenia and neutropenia secondary to chemotherapy. she also had a history of prolonged hospitalization for chemotherapy and complications related to chemotherapy, and she was treated with multiple classes of antibiotics, including quinolones, and she had prolonged corticosteroids use. in the published literature, we found haematological patients with stenotrophomonas maltophilia and pulmonary haemorrhage [ , ] . most patients ( out of ) were diagnosed with acute myeloid leukaemia, and the mortality rate was %, and the survival length was - days. it is important to notice the high early death rate: almost % of patients died in the first days after the onset of the respiratory symptoms. another the particularity of our case is that the patient recovered very soon from severe aplasia after icu admission (day ) permitting the respiratory stabilization in the absence of recurrent hemoptysis. also, we speculate that the empirically introduced colistin at the moment of icu admission for ards, associated with neutrophil count recovery, might have been efficient in stopping the bacterial proliferation. the only available options to treat the stenotrophomonas maltophilia infection, in this case, were tmp/smx and colistin -which has not been tested because of laboratory unavailability of the antibiogram kit. the literature-reported resistance of stenotrophomonas maltophilia to colistin was < % [ ] . there is no standard therapy for the treatment of severe stenotrophomonas maltophilia pneumonia with pulmonary haemorrhage, but combination antibiotic therapy represents an alternative to consider in critical situations [ ] . in our case, the patient received colistin and tmp/smx combination for days, the time between the germ identification and the antibiogram results, followed by further de-escalation to tmp/smx only. the decision to continue iv colistin has been taken considering the fact that the patient has been already exposed to levofloxacin, the possibility of a mdr germ and the unknown bioavailability of enterally administered tmp/smx in a severely ill patient with reactive digestive ileus and gastric stasis (the iv form is not available in our country). some retrospective studies have shown that, during icu stay, the absence of neutropenia recovery and the presence of organ failure are associated with poor outcome in the critically ill patient with malignancy [ , ] . furthermore, according to other reports, survival was higher for patients who underwent a first-line chemotherapy, had lobar ards and who received antibiotic treatment active on difficult-to-treat bacteria like pseudomonas aeruginosa and stenotrophomonas maltophilia [ ] . the duration of neutropenia seems to be correlated with short-term mortality, while -day mortality is affected by organ dysfunction [ , ] . one explanation for the high mortality in this clinical situation could be that the patients do not survive the first days of icu because of the difficulty of proper pathogen isolation and its corresponding antibiogram, allowing targeted antibiotic treatment [ ] . indeed, days were needed to identify the pathogen in the respiratory samples, and days to have complete cultures and susceptibilities. the consequence of initial wide spectrum antibiotic treatment was the development of a late vap with mdr pseudomonas aeruginosa. we are not able to provide a full explanation for this pneumonia with a mdr germ susceptible to colistin in a patient who already received colistin, as a serum colistin level was not measured (logistically unavailable). nevertheless, we may speculate that this might have happened due to changes in the volume of distribution in the patient with prolonged icu fig. chest x-rays after extubation (day of icu). the regression of the bilateral infiltrates and mild bilateral pleural effusion can be noticed hospitalization. the efficacy of associated nebulized colistin might be an argument for an increased active concentration in the targeted organ. overall, the prolonged treatment with colistin was well tolerated with no neurotoxicity, nor nephrotoxicity. the clinical management of this case had limitations and debatable aspects, such as the unavailable quantitative sputum culture, a long delay in obtaining germ identification and antibiogram, the unavailable colistinresistance kit for stenotrophomonas maltophilia, the unavailable iv form for tmp/smx, or the impossibility to determine the colistin serum levels. the rapid escalation in the antibiotic cover might be partially explained by our national known struggle and local experience with bacterial resistance. infections with multi-resistant opportunistic pathogens in haematological patients treated with chemotherapy is a complication that associates therapeutic challenges and high mortality rate. this clinical case highlights the severity and rapid progression of stenotrophomona smaltophilia pneumonia in a patient with acute lymphoblastic leukaemia. the patient had a good outcome following treatment with colistin and tmp/smx, associated with rapid recovery cell count after the pneumonia onset. this case might be an argument that the clinician might consider the empirical covering of stenotrophomonas maltophilia, particularly in the immunocompromised haematological patient presenting with hemoptysis, as it proves that stenotrophomonas maltophilia is not always lethal in fragile haematological patients. stenotrophomonas maltophilia: an emerging global opportunistic pathogen life-threatening hemorrhagic pneumonia caused by stenotrophomonas maltophilia in the treatment of hematologic diseases haemorrhagic pneumonia caused by stenotrophomonas maltophilia in two newborns stenotrophomonas maltophilia infection during allogeneic hematopoietic stem cell transplantation: a single-center experience stenotrophomonas maltophilia infection in hematopoietic sct recipients: high mortality due to pulmonary hemorrhage lethal pulmonary hemorrhage caused by a fulminant stenotrophomonas maltophilia respiratory infection in an acute myeloid leukemia patient fatal hemorrhagic pneumonia: don't forget stenotrophomonas maltophilia clinical characteristics of rapidly progressive fatal hemorrhagic pneumonia caused by stenotrophomonas maltophilia infections caused by stenotrophomonas maltophilia in recipients of hematopoietic stem cell transplantation prevalence and antibiotic resistance of stenotrophomonas maltophilia in respiratory tract samples: a -year epidemiological snapshot prognosis of acute respiratory distress syndrome in neutropenic cancer patients sepsis and septicshock in patients withmalignancies: a groupe de recherche respiratoire en réanimation onco-hématologique study impact of neutropenia duration on short-term mortality in neutropenic critically ill cancer patients publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. authors' contributions sa and ag reviewed the published literature, drafted the manuscript, and managed the case. lb, cm and an were involved in data collection and clinical management. dc and gd provided critical reviewing of the manuscript and clinical expertise. all authors approved the final version of this manuscript. the authors received non funding for this publication.availability of data and materials supplementary medical data are available at request. this case report has the approval of the ethics committee of our university hospital according to local and national rules. written informed consent was obtained from the patient for publication of this case report. the authors declare no conflict of interest. key: cord- -a qyadm authors: pinto neto, osmar; reis, josé clark; brizzi, ana carolina brisola; zambrano, gustavo josé; de souza, joabe marcos; pedroso, wellington; de mello pedreiro, rodrigo cunha; de matos brizzi, bruno; abinader, ellysson oliveira; zângaro, renato amaro title: compartmentalized mathematical model to predict future number of active cases and deaths of covid- date: - - journal: res doi: . /s - - - sha: doc_id: cord_uid: a qyadm introduction: in december , china reported a series of atypical pneumonia cases caused by a new coronavirus, called covid- . in response to the rapid global dissemination of the virus, on the th of mars, the world health organization (who) has declared the outbreak a pandemic. considering this situation, this paper intends to analyze and improve the current seir models to better represent the behavior of the covid- and accurately predict the outcome of the pandemic in each social, economic, and political scenario. methodology: we present a generalized susceptible-exposed-infected-recovered (seir) compartmental model and test it using a global optimization algorithm with data collected from the who. results: the main results were: (a) our model was able to accurately fit the either deaths or active cases data of all tested countries using optimized coefficient values in agreement with recent reports; (b) when trying to fit both sets of data at the same time, fit was good for most countries, but not all. (c) using our model, large ranges for each input, and optimization we predict death values for , , , and days ahead with errors in the order of , , , and %, respectively; (d) sudden changes in the number of active cases cannot be predicted by the model unless data from outside sources are used. conclusion: the results suggest that the presented model may be used to predict days ahead values of total deaths with errors in the order of %. these errors may be minimized if social distance data are inputted into the model. in december , in china, a series of atypical pneumonia cases have emerged caused by a new coronavirus, nowadays officially called covid- by the world health organization (who). it has spread rapidly throughout the country, having had its epicenter the city of wuhan, in which , people were infected and people have died. in response to the rapid global dissemination of the virus, on the th of mars the who has declared the outbreak a pandemic. since then, the global impact of the covid- became a great threat to the public health. considering this emergency, different areas of science need to focus its attention to the challenges imposed by this new coronavirus. in such scenarios, it is imperative the necessity of new, improved, and specific mathematical modeling. there are many uncertainties regarding the gravity of the infection caused by . nevertheless, based on epidemiological investigations, the period of incubation is to days, more evidently between and days, and the virus is contagious still on its latency period (guo et al. ) . the majority of the infected adults and children have developed mild symptoms alike those of a common cold, and some patients evolved rapidly to an acute respiratory discomfort, followed by respiratory failure, multiple organ failure, and death. the probability of death in the usa, according to the centers for disease control and prevention (cdc), has ranged from . % to ages of - to . % to ages - and growing on a constant rate with age. pre-existing comorbidities, affecting the vulnerability to the infection, also increase the probability of death. covid- seems to have a relatively higher rate of transmissibility when compared with other coronavirus infections and, to better understand it, it is very important to multiple factors (chen et al. ; wang et al. ) . family environment, age, and wealth distribution are essential factors related to the transmission and mortality rate of covid- (walker et al. ) . another important that must be considered, especially in the mortality rate, is the number of hospital beds and the capacity of intensive care unities (icu). the relationship between the age ranges that require attention and the mortality rate by infection was scrutinized by china and, assuming that % of the hospitalized will demand intensive care (icu), and among those % will die, it has been calculated the demand for hospital beds assuming the average stay of days in the hospital (ferguson et al. ) . the experience of covid- in many countries, concerning medical assistance, has indicated that the demand for hospital beds and the need for mechanical ventilation have overcome the availability of those in countries with higher per capita income. therefore, the consequences in countries with scarcity of these services are expected to be larger (walker et al. ) . previous experiences in some countries highlight the need to anticipate the impacts of the pandemic outbreak and to develop researches with epidemiological models. these mathematical models are necessary to the comprehension of the present outbreak's behavior, so that countries might develop strategies to minimize the impacts on the healthcare system and preserve life (wu et al. ; peng et al. ) . as an example, public administrators may find comprehensive ground to define policies such as enforcing social distance measures, the available versus need of laboratorial tests, planning for hospital beds, and health system resources. in the absence of a vaccine, mathematical modeling may assess the effectiveness of non-pharmaceutical interventions and in its role in decreasing population contact and viral transmission to control the pandemic outbreak. china has managed to control the outbreak with the deployment of isolation of its cases and social distancing of the population (ferguson et al. ) . there are some non-pharmaceutical strategies to control an outbreak, such as containment, mitigation, and suppression. when the containment measures fail to control the outbreak, mitigation and suppression strategies may be adopted to postpone and mitigate its effects on society and the healthcare system. mitigation will concentrate in retarding but not necessarily impeding the spread of the outbreak, reducing the peak of medical assistance and protecting the higher risk groups. suppression aims to reverse the outbreaks' growth, diminishing the number of cases and maintaining this frame for an indefinite time, through more extreme measures, such as quarantining, police enforcement, mass testing, compulsory notification, and finance support to the population in isolation, among other actions. (ferguson et al. ; walker et al. ) . concerning mathematical modeling, which supplies detailed mechanisms about the outbreak dynamics, the susceptible-exposed-infected-recovered (seir) epidemiological model is widely adopted to characterize a pandemic caused by covid- . for instance, this method was used for decision making in hubei, wuhan, and beijing (peng et al. ) . this paper intends to analyze and improve up on the traditional seir model by adding important new compartments, as well as consider the effects of non-pharmaceutical interventions and the possibility of death coming from lack of available icu beds. moreover, such a model can also be used to prototype and analyze the cause/effect relation of a multitude of actions and public health strategies, so the most effective ones can be chosen for each country, city, or province. since every affected region is different, it is of utmost importance to help organizations to determine not only the number of active cases but also the number of hospital beds, and icus will be needed at a certain point in time to maximize the usage of public resources. we present a generalized seir compartmental model using novel and recently suggested ideas and concepts (apmonitor optimization suite ; peng et al. , university of basel ). an application of our model using real mobility data to investigate different future projections for the usa has been recently reported (kennedy et al. ) . it is composed of eight compartments: susceptible, unsusceptible, exposed, infected, hospitalized, critical, dead, and recovered (sueihcdr; fig. ). the model assumes, at first that, the whole population is susceptible (eq. ) to the disease. as time progresses, a susceptible person can either become exposed (eq. ) to the virus or unsusceptible (eq. ). where i(t) is the number of infectious people at time t, n pop is the population of the country, β is the infection rate, α is a protection rate, and sd is a social distancing factor. as in peng et al. ( ) we introduced a protection rate α factor to our susceptible equation (eq. ). this protection rate was introduced to account for possible decreases in the number of susceptible people to the virus caused by factors other than social distancing, such as the usage of face masks, better hygiene, more effective contact tracing, and possible vaccines and or drugs that may prevent infection. different from the aforementioned study of peng et al. ( ) , however, we varied α across time (eq. ). this time variation was introduced to reliably model people's behavior, who are not commonly too concerned about the disease in the earlier stages of the epidemic, but as the number of infected and deaths increases, become more cautious about the virus. where α is the reference value that is the maximum value and t f is the final time for the prediction. furthermore, we also introduced a social distancing factor sd, which also varies with time (eq. ). social distancing was modeled as a logistic curve so that the model could account for the date (t sd ) when a possible quarantine measurement starts. as mentioned before, real data for mobility can be used in our model when available; using real mobility data have been shown to be important when long-term future projections are intended (kennedy et al. ) . where sd is sd reference value, that is the maximum value, and t sd is the time the sd increases until reaching sd . exposed people become infectious after an incubation time of /γ (eq. ). infected people stay infected for a period of /δ (eq. ) days and can have three different outcomes. considering m as a specific parameter to account the fraction of infectious that is asymptomatic, it is possible to determine that a percentage of the infected ( − m) go hospitalized, another percentage of them (l) may die without hospitalization, and the rest of them (m − l) recover. l was introduced as a function of time (eq. ) so that the time when hospital bed became unavailable could be modeled (t m ), as well as the duration that hospital was full (dur). fig. sueihcdr model info graphic description; it is composed of eight compartments susceptible, unsusceptible, exposed, infected, hospitalized, critical, dead, and recovered. β is the infection rate, sd is a social distancing factor, α is a protection rate, m is the fraction of infectious that are asymptomatic, − m is the percentage of the infected go hospitalized, l is the percentage of infected people that may die without hospitalization, − c is the percentage of hospitalized people that recovers, c is the fraction of hospitalized that becomes critical cases needing to go an intensive care unit (icu), and f is the fraction of people in critical state that dies where l is the inclination of the angular coefficient of the ramp up until reaching the maximum value reference value and t l is the time when people started dying due the lack of available icus. hospitalized people (eq. ) stay hospitalized for /ζ days and can either recover ( − c) or become critical (c-specific parameter to account the fraction of hospitalized that becomes critical cases) needing to go an intensive care unit (icu). where ε is the inverse of the time people stay in the icu. a person stays on average /ε in the icu (eq. ) and can either go back to the hospital ( − f) or die (f-specific parameter to account the fraction of people in critical state that died). therefore, recovered people (eq. ) can either come straight from infection when the case is mild (m − l) or from the hospital when the case is no critical ( − c). death (eq. ) arises either from lack of available treatment (l), or from critical cases in the icu ( f ). at last, the effective reproduction number r t (eq. ) of our model can be estimated as solving and testing the model we used the fourth order runge-kutta numerical method to solve our system of ordinary differential equation in matlab (mathworks inc.r a). to test our model we gathered active cases, recovered cases, accumulated deaths, and tests per million people data from the who of ten different countries in different stages of the epidemic: germany, brazil, spain, italy, south korea, portugal, switzerland, thailand, and usa. lack of testing and under-notification of active cases has been largely reported for the covid- (hasell et al. ; worldometer, ; ufpel, ) ; in consequence, active cases data were corrected by a factor. the correction factor was found via optimization, as described in the next paragraph, using a range of possibilities estimated based on previous reports. lower bound was determined considering the death rate of the country to be as described in verity et al. ( ) , corrected by age (young: . %; older adults ( +): . %; senior older adults ( +): . %). upper bound was set by considering the same age proportional differences in death rate, as previously mentioned, but adjusting death rate of each country by the death rate in iceland (country with the greatest percentage of test per inhabitant gudbjartsson et al. ) . we used a custom build matlab global optimization algorithm using monte carlo iterations algorithm and multiple local minima searches. the algorithm was tested for the best solution considering different inputs to the model within ranges obtained from the who and several publications (liu et al. ; ranjan ; wu et al. ; table ) and correction factor (f) for the active cases ( table ). the algorithm was used to minimize a goal function (j) as a combination of active cases and death time series (eq. ). optimization algorithm results after , runs. the pareto front was determined considering two simultaneous objectives active cases rmse and deaths rmse. the best solutions were used to initialize the matlab multi-objective genetic algorithm data under active cases were discarded. initial values for each compartmental parameter had ranges proportional to the following initial values (table ) : infected initial values (i ) were determined as the corrected actives cases first value greater than ; exposed initial values (e ) were . × i ; hospitalized initial values (h ) were . × i ; critical cases initial values (c ) were . × i ; death initial values (d ) were obtained from the accumulated deaths real data; similarly, recovered initial values (rec ) were obtained from the recovered real data. optimization algorithm results were considered after , runs; from them, the best solutions were used as initial population for a multi-objective genetic algorithm (matlab function: gamultiobj) to determine a pareto front of solutions considering two simultaneous objectives rmse (active cases) and rmse (deaths) (fig. ) . lower and upper bounds for the genetic algorithm were set as % variations to the best solution found out of the previous optimization algorithm runs, and generations were created. all fitting processes were done for data from the day of the outbreak for each country up to april , may , may , june , and june , , to test the accuracy of the future predictions that can be made based on the model and optimization results. furthermore, % perturbations to the model coefficients were used to determine via monte carlo a % confidence interval for the results. results are presented as mean (standard deviation). besides introducing more compartments than a traditional seir model (e.g., hospitalized) the three main differences of our model sueihcdr to a standard seir model is the addition of α sd and l. our results suggest that our model was able to accurately fit the data of all countries when one goal is considered (figs. and ) . however, when we tried to fit the model two both accumulated deaths and active cases, we found that we could not reproduce with the same accuracy the data for all analyzed countries (fig. ). table shows the optimization parameter results for june , , for germany, brazil, spain, italy, south korea, portugal, switzerland, thailand, and the usa considering the solution from the pareto front (fig. ) that minimized j (eq. ). mean protective rate (α) was . ( . ); mean infectious rate (β) was . ( . ); mean fraction of infectious that are asymptomatic or mild (m) was . ( . ); the mean fraction of infectious people that died with no treatment (l) was . ( . ); the fraction of severe cases that turn critical (c) was . ( . ); the mean fraction of critical cases that are fatal ( f ) was . ( . ), and the mean social distancing parameter (sd) was . ( . ). table shows the inverse values of γ, δ, ζ, and ε: the mean latent period was ( . ) days; the mean infectious period was . ( . ); the mean hospitalized period was . ( . ) days, and the mean period in icu was . ( . ) days. the basic reproduction number (r ) was . ( . ), and the death rate was . ( . )%. figures , , and show the model results for all studied countries. figure shows results considering the two-goal optimization pareto front that minimized death rmse. optimization was done considering end-date june (black circles for deaths and green circle for active cases). the red circles (deaths) and blue circles (active cases) indicate "future" real data for the next days. similarly, fig. shows the results for the two-goal optimization, but now minimizing active cases rmse and end-date may . finally, fig. shows the results considering the solution from pareto front that minimized j for end-date may th. table shows the model future projection of , , , and days for total number of infected, deaths, hospitalized, peak hospitalization, icu patients, peak day icu, and recovered patients. results indicate deaths in the thousands for every country but korea and thailand. usa has a peak day of more than thousand hospitalized patients. additionally, spain projects almost million recovered people by the end of august . according to the model estimations, brazil will have more than thousand icu patients treated by the end of july and thousand more in the following days; peak day will demand thousand icu beds. finally, tables , , and shows the percentage errors comparing model results to real data for the day of the analyses and future projections of , , , and days. table shows the results for the optimization minimizing j, table shows the minimizing death rmse, and table shows the minimizing active case rmse. thirty-day projections were performed twice: first, as for the other time windows, considering future date june , and second considering future data may . as expected, errors got larger for farther into the fig. model results for active cases and accumulated deaths for all studies countries, considering minimizing active cases rmse. optimization was done considering end-date may (black circles for deaths and green circle for active cases). the red circles (deaths) and blue circles (active cases) indicate real data up to june future projections. in general, projected deaths had smaller percentage errors. because of recent re-opening of countries such as portugal and spain -day future projections considering data from days ago to estimate days ago yielded better results than data from days ago to estimate present day (may ). as it can be seen in fig. , there was a sudden increase in the number of active cases for both countries in the past days that were not predicted by the model whose active case curves kept on a steady decline. considering the rapid growing covid- pandemic and the necessity of modeling the phenomenon to make future predictions in the number of cases, deaths, but ultimately in the number of hospital and icu beds, we present a novel generalized seir compartmental model with the addition of the unsusceptible, hospitalized, critical, and dead compartments. furthermore, we introduce three new parameters to the model (α, sd, and l). we tested our model using a global optimization algorithm and data collected from the who for several countries. our main findings were as follows: (a) our model was able to accurately fit the either deaths or active cases data of all countries tested independent of what stage of the epidemic they were using optimized coefficient values in agreement with recent reports; (b) when trying to fit both sets of data at the same time, fit was good for some countries, but not for all; (c) using our model, large ranges for each input, and (black circles for deaths and green circle for active cases). the red circles (deaths) and blue circles (active cases) indicate real data up to june table inverse of the model optimized coefficients of γ, δ, ζ, and ε representing latent, infectious, hospitalization, and critical cases mean duration in days, as well as the model estimated basic reproductive number (r ) and the death rate (dr) for june , , for germany, brazil, spain, italy, south korea, portugal, switzerland, thailand, and usa, respectively. μ stands for the mean across countries and std for the standard deviation our results show that that our model can fit data from several countries, despite obvious different covid- scenarios among them, such as south korea and spain for example. in order to do that, among other things, we estimated the infection rate (β) as an important determinant in the growth of the infected cases mainly in the early stages of the epidemic and a social distancing coefficient (sd) and a protective coefficient (α) that can cause decreases in rate of transmission. this estimation process provides information to compare different social distance measures adopted among several countries. south korea results, for instance, exhibits decreased effective transmission rate β ( − sd) compared with other countries and the best social distancing at a rate of %. this result concurs with south korea political decisions (shin ). as our model does not have a quarantined state, the effective testing, contact tracing, and quarantining implemented by korea was reflected not only in a greater sd values but also an increased protection rate of α = . . the worse protection rates were found for brazil (α = . ) and the usa (α = . ) most likely caused by poor political decision and downplaying by officials of the seriousness of the virus in the beginning of the crisis (abutaleb et al. ; andreoni ) . furthermore, in order to adequately model, countries where the number of deaths are critically above the expected number considering covid- death mortality rates even considering possible age effects (li et al. ; who ), we introduced a coefficient l to the model. this coefficient represents the percentage of people that went from infectious to death without access to hospital care. introducing l was a novel idea in seir model studies. it was done to account for the sad reality that many people are facing during the covid- pandemic, as many people have passed away for the lack of available icu and/or hospital beds, especially in some regions where the outbreak was not early contained, italy for example (tondo ) . nevertheless, in order to accurately estimate the value of l, one need to know c (specific parameter to account the fraction of hospitalized that becomes critical cases) and f (specific parameter to account the fraction of people in critical state that died) from outside sources. our model predicted a basic reproduction number r of . ( . ). the basic reproduction number represents the average number of secondary cases that result from the introduction of a single infectious case in a susceptible population (anastassopoulou et al. ) . considering the importance of such parameter, several other papers have tried using different methods to estimate this parameter for covid- , and our values fall within the range of values reported so far. in their review, liu et al. ( ) reported two studies using stochastic methods that estimated r ranging from . to . , six studies, where mathematical methods, with results ranging of . to . , and finally three studies that used statistical methods such as exponential growth with estimations ranging from . to . . additionally, we found a worldwide mean of latent period of ( . ) and infectious period of approximately . ( . ) days. the mean estimated latent period found here is smaller than some previously reported, such as in peng et al. ( ) and guan et al. ( ) who reported estimates the latent median times around - days. nevertheless, our results corroborate with the idea that covid- transmission may occur in the pre-symptomatic phase and that covid- patients may have an inconsiderable latent non-infectious period. the mean infectious period of days is within expected range estimated by recent publications (guo et al. ; hou et al. ) . our results indicate that, despite all uncertainty and biases in the data collected, lack of testing in several countries and possible changes in policies and people's behavior regarding the covid- our proposed mathematical modeling may help predict days ahead values of total deaths with errors in the order of % and days ahead values of active cases with errors in the order of %. moreover, a reliable -week prediction of the number of deaths suggests that the model may also be used to determine the number of hospital and icu beds that a region will need ahead of time enough for people to prepare themselves for it. unfortunately, we could not get reliable data of number of hospitalizations and icu patients in the different countries studied here to verify the certainty of our predictions for the values estimated by the model, and we urge future research to do so. furthermore, future application of our model should consider including stratification by age groups (li et al. ) and coefficients to account for temperature variations and people's density (chen et al. ; wang et al. ). additionally, for brazil where the active cases are still fastgrowing errors in prediction can be large (fig. ) . the larger errors in such cases happened because there is less data for the optimization process to fit the data to the models' parameters and the fact the active cases and accumulated death curves are still, approximately, exponentially growing (ranjan ) . because of the simplicity of the curve, different optimization solutions can fit the data but yield quite different future projections. for example, different combinations of α and β may cause similar behavior patterns for the beginning of the curve. our results are in agreement with recent study by ranjan ( ) , who adds that modeling of an epidemic during its progress is very challenging as the parameters such as transmission rate and basic reproduction number are different for different geographical regions and depend on many social and environmental factors. they also concluded that the early stage of an epidemic is relatively easy to model and the modeling of later stages to predict the decline and eventual flattening of the curve is very challenging as more known parameters need to be included in the model. the inclusion of effects due to isolation and quarantine adds to the complication. although technically we solved this issue by including in our model three time-changing coefficients α, sd, and l, they are hard to find by optimization for countries in the beginning stages. this happens mainly because sd and l are time-dependent triggered and the optimization process attributes random values for both these coefficients and their time "activations." with larger t sd and t l than current time, different values of sd and l can yield the same temporal trends for the beginning of the curves but significantly different behaviors after times t sd and t l . in other words, in countries where the epidemic is still in its pre-peak stages, especially during the fast-initial growing phase, some of the model coefficients, especially sd, α, t sd , and t l , should be estimated from outside sources and/or used to infer possible future scenarios dependent upon future defined policies, such as, for example, an enforcement of social distance measures. furthermore, sudden changes in sd after a period may also cause a rapid increase in active cases that cannot be predicted by the model (e.g., figure ; spain, and portugal); to predict such cases, data from sd and ideally protection rates should be obtained from outside sources. studies to test such hypothesis should be made. in response to the rapid global dissemination of the covid- , on the th of mars the who has declared the outbreak a pandemic motivating further research in epidemiological mathematical modelling. the results suggest that the presented model may be used to predict days ahead values of total deaths with errors in the order of %. these errors may be minimized if social distance data are inputted into the model. sudden changes in social distance measures could not be predicted by the model using optimization alone. the u.s. was beset by denial and dysfunction as the coronavirus raged. the washington post data-based analysis, modelling and forecasting of the covid- outbreak what you need to know. new york times roles of meteorological conditions in covid- transm i s s i impact of non-pharmaceutical interventions (npis) to reduce covid- mortality and healthcare demand clinical characteristics of novel coronavirus infection in china early spread of sars-cov- in the icelandic population the origin, transmission and clinical therapies on coronavirus disease (covid- ) outbreak -an update on the status to understand the global pandemic, we need global testing-the our world in data covid- testing dataset the effectiveness of the quarantine of wuhan city against the corona virus disease (covid- ): well-mixed seir model analysis modeling the effects of intervention strategies on covid- transmission dynamics risk factors for severity and mortality in adult covid- inpatients in wuhan the reproductive number of covid- is higher compared to sars coronavirus epidemic analysis of covid- in china by dynamical modeling estimating the final epidemic size for covid- south korea extends intensive social distancing to reach daily coronavirus cases. reuters italian hospitals short of beds as coronavirus death toll jumps. the guardian. palermo estimates of the severity of coronavirus deases : a model-based analysis the global impact of covid- and strategies for mitigation and suppression. imperial college, n high temperature and high humidity reduce the transmission of covid- . ssrn electron j, . who director-general's opening remarks at the media briefing on covid- . world health organization (who) estimating clinical severity of covid- from the transmission dynamics in wuhan, china apmonitor optimization suite. covid- optimal control response university of basel. covid- scenarios developed at the university of basel. © covid- publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgments the authors would like to thank dr. osmar pinto jr, dra. iara rca pinto, emely flores, leandro dalmarco, fernando torres balbina, fabricio duarte, henrique touguinha, guilherme ferro, marco antonio ridenti, and all others who have helped us by sharing data and information during this project. conflict of interest the authors declare that they have no conflict of interest. key: cord- -e am pa authors: piccioni, federico; droghetti, andrea; bertani, alessandro; coccia, cecilia; corcione, antonio; corsico, angelo guido; crisci, roberto; curcio, carlo; del naja, carlo; feltracco, paolo; fontana, diego; gonfiotti, alessandro; lopez, camillo; massullo, domenico; nosotti, mario; ragazzi, riccardo; rispoli, marco; romagnoli, stefano; scala, raffaele; scudeller, luigia; taurchini, marco; tognella, silvia; umari, marzia; valenza, franco; petrini, flavia title: recommendations from the italian intersociety consensus on perioperative anesthesa care in thoracic surgery (pacts) part : intraoperative and postoperative care date: - - journal: perioper med (lond) doi: . /s - - -z sha: doc_id: cord_uid: e am pa introduction: anesthetic care in patients undergoing thoracic surgery presents specific challenges that require a multidisciplinary approach to management. there remains a need for standardized, evidence-based, continuously updated guidelines for perioperative care in these patients. methods: a multidisciplinary expert group, the perioperative anesthesia in thoracic surgery (pacts) group, was established to develop recommendations for anesthesia practice in patients undergoing elective lung resection for lung cancer. the project addressed three key areas: preoperative patient assessment and preparation, intraoperative management (surgical and anesthesiologic care), and postoperative care and discharge. a series of clinical questions was developed, and literature searches were performed to inform discussions around these areas, leading to the development of recommendations. the quality of evidence and strength of recommendations were graded using the united states preventive services task force criteria. results: recommendations for intraoperative care focus on airway management, and monitoring of vital signs, hemodynamics, blood gases, neuromuscular blockade, and depth of anesthesia. recommendations for postoperative care focus on the provision of multimodal analgesia, intensive care unit (icu) care, and specific measures such as chest drainage, mobilization, noninvasive ventilation, and atrial fibrillation prophylaxis. conclusions: these recommendations should help clinicians to improve intraoperative and postoperative management, and thereby achieve better postoperative outcomes in thoracic surgery patients. further refinement of the recommendations can be anticipated as the literature continues to evolve. thoracic surgery requires an evidence-based multidisciplinary approach that extends across the perioperative period, from preadmission evaluation to postoperative care and discharge. although such perioperative care protocols, known as the enhanced recovery after surgery (eras ® ) "philosophy," have been developed in many surgical settings, including lung surgery (batchelor et al. ) , and have been shown to be effective in reducing postoperative complications and length of hospital stay (los) (nicholson et al. ) , systematic reviews of studies in thoracic surgery (cerfolio et al. a; das-neves-pereira et al. ; muehling et al. ; salati et al. ) have highlighted significant heterogeneity and methodological flaws in many trials (fiore jr et al. ; li et al. ). to address this, an italian expert group, the perioperative anesthesia care in thoracic surgery (pacts) group, was convened to develop evidence-based recommendations for the management of thoracic surgery patients. the pacts group is a joint task force of the italian society of anesthesia, analgesia, resuscitation, and intensive care the methods used to develop the pacts recommendations have been described in full in an accompanying paper. in brief, the project focused on preoperative patient assessment and preparation, intraoperative management (surgical and anesthesiologic), and postoperative procedures and discharge in adult patients undergoing elective lung resection for lung cancer. a series of clinical questions were framed using the pico (patients, intervention, comparison, outcome) approach, and a delphi consensus method was used to reach agreement based on comprehensive literature searches. the quality of evidence and strength of recommendations were graded according to the united states preventive services task force (uspstf) criteria (united states preventive services task force ); in addition, the panel classified as "best practice" the recommendations considered to have a high level of certainty despite a lack of direct evidence. for uspstf grade a, b, or c recommendations, consensus required > % a/b/c ratings with < % d/i ratings. for grade d or i recommendations, consensus required > % d/i ratings and < % a/b/c ratings. the uspstf system was used in preference to the grade system, which has been used in the eras lung surgery guidelines (batchelor et al. ) , because the intention was to produce a position statement rather than full practice guidelines. the grade system involves full appraisal of a limited number of pico questions, and is therefore timeand resource-consuming. it is not always feasible where a number of recommendations are required in fields where no large evidence base exists, or which cannot easily be addressed using a pico framework. each author approved the final version prior to submission. this paper summarizes the final recommendations for intraoperative and postoperative care (table ) , and the supporting evidence for each recommendation. the recommendations for preadmission and preoperative care are presented in the accompanying paper. airway management recommendation : the use of videolaryngoscopy for tracheal intubation with a double-lumen tube might improve visualization of the glottis and the success rate at the first attempt, reducing difficulty and positioning time. videolaryngoscopy can be used in cases of unexpected difficult intubation. level of evidence: poor the use of videolaryngoscopy for tracheal intubation with a double-lumen tube might improve visualization of the glottis and the success rate at the first attempt, reducing difficulty and positioning time. videolaryngoscopy can be used in cases of unexpected difficult intubation. poor c we recommend the use of a double-lumen tube to manage one-lung ventilation. a single lumen tube with a bronchial blocker, rather than a double-lumen tube, is recommended for patients with difficult airways. good a we recommend the use of a flexible bronchoscope to control the position of the lung isolation device. flexible bronchoscopy must always be available, even if not used routinely. thoracic anesthesiologists must have adequate bronchoscopy skills to manage dlt and bronchial blockers for one-lung ventilation. good a we recommend monitoring arterial blood pressure with invasive (intra-arterial) techniques, rather than the non-invasive oscillometric cuff technique, in patients undergoing major thoracic surgery, or when sudden changes in hemodynamics, hemoglobin and blood gas concentrations (oxygen and carbon dioxide) are expected. we suggest considering the use of a central venous catheter on a case-by-case basis in patients undergoing thoracic surgery. peripheral catheters are safe for short-term and low-dose treatment with inotropic vasoactive drugs. in patients undergoing thoracic surgery who are considered at higher risk of postoperative complications, we suggest the use of hemodynamic monitoring with cardiac output estimation systems. we do not recommend the use of dynamic preload indices during open-chest thoracic surgery, because these parameters might not be reliable. we suggest that patients undergoing thoracic surgery under general anesthesia are monitored with processed electroencephalography (peeg) in order to titrate anesthetic administration. we recommend that intraoperative temperature be monitored using an appropriate system in all patients undergoing thoracic surgery lasting more than minutes. a core temperature of at least °c should be maintained. we recommend monitoring neuromuscular blockade in all patients receiving neuromuscular blocking agents during general anesthesia for thoracic surgery. in low risk patients (simple procedures, younger patients and without cardiac or renal comorbidities), the use of a bladder catheter is not recommended. we recommend using balanced crystalloid solutions, rather than normal saline (nacl . %), as standard fluid of choice. we do not recommend the use of hydroxyethyl starch as routine fluid therapy in patients undergoing thoracic surgery. we recommend a near-zero, rather than restricted or permissive, fluid balance to patients undergoing thoracic surgery. in high-risk patients a goal-directed approach to fluid therapy should be applied. we suggest using serum hemoglobin concentration in the evaluation of volume status in nonbleeding patients undergoing thoracic surgery. we recommend a protective ventilation approach during one-lung ventilation, based on the combination of low tidal volumes (≤ ml/kg ideal body weight) with alveolar recruitment maneuvers, adequately titrated positive end-expiratory pressure (peep) and the lowest fraction of inspired oxygen (fio ) to maintain satisfactory arterial oxygen saturation. fair a volatile anesthesia cannot be recommended over intravenous propofol administration in order to reduce postoperative complications, although there is evidence of a lower degree of both systemic and local inflammation when volatile anesthetics are used. we recommend the early removal of urinary catheters to promote mobilization in patients undergoing lung surgery, including those receiving thoracic epidural catheters. fair a we recommend the use of pre-emptive locoregional analgesia as part of a multimodal analgesic approach for thoracic surgery. systemic opioids, nonsteroidal anti-inflammatory drugs, and paracetamol have shown no evidence of benefit when used as pre-emptive analgesics. currently, there are no elements to suggest the routine perioperative use of gabapentinoids in patients undergoing thoracic surgery, but their use can be effective in a comprehensive multimodal analgesia protocol. we suggest intraoperative intravenous administration of ketamine to reduce postoperative pain after thoracic surgery. there is no evidence about the best dose and timing of administration of ketamine. we suggest intraoperative intravenous administration of magnesium sulfate to reduce postoperative pain after thoracic surgery. there is no evidence to suggest the routine use of α -agonists as part of a multimodal analgesia regimen to reduce postoperative pain after thoracic surgery. there is no consensus on the best timing and schedule for administration of these drugs. we suggest considering the use of intravenous steroids as part of a multimodal approach to reduce peripheral sensibilization of inflammatory-induced pain in patients undergoing thoracic surgery. adverse effects of single doses of steroids are of trivial clinical impact. we recommend the use of intravenous nonsteroidal anti-inflammatory drugs (nsaids) to reduce peripheral sensitization to inflammation-induced pain in patients undergoing thoracic surgery. combined use of nsaids and paracetamol may give a further analgesic advantage. we recommend the use of locoregional anesthesia for intraoperative and postoperative pain management. poor a we recommend the use of thoracic epidural analgesia in high-risk patients or in major surgical procedures where the parietal pleura (eg chest wall resection) is violated (i.e. thoracotomy, thoracosternotomy, chest wall resection). we recommend thoracic paravertebral block for vats, as part of a multimodal approach. good a we recommend paravertebral block in preference to thoracic epidural analgesia in patients with known or suspected coagulopathy. we suggest that intercostal nerve blockade should be considered only as a second choice for analgesia after thoracic surgical procedures. we suggest erector spinae plane block as part of a multimodal analgesia for thoracic surgery, especially for vats. we suggest the use of fascial pain blocks as part of multimodal analgesia for thoracic surgery, particularly for vats. we suggest considering the use of adjuvants (i.e. opioids, clonidine, dexmedetomidine b , dexamethasone, magnesium) when loco-regional anesthesia is performed, because the use of adjuvants can potentiate and prolong the effect of local anesthetics. we suggest considering the use of a single large-bore chest tube instead of a double tube after thoracic surgery. insertion of more than one chest tube may be considered in selected cases (e.g., bi-lobectomy or bleeding patients). we suggest considering the use of digital chest drainage systems to promote early mobilization of the patient. the routine use of drainage with suction is not recommended in the absence of complications, provided there is full re-expansion of the residual parenchyma after lung resection. we suggest removing chest tubes in lung resection patients when liquid output is ≤ cm /kg/ h of serous fluid. we do not recommend systematic icu admission after thoracic surgery. poor d we recommend that, in adult patients undergoing thoracic surgery, oral intake, including clear liquids, can be initiated - hours after surgery, in the absence of nausea and vomiting. oral intake should, however, be adapted to individual tolerance. we recommend early mobilization of patients within the first h after both minor and major fair a strength of recommendation: c several studies have compared videolaryngoscopy with the macintosh blade laryngoscope for tracheal intubation, in order to determine whether videolaryngoscopy improves the speed and success of double-lumen tube (dlt) positioning and reduces malpositioning rates (el-tahan et al. ; hamp et al. ; lin et al. ; purugganan et al. ; russell et al. ; wasem et al. ). these studies have yielded conflicting results: while some authors have reported that videolaryngoscopy is superior to the macintosh laryngoscope blade in terms of ease of use and higher rates of correct positioning of the dlt (lin et al. ; purugganan et al. ) , others have found no significant differences between the two techniques in terms of time to intubation and hemodynamic stress response (hamp et al. ; russell et al. ; wasem et al. ). there are limited data to suggest that videolaryngoscopy may improve visualization of the glottis, resulting in higher success rates at the first attempt, and reduced difficulty and positioning time (lin et al. ; purugganan et al. ). however, the success rate is highly dependent on the operator's experience (el-tahan et al. ) . recommendation : we recommend the use of a double-lumen tube to manage one-lung ventilation. a single lumen tube with a bronchial blocker, rather than a double-lumen tube, is recommended for patients with difficult airways. level of evidence: good strength of recommendation: a lung isolation techniques are designed to facilitate surgical exposure of the lung and achieve one-lung ventilation in patients undergoing thoracic surgery (campos and kernstine ; narayanaswamy et al. ). these techniques use either a dlt with both an endotracheal and an endobronchial lumen, or a bronchial blocker inside a single-lumen endotracheal tube, which allows collapse of the lung distal to the site of occlusion. dlts offer a number of advantages over bronchial blockers, including faster and easier positioning (campos and kernstine ; narayanaswamy et al. ; clayton-smith et al. ; dumans-nizard et al. ; ruetzler et al. ) , and a lower likelihood of displacement requiring repositioning under bronchoscopy (campos and kernstine ; narayanaswamy et al. ). in addition, pulmonary collapse can be achieved more quickly with dlts, because bronchial blockers do not allow adequate suction to cause lung collapse (campos ; yoo et al. ) . dlts also ensure pulmonary isolation, protecting the contralateral lung from blood or infections (santana-cabrera et al. ) , although the incidence of trauma during intubation is comparable with the two types of device (clayton-smith et al. ; knoll et al. ) . for these reasons, siaarti guidelines recommend dlts for routine clinical use (merli et al. ). the decision to use a bronchial blocker, rather than a dlt, in an individual patient should be based on the specific clinical circumstances (merli et al. ; campos ) . recommendation : we recommend the use of a flexible bronchoscope to control the position of the lung isolation device. flexible bronchoscopy must always be available, even if not used routinely. thoracic anesthesiologists must have adequate bronchoscopy skills to manage dlt and bronchial blockers for one-lung ventilation. level of evidence: good strength of recommendation: a the use of a flexible bronchoscope to confirm the correct placement of dlts for lung resection is we recommend a physiotherapy program after thoracic surgery. fair a we suggest considering daily chest radiographs only in selected cases under specific clinical indications. we do not recommend the routine use of either continuous positive airway pressure (cpap) or non invasive ventilation (niv) to prevent postoperative pulmonary complications, prolonged length of stay, and mortality (both in icu and in hospital) in patients undergoing major thoracic surgery. cpap or niv could be considered case by case in selected high risk patients. we suggest the use of niv or cpap to treat acute respiratory failure complicating thoracic surgery. poor b we suggest considering the use of high-flow nasal cannula oxygen therapy (hfnc) as an alternative or integrative support to cpap or niv to prevent or treat acute respiratory failure complicating thoracic surgery. dexmedetomidine is currently approved in italy only for sedation, and thus cannot be recommended for analgesic use in italian settings recommended. studies have shown that flexible bronchoscopy after auscultatory or tactile confirmation of the location of the dlt can identify malpositioning in more than one-third of patients (klein et al. ; de bellis et al. ) , and hence some authors have recommended that the position of the dlt should routinely be confirmed by fiberoptic bronchoscopy (klein et al. ; cohen ) . however, this requires technical expertise in flexible bronchoscopy, and a detailed knowledge of tracheobronchial anatomy (cohen ; campos ; solidoro et al. ) . it remains unclear whether routine bronchoscopic confirmation of the position of the dlt is necessary. malpositioning of the dlt is a major cause of intraoperative hypoxemia: in one case series, of patients in whom the dlt was positioned too deeply in the left bronchus developed hypoxemia during one-lung ventilation of the left lung (brodsky and lemmens ) . for this reason, the position of the dlt must be rechecked by flexible bronchoscopy after the onset of intraoperative hypoxemia, with the patient in the lateral decubitus position (brodsky and lemmens ; inoue et al. ) . obstruction of the left or right upper lobe bronchus is the most common significant malposition with dlts (slinger ), but there is no consensus as to the optimal position of the dlt. many malpositions may be attributable to an inappropriate choice of dlt or suboptimal positioning technique (slinger ; fortier et al. ; seymour and lynch ) . to date, no data have demonstrated the clinical relevance of malpositioning to patient outcomes, except in cases of dangerous or critical malposition, and there is no evidence that routine confirmation of dlt positioning by flexible bronchoscopy reduces morbidity after thoracic surgery. when a left dlt is inserted, the use of tubes with integrated high-resolution cameras can facilitate correct positioning and easier one-lung ventilation (massot ; schuepbach et al. ) . in one study, the mean time to successful intubation was significantly shorter with the vivasight-dl (etview medical ltd, misgav, israel) than with conventional dlts ( s versus s, respectively, p = . ), and all vivasight-dl tubes were correctly positioned (schuepbach et al. ) . furthermore, compared with blind placement, the use of tubes with integrated high-resolution cameras can shorten the intubation time and permits continued monitoring of the carina, thereby allowing prompt management of intraoperative tube displacement (massot ; schuepbach et al. ; belze et al. ; chen et al. ; heir et al. ) . recommendation : we recommend monitoring arterial blood pressure with invasive (intra-arterial) techniques, rather than the non-invasive oscillometric cuff technique, in patients undergoing major thoracic surgery, or when sudden changes in hemodynamics, hemoglobin and blood gas concentrations (oxygen and carbon dioxide) are expected. level of evidence: good strength of recommendation: a limited data suggest good concordance between invasive and non-invasive arterial pressure measurements in patients undergoing major thoracic surgery (bardoczky et al. ; d'antini et al. ; martina et al. ) , but further studies are needed in this area. due to the possibility of rapid changes in stroke volume and arterial blood pressure, and the potential usefulness of arterial blood sampling for gas, hemoglobin, and electrolyte analysis, invasive (intra-arterial) monitoring of arterial blood pressure is recommended in patients undergoing major thoracic surgery. in general, the risk of significant blood loss is very low in patients with no history of radiotherapy or chemotherapy who are undergoing primary lung surgery. for patients undergoing minor resections, the use of invasive blood pressure monitoring should be considered on a case-by-case basis according to the patient's comorbidity and surgical complexity. although specific studies on thoracic surgery patients are lacking, studies in mixed surgical populations have demonstrated that even short periods of hypotension significantly increase postoperative complications such as acute kidney injury (aki), myocardial injury after non-cardiac surgery (mins), and death (van waes et al. ; walsh et al. ; sessler et al. ) . in a review of data from , patients undergoing non-cardiac surgery, the relative risks of both aki and mins increased progressively with increasing duration of hypotension (mean arterial pressure < mmhg), compared with patients with mean arterial pressure above this threshold, even when the duration of hypotension was only - min (walsh et al. ) . a mean arterial pressure threshold of mmhg, or - mmhg with a systolic arterial pressure of mmhg, has been identified as critical to reduce the occurrence of aki, mins and mortality (sessler et al. ; salmasi et al. ) . recommendation : we suggest considering the use of a central venous catheter on a case-by-case basis in patients undergoing thoracic surgery. peripheral catheters are safe for short-term and low-dose treatment with inotropic vasoactive drugs. level of evidence: fair strength of recommendation: c there is no evidence that central venous catheters are essential for the intraoperative and postoperative management of thoracic surgery patients. measurement of central venous pressure to predict the response to volume expansion may be inconclusive in a significant proportion of patients (cannesson et al. ). furthermore, several studies have shown that low doses of vasoactive medications can be safely administered via peripheral intravenous catheters, with extravasation rates of approximately - % (cardenas-garcia et al. ; lewis et al. ; medlej et al. ) . for these reasons, the routine use of central venous catheters is not recommended in patients undergoing thoracic surgery: the need for central venous catheterization should be evaluated on a case-by-case basis. recommendation : in patients undergoing thoracic surgery who are considered at higher risk of postoperative complications, we suggest the use of hemodynamic monitoring with cardiac output estimation systems. level of evidence: poor strength of recommendation: c there is evidence that hemodynamic monitoring using cardiac output estimation systems to inform goal-directed fluid management is beneficial in thoracic surgery patients at higher risk of postoperative complications (cecconi et al. ; kaufmann et al. ; michard et al. ; searl and perrino ; zhang et al. ) . furthermore, such monitoring can be useful to avoid hypoxemia during one-lung ventilation, because extreme increases or decreases in cardiac output can impair the hypoxic pulmonary vasoconstriction (lumb and slinger ) . the use of this approach should be based on the estimated risk of complications in the individual patient. recommendation : we do not recommend the use of dynamic preload indices during open-chest thoracic surgery, because these parameters might not be reliable. level of evidence: good strength of recommendation: d a recent meta-analysis of seven trials has found that pulse pressure and stroke volume are inaccurate predictors of fluid responsiveness in patients undergoing open thoracotomy (piccioni et al. ) , and a subsequent study has shown that this is also true in patients undergoing vats procedures (jeong et al. ) . recommendation : we suggest that patients undergoing thoracic surgery under general anesthesia are monitored with processed electroencephalography (peeg) in order to titrate anesthetic administration. level of evidence: fair strength of recommendation: b processed electroencephalography (peeg) based on bispectral index (bis) reduces recovery times (punjasawadwong et al. ; chiang et al. ). however, the impact of peeg on the risk of intraoperative awareness is unclear (punjasawadwong et al. ) . postoperative delirium occurs in approximately % of patients (berian et al. ) , and it is believed that monitoring the depth of anesthesia by peeg is associated with reductions in the incidence of postoperative delirium and cognitive dysfunction (pocd) (aldecoa et al. ; fritz et al. ) . a recent meta-analysis of six randomized controlled trials showed moderate-quality evidence that peeg-guided anesthesia could reduce the risk of postoperative delirium and pocd (punjasawadwong et al. ) . conversely, the engages study, a rct of patients undergoing major surgery under volatile general anesthesia, did not find any decrease in the incidence of postoperative delirium among patients managed with peeg, compared with usual care (wildes et al. ). peeg has been included in guidelines for the prevention of postoperative delirium from a number of organizations (aldecoa et al. ; j am coll surg ; gelb et al. ) . advanced peeg technology is considered useful to improve anesthesia monitoring, individual titration of anesthetics and optimized patient care (eagleman and drover ; fahy and chau ; montupil et al. ) . recommendation : we recommend that intraoperative temperature be monitored using an appropriate system in all patients undergoing thoracic surgery lasting more than min. a core temperature of at least °c should be maintained. level of evidence: good strength of recommendation: a hypothermia occurs in approximately - % of thoracic surgery patients because the pleural surface on one side of the thorax is exposed to dry air during surgery, leading to evaporative heat loss (batchelor et al. ) . avoidance of hyperthermia is essential to prevent deleterious effects on homeostasis and reduce the risk of a systemic inflammatory response. hence, the eras guidelines for thoracic surgery recommend that body temperature should be continuously monitored to guide therapy, and that active warming should be continued postoperatively until the patient's temperature is greater than °c (batchelor et al. ) . siaarti guidelines recommend that intraoperative temperature should be monitored in all patients undergoing thoracic surgery lasting more than min, and that the aim should be to maintain a core temperature of at least °c (di marco and cannetti ). suitable monitoring systems include heated servo-controlled sensors, intra-vascular catheters with thermistor tips, or rectal or bladder probes, but esophageal probes may be less accurate (di marco and cannetti ). a number of studies in various surgical settings have found that zero-heat-flux systems can be used for non-invasive temperature measurement, and show good agreement with conventional core temperature measurements (eshraghi et al. ; iden et al. ; makinen et al. ) . recommendation : we recommend monitoring neuromuscular blockade in all patients receiving neuromuscular blocking agents during general anesthesia for thoracic surgery. level of evidence: good strength of recommendation: a neuromuscular blockade should be monitored in all patients receiving neuromuscular blocking agents (nmbas) during general anesthesia for thoracic surgery (ortega et al. ) . quantitative (objective) neuromuscular monitoring is more reliable than subjective and clinical tests to assess the neuromuscular block level and, more importantly, recovery before extubation (naguib et al. ). neuromuscular monitoring is essential for correct administration of both nmbas and reversal agents. recommendation : in low-risk patients (simple procedures, younger patients and without cardiac or renal comorbidities), the use of a bladder catheter is not recommended. level of evidence: fair strength of recommendation: d there is no evidence that urine output should be monitored in all patients undergoing thoracic surgery. recommendation : we recommend using balanced crystalloid solutions, rather than normal saline (nacl . %), as standard fluid of choice. level of evidence: good strength of recommendation: a balanced crystalloid solutions differ from normal saline (nacl . %) in that they contain anions other than chloride, such as lactate, acetate, malate, and gluconate, which act as physiological buffers (reddy et al. ; vincent and de backer ) . although specific studies in thoracic surgery patients are lacking, the available evidence suggests that normal saline is associated with risks of hyperchloremia, hyperchloremic acidosis and aki (reddy et al. ; zampieri et al. ) . for example, in a study in noncritically ill patients, the -day incidence of major renal adverse events in patients receiving balanced crystalloids or saline was . % and . %, respectively (odds ratio [or] . , % confidence interval [ci] . - . , p = . ), although there was no difference in the number of hospital-free days between the two treatments (self et al. ) . in general, most authors recommend that balanced crystalloids should be used in preference to normal saline (reddy et al. ; vincent and de backer ) . administration of normal saline is indicated only in specific circumstances, such as metabolic alkalosis, hyponatremia, or severe brain injury requiring normotonic fluid administration (vincent and de backer ) . recommendation : we do not recommend the use of hydroxyethyl starch as routine fluid therapy in patients undergoing thoracic surgery. level of evidence: good strength of recommendation: d patients undergoing lung resection surgery are at risk of postoperative respiratory failure, which could be related to the volume of fluid administered during surgery. hydroxyethyl starches could be administered in order to reduce the total amount of fluid given during surgery, but are associated with an increased risk of renal impairment (ahn et al. ). hence, the use of hydroxyethyl starch as routine fluid therapy should be avoided in patients undergoing thoracic surgery, although it could be considered in patients with severe hemorrhage who are not responding to crystalloid infusion (de hert and de baerdemaeker ). recommendation : we recommend a near-zero, rather than restricted or permissive, fluid balance to patients undergoing thoracic surgery. in high-risk patients, a goal-directed approach to fluid therapy should be applied. level of evidence: fair strength of recommendation: a there is evidence that a near-zero, rather than restricted or permissive, fluid balance is beneficial for patients undergoing thoracic surgery (searl and perrino ) , and hence this approach is recommended in normovolemic patients (chappell et al. ; licker et al. ). in highrisk patients, a goal-directed approach to fluid therapy is recommended because this has been shown to significantly reduce mortality and morbidity, compared with standard hemodynamic fluid management (cecconi et al. ; kaufmann et al. ; michard et al. ; zhang et al. ) . for example, a recent meta-analysis of trials involving over patients found that goal-directed therapy was associated with a significant decrease in postoperative morbidity, compared with controls (or . , % ci . - . , p < . ) (michard et al. ). similarly, a meta-analysis of trials involving approximately patients found a significant reduction in postoperative mortality with goal-directed therapy, compared with controls, in patients at highest risk of postoperative complications (or . , % ci . - . , p < . ); there was also a significant reduction in complication rates (or . , % ci . - . , p < . ), which was particularly marked in the highest risk subgroup (or . , % ci . - . , p < . ) (cecconi et al. ) . recommendation : we suggest using serum hemoglobin concentration in the evaluation of volume status in nonbleeding patients undergoing thoracic surgery. level of evidence: poor strength of recommendation: c because hemoglobin concentrations reflect plasma volume changes in patients without significant bleeding, monitoring of hemoglobin levels may play a role in the evaluation of volume status in patients undergoing thoracic surgery (perel ; otto et al. ) . recommendation : we recommend a protective ventilation approach during one-lung ventilation, based on the combination of low tidal volumes (≤ ml/kg ideal body weight) with alveolar recruitment maneuvers, adequately titrated positive end-expiratory pressure (peep) and the lowest fraction of inspired oxygen (fio ) to maintain satisfactory arterial oxygen saturation. level of evidence: fair strength of recommendation: a although there is an emerging consensus in favor of protective ventilation during one-lung ventilation (lohser and slinger ) , relatively few well-designed randomized trials have compared protective and conventional onelung ventilation (lohser and slinger ; ahn et al. ; kim et al. ; yang et al. ; zhu et al. ) : most published studies have involved small patient populations, or had other methodological limitations. in one of the largest randomized trials, patients undergoing elective lobectomy were randomized to receive either protective ventilation with an inspired oxygen fraction (fio ) of . , a tidal volume of ml/kg, a positive end-expiratory pressure (peep) of cm h o, and pressure-controlled ventilation, or conventional ventilation with higher fio and tidal volume, zero end-expiratory pressure, and volume-controlled ventilation (yang et al. ) . the incidence of pulmonary dysfunction (defined as pao /fio < mmhg, lung infiltration or atelectasis) was significantly lower in patients receiving protective ventilation than in those receiving conventional ventilation ( % versus % respectively, p < . ). a further randomized trial, involving patients undergoing vats lobectomy, found no significant difference in postoperative complication rates between patients receiving either volume-controlled or pressure-controlled protective ventilation (zhu et al. ) . by contrast, a randomized study in patients found that protective ventilation did not offer any significant advantage, compared with conventional ventilation, in terms of postoperative pulmonary dysfunction (pao / fio < mmhg or radiographic abnormalities) in patients undergoing vats (ahn et al. ) . further evidence supporting the use of protective ventilation in thoracic surgery patients comes from observational studies (blank et al. ; okahara et al. ) . in a review of data from thoracic surgery patients (blank et al. ) , there was an inverse relationship between tidal volume and the incidence of respiratory complications (or . , % ci . - . ); however, a low (physiologically appropriate) tidal volume had no protective effect in the absence of an adequate peep. a further study found that fio during one-lung ventilation was an independent predictor of the risk of postoperative pulmonary complications: the risk of such complications increased by % for each . increase in fio (okahara et al. ) . two small studies have examined the effect of protective ventilation on inflammatory responses following one-lung ventilation. a small randomized study in vats patients found that the combination of protective ventilation with a recruitment maneuver was associated with attenuated inflammatory responses, compared with either conventional ventilation or protective ventilation alone (kim et al. ) . by contrast, a non-randomized study in patients found no significant difference in local inflammatory cytokine responses between lung resection patients receiving protective or conventional ventilation (fiorelli et al. ) . recommendation : volatile anesthesia cannot be recommended over intravenous propofol administration in order to reduce postoperative complications, although there is evidence of a lower degree of both systemic and local inflammation when volatile anesthetics are used. level of evidence: good strength of recommendation: i the clinical impact of the choice of anesthetic in thoracic surgery patients is unclear because published studies differ markedly in their design, and have yielded conflicting findings. it has been suggested that only patients with severe surgical injuries (i.e., those undergoing pneumonectomy) may benefit clinically from the anti-inflammatory effects of volatile anesthetics (beck-schimmer et al. ) , but further studies are needed to clarify this. several studies have compared the use of volatile halogenated anesthesia and intravenous propofol administration, most of which have found that volatile anesthetics are associated with a lower degree of alveolar-and possibly systemic-inflammatory responses (de conno et al. ; de la gala et al. ; potocnik et al. ; schilling et al. ; sun et al. ) . in a meta-analysis of eight randomized controlled trials in patients undergoing one-lung ventilation, volatile anesthetics were associated with significant decreases, compared with intravenous anesthetics, in alveolar concentrations of inflammatory mediators (sun et al. ) . other studies have shown that, compared with propofol, the volatile halogenated anesthetics desflurane and sevoflurane reduce the expression of inflammatory mediators in bronchoalveolar lavage fluid, and the inflammatory response of alveolar epithelial cells to one-lung ventilation; these effects may be attributable to protective effects on the endothelial glycocalyx (de conno et al. ; de la gala et al. ; schilling et al. ; duthie ; schilling et al. ) . in contrast to the consistent evidence for antiinflammatory effects of volatile anesthetics, studies of the effects of volatile or intravenous anesthetics on postoperative complications have yielded conflicting results, possibly due to differences in study designs and the definition of postoperative complications. several studies have shown lower rates of postoperative pulmonary complications with volatile anesthetics, compared with propofol, in patients receiving one-lung ventilation (de conno et al. ; de la gala et al. ; potocnik et al. ). in the meta-analysis cited above (sun et al. ) , the relative risk of pulmonary complications in patients receiving inhalation anesthetics, compared with those receiving intravenous anesthetics, was . ( % ci . - . , p = . ), and the mean duration of hospitalization was approximately days shorter. however, a recent large, multicenter, randomized trial involving thoracic surgery patients found no significant difference in complication rates between patients receiving desflurane or propofol (beck-schimmer et al. ) . the proportion of patients with major complications was . % and . %, respectively, during hospitalization (hazard ratio [hr] . , % ci . - . ; p = . ) and . % and . %, respectively, at months (hr . , % ci . - . , p = . ). subgroup analyses suggested that only patients with severe surgical injuries benefit from the anti-inflammatory effects of volatile anesthetics (beck-schimmer et al. ) . recommendation : we recommend the use of a steroid neuromuscular blocking agent because of the availability of sugammadex, a reversal agent that, unlike acetylcholinesterase inhibitors, can be used even in cases of deep residual block, and reduces both extubation time and adverse events (bradycardia, postoperative nausea and vomiting, and postoperative residual paralysis). level of evidence: fair strength of recommendation: a deep neuromuscular blockade, with appropriate reversal prior to extubation, is recommended for patients undergoing thoracic surgery (umari et al. ; granell et al. ; végh et al. ) . complete reversal of neuromuscular blockade after surgery is important because it facilitates ventilator movements and expectoration, thereby decreasing the risk of postoperative respiratory complications (végh et al. ) . the use of a steroid nmba, such as rocuronium, with complete reversal, reduces the extubation time, compared with non-steroidal nmbas (carron et al. ; hristovska et al. ) . the use of a selective relaxant-binding agent such as sugammadex is more efficient and safer than neostigmine for reversing moderate or deep induced paralysis (flockton et al. ) . in a prospective observational study involving patients, the use of neostigmine for reversal of neuromuscular blockade did not improve oxygenation at the time of admission to the postanesthesia care unit, and was associated with a higher rate of atelectasis, compared with patients who did not receive neostigmine ( . % versus . %, or . , % ci . - . ) (sasaki et al. ). in addition, high-dose neostigmine (> μg/kg) was associated with longer stays in the post-anesthesia unit (mean versus min) and longer postoperative hospitalization (mean . versus . days). by contrast, a cochrane review found that patients receiving sugammadex for reversal of neuromuscular blockade had % fewer adverse events (risk ratio [rr] . , % ci . - . ), including less postoperative nausea and vomiting (ponv), bradycardia, or postoperative residual paralysis, than those receiving neostigmine (hristovska et al. ) . furthermore, sugammadex produced faster reversal of neuromuscular blockade than neostigmine, irrespective of the depth of blockade (hristovska et al. ) . recommendation : we recommend evaluation of the risk of postoperative nausea and vomiting, and the use of appropriate prophylaxis according to the level of risk, in all patients undergoing lung surgery. level of evidence: good strength of recommendation: a there is a lack of specific data on ponv after thoracic surgery. recently, a randomized controlled trial in patients undergoing vats procedures showed a lower incidence of nausea on the day of surgery in patients receiving preoperative treatment with methylprednisolone, compared with placebo-treated patients, although there was no difference between the groups on postoperative days and (bjerregaard et al. ) . the society for ambulatory anesthesia guidelines for the management of postoperative nausea and vomiting recommend preoperative evaluation of ponv risk using validated scores, such as the simplified apfel score, and the use of appropriate prophylaxis (gan et al. ). strategies to reduce the risk of ponv suggested in these guidelines include the use of propofol rather than volatile anesthetics, and minimization of intra-and postoperative opioids. prophylaxis against ponv is also recommended in eras guidelines (batchelor et al. ; ljungqvist and hubner ) . recommendation : we recommend avoiding the routine placement of a nasogastric tube, and early removal in patients in whom a nasogastric tube is used. level of evidence: fair strength of recommendation: a nasogastric tubes can be used to identify the esophagus, and to reduce gastric distension and risk of aspiration. there are no specific data in the literature on the use of nasogastric tubes in patients undergoing lung surgery, but several studies have identified perioperative nasogastric tube use as a risk factor for postoperative pulmonary complications after abdominal surgery (miskovic and lumb ) . guidelines published by the eras society recommend avoiding routine nasogastric tube placement in patients undergoing liver and gastric surgery (melloul et al. ; mortensen et al. ) , and the removal of nasogastric tubes before anesthesia reversal following elective colonic surgery (gustafsson et al. ) . recommendation : we recommend the early removal of urinary catheters to promote mobilization in patients undergoing lung surgery, including those receiving thoracic epidural catheters. level of evidence: fair strength of recommendation: a monitoring of urine output to evaluate perioperative aki is included in all classification systems for renal dysfunction (goren and matot ) , but a large prospective observational study found no association between intraoperative oliguria (urine output < . ml/kg/h) and postoperative aki in patients undergoing major noncardiac surgery (kheterpal et al. ) . higher rates of urinary retention after early urinary catheter removal (within - h after surgery), compared with later removal, have been reported in patients who received epidural analgesia for pain management after thoracotomy (allen et al. ; hu et al. ) , but other studies have found no association between early removal and increased complication rates (chia et al. ; ladak et al. ; young et al. ) . a systematic review recommended early removal of the urinary catheter, on the first postoperative day, in order to promote mobilization and reduce pain and discomfort (zaouter and ouattara ) . early removal of urinary catheters is one of the overall eras items intended to promote mobilization and ambulation (ljungqvist and hubner ) . in addition, the eras guidelines for lung surgery strongly recommend not to routinely use urinary catheterization solely to monitor urine output in patients with normal kidney function, but to use a urinary catheter in patients receiving epidural analgesia (batchelor et al. ). pre-emptive analgesia recommendation : we recommend the use of preemptive locoregional analgesia as part of a multimodal analgesic approach for thoracic surgery. systemic opioids, nonsteroidal anti-inflammatory drugs, and paracetamol have shown no evidence of benefit when used as preemptive analgesics. level of evidence: fair strength of recommendation: a multiple studies in various surgical settings have shown that the use of pre-emptive locoregional analgesia attenuates postoperative pain scores, decreases supplemental analgesic requirements, and prolongs the average time to first use of rescue analgesia (nosotti et al. ; ong et al. ; yang et al. ) . as a result, preemptive locoregional analgesia is recommended as part of a multimodal analgesic strategy for thoracic surgery patients. there is currently no evidence to support the use of one form of analgesia (opioids, nonsteroidal antiinflammatory drugs [nsaids] , paracetamol, etc) over another. recommendation : currently, there are no elements to suggest the routine perioperative use of gabapentinoids in patients undergoing thoracic surgery, but their use can be effective in a comprehensive multimodal analgesia protocol. level of evidence: poor strength of recommendation: i studies evaluating gabapentin in thoracic surgery patients are limited, and have yielded conflicting results. a randomized, active placebo (lorazepam)-controlled, trial in a mixed surgical cohort found that perioperative gabapentin administration until the third postoperative day had no effect on the time to cessation of acute postoperative pain (hr . , % ci . - . , p = . ), but had a moderate effect on the time to opioid cessation (hr . , % ci . - . , p = . ) (hah et al. ) . two further studies found no benefit of gabapentin treatment, in terms of postoperative pain relief, opioid consumption, and the incidence of chronic pain months after thoracotomy (grosen et al. ; kinney et al. ); similarly, a small randomized trial found that gabapentin had no significant effect, compared with placebo, on the incidence or severity of post-thoracotomy shoulder pain (huot et al. ). on the basis of such findings, a review concluded that there is no evidence to support the role of a single preoperative oral dose of gabapentin in reducing pain scores or opioid consumption following thoracic surgery (zakkar et al. ) . more recently, a randomized, placebo-controlled, trial involving patients concluded that pregabalin administration before thoracotomy is effective in reducing postoperative pain, but in this study pregabalin did not form part of a multimodal analgesic strategy (sattari et al. ) . in contrast to the studies described above, there are data to support the use of pregabalin or gabapentin as part of a multimodal analgesic strategy to improve postoperative pain and reduce opioid consumption (mishriky et al. ; tiippana et al. ). in a systematic review of studies in surgical patients, pregabalin was associated with significant reductions, compared with placebo, in pain scores and opioid consumption h after surgery; however, it was also associated with significantly higher rates of sedation, dizziness, and visual disturbances (mishriky et al. ) . current guidelines for the management of postoperative pain issued by the american society of anesthesiology recommend the use of pregabalin and gabapentin as part of a postoperative multimodal analgesia regimen: this is considered a strong recommendation with a moderate level of evidence (chou et al. ) . recommendation : we suggest intraoperative intravenous administration of ketamine to reduce postoperative pain after thoracic surgery. there is no evidence about the best dose and timing of administration of ketamine. level of evidence: fair strength of recommendation: b a systematic review of randomized controlled trials including patients found that the use of intravenous ketamine for postoperative pain management resulted in consistent reductions, compared with controls, in opioid consumption, and increases in the time to first use of analgesic (laskowski et al. ). the greatest benefits were seen in patients undergoing thoracic, upper abdominal or major orthopedic surgery. based on such evidence, us guidelines for the management of postoperative pain recommend evaluating the use of intravenous ketamine in multimodal analgesia regimens (chou et al. ). however, there is currently no evidence to determine the optimal dosage of perioperative ketamine. there is evidence that a single dose of ketamine may be inadequate, and therefore some authors recommend the administration of a pre-operative bolus and intraoperative maintenance dosing (mishriky et al. ; himmelseher and durieux ) . one randomized controlled trial in patients undergoing major abdominal surgery has found that a reduced infusion regimen ( . mg/kg/h infusion following a saline bolus) and a conventional low-dose regimen ( . mg/kg bolus and . mg/kg/ h infusion for h) were comparable in analgesic efficacy, in terms of postoperative opioid consumption and rates of hyperalgesia (bornemann-cimenti et al. ). other authors have suggested that ketamine can be administered in a series of boluses depending on the duration of the procedure (bell et al., ) . ketamine should be used with caution in elderly patients. recommendation : we suggest intraoperative intravenous administration of magnesium sulfate to reduce postoperative pain after thoracic surgery. level of evidence: fair strength of recommendation: b magnesium blocks n-methyl-d-aspartate (nmda) receptors, which mediate central sensitization to pain and thus contribute to postoperative pain and hyperalgesia (ko et al. ; wilder-smith et al. ) . hence, many trials have investigated the use of intravenous magnesium to reduce postoperative pain (albrecht et al. ). in a meta-analysis of randomized trials including over surgical patients, magnesium treatment was associated with significant improvements, compared with controls, in pain at rest and on movement, and with reductions in postoperative opioid consumption (de oliveira jr et al. ) . a further meta-analysis of trials found that perioperative magnesium administration reduced opioid consumption, and to a lesser extent pain scores, during the first h after surgery (albrecht et al. ) . however, other studies have reported that intravenous magnesium does not reduce postoperative pain and opioid consumption (ko et al. ; wilder-smith et al. ) . a study in gynecological surgery patients suggests that variability in the efficacy of magnesium may be related to baseline magnesium levels: low preoperative magnesium levels were significantly (p < . ) associated with increased postoperative pain (ulm et al. ). clinical trials have consistently shown that intravenous magnesium has a favorable safety profile, even at high doses (albrecht et al. ; de oliveira jr et al. ; fawcett et al. ) . recommendation : there is no evidence to suggest the routine use of α -agonists as part of a multimodal analgesia regimen to reduce postoperative pain after thoracic surgery. there is no consensus on the best timing and schedule for administration of these drugs. level of evidence: fair strength of recommendation: i a meta-analysis of studies involving almost surgical patients showed that both dexmedetomidine, and to a lesser extent clonidine, reduce postoperative opioid consumption and postoperative nausea, compared with controls (blaudszun et al. ). however, dexmedetomidine was associated with an increased risk of postoperative bradycardia, while clonidine increased the risks of both intraoperative and postoperative hypotension, although none of these adverse events required specific interventions, and recovery times were not prolonged (blaudszun et al. ) . furthermore, in a rct involving , patients undergoing noncardiac surgery, clonidine was associated with an increased rate of important hypotension and nonfatal cardiac arrest, compared with placebo (devereaux et al. ) . dexmedetomidine is currently approved in italy only for sedation, and thus cannot be recommended for analgesic use in italian settings. recommendation : we suggest considering the use of intravenous steroids as part of a multimodal approach to reduce peripheral sensibilization of inflammatoryinduced pain in patients undergoing thoracic surgery. adverse effects of single doses of steroids are of trivial clinical impact. level of evidence: fair strength of recommendation: c a meta-analysis of studies including almost patients showed that a single perioperative dose of intravenous dexamethasone resulted in significant reductions in pain scores and opioid use, and was associated with shorter stays in the post-anesthesia recovery room, compared with placebo or antiemetic treatment (waldron et al. ) . a further meta-analysis of randomized controlled trials found that preoperative dexamethasone, at doses > . mg/kg, had a greater analgesic effect than perioperative treatment, although there was no difference in los between the two dosing schedules (de oliveira jr et al. ) . in a randomized, placebo-controlled trial in patients undergoing uterine artery embolization, administration of dexamethasone h before surgery resulted in significant reductions in postoperative concentrations of cortisol and inflammatory mediators, and less pain and severe ponv, compared with placebo . although long-term glucocorticosteroid treatment is associated with significant adverse events such as hyperglycemia, increased infection risk, bleeding, and recurrence of disease in cancer patients, such events do not appear to be a concern when dexamethasone is used as part of a multimodal analgesic strategy. studies have generally shown few serious adverse events, and no delay in wound healing, following single perioperative doses of dexamethasone in surgical patients (de oliveira jr et al. ; holte and kehlet ; snall et al. ; thoren et al. ). recommendation : we recommend the use of intravenous nonsteroidal anti-inflammatory drugs (nsaids) to reduce peripheral sensitization to inflammationinduced pain in patients undergoing thoracic surgery. combined use of nsaids and paracetamol may give a further analgesic advantage. level of evidence: good strength of recommendation: a a meta-analysis of trials evaluating the efficacy of nsaids in surgical patients found that these drugs were effective in reducing a composite endpoint of pain intensity scores, supplemental analgesic consumption, and time to first analgesic consumption, compared with controls (effect size . , % ci . - . ) (ong et al. ) . however, although preoperative administration reduced opioid consumption and lengthened the time to first use of rescue analgesic, it reduced postoperative pain scores in only six of randomized controlled trials. nsaid treatment has also been reported to reduce opioid-related adverse events such as ponv (gan et al. ; maund et al. ) . there is evidence that the analgesic effects of nsaids on postoperative pain are potentiated by concomitant administration of paracetamol (ong et al. ) . a number of studies have examined the efficacy and safety of ketorolac in surgical patients. a meta-analysis of randomized, double-blind, trials in patients undergoing major abdominal surgery, neurosurgery, or orthopedic surgery showed that ketorolac does not increase clinically significant bleeding, compared with controls (or . , % ci . - . , p = . ); however, there appeared to be a slight trend toward more bleeding with higher doses (> mg) (gobble et al. ) . these results suggest that increases in bleeding time observed with ketorolac are not clinically relevant, and that there does not appear to be a significant risk of postoperative bleeding with ketorolac, compared with controls. low doses of ketorolac ( and mg) appear to be equivalent in analgesic efficacy to ketorolac mg. although no studies were identified that directly compared the analgesic efficacy of different doses of ketorolac in thoracic surgery patients, a double-blind, randomized, controlled trial in patients with moderate or severe acute pain treated in the emergency department found no significant differences in pain score reductions or adverse event profiles between patients receiving ketorolac mg, mg, or mg (motov et al. ) . these findings are consistent with those of a prospective, randomized, non-inferiority trial in patients undergoing spine surgery, which found that ketorolac mg was not superior to mg for postoperative pain management (duttchen et al. ) . based on such findings, we suggest the use of low doses of intravenous ketorolac ( mg - times a day) for a maximum of days; however, we suggest caution in using ketorolac in elderly patients (> years). ketorolac can be also administered orally ( mg - times a day) for a maximum of days. recommendation : we recommend the use of locoregional anesthesia for intraoperative and postoperative pain management. level of evidence: poor strength of recommendation: a recommendation : we recommend the use of thoracic epidural analgesia in high-risk patients or in major surgical procedures where the parietal pleura (e.g., chest wall resection) is violated (i.e., thoracotomy, thoracosternotomy, chest wall resection). level of evidence: fair strength of recommendation: a recommendation : we recommend thoracic paravertebral block for vats, as part of a multimodal approach. level of evidence: good strength of recommendation: a recommendation : we recommend thoracic paravertebral block in preference to thoracic epidural analgesia in patients with known or suspected coagulopathy. level of evidence: fair strength of recommendation: a multiple clinical trials have shown that, in patients undergoing open thoracotomy or other major surgical procedures, thoracic epidural analgesia (tea) is superior to intravenous opioid administration in terms of postoperative pain relief, length of hospital stay, and incidence of postoperative complications (hazelrigg et al. ; block et al. ; della rocca et al. ; meierhenrich et al. ; wheatley et al. ) . however, in patients undergoing vats procedures, less invasive procedures such as paravertebral block (tpvb) appear to be at least as effective as tea (kosinski et al. ; steinthorsdottir et al. ). there is moderate-quality evidence that tea may reduce the risk of developing persistent postoperative pain - months after thoracotomy (weinstein et al. ) . clinical trials and meta-analyses have consistently shown that tea and tpvb are comparable in efficacy for the management of postoperative pain in thoracotomy patients (baidya et al. ; ding et al. ; júnior ade et al. ; kobayashi et al. ; raveglia et al. ; scarfe et al. ; yamauchi et al. ) . there is also clear evidence that tpvb is associated with fewer intraoperative complications than tea, with improved hemodynamic stability and less need for intravenous colloid therapy (pintaric et al. ) , probably due to unilateral segmental block. compared with tea, tpvb is associated with lower rates of minor postoperative complications such as urinary retention, nausea and vomiting, and hypotension (baidya et al. ; ding et al. ; raveglia et al. ; scarfe et al. ; biswas et al. ; gulbahar et al. ; yeung et al. ) , and the majority of studies have shown no significant differences in pulmonary function and pulmonary complications between the two procedures (ding et al. ; biswas et al. ; blackshaw et al. ) . furthermore, some studies have found that epidural anesthesia may be associated with serious complications such as epidural hematoma, epidural abscess, and nerve injury: the risk of these potentially devastating complications may be reduced with tpvb, particularly in patients with known or suspected coagulopathy (davies et al. ; horlocker et al. ) . although data from randomized controlled trials are lacking, several studies have shown that tpvb is associated with a low risk of bleeding complications (naja and lönnqvist ; katayama et al. ; okitsu et al. ) . in some studies, tea has also been associated with higher rates of procedural failure, compared with tpvb (kosinski et al. ; ding et al. ; gulbahar et al. ; hermanides et al. ) . there are no studies comparing the efficacy and safety of tpvb when performed by the anesthetist before the beginning of surgery, or by the surgeon under direct vision at the end of surgery. together, the available evidence indicates that tpvb and tea provide comparable analgesia in thoracotomy patients, but tpvb offers advantages in terms of its technical simplicity and better safety profile. tpvb is therefore a valid alternative to tea, particularly in patients who are not suitable for tea. recommendation : we suggest that intercostal nerve blockade should be considered only as a second choice for analgesia after thoracic surgical procedures. level of evidence: good strength of recommendation: c several studies have shown that intercostal nerve blockade is not comparable in terms of analgesia to tea or tpvb in thoracic surgery patients (meierhenrich et al. ; joshi et al. ; wurnig et al. ) . this is at least partially due to the shorter duration of analgesia achievable with intercostal nerve blockade (wurnig et al. ; linden et al. ) , although a recent study has shown that this can be prolonged by a combination of intravenous and perineural dexamethasone (maher et al. ) . as a result, we suggest that intercostal nerve blockade should be considered only as a second choice for analgesia after thoracic surgical procedures, because more effective techniques are available. suitable alternatives include tea and (especially for vats) tpvb, and possibly erector spinae plane blockade and serratus anterior plane blockade (see below). recommendation : we suggest erector spinae plane block as part of a multimodal analgesia for thoracic surgery, especially for vats. level of evidence: poor strength of recommendation: b erector spinae plane blockade (espb) is a recently developed fascial block that allows sensory blockade over both the posterior and anterolateral thorax. it is relatively safe and simple to administer, because it is performed in a musculofascial plane away from the neuraxis, with minimal risk of serious complications (other than local anesthetic systemic toxicity) (forero et al. ; forero et al. ) . in an initial series of seven patients with post-thoracotomy pain syndrome, who underwent espb as part of a multimodal analgesia strategy, all patients experienced immediate pain relief and four experienced prolonged pain relief for weeks or longer (forero et al. ) . randomized controlled trials are needed to confirm the effectiveness of this technique in thoracic surgery. recommendation : we suggest the use of fascial pain blocks as part of multimodal analgesia for thoracic surgery, particularly for vats. level of evidence: fair strength of recommendation: b serratus anterior plane blockade (spb) provides good analgesia, comparable to that provided by tea, for acute post-thoracotomy pain, while maintaining a more stable blood pressure (khalil et al. ; okmen and okmen ) . like espb, spb offers a less invasive approach in patients with contraindications to more invasive techniques (park et al. ) . a recent placebo-controlled trial has suggested that spb reduces postoperative pain and opioid consumption during the first h after vats , but further studies are needed to confirm the potential of the technique in thoracic surgery (park et al. ; okmen and okmen ) . nevertheless, we suggest the use of fascial plane blocks as part of multimodal analgesia for thoracic surgery, particularly for vats patients. a recent study, involving patients undergoing minimally invasive thoracic surgery, has found that espb provides superior quality of recovery, with lower morbidity and better pain control, compared with spb (finnerty et al. ) . recommendation : we suggest considering the use of adjuvants (i.e., opioids, dexamethasone) when locoregional anesthesia is performed, because the use of adjuvants can potentiate and prolong the effect of local anesthetics. level of evidence: poor strength of recommendation: c low-to moderate-quality evidence suggests that, when used as an adjuvant to peripheral nerve blockade in upper limb surgery, both perineural and intravenous dexamethasone may prolong the duration of sensory blockade and reduce postoperative pain intensity and opioid consumption (pehora et al. ) . specific evidence regarding the use of dexamethasone as an adjuvant in thoracic anesthesia is not available. recommendation : we suggest considering the use of a single large-bore chest tube instead of a double tube after thoracic surgery. insertion of more than one chest tube may be considered in selected cases (e.g., bilobectomy or bleeding patients). level of evidence: poor strength of recommendation: c a meta-analysis of nine studies, including patients undergoing pulmonary resection by vats, found that approximately % of patients did not have a chest tube inserted. in these patients, postoperative pain scores and los were significantly reduced, compared with patients who had a chest tube inserted, with no difference in day morbidity or re-intervention rates between the two groups (li et al. ) . these findings suggest that omitting the chest tube is safe and feasible in selected patients. in patients in whom a chest tube is considered necessary, there is consistent evidence that the use of a single large-bore tube to remove both air and fluid is as effective as the use of double chest tubes (filosso et al. ; zhou et al. ) . furthermore, comparative studies and meta-analyses have shown that, compared with double chest tubes, the use of a single chest tube is associated with less pain, decreases in the amount and duration of drainage, and reduced healthcare costs (zhou et al. ; okur et al. ; zhang et al. ) . recommendation : we suggest considering the use of digital chest drainage systems to promote early mobilization of the patient. level of evidence: fair strength of recommendation: b external pleural suction is commonly used after lung resection to promote lung expansion and minimize the duration of air leakage (lang et al. ; leo et al. ). the airintrial, which involved lung resection patients, found that the incidence of prolonged air leakage (defined as still having a chest drain in place days after surgery) was not significantly different in patients in whom external suction was used, compared to those without suction ( % versus %, respectively, p = . ), although a trend toward significance favoring the use of external suction was seen in patients undergoing anatomical resection ( . % versus . %, p = . ) (leo et al. ). however, a subsequent meta-analysis of eight randomized, controlled, trials found that, although the use of suction reduced the incidence of postoperative pneumothorax, it was associated with significant increases in los, duration of chest tube drainage, and air leak duration (lang et al. ) . the effect of digital chest drainage systems on outcomes after pulmonary resection was studied in a trial including patients who were randomized to either analog or digital drainage systems (de waele et al. ) . the use of digital systems had no significant effect on pleural fluid formation, but was associated with a significantly lower incidence of prolonged air leakage, compared with analog systems ( . % versus %, respectively, p = . ). there was also a trend toward a shorter duration of chest tube drainage with digital systems, but this did not reach statistical significance. by contrast, an international randomized trial involving lung resection patients found that, compared with traditional drainage systems, digital drainage systems were associated with a significantly shorter duration of chest tube placement, shorter hospital stays, and higher satisfaction scores (pompili et al. ) . we suggest using digital chest drainage systems, rather than traditional water seal devices, in order to promote early mobilization. recommendation : the routine use of drainage with suction is not recommended in the absence of complications, provided there is full re-expansion of the residual parenchyma after lung resection. level of evidence: good strength of recommendation: d in a prospective randomized trial involving lung resection patients with full parenchymal re-expansion, suction drainage was found to be less effective than nonsuction drainage in terms of time to chest tube removal ( . days versus . days, respectively, p = . ) and incidence of prolonged air leakage ( . % versus . %, p = . ) (gocyk et al. ). however, no-suction drainage was associated with a significantly higher incidence of asymptomatic residual air spaces, compared with suction drainage ( . % versus . %, respectively, p = . ). other studies have found that suction drainage does not reduce prolonged air leakage or duration of drainage in patients without complications such as large expiratory leaks (alphonso et al. ; brunelli et al. ; cerfolio et al. b; coughlin et al. ; marshall et al. ) . recommendation : we suggest removing chest tubes in lung resection patients when liquid output is ≤ cm /kg/ h of serous fluid. level of evidence: poor strength of recommendation: b in a prospective observational study in patients who underwent posterolateral thoracotomy for lung resection, early removal of the chest tube resulted in an statistically significant improvement in static and dynamic pain scores, and in better functional respiratory outcome (dokhan and abd elaziz ) . the criteria for chest tube removal in this study were resolution of air leaks and fluid drainage ≤ ml/day, provided that the drained fluid was macroscopically non-chylous and nonhemorrhagic. several authors have suggested that a cut-off of - cm /kg of serous liquid is a good option because this is within the normal physiological range of daily pleural fluid filtration, and is suitable for early chest drain removal without increasing complications and re-admission rates (brunelli et al. ; mesa-guzman et al. ; miserocchi ) . based on this clinical evidence, we suggest chest tube removal when fluid output is ≤ cm /kg/ h of serous liquid. recommendation : we do not recommend systematic icu admission after thoracic surgery. level of evidence: poor strength of recommendation: d postoperative pulmonary complications occur in as many as - % of patients after major thoracic surgery, and are associated with prolonged los, and poor longterm outcomes (brunelli et al. ; agostini et al. ) . although vats procedures are associated with a reduced incidence of postoperative pulmonary complications, compared with thoracotomy, such complications still lead to significant short-term morbidity and mortality in these patients (agostini et al. ) . implementation of appropriate postoperative medical strategies, and monitoring and treatment of high-risk patients in dedicated care units, are aimed at improving postoperative outcomes (brunelli et al. ). currently, many centers routinely admit patients to the icu after surgery, whereas in others icu admission is reserved for patients requiring ventilator support, emergency treatment of perioperative complications, or both (brunelli et al. ). multiple preoperative factors can influence the likelihood of postoperative admission to the icu in patients undergoing lung resection (brunelli et al. ; agostini et al. ; ferguson et al. ; brunelli et al. ; brunelli et al. ; cywinski et al. ; dulu et al. ; keegan et al. ; mccall et al. ; pinheiro et al. ) . these include open thoracotomy, rather than vats (brunelli et al. ; dulu et al. ; mccall et al. ; pinheiro et al. ) , more extensive resection (cywinski et al. ), and impaired preoperative lung function or pulmonary comorbidities such as chronic obstructive pulmonary disease (copd) (brunelli et al. ; cywinski et al. ; pinheiro et al. ) . however, there is evidence that routine admission of thoracic surgery patients to the icu does not reduce mortality rates (brunelli et al. ) , and may result in inappropriate icu admission, increased healthcare costs, delayed mobilization, and increased risks of nosocomial infections (brunelli et al. ). to date, no studies have compared outcomes in thoracic surgery patients admitted to icus, high dependency units (hdus), or surgical wards (brunelli et al. ) , and there are no data to identify patients who might benefit from postoperative intensive care, or to determine the necessary degree of postoperative care for an individual patient. for these reasons, we do not recommend systematic icu admission after thoracic surgery. we suggest postoperative admission of high-risk patients to dedicated care units (hdus or dedicated thoracic surgical wards). these facilities may allow icu admission to be limited to patients requiring support for organ failure. identification of high-risk patients, and management of their postoperative course, should be planned according to the number and type of complications, and the available resources. ers/ests working group recommendations (brunelli et al. ) state that lung resection patients should be managed in a dedicated thoracic surgical ward or respiratory hdu (scala et al. ) if available, and that icu admission should be limited to patients requiring organ support. the appropriateness of this policy, and its influence on early outcomes, is still controversial. recommendation : we recommend that, in adult patients undergoing thoracic surgery, oral intake, including clear liquids, can be initiated - h after surgery, in the absence of nausea and vomiting. oral intake should, however, be adapted to individual tolerance. level of evidence: fair strength of recommendation: a although it has traditionally been believed that enteral nutrition should not be resumed in postoperative surgical patients until normal bowel function has been restored, studies have consistently shown that early resumption of oral feeding is safe and well tolerated, and is associated with decreased wound morbidity, fewer septic complications, and less weight loss, compared with delayed enteral nutrition (warren et al. ). hence, early oral feeding has been endorsed in a number of guidelines in different surgical settings, including the eras/ests lung surgery guidelines (batchelor et al. ; muehling et al. ; smith et al. ; weimann et al. ; nelson et al. ; nygren et al. ) . in patients undergoing lung resection, early resumption of oral feeding does not depend on the surgical technique (open versus minimally invasive) (batchelor et al. ; smith et al. ; jones et al. ) . hence, we recommend that, in the absence of nausea and vomiting, oral intake, including clear liquids, can be initiated - h after surgery in adult patients undergoing elective pulmonary lobectomy. oral intake should, however, be adapted according to the individual patient's tolerance and the type of surgery carried out. recommendation : we recommend early mobilization of patients within the first h after both minor and major thoracic surgery. level of evidence: fair strength of recommendation: a recommendation : we recommend a physiotherapy program after thoracic surgery. level of evidence: fair strength of recommendation: a delayed mobilization in patients undergoing lung resection is predictive of increased postoperative morbidity and delayed hospital discharge (das-neves-pereira et al. ; rogers et al. ) , and hence early ambulation and physiotherapy have been recommended irrespective of the surgical approach (nygren et al. ) . several studies have shown that eras programs that include early ambulation are feasible in lung resection patients, and can improve outcomes (das-neves-pereira et al. ; cywinski et al. ; dulu et al. ; keegan et al. ; mccall et al. ; pinheiro et al. ; scala et al. ; warren et al. ; nygren et al. ; jones et al. ; rogers et al. ; dumans-nizard et al. ; kendall et al. ; martin et al. ). there is evidence from a propensity score matching study in patients that patients undergoing vats lung resection require less physiotherapy than those undergoing open thoracotomy (agostini et al. ) . recommendation : we suggest considering daily chest radiographs only in selected cases under specific clinical indications. level of evidence: good strength of recommendation: c two meta-analyses have concluded that routine chest radiographs offer no advantage over clinically indicated radiographs in cardiothoracic surgery patients (sepehripour et al. ; reeb et al. ) . in one of these analyses, pulmonary pathology was detected in - % of routine chest radiographs, compared with % (p = . ) of radiographs that were taken only when clinically indicated (sepehripour et al. ). furthermore, a prospective comparative study in cardiothoracic surgery patients in an icu/post-icu ward showed that the elimination of daily routine chest radiographs reduced the total number of radiographs per patient per day in the icu, but had no effect on chest radiography practice in the post-icu ward (mets et al. ). there is also evidence that chest radiographs are poor predictors of postoperative complications in patients undergoing lung resection. in a retrospective chart review of patients undergoing vats lung resection, the sensitivity and specificity of chest radiographs for pulmonary complications ranged from - % and - %, respectively, depending on the reviewer, and there was only slight overall agreement between reviewers (troquay et al. ) . for these reasons, we suggest considering daily chest radiographs only in selected patients. bedside, lung ultrasound may also be useful in some patients (chiappetta et al. ; touw et al. ) . recommendation : we do not recommend the routine use of either continuous positive airway pressure (cpap) or non invasive ventilation (niv) to prevent postoperative pulmonary complications, prolonged length of stay, and mortality (both in icu and in hospital) in patients undergoing major thoracic surgery. cpap or niv could be considered on a case by case basis in selected high-risk patients. level of evidence: poor strength of recommendation: d postoperative pulmonary complications are the principal cause of mortality and morbidity after lung resection (torres et al. ) . acute respiratory failure has been reported to occur in - % of patients after lung resection (lorut et al. ) , and overall pulmonary complication rates have been reported to be as high as % (nery et al. ) . because prolonged invasive mechanical ventilation has been shown to be an important risk factor for such complications, prophylactic non-invasive ventilation (niv) has been proposed as a means of reducing this intubation-related risk (riviere et al. ) . although niv offers the potential to improve lung function, unload respiratory muscles and reduce postoperative hypoxemia and atelectasis, randomized controlled trials have not shown consistent evidence that the addition of either niv or continuous positive airway pressure (cpap) to standard medical therapy offers no significant benefit (lorut et al. ; nery et al. ; aguilo et al. ; barbagallo et al. ; danner et al. ; garutti et al. ; liao et al. ; perrin et al. ). in a recent cochrane review of eight trials involving a total of patients, there were no significant differences between patients receiving niv and control groups in terms of pulmonary complications (rr . , % ci . - . ), intubation rates (rr . , % ci . - . ), mortality (rr . , % ci . - . ), length of icu stay (mean difference − . days, % ci − . - . ) or length of hospital stay (mean difference − . days, % ci − . - . ) (torres et al. ) . however, the quality of the evidence was poor, due to the limited number of studies, heterogeneity of the patient populations and of the scheduled ventilator treatment, small sample sizes, and low frequencies of outcomes (torres et al. ) . however, it could be speculated that selected patients at higher risk of developing pulmonary complications (e.g., obese patients or patients with copd, obese, chronic heart failure, or chronic hypersecretion) are likely to benefit from the administration of cpap or niv in addition to standard medical and physiotherapy, consistent with the established use of these techniques for the prevention of post-extubation failure (rochwerg et al. ; scala and pisani ) . recommendation : we suggest the use of niv or cpap to treat acute respiratory failure complicating thoracic surgery. level of evidence: poor strength of recommendation: b one small study (n = ) in patients with acute hypoxemic respiratory insufficiency after lung resection found that the addition of niv to standard therapy was associated with significant reductions, compared with controls, in the need for endotracheal mechanical ventilation ( . % versus %, respectively, p = . ) and -day mortality ( . % versus . %, p = . ); however, there were no differences in length of icu and hospital stays between the two groups (auriant et al. ). on the basis of these findings, it is suggested that niv or cpap could be used in the management of acute respiratory insufficiency following thoracic surgery, but it should be noted that the availability of only a single study limits the strength of this recommendation. however, it should be remembered that niv is associated with a number of adverse events (e.g., poor compliance, leaks, sensory dysfunction, hypersecretion, unprotected airways, patient-ventilator asynchronies) that are likely to be associated with the need for intubation (scala and pisani ) . furthermore, niv failure occurs in approximately % of patients, and is associated with increased rates of nosocomial pneumonia and postoperative mortality (riviere et al. ). in a prospective study of patients admitted to the icu after lung resection or pulmonary thrombendarterectomy, four independent risk factors for niv failure within the first h were identified: increased respiratory rate (or . , % ci . - . ), increased sequential organ failure assessment (sofa) score (or . , % ci . - . ), number of fiberoptic bronchoscopies performed (or . , % ci . - . ), and number of hours on niv (or . , % ci . - . ) (riviere et al. ) . risk stratification of candidates for thoracic surgery is likely to be useful for selecting sub-sets of patients who may benefit from either prophylactic or therapeutic niv. these might include patients with copd or severely impaired respiratory function (danner et al. ; garutti et al. ; perrin et al. ) and obese patients (stephan and berard ) . further research is needed to clarify the potential usefulness of prophylactic or therapeutic niv in such groups, and to determine the most efficacious scheduled regimens. recommendation : we suggest considering the use of high-flow nasal cannula oxygen therapy as an alternative or integrative support to cpap or niv to prevent or treat acute respiratory failure complicating thoracic surgery. level of evidence: poor strength of recommendation: c high-flow nasal cannula (hfnc) oxygen therapy is considered to be a non-invasive form of respiratory assistance for spontaneously breathing hypoxemic patients with early stages of acute respiratory failure. this technique delivers high inspiratory flow rates (up to l/ min) that match the oxygen demands of ventilated patients; in addition, hfnc oxygen therapy offers good comfort, efficient wash-out of the upper airway and clearance of co , provision of adequate humidification, and reduction of respiratory effort (although this latter effect is less than can be achieved with niv) (stephan and berard ) . a post hoc analysis of a large randomized trial in obese patients undergoing major thoracic surgery investigated the impact of hfnc on rates of treatment failure, defined as the need for re-intubation or switching to alternative treatments, or premature discontinuation (stephan and berard ) . this analysis found that hfnc is not inferior to niv in terms of treatment failure rates ( . % versus . %, respectively, p = . ), icu mortality ( . % versus . %, p = . ), length of icu stay (median . versus . days, p = . ), or length of hospital stay (median . versus . days, p = . ). however, skin breakdown at h was significantly more common with niv than with hfnc ( . % versus . %, respectively, p = . ). on the basis of these findings, it is suggested that hfnc may be considered as an alternative to cpap or niv for the prevention or treatment of acute respiratory failure complicating thoracic surgery. it should be noted that the lack of corroborating randomized trials limits the strength of this recommendation. however, the demonstration of the effectiveness and acceptability of hfnc in milder degrees of acute (particularly hypoxemic) respiratory failure is consistent with the potential use of hfnc in patients with postoperative pulmonary complications following major thoracic surgery (rochwerg et al. ) . it should also be noted that the integrated use of hfnc during times off niv could be an effective strategy, especially in patients showing poor tolerance to the niv interface (scala and pisani ; longhini et al. ) . recommendation : for prophylaxis and management of atrial fibrillation after thoracic surgery, we recommend reference to the society of thoracic surgery (sts) guidelines. level of evidence: good strength of recommendation: a postoperative cardiac arrhythmias, particularly atrial fibrillation, occur in approximately - % of patients undergoing major noncardiac thoracic surgery, including both thoracotomy and vats lobectomy (garner et al. ; onaitis et al. ; park et al. ). potential risk factors for atrial fibrillation include increasing age, male gender, hypertension, comorbidities such as copd or heart failure, extent of lung resection, and postoperative infection (batchelor et al. ; garner et al. ; onaitis et al. ) . postoperative atrial fibrillation can lead to hemodynamic instability, potentially prolonging icu and hospital stay (frendl et al. ) . furthermore, atrial fibrillation may persist beyond hospital discharge in a proportion of patients, and some patients may require long-term anticoagulation (garner et al. ) . it is recommended that the society of thoracic surgery (sts) guidelines for the prophylaxis and management of atrial fibrillation (fernando et al. ) should be followed in patients undergoing pulmonary lobectomy. these guidelines recommend pharmacological prophylaxis with β-blockers or diltiazem: amiodarone is not recommended for patients undergoing pneumonectomy. electrical cardioversion is recommended for patients who develop hemodynamically unstable atrial fibrillation, and for patients with symptomatically intolerable atrial fibrillation in whom treatment with metoprolol (or diltiazem for patients with severe copd), alone or followed by flecainide, is ineffective. anticoagulation with aspirin (for patients at low thromboembolic risk), or warfarin or heparin (for high-risk patients), is recommended for patients with persistent or recurrent atrial fibrillation after h of metoprolol treatment (fernando et al. ) . it should be noted, however, that to date no scoring system has been developed to identify lung resection patients at high risk of atrial fibrillation, although promising results have been obtained with the chads score (kotova et al. ) . furthermore, there is little evidence that prophylaxis for atrial fibrillation improves outcomes after thoracic surgery [ ]. anesthesia in patients undergoing thoracic surgery is a complex undertaking that requires a multidisciplinary approach to risk assessment, perioperative monitoring, and postoperative care. recognizing this, the pacts group has sought to identify critical issues in the preoperative, intraoperative and postoperative care of patients undergoing lung resection, and to provide appropriate guidance. wherever possible, our recommendations are based on good-quality supporting evidence: where such evidence is limited, the recommendations are framed as suggestions or possibilities for consideration. in a few cases, there was insufficient evidence to make formal recommendations: in such cases, our guidance is based on expert opinion, supported by published literature where possible. our literature reviews and discussions highlighted the importance of the choice of anesthetic and lung isolation procedure, attention to airway management, and comprehensive monitoring of vital signs, hemodynamics, neuromuscular blockade, and depth of anesthesia, for achieving optimal outcomes. postoperatively, a multi-modal analgesic strategy that includes pre-emptive analgesia and locoregional blockade is required for optimal pain control. finally, decisions on icu care, chest drainage, and other interventions should be individualized for each patient. the eras lung surgery guidelines (batchelor et al. ) were published while our recommendations were in development. we believe that these recommendations extend and complement those of the eras guidelines for a number of reasons. first, aspects of anesthesiologic care such as depth of anesthesia monitoring, neuromuscular blockade, and hemodynamic monitoring are covered in greater detail than in the eras guidelines. in addition, our recommendations focus specifically on elective surgery for lung cancer. it is hoped that these recommendations will help to achieve optimal postoperative outcomes in the greatest number of thoracic surgery patients. further refinement of our recommendations can be anticipated as the literature continues to evolve. postoperative pulmonary complications and rehabilitation requirements following lobectomy: a propensity score matched study of patients undergoing video-assisted thoracoscopic surgery versus thoracotomy risk factors and short-term outcomes of postoperative pulmonary complications after vats lobectomy noninvasive ventilatory support after lung resectional surgery the risk of acute kidney injury from fluid restriction and hydroxyethyl starch in thoracic surgery comparison between conventional and protective one-lung ventilation for ventilator-assisted thoracic surgery peri-operative intravenous administration of magnesium sulphate and postoperative pain: a meta-analysis european society of anaesthesiology evidence-based and consensus-based guideline on postoperative delirium optimal timing of urinary catheter removal after thoracic operations: a randomized controlled study a prospective randomized controlled trial of suction versus non-suction to the under-water seal drains following lung resection noninvasive ventilation reduces mortality in acute respiratory failure following lung resection analgesic efficacy and safety of thoracic paravertebral and epidural analgesia for thoracic surgery: a systematic review and meta-analysis. interact cardiovas thorac surg prophylactic use of helmet cpap after pulmonary lobectomy: a prospective randomized controlled study continuous noninvasive blood pressure monitoring during thoracic surgery guidelines for enhanced recovery after lung surgery: recommendations of the enhanced recovery after surgery (eras(r)) society and the european society of thoracic surgeons (ests) which anesthesia regimen is best to reduce morbidity and mortality in lung surgery?: a multicenter randomized controlled trial perioperative ketamine for acute postoperative pain glidescope versus airtraq dl for double-lumen tracheal tube insertion in patients with a predicted or known difficult airway: a randomised study postoperative delirium as a target for surgical quality improvement comparison between thoracic epidural block and thoracic paravertebral block for post thoracotomy pain relief high-dose methylprednisolone in video-assisted thoracoscopic surgery lobectomy: a randomized controlled trial propensity score-matched outcomes after thoracic epidural or paravertebral analgesia for thoracotomy management of one-lung ventilation: impact of tidal volume on complications after thoracic surgery effect of perioperative systemic alpha agonists on postoperative morphine consumption and pain intensity: systematic review and meta-analysis of randomized controlled trials efficacy of postoperative epidural analgesia: a meta-analysis the effects of minimal-dose versus low-dose s-ketamine on opioid consumption, hyperalgesia, and postoperative delirium: a triple-blinded, randomized, active-and placebo-controlled clinical trial left double-lumen tubes: clinical experience with , patients consensus definitions to promote an evidence-based approach to management of the pleural space. a collaborative proposal by ests, aats, sts, and gtsc ers/ests clinical guidelines on fitness for radical therapy in lung cancer patients (surgery and chemo-radiotherapy) a scoring system predicting the risk for intensive care unit admission for complications after major lung resection: a multicenter analysis comparison of water seal and suction after pulmonary lobectomy: a prospective, randomized trial elective intensive care after lung resection: a multicentric propensity-matched comparison of outcome current techniques for perioperative lung isolation in adults which device should be considered the best for lung isolation: double-lumen endotracheal tube versus bronchial blockers update on tracheobronchial anatomy and flexible fiberoptic bronchoscopy in thoracic anesthesia a comparison of a left-sided broncho-cath with the torque control blocker univent and the wire-guided blocker assessing the diagnostic accuracy of pulse pressure variations for the prediction of fluid responsiveness: a "gray zone" approach safety of peripheral intravenous administration of vasoactive medication role of sugammadex in accelerating postoperative discharge: a meta-analysis clinical review: goal-directed therapy-what is the evidence in surgical patients? the effect on different risk groups prospective randomized trial compares suction versus water seal for air leaks fast-tracking pulmonary resections a rational approach to perioperative fluid management a randomised trial comparing real-time double-lumen endobronchial tube placement with the disposcope((r)) with conventional blind placement optimal duration of urinary catheterization after thoracotomy in patients under postoperative patient-controlled epidural analgesia bispectral index and non-bispectral index anesthetic protocols on postoperative recovery outcomes postoperative chest ultrasound findings and effectiveness after thoracic surgery: a pilot study management of postoperative pain: a clinical practice guideline from the american pain society, the american society of regional anesthesia and pain medicine, and the american society of anesthesiologists' committee on regional anesthesia, executive committee, and administrative council a comparison of the efficacy and adverse effects of double-lumen endobronchial tubes and bronchial blockers in thoracic surgery: a systematic review and meta-analysis of randomized controlled trials double-lumen tube position should be confirmed by fiberoptic bronchoscopy management of chest tubes after pulmonary resection: a systematic review and meta-analysis predictors of prolonged postoperative endotracheal intubation in patients undergoing thoracotomy for lung resection non-invasive pressure support ventilation in major lung resection for high risk patients: does it matter? noninvasive cardiac output and pressure measurements with finger cuff during lateral decubitus and one lung ventilation in thoracic surgery: preliminary results fast-track rehabilitation for lung cancer lobectomy: a five-year experience a comparison of the analgesic efficacy and side-effects of paravertebral vs epidural blockade for thoracotomy--a systematic review and meta-analysis of randomized trials is flexible bronchoscopy necessary to confirm the position of double-lumen tubes before thoracic surgery? anesthetic-induced improvement of the inflammatory response to one-lung ventilation why hydroxyethyl starch solutions should not be banned from the operating room postoperative pulmonary complications, pulmonary and systemic inflammatory responses after lung resection surgery with prolonged one-lung ventilation. randomized controlled trial comparing intravenous and inhalational anaesthesia perioperative single dose systemic dexamethasone for postoperative pain: a meta-analysis of randomized controlled trials perioperative systemic magnesium to minimize postoperative pain: a meta-analysis of randomized controlled trials does the usage of digital chest drainage systems reduce pleural inflammation and volume of pleural effusion following oncologic pulmonary resection?-a prospective randomized trial postthoracotomy analgesia: epidural vs intravenous morphine continuous infusion clonidine in patients undergoing noncardiac surgery buone pratiche cliniche siaarti -normotermia perioperatoria a comparison of the analgesia efficacy and side effects of paravertebral compared with epidural blockade for thoracotomy: an updated meta-analysis influence of timing of chest tube removal on early outcome of patients underwent lung resection prevalence and mortality of acute lung injury and ards after lung resection feasibility and results of a fast-track protocol in thoracic surgery a comparison of the deflecting-tip bronchial blocker with a wire-guided blocker or left-sided double-lumen tube anaesthetic agents for thoracic surgery: what's best? intraoperative ketorolac dose of mg versus the standard mg on early postoperative pain after spine surgery: a randomized, blinded, non-inferiority trial calculations of consciousness: electroencephalography analyses to determine anesthetic depth a comparison of videolaryngoscopes for double-lumen tube intubation in humans by users with mixed experience: a randomized controlled study an evaluation of a zero-heat-flux cutaneous thermometer in cardiac surgical patients the technology of processed electroencephalogram monitoring devices for assessment of depth of anesthesia magnesium: physiology and pharmacology pulmonary complications after lung resection in the absence of chronic obstructive pulmonary disease: the predictive role of diffusing capacity the society of thoracic surgeons practice guideline on the prophylaxis and management of atrial fibrillation associated with general thoracic surgery: executive summary management of chest drains after thoracic resections comparing erector spinae plane block with serratus anterior plane block for minimally invasive thoracic surgery: a randomised clinical trial systematic review of the influence of enhanced recovery pathways in elective lung resection short-term one-lung ventilation does not influence local inflammatory cytokine response after lung resection reversal of rocuronium-induced neuromuscular block with sugammadex is faster than reversal of cisatracurium-induced block with neostigmine the erector spinae plane block: a novel analgesic technique in thoracic neuropathic pain erector spinae plane (esp) block in the management of post thoracotomy pain syndrome: a case series new landmarks improve the positioning of the left broncho-cath double-lumen tube -comparison with the classic technique aats guidelines for the prevention and management of perioperative atrial fibrillation and flutter for thoracic surgical procedures intraoperative electroencephalogram suppression predicts postoperative delirium consensus guidelines for the management of postoperative nausea and vomiting presurgical intravenous parecoxib sodium and follow-up oral valdecoxib for pain management after laparoscopic cholecystectomy surgery reduces opioid requirements and opioid-related adverse effects newonset atrial fibrillation after anatomic lung resection: predictive factors, treatment and follow-up in a uk thoracic centre comparison of gas exchange after lung resection with a boussignac cpap or venturi mask world health organization-world federation of societies of anaesthesiologists (who-wfsa) international standards for a safe practice of anesthesia ketorolac does not increase perioperative bleeding: a meta-analysis of randomized controlled trials comparison of suction versus nonsuction drainage after lung resections: a prospective randomized trial perioperative acute kidney injury review of difficult airway management in thoracic surgery perioperative gabapentin for the prevention of persistent pain after thoracotomy: a randomized controlled trial a comparison of epidural and paravertebral catheterisation techniques in postthoracotomy pain management guidelines for perioperative care in elective colonic surgery: enhanced recovery after surgery (eras((r))) society recommendations effect of perioperative gabapentin on postoperative pain resolution and opioid cessation in a mixed surgical cohort: a randomized clinical trial haemodynamic response at double lumen bronchial tube placement-airtraq vs. macintosh laryngoscope, a randomised controlled trial acute and chronic pain syndromes after thoracic surgery a retrospective evaluation of the use of video-capable double-lumen endotracheal tubes in thoracic surgery failed epidural: causes and management ketamine for perioperative pain management perioperative single-dose glucocorticoid administration: pathophysiologic effects and clinical implications regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: american society of regional anesthesia and pain medicine evidence-based guidelines (fourth edition) efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade in adults early removal of urinary catheter after surgery requiring thoracic epidural: a prospective trial gabapentin does not reduce post-thoracotomy shoulder pain: a randomized, doubleblind placebo-controlled study intraoperative temperature monitoring with zero heat flux technology ( m spoton sensor) in comparison with sublingual and nasopharyngeal temperature: an observational study double lumen tube location predicts tube malposition and hypoxaemia during one lung ventilation postoperative delirium in older adults: best practice statement from the american geriatrics society stroke volume variation and pulse pressure variation are not useful for predicting fluid responsiveness in thoracic surgery a review of enhanced recovery for thoracic anaesthesia and surgery a systematic review of randomized trials evaluating regional techniques for postthoracotomy analgesia comparison between continuous thoracic epidural and paravertebral blocks for postoperative analgesia in patients undergoing thoracotomy: systematic review safety of the paravertebral block in patients ineligible for epidural block undergoing pulmonary resection oesophageal doppler guided goal-directed haemodynamic therapy in thoracic surgery-a single centre randomized parallel-arm trial the acute physiology and chronic health evaluation iii outcome prediction in patients admitted to the intensive care unit after pneumonectomy the role of physiotherapy in patients undergoing pulmonary surgery for lung cancer. a literature review ultrasound-guided serratus anterior plane block versus thoracic epidural analgesia for thoracotomy pain predictors of postoperative acute renal failure after noncardiac surgery in patients with previously normal renal function efficacy of ultrasound-guided serratus plane block on postoperative quality of recovery and analgesia after video-assisted thoracic surgery: a randomized, triple-blind, placebo-controlled study effect of combining a recruitment maneuver with protective ventilation on inflammatory responses in video-assisted thoracoscopic lobectomy: a randomized controlled trial the effects of single-dose dexamethasone on inflammatory response and pain after uterine artery embolisation for symptomatic fibroids or adenomyosis: a randomised controlled study preoperative gabapentin for acute post-thoracotomy analgesia: a randomized, double-blinded, active placebo-controlled study role of fiberoptic bronchoscopy in conjunction with the use of double-lumen tubes for thoracic anesthesia: a prospective study airway injuries after one-lung ventilation: a comparison between double-lumen tube and endobronchial blocker: a randomized, prospective, controlled trial magnesium sulfate does not reduce postoperative analgesic requirements paravertebral block via the surgical field versus epidural block for patients undergoing thoracotomy: a randomized clinical trial comparison of continuous epidural block and continuous paravertebral block in postoperative analgaesia after video-assisted thoracoscopic surgery lobectomy: a randomised, non-inferiority trial chads score predicts postoperative atrial fibrillation in patients undergoing elective pulmonary lobectomy incidence of urinary retention in patients with thoracic patient-controlled epidural analgesia (tpcea) undergoing thoracotomy suction on chest drains following lung resection: evidence and practice are not aligned a systematic review of intravenous ketamine for postoperative analgesia does external pleural suction reduce prolonged air leak after lung resection? results from the airintrial after randomized cases safety of the peripheral administration of vasopressor agents it is safe and feasible to omit the chest tube postoperatively for selected patients receiving thoracoscopic pulmonary resection: a meta-analysis enhanced recovery programs in lung cancer surgery: systematic review and meta-analysis of randomized controlled trials prophylactic use of noninvasive positive pressure ventilation in post-thoracic surgery patients: a prospective randomized control study fluid therapy in thoracic surgery: a zero-balance target is always best! turk a randomised trial comparing the cel- videolaryngoscope(tm) with the macintosh laryngoscope blade for insertion of double-lumen tubes in patients with resectable non-small-cell lung cancer, is video-assisted thoracoscopic segmentectomy a suitable alternative to thoracotomy and segmentectomy in terms of morbidity and equivalence of resection? enhanced recovery after surgery-eras-principles, practice and feasibility in the elderly lung injury after one-lung ventilation: a review of the pathophysiologic mechanisms affecting the ventilated and the collapsed lung high-flow oxygen therapy after noninvasive ventilation interruption in patients recovering from hypercapnic acute respiratory failure.a physiological crossover trial early postoperative prophylactic noninvasive ventilation after major lung resection in copd patients: a randomized controlled trial hypoxic pulmonary vasoconstriction: physiology and anesthetic implications the combination of iv and perineural dexamethasone prolongs the analgesic duration of intercostal nerve blocks compared with iv dexamethasone alone novel zero-heat-flux deep body temperature measurement in lower extremity vascular and cardiac surgery suction vs water seal after pulmonary resection: a randomized prospective study implementing a thoracic enhanced recovery program: lessons learned in the first year noninvasive continuous arterial blood pressure monitoring with nexfin(r) evaluation of the doublelumen tube vivasight-dl (dlt-etview): a prospective single-center study paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after major surgery: a systematic review critical care after lung resection: calor , a single-centre pilot study complications from administration of vasopressors through peripheral venous catheters: an observational study analgesia and pulmonary function after lung surgery: is a single intercostal nerve block plus patient-controlled intravenous morphine as effective as patientcontrolled epidural anaesthesia? a randomized non-inferiority clinical trial guidelines for perioperative care for liver surgery: enhanced recovery after surgery (eras) society recommendations recommendations for airway control and difficult airway management in thoracic anesthesia and lung separation procedures determining optimal fluid and air leak cut off values for chest drain management in general thoracic surgery elimination of daily routine chest radiographs does not change on-demand radiography practice in post-cardiothoracic surgery patients perioperative goal-directed therapy with uncalibrated pulse contour methods: impact on fluid management and postoperative outcome physiology and pathophysiology of pleural fluid turnover impact of pregabalin on acute and persistent postoperative pain: a systematic review and meta-analysis postoperative pulmonary complications the raw and processed electroencephalogram as a monitoring and diagnostic tool consensus guidelines for enhanced recovery after gastrectomy: enhanced recovery after surgery (eras(r)) society recommendations comparison of intravenous ketorolac at three single-dose regimens for treating acute pain in the emergency department: a randomized controlled trial reduction of postoperative pulmonary complications after lung surgery using a fast track clinical pathway consensus statement on perioperative use of neuromuscular monitoring somatic paravertebral nerve blockade. incidence of failed block and complications choosing a lung isolation device for thoracic surgery: a randomized trial of three bronchial blockers versus double-lumen tubes guidelines for postoperative care in gynecologic/oncology surgery: enhanced recovery after surgery (eras(r)) society recommendations--part ii cpap increases -minute walk distance after lung resection surgery systematic review and meta-analysis of enhanced recovery programmes in surgical patients preventive analgesia in thoracic surgery: controlled, randomized, double-blinded study guidelines for perioperative care in elective rectal/pelvic surgery: enhanced recovery after surgery (eras((r))) society recommendations associations between intraoperative ventilator settings during one-lung ventilation and postoperative pulmonary complications: a prospective observational study risk of hematoma in patients with a bleeding risk undergoing cardiovascular surgery with a paravertebral catheter the efficacy of serratus anterior plane block in analgesia for thoracotomy: a retrospective study evaluation of the effect of serratus anterior plane block for pain treatment after video-assisted thoracoscopic surgery comparison of the single or double chest tube applications after pulmonary lobectomies risk factors for atrial fibrillation after lung cancer surgery: analysis of the society of thoracic surgeons general thoracic surgery database the efficacy of preemptive analgesia for acute postoperative pain management: a meta-analysis monitoring neuromuscular function hemoglobin concentration, total hemoglobin mass and plasma volume in patients: implications for anemia video-assisted thoracic surgery does not reduce the incidence of postoperative atrial fibrillation after pulmonary lobectomy a randomised trial of serratus anterior plane block for analgesia after thoracoscopic surgery dexamethasone as an adjuvant to peripheral nerve block iatrogenic hemodilution: a possible cause for avoidable blood transfusions? critical care prophylactic use of noninvasive ventilation in patients undergoing lung resectional surgery a systematic review of pulse pressure variation and stroke volume variation to predict fluid responsiveness during cardiac and thoracic surgery preoperative predictive factors for intensive care unit admission after pulmonary resection comparison of continuous thoracic epidural with paravertebral block on perioperative analgesia and hemodynamic stability in patients having open lung surgery multicenter international randomized comparison of objective and subjective outcomes between electronic and traditional chest drainage systems antiinflammatory effect of sevoflurane in open lung surgery with one-lung ventilation processed electroencephalogram and evoked potential techniques for amelioration of postoperative delirium and cognitive dysfunction following non-cardiac and non-neurosurgical procedures in adults bispectral index for improving anaesthetic delivery and postoperative recovery video laryngoscopy versus direct laryngoscopy for double-lumen endotracheal tube intubation: a retrospective analysis analgesia in patients undergoing thoracotomy: epidural versus paravertebral technique. a randomized, double-blind, prospective study crystalloid fluid therapy are daily routine chest radiographs necessary after pulmonary surgery in adult patients? failure of noninvasive ventilation after lung surgery: a comprehensive analysis of incidence and possible risk factors official ers/ats clinical practice guidelines: noninvasive ventilation for acute respiratory failure high flow nasal cannula compared with conventional oxygen therapy for acute hypoxemic respiratory failure: a systematic review and meta-analysis the impact of enhanced recovery after surgery (eras) protocol compliance on morbidity from resection for primary lung cancer randomized clinical trial comparing double-lumen tube and ez-blocker for single-lung ventilation a randomised controlled trial comparing the glidescope((r)) and the macintosh laryngoscope for double-lumen endobronchial intubation does fast-tracking increase the readmission rate after pulmonary resection? a case-matched study relationship between intraoperative hypotension, defined by either reduction from baseline or absolute thresholds, and acute kidney and myocardial injury after noncardiac surgery: a retrospective cohort analysis double-lumen endobronchial tube in the emergency management of massive hemoptysis effects of neostigmine reversal of nondepolarizing neuromuscular blocking agents on postoperative respiratory outcomes: a prospective study preoperative oral pregabalin reduces acute pain after thoracotomy. open access maced increased number and expertise of italian respiratory high-dependency care units: the second national survey noninvasive ventilation in acute respiratory failure: which recipe for success? continuous paravertebral block for post-cardiothoracic surgery analgesia: a systematic review and meta-analysis effects of propofol and desflurane anaesthesia on the alveolar inflammatory response to one-lung ventilation effects of volatile and intravenous anesthesia on the alveolar and systemic inflammatory response in thoracic surgical patients intubation with vivasight or conventional left-sided double-lumen tubes: a randomized trial fluid management in thoracic surgery balanced crystalloids versus saline in noncritically ill adults is routine chest radiography indicated following chest drain removal after cardiothoracic surgery? perioperative quality initiative consensus statement on intraoperative blood pressure, risk and outcomes for elective surgery an audit of robertshaw double lumen tube placement using the fibreoptic bronchoscope fiberoptic bronchoscopic positioning of double-lumen tubes perioperative fasting in adults and children: guidelines from the european society of anaesthesiology impairment of wound healing after operative treatment of mandibular fractures, and the influence of dexamethasone competence in bronchoscopy for icu, anesthesiology, thoracic surgery and lung transplantation regional analgesia for video-assisted thoracic surgery: a systematic review high-flow nasal cannula therapy versus intermittent noninvasive ventilation in obese subjects after cardiothoracic surgery effects of volatile vs. propofol-based intravenous anesthetics on the alveolar inflammatory responses to one-lung ventilation: a meta-analysis of randomized controlled trials does perioperative glucocorticosteroid treatment correlate with disturbance in surgical wound healing after treatment of facial fractures? a retrospective study do surgical patients benefit from perioperative gabapentin/pregabalin? a systematic review of efficacy and safety non-invasive positive pressure ventilation for prevention of complications after pulmonary resection in lung cancer patients lung ultrasound compared with chest x-ray in diagnosing postoperative pulmonary complications following cardiothoracic surgery: a prospective observational study chest xray prior to discharge after video-assisted thoracic anatomical pulmonary resection: friend or foe? hypomagnesemia is prevalent in patients undergoing gynecologic surgery by a gynecologic oncologist anesthesia and fast-track in video-assisted thoracic surgery (vats): from evidence to practice united states preventive services task force. grade definitions association between intraoperative hypotension and myocardial injury after vascular surgery clinical observations on reversal of rocuronium-induced residual neuromuscular blockade by sugammadex after thoracic surgery saline versus balanced solutions: are clinical trials comparing two crystalloid solutions really needed? critical care impact of perioperative dexamethasone on postoperative analgesia and side-effects: systematic review and meta-analysis relationship between intraoperative mean arterial pressure and clinical outcomes after noncardiac surgery: toward an empirical definition of hypotension postoperative diet advancement: surgical dogma vs evidence-based medicine comparison of the airtraq and the macintosh laryngoscope for double-lumen tube intubation: a randomised clinical trial espen guideline: clinical nutrition in surgery local anaesthetics and regional anaesthesia versus conventional analgesia for preventing persistent postoperative pain in adults and children safety and efficacy of postoperative epidural analgesia perioperative magnesium infusion and postoperative pain effect of electroencephalography-guided anesthetic administration on postoperative delirium among older adults undergoing major surgery: the engages randomized clinical trial is intercostal block for pain management in thoracic surgery more successful than epidural anaesthesia? continuous paravertebral block using a thoracoscopic catheter-insertion technique for postoperative pain after thoracotomy: a retrospective case-control study pain control of thoracoscopic major pulmonary resection: is pre-emptive local bupivacaine injection able to replace the intravenous patient controlled analgesia? does a protective ventilation strategy reduce the risk of pulmonary complications after lung cancer surgery?: a randomized controlled trial paravertebral block versus thoracic epidural for patients undergoing thoracotomy disconnection technique with a bronchial blocker for improving lung deflation: a comparison with a doublelumen tube and bronchial blocker without disconnection risk factors for reinsertion of urinary catheter after early removal in thoracic surgical patients is there a role for gabapentin in preventing or treating pain following thoracic surgery? fluid composition and acute kidney injury how long is a transurethral catheter necessary in patients undergoing thoracotomy and receiving thoracic epidural analgesia? literature review goal-directed fluid optimization based on stroke volume variation and cardiac index during one-lung ventilation in patients undergoing thoracoscopy lobectomy operations: a pilot study the single chest tube versus double chest tube application after pulmonary lobectomy: a systematic review and metaanalysis single chest tube drainage is superior to double chest tube drainage after lobectomy: a meta-analysis pressure-controlled versus volumecontrolled ventilation during one-lung ventilation for video-assisted thoracoscopic lobectomy publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations medical writing and editorial assistance was provided by michael shaw phd, on behalf of editamed srl, torino, italy. the authors wish to thank the following colleagues who served as external independent reviewers for the final manuscript editing: prof. paolo navalesi (anesthesiology and intensive care unit -university of padua, italy), dr. alessandro pardolesi (thoracic surgery unit -fondazione irccs istituto nazionale dei tumori, milan, italy), dr. giulio rosboch (department of anesthesia and intensive care -azienda ospedaliera città della salute e della scienza, turin, italy), dr. domenico santonastaso (anesthesia and intensive care unit -ausl romagna bufalini hospital, cesena, italy). all the authors contributed equally to the consensus. all the authors revised and approved the final manuscript. this work, including travel and meeting expenses, was supported by an unrestricted grant from msd italia srl. the sponsor had no role in selecting the participants, reviewing the literature, defining consensus recommendations, drafting or reviewing the paper, or in the decision to submit the manuscript. data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.ethics approval and consent to participate not applicable. not applicable. key: cord- -er llst authors: carboni bisso, i.; prado, e.; cantos, j.; masso, a.; staneloni, i.; san roman, e.; huespe, i.; las heras, m. title: influenza season : analysis of hospitalized cases date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: er llst introduction influenza virus infection is a latent public health problem, affecting millions of people through the planet, and it is an important cause of morbidity and mortality. in argentina, there is a significant absence of data regarding influenza severe respiratory disease and, therefore, a lack of knowledge about the impact of this disease at health institutions. objectives analysis of clinical characteristics, image findings and laboratory variables in patients with influenza viruses during . methods retrospective, single-centre study, we analyzed all confirmed cases of influenza in a high complexity hospital from buenos aires. results patients with influenza virus were hospitalized in this period of time. the . % were infected by type a influenza, and most of them . % were h n subtype. median age was years (iqr - ), . % were older than years, and . % had at least one coexisting illness. . % of the patients required intensive care, . % invasive mechanical ventilation and . % died during hospitalization. conclusion mortality and severity were similar to previous series of non-pandemic influenza. analysis of annual data would be valuable in order to document the severity of influenza hospitalizations by age-group and comorbidities according to the circulating influenza viruses. influenza virus infection is a latent public health problem, affecting millions of people through the planet, and it is an important cause of morbidity and mortality, especially for certain susceptible populations. influenza virus is a single stranded rna virus, characterized by types (a, b, c and d). this virus has important surface glycoproteins, hemagglutinin (h , h and h , the most common in humans) and neuraminidase (n and n , the most common in humans), which are used to classify the different subtypes and give the virus a changing antigenicity as its main characteristic. the term "antigenic drift" makes reference to the periodic changes in the antigenicity of the virus that occur year by year, while "antigenic shift" describes the generation of large genetic recombinations which are responsible for pandemics, such as the one that took place in . influenza infection can evolve, due to the same pathogenicity of the virus or bacterial superinfection, into a severe respiratory infection. among the risk factors for presenting a severe influenza disease, it is possible to recognise increasing age, cardiovascular disease, malignancy, immunosuppression, hypertension, neuromuscular disease, diabetes mellitus, chronic lung, liver, or metabolic renal disease. also obesity and pregnancy were associated with increased risk of negative outcomes in some studies , . among the patients hospitalized due to influenza severe respiratory infection, it has been estimated that to % require admission to the intensive care unit (icu). a recent multicentre european study which analyzed the characteristics and outcomes of hospitalized patients with diagnosis of influenza from to reported that % of the patients admitted to the icu did not have predisposing factors and % of hospital mortality. in argentina, there is a significant absence of data regarding influenza severe respiratory disease and, therefore, a lack of knowledge about the impact of this disease at health institutions, hospital mortality, and the profile of patients requiring icu. thus, the objective of this work is to describe the history of comorbidities as well as the clinical, laboratory and imaging findings of patients who required hospitalization in a general ward or icu during in a high-complexity care hospital from buenos aires, capital of argentina. in this retrospective, observational single-centre study, we included patients from january to december at a high complexity hospital from buenos aires. the study was approved by the ethics committee from our hospital in october . . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint we obtained epidemiological, demographic, clinical, laboratory, management, and outcome data from patients' medical records. clinical outcomes were followed up to march, . throat-swab specimens from the upper respiratory tract that were obtained from all patients at admission were maintained in viral-transport medium. influenza and other respiratory viruses including adenovirus, respiratory syncytial virus, parainfluenza viruses, rhinovirus, enterovirus, coronavirus and bocavirus were confirmed by using real time reverse transcription polymerase chain reaction (real time rt-pcr). due to sequence similarity, rhinovirus and enterovirus may not be discriminated by the technique used. sputum or endotracheal aspirates were obtained at admission for identification of possible causative bacteria or fungi. additionally, all patients were given chest x-rays or chest computed tomography scans (cts). we describe epidemiological data, demographics, signs and symptoms on admission, comorbidity, laboratory results; co-infection with other respiratory pathogens, chest radiography and ct findings, treatment received and clinical outcomes. continuous variables were expressed as medians and interquartile ranges or simple ranges, as appropriate. categorical variables were summarized as counts and percentages. no imputation was made for missing data. because the cohort of patients in our study was not derived from random selection, all statistics are deemed to be descriptive only. we used rstudio developed by r-tools technology inc for all analyses. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint patients with influenza were included in this study, patients were female and men. median age was years (iqr - ). among the overall population, . % ( ) were older than years, and . % ( ) had at least one coexisting illness. chronic obstructive pulmonary disease (copd) was the most frequently observed ( . %), followed by immunosuppression ( . %) and cardiovascular disease ( . %). patients ( . %) required icu admission and the rest of them were treated in general ward. patients ( . %) underwent invasive mechanical ventilation (imv), ( . %) non invasive ventilation or high-flow nasal cannula and patients ( . %) died during hospitalization. table . influenza viruses were detected by real-time rt-pcr. . % of patients were infected by type a influenza, . % had subtype h n and . % h n . most of the cases were reported during the th to nd epidemiological weeks of winter season in the southern hemisphere. annual distribution of the cases is detailed in figure and the distribution of cases by viral type and subtype in figure . regarding clinical findings, fever was present on admission in . % ( ) of the patients. the second most common symptom was shortness of breath ( . %), followed by cough ( . %) and rhinorrhoea ( . %) diarrhoea, nausea or vomiting ( . %) were uncommon. also dyspnoea was more frequent in icu patients ( . % vs. . %). among laboratory findings, lymphocytopenia was present in . % of the patients, leukocytosis in . % and neutrophilia in . %. hyponatremia was found in . % of the patients, and . % presented elevated serum creatinine and urea. half of the patients [ . % ( )] who underwent admission to icu presented elevated serum pro b-type natriuretic peptide (probnp) (median pg/ml, iqr - ) that was also elevated in . % ( ) of the non-icu patients. in addition, elevation of serum transaminases was more frequently seen in icu patients ( , % vs. . %), without associated involvement of alkaline phosphatase, bilirubin or prothrombin time. table shows clinical presentation and laboratory findings. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . in this cohort study, we reported the clinical characteristics and risk factors associated with clinical outcomes in patients with laboratory-confirmed influenza who required hospitalization during . we found that overall mortality was similar to previous series. however, in icu cases, mortality was significantly lower ( % vs. to % range), despite the fact that the majority of the cases reported in this study were older than years and had at least one coexisting illness - . also, the relative amount of patients admitted to icu was higher. this may be attributed to the icu criteria of our unit, where age is not a restriction for invasive vital support. nevertheless, it is important to point out the lack of post-icu follow up, therefore, we do not evaluate cognitive, emotional or physical status after discharge. in this series, vaccination acted as a protective factor against severe illness, with less icu admission, less imv requirement and a decreased length of stay. it is well documented that influenza vaccines provide substantial protection against severe influenza illness among adults. but also, they seem to provide low protection for elderly patients in seasons where vaccine and circulating a(h n ) strains were antigenically variant , . during , a double viral circulation was registered in argentina with the presence of subtypes h n and h n . these findings should be taken into account to improve vaccination strategies and achieve better vaccination coverage in order not only to decrease flu cases, but also their severity. as regards chronic medical illnesses, we found a lower quantity of immunosuppressed patients in icu against the group that required hospitalization in general ward ( . % vs. . %). additionally, mortality was higher among immunocompetent patients ( . % vs. . %) with no difference in median length of stay or imv requirement. in this sense it is reported that a lower inflammatory response in immunosuppressed patients against the pathogen is associated with better outcomes and less organic failure , . it is interesting to analyze the behavior of influenza in immunosuppressed patients in order to draw conclusions and extrapolate information to the general of this population. however, we believe that it is worth highlighting these findings that we mentioned in order to inform professionals and undertake future research. in relation to the laboratory findings, hepatic enzymes impairment, mainly asat, was far more frequent in icu cases than in general patients. in a recently published research, asat rate superior to iu/l was identified as a predictor of -month mortality with other variables such as creatinine and pao /fio with a hazard ratio (hzr) of . (ic % . - . ), the highest hzr among them . additionally, probnp was higher in icu patients (median pg/ml, iqr - vs. , iqr - ), in fact . % of critical patients had . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint values higher than normal range ( pg/ml) vs. . % of non icu patients. probnp has been reported to be useful as a predictor in patients with confirmed influenza . regarding images studies, it is important to pinpoint that in our series only one patient of those who required critical care had a normal result. likewise, greater radiological impact was seen in icu cases, with more bilateral compromise in both chest x-rays ( . % vs. . %) and chest cts ( . % vs. . %) in comparison with non-icu patients. similar data was found in other series where a high percentage of pathological radiographic findings were detected in patients with a worse prognosis [ ] [ ] [ ] . our study has several limitations. it is an observational study of a single center and data from other argentine centers are necessary to know the impact of the influenza in hospitalizations. also, as previously noted, no post-icu follow up was performed. regarding the behavior of the virus in , we conclude that both mortality and severity of the cases were similar to those published in previous series of non-pandemic influenza. analysis of annual data would be valuable in order to document the severity of influenza hospitalizations by age group and comorbidities according to the circulating influenza viruses. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . ( ) . % ( ) multiple mottling opacity . % ( ) . % ( ) . % ( ) . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint spatiotemporal trends of cases of pandemic influenza a(h n )pdm in argentina risk factors for severe outcomes following influenza a (h n ) infection: a global pooled analysis populations at risk for severe or complicated influenza illness: systematic review and meta-analysis characteristics of hospitalizations with an influenza diagnosis mortality of critically ill patients with severe influenza starting four years after the pandemic hospitalization and death among patients with influenza effectiveness of influenza vaccines in preventing severe influenza illness among adults: a systematic review and meta-analysis of test-negative design case-control studies variable influenza vaccine effectiveness by subtype: a systematic review and meta-analysis of test-negative design studies maintenance immunosuppression is associated with better outcome in the immunosuppression is associated with lower morbidity and mortality in the / influenza epidemic. respiratory infections outcome of critically ill patients with influenza infection: a retrospective study prognostic value of pro-adrenomedullin and nt-probnp in patients referred from the emergency department with influenza syndrome spectrum of clinical and radiographic findings in patients with diagnosis of h n and correlation with clinical severity leucocytes median (iqr) -per mm neutrophils median (iqr) -per mm ng/ml (no.) /ml non-icu (n = ) (n = ) (n = )signs and symptoms -% (no.) key: cord- -lphr prl authors: grundel, sara; heyder, stefan; hotz, thomas; ritschel, tobias k. s.; sauerteig, philipp; worthmann, karl title: how much testing and social distancing is required to control covid- ? some insight based on an age-differentiated compartmental model date: - - journal: nan doi: nan sha: doc_id: cord_uid: lphr prl in this paper, we provide insights on how much testing and social distancing is required to control covid- . to this end, we develop a compartmental model that accounts for key aspects of the disease: ) incubation time, ) age-dependent symptom severity, and ) testing and hospitalization delays; the model's parameters are chosen based on medical evidence, and, for concreteness, adapted to the german situation. then, optimal mass-testing and age-dependent social-distancing policies are determined by solving optimal control problems both in open loop and within a model predictive control framework. we aim to minimize testing and/or social distancing until herd immunity sets in under a constraint on the number of available intensive care units. we find that an early and short lockdown is inevitable but can be slowly relaxed over the following months. the severe acute respiratory syndrome coronavirus (sars-cov- ) is a strain of coronavirus which causes the respiratory illness coronavirus disease . in , on march th , the world health organization (who) declared the outbreak of sars-cov- a pandemic [ ] . due to the novelty of the virus, there was (and, at the time of submitting this manuscript, still is) significant uncertainty concerning the severity and mortality of covid- . furthermore, as of october , no vaccine has completed the trials necessary for approving widespread use [ ] . therefore, many countries are enforcing nonpharmaceutical countermeasures [ , ] , e.g. ) social distancing, ) increased public hygiene, ) travel restrictions, ) self-isolation (quarantine), and ) population-wide mass testing for sars-cov- infection. however, enforcing these countermeasures for long periods of time can have severe economic and social consequences, both at the national and the global scale [ ] . therefore, there is a need for identifying economic strategies for simultaneously relaxing the countermeasures and containing the pandemic. model-based decision support systems can be used for exactly this purpose. they use predictive models to assist decision makers in identifying and evaluating candidate strategies (e.g. [ ] ). in particular, given a dynamical model of the spread of sars-cov- , economically optimal (open-loop) mitigation strategies can be identified by solving optimal control problems (ocps) over several months or even years. a key advantage of this approach is that it can directly account for constraints, e.g. related to the capacity of public healthcare systems. however, given the uncertainty surrounding sars-cov- and covid- , it is advisable to implement the optimal mitigation strategies in closed-loop, i.e. to repeatedly update the strategies when new data becomes available. this is referred to as model predictive control (mpc) [ ] and is an established method for advanced process control [ ] . the predictive capabilities of the underlying model are crucial for the efficacy of the resulting mitigation strategy, and a common challenge is to identify suitable model parameters. epidemics are often modelled using deterministic compartmental models [ ] , e.g. the classical sir model, where individuals are either susceptible, infectious, or removed, or the seir model which, additionally, takes the incubation time into account. optimal control of compartmental models was already an active research topic before the sars-cov- pandemic (see [ ] for a review). in particular, optimal control of sir models has been considered, e.g. for arbitrary social interaction models [ ] and to identify time-optimal mitigation strategies [ , ] . optimal control of more complex models has also been considered. for instance, fischer et al. [ ] consider optimal control of a model with two species, bussell et al. [ ] demonstrate the importance of closed-loop mitigation strategies (i.e. of incorporating feedback), and watkins et al. [ ] consider mpc of stochastic compartmental models. in [ ] the authors determine control strategies to maintain hard infection caps in a disease-vector model based on the theory of barriers. this approach, however, exploits the low dimensionality of the model. application of these techniques to complex compartmental models, therefore, requires model order reduction. in response to the sars-cov- pandemic, many researchers have presented optimal control strategies, for instance based on pontryagin's maximum principle (e.g. [ , , ] ). these strategies typically involve ) extended sir or seir models, ) nonpharmaceutical countermeasures (often social distancing), and ) minimization of the number of infected as well as the economic cost of the countermeasures (and often other quantities as well, e.g. the number of deaths). furthermore, they rarely satisfy hard constraints, for instance related to health care or testing capacities. in the following, we highlight some of the key developments in decision support for sars-cov- mitigation based on optimal control. gondim and machado [ ] use a model with three age groups to compute optimal quarantine strategies (for susceptible individuals) which minimize the number of infected and the cost of quarantining. bonnans and gianatti [ ] compute social distancing strategies based on a model with a continuous age structure. here, the strategies minimize a combination of ) the number of deaths, ) the peak number of hospitalized, and ) the cost of social distancing. similarly, richard et al. [ ] present optimal social distancing strategies based on a model with a continuous age and infection duration structure, which minimize the number of deaths and the cost of social distancing. morato et al. [ ] compute on-off (also called bang-bang) social distancing strategies which minimize ) the number of symptomatic infectious people and ) the duration of the social distancing policies, subject to constraints on intensive care unit (icu) occupancy. they use extended sir models. carli et al. [ ] use mpc to compute social distancing and travel restriction strategies for an extended multi-region sir model, minimizing the cost of the countermeasures and preventing an overload on the hospitals. köhler et al. [ ] use mpc to minimize the number of fatalities caused by covid- , subject to constraints on the economic cost of social distancing. they take a modified sidarthe model [ ] as basis and use interval arithmetic in the mpc to propagate model uncertainties. finally, tsay et al. [ ] use mpc to minimize the cost of social distancing and testing, subject to an upper bound on the peak number of infectious people who have been tested positive. they use the unscented kalman filter to estimate the noisy state variables of an extended seir model. in this work, we address some of the key questions that decision makers involved in the mitigation of the sars-cov- pandemic are facing: ) is mass testing alone sufficient to avoid overloading of icus? ) if not, how much social distancing is then required? ) how much can social distancing measures be reduced by targeting specific age groups? ) how do strategies obtained by short and long-term planning differ? ) what are the benefits of increasing the daily testing capacity or the icu capacity? here, the limited icu capacity is considered as an example for constraints imposed by the health care system or political considerations. of course, different constraints such as limited personnel for contact tracing could be incorporated as well. we address the above questions by proposing a novel compartmental model and using optimal control as well as mpc to compute open and closed-loop social distancing and testing strategies. the model contains three age groups, and it accounts for several of the key challenging characteristics of covid- , i.e. ) the incubation time, ) different levels of symptom severity depending on age, ) delay of testing results (and the following self-isolation), and ) delay of hospitalization. furthermore, we choose values of the epidemiological model parameters based on the current state of knowledge in order to ensure that our numerical results match reality. for concreteness, we use the covid- outbreak in germany to determine parameters depending on demographics and the health care system. however, we expect our conclusions to carry over to outbreaks in other developed countries as well. the remainder of this paper is structured as follows. in section , we describe the novel compartmental model of the sars-cov- outbreak in germany, and in section , we motivate our choice of model parameters. in section , we demonstrate that optimal control can be used as a decision support tool based on the proposed model, and we conclude the paper in section . in this section, we propose a dynamical model tailored to covid- . the aim is to be able to evaluate the effect of population-wide mass testing (in combination with quarantine) and social distancing measures on the development of the pandemic. to this end, we extend the well-known sir model. we start with an illustration of the connection between ) infectious disease models based on randomly acting individual agents and ) their approximation by ordinary differential equation compartmental models. this exposition will highlight the interpretation and conversion of parameters when moving from a random to a deterministic model. for simplicity, we consider the classical sir model in this subsection. however, the connection, especially the interpretation of parameters, is similar for more complex models such as the one described in section . . consider a population of n pop individuals or agents each being either susceptible, infectious or removed. at time t ∈ [ , ∞) denote the (random) set of susceptibles by s t , the set of infectious by i t and the set of removed by r t . time is modeled continuously and measured in days. we assume a homogeneous population with contacts between agents a and b following a poisson process with intensity λ which does not depend on the agents considered. infections occur randomly upon contact with a fixed probability α if one of the agents is susceptible and the other infectious. thus, potentially infectious contacts also follow a poisson process with respective intensity αλ. similarly, we model other events, in this simple model only recoveries, to occur according to a poisson process. this implies that the time an agent spends in the infectious compartment is exponentially distributed with rate η, say, which we also assume to be the same for each agent (see [ ] for models where these quantities follow other distributions). we denote by s(t) = e |st| npop , i(t) = e |it| npop and r(t) = e |rt| npop the expected share of the population which are susceptible, infectious and removed, respectively. since for large n pop the change of |st| npop over a short time interval can, due to the law of large numbers, be well approximated by its expectation, s(t) will provide a sufficient approximation of |st| npop over the finite time horizon considered for a country the size of germany. by the same argument, i(t) and r(t) approximate |it| npop and |rt| npop , respectively, sufficiently well. if a is susceptible he will transition to the infectious compartment upon having an infectious contact. at a fixed time t with a ∈ s t , there are two possible sources of infection for a: either some b ∈ i t which is already infectious or some c ∈ s t which will become infectious himself at some later time. to determine the probability that b infects a in the time frame (t, t + ∆t], we analyze two competing events: the first is an infectious contact between a and b, and the second is b's recovery from the infectious state. both events happen independently of one another with exponentially distributed time of occurrence, the first with rate αλ and the second with rate η. thus the first time of occurrence of one of these is again exponentially distributed with rate αλ+η and the probability that the first occurrence is an infectious contact is αλ αλ+η . in total for c ∈ s t to infect a in (t, t + ∆t], c has to become infectious himself before he in turn can infect a. this happens only with probability o((∆t) ) and can, thus, be neglected in the following calculations. in total a is moved out of the susceptible compartment with probability approximating |st| npop and |it| npop by s(t) and i(t) using the law of total expectation yields as we assume the time from infection to removal to be exponentially distributed with rate η, a similar but more straight-forward calculation reveals where η − is the mean stay of a single agent in the infectious compartment. we now set β = n pop αλ, which can be interpreted in this model as the daily amount of (potentially) infectious contacts a single agent has. since s(t) + i(t) + r(t) = for all t, we obtain the following system of odes: to determine suitable parameter values for β and η in this simplistic model, we reiterate that these are best thought of in the probabilistic setting. for the coefficients of the linear terms on the right-hand side, the interpretation is straight-forward: it is the rate of the exponential distribution underlying the time until an agent leaves the compartment. its inverse is the mean stay in this compartment. for coefficients of interaction (product) terms, here β, the interpretation is the rate at which an agent in the first compartment causes other agents to leave the second compartment. in our setting, this is the daily amount of infections one infectious agent causes which can readily be seen from the definition of β. see section for a more detailed discussion of the parameter values we use in our model. as above mentioned, these interpretations for the parameters carry over in a straight-forward manner to more sophisticated models such as the one considered in the following. the sir model provides a good starting point to study the dynamics of pandemics. however, due to its simple structure it is not suited to model the covid- pandemic adequately. in particular it does not include hospitalization, age-specific disease progressions and interventions. therefore, we extend the sir model in three ways. . we introduce eight additional compartments. in detail, we take into account that people can be infected, but not yet infectious. we call them exposed (or latent) and denote the compartment by e, see also [ ] . moreover, we split the infectious compartment into three depending on how the course of the infection will be. we distinguish between severe cases i s that are going to need intensive care, i.e. they will move to h icu at some point in time; mild cases i m that are going to visit a physician and hence be quarantined, i.e. removed; and asymptomatic cases i a that might recover without being detected. furthermore, we incorporate the possibility of being tested but not yet detected by introducing the compartments t s (severe) and t o (other). we assume that the patients with severe cases will visit a physician at some point before being sent to an icu. to this end, we introduce p as a pre-icu compartment which comprises isolated patients at home or on a regular hospital ward. moreover, we split the compartment of removed people into known and unknown cases r = r u + r k . . each compartment is further divided into n g groups, n g ∈ n, depending on the age of a subject in order to study how these groups affect each other. . social distancing and hygiene measures affect the contact rate as well as the transmission probability. therefore, β can be used as a time-dependent control input β(t). the resulting seitphr model reads aṡ where the subscript i ∈ { , , . . . , n g } denotes the age group in ascending order. we enforce ng i= n i = , where n i denotes the relative size of age group i. we assume a mean incubation time γ − independent of both the course of infection and the age of the patient. however, depending on the age, there are different probabilities π s i , π m i , and π a i for the three courses of infection, where π s i + π m i + π a i = for all i. similar to the sir model ( ), the parameters denoted by η correspond to people being removed from the system, i.e. η s and η m denote those who visit a physician and, therefore, are put into quarantine immediately, while η a represents unreported recovery. we denote the total number of susceptibles and unreported cases by describes the rate of those being tested per day, where tests are distributed uniformly at random among all individuals in u i . in addition, symptomatic cases who visit physicians are assumed to be tested as well. therefore, the total number of tests at time t ≥ is given by note that testing does not affect the state of non-infectious subjects. parameters τ s and τ o denote the rate from being tested positive to being detected, and hence being put into quarantine. furthermore, ρ is the rate from pre-hospital quarantine to hospitalization and σ from hospitalization to being reportedly removed, i.e. σ incorporates both mortality and recovery rate of hospitalized patients. the basic structure of the seitphr model ( ) is depicted in figure . figure : flow of the seitphr model for one age group. the controls are indicated with dashed red edges. unreported compartments are highlighted by the left red triangle, while tested and detected compartments are highlighted by the right blue trapezium. for a concise notation we stack the state vectors into x = (x , . . . x ng ) and the controls into u = (β, θ), where and β = (β ij ) ng i,j= with β ij : r ≥ → r ≥ and θ = (θ , . . . , θ ng ). similarly, we denote π ∈ r ng , τ ∈ r , and η ∈ r . thus, we write system ( ) aṡ where p = (π, η, τ, ρ, σ, γ) ∈ r ng+ collects all parameters. furthermore, we introduce the initial condition before we present our choices for the parameters of model ( ), let us reiterate that some of the parameters of our model depend on age. we indicate this dependence by an appropriate index which we drop if the parameter is constant across agegroups. for example, π s i is the age-dependent probability of having a severe course of disease while we assume η a , the rate with which asymptomatic cases recover, to be age-independent. n i we use data on the population size of germany at the end of from the genesis-online database of the destatis [ ] . the first age group consists of individuals aged younger than years, the second of those older than but younger than years, and the last comprises all individuals older than years. these groupings result in proportions n = . , n = . and n = . . the rate at which an infected agent in compartment i j infects susceptibles in compartment s i depends on the contact structure of a population as well as the probability that a contact between a susceptible and infectious agent leads to a transmission of the disease. we base our contact process on data from the polymod study on daily contacts in several european countries [ ] . from this data we calculate a contact matrix c = (c ij ) whose (i, j)-th entry is the mean amount of contacts an individual in age group i has with age group j; here we only consider those contacts labeled as physical, since those are more likely to lead to viral transmission. let us denote by β ij the rate at which a single infectious agent from age group j infects susceptible agents from age group i if no countermeasures, such as social distancing, are in place. we model β ij to be proportional to c ij and let α be the corresponding proportionality constant. if a single infectious agent is introduced without interventions such as test, quarantine and social distancing measures in place into the otherwise completely susceptible, i.e. virgin, population, the mean amount of secondary cases he causes is the basic reproduction number there is a wide variety of estimates for r in the literature [ ] , with most estimates in the interval [ , . ] . we choose a value of r = . as early, higher estimates might be biased upwards due to imported and undetected cases. fixing η − = (see the discussion on η a below) we calculate α = . % and in turn β ij from ( ): γ the rate at which latent cases become infectious is the inverse of the mean incubation time. this parameter is modeled age-independent and chosen to be . , which corresponds to a mean incubation time of . days [ ] . these parameters denote the proportion of individuals in age group i that have severe, mild or asymptomatic course of disease. for germany, the robert koch institut (rki) has published data on severity of disease progression for , cases by age-groups [ ] . for our purposes we define a severe case to be a case that will eventually be admitted to intensive care, a mild case being one developing influenza-like symptoms, pneumonia or being admitted to hospital for other reasons. all other cases we classified as asymptomatic. thus we obtain π i = (π s i , π m i , π a i ), the proportion of severe, mild and asymptomatic cases in age group i, respectively, as (π , π , π ) = observe that the oldest age group is at highest risk with . % of infected individuals admitted to icu. also the proportion of severe cases in the youngest age group is higher than in the middle age group. this might be explained by the fact that cases in the youngest age group are detected less frequently due to them being tested less, leading to overreporting of severe cases. η s , η m , η a these are the rates at which infectious individuals are removed from the infection process, if no mass-testing is implemented, i.e. if θ i = . for individuals with severe or mild course of disease when they develop symptoms leading to self-isolation, quarantine prescribed by a physician, or to direct hospitalization. one characteristic of covid- is that even presymptomatic cases transmit sars-cov [ ] . we assume the time from being infectious to symptom onset to be days after which we add more days which it takes before the infectee visits a physician. thus we choose η s = . . for mild progressions we assume the same mean duration from being infectious to symptomatic, though in this case individuals self-isolate, visit a physician or receive a positive test result after a mean waiting time of again more days; consequently, we also set η m = . . for asymptomatic cases in i a i the only way to be removed from the infection process is by recovery from the infection. in [ ] positive virus samples were found in patient's throats for up to days after symptom onset. assuming a lower viral load for asymptomatic cases with only days of potential infectiousness and adding the days of presymptomatic transmission we chose η a = . , corresponding to a mean time of days to recovery for asymptomatic cases. τ o , τ s as we assume the testing related to the controls θ i to be of a random nature, tested individuals are not yet removed from the infection process. instead we assume positive test results to become available after a mean delay of days. however, severe cases may visit a physician and thus go into immediate quarantine before receiving their test result. the latter transition occurs with rate η s , and hence the faster transition occurs with rate τ s = + η s = . . non-severe cases that are tested, t o i , are removed if they recover naturally (with rate η a ), or receive a positive test result, or visit a physician. that leads to τ o = η m + η a + = . for each age group. ρ this parameter is the rate at which severe cases move from being in the pre-icu state to the intensive care unit. this includes time spent in quarantine at home as well as time spent in the hospital in normal care while being isolated. in [ ] the median time from symptom onset to being in intensive care for patients was days. as the median of an exponential distribution exp(ζ) is log ζ we choose a mean stay of log − ≈ . = ρ − days, accounting for the mean two days from symptom onset to the transition into the pre-icu compartment. σ this is the mean time spent on intensive care until discharge or death. according to [ ] patients with acute respiratory distress symptoms (ards) spent a median amount of days in intensive care and patients without ards spent a median amount of days in intensive care. of the patients considered in this study, were afflicted with ards. converting again between median and mean for the assumed exponential distribution yields a mean time of σ − = the divi-intensivregister offers daily information on the amount of free intensive care hospital beds in germany. on october they reported a capacity of , free beds with actively treated covid- patients [ ] . we therefore round the maximal icu-beds available for covid- patients to , . t max in late august until the beginning of october the rki conducted between and . million weekly sars-cov- tests in germany. this motivates our upper bound t max = , , of daily tests. x we initialize our model at time t = with entries of x set to except for those related to the susceptible, latent and infectious compartments. our choice of initial values is informed by the number of active cases reported by the rki in late march assuming the proportion of underreporting to be %. we hence set the total number of infectious agents at t = to and the number of latent agents to distributed among the age-groups according to n i . as we explain in remark our model is robust against misspecification of the initial values. figure demonstrates the simulation capabilities of our model. here, the course of the pandemic is visualized if no countermeasures are implemented, i.e. no social distancing (β(t) = β ) and no mass-testing (θ(t) = ). as expected, the pandemic evolves too fast to satisfy any reasonable cap on the number of required icus. in particular, the number h icu of required icus exceeds , whereas we noted above that in germany only about , icus are available to treat covid- patients. therefore, countermeasures are indispensable to avoid an overload on the hospitals. note that if we distinguish different age groups the pandemic evolves faster, but less icus are required, as the pandemic spreads mostly in the less vulnerable, younger age groups. similar observations, viz. herd immunity being achieved faster in heterogeneous populations in comparison to homogeneous ones, have already been made by [ ] . in this section, we provide information on how to keep the epidemic manageable. to this end, we formulate suitable optimal control problems (ocps) and solve them numerically. since we neither take vaccines nor re-infections into account, we consider the epidemic to be over once herd immunity is achieved, i.e. a state where the introduction of new infectious agents does not lead to an outbreak. therefore, our main goal is to reach herd immunity with as few social distancing as possible while maintaining strict limits on the icu occupancy to avoid a breakdown of the health care system. we call a control u = (β, θ) of the system ( ) , . . . , n g }, and is satisfied for all t. a natural stopping point for simulations is when the share of susceptibles has decreased enough to ensure herd immunity even when all countermeasures are lifted completely. the time-dependent effective reproduction number r(t), that is the mean number of secondary cases a primary cases will cause at time t, can be used to determine whether herd-immunity has been reached: this will be the case if r(t) is less than . if there is only one infected compartment, as in a simple sir model, the latter condition is equivalent toİ(t) < . if there is more than one infected compartment, as in model ( ), [ , ] have suggested to compute r ngm (t), based on the so-called next-generation matrix, as a proxy for the effective reproduction number. then, r ngm (t) exhibits the same threshold property as r(t), that is r ngm (t) < implies herd immunity. thus we use r ngm (t) to check whether our simulations have reached herd immunity. a time horizon of two years ( weeks) sufficed for all our simulations. this section is structured as follows. first, we verify the existence of a feasible testing strategy, i.e. without enforcing social distancing. note that due to delays in testing, the existence of a solution is not trivial and depends on the initial value. next, we establish an upper bound on the maximal number of tests per day and investigate to what extent social distancing is required in order to ensure feasibility. throughout our simulations, we assume the length of one control interval to be one week. this reflects the practical constraint that the government cannot change policies arbitrarily often but more realistically on a weekly basis. throughout our simulations we use the matlab-inherent sequential quadratic programming (sqp) tool to solve the ocps. here, our goal is to maintain a hard cap on the number of required icus with as few tests as possible without enforcing social distancing, i.e. β ≡ β . to this end, we solve the ocp the objective function penalizes the total number of tests over the entire time horizon [t , t f ] with t f > t ≥ . the equality constraint ( c) captures the system dynamics while the one-sided box constraints ( e) ensure that the testing rates cannot be negative. figure depicts the optimal controls as well as the total number of tests and the number of detected cases per day while figure shows the impact on the evolution of the epidemic. here, we computed the effective reproduction number r ngm (t) at each time step, demonstrating that we reached herd immunity. we observe that there exists a testing strategy that ensures feasibility, which was not obvious from the outset because of the assumed delays. in particular, the bound ( b) is active once it's reached, i.e. h icu ≡ h icu max , and becomes inactive when the number of susceptible people falls below a certain threshold and r ngm (t) < indicating the onset of herd immunity. ( ) satisfies the socalled turnpike property [ ] . typically, turnpikes indicate the optimal operating state of a system. these are steady states at which the running costs are minimized. in our example, since we do not penalize the number of required icus, the best strategy is to stay at the upper bound while saving tests. once the objective function value is zero the system leaves the state eventually. in particular, regardless of the initial value, the system is steered towards this optimal operating point. as a consequence, a rough estimation suffices as initial guess for our simulations. a rigorous analysis of these turnpikes, however, is left for future research. however, these results are only of theoretical interest, since this optimal testing strategy would be prohibitively expensive and might not even be implementable at all. for instance, regarding figure , one observes that the mean testing rate reaches about . , which corresponds to being tested every two days on average. moreover, the total number of tests per day required for this approach is more than , , on average (over weeks), compared to t max ≈ , daily tests which are currently conducted in germany. note that, even with this enormous testing effort, the number of detected cases, t s + t o , is rather small since the number of infectious individuals is small compared to the total population. in conclusion, mass-testing alone currently does not suffice to maintain hospitalization caps in reality. these arguments support the government's decision to introduce additional measures like social distancing and hygiene concepts. however, cheap rapid test kits might change the situation favorably as they could be made widely available, self-administered while giving immediate test results. in the following subsections, we enforce t max as an upper bound on the amount of daily tests. under this additional constraint we then determine the minimal amount of social distancing required to reach herd immunity. the success of such measures depends on the acceptance and thus compliance by the general population. in a first step, we determine an optimal social distancing strategy by penalizing the deviation of β from β equally over all age groups. this might increase acceptance in the general population due to the (perceived) fairness of such measures: everyone is treated equally and contacts are reduced by the same proportion for everyone. in reality such strategies may be hard to conceive as different measures affect the age groups differently, i.e. closing schools and nurserys affects those in the lowest age group the most while leaving the oldest age group unaffected. nevertheless a mixture of many different non-pharmaceutical measures may be able to achieve such a reduction in contacts. we introduce a time-varying factor δ = δ(t) describing the amount of social distancing that is implemented. moreover, we choose to penalize the deviation of this control input from δ = in the objective function in order to smooth the optimal control. for instance, penalizing the deviation yields bang-bang controls, i.e. the optimal solution jumps back and forth between the two extremal options: no contact restrictions and lock down (simulations not shown). therefore, we determine an optimal homogeneous social-distancing policy by solving min θ,δ note that we allow to distribute the tests among the age groups by not fixing θ i , but enforcing ( e) and ( g). furthermore, we introduce a regularization term with weight κ = − . the choice of κ is based on simulations. in contrast to ( ), we always find a feasible solution of ( ) if the epidemic has not yet evolved too far. more precisely, by choosing δ = , which corresponds to a complete lockdown, we are (theoretically) able to stop the spread. therefore, if the initial number of people with a severe course of infection is sufficiently low, the upper bound on the number of icus will not be violated. a highly fluctuating social distancing strategy may lead to low acceptance in the general population, because people have to adapt to new rules every few weeks. thus before we solve ( ) let us have a look at what happens if we consider a constant value for δ over time, i.e. a social distancing strategy without fluctuations. figure (left) shows that fewer contacts result in a longer time for the epidemic to abate on the one hand, but a lower number of total infections within the considered time horizon on the other hand. moreover, figure (middle) visualizes that quite strict social distancing is needed in order to meet the icu capacities. the maximal value of δ to stay feasible is . , i.e. contacts needed to be more than halved over three years. furthermore, once we lift the restrictions, see figure , there might be another outbreak. in particular, the stronger the restrictions were in the beginning, the stronger the second outbreak will be. therefore, it is essential to establish herd immunity before lifting all restrictions, and to adapt the policy over time. a visualization of the optimal solution of ( ) can be found in figures and . as mentioned above, the bound on h icu is not violated. since the weight κ is chosen sufficiently small, the upper bound on the total number of tests per day is active as long as the upper bound on δ is not. however, note that not all age groups are tested equally. more precisely, only the middle-aged group is tested at all. the reason is that this group is the largest (n > n + n ) and has the highest contact rates (c.f. ( ) ) and therefore, contributes more to the spread of the epidemic than the other groups. furthermore, we observe that the social distancing policy has to be quite strict in the beginning. in particular, min t δ(t) ≈ . which corresponds to a reduction of average contacts per person by %. however, this can be qualitatively compared to the measures taken in germany starting in mid march when contacts were reduced by school and restaurant closures as well as other contact restrictions. in conclusion, social distancing is an effective tool to keep the epidemic manageable. comparing the results of ( ) to the simulations with constant δ we see that a (partial) lockdown appears inevitable. however, our simulations suggest to let the epidemic evolve for a few weeks, then enforce a contact reduction down to approximately % for - weeks before slowly lifting the restrictions over the next months until herd immunity is achieved. the constraint that contacts are reduced by the same proportion for each age group is restrictive and it is plausible that more efficient solutions exist when contact reductions are distributed differently across age groups. one reason to consider such a strategy is that it may be more efficient at stopping the spread of the epidemic; as mentioned above the middle-age group is the driver of the epidemic while the oldest age group consists of the most vulnerable individuals. in any case, such an age-differentiated social distancing strategy needs to be accepted by the whole population to be successful. hence, we improve the social distancing policy computed above by allowing it to depend on age. given the solution (θ , δ ) of ( ), we solve the ocp min θ,β here, we use δ to define β min ij = min t δ (t)β nom ij , i.e. the lower bound on β in ( ) is the worst case of ( ). therefore, no one is treated worse than when applying homogeneous social distancing. note that (θ , β) with β = δ β is feasible for problem ( ) . as in ( ) we penalize testing as soon as β(t) = β holds. results for ( ) can be found in figures and , wherē describes the average number of contacts per person and day in a heterogeneous population. here, we used κ = − . the corresponding value for β isβ = figure : optimal age-dependent social-distancing strategy for three age groups over two years. figure : evolution of the compartments associated with controls depicted in figure . . . this allows to compare the solution β ij (t) withβ δ (t) obtained from ( ) . similar to the solution of ( ), the upper bound on testing is active most of the time, while essentially only the middle-aged group is tested. the social distancing measures are less restrictive than for ( ) which makes compliance with the measures more likely. however, the measures could be perceived as unfair, since the contacts of the oldest age group are restricted most. moreover, the contacts of the middle-age group are least restricted. therefore, the working class would be allowed to go to work which benefits the economy. in conclusion, social distancing is crucial to avoid an overload on the hospitals. in addition, testing middle-aged people helps to reduce the required amount of social distancing. furthermore, all presented strategies support a lock down a few weeks into the epidemic, which is followed by lifting the restrictions step by step until herd immunity sets in. age-differentiated social distancing might be hard to argue for, but it helps to end the epidemic several months earlier and, therefore, support the economy. the control strategies derived in the previous subsections provide rough guidelines for how the epidemic can be controlled. however, from a decision maker's perspective, it will be hard to argue for policies taking effect in the far future. in particular, there are many uncertainties that might affect the performance of the control strategy over the time span of two years, and hence the control strategy needs to be adjusted over time. therefore decision need to be revised constantly adapting to the changing conditions during the epidemic's progress. model predictive control (mpc) provides a state of the art methodology to tackle such figure : optimal control for solving ( ) in closed loop for varying prediction horizon length. for the sake of readability, we depicted average values of θ and sums of t tot over the age groups. figure : evolution of the epidemic based on the controls depicted in figure . for the sake of readability, only the sum over the age groups is visualized. problems. the basic idea of mpc is to consecutively solve a series of ocps over a smaller horizon of k control intervals rather than solving a single ocp over the whole horizon. more precisely, only the first part of the optimal control derived by solving such an auxiliary ocp is implemented. then, the time window is shifted, and the procedure is repeated based on updated measurements. for a detailed introduction to mpc we refer to [ ] . here, we tackle ( ) via mpc; the earlier problems can be treated analogously. the mpc scheme for ( ) is summarized in algorithm . input: prediction horizon length k, length of control interval ∆t. set time t = t . repeat: . obtain current statesx = x(t). results based on varying prediction horizon lengths can be found in figures and . the basic structure of both the optimal control and the associated states is comparable to the open-loop solution presented in the previous subsection. therefore, we stopped the simulations after one and a half years. the length of the prediction horizon affects mainly the optimal social distancing policy. in particular, the larger the prediction horizon, the less social distancing is needed in total. more precisely, for bigger k, we implement a slightly stricter lockdown but can start it later and relax it earlier. furthermore, the larger k gets the closer the optimal solution is to the open-loop solution. in particular, the mpc solutions qualitatively resemble the open-loop solution: after an early lockdown, social distancing is slowly lifted. for k = , the icu capacity reaches its upper limit earlier due to the laissezfaire policy in the beginning. however, this constraint also becomes inactive earlier. for even shorter prediction horizons recursive feasibility cannot be guaranteed, i.e. the icu cap might be violated (simulations not shown). so far, we assumed both the upper bounds on the number of tests per day, and on the number of icus to be fixed at our chosen values. in practice, these conditions may change: free icu capacity might exhibit seasonal patterns and the number of possible tests per day depends on infrastructure and available personnel. in addition, varying the upper bounds is useful to illustrate the benefits of increased testing and higher icu capacities. in this subsection, we investigate the impact of these parameters on the optimal social distancing policy numerically. first, we study the effect t max has on the social distancing by solving ( ) via mpc, see figure (left). as pointed out in the previous subsection, the prediction horizon length affects the start and end time of measures as well as its peak (simulations not shown). in addition, increasing t max by some factor t max fac ≥ shifts the whole δ curve upwards, i.e., as expected, the more tests are available, the less social distancing is required. furthermore, figure (left) visualizes the impact of t max on the objective function value of ( ). figure : impact of t max on social-distancing costs (left) and of h max on both social-distancing costs (middle) and testing (right). in the last two subfigures the currently available number of icus in germany is highlighted by a vertical dashed line. the dashed horizontal lines in the right-most figure indicate the total testing capacities over the entire simulation horizon. factor of modification of t max denoted by t max fac . second, we investigate the impact of the number of icus on the optimal solution of ( ) . results can be found in figures and . for the simulations in figure (middle and right) we used mpc with prediction horizon k = weeks. figure (middle) clearly shows that the number of available icus directly affects the cost function value. while for a small value of h icu max , every additional icu contributes, for large values, a saturation seems to take place. in particular, doubling the current number of available icus does help, but the benefit becomes negligible when increasing it further. these phenomena are almost unaffected by doubling or halving t max . however, when there are not enough icus, then the upper bound on t tot is always active, see figure (right), where t tot is at its maximum value all the time. moreover, an increase in the number of icus clearly figure : impact of the available number h icu max of icus and the prediction horizon k on the average social distancing. the dotted cyan line refers to the number of currently available icus in germany. the vertical dotted black line marks the end of social distancing measures for that setting. leads to a reduction in the social distancing measures, as can be seen in figure . in summary, increasing test capacities and/or icu capacities helps to reduce measures like social distancing. however, the impact of the number of available icus appears to be much stronger. nonetheless the qualitative shape of the solutions over time is not affected by varying these constraints. in this paper, we demonstrated how mitigation of the covid- epidemic can be achieved by a combination of age-stratified testing and social distancing measures while avoiding a breakdown of the health care system. we showed that in our compartmental model mass testing alone is insufficient to achieve this goal, as it would require unrealistic testing capacities. as a remedy, we designed optimal social distancing strategies with a focus on applicability and acceptance in the general population, i.e. strategies with slowly changing contact reductions. the resulting social distancing measures imitate the measures actually taken in germany, but are lifted at a much slower pace. agedifferentiated contact reductions may improve upon these results as they yield qualitatively similar social distancing strategies and prioritize relaxing restrictions for the work-force and children. to model the process of policy making more realistically, we used mpc which allows to adapt to deviations from the envisioned course of the epidemic by solving the optimal control problem repeatedly. our analysis reveals that longer prediction horizons allow for faster lifting of restrictions although long-term predictions may be infeasible in practice. additionally we showed that the amount of available intensive care units is a key factor influencing the required amount of social distancing. we believe that our model with the chosen parameters reflects reality sufficiently well to provide qualitatively valid insight on how testing and social distancing can control the spread of sars-cov- . we learned that mass testing alone is, assuming realistic testing capacities, not sufficient to avoid a breakdown of the health care system in germany. to prevent this, one has to implement strict contact reductions early on, which, ideally, should then be eased slowly. if one allows these reductions to vary by age, one is able to relax restrictions for the (working) middle age group, at the cost of reducing contacts of the more vulnerable older population. while short-term planning of measures is unable to control the exponential growth of cases, medium-term planning produces strategies that, qualitatively, do not differ from optimal ones while being flexible enough to adapt to new circumstances. finally, as expected, the number of available intensive care units dictates how fast herd-immunity can be reached and how much total social distancing is necessary. however, we caution the reader against interpreting these results in a quantitative way, as our model has not been devised to produce precise predictions. similarly, we want to stress that we do not provide concrete policies to implement, as the impact of particular countermeasures on β is not easily quantified. concerning other influences on the epidemic's evolution, note that we have not yet considered vaccinations nor re-infections, both of which could be included in our model without difficulties, if parameters are available to model them. as our model is based on odes, interaction effects such as contact tracing cannot be included. agent-based (stochastic) models are able to handle these critical effects and could be seen as a natural extension of our (deterministic) compartmental model. to solve the resulting stochastic optimal control problems would then require more sophisticated techniques, however. a model for covid- with isolation optimal control of deterministic epidemics time-optimal control strategies in sir epidemic models optimal control techniques based on infection age for the study of the covid- epidemic a mathematical model reveals the influence of population heterogeneity on herd immunity to sars-cov- applying optimal control theory to complex epidemiological models to inform real-world disease management model predictive control to mitigate the covid- outbreak in a multi-region scenario on the definition and the computation of the basic reproduction ratio r in models for infectious-diseases in heterogeneous populations charakteristik von hospitalisierten covid- -patienten mit und ohne ards maintaining hard infection caps in epidemics via the theory of barriers. e-print optimal vaccination and control strategies against dengue modelling the covid- epidemic and implementation of population-wide interventions in italy optimal quarantine strategies for the covid- pandemic in a population with a discrete age structure approximation properties of receding horizon optimal control optimal control of epidemics with limited resources temporal dynamics in viral shedding and transmissibility of covid- the mathematics of infectious diseases policy responses to covid- world economic outlook: a long and difficult ascent beyong just flattening the curve: optimal control of epidemics with purely non-pharmaceutical interventions the incubation period of coronavirus disease (covid- ) from publicly reported confirmed cases: estimation and application evolution of the covid- vaccine development landscape an optimal predictive control strategy for covid- (sars-cov- ) social distancing policies in brazil social contacts and mixing patterns relevant to the spread of infectious diseases stability of sis spreading processes in networks with non-markovian transmission and recovery the territorial impact of covid- : managing the crisis across levels of government a systematic review of covid- epidemiology based on current evidence optimal control of the covid- pandemic with non-pharmaceutical interventions a survey of industrial model predictive control technology model predictive control: theory, computation, and design age-structured non-pharmaceutical interventions for optimal control of covid- epidemic. e-print, medrxiv vorläufige bewertung der krankheitsschwere von covid- in deutschland basierend aufübermittelten fällen gemäß infektionsschutzgesetz bevölkerung: deutschland, stichtag, altersjahre modeling, state estimation, and optimal control for the us covid- outbreak reproduction numbers and subthreshold endemic equilibria for compartmental models of disease transmission robust economic model predictive control of continuous-time epidemic processes clinical presentation and virological assessment of hospitalized cases of coronavirus disease world health organization. coronavirus disease (covid- ) situation report non pharmaceutical interventions for optimal control of covid- we thank kurt chudej (university of bayreuth) for insights on modelling pandemics and manuel schaller (tu ilmenau) for fruitful discussions on optimal control and the turnpike property. key: cord- -sbalcd v authors: ma, xiya; vervoort, dominique title: critical care capacity during the covid- pandemic: global availability of intensive care beds date: - - journal: j crit care doi: . /j.jcrc. . . sha: doc_id: cord_uid: sbalcd v nan as the covid- pandemic grows, the need for rapid, innovative, and cost-effective emergency response mechanisms and the presence of gaps in critical care capacity become glaringly obvious in most countries and territories worldwide. in the united states, models project that major academic centres' hospitalization capacity will be saturated within weeks, notably including their intensive care unit (icu) capacity. furthermore, low-and middleincome countries (lmics) are at-risk for an inability to manage an anticipated surge of critically ill covid- patients, with current estimates suggesting the availability of . to . icu beds per , population. while several studies have evaluated critical care capacity in some regions, there has yet to be a comprehensive survey of icu beds worldwide. the objective of this study consists of mapping the global availability of critical care infrastructure with a focus on the distribution of icu beds. a literature search was performed using the pubmed/medline and google scholar databases to identify the most recent number of icu beds per country or territory, including pediatric and neonatal icu but excluding psychiatric icus. additionally, national and international media and grey literature were searched in english and all official languages of each country. countries were categorized as lmic versus high-income countries (hics) according to the world bank income group classification. for low-income countries, it was assumed that icu beds were only available in teaching and referral hospitals. data was available for countries and territories, ranging from to . icu beds per , population (figure ; appendix table ) . globally, at least countries and j o u r n a l p r e -p r o o f journal pre-proof territories had a density of less than . icu beds per , population. the availability of icu beds ranged from none (nauru, solomon islands, and south sudan) to . per , population (kazakhstan) in lmics and none (liechtenstein and palau) to . per , population (monaco) in hics. in africa, densities ranged from (south sudan) to . (egypt) per , population. apart from seychelles ( . ), south africa ( . ), and egypt ( . ), all african countries had a density of less than . icu beds per , population. traditionally, icu beds have a high baseline occupancy rate. % of covid- cases are expected to require icu admission, mathematically already overwhelming a handful of countries based on real-time case numbers, and disregarding the need for icu beds for non-covid- emergencies. to respond to the growing shortages of icu beds and ventilators, frameworks for rationing have been developed to ensure the fair allocation of scarce resources. as the world responds to the growing covid- pandemic, a shift in contemporary global public health priorities exposes critical gaps in health systems around the world. whilst the critical care capacity in lmics was insufficient prior to the pandemic, deficiencies grow to include highly-resourced health systems around the world. our study has several limitations. first, the scarcity of comprehensive data available in peer-reviewed literature or white papers required the reliance on local and national media to collect data on the number of icu beds for countries and territories. our results are limited to internet-searchable information, and we cannot disregard the possibility of the numbers to be under-estimates because of publicly under-reporting. second, accessibility to icu care, a challenge in many countries with (partially) private health care systems, is not taken into account when assessing capacity. the availability of an icu bed does not j o u r n a l p r e -p r o o f journal pre-proof locally informed simulation to predict hospital capacity needs during the covid- pandemic achieving affordable critical care in lowincome and middle-income countries world bank country and lending groups an interactive web-based dashboard to track covid- in real time a framework for rationing ventilators and critical care beds during the covid- pandemic key: cord- -tj wo s authors: chelly, jonathan; mazerand, sandie; jochmans, sebastien; weyer, claire-marie; pourcine, franck; ellrodt, olivier; thieulot-rolin, nathalie; serbource-goguel, jean; sy, oumar; vong, ly van phach; monchi, mehran title: automated vs. conventional ventilation in the icu: a randomized controlled crossover trial comparing blood oxygen saturation during daily nursing procedures (i-nursing) date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: tj wo s background: hypoxia is common during daily nursing procedures (dnps) routinely performed on mechanically ventilated patients. the impact of automated ventilation on the incidence and severity of blood oxygen desaturation during dnps remains unknown. methods: a prospective randomized controlled crossover trial was carried out in a french intensive care unit to compare blood oxygen pulse saturation (spo( )) during dnps performed on patients mechanically ventilated in automated and conventional ventilation modes (av and cv, respectively). all patients with fio( ) ≤ % and without prone positioning or neuromuscular blocking agents were included. patients underwent two dnps on the same day using av (intellivent-asv®) and cv (volume control, biphasic positive airway pressure, or pressure support ventilation) in a randomized order. the primary outcome was the percentage of time spent with spo( ) in the acceptable range of – % during the dnp. results: of the included patients, % had been admitted for a medical pathology, the majority for acute respiratory failure ( %). there was no difference between the two periods in terms of dnp duration, sedation requirements, or ventilation parameters, but patients had more spontaneous breaths and lower peak airway pressures during the av period (p < . ). the percentage of time spent with spo( ) in the acceptable range during dnps was longer in the av period than in the cv period ( ± vs. ± , percentage of dnp period; p = . ). after adjustment, av was associated with a higher number of dnps carried out with spo( ) in the acceptable range (odds ratio, . ; % ci, . to . ; p = . ) and a lower incidence of blood oxygen desaturation ≤ % (adjusted odds ratio, . ; % ci, . to . ; p = . ). conclusion: av appears to reduce the incidence and severity of blood oxygen desaturation during daily nursing procedures (dnps) in comparison to cv. trial registration: this study was registered in clinical-trial.gov (nct ) in june . graphical abstract: [image: see text] daily nursing procedures (dnps) are routinely performed several times per day in the intensive care unit (icu) and are crucial for patients' hygiene and rehabilitation, and to prevent/treat complications due to immobilization [ ] [ ] [ ] [ ] . however, these dnps induce physiological changes with potential adverse effects, especially in patients undergoing mechanical ventilation (mv) [ ] [ ] [ ] [ ] [ ] . respiratory events, in particular oxygen desaturation, are often observed during dnps but are not well documented [ ] . although the potential adverse effects may be serious (e.g., severe hypoxemia and cardiac arrest), these events are often downplayed, considered as a normal part of dnps, or ignored in interventional studies regarding mv in icu patients [ ] . as suggested by previous works, protocols should be developed to prevent such respiratory events [ , ] . intellivent-asv® (hamilton medical, bonaduz, switzerland) is an automated ventilation mode (av) that automatically adjusts ventilation and oxygenation settings to keep end-tidal co (petco ) and spo in target ranges set by the clinician [ ] . briefly, minute volume is adjusted according to petco information or respiratory rate in passive or spontaneously breathing patients respectively and fio and peep are adjusted according to blood oxygen pulse saturation (spo ) information. the safety, feasibility, and efficacy of this mode have been demonstrated with promising results that show a reduction in both the number of manual interventions needed and the incidence of blood oxygen desaturation for various patient conditions, including acute respiratory failure, post-cardiac surgery, and weaning from mv [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . to our knowledge, however, no study has assessed the impact of av on the incidence of respiratory events during dnps. the aim of our study was to compare the incidence and severity of blood oxygen desaturation during dnps performed on patients ventilated in av and in conventional ventilation mode (cv). this single-center randomized controlled crossover study was conducted from september to march in a -bed, mixed icu of a french tertiary center. all patients of both sexes mechanically ventilated for at least h with a fraction of inspired oxygen (fio ) ≤ % were included. exclusion criteria were prone positioning, use of neuromuscular blocking agents, age < years old, pregnant women, patients with a contraindication to av (delirium, broncho-pleural fistula, respiratory drive disorder such as cheyne-stokes breathing), and patients with a low-quality measurement for spo . the study was initiated and supported by the groupe hospitalier sud ile de france (melun, france). the study protocol was approved on the th of september by the ethical committee (comité de protection des personnes ile de france vi) and registered in clinicaltrials.gov (nct ). patients or their next-of-kin gave their informed consent before randomization. all included patients were ventilated using a hami lton-s ventilator (hamilton medical, bonaduz, switzerland) and spo was monitored using a dedicated sensor (masimo set®, masimo corporation, irvine, usa) connected to the patient's monitor (beneview t ®, mindray, shenzhen, china). after randomization, each patient underwent two dnps on the same day, with h between the two. one was performed in cv and the other in av in a randomized order defined at inclusion. dnps were performed by two nurses and included a bundle of care covering patient hygiene (bathing, change of bed linen), mobilization (repositioning), ventilatorassociated pneumonia prevention (oral hygiene care, subglottic secretion drainage, adjustment of endotracheal tube cuff pressure), and pressure ulcer prevention and treatment (massage of back and pressure points). all the patient's monitoring and ventilation parameters, including heart rate, mean arterial pressure, spo , fio , expiratory tidal volume, total and spontaneous respiratory rate, positive end-expiratory pressure (peep), and inspiratory and mean airway pressure, were automatically recorded every minute during the dnp using evolucare intensive . ® (evolucare technologies, villers-bretonneux, france). arterial blood gas samples were performed min before each dnp to determine the pao /fio ratio. all events that occurred during the dnps, such as blood oxygen desaturation, change of ventilation mode, accidental disconnection of the ventilator, the need for manual ventilation, activation of an oxygen bypass, or endotracheal suctioning, were also reported by the nurse in charge. at least min before each of the two dnps, the attending physician set the mv mode according to the randomized order. for the cv period, the mode and ventilator settings were selected by the attending physician according to patient's pathologies and conditions: either volume control (vc), biphasic positive airway pressure (bipap), or pressure-support ventilation (psv). in vc mode, the tidal volume (v t ) was set below ml/ kg predicted body weight (pbw) for acute respiratory distress syndrome, below ml/kg pbw for subjects with normal lungs, and below ml/kg pbw for subjects with chronic obstructive pulmonary disease. in bipap and psv, inspiratory pressure and pressure support were set according to the same v t limits as in vc. plateau pressure was limited to cmh o, while positive endexpiratory pressure (peep) and fio were set to maintain spo before the dnps at between and % [ , ] . during the dnps, nurses were responsible for maintaining spo within an acceptable range of - % by adjusting the fio setting. the basic principles of inte llivent-asv® are detailed as previously described [ ] in the online supplemental content . before the dnp in av, automated fio and peep controllers were set by the attending physician with a lower limit for spo at % and a peep limited to - cmh o. the high limit for airway pressure was set at a maximum of cmh o. for both dnps, alarm limits were set by the clinicians. in the case of major blood oxygen desaturation (spo ≤ % according to guidelines [ ] ), the nurse in charge was required to apply a specific protocol (see online supplemental content ) and a physician was always present in the icu in case a problem persisted. sedation infusion, inspiratory trigger, pressure rise, expiratory trigger, and ventilator circuit were the same in both periods. the primary outcome was the time spent with spo values of - % (considered to be the acceptable spo range during the dnp). secondary outcomes were as follows: incidence of spo in the acceptable range during the dnp; mean, minimum, and maximum spo during the dnp (spo mean , spo min , and spo max , respectively); incidence and time spent with spo lower than %; incidence and time spent with spo lower than %; and time spent with fio at %. the safety outcome parameters were the occurrence of major adverse events (accidental endotracheal tube removal, bradycardia lower than bpm, or cardiac arrest) during the dnp. two interim analyses for primary and safety outcome parameters were planned after and patients were enrolled. based on previous studies on dnps [ , ] and retrospective data collected in our institution, we estimated that patients spent % of the dnp duration with spo between and %. we calculated a sample size of patients by group to detect a % increase in the primary outcome for dnps performed in av as compared to cv ( -sided α = . ; power %). continuous variables are expressed by mean ± standard deviation and nominal variables as n (%). continuous variables were compared using the non-parametric wilcoxon test and nominal variables were compared using fisher's exact test. after a univariate analysis to assess all risk factors for primary and secondary outcomes, a multivariate analysis was performed including all univariate factors with p < . . differences were considered significant where p < . . all calculations were performed using spss statistics v ® (ibm, new york, usa). there were no safety issues that required premature interruption. among the patients assessed for eligibility, were excluded, leaving for inclusion ( fig. ) . fifteen patients in both periods were subsequently excluded from the analysis due to recording failure, resulting in patients with one dnp in each period for the final analysis. baseline characteristics of the overall cohort are detailed in table . patients were primarily admitted for a medical pathology ( %) and half were intubated for acute respiratory failure ( %). the mean time of mv before inclusion and the total mv duration were ± and ± days, respectively. of the patients, ( %) were successfully weaned from mv and ( %) died before icu discharge. the interval between both dnps was ± min. before the dnp, spo was significantly lower in av than in cv ( ± % vs. ± %, respectively; p < . ), whereas pao /fio and spo /fio were similar (p = . and . , respectively). dnp duration varied from to min in the overall cohort. as detailed in table , dnp duration and patient sedation levels were similar during both periods, as were hemodynamic parameters, tidal volume, total breathing rate, and peep level. during the cv period, bipap mode was largely used ( %) and patients had a significantly lower spontaneous breathing rate than during the av period ( ± vs. ± breath/min, respectively; p < . ). patients had a lower peak airway pressure ( ± vs. ± cmh o; p < . ) and mean airway pressure ( ± vs. ± cmh o; p < . ) during the av period than during the cv period. data for the primary and secondary endpoints are provided in table . patients spent significantly more time in the acceptable spo range during the av period ( ± vs. ± % of dnp period; p = . ). in patients ( %), spo was in the acceptable range during the av period as compared to patients ( %) during the cv period (p = . ). after adjustment for confounding factors, av was associated with a greater number of dnps performed with spo in the acceptable range (odds ratio [or], . ; % confidence interval [ci], . to . ; p = . ; see online supplemental content ). in the overall cohort, blood oxygen desaturation to levels < % and ≤ % occurred in ( %) and ( %) patients, respectively. incidences of blood oxygen desaturation to lower than % were less frequent during the av period than during the cv period ( [ %] vs. [ %], episodes > min; p = . ) and were also shorter ( ± vs. ± , % of dnp period; p = . ). incidences of major blood oxygen desaturation (≤ %) were less frequent during the av period than during the cv period ( [ %] vs. [ %] , episodes > min; p = . ) and were also shorter ( ± vs ± , percentage of dnp period; p = . ). after adjustment for confounding factors, av was associated with a lower incidence of blood oxygen desaturation ≤ % during dnps (or, . ; % ci, . to . ; p = . ; see online supplemental content ). as shown in fig. , more patients had spo min in the optimal range during the av period (p = . ), while more patients had the spo min ≤ % during the cv period (p = . ). there was no difference between the two periods for the other secondary endpoints (table ) . nurse/physician/ventilator interventions, safety, and major adverse events all the unplanned interventions performed by a nurse or physician during dnps are detailed in the online this is the first study to test the ability of av to reduce the occurrence of oxygen desaturation during dnps routinely performed in icu patients undergoing mv. in this randomized crossover trial, the use of av (in this case intellivent®-asv®) was superior to cv with respect to maintaining spo within an acceptable range and reducing the incidence and severity of oxygen desaturation. although icu nurses and physicians frequently observe blood oxygen desaturation relating to dnps in their daily practice, these respiratory events remain poorly documented. in a cohort of icu patients (including % under mv), de jong et al. observed blood oxygen desaturation ≤ % and ventilatory distress (severe patient-ventilator asynchrony, nonstop coughing, impossible ventilation, and/or tachypnea) in and %, respectively, of the dnps performed [ ] . in a prospective study on icu patients undergoing mv, nursing procedures were observed and blood oxygen desaturation ≤ % was the most frequent adverse event described, representing % of the overall major physiological changes reported by the authors [ ] . for our overall cohort, we reported blood oxygen desaturation < and ≤ % during dnps in and %, respectively. various physiological changes may be implicated by the occurrence of blood oxygen desaturation during dnps. patient mobilization is one of the most important, and in particular lateralization, which can induce a decrease in lung compliance, alveolar derecruitment, mobilization of respiratory-tract secretions, airway irritations and coughing, ventilator-patient asynchrony [ , [ ] [ ] [ ] [ ] , and an increase in oxygen consumption [ , ] . all those physiological events could be induced by mobilization itself and/or the stress response associated with pain [ , [ ] [ ] [ ] . the impact on patient outcomes of dnps and their related adverse events remains unclear. previous studies have suggested that early mobilization of the patient would be associated with a greater chance of achieving rehabilitation objectives in the icu setting [ ] [ ] [ ] [ ] . de jong et al. observed an incidence of cardiac arrest in % of the dnps performed, while we did not report any incidence of cardiac arrest or death related to dnps in our overall cohort. our study suggests av may have a protective effect when compared to cv in terms of spo values and the incidence and severity of blood oxygen desaturation during dnps. a prospective randomized controlled study of post-cardiac surgery patients showed that in comparison to cv, intellivent-asv® significantly reduces mv duration before inclusion-days ± ( - ) chest radiograph opacities-quadrants ± ( - ) categorical variables are expressed as n (%) and continuous variables as mean ± standard deviation ( % confidence interval) copd chronic obstructive pulmonary disease, saps- simplified acute physiological score , sofa sepsis-related organ failure assessment, icu intensive care unit, mv mechanical ventilation the percentage of time, as well as the total duration and number of episodes per patient of ventilation parameters (including tidal volume, etco , plateau pressure, and spo ) being within a "not acceptable" zone [ ] . during the weaning period in icu patients, intellivent-asv® improved the pao /fio ratio compared to psv [ ] . in accordance with our results, another randomized trial including icu patients showed that intelli-vent-asv® was superior to pressure assist-control and psv for maintaining spo in an optimal range defined by the authors as between and % [ ] . the positive results of av on the incidence of blood oxygen desaturation may be explained by many factors: intellivent-asv® continuously and quickly adapts oxygenation, increasing peep and fio when spo decreases, but also by automatically decreasing peep and fio when spo is supranormal. in contrast, nurses and physicians are not able to adjust fio every time while they are providing care, especially during mobilization of a patient. as suggested by our results, the need for endotracheal suctioning during dnps seems less frequent in av, which could be interpreted as the cause or the consequence of a lower incidence of blood oxygen desaturation. several factors may limit the interpretation of our data. first, this was a single-center study in a single-blinded design, carried out in an icu staffed by nurses and physicians considered as advanced users of av. however, previous studies have consistently reported on the efficacy and safety advantages of using av over cv [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . second, patients in unstable respiratory conditions, such as high fio > % with or without the use of neuromuscular blocking agents and/or with prone positioning, were excluded from the study. in our icu, as is general practice in many icus, dnps in patients with unstable respiratory conditions are delayed until the patient's condition peep-cmh o † ± ( - ) ± ( - ) . categorical variables are expressed as n (%) and continuous variables as mean ± standard deviation ( % confidence interval) pbw predicted body weight, rr respiratory rate, petco end-tidal co partial pressure, peep positive end-expiratory pressure *measured the minute before starting the dnp **measured min before starting the dnp ***defined as no spontaneous breathing detected by the ventilator † mean of the overall parameters monitored every minute during the dnp improves or performed with fio set at % by default. third, we should have systematically assessed and prevented pain related to patient's care. indeed, the incidence of respiratory events decrease significantly with the application of an analgesic protocol before and during dnp, as previously described by de jong et al. future studies on dnp should take pain prevention and treatment into account [ ] . moreover, we cannot draw any conclusions with respect to a protective or harmful effect of av in terms of ventilator-induced lung injury (vili) during dnps. tidal volumes were higher than the initial setting for both periods, probably due to an increase in the patient's ventilatory drive during mobilization (induced by stress, pain, etc.). however, inspiratory pressure was lower and spontaneous breathing was higher during dnps in av. future studies are needed to assess mechanical power and the risk of vili during dnps [ ] . fourth, we may have underestimated the incidence of short oxygen desaturation (< min) because we have not performed a breath by breath monitoring. fifth, the accuracy of spo measurements remains controversial, particularly in icu patients with acute organ failure, as previously observed [ ] . however, blood gas samples are not easy to perform during dnp and spo represents the only parameters to assess oxygenation at bedside during this procedure. finally, although we found a significant difference in the primary outcome in favor of av during dnps, the clinical impact remains unknown. further studies are warranted to confirm our results and to assess the real impact on patient outcomes and management. categorical variables are expressed as n (%) and continuous variables as mean ± standard deviation ( % confidence interval) dnp daily nursing procedure, spo blood oxygen pulse saturation, fio fraction of inspired oxygen, spo mean mean spo during dnp, spo min minimal spo recorded during dnp, spo max maximal spo recorded during dnp *spo acceptable range was ≥ and ≤ % **for more than min fig. comparison between conventional and automated ventilation in terms of minimal, mean, and maximal blood oxygen saturation (spo ) during daily nursing procedures (*p < . ) creating the animated intensive care unit strategies for post icu rehabilitation body positioning of intensive care patients: clinical practice versus standards a prospective observational study of icu patient position and frequency of turning increased splanchnic oxygen extraction because of routine nursing procedures body position change and its effect on hemodynamic and metabolic status secondary insults related to nursing interventions in neurointensive care: a descriptive pilot study the effect of nursing interventions on the intracranial pressure in paediatric traumatic brain injury decreasing severe pain and serious adverse events while moving intensive care unit patients: a prospective interventional study (the nurse-do project) physiological changes associated with routine nursing procedures in critically ill are common: an observational pilot study daily nursing care on patients undergoing venous-venous extracorporeal membrane oxygenation: a challenging procedure oxygen desaturation and nursing practices in critically ill patients. iosr jnhs safety and efficacy of a fully closed-loop control ventilation (intellivent-asv(r)) in sedated icu patients with acute respiratory failure: a prospective randomized crossover study evaluation of fully automated ventilation: a randomized controlled study in post-cardiac surgery patients prospective randomized crossover study of a new closed-loop control system versus pressure support during weaning from mechanical ventilation fully automated closed-loop ventilation is safe and effective in post-cardiac surgery patients feasibility study on full closed-loop control ventilation (intellivent-asv) in icu patients with acute respiratory failure: a prospective observational comparative study closed-loop ventilation mode (intellivent®-asv) in intensive care unit: a randomized trial of ventilation delivered closed loop ventilation mode in intensive care unit: a randomized controlled clinical trial comparing the numbers of manual ventilator setting changes airway and transpulmonary driving pressures and mechanical powers selected by intellivent-asv in passive, mechanically ventilated icu patients effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit: the oxygen-icu randomized clinical trial british thoracic society guideline for oxygen use in adults in healthcare and emergency settings positional hypoxemia during artificial ventilation lateral positioning of ventilated intensive care patients: a study of oxygenation, respiratory mechanics, hemodynamics, and adverse events effects of patients positioning on respiratory mechanics in mechanically ventilated icu patients the effect of patient positioning on dynamic lung compliance prevention of endotracheal suctioning-induced alveolar derecruitment in acute lung injury a meta-analysis of the effects of various interventions in preventing endotracheal suction-induced hypoxemia changes in lung volume with three systems of endotracheal suctioning with and without pre-oxygenation in patients with mild-to-moderate lung failure ventilator-related causes of lung injury: the mechanical power comparative evaluation of accuracy of pulse oximeters and factors affecting their performance in a tertiary intensive care unit publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we are indebted to caroline huber-brown for editorial assistance. all authors have contributed to the final version of the manuscript as follows: jc and sj contributed to the study concept and design; jc, sm, sj, cw, fp, oe, nt, js, os, and lv contributed to patient's inclusion; jc and sm contributed to data collection; jc and sj contributed to data analysis; and jc, sj, and mm drafted and revised the manuscript. the authors read and approved the final manuscript. the study was integrally supported by the groupe hospitalier sud ile de france (melun, france). av used during dnps routinely performed on icu patients undergoing mv appears to be superior to cv in maintaining spo within an acceptable range and reducing the incidence and severity of desaturation, with more spontaneous breathing and lower peak and mean airway pressure. supplementary information accompanies this paper at https://doi.org/ . /s - - - .additional file : online supplemental content . basic principles of intellivent-asv®. supplemental content . protocol for nurses in case of major blood oxygen desaturation (spo ≤ %) during the daily nursing procedure (dnp). supplemental content . multivariate logistic regression test for spo in the acceptable range (between % and %) during the daily nursing procedure (dnp). supplemental content . multivariate logistic regression test of risk factors for occurrence of at least one major oxygen desaturation (spo ≤ %) during the daily nursing procedure (dnp). supplemental content . nurse/physician interventions during the daily nursing procedure (dnp) according to ventilation mode (cv conventional ventilation; av automated ventilation). the dataset used and/or analyzed during the current study are available from the corresponding author on reasonable request. the study protocol was approved on the th of september by the ethical committee (comité de protection des personnes ile de france vi; id number -a - ) and registered in clinical-trial.gov (nct ). patient or their next-of-kin gave their informed consent before randomization. competing interests jc and sj received fees from hamilton medical for lecturing. the remaining authors declare that they have no competing interests.received: february accepted: july key: cord- -svjajpp authors: kohler, j.; schwenkel, l.; koch, a.; berberich, j.; pauli, p.; allgower, f. title: robust and optimal predictive control of the covid- outbreak date: - - journal: nan doi: nan sha: doc_id: cord_uid: svjajpp we investigate adaptive strategies to robustly and optimally control the covid- pandemic via social distancing measures based on the example of germany. our goal is to minimize the number of fatalities over the course of two years without inducing excessive social costs. we consider a tailored model of the german covid- outbreak with different parameter sets to design and validate our approach. our analysis reveals that an open-loop optimal control policy can significantly decrease the number of fatalities when compared to simpler policies under the assumption of exact model knowledge. in a more realistic scenario with uncertain data and model mismatch, a feedback strategy that updates the policy weekly using model predictive control (mpc) leads to a reliable performance, even when applied to a validation model with deviant parameters. on top of that, we propose a robust mpc-based feedback policy using interval arithmetic that adapts the social distancing measures cautiously and safely, thus leading to a minimum number of fatalities even if measurements are inaccurate and the infection rates cannot be precisely specified by social distancing. our theoretical findings support various recent studies by showing that ) adaptive feedback strategies are required to reliably contain the covid- outbreak, ) well-designed policies can significantly reduce the number of fatalities compared to simpler ones while keeping the amount of social distancing measures on the same level, and ) imposing stronger social distancing measures early on is more effective and cheaper in the long run than opening up too soon and restoring stricter measures at a later time. social distancing is an effective way to contain the spread of a contagious disease, particularly when little is known about the virus and no vaccines or other pharmaceutical interventions are available. social distancing and isolation (together with other non-pharmaceutical measures such as hygiene and face masks) have a direct influence on the infection rates and hence on the spread of the virus [ , , ] . while this combination has proven effective during the last weeks, e.g. in the german outbreak of covid- , strict social distancing is also very costly in terms of economical and psychological damage, which naturally leads to a multi-objective decision problem. there have been numerous approaches to model the covid- outbreak and to predict future behavior for different distancing policies in simulation studies. the most commonly used modeling approaches are different extensions of the sir (susceptible-infected-removed) model formulated either as system dynamics or as agent-based simulations (e.g. for germany [ , , ] ). in many such studies, different policies are simulated and compared with respect to the goals that both the health care system is not overwhelmed such that every patient in need receives treatment and the mortality rate is kept low, and also such that the majority of people can resume social interaction as soon as possible. however, in line with [ ] and others, we advocate to go from mere model predictions to (model predictive) control, since control generally offers the theory to develop and apply optimal or robust decision making under uncertainties. while mathematical modeling and control of epidemics is a topic with rich history (see, e.g., the survey in [ ] and the references therein), there have also been numerous approaches to apply control theory to the covid- spread. in [ ] , the author applies control theoretic principles and insights to a simple model of the outbreak to point out the difficulties of the system at hand: fast unstable dynamics with significant delays. in more recent literature, multiple works have addressed the problem of open-loop optimal control for the covid- pandemic. in [ , ] , for example, the authors argue in favor of 'on and off'-policies of the social distancing measures, yielding a bang-bang like optimal control strategy. such 'on and off'-policies, where the control input switches between two states, however, could pose great challenges, amongst others, for the society, but also for production lines, supply chains and the economy in general. in this paper, we propose optimal open-loop and feedback control strategies to handle the german covid- outbreak. we employ the recently developed sidarthe model [ ] in order to design control policies which minimize the number of fatalities within a time horizon of two years, without using excessive social distancing measures. we also address robustness of our policies w.r.t. model and measurement uncertainties via a (robust) model predictive control (mpc) feedback strategy. similar to the setup in this paper, the authors in [ ] explore the best policy to implement while waiting for the availability of a vaccine. in their paper, they also distinguish between varying severity of symptoms ('mild' or 'severe') and seek a solution to the multi-objective optimization problem of minimizing fatalities and costs due to the implementation of the control strategy itself. their main outcome of the open-loop input strategy is qualitatively similar to our results in section . : start with a loose strategy, soon increase all distancing measures such that the health care system capacities are never extorted and then relax the social distancing measures gradually and slowly. another example for an open-loop optimal policy applied to the covid- pandemic is presented in [ ] where the authors consider optimal control of the german outbreak using a slightly simpler model as the one chosen in the present paper (without distinguishing between detected and undetected individuals), which also includes an increased mortality rate if the icu capacity is exceeded. therein, the objective is not only to minimize the number of fatalities but also the number of susceptible individuals at the end of the time horizon, thus aiming for herd immunity. our investigations in section , however, indicate that herd immunity cannot be reached in a reasonable amount of time without overwhelming the hospital capacities. therefore, our approach minimizes the number of fatalities after two years, with the underlying assumption that a vaccine will be available thereafter. however, an open-loop optimal policy cannot suffice to control the covid- pandemic given all the uncertainties in the spreading of the virus and the disease progression, as we will see in the numerical results. we argue, similar to [ ] , that an mpc-based feedback strategy is the right tool to develop optimal and robust social distancing policies, especially in the presence of model inaccuracies. by using online measurements of the current outbreak, feedback inherently introduces robustness with respect to uncertainties and disturbances to the policy. we also robustify the feedback mechanism by introducing a robust mpc-based feedback strategy for uncertain state measurements which is crucial in a situation where only a limited amount of data is available and, for example, the number of the currently infected persons can only be estimated roughly by applying different studies. our results are also in accordance with a very recently published joint strategy paper for germany by authors from different german research institutions (fraunhofer-gesellschaft, helmholtz association, leibniz association and max planck society) [ ] . firstly, they also state that reaching herd immunity without the availability of a vaccine would either exceed the health care capacities (with a resulting high mortality rate) or take several years (cf. our results in section ). secondly, they state that the goal of wiping out the virus can only be a robust solution if this eradication would be a worldwide effort with very high social and economic costs (cf. our results in section . . ), which seems impossible to realize. finally, they suggest an adaptive strategy for all policies influencing the infection rates with the goal to keep the spread of covid- at bay while requiring the least possible restraints on the society and economy. with exactly this reasoning, we develop suitable control approaches in section . , section , and section for such an 'adaptive' strategy. to summarize, our key contributions are the following: • we extend the model in [ ] by a mortality rate dependent on the state of the health care capacity and fit the parameters with data from germany (section ). • we develop an optimization problem for finding the optimal input (in terms of setting infection rates) that minimizes the number of fatalities while keeping the costs occurring due to distancing measures low (section ). moreover, we show that such an optimal input has significant advantages compared to simpler baseline policies. • we show that simply applying a precomputed (optimized) input is dangerous if the model is uncertain and explain why feedback is of utmost importance when dealing with such an unstable and uncertain system. further, we demonstrate how such feedback can be incorporated via mpc, and we showcase the advantages of this control policy (section ). • we develop a robust mpc-based feedback strategy, which takes model inaccuracies, uncertain state measurements, and inexact inputs into account and can thus handle the covid- outbreak cautiously and safely (section ). although based on a simple model fitted with limited data, we hope that these high-level insights inspire further investigations, possibly on more complex epidemiological models, and can ultimately help decision makers to improve and optimize their policies to mitigate the spread of epidemics while keeping the toll on the society and economy low. in this section, we describe the model of the covid- epidemic that we use for our subsequent control approach. our model is adapted from the sidarthe model proposed in [ ] with the key differences that (i) we use more recent data to estimate new parameters to model the german covid- outbreak (in [ ] , the italian outbreak was considered) and (ii) we model the fact that the mortality rate increases if the number of critically ill patients exceeds the capacity of the german health care system. in section . , we describe the model of [ ] and explain its ingredients. thereafter, in section . , we provide details on our parameter estimation algorithm which fits the model to the german covid- outbreak. finally, we propose an extension of the model by increasing the mortality rate when the health care system is overwhelmed in section . . the considered model based on [ ] is shown in figure and includes eight states: s -susceptible, i -infected (asymptomatic, undetected), d -diagnosed (asymptomatic, detected), a -ailing (symptomatic, undetected), r -recognized (symptomatic, detected), t -threatened (symptomatic with life-threatening symptoms, detected), h -healed (immune after prior infection, detected or undetected), e -extinct (dead, detected). in accordance with in the equations ( ), capital letters describe fractions of the whole population that are currently in the respective state. since the model represents the whole population, the states sum up to , i.e., they must satisfy s + i + d + a + r + t + h + e = at all times. therefore, one equation in ( ) is redundant and hence, e.g., the state h can be expressed via the algebraic relation h = − (s + i + d + a + r + t + e) instead of equation ( g), as it is common in the field of differential algebraic equations. in most parts of this section, we omit time arguments for simplicity. further, greek letters are the model parameters which are briefly summarized in the following: • α, β, γ describe the infection rates for susceptible individuals, i.e., the rate at which susceptible individuals are infected by the states i, d or r, and a, respectively, and hence join the state i. • ǫ, θ describe the testing rate, i.e., at which rate (asymptomatic or symptomatic) infected individuals go from undetected to detected. • ζ describes the rate of asymptomatic (detected or undetected) infected individuals exhibiting symptoms, i.e., going from states i or d to a or r, respectively. • µ is the rate at which infected individuals in a or r develop life-threatening symptoms, i.e., join the state t . • λ, κ, σ(t ) are recovery rates for individuals affected by covid- . the recovery rate for threatened individuals σ(t ) depends on t , compare section . . • τ (t ) is the mortality rate, i.e., the rate at which individuals with lifethreatening symptoms decease, and it depends on t , compare section . . key features of the considered model for the covid- pandemic compared to simpler ones (e.g., sir models, compare [ ] ) are that it distinguishes between detected and undetected cases, symptomatic and asymptomatic individuals, and it includes a separate state t for patients with life-threatening symptoms (compare [ ] for a more detailed explanation of the key ingredients). the present model, i.e., equations ( ) as well as figure , is a mild modification of the model suggested in [ ] . first, we reduce the number of parameters by including the following assumptions. we assume that the rate for developing (severe) symptoms is the same for detected and undetected cases, since (to this day) no effective medication of covid- is known. more precisely, the transitions from i to a and d to r have the same dynamics with rate ζ, and similarly for the respective recovery rates as well as for the transitions from a to t and r to t . moreover, we assume that the rate β at which susceptible individuals are infected is the same from states d and r, since the state d is neglected for the parameter identification step (compare section . ). finally, as a key difference to [ ] , we consider t -dependent rates τ (t ) and σ(t ) for threatened patients, i.e., the mortality and recovery rates depend on the current number of threatened patients. essentially, τ (t ) increases and σ(t ) decreases if t exceeds the capacity of the german health care system (see section . for a detailed description of this model refinement). in this section, we adjust the model parameters and the initial condition given in [ ] to the covid- outbreak in germany. this is necessary, because the outbreaks in germany and italy evolved differently due to differences in the testing policy, the testing capacity, the health care system, the reaction of the governmental authorities, and the underlying counting method of confirmed cases. in order to compute realistic parameters for germany, we will use a pragmatic approach that enables us to easily include prior knowledge about relations between parameters. the approach is a least squares optimization of the available data, where prior knowledge is incorporated via hard constraints in the optimization problem. the available data is marked by a tilde and is given by: • the confirmed covid- casesc, deathsẼ, and recoveriesh c from [ ] , [ ] for the days t ∈ [ , ] from february , (t = ) to april , (t = ). we filtered this data set using the matlab function kaiser( , ) with window length and shape factor to reduce the effect of noise corruption and having less confirmed cases during weekends. further, we have to divide the data set by the total german population n total = . this data set, however, is rather small compared to the complexity of the model ( ) consisting of eight states and parameters. therefore, we need to leverage additional prior knowledge in order to avoid over-fitting and ensure a realistic resulting parameter set and initial conditions. based on other studies and the interpretation of our model states and parameters, we enforce the following assumptions. • the detection rate of asymptomatic cases is negligible, as the german policy is to test only people showing symptoms [ ] , i.e., ǫ = . • at february , the initial date for our fit, there were confirmed cases, hence, we assume r( ) = /n total , t ( ) = d( ) = h( ) = e( ) = , and i( ), a( ), s( ) appear as decision variables with s( ) = − r( ) − i( ) − a( ). • the test rate θ is approximately constant. please note that this does not mean that the absolute number of tests is constant per day, as this value is rather proportional to θa than to θ. • the infection rates α and γ were influenced by the countermeasures that the german authorities installed to fight the spread of the pandemic. according to [ ] , three main events changed the spreading rates: ( ) march -canceling large events, ( ) march -closing schools and non-essential stores, and ( ) march -contact ban (kontaktsperre) that prohibits groups of more than two people and requires people to maintain a distance of at least . m in public. hence, there are four different policies u i , i = , , , monotonically increasing from no countermeasures u = to full lockdown u = resulting in α i = α max + u i (α min − α max ) and γ i = γ max + u i (γ min − γ max ). this yields the following six decision variables α min , α max , γ min , γ max , u , and u . • one of the main reasons why the covid- pandemic is spreading so fast is that infectiousness peaks even before the onset of symptoms [ ] . as asymptomatic individuals have no indication of their infection, they are on top of that also not as cautious as people with symptoms. therefore, we require α ≥ γ when searching for realistic parameters. further, we want to ensure that people tested positive are significantly less contagious while in quarantine, such that we require γ ≥ β. • the percentage of confirmed covid- cases is estimated in the study [ ] as . % in germany. in our model, this value approaches the constant φ = ζ λ+ζ θ+µ κ+θ+µ , which is the proportion of people that develop symptoms (i to a, i to d can be ignored as ǫ = ) and get detected (a to r or t ); that is the percentage of confirmed accumulated cases in a steady state (i = d = a = r = t = ). to make sure our model coincides with the findings of [ ] , we expect φ to be slightly above of the estimated . % as a steady state is not reached yet and the proportion of detected cases increases over time, i.e., we constrain φ ∈ [ . , . ]. • the percentage of asymptomatic disease progressions was estimated at % in a population screening study in iceland [ ] , at . % in a comprehensive testing of the whole municipality of vo, italy [ ] and at . % [ ] in a study regarding the cruise ship diamond princess. to ensure that our model has a comparable ratio, we add the constraint λ λ+ζ ∈ [ . , . ] to the optimization problem. • the (base) reproduction rate in the beginning of march was estimated as approximately [ ] . thus, for the parameters α max , γ max with no active countermeasures we require r (α max , γ max ) ∈ [ . , . ] where r (α, γ) is given by (see [ ] for details) • the median of the incubation time is - days [ ] , [ ] , [ ] , which we identify as the half life period a person is in the state i, i.e. log( )/(λ+ζ) ∈ [ , ] . further, the median time from onset of symptoms until intensive care is - days [ ] , [ ] . hence, we constrain the half life period of a ailing or recognized individuals to log( )/(κ + µ) ∈ [ , ] . in the state h of ( ) the confirmed recovered cases are not distinguished from the undetected ones, thus we define the number of confirmed recovered figure : the threatened state t is split up in icu cases t and non-icu cases t . cases as h c , with h c ( ) = andḢ c = ρd + ξr + σ t + σ t and further the number of confirmed accumulated cases as c = d + r + t + h c + e in order to match the datah c andc. considering the covid- patients in intensive caret , a natural choice would be to identify them with threatened state t , however, all deaths in the model have been in t before, but in reality only half to a third of the deaths happens in icu [ ] , [ ] . hence, as the patients in icu are only a part of t , we split t into t and t , where t represents the number of people in intensive care and t are all otherwise threatened covid- cases. we assume that there are no transitions from t to t and vice versa, such that t = t + t can be modeled asṪ with µ +µ = µ such thatṪ = µ µ Ṫ and further t = µ µ t = µ µ t since before the outbreak it was t ( ) = t ( ) = . therefore, we can ensure σt = σ t + σ t and τ t = τ t + τ t by setting σ = µ µ σ + µ µ σ and τ = µ µ τ + µ µ τ . hence, we can equivalently transform the more complex model with t and t into the form described in section . as sketched in figure . further, we define h (e ) to be the numbers of people that recovered (died) from t . finally, we perform the parameter optimization by solving a least squares problem via casadi [ ] to fit c, e, h c , t , e , h to the datac,Ẽ,h c , t ,Ẽ ,h . the best fitting parameters are given in table and the resulting fit is shown in figure . many of the constraints listed above are active at the optimal set of parameters, e.g., α = γ, which is not surprising since we use the constraints to keep the parameters in a realistic range without further regularization. this fit further enables us to specify the full model state of today x( ) =: x , which will be used in the following sections as the initial condition where t = corresponds to april please note that the model is quite sensitive to changes in the parameters and one obtains quite different parameter values if, e.g., the estimated range of α min = . u = . table scaled by n total compared to the actual data [ ] , [ ] . the horizontal axis represents the time in days, where t = is february and t = is april . unknown cases or the percentage of asymptomatic cases deviate from the assumptions. it has been recognized as a key difficulty in handling the covid- pandemic that the virus is highly contagious, thus infecting large numbers of individuals. in addition, since many elderly and ill people require hospitalization and/or intensive care [ ] , large waves of infections can quickly exceed the capacities of local health care systems [ ] . hence, ensuring that health care resources are sufficient is a key issue in handling the outbreak [ ] , given that an overwhelmed health care system even correlates positively with the mortality rate [ ] . in this section, we describe how the mortality and recovery rates τ (t ) and σ(t ) in ( ) depend on the number of threatened patients t . the basic idea is that they are constant as long as the health care system's capacity is not at its limit, and the mortality rate τ (the recovery rate σ) increases (decreases) significantly if it is overwhelmed. according to [ ] , there are (on april ) covid- patients in an icu and icu spots are available. hence, the overall icu capacity currently available for covid- patients is + = , and we define the relative icu capacity as t icu = n total , where n total = . · . we consider a constant value of t icu for simplicity, although it is likely that it will further increase in the future. we assume that the mortality rate increases if the number of individuals requiring treatment in an icu exceeds t icu , i.e., if t > t icu , with t as in ( ) . more precisely, we assume that if a patient requiring intensive care does not receive it, then the patient deceases (i.e., for such patients, the mortality rate increases and the recovery rate is zero). according to data of deceased individuals from italy, those who were not admitted to an icu deceased in median within days [ ] . hence, we model those individuals in t which are not admitted to an icu via decaying first order dynamics with a half-life period of days, i.e, the corresponding time constant τ crit satisfies e − τcrit = . , thus leading to τ crit = . . note that t = µ µ t , compare section . , and hence we only modify the mortality rate τ in case that µ µ t > t icu . in the model ( ), τ (t ) and σ(t ) only occur jointly with t , which leads us to the following modification of τ (t )t and if µ µ t ≤ t icu , then ( ) implies τ (t )t = ( µ µ τ + µ µ τ )t and σ(t )t = ( µ µ σ + µ µ σ )t , i.e., the previous model is recovered as long as the icu capacity is not exceeded. if however µ µ t > t icu , then the mortality rate increases to τ crit for those µ µ t − t icu patients which require intensive care but do not receive it. similarly, for this fraction, the recovery rate is set to zero implicitly in ( b). the individuals t = µ µ t not receiving intensive care are not affected by this mechanism. clearly, the modified rates in ( ) are just a simple approximation of the effect that the mortality rate increases if hospitals are overwhelmed. this modification in the model is crucial when studying the effect of loosening quarantine measures and corresponding optimal policies, as done in the remainder of this paper. since (fortunately) the german health care system has not been overwhelmed to this date, there are no quantitative data to validate the above modification and in particular, the exact value of τ crit . nevertheless, the refinement is confirmed qualitatively by experiences in other countries [ , , ] . moreover, even a substantial change of τ crit has little effect on the overall dynamics since it only affects the exact number of fatalities. in particular, changing τ crit does not lead to a qualitative change in an optimal policy to control the outbreak as long as τ crit is sufficiently larger than τ and it is possible not to exceed the icu capacity. in this section, we discuss different policies that can be considered to keep the number of fatalities due to covid- low while at the same time also impose as little constraints as possible on the public. the most significant degree of freedom currently is certainly influencing the infection rates α and γ. measures for influencing the infection rates include hygienic measures, face masks, and different nuances of distancing policies, up to a mandated lockdown. therefore, we define u as introduced in section . as our input, representing distancing policies or other measures that have a direct influence on the infection rates α and γ. we model this influence via where a value of u = hence represents the policies in germany as of mid april (lockdown) and u = represents no social distancing or other measures (i.e. corresponding to infection rates as in the beginning of march). furthermore, we assume that the policies affecting the infection rates α, γ (i.e. u) stay constant for at least one week and can only be changed every seven days. in the first subsection, we will introduce different baseline policies which can give insights into the effects of different inputs u and which will serve as a comparison to the optimal controller in the following subsection. more specifically, these baseline strategies will be used to define an upper bound on the social distancing measures that the optimal control in section . and later on the feedback strategies in sections and can employ to minimize the fatalities. in addition to varying the infection rates α and γ, another degree of freedom to influence the model ( ) lies in adapting the testing policy. testing individuals on covid- is represented in the current model by parameters θ and ǫ for symptomatic and asymptomatic individuals, respectively. in the following, we assume that only a fixed number of tests can be carried out every day. if we wish to only test symptomatic individuals, this includes both symptomatic individuals infected with covid- (i.e., members of the state a) and individuals suffering from other illnesses with similar symptoms. in [ ], the robert koch institute estimates numbers on influenza-like illnesses (ili) in germany. while the numbers show clear seasonal differences, approximately . % of the population become newly infected with ili on average per week, and approximately % of them see a doctor (an indication for more severe symptoms). moreover, influenza symptoms usually last - days leaving us with an approximate average of p sick = . % of the population showing significant influenza-like symptoms at an arbitrary time of the year. when testing asymptomatic individuals, this includes infected persons without symptoms but also any other individual not known to be infected or healed and not showing any symptoms (i.e. s + i + h − h c − p sick , where h c are the confirmed healed cases, compare section . ). the total amount of resources used for testing is then captured by the following cost: denoting the parameter θ from table as θ n , we assume a fixed bound c > on the amount of resources for testing c test and that θ n corresponds to the nominal value for a = , i.e., c := c test ( , θ n , ). in the following, we assume that the current policy with respect to testing stays in place: all available tests are used on a daily basis for as many symptomatic people as tests are available. then the testing policy used throughout this section reads ǫ(t) = (as is current practice) and note that this also implies that throughout this paper the state d ≡ . the allocation of tests (with the possibility of also saving test resources for later) can also be modeled as control inputs. however, in the present model the effects of temporarily saving tests (under the current resource constraints) are negligible compared to the effects of changes in the infection rates. increasing the overall test capacity or improving the choice of test subjects (e.g. with tracing of cases), which corresponds to increasing values of θ n /c, on the other hand, can potentially improve the evolution of the pandemic significantly, since detected individuals are less contagious than undetected ones. however, increasing test capacities or better allocated testing (especially with regard to ǫ, i.e. tracing of also asymptomatic infections) is at the current stage not included in our consideration but could be addressed in future work with the presented model by choosing ǫ = and making θ n /c an increasing and time-varying variable. given the introduced control input u, different control goals can be formulated. one such goal could be to obtain herd immunity. herd immunity corresponds to the only stable equilibrium given no social distancing measures (i.e. with α max , γ max ) and requires a large part of the society to be immune. more precisely, herd immunity is reached if s < s ⋆ , where [ ] provide a formula for calculating s ⋆ (see section . . for more details). given our model, we can now calculate the minimum time that is needed to reach herd immunity. for this, we assume that we can choose a policy that utilizes the full health care capacity at all times. gives a lower bound on the time required to reach herd immunity without exceeding the health care capacity given the introduced model. the herein identified model parameters yield a time span t herd of more than six years. a stable steady state in the absence of a vaccine (i.e. herd immunity) can hence only be obtained either after many years or by overstraining the health care system and a corresponding significant rise in the number of fatalities. therefore, our ongoing assumption throughout this section is that prior to herd immunity, a vaccine will be available and we assume the availability of the vaccine in approximately two years. our goal is thus to find an optimal policy minimizing the number of fatalities for the next two years while imposing as little constraints as possible on the public and the economy. in the next subsection, we simulate and discuss the following policies: . keeping the social distancing measures in place (or even increasing the measures) until the virus is eradicated in germany . slowly (or more aggressively) loosening the distancing measures without overwhelming the health care capacities (while possibly risking a second wave). in fact, the presented baseline policies are similar to the policies suggested by the german "helmholtz-initiative" in [ ] . we will discuss our conclusions in comparison to theirs at the end of the section. in section . , we will then improve these baseline policies by applying optimal control techniques and we will discuss the importance and significance of the improvements. in the following, we argue that a consistent lockdown strategy necessitates strong lockdown measures over a long time horizon to fully eradicate the virus as otherwise, dropping the social distancing measures too early leads to a second outbreak wave. based on the sidarthe model fitted to the german outbreak, described in section . , we simulate how long we would need to remain in lockdown and simply wait for the virus to disappear. we define the disappearance of the virus as follows: if -most probably -there is less than one active contagious case, i.e., i + d + a + r + t < . /n total , the virus is eradicated. it takes days, which is almost one year, until this condition is fulfilled and clearly the economical and psychological damage caused by a lockdown period this long is excessive such that staying and waiting in lockdown is not an option. with even stricter measures, such as α = . α , γ = . γ , we could only marginally accelerate this process to days while increasing social distancing is costly, cf. the cost function in section . . note that the equilibrium attained under the above lockdown policy is an unstable one that is not robust to uncertainties. in particular, if only one person remains infected when the measures are suspended they could cause a new outbreak. also, the virus may be reimported from other countries or humans might be reinfected by an interim host. next, we simulate the following three scenarios in all of which the german population is kept in lockdown for a predefined period of time, followed by no measures at all. the only difference is the length of the lockdown period. in the first scenario, the measures are abolished immediately (april ). the second one keeps the current strict measures for an additional days. the third variant simulates an even longer lockdown period, ending after days counting from april . in figure , we compare the three scenarios. we clearly see that in all three cases the number of currently infected people i +d+a+r+t rises drastically a few days after the measures are removed independent of how long the lockdown persisted before. in any case, we experience a second outbreak wave. staying longer in lockdown slightly delays the following peak of the share of active cases i + d + a + r + t , yet the peak amplitude is almost the same in all three scenarios. this behavior can be explained as follows. if there is no one who currently has the virus, i.e., i eq = d eq = a eq = r eq = t eq = , such that s eq + h eq + e eq = , an equilibrium point is attained. the stability of the equilibrium point depends on the value of s eq and the model parameters. in [ ] , the authors show that the idart subsystem is asymptotically stable if and only if s eq < s ⋆ , where s eq is the susceptible state at equilibrium for a given initial condition x and the corresponding parameters, especially for α and γ that are actively adjusted according to an underlying policy. the value of s ⋆ follows from the stability analysis of the linearized idart subsystem and has the following structure with respect to α and γ where a i , i = . . . are constants, see [ ] for details and the definition of s ⋆ . note further that the commonly stated base reproduction rate ( ) is directly linked to the value s ⋆ via r = /s ⋆ . the stability of an equilibrium that depends on the parameters changes once we adjust α and γ. for strict measures (α min , γ min ), the value s ⋆ is high (s ⋆ = . ), such that a stable equilibrium is attained for any s. this means that only a small number of people is infected by the virus before the equilibrium is attained. with no measures (α max , γ max ), a stable equilibrium requires the share of susceptible people to be smaller than s ⋆ = . , i.e., herd immunity. we can hence conclude that if s eq (x , α , γ ) > s ⋆ (α , γ ), the equilibrium attained during lockdown is unstable with no measures. this means, there inevitably is a second outbreak wave once the lockdown ends. for the fitted model of the german outbreak, s eq (x , α , γ ) = . is attained after the first wave. hence, at least another . % of the german population get infected in the second wave before a stable equilibrium is attained. altogether, this leaves us with the following conclusion of two possible outcomes when choosing a consistent lockdown strategy: • strong lockdown measures over long time horizons have to be taken to eradicate the virus in germany. however, this takes a big toll on the public and any infected person, e.g. from abroad, could spark a second wave at any point. • any lockdown strategy that does not fully wipe out the virus inevitably yields a second outbreak wave once all measures are suspended. as argued in the previous subsection, keeping the lockdown policy strict can never lead to a stable equilibrium when ending the lockdown, no matter how long it did take place before all measures were suspended. hence, many countries are now discussing or have even already started to loosen the lockdown in very small steps. indeed, experts consulting the german government ("nationale akademie der wissenschaften leopoldina") have recently published their recommendations concerning a possible strategy for loosening the lockdown gradually in small steps [ ] . they name the following conditions for looseing the lockdown in small steps: a) the number of new infections remains at a low value. b) the capacity of the health care system must not be exceeded. c) precautions (such as hygienic measures, face masks, distancing) remain in force. in the following, we try to translate these recommendations into a policy for our simplified model to first analyze the results and second, to use this as a baseline policy for the optimizer in the following subsection. we implement the conditions presented above via the following policy strategy: a) u can only be decreased if, over the last n stab days, the number of newly infected persons (i.e. s(t − ) − s(t)) is decreasing and u has not been increased b) u can only be decreased if less than x lower of the icus are occupied c) the decrease in u can only be a small decrease at a time and therefore, the interval between u max = (lockdown) and u min = (no measures) is divided into n steps equidistant steps. additionally, we add that u will be increased again (with the same step size as the decrease) if more than x upper of the icus are occupied and no decrease in the amount of necessary icu is witnessed. this policy results in four 'tuning parameters' of the policy: n stab , x lower , x upper and n steps . in fact, it turns out that the outcome of the simulation is not very sensitive to the tuning parameters of the policy, but can be tuned to be slightly more careful or more aggressive. in the following subsection, we choose two different sets of parameters as baseline policies for the optimal control approach. in this section, we contrast the baseline policy from section . . with an optimal control policy, under idealized assumptions (exact model and state measurement). the purpose of this section is twofold: a) understand how an optimal policy differs qualitatively from the baseline policies. b) quantify the loss of performance (in terms of increased fatalities and/or unnecessary social policy u) resulting from using a suboptimal baseline policy. the degree of freedom is the input u ∈ [ , ] affecting the social policy and we consider the fact that the policy can only be changed every t s = days. in the following, we consider the problem only for the next n = weeks, assuming that thereafter a vaccine might be developed that would ideally prevent (almost all) further fatalities in the future. the overall control problem can be seen as a multi-objective optimal control problem, where we wish to simultaneously minimize the number of fatalities e and the societal and ecomical cost of the social policy measures, which will be measured by the function c policy (u) = /α(u). we point out that due to the parametrization ( ) this cost also inherently considers the infection rate γ. this cost function is such that the social cost of achieving an arbitrarily small infection rate α grows unbounded, while for large values of u incremental differences are less relevant. in order to suitably characterize an optimal solution to this multi-objective problem we use the baseline policies in section . . the resulting optimal control problem is given by ( ) below, which will be explained in the following. in particular, our goal is to find an input policy that minimizes the number of accumulated fatalities, while having using less resources than the baseline policy in terms of accumulated social impact of c policy (c. f. ( d) ). we point out that similar "stabilization" problems subject to resource constraints for the control of epidemic outbreaks can be found in the literature, also using a fractional cost c policy , compare e.g. [ , ] . when minimizing the number of accumulated fatalities, it is important to consider not only the extinct individuals e(n · t s ) at the end of the two year horizon, but to account as well for the part of the already infected individuals that will decease after the two year horizon. the reason for this is, while the availability of a vaccine at the end of the horizon might prevent future infections, it cannot cure already infected people. hence, if we do not account for the inevitable fatalities among the individuals infected at the end of the prediction horizon, the optimal controller does not take any efforts to keep them low and as a result a lot of people would die shortly after the two year horizon. therefore, we propose an optimization objective that includes all past and inevitable future fatalities. based on the model ( ), we know that a total of ζ ζ+λ (i +d) of the infected people i +d will develop symptoms in the future and further that a total of µ µ+κ ζ ζ+λ (i + d)+ a+ r) will become threatened. thus, assuming the capacity t icu is not exceeded afterwards, i.e., setting constant values τ = τ ( ) = µ µ τ + µ µ τ and σ = σ( ) = µ µ σ + µ µ σ , the amount of inevitable fatalities is exactly given by hence, given a baseline solution u b , x b from section . . , the corresponding optimal control problem reads as follows: since we only change the policy every week, the index k in ( ) corresponds to weeks and f (n · t s ) corresponds to the objective function in ( ), where the states result from simulating the system ( ) with the parameters and the initial condition from section and the input u(·) over k-weeks. condition ( d) ensures that the encountered social cost is smaller than the cost of the baseline policy. this optimal control problem is such that the baseline policy u = u b is a feasible solution and thus the resulting fatalities f (n · t s ) will always be lower than that of the baseline policy. we point out that it is possible to consider a more restrictive transient constraint on the policy cost instead of ( d), which is discussed in detail in appendix b. the optimal control problem ( ) can be formulated as a nonlinear program (nlp) and is subsequently solved using casadi [ ] . for comparison and to implement the constraint ( d), we use the baseline policy from section . . with x lower = . , x upper = . , n steps = , n stab = , which overall is rather cautious and does not exceed the icu capacity. the corresponding results for the baseline policy and the optimal control strategy can be seen in figure . although the optimal control input yields initially (first days) a slightly larger number of infected individuals and thus slightly more fatalities in the first days, the number of infected individuals is subsequently significantly lower and the overall number of fatalities is reduced to only %. the optimal controller allows for a smooth increase of the infection rate α, while keeping the number of threatened individuals (t ) consistently below the corresponding value of the baseline policy after the first days, thus yielding a small number of fatalities. the rising number of infected individuals (i) at the end results from the finite-horizon and will be considered later in more detail. we also consider a second baseline policy using x lower = . , x upper = . , n steps = , n stab = , which slightly relaxes the social policy, but also exceeds the icu capacity. the result is shown in figure . we can see that in comparison to this second baseline policy the optimal policy significantly reduces the number of fatalities to only %. the optimal strategy is a lot more cautious in reducing the social policy, while the baseline is more aggressive and goes back and forth between increasing and decreasing α, resulting in significant violations of the icu capacity. furthermore, the simple baseline policy results in a second wave as the restrictions are loosened too quickly, while the optimal strategy slowly but steadily increases α after the first days, and thereby avoids a second wave. in both examples, a further observation should be highlighted. after an initial phase of containing the outbreak, the measures are slowly but steadily relaxed until a larger release at the end of the horizon. similar behavior can be observed for many optimal control problems with finite horizons and is commonly referred to as "turnpike" behavior, which goes back to [ ] . an explanation for this is that the consequences of decisions taken at later points in time mainly occur after the end of the horizon, such that a more aggressive policy towards the end is optimal, when only considering the finite two year horizon. of course, one would not implement the "leaving arc" if the development of a vaccine would not be finalized after two years, since implementing such a policy may lead to an uncontrollable increase of infections towards the end of the time horizon in case that the model is inaccurate and should thus be avoided in practice. in appendix a, we therefore discuss how adding "terminal constraints" to the optimization problem can prevent this turnpike behavior of the optimal solution, at the price of an increasing number of fatalities. if we compare the results in section . with the consistent full lockdown from section . . , we can see that it is possible to appropriately increase α without exceeding the icu capacities, while the consistent full lockdown strategy would require a lockdown that takes approximately a year to be effective. hence, while a consistent lockdown can effectively minimize the number of deaths, this strategy is only viable in case this lockdown can be prolonged over the corresponding time horizon, unless a vaccine is developed earlier. on the other hand, both the optimal controller and the baseline controller allow for a significant relaxation of the lockdown (on average a doubling of α), without significantly increasing the number of fatalities. in comparison to the baseline policy suggested in section . . , the optimal control policy results in a slower but smooth loosening of the distancing policies. without increasing the social cost over the full time horizon, this optimal policy avoids any violation of the maximum icu capacity and hence results in a significantly smaller fatality rate. we point out that the resulting optimal policy of slowly increasing α is qualitatively similar to the resulting optimal policy in [ ] , albeit for a different control goal. it can be seen that an initially "stronger" lockdown (i.e., a smaller value of α) over a longer time period with subsequent loosening leads to a better handling of the pandemic, compared to repeated tightening and loosening of distancing measures. moreover, a smooth and monotone loosening of distancing policies is also desirable from an economic aspect since repeated lockdowns after interim-periods of relaxed distancing guidelines may be even more damaging to the economy, compared to an initially longer lockdown. comparing our results with the proposed scenarios by the helmholtz association [ ] , we find that we agree that the goal of herd immunity without overwhelming the health care capacity would require years. our results further agree with [ ] that the contact restrictions can only be loosened slowly if the health care capacity must not be overwhelmed. however, since the authors in [ ] do not consider the availability of a vaccine, their conclusion is keeping or even increasing the lockdown until the number of infected persons is small and all infections can be traced efficiently and effectively via strategically allocated (and increased) testing. with the assumption of a vaccine within the next two years, we argue that a slow and smooth loosening of the lockdown does not lead to many more fatalities while decreasing the social and economic cost significantly according to our model. concurrently, increased and strategically better allocated testing, e.g., via a contact tracing mobile app [ ] , is of course highly beneficial and greatly advisable to improve the performance (even if it this was not accounted for in our model). to summarize, it seems possible to reduce the current restrictions and thus allow α to increase without exceeding the icu capacity. furthermore, optimized policies can significantly improve the outcome (in terms of fewer deaths and/or less social restrictions). however, the result is highly sensitive w.r.t. the change in the infection rate, while an accurate control of the infection rate α (e.g. ± %) through governmental policies seems difficult/unrealistic. in the next section, we will therefore deal with these issues by formulating a robust control strategy that takes uncertainty in our covid- model into account and uses feedback based on uncertain state information. section . shows that an optimal control policy can significantly reduce the number of fatalities compared to a baseline policy that allows for iterative loosening of social distancing measures. this optimal control policy is computed by optimizing over all possible policies to find the one minimizing the number of fatalities predicted by the model equations ( ) without using stronger shutdown measures than the baseline. hence, the policy proposed in section . strongly relies on the accuracy of the model identified in section and thus may fail to effectively control the outbreak in case of a model mismatch. however, such a model mismatch is inevitable in practice, especially since the model itself is a simplification of a much more complex reality and the identification outlined in section . strongly depends on the (sparse) available data and the additional prior knowledge based e.g. on further studies concerning covid- , which also provide only estimates. in addition, the optimal control policy relies on exact knowledge of all states and on the assumption that values for α and γ can be exactly imposed up to arbitrary precision via social distancing measures, both of which are unrealistic assumptions when applying the policy in practice. in this section, we show how online measurements can be utilized via feedback to effectively and robustly control the german covid- outbreak in the presence of uncertain parameters. more precisely, we illustrate that the optimal open-loop policy of section . may lead to poor performance when applied to validation models with a different set of parameters, although these validation models result from adjusting only one prior assumption in the identification and still fit the past data well. on the other hand, we show that a model predictive control (mpc) feedback strategy, based on repeatedly computing an open-loop policy for the nominal model from section , is inherently robust w.r.t. model inaccuracies and successfully handles the outbreak. at each time step k = , . . . , n , where k corresponds to weeks and n = as in section . , we solve the optimization problem ( ) over the time horizon k, . . . , n using the current measurements as initial condition at week k. then, we apply the computed optimal policy over one week before solving the problem for the new measurements again. in this way, since the initial conditions in the optimal control problem are updated, a feedback mechanism is included as is standard in mpc [ ] . as a result, the prediction horizon n − k of the optimization problem is shrinking with each time step k, such that it never exceeds the considered total time horizon of n = weeks, after which we assume the availability of a vaccine. hence, since the constraint ( d) needs to hold over the whole time horizon n , we replace it by with c policy = n − k= c policy (u b (k · t s )) being the cost of the first baseline policy in section . . . as a second modification, we adapt the bound on the social distancing cost online, depending on the predicted states, as is detailed in the following. in section . , we proposed an open-loop optimal control strategy, where the inputs were the infection rates α and γ. loosely speaking, the control goal was to achieve a minimum number of fatalities without imposing stronger social distancing measures than a simple baseline policy (compare ( d)). since this constraint heavily depends on the model to which the baseline is applied, a realistic setting with imperfect model knowledge should allow to adapt the constraints on the policy online in case that the nominal model is overly optimistic or pessimistic. instead of simply requiring that the cost of the mpc-based feedback cannot exceed c policy , we increase the maximum cost in case that the predicted number of patients requiring intensive care lies above % of the maximum capacity t icu at least once during the horizon, and we decrease it in case that the number consistently lies below % of t icu . this adaption is natural, as in reality one would increase the efforts to contain the outbreak if the current measures are insufficient, and on the other hand, the population cannot be expected to accept strict measures when there are only few (severe) cases across the country. therefore, the maximum cost in week k, denoted by c b (k), varies online with k and is initialized as c b ( ) = c policy . the amount by which we change c b online is ±∆ u n −k n , where ∆ u = αmin − αmax with α min and α max as in section . . if, for instance, the model predicts large numbers of future icu patients, then the cost bound c b is increased by the difference between the minimum and the maximum social distancing cost, scaled by the remaining time horizon. this increase corresponds to the social cost of an additional week in full lockdown, scaled by the remaining time horizon via the factor n −k n . the proposed mpc-based feedback strategy is summarized in algorithm . in the algorithm, t (j ·t s | k·t s ) denotes the number of threatened individuals at time j·t s , predicted by the optimal solution of ( ) at time k·t s . essentially, the algorithm repeatedly applies the open-loop optimal control policy of section . with the key difference that, at time k, all past measurements j = , . . . , k are used in the optimization problem, thus including an online feedback. in addition, in step of the algorithm, the social policy constraints is adapted as described above. with the state-dependent cost f as in ( ), based on simulating the model ( ) over the remaining horizon n −k subject to the input u, starting at the current measured state at time k. . apply the optimal policy u * (k · t s ) for the next t s = days. . update the social policy cost as to assess the improved robustness of algorithm compared to open-loop optimal control, we produce two validation models. more precisely, we identify two new sets of parameters a and b by proceeding exactly as in section . with the only difference that we change the prior assumption that the stationary ratio of confirmed covid- cases is in the interval [ . , . ]. instead, we assume that this value is in [ . , . ] for set a and in [ . , . ] for set b. when performing parameter identification based on these modified prior assumptions, we also obtain sets of parameters that can accurately explain the existing past data on covid- cases in germany. however, the resulting models have different dynamics and different reproduction rates for the same lockdown policy. increasing the above ratio as in parameter set a decreases the number of infected and undetected individuals resulting in a higher reproduction rate to explain the same amount of confirmed cases. hence, if an open-loop policy based on the nominal model (i.e., with parameters described in section . ) is applied to the validation model with parameters a, then the number of infections and thus the number of fatalities increases significantly. to illustrate this effect, we apply the open-loop optimal control policy based on the model with parameters as in section . to the new models with parameter sets a and b. the control effort of this policy, i.e., the amount of social distancing, is constrained as in ( d) by the cost of the baseline policy when applied to the nominal model identified in section . . the results for the model with parameters a can be seen in figure . since this validation model has a higher reproduction rate for similar inputs as explained above, the number of fatalities after n = weeks increases significantly compared to the simulations in section . this is due to the fact that the open-loop policy is only computed once, at the beginning of the time horizon, and is then applied over the whole time span of two years without any online adaption based on new measurements. therefore, it cannot handle the model mismatch and thus has a significantly worse performance. in addition, figure shows the evolution under the proposed mpc-based feedback, which leads to a significantly lower number of fatalities compared to the open-loop policy. we point out that the feedback (partially) compensates the fact that the control action is computed based on the nominal model parameters from section . , which differ significantly from parameter set a. due to the larger number of infected individuals, the maximum social cost c b is increased at multiple time steps, which is indicated by the step-like increases of the input. finally, an open-loop optimal control policy is computed which is allowed to use the same amount of resources as the mpc-based feedback (in hindsight), i.e., the adapted social and economical cost c b (n ). while this policy performs better than the initial open-loop policy with fewer resources, it leads to a similar number of fatalities at the end of the horizon compared to the feedback controller. however, the number of threatened patients is very large at time k = n , which would lead to a significant increase in fatalities after the considered time period, even if a vaccine is available. figure also shows the same comparison for the model with parameter set b. in this case, since the reproduction rate is lower, the open-loop optimal policy leads to fewer fatalities than in section . . the mpc-based feedback leads to almost identical performance, but it reduces the cost budget at several time instants, i.e., it can handle the outbreak similarly well but with significantly lower social and economic costs. when restricting the budget of the open-loop optimal policy to the one of the feedback strategy, i.e., c b (n ), then it leads to a dramatic increase in fatalities. to conclude, the above discussion reveals that a combination of open-loop optimal control with feedback is inherently robust in the sense that it effectively controls the german covid- outbreak even if the employed model is inaccurate. when comparing the result to an open-loop strategy, then the mpc-based feedback strategy can dramatically decrease the number of fatalities or the necessary amount of social distancing, respectively. such robustness is an important property for applying any control strategy in a real-world scenario, where accurate model knowledge is rarely available. in the next section, we propose a more systematic robust mpc approach which explicitly takes model inaccuracies as well as uncertain state measurements and control inputs into account in order to safely and cautiously control the covid- pandemic. while the mpc-based feedback policy proposed in section is significantly more successful in handling the outbreak compared to a simple open-loop policy, it relies on the assumption that exact measurements of the state in ( ) are available at each time step. in this section, we consider a more realistic scenario of uncertain measurements in terms of biased state estimates, and we analyze the impact on the closed-loop operation. in particular, we develop a robust mpcbased feedback strategy using interval arithmetic that takes the uncertainty into account during the predictions and thus leads to a safer policy minimizing the number of fatalities. in the following, we consider the case where at each day k instead of the true state x(k) we only obtain an estimated statex(k), which is subject to an additional bias. in table , we summarize the uncertainties in the states. for individuals in states d and r, the disease covid- was detected by tests. hence, their values are well known, nevertheless, we assume that they can slightly differ from the true states by ± %, as there might be cases on the borderline between d and r that are hard to assign to either of the states. the number of people in icus is well documented. however, the state t contains not only patients in icus (t icu ± %) but also other infected members of the risk group (t ± %), cf. section . , such that the uncertainty we use is ±( µ µ · % + µ µ · %). we assume that the number of deaths is certain by ± % as it includes some people that died of different causes. as the undetected cases can by definition not be measured, they must be estimated using random sampling or strategies like [ ] . therefore, the states i and a are much less certain, especially without symptoms (i ± %, a ± %). recovering from the disease is a resulting state from both rather certain states, d and r, and highly uncertain states, i and a such that overall it is uncertain itself (h ± %). the uncertainty of the state of susceptible persons s results from the other states: i . it is possible to directly use this biased state estimatex(k) in algorithm and compensate the bias through the inherent robustness in the feedback implementation. in the following, we derive an alternative robust formulation that explicitly considers the uncertainty in the prediction. first, given a biased state estimatex(k) and known bounds on the bias (tab. ), it is possible to compute interval bounds x(k), x(k) such that the true state is guaranteed to lie in that interval, i.e., the following formulation will predict the interval bounds x i and x i instead of using some nominal prediction. this methods is similar to interval arithmetic employed in robust mpc [ ] and the robust moment enclosure for an seiv epidemic model in [ ] . using the fact that the system is positive (x i and all the parameters are positive), it is possible to derive an interval prediction of the forṁ x =f (x, x, u), for all t ≥ , given suitable bounds on the uncertain parameters in the system model ( ). the detailed derivation of the interval prediction model ( ) can be found in appendix c (more precisely, equations (c. )). since deriving reliable bounds on all parameters in the model ( ) is rather difficult or unnecessarily complex, we only focus on the uncertainty associated with the infection rate α. in particular, we consider an uncertainty of ± % on the infection rate α. thereby, we explicitly consider the problem that the infection rate cannot be precisely specified via social distancing measures. we will see later in the simulations that, although we do not account for all possible mismatches in the prediction model, we nevertheless obtain the desired properties in closed loop. given this interval prediction model, the proposed robust formulation now predicts an interval for the different state variables and minimizes the worst-case number of fatalities f based on x(n · t s ). the overall procedure is summarized in algorithm . algorithm . robust mpc strategy using interval arithmetic . given biased state estimatex(k · t s ), compute set [x(k · t s ), x(k · t s )]. . solve the following problem min u(·) with f based on ( ) using x, which results from the interval predictions of the model ( ) over the emaining horizon n − k subject to the input u, starting at the current set estimate [x(k · t s ), x(k · t s )]. . apply the optimal policy u * (k · t s ) for the next t s = days. . update the social policy cost as in algorithm using t instead of t . . set k = k + . in the following simulations, we consider the extreme case where the number of estimated infected or previously infected individuals (i, d, a, r, t , h, e) is underestimated. the results for the robust mpc and the nominal mpc in comparison to open-loop optimal control strategies for the two validation parameter sets a and b (compare section ) can be seen in figure . due to the worst-case prediction in the robust mpc, at t = the robust mpc already increases the resources two times, for both parameter sets, such that at t = t s the predictions satisfy µ µ t (k · t s ) ≤ . t icu . in the simulation with the model based on parameter set a, we can directly see that both the nominal mpc and the robust mpc reduce the number of fatalities compared to an open-loop optimal control strategy. furthermore, if we compare the robust mpc and the nominal mpc, we can see that after t = days the nominal mpc implementation realizes that the spread is worse than initially assumed. this leads to a strong increase in social measures u at t = . with the robust formulation, u decreases almost monotonically. furthermore, the nominal implementation results in twice the number of fatalities, while the applied resources c policy over the two year horizon differ by less than ∆ u , which corresponds to one week of lockdown. this indicates that the robust mpc, planning cautiously from the beginning, exploits its resources more efficiently by imposing stricter social distancing measures early on, which results to be beneficial in the long run. for the second parameter set b, we can see that the worst-case robust formulation uses initially an unnecessarily high control effort. nevertheless, overall the applied resources c policy differ by less than ∆ u compared to the nominal mpc, while the number of fatalities is still reduced by %. in comparison to the open-loop policies, both mpc policies require less or equally restrictive policy measures u, while the number of fatalities are significantly reduced. in the following, we summarize our findings on a high-level and highlight the main take-away messages: • our results in section confirm the conclusions in [ ] that neither eradication of the virus nor herd immunity without the availability of a vaccine are viable solutions to handle the current covid- outbreak. • applying an optimizer to the mathematical model describing the outbreak, one can significantly reduce the number of fatalities without increasing the costs associated to decreasing the infection rate (social distancing policies, closing schools, etc.), compare section . . • since the proposed model can never exactly predict the covid- pandemic, applying a nominal optimal policy introduces unnecessary conservatism, at best, up to posing a great danger (i.e. overwhelming the health care capacities risking high mortality rates). therefore, our findings in section support [ ] by showing that any policy to control the covid- outbreak successfully has to be an adaptive strategy. this means we need to constantly measure, monitor and estimate the current numbers and adapt our policy accordingly, i.e., feedback is necessary for reliably handling the outbreak. • if we already a priori take into account that our model includes mismatches and that all measured and estimated numbers are not exact and can have a bias, we can further improve the outcome, as shown in section . more specifically, we developed a robust mpc-based feedback strategy using interval arithmetic. the application of feedback without the robust description of the considered model can lead to intermediate increases in the number of new infections necessitating another period of lockdown. on the contrary, a robust feedback strategy can take these model mismatches and other uncertainties into account and is hence able to avoid such behavior, thus significantly reducing the number of fatalities. • when looking at the qualitative results the robust mpc-based feedback offers, one can see that, accounting for the instability and uncertainty of the spread of the virus, the controller suggests a rather strict policy at the beginning and only then allows for a gradual increase in the infection rate. keeping this loosening slow at the beginning shows a beneficial effect in the long run. this qualitative result of the robust mpc underpins also the german policy and reaction to the outbreak of covid- in germany where initially strong measures (what we here refer to as lockdown) were applied. only very recently the german government started to loosen these measures slowly and gradually. there are also influences on the course of the outbreak that were not taken into account in the present paper but which are important in an overall strategy towards the spread of covid- (e.g. increasing testing capacities, tracking of infections, as well as investigating which measures lead to the desired infection rate). however, controlling the infection rate is certainly one of the key factors and hence, this paper contributes towards mitigating the spread of covid- under manageable societal and economic costs. we hope that the proposed feedback strategies inspire further investigations in this direction and offer qualitative and high-level insights that underpin the current policies or strategy papers. . a) ). in addition, at the end of the horizon the number of contagious individuals should be nonincreasing, which is implemented as (a. b). hence, in the following, we replace the cost f by the number of fatalities e, and we add the following constraints to the optimal control problem ( ) from section . : again, the index k in ( ) corresponds to weeks and the states idart (k · t s ) correspond to the result of simulating the system ( ) with the parameters and initial condition from section . these terminal conditions (a. a)-(a. b) (which should be interpreted element-wise) ensure that the final state after the finite horizon n is "better" than the baseline solution (c.f. (a. a) ) and the outbreak can be contained (c.f. (a. b) ). the simulation results with the two baseline policies shown in figure a. and a. demonstrate that the terminal constraints indeed effectively prevent the turnpike behavior. however, the additional constraints also lead to a slight increase in the number of fatalities. we wish to briefly mention a stronger restriction on the societal cost of the optimal control strategy. in particular, instead of only restricting the cost over the considered horizon of n = weeks, a stronger property is to ensure that at any time t, the previously accumulated policy cost is smaller than the corresponding cost of the baseline policy. this can be done by replacing condition ( d) with the following transient constraint: the corresponding results for both baselines considered in section . can be seen in figure b . . in this case the number of fatalities are reduced by % and %, respectively. thus, also for this more restrictive setting, the optimal controller can significantly reduce the number of fatalities. in addition, in the comparison to the more aggressive baseline we also see that early measures are absolutely crucial, since the two policies are essentially equivalent in the period from days - days, i.e., including the critical time period where the icu capacity is exceeded, but differ significantly over weeks prior to the violation of the icu capacity. controlling epidemic spread by social distancing: do it well or not at all social distancing strategies for curbing the covid- epidemic, medrxiv preprint effective containment explains subexponential growth in recent confirmed covid- cases in china inferring covid- spreading rates and potential change points for case number forecasts a first study on the impact of current and future control measures on the spread of covid- in germany, medrxiv preprint modeling exit strategies from covid- lockdown with a focus on antibody tests, medrxiv preprint covid- : from model prediction to model predictive control analysis and control of epidemics can the covid- epidemic be managed on the basis of daily data? on fast multi-shot epidemic interventions for post lockdown mitigation: implications for simple covid- models modeling, state estimation, and optimal control for the us covid- outbreak modelling the covid- epidemic and implementation of population-wide interventions in italy optimal covid- epidemic control until vaccine deployment, medrxiv preprint beyond just "flattening the curve": optimal control of epidemics with purely non-pharmaceutical interventions adaptive strategien zur eindämmung der covid- -epidemie a contribution to the mathematical theory of epidemics an interactive web-based dashboard to track covid- in real time novel coronavirus covid- ( -ncov) data repository by johns hopkins csse temporal dynamics in viral shedding and transmissibility of covid- average detection rate of sars-cov- infections is estimated around nine percent spread of sars-cov- in the icelandic population estimating the asymptomatic proportion of coronavirus disease (covid- ) cases on board the diamond princess cruise ship schätzung der aktuellen entwicklung der sars-cov- -epidemie in deutschland -nowcasting report of the who-china joint mission on coronavirus disease (covid- ) incubation period and other epidemiological characteristics of novel coronavirus infections with right truncation: a statistical analysis of publicly available case data clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in casadi: a software framework for nonlinear optimization and optimal control estimates of the severity of coronavirus disease : a model-based analysis critical care utilization for the covid- outbreak in lombardy, italy: early experience and forecast during an emergency response forecasting covid- impact on hospital bed-days, icu-days, ventilator-days and deaths by us state in the next months, medrxiv preprint potential association between covid- mortality and health-care resource availability systemische epidemiologische analyse der covid- -epidemie', stellungnahme der helmholtz-initiative 'systemische epidemiologische analyse der covid- -epidemie optimal resource allocation for network protection against spreading processes dynamic resource allocation to control epidemic outbreaks a model predictive control approach mobile phone data and covid- : missing an opportunity?, ( ) model predictive control: theory, computation, and design robust mpc of constrained nonlinear systems based on interval arithmetic robust economic model predictive control of continuous-time epidemic processes optimal control formulation using terminal constraints in order to avoid artefacts of considering a finite-horizon problem (e.g. a lot of infected people at the end of the horizon) in the following, we derive the dynamics of the interval predictions f , f used in ( ) . note that the following property holds for any scalarsand similarlyẋfor all i = , . . . , . essentially, we use the property (c. ) together with the fact that x i and the parameters are positive to ensure that (c. )and (c. ) hold in order to derive the differential equations for the interval. more precisely, assuming that every parameter is uncertain in some bounds (e.g. β ∈ [β, β]) yields the following · odes:i =s(αi + βd + γa + βr) − (ǫ + ζ + λ)i, (c. c)since these dynamics only correspond to possibly conservative overapproximations, we can use i= x i = to possibly improve the resulting bounds for s using the following projections:in principle it would also be possible to directly set s, s using the other states x i , x i instead of simulating (c. a)-(c. b), but this may not necessarily ensure s ≤ and s ≥ . key: cord- -nrzwn oz authors: mayer, kirby p.; sturgill, jamie l.; kalema, anna g.; soper, melissa k.; seif, sherif m.; cassity, evan p.; hatton kolpek, jimmi; dupont-versteegden, esther e.; montgomery-yates, ashley a.; morris, peter e. title: recovery from covid- and acute respiratory distress syndrome: the potential role of an intensive care unit recovery clinic: a case report date: - - journal: j med case rep doi: . /s - - -y sha: doc_id: cord_uid: nrzwn oz background: in this case report, we describe the trajectory of recovery of a young, healthy patient diagnosed with coronavirus disease who developed acute respiratory distress syndrome. the purpose of this case report is to highlight the potential role of intensive care unit recovery or follow-up clinics for patients surviving acute hospitalization for coronavirus disease . case presentation: our patient was a -year-old caucasian woman with a past medical history of asthma transferred from a community hospital to our medical intensive care unit for acute hypoxic respiratory failure due to bilateral pneumonia requiring mechanical ventilation (ratio of arterial oxygen partial pressure to fraction of inspired oxygen, ). on day of her intensive care unit admission, reverse transcription–polymerase chain reaction confirmed coronavirus disease . her clinical status gradually improved, and she was extubated on intensive care unit day . she had a negative test result for coronavirus disease twice with repeated reverse transcription–polymerase chain reaction before being discharged to home after days in the intensive care unit. two weeks after intensive care unit discharge, the patient returned to our outpatient intensive care unit recovery clinic. at follow-up, the patient endorsed significant fatigue and exhaustion with difficulty walking, minor issues with sleep disruption, and periods of memory loss. she scored / on the short performance physical battery, indicating good physical function. she did not have signs of anxiety, depression, or post-traumatic stress disorder through self-report questionnaires. clinically, she was considered at low risk of developing post–intensive care syndrome, but she required follow-up services to assist in navigating the healthcare system, addressing remaining symptoms, and promoting return to her pre–coronavirus disease societal role. conclusion: we present this case report to suggest that patients surviving coronavirus disease with subsequent development of acute respiratory distress syndrome will require more intense intensive care unit recovery follow-up. patients with a higher degree of acute illness who also have pre-existing comorbidities and those of older age who survive mechanical ventilation for coronavirus disease will require substantial post–intensive care unit care to mitigate and treat post–intensive care syndrome, promote reintegration into the community, and improve quality of life. the emergence of the novel coronavirus, severe acute respiratory syndrome coronavirus (sars-cov- ), has had a significant impact on patients, families, healthcare systems, and communities. on march , , the world health organization officially declared the sars-cov- virus outbreak a pandemic, officially known as coronavirus disease (covid- ) [ ] . patients diagnosed with covid- have a broad range of presentations, from asymptomatic carriers to those with severe critical illness with pneumonia, acute respiratory distress syndrome (ards), and multiorgan failure. in this case report, we describe the trajectory of recovery in a young, healthy patient diagnosed with covid- who developed ards. we suggest the importance of intensive care unit (icu) follow-up clinics to treat patients surviving mechanical ventilation or long-term icu stay for covid- . our patient was a -year-old caucasian woman with a past medical history of asthma. her medical history was otherwise unremarkable. she was employed in customer service, was living with her husband, and denied a history of smoking or illicit drug use. she first noticed symptoms of dry cough, body aches, and low-grade fever (day ). four days later, she was diagnosed with bronchitis at a local community urgent treatment care center. she was prescribed azithromycin, a bronchodilator inhaler, and a steroid. she reported improvement of symptoms initially, but within days, she had notable shortness of breath with minimal exertion with progressive dry cough, pain, and perfuse sweating. she reported significant shortness of breath when attempting to eat. subsequently, she decided to seek treatment at her local community hospital. on day , she was admitted for room air oxygen saturation reported between % and % and profound dyspnea. the result of her respiratory viral panel was negative. she continued to have respiratory compromise with increasing oxygen requirements. on day , she was intubated for acute hypoxic respiratory failure due to bilateral pneumonia and was transferred to the medical intensive care unit (micu) at our academic medical center. the patient remained intubated ( % fraction of inspired oxygen with positive end-expiratory pressure [peep] of cmh o and ratio of arterial oxygen partial pressure to fraction of inspired oxygen, ) and minimally sedated (propofol and hydromorphone) for ards upon admission to the micu (day ). her chest radiograph revealed bibasilar airspace disease (fig. ) , and chest computed tomography demonstrated bilateral lower lobe consolidation and volume loss with atelectatic changes in mild lower lung zones with scattered ground-glass opacities in the upper lobe, mostly central, consistent with bilateral pneumonia with lung volume loss and/or atelectasis (fig. ) . the patient's sequential organ failure assessment score in the first hours of icu admission was . she was started on vancomycin, ceftriaxone, and azithromycin for empiric coverage of communityacquired pneumonia. her brain natriuretic peptide and lactate levels were within normal limits, and aerobic and anaerobic blood cultures revealed no growth. the results of testing for urine legionella and streptococcal pneumonia antigens were also negative. the patient's family reported no travel history or exposure risk, but, given the fig. chest radiograph obtained on day of admission to intensive care unit revealed bibasilar airspace disease patient's clinical symptoms, a test for covid- was performed. a positive test result for covid- was confirmed on day . in addition to ards, she met the criteria for a diagnosis of acute kidney injury (aki; kidney disease improving global outcomes stage ) on the basis of decreased urine output and elevated creatinine level (increased from . mg/dl on first day in icu to . mg/ dl within hours). her liver enzyme levels were within normal limits (c-reactive protein, . mg/l). the patient's clinical status gradually improved from days - of her illness. she tolerated weaning of oxygen and peep (fig. ). her lung compliance was reported by her primary physician as "good" with low driving pressures ( - cmh o). her aki improved with increasing urine output. on day , sedative medications were weaned fully, and the patient passed a spontaneous breathing trial. she was extubated to a high-flow nasal cannula. the patient's respiratory status gradually improved with her being able to wean from supplemental oxygen on day . on day , physical and occupational therapy consults were performed, with the patient demonstrating modified independence with mobility and activities of daily of living. a physical therapist and an occupational therapist provided education on activity and exercise to promote strength and endurance. on day , the patient had a negative test result for covid- by reverse transcription-polymerase chain reaction. a second test on day confirmed the negative test result, and the patient was discharged to home from the micu with her family later that afternoon. on day , the patient returned to the icu recovery clinic at our academic medical center. during her follow-up appointment, she complained of general fatigue and exhaustion. she stated she generally felt "wiped out." she expressed minor difficulty with walking from the clinic garage, less than feet from the clinic lobby due to fatigue. physically, the patient participated in the short performance physical battery (sppb), demonstrating a . m/second gait speed on -m habitual walk, . seconds to perform five times sit-to-stand testing, and > seconds in tandem stance (total score / ), thus demonstrating a minor slowing in gait speed and minor difficulty with sit-to-stand performance, indicating minimal weakness in the lower extremities. the patient did have signs of mild depression ( / in the depression category of the hospital anxiety and depression scale [hads]) related to her situation or memories of her illness, but her symptoms were not affecting her day-to-day life or preventing her from enjoying things she previously enjoyed. she did not have anxiety or signs of distress (hads anxiety = / , impact of events scale-revised / ). the patient did complain of short-term memory problems, which included no memory of her first days in the icu. she reported subsequent minor difficulty with daily short-term memory and word finding since her hospital discharge. she scored / on the montreal cognitive assessment, missing point removed for the cube copy test, which requires visual motor integration, depth perception, and spatial awareness. the patient also endorsed minor difficulty with sleep, including a few nights of disordered sleep with frequent waking. she reported a score of / on the eq- d visual analog scale. on day , the patient reported returning to driving and return to work with modifications due to fatigue, including more frequent rest breaks, limited lifting of > lb, and a stool to reduce time in prolonged standing. on day (approximately months after discharge from the hospital), the patient returned to the icu recovery clinic. she reported significant improvement overall, with only one episode of anxiety related to work that was alleviated with deep breathing strategies. the patient's performance on physical, emotional, and cognitive outcome measures had improved (fig. ) . the patient continued to endorse reduced endurance and periods of fatigue but was generally improved. at this time point, the patient performed the -minute-walk test ( mwd) with total distance ambulated m, equating to % of her percent predicted mwd [ ] . she also complained of insomnia, but she believed it to be unrelated to her icu admission. we present a case report of a young, previously healthy patient who developed ards due to covid- . the purpose of this report is to demonstrate the clinical trajectory and suggest the importance of icu follow-up visits with objective physical battery testing as well as memory and cognitive testing. the patient responded well to supportive treatment in the icu, including mechanical ventilation for days and a total icu stay of days. on the basis of her glasgow coma scale scores (ranging from to ), she never required deep sedation; in addition, on the basis of synchrony demonstrated with the ventilator and ratios of arterial oxygen partial pressure to fraction of inspired oxygen > , she did not receive neuromuscular blockers or undergo prone positioning for ventilation-perfusion matching. upon awakening and extubation, she did have minor confusion with memory deficits, but she had no delirium noted by the primary physician. she did have aki in the icu, which recovered quickly. it is important to note that patients who develop aki, especially when severe, with covid- have increased secondary complications, including higher risk of death [ ] . our patient, however, continued to improve each day, with oxygen requirements gradually reducing, and she was discharged to home after two negative quantitative polymerase chain reaction test results. two weeks after discharge and month after initial presentation of symptoms, the patient returned for her icu recovery clinic appointment. our icu recovery clinic consists of a transdisciplinary team that includes a physician, an advanced practice registered nurse (aprn), a pharmacist, a physical therapist, and a social worker focused on improving quality of life after critical illness, organizing subspecialty follow-up care, and promoting rehabilitation. the primary objectives of icu follow-up or recovery clinics are to address and treat post-intensive care syndrome (pics) and help patients reintegrate into their societal roles following an admission to the icu [ ] [ ] [ ] [ ] . post-icu follow-up clinics also address traumatic emotional experiences of family members and engage all parties to optimize outcomes [ ] [ ] [ ] [ ] . we are aligned with the national icu recovery clinic movement organized by the critical and acute illness recovery organization. within this framework, we deploy a series of standardized evaluations for patients recovering from their icu stay to assess emotional, cognitive, and physical health as well as health-related quality of life. outcome measures assist in the development of the plan of care and referral for interventions such as post-icu mental health interventions. given our patient's prior level of function (independent and employed), younger age, and scores on outcome measures, her trajectory of recovery is predicted to be strong. on the basis of her sppb and quality of life data, she had already returned to nearly % of her baseline predicted physical function, except for slightly low gait speed, fatigue, and endurance during ambulation. the patient scored much higher ( / on sppb) than previously reported data in an icu follow-up clinic month after icu discharge ( / in patients) [ ] . she did not have signs or symptoms consistent with anxiety, depression, or post-traumatic stress disorder (ptsd). compared with previously published icu follow-up data [ , ] , the patient would be considered at low risk of developing pics. however, considering her symptoms of reduced respiratory endurance and muscle weakness when performing the sit-to-stand test as well as her increased likelihood of anxiety related to isolation and frequent reminders of the pandemic [ , ] , she may benefit from continued icu follow-up. our icu recovery clinic physical therapist and our aprn educated the patient on exercise and activity at home to improve her functional status. sleep, nutrition, and medications were addressed at both clinic appointments. the patient and her family were provided education on the importance of extensive hand hygiene and use of a face mask to reduce the likelihood of secondary transmission in the home and in public [ ] , especially given the reproductive number (r ) of covid- [ ] . in addition, education was provided on when to return to work and to driving, which focused on a gradual progression, such as practicing driving in areas of less traffic in and around her neighborhood and building up tolerance to full workload by starting part-time or modifying her physical requirements at work. the patient did report returning to driving as well as a modified work schedule about months after hospital discharge. in addition, she was provided access to a shared icu recovery email with all team members able to respond to inquiries, should she have questions about her recovery. the patient demonstrated significant improvements during her short-term recovery, but, even months after discharge, she continues to have reduced endurance and exercise capacity ( % predicted mwd) and infrequent bouts of isolated anxiety and situational depression. thus, the patient and the clinic team developed a shortterm plan to have the patient continue to seek care in the icu recovery clinic with a long-term goal to establish a primary care provider in her city of residence. we present this case report as a precursor to suggest that patients surviving covid- with subsequent development of ards will require more intense icu recovery follow-up. even with her lower severity of illness and less complex icu course, our patient will still have benefited from follow-up services and education to maximize her outcomes. we suggest that patients with a higher degree of acute illness who also have preexisting comorbidities and who are of older age who survive mechanical ventilation for covid- will require substantial post-icu care. prior data of patients surviving acute respiratory failure suggest that icu covid- survivors will have substantial difficulties with anxiety, depression, ptsd, and physical disabilities as well as risk of secondary neurologic and cardiac complications [ ] [ ] [ ] [ ] [ ] [ ] . interdisciplinary follow-up care delivered using a recovery or pics model will be of vital importance for positive outcomes in this population. world health organization. coronavirus disease (covid- ) pandemic reference equations for the six-minute walk in healthy adults survival rate in acute kidney injury superimposed covid- patients: a systematic review and meta-analysis implementation of an icu recovery clinic at a tertiary care academic center comprehensive care of icu survivors: development and implementation of an icu recovery center ce: critical care recovery center: an innovative collaborative care model for icu survivors the icu follow-up clinic: a new paradigm for intensivists chaos theory: optimizing critical illness outcomes through the family experience -a theoretical review clinical practice guidelines for support of the family in the patient-centered intensive care unit: american college of critical care medicine task force family response to critical illness: postintensive care syndrome -family key components of icu recovery programs: what did patients report provided benefit? physical function impairment in survivors of critical illness in an icu recovery clinic understanding, compliance and psychological impact of the sars quarantine experience the psychological impact of quarantine and how to reduce it: rapid review of the evidence comprehensive review of mask utility and challenges during the covid- pandemic public health measures and the reproduction number of sars-cov- depressive symptoms and impaired physical function after acute lung injury: a -year longitudinal study physical complications in acute lung injury survivors: a two-year longitudinal prospective study functional disability years after acute respiratory distress syndrome depression, post-traumatic stress disorder, and functional disability in survivors of critical illness in the brain-icu study: a longitudinal cohort study co-occurrence of post-intensive care syndrome problems among survivors of critical illness scoping review of prevalence of neurologic comorbidities in patients hospitalized for covid- publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors acknowledge each and every clinician in the medical icu and icu recovery clinic who treated and cared for the patient described in this case report. authors' contributions kpm and pem developed the manuscript idea and drafted the first version. sms and epc provided clinical support to extract data and images. jls, agk, mks, eedv, and aamy contributed to writing and editing of the drafted version. all authors read and approved the final manuscript. no funding was provided for completion of this case report.availability of data and materials n/a. this case report was approved by the patient with written informed consent. written informed consent was obtained from the patient for publication of this case report and any accompanying images. a copy of the written consent is available for review by the editor-in-chief of this journal. the authors declare that they have no competing interests. key: cord- -rgae jy authors: terrasi, benjamin; arnaud, emilien; guilbart, mathieu; besserve, patricia; mahjoub, yazine title: french icus fight back: an example of regional icu organisation to tackle the sars cov- outbreak date: - - journal: anaesth crit care pain med doi: . /j.accpm. . . sha: doc_id: cord_uid: rgae jy nan since the beginning of the sars-cov- (also called covid- ) outbreak in the hubei province in china, half a million people have been infected and more than died worldwide by the end of march [ ] . in europe, the third most infected country is france (after italy and spain) with more than cases and about deaths by the end of the last week of march [ ]. one of the first french regions hit by the outbreak was picardy, located at the northeast of the country. the first case in picardy was diagnosed on february th , in the cardiac thoracic and respiratory icu of the amiens-picardy university hospital. the number of patients admitted to the region's icus rapidly increased after that first case. to tackle this surge, an organisation was set in order to coordinate and facilitate the admission of critically ill covid- infected patients, and to avoid or at least delay the overrun of icu capacities in the region. we based the organisation on a centralised on-call dispatch icu consultant and efficient bed manager software. the picardy sub-region is situated at the northern part of france. picardy has about million inhabitants on . km . there are about public hospitals and private hospitals, for a total number of icu beds and post icu beds [ ] . there is only one tertiary teaching hospital: the amiens-picardy university hospital (chu amiens-picardie). to tackle the outbreak, the number of icu beds doubled in less than weeks in these public and private hospitals. in france, all anaesthesiologists are in the same time intensivists. indeed, anaesthesia residents receive icu training for at least one and a half year, and the majority of french icus are managed by anaesthesiologists. after the start of the covid- outbreak, all non-urgent surgery operations were delayed. hence, anaesthesiologists and anaesthesia residents of picardy who worked in operating theatres were made available for icus. specially trained staff was immediately ready for the regional increase of icu capacity. . -h on-call regional icu dispatcher an icu consultant from the amiens university hospital was designated to centralise all calls from emergency departments, wards, and remote icus of the region. a unique phone number was created and sent to all public and private hospitals. the on-call intensivist dispatcher was available h a day, days a week. this on-call intensivist dispatcher answers to phone calls, gives advices for patient management and finds an available icu bed if required. during the first two weeks of the outbreak, the on-call intensivist dispatcher answered to calls daily. in order to accurately and timely dispatch patients on a regional level, the on-call regional intensivist dispatcher needs to know precisely and timely the number of available beds. for this purpose, a responsive web application based on spring framework [ ] . . for the backend api (application program interface) and react [ ] . . for the frontend ui (user interface) named coord-rea® was created by a consultant (ea). it has been packaged in a docker image and secured using keycloak®. the software was hosted by amiens-picardy university hospital. hence, the on-call regional intensivist dispatcher can access in real time to a synthesis of beds availability (fig. ) using a web browser or a smart phone. the software was shared online by all icus in picardy. it was asked for all icus to timely update the number of available beds. all icus are divided in two areas, for covid- infected and non-infected patients, respectively. hence, the on-call regional intensivist dispatcher was immediately able to find an available icu bed for every patient in the region. the cardiac thoracic and respiratory icu of amiens university hospital, a -bed facility, is the only icu in picardy with the ability to initiate ecmo therapy. since the beginning of the outbreak, a regional mobile ecmo team was created in the amiens university medical centre. this team is composed by an intensivist, a thoracic surgeon and an ecmo specialised nurse. the team is / available for all emergency departments and icus of the region. the team is able to reach in less than hour all hospitals in the region. ecmo is initiated on site and patients are retrieved by helicopter or by road to the cardiac thoracic and respiratory icu of amiens university hospital. since the beginning of the outbreak, the team received between one and three calls every day for ecmo. in two weeks, seven ecmo therapies were initiated for patients with covid- related ards. with the help of a local private company (come-scape®, amiens, france) a free-app named "covid- practical sheets" (covid- fiches pratiques) has been designed [ ] . after creating a website on wordpress®, an extension was added in order to build a progressive web app (wpa). this kind of application allows a web page to appear as a mobile application combining functionalities of a modern web browser and usefulness of mobile phones. an icu consultant (bt) was dedicated to daily update all information given on the app. the app was initially designed for anaesthesiologists and intensivists from picardy. however, hours after its launch, more than connections were registered, not only from france but from several french speaking countries in europe, north africa and north america. this letter describes an example of regional organisation settled to tackle the covid- outbreak. we advise our colleagues from all over the world to adapt this organisation to their area. nevertheless, the increase of patients with covid- related ards may overrun icu capacity whatever the organisation. we are confident that the commitment and seriousness of icu staff will prevail. professional java development with the spring framework learning react: functional web development with react and redux covid- . fiches pratiques the authors thank pr hervé dupont, pr vincent jounieaux and dr geneviève barjon for their insight. key: cord- - y aqx authors: gauss, tobias; pasquier, pierre; joannes-boyau, olivier; constantin, jean-michel; langeron, olivier; bouzat, pierre; pottecher, julien title: preliminary pragmatic lessons from the sars-cov- pandemic from france date: - - journal: anaesth crit care pain med doi: . /j.accpm. . . sha: doc_id: cord_uid: y aqx abstract the first wave of the sars-cov- pandemic required an unprecedented and historic increase in critical care capacity on a global scale in france. authors and members from the acute and reanimation committees of the french society of anaesthesiology and critical care (sfar) wished to share experience and insights gained during the first weeks of this pandemic. these were summarised following the world health organisation response checklist and detailed according to the subsequent subheadings: . command and control, . communication, . safety and security, . triage, . surge capacity, . continuity of essential services, . human resources, . logistics and supply management, . training/preparation, . psychological comfort for patients and next of kin, . learning and . post disaster recovery. these experience-based recommendations, consensual across all members from both committees of our national society, establish a practical framework for medical teams, either spared by the first wave of severe covid patients or preparing for the second one. post disaster recovery. these experience-based recommendations, consensual across all members from both committees of our national society, establish a practical framework for medical teams, either spared by the first wave of severe covid patients or preparing for the second one. keywords: sars-cov- ; critical care; surge capacity; recommendations; pandemic the sars-cov- pandemic requires an unprecedented and historic increase in critical care capacity on a global scale. the ongoing fight against the pandemic and potential resurgence of the virus made it compelling for the authors to share specific concepts for the management of critical care surge capacity. this short report reflects impressions the authors gained within the first weeks of the pandemic. these may evolve over the coming weeks and months. despite its unprecedented dimensions, we feel that all elements of the world health organisation (who) hospital response checklist ( ) apply to the current situation. nevertheless, we suggest a slight adaption by adding three categories and change the order. this provides a methodology for planning, briefings, training, and analysis of the situation: . command and control, . communication, . safety and security, . triage, . surge capacity, . continuity of essential services, . human resources, . logistics and supply management, . training/preparation, . psychological comfort for patients and next of kin, . learning, and . post disaster recovery. the importance of command/control and communication at local and regional level cannot be overemphasised. it is beyond the scope of this paper to describe the detailed working of a hospital crisis committee or regional crisis coordination. however, the authors would like to share a few experiences specific to the pandemic. one particularity of any exceptional situation (mass casualty, pandemic, etc.) is the activation of a structured crisis mode during which authority lies within the crisis committee, relying on a chain of command and clearly defined principles of control. the particularity of the pandemic situation is its unknown duration casting uncertainties for how long the hospital will function in crisis mode. the imperatives of the situation imposed a complete overhaul of the entire hospital organigram and structure within days. the principle of a chain of command is not in the dna of the medical community in general and some of its members may struggle to adapt to it. in consequence, the committee should anticipate and mitigate the possible challenges that a prolonged crisis mode may signify for the pre-crisis hospital mentality hierarchy and the change in leadership it embodies. communication is vital and remains a major challenge in any exceptional situation. as debriefs of many events have demonstrated, the situation on the ground and information often evolves more rapidly than the capacity to convey information. distortion ensues, generating contradictions, disinformation, misinterpretation and confusion. in terms of communication, the specificity of the pandemic situation is again its unknown duration. designating a communication officer seems vital. disinformation is as contagious as the virus and spreads quickly often through official and social media; it affects health professionals as much as the general public and generates anxiety. professionals should be advised to limit their use of social media. from our experience, official channels of information are essential to diffuse trusted and validated information, doctrine and procedures. for instance, hospital department-based website, regularly fed with physician-approved protocols and available through secured login and password turned out to be very efficient. the flow of communication needs to travel down, but also up the chain of command to allow adjustments and revision of strategic plans and prevent potential non-alignment or conflict with local needs and hospital-based guidelines. a single channel and medium of communication may not be enough. several identified official channels are required to spread information (mailing, posters, meetings/briefings, whatsapp groups…). in several areas, existing networks (trauma, cardiology…) provided these trusted channels of communication and were tremendously useful, facilitating the federation and mobilisation of professionals. newly designed information technology and data science tools (applications, dashboards…) were deployed and put to use to share and structure information (patient flow, available resources, bed-management…). some proved useful and well-adapted and those were adopted by professionals. complex tools or those requiring a lot of user input or learning were neglected. design and deployment of these tools require time and health professional input beforehand. anticipated deployment and training of integrated command and control and communication tools before the next crisis is strongly recommended. registries and data extraction facilitated data-based decision-making and prediction. in this crisis, the predominant security issue was the protection of staff against contamination with appropriate use of personal protective equipment (ppe) and its procurement. concerns of ppe procurement and new evidence required frequent adaption of standard operating procedures (sops). those adaptations were sometimes met with distrust and anxiety by health care professionals, as they were considered as a consequence of ppe shortage and not evidence-based. defusing these anxieties and frustrations required a considerable effort in terms of training, information and reassurance. the ethical and logistical challenges of triage and allocation of intensive care unit (icu) resources during a pandemic have been extensively discussed ( ) . in many places, the overall context enforced clinicians to adapt triage to a prioritisation in alignment with available resources (resource-based triage). in the vast majority the decisions made remained individualised and patient-and contextdependant according to national guidelines ( ). in all circumstances, even if increasingly limited resources impose ever more restrictive prioritisation ( ), withdrawal or withholding of critical care must remain a shared and documented decision-making process. maintaining this level of accountability is imperative. a detailed and thorough analysis of the withholding and withdrawal of care during the peak of this first wave should be a research priority. scale of this flow model is not measured in hours but days, compared to classic mc events. application of this doctrine requires keeping length of stay in each zone to a minimum and thinking about the potential discharge pathway on admission to the icu. anticipation to increase capacities and to adapt or innovate pathways for recovery and rehabilitation are as important as for acute care. in the icu, treatment strategies were adapted to implement an "icu damage control pathway". in this context, damage control is to be understood as an acceptable simplification or modification of existing treatment modalities to shorten length of stay (use of high-flow oxygen instead of intubation, keeping sedation and muscle relaxation to a minimum, prone positioning without muscle relaxation…) and avoiding iatrogenesis for the individual patient allowing to treat more patients, instead of attempting implementation of a sophisticated new strategy, less often proved to be more. the capacity of clinicians to absorb new and complex information is limited if their cognitive load is already high. in such contexts, it appears easier to readapt the existing strategy than to reinvent or adopt a completely new or less known strategy (e.g. complex forms of ventilation). patients and balance these with the capacities required for sars-cov- patients. icu/hdu capacities management required conscious effort to preserve protected space for non-sars-cov- critical care and respond to the evolving situation. even with confinement, the need for major trauma care never fully ebbed down. given the tremendous pressure on the integral health system, the continuity of many essential services was seriously impaired. early in the crisis, the local situation and a ministerial instruction imposed a cessation of all non-essential surgical care, effectively shutting down any non-vital surgical or interventional activity. the transfer of many operating theatre professionals, in particular anaesthetists and nurse anaesthetists, was crucial to increase icu capacity, and they all demonstrated their broad range of skills in anaesthesia and critical care. from the current perspective, vital essential services were maintained in the worst affected areas. this preliminary impression requires thorough analysis, based for example on registry data. in contrast, many centres suspended or transferred all oncological activity to less or non-affected centres; some institutions managed to perform interventions exclusively for cases where any delay would have resulted in reduced chances of survival. as in any event, human resource management remains a persistent key matter. mitigation and anticipation of fatigue, frustration, underuse, exposure, absenteeism and of course affection of health professionals require the full attention of crisis leaders. it was obvious from the start that all human resources management had to be performed in a sustainable and parsimonious way over weeks to months and coordinated at regional level, for some professional groups at national level. to plan and anticipate moments of uninterrupted rest even for crisis leaders is crucial. human resource management implies caring for the physical and psychological well-being of all healthcare professionals. in many hospitals, unemployed surgeons constituted "surgical task forces" whose aims were helping icu teams in prone positioning patients, providing medical information to relatives and filling in medical charts. overall, the medical community demonstrated an impressive capacity to adapt to an unprecedented situation. the covid- pandemic challenged our capacities to provide the necessary and usual human and psychological support patients and next of kin deserve. patients were submitted to profound neurological and psychological stress ( ) while the next of kin were not allowed to visit their loved ones for the sake of public health in most institutions. some centres implemented a much-protocolised access to patients in the icu or for the end of life; others used videoconference solutions to allow for some form of contact. training was crucial. any centre with an active mass casualty or disaster training program or regularly rehearsed disaster plans adapted better and faster. training was essential to prepare healthcare professionals in the first days of the pandemic for ppe use, airway management, cleaning, cardiac arrest, etc. ad hoc programs enabled the training of a considerable number of healthcare professionals (protection, airway management) in a short amount of time. training proved to be an excellent way to prepare professionals psychologically, reduce anxiety and convey validated messages and information. disaster planning, preparedness, operational and psychological trainings for all healthcare professionals within an institution should become a mandatory part of the annual calendar to develop a resilience culture. as tragic as the pandemic may be, it is a unique lesson in humility and a unique opportunity to learn and improve our healthcare systems at every level. connections and bonds created should be continued (for example between clinicians and the administration and between private and public hospitals) to rethink working, decision and communication patterns within our hospitals and institutions. there needs to be a before and after sars-cov- . many dogmas, fully endorsed at the beginning of the pandemic (early intubation, deep sedation and neuromuscular blockade for every patient, antiviral drugs) were subsequently questioned after the first debriefings and publication of clinical trial results. it is crucial to share clinical information, including observational data and case series, preserving usual scientific standards. it is definitely too early to talk about "post pandemic recovery", because we are still in the midst of it. at least for several months we will have to live with sars-cov- and develop new modes of organisation to live and work. for an unpredictable amount of time, the sars-cov- mode may be the new normal in our hospitals. some challenges and questions are already obvious: sustainable longterm human resource management, protection and testing of healthcare professionals, protection of patients admitted for other reasons, protect and care for the chronically ill, elderly and immunocompromised patients, rebalance the available resources for non sars-cov- care and an sars-cov- pandemic expected to ebb up and down. we are confident that the global medical community is ready to take up the challenges that lie ahead. the toughest triage -allocating ventilators in a pandemic neurologic features in severe sars-cov- infection key: cord- - zxkd jy authors: schwab, patrick; schutte, august dumont; dietz, benedikt; bauer, stefan title: predcovid- : a systematic study of clinical predictive models for coronavirus disease date: - - journal: nan doi: nan sha: doc_id: cord_uid: zxkd jy coronavirus disease (covid- ) is a rapidly emerging respiratory disease caused by the severe acute respiratory syndrome coronavirus (sars-cov- ). due to the rapid human-to-human transmission of sars-cov- , many healthcare systems are at risk of exceeding their healthcare capacities, in particular in terms of sars-cov- tests, hospital and intensive care unit (icu) beds and mechanical ventilators. predictive algorithms could potentially ease the strain on healthcare systems by identifying those who are most likely to receive a positive sars-cov- test, be hospitalised or admitted to the icu. here, we study clinical predictive models that estimate, using machine learning and based on routinely collected clinical data, which patients are likely to receive a positive sars-cov- test, require hospitalisation or intensive care. to evaluate the predictive performance of our models, we perform a retrospective evaluation on clinical and blood analysis data from a cohort of patients. our experimental results indicate that our predictive models identify (i) patients that test positive for sars-cov- a priori at a sensitivity of % ( % ci: %, %) and a specificity of % ( % ci: %, %), (ii) sars-cov- positive patients that require hospitalisation with . auc ( % ci: . , . ), and (iii) sars-cov- positive patients that require critical care with . auc ( % ci: . , . ). in addition, we determine which clinical features are predictive to what degree for each of the aforementioned clinical tasks. our results indicate that predictive models trained on routinely collected clinical data could be used to predict clinical pathways for covid- , and therefore help inform care and prioritise resources. c oronavirus disease (covid- ) was first discovered in december in china, and has since rapidly spread to over countries [ ] . the covid- pandemic challenges healthcare systems worldwide as a high peak capacity for testing and hospitalisation is necessary to diagnose and treat affected patients, particularly if the spread of sars-cov- is not mitigated. to avoid exceeding the available healthcare capacities, many countries have adopted social distancing policies, imposed travel restrictions, and postponed non-essential care and surgeries in order to reduce peak demand on their healthcare systems [ ] , [ ] , [ ] . we study the use of predictive models (light purple) to estimate whether patients are likely (i) to be sars-cov- positive, and whether sars-cov- positive patients are likely (ii) to be admitted to the hospital and (iii) to require critical care based on clinical, demographic and blood analysis data. accurate clinical predictive models stratify patients according to individual risk, and, in this manner, help prioritise healthcare resources, such as testing, hospital and critical care capacity. the adoption of clinical predictive models that accurately predict who is likely to require testing, hospitalisation and intensive care from routinely collected clinical data could potentially further reduce peak demand by ensuring resources are prioritised to those individuals with the highest risk ( figure ). for example, a clinical predictive model that accurately identifies patients that are likely to test positive for sars-cov- a priori could help prioritise limited sars-cov- testing capacity. however, developing accurate clinical prediction models for sars-cov- is difficult as relationships between clinical data, hospitalisation, and intensive care unit (icu) admission have not yet been established conclusively due to the recent emergence of sars-cov- . in this systematic study, we develop and evaluate clinical predictive models that use routinely collected clinical data to identify (i) patients that are likely to receive a positive sars-cov- test, (ii) sars-cov- positive patients that are likely to require hospitalisation, and (iii) sars-cov- positive patients that are likely to require intensive care. using the developed predictive models, we additionally determine which clinical features are most predictive for each of the aforementioned clinical tasks. our results indicate that predictive models could be used to predict clinical pathways for covid- patients. such predictive models may be of significant utility for healthcare systems as preserving healthcare capacity has been linked to successfully combating sars-cov- [ ] , [ ] . this work contains the following contributions: • we develop and systematically study predictive models for estimating the likelihoods of (i) a positive sars-cov- test in patients presenting at hospitals, (ii) hospital admission in sars-cov- positive patients, and (iii) critical care admission in sars-cov- positive patients. • we validate the performance of the developed clinical predictive models in a retrospective evaluation using realworld data from a cohort of patients. • we determine and quantify the predictive power of routinely-collected clinical, demographic, and blood analysis data for the aforementioned clinical prediction tasks. a substantial body of work is dedicated to the study, validation and implementation of predictive models for clinical tasks. clinical predictive models have, for example, been used to predict risk of septic shock [ ] , [ ] , risk of heart failure [ ] , readmission following heart failure [ ] , [ ] , [ ] , false alarms in critical care [ ] , risk scores [ ] , outcomes [ ] and mortality in pneumonia [ ] , [ ] , and mortality risk in critical care [ ] , [ ] , [ ] . predicting clinical outcomes for individual patients is difficult because a large number of confounding factors may influence patient outcomes, and collecting and accounting for these factors in an unbiased way remains an open challenge in clinical practice [ ] . systematic studies, such as the one presented in this work, enable medical practitioners to better understand, assess and potentially overcome these issues by systematically evaluating generalisation ability, expected predictive performance, and influential predictors of various clinical predictive models. beyond the need for systematic evaluation, missingness [ ] , [ ] , [ ] , [ ] , noise [ ] , [ ] , multivariate input data [ ] , [ ] , [ ] , [ ] , and the need for interpretability [ ] , [ ] , [ ] , [ ] have been highlighted as particularly important considerations in healthcare settings. in this work, we build on recent methodological advances to develop and systematically study clinical predictive models that may aid in prioritising healthcare resources [ ] for covid- , and thereby help prevent a potential overextension of healthcare system capacity. several clinical predictive models have recently been proposed for covid- , for example, for predicting potential covid- diagnoses using data from emergency care admission exams [ ] and chest imaging data [ ] , [ ] , [ ] , [ ] , [ ] , [ ] , for predicting covid- related mortality from clinical risk factors [ ] , [ ] , and for predicting which patients will develop acute respiratory distress syndrome (ards) from patients' clinical characteristics [ ] . [ ] presented a review of epidemiology and clinical features associated with covid- , and [ ] a critical review that assessed limitations and risk of bias in diagnostic and prognostic models for covid- . in addition, [ ] performed a cohort study for clinical and laboratory predictors of covid- related inhospital mortality that identified baseline neutrophil count, age fig. : the presented multistage machine-learning pipeline consists of preprocessing (light purple) the input data x, developing multiple candidate models using the given dataset (orange), selecting the best candidate model for evaluation (blue), and evaluating the selected best model's outputsŷ. and several other clinical features as top predictors of mortality. beyond prediction, [ ] have argued for the responsible use of data in tackling the challenges posed by sars-cov- . owing to the recent emergence of sars-cov- , there currently exists, to the best of our knowledge, no prior systematic study on clinical predictive models that predict likelihood of a positive sars-cov- test, hospital and intensive care unit admission from clinical, demographic and blood analysis data that accounts for the missingness that is characteristic for the clinical setting. we additionally assess the influence of various clinical, demographic, and blood analysis measurements on the predictions of the developed clinical predictive models. ) problem setting: in the given setting, we are given routine clinical, laboratory and demographic measurements, or features, x i ∈ x for presenting patients. features may be discrete or continuous, and some features may be missing as not all tests are necessarily performed on all patients. the clinical predictive tasks consist of utilising the routine clinical features x i to predict, for a newly presenting patient, (i) the likelihoodŷ sars-cov- of receiving a positive sars-cov- test result, (ii) the likelihoodŷ admission of requiring hospital admission, and the (iii) likelihoodŷ icu of requiring intensive care. in addition, we are given a development dataset consisting of n patients, their corresponding observed routine clinical features x i , sars-cov- test results y sars-cov- ∈ { , }, hospital admissions y admission ∈ { , }, and icu admissions y icu ∈ { , }, where indicates the presence of an outcome. using this development dataset, our goal is to derive clinical predictive modelsf sars-cov- ,f admission andf icu for the respective before-mentioned tasks in order to inform care and help prioritise scarce healthcare resources. ) methodology: to derive the clinical predictive modelŝ f sars-cov- ,f admission andf icu from the given development dataset, we set up a systematic model development, validation, and evaluation pipeline (fig. ) . to evaluate the generalisation ability of the developed clinical predictive models and to rule out overfitting to patients in the evaluation cohort, the development data is initially split into independent and stratified training, validation, and test folds without any patient overlap. concretely, the multistage pipeline consists of (i) preprocessing, (ii) model development, (iii) model selection, and (iv) model evaluation stages. for preprocessing and model development, only the training fold is used, and only the validation and test folds of the development data are used for model selection and model evaluation, respectively. we outline the pipeline stages in detail in the following paragraphs. ) preprocessing: in the preprocessing stage, we first drop all input features that are missing for more than . % of all training set patients to ensure we have a minimal amount of data for each feature. this removes a total of features from the original routine clinical, laboratory and demographic features. we then transform all discrete features for each patient into their one-hot encoded representation with one out of p indicator variables set to to indicate the discrete value for this patient, and all others set to with p being the number of unique values for the discrete feature. we defined those features as discrete that have fewer than unique values across all patients in the training fold. for discrete features, missing features were counted as a separate category in the one hot representation. next, we standardised all continuous features to have zero mean and unit standard deviation across the training fold data. lastly, we performed multiple imputation by chained equations (mice) to impute all missing values of every continuous feature from the respective other features in an iterative fashion [ ] . we additionally added a missing indicator that indicates if the feature was imputed by mice and if it was originally present in order to preserve missingness information in the data after imputation. after the preprocessing stage, continuous input features are standardised and fully imputed, and discrete input features are one-hot encoded. all preprocessing operations are derived only from the training fold, and naïvely applied without adjustment to validation and test folds in order to avoid information leakage. ) model development: in the model development stage, we train candidate clinical predictive modelsf sars-cov- ,f admission andf icu using supervised learning on the training fold of the preprocessed data. to derive the models from the preprocessed training fold data, we optimise various types of predictive models, and perform a hyperparameter search with m runs for each of them. the model development process yields m candidate models with different hyperparameter choices and predictive performances for each model category. ) model selection: in order to select the best model amongst the set of candidate models, we evaluate their predictive performance against the held-out validation fold that had not been used for model development. we choose the top candidate model by ranking all models by their evaluated predictive performance. the model selection stage using the independent validation fold enables us to optimise hyperparameters without utilising test fold data. ) model evaluation: in the model evaluation stage, we evaluate the selected best clinical predictive model against the held-out test fold that had not been used neither for training nor model selection in order to estimate the expected generalisation error of the models on previously unseen data. using this approach, every selected best model from the model selection stage is evaluated exactly once against the test fold. using the presented standardised model development, selection and evaluation pipeline, we compare various types of clinical predictive models in the same test setting, with exactly the same amount of hyperparameter optimisation and input features against the same test fold. this process enables us to systematically study the expected generalisation ability, predictive performance and influential features of clinical predictive models for predicting sars-cov- test results, hospital admission for sars-cov- positive patients, and icu admission for sars-cov- positive patients. we conducted retrospective experiments to evaluate the predictive performance of a number of clinical predictive models on each of the presented clinical prediction tasks using the standardised development, validation and evaluation pipeline. concretely, our experiments aimed to answer the following questions: what is the expected predictive performance of the various clinical predictive models in predicting (i) sars-cov- test results for presenting patients, (ii) hospital admission for sars-cov- positive patients, and (iii) icu admission for sars-cov- positive patients? which clinical, demographic and blood analysis features were most important for the respective best encountered predictive models for each clinical prediction task? the following subsections describe the conducted experimental evaluation in detail. we used anonymised data from a cohort of patients seen at the hospital israelita albert einstein in são paulo, brazil in the early months of . over the data collection time frame, the rate of sars-cov- positive patients at the hospital was around % of which around . % and . % required hospitalisation and critical care, respectively (table i) . notably, younger patients were underrepresented in the sars-cov- positive group relative to the general patient population which may have been caused by the reportedly more severe disease progression in older patients [ ] . information on patient sex was not included in our dataset. we randomly split the entire available patient cohort into training ( %), validation ( %) and test folds ( %) within strata of patient age, sars-cov- test result, hospital admission status, and icu admission status. after stratification, the three folds were approximately balanced across the stratification dimensions. using the presented systematic evaluation methodology, we trained five different model types: logistic regression (lr), neural network (nn), random forest (rf), support vector machine (svm), and gradient boosting (xgb) [ ] . the nn was a multi-layer perceptron (mlp) consisting of l hidden layers with n hidden units each followed by a non-linear activation function (relu [ ] , selu [ ] , or elu [ ] ) and batch normalisation [ ] , and was trained using the adam optimiser [ ] for up to epochs with an early stopping patience of epochs on the validation set loss. we followed an unbiased, systematic approach to hyperparameter selection and optimisation. for each type of clinical predictive model, we performed a maximum of hyperparameter optimisation runs with hyperparameters chosen from predefined ranges (table ii) . the performance of each hyperparameter optimisation run was evaluated against the validation cohort. after computing the validation set performance, we selected the best candidate predictive model across the hyperparameter optimisation runs by area under the receiver operator curve for further evaluation against the test set. d. metrics ) predictive performance: to assess the predictive performance of each of the developed clinical predictive models, we evaluated their performance in terms of area under the receiver operator curve (auc), area under the precision recall curve (aupr), sensitivity, specificity, and specificity at greater than % sensitivity (spec.@ %sens.) on the held-out test set cohorts for each task (table i) . after model development and hyperparameter optimisation, we evaluated each model type exactly once against the test set to calculate the final performance metrics. operating thresholds for each model were the operating points on the receiver operator characteristic curve closest to the top left coordinate as calculated for the validation cohort. we chose a variety of complementary evaluation metrics in order to give a comprehensive picture of the expected performance of each clinical predictive model on the evaluated tasks. for each of the performance metrics, we additionally computed % confidence intervals (cis) using bootstrap resampling with bootstrap samples on the test set cohort in order to quantify the uncertainty of our analysis results. we also assessed whether differences between clinical predictive models were statistically significant at significance level α = . using pairwise t-tests with the respective best models for each task as measured by auc. ) importance of test types: to quantify the importance of specific clinical, demographic and blood analysis features on each of the predicted outcomes, we utilised causal explanation (cxplain) models [ ] . cxplain provides standardised relative feature importance attributions for any predictive model by computing the marginal contribution of each input feature towards the predictive performance of a model [ ] , and is therefore particularly well-suited for assessing feature importance in our diverse set of models. we used the test fold's ground truth labels to compute the exact marginal contribution of each input feature without any estimation uncertainty. in terms of predictive performance (table iii) , we found that the overall best identified models by auc were xgb for predicting sars-cov- test results, rf for predicting hospital admissions for sars-cov- positive patients, and svm for predicting icu admission for sars-cov- positive patients . notably, we found that predicting positive sars-cov- results from routinely collected clinical measurements was a considerably more difficult task for clinical predictive models than predicting hospitalisation and icu admission. nonetheless, the best encountered clinical predictive model for predicting sars-cov- test results (xgb) achieved a respectable sensitivity of % ( % ci: %, %) and specificity of % ( % ci: %, %). after fixing the operating threshold of the model to meet a sensitivity level of at least % (spec.@ % sens.), the best xgb model for predicting sars-cov- test results would achieve a specificity of % ( % ci: %, %). we additionally found that the differences in predictive performance between the best xgb model for predicting sars-cov- test results and the other predictive models was significant at a pre-specified significance level of α = . (ttest) for all but the aupr metric, where nn achieved a significantly better aupr of . and the difference to svm was not significant at the pre-specified significance level. on the task of predicting hospital admissions for sars-cov- positive patients, the best encountered rf model achieved a sensitivity of % ( % ci: %, %), a high specificity of % ( % ci: %, %), and a specificity at a fixed sensitivity of at least % (spec.@ % sens.) of % ( % ci: %, %). owing to the lower sample size due to the smaller cohort of sars-cov- positive patients, the performance results for predicting hospital admission generally had wider uncertainty bounds but were nonetheless significantly better for rf than the other predictive models at the pre-specified significance level of α = . (t-test) for most performance metrics with the exception of auc where xgb achieved an auc of . and aupr where lr achieved an aupr of . . on the task of predicting icu admission for sars-cov- positive patients, svm had a sensitivity of % ( % ci: %, %), a specificity of % ( % ci: %, %), and a specificity at a fixed sensitivity of at least % (spec.@ % sens.) of % ( % ci: %, %). due to the small percentage of around % of sars-cov- positive patients that were admitted to the icu (table i) , uncertainty bounds were wider than for the models predicting hospital admissions, and the results of the best encountered svm were found to be not significantly better than lr and rf in terms of auc, lr and nn in terms of sensitivity, and nn in terms of spec.@ % sens. at the pre-specified significance level of α = . (t-test). in terms of feature importance, we found that importance scores were distributed highly unequally, relatively uniform and highly uniform for the best models encountered for predicting sars-cov- test results, for predicting hospital admissions for sars-cov- positive patients, and for predicting icu admission, respectively (figure ). most notably, we found that . % of the importance for the best xgb model for predicting sars-cov- test results was assigned to the missing indicator corresponding to the arterial lactic acid measurement, i.e. much of the marginal predictive performance gain of the xgb model was attributed to whether or not the arterial lactic acid test had been ordered. beyond arterial lactic acid being missing, age, leukocyte count, platelet count, and creatinine were implied to be associated with a positive sars-cov- test result by the best encountered predictive model, which further substantiates recent independent reports of those factors being potentially associated with sars-cov- [ ] , [ ] , [ ] , [ ] , [ ] . similarly to the best encountered xgb model for predicting sars-cov- test results, the top encountered predictive models for hospital admission and icu admission for sars-cov- positive patients assigned a considerable degree of importance to missingness patterns associated with a number of measurements. a possible explanation for missingness appearing as a top predictor across the different tasks is that decisions whether or not to order a certain test to be performed for a given patient were influenced by patient characteristics that were not captured in the set of clinical measurements that were available to the predictive models. a controlled setting with standardised testing guidelines would be required to determine which confounding factors are behind the predictive power of the missingness patterns that have been implied to be associated with covid- by the predictive models. beyond missingness patterns, top predictors for predicting hospital admission were lactate dehydrogenase [ ] , gammaglutamyltransferase, which through abnormal liver function has been reported to be implicated in covid- severity [ ] , and hco [ ] . for predicting icu admission in sars-cov- positive patients, pco and ph [ ] were top predictors. blood ph, and in particular respiratory alkalosis, has been reported to be associated with severe covid- [ ] . we presented a systematic study of predictive models that predict sars-cov- test results, hospital admission for sars-cov- positive patients, and icu admission for sars-cov- positive patients using routinely collected clinical measurements. models that predict sars-cov- test results could help prioritise scarce testing capacity by identifying those individuals that are more likely to receive a positive result. similarly, predictive models that predict which sars-cov- positive patients would be most likely to require hospital and critical care beds could help better utilise existing hospital capacity by prioritising those patients that have the highest risk of deterioration. facilitating the efficient utilisation of scarce healthcare resources is particularly important in dealing with sars-cov- as its rapid transmission significantly increases demand for healthcare services worldwide. the main limitation of the presented study is that its experimental evaluation was based on data collected from a single study site, and its results may therefore not generalise to settings with significantly different patient populations, admission criteria, patterns of missingness, and testing guidelines. in addition, we did not have access to mortality data for the analysed cohort, and we were therefore not able to correlate our predicted individual risk scores with patient mortality, which is another related prediction task that may be of clinical importance. future studies should include a broader set of clinical measurements and outcomes, cohorts from multiple distinct geographical sites and under varying patterns of missingness in order to determine the robustness of the clinical predictive models to these confounding factors. finally, we believe that the inclusion of data from other modalities, such as genomic profiling and medical imaging, and data on co-morbidities, symptoms and treatment histories could potentially further improve predictive performance of clinical predictive models across the presented prediction tasks. we presented a systematic study in which we developed and evaluated clinical predictive models for covid- that estimate (i) the likelihood of a positive sars-cov- test in patients presenting at hospitals, (ii) the likelihood of hospital admission and (iii) intensive care unit admission in sars-cov- positive patients. we evaluated our developed clinical predictive models in a retrospective evaluation using a cohort of hospital patients seen in são paulo, brazil. in addition, we determined the clinical, demographic and blood analysis measurements that were most important for accurately predicting sars-cov- status, hospital admissions, and icu admissions. our experimental results indicate that clinical predictive models may in the future potentially be used to inform care and help prioritise scarce healthcare resources by assigning personalised risk scores for individual patients using routinely collected clinical, demographic and blood analysis data. furthermore, our findings on the importance of routine clinical measurements towards predicting clinical pathways for patients increase our understanding of the interrelations of individual risk profiles and outcomes in sars-cov- . based on our study's results, we conclude that healthcare systems should explore the use of predictive models that assess individual covid- risk in order to improve healthcare resource prioritisation and inform patient care. the anonymised data used in this manuscript were generously contributed by patients at hospital israelita albert einstein in são paulo, brazil, and are freely available at https://www.kaggle.com/einsteindata u/covid . coronavirus disease (covid- ) pandemic the effect of travel restrictions on the spread of the novel coronavirus update: public health response to the coronavirus disease outbreak -united states a conceptual model for the coronavirus disease (covid- ) outbreak in wuhan, china with individual reaction and governmental action response to covid- in taiwan: big data analytics, new technology, and proactive testing interrupting transmission of covid- : lessons from containment efforts in singapore a targeted real-time early warning score (trewscore) for septic shock creating an automated trigger for sepsis clinical decision support at emergency department triage using machine learning prediction modeling using ehr data: challenges, strategies, and a comparison of machine learning approaches prediction of -day all-cause readmissions in patients hospitalized for heart failure: comparison of machine learning and other statistical approaches predictive modeling of hospital readmission rates using electronic medical recordwide machine learning: a case-study using mount sinai heart failure cohort a machine learning model to predict the risk of -day readmissions in patients with heart failure: a retrospective analysis of electronic medical records data not to cry wolf: distantly supervised multitask learning in critical care intelligible models for healthcare: predicting pneumonia risk and hospital -day readmission patient-specific models for predicting the outcomes of patients with community acquired pneumonia an evaluation of machine-learning methods for predicting pneumonia mortality using data-driven rules to predict mortality in severe community acquired pneumonia predicting hospital mortality for patients in the intensive care unit: a comparison of artificial neural networks with logistic regression models unfolding physiological state: mortality modelling in intensive care units reproducibility in critical care: a mortality prediction case study predicting the futureâȂŤbig data, machine learning, and clinical medicine multiple imputation versus data enhancement for dealing with missing data in observational health care outcome analyses strategies for handling missing data in electronic health record derived data directly modeling missing data in sequences with rnns: improved classification of clinical time series recurrent neural networks for multivariate time series with missing values computational phenotype discovery using unsupervised feature learning over noisy, sparse, and irregular clinical data beat by beat: classifying cardiac arrhythmias with recurrent neural networks phonemd: learning to diagnose parkinson's disease from smartphone data a multivariate timeseries modeling approach to severity of illness assessment and forecasting in icu with sparse, heterogeneous clinical data a deep learning approach to diagnosing multiple sclerosis from smartphone data retain: an interpretable predictive model for healthcare using reverse time attention mechanism towards a rigorous science of interpretable machine learning right for the right reasons: training differentiable models by constraining their explanations cxplain: causal explanations for model interpretation under uncertainty machine learning and prediction in medicineâȂŤbeyond the peak of inflated expectations covid- diagnosis prediction in emergency care patients: a machine learning approach covid-net: a tailored deep convolutional neural network design for detection of covid- cases from chest radiography images automatic detection of coronavirus disease (covid- ) using x-ray images and deep convolutional neural networks artificial intelligence distinguishes covid- from community acquired pneumonia on chest ct artificial intelligence applied on chest x-ray can aid in the diagnosis of covid- infection: a first experience from lombardy a deep learning algorithm using ct images to screen for corona virus disease (covid- ) deep learning system to screen coronavirus disease pneumonia a machine learning model reveals older age and delayed hospitalization as predictors of mortality in patients with covid- prediction of criticality in patients with severe covid- infection using three clinical features: a machine learning-based prognostic model with clinical data in wuhan towards an artificial intelligence framework for data-driven prediction of coronavirus clinical severity epidemiology and clinical features of covid- : a review of current literature prediction models for diagnosis and prognosis of covid- infection: systematic review and critical appraisal clinical and laboratory predictors of in-hospital mortality in patients with covid- : a cohort study in wuhan, china on the responsible use of digital data to tackle the covid- pandemic multiple imputation using chained equations: issues and guidance for practice covid- and italy: what next xgboost: a scalable tree boosting system rectified linear units improve restricted boltzmann machines selfnormalizing neural networks fast and accurate deep network learning by exponential linear units (elus) batch normalization: accelerating deep network training by reducing internal covariate shift adam: a method for stochastic optimization granger-causal attentive mixtures of experts: learning important features with neural networks severe outcomes among patients with coronavirus disease (covid- ) -united states the epidemiology and pathogenesis of coronavirus disease (covid- ) outbreak thrombocytopenia is associated with severe coronavirus disease (covid- ) infections: a metaanalysis kidney disease is associated with in-hospital death of patients with covid- clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study clinical features of covid- -related liver damage respiratory support in novel coronavirus disease (covid- ) patients, with a focus on resource-limited settings covid- in iran, a comprehensive investigation from exposure to treatment outcomes key: cord- -h h vd r authors: scabini, leonardo f. s.; ribas, lucas c.; neiva, mariane b.; junior, altamir g. b.; farf'an, alex j. f.; bruno, odemir m. title: social interaction layers in complex networks for the dynamical epidemic modeling of covid- in brazil date: - - journal: nan doi: nan sha: doc_id: cord_uid: h h vd r we are currently living in a state of uncertainty due to the pandemic caused by the sars-cov- virus. there are several factors involved in the epidemic spreading such as the individual characteristics of each city/country. the true shape of the epidemic dynamics is a large, complex system such as most of the social systems. in this context, complex networks are a great candidate to analyze these systems due to their ability to tackle structural and dynamical properties. therefore this study presents a new approach to model the covid- epidemic using a multi-layer complex network, where nodes represent people, edges are social contacts, and layers represent different social activities. the model improves the traditional sir and it is applied to study the brazilian epidemic by analyzing possible future actions and their consequences. the network is characterized using statistics of infection, death, and hospitalization time. to simulate isolation, social distancing, or precautionary measures we remove layers and/or reduce the intensity of social contacts. results show that even taking various optimistic assumptions, the current isolation levels in brazil still may lead to a critical scenario for the healthcare system and a considerable death toll (average of , ). if all activities return to normal, the epidemic growth may suffer a steep increase, and the demand for icu beds may surpass times the country's capacity. this would surely lead to a catastrophic scenario, as our estimation reaches an average of , deaths even considering that all cases are effectively treated. the increase of isolation (up to a lockdown) shows to be the best option to keep the situation under the healthcare system capacity, aside from ensuring a faster decrease of new case occurrences (months of difference), and a significantly smaller death toll (average of , ). although we have experienced several pandemics throughout history, covid- is the first major pandemic in the modern era. the last critical global epidemic occurred in and became known as the spanish flu. but, in , the reality was quite different. scientific and medical knowledge was much more limited, making it difficult to fight the disease. furthermore, the world was not globalized, the means of transport were not as agile as the current ones and the population was much smaller. the st century is marked by globalization and an intricate and intense social network, which connects in one way or another to everyone on the planet. the latter fact increases the danger that a local epidemic disease will rapidly evolve into a pandemic like what happened in wuhan, china, and now is all over the world. the form of propagation and contagion of the sars-cov- virus occurs by direct contact between individuals, through secretions, saliva, and especially by droplets expelled during breathing, speeching, coughing, or sneezing. the virus also spreads by indirect contact, when such secretions reach surfaces, food, and objects [ ] . besides, infected people take a few days to manifest symptoms, which can be severe or as mild as a simple cold. there is even a large proportion of infected people who remain asymptomatic [ ] . this makes it practically impossible to quickly identify the infected and apply effective measures to limit the spread of the disease. also, sars-cov- was discovered in december , which makes it very recently in the face of the current epidemic. little is known about the covid- disease, which appears to be highly lethal, with no drugs to prevent or treat. the concern is greater since direct (individual -individual) and indirect (individual -objects -individual) social relations are the means of spreading the disease. thus, the social interaction structure is the key to create strategies and guide health organizations and governments to take appropriate actions to combat the disease. one of the main concerns is overloading the health system. the first case in brazil was confirmed on february , a -year-old man who traveled to the lombardy region in northern italy. now, in the middle of may, there are more than , cases and , deaths in all states of brazil [ ] . the concern is even worse due to the country's social inequality, over % of the population relies solely on the public health system and this distribution is not uniform. according to [ ] , there are only hospital beds per , people in the north region while southeast accounts for hospital beds. the treatment of severe cases requires the use of respirators/ventilation in intensive care units (icu), and if simultaneous infections occur there will be no beds to meet the demand and a possibly large number of victims. thus, it is urgent to develop models and analyses to try to predict the evolution of the virus. also, as noted in figure , brazil is running towards being the next epicenter of the pandemic. it has already exceeded the number of cases in important countries such as germany, china, japan, italy, iran, south korea, and france (the rates consider the population size of each country and are on a logarithmic scale). [ ] ). it is possible to notice that brazil is surpassing countries such as italy, south korea, japan, and china, and it is reaching the relative number of cases in the united kingdom and france. as of the date of this study, the united states is the epicenter of the pandemic. since covid- presents a unique and unprecedented situation, this work proposes a specific model for the current pandemic. based on the classic epidemic model sir, also extended to sid [ ] , siasd [ ] and siqr [ ] , we propose a more realistic model to better represent the effects of the covid- disease by adding more infection states. the proposed approach also considers social structures and demographic data for complex network modeling. each individual is represented as a node and edges represent social interaction between them. the multi-layer structure is implemented by different edges representing specific social activities: home, work, transports, schools, religious activities, and random contacts. the probability of contagion is composed of a dynamic term, which depends on the circumstances of the social activity considered, and a global scaling factor β for controlling characteristics such as isolation, preventive measures, and social distancing. the proposed model can be used to analyze any society given sufficient demographic data, such as medium/big cities, countries, or regions. here we analyze in depth the brazilian data. the sir model is applied through the network using an agent model, and each iteration of the system is simulated using the -hour pattern, allowing us to understand the dynamics of the disease throughout the days. the results show the importance of social distancing recommendations to flatten the curve of infected people over time. this is currently maybe the only way to avoid a collapse of the health system in the country. the paper is divided as follows: section presents important concepts about complex networks, the sir model and its applications. section explains our proposed approach and sections and presents the results, discussion, and conclusions of the work. created from a mixture of graph theory, physics, and statistics, complex networks (cn) are capable to analyze not only the elements themselves but also their environment to find patterns and obtain information about the dynamics of a system. as most of the natural structures are composed of connected elements, graphs are suitable to analyze most of the real-world phenomena. over the past two decades researchers have been showing that many real networks do not present a random structure, and its emergent patterns can be used to understand and characterize a model [ , ] . complex network analysis has then been applied to sociology, physics, nanotechnology, neuroscience, biology, among other areas [ , ] . to start with a formal definition, a graph g is a set {v,e} where v is composed by n vertices (also known as nodes or elements) {v i , v n } and e is the set e(v i , v j ) of edges (or connections) among its elements. edges represents the relationships between two elements and its value can also represent the strength or weight of a connection if usually, applications with complex networks consist of two main steps: i) transform the real structure into a complex network, and ii) analyze the model and extract its features or understand its dynamics. one natural phenomenon that has a straight forward connection to a complex network in society. people are connected due to several aspects such as members of a family, religious groups, co-workers, members of the same school, or faculty, among other social relationships. therefore cns have been widely employed for social network analysis [ ] . extended from social interactions, the epidemic spread has also been studied by researchers in the last decades. in this context, one of the best known and widely used epidemic models in infectious diseases is the susceptible-infectedrecovered (sir) model, which is composed of three categories of individuals [ , ] • susceptible: the ones who are not infected but could change its status to a state to infected if in contact with a sick person combined with a probability β of contagion • infected: the ones that have the disease • recovered: usually after some time, a person recovers from the illness and it is not able to be infected again due to the immunity process (in this case, this is an assumption of the process). the recovery rate of infected people is aligned with a probability of γ also, the model can be described as where s, i and r represents the ratio of susceptible, infected and recovered people in the population, respectively. usually, the problem is solved with differential equations, however, agent-based techniques in networks can represent the nature of the spread of viral diseases in a more complex scenario. if a network is fully connected, meaning that e(v i , v j ) = { , ∀ i,j < i, j <= n }, equation fits the structure perfectly. however, in the real world, not everyone is connected and people only contract the disease if in contact with an infected individual or object. this is why a complex network approximates the dynamics of real viruses and can help us to understand the disease behavior. there are various approaches to represent people and society as networks, named social network analysis. small world networks [ ] can be used as a good approximation of the social connections. in , moore [ ] emphasized that the use of small-world networks, where the distance among two elements is usually small in comparison to the size of the population, showed a faster spread of the viral disease than classical diffusion methods. the approximation of real social phenomena was first explained by milgram [ ] in [ ] , the sociologist is the author of the well-known idea that there are up to six people separating any two individuals in the world, which reinforces the importance of analyzing the epidemic spread from a graph view. in [ ] , the authors used small-world networks to simulate a sir model, however, they considered that every contact with an infected person resulted in contamination, which is not realistic. therefore, other researchers improved the model over the years, adding new constraints to approximate the simulation to real scenarios [ ] . the sir model on networks works as follows: each node represents a person and, the elements are connected according to some criteria and the epidemic propagation happens through an agent-based approach. it starts from a random node, and for each time step nodes with the susceptible state can contract the disease from a linked infected node with a predefined probability. the same idea occurs with the recovered category. after a certain period, a node can recover or can be removed from the system (case of death) according to a certain probability. at the end of the evolution of a sir model applied to a network, the number of nodes in each sir category (susceptible, infected and recovered) can be calculated for each unit of time evaluated and then compare these data with real information, for example, the hospital capabilities of the health system. also, the probability of infection and recovery can be adjusted over time considering social distancing, hygiene, and health conditions. the proposed model extends the sir model to a more realistic scenario to achieve a better correlation to the covid- disease, since the model was created specifically for the disease, we named the model as complexvid- . our strategy is based on a multi-layer network to represent the brazilian demography and its different characteristics of social relationships. each layer is composed of a set of groups representing how people interact in a given social context. in the network, a node represents a person and the edges are the social relationships between persons, and they are also the means through which the disease can be transmitted. the virus spreads from an infected node to neighboring nodes at each iteration step ( step = day), according to a given infection probability. first, we describe how the layers are built based on social data from brazil. to define the different social relations, the first information needed is the age distribution so that groups such as schools and work can be separated. we consider the brazilian age distribution in relation to the total population in [ ] , details are given on table . this distribution is used to define an age group for each node, which is then used to determine its social activities through the creation of edges on different layers. in this approach, each network-layer represents a kind of social relationship or activity that influences the transmission of the covid- . in this way, it is possible to evaluate and understand what is the impact of each social activity in the epidemic propagation. basically, in this work, a network layer is represented by a set of edges connecting some nodes. the following social activities are considered, composing different layers: • home: in this layer, all people that live in the same residence are connected. • work: connects people that work in the same environment/company. • transport: this layer represents people that eventually take the same vehicle at public transports. • school: represents the social contact of students that belong to the same school class. • religious activities: connects people of the same group of some religious activity. • random: this layer represents activities of smaller intensity, such as indirect contact (through objects/surfaces). the first layer represents home interactions and is composed of a set of groups with varying size which are fully connected internally. these groups have no external connections, i.e. the network starts with disconnected components representing each family. to create each group, we consider the brazilian family size distribution for [ ] , the year with more detailed information on family sizes from up to members. we consider the probability of a family having sizes from to , therefore the probability of a family having persons is the sum of the higher sizes, the details of this distribution are given in table . the first layer is then created following the family size distribution and ensuring that each family has at least adult. figure (a) shows the structure of such a layer built for a population of n = . a large fraction of the population in any country needs to work or practice some kind of economic activity, which also means interacting with other people. thus, work represents one of the most important factors of social relations, which is also very important in an epidemic scenario. to represent the work activity we propose a generic layer to connect people with ages from to years, i.e. % of the total population in the case of brazil. there is a wide variety of jobs and companies, therefore it is not trivial to create a connection rule that precisely reflects the real world. here, we consider an average scenario with random groups of sizes around [ , ] , uniformly distributed, and internally connected (such as the "home" layer). an example of this layer is shown on figure (b), using n = . although the nodes of a group are fully connected, the transmission of the virus depends directly on the edge weights, which we discuss in-depth on section . . . collective transports are essential in most cities, however, it is one of the most crowded environments and plays an important role in an epidemic scenario also due to the possibility of geographical spread, as vehicles are constantly moving around. the third layer we propose represents this kind of transports, such as public transports, and includes people that do not possess or use a personal vehicle. in brazil the number of people using public transport depends on the size of the city, with . % in the capitals and . % in other cities [ ] , with an average use of around . hours a day . here we consider the average of the population between the two cases ( %), randomly sampled, to participate in the "transports" layer. random groups are created with sizes between [ , ] , uniformly sampled, and the nodes within each group are fully connected. this variation of sizes is considered to represent cases such as low and high commuting times, and also the differences between vehicle sizes. other factors such as agglomeration and contact intensity are discussed in section . . . this layer is illustrated on figure (c). schools are another environment of great risk for epidemic propagation. the proposed layer considers the characteristics of schools from primary to high school and how children interact. we consider that all persons from to years ( % of the brazilian population) participate in this layer, and the size of the groups, which represents different school classes, varies uniformly between [ , ] [ ]. this layer is illustrated on figure (d). brazil is a very religious country, in which by only around . % of the population claimed not to belong to any religion [ ] . . % claimed to be catholic and . % to be protestant, summing up to . % of the total population. here we consider that nearly half of these people ( % of the total population) actively participate in religious activities (weekly). the distribution of religious temple sizes is defined as a pareto distribution in the interval [ , ] . taking into account that wage distribution follows the pareto distribution approximately, we model real estate predominance according to their capacity. the assumption here is that building costs (for churches, offices, homes, etc.) have a linear relationship to their internal capacity, and thus any given capacity has a power-law relationship with the number of such buildings within a region. we consider a random layer to represent all kinds of contacts not related to the specific previous social layers. this includes small direct contacts (person-to-person) and indirect contacts (individual -objects -individual) that may happen throughout the week, such as random friend/neighbor meetings, shopping, and other activities that involve surface contacts. for that n new random edges are created, that can connect any node. on the one hand, this yields an average of random connections to each node, which can randomly connect any other node. on the other hand, the impact of this layer on the epidemic is smaller than the others, as it represents rapid contacts in comparison to the other activities described, thus its infection probability is smaller. in the following section we discuss the details concerning this aspect, deriving from the edge weights of each layer. in figure (f) an example of this layer is shown. the overall structure of social interactions in our model can be compared to the statistical analysis in [ ] , however here we introduce a more detailed model of social contacts with specific layers and connection patterns to better fit the particularities of a given country or city. unlike the traditional sir model, which consists of a single β term to describe the probability of infection, here we propose a dynamic strategy to better represent the real world and the new covid- disease. the idea is to incorporate important characteristics in the context of epidemic propagation according to each layer. firstly, to a given layer a fixed probability term is calculated to represent its characteristic of social interaction. for this, we considered local terms: the contact time per week, the average number of people close to each other (agglomeration level), and the total number of people involved in the respective activity. considering two nodes v x and v y , connected at group j of layer i, its edge weight is then defined by where t i represents the average weekly contact time on layer i, k i is the agglomeration level (average number of nearby people) and n ij represents the size of the group j in which the nodes participates on layer i. the first fraction represents the contact time normalized by the total time of the week ( * = ), and the second fraction represents the proportion among the local people closest to the total number of people on that activity group. the first part of the infection probability equation is multiplied by a β term, which scales the original probability. the β term is then the only parameter to tune the infection rates for the entire network, and the other properties are specific for the studied society, based on its population characteristics and the nature of the activities (layers). table shows these specific properties that we considered for the brazilian population, and how the infection probabilities are calculated for each layer. in the table, we have the following information: who or how many people are part of the activity represented by a layer (column "who", discussed in the previous section); contact time according to activity (column "time of contact"); the average number of people close to each other in each activity (column "nearest", represents the agglomeration level); the number of connections between people (column "group size"); the probability of infection (column "probability"). • susceptible: traditional case, it means that a person can be infected at any time. this is the initial state of every node. • infected -asymptomatic: people who do not show any symptoms ( % of the total cases of infection) and remain contagious for up to days (they may recover after days). this is the most dangerous case for the epidemic spreading because the person is not aware of its infection. • infected -mild: % of the cases, present mild and moderated symptoms with no need for hospitalization, remain contagious for up to days, and may recover after days of infection. • infected -severe: % of the cases, present strong symptoms, and need hospitalization, remain contagious for up to days. has a death rate of % and may recover after days. • infected -critical: present worst symptoms and remain contagious for up to days, need icu and ventilation, have a death rate of % and may recover after days. • recovered: people who went through one of the infection cases and overcame the disease, ceasing to contaminate and supposedly becoming immune. these nodes no longer interact with other nodes anymore and are therefore removed from the network. • dead: people who went through severe or critical cases and eventually died. these nodes are also removed from the network. estimates for the proportion of asymptomatic cases vary from % ( % confidence, [ . , . %]) [ ] to % ( % confidence, [ . , . %]) [ ] . considering the confidence intervals, here we roughly approximate it to an average of % of the total number of infected cases. however, it is very difficult to study asymptomatic cases due to several reasons, such as the lack of available tests and the difficulty in identifying potential cases, which would include every person who had contact with known symptomatic cases. some studies indicate that asymptomatic cases may remain contagious for up to days, with an incubation period of days [ ] , but the viral load may be smaller at the end of the infection. here we take an optimistic approach considering that they may recover (become immune and cease to contaminate) uniformly after days of infection, up to around days. as for the recovered nodes, we are considering that people become immune or at least acquire a long-term resistance to the virus, up to a maximum of days (limit of our simulations). however, this should be taken cautiously as these properties are not yet fully understood [ ] . the infection grows through the contact (edges) between infected and susceptible nodes, and the probability of being infected is the edge weight. if infection occurs, then one of the infection cases are chosen based on the probability described above ( %, %, % and %). this distribution plays an important role in the structure and dynamics of the network. the node structure of asymptomatic cases does not change during the simulation, except for the time it takes to cease contamination and recover. it means that as these persons are not aware of their contamination, they will remain acting normally on the network (according to the active layers and edge weights). their contagious time varies from to days after infection. concerning the other cases (mild, severe, and critical), we consider the incubation time of the virus, the recovery time, the contagion time, the death rates of each case, and the usual action taken by the infected person or health professionals at hospitals. various works [ , , ] point out that the average incubation period of covid- is around days, but some cases may take much less or more time. the official who report [ ] states that the average incubation time is around to days, with cases up to days. the results in [ ] show that the average shape of the incubation time follows a log-normal distribution (weibull distribution) with an average of . days and a standard deviation of . days. in this context, we consider the day when an infected person begins to show symptoms by randomly sampling from this distribution ( repetitions), with cases varying from to days. for mild cases, the nodes are isolated at home, maintaining the connections of the first layer, and then only % of the cases are diagnosed. considering the ratio of diagnosed cases, patients who are asymptomatic or with mild symptoms of covid- may not seek health care, which leads to the underestimation of the burden of covid- [ ] . moreover, our diagnosis rule is also based on the fact that ongoing tests in brazil are increasing more slowly than in most european countries and the usa (tests are being performed mostly on people that need hospitalization). if a given case is severe or critical, the patient goes to a hospital and is fully isolated, i.e. we remove all of its connections. this is a rather optimistic assumption, considering that these patients still may infect the hospital staff. concerning the time that patients usually stay at hospitalization/icu, the works [ , ] points to an average of days for all cases. for standard hospitalization, we considered a minimum of days and a maximum of days of stay, and for the icu/ventilation, a minimum of and a maximum of days of stay. the time of each case will depend on the day the symptoms start and the day of recovering/death. figure illustrates all the infected states and mechanisms described here. this configuration results in an overall lethality of %. it is important to stress that here we consider a maximum of days of infection time, which is the time frame based on most studies we have seen so far in the literature. we are still at the beginning of the pandemic and a better characterization of the long-term impact is very difficult. nonetheless, the available information allows to represent the most obvious features of the sars-cov- virus and to evaluate its main impacts on society. to simulate the reduction or increase of social distancing/quarantine, we remove/include some layers of the network, or change their edge weights. similarly to the approach on [ ] to improve home contact when in quarantine, we increase the home layer edge weights by % for each removed layer. to balance that we considered a smaller number of hours of contact in the base calculation for the home layer ( hours a day), also taking into consideration that this layer has full contact between people of the same family. when the home contacts are increased according to our approach of layer removal, the time/intensity of contacts may increase up to its double. for each experiment with the proposed model, we consider the average and standard deviation (error) of random repetitions to extract statistics of infection, death, and hospitalization time. due to the random nature of these networks, it is possible that extreme cases occur within the repetitions, i.e. when the infection starts at a node that is not capable of further propagation, leading the epidemic to end at few iterations. considering the real data we know that this is not the case, at least not for brazil, therefore we manually remove these networks and they are not considered for the average/error calculations. it is important to notice, however, that this rarely happens, in all our experiments we noticed a maximum of networks of this kind. due to time and hardware constraints, our simulation considers , nodes, and the results need to be scaled up by a factor of to match the brazilian population statistics. this factor was empirically found by approximating the model results in the number of reported cases in brazil. it is important to stress that for better statistics it should be considered the largest possible number of nodes to represent a population, i.e. the ideal case would be n = total country/city population. however, the computational cost of the simulation grows directly proportional to the number of nodes and edges of the network, and considering the critical situation of the moment at hand, , nodes are our limit to promptly present results of the epidemic dynamics. in the experiments when varying the social distancing, the same network is considered in each iteration, i.e. comparisons of including/excluding layers are made in the same random network. we considered the epidemic began on february , which is the day the first confirmed case was officially reported. it is important to emphasize that we made various optimistic assumptions throughout the model construction and simulation, such as to consider that people are behaving with more caution by reducing direct contact, wearing masks, and doing proper home/hospital isolation when infected. it is also important to notice that we are not considering the number of available icu/regular hospitalization beds for the death count, i.e. all the critical and severe cases are effectively treated. it is not trivial to estimate the direct impact of these numbers on the epidemic, however, this is an essential factor that directly impacts the number of deaths. here we focus on the impacts of different actions on the overall epidemic picture, such as the increase and reduction of cases, deaths, and occupied beds in hospitals. the social network starts normally, with all its layers and the original infection probabilities. the infection starts at a node with the closest degree to the average network degree and propagates at iterations of day (up to days). we consider an optimistic scenario, in which people are aware of the virus since the beginning, thus the initial infection probability is β = . . this represents a natural social distancing, a reduction of direct contacts that could cause infection (hugs, kisses, and handshakes), and also precautions when sneezing, coughing, etc. we empirically found that this initial value of β yields results with a higher correlation to the brazilian pandemic. a moderated quarantine is applied after days, representing the isolation measures applied on march by most brazilian states, such as são paulo [ ]. to simulate this quarantine we remove the layers of religious activities and schools and reduce the contacts on transports and work down to % of its initial value, i.e. β = . . the remaining activities on these layers represent services that could not be stopped, such as essential services, activities that are kept taking higher precautionary measures, and also those who disrespect the quarantine. we compare the output of the model in the first days with real data available from the brazilian epidemic (up to may ) [ , , , ] . the model achieves a significant overall similarity within its standard deviation. the greatest difference in the number of diagnosed cases at the last days may be related to the increase in the number of tests being performed in brazil, or yet, the constant decrease of isolation levels in the country (below % for most days of the past month) [ ] . we considered here a fixed isolation level around what was observed in the first days after the government decrees in brazil, but data in ref. shows that these levels are constantly changing. therefore, the number of diagnosed cases and deaths for the remaining simulation may be greater than the reported on this paper (see the "keep isolation" scenario in the next section). concerning the daily death toll, the average number of the proposed model is greater than the official numbers. this is somehow expected, considering that the underdetection rates may be greater in contrast to the fewer number of tests being performed. to better understand this, we analyzed the number of death in brazil from january to april , comparing cases between and , the results are shown in figure . it is possible to observe a clear increasing pattern after february , which is the day of the first officially confirmed case of covid- in brazil. this indicates that the real death toll for the disease may be significantly greater than the official numbers. [ ] , and world health organization (who) [ ] . the dotted lines represent the standard deviation, in the case of the real data the curve is the average over a -day window, and the solid lines the real raw data. the greatest average number of deaths produced by the proposed model may be related to underdetection (see figure ). [ ] . then the total death difference is compared to the covid- records of the who [ ] and the brazilian government [ ] data. the largest difference that appears right after the first confirmed case may indicate a significant underdetection of covid- cases. after the initial epidemic phase, we consider possible actions that can be taken after days (may ): a) do nothing more, maintaining the current isolation levels; b) stop isolation, returning activities to normal (initial network layers and weights); c) return only work activities, restoring the initial probability of the layer; or d) increase isolation, stopping the remaining activities in the work and transports layers (home and random remains). firstly, we analyze the impacts on the number of daily new cases and deaths, results are shown in figure . as previously mentioned, at the start of the covid- pandemic, brazil was performing a fewer number of tests by an order of magnitude, in comparison to other countries with similar epidemic numbers, therefore we considered as diagnosed only the severe and critical cases, which are pronounced subjects for testing, and % of the mild cases. the total infection ratio is discussed later. considering keeping the current isolation levels, the peak of daily new cases occurs around days after the first case (june ), with around , confirmed cases. after days (september ), the average daily cases is around , and it goes below daily cases after around days (october ). the peak of daily new deaths occurs around days (june ), with an average of deaths, and goes below new occurrences after around days (september ). it is important to stress that this is a hypothetical scenario where the isolation level remains the same from day to , which is hardly true in the real world where it is constantly changing [ ] . the total numbers after the last day ( ) account for , (± , ) diagnosed cases and , (± , ) deaths. when we consider the return of all activities after days, the number of cases and deaths grows significantly in an exponential fashion. the peak occurs at days (june ) with an average of , (± , ) new cases, and at days (june ) with an average of , (± , ) new deaths. although the peak of cases/deaths and the decrease of the numbers occur early, in this case, the final result is critically worse, with a total of , , (± , ) diagnosed cases and , (± , ) deaths. here it is important to notice that we considered that all the activities return after days and remain fully operational until the last day ( ). moreover, we do not account for the overloading of hospitals, which directly impacts the final death count. therefore, the number of deaths may be considerably higher. another possible scenario is the return of only the work layer, keeping reduced transports and no schools and religious activities, however, the pattern is similar to returning all activities, considering the growth time, peak, and decay time. the final numbers in this case are , , (± , ) diagnosed cases and , (± , ) deaths. if the isolation is strictly increased after days (lockdown), the infection and death counts drop significantly in comparison to the other approaches. moreover, the recovering time is much faster, as daily new cases stop earlier than the other scenarios. the peak of daily new cases happens around day (june ), and of daily new deaths around day (june ). the total numbers of diagnosed cases and deaths after day are, respectively, , (± , ) and , (± , ). considering the hospitalization time described in the scheme of figure it is possible to estimate the number of occupied beds for regular hospitalization (severe cases) and icu/ventilation (critical cases). we also show the difference between the cumulative growth of diagnosed and undiagnosed cases and recovered cases. the same approach as the previous experiment is considered (except for "return work") with possible actions after days (may ), results are shown in figure . the overall pattern of results is similar to the previously observed for the number of diagnosed cases and deaths. it is possible to notice that the number of undiagnosed cases is much higher than the diagnosed cases. this reflects the number of asymptomatic cases and the lack of tests for mild cases. in the worst scenario, which means ending the isolation, the total infected number may go above million cases. the recovered rate is directly proportional to the infected rate, as one needs to be infected to either die or become resistant to the disease. if the infected rate is high, so is the recovered rate, e.g. the scenarios of keeping or ending isolation, and a high recovered rate also helps in mitigating the epidemic propagation (natural immunization). however, increasing isolation decreases the propagation much faster than natural immunization, with a considerably smaller death toll. it is also possible to observe the differences at the start of effective recovering, i.e. when the recovered rate surpasses the infected rates, this is due to the early increase in isolation levels. the peak of hospitalization occupancy occurs around a week before the death peaks, in any scenario. in this case, icus are very important because critical patients are treated there, which represents the cases of higher death rates. within the "end isolation" setting, patients may occupy up to an average of , (± , ) regular beds and , (± , ) icu beds. these numbers are by far greater than entire brazil's capacity, as publicly-available and private icu beds sum up to , [ ] . even considering the better scenario, i.e. the lower bound of the standard deviation, the number of occupied icu beds may reach around , , which is also critical for brazil's capacity (almost times it's capacity). in this setting of "end isolation", the healthcare system would surely collapse. when the isolation levels are kept, the numbers are significantly lower. however, the occupancy of , (± , ) regular beds and , (± , ) icu beds is still critical for the brazilian health system. considering the creation of new provisional icu units and good patient logistics, the situation may still remain under control during the peak of hospitalization occupancy. however, the results show that the hospital occupancy is prolonged considerably in this scenario, and they may stay functioning around their maximum capacity for up to a month (with an average of occupied icu beds above , ). when increasing the isolation the peak of occupied beds is smaller, with an average of , (± , ) regular beds and , (± , ) icu beds. moreover, the shape of the curve throughout the days is different and the final numbers are considerably smaller. the peak also occurs around a week earlier and then decreases much faster. this scenario would be preferable as it has much more chances of not overloading the brazilian healthcare system, relieving the hospital occupancy considerably faster and, therefore, contributing to the reduction of the number of deaths. this work presents a new approach for the modeling of the covid- epidemic dynamics based on multi-layer complex networks. each node represents a person, and edges are social interactions divided into layers: home, work, transports, schools, religions, and random relations. each layer has its own characteristics based on how people usually interact in that activity. the propagation is performed using an agent-based technique, a modification of the sir model, where weights represent the infection probability that varies depending on the layers and the groups the node interacts, scaled by a β term that controls the chances of infection. the network structure is built based on demographic statistics of a given country, region, or city, and the propagation simulation is performed at time iterations, that represent days. here, we studied in depth the case of the brazilian epidemic considering its population properties and also specific events, such as when the first isolation measures were taken, and the impacts of future actions. brazil is a large and populated country with a wide variety of geographical location types, climates, and it also has a lengthy border with other countries to the west. it is a challenging setting for any epidemiological study. here we consider an average over all the country population, as we adjust the model output to match some statistics of the epidemic official reports. brazil is performing fewer tests in comparison to other countries at the same epidemic scale, however, it is known that testing for infection is always limited, either due to the low number of tests or to the velocity of infections which the testing procedure cannot keep up to. we then considered that only hospitalization cases and % of the mild cases are diagnosed. asymptomatic cases are not diagnosed and keep acting normally in the network, considering the active layers. regarding the isolation of infected nodes, we take some optimistic assumptions: mild cases (even those not diagnosed) are aware of its symptoms and isolate themselves at home. severe and critical cases are eventually hospitalized, and then fully isolated from the network (removal of all its edges). under the described scenario, the network starts with all its layers and β = . , representing that people are aware of the virus since the beginning (even before isolation measures). after days of the first confirmed case, the first isolation measures are taken where schools and religious activities are stopped and work and transports keep functioning at % of the initial scale (achieved further reducing the β term). different actions are then considered after days of the first case: keep the current isolation levels, increase isolation, end isolation returning all activities to %, or returning only the work activities. the results show that keeping approximately the current isolation levels results in a prolonged propagation, as we are near the estimated peak (around june ) with an average of , daily new cases and daily new deaths, and an average of , diagnosed cases (up to , million infected) and , deaths until the end of the year. in this scenario, hospitals may exceed its maximum capacity around june , but the efficient implementation of new icu beds and good logistic management of patients may still keep the situation under control. however, this is a very optimistic assumption, considering that our definition of "keep isolation" considers social isolation above % as registered at the beginning of the brazilian quarantine [ ] . the social isolation levels in brazil are constantly decreasing even when we are still in a state of moderated quarantine, and it is possible to observe average isolation below % in most days of the past month (middle of april to middle of may ). moreover, the results show that this prolonged scenario may cause hospitals to keep functioning at maximum capacity for up to a month. when analyzing other possible scenarios the situation may be considerably different. relaxing isolation measures from now on causes an abrupt increase in the daily growth of cases and deaths, up to times higher in comparison to the current isolation levels. even if only work activities return while schools, religion, and transport activities remain inactive/reduced, the impact is very similar to returning all the activities, with a possible number of above , million diagnosed cases (up to , million infected), and around , deaths until the end of the year. this is, again, a very optimistic assumption as we do not consider the hospital overflow to calculate the death toll. considering this aspect, icu beds may be fully occupied in early june, and around the middle of the month their demand may reach up to , beds, which is around times higher than the entire country's capacity. the other alternative, which is the increase of isolation levels (lockdown), appears to be the only alternative to stop the healthcare system from entering a very critical situation. in this scenario, the growth in the number of daily cases and deaths would be mitigated, and faster. as we are near the peak of new cases at current isolation levels, estimated to be between the beginning and middle of june, increasing the isolation levels does not cause a significant impact on when the peak occurs or its magnitude. however, the disease spreading and the occurrences of new cases decrease much faster in this scenario in comparison to any other scenario studied here, with a difference of months. moreover, the final numbers are considerably smaller, with an average of , diagnosed cases (up to . million infected) , deaths until the end of the year. although the proposed method includes various demographic information for the network construction, and an improved sir approach to covid- , it still does not cover all factors that impact the epidemic propagation. as future works, one may consider more information such as the correlation between the age distribution within the social organization and the clinical spectrum of the infection types (e.g. severe and critical cases are mostly composed of risk groups). another possible improvement consists of increasing n (number of nodes of the networks), e.g. using a value near the real population of the studied society, which we avoided here due to hardware and time constraints (graph processing is costly). another important point regarding the obtained results is related to the "keep isolation" scenario, which may be underestimated as we take various optimistic assumptions and also consider a fixed isolation level based on previously observed data, while most recent data shows that these levels are decreasing [ ] . therefore, during the network evolution, a possible improvement is the use of dynamic isolation levels to better represent reality. it is also possible to consider various scenarios for future actions, such as or more measures of increasing/reducing isolation. this may allow the discovering of new epidemic waves if social activities return too soon after the isolation period, such as what happened in with the spanish flu. portal da transparência -painel covid registral amib. brazilian intensive care medicine association: updated data on icu beds in brazil, , visited on - - infectious diseases of humans: dynamics and control incubation period of novel coronavirus ( -ncov) infections among travellers from wuhan, china presumed asymptomatic carrier transmission of covid- the mathematical theory of infectious diseases and its applications emergence of scaling in random networks modeling and forecasting the covid- pandemic in brazil covid- in critically ill patients in the seattle region-case series demand for hospitalization services for covid- patients in brazil analyzing and modeling real-world phenomena with complex networks: a survey of applications complex networks: the key to systems biology data analysis and modeling of the evolution of covid- in brazil epidemic spreading with awareness and different timescales in multiplex networks impact of non-pharmaceutical interventions (npis) to reduce covid mortality and healthcare demand clinical features of patients infected with novel coronavirus in wuhan, china tabela -população residente, por religião tabela -domicílios particulares permanentes por situação e número de moradores ibge. pesquisa nacional por amostra de domicílios contínua trimestral: tabela -população, por grupos de idade instituto nacional de estudos e pesquisas educacionais anísio teixeira: dados do censo escolar: ensino médio brasileiro tem média de alunos por sala instituto de pesquisa econômica aplicada: sistema de indicadores de percepção social (sips) coronavirus resource center asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus (sarscov- ): facts and myths positive rt-pcr test results in patients recovered from covid- the incubation period of coronavirus disease (covid- ) from publicly reported confirmed cases: estimation and application incubation period and other epidemiological characteristics of novel coronavirus infections with right truncation: a statistical analysis of publicly available case data the small world problem portal do covid- estimating the asymptomatic proportion of coronavirus disease (covid- ) cases on board the diamond princess cruise ship, yokohama, japan epidemics and percolation in small-world networks scaling and percolation in the small-world network model covid- coronavirus data model studies on the covid- pandemic in sweden the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- )-china clinical characteristics of asymptomatic and symptomatic patients with mild covid- collective dynamics of 'small-world'networks world health organization -coronavirus disease (covid- ): situation report, world health organization -modes of transmission of virus causing covid- : implications for ipc precaution recommendations world health organization coronavirus disease (covid- ) dashboard clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study key: cord- -i rdubix authors: vaschetto, rosanna; barone-adesi, francesco; racca, fabrizio; pissaia, claudio; maestrone, carlo; colombo, davide; olivieri, carlo; de vita, nello; santangelo, erminio; scotti, lorenza; castello, luigi; cena, tiziana; taverna, martina; grillenzoni, luca; moschella, maria adele; airoldi, gianluca; borrè, silvio; mojoli, francesco; della corte, francesco; navalesi, paolo; cammarota, gianmaria; baggiani, marta; baino, sara; balbo, piero; bazzano, simona; bonato, valeria; carbonati, sara; crimaldi, federico; daffara, veronica; de col, luca; maestrone, matteo; malerba, mario; moroni, federica; perucca, raffaella; pirisi, mario; rondi, valentina; rosalba, daniela; vanni, letizia; vigone, francesca title: outcomes of covid- patients treated with continuous positive airway pressure outside icu date: - - journal: erj open res doi: . / . - sha: doc_id: cord_uid: i rdubix aim: we aim at characterising a large population of coronavirus (covid- ) patients with moderate-to-severe hypoxemic acute respiratory failure (arf) receiving cpap outside intensive care unit (icu), and ascertaining whether the duration of cpap application increased the risk of mortality for patients requiring intubation. methods: in this retrospective, multicentre cohort study, we included covid- adult patients, treated with cpap outside icu for hypoxemic arf from march (st) to april (th), . we collected demographic and clinical data, including cpap therapeutic goal, hospital length of stay (los), and -day in-hospital mortality. results: the study includes patients with a median age of (iqr, – ) years. males were ( %). according to predefined cpap therapeutic goal, ( %) patients were included in full treatment subgroup, and ( %) in the do-not intubate (dni) subgroup. median cpap duration was (iqr, – ) days, while hospital los (iqr, – ) days. sixty-day in-hospital mortality was overall % ( %ci, . – . ), and % ( %ci, . – . ) and % ( %ci, . – . ) for full treatment and dni subgroups, respectively. in the full treatment subgroup, in-hospital mortality was % ( %ci, . – . ) for ( %) cpap failures requiring intubation, while % ( %ci, . – . ) for the remaining ( %) patients who succeeded. delaying intubation was associated with increased mortality [hr, . ( %ci, . – . )]. conclusions: we described a large population of covid- patients treated with cpap outside icu. intubation delay represents a risk factor for mortality. further investigation is needed for early identification of cpap failures. noninvasive ventilation (niv) administered as bi-level positive airway pressure (bipap) or continuous positive airway pressure (cpap) is commonly used in various critical care settings across a variety of aetiologies of acute respiratory failure (arf). for hypercapnic arf, mainly consequent to chronic obstructive pulmonary disease exacerbation, bipap can be used at an early stage to prevent intubation, at a later stage as alternative to first-line endotracheal intubation, or as a mean to facilitate weaning [ ] . for hypoxemic arf, recommendations strongly support the use of both bipap and cpap in patients with episodes of cardiogenic pulmonary edema [ , ] , while fewer data suggest their use in immunosuppressed [ , ] and in post-operative [ , ] patients. in patients with de novo hypoxemic arf evidences and recommendations on the use of niv are still to be determined [ ] . moreover, the application of niv in patients with acute respiratory distress syndrome (ards) complicating viral pneumonia is controversial [ ] . during coronavirus disease pandemic, piedmont together with lombardy, emilia-romagna and veneto was one of the most affected italian regions. due to the exceptional demand on intensive care unit (icu) resources, hospitals increased the number of icu beds and converted many general wards in respiratory intermediate care units (ricu) to treat patients with severe pneumonia and ards-needing respiratory support and monitoring. indeed, niv in patients with different therapeutic indications i.e., full-treatment and do-not-intubate [ ] has been shown to be successfully applicable also outside the icu [ , ] , when appropriate monitored setting and trained personnel are employed. data on niv during covid- pandemic, so far, consider predominantly patients admitted to the icu [ , , , , ] . the rate of patients receiving niv at icu admission ranges from %, as reported by an italian multicentre investigation [ ] , to % according to a chinese single centre study [ ] . exposure to noninvasive forms of respiratory support might have been even more diffuse outside icu, though only data from two monocentre studies are presently available, accounting overall for patients, treated with cpap [ ] and two with niv or high flow oxygen therapy [ ] . we designed this retrospective multicentre study to describe the clinical characteristics of patients with laboratory-confirmed covid- treated with cpap outside icu, to assess -day in-hospital mortality, and hospital length of stay (los), and to ascertain whether the duration cpap application prior to cpap failure affects outcome in patients requiring endotracheal intubation. this is a multicentre, retrospective observational study performed in six hospitals from the area of eastern piedmont in northern italy. all the participating centres obtained ethic committee approval. more details on study design and ethics approval are provided in the supplementary material. all patients admitted to one of the participating hospitals from march st to april th with hypoxemic arf secondary to confirmed sars-cov- . inclusion criteria were: ) age ≥ years, ) respiratory distress and partial pressure of arterial oxygen to fraction of inspired oxygen ratio < mmhg during venturi mask oxygen therapy, ) cpap initiation outside icu. patients who received post-extubation cpap were excluded. patients were classified according to predefined cpap therapeutic goal applied by the medical team, in two subgroups [ ] : ) full treatment, i.e. patients scheduled to receive intubation in the case of cpap failure; and ) do-not-intubate (dni), when cpap was ceiling of treatment. in case patient changed the therapeutic goal during hospital stay, the last cpap goal has been considered. the therapeutic goal of cpap was collegially discussed within the multidisciplinary teams, with the patients and with the families, taking into account comorbidities [ ] , quality of life and patient wishes. possible discrepancies between patients and relatives were solved through additional discussions between patient, relatives, and the medical team. demographic characteristics, body mass index (bmi), blood sample exams performed at hospital entrance (white blood cell count, lymphocytes count, creatinine, alanine transaminase, aspartate transaminase, lactate dehydrogenase, c-reactive protein, d-dimer, ferritin), arterial blood gas (abg) values obtained prior to cpap initiation and to hours after; and coexisting comorbidities were also recorded. charlson comorbidity index (cci) [ ] was also computed on the first day of hospital admission. this index contemplates categories of comorbidity recorded via anamnesis. age is not included as comorbidity in the cci version adopted. finally, we collected data about the clinical outcomes such as duration of cpap use, hospital length of stay (los), intubation and hospital mortality. for patients still in the hospital on may th (n= ), the outcomes have been censored on that day. details on cpap setting, schedule, ricu organization and criteria for intubation are described in the supplementary material. descriptive statistics are used to summarize the main demographic characteristics and the results of laboratory findings of all patients included in the study. categorical variables are reported as absolute frequencies and percentages, while numerical variables as median and interquartile range (iqr). the frequency and percentage of missing values for all variables is also reported. mann whitney u test is used to assess the difference between two independent samples, while wilcoxon signed-rank test for repeated measurements. chi-square statistic is used for testing relationships of categorical variables. curves of cumulative incidence of in-hospital mortality are drawn to describe mortality along days, either overall and stratified for treatment goal, and in the full treatment subgroup separately for patients succeeding cpap or receiving intubation. in order to avoid immortal time bias, in the survival analysis of patients receiving intubation, observation period started at the day of intubation. in the other analyses, observation period started at the day of cpap initiation. since discharge must be considered an informative censoring [ ], cumulative incidence was calculated using methods accounting for competing risk. to evaluate the cumulative incidence of in-hospital mortality for patients not undergoing intubation, all full treatment subjects are considered, and intubation is treated as a competing event allowing to account for the contribution of the time spent by intubated patients on cpap. the gray's test is used to assess the difference between cumulative incidence functions. fine and gray multivariate competing risk model is adopted to calculate the sub-distribution hazard ratios (shr) and the corresponding % confidence intervals ( %ci) for the association between cpap duration and in-hospital mortality risk in intubated patients, considering discharge as competing event. in the main analyses, missing data are managed by listwise deletion. we also carried out a secondary analysis using multiple imputation to evaluate the impact of missing values on the association estimates. missing imputation is performed using the expectation-maximization algorithm ( imputations) and considering the "missing at random" mechanism. more details about the model are provided in the supplementary material. all hypothesis tests are two-tailed and a significance level of . is considered. all statistical analysis was performed using stata (stata statistical software: release . college station, tx, usa: statacorp llc), sas (version . ; sas institute cary, nc, usa) and r (version . . ). from march st to april th , a total of patients with confirmed covid- were admitted to the six hospitals of the eastern piedmont ( figure s ). of these, ( %) patients were treated in icu, ( %) and ( %) with noninvasive and invasive mechanical ventilation, respectively. cpap was applied to ( %) patients in ricu. . median white blood cell count was . (iqr, . - . ) x /µl, with lymphopenia, i.e., . ( . - . ) x /µl. median values of creatinine, aspartate-aminotransferase, alanine-aminotransferase were in the normal range, while c-reactive protein, ferritin, lactate dehydrogenase and d-dimer were all above the normal range. cci median value was (iqr, - ), chronic arterial hypertension was present in ( %) patients, diabetes in ( %) patients, and ischaemic heart disease in ( %) patients. the most common interface was the helmet, in ( %) patients, while face masks were used in patients ( %); patients ( %) alternated both interfaces. median cpap duration was (iqr, [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days. overall cumulative -day in-hospital mortality was % (cumulative incidence, . , %ci, . - . ), as depicted in figure a , while hospital los was (iqr, [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days. demographic and clinical patients' characteristics stratified by pao /fio performed to hours after cpap initiation and interface applied, are provided in the supplementary material in table s and s, respectively. overall cumulative -day in-hospital mortality stratified according to pao /fio and interface applied is also depicted in figure s a within the full treatment subgroup, -day in-hospital mortality was % (cumulative incidence . , %ci, . - . ) for patients receiving intubation (figure ), and % (cumulative incidence . , %ci, . - . ) for patients succeeding cpap (figure s ). cpap duration was days (iqr, - days) in patients who survived and days (iqr. - days) in patients who died (p= . ). table shows that duration of cpap application was an independent predictor of mortality for patients requiring intubation. the model, adjusting for age, gender, comorbidities, ldh, c-reactive protein values, and lymphocyte count, indicates a . % [hr, . ( %ci, . - . )] increase of the risk of death for each day of treatment. the association between duration of cpap and mortality does not substantially change in the secondary analysis using multiple imputation [hr, . ( %ci, . - . )], as presented in table s . -day in-hospital mortality was significantly higher in patients subjected to cpap for more than days (cumulative incidence . , %ci, . - . ) as compared to those receiving cpap for days or less (cumulative incidence . , %ci, . - . ), as shown in figure s . this multicentre retrospective observational study on patients hypoxemic arf secondary to laboratory-confirmed covid- infection, shows that cpap applied to different therapeutic goals i.e., candidate to intubation in the case of cpap failure and do-not-intubate in which cpap is considered the ceiling of treatment, is feasible outside icu. treatment duration for patients failing cpap prior to intubation represents a risk factor for mortality. cpap can be delivered both in icu and outside icu. grasselli et al. [ ] , found that % of the patients entering icu needed niv, while early data from china revealed a higher percentage i.e., . % [ ] , . % [ ], % [ ] , % [ ] . in keeping with data by grasselli et al. [ ] , as cpap was delivered to out of patients ( . %) entering icu. data on the use of cpap in covid- patients treated outside icu are scarce. two over patients ( %) received niv or hfnc outside icu in a single centre study in wuhan [ ] . oranger et al., treated patients with cpap in a respiratory ward [ ] . although the study included a limited patients' number, cpap resulted to be feasible and the authors also suggest a potential benefit for both full treatment and dni patients, as opposed to those treated with oxygen only [ ] . as far as mortality concerns, we showed an overall cumulative -day in-hospital mortality of % in patients with moderate to severe forms of arf covid- -related needing cpap. the rate of mortality observed in our study, is not divergent from those reported in several prior studies [ , , , , ] for icu patients, predominantly intubated, which varied from % [ ] to % [ ] . lastly, our study includes % of dni patients, for whom cpap was considered ceiling of treatment. rate of dni patients reported in our study is similar to % observed in a small cohort of patients treated outside icu during covid- pandemic [ ] , i.e., as well as to % reported by a large italian multicentre observational study in patients with pneumonia non-covid- related, treated with niv outside icu [ ] . in our study, -day in-hospital mortality for dni patients was %. a major concern when treating patients with hypoxemic arf with niv, is related to niv-failure rate that might occur in up % of the cases with consequent recourse to intubation [ ] . undue prolongation of niv may worsen lung injury resulting in the so-called patient self-inflicted lung injury [ ] , while the direct consequence of niv failure is delaying intubation and adequate treatment with invasive ventilation [ , ] . our data confirm that intubation delay for those requiring afterward invasive ventilation is associated with increased risk for mortality. in other pandemics, such as influenza, h n , and severe acute respiratory syndrome (sars), niv failure ranges from to more than % [ ], reaching % with middle east respiratory syndrome [ ] . in our study, cpap failure rate was %, which indicates that effective treatment occurred in more than half of patients, who avoided invasive ventilation through an endotracheal tube, which is a life-saving procedure, but it is also prone to several side-effects and complications [ ] . the study has several limitations. first, we were not able to compare our population with an historical control. second, most of data have been retrospectively derived from the medical records. according to the retrospective nature of the study, formal criteria to start cpap treatment were not defined a priori, and the time span between cpap initiation and control abg was relatively long. third, definitions of full treatment and dni patients, although internationally accepted [ ] , are influenced by patients, families, and clinicians thinking and might be influenced by cultural, religious and geographical factors. fourth, due to the diversity of interfaces and devices used in our study, the actual applied pressure could somewhat differ from the preset value [ ] . fifth, due to the number of missing data among many important variables such as d-dimer and respiratory rate, we were not able introduce them in the model that explore the correlation between cpap duration and mortality. lastly, because of the exceptionality of pandemic outbreak, our results are not generalizable to other conditions. to the best of our knowledge, this is the largest retrospective cohort study on patients with covid - treated with cpap outside icu. we show that cpap is feasible outside icu with overall in-hospital mortality similar to that reported in other studies treating critically ill icu patients. in-hospital mortality is closely related to the therapeutic goal, patients having dni order being affected by much higher mortality. intubation delay is confirmed to be an independent risk factor for mortality. further studies are necessary to ascertain the potential infective risk related to cpap treatment outside icu among healthcare workers. chronic arterial hypertension, n (%) ( ) diabetes, n (%) ( ) ischaemic heart disease, n (%) ( ) cpap, days ( - ) curves and corresponding % confidence intervals (dashed lines). cpap, noninvasive continuous positive airway pressure; dni, do not intubate. eti, endo-tracheal intubation. outcomes of covid- patients treated with continuous positive airway pressure outside icu this was a multicentre, retrospective observational study performed in six hospitals of the eastern piedmont region, northern italy i.e., "maggiore della carità" university hospital in novara, "ss. antonio biagio e cesare arrigo", hospital in alessandria, "s. andrea" hospital in vercelli, "vco asl" in domodossola, "nuovo ospedale degli infermi" hospital in biella. one centre i.e., an as-needed basis. when respiratory parameters improved, cpap support was gradually reduced with a progressive increase of time off cpap, until discontinuation. nurse to patient ratios varied from a maximum of : both during day and night to a minimum of : and : , respectively during days and nights. in three hospitals, medical staff treating cpap covid- patients was an ad-hoc mixed team, mainly internists, pneumologists, emergency physicians, cardiologists, anaesthesiologists/icu physicians, while in the other three hospitals the medical team was the same as before covid- pandemic. cpap was prescribed mainly by anaesthesiologists actively working with the ad-hoc covid- ward team, but also by pneumologists and emergency doctors or by consulting anaesthesiologists. personnel was adequately trained for niv; those who were not, received a short-organized training during pandemic. ward monitoring included spo , non-invasive blood pressure, ecg applied continuously or at a defined time point depending on the severity of the patient. blood gas analysis was performed when clinically relevant. patients received daily visit from the consulting physician who prescribed cpap if not present in the ad-hoc ward team. fine and gray model included as adjustment age, gender, comorbidities i.e., charlson comorbidity index and hypertension, ldh, c-reactive protein levels and lymphocyte count. the model was further adjusted by centre. the adjustment variables were selected on the base of their clinical relevance. multiple imputation procedures were applied to account for missing data. ospedale ss. trinità, department of anesthesia and critical care azienda ospedaliera sant'andrea, department of anesthesia and critical care maggiore della carità via dei ponderanesi, - ponderano via gallucci maggiore della carità raoof s members of the task force. official ers/ats clinical practice guidelines: noninvasive ventilation for acute respiratory failure effect of noninvasive ventilation vs oxygen therapy on mortality among immunocompromised patients with acute respiratory failure: a randomized clinical trial effect of noninvasive ventilation on tracheal reintubation among patients with hypoxemic respiratory failure following abdominal surgery: a randomized clinical trial noninvasive positive pressure ventilation in critical and palliative care settings: understanding the goals of therapy noninvasive ventilation outside the intensive care unit from the patient point of view: a pilot study an international survey on noninvasive ventilation use for acute respiratory failure in general non-monitored wards characteristics and outcomes of critically ill patients with covid- in washington state clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china continuous positive airway pressure to avoid intubation in sars-cov- pneumonia: a two-period retrospective case-control study clinical features of patients infected with novel coronavirus in wuhan, china a new method of classifying prognostic comorbidity in longitudinal studies: development and validation clinical characteristics of coronavirus disease in china non-invasive positive pressure ventilation in pneumonia outside intensive care unit: an italian multicenter observational study high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure mechanical ventilation to minimize progression of lung injury in acute respiratory failure noninvasive mechanical ventilation in high-risk pulmonary infections: a clinical review noninvasive ventilation in critically ill patients with the middle east respiratory syndrome evolution of mortality over time in patients receiving mechanical ventilation helmet with specific settings versus facemask for noninvasive ventilation mg/dl noninvasive continuous positive airway pressure; feu, fibrinogen-equivalent unit table s general characteristics of patients according to cpap interface applied values are median (interquartile range) or number (percentage) feu, fibrinogen-equivalent unit helmet vs. mask: * p = . , † p= . , § p= . , °p< . , ‡ p= . . helmet (n= ) mask (n= ) mask and helmet (n= ) we acknowledge all health-care workers involved in the diagnosis and treatment of patients in the eastern piedmont region. we thank dr. davide crimaldi for database support. the study received no funding. preliminary data have been sent, in abstract form, to the european society of intensive care medicine congress . male body mass index white blood cell count lymphocyte count creatinine aspartate-aminotransferase alanine-aminotransferase abbreviations: abg, arterial blood gas analysis; cpap, noninvasive continuous positive airway pressure; paco , arterial partial pressure of carbon dioxide; pao , arterial partial pressure of oxygen; spo , peripheral oxygen saturation; hco -, bicarbonate; fio , inspired oxygen fraction; pao /fio , arterial partial pressure of oxygen to inspired oxygen fraction ratio; spo /fio , peripheral oxygen saturation to inspired oxygen fraction ratio a arterial blood gas analysis performed before cpap initiation b first arterial blood gas analysis performed - hours after cpap outset key: cord- -nzk m authors: milbrandt, eric b; angus, derek c title: bench-to-bedside review: critical illness-associated cognitive dysfunction – mechanisms, markers, and emerging therapeutics date: - - journal: crit care doi: . /cc sha: doc_id: cord_uid: nzk m cognitive dysfunction is common in critically ill patients, not only during the acute illness but also long after its resolution. a large number of pathophysiologic mechanisms are thought to underlie critical illness-associated cognitive dysfunction, including neuro-transmitter abnormalities and occult diffuse brain injury. markers that could be used to evaluate the influence of specific mechanisms in individual patients include serum anticholinergic activity, certain brain proteins, and tissue sodium concentration determination via high-resolution three-dimensional magnetic resonance imaging. although recent therapeutic advances in this area are exciting, they are still too immature to influence patient care. additional research is needed if we are to understand better the relative contributions of specific mechanisms to the development of critical illness-associated cognitive dysfunction and to determine whether these mechanisms might be amenable to treatment or prevention. since its advent more than years ago, the specialty of critical care has made remarkable advances in the care of severely ill patients. mortality rates for many commonly encountered critical illnesses such as severe sepsis [ ] and acute respiratory distress syndrome (ards) [ ] have declined sharply over the past decades. as greater numbers of patients survive intensive care, it is becoming increasingly evident that quality of life after critical illness is not always optimal. for instance, nearly half of ards survivors manifest neurocognitive sequelae years after their illness, falling to below the th percentile of the normal distribution of cognitive function [ ] . considering that % of americans would not wish to be kept alive if they had severe, irreversible neurologic damage [ ] , these findings are quite concerning. cognitive dysfunction (cd) is quite common in critically ill patients, not only during the acute illness but also long after the acute illness resolves [ ] . delirium, a form of acute cd that manifests as a fluctuating change in mental status, with inattention and altered level of consciousness, occurs in as many as % of mechanically ventilated intensive care unit (icu) patients [ ] . most clinicians consider icu delirium to be expected, iatrogenic, and without consequence. however, recent data associate delirium with increased duration of mechanical ventilation and icu stay [ ] , worse -month mortality [ ] , and higher costs [ ] . chronically, critical illnessassociated cd manifests as difficulties with memory, attention, executive function, mental processing speed, spatial abilities, and general intelligence. interestingly, patients who develop acute cd often go on to develop chronic cd after hospital discharge [ ] [ ] [ ] [ ] , suggesting that the two entities may share a common etiology. although there are clearly defined risk factors for critical illness-associated cd, there is little understanding of the underlying pathophysiology. the precise mechanisms are unknown and there are likely to be multiple mechanisms at work in any given patient ( figure ) [ , , ] . we have chosen to focus on two mechanisms that appear to have the greatest merit: neurotransmitter abnormalities and occult diffuse brain injury. in this bench-to-bedside review, we discuss the evidence supporting these mechanisms, potential markers that could be used to evaluate each mechanism in individual patients, and emerging therapies that may prevent or mitigate critical illness-associated cd. relative dopamine excess in the central nervous system (cns). antipsychotics such as haloperidol, which antagonize central dopamine receptors, can counteract the cognitive effects of anticholinergic medications, further supporting the anticholinergic hypothesis. drugs with potent central anticholinergic effects, such as tricyclic antidepressants and antihistamines, are particularly likely to cause delirium. many medications that are commonly used in the icu yet not generally considered to be anticholinergic, such as h blockers, opiates, furosemide, digoxin, glucocorticoids, and benzodiazepines, were recently shown to have central anticholinergic properties [ , ] . volatile anesthetics, such as sevoflurane, and intravenous anesthetics, such as propofol, also have anticholinergic effects and may be responsible not only for postoperative delirium but also for the more complex phenomena of postoperative cognitive dysfunction [ ] . acute illness itself may be associated with production of endogenous anticholinergic substances [ ] . in one study, out of elderly medical inpatients had had detectable anticholinergic activity in their serum, even though no medication used by these individuals had anticholinergic activity. characterization of such substances might improve our understanding of delirium and lead to useful intervention strategies. considering that activation of specific cholinergic pathways can inhibit proinflammatory cytokine synthesis and protect against endotoxemia and ischemia-reperfusion injury [ ] , it is tempting to speculate that inhibition of these pathways, whether exogenous or endogenous, might contribute not only to cd but also to other outcomes of critical illness. in assessing the overall risk for developing cd posed by medications with central anticholinergic activity in a given patient, individual differences in drug pharmacokinetics make the dose received a poor estimate of a patient's overall anticholinergic burden [ , ] . however, we can objectively measure anticholinergic burden in individual patients using an assay referred to as serum anticholinergic activity (saa) [ ] . first described by tune and coyle [ ] , saa measures the ability of a individual's serum to block central muscarinic receptors using a rat forebrain preparation. elevated saa levels are associated with cognitive impairment in studies of medical ward inpatients and community dwelling seniors [ , [ ] [ ] [ ] [ ] . only a single, small study has used this assay to investigate cd in icu patients. golinger and colleagues [ ] examined saa levels in surgical icu patients and found the mean saa level drawn hours after mental status change was significantly greater in delirious patients (n = ) than in those without delirium (n = ; . ng/ml versus . ng/ml; p = . ). whether these results apply to all critically ill patients is uncertain because no study has examined saa across a broad range of icu admitting diagnoses or in medical icu settings. furthermore, because saa measurement requires fresh rat brain preparations, its use is likely to remain limited to research settings for the foreseeable future. pathophysiologic mechanisms and predisposing factors thought to underlie critical illness-associated cognitive dysfunction [ , , ] . apo, apolipoprotein; hiv, human immunodeficiiency virus; -ht, serotonin ( -hydroxytryptamine); gaba, γ-aminobutyric acid; ne, norepinephrine (noradrenaline). other neurotransmitter systems such as dopamine, serotonin, γ-aminobutyric acid (gaba), norepinephrine (noradrenaline), and glutamate are also thought to contribute to critical illnessassociated cd. dopaminergic hyperfunction is thought to underlie the cognitive symptoms of schizophrenia, and dopamine administration itself may be a risk factor for delirium [ ] . serotonin syndrome, a consequence of excess serotonergic agonism, can be seen not only with selective serotonin reuptake inhibitors but also with a variety of drugs and drug combinations [ ] . even a single therapeutic dose of an selective serotonin reuptake inhibitor can cause the syndrome, which manifests as mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. gaba abnormalities are thought to contribute to hepatic encephalopathy, perhaps mediated by branched chain and aromatic amino acids acting as false neurotransmitters [ ] . excess gaba activity, such as that which occurs after withdrawal from chronic ethanol or benzodiazepine use, is a well known and quite dangerous cause of delirium [ ] . acutely, sedatives that stimulate gaba receptors, such as benzodiazepines and (probably) propofol, impair cognitive function and are deliriogenic [ , [ ] [ ] [ ] . this raises the possibility that strategies to minimize sedative drug accumulation, such as daily interruption of sedative infusions [ ] , which have been shown to reduce duration of mechanical ventilation, and icu and hospital length of stay, might also reduce the incidence or duration of delirium. whether these sedative drugs lead to neurocognitive deficits long after their use is unknown, but this has been suggested in certain high-risk groups, such as the very old (> years) and those with pre-existing cognitive impairment [ , ] . noradrenergic hyperfunction, as part of the 'fight or flight' response, can lead to panic attacks and delusions. glutamate has been implicated in the 'chinese food syndrome', in which food with high amounts of monosodium glutamate interferes with normal neurotransmission causing confusion [ ] . for a more complete review of the other neurotransmitter abnormalities that may underlie delirium, the reader is referred elsewhere [ , ] . if critical illness-associated cd were solely due to acute medication effects, it would probably resolve after the exposure has ended. however, a significant percentage of individuals developing delirium in the hospital continue to demonstrate symptoms of cd after discharge [ ] [ ] [ ] [ ] . these patients manifest decreased cerebral activity and increased cognitive deterioration, and are more likely to develop dementia than patients without delirium. also, patients who develop delirium have a greater rate of decline on cognitive tests than do nondelirious patients [ ] [ ] [ ] [ ] . taken together, these observations raise the possibility that some degree of occult diffuse brain injury, as a consequence of the local hypoxia, hypoperfusion, cytokine-mediated inflammation and microvascular thrombosis that characterize the multisystem organ dysfunction of critical illness, might have occurred in these patients [ ] . given that every other organ system can be damaged by these forces, it seems implausible that the brain would be uniquely spared. many of the data supporting occult diffuse brain injury as a cause of critical illness-associated cd come from studies of sepsis and septic encephalopathy, a form of delirium. in animal models of sepsis, oxidative damage occurs early in the hippocampus, cerebellum, and cortex [ ] , and significant alterations in cerebral vascular hemodynamics and tissue acid-base balance indicate that cerebral ischemia and acidosis do occur [ ] [ ] [ ] [ ] [ ] . sharshar and colleagues completed several studies comparing brain pathology in small numbers of patients who died from septic shock with that in patients who died from other causes. septic patients demonstrated diffuse severe ischemic and hemorrhagic cns lesions [ ] , which correlated with persistent hypotension and severe coagulation disorders. multiple microscopic foci of necrosis involving the white matter of the pons [ ] were seen, as well as ischemia and apoptosis within the cerebral autonomic centers [ ] . the white matter lesions were associated with elevated levels of proinflammatory cytokines, suggesting a possible role of inflammation and microvascular thrombosis in the genesis of cns injury [ ] . although those studies demonstrated that ischemic brain injury occurs in sepsis, they did not determine whether delirium occurred. two studies attempted to examine the relationship of ischemic brain injury to delirium. in one study of patients with severe sepsis and multiple organ dysfunction [ ] , severe hypotension was the only factor in multivariable analyses that was associated with delirium, suggesting that sepsis-related encephalopathy may be caused by ischemic damage rather than metabolic abnormalities. another study examined cerebral blood flow and cerebral oxygen metabolic rates in patients with septic encephalopathy and multiple organ dysfunction [ ] , and it found that both were significantly lower than those in normal awake individuals. although these studies support the idea of occult brain injury as a cause of delirium, the authors did not use a standardized diagnostic and statistical manual of mental disorders (dsm)-iv based tool to diagnose delirium, such as the confusion assessment method for the icu [ ] . lending support to the hypothesis that acute inflammation leads to brain injury and subsequent development of delirium, a recent study found that delirium in postoperative hipfractured patients was significantly associated with serum levels of c-reactive protein, an acute-phase protein that is a marker of acute inflammation [ ] . importantly, patients in the study were diagnosed with delirium using the confusion assessment method (the ward-based predecessor to the confusion assessment method for the icu), providing the first dsm-iv based evidence that acute inflammation may be in the causative pathway of delirium. the brain is a target for free radical damage because of its large lipid content, high rate of metabolism, and low antioxidant capacity. free radical induced oxidative stress may play a role in the delirium seen after cardiopulmonary bypass. karlidag and colleagues [ ] noted that patients with low preoperative levels of catalase, a erythrocyte-based antioxidant enzyme, were more susceptible to delirium postoperatively. they suggested that preoperative catalase levels might some day be used to identify at-risk patients who could then be put on antioxidant treatment preoperatively. whether this would reduce the incidence of delirium remains speculative. regional cerebral blood flow appears to be reduced in delirium. using xenon-enhanced computed tomography (ct), yakota and colleagues [ ] demonstrated significant focal and global brain hypoperfusion in icu patients with hypoactive delirium. after recovery from delirium cerebral blood flow returned to normal, implying that cerebral hypoperfusion may contribute to the development of delirium. studies of ards survivors suggest that a combination of acute hypoxia, hypoperfusion, and hyperglycemia plays an important role in the long-term cognitive sequelae of critical illness [ , , ] . however, it has been difficult to demonstrate a clear relationship, given the lengthy interval between stimulus and effect and the great number of additional contributing variables that can obscure downstream effects. among ards survivors, hopkins and colleagues showed that the degree of cd at year is significantly correlated with the durations of hypoxia [ ] and mean arterial blood pressure less than mmhg during the icu stay [ ] . in animals, hyperglycemia markedly enhances hypoxic-ischemic brain damage due to increased brain edema and disrupted cerebral metabolism [ ] . in ards survivors, the duration of blood glucose greater than mg/dl has been shown to correlate with worse visual spatial abilities, visual memory, processing speed, and executive function at year [ ] . given the recent interest in maintaining tight glucose control during critical illness as a means of reducing mortality, it will be interesting to see whether patients managed using this technique have better cognitive outcomes. clearly, such an approach will need to balance the benefits of tight glucose control with the known risks that hypoglycemia poses to the cns. one of the perceived difficulties with looking for evidence of occult brain injury in humans is the apparent need for cns tissue specimens to prove that brain injury actually occurred. however, studies of stroke, trauma, and cardiopulmonary bypass-associated brain injury show that serum markers of brain injury correlate well with the extent of cns damage. s- β, neuron-specific enolase (nse), and myelin basic protein (mbp) are three such markers that could be used to look for evidence of occult brain injury in critical illnessassociated cd. s- is a dimeric calcium-binding protein consisting of two subunits (α and β) [ ] . the β unit (s- β) is highly brain specific, located mainly in astrocytes. circulating levels of s- β are elevated in patients with cerebral ischemia [ ] , cardiopulmonary bypass-associated decline in explicit memory function [ , ] , and traumatic brain injury (tbi) [ ] [ ] [ ] . even in mild head injury, serum levels of s- β are correlated with clinical measures of injury severity, neuroradiologic findings, and outcomes, including postconcussion symptoms [ ] . elevated serum s- β levels were recently demonstrated in critically ill patients with respiratory failure [ ] and in porcine models of endotoxic shock [ ] and acute lung injury [ ] . in this latter group, elevated s- β levels were associated with hippocampal histopathologic changes, including basophilic shrunken neurons in the pyramidal cell layer [ ] . interestingly, s- β may have both beneficial and detrimental effects, in that lower levels may have protective neurotrophic effects, yet higher levels can lead to exacerbation of neuroinflammation and neuronal dysfunction [ ] . whereas s- β is a marker of astrocyte damage, nse and mpb are markers of neuron and white matter (myelin) damage, respectively. nse is protein-based enzyme that is found primarily in neurons. serum levels of nse are elevated after tbi, exhibiting a close relationship with outcome in severe head injury [ , ] and with volume of contusion in minor head injuries [ ] . interestingly, elevated nse levels were recently shown to predict death in one small study (n = ) of patients with severe sepsis [ ] , even though these patients had no acute cns disorders, such as stroke or neurotrauma. mbp is the major protein component of myelin. serum levels of mbp are elevated in diseases in which there is myelin breakdown. studies of patients with tbi have shown that mbp levels correlate with clinical measures of severity and may allow early prediction of outcomes [ , , ] . new developments in neuroimaging, such as functional magnetic resonance imaging (mri) and positron emission tomography, have revolutionized our understanding of abnormal brain function in many disease states, including schizophrenia, parkinson's disease, and post-traumatic stress disorder. to study further whether critical illness-associated cd is associated with occult brain injury in humans, it would be useful to have an imaging test that can detect subtle evidence of brain injury. unfortunately, traditional ct scans and mri do not appear to be sensitive enough to pick up the microscopic cellular changes that may underlie cd [ ] . two small studies assessed brain ct findings in critically ill patients with sepsis [ , ] . neither study demonstrated any ct abnormalities, although brain pathology in nonsurvivors was consistent with the previously cited findings of sharshar and colleagues [ ] [ ] [ ] [ ] . a recent study of ards survivors (n = ) [ ] found that many of these individuals exhibited signs of significant brain atrophy and ventricular enlargement on head cts obtained during their acute illness, but there were no significant correlations between these abnormalities and subsequent neurocognitive scores. a new mri technique may prove useful for identifying occult brain injury in critically ill patients. specifically, highresolution, three-dimensional mri can be used to assess noninvasively differences in brain tissue sodium concentration, which is a highly sensitive marker of tissue viability that highlights areas that traditional mri can miss [ ] [ ] [ ] [ ] [ ] . the method is based on sodium ion homeostasis, which is tightly regulated in the body and is a major energy consuming process. any event that perturbs the energy level of the cell enough to disrupt the sodium ion gradient, such as ischemia, has an important impact on cell viability. although tissue sodium concentration mri has been successfully used to evaluate the cns, including nonhuman primate studies and clinical studies of stroke and reversible focal brain ischemia [ ] [ ] [ ] , it has not been used to assess patients with either acute or chronic critical illnessassociated cd. there are several recent developments that, although preliminary, are of interest because of their potential to prevent or mitigate critical illness-associated cd. haloperidol has been used for many years to manage agitation in mechanically ventilated icu patients, and it is the recommended drug for treatment of icu delirium [ ] . kalisvaart and colleagues [ ] compared the effect of haloperidol prophylaxis ( . mg/day preoperatively and up to days postoperatively) with that of placebo in elderly hip surgery patients at risk for delirium. although there was no difference in the incidence of postoperative delirium between treatment and control groups, those in the haloperidol group had significantly reduced severity and duration of delirium ( . days versus . days; p < . ). haloperiodol also appeared to reduce the length of hospital stay among those who developed delirium ( . days versus . days; p < . ). a recent retrospective cohort study examined haloperidol use in patients who were mechanically ventilated for longer than hours [ ] . despite similar baseline characteristics, patients treated with haloperidol had significantly lower hospital mortality than did those who never received the drug ( . % versus . %; p = . ), an association that persisted after adjusting for potential confounders. because of the observational nature of the study and the potential risks associated with haloperidol use, these findings require confirmation in a randomized, controlled trial before they may be applied to routine patient care. leung and colleagues [ ] tested the hypothesis that using gabapentin as an add-on agent for treating postoperative pain reduces the occurrence of postoperative delirium. patients aged years or older undergoing spine surgery were randomly assigned to gabapentin mg or placebo by mouth to hours before surgery and continued for the first days postoperatively. postoperative delirium occurred in % ( / ) of gabapentin-treated patients and % ( / ) of placebo patients (p = . ). reduction in delirium appeared to be due to the opioid-sparing effect of gabapentin. given the small size of the study, these results require confirmation. donepezil, a cholinesterase inhibitor that increases synaptic availability of acetylcholine, improves cognitive function in alzheimer's disease. sampson and colleagues [ ] randomly assigned elderly patients undergoing elective total hip replacement to donepezil mg or placebo immediately following surgery and every hours for days. donepezil was well tolerated with no serious adverse events. although the drug did not significantly reduce the incidence of delirium ( . % versus . %; p = . ) or length of hospital stay (mean ± standard error: . ± . days versus . ± . days; p = . ), both outcomes showed a consistent trend suggesting possible benefit. the authors project that a sample size of patients would be required for a definitive trial. dexmedetomidine's sedative effects are due to selective stimulation of α -adrenoreceptors in the locus ceruleus of the cns. because it does not have anticholinergic or gaba-stimulating effects, it has the potential to be a delirium-sparing sedative. in preliminary results presented in abstract form [ ] , cardiac surgery patients (n = ) randomly assigned to dexmedetomidine for postoperative sedation had a nonsignificantly lower incidence of postoperative delirium as compared with those sedated with propofol or a combination of fentanyl and midazolam ( % versus % versus %). the authors of that report plan to enroll a total of patient in the study; perhaps these impressive differences will be statistically significant with a greater number of patients. recombinant human erythropoietin (rhuepo) has received considerable attention as a potential transfusion sparing strategy in the icu. interestingly, epo and its receptor are both expressed by the nervous system, and systemically administered rhuepo can reach sites within the brain. in preclinical studies, rhuepo reduced neuronal injury produced by focal ischemia, tbi, spinal cord injury, and subarachnoid hemorrhage [ ] [ ] [ ] . enthusiasm regarding its use as a general neuroprotectant in the icu has been tempered by potential risks such as thromboembolism and the considerable cost of the drug. concerns over safety may be at least partially addressed by the recent finding of erythropoietin derivatives with tissue protective but not hematopoietic properties [ ] . xenon is a chemically inert gas that has been used as an anesthetic agent and for contrast enhancement in ct scans. in rats xenon appears to protect the brain from the neurologic damage associated with the use of cardiopulmonary bypass, an effect that is potentially related to n-methyl-d-aspartate receptor antagonism [ ] . however, its tendency to expand gaseous bubbles, such as bypass-associated cerebral air emboli, could abolish any beneficial effect or even worsen cerebral outcome [ ] . in the setting of ischemic stroke or tbi, there are a variety of compounds with the potential to improve neurologic outcomes. for example, nxy- , a free radical trapping agent, reduced disability at days when given within hours of stroke onset [ ] . in a pilot randomized trial in patients, simvastatin given up to hours after stroke onset significantly improved neurologic functioning (national institutes of health stroke scale score) at days [ ] . ethyl pyruvate, a pyruvate derivative that prevents mortality in murine sepsis models, reduced motor impairments, neurologic deficits, and infarct volume in a rat stroke model when given as late as hours after middle cerebral artery occlusion [ ] . in rodent models of tbi, cyclosporin a reduced acute motor deficits and improved cognitive performance, even when given after the traumatic insult [ ] . a phase ii dose escalation trial is currently underway in humans. mounting evidence suggests that mild-to-moderate hypothermia can mitigate neurologic injury. shankaran and colleagues [ ] found that whole-body hypothermia ( . °c for hours) reduced the risk for death or disability in infants with moderate or severe hypoxic-ischemic encephalopathy. in adults successfully resuscitated after cardiac arrest, moderate hypothermia ( - °c for to hours) increased rates of favorable neurologic outcomes and reduced mortality [ , ] . a practical limitation of therapeutic hypothermia is that reaching target temperatures takes at least hours using the fastest currently available cooling techniques. however, polderman and colleagues [ ] demonstrated that hypothermia could be induced safely and quickly (about min) by means of ice-cold intravenous fluid combined with icewater cooling blankets. cognitive rehabilitation involves the teaching of skills and strategies to target specific problems in perception, memory, thinking and problem solving, with the goal of improving function and compensating for deficits. the benefits of cognitive rehabilitation are well known to those that care for patients with stroke, anoxia, or tbi. predicting who will benefit and how much has proven challenging, but even severely disabled patients sometimes make dramatic neurocognitive recoveries [ ] . although there are no studies evaluating the effectiveness of cognitive rehabilitation in patients recovering from non-neurologic critical illness, it stands to reason that such patients could benefit when they are found to be cognitively impaired. because cognitive impairments in critically ill patients appear to be underrecognized by icu and physical rehabilitation providers [ ] , few patients are referred for cognitive rehabilitation therapy [ ] . education regarding the cognitive sequelae of critical illness is needed to enhance referrals for rehabilitation, not only for weakness and physical debilitation but also for cognitive impairments. cognitive function is an important and relatively understudied outcome of critical illness. evidence suggests that neurotransmitter abnormalities and occult diffuse brain injury are important pathophysiologic mechanisms that underlie critical illness-associated cd. markers that could be used to evaluate the influence of these mechanisms in individual patients include the following: saa, certain brain proteins (s- β, nse, and mpb), and mri tissue sodium concentration. although recent advances in this area are exciting, they are still too immature to influence patient care. additional research is needed if we are to understand better the relative contributions of specific mechanisms to the development of critical illness-associated cognitive dysfunction and to determine whether these mechanisms might be amenable to treatment or prevention. this article is part of a thematic series on translational research, edited by john kellum. other articles in the series can be found online at http://ccforum.com/articles/ theme-series.asp?series=cc_trans the epidemiology of sepsis in the united states from through improved survival of patients with acute respiratory distress syndrome (ards): - two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome understanding the treatment preferences of seriously ill patients potential mechanisms and markers of critical illness-associated cognitive dysfunction delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (cam-icu) the impact of delirium in the intensive care unit on hospital length of stay delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit costs associated with delirium in mechanically ventilated patients marcantonio er: delirium among newly admitted postacute facility patients: prevalence, symptoms, and severity the occurrence and persistence of symptoms among elderly hospitalized patients delirium symptoms in post-acute care: prevalent, persistent, and associated with poor functional recovery delirium in the intensive care unit: occurrence and clinical course in older patients apolipoprotein e polymorphism as a genetic predisposition to delirium in humans delirium in older persons serum anticholinergic activity in a community-based sample of older adults: relationship with cognitive performance a critical appraisal of the utility of the serum anticholinergic activity assay in research and clinical practice drugs of anesthesia acting on central cholinergic system may cause post-operative cognitive dysfunction and delirium endogenous anticholinergic substances may exist during acute illness in elderly medical patients neural inhibition of inflammation: the cholinergic anti-inflammatory pathway the relationship of an anticholinergic rating scale with serum anticholinergic activity in elderly nursing home residents comparing models for estimating anticholinergic burden from medications using serum anticholinergic activity as the gold standard serum levels of anticholinergic drugs in treatment of acute extrapyramidal side effects association of postoperative delirium with raised serum levels of anticholinergic drugs the association of serum anticholinergic activity with delirium in elderly medical patients clarifying confusion: the confusion assessment method. a new method for detection of delirium importance of serum anticholinergic activity in the assessment of elderly patients with delirium association of elevated plasma anticholinergic activity with delirium in surgical patients is dopamine administration possibly a risk factor for delirium? the serotonin syndrome the effect of normalization of plasma amino acids on hepatic encephalopathy in man overexcitement and disinhibition. dynamic neurotransmitter interactions in alcohol withdrawal association between psychoactive medications and delirium in hospitalized patients: a critical review sedative and analgesic medications: risk factors for delirium and sleep disturbances in the critically ill lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation exposure to anaesthetic agents, cognitive functioning and depressive symptomatology in the elderly postoperative cognitive deficit in the elderly surgical patient agitation in the icu: part one -anatomical and physiologic basis for the agitated state neural mechanisms of delirium: current hypotheses and evolving concepts the brain in sepsis dal pizzol f: oxidative variables in the rat brain after sepsis induced by cecal ligation and perforation cerebral circulation during endotoxic shock with special emphasis on the regional cerebral blood flow in vivo cerebral hemodynamics, oxygen uptake and cerebral arteriovenous differences of catecholamines following e. coli endotoxin in dogs cerebral blood flow and oxygen uptake in endotoxic shock. an experimental study in dogs cerebral hemodynamics, vascular reactivity, and metabolism during canine endotoxin shock group b streptococcal sepsis impairs cerebral vascular reactivity to acute hypercarbia in piglets neuropathology of septic shock multifocal necrotizing leukoencephalopathy in septic shock apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock the neuropathology of septic shock the role of hypotension in septic encephalopathy following surgical procedures cerebral circulation and metabolism in patients with septic encephalopathy different c-reactive protein kinetics in post-operative hip-fractured geriatric patients with and without complications the role of oxidative stress in postoperative delirium regional cerebral blood flow in delirium patients neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome hyperglycemia and neurocognitive outcome in ards survivors hyperglycemia augments ischemic brain injury: in vivo mr imaging/spectroscopic study with nicardipine in cats with occluded middle cerebral arteries signs of brain cell injury during open heart operations: past and present release of glial tissue-specific proteins after acute stroke: a comparative analysis of serum concentrations of protein s- b and glial fibrillary acidic protein is there an association between release of protein s b during cardiopulmonary bypass and memory disturbances? scand cardiovasc j significance of serum s release after coronary artery bypass grafting s- protein and neuron-specific enolase in csf after experimental traumatic or focal ischemic brain damage correlation of computed tomography findings and serum brain damage markers following severe head injury serum s- b protein in severe head injury biochemical serum markers for brain damage: a short review with emphasis on clinical utility in mild head injury increased levels of serum s b protein in critically ill patients without brain injury bloodbrain barrier damage is an early event in porcine endotoxemic shock s- protein and neurohistopathologic changes in a porcine model of acute lung injury the janus face of glial-derived s b: beneficial and detrimental functions in the brain severe head trauma and the changes of concentration of neuron-specific enolase in plasma and in cerebrospinal fluid diagnostic significance of serum neuron-specific enolase and myelin basic protein assay in patients with acute head injury increased serum creatine kinase bb and neuron specific enolase following head injury indicates brain damage bardenheuer hj: neuron-specific enolase as a marker of fatal outcome in patients with severe sepsis or septic shock serum-myelin-basicprotein assay in diagnosis and prognosis of patients with head injury serum myelin basic protein, clinical responsiveness, and outcome of severe head injury the encephalopathy of sepsis neurologic complications of systemic critical illness brain atrophy and cognitive impairment in survivors of acute respiratory distress syndrome fast three dimensional sodium imaging mr imaging of sodium in the human brain with a fast three-dimensional gradient-recalled-echo sequence at t noninvasive quantification of total sodium concentrations in acute reperfused myocardial infarction using na mri three-dimensional triplequantum-filtered ( )na imaging of in vivo human brain direct, longitudinal comparison of ( )h and ( )na mri after transient focal cerebral ischemia sodium mri of reversible focal brain inchemia in the monkey comprehensive mr imaging protocol for stroke management: tissue sodium concentration as a measure of tissue viability in nonhuman primate studies and in clinical studies direct, longitudinal comparison of ( )h and ( )na mri after transient focal cerebral ischemia clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: a randomized placebo-controlled study haloperidol use in mechanically ventilated patients is associated with lower hospital mortality pilot clinical trial of gabapentin to decrease postoperative delirium in older patients a randomized, double-blind, placebo-controlled trial of donepezil hydrochloride (aricept) for reducing the incidence of postoperative delirium after elective total hip replacement dexmedetomidine: can it reduce the incidence of icu delirium in postcardiotomy patients? a potential role for erythropoietin in focal permanent cerebral ischemia in mice erythropoietin crosses the bloodbrain barrier to protect against experimental brain injury beneficial effects of systemic administration of recombinant human erythropoietin in rabbits subjected to subarachnoid hemorrhage derivatives of erythropoietin that are tissue protective but not erythropoietic xenon attenuates cardiopulmonary bypass-induced neurologic and neurocognitive dysfunction in the rat xenon impairs neurocognitive and histologic outcome after cardiopulmonary bypass combined with cerebral air embolism in rats nxy- for acute ischemic stroke safety and efficacy of statin in the acute phase of ischemic stroke: the mistics trial inhibition of the cerebral ischemic injury by ethyl pyruvate with a wide therapeutic window cyclosporin a improves brain tissue oxygen consumption and learning/memory performance after lateral fluid percussion injury in rats whole-body hypothermia for neonates with hypoxicischemic encephalopathy hypothermia after cardiac arrest study group: mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest treatment of comatose survivors of out-ofhospital cardiac arrest with induced hypothermia induction of hypothermia in patients with various types of neurologic injury with use of large volumes of ice-cold intravenous fluid anoxic-hypotensive brain injury: neuropsychological performance at month as an indicator of recovery chronic neurocognitive effects of critical illness this work was performed at the university of pittsburgh school of medicine, pittsburgh, philadelphia, usa. the authors declare that they have no competing interests. key: cord- -slbfft authors: gomez rial, j.; curras tuala, m. j.; rivero calle, i.; gomez carballa, a.; cebey lopez, m.; rodriguez tenreiro, c.; dacosta urbieta, a.; rivero velasco, c.; rodriguez nunez, n.; trastoy pena, r.; rodriguez garcia, j.; salas, a.; martinon torres, f. title: increased serum levels of scd and scd indicate a preponderant role for monocytes in covid- immunopathology date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: slbfft background. emerging evidence indicates a potential role for monocyte in covid- immunopathology. we investigated two soluble markers of monocyte activation, scd and scd , in covid patients with the aim of characterizing their potential role in monocyte-macrophage disease immunopathology. to the best of our knowledge, this is the first study of its kind. methods. fifty-nine sars-cov- positive hospitalized patients, classified according to icu or non-icu admission requirement, were prospectively recruited and analyzed by elisa for levels of scd and scd , along with other laboratory parameters, and compared to a healthy control group. results. scd and scd levels were significantly higher among covid- patients, independently of icu admission requirement, compared to the control group. we found a significant correlation between scd levels and other inflammatory markers, particularly interleukin- , in the non-icu patients group. scd showed a moderate positive correlation with the time at sampling from admission, increasing its value over time, independently of severity group. conclusions. monocyte-macrophage activation markers are increased and correlate with other inflammatory markers in sars-cov- infection, in association to hospital admission. these data suggest a potentially preponderant role for monocyte-macrophage activation in the development of immunopathology of covid patients. background. emerging evidence indicates a potential role for monocyte in covid- immunopathology. we investigated two soluble markers of monocyte activation, scd and scd , in covid patients with the aim of characterizing their potential role in monocyte-macrophage disease immunopathology. to the best of our knowledge, this is the first study of its kind. methods. fifty-nine sars-cov- positive hospitalized patients, classified according to icu or non-icu admission requirement, were prospectively recruited and analyzed by elisa for levels of scd and scd , along with other laboratory parameters, and compared to a healthy control group. results. scd and scd levels were significantly higher among covid- patients, independently of icu admission requirement, compared to the control group. we found a significant correlation between scd levels and other inflammatory markers, particularly interleukin- , in the non-icu patients' group. scd showed a moderate positive correlation with the time at sampling from admission, increasing its value over time, independently of severity group. emerging evidence from sars-cov- infected patients suggests a key role for monocyte-macrophage in the immunopathology of covid- infection, with a predominant monocyte-derived macrophage infiltration observed in severely damaged lungs [ ] , and morphological and inflammation-related changes in peripheral blood monocytes that correlate with the patients' outcome [ ] an overexuberant inflammatory immune response with production of a cytokine storm and t-cell immunosuppression are the main hallmarks of severity in these patients [ ] . this clinical course resembles viral-associated hemophagocytic syndrome (vash), a rare severe complication of various viral infections mediated by proinflammatory cytokines, resulting in multiorgan failure and death [ ] . a chronic expansion of inflammatory monocytes and over-activation of macrophages have been extensively described in this syndrome [ ; ; ] . vahs has been identifies as a major contributor to death of patients in past pandemics outbreaks [ ] including previous sars and mers outbreaks [ ] and is currently suggested for sars-cov- outbreak. [ ] cd and cd are both myeloid differentiation markers found primarily on monocytes and macrophages, and detection of soluble release of both in plasma is considered a good biomarker of monocyte-macrophage activation [ ; ] . elevated plasma levels of soluble cd (scd ) are associated to poor prognosis in vih-infected patients, are a strong predictor of morbidity and mortality [ ; ] , and associated with diminished cd +-t cell restoration [ ] . in addition, soluble cd (scd ) plasma levels are a good proxy for monocyte expansion and disease progression during hiv infection [ ] . in measles infection, a leading cause of death associated with increased susceptibility to secondary infections and immunosuppression, scd and scd levels were found to be significantly higher, indicating an important and persistent monocytemacrophage activation [ ] . we hypothesized that monocytes/macrophages may be an important component of immunopathology associated to sars-cov- infection. in this paper, we analyze plasma levels of soluble monocyte activation markers in covid- patients and their correlation with severity and other inflammatory markers. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint we recruited patients with confirmed pcr-positive diagnostic for sars-cov- infection, classified according icu admission requirement (n= patients), or non-icu requirement (n= ), and age-matched healthy individuals (n= ) as control group. demographic data, main medication treatment and routine lab clinical parameters including inflammatory biomarkers were collected for all infected patients. leftover sera samples from routine analytical control were employed for the research analysis, after obtaining corresponding informed consent. time elapsed from hospital admission to sample extraction was also recorded. to determine levels of soluble monocyte activation markers in serum specimens, appropriate sandwich elisa (quantikine, r&d systems, united kingdom) were used following manufacturer indications. briefly, diluted sera samples were incubated for hours at room temperature in the corresponding microplate strips coated with capture antibody. after incubation, strips were properly washed and incubated with the corresponding human antibody conjugate for hour. after washing, reactions were revealed and optical density at nm was determined in a microplate reader. concentration levels were interpolated from the standard curve using a four-parameter logistic ( -pl) curve-fit in prism graphpad software. final values were corrected applying the corresponding dilution factor employed. data are expressed as median and interquartile range. all statistical analyses were performed using the statistical package r. mann-whitney tests were used for comparison between icu and non-icu groups versus healthy controls. pearson's correlation coefficients were used to quantify the association between scd and scd concentration and other lab parameters in non-icu patients. data outliers, falling outside the . interquartile range, were excluded from the all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint statistical analysis. the nominal significance level considered was . . bonferroni adjustment was used to account for multiple testing. patients in the icu group showed significant differences in several clinical laboratory parameters when compared to non-icu group: lymphocytes, ferritin, d-dimer, lactate dehydrogenase (ldh), procalcitonin (pct), interleukin- (il- ). the absolute value for circulating monocytes did not show significant differences between groups. however, these values may have been distorted by the use of tocilizumab, an il- blocking drug extensively employed in the icu group which interferes with monocyte function. age and time elapsed from admission to sample extraction did not show differences between groups. values are summarized in table . median levels for scd in sera from icu patients were . ( %ci: . - . ) ng/ml, compared to . ( %ci: . - . ) ng/ml in non-icu patients. the healthy control group median value was . ( %ci: . - . ) ng/ml. we observed significant differences for values from infected patients relative to control group (p-value< . ), however no significant differences were observed between icu and non-icu groups. median levels for scd in sera from icu patients were . ( %ci: . - . ) ng/ml, and . ( %ci: . - . ) ng/ml in non-icu patients. the healthy control group value was . ( %ci: . - . ) ng/ml. in the same way as with scd , we observed significant differences for values from infected patients compared to control group (p-value< ), but no differences between icu and non-icu infected patients. values are summarized in table and figure . we assessed correlation between scd and scd levels and time elapsed from hospital admission to sample extraction (figure ) . we found a significant positive correlation between scd levels and time elapsed (r = . , p-all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . (figure ) . particularly, il- also shows a significant positive correlation with scd (r = . , p-value= . ) (figure ). we analyzed possible age-dependence of scd and scd levels. values did not show association between these biomarker levels and the age of patients. our results show, for the first time, increased levels of scd and scd in sera from sars-cov- infected patients admitted to hospital. we did not observe any differences between icu or non-icu patients, probably due to the interference on monocyte function produced by the use of tocilizumab and/or corticoid treatment in icu patients as previously demonstrated [ ; ] . however, levels of scd showed a strong correlation with clinical laboratory parameters, including acute phase reactants (ferritin, ldh, c-reactive protein, procalcitonin) and a strong correlation with il- levels in the non-icu patient group, where no tocilizumab and/or corticoids treatments were used. furthermore, scd levels all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint showed a correlation with the time elapsed from hospital admission to sample extraction, increasing its value over time of hospital admission, suggesting a potential indicator of progression of disease. monocytes and macrophages constitute a key component of immune responses against viruses, acting as bridge between innate and adaptive immunity [ ] . activation of macrophages has been demonstrated to be pivotal in the pathogenesis of the immunosuppression associated to several viral infections (vih, measles), where expansion of specific subsets of monocytes and macrophages in peripheral blood are observed, and considered to be drivers of immunopathogenesis [ ] . our results support the hypothesis of a preponderant role for monocytes in sars-cov- immunopathology, associated to an over exuberant immune response. increased levels of monocyte-macrophage activation markers and the correlation with other inflammatory biomarkers (particularly il- ), indicate a close relationship between monocyte activation and immunopathology in these patients. inflammatory markers are closely related to severity in covid- pathology [ ] and selective blockade of il- has been demonstrated to be a good therapeutic strategy in covid- pathology [ ] . our results thus suggest that monocyte-macrophage activation can act as driver cells of the cytokine storm and immunopathology associated to severe clinical course of covid- patients. further, monitorization of monocyte activity trough these soluble activation markers and/or follow-up of circulating inflammatory monocytes in peripheral blood, could be useful to assess disease progression in the same way as in other viral infections [ ] . in addition, our results identify monocyte-macrophage as a good target for the design of therapeutic intervention using drugs that inhibit monocytemacrophage activation and differentiation. in this sense, anti-gm csf inhibitor drugs, currently under clinical trials for rheumatic and other auto-inflammatory diseases, might provide satisfactory results in covid- patients. other drugs targeting monocyte and/or macrophage could also be useful in covid- , as in other inflammatory diseases [ ] . the strategy of inhibiting monocyte differentiation has proved useful in avoiding cytokine storm syndrome after car-t cell immunotherapy [ ] , suggesting a possible therapeutic application to covid- immunopathology [ ] the present study has several limitations, all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint including the relatively low numbers of patients tested and the interference of tocilizumab and corticoids in icu patients' results. however, these preliminary results are strongly suggestive of an important implication of monocytemacrophage in covid- immunopathology, as highlighted by the correlations found between these biomarker levels and inflammatory parameters. further studies using broader series are needed to confirm our findings. in summary, our data underscore the preponderant role of monocyte and macrophage immune response in covid- immunopathology and provide pointers for future interventions in drug strategies and monitoring plans for these patients. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential we want to acknowledge the effort of all first-line healthcare workers of the patients included in this study. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint [ ] j. gomez-rial, and f. martinon-torres, a strategy targeting monocytemacrophage differentiation to avoid pulmonary complications in sars-cov infection. clinical immunology in press ( ). all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint table . concentration (ng/ml) of serum levels of scd and scd in patients from icu and non-icu groups, and healthy controls. data are represented as median and interquartile range. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . the landscape of lung bronchoalveolar immune cells in covid- revealed by single-cell rna sequencing covid- infection induces readily detectable morphological and inflammationrelated phenotypic changes in peripheral blood monocytes, the severity of wich correlate with patient outcome hlh across speciality collaboration, covid- : consider cytokine storm syndromes and immunosuppression virus associated hemophagocytic syndrome cd (dim)/cd (bright) how viruses contribute to the pathogenesis of hemophagocytic lymphohistiocytosis recommendations for the management of hemophagocytic lymphohistiocytosis in adults virus-associated hemophagocytic syndrome as a major contributor to death in patients with influenza a (h n ) infection is secondary hemophagocytic lymphohistiocytosis behind the high fatality rate in middle east respiratory syndrome corona virus the pathogenesis and treatment of the `cytokine storm' in covid- soluble cd is a nonspecific marker of monocyte activation differential expression of cd on monocyte subsets in healthy and hiv- infected individuals plasma levels of soluble cd independently predict mortality in hiv infection elevated levels of serum-soluble cd in human immunodeficiency virus type (hiv- ) infection: correlation to disease progression and clinical events immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory cd cells increased monocyte turnover from bone marrow correlates with severity of siv encephalitis and cd levels in plasma persistent high plasma levels of scd and scd in adult patients with measles virus infection modulation of human monocyte/macrophage activity by tocilizumab, abatacept and etanercept: an in vitro study effects of corticosteroids on human monocyte function co-ordinating innate and adaptive immunity to viral infection: mobility is the key soluble cd , a novel marker of activated macrophages, is elevated and associated with noncalcified coronary plaque in hiv-infected patients correlation analysis between disease severity and inflammation-related parameters in patients with covid- the cytokine release syndrome (crs) of severe covid- and interleukin- receptor antagonist tocilizumab may be the key to reduce the mortality drug delivery to macrophages: a review of targeting drugs and drug carriers to macrophages for inflammatory diseases gm-csf inhibition reduces cytokine release syndrome and neuroinflammation but enhances car-t cell function in xenografts no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted key: cord- -kvyzuayp authors: christ, andreas; quint, franz title: artificial intelligence: research impact on key industries; the upper-rhine artificial intelligence symposium (ur-ai ) date: - - journal: nan doi: nan sha: doc_id: cord_uid: kvyzuayp the trirhenatech alliance presents a collection of accepted papers of the cancelled tri-national 'upper-rhine artificial inteeligence symposium' planned for th may in karlsruhe. the trirhenatech alliance is a network of universities in the upper-rhine trinational metropolitan region comprising of the german universities of applied sciences in furtwangen, kaiserslautern, karlsruhe, and offenburg, the baden-wuerttemberg cooperative state university loerrach, the french university network alsace tech (comprised of 'grandes 'ecoles' in the fields of engineering, architecture and management) and the university of applied sciences and arts northwestern switzerland. the alliance's common goal is to reinforce the transfer of knowledge, research, and technology, as well as the cross-border mobility of students. in the area of privacy-preserving machine learning, many organisations could potentially benefit from sharing data with other, similar organisations to train good models. health insurers could, for instance, work together on solving the automated processing of unstructured paperwork such as insurers' claim receipts. the issue here is that organisations cannot share their data with each other for confidentiality and privacy reasons, which is why secure collaborative machine learning where a common model is trained on distributed data to prevent information from the participants from being reconstructedis gaining traction. this shows that the biggest problem in the area of privacy-preserving machine learning is not technical implementation, but how much the entities involved (decision makers, legal departments, etc.) trust the technologies. as a result, the degree to which ai can be explained, and the amount of trust people have in it, will be an issue requiring attention in the years to come. the representation of language has undergone enormous development of late: new models and variants, which can be used for a range of natural language processing (nlp) tasks, seem to pop up almost monthly. such tasks include machine translation, extracting information from documents, text summarisation and generation, document classification, bots, and so forth. the new generation of language models, for instance, is advanced enough to be used to generate completely realistic texts. these examples reveal the rapid development currently taking place in the ai landscape, so much so that the coming year may well witness major advances or even a breakthrough in the following areas: • healthcare sector (reinforced by the covid- pandemic): ai facilitates the analysis of huge amounts of personal information, diagnoses, treatments and medical data, as well as the identification of patterns and the early identification and/or cure of disorders. • privacy concerns: how civil society should respond to the fast increasing use of ai remains a major challenge in terms of safeguarding privacy. the sector will need to explain ai to civil society in ways that can be understood, so that people can have confidence in these technologies. • ai in retail: increasing reliance on online shopping (especially in the current situation) will change the way traditional (food) shops function. we are already seeing signs of new approaches with self-scanning checkouts, but this is only the beginning. going forward, food retailers will (have to) increasingly rely on a combination of staff and automated technologies to ensure cost-effective, frictionless shopping. • process automation: an ever greater proportion of production is being automated or performed by robotic methods. • bots: progress in the field of language (especially in natural language processing, outlined above) is expected to lead to major advances in the take-up of bots, such as in customer service, marketing, help desk services, healthcare/diagnosis, consultancy and many other areas. the rapid pace of development means it is almost impossible to predict either the challenges we will face in the future or the solutions destined to simplify our lives. one thing we can say is that there is enormous potential here. the universities in the trirhenatech alliance are actively contributing interdisciplinary solutions to the development of ai and its associated technical, societal and psychological research questions. utilizing toes of a humanoid robot is difficult for various reasons, one of which is that inverse kinematics is overdetermined with the introduction of toe joints. nevertheless, a number of robots with either passive toe joints like the monroe or hrp- robots [ , ] or active toe joints like lola, the toyota robot or toni [ , , ] have been developed. recent work shows considerable progress on learning model-free behaviors using genetic learning [ ] for kicking with toes and deep reinforcement learning [ , , ] for walking without toe joints. in this work, we show that toe joints can significantly improve the walking behavior of a simulated nao robot and can be learned model-free. the remainder of this paper is organized as follows: section gives an overview of the domain in which learning took place. section explains the approach for model free learning with toes. section contains empirical results for various behaviors trained before we conclude in section . the robots used in this work are robots of the robocup d soccer simulation which is based on simspark and initially initiated by [ ] . it uses the ode physics engine and runs at an update speed of hz. the simulator provides variations of aldebaran nao robots with dof for the robot types without toes and dof for the type with toes, naotoe henceforth. more specifically, the robot has ( ) dof in each leg, in each arm and in its neck. there are several simplifications in the simulation compared to the real nao: all motors of the simulated nao are of equal strength whereas the real nao has weaker motors in the arms and different gears in the leg pitch motors. joints do not experience extensive backlash rotation axes of the hip yaw part of the hip are identical in both robots, but the simulated robot can move hip yaw for each leg independently, whereas for the real nao, left and right hip yaw are coupled the simulated naos do not have hands the touch model of the ground is softer and therefore more forgiving to stronger ground touches in the simulation energy consumption and heat is not simulated masses are assumed to be point masses in the center of each body part the feet of naotoe are modeled as rectangular body parts of size cm x cm x cm for the foot and cm x cm x cm for the toes (see figure ). the two body parts are connected with a hinge joint that can move from - degrees (downward) to degrees. all joints can move at an angular speed of at most . degrees per ms. the simulation server expects to get the desired speed at hz for each joint. if no speeds are sent to the server it will continue movement of the joint with the last speed received. joint angles are noiselessly perceived at hz, but with a delay of ms compared to sent actions. so only after two cycles, the robot knows the result of a triggered action. a controller provided for each joint inside the server tries to achieve the requested speed, but is subject to maximum torque, maximum angular speed and maximum joint angles. the simulator is able to run simulated naos in real-time on reasonable cpus. it is used as competition platform for the robocup d soccer simulation league . in this context, only a single agent was running in the simulator. the following subsections describe how we approached the learning problem. this includes a description of the design of the behavior parameters used, what the fitness functions for the genetic algorithm look like, which hyperparameters were used and how the fitness calculation in the simspark simulation environment works exactly. the guiding goal behind our approach is to learn a model-free walk behavior. with model-free we depict an approach that does not make any assumptions about a robot's architecture nor the task to be performed. thus, from the viewpoint of learning, our model consists of a set of flat parameters. these parameters are later grounded inside the domain. the server requires values per second for each joint. to reduce the search space, we make use of the fact that output values of a joint over time are not independent. therefore, we learn keyframes, i.e. all joint angles for discrete phases of movement together with the duration of the phase from keyframe to keyframe. the experiments described in this paper used four to eight of such phases. the number of phases is variable between learning runs, but not subject to learning for now, except for skipping phases by learning a zero duration for it. the robocup server requires robots to send the actual angular speed of each joint as a command. when only leg joints are included, this would require to learn parameters per phase ( joints + for the duration of the phase), resulting in , and parameters for the , , phases worked with. the disadvantage of this approach is that the speed during a particular phase is constant, thus making it unable to adapt to discrepancies between the desired and the actual motor movement. therefore, a combination of angular value and the maximum amount of angular speed each joint should have is used. the direction and final value of movement is entirely encoded in the angular values, but the speed can be controlled separately. it follows that: -if the amount of angular speed does not allow reaching the angular value, the joint behaves like in version . -if the amount of angular speed is bigger, the joint stops to move even if the phase is not over. this almost doubles the amount of parameters to learn, but the co-domain of values for the speed values is half the size, since here we only require an absolute amount of angular speed. with these parameters, the robot learns a single step and mirrors the movement to get a double step. feedback from the domain is provided by a fitness function that defines the utility of a robot. the fitness function subtracts a penalty for falling from the walked distance in x-direction in meters. there is also a penalty for the maximum deviation in y-direction reached during an episode, weighted by a constant factor. in practice, the values chosen for f allenp enalty and a factor f were usually and respectively. this same fitness function can be used without modification for forward, backward and sideward walk learning, simply by adjusting the initial orientation of the agent. the also trained turn behavior requires a different fitness function. f itness turn = (g * totalt urn) − distance ( ) where totalt urn refers to the cumulative rotation performed in degrees, weighted by a constant factor g (typically / ). we penalize any deviation from the initial starting x / y position (distance) as incentive to turn in-place. it is noteworthy that other than swapping out the fitness function and a few more minor adjustments mentioned in . , everything else about the learning setup remained the same thanks to the model-free approach. naturally, the fitness calculation for an individual requires connecting an agent to the simspark simulation server and having it execute the behavior defined by the learned parameters. in detail, this works as follows: at the start of each "episode", the agent starts walking with the old model-based walk engine at full speed. once simulation cycles (roughly . seconds) have elapsed, the robot starts checking the foot force sensors. as soon as the left foot touches the ground, it switches to the learned behavior. this ensures that the learned walk has comparable starting conditions each time. if this does not occur within cycles (which sometimes happens due to non-determinism in the domain and noise in the foot force perception), the robot switches anyway. from that point on, the robot keeps performing the learned behavior that represents a single step, alternating between the original learned parameters and a mirrored version (right step and left step). an episode ends once the agents has fallen or seconds have elapsed. to train different walk directions (forward, backward, sideward), the initial orientation of the player is simply changed accordingly. in addition, the robot uses a different walk direction of the model-based walk engine for the initial steps that are not subject to learning. in case of training a morphing behavior (see . ) , the episode duration is extended to seconds. when a morphing behavior should be trained, the step behavior from another learning run is used. this also means that a morphing behavior is always trained for a specific set of walk parameters. after seconds, the morphing behavior is triggered once the foot force sensors detect that the left foot has just touched the ground. unlike the step / walk behavior, this behavior is just executed once and not mirrored or repeated. then the robot switches back to walking at full speed with the model-based walk engine. to maximize the reward, the agent has to learn a morphing behavior that enables the transition between learned model-free and old model-based walk to work as reliably as possible. finally, for the turn behavior, the robot keeps repeating the learned behavior without alternating with a mirrored version. in any case, if the robot falls, a training run is over. the overall runtime of each such learning run is . days on our hardware. learning is done using plain genetic algorithms. the following hyperparameters were used: - more details on the approach can be found in [ ] . this section presents the results for each kind of behavior trained. this includes three different walk directions, a turn behavior and a behavior for morphing. the main focus of this work has been on training a forward walk movement. figure shows a sequence of images for a learned step. the best result reaches a speed of . m/s compared to the . m/s of our model-based walk and . m/s for a walk behavior learned on the nao robot without toes. the learned walk with toes is less stable, however, and shows a fall rate of % compared to % of the model-based walk. regarding the characteristics of this walk, it utilizes remarkably long steps . table shows an in-depth comparison of various properties, including step duration, length and height, which are all considerably bigger compared to our previous model-based walk. the forward leaning of the agent has increased by . %, while . % more time is spent with both legs off the ground. however, the maximum deviation from the intended path (maxy ) has also increased by . %. table : comparison of the previously fastest and the fastest learned forward walk once a working forward walk was achieved, it was natural to try to train a backward walk behavior as well, since this only requires a minor modification in the learning environment (changing the initial rotation of the agent and model-based walk direction to start with). the best backward walk learned reaches a speed of . m/s, which is significantly faster than the . m/s of its model-based counterpart. unfortunately, the agent also falls % more frequently. it is interesting just how backward-leaning the agent is during this walk behavior. it could almost be described as "controlled falling" (see figure ). sideward walk learning was the least successful out of the three walk directions. like with all directions, the agent starts out using the old walk engine and then switches to the learned behavior after a short time. in this case however, instead of continuing to walk sideward, the agent has learned to turn around and walk forward instead, see figure . the resulting forward walk is not very fast and usually causes the agent to fall within a few meters , but it is still remarkable that the learned behavior manages to both turn the agent around and make it walk forward with the same repeating step movement. it is also remarkable that the robot learned that it is quicker with the given legs at least for long distances to turn and run forward than to keep making sidesteps. with the alternate fitness function presented in section , the agent managed to learn a turn behavior that is comparable in speed to that of the existing walk engine. despite this, the approach is actually different: while the old walk engine uses small, angled steps , the learned behavior uses the left leg as a "pivot", creating angular momentum with the right leg . figure shows the movement sequence in detail. unfortunately, despite the comparable speed, the learned turn behavior suffers from much worse stability. with the old turn behavior, the agent only falls in roughly % of cases, with the learned behavior it falls in roughly % of the attempts. one of the major hurdles for using the learned walk behaviors in a robocup competition is the smooth transition between them and other existing behaviors such as kicks. the initial transition to the learned walk is already built into the learning setup described in by switching mid-walk, so it does not have to be given special consideration. more problematic is switching to another behavior afterwards without falling. to handle this, the robot simply attempted to train a "morphing" behavior using the same model-free learning setup. the result is something that could be described as a "lunge" (see figure ) that reduces the forward momentum sufficiently to allow it to transition to the slower model-based walk when successful. however, the morphing is not successful in about % of cases, resulting in a fall. we were able to successfully train forward and backward walk behaviors, as well as a morphing and turn behavior using plain genetic algorithms and a very flexible model-free approach. the usage of the toe joint in particular makes the walks look more natural and human-like than that of the model-based walk engine. however, while the learned behaviors outperform or at least match our old modelbased walk engine in terms of speed, they are not stable enough to be used during actual robocup d simulation league competitions. we think this is an inherent limitation of the approach: we train a static behavior that is unable to adapt to changing circumstances in the environment, which is common in simspark's non-deterministic simulation with perception noise. deep reinforcement learning seems more promising in this regard, as the neural network can dynamically react to the environment since sensor data serves as input. it is also arguably even less restrictive than the keyframe-based behavior parameterization we presented in this paper, as a neural network can output raw joint actions each simulation cycle. at least two other robocup d simulation league teams, fc portugal [ ] and itandroids [ ] , have had great success with this approach, everything points towards this becoming the state-of-the-art approach in robocup d soccer simulation in the near future, so we want to concentrate our future efforts here as well. retail companies dealing in alcoholic beverages are faced with a constant flux of products. apart from general product changes like modified bottle designs and sizes or new packaging units two factors are responsible for this development. the first is the natural wine cycle with new vintages arriving at the market and old ones cycling out each year. the second is the impact of the rapidly growing craft beer trend which has also motivated established breweries to add to their range. the management of the corresponding product data is a challenge for most retail companies. the reason lies in the large amount of data and its complexity. data entry and maintenance processes are linked with considerable manual effort resulting in high data management costs. product data attributes like dimensions, weights and supplier information are often entered manually into the data base and are often afflicted with errors. another widely used source of product data is the import from commercial data pools. a means of checking the data thus acquired for plausibility is necessary. sometimes product data is incomplete due to different reasons and a method to fill the missing values is required. all these possible product data errors lead to complications in the downstream automated purchase and logistics processes. we propose a machine learning model which involves domain specific knowledge and compare it a heuristic approach by applying both to real world data of a retail company. in this paper we address the problem of predicting the gross weight of product items in the merchandise category alcoholic beverages. to this end we introduce two levels of additional features. the first level consists of engineered features which can be determined by the basic features alone or by domain specific expert knowledge like which type of bottle is usually used for which grape variety. in the next step an advanced second level feature is computed from these first level features. adding these two levels of engineered features increases the prediction quality of the suggestion values we are looking for. the results emphasize the importance of careful feature engineering using expert knowledge about the data domain. feature engineering is the process of extracting features from the data in order to train a prediction model. it is a crucial step in the machine learning pipeline, because the quality of the prediction is based on the choice of features used to training. the majority of time and effort in building a machine learning pipeline is spent on data cleaning and feature engineering [domingos ] . a first overview of basic feature engineering principles can be found in [zheng ]. the main problem is the dependency of the feature choice on the data set and the prediction algorithm. what works best for one combination does not necessarily work for another. a systematic approach to feature engineering without expert knowledge about the data is given in [heaton ]. the authors present a study whether different machine learning algorithms are able to synthesize engineered features on their own. as engineered features logarithms, ratios, powers and other simple mathematical functions of the original features are used. in [anderson ] a framework for automated feature engineering is described. the data set is provided by a major german retail company and consists of beers and wines. each product is characterized by the seven features shown in table . the product name obeys only a generalized format. depending on the user generating the product entry in the company data base, abbreviating style and other editing may vary. the product group is a company specific number which encodes the product category -dairy products, vegetables or soft drinks for example. in our case it allows a differentiation of the product into beer and wine. additionally wines are grouped by country of origin and for germany also into wine-growing regions. note that the product group is no inherent feature like length, width, height and volume, but depends on the product classification system a company uses. the dimensions length, width, height and the volume derived by multiplicating them are given as float values. the feature (gross) weight, also given as a float value, is what we want to predict. as is often the case with real world data, a pre-processing step has to be performed prior to the actual machine learning in order to reduce data errors and inconsistencies. for our data we first removed all articles missing one or more of the required attributes of table . then all articles with dummy values were identified and discarded. dummy values are often introduced due to internal process requirements but do not add any relevant information to the data. if for example the attribute weight has to be filled for an article during article generation in order to proceed to the next step but the actual value is not know, often a dummy value of or is entered. these values distort the prediction model when used as training data in the machine learning step. the product name is subjected to lower casing and substitution of special german characters like umlauts. special symbolic characters like #,! or separators are also deleted. with this preprocessing done the data is ready to be used for feature engineering. following this formal data cleaning we perform an additional content-focused pre-processing. the feature weight is discretized by binning it with bin width g. volume is likewise treated with bin size ml. this simplifies the value distribution without rendering it too coarse. all articles where length is not equal to width are removed, because in these cases there are no single items but packages of items. often the data at hand is not sufficient to train a meaningful prediction model. in these cases feature engineering is a promising option. identifying and engineering new features depends heavily on expert knowledge of the application domain. the first level consists of engineered features which can be determined by the original features alone. in the next step advanced second level features are computed from these first level and the original features. for our data set the original features are product name and group as well as the dimensions length, width, height and volume. we see that the volume is computed in the most general way by multiplication of the dimensions. geometrically this corresponds to all products being modelled as cuboids. since angular beer or wine bottles are very much the exception in the real world, a sensible new feature would be a more appropriate modelling of the bottle shape. since weight is closely correlated to volume, the better the volume estimate the better the weight estimate. to this end we propose four first level engineered features: capacity, wine bottle type, beer packaging type and beer bottle type which are in turn used to compute a second level engineered feature namely the packaging specific volume. figure shows all discussed features and their interdependencies. let us have a closer look at the first level engineered features. the capacity of a beverage states the amount of liquid contained and is usually limited to a few discrete values. . l and . l are typical values for beer cans and bottles while wines are almost exclusively sold in . l bottles and sometimes in . l bottles. the capacity can be estimated from the given volume with sufficient certainty using appropriate threshold values. outliers were removed from the data set. there are three main beer packaging types in retail: cans, bottles and kegs. while kegs are mainly of interest to pubs and restaurants and are not considered in this paper, cans and bottles target the typical super market shopper and come in a greater variety. in our data set, the product name in case of beers is preceded by a prefix denoting whether the product is packaged in a can or a bottle. extracting the relevant information is done using regular expressions. not, though, that the prefix is not always correct and needs to be checked against the dimensions. the shapes of cans are the same for all practical purposes, no matter the capacity. the only difference is in their wall thickness, which depends on the material, aluminium and tin foil being the two common ones. the difference is weight is small and the actual material used is impossible to extract from the data. a further distinction for cans in different types like for beer and wine is therefore unnecessary. regarding the german beer market, the five bottle types shown in figure the engineered feature beer packaging type assigns each article identified as beer by its product group to one of the classes bottle or can. the feature beer bottle type contains the most probably member of the five main beer bottle types. packages containing more than one bottle or can like crates or six packs are not considered in this paper and were removed from the data set. compared to beer the variety of commercially sold wine packagings is limited to bottles only. a corresponding packaging type attribute to distinguish between cans and bottles is not necessary. again there are a few bottle types which are used for the majority of wines, namely schlegel, bordeaux and burgunder ( figure ). deciding what product is filled in which bottle type is a question of domain knowledge. the original data set does not contain a corresponding feature. from the product group the country of origin and in the case of german wines the region can be determined via a mapping table. this depends on the type of product classification system the respective company uses and has not to be valid for all companies. our data set uses a customer specific classification with focus on germany. a more general one would be the global product classification (gpc) standard for example. to determine wine growing regions in non-german countries like france the product name has to be analyzed using regular expressions. the type of grape is likewise to be deduced from the product name if possible. using the country and specifically the region of origin and type of grape of the wine in question is the only way to assign a bottle type with acceptable certainty. there are countries and region in which a certain bottle type is used predominantly, sometimes also depending on the color of the wine. the schlegel bottle, for example, is almost exclusively used for german and alsatian white wines and almost nowhere else. bordeaux and burgunder bottles on the other hand are used throughout the world. some countries like california or chile use a mix of bottle types for their wines, which poses an additional challenge. with expert knowledge one can assign regions and grape types to the different bottle types. as with beer bottles this categorization is by no means comprehensive or free of exceptions but serves as a first step. the standard volume computation by multiplying the product dimensions length, width and height is a rather coarse cuboid approximation to the real shape of alcoholic beverage packagings. since the volume is intrinsically linked to the weight which we want to predict a packaging type specific volume computation is required for cans and especially bottles. the modelling of a can is straightforward using a cylinder with the given height ℎ and a diameter of the given width and length . thus the packaging type specific volume is: a bottle on the other hand needs to be modelled piecewise. its height can be divided into three parts: base, shoulders and neck as shown in figure . base and neck can be modeled by a cylinder. the shoulders are approximated by a truncated cone. with the help of the corresponding partial heights ℎ , ℎ ℎ and ℎ we can compute coefficients , ℎ and as fractions of the overall height ℎ of the bottle. the diameters of the bottle base and the neck opening are given by and and are likewise used to compute the ratio . since bottles have circular bases, the values for width and length in the original data have to be the same and either one may be used for . these four coefficients are characteristic for each bottle type, be it beer or wine (table ) . with their help, a bottle type specific volume from the original data length, width and height can be computed which is a much better approximation to the true volume than the former cuboid model. the bottle base can be modelled as a cylinder as follows: the bottle shoulders have the form of a truncated cone and are described by formula : the bottle neck again is a simple cylinder: summing up all three sections yields the packaging type specific volume for bottles: ur-ai // the experiments follow the multi-level feature engineering scheme as shown in figure . first, we use only the original features product group and dimensions. then we add the first level engineered features capacity and bottle type to the basic features. next the second level engineered feature packaging type specific volume is used along with the basic features. finally all features from every level are used for the prediction. after pre-processing and feature engineering the data set size is reduced from to beers and from to wines. for prediction of the continuous valued attribute gross weight, we use and compare several regression algorithms. both the decision-tree based random forests algorithm (breimann, ) and support vector machines (svm) (cortes, ) are available in regression mode (smola, ) . linear regression (lai, ) and stochastic gradient descent (sgd) (taddy, ) are also employed as examples of more traditional statics-based methods. our baseline is a heuristic approach taking the median of the attribute gross weight for each product group and use this value as a prediction for all products of the same product group. practical experience has shown this to be a surprisingly good strategy. the implementation was done in python . using the standard libraries sk-learn and pandas. all numeric features were logarithmized prior to training the models. the non-numeric feature bottle type was converted to numbers. the final results were obtained using tenfold cross validation (kohavi, ) . for model training % of the data was used while the remaining % constituted the test data. we used the root mean square error (rsme) ( ) as well as the mean and variance of the absolute percentage error ( ) as metrics for the evaluation of the performance of the algorithms. all machine learning algorithms deliver significant improvements regarding the observed metrics compared to the heuristic median approach. the best results for each feature combination are highlighted in bold script. the results for the beer data set in table show that the rsme can be more than halved, the mean almost be reduced to a third and the variance of quartered compared to the baseline approach. the random forest regressor achieves the best results in terms of rsme and for almost all feature combinations except basic features and basic features combined with the packaging type specific volume, in which cases support vector machines prove superior. linear regression and sgd are are still better than the baseline approach but not on par with the other algorithms. linear regression shows the tendency to improved results when successively adding features. sgd on the other hand exhibits no clear relation between number and level of features and corresponding prediction quality. a possible cause could be the choice of hyper parameters. sgd is very sensitive in this regard and depends more heavily upon a higher number of correctly adjusted hyper parameters than the other algorithms we used. random forests is a method which is very well suited to problems, where there is no easily discernable relation between the features. it is prone to overfitting, though, which we tried to avoid by using % of all data as test data. adding more engineered features leads to increasingly better results using random forest with an outlier for the packaging type specific volume feature. svm are not affected by only first level engineered features but profit from using the bottle type specific volume. regarding the wine data set the results depicted in table are not as good as for the beer data set though still much better than the baseline approach. a reduction of the rsme by over % and of the mean by almost % compared to the baseline were achieved. the variance of could even be limited to under % of the baseline value. again random forests is the algorithm with the best metrics. linear regression and svm are comparable in terms of while sgd is worse but shows good rsme values. in conclusion the general results of the wine data set show not much improvement when applying additional engineered features. discussion and conclusion the experiments show a much better predicting quality for beer than for wine. a possible cause could be the higher weight variance in bottle types compared to beer bottles and cans. it is also more difficult to correctly determine the bottle type for wine, since the higher overlap in dimensions does not allow to compute the bottle type with the help of idealized bottle dimensions. using expert knowledge to assign the bottle type by region and grape variety seems not to be as reliable, though. especially with regard to the lack of a predominant bottle type in the region with the most bottles (red wine from baden for example), this approach should be improved. especially bordeaux bottles often sport an indentation in the bottom, called a 'culot de bouteille'. the size and thickness of this indentation cannot be inferred from the bottle's dimensions. this means that the relation between bottle volume and weight is skewed compared to other bottles without these indentations, which in turn decreases prediction quality. predicting gross weights with machine learning and domain-specifically engineered features leads to smaller discrepancies than using simple heuristic approaches. this is important for retail companies since big deviations are much worse for logistical reasons than small ones which may well be within natural production tolerances for bottle weights. our method allows to check manually generated as well as data pool imported product data for implausible gross weight entries and proposes suggestion values in case of missing entries. the method we presented can easily be adapted to non-alcoholic beverages using the same engineered features. in this segment, plastics bottles are much more common than glass ones and hence the impact of the bottle weight compared to the liquid weight is significantly smaller. we assume that this will cause a smaller importance of the bottle type feature in the prediction. a more problematic kind of beverage is liquor. although there are only a few different standard capacities, the bottle types vary so greatly, that identifying a common type is almost impossible. one of the main challenges of our approach is determining the correct bottle types. using expert knowledge is a solid approach but cannot capture all exemptions. especially if a wine growing region has no predominant bottle type and is using mixed bottle types instead. additionally many wine growers use bottle types which haven't been typical for their wine types because they want to differ from other suppliers in order to get the customer's attention. assuming that all rieslings are sold in schlegel bottles, for example, is therefore not exactly true. one option could be to model hybrid bottles using a weighted average of the coefficients for each bottle type in use. if a region uses both burgunder and bordeaux bottles with about equal frequency, all products from this region could be assigned a hybrid bottle with coefficients computed by the mean value of each coefficient. if an initially bottle type labeled data set is available, preliminary simulations have shown that most bottle types can be predicted robustly using classification algorithms. the most promising strategy, in our opinion, is to learn the bottle types directly from product images using deep neural nets for example. with regard to the ever increasing online retail sector, web stores need to have pictures of their products on display, so the data is there to be used. quality assurance is one of the key issues for modern production technologies. especially new production methods like additive manufacturing and composite materials require high resolution d quality assurance methods. computed tomography (ct) is one of the most promising technologies to acquire material and geometry data non-destructively at the same time. with ct it is possible to digitalize subjects in d, also allowing to visualize their inner structure. a d-ct scanner produces voxel data, comprising of volumetric pixels that correlate with material properties. the voxel value (grey value) is approximately proportional to the material density. nowadays it is still common to analyse the data by manually inspecting the voxel data set, searching for and manually annotating defects. the drawback is that for high-resolution ct data, this process it very time consuming and the result is operator-dependent. therefore, there is a high motivation to establish automatic defect detection methods. there are established methods for automatic defect detection using algorithmic approaches. however, these methods show a low reliability in several practical applications. at this point artificial neural networks come into play that have been already implemented successfully in medical applications [ ] . the most common networks, developed for medical data segmentation, are by ronneberger et al., the u-net [ ] and by milletari et al., the v-net [ ] and their derivates. these networks are widely used for segmentation tasks. fuchs et al. describes three different ways of analysing industrial ct data [ ] . one of these contains a d-cnn. this cnn is based on the u-net architecture and is shown in their previous paper [ ] . the authors enhance and combine the u-net and v-net architecture to build a new network for examination of d volumes. in contrast, we investigate in our work how the networks introduced by ronneberger et al. and milletari et al. perform in industrial environments. furthermore, we investigate if derivates of these architectures are able to identify small features in industrial ct data. in industrial ct systems, not only in the hardware design but also in the resulting d imaging data differs from medical ct systems. voxel data from industrial parts differ from medical data in the contrast level and the resolution. state-of-the-art industrial ct scanner produce one to two order of magnitude larger data sets compared to medical ct systems. the corresponding resolution is necessary to resolve small defects. medical ct scanners are optimised for a low xray dose for the patient, the energy of x-ray photons are typically up to kev, industrial scanner typically use energies up to kev. in combination with the difference of the scan "object", the datasets differ significantly in size and image content. to store volume data there are a lot of different file formats. some of them are mainly used in medical applications like dicom [ ] , nifti or raw. in industrial applications vgl , raw and tiff are commonly used. also depending on the format, it is possible to store the data slice wise or as a complete volume stack. industrial ct data, as mentioned in previous section, has some differences to medical ct data. one aspect is the size of the features to be detected or learned by the neural network. our target is to find defects in industrial parts. as an example, we analyse pores in casting parts. these features may be very small, down to to voxels in each dimension. compared to the size of the complete data volume (typically larger than x x voxel), the feature size is very small. the density difference between material and pores may be as low as % of the maximum grey value. thus, it is difficult to annotate the data even for human experts. the availability of real industrial data of good quality, annotated by experts, is very low. most companies don't reveal their quality analysis data. training a neural network with a small quantity of data is not possible. for medical applications, especially ai applications, there are several public datasets available. yet these datasets are not always sufficient and researchers are creating synthetic medical data [ ] . therefore, we decided to create synthetic industrial ct data. another important reason for synthetic data is the quality of annotations done by human experts. the consistency of results is not given for different experts. fuchs et al. have shown that training on synthetic data and predicting on real data lead to good results [ ] . however, synthetic data may not reflect all properties of real data. some of the properties are not obvious, which may lead to ignoring some varieties in the data. in order to achieve a high associability, we use a large numbers of synthetic data mixed with a small number of real data. to achieve this, we developed an algorithm which generates large amounts of data, containing a large variation of aspects, needed to generalize a neural network. the variation includes material density, pore density, pore size, pore amount, pore shape and size of the part. there are some samples that could be learned easily, because the pores are clearly visible inside the material. however, some samples are more difficult to be learned, because the pores are nearly invisible. this allows us to generate data with a wide variety and hence the network can predict on different data. to train the neural networks, we can mix the real and synthetic data or use them separately. the real data was annotated manually by two operators. to create a dataset of this volume we sliced it into x x blocks. only the blocks with a mean density greater than % of the grayscale range are used, to avoid too much empty volumes in the training data. another advantage of synthetic data is the class balance. we have two classes, where corresponds to material and surrounding air and for the defects. because of the size of the defects there is a high imbalance between the classes. by generating data with more features than in the real data, we could reduce the imbalance. reducing the size of the volume to x x also leads to better balance between the size of defects compared to full volume. in table details of our dataset for training, evaluation and testing are shown. the synthetic data will not be recombined to a larger volume as they represent separate small components or full material units. the following two slices of real data ( figure ) and synthetic data (figure ) with annotated defects show the conformity between the data. ur-ai // hardware and software setup deep learning (dl) consist of two phases: the training and its application. while dl models can be executed very fast, the training of the neural network can be very time-consuming, depending on several factors. one major factor is the hardware. the time consumed can be reduced by the factor of around ten when graphics cards (gpus) are used. [ ] to cache the training data, before it is given into the model, calculated on the gpu, a lot of random-access memory (ram) is used [ ] [ ] [ ] . our system is built on a dual cpu hardware with cores each running at . ghz and a nvidia gpu titan rtx with gb of vram and gb of regular ram. all measurements in this work concerning training and execution time are related to this hardware setup. the operating system is ubuntu . lts. anaconda is used for python package management and deployment. the dl-framework is tensorflow . and keras as a submodule in python . based on the du-net [ ] and dv-net [ ] architecture compared from paichao et al. [ ] we created modified versions which differ in number of layers and their hyperparameters. due to the small size of our data, no patch division is necessary. instead the training is performed on the full volumes. we actually do not use the z-net enhancement proposed in their paper. the input size, depending on our data, is defined to x x x with dimension for channel. the incoming data will be normalized. as we have a binary segmentation task, our output activation is the sigmoid [ ] function. based on paichao et al. [ ] the convolutional layer of our du-nets have a kernel size of ( , , ) and the dv-nets have a kernel size of ( , , ). as convolution activation function we are using elu [ ] [ ] and he_normal [ ] as kernel initialization [ ] . the adam optimisation method [ ] [ ] is used with a starting learning rate of . , a decay factor of . and the loss function is the binary cross-entropy [ ] . figure shows a sample du-net architecture where downwards max pooling and upwards transposed convolution are used. compared to figure , the dv-net, where we have a fully convolutional neural network, the descend is done with a ( , , ) convolution and a stride of and ascent with transposed convolution. it also has a layer level addition of the input of this level added to the last convolution output of the same level, as marked by the blue arrows. to adapt the shapes of the tensors for adding them, the down-convolution and the last convolution of the same level, have to have the same number of kernel filters. our modified neural network differ in the levels of de-/ascending, the convolution filter kernel size and their hyperparameters, shown in table . the convolutions on one level have the same number of filter kernel. after every down convolution the number of filters is multiplied by and on the way up divided by . training and evaluation of the neural networks the conditions of a training and a careful parameters selection is important. in table the training conditions fitted to our system and networks are shown. we are also taking into account that different network architectures and number of layers are better performing on different learning rates, batch size, etc. to evaluate our trained models, we are mainly focusing on the iou metric, also called jackard index, which is the intersection over union. this metric is widely used for segmentation tasks and compares the intersection over union between the prediction and ground truth for each voxel. the value of iou range between and , whereas the loss values range between and infinite. therefore, the iou is a much clearer indicator. an iou close to indicates a high intersectionprecision between the prediction and the groundtruth. our networks where trained between and epochs until no more improvement could be achieved. both datasets consist of a similar number of samples, which means the epoch time is equivalent. one epoch took around minutes. figure shows the loss determined based on the evaluation data. as described in fehler! verweisquelle konnte nicht gefunden werden., all models are trained on and evaluated against the synthetic dataset gdata and on the mixed dataset mdata. in general, the loss achieved by all models is higher on mdata because the real data is harder to learn. a direct comparison between the models is only possible between models with the same architecture. the iou metric shown in figure . here the evaluation is sorted based on the iou metric. if we compare the loss of unet-mdata with unet-gdata, which are nearly the same for mdata, with their corresponding iou (unet-mdata (~ . ) and unet-gdata (~ . )), we can see that a lower loss does not necessarily lead to higher iou score. if only the loss and iou are considered, the unets tend to be better than the vnets. as a conclusion, considering the iou metric for model selection, the unet-gdata is the best performing model and vnet-gdata the least performing. the evaluation loss determined based on the evaluation data sorted from lowest to highest. the evaluation iou determined based on the evaluation data sorted from lowest to highest. after comparing the automatic evaluation, we show prediction samples of different models on real and synthetic data ( table ) . rows and show the comparison between unet-gdata and vnet-gdata, predicting on a synthetic test sample. the result of unet-gdata exactly hits the groundtruth, whereas the vnet-gdata prediction has a % overlap to the groundtruth but with surrounding false positive segmentations. in row and both models predict the groundtruth plus some false positive segmentations in the close neighbourhood. in row and the prediction results of the same two models on real data is shown, taking into account that both models are not trained on real data. unet-gdata delivers a good precision with some false positive segmentations in thegroundtruth area and one additional segmented defect. this shows that the model was able to find a defect which was missed by the expert. vnet-gdata shows a very high number of false positive segmentations. in this paper, we have proposed a neural network to find defects in real and synthetic industrial ct volumes. we have shown that neural networks, developed for medical applications can be adapted to industrial applications. to achieve high accuracy, we used a large variety of features in our data. based on the evaluation and manually reviewing random samples we have chosen the unet architecture for further research. this model achieved great performance on our real and synthetic dataset. in summery this paper shows that the artificial intelligence and their neural networks will take an import enrichment in industrial issues. stress can affect all aspects of our lives, including our emotions, behaviors, thinking ability, and physical health, making our society sick -both mentally and physically. among the effects that the stress and anxiety can cause are heart diseases, such as coronary heart disease and heart failure [ ] . due this information, this research will present a proposal to help people handling stress using the benefit of technology development and to set patters of stress status as way to propose some intervention, once the first step to controlling stress is to know the symptoms of stress. the stress symptoms are very board and can be confused with others diseases according the american institute of stress [ ] , for example the frequent headache, irritability, insomnia, nightmares, disturbing dreams, dry mouth, problems swallowing, increased or decreased appetite, or even cause other diseases such as frequent colds and infections. in view of the wide variety of symptoms caused by stress, this research intends to define, through physiological signals, the patterns generated by the body and obtained by wearable sensors and develop a standardized database to apply the machine learning. hand, advances in sensor technology, wearable devices and mobile growth would help to online stress identification based on physiological signals and delivery of psychological interventions. currently with the advancement of technology and improvements in the wearable sensors area, made it possible to use these devices as a source of data to monitor the user's physiological state. the majority of the wearable devices consist of low-cost board that can be used to the acquisition of physiological signals [ , ] . after the data are obtained it is necessary apply some filters to clear signal, without noise or distortions aiming to use some machine learning approaches to model and predict these stress states [ , ] . the wide-spread use of mobile devices and microcomputers, as raspberry pi, and its capabilities presents a great possibility to collect, and process those signs with an elaborated application. these devices can collect the physiological signals and detect specific stress states to generate interventions following the predetermined diagnosis based on the standards already evaluated in the system [ , ] . during the literature review it was evident the presence of few works dedicated to evaluating comprehensively the complete cycle of biofeedback, which comprises using the wearable devices, applying machine learning patterns detection algorithms, generate the psychologic intervention, besides monitoring its effects and recording the history of events [ , ] . stress is identified by professionals using human physiology, so wearables sensors could help on data acquisition and processing, through machine learning algorithms on biosignal data, suggesting psychological interventions. some works [ , ] are dedicated to define patterns as experiment for data acquisition simulation real situations. jebelli, khalili and lee [ ] showed a deep learning approach that was used to compare with a baseline feedforward artificial neural network. schmidt et al. [ ] describes wearable stress and affect detection (wesad), one public dataset used to set classifiers and identify stress patterns integrating several sensors signals with the emotion aspect with a precision of % in the experiments. the work of gaglioli et al. [ ] describe the main features and preliminary evaluation of a free mobile platform for the selfmanagement of psychological stress. in terms of the wearables, some studies [ , ] evaluate the usability of devices to monitory the signals and the patient's well-being. pavic et al. [ ] showed a research performed to monitor cancer patients remotely and as the majority of the patients have a lot of symptoms but cannot stay at hospital during all treatment. the authors emphasize that was obtained good results and that this system is viable, as long as the patient is not a critical case, as it does not replace medical equipment or the emergency care present in the hospital. henriques et al. [ ] focus was to evaluated the effects of biofeedback in a group of students to reduce anxiety, in this paper was monitored the heart rate variability with two experiments with duration of four weeks each. the work of wijman [ ] describes the use of emg signals to identify stress, this experiment was conducted with participants, evaluating both the wearables signals and questionnaires. in this section will be described the uniqueness of this research and the devices that was used. this solution is being proposed by several literature study about stress patterns and physiological aspects but with few results, for this reason, our project will address topics like experimental study protocol on signals acquisition from patients/participants with wearables to data acquisition and processing, in sequence will be applied machine learning modeling and prediction on biosignal data regarding stress (fig. ) . the protocol followed to the acquisition of signals during all different status is the trier social stress test (tsst) [ ] , recognized as the gold standard protocol for stress experiments. the estimated total protocol time, involving pre-tests and post-tests, is minutes with a total of thirteen steps, but applied experiment was adapted and it was established with ten stages: initial evaluation: the participant arrives, with the scheduled time, and answer the questionnaires; habituation: it will take a rest time of twenty minutes before the pre-test to avoid the influence of events and to establish a safe baseline of that organism; pre-test: the sensors will be allocated ( fig. ), collected saliva sample and applied the psychological instruments. the next step is explanation of procedure and preparation: the participant reads the instructions and the researcher ensures that he understands the job specifications, in sequence, he is sent to the room with the jurors (fig. ) , composed of two collaborators of the research, were trained to remain neutral during the experiment, not giving positive verbal or non-verbal feedback; free speech: after three minutes of preparation, the participant is requested to start his speech, being informed that he cannot use the notes. this will follow the arithmetic task: the jurors request an arithmetic task in which the participant must subtract mentally, sometimes, the jurors interrupt and warn that the participant has made a mistake; post-test evaluation: the experimenter receives the subject outside the room for the post-test evaluations; feedback and clarification: the investigator and jurors talk to the subject and clarify what the task was about; relaxation technique: a recording will be used with the guidelines on how to perform a relaxation technique, using only the breathing; final post-test: some of the psychological instruments will be reapplied, saliva samples will be collected, and the sensors will still be picking up the physiological signals. based on literature [ ] and wearable devices available the signals that was selected to analysis is the ecg, eda and emg for an initial experiment. this experimental study protocol on data acquisition started with participants, where data annotation each step was done manually, from protocol experiment, preprocessing data based on features selection. in the machine learning step, it was evaluated the metrics of different algorithms as decision tree, random forest, adaboost, knn, k-means, svm. the experiment was made using the bitalino kit -plux wireless biosignals s.a. (fig. ) composed by ecg sensor, which will provide data on heart rate and heart rate variability; eda sensor that will allow measure the electrical dermal activity of the sweat glands; emg sensor that allows the data collect the activity of the muscle signals. this section will describe the results in the pre-processing step and how it was made, listing all parts regarded to categorization and filtering data, evaluating the signal to know if it has plausibility and create a standardized database. the developed code is written in python due to the wide variety of libraries available, in this step was used the libraries numpy and pandas, both used to data manipulation and analysis. in the first step it is necessary read the files with the raw data and the timestamp, during this process the used channels are renamed to the name of the signal, because the bitalino store the data with the channel number as name of each signals. in sequence, the data timestamp is converted to a useful format, with goal to compare with the annotations, after time changed to the right format all channels unused are discarded to avoid unnecessary processing. the next step is to read the annotations taken manually in the experiment, as said before, to compare the time and classify each part of the experiment with its respective signal. after all signals are classified with its respective process of the tsst, each part of the experiment is grouped in six categories, which will be analyzed later. the first category is the "baseline", with just two parts of the experiment, representing the beginning of the experiment, when the participants had just arrived. the second is called of "tsst" comprises the period in which the participant spoke, the third category is the "arithmetic" with the data in acquired in the arithmetic test. the others two relevant categories are the "post_test_sensors_ " and "post_test_sensors_ ", with its respective signals in the parts called with the same name. every other part of the experiment was categorized as "no_category", in sequence, this category is discarded in function of it will not be necessary in the machine learning stage. after the dataframe is right with all signals properly classified, the columns with the participants number and the timestamp are removed of the dataframe. the next step is evaluated the signal, to verify if the signal is really useful in the process of machine learning. for this, it is analyzed the signals using the biosppy library, which performs the data filtering process and makes it possible to view the data. finally, the script checks the volume of data present in each classification and returns the value of the smallest category. this is done because it was found that the categories have different volumes of data, which would become a problem in the machine learning stage, by offering more data from a determinate category than from the others. due this fact, the code analyzes the others categories and reduce its size until all categories stay with the same number of rows in each category (); after this the dataframe is exported in a csv file, to be read in the machine learning stage. the purpose of this article is to describe some stages of the development of a system for the acquisition and analysis of physiological signals to determine patterns in these signals that would detect stress states. during the development of the project was verified that there are data gaps in the dataframe in the middle of the experiment in some participants; a hypothesis about the motivation of this had happened is the sampling of the acquisition of bitalino regarding communication issues in some specifics sampling rates. it evaluate the results obtained when reducing this acquisition rate, however, it is necessary to carefully evaluate the extent to which the reduction in the sampling rate will interfere with the results. during the evaluation of the plausibility of the signals, it was verified that there are evident differences between the signals patterns in the different stages of the process, thus validating the protocol followed in the acquisition of the standards. the next step in this project is implement the machine learning stage, applying different algorithms as svm, decision tree, random forest, adaboost, knn and k-means; besides to evaluate the results using metrics like accuracy, precision, recall and f . the next steps of this research will support the confirmation of the hypothesis raised about being able to define patterns of physiological signals to detect stress states. from the definition of the patterns, a system can be applied that identifies the acquisition of the signals and, in real time, performs the analysis of these data based on the machine learning results. therefore we can detect the state of the person and that the psychologist can indicate a proposal intervention and monitor whether the decrease is occurring. technological developments have been influencing all kinds of disciplines by transferring more competences from human beings to technical devices. the steps inculde [ ]: . tools: transfer of mechanics (material) from the human being to the device . machines: transfer of energy from the human being to the device . automatic machines : transfer of information from the human being to the device . assistants: transfer of decisions from the human being to the device with the introduction of artificial intelligence (ai), in particular its latest developments in deep learning, we let the system (in step ) take over our decisions and creation processes. thus, tasks and disciplines that were exclusively reserved for humans in the past can now co-exist or even take the human out of the loop. it is no wonder that this transformation is not stopped at disciplines such as engineering, business, agriculture but also affects humanities, art and design. each new technology has been adopted for artistic expression-just see the many wonderful examples in media art. therefore, it is not surprising, that ai is going to be established as a novel tool to produce creative content of any form. however, in contrast to other disruptive technologies, ai seems particular challenging to be accepted in the area of art because it offers capabilities we thought once only humans are able to perform-the art is no longer done by artists using new technology to perform their art, but the art is done by the machine itself without the need for a human to intervene. the question of "what is art" has always been an emotionally debated topic in which everyone has a slightly different definition depending on his or her own experiences, knowledge base and personal aesthetics. however, there seems to be a broad consensus that art requires human creativity and imagination as, for instance, stated by the oxford dictionary "the expression or application of human creative skill and imagination, typically in a visual form such as painting or sculpture, producing works to be appreciated primarily for their beauty or emotional power." every art movement challenges old ways and uses artistic creative abilities to spark new ideas and styles. with each art movement diverse intentions and reasons for creating the artwork came along with critics who did not want to accept the new style as an artform. with the introduction of ai into the creation process another art movement is trying to be established which is fundamentally changing the way we see art. for the first time, ai has the potential to take the artist out of the loop, to leave humans only in the positions of curators, observers and judges to decide if the artwork is beautiful and emotionally powerful. while there is a strong debate going on in the arts if creativity is profoundly human, we investigate how ai can foster inspiration, creativity and produce unexpected results. it has been shown by many publications that ai can generate images, music and the like which can resemble different styles and produce artistic content. for instance, elgammal et al. [ ] have used generative adversarial networks (gan) to generate images by learning about styles and deviating from style norms. the promise of ai-assisted creation is "a world where creativity is highly accessible, through systems that empower us to create from new perspectives and raise the collective human potential" as roelof pieters and samim winiger pointed out [ ] . to get a better understanding of the process on how ai is capable to propose images, music, etc. we have to open the black box to investigate where and how the magic is happening. random variations in the image space (sometimes also referred to as pixel space) are usually not leading to any interesting result. this is because semantic knowledge cannot be applied. therefore, methods need to be applied which constrain the possible variations of the given dataset in a meaningful way. this can be realized by generative design or procedural generation. it is applied to generate geometric patterns, textures, shapes, meshes, terrain or plants. the generation processes may include, but are not limited, to self-organization, swarm systems, ant colonies, evolutionary systems, fractal geometry, and generative grammars. mccormack et al. [ ] review some generative design approaches and discuss how art and design can benefit from those applications. these generative algorithms which are usually realized by writing program code are very limited. ai can change this process into data-driven procedures. ai, or more specifically artificial neural networks, can learn patterns from (labeled) examples or by reinforcement. before an artificial neural network can be applied to a task (classification, regression, image reconstruction), the general architecture is to extract features through many hidden layers. these layers represent different levels of abstractions. data that have a similar structure or meaning should be represented as data points that are close together while divergent structures or meanings should be further apart from each other. to convert the image back (with some conversion/compression loss) from the low dimensional vector, which is the result of the first component, to the original input an additional component is needed. together they form the autoencoder which consists of the encoder and the decoder . the encoder compresses the data from a high dimensional input space to a low dimensional space, often called the bottleneck layer. then, the decoder takes this encoded input and converts it back to the original input as closely as possible. the latent space is the space in which the data lies in the bottleneck layer. if you look at figure you might be wondering why a model is needed that converts the input data into a "close as possible" output data. it seems rather useless if all it outputs is itself. as discussed, the latent space contains a highly compressed representation of the input data, which is the only information the decoder can use to reconstruct the input as faithfully as possible. the magic happens by interpolating between points and performing vector arithmetic between points in latent space. these transformations result in meaningful effects on the generated images. as dimensionality is reduced, information which is distinct to each image is discarded from the latent space representation, since only the most important information of each image can be stored in this low-dimensional space. the latent space captures the structure in your data and usually offers some semantic meaningful interpretation. this semantic meaning is, however, not given a priori but has to be discovered. as already discussed autoencoders, after learning a particular non-linear mapping, are capable of producing photo-realistic images from randomly sampled points in the latent space. the latent space concept is definitely intriguing but at the same time non-trivial to comprehend. although latent space means hidden, understanding what is happening in latent space is not only helpful but necessary for various applications. exploring the structure of the latent space is both interesting for the problem domain and helps to develop an intuition for what has been learned and can be regenerated. it is obvious that the latent space has to contain some structure that can be queried and navigated. however, it is non-obvious how semantics are represented within this space and how different semantic attributes are entangled with each other. to investigate the latent space one should favor a dataset that offers a limited and distinctive feature set. therefore, faces are a good example in this regard because they share features common to most faces but offer enough variance. if aligned correctly also other meaningful representations of faces are possible, see for instance the widely used approach of eigenfaces [ ] to describe the specific characteristic of faces in a low dimensional space. in the latent space we can do vector arithmetic. this can correspond to particular features. for example, the vector a smiling woman representing the face of a smiling woman minus the vector a neutral woman representing a neutral looking woman plus the vector a neutral man representing a neutral looking man resulted in the vector a smiling man representing a smiling man. this can also be done with all kinds of images; see e.g. the publication by radford et al. [ ] who first observed the vector arithmetic property in latent space. a visual example is given in figure . please note that all images shown in this publication are produced using biggan [ ] . the photo of the author on which most of the variations are based on is taken by tobias schwerdt. in latent space, vector algebra can be carried out. semantic editing requires to move within the latent space along a certain 'direction'. identifying the 'direction' of only one particular characteristic is non-trivial since editing one attribute may affect others because they are correlated. this correlation can be attributed to some extent to pre-existing correlations in 'the real world' (e.g. old persons are more likely to wear eyeglasses) or bias in the training dataset (e.g. more women are smiling on photos than men). to identify the semantics encoded in the latent space shen et al. proposed a framework for interpreting faces in latent space [ ] . beyond the vector arithmetic property, their framework allows decoupling some entangled attributes (remember the aforementioned correlation between old people and eyeglasses) through linear subspace projection. shen et al. found that in their dataset pose and smile are almost orthogonal to other attributes while gender, age, and eyeglasses are highly correlated with each other. disentangled semantics enable precise control of facial attributes without retraining of any given model. in our examples, in figures and , faces are varied according to gender or age. it has been widely observed that when linearly interpolate between two points in latent space the appearance of the corresponding synthesized images 'morphs' continuously from one face to another; see figure . this implies that also the semantic meaning contained in the two images changes gradually. this is in stark contrast to having a simple fading between two images in image space. it can be observed that the shape and style slowly transform from one image into the other. this demonstrates how well the latent space understands the structure and semantics of the images. other examples are given in section . even though our analysis has focused on face editing for the reasons discussed earlier it holds true also for other domains. for instance, bau et al. [ ] generated living rooms using similar approaches. they showed that some units from intermediate layers of the generator are specialized to synthesize certain visual concepts such as sofas or tvs. so far we have discussed how autoencoders can connect the latent space and the image semantic space, as well as how the latent code can be used for image editing without influencing the image style. next, we want to discuss how this can be used for artistic expression. while in the former section we have seen how to use manipulation in the latent space to generate mathematical sound operations not much artistic content has been generatedjust variations of photography like faces. imprecision in ai systems can lead to unacceptable errors in the system and even result in deadly decisions; e.g. at autonomous driving or at cancer treatment. in the case of artistic applications, errors or glitches might lead to interesting, non-intended, artifacts. if those errors or glitches are treated as a bug or a feature lies in the eye of the artist. to create higher variations in the generated output some artists randomly introduce glitches within the autoencoder. due to the complex structure of the autoencoder these glitches (assuming that they are introduced at an early layer in the network) occur on a semantic level as already discussed and might cause the models to misinterpret the input data in interesting ways. some could even be interpreted as glimpses of autonomous creativity; see for instance the artistic work 'mistaken identity' by mario klingemann [ ] . so far the latent space is explored by humans either by random walk or intuitive steering into a particular direction. it is up to human decisions if the synthesized image of a particular location in latent space is producing a visually appealing or otherwise interesting result. the question arises where to find those places and if those places can be spotted by an automatized process. the latent space is usually defined by a space of ddimensions for which it is assumed the data to be represented as multivariate gaussian distributions n ( , i d ) [ ] . therefore, the mean representation of all images lies in the center of the latent space. but what does that mean for the generated results? it is said that "beauty lies in the eyes of the beholder", however, research shows that there is a common understanding of beauty. for instance, averaged faces are perceived as more beautiful [ ] . adopting these findings to latent space let us assume that the most beautiful images (in our case faces) can be found in the center of the space. particular deviations from the center stand for local sweet spots (e.g. female and male, ethnic groups). these types of sweet spots can be found by common means of data analysis (e.g. clustering). but where are interesting local sweet spots if it comes to artistic expression? figure demonstrates some variation in style within the latent space. of course, one can search for locations in the latent space where particular artworks from a given artist or art styles are located; see e.g. figure where the styles of different artists, as well as white noise , have been used for adoption. but isn't lingering around these sweet spots not only producing "more of the same"? how to find the local sweet spots which can define a new art style and can be deemed truly creative? or do those discoveries of new art style lie outside of the latent space, because the latent space is trained within a particular set of defined art styles and can, therefore, produce only interpolations of those styles but nothing conceptually new? so far we have discussed how ai can help to generate different variations of faces and where to find visually interesting sweet spots. in this section, we want to show how ai is supporting the creation process by applying the discussed techniques to other areas of image and object processing. probably, different variations of image-to-image translation are the most popular approach at least if looking at the mass media. the most prominent example is style transfer -the capability to transfer the style of one image to draw the content of another (examples are shown in figure ). but mapping an input image to an output image is also possible for a variety of other applications such as object transfiguration (e.g. horse-to-zebra, apple-to-orange, season transfer (e.g. summer-to-winter) or photo enhancement [ ] . while some of the just mentioned systems are not yet in a state to be widely applicable, ai tools are taking over and gradually automating design processes which used to be time-consuming manual processes. indeed, the most potential for ai in art and design is seen in its application to tedious, uncreative tasks such as coloring black-and-white images [ ] . marco kempf and simon zimmerman used ai in their work dubbed 'deepworld' to generate a compilation of 'artificial countries' using data of all existing countries (around ) to generate new anthems, flags and other descriptors [ ] . roman lipski uses an ai muse (developed by florian dohmann et al.) to foster his/her inspiration [ ] . because the ai muse is trained only on the artist's previous drawings and fed with the current work in progress it suggests image variations in line with roman's taste. cluzel et al. have proposed an interactive genetic algorithm to progressively sketch the desired side-view of a car profile [ ] . for this, the user has taken on the role of a fitness function through interaction with the system. the chair project [ ] is a series of four chairs co-designed by ai and human designers. the project explores a collaborative creative process between humans and computers. it used a gan to propose new chairs which then have been 'interpreted' by trained designers to resemble a chair. deep-wear [ ] is a method using deep convolutional gans for clothes design. the gan is trained on features of brand clothes and can generate images that are similar to actual clothes. a human interprets the generated images and tries to manually draw the corresponding pattern which is needed to make the finished product. li et al. [ ] introduced an artificial neural network for encoding and synthesizing the structure of d shapes which-according to their findings-are effectively characterized by their hierarchical organization. german et al. [ ] have applied different ai techniques trained by a small sample set of shapes of bottles, to propose novel bottle-like shapes. the evaluation of their proposed methods revealed that it can be used by trained designers as well as nondesigners to support the design process in different phases and that it could lead to novel designs not intended/foreseen by the designers. for decades, ai has fostered (often false) future visions ranging from transhumanist utopia to "world run by machines" dystopia. artists and designers explore solutions concerning the semiotic, the aesthetic and the dynamic realm, as well as confronting corporate, industrial, cultural and political aspects. the relationship between the artist and the artwork is directly connected through their intentions, although currently mediated by third-parties and media tools. understanding the ethical and social implications of ai-assisted creation is becoming a pressing need. the implications, where each has to be investigated in more detail in the future, include: -bias: al systems are sensitive to bias. as a consequence, the ai is not being a neutral tool, but has pre-decoded preferences. bias relevant in creative ai systems are: • algorithmic bias occurs when a computer system reflects the implicit values of the humans who created it; e.g. the system is optimized on dataset a and later retrained on dataset b without reconfiguring the neural network (this is not uncommon, as many people do not fully understand what is going on in the network, but are able to use the given code to run training on other data). • data bias occurs when your samples are not representative of your population of interest. • prejudice bias results from cultural influences or stereotypes which are reflected in the data. -art crisis: until years ago painting served as the primary method for visual communication and was a widely and highly respected art form. with the invention of photography, painting began to suffer an identity crisis because painting-in its current form then-was not able to reproduce the world as accurate and with as low effort as photography. as a consequence visual artists had to change to different forms of representations not possible by photography inventing different art styles such as impressionism, expressionism, cubism, pointillism, constructivism, surrealism, up to abstract expressionism. at the time ai can perfectly simulate those styles what will happen with the artists? will artists still be needed, be replaced by ai, or will they have to turn to other artistic work which yet cannot be simulated by ai? -inflation: similar to the image flood which has reached us the same can happen with ai art. because of the glut, nobody is valuing and watching the images anymore. -wrong expectations: only esthetic appealing or otherwise interesting or surprising results are published which can be contributed to similar effects as the well-known publication bias [ ] in other areas. eventually, this is leading to wrong expectations of what is already possible with ai. in addition, this misunderstanding is fueled by content claimed to be created by ai but has indeed been produced-or at least reworked-either by human labor or by methods not containing ai. -unequal judgment: even though the raised emotions in viewing artworks emerge from its underlying structure in the works, people also include the creation process in their judgment (in the cases where they know about it). frequently, becoming to know that a computer or an ai has created the artwork, in the opinion of the people it turns boring, has no guts, no emotion, no soul while before it was inspiring, creative and beautiful. -authorship: the authorship of ai-generated content has not been clarified. for instance, is the authorship of a novel song composed by an ai trained exclusively on songs by johann sebastian bach belonging to the ai, the developer/artist, or bach? see e.g. [ ] for a more detailed discussion. -trustworthiness: new ai-driven tools make it easy for non-experts to manipulate audio and/or visual media. thus, image, audio as well as video evidence is not trustworthy anymore. manipulated image, audio, and video are leading to fake information, truth skepticism, and claims that real audio/video footage is fake (known as the liar's dividend ) [ ] . the potential of ai in creativity has just been started to be explored. we have investigated on the creative power of ai which is represented-not exclusively-in the semantic meaningful representation of data in a dimensionally reduced space, dubbed latent space, from which images, but also audio, video, and d models can be synthesized. ai is able to imagine visualizations that lie between everything the ai has learned from us and far beyond and might even develop its own art styles (see e.g. deep dream [ ] ). however, ai still lacks intention and is just processing data. those novel ai tools are shifting the creativity process from crafting to generating and selecting-a process which yet can not be transferred to machine judgment only. however, ai can already be employed to find possible sweet spots or make suggestions based on the learned taste of the artist [ ] . ai is without any doubt changing the way we experience art and the way we do art. doing art is shifting from handcrafting to exploring and discovering. this leaves humans more in the role of a curator instead of an artist, but it can also foster creativity (as discussed before in the case of roman lipski) or reduce the time between intention and realization. it has the potential, just as many other technical developments, to democratize creativity because the handcrafting skills are not so much in need to express his/her own ideas anymore. widespread misuse (e.g. image manipulation to produce fake pornography) can limit the social acceptance and require ai literacy. as human beings, we have to ask ourselves if feelings are wrong just because the ai never felt alike in its creation process as we do? or should we not worry too much and simply enjoy the new artworks created no matter if they are done by humans, by ai or as a co-creation between the two ones? [ ] aims to design and implement a machine learning system for the sake of generating prediction models with respect to quality checks and reducing faulty products in manufacturing processes. it is based on an industrial case study in cooperation with sick ag. we will present first results of the project concerning a new process model for cooperating data scientists and quality engineers, a product testing model as knowledge base for machine learning computing and visual support of quality engineers in order to explain prediction results. a typical production line consists of various test stations that conduct several measurements. those measurements are processed by the system on the fly, to point out problematic products. among the many challenges, one focus of the project is on support for quality engineers. preparation of prediction models is usually done by data scientists. but the demand for data scientists is increasing too fast, when a big number of products, production lines and changing circumstances have to be considered. hence, a software is needed which quality engineers can operate directly and leverage the results from prediction models. based on quality management and data science standard processes [ ] [ ] we created a reference process model for production error detection and correction which includes needed actors and associated tasks. with ml system and data scientist assistance we bolster the quality engineer in his work. to support the ml system, we developed a product testing model which includes crucial information about a specific product. in this model we describe the relation to product specific features, test systems, production lines sequences etc. the idea behind this, is to provide metadata information which in turn is used by the ml system instead of individual script solutions for each product. a ml model with good predictions has often a lack of information about the internal decisions. therefore, it is beneficial to support the quality engineer with useful feature visualizations. by default, we support the quality engineer with d - d feature plots and histograms, in which the error distribution is visualized. on top, we developed further feature importance measures based on shap values [ ] . these can be used to get deeper insight for particular ml decisions to significant features which get lower ranked by standard feature importance measures. medicine is a highly empirical discipline, where important aspects have to be demonstrated using adequate data and sound evaluations. this is one of the core requirements, which were emphasized during the development of the medical device regulation (mdr) of the european union (eu) [ ] . this applies to all medical devices, including mechanical and electrical devices as well as software systems. also, the us food & drug administration (fda) recently set a focus on the discussions about using data for demonstrating the safety and efficacy of medical devices [ ] . beside pure approval steps, they foster the use of data for optimization of the products, as nowadays data can be acquired more and more, using modern it technology. in particular, they pursue the use of real world evidence, i.e. data that is collected through the lifetime of a device, for demonstrating improved outcomes. [ ] such approaches require the use of sophisticated data analysis techniques. beside classical statistics, artificial intelligence (ai) and machine learning (ml) are considered to be powerful techniques for this purpose. currently, they gain more and more attention. these techniques allow to detect dependencies in complex situations, where inputs and/or outputs of a problem have high-dimensional parameter spaces. this can e.g. be the case when extensive data is collected from diverse clinical studies or also treatment protocols from local sites. furthermore, ai/ml based techniques may be used in the devices themselves. for example, devices may be developed which are considered to improve complex diagnostic tasks or find individualized treatment options for specific medical conditions (see e.g. [ , ] for an overview). for some applications, it already has been demonstrated that ml algorithms are able to outperform human experts with respect to specific success rates (e.g. [ , ] ). in this paper, it will be discussed how ml based techniques can be brought onto the market including an analysis of appropriate regulatory requirements. for this purpose, the main focus lies on ml based devices applied in the intensive care unit (icu) as e.g. proposed in [ , ] . the need for specific regulatory requirements comes from the observation, that ai/ml based techniques pose specific risks which need to be considered and handled appropriately. for example, ai/ml based methods are more challenging w.r.t. bias effects, reduced transparency, vulnerability to cybersecurity attacks, or general ethical issues (see e.g. [ , ] ). in particular cases, ml based techniques may lead to noticeably critical results, as it has been shown for the ibm watson for oncology device. in [ ] , it was reported that the direct use of the system in particular clinical environments resulted in critical treatment suggestions. the characteristics of ml based systems led to various discussions about their reliability in the clinical context. it requires to find appropriate ways to guarantee their safety and performance. (cf. [ ] ) this applies to the field of medicine / medical devices as well as ai/ml based techniques in general. the latter was e.g. approached by the eu in their ethics guidelines for trustworthy ai [ ] . driven by this overall development, the fda started a discussion regarding an extended use of ml algorithms in samd (software as a medical device) with a focus in quicker release cycles. in [ ] , it pursued the development of a specific process which makes it easier to bring ml based devices onto the market and also to update them during their lifecycle. current regulations for medical devices, e.g. in us or eu, do not provide specific guidelines for ml based devices. in particular, this applies to systems which continuously collect data in order to improve the performance of the device. current regulations focus on a fixed status of the device, which may only be adapted in a minor extent after the release. usually, a new release or clearance by the authority is required, when the clinical performance of a device is modified. but continuously learning systems exactly want to do such improvement steps using additional real-world data from daily applications without extra approvals (see fig. ). basic approaches for ai/ml based medical devices. left side: classical approach, where the status of the software has to be fixed after the release / approval stage. right side: continuously learning system where data is collected during the lifetime of the device without a separated release / approval step. in this case, an automatic validation step has to guarantee proper safety and efficacy. in [ ] , the fda made suggestions how this could be addressed. it proposed the definition of so called samd pre-specifications (sps) and an algorithm change protocol (acp), which are considered to represent major tools for dealing with modifications of the ml based system during its lifetime. within the sps, the manufacturer has to define the anticipated changes which are considered to be allowed during the automatic update process. in addition, the acp defines the particular steps which have to be implemented to realize the sps specifications. see [ ] for more information about sps and acp. but the details are not yet well elaborated by the fda at the moment. the fda requested for suggestions with respect to this. in particular, these tools serve as a basis for performing an automated validation of the updates. the applicability of this approach depends on the risk of the samd. in [ ] , the fda uses the risk categories from the international medical device regulators forum (imdrf) [ ] . this includes the categories state of healthcare situation or condition (critical vs. serious vs. noncritical) and significance of information provided by samd to healthcare decision (treat or diagnose vs. drive clinical management vs. inform clinical management) as the basic attributes. according to [ ] , the regulatory requirements for the management of ml based systems are considered to depend on this classification as well as the particular changes which may take place during the lifetime of the device. the fda categorizes them as changes in performance, inputs, and intended use. such anticipated changes have to be defined in the sps in advance. the main purpose of the present paper is to discuss the validity of the described fda approach for enabling continuously learning systems. therefore, it uses a scenario based technique to analyze whether validation in terms of sps and acp can be considered adequate tools. the scenarios represent applications of ml based devices in the icu. it checks its consistency with other important regulatory requirements and analyzes pitfalls which may jeopardize the safety of the devices. additionally, it discusses whether more general requirements can be sufficiently addressed in the scenarios, as e.g. proposed in ethical guidelines for ai based systems like [ , ] . this is not considered as a comprehensive analysis of the topics, but as an addition to current discussions about risks and ethical issues, as they are e.g. discussed in [ , ] . finally, the paper proposes own suggestions to address the regulation of continuously learning ml based systems. again, this is not considered to be a full regulatory strategy, but a proposal of particular requirements, which may overcome some of the current limitations of the approach discussed in [ ] . the overall aim of this paper is to contribute to a better understanding of the options and challenges of ai/ml based devices on the one hand and to enable the development of best practices and appropriate regulatory strategies, in the future. within this paper, the analysis of the fda approach proposed in [ ] is performed using specific reference scenarios from icu applications, which are particularly taken from [ ] itself. the focus lies on ml based devices which allow continuous updates of the model according to data collected during the lifetime of the device. in this context, sps and acp are considered as crucial steps which allow an automated validation of the device based on specified measures. in particular, the requirements and limitations of such an automated validation are analyzed and discussed, including the following topics / questions.  is automated validation reasonable for these cases? what are limitations / potential pitfalls of such an approach when applied in the particular clinical context?  which additional risks could apply to ai/ml based samd, in general, which go beyond the existing discussions in the literature as e.g. presented in [ , , ] ?  how should such issues be taken into account in the future? what could be appropriate measures / best practices to achieve reliability? the following exemplary scenarios are used for this purpose. ur-ai //  base scenario icu: ml based intensive care unit (icu) monitoring system where the detection of critical situations (e.g. regarding physiological instability, potential myocardial infarcts or sepsis) is addressed by using ml. using auditory alarms, the icu staff is informed to initiate appropriate measures to treat the patients in these situations. this scenario addresses a 'critical healthcare situation or condition' and is considered to 'drive clinical management' (according to the risk classification used in [ ] ).  modification "locked": icu scenario as presented above, where the release of the monitoring system is done according to a locked state of the algorithm.  modification "cont-learn": icu scenario as presented above, where the detection of alarm situations is continuously improved according to data acquired during daily routine, including adaptation of performance to sub-populations and/or characteristics of the local environment. in this case, scs and acp have to define standard measures like success rates of alarms/detection and requirements for the management of data, update of the algorithm, and labeling. more details of such requirements are discussed later. this scenario was presented as scenario a in [ ] with minor modifications. this section provides the basic analysis of the scenarios according to the particular aspects addressed in this paper. it addresses the topics automated validation, man-machine interaction, explainability, bias effects, and confounding, fairness and non-discrimination as well as corrective actions to systematic deficiencies. according to standard regulatory requirements [ , , ] , validation is a core step in the development and for the release of medical devices. according to [ ] , a change in performance of a device (including an algorithm in a samd) as well as a change in particular risks (e.g. new risks, but also new risk assessment or new measures) usually triggers a new premarket notification ( (k)) for most of the devices which get onto the market in the us. thus, such situations require an fda review for clearance of the device. for samd, this requires to include an analytical evaluation, i.e. correct processing of input data to generate accurate, reliable, and precise output data. additionally, a clinical validation as well as the demonstration of a valid clinical association need to be provided. [ ] this is intended to show that the outputs of the device appropriately work in the clinical environment, i.e. have a valid association regarding the targeted clinical condition and achieve the intended purpose in the context of clinical care. [ ] thus, based on the current standards, a device with continuously changing performance usually requires a thorough analysis regarding its validity. this is one of the main points, where [ ] proposes to establish a new approach for the "cont-learn" cases. as already mentioned, sps and acp basically have to be considered as tools for automated validation in this context. within this new approach, the manual validation step is replaced by an automated process with only reduced or even no additional control by a human observer. thus, it may work as an automated of fully automatic, closed loop validation approach. the question is whether this change can be considered as an appropriate alternative. in the following, this question is addressed using the icu scenario with a main focus on the "cont-learn" case. some of the aspects also apply to the "locked" cases. but the impact is considered to be higher in the "cont-learn" situation, since the validation step has to be performed in an automated fashion. human oversight, which is usually considered important, is not included here during the particular updates. within the icu scenario, the validation step has to ensure that the alarm rates stay on a sufficiently high level, regarding standard factors like specificity, sensitivity, area under curve (auc), etc. basically, these are technical parameters which can be analyzed according to an analytical evaluation as discussed above. (see also [ ] ) this could also be applied to situations, where continuous updates are made during the lifecycle of the device, i.e. in the "cont-learn". however, there are some limitations of the approach. on the one hand, it has to be ensured, that this analysis is sound and reliable, i.e. it is not compromised according to statistical effects like bias or other deficiencies in the data. on the other hand, it has to be ensured that the success rates really have a valid clinical association and can be used as a sole criterion for measuring the clinical impact. thus, the relationship between pure success rates and clinical effects has to be evaluated thoroughly and there may be some major limitations. one major question in the icu scenario is, whether better success rates really guarantee a higher or at least sufficient level of clinical benefit. this is not innately given. for example, a higher success rate of the alarms may still have a negative effect when the icu staff relies more and more on the alarms and subsequently reduces attention. thus, it may be the case that the initiation of appropriate treatment steps may be compromised even though the actually occurring alarms seem to be more reliable. in particular, this may apply in situations where the algorithms are adapted to local settings, like in the "cont-learn" scenario. here, the ml based system is intended to be optimized to subpopulations in the local environment or to specific treatment preferences at the local site. according to habituation effects, the staff's expectations get aligned to the algorithm's behavior to a certain degree after a period of time. but when the algorithm changes or an employee from another hospital or department takes over duties in the local unit, the reliability of the alarms may be affected. in these cases, it is not clear whether the expectations are well aligned with the current status of the algorithmeither in the positive or negative direction. since the data updates of the device are intended to improve its performance w.r.t. detection rates, it is clear that significant effects on user interaction may happen. under some circumstances, the overall outcome in terms of the clinical effect may be impaired. evaluation of such risks have to be addressed during validation. it is questionable whether this can be performed by using an automatic validation approach which focuses on alarm rates but does not include an assessment of the associated risks. at least a clear relationship between these two aspects has to be demonstrated in advance. it is also unclear, whether this could be achieved by assessment of pure technical parameters which are defined in advance as required by the sps and acp. usually, ml based systems are trained to a specific scenario. they provide a specific solution for this particular problem. but they do not have a more general intelligence and reasoning about potential risks, which were not under consideration at that point of time. such a more general intelligence can only be provided when using human oversight. in general, it is not clear whether technical aspects like alarms lead to valid reactions by the users. in technical terms, alarm rates are basically related to the probability of occurrence of specific hazardous situations. but they do not address a full assessment of occurrence of harm. however, this is pivotal for risk assessment in medical devices, in particular for risks related to potential use errors. this is considered to be one of the main reasons why a change in risk parameters triggers a new premarket approval in the us according to [ ] . also, the mdr [ ] sets high requirements to address the final clinical impact and not only technical parameters. basically, the example emphasizes the importance to consider the interaction between man and machine, or in this case, the algorithm and its clinical environment. this is addressed in the usability standards for medical devices, e.g. iso [ ] . for this reason, the iso requires that the final (summative) usability evaluation is performed using the final version of the device (in this case, the algorithm) or an equivalent version. this is in conflict with the fda proposal which allows to perform this assessment based on previous versions. at most, a predetermined relationship between technical parameters (alarm rates) and clinical effects (in particular, use related risks) can be obtained. for usage of ml based devices, it remains crucial to consider the interaction between the device and the clinical environment as there usually are important interrelationships. the outcome of an ml based algorithm always depends on the data it gets provided. whenever an input parameter is omitted, which is clinically relevant, the resulting outcome of the ml based system is limited. in the presented scenarios, the pure alarm rates may not be the only clinically relevant outcomes. even though, such parameters are usually the main focus regarding the quality of algorithms, e.g. in publications about ml based techniques. this is due to the fact, that such quality measures are commonly considered the best available objective parameters, which allow a comparison of different techniques. this even more applies to other ml based techniques which are also very popular in the scientific community, like segmentation tasks in medical image analysis. here the standard quality measures are general distance metrics, i.e. differences between segmented areas. [ ] they usually do not include specific clinical aspects like the accuracy in specific risk areas, e.g. important blood vessels or nerves. but such aspects are key factors to ensure the safety of a clinical procedure in many applications. again, only technical parameters are typically in focus. the association to the clinical effects is not assessed accordingly. this situation is depicted in fig. for the icu as well as image segmentation cases. additionally, the validity of an outcome in medical treatments depends on many factors. regarding input data, multiple parameters from a patient's individual history may be important for deciding about a particular diagnosis or treatment. a surgeon usually has access to a multitude of data and also side conditions (like socio-economic aspects) which should be included in an individual diagnosis or treatment decision. his general intelligence and background knowledge allow him to include a variety of individual aspects, which have to be considered for a specific case-based decision. in contrary, ml based algorithms rely on a more standardized structure of input data and are only trained for a specific purpose. they lack a more general intelligence, which allows them to react in very specific situations. even more, ml based algorithms need to generalize and thus to mask out very specific conditions, which could by fatal in some cases. in [ ] , the fda presents some examples where changes of the inputs in an ml based samd are included. it is surprising, that the fda considers some of them as candidates for a continuous learning system, which does not need an additional review, when a tailored sps/acp is available. such discrepancies between technical outcomes and clinical effects also apply to situations like the icu scenario, which only informs or drives clinical management. often users rely on automatically provided decisions, even when they are informed that this only is a proposal. again, this is a matter of man-machine interaction. this gets even worse due to the lack of explainability which ml based algorithms typically have. [ , ] when surgeons or more general users (e.g, icu staff) detect situations which require a diverging treatment because of very specific individual conditions, they should overrule the algorithm. but users will often be confused by the outcome of the algorithm and do not have a clear idea how they should treat conflicting results between the algorithm's suggestions and their own belief. as long as the ml based decision is not transparent to the user, they will not be able to merge these two directions. the ibm watson example, referenced in the introduction shows, that this actually is an issue [ ] . this may be even more serious, when the users (i.e. healthcare professionals) fear litigation because they did not trust the algorithm. in a situation, where the algorithm's outcome finally turns out to be true, they may be sued because of this documented deviation. because of such issues, the eu general data protection regulation (gfpr) [ ] requires that the users get autonomy regarding their decisions and transparency about the mechanisms underlying the algorithm's outcome. [ ] this may be less relevant for the patients, who usually have only limited medical knowledge. they will probably also not understand the medical decisions in conventional cases. but it is highly relevant for responsible healthcare professionals. they require to get basic insights how the decision emerged, as they finally are in charge of the treatment. this demonstrates that methods regarding the explainability of ml based techniques are important. fortunately, this currently gets a very active field. [ , ] this need for explainability applies to locked algorithms as well as situations where continuous learning is applied. based on their own data-driven nature, ml based techniques highly depend on a very high quality of data which are provided for learning and validation. in particular, this is important for the analytical evaluation of the ml algorithms. one of the major aspects are bias effects due to unbalanced input data. for example, in [ ] a substantially different detection rate between white and colored people was recognized due to unbalanced data. beside ethical considerations, this demonstrates dependencies of the outcome quality on sub-populations, which may be critical in some cases. even though, the fda proposal [ ] currently does not consequently include specific requirements for assessing bias factors or imbalance of data. however, high quality requirements for data management are crucial for ml based devices. in particular, this applies to the icu "cont-learn" cases. there have to be very specific protocols that guarantee that new data and updates of the algorithms are highly reliable w.r.t. bias effects. most of the currently used ml based algorithms fall under the category of supervised learning. thus, they require accurate and clinically sound labeling of the data. during the data collection, it has to be ensured how this labeling is performed and how the data can be fed back into the system in a "cont-learn" scenario. additionally, the data needs to stay balancedwhatever this means in a situation where adaptions to sub-populations and/or local environments are intended for optimization. it is unclear, whether and how this could be achieved by staff who is only operating with the system but possibly does not know potential algorithmic pitfalls. in the icu scenario, many data points probably need to be recorded by the system itself. thus, a precise and reliable recording scheme has to be established which automatically avoids imbalance of data on the one hand and fusion with manual labelings on the other hand. basically, the sps and acp (proposed in [ ] ) are tools to achieve this. the question is whether this is possible in a reliable fashion using automated processes. a complete closed loop validation approach seems to be questionable, especially when the assessment of clinical impact has to be included. thus, the integration of humans including adequate healthcare professionals as well as ml/ai experts with sufficient statistical knowledge seems reasonable. at least, bias assessment steps should be included. as already mentioned, this is not addressed in [ ] in a dedicated way. further on, the outcomes may be compromised by side effects in the data. it may be the case, that the main reason for a specific outcome of the algorithm is not a relevant clinical parameter but a specific data artifact, i.e. some confounding factor. in the icu case, it could be the case, that the icu staff reacts early to a potentially critical situation and e.g. gives specific medication in advance to prevent upcoming problems. the physiological reaction of the patient can then be visible in the data as some kind of artifact. during its learning phase, the algorithm may recognize the critical situation not based on a deeper clinical reason, but on detecting the physiological reaction pattern. this may cause serious problems as shown subsequently. in the presented scenario, the definition of clinical situation and the pattern can be deeply coupled by design, since the labeling of the data by the icu staff and the administration of the medication will probably be done in combination at the particular site. this may increase the probability of such effects. usually, confounding factors are hard to determine. even when they can be detected, they are hard to be communicated and managed in an appropriate way. how should healthcare professionals react, when they get such potentially misleading information (see discussion about liability). this further limits the explanatory power of ml based systems. when confounders are not detected, they may have unpredictable outcomes w.r.t. the clinical effects. for example, consider the following case. in the icu scenario, an ml based algorithm gets trained in a way that it basically detects the medication artifact as described above during the learning phase. in the next step, this algorithm is used in clinical practice and the icu staff relies on the outcome of the algorithm. then, on the one hand, the medication artifact is not visible unless the icu staff administers the medication. on the other hand, the algorithm does not recognize the pattern and thus does not provide an alarm. subsequently, the icu staff does no act appropriately to manage the critical situation. in particular, such confounders may be more likely in situations where a strong dependence between the outcome of the algorithm and the clinical treatment exists. further examples of such effects were discussed in [ ] for icu scenarios. the occurrence of confounders may be a bit less probable in pure diagnostic cases without influence of the diagnostic task onto the generation of data. but even here, such confounding factors may occur. the discussion in [ ] provided examples where confounders may occur in diagnostic cases e.g. because of rulers placed for measurements on radiographs. in most of the publications about ml based techniques, such side effects are not discussed (or only in a limited fashion). in many papers, the main focus is the technical evaluation and not the clinical environment and the interrelation between technical parameters and clinical effects. additional important aspects which are amply discussed in the context of ai/ml based systems are discrimination and fairness (see e.g. [ ] ). in particular, the eu puts a high priority of their future ai/ml strategy on fairness requirements [ ] . fairness is often closely related to bias effects. but it goes beyond to more general ethical questions, e.g. regarding the natural tendency of ml based systems to favor specific subgroups. for example, the icu scenario "cont-learn" is intended to optimize w.r.t. to specifics of sub-populations and local characteristics, i.e. it tries to make the outcome better for specific groups. based on such optimization, other groups (e.g. minorities, underrepresented groups) which are not well represented may be discriminated in some sense. this is not a statistical but a systematic effect. superiority of a medical device for a specific subgroup (e.g. gender, social environment, etc.) is not uncommon. for example, some diagnosis steps, implants, or treatments achieve deviating success rates when applied to women in comparison to men. this also applies to differences between adults and children. when assessing bias in clinical outcome in ml based devices, it will probably often be unclear whether this is due to imbalance of data or a true clinical difference between the groups. does an ml based algorithm has to adjust the treatment of a subgroup to a higher level, e.g. a better medication, to achieve comparable results, when the analysis recognized worse results for this subgroup? another example could be a situation where the particular group does not have the financial capabilities to afford the high-level treatment. this could e.g. be the case in a developing country or in subgroups with a lower insurance level. in these cases, the inclusion of socio-economical parameters into the analysis seems to be unavoidable. subsequently, this compromises the notion of fairness as basic principle in some way. this is nothing genuine to ml based devices. but in the case of ml based systems with a high degree of automation, the responsibility for the individual treatment decision more and more shifts from the health care professional to the device. it is implicitly defined in the ml algorithm. in comparison to human reasoning, which allows some weaknesses in terms of individual adjustments of general rules, ml based algorithms are rather deterministic / unique in their outcome. for a fixed input, they have one dedicated outcome (when we neglect statistical algorithms which may allow minor deviations). differences of opinions and room for individual decisions are main aspects of ethics. thus, it remains unclear how fairness can be defined and implemented at all when considering ml based systems. this is even more challenging as socioeconomical aspects (even more than clinical aspects) are usually not included in the data and analysis of ml based techniques in medicine. additionally, they are hard to assess and implement in a fair way, especially when using automated validation processes. another disadvantage of ml based devices is the limited opportunities to fix systematic deficiencies in the outcome of the algorithm. let us assume that during the lifetime of the icu monitoring system a systematic deviation of the intended outcome was detected, e.g. in the context of post-market surveillance or due to an increased number of serious adverse events. according to standard rules, a proper preventive respectively corrective action has to be taken by the manufacturer. in conventional software devices, the error simple should be eliminated, i.e. some sort of bug fixing has to be performed. for ml based devices it is less clear, how bug fixing should work especially when the systematic deficiency is deeply hidden in the data and/or ml model. in these cases, there usually is no clear reason for the deficiency. subsequently, the deficiency cannot be resolved in a straightforward way using standard bug fixing. there is no dedicated route to find the deeper reasons and to perform changes which could cure the deficiencies, e.g. by providing additional data or changing the ml model. even more, other side effects may easily occur, when data and model are changed manually by intent to fix the issue. discussion and outlook in summary, there are many open questions, which are not yet clarified. there still is little experience how ml based systems work in clinical practice and which concrete risks may occur. thus, the fda's commitment to foster the discussion about ml based samd is necessary and appreciated by many stakeholders as the feedback docket [ ] for [ ] shows. however, it is a bit surprising that the fda proposes to substantially reduce its very high standards in [ ] at this point of time. in particular, it is questionable whether an adequate validation can be achieved by using a fully automatic approach as proposed in [ ] . ml based devices are usually optimized according to very specific goals. they can only account for the specific conditions that are reflected in the data and the used optimization / quality criteria. they do not include side conditions and a more general reasoning about potential risks in a complex environment. but this is important for medical devices. for this reason, a more deliberate path would be suited, from the author's perspective. in a first step, more experience should be gained w.r.t. to the use of ml based devices in clinical practice. thus, continuous learning should not be a first hand option. first, it should be demonstrated that a device works in clinical practice before a continuous learning approach should be possible. this could also be justified from a regulatory point-of-view. the automated validation process itself should be considered as a feature of the device. it should be considered as part of the design transfer which enables safe use of the device during its lifecycle. as part of the design transfer, it should be validated itself. thus, it has to be demonstrated that this automated validation process, e.g. in terms of the sps and acp, works in a real clinical environment. ideally, this would have been demonstrated during the application of the device in clinical practice. thus, one reasonable approach for a regulatory strategy could be to reduce or prohibit the options for enabling automatic validation in a first release / clearance of the device. during the lifetime, direct clinical data could be acquired to demonstrate a better insight into the reliability and limitations of the automatic validation / continuous learning approach. in particular, the relation between technical parameters and clinical effects could be assessed on a broader and more stable basis. based on this evidence in real clinical environments, the automated validation feature could then be cleared in a second round. otherwise, the validity of the automated validation approach would have to be demonstrated in a comprehensive setting during the development phase. in principle, this is possible when enough data is available which truly reflects a comprehensive set of situations. as discussed in this paper, there are many aspects which do not render this approach impossible but very challenging. in particular, this applies to the clinical effects and the interdependency between the users and clinical environment on the one hand and the device, including the ml algorithm, data management, etc., on the other hand. this also includes not only variation in the status and needs of the individual patient but also the local clinical environment and potentially also the socioeconomic setting. following a consequent process validation approach, it would have to be demonstrated that the algorithm reacts in a valid and predictable way no matter which training data have been provided, which environment have to be addressed, and which local adjustments have been applied. this also needs to include deficient data and inputs in some way. in [ ] , it has been shown that the variation of outcomes can be substantial, even w.r.t. rather simple technical parameters. in [ ] , this was analyzed for scientific contests ("challenges") where renowned scientific groups supervised the quality of the submitted ml algorithms. this demonstrates the challenges validation steps for ml based systems still include, even w.r.t. technical evaluation. for these reasons, it seems adequate to pursue the regulatory strategy in a more deliberate way. this includes the restriction of the "cont-learn" cases as proposed. this also includes a better classification scheme, where automated or fully automatic validation is possible. currently, the proposal in [ ] does not provide clear rules when continuous learning is allowed. it does not really address a dedicated risk-based approach that defines which options and limitations are applicable. for some options, like the change of the inputs, it should be reviewed, whether automatic validation is a natural option. additionally, the dependency between technical parameters and clinical effects as well as risks should get more attention. in particular, the grade of interrelationship between the clinical actions and the learning task should be considered. in general, the discussions about ml based medical devices are very important. these techniques provide valuable opportunities for improvements in fields like medical technologies, where evidence based on high quality data is crucial. this applies to the overall development of medicine as well as to the development of sophisticated ml based medical devices. this also includes the assessment of treatment options and success of particular devices during their lifetime. data-driven strategies will be important for ensuring high-level standards in the future. they may also strengthen regulatory oversight in the long term by amplifying the necessity of post-market activities. this seems to be one of the promises the fda envisions according to their concepts of "total product lifecycle quality (tplc)" and "organizational excellence" [ ] . also, the mdr strengthens the requirements for data-driven strategies in the pre-as well as postmarket phase. but it should not shift the priorities for a basically proven-quality-in-advance (exante) to a primarily ex-post regulation, which boils down to a trial-and-error oriented approach in the extreme. thus, we should aim at a good compromise between pushing these valuable and innovative options on the one hand and potential challenges and deficiencies on the other hand. computer-assisted technologies in medical interventions are intended to support the surgeon during treatment and improve the outcome for the patient. one possibility is to augment reality with additional information that would otherwise not be perceptible to the surgeon. in medical applications, it is particularly important that demanding spatial and temporal conditions are adhered to. challenges in augmenting the operating room are the correct placement of holograms in the real world, and thus, the precise registration of multiple coordinate frames to each other, the exact scaling of holograms, and the performance capacity of processing and rendering systems. in general, two different scenarios can be distinguished. first, applications exist, in which a placement of holograms with an accuracy of cm and above are sufficient. these are mainly applications where a person needs a three-dimensional view of data. an example in the medical field may be the visualization of patient data, e.g. to understand and analyse the anatomy of a patient, for diagnosis or surgical planning. the correct visualization of these data can be of great benefit to the surgeon. often only d patient data is available, such as ct or mri scans. the availability of d representations depend strongly on the field of application. in neurosurgery d views are available but often not extensively utilized due to their limited informative value. additionally computer monitors are a big limitation, because the data can not be visualized in real world scale. further application areas are the translation of known user interfaces into augmented ur-ai // reality (ar) space. the benefit here is that a surgeon refrains from touching anything, but can interact with the interface in space using hand or voice gestures. applications visualizing patient data, such as ct scans, only require a rough positioning of the image or holograms in the operation room (or). thus, the surgeon can conveniently place the application freely in space. the main requirement is then to keep the holograms in a constant position. therefore, the internal tracking of the ar device is sufficient to hold the holograms at a fixed position in space. the second scenario covers all applications, in which an exact registration of holograms to the real world is required, in particular with a precision below cm. these scenarios are more demanding, especially when holograms must be placed precisely over real patient anatomy. to achieve this, patient tracking is essential to determine position and to follow patient movements. the system therefore needs to track the patient and adjust the visualization to the current situation. furthermore, it is necessary to track and augment surgical instruments and other objects in the operating room. the augmentation needs to be visualized at the correct spatial position and time constraints need to be fulfilled. therefore, the ar system needs to be embedded into the surgical workflow and react to it. to achieve these goals modern state of the art machine learning algorithms are required. however, the computing power on available ar devices is often not yet sufficient for sophisticated machine learning algorithms. one way to overcome this shortcoming is the integration of the ar system into a distributed system with higher capabilities, such as the digital operating theatre op:sense (see fig. ). in this work an augmented reality system holomed [ ] (see fig. ) is integrated into the surgical research platform for robot assisted surgery op:sense [ ] . the objective is to enable high-quality and patient-safe neurosurgical procedures in order to increase the surgical outcome by providing surgeons with an assistance system that supports them in cognitively demanding operations. the physician's perception limits are extended by the ar system, which bases on supporting intelligent machine learning algorithms. ar glasses allow the neurosurgeon to perceive the internal structures of the patient's brain. the complete system is demonstrated by applying this methodology to the ventricular puncture of the human brain, one of the most frequently performed procedures in neurosurgery. the ventricle system has an elongated shape with a width of - cm and is located in a depth of cm inside the human head. patient models are generated fast (< s) from ct-data [ ] , which are superimposed over the patient during operation and serve as a navigation aid for the surgeon. in this work the expanded system architecture is presented to overcome some limitations of the original system where all information were processed on the microsoft hololens, which lead to performance deficits. to overcome these shortcomings the holomed project was integrated into op:sense for additional sensing and computing power. to achieve integration of ar into the operation room and the surgical workflows, the patient, the instruments and the medical staff need to be tracked. to track the patient, a marker system is fixated on the patient head and registration from the marker system to the patient is determined. a two-stage process was implemented for this purpose. first the rough position of the patient's head is determined on the or table by applying a yolo v net to reduce the search space. then a robot with a mounted rgb-d sensor is used to scan the acquired area and build a point cloud of the same. to determine the patient's head in space as precisely as possible a two-step surface matching approach is utilized. during recording, the markers are also tracked. with known position of the patient and the markers, the registration matrix can be calculated. for the ventricular puncture a solution is proposed to track the puncture catheter to determine the depth of insertion into the human brain. by tracking the medical staff the system is able to react to the current situation, e.g. if an instrument is passed. in the following the solutions are described in detail. our digital operating room op:sense (illustrated in fig. a) to detect the patient's head, the coarse position is first determined with the yolo v cnn [ ] , performed on the kinect rgb image streams. the position in d is determined through the depth stream of the sensors. the or table and the robots are tracked with retroreflective markers by the arttrack system. this step reduces the spatial search area for fine adjustment. the franka panda has an attached intel realsense rgb-d camera as depicted in fig. . the precise determination of the position is performed on the depth data with surface matching. the robot scans the area of the coarsely determined position of the patient's head. a combined surface matching approach with feature-based and icp matching was implemented. the process to perform the surface matching is depicted in fig. . in clinical reality, a ct scan of the patient head is always performed prior to a ventricular puncture for diagnosis, such that we can safely assume the availability of ct data. a process to segment the patient models from ct data was proposed by kunz et al. in [ ] . the algorithm processes the ct data extremely fast in under two seconds. the data format is '.nrrd', a volume model format, which can easily be converted into surface models or point clouds. the point cloud of the patient's head ct scan is the reference model that needs to be found in or space. the second point cloud is recorded from the realsense depth stream mounted on the panda robot by scanning the previously determined rough position of the patient head. all points are recorded in world coordinate space. the search space is further restricted with a segmentation step by filtering out points that are located on the or table. additionally, manual changes can be made by the surgeon. in a performance optimization, the resolution of the point clouds is reduced to decrease processing time without loosing too much accuracy. the normals of both point clouds generated from ct data and from the recorded realsense depth stream are subsequently calculated and harmonised. during this step, the harmonisation is especially important as the normals are often misaligned. this misalignment occurs because the ct data is a combination of several individual scans. for alignment of all normals, a point inside the patient's head is chosen manually as a reference point, followed by orienting all normals in the direction of this point and subsequently inverting all normals to the outside of the head (see fig. ). after the preprocessing steps, the first surface fitting step is executed. it is based on the initial alignment algorithm proposed by rusu et al. [ ] . an implementation within the point cloud library (pcl) is used. therefore fast point feature histograms need to be calculated as a preprocessing step. in the last step an iterative closest point (icp) algorithm is used to refine the surface matching result. after the two point clouds have been aligned to each other the inverse transformation matrix can be calculated to get the correct transformation from marker system to patient model coordinate space. as outlined in fig. , catheter tracking was implemented based on semantic segmentation using a full-resolution residual network (frrn) [ ] . after the semantic segmentation of the rgb stream of the kinect cameras, the image is fused with the depth stream ur-ai // to determine the voxels in the point cloud belonging to the catheter. as a further step a density based clustering approach [ ] is performed on the chosen voxels. this is due to noise especially on the edges of the instrument voxels in the point cloud. based on the found clusters an estimation of the three dimensional structure of the catheter is performed. for this purpose, a narrow cylinder with variable length is constructed. the length is changed accordingly to the semantic segmentation and the clustered voxels of the point cloud. the approach is applicable to identify a variety of instruments. the openpose [ ] library is used to track key points on the bodies of the medical staff. available ros nodes have been modified to integrate openpose in the op:sense ros environment. the architecture is outlined in fig. . in this chapter the results of the patient, catheter and medical staff tracking are described. the approach to find the coarse position of a patient's head was performed on a phantom head placed on the or table within op:sense. multiple scenarios with changing illumination and occlusion conditions were recorded. the results are depicted in fig. and the evaluation results are depicted in table . precision detection of the patient was performed with a two-stage surface matching approach. different point cloud resolutions were tested with regard to runtime behaviour. voxel grid edge sizes of , and mm have been tested, with a higher edge size corresponding to a smaller point cloud. the matching results of the two point clouds were analyzed manually. an average accuracy of . mm was found with an accuracy range between . and . mm. in the first stage of the surface matching, the two point clouds are coarsely aligned as depicted in fig. . in the second step icp is used for fine adjustment. a two-stage process was implemented as icp requires a good initial alignment of the two point clouds. ur-ai // for catheter tracking a precision of the semantic segmentation between % and % is reached (see table ). tracking of instruments, especially neurosurgical catheters, are challenging due to their thin structure and non-rigid shape. detailed results on catheter tracking have been presented in [ ] . the d estimation of the catheter is shown in fig. . the catheter was moved in front of the camera and the d reconstruction was recorded simultaneously. over a long period of the recording over % of the catheter are tracked correctly. in some situations this drops to under % or lower. the tracking of medical personnel is shown in fig. . the different body parts and joint positions are determined, e.g. the head, eyes, shoulders, elbows, etc. the library yielded very good results as described in [ ] . we reached a performance of frames per second on a workstation (intel i - k, geforce ti) processing stream. fig. . results of the medical staff tracking. ur-ai // discussion as shown in the evaluation, our approach succeeds in detecting the patient in an automated two-stage process with an accuracy between and mm. the coarse position is determined by using a yolo v net. the results under normal or conditions are very satisfying. the solution performance drops strongly under bright illumination conditions. this is due to large flares that occur on the phantom as it is made of plastic or silicone. however, these effects do not occur on human skin. the advantage of our system is that the detection is performed on all four kinect rgb streams enable different views on the operation area. unfavourable illumination conditions normally don't occur on all of these streams. therefore a robust detection is still possible. in the future the datasets will be expanded with samples with strong illumination conditions. the following surface matching of the head yields good results and a robust and precise detection of the patient. most important is a good preprocessing of the ct data and the recorded point cloud of the search area, as described in the methods. the algorithm does not manage to find a result if there are larger holes in the point clouds or if the normals are not calculated correctly. additionally, challenges that have to be considered include skin deformities and noisy ct data. the silicone skin is not fixed to the skull (as human skin is), which leads to changes in position, some of which are greater than cm. also the processing time of minutes is quite long and must be optimized in the future. the processing time may be shortened by reducing the size of the point clouds. however, in this case the matching results may also become worse. catheter tracking [ ] yielded good results, despite the challenging task of segmenting a very thin ( . mm) and deformable object. additionally, a d estimation of the catheter was implemented. the results showed that in many cases over % of the catheter can be estimated correctly. however, these results strongly depend on the orientation and the quality of the depth stream. using higher quality sensors could improve the detection results. for tracking of the medical staff openpose as a ready-to-use people detection algorithm was used and integrated into ros. the library produces very good results, despite medical staff wearing surgical clothing. in this work the integration of augmented reality into the digital operating room op:sense is demonstrated. this makes it possible to expand the capabilities of current ar glasses. the system can determine the precise patient's position by implementing a two-stage process. first a yolo v net is used to coarsly detect the patient to reduce the search area. in a second subsequent step a two-stage surface matching process is implemented for refined detection. this approach allows for precise location of the patient's head for later tracking. further, a frnn-based solution to track the surgical instruments in the or was implemented and demonstrated on a thin neurosurgical catheter for ventricular punctures. additionally, openpose was integrated into the digital or to track the surgical personnel. the presented solution will enable the system to react to the current situation in the operating room and is the base for an integration into the surgical workflow. due to the emergence of commodity depth sensors many classical computer vision tasks are employed on networks of multiple depth sensors e.g. people detection [ ] or full-body motion tracking [ ] . existing methods approach these applications using a sequential processing pipeline where the depth estimation and inference are performed on each sensor separately and the information is fused in a post-processing step. in previous work [ ] we introduce a scene-adaptive optimization schema, which aims to leverage the accumulated scene context to improve perception as well as post-processing vision algorithms (see fig. ). in this work we present a proof-of-concept implementation of the scene-adaptive optimization methods proposed in [ ] for the specific task of stereomatching in a depth sensor network. we propose to improve the d data acquisition step with the help of an articulated shape model, which is fitted to the acquired depth data. in particular, we use the known camera calibration and the estimated d shape model to resolve disparity ambiguities that arise from repeating patterns in a stereo image pair. the applicability of our approach can be shown by preliminary qualitative results. in previous work [ ] we introduce a general framework for scene-adaptive optimization of depth sensor networks. it is suggested to exploit inferred scene context by the sensor network to improve the perception and post-processing algorithms themselves. in this work we apply the proposed ideas in [ ] to the process of stereo disparity estimation, also referred to as stereo matching. while stereo matching has been studied for decades in the computer vision literature [ , ] it is still a challenging problem and an active area of research. stereo matching approaches can be categorized into two main categories, local and global methods. while local methods, such as block matching [ ] , obtain a disparity estimation by finding the best matching point on the corresponding scan line by comparing local image regions, global methods formulate the problem of disparity estimation as a global energy minimization problem [ ] . local methods lead to highly efficient real-time capable algorithms, however, they suffer from local disparity ambiguities. in contrast, global approaches are able to resolve local ambiguities and therefore provide high-quality disparity estimations. but they are in general very time consuming and without further simplifications not suitable for real-time applications. the semi-global matching (sgm) introduced by hirschmuller [ ] aggregates many feasible local d smoothness constraints to approximate global disparity smoothness regularization. sgm and its modifications are still offering a remarkable trade-off between the quality of the disparity estimation and the run-time performance. more recent work from poggi et al. [ ] focuses on improving the stereo matching by taking additional high-quality sources (e.g. lidar) into account. they propose to leverage sparse reliable depth measurements to improve dense stereo matching. the sparse reliable depth measurements act as a prior to the dense disparity estimation. the proposed approach can be used to improve more recent end-to-end deep learning architectures [ , ] , as well as classical stereo approaches like sgm. this work is inspired by [ ] , however, our approach does not rely on an additional lidar sensor but leverages a priori scene knowledge in terms of an articulated shape model instead to improve the stereo matching process. we set up four stereo depth sensors with overlapping fields of view. the sensors are extrinsically calibrated in advance, thus their pose with respect to a world coordinates system is known. the stereo sensors are pointed at a mannequin and capture eight greyscale images (one image pair for each stereo sensor, the left image of each pair is depicted in fig. a) . for our experiments we use a high-quality laser scan of the mannequin as ground truth. we assume that the proposed algorithm has access to an existing shape model that can express the observed geometry of the scene in some capacity. in our experimental setup, we assume a shape model of a mannequin with two articulated shoulders and a slightly different shape in the belly area of the mannequin (see fig. ). in the remaining section we use the provided shape model to improve the depth data generation of the sensor network. first, we estimate the disparity values of each of the four stereo sensors with sgm without using the human shape model. let p denote a pixel and q denote an adjacent pixel. let d denote a disparity map and d p ,d q denote the disparity at pixel location p and q. let p denote the set of all pixels and n the set of all adjacent pixels. then the sgm cost function can be defined as where d(p, d p ) denotes the matching term (here the sum of absolute differences in a × neighborhood) which assigns a matching cost to the assignment of disparity d p to pixel p and r(p, d p , q, d q ) penalizes disparity discontinuities between adjacent pixels p and q. in sgm the objective given in ( ) is minimized with dynamic programming, leading to the resulting disparity mapd = arg min d e(d). as input for the shape model fitting we apply sgm on all four stereo pairs leading to four disparity maps as depicted in fig. a . to be able to exploit the articulated shape model for stereo matching we initial need to fit the model to the d data obtained by classical sgm as described in . . to be more robust to outliers we do only use disparity values from pixels with high contrast and transform them into d point clouds. since we assume that the relative camera poses are known, it is straight forward to merge the resulting point clouds in one world coordinate system. finally the shape model is fitted to the merged point cloud by optimizing over the shape model parameters, namely the pose of the model and the rotation of the shoulder joints. we use an articulated mannequin shape model in this work as a proxy for an articulated human shape model (e.g. [ ] ) as proof-of-concept and plan to transfer the proposed approach on real humans in future work. once the model parameters of the shape model are obtained we can reproject the model fit to each sensor view by making use of the known projection matrices. fig. b shows the rendered wireframe mesh of the fitted model as an overlay on the camera images. for our guided stereo matching approach we then need the synthetic disparity map which can be computed from the synthetic depth maps (a byproduct of d rendering). we denote the synthetic disparity image by d synth . one synthetic disparity image is created for each stereo sensor, see fig. b . in the final step we exploit the existing shape model fit, in particular the synthetic disparity image d synth of each stereo sensor and combine it with sgm (inspired by guided stereo matching [ ] ). our augmented objective is defined as with the introduced objective is very similar to sgm and can be minimized in a similar fashion leading to the final disparity estimation in our scene-adaptive depth sensor network to summarize our approach, we exploit an articulated shape model fit to enhance sgm with minor adjustments. to show the applicability of our approach we present preliminary qualitative results. the results are depicted in fig. . using sgm without exploiting the provided articulated shape model leads to reasonable results, but the disparity map is very noisy and no clean silhouette of the mannequin is extracted (see fig. a ). fitting our articulated shape model to the data leads to clean synthetic disparity maps as shown in fig. c , with a clean silhouette. in the belly area the synthetic model disparity map (fig. b) does not agree with the ground truth (fig. d) . the articulated shape model is not general enough to explain the recorded scene faithfully. using the guided stereo matching approach, we construct a much cleaner disparity map than sgm. in addition, the approach takes the current sensor data into account and exploits an existing articulated shape model. in this work we have proposed a method for scene-adaptive disparity estimation in depth sensor networks. our main contribution is the exploitation of a fitted human shape model to make the estimation of disparities more robust to local ambiguities. our early results indicate that our method can lead to more robust and accurate results compared to classical sgm. future work will focus on a quantitative evaluation as well as incorporating sophisticated statistical human shape models into our approach. inverse process-structure-property mapping abstract. workpieces for dedicated purposes must be composed of materials which have certain properties. the latter are determined by the compositional structure of the material. in this paper, we present the scientific approach of our current dfg funded project tailored material properties through microstructural optimization: machine learning methods for the modeling and inversion of structure-property relationships and their application to sheet metals. the project proposes a methodology to automatically find an optimal sequence of processing steps which produce a material structure that bears the desired properties. the overall task is split in two steps: first find a mapping which delivers a set of structures with given properties and second, find an optimal process path to reach one of these structures with least effort. the first step is achieved by machine learning the generalized mapping of structures to properties in a supervised fashion, and then inverting this relation with methods delivering a set of goal structure solutions. the second step is performed via reinforcement learning of optimal paths by finding the processing sequence which leads to the best reachable goal structure. the paper considers steel processing as an example, where the microstructure is represented by orientation density functions and elastic and plastic material target properties are considered. the paper shows the inversion of the learned structure-property mapping by means of genetic algorithms. the search for structures is thereby regularized by a loss term representing the deviation from process-feasible structures. it is shown how reinforcement learning is used to find deformation action sequences in order to reach the given goal structures, which finally lead to the required properties. keywords: computational materials science, property-structure-mapping, texture evolution optimization, machine learning, reinforcement learning the derivation of processing control actions to produce materials with certain, desired properties is the "inverse problem" of the causal chain "process control" -"microstructure instantiation" -"material properties". the main goal of our current project is the creation of a new basis for the solution of this problem by using modern approaches from machine learning and optimization. the inversion will be composed of two explicitly separated parts: "inverse structure-property-mapping" (spm) and "microstructure evolution optimization". the focus of the project lies on the investigation and development of methods which allow an inversion of the structure-property-relations of materials relevant in the industry. this inversion is the basis for the design of microstructures and for the optimal control of the related production processes. another goal is the development of optimal control methods yielding exactly those structures which have the desired properties. the developed methods will be applied to sheet metals within the frame of the project as a proof of concept. the goals include the development of methods for inverting technologically relevant "structure-property-mappings" and methods for efficient microstructure representation by supervised and unsupervised machine learning. adaptive processing path-optimization methods, based on reinforcement learning, will be developed for adaptive optimal control of manufacturing processes. we expect that the results of the project will lead to an increasing insight into technologically relevant process-structure-property-relationships of materials. the instruments resulting from the project will also promote the economically efficient development of new materials and process controls. in general, approaches to microstructure design make high demands on the mathematical description of microstructures, on the selection and presentation of suitable features, and on the determination of structure-property relationships. for example, the increasingly advanced methods in these areas enable microstructure sensitive design (msd), which is introduced in [ ] and [ ] and described in detail in [ ] . the relationship between structures and properties descriptors can be abstracted from the concrete data by regression in the form of a structure-property-mapping. the idea of modeling a structure-property-mapping by means of regression and in particular using artificial neural networks was intensively pursued in the s [ ] and is still used today. the approach and related methods presented in [ ] always consist of a structure-property-mapping and an optimizer (in [ ] genetic algorithms) whose objective function represents the desired properties. the inversion of the spm can be alternatively reached via generative models. in contrast to discriminative models (e.g. spm), which are used to map conditional dependencies between data (e.g. classification or regression), generative models map the composite probabilities of the variables and can thus be used to generate new data from the assumed population. established, generative methods are for example mixture models [ ] , hidden markov models [ ] and in the field of artificial neural networks restricted boltzmann machines [ ] . in the field of deep learning, generative models, in particular generative adversarial networks [ ] , are currently being researched and successfully applied in the context of image processing. conditional generative models can generalize the probability of occurrence of structural features under given material properties. in this way, if desired, any number of microstructures could be generated. based on the work on the spm, the process path optimization in the context of the msd is treated depending on the material properties. for this purpose, the process is regarded as a sequence of structure-changing process operations which correspond to elementary processing steps. shaffer et al. [ ] construct a so called texture evolution network based on process simulation samples, to represent the process. the texture evolution network can be considered as a graph with structures as vertices, connected by elementary processing steps as edges. the structure vertices are points in the structure-space and are mapped to the property-space by using the spm for property driven process path optimization. in [ ] one-step deformation processes are optimized to reach the most reachable element of a texture-set from the inverse spm. processes are represented by so called process planes, principal component analysis (pca) projections of microstructures reachable by the process. the optimization then is conducted by searching for the process plane which best represents one of the texture-set elements. in [ ] , a generic ontology based semantic system for processing path hypothesis generation (matcalo) is proposed and showcased. the required mapping of the structures to the properties is modeled based on data from simulations. the simulations are based on taylor models. the structures are represented using textures in the form of orientation density functions (odf), from which the properties are calculated. in the investigations, elastic and plastic properties are considered in particular. structural features are extracted from the odf for a more compact description. the project uses spectral methods such as generalized spherical harmonics (gsh) to approximate the odf. as an alternative representation we investigate the discretization in the orientation-space, where the orientation density is represented by a histogram. the solution of the inverse problem consists of a structure-property-mapping and an optimizer: as [ ] described, the spm is modeled by regression using artificial neural networks. in this investigation, we use a multilayer perceptron. differential evolution (de) is used for the optimization problem. de is an evolutionary algorithm developed by rainer storn and kenneth price [ ] . it is a optimization method, which repeatedly improves a candidate solution set under consideration of a given quality measure over a continuous domain. the de algorithm optimizes a problem by taking a population of candidate solutions and generating new candidate solutions (structures) by mutation and recombination existing ones. the candidate solution with the best fitness is considered for further processing. so, for the generated structures the reached properties are determined using the spm. the fitness f is composed of two terms: the property loss l p , which expresses, how close the property of a candidate is to the target property, and the structure loss l s , which represents the degree of feasibility of the candidate structure in the process the property loss is the mean squared error (mse) between the reached properties p r ∈ p r and the desired properties p d ∈ p d : considering the goal that the genetic algorithm generates reachable structures, a neural network is formed which functions as an anomaly detector. the data basis of this neural network are structures that can be reached by a process. the goal of anomaly detection is to exclude unreachable structures. the anomaly detection is implemented using an autoencoder [ ] . this is a neural network (see fig. ) which consists of the following two parts: the encoder and the decoder. the encoder converts the input data to an embedding space. the decoder converts the embedding space as close as possible to the original data. due to the reduction to an embedding space, the autoencoder uses data compression and extracts relevant features. the cost function for the structures is a distance function in the odf-space, which penalizes the network if it produces outputs that differ from the input. the cost function is also known as the reconstruction loss: with s i ∈ s as the original structures,ŝ i ∈ˆ s as the reconstructed structures and λ = . to avoid division by zero. when using the anomaly detection, the autoencoder determines a high reconstruction loss if the input data are structures that are very different from the reachable structures. the overall approach is shown in fig. and consists of the following steps: . the genetic algorithm generates structures. . the spm determines the reached properties of the generated structures. . the structure loss l s is determined by the reconstruction loss of the anomaly detector for the generated structures with respect to the reachable structures. . the property loss l p is determined by the mse of the reached properties and the desired properties. . the fitness is calculated as the sum of the structure loss l s and the property loss l p . the structures, resulting from the described approach form the basis for optimal process control. due to the forward mapping, the process evolution optimization based on texture evolution networks ( [ ] ) is restricted to a-priori sampled process paths. [ ] relies on linearization assumptions and is applicable to short process sequences only. [ ] relies on a-priori learned process models in the form of regression trees and is also applicable to relatively short process sequences only. ur-ai // as an adaptive alternative for texture evolution optimization, that can be trained to find process-paths of arbitrary length, we propose methods from reinforcement learning. for desired material properties p d . the inverted spm determines a set of goal microstructures s d ∈ g, which are very likely reachable by the considered deformation process. the texture evolution optimization objective is then to find the shortest process path p * starting from a given structure s , and leading close to one of the structures from g. where p = (a k ) k= ,...,k ; k t is a path of process actions a, t is the maximum allowed process length. the mapping e(s, p) = s k delivers the resulting structure, when applying p to the structure s. here, for the sake of simplicity, we assume the process to be deterministic, although the reinforcement learning methods we use are not restricted to deterministic processes. g τ is a neighbourhood of g, the union of all open balls with radius τ and center points from g. to solve the optimization problem by reinforcement learning approaches, it must be reformulated as markov decision process (mdp), which is defined by the tuple (s, a, p, r). in our case s is the space of structures s, a is the parameter-space of the deformation process, containing process actions a, p : s × a → s is the transition function of the deformation process, which we assume to be deterministic. r g : s × a → r is a goalspecific reward function. the objective of the reinforcement learning agent is then to find the optimal goal-specific policy π * g (s t ) = a t that maximizes the discounted future goal-specific reward where γ ∈ [ , ] discounts early attained rewards, the policy π g (s k ) determines a k and the transition function p (s k , a k ) determines s k+ . for a distance function d in the structure space, the binary reward function r g (s, a) = , if d(p (s, a), g) < τ , otherwise ( ) if maximized, leads to an optimal policy π * g that yields the shortest path to g from every s for γ < . moreover, if v g is given for every microstructure from g, p from eq. is identical with the application of the policy π * ζ , where ζ = arg max g [v g ]. π * g can be approached by methods from reinforcement learning. value-based reinforcement learning is doing so by learning expected discounted future reward functions [ ] . one of these functions is the so called value-function v . in the case of a deterministic mdp and for a given g, this expectation value function reduces to v g from eq. and ζ can be extracted if v is learned for every g from g. for doing so, a generalized form of expectation value functions can be learned as it is done e.g. in [ ] . this exemplary mdp formulation shows how reinforcement learning can be used for texture evolution optimization tasks. the optimization thereby is operating in the space of microstructures and does not rely on a-priori microstructure samples. when using off-policy reinforcement learning algorithms and due to the generalization over goal-microstructures, the functions learned while solving a specific optimization task can be easily transferred to new optimization tasks (i.e. different desired properties or even a different property space). industrial robots are mainly deployed in large-scale production, especially in the automotive industry. today, there are already . industrial robots deployed per , employees on average in these industry branches. in contrast, small and medium-sized enterprises (smes) only use . robots per , employees [ ] . reasons for this low usage of industrial robots in smes include the lack of flexibility with great variance of products and the high investment expenses due to additional peripherals required, such as gripping or sensor technology. the robot as an incomplete machine accounts for a fourth of the total investment costs [ ] . due to the constantly growing demand of individualized products, robot systems have to be adapted to new production processes and flows [ ] . this development requires the flexibilization of robot systems and the associated frequent programming of new processes and applications as well as the adaption of existing ones. robot programming usually requires specialists who can adapt flexibly to different types of programming for the most diverse robots and can follow the latest innovations. in contrast to many large companies, smes often have no in-house expertise and a lack of prior knowledge with regard to robotics. this often has to be obtained externally via system integrators, which, due to high costs, is one of the reasons for the inhibited use of robot systems. during the initial generation or extensive adaption of process flows with industrial robots, there is a constant risk of injuring persons and damaging the expensive hardware components. therefore, the programs have to be tested under strict safety precautions and usually in a very slow test mode. this makes the programming of new processes very complex and therefore time-and cost-intensive. the concept presented in this paper combines intuitive, gesture-based programming with simulation of robot movements. using a mixed reality solution, it is possible to create a simulation-based visualization of the robot and project, to program and to test it in the working environment without disturbing the workflow. a virtual control panel enables the user to adjust, save and generate a sequence of specific robot poses and gripper actions and to simulate the developed program. an interface to transfer the developed program to the robot controller and execute it by the real robot is provided. the paper is structured as follows. first, a research on related work is conducted in section , followed by a description of the system of the gesture-based control concept in section . the function of robot positioning and program creation is described in section . last follow the evaluation in section and conclusion in section . various interfaces exist to program robots, such as lead-trough, offline or walk-trough programming, programming by demonstration, vision based programming or vocal commanding. in the survey of villani et al. [ ] a clear overview on existing interfaces for robot programming and current research is provided. besides the named interfaces, the programming of robots using a virtual or mixed reality solution aims to provide intuitiveness, simplicity and accessibility of robot programming for non-experts. designed for this purpose, guhl et al. [ ] developed a generic architecture for human-robot interaction based on virtual and mixed reality. in the marker tracking based approach presented by [ ] and [ ] , the user defines a collision-free-volume and generates and selects control points while the system creates and visualizes a path through the defined points. others [ ] , [ ] , [ ] and [ ] use handheld devices in combination with gesture control and motion tracking. herein, the robot can be controlled through gestures, pointing or via the device, while the path, workpieces or the robot itself are visualized on several displays. other gesture and virtual or mixed reality based concepts are developed by cousins et al. [ ] or tran et al. [ ] . here, the robots perspective or the robot in the working environment is presented to the user on a display (head-mounted or stationary) and the user controls the robot via gestures. further concepts using a mixed reality method enable an image of the workpiece to be imported into cad and the system automatically generates a path for robot movements [ ] or visualizing the intended motion of the robot on the microsoft hololens, that the user knows where the robot will move to next [ ] . other methods combine pointing at objects on an screen with speech instructions to control the robot [ ] . sha et al. [ ] also use a virtual control panel in their programming method, but for adjusting parameters and not for controlling robots. another approach pursues programming based on cognition, spatial augmented reality and multimodal input and output [ ] , where the user interacts with a touchable table. krupke et al. [ ] developed a concept in which humans can control the robot by head orientation or by pointing, both combined with speech. the user is equipped with a head-mounted display presenting a virtual robot superimposed over the real robot. the user can determine pick and place position by specifying objects to be picked by head orientation or by pointing. the virtual robot then executes the potential pick movement and after the user confirms by voice command, the real robot performs the same movement. a similar concept based on gesture and speech is persued by quintero et al. [ ] , whose method offers two different types of programming. on the one hand, the user can determine a pick and place position by head orientation and speech commands. the system automatically generates a path which is displayed to the user, can be manipulated by the user and is simulated by a virtual robot. on the other hand, it is possible to create a path on a surface by the user generating waypoints. ostanin and klimchik [ ] introduced a concept to generate collision-free paths. the user is provided with virtual goal points that can be placed in the mixed reality environment and between which a path is automatically generated. by means of a virtual menu, the user can set process parameters such as speed, velocity etc.. additionally, it is possible to draw paths with a virtual device and the movement along the path is simulated by a virtual robot. differently to the concept described in this paper, only a pick and place task can be realized with the concepts of [ ] and [ ] . a differentiation between movements to positions and gripper commands as well as the movement to several positions in succession and the generation of a program structure are not supported by these concepts. another distinction is that the user only has the possibility to show certain objects to the robot, but not to move the robot to specific positions. in [ ] a preview of the movement to be executed is provided, but the entire program (pick and place movements) is not simulated. in contrast to [ ] , with the concept presented in this paper it is possible to integrate certain gripper commands into the program. with [ ] programming method, the user can determine positions but exact axis angles or robot poses cannot be set. overall, the approach presented in this paper offers an intuitive, virtual user interface without the use of handheld devices (cf. [ ] , [ ] , [ ] , [ ] , [ ] and [ ] ) which allows the exact positions of the robot to be specified. compared to other methods, such as [ ] , [ ] , [ ] , [ ] or [ ] , it is possible to create more complex program structures, which include the specification of robot poses and gripper positions, and to simulate the program in a mixed reality environment with a virtual robot. in this section the components of the mixed reality robot programming system are introduced and described. the system consists of multiple real and virtual interactive elements, whereby the virtual components are projected directly into the field of view using a mixed reality (mr) approach. compared to the real environment, which consists entirely of real objects and virtual reality (vr), which consists entirely of virtual objects and which overlays the real reality, in mr the real scene here is preserved and only supplemented by the virtual representations [ ] . in order to interact in the different realities, head-mounted devices similar to glasses, screens or mobile devices are often used. figure provides an overview of the systems components and their interaction. the system presented in this paper includes kukas collaborative, lightweight robot lbr iiwa r combined with an equally collaborative gripper from zimmer as real components and a virtual robot model and a user interface as virtual components. the virtual components are presented on the microsoft hololens. for calculation and rendering the robot model and visualization of the user interface, the d-and physics-engine of the unity d development framework is used. furthermore, for supplementary functions, components and for building additional mr interactable elements, the microsoft mixed reality toolkit (mrtk) is utilized. for spatial positioning of the virtual robot, marker tracking is used, a technique supported by the vuforia framework. in this use case, the image target is attached to the real robot's base, such that in mr the virtual robot superimposes the real robot. the program code is written in c . the robot is controlled and programmed via an intuitive and virtual user interface that can be manipulated using the so-called airtap gesture, a gesture provided by microsoft hololens. ur-ai // to ensure that the virtual robot mirrors the motion sequences and poses of the real robot, the most exact representation of the real robot is employed. the virtual robot consists of a total of eight links, matching the base and the seven joints of iiwa r : the base frame, five joint modules, the central hand and the media flange. the eight links are connected together as a kinematic chain. the model is provided as open source files from [ ] and [ ] and is integrated into the unity d project. the individual links are created as gameobjects in a hierarchy, with the base frame defining the top level and are limited similar to those of the real robot. the cad data of the deployed gripping system is also imported into unity d and linked to the robot model. the canvas of the head-up displayer of the microsoft hololens is divided into two parts and rendered at a fixed distance in front of the user and on top of the scene. at the top left side of the screen the current joint angles (a to a ) are displayed and on the left side the current program is shown. this setting simplifies the interaction with the robot as the informations do not behave like other objects in the mr scene, but are attached to the head up display (hud) and move with the user's field of view. the user interface, which consists of multiple interactable components, is placed into the scene and is shown at the right side of the head-up display. at the beginning of the application the user interface is in "clear screen" mode, i.e. only the buttons "drag", "cartesian", "joints", "play" and "clear screen" and the joint angles at the top left of the screen are visible. for interaction with the robot, the user has to switch into a particular control mode by tapping the corresponding button. the user interface provides three different control modes for positioning the virtual robot: -drag mode, for rough positioning, -cartesian mode, for cartesian positioning and -joint mode, for the exact adjustment of each joint angle. figure shows the interactable components that are visible and therefore controllable in the respective control modes. depending on the selected mode, different interactable components become visible in the user interface, with whom the virtual robot can be controlled. in addition to the control modes, the user interface offers further groups of interactable elements: -motion buttons, with which e.g. the speed of the robot movement can be adjusted or the robot movement can be started or stopped, -application buttons, to save or delete specific robot poses, for example, -gripper buttons, to adjust the gripper and -interface buttons, that enable communication with the real robot. this section focuses on the description of the usage of the presented approach. in addition to the description of the individual control modes, the procedure for creating a program is also described. as outlined in section . , the user interface consists of three different control modes and four groups of further interactable components. through this concept, the virtual robot can be moved efficiently to certain positions with different movement modes, the gripper can be adjusted, the motion can be controlled and a sequence of positions can be chained. drag by gripping the tool of the virtual robot with the airtap gesture, the user can "drag" the robot to the required position. additionally, it is possible to rotate the position of the robot using both hands. this mode is particularly suitable for moving the robot very quickly to a certain position. cartesian this mode is used for the subsequent positioning of the robot tool with millimeter precision. the tool can be translated to the required positions using the cartesian coordinates x, y, z and the euler angles a, b, c. the user interface provides a separate slider for each of the six translation options.the tool of the robot moves analogously to the respective slider button, which the user can set to the required value. joints this mode is an alternative to the cartesian method for exact positioning. the joints of the virtual robot can be adjusted precisely to the required angle, which is particularly suitable for e.g. bypassing an obstacle. there is a separate slider for each joint of the virtual robot. in order to set the individual joint angles, the respective slider button is dragged to the required value, which is also displayed above the slider button for better orientation. to program the robot, the user interface provides various application buttons, such as saving and removing robot poses from the chain and a display of the poses in the chain. the user directs the virtual robot to the desired position and confirms using the corresponding button. the pose of the robot is then saved as joint angles from a to a and one gripper position in a list and is displayed on the left side of the screen. when running the programmed application, the robot moves to the saved robot poses and gripper positions according to the defined sequence. for a better orientation, the robots current target position changes its color from white to red. after testing the application, the list of robot poses can be sent to the controller of the real robot via a webservice. the real robot then moves analogously to the virtual robot to the corresponding robot poses and gripper positions. the purpose of the evaluation is how the gesture-based control concept compares to other concepts regarding intuitiveness, comfort and complexity. for the evaluation, a study was conducted with seven test persons, who had to solve a pick and place task with five different operating concepts and subsequently evaluate them. the developed concept based on gestures and mr was evaluated against a lead through procedure, programming with java, programming with a simplified programming concept and approaching and saving points with kuka smartpad. the test persons had no experience with microsoft hololens and mr, no to moderate experience with robots and no to moderate programming skills. the questionnaire for the evaluation of physical assistive devices (quead) developed by schmidtler et al [ ] was used to evaluate and compare the five control concepts. the questionnaire is classified into five categories (perceived usefulness, perceived ease of use, emotions, attitude and comfort) and contains a total of questions, rated on an ordinal scale from (entirely disagree) to (entirely agree). firstly, each test person received a short introduction to the respective control concept, conducted the pick and place task and immediately afterwards evaluated the respective control concept using quead. all test persons agreed that they would reuse the concept in future tasks ( mostly agree, entirely agree). in addition, the test persons considered the gesture-based concept to be intuitive ( mostly agree, entirely agree), easy to use ( mostly agree, entirely agree) and easy to learn ( mostly agree, entirely agree). two test persons mostly agree and four entirely agree that the gesture-based concept enabled them to solve the task efficiently and four test persons mostly agree and two entirely agree that the concept enhances their work performance. all seven subjects were comfortable using the gesturebased concept ( mostly agree, entirely agree). overall, the concept presented in this paper was evaluated as more comfortable, more intuitive and easier to learn than the other control concepts evaluated. in comparison to them, the new operating concept was perceived as the most useful and easiest to use. the test persons felt physically and psychologically most comfortable when using the concept and were most positive in total. in this paper, a new concept for programming robots based on gestures and mr and for simulating the created applications was presented. this concept forms the basis for a new, gesture-based programming method, with which it is possible to project a virtual robot model of the real robot into the real working environment by means of a mr solution, to program it and to simulate the workflow. using an intuitive virtual user interface, the robot can be controlled by three control modes and further groups of interactable elements and via certain functions, several robot positions can be chained as a program. by using this concept, test and simulation times can be reduced, since on the one hand the program can be tested directly in the mr environment without disturbing the workflow. on the other hand, the robot model is rendered into the real working environment via the mr approach, thus eliminating the need for time-consuming and costly modeling of the environment. the results of the user study indicate that the control concept is easy to learn, intuitive and easy to use. this facilitates the introduction of robots and especially in smes, since no expert knowledge is required for programming, programs can be created rapidly and intuitively and processes can be adapted flexibly. in addition, the user study showed that tasks can be solved efficiently and the concept is perceived as performance-enhancing. potential directions of improvement are: implement various movement types, such as point-to-point, linear and circular movements in the concept. this makes the robot motion more flexible and efficient, since positions can be approached in different ways depending on the situation. another improvement is to extend the concept with collaborative functions of the robot, such as force sensitivity or the ability to conduct search movements. in this way, the functions that make collaborative robots special can be integrated into the program structure. a further approach for improvement is to engage in a larger scale study. in the world's commercial fleet consists of , ships with a total capacity of , , thousand dwt. (a plus of . % in carrying capacity compared to last year) [ ] . according to the international chamber of shipping, the shipping industry is responsible for about % of all trade [ ] . in order to ensure the safe voyage of all participant in the international travel at sea, the need for monitoring is steadily increasing. while more and more data regarding the sea traffic is collected by using cheaper and more powerful sensors, the data still needs to be processed and understood by human operators. in order to support the operators, reliable anomaly detection and situation recognition systems are needed. one cornerstone for this development is a reliable automatic classification of vessels at sea. for example by classifying the behaviour of non cooperative vessels in ecological protected areas, the identification of illegal, unreported and unregulated (iuu) fishing activities is possible. iuu fishing is in some areas of the world a major problem, e. g., »in the wider-caribbean, western central atlantic region, iuu fishing compares to - percent of the legitimate landings of fish« [ ] resulting in an estimated value between usd and million per year. one approach for gathering information on the sea traffic is based on the automatic identification system (ais) . it was introduced as a collision avoidance system. as each vessel is broadcasting its information on an open channel, the data is often used for other purposes, like training and validating of machine learning models. ais provides dynamic data like position, speed and course over ground, static data like mmsi , shiptype and length, and voyage related data like draught, type of cargo, and destination about a vessel. the system is self-reporting, it has no strong verification of transmission, and many of the fields in each message are set by hand. therefore, the data can not be fully trusted. as harati-mokhtari et al. [ ] stated, half of all ais messages contain some erroneous data. as for this work, the dataset is collected by using the ais stream provided by aishub , the dataset is likely to have some amount of false data. while most of the errors will have no further consequences, minor coordinate inaccuracies or wrong vessel dimensions are irrelevant, some false information in vessel information can have an impact on the model performance. classification of maritime trajectories and the detection of anomalies is a challenging problem, e.g., since classifications should be based on short observation periods, only limited information is available for vessel identification. riveiro et al. [ ] give a survey on anomaly detection at sea, where shiptype classification is a subtype. jiang et al. [ ] present a novel trajectorynet capable of point-based classification. their approach is based on the usage of embedding gps coordinates into a new feature space. the classification itself is accomplished using an long short-term memory (lstm) network. further, jiang et al. [ ] propose a partition-wise lstm (plstm) for point-based binary classification of ais trajectories into fishing or non-fishing activity. they evaluated their model against other recurrent neural networks and achieve a significantly better result than common recurrent network architectures based on lstm or gated recurrent units. a recurrent neural network is used by nguyen et al. in [ ] to reconstruct incomplete trajectories, detect anomalies in the traffic data and identify the real type of a vessel. they are embedding the position data to generate a new representation as input for the neural network. besides these neural network based approaches, other methods are also used for situation recognition tasks in the maritime domain. especially expert-knowledge based systems are used frequently, as illegal or at least suspicious behaviour is not recorded as often as desirable for deep learning approaches. conditional random fields are used by hu et al. [ ] for the identification of fishing activities from ais data. the data has been labelled by an expert and contains only longliner fisher boats. saini et al. [ ] propose an hidden markov model (hmm) based approach to the classification of trajectories. they combine global-hmm and segmental-hmm using a genetic algorithm. in addition, they tested the robustness of the framework by adding gaussian noise. in [ ] fischer et al. introduce a holistic approach for situation analysis based on situation-specific dynamic bayesian networks (ssdbn). this includes the modelling of the ssdbn as well as the presentation to end-users. for a bayesian network, the parametrisation of the conditional probability tables is crucial. fischer introduces an algorithm for choosing these parameters in a more transparent way. important for the functionality is the ability of the network to model the domain knowledge and the handling of noisy input data. for the evaluation, simulated and real data is used to assess the detection quality of the ssdbn. based on dbns, anneken et al. [ ] implemented an algorithm for detecting illegal diving activities in the north sea. as explained by de rosa et al. [ ] an additional layer for modelling the reliability of different sensor sources is added to the dbn. in order to use the ais data, preprocessing is necessary. this includes cleaning wrong data, filtering data, segmentation, and calculation of additional features. the whole workflow is depicted in figure . the input in form of ais data and different maps is shown as blue boxes. all relevant mmsis are extracted from the ais data. for each mmsi, the position data is used for further processing. segmentation into separate trajectories is the next step (yellow). the resulting trajectories are filtered (orange). based on the remaining trajectories, geographic (green) and trajectory (purple) based features are derived. for each of the resulting sequences, the data is normalized (red), which results in the final dataset. only the major shiptypes in the dataset are used for the evaluation. these are "cargo", "tanker", "fishing", "passenger", "pleasure craft" and "tug". due to their similar behaviour, "cargo" and "tanker" will combined to a single class "cargo-tanker". figure : visualization of all preprocessing steps. input in blue, segmentation in yellow, filtering in orange, geographic features in green, trajectory feature in purple and normalization in red. four different trajectory features are used: ur-ai // -time difference -speed over ground -course over ground -trajectory transformation as the incoming data from ais is not necessarily uniformly distributed in time, there is a need to create a feature representing the time dimension. therefore, the time difference between two samples is introduced. as the speed and course over ground is directly accessible through the ais data, the network will be directly fed with these features. the vessel's speed is a numeric value in . -knot resolution in the interval [ ; ] and the course is the negative angle in degrees relative to true north and therefore in the interval [ ; ]. the position will be transformed in two ways. the first transformation, further called "relative-to-first", will shift the trajectory to start at the origin. the second transformation, henceforth called "rotate-to-zero", will rotate the trajectory, in such a way, that the end point is on the x-axis. additional to the trajectory based features, two geographic features are derived by using coastline maps and a map of large harbours. the coastline map consists of a list of line strips. in order to reduce complexity, the edge points are used to calculate the "distance-to-coast". further, only a lower resolution of the shapefile itself is used. in figure , the resolution "high" and "low" for some fjords in norway are shown. due to the geoindex' cell size set to km, a radius of km can be queried. the world's major harbours based on the world port index are used to calculate the "distance-to-closest-harbor". as fishing vessels are expected to stay near to a certain harbour, this feature should support the network to identify some shiptypes. the geoindex' cell size is set for this feature to , km, resulting in a maximum radius of , km. the data is split into separate trajectories by using gaps in either time or space, or the sequence length. as real ais data is used, package loss during the transmission is common. this problem is tackled by splitting the data if the time between two successive samples is larger than hours, or if the distance between two successive samples is large. regarding the distance, even though the great circle distance is more accurate, the euclidean distance is used. for simplification the distance value is squared and as a threshold − is used. depending on latitude this corresponds to a value of about km at the equator and only about m at • n. since the calculation includes approximation a relatively high threshold is chosen. as the neural network depends on a fixed input size, the data is split into fitting chunks by cutting and padding with these rules: -longer sequences are split into chunks according to the desired sequence length. -any left over sequence shorter than % of the desired length is discarded. -the others will be padded with zeroes. this results in segmented trajectories of similar but not necessarily same duration. as this work is about the vessel behaviour at sea, stationary vessels (anchored and moored vessels) and vessels traversing rivers are removed from the segmented trajectories. the stationary vessels are identified by using a measure of movement in a trajectory: where n as the sequence length and p i its data points. a trajectory will be removed if α stationary is below a certain threshold. a shapefile containing the major and most minor rivers (compare ??) is used in order to remove the vessels not on the high seas. a sequence with more than % of its points on a river is removed from the dataset. in order to speed up the training process, the data is normalized in the interval [ ; ] by applying here, for the positional features a differentiation between "global normalization" and "local normalization" is taken into account. the "global normalization" will scale the input data for the maximum x max and minimum x min calculated over the entire data set, while "local normalization" will estimate the maximum x max and minimum x min only over the trajectory itself. as the data is processed parallel, the parameters for the "global normalization" will be calculated only for each chunk of data. this will result in slight deviations in the minimum and maximum, but for large batches this should be neglectable. all other additional features are normalized as well. for the geographic features "distance-to-coast" and "distance-to-closest-harbor" the maximum distance, that can be queried depending on grid size, is used as x max and is used as the lower bound x min . the time difference feature is scaled using a minimum x min of and the threshold for the temporal gap since this is the maximum value for this feature. speed and course are normalized using and their respective maximum values. for the dataset, a period between - - and - - is used. altogether , unique vessels with , , , raw data points are included. using this foundation and the previously described methods, six datasets are derived. all datasets use the same spatial and temporal thresholds. in addition, filter thresholds are identical as well. the datasets differentiate in their sequence length and by applying only the "relativeto-first" transformation or additionally the "rotate-to-zero" transformation. either , , , or , points per sequence are used resulting in approximate h, h, or h long sequences. in figure , the distribution of shiptypes in the datasets after applying the different filters is shown. for the shiptype classification, neural networks are chosen. the different networks are implemented using keras [ ] with tensorflow as backend [ ] . fawaz et al. [ ] have shown, that, despite their initial design for image data, a residual neural network (resnet) can perform quite well on time-series classification. thus, as foundation for the evaluated architectures the resnet is used. the main difference to other neural network architectures is the inclusion of "skip connections". this allows for deeper networks by circumventing the vanishing gradient problem during the training phase. based on the main idea of a resnet, several architectures are designed and evaluated for this work. some information regarding the structure are given in table . further, the single architectures are depicted in figures a to f . the main idea behind these architectures is to analyse the impact of the depth of the networks. furthermore, as the features itself are not necessarily logically linked with each other, the hope is to be able to capture the behaviour better by splitting up the network path for each feature. to verify the necessity of cnns two multilayer perceptron (mlp) based networks are tested: one with two hidden layers and one with four hidden layers, all with neurons and fully connected with their adjacent layers. the majority of the parameters for the two networks are bound in the first layer. they are necessary to map the large number of input neurons, e. g., for the samples dataset * = , input neurons, to the first hidden layer. each of the datasets is split into three parts: % for the training set, % for the validation set, and % for the test set. for solving or at least mitigating the problem of overfitting, regularization techniques (input noise, batch normalization, and early stopping) are used. small noise on the input in the training phase is used to support the generalization of the network. for each feature a normal distribution with a standard deviation of . and a mean of is used as noise. furthermore, batch normalization is implemented. this means, before each relulayer a batch normalization layer is added, allowing higher learning rates. therefore, the initial learning rate is doubled. additionally, the learning rate is halved if the validation error does not improve after ten training epochs, improving the training behaviour during oscillation on a plateau. in order to prevent overfitting, an early stopping criteria is introduced. the training will be interrupted if the validation error is not decreasing after training epochs. to counter the dataset imbalance, class weights were considered but ultimately did not lead to better classification results and were discarded. the different neural network architectures are evaluated on a amd ryzen threadripper batch normalization and the input noise is tested. the initial learning rate is set to . without batch normalization and . with batch normalization activated. the maximum number of epochs is set to . the batch sizes are set to , , and for , , , and , samples per sequence respectively. in total different setups are evaluated. furthermore, additional networks are trained on the samples dataset with "relative-to-first" transformation. two mlps to verify the need of deep neural networks, and the shallow and deep resnet trained without geographic features to measure the impact of these features. (f) "rtz" with , samples shown. the first row shows the results for the "relative-to-first" (rtf) transformation, the second for the "rotate-to-zero" (rtz) transformation. the results for the six different architectures are depicted in figure . for samples the shallow resnet and the deep resnet outperformed the other networks. in case of the "relative-to-first" transformation (see figure a ), the shallow resnet achieved an f -score of . , while the deep resnet achieved . . for the "rotate-to-zero" transformation (see figure d ), the deep resnet achieved . and the shallow resnet . . in all these cases the regularization methods lead to no improvements. the "relative-to-first" transformation performs slightly better overall. for the datasets with samples per sequence, the standard resnet variants achieve higher f -scores compared to the split resnet versions. but this difference is relatively small. as expected, the tiny resnet is not large and deep enough to classify the data on a similar level. for the "relative-first" transformation and trajectories based on samples (see figure b ), the split resnet and the total split resnet achieve the best results. the first performed well with an f -score of . , while the latter is slightly worse with . . in both cases again the regularization did not improve the result. for the "rotateto-zero" transformation (see figure e ), the shallow resnet achieved an f -score of . without any regularization and . with only the the noise added to the input. for the largest sequence length of , samples, the split based networks slightly outperform the standard resnets. for the "relative-to-first" transformation (see figure c ), the split resnet achieved an f -score of . , while for the "rotate-to-zero" transformation (see figure f ) the total split resnet reached an f -score of . . again without noise and batch normalization. to verify, that the implementation of cnns is actually necessary, additional tests with mlps were carried out. two different mlps are trained on the samples dataset with "relative-to-first" transformation since this dataset leads to best results for the resnet architectures. both networks lead to no results as their output always is the "cargo-tanker" class regardless of the actual input. the only thing the models are able to learn is, that the "cargo-tanker" class is the most probable class based on the uneven distribution of classes. an mlp is not the right model for this kind of data and performs badly. the large dimensionality of even the small sequence length makes the use of the fully connected networks impracticable. probably, further hand-crafted feature extraction is needed to achieve better results. to measure the impact the feature "distance to coast" and "distance to closest harbor" have on the overall performance, a shallow resnet and a deep resnet are trained on the sample length data set with the "relative-to-first" transformation excluding these features. the trained networks have f -scores of . and . respectively. this means, by including this features, we are able to increase the performance by . %. the "relative-to-first" transformation compared to the "rotate-to-zero" transformation yields the better results. especially, this is easily visible for the longest sequence length. a possible explanation can be seen in the "stationary" filter. this filter removes more trajectories for the "relative-to-first" transformation than for the additional "rotate-to-zero" transformation. a problem might be, that the end point is used for rotating the trajectory. this adds a certain randomness to the data, especially for round trip sequences. in some cases, the stretched deep resnet is not able to learn the classes. it is possible, that there is a problem with the structure of the network or the large number of parameters. further, there seems to be a problem with the batch normalization, as seen in figures c and e . the overall worse performance of the "rotate-to-zero" transformation could be because of the difference in the "stationary" filter. in the "rotate-to-zero" dataset, fewer sequences are filtered out. the filter leads to more "fishing" and "pleasure craft" sequences in relation to each other as described in section . . this could also explain the difference in class prediction distribution since the network is punished more for mistakes in these classes because more classes are overall from this type. for the evaluation, the expectation based on previous work by other authors was, that the shorter sequence length should perform worse compared to the longer ones. instead the shorter sequences outperform the longer ones. the main advantages of the shorter sequences are essentially the larger number of sequences in the dataset. for example the samples dataset with "relative-to-first" transformation contains about . million sequences, while the corresponding , sample dataset contains only approximately , sequences. in addition, the more frequent segmentation can yield more easily classifiable sequences: the behaviour of a fishing vessel in general contains different characteristics, like travelling from the harbour to the fishing ground, the fishing itself, and the way back. the travelling parts are similar to other vessels and only the fishing part is unique. a more aggressive segmentation will yield more fishing sequences, that will be easier to classify regardless of observation length. the shallow resnet has the overall best results by using the samples dataset and the "relative-to-first" transformation. the results for this setup are shown in the confusion matrix in figure . as expected, the tiny resnet is not able to compete with the others. the other standard resnet architectures performed well, especially on shorter sequences. the split architectures are able to perform better on datasets with longer sequences, with the shallow resnet achieving similar performance. comparing the number of parameters, all three architectures have about , the shallow resnet about , more, the total split resnet about , less. only on the dataset with more sequences, the deep resnet performs well. this correlates with the need of more information due to the larger parameter count. due to the reduced flexibility, the split architecture can be interpreted as a "head start". this means, that the network has already information regarding the structure of the data, which in turn does not need to be extracted from the data. this can result in a better performance for smaller datasets. all in all, the best results are always achieved by omitting the suggested regularization methods. nevertheless, the batch normalization had an effect on the learning rate and needed training epochs: the learning rate is higher and less epochs are needed before convergence. based on the resnet, several architectures are evaluated for the task of shiptype classification. from the initial dataset based on ais data with over . billion datapoints six datasets with different trajectory length and preprocessing steps are derived. further to the kinematic information included in the dataset, geographical features are generated. each network architecture is evaluated with each of the datasets with and without batch normalization and input noise. overall the best result is an f -score of . with the shallow resnet on the samples per sequence dataset and a shift of the trajectories to the origin. additionally, we are able to show, that the inclusion of geographic features yield an improvement in classification quality. the achieved results are quite promising, but there is still some room for improvement. first of all, the the sequence length used for this work might still be too long for real world use cases. therefore, shorter sequences should be tried. additionally, interpolation for creating data with the same time delta between two samples or some kind of embedding or alignment layer might yield better results. as there are many sources for additional domain related information, further research in the integration of these sources is necessary. comparison of cnn for the detection of small ojects based on the example of components on an assembly many tasks which only a few years ago had to be performed by humans can now be performed by robots or will be performed by robots in the near future. nevertheless, there are some tasks in assembly processes which cannot be automated in the next few years. this applies especially to workpieces that are only produced in very small series or tasks that require a lot of tact and sensitivity, such as inserting small screws into a thread or assembling small components. in conversations with companies we have found out that a big problem for the workers is learning new production processes. this is currently done with instructions and by supervisors. but this requires a lot of time. this effort can be significantly reduced by modern systems, which accompany workers in the learning process. such intelligent systems require not only instructions that describe the target status and the individual work steps that lead to it, but also information on the current status at the assembly workstation. one way to obtain this information is to install cameras above the assembly workstation and use image recognition to calculate where an object is located at any given moment. the individual parts, often very small compared to the work surface, must be reliably detected. we have trained and tested several deep neural networks for this purpose. we have developed an assembly workstation where work instructions can be projected directly onto the work surface using a projector. at a distance, containers for components are arranged in three rows, slightly offset to the rear, one above the other. these containers can also be illuminated by the projector. thus a very flexible pick-by-light system can be implemented. in order for the system behind it to automatically switch to the next work step and, in the event of errors, to point them out and provide support in correcting them, it is helpful to be able to identify the individual components on the work surface. we use a realsense depth camera for this purpose, from which, however, we are currently only using the colour image. the camera is mounted in a central position at a height of about two meters above the work surface. thus the camera image includes the complete working surface as well as the containers and a small area next to the working surface. the objects to be detected are components of a kit for the construction of various toy cars. the kit contains components in total. some of the components vary considerably from each other, but some others are very similar to each other. since it is the same with real components of a production, the choice of the kit seemed appropriate for the purposes of this project. object detection, one of the most fundamental and challenging problems in computer vision, seeks to local object instances from a large number of predefined categories in natural images. until the beginning of , a similar approach was mostly used in object detection. keypoints in one or more images of a category were searched for automatically. at these points a feature vector was generated. during the recognition process, keypoints in the image were again searched, the corresponding feature vectors were generated and compared with the stored feature vectors. after a certain threshold an object was assigned to the category. one of the first approaches based on machine learning was published by viola and jones in [ ] . they still selected features, in their case they were selected by using a haar basis function [ ] and then using a variant of adaboost [ ] . starting in with the publication of alexnet by krizhevsky et al. [ ] , deep neural networks became more and more the standard in object detection tasks. they used a convolutional neural network which has million parameters in five convolutional layers, some of them are followed by max-pooling layers, three fully-connected layers and a final softmax layer. they won the imagenet lsvrc- competition with a error rate almost half as high as the second best. inception-v is mostly identical to inception-v by szegedy et al. [ ] . it is based on inception-v [ ] . all inception architectures are composed of dense modules. instead of stacking convolutional layers, they stack modules or blocks, within which are convolutional layers. for inception-v they redesigned the architecture of inception-v to avoid representational bottlenecks and have more efficient computations by using factorisation methods. they are the first using batch normalisation in object detection tasks. in previous architectures the most significant difference has been the increasing number of layers. but with the network depth increasing, accuracy gets saturated and then degrades rapidly. kaiming et al. [ ] addressed this problem with resnet using skip connections, while building deeper models. in howard et al. presented mobilenet architecture [ ] . mobilenet was developed for efficient work on mobile devices with less computational power and is very fast. they used depthwise convolutional layers for a extremely efficient network architecture. one year later sandler et al. [ ] published a second version of mobilenet. besides some minor adjustments, a bottleneck was added in the convolutional layers, which further reduced the dimensions of the convolutional layers. thus a further increase in speed could be achieved. in addition to the neural network architectures presented so far, there are also different methods to detect in which area of the image the object is located. the two most frequently used are described briefly below. to bypass the problem of selecting a huge number of regions, girshick et al. [ ] proposed a method where they use selective search by the features of the base cnn to extract just regions proposals from the image. liu et al. [ ] introduced the single shot multibox detector (ssd). they added some extra feature layers behind the base model for detection of default boxes in different scales and aspect ratios. at prediction time, the network generates scores for the presence of each object in each default box. then it produces adjustments to the box to better match the object shape. there is just one publication over the past few years which gives an survey of generic object detection methods. liu et al. [ ] compared common object detection architectures for generic object detection. there are many other comparisons of specific object detection tasks. for example pedestrian detection [ ] , face detection [ ] and text detection [ ] . the project is based on the methodology of supervised learning. thereby the models are trained using a training dataset consisting of many samples. each sample within the training dataset is tagged with a so called label (also called annotation). the label provides the model with information about the desired output for this sample. during training, the output generated by the model is then compared to the desired output (labels) and the error is determined. this error on the one hand gives information about the current performance of the model and, on the other hand it is used for further mathematical computations to adjust the model's parameters, so that the model's performance improves. for the training of neural networks in the field of computer vision the following rule of thumb applies: the larger and more diverse the training dataset, the higher the accuracy that can be achieved by the trained model. if you have too little data and/or run it through the model too often, this can lead to so-called overfitting. overfitting means that instead of learning an abstract concept that can be applied to a variety of data, the model basically memorizes the individual samples [ , ] . if you train neural networks for the purpose of this project from scratch, it is quite possible that you will need more than , different images -depending on the accuracy that the model should finally be able to achieve. however, the methodology of the so-called transfer learning offers the possibility to transfer results of neural networks, which have already been trained for a specific task, completely or partially to a new task and thus to save time and resources [ ] . for this reason, we also applied transfer learning methods within the project. the training dataset was created manually: a tripod, a mobile phone camera ( megapixel format x ) and an apeman action cam ( megapixel format x ) were used to take images for each of the classes. this corresponds to , images in total (actually images were taken per class, but only were suitable for use as training data). all images were documented and sorted into close-ups (distance between camera and object less than or equal to cm) and standards (distance between camera and object more than cm). this procedure should ensure the traceability and controllability of the data set. in total, the training data set contains approx. % close-ups and approx. % standards, each taken on different backgrounds and under different lighting conditions (see fig. ). the labelimg tool was used for the labelling of the data. with the help of this tool, bounding boxes, whose coordinates are stored in either yolo or pascval voc format, can be marked in the images [ ] . for the training of the neural networks the created dataset was finally divided into: ur-ai // -training data ( % of all labelled images): images that are used for the training of the models and that pass through the models multiple times during the training. -test data ( % of all labelled images): images that are used for later testing or validation of the training results. in contrast to the images used as training data, the model is presented these images for the first time after training. the goal of this approach, which is common in deep learning, is to see how well the neural network recognizes objects in images, that it has never seen before, after the training. thus it is possible to make a statement about the accuracy and to be able to meet any further training needs that may arise. the training of deep neural networks is very demanding on resources due to the large number of computations. therefore, it is essential to use hardware with adequate performance. since the computations that run for each node in the graph can be highly parallelized, the use of a powerful graphical processing unit (gpu) is particularly suitable. a gpu with its several hundred computing cores has a clear advantage over a current cpu with four to eight cores when processing parallel computing tasks [ ] . these are the outline parameters of the project computer in use: -operating system (os): ubuntu . . lts -gpu: geforce r gtx ti ( gb gddr x-memory, data transfer speed gbit/s) for the intended comparison the tensorflow object detection api was used. tensorflow object detection api is an open source framework based on tensorflow, which among other things provides implementations of pre-trained object detection models for transfer learning [ , ] . the api was chosen because of its good and easy to understand documentation and its variety of pre-trained object detection models. for the comparison the following models were selected: -ssd mobilenet v coco: [ , , ] -ssd mobilenet v coco: [ , , ] -faster rcnn inception v coco: [ ] [ ] [ ] -rfcn resnet coco: [ ] [ ] [ ] to ensure comparability of the networks, all of the selected pre-trained models were trained on the coco dataset [ ] . fundamentally, the algorithms based on cnn models can be grouped into two main categories: region-based algorithms and one-stage algorithms [ ] . while both ssd models can be categorized as one-stage algorithms, faster r-cnn and r-fcn fall into the category of region-based algorithms. one-stage algorithms predict both -the fields (or the bounding boxes) and the class of the contained objects -simultaneously. they are generally considered extremely fast, but are known for their trade-off between accuracy and real-time processing speed. region-based algorithms consist of two parts: a special region proposal method and a classifier. instead of splitting the image into many small areas and then working with a large number of areas like conventional cnn would proceed, the region-based algorithm first proposes a set of regions of interest (roi) in the image and checks whether one of these fields contains an object. if an object is contained, the classifier classifies it [ ] . region-based algorithms are generally considered as accurate, but also as slow. since, according to our requirements, both accuracy and speed are important, it seemed reasonable to compare models of both categories. besides the collection of pre-trained models for object detection, the tensorflow object detection api also offers corresponding configuration files for the training of each model. since these configurations have already shown to be successful, these files were used as a basis for own configurations. the configuration files contain information about the training parameters, such as the number of steps to be performed during training, the image resizer to be used, the number of samples processed as a batch before the model parameters are updated (batch size) and the number of classes which can be detected. to make the study of the different networks as comparable as possible, the training of all networks was configured in such a way that the number of images fed into the network simultaneously (batch size) was kept as small as possible. since the configurations of some models did not allow batch sizes larger than one, but other models did not allow batch sizes smaller than two, no general value for all models could be defined for this parameter. during training, each of the training images should be passed through the net times (corresponds to epochs). the number of steps was therefore adjusted accordingly, depending on the batch size. if a fixed shape resizer was used in the base configurations, two different dimensions of resizing (default: x pixels and custom: x pixels) were selected for the training. table gives an overview of the training configurations used for the training of the different models. in this section we will first look at the training, before we then focus on evaluating the quality of the results and the speed of the selected convolutional neural networks. when evaluating the training results, we first considered the duration that the neural networks require for epochs (see fig. ). it becomes clear that especially the two region based object detectors (faster r-cnn inception v and rfcn resnet ) took significantly longer than the single shot object detectors (ssd mobilenet v and ssd mobilenet v ). in addition, the single shot object detectors clearly show that the size of the input data also has a decisive effect on the training duration: while ssd mobilenet v with an input data size of x pixels took the shortest time for the training with hours minutes and seconds, the same neural network with an input data size of x pixels took almost three hours more for the training, but is still far below the time required by rfcn resnet for epochs of training. the next point in which we compared the different networks was accuracy (see fig. ). we focused on seeing which of the nets were correct in their detections and how often (absolute values), and we also wanted to see what proportion of the total detections were correct (relative values). the latter seemed to us to make sense especially because some of the nets showed more than three detections for a single object. the probability that the correct classification will be found for the same object with more than one detection is of course higher in this case than if only one detection per object is made. with regard to the later use at the assembly table, however, it does not help us if the neural net provides several possible interpretations for the classification of a component. figure shows that, in this comparison, the two region based object detectors generally perform significantly better than the single shot object detectors -both in terms of the correct detections and their share of the total detections. it is also noticeable that for the single shot object detectors, the size of the input data also appears to have an effect on the comparison point on the result. however, there is a clear difference to the previous comparison of the required training durations: while the training duration increased uniformly with increasing size of the images with the single shot object detectors, such a uniform observation cannot be made with the accuracy, concerning the relation to the input data sizes. while ssd mobilenet v achieves good results with an input data size of x pixels, ssd mobilenet v delivers the worst result of this comparison for the same input data size (regarding the number of correct detections as well as their share of the total detections). with an input data size of x pixels, however, the result improves with ssd mobilenet v , while the change to a smaller input data size has a deteriorating effect on the result with ssd mobilenet v . the best result of this comparison -judging by the absolute values -was achieved by faster r-cnn inception v . however, in terms of the proportion of correct detections in the total detections, the region based object detector is two percentage points behind rfcn resnet , also a region based object detector. we were particularly interested in how neural networks would react to particularly similar, small objects. therefore, we decided to investigate the behavior of neural networks within the comparison using an example to illustrate the behavior of the three very similar objects. figure shows the selected components for the experiment. for each of these three components we examined how often it was correctly detected and classified by the compared neural networks and how often the network misclassified it with which of the similar components. the first and the second component was detected in nearly all cases by both region based approaches. the classification by inception-v and resnet- failed in about one third of images. the ssd networks detected the object in just one of twenty cases but mobilenet classified this correct. it has been surprising, that the results for the third component looks very different to the others (see fig. ). ssd mobilenet v correctly identified the component in seven of ten images and did not produce any detections that could be interpreted as misclassifications with one of the similar components. ssd mobilenet v did not detect any of the three components, as in the two previous investigations. the results of the two region based object detectors are rather moderate. faster r-cnn inception v has detected the correct component in four of ten images, but still five misclassifications with the other two components. rfcn resnet has caused many misclassifications with the other two components. only two of ten images were correctly detected but it had six misclassifications with the similar components. an other important aspect of the study is the speed, or rather the speed at which the neural networks can detect objects, especially with regard to later use at the assembly table. for the comparison of the speeds on the one hand the data of the github repository of the tensorflow object detection api for the individual neural nets were used, on the other hand the actual speeds of the neural nets within this project were measured. it becomes clear that the speeds measured in the project are clearly below the achievable speeds that are mentioned in the github repository of the tensorflow object-detection api. on the other hand, the differences between the speeds of the region based object detectors and the single shot object detectors in the project are far less drastic than expected. we have created a training dataset with small, partly very similar components. with this we have trained four common deep neural networks. in addition to the training times, we examined the accuracy and the recognition time with general evaluation data. in addition, we examined the results for ten images each of three very similar and small components. none of the networks we trained produced suitable results for our scenario. nevertheless, we were able to gain some important insights from the results. at the moment, the runtime is not yet suitable for our scenario, but it is also not far from the minimum requirements, so that these can easily be achieved with smaller optimizations and better hardware. it was also important to realize that there are no serious runtime differences between the different network architectures. the two region based approaches delivered significantly better results than the ssd approaches. however, the results of the detection of the third small component suggest that mobilenet in combination with a faster r-cnn could possibly deliver even better results. longer training and training data better adapted to the intended use could also significantly improve the results of the object detectors. team schluckspecht from offenburg university of applied sciences is a very successful participant of the shell eco marathon [ ] . in this contest, student groups are to design and build their own vehicles with the aim of low energy consumption. since the event features the additional autonomous driving contest. in this area, the vehicle has to fulfill several tasks, like driving a parcour, stopping within a defined parking space or circumvent obstacles, autonomously. for the upcoming season, the schluckspecht v car of the so called urban concept class has to be augmented with the according hardware and software to reliably recognize (i. e. detect and classify) possible obstacles and incorporate them into the software framework for further planning. in this contribution we describe the additional components in hard-and software that are necessary to allow an opitcal d object detection. main criteria are accuracy, cost effectiveness, computational complexity for relative real time performance and ease of use with regard to incorporation in the existing software framework and possible extensibility. this paper consists of the following sections. at first, the schluckspecht v system is described in terms of hard-and software components for autonomous driving and the additional parts for the visual object recognition. the second part scrutinizes the object recognition pipeline. therefore, software frameworks, neural network architecture and final data fusion in a global map is depicted in detail. the contribution closes with an evaluation of the object recognition results and conclusions. the schluckspecht v is a self designed and self build vehicle according to the requirements of the eco marathon rules. the vehicle is depicted in figure . the main features are the relatively large size, including driver cabin, motor area and a large trunk, a fully equipped lighting system and two doors that can be opened separately. for the autonomous driving challenges, the vehicle is additionally equipped with several essential parts, that are divided into hardware, consisting of actuators, sensors, computational hardware and communication controllers. the software is based on a middle ware, can-open communication layers, localization, mapping and path planning algorithms that are embedded into a high level state machine. actuators the car is equipped with two actors, one for steering and one for braking. each actor is paired with sensors for measuring steering angle and braking pressure. environmental sensors several sensors are needed for localization and mapping. backbone is a multilayer d laser scanning system (lidar), which is combined with an inertial navigation system that consists of accelerometers, gyroscopes and magnetic field sensors all realized as triads. odometry information is provided from a global navigation satellite system (gnss) and two wheel encoders. the communication is based on two separate can-bus-systems, one for basic operations and an additional one for the autonomous functions. the hardware can nodes are designed and build from the team coupling usb-, i c-, spi-and can-open-interfaces. messages are send from the central processing unit or the driver depending on drive mode. the trunk of the car is equipped with an industrial grade high performance cpu and an additional graphics processing unit (gpu). can communication is ensured with an internal card, remote access is possible via generic wireless components. software structure the schluckspecht uses a modular software system consisting of several basic modules that are activated and combined within a high level state ma-chine as needed. an overview of the main modules and possible sensors and actuators is depicted in figure localization and mapping the schluckspecht v is running a simultaneous localization and mapping (slam) framework for navigation, mission planning and environment representation. in its current version we use a graph based slam approach based upon the cartographer framework developed by google [ ] . we calculate a dynamic occupancy grid map that can be used for further planning. sensor data is provided by the lidar, inertial navigation and odometry systems. an example of a drivable map is shown in figure . this kind of map is also used as base for the localization and placement of the later detected obstacles. the maps are accurate to roughly centimeters, providing relative localization towards obstacles or homing regions. path planning to make use of the slam created maps, an additional module calculates the motion commands from start to target pose of the car. the schluckspecht is a classical car like mobile system which means that the path planning must take into account the non holonomic kind of permitted movement. parking maneuvers, close by driving on obstacles or planning a trajectory between given points is realized as a combination of local control commands based upon modeled vehicle dynamics, the so called local planner, and optimization algorithms that find the globally most cost efficient path given a cost function, the so called global planner. we employ a kinodynamic strategy, the elastic band method presented in [ ] , for the local planning. global planning is realized with a variant of the a* algorithm as described in [ ] . middleware and communication all submodules, namely, localization, mapping, path planning and high-level state machines for each competition are implemented within ur-ai // the robot operating system (ros) middleware [ ] . ros provides a messaging system based upon the subscriber/publisher principle. the single modules are capsuled in a process, called node, capable to asynchronously exchange messages as needed. due to its open source character and an abundance on drivers and helper functions, ros provides additional features like hardware abstraction, device drivers, visualization and data storage. data structures for mobile robotic systems, e. g. static and dynamic maps or velocity control messages, allow for rapid development. the lidar sensor system has four rays, enabling only the incorporation of walls and track delimiters within a map. therefore, a stereo camera system is additionally implemented to allow for object detection of persons, other cars, traffic signs or visual parking space delimiters and simultaneously measure the distance of any environmental objects. camera hardware a zed-stereo-camera system is installed upon the car and incorporated into the ros framework. the system provides a color image streams for each camera and a depth map from stereo vision. the camera images are calibrated to each other and towards the depth information. the algorithms for disparity estimation are running around frames per second making use of the provided gpu. the object recognition relies on deep neural networks. to seamlessly work with the other software parts and for easy integration, the networks are evaluated with tensorflow [ ] and pytorch [ ] frameworks. both are connected to ros via the opencv image formats providing ros-nodes and -topics for visualization and further processing. the object recognition pipeline relies on a combination of mono camera images and calibrated depth information to determine object and position. core algorithm is a deep learning approach with convolutional neural networks. ur-ai // main contribution of this paper is the incorporation of a deep neural network object detector into our framework. object detection with deep neural networks can be subdivided into two approaches, one being a two step approach, where regions of interest are identified in a first step and classified in a second one. the second are so called single shot detectors (like [ ] ), that extract and classify the objects in one network run. therefore, two network architectures are evaluated, namely yolov [ ] as a single shot approach and faster r-cnn [ ] as two step model. all are trained on public data sets and fine tuned to our setting by incorporating training images from the schluckspecht v in the zed image format. the models are pre-selected due to their real time capability in combination with the expected classification performance. this excludes the current best instance segmentation network mask r-cnn [ ] due to computational burdens and fast but inaccurate networks based on the mobilenet backbone [ ] . the class count is adapted for the contest, in the given case eight classes, including the relevant pedestrian, car, van, tram and cyclist. for this paper, the two chosen network architectures were trained in their respective framework, i. e. darknet for the yolov detector and tensorflow for the faster r-cnn detector. yolov is used in its standard form with the darknet backbone, faster r-cnn is designed with the resnet [ ] backbone. the models were trained on local hardware with the kitti [ ] data set. alternatively, an open source data set from the teaching company udacity, with only three classes (truck, car, pedestrian) was tested. to deal with the problem of domain adaptation, the training images for yolov were pre-processed to fit the aspect ratio of the zed camera. the faster r-cnn net can cope with ratio variations as it uses a two stage approach for detection based on regions of interest pooling. both networks were trained and stored. afterward, their are incorporated into the system via a ros node making use of standard python libraries. the detector output is represented by several labeled bounding boxes within the d image. three dimensional information is extracted from the associated depth map by calculating the center of gravity of each box to get a x and y coordinate within the image. interpolating the depth map pixels accordingly one gets the distance coordinate z from the depth map to determine the object position p(x, y, z) in the stereo camera coordinate system. the ease of projection between dieeferent coordinate systems is one reason to use the ros middleware. the complete vehicle is modeled in a so calle tranform tree (tf-tree), that allows the direct interpolation between different coordinate systems in all six spatial degrees of freedom. the dynamic map, created in the slam subsystem, is now augmented with the current obstacles in the car coordinate system. the local path planner can take these into account and plan a trajectory including kinodynamic constraints to prevent collision or initiate a breaking maneuver. both newly trained networks were first evaluated upon the training data. exemplary results for the kitti data set are shown in figure . the results clearly indicate an advantage for the yolov system, both in speed and accuracy. the figure depicts good results for occlusions (e. g. the car on the upper right) or high object count (see the black car on the lower left as example). the evaluation on a desktop system showed fps for yolov and approximately fps for faster r-cnn. after validating the performance upon the training data, both networks were started as a ros node and tested upon real data of the schluckspecht vehicle. as the training data differs from the zed-camera images in format and resolution, several adaptions were necessary for the yolov detector. the images are cropped in real time before presented to the neural net to emulate the format of the training images. the r-cnn like two stage networks are directly connected to the zed node. the test data is not labeled as ground truth. it is therefore not possible to give quantitative results for the recognition task. table gives a quantitative overview of the object detection and classification, the subsequent figures give some expression of exemplary results. the evaluation on the schluckspecht videos showed an advantage for the yolov network. main reason is the faster computation, which results in a frame rate nearly twice as high compared to two stage detectors. in addition, the recognition of objects in the distance, i. e. smaller objects is a strong point of yolo. the closer the camera gets, the bigger is the balance shift towards faster r-cnn, that outperforms yolo on all categories for larger objects. what becomes apparent is a maximum detection distance of approximately meters, from which on cars become to small in size. figure shows an additional result demonstrating the detection power for partially obstructed objects. another interesting finding was the capability of the networks to generalize. faster r-cnn copes much better with new object instances than yolov . persons with so far unknown cloth color or darker areas with vehicles remain a problem for yolo, but ur-ai // commonly not for the r-cnn. the domain transfer from training data in berkeley and kitti to real zed vehicle images proved problematic. this contribution describes an optical object recognition system in hard-and software for the application in autonomous driving under restricted conditions, within the shell eco marathon competition. an overall overview of the system and the incorporation of the detector within the framework is given. main focus was the evaluation and implementation of several neural network detectors, namely yolov as one shot detector and faster r-cnn as a two step detector, and their combination with distance information to gain a three dimensional information for detected objects. for the given application, the advantage clearly lies with yolov . especially the achievable frame rate of minimum hz allows a seamless integration into the localization and mapping framework. given the velocities and map update rate, the object recognition and integration via sensor fusion for path planning and navigation works in quasi real-time. for future applications we plan to further increase the detection quality by incorporating new classes and modern object detector frameworks like m det [ ] . this will additionally increase frame rate and bounding box quality. for more complex tasks, the data of the d-lidar system shall be directly incorporated into the fusion framework to enhance the perception of object boundaries and object velocities. a few useful things to know about machine learning feature engineering for machine learning an empirical analysis of feature engineering for predictive modeling input selection for fast feature engineering random forests support vector regression machines strong consistency of least squares estimates in multiple regression ii business data science: combining machine learning and economics to optimize, automate, and accelerate business decisions global product classification (gpc) a study of cross-validation and bootstrap for accuracy estimation and model selection automatic liver and tumor segmentation of ct and mri volumes using cascaded fully convolutional neural networks convolutional networks for biomedical image segmentation v-net: fully convolutional neural networks for volumetric medical image segmentation self-supervised learning for pore detection in ct-scans of cast aluminum parts generating meaningful synthetic ground truth for pore detection in cast aluminum parts nema ps / iso , digital imaging and communications in medicine (dicom) standard, national electrical manufacturers association ct-realistic lung nodule simulation from d conditional generative adversarial networks for robust lung segmentation deep learning hardware: past, present, and future a survey on specialised hardware for machine learning a survey on distributed machine learning hardware for machine learning: challenges and opportunities d u-net: learning dense volumetric segmentation from sparse annotation z-net: an anisotropic d dcnn for medical ct volume segmentation activation functions: comparison of trends in practice and research for deep learning fast and accurate deep network learning by exponential linear units (elus) delving deep into rectifiers: surpassing human-level performance on imagenet classification toward deeper understanding of neural networks: the power of initialization and a dual view on expressivity adam: a method for stochastic optimization diffgrad: an optimization method for convolutional neural networks tversky loss function for image segmentation using d fully convolutional deep networks a low-power multi physiological monitoring". processor for stress detection. ieee sensors using heart rate monitors to detect mental stress positive technology: a free mobile platform for the self-management of psychological stress exploring the effectiveness of a computer-based heart rate variability biofeedback program in reducing anxiety in college students psychological stress and incidence of atrial fibrillation continuously updated, computationally efficient stress recognition framework using electroencephalogram (eeg) by applying online multitask learning algorithms (omtl) ten years of research with the trier social stress test trapezius muscle emg as predictor of mental stress poptherapy: coping with stress through pop-culture du-md: an open-source human action dataset for ubiquitous wearable sensors stress recognition using wearable sensors and mobile phones introducing wesad, a multimodal dataset for wearable stress and affect detection feasibility and usability aspects of continuous remote monitoring of health status in palliative cancer patients using wearables detection of diseases based on electrocardiography and electroencephalography signals embedded in different devices: an exploratory study stress effects". the american institute of stress der smarte assistent can: creative adversarial networks, generating" art" by learning about styles and deviating from style norms creative ai: on the democratisation & escalation of creativity generative design: a paradigm for design research eigenfaces for recognition unsupervised representation learning with deep convolutional generative adversarial networks large scale gan training for high fidelity natural image synthesis interpreting the latent space of gans for semantic face editing visualizing and understanding generative adversarial networks mistaken identity spectral normalization for generative adversarial networks beauty is in the ease of the beholding: a neurophysiological test of the averageness theory of facial attractiveness unpaired image-to-image translation using cycleconsistent adversarial networks colorization for anime sketches with cycle-consistent adversarial network artificial muse using evolutionary design to interactively sketch car silhouettes and stimulate designer's creativity the chair project-four classics deepwear: a case study of collaborative design between human and artificial intelligence grass: generative recursive autoencoders for shape structures co-designing object shapes with artificial intelligence systematic review of the empirical evidence of study publication bias and outcome reporting bias ki-kunst und urheberrecht -die maschine als schöpferin? public law research paper no. ; u of maryland legal studies research paper no inceptionism: going deeper into neural networks proactive error prevention in manufacturing based on an adaptable machine learning environment. artificial intelligence: from research to application: the upper-rhine artificial intelligence symposium ur-ai the benefits fo pdca crisp-dm . : step-by-step data mining guide interpretable machine learning for quality engineering in manufacturing-importance measures that reveal insights on errors regulation (eu) / of the european parliament and of the council of april on medical devices -medical device regulation (mdr) use of real-world evidence to support regulatory decision-making for medical devices. guidance for industry and food and drug administration staff high-performance medicine: the convergence of human and artificial intelligence artificial intelligence powers digital medicine dermatologist-level classification of skin cancer with deep neural networks chestx-ray : hospital-scale chest x-ray database and benchmarks on weaklysupervised classification and localization of common thorax diseases an attention based deep learning model of clinical events in the intensive care unit the artificial intelligence clinician learns optimal treatment strategies for sepsis in intensive care the european commission's high-level expert group on artificial intelligence: ethics guidelines for trustworthy ai key challenges for delivering clinical impact with artificial intelligence ibm's watson supercomputer recommended 'unsafe and incorrect' cancer treatments, internal documents show towards international standards for the evaluation of artificial intelligence for health proposed regulatory framework for modifications to artificial intelligence/machine learning (ai/ml)-based software as a medical device (samd) artificial-intelligence-and-machine-learning-discussion-paper.pdf . international medical device regulators forum (imdrf) -samd working group medical device software -software life-cycle processes general principles of software validation. final guidance for industry and fda staff deciding when to submit a (k) for a change to an existing device. guidance for industry and food and drug administration staff software as a medical device (samd): clinical evaluation. guidance for industry and food and drug administration staff international electrotechnical commission. iec - : -part : application of usability engineering to medical devices why rankings of biomedical image analysis competitions should be interpreted with care what do we need to build explainable ai systems for the medical domain / of the european parliament and of the council of april on the protection of natural persons with regard to the processing of personal data and on the free movement of such data (general data protection regulation -gdpr) artificial intelligence in healthcare: a critical analysis of the legal and ethical implications explainable artificial intelligence: understanding, visualizing and interpreting deep learning models association between race/ethnicity and survival of melanoma patients in the united states over decades docket for feedback -proposed regulatory framework for modifications to artificial intelligence/machine learning (ai/ml)-based software as a medical device (samd) openpose: realtime multi-person d pose estimation using part affinity fields a density-based algorithm for discovering clusters in large spatial databases with noise fast volumetric auto-segmentation of head ct images in emergency situations for ventricular punctures a system for augmented reality guided ventricular puncture using a hololens: design, implementation and initial evaluation op sense-a robotic research platform for telemanipulated and automatic computer assisted surgery yolov : an incremental improvement. arxiv deep learning based d pose estimation of surgical tools using a rgb-d camera at the example of a catheter for ventricular puncture fast point feature histograms (fpfh) for d registration joint probabilistic people detection in overlapping depth images towards end-to-end d human avatar shape reconstruction from d data scene-adaptive optimization scheme for depth sensor networks a taxonomy and evaluation of dense two-frame stereo correspondence algorithms advances in computational stereo a comparative analysis of cross-correlation matching algorithms using a pyramidal resolution approach fast approximate energy minimization via graph cuts stereo processing by semiglobal matching and mutual information guided stereo matching a large dataset to train convolutional networks for disparity, optical flow, and scene flow estimation pyramid stereo matching network microstructure-sensitive design of a compliant beam microstructure sensitive design of an orthotropic plate subjected to tensile load microstructure sensitive design for performance optimization on the design, analysis, and characterization of materials using computational neural networks texture optimization of rolled aluminum alloy sheets using a genetic algorithm finite mixture models a tutorial on hidden markov models and selected applications in speech recognition information processing in dynamical systems: foundations of harmony theory generative adversarial nets building texture evolution networks for deformation processing of polycrystalline fcc metals using spectral approaches: applications to process design for targeted performance linear solution scheme for microstructure design with process constraints matcalo: knowledge-enabled machine learning in materials science differential evolution -a simple and efficient adaptive scheme for global optimization over continuous spaces reinforcement learning: an introduction hindsight experience replay industrieroboter für kmu. flexible und intuitive prozessbeschreibung toward efficient robot teach-in and semantic process descriptions for small lot sizes survey on human-robot collaboration in industrial settings: safety, intuitive interfaces and applications concept and architecture for programming industrial robots using augmented reality with mobile devices like microsoft hololens robot programming using augmented reality robot path and end-effector orientation planning using augmented reality spatial programming for industrial robots based on gestures and augmented reality spatial programming for industrial robots through task demonstration augmented reality based teaching pendant for industrial robot intuitive robot tasks with augmented reality and virtual obstacles development of a mixed reality based interface for human roboter interaction a hands-free virtual-reality teleoperation interface for wizard-of-oz control mixed reality as a tool supporting programming of the robot communicating robot arm motion intent through mixed reality head-mounted displays intuitive industrial robot programming through incremental multimodal language and augmented reality development of mixed reality robot control system based on hololens interactive spatial augmented reality in collaborative robot programming: user experience evaluation comparison of multimodal heading and pointing gestures for co-located mixed reality human-robot interaction robot programming through augmented trajectories in augmented reality interactive robot programming using mixed reality a taxonomy of mixed reality visual displays experimental packages for kuka manipulators within ros-indus-trial . siemens: ros-sharp a questionnaire for the evaluation of physical assistive devices (quead) unctad: review of maritime transport ( ) last accessed - - . . international chamber of shipping report of the second meeting of the regional working group on illegal, unreported and unregulated (iuu) fishing automatic identification system (ais): data reliability and human error implications maritime anomaly detection: a review trajectorynet: an embedded gps trajectory representation for point-based classification using recurrent neural networks partition-wise recurrent neural networks for point-based ais trajectory classification a multi-task deep learning architecture for maritime surveillance using ais data streams identifying fishing activities from ais data with conditional random fields a segmental hmm based trajectory classification using genetic algorithm wissensbasierte probabilistische modellierung für die situationsanalyse am beispiel der maritimen Überwachung detecting illegal diving and other suspicious activities in the north sea: tale of a successful trial source quality handling in fusion systems: a bayesian perspective tensorflow: large-scale machine learning on heterogeneous systems deep learning for time series classification: a review rapid object detection using a boosted cascade of simple features general framework for object detection a decision-theoretic generalization of on-line learning and an application to boosting imagenet classification with deep convolutional neural networks rethinking the inception architecture for computer vision going deeper with convolutions deep residual learning for image recognition mobilenets: efficient convolutional neural networks for mobile vision applications mobilenetv : inverted residuals and linear bottlenecks rich feature hierarchies for accurate object detection and semantic segmentation ssd: single shot multibox detector deep learning for generic object detection: a survey pedestrian detection: an evaluation of the state of the art a survey on face detection in the wild: past, present and future text detection and recognition in imagery: a survey information visualizations used to avoid the problem of overfitting in supervised machine learning data science for business: what you need to know about data mining and data-analytic thinking automatic object detection from digital images by deep learning with transfer learning gpu asynchronous stochastic gradient descent to speed up neural network training tensorflow: tensorflow object detection api: ssd mobilenet v coco faster r-cnn: towards real-time object detection with region proposal networks tensorflow object detection api: faster rcnn inception v coco. online . tensorflow: tensorflow object detection api: faster rcnn inception v coco r-fcn: object detection via region-based fully convolutional networks . tensorflow: tensorflow object detection api: rfcn resnet coco multi-scale feature fusion single shot object detector based on densenet references . shell: the shell eco marathon real-time loop closure in d lidar slam kinodynamic trajectory optimization and control for car-like robots experiments with the graph traverser program robot operating system automatic differentiation in pytorch ssd: single shot multibox detector yolov : an incremental improvement rich feature hierarchies for accurate object detection and semantic segmentation mobilenets: efficient convolutional neural networks for mobile vision applications deep residual learning for image recognition are we ready for autonomous driving? the kitti vision benchmark suite m det: a single-shot object detector based on multi-level feature pyramid network the upper-rhine artificial intelligence symposium ur-ai we thank our sponsor! main sponsor: esentri ag, ettlingen this research and development project is funded by the german federal ministry of education and research (bmbf) and the european social fund (esf) within the program "future of work" ( l c ) and implemented by the project management agency karlsruhe (ptka). the author is responsible for the content of this publication. underlying projects to this article are funded by the wtd of the german federal ministry of defense. the authors are responsible for the content of this article.this work was developed in the fraunhofer cluster of excellence "cognitive internet technologies". the upper-rhine artificial intelligence symposium key: cord- -vm wq m authors: rößler, steve; ankert, juliane; baier, michael; pletz, mathias w.; hagel, stefan title: influenza-associated in-hospital mortality during the / influenza season: a retrospective multicentre cohort study in central germany date: - - journal: infection doi: . /s - - -x sha: doc_id: cord_uid: vm wq m the aim of this retrospective cohort study at eight hospitals in germany was to specify influenza-associated in-hospital mortality during the / flu season, which was the strongest in germany in the past years. a total of patients were included in the study. overall, in-hospital mortality was . % (n = ), in patients treated in the intensive care unit (n = ) mortality was . %. the proportion of deceased patients per hospital was between % and . %. influenza was the immediate cause of death in . % (n = ) of the decedents. it is estimated that - % of the population contracts influenza in an average flu season [ ] . among the most relevant infectious diseases in europe, influenza, with . infections per , inhabitants annually, has the highest incidence and the highest mortality ( . deaths per , inhabitants per year) [ ] . approximately one-third of the total burden of all infectious diseases, measured in disability-adjusted life years, is attributable to influenza [ ] . however, it has been recognized for many years that influenza is underreported on death certificates. it is, therefore, common practice to estimate mortality attributed to influenza with statistical methods [ ] . this so-called excess mortality is obtained by subtracting the expected mortality (i.e. background mortality) from the observed mortality during an influenza season. if an increase in mortality is observed which is significantly higher than background mortality, this is attributed to influenza. for example, according to the robert koch institute (rki), an estimated , people in germany died due to influenza during the / flu season, but only influenza-associated deaths were officially reported [ ] . as in-hospital mortality is not collected as part of rki influenza surveillance, no data are available on this. however, accurate data on the burden of disease are important for making comparisons with other diseases, e.g., coronavirus disease (covid- ) [ ] . therefore, the primary aim of this study was to specify influenza-associated in-hospital mortality during the / influenza season, the strongest influenza season in the past years. in addition, the need for intensive care support was assessed, an important number to describe severity of disease. this retrospective cohort study was performed at eight hospitals with beds (median (range - ) beds) in central germany (table ) . six hospitals were small regional hospitals providing basic and standard care, and the two largest hospitals were hospitals providing maximum care. all hospitalized patients with a discharge diagnosis of influenza infection (j. .-) between december and april were included in the analysis. in addition to demographics, length of hospital stay, intensive care unit (icu) stay and hospital discharge data were collected from all patients. in patients who died during steve rößler and juliane ankert contributed equaly. their hospital stay, chart review was performed to document information about comorbidities, the cause of death and therapy. immunosuppression was defined as the presence of congenital or acquired immunosuppression (e.g., chronic therapy with corticosteroids > mg/day, radio/ chemotherapy, transplantation, hiv/aids). to summarize characteristics of deceased patients, we provide absolute and relative frequencies and the median complemented by the first and third quartiles (q , q ). we applied the χ test or, if indicated, fisher's exact test and the mann-whitney u test to assess differences between deceased patients with icu care and without icu care. ethical approval for the study was provided by the ethics committee of the jena university hospital, with a waiver for informed consent from the patients ( - / ). a total of patients were diagnosed with influenza infection during the study period. in patients, data were incomplete; therefore, patients were included in the subsequent analysis. table shows an overview of the number of influenza cases per hospital. the median age of the patients was (range - ) years, and ( %) patients were male. the average length of hospital stay was . ± . days (median days, range - days). overall, [ . %, % confidence interval (ci) . - . %] out of patients died during their hospital stay. the proportion of deceased patients per hospital was between % and . % (table ). in . % (n = ) of the cases, influenza infection was considered to be the direct cause of death; in . % (n = ) of the cases, it was an indirect cause of death; and in % (n = ) of the cases, it did not affect patient death. in total, patients ( . %) were treated in an icu during their hospital stay. the median age of these patients was (range - ) years, and % (n = ) were male. detailed information on the course of the disease was obtained from patients receiving intensive medical care. in . % (n = ) of the patients, influenza infection was the immediate and primary reason for admission to the icu; in . % (n = ) of patients, infection was acquired in the icu. influenza infection was present in . % (n = ) of patients, but it had no influence on admission to the icu. in another . % (n = ) of patients, influenza infection worsened the underlying illness, leading to icu admission. extracorporeal membrane oxygenation was successfully performed in one patient. a total of patients ( . %, % ci . - . ) died during their stay in the icu. influenza infection was the immediate cause of death in patients ( . %) and an indirect cause in ( . %) patients. influenza subtyping was performed in patients in the icu. sixty-seven patients ( . %) had influenza b infection, and patients ( . %) had influenza a infection (p < . ) ( table ). during the / influenza season, approximately , laboratory-confirmed influenza cases were reported to the rki. approximately , ( %) patients were reported to be hospitalized. in the present study involving eight hospitals in central germany, influenza-related in-hospital mortality in the examined patient population was . %, and every tenth patient was cared for in an icu during their hospital stay. the in-hospital mortality in this group of patients was significantly higher ( . %) than that in those who did not require admission to an icu. our observed in-hospital mortality rate of . % was comparable to the in-hospital mortality rate of . % reported by another german university hospital [ ] but lower than the in-hospital mortality ( . %) rate reported by a tertiary hospital in austria [ ] . interestingly, the in-hospital mortality observed in this season was significantly lower compared to the in-hospital mortality in the / season ( . % vs. . %) in study hospital no. [ ] . applying our observed in-hospital mortality of . % to the , hospitalized patients with a laboratoryconfirmed influenza infection reported to the rki would correspond to approximately deceased hospitalized patients during the / flu season in germany. this in contrast to the influenza-associated deaths officially reported to the rki, for both, hospitalized and non-hospitalized patients, clearly underlying the notion that influenza-associated deaths are underreported. however, our observed in-hospital mortality does not allow to draw conclusions about the overall influenza-associated mortality and burden of disease. for one thing, the mortality in non-hospitalized patients with influenza most probably differs from hospitalized patients with influenza. on the other hand, the overall number of patients infected with influenza each season is unknown. not every person who truly has influenza will seek medical care, will be tested for influenza, have a positive test, and, therefore, be reported through influenza surveillance [ ] . routinely available influenza diagnostic tests also vary in sensitivity. thus, data collected through influenza surveillance and case finding represent only a fraction of persons infected with influenza. for example, a recently published study calculated that in the us, only between . - . % and . - . % of symptomatic influenza illnesses were laboratory-confirmed in the - and - seasons, respectively [ ] . in ( . %) influenza-associated deaths reported to the rki, it was stated that the patient died from influenza disease and its consequences [ ] . this proportion was lower than that in our study, in which influenza infection was considered to be the immediate cause of death in . % of the deceased patients. this discrepancy could be because, unlike in the current study in which a doctor made a decision regarding whether death was associated with influenza infection based on a medical chart review, the health authorities made the decision solely on the basis of the information available to them. these decisions considered assessments by the supervising doctor or information on the death certificate. however, these types of assessments are problematic because, in contrast to other diseases, influenza is often not recorded on the death certificate as the cause of death, even if influenza had been confirmed by laboratory testing in the course of the disease. there are several limitations in the current study. patients with influenza infection were identified retrospectively on the basis of the diagnosis code at discharge. since it is possible that not every microbiologically confirmed influenza infection was coded at discharge and that microbiological diagnostics were not always performed to ensure the clinically suspected diagnosis, the true number of hospitalized influenza patients could be correspondingly higher than that reported here. in addition, as the assessment of whether the death of a patient was related to influenza infection was made by a study physician, the results may be subject to bias. nevertheless, the results of the present study underline the high burden of disease in hospitalized patients with influenza and allow a comparisons with other diseases, e.g., coronavirus disease (covid- ). funding open access funding enabled and organized by projekt deal. conflict of interest on behalf of all authors, the corresponding author states that there is no conflict of interest. open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/ . /. erkrankungen durch saisonale influenzaviren impact of infectious diseases on population health using incidence-based disability-adjusted life years (dalys): results from the burden of communicable diseases in europe study, european union and european economic area countries bericht zur epidemiologie der influenza in deutschland assessment of deaths from covid- and from seasonal influenza clinical characteristics of influenza in season / in a german emergency department: a retrospective analysis intrahospital mortality of influenza patients during the - influenza season: report from a tertiary care hospital in austria characteristics and management of patients with influenza in a german hospital during the / influenza season quantifying the annual incidence and underestimation of seasonal influenza: a modelling approach key: cord- -dzsyuwpy authors: bangash, mansoor n; owen, andrew; alderman, joseph e; chotalia, minesh; patel, jaimin m; parekh, dhruv title: covid- recovery: potential treatments for post-intensive care syndrome date: - - journal: lancet respir med doi: . /s - ( ) - sha: doc_id: cord_uid: dzsyuwpy nan the long-term effects of surviving covid- have become a new focus of attention for clinicians and researchers. this focus has been driven partly by concerns about late ill-effects of a previously unknown virus, but recognised generic patterns of chronic disease after critical illness also exist. these patterns are termed pics, an acronym both for post-intensive care syndrome and for persistent inflammation, immunosuppression, and catabolism syndrome. we recommend unifying post-covid- research aims with those of pics research and propose a novel approach to its management by repurposing drugs that are approved, inexpensive, and safe. severe covid- pneumonia causes acute respiratory distress syndrome (ards). intensive care unit (icu) stays of patients with ards are lengthy and characterised by severe hypoxaemia, extrapulmonary organ failures, and a marked inflammatory response. follow-up data from young (< years) populations with a range of critical illnesses and no comorbidities, and studies assessing dose-responses (dose of illness vs response of morbidity) of organ dysfunction and tissue injury, suggest that an adverse long-term reprogramming of multiple organ systems can occur during such critical illness. people who survive lose weight and are debilitated, often with cognitive impairments. a hysteresis of body-mass recovery in different tissue compartments occurs and metabolic control is often disrupted, with the development of type diabetes and adipose gain commonly reported in affected individuals. organs undergo microscopic damage at the time of acute inflammation and display imperfect repair, with acute kidney injury and cardiovascular dysfunction transitioning to chronic kidney disease and post-icu major adverse cardiac events. these processes occur in the context of low-grade inflammation and functional immunosuppression, which predisposes individuals who survive admission to icu, and particularly those with pics, to secondary infections. although physical activity counters the proinflammatory effects of sedentarism, enhanced recovery programmes against a backdrop of residual inflammation have not translated to benefit, suggesting a potential role for pharmacological intervention. if prolonged critical illness, including that associated with covid- , causes patients to develop chronic inflammation, thrombosis, and fibrosis, antagonists of these processes might be beneficial for survivors. the cantos trial showed that major adverse cardiac events, lung cancer, and anaemia rates were reduced in groups with evidence of low-grade inflammation when treated for secondary prevention with the interleukin- β (il- β) monoclonal antibody canakinumab. however, our opinion is that the critical care specialty is not yet in a position to conduct large-scale trials of such powerful anti-inflammatory drugs in icu survivors. the cantos and colcot trials showed that reducing il- β-related inflammation increases infection risk, an important consideration in the functionally immunosuppressed pics population. however, other established cardiometabolic therapeutics with good clinical rationale and excellent safety profiles already exist and hold great promise for icu survivors. these drugs are in a prime position to be trialled immediately in large numbers of patients with covid- -associated pics, and such studies might provide a better understanding of who, if anyone, might benefit from il- β targeting. non-randomised studies suggest that renin-angiotensinaldosterone system (raas) inhibitors reduce mortality after discharge from the icu in people who had critical illness with acute kidney injury, whereas preclinical studies suggest a potentially beneficial modulation of frailty in models of age-associated frailty. the sscill trial aims to test whether a raas modulator with suspected antiinflammatory and known antifibrotic effects could be used in this group of patients with pics to reduce major adverse cardiac events. however, other drugs, including raas modulators, should also be trialled while data for pics biology accumulates. statin trials in healthy patients with elevated high-sensitivity c-reactive protein (crp) and older patients (> years) without atherosclerosis show how reductions in cardiovascular risk, high-sensitivity crp, and rates of pneumonia and deep vein thrombosis can be achieved with low-risk drugs that, among other things, increase concentrations of proresolution mediators (eg, resolvins). other drugs, or dietary supplementation with compounds that increase proresolution mediators and reduce thrombo-inflammation, might also be expected to reduce cardiovascular and overall morbidity in patients with pics; cardiovascular trials of aspirin and icosapent ethyl provide evidence of efficacy. in the manage trial, a population having non-cardiac surgery, which overlaps covid- recovery: potential treatments for post-intensive care syndrome and shares similarities with the pics population through the presence of non-ischaemic myocardial injuries, was found to have reduced cardiovascular morbidity at follow-up when treated with the antithrombotic dabigatran; further trials of dabigatran in patients with pics are warranted. modulators of metabolism could also counteract numerous problems reported in patients with pics. multiple phase studies of sglt inhibitors repeatedly show improve ments in metabolic and fibrotic cardiorenal outcomes even in the absence of diabetes. metformin could similarly improve cardiometabolic profiles while also modulating the immunoparesis noted during and after critical illnesses. systemic metabolism, energy balance, and immunity are neurally mediated through the sympathetic nervous system. β-adrenoceptor blockers are anti-arrhythmics with proven benefit in the cardiovascular arena, but might also benefit patients with pics by reducing systemic metabolic rate and catabolism, decreasing bone marrow replicative stress, and modulating immune dysfunction. nutritional supplements, such as niacin and folic acid, should also be trialled in pics, because beneficial effects on muscle and the cardiovascular system, mediated through effects on dna methylation and cellular energetics, are potentially attainable at low risk. through large international, collaborative research projects, the icu community has the opportunity to reduce readmission to hospital and the icu while improving overall quality of life, healthspan, societal productivity, and the lifespan for people who have been in icu (panel). the james lind alliance research prioritisation exercise in intensive care shows that patients would welcome trials in this area. therefore, we propose that the icu community should organise large, international, pragmatic, multicentre platform trials for icu survivors, in a manner analogous to the recovery trial, to potentially decipher whether or not these drugs can be efficacious for those who have survived critical illnesses such as covid- . we suggest that the research pathway for such trials should be based on prognostic enrichment through clinical and cardiovascular or immune biomarker profiles, and initially use established drugs that modify cardiometabolic risk in icu survivors who might not have traditionally recognised cardiovascular risk factors, through randomised controlled trials led by intensive care specialists. we are already on the path to starting this process with sscill in sepsis, polytrauma, and ards, and we encourage others to join us. mnb has received research awards from the uk intensive care society for the pilot randomised controlled trial sscill. all other authors declare no competing interests. for more on james lind alliance priority setting in intensive care see https://www.jla.nihr.ac. uk/priority-setting-partnerships/ intensive-care post-intensive care syndrome (pics) often occurs after prolonged critical illnesses, such as covid- -associated acute respiratory distress syndrome, and involves persistent inflammation, immunosuppression, and catabolism. substantial cardiovascular morbidity and mortality accompany pics, even in young, fit populations without traditional cardiovascular risk factors. the harms of potent anti-inflammatory drugs that are used to counter chronic cardiovascular disease and fibrosis are unquantified in pics; further data could show whether these therapies offer some benefit. low-risk cardiometabolic and antithrombotic drugs might be beneficial and large international, multicentre trials are needed to formally test their efficacy. avoiding polypharmacy while prognostically enriching the trial population (and so increasing the study's signal to noise ratio) could be done through the use of clinical characteristics or cardiovascular and immune biomarkers to select patients more appropriate for specific trials. study designs should involve optimising discharge therapy before patients start any new trial drug and account for the fact that many survivors of critical illness already take one or more of the drugs of interest. involving individuals with pics to help guide research priorities is crucially important to ensure that research remains patient-centred. for more on the recovery trial see https://www.recoverytrial.net broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis β adrenergic receptormediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells niacin cures systemic nad + deficiency and improves muscle performance in adult-onset mitochondrial myopathy key: cord- -xz wg authors: sills, marion r.; hall, matthew; fieldston, evan s.; hain, paul d.; simon, harold k.; brogan, thomas v.; fagbuyi, daniel b.; mundorff, michael b.; shah, samir s. title: inpatient capacity at children’s hospitals during pandemic (h n ) outbreak, united states date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: xz wg quantifying how close hospitals came to exhausting capacity during the outbreak of pandemic influenza a (h n ) can help the health care system plan for more virulent pandemics. this ecologic analysis used emergency department (ed) and inpatient data from us children's hospitals. for the -week pandemic (h n ) period during fall , inpatient occupancy reached %, which was lower than the % occupancy during the - seasonal influenza period. fewer than additional admission per inpatient beds would have caused hospitals to reach % occupancy. using parameters based on historical precedent, we built models projecting inpatient occupancy, varying the ed visit numbers and admission rate for influenza-related ed visits. the scenarios projected median occupancy as high as % of capacity. the pandemic did not exhaust inpatient bed capacity, but a more virulent pandemic has the potential to push children's hospitals past their maximum inpatient capacity. quantifying how close hospitals came to exhausting capacity during the outbreak of pandemic infl uenza a (h n ) can help the health care system plan for more virulent pandemics. this ecologic analysis used emergency department (ed) and inpatient data from us children's hospitals. for the -week pandemic (h n ) period during fall , inpatient occupancy reached %, which was lower than the % occupancy during the - seasonal infl uenza period. fewer than additional admission per inpatient beds would have caused hospitals to reach % occupancy. using parameters based on historical precedent, we built models projecting inpatient occupancy, varying the ed visit numbers and admission rate for infl uenza-related ed visits. the scenarios projected median occupancy as high as % of capacity. the pandemic did not exhaust inpatient bed capacity, but a more virulent pandemic has the potential to push children's hospitals past their maximum inpatient capacity. d uring march and april , a novel infl uenza a (h n ) virus began to spread in north america that disproportionately affected children, who constituted half of patients hospitalized for infl uenza-related illness (iri) during spring ( - ). after a summertime decline, the virus returned to full activity in the fall, and children continued to have the highest rates of illness and hospitalization ( ) . as a result, pediatric providers and children's hospitals cared for large numbers of patients with pandemic (h n ) virus ( , ) . despite the high attack rate for children, the pandemic virus was milder than prior pandemic viruses. the attack rate for pandemic (h n ) was lower for children ( . %) ( ) than it was for each of the past pandemics in the united states ( , , and ) ( %- %) ( ) , and the hospitalization rate was lower for children by > -fold ( . / , symptomatic children ( ) vs. estimates as high as . / , symptomatic children [ ] ). because of relatively low virulence, pandemic (h n ) resulted in comparatively fewer hospitalizations than feared, but it greatly affected ambulatory settings and emergency departments (eds) ( ) ( ) ( ) . the exact effect on children's hospitals remains unknown because published studies have reported only regional data and have quantifi ed hospital admissions rather than inpatient occupancy ( ) ( ) ( ) . assessing use of capacity in the context of a lowvirulence infl uenza pandemic can provide insight into how a more virulent virus might directly affect children's hospitals and indirectly affect all health care systems throughout their catchment areas. occupancy levels above and beyond existing capacity limits would represent a true crisis that would dramatically affect the already-stretched health care-delivery system ( ) . because children's hospitals play an integral role in coordinating health delivery ( ) , defi ning the limits of capacity reserve and quantifying how close these hospitals came to exhausting these limits can help the entire health care system better plan for more virulent pandemics or other disaster-type events. with the effect of pandemic (h n ) on children's hospitals as a collective case study, we evaluated how close to full capacity us children's hospitals functioned during the outbreak of pandemic (h n ) and the implications for the health care systems had we not been fortunate regarding the low virulence of subtype h n infl uenza ( ) . the objectives of this study were to ) compare occupancy at us tertiary care children's hospitals during the pandemic period with occupancy during the - seasonal infl uenza outbreak, ) measure how close each hospital came to exhausting capacity for inpatient beds, and ) measure the effect on capacity if pandemic (h n ) during fall had been more severe. this ecologic analysis used data from the pediatric health information system (phis), which includes ed and inpatient data from free-standing nonprofi t tertiary care children's hospitals in all regions of the united states. the child health corporation of america (shawnee mission, ks, usa) and participating hospitals jointly validate data quality and reliability ( ) . this analysis comprises data from the phis hospitals that provided codes indicating intensive care unit (icu) and non-icu bed designations for the study period. we defi ned the pandemic (h n ) period and other infl uenza epidemic periods using national infl uenza circulation data obtained from the world health organization collaborating laboratories and the national respiratory and enteric virus surveillance system ( ) . using as a threshold the weeks with > % positive test results as reported in the morbidity and mortality weekly report (centers for disease control and prevention, atlanta, ga, usa) ( , ), we defi ned the period of pandemic (h n ) as september -november , . to compare inpatient resource use during this period with that during a seasonal infl uenza period, we used the weeks of seasonal infl uenza from the - season (january -march , ), defi ned using the same % threshold ( ) . because specifi cally identifying patients with pandemic (h n ) was not feasible, we used a standard list of international classifi cation of diseases, th revision, codes developed for measuring iri to determine resource use of inpatient beds ( ) . this list comprises international classifi cation of diseases, th revision, codes - or - as the primary or secondary discharge diagnosis and captures not only primary infections with infl uenza, but also secondary infections (e.g., bacterial pneumonia) and exacerbations of other conditions (e.g., asthma). our primary measure was midnight occupancy for non-icu beds and for icu beds. the numerator for occupancy comprised all children (age - y; median age . y, interquartile range [iqr] . - . y) occupying non-icu and icu beds on each day of the study period. we obtained denominator data (i.e., annual number of licensed, in-service beds) from the child health corporation of america and confi rmed them by an email survey to each hospital's designated phis contact. step-down beds were categorized as non-icu. if a patient spent at least midnight in an icu bed during his or her hospital stay, admission was considered an icu admission and was not counted as a non-icu admission. we included all hospitalized patients of any admission status (observation or inpatient) to fully quantify hospital occupancy. we excluded newborn nursery and mental health admissions and those designated beds from the analysis. for our second objective, we defi ned the threshold as % occupancy on the basis of licensed, in-serviced beds as capacity. although lower thresholds have been suggested as the point at which quality and safety decline ( , ), % represents the scenario in which a hospital has actually exhausted its typical capacity of in-service beds. in calculating non-icu and icu occupancy, we counted the number of patients in each bed type at the midnight at the end of the day. for our third objective, we analyzed the phis hospitals for which ed data were available. in our models, we varied parameters and described the effect on inpatient occupancy: ) number of ed iri visits and ) ed-to-hospital admission rate. for the fi rst, we used estimates from the most recent, severe prior infl uenza pandemics ( and ), when the estimated upper bound of the attack rate was % ( , ). estimates of the attack rate for pandemic (h n ) for april-december were . %, based on million cases ( ) in a july population of million ( ) . assuming the percase rate of ed visits remained fi xed, we estimated that ed iri visits could have been × what they were if the attack rate had been similar to these prior pandemics. for the second parameter, we used the ed admission rate of . % observed during the - seasonal infl uenza weeks (november , -january , ), of the most severe recent infl uenza seasons ( , ). we also modeled a % admission rate (the upper end of overall ed admission rate for study hospitals in ), which actually falls well below the rate projected from hospitalization estimates of earlier infl uenza pandemics and epidemics ( , ) . to compare occupancy during the fall pandemic (h n ) period with baseline, we calculated the number of admissions, bed-days, and the occupancy for all beds, non-icu beds, and icu beds for the pandemic period and for comparison periods: the entire prior calendar year ( ) and the prior seasonal infl uenza period. we assessed the statistical signifi cance of the difference in median occupancy between the pandemic period and the seasonal infl uenza comparison period using the wilcoxon rank-sum test. to measure how close each hospital came to exhausting capacity, we calculated how many additional non-icu and icu patients could have been admitted by each hospital. for each day, we counted the number of unoccupied beds of each type and modeled how many additional patients were needed to fi ll all available beds for each hospital. for hypothetical additional patients, we modeled patients' continued presence iteratively for each day of the study period as non-icu and icu patients on the basis of the characteristics of patients admitted during the fall pandemic with iri (e.g., % with a -day length of stay, % with a -day stay, % with a -day stay). for both models, we assigned bed-days of each stay to each respective area, icu and non-icu. to index the total number of additional patients needed to fi ll the hospital to capacity across hospitals, we then calculated the number of additional patients per beds (non-icu or icu). to measure the effect on capacity of a more severe outbreak of pandemic (h n ) , we calculated the number of ed iri visits and the ed-to-inpatient admission rate for ed iri visits for the phis hospitals for which ed data were available. we then used the same modeling methods described above to model the number of additional bed-days (non-icu, icu) in each scenario. we expressed fi ndings from the scenarios in ways: ) percentage of hospital days > % and ) as median (iqr) occupancy. in these models, we made assumptions. first, we assumed that the rate of non-iri ed admissions remained unchanged. second, we assumed that hospitals did not react to high occupancy by rescheduling elective admissions, an assumption based on a prior analysis of the same data set ( ) . third we assumed that the number of icu and non-icu beds remained fi xed for each calendar year. fourth, we assumed that the inpatient length-of-stay distribution was not shifted toward longer hospitalizations during a more virulent pandemic. we performed all analyses with sas version . (sas institute, inc., cary, nc, usa) and considered p values < . statistically signifi cant. the study protocol was approved by the colorado multiple institutional review board with a waiver of informed consent. the -week period of evaluation during the fall pandemic period included a median of , (iqr , - , ) admissions and , (iqr , - , ) bed-days (table ) . median overall inpatient occupancy was % (iqr %- %), whereas median overall occupancy during the - seasonal infl uenza period was % (iqr %- %) and, for the entire calendar year , % (iqr %- %). hospitals' experiences varied considerably, with hospital-level median occupancy ranging from . % to . % (online technical appendix, www.cdc.gov/eid/content/ / / -techapp.pdf). to reach % occupancy during the pandemic period, for every beds of each type, hospitals would have needed to admit a median of . (iqr . - . ) additional patients per day for non-icu beds and . (iqr . - . ) per day for icu beds (table ) . for the hospitals for which ed and inpatient data were available, the median ed-to-hospital admission rate for iri patients was . % (iqr . %- . %). different hypothetical scenarios for ed iri volume and admission rates would have differently affected the frequency of hospital days exceeding the % occupancy threshold for exhausting capacity reserves ( individual hospital experience varied considerably (figure) . for each hospital, the dot-plots we constructed show the distribution of occupancy data across hospitals for each of the scenarios. for our worst-case scenario (scenario f), median occupancy would have been % (iqr %- %). we examined the effect on children's hospitals' resources during fall when pandemic infl uenza a (h n ) virus was active. we demonstrated that children's hospitals faced high levels of occupancy (median %) in regular inpatient care areas and icus, but this situation did not differ from typical levels of high occupancy commonly experienced at some hospitals. despite the mild virulence of pandemic (h n ) virus, children's hospitals needed only < additional admission per inpatient beds to reach % occupancy. additionally, the pandemic occurred during early fall, when viruses that cause respiratory and gastrointestinal illnesses (which typically increase occupancy at children's hospitals) were not circulating widely. models representing an outbreak of a more virulent infl uenza virus based on historical comparisons demonstrate that modest increases in ed visits or ed admission rates would have resulted in substantial overcrowding among the large cohort of children's hospitals in our study. these fi ndings are notable in the context of national disaster planning related to children. the national commission on children and disasters' report to the president and congress recommended that additional resources provide a "formal regionalized pediatric system of care to support pediatric surge capacity" and emphasizes that children's hospitals are central to such regionalization ( ) . our study shows that children's hospitals, the central component of this proposed regionalized system, routinely operate so close to capacity that little available reserve exists for even a modest surge of inpatients. for a hospital with non-icu beds and icu beds, an additional . non-icu and . icu admissions per day would have exhausted capacity. although the infl uenza pandemic did not do so, surge capacity is scarce, as demonstrated by the many hospitals that are already operating at or near maximum capacity in their eds and inpatient areas ( , ) . federal planners have suggested that surge capacity should accommodate inpatients per million population, but such capacity does not exist for children under normal circumstances; capacity for only inpatients per million children is available during typical winter weekdays ( ) ( ) ( ) . although we expressed our fi ndings in terms of hospital occupancy rather than on a population basis, our fi ndings are similar to those raising alarm about limited inpatient capacity in the face of a pandemic or disaster. pandemics extend over many weeks and affect large regions, if not the entire country. although the hospitals may be able to handle such levels of occupancy on a shortterm basis, whether they could do so for prolonged periods is unclear. even though a health care system's capacity reserve cannot be designed on a daily basis to handle a pandemic, the frequent level of high occupancy already experienced by children's hospitals and the resulting lack of a buffer for a pandemic-associated surge should be considered by individuals and organizations involved with planning and disaster preparedness ( , ) . planning for such events at hospital and regional levels may be improved with data about current capacity reserves and how perturbations can affect that capacity. in previous studies of large-scale epidemics, hospitals have altered standards of care-as occurred in toronto during the outbreak of severe acute respiratory syndrome-to meet increased patient needs ( , , ) . during the outbreak of severe acute respiratory syndrome, restrictions on scheduled (i.e., elective) admissions were imposed in toronto ( ) . although we did not study scheduled admissions, our analysis suggests in a more virulent pandemic (scenario f), hospitals would have run out of space even if they had rescheduled the %- % of scheduled pediatric admissions; this percentage includes the % of elective admissions for chemotherapy, a treatment that is not amenable to prolonged postponement ( ) . our fi ndings are subject to several limitations. the hospitals in this study represent a subset of the ≈ us children's hospitals and may not be representative of these children's hospitals or of other hospitals that admit children, even though the study included children's hospitals in all regions of the country. the analysis did not consider measures that individual hospitals and regional systems might use to reduce occupancy, such as canceling scheduled admissions, which would have caused us to overestimate occupancy. on the other hand, our assumption about length of stay would have caused us to underestimate occupancy. our analysis used midnight census; actual daytime occupancy most likely was higher ( ) , and thus true surge capacity was even lower than estimated. finally, the modeled scenarios were based on historical comparisons, which represent a range of potential demands on the health care system. for hospitals and government agencies, the results of our study should prompt review of preparedness planning and reconsideration of surge capacity. systemwide resource limitations must be considered because ambulatory and inpatient services interrelate. the outbreak of lowvirulence pandemic (h n ) virus affected eds disproportionately but left inpatient services relatively unaffected ( ) . exploring the parameters of more severe epidemics might allow planners at individual hospitals, as well as regional health administrators, to consider what alterations in standards may be necessary. pandemic influenza, wk, median (iqr) ‡ overall § beds bed-days pediatric health information system mmwr, morbidity and mortality weekly report §excluding neonatal and behavioral health patients and designated beds infl uenza-associated hospitalizations in the united states hospitalized patients with h n infl uenza in the united states estimates of the prevalence of pandemic (h n ) , united states infl uenza and the rates of hospitalization for respiratory disease among infants and young children incidence of outpatient visits and hospitalizations related to infl uenza in infants and young children updated cdc estimates of h n infl uenza cases, hospitalizations and deaths in the united states emerging infections: pandemic infl uenza the severity of pandemic h n infl uenza in the united states the economic impact of pandemic infl uenza in the united states: priorities for intervention pandemic h n infl uenza in the pediatric emergency department: a comparison with previous seasonal infl uenza outbreaks novel infl uenza a(h n ) in a pediatric health care facility in new york city during the fi rst wave of the pandemic resource burden at children's hospitals experiencing surge volumes during the spring h n infl uenza pandemic pandemic infl uenza a (h n ) virus infections evaluation of multiple test methods for the detection of the novel infl uenza a (h n ) during the new york city outbreak factors associated with death or hospitalization due to pandemic infl uenza a(h n ) infection in california children's hospitals do not acutely respond to high occupancy national commission on children and disasters. report to the president and congress. ahrq publication no. -m time to get back on track to meet the millennium development goals: address to sixty-third world health assembly achieving data quality. how data from a pediatric health information system earns the trust of its users h n fl u: situation update infl uenza viruses isolated by who/nrevss collaborating laboratories, - season the effect of hospital bed occupancy on throughput in the pediatric emergency department hospital capacity, patient fl ow, and emergency department use in new jersey. new brunswick (nj): rutgers center for state health policy update: infl uenza activity-united states and worldwide, - season, and composition of the - infl uenza vaccine estimates of deaths associated with seasonal infl uenza-united states pediatric mass critical care in a pandemic pediatric hospital and intensive care unit capacity in regional disasters: expanding capacity by altering standards of care hospital emergency surge capacity: an empiric new york statewide study concept of operations for triage of mechanical ventilation in an epidemic matching supply with demand: an introduction to operations management surge capacity associated with restrictions on nonurgent hospital utilization and expected admissions during an infl uenza pandemic: lessons from the toronto severe acute respiratory syndrome outbreak institute of medicine. guidance for establishing standards of care for use in disaster situations effect of widespread restrictions on the use of hospital services during an outbreak of severe acute respiratory syndrome characteristics of weekday and weekend hospital admissions annual bed statistics give a misleading picture of hospital surge capacity dr sills is an associate professor of pediatrics at the university of colorado school of medicine and a pediatric emergency medicine physician at children's hospital colorado, aurora, colorado, usa. her primary research interests include crowding, quality of care, and the medical home. key: cord- -t dtabi authors: bousbia, sabri; papazian, laurent; saux, pierre; forel, jean marie; auffray, jean-pierre; martin, claude; raoult, didier; la scola, bernard title: repertoire of intensive care unit pneumonia microbiota date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: t dtabi despite the considerable number of studies reported to date, the causative agents of pneumonia are not completely identified. we comprehensively applied modern and traditional laboratory diagnostic techniques to identify microbiota in patients who were admitted to or developed pneumonia in intensive care units (icus). during a three-year period, we tested the bronchoalveolar lavage (bal) of patients with ventilator-associated pneumonia, community-acquired pneumonia, non-ventilator icu pneumonia and aspiration pneumonia, and compared the results with those from patients without pneumonia (controls). samples were tested by amplification of s rdna, s rdna genes followed by cloning and sequencing and by pcr to target specific pathogens. we also included culture, amoeba co-culture, detection of antibodies to selected agents and urinary antigen tests. based on molecular testing, we identified a wide repertoire of bacterial species of which have not been previously reported in pneumonia. moreover, we found putative new bacterial phylotypes with a s rdna gene divergence ≥ % from known phylotypes. we also identified fungal species of which have not been previously reported in pneumonia and viruses. patients can present up to different microorganisms in a single bal (mean ± sd; . ± . ). some pathogens considered to be typical for icu pneumonia such as pseudomonas aeruginosa and streptococcus species can be detected as commonly in controls as in pneumonia patients which strikingly highlights the existence of a core pulmonary microbiota. differences in the microbiota of different forms of pneumonia were documented. the cause of pneumonia in intensive care units (icus) remains unknown in nearly % of cases despite extensive microbiological investigations [ , ] . microbial communities previously identified, in deep respiratory samples, include bacteria, fungi and viruses for which the role in the observed pathology is not clear. microorganisms frequently identified in respiratory samples from icupneumonia patients included pseudomonas aeruginosa, staphylococci, enterobacteria, candida albicans, influenza virus, herpes simplex virus (hsv) and cytomegalovirus (cmv) [ ] [ ] [ ] [ ] [ ] . in some investigations, a pathogenic bacterium is isolated, whereas in other cases, the number of colony forming units (cfu) is considered to determine the pathogenic character [ ] . recently, the bacterial microbiota of patients with cystic fibrosis and ventilator-associated pneumonia (vap) were studied using s rdna gene amplification followed by clone libraries sequencing [ ] [ ] [ ] . our laboratory has contributed to this work and has shown, by different sequencing approaches, that the microbial population of patients with cystic fibrosis was more diverse than expected [ , ] . here, we use a comparable approach in order to study episodes of icu pneumonia and control cases. these patients were studied using broad-range primer amplification of the s rdna gene of bacteria and the intergenic spacer of s rdna gene of fungi followed by cloning and sequencing. we also used specific quantitative pcr (qpcr) to target fastidious bacteria and a spectrum of viruses. moreover, we tested samples from our patients by standardized routine culture, amoebal co-culture, blood culture, elisa targeted antibody detection, immunofluorescent assay antigenemia and antigenuria testing as routinely performed in such cases to compare these routine tests with molecular approaches. in preliminary results, we have reported the likely frequency of tropheryma whipplei and the occurrence of vegetable dna in pneumonia patients [ , ] . in this work, we highlight the different compositions of microbiota in patients with four different types of icu-pneumonia. bacterial microbiota as evaluated by s rdna molecular assays were positive for at least one bacterium for out of bronchoalveolar lavage (bal) samples from patients with pneumonia as well as from out of from control individuals (p = . ). bacterial clone libraries from amplified s rdna genes (nearly , clones that contained exploitable sequences were included) identified different bacteria at the species level. detailed data about the relative abundance and richness of each species in their corresponding library are summarized in data s and s in supplementary informations. bacterial clone libraries of patients showed that libraries were characterized by the presence of only one bacterium, libraries were polybacterial but dominated by one bacterium ( % of the clones in the library), whereas libraries were polybacterial without any dominant bacterium (fig. ) . bacterial clone libraries of controls showed that libraries were characterized by the presence of only one bacterium, libraries were polybacterial but dominated by one bacterium ( % of the clones in the library), whereas libraries were polybacterial but without any dominant bacterium (fig. ) . patients exhibited up to bacteria in their bal fluids (mean sd; . . ) (tables and ). overall, patients exhibited different species belonging to different phyla ( classes, orders, families and genera) of which had not been previously observed in bal from pneumonia, whereas bacterial clone libraries of controls identified species belonging to different phyla ( classes, orders, families and genera). in patients, aerobic gram-negative bacilli, gram-positive cocci, and anaerobic bacteria from oropharyngeal flora were the most frequent bacteria identified (tables s ,s ,s ,s , fig. ) . surprisingly, bacteria that are usually associated with other diseases such as the gram-positive anaerobe atopobium vaginae, or from unexpected animal origins, such as enterococcus canintestini, were alsoc found. moreover, strictly anaerobic bacteria ( %) were found in patients versus anaerobic bacteria ( %) found in controls (p = . ). among those bacteria which were identified in controls, bacteria were also identified in patients (fig. s , tables s ,s ,s ), including pseudomonas aeruginosa sequences respectively identified in % and % from different clones libraries from immunocompromised controls. in the second clone library, the % of the remaining sequences included achromobacter xylosoxidans, which also is a typical bacterium of nosocomial pneumonia. stenotrophomonas maltophilia sequences were found in % of clone library of another immunocompromised control, along with other bacteria. similarly, sequences of streptococcus mitis ( % of the clone library) was identified along with other bacteria in a control with acute respiratory distress syndrome (ards) and a history of aspiration pneumonia (ap) days before bal sampling. additionally, arcobacter cryaerophilus, atopobium parvulum, lachnospiraceae bacterium, prevotella melaninogenica, and prevotella pallens were significantly more frequent in controls than in patients (p = . , . , . , . and . respectively) (table s ) . bacterial clone libraries surprisingly showed new phylotypes with s rdna sequence similarity lower than % to known bacteria available in the genbank database (data s and s ). among them, novel bacterial phylotypes were identified in bal from patients, whereas novel phylotypes were identified in bal from controls (fig. ) . novel bacterial phylotypes identified in patients were more diversified, as they belonged to different phyla including bacteroidetes ( phylotypes), firmicutes ( phylotypes), proteobacteria ( phylotypes), actinobacteria (one phylotypes), acidobacteria (one phylotype) and spirochaetes (one phylotype). novel species identified in controls belong to bacteroidetes ( phylotypes), firmicutes ( phylotypes) and actinobacteria (one phylotype). prevotellaceae phylotypes represent % of all novel phylotypes identified and they were exhibited in patients with pneumonia as well as in control subjects (fig. ) . results obtained using routine bal and blood culture are available text s . fungal microbiota as evaluated by the intergenic spacer of s rdna at least one fungus was found in bal patient samples and in from controls (p = . ). positive patients exhibit up to fungi in their bal fluids (mean sd; . . ) (tables and ) . detailed data about the relative abundance and richness of each species in their corresponding library are also summarized in summary files (data s and s ) in supplementary informations. fungal microbiota obtained from patients showed the presence of different species belonging to phyla ( orders, families and genera) among which phylotypes had not been previously identified in bal fluids from pneumonia. clone libraries from controls, identified fungi belonging to one phylum ( orders, families and genera) among which fungi were also identified in patients. candida species were the most common fungal species identified (tables s ,s ,s and s ). environmental fungi, which usually colonize water, food debris and humid building surfaces, were more notably identified in our study than in previous pneumonia studies. furthermore, tree fungi belonging to basidiomycota phylum, sporidiobolales sp., cryptococcus victoriae and hyphoderma praetermissum, were found for the first time in pneumonia bal samples in the present study, while candida utilis and periconia macrospinosa were identified only in controls. additionally, candida utilis was significantly more frequent in controls than in patients (p = . ). results of fungi obtained using a routine bal culture are available in text s . four pneumonia patients were found to be positive for fastidious bacteria chlamydia pscitacii ( case), mycobacterium sp. ( cases) and mycoplasma pneumoniae ( cases) by qpcr. in addition, qpcr enabled the detection of different viruses. quantitative data of microorganisms identified by qpcr (loads or cycle threshold) are also provided and summarized in supplementary information (data s and s ). our study showed that at least one virus was identified in bal samples from patients, and from controls (p = . ). hsv and cmv were the most commonly identified viruses. while the prevalence of these two viruses in patients was not significantly different from that of controls (table s ) , cmv was more frequently identified in pneumonia patients than in controls. hsv and cmv coinfection was found in bal samples from vap patients, community-acquired pneumonia (cap) patients and non-ventilator icu pneumonia (nv icu-p) patients and one control subject. coinfection with cmv and respiratory syncytial virus type a was detected in a bal from one nv-icu-p patient, and both hsv and vzv were identified in a bal from a cap patient. rhinovirus was identified in a control with ards, urinary infection and sinusitis. parainfluenza virus- was detected in vap patients and an immunocompetent control with a pulmonary contusion. results obtained using routine serology and antigenemia for viruses and fastidious pathogens are available in text s overall, bacterial difference between patients and controls showed that bacteria belonging to bacilli and gammaproteobacteria were dominant in patients, whereas anaerobic bacteria related to bacteroidia (represented essentially by prevotella species) and clostridia were dominant in controls ( fig. ) (p, . ). mollicutes, which are represented by the mycoplasma genus, were only detected in patients with cap and vap (fig. ) . as for fungal species, members of saccharomycetes were ubiquitously identified in all cohorts. eurotiomycetes, which are represented by aspergillus, penicillium and cladophialophora genera, were dominant in the cap cohort (fig. ) . tremellomycetes, represented by the cryptococcus genus, was only identified in the nv-icu-p cohort, whereas figure . a phylogenetic tree inferred from s rdna sequences of novel bacterial phylotypes. these novel phylotypes exhibited sequence similarities of less than % to known bacteria available in the genbank database, and they were classified in silico using ''classifier'' program. phylotypes are reported according to their genus or by the last possible classification determined by the program. when possible, phylotypes with the same classification are clustered together. the frequency of phylotypes in each cohort is shown on the right.. bacteroidetes are shown in purple, firmicutes in red, proteobacteria in blue, actinobacteria in yellow, acidobacteria in orange and spirochaetes in green. cap, community-acquired pneumonia; vap, ventilator-associated pneumonia; nv icu-p, non-ventilator icu pneumonia; ap, aspiration pneumonia; and cs, control subjects. doi: . /journal.pone. .g agaricomycetes and an unclassified ascomycota (melanized limestone ascomycetes) were only identified in the vap cohort. in addition, sordariomycetes, which is represented by the periconia genus, was only identified in controls. at the specie-level, bacteria, fungi and viruses were common to at least two cohorts, among which pseudomonas aeruginosa, streptococcus mitis, prevotella melaninogenica, peptostreptococcus stomatis, candida albicans and hsv were commonly identified irrespective of cohorts, whereas haemophilus influenzae, staphylococcus aureus, streptococcus genomosp. c , streptococcus parasanguinis and streptococcus pneumoniae were commonly identified in patients regardless of pneumonia type (fig. s ) . additionally, bacteria, fungi and viruses were common to controls and at least one pneumonia cohort, whereas bacteria, fungi and viruses were common to at least two pneumonia cohorts (fig. s ). in contrast, many microorganisms ( bacteria, fungi and viruses) were restricted to one of cohorts ( bacteria and fungi only were identified in the cap cohort; bacteria and fungi only were identified in the vap cohort; bacteria, fungi and one virus only were identified in the nv icu-p cohort; bacteria only were identified in the ap cohort; bacteria, fungi and one virus only were identified in controls) (fig. s ). microbial profiles of positive pneumonia bal fluids showed that ( %) were characterized by the presence of one microorganism, whereas ( %) were polymicrobial. in controls, ( %) of bal fluids were characterized by the presence of one microorganism, whereas ( %) were polymicrobial (data s and s ). available clinical data for patients and controls showed that monobacterial patients were more frequently, but statistically insignificant, subjected to initial antibiotic therapy than polymicrobial ones (p = . ; table and table s ). in ventilated subjects, monomicrobial patients have a slightly shorter period of mechanical ventilation prior to the pneumonia episode as compared to polymicrobials. monomicrobial controls have a remarkably shorter period of mechanical ventilation before sampling compared to polymicrobials (p = . ; table ). the same observation was showed for length of icu stay prior to sampling and for total length of hospital stay. according to these observations, the polymicrobial profiles of controls seem to be partially related to the high duration of icu stay before sampling. however, the icu mortality was higher in monomicrobial patients than in polymicrobial ones (p = . ). the icu mortality rate was higher in pneumonia patients for whom bal fluids exhibited only viruses or fungi, or both than in monobacterial or polybacterial patients (p = . ; table s ). a higher but not statistically significant icu mortality was also observed in pneumonia patients for whom bal fluids exhibited only viruses or fungi, or both than in controls with the same profile (p = . ; table s ). we next compared the bacterial communities found in our study to those found in lung specimens in five previous studies which were based on s rdna amplification [ , , [ ] [ ] [ ] . comparative analyses of lung microbiota between these studies showed that different genera were found in all of them. among these genera, genera are widely distributed within the studies including gemella, haemophilus, megasphaera, neisseria, porphyromonas, prevotella, pseudomonas, staphylococcus and streptococcus genera which have commonly been found irrespective of study. in contrast, genera were restrictively identified across the studies (table ) . however, at the species level (only the studies that determined bacterial species were included [ , , ] ), comparative analyses showed that from bacteria commonly distributed within the studies, escherichia coli, haemophilus influenzae, prevotella oris, pseudomonas aeruginosa, staphylococcus aureus and streptococcus mitis were commonly found in the four studies. in contrast, bacteria were restrictively identified across the studies (fig. s ) . consequently, comparative analysis at the specie-level showed that some bacteria, such as pseudomonas aeruginosa and staphylococci, are commonly found in pulmonary specimens. however, the pattern of distribution of many other species is distinctly heterogeneous and depending on the specific study and disease. variation of lung microbiota, from one individual to another and from one study to another, suggests that the repertoire of microorganisms associated with respiratory infections still remains incompletely understood. previous studies performed on respiratory specimens showed that unexpected bacteria are increasingly identified, as well as studies describing isolated cases of respiratory infection due to an unexpected bacterium that was detected using molecular techniques [ , , , [ ] [ ] [ ] [ ] . this study extends the analyses to bacteria, fungi and viruses in a large population of icu pneumonia using comprehensive molecular testing. our results demonstrate that nearly % of the microbial species found had not been previously reported in lung samples from pneumonia. therefore, the composition of icu-pneumonia microbiota is more complex, more extensive and more diverse than originally expected. however, we raise the question on the actual role of these microorganisms in pneumonia. indeed, our study reveals that some pathogens that till now had been considered typical for icu pneumonia, such as pseudomonas aeruginosa and streptococcus species, or viruses, such cmv and hsv, can be detected as commonly in controls as in patients (fig. s and s ). this result is emphasized by more recent studies by erb-downward et al. and hilty et al. who showed that a community of lung-resident bacteria including pseudomonas and streptococcus genera can be identified in patients with chronic obstructive disease or asthma, as well as in healthy people [ , ] . our study agrees with the recent literature and highlights the existence of a core pulmonary microbiota, confirming the non-sterility of the lung [ , ] . more interestingly, we showed that pulmonary microbiota heterogeneity can be observed between patients and controls, among pneumonia cohorts and among patients within the same cohort. high pulmonary microbiota heterogeneity was also observed between our study and other previous works performed on cystic fibrosis or vap [ , , ] (fig. s ) . we found that some bacteria were commonly identified in all studies, whereas many others were only identified in one study, and most of these were unexpected. consequently, lung microbiota can vary greatly between individuals, depending on underlying diseases, habits and geographic origin. additionally, these unexpected microorganisms may explain a lack of response to drug therapies in some pneumonia patients. therefore, the possible extension of empiric treatments to cover a large spectrum of microorganisms, especially for patients who do not respond adequately to initial treatment, is questionable. another interesting observation was that mixed infection was observed in many bal fluids from pneumonia patients. interestingly, recent works report that probable interactions between parasitic species can occur in their host, and these reports also show that infection with a given microorganism may increase or decrease susceptibility to infection by another one or can create a cross-immunity response [ ] [ ] [ ] [ ] [ ] [ ] [ ] . such interaction remains to be investigated. moreover, by comparing molecular testing to standard routine methods, this study reveals that many pneumonia-associated pathogens are fastidious or uncultured and highlights a wide discrepancy between culture and molecular microorganism repertoire. our study also shows that the molecular assay remains a more efficient method to detect microorganisms in the pneumonia samples, independently of atmospheric conditions and medium nutrient supplements, which are particularly important for culture, especially for fastidious microorganisms. in addition, microorganism diagnosis was obtained for ( %) episodes of pneumonia by molecular tools compared with ( %) pneumonia episodes for which microorganism diagnosis was successfully done by culture (table s ). in particular, molecular tools seem to be far more sensitive than culture for bacterial detection. this observation is based on the high number of microorganisms, especially bacteria which were identified by molecular methods compared with those detected by culture. in fact, standard and special bal cultures identified few, essentially easily-grown and strictly aerobic or facultative anaerobic bacteria ( species) compared to molecular tools which identified bacterial species (p, . ) (fig s and s ). molecular tools enabled the identification of unexpected bacteria which usually colonize vaginal tracts, such as atopobium vaginae and peptoniphilus lacrimalis, or of other bacteria coming from unexpected animal origins, such as chlamydia pscittasi, enterococcus canintestini and streptococcus bovis, or of potentially known to be associated with other diseases, such as tropheryma whipplei, which were not identified by culture. furthermore molecular tools allowed the detection of pathogenic bacteria such as mycobacterium sp. and mycoplasma pneumoneae, for which identification attempts by culture using specific media were failed due to culture biases. moreover, all bacteria that were first associated with pneumonia in the present study were exclusively identified by molecular methods. these findings are coherent to results from previous studies on bacterial communities of respiratory diseases, including pneumonia, which showed that molecular assays are more sensitive than culture [ , , ] . however, although molecular approaches identified more fungal species than culture, fungal diagnoses were positive for ( %) episodes of pneumonia by culture compared with ( %) pneumonia episodes for which fungal diagnosis was successfully obtained using molecular tools. thus, fungal bal culture was more sensitive to detect some cultured fungi, such as candida species, than molecular approaches. another important finding was the high number of novel bacterial species never previously described to date (bacteria with blastn similarity less than %). this result is concordant with similar studies of pneumonia and cystic fibrosis subjects [ , ] and shows that in respiratory infections, more complex bacteria populations can exist, among which novel bacteria had never been previously identified. moreover, this finding was also supported by other studies performed on endodontic infections, demonstrating that many novel bacteria essentially resident in the oropharyngeal and dental plaque flora can be detected in these infections [ , ] . the oropharyngeal and dental plaque flora is potentially suspected to be a reservoir and, thus, the source of icu pneumonia pathogens, which could suggest that these novel bacteria were inhaled through oropharyngeal tracts [ , ] . nevertheless, molecular tools alone cannot give positive results in some cases, or they could just identify microorganisms known to be commensal or less pathogenic, where it may be useful to perform other tests, such as serology. this was the situation for pneumonia patients for whom serology provided evidence for influenza a virus infection, whereas qpcr performed on their bal fluids was negative. moreover, by combining culture-based methods, blood culture and serology to molecular approaches we significantly increase the probability to detect microorganisms in the pneumonia episodes. in fact, by using these exhaustive laboratory diagnostic tools, we failed to identify a microbial agent in only % of the pneumonia episodes, which is significant when compared to previous studies where the microbial agent was not found in more than % of episodes of pneumonia (p, . ) [ ] . however, the clinical significance of these microorganisms and their role in the etiology of pneumonia remain difficult to be cleared as their correlation with the disease causation remains to be studied and confirmed in the future. nevertheless, our findings suggest that it would be highly recommended to develop a rapid molecular test to target, besides typical pathogens, potential pathogens known to be fastidious or uncultured (such as anaerobic ones), and that it would be useful to add it to existing routine standard techniques. in summary, our study reveals that the respiratory microbiota is more complex than expected. a large study was implemented in our laboratory over a threeyear period (january through december ) to perform an exhaustive etiologic diagnosis of pneumonia. the study involved three icus in the public hospitals of marseille, france (one medical icu and two medico-surgical icus). a total of bal fluids, blood samples and urinary samples from icu pneumonia patients were studied. a diagnosis of community-acquired pneumonia, ventilator-associated pneumonia and aspiration pneumonia was defined as previously described [ ] [ ] [ ] . bal and blood sampling were performed as previously described [ ] . a cohort of icu patients without pneumonia was studied as controls. pneumonia patients exhibited episodes of community-associated table . comparison of lung microbiota between different studies. harris et al. [ ] bittar et al. [ ] bahranimougeot et al. [ ] erb-downward et al. [ ] hilty et al. [ ] studied nucleic acid extraction, pcr amplification, cloning and sequencing bacterial and fungal dna extraction from bal samples was performed on a magnapure lc workstation (roche diagnostics, meylan, france), using a magna pure lc dna isolation kit ii (roche diagnostics) as previously described [ ] . viral nucleic acids were extracted from ml of bal fluids using an mdx workstation and the qiaamp virus biorobot mdx kit according to the manufacturer's instructions. dna was tested by pcr for bacteria using broad-range primers targeting the s rdna gene; pcr was also used to test for universal fungi using broad-range primers targeting intergenic spacer of s rdna gene (eurogentec, seraing, belgium) ( table ). pcr product was cloned and approximately clones were screened per library. pcr, cloning and sequencing were performed as previously described [ ] . the obtained sequences were assembled and analyzed by chromaspro software and then blasted against those available in the genbank database (www.ncbi.nlm.nih.gov) for species identification. chimeric sequence search was performed with black box chimera check (b c ) program [ ] and by examining the blast profile of each sequence. suspected chimeric sequences were discarded from the study. sequences showing a similarity of . % were considered to be known species, whereas sequences showing a similarity of , % were considered to be novel species. legionella sp., afipia sp.,bradyrhizobium sp., azorhizobium sp., mesorhizobium sp., balneatrix alpaca and pneumocystis carinii were tested by pcr using specific primers followed by sequencing of pcr products ( table ). the sequences have been deposited in the genbank database (accession nu jf -jf ). standard bacteriological bal culture and blood culture as phenotypic identification of isolated bacteria were performed as previously described [ , ] . a cfu cut-off defined a positive bal culture. blood culture were processed as previously described [ ] . identification of fungi present in bal or blood samples was performed using a standard culture as previously described [ , ] . viral culture for cytomegalovirus, herpes simplex virus, parainfluenza viruses (types and ), respiratory syncytial virus, varicella-zoster virus, influenza viruses (type a and b), and enterovirus was performed using shell-vial culture as previously described [ , ] . amoeba co-culture were performed in microplates on acanthamoeba polyphaga as previously described [ ] . tentative isolations of mycobacterium sp., legionella sp. and mycoplasma pneumoniae were performed by using bactec mb automate, bcye agar plates and sp medium as previously described [ ] [ ] [ ] . results obtained using routine culture are available in table s ,s ,s ). mycobacterium sp., m. tuberculosis, m. avium group, bosea sp, parachlamydia sp., coxiella burnetii, chlamedia pneumoniae, chlamedia psittaci, mycoplasma pneumoniae, aspergillus sp., mimivirus, cmv, hsv, parainfluenza viruses and , respiratory syncytial virus, rhinovirus, metapneumovirus, varicella-zoster virus, influenza viruses a and b, enterovirus, and coronaviruses oc- , -e and nl- were detected using quantitative pcr. quantitative pcr was performed using a lightcyclerh instrument (roche diagnostics, meylan, france) in conjunction with the quantitect probe pcr kit. primers and probes used to identify these microorganisms are reported in table . the reaction was performed as previously described [ ] . for rna viruses, rna was first reverse transcribed using multiscribe tm reverse transcriptase (applied biosystems, courtaboeuf, france) as previously described [ ] . sera from patients were tested by immunofluorescent assay (ifa) for coxiella burnetii, bartonella quintana, bartonella henselae, legionella pneumophila, legionella anisa [ , , ] . viral serologies for adenovirus, cytomegalovirus, herpes simplex, parainfluenza viruses and , varicella-zoster virus and, influenza viruses a and b were performed using standard serologic methods (immunofluorescent assay or enzyme linked immunosorbent assay) [ ] . hemagglutination inhibition, immunoperoxidase staining and elisa techniques were used in-house to identify aspergillosis. l. pneumophila antigenuria and cmv pp antigenemia were tested for as previously reported [ , ] . results obtained using routine serology and antigenemia for viruses and fastidious pathogens are available in table s . bacterial and fungal nucleic acid sequences obtained from broad-range primer pcr were aligned with bioedit program (http://www.mbio.ncsu.edu/bioedit/bioedit.html) and phylogenetic trees were create with mega software version . using the neighbor-joining method and the kimura- parameter [ ] . species having sequence similarities , % with those available in genbank databases were also blasted and classified in silico using ''classifier'' program in the ribosomal database project (http:// rdp.cme.msu.edu/) [ ] . statistical analyses were performed using chi square test, fisher's exact test, students t-test or mantel-haenszel's chi square test when appropriate. p values that were less than or equal to . were considered significant. the pubmed database (www.ncbi.nlm.nih.gov/pubmed/) and google website (http://www.google.fr/) were used to search whether species identified in our study had been previously reported in cases of pneumonia for articles published between and march , with the combined search term ''species name'' and ''pneumonia'', ''lung'' or ''infection.'' additional articles were identified by hand-searching the references of selected papers. additional search terms included ''microbiology'', ''diagnosis'', '' s'' and ''molecular detection'' were used. only publications in english were considered. papers in languages other than english were considered only when their abstracts in english were available. figure s schematic representation of microorganisms commonly identified in pneumonia and control cohorts, and those only detected in one cohort. fungi are shown in rectangles, viruses in octagons, and bacteria in circles. the name of each microorganism is indicated. (tif) figure s schematic representation of microorganisms that were commonly identified between each pneumonia form and controls, and those which were detected in only one cohort. fungi are shown in rectangles, viruses in octagons, and bacteria in circles. actinobacteria are shown in red, bacteroidetes in yellow, chlamydiae in orange, firmicutes in green, fusobacteria in purple, proteobacteria in blue and tenericutes in sky blue. cap, community-acquired pneumonia; vap, ventilatorassociated pneumonia; nv icu-p, non-ventilator icu pneumonia; ap, aspiration pneumonia; and cs, control subjects. (tif) figure s comparison of the bacterial communities found in our study with those found in lung specimens in three previous studies. novel phylotypes are not shown. actinobacteria are shown in red, bacteroidetes in yellow, chlamydiae in orange, firmicutes in green, fusobacteria in purple, proteobacteria in blue and tenericutes in sky blue. the name of the first author of each study and the name of each bacterium are indicated. the comparative analysis was conducted using cytoscape software. vap, ventilator-associated pneumonia; cf, cystic fibrosis. (tif) figure s molecular methods compared to standard routine culture for bacteria identification. text s bal culture, blood culture and serology results. data s detailed data about the relative abundance and richness of each species in their corresponding library. data s schematic data about the relative abundance and richness of each species in the corresponding library. table s species only detected in bal from pneumonia patients by molecular assays. (docx) nosocomial pneumonia in the intensive care unit acquired during mechanical ventilation or not etiology and diagnosis of pneumonia requiring icu admission guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia active cytomegalovirus infection is common in mechanically ventilated medical intensive care unit patients cytomegalovirus. an unexpected cause of ventilator-associated pneumonia viral infections in the icu herpes simplex virus: a marker of severity in bacterial ventilator-associated pneumonia bronchoscopic bal in the diagnosis of ventilatorassociated pneumonia molecular identification of bacteria in bronchoalveolar lavage fluid from children with cystic fibrosis microbial diversity in the sputum of a cystic fibrosis patient studied with s rdna pyrosequencing molecular detection of multiple emerging pathogens in sputa from cystic fibrosis patients tropheryma whipplei in patients with pneumonia detection of plant dna in the bronchoalveolar lavage of patients with ventilator-associated pneumonia molecular analysis of oral and respiratory bacterial species associated with ventilator-associated pneumonia analysis of the lung microbiome in the ''healthy'' smoker and in copd disordered microbial communities in asthmatic airways chlamydia-like bacteria in respiratory samples of community-acquired pneumonia patients acetobacter indonesiensis pneumonia after lung transplant francisella philomiragia adenitis and pulmonary nodules in a child with chronic granulomatous disease severe pneumonia with leptotrichia sp. detected predominantly in bronchoalveolar lavage fluid by use of s rrna gene sequencing analysis human polymicrobial infections selection for staphylococcus aureus small-colony variants due to growth in the presence of pseudomonas aeruginosa burkholderia pseudomallei, b. thailandensis, and b. ambifaria produce -hydroxy- -alkylquinoline analogues with a methyl group at the position that is required for quorum-sensing regulation pseudomonas aeruginosa extracellular products inhibit staphylococcal growth, and disrupt established biofilms produced by staphylococcus epidermidis analysis of pseudomonas aeruginosa -hydroxy- -alkylquinolines (haqs) reveals a role for -hydroxy- -heptylquinoline in cell-to-cell communication prokaryote-eukaryote interactions identified by using caenorhabditis elegans candida albicans impairs macrophage function and facilitates pseudomonas aeruginosa pneumonia in rat molecular analysis of bacteria in asymptomatic and symptomatic endodontic infections molecular and cultural analysis of the microflora associated with endodontic infections colonization of dental plaque: a source of nosocomial infections in intensive care unit patients genetic relationships between respiratory pathogens isolated from dental plaque and bronchoalveolar lavage fluid from patients in the intensive care unit undergoing mechanical ventilation infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults amoebaresisting bacteria and ventilator-associated pneumonia aspiration pneumonitis and aspiration pneumonia clinical significance of a positive serology for mimivirus in patients presenting a suspicion of ventilator-associated pneumonia black box chimera check (b c ): a windows-based software for batch depletion of chimeras from bacterial s rrna gene datasets direct identification of bacteria in positive blood culture bottles by matrix-assisted laser desorption ionisation time-of-flight mass spectrometry evaluation of nested and real-time pcr assays in the diagnosis of candidaemia quantification of leishmania infantum dna by a real-time pcr assay with high sensitivity ameba-associated microorganisms and diagnosis of nosocomial pneumonia isolation of new fastidious alpha proteobacteria and afipia felis from hospital water supplies by direct plating and amoebal co-culture procedures cost-effectiveness of blood agar for isolation of mycobacteria diagnosis of legionnaires' disease. an update of laboratory methods with new emphasis on isolation by culture mycoplasma and ureaplasma. - q fever serology: cutoff determination for microimmunofluorescence value of microimmunofluorescence for diagnosis and follow-up of bartonella endocarditis detection of legionella pneumonophila antigen in urine by enzyme-linked immunospecific assay mega : molecular evolutionary genetics analysis (mega) software version . naive bayesian classifier for rapid assignment of rrna sequences into the new bacterial taxonomy key: cord- -ksfs kv authors: nadeem, ashraf; hamed, fadi; saleh, khaled; abduljawad, baraa; mallat, jihad title: icu outcomes of covid- critically ill patients: an international comparative study date: - - journal: anaesth crit care pain med doi: . /j.accpm. . . sha: doc_id: cord_uid: ksfs kv nan the observed icu mortality rate of covid- is highly variable [ ] [ ] [ ] [ ] . also, no studies have reported the icu outcomes of covid- critically ill patients in the united arab emirates. the aim was to compare the published icu case series [ ] [ ] [ ] [ ] [ ] , including ours, to understand the reasons for the differences in icu mortality and if it is related to different icu management of these patients (different rates of mechanical ventilation). the institutional ethics committee of cleveland clinic abu dhabi approved the study (number: a- - ), and a waiver of informed consent was obtained. series of icu patients with confirmed covid- infection from published cohorts were included [ ] [ ] [ ] [ ] [ ] . regarding our study, all consecutive adult patients admitted to our icu between march and may , , with confirmed sars-cov- infection (virus detected by a real-time reverse transcriptase-polymerase chain reaction assay of a nasopharyngeal sample) were included. de-identified data from the electronic medical record were collected. continuous variables are expressed as mean ± sd or as median [interquartile range], and proportions were used for categorical variables. five icu cohorts from four different countries (china, usa, italy, and spain) [ ] [ ] [ ] [ ] [ ] were included along with our case series. the mean/median age was comparable between all these reported cohorts ( - years) except for our report, which was lower ( ± years) (table ) . sofa score was similar in atlanta and vitoria cohorts, but was higher than observed in our study. apache ii score was comparable between the different reports (table ) . mechanical ventilation (mv) rate in our patients was the same as in seattle and atlanta reports ( % and %, respectively), but higher than in the wuhan series ( %), and lower than in lombardy and vitoria series ( % and %, respectively) ( table ) . prone position rate was comparable in the usa, china, and italy cohorts (~ %), higher in the spain report ( %), but much higher in our study ( %). the use of extracorporeal membrane oxygenation (ecmo) was similar in our and wuhan reports ( %), but much higher than in the other cohorts (table ) . the mortality rate in wuhan and seattle were much higher ( % and %, respectively) compared with the other reported icu cohorts ranging from % to % (table and figure ). the mortality rate among patients who required mv was not reported in the lombardy, and seattle cohorts. the mortality rate among mechanically ventilated patients was much higher in the wuhan study ( %) than in the other case series ( % to %) ( table ) . as of june , , our overall mortality rate was % and % among mechanically ventilated patients. the median duration of mv was comparable between the seattle and atlanta cohorts, but lower than in our study, which was . days [ - ] ( table ). the median icu length of stay (los) was also similar in the different reports, but much shorter than in our cohort ( [ - ] days) ( table ) . [ , ] , italy [ ] , and spain [ ] . the rate of mv varied between the different cohorts [ ] [ ] [ ] [ ] [ ] (table ) some icus might be in favour of the early intubation approach in patients with high oxygen requirements [ ] . another explanation could be due to practice variation between centres. in some countries, high-flow oxygen therapy or non-invasive ventilation might be delivered mainly in hospital wards [ ] , whereas only patients at high risk of intubation were admitted to the icu. our rates of prone position and ecmo use were markedly higher than the other cohorts [ ] [ ] [ ] [ ] , reflecting the severity of our patients. in the earliest reports from wuhan [ ] , and seattle [ ] , the mr of icu covid- patients were very high, raising concerns about the unfortunate outcome of these patients, especially among those who required mv. however, in the recent reports from atlanta [ ] , italy [ ] , and spain [ ] , the mortality rate was much lower, ranged from % to % (figure ). the use of mv cannot explain the difference in mortality rate between the earliest [ , ] and recent cohorts [ ] [ ] [ ] . indeed, the observed mortality rate among patients requiring mv were % to % in the latest reports, even with higher rates of mv [ , ] . in more recent data from the united kingdom, % of those who received mv died [ ] . the later arrival of the covid- pandemic in different countries or regions might have provided time to establish organisational structures, prepare personnel, and create clinical protocols, which might explain the difference in mortality rate between cohorts [ ] [ ] [ ] [ ] [ ] . a lower mortality rate ( %) was reported in our patients, even among those who received mv ( %). the younger age, lower sofa score, and a higher rate of prone position might explain the mortality difference between our and the reported studies (table ) our data, along with the recent findings, suggest that the mortality rate in icu covid- patients are comparable and might be lower than those observed with acute respiratory distress syndrome (ards) caused by other viral infections [ ] . the longer duration of mv and icu los, in our study, is due to the longer follow-up period (median days) compared with the other cohorts [ ] [ ] [ ] [ ] [ ] . this study has several limitations. first, the retrospective and descriptive design of all the included cohorts. second, data from other countries are not represented in our study. third, outcome data should be interpreted with caution as most patients were still hospitalised in icu in many of the included cohorts. however, in our case series, only nine patients ( %) remained in hospital at the time of data censoring on june , . among them, only five patients were still in icu. as a result, our reported mr would not change too much. in conclusion, icu mortality of covid- patients is highly variable between the different cohorts and not explained by the mv's different rates. in the recent reports, the observed mortality rate for patients who required mv ranged from % to %, which are comparable to those seen with ards from other origins. clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study covid- in critically ill patients in the seattle region -case series icu and ventilator mortality among critically ill adults with coronavirus disease baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region sars-cov- in spanish intensive care units: early experience with -day survival in vitoria. anaesth crit care pain med wuhan (china) (n = ) [ ] lombardy (italy) (n = ) [ key: cord- -w h rir authors: nan title: abstracts cont. date: - - journal: clin microbiol infect doi: . /j. - . . c.x sha: doc_id: cord_uid: w h rir nan objectives: in this study we wanted to examine the prevalence of caga, vaca and baba status in helicobacter pylori (hp) isolates from patients with gastritis or peptic ulcer; to compare them and to know if there were any relationships between those virulence factors in each group. methods: gastric biopsy specimens from hp positive patients with peptic ulcer ( cases) and gastritis ( cases) were studied. dna was extracted and pcr performed to detect caga, vaca s / s alleles and baba gene. results: gastritis: in % of strains, the expected caga fragment was amplified by pcr; % carried the s -allele and % the s allele; baba gene was detected in % of strains. peptic ulcer: % of strains were caga+; % were vaca s -allele and % were vaca s -allele; baba gene was detected in % of strains. no significant differences in the prevalence of caga, vaca or baba were found in both groups. neither of them showed relationship between the presence of baba gene and caga gene or vaca s /s -alleles. conclusions: although the risk of developing more serious gastric lesions increased as the number of virulence factor genes are accumulated in a given hp strain, we did not find any significant differences or relationship in the caga, vaca or baba status between the hp isolates from patients with gastritis or peptic ulcer in this study. a low percentage of baba gene was found in both groups. helicobacter pylori cells in clinical and wastewater samples p. piqueres, y. moreno, a. jimenez, j. hernández, m. ferrú s valencia, e introduction: the presence of viable but non-cultivable helicobacter pylori cells in environmental samples may underestimate the importance of this way for its transmission. the determination of resistance to antibiotics in these strains is important to a better understanding of the epidemiology of the infection. objectives: we have evaluated the use of a fluorescent in situ hybridisation (fish) assay directly from biopsies and wastewater to detect h. pylori and simultaneously its macrolide resistance genotype. methods: a total of gastric biopsies samples from ulcerpatients were homogenised in ml of selective broth, and a ll aliquot was used for fish detection. twenty-nine wastewater samples collected from different treatment plants were centrifuged and subsequently fixed with % paraformaldehyde solution for h at c and then washed with % pbs buffer. hpy probe, a s rrna targeted fitc-labelled oligonucleotide sequence was used for the detection of all h. pylori strains. in addition to cla - , a set of three cy -labelled probes was used for the detection of s rrna mutations associated with resistance to clarithromycin. hybridisation was performed with % formamide at c for h. results: fish allowed the detection of h. pylori in out of clinical samples and samples were positive in wastewater. the % of the positive biopsies showed the presence of clarithromycin resistant strains and . % of the positive wastewater samples yielded resistance genotype to this macrolide. by using a double filter set we could observe directly the clarithromicyn resistant h. pylori organisms in the samples and its morphology in the different types of environments. the predominant cells' morphology in both clinical and wastewater samples was of helicoidal form. conclusions: the fish is a specific and rapid culture-independent method to determine directly the presence of clarithromycinresistant h. pylori cells in clinical and environmental samples. results showed the presence of macrolide resistant cells in water and, therefore, water must be considered a potential route of h. pylori transmission. acknowledgement: this work was supported by ministerio españ ol de ciencia y tecnología, project agl - -c - . objectives: helicobacter pylori is a leading cause of various gastrointestinal diseases such as atrophic gastritis and gastroduodenal ulcer. the caga gene product caga is directly injected into the bacteria-attached host cells and deregulates intracellular signalling pathways and thereby initiates pathogenesis. caga gene is located on pathoginicty island but the function of other genes on the island is unknown. the goal of the work was to evaluate the impact of cag island genotype on the outcome of the therapy. materials and methods: three groups of patients each with total number of patients were investigated. first group was taking a typical antibiotic therapy (amoxicillin, claritromycin, rabeprasol), patients in the second group were treated with the same antibiotics together with probiotic laminolact (e. faecium strain l- in the form of bon-bons together with pectin, soy bean amino acids and sea weed), and the third group was taking only laminolact without any antibiotic. the genotype was determined by pcr with dna primers against three h. pylori genes ureb, caga and cagh. cagh was used as a marker cag island integrity and ureb was a marker of h. pylori presence. five different genotypes were determined: ureb+,cagaÀcaghÀ, ure+,cagaÀcagh+, ureb+,caga+cagh+, ureb+,cagaÀcagh+ and ureb+,caga+caghÀ . treatment with antibiotics alone was leading to % of eradication. the best eradication percentage ( %) took place in the second group where classical antibiotic treatment was taken together with probiotics. interestingly, probiotic treatment alone was giving % of eradication. results of the therapy were highly consistent with cag genotype. patients were found to be statistically less susceptible (p < . ) to the therapy in case when the entire cag regulon was present regardless of the therapy used. this fact suggests immunosuppressant function of caga or other proteins encoded by the genes on cag pathogenicity island. conclusion: the effect of h. pylori eradication depends on cag pathogenicity island genotype. probiotics including e. faecium l- might significantly improve the anti-h. pylori treatment. screening of p. aeruginosa isolates. this study was done to determine if the p. aeruginosa strains isolated from the cultures of patients hospitalised in the infectious diseases unit were from an individual strain. this technique was preferred because it is cheap and provides a rapid detection opportunity. methods: samples obtained from the clinical specimens of the patients and from the hands of the staff of the infectious diseases unit were cultured. of the samples, were isolated from blood, six from sputum, from drainage and from the hands of the medical staff. p. aeruginosa identification was made by api ne system. dna was extracted from the culture material by phenol-chloroform extraction method. ap-pcr was performed by using the primer ¢-gtt gcg atcc- ¢, and subjected % page. band patterns were visualised by silver staining. results: in none of the isolates of the hospital staff p. aeruginosa was cultured. out of the clinical samples of the patients, different genotypes were determined. conclusions: the p. aeruginosa strains of the patients were individual strains, neither related to the staff of the department nor to a specific patient. objectives: pseudomonas aeruginosa is a leading cause of nosocomial infections, particularly pneumonia or sepsis, on intensive care units. its high intrinsic antibiotic resistance and the ability to develop multidrug resistance pose, especially for critically ill patients, serious therapeutic problems. since, culture based techniques for pathogen identification and resistance determination requires at least days, a calculated antibiotic therapy may harbour the risk of an increase in antibiotic resistance and therapy failure. therefore, the development of a fast and reliable identification and antimicrobial susceptibility test is essential for the improvement of the therapy. the aim of the present study was to develop an oligonucleotide-array for a quick, genotypic test of antibiotic susceptibility combined with the determination of relevant virulence factors. methods: dna from different clinical specimen was isolated with a modified qiamp dna blood mini kit. template dna was amplified and simultaneously labelled with cy during multiplex pcr. oligonucleotide capture probes ( - mer), containing a poly-t( )-spacer at the ¢-end, were spotted on epoxy-slides to build an array covering regulatory genes of multidrug efflux pumps (mexr, mext, nfxb), alginate synthesis (muca), metallo-beta-lactamases (bla-vim, bla-imp), aminoglycoside modifying enzymes (aac, aad, aph) and virulence factors (exou, exos, exot) . results: of clinical p. aeruginosa isolates could be correctly genotyped. three isolates displayed a hybridisation pattern that could be assigned neither to wild-type nor to known mutations. a sequence analysis of these isolates revealed an unknown mutation in mexr and nfxb. hybridisation with dna from other non-fermenter or enterobacteriacea showed no crossreactivity. genotypic resistance profile of p. aeruginosa deduced from the array data correlated fully with the susceptibility pattern obtained by standard tests. the sensitivity of the array was genome equivalent even with an exp -fold excess of non-pseudomonas dna. the whole analysis, including dna processing, array hybridisation and data evaluation could be performed in less than h. conclusions: due to the good correlation with standard procedures, the pseudomonas-array may be used for a rapid susceptibility test even directly from clinical samples. combined analysis of antibiotic resistance and virulence factors may improve the outcome of an antimicrobial therapy. objectives: because of a high prevalence of pseudomonas aeruginosa infections in cystic fibrosis (cf) patients, we conducted a study to assess p. aeruginosa isolates collected over years from the sputa of cf adult patients attending an italian cf centre. some phenotypic characters of bacteria (o-serotype, motility, production of enzymes and resistance to antibiotics) and their pfge genotypic patterns were evaluated to analyse for the presence of epidemic strains. moreover some sequential isolates collected from cf patients were investigated to look for the chronicisation of the infection. the strains were identified biochemically. the o-serotype was determined by slide agglutination; the production of enzymes (protease, elastase, gelatinase, haemolysin, betalactamase) and motility were detected using specific techniques. the antibiotic susceptibility was analysed by the vitek ams system and disc diffusion method. pfge was used to discriminate the genotypes of p. aeruginosa. results: in our hands, o serotyping failed to identify . % of isolates, considering the bacteria collected at the onset of colonisation; the most frequent serotypes were o: , o: and o: . moreover, the percentages of protease, haemolysin, gelatinase and elastase production were respectively . , . , . and . , whereas . % of the microorganisms were non-motile. pfge allowed the typing of all strains except one. the heterogeneity of isolates indicated that cross-infection is unusual; we also observed in several strains isolated in the last years a predominant pattern. some cf patients were harbouring the same p. aeruginosa genotype in sequential isolates and the susceptibility of bacteria to antibiotics tested varies greatly, also in strains belonging to the same pfge profile. conclusion: our results indicate no relationship between genotype and phenotype suggesting that the phenotypic variability is due to an adaptation of the microorganism to the host. moreover, the presence of several strains with the same genotypic profile suggests a possible cross-colonisation in cf patients due to the circulation of a transmissible strain. for ser/thr protein kinases and phosphoprotein phosphatase of pseudomonas aeruginosa and analysis of their properties j. nedvedova, p. lnenicka, k. hercik, p. branny prague, cz objectives: pseudomonas aeruginosa is an opportunistic pathogen that causes infections in eye, urinary tract, burn, and immunocompromised patients. three genetic loci of p. aeruginosa which encodes ser/thr protein kinases were identified. two of them, ppka and stk , were also characterised but little is known about their function in cell signalling. gene stp localised upstream of stk encodes stk cognate phosphoprotein phosphatase. a possible relationship between quorum sensing and protein phosphorylation in gram-negative bacteria has already been described. the aim of this work was to prepare unmarked deletion mutants in ppka, stk and stp genes and to find out if the linkage between quorum sensing and protein phosphorylation in p. aeruginosa exists. to prepare the unmarked deletion mutants an improved method for gene replacement in p. aeruginosa which employs a broad-host-range flp-frt recombination system for site-specific excision of chromosomally located dna sequences was used. the phosphorprotein pattern and biochemical properties of the mutants were examined. double mutant in homoserine lactone synthase genes (lasi and rhli) was also subjected to phosphoprotein pattern analysis. results and conclusion: stk , stp and a double mutant stk /stp were prepared. no differences were found in either biochemical properties or phosphoprotein pattern. deletion of ppka gene failed due to the integration of vector into the unknown, but specific site of p. aeruginosa genome. the comparison of phosphoprotein patterns of lasi, rhli double mutant and wild type strain showed important differences. this result suggested that phosphorylation circuit operating in p. aeruginosa is related to quorum sensing system(s). objectives: botulism is a rare but potentially fatal disease generally caused by the neurotoxin produced by clostridium botulinum. symptoms of the disease include paralysis which is due to bont inhibiting neuro-transmitter release. laboratory diagnosis of botulism relies on detecting bont in clinical or food specimens using in vivo tests. diagnosis also includes isolation and identification of the bacterium which again relies on in vivo tests for detection of toxin production from the bacterium growing in vitro. we previously described the development of real-time pcr assays for bonta, b and e gene fragments, and here presented further evaluation data. methods: dna was extracted from faeces, enrichment cultures of naturally contaminated food and clinical samples and from colonies growing on agar plates. taqman-based assays for bonta, b and e gene fragments were performed using a sequence detector (applied biosystems). the assays were performed as a duplex reaction for bonta and b using fam and vic labelled probes, respectively, and as a monoplex for bonte using a single fam labelled probe. all samples were tested by using the conventional bio-assay and results were compared with real-time pcr assay results. results: pcr and bio-assay were found to be consistent in all samples except those that contained 'silent b' neurotoxin genes in addition to bonta genes. the samples tested comprised: direct examination of six faecal samples, enrichment cultures for six clinical and foods and pure culture growing in vitro. conclusion: this study is the first to report the successful identification of different c. botulinum toxin types for wild type bonta, b and e by using taq-man real-time pcr assay. this assay has already provided a useful adjunct to in vivo tests for the rapid identification of bacteria containing bont genes in wild type c. botulinum. (vntrs) polymorphisms for genotyping 'rickettsia conorii complex' strains l. vitorino, r. de sousa, l. zé-zé, f. bacellar, r. tenreiro lisbon, p introduction: mediterranean spotted fever (msf) is an acute, febrile tick transmitted rickettsiosis caused by strains of rickettsia conorii complex. msf is endemic in portugal and is an obligatory notifiable disease. during - the annual incidence rate of the disease was . / inhabitants. in portugal, msf is caused by two strains: r. conorii malish and israeli tick typhus (itt). this strain was isolated, for the first time in , from a patient. moreover, data from the national institute of health points out that half of msf cases occurring in portugal are caused by itt, showing a similar prevalence of infection as r. conorii malish. objective: in this work we present a pcr-based method to detect vntr sequences that enables amplicon size differentiation between r. conorii malish and itt human isolate. vntrs have a high discriminatory capacity not only because they contain greater diversity but also because they often vary in copy, therefore they are being used for molecular typing of many bacteria species. methods: human strains were isolated by shell-vial technique from patient's total blood. dna from tick isolates and reference strains were also used for comparative purposes. vntr loci were identified by the tandem repeats finder software within the r. conorii genome. the vntr locus was selected based on the following criteria: repeat units nucleotides in length, % nucleotide sequence identity between individual repeat units, and two or more copies of the repeat unit. primers flanking this sequence were designed to enable vntr-pcr amplification. the clinical isolates' identification was also confirmed by ompa gene sequencing. results: the vntr sequence chosen was highly informative since it possesses different repeats of the consensus pattern among the strains tested, namely r. conorii malish and itt. the former contains five tandem repeats and the later only have three repeats of the bp motif unit, which can be easily detected by agarose gel electrophoresis. therefore, the polymorphism observed enabled discrimination between these two strains. these results are in agreement with ompa gene sequence. conclusion: this pcr-based method provides a useful and rapid way for genotyping r. conorii malish and itt isolates (r. conorii complex) which are responsible for msf in portugal. ompa and glta gene amplification are currently the most widely rickettsiae detection method used. however, strain identification is only accomplished by sequencing. p monitoring the ability of the human intestinal microflora to become re-established after antibiotic treatment using t-rflp c. jernberg, Å . sullivan, c. edlund, j. jansson huddinge, stockholm, s objectives: to study the composition of the human normal faecal microflora during administration of clindamycin and a probiotic or placebo product. since only a small portion of the faecal flora is cultivable the samples were primarily analysed using a culture independent molecular fingerprinting technique, terminal-restriction fragment length polymorphism (t-rflp). methods: the study included eight healthy volunteers. all subjects received clindamycin orally for days. four subjects received a probiotic yoghurt concomitantly containing exp cfu/ml of the strains lactobacillus f , lactobacillus acidophilus ncfb and bifidobacterium lactis bb . the placebo group received ordinary yoghurt. faecal samples were taken before the administration (day ), the last day of administration (day ) and days after the administration (day ). the samples were analysed both by conventional cultivation and by t-rflp. both universal bacterial primers and lactobacillus specific primers were used when analysing the samples using t-rflp. the areas of the different terminal restriction fragments (trfs), each of which theoretically corresponds to one or a group of closely related species, were used to calculate the relative abundance values for the trfs. these values were used for principal components analyses (pca) and upgma analyses to compare the microbial flora at the three different time points. results and conclusions: in the group ingesting the probiotic, the microflora in three out of four subjects became re-established close to their original compositions weeks after antibiotic treatment ceased. by contrast, only one subject out of four in the placebo group had an intestinal microflora that showed tendencies towards normalisation during the same time period. these findings were in accordance with the results from the culture-based analysis. t-rflp was also used to monitor specific bacterial populations that were either positively or negatively impacted by clindamycin. for example, one of the dominating populations, belonging to the clostridium coccoides subgroup, was highly negatively impacted by clindamycin administration in all subjects. when using lactobacilli specific primers, l. acidophilus and lactobacillus f were the two dominating populations in the group receiving the probiotic. t-rflp was shown to be a reproducible technique for analyses of antibiotic and probiotic induced alterations in the normal intestinal microflora. campylobacter species using maldi-tof mass spectrometry d. dare, h. sutton, c. keys, h. shah, m. lunt, g. wells manchester, london, uk laser interrogation of bacteria by matrix assisted laser desorption/ ionisation time of flight (maldi-tof) mass spectrometry (ms) reveals unique fingerprint patterns of biomarkers. these patterns are reproducible for a given set of conditions and can be used as the basis for bacterial identification against a database of known bacterial spectra. manchester metropolitan university in collaboration with the health protection agency (uk) and waters corporation have created a maldi-tof mass spectral database of clinical, environmental and food borne pathogens. these pathogens are all supplied from the uk national collection of type cultures (nctc). the database spectra are therefore representative of organisms from a world-renowned collection. this database has continued to grow over the last years from the initial to currently over spectral entries covering $ different genera. bacterial identification using this database is often conclusive with the top five matches suggesting the same genera/species. however for identification to be robust, the strains within the database must be well characterised and their identity well established. for campylobacter the number of representative strains in the database has increased significantly from around to over years. the species covered within this taxa are: c. coli, c. consicus, c. curvus, c. fetus, c. gracilis, c. helveticus, c. hyolei, c. hyointestinalis, c. jejuni, c. lari, c. rectus, c. sputorum and c. upsaliensis. this study presents the results of analysing the same datasets for campylobacter strains against the expanding databases containing , , and > mass spectral entries respectively. the results demonstrate a significant improvement (i.e. - %) in the number of campylobacter sp. correctly identified as the number of representative strains increase. therefore maldi-tof ms provides a potential rapid identification system for campylobacter sp. p application of s- s intergenic spacer sequencing for the detection and molecular differentiation of legionella species f. grattard, c. ginevra, s. riffard, a. ros, j. etienne, b. pozzetto saint-etienne, f objectives: among the more than species of legionella that have been identified so far, have been reported to be pathogenic for humans. by now, the precise identification of clinical isolates in reference laboratories needs the use of monoclonal antibodies or of molecular markers such as s rrna-, mip-, rpob-or dota-gene sequencing. we developed a rapid and convenient technique based on the sequencing of the s- s intergenic spacer using nondegenerated primers specific for legionella spp. methods: we tested legionella species (reference and clinical isolates), including serogroups of l. pneumophila subsp. pneumophila. the amplification step was performed by using a real-time pcr (lightcycler, roche diagnostics) and sequencing was performed on the ceq sequencer (beckman). the comparative analysis of the sequences was done with the computer program mega and the dendrograms obtained by the neighbour-joining method. results: the phylogenic tree of the s- s intergenic spacer sequences was found able to clearly differentiate all legionella species at the subspecies level. actually three subspecies of l. pneumophila (subsp. pneumophila, subsp. fraseri and subsp. pascullei) were clearly distinguished. species sharing the same autofluorescence properties and ubiquinone and fatty acid composition were shown to be phylogenetically related. in addition to rpob sequen-cing that was shown previously to exhibit similar results, our technique was found able to detect and identify strains present in clinical or environmental specimens that could not be cultured on agar medium. although this tool was not discriminatory enough to differentiate all strains of l. pneumophila subsp. pneumophila at the serogroup level, it was used in two different outbreaks to demonstrate rapidly the identity of the sequences between strains responsible for severe human infection and those isolated in the hot water reservoir, suggesting a common origin. conclusion: the s- s intergenic spacer sequencing was found to be suitable for rapid detection and powerful identification of legionella species in clinical settings. whipple's disease (wd) is a rare multisystemic bacterial infection, with variable clinical manifestations occasionally involving the central nervous system. as the cultivation of the aetiologic agent, tropheryma whippelii, is difficult, the laboratory diagnosis is usually based on histological methods. in the last few years, molecular detection of the bacterial srrns genes by the polymerase chain reaction (pcr) with two primer sets, has greatly contributed to the diagnosis. we present a cerebral case of wd in a -year-old male, successfully diagnosed by pcr of t. whippelii in the blood and the faeces. as far as we know this is the first case reported from greece. for the diagnosis of wd histological examination of duodenum biopsy for diastase resistant, non-acid fast, periodic acid schiff (pas)-positive inclusions in macrophages, and molecular detection of the srrna genes of by pcr in csf, blood and faeces were performed. the histological detection was negative. pcr was positive in the blood and the faeces of the patient and negative in the csf. seven months after the onset of antimicrobial therapy, pcr was negative in all three clinical specimens. in conclusion, the application of pcr proved to be an invaluable tool for the recognition, the differential diagnosis and the early start of the antimicrobial therapy of wd, a generally fatal disease, if it remains untreated. results: only one clinical isolate had the same api code profile as the reference strain. fifteen per cent of clinical strains were tested urease positive, as was the reference strain. by fatty acid analysis, clinical isolates could be separated in four different groups (i-iv), containing , , and isolates, respectively. atcc was grouped to group ii. sequences were obtained from three strains of groups i and ii, respectively, and from one strain of groups iii and iv, respectively. comparison of the determined eight sequences with public databases showed the greatest similarity score with c. asperum (x . ) with values between . and %. c. asperum and c. amycolatum are considered as synonyms, because they exhibit a level of dna-dna relatedness greater than % (ruimy r et al. int j syst bacteriol ; : ) . homology with c. amycolatum atcc (x . ) was only between . and . %. sequencing of the c. amycolatum reference strain yielded % homology with the published sequence (x . ). conclusions: our data confirm the hypothesis that atcc is atypical for clinical c. amycolatum strains. furthermore, our data are in concordance with the observation, that by pyrolysis-gasliquid chromatography c. amycolatum isolates can be separated in two different groups (voisin s et al. res microbiol ; : ) . p detection of mutations associated with resistance to tetracycline and clarithromycin in helicobacter pylori using the pyrosequencer a. lawson, c. arnold, r. owen london, uk objectives: clarithromycin and tetracycline are key components of h. pylori eradication therapy. resistance to clarithromycin occurs due to single nucleotide mutations in s rdna and an assay to detect these was amongst the first to be developed for the pyrosequencer. recently it has been shown that resistance and reduced susceptibility to tetracycline occur due to single, double or triple mutations in s rdna. the aim of this study was to develop a single multiplex assay using the pyrosequencer to determine susceptibility to clarithromycin and tetracycline from h. pylori isolates and direct from gastric biopsy samples. methods: pyrosequencer assays to detect mutations conferring tetracycline and clarithromycin resistance were designed to work singly and in multiplex. the assays were evaluated using isolates with fully characterised s and s rdna sequences. subsequently, dna extracts from clinical isolates and h. pyloripositive human gastric biopsies -all of unknown antibiotic susceptibility -were examined and the results compared with those achieved by conventional culture-based techniques, namely antibiotic disc diffusion and etest. results: the pyrosquencer multiplex assay correctly determined the s and s rdna sequences of the characterised control isolates. when applied to dna extracted from clinical isolates and gastric biopsy samples, the pyrosequencer assay was in agreement with the clarithromycin and tetracycline susceptibilities determined by culture-based analysis. conclusion: the pyrosequencer assay allowed rapid determination of clarithromycin and tetracycline susceptibility from both h. pylori isolates and gastric biopsy samples. the sequence data obtained for the mutations occurring in each strain may provide useful epidemiological information and guide patient management. diseases. the aim of this prospective pilot study was to detect iga, igg and anti-caga antibody status and to evaluate the correlation with anti-h. pylori iga, igg western blot and elisa tests in adult dyspeptic patients. methods: upper gastrointestinal endoscopy, two from gastric antrum and two from corpus, was performed in patients (mean age ae . ) with dyspeptic symptoms. h. pylori was assessed by rapid urease test and by histopathologic examination in these biopsy specimens. patients' sera were tested by anti-h. pylori iga, igg western blot, iga, igg elisa and anti-caga-iga, igg elisa (euroimmun medizinische labordiagnostika, lü beck) tests. results: a total of patients were evaluated and h. pylori infection was diagnosed in ( . %) patients by rapid urease test and/or histopathology. serological anti-h. pylori test results were shown as below (table ) . twenty-eight ( %) of adult dyspeptic patients sera were positive for anti-caga-igg elisa and ( . %) were positive for anti-caga-iga elisa. conclusion: infection with h. pylori results in the production of local and systemic antibodies. cag a is the important pathologic marker with high immunogenic power. a set of serological tests may give more accurate determination of h. pylori infection than one test detecting specific antibody or bacterial antigen. it seems that there is a good correlation with western blot and elisa test results and gold standards. acknowledgement: this work was supported by euroimmun medizinische labordiagnostika, lü beck, germany. p susceptibility of helicobacter pylori isolates to the anti-adhesion activity of a high-molecular-weight constituent of cranberry h. shmuely, o. burger, i. neeman, j. yahav, z. samra, y. niv, n. sharon, e. weiss, m. tabak, a. athamna, i. ofek petach tiqva, haifa, rehovot, jerusalem, kfar qaraa, tel aviv, il background: previous studies have shown that a high molecular mass non-dialysable constituent derived from cranberry juice inhibited the adhesion of helicobacter pylori to human gastric mucus and to human erythrocytes. the aim of the present study was to determine the sensitivity of a large number of both antibiotic-resistant and susceptible clinical isolates of h. pylori to the anti-adhesion effect of the cranberry constituent. material and methods: confluent monolayer of gastric cell line in wells of a microtitre plate was exposed to bacterial suspensions prepared from h. pylori clinical isolates, including from patients after treatment failure. adhesion was estimated by the urease assay to calculate the percent inhibition of adhesion by the non-dialysable material. antibiotic susceptibility of h. pylori isolates to metronidazole, tetracycline and amoxicillin were tested by the etest. results: in two-thirds of the isolates, adhesion to the gastric cells was inhibited by . mg/ml of the non-dialysable material. all isolates were susceptible to amoxicillin and tetracycline and isolates ( %) were resistant to metronidazole. there was no relationship between the anti-adhesion effect of the cranberry material and the resistance to metronidazole in isolates from either the antibiotic-treated or untreated patients. most important, only isolates ( %) were resistant to both non-dialysable material and metronidazole and isolates ( %) were resistant to the non-dialysable material alone. no cross-resistance of the isolates to cranberry constituent and metronidazole was found. conclusions: the data suggest that a combination of antibiotics and a cranberry preparation may improve the eradication of h. pylori. methods: for the seroprevalence study a total of people of different states from the country were evaluated: symptomatic and asymptomatic adults; symptomatic and asymptomatic children. the determination of specific igg antibodies was made by commercial elisa. the presence of the gene caga was evaluated in patients of the metropolitan area and the center of gastric cancer control of san cristó bal (endemic zone of gastric cancer). the detection of vaca was determined in biopsy from patients of san cristó bal and biopsy from patients of the metropolitan area. the biopsies were analysed by different methods for diagnosis of h. pylori: culture, urease test, polymerase chain reaction and rapds for genotyping the h. pylori isolates. results: the percentage of asymptomatic children with values of specific igg antibodies anti-h. pylori (over u) varies from to % (metropolitan area vs. san cristó bal). in symptomatic adults groups, the seroprevalence was between and % according to the studied geographic area. a decreased title of igg antibodies anti-h. pylori was observed in patients with diffuse antral gastritis associated with metaplasia type ii. in the group of endemic cancer area the titles of igg anti-hp were elevated in patients with antral diffuse gastritis. the caga gene was detected in % of patients of the metropolitan area unlike the group of patients of san cristó bal a smaller frequency was observed ( . %) (p < . ). a high incidence of s a and m genotype was observed in the h. pylori isolated from the patients of endemic gastric cancer area ( %), unlike what we observed in the metropolitan h. pylori isolates where an elevated prevalence of s b and m genotypes was found. samples from gastric antro. no current resident in our area and patients treated previously with eradicated therapy have been excluded. samples were homogenised and cultured in blood-agar, chocolate-agar, pylori-agar and tioglicolate broth. it was incubated to c in microaerofile atmosphere during - days. we studied the susceptibility to: amoxicillin (am), claritromicin (ch), metronidazole (mz), tetracycline (te) and ciprofloxacin (cp) by detection of imc by e-test (biodiskâ). we have followed nccls criteria for antibiogram lecture. results: from samples, were males and females. we found the follow primary resistance; ch ( . %), mz ( . %), te ( . %), am ( . %), cp ( . %) and samples ( . %) with a mix resistance to ch and mz. ch and mz resistance are more common in females, but the difference is only statistically significant for mz (p: . ). conclusions: there is a progressive increased antibiotic resistance in h. pylori in our area. this may be related with a raised used of antibiotics for other indications. ch resistance data agree with other spanish and multicentre european studies, which show a foremost rate in the mediterranean area. the mz resistance is higher than other spanish works. our high prevalence of resistance supports the idea of avoiding imidazol therapy as primary choice treatment. p the prevalence and consequences of antibiotic resistance in danish h. pylori strains isolated with an interval of years objectives and background: the treatment of h. pylori (hp) infections is complex and the use of combination therapy is imperative. the choice of the antibiotics is often made exclusively on empirical basis although resistance to many therapeutically relevant antibiotics has been described. the mainstay of hp treatment in denmark is various combinations of normally two of the following antibiotics: metronidazole, amoxicillin, tetracycline and clarithromycin. to clarify whether these compounds were to remain the drugs of choice we decided to determine the susceptibilities of metronidazole, clarithromycin, tetracycline, and amoxicillin against hp strains recently isolated from patients with duodenal ulcer. the results were compared with results previously obtained by us in using a similar methodology. over a period of years only the development of resistance to metronidazole appears to constitute a problem. otherwise hp has remained remarkably susceptible to these therapeutically relevant antibiotics. on the basis of our results we recommend that surveillance of especially metronidazole resistance in denmark is markedly intensified, e.g. by increasing the use of diagnostic methods of hp infections that allow susceptibility testing. in cases where treatment with metronidazole is considered, susceptibility testing is of course of major importance, if not downright necessary. objectives: helicobacter pylori is the main causative agent of peptic ulcer disease. clarithromycin resistance of h. pylori is the common reason of failure of the eradication therapy, which includes amoxicillin-clarithromycin and proton pomp inhibitor. the aim of this study was to determine the prevalence of clarithromycin resistance among h. pylori strains isolated from gastric biopsies obtained during routine endoscopies at the baskent university medical faculty in ankara, turkey. methods: h. pylori strains were isolated from antral biopsy specimens taken from dyspeptic patients. antibiotic susceptibilities of the isolates to clarithromycin were performed using the nccls approved agar dilution and the e test methods. results: h. pylori isolates were included in the study. clarithromycin resistance was found in ( . %) of the isolates. the resistance rates were similar by the e test and agar dilution methods. conclusion: the percentage of the clarithromycin resistance among h. pylori strains in our population is significantly high. this information is important to monitoring the eradication therapy and defines regional treatment policies. introduction: helicobacter pylori has been the subject of many studies that contributed to a better understanding of its epidemiology and its clinical importance in the pathology of the upper gastrointestinal tract, being an important cause of duodenal, gastric ulcers and a definite cause of gastric adenocarcinoma in human. objectives: to determine the seroprevalence of h. pylori among population living in rural community, in relation to the epidemiological aspect, and to study the seroprevalence of anti-caga as a virulence factor in a step that might be helpful in studying the magnitude of h. pylori infection. also, to determine a cut-off value among the population in this community. subjects and methods: this is a community based, field study which was performed on randomly chosen subjects representing villagers of eight villages in giza governorate egypt. serological testing for anti-h. pylori and anti-cag a were performed by elisa. results: the overall seroprevalence of anti-h. pylori igg was . % with different degrees of positivity: . % mild, . % moderate and . % high. anti-cag a was present in . %. there was a significant agreement between the presence of the two antibodies; however, on studying the relation of anti-h. pylori igg level with anti-caga no statistically significant relation was found denoting that the level of infection even if mild does not rule out the possible association of virulent strain of h. pylori. no age or sex difference was noted as regards anti-h. pylori seropositivity but subjects seropositive for anti-cag a had a statistically significant higher mean age. when relating the seroprevalence of anti-h. pylori to type of community, it was found to be the same in semi-rural communities and rural ones and when investigating the respective conditions in both communities it was found that the prevalence is rather related to pattern of life, socioeconomic status and to other possible vehicle of transmission as animals or flies than faecaly contaminated water which is not considered the only vehicle for h. pylori transmission in our study. conclusion: h. pylori is holoendemic in egypt; however, infection by virulent strains is not common. objectives: extended-spectrum beta lactamases (esbls) are an increasing cause of resistance in enterobacteriaceae. unfortunately, the laboratory detection of esbls can be complex and, at times, misleading. the aim of this study was to determine whether routine methods performed in a clinical microbiology laboratory of a tertiary care hospital, are adequate for detecting emerging esbl producing clinical isolates. methods: to evaluate the esbl confirmation protocol, we collected enterobacteriacae strains, isolated in our laboratory. each isolate met the nccls screening criteria for potential esbl producers (ceftazidime or cefotaxime mics were ! for all isolates). we tested kl. pneumoniae, five ent. cloacae, two ent. aerogenes, five e. coli and four pr. mirabilis strains, by methods routinely used in our laboratory. initially, the isolates were tested for clavulanic acid effect by disk diffusion method and all were analysed by the vitek automated system (biomerieux, france), which performs a susceptibility testing, by determining the mic breakpoints. the advanced expert system (aes) of vitek was set on the phenotypic resistance knowledge-based system and the panel gn was used. in parallel, the isolates were tested by the esbl e-test with ceftazidime and cefotaxime plus beta lactamase inhibitor (ab, biodisk, sweden). in order to confirm the esbl production, all strains were tested by isoelectric focusing (ief) followed by pcr for blatem, blashv, blaoxa, blaibc and blactx genes. results: twenty-one out of isolates proved to produce esbls by molecular methods. all enterobacter strains and one proteus mirabilis were not esbl producers. no blaoxa or blaibc genes were detected. the pcr detection of esbl genes results were compared with the double disk diffusion, vitek and esbl e-test to estimate the sensitivity, specificity and the predictive value of the methods tested. the sensitivity of the methods was . , . and . %, respectively, the specificity . , . and . %, respectively, and the predictive value . , . and %, respectively. discussion: given the increasing incidence of esbl producing clinical isolates, it is important that esbl screening is incorporated into routine diagnostic testing. the backup of the simple disk diffusion method by the automated vitek system increases the possibility of identifying esbl activity of clinical strains in the hospital microbiology laboratory setting. objectives: extended-spectrum beta-lactamases (esbl) are plasmid-mediated beta-lactamases and most of them are mutant of tem or shv beta-lactamases. esbls have been associated with clinical failures due to serious interpretive problems of standard laboratory tests. detection of esbls remains a challenge for the laboratory, since routine tests for monitoring a susceptibility to oxyimino-cehalosporins and aztreonam have not been sensitive enough to detect esbl strains and require up to days. we describe an oligonucleotide array for rapid identification of single nucleotide polymorphisms (snps) of the esbl tem beta-lactamases. methods: plasmid dna was amplified and cy labelled during pcr with consensus primer pair flanking the blatem gene. oligonucleotide arrays were constructed with oligonucleotide capture probes. the probes were designed with the snp at the central base of the probe sequence for maximum perfect match/ mismatch discrimination. results: of snp positions were correctly identified. the signal intensity values ranged up to for the perfect match probes. the discriminatory power of the array expressed as relative intensity of mismatches (rimm) remained for % of the mismatches below . . a perfect match was considered as correctly identified, if rimm did not exceed . . analysis of the array reproducibility revealed that in analysed blatem- samples all snp positions could be identified. the mean rimm values varied, but % remained below . . in dna isolated from clinical samples all mismatches in blatem were identified without ambiguity, and % of them remained below the rimm limit. since the reduction of the array-hybridisation time to min had no influence on rimm (rimm limit less than . for % mismatch positions), the assay may be performed within . h while keeping its discriminatory power. conclusion: the blatem gene variants could be amplified by the use of a single consensus primer pair. using dna-array we were able to discriminate snps in of the tem variants. snp mismatches could be analysed by array within . h enabling the identification of the corresponding esbls or inhibitor resistant tems. the nccls recommendations. the production of extended-spectrum beta-lactamases (esbl) was detected by double diffusion test. the presence of blatem gene was determined by pcr method. transferability of resistance determinants was studied by bacterial conjugation. results: . % of the clinical isolates were resistant to ampicillin (ampi); . % to cefoxitine (cfox); . % to cefotaxime (ctax); . % to ceftazidime (ctaz); . % to ceftriaxone (ciax); . % to cefepime (cepi); . % to azthreonam (aztr); . % to meropenem (merp); . % to gentamicin (gen); . % to tobramycin (tob); . % to netilmicin (net); . % to amikacin (ami); . % to isepamicin (ise); . % to ciprofloxacin (cip). a total of . % of clinical isolates were identified as esbl producers. the presence of blatem gene coding for tem-type beta-lactamases was detected in . % of clinical isolates tested. resistance determinants to all antibiotics tested, with only one exception of merp, were transferable by bacterial conjugation to the recipient strain escherichia coli k- . frequency of transfer ranged from .  À to .  À . conclusions: the occurrence of resistance to beta-lactam antibiotics was very high. the most efficient beta-lactams were the carbapenem meropenem and the fourth-generation cephalosporin cefepime. aminoglycoside antibiotics netilmicin, amikacin and isepamicin had high efficiency, too. on the other hand, more than one half of the clinical isolates tested were resistant to the fluoroquinolone ciprofloxacin. beta-lactam resistance was due to the production of esbl and to the presence of the bla-tem gene in the majority of clinical isolates. transferability of beta-lactam and aminoglycoside resistance determinants by bacterial conjugation is important from the epidemiological point of view. objectives: today there are very few significant data on the effectiveness of cephalosporin antibiotics in nosocomial infections caused by the microorganisms producing esbl. methods: the cases of nosocomial infections caused by enterobacteriaceae with a proved esbl production were analysed. esbl producing enterobacteriaceae strains were assayed for susceptibility to different antimicrobials and mics were determined by a broth microdilution method. to determine molecular typing of esbl genes polymerase chain reactions and sequencing reactions were used. patients received initial empiric intravenous antibacterial therapy with third-generation cephalosporin (cefotaxime). in case of failure cefepime g a day was prescribed. results of those infections treatment with third-and fourth-generation cephalosporins were assessed depending on mic. results: esbl production with specific shv and ctx oligonucleotids was proved for six strains of enterobacteriaceae in four patients with nosocomial pneumonia (in two cases mixed infection took place), among them four strains were klebsiella spp. and two strains e. coli. the analysis of the dependence of mic on the results of the treatment gave the following results (table ) . it may be stated that with the proved enterobacteriaceae esbl production mic values for third-generation cephalosporins of the majority of strains were within the resistance range (more than lg/ml), and these antibiotics were not effective in all cases. as for cefepime, mic showed intermediate sensitivity ( lg/ml) to the drug only in . % cases; the rest of the strains (mic ¼ - lg/ml) were sensitive. the therapy with cefepime was effective in three of four patients. , À / a (n ¼ ), À (n ¼ ), À /À (n ¼ ) and À / (n ¼ ). conclusions: (i) using mic breakpoint > mg/l for reduced susceptibility to third-generation cephalosporins we detected esblproducing e. coli and k. pneumoniae with low mic-values ( . - mg/l). (ii) cefotaxime-hydrolysis was the dominating profile in esbl-positive e. coli strains whereas ceftazidime was the most sensitive substrate for detection of esbl-production in k. pneumoniae. (iii) the different methods showed almost the same sensitivity in detecting esbl production assuming that more than one substrate was used, i.e. both cefotaxime and ceftazidime. (iv) ctx-m was the dominating esbl-type. objectives: during , the srmd received isolates of escherichia coli for confirmation of esbl production with a phenotype implying a ctx-m-type beta-lactamase, i.e. cefotaxime (ctx) mics fourfold greater than ceftazidime (ctz) mics. isolates were from hospital patients and, in some instances, from community patients with little or no recent hospital contact. tem-and shv-type esbls are largely confined to nosocomial isolates, so the apparent spread of ctx-m enzymes in the community is cause for concern. we compared the isolates and investigated the genetic basis of their ctx-m phenotype. methods: isolates were compared by pfge of xbai-digested genomic dna and data were analysed using bionumerics software. mics were determined by etest or agar dilution, and interpreted using bsac breakpoints. isolates with a ctx-m phenotype were tested for blactx-m alleles by pcr, initially with universal primers, and then with primers specific for various blactx-m groups. selected amplicons were sequenced, either directly or after cloning into pcr . . transfer of ctx-m to e. coli j was attempted in broth and on agar plates. results: over ctx-m-producing e. coli were obtained from more than uk centres. these isolates represented multiple strains, although clusters of related isolates (> % similarity) were observed, some including isolates from more than one centre. sequencing confirmed that e. coli from different centres all produced ctx-m- . most isolates had substantial resistance to ctx (mics > mg/l) and ctz (mics > mg/l), consistent with ctx-m- . isolates (n ¼ ) associated with a large community cluster produced atypically large amplicons with group i ctx-m primers, as did two related isolates from another centre. these isolates were less resistant to ctx (mics - mg/l) and ctz (mics - mg/l), and susceptible to gentamicin; sequencing of a representative isolate identified is within the terminal inverted repeat of the isecpi element upstream of blactx-m- , separating the allele from its usual promoter, and the spacer between isecpi and blactx-m- had a t/c polymorphism not seen in other sequenced isolates. we studied also antimicrobial sensitivity of the strains, co-resistance to non-beta-lactam antimicrobials and relationship with antibiotic use. methods: data of monthly non-duplicate ebsl-ec and antibiotic use (hospital: ddd/ pat-day and community: ddd/ inhabitants-day) were collected for january to october . time series dynamic regression models were adjusted to evaluate the relationship between the use of antimicrobials and the emergence of the bacteria. sensitivity testing was determined by microdilution with gram-negative and urine panels (microscanâ). esbl producing strains were initially selected by screening with microscanâgram-negative and urine panels (mic > lg/ml for cefotaxime, ceftazidime or aztreonam, and/or a difference of three or more dilutions between ceftazidime and ceftazidime with lg/ml of clavulanic acid . on univariate analysis only connective tissue disease (p < . ), genitourinary pathology (p < . ), infections in the past year (p < . ) and previous exposure to second-generation cephalosporins (p < . ) were factors associated with ca infection due to esbl ec. in our regression model, only previous exposure to secondgeneration cephalosporins was strongly associated (or . , . conclusions: in the last years there has been a marked increase in infections due to esbl ec, especially from the community. only previous exposure to second-generation cephalosporins (not to ciprofloxacin, third-generation cephalosporins or aminoglycosides) was predictive of an esbl ec ca infection. strikingly, neither comorbidity nor previous contact with the healthcare system was risk factors for esbl ec. enzymes of the ctx-m family are currently classified as extended-spectrum beta-lactamases (esbls). over the last decade, ctx-m-type enzymes have been increasingly reported from several countries in europe. the aim of this study was to search for ctx-m-type enzymes in escherichia coli isolates obtained at our institution (varese, northern italy). methods: we studied consecutive e. coli isolates recovered over a -year period ( ) ( ) ( ) . stains suspected of producing esbls (according to nccls criteria) were further investigated. the double-disk synergy test and etest esbl strips (ab biodisk, solna, sweden) were used to confirm esbl production. the etest method was also used to evaluate mics of amikacin, gentamicin, ciprofloxacin, and beta-lactams (including last-generation cephalosporins, carbapenems, and aztreonam). esbl-positive isolates were evaluated for the presence of ctx-m-type genes using specific dna probes. patient records were examined to assess risk factors for infections and underlying clinical conditions. results: a total of consecutive e. coli isolates were studied. overall, out of esbl-positive strains were found to carry a ctx-m-type gene and to produce a ctx-m-type enzyme. most isolates ( / ) showed high mic values for cefotaxime (> mg/l) and borderline values for ceftazidime ( - mg/l). the remaining five isolates had also high mics for ceftazidime. ctx-m-positive isolates were obtained both from inpatients (n ¼ ) and outpatients (n ¼ ). epidemiological analysis showed that most strains were isolated from urinary tract infections, even though some isolates were recovered from the lower respiratory tract, wounds and blood. most patients ( / ) were treated with immunosuppressive therapy. recurrent urinary infections occurred in five outpatients. conclusions: ctx-m-type enzymes appear to be emerging among e. coli isolates in both the hospital and community environments. the analysis of clinical records demonstrated that these microorganisms can cause severe and persistent infections. therefore, despite the currently low prevalence of ctx-m phenotype, we suggest that a monitoring of this resistance phenotype should be established to avoid the spreading of resistance traits. background and objectives: class c beta-lactamases (cbls) are enzymes that confer broad-spectrum beta-lactam resistance (including penicillin, expanded-spectrum cephalosporins, and cephamycins) and are poorly or not susceptible to commercially available beta-lactamase inhibitors. in strains with reduced outer membrane permeability, they can also provide resistance to carbapenems. a number of these enzymes are chromosomally encoded, but plasmid-mediated cbls are also known as a cause of acquired resistance to expanded-spectrum cephalosporins and cephamycins in clinical isolates of enterobacteriaceae. in italy, only the fox- acquired cbl has previously been reported, in klebsiella spp. in this work we report the first detection of acquired cbls of the cmy-lat lineage in escherichia coli and klebsiella pneumoniae clinical isolates from an italian hospital. methods: ten consecutive non-replicate clinical isolates of e. coli (eight) and k. pneumoniae (two) resistant to expanded-spectrum cephalosporins and cephamycins were collected, during , at the laboratory of microbiology of the s. matteo hospital of pavia (northern italy). in vitro susceptibility testing was determined by a microdilution method according to nccls. beta-lactamase production was investigated by analytical isoelectric focusing (ief) coupled with a bio-assay. molecular characterisation of beta-lactamase genes was carried out by a multiplex pcr approach designed for detection of all major lineages of acquired cbls genes, and by sequencing. transferability of resistance genes was tested by mating assays in liquid medium. results: two isolates, one of e. coli and one of k. pneumoniae, were found to be resistant to expanded-spectrum cephalosporins, except for cefepime, and cephamycins (cefoxitin mics > mg/l). both isolates produced a beta-lactamase of pi > . that showed hydrolytic activity against cefoxitin, cefotaxime and ceftazidime. molecular characterisation revealed, in both cases, the presence of an acquired cbl gene of the cmy-lat lineage, which was compatible with blacmy- /lat- (the leader peptide-encoding region was not sequenced). the cbl determinant was transferable by conjugation from the e. coli isolate, while conjugal transfer was not detected from the k. pneumoniae isolate. conclusions: these findings reveal that acquired cbls of the cmy-lat lineage, which are the most common acquired cbls, can also be encountered in nosocomial settings from northern italy. enteropathogens p dissemination of sulphonamide resistance genes: first sul found in salmonella from portugal p. antunes, j. machado, j.c. sousa, l. peixe porto, lisbon, p objectives: the purpose of this study was to determine the distribution of sulphonamide resistance genes sul , sul and sul and class integrons in portuguese salmonella isolates collected during - , from human and nonhuman sources. methods: eight hundred and seventy-five isolates were tested for resistance to antimicrobial agents by the agar dilution method. sulphonamide resistant isolates were screened for resistance genes sul , sul , and sul and class integrons by pcr assays. results: resistance was found in % and multiresistance in % of the isolates. in ( %) sulphonamide-resistant isolates (mics mg/l), ( %) sul genes, ( %) sul genes and nine ( %) sul genes were detected. in isolates, more than one gene encoding sulphonamide resistance was present: sul and sul in , sul and sul in three and sul , sul and sul in four. class integrons were found in % of those isolates. among the isolates carrying class integrons, presented sul gene, found alone ( isolates) or simultaneously with sul ( ) or sul ( ) and with sul and sul ( ). the two strains with class integrons, which lacked the qaced and sul genes, carried a sul gene. of the sul -positive isolates, harboured class integrons. conclusion: class integrons and sulphonamide resistance genes are widespread among salmonella. the newly described sul gene has now been identified in nine salmonella isolates collected from human and nonhuman sources in portugal. salmonella from portugal p. antunes, j. machado, j.c. sousa, l. peixe porto, lisbon, p objectives: the aim of this study was the characterisation of betalactamase production in portuguese salmonella isolates collected during - , from human and non-human sources. methods: eight hundred and seventy-five isolates were tested for resistance to antimicrobial agents by the agar dilution method. a double-disk synergy test for the detection of extended-spectrum beta-lactamase production was performed by disk diffusion method. the identification of beta-lactamases was done in ampicillin resistant isolates by ief and pcr assays, with primers, which detects genes encoding tem, pse- and oxa group iii enzymes. to evaluate the association of beta-lactamase genes to class integrons, cs- cs primers were used in a pcr assay. pcr products were purified and both strands sequenced. results: in total, % of the isolates exhibited resistance to ampicillin, with mics mg/l. resistance to ampicillin was conferred by a tem- beta-lactamase in ( %) of the isolates, pse- in ( %) and oxa- in nine isolates. it is to be noted that there is the detection of the extended-spectrum beta-lactamase (esbl) tem- in one isolate. the tem-type beta-lactamases was not associated with class integrons. in contrast, all the blapse- and blaoxa- genes were inserted in and bp class integrons, respectively. conclusion: a considerable percentage of portuguese salmonella were resistant to beta-lactams, mostly due to the production of tem- like beta-lactamase and pse- inserted in integrons. the detection of an isolate that produce an esbl, such as tem- , and nine isolates carrying a class integron with oxa- , are causes of concern due to the possible therapeutic failures with broad-spectrum beta-lactams. p increasing incidence of salmonella typhii with reduced susceptibility to ciprofloxacin in kuwait a.a. dashti, p.w.j. west, d. panigrahi suleibikhat, kwt objectives: to determine the current incidence of reduced ciprofloxacin susceptibility in salmonella typhi, to compare with previous data and to investigate the mechanism responsible. methods: isolates of s. typhi collected in - were tested for susceptibility to ciprofloxacin and other antibiotics using the vitek and e-test. isolates showing reduced ciprofloxacin susceptibility were subjected to pcr to determine if a mutation of the gyra gene was responsible. pcr was carried out using two primers (atgagcgaccttgcgagagaaattacaccg) and (ttcc-atcagcccttcaatgctgatgtcttc). results were compared with those for isolates collected from - . results: out of ( %) of the isolates were resistant to multiple antibiotics, including ampicillin, chloramphenicol tetracycline and trimethoprim. of these ( %) showed resistance to nalidixic acid and reduced susceptibility to ciprofloxacin (mic . - . mg/l). of the susceptible isolates, seven ( %) showed reduced ciprofloxacin susceptibility. isolates from to showed % of multi-resistant strains, but none of susceptible isolates with reduced ciprofloxacin susceptibility. pcr results showed mutations of the gyra gene. conclusion: reduced susceptibility to ciprofloxacin in multi-resistant s. typhi has increased from % in - to % in - and from to % in susceptible strains. mutation of gyra is the mechanism responsible. p comparison of antimicrobial resistance in diarrhoeagenic escherichia coli isolates causing traveller's diarrhoea between two periods, - and - e. mendez arancibia, j. ruiz, r. cabrera, j. gascon, j. vila barcelona, e objectives: to compare the antimicrobial resistance levels in escherichia coli clinical isolates causing traveller's diarrhoea in two periods, - and - . material and methods: presence of enteroaggregative (eaec) and enterotoxigenic e. coli (etec) was established by pcr among those isolated from travellers with diarrhoea during the periods - and - . susceptibility to ampicillin (amp), amoxicillin plus clavulanic acid (amc), tetracycline (tet), chloramphenicol (chl), cotrimoxazole (sxt), nalidixic acid (nal) and ciprofloxacin (cip) was determined by disk diffusion. results: one hundred thirty-two ( eaec, etec) and ( eaec, etec) diarrhoeagenic e. coli were recovered during two periods, - and - , respectively . the levels of resistance of eaec to all tested antibacterial agents increased in the second period: amp from to %, amc from to %, tet from to %, sxt from to %, nal from to % and cip from to % (p < . ), whereas the leaves of resistance to chl showed a slight decrease ( - %) but not statistically significant. in etec strains resistance to amp, nal, cip and amc increased from to %; to %; to %; to %, respectively, while resistance to chl decreased from to %. the levels of resistance to tet and sxt did not present greater differences, but suggested a slight increase in the resistance ( - % and - % respectively). conclusions: a trend to an increase in the resistance of eaec and etec to amp, amc, nal, and cip has been detected, and the decrease of resistance to cip is worthy of note due to the fact that this antimocrobial agent is considered a first choice treatment for traveller's diarrhoea. a.j. hakanen, s. pitkänen, a. siitonen, p. kotilainen, j. jalava, p. huovinen turku, helsinki, fin objectives: quinolone-resistant salmonella isolates emerged in finland in the mid- s. the main origin of these strains is travellers returning from southeast asia. this study was performed to evaluate the incidence and changes of fluoroquinolone resistance in salmonella isolates between and in finland. methods: we collected a total of salmonella enterica isolates which were considered to be epidemiologically unrelated. the isolates were divided into two groups (finnish and foreign isolates) on the basis of travel history. the collection was performed in four phases: each year in , , and starting in january, we consecutively collected finnish and foreign isolates. mics for nalidixic acid, ciprofloxacin and additional fluoroquinolones were determined by the standard agar dilution method (nccls). results: during the study period, the number of isolates with decreased ciprofloxacin susceptibility (mic of ciprofloxacin > . lg/ml) increased from to % of all isolates (p < . ). a similar trend could be seen both among the isolates of foreign and finnish origin. in addition, within the non-susceptible population the mic values were increasing. mic of ciprofloxacin increased from . to . lg/ml among the isolates with decreased ciprofloxacin susceptibility between and . the respective figures for mic were . and lg/ml. all isolates with decreased ciprofloxacin susceptibility had also increased mics to additional fluoroquinolones. conclusion: the number of salmonella isolates with decreased ciprofloxacin susceptibility continues to grow in finland. moreover, the mic levels of these isolates have increased. this phenomenon might have serious clinical implications. p bacteraemia caused by esbl-producing salmonella enterica serovar. virchow . :r: , -a cause for concern a. guleri, g.d. corcoran, s.r. alcock, d.j. brown glasgow, uk background: antibiotic resistance in salmonellae is now common. in developed countries such strains are largely zoonotic and acquire resistance in the animal host before transmission to humans in food. we present our first case of bacteraemic illness with multi-resistant, extended spectrum beta lactamase (esbl) producing non-typhoidal salmonella. case summary: a -year-old male, with a history of recent foreign travel was admitted to hospital with a - day history of gastrointestinal symptoms/fever. on admission he was febrile and splenomegaly was detected. physical examination was otherwise normal. biochemistry revealed mildly deranged liver function. salmonella enterica serovar. virchow . :r: , was isolated from blood culture. it was sensitive in vitro (nccls disk test) to ciprofloxacin and gentamicin but resistant to ampicillin, cefuroxime, cefotaxime, ceftriaxone, ceftazidime, co-trimoxazole, nalidixic acid and streptomycin. mic of ciprofloxacin was . mg/l. antibiotic treatment was with ciprofloxacin, to which he responded well. esbl detection: the isolate was identified as salmonella enterica serovar. virchow . :r: , [api identification system (bio-mérieux), serogrouping, serotyping and phagetyping]. the isolate, resistant in vitro (nccls) to cefotaxime and ceftazidime, was tested for extended-spectrum beta lactamase/ampc production by phenotypic methods. ab biodisk esbl e-tests (cefepime, ceftazidime and cefotaxime, each ae clavulanic acid) and oxoid esbl combination disks (cefpodoxime, ceftazidime, cefotaxime and cefpirome, each ae clavulanic acid) and cefoxitin alone were used based on modified nccls/manufacturer's guidelines. the isolate tested positive for esbl production by both esbl e-tests and combination disks. molecular typing of the esbl is awaited. conclusion: invasive infection with salmonella virchow is uncommon. the source of infection in this case appears to have been undercooked chicken. the emergence of resistance to antimicrobial agents within the salmonellae is a worldwide problem that has been associated with the use of antibiotics in livestock. invasive infection with s. virchow, resistant to broad-spectrum beta-lactams, is a cause for concern. if antimicrobial therapy is indicated for travellers with a history of recent foreign travel, physicians should be aware of the possibility of treatment failures and in such cases mics of third-generation cephalosporins and ciprofloxacin should be determined. the aim of the present study was to assess the distribution and the antibiotic resistance rates (arr) of the various nontyphoidal salmonella serotypes originated from non-human sources in greece, during a -year period ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . material and methods: a total of isolates, belonging to different serotypes, were selected from the collection of national reference center for salmonella and shigella (nrcss), in order to reflect the prevalence of these serotypes during the mentioned period. the sample consisted of isolates from animals, isolates from foods, and environmental isolates. susceptibilities to antibiotics of various classes were determined using mics broth micro-dilution method. results and conclusions: the highest arr and also the higher incidence of multiresistance have been observed for s. virhow, followed by s. hadar and s. typhimurium. the vast part of s. typhimurium isolates was resistant at least to ampicillin, tetracycline and chloramphenicol, while the main resistance phenotype of s. enteritidis isolates was the monoresistance to ampicillin (table) . the arr and the phenotypes of resistance for the isolates of the above four serotypes were similar with the corresponding ones of human isolates as resulted from a recent greek study derived also from nrcss (eur j epidemiol ; : - ) a fact consistent with possible transfer of antibiotic resistant strains from animals to humans through the food chain. the incidence of resistance for the rest of serotypes was very low. all the examined isolates were susceptible to ceftriaxone and ciprofloxacin. interestingly, almost all the examined isolates belonged to animals bred at a non-industrial scale (e.g. pigeons) and the environmental isolates were sensitive to all tested antimicrobials, possibly because of the reduced antibiotic pressure in these isolates. - and - . the isolation rates of s. enteritidis, s. typhimurium and the others were . , . and . %, respectively, in the first period. in the second period isolation rates were found . , and . %, respectively. antimicrobial resistance for (amp and tmp-sxt) in s. enteritidis, s. typhimurium and others were found ( . / . %), ( . the laboratory data were analysed in shigella spp. isolated from stool materials of adult patients over a -year period ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) retrospectively. shigella isolates were identified by standard biochemical reactions and using specific antisera. antimicrobial susceptibility for ampicillin (amp), trimethoprim-sulfamethoxazole (tmp-sxt) and ciprofloxacin (cip) were determined by the disk diffusion method according to national committee for clinical laboratory standards. results: in order to show the differences in epidemiology and antimicrobial resistance, the study was divided into two periods. the first period was from to , and the second period was from to . a total of shigella spp. isolates were obtained in the first period and isolates in the second period. isolation rates of the strains in the first and second periods were, respectively, for shigella flexneri . and . %; for shigella sonnei . and . %; for shigella dysenteria . and . %; and for shigella boydii . and . %. the rates of resistance to (amp) in the first and second periods were respectively in s. flexneri . and . %; s. sonnei . and . %, s. dysenteria . and . %; s. boydii . and . %. the rates of resistance to tmp-sxt in s. flexneri . and . %; s. sonnei . and . %; s. dysenteria . and . %; s. boydii . and . %. all strains were susceptible to ciprofloksasin. conclusions: s. flexneri was the most common species isolated in the first period and s. sonnei was the common species in the second period. in ankara, the data showed an increase in the resistance to the commonly used antimicrobial agents are ampicillin and trimethoprim-sulfamethoxazole. ciprofloxacin seemed to be the best choice for the treatment of shigelliosis. to determine the antimicrobial resistance in salmonella and shigella strains isolated from stool specimens during a -year period, from patients admitted to our clinics with a diagnosis of diarrhoea. methods: the identification and susceptibility testing was done by vitec (biomerieux, fr) automated system. the antibiotics tested for the study were ampicillin, ampicillin-sulbactam, cefotaxime, cefepim, ciprofloxacin, ofloxacin, and trimethoprim-sulfametaxazole. results: nineteen salmonella and seven shigella isolates obtained between january and november were tested for their susceptibilities to seven antimicrobial agents. the total numbers of isolates during - (including the year of big marmara earthquake) were . five of six shigella isolates were s. sonnei, one was s. flexneri. thirteen of salmonella isolates were s. typhimurium, three were s. enteritidis, two were identified as salmonella spp., one was s. arizonae. although all of the isolates were found susceptible to the therapeutic agents, ampicillin susceptibility was decreased to % from % and trimethoprimsulfametaxazole susceptibility was decreased to % from % in salmonella strains during a -year period. only one strain was resistant to cefotaxime. no resistance was found against ofloxacin and ciprofloxacin. all of the shigella isolates were susceptible to all tested antibiotics. conclusions: ( ) the incidence of salmonella and shigella infections seemed to decrease significantly over a -year period. ( ) s. typhimurium and shigella sonnei are the most commonly identified serotypes. ( ) there is no significant change in resistance to 'old' and 'new' antibiotics. ( ) all of the isolates showed a very good sensitivity all the antimicrobials tested. ( ) a careful rotational use of antibiotics might be the best policy to make old drugs again active, and abuse of new agents. objectives: since the incidence of human campylobacteriosis has shown a significant increase in austria. consumption of contaminated poultry products is a well known risk factor for human infections. during the slaughter process meat products can become contaminated with intestinal organisms. furthermore antibiotic resistance is increasing in humans and animals. the aim of the study was to determine the resistance patterns and the transmission routes of campylobacter sp. on the chicken-carcasses along the slaughter line. to compare the frequency of isolation and occurrence of antimicrobial resistance among c. jejuni and c. coli isolated in humans, retail poultry meat and farm broilers in . methods: fifty-three human, retail poultry meat and campylobacter spp. isolates from broiler cloacal swab were investigated for antibiotic susceptibility to antimicrobials by disk-diffusion method. mics were further determined for erythromycin-and ciprofloxacin-resistant isolates by etest. to confirm ciprofloxacinresistance we used a mismatch amplification mutation assay (mama) pcr to detect the gyra mutation. species were determined by multiplex pcr and genetic diversity by pfge typing. results: c. coli isolated in significant proportion in all three sources, . , . and . %, respectively. resistance to one or more antibiotic tested was . , . , and . % and multiresistance . , . and . % in human, retail poultry and farm isolates, respectively. no significant difference was found in the overall resistance rates, and for each antibiotic tested between c. jejuni and c. coli isolates from all three sources, which is unusual finding. moreover, they were higher in c. jejuni. given that after the war population in this region were mostly the muslim, c. coli in humans originated from other sources than pigs. thus, it may suggest that c. coli resistance is origin-related. erythromycin-and ciprofloxacin-resistance was high and almost equal in all three sources ( . , . , . %, and . , . , . %, respectively) .imported retail poultry meat (from five countries) had higher resistance rates for erythromycin than domestic one, . vs. . %, but ciprofloxacin resistance was higher in domestic one, . vs. . %. conclusion: the distribution of c. jejuni and c. coli species and drug resistance in isolates from chicken and farm animals were similar to that seen in humans, even in the absence of antibiotic pressure ( % of patients were under years of age, and growth promoters ban in bosnia and herzegovina), suggesting that poultry may play a role in human infections. when pfge patterns were considered, they were remarkably diverse, suggesting considerable genetic heterogeneity. it may support the hypothesis that campylobacter spp. from food animals and humans may not be represented by discrete populations but rather, form part of a common population shared by food animals and humans, suggesting related sources of infection. objectives: this investigation was designed to study the potential usefulness and economic benefits of oral linezolid as an alternative to outpatient parenteral antibiotic therapy (opat) in the treatment of primary cellulitis. methods: patients with moderately severe cellulitis referred to an infusion centre for antibiotic treatment were enrolled into an open, non-randomised, pilot study. after informed written consent, patients were treated with oral linezolid, mg q h, in place of their prescribed parenteral antibiotic. patients were followed with clinic visits and lab monitoring. results: a total of patients, five males and five females (mean age, years), were enrolled. seven were obese (mean weight, kg; range, - kg), six had lower extremity cellulitis, one had lymphedema, and two were smokers. the average length of linezolid therapy was days (range, - days). all were compliant with the treatment regimen and had a clinical cure of their infection. mild side-effects (nausea, loose stools, headache, metallic taste) were reported by four patients. none developed thrombocytopenia or prematurely discontinued therapy. a -day course of linezolid therapy (drug costs, clinic visits, and lab monitoring) was found to be less expensive than days of vancomycin treatment ( g q h) in the infusion centre. conclusions: in this study, we found that oral linezolid was safe and effective in the treatment of moderately severe cellulitis and could be a suitable replacement for opat. furthermore, oral linezolid has the potential to improve patient satisfaction as well as lower overall treatment costs when compared with opat. objective: vancomycin (v) in combination with rifampin (r) and gentamicin (g) has been the recommended regimen for the treatment of pve caused by mrsa but intolerance to these agents and emergence of mrsa strains with reduced susceptibility to the glycopeptides create the need for alternative agents. we describe the case of a patient with mrsa tricuspid pve who was successfully treated with linezolid (l) after failure of glycopeptides. case: a -year-old man was admitted for persistent mrsa bacteraemia. he had been treated with v, g, r, and trimethoprim/ sulfamethoxazole (t/s) for mrsa pve of the tricuspid valve which had recurred after a -day course of v and a -day course of t/s. due to acute renal failure g was discontinued and v was changed to teicoplanin (t). he was transferred to our department because of persistent bacteraemia of days duration despite adequate blood levels of t. blood cultures revealed a mrsa strain with mics of v, t, and l of , , and . mg/l, respectively. he was started on l ( mg bid) and r ( mg tid) and bacteraemia cleared the seventh day of treatment. he completed a -week course of l and a -week course of r. during his treatment he developed anaemia which was managed with blood transfusions and erythropoetin, mild leucopenia and mild thrombocytopenia. he was discharged afebrile with sterile blood cultures and a tee showing reduction in the size of the vegetation. the patient remained well and blood cultures were sterile one month later while pancytopenia fully recovered. the mrsa isolate was investigated for heteroresistance to glycopeptides with ( ) a simplified and ( ) a detailed population analysis profile method. ( ) . ml of a cfu/ml bacterial suspension was plated on bhi agar with v ( mg/l). subclones that grew after h were submitted to mic determination. ( ) tenfold serial diluents of an inoculum of cfu/ml were plated on bhi agar plates with increasing concentrations of v or t alone or with % nacl. viable colonies were counted at h and plotted against the antibiotic concentration. subclones with v mic - mg/l were identified, suggesting that the isolate had heterogeneously reduced susceptibility to v which probably explained the failure of v treatment. the population curve showed that % of the original inoculum survived on t concentration ! mg/l suggesting heteroresistance to t. in all three studies, patients treated with lnz had shorter intravenous antibiotic treatment (ivat) duration than patients in comparator groups, which results in increased rates of early patient discharges and reduced use of resources. in two of the studies, patients had significantly shorter mean los and greater odds of early discharge from hospital. indeed, compared with tei, treatment with lnz had % greater odds of early discharge (p ¼ . ); a similar early discharge potential was also seen when lnz was compared with van (p ¼ . ). in select patient populations, such as those with cssti due to suspected/confirmed mrsa, reduction in los may be even more pronounced in lnz-vs. van-treated patients. for the cost comparison in the third study, total mean adjusted cost was also reduced by us $ (p > . ) in the lnz group compared with the tei group in patients from south america and mexico. conclusions: across multiple studies, there is consistent evidence of significant reductions in los and ivat associated with lnz treatment, with significant differences in the rate of early patient discharge. therapy with lnz shows pharmacoeconomic advantages that have the potential to reduce total costs of treatment. in vitro activity against mrsa and its oral administration represents an excellent alternative to iv vancomycin, which is currently recommended for cf patients colonised with mrsa. material and methods: oral lnz ( mg/ bid) was administrated in two male cf patients ( and years) during and days, respectively. s. aureus isolates were cultured from different sputum samples recovered before, during, and after lnz treatment. antibiotic susceptibility was performed by nccls microdilution method using the wider system (fco. soria melguizo, s.a., madrid, spain). pfge-smai was applied to analyse genetic relatedness of s. aureus isolates. results: in the first patient, a total of isolates were analysed during the studied period; six of them recovered in the previous year to lnz administration, two isolates during lnz administration period, and two isolates and months after the end of treatment. with the exception of one isolate that was methicillinsusceptible recovered during lnz treatment period, all isolates were mrsa and presented homogeneous antibiotic susceptibility pattern. a single clone, with a subtype variant that included two isolates, was identified in all isolates, except in the meticillin-susceptible one. in the second patient, two mrsa and one meticillinsusceptible isolates were recovered during months before lnz therapy. another methicillin-susceptible isolate was recovered after the lnz therapy and no s. aureus were identified in the following cf controls during months. mrsa isolates shared the same pfge and antibiotic susceptibility pattern, whereas meticillin-susceptible isolates corresponded to two different clones unrelated with the mrsa clone. independently of microbiology results, patients' pulmonary function remains unchanged after lnz administration. conclusion: oral lnz treatment in cf may affect population dynamics of s. aureus colonisation, being effective in mrsa eradication. despite this fact and assuming the brief follow-up period, maintenance or eradication of mrsa colonisation after lnz treatment seems not to affect pulmonary function, which may be related to the uncertain role of this pathogen in cf patients. p in vitro spectrum of linezolid and other agents against clinical isolates of anaerobes k. aldridge, c. manders, s. broyles new orleans, usa objectives: linezolid is an oxazolidinone antimicrobial with established in vitro and in vivo activity against aerobic gram-positive cocci. in infections such as wounds these gram-positive pathogens may be mixed with other pathogens including anaerobes. the role of linezolid as an anti-anaerobe agent has yet to be determined. this study was performed to establish the in vitro activity of linezolid and comparative agents against recently isolated anaerobes. methods: approximately anaerobes were tested for susceptibility to linezolid (lzd), ceftriaxone (axo), cefoxitin (fox), clindamycin (cl), and metronidazole (mrd) using twofold dilutions ( . - mg/l) of each agent using the nccls-recommended broth microdilution method. the sources of test isolates included wounds, abscesses, body fluids, and tissues. results: against all test isolates lzd had an mic range of . - mg/l, a mode mic of mg/l, and mic and mic values of and mg/l, respectively. lzd activity was judged by percentage of isolates inhibited at and mg/l. overall lzd inhibited and % of isolates at and mg/l, respectively; at and mg/l, respectively, lzd inhibited and % of bacteroides fragilis group; and % of clostridium isolates; and % of prevotella isolates; % of fusobacterium isolates; and % of peptostreptococcus isolates. by comparison of mic values lzd was -to -fold more active than axo, -to -fold more active than fox, and -to -fold more active than cl against these same groups of isolates. lzd and mrd had virtually equal in vitro activity. interestingly, all isolates with mics of mg/l or higher to lzd had mics of mg/l or less to mrd, while isolates with mics of mg/l or higher to mrd had mics of mg/l or less to lzd. conclusions: based on these results and arbitrary use of nccls breakpoints for gram-positive isolates, we conclude that lzd is highly active against anaerobe pathogens, but this needs to be verified by pharmacokinetic and clinical studies. results: on comparing the mics from the current study with the results from years ago, an unmistakable and very alarming decline in susceptibility was noted for all the antimicrobial agents tested. the greatest difference in susceptibility was noted for cefoxitin (from to %), metronidazole (from to %), piperacillin (from to %) and amoxicillin (from to %). the antimicrobial agents for which < % decrease in susceptibility was found, included meropenem (from to %), clindamycin ( to %) and ciprofloxacin (from to %). a great concern, however, was an % decrease found in the susceptibility for imipenem (from to %). conclusions: a decade ago, most anaerobic bacteria were susceptible to antimicrobial agents usually used for infections caused by these bacteria. the results from this study, however, indicate a situation that has undergone some dramatic changes in a relatively short period. it is of concern that the agents most frequently used in the empirical treatment of anaerobic infections, such as metronidazole and the b-lactams such as cefoxitin and piperacillin have shown the most alarming decrease in susceptibility. there is now, more than ever before, a definite need for continuous susceptibility testing of anaerobes and a serious restructuring of the treatment regimes for anaerobic infections. a. camarda, d. pennelli, p. battista, m. corrente, i. alloggio valenzano, i objectives: escherichia coli isolated from fattening-rabbits dead for enteritis were biotypised, tested with pcr for the presence of virulence genes eae and afr coding for intimin and the fimbrial adhesin af/r and investigated for antimicrobial resistance. methods: fifty-six strains of e. coli isolated in farms were biotypised using the fermentation of sorbose, dulcitol, raffinose, sucrose and l l-rhamnose. detection of drug resistance was determined using the method of kirby-bauer on mueller-hinton agar with antibiotic disks containing gentamicin (gm ), amikacin (an ), tetracycline (te ), erythromicin (e ), spiramicin (sp ), enrofloxacin (enr ), flumequine (ar ), trimethoprim/ sulphametoxazole (sxt), amoxicilline (amx ), apramycin (apr ), difloxacine (dfx ), marbofloxacine (mar ), nalidixic acid (na ), neomycin (n ), colistin (cl ), streptomycin (s ). results: biotypes (b , b , b , b , b , b , b , b , b , b ) were detected: biotypes and were predominant in rabbitries. eae and afr genes were almost observed in e. coli strains belonging to them. results of antibiograms have shown that all the isolates ( %) were e resistant. high rate of resistance were also found towards sp ( . %), sxt ( . %), te ( . %), s ( . %), gm ( . %), n ( . %). about % of e. coli tested showed the same susceptibility rate ( . %) to mar and cl . susceptibility to dfx , enr , ar , na , was exhibited by the . , . , , . %, of the strains, respectively. sensitivity against amx was quite high ( . %). multiple antibiotic resistance was expressed by all e. coli tested. the most prevalent resistotypes were resistant to te -e sp -sxt, detected in strains ( . %), te -e -sp -sxt-s , which accounted for over % and te -e -sp -sxt-gm detected in . % of isolates. conclusions: no significant correlation was observed between enteropathogenic e. coli (eae+ and af/r +) and pattern of antibiotic resistance. quinolones have shown very good activity; in particular mar , which has been recently adopted in veterinary medicine seems to possess high efficacy. on the other hand, e. coli strains exhibited high-level of resistance to antimicrobials. like human e. coli, rabbit strains revealed different patterns of multiresistance, which could make disease control difficult in rabbits and also promote dissemination and increasing of antimicrobial resistance in human strains. objective: to determine the frequency and susceptibility patterns of bacterial pathogens isolated from bloodstream (bsi) of haematology-oncology patients hospitalised at latin american medical centres. material and methods: as part of the sentry antimicrobial surveillance program, a total of bsi isolates were recovered from haematology-oncology patients from to . the isolates were susceptibility tested to > antimicrobial agents in a central laboratory using nccls broth microdilution method. results: the most frequent isolated pathogen was coagulase-negative staphylococci (cons; . %), followed by escherichia coli ( . %), staphylococcus aureus ( . %), klebsiella pneumoniae ( . %), pseudomonas aeruginosa ( . %), enterobacter spp. ( . %), acinetobacter spp. ( . %), and enterococcus spp. ( . %). oxacillinresistance rates were . and . % among s. aureus and cons, respectively, isolates. the prevalence of esbl-producing strains ranged from . % for e. coli to . % for k. pneumoniae. for enterobacter spp., susceptibility rates were . and . % to ceftazi-dime and cefepime, respectively. all enterobacteriaceae isolates tested were susceptible to carbapenems. the susceptibility of p. aeruginosa to imipenem and meropenem was . and . %, respectively; . and . % of the gram-negative bacilli were susceptible to cefepime and meropenem, respectively. only . % of the enterococcus spp. isolates were resistant to vancomycin. conclusions: in contrast to american and european reports, gram-negative bacilli represented the major cause of bsi among haematology-oncology patients in the latin american hospitals evaluated. the antimicrobial agents with the best covered against such pathogens were the carbapenems and cefepime. however, none of the evaluated antimicrobial agents inhibited the growth of . % of the gram-negative bacilli. thus, continued monitoring by surveillance programs is necessary to determine if the observed trends would continue to be recorded. objective: we attempted to verify if the frequency of occurrence (fo) and antimicrobial susceptibility profile (asp) of bacterial isolates responsible for causing bloodstream infections (bsi) in paediatric patients varied along the years and age categories. methods: a total of bloodstream isolates were collected from paediatric patients hospitalised in latin american hospitals through the sentry program between and . the asp to various antimicrobials was determined by the nccls broth microdilution method. the fo and asp were studied according to age categories (ac): year, - years, and - years. results: overall, s. aureus (sa) was the most frequently isolated pathogen among children year ( . %) and - years ( . %) followed by coagulase negative staphylococci (cons). among children year and - years, s. pneumoniae (spn) ranked among the top five pathogens. in contrast, it has caused less than . % of bsi among children - years. curiously, in this age group, acinetobacter spp. and p. aeruginosa ( . %) assumed the fifth position in the rank order of frequency. in general, among sa, the oxacillin resistance (or) rates were lower in the - -year-old ac ( . %; p . ) than in children year ( . %) and - years ( . %). in contrast, among the cons, elevated rates of or were noticed in all acs ( year, . %; - years, . %; - years, . %; p > . ). esbl-producing k. pneumoniae were more frequently detected in the ac year ( . % of the k. pneumoniae isolates) and - years ( . %) than - years ( . %). on the contrary, esbl-producing e. coli isolates were less frequently encountered among children year ( . %) than children ! years ( . %). however, these differences did not reach statistical significance (p > . ). spn isolates showing reduced susceptibility to penicillin were detected more frequently in the ac of year ( . %) and - years ( . %) than in - years ( . %; p . ). conclusions: although only slight differences in the fo of bsi pathogens was noticed along the years and ac, important differences were observed on the asp of the bsi pathogens according to the age categories, especially for spn and sa isolates. objectives: the aim of this prospective, multicentric study was to assess incidence of gram-positive bacteria in bloodstream infections (bsi) and characteristics of their resistance to antibiotics in the czech republic. methods: the study was done in sites in the czech republic from january to april . consecutive gram-positive strains isolated from blood were assessed and their clinical significance was evaluated. results: the strains of staphylococcus aureus ( %), coagulase-negative staphylococci ( %), streptococcus pneumoniae ( %) and enterococcus spp. ( %) were identified as the etiologic agent of gram-positive bsi. the frequency of oxacillin-resistant strains was in staphylococcus aureus and in coagulase-negative staphylococci and %, respectively. all streptococcus pneumoniae strains were susceptible to penicillin and chloramphenicol. no strains resistant to glycopeptides were found in enterococci. clinical significance of isolated gram-positive bacteria was significantly conditioned by bacterial species (p ¼ . ) and reached % in streptococcus pneumoniae, % in staphylococcus aureus, % in enterococcus spp. strains and % in coagulase-negative staphylococci. production of bacterial biofilm was shown in % staphylococcus aureus strains and in % coagulase-negative staphylococci. bsi was the immediate cause of death of the patient in %. conclusion: we could confirm that presence of artificial material means significant risk factor for bsi. catheter-related infections were present in % of cases. forty-six per cent of bsi can be characterised as secondary and pneumonias, git infections and urinary tract infections were the most common sources. the frequency of staphylococcus spp. with positive finding of biofilm was % in this study; this finding supports its clinical significance. methods: a total of s. aureus positive sample isolates between january and december from the laboratory were analysed. the susceptibility to antibiotics was assessed by antibiogram based on the api system (biomérieux Ò ) according to the french guidelines (ca-sfm). the sa strains were classified as methicillin susceptible and gentamicin susceptible (gentas-mssa), methicillin resistant and gentamicin susceptible (gentas-mrsa), methicillin susceptible and gentamicin resistant (gentar-mssa) or methicillin resistant and gentamicin resistant (gentar-mrsa). the number of isolates was calculated for admissions. means per year were compared using kruskal wallis test. the spearman coefficient (r) was used to calculate the correlation between the proportion of isolates (for each antibiotic resistance profile) and months. results: the overall proportion of sa positive samples for admissions during the study period was: . , . , . , . , . and . for , , , , and , respectively (r ¼ À . ; p ¼ . ). the percentage of mssa was . ( . for gentas, . for gentar) and the percentage of mssa was . ( . for gentas, . for gentar) for the total period. patients with mrsa were older ( . years) compared with patients with mssa (mean age . , p < . ) but patients with gentar-mrsa were younger ( . years) compared with patients with gentas-mrsa (mean age . , p ¼ . ). the proportion of gentas-mssa for admissions was similar by time ( . , . , . , . , . , . , p ¼ . ) (r ¼ À . ; p ¼ . ). however, the proportion of gentas-mrsa strains increased significantly ( . , . , . , . , . , . , p ¼ . ) (r ¼ . ; p < . ) while the proportion of gentar-mrsa strains decreased significantly during the period ( . , . , conclusion: although the proportion of sa positive samples for admissions remains constant during the last years, there is a continuous increasing trend of isolates with gentas-mrsa and a decreasing trend of isolates with gentar-mrsa. the age difference between these two sub-groups should be explored. greek region -corfu island e. gatsouli, m. ovrenovits, a. pasxali, a. tzanavari corfu, gr background: in order to assess the regional trends of microbiological resistance pattern, all cultured bacteria isolated in in our laboratory were reviewed as to specimen source and susceptibility profile. materials and methods: in , samples were cultured, % ( ) of hospitalised patients and % ( ) from ambulatory patients. the samples were: urine, blood cultures, lesions and samples of other secretions. classic culture methods, vitek system and nccls breakpoints were used. results: cultivations were positive in % ( , adults and children samples). the distribution of bacteria differed according to the types of specimens. the distribution of gram(À) was enterobacteriaceae and nonfermentative bacilli. there were gram(+) cocci and yeasts, too. e. coli predominated in enterobacteriaceae ( %), followed by klebsiella sp., p. aeruginosa in non-fermentative bacilli ( %) and a. baumanii ( %). among the gram(+) s. aureus was the most frequent ( . %), followed by cns. ampicillin inhibited growth of % for e. coli. ttime/sulfa combination could inhibit less than % and the second-generation cephalosporins less than %, while fluoroquinolons were very effective against enterobacteriaceae strains (more than %). piperacillin inhibited growth of % of p. aeruginosa and quinolons less than %. enterococcus strains were highly sensitive to teicoplanin ( %) and nitrofurantoin ( . %). mrsa were % but gisa were %. a. baumanii and gisa were in icu. conclusion: a permanent surveillance of frequency and sensitivity levels of the most common pathogens responsible for infectious enables to identify local antimicrobial activity and plays a key role in starting empiric therapy pending bacterial identification and in vitro assay. objectives: the biochemistry and genetics of antibiotic resistance are well documented; however, information regarding the medical and social factors that influence its occurrence remains lacking. the aim of this study was to elucidate these latter relationships and to examine the dynamics of their effects. methods: antibiotic resistance data for bacterial isolates obtained from the community was collected from all microbiology laboratories in wales from to . antibiotic prescribing data, practice demographics, deprivation indices, general practitioner demographics, and details of sampling behaviour was also obtained for the same period for all general practices in wales. initial analyses exploring the nature of these data and the relationships of the various components were undertaken using excel and spss. results: preliminary analyses indicate that both antibiotic resistance and prescribing varied between practices. for coliform utis, there was a clear association between high prescribing and higher levels of resistance, with prescribing accounting for - % of variation in resistance. the correlation between prescribing and resistance was not confined to the urinary coliforms but seen throughout a range of pathogens including those responsible for respiratory and skin infections. there was an association between resistance and social deprivation exceeding that expected from high prescribing in deprived areas and an apparent association between resistance and the number of practitioners in a practice and the practice list size. resistance was more common in infections in the young (< years), the aged (> years) and for some pathogens resistance was significantly greater in males. multilevel modelling, regression analysis and time series analysis of this complex data set is in progress. conclusions: antibiotic usage appears to affect resistance at practice level and the dynamics of this selection process are currently being investigated. it is hoped that these studies will assist in the design of interventions to limit the future impact of resistance and contribute to our ability to predict their outcomes. objectives: data about the prevalence of antimicrobial resistance in indonesia are limited. the amrin study measured the prevalence of antimicrobial resistance in the indonesian population inside and outside hospitals. methods: individuals were targeted to be screened constituting four different populations in each of two cities: patients admitted to hospital, patients discharged from hospital, patients visiting primary health centres, and relatives of patients admitted to hospital. nasal swabs and rectal swabs were taken and cultured using phenol red mannitol agar for the isolation of staphylococcus aureus, and chrom agar orientation medium for escherichia coli. susceptibility testing was performed by disk diffusion method recommended by nccls. results: individuals were included in the study between july and october in surabaya and between january and may in semarang equally distributed over the four groups and two cities. s. aureus isolates (n ¼ ) were frequently resistant to tetracycline ( %) and oxacillin ( %) without obvious differences between the four populations. none of the oxacillin resistant strains of s. aureus harboured mec a gene. e. coli isolates (n ¼ ) showed considerable levels of resistance against a number of commonly used antibiotics. the highest levels of resistance to ampicillin ( . %), chloramphenicol ( . %), gentamicin ( . %), cefotaxim ( . %), ciprofloxacin ( . %), and cotrimoxazole ( . %) were among e. coli isolated from patients on the day of discharge from hospitals. resistance rates were consistently lowest among e. coli from relatives of patients on admission to hospital and among patients visiting primary health care centres. conclusions: the results show that antimicrobial resistance among common bacterial pathogens has emerged in indonesia. among e. coli the prevalence of resistance to ciprofloxacin and other antibiotics is remarkable high, especially in individuals after hospitalisation. although the prevalence of mrsa is low, tetracycline resistance is common among s. aureus and not associated with hospital stay. methods: isolates from patients with invasive diseases caused by haemophilus influenzae (hi), neisseria meningitidis (nm), group a streptococcus (gas), and group b streptococcus (gbs) were forwarded to reference laboratories in alaska ( alaska ( - , canada ( canada ( - , and greenland ( greenland ( - for confirmation and serotyping. chart reviews were conducted on confirmed cases to verify illness episode information. data reported for are preliminary. results: the total numbers of reported cases were hi, nm, gas, and gbs. crude annual rates of invasive disease per population varied by country and organism [hi conclusion: native peoples of ak and n can have high rates of invasive bacterial disease caused by hi, nm, gas and gbs. overall rates of nm disease are higher in gn than ak and n can. cases of invasive hib disease continue to occur in children < years of age. rates of hia appear to be elevated in n can and increasing in ak, however, caution needs to be used when interpreting rates due to the small number of cases. this trend merits further surveillance. elevated case fatality rates in ak for hi and nm also warrant further investigation. objectives: for tertiary care hospitals, knowing the local patterns of spectrum and susceptibility at the referring institutes can add significantly to the selection of appropriate antimicrobial therapy. our objective was to get information regarding the region specificity, frequency of occurrence and pattern of antimicrobial susceptibility of common bacterial infections in central illinois. methods: we used hospital antibiogram data to assess predominant pathogens and pattern of in vitro antimicrobial susceptibility of bacterial infections in the four regions (west, southwest, central and south) of central illinois from january to june . results: gram-negative bacteria were predominant in four regions ( , , and % respectively). in all regions, e. coli was the most common organism ( , , , and %) followed by s. aureus ( , , , and %). e. faecalis, p. aeruginosa, and k. pneumoniae were also among the five most frequently reported species. on the other hand, the frequency of occurrence of s. pneumoniae was - % in the four regions. the pattern of methicillin-resistant s. aureus was different in the four regions ( , , , and %) with only . % of the total number of s. aureus showing intermediate resistance to vancomycin. e. faecalis, , , and %, respectively, were susceptible to vancomycin. susceptibility of s. pneumoniae to penicillin was almost the same in the four regions ( , , , and %). it was not surprising that p. aeruginosa was the least susceptible species among gram-negative bacteria, and this species showed decreased susceptibility to gentamicin ( , , , and %) and to ciprofloxacin ( , , , and %). conclusions: our data show that different communities in central illinois have variable occurrence and pattern of antimicrobial susceptibility of common bacterial infections. we plan to formulate a regional antibiogram, distribute it to all hospitals in the area, and follow the patterns prospectively with renewal of the antibiogram once a year. p antimicrobial resistance surveillance of gramnegative anaerobic bacteria isolated in six greek hospitals j. papaparaskevas, n.j. legakis, a. katsandri, a. avlamis -the hellenic study group for gram-negative anaerobic bacteria objectives: the antimicrobial resistance surveillance of gram-negative anaerobic bacteria isolated in six greek hospitals. methods: a total of gram-negative anaerobic clinical strains ( bacteroides fragilis group, other bacteroides spp. non-fragilis, prevotella spp., fusobacterium spp. and miscellaneous) isolated during the period november to november were tested using the etest method on brucella blood agar plates. incubation in a chellab . anaerobic chamber was performed for h and interpretation was according to nccls guidelines. results: overall gram-negative non-susceptible (intermediate and fully resistant) rates to penicillin, ticarcillin + clavulanic acid, cefoxitin, tetracycline, clindamycin, metronidazole, imipenem and ertapenem were , , , , , , and %, respectively. bacteroides fragilis group rates were , , , , , , and %, respectively. prevotella spp. rates were , , , , , , and %, respectively. overall gram-negative mic s were , , , , , , . and mg/l, respectively. bacteroides fragilis group mic s were , , , , , , and , respectively. prevotella spp. mic s were , , , , , , . and . , respectively. metronidazole resistance was detected among four prevotella spp., one bacteroides spp., one porphyromonas spp. and one fusobacterium spp. isolates. additionally, a b. fragilis strain was found highly resistant (mic > mg/l) both to imipenem and ertapenem and resistant to all other antimicrobials tested except metronidazole. conclusions: carbapenems, beta-lactam + inhibitor combinations and metronidazole remain the antimicrobial agents of choice against most gram-negative anaerobes. however, metronidazole resistance seems to be an emerging problem in greece, especially among prevotella spp. isolates. in that respect species identification and periodic susceptibility surveillance is mandatory. imipenem and ertapenem activity was comparable, though ertapenem mics were slightly higher. acknowledgements: members of the hellenic study group for gram negative anaerobic bacteria are drs a. avlamis, c. koutsia-karouzou, c. kontou-kastelanou, a. pangalis, e. papafrangas and e. trika-grafakos. the value of quality control strains in susceptibility tests k. huppertz, i. noll, b. wiedemann and the genars group objectives: the goals of a quality control programme are to assist in monitoring the precision and accuracy of the susceptibility test procedure, the performance of reagents used in the test and the performance of persons who carry out the tests and read the results. they are best accomplished by the testing of quality control (qc) strains with known susceptibility to the antimicrobial agents to be tested (nccls). therefore, qc strain measurements done by laboratories taking part in the genars-project (german network for antimicrobial resistance surveillance) were used for a comparison of the performance of three different methods for mic determination. methods: in the genars-project two commercial mic test systems and one manual microdilution system according to nccls are used for the determination of antimicrobial susceptibility. the commercial systems are the vitek (biomérieux) and the micronaut system (merlin diagnostics) with -well microtitre-plates. qc strains measured by all test systems were evaluated for those antibiotics where a range of ae dilution step of the modal value of the respective qc strain is included in the range of concentrations tested. for reliable assessment of the test quality the distance of the modal value from the lowest and highest concentration tested has to be two or more dilution steps. results: from a multitude of antibiotics tested only few drugs are tested with a range of concentrations which meets the above mentioned requirements. table indicates the number of test combinations available for evaluation. the vitek system offers the shortest ranges of concentrations. however, from the range of concentrations only few are tested, while the others are calculated, e.g. for gentamicin the range includes six concentrations while only three are measured (ast-p ). conclusions: an evaluation of qc strain measurements should be possible for all antibiotics tested. however, due to the concentrations chosen and the short ranges of concentrations available in the different test-systems only few antimicrobial agents can be used for a comparison of the performance of the test methods. therefore, either the range of concentrations has to be extended, or more suitable qc strains have to be implemented in a way that their mics fall into the range of concentrations which are sufficient in clinical terms. p lack of evidence for dna in antibiotic preparations as a source of antibiotic resistance genes s.k.p. lau, p.c.y. woo, a.p.c. to, a.t.k. lau, k.y. yuen hong kong, hk objective: to investigate the significance of dna encoding antibiotic resistance genes present in antibiotic preparations in the rapid development of antibiotic-induced antimicrobial resistance. methods: a comprehensive study using sequence alignments and phylogenetic analysis of genes encoding antibiotic resistance in antibiotic-producing bacteria and the corresponding ones in nonantibiotic-producing human or animal bacterial isolates [erythromycin resistant methylase (erm), aminoglycoside -phosphotransferase (aph ), aminoglycoside -phosphotransferase (aph ), aminoglycoside acetyltransferase (aac), class a beta-lactamase, tetracycline resistance efflux protein, tetracycline resistance ribosomal protection protein and vancomycin resistance proteins (vana, vanh, vanx) and bacitracin transport proteins (bcra, bcrb, bcrc)] was carried out. if dna encoding antibiotic resistance genes present in antibiotic preparations has been important in the development of antibiotic resistance, genes of almost identical amino acid sequences would be expected to be present in antibiotic-producing organisms and other human or animal bacteria, inferring that horizontal transfer of antibiotic-resistance genes had occurred from the former to the latter. results: the maximum amino acid identities of genes among different non-antibiotic-producing bacterial isolates were close to % for most genes, but those between antibiotic-producing and human or animal bacteria ranged from < to < %. therefore, recent horizontal transfer of antibiotic resistance genes has not occurred from antibiotic-producing organisms to human or animal bacteria. on the other hand, frequent horizontal transfer of antibiotic resistance genes was observed among the human or animal bacteria, even if they were phylogenetically distantly related. moreover, such transfer was particularly common among gastrointestinal tract flora or pathogens. conclusion: dna encoding antibiotic resistance genes in antibiotic preparations has not been an important source of antibiotic resist-ance genes. dna decontamination during the process of antibiotic synthesis is probably not necessary. the human gastrointestinal tract has been an important place for bacterial gene exchange. the role of the human gut in the dissemination of antibiotic resistance should be further investigated. enterococci and other gram-positive bacteria p glycopeptide-resistant enterococci (gre) have emerged as important pathogens since the late s. an important factor associated with the appearance of gre in the community in europe has been avoparcin, a glycopeptide antimicrobial drug used for years in many european countries as a growth promoter in food-producing animals. in europe, evidence suggests that food-borne gre may cause human colonisation or infection. objectives: the objective of this study was to investigate the prevalence and to determine the genotypes of gre from different human and animal sources in styria, austria. methods: stool specimens from each patients with precedent antibiotic therapy and non-hospitalised humans without precedent antibiotic therapy, faecal cattle specimens, faecal pig specimens and faecal poultry specimens were collected in . one millilitre of diluted faeces was added to ml of enterococcosel bouillon (bd) for enrichment. after incubation, ml was subcultured on vre screen agar (bd). species identification was performed with the api strep systems and vitek (bio-mérieux). resistance to vancomycin and teicoplanin was determined by the e-test method (ab biodisk). determination of glycopeptide resistance genotypes (vana, vanb, vanc , vanc / ) was performed by pcr. results: % of the patients with precedent antibiotic therapy harboured vre. among these, two were identified as e. faecium vana, two as e. gallinarum vanc and e. casseliflavus vanc , respectively. eight per cent of the non-hospitalised human specimens contained vre (six e. gallinarum, two e. casseliflavus). a total of vre strains were isolated out of the animal samples, . % e. faecium, . % e. gallinarum, and . % e. casseliflavus strains. no resistant e. faecalis strains were detected. pcrs confirmed that all e. gallinarum were of the vanc , all the e. casseliflavus of the vanc and all the e. faecium strains of the vana genotype. about . % of all e. faecium vana strains were isolated out of the poultry samples. one strain was isolated from a cattle sample, no specimen from pigs yielded glycopeptide-resistant e. faecium. conclusion: the present study indicates that the prevalence of gre in humans and in pig and cattle husbandry appears to be low, but it reveals a high prevalence of gre (e. faecium) in styrian poultry years after the use of avoparcin was banned. glycopeptide resistant enterococci (gre) have become an increasing problem in the us and in europe. enterococci are intrinsically resistant against cephalosporins, aminoglycosides (low-level), polymixins, lincomycin and clindamycin. furthermore, enterococci are able to acquire resistance to a wide range of antibiotics. there remain concerns that antibiotic use for growth promotion, prophylaxis and therapy in animal husbandry may lead to increased resistance to antibiotics used in human medicine. objectives: the aim of this study was to evaluate the species distribution and the antibiotic resistance of gre isolated from styrian food-producing animals. methods: a total of gre strains isolated from cattle, pig and poultry faecal specimens in were collected. the strains were identified using the vitek automated methods (gpc) and the api strep systems (biomérieux). antimicrobial susceptibilities were determined by vitek p card and by disk diffusion (linezolid). the strains were studied for susceptibility to antibiotics: ampicillin (am), amoxicillin/sulbactame (amc), ciprofloxacin (cip), erythromycin (ery), gentamicin high level (ge), linezolid (li), norfloxacin (nor), penicillin (p), quinupristin/ dalfopristin (syn), streptomycin high level (str), teicoplanin (tp), tetracycline (te) and vancomycin (va). results: e. casseliflavus was the most common gre species isolated ( . %), followed by e. gallinarum ( . %) and e. faecium ( . %). all e. gallinarum and e. casseliflavus were of the vanc, all e. faecium of the vana phenotype. all investigated strains were sensitive against linezolid and gentamicin high level. p and am resistance ( . %) and reduced susceptibility to cip ( . %) was seen in e. faecium only. ery resistance for e. faecium revealed . %, for e. casseliflavus . % and for e. gallinarum . %. resistance against te for e. faecium was . %, for e. casseliflavus . % and for e. gallinarum . %. about . % of e. faecium strains were not susceptible to quinupristin/dalfopristin. conclusions: resistance phenotypes to p, am, cip, ery and te differed among enterococcus species. resistances found against tetracyclines, quinupristin/dalfopristin and erythromycin are causes of concern. high levels of antibiotic and multidrug resistance were observed among the e. faecium strains. the identification was carried out by the vitek system (biomerieux). the susceptibility test was performed either by the breakpoint system:mini api or the vitek system (biomerieux). results: ( %) and ( %) streptococci strains were isolated from outpatients' and inpatients' urine cultures, respectively. the distribution by sex was % women/ % men in outpatients and % women/ % men in inpatients. a total of ( %) of streptococci strains were enterococcus faecalis, ( %) were enterococcus faecium, ( %) were enterococcus gallinarum and ( %) were streptococci group b. the in vitro antibiotic resistance of enterococci spp. was: penicillin . % ( / ), ampicillin % ( / ), gentamicin % ( / ), nitrofurantoin . % ( / ), ciprofloxacin % ( / ), tetracyclines % ( / ), vancomycin % ( / ), linezolid %. eight vre strains were enterococcus faecium, three were enterococcus gallinarum and two were enterococcus faecalis. the in vitro antibiotic resistance of group b streptococci was: vancomycin %, nitrofurantoin . % ( / ), ampicillin . % ( / ), penicillin . % ( / ), erythromycin . % ( / ), tetracyclines % ( / ). conclusions: streptococci are responsible only for the . % of urinary tract infections. enterococcus faecalis was the most frequent pathogen ( %). enterococci spp. showed high resistance in ciprofloxacin, tetracyclines, gentamicin, penicillin, and ampicillin. objectives: enterococcal infections are becoming an increasing concern, particularly due to the emergence and spread of resistance to animicrobial agents. we have investigated the phenotypic and genotypic properties of enterococcus faecium clinical isolates, expressing resistance to the combination of quinupristin/ dalfopristin, recovered during a -year period in the university hospital of patras. methods: all isolates were characterised at species level by gram stain, catalase production and by the crystal id gram positive system (bbl). minimal inhibitory concentrations (mics) to ampicillin (amp), erythromycin (em), chloramphenicol (chl), gentamicin (gm), ciprofloxacin (cip), vancomycin (va), teicoplanin (tp), quinupristin/dalfopristin (rp) and linezolid (lin) were performed by the e-test (ab biodisk) according to nccls recommendations. the presence of vana and vanb genes was investigated by the evigene commercial kit (statens serum institut), while the presence of vga, vgb and sat genes by pcr with specific primers. clonal types were characterised by pfge of smai dna digests. results: in a collection of e. faecium, ( %) expressed mic of rp ! mg/l, and among them isolates ( %) showed mic > mg/l. high-level resistance to gm was detected in ( %) isolates, ( %) to cip, ( . %) to chl, ( %) to amp and ( %) to em. forty-three ( %) isolates were vancomycinresistant, carrying the vana gene. no isolate was found to carry vga, vgb and sat genes. pfge classified isolates to clonal type a, to type b, to type c and the remaining isolates belonged to more types. conclusions: high prevalence of low-level resistance to quinupristin/dalfopristin (mic: - mg/l) was detected in this collection of e. faecium, with strains expressing higher mic levels. this was mainly due to the dissemination of certain clones in the hospital. in a previous work, we described the dissemination of renc and renc e. faecalis multiresistant clones colonising patients of four different icus. the renc clone was frequently found in bacteraemias, suggesting a blood invasion from an intestinal origin. the aim of this study was to analyse the dynamic population evolution of enterococcal intestinal isolates and if the acquisition of epidemic hospital clones may occurs during icu admittance. material and methods: a close follow-up of four patients from the neurosurgery icu who were admitted after acute traumatism was performed. rectal swabs were collected at the admittance and daily until they were discharged from the icu. stool samples were seeded in m-enterococcus agar, eventually supplemented with selective antibiotics, and multiple colonies were analysed in each sample. pfge-smai and the phoretrix . software were applied to analyse the genetic relatedness among these isolates and the previously described hospital endemic clones. results: patient and stayed in the icu for days, and patient and for days. patient carried along the days the original e. faecalis and e. faecium clones. moreover, five e. faecalis clones, one identical to the epidemic clone renc , and one e. faecium clone were acquired during the icu stay, all of them persisting over the rest of the studied period. patient presented at admission three e. faecalis and two e. faecium clones; two e. faecalis were lost in days, and e. faecium were lost at the second day. four new e. faecalis and one e. faecium clones were found during all stays, whereas five more clones were occasionally isolated without persistence. in patient an e. faecium clone was identified along all the studied period, and two new e. faecium clones were later acquired. patient had two e. faecium clones at admission, one of them being lost after the first day; the second persisted during all days; a new e. faecium clone was acquired during the icu stay. patient and methods: the patient was a -year-old woman hysterectomised years ago. she reported four surgical interventions due to a cystocele. the last operation took place years ago and she reported no further admittances at any hospital. in the last years the patient also suffered from repeated urinary tract infections. in the present episode she consulted because of typical uti symptoms (dysuria, bladder tenesmus) and a urine sample was collected. after h of incubation, a gram positive coccus was isolated (more than ufc/ml). the identification and susceptibility were preliminarily achieved by a commercially available method following manufacturer's recommendations (microscan, dade). identification was confirmed by api rapid strep system (biomerieux). to discard enterococcus species intrinsically resistant to vancomycin the absence of motility was observed with direct microscopic detection and the absence of pigmentation was determined by culture on tsa agar. susceptibility to vancomycin, teicoplanin and ampicillin were assessed by disk diffusion, e-test and broth mcrodilution. results: the isolated microorganism was identified as enterococcus faecalis and showed high mics to vancomycin (> mg/l by broth microdilution and mm by disk diffusion) and teicoplanin ( mg/l by broth microdilution and mm by disk diffusion) but was susceptible to ampicillin ( . mg/l by broth microdilution). to characterise the resistance mechanism involved in a series of vancomycin resistant enterococcus faecium (vref) strains recovered in two spanish hospitals of the same city, and to determine their clonal relationship. methods: a surveillance programme was carried out during a -year period in ms-hospital in order to detect vref intestinal colonisation. seven vref strains were recovered from seven faecal samples which represents < % of vref intestinal colonisation. in the same period, four clinical vref strains, implicated in infectious processes were recovered in ms-hospital (n ¼ ) and rv-hospital (n ¼ ). all vref strains (n ¼ ) were recovered from unrelated patients, most of them previously treated with glycopeptides or broad spectrum antibiotics and diagnosed with severe diseases. antibiotic susceptibility testing was performed by agar dilution method and vancomycin resistance genes (vana, vanb, vanc , vanc- / , and vand) were studied by pcr. vanb amplicons were sequenced to determine the subtype and the vanb cluster of genes were also characterised. other resistance genes were studied by pcr: aph( ¢)-iiia, ant( ¢)-ia and erm(b). pfge assays were performed with smai digestion. results: nine of the vref strains (eight of ms-hospital and one of rv-hospital) showed a vanb phenotype [mic (mg/l): vancomycin ( - ) and teicoplanin ( . )]. the vanb gene was detected in these nine strains and in addition, the intergenic vansb-yb region showed the characteristic mutations of the vanb subtype. the vanb gene cluster was integrated into the tn like element in all of them, as it was demonstrated by specific pcrs and sequencing. these strains were resistant to streptomycin, kanamycin and erythromycin and ant( ¢)-ia, aph( ¢)-iiia and erm(b) genes were detected by pcr. all of them were included in the same pfge clonal type a and two closely related subtypes were distinguished: a (seven strains from both hospitals) and a (two strains from ms-hospital). both subtypes were found in clinical strains as well as in strains recovered from faecal samples. only three of them were from serious infections, the rest was isolated from carriers. all but one present vana phenotype and harbour vana gene. the only vanb harbouring strain was resistant to teicoplanin. the outbreak at haematology was at the beginning polyclonal ( pfge clones) but eventually three of them became predominant in both wards. the outbreak in cracov centre was spread to two other wards of this hospital (surgery and geriatry) with , and vrem isolated up to now, respectively. five were from serious infections, were from wounds in the surgery, the rest represents for carriers detected during infection-control measurements. all but two of them were vana phenotype/genotype ( vanb phenotype/genotype isolates). one predominant pfge clone was observed, differentiated into pfge sub-types ('hospital clone'). five other pfge clones detected seemed to be unique (one to five isolates). in both outbreaks two basic mechanisms of vre spread were detected, clonal spread of vre strains and the vana-elements horizontal transfer. conclusion: after time of vrem presenting vanb phenotype caused sporadic outbreaks two of haematology centres in poland become the stages of multi-drug-resistant vana vrem outbreaks, eventually turning into endemic. the colonisation rate was - times higher than infection in both cases. the danger of transmission to other centres and non-haematological hospitals in the country appears very high in these circumstances. material and methods: thirty-three selected vrefls from different patients at three hospitals (huc, hsa and hst) in the north and centre of portugal ( portugal ( - were studied. susceptibility to antibiotics was performed by the agar dilution method (nccls). isolates were searched for genes coding for resistance to glycopeptides, macrolides, and aminoglycosides. tn characterisation was done by an overlapping pcr strategy and sequencing when necessary. clonal relatedness was performed by smai-pfge. virulence traits (cyl, agg, gele, esp) were investigated by a multiplex pcr assay. results: all vrefls showed vana phenotype and were mostly resistant to ery, cipro, hlrgm, and hlrkm ( , , , and %, respectively). resistance genes found were vana, erm(b), aac -aph , and aph -iiia. nine pfge types were isolated: eight from eight patients and one (clone b) from patients. clone b was disseminated among the three hospitals for years giving eight pfge subtypes, each one characteristic of a specific hospital. vsefls showing pfge patterns identical to two clone b subtypes were found in hst. six variants of tn were found, five of them among isolates of clone b. tn -pp was found in all hospitals for years and predominates in huc and hst. it contains an isef insertion in the intergenic vanx-vany region. tn -pp , only found in hsa, lacks genes involved in transposition. pp and pp were variants of pp and were recovered at huc. pp was a pp- variant found in hsa. all vre but one isolate of clone b were agg+ and gel+. cyl and esp were present in % of the vre. conclusion: our findings indicate that the dissemination and establishment of successful e. faecalis clones in the hospital setting amplify particular genetic determinants in local metagenomes resistant to vancomycin, and therefore influences future evolutionary events. we also report the first tn -variant containing an isef insertion. staphylococcus spp. is widely distributed in medical and veterinary pathology and represents one of the most important causes of infection. many strains are antibiotic-resistant even for the presence of an eso-polysaccharide matrix. the aim of this work was to individuate, among different staphylococci of human and animal origin, the slime producing strains and to correlate the presence of biofilm to the resistance to eight antibiotics. a total of coagulase negative staphylococci (cns) and s. aureus isolated from different sources and identified with sceptor system, were tested for antibiotic susceptibility (kirby bauer method) and for slime production (polystyrene plates -stained with alcian blue -spectrophotometric reading at nm). the strains were classified as weak, strong and no slime-producing on the basis of od results. the results were submitted to statistical analysis using student's t-test and chi-square tests. evaluating the differences of slime production among medical and veterinary strains, we found different statistical frequencies (p > . ). no statistical differences were obtained between s. aureus and the other cns. instead, the statistical analysis on s. epidermidis vs. the other staphylococci has shown no statistical differences among average values using student's ttest (p < . ) and significant frequency differences using chi square tests (p < . ). finally in the cns, between s. epidermidis and the other strains, no statistical differences were found. the relation between slime production and the origin of strains was evaluated and no correlation was found. about the correlation between antibiotic-resistance and slime production a resistance increment of about % was obtained in strongly slime producing strains. staphylococcus spp. is often involved in nosocomial infections as complication of post-surgery wounds, catheters and orthopaedic devices. the presence of antibiotic-resistant strains interferes in the therapy successes and seems to be strictly related to biofilm production beyond that genetically acquired. human and veterinary strains have shown a similar behaviour towards biofilm production and antibiotic-resistance. the results confirm that s. epidermidis is one of the most slime-producer and introduce s. aureus as a new high slime-producer. ( ) recommendations. the macrolide resistance phenotypes were determined using the erythromycin-clindamycin double disk test. results: all the s. agalactiae isolates tested were found susceptible to penicillin g and vancomycin while the resistance rate to erythromycin was . % (seven strains). the expression (%) of the macrolide resistance phenotypes among the resistant strains as they were evaluated by the double disk test were: constitutive (cmlsb) phenotype % (four isolates) and inducible (imlsb) phenotype % (three isolates). no s. agalactiae strain was assigned to the m resistance phenotype. the overall resistance rate to clindamycin was . %. conclusions: our findings demonstrate that s. agalactiae remains fully susceptible to penicillin and vancomycin while there are relatively low resistance values to macrolides and lincosamides. the mlsb phenotype predominated among the macrolide-resistant strains, a finding that raises concern about the use of clindamycin instead of erythromycin in prophylaxis or treatment of s. agalactiae infection in patients allergic to beta lactams. however, continuing surveillance is needed to detect any change in susceptibility patterns. effect of enterovirus infection on the risk of type diabetes mellitus has been studied mainly using indirect serological evidence of past infections, or using rt-pcr detection of the virus in plasma. with respect to enterovirus biology, we decided to assess the exposure to enterovirus using real-time rt-pcr detection and quantification from stool samples. this exposure is studied in relation to signs of autoimmune process ultimately leading to type diabetes. methods: the study population comes from the norwegian 'midia' study which screens newborns from the general population for the highest hla-encoded risk of type diabetes mellitus. the high-risk babies are followed-up by questionnaires, serum samples for markers of beta-cell autoimmunity, and stool samples collected in monthly intervals from month to month . the stool samples are collected by parents and mailed to the laboratory where rna and dna is co-purified on qiagen columns together with a low quantity of exogenous control rna. enterovirus is quantified by real-time rt-pcr using armored rna as a standard. control rna is detected in late cycles in the same reaction using a differently coloured probe reporter. adenovirus quantity is simultaneously investigated as a viral exposure which has not been implicated in triggering type diabetes. here we present the results of the pilot study. objective: there are conflicting reports regarding cmv-dna positivity among healthy cmv-seropositive individuals. we aimed to determine the frequency of cmv-dna positivity among healthy subjects and to evaluate its association with physical and mental stress in a longitudinal study. subjects and methods: weekly peripheral blood samples were drawn into from healthy cmv seropositive subjects aged between and years during a -week study period. each subject rated their physical and mental stress and they also recorded their alcohol consumption and any change in their health status. cmv dna was screened in plasma and peripheral blood leukocyte samples with a nested pcr using primers targeting mie gene of cmv. results: in total, samples ( plasma and peripheral blood leukocytes, each) were screened and only one peripheral blood sample obtained during the second week of the study gave positive result. this sample belonged to the oldest subject of the study. according to our results, cmv-dna positivity among healthy cmv seropositive individuals seems to be a rare event. results: all centres reported qualitative results; four centres also reported quantitative results. all samples were correctly identified by all centres. various extraction and amplification methods were used. fourteen centres reported results of internal controls. most of the centres controlled only the amplification step and did not adjust the detection sensitivity of the internal control to the detection limit of the target. three centres failed to detect one internal control in two positive samples and one negative sample. for quantification of hcmv dna all centres used real-time quantitative pcr. cv of hcmv dna load between centres were low ( . - %) except for one sample ( %), but this could be attributed to a heterogeneous preparation of this sample by the organisers. using student's t-test, no statistically significant difference was observed between hcmv load whatever the medium or the number of added cells. conclusion: results of this external quality assessment for molecular detection and quantification of hcmv dna were excellent. almost all centres used internal control of pcr inhibition; however, control of the whole pcr process, including extraction and better adjustment of the detection sensitivity of the internal control to the sensitivity limit of the pcr target is desirable. the most accurate way to identify false negative results, e.g. those caused by pcr inhibitors, in real-time pcr assays is to spike samples with an internal control that will be co-amplified with the target (pathogen) dna. however, current internal control procedures, which usually involve the introduction of a dna fragment, are complex, time consuming and expensive. we present a novel technique for simple internal control of real-time amplification assays. methods: single-stranded oligonucleotides, which contain little more than primer and probe binding sites, were used as internal controls in real-time pcr assays. mismatches were included in the probe-binding region of the internal control oligonucleotide (ico) to prevent probe-control hybridisation during the fluorescence acquisition step of the pcr. icos could be added directly to the sample material prior to dna extraction. results: to demonstrate the feasibility of the new approach, we designed icos for the following lightcycler hybridisation probe assays: mycobacterium tuberculosis complex, hepatitis b virus, herpes simplex virus and varicella zoster virus. in each case, the controls did not interfere with detection of the pathogen, but were clearly detectable during a subsequent melting point analysis of the pcr products. conclusion: a single-stranded oligonucleotide, which mimics the target region of the pathogen yet is clearly distinguishable from the target during analysis, can serve as a simple, cost-effective internal control for real-time amplification assays. such control oligonucleotides are easy to design and cheap. a costly second probe system is not necessary. moreover, the internally controlled assay uses only one fluorescence detection channel of the instrument, leaving the second channel free for multiplex applications. objectives: biomérieux has developed a new nucleic acid isolation method (nuclisens magnetic extraction reagents) that uses boom chemistry in combination with magnetic silica particles. the nuclisens mini mag instrument is facilitating the washing and collection of the silica particles in a user friendly and efficient way. in principle the extraction method is generic and can be applied to a broad range of different sample types. the objective of this study was to measure the performance of this new extraction platform in terms of rna and dna recovery, purity and integrity. in addition, user aspects were also addressed in the study. methods: rna recovery was measured by spiking e. coli rna to human normal edta plasma, extracted rna was quantified by using a fluorescence dye for rna detection (sybr green ii). dna recovery was measured by spiking plasmid dna (pbr ); extracted dna was determined by a measurement. an indication of rna and dna purity was obtained by measuring a / a ratios. the integrity/intactness of the extracted nucleic acid was determined by gel analysis or by using the bioanalyzer (agilent technologies) for rna and dna, respectively. the extraction method was tested on three external test sites in order to score relevant user aspects. results: the average recovery rates were and % for rna and dna, respectively. for rna extracts an average a /a ratio of . was measured, whereas for dna this value was . . these values indicate that the purity of both preparations is high since for pure preparation the expected values are . and . for rna and dna, respectively. in addition, it was found that both rna and dna were intact recovered since no degradation products were detected. in addition, all users scored the method as labour friendly. the total amount of time needed to process samples was < min, the throughput time was improved further by using two instruments in parallel, in this way samples can be completed within min. in addition the method was also verified for a broad range of different sample types including plasma, serum, csf, sputum and stool. dna sequencing is the gold standard method for accurate genotyping of human papillomaviruses (hpv) and provides nucleic acid sequence information, which is the core of every organism. pyrosequencing method has been successfully used for hpv genotyping with sequencing of only - bases. multiple hpv infections are a common phenomenon in clinical samples with a varying rate depending on the group investigated. dna sequencing techniques cannot differentiate between different genotypes as uninterruptible sequence results are obtained when multiples infections and unspecific amplification products are present in the amplicon. to address these problems, a type-specific multiplesequencing primer dna sequencing strategy, suitable for genotyping and detection of hpv- , - , - , - , - , - and - has been developed. in the new method seven type-specific sequencing primers, combined in a pool, are added to the dna sample. the oligonucleotide hybridising to the dna sample will function as a primer during the subsequent dna sequencing procedure. the new method is especially suited for detection and typing of samples harbouring different hpv genotypes (multiple infections) and unspecific amplifications, which eliminates the need for nested pcr, stringent pcr conditions and cloning. furthermore, the method has proved to be useful for samples containing subdominant types/species, and samples with low pcr yield, which avoids re-performing 'failed' pcrs. we also introduce the sequence pattern recognition when there is a plurality of genotypes in the sample, which facilitates typing of more than one target dna in the sample. moreover, target specific sequencing primers could be easily tailored and adapted according to the desired applications or clinical settings based on regional prevalence of hpv as well as other microorganisms and viruses. as the cost for dna sequencing is dropping, a sample could be sequenced in parallel with two or three different target specific primer pools covering a broader range of genotypes. the pyrosequencing hpv detection assay is fully automated and could be used for detection and identification of different microorganisms and viruses. reagents to reference extraction methods for the isolation of rna and dna from various sample types results: by performing several extractions (up to ) of a dilution series of strain coxacksie b in csf, it was shown that the analytical sensitivity of the enterovirus rt-pcr was found to be independent of the extraction method used, whereas in very low frequency higher sensitivities were obtained in combination with magnetic extraction. as expected the higher input samples gave better reproducible results than lower input samples. after evaluation of the enterovirus pcr using csf and stool samples a % correlation between the two extraction methods was found. in addition, using a broad panel of clinical specimens for m. tuberculosis pcr, the same samples were identified as positive using the boom extraction method and magnetic extraction. however, the latter method resulted in less samples having inhibition in pcr, but this needs to be confirmed in a larger study group. methods: conjunctival scrapings were sent to our laboratory in ml of viral transport medium and were inoculated to monolayers of a- and mrc- cells in tubes, incubated at c in stationary phase, and scored daily for cytophathic effect (cpe) for days or until cpe developed. when a characteristic adenovirus cpe was observed (usually after days of culture), a passage was done to two homologous monolayers in shell vials that were incubated h at c and stained with specific fluorescent reagents to adenovirus. dna from . ml of the remaining transport medium was purified by a commercial procedure and resuspended to a final volume of ll. five microlitres of this purified dna was used for real-time amplification in a final ll reaction volume, using  fast start sybr green i master mix (roche), mgcl ( mm m), and . lm m of each primer. the region amplified belongs to the hexon gene. total processing time was less than h. results: adenovirus was isolated in of samples processed by conventional cell culture and all theses culture-positive samples were positive by real-time pcr; of samples testing negative with conventional cell culture, real-time pcr detected eight as negative and five as positive. gel electrophoresis analysis showed amplification bands of the expected molecular weight in all these real-time pcr positive, cell culture negative samples. a control group of samples from patients with bacterial conjunctivitis was tested and all of them were negative by pcr. a plasmid containing the hrv- sequence spiked into a negative synovial tissue or blood specimen was used as a positive control. extracted dna from a negative synovial tissue or blood specimen was included between every two specimens as a negative control. suitability of dna for pcr was verified using a pcr assay for beta-globin. positive specimens were subjected to bidirectional sequencing. fisher exact test (two-tailed) was used for statistical analysis. results: all specimens were positive for beta-globin (extraction control). cloned hrv- proviral dna spiked into tissue, mononuclear cells and granulocytes followed by extraction yielded an amplified product in all cases. the limit of detection of the assay was . copies/ml blood and . copies/mg tissue. two hundred tissue specimens, mononuclear cells, and of granulocyte specimens tested negative for hrv- proviral dna. two ra and two oa granulocyte specimens, however, yielded a positive signal for hrv- proviral dna. all were detected at a low copy number (quantitated by comparison to a known quantity of cloned hrv- proviral dna spiked into blood), range - copies of hrv- proviral dna/ml blood. all four showed - % identity to genbank sequence af by ncbi blast search. conclusion: we did not find an association between hrv- and ra or oa ( p ¼ . ) using a real time pcr assay. recently it has been shown that hrv- is actually rabbit endogenous retrovirus h (j virol : ; - ). we hypothesise that experimental rabbit studies ongoing in our laboratory while the granulocyte specimens were being prepared account for the low level of 'hrv- ' proviral dna detected in . % of the specimens tested. results: csf virus load ranged from to  copies per millilitre. in comparison the virus load in vesicular fluid was  copies per millilitre. the highest virus loads (  and  ) were detected in a patient with paresis of facial nerve and a young patient with relatively mild disease. the lowest virus load (  copies per millilitre) had a child with varicella meningitis and an old patient with severe herpes zoster of the trunk. quantitative pcr has good reproducibility and is useful for assessment of viral load in csf samples. however, the correlation between virus load and severity of illness remains uncertain. the purpose of this study was to develop enzyme immunoassay (eia) for the detection of igg anti-hsv- activity using two new recombinant proteins as antigenic targets, and to evaluate these eia with the aid of statistical methods. methods: fragments of glycoprotein g (gg- ), comprising residues to aa of herpes simplex virus type (hsv- ) and glycoprotein d of hsv- (gd- ( - aa)), were expressed in the e. coli as gst fusion proteins to develop an assay for the detection and hsv- type-specific antibodies. results: a new enzyme immunoassay for the detection of igg anti-hsv- (igg-eia) in sera was developed using two new recombinant proteins. the igg-eia was evaluated using serum specimens obtained from patients with culture-proven hsv- infection (cp) (n ¼ ) and from normal blood donors (bd) (n ¼ ). all specimens were additionally tested for igg anti-hsv- activity by two commercially available eias. this new igg-eia detected anti-hsv activity in all specimens from hsv infected patients. when bd were tested the overall concordance between these three assays varied between and . %, concordance between positive samples ranged from . to . %. in the absence of a gold standard the accuracy of these eias was assessed by the computer program based on a maximum likelihood approach using a 'latent class' model. this analysis estimated the igg-eia sensitivity and specificity to be within the range - % and - %, respectively. dna was detected in one csf specimen from a patient with aseptic meningitis, in three aqueous humor specimens from patients with uveitis, in one swab from a patient with herpetic vesicular skin lesions and in three conjunctival swabs from patients with conjunctivitis, and (b) vzv dna was detected in two aqueous humor specimens from patients with iridocyclitis, in two swabs from patients with vesicular skin lesions, and in the vesicle aspirate and bronchoalveolar lavage from the patient with varicella pneumonitis. the precise diagnosis of herpetic infection was available within - h, which allowed for an early initiation of adapted antiviral therapy. conclusion: the detection of the six commonest human herpesviruses in clinical specimens by the herpesvirus consensus pcr methodology allowed rapid, sensitive and specific results. objectives: bovine herpesvirus- (bhv- ) is the aetiological agent of many infections and may predispose infected animals, possibly through immunosupression, to secondary bacterial infections. immunosupression may directly be associated with the induction of programmed cell death (pcd) in some virus infected cells. nitric oxide (no) has an important mediating role against fungal, bacterial, protozoal, viral pathogens and tumours. in this study, role of no was questioned in the pcd process. methods: this study was planned in two consecutive stages. in the first stage, the morphological (with and without staurosporin) and biochemical changes caused by virus-induced pcd in mdbk cells were investigated. morphological assessment of pcd was performed using hoechst nuclear staining and fluorescence microscopy technique. in the second phase of the study, the induction of pcd with staurosporin (ss) (alone or with bhv- addition) and apoptotic route of bhv- infections (with/without staurosporin) were analysed by applying , , , caspase inhibitors (r&d, germany). results: it was interesting to see that bhv- inhibited pcd following h of poi instead of being induced by staurosporin and induced apoptosis alone between . and h of poi in mdbk cells, however, between and h of poi, pcd response has found to be decreased. these results showed similarities with those obtained from herpes simplex type- infections in human epithelial cells. following caspase , , , and inhibitors applications pcd responses decreased after h whereas no responses increased following h of infections with caspase , , , and inhibitory peptides. conclusion: in conclusion, bhv- inhibited the apoptotic response in a caspase-independent way and bhv- may modulate the no response through the apoptotic pathways. objectives: the aim of this study is the questioning the programmed cell death (pcd) process in acute phase of bhv- infection in cultured epithelial like cells' microenvironments and to investigate its relation with possible nitric oxide responses in hep- cells infected with bhv- with and without staurosporin induction. methods: this study was planned in two consecutive stages. in the first stage, the morphological (with and without staurosporin) and biochemical changes caused by virus-induced pcd in hep- cells were investigated. morphological assessment of pcd was performed using hoechst nuclear staining and fluorescence microscopy technique. in the second phase of the study, the induction of pcd with staurosporin (ss) (alone or with bhv- addition) and apoptotic route of bhv- infections (with/without staurosporin) were analysed by applying , , , , and total caspase inhibitors (r&d, germany). results: it is known that following hsv- infection of - h of poi anti-apoptotic activity is triggered in human cells. and this activity is through caspase . it is interesting to see that in these experiments following h of bhv- infection the number of apoptotic cells reduced whereas no response continuously increased following -h poi. conclusion: anti-apoptotic activity of bhv- seems to be activated through caspase like hsv- , and this inversely proportional relation between no and pcd responses seem to be related with the triggering effect of no on pcd response. this effect was explained as non-specific stimulation of the host immune system. however, direct anti-viral effect cannot be excluded. the goal of present study was to evaluate the effect of probi-otics strains derivative metabolites on the reproduction of herpes simplex virus type (hsv- ). materials and methods: probiotic strains used were: lactobacillus plantarum a-p , enterococcus faecium-l , escherichia coli m . one hundred and six vero cells were infected with - id of hsv- and then incubated with supernatants from bacteria or bacteriocin preparations applied in serial dilutions. acyclovir % (lek, slovenia) was used as anti-viral drug control. cytopathic effect of the virus was determined by light or immunoflourescence microscopy after h. results: hsv- alone or in the presence of the e. coli m extracts caused the most profound cytopathic effect. addition of acyclovir completely inactivated the effect of the virus that was taken for %. supernatants obtained from l. plantarum, and e. faecium generated dose dependant effect from to % of viral inhibi-tion. e. faecium strain l- extract was - % more active than l. plantarum. extract from the strain l- was analysed for the presence of bacteriocins. two types of peptides were determined -enterocin a and enterocin b ( . - . kd). bacteriocin preparation demonstrated similar anti-viral effect ( - % of inhibition) which allows to consider enterococcal bacteriocins as major antiviral agents in present model. conclusions: extracts of several probiotic bacterial strains express a specific activity against reproduction of hsv- in vitro. antiviral effect of e. faecium strain l- was the strongest due to the presence of enterocins a and b in the supernatant. acknowledgement: work was supported by public health service grants ai and tw from nih, grant - - from rffi and regional foundation of support to new technologies in medicine. we detected ribotypes, among toxin b producing strains (tcdaÀtcdb+) only one ribotype was detected. among non-toxigenic strains four ribotypes were detected. it seemed to be interesting to observe the dominating ribotypes. between toxigenic (tcda+tcdb+) five belonged to ribotype and four to . all strains (n ¼ ) (tcdaÀtcdb+) belonged to one ribotype - . in summary, pcr-ribotyping is a good method to discriminate c. difficile strains. we decided to continue further epidemiological study in poland. objectives: the aim of the study was to identify risk factors of c. difficile-associated diarrhoea due to adp-ribosyl transferase producing strains. materials and method: a retrospective case control study was performed. each case (patient with a diarrhoea due to an actin-specific adp-ribosyl transferase producing strain) was compared with two controls (patient with diarrhoea due to a c. difficile strain which does not produce an actin-specific adp-ribosyl transferase) matched on ward and on date of hospitalisation. cdta and cdtb genes were screened by pcr (stubbs et al., fems microbiol letters ; ; - ) . production of cdt was studied by western blot using an antiserum anti ia and ib from c. perfringens and the activity of the toxin was assessed using an adp-ribosyl transferase assay. results: twenty-six cases ( males and females) were identified in and . they were hospitalised in six different hospitals of paris and its surrounding area. all the cdt positive strains were also positive for toxins a and b. cases were compared with controls. cases and controls did not differ significantly for sex, age, previous administration of antibiotics, of chemotherapy or immunosuppressive treatment. endoscopic examination was performed in . % of cases and in . % of controls (p ¼ . ) and frequency of mucosal abnormalities was similar. diarrhoea was more often community-acquired in cases than in controls ( . vs. . %, p ¼ . ) and represented more often the cause of hospitalisation ( . vs. . %, p ¼ . ). moreover, diarrhoea from cases was more frequently associated to abdominal pain ( . vs. . %, p ¼ . ) and to liquid stools ( . vs. . %, p ¼ . ). conclusions: these results suggest that there could be a correlation between the production of binary toxin and the severity of diarrhoea. the binary toxin could induce intestinal lesion independently of toxins a and b or it may act in synergy with these toxins. methods: outbreak was detected by the c. difficile surveillance programme survey of the infection control unit. c. difficile infection was diagnosed by stool culture and by detection of toxin a with a qualitative rapid immunoassay. isolates of c. difficile were genotyped using pulsed-field gel electrophoresis. results: incidence of c. difficile-associated diarrhoea increased from cases per patient-days before to cases per patient-days during the outbreak. this outbreak involved patients of four geriatrics wards, located on two geographically distinct sites (with the same medical team). mean age was (range - ) years; sex-ratio (f/m) ¼ . ; % ( / ) of cases had received one or more antibiotics before onset of diarrhoea. about % ( / ) of cases were long-term care facilities-acquired diarrhoea, and secondary hospital transmission resulted in three clusters involving cases. serotyping and genotyping were performed on isolates from different stools; of these strains belonged to the same type a whereas three displayed profiles different from the outbreak strain. management of this outbreak consisted in reinforcement of contact isolation precautions for patients with diarrhoea, cohortage of infected patients in the same ward and in promotion of hand disinfection with an alcoholic solution. environmental disinfection with hypochlorite was introduced during the outbreak. the ward where most transmission occurred was closed during days for a completed disinfection after last patient discharge. after resolution of the outbreak, incidence for acquisition was cases per patient-days. ninety per cent ( / ) of patients were treated by metronidazole or vancomycin. relapses occurred in % ( / ) of patients. two patients died with severe colitis. mean hospital stay was (range - ) days (annual mean of length of stay in the department ¼ days). conclusion: rapid control of this nosocomial outbreak of c. difficile among geriatric patients was obtained with early implementation of cohortage and ward closure associated to reinforcement of environmental disinfection, hand hygiene and enteric isolation. introduction: toxigenic clostridium difficile is the main cause of nosocomial diarrhoea and has recently been described as involved in community acquired infections. two main toxins have been classically described as the main virulence factors although strains that lack one of them are emerging with increasing frequency. objective: we aimed to characterise toxigenic phenotypes in an institution with high prevalence of c. difficile-associated diarrhoea (cdad). materials and methods: c. difficile isolates were obtained and collected over a -month period from diarrheic stools submitted to our laboratory. specimens were cultured in ccfa plates with blood and presumptive colonies identified by standard procedures. toxin b was detected with a standard cytotoxicity assay on human fibroblast culture using both diluted samples and pure broth cultures of the microorganism. toxin a was detected by a commercial enzyme-immunoassay (cdtox a oia, biostar, finland) using colony suspensions in order to increase the sensitivity of the test. all negative results for any of both toxins were checked by pcr using previously published primers and conditions. results: a total of c. difficile isolates were obtained during the study period. one hundred and ninety-nine isolates ( . %) produced both toxins (a+b+); isolates ( . %) were classified as non-toxigenic (aÀbÀ) by phenotypic procedures; in isolates ( %) only toxin b was detected (aÀb+), while no isolates were classified as producers of toxin a exclusively (a+bÀ). all non-toxigenic strains showed pcr positive results for gene b and four of them also for gene a (six isolates were aÀb+ and four were a+b+). from all aÀb+ isolates, only five were confirmed by pcr, while in six of them, toxin a gene was also detected. conclusion: the vast majority of c. difficile isolates obtained in our laboratory were toxigenic (a+b+) by traditional approaches. we have detected, using classical methods and confirmation by pcr, the presence of aÀb+ isolates in our collection. all isolates considered as non-toxigenic by phenotypical methods were pcr-positive for one or both toxins. disagreements between results of phenotypical and genetic methods can be justified as the presence of incomplete or unexpressed genes or a lack of sensitivity of the former methods. background: it has been estimated that the extra cost to the nhs for every patient that contracts c. difficile in hospital is £ . in light of this it seemed imperative that the possible components involved in the mode of transmission of this nosocomial infection be investigated with a view to control the spread. objective: to look at the level of contamination of health care workers' hands with c. difficile after dealing with a known positive patient. methods: hands were sampled using the finger streak method on a c. difficile moxalactam norfloxacin (cdmn) agar plate. plates were incubated for h under anaerobic conditions and then examined for any possible colonies of c. difficile. these were identified using the gram stain and rapid ana ii system. hands were sampled directly after patient contact and the type of contact was also noted. hands were also sampled after the removal of gloves and after hand washing. in all, duplicate samples were taken after various contacts with colonised patients. results: % of samples taken immediately after patient contact were positive. nine per cent of samples taken after the removal of gloves were positive. no samples taken after hand washing were positive. conclusion: this study showed that hands do readily and regularly become contaminated after contact with a known positive patient and that this contamination can follow fairly minimal contact with the patient. objectives: during the conduct of a phase clinical trial on the efficacy of tolevamer or g tid for days compared with vancomycin mg qid for days, we collected serial faecal samples on study entry, days , , , , , and to determine if non-antibiotic therapy can neutralise c. difficile toxin b in faecal filtrates, promote restoration of the normal microbiota and achieve clinical response. methods: patients were randomised into the study at calgary study sites (out of patients/ centres). faecal filtrate concentrations of c. difficile cytotoxin b, quantitative counts of c. difficile vegetative organisms, c. difficile spore counts were determined. quantitative aerobic/anaerobic cultures using serial dilutions of faeces e- , , , , g À wet weight were performed using criteria as outlined in the wadsworth anaerobe laboratory manual. stools from healthy donors served as normal microflora controls. results: thirty of patients provided one or more samples, and / provided serial samples beyond days and up to days. normal flora controls showed an average of four different bacteroides species in counts of À g À faeces wet weight, plus other anaerobic genera in a more inconsistent manner. using bacteroides species as a marker genus for the anaerobic microflora, , , and patients had bacteroides counts below the limit of detection, between À , or > cfu/g faeces, respectively, at study entry. vancomycin treatment eliminated vegetative c. difficile with variable spore persistence, and the bacteroides genera remained suppressed in the majority of patients during and after the course of therapy. on the other hand, response to tolemaver therapy appears to be accounted for by the inter-relationship between toxin neutralisation, c. difficile growth/persistence, and the pattern of recovery of the microflora. in general, patients who responded to toxin binding therapy exhibited non-emergence of toxin combined with increase in the numbers of anaerobic organisms. recovery of the anaerobic microflora appeared not to be complete at days in the majority of patients. objectives: the treatment of choice for a. baumannii bacteraemia has not been established. there are few data to guide the selection of agents for treating these infections. carbapenems are generally considered the drugs of choice, but an increasing of the resistant strains has been described. several alternatives guide lines have been proposed: ampicillin-sulbactam (sam) alone or associated with an aminoglycoside, piperacillin-tazobactam (tzp) or tetracyclines. the aim of this study is to know the best alternative in the empirical treatment of these infections according to the temporal evolution of the nosocomial outbreaks or endemic infections in our hospital. methods: from june to december we collected all a. baumannii strains from bacteraemia infections and their related focus. all the isolates were characterised by molecular methods in order to obtain different clones using pfge and rep-pcr. susceptibility study was performed by disk diffusion to antibiotics and mic-e-test in the mainly treatment alternatives (imipenem, meropenem, sam, tzp, tobramicine (tm), amikacine (an), and ceftazidime) and interpreted according to nccls criteria. results: in - the empirical antimicrobial treatment (eat) of choice was imipenem because all isolates were carbapenem sensible (s), with two mainly molecular clones ( isolates c -aminoglycosides resistant (r), and c -gentamicin-r, but an, netilmicin and tm-s). according to detection of an outbreak carbapenem-r in ( of the isolates) clone c multiresistant (only some strains sam or an-tn-sensible) the eat changed to sam and an or tm. this clone was persistent until and replaced with another multiresistant outbreak (c b - % sam-r and - % aminoglycosides-r). then the eat was chosen as monotherapy with an or tn (the only ones sensible of the antimicrobial tested). in the last period ( - ) emerges a new clone (c -carbapenems, sam, aminoglycosides and doxycycline-s) and imipenem returns like the actual eat in our hospital to control bloodstream a. baumannii infections. conclusions: empirical antimicrobial treatment on patients with bloodstream a. baumannii infections in a hospital, with changes in the temporal evolution of the clones associated to outbreaks or endemic infections must be established according to the susceptibility test and molecular characterisation of the strains in different clones. gentamicin-resistant enterococci in paediatric blood-stream infections in a tertiary hospital in tanzania b. blomberg, s.c. mohn, k.p. manji, n. langeland on behalf of the joint study group on antimicrobial resistance at muhimbili national hospital, dar es salaam, tanzania and the university of bergen, norway objectives: enterococci have emerged as major pathogens causing urinary tract, wound and blood stream infections (bsi). nosocomial spread of enterococci resistant to multiple antimicrobials is a great therapeutic challenge. little is known about the role of these pathogens in bsi in east africa. the objective of the study was to assess the prevalence and resistance patterns of enterococcal isolates causing bsi in children at muhimbili national hospital, dar es salaam, tanzania. methods: blood cultures were obtained from children (age - years) with fever or signs of serious infection admitted to the hospital during the period august to august . isolates were identified by standard methods. the identities of enterococcus fecalis and e. faecium isolates were confirmed by polymerase chain reaction (pcr), the isolates were susceptibility tested by e-test and assessed for genetic relatedness by pulsed field gel electrophoresis (pfge). twelve e. faecium isolates were also investigated by mlst. results: thirty-two of children ( . %) had growth of enterococcal isolates in blood culture. nine of e. faecium isolates showed combined resistance to ampicillin (are), ciprofloxacin and high-level gentamicin resistance (hlgre). six of e. fecalis isolates were hlgre, but none of these were resistant to ampicillin or ciprofloxacin. all except one of the hlgre were also resistant to chloramphenicol. the resistant strains were recovered from several geographically separated wards, including the neonatal ward. the majority of the e. faecium and e. fecalis were closely related when investigated by pfge. mlst conducted on e. faecium strains also confirmed this result. conclusion: this is the first study to identify outbreaks of bloodstream infections caused by combined are/hlgre e. faecium and hlgre e. fecalis in tanzania. e. faecium was more frequent than e. fecalis. the commonly used treatment regimens at the hospital (ampicillin and gentamicin or penicillin and chloramphenicol) are insufficient for infections caused by are/hlgre enterococci. nonrepetitive (one per patient) resistant to fox k. pneumoniae strains were isolated from clinical specimens ( from blood, two from bronchial secretions, four from urine, two from wound and five from catheter tips). patients were cared in different wards including intensive care unit (icu) and neonatal intensive care unit (nicu). species identification was done by using the vitek system (biomerieux, france). mics were determined with vitek automated microdilution system and by disk diffusion method. the criteria of the nccls were used to define susceptibility or resistance to antimicrobial agents. expanded spectrum a-lactamase (esbl) production was assessed by the double disk synergy test. the isolates were typed by enterobacterial repetitive intergenic consensus (eric) pcr with the eric- primer. isoelectric focusing (ief) of blactamases was performed to representative group isolates. results: antimicrobial profiles demonstrated that all isolates were resistant to third-generation cephalosporins, to aztreonam, cefoxitin, amoxicillin/clavulanate, ticarcillin/clavulanate and piperacillin/tazobactam. four isolates were also resistant to cefepime and cefpirome. all isolates were susceptible to imipenem. ief showed that all isolates expressed two b-lactamases, one with pi of . which correlated with the shv- and one with pi of . which corresponded to lat- . eric-pcr analysis demonstrated three strain types. type i, consisting of two subtypes, was common to strains, indicating that the clonal spread was mainly responsible for the outbreak. type ii comprised two isolates and type iii was unique. five isolates were not identified with eric-pcr. conclusions: k. pneumoniae strains, harbouring plasmid-coding for ampc-type b-lactamase, have been established in our hospital. nosocomial infection surveillance, such as restriction of particular antibiotics and adjustment of the infection control measures, has been recommended. acinetobacter baumannii producing the per- extendedspectrum b-lactamase objectives: recently per- extended-spectrum b-lactamase (esbl) was discovered in a peudomonas aeruginosa strain in france and was subsequently detected in acinetobacter spp. and pseudomonas aeruginosa in other countries including turkey. the purpose of this study was to clarify the molecular epidemiology of infection caused by a strain of cefepime-resistant a. baumannii and also to determine the mechanism of drug resistance. methods: cefepime-resistant a. baumannii strains were isolated from clinical specimens of nine patients hospitalised in an intensive care unit in busan, korea. antimicrobial susceptibilities were determined by the disk diffusion and agar dilution methods. the double disk synergy (dds) test was performed for screening of esbl production. isoelectric focusing and conjugation experiments were performed. blaper- and blaper- alleles were detected by pcr, and sequences of amplified products were determined by using the dideoxy-chain termination method. pulsed-field gel electrophoresis (pfge) was performed for molecular typing of isolates. results: the isolates showed same antimicrobial susceptibility pattern, positive dds results and pfge patterns. the isolates contained three b-lactamase bands: pi . , . , and . . pcr-based experiments detected blaper- genes. mics of ampicillin, piperacillin, cephalothin, cefoxitin, cefoperazone, ceftazidime, cefotaxime, cefepime, and aztreonam to these isolates were ! mg/l, respectively, and those of imipenem were - mg/l. despite repeated attempts, the resistance to cefepime of a. baumannii isolates was not transferred to the recipient. conclusions: a. baumannii isolates from clinical specimens of nine patients hospitalised in a same intensive care unit were shown to be of the same clone. all these isolates contained blaper- gene which caused resistance to cefepime. to the best of our knowledge, outbreaks caused by per- esbl-producing a. baumannii have not previously been described. objectives: hospital outbreaks of salmonella spp. infections are not uncommon not only in europe but also in the united states, but in neonatal units it is rarer. the maternity unit has approximately deliveries each year. we described the results as well as infection control that stopped the outbreak. methods: from october to january six neonates were infected in the neonatal unit of our hospital. the index case corresponding to a newborn delivered in our hospital, she was born by normal vaginal delivery. the -day-old patient was admitted again by neurological deficits. seven days at the hospital she developed diarrhoea. the group included five prematures, only case index was not premature. all stool specimens from family case index were negative. stool samples were request for culture from asymtomatic staff and all babies from the neonatal unit (n ¼ ). the isolates were identified by standard methods and serotyped by agglutination with monospecific antisera. the antibiotics (ab) taken in the study were: ampicillin (a), ticarcillin (t), amoxicillin/clavulanate (a/c), cefalothin (ce), ciprofloxacin (cp), co-trimoxazole (co), nalidixic acid (na), gentamicin (g), thirdgeneration cephalosporins ( gc). its was evaluated by a microdilution method and confirmation by e-test. results: eight strains of salmonella enteritidis serotype o , :h g,m were identified. the phage type (pt) involved was same in all cases, pt a. seven were isolated from faeces and one from blood culture. all isolates demonstrated same antibiotic susceptibility pattern with resistance to ampicillin and ticarcillin. fortunately no babies died. no salmonella from stools of nurses, staff personnel and mothers was isolated. conclusions: a hand washing was not sufficiently frequent the infection was probably transmitted by hand contact to prepared milk, infusion and other equipment from the index case. this hypothesis was subsequently confirmed as the outbreak was terminated after eradication of the presumed contamination sources by changing the mattresses, disinfecting the unit and ensuring strict observance of hand washing before and after every manipulation. salmonella enteritidis pt is third commonest phage type in spain. objectives: to investigate the cause of an outbreak of pseudomonas aeruginosa isolations following bronchoscopic procedures. methods: from to january , we detected a cluster of p. aeruginosa isolates associated with bronchoscopy (nine samples from eight patients). laboratory culture, bronchoscope and medical records of all cases were reviewed. all of them were related with one bronchoscope and environmental samples were obtained from it. microbiological identification and susceptibility testing were performed with the microscan walkaway system (dade behring). random amplified polymorphic dna analysis (rapd) and pulsed field gel electrophoresis (pfge) were performed on all available isolates of p. aeruginosa (eight clinical isolates from seven patients and six bronchoscope related isolates). results: two of the eight patients showed clinical evidence of infection and required specific antimicrobial therapy (the index case and other patient with two isolates separated by days). all isolates were ceftazidime, aminoglycosides and ciprofloxacin susceptible and imipenem resistant. rapd and pfge patterns revealed that all the clinical and bronchoscope isolates (eight and six, respectively) were indistinguishable. the bronchoscope was replaced and no further cases appeared. conclusions: we documented contamination of a bronchoscope with p. aeruginosa and possible secondary infection of at least one patient. microbiologists have an essential role in the detection of medical devices contamination, especially by surveillance of the emergence of infrequent bacterial recovery. in all three cases klebsiella pneumoniae was isolated from the blood cultures. the aim of this study was to investigate the epidemiological relation among the isolates and to try to find a common source for the infection. methods: environmental samples, including different i.v. fluids and drugs, and skin samples were obtained in order to detect the source of the infection. microbial identification and in vitro susceptibility tests were carried out automatically with the microscan system (dade). clinical isolates were molecular typed by random amplification of polymorphic dna (rapd) using one mer oligonucleotide, pcr-ribotyping with oligonucleotide of the intergenic s/ s region and pfge using xbai as a restriction enzyme. an unrelated strain was also included in all the experiments, as a control, in order to check the discrimination power of the techniques. results: all three clinical isolates of k. pneumoniae obtained from blood cultures shared the same biotype and antibiotype, and were all resistant to ampicillin, gentamycin and tobramycin. molecular typing methods proved clonal identities among the clinical strains. patterns generated were different from those of the control strain. the source of the infection could not be demonstrated in any of the environmental or newborn skin samples. conclusions: a single k. pneumoniae strain was the cause of the fulminant sepsis in the three newborns. all three molecular typing methods, rapd, pcr-ribotyping and pfge accurately demonstrated clonal identities of the isolates. the common source of the infection could not be detected due, probably, to the logical delay in culture growth and identification. the objectives of this presentation are to describe the outbreak and the infection control measures implemented, and to constitute an example for handling possible future outbreaks with limited resources. this is the first ekc outbreak reported from turkey. methods: eye clinic of kou hospital is equipped with modern devices; however it has limited physical conditions (e.g. insufficient hand-washing facilities) because of temporary settlement of the hospital after the earthquake of .on december , the infection control team (ict) was alerted to ekc cases. an investigation began and infection control measures (icm) were implemented. conjunctival swabs of patients with ekc and environmental swabs were obtained and studied in gata and hacettepe university microbiology laboratories. infection control protocol (icp) was implemented as recommended by apic guidelines with some modifications. in addition, terminal disinfection (td) was applied two times and after tds clinic was closed for first and than days (figure ) . results: a total of ekc cases were diagnosed among the patients who visited the eye clinic during the outbreak (general attack rate: . %). seventy-five of the ekc cases were male and average age was . ae . (range: months to years). primary and secondary attack rates were found to be and %, respectively. adenovirus type d was isolated from patient samples, biomicroscope and device solution. with the implementation of icp and td, ekc cases decreased by time and outbreak disappeared about days after the second td and closing the clinic for four days (figure ) . conclusion: this is the first outbreak reported from turkey. isolation of virus from biomicroscope and device solutions which are used for more than one patient is an evidence of transmission from environment. although several reports have described icm that terminated outbreaks of nosocomial ekc, this study demonstrates that implementing td and/or closing the clinic for four days in addition to icm, may control nosocomial ekc outbreaks. background: because of severity of underlying disease, multiple venous accesses, parenteral nutrition and often increased length of stay, intensive care unit (icu) patients are at increased risk for catheter-related candidemia (crc). we investigated health and economic outcomes in icu patients with crc. methods: in a retrospective matched cohort study ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) attributable mortality and excess length of stay for crc was investigated. matching was ( : ratio) based on severity of underlying disease and acute illness (apache ii score and admission diagnosis) and length of icu stay prior to the onset of the candidemia. as expected mortality can be derived from apache ii; this matching procedure results in an equal prognosis for cases and control subjects. attributable mortality is determined by subtracting the hospital mortality rate of the controls from this of the candidemic cases. excesses in length of icu stay and hospitalisation were determined by subtracting the median length of stay of the controls from this of the cases. results: during the study period icu patients developed a microbiologically documented crc (out of a total of candidemic patients). nineteen catheters were removed within h. cases (n ¼ ) and controls (n ¼ ) had an equal age (resp. ae vs. ae year; p ¼ . ), apache ii score (resp. ae vs. ae ; p ¼ . ) and incidence of respiratory failure ( vs. %; p ¼ . ), acute renal failure ( vs. %; p ¼ . ) and haemodynamic instability ( vs. %; p ¼ . ). the excess length of icu stay was days (median vs. days; p ¼ . ). although patients with crc had a longer length of hospital stay this difference was not significant ( vs. days; p ¼ . ). the attributable mortality of crc was . % ( % ci: À to %) as hospital mortality rates in cases and controls were . and . %, respectively (p ¼ . ). conclusion: our data revealed that, after careful adjustment for severity of underlying disease and acute illness, crc is not associated with a significantly higher mortality in icu patients. it is, however, associated with a significant excess in length of icu stay, thereby representing an important economic burden. patients were hospitalised in two internal medicine departments, two surgical departments, the nephrology department and the intensive care unit, during the period july to november . the catheter tips were cultured using the following methods: (a) semi-quantitative maki's and co. and (b) quantitative cleri's and co. samples for culture were taken also from the site of catheter insertion into the skin and from the hub. blood culture samples were taken from a peripheral vein in cases of clinical suspicion of bacteraemia or sepsis and they were incubated using the bactalert (organon teknika) automated system for days. results: cases of ccbri were recorded. the incidence of ccbri was . per catheter days. in of the cases of ccbri the origin of colonisation was determined. in cases which all had positive catheter tip and hub cultures with the same strain, the gram-negative bacteria prevailed ( / , analytically e. aerogenes three, k. pneumoniae two and p. aeruginosa one) while in four cases candida spp. (three cases) and coagulase negative staphylococcus (cons) (one case) were isolated. in contrast, in cases of ccbri with positive catheter tip and skin point entry cultures with the same strain, the gram-positive bacteria prevailed ( / , analytically s. aureus eight, cons six and corynobacterium spp. one). conclusions: ( ) the incidence of ccbri was . per catheter days. ( ) ccbri caused from gram-positive bacteria was mainly derived from the catheter site entry, whilst colonisation of hub caused mainly gram-negative ccbri. ( ) the preventive measures should be focused on better aseptic techniques and hand hygiene, care of the catheter's entry site and better training of the medical staff. we studied patients, suspect for catheter-related infections (cri) - from icu and from hdu with central venous catheters used for parenteral nutrition, drug administration or haemodialysis. the preferred vein in icu was v.subclavia, , and in hdu, v. femoralis, catheters. mean duration of catheterisation - days in icu and . days in hdu. signs for colonisation of the catheters were found in cases - in icu and in hdu. the most common microorganisms in icu were gram-negative rods (kesgroup, b. cepacia, pseudomonas spp.) - ( . %) followed by coagulase-negative staphylococci (cns) - ( . %). in hdu in most of cases were isolated cns - ( . %) and s. aureus - ( . %) (p < . ). as catheter-related bacteraemias (crb) were considered in cases, of them in icu and in hdu. causative microorganisms of crb in icu were most gram-negative rods - ( . %) and syaphylococcus spp. ( . %) in hdu (p < . ). conclusions: the frequency of crb in icu is significantly higher, . - . %, in hdu (p < . ).they developed earlier and were caused by gram-negative rods. more probable way to development of crb in icu is the catheter hub and hdu is the skin of the patients. catheter-related infection (cri) is considered as a cause of increased hospital morbidity but its influence on hospital mortality remains a matter of debate. in critically ill patients, baseline severity, underlying conditions and various confounding factors may explain the observed increased mortality rather than cri itself. in order to determine the influence of cri on hospital mortality in icu, all episodes of nosocomial septicaemia were reviewed. material and methods: retrospective analysis of all nosocomial septicaemia occurring over a -year period in a teaching hospital. septicaemia episodes were separated in secondary, primary and proven catheter-related bloodstream infections. baseline severity (saps score), delay between admission and infection, and hospital mortality were determined. results: over this -year period, patients were admitted to the hospital and episodes of cri were recorded ( . %, . / catheter-day (ktd)). hospital mortality for all septicaemia was . % while mortality related to secondary septicaemia was . % (p < . ). during the same period, patients were admitted to the icu, corresponding to ktd. four hundred twenty-four episodes of septicaemia occurred in these patients ( / ktd), of which were primary septicaemia and were proven cri ( . / ktd). mean saps score for all icu patients was and hospital mortality . %. icu patients developing infection had a mean baseline saps score > . cri occurred more than weeks after icu admission (median : days, mean . days). pathogen-associated cri were scn %, s. aureus %, e. faecalis %, candida spp. %, other %. hospital mortality in patients developing cri was / ( . %). conclusions: in this study, hospital mortality in critically ill patients developing cri was high but seemed to be primarily determined by baseline severity and underlying conditions as reflected by saps score and prolonged delay between icu admission and septicaemia. staphylococcus epidermidis is the most important pathogen of these systemic infections. objectives: to study the genomic dna profiles of s. epidermidis isolated from catheter-related infections and bloodstream infections comparing with the strains isolated from skin and nasal swab in patients hospitalised in a tertiary care university hospital. methods: catheter-related infections were defined according to the cdc definitions. patients with a culture for s. epidermidis from blood and catheter tip (> cfu) were selected to have swabs from skin and nasal for s. epidermidis. the s. epidermidis were typed using pfge, antibiotic susceptibility testing and biofilm detection, by congo red method, were performed. results: twelve patients with episodes of catheter-related infections were included in this study and strains were analysed. in episodes, the same dna profile was detected in cvc/blood and in the skin/nasal and in seven episodes the clone causing cvc/blood infections were not found in skin/nasal. the mean time of isolation of s. epidermidis with clonal relation between cvc/blood and skin/ nasal colonisation from the first day of hospitalisation until the detection in cvc/blood was . days. in episodes without s. epidermidis clonal relation, the mean time was . days. pfge identified three hospital endemic profiles that were present in . % ( / ) of all strains from episodes, including the strains from cvc/blood infections and in skin/nasal colonisation. in the strains from skin/nasal colonisation, the endemic profiles were present in . % ( / ) of the strains. the endemic dna profiles were biofilm producers and were resistant to penicillin g, oxacillin and ciprofloxacin, variable susceptibility to aminoglycosides and were susceptible to vancomycin. conclusion: patients with long term hospitalisation were previously colonised by hospital endemic s. epidermidis strains that were responsible for catheter-related infections. , and requiring a cvc were included in this retrospective cohort. the following data were analysed: patient and cvc characteristics, risk factors and microbiological results. the diagnosis of cvc-ri was based on brun-buisson methodology ( ) . the comparisons were done using the chi-square and student's t-tests. a multiple logistic-regression model was used to identify risk factors of cvc-ri according to their adjusted odds ratio (aor; % ci) and completed by a survival analysis adjusted on duration of hospitalisation and cvc, the unit and the timing of cvc implementation (before or after admission in the unit). results: a total of patients were included who required cvc ( cvc were implanted as per the hospitalisation in this study units [gr# ] and before the patient admission in this same units [gr# ]). the total of catheter days was (respectively for gr# and for gr# ). the number of cvc-ri was that is . % of cvc and the incidence rate per patient was %. the part number of cvc-ri were respectively ( %) for gr# and ( . %) for gr# . the incidence density of cvc-ri was . / catheter days for the totally cohort, . / for gr# and . / for gr# . in the totally cohort cvc-ri was monomicrobial in cases ( . %). in that case the most prevalent bacteria were: coagulase-negative staphylococcus spp. ( . %) and staphylococcus aureus ( . %) and in case of plurimicrobial infection the most prevalent agents were: staphylococcus aureus ( %), coagulase-negative staphylococcus spp. and enterococcus faecalis ( % for each). intestinum somatoplasty was not was a risk factor for cvc-ri in this study. the crude mortality rate was . % ( / ) and % ( / ) for cvc-ri and non-cvc-ri, respectively (p ¼ . ). conclusion: in these surgical units, the incidence of cvc-ri is high and was related to the frequency of manipulations of the line such as infusion, parenteral nutrition, injections and dressing even after adjustment on the duration of cvc and timing of cvc implantation. an intervention focused on these risk factors is planned to reduced cvc-ri and improve the quality of care. case : a schizophrenic -year-old man was admitted to the hospital because of fever of weeks duration; he was affected by diabetes type ii and nh lymphoma diagnosed months earlier and treated with chemotherapy through a groshong cvc and, subsequently, with chronic steroid. multiple blood cultures, performed from cvc and peripheric veins, were positive for e. faecalis and e. coli; the patient was treated with ceftriaxone g ev qid  w + lock-in therapy with teicoplanin mg (in ml) and ciprofloxacin mg (in ml) for h a day for days. it was obtained a clinical and microbiological resolution without removal of cvc. case : a -year-old man was admitted to the hospital for septic fever; months earlier a groshong cvc had been placed to treat with chemotherapy a rhinopharyngeal carcinoma. multiple blood cultures (from cvc and peripheric veins) were positive for a multi-drug-resistant stenotrophomonas maltophilia (s only to chloramphenicol, trimethoprim-sulfamethoxazole and levofloxacin). the patient was successfully treated, without removal cvc, with systemic trimethoprim-sulfamethoxazole + levofloxacin combined to antibiotic lock (ciprofloxacin mg in ml for h a day for days). conclusion: the cases reported by the aa confirm that many catheter infections can be maintained in place and sterilised with lock-in therapy avoiding to replace expensive intravascular lines with unnecessary and risky insertions. one of the questions to resolve will be whether or not concomitant systemic antibiotic therapy is necessary. background: nosocomial infections influence upon the mortality, quality of patients' life, costs and length of hospitalisation. the source of those infections might be staff members, contaminated water system, air-conditioning or pests. disinfectants are helpful in reducing or eradicating harmful pathogens existing in hospital environment. some bacteria are able to grow on a surface as a biofilm. this form is more resistant to external harmful conditions such as antibiotics, disinfectants or host defence. bacterial adhesion was recognised as the important virulence factor for colonisation of patient or biofilm formation. in our study the susceptibility of bacterial strains isolated in hospital environment (colonising or infecting patients or carried by german cockroaches) to antibiotics and chemical disinfectants was determined. moreover the efficacy of the disinfectant working solution (active ingredients: sodium dichloroisocyanorate . mg/l; glucoprotamine mg/l; potassium persulphate mg/l) on selected bacterial strains adherent to catheter (after growing for days on it) by treating then for min was determined. results: susceptibility profile to antibiotics varied; among grampositive bacteria the mlsb, mrcns strains were found; among gram-negative bacteria the esbl, ampc phenotype were described. determined mic values or disinfectants were in range: sodium dichloroisocyanorate . - mg/l; glucoprotamine . - mg/l; potassium persulphate . - mg/l. the results indicate that the working solution of the disinfectant might be ineffective to some strains of well-known pathogens: serratia marcescens, citrobacter freundii, enterobacter cloacae and staphylococcus epidermidis. the examination of disinfectants efficacy on selected strains showed that some bacterial strains were more resistant when they were grown on catheter for days. the mic value was lower than working solution of that chemical even more than times. moreover it was found that all tested disinfectants were ineffective to some strains adherent to catheter ex. s. marcescens and e. cloacae strains isolated from the body surface of german cockroaches. conclusions: the possibility of biofilm formation could explain the increase of resistance to disinfectants of some strains. german cockroaches carrying them in hospital should be considered not only as nuisance insects, but also as a real source of resistant to antibiotics and disinfectants bacteria. background: indwelling catheters are commonly colonised by skin flora. propionibacterium spp. are among the commonest bacteria of normal human skin but currently recommended catheter-culture procedures would not detect its presence. furthermore, propionibacterium is nearly always regarded as a blood culture contaminant and automated blood culture methods may not detect a proportion of them. our objective was to determine the rate of catheter colonisation by propionibacterium spp. in unselected intravascular catheters submitted for culture. methods: intravascular catheters were processed by the rollplate technique and incubated in air at c for at least days. organisms that were present in significant counts were subcultured for identification and susceptibility testing. when the conventional aerobic processing was finished, all primary culture plates were reincubated in an anaerobic jar. after days of anaerobic incubation the plates were read looking for bacterial colonies that were not initially present. control plates were inoculated with a suspension of p. acnes to assess the influence of aerobic preincubation on the final number of colony forming units (cfu). conventional processing detected significant growth of bacteria in . % of all catheters and no significant number of colonies (< ) in an additional . % samples. anaerobic reincubation yielded p. acnes in significant counts in . % of all catheters ( % of all positive catheters) and no significant number of colonies in an additional . % of samples. three samples yielded significant growth of both aerobic and anaerobic bacteria. of all the organisms recovered in significant counts, coagulase-negative staphylococci represented . %, p. acnes . %, s. aureus . % and corynebacterium spp. %, enterococcus spp. . % and other bacteria and yeast . %. anaerobic bacteria other than p. acnes were rarely recovered in non-significant counts. aerobic preincubation for days did not substantially affect the final number of cfu. conclusion: p. acnes is the second most frequent coloniser of intravascular catheters. anaerobic reincubation of plates used in standard routine is a simple method that could be useful for catheterrelated research projects. the potential of p. acnes as a cause of catheter-related bacteraemia merits further studies. results: nineteen patients included males and nine females, whose ages ranged from to years (mean years). all of the patients were hospitalised in the neurosurgical department. the most common underlying conditions were intracranial haemorrhage ( / cases), followed by hydrocephalus ( / cases) and cranial injury secondary to trauma ( / ). all patients underwent surgical procedures prior to infection, which included craniotomies and four ventriculostomies. all patients were receiving antibiotic therapy at the onset of infection. mean time between surgical procedure and diagnosis of meningitis was days ( - days) . fever and neck stiffness was found in eight and seven patients, respectively. in patients serum leukocyte count was higher than  /cu mm. mean leukocyte count in serum and cerebrospinal fluid was  /cu mm (min  /cu mm, max;  /cu mm) and  / cu mm (min /cu mm, max; /cu mm) respectively. mean csf protein concentration was mg/dl and mean csf glucose concentration was mg/dl. only in of cases the microorganism was isolated from cerebrospinal fluid. acinetobacter spp. ( cases), k. pneumoniae (two cases) and e. cloacae were the isolated microorganisms. most of the acinetobacter isolates were susceptible to carbapenems but all of them were resistant to thirdgeneration cephalosporins. a combination of carbapenem plus an aminoglycoside and/or vancomycin therapy was applied most of the patients. an additional intrathecal aminoglycoside dosage was needed for seven patients who responded poorly. the overall mortality rate in these patients was %. conclusion: there has been an increase of post neurosurgery meningitis cases. in addition, the emergence of strains resistant to third-generation cephalosporins in this group has also been noted in recent years, and has become a great therapeutic challenge. early diagnosis and initiation of appropriate antibiotic therapy is needed in this potentially fatal disease. objectives: pulmonary resection is associated with considerable risk of infection, so antimicrobial prophylaxis has become routine practice in thoracic surgery. the aim of this study was to assess changes in microflora of upper respiratory tract in hospitalised patients with non-small cell lung cancer (nsclc) before and after preoperative antimicrobial prophylaxis. methods: patients with nsclc aged - years were subdivided into two groups: (a) control group ( patients without antimicrobial prophylaxis and surgery), (b) 'prophylaxis' group ( patients undergoing pulmonary operation with preoperative antimicrobial prophylaxis, including piperacillin, cefuroxime or ceftriaxone alone or in combination with amikacin). throat and nasal specimens were taken up two times: examination i -on the day of hospital admission and examination ii -on the third or fourth day of hospitalisation in group a and on the third or fourth day after the surgery in group b. the routine microbiological methods were used for isolation and identification of bacteria and fungi. statistical analyses were performed by nonparametric tests. results: the colonisation of nasal mucous membranes by pathogenic microflora did not differ significantly during hospitalisation between group a and b. similar situation was observed in the case of pathogenic microflora on throat mucous membranes in group a. different results were obtained in group b. the increased prevalence of pathogenic microflora on throat mucous membranes was observed -from . % in examination i to % in examination ii. this difference was statistically significant (p ¼ . ). in group b colonisation of throat mucous membranes by enterobacteriaceae family and candida spp. was increased significantly during hospitalisation (from to . % and from . to %, respectively). conclusion: our results indicate that antimicrobial prophylaxis can be regarded as an important predisposing factor for changes of upper respiratory tract microflora and for colonisation of mucous membrane of throat with enteric gram-negative rods and yeast-like fungi -candida spp. these microorganisms are potential causative agents of endogenous infections in immunocompromised patients with lung cancer. objectives: the purpose of this study was to determine aerobic and anaerobic bacteria colonising pleural drains in patients with non-small cell lung cancer (nsclc) undergoing thoracic surgery and to define antimicrobial agents susceptibility of isolated strains. routine antimicrobial prophylaxis included piperacillin or cefuroxime. in some cases beta-lactam was used in combination with amikacin. methods: material for research was fluid from pleural drains collected from patients aged - years two times -on the day of pulmonary resection and on the fourth day after operation. samples were routinely cultured under aerobic and anaerobic conditions and determined using api system (biomerieux). antimicrobial resistance was estimated by the disc diffusion method according nccls recommendations. results: aerobic ( strains) and anaerobic ( strains) bacteria were found in ( %) and ( %) samples, respectively. among aerobic bacteria, gram-negative rods ( strains; -belonging to non-fermenting rods) and coagulase negative staphylococci (cns; strains) were most often cultured. fifteen strains of non-fermenting rods and isolates of cns were classified as multidrug resistant (mdr) organisms. two isolates of s. marcescens were producers of extended spectrum beta-lactamases (esbls) and inducible beta-lactamases (ibls). all staphylococci were susceptible to vancomycin and teicoplanin. cns strains resistant to penicillin and oxacillin but sensitive to amoxicillin/clavulanate were most frequently isolated. only two methicillin-resistant strains, belonging to s. haemolyticus were found. the most common anaerobic bacteria were from the genera eubacterium (nine strains) and actinomyces (six strains). all of them were highly susceptible to antimicrobial agents except metronidazol ( . % resistant strains) and chloramphenicol ( . % resistant isolates). conclusion: colonisation of pleural drains does not mean infection, however knowledge about bacterial species found in drain fluid in a local population and antimicrobial resistance (especially mdr strains) has a major impact on the success of prophylaxis and therapy of potential postoperative infections. a. artero, j.j. camarena, r. zaragoza, s. sancho, j. tamarit, r. gonzález, j. nogueira valencia, e objectives: to know the clinical and microbiological characteristics of diabetic patients with severe bacteraemia. to identify the differential features of severe bacteraemia between patients with and without diabetes mellitus (dm). materials and methods: during a -year period ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) we have evaluated all bacteraemias with severe sepsis or septic shock in an intensive care unit of a teaching hospital. clinical and microbiological features were recorded from clinical charts. the spss package ( . ) was used to identify significant differences between dm and no-dm cases, and to determine if the presence of dm was associated with mortality by a multivariate analysis. results: the prevalence of dm in patients with severe bacteremic infections was . % (n ¼ ). in the group of dm the mean age of patients was . ae . years, the relation between men/women was . , the origin of the bacteraemias was nosocomial in . %, severe sepsis was present in . % and septic shock in . %. the focus of infection in diabetic patients was: unknown (n ¼ ), catheter (n ¼ ), respiratory (n ¼ ), urinary (n ¼ ), abdominal (n ¼ ), vascular (n ¼ ) and cutaneous (n ¼ ). the main microorganisms causing of bacteraemias in patients with dm were: cns ( . %), acinetobacter baumannii ( %), staphylococcus aureus ( . %), escherichia coli ( . %) and enterococcus spp. ( . %). a higher proportion of nosocomial cases in dm was the only differential feature between patients with and without dm (p ¼ . ). the global mortality in patients with and without dm were . and . % (p ¼ . ), respectively, and the related mortality were . and . % (p ¼ . ), respectively. dm was related neither to global (or ¼ . , % ic . - . ) nor related mortality (or ¼ . , % ic . - . ) by multivariate analysis. conclusion: dm is prevalent between critically ill patients with severe bacteraemic sepsis and bacteraemic septic shock. diabetic patients had a higher proportion of nosocomial origin of bacteraemia. we did not find that dm was related to mortality in severe bacteraemic infections. a. poulou, f. markou, x. efthimiou, f. mountaki objectives: brucellosis is a zoonotic disease whose prevalence in northern greece is high and constitutes a significant problem for the local health authorities. the aim of this study is to report a rare case of transmission of brucella melitensis. patients: a female infant showed signs of respiratory distress during delivery. the obstetrician in charge tried to clear the respiratory tract of saliva and amniotic fluid. in his attempt he swallowed some secretions. a blood culture from the infant was incubated in the bactec . after days b. melitansis was isolated. the case was proved to be a rare case of congenital brucellosis. the family of the infant was checked and the mother was found to be positive at / titre by brucella agglutination test though her blood culture was negative. neither her husband nor her other two children were positive on the wright agglutination test. both parents were involved in animal husbandry. two months after the delivery of the infected infant the obstetrician reported pains in the back of his neck and low fever. a blood test revealed leucopenia and neutropenia (white cell count /mm ). the wright agglutination test was positive at titre / . a blood culture was taken and b. melitensis was isolated. transaminases were normal. the obstetrician reported that he had not consumed unpasteurised milk or dairy products. he was treated with vibramycin and rifadin for days. two months later the wright agglutination test was found negative and the white cell count was normal. conclusions: b. melitansis is usually transmitted through consumption of unpasteurised diary products. in these cases we had transplacental transmission and transmission through infectious secretions via the gastro-intestinal tract. therefore it is essential that detailed medical case histories should be taken from pregnant women in order to avoid congenital infections and that medical personnel should be aware of the possibility of such transmission. objectives: coryneforme bacteria have gradually acquired greater importance in infectious pathologies, especially as opportunistic nosocomial pathogens, some of them displaying resistance to various antibiotics. the aim of this report is to describe some of these bacteria with significant implication in different clinical pictures. methods: over a -year period we characterised the coryneforme isolates with presumable clinical significance. clinical significance of the isolates was evaluated according to clinical information received (fever, intravascular devices, underlying disease, prolonged antibiotic therapy, etc.) as well as microbiological criteria (more than one isolation from habitually sterile anatomical areas and/or repeated isolations as predominant flora in sites contaminated with comensal flora). results: in patients the isolations were clinically significant. the most frequent isolations ( ) were found in blood culture: seven corynebacterium amycolatum, five corynebacterium jeikeium, two corynebacterium minutissimum, two dermabacter hominis, one corynebacterium group g, one brevibacterium sp. in another eight cases bacteraemia was accompanied by isolation of the same species in intravenous catheters (two c. amycolatum, one c. striatum, one c. jeikeium, one c. group g), a pace-maker cable (c. minutissimum) or soft tissue wound (one c. urealyticum, one brevibacterium sp.). in addition, four c. striatum were isolated (three in respiratory secretions and one in a lower limb abcess), two c. amycolatum in mammary abscesses, one c. jeikeium in articular fluid and two c. urealyticum in urine. all the isolates were sensitive to vancomycin (mics < . mg/l), while sensitivity to beta-lactamics, macrolides and fluorquinolones was variable. conclusions: ( ) c. amycolatum and c. jeikeium were the most frequently found corynebacteria with presumable clinical significance. dermabacter and brevibacterium were the genera identified among the non-corynebacterias. ( ) outbreaks of nosocomial ssss and impetigo bullosa in infants have been well-described to be associated with the well baby nursery. the source of infection has been traced to health care workers in the delivery room or the newborn nursery. the initial site of s.a. colonisation/infection may be the anterior nares, nasopharynx, conjuctiva, umbilicus and/or the blood rather than the skin. often the personnel are asymptomatic carriers of the epidemic strain of s.a. objectives: the aim was determine the genetic relatedness of s.a. isolated from patients and staff and investigation of the potential source of the infection. material and methods: in november strains of s.a. were isolated from various materials from newborns hospitalised at neonatological and obstetrician departments as well as from the staff. biochemical test api staph was used for the species identification. to molecular typing of isolates was used pulsed field gel electrophoresis (pfge). interpretation criteria for the gels followed manufacturer's guidelines: isolates with identical restriction profiles were assigned the same type, isolates that differed by one genetic event (one to three bands) were considered closely related, isolates with a four-to five-band difference were considered possibly related, and isolates that differed by more than six bands were different strains. results: comparative analysis of the banding pattern for the isolates can be divided into several categories: genetic: type asix strains from newborns with impetigo bullosa and one from staff (baby nursery); type b -two strains from the staff; type c -seven strains from the staff; type d -two strains from the staff; nine other types -each one from one person from the staff. conclusions: all the cases of impetigo bullosa were caused by one genetic type of s. aureus which allows to characterise the infection as a hospital infection. strains isolated from the staff (except one person) belonged to different genetic types (unrelated strains). isolation of the same genetic type from infected newborns and a person from the stuff may suggest that this person was the source of the infection, but we can not exclude that she was accidentally colonised during the hospital outbreaks. to define whether bacterial translocation is a process involved in the series of events following multiple trauma. methods: crushing fracture of the middle of the right femor was performed in new zealand rabbits. blood sampling was performed before and h after fracture for the determination of tumour necrosis factor-alpha (tnf-alpha) and of nitric oxide (no). tnf-alpha was estimated by a bioassay on l fibrosarcoma cell line and no by a colorimetric assay. survival was recorded and after death segments of liver, spleen and lower lobe of the right lung were cut for quantitative culture. < . . conclusion: in this in vivo model of pp ( ) gat was strongly effective on the fully susceptible strain and its efflux derivative, despite the emergence of rm for this later one. ( ) gat was ineffective, as expected on resistant gyra strain, but more surprisingly on parc mutated strains, mainly due to the presence of rm. ( ) these mutants were selected in vivo in a msw more precisely defined by pkpd parameters using mpc. ( ) low levels of resistance to fq should be detected by simple tests to guide the therapeutic options. objective: boost of systemic neutrophil count by g-csf prior to infection leads to diminished growth of pneumococci in experimental meninigitis and improves survival. whether this protective effect also includes attenuation of hearing loss is reported here. materials and methods: rats -infected intracisternally with $  s. pneumoniae serotype -were randomly allocated to receive g-csf ( lg/kg s.c. td) h prior to infection (n ¼ ), late treatment ( h postinfection, n ¼ ) or no g-csf (n ¼ ). all animals also received ceftriaxone started h postinfection. infection was documented by blood and csf tap h post infection. just before, h and days after infection, assessments of hearing was made by measurements of distortion product otoacoustic emissions (dpoae) at f ¼ - khz and by assessment of hearing thresholds by auditory brain stem responses (abr) at khz in levels from to db spl. results: -h postinfection hearing loss was significantly increased in g-csf treated animals compared with untreated (hearing loss in . vs. . % of animals from f ¼ - hz and vs. . % f > hz, respectively, mann-whitney, p ¼ . ). on day postinfection among surviving animals, severity of hearing loss in g-csf pretreated animals was furthermore increased compared with the control group (severe hearing loss in . vs. % from f ¼ - hz, respectively, mann-whitney, p ¼ . ). late g-csf treatment did not affect hearing loss significantly compared with the control group. objective: bacterial meningitis is characterised by an intense inflammatory host response that contributes to the high mortality and morbidity of the disease. doxycycline is a clinically used antibiotic which has anti-inflammatory effects that are separate and distinct from its antimicrobial action, including the reduction of cytokine release and the inhibition of matrix metalloproteases. the present study assessed the effect of doxycycline, when given as adjuvant therapy in experimental pneumococcal meningitis. methods: eleven-day-old rats were infected intracisternally with ll of saline containing . - .  cfu/ml streptococcus pneumoniae. at h after infection all animals received ceftriaxone ( mg/kg i.p., q h) and were randomised for administration of a single dose of doxycycline ( mg/kg s.c.; n ¼ ) or an equal volume of saline ( ll; n ¼ ). at h after infection, surviving animals were sacrificed. albumin concentration in the brain was assessed as an index for blood-brain barrier (bbb) leakage. brain damage was quantified by histomorphometry. results: a single dose of doxycycline ( mg/kg) vs. saline improved survival (survival rate: vs. %, p < . ), protected the bbb (cortical albumin/total protein: . vs. . lg/mg, p < . ) and reduced injury in the cerebral cortex (damage in percent of cortex; median [range] [ - . ] vs. [ - . ], p < . ). conclusion: adjuvant treatment with doxycycline may be a promising approach to prevent death or neuronal injury as a consequence bacterial meningitis. establishing conditions resulting in null survival by antibodies protection or antibiotic treatment. methods: a fully amoxicillin-resistant (mic of mg/l) serotype b streptococcus pneumoniae was used as infecting strain. amoxicillin was administered at a dose ( . mg/kg) producing serum concentration lower than the mic of the infecting strain all over the treatment period (c max : . mg/l). passive immunisation was performed with hyperimmune serum (hs; obtained from mice weekly inoculated with whole cell heat-inactivated inoculum for weeks) diluted in pbs up to dilution / that had shown null protection ( % survival) in preliminary experiments. groups of balb/c mice weighing - g were passively immunised with one-single intraperitoneal (ip) injection of the / dilution of hs, h prior to infection with the b pneumococcus. amoxicillin treatment was started h after inoculation and continued t.i.d for h. groups of animals receiving placebo (pbs), non-immune serum, non-diluted hs, / dilution of hs or amoxicillin . mg/kg alone were included as control groups. mortality was recorded over the -day follow-up period. results: survival rates in all control groups were lower than % except in the non-diluted hs that was %. antibiotic treatment in passively immunised animals produced survival rates of %, with significant differences vs. controls (except the non-diluted hs). conclusion: since amoxicillin concentrations were below the mic ( mg/l) of the infecting organisms all over the treatment period (c max of . mg/l), the presence of specific antibodies produced in vivo efficacy of sub-inhibitory concentrations. the in vivo combined effect antibodies/amoxicillin is synergistic and not only additive considering the survival rates obtained by the antibodies ( % survival) and amoxicillin sub-inhibitory concentrations ( % survival) alone and those obtained when acting together ( % survival). ( mg/kg) and cro ( mg/kg) were injected at hour and v ( mg/kg) were injected at hours and . cro and v were standard doses. d corresponded to high doses in humans. csf samples were repeatedly collected during therapy in order to determine antibiotic levels and killing rates. d serum levels peaked at mg/l decreasing slowly to mg/l h later. d csf levels ranges between and mg/l. d penetration into inflamed meninges was %. results of bactericidal activity of the different regimens are expressed in delta log cfu/ml h and delta log cfu/ml over h. results are presented in table . conclusions: ( ) d is highly efficacious against penr and penr+ qurr pneumococci in experimental meningitis, sterilising the csf of rabbits within h ( out of in both d treatment groups). ( ) d as monotherapy is significantly superior to the standard regimen based on a combination of cro with v against both strains. ( ) the efficacy of d was also confirmed in time-killing assays over h. objectives: skin-temperature is an effective measure of the severity of pneumococcal pneumonia in mice and can be used to predict lung bacterial counts and imminent death. skin-temperatures vary considerably in groups of infected mice and thus, drug intervention at a particular skin-temperature more closely resembles that which is used in humans. in this study, we compared the efficacy of moxifloxacin (mfx) with levofloxacin (lvx) in the treatment of pneumococcal pneumonia using our novel skin-temperature model. methods: swiss webster mice were inoculated endotracheally with -log cfu of the streptococcus pneumoniae a strain (mics: mfx, . lg/ml; lvx, . lg/ml). skin temperature at h was used to assess disease severity prior to drug treatment. a skin temperature of ! c is indicative of a moderate infection with a pulmonary bacterial count of -log cfu whereas temperatures < c but > c are suggestive of a severe infection with a count of -log cfu. all mice with a temperature of c were excluded from the study, as death is imminent within h. a mg/kg subcutaneous dose of mfx or lvx was given twice daily for days. skin temperature was measured daily to monitor clinical improvement or failure ( c for at least h). all mice deemed to have failed therapy were euthanised immediately. viable counts in the lungs were determined for all mice. results: of the mice classed as moderate, / ( %) mice treated with mfx and / ( %) mice treated with lvx survived. complete eradication was obtained in and % of mice treated with mfx and lvx, respectively, in this group. of the mice classed as severe, / ( %) and / ( %) mice treated with mfx and lvx, respectively, survived. complete eradication was obtained in and % of mice treated with mfx and lvx in this group. conclusions: mfx showed significantly enhanced activity over lvx at both an early and late stage pneumococcal lung infection. . a partial knee replacement was performed with a silicone implant fitting into the intramedullary canal of the tibia, and cfu of mrsa, were injected into the knees. rx was started days after inoculation and continued for days intramuscularly. results: mics (mg/l) of lzd, van and rif were . , . and . , respectively. in vivo, lzd reduced significantly the mean log cfu/g of bone ( . ae . , n ¼ ) vs. controls and van ( . ae . , n ¼ ; . ae . , n ¼ ), respectively (p < . ). both rx were not sufficient to sterilise animals ( / and / respectively). the combination of rif with lzd ( . ae . , cfu/ g of bone, / sterile animals) or with van ( . ae . cfu/g of bone, / sterile animals), was significantly more effective than monotherapy (p < . ). emergence of resistance to rif was not detected in vivo. conclusion: in this mrsa joint prosthesis infection, lzd combined with rif was highly effective in vivo and prevented the selection of mutant resistant of rifampin. lzd should be of interest for treating mrsa joint prothesis infection. staphylococcus aureus nasal decolonisation model to study the role of the multidrug efflux system acrab-tolc in resistance of salmonella typhimurium dt to detergents and bile salts. to evaluate the importance of the components acrb and tolc of this efflux system in the colonisation of a multidrug-resistant s. typhimurium dt strain in chicks. methods: acrb and tolc mutants of a multidrug-resistant s. typhimurium dt strain were constructed by deletion or insertional inactivation of the genes. mics of detergents and bile salts were determined for the acrb and the tolc mutants, comparatively to the wild type mutidrug-resistant strain. the effect of sodium choleate on the in vitro growth of these three strains was evaluated. the ld s of the strains were measured in a one day old chicken model, inoculated with several doses ( - log cfu) by the oral route, during days post-inoculation. the colonisation levels were assessed at the subletal dose days post-inoculation by determining the number of cfu of salmonella in the faeces, caeca, spleen, and liver. results: the decrease of resistance to detergents and bile salts was much more important for the tolc mutant than for the acrb mutant. for example, mics of sds decreased of and times, mics of sodium deoxycholate decreased of and times, for the tolc and acrb mutants, respectively. addition of choleate in culture medium had no effect on the growth of the wild type strains and of the acrb mutant but inhibited the growth of the tolc mutant. the ld s in the -day old chicken model, were log cfu and log cfu for the wild type strain and the acrb mutant, respectively, and not calculable for the tolc mutant because of a too small number of dead chicks. furthermore, in contrast to the acrb mutant, the tolc mutant was unable to colonise the caeca, spleen, and liver after week of infection. moreover, in most chicks no intestinal excretion was detected for the tolc mutant. the colonisation levels of the acrb mutant were the same as those of the parental strain. conclusion: tolc but not acrb appears to be essential in multidrug-resistant s. typhimurium dt colonisation of chicks, which is in accordance with their respective roles in resistance to detergents and bile salts. therefore, tolc could be a better target than acrb for the development of efflux system inhibitors. (kp ) and its derivative producing the plasmid-mediated ampc-type b-lactamase cmy- (kp ). in vitro studies: mic/mbc: microdilution method (nccls), inoculum: , and cfu/ml. the in vitro postantibiotic effect (pae) was investigated by exposing the bacteria to imp and cep at concentration equal to two and six times the mics for . h. the pae was quantitated calculating the difference between the times required for the numbers of drug-exposed and untreated organism to increase -fold above the numbers present immediately after removal of the antibiotic. pk/pd parameters (c max and time above the mic) were determined after a single dose of antimicrobials. in vivo studies: experimental pneumonia in c bl/ mice, with intratracheal inoculum of cfu/ml. the animals were grouped in: con (no treatment), cfp ( mg/kg/day) and imp ( mg/kg/day), during h. variables: mortality rates and bacterial clearance from lungs. statistical analysis: chi-squared and fisher tests, anova, and posthoc tests. results imp ( . , . , . ) . in vivo: for kp , cfp and imp decreased the mortality respect to con ( vs. %, p < . ) and ( . vs. %, p < . ); for kp , imp was the only therapy that decreased the mortality compared with con and cfp ( vs. % and %, p < . ). bacterial clearance from lungs: for kp , cfp and imp cleared the lungs respect to con ( . and . vs. . log cfu/ml, p < . ), cfp being better than imp (p < . ); for kp , cfp and imp cleared the lung respect to con ( . and . vs. . log cfu/ ml, p < . ). conclusions: the presence of plasmid-mediated ampc-type b-lactamase cmy- in k. pneumoniae diminished the in vivo efficacy of cefepime and not that of imipenem. the inoculum effect for cefepime and the pae of imipenem partially explain these results. m. abscessus is a rapidly growing mycobacterium (rgm) that is emerging as a significant pathogen in humans, both as a respiratory pathogen in patients with or without recognised comorbidities, and as the agent of inoculation infections. the histopathologic features of the human infection suggest that m. abscessus causes a tuberculosis-like infection. we investigated the systemic challenge of c bl/ mice with the type strain of m. abscessus through intravenous and intraperitoneal routes. with both high ( cfu) and low ( cfu) doses, the initial bacterial load remained stable for days in liver and spleen until the establishment of a granulomatous response. the differentiation of the granuloma (central f / + epithelioid cells with a peripheral cd + and cd + lymphocytic crown) was contemporary to a drastic decrease of the bacterial load in the organs studied. however, days following the challenge some mice still harboured bacteria capable of in vitro growth in their livers and spleens despite an overall effective control of the infection, and all mice infected presented granulomas of various differentiation stages in their livers. this response is highly reminiscent of the ifnc dependent response to m. tuberculosis. mice deleted for the gene encoding ifnc were challenged intraperitoneally with m. abscessus and significantly failed to reduce the bacterial load by day . we show for the first time that the rapidly growing m. abscessus can cause a long lasting, tuberculosis-like, ifnc dependent infection in c bl/ mice. these results show promise for the elucidation of m. abscessus disease since data from m. tuberculosis might be relevant. reciprocally, m. abscessus faithfully models key features of mycobacterial infection. campylobacter jejuni infection is the most common antecedent in the axonal variant of guillain-barré syndrome (gbs). antibodies against nerve gangliosides found in gbs patients recognise cross reactive epitopes in the lipopolysaccharide (lps) of c. jejuni. this led to the molecular mimicry hypothesis of gbs. to investigate the connection among c. jejuni, antibodies anti gangliosides and gbs we designed an animal model employing a lps isolated from a gbs patient. methods: we immunised eleven rabbits with a lps extracted from penner serotype : c. jejuni strain isolated from patient with gbs and freund's adjuvant (cfa) (group i). in a second experiment we immunised seven rabbits with lps, cfa and keyhole limpet hemocyanin (klh) (group ii). results: all rabbits of groups i and ii developed a strong humoral response to lps. elevated igm and igg antibodies to lps could be detected as early as weeks after the first immunisation. igg raised during the immunisation period up to in group i and in group ii. anti-gm igm antibodies were detectable at low titres weeks after the first immunisation in both groups and raised up to in group i and to in group ii. igg anti-gm could already be detected at low titres in both groups weeks after the first immunisation and increased up to in group i and up to in group ii. titre of anti-gm igg showed a steep rise during the weeks following the first immunisation. in western immunoblotting of c. jejuni lps, the serum of immunised rabbits reacted strongly with a band that co-migrated at kd at the same level of ct, pna and serum of the patient with anti-gm antibodies. the kinetics of igm and igg anti-gd b was similar to that of antibody anti-gm but the maximal titres were lower as igg raised up to in group i and in group ii. igm anti-gd a were at low titre in both groups throughout the experiment whereas igg anti-gd a raised up to in group i and to in group ii. igm and igg anti-gq b were not detectable in group i and ii sera. conclusion: c. jejuni lps is a potent b-cell stimulator capable to induce a strong antiganglioside response in rabbits. however to induce the neuropathy is crucial to employ klh a glycoprotein known to stimulate both humoral and cellular responses. this is the first animal model reproducing the pathogenetic process hypothesised in axonal gbs with antiganglioside antibodies post-c. jejuni infection. methods: three separate experiments were conducted in order to screen the ability of five clinical c. concisus isolates and the atcc type strain of oral origin to infect balb/ca mice. all mice were pre-treated with vancomycin, and half of the animals received cyclophosphamide to disturb immune functions, prior to c. concisus challenge by direct intragastrical inoculation with . ml cfu, controls received . ml of pbs. measured parameters were bacterial isolation from stool and internal organs, loss of body weight and histological examinations of tissue samples. mice were sacrificed on days , and of the studies. isolation of c. concisus was performed by the selective filter method and pcr. results: isolation and identification: c. concisus was isolated on day from the cyclophosphamide treated group infected with the clinical isolate (study ). liver ( / ), ileum ( / ) and jejunum ( / ) were culture positive. pcr results from tissue samples were only positive in one mouse from the same group (liver, ileum and jejunum). faecal pellets were consistently negative. during the two following studies, no isolation of c. concisus was possible. histological examination: microabscesses ( / ) were found in the liver in two untreated groups. oedema of villi in the ileum was occasionally noted in infected groups, but not in controls (study ). two mice in the untreated group infected with the atcc type strain, presented leukocyte infiltration of colon. loss of body weight: compared with controls, the c. concisus infected mice had a significant weight loss (p < . ) (study ). loose stools: on days and , c. concisus inoculated groups had loose and slimy stools compared with control groups (study ). one mouse inoculated with the clinical isolate died on day (study ). discussion: the present model mimics a relevant intragastrical exposure to c. concisus infection of imunocompetent balb/ca mice upon cyclophosphamide treatment and results indicate a possible transient colonisation of liver and ileum, with clinical signs of illness as loss of bodyweight and loose stools. histological examination was inconclusive. isolation of c. concisus was not reproducible in two subsequent studies, which severely hampers the present model. future studies should concentrate on the first days of infection, as the organism is rapidly cleared from the gi tract. . they were co-adminis-tered with antimicrobials in an experimental model of sepsis by an mdr isolate. methods: sepsis was induced in rabbits after the iv infusion of an log inoculum of a p. aeruginosa isolate resistant to ceftazidime (cz), imipenem, ciprofloxacin and amikacin (am) by a catheter inserted into the right jugular vein. animals were assigned into five groups of treatment of six animals each: a controls; b iv cz and am; c iv cz, am and alcohol %; d iv cz, am and an alcoholic solution of gla; and e iv cz, am and an alcoholic solution of aa. therapy was administered min after bacterial challenge. cz was given at a mg/kg dose, am at mg/kg and both n À pufas at mg/kg. n À pufas were infused within min. all agents were administered by a catheter inserted into the left jugular vein. survival was recorded; after death segments of various organs were cut for quantitative cultures. results this synergy is tested in an experimental model. methods: thirty-five wistar rats became neutropenic by the intraperitoneal injection of mg/kg of cyclophosphamide on day and mg/kg on day . on day an log inoculum of one mdr isolate was intramuscularly injected into the right femor of animals. rats were assigned into four groups of treatment: a (n ¼ ) controls; b (n ¼ ) rf treated; c (n ¼ ) cl treated; and d (n ¼ ) treated with both agents. therapy was given four hours after bacterial challenge. cl was administered im mg/kg into the left femor and rf iv from a catheter inserted into the right jugular vein at mg/kg. survival was recorded. results: mean ae se survival of animals of groups a, b, c and d were . ae . days, . ae . days (p: . compared with a), . ae . (p: . compared with a) and . ae . (p: . compared with a) respectively. conclusions: co-administration of cl and rf is beneficiary accompanied by prolonged survival in an experimental model of sepsis by mdr a. baumannii. infections by acinetobacter baumannii (ab) with high-degree resistance (hdr) to carbapenems have recently increased. only colistin seems to keep its in vitro efficacy, but clinical practice is scarce. to our knowledge, no clinical data are currently available to evaluate the systematic use of the beta-lactam (bl)-aminoglycoside (ag) combination to treat serious ab infections in a way similar to that in other infections by gram-negative bacteria. objective: to analyse the efficacy of the combination of two bl (imipenem [i] methods: we used immunocompetent c bl/ mice and three strains of ab with susceptibility, moderate-degree resistance and hdr to carbapenems (a, d and e respectively). mics (mg/l) were (strains a, d, e): i: , , ; s: , , ; and t: , , . the in vivo activity was examined by quantitative evaluation of the lung homogenate cultures after h of induction of pneumonia. results: in control (con) animals (n ¼ ), the bacterial counts in lungs at h were (mean ae sd): . ae . , . ae . and . ae . log cfu/g of tissue for strains a, d and e, respectively (p ¼ ns between strains). results of antibiotic activity were expressed as differences between treated (n ¼ in each therapy) and con groups (delta log cfu/g) (see table) . conclusions: in this mice pneumonia model, i or s kept his efficacy for ab with moderate resistance to carbapenems. in infections caused by this strain d, t in combination conferred a possible greater efficacy on these bls. in infections by ab with hdr to carbapenems, t alone was also effective. interestingly the combination bl + ag also showed a higher effect on the infection by this hdr strain e, against which monotherapy with i or s were totally ineffective. although the pharmacodynamics of t in this model may have been overestimated, because of the peak levels achieved are not usually found in humans at the recommended doses (c max . ae . mg/l), these results are promising to treat multiresistant ab infections. objectives: to investigate the effect of orally administered cranberry juice and its organic acids on escherichia coli in an experimental mouse model of ascending urinary tract infection. methods: e. coli c - , a clinical isolate from a patient with uti was used. it expresses type fimbriae but not p or s fimbriae. the transurethrally infected mice were at all times were allowed free access to chow and water (control group) or treatments. the control group and the treated groups all consisted of six mice in every trial; after week, the mice were sacrificed and urine, bladders and kidneys collected for determination of bacterial counts. most of the treatments were repeated two or more times in independent trials and these data were pooled. treatments were commercially available cranberry juice cocktail, freshly prepared cranberry juice, the hydrophilic fraction of cranberry juice (contains sugars and organic acids) and organic acids (quinic, malic, shikimic and citric acid in concentrations corresponding to cranberry juice). results: a reduced number of organisms could be recovered from the bladder (p < . ) and urine (p < . ) of mice orally treated with unsweetened cranberry juice. commercially available cran-berry juice cocktail also reduced the cfu in the bladder (p < . ), as did the hydrophilic fraction of cranberry juice (p < . ). quinic, malic, shikimic and citric acid were administered in combination and one by one. the four organic acids decreased the cfu in the bladder when administered together (p < . ), and so did the combination of malic plus citric acid (p < . ) and malic plus quinic acid (p < . ). these data indicate that the beneficial effect of the organic acids from cranberry juice during urinary tract infection is obtained when the acids are administered together. conclusion: for the fist time the effect of cranberry juice and its dominating organic acids has been tested in an experimental mouse model of long-term ascending urinary tract infection under controlled conditions. cranberry juice inhibited e. coli colonisation of the bladder, and the organic acids were the active component involved. the active treatments reduced the bacterial load in the bladder to sub therapeutic concentrations, which indicates that cranberry juice is no final treatment but a remedy that could help the patient to clear the infection, before it eventually becomes a final cystitis. (mellado et al., mol microbiol ; : - ) . we describe a kinetic microbroth method of measuring the growth rates of aspergillus fumigatus spectrophotometrically. using this method, growth rates (as defined by v max values) were determined for nine aspergillus fumigatus isolates for which an ld value in temporarily neutropenic cd- mice, infected intravenously, had previously been obtained. methods: an inoculum of spores in ll sab medium gave us uniformly shaped growth curves and allowed the measurement of v max values with greater sensitivity. soft max pro software was used to determine the v max value for each growth curve by performing linear regression on as many five data point line segments as possible, calculating the slope for each line segment and reporting the steepest slope as the v max (mod/min). growth rate was determined in quadruplicate in three separate experiments and the average v max measurement across these experiments calculated. results: mean growth rate varied from . (af ) to . (af ). ld varied from  to  . comparison of the growth rates and ld values of these isolates suggests a correlation exists between the two parameters, omitting the one significant outlier (af , which is amphotericin b resistant), r ¼ . . conclusion: these data are important in describing a simple method for measuring the growth rate of the common filamentous fungus a. fumigatus, and proving a direct link between pathogenicity in vivo and growth rate in vitro. objective: to compare the histological changes, viral persistence and localisation of the virus in the pancreas and the small intestines of mice, experimentally infected by oral or intraperitoneal route. method: mice were infected with cvb (nancy) by the oral or intraperitoneal route. doses ranged from  to  tcid . selected organs from each mouse were embedded into paraffin and sections were attached on silanised slides. for histological observation the sections were stained by mayer's haematoxylin eosin method. for localisation of the antigen by immunohistochemical staining, the vp protein served as an indicator for the presence of the virus. the method was standardised. the tissue sections were processed and stained by the avidinbiotin method, using the monoclonal mouse anti-enterovirus antibody against vp protein. results: the histological observations reveal that the tissue of exocrine pancreas showed inflammatory changes on the rd, th, th, th and st day post-infection in exocrine pancreas of the intraperitoneally infected mice. after oral infection no destruction of the exocrine pancreas was observed, but on day th post-peroral infection liposis was seen. vp was detected mainly on the third and seventh days after infection in the small intestine. we found differences in vp localisation between oral and intraperitoneal infection. in small intestine of orally infected mice positive staining was localised in smooth intestinal muscles whereas after intraperitoneal infection. vp was detected within the villi. there was no correlation between the virus concentration and tissue damage. conclusions: the pathogenesis of cvb infection is influenced by the route of virus administration, which has direct implications for the use of mouse models to study the pathogenesis of coxsackieviruses. objectives: the portal of entry of coxsackieviruses may influence the pathogenesis of infections caused by these viruses. in this study an outbred murine model (swiss albino mice) was used for experimental infection with coxsackie b virus (cvb ), strain nancy to follow-up the virus shedding in the stool and the presence of replicating virus in the small intestine of mice after oral and intraperitoneal route of infection. methods: for infection of mice different concentrations of the virus ( , , and ) were used. the stool and small intestine specimens of dissected mice were collected on days , , post-infection (p.i.) and from day in weekly intervals up to a day p.i. the suspensions made from the collected specimens were studied for presence of replicating virus in hep- cell cultures. the virus titre was determined in hep- monolayers on microtitre plates and calculated by reed and muench method. results: the replicating virus in the stool pellets was detectable from day p.i. to day p.i. in both orally and intraperitoneally infected mice with a virus titre reaching the level : tcid / ml. in the small intestine of orally infected mice the presence of replicating virus was detected up to day p.i. in the small intestine of intraperitoneally infected mice the replicating virus was present for a shorter time, up to day p.i., irrespective of the dose of infection. conclusion: there was no difference in the length of virus shedding in stool specimens of mice infected by oral or intraperitoneal route. however a longer presence of replicating virus in the small intestine of orally infected mice in contrast to intraperitoneally infected mice was observed. this was confirmed by the immunohistopathological studies, these observations support the suggestion that the pathogenesis of coxsackieviral infections is influenced by the route of virus administration. object: in xenotransplantation with porcine neonatal pancreatic cell clusters (npccs), the risk of cross-species porcine endogenous retrovirus (perv) infection remained as problem. we used the severe combined immunodeficient (scid) mouse and the lewis rat model to identify the perv transmission with the time course and the differences between the models. methods: npccs were transplanted to scid mice and lewis rats and left for - days before being sacrificed. dna and rna were extracted from the liver, spleen, pancreas, lung, kidney and testis. to examine the perv transmission, nested-pcr and rt-pcr were used upon pol/env/gag regions of perv. the pig mitochondrial cytochrome oxidase ii subunit gene (coii) was amplified simultaneously to monitor the microchimerism. results: total samples from seven mice and five rats were tested. ten weeks after xenotransplantation, two mice and four rats were identified to have permissive perv infection. in the scid mice, . % of tested organs were positive for perv-pol gene and . % were positive for coii gene with dna examination. in the lewis rats, . % of organs were positive for perv-pol gene and . % for coii gene with dna examination. examinations of organs of mice showed that ( . %) organs were positive for the perv-pol gene and coii gene simultaneously that presumed as microchimerism, but ( %) organs of rats were presumed as microchimerism. results of perv-pol positive and coii negative that presumed as permissive perv infection were observed in . % of organs in the scid mice and . % in the lewis rats. organs presumed as permissive perv infection were the spleen (day ), liver (day ), lung (day ), and testis (day ) in the scid mice by dna examinations. in the lewis rats, the spleen and testis of day ; the liver, spleen, and kidney of day ; the testis and kidney of day ; the liver, spleen, lung, and testis of day were identified to have permissive perv infection. conclusion: the cross-species perv infection was identified from these animal models. expression of perv depends on the immunity of the recipients, because the xenotransplanted scid mice had more perv microchimerism but less permissive infection than that of the lewis rats. detection rate was increased with the time course, accordingly in the early period after transplantation, perv considered to exist as an inactive form. the therapy of numerous antimicrobial classes including the recently introduced quinupristin/dalfopristin, telithromycin and the oxazolidinones. clearly the need for antimicrobial discovery persists, and this should be a continued priority for the pharmaceutical industry. this report addresses the spectrum of activity for pdf tested against a collection of recent ( ) clinical isolates cultured from patients infected with pathogens within the spectrum for peptide deformylase inhibitors. methods: pdf was acquired from novartis. the compound was dispensed into reference broth microdilution trays in appropriate media over the range of . - mg/l. mueller-hinton broth was supplemented with - % lysed horse blood when testing fastidious streptococci, and the corynebacteria. nccls qc strains were used concurrently and all pdf mic results were within proposed ranges. results: gram-positive strains were tested with a species rank order of s. aureus ( strains) > cons ( ) objective: nvp-pdf is a new peptide deformylase inhibitor active against a wide variety of gram-positive and -negative bacteria. the current study examines the activity of nvp-pdf compared with those of ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, vancomycin, teicoplanin, linezolid, ranbezolid, dap-tomycin, oritavancin and quinupristin/dalfopristin against s. aureus ( methicillin resistant) and coagulase-negative staphylococci ( methicillin resistant). microdilution using frozen trays containing cation-adjusted mueller-hinton broth and inocula of  cfu/ ml with trays incubated in air. results: mic and mic values (lg/ml) were as seen in the following table. nvp-pdf was equally active against all staphylococcal strains (mics < . - lg/ml), irrespective of susceptibility to other agents. quinolone resistance was mainly seen in methicillin r strains. vancomycin, linezolid, ranbezolid, daptomycin, oritavancin and quinupristin/dalfopristin were all active at mics < . lg/ml and teicoplanin was less active against coagulase-negative strains. conclusions: nvp-pdf , a new peptide deformylase inhibitor, was active in vitro against staphylococci. p antipneumococcal activity of nvp-pdf compared with other agents p. appelbaum, l. ednie, m. jacobs hershey, cleveland, usa background: drug resistance in pneumococci is found worldwide. objective: nvp-pdf is a new peptide deformylase inhibitor active against gram-positive and -negative bacteria. this study tests activities of nvp-pdf , amoxicillin ae clavulanate, imipenem, meropenem, ceftriaxone, cefuroxime, cefpodoxime, cefdinir, ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, azithromycin, clarithromycin, linezolid, quinupristin/dalfopristin, vancomycin and teicoplanin against pen s, pen i, pen r pneumococci ( macrolide r and quinolone r strains with defined r genotypes). methods: agar dilution using cation-adjusted mueller-hinton agar + % sheep blood and inocula of  cfu/spot; plates incubated in air. results: mic and mic values (lg/ml) are shown in table . nvp-pdf was equally active against all pneumococci, irrespective of activity of other drugs. beta-lactam mics rose with those of pen g. moxi was the most potent quinolone followed by gati, levo cipro. vanco, teico, linez, quin/dalf were all active at mics < . lg/ml. conclusions: nvp-pdf was active in vitro against beta-lactam, macrolide and quinolone s and r pneumococci. objective: nvp pdf- is a new peptide deformylase inhibitor active against gram-positive and gram-negative strains. this study tested activity of nvp pdf- , ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, vancomycin, teicoplanin, linezolid, ranbezolid, daptomycin, tigecycline, oritavancin and quinupristin/ dalfopristin against six s. aureus ( methi r) and six cons ( methi r). methods: nccls macrodilution mic was used. for time-kills,  -  cfu/ml inocula in cation-adjusted mueller-hinton broth were incubated aerobically in a shaking water bath at Â, Â,  mic. viabilities were done after , , , h. ca þ was added for dapto. results: mic ranges (lg/ml) were: nvp pdf- , . - ; cipro, . to > ; levo, . - ; gati, . - ; moxi, . - ; vanco, - ; teico, . - ; linez, - ; ranbez, . - ; dapto, . - ; tige, nvp / / / / / / / / / / / / cipro / / / / / / / / / / / / levo / / / / / / / / / / / / gati / / / / / / / / / / / / moxi / / / / / / / / / / / / vanco / / / / / / / / / / / teico / / / / / / / / / / / linezolid / / / / / / / / / / / ranbez / / / / / / / / / / / depto / / / / / / / / / / / tigecyt / / / / / / / / / / / oritavan / / / / / / / / / / / quin/dalf / / / / / / / / / / / . - ; orita, . - ; quinu/dalfo, . - . no. of strains at mic/  mic with delta- log cfu/ml ( %), delta- log cfu/ ml ( %) and delta- log cfu/ml ( . %) killing at the various time periods are shown in table . nvp pdf- was not cidal at  mic and  mic, but was static against all strains at mic after h. cipro and moxi were cidal against four to seven strains at  mic after h. vanco was cidal at  mic for nine strains after h. oxazolidinones, tigec and quinu/dalfo were mainly bacteriostatic and dapto and orita rapidly cidal. conclusions: nvp pdf- gave low mics and static activity against all strains, irrespective of methicillin susceptibility status. p time-kill study of the antipneumococcal activity of nvp pdf- , a new peptide deformylase inhibitor, compared with other agents p. appelbaum, g. pankuch, m. jacobs hershey, cleveland, usa background: drug-resistant pneumococci are an increasing worldwide problem. objective: nvp pdf- is a new peptide deformylase inhibitor. this study used time-kill analysis to examine the antipneumococcal activity of nvp pdf- compared with imipenem, meropenem, ceftriaxone, moxifloxacin, levofloxacin, gatifloxacin, azithromycin, clarithromycin, vancomycin, teicoplanin, linezolid, daptomycin, and quinupristin/dalfopristin. twelve strains were tested: three penicillin sensitive, two intermediate, and seven resistant pneumococci. of the strains tested; were macrolide resistant [ erm (b), mef, l ], and two quinolone resistant. methodology: nccls macrodilution mic methodology was used. time-kill analyses were in cation-adjusted mueller-hinton broth with % lysed horse blood, and final inocula of  -  cfu/ml. mueller-hinton broth was supplemented to a final concentration of mg ca þ /l for testing daptomycin. viability counts were done after , , , , and h. results: mics (lg/ml) were as follows: nvp pdf- , . - . ; imipen, . - . ; meropen, . - . ; ceftriax, . - . ; moxi, . - . ; levo, . - ; gati, . - . ; azithro, . to > ; clarithro, . to > ; vanco . - . ; teico, . - . ; linez, . - . ; dapto, . - . ; quin/dal, . - . . the number of strains at mic/  mic with log cfu/ml values of À ( % killing), À ( % killing) and À ( . % killing) at the various time periods are shown in table . conclusions: nvp pdf- had kill kinetics similar to those of linezolid. nvp pdf- at  mic was bactericidal ( . % killing) against six strains after h. linezolid at  mic was bactericidal against seven strains at the same period. daptomycin and quinupristin/dalfopristin showed rapid killing. imipenem, meropenem, vancomycin, and quinupristin/dalfopristin were bactericidal against all strains at  mic after h. objectives: nvp-pdf- is a new peptide deformylase inhibitor antimicrobial with excellent activity against gram-positive cocci, including methicillin-resistant staphylococcus aureus (mrsa) and penicillin-resistant streptococcus pneumoniae (prsp). we used the neutropenic murine thigh-infection model to measure in vivo postantibiotic effects (paes) and determine which pk/pd parameter best correlated with in vivo efficacy. methods: mice had . - . cfu/thigh of staphylococcus aureus atcc and streptococcus pneumoniae atcc when treated for h with - mg/kg/day of nvp-pdf- fractionated for -, -, -, and -h dosing. mice were sacrificed at the end of therapy. ten per cent thigh homogenates were prepared, and serial dilutions were plated for cfu determinations. serum levels after both oral and subcutaneous injection of doses of , and mg/kg were measured by microbiologic assay. non-linear regression analysis was used to determine which pk/pd parameter ( -h auc/mic, peak/mic or time above mic) best correlated with cfu/thigh at h. in vivo paes were measured from serial - h cfu/thigh values after doses of and mg/kg. results: pharmacokinetic studies exhibited linear kinetics with doses from to mg/kg, with peak/dose values of . - . , auc/dose values of . - . and half-lives of - min. oral bioavailability was - %. protein binding in mouse serum was low at %. nav-pdf- produced in vivo paes of - h with s. aureus and - . h with s. pneumoniae. the -h auc/mic was highly correlated with efficacy (r ¼ - % for -h auc/mic compared with - % for peak/mic and - % for time above mic for s. pneumoniae and s. aureus, respectively). because of the rapid half-life in mice, oncedaily dosing was slightly less effective than the more frequent dosing regimens. conclusions: the -h auc/mic is the parameter that best correlates with in vivo activity of nvp-pdf- . the prolonged in vivo paes would support at least twice daily dosing. p in vivo pharmacodynamic activity of nvp-pdf- against multiple bacterial pathogens w. craig, d. andes madison, wisconsin, usa objectives: the -h auc/mic is the pk/pd parameter that best correlates with in vivo activity of nvp-pdf- , a new peptide deformylase inhibitor. we used the murine thigh-infection model nvp / / / / / / / / / / / / imipen / / / / / / / / / / / / meropen / / / / / / / / / / / / ceftriax / / / / / / / / / / / / moxi / / / / / / / / / / / / levo / / / / / / / / / / / / gati / / / / / / / / / / / / azithro / / / / / / / / / / / / clarithro / / / / / / / / / / / / vanco / / / / / / / / / / / / teico / / / / / / / / / / / / linez / / / / / / / / / / / / depto / / / / / / / / / / / / quin/dal / / / / / / / / / / / / in normal and neutropenic mice to determine ( ) the magnitude of the -h auc/mic needed for efficacy of nvp-pdf- with various pathogens (including mrsa and penicillin-, macrolideand tetracycline-resistant strains of s. pneumoniae) and ( ) the impact of neutrophils on the drug's in vivo activity. methods: mice had . - . cfu/thigh of five isolates of staphylococcus aureus (two mrsa) and six isolates of streptococcus pneumoniae (five penicillin-resistant, four macrolide-resistant, three tetracycline-resistant strains) when treated for h with - mg/kg of nvp-pdf- subcutantously every h. streptococcus pneumoniae atcc and staphylococcus aureus atcc were studied simultaneously in normal and neutropenic mice. mice were sacrificed at the start and end of therapy. ten per cent thigh homogenates were prepared and serial dilutions were plated for cfu determinations. serum levels were determined by microbiologic assay after subcutaneous doses of , and mg/kg. a sigmoid dose-response model was used to estimate the dose (mg/kg/ h) required to achieve a net bacteriostatic effect over h. results: pk studies exhibited linear kinetics with auc/dose values . - . and half-lives of - min. protein binding was %. mics ranged from . to . mg/l. static doses for the various organisms ranged from to mg/kg/day. mean -h auc(free)/mic values (aesd) were . ae . for s. aureus and . ae . for s. pneumoniae. the differences were not significant. methicillin and penicillin resistance did not alter the magnitude of the auc/mic required for efficacy. the presence of neutrophils reduced the -auc(free)/mic required for efficacy by about fourfold. conclusion: the -h auc/mic of nvp-pdf- required for in vivo efficacy was relatively similar among various pathogens, was not altered by drug resistance, and was reduced fourfold by the presence of neutrophils. p determination of quality control guidelines for mic dilution and disk diffusion methods when testing nvp-pdf , a novel peptide deformylase inhibitor t. fritsche, t. anderegg, r. jones north liberty, usa background: quality control (qc) guidelines remain necessary for accurate determination of antimicrobial susceptibility testing and should be established early in the development of new antimicrobial classes. nvp-pdf is a pdf inhibitor rapidly progressing into phase ii and iii human clinical trials, thus qc guidelines appear necessary for nccls methods. methods: multi-laboratory (seven or eight sites) trials were initiated using the nccls m -a guideline for qc determinations. key technical details were: mic phase -four mueller-hinton (mh) broth lots, eight participant sites and replicates of four appropriate qc strains; and disk diffusion phase -three mh agar lots, seven sites and replicates of three qc strains. results were analysed by statistical methods found in m -a . control drugs included vancomycin, clarithromycin, linezolid and levofloxacin; . - . % of control results were within published nccls ranges ( and results for mic and zone tests, respectively). inoculum concentration controls averaged .  (mic trial only). results: seven or eight participants provided qualifying results in the two separate qc studies, and the calculated (proposed) ranges were (range; % results in range): e. faecalis atcc ( - mg/ l; . ), s. aureus atcc ( . - mg/l; . ), s. pneumoniae atcc ( . - mg/l; . and - mm; . ), h. influenzae atcc ( - mg/l; . and - mm; . ), and s. aureus atcc ( - mm; . ). all qc ranges were maximised to contain % % of reported results and zone sise variation was elevated due to the bacteriostatic character of this pdf inhibitor, creating non-discreet zone edges. conclusions: qc ranges for nccls methods when testing nvp-pdf have been established. results from these nccls m -a -conforming trials can be utilised to control the accuracy of the susceptibility testing of this pdf inhibitor projected to be among the 'first' to reach human clinical studies. p determination of dry-form commercial reagent reproducibility and mic validations for nvp-pdf , a novel peptide deformylase inhibitor g. moet, r. jones, p. rhomberg, t. fritsche north liberty, usa background: nvp-pdf is a new pdf inhibitor rapidly being advanced to human clinical trials. commercial reagent broth microdilution mic panels will be required for investigator laboratory use, especially those products with extended shelf-lives (dry-form). this study reports the results of reagent qualifying tests. methods: the experiment was performed by nccls m -a guidelines to assess dry-form mic reproducibility ( organisms  tests/day  days ¼ tests) and comparative mic accuracy to the reference mic (ref; m -a , ) using % strains representing the following organism groups: staphylococci, enterococci, s. pneumoniae, other streptococci, h. influenzae, and selected species refractory to pdf inhibitor action. all trays were manufactured by sensititre (trek diagnostics, cleveland, oh). results: reproducibility results showed % of mics were identical and . % of mics were within one log dilution step. validation test results comparing dry-form to ref mics were (% identical/twofold/fourfold): for staphylococci ( / / %), for enterococci ( / / %), for s. pneumoniae ( / / %), for other streptococci ( / / %) and for h. influenzae ( / / %). consistent variations were detected with spn ( % of dry-form panel results being one dilution higher than ref) and hi ( % of results being one dilution lower than ref). nvp-pdf mics were off-scale (mic values, > mg/l) for enterobacteriaceae and non-fermentative gram-negative bacilli ( strains). overall, % of sensititre mic results for were within one log dilution of ref mic values. conclusions: nvp-pdf dry-form diagnostic mic panels have been validated for accuracy and reproducibility using recent clinical isolates from five major pathogen groups. the spectrum of activity for this pdf inhibitor compound appears focused toward gram-positive cocci and specific fastidious respiratory tract pathogens. objectives: the emergence of antibiotic resistance among grampositive pathogens has impacted the clinical management of these infections. paratek pharmaceuticals initiated a programme to apply medicinal chemistry to the core structure of tetracycline (tet) with the goal of creating novel classes of proprietary antibiotics that would (a) be unaffected by the known tet resistance mechanisms and (b) retain the safety and tolerability profile of the tet family. since there is no cross-resistance between the tets and other antibiotics, such new agents would be expected to be active against isolates resistant to all other currently available classes. the aim of the programme was to synthesise new agents active against gram-positive, common gram-negative, atypical and anaerobic bacteria. methods: a series of -position and , -position derivatives of sancycline were synthesised and tested for activity in vitro against mrsa, vre, enterococcus faecalis and streptococcus pneumoniae by microdilution. the presence of tet-resistance determinants was assessed by pcr and confirmed by resistance to currently available tets. results: a number of -dimethylamino- -aminomethylcyclines (amc) and -aryl or heteroaryl sancyclines with potent activity in vitro (mic range less than or equal to . - . mg/l) were identified. both novel series were more potent against one or more of the resistant strains than currently available antibiotics tested (mic range - mg/l). the amc derivatives were active against bacteria resistant to tet by both efflux and ribosome-protection mechanisms. conclusions: this study identified the amcs as a novel class of antibiotics evolved from tet that exhibit potent activity in vitro against tet-resistant bacteria, including gram-positive bacteria resistant to currently available antibiotics. one agent of this class, bay - (discovered by paratek pharmaceuticals, inc., boston, ma, and designated ptk ) has been chosen for development. bay - is a novel antibiotic compound being developed for the treatment of severe bacterial infections. it is the first compound selected from the novel class of aminomethylcyclines and was designed to meet an increasingly significant need for additional therapies for treatment of infections, including those resistant to currently available antibiotics. the efficacy of bay - in different mouse models of skin and soft tissue infection (ssti) was compared with that of vancomycin (van) and linezolid (lin). methods: two mouse models were employed to determine the efficacy of bay - : ( ) infected abscess model (induced by implantation and subsequent infection of gelfoam (tm)) and ( ) infected thigh muscle model in neutropenic mice. staphylococcus aureus strain dsm (mssa) was used to infect the respective structures in the skin and soft tissues. infected abscess bearing mice were treated i.v. bid for days, while thigh muscle infection model mice were treated s.c. min post-infection. cfu reduction of infected tissues and bacterial load in different organs (spread from the infection site) were used as read-out for therapeutic efficacy. results: as measured by reduction of bacterial load, therapy of infected abscesses with bay - (cfu reduction > log units at mg/kg) was superior to van and lin (no reduction in bacterial load) . furthermore, bay - reduced the overall bacterial load in spleen, liver, lung and heart. in the reduction of organ load, bay - was as efficacious as van conclusions: this dal activity survey indicates that this new glycopeptide has significant gram-positive activity ( . - . % inhibited at mg/l), superior to available agents in the class, and the potency was similar for european isolates when compared with prior experience in other geographic areas. background: tigecycline (tig) is a novel glycylcycline with broad spectrum activity. increasing reports of resistance (r) among commonly occurring gram-positive cocci (gpc) that produce respiratory tract and skin and soft tissue infections has created a need for development of new antimicrobial agents. in this study the activity and potency of tig, tetracycline (tc) and other comparator agents was evaluated using contemporary isolates of commonly occurring species of gpc, including the presence of r organism subsets. table. organism ( methods: the activity of tig and nine comparators was challenged with a collection of gpc including oxacillin (oxa)-susceptible (s; strains) and -r ( strains) s. aureus (sa); oxa-s ( strains) and -r ( strains) coagulase-negative staphylococci (cons); penicillin (pen)-s ( strains) and non-susceptible (ns; strains) s. pneumoniae (spn); penicillin-s ( strains) and -ns ( strains) viridans-group streptococci (vgs); beta-haemolytic streptococci (bhs; strains); and vancomycin-s ( strains) and -r ( strains) enterococci (ent). broth microdilution susceptibility tests were performed and analysed using nccls reference methods and interpretive criteria. results: whereas oxa-r subsets of both sa and cons displayed cross-resistance to tc, macrolides, clindamycin and quinolones, no differences were seen with tig (mic / being . and . mg/l, respectively). among streptococci, all spn and vgs (regardless of pen-s), and bhs demonstrated tig mic / s of . mg/l (one exception being pen-intermediate vgs with the mic at . mg/l). tig was also uniformly active against enterococcal isolates, with mic / s of vancomycin-s and -r subsets being . and . mg/l, and . and . mg/l, respectively. when using the nccls tc s breakpoint of mg/l, all staphylococci, streptococci and enterococci tested would be classified as s to tig. conclusions: tig displays a remarkable spectrum of activity and potency against s and r subsets of gpc with the highest mic being . mg/l. in addition to for use in treating communityacquired respiratory tract infections, tig may also be a candidate for treatment of complicated skin and soft tissue infections and, possibly, urinary tract infections caused by gpc. p endemic, highly resistant acinetobacter in the intensive care unit -is tigecycline the answer? objective: to find satisfactory antibiotic treatment against an organism, acinetobacter baumanii, that became endemic on the intensive care unit of a busy district general hospital. this organism is resistant to many antibiotics and in one case was ultimately resistant to all currently marketed antibiotics. methods: ( ) surveillance of patients in the intensive care unit for the presence of acinetobacter baumanii. ( ) clinical assessment of patients with the organism to establish those needing antibiotic therapy. ( ) patients requiring treatment were given an antibiotic combination using colistin (usually combined with oral minocycline) or tigecycline monotherapy, a first-in-class glycylcycline agent. ( ) treatment and outcome were monitored. the study was observational. allocation to treatment categories was not randomised or blinded. the tigecycline was used on a compassionate basis. results: the intensive care unit was free of acinetobacter until the beginning of . by the end of , - new isolates of acinetobacter baumanii were isolated per quarter. initially these pathogens were sensitive to imipenem, meropenem, tobramycin, amikacin, colistin, and minocycline. this sensitivity began to wane and, by the end of , one patient had died with acinetobacter baumanii in his bloodstream that was resistant to everything available. after this death, we tested further isolates of acinetobacter against tigecycline, a new broad spectrum agent currently in phase development, and found it to be active against the endemic strain. two patients with ventilator-associated pneumonia caused by this organism were treated with tigecycline and made a full recovery. there were no adverse effects related to tigecycline treatment. conversely, five patients with ventilator-associated pneumonias caused by the same organism were treated with colistin and failed to respond. acinetobacter finds the respiratory system a favourable environment, and this, combined with the fact that the vast majority of the patients were ventilated resulted in ventilator-associated pneumonia being the commonest infection. conclusion: tigecycline is likely to be a useful agent in clinical practice on intensive care units when dealing with this difficult organism. further evaluation is warranted. it may well be the antibiotic of choice. p antimicrobial activity of tigecycline (gar- ) tested against enterobacteriaceae, and selected non-fermentative gram-negative bacilli, a worldwide sample r. jones, t. fritsche, h. sader, m. beach north liberty, usa background: as resistances (r) among gram-negative bacilli (gnbs) expand, few antimicrobial agents have been developed to address this clinical problem. tigecycline (tig), a novel glycylcycline, has an expanded spectrum of activity and potency, tigecycline covers many routine gram-negative resistant strains and additionally possesses activity versus some uncommonly isolated non-fermentative gnbs. this study compares tig with contemporary broad-spectrum agents using recent clinical isolates from europe and other continents. methods: all strains ( ) were centrally processed by reference, broth microdilution methods against more than antimicrobials. all concurrent qc results were within nccls published ranges, with identifications performed by traditional methods and/or the vitek system. over isolates were tested from the enterobacteriaceae (ent) and non-fermentative gnbs categories. susceptibility (s) for tig was defined as mg/l, that breakpoint used for all tetracyclines by the nccls. results: the ent were divided into three groups for analysis: esbl-producing isolates ( strains), proteae group ( strains; includes p. mirabilis and indole-positive species) and all enteric bacilli. tig was very active against all esbl-producing isolates (mic , . - mg/l; highest among tc-r subsets), and all ent (mic / , . / mg/l). proteae had a mic at mg/l and all but one of tig-r or intermediate strains (mics, and mg/l) were m. morganii or p. mirabilis. p. aeruginosa was marginally inhibited by tig (mic , mg/l). in contrast, acinetobacter spp. (mic , mg/l; . % s) and s. maltophilia (mic , mg/l; . % s) were readily inhibited by tig. among all ent studied, . % were tc-r, but only one strain (p. mirabilis) was tig-r (mic at mg/l). conclusions: remarkable potency and breadth of spectrum was observed for tig against ent ( . % at mg/l vs. . % for tc), s. maltophilia and acinetobacter spp. limited activity was noted versus p. aeruginosa ( . % at mg/l) and some proteae (mic , mg/l). tig should be of value for the treatment of infections caused by several commonly r gnb groups. background: tigecycline (tig, formerly gar- ), is a novel glycylcycline which is currently in phase clinical trials. the in vitro activity of the tig was evaluated in comparison with tetracycline (tet) and other antimicrobial agents against recent ( ) ( ) ( ) clinical isolates collected worldwide from patients with respiratory infections and meningitis. methods: a total of isolates were tested against tig and more than comparator agents by broth microdilution according to the nccls reference methods and interpretative criteria. the collection included, h. influenzae (hi; strains, % betalactamase-producing), m. catarrhalis (mcat; strains, % beta-lactamase-producing), and n. meningitidis (nm; strains). results: tig demonstrated excellent activity against these organisms with all isolates being inhibited at mg/l (tet susceptibility breakpoint). tig was highly active against hi (mic , mg/l) and mcat (mic , . mg/l), and its potency against these pathogens was not affected by beta-lactamase production. tig was fourfold more potent than tet against hi and tetresistant isolates showed low ( mg/l) tig mics. nm isolates were highly susceptible to tig (mic , . mg/l) and to the vast majority of antimicrobial agents evaluated. conclusions: these results indicate that tigecycline has potent in vitro activity against clinically important gram-negative bacteria that cause community-acquired respiratory infections and meningitis, including tet-r isolates. further evaluations of tig activity, as well as, clinical studies are necessary to assess the role of this compound in the treatment of both community-and hospitalacquired infections. background and objectives: beta-lactamase production is the major mechanism of bacterial resistance to beta-lactam antibiotics in gram-negative pathogens, and surveillance of beta-lactamase determinants is an important issue of microbial drug resistance. given the great diversity of beta-lactamases and their overlapping substrate specificities, molecular analysis is necessary to identify the nature of beta-lactamase genes in clinical isolates. in this work we investigated the potential of the dna microarray technology for a rapid and comprehensive detection of beta-lactamase genes in drug-resistant bacteria. methods: a total of oligonucleotide probes were designed for specific recognition of beta-lactamase genes of different lineages ( of molecular class a, of class b, of class c and of class d). a dna chip was designed including a triplicate set of probes, as well as positive hybridisation controls. the microarray was printed on epoxy-modified glass slides using an affymetrix gms robotic spotter. genomic dna was labelled with cy or cy by random priming. hybridisation signals were then detected using an affymetrix laser scanner and images were analysed by the genepix pro (version . ) software. results: the dna chip was tested with gram-negative strains (including both reference strains and clinical isolates) in which the repertoire of beta-lactamase genes was partially known or unknown. all the predicted beta-lactamase genes (among which there were members of the blatem, blashv, blactx-m, blaper, blavim, blaimp, blacmy-lat groups of acquired genes) were correctly detected by microarray hybridisation. in clinical isolates of unknown beta-lactamase content, the microarray detected genes whose presence was subsequently confirmed by conventional pcr assays. false-positives were observed with a subset of probes, which had to be redesigned to overcome the problem. conclusions: successful detection of several different beta-lactamase genes of clinical importance was achieved by using a dna microchip. the dna microarray technology appears to be a sensitive and specific tool for rapid detection and characterisation of beta-lactamase genes in clinical isolates. objectives: some members of the genus citrobacter are potential pathogens of debilitated hospital patients. they can become resistant to beta-lactamases, including third generation cephalosporins due to over-expression of a chromosomal beta-lactamase. eleven species are currently known, but speciation is often difficult using biochemical tests. isolates previously typed as citrobacter diversus are now known as citrobacter koseri. here we measured sequence variation at the beta-lactamase structural gene amongst a group of clinical isolates, originally identified as c. diversus by api e profiling. methods: nine c. diversus isolates were collected from faecal samples of children being treated in the oncology department of bristol children's hospital in the early s. beta-lactamase and s rrna genes were amplified by pcr and sequenced by standard methods. beta-lactamase induction was attempted in liquid-grown cultures using cefoxitin ( mg/l for h). nitrocefin hydrolysis assays were performed using a spectrophotometer. results: analysis of s rrna gene sequences confirm that, of the nine clinical isolates, five, which all have an inducible betalactamase gene whose sequence is closely related to c. diversus nf and ula , are actually citrobacter amalonaticus. given that c. diversus isolates have all been renamed c. koseri, this error in nomenclature must be addressed. the reason for the error is that c. diversus was known to have variability in its ability to utilise malonate, the only differentiation between c. koseri and c. diversus. four of the test isolates do type as c. koseri using s rrna sequencing. these true c. koseri isolates produce a novel, acidic, class a beta-lactamase, named ckoa, constitutively. the sequence of this beta lactamase gene was determined, and is only % identical to the c. diversus (now c. amalonaticus cdia). conclusions: we present a new beta-lactamase sequence, from c. koseri and shows that c. koseri nf and ula should be retyped as c. amalonaticus. beta-lactamase-specific pcr may provide a valuable tool for typing citrobacter spp. isolates, and is very suitable for separating c. amalonaticus and c. koseri, which are very closely related biochemically. the knowledge that clinical c. koseri isolates produce a beta-lactamase constitutively at low levels may be useful clinically. p a single-tube pcr with mgb eclipse probes for detection of shv-type extended-spectrum beta-lactamases (esbls) a. ekimov, m. edelstein, e. belousov smolensk, rus; bothell, usa objectives: esbls of the shv-type are one of the most common and clinically significant beta-lactamases. the number of shv variants is continuously growing; however esbl activity of shv enzymes has been associated with mutations at relatively few amino acid positions (aa-s) as compared with the tem enzymes. here we propose a simple and rapid method that allows detection of all the known shv esbls in a single real-time pcr reaction. methods: the proposed method is based on amplification of blashv genes in the presence of short ( - nt) fluorogenic probes capable of hybridisation-triggered fluorescence. these probes commercially known as mgb eclipse probes contain a dark quencher with a conjugated minor groove binder at the ¢-end and a fluorescent dye at the -end. this structure allows detection and differentiation of nucleotide polymorphisms at targeted sites by post-pcr melting curve analysis. four probes were designed to perfectly match the wild-type (wt) sequences at mutation sites corresponding to aa-s , , , and . thus, mutations conferring esbl activity were expected to specifically lower the melting temperatures (tm-s) of the probe-template duplexes. each probe was labelled with a unique dye permitting analysis of mutations at multiple sites in a single reaction. results: the method was validated using laboratory strains producing the shv- (wt, non-esbl control), shv- , , , (g s), shv- (g a), shv- (d a), shv- (d n) and strains carrying cloned blashv fragments to which the naturally occurring mutations d g, g d, t s and a v were introduced by site-directed mutagenesis. following careful design of the probes and optimisation of pcr conditions, all the above mutations were successfully detected and discriminated from the wt sequence and each other according to specific tm-s. the detection was precise and highly reproducible in repeated experiments. furthermore, when applied to the analysis of clinical isolates of klebsiella pneumoniae expressing esbl phenotype, the method was able to detect multiple shv alleles (wt and g s or d a) in the same isolates. this observation is particularly important considering the high frequency of co-production of the shv- and esbls in klebsiellae. conclusions: a pcr with mgb eclipse probes has a great potential for studying the epidemiology of shv esbls and possibly for analysis of other antimicrobial resistance mechanisms associated with mutations at defined loci. methods: a total of non-repeat enterococcal blood isolates ( e. faecalis and e. faecium) were collected during to from hospitals located in south east of sweden. the bacterial isolates were identified by standard microbiological methods and susceptibility testing was performed with a -lg gentamicin disk on pdm-agar (ab biodisk) to detect hlgr isolates. all isolates were tested for the presence of the aac( ¢)ie-aph( ¢¢)ia gene using the polymerase chain reaction (pcr) technique. results: there was complete correlation between the gentamicin disk diffusion test and the pcr results. all hlgr isolates, as defined by disk diffusion, and the positive control (e. faecalis atcc ) carried the aac( ¢)ie-aph( ¢¢)ia gene as judged from the pcr results. the resistant gene was not found in the negative control atcc or any of the non-hlgr enterococci. conclusion: this study shows that in our setting the sensitivity and specificity of the disk diffusion method for the detection of hlgr enterococci is very high and there is a total agreement with the results obtained by using a pcr technique for detection of the aac( ¢)ie-aph( ¢¢)ia aminoglycoside modifying gene. objectives: the main objective was to develop a pyrosequencing method for identification of enterococcus spp. species with pyrosequencing method. also, development of antibiotic resistance with special reference to macrolide resistance will be studied by susceptibility testing in samples isolated serially from subject exposed to clindamycin. methods: biochemical identification of the enterococcal strains from faecal samples was done by growth at c, catalase and hydrolyse of -pyrridonyl-beta-naphtylamide (pyr). species identification was done with pyrosequencing method. psq ma pyrosequencing technique enabled identification of different enterococcus species based on their s rrna v -regions signature-sequences. antibiotic susceptibility testing was done by agar dilution method on mü ller-hinton ii medium, according to nccls. mic values were tested against erythromycin, clindamycin, ciprofloxacin, ampicillin, gentamicin, vancomycin and tetracycline. macrolide resistance genes; erm(b), erm(tr) and mef(a) was studied by multiplex-pcr. results: with pyrosequencing method, we identified enterococcus faecium, e. faecalis, e. avium and e. casseliflavus species, and non-enterococci species. the antibiotic susceptibility testing showed that . % of the enterococcus strains were resistant to erythromycin, . % to ciprofloxacin and . % to tetracycline. about . % of the enterococcae had erm(b)-gene. conclusion: pyrosequencing was rapid and easy method for identification of bacterial strains even to the species level. antibiotic resistance varied a lot between different bacterial strains, as e. faecium and e. casseliflavus species being the most resistant ones. pyrosequencing results correlated well with species phenotype and antibiotic resistance. objectives: to determine the species distribution of vancomycin resistant enterococci (vre) isolated from hospitalised patients and detect genes encoding resistance to vancomycin and teicoplanin, by sandwich hybridisation method. and cpha genes by pcr, but not actual enzyme production, may be attributed to so-called 'silent' genes. susceptible strains are known to be able to convert to high-level beta-lactam/carbapenem resistance by increasing the expression of 'nearly' silent metallobeta-lactamase genes. metallo-beta-lactamases have been found to be carried on a small plasmid ( . kb) that appears to be selftransmissible, posing a potential threat of rapid spread of resistance. therefore early recognition of metallo-beta-lactamase producing strains is imperative. to describe the distribution of species in our nocardia isolates and to evaluate the usefulness of an easy and rapid method based on a short battery of susceptibility tests to identify clinical nocardia isolates compared with pcr and restriction analysis of hsp routinely used in our laboratory. methods: nocardia sp. isolated from to were selected to study. molecular identification was performed by hsp pcr-rflp. identification by susceptibility testing was by disk diffusion with gentamicin (cn), tobramycin (tob), amikacin (ak) and erythromycin (e) and by broth microdilution and e-test with ampicillin (amp), ciprofloxacin (c), cefotaxime (ctx) and amoxicillinclavulanate (aug). results: isolates of nocardia sp. were studied. distribution of species according to results from pcr-rflp was: n. asteroides i ( ), n. asteroides vi ( ), n. farcinica ( ), n. nova ( ), n. otitidis-caviarum ( ). n. asteroides i isolates had two different susceptibility patterns, two isolates were cn-s, tob-s, ak-s, e-r and the other two were cn-r, tob-s, ak-s, e-r. all n. asteroides i isolates were amp > lg/ml and c > lg/ml and ctx < lg/ml. eightyseven per cent of n. asteroides vi were cn-s, tob-s, ak-s, e-r, amp > lg/ml, ctx < lg/ml whereas c was variable. hundred per cent of isolates of n. farcinica were cn-r, tob-r, ak-s, e-r, amp > lg/ml, c < lg/ml and ctx > lg/ml. n. nova isolates were cn-s, tob-s, ak-s, e-s, amp < lg/ml, ctx < lg/ml and c < lg/ml. n. otitidis-caviarum isolates were cn-s, tob-s, ak-s, e-r, amp > lg/ml, ctx > lg/ml and c < lg/ml. medium time to obtain results by both methods was h. conclusions: % of isolates belonged to the former n. asteroides complex. n. farcinica and n. nova were easily distinguished from other nocardia species by its susceptibility patterns. the main group n. asteroides vi was more difficult to distinguish from n. asteroides i and n. otitidis-caviarum. a short battery of susceptibility tests permits rapid differentiation of our most frequent nocardia isolates, although genotypic tests are more discriminatory. the ixodes ricinus tick, common ectoparasite of animals and humans, is the main vector of lyme disease in the czech republic. detection of borrelia under microscope, isolation in bsk-h medium and pcr identification was the aim of this work. methods: a tick was crushed in drop of sterile phosphate buffer saline and admired under microscope in dark-field. samples, in which spirochetes had been detected, were incubated in liquid bsk-h medium (sigma) at c and admired weekly for weeks. each strais was passaged twice and was frozen in . -ml aliquots at À c. direct fluorescence assay (dfa) with fluorescein labelled polyclonal antibody to borrelia burgdorferi was used for screening. deoxyribonucleic acid of borrelial strains was isolated with invisorb genomic dna kit iii (invitec). three sets of primers (for b. burgdorferi sensu lato, b. garinii and b. afzelii) derived from srrna gene (rosa and schwan) were used for elementary identification of strains. detailed analysis of strains was made by light cycler real-time pcr (rt-pcr). primers and probe derived from reca gene were used in this method. results: there was a collection of ticks in urban and suburban localities of the czech republic from to years. incidence of spirochetes in tick population differed from to . % in different localities. spirochetes were cultured from at least one of six ticks ( out of ) that were tested positive by dark-field microscopy. all strains reacted positively by dfa and gave positive response with primers specific for b. burgdorferi sensu lato complex. nineteen strains belonged to b. garinii, four to b. afzelii and two to b. burgdorferi sensu stricto genospecies. one strain did not react with srrna primers for b. garinii but had melting temperature of reca gene product identical with b. garinii type strain. we identified the genotype of two strains determined as b. burgdorferi sensu lato neither by pcr, nor by rt-pcr. uors, blood and tissue were subjected to sequencing with the dideoxy chain termination technique using ceq cx sequencer. cultivation, immunocytochemistry and western blots were used for confirmation. results: we cultured four blood, six skin, six csf isolates, numerous tick and two animal isolates. real-time pcr targeted reca, s and ospa genes showed that involvement of the nervous system, joints and skin in czech patients was predominantly caused by b. garinii, serotypes , , ( %), then b. burgdorferi ss ( %) and b. afzelii ( - %). the remaining - % comprise coinfection with anaplasma phagocytophila or mixed borrelial infections. similar results were found in animals. among game animals % tested positive with b. garinii and b. burgdorferi. wild boars and murids hosted borrelia sp. in and % with prevalence of b. afzelii. no significant differences were noticed between the infection of adult and nymphal ticks, both reaching and % in june and september, respectively. diferences were also between regions, in east bohemia with b. garinii prevailing and in moravia with prevalence of b. afzelii and human cases of erythema migrans and acrodermatitis atrophicans. infection prevalence data for patients were in agreement with data for the tick and animals. objectives: the aim of our study was to identify the strains of borrelia isolated from ticks and lyme disease patients in the russian far east and to analyse their taxonomic positions based on ospa gene phylogeny. methods: we have analysed strains of borrelia burgdorferi sensu lato isolated from ixodes persulcatus ticks ( ) and skin biopsies of erythema migrans from lyme disease patients ( ) isolated by standard methods during last years in the russian far east. after amplification with newly designed primers, we obtained full-length ospa gene sequence of each of the strains. results: we identified four strains as b. afzelii completely identical to the strain xj , isolated in japan. all of them were isolated from ticks. the other strains were found to be genetically variable, but the closest homology found was with b. garinii. after phylogenetic analysis of ospa gene we found that these strains form three distinct and well-defined clades at the phylogenetic tree. genogroups and represent only species isolated in the far easter regions of the russian federation and in japan only, whereas genogroup represents mostly european isolates, including seroand genogroups defined in the works of b. wilsske et al. and g. will et al. and four isolates from the russian far east. european serogroups and form the clade localised between genogroups and . human strains were found within genogroups and . conclusion: b. garinii was found to dominate among other b. burgdorferi sensu lato strains isolated from ticks and lyme disease patients form the russian far east. phylogenetic analysis showed that the species identified as b. garinii have significant variability in the ospa gene and form three major groups. two groups consisting only of strains isolated in the far east are significantly remote from all other b. burgdorferi sensu lato species. bootstrap values and distances among these groups suggest their solidity, especially genogroup . this, probably, indicates the distinct origin of defined genogroups and of b. garinii and may suggest another taxonomic status. objectives: for diagnosis of lyme borreliosis (lb) a two-step approach is recommended by cdc and dghm (screening elisa followed by immunoblot (ib) in case of reactive elisa). though borrelia ibs are widely used, they are still poorly defined regarding sensitivity, specificity and standardisation. a recently described recombinant western immunoblot (wib) complemented with borrelia antigens produced in vivo but not in culture (i.e. vlse) could improve previous tests ( ). here a recombinant borrelia line ib (lib) was developed where each recombinant antigen is separately detectable, even those antigens with identical molecular weight. methods: the following recombinant igg and igm ibs were compared: (a) the wib described in ( ) with p /p (strain pko, b. afzelii), p (strain pbi, b. garinii ospa-type ), bmpa (strains pka , b. burgdorferi sensu stricto, pko, and pbi), vlse (strain pka ), ospc (strains pka , pko, pbi, and b. garinii strain ) , and dbpa (strains pko and pbr, b. garinii ospa-type ). (b) the lib with all antigens of the wib and in addition vlse (strains pko and pbi), ospc (strain ple, b. afzelii) and dbpa (strains b and pbi). to verify sensitivity and specificity, sera of patients with early lb ( early neuroborreliosis, erythema migrans) and control sera ( blood donors, rheumatoid factor positive, syphilis patients and patients with fever of unknown origin) were studied. results: ib interpretation criteria defining a serum as positive with at least two reactive bands or in case of igm at least one strong ospc band were used ( ). sensitivity significantly increased from % (wib) to % (lib) for igg and from % (wib) to % (lib) for igm while specificity remained unchanged ( % for igg tests and % for igm tests). the increase of sensitivity was mainly due to the line blot technique, which allows detection and identification of antibodies differently reactive with homologues of the same protein. conclusion: the lib is more sensitive than the wib for both igg and igm antibody detection in acute lb while specificity remains unchanged. the lib is better to standardise and results are easier to interpret. background: tick of the ixodes ricinus group are well known as major vectors of the causative agents of lyme borreliosis, granulocytic anaplasmosis, ehrlichiosis and babesiosis in european countries. the humans infected with these agents can experience a wide range of clinical manifestations. i. ricinus is a widely distributed tick in lithuania and may transmit pathogens to mammalian hosts, including human beings. a single tick may contain several different pathogens so double-infection with borreliosis and ehrlichiosis may be seen. objectives: the aim of this study was to determine whether i. ricinus ticks collected in different regions of lithuania were infected with the causative agents of lyme borreliosis, anaplasmosis, ehrlichiosis and babesiosis agents and to estimate the prevalence of mixed infections in them by pcr. no investigations have been carried out to assess the prevalence of borrelia, anaplasma, ehrlichia and babesia infection in i. ricinus in lithuania using the pcr method before. methods: altogether, i. ricinus ticks collected from different regions of lithuania, were included in this study. all ticks were analysed individually. the presence ehrlichia/anaplasma group pathogen was determined by using pcr with ehrlichia/anaplasma-specific primers hr /ehr , multiplex pcrs using species-specific borrelia primers gi-r/gi-l (borrelia burgdorferi s.s.), gii-r/gii-l (b. garinii), giii-r/giii-l (b. afzelii). real-time pcr method with the abi prism system was used to detect babesia divergens. ehrlichia/anaplasma species were determined using the reverse line blot hybridisation. results: of the individually processed ticks, ( %) were positive for ehrlichia/anaplasma (hge - , hge variant - , e schotii - and were not identified), ( %) for borrelia (b. burgdorferi s.s -one ( . %), b. garinii - ( %), b. afzelii - ( %) and ( %) were positive for babesia divergens. one tick contained both ehrlichia/anaplasma and babesia, two contained both babesia and b. afzelii and one ehrlichia/anaplasma and b. garinii. conclusions: our results represent the first study in lithuania in which borrelia, ehrlichia, anaplasma and babesia parasites were directly identified in i. ricinus ticks by pcr, multiplex pcr, reverse line blot hybridisation and real-time pcr. it was detected that b. afzelii was the dominant genospecies in lithuanian ticks ( %) and ehrlichia/anaplasma and babesia were found in ticks too and might cause human diseases. molecular bacteriology: characterisation of agents p improved automated ribotyping using hindiii to discriminate previously uniform listeria monocytogenes serotype b strains i. heller, k. grif, m. dierich, r. wü rzner innsbruck, a objectives: to develop improved automated subtyping approaches for listeria monocytogenes, we characterised the discriminatory power of different restriction enzymes for ribotyping. pvuii and hindiii were evaluated for their ability to differentiate among isolates representing one of the two major serotype b epidemic clones, having ribotype reference pattern dup- (which differs from the other clone dup- in the ecori pattern only). this is of utmost importance, as the presence of only two major patterns within the serotype b does not allow sufficient epidemiology of listeria infections. methods and results: the eight selected l. monocytogenes isolates (serotype b) with the ribotype reference pattern dup- were responsible for human listeriosis outbreaks in france, canada, switzerland and turkey from to , and for sporadic foodborne cases in austria ( ), england ( and ) and the usa. ribotyping was performed using the riboprinter microbial characterisation system according to the manufacturer's instructions using ecori, pvuii and hindiii as restriction enzymes. we found that the eight isolates belonging to dup- (i.e. indistinguishable by ecori) were also indistinguishable by pvuii but yielded two clearly different patterns when using hindiii. conclusions: we conclude that automated ribotyping using hin-diii allows discriminating previously uniform l. monocytogenes b isolates. this discrimination may facilitate the tracing of outbreaks and may also improve epidemiological surveys. p detection of bft, the isoforms of the enterotoxin gene and cfia gene in bacteroides fragilis isolates of different origins g. terhes, j. soki, k. ago, e. urban, e. nagy szeged, hun objectives: bacteroides fragilis is an obligate anaerobic, gram-negative rod constituting % of the normal intestinal flora of humans, and is the gram-negative anaerobic rod most frequently isolated from human clinical samples. some of the b. fragilis isolates produce a zinc-dependent metallo-protease, enterotoxin coded by the bft gene. this protein has enterotoxic activity; it causes fluid accumulation in a lamb ligated ileal loop model. to date, three different isoforms, designated bft- , bft- and bft- , have been identified. the literature regards the enterotoxin-producing property of b. fragilis as a virulence factor since these strains can be isolated more often from severe infections such as sepsis, or abdominal and deep soft-tissue abscesses. it is also thought to be involved in diarrhoea in - -year-old children. aims and methods: the aim of the present study was to examine the prevalence of enterotoxin production among b. fragilis strains isolated between and from specimens originating in clinical wards of our university or in other hospitals by ht- cytotoxicity testing or pcr detection of the bft gene. the results obtained with the two methods were compared. the frequencies of three alleles of bft genes in enterotoxigenic strains from different sources were determined by using pcr-restriction fragment length polymorphism analysis. the b. fragilis strains can be divided into two major groups by molecular typing methods and most importantly according to the carriage of the cfia gene. we therefore also examined the occurrence of the cfia gene by pcr and the co-incidence of bft and cfia among the above collection of strains. results: the average occurrence of toxigenic b. fragilis strains in the different groups of clinical samples was % and in deep-tissue infections was % by both the pcr method and the cytotoxicity assay. bft genes were found only in the cfia-negative group. the prevalence of the cfia gene corresponded to our earlier findings and data from the literature and we did not observe co-incidence of the bft and cfia genes in this study. introduction: in addition to the two large clostridial cytotoxins (lct -toxins a and b) some strains of clostridium difficile also produce an actin-specific adp-ribosyltransferase (binary toxin cdt). cdt may serve as an additional virulence factor. methods: we used pcr and southern blotting methods for detection of genes encoding the enzymatic (cdta) and binding (cdtb) components of binary toxin in strains isolated from patients with suspected c. difficile-associated diarrhoea or colitis. binary toxin production was assessed by western blotting using antisera against the iota toxin of c. perfringens (anti-ia and ib). toxin activity was detected with an adp-ribosyltransferase assay. pcr amplification was performed to detect the gene encoding for toxin b. binary positive strains were subjected to toxinotyping and were characterised by phenotypic (serogrouping) and genotypic markers (pcr-ribotyping, arbitrarily primed pcr (ap-pcr) and pulsed-field gel electrophoresis (pfge)). results: twenty-two strains (prevalence %) harboured both genes cdta and cdtb; out of the strains reacted with antisera against the iota toxin of c. perfringens; the binary toxin activity was positive in only of the strains. all strains also produced toxins b. however, they had significant changes in tcda and tcdb genes and belonged to variant toxinotypes iii, iv, v, vii, ix and xiii. with typing methods used we could differentiate profiles, indicating that most of binary toxin positive strains were unrelated. conclusion: binary toxin-producing isolates of c. difficile are widespread but prevalence varies from one country to another. more studies are needed to define the role of binary toxin in pathogenesis. clostridium difficile in singapore w.y. leong, r. das ramadas, t.h. koh, k.p. song singapore, sgp objective: occurrence of nosocomial clostridium difficile-associated diarrhoea and pseudomembranous colitis is related to the production of toxins a and b (encoded by tcda and tcdb, respectively) from the pathogen. tcda and tcdb, together with their accessory genes, tcdc-e are arranged within a well-defined chromosomal region termed pathogenicity locus (paloc). another virulence factor, adp-ribosyltransferase binary toxin (encoded by cdt genes) was reported to be found in approximately % of pathogenic strains of c. difficile. despite the availability of a number of detection methods, the identification methods commonly used are not designed to detect all the virulence factors known. we present here an alternative characterisation of the toxigenic and the related genes of c. difficile based on genotyping. the correlation between paloc and cdt genes was also examined. methods: all clinical isolates from singapore general hospital (sgh) were screened with pcr and multiplex pcr for the presence of tcda-e and cdta-b in the paloc region and cdt operon, respectively. the production and activity of toxins a and b were analysed by commercial kit and cytotoxicity testing. results: the isolates could be classified into groups based on the genotypic analysis of the paloc and cdt genes. approximately % of them shared a common profile with the reference strain vpi , and about % were completely devoid of the genes tested. variations demonstrated in tcdc-e were complicated and no specific profile could be attributed to a particular genotype. an atypical toxigenic variant was discovered which contains only tcdb. in contrast to data reported elsewhere, none of the pathogenic strains was found to contain complete cdt genes. when tested for tcda and tcdb production, six strains were identified to be toxins a-negative, b-positive. conclusion: the great genetic polymorphisms displayed by the c. difficile isolates here confirm that these strains were highly heterogeneous and could originate from endogenous source. there is no significant correlation between presence of the structural genes (tcda-b), accessory genes (tcdc-e) and cdt genes. pathogenic strains do not necessarily contain all the genes in the paloc. in conclusion, our results using this toxino-genotyping method for the studies of genetic distribution of toxinogenic genes correlates well with the phenotype of the bacteria i.e. toxin expression. p characterisation of clostridium difficile strains isolated in different time periods and belonging to different ribotypes p. spigaglia, v. carucci, p. mastrantonio rome, i objectives: seventy-four clostridium difficile clinical isolates, collected in different time periods, were typed by pcr-ribotyping. strains belonging to the two main pcr-ribotypes were characterised for virulence determinants and for antibiotics resistance. methods: paloc genes analysis, detection of binary toxin gene and antibiotic resistance determinants (ermb, tetm and catd) were performed by pcr assays. erm(b) sequence type was identified by a rflp-pcr. mics for erythromycin, clindamycin, tetracycline and chloramphenicol were determined by e-test. results: two main pcr-ribotypes named a and r, respectively, were identified. pcr-ribotype a collected strains whereas strains belonged to pcr-ribotype r. old strains (from to ) belonged to pcr-ribotype a, whereas recent strains (from to ) belonged to pcr-ribotype r. all strains with pcr-ribotype a had classical paloc genes and did not have the binary toxin gene. ninety percent of these strains were multiresistant and the sequence type of the ermb genes was similar to that of c. difficile . all strains belonging to pcr-ribotype r had the binary toxin gene, four of them showed major variations in the toxin a gene and % had a mutated toxin negative regulator. none of these strains was multi-resistant although one showed all three antibiotic resistance determinants. fifty three percent had a tetm gene, % tetm and ermb genes and % only an ermb gene with a sequence similar to that of c. perfringens cp . interestingly, as far as resistance is concerned, there was no correspondence between phenotype and genotype in % of these strains. in particular, all strains with a tetm or a catd gene were susceptible to tetracycline and chloramphenicol in vitro, whereas five strains, resistant to erythromycin but not to clindamycin, did not have an ermb gene. all these strains showed, after induction with erythromycin, some clindamycin resistant colonies. conclusions: the results seem to indicate a recent spread of c. difficile clones that add together a potential increase of virulence by acquisition of the binary toxin, variations in genes belonging to the paloc and acquisition of different mechanisms of antibiotic resistance. enterococci are natural inhabitants of the gastrointestinal flora of humans and animals and are widely distributed in the environment. members of this genus are recognised as important opportunistic pathogens responsible for serious infections but the molecular mechanisms of enterococcal virulence are not yet completely understood. in this study enterococci from different sources, including clinical isolates (from human and veterinarian origin), non-clinical isolates and reference strains from enterococcal species, were typified and their virulence potential characterised. the relationships among these enterococci were first analysed using smai pulsed-field gel electrophoresis and m pcr-fingerprinting, in order to evaluate the genomic heterogeneity of the isolates. enterococci were also screened for several virulence traits such as cytolysin (cyl genes), adhesins (agg, esp, efaafs and efaafm genes) and gelatinase (gele), revealing distinct virulence potentials. in enterococcus faecalis, it was recently described that some virulence determinants can be clustered on large pathogenicity islands and not only in pheromone-responsive plasmids. dot-blot dna-dna hybridisation was used to locate virulence determinants in the bacterial genome of the enterococci under study. no conclusive results were obtained for esp and gele, whereas efaafs and efaafm were found on the chromosome as expected. although cyl genes and agg are plasmidic, in most isolates, they were detected on the chromosome of five strains, suggesting that these enterococci may harbour a pathogenicity island. beyond the widespread nature of virulence traits, chromosomal integration of virulence genes seems to occur in different enterococcal species and isolates from non-clinical sources. p identification of salmonella serotypes in sheep by pcr t. zahraei-salehi tehran, ir introduction: salmonella abortusovis, s. dublin, s. montevideo and s. typhimurium are more common serotypes in sheep. one way of transferring of contamination is from visceral organs specially gallbladder, intestine and liver, which can be transferred from meat to human. because of this, this research was essential to consider about it. objectives: ( ) isolation of salmonella serotypes from visceral organs of sheep and goats. ( ) detection of inva gene in isolated serotypes by pcr. materials and methods: for these goals, samples from livers, gallbladders, mesenteric lymph nodes and faeces (totally samples) were taken, and then cultured in enrichment and selective media. doubtful colonies were selected and transferred to tsi agar, urea agar, sim, mr-vp broth and nitrate broth. pcr reaction was carried out in master cycle (eppendorf). for dna extraction isolated salmonella serotypes was cultured in lb broth for h at c. lb broth ( ll) was boiled for min and centrifuged at Âg for min. a total of . ll of the supernatant was used for amplification by pcr with salmonella-specific ( and ) primers. results: three salmonella serotypes were isolated from mesenteric lymph nodes (two cases) and gallbladder (one case). serotyping test showed that two of them belong to group b and one of them to group d of salmonella. when subjected to salmonellaspecific primer inva, all isolates, including positive control, generated a single -bp amplified dna fragment, on . % agarose gel. conclusion: salmonella-specific pcr with primer set inva is rapid, sensitive, and reliable for detection of salmonella in many clinical samples. the present research supports the ability of this specific primer set to confirm the isolates as salmonella. all isolates, including positive controls (s. typhimurium and s. dublin), screened by pcr resulted in -bp amplified product. no amplified products were obtained from negative controls (water and o k escherichia coli serotype). objectives: the variability of salmonella typhimurium strains was studied by pcr-based methods. methods: strains of s. typhimurium were isolated from food or animal sources in the course of surveillance programmes. strains were phagotyped and their antibiotic resistance was determined by disk diffusion method. fluorescent aflp was done using eco-ri and msei enzymes and aflp products were separated by capillary electrophoresis. results: the presence of integrons was analysed in all strains of s. typhimurium and three different integron profiles (ips) were detected by amplification of variable region of the integrons. the ip- profile, characterised by two pcr products of . and . kb, was present in six strains. all these strains were multiresistant with resistance acssut or acssutna. the ip- profile contained single . kb pcr product and was present in six strains resistant to asutmp or assutmp. the dhfra gene was confirmed to be an integral part of ip- integron. a total of . kb pcr product (ip- ) was amplified in two strains sensitive to all antimicrobials. as lysogenic bacteriopahges could frequently transfer their dna into the bacterial cell and thus change chromosomal composition, phage-related sequences were probed in s. typhimurium strains by pcr with primers complementary to four genes of phage p (g , g , eae, eac). three different types of pcr products were detected in multiplex reaction: the presence of g sequence only, the simultaneous occurrence of g and eac or presence of g and g . nine strains did not contain any from the tested phagerelated genes. the relatedness between strains was further monitored by aflp. we observed high strain-to-strain similarity as dice coefficients fell in the range of - %. according to the presence of several dna fragments, strains were separated into eight aflp clusters. conclusions: by comparison of all methods we obtained corresponding results in strain clustering. all methods can be used for subtyping of s. typhimurium strains. producing klebsiella strains isolated from nosocomial infections k. matusiewicz, b. maczynska, d. olejniczak, a. przondo-mordarska, r. franiczek wroclaw, pl objectives: klebsiella bacilli present many pathogenic properties, which determine their ability to survive and rapid spreading in hospital environment. the adhesive properties of klebsiella bacilli associated with the presence of fimbrial and non-fimbrial adhesins play a very important role in pathogenicity of these bacteria. rapid spread of patogenical factors is often connected with presence of their plasmid-mediated genes. the aim of our study was to detect plasmid and chromosomally born fimh and mrkd genes encoding main adhesins: ms and mr, respectively. methods: a total of klebsiella clinical isolates obtained from patients hospitalised in different hospital wards were studied. the phenotypic activity of fimbriae was characterised by haemagglutination method. the genomic and plasmid dna were isolated using manual method as well as qiagen dna kits. the presence of genes encoding main adhesins were detected using pcr-method with primers detected fimh and mrkd genes results: % of strains displayed phenotypic activity of both type and type fimbriae, . % showed only activity of type fimbriae, . % only of type fimbriae and . % strains showed the lack of hemagglutination activity. the percentage of detected genes using pcr, was higher then showed results of phenotypic activity. the presence of mrkd genes was detected in % investigated strains in chromosomal dna and . % showed both mrkd and fimh genes. a total of . % strains demonstrated only fimh genes in chromosomal dna and . % strains showed no genes. in plasmid dna, the presence of main adhesin genes confirmed in % klebsiella strains (mrkd genes in % strains, both fimh and mrkd in % and only fimh in % strains). conclusions: the presence of fimh and mrkd genes in genomic and plasmid dna not always leads to phenotypic expression of fimbrial adhesins. the activity of type fimbriae is connected with chromosomal variant of mrkd gene. in case of fimh genes, the plasmid variant is enough for haemagglutination activity of type fimbriae. the percentage of detected fimh and mrkd plasmid genes depended on hospital units from which these strains were isolated. this suggests the spread of plasmid-encoded adhesins among klebsiella strains. objectives: bacteria of the genus klebsiella are opportunistic pathogens responsible for an increasing number of multiresistant infections in hospitals. the two clinically and epidemiologically most important species, klebsiella pneumoniae and k. oxytoca, have recently been shown to be subdivided into three and two respective phylogenetic groups. the aim of this study was in-depth evaluation of the amplified fragment length polymorphism (aflp) genetic characterisation method. methods: first, we investigated the variability of aflp patterns for klebsiella strains within and between different outbreaks. second, by use of carefully characterised, phylogenetically representative strains, we examined whether different klebsiella species and phylogenetic groups can be discriminated using aflp. twenty-four strains originating from seven presumed outbreaks and non-associated strains were investigated. results: the aflp fingerprints of all epidemiologically associated strains showed three or fewer fragment differences, whereas unrelated strains differed by at least four fragments. cluster analysis of the aflp data revealed a very high concordance with the phylogenetic assignation of strains based on gyra sequence and ribotyping data. the species k. pneumoniae, k. oxytoca, k. terrigena and the possibly synonymous pair k. planticola/k. ornithinolytica each formed a separate cluster. similarly, strains of the phylogenetic groups of k. pneumoniae and k. oxytoca fell into their corresponding cluster, with only two exceptions. conclusion: this study provides a preliminary cut-off value for distinguishing epidemiologically non-related klebsiella isolates based on aflp data, confirms the sharp delineation of the recently identified phylogenetic groups and demonstrates that aflp is suitable for identification of klebsiella species and phylogenetic groups. objectives: k-serotyping, i.e. determination of the capsular antigen, has been the preferred typing method for klebsiella isolates, as it is highly discriminatory ( -types are known) and as k-types are known to differ in their pathogenic potential. unfortunately, k-serotyping requires a large collection of sera and is restricted to a few reference centres. moreover, k-serotyping suffers from cross-reactions and is not applicable to non-capsulated strains. the objective of this work was to develop a molecular method that would enable to determine the k-serotype without using antiserum. methods: we amplified by pcr the capsular antigen gene cluster (cps) and the pcr product ( - kb long) was digested with hincii, followed by agarose gel electrophoresis (cps pcr-rflp). results: the profiles (called c-patterns) obtained for strains representing the known k-serotypes showed four to bands in the size range . - . kb. a total of distinct c-patterns were obtained. the following important observations were made: (i) the c-patterns obtained for strains of any k-serotype were distinct from the c-pattern of all other k-serotypes, with the only exception of serotypes k and k , which are known to cross-react. (ii) for k-types, c-pattern variation was found among strains with the same k-serotype; in most cases, the strains with variant c-patterns belonged to other klebsiella species than the reference strain. thus, cps pcr-rflp has a higher discriminatory power than classical k-serotyping. (iii) within k. pneumoniae, we observed c-pattern identity among strains of a given k-type, for example k or k , that were collected many years apart and from distinct sources. this stability of the c-pattern indicates that cps pcr-rflp is suitable for long-term epidemiology of capsular types. (iv) only . % (compared with - % for classical k-serotyping) of the strains analysed by cps pcr-rflp were non-typable, because pcr amplification failed. (v) the value of cps pcr-rflp for k-serotype determination was tested on recent k. pneumoniae clinical isolates. the k-serotype of ( %) of them could be deduced from the comparison of their c-pattern with the database. (vi) four of five non-capsulated strains analysed showed a recognisable c-pattern. conclusions: cps pcr-rflp allows determination of the k-serotype, while being easier to perform and more discriminatory than classical serotyping, and allowing the characterisation of non-capsulated strains. ( ) the composition of the vaginal microbial community of eight of these vaginal swabs (three grade i, two grade ii and three grade iii), were studied by culture and by cloning of the s rrna genes obtained after direct amplification. ( ) species-specific pcr for atopobium vaginae and gardnerella vaginalis was carried out for all vaginal swab samples. ( ) forty-six cultured isolates were identified by tdna-pcr and cloned s rrna gene fragments were sequenced, yielding a total of species. results: cloning revealed that a. vaginae was abundant in four out of the five non-grade i specimens and that lactobacillus iners was the only lactobacillus species that was present in non-grade i specimens, while it was absent from grade i samples. respectively . % (grade i), . % (grade ii) and . % (grade iii) of the vaginal swab samples were positive for both a. vaginae and g. vaginalis species-specific pcr (p < Á , chi square). discussion: culture independent, molecular analysis revealed a higher microbial diversity in non-grade i specimens than did culture. together, culture, s rrna gene cloning and species-specific pcr point to the presence of nine presumptively novel bacterial species and to a strong association between a. vaginae, g. vaginalis and bacterial vaginosis and to an ambiguous role for l. iners. it appears as if a. vaginae may be a constituent -in low numbers -of the human vagina, possibly attaining replicative dominance in association with decreasing lactobacillary grading. the presence of a. vaginae in bacterial vaginosis(-like) microflora may shed new light on the aetiology of this condition. using multilocus pcr tests with various primers in the genomes of strains isolated in the territories of russia and turkmenistan we were able to detect three housekeeping genes (hapa, toxr, rtxa) and nine virulence genes located in prophages and 'pathogenicity' and 'persistence' islands: ctxphi (ctxa, zot, ace), rs phi (rstc), vpi (tcpa, alda, toxt), vpi- (nanh), epi (mshq). besides, we used the methods of ribotyping and pcr typing which involved the 'random' primer, , to elucidate genetical relationship between the strains of varying epidemic significance. the genome of clinical isolates obtained from patients during several epidemic outbreaks, was shown to be stable and to contain all the genes tested. c. vibrios isolated during the interepidemic period from natural ecosystems, formed a heterogenous population represented by single virulent clones that had retained the complete set of the genes under study, by non-toxinogenic strains, that had lost only individual genes and (or) pathogenicity blocks of genes, i.e. either ctxphi and rs phi, or ctxphi, vpi and rs phi, or by those carrying deficient prophages ctxphi (ctxaÀ zot+ ace+) and vpi (ctpaÀ alda+ toxt+), as well as by clones containing only housekeeping chromosomal genes and sometimes a gene from the 'persistence island'. as soon as virulent clones get into water environment, they lose their virulence blocks in the following order: ctxphi and rs phi, then vpi, gene vpi- being the last one to be lost. in conformity with the results of the above three genotyping methods, epidemically hazardous strains, represented a homogenous group, suggesting a single clonal origin. close genetical relationship between these strains and non-toxinogenic vibrios, that partly retained their virulence genes, was also established. at the same time, as shown by ribotyping and pcr typing studies, avirulent 'water' vibrios formed an independent group, because their genotypes manifested quite distinct features, in contrast to the first two vibrio groups. thus, the observed genotype heterogeneity of el tor cholera vibrios living in water ecosystems was likely to be a result of the loss of dna fragments varying in their length and functions. the genotyping procedures used in the work made it possible to discover evolutional relationships among the bacterial strains under study. bacteroides fragilis gram-negative anaerobic rods, strains isolated in poland and in france (from intestinal and extraintestinal sources) were compared in this study. the identification of bacterial strains was done on the basis of gram staining, growth on selective bbe (bacteroides bile esculine) medium, and biochemical characteristics determined by the api a test (biomérieux, france). for assessment of the presence of enterotoxin (fragilysin) gene in analysed strains, the pcr method was used. dna for pcr was isolated using genomic dna prep plus (a&a biotechnology, poland) and amplification was performed in a techne thermocycler with primers ( ¢-gag ccg aag acg gtg tat gtg att tgt- ¢-tgc tca gcg ccc agt ata tga cct agt- ¢). the pcr program consisted of the following steps: °c for min, cycles of c ( min), c ( min) and c ( min). among the polish strains, contained the fragilysin gene. of the french strains contained the fragilysin gene. for all these strains, pulsed field gel electrophoresis (pfge) was performed. bacteria were suspended in se buffer ( mm nacl, . edta ph . ), embedded in . % agarose plugs and lysed overnight at c. plugs were washed five times in se at room temperature afterwards. dna in the plugs was digested using not i (boehringer mannheim, germany). electrophoresis was performed in a chef mapper (biorad, venendaal, the netherlands). the voltage was v/cm for h with linear ramping from to s at ae angles. in conclusion, % strains isolated in france and % of those isolated in poland contained the fragilysin gene. the pfge analysis revealed that strains isolated in poland and in france show genetically differentiation (these strains are genetically not homogenous). objectives: different molecular mechanisms of resistance to azole antifungal agents, that can exist simultaneously, have been described in candida albicans strains. one of these mechanisms includes alterations in the gene encoding the target enzyme erg . in the present study we used pyrosequencing method to conduct an epidemiologic survey in ketoconazole-susceptible and -resistant strains of clinical c. albicans strains isolated in our region, to determine differences in the gene encoding lanosteroldemethylase (erg ). methods: the strains of c. albicans were obtained by swabbing the oral mucosa of subjects with oropharyngeal candidiasis. susceptibility to ketoconazole was tested using the broth microdilution method recommended by the nccls document m -a. concentrations of ketoconazole tested were in the range . - mg/ml. the mic endpoint was defined as the lowest concentration at which % of growth was inhibited, compared with the drug-free control. yeasts were grown in sabouraud agar and dna was extracted by using qiaamp dna mini kit (quiagen). pcr primers matched an erg gene region of bp. one of the primers of pcr fragment was biotinylated, a single strand of pcr products was obtained with streptavidin-coated beads method. samples were analysed using a psq system with sqa software and sqa reagent. results: a total of . % of strains exhibited dds or resistance to ketoconazole (mic > . lg/ml). the sequence analysis was designed to cover a region of the erg gene including codons - . previous studies showed that in this region, the mutations g s, g s, r k and i t are associated with azole resistance in c. albicans. in our study the sensitive strains have shown no mutations. among dds and resistant strains, only the mutation g s was found in two strains, while no mutations were demonstrated in the remaining isolates. conclusion: this study is the first to use the pyrosequencing system to characterise changes in nucleotide sequence of the erg gene fragment involved in azole resistance of c. albicans strains. the observation of one point mutation in only two resistant strains tested suggests a limited role of the region of the erg gene analysed in the azole resistance among c. albicans strains present in our region. however, the pyrosequencing system has shown to be a fast and specific technique for detection of point mutations in the region of erg gene of c. albicans strains. escherichia coli verocytotoxin variants. correlations to the clinical manifestations s. persson, f. scheutz, k.e.p. olsen copenhagen, dk background: verocytotoxin (vt ) of verocytotoxin producing escherichia coli (vtec) is a potent toxin, capable of producing serious complication, when excreted from the bacteria colonising the intestinal tracts. the mature toxin is composed of one a-subunit and five identical b-subunits, and is encoded by the approximately bp vtx ab operon. based on the variable nucleic acid sequence of both subunits, several toxin variants have been identified. objectives: the subtype designation, important sequence motifs and clinical significance of the vtx variants, are not consistent throughout the literature. to shed more light on these features, a novel typing method was developed for the investigation of subtype-specific correlations to the clinical outcome. methods: the subtyping method relies on pcr and sequencing. by use of vtx universal primers, a -bp fragment covering the most variable regions of subunit a and b was amplified by pcr, and subsequently sequenced. results and conclusion: the present method was used for the analysis of vtx -positive strains from our strain collection, counting strains, isolated from patients with known clinical manifestations (hus, hc, bloody diarrhoea, diarrhoea, fever, etc.). compared with traditional subtyping, our preliminary results indicate that most strains in our strain collection harbour the vtx or vtx c subtype, in addition to a few strains containing the activatable carboxy-terminus of subunit a, referred to as vtx d. correlations between these subtypes and the clinical complications will be presented. additionally, the novel sequences from our strain collection will be investigated for other sequence motifs connected to the clinical outcome. as sequencing has become more accessible and less expensive, we believe that this method, offers a good and reliable alternative for diagnostic subtyping of vtec strains from these infections. p shiga toxin-producing escherichia coli o in slovenia p. zabukovnik, a. andlovic, a. zore ljubljana, si objectives: in the institute of microbiology and immunology (department for bacterial diagnostics of diarrhoeal infections), medical faculty in ljubljana, we wanted to introduce multiplex pcr test for detection of shiga toxin-producing escherichia coli (stec). until recently we used only enzyme immunoassay (eia) to detect production of shiga toxin (stx) in specimens. institute of microbiology and immunology has extensive collection of e. coli isolates from human faeces (mostly from hospitals in ljubljana). we decided to test isolates in our collection from to , with serogroup o . we used multiplex pcr assay that amplified sequences in four virulence genes (shiga toxin (stx ), shiga toxin (stx ), intimin (eaea), enterohemolysin (ehxa)). methods: all isolates were serotyped with rabbit o antisera. we used multiplex pcr to detect presence of shiga toxin , shiga toxin (and sub variants, but did not discriminate between them), intimin and enterohemolysin genes. we also tested those strains for production of stx with eia. results: we tested e. coli isolates with serogroup o and found stec. stx and ehxa genes were present in almost all stec o isolates. the most common pcr profile (five of ) of o isolates had stx , eaea and ehxa genes. one isolate had stx gene but did not produce shiga toxin (or possibly eia did not detect produced shiga toxin). most of those stec o were isolated in summer months of july and august. two o stec were isolated in the year shortly one after another. they had identical multiplex pcr profile. the same happened in the year . conclusion: we notice increase in the number of stec o isolates per year in years after . this may be because of use of better diagnostic methods. in last years stec o with pcr profile stx , eaea and ehxa is dominant. in years to the dominant pcr profile had stx , stx , eaea and ehxa genes. background: chronic prostatitis is recognised to be caused by infectious and non-infectious prostatic inflammation as well as non-inflammatory diseases, but the separation of various prostatitis syndromes is difficult to perform. bacterial prostatitis is a common diagnosis and a frequent indication for antimicrobial therapy. however, confirmation of aetiology of inflammation is exceedingly uncommon. objectives: the aim of this study was to determine the prevalence and aetiology of chronic bacterial prostatitis among the patients with clinically confirmed diagnosis. methods: between october and october the patients with suspected prostatitis were examined. the clinical diagnosis was confirmed in patients within months or greater duration of the following signs and symptoms: perineal discomfort, pain following ejaculation, urinary frequency, urgency, dysuria, low back pain, suprapubic pain, palpation of a tender prostate on physical examination. the bacteriological diagnosis was determined in patients, who had not been taking antibiotics in the previous month, by meares and stamey technique. prostatitis was categorised according to nih classification. results: a total of patients were examined. chronic bacterial prostatitis (nih category ii) was found in nine patients ( . %), inflammatory chronic pelvic pain syndrome (nih category iiia) -in ( . %), non-inflammatory chronic pelvic pain syndrome (nih category iiib) -in ( . %). the following pathogens were isolated in nih category ii: staphylococcus spp. -in three ( . %), anaerobic bacteria (prevotella spp., prevotella spp. and peptostreptococcus spp.) -in three ( . %), escherichia coli -in two patients ( . %), acinetobacter lwoffii -in one ( . %). conclusions: chronic bacterial prostatitis is an important but rare clinical entity. careful examination using quantitative segmented bacteriologic cultures leads to proper categorisation into the recognised forms of the prostatic syndrome. the most common pathogens of chronic bacterial prostatitis were staphylococcus spp., anaerobic bacteria (prevotella spp. and peptostreptococcus spp.) and e. coli. objectives: a prospective multicenter urology outpatient survey, undertaken to examine prostatitis in italy, is used to compare the prevalence, characterisation, diagnosis and treatment of prostatitis patient with the north american (na) prostatitis patient. methods and materials: seventy urologists, representing a crosssection of urologic centres in italy, counted and recorded the overall total male patients reported in the clinic and the overall total patients diagnosed with prostatitis over a -week period. results were compared with published practice prevalence and cohort data (in particular the nih chronic prostatitis cohort study -cpc and seattle prostatitis cohorts) examining similar data in na. results: a total of patients were identified with prostatitis ( . %). the mean age of the prostatitis patients was . (range - ). the most common urinary diseases were benign prostatic hyperplasia ( . %), recurrent urinary tract infections ( . %) and urinary calculogenesis ( . %), while the most common concurrent diseases were diabetes ( . %) and depression ( . %). the most frequently reported and most severe symptoms at time of evaluation were irritative voiding symptoms, perineal and suprapubic pain and discomfort. over three quarters of the patients were dissatisfied with their quality of life. bacteria were cultured in . , . and . % of eps, vb and semen specimens, respectively. comparison to na data suggests that the european prostatitis patient and the european urologists' approach to the diagnosis and treatment of prostatitis are not that dissimilar to prevalence and management of prostatitis in na. conclusion: prostatitis is a common worldwide outpatient diagnosis, comprising a significant percentage of male outpatient visits to urologists in both europe and na. the similarities in prevalence, characterisation and management of the typical prostatitis suggests that an international collaborative research effort is indicated in this important urological condition. observation unit for < h. before discharge ( . %) or admitted ( . %). the two factors that significantly correlate to hospital admission were the severity of uti ( % of complicated ac, % of aup, % of complicated ap and . % of acute prostatitis) and patients' age ( . ae . years in those admitted with complicated ac vs. . ae . years in the non-admitted, . ) . demographic factors, underlying conditions, symptoms and signs, laboratory, radiological and microbiological data, antimicrobial therapy, outcome and final diagnosis were evaluated. results are expressed by percentages or median as appropriate. results: median age was years, % were female and % were nursing home residents. seventy-four per cent were dependent for activities of daily living, % had a permanent urinary catheter and % had cognitive impairment. the most frequent symptoms were fever ( %), decline in function ( %) and dyspnoea ( %); only % referred dysuria. stupor ( %), crackles ( %) and ronchi ( %) were the commonest signs. leucocytosis ( /ul), elevated urea ( mg/dl), respiratory failure ( %) and high c-reactive protein ( mg/l) were the main laboratory abnormalities. pyuria was observed in %, chest x-ray showed a pulmonary infiltrate in %, and % of cases fulfilled criteria of severe sepsis. blood and urine cultures were positive in and % of patients, respectively; gramnegative bacilli (gnb) were found in % of positive cultures, escherichia coli being the most common agent. no pneumococci were isolated either in blood or sputum. amoxicillin-clavulanate was the antimicrobial therapy most frequently administered ( %). median hospital stay and mortality were days and % respectively. urinary tract infection was the commonest final diagnosis ( %). conclusion: respiratory manifestations predominate in disabled old patients with gnb severe urinary sepsis initially diagnosed as suari. respiratory distress may underlie this presentation. further studies are required to support this contention. enterococcus in patients hospitalised through the emergency department d. raveh, i. rosenzweig, b. rudensky, a.m. yinnon jerusalem, il objectives: to determine the incidence of, and risk factors for, isolation of pseudomonas aeruginosa or enterococcus from urine cultures obtained from patients in the emergency department (ed). methods: one year prospective, non-interventional study of all urine specimens collected in the ed, out of which one organism was isolated at a concentration of > cfu/ml. in this study were included all patients with p. aeruginosa or enterococcus bacteriuria (study patients), and control patients with escherichia coli bacteriuria subsequently hospitalised, at a ratio of two controls for each study case. patients were interviewed with a structured questionnaire and charts were reviewed for demographic, clinical and laboratory indicators of enterococcus or pseudomonas bacteriuria as compared with e. coli bacteriuria. results: over the -year study period, positive urine samples were obtained from ed patients: ( %) enterobacteriaceae (including isolates of e. coli) and ( %) other organisms, of which ( %) were p. aeruginosa and enterococcus ( %). comparison with a randomly chosen control cohort of patients with e. coli bacteriuria revealed several indicators for pseudomonas bacteriuria, including male gender (odds ratio . , %ci . - . , p < . ), presence of a permanent urinary catheter (or . , %ci . - , p < . ), past prostatectomy (or . , % ci . - , p < . ), hospitalisation in the previous months (or . , % ci . - . , p < . ), and pregnancy (or . , %ci . - . , p < . ). in addition, both enterococcus and pseudomonas, as compared with e. coli, significantly more often indicated asymptomatic bacteriuria in patients with other diagnoses, as opposed to clinically manifest bacteriuria, than isolation of e. coli (or . , %ci . - . , p < . ). conclusions: pseudomonas ( %) and enterococcus ( %) are isolated from a significant minority of urine samples obtained from ed patients with clinically suspected bacterial infection. isolation of these organisms, as compared with e. coli, more often indicates asymptomatic bacteriuria in patients with other infectious disease diagnoses. in addition, several independent clinical indicators for pseudomonas bacteriuria were identified. these data may assist in selecting optimal antibiotic treatment for patients admitted with suspected urinary tract infection. objectives: certain virulence factors (vf), particularly pap fimbriae, are able to trigger production of cytokines, especially through activation of toll-like receptor (tlr- ), and therefore produce inflammation. the aim of this study was to assess the influence of certain vf in the degree of inflammation in febrile urinary tract infections (futi). methods: from to adult patients with febrile community acquired futi ( female with acute pyelonephritis (mean age (sd ¼ )) and acute prostatitis (mean age (sd ¼ )) caused by escherichia coli were prospectively included. levels of c reactive proteins (crp), white blood cell count (wbcc) and days until apirexia after beginning antibiotic treatment were recorded in all patients and considered as indirect markers of inflammation. genes encoding haemolysin, type fimbriae, pap g fimbriae, cytotoxic necrotising factor, aerobactin and autotransporter toxin were detected by a pcr. additionally expression of type fimbriae and haemolysin were detected by agglutination and growth on blood agar. results: strains carrying pap g fimbriae were involved in futi with higher crp levels than pap g fimbriae negative strains ( . vs. . ; p ¼ . ). the relation between the rest of vf and crp levels did not reach statistical significance. no differences were found regarding the wbcc and the duration of the fever. conclusions: these data indirectly suggest that the degree of inflammation in futi caused by e. coli is associated with the presence of pap g fimbriae, which is coherent with the fact that pap g fimbriae are coreceptors of tlr . mycology: candida and aspergillosis p initiation of an active surveillance programme on yeast-related bloodstream infections in france (aspyrif) an active surveillance program has been implemented in france to prospectively analyse yeast-related blood stream infections. a pilot study was conducted from october through september in medical centres in paris and suburbs. for each patient, one isolate of each identified species was sent to the nrcm together with clinical data filled on a standard form. identification was confirmed using phenotyping tests and a pcr assay was performed on all candida albicans isolates to identify c. dubliniensis. antifungal susceptibility testing to amphotericin b, flucytosine, fluconazole, itraconazole, voriconazole and caspofungin was performed according to eu-cast recommendations. the median age of the patients was years [ - years], with a male predominance ( %). underlying factors for yeast-related blood stream infections were often multiple for a given patient dominated by recent surgery ( %), central venous catheter ( %), hospitalisation in intensive care unit ( %), malignancy ( %), immunosuppressive therapy ( %), hiv infection ( %), solid organ ( %) or bone marrow ( %) transplantation and prosthetic devices ( %). overall, the mortality rate was high with % of deaths within days after the first positive blood culture. candida spp. was the most frequent genus ( %) with c. albicans ( %), c. glabrata ( %), c. parapsilosis ( %) and c. tropicalis ( %) being the most frequent species isolated. other candida were recovered below % (c. krusei, c. kefyr, c. lusitaniae). non-candida spp. were trichosporon asahii, t. mucoides, geotrichum capitatum and cryptococcus neoformans. our data show that the percentage of nonalbicans species equal that of c. albicans among the yeasts recovered during fungaemia. the proportion of the four major species differed significantly according to the presence of central venous catheter (p ¼ . ). analysis of the antifungal susceptibility testing results revealed that most of the isolates had usual antifungal susceptibility profiles. in conclusion, aspyrif is a powerful tool that should allow us to accurately describe the epidemiology of yeast-related blood stream infec-tions in france without restriction to any underlying disease or species. background: nosocomial candidaemia is associated with significant morbidity and mortality in the critically ill. emergence of fluconazole resistance raises further problems, but the newer antifungal drugs [voriconazole, caspofungin, ambisome and abelcet] offer alternative therapeutic options. they also raise the issue of treatment-associated costs. an -year [ to november clinical audit was conducted across two tertiary care hospitals [western infirmary and gartnavel general hospital, glasgow] . the distribution of candida species and fluconazole/itraconazole resistance, with emphasis on high-risk areas was studied. it also addresses the newer antifungal options, cost implications and patient risk-stratification approach. objectives: to evaluate the outcome and complications in patients with candidaemia treated with antifungals. to identify the most common candida species isolated in the vamc patients with candida and evaluate the risk factors and epidemiological data of the patients. methods: all patients admitted in the vamc from august to august with blood cultures positive for candida were included in this study. epidemiological data, medical history, risk factors, co-morbid diseases and laboratory results were evaluated in record review. candida species were identified to determine the prevalence of candida species in the vamc. the patients were assigned to three different groups according to the therapeutic regime provided to the patient by the primary physician. outcome and complications including nephrotoxicity, electrolytes disturbances and hepatotoxicity were evaluated in each therapeutic group. statistical analysis was performed using the spss (statistical package or social science). a regression model was used for the analysis of risk factors associated with mortality in patients with candidaemia. results: one hundred and seven patients were randomised in the study. c. tropicalis was the most commonly isolated candida species %, followed by c. albicans %. mortality rate is high %, especially in those patients infected with c. tropicalis and c. glabrata % (p ¼ . ). the mortality rate increased to . % if no treatment was given (p < . ) and was worse if c. tropicalis was isolated and not treated %. the patients treated had a similar mortality rate irrespective of the administered agent, amphotericin ( %), abelcet ( %) and diflucan ( %), but was worse in those patients admitted to an icu, amphotericin ( . %), abelcet ( %) and diflucan . % (p < . ). response rate in the patients infected with c. albicans was . vs. % in patients with c. tropicalis. nephrotoxicity developed in % of patients and no difference was found in those patients treated with amphotericin b vs. abelcet. conclusion: candidaemia has been increasing in frequency. c. tropicalis is the most commonly isolated candida species in our institution. candidaemia has a high mortality rate and is worse if c. tropicalis is isolated and the patient is admitted to an icu and no treatment is given. there is no difference in response rate within the different therapeutic options. nephrotoxicity is higher in patients treated with amphotericin irrespective of the formulations administered. background: invasive candidaemia is a life-threatening complication occurring especially in hospitalised cancer patients due to surgical operation and application of aggravating chemotherapy. candida colonisation, dysfunction of humoral and cellular immune system and prolonged periods of hospitalisation are considered to be the risk factors of invasive candidaemia development. early diagnosis and evaluation of the risk factors are still a major challenge. objectives: the aim of our study was to evaluate the relationship between the rate of candida colonisation, disorders in immune responses (associated with adverse changes in concentration of tnf-alpha, il- , and myeloperoxidase) and development of invasive candidaemia in hospitalised cancer patients. methods: study group included patients with lung cancer admitted for surgical operation and women with carcinoma ovariorum after the third course of treatment with taxol and cisplatin. patients were examined for fungal colonisation of mucosal membranes with culture methods. presence of candida antigens and dna of the pathogen in the bloodstream was determined with elisa and pcr assay, respectively. cytokine and myeloperoxidase concentration in serum of the patients was specified with elisa commercial kits. results: the study revealed that ( %) lung cancer patients were colonised with candida in nosepharynx before the operation. pneumonia and wound infections were observed in patients of this group, candida albicans was isolated as the only pathogen from three patients colonised previously with candida. in case of patient group with ovariorum carcinoma, colonisation with candida of two or three sites was demonstrated in five ( %) of women. the candida antigen was present in blood in four of them; positive pcr result was found in blood sample collected from one of them. significant relationships between candida colonisation or infection and myeloperoxidase concentration were found ( . - . vs. ng/ml in healthy persons). conclusions: high rate of candida colonisation and drastic decrease in myeloperoxidase serum concentration in patients with lung and ovariorum cancer are predisposing risk factors for invasive candida infection. detection of candida antigens and dna of the pathogen may improve early diagnosis of the candidosis. p evaluation of bact/alert d system to diagnose bloodstream infections due to yeasts p effect of voriconazole on ergosterol content of s. costa-de-oliveira, c. pina-vaz, e. pinto, a. oliveira, c. tavares, a. gonc¸alves rodrigues porto, p voriconazole (vor) is a new azole antifungal agent with a similar structure to fluconazole (flu). as with other azoles, its primary mechanism of action is through disrupting the normal sterol biosynthetic pathway, leading to a reduction in ergosterol content ( ). nevertheless vor is more potent against most candida spp., and shows a wide spectrum of activity. thus candida krusei, which is intrinsically resistant to fluconazole (by unknown mechanism), shows low mic values to vor. this lack of cross-resistance and the fact of being fungicidal to some fungi suggest a distinct mechanism of action. objective: to study the effect of vor on the amount of ergosterol of c. krusei strains, in comparison with flu. methods: the mic to vor was determined according to the nccls protocol m -a on strains of c. krusei, all resistant to flu (mic ! lg/ml). ergosterol was isolated from c. krusei cells by saponification and the non-saponifiable lipids were extrac-ted with heptane. ergosterol was identified by its spectrophotometric absorbance profile ( - nm) ( ). a quantification of ergosterol was determined after incubation with and without both azoles at mic and sub-inhibitory concentrations. results: in all the strains, mic to vor ranged between . and . ug/ml. all c. krusei have a significant amount of ergosterol, with no significant differences among the strains. after incubation with mic concentrations of vor an - % reduction of the ergosterol content was observed. a similar effect was obtained with fluconazole but only with highest concentrations ( ug/ ml). conclusion: the vor induces a considerable impairment on the biosynthesis of ergosterol by c. krusei strains. it is much more potent inhibitor of ergosterol biosynthesis than flu. background: mycotic infections of hospitalised patients are emerging as a significant public health issue. numerous studies have shown that candidaemia is associated with a significant attributable mortality and prolonged hospital stay, but only a few reports analyse the incidence of candida spp. in wounds. objective: to analyse the species distribution and antifungal susceptibility of candida infection in wounds in our hospital during a -year period ( - ) . methods: the in vitro activities of amphotericin b (ab), fluconazole (fz), itraconazole (iz), ketoconazole (kz) and flucytosine were determined by the broth microdilution method following nccls criteria. mics were visually determined after and h incubation at c results: from to we processed wound samples in our laboratory. of these, ( . %) were positive, ( . %) showed bacterial growth without candida and ( . %) with candida. the rate of isolation of candida in wounds/year was as follows: ( . %), ( . %), ( . %), ( . %), ( . %) and ( . %). globally, candida albicans was the most frequently isolated species per patient ( ; . %), followed by c. parapsilosis ( ; . %), c. glabrata ( ; . %) and c. tropicalis ( ; . %). the trends in species distribution were similar in both the adult and paediatric population. the evolution in the successive years of wounds with more than one species of candida was as follows: / , / , / , / , / and / . overall, the percentages of resistance of candida spp. isolated were: ab ( . %), fz ( . %), iz ( %), kz ( . %) and fc ( . %). conclusion: our study shows an increasing presence of candida spp. among the wound isolates in the microbiology laboratory. a high proportion is due to species other than c. albicans and it can be probably attributed to the increase in antibiotic burden in our hospital. infants were performed to estimate disease burden, short-term outcome and microbiological characteristics of causative organisms. methods: prospective enhanced surveillance of invasive fungal infections in vlbw (< g) infants began in february , with cases defined as meeting of one or more of the following diagnostic criteria: ( ) culture from a sterile site -csf, blood (peripheral sample), urine (supra-pubic aspirate or in-out catheter sample), bone/joint, peritoneal or pleural space; ( ) pathognomonic findings on ophthalmological examination; ( ) pathognomonic findings on renal ultrasound examination; and ( ) autopsy diagnosis of invasive fungal infection. cases were identified through three separate surveillance schemes: monthly notifications from paediatricians to the british paediatric surveillance unit; continuous reports from microbiology laboratories to the communicable disease surveillance centre (england) and scottish centre for infection and environmental health (scotland). reports from the three systems were reconciled and analysed. rates were calculated using office for national statistics total live birth estimates. results: between february and july, confirmed cases of invasive fungal infection in vlbw infants were reported, . / births of vlbw. median age at diagnosis was days (range - ) and birth weight ( - ) g. thirty-four of the infants were of extremely low birth weight (< g). candida albicans was the most common pathogen, found in % of cases, and c. parapsilosis in %. organisms were most commonly isolated from blood ( %), followed by urine ( %), csf ( %) and central line tips ( %). just over a third of cases ( %) had received prophylactic antifungal therapy. one case of drug resistance was identified during this period (fluconazole resistance in a non-albicans candida spp.). of the infants for whom outcome data were available, were alive at weeks post-conceptional age. conclusion: preliminary findings from enhanced surveillance suggest an incidence of invasive mycoses in vlbw infants of one in . as per adult cases, c. albicans was the most common fungal pathogen involved, although c. parapsilosis was relatively more common than in adults. the majority of cases occurred in extremely low birth weight infants, and mortality was found to be high. methods: surveillance swabs of throat and rectum were taken on admission and twice weekly afterwards. diagnostic samples were obtained on clinical indication. all samples were processed using standard mycological techniques. overgrowth was defined as ! + or ! yeast cells/ml of saliva and/or gram of faeces. carriage index is the ratio of the sum of all semi-quantitative growth densities of positive surveillance swabs divided by the total number of swabs; on a particular sampling day. oral polyenes were started following the identification of the carrier state. results: a total of children requiring minimally days of ventilation were enrolled in this -year observational, prospective study [ / / to / / ]. the median paediatric index of mortality was . [iqr . - . ], and the actual mortality was . %. enteral polyenes as part of selective digestive decontamination [sdd] were administered to half of the study population [ %] . the median length of stay was days objective: candida dubliniensis is a newly described pathogenic species, first isolated from hiv-infected patients with oropharyngeal candidiasis. it shares many phenotypic features with c. albicans, including the ability to form germ tubes and chlamydospores. these similarities have caused significant problems in its differentiation from c. albicans in routine clinical microbiology laboratories. this study reports isolation and identification of c. dubliniensis for the first time from kuwait and presents data on antifungal susceptibility profile. methods: over a period of months, germ-tube positive yeasts identified as c. albicans and recovered from different clinical specimens were screened for their ability to grow at c on sabouraud dextrose agar. isolates which failed to grow at c were presumptively identified as c. dubliniensis. the identity of c. dubliniensis isolates was further confirmed by formation of rough colonies and chlamydospores on sunflower seed agar, by vitek system, and by semi-nested pcr using species-specific primers corresponding to unique sequences within the internally transcribed spacer (its ) of c. dubliniensis and by direct sequencing of its . the antifungal susceptibility testing was performed on rpmi medium as recommended in nccls, m a document. results: of the germ tube positive yeast isolates, ( . %) were identified as c. dubliniensis. they were isolated from sputum (n ¼ ), vaginal swabs (n ¼ ), endotracheal secretion (n ¼ ), throat swabs (n ¼ ), urine (n ¼ ) and one each from bronchoalveolar lavage, catheter tip and peritoneal fluid. none of the isolates originated from hiv-positive patients. all the c. dubliniensis isolates were susceptible to amphotericin b, fluconazole, itraconazole and voriconazole. however, % of the isolates were resistant to -flucytosine (> lg/ml) without any known previous exposure. conclusion: identification of c. dubliniensis from . % of the yeast isolates in our study suggests that this species is not uncommon in kuwait. there is a need to carry out a systematic study in high-risk patient groups to know its epidemiologic significance. acknowledgement: the work is supported by kuwait university research grant mpi- . background: fungaemia remains a severe nosocomial complication and the emergence of non-albicans species is posing new challenges both to clinicians and to microbiologists. objective: to assess the incidence and clinical presentation of c. glabrata fungaemia, its susceptibility and its clinical outcome. methods: from to , we had episodes of fungaemias and cases corresponded to c. glabrata ( . %). thirty cases were six cirrhosis patients and miscellaneous). following the eortc/msg criteria, these patients were classified as proven ia (n ¼ ), probable ia (n ¼ ), possible ia (n ¼ ) and 'colonisation' (n ¼ ). mean saps ii score was with a predicted mortality of . %. overall mortality was % (n ¼ ). mortality of the proven and probable group was . and . %, respectively. among the patients who survived, just had 'colonisation' with aspergillus. post-mortem examination in the non-haematooncological group was done in out of the patients who died ( %) and / autopsies ( %) showed hyphael invasion with aspergillus (mainly the lung as target organ). there were five proven cases in patients without compromising host factors according to the eortc/msg definitions (three liver cirrhosis, one pneumonia in a -year-old man, one klebsiella sepsis with mof). conclusion: ia is an emerging infectious disease in non-haematooncological icu patients. there seems to be a broad group of patients at risk of ia. ia was diagnosed in patients without characteristics described in the eortc/msg definitions. it seems worthwhile to investigate the validity of the available diagnostic tools in non-haemato-oncological patients at risk for ia in a prospective manner. p epidemiology of invasive aspergillosis in a teaching hospital, france: a -year survey ( - ) a. cornillet, c. camus, s. nimubona, v. gandemer, p. tattevin, c. belleguic, s. chevrier, c. meunier, c. lebert, m. aupée, b. lelong, c. guiguen, j.-p. gangneux for the aspergillosis study group objectives and methods: the aim of this survey was to characterise a file of patients who developed an invasive aspergillosis (ia) in our institution, their risk factors and management. we analysed retrospectively the cases of ia, which occurred between and , then prospectively all new cases until the end of . the overall survey covered a -year period. cases were classified as suspected, probable or proven ia, using criteria derived from the eortc/msg classification. results and discussion: until / , out of the cases of ia analysed, nine were histologically proven, were probable ia and were suspected ia. the sex ratio was . male:one female with a mean age of years (ranging from to years). fifty percent of cases were diagnosed in the intensive care units, and % in haematology units ( % in adults and % in paediatrics). neutropenia was the major risk factor in % of the patients (during haematological malignancies and solid cancers). however, we also noted an increasing number of ia in patients under corticosteroid therapy for cobp, asthma, rheumatoid arthritis, horton and microvascular diseases, in comparison to available data in the literature. other cases occurred in solid organ transplant recipients and only one out of the patients was infected by hiv. prognosis factors will be discussed. regarding biological diagnosis, good sensitivities of the mycologic examination (microscopy + culture) and the galactomannan antigen detection by enzyme immunoassay (platelia aspergillus, biorad) were noted: and %, respectively. the sensitivity reached % when both tests were combined. pulmonary imagery was less efficient, probably due to the fact that, in our institution, ct scans are performed later than proposed in the literature. during this survey, we observed great modifications in therapeutic approaches. first line treatment progressively switched from deoxycholate amphotericin b (amb) to voriconazole and second line treatments now include lipid formulations of amb and caspofungin acetate. amb deoxycholate and voriconazole were the two drugs used for empirical therapy. the overall mortality was > %. conclusion: ia remains a major life-threatening infection among immunosuppressed patients, although protective measures such as air filtration significantly reduced its incidence in neutropenic patients. however, this -year-survey points out the increasing number of cases in non-neutropenic patients hospitalised in wards without air filtration. this emerging population of patients must be taken into account and imposes to reinforce surveillance for high-risk groups and to rethink our preventive measures. priate chest ct appearance) was the sole basis of the diagnosis in ( %) pts. in the remaining seven ( %) pts, positive elisa accompanied either histopathological or microbiological evidence of ia. five ( %) of these pts were later upgraded to definite ia. nineteen of the pts were assessed for efficacy at the end of cas rx. the favourable response rate was % ( / ). pts whose only evidence of ia at cas onset was elisa (and characteristic chest ct findings) had a % ( / ) success rate. follow-up elisa data was available in pts. four of five pts with a favourable response to cas had negative elisa by the end of rx. the one other pt with a favourable response had quantitative elisa improvement that was temporally associated with clinical and radiographic response. of the pts with unfavourable responses and follow-up elisa data, had no elisa improvement and two had normalisation of elisa while on cas. conclusions: in this study, the use of elisa did not result in an exaggerated favourable response rate. in general, the elisa was associated with clinical/radiographic response. paradoxical elisa increases in pts clinically/radiographically responding to cas were not noted. best rapd patterns with respect to number, spreading and intensity of the bands, but the highest level of discrimination was achieved by a combination of data generated by both of them. therefore, we emphasise the convenience of using at least two primers for rapd typing. objectives: to gain insight into the molecular epidemiology of staphylococcus aureus at a tertiary hospital. methods: all s. aureus isolates recovered from blood samples over a -year period were analysed. demographic, clinical and microbiological data from these patients were collected. antimicrobial susceptibility tests were performed by the wider system and the disk diffusion method; all methicillin-resistant s. aureus (mrsa) isolates underwent confirmatory pcr analysis for the meca gene. molecular characterisation was performed by pulsed-field gel electrophoresis (pfge) following dna extraction and smai digestion. patterns differing by less than seven dna fragments and with a dice coefficient of correlation > % were considered a common bacterial type while subtypes included isolates with indistinguishable pfge patterns. univariate and multivariate analyses were performed with epi-info and spss . softwares. results: one hundred and sixty-two episodes of s. aureus bacteraemia, whether methicillin-resistant or methicillin-susceptible (mssa), were nosocomial in origin ( . %) or were cases associated with the healthcare system ( . %). only a total of cases of bacteraemia ( . %), one mrsa and mssa, were strictly considered to be community-acquired. thirty-five unique s. aureus pfge types were identified among dna macrorestriction patterns. within the isolates of mrsa, four major genotypes were identified, with isolates ( . %) represented by a single pfge type. in contrast, the isolates of mssa comprised different pfge types, of which represented more than one isolate. three pfge types were found to represent % of all mssa isolates. these common strains were found with equal frequency among adults and paediatric patients, and were evenly distributed between nosocomial and community-acquired cases. conclusion: our results provide indirect evidence of ongoing transmission of mrsa and mssa in our hospital. in the case of mrsa, the spread is predominantly due to a single clone, with transmission favoured by increased length of stay in hospital and the administration of beta-lactam antibiotics. in contrast, the spread of mssa bacteraemia in this population is associated with multiple, genetically distinct strains. ( ) to use a real-time pcr to detect the presence of meca gene in s. aureus clinical isolates. methods: seventy-three strains obtained from clinical specimens were identified by microscan (dade behring) and coagulase test ( s. aureus, s. epidermidis and other coagulase negative staphylococci). in vitro susceptibility was determined by microscan and disc diffusion. a total of s. aureus strains were classified according to methicillin susceptibility: resistant and susceptible to methicillin. dna was obtained by incubation at c in lysis buffer. real-time pcr was performed in a lightcycler instrument (roche diagnostics, spain) using two commercially available kits: ( ) lightcycler staphylococcus kit mgrade: pcr was positive in all staphylococci and they were differentiated according to melting temperature ( . ae c for s. aureus, and . - c for cns) and ( ) lightcycler mrsa detection kit: pcr was positive in meca positive s. aureus. an internal control excludes the presence of inhibition. once the dna was extracted the whole process takes h. results: twenty-seven out of s. aureus strains were clearly identified by real-time pcr due to the melting temperature (range from . to . c). one s. aureus showed melting temperature of . c. all s. epidermidis strains showed melting temperature from . to . c. s. lugdunensis showed melting temperature of . , . and . c. other cns showed melting temperature from to . c. twenty-five out of ( . %) strains tested were meca positive by using this lightcycler mrsa kit and realtime pcr. among the meca positive, were fenotipically methicillin resistant ( %) whilst four were methicillin susceptible ( %). all meca negative strains were susceptible to methicillin by phenotypic methods. conclusions: real-time pcr (lightcycler) seems to be an accurate method to identify s. aureus and differentiate it from different cns and to detect resistance to methicillin in s. aureus. both reactions could be done simultaneously and the whole process takes less than h (dna extraction plus real-time pcr). objectives: surveillance of methicillin resistant staphylococcus aureus (mrsa) in canada began in . from this surveillance, six epidemic strains of mrsa have been identified and named cmrsa - . in order to better understand the relatedness of these strains, as well as their genetic content, we have used microarrays to compare their genomes to that of the fully characterised genome of the mrsa strain col. methods: genomic dna from representatives of the six epidemic strains, as well as col was fragmented and labelled using random primers with cy or cy labelled dctp. col and each of the epidemic strains (labelled with different dyes) were hybridised to arrays containing pcr products or bp oligomers representing of the open reading frames (orfs) in the col genome. data were processed with the arraypro software package, positive/ negative cut-off values were determined using genomotyping analysis by charles kim and then analysed using the genemaths program. macrorestriction digest patters were generated using smai. results: results indicate that all canadian epidemic strains have six common regions of deletion, a portion of the type i sccmec region, bacteriophage l a, and four smaller areas composed of two to four orfs. the only gene of known function in these smaller areas was the staphylococcal enterotoxin b. apart from these major deletions, many sporadic, single deletions are seen throughout the strains. larger regions of deletion that are not present in all strains also occur. the only obvious orf duplication is of is in cmrsa , and , which is found in multiple copies in the typeiii sccmec region in these strains. macrorestriction digest data were used to approximate the sizes of the cmrsa genomes. cmrsa shows the smallest genome ($ kb), and the least genetic content in common with col ( %). though cmrsa and appear to have larger genomes ($ and $ kb, respectively), they show fewer orfs in common with col than other strains ( and %, respectively), suggesting a substantial portion of the genome may be novel. conclusions: this is the first study of epidemic mrsa using the comparative genomic hybridisation approach. while the cmrsa strains show a high degree of relatedness to col, there are considerable differences in genetic content. this study also indicates that there may be genetic content which is unaccounted for in the col genome. other studies are being devised to identify and characterise the novel genetic content. objectives: in finland, the annual number of mrsa isolates notified to the national infectious disease register (nidr) has constantly increased, especially outside helsinki metropolitan area. molecular typing has revealed numerous outbreak strains of mrsa, and some of them have been associated with community acquisition. we analysed strain types identified by pulsed-field gel electrophoresis (pfge) of mrsa isolates sent to the national reference laboratory (nrl) during - . methods: all isolates of mrsa notified by the finnish clinical microbiology laboratories were sent to nrl for further verification and characterisation, including pfge analysis. pfge profiles differing by fewer than six bands were interpreted as identical or closely related. one isolate per person were included in the analysis. strain types were categorised as sporadic (strain type only found from one person), domestic outbreak or international epidemic (strain type found from more than one person) as well as community-acquired (strain type associated with community acquisition in our previous study). the proportions of mrsa isolates included in each category were assessed. results: a total of mrsa isolates were studied. the number of mrsa isolates increased from in to in . pfge identified more than different strain types. of the mrsa isolates, % were sporadic, % domestic outbreak and % international epidemic. one strain type disappeared compared with years before , and new strain types appeared during - . the proportion of sporadic strains varied between and % during the study period. of the international epidemic strains, bel ec- increased from < % in to % in , mainly outside helsinki metropolitan area. uk emrsa- decreased from % in to < % in , and helsinki i (a representative of mlst st- strains) from to %, respectively. uk emrsa- varied between and %. the three main strains with community-acquisition fluctuated during the study period (range, - %). conclusions: intensive national surveillance with molecular typing revealed that the predominant mrsa strains change over time. the internationally spread epidemic strains of mrsa have also been found in finland. however, most of them show a decreasing trend or have disappeared. these results encourage us to continue aggressive interventions with each new mrsa case. introduction: according to recent studies, community-acquired (ca)-methicillin-resistant staphylococcus aureus (mrsa) strains often contain a type iv sccmec cassette and panton-valentine leukocidin (pvl) locus. it has also been shown that certain multilocus sequence types (st) seem to be connected to ca-mrsa strains from different continents. materials and methods: we studied finnish ca-mrsa strains for their genotype by pulsed-field gel electrophoresis (pfge) and multilocus sequence typing (mlst), the methicillin resistance genes by sccmec pcr and the presence of pvl gene locus by pcr. mrsa was defined as community acquired if the mrsa specimen was obtained outside hospital settings or within days of hospital admission from a person who had not been hospitalised within years before the date of mrsa isolation. to confirm the functionality of the pvl-pcr reaction and the quality of the dna, nuc gene was amplified at the same time. results: the majority of ca-mrsa strains studied ( / , %) possessed sccmec cassette type iv but only ( %) were pvl positive. all but two pvl positive strains contained sccmec type iv. one strain had sccmec cassette iii subtype, and for one strain the type was not determined. the pvl positive strains were mostly ( / , %) of multilocus st . the four remaining pvl-positive strains were of st (two strains) and st and . the sequence types correlated well with the pfge results: all strains with st were analysed as pfge profile hkiviii and strains with st as pfge profile nurmes. st (sccmec cassette -iii subtype) and st (sccmec not determined) strains were considered as sporadic. the pvl negative ca-mrsa strains belonged to different shared and four sporadic pfge profile types. the mlst analysis of pvl negative strains is currently underway. conclusions: most of the finnish ca-mrsa strains have sccmec cassette type iv but only a minority contain pvl gene locus, which is in contrast to previous reports. majority of the pvl gene positive strains possessed st . in spite of the strict definition for community-acquisition we used, majority ( %) of finnish ca-mrsa were pvl negative and showed heterogeneous pfge profiles. objectives: methicillin-resistant staphylococcus aureus (mrsa) is among the major pathogens. the most common methods currently used for identifying methicillin (oxacillin) resistance in many clinical laboratories are susceptibility tests. the performance of these tests has been erratic because the expression of resistance is variable and commonly heterogeneous within strains. methods: a retrospective laboratory-based study was carried out with clinical isolates of s. aureus in a tertiary care providing uni-versity hospital in thrace, greece. methicillin (oxacillin) susceptibility of s. aureus isolates, which were recovered from various clinical specimens (blood cultures, tracheal aspirates, wound swabs and central venous catheters) were studied by four different methods: ( ) agar screening test [mh-oxacillin ( lg/ml) agar supplemented with % nacl], ( ) susceptibility determination by the vitek (biomerieux), ( ) mic was determined by e-test (ab biodisk), ( ) mec-a gene detection by pcr, using specific primers. the strains were evaluated by using the presence of meca gene detected by pcr, as definitive criteria for mrsa and non-mrsa. the susceptibility tests were carried out as recommended by the nccls. results: among all the isolates, were identified as meca-positive and the remaining as meca-negative. the percentages of correct results (% sensitivity/% specificity) were: oxacillin agar screen, / ; e-test, / ; and vitek- , / . ten isolates, negative for the mec-a gene by pcr, were recognised by at least one phenotyping method as oxacillin resistant. only one strain meca-positive was incorrectly identified as oxacillin-negative by the oxacillin agar screen. conclusions: as shown in this and other studies, no phenotypic method is completely reliable for the detection of oxacillin resistance in s. aureus. the specificity was generally high, especially with the agar screening and e-test methods, while the sensitivity varied between the different methods. in particular, the oxacillin screen test is the most accurate test and approaches the accuracy of pcr. although, the presence of the meca gene, as detected by pcr, still remains the 'gold standard', agar-screening test should be considered in association with other susceptibility methods to maximise the ability to correctly detect oxacillin-susceptibility in s. aureus. p amplification of dna fragments surrounding rare restriction sites (adsrrs-fingerprinting) for typing staphylococcus aureus isolated from patients with recurrent furunculosis w. baranska-rybak, r. nowicki, e. scieburako, j. kur, e. arlukowicz, a. samet gdansk, pl introduction: in the present study we report data on phenotypic and genotypic characteristics of staphylococcus aureus strains. the aim of our research was to identify sa genotypes in the patients suffering from recurrent furunculosis. materials: we obtained isolates from patients with recurrent furunculosis. purulent discharge from furuncle, nasal and throat swabs were taken for culture. methods: the identity strain of sa was confirmed by novel dna-typing technique. amplification of dna fragments surrounding rare restriction sites (adsrrs-fingerprinting ) is an effective and rapid method for molecular typing of isolates of bacteria. this method is based on suppression of pcr (polymerase chain reaction) reaction. sa dna was digested with two restriction enzymes: bamhi ( u/ml) (sigma) and xbai ( u/ml) (sigma). cohesive ends of dna were ligated with adapters (xbai short adapter and bamhi long adapter) and amplified. pcr products were electrophoresed on polyacrylamide gels, stained by ethidium bromide and photographed under uv. results: adsrrs-fingerprinting of sa isolates revealed unique patterns. in most cases the strains isolated from the same patient (nose, throat and furuncle) gave identical pattern. the reverse situation was found in five patients. conclusions: ( ) in most cases we confirmed the identity between nasal/throat and furuncle sa isolates. ( ) we found no specific genotype, which is responsible for recurrent furunculosis. ( ) adsrrs-fingerprinting seems to be a very useful method for epidemiological studies of sa. objectives: rapid and efficient epidemiologic typing systems may be useful to investigate dissemination of the lineages of staphylococcus aureus. we have compared the usefulness of well-established methods to those of newly developed rapid typing methods as epidemiological tools. methods: a total of s. aureus isolates were analysed by pulsedfield gel electrophoresis (pfge), multilocus sequence typing (mlst), repetitive-element pcr technique (rep-pcr) based on the presence of dna sequence that are homologous to mp repeat in mycoplasma pneumoniae, multiple-locus variable-number tandem repeat analysis (mlva), and multiplex pcr-based method with primer mix of the spa gene, the coa gene, and the hypervariable region adjacent to meca gene. results: fifty-nine s. aureus isolates clustered by pfge in different genotypes. mlva, which had the highest compatibility with pfge of all testing methods in this study, clustered into different genotypes, multiplex pcr-based method clustered into , and rep-pcr clustered into different genotypes. rep-pcr differentiated s. aureus isolates in a way similar to mlst that clustered these isolates in groups. conclusion: although pfge is still the gold standard, owing to its high discriminatory power amongst molecular typing methods, genotyping methods based on pcr may be useful in respect of speed and ease of performance. mlva, multiplex pcr-based methodology and rep-pcr are rapid, reproducible, and easy to perform. however, mlva and multiplex pcr-based method generate more unambiguous results than those of rep-pcr. objectives: to determine whether the variable visual outcome in endophthalmitis secondary to coagulase-negative staphylococci spp. are due to different strains causing intraocular infection, with a possible difference in virulence of each strain or resistance to the antibiotics given. methods: twenty-eight intraocular samples infected with coagulase-negative staphylococci spp. were analysed using both biotyping and pulsed-field gel electrophoresis for strain identification. the results were correlated with the visual outcome after months post-treatment. results: four different strains of coagulase-negative staphylococci spp. were found to cause endophthalmitis; s. epidermidis, s. haemolyticus, s. equorum and s. warneri. twenty-one out of the isolates were identified as s. epidermidis and the others were grouped as non-s. epidermidis for correlation with the clinical data. comparing the s. epidermidis with the non-s. epidermidis infected cases, it was found that the mean visual gain was significantly better for the non-s. epidermidis infected cases [(mean visual gain of . vs. . logmar letters, respectively) (p ¼ . )].the visual outcome was significantly worse for patients infected with s. epidermidis and antibiotic resistance was more common among these isolates although all were sensitive to at least one of the three/four antibiotics given. comparing the non-s. epidermidis infected cases to the s. epidermidis infected cases that were sensitive to all four antibiotics used, the visual outcome was still significantly better in the non-s. epidermidis group [mean visual gain . vs. . logmar letters, respectively) (p ¼ . )]. use of arbitrarily primed pcr to study salmonella ecology in turkey production environment detection of salmonella serovars from clinical samples by enrichment broth cultivation -pcr procedure p aetiology and resistance of community urinary tract infections in são paulo, brazil: a three-year survey with positive cultures %) positive cultures were analysed in this survey. chi-square test for trend (altman, ) was performed to evaluate the resistance prevalence ordering in the years surveyed (p < . was considered significant). results: among the positive cultures, . % were from female and . % from male patients. among the positive cultures . % presented growth of enterobacteriaceae followed by . % of gram-positive cocci conclusions: an important difference in the resistance pattern was observed among pathogens and age groups. the difference in age groups suggests the possibility of selective pressure due to previous antimicrobial use in the community setting. ciprofloxacin could be used for empiric therapy in community uti. however, its apparent ascending resistance should raise awareness as to possible usage restriction in this setting. surveillance studies are useful for guiding therapy and helping curbing resistance. p resistance of escherichia coli isolates from pregnant and non-pregnant women with community-acquired urinary tract methods: one hundred and forty-four non-pregnant and pregnant women with signs of upper or lower communityacquired uncomplicated utis were enrolled in two multicentre prospective epidemiological studies (eight medical centres), utiap- and arimb, respectively. the strains isolated from the patients who had significant bacteriuria (> cfu/ml) were included in the microbiological analysis. the mics of antibiotics (ampicillin -amp, amoxicillin-clavulanate -amx-clv, cefuroxime -cfr, cefotaxime -cft, gentamicin -gnt, co-trimoxazole -ctz, nitrofurantoin -ntf, fosfomycin -fsf) were determined by the agar dilution, as described in the nccls ( ) guidelines. quality control was performed using reference strains including e. coli atcc , e. coli atcc . results: resistance rates of e. coli from pregnant and non-pregnant women with ca-uti in russia are shown in figure. there are some statistically significant differences in antimicrobial resistance between studied groups. ampicillin resistance was higher among uti isolates of e. coli in non-pregnant women ( . %) than in pregnant women ( . %), p < . (chi-square statistic) methods: consecutive patients with presumed uti were included during days if they were older than years and had a positive urine dipstick. subsequently, urine culture (uc) was prescribed and patients classified according to nine uti categories. centres were also required to notify all visits motivated by infectious diseases (id) during the study period. results: of potential participants, included uti period, prevalence of id is estimated at . % of nontrauma visits and prevalence of uti at . % of all id. the main uti categories were acute cystitis (ac ¼ . %), acute pyelonephritis (ap ¼ . %), bacterial prostatitis (bp ¼ . %). mean age of patients was . ae . years and sex ratio f in %. however, both differ significantly according to uti category all bc received in the microbiology service were included in our study. all the specimens were performed with bact/alert d (biomerieux) initially during days or days in special cases related to the detection time in aerobic bottles, . % gave a positive result in the first h of incubation (average . h) cumulative percentage of % at h. in the second day, . % were positive. in anaerobic bottles . % gave a positive result in the first h of incubation (average . h) cumulative percentage of . % at h. in the second day . % were positive. candida albicans was isolated in . % cases methods: from / / to / / we studied all yeasts considered pathogens from all body sites, from paediatric pts in all in-hospital locations. isolation and yeasts species identification were carried out by conventional methods. on isolates, flu and vor susceptibilities were assessed by the nccls m -p method, with disks tested in mueller-hinton medium with glucose and methylen blue, . macfarland inoculum. all susceptibility test results were read by biomic plate reader system (giles scientific). c. albicans (ca) atcc was included. nccls flu breakpoints (mcg/ml) were s < , s-dd - , r > with corresponding zone interpretative criteria (mm) s > , s-dd - , r < . breakpoints for vor have not yet been established. results: in the study period we recovered ca, c. parapsilosis (cp), c. tropicalis (ct), two c. krusei, two c. glabrata (cg), two c. lusitaniae (cl) and one tricosporon beigelii. species were isolated: % from urinary tract, %, upper respiratory tract, % miscellaneous fluids, % lower respiratory tract, % blood, % cvc, % various. patients with yeasts infections were hospitalised: % in picu/nicu, % haematology-oncology, % surgery, % infectious diseases, % nephrology, % pneumology, % medicine, % orthopedics, % dermathology. distribution of bloodstream isolates were: four cp, three ct, one ca and one cl. seventy percent of cp strains were recovered from picu/nicu pts. the average zone diameter (mm) -mic /mic (mcg/ml) (agar disk gradients) were: ca flu flu with vor mics > mcg/ml, one ct was flu sdd, one gg was r to flu and inhibited with . mcg/ml of vor. conclusions: our results show that ca is still the predominant species recovered from paediatric pts; cp and ct appear to be recovered with increased frequency in serious infections of critically ill pts p trends in species distribution and antifungal susceptibility in candida wound infections: an overview of a -year period when compared with c. albicans, patients with c. glabrata fungaemia were older ( vs. ), had received more previous antifungals ( vs. %, p ¼ . ) and antimicrobial agents ( vs. %, p ¼ . ), had more indwelling bladder catheters ( vs. %, p < . ) and had more septic metastasis ( vs. %, p ¼ . ). iv catheters were more commonly withdrawn in patients with c. glabrata fungaemia ( vs. %, p ¼ . ), whereas these patients received fewer antifungals ( vs. %, ns). mic of c. glabrata were fluconazole (flu) mg/l, itraconazole mg/l, amphotericin b (amb) mg/l and voriconazole . mg/l. surprisingly, flu was more frequently selected to treat patients with c. glabrata ( vs. %). mortality was similar ( vs. %). six of the patients treated with flu died, as well as four of the seven treated with amb. two patients had persistent fungaemia despite catheter withdrawal and flu therapy cs p invasive aspergillosis in patients with copd of patients with copd and aspergillus spp. in respiratory samples to determine risk factors and outcome. results: we identified patients with copd and aspergillus spp. in respiratory samples. median age was ae . years. eighty-three percent were men. forty-one patients had criteria for 'probable' ifi none of cases had criteria to suspect an ifi, however, nine were treated and all but one died. the remainder were colonisations. conclusions: a progressive increase of copd patients with aspergillus spp. has been observed but frequently, this is a colonisation. however, we observed that patients in 'probable' category have a high rate ( %) of 'proven' ifi, similar to other known risk groups. we think that these categories could help in clinical practice and to identify homogeneous groups for clinical research in diagnostic methods and therapeutic interventions p evaluation of serum galactomannan elisa during caspofungin therapy: results from the caspofungin salvage invasive aspergillosis study a sandwich elisa assay, which detects circulating aspergillus galactomannan antigen using a rat monoclonal antibody has recently been licensed (plateliaâ, biorad). yet, animal models of ia have shown that treatment (rx) with an echinocandin may result in a paradoxical increase in antigenemia despite clinical/radiographic improvement. concern also remains that using elisa as the sole means of ia diagnosis may result in exaggerated favourable outcomes. to address these concerns, we reviewed the elisa experience from the caspofungin (cas) salvage invasive aspergillosis (ia) study. methods: patients (pts) with proven/probable ia were eligible for enrolment. probable ia was limited to pulmonary sites. probable pulmonary ia could be diagnosed serologically provided the pt had an appropriate chest ct appearance (halo sign, air-crescent sign) and positive elisa on more than two consecutive tests. all pts were refractory (> days) or intolerant of prior antifungal rx. cas, with doses ranging from - mg/day, was administered as monorx. efficacy was assessed at the end of cas rx. favourable responses were limited to complete or partial responses. results: of the pts enrolled, ( %) had consecutively positive serum elisa at the onset of cas underlying diseases were: lymphoid: %; myeloid: %; non-malignant: %. clinical efficiency of the test was tested at three different cut-off values . , . and . . results: results are summarised in the table. the overall incidence of invasive aspergillosis (ia) was . % ( / admissions). following eortc definition criteria, the repartition was: two definite ia, probable ia and possible ia. the definition of 'probable' ia was substantiated by positive gm antigen tests (eight cases); both by microbiological (positive cultures) and positive gm antigen tests (four cases) or only by microbiological criteria (four cases). gm antigen was detected at all different cut-off values in cases corresponding to: / definite ia, / probable ia. results were considered as false-positives in patients: four cases without clinical context; cases with a negative chest ct-scan conclusion: detection of circulating gm antigen may be helpful for the diagnosis of ia, particularly in the absence of microbiological data, but a substantiated number of false-positive results do occur among patients undergoing antibiotic therapy with pipera/ tazobactam or amoxi/clavulanate. considering different cut-off values did not improve the sensitivity or the specificity of the assay a results were reported as the number of isolates of each species per plate of the pair. results: a total of pairs of samples were evaluated. of these, showed growth of mucor spp. ( in sd and two in czapeck) and could not be studied for aspergillus. of the remaining pairs, pairs ( . %) were positive for aspergillus spp a. fumigatus was the most frequently isolated species, pairs ( . %) were positive [ ( . %) on both plates, ( . %) only in sd and ( . %) only in czapeck conclusions: our data supports the recommendation that both media (czapeck and sd) should be used for correct air sampling antifungal combination of caspofungin with flucytosine has been shown to be additive to synergistic in vitro against aspergillus fumigatus. the aim of the present study was to evaluate the interaction between these two drugs in vivo in an animal model of disseminated aspergillosis. methods: for in vivo experiments survival rates of mice treated with the combination of caspofungin at . mg/kg/day with flucytosine at and mg/ kg/day were and %, respectively. mice treated with caspofungin at . mg/kg/day combined with flucytosine at and mg/kg/day had a and % survival the study was performed on strains of enterococci all from patients with severe underlying diseases. strains were isolated from urine ( . %), blood cultures ( . %), pus ( . %), peritoneal fluid ( . %), intravenous catheter ( . %), infection of the drainage site ( . %). identification to the species level was performed by vitek (bio-merieux, france). antibiotic susceptibility testing was done by kirby-bauer and mic by e-test and vitek . the sandwich hybridisation method was performed in all strains using the commercially available evigenetm vre detection kit (statens serum institute), for the presence of vana and vanb genes.results: from the stains tested, were vancomycin and teicoplanin resistant (vana phenotype) and susceptible to these antibiotics, as determined by kirby-bauer and mics by vitek and e-test methods. of them, were e. faecalis, e. faecium, three e. casseliflavus and two e. hirae. all the vres strains, which were suggesting the presence of vana phenotype by kirby-bauer and mic, were identified to be vana positive by the sandwich hybridisation method. the susceptible strains were negative for the detection of the genes vana and vanb. conclusions: identification of vre to the species level and knowledge of the type and the profile of resistance is critical for infection control purposes in the hospital environment. the sandwich hybridisation is a rapid ( . h) and easy to use commercially available molecular method to detect the vana and vanb genes, while the phenotypic resistance determination requires incubation for at least h and other molecular methods require specific instruments and experienced technicians. the sensitivity and specificity of the method is %.p evaluation of the evigene tm vre detection kit for detecting of enterococci including vancomycin resistance genes a. kilic, m. baysallar, g. bahar, a. kucukkaraaslan, l. doganci ankara, tr objectives: evaluating the correlation of the evigenetm vre detection kit using pcr, which is the golden standard for gene detection and correlating the minimum inhibitory concentration (mic) for vancomycin and teicoplanin are the aim of this study. methods: the vancomycin-resistant enterococci (vre) detection kit is based on microwell plates where to dna probes specific for the bacterial targets dna are bound. test wells include: a positive ( s rrna) and a negative control, a vana microwell and a vanb microwell. the pcr detects the vana, vanb, and vanc- genes. the mic determination was performed by e-test according to the nccls guidelines. results: we tested a total of diverse vancomycin resistant enterococci: enterococcus casseliflavus (n ¼ ) and enterococcus faecium (n ¼ ). all strains were vana positive (od: all strains > . ). all results obtained with the vre kit were confirmed by the pcr. the mic determination correlated with the pcr and kit results for all vana positive strains with high mic for vancomycin. conclusion: as a result, the evigene vre detection kit can clearly distinguish vre with the vana and vanb genotypes among a large collection of enterococci and with the same specificity as pcr.p development of antibiotic resistance in enterobacteria s.d. nyberg, a. hakanen, m. Ö sterblad, p. huovinen, c. edlund, j. jalava turku, fin; stockholm, s objectives: the main objective is to get a better knowledge of the human microflora in gastro-intestinal organ by following variations among intestinal enterobacteria in four healthy subjects receiving oral clindamycin. the microflora in the chosen subjects will be monitored for a -year period. the presence and stability of specific resistance genes will be studied in samples collected serially from selected antibiotic exposed subjects. blatem and blashv that code for an extended spectrum beta-lactamase in enterobacteriaceae will be studied. the study will be done by using identification, susceptibility testing, pcr and molecular fingerprinting methods. methods: serially collected faecal samples from four healthy subjects who had received clindamycin perorally for days were cultured and screened for enterobacteriaceae. sampling was performed pretreatment, day , weeks, , , , and months after clindamycin administration. between and colonies of suspected enterobacteriaceae were picked from each sample. biochemical identification of the bacterial isolates was done by oxidase, indole production and activity of beta-glucoronidase. mics were determined according to nccls by standard agar dilution method on mü ller-hinton ii medium. the following antimicrobials were tested: ampicillin, cephalothin, cefuroxime, piperacillin/ tazobactam, amoxicillin-clavulanic acid, ceftazidime, cefotaxime, imipenem, aztreonam, gentamicin, streptomycin, chloramphenicol, tetracycline, nalidixic acid, trimethoprim, sulfamethoxazole and ciprofloxacin. results: a total of isolates were identified as oxidase negative, gram-negative rods and thus belonged to the enterobacteriaceae. the isolates were then screened for indole and betaglucoronidase activity. these results showed that % of all strains were e. coli. of all strains, % were resistant to ampicillin, % against sulfamethoxazole, . % against cephalothin and . % against nalidixic acid. the variation of antibiotic resistance between subjects is broad. conclusion: enterobacteriaceae are naturally resistant to clindamycin. however, after clindamycin treatment alterations in the susceptibility to other antimicrobial agents still occur in the microflora. additional research needs to be done to clarify if these alterations in antibiotic resistance are caused by variation of strains/species or exchange of resistant elements.p prevalence and implication of the cfia and cpha genes in imipenem resistance among bacteroides spp.m. theron, m.n. janse van rensburg, c. roussouw bloemfontein, za objectives: bacteroides is a major cause of intra-abdominal and female genital tract infections as well as subcutaneous abscesses. beta-lactam agents and carbapenems are currently used in monotherapy against anaerobic infections. the study was done to: ( ) investigate the susceptibility of bacteroides strains isolated from bloemfontein academic hospitals; ( ) compare results with a previous study; ( ) determine the prevalence of carbapenemases/ metallo-beta-lactamases in bacteroides spp. methods: fifty-one bacteroides spp. strains were isolated from patients in the universitas and pelonomi hospitals in bloemfontein. mics of antimicrobial agents were determined by the nccls agar dilution method. a bioassay was used to screen for carbapenemase or metallo-beta-lactamase production. pcr amplification was performed for the detection of cfia and cpha genes. plasmids were extracted using a high pure plasmid isolation kit. results: susceptibility levels were relatively high for imipenem ( %), meropenem ( %) and metronidazole ( %). comparing the results with a previous study (isolates from / ), showed a reduction in susceptibility to imipenem ( - %), meropenem ( - %) and metronidazole ( - %). the bioassay results gave no indication of the presence of significant concentrations of a carbapenemase or metallo-beta-lactamase. pcr amplification showed the cfia gene ( bp) in / strains (imipenem mic to > lg/ml) and the cpha gene ( bp) in / of the isolates (imipenem mic - lg/ml). no plasmids were detected. conclusions: although > % of the isolates were susceptible to the carbapenems, it is evident that resistance has increased over the last decade. fortunately the production of metallo-beta-lactamases has been found to give rise to mics that only range from to lg/ml. this study supports these findings with the exception of one isolate with a mic > lg/ml. demonstration of the cfia p application of molecular biological techniques to the study of alterations in hamster gut microflora and assessment of treatment with saccharomyces boulardii l. coroler, g. philippe-taine, e. bayart, t. cécile, j.-m. gillardin, h. goïot compie`gne, f objectives: studies of the intestinal microbial ecosystem by classical culture techniques suggest that only % of the microflora can be cultured. pcr procedures based on s rrna gene specific for bacteria were developed to detect bacterial populations in hamster faeces. methods: a total of populations of bacteria were characterised by their genomic dna sequences and targeted by pcr probes: actinomyces group, bacteroides distasonis, bacteroides fragilis, bifidobacterium group, b. adolescentis, b. angulatum, b. catenulatum, b. infantis, b. longum, clostridium group, c. clostridiiforme, c. coccoides, c. difficile, c. leptum, c. perfringens, fusobacterium prausnitzii, lactobacillus group, peptosteptococcus productus, propionibacterium group, pseudomonas aeruginosa, ruminococcus obeum, citrobacter group, c. freundii, escherichia group, enterobacteria group, enterobacter cloacae, morganella morganii, proteus mirabilis, staphylococcus group, salmonella group. results: sensitivity was measured by extraction of total genomic dna and pcr amplification and a significant detection level of bacteria/faecal sample was obtained. qualitative variations of bacteria population were observed during the first weeks of acclimatisation, suggesting a stabilisation period for hamster microflora in new environmental conditions. after oral antibiotherapy, with one dose of mg/kg amoxicillin-clavulanic acid, some groups were eradicated from hamster faeces: propionibacterium, staphylococcus and c. leptum, c. clostridiiforme. as reported in the literature, no antibiotic effect was observed on levels of dominant faecal groups: bifidobacterium, peptostreptococcus. antibioticassociated perturbations are linked with the disruption of the normal intestinal flora leading to a colonisation of pathogen bacteria species. in order to understand the role of saccharomyces boulardii (s.b.) in prevention of antibiotic-associated diarrhoea,  cfu/kg/day of s.b. were administered to hamsters during oral antibiotic treatment. the results showed that populations that were eradicated by antibiotic administration remained expressed and stabilised with concomitant s.b. treatment, suggesting an effective protection by s.b. on the intestinal flora. conclusions: these pcr results should be used to quantify the intestinal microflora by dna microarray analysis. objectives: the acinetobacter calcoaceticus-acinetobacter baumannii complex (acb complex) includes a. calcoaceticus (genospecies ), a. baumannii (genospecies ), unnamed genospecies and tu. these species are difficult to differentiate by phenotype. in this study, the feasibility of using sequences of the s- s rdna spacer region (its) for identification of the acb complex was evaluated. methods: the bacteria-specific universal primers bf (gtgaa tacgt tcccg ggcct) and r (gggtt ycccc rttcr gaaat) (y ¼ c or t, and r ¼ a or g) were used to amplify a dna fragment that encompassed a small portion of the s rdna region, the its, and a small portion of the s rdna region. the its regions from reference strains ( species) of nonfermenters including strains of acb complex were amplified by pcr and sequenced; the sequence data in combination with those available in genbank were used to construct an its sequence database for the identification of acb complex. for reference strains of each species of the acb complex, the sequence similarities of the its regions were obtained by comparing their its sequences with that of the type strain of the same species. the database was used to test clinical isolates of acb complex, including isolates of a. baumannii and isolates of a. calcoaceticus, as identified by api ne. results: a. baumannii had the shortest its fragment ( - bp) followed by genospecies tu ( - bp), genospecies ( - bp) and a. calcoaceticus ( - bp). the intraspecies its similarity of the acb complex was very high, ranging from . to . , whereas the interspecies its similarity was relatively low (range: . - . ). among the clinical isolates of a. baumannii, two isolates were genospecies and isolates were ungroupable, as revealed by its sequence analysis. therefore, about % of clinical isolates of a. baumannii was misidentified. furthermore, among the clinical isolates of a. calcoaceticus, isolates were genospecies and three isolates were ungroupable. therefore, the designation of a. calcoaceticus to clinical isolates is, under most conditions, not correct. these results were confirmed by amplified rdna restriction analysis (ardra). conclusions: its sequence analysis provides a simple and useful alternative for species delineation of the acb complex. objectives: enteroaggregative escherichia coli (eaec) are increasingly implicated in acute and persistent diarrhoea around the world. phenotypically, eaec have a defining 'stacked brick' pattern of aggregative adherence (aa) to epithelial cell lines in vitro. genotypically, they are diverse, and while a range of eaec pathogenicity factors are known, their distribution amongst strains varies. the most widely used dna probe for eaec is cvd , which has been reported to have limited sensitivity in some studies, but it is presumed to be specific for eaec. the aim of this study was to determine whether the cvd probe is a specific tool for identifying eaec strains imported into the uk. methods: a total of e. coli isolates (four per patient) were obtained from consecutive stool samples of diarrhoeal patients with a recent history of foreign travel ( different countries). all were screened for hybridisation with the cvd probe, as well as eaec plasmid encoded virulence factors aggr (aggregative adherence regulator), aap (dispersin) and the chromosomal pathogenicity-island-encoded mucinase pic. other pathogenic e. coli were identified using standard probes. cvd probe positive strains were then examined for adherence to hep cells after coincubation for h. results: the prevalence of eaec-associated genes amongst the isolates was: cvd . %; aggr . %; aap %; pic . %. adherence assays on the isolates that were cvd positive revealed a mixture of aggregative ( isolates) and non-adherent strains (nine isolates) plus isolates that gave an unusual pattern of loose, highly localised aggregation, present on < % of the hep- cells. of the cvd positive strains, % were aap, aggr, and pic positive as well, but this group also contained strains of all three adherence types. none of the other eaec-associated probes was unequivocally predictive of actual aa among cvd positive strains. unexpectedly, cvd positive isolates that hybridised with the enteropathogenic e. coli probe eae were isolated from one patient (returning from turkey). conclusions: this study suggests that the cvd probe may not be specific for true eaec, even when combined with the other probes used here. the significance of the newly described adherence pattern in relation to diarrhoeal disease remains to be elucidated, as does the finding of e. coli with both eaec and epec properties. objectives: otomycosis represents a significant percentage of clinical external otitis and is usually caused by candida, aspergillus, penicillium and malassezia. clinical symptoms such as otorrea, erythema and stenosis of the external auditory canal are commonly present and create appropriate conditions for fungal growth. the objectives of this study were to determine the prevalence of candida otomycoses and to evaluate the relationship between albicans and non-albicans species. methods: from april to november , a total number of patients were found to be suffering from symptoms indicating otitis externa. the specimens were taken by cotton swab from bony portion of external ear. all specimens were inoculated on sabouraud dextrose agar, incubated at and c for days and examined macroscopically every day. suspected cultures were examined microscopically in order to confirm finding of candida spp. the identification of isolated candida strains was carried out by germ tube test and api c aux assimilation test (biomerieux, france). results: in a base of microbiological findings ( . %) patients considered to be negative, ( . %) confirm bacterial or mould results and in ( . %) patients candida spp. was found. out of patients with diagnosed candida otomycosis, in patients only candida spp. was isolated and in five patients otitis externa was caused by candida associated with bacterial or mould infection. c. albicans was identified in three ( / ) cases, while all other was non-albicans strains as three cases of c. guilliermondii ( / ), four of c. famata ( / ) and six of c. parapsilosis ( / ) . conclusion: in clinical finding of otitis externa mycological examination could be very important in setting the accurate diagnosis and appropriate therapy. these results suggest that c. albicans is not the predominant causative agent of otitis externa. isolation of non-albicans species has particular interest in therapy of otitis externa because of their reduced susceptibility to antifungal agents. the study was focused on the species involved and their in vitro antifungal susceptibility. molecular typing of the isolates involved in subsequent episodes of rvvc allowed establishing if the strains showed the same dna type. methods: isolates were identified by standard morphological and biochemical methods. mics of amphotericin-b, itraconazole, fluconazole, ketoconazole, -fluorocytosine, voriconazole were determined by sensititre yeastone colorimetric antifungal panel plates according to nccls document m -a. the strains were typed using pulsed-field gel electrophoresis (pfge) and repetitive extragenic palindromic-pcr dna fingerprints. results: c. glabrata was isolated in . %, c. albicans in . %, c. krusei in . % of cases. the yeasts involved in each recurrence were characterised by identical biochemical profiles and drug resistance phenotypes. c. albicans strains isolated from one rvvc resulted in in vitro resistant to azoles. the genotyping by pfge revealed that c. albicans and c. glabrata obtained from different patients were clinically unrelated to each other while an identical profile, indicating clonal relatedness, was observed with yeasts recovered from the same patient. conclusion: our data underline the persistence of strains, with the same antifungal susceptibility profile and clinically related genotypes in patient with recurrent infections, suggesting a colonisation with the same strain over different periods of time despite therapy. these results stress the need for molecular tools for strain typing in order to clarify the epidemiology of the rvvc and to control drug-resistant fungal agent spread. objectives: using criteria designed for invasive aspergillosis (ia) in neutropenic patients, the present study aimed to determine the impact of invasive aspergillosis in different groups of non-haematooncological icu patients. methods: this study is a retrospective analysis of all patients that were hospitalised in the -bed medical intensive care unit (micu) between january and january . any admitted patient fulfilling one or more of the following criteria was included in the study: (a) histopathological evidence of aspergillosis (including autopsy) or (b) microbiological evidence of aspergillosis during stay in the micu (positive culture or positive circulating galactomannan). ia was classified as proven, probable or possible, according to the eortc/msg definitions. aspergillus isolation from a non-sterile site in patients without appropriate clinical setting was considered as 'colonisation'. results: between and , of patients ( . %) fulfilled the inclusion criteria. thirty-eight patients ( %) had haematological malignancies and were not further analysed. eightynine ( %) were non-haemato-oncological patients ( copd, nine solid organ transplant recipients, autoimmune diseases, objectives: we evaluated the value of aspergillus pcr as a tool for diagnosing invasive aspergillosis during antifungal therapy from whole blood samples. methods: in a -year study, patients receiving antifungal therapy due to chest radiographic findings highly suggestive for fungal pneumonia were evaluated. the pcr results of whole blood samples were compared with those obtained from bronchoalveolar lavage fluids and/or tissue specimens. results: a total of whole blood samples, fine needle aspirations or tissue biopsy specimens, bronchoalveolar lavage fluids and tracheal secrets were analysed using pcr. fifteen patients had proven, nine probable and possible invasive aspergillus infections according to european organization for research and treatment of cancer/mycosis study group definitions. in patients with proven infections, the sensitivities of pcr of lung and blood samples were and %, respectively. the specificities were %. the negative predictive value of blood monitoring under antifungal treatment was %. in patients with probable infections, the sensitivities of pcr of lung fluids and blood were and %, respectively. the specificities were %. the negative predictive value of blood monitoring under antifungal therapy was %. conclusions: the benefits of pcr diagnosing of whole blood are limited if sampling takes place once treatment has started. the performance of aspergillus pcr should be recommended in addition to microscopic examination and culture technique for sensitive detection of fungal infection. objective: air is considered the main vehicle of aspergillus spores causing community or nosocomially-acquired invasive aspergillosis (ia). air surveillance is nowadays performed in protected air environments in many institutions. sabouraud dextrose agar irradiated (sd) is used for the control of air in our institution but czapeck agar is also recommended for this purpose. the aim of our study was to compare the efficiency of both media for aspergillus isolation in air samples. methods: we collected samples using the merck air sampler mas Ò with a volume of air per culture of l. every sample was cultured in both media (pair of samples), and agar plates were incubated at c for days. aspergillus spp. was identified by conventional methods. the pairs were checked daily to observe the growth of fungi and after the incubation period the objectives: the spreading of aspergillus hyphae into the brain of immunocompromised patients is a complication of invasive asper-gillosis that leads to death in nearly % of the cases. the most frequent species for induction of cerebral aspergillosis is aspergillus fumigatus. our aim was to study the interaction of a. fumigatus with the complement system to determine the reason for the failure of the cerebral immune system. furthermore, these experiments might give first approaches for a putative immune therapy to support current antimycotical treatment. methods: different pools of cerebrospinal fluid (csf) were tested for their ability to opsonise fungal hyphae with different complement factors. germinated conidia were fixated, incubated in csf, and the deposition of complement was shown via indirect immunofluorescense (if) by suitable specific antibodies. the extent of surface labelling on aspergillus was compared with pseudallescheria boydii, another neurotropic fungus. immunohistochemical (ihc) staining of paraffin-embedded tissue sections derived from patients with cerebral aspergillosis allowed the comparison with the complement deposition in vivo.results: the levels of the complement factors c q, c , c , c , c and c in the csf of normal persons were sufficient for opsonisation of the fungal hyphae, although the deposition was much weaker than in human serum. however, the recognition of aspergillus surface was not optimal in comparison to p. boydii that showed a clearly stronger deposition. concentrations of different complement proteins and complement activation products were highly elevated in csf derived from a patient with cerebral aspergillosis. this csf showed a significantly stronger complement deposition on the fungal surface than the non-inflammatory csf. however, ihc-analyses in tissue sections of patients with cerebral aspergillosis showed only limited opsonisation on the fungus. conclusion: csf harbours the ability of complement deposition on the surface of neurotropic fungi. frequent pathogens like aspergillus fumigatus have adopted their surface to minimise recognition by the complement cascade. cerebral complement production is upregulated as a consequence of fungal infection, which might contribute to antifungal immune defence but also to inflammation and tissue damage. the amount of deposited factors on the fungal hyphae in vivo is low, indicating the expression of complement inhibitory factor(s) by a. fumigatus. objectives: staphylococcus epidermidis is a major pathogen in nosocomial infections, and infectious isolates display a high prevalence of oxacillin resistance (oxar). tn mutagenesis of rsbu, encoding a positive regulator of the alternative sigma factor sigma b lead to a reduced oxar in s. epidermidis . however, the mechanism of this regulatory pathway is still unknown. the role of sigma b in the regulation of oxar in s. epidermidis was investigated in this study. methods: two mutants with inactivation of the entire sigma b operon ( rsbuvwsigb) or the regulatory cascade rsbuvw ( rsbuvw) were generated by allelic gene replacement in s. epidermidis , which displays a heterogeneous oxacillin resist-ance phenotype. rna was extracted at and h from cultures in mueller hinton + % nacl (mhnacl) and mhnacl supplemented with lg/ml oxacillin (mhoxa). quantitative transcriptional analysis of meca, femabcdf, fmta, mrp (fmtb), and mprf (fmtc) were performed by real-time rt-pcr. at least a . -fold difference compared with the wild type in the average of three independent experiments was defined as cut-off for differentially expressed genes. results: population analysis of the mutants and the wild type strain revealed that mutant rsbuvwsigb displayed a more heterogeneous phenotype with a smaller subpopulation expressing methicillin resistance compared with the wild type. mutant rsbuvw with constitutive expression of sigma b displayed a strong increase of methicillin resistance and a homogeneous resistance phenotype compared with the wild type. transcriptional analysis revealed that the homogeneously resistant mutant rsbuvw displayed no differences compared with the wild type under all conditions investigated, except of the gene fmta, which was downregulated in mhoxa at h. interestingly, in the less resistant mutant rsbuvwsigb the genes meca, femb, femd, fmta, and mprf were upregulated in mhnacl compared with the wild type at both time points, whereas in mhoxa only the genes femd, fmta, and mprf were upregulated at or h. conclusions: none of the investigated genes including meca is responsible for the homogeneous expression of oxar in mutant rsbuvw. mutant rsbuvwsigb displayed a less resistant phenotype compared with the wild type strain, despite the upregulation of several genes required for oxar. therefore, an additional sigma b dependent factor must be required for homogeneous expression of oxar in s. epidermidis. objectives: to develop methods to measure the initial response of s. aureus after exposure to antimicrobial agents. such an approach has the potential to allow both the sensitivity and mechanism of resistance to be rapidly determined from isolated bacterial strains. methods: mrna was extracted from a selection of s. aureus isolates either with or without min exposure to antimicrobial agents (including oxacillin and mupirocin). the mrna extracted was then used to produce labelled nucleic acid suitable for hybridisation to a low-density flow through oligonucleotide array targeting specific genes. these arrays are suitable for high throughput screening and provide very rapid hybridisation kinetics.results: distinctive changes in mrna levels were detected for each agent tested and for isolates with different phenotypic susceptibilities. oxacillin resulted in a significant increase in the levels of penicillin binding protein (pbp ) mrna in both sensitive and resistant isolates and an increase in the levels of pbp prime mrna in resistant isolates only. in contrast mupirocin resulted in very high levels of ile-trna synthetase in both strains with high-or low-level mupirocin resistance but not in sensitive strains. conclusion: future developments in rna extraction and labelling as well as the increased availability of dna array technology will allow this approach to be more widely used. this and similar methods have the potential to provide information on both the resistance phenotype of the isolate and the mechanism of resistance, in contrast to 'classical' molecular tests for drug resistance which generally target known genotypes. key: cord- -f rr el authors: Østby, anne‐cathrine; gubbels, sophie; baake, gerben; nielsen, lars peter; riedel, casper; arpi, magnus title: respiratory virology and microbiology in intensive care units: a prospective cohort study date: - - journal: apmis doi: . /apm. sha: doc_id: cord_uid: f rr el our aim was to determine the frequency of common respiratory viruses in patients admitted to intensive care units with respiratory symptoms, evaluate the clinical characteristics and to compare the results to routine microbiological diagnostics. throat swabs from intensive care‐patients > years with acute respiratory symptoms were collected upon admission and analysed with multiplex real‐time polymerase chain reaction, for community respiratory viruses. blood and respiratory tract specimens were analysed for bacteria and fungi upon clinicians' request. clinical and paraclinical data were collected. viruses were detected in ( %) of the study patients. five virus‐positive patients ( %) had possible clinically relevant bacteria or fungi co‐detected. patients with exacerbation in copd were associated with a viral infection (p = . ). other comorbidities, clinical and paraclinical parameters, and death were independent of a viral infection or co‐detection of bacteria/fungi. in conclusion, respiratory viruses were frequently detected in the patients. the investigated clinical and paraclinical parameters were not different in viral infections compared to other agents, thus respiratory viruses likely have similar impact on the clinical course as other agents. in % of the virus‐positive patients, polymicrobial aetiology was identified. comprehensive and sensitive diagnostic methods should be emphasized to enhance respiratory diagnostics. community respiratory viruses are frequent causes of acute respiratory tract infections and community-acquired pneumonia ( ) ( ) ( ) ( ) ( ) . respiratory viruses may also trigger acute exacerbations in pre-existing chronic conditions such as asthma, chronic obstructive pulmonary disease (copd) and congestive heart failure ( , ) . some of these patients need hospitalization and even intensive care treatment. still, respiratory viruses are generally not considered of clinical relevance when monitoring critically ill patients ( , ) . today, a large number of pathogens, mainly viruses, can be identified with rapid, highly sensitive and specific molecular methods, such as polymerase chain reaction (pcr). clinically, it is difficult to determine the microbiological aetiology of respiratory tract infections. the microbiological findings are often influenced by antibiotic treatment before admission to intensive care units (icu), which makes the microbiological test results difficult to interpret, and may disguise significant pathogens. furthermore, the differentiation between pathogens causing invasive infection and colonization is often impossible. this has implications for the patients, as infections with different pathogens have different prognosis and response to treatment. viral diagnostics are often used as second-line diagnostics and saved for cases where no significant bacterial pathogen has been revealed during the initial analyses, or for cases with deterioration in clinical symptoms despite treatment of revealed bacteria. this approach can lead to a delay in potentially beneficially antiviral treatment. the aetiology of severe acute respiratory disease remains undetermined in more than % of the patients ( ) ( ) ( ) . virological molecular methods have improved markedly during the recent years by the introduction of molecular techniques ( , , ) . however, there are still few studies using these methods for detection of a large number of viruses in icu-patients ( ) ( ) ( ) . the purpose of this study was to determine the frequency of respiratory viruses in adult icu-patients without selection for predisposing conditions, describe the clinical characteristics and epidemiology, and to compare the results of current practice respiratory diagnostics in these patients. this study is one of few which include both comprehensive virological pcr-analyses and conventional microbiological analyses, while mimicking the clinical everyday reality at an icu. all adult patients > years of age admitted successively with clinical suspicion of acute respiratory infection at the intensive care units of two university hospitals in copenhagen, denmark, were tested for the presence of respiratory viruses on throat swabs. one icu, with beds (icu-a), collected swabs from december to november , and the other, with six beds (icu-b), collected swabs from january to august . only throat swabs taken upon admission were included, and no additional virological analyses were requested from sample material sent for bacterial diagnostics. throat swabs were chosen for the study due to the non-invasive nature of sample collection, combined with minimal discomfort for the patients and an acceptable sensitivity. the inclusion of patients was based upon the assessment of the attending physicians. inclusion criteria were wide, as respiratory viruses do not always appear as a uniform clinical picture. a patient was included if any sign of respiratory distress or failure was apparent, including exacerbation in copd or asthma, and pneumonia. patients with fever, if accompanied by uncompensated congestive heart failure or multiple organ dysfunction syndrome, metabolic acidosis, sepsis or cardiac arrest, were also included. all throat swabs were analysed consecutively for the presence of respiratory viruses upon arrival at department of virology, statens serum institut, copenhagen, denmark. analyses included influenza a and b, respiratory syncytial virus (rsv), human metapneumovirus (hmpv), parainfluenza virus , and , coronaviruses oc (cov oc ), e (cov e) and nl- (cov nl- ), rhinovirus and adenovirus, using a modified version of the multiplex real-time pcr-assay published previously by brittain-long et al. ( ) , which also included analyses of enterovirus, chlamydophila pneumoniae and mycoplasma pneumonia. for technical purposes, these were omitted from our assay. the amplifications were performed on a stratagene mx thermocycler with mxpro software, (stratagene, la jolla, california, usa), following the manufacturer's instructions. the subtyping of influenza a was based on an in-house accredited pcr-assay, detecting the haemagglutinin-and neuraminidaseregions of h n , (h n )pdm and h n . the bacterial and fungal analyses were performed at the department of clinical microbiology, herlev hospital, herlev, denmark, serving both hospitals. the analyses consisted of culture, identification and antibiotic susceptibility testing. pcr for legionella pneumophila, chlamophila pneumoniae and mycoplasma pneumoniae was performed upon request from the clinicians. the material included blood, tracheal aspirations, bronchoalveolar lavage, sputum and pleural fluid. samples collected within days before or after the viral sample date were included. evaluation of bacterial and fungal content of the sample was done according to the normal procedure for the department of clinical microbiology. gram-staining of each respiratory secretion was evaluated by technicians and microbiologists. secretions containing epithelium from the deeper parts of the airways by microscopic evaluation were considered sufficient materials. bacteria in association with such epithelium were considered as being possible pathogens. culture of these bacteria was done to distinguish between usually non-pathogenic and possible pathogenic organisms. blood cultures were performed according to well recognized methods ( , ) . clinical information regarding the hospitalization, epidemiology and comorbidity was recorded from the medical records. the information included the following: age, gender, underlying comorbidity, use of immunosuppressant drugs, respiratory symptoms, diagnoses on admission, diagnoses on discharge, length of hospital stay, icu stay and intubation, simplified acute physiology score ii (saps ii)scores, administration of antibiotics, non-invasive ventilation, chest x-ray, laboratory analyses and results of the physical examination, which included temperature, saturation, stethoscopic findings and clinical signs of respiratory infection or distress. the saps ii-score is a severity of disease classification system applied during the first h of admission to icu. the resulting point score interval is - , and the predicted mortality between and %. the patients at icu-a were routinely scored according to the saps ii-guidelines at admission. this was not an established routine at icu-b during the study period. in this case, patients were scored retrospectively according to the international saps ii-guidelines by one anaesthesiologist, blinded as regards other results of the study. immunosuppression was defined either by a malignant disease, by administration of chemotherapy or radiotherapy within one year before admission, or by the use of corticosteroids at doses exceeding the equivalent of mg/day of prednisolone for at least months, or mg/kg/day for at least a week during the last months before admission ( , ) . intergroup characteristics were compared using the wilcoxon rank sum test for numerical variables, and chi-square test or fisher's exact test for dichotomous variables. for continuous variables, median and interquartile ranges (iqr) were estimated. multiple groups with numerical variables were compared using the kruskal-wallis test. multiple groups with dichotomous variables were compared using chi-square test or fisher's exact test, where appropriate. the p-values < . were considered significant. epidata, version . (epidata association denmark), was used for data entry, and all statistical analyses were performed using stata/ic, version . (statacorp lp, usa). the national board of health, denmark, and the danish data protection agency approved the data collection (ref. ). according to danish law, and given the observational nature of the study without deviation from current medical practice, an approval was not necessary, and informed consent was waived. a total of throat swabs were collected at icu-a, and throat swabs were collected at icu-b (fig. ). of these, five patients were incorrectly registered at the laboratory, six medical records were unavailable, and patients were retrospectively found not to meet the inclusion criteria when assessing the admission. these patients were excluded. the final study group consisted of patients, all suspected of respiratory infection upon admission to icu-a (n = ) and icu-b (n = ). geographical location, patient population and medical care of the two units were comparable. the median age of the final study group was years (iqr, - years), and ( %) were men. a total of patients ( %) had a virus detected (fig. ) . clinical and paraclinical characteristics are shown in table . the frequency of patients admitted to hospital with exacerbation in chronic obstructive pulmonary disease (copd) was higher in the virus-positive group: five patients ( %) vs eight patients ( %) (x -test, p = . ). pneumonia was the most frequent reason for admission in both groups. among the virus-positive, pneumonia occurred in nine of influenzapatients, and was also observed for patients with hmpv, rsv and adenovirus. the plasma concentrations of c-reactive protein (crp) were independent of a viral infection, with large interquartile ranges also detected in virus-positive patients. clinical intervention and diagnoses upon discharge are presented in table . all virus-positive patients received antibiotics, compared to of the virus-negative patients ( %). twelve ( %) of the virus-positive patients received combination antibiotic therapy, which was also the case for ( %) of virus-negative patients (x -test, p = . ). oseltamivir was administered to three viruspositive patients ( %) during the period of the pandemic. additional clinical parameters, comorbidity, intervention and discharge diagnoses did not differ significantly between the patient groups. in the virus-positive group, of patients ( %) were transferred to icu days or less after hospital admittance. in the virus-negative group, this was the case for of patients ( %). viruses -of the patients included in the study group, ( %) were positive for a virus, of which the most frequently detected were influenza a (n = ) and rsv (n = , fig. ). regarding influenza a, the subtypes were h n in four patients and (h n )pdm in three. the remaining two patients were positive for influenza a during season - , but the subtype could not be determined. bacteria and fungi -a negative viral swab was found in patients (fig. ). of these, patients ( %) had bacteria or fungi in their respiratory specimens (n = ), blood (n = ) or both (n = ) within days of the viral sample collection date. overall, the isolate most frequently detected in respiratory specimens was candida albicans (n = , fig. ). the most frequently detected isolates in blood were coagulase-negative staphylococci (cons) (n = ). of the patients with any positive culture, ( %) had culture results of considered clinical significance for the respiratory disease. of the patients with a positive respiratory culture, bacteria of considered clinical relevance were isolated in respiratory specimens from patients ( %). the isolates included streptococcus pneumoniae (n = ), staphylococcus aureus (n = ), pseudomonas aeruginosa (n = ), haemophilus influenza (n = ), klebsiella pneumoniae (n = ) and legionella pneumophila (n = ). of virus-negative patients with a positive blood culture, bacteria of likely clinical relevance for the respiratory disease were isolated from seven patients ( %). the isolates included s. pneumoniae (n = ), s. aureus (n = ) and p. aeruginosa (n = ). for the remaining of the virus-negative patients ( %) without positive microbiology, tracheal aspirations were performed in eight patients, sputum in three, bronchoalveolar lavage in one and blood culture in patients. two patients did not have respiratory or blood cultures collected. co-detection of microbiological agents -of the above-mentioned virus-positive patients, a total of patients ( %) were found to have a coinfection or colonization with bacteria or fungi. five culture results ( %) were considered to be of clinical relevance to the respiratory symptoms ( table ). the five coinfections were detected in tracheal aspirations, and represented % of the total study population. in addition, one patient, had hmpv and both cons and candida dubliniensis of unknown clinical significance isolated in blood cultures. nearly half of the patients with a co-detection of a microbe, including those with a clinically significant agent, were admitted directly to icu, and only one patient was admitted more than days after hospital admission. the most prevalent virus in the patients with coinfections or colonizations was influenza a (two h n , three h n pdm ). the other viruses were influenza b, cov oc , cov e, hmpv and rhinovirus, each detected once. the most frequent microbiological isolate in tracheal aspirations considered to be of possible clinical significance was s. aureus (n = ), while p. aeruginosa and k. pneumoniae were detected once. fig. . distribution of viruses and the most frequently isolated microorganism in the study population the influenza a subtypes included h n , (h n )pdm , and untyped strains. *coagulase-negative staphylococci **m. catharrhalis, s. marcescens, e. cloacae, k. oxytoca, p. vulgaris, p. acnes, pseudomonasspecies, micrococcus-species, bacillus-species ***c. dubliniensis, c. koseri, c. glabrata, c. tropicalis, c. krusei, unspecified candida-species a total of patients were tested for viruses, including parainfluenza viruses - . nineteen were virus-positive. co-infections with clinically significant microbiological pathogens were found in four virus-positive patients. of the virus-negative patients, were positive for either bacteria or fungi, and two patients were not tested. thirty-four were negative for bacteria/fungi. agents of considered relevance for the respiratory symptoms were isolated in of the patients; seven from blood and from tracheal aspiration. table summarizes clinical parameters in four groups of patients detected with and without viruses and with and without bacteria/fungi identified in blood or respiratory specimens within five days from the viral sample date. chronic obstructive pulmonary disease (copd) was a frequent predisposing comorbidity in the group of patients with a virus-only infection, compared to the other patients. the copd-patients were also frequently observed with a virus-only infection when admitted with exacerbation. the saps-ii score was independent of microbiological agent detected. biochemical and radiological results could not reliably differ between the groups. however, it appeared that the virus-only patients had a lower median level of c-reactive protein in comparison with the bacteria/fungi-only patients ( mg/l compared to mg/l, wilcoxon rank sum, p = . ) when separated from the other groups. the same two groups also differed regarding median duration of mechanical ventilation, which appeared to be shorter among patients with a virus-only infection ( days compared to days in bacteria/ fungi-only patients, wilcoxon rank sum, p = . ). in all groups, positive for any microbiology, there was a high frequency of development of pneumonia, also for the patients with a virus-only infection. of the patients included in the study, ( %) died within days of the viral sample date. the non-survivors had a median age of years (iqr - years), which was higher than that of survivors, who had a median age of years (iqr - years, wilcoxon rank sum, p = . ). immunosuppression was seen in ( %) of the non-survivors, and in nine ( %) of the survivors (x -test, p = . ). the median saps ii-score in non-survivors was (iqr - ), which was higher than that in the survivors (score , iqr - , wilcoxon rank sum, p = . .) of the virus-positive patients, ( %) died, out of which four patients were detected with influenza a and two patients were detected with rsv. the remaining five had positive tests for adenovirus, rhinovirus, hmpv, cov e and cov oc . in total, four of the nine influenza a-positive patients ( %) in the study population, of which two had the pandemic strain, and two of the three rsv-positive patients ( %) died. of the virus-positive non-survivors, five ( %) had a co-detection of bacteria/fungi in a respiratory specimen, of which two patients were detected with influenza a and c. albicans, one with rhinovirus and c. albicans, one with cov oc and s. aureus and one with cov e, e. coli and c. albicans. there were no significant differences between the virus-positive survivors and non-survivors in demographics or clinical characteristics to predict fatal outcome. of the above-mentioned virus-negative patients with positive respiratory or blood cultures for bacteria or fungi, ( %) died. the most frequent isolates were c. albicans (n = ), enterococci (n = ), s. aureus (n = ), s. pneumoniae (n = ), p. aeruginosa (n = ), k. pneumoniae (n = ), and h. influenzae (n = ). fatal outcome was independent of infection with different microbiological agents. this study is to our knowledge one of a few studies ( , , , , ) , which compares comprehensive virological pcr methods and microbiological findings in adult icu-patients without selecting for predisposing conditions. the study mimics the clinical everyday reality at an icu in an attempt to ease the comparison between the results of the study and clinical practice. the virological analyses were based on multiplex real-time pcr-methods, detecting a large number of respiratory viruses, which now gradually are replacing the previous, less sensitive methods for rapid diagnostics of viruses. icu-patients are a heterogeneous group, often with several concurrent diseases and complex medical histories. although there are major guidelines on the management of community-acquired pneumonia, consensus regarding the microbiological diagnostic approach is still lacking ( ). there are for instance different copd, chronic obstructive respiratory disease; icu, intensive care unit; saps ii, simplified acute physiology score ii; crp, c-reactive protein. cardiac disease includes congestive heart failure, former myocardial infarction, angina pectoris or arterial hypertension. the difference is significant when comparing these two groups only, p = . . the difference is significant when comparing these two groups only, p = . . numerical data are presented as medians and interquartile range, categorical data as frequencies and percentages. approaches and opinions on which sample material is most suitable for identification of respiratory agents, and also on how proper sample collection is verified. previously administered antibiotics may influence the results markedly, eventually disguising pathogens and promoting selection of other microorganisms present in the patient. the presence of bacteria or fungi in samples from the airways in icusettings will only rarely be considered diagnostic for a given infection, as most of the isolations could represent both an infection and a colonizing organism. even in blood cultures, the microorganism detected may not necessarily represent an infection. the results in our study illustrate both issues, as only % of the respiratory isolates and % of isolates detected in blood cultures from virus-negative patients were considered to be clinically relevant for the respiratory disease. the previously estimated frequencies of respiratory viruses in icu-patients vary from to % ( , ( ) ( ) ( ) . the detection rate of % viruses in our study population confirms together with other studies that respiratory viruses are common in icu-patients, and confirms the validity of the pcr method used. influenza a was the virus most frequently detected, followed by rsv, which supports previous results ( , , ) . the detection of respiratory viruses such as influenza, parainfluenza viruses and coronaviruses in the presence of acute respiratory symptoms have previously been shown to cause severe pneumonia, requiring intensive care treatment and mechanical ventilation ( , , , ) . the other respiratory viruses detected in our study, such as rhinoviruses, rsv and hmpv, have also been shown by several studies to cause significant symptoms, morbidity and potential need of intensive care treatment ( , ) . most of the respiratory viruses detected in the multiplex pcr presented show seasonal variations of frequency ( ) ( ) ( ) . although some weeks were missing at the beginning of the influenza season in our study, the main seasons for the different viruses were covered. any seasonal variations of the viruses during the study period should be accommodated. the timing of the sample collection could have interfered in the number of positive samples if performed late in the clinical course of the infection, but % of the samples were taken within days of admission with acute respiratory disease. regarding the clinical impact of the respiratory viruses detected, we found no parameters which reliably could distinguish virus-positive and virus-negative patients. there were no differences in the results of the clinical or paraclinical analyses. this underlines the importance of comprehensive and sensitive diagnostic measures when accurate diagnoses are sought, as clinical judgment alone cannot distinguish between the different aetiologies. clinical intervention and outcome between virus-positive and virus-negative patients were also similar in both groups, even when considering co-detection of other microbiological agents. the only exception was a slightly shorter ventilation time for the patients with a virus-only infection. the results may suggest that respiratory viruses have a similar influence on the clinical course as bacteria and fungi. the diagnoses upon discharge showed a large amount of patients developing pneumonia among both virus-positive and virus-negative patients. although most virus-positive patients were treated with antibiotics, only a third of the influenza-positive patients with pneumonia received oseltamivir, which for all these cases occurred during the pandemic when the focus on influenza was high. coincident detection of a virus and one or more respiratory microbiological agents constituted more than % of the viral infections in our study, and % of the total study population, which fits well with the results of similar studies ( , , ) . several studies throughout the last century have demonstrated the association between respiratory viruses and bacterial infections ( , ( ) ( ) ( ) . the most frequent combination of virus and bacteria in our study was influenza a and s. aureus, which is a welldescribed relationship. most patients were admitted either directly at the icu or less than days after hospital admission, which makes nosocomial infection or selection of opportunistic agents less likely. influenza-positive patients frequently had a coincident finding in respiratory cultures, of which two thirds of the microorganisms were considered clinically significant and likely to represent a severe superinfection. a recent study reported similar results; approximately half of influenzapatients presenting with a coinfection ( ) . these findings demonstrate that neither bacteriological nor virological analyses should stand alone. in this study, patients with a virus plus a microbiological agent tended to be admitted and ventilated for a similar period as the virus-negative, bacteria/fungi-positive patients. this could indicate a more severe morbidity caused by the combination of agents. we found no association between the number of deaths and different combinations of microbiological agents, but a large frequency of pneumonia was noted even among virus-only infected patients. the findings are in line with some recent studies ( , , ) , and partly supported by a study on nearly . icupatients which found a strong association between being infected with viruses and bacteria during the same hospitalization and developing septic shock or multiple organ dysfunction syndrome ( ) . as opposed to our results, this study also demonstrated a strong association with mortality in these patients ( ) . infections inevitably have an important influence on the clinical course in patients admitted to icu. however, current microbiological diagnostic practices leave many patients undiagnosed, and the interpretation of the bacterial results are often difficult. adding a comprehensive multiplex real-time pcr increased the sensitivity of the respiratory diagnostics in our study, and results on microbiological agents were provided for % of the patients, though not all agents were likely to be of further clinical interest. the results for the virus-positive patients with co-detected microorganisms were equally difficult to interpret, with only % of the isolates being of clinical interest. a potential pathogenic effect of presumably colonizing organisms in the remaining culture-positive patients cannot be ruled out, though. this supports the fact that interpreting current practice microbiological analyses is difficult in icupatients. this was also recently pointed out in a study investigating biomarkers in bronchoalveolar lavages for diagnosing respiratory viral infections ( ) . the clinical picture of respiratory tract infections in icu is further complicated by the fact that severe infections with focus outside of the respiratory system may also result in pulmonary congestion and infiltrates due to ards. these changes may resemble pneumonia, but the pathogen may not be found in either the respiratory secretions or in the blood. improving the sensitivity of microbiological analyses with molecular methods, or adding other detection methods or biomarker analyses may reduce the number of severely ill patients with undetermined aetiology of their respiratory disease. the virus-negative patients received combination antibiotic therapy significantly more frequently, which might be connected to a generally worse clinical condition. it is noteworthy that all of the virus-positive patients received antibiotics, and % even combination therapy. this may further cloud interpretation of bacterial analyses, and contribute to the lack of diagnoses in some patients. a more comprehensive diagnostic programme than today's practice, including a wider use of molecular methods in bacteriology, could possibly result in more accurate diagnoses and a reduction in the use of empirical broad-spectrum antibiotic treatment. in greater perspectives, this could contribute to relieving the increasing issues with antibiotic resistance. there is still a need for great awareness, refined clinical guidelines and implementation of comprehensive microbiological and virological analyses to address these issues. we are aware of the limitations of this study, of which the main are the low number of viruspositive patients and the lack of a control group of patients without respiratory symptoms. the saps-ii-scores were performed retrospectively at one of the hospitals, although performed blinded regarding the other results; this may have influenced the scores. more than % of the patients were admitted either directly at the icu or were transferred less than days after hospital admission. still, antibiotic treatment, nosocomial infections and selection of opportunistic agents may have happened prior to entering the study. unfortunately, information regarding this was not available for a suitable amount of the patients. in this study, death was independent of the presence of viruses, and a fairly large proportion of the virus-positive patients developed pneumonia. the investigated clinical and paraclinical parameters were not different in viral infections compared to other agents. this may suggest that respiratory viruses have a similar impact on the clinical course as other pathogens. interpretation of microbiological results in icu-settings is difficult, as several diseases and conditions may be combined in each patient and the results might be influenced by previously administered antibiotics. in more than % of the virus-positive patients in our study, respiratory bacteria or fungi considered to be clinically significant were identified, which demonstrates that neither virological nor bacteriological analyses should stand alone. the patients should be tested with optimized, sensitive and comprehensive methods, and interpretations should preferably be done in collaboration with a clinical microbiologist or specialists in infectious diseases to enhance the diagnostic process. the authors declare that they have no competing interest of any nature. infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults high prevalence of respiratory viral infections in patients hospitalized in an intensive care unit for acute respiratory infections as detected by nucleic acid-based assays viral communityacquired pneumonia in nonimmunocompromised adults incidence and characteristics of viral community-acquired pneumonia in adults viral infections in the icu role of viruses in exacerbations of chronic obstructive pulmonary disease virus-induced asthma attacks the potential influence of common viral infections diagnosed during hospitalization among critically ill patients in the united states value of rvp in clinical settings: intensive care community-acquired pneumonia on the intensive care unit: secondary analysis of cases in the icnarc case mix programme database severe communityacquired pneumonia: an australian perspective communityacquired polymicrobial pneumonia in the intensive care unit: aetiology and prognosis acute febrile respiratory illness in the icu-reducing disease transmission epidemiology and clinical outcome of virus-positive respiratory samples in ventilated patients: a prospective cohort study multiplex real-time pcr for detection of respiratory tract infections the clinical-significance of positive blood cultures -a comprehensive analysis of episodes of bacteremia and fungemia in adults . . laboratory and epidemiologic observations douglas, and bennett′s principles and practice of infectious diseases a casecontrol study on risk factors for early-onset respiratory tract infection in patients admitted in icu acute respiratory distress syndrome and pneumonia: a comprehensive review of clinical data nosocomial viral ventilator-associated pneumonia in the intensive care unit: a prospective cohort study virus infection in exacerbations of chronic obstructive pulmonary disease requiring ventilation respiratory viruses and severe lower respiratory tract complications in hospitalized patients influenza in the intensive care unit the pathogens seasonal variations of respiratory agents illustrated by the application of a multiplex polymerase chain reaction assay occurrence of respiratory virus: time, place and person respiratory viruses in bronchoalveolar lavage: a hospitalbased cohort study in adults epidemiology, microbiology, and treatment considerations for bacterial pneumonia complicating influenza. international journal of infectious diseases: ijid: official publication of the international society for infectious predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness high incidence of pulmonary bacterial co-infection in children with severe respiratory syncytial virus (rsv) bronchiolitis community-acquired respiratory coinfection in critically iii patients with pandemic influenza a(h n ) virus importance of viral and bacterial infections in chronic obstructive pulmonary disease exacerbations detection of respiratory viruses and the associated chemokine responses in serious acute respiratory illness we thank dr. med asger bendtsen (department of anaesthesiology, glostrup hospital, glostrup, denmark), md kirsten gani (department of anaesthesiology, herlev hospital, herlev, denmark) and prof., dr. med henrik birgens (department of haematology, herlev hospital, herlev, denmark) for invaluable contribution to the study concept and execution, chief nursing officer marlene klarskov fleischer (department of anaesthesiology, glostrup hospital, glostrup, denmark) for execution of the study, and jens nielsen (department of epidemiology, statens serum institut, copenhagen, denmark) for advice on statistics. furthermore, we are greatly indebted to nursing staff and attending physicians of the two icus for their kind cooperation in this study. key: cord- - poiheen authors: de brouwer, e.; raimondi, d.; moreau, y. title: can herd immunity be achieved without breaking icus? date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: poiheen the current covid- pandemic led to the rapid overload of intensive care units (icus) in countries where the outbreaks was not quickly controlled. the containment measures put in place to control the outbreaks had a huge social and economic impacts, and countries are looking for strategies to relax these measures while maintaining the r_ close or below , in an attempt to safely reach herd immunity. in this paper we analyse the feasibility of reaching herd immunity without saturating icus across countries. we provide an online tool, available at www.about-the-curve.net that simulates the time required for such a scenario with a sir model. for united states, we find that a minimum of months would be required, months for uk, year for italy and months for belgium. the presented results are preliminary and have not been peer-reviewed. a key aspect of the current covid- pandemic has been the rapid overload of intensive care units (icus) in countries and regions where the epidemic was not quickly controlled [ , ] because many patients infected with sars-cov- develop acute respiratory distress syndrome (ards) and need respiratory support [ ] . while mortality currently appears significant in high-risk groups, it seems fairly low outside those groups [ ] , with a case fatality rate (cfr) higher for patients > yrs old and with comorbidities, such as hypertension (odds ratio . ( % ci: . to . )), respiratory disease ( . ( . to . )), and cardiovascular disease ( . ( . to . )) [ , ] . the relatively low mortality outside the high-risk group, the absence of a vaccine and of an antiviral treatment, and the huge socioeconomic impact of the pandemic (which will itself cause significant mortality, morbidity, psychological distress, and economic suffering) suggest that strategies aiming at achieving herd immunity, even at the cost of substantial mortality, could be evaluated. once herd immunity has been achieved, high-risk individuals are protected. by contrast, strategies based on containment are inherently fragile as temporary failure to maintain the effective reproduction number r below leads to the flare-up of the disease. the outbreaks in several major cities or regions (wuhan, lombardy, new york, france's grand est region, etc. ) have shown that letting the disease run its course, even for a few weeks, leads to the rapid oversaturation of icus [ ] . as a result, many countries, regions, and cities have had to resort to draconian lockdown measures, which have brought outbreaks under control after about weeks with a plateau in hospitalizations followed by a later decrease. however, such a drop only results from the severe lockdown measures with harsh social and economic consequences. the complete lifting of those lockdown measures without appropriate alternative measures would automatically lead to a dramatic rebound of the epidemic. as such, locations currently under lockdown are partly cornered by this choice as they search for strategies to prevent a rebound when they lift lockdown. in the classical susceptible-infected-recovered model [ ] , herd immunity is achieved when a fraction ( − /r ) of the population is immune against the disease and the height of the epidemic peak is given by ( − /r − ln(r )/r ) in an immunologically naive population (no individual immune at the start of the epidemic). for example, for r = . [ ] , herd immunity would be achieved if % of the population is immune, and % of the population would be infectious at the epidemic peak. although it is still unclear which fraction of the population requires icu care following sars-cov- infection, the figure of % can be used as an estimate [ , ] for populations with a constrictive ("older") age pyramid (current reports of % are for laboratory confirmed cases, which is likely to miss mild and asymptomatic cases). if correct, this would imply that in , people would require icu care at the epidemic peak, while preexisting icu bed capacity in high-income countries [ ] ranges from . per , inhabitants (portugal) to . per , (united states). (note that turkey's icu bed capacity is per , .) even if the sir model only gives a crude estimate, it clearly shows that baseline icu capacity and possible peak need are simply on different scales. so, to avoid oversaturation of icu capacity, one could imagine pushing down the effective reproduction number r. in fact, an r that does not lead to oversaturation . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . of icu capacity would have to be very close to . under the sir model, an icu bed capacity of per , inhabitants and % of infected individuals requiring icu care, r would have to be around . . a more practical setup would be bringing the icu load to a fixed capacity that the local healthcare system can handle over the longterm by and then "work through the population" until herd immunity is achieved. this is essentially the position currently defended by some countries (netherlands [ ] , sweden [ ] ): avoid overburdening the icu, but let the disease move forward in a controlled manner to build the immunity of the population and eventually achieve herd immunity. note that this would require that r equal on average. such an approach would however raise two important questions. first, how much time would be required to achieve herd immunity? second, how do you control the number of (icu) cases at a fixed level. we tackle here the first question by providing an online app (www.about-the-curve.net) that allows running different scenarios and estimating the period needed to achieve herd immunity. concerning the period of time needed to achieve herd immunity, two important remarks need to be made. first, if this period is longer than the time needed to develop a vaccine, then the usefulness of the strategy is questionable. second, if this period is longer than the duration of the immunity, part of the individuals who had become immune will have become susceptible again, so that herd immunity might be completely out of reach. there is considerable uncertainty about the duration of immunity following covid- recovery. immunity has been documented to be around months to years following sars recovery [ ] . this has been considered the default scenario. however, some coronaviruses (hcov-oc , hcov-hku ) generate little immunity [ ] . there have been several reports of reinfections following covid- recovery and the issue is still debated [ , , ] , since it is unclear whether such reports could have been the results of false negative diagnostic results [ ] . our web application allows computing the period for reaching herd immunity taking uncertainty into account. to illustrate the model, we can consider a range of scenarios for the united states ( million inhabitants) with a baseline icu capacity of . beds per , inhabitants (= , beds). assuming r between and , a covid icu capacity between and beds per , inhabitants (or between , and , beds), an average icu stay duration between and days, and a percentage of icu admission following sars-cov- infection in the general population between . % and . %, we obtain a time to herd immunity ranging between and months. assuming a fatality rate among icu patients ranging between % and %, we obtain a number of covid fatalities at icus ranging between , and , , . while the time to herd immunity could be acceptable in the best case scenario, it . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . could be equal to the time necessary to develop a vaccine and/or the average duration of the immunity in the worst-case scenario. by contrast, taking the case of the united kingdom with a baseline capacity of . beds per , inhabitants, assuming a long-term covid icu bed capacity between and beds per , inhabitants, and keeping all the other parameters the same as for the us scenarios, the range for the time to immunity would be between and months. obviously, all parameters are open for discussion, so that the application does not return one specific prediction, but rather a range for estimates for a range of scenarios. note that if the user wishes to consider a single value for a given parameter, both limits of the range can simply be set to be equal. regarding the second question raised by keeping the icu load constant, we note that such strategies would require tightly controlling the effective reproduction number r e (the equivalent of r when measures are implemented to control the epidemic, which may vary over time) on average at . whenever r e is above , the epidemic will flare up, which will quickly overload a healthcare system already at saturation. whenever r e is below , the disease starts vanishing, thereby extending the time needed to achieve herd immunity. given that it is unclear what the precise impact of any containment measure is on r e , a strategy based on lifting and reimposing measures to switch between r e slightly below and r e slightly above could be challenging. moreover, constantly piloting r e on demand would require frequent changes of the npis imposed on the community, which might be socially infeasible. if it turned out that the percentage of the population that has recovered from the disease asymptomatically or with minimal symptoms is significantly larger than expected, this would bring the percentage c of complications significantly lower and could significantly decrease the period needed to achieve herd immunity. the availability of a medical treatment that would greatly decrease the chances of complications among symptomatic patients would have a similar effect. an effective prophylactic pharmaceutical treatment [ ] , if only used among high-risk individuals would also have a similar effect. the first parameter is the r of covid- in a population without containment measures. this allows calculating the fraction of the population − /r needed to reach herd immunity. given that r is uncertain, the application takes a range [r − , r + ] as input. this allows calculating a range of herd immunity thresholds is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . containment measures (hygienic measures, some level of physical distancing, such as no handshake) were to be maintained after the immunity building period, the value of r used could be lowered, although it is difficult to quantify the effect of such measures. next to the herd immunity target, we also need the icu bed capacity in beds per , inhabitants. this is not the baseline icu capacity in the population considered [ ] , but the icu capacity fully dedicated to covid- patients over the course of multiple months [ ] . this figure should take into account ( ) the icu bed capacity that can be additionally deployed in a given population, ( ) that the current deprioritization of all non-urgent icu capacity is difficult to maintain in the long term, and ( ) that constantly running icus at full capacity would make it extremely difficult to deal with other mass emergencies (such as natural or industrial disasters). this icu bed capacity is input as an error range [b − = b − ε b ; b + = b + ε b ] (in beds per , inhabitants). the next variable is the average duration at icu as this determines the average number of daily admissions because the number of icu covid patients needs to stay constant. because there is a large difference in length of stay for fatalities vs. survivors, we use two ranges: next, we need the fraction of the population that will require icu care following sars-cov- , which is the most uncertain factor. the fraction of the general population that recovers from sars-cov- infection asymptomatically or with only mild symptoms is poorly characterized at this point because testing efforts have focused on symptomatic cases and/or people who have been in contact with infectious patients. systematic serological surveys are needed to reduce the uncertainty for this factor. this fraction is also input as a range [c − = c − ε c ; c + = c + ε c ] (in percent of the population). strategies that aim at segregating high-risk patients from the rest of the population could use a lower fraction, with the aim at achieving a level of immunity in the low-risk population sufficient to guarantee herd immunity for the total population. it is important to note that if the population-wide herd immunity threshold is given . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint by − /r , and a proportion p of the population remains segregated, then the immunization rate that needs to be achieve in the exposed population needs to be increased to (r − )/(r . ( − p ) ). the average number of days till herd immunity can then be computed as the error range can be calculated using error analysis: and a range can be returned as [p − = p − ε p ; p + = p + ε p ]. we can also consider further the number of fatalities among icu covid patients in such a strategy. ultimately, the percentage of the population that will have been infected will be in the range [h − ; h + ], the fraction of the population needed to achieve herd immunity. the range for the percentage of fatalities in the population is then given by d = h.f , ε d = d. covid- and italy: what next? modeling the covid- outbreaks and the effectiveness of the containment measures adopted across countries covid- : risk factors for severe disease and death are patients with hypertension and diabetes mellitus at increased risk for covid- infection? clinical characteristics of coronavirus disease in china compartmental models in epidemiology covid- -navigating the uncharted care for critically ill patients with covid- the variability of critical care bed numbers in europe dutch measures against coronavirus the government's work in response to the virus responsible for covid- duration of antibody responses after severe acute respiratory syndrome the time course of the immune response to experimental coronavirus infection of man reinfection could not occur in sars-cov- infected rhesus macaques can you be re-infected after recovering from coronavirus? here's what we know about covid- immunity virological assessment of hospitalized patients with covid- a prospect on the use of antiviral drugs to control local outbreaks of covid- the authors declare no competing interests. key: cord- -mr gai authors: sher, yelizaveta; rabkin, beatrice; maldonado, jose r.; mohabir, paul title: a case report of covid- associated hyperactive icu delirium with proposed pathophysiology and treatment date: - - journal: psychosomatics doi: . /j.psym. . . sha: doc_id: cord_uid: mr gai there have been increasing reports of neuropsychiatric presentations and symptoms of covid- , more commonly seen in severely ill patients. delirium, which is highly prevalent in general intensive care unit (icu) populations, is expected to be frequent and prominent in covid- patients hospitalized with acute respiratory distress syndrome (ards) in icu. in this case report with associated review, we present a case of a critically ill patient with covid- managed in icu for ards. psychiatry was consulted for management of her hyperactive delirium, likely complicated by environmental factors inherent in management of covid- patients as well as the use of multiple sedatives. patient was successfully managed by psychiatry with a combination of high-dose melatonin, suvorexant, guanfacine, intravenous haloperidol, and intravenous valproic acid. in addition to case presentation, we discuss a proposed delirium pathophysiology in covid- associated delirium and a systematized approach to evaluation and management of such patients. there have been increasing reports of neuropsychiatric presentations and symptoms of covid- , more commonly seen in severely ill patients. delirium, which is highly prevalent in general intensive care unit (icu) populations, is expected to be frequent and prominent in covid- patients hospitalized with acute respiratory distress syndrome (ards) in icu. in this case report with associated review, we present a case of a critically ill patient with covid- managed in icu for ards. psychiatry was consulted for management of her hyperactive delirium, likely complicated by environmental factors inherent in management of covid- patients as well as the use of multiple sedatives. patient was successfully managed by psychiatry with a combination of high-dose melatonin, suvorexant, guanfacine, intravenous haloperidol, and intravenous valproic acid. in addition to case presentation, we discuss a proposed delirium pathophysiology in covid- associated delirium and a systematized approach to evaluation and management of such patients. coronavirus disease (covid- ) was first described in wuhan, hubei province, china in december of ( ). worldwide, at the time of this publication, there have been over . million confirmed cases and over , deaths ( ). clinical manifestations vary from asymptomatic to an acute respiratory illness with progression to respiratory distress and failure ( ) . treatment challenges in the intensive care unit (icu) include severe acute respiratory distress syndrome (ards) due to severe acute respiratory syndrome coronavirus (sars-cov- ), cardiac and other organ dysfunction, and superimposed infections ( , ). in addition, emerging data support a viral neuro-invasive component ( ) . mao and colleagues described numerous neurological symptoms imposing further challenges ( ) . delirium, not surprisingly, emerges, as an additional significant complication and burden in these patients. this case report details complexities in the management of hyperactive delirium associated with covid- infection in the icu. in general, delirium is associated with increased length of hospital stay, morbidity and mortality in mechanically ventilated icu patients ( ) . however, there is a paucity of literature discussing the management and impact of delirium on covid- patients. we discuss the proposed pathophysiology of delirium associated with covid- infection and provide a framework for the evaluation and management of delirium occurring in patients with sars-cov- . a previously healthy year old woman presented to an urgent care with days of fever, malaise, headache, and dry cough. chest radiography revealed right lung airspace opacities. she was prescribed azithromycin and amoxicillin/clavulanic acid. over the next day, her shortness of breath worsened and her viral pcr for sars-cov- returned positive. she presented for a scheduled hospital admission, where she was febrile to . f and tachypneic. absolute lymphocyte count was , interleukin- pg/ml, ferritin , ng/ml, c-reactive protein (crp) . mg/dl, and procalcitonin . ng/ml. renal function demonstrated impairment above her baseline (estimated glomerular filtration rate ml/min/ . m .) aspartate aminotransferase and alanine aminotransferase were mildly elevated at and units/l, respectively. her initial qtc was ms. she was treated with days of ceftriaxone and azithromycin due to concern for bacterial coinfection and days of remdesivir as a part of trial for treatment of covid- . she was transferred to the icu for worsening hypoxic respiratory failure on admission day and intubated on admission day . while she was briefly extubated on day , she required reintubation on the same day. to facilitate mechanical ventilation and combat significant agitation, patient received numerous sedative drips, including dexmedetomidine, hydromorphone, propofol, midazolam, and ketamine, as well oxycodone (up to mg daily) and chlordiazepoxide (up to mg daily). other psychotropic agents used by her primary team included quetiapine (up to mg daily) and melatonin mg nightly. she remained restless and agitated. psychiatry was consulted on admission day to assist with management of agitation, one day prior to tracheostomy placement on hospital day . due to strict covid- infection control policies, patient was assessed virtually, by chart review, and via discussions with her nurses, icu team, and family. the under the psychiatry's recommendations, melatonin was increased to mg nightly to regulate sleepwake cycle and for the antioxidant and anti-inflammatory effects and suvorexant, an orexin antagonist, was added at mg, for sleep-wake cycle regulation. guanfacine, an alpha- agonist, was started at . mg twice daily and titrated to mg thrice daily to reduce sympathetic outflow, manage agitation, and assist in weaning intravenous sedatives. intravenous valproic acid (vpa; titrated to mg per day) was also started for management of agitation and symptoms of hyperactive delirium and to facilitate tapering of multiple other sedative deliriogenic medications. quetiapine was initially titrated to mg distributed throughout the day, but due to its ineffectiveness, it was discontinued on day of psychiatric consultation and instead intravenous haloperidol (titrated to mg per day) was used to manage symptoms of hyperactive delirium. of note, nursing staff was educated and asked to examine for extrapyramidal side effects of antipsychotics during their regular patient evaluation and care. over the following five days, the patient tolerated discontinuation of all sedative drips with gradual tapering of chlordiazepoxide (discontinued on day of psychiatric consultation) and oxycodone (discontinued on day of psychiatric consultation). she had ongoing medical complications, including fevers and pneumothorax, during this phase of her treatment. regardless, her mental status continued to improve. vpa was discontinued on day of consultation, and haloperidol was discontinued on day of consultation. on day of psychiatric consultation, , the patient was fully cognizant, awake, alert, oriented, following simple and complex commands, communicative via the use of mouthing and writing (assessed virtually), and displayed no evidence of ongoing delirium on assessment by a psychiatry team and according to the dsm- . she was discharged on day after her initial hospitalization to a long-term acute care facility. the patient provided verbal consent for the case report, but was unable to physically sign associated documentation due to infection control measures. neuropsychiatric presentations of covid- are increasingly described in the literature. a retrospective case series of hospitalized patients in china demonstrated that . % had central nervous system (cns) manifestations (e.g., dizziness, impaired consciousness, acute cerebrovascular disease, seizures), . % had peripheral nervous system manifestations (taste, smell, and/or vision impairment), and . % -skeletal muscular injury manifestations ( . %) ( ) . neurological abnormalities were observed in . % of those severely ill with covid- as compared to those less severely ill (p= . ), including impaired consciousness ( . % versus . %, p < . ) ( ). in general, delirium is present in up to % of icu intubated patients ( ). not surprisingly, icu patients with covid- and ards are similarly expected to have a high delirium incidence. helms and colleagues reported on severely ill covid- patients with % agitated when weaning off sedation, and % of those able to participate in the cam-icu scoring positively, suggesting delirium. the differential diagnosis of neuropsychiatric symptoms, including delirium, in patients with covid- is extensive. cases of encephalitis and meningitis have been documented with specific sars-cov- rna detected in cerebral spinal fluid ( ) . in addition, patients with covid- might have elevated d-dimer and impaired platelet functioning, thus placing them at risk for acute cerebrovascular accidents ( ) . non-convulsive seizures should also be entertained on the differential, based on the clinical picture. various pathophysiological mechanisms for delirium development and propagation have been proposed ( ) , many of which co-exist in patients with covid- . some of these are unique to individual patients (i.e., substrates), some are related to the treatment environment (e.g., icu, sedatives), and others are related to the acute effects of the virus and its comorbidities (i.e., precipitants). however, there are unique considerations in covid- patients, including cns viral effects, covid- specific treatment side effects, and environmental factors. evidence suggests that direct cns invasion of the sars-cov- is possible, which might lead to deleterious neuropsychiatric effects. in fact, animal studies have demonstrated that sars-cov- is neuro-invasive, likely entering the brain parenchyma via ascending olfactory nerves, then spreading to the thalamus and brainstem ( ) . additionally, a subset of covid- patients experience a cytokine storm ( ) . while an immune response is important to fight the infection, an excessive and dysregulated immune overactivation is likely to contribute to the development of ards and multi-organ failure, including "brain failure" or delirium ( ) . many pro-inflammatory cytokines (e.g., interleukin- , interleukin- , interleukin- β) and chemokines (e.g., ccl , ccl- ) have been linked to the development of ards, a frequent cause of mortality in patients with covid- ( ); the same have been associated with the development of delirium . specifically, qin et al described extensive dysregulation of the immune response in patients with covid- ( ) . moreover, cytokine storm is fueled by the release of catecholamines by immune cells via a self-amplifying circuit ( ) . catecholamines, such as norepinephrine, might also be elevated in hyperactive delirium contributing to its pathophysiology and symptomology ( ) . our patient's course was characterized by significant agitation, requiring use of multiple high-dose sedatives. this agitation, along with ards, might be one presentation of the cytokine storm and catecholamine release in this patient population. among specific patient's characteristics, older age among covid- patients is associated with higher morbidity and mortality rates ( ) . similarly, older age and associated medical comorbidities are recognized as major risk factors for delirium development ( ) . in addition, patients with pneumonia and respiratory failure might experience cns hypoxia and increasing anaerobic metabolism in the mitochondria of brain cells. this can then lead to cerebral vasodilation, brain cell and interstitial edema, and obstruction of cerebral blood flow ( ) . these same mechanisms have been described as causative factors in delirium development ( ) . our patient was an older woman. regarding treatment-related factors, patients with severe covid- often require management in icu settings and/or ventilatory support. ventilated patients are frequently placed on combinations of cns depressants to facilitate ventilatory compliance. many of these sedatives are associated with an increased incidence of delirium ( ) . in fact, due to significant agitation in many covid- icu patients and the risk to patients and staff associated with patients dislodging lines and endotracheal tubes in context of high viral infectivity, patients have anecdotally required combinations of multiple sedatives with very high doses. in our case, the patient had required propofol, opiods, and high-dose benzodiazepines, among other agents, which could have all further worsened her confusion and agitation. in addition, some medications that have been specifically used in the treatment of covid- may themselves induce neuropsychiatric side effects. for example, hydroxychloroquine has been known to cause such side effects, including delirium ( ) . these effects may be exacerbated by a cytokine storm-mediated increase in blood-brain permeability. while our patient was not treated with hydroxychloroquine, it might be an important consideration for others. moreover, secondary complications, such as renal failure and secondary infections, can contribute to or worsen delirium. environmental factors also increase the risk of delirium during these challenging times. due to the high infectivity of this virus, shortage of personal protective equipment (ppe), and medical isolation to decrease virus transmission, covid- patients might not have the benefit of conventional nonpharmacological prevention strategies or the support of loved ones ( ) . the staff is unable to spend time and provide frequent re-orientation and cognitive stimulation for the patients, while family members are not allowed to visit and provide visual cues, reassurance, and practical support. in addition, unusual configuration of the rooms, inability to recognize faces due to staff's extensive ppe, and potentially even the use of the virtual modalities to communicate (e.g., remote telemedicine and virtual visits with family members) as opposed to live visits, all might worsen patients' perception of the reality and contribute to disorientation and confusion. the diagnosis of delirium in patients with covid- is challenging due to limited interactions between staff and patients due to isolation protocols. a live neuropsychiatric evaluation (gold standard) might not be available and/or safe; thus screening tools, such as cam-icu ( ) and the intensive care delirium screening checklist (icdsc) ( ) might be especially useful. yet, up to % of patients might not be able to complete screening tools that require patient participation ( ) . thus, a novel tool, the s-ptd, might be particularly helpful as it relies on nursing report of patients' cognition and behaviors, rather than on patient's participation ( , ) . our patient was initially evaluated remotely from outside of the room integrating review of the chart and descriptions of her behavior and mental status from her nursing and medical staff. cam-icu and s-ptd were also used in her evaluation and diagnosis. as patient improved and was able to engage in an evaluation, she was interviewed virtually with the use of telemedicine. in addition to usual infectious and metabolic work-up for delirium, pharmacological agents that can contribute to mental status alterations must be reviewed. our patient received significant amounts of deliriogenic medications (e.g., propofol, hydromorphone, oxycodone, chlordiazepoxide). based on the differential diagnosis, brain imaging, a lumbar puncture, and an electroencephalogram might be indicated. since our patient did not display focal neurologic deficits, abnormal movements or consistently depressed mental status, these studies were not indicated or pursued. renal and liver function as well as qtc on electrocardiogram should be established to safely choose an appropriate pharmacological regimen. our patient had baseline elevated liver function tests (likely due to covid- infection) and these were carefully monitored on daily basis while vpa was administered on short-term basis. lahue and colleagues have suggested practical non-pharmacological interventions to prevent delirium in patients with covid- , given the unique challenges ( ) . some practical nonpharmacological interventions in this population include maintaining light-dark environment consistent with the diurnal cycle; minimization of nighttime disruptions; re-orientation and cognitive stimulation of the patient whenever possible; encouragement of family photos, phone calls, and virtual visits; provision of physical mobilization whenever possible; ensuring availability of glasses, hearing aids, and communication devices. delirium-related agitation places the patient and healthcare providers at risk, thus medications should be available for acute management. while no studies have demonstrated pharmacological efficacy in the management of delirium among covid- patients, we provide a framework for choosing psychotropic medications to assist in achieving behavioral control in icu patients. agents chosen to treat symptoms of delirium in our patient and included in table were specifically selected due to their own low deliriogenic potential and with the goal to minimize the use of conventional sedatives which are associated with worsening delirium, longer recovery, and impaired long-term cognition. at our center, the following medications have been used in management of agitation in patients with covid- icu-associated hyperactive delirium, including the described patient, with following considerations. high-dose melatonin is used for treatment of delirium and sleep-wake cycle regulation, and postulated to be useful in treatment of covid- in general, given its anti-inflammatory and antioxidant effects ( ) . we have maximized melatonin in this patient. suvorexant regulates sleep-wake cycle and assists in treatment of delirium, especially in combination with melatonin or melatonin receptor agonist ( , ) . thus, it was added for management of sleep-wake cycle in this patient with hyperactive covid- associated delirium. alpha- agonists decrease noradrenergic upregulation secondary to cytokine storm. while dexmedetomidine can be used for acute agitation and cycling at night, guanfacine can help taper off dexmedetomidine and other sedatives. our patient had already been managed with dexmedetomidine. addition of guanfacine appears to have facilitated tapering off her other sedative drips, including dexmedetomidine. antipsychotics can assist in delirium symptom control, while patients must be monitored for qtc prolongation and neurologic and sedative side effects. specifically in this patient population, antipsychotic agents must be carefully monitored, given the potential use of covid- specific medications that may prolong qtc (e.g., hydroxychloroquine, azithromycin), leading to a potentially increased risk of torsade's de pointes ( ) , as well as rare cardiac manifestations of covid- . qtc was monitored on daily basis and did not demonstrate prolongation in our patient. while increasing doses of quetiapine did not seem helpful in our patient, switching to haloperidol in combination with other interventions, was correlated with improvement in patient's mental status. haloperidol might have been more helpful due to its more potent dopamine blockade and minimal antihistaminic and anticholinergic activity as compared to quetiapine. in addition, haloperidol has been found to be an effective antagonist of sigma- receptors, which, in theory, might potently protect against oxidative stress-related cell death ( ) . nursing staff was educated on assessing for extrapyramidal side effects associated with antipsychotics, integrating this into their regular patient assessment and care. vpa is used for management of hyperactive and/or mixed (i.e., fluctuating between agitation and hypoactivity) delirium, has potential anti-inflammatory and anti-oxidant effects, and might decrease transcription of interleukin- ( ). evidence also suggests potential neuroprotective effects of vpa ( ) . vpa might assist to minimize or taper off sedative agents, however, liver function tests and platelets must be closely monitored. addition of vpa seemed crucial in decreasing agitation of the patient and assisting in tapering off multiple sedating drips and as well as benzodiazepines and opiates. this case report discusses the proposed pathophysiology of covid- associated icu delirium. derived from the clinical complexity of the patient described, we provide a framework to delirium evaluation and management in similar patients. as the number of cases of covid- continues to increase, so will the hospital length of stay and inevitable incidence of delirium and agitation in these patients. thus, a systematic approach to delirium prophylaxis, screening, diagnosis, and treatment are paramount to patients' management and improved outcomes. this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. the authors report no conflict of interest. a novel coronavirus from patients with pneumonia in china characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention intensive care management of coronavirus disease (covid- ): challenges and recommendations. the lancet respiratory medicine the neuroinvasive potential of sars-cov may play a role in the respiratory failure of covid- patients neurologic manifestations of hospitalized patients with coronavirus disease delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit apa. diagnostic and statistical manual of mental disorders (dsm- ) evaluation of delirium in critically ill patients: validation of the confusion assessment method for the intensive care unit (cam-icu) a study of the psychometric properties of the "stanford proxy test for delirium" (s-ptd): a new screening tool for the detection of delirium validation of the stanford proxy test for delirium (s-ptd) among critical and noncritical patients neurologic features in severe sars-cov- infection. the new england journal of medicine a first case of meningitis/encephalitis associated with sars-coronavirus- . international journal of infectious diseases : ijid : official publication of the international society for nervous system involvement after infection with covid- and other coronaviruses. brain, behavior, and immunity cytokine storm in covid- and treatment delirium pathophysiology: an updated hypothesis of the etiology of acute brain failure dysregulation of immune response in patients with covid- in clinical infectious diseases : an official publication of the infectious diseases society of america disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome clinical characteristics and outcomes of older patients with coronavirus disease (covid- ) in wuhan, china ( ): a single-centered, retrospective study. the journals of gerontology series a, biological sciences and medical sciences neuropsychiatric clinical manifestations in elderly patients treated with hydroxychloroquine: a review article comparison of delirium assessment tools in a mixed intensive care unit covid- : melatonin as a potential adjuvant treatment addition of suvorexant to ramelteon therapy for improved sleep quality with reduced delirium risk in acute stroke patients postoperative delirium after pharyngolaryngectomy with esophagectomy: a role for ramelteon and suvorexant considerations for drug interactions on qtc in exploratory covid- (coronavirus disease ) treatment. circulation a prototypical sigma- receptor antagonist protects against brain ischemia valproic acid for treatment of hyperactive or mixed delirium: rationale and literature review key: cord- - uckmya authors: nan title: akzeptierte abstracts für die covid- -bedingt abgesagte dgiin/Ögiain-jahrestagung date: - - journal: med klin intensivmed notfmed doi: . /s - - - sha: doc_id: cord_uid: uckmya nan sehr geehrte leserinnen und leser, dieses jahr hätte die gemeinsame jahrestagung der dgiin und Ögiain als . jahrestagung in salzburg stattfinden sollte. leider kam die covid- -krise dazwischen, und trotz der weit fortgeschrittenen planungen war es unter einhaltung der gesetzlichen vorgaben nicht mehr möglich, eine so große tagung durchzuführen. die planungen beinhalteten auch bereits die evaluierung der eingereichten abstracts. da wir trotz der absage der tagung die autoren, die sich der mühe unterzogen, ihre arbeiten in einem abstract zusammenzufassen, nicht leer ausgehen lassen wollten, haben wir uns entschieden, die von den gutachtern akzeptierten abstracts in dieser ausgabe der zeitschrift medizinische klinik -intensivmedizin und notfallmedizin zu publizieren. somit soll den autoren gelegenheit gegeben werden, ihre daten trotzdem einem breiteren publikum präsentieren zu können. nach den derzeitigen planungen wird die jahrestagung im jahr wieder in salzburg stattfinden. wir hoffen, dass uns die mitglieder der dgiin und Ögiain dann auch wieder die treue halten, und wünschen ihnen eine interessante lektüre mit den abstracts der heuer leider ausgefallenen jahrestagung. results: in septic patients we observed a statistically significant decrease in the density of capillaries with a diameter of µm (d : . vs. . mm - , p = . ), µm (d : . vs. . mm - , p = . ) and µm (d : . vs. . mm - , p = . ) compared to healthy controls. furthermore, d , d and d correlated well with several markers of inflammation and critical illness such as lactate (d : rs = - . , p = . ; d : rs = - . , p = . ; d : rs = - . , p = . ), sequential organ failure assessment (sofa) score (d : rs = - . , p = . ; d : rs = - . , p = . ; d : rs = - . , p = . ), interleukin- (d : rs = - . , p = . ; d : rs = - . , p = . ) and procalcitonin (d : rs = - . , p = . ; d : rs = - . , p = . ). of note, capillary density in the larger diameter classes of - µm were neither different between patients and controls, nor did they show a meaningful correlation with relevant clinical parameters. conclusion: our data support the hypothesis that microcirculatory impairment in sepsis does not affect all microvessels under µm, but especially the "real capillaries" with a diameter between - µm. therefore, a detailed diameter-based assessment of the microvasculature should be evaluated in the future. aim: improvements in cannula removal techniques and in particular, a standardized decannulation technique with a suitable closure device, are needed to further improve patient outcomes after percutaneous cannulation. the decannulation techniques described so far are neither sufficiently standardized nor proven enough to be used in the large group of venoarterial extracorporeal membrane oxygenation patients. to meet this challenge, we have established a highly standardized and safe decannulation technique based on the perclose proglide closure system (abbott vascular). methods: establishment of a highly standardized and safe decannulation technique based on the perclose proglide closure system, which is described in detail with comprehensive instructions for the executive clinician and first application in the context of a pilot study. results: so far our technique has already been used successfully in patients since january as a standard procedure on our intensive care unít (icu) with only one minor complication after the first procedure, i. e. a small pseudoaneurysm likely originating from antegrade perfusion puncture site which was sealed by thrombin injection. conclusions: our crossed proglide technique using a hemostasis valve y connector ensuring no blood loss seems to be a very promising decannulation technique. purpose: dysfunctional alterations of the microcirculation play a key role in the development of organ damage in sepsis. therefore, early detection and monitoring of microvascular alterations has been recognized as an important goal in critical care medicine. in this study, we highlight the importance of a quantitative diameter-based analysis approach. methods: this prospective, observational, cross-sectional study included critically ill septic patients (sepsis ) recruited from the intensive care units of a university hospital and healthy volunteers served as controls. we used a sidestream dark field (sdf) camera paired with a data acquisition and analysis software (glycocheck™) to assess the sublingual microvessels. about videos ( vascular segments) per participant were acquired. using an automated data analysis, the density of red blood cells contained in microvessels (diameter - µm) was quantified and subdivided according to their particular diameter classes ( µm each). dererlangung des kreislaufes (rosc) war median ( - ) min. ein erneuter herz-kreislauf-stillstand im rahmen des icu-aufenthaltes wurde bei % (n = ) der patienten beobachtet. insgesamt überlebten % (n = ) der patienten nach hks den icu-aufenthalt, davon ein großteil ( %, n = ) mit gutem neurologischem outcome (cpc i/ii) nach reanimation. schlussfolgerung ("conclusion"): das auftreten eines hks auf der icu ist mit einer hohen mortalität vergesellschaftet. der hks ereignet sich in etwa der hälfte der fälle innerhalb der ersten h nach icu-aufnahme und ist selten kardialer genese. high to low bicarbonate replacement fluid switch in alkalotic patients during continuous venovenous hemofiltration with regional citrate anticoagulation-a retrospective single centre analysis goal of the study: the aim of our study was to compare the replacement fluids (rf) phoxilium ( mmol/ l hco -) and biphozyl ( mmol/ l hco -) during continuous renal replacement therapy (cvvh) with regional citrate anticoagulation (rca) in alkalotic critically ill patients. consequently, we hypothesized that the hco -, hypothesis (h ), be (h ) and co (h ) levels would significantly decrease after the rf change (phoxilium to biphozyl), with the ph (h ) stabilizing thereafter at physiological levels. methods: this retrospective study evaluated intensive care unit patients who underwent cvvh with rca between and . patients were eligible for inclusion if they were ) aged ≥ years, ) admitted to icu, had ) the indications for cvvh as determined by the attending physician, ) a change of replacement fluid from phoxilium® to biphozyl® based on a persistent blood hco -concentration ≥ mmol/ l. patients were excluded in case of cvvh duration less than h and < h of cvvh treatment duration with phoxilium® as well as biphozyl®. overall targeted observation period including data collection was from - h until + h around rf switch. student's t-test was used to test h - . all tests were -sided (significance level %). results: in the study ( male, female, mean age years, bmi ) out of cvvh-rca patients were eligible for analysis. after switching the rf the mean hco -[h ] significantly decreased from . mmol/l (sd± . mmol/l) to . mmol/l (sd± . mmol/l) within h (p = . ). the mean be [h ] significantly decreased from . mmol/l (sd± . mmol/l) to . mmol/l (sd± . mmol/l) within h (p = . ). the mean paco [h ] decrease from . mmhg (sd± . mmhg) to . mmhg (sd± . mmhg) within h was not significant (p = . ). during the rf change the mean ph [h ] was . (sd± . ) and did not change significantly for at least h (ph . , sd± . ) thereafter (p = . ) (. fig. ) . conclusions: switching from high to low bicarbonate rf in alkalotic patients during cvvh with rca seems to be an appropriate approach for acid-base control, although the paco was not significantly decreased. further research is warranted. gender differences in acid-base metabolism during continuous venovenous hemofiltration with regional citrate anticoagulation goal of the study: the aim of our study was to compare the replacement fluids (rf) phoxilium ( mmol/ l hco -) and biphozyl ( mmol/ l hco -) during continuous renal replacement therapy (cvvh) with regional citrate anticoagulation (rca) in alkalotic critically ill women and men. it was hypothesized that the hco -(hypothesis h ), base excess (be) (h ) and ph (h ) levels as well as the death rate at days (h ) dif-goal of the study: neither the feasibility nor the cardiodepressive and vasodepressive effects of isoflurane sedation in patients undergoing venoarterial extracorporeal membrane oxygenation (va-ecmo) treatment for cardiogenic shock have been investigated. as the vast majority of patients with severe cardiogenic shock treated with va-ecmo are unconscious and mechanically ventilated, the question arises to what extent a volatile sedation strategy using isoflurane is feasible in these patients, impacts the ventilation duration and intensive care unit (icu) stay, influences catecholamine dosages and va-ecmo flow support, and impacts treatment costs. methods: a total of cardiogenic shock patients with va-ecmo treatment under sedation with volatile isoflurane on our cardiac icu were enrolled in this retrospective single center study and were matched by propensity score in a : ratio with intravenously (iv) sedated patients. results and discussion: in this study patients in our registry treated with va-ecmo were sedated with isoflurane. the mean age of the patients was . ± . years for conventional sedation and . ± . years for isoflurane sedation (p = . ). administration of isoflurane was associated with lower iv sedative drug use during va-ecmo treatment ( % versus %, p = . ). mean systolic arterial pressure was similar ( . ± . mmhg versus . ± . mmhg, p = . ), but mean heart rate was significantly higher in the conventional sedation group in contrast to the isoflurane group ( . ± . /min versus . ± . /min; p = . ). importantly, catecholamine dose, va-ecmo blood flow and va-ecmo gas flow during the first days, ventilation time of survivors ( ± h versus ± h, p = . ), bleeding complications at least classified as bar-c a or higher ( . % versus . %, p = . ) and -day mortality ( . % versus . %, p = . ) were similar in both groups. the overall sedation cost per patient was significantly lower in the conventional group in comparison to the isoflurane group ( ± € versus ± €, p < . ). conclusion: volatile sedation with isoflurane is feasible, albeit with higher costs, in patients with cardiogenic shock and va-ecmo treatment and was not associated with higher catecholamine dosage and ecmo flow rate compared to iv sedation. background: acute kidney injury (aki) is a major problem in critically ill patients admitted to an intensive care unit (icu) causing both high mortality and morbidity. the aim of this study was to explore sex differences in critically ill patients admitted to an icu who had at least one episode of aki methods: all patients admitted to the icu of the university hospital innsbruck between -january and december were eligible for inclusion, if they developed at least one aki episode after icu admission. severity of aki was categorized according to kdigo methods: this retrospective study evaluated intensive care unit patients who underwent cvvh with rca between and . patients were found eligible for inclusion if they were ) aged ≥ years, ) admitted to icu, had ) the indications for cvvh as determined by the attending physician, ) a change of rf from phoxilium® to biphozyl® based on a persistent blood hco -concentration ≥ mmol/ l. patients were excluded in case of cvvh duration less than h and < h of cvvh treatment duration with phoxilium® as well as biphozyl®. overall targeted observation period including data collection was ± h from the switch of the rf. mann-whitney u-test and student's t-test was used to test h - , kaplan-meier method and logrank test was used for h . all tests -sided. results: in this study of cvvh-rca patients were eligible for analysis. of these ( %) were women (mean age years, height cm, median weight kg, bmi ) and ( %) men (mean age years, height cm, median weight kg, bmi ). during therapy with phoxilium hco -(p = . , h ) and be (p = . , h ) levels differed significantly (p < . ) between women and men, whereas ph (p = . , h ) did not. during therapy with biphozyl hco -(p = . , h ), be (p = . , h ) and ph (p = . , h ) did not differ significantly between women and men. mortality at days (p = . , h ) showed no significant difference between women and men (. fig. ) . conclusions: we found significant differences for hco -and be levels during therapy with phoxilium in alkalotic critically ill women and men, without an effect based on the volume of distribution. since no significant differences between women and men were found during therapy with biphozyl, this possibly indicates that rf with lower hco -concentrations may be beneficial for both sexes; however, we did not find significant differences in mortality. further research is warranted. fig. ( zu "high to low bicarbonate replacement fluid switch in alkalotic patients during continuous venovenous hemofiltration with regional citrate anticoagulation-a retrospective single centre analysis") trends of hco -, be, paco and ph over h before and after switching (t ) the replacement fluid from phoxilium® to biphozyl® methods: this was a post hoc analysis of patients ( female and male) from a prospective study, which investigated the potential influence of altered ca on the incidence of postoperative cognitive disorders (pocd) after major noncardiac surgery with the patient under general anesthesia. patients enrolled in this study were aged years or older and had no history of cerebrovascular or neurodegenerative disease. the ca monitoring was performed using continuous measurement of the cerebral oximetry index (cox) from incision to closure, where cox represents the moving correlation coefficient between near infrared spectroscopy (nirs) based measurement of regional cerebral oxygen saturation and mean arterial blood pressure (map). for data processing and cox calculation the icm+ software (university of cambridge, cambridge, uk) was used. a cox < . indicated intact ca, whereas a cox ≥ . indicated impaired ca and represents an increasing correlation between cbf and map. the association of gender with intraoperative cox and variables that were considered clinically relevant were analyzed with multivariate analysis. results: the time with cox ≥ . was significantly higher in male patients (males, . %, iqr . - . ); females, . %, iqr . - . , p = . ). average cox during the monitored time period was also higher in men (males, . , iqr . - . ); females, . , iqr . - . , p = . ). male gender was significantly associated with impaired ca in the multivariable analysis (b = - . , % ci: - . ;- . , p = . ). interestingly, there were no significant differences in average map, maximum map and minimum map between men and women. conclusion: women demonstrated better intraoperative ca at the same intraoperative map levels as men. our findings underline the importance of individualized blood pressure targets that may be sex-dependent. future clinical studies investigating the impact of our findings on perioperative neurological outcome are urgently needed. c (mean . ± . vs. . ± . ; p < . ). glomerular filtration rates (gfr) also showed significant differences between women and men when derived from creatinine (mean . ± . vs. . ± . ; p < . ) and from cystatin c (mean . ± . vs. . ± . ; p < . ). conclusion: while most assessed parameters showed no significant differences between women and men, both maximum creatinine and maximum cystatin c and their correspondingly minimum gfrs were significantly different between both sexes. this is an important finding, since the same creatinine criteria are considered for staging of aki, independent of possible influencing factors on creatinine, such as muscle mass. background: cerebral autoregulation (ca) is a mechanism that keeps cerebral blood flow (cbf) constant over a wide range of blood pressures, thereby ensuring the high metabolic demand of the brain [ , ] . previous studies have shown better cerebrovascular reactivity, and higher blood flow velocities in women under various conditions [ ] [ ] [ ] ; however, sex-related differences in ca in the perioperative setting are widely unexplored despite their potential impact on an individualized hemodynamic management. therefore, this study aimed to investigate sex-related differences in ca in patients undergoing major noncardiac surgery with the patient under general anesthesia. Üblicherweise erfolgt eine lagekontrolle mittels röntgen-thorax sowie ekg-ableitung, doch auch hier kann eine fehlerhafte lage nicht ausgeschlossen werden [ ] . die komplikationsraten können durch sonographisch gesteuerte punktion deutlich ( , % vs. , %) reduziert werden, auch eine sonographische lagekontrolle des seldinger-drahtes und des katheters ist so möglich [ ] . objective: percutaneous dilatational tracheotomy has become a routine procedure in intensive care units (icus); however, given the high and steadily growing number of patients receiving anticoagulation, dual antiplatelet therapy, or even a combination of both (also known as triple therapy), there are concerns about the safety of the procedure, in particular for critically ill patients with a high risk of bleeding. in this retrospective study, we investigated whether percutaneous dilatational tracheotomy in this high-risk population was associated with elevated procedural complications. design: retrospective single center study with analysis of all percutaneous dilatational tracheotomies performed in our cardiac icu from january to may . setting: munich university hospital cardiac icu. patients and interventions: a total of patients who underwent percutaneous dilatational tracheotomy according to the ciaglia technique with accompanying bronchoscopy in our cardiac icu from january to may were included. patients were stratified into clinically relevant risk groups based on anticoagulation and antiplatelet therapy considering regulation of cerebral autoregulation by carbon dioxide cerebral blood flow autoregulation and dysautoregulation sex dependency of cerebrovascular co reactivity in normal subjects influence of biological factors on changes in mean cerebral blood flow velocity in normal ageing: a transcranial doppler study elderly women regulate brain blood flow better than men do seltene ursache zerebraler ischämien: intraarterielle fehllage eines zvk -ein fallbericht abb. a röntgen-thorax nach zvk-anlage; zvk-spitze: roter pfeil. b sonographie der halsgefäße rechts nach Übernahme; zvk: roter pfeil standard laboratory coagulation parameters, i. e. activated partial thromboplastin time, international normalized ratio, and platelet count with differentiated analysis of procedure-related complications in each risk group until hospital discharge. measurements and main results: a total of patients who underwent percutaneous dilatational tracheotomy were included and assigned to clinically relevant treatment groups: iv unfractionated heparin (prophylactic dosage, n = ), iv unfractionated heparin (therapeutic dosage, n = ), aspirin and iv unfractionated heparin (therapeutic dosage, n = ), dual antiplatelet therapy with iv unfractionated heparin (prophylactic dosage, n = ), and dual antiplatelet therapy with iv unfractionated heparin (therapeutic dosage, n = ). bleedings without surgical intervention or blood transfusion was documented in three patients in the whole cohort, but no bleeding occurred in the triple therapy group. these were exclusively caused by skin bleeding at the immediate puncture site, each of which could be easily treated with one or two single stitches. there were no severe bleeding complications or potentially life-threatening procedure-related complications. additionally, the rate of complications in patients with elevated body mass index was not increased. conclusions: bronchoscopy-guided percutaneous dilatational tracheotomy according to the ciaglia technique with careful consideration of all potential indications and contraindications may be a safe and low-complication procedure for airway management, even in patients receiving dual antiplatelet therapy and therapeutic anticoagulation simultaneously in our cohort with a high risk of bleeding. interdisziplinäre operative intensivstation, klinik für anästhesiologie, intensivmedizin und schmerztherapie, universitätsklinikum des saarlandes, homburg/saar, deutschlandwir berichten über eine -jährige zeugin jehovas, die nach spontanabort in der . schwangerschaftswoche ein akutes nierenversagen und eine schwere anämie bedingt durch blutverlust und hämolyse erlitt. trotz umsetzung aller empfehlungen des "patient blood management" fiel der hämoglobinwert (hb) kontinuierlich ab. an tag wurde sie bei hb , g/ dl plötzlich bewusstlos und musste intubiert und beatmet werden. wegen organprotektiver effekte und der guten steuerbarkeit wurde sie inhalativ mit isofluran sediert. isofluran ermöglichte jeweils eine rasche neurologische beurteilbarkeit in sedierungsfenstern sowie eine regelmäßige, ruhige spontanatmung bei tiefer sedierung mit reduziertem sauerstoffverbrauch. als ausdruck einer posthypoxischen enzephalopathie zeigte sie in den sedierungsfenstern krampfanfälle, die im eeg bestätigt und antikonvulsiv behandelt wurden. bei hb , g/dl erhielt sie infusionsbeutel mit polymerisiertem bovinem hämoglobin (hemopure, hbo therapeutics llc, souderton, pa, usa), wegen der kurzen halbwertszeit mehrmals wiederholt an den folgetagen. eine beachtliche methämoglobinämie wurde festgestellt. auch nach abzug des met-hb zeigte das gesamt-hb anstiege um , - , g/dl nach den gaben. die sauerstofftransportkapazität konnte damit initial um % gesteigert werden. es kam zu einer vollständigen neurologischen erholung, und die patientin wurde schließlich vom respirator entwöhnt, jedoch weiterhin dialysepflichtig nach tagen in eine andere klink verlegt. schlussfolgerung: wenn die gabe von fremdblut keine option darstellt, kann durch gabe von polymerisiertem bovinem hämoglobin als ultima-ratio-therapie die sauerstofftransportkapazität vorübergehend erhöht werden. eine inhalative sedierung mit isofluran zur senkung des sauerstoffverbrauchs. key: cord- -pvf uon authors: zeitoun, jean-david; faron, matthieu; lefèvre, jérémie h. title: impact of local care environment and social characteristics on aggregated hospital-fatality rate from covid- in france: nationwide observational study date: - - journal: public health doi: . /j.puhe. . . sha: doc_id: cord_uid: pvf uon objectives we aimed to investigate possible differences in aggregated hospital-fatality rate from covid- in france at the early phase of the outbreak, and to determine whether factors related to population or healthcare supply before the pandemic could be associated with outcome differences. study design nationwide observational study including all french hospitals from january , to april , . methods we analysed aggregated hospital-fatality rate. a poisson regression was performed to investigate associations between characteristics pertaining to populational health, socioeconomic context and local healthcare supply at baseline, and the chosen outcome. results on april , , a total number of patients were hospitalized among the french healthcare facilities, including patients in intensive care unit (icu). a total of deaths due to covid- had been recorded, with a median mortality rate per people per department of . (iqr: . - . ). there were significant variations between the french departments even after adjusting on outbreak inception (p< . ). after multivariable analysis, four factors were independently associated with a significantly higher aggregated hospital-fatality rate: a higher icu capacity at baseline (estimate= . ; p= . ), a lower density of general practitioners (estimate= . ; p= . ), a higher fraction of activity from the for-profit private sector (estimate= . ; p< . ), and the ratio of people over (estimate= . ; p= . ). conclusions aggregated hospital-fatality rate from covid- in france seems to vary among geographic areas, with some factors pertaining to local healthcare supply being associated with outcome. first cases of coronavirus disease , the viral pneumonia related to severe acute respiratory syndrome coronavirus (sars-cov- ), were officially identified in december in china and were notified to the world health organization (who) on december , . since then, the epidemic has expanded well beyond china and the pandemic has officially been declared by the who on march , . while italy has been the earliest disease cluster in europe , france has rapidly followed. on february , , the french ministry of health issued the phase i of the national epidemic. phases ii and iii were respectively announced on february , and march , . fatality rate, defined as the number of deaths of patients in whom covid- was confirmed, divided by the total number of covid- cases, seems to vary among countries. italian reports have shown a casefatality rate ranging from approximately % to % , while other countries such as south korea have observed much lower figures. even if there is uncertainty due to variations in case recording, we lack definitive explanations for possible differences in case-fatality rates between countries. the number of tests that could be made to screen and insulate patients has been raised as a possible factor contributing to differences. also, it is not known whether this outcome varies within a country. several factors can likely explain differences such as affected population profile, healthcare environment and quality of care. there has been concern in france regarding critical care capacity with respect to the probable high number of simultaneous severe cases during the outbreak peak. it has been estimated by the french ministry of health that there were approximately , intensive care unit (icu) beds in france yet with differences between regions. estimates forecasted that this capacity would be exceeded. j o u r n a l p r e -p r o o f therefore, we sought to measure aggregated hospital-fatality rate from covid- in france, and to examine the association between populational and local healthcare supply characteristics, and this outcome. we used official and publicly available sources to retrieve and gather the needed data: we also retrieved the number of hospital beds per people, including surgery beds, medicine beds, obstetrical beds, physical medicine beds, psychiatry beds and those in long-term care facilities ( ) according to a report from the french ministry of health, and the total number of adult intensive care beds in each department at baseline, i.e. before the outbreak ( ). last, the fraction of hospital care activity as measured by hospital-days, performed by the for-profit private sector was collected ( ). for each department, the following health indicators were retrieved: overall mortality aggregated hospital-fatality rate was chosen as study outcome (i.e. for each day of the study period, the number of hospital deaths divided by the number of admitted patients). we chose not to analyze case-fatality rate since it would be unreliable in the french case. indeed, france has not performed systematic or large sars-cov- testing, and the number of recorded cases has repeatedly been recognized as being orders of magnitude below actual frequency. conversely, all serious cases of suspected covid- were required to be tested for confirmation. hospitalized cases, whether in regular wards or intensive care units (icus), therefore represent a reliable denominator for calculation. for each day of study period and in each of the french departments, the number of hospitalized covid- patients and the number of covid- patients in icus were collected. also, for each day of study sample, the j o u r n a l p r e -p r o o f cumulative number of covid- -related in-hospital deaths over study period was collected. to account for gaps in outbreak start between areas, the time origin for each department was set to the first day where at least deaths due to covid- had been recorded in total. to investigate the relationship between our covariates and the selected outcome, a mixed-effects poisson generalized linear regression was used. models were adjusted for the number of people living in the department and the corrected day since the beginning coded as a third order polynomial as fixed effects. to account for the hierarchical structure of our data, the department (grouping variable) was used as a random effect. both a random intercept and random slope (for the corrected days since the beginning) were used. any variable achieving a pvalue < . in the univariable analysis was proposed in the multivariable model. in there were a total number of healthcare facilities (including public hospitals, table . the median area of the departments was km (iqr: - km ). the study included data from january , (first french case) to april , . the details of univariate and multivariable analyses are given in table . following univariate analysis, eleven factors were included in the multivariable analysis. apart from the population, four factors were independently associated with a significantly higher aggregated hospital-fatality rate from covid- : a higher icu capacity at baseline (estimate= . ; p= . ), a lower density of general practitioners (estimate= . ; p= . ), a higher fraction of activity from the for-profit private sector (estimate= . ; p< . ) and the ratio of people over (estimate= . ; p= . ). no health indicator was associated with our outcome in the multivariable analysis. in this nationwide observational study regarding covid- in france, we found significant differences between areas in terms of aggregated hospital-fatality rate. four factors were associated with our study outcome: a higher density of icu beds at baseline, a lower fraction of hospital care activity from the for-profit private sector, a j o u r n a l p r e -p r o o f lower density of general practitioners, and a greater proportion of people over were all predictors of higher aggregated hospital-fatality rate in the current model. our study has several strengths. first, it is a nationwide analysis gathering exhaustive data from reliable sources. for most of covariates, year of availability was very recent, thereby limiting timeliness issues. in addition, the variables of interest are unlikely to significantly change across a relatively short period of time. second, we collected a very diverse set of data regarding demographics, populational health, wealth, and also characteristics of care supply and local healthcare ecosystems. populational health data were in particular critical to incorporate in the model since they are factors likely to influence disease outcome. we had very fine health data beyond age, namely prevalence of chronic conditions that have already been recognized as risk factors for covid- outcome. , , third, we used a robust statistical model to analyse the data, namely a poisson linear model as the variables were daily counts and a mixed model as the observed data were not independent (repeated measures within a department), which allows separate intercept and slopes for each department. also, time-adjustment was made so as to align all departments on a similar basis and take into account timeliness issues. our findings have implications. critical care capacity has been a matter of concern regarding covid- outbreak. it has been predicted that france did not have enough icu beds to absorb all of the patients in need along several days or weeks. yet we found no evidence that less icu beds at baseline in a given area were associated with a worst outcome. conversely, we found that areas with an initial higher density of icu beds were associated with a higher aggregated hospital-fatality rate. we do not have any certain explanation for those unexpected findings. it may be that critically ill patients were more often transferred from rural areas or smaller facilities to more j o u r n a l p r e -p r o o f comprehensive facilities. it also should be underlined that hospitals have anticipated the outbreak progression by resetting their organization and creating new icu capacity in other wards. we could not measure actual icu beds at a given time since those data were not consistently reported. this will need further investigation. we also found that areas in which the density of general practitioners was higher were associated with a better outcome. even though this should be interpreted with caution, one may hypothesize that general practitioners played a critical role in the epidemic, through adequate orientation of covid- patients to hospitals while maintaining others at home. last, it is remarkable that social and wealth factors were not associated with the chosen outcome. the relationship between wealth and health has been consistently documented by a huge body of literature. again, we cannot certainly explain why herein departments with more deprivation were not associated with a higher aggregated hospital-fatality rate yet it should be recalled that france has a very protective social system with a great safety net. perhaps it helped to attenuate the social risk in the case of the epidemic. this study has limitations. firstly, as an observational study, it cannot establish definitive causality. we cannot exclude the possibility that our results might be confounded by factors that were not measured. in particular, we cannot rule out that criteria for admitting patients were different among areas and that some hospitals had more serious cases than others, whether in regular wards or icus. also, we did not have access to age-and gender-structure of hospitalized patients. last, we did not take into account control measures implemented in the different departments even though those measures were thought to be very similar. secondly, the follow-up was intentionally limited. however, given the high urgency that many healthcare systems are currently facing worldwide, we aimed at rapidly providing a first evaluation of j o u r n a l p r e -p r o o f hospital-fatality rates from covid- in a markedly affected country. subsequent work over the outbreak course will say whether local differences and their associated factors persist. thirdly, we did not have access to hospital data or patient data. thus, we could not calculate individual hospital-fatality rate and had to deal with aggregate measures which have been updated on a daily basis at the department level over the study period. fourth, we intentionally excluded nursing home since the related data were not available across the whole study period. this represents a selection bias. last, as of march , , the french government decided to implement targeted transfers of seriously ill patients by medicalized trains or helicopters in order to improve resource allocation within the whole territory. those transfers may have interfered with our results even though we believe it is unlikely. indeed, reported counts of those transfers showed it involved very few patients as compared to the magnitude of the epidemic. it seems implausible that it significantly influenced the findings from the regression analysis, which were otherwise consistent over time. in conclusion, we found significant differences in aggregated hospital-fatality rate across french areas over the early period of the covid- outbreak. several factors pertaining to local healthcare supply were associated with a worst outcome, such as a higher icu capacity at baseline and a lower involvement from the private sector as well as a lower density of general practitioners. those findings clearly deserve further investigation with hospital-or patient-level data and over a longer follow-up. those departments have been chosen to illustrate the heterogeneity of situations across the whole french territory (see figure ). world health organization. who director-general's opening remarks at the media briefing on covid- - critical care utilization for the covid- early experience and forecast during an emergency response arrêté du mars portant diverses mesures relatives à la lutte contre la propagation du virus covid- case-fatality rate and characteristics of patients dying in relation to covid- in italy transmission potential and severity of covid- in south korea coronavirus : les simulations alarmantes des épidémiologistes pour la france health as an independent predictor of the french presidential voting behaviour: a crosssectional analysis les établissements de santé -édition the association between income and life expectancy in the united states clinical characteristics of coronavirus disease in china characteristics of and important lessons from the covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention key: cord- - q vbvvd authors: lee, james s.; godard, aurélie title: critical care for covid- during a humanitarian crisis—lessons learnt from yemen date: - - journal: crit care doi: . /s - - -y sha: doc_id: cord_uid: q vbvvd nan on day , while assessing the site to plan patient flow, a newly recruited doctor approached and asked, "where do we get ppe? how does the centre work?" the response given, "i don't know yet, but we will figure this out together." patients had already arrived. in may , médecins sans frontières/doctors without borders (msf) opened three covid- treatment centres (ctc) in sanaa and aden, yemen [ ] . we report our experience from rapidly setting up ctcs with intensive care units (icu) . working in humanitarian crises presents numerous contextual and cultural issues [ ] , but providing critical care in a war-torn country during a pandemic has further challenges. in the first week of opening the aden ctc, a surge of war-wounded resulted in a mass-casualty plan activation at the msf aden trauma hospital, which functioned as our covid- response support base. additionally, some hospitals were closed from fear of covid- , resulting in the aden ctc becoming rapidly overwhelmed and a second ctc opening. resource constraints, high influx of patients, and societal pressures were encountered in all ctcs, requiring that lessons learnt be applied in real-time. msf's three ctcs included wards and icus. invasive mechanical ventilation (imv) received global attention but is only the visible "tip of the iceberg" for covid- care. a full package of critical care includes, but not limited to, critical care trained staff, allied health and logistics staff, clinical mentoring for juniors, biomedical equipment, oxygen, medications, and a reliable supply chain. our icus emulated a closed-unit model with local nurses and generalist doctors supervised by an international intensivist and nurse. each icu had contextspecific resource constraints resulting in differences in the package of care related to equipment (ultrasound), investigations (laboratory, x-ray), oxygen supply, nutrition, medications, and staff (specialist doctors, nurses, physiotherapists, social workers, pharmacists, logisticians). due to limited icu beds, many critically ill patients remained in the ward where the maximal oxygen therapy was a non-rebreather mask (nrm) combined with a regular nasal cannula. this double oxygen set-up, in addition to prone positioning, successfully treated some patients, avoiding the need for ventilatory support. all three ctcs had rapid increases in admissions and community/contextual pressure to open immediately leaving no time for pre-opening training. local intensivists were not available and recruiting internationally was difficult, as the pandemic has increased the need for intensivists/icu nurses worldwide, many who are obliged to work in their home country. closure of airports/borders and security constraints limited the ability to move staff and supplies. this placed further pressure on local staff, many of whom had no or limited icu experience. routine icu care, such as ventilator settings, ventilator-associated pneumonia prevention bundles, infusion pump usage, and early mobility, amongst others, were unfamiliar. clinical protocols were developed and taught on-the-job. prone positioning had never been performed locally, but successfully taught in all icus. teaching critical care concepts within a few days (which typically take years of training) was challenging enough, but further complexity was added by simultaneously managing patients with a new disease, where medical knowledge of covid- was evolving daily. the aim of msf's covid- response in yemen was to provide oxygen to the maximum number of patients possible, irrespective of ventilator capacity. our ctcs were new structures without centralized oxygen, but solutions developed. in the first days at one icu, each ventilator was attached to one oxygen cylinder, which meant the patient was deprived of oxygen when the cylinder was changed. malfunctioning regulators delivered too much pressure, which damaged the ventilator and/or did not accurately measure the amount of oxygen remaining; thus, staff did not know when the cylinder was empty until the ventilator detected a sudden drop in fio . to overcome the above problems, a y-connection circuit with cylinders was created, ensuring that a ventilated patient was never deprived of oxygen. providing critical care requires a steady supply of medications, but supply challenges were numerous. we were unable to rely on msf's usual mechanisms for international procurement. a shortage of analgesia/sedation/ neuromuscular blocking agents in addition to inconsistent oxygen supply forced us to adapt. when the medications for imv were unavailable, non-invasive ventilation (niv) was favoured-and sometimes the only option (high flow nasal cannula oxygen was unavailable). bilevel positive airway pressure was commonly used because many patients presented late with silent hypoxia and increased work of breathing, requiring inspiratory pressure support. initially, we did not have niv masks and used ambu-bag masks with a bandage wrap to secure them. this apparatus frequently had a poor mask seal, resulting in excessive oxygen use further straining our supply issues, but was life-saving in some cases. our protocol for niv in covid- incorporated a weaning schedule alternating niv with nrm by gradually decreasingincreasing the time on niv-nrm over days. this avoided intubation in some patients who survived to icu discharge after a mean . days of niv (range to days). overtime, imv medications became available locally and sometimes the quality was uncertain (e.g., ineffective atracurium likely due to a lack of cold chain storage), but there was no alternative option. a consistent supply was needed and contributed to successful application of imv. survivors of imv required a mean . ventilator days (range to days). patient outcomes for the first weeks of operations for one icu are shown in fig. , but the high crude mortality provides an incomplete picture of outcomes, as quality of care improved overtime. additionally, there were important secondary benefits from introducing critical care with imv. patients inside and outside of the icu benefited overtime due to an increase in knowledge and awareness from monitoring, increase in staff skills, fig. confirmed covid- (by pcr or ct scan) admitted to one intensive care unit (icu) from june to july and ability to provide a higher level of care. multidisciplinary teamwork was strongly encouraged in the icu and this effect extended to the ward, where the icu team frequently assisted in patient care. in summary, providing critical care with imv for patients with covid- during a humanitarian crisis in a war-torn country such as yemen is feasible but requires implementation of a full package of care adapted to the context. catastrophe unfolding in aden's only covid- treatment centre caring for critically ill patients in humanitarian settings publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank all field staff, local collaborators, patients, and families from all msf yemen field projects that we have had the pleasure of participating in. we thank dr. clair mills for her review of the manuscript and all departments from msf operational centre brussels and operational centre paris for their support. both authors equally contributed to the manuscript. both authors read and approved the final manuscript. authors' information jl is an intensivist and emergency care advisor for médecins sans frontières. ag is an intensivist and intensive care advisor for médecins sans frontières. availability of data and materials routine monitoring data was assessed as part of routine field operations. data sharing is not applicable to this article as no datasets were generated or analysed for this article.ethics approval and consent to participate not applicable. need for approval was waived by the medical director for médecins sans frontières. not applicable. the authors declare that they have no competing interests. received: august accepted: september key: cord- - gmn fcj authors: almazrou, saja h.; almalki, ziyad s.; alanazi, abdullah s; alqahtani, abdulhadi m.; alghamd, saleh m. title: comparing the impact of hydroxychloroquine based regimens and standard treatment on covid- patient outcomes: a retrospective cohort study date: - - journal: saudi pharm j doi: . /j.jsps. . . sha: doc_id: cord_uid: gmn fcj background pharmacological treatments including antivirals (lopinavir/ritonavir), immuno-modulatory and anti-inflammatory drugs including, tocilizumab and hydroxychloroquine (hcq) has been widely investigated as a treatment for covid- . despite the ongoing controversies, hcq was recommended for managing mild to moderate cases in saudi arabia . however, to our knowledge, no previous studies have been conducted in saudi arabia to assess its effectiveness. methods a hospital-based retrospective cohort study involving patients with covid- was conducted from march to may , . the study was conducted at prince mohammed bin abdul aziz hospital (pmah). the population included hospitalized adults (age ≥ years) with laboratory-confirmed covid- . each eligible patient was followed from the time of admission until the time of discharge. patients were classified into two groups according to treatment type: in the hcq group, patients were treated with hcq; in the sc group, patients were treated with other antiviral or antibacterial treatments according to ministry of health (moh) protocols the outcomes were hospitalization days, icu admission, and the need for mechanical ventilation. we estimated the differences in hospital length of stay and time in the icu between the hcq group and the standard care (sc) group using a multivariate generalized linear regression. the differences in icu admission and mechanical ventilation were compared via logistic regression. all models were adjusted for age and gender variables. results a total of patients fulfilled the inclusion criteria. approximately % (n= ) received hcq-based treatment, and % (n= ) received sc. length of hospital stay and time in icu in for patients who received hcq based treatment was shorter than those who received sc. similarly, there was less need for icu admission and mechanical ventilation among patients who received hcq based treatment compared with sc, ( . % vs. . and . % vs. . %). however, the regression analysis showed no significant difference between the two groups in terms of patient outcomes. conclusion hcq had a modest effect on hospital length stay and days in icu compared with sc. however, these results need to be interpreted with caution. larger observational studies and rcts that evaluate the efficacy of hcq in covid- patients in the saudi population are urgently needed. the world health organization (who) announced coronavirus disease at the beginning of , naming it a public health emergency of international concern (world health organization. who, n.d.) . as of july nd , , the who has reported a total of , , confirmed cases and , deaths (world health organization. who, n.d.) . covid- has been associated with a substantial symptomatic burden, including dyspnea that leads to death due to respiratory and heart failure (keeley et al., ) . the economic burden of such a pandemic is also troublesome. in the united states, the direct medial cost for one patient is $ , per infection course (bartsch et al., ) . if % of the u.s. population becomes infected, the total direct medical cost will be approximately $ billion. direct medical costs are mainly incurred via hospitalization, intensive care unit (icu) admissions, and ventilator use. the burden of covid- therefore extends beyond health care and affects the societal and national economies of affected countries (keni et al., ) . because covid- is an emerging disease, treatment protocols and guidelines are being developed and updated rapidly (national institutes of health, ; world health organization. who, n.d.) . several observational and interventional studies have evaluated the effectiveness of various pharmacological treatments for covid- (matera et al., ; siemieniuk et al., ) . the main therapies being used to treat covid- are antiviral drugs which include remdesivir and lopinavir/ritonavir combination which inhibits viral protease (pascarella et al., ) . other treatments such as respiratory therapy which delivers oxygen in case of hypoxia or symptoms of respiratory distress. chloroquine and hydroxychloroquine (hcq) is among the promising treatment modalities for covid- patients geleris et al., ; rosenberg et al., ; shen et al., ) . hcq is an antimalarial drug that have been used for decades to treat autoimmune diseases such as systemic lupus erythromatus (sle) and rheumatoid arthritis (ra) (ponticelli and moroni, ) . hcq work by increasing the endosomal ph and thus enhancing the fusion between the virus and host cell (pascarella et al., ) . in addition, it has some immunomodulatory effect by interfering with the ace cell receptors. the recommended regimen is to start with a loading dose of mg bid for the first day followed by mg bid (colson et al., ) . the common side effects include nausea, vomiting and diarrhea. arrhythmogenic cardiotoxicity was also associated with the use of hcq, which require qt interval monitoring. several in vitro studies demonstrated the antiviral efficacy of hcq not only have in vitro studies suggested hcq's activity against the sars-cov- virus, but observational studies have also suggested its effectiveness in covid- patients (mahévas et al., ) . several ongoing clinical trials are aimed at examining the efficacy and safety of hcq in covid- patients ("clinicaltrials.gov-searching for covid and hydroxychloroquine," ). despite the large number of studies assessing the effectiveness of hcq, evidence is still limited and inconclusive (pascarella et al., ) . on march , , the saudi ministry of health (moh) issued the first protocol for treating adults with a confirmed diagnosis of covid- ( saudi moh and cdc, ) . in this version, hcq was one of the recommended treatments for mild to moderate cases of the disease. for severe cases, the protocol still recommends hcq, but alternatives such as lopinavir/ritonavir can also be used (saudi moh and cdc, ) . despite the recommendation to use hcq in covid- patients in the moh protocol, no observational studies or rcts that evaluate the efficacy of these drugs in the saudi arabian population have been published. therefore, the objective of this observational study is to compare the effects of hcq and standard care (sc) on length of hospital stay, icu admission, and mechanical ventilation use among covid- patients. a hospital-based cohort study involving confirmed cases of patients with covid- was conducted retrospectively from march , , to may , . the strobe guideline for cohort studies was followed (von elm et al., ) . we conducted the study at prince mohammed bin abdul aziz hospital (pmah), an infectious disease center in riyadh ("prince mohammed bin abdulaziz hospital (pmah)," n.d.). in the response to the covid- pandemic, this hospital was among the leading hospitals designated as covid- centers. as such, patients with covid- symptoms were escorted to this hospital. the population included hospitalized males and females (age ≥ years) with laboratory- patients who were transferred to other facilities, had incomplete or missing data, or received supportive treatment that only included analgesics were excluded from the final dataset. data were collected from patients' medical records by trained medical personnel. collected data included patients' basic information (e.g. age, gender, nationality); medication prescribed; and information on hospitalization, cases requiring icu care, and mechanical ventilation. a well-designed, organized checklist was used to obtain and extract necessary information from patients' medical records. the primary outcomes of interest for this study were hospital length of stay (number of days from the patient's arrival at the hospital until discharge) and time in icu (calculated as the number of calendar days from the day of admission to the day of discharge). we also assessed the patients' need for icu care and mechanical ventilation. data were cleaned, edited, and entered into sas version . for analysis. descriptive data were reported for dichotomous polychotomous frequencies and percentages to examine the distribution of study variables among members of the hcq and sc groups. a chi-square test was utilized to compare categorical variables between groups. continuous variables were presented as means ± standard deviation (sd) and/or median with interquartile range (iqr). we estimated the differences in length of hospital stay and time in icu between the two groups using a multivariate generalized linear model regression. the differences in the need for icu admission and mechanical ventilation were compared via logistic regression. all models were adjusted for age and gender variables. no imputation was performed for all tests, and statistical significance was considered at a p-value of less than . . ethical clearance was obtained from the institutional review board (irb) at king fahad medical city with irb log no. - . hospital management's permission was obtained to conduct this study. the information and data collected were kept confidential. this study included no personal information or identifiers such as names or id number. a total of patients fulfilled the inclusion criteria and were included in the study. a total of regimens were prescribed for these patients. in the hcq group, hcq, azithromycin, and ceftriaxone comprised the most prescribed regimen ( %), whereas in the sc group, an azithromycin and ceftriaxone regimen accounted for % of the participants (see appendix a for additional information). approximately % of patients received hcq based treatment, and % received sc treatment. no differences were observed between the two groups with respect to age, whereas the number of male and non-saudi patients were more in the hcq group (p= . and p= . , respectively). table illustrates the demographic characteristics of the included study patients. length of hospital stay and time in icu in for patients who received hcq based treatment was shorter than those who received sc. similarly, there was less need for icu admission and mechanical ventilation among patients who received hcq based treatment compared with sc, ( . % vs. . and . % vs. . %), respectively; see table ). the results of the regression analyses after controlling for age and gender are shown in table . despite the shorter length of hospital stay and time in icu among patients who received hcq based treatment, as well as the smaller proportions of patients who needed icu care and mechanical ventilation in this group, the results indicated no significant differences in these outcomes between the two cohorts. in this study, we employed a multivariate linear regression with adjustment for gender and age and found that treatment with hcq was associated with shorter length of hospital stay and fewer days in icu when compared with sc treatment. however, the difference was not significant. in addition, the percentage of patients who required icu admission and mechanical ventilation was lower in the hcq group than in the sc group, but the difference was not significant. our results were consistent with those of other observational studies. for instance, a retrospective cohort study was conducted at new york-presbyterian hospital (nyp)-columbia university irving medical center (cuimc) and published in nejm (geleris et al., ) . in this study, the outcomes were intubation rate and death rate (geleris et al., ) . hcq use was not associated with a significant decrease in intubation or death (geleris et al., ) . the second study that evaluated the effectiveness of hcq in covid- patients was a systematic review that evaluated the efficacy of hcq based on peer reviewed articles and preprint studies. hcq showed controversial results among studies (das et al., ) . in conclusion, our study results are consistent with other observational studies on the effectiveness of hcq in covid- patients. generally, the effectiveness of pharmacological treatments of covid- including antivirals such as remdesivir and lopinavir/ritonavir, chloroquine and hydroxychloroquine is limited and inconclusive (cortegiani et al., ; das et al., ; siemieniuk et al., ) . this is mainly due to small sample size of most studies, lack of randomization and potential risk of selection bias (pascarella et al., ) . according to a recently published meta-analysis which aim to assess the effectiveness of pharmacological intervention in covid- (siemieniuk et al., ) . the only promising treatment that demonstrated a substantial impact on mortality, length of stay and mechanical ventilation is glucocorticoids. however, glucocorticoid are only recommended for covid- patients having severe acute respiratory distress syndrome (ards) . the potential benefits of glucocorticoid for patients with no symptoms of ards is still inconclusive (matera et al., ) . to our knowledge, this is the first study in saudi arabia that clearly describes treatment options for covid- patients. other published studies in saudi arabia mainly described patient characteristics with a minimal emphasis on treatments and outcomes (alsofayan et al., ) . the treatment options recommended by the moh protocol (saudi moh and cdc, ) were summarized in a disaggregated method to fully understand the prescribing pattern of covid- treatments. in addition, the choice of various outcomes, including hospitalization, icu admission, and mechanical ventilations targeted various levels of disease severity and facilitated comparison with other published studies that used these outcomes to assess treatment success. however, this study has some limitations. first, randomization was not feasible as this stage of study, which potentially limits the selection bias. second, the study did not have sufficient power to detect any statistical difference due to small sample size. therefore, inferential statistical analyses cannot capture the potential effect of the intervention. second, in saudi arabia, the moh provides % of health care services, whereas other governmental sectors, including teaching hospitals, the ministry of defense, and security forces provide the remainder (almalki et al., ) . this diversity in the provision of health care generates some inevitable issues, including those related to the definition of sc and generalizability. the definition of sc for covid- might vary considerably across various hospitals within the moh and other referral hospitals. moreover, this study recruited people from only one hospital; therefore, the sample might not be representative of people with covid- throughout the kingdom. covid- treatment options and guidelines continue to evolve on a daily basis. therefore, decision-makers need a dynamic source of data that captures such ongoing progress. the health electronic surveillance network (hesn) is a web based platform managed by the moh that records and analyzes infectious diseases and pandemic data (saudi moh and hesn, ) . the current use of the hesn is quite limited, as it only collects patient demographics and laboratory data (alsofayan et al., ) . therefore, decision-makers should consider expanding the scope of such platforms to include treatment regimens and patient outcomes. in addition, decision-makers should mandate that all moh and non-moh hospitals register covid- patients and record their treatments and outcomes on a daily basis. this will ultimately generate a valuable representative data source that could help clinicians, researchers, and decision-makers assess the impact of emerging treatments on patient outcomes. in this study, the choice of hydroxychloroquine and the comparators (mainly antivirals) was mainly informed by the moh guidelines for managing covd- patients ( ). the guideline gave a range of therapeutic options according to the disease severity. additionally, the guideline did not provide any preference as for st and nd line treatment. therefore, it was left to the treating physician to start either with hcq or antiviral. we believe that the selection of st line therapy was based on the availability of the medication and the potential side effect of hcq which need to be used cautiously for patients with arrythmia. future clinical practice guidelines should consider the cost, availability of medication, patient preference and potential side effect to ensure the consistency of clinical practice among different hospitals. despite that hcq based regimens reduce hospitalization and icu admission, the results were not statistically significant. this was mainly due to the small size. in addition, the study's participants were recruited from a single hospital, which limits the generalizability of our results. larger observational studies and rcts that evaluate the efficacy of hcq in covid- patients in the saudi population are urgently needed. health care system in saudi arabia: an overview clinical characteristics of covid- in saudi arabia: a national retrospective study the potential health care costs and resource use associated with covid- in the united states. health aff efficacy of hydroxychloroquine in patients with covid- : results of a randomized clinical trial gov-searching for covid and hydroxychloroquine chloroquine and hydroxychloroquine as available weapons to fight covid- a systematic review on the efficacy and safety of chloroquine for the treatment of covid- an updated systematic review of the therapeutic role of hydroxychloroquine in coronavirus disease- (covid- ) observational study of hydroxychloroquine in hospitalized patients with covid- symptom burden and clinical profile of covid- deaths: a rapid systematic review and evidence summary covid- : emergence, spread, possible treatments, and global burden clinical efficacy of hydroxychloroquine in patients with covid- pneumonia who require oxygen: observational comparative study using routine care data pharmacological management of covid- patients with ards (cards): a narrative review coronavirus disease (covid- ) treatment guidelines covid- diagnosis and management: a comprehensive review hydroxychloroquine in systemic lupus erythematosus (sle) prince mohammed bin abdulaziz hospital (pmah) [www document association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with covid- in new york state saudi ministry of health (moh), n.d. saudi moh protocol for patients suspected of saudi ministry of health (moh), n.d. health electronic surveillance network (hesn) [www document saudi ministry of health (moh) and the saudi center for disease prevention and control (cdc), . coronavirus disease (covid- ) guidelines treatment of critically ill patients with covid- with convalescent plasma drug treatments for covid- : living systematic review and network meta-analysis the strengthening the reporting of observational studies in epidemiology (strobe) statement: guidelines for reporting observational studies who director-general's remarks at the media briefing on world health organization. who, n.d. who coronavirus disease (covid- ) dashboard [www document clinical management of covid- : interim guidance [www document in vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus (sars-cov- ) efficacy and safety of corticosteroids in covid- based on evidence for covid- , other coronavirus infections, influenza, communityacquired pneumonia and acute respiratory distress syndrome: a systematic review and *data expressed as mean ± sd and median (iqr) abbreviations: hcq, hydroxychloroquine; sc key: cord- -tqzvdssb authors: dubost, clément; pasquier, pierre; kearns, kévin; ficko, cécile; rapp, christophe; wolff, michel; richard, jean-christophe; diehl, jean-luc; le tulzo, yves; mérat, stéphane title: preparation of an intensive care unit in france for the reception of a confirmed case of ebola virus infection() date: - - journal: anaesth crit care pain med doi: . /j.accpm. . . sha: doc_id: cord_uid: tqzvdssb the current ebola virus disease (evd) outbreak in west africa is a major challenge for the worldwide medical community. on april th , the world health organization (who) declared , infected cases; among them, , have deceased. the epidemic is still ongoing, particularly in sierra leone. it is now clear that northern countries will be implicated in the care of evd patients, both in the field and back at home. because of the severity of evd, a fair amount of patients may require intensive care. it is highly probable that intensive care would be able to significantly reduce the mortality linked with evd. the preparation of a modern intensive care unit (icu) to treat an evd patient in good conditions requires time and specific equipment. the cornerstone of this preparation includes two main goals: treating the patient and protecting healthcare providers. staff training is time consuming and must be performed far in advance of patient arrival. to be efficient, preparation should be planned at a national level with help from public authorities, as was the case in france during the summer of . due to the severity of the disease, the high risk of transmission and scarce knowledge on evd treatment, our propositions are necessarily original and innovative. our review includes four topics: a brief report on the actual outbreak, where to receive and hospitalize the patients, the specific organization of the icu and finally ethical aspects. the ongoing ebola virus disease (evd) outbreak in west africa is due to the zaire ebola virus, an enveloped, non-segmented, negative-stranded rna virus from the filoviridae family [ ] . ebola virus, like margburg virus, is a highly transmissible, category a biothreat pathogen [ ] . in this useful classification, a represents the highest risk and highest priority agents, b the second highest priority and c the third highest priority, including emerging pathogens that could be engineered for mass spread in the future. evd causes fever, headache, gastrointestinal symptoms, diffuse haemorrhage, multiple organ failure and has a high fatality rate. ideally, all the deceased patients should have been treated in an intensive care unit (icu), meaning that at least % of the cases would have been admitted to the icu. preparation of northern countries for evd treatment is based on two transmission models. firstly, certain healthcare workers are involved in non-governmental organizations that help treat infected people [ ] . as health workers, they are exposed to contaminated blood and other body fluids. thus, they are particularly at risk of infection and may develop the disease, either in west africa or back at home. the current ebola virus disease (evd) outbreak in west africa is a major challenge for the worldwide medical community. on april th , the world health organization (who) declared , infected cases; among them, , have deceased. the epidemic is still ongoing, particularly in sierra leone. it is now clear that northern countries will be implicated in the care of evd patients, both in the field and back at home. because of the severity of evd, a fair amount of patients may require intensive care. it is highly probable that intensive care would be able to significantly reduce the mortality linked with evd. the preparation of a modern intensive care unit (icu) to treat an evd patient in good conditions requires time and specific equipment. the cornerstone of this preparation includes two main goals: treating the patient and protecting healthcare providers. staff training is time consuming and must be performed far in advance of patient arrival. to be efficient, preparation should be planned at a national level with help from public authorities, as was the case in france during the summer of . due to the severity of the disease, the high risk of transmission and scarce knowledge on evd treatment, our propositions are necessarily original and innovative. our review includes four topics: a brief report on the actual outbreak, where to receive and hospitalize the patients, the specific organization of the icu and finally ethical aspects. ß socié té française d'anesthé sie et de ré animation (sfar). published by elsevier masson sas. all rights reserved. secondly, direct dissemination has been limited, despite the occurrence of the outbreak in cities with major commercial airports. during the current outbreak, imported cases of ebola have been reported in countries (italy, mali, senegal, spain, the united kingdom and the united states). among the latter, died. but due to the incubation period (from to days), it cannot be excluded that some people coming back from west africa would declare the infection after their arrival in northern countries. because of the severity of evd, a fair amount of patients may require intensive care. as recently shown in two reports, renal failure and rhabdomyolysis were frequent in severe evd cases [ , ] . common icu therapy, including fluid therapy and dialysis, would help decrease mortality rates [ , ] . thus, the preparation of intensive care units in affluent countries is necessary in order to be able to receive a confirmed case of evd with two main goals: (i) to treat the patient and (ii) to protect the healthcare providers. the french government has required that our unit be able and ready to receive evd cases in severe condition. we recently published a picture presenting a dedicated icu room for evd patients [ ] . in this article, we will detail the preparation of the latter. we purposely decided to limit our presentation to confirmed cases of evd in the setting of hospital care. due to the severity of the disease, the high risk of transmission and scarce knowledge on evd treatment, our propositions are necessarily original and innovative. the first confirmed case of the current outbreak was declared in march but it is most probable that the epidemic started in december [ ] . on april th, , the world health organization (who) declared , infected cases, , of whom have deceased ( %) [ ] . the evd epidemic is the largest in history and is affecting multiple countries in west africa. the risk of an outbreak in northern countries seems highly improbable because of the difference in diagnostic and medical facilities and due to the absence of a reservoir. one of the main risks of contamination is contact with an infected patient, repatriated with the disease, be it already declared or not. healthcare workers are particularly at risk of contamination [ ] . to date, no aerosol transmission has been documented, nor transmission following healthy skin exposure. after contamination through human liquids (including saliva, blood, vomit, urine, etc.), the virus spreads in the organism and replicates itself at a high rate [ ] . this leads to virus particles in the blood that can be as high as plaque-forming unit/ml. the risk of transmission is very high, particularly for the medical teams. one of the goals when receiving an infected patient is to guarantee the best level of protection for healthcare providers. the risk of contamination for laboratory personnel is low thanks to laboratory procedures. to date, accidents during laboratory work with ebola virus have been reported: case was fatal, case was symptomatic and survived and in cases there was no evidence that the accident resulted in infection and the patients survived [ ] . thus, one can assume the same level of risk for health team members. as recently seen in spain, despite wearing personal protective equipment (ppe), a nurse was contaminated during the care of an infected patient [ ] . in texas, a delay in evd diagnosis for a case in the emergency department led to the death of a healthcare worker and fear of several secondary cases [ ] . these events underline the importance of hospital organization and the need for informing both public and healthcare workers. the ppes in use in our centre are fluid impermeable. according to our experience, there are only two choices available when hospitalizing a confirmed case of evd: the infectious ward or the icu. during the preparation of the begin military teaching hospital, a dedicated access to both the icu and the infectious disease ward was identified, and a protected way to move a patient from the infectious ward to the icu implemented. the procedures for corridor decontamination must be known and established. to ensure that healthcare workers are efficient in dressing with the ppe, several training sessions should be planned and supervised by experts (fig. ). this implies that the hospital provides wards with a sufficient number of ppes. even when they are considered skilled at putting on or taking off their ppe, healthcare workers must proceed in pairs, in order to verify they are not making any mistakes. particular attention should be paid when undressing, which is the time period most as risk for contamination. our team was taught how to undress correctly in order to avoid contact with the contaminated part of the ppe. once the ppe is off, workers must thoroughly wash their hands with alcohol gel. in the icu, physical barriers must be in place to prevent visitors or unprotected staff from accessing the high-risk area. this highrisk area should be clearly marked out using coloured panels and stickers. three kinds of area can be differentiated within the unit (table ). there are no clear recommendations concerning the organization of the patient's room, but the following conclusions can be drawn from knowledge from biosafety level- (bsl- ) laboratories [ ] : rooms should be maintained under continuous negative pressure with an increasing pressure gradient from the airlock to the patient room. if possible, the room must include a one-way access or keep forward access. if not possible, a dressing room should be provided close to the patient's room and the airlock will be used to get undressed, thus being considered an ''orange'' area ( table ). the negative pressure within the patient's room is not mandatory but it cannot be excluded that severely infected patients with diffuse bleeding might excrete viruses in the air. dealing with the patient's waste is a major problem and must be anticipated. to ensure a safe evacuation of contaminated biological materials, a high number of bins should be available and specific treatment pathways for these wastes established in advance. as stated previously, a choice must be made between the infectious ward and the icu. if the patient presents with one or more organ failure(s), then the choice for icu is straightforward. if there is no organ failure, one must keep in mind the natural evolution of evd. the occurrence of diarrhoea, nausea/vomiting, electrolyte disturbances, neurological impairment or bleeding (even minimal) may indicate a risk for progression towards severe illness and the patient should be addressed to the icu. a key point in the decision between using an infectious ward or an icu depends on how secure the transfer of a patient from ward to icu would be. scientific evidence that might help guide the physician in this unfamiliar decision is currently scarce [ ] . if biological results are available, some of the following should be considered as severity markers: leukopenia, lymphopenia, thrombocytopenia [ ] , massive activation of monocytes/macrophages [ ] , disseminated intravascular coagulation [ ] , elevated liver enzyme or metabolic disturbances [ ] . in west africa, the mortality of the current outbreak is %, meaning that at least % of the patients may require icu care due to severity. due to the high probability of complications, patients repatriated from the field during the first days of evd should be directly oriented to an icu. only patients repatriated after the th day or very early can be oriented to the infectious ward. another point to take into account when making the decision is the difficulty of transferring patients from the infectious ward to icu. importantly, at all times, discussion between infectious specialists and intensivists is essential when dealing with these high-risk patients. there are currently no specific recommendations for icu care of confirmed evd cases. all the following propositions are based on common sense and on our hospital experience. the dedicated team comprises at least two health workers: one nurse and one doctor or two nurses for usual care, if the patient is stable. the staff includes only senior and experienced workers. people suffering from respiratory disease, claustrophobia and pregnant women should be excluded. staff must pay attention to eat, drink and go to the toilets before wearing the ppe. all the patient's care must be done when wearing the full ppe, including goggles and respiratory devices. we found it useful to install a mirror in the airlock just before entering the patient's room, so that everyone can personally check his/her protection (fig. ) . all care provided to the patient must be weighed from a benefit/ risk perspective. due to the high risk of contamination during accidents for health workers, procedures that have not proven their utility should probably be avoided. the following care should be performed: central venous access, arterial catheterization, pleural drain, mechanical ventilation, and continuous renal replacement therapy. ultrasonography is really a cornerstone in the care of evd cases. technical difficulties and risk of contamination render the availability of dedicated us devices and probes mandatory for each evd room. as concerns the risk of blood handling, ecmo and ecls should be avoided and increased haemorrhagic risk in balance with the current scarce evidence of benefit in critical patients [ ] . if the patient will require a lot of blood work, the insertion of an arterial line should be considered in order to decrease the risk associated with needle handling. if the patient is haemodynamically stable and invasive blood pressure monitoring is not required, insertion of a central venous line is the best solution both for fluid administration and blood analyses. finally, a peripheral line should be kept only for stable patients who may not require daily blood analyses. to be able to safely take care of an agitated patient without any venous access, we decided to have a sedative gas ready in the room. the latter can be a nitrous oxide cylinder, or if not available, an anaesthesia workstation for using inhaled anaesthetics. the aforementioned proposition must remain exceptional, bearing in mind the high risk of aspiration and haemodynamic instability. in all other cases where the patient remains still and cooperative, vascular access should be managed as usual, including local anaesthesia and ultrasonographic guidance [ ] . the jugular site should be preferred for its ease, safe access with us guidance, low risk of infection compared to femoral sites and the possibility of external compression in case of bleeding. hygienic precautions must be respected in as much as possible but reaching the usual aseptic conditions may not always be possible. ppes are not sterile. a surgical gown and two pairs of gloves should be worn. the second pair of gloves can be g-vir (hutchinson santé , paris, france) gloves. the latter are sterile surgical gloves incorporating a disinfecting liquid, reducing the transmitted viral load in the event of a blood exposure accident. the argument to propose such gloves is only theoretical as there is currently no proof that they could decrease the risk of transmission for evd. here again, recommendations are based on those drawn from our experience with severe acute respiratory syndrome-associated coronavirus infection. aerial transmission is not the major mode of transmission for evd, unless one considers end-stage disease with diffuse bleeding including alveolar haemorrhage. nevertheless, few situations are associated with a particularly high risk, justifying the use of an ffp mask ( table ) . tracheal intubation is done with full ppe, including goggles and an ffp mask. rapid sequence induction without facial mask ventilation should be preferred and intubation should be anticipated if possible. during invasive ventilation, interventions must be limited to the ones strictly necessary. a closed suction system must be used, that can work for up to days. all the interventions on the respiratory circuit (change of filter, circuit or suction system) are at high risk of viral particle aerosolization, particularly if secretions are blood-tinted. the circuit should be changed only if needed and not systematically. inhalation should be avoided and replaced by intravenous administration each time it is equivalent. non-invasive ventilation (niv) creates a particular risk of aerosols during a patient's plugging and unplugging, as well as if leaks exist around the mask. due to the high risk of failure and the need for tracheal intubation, niv should probably be avoided, at least if the patient with bleeding disorders. in view of the results of the recent florali study, high-flow oxygen through a nasal cannula may be less dangerous in terms of aerosolization and may be considered as an alternative therapy [ ] . bronchial analysis by suctioning leads to high risk of contamination, particularly if alveolar haemorrhage is present. due to the high prevalence of multidrug-resistant bacteria among patients coming from africa [ , ] , bacterial cultures may be very helpful to adapt antibiotics. disinfection of the fiberscope may be problematic. it is proposed to use non-guided suction or disposable fiberscopes. some disposable fiberscopes have an operator channel allowing performance of bronchoalveolar lavage. two devices are currently available: the bronchoflex su (axess vision technology, st pierre des corps, france) and the ambu ascope tm (ambu, dk- ballerup, denmark). the evaluation of the benefit/cost balance must be evaluated for each clinical situation. in the absence of strong evidence, crrt should be limited to validated indications: hypokalaemia, pulmonary oedema, metabolic acidosis. several elements favour the haemofiltration technique over conventional dialysis: no effluent requiring sewer elimination, less intervention required on the circuit once connected, all the materials are disposable, effluent bags can be disposed directly in hermetic bins. anticoagulation using non-fractioned heparin is easier because it requires less blood checks than citrate. connor et al. [ ] reported the use of citrate on one patient but recommendations cannot be drawn from a single patient. the habits and protocols of the unit should be taken into account in the final choice. the use or not of anticoagulation in case of major bleeding with intravascular disseminated coagulation should be discussed individually. apart from the case of severe hyperkalaemia, low outputs are recommended to limit interventions on the circuit (i.e. ml/kg/h). two situations must be individualized: health workers are present in the room with their full ppe. then the cardiac massage should start immediately even if the doctor is not yet in the room; no health worker is present in the room. the staff members must absolutely take the time to dress in their ppe in the changing room before providing life support procedures. this will clearly lead to a loss of chance for the patient but it is not possible to take the risk of starting a cardiac massage without protection. in this case, the risk of contamination would be particularly high. this procedure should be performed as under normal circumstance, without any extra precautions on top of the usual evd precautions. emergent needs for surgery should not occur frequently during the course of evd but can appear, for example, as a consequence of severe sepsis. this leads to a fair amount of problems, particularly if the patient is bleeding. surgery will expose the theatre staff to contamination, transportation of the patient to the theatre can be tricky, protection of the surgeons during the intervention is problematic and the theatre room should be in negative pressure with careful treatment of used air. surgery should probably be limited to a restricted number of ''simple'' interventions but no list can be a priori established. one way of dealing with this problem could be to limit interventions to the ones that can be performed in the patient's room. this is another reason pleading for the installation of an anaesthesia workstation in the icu room. patient examination is limited due to the ppe. inspection and palpation remain possible but auscultation with a traditional stethoscope is not possible because ears are totally covered by the equipment. we implemented an original system using two electronic stethoscopes. the first stethoscope is placed on the body area of interest. a wireless communication is established between the first stethoscope and a computer staying outside the room, in the ''green'' area ( table ). the bluetooth technology used allows a distance up to meters between the stethoscope and the recording computer. the second stethoscope is used by another doctor, to listen to the recorded files on the computer. for instance we performed this exam using a pair of m tm littmann electronic stethoscopes model ( m corporate headquarters, st. paul, mn - , usa). the physical exam done in the room by the doctor is written on a whiteboard, which is placed against the room's window. thus, the exam and all the information collected during the time in the room are written in a second time, in the patient's files in the green area. this procedure keeps the patient's files clean. nowadays, common monitoring in icus systematically includes a central monitor outside the patient's room. all the parameters that cannot be automatically reported (i.e. neurological state, temperature, etc.) could be written using the whiteboard and recorded in the patient's files afterwards. for safety reasons, only a limited number of parameters can be analysed in bsl- . the time needed to obtain results can be long, depending on the distance and the availability of the bsl- automates and staff. this is not acceptable for a patient in a critical state who may require frequent checking of blood results. we implemented a field laboratory, available in each room dedicated for evd cases, allowing analysis of essential parameters ( table ). the device used for biological analyses, the i-stat (abbott, princeton, nj , usa), includes a wireless printer. communication between the i-stat and the printer was feasible through the window, thus printed results were added to the patient's files (fig. ) . to prevent blood exposure, all the analyses are performed under a captair field pyramid glovebox (fig. ) . all the staff members received theoretical and practical learning for use of the devices. for blood group and antibodies, it was decided to perform analyses of abo, d, k and rhesus subgroup using the mdmulticard (medion diagnostics ag, ch- duedingen, switzerland) [ ] . thanks to this, we are able to transfuse patients in their own group and respecting the dell, kell and rhesus phenotypes. we used a point-of-care test for paludism: palutop + optima (alldiag, cs - strasbourg cedex, france), which allow diagnosis of the four plasmodium species. the use of this test is quite easy and a single training episode for the staff has been judged sufficient. we prepared a mobile x-ray system in the room. after utilization, the x-ray digital radiography detector is disinfected and developed outside the room. the x-ray system is dedicated to the evd patient's room only, for his whole length of stay in the icu. we obtained several models of portable ultrasonographers, both for diagnostic purposes and for us-guided procedures like vascular access. for safety reasons, we decided that a disposable sterile cover would always cover us probes. to sum up, the specific room organization includes, on top of classical icu materials: an anaesthesia workstation, x-ray system, portable us, and a field laboratory with a captair pyramid . see figs. and , which present an ideal icu room for evd patients and a picture of a fully equipped room in begin military hospital, respectively. direct communication with the patient is possible when staff members are in the room but it implies that they are protected by the ppe. to allow a more casual communication and permit communication of the patient with his/her family, we planned to use a webcam and a computer in the patient's room. this would allow good communication and helps the family accept the patient's isolation. the care of evd patients should follow the two following prerequisites. first, there is no specific restriction of care due to evd but only specific limitations due to the increased risk of contamination and diffusion of evd. these limitations can include, among others, surgery or care associated with potential table analysis performable under the captair field pyramid glovebox. parameters analysed comments haemorrhagic risk. secondly, all evd care must be performed under a benefit/risk balance. there are currently no validated ethical recommendations about the care of evd cases. the cornerstone of the care of such patients is to respect the general principles of medical ethics and keep in mind that such a patient may require tailored care. on top of the medical discussion between infectious doctors and intensivists, it may be useful to obtain advice from the local ethics committee. the following points should be discussed at a multidisciplinary level in the hospital before receiving a patient. if the patient is deemed unable to survive, the decision not to admit him/her into an icu on the basis of futility can be made. ppes are effective means of protecting staff members. thus, invasive procedures should not be prohibited but strictly limited to the ones necessary. the decision to undergo, or not, a surgical intervention should probably be made with the help of an ethics committee. informing staff members about evd and the risk of transmission is essential. staff training must take place before and during patient care to obtain a safe and positive attitude toward an infected patient. due to the physical constraints linked with the ppe, pregnant women, people suffering from claustrophobia or respiratory disease should not be included in the staff taking care of an evd case. to decrease the risk of errors due to fatigue, the nurse's schedule was modified for -hour shifts. evd teams were dedicated to the care of evd patients only and would return to the common unit only after the evd patient's discharge. as the protocols in the infectious ward and the icu were similar, nursing teams from both wards were pooled. so, in case of a single admission, the nurses from the other ward could be called for help. the practice of critical care should follow national guidelines, especially concerning the limitation of care and do not reanimate orders. for our part, we are following the recommendations of the french icu society [ ] . for obvious reasons, direct communication between an evd case and his/her relatives is not permitted. but communication should be possible, for instance by using a webcam system or at least by phone and viewing through a window. one must keep in mind that malaria is endemic in west africa. on top of evd, the patient could present other infections, particularly bacterial. the risks associated with handling blood may limit the availability of bacterial tests to bsl- tests only. as the sensibility of the malaria test we used is high, the question of malaria can be dealt with in this way. but concerning bacterial infections, the prescription of empirical wide-spectrum antibiotics without formal bacterial identification may be justified, particularly during the first days evd. one must keep in mind the risk of multidrug-resistant bacteria, as recently described in a case of severe evd [ ] . if bacterial infection is suspected, every effort should be made to obtain bacterial cultures. the current evd outbreak in west africa is a major challenge for the worldwide medical community. the epidemic is still ongoing and according to specialists, the number of cases may exceed , by the end of the current year [ ] . it is now clear that northern countries will be implicated in the care of evd patients, both in the field and back at home. in this perspective, it is fundamental that certain identified, specific centres are ready to take care of such patients. the preparation of a modern icu to treat an evd patient in good conditions requires time and specific equipment. staff training also requires time and must be done well prior to receiving the patient. to be efficient, preparation should be planned at a national level with help from public authorities, as was the case in france during the summer of . financial support: intensive care unit, begin military hospital ( , avenue de paris, saint-mande france). the authors declare that they have no competing interest. ebola haemorrhagic fever face to face with ebola -an emergency care center in sierra leone organ failures on admission in patients with ebola virus disease rhabdomyolysis in ebola virus disease. results of an observational study in a treatment center in guinea a case of severe ebola virus infection complicated by gram-negative septicemia doing today's work superbly well-treating ebola with current tools preparing an icu room to welcome a critically ill patient with ebola virus disease emergence of zaire ebola virus disease in guinea situation assessments: ebola virus disease management of accidental exposure to ebola virus in the biosafety level laboratory spanish authorities investigate how nurse contracted ebola texas healthcare worker is diagnosed with ebola triage and management of accidental laboratory exposures to biosafety level- and - agents clinical presentation and management of severe ebola virus disease analysis of human peripheral blood samples from fatal and nonfatal cases of ebola (sudan) hemorrhagic fever: cellular responses, virus load, and nitric oxide levels inflammatory responses in ebola virus-infected patients mechanisms underlying coagulation abnormalities in ebola hemorrhagic fever: overexpression of tissue factor in primate monocytes/macrophages is a key event haematological, biochemical and coagulation changes in mice, guinea-pigs and monkeys infected with a mouseadapted variant of ebola zaire virus real-time two-dimensional ultrasound guidance for central venous cannulation: a meta-analysis high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure multidrug-resistant acinetobacter baumannii infections in three returning travelers evacuated from algeria, thailand, and turkey after hospitalization in local intensive care units imported enteric fever: case series from the hospital for tropical diseases successful delivery of rrt in ebola virus disease application of a multivariant, caucasian-specific, genotyped donor panel for performance validation of mdmulticard(r) limitation et arrêt des traitements en ré animation adulte. actualisation des recommandations de la socié té de ré animation de langue française who ebola response team. ebola virus disease in west africa -the first months of the epidemic and forward projections organization of the icu room at the begin military hospital with dedicated devices key: cord- - ubt k authors: wilson, lauren a.; zhong, haoyan; liu, jiabin; poeran, jashvant; memtsoudis, stavros g. title: return to normal: prioritizing elective surgeries with low resource utilization date: - - journal: anesth analg doi: . /ane. sha: doc_id: cord_uid: ubt k supplemental digital content is available in the text. to the editor s uspension of elective surgeries was among the first mitigation efforts in anticipation of a surge in demand for critical care services during the coronavirus disease (covid- ) pandemic. as the united states nears the peak of this pandemic, policymakers need to determine the optimal strategy to safely return to "normal" operations while remaining vigilant and prepared for future recurrent outbreaks. we therefore evaluated intensive care unit (icu) utilization and mechanical ventilation following common elective surgical procedures to ( ) determine which procedures are the least resource intensive and ( ) which patient populations are less likely to require postoperative icu admission or ventilation. after institutional review board approval (irb no. - ), we conducted a retrospective analysis of patients captured in the premier healthcare database ( - ) who underwent common elective inpatient procedures (supplemental digital content, appendix, http://links.lww.com/aa/d ). for each surgical cohort, we identified icu admission, length of icu (and hospital) stay, and use and length of (non-) invasive ventilation (≥ or < hours). multivariable logistic regression models measured the association between patient age/comorbidity burden as measured by charlson-deyo index, and the outcomes of icu admission and ventilation, to validate the perception that younger and healthier patients are less likely to require these resources. of the elective surgeries evaluated, cardiac procedures were the most resource intensive with . % of patients admitted to the icu and . % requiring ventilation, followed by abdominal procedures that had an average icu admission rate of . %. gynecological surgeries and joint arthroplasties appeared to be the least resource intensive with fewer than . % of patients admitted to the icu and < % requiring postoperative ventilation (table) . in regression models, greater comorbidity burden was associated with significantly increased odds of icu admission or any form of ventilation in almost all procedure cohorts; this association was more subdued and sometimes reversed for older age (figure) . the highest icu utilization was seen in cardiac, abdominal, and spine surgeries. outside of cardiac procedures, postoperative ventilation was relatively uncommon, indicating that limiting elective procedures is primarily beneficial in maximizing icu capacity rather than freeing up ventilators. in almost all procedure cohorts, younger patients with a low comorbidity burden were less likely to require icu admission and/or ventilation. comorbidity burden was a stronger risk factor and thus should be prioritized over age for optimal patient selection. there is a -fold impact of restricting these surgeries to younger patients with a low comorbidity burden. these patients are not only less likely to require icu or ventilation, but they are also at lower risk of developing severe covid- symptoms were they to contact the virus during their hospital stay. however, if patients do not meet these criteria and their health could worsen from delaying surgery, it may be advisable to instead space out surgeries of older patients with underlying conditions to optimize resource utilization. limitations of this study include our simplified analysis that only considered patient age and comorbidity burden. while there are a number of other factors associated with icu admission and ventilation, our findings should provide a useful starting point in strategizing to return to normal operations. additionally, some procedures classified as elective in this database may not truly be elective; however, given that they will still be performed during the covid- pandemic, we felt valuable information could still be gained from retaining them in our analyses. these data suggest that, in the transition back to elective surgery, cardiac and abdominal procedures should be limited if possible in favor of "safer" and less resource-intensive surgeries such as gynecological and nontraumatic orthopedic procedures. across all procedure cohorts, it would be ideal to restrict or at least prioritize younger patients with fewer comorbidities. maximizing the calm before the storm: tiered surgical response plan for novel coronavirus (covid- ) overview of operating room procedures during inpatient stays in us hospitals adapting a clinical comorbidity index for use with icd- -cm administrative databases clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study plot of adjusted odds ratios and % confidence intervals for the association between patient age/deyo comorbidity index and the outcomes of postoperative icu admission and any ventilation, stratified by surgical cohort ( - ) key: cord- -kvezhyt authors: kim, l.; garg, s.; o'halloran, a.; whitaker, m.; pham, h.; anderson, e. j.; armistead, i.; bennett, n. m.; billing, l.; como-sabetti, k.; hill, m.; kim, s.; monroe, m. l.; muse, a.; reingold, a.; schaffner, w.; sutton, m.; talbot, h. k.; torres, s. m.; yousey-hindes, k.; holstein, r. a.; cummings, c.; brammer, l.; hall, a.; fry, a.; langley, g. e. title: interim analysis of risk factors for severe outcomes among a cohort of hospitalized adults identified through the u.s. coronavirus disease (covid- )-associated hospitalization surveillance network (covid-net) date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: kvezhyt background: as of may , , the united states has reported the greatest number of coronavirus disease (covid- ) cases and deaths globally. objective: to describe risk factors for severe outcomes among adults hospitalized with covid- . design: cohort study of patients identified through the coronavirus disease -associated hospitalization surveillance network. setting: acute care hospitals in counties in states. patients: patients hospitalized with laboratory-confirmed covid- during march -may , . measurements: age, sex, race/ethnicity, and underlying medical conditions. results: ninety-two percent of patients had at least underlying condition; % required intensive care unit (icu) admission; % invasive mechanical ventilation; % vasopressors; and % died during hospitalization. independent factors associated with icu admission included ages - , - , - and + years versus - years (adjusted risk ratio (arr) . , . , . and . , respectively); male sex (arr . ); obesity (arr . ); immunosuppression (arr . ); and diabetes (arr . ). independent factors associated with in-hospital mortality included ages - , - , - and + years versus - years (arr . , . , . and . , respectively); male sex (arr . ); immunosuppression (arr . ); renal disease (arr . ); chronic lung disease (arr . ); cardiovascular disease (arr . ); neurologic disorders (arr . ); and diabetes (arr . ). race/ethnicity was not associated with either icu admission or death. limitation: data were limited to patients who were discharged or died in-hospital and had complete chart abstractions; patients who were still hospitalized or did not have accessible medical records were excluded. conclusion: in-hospital mortality for covid- increased markedly with increasing age. these data help to characterize persons at highest risk for severe covid- -associated outcomes and define target groups for prevention and treatment strategies. in december , an outbreak of a novel coronavirus disease, termed coronavirus disease- , was reported in china caused by a newly identified coronavirus, severe acute respiratory syndrome coronavirus- (sars-cov- ). since then, approximately . million cases of covid- have been reported globally ( ). as of may , approximately . million cases, including nearly , deaths, have been reported in the united states, and case counts continue to rise ( ) with evidence of widespread community transmission ( ). previous reports from china, italy, and new york city have demonstrated that hospitalized patients are generally older and have underlying medical conditions, such as hypertension and diabetes ( ) ( ) ( ) . these studies have also found that older patients and those with certain underlying medical conditions like diabetes were at higher risk for severe outcomes ( , , ). among cases reported to the u.s. centers for disease control and prevention (cdc) from local and state health departments, the prevalence of underlying medical conditions increased as severity of infections increased ( , ) , although findings were limited by missing or incomplete information. questions remain about the independent association of sex, race/ethnicity and specific underlying conditions with severe outcomes among persons hospitalized with covid- , after adjusting for age and other important potential confounders. comprehensive data on u.s. patients with severe covid- infections are needed to better inform clinicians' understanding of groups at risk for poor outcomes and to inform current prevention efforts and future interventions. we rapidly implemented population-based surveillance for laboratory- confirmed covid- -associated hospitalizations, collecting clinical data from hospitalized patients in hospitals in states since march , . in this interim analysis restricted to patients who were and/or review of hospital discharge records. laboratory tests were ordered at the discretion of the treating healthcare provider. medical chart reviews for demographic and clinical data were conducted by trained surveillance officers using a standard case report form. underlying medical conditions were categorized into major groups (appendix table ). obesity and severe obesity were defined as a calculated body mass index (bmi) ≥ kg/m and bmi ≥ kg/m , respectively. chest radiograph results were obtained from the radiology reports and not from review of the original radiograph. we defined severe outcomes as either icu admission or in-hospital mortality. we hypothesized that increasing age and underlying medical conditions would be associated with an increased risk of icu admission and in-hospital mortality. after the exclusions noted above, we included adults hospitalized within acute care hospitals in counties in states with an admission date during march -may , who had either been discharged from the hospital or died during hospitalization and had complete medical chart abstractions. we calculated proportions using the number of patients with data available on each characteristic as the denominator. to construct multivariable models for icu admission and in-hospital mortality, we first assessed collinearity among underlying medical condition categories and outpatient use of ace-inhibitors and arbs. we examined the association of demographic factors, underlying medical conditions, and outpatient use of ace-inhibitors and arbs with icu admission and in-hospital death using chi square tests. variables considered for inclusion in the final models included current or former smoker, hypertension, obesity, diabetes, chronic lung disease (cld), cardiovascular disease (cvd) (excluding hypertension), neurologic disorders, renal disease, immunosuppression, gastrointestinal/liver disease, hematologic conditions, rheumatologic/autoimmune conditions, and outpatient use of ace-inhibitors or for use under a cc license. this article is a us government work. it is not subject to copyright under usc and is also made available (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / arbs. all multivariable models included age categorized into the following groups ( - , - , - , - , - , and ≥ years) , sex, and race/ethnicity. other variables with p-values < . in bivariate analyses were included in the multivariable analyses. log-linked poisson generalized estimating equations regression with an exchangeable correlation matrix ( , ) , clustered by site, was used to generate adjusted risk ratios (arr), % confidence intervals (ci), and two-sided p-values for the risk of icu admission and in-hospital death. we also constructed separate multivariable models to examine the association between the number of underlying medical conditions and icu admission or in- hospital death. two-sided p-values < . were considered statistically significant. all analyses were performed using the sas . software (sas institute inc., cary, nc, usa). these data were collected as part of routine public health surveillance and determined to be this article is a us government work. it is not subject to copyright under usc and is also made available (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / from % ( / ) of the acute care hospitals included in covid-net surveillance across the surveillance sites (appendix table ). the percentage of facilities contributing data out of the total number of facilities by site ranged from % to %. the median age of included and excluded patients ( vs. years, respectively) was similar (appendix table ). the highest proportion of patients included in this analysis were from minnesota ( %), tennessee ( %), new york ( %), and maryland ( %), and connecticut ( %) (appendix table (figure a ). prevalence of cld, neurologic conditions, obesity, and renal disease varied between males and females (p< . , figure b ). cvd, cld, and neurologic conditions were more prevalent among non-hispanic whites, while diabetes, hypertension, obesity and renal disease were more common among non-hispanic blacks (p< . , figure c ). cough ( %), fever or chills ( %), and shortness of breath ( %) were commonly documented symptoms at admission (table and appendix table ). gastrointestinal symptoms, for use under a cc license. this article is a us government work. it is not subject to copyright under usc and is also made available (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / including nausea, vomiting, and diarrhea, were documented in almost % of patients. median length of hospitalization was days (iqr, - ), and median days from symptom onset to hospital admission was days (iqr, ( ) ( ) ( ) ( ) ( ) ( ) . median values of initial vital signs were within normal range, except for elevated blood pressure (table ) . thirty-three individuals had a pathogen detected from positive blood cultures (appendix table ). viral co-detections from respiratory specimens were rare among those who were tested (n= / , . %) (appendix table ). among patients with chest radiograph performed, % (n= ) were documented as abnormal with infiltrate or consolidation (n= / , %) documented most frequently (appendix table ). ninety-five percent (n= / ) of patients with chest computerized tomography (ct) had abnormal findings, and ground glass opacity was documented in % (n= / ) (appendix table ). forty-five percent (n= / ) of patients received investigational medication regimens for covid- during hospitalization ( table ). the most common regimens included hydroxychloroquine (n= / , %) and the combination of azithromycin and ≥ covid- treatment (n= / , %) (non-mutually exclusive categories). the most frequent discharge diagnoses recorded in hospital discharge summaries were pneumonia (n= / , %), acute respiratory failure (n= / , %), acute renal failure (n= / , , %), and sepsis (n= / , , %). thirty-two percent (n= / ) of patients required icu admission, with a median length of icu stay of days (range, - ; iqr, - ) ( table ). median days from symptom onset to icu admission was days (range, - ; iqr, - ), and median days from hospital admission to icu admission was day (range, - ; iqr, - ). among , hospitalized patients, the highest respiratory support received was invasive mechanical ventilation in % (n= ), bilevel positive airway pressure (bipap) or continuous positive airway pressure (cpap) in % (n= ), and high flow nasal cannula (hfnc) in % (n= ). fifty-three percent (n= / ) of patients that received invasive mechanical ventilation died in-hospital (median age, years; iqr, - ); the proportion of patients receiving mechanical for use under a cc license. this article is a us government work. it is not subject to copyright under usc and is also made available (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint ventilation who died increased with age (p< . ). vasopressors were used in % (n= / ) of patients, while renal replacement therapy was used in % (n= / ). as age increased, so did the proportion of patients who required icu admission, invasive mechanical ventilation, and vasopressors (p< . , figure a ). males were admitted to the icu and treated with invasive mechanical ventilation, hfnc, or vasopressors more frequently than females (p< . ) ( figure b ). non-hispanic whites more frequently received bipap, cpap or hfnc (p< . , figure c ). overall, seventeen percent (n= / ) of patients died during hospitalization ( table ). the proportion of patients who died increased with increasing age groups, ranging from % among - years to % among - years to % among ≥ years ( figure a ). males died more frequently compared to females (p< . ) ( figure b ), as did non-hispanic whites compared to other race/ethnicities (p< . , figure c ). among patients who died, median age was years (range, - ; iqr, - ); % (n= ) were male; % (n= ) were admitted to the icu; and % (n= ) received invasive mechanical ventilation. the median length of hospitalization among patients who died was days (range, - ; iqr, - ). factors independently associated with icu admission included age - years (adjusted risk ratio (arr) = . ; % confidence interval (ci), . to . ); - years (arr = . ; ci, . to . ); - years (arr = . ; ci, . to . ); ≥ years (arr = . ; ci, . to . ); male sex (arr = . ; ci, . to . ); obesity (arr = . ; ci, . to . ); diabetes (arr = . ; ci, . to . ); and immunosuppression (arr = . ; ci, . to . ) (table a) . independent factors associated with in-hospital mortality included age - years (arr = . ; ci . to . ); age - years (arr = . ; ci, . to . ); age - years (arr = . ; ci, . to for use under a cc license. this article is a us government work. it is not subject to copyright under usc and is also made available (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint . ); age ≥ years (arr = . ; ci, . to . ); male sex (arr = . ; ci, . to . ); diabetes (arr = . ; ci, . to . ); cld (arr = . ; ci, . to . ); cvd (arr = . ; ci, . to . ); neurologic disorders (arr = . ; ci, . to . ); renal disease (arr = . ; ci, . to . ); and immunosuppression (arr = . ; ci, . to . ) (table b) . having ≥ underlying medical conditions was significantly associated with higher risk of icu admission and death after adjusting for age group, sex, and race/ethnicity (appendix table ). discussion using a geographically diverse, multi-site, population-based u.s. surveillance system, we found that among adults hospitalized with laboratory-confirmed covid- , almost one-third required icu admission, % received invasive mechanical ventilation, and % died during hospitalization. about % of patients were ≥ years, and > % had underlying medical conditions. older age, being male, and the presence of certain underlying medical conditions were associated with a higher risk of icu admission and in-hospital mortality. race/ethnicity was not independently associated with either outcome among hospitalized patients. this information can alert healthcare providers to patients at greatest risk of severe outcomes and help target prevention strategies and future interventions. in a published covid-net analysis, we found that when comparing the racial/ethnic distribution of residents of the surveillance catchment areas to the racial/ethnic distribution of covid- -associated hospitalizations, non-hispanic blacks were disproportionately hospitalized with covid- compared to non-hispanic whites ( ). in this analysis, however, we found that once hospitalized, non-hispanic blacks did not have increased risk of poorer outcomes compared to other race/ethnicities after adjusting for age and underlying conditions. in a preprinted article of u.s. veterans seeking care at va hospitals, rentsch et al. found no association between black race and icu admission ( ). similarly, a large study for use under a cc license. this article is a us government work. it is not subject to copyright under usc and is also made available (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint of patients hospitalized in new york city did not find race/ethnicity to be associated with icu admission or death ( ). covid- -associated hospitalizations, icu admissions, and deaths have been shown to occur more frequently with increasing age ( , , ) . in our study, age ≥ years was the strongest independent predictor of icu admission and in-hospital mortality. persons aged - years had the highest the risk of icu admission compared to - years old, and those ≥ years experienced times the risk of death. these findings are similar to other studies from china, europe, and the united states ( , , ( ) ( ) ( ) ( ) . our data provide support that older persons are particularly vulnerable to severe covid- disease and should be targeted for aggressive preventive measures ( ). being male was associated with a higher risk of icu admission and death after adjusting for age, race/ethnicity and underlying conditions. other studies have similarly shown male sex to be associated with covid- -associated hospitalizations ( , ), icu admissions ( ) this article is a us government work. it is not subject to copyright under usc and is also made available (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint neurologic disease, renal disease and immunosuppression associated with in-hospital death, and diabetes, obesity, and immunosuppression associated with icu admission. while hypertension was highly prevalent in our patient population, it was not associated with icu admission or death. additional studies are needed to determine whether hypertension, which is also highly prevalent in the u.s. population, increases the risk of covid- -associated hospitalizations and whether the duration of hypertension and the degree to which it is controlled impact the risk for severe similarly, the associations between the duration and degree of glycemic control in diabetes and severity of covid- disease require further investigation. obesity, which was also highly prevalent in this cohort, imparted increased risk for icu admission, but not death. this finding may, in part, be explained by a trend of decreasing obesity prevalence with increasing age, which was a strong risk factor for mortality. healthcare providers should be aware of these findings to appropriately triage and manage patients with high-risk conditions that may either increase risk for hospitalization or poorer outcomes once hospitalized ( , ). we collected data on initial symptoms, vital signs and laboratory values to characterize disease severity at admission. while approximately % of patients had shortness of breath at admission, the median oxygen saturation at admission was % on room air. other admission vital signs and laboratory values were also largely within normal ranges. because we did not collect data on vital signs or laboratory values during the hospital course, we may not have fully captured the onset of clinical deterioration that has been reported during the second week after illness onset ( ). we limited our analysis to patients that had either been discharged or died in-hospital and found that % of patients received vasopressor support, and % received invasive mechanical ventilation. other u.s. studies have found that up to % of hospitalized patients have received vasopressors and - % have received invasive mechanical ventilation ( , ), though some of these studies included patients who were still hospitalized at the time of analysis. in our study, % of patients requiring mechanical for use under a cc license. this article is a us government work. it is not subject to copyright under usc and is also made available (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint ventilation died, which is higher than the % reported in a recent study from new york city ( ). in general, the proportion of patients with severe outcomes was higher in the united states than reported from china ( ). differences between patients' outcomes in the united states and china may reflect differences in clinical practices or varying thresholds for hospitalization ( ). these proportions of severe outcomes among u.s. patients are also generally higher than those found in u.s. adults hospitalized with seasonal influenza ( , ). our findings may help to inform resource planning and allocation in healthcare facilities during the covid- pandemic. there are several limitations to our analysis. first, it is likely that not all covid- -associated hospitalizations were captured because of the lack of widespread testing capability during the study period and because identification of covid- patients was largely reliant on clinician-directed testing. second, clinical practices and availability of specific interventions may differ across hospitals, which might have influenced findings. third, covid-net is an ongoing surveillance system, and only % of the , covid- hospitalized patients were included, representing those who were discharged or died in-hospital during march -may , and for whom medical records were available and chart abstractions were completed. these restrictions may have resulted in selection bias. however, there was no difference in the age and sex distribution between cases included and excluded from the analysis. the geographic distribution of cases included versus excluded from this analysis differed, which may have impacted the racial and ethnic distribution of cases included in this analysis as compared to the racial and ethnic distribution of the surveillance catchment population; however, as we do not yet have complete data on race/ethnicity for all identified cases, we were not able to assess this further. nevertheless, covid-net encompasses a large geographic area with multiple hospitals and likely offers a more racially and ethnically diverse patient population compared to other single-center or state-based studies. lastly, small counts limited our ability to determine risk factors for severe outcomes among all racial and ethnic groups. covid-net data will become more robust as additional for use under a cc license. this article is a us government work. it is not subject to copyright under usc and is also made available (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / medical chart reviews are completed and may allow further investigation within these racial and ethnic groups over time. based on preliminary findings from this multi-site, geographically diverse study, a high proportion of patients hospitalized with covid- received aggressive interventions and had poor outcomes. increasing age was the strongest predictor of in-hospital mortality. prevention strategies, such as social distancing and rigorous hand hygiene, are key to minimizing the risk of infection in high- risk patients. these data help to characterize persons at highest risk for severe covid- -associated disease in the united states and to define target groups for future prevention and treatment strategies this article is a us government work. it is not subject to copyright under usc and is also made available (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint excluded site's cases (no clinical data available) n= excluded cases due to incomplete medical chart reviews n= , for use under a cc license. this article is a us government work. it is not subject to copyright under usc and is also made available (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / this article is a us government work. it is not subject to copyright under usc and is also made available (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / for use under a cc license. this article is a us government work. it is not subject to copyright under usc and is also made available (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / this article is a us government work. it is not subject to copyright under usc and is also made available (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint *p-value < . cvd = cardiovascular disease (excluding hypertension); htn = hypertension; cld = chronic lung disease. * the underlying medical condition categories are not mutually exclusive. patients can have more than once underlying medical condition. this article is a us government work. it is not subject to copyright under usc and is also made available (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. this article is a us government work. it is not subject to copyright under usc and is also made available (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / this article is a us government work. it is not subject to copyright under usc and is also made available (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint *p-value < . icu = intensive care unit; bipap = bilevel positive airway pressure; cpap = continuous positive airway pressure; hfnc = high flow nasal cannula; rrt = renal replacement therapy * for mechanical ventilation, bipap/cpap, and hfnc, patients are assigned based on the highest level of respiratory support required during hospitalization (i.e. invasive mechanical ventilation followed by bipap or cpap, followed by high flow nasal cannula). this article is a us government work. it is not subject to copyright under usc and is also made available (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / comorbidity and its impact on patients with covid- in china: a nationwide analysis factors associated with hospitalization and critical illness among , patients with covid- disease covid- surveillance group. characteristics of covid- patients dying in italy: report based on available data on clinical characteristics of coronavirus disease in china covid- in critically ill patients in the seattle region -case series among patients with coronavirus disease -united states severe outcomes among patients with coronavirus disease united states hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease -covid-net, states longitudinal data analysis using generalized linear models comparison of two different approaches for the analysis of data from a prospective cohort study: an application to work related risk factors for low back pain hospital admission, and intensive care among , , united states veterans aged clinical characteristics of deceased patients with coronavirus disease : retrospective study clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study case-fatality rate and characteristics of patients dying in relation to covid- in italy risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease presenting characteristics, comorbidities, and outcomes among patients hospitalized with key: cord- - bselbkq authors: lotz, christopher; notz, quirin; kranke, peter; kredel, markus; meybohm, patrick title: unconventional approaches to mechanical ventilation—step-by-step through the covid- crisis date: - - journal: crit care doi: . /s - - -y sha: doc_id: cord_uid: bselbkq nan unconventional approaches to mechanical ventilation-step-by-step through the covid- crisis christopher lotz , quirin notz, peter kranke, markus kredel and patrick meybohm * health care systems around the world face extreme challenges during the pandemic of sars-cov- . it has been reported that up to % of the patients develop an acute respiratory distress syndrome (ards) and approximately % require mechanical ventilation. in many countries, this may lead to a rapid shortage of intensive care (icu) ventilators. as such, a stepwise approach and triage utilizing all available types of ventilators might be necessary. this includes unconventional ideas that have been recently promoted in social media (https://www.youtube.com/watch?v= uclq oohy, https://www.youtube.com/watch?v=esvb wwanqri). as uncertainties of the correct sequence of ventilator utilization seem to exist, we aim to provide a quick overview of the possibilities and shed some light on recently discussed ideas. under normal circumstances, all patients in the icu requiring mechanical ventilation are ventilated with an intensive care ventilator. icu ventilators provide the highest performance, fast responding efficient triggering mechanisms, and often a plethora of different ventilation modes to best suit the individual patient. however, anesthesia ventilators as the next step in line have made considerable technical progress. their performance is comparable to icu ventilators, in particular when using controlled ventilation modes. current generation piston ventilators include fresh-gas decoupling to minimize volu-or barotrauma and offer pressure-support modes with sufficient triggering and pressurization even under low fresh-gas flows. as such, one should not hesitate to use them if icu ventilators are not available. a current apsf/asa guidance on purposing anesthesia machines as icu ventilators emphasizes this (https://www.asahq.org/ in-the-spotlight/coronavirus-covid- -information/purposi ng-anesthesia-machines-for-ventilators). third in line are transport ventilators, which vary largely in performance according to generation and model. many different models are marketed. the simplest pneumatic models are gasdriven pumps that provide % oxygen, control of rate and tidal volumes, and a pressure relief valve. on the other hand, new sophisticated transported ventilators offer a variety of modes including pressure-support ventilation and advanced monitoring. turbine-driven transport ventilators even demonstrated performance comparable with that of icu ventilators. however, as they are supplied by ambient air, they can only be used with % oxygen to prevent contamination of the device itself and its surroundings. this is a major downfall and limits their use to bridging, e.g., during the required testing of anesthesia ventilators. however, limited accuracy exists when prompted to deliver small tidal volumes (tidal volumes ≈ ml). this would be required in small children [ , ] . unconventional, improvised, and desperate methods as recently emphasized on social media (https://www. youtube.com/watch?v=uclq oohy, https://www.youtu be.com/watch?v=esvbwwanqri) might be the next step if all of these resources are exhausted. the concept of supporting multiple patients with a single ventilator emerged in the aftermath of september , . neyman et al. created a setup where a single ventilator could deliver a sufficient tidal volume to four identical human lung simulators in parallel [ ] . the concept was further supported by an animal experiment in which four sheep were successfully oxygenated for h with a single ventilator [ ] . there is also a case study reporting a oneventilator technique during air medical transport of twin newborns [ ] and an article that pressure controlled ventilation was simultaneously achieved in two healthy volunteers via mask ventilation [ ] . however, branson et al. further investigated this concept with detailed measurements of tidal volumes (v t ) while varying the compliance and resistance. they found that four test lungs with different compliances (here - ml/cmh o) received a wide fluctuation of v t ( - ml) in parallel ventilation. tidal volumes could not be controlled for each subject. the authors concluded that the concept of parallel ventilation for mass-casualty respiratory failure should not be supported [ ] . this seems particularly true in case of a mass outbreak of sars-cov- and subsequent ards. differences in lung compliance, required f i o , and peep levels are paramount in these patients. insufficient ventilation of one or more patients may be the consequence, which could go undetected as the monitored ventilation parameters reflect the whole group of patients. it is of further importance to emphasize that in case of icu ventilator shortage, the allocation of the ventilators to each patient requires triage. as clearly outlined by emanuel et al., the allocation of resources cannot be done on a first come first served basis [ ] . a triage committee might be the best answer to spread the burden of these difficult decisions [ ] . however, exact knowledge of the individual cases is required. ventilator triage would likely require switching of the ventilators during the course of treatment according to disease severity and stage as well as weaning capabilities, e.g., from anesthesia ventilator to icu ventilator. in conclusion, modern anesthesia ventilators as well as new-generation transport ventilators provide a valuable resource. in case of icu ventilator shortage, this resource can and should be primarily used with a clear conscience in ards patients (fig. ) . furthermore, it must be emphasized that unconventional, improvised methods are only justified if all of these resources are exhausted as the risks go up and the quality of care rapidly declines. fig. although intensive care ventilators represent the standard of care, anesthesia ventilators can be used without difficulty if their conceptual differences are accounted for (e.g., the presence of trained personnel). modern transport ventilators, albeit comparable in performance, can only be used for bridging as they are supplied by ambient air. unconventional methods such as ventilator splitting should be treated with great caution and are only justified if all other resources are exhausted evaluation of ventilators used during transport of critically ill patients: a bench study evaluation of new generation portable ventilators a single ventilator for multiple simulated patients to meet disaster surge increasing ventilator surge capacity in disasters: ventilation of four adult-human-sized sheep on a single ventilator with a modified circuit simultaneous transport of twin newborns simultaneous ventilation of two healthy subjects with a single ventilator use of a single ventilator to support patients: laboratory evaluation of a limited concept fair allocation of scarce medical resources in the time of covid- the toughest triage -allocating ventilators in a pandemic publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. christopher lotz, quirin notz, and patrick meybohm wrote the manuscript. peter kranke and markus kredel co-wrote and revised the manuscript for intellectual content. all authors agree to be accountable for all aspects of the work. the authors read and approved the final manuscript. none received for this study.availability of data and materials not applicable.ethics approval and consent to participate not applicable. all authors provided their final approval for manuscript submission. none.received: april accepted: may key: cord- -odlcfhcr authors: alviset, s.; riller, q.; aboab, j.; dilworth, k.; billy, p. a.; lombardi, y.; azzi, m.; ferreira vargas, l.; laine, l.; lermuzeaux, m.; memain, n.; silva, d.; tchoubou, t.; ushmurova, d.; dabbagh, h.; escoda, s.; lefrancois, r.; nardi, a.; ngima, a.; ioos, v. title: continuous positive airway pressure face-mask ventilation to manage massive influx of patients requiring respiratory support during the sars-cov- outbreak date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: odlcfhcr background: since december , a global outbreak of coronavirus disease (covid- ) is responsible for massive influx of patients with acute respiratory failure in hospitals. we describe the characteristics, clinical course, and outcomes of covid- patients treated with continuous positive airway pressure (cpap) in a large public hospital in france. method: it is a single centre retrospective observational cohort. from th march to rd april, consecutive patients receiving to l/min of oxygen with a non-rebreather mask, who had signs of respiratory failure or were unable to maintain an spo > %, were treated by cpap with a face-mask unless the icu physician judged that immediate intubation was indicated. the main outcome under study was reasons for cpap discontinuation. results: a total of patients were admitted in delafontaine hospital for covid- . icu was quickly overwhelmed. fifty-nine out of ( %) patients requiring icu care had to be referred to other hospitals. cpap therapy was initiated in patients and performed out of icu in ( %). reasons for discontinuation of cpap were intubation for invasive ventilation in ( %) patients, improvement in ( %), poor tolerance in ( %) and death in ( %). a decision not to intubate had been taken for the patients who died while on cpap. conclusions: treatment with cpap is feasible and safe in a non-icu environment in the context of a massive influx of patients. one third of these patients with high oxygen requirements did not eventually need invasive ventilation. the outbreak of the novel coronavirus disease (covid- ) began in wuhan, china in december . since then, it has rapidly spread around the world. as of may th, , the who reported a total of covid- cases globally, with . % mortality. in a large uk cohort, death from covid- was strongly associated with being male, older age, deprivation, uncontrolled diabetes and severe asthma . the nature of the pulmonary lesions triggered by sars-cov- is still a matter of debate. some histopathological studies suggest that diffuse alveolar damage is not the single pattern , . disorders of the pulmonary circulation (thrombosis, endothelial injury) and organizing pneumonia may also be present. many intensivists have observed that the classical clinical features of ards after intubation such as low pulmonary compliance are not found in all patients. a classification of mechanicallyventilated patients according to the driving pressure level after intubation has been proposed (l and h phenotypes) , . in terms of clinical management, initial recommendations suggested early intubation and ards-type ventilator settings . although some studies suggest a role for noninvasive ventilation in mild ards - , invasive mechanical ventilation remains the standard of care, especially for severe cases. during the chinese and european covid- outbreaks, a number of critical care teams proposed using high flow nasal cannula or non-invasive ventilation at least for initial management [ ] [ ] [ ] [ ] . optimal respiratory support for covid- patients presenting with acute hypoxemic respiratory failure, however, remains unknown. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint the district of seine saint denis has been the worst affected area during the sars-cov- outbreak in parisian region . it is densely populated and has a highdeprivation index. from mid-march until end-april , the delafontaine hospital, a large public hospital in saint denis, experienced a massive influx of patients requiring mechanical ventilation for acute respiratory failure due to covid- . during this period, the hospital in-patient bed capacity for non-icu covid- patients expanded to beds. a total of patients with sars-cov- infection were hospitalised. despite increasing the number of intensive care beds from to , the icu was quickly overwhelmed. fifty-nine ( %) out of patients requiring icu care had to be referred to other hospitals ( figure ). to manage the flow of patients presenting from th march onwards, continuous positive airway pressure (cpap) via face mask interface was considered in all patients with signs of respiratory failure despite to l/min of oxygen delivered by non-rebreather mask. in this single centre retrospective observational cohort study, we aim to describe the outcomes, in terms of clinical improvement without progression to intubation, need for intubation and mortality of patients supported with cpap in our hospital during the sars-cov- outbreak. we reviewed the characteristics, clinical course and outcomes of all consecutive adults with proven covid- treated with cpap in icu or in wards between th march and april. during this week-period, patients receiving - l/min oxygen through a non-rebreather mask who had clinical signs of respiratory failure or were all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint unable to maintain an spo > % were assessed for treatment with cpap via facemask unless the icu physician judged that immediate intubation was indicated. every patient included in the study had a thoracic ct scan compatible with covid- pneumonia and/or a positive sars-cov- pcr on naso-pharyngeal swab or broncho-alveolar lavage. the following baseline patient characteristics were retrieved from patient electronic medical record : sex, age, comorbidities, body mass index (bmi), withholding / withdrawal of life-sustaining therapies, associated covid- therapies (antivirals, steroids, immuno-modulating therapies, prone positioning), oxygen flow rate and spo before and after starting cpap treatment, duration of cpap treatment, medical unit where cpap treatment was performed, reasons for discontinuation of cpap, duration of invasive mechanical ventilation, saps score for patients admitted in icu, driving pressure and p/f ratio on first day of mechanical ventilation. the clinical outcomes (i.e. discharges from hospital, mortality) were recorded until the final day of follow-up on may th . cpap of to cm h o was delivered via a face mask dedicated to non-invasive ventilation (performa track®) with one of types of cpap valve (boussignac™ or cpap-o-two™) or alternatively, an icu ventilator (servo i® or evita infinity v ®). treatment was undertaken in a medical ward, the emergency department (ed) shortstay unit or the icu. an electrostatic heat and moisture exchanger filter (dar™) was placed between the mask and the cpap valve to prevent aerosolization of virus through expired gases. all patients were admitted to a single room with all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint implementation of contact and airborne precautions; however some rooms were without a window. medical and nursing staff in wards unfamiliar with non-invasive ventilation were trained by the intensivist who initiating the cpap treatment. patients received an initial prolonged session lasting at least hours before being reassessed of their need of invasive mechanical ventilation. if the patient could be temporarily taken off cpap without an immediate fall of spo below % (on o l/min via non-rebreather mask) or recurrence of clinical signs of acute respiratory failure, cpap treatment was resumed for hours every hours. progressive weaning of cpap was performed according to clinical signs, pulse oximetry and arterial blood gases. if possible, patients were managed in the icu (nurse/patient ratio : ). if no icu bed was available (as in over % cases), patients with cpap were shifted to the ed short-stay unit ( beds) adjacent to the icu (nurse/patient ratio : ) which allowed frequent re-evaluation of the patient's state by the intensivist on call. in the eventuality of no bed availability in the ed short stay unit, cpap treatment was instituted and managed in the medical ward were the patient had been admitted (nurse/patient ratio : during the outbreak). ward patients on cpap (and those with high o requirements) were systematically reviewed overnight by the duty resident responsible for the covid- medical wards. non-invasive ventilation (niv) with bi-level pressure modes was not used for three reasons: firstly the number of ventilators available could not ensure surge capacity in the context of massive patient influx. secondly, the increase in positive pressure during inspiration carries a greater risk of aerosolization of virus particles. the final reason was to keep pressure support ventilation as an option for pre-oxygenation before intubation in case it was indicated. using bi-level pressure modes would have also required more intensive training of ward staff unfamiliar with niv techniques. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint no a priori statistical sample size calculation was performed. sample size was equal to the number of patients treated during the study period. quantitative values are expressed as the median (interquartile range, iqr), and qualitative values are presented as numbers (percentages). univariate analysis was performed using fisher exact test or wilcoxon test, as appropriate. all tests were two-sided and a p value < . was considered statistically significant. because of alpha inflation due to multiple comparisons, findings should be interpreted as exploratory. a cox hazard proportional model was fit for time to intubation, controlling for potential confounders in the cohort of patients analysed. all variables available at baseline and associated with intubation in univariate analysis with a p-value < . were selected. variables selected are: ct-scan severity (< % vs. missing data for spo (n= ) at cpap initiation were imputed based on the maximal bias assumption (i.e., low spo in non-intubated patients and high spo in intubated patients). variables with more than % missing values were not implemented in the multivariate analysis. the analyses were carried out using r version . . (the r project for statistical computing, vienna, austria; http://www.r-project.org). the study was approved by the national ethics review board (cnriph -commission nationale des recherches impliquant la personne humaine) under the number all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . forty-nine consecutive patients were treated with cpap between th march and rd april ( figure ). initiation of cpap occurred throughout the entire study period and followed the epidemic curve ( figure ). sars-cov- pneumonia was confirmed by pcr from upper or lower respiratory tract in ( %) patients and by thoracic ct scan in the remaining patients. twenty-six ( %) patients were eventually intubated and a total of ( %) died. patients' characteristics are presented in table . the median age was years (iqr= - ) and ( %) were men. forty-one ( %) patients had at least one comorbidity. the most frequent were hypertension ( patients, %), obesity ( patients, %) and diabetes ( patients, %). the median duration of symptoms before hospital admission was days (iqr = - ). thoracic ct-scan at admission showed mild ( to %), moderate ( to %) or severe (> %) lung involvement in ( %), ( %) and ( %) patients respectively. modalities of cpap therapy and associated interventions are described in table . cpap was performed out of icu in ( %) cases. median duration of cpap therapy was days (iqr= - ). reasons for discontinuation of cpap were intubation for invasive ventilation in ( %) patients, improvement in ( %), poor tolerance in ( %) and death in ( %). a decision not to intubate had been taken with the patient and their family for the patients who died while on cpap. all patients all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . patients who improved with cpap were compared to the group who ultimately progressed to needing intubation. characteristics regarding age, sex, comorbidities and disease presentation were similar in both groups. patient who improved on cpap were treated later in their hospital stay, had higher oxygen saturation before cpap initiation, longer duration of cpap and received more often concomitant double dose prophylactic anticoagulation. a cox proportional hazard model was made to assess for confounding factors, variables associated with the risk of intubation in univariate analysis (p value < . ) were selected. thoracic ct-scan all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . this single center retrospective observational study describes the largest cohort to date of covid- adult patients treated with cpap via face mask. the main purpose of using cpap was to facilitate management of the patient flow of those potentially requiring invasive ventilation during this sars-cov- outbreak. cpap via face mask does not require a ventilator, and could thus be instituted and run on non-icu wards. this proved critical in this particular instance. fifteen ( %) patients improved with cpap treatment, and eventually did not go on to require invasive ventilation though they were very hypoxemic ( ( %) of them required l/min oxygen). other than patients with a do-not-intubate order, no death occurred during cpap therapy. mortality was . % in the patient group requiring intubation. this was related to the severity of illness (median saps score of ) but may be also due to difficulties in maintaining the quality of icu care during a crisis all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint situation. mortality data for covid- patients on invasive ventilation is still scarce, but early reports from china and the us showed mortality rate ranging between and % [ ] [ ] [ ] [ ] . in bergamo (italy), an overall mortality of . % was reported among patients necessitating ventilator support by helmet cpap ( %), non-invasive ( %) or invasive ( %) ventilation in the setting of the sars-cov- outbreak . in a larger study in lombardy, of icu patients admitted with covid- , % were mechanically ventilated while % were treated with non-invasive ventilation. mortality rate was % at the end of the study period with ( %) patients were still in icu . in vancouver (canada), the mortality rate among patients (of which . % were on mechanical ventilation) admitted in icus was . %, while . % remained in the icu . use of cpap has already been reported in outbreaks of acute severe respiratory infection such as the sars epidemic. however it was used in patients with less profound hypoxemia than in our cohort ( to l/m), and a lower percentage ( to %) of patients required intubation , . this study has several limitations. firstly, due to its retrospective design, we were unable to collect additional data that could have contributed to a better understanding of the role of cpap in managing hypoxemic respiratory failure in covid- . data on actual pressure levels delivered to each patient and the number of hours per day of cpap therapy could not be retrieved. in addition, it was not possible to ascertain in all patients whether vital signs (spo , respiratory rate) and arterial blood gases were taken while on cpap or while on non-rebreather mask. finally, the absence of a control group does not allow us to make any firm conclusion on the role of cpap in avoiding intubation. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . choosing the appropriate interface is critical to decrease leaks and minimize aerosolization and there may be some advantages to select full face masks. helmet is another option but is more difficult to handle in a non-icu setting. patients with profound hypoxemia and high respiratory rate who are treated with cpap may be exposed to self-induced lung injury. we attempted to collect the values for driving pressures immediately after intubation, but these data was unfortunately only available in a few cases. this should be investigated in further studies. on one hand, cpap treatment may have in fact triaged a group of patients who were less severe. this selection effect is suggested by the higher levels of spo at initiation of cpap in the group of patients who improved compared with the group of all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . patients who progressed to intubation. cpap therapy could have potentially worsened the condition of patients whose intubation was then effectively delayed. the high saps scores of the intubated patients in the study provide some evidence to this effect. on the other hand, there may be some advantages of using cpap even for patients who are subsequently intubated. cpap prior to intubation may reduce the duration of however, the likely increased risk of contamination of heath care workers, notably if personal protective equipment is inadequate, must be taken in account. cpap could also be considered as a first-line respiratory support strategy in less hypoxemic patients without significant respiratory failure in association with other strategies to improve oxygenation, such as prone positioning , . in conclusion, we found treatment with face mask cpap to be feasible and safe in a non-icu environment and in the context of a massive influx of patient. it was useful to post-pone intubation and to manage the flow of patient requiring invasive ventilation. we also found, that among patients who have low spo and /or signs of respiratory failure while on l/min o via non rebreather mask about one third eventually did not need invasive ventilation. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . hazard ratio of intubation adjusted for ct-scan severity (more or less of % of lung involved by sars-cov induced lesions), low saturation (spo , < % or > %), delay in days between hospitalisation and cpap initiation (two groups based on the median value of cpap delay), use of anticoagulant treatment grouped by dosage: simple dose prophylaxis ( ), double dose prophylaxis ( ) or curative treatment ( ) . p values are indicated as the result of likelihood-ratio test. the validity of the proportional hazards assumption was tested using cox.zph() function in r (p values > . ) and by visualisation of schoenfeld residuals. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint opensafely: factors associated with covid- -related hospital death in the linked electronic health records of million adult nhs patients. medrxiv facing covid- in the icu: vascular dysfunction, thrombosis, and dysregulated inflammation time to consider histologic pattern of lung injury to treat critically ill patients with covid- infection covid- pneumonia: different respiratory treatments for different phenotypes? intensive care med management of covid- respiratory distress surviving sepsis campaign: efficacy and safety of early prone positioning combined with hfnc or niv in moderate to severe ards: a multi-center prospective cohort study the experience of high-flow nasal cannula in hospitalized patients with novel coronavirus-infected pneumonia in two hospitals of chongqing la surmortalité durant l'épidémie de covid- dans les départements franciliens clinical course and outcomes of intensive care patients with covid- clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study severity of respiratory failure and outcome of patients needing a ventilatory support in the emergency department during italian novel coronavirus sars-cov- outbreak: preliminary data on the role of helmet cpap and non-invasive ventilation baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region, italy baseline characteristics and outcomes of patients with covid- admitted to intensive care units in vancouver, canada: a case series effectiveness of noninvasive positive pressure ventilation in the treatment of acute respiratory failure in severe acute key: cord- - uwtwsug authors: settembre, nicla; maurice, pauline; paysant, jean; theurel, jean; claudon, laurent; hani, hind; chenuel, bruno; ivaldi, serena title: the use of exoskeletons to help with prone positioning in the intensive care unit during covid- date: - - journal: ann phys rehabil med doi: . /j.rehab. . . sha: doc_id: cord_uid: uwtwsug nan j o u r n a l p r e -p r o o f patients with severe covid- -related acute respiratory distress syndrome (ards) and requiring prone positioning (pp). the pp procedure is of crucial importance for severe ards patients ( ) , especially when related to covid- ( ) . although turning a patient into the prone position is not an invasive procedure, it is complex and has many potential adverse effects requiring adequate and well-trained staff. it is also an exhausting and time-consuming task for icu staff under stressful conditions. therefore, at the university hospital of nancy, dedicated medical teams helped intensivist physicians strictly follow pp guidelines, thereby ensuring the full medical care for critical ards patients. each pp team (ppt) consisted of non-intensivist senior physician, residents, and medical students. volunteers were trained in a simple ad-hoc training session consisting of to real pp procedures supervised by permanent physicians and nurses of the icu. ppts were deployed from march to april , , in an extended icu (from to beds). during this period, they performed a mean [sd] of . [ . ] placements per day, with up to placements (pp or its opposite, supine positioning [sp]) at the surge of the outbreak on april . overall, more than placements were performed during this month, corresponding to a total manipulated weight > tons. the pp task is not only physically difficult but also a risk factor for back injuries due to recurrent forward-bending postures. to deal with this repetitive and depleting task, we investigated whether the use of back-support exoskeletons was helpful and feasible in the context of an icu facing the codiv- pandemic. our pilot study consisted of two steps: first, an exploratory study with whole-body kinematics assessment and evaluation of potential exoskeletons, carried out under simulated conditions, then implementation in a real-life situation with the selected exoskeletons. the exploratory study was carried out at the hospital simulation center of the university of lorraine. we recorded the whole-body kinematics of one experienced ppt volunteer (male, years old, cm) by using the xsens inertial motion capture system. postural analysis of the pp maneuver without after testing each exoskeleton, these participants completed a technology acceptance questionnaire adapted from ( ) to evaluate the perceived effort, safety, comfort, efficacy, installation, and intention to use. each construct of the questionnaire regroups several items on a -point likert scale, with indicating "strongly negative" and "strongly positive"; is the neutral answer. the reported scores are described according to the mean [sd] of all questions related to each construct (safety, comfort, usability, etc.). the participants also reported on their experience in a semi-directed interview. both participants perceived a reduction in physical effort when using all exoskeletons except corfor both participants reported that crayx was too cumbersome to wear in an icu, whereas the mechanical design of backx unpleasantly hindered several arm movements of the pp maneuver. corfor was not helpful. conversely, participants were satisfied with laevo in terms of perceived assistance during bent postures, ease of use, and freedom of movement. importantly, they mentioned that laevo did not modify their movements during the pp maneuver, which was confirmed by the analysis of the kinematic data (fig. ) . building upon these promising pilot results and given the urgency associated with the covid- crisis, we proceeded to test under real-life conditions to demonstrate the feasibility of using laevo in a covid- icu situation. the same volunteers were each equipped with a laevo in a way that complies with the drastic hygiene rules of the icu during the outbreak. during a typical -hr shift, they cardiac activity of the participants was monitored with a holter-ecg during the whole shift in the icu. unfortunately, the analysis of the ecg data was inconclusive because of the multiple bias in this j o u r n a l p r e -p r o o f real-life condition, such as the elevated stress of the participants due to the covid- context and the frequency of multiple gestures performed during the pp maneuver preventing the precise characterization of the help of exoskeleton in terms of heart rate data. although we could not reliably measure the physiological and biomechanical effects of laevo in the icu, we expect beneficial effects such as those reported by previous laboratory studies with similar postures ( , ). the participants found laevo comfortable (questionnaire score: . [ . ]), except when walking, which is a well-known issue of laevo v ( ) that was improved in recent versions. laevo did not prevent or constrain the usual gestures and activity in the icu. accordingly, their teammates did not notice any particular changes in the practice, and no physical or psychological side effects were observed. these results are important for a potential adoption of laevo by the ppt in current practice because the positive attitude of co-workers is fundamental for the acceptance of a new technology at work ( ) . the use of exoskeletons to cope with an exhausting task such as prone positioning in the icu to safely maintain a large number of patients on mechanical ventilation during the surge of the covid- outbreak is a consistent topic of research. our pilot study showed that using an exoskeleton to assist medical staff could be helpful and be readily feasible, even in the dreadful context of the covid- pandemic. previous studies generally agree on the efficiency of passive back-support exoskeletons to reduce lumbar muscular activity and perceived exertion/discomfort, particularly during operations involving trunk flexion/extension in the sagittal plane ( , ). however, although occupational exoskeletons are deployed in the industrial sector ( ) , their use in the healthcare system is rarely reported, with no reported use in icus. the medical staff using the passive exoskeleton laevo during the pp maneuvers in the icu perceived physical relief in the low back during bent postures, particularly when working at the patient's head. subjective evaluation, which is used in field studies to evaluate the adoption of exoskeletons in prone positioning in severe acute respiratory distress syndrome covid- : interim guidance on management pending empirical evidence flexion and rotation of the trunk and lifting at work are risk factors for low back pain: results of a prospective cohort study processus d'acceptabilité et d'acceptation des exosquelettes: évaluation par questionnaires the effects of a passive exoskeleton on muscle activity, discomfort and endurance time in forward bending work effects of a passive exoskeleton on the mechanical loading of the low back in static holding tasks the effect of a passive trunk exoskeleton on metabolic costs during lifting and walking ethical and social considerations for the introduction of human-centered technologies at work an introduction to the special issue on occupational exoskeletons exoskeletons for industrial application and their potential effects on physical work load subjective evaluation of a passive industrial exoskeleton for lower-back support: a field study in the automotive sector key: cord- -y vefr authors: renke, christine; callow, louise; egnor, tara; honstain, chelsea; kellogg, kimberly; pollack, blythe; reske, janella; robell, stephanie; sinicropi, natalie title: utilization of pediatric nurse practitioners as adult critical care providers during the covid- pandemic: a novel approach date: - - journal: j pediatr health care doi: . /j.pedhc. . . sha: doc_id: cord_uid: y vefr nan the coronavirus disease pandemic is a global health emergency creating unprecedented social, political, and economic crises. first noted in wuhan, china in december , severe acute respiratory syndrome coronavirus (sars-cov- ) has infected more than . million people in countries as of may (world health organization, ). it was formally declared a pandemic in march (centers for disease control and prevention, ). unlike other coronavirus strains, this highly contagious disease has resulted in significant morbidity and mortality with severity ranging from asymptomatic carriers to critical illness, rapid decompensation, and death. healthcare infrastructure was faced with extraordinary challenges to provide care for the mass influx of infected patients. this response revealed scarcities of critical resources required to treat these patients while ensuring staff safety. the state of michigan documented its first covid- patient on march , with cases quickly escalating to over , in the next three weeks, creating a state of emergency and prompting a stay-at-home order on march (whitmer, b) . four detroit-area counties: washtenaw, wayne, oakland, and macomb comprised approximately % of michigan's covid- cases as of early may (state of michigan, ). detroit-area hospitals were tasked with mobilizing institutional resources including personnel, personal protective equipment (ppe) , and the necessary medical supplies required to provide care for the surge of covid- patients. a large academic medical center, located approximately miles outside of detroit, postponed elective surgeries, shifted outpatient clinics to telemedicine visits, and limited outside hospital transfers to only covid- positive patients. on march , this academic medical center opened a dedicated covid- intensive care unit (icu) as phase one of the pandemic response. ultimately, icu bed capacity increased by adult beds for a total of icu beds. expanding icu bed capacity identified a need for additional care providers. this strain was felt across the state resulting in executive order - , which suspended restrictions in scope of practice, supervision, and delegation to nurse practitioners (nps) professionally employed and responding to increase their facility's response to the pandemic (whitmer, a) . the order permitted nps "…to provide medical services appropriate to the professional's education, training, and experience, without physician supervision and without criminal, civil, or administrative penalty related to a lack of such supervision" (whitmer, a, para. ) . to meet the challenge of the frontline provider deficit, pediatric nurse practitioners (pnps), with experience in the management of acute and critically ill patients, were a valuable resource to the covid- icu. as a result, emergency credentialing privileges were granted to a group of pnps who were then deployed to the covid- icu as frontline providers. this group of pnps, equipped with evolving global and institutional covid- standards of care and adult critical care guidelines, combined with support from adult critical care medicine faculty, provided frontline care to critically ill covid- patients. an initial call for volunteers to staff the covid- icu was sent to inpatient advanced practice providers (apps), including nps, certified registered nurse anesthetists (crnas), and physician assistants (pas). with surgeries postponed and the stay-at-home order in effect, many areas of the hospital experienced low patient census thus allowing for apps to redeploy to the covid- icu. once deployed, the majority of apps committed to a period of time in the covid- icu, only returning to their home unit once they fulfilled this commitment or if their home unit required their return for other patient care needs. following deployment, an email survey was sent to all apps who worked in the covid- icu regarding their background, education, usual scope of practice, and overall experience during deployment. the survey results depicted varied backgrounds and levels of experience of the apps who worked in the covid- icu. of those deployed, . % were pnps from pediatric critical care and . % were pnps from pediatric acute care. crnas accounted for . % of the apps; . % were adult nps, deployed from adult critical care. the remaining . % were a mix of pas and nps, originally based in adult acute care units. of all apps, . % had been in practice for over years. over half, . %, of apps reported responsibilities in the covid- icu were beyond their typical scope of practice. of the pnps, % routinely managed ventilators and vasoactive medications prior to deployment. educational resources were shared via cloud computing and were frequently updated as information evolved. this included literature pertaining to covid- treatment, ppe, unit workflow, and covid- icu orientation guidelines. given the diverse backgrounds of the apps, standardized protocols were put in place to guide nearly all facets of patient care. protocol topics included sedation, ventilator management strategies, resuscitation and hemodynamic support, nutrition plans, tracheostomy guidelines, and venous thromboembolism management. pnps were provided four hours of orientation to the covid- icu. upon survey, % of pnps described their perception of preparedness ranging from neutral to definitely prepared. data were collected from the university of michigan health system's data direct bank from march , to may , . during this time there were covid- positive patients admitted; figure graphs the age distribution of all admitted patients. of the admitted patients, were icu status; of whom were female and were male with an average age of . years and . years, respectively. the most common comorbidities were hypertension, disorders of electrolyte and fluid balance, diabetes, obesity, cardiac arrhythmia, renal failure, chronic pulmonary disease, and congestive heart failure. all icu patients required respiratory support; figure demonstrates the mode of respiratory support utilized: heated high flow nasal cannula (hhfnc), hhfnc with escalation to mechanical ventilation (mv), or mv. the average ventilator days for patients discharged as "alive" was . days, for patients discharged as "deceased' 'or "to hospice" was . days, and . days for those discharged as "undetermined". undetermined accounts for patients who fall outside the dates of data collection. continuous renal replacement therapy was required in % of icu patients and % of patients qualified for extracorporeal membrane oxygenation (ecmo) support, based on institutional criteria specific to covid- . the covid- icu care teams were multi-disciplinary and consisted of members from a variety of backgrounds and experiences. standardized roles and responsibilities were developed to support staff in an environment of rapidly changing work processes and standards of care, with special attention to staff safety. acknowledging potential staffing shortages, provider teams were organized using a hybrid of a tiered staffing strategy adapted by the society of critical care medicine. in this model, the shortage of adult intensivists requires the support of other physicians and apps to meet patient care needs (halpern & tan, ) . most notably, apps who have both critical care training and experience are utilized to directly augment the critical care physician leading the care team (halpern & tan, ) . the covid- icu team included an attending physician, a critical care medicine fellow, and two to four apps. one side of the covid- icu was staffed by adult critical care medicine faculty, and the other side was staffed by pediatric critical care medicine faculty, with adult critical care medicine faculty readily available for consultation and/or present for daily rounds. in addition, a combination of critical and acute care nurses, and a respiratory therapist, were assigned to groups of patients. the daily rounding team also included a pharmacist and infectious disease consultant, with other subspecialty consultants available as needed. apps were frontline providers, responsible for the care of four to six patients on day shift and up to ten patients on night shift. shifts were hours long and apps were usually scheduled in stretches of days in a row to ensure patient continuity. table describes the specific responsibilities of providers on the care team. one provider, usually the attending or app, conducted daily patient physical examinations. the most experienced provider available performed procedures, in order to promote efficiency and reduce the time and number of providers exposed. accordingly, anesthesia providers performed intubations. as pediatric providers deployed to a covid- icu, lessons learned extend beyond the pathophysiology and pharmacology unique to the adult and geriatric population. pnps adapted to a new unit, learned to identify variations in nursing background among new colleagues, and practiced with an extended scope of practice. these were not without challenges, including workflow, communication, and emotional burdens unique to pandemic medicine. the daily realities of the covid- icu were outside of every provider's typical prepandemic workflow. in preparation for work in the covid- icu, a four-hour orientation to the unit and patient population was provided. the remainder of education was a self-driven review of evolving guidelines for treatment of covid- . the brevity of this orientation provoked fear and anxiety; however, education and clinical experience as nps provided the skills to adapt to this unforeseen change in practice. in typical practice, colleagues are familiar and have established rapport; as such, team members can adapt to compliment the expertise of individuals. upon deployment to the covid- icu, not only were pnps faced with a new environment and patient population, each day they joined a new team with different members. each team member's strengths and weaknesses were unknown. this was a systematic flaw based on circumstances beyond individual control. an unexpected but pleasant outcome of working with a group of unfamiliar colleagues was the convivial spirit. in a situation plagued with unknowns, there was an abundance of wellintentioned people doing their best to provide the most comprehensive care in their power. common themes throughout the covid- icu were kindness, support, and understanding, all while working together to meet the needs of critically ill patients. the team's focus expanded beyond individual patient care to include overall global health. efforts to limit provider exposure and preserve ppe altered the flow of patient care, and required unconventional communication methods when face-to-face communication was not possible. this often required pnps to be outside of patient rooms, peering through windows to communicate with the team inside via phone or walkie-talkie. in an effort to limit exposure of all team members, pnps coordinated with bedside staff and adjusted the plans of care based on timing of room reentry. likewise, timing of lab collections, ventilator changes, and patient repositioning was more fluid than usual; at times the pnps performed these tasks themselves. interactions with patients' families were also disrupted; visitation by family and friends of patients was not permitted to minimize exposure of both visitors and staff. patients' families were updated regularly via phone; without in-person interactions there was a loss of intimacy, especially when sharing bad news. this proved challenging, as it is difficult to deliver bad news when families were not present to witness the patient's condition. media coverage surrounding covid- exacerbated communication barriers with families, as public information was not always accurate and was frequently changing; thus providers spent a lot of time educating patients' families and debunking misinformation. the emotional hardship endured throughout this pandemic was one of the most challenging aspects, affecting every clinician. the majority of pnps felt their work in the covid- icu was both more stressful and emotionally challenging than their typical work. while caring deeply for the patients, pnps often felt helpless in the face of their care. all the while, providers were concerned for their own health and risk of contracting covid- , as well as spreading the virus to their families. this resulted in decontamination practices and even isolation or self-quarantine. despite the circumstances, the pnps returned day after day to serve on the frontlines of the pandemic. at the beginning of the pandemic, % of the pnps voluntarily deployed to work in the covid- icu and % were assigned on behalf of their home units. nevertheless, upon completion of deployment, . % of pnps stated they would "definitely" volunteer for redeployment in the case of a covid- resurgence, and . % stated they "probably" would. pnps were vital to the provision of care during the covid- pandemic, demonstrating their value in future pandemic planning. their successful deployment to a covid- icu provided an opportunity to examine processes and resulting outcomes. for future situations requiring rapid deployment of providers, it is recommended that education is streamlined, team roles and responsibilities are well defined, state and institutional support is elicited, and provider health is prioritized. as previously mentioned, orientation was minimal and often self-directed. in order to deploy pnps to an adult icu, education and preparation is paramount. pnps should be provided with a concise orientation to workflow processes, rounding practices, and patient care protocols. a repository for resources should be established utilizing an online platform to collect and disperse resources in real time. resources should also include adult critical care order sets, lectures, webinars, evidence-based protocols, and medication research trials. pnps should be held responsible for ongoing re-education to stay informed of practice changes. the success of a rapid deployment included temporary state expansion of the np scope of practice and institutional emergency privileges. these processes were necessary to permit pnps to practice to their full scope and ability in the provision of care to an overwhelming number of covid- icu patients. therefore, in future pandemic planning, we recommend early state level expansion of scope of practice and for institutions to establish a process for rapid credentialing to support the expanded scope of practice. finally, there is a monumental toll on mental health during a pandemic making it essential that self-care not only be practiced, but also prioritized. healthcare providers are vulnerable to psychological distress related to patient care, and quarantine or isolation required as a result of this work (torales, o'higgins, castaldelli-maia, & ventriglio, ; wu, styra, & gold, ). an institutional mechanism to provide mental health support to staff needs to be available and shared broadly; staff health is essential to ensure ongoing patient care needs are met (wu et al., ) . palliative care and social work teams should be utilized to assist pnps with management of patient and family grief and clarifying goals of care, thus helping to off-load this emotionally draining work. further, when possible, staffing models should cluster days of service to allow for stretches of days off in order to allow for providers' emotional and physical recovery. the covid- pandemic has overwhelmed healthcare infrastructure, revealing imperfections in the medical system and scarcities of all resources necessary for the delivery of patient care. providers were an identified scarce resource, leaving open opportunity for pnps to rise to the challenge and fill this void. practicing on the front lines required flexibility; it was emotionally draining and difficult work. despite the adversities, pnps were resilient and vital to the successful institutional pandemic response, thus reinforcing their role in future pandemic planning. coronavirus disease united states resource availability for covid- coronavirus michigan data the outbreak of covid- coronavirus and its impact on global mental health executive order - (covid- ) executive order - (covid- ) mitigating the psychological effects of covid- on health care workers we would like to acknowledge the michigan medicine pnps who deployed to the covid- icu during the pandemic, including louise callow, courtney cherniak, tara egnor, chelsea honstain, kimberly kellogg, laura meeker, max pizzo, blythe pollack, christine renke, janella reske, stephanie robell, kayleigh schwartz, stacey sears, kimberly siebert, natalie sinicropi, and rebecca tompkins. we also recognize the other apps and critical members of the multidisciplinary team who worked alongside us. we are grateful for the support of the pediatric and adult critical care faculty who provided education and guidance throughout our experience.thank you to dr. christopher fung who assisted with patient data collection. finally, we thank key: cord- -ggnd y authors: flythe, jennifer e.; assimon, magdalene m.; tugman, matthew j.; chang, emily h.; gupta, shruti; shah, jatan; sosa, marie anne; demauro renaghan, amanda; melamed, michal l.; wilson, f. perry; neyra, javier a.; rashidi, arash; boyle, suzanne m.; anand, shuchi; christov, marta; thomas, leslie f.; edmonston, daniel; leaf, david e. title: characteristics and outcomes of individuals with pre-existing kidney disease and covid- admitted to intensive care units in the united states date: - - journal: am j kidney dis doi: . /j.ajkd. . . sha: doc_id: cord_uid: ggnd y rationale & objective: underlying kidney disease is an emerging risk factor for more severe covid- illness. we examined the clinical courses of critically ill covid- patients with and without pre-existing kidney disease and investigated the association between degree of underlying kidney disease and in-hospital outcomes. study design: retrospective cohort study settings & participants: , critically ill covid- patients ( dialysis patients, chronic kidney disease [ckd] patients, and , patients without ckd) admitted to icus at hospitals in the united states. predictor(s): presence (versus absence) of pre-existing kidney disease outcome(s): in-hospital mortality (primary); respiratory failure, shock, ventricular arrhythmia/ cardiac arrest, thromboembolic event, major bleed, and acute liver injury (secondary) analytical approach: we used standardized differences to compare patient characteristics (values > . indicate a meaningful difference between groups) and multivariable adjusted fine and gray survival models to examine outcome associations. results: dialysis patients had a shorter time from symptom onset to icu admission compared to other groups (median [quartile -quartile ] days: [ - ] for dialysis patients; [ - ] for ckd patients; [ - ] for patients without pre-existing kidney disease). more dialysis patients ( %) reported altered mental status than those with ckd ( %, standardized difference = . ) and no kidney disease ( %, standardized difference = . ). half of dialysis and ckd patients died within -days of icu admission versus % of patients without pre-existing kidney disease. compared to patients without pre-existing kidney disease, dialysis patients had a higher risk of -day in-hospital death (adjusted hr . ; % ci . , . ), while patients with ckd had an intermediate risk (adjusted hr . ; % ci . , . ). limitations: potential residual confounding conclusions: findings highlight the high mortality of individuals with underlying kidney disease and severe covid- , underscoring the importance of identifying safe and effective covid- therapies for this vulnerable population. individuals with underlying kidney disease may be particularly vulnerable to severe covid- illness, marked by multi-system organ failure, thrombosis, and a heightened inflammatory response. among , critically ill adults with covid- admitted to intensive care units across the u.s., we found that both chronic kidney disease and dialysis patients had a ~ % -day in-hospital mortality rate. patients with underlying kidney disease had higher in-hospital mortality than patients without kidney disease, with patients on maintenance dialysis having the highest risk. as evidenced by differences in symptoms and clinical trajectories, patients with pre-existing kidney disease may have unique susceptibility to covid- -related complications which warrants additional study and special consideration in the pursuit and development of targeted therapies. (covid- ) caused by severe acute respiratory syndrome coronavirus (sars-cov- ) has snowballed into a global pandemic, infecting over million people across the globe and killing more than , as of mid-september . emerging data suggest that individuals with underlying kidney dysfunction have worse covid- -related outcomes than those without kidney dysfunction. [ ] [ ] [ ] [ ] [ ] [ ] [ ] similar outcome differences across patients with and without kidney dysfunction have been observed in other illness states (e.g., general critical illness, influenza ), and may relate, in part, to the innate immunity impairment, vascular dysfunction, and heightened inflammatory state that are characteristic of advanced kidney disease (ckd). [ ] [ ] [ ] as such, individuals with underlying kidney dysfunction may be particularly vulnerable to covid- -related critical illness, marked by multi-system organ failure, thrombosis, and a heightened inflammatory response. covid- -related critical illness affects ~ % of patients hospitalized with covid- and has an exceedingly high mortality rate. [ ] [ ] [ ] [ ] data from the united states (u.s.) indicate that patients with critical covid- illness complicated by acute kidney injury (aki) have worse outcomes than those without aki. - single-center and regional studies suggest similarly poor outcomes among individuals with critical covid- illness and pre-existing kidney dysfunction, especially dialysis-dependent kidney failure, but sample sizes were limited, and most lacked comparator populations. - given the rapidly changing landscape of covid- therapeutics and potential for impaired kidney function to limit therapeutic options (e.g., remdesivir), granular, broadly representative data characterizing clinical courses of critically ill patients with covid- and pre-existing kidney disease are needed to inform management of this vulnerable population. to address this knowledge gap, we used data from study of the treatment and outcomes in critically ill patients with covid- (stop-covid), a cohort study of > , patients with covid- admitted to icus at hospitals across the u.s., and examined the clinical courses of critically ill covid- patients with and without pre-existing kidney disease. we also investigated the association between degree of underlying kidney disease and occurrence of inhospital mortality and other outcomes (e.g., respiratory failure, shock, thromboembolic events). we used data from stop-covid, a multicenter cohort study that enrolled consecutive adults (≥ years old) with laboratory-confirmed covid- admitted to icus at geographically diverse u.s. hospitals (supplemental material). cohort compilation and initial results have been previously reported. the stop-covid parent study was approved by the institutional review boards (irbs) at each participating site. this ancillary study was approved by the university of north carolina at chapel hill irb (# - ). a waiver of informed consent was granted due to the anonymity of the stop-covid limited dataset used for this project. in this study focused on pre-existing kidney disease, we included , critically ill covid- patients with and without pre-existing kidney disease admitted to icus between march , and may , . using a retrospective cohort study design, we followed patients forward in historical time from icu admission to in-hospital death, hospital discharge, or june , -the date of database locking for these analyses. all patients still hospitalized at the time of analysis had at least -days of follow-up. we excluded patients without documented vital signs on icu day (n = ). j o u r n a l p r e -p r o o f study personnel at each stop-covid site collected data by detailed medical chart review and used a standardized electronic case report form to enter data into a secure research electronic data capture (redcap) database. abstracted data included: demographics, comorbidities, and home medications; symptoms and vital signs at icu admission; longitudinal laboratory and physiologic parameters, therapeutic interventions, and acute organ injury and support during the first days after icu admission; and dates and contributing causes of inhospital death. for individuals with pre-existing dialysis-dependent kidney failure, we also collected data on dialysis modality, length of time receiving maintenance dialysis, and vascular access type (for hemodialysis patients), all preceding hospital admission. the exposures of interest were the presence of pre-existing ckd and dialysis-dependent kidney failure. we defined pre-existing ckd as a baseline estimated glomerular filtration rate (egfr) < ml/min/ . m (based on either the modification of diet in renal disease [mdrd] study or ckd epidemiology collaboration [ckd-epi] equations ) prior to hospitalization on at least consecutive occasions at least weeks apart or, in cases where prehospitalization egfrs were unavailable, the presence of ckd in the medical chart problem list or past medical history. individuals with prior kidney transplant were classified according to their baseline egfr. we defined pre-existing dialysis-dependent kidney failure as medical chartdocumented maintenance dialysis therapy prior to hospital admission. we categorized patients without evidence of ckd or dialysis-dependent kidney failure as having no pre-existing kidney disease. the primary outcomes were -and -day in-hospital mortality. the secondary outcomes included -day in-hospital respiratory failure, shock, ventricular arrhythmia or cardiac arrest, thromboembolic event (including ischemic stroke, pulmonary embolism, or deep vein thrombosis), major bleed, and acute liver injury (supplemental table s ). all statistical analyses were performed using sas version . (sas institute inc, cary, nc). we described patient characteristics on icu day , therapies administered, and laboratory parameters across exposure groups as count (%) for categorical variables and as median [quartile , quartile ] for continuous variables. we compared baseline covariate distributions using absolute standardized mean differences (asmds). an asmd > . represents an imbalance (i.e. difference) between exposure groups. , a larger asmd is indicative of a larger between group difference. we assessed the association between the presence of kidney disease (ckd and dialysisdependent eskd, separately) vs. no pre-existing kidney disease and -and -day in-hospital mortality using fine and gray proportional subdistribution hazards models. individuals were followed forward in historical time from icu admission to the first occurrence of an outcome, censoring event (completion of and days of follow-up), or competing event (hospital discharge). pre-specified subgroup analyses evaluated the association between vascular access type prior to hospital admission and dialysis vintage (separately) and mortality in hemodialysis patients, and the degree of baseline creatinine (pre-hospital serum creatinine < . , . - . , and ≥ . mg/dl) and mortality in ckd patients. we used similar methods to examine the association between the presence (vs. absence) of pre-existing kidney disease and the occurrence of select secondary outcomes during the j o u r n a l p r e -p r o o f days after icu admission. we restricted these secondary analyses to individuals who were alive and free of the outcome of interest on icu day . follow-up began on icu day , with both inhospital death and hospital discharge treated as competing events. we adjusted associative models for demographics (model ), and separately for demographics and comorbid conditions (model ) when the number of outcome events was sufficient. model assesses the association of outcomes and underlying kidney disease overall, while model assesses the association of outcomes and underlying kidney disease independent of comorbid conditions known to associate with covid- outcomes. , , - using analogous methods, we performed separate sensitivity analyses excluding patients on therapeutic-level anticoagulation on icu day from models examining major bleed and thromboembolic events, and excluding patients with histories of liver disease from models examining acute liver injury. a total of , individuals with covid- critical illness were included in the study: ( %) with pre-existing dialysis-dependent kidney failure, ( %) with pre-existing nondialysis-dependent ckd, and , ( %) without pre-existing kidney disease. table and supplemental tables s -s display the demographic and clinical characteristics on icu day across study groups. the majority of patients in the study ( %) were cared for in icus located in the northeastern u.s. ckd patients were older than dialysis patients (median [quartile - of the individuals with pre-existing dialysis-dependent kidney failure, ( %) received in-center hemodialysis, ( %) received peritoneal dialysis, ( %) received home hemodialysis, and ( %) had an undocumented modality prior to hospital admission. of the hemodialysis patients with known vascular access type, ( %), ( %), and ( %) dialyzed via a fistula, catheter, and graft, respectively, prior to admission. the median time from covid- -related symptom onset to icu admission was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days among dialysis patients, [ - ] days among ckd patients, and [ - ] days among patients without pre-existing kidney disease. in general, dialysis patients reported covid- related symptoms prior to icu admission at a lower frequency than patients without kidney disease, with one exception: the percentage of dialysis patients reporting altered mental status was more than twice that of patients without kidney disease ( % vs. %, asmd = . ) and slightly more than patients with ckd ( % vs. %, asmd = . ). in addition, respiratory symptoms were less frequent in dialysis patients compared to the other groups. table and supplemental tables s -s display covid- severity and laboratory findings on icu day across study groups. a modestly higher percentage of patients without kidney disease ( %) required invasive mechanical ventilation on icu day compared to dialysis patients ( %, asmd = . ). median white cell counts, platelet counts, and fibrinogen concentrations on icu day were lower in dialysis patients compared to patients without kidney disease, whereas median c-reactive protein, interleukin- , ferritin, and troponin levels were higher in dialysis patients (all asmds > . ). similar laboratory patterns were observed for platelet count, fibrinogen, and troponin levels when comparing ckd patients to patients without kidney disease, but the differences were of lower magnitudes. targeted therapies and clinical trajectories table displays covid- -targeted therapies administered during the days after icu admission in each group (supplemental table s : corresponding asmds). compared to dialysis patients, a higher percentage of patients without pre-existing kidney disease were mechanically ventilated ( % vs. %, asmd = . ). proned positioning was used in a higher percentage of patients without kidney disease ( %) compared to ckd ( %, asmd = . ) and dialysis ( %, asmd = . ) patients. remdesivir was more commonly administered to patients without kidney disease ( %) compared to ckd patients ( %, asmd = . ). no dialysis patients received remdesivir. patients without kidney disease received tocilizumab ( %) more often than those with ckd ( %, asmd = . ) and dialysis-dependent kidney failure ( %, asmd = . ). figure s display laboratory parameter trajectories during the first days after icu admission across groups. in general, dialysis and ckd patients had lower platelet counts and higher levels of c-reactive protein compared to patients without kidney disease. lactate levels on icu day were similar across groups, but elevated levels persisted longer in dialysis patients compared to the other groups. longitudinally, ferritin and troponin levels were highest in dialysis patients and lowest in patients without kidney disease. figure s ). compared to no pre-existing kidney disease, pre-existing ckd and dialysisdependent kidney failure associated with higher risks of -and -day in-hospital mortality ( table ). in models examining the association between in-hospital mortality and pre-existing j o u r n a l p r e -p r o o f kidney disease status, independent of other comorbid conditions (i.e. models adjusted for demographic and comorbid conditions), the associations were slightly attenuated but remained statistically significant (fully adjusted hr ( % ci) for -day in-hospital mortality): . ( . , . ) for ckd and . ( . , . ) for dialysis-dependent kidney failure. models evaluating day in-hospital mortality produced similar results. of the patients who died during the -days following icu admission, the median [quartile -quartile ] time from icu admission to death was [ ] [ ] [ ] [ ] [ ] [ ] [ ] , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , and [ - ] days for the dialysis, ckd, and no kidney disease groups, respectively. mortality rates across exposure groups were stable during the study period (supplemental table s ). table s display secondary outcomes across patient groups. dialysis patients trended toward having higher risks of shock, ventricular arrhythmia or cardiac arrest, major bleeding events, and acute liver injury during the days after icu admission. the occurrence of thromboembolic events was similar across patient groups. sensitivity analyses excluding patients receiving therapeutic anticoagulation from major bleed and thromboembolic event models and patients with histories of liver disease from acute liver injury models produced similar results (supplemental tables s -s ) . supplemental tables s -s display results from all pre-existing kidney disease subgroup analyses. of the individuals with pre-existing non-dialysis-dependent ckd and known baseline creatinine levels, a higher baseline creatinine trended toward associations with higher in-hospital mortality, but results did not reach statistical significance. among the incenter hemodialysis patients, dialysis via a catheter (vs. arteriovenous access) was associated with higher -day in-hospital mortality, demographic-adjusted hr ( % ci): . ( . , . ). in this study of over , critically ill adult patients admitted to u.s. icus with covid- , we found that having pre-existing kidney disease was associated with higher inhospital mortality rates, with the strength of this association varying by degree of baseline kidney dysfunction. compared to no pre-existing kidney disease, the presence of pre-existing kidney failure (dialysis-dependent) was associated with the highest hazard of in-hospital death, while pre-existing ckd (non-dialysis-dependent) had an intermediate association. our findings highlight the importance of identifying effective covid- therapies that can be safely administered to patients with underlying kidney dysfunction. moreover, they underscore the urgency of proactive, pre-hospital advanced care planning conversations with this vulnerable population. our findings, from a large, geographically diverse sample of critically ill covid- patients, expand on the existing evidence base demonstrating higher in-hospital mortality among patients with underlying kidney disease and newly report detailed clinical trajectories and outcomes among ckd patients. the observed association between pre-existing kidney disease and in-hospital mortality persisted in models adjusted for medical conditions known to associate with poorer covid- outcomes, suggesting that underlying kidney disease confers risk for individuals with severe covid- beyond that related to the comorbid disease burden characteristic of the disease state. such findings may relate, in part, to uremia-induced innate immune system changes that hinder neutrophil, monocyte, and b-and t-cell function, thereby impairing bactericidal capacity and antimicrobial ability. - we also found that dialysis patients receiving icu-level care for covid- had an in-j o u r n a l p r e -p r o o f hospital death rate of %, which is lower than rates reported in regional studies. - strikingly, the unadjusted death rate among ckd patients ( %) was equivalent to that of dialysis patients ( %) yet notably higher than that of patients without underlying kidney disease ( %). these findings not only highlight the importance of discussing covid- risks with both dialysis and ckd patients, but also engaging in advanced care planning conversations in the ambulatory setting, prior to patients falling ill with covid- . these discussions are particularly germane for individuals with kidney disease since remdesivir, one of the few evidence-based covid- therapeutic options currently available, is generally not recommended for adults with an egfr < ml/min/ . m . however, the purported risks of remdesivir in the setting of kidney dysfunction that stem from concerns related to accumulation of its carrier, sulfobutylether-βcyclodextrin, may be overstated. our study has several strengths. first, we used data from a cohort of over critically ill individuals with covid- who were admitted to geographically diverse u.s. icus, increasing the generalizability of our findings and substantially expanding the evidence base about critically ill covid- patients with pre-existing kidney disease. second, we performed detailed chart reviews using standardized data extraction tools to collect daily, granular information on patients' clinical courses. this obviated the need for reliance on administrative billing codes that may lead to misclassification and supported the study of detailed comparisons across study groups. third, data were collected from critically ill patients consecutively admitted to each icu, minimizing potential selection bias. fourth, whereas some prior studies of dialysis patients hospitalized with covid- had limited follow-up time, we followed patients until the occurrence of hospital discharge, death, or -days. we also acknowledge several study limitations. first, as with all observational studies, residual confounding may exist. however, to examine the association between underlying kidney disease and outcomes independent of coexistent medical conditions, we accounted for key demographic factors and comorbid conditions known to have strong associations with outcomes in individuals with covid- in our multivariable models. second, we defined pre-existing kidney disease based on the presence of prior egfr measurements or documentation of ckd in the admitting hospital's medical record. it is possible that some exposure misclassification may have occurred. third, data on organ injury and organ support were captured during the first days following icu admission only. events after the -day time period may have been missed. however, it is reassuring that most of the observed events occurred early in icu courses, suggesting that the majority of events were likely captured. fourth, data on inflammatory markers were not available for many patients (supplemental table s ) and may not have been j o u r n a l p r e -p r o o f missing at random (i.e., laboratory values were likely drawn more often in patients with more severe covid- ). as such, it is possible that the observed trends in such markers may not generalize to individuals with less severe covid- . related, it is possible that individuals with pre-existing kidney disease may have been preferentially declined icu admission or died prior to icu admission, raising the possibility of potential selection bias in our cohort. however, such selection bias would likely bias our findings toward the null. fifth, we did not have information on -and -day vital status for patients discharged from the hospital prior to these time points. finally, limited numbers of some secondary outcomes (e.g., major bleeding events, acute liver injury) in the pre-existing kidney disease groups may have limited our ability to detect significant associations. therefore, these findings should be considered hypothesis generating and fodder for future study. in conclusion, in this multicenter, nationally representative cohort of u.s. adults with covid- critical illness, we found that both ckd and dialysis patients had a ~ % -day inhospital mortality rate and that patients with underlying kidney disease had higher in-hospital mortality than patients without kidney disease, with maintenance dialysis patients having the highest risk in adjusted analyses. as evidenced by differences in symptoms and clinical trajectories, patients with pre-existing kidney disease may have unique vulnerability to covid- -related complications that warrant additional study and special consideration in the pursuit and development of targeted therapies. table s . association between pre-existing kidney disease and -day in-hospital outcomes among critically ill covid- patients j o u r n a l p r e -p r o o f supplemental table s . sensitivity analyses evaluating the association between pre-existing kidney disease and -day in-hospital major bleeding and thromboembolic events excluding patients on therapeutic anticoagulation on icu day supplemental table s . sensitivity analyses evaluating the association between pre-existing kidney disease and -day in-hospital acute liver injury excluding patients with histories of liver disease supplemental table s . association between baseline serum creatinine and -and -day inhospital mortality among critically ill ckd patients with covid- supplemental table s . association between vascular access type and -and -day inhospital mortality among critically ill hemodialysis patients with covid- supplemental table s . association between dialysis vintage and -and -day in-hospital mortality among critically ill hemodialysis patients with covid- supplemental table s . icu day variables with missing data fine and gray proportional subdistribution hazards models were used to estimate the association between the presence of pre-existing kidney disease (dialysis-dependent kidney failure and ckd, separately) vs. no pre-existing kidney disease and -and -day in-hospital mortality. hospital discharge was treated as a competing event. a model was adjusted for age, sex, race, and hispanic ethnicity. values presented in the figure are medians. dialysis represents patients with pre-existing dialysis-dependent kidney failure. ckd represents patients with pre-existing non-dialysis-dependent ckd. no kidney disease represents patients without pre-existing kidney disease. supplemental figure s displays analogous figures for the laboratory values of creatinine, interleukin- , fibrinogen, d-dimer, direct bilirubin, and troponin i. abbreviations: ckd, chronic kidney disease; crp, c-reactive protein; icu, intensive care unit; il, interleukin. dialysis represents patients with pre-existing dialysis-dependent kidney failure. ckd represents patients with pre-existing non-dialysisdependent ckd. no kidney disease represents patients without pre-existing kidney disease. abbreviations: ckd, chronic kidney disease; icu, intensive care unit. dialysis represents patients with pre-existing dialysis-dependent kidney failure. ckd represents patients with pre-existing non-dialysisdependent ckd. no kidney dis represents patients without pre-existing kidney disease. fine and gray proportional subdistribution hazards models were used to estimate the association between the presence of pre-existing kidney disease (dialysis-dependent kidney failure and non-dialysis-dependent ckd, separately) vs. no pre-existing kidney disease and -day in-hospital outcomes. in mortality analyses, hospital discharge was treated as a competing event. in analyses of other outcomes both death and hospital discharge were treated as competing events. analyses assessing mortality, respiratory failure, shock, and ventricular arrhythmia or cardiac arrest were adjusted for age, sex, race, hispanic ethnicity, diabetes, hypertension, coronary artery disease, heart failure, and atrial fibrillation or flutter. analyses evaluating thrombotic events, major bleeding, events, and acute liver injury were only adjusted for age, sex, race, hispanic ethnicity only due to the low number of event counts. factors associated with covid- -related death using opensafely chronic kidney disease is associated with severe coronavirus disease (covid- ) infection epidemiology, clinical course, and outcomes of critically ill adults with covid- in new york city: a prospective cohort study male sex, severe obesity, older age, and chronic kidney disease are associated with covid- severity and mortality in new york city ckd is a key risk factor for covid- mortality defective expression of b - (cd ) on monocytes of dialysis patients correlates to the uremia-associated immune defect immune dysfunction and risk of infection in chronic kidney disease transmission, diagnosis, and treatment of coronavirus disease (covid- ): a review presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area characteristics and outcomes of critically ill patients with covid- in washington state values are n (%) for categorical variables and median a renal component of the sofa score was based on serum creatinine levels. patients who did not have a serum creatinine drawn on icu day were classified as having a renal sofa score of , and patients on rrt were classified as having a renal sofa score of key: cord- -qcijsyo authors: eichberg, daniel g; shah, ashish h; luther, evan m; menendez, ingrid; jimenez, andrea; perez-dickens, maggy; o’phelan, kristine h; ivan, michael e; komotar, ricardo j; levi, allan d title: letter: academic neurosurgery department response to covid- pandemic: the university of miami/jackson memorial hospital model date: - - journal: neurosurgery doi: . /neuros/nyaa sha: doc_id: cord_uid: qcijsyo nan neurosurgeons often treat patients with conditions in which time is of the essence and delaying surgery may negatively affect outcome. we have halted all elective cases, but will continue to schedule urgent and emergent cases. emergent cases such as head and spine trauma, cauda equina syndrome, embolic stroke, ruptured aneurysms, and acute hydrocephalus are relatively noncontroversial; however, urgent cases such as malignant brain tumors and progressive cervical spondylotic myelopathy may require a more nuanced discussion. therefore, we have empowered a small neurosurgery covid team consisting of senior neurosurgeons with multidisciplinary backgrounds who review a brief history and select imaging studies and make decisions for urgent surgical cases. the presence of an independent adjudicating body will improve surgical decision-making consistency and decrease suboptimal use of hospital resources and unnecessary exposure of staff to disease. additionally, screening all surgical cases preoperatively for covid- is critical. we impose a -d delay for cases with this concern. finally, to minimize the need to physically return to clinic, we use dissolvable sutures. , this step allows postoperative patients to be seen via our telemedicine protocols noted below. all elective clinic visits have been canceled. postoperative visits are only performed if sutures need to be removed; otherwise these have also been cancelled. these visits have been replaced by telemedicine clinic visits, which have previously been validated in the neurosurgery population. [ ] [ ] [ ] [ ] [ ] we have implemented health insurance portability and accountability act (hippa)-compliant telehealth technology integrated into our electronic medical record (epic, epic systems corporation, verona, wisconsin). neurosurgeons and their patients can communicate via secure video-conference feed using a computer, mobile device, or tablet. properly documented video conferencing, email, and phone call visits are now reimbursable, meaning that telehealth clinic visits may be financially and medicolegally viable for remote neurosurgical clinical care. we continue to schedule clinic visits to evaluate potentially urgent surgical patients, which are determined during a clinic prescreen. after appropriate screening questions and temperature evaluation, only the patient is allowed to enter the clinic. since implementation, we have decreased the number of clinic visits by %; however, we continue to see and evaluate the same number of patients prior to this protocol. all in-person conferences such as grand rounds, resident education conferences, and multidisciplinary board meetings have been replaced by video teleconferences. multiple software products exist to enable video teleconferences and are easily implemented with devices and applications currently in use. these conferences continue with the use of visual sharing of radiographic images and pathological images via these teleconference applications. thus far, we have been able to cover the same amount of material and patient cases as we have done in the past. only the minimal number of residents and/or fellows required for patient care are allowed to come to the hospital. rotating resident schedules have been devised to minimize resident viral exposure and burnout. we have designated a healthy "second responder" or "off shift" group to stay home, unless the active "first responder" group becomes sick. this will ensure enough providers to be continuously available for the duration of the pandemic. all residents seeing consults are provided with appropriate personal protective equipment (ppe). the overall volume of neurosurgical cases has diminished by about %, but the on-call obligations for many hospitals and individual sub-specialties have not. to minimize faculty exposure, we have re-organized the call schedules so that one provider covers multiple hospitals and sub-specialties -with appropriate at home we have purchased multiple laptop computers for the department enabling % of our administrative staff to work at home. postoperative neurosurgical patients are often medically fragile; thus exposure to covid- may be extremely deleterious. we screen patients who may be covid- positive either upon entrance to the hospital. if they require intensive care unit (icu) level of care they are routed to an icu setting that is physically separated from the neurosciences icu in order to limit exposure to our neurosurgery patients and team. additionally, visitors to the icu are currently limited to person per day. however, there are ongoing discussions to transition to no visitors in the icu. we have also begun transferring patients that are status post uncomplicated craniotomies and endoscopic skull base patients from the operating room to the step down unit rather than the icu, in order to maximize the number of available icu beds for potential covid- patients. we also make every effort to optimize patients for discharge home on postoperative day . during the covid- pandemic, emergent and urgent neurosurgical procedures should continue to be performed, while deferring elective surgeries. appropriate ppe for all staff, and minimal resident coverage in the hospital, should be the norm. video teleconferencing for both clinical patients and conferences should be utilized. minimizing exposure for residents, attendings, and staff will benefit all involved. with appropriate strategy, it is possible for an academic neurosurgical department to maintain its commitments to neurosurgical patients as well as their community at large and provide safe and effective neurosurgical treatment. world health organization. coronavirus disease (covid- ) situation report- the outbreak of covid- : an overview intradermal scalp closure using barbed suture in cranial tumor surgeries: a technical note hair-sparing technique using absorbable intradermal barbed suture versus traditional closure methods in supratentorial craniotomies for tumor neurosurgery and telemedicine in the united states: assessment of the risks and opportunities comparison of telemedicine with inperson care for follow-up after elective neurosurgery: results of a cost-effectiveness analysis of patients using patient-perceived utility scores prospective and retrospective study of videoconference telemedicine follow-up after elective neurosurgery: results of a pilot program stimulated raman histology for rapid and accurate intraoperative diagnosis of cns tumors: prospective blinded study near real-time intraoperative brain tumor diagnosis using stimulated raman histology and deep neural networks cms adult elective surgery and procedures recommendations: limit all non-essential planned surgeries and procedures brain tumor surgery is safe in octogenarians and nonagenarians: a single-surgeon patient series copyright c by the congress of neurological surgeons the authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. key: cord- - ke nqy authors: sabir, a. m.; alvi, i. a.; alharbi, m.; basabrain, a.; aljundi, m.; almohammadi, g.; almuairfi, z.; alharbi, r. title: effects of anticoagulants and corticosteroids therapy in patients affected by severe covid- pneumonia date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: ke nqy background in the absence of a standard of treatment for covid- , the combined use of anti-inflammatory (corticosteroids and enoxaparin) and antiviral drugs may be more effective than using either modality alone in the treatment of covid- . methods patients hospitalized between april th, , through may th, , who had confirmed covid- infection with clinical or radiographic evidence of pneumonia, in which patients have moderate covid- pneumonia, and patients have severe covid- pneumonia. all patients received early combination therapy of anti-inflammatory (corticosteroids and enoxaparin) and antiviral drugs. they assessed for type and duration of treatment, and days need to wean from oxygen therapy, length of stay, virus clearance time, and complication or adverse events. all patients had more than days follow up after discharge from the hospital. results moderate covid- pneumonia group were patients who received enoxaparin, antiviral drugs, empirical antibiotics for pneumonia, and standard treatment for comorbidity. male patients were ( . %) and female patients were ( . %). ( . %) patients have comorbidity, ( . %) patients have diabetes mellitus and ( . %) pregnant ladies. ( . %) patients were on low flow oxygen therapy, l oxygen or less to maintain oxygen saturation more than %. all patients discharged home with no major or minor bleeding complications or significant complications. severe covid- pneumonia group were patients who received methylprednisolone, enoxaparin, antiviral drugs, empirical antibiotics for pneumonia, and standard treatment for comorbidity. male patients were ( . %) and female patients were ( . %). ( . %) patients have comorbidity, and ( . %) patients have diabetes mellitus. ( . %) patients were on low flow oxygen therapy, - l oxygen, and ( . %) patients were on low flow oxygen therapy, l oxygen or more, including patients on a non-rebreathing mask. patients received methylprednisolone were ( . %) for days, ( . %) for days and ( . %) for more than days. sixty-two patients discharged home with one patient had a long stay, and the other two transferred to icu. one long-stay patient transferred to icu on low flow oxygen therapy. conclusion early use of a combined anti-inflammatory (corticosteroids and enoxaparin) and antiviral drugs treatment in patients with moderate to severe covid- pneumonia prevent complications of the disease and improve clinical outcomes. the novel coronavirus was first reported on in wuhan, china, in late december . the outbreak was declared a public health emergency of international concern in january , and on march th , , the outbreak was declared a global pandemic . the virus has been named severe acute respiratory syndrome coronavirus- (sars-cov- ), and the disease it causes has become known as coronavirus disease . an estimated % of covid- cases are sick enough to require hospitalization, with a subset of % of patients requiring intensive care. although most reported covid- cases in china were mild ( %). among hospitalized patients with covid- , about - % of patients are admitted to icu, - % require intubation, and - % die. as of april th, the case fatality rate prediction interval is . - . %. to date, there is no specific antiviral drug or vaccine for covid- . all the treatment options come from experience treating sars, mers, or some other new influenza virus previously. treatments are mainly symptomatic and respiratory support. there is no current evidence from rcts to recommend any specific treatment for patients with suspected or confirmed no studies were found explicitly examining the role of steroids for the treatment of the covid- pneumonia. corticosteroids were widely used in china to prevent the development of ards in patients with covid- pneumonia. among patients who have been admitted to the hospital with covid- pneumonia, the idsa guideline panel suggests against the use of corticosteroids. surviving sepsis campaign guideline on managing critically ill adults with covid- supports using corticosteroids in mechanically ventilated patients with covid- and acute respiratory distress syndrome (but not those with respiratory failure in the absence of that syndrome) and patients with covid- and refractory shock; short-course, low-dose regimens are preferred. in the absence of a standard of treatment for covid- , the combined use of anti-inflammatory (corticosteroids and enoxaparin) and antiviral drugs may be more effective than using either modality alone in the treatment of covid- . this study evaluates the effectiveness of a combination treatment of anti-inflammatory (corticosteroids and enoxaparin) and antiviral drugs to treat severe covid- pneumonia. this study was done at al madinah al munawarah hospital in al madinah, saudi arabia, from april th to june th , . patients were received and admitted through the emergency department. cases were positive for sars-cov- by rt-qpcr with findings of pneumonia clinically or radiologically on a chest xray or ct scan. all patients were followed by the infectious diseases team from admission to discharge, and more than days post-discharge follow up for complications or readmission. all patients signed informed consent for receiving medical acts and care. all patients hospitalized between april th , through may th, , were eligible for inclusion if they were years of age or older, had confirmed covid- infection with clinical or radiographic evidence of pneumonia. patients were excluded if they were immunocompromised with cancer, chemotherapy, transplant, or end-stage renal disease on renal replacement therapy. a confirmed case of covid- was defined as a patient that had a positive reverse-transcriptasepolymerase-chain-reaction (rt-pcr) assay for sars-cov- in a nasopharyngeal sample tested by al-madinah region central lab. severe covid- pneumonia defined as confirmed covid- infection, with clinical or radiographic evidence of pneumonia, and oxygen saturation less than with pulse oximetry. moderate covid- pneumonia defined as confirmed covid- infection, with clinical or radiographic evidence of pneumonia, and oxygen saturation more than with pulse oximetry. ) intravenous methylprednisolone: only for severe covid- pneumonia; if the patient needs more than l oxygen therapy, methylprednisolone is mg four times daily for to days, if the patient does not improve, continue until his oxygen saturation becomes more than % on ambient air, then methylprednisolone is tapering to once daily and to be stopped if oxygen saturation more than % on ambient air. if the patient needs less than l oxygen therapy, methylprednisolone is mg three times daily for to days if the patient does not improve, continue until his oxygen saturation becomes more than % on ambient air, then methylprednisolone is tapering to once daily and to be stopped if oxygen saturation more than % on ambient air. ) enoxaparin treatment according to d-dimer, patient weight, and severity of pneumonia. enoxaparin mg bid duration of enoxaparin treatment: moderate covid- pneumonia is three to five days; if the patient does not improve, continue enoxaparin until oxygen saturation becomes more than % on ambient air, then change enoxaparin dose to mg once daily until home discharge. enoxaparin duration for severe covid- pneumonia is three to five days, if the patient doesn't improve, continue enoxaparin until oxygen saturation becomes more than % on ambient air, then decrease the enoxaparin according to his weight, continue enoxaparin until oxygen saturation becomes more than % on ambient air, then change enoxaparin dose to mg once daily until home discharge. ) antiviral drugs were hydroxychloroquine mg every hours for one day, followed by mg twice daily for - days or lopinavir/ritonavir / mg twice daily for ten days. ) empirical antibiotics for pneumonia. ) other treatments: standard treatment for comorbidity. all patients assessed for type and duration of treatment, days need to wean from oxygen therapy, length of stay, virus clearance time, and complication or adverse events. all patients had days follow up or more after discharge from the hospital by mobile phone or emergency department visit for hospital readmission or complication. outcome definitions ) icu transfer after admission in the medical ward due to respiratory failure or any reason. ) patient discharged home. ) long stay mor than days. ) death due to any cause. data were analyzed using ibm spss for windows. statistical analyses of demographics, clinical, laboratory, treatment, length of stay, virus clearance time, and outcome descriptive data are tabulated. descriptive statistics such as means and standard deviation mean (±sd) were used for quantitative variables, absolute and relative frequency (%) for qualitative variables. between april th to may th , , a total of patients with covid- were enrolled, in which patients have moderate covid- pneumonia, and patients have severe covid- pneumonia. , and virus clearance time mean was . days ( - ). all patients in the group discharged home with no major or minor bleeding complication or significant complication. all patients have days follow up, or more after discharge without readmission or complication noticed. the length of stay was higher among patients with comorbidity, and the mean was . ( - ) days. it also was higher among patients who received lopinavir/ritonavir only, and the mean was . ( - ) days, where the mean was . ( - ) days among patients received azithromycin and hydroxychloroquine treatment. virus clearance time was prolonged among patients had low flow oxygen therapy with mean of . ( - ) day and prolonged among patients who received lopinavir/ritonavir only, and the mean was . ( - ) day, where the mean was . ( - ) day among patients received azithromycin and hydroxychloroquine treatment. patients with comorbidity ( . %) needed more low flow oxygen therapy than patients with no comorbidity. severe covid- pneumonia group received methylprednisolone, enoxaparin, antiviral drugs, empirical antibiotics for pneumonia, and standard treatment for comorbidity. male patients were ( . %) and female patients were ( . %). ( . %) patients have comorbidity, and ( . %) patients have diabetes mellitus. ( . %) patients were on low flow oxygen therapy, - l oxygen, and ( . %) patients were on low flow oxygen therapy, l oxygen or more, including patients on the nonrebreathing mask. patients received methylprednisolone were ( . %) for days, ( . %) for days and ( . %) for more than days. ( . %) patients received azithromycin, and hydroxychloroquine treatment and ( . %) patients received lopinavir/ritonavir. length of stay mean was . days ( - ), and virus clearance time mean was . ( - ). a ( . %) patients in the group discharged home with no major or minor bleeding complication or septic shock. the most common complication was hyperglycemia among diabetic patients. there are two patients transferred to icu due to respiratory failure and managed with non-invasive ventilation (bipap) for three days, then transferred back to the medical ward and discharged home. there is one patient in medical ward needs low flow oxygen therapy and methylprednisolone for more than days due to unknown reason or confirmed significant lung disease or infection, but bactrim was given empirically for possible pneumocystis pneumonia, then improved and discharged home. there is also one patient with diabetes mellitus and ischemic heart disease transferred to icu due respiratory failure and managed with an invasive ventilator for days and ended with a tracheostomy tube and severe lung fibrosis, currently he is conscious and pulmonary rehabilitation started. all patients have days follow up, or more after discharge without readmission or complication noticed. length of stay was higher among patients with comorbidity, and the mean was . ( - ) day. it also was higher among patients who received l or more low flow oxygen therapy, and the mean was . ( - ) day. it also was high among patients who received lopinavir/ritonavir only, and the mean was . ( - ) day, where the mean was . ( - ) day among patients received azithromycin and hydroxychloroquine treatment. virus clearance time was prolonged among patients who had low flow . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . oxygen therapy with a mean of . ( - ) day and prolonged among patients who received methylprednisolone for more than five days, and the mean was . ( - ) day. patients with comorbidity ( . %) needed more low flow oxygen therapy, l oxygen, or more than patients with no comorbidity. d-dimer level was measured in all patients on admission in both groups-no significant association between d-dimer level and hypoxemia, length of stay, or virus clearance time. the clinical course of covid- could be divided into three phases: viremia phase, acute phase (pneumonia phase) and severe or recovery phase. patients with competent immune functions and without apparent risk factors (old age, comorbidities, etc.) may generate effective and adequate immune responses to suppress the virus in the first or second phase without immune over-reaction. in contrast, patients with immune dysfunction may have a higher risk of failing the initial phase and becoming severe or critical type with higher mortality. therefore, treatment of covid- should be based on the staging of patients, and the window of opportunity may lie between the first and the second phases, when clinical deterioration is observed with evidence of abrupt inflammation and hypercoagulable states. with no proved antivirals, early intervention has mainly focused on the correct timing of disease stages and implementing ways to stop or slow disease progression. once the patients enter the critical status, nothing could be relied on other than comprehensive management. the combined use of anti-inflammatory and antiviral drugs may be more effective than using either modality alone. based on in vitro evidence for inhibiting sars-cov- replication and blocking sars-co- infection-induced pro-inflammatory cytokine production. clinical-therapeutic staging proposal , • stage i: mild (early infection) administration of steroid during the early infection could increase viral replication and perhaps delay development of adaptive immunity. this might be expected to be detrimental. • stage iia: moderate (pulmonary involvement without hypoxia) • stage iib: moderate (pulmonary involvement with hypoxia) low-dose steroid administration during the pulmonary involvement might be expected to be beneficial (by blunting the severity of inflammation and thereby preventing a severe hyper-inflammation phase). • stage iii: severe (systemic hyperinflammation) for those patients who develop a marked hyper-inflammation phase, low-dose steroid might be inadequate to treat this. higher doses of steroid or targeted immunosuppressive (e.g. tocilizumab) could be necessary to treat established hyper-inflammation. however, higher doses of steroids have greater side-effects -so delaying steroid administration until stage iii could result in missing the window of optimal intervention . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . low peripheral capillary oxygen saturation (spo ; with the cutoff of %) after receiving oxygen support along with the presence of dyspnea were found to be a strong predictor of mortality. exertional dyspnea, an easily assessed symptom, is associated with death in patients with covid- associated pneumonia independently of age and sex. among patients who developed severe disease, the mean duration to develop dyspnea is - days, acute respiratory distress syndrome (ards) from - days, icu admission is - days. some patients can rapidly deteriorate one week after illness onset. mortality among patients admitted to the icu is % - %, and the median length of hospitalization among survivors is - days. , acute respiratory distress syndrome (ards) is the leading cause of mortality in covid- pneumonia. therefore, covid- patients with exertional dyspnea with or without hypoxia should be admitted to hospitals, evaluated for pulmonary involvement clinically and radiologically, and treated early with anti-inflammatory and antiviral drugs. proper management of covid- mandates a better understanding of disease pathogenesis. two main features preceding severe respiratory failure associated with covid- : the first is macrophage activation syndrome-like state; the second is defective antigen-presentation driven by interleukin- . the peculiar clinical course of cap caused by sars-cov- , including the sudden deterioration of the clinical condition - days after the first symptoms, generates the hypothesis that this illness is driven by a unique pattern of immune dysfunction that is likely different from sepsis. the features of lymphopenia with hepatic dysfunction and increase of d-dimers in these patients with severe disease further support this hypothesis . , it was reported that il- and il- could cause hypercoagulation, leading to scattered fibrin clots, shortening the clot dissolution time, and maximizing the dissolution rate. it was also observed that severe covid- patients had higher levels of il- , , suggesting that the hypercoagulation status of covid- patients may be related to the elevated levels of cytokines. pathological observations support the current concept of a hypercoagulative state in critically ill patients, showing that the frequency of pulmonary micro-thrombosis is high. because organ dysfunction is mainly limited in lung and virus is the primary pathogen, the coagulation feature of severe covid- might not be identical with sepsis in general. american society of hematology recommends lmwh should be considered in all patients (including non-critically ill) who require hospital admission for covid- infection, in the absence of any contraindications like active bleeding, platelet count < × /l, monitoring advised in severe renal impairment and abnormal pt or aptt is not a contraindication. despite the lack of quality published evidence, many institutional protocols have adopted an intermediate-intensity (i.e., administering the usual daily lmwh dose twice daily) or even a therapeutic-intensity dose strategy for thromboprophylaxis based on local experience. lmwh not only improves the coagulation dysfunction of covid- patients but exerts an antiinflammatory effect through reducing il- and increasing lymphocyte%. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . if a mas-like state exists and excessive il- levels are detrimental, why shouldn't corticosteroids be firstline therapy as these will vigorously suppress il- and a raft of other cytokines? although the recent open-label study from wu and colleagues showed a benefit for corticosteroids, the consensus is that these should not be used based on clinical experience in sars-cov, mers-cov, and other infections including influenza and respiratory syncytial virus infection, where collectively there is evidence for delayed viral clearance. an early short course of methylprednisolone in patients with moderate to severe covid- reduced escalation of care and improved clinical outcomes in a multi-center pre/post study evaluating the effect of a protocol involving early steroid administration within a health system in michigan (including five hospitals). in this study, enoxaparin was given as anti-inflammatory to covid- pneumonia without major or minor bleeding complications. enoxaparin dose based on d-dimer level and oxygen saturation +/methylprednisolone plus antiviral drugs is associated with better outcome in covid- pneumonia. enoxaparin was given for three to five days or more until oxygen saturation is more than %. methylprednisolone mg three or four times daily according to the severity of hypoxia. patients oxygen saturation often improved to more than % on ambient air after to days of methylprednisolone treatment. during methylprednisolone treatment, oxygen saturation sometimes becomes abruptly normal, even if patients were on more than l oxygen therapy. hyperglycemia, hypernatremia, and hypokalemia were monitored and treated. routine sepsis monitoring, including bloodwork and monitoring for recurrence of inflammation and signs of adrenal insufficiency after stopping methylprednisolone, were performed. some patients had high blood pressure, gastritis/duodenitis, and insomnia during methylprednisolone treatment. the rate of occurrence of infectious complications increases, and mild infection may become severe and fatal. corticosteroids may also mask some signs of current infection. latent infections may be activated, or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by amoeba, candida, cryptococcus, mycobacterium, nocardia, pneumocystis, toxoplasma, and fungal infection. there is one patient who was given methylprednisolone for more than days, after ten days of steroids therapy, workup for possible infections were done, no confirmed significant lung disease or infection was found, and bactrim was given empirically for possible pneumocystis pneumonia, then improved and discharged home. some patients were treated by methylprednisolone for ten days and more due to slowly improved hypoxemia. those patients routinely monitored for pulmonary and extrapulmonary infections. antiviral drugs available at study time were hydroxychloroquine and lopinavir/ritonavir. lopinavir/ritonavir was given to patients who cannot take hydroxychloroquine because of prolonged qtc interval, old age, and multiple comorbidities, which explained the prolonged duration of virus clearance time and the length of stay in hospital inpatients taking lopinavir/ritonavir. the antiviral drugs with evidence of improving covid- pneumonia can be combined with anti-inflammatory drugs to treat covid- patients in hospitals. empirical antibiotics with standard community-acquired pneumonia regimen (ceftriaxone plus azithromycin or levofloxacin) in moderate covid- pneumonia was given to ( . %) patients. most . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . patients with diabetes mellitus (especially longstanding and uncontrolled) not improved on standard regimen or worse after hours of admission, so hospital-acquired pneumonia regimen (cefepime or meropenem or pip-tazo + azithromycin or levofloxacin) was given and patients improved and discharged home. extra days of length of stay, and virus clearance time, higher oxygen therapy among patients with comorbidity and moderate covid- pneumonia. mrsa coverage was given to patients with a high risk of mrsa and not improved with hospital-acquired pneumonia regimen. diabetes is a risk factor for hospitalization and mortality of the covid- infection. diabetes was a comorbidity in % of non-survivors in a study of intensive care patients. in another study of patients with severe disease, . % had diabetes, and in further study of hospitalized patients, % had diabetes. , when comparing intensive care and non-intensive care patients with covid- , there appears to be a twofold increase in the incidence of patients in intensive care having diabetes. mortality seems to be about threefold higher in people with diabetes compared with the general mortality of covid- in china. , in patients with severe covid- pneumonia, empirical antibiotics with hospital-acquired pneumonia regimen (cefepime or meropenem or pip-tazo + azithromycin or levofloxacin) was given because of steroids therapy. standard community-acquired pneumonia regimen with steroid therapy was failed many times because the patients have bilateral pulmonary involvement with hypoxemia. comorbidity in severe covid- pneumonia required more oxygen therapy and length of stay. mrsa coverage was given to patients with a high risk of mrsa and not improved with hospital-acquired pneumonia regimen. empirical bactrim was given once due to the possibility of pneumocystis pneumonia. larger randomized studies and more analysis of patient subtypes to determine benefit from the use of combined anti-inflammatory (corticosteroids and enoxaparin) and antiviral drugs treatment. it is hoped that the above analysis can provide a testable theoretical framework to allow for advances in our understanding and control of this deadly viral epidemic. in conclusion, early use of a combined anti-inflammatory (corticosteroids and enoxaparin) and antiviral drugs treatment, an inexpensive and readily available agents, in patients with moderate to severe covid- pneumonia prevent complications of the disease and improve clinical outcomes. the combination therapy of anti-inflammatory and antiviral drugs can over great benefits to covid- patients with ongoing covid- pandemic and icu bed and mechanical ventilator shortages. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . - ( . %) ( . %) - ( . %) ( . %) - ( . %) ( . %) - ( . %) ( . %) - ( . %) ( . %) more than days ( . %) ( . %) no icu +discharge home ( %) ( . %) yes icu +discharge home ( . %) no icu + long stay ( . %) yes icu + long stay ( . %) death . days ( - ) . days ( - ) . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . death . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint days ( . %) ( . %) ( . %) ( . ) days ( . %) ( %) ( . %) ( . %) more than days ( . %) ( %) ( %) ( %) ceftriaxone + azithromycin or levofloxacin ( . %) ( %) ( %) ( %) - ( . %) ( . %) ( %) ( . %) ( . %) ( . %) ( %) - ( . %) ( %) ( . %) ( . %) ( . %) ( . %) ( %) - ( . %) ( %) ( . %) ( . %) ( . %) ( . %) ( . %) - ( . %) ( . %) ( . %) ( %) ( . %) ( %) ( . %) - ( . %) ( %) ( . %) ( . %) ( . %) ( . %) ( . %) more than days ( . %) ( %) ( %) ( %) ( %) ( %) ( %) no icu +discharge home ( . %) ( . %) ( . %) ( . %) ( . %) ( . %) ( . %) yes icu +discharge home ( . %) ( %) ( %) ( %) ( %) ( %) ( %) no icu + long stay ( . %) ( %) ( %) ( %) ( %) ( %) ( %) yes icu + long stay ( . %) ( %) ( %) ( %) ( %) ( %) ( %) death ( %) a including patients on non re-breathing mask . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / days of corticosteroids treatment -no. (%) empirical antibiotics -no. (%) cefepime or meropenem or pip-tazo + azithromycin or levofloxacin + vancomycin or linezolid ( . %) . ( - ) days need to wean from oxygen therapy -no. (%) key: cord- -csdf a authors: raffiq, azman; seng, liew boon; san, lim swee; zakaria, zaitun; yee, ang song; fitzrol, diana noma; hassan, wan mohd nazaruddin wan; idris, zamzuri; ghani, abdul rahman izaini; rosman, azmin kass; abdullah, jafri malin title: covid- pandemic and its impact on neurosurgery practice in malaysia: academic insights, clinical experience and protocols from march till august date: - - journal: malays j med sci doi: . /mjms . . . sha: doc_id: cord_uid: csdf a the newly discovered coronavirus disease (covid- ) is an infectious disease introduced to humans for the first time. following the pandemic of covid- , there is a major shift of practices among surgical departments in response to an unprecedented surge in reducing the transmission of disease. with pooling and outsourcing of more health care workers to emergency rooms, public health care services and medical services, further in-hospital resources are prioritised to those in need. it is imperative to balance the requirements of caring for covid- patients with imminent risk of delay to others who need care. as malaysia now approaches the recovery phase following the pandemic, the crisis impacted significantly on neurosurgical services throughout the country. various emergency measures taken at the height of the crisis may remain as the new normal in the provision of neurosurgical services and practices in malaysia. the crisis has certainly put a strain on the effective delivery of services and as we approach the recovery era, what may have been a strain may prove to be a silver lining in neurosurgical services in malaysia. the following details are various measures put in place as the new operational protocols for neurosurgical services in malaysia. the novel coronavirus, otherwise known as coronavirus disease (covid- ) pandemic in malaysia, is part of the worldwide ongoing pandemic which was first reported in wuhan china in december . malaysia's first case was confirmed on january , detected among travellers from china entering malaysia via singapore. malaysia's response overseen by the national crisis preparedness and response centre (cprc) under the health ministry began as early as january following world health organization (who) initial report of the disease in china. various hospital was designated specifically as covid- pandemic hospitals, gazettement of quarantine centres, reorganisation of health services, formulation of new operational protocols, stockpiling of essential equipment and redeployment of essential medical workforce and manpower to these centres; as well active detection, monitoring and treating covid- patients. these early response measures were escalated to a total lockdown of movement on march , intended to mitigate the spread of covid- , following the declaration of a worldwide covid- pandemic by who on march . the movement control order (mco) in malaysia lasting for a period of months, coupled by the intense proactive measures by the health ministry has successfully kept the number of cases relatively low comparatively, with a total recorded case of , with deaths. malaysia's proactive and stringent measures have and continue to receive international praise and recognition in successfully mitigating the spread and containing covid- transmission. as malaysia now approaches the recovery phase following the pandemic, the crisis impacted significantly on neurosurgical services throughout the country. various emergency measures taken at the height of the crisis may remain as the new normal in the provision of neurosurgical services and practices in malaysia. the crisis has certainly put a strain on the effective delivery of services, and as we approach the recovery era, what may have been a strain may prove to be a silver lining in neurosurgical services in malaysia. the following details the various measures put in place as the new operational protocols for neurosurgical services in malaysia. role and importance of dedicated operating theatre, instruments and icu care all tertiary hospital should have a dedicated operating theatre (ot) for suspected covid- patients ( ) . the ot requirements should be fully equipped with negative pressure ventilation (recommended). the maximal number of staff is six: i) one specialist; ii) one medical officer; iii) one anaesthetist; iv) one anaesthetist mo; v) one scrub nurse; and vi) one circulating nurse. for elective surgery, kindly refer to its section further below ( ) . limiting ot staff to essential members will help preserve the surgical workforce. the types of neurosurgery cases done are either cranial surgery or spine surgery. endonasal surgery should be avoided during covid- pandemic ( ) . table shows tiers for neurosurgery cases ( ) . a neurosurgical emergency includes cerebral haemorrhages (subarachnoid and intraparenchymal), acute hydrocephalus, tumours at risk of intracranial hypertension, spinal cord compressions with, or at risk of neurological deficit, and traumatic cranial and spinal trauma emergencies ( ) . (table ) ( ) for green level, all elective cases proceed as scheduled. for yellow level, the ot schedule is capped for weeks to % of capacity, yielding a % reduction in all elective and procedural cases. all outpatient procedures black level, significant state or federal resources are needed to fight the outbreak. all urgent scheduled surgical cases will be cancelled. this 'volume limiting approach' encourages maximal adaptability, in which the supply of hospital capability meets the demand for scheduling needs. should be designated to an off-site hospital where covid- patients are not expected to be admitted. there is a hard cap on the number of cases requiring post-operative admission; the -patient limit for all surgical cases (including non-neurosurgical cases). for red level, there is a % reduction in all elective case scheduling. for the team-based paired coverage will go into effect during red levels of covid- . in this model, each hospital (columns) will have three groups of providers. there will be two teams that switch coverage on a -day cycle. each team will cover for days, and then have days off while the second team covers. the transition between teams will occur virtually, avoiding unnecessary team-to-team contact. a backup group substitutes for any team member who shows signs of illness. if a team becomes contaminated, the other team will take over and the alternates will fill the gap. contact between teams and alternate is prohibited. each team will only rotate at one hospital (no cross-covering) and will only have contact with members within their team. teams at the same site will not have any overlapping clinical time with each other. this system ensures adequate coverage, minimises hand-off issues, and, most importantly, minimises transmission risk across teams. due to the likelihood of infection among inpatient providers, there will be a designated 'alternate pool' of providers that will substitute for those who show covid- symptoms. activation of paired coverage system (pcm) ( ) is triggered by a red level of surge. all residents are aware of their role in the pcm ahead of time. site-specific needs are addressed within the team. for example, teams at the main hospital are larger than teams at other satellite hospitals. the pcm is adaptable such that the number of team members can vary, along with the experience level of the team. the core function of the pcm (limiting healthcare worker transmission of the virus) remains. it is also important that neurosurgeons provide their anaesthesia colleagues, nursing staff and the ot with objective data about which cases should be expected to proceed during a covid- outbreak. neurosurgeons need to predict what cases should be classified as an emergency. a checklist that can be applied to neurosurgical cases during the covid- pandemic is as per figure . the checklists help organise surgical staff during times of crisis, such as guiding action during 'red alerts' from neuromonitoring during spinal surgery. the checklist strategy organises surgical staff around the common goal of booking cases during the outbreak. distribution of the checklist to all surgical staff will facilitate effective communication and the ease with which appropriate neurosurgical cases can be scheduled. surgical workforce ( ) the surgical workforce must be able to maintain emergency surgery capabilities including major trauma. it is important to protect and preserve the surgical workforce as well. these will include rotas where some members of the team do not come into work and act as a healthy reserve (refer to a -group setting [surgical team]). when not vital to the effort, keep surgical and anaesthetic staff out of hospital and self-isolating at home to preserve human resources. this will also allow personnel to rest before they return to clinical work. non-surgical solutions to be used to avoid surgery where possible. personal protective equipment (ppe) must be used correctly in line with national guidance. rest, recuperation and psychological support should be factored into all planning. ( , , ) pre-operatively, the patient must be tested for covid- and proceed if negative. full powered air purifying respirators (paprs) for surgeons and all team members in the ot for any of these cases that do actually need to move forward, either for cases in which we cannot wait for test results or for cases that test positive but still need to proceed. for urgent cases (that should be done within week), two covid- tests separated by h with the patient quarantined in the interval between tests before the surgery, with the surgery proceeding only if the results are negative for both tests. if covid positive, papr for all ot staff may be necessary until further data is available. for emergent/unavoidable case for a known or undetermined covid- patient, the surgeon and all ot personnel in the surgical suite should use papr, which filter the air being breathed in addition to face shields and other standard ppe. it is also vital for a cessation of positive pressure ventilation in ot during the procedure until min after the patient leaves ( ). the patient should be isolated and medical personnel should wear full ppe when nursing post-operative patients until covid- status is known. ( , ) regional anaesthesia (ra) is preferred than general anaesthesia (ga) to reduce aerosols. in ga, a negative pressure setting (risk of aerosol transmission) is required. the intubation and extubation are done with full ppe including papr or its equivalent. only essential staff should be present in the ot. postop management is done in the isolation room. thromboprophylaxis should be considered throughout the hospital stay. non-invasive ventilation should not be used. ( ) proper droplet precautions or proper decontamination processes should be followed. there should be an escalation of standard of practice during airway management for all patients to reduce exposure to secretions. hand hygiene should be taken care of with frequent hand washing using alcohol-based hand wash gels, which should be available near every anaesthesia station. the number of staff members present for intubations/ extubations should be limited to reduce the risk of unnecessary exposure. it is also recommended to strongly consider prophylactic antiemetics to reduce the risk of vomiting and possible viral spread. ( , , ) rapid sequence induction (rsi) and use a video laryngoscope (vl) with the goal of a high first pass success rate (fps) is recommended. iv sequence induction without bag mask ventilation is preferred to minimise exposure risks and aerosolisation. preoxygenation for a minimum of min with % oxygen and perform a rsi to avoid manual ventilation of patient's lungs and potential aerosolisation of virus from airways ( ) . rsi (ensure a skilled assistant is available to perform cricoid pressure) or a modified rsi should be performed as clinically indicated. if manual ventilation is required, apply small tidal volumes ( ). placement of a high quality heat and moisture exchanging filter (hmef) rated to remove at least . % of airborne particles . microns or greater in between the facemask and breathing circuit or in between facemask and reservoir bag is required. awake fibreoptic intubations are essentially contraindicated unless specifically indicated. ppe should be provided when performing an aerosol generating procedure. preoxygenation using a bag-valve-mask (bvm) that can be purposely modified for covid- patients with a viral filter, without squeezing the bag. the most experienced anaesthesia professional available should perform intubation if possible. a trainee should avoid intubations of sick patients during this time. the laryngoscope should be resheathed immediately post-intubation (double glove technique). used airway equipment should be sealed in a double zip-locked plastic bag and must then be removed for decontamination and disinfection. there should be no airway carts in the room. thus, appropriately sized equipment should be pre-packed for that patient. the use of deeper sedation extubation to prevent coughing is also preferable as long as the airway is safe. ( , , ) all anaesthesia professionals should utilise ppe appropriate for aerosol-generating procedures for all patients when working near the airway. 'rescue like' crash intubations where ppe cannot be fully adhered to should be avoided. correct donning and doffing of ppe should be adhered to. properly fitted n masks or paprs should be used for all patient. at a minimum, n masks should be used for all patients. for those who are not n fit-tested, have facial hair or fail n fit-testing, paprs should be used if possible. issuance of n masks or availability of paprs for all clinical anaesthesia personnel should be a priority. extended use and/or limited reuse of n masks should follow the centres for disease control and prevention (cdc) and institutional guidelines. a papr provides superior protection and may be warranted for airway procedures in patients with known or suspected covid- . for aerosol-generating procedures, this includes eye protection (goggles or a disposable face shield that covers the front and sides of the face), a gown and gloves, in addition to airway protection with n masks or paprs. effective hand hygiene before putting on and after removing ppe must be ensured. procedures for proper donning and doffing, disposal of contaminated ppe, and cleaning of contaminated reusable ppe and anaesthesia equipment should be established following cdc and institutional recommendations. the double gloving technique is used during intubation. the outer gloves are used to sheath the laryngoscope blade and change the inner gloves as soon as possible afterwards. after removing protective equipment, remember to avoid touching your hair or face before washing hands. during extubation, maintain strict hands hygiene, wear a mask with a face shield and carefully dispose of contaminated equipment. the use of two providers for ppe donning and doffing procedures should be encouraged, to allow one person to observe and coach the other through the steps of the routine. appropriate ppe and the procedures for donning and doffing ppe are available at the cdc webpage. approaches to conserve supplies ( , ) the administration should minimise the number of individuals involved. where feasible, use alternatives to n masks (e.g. other classes of filtering facepiece masks, facepiece air purifying respirators and paprs). n masks should be allowed for extended use and/or limited reuse. the use of n masks should be prioritised for that personnel at highest risk of covid- exposure and/or those anaesthesia professionals in high risk categories (e.g. those with prior health conditions, older age). staff should receive training in the appropriate donning and doffing of ppe taught through simulation and videos without using precious resources. in resource-limited situations, extended use of n masks (continuous wearing while seeing multiple patients) is preferred to limit the reuse of n masks (doffing and redonning between patients). n mask life may be lengthened and surface contamination reduced by wearing a plastic face shield or a surgical mask over the n (cdc respirator guidance). use of chlorine or alcohol solution to sanitise n masks is not recommended as it damages mask integrity. heating n masks to °c ( °f) in a dry oven for min seems a promising solution to disrupt viral particles and maintain mask integrity for reuse. further guidance from cdc and partners in health (pih) on reuse of n masks or best practices when no respirators are available (such as wearing two surgical masks) are available. in routine clinical care of covid- suspected or confirmed infections, surgical masks are acceptable ppe, except in the case of aerosol generating procedures (intubation, high flow nasal cannula, non-invasive ventilation, bronchoscopy, administration of nebulised medications, etc). facilities which do not have disposable surgical attire, theatre garb in the form of cloth scrub hats or bonnets should be washed between each use if possible and no less than daily. theatre gowns and drapes should be washed and sterilised between each patient as is currently expected. if theatre gowns are repurposed for isolation units, they should be washed after each prolonged care routine. if surgical ppe is not impermeable, consider wearing rubber aprons under linen gowns and always perform handwashing after doffing surgical ppe and before touching clean items or self. ot management and preparation during covid- ( , ) surveillance on possible further transmission to patients and other personnel should be done. covid- in a patient receiving surgery is sporadically reported with a special focus of management technique. surgical infection usually focuses on patient but it is important to give attention to the practitioner who works in the operation room. an ot with a negative room pressure environment located at a corner of the operating complex, and with separate access, is designated for all confirmed (or suspected) covid- cases. the ot consists of five interconnected rooms, of which only the anteroom and anaesthesia induction rooms have negative atmospheric pressures. the ot proper, preparation and scrub rooms all have positive pressures. understanding the airflow within the ot is crucial to minimising the risk of infection. the same ot and the same anaesthesia machine will only be used for covid- cases for the duration of the epidemic. an additional heat and moisture exchanger (hme) filter are placed on the expiratory limb of the circuit. both hme filters and the soda lime are changed after each case. the anaesthetic drug trolley is kept in the induction room. no unnecessary items should be brought into the ot, including personal items such as mobile phones and pens. before the start of each operation, the anaesthesiologist puts all the drugs and equipment required for the procedure onto a tray to avoid handling of the drug trolley during the case. nevertheless, if there is a need for additional drugs, hand hygiene and glove changing are performed before entering the induction room and handling the drug trolley. a fully stocked airway trolley is also placed in the induction room, as far as possible, disposable airway equipment is used. if single-use plastic anaesthesia or surgical equipment (endotracheal tubes, ventilator circuit tubing, plastic suction tubing, electrocautery handpieces) must be reused, ensure that disinfection aiming for 'high-level disinfection' or 'sterility' is employed. this includes immersion in appropriate concentration glutaraldehyde, phenol, or hydrogen peroxide solution for the recommended duration. the airway should be secured using the method with the highest chance of first-time success to avoid repeated instrumentation of the airway, including using a video-laryngoscope. equipment in limited supply such as bispectral index monitors or infusion pumps may be requested but need to be thoroughly wiped down after use. hospital security is responsible for clearing the route from the ward or intensive care unit (icu) to the ot, including the elevators. traffic should be minimised, especially opening and closing of theatre doors. patients with known or suspected covid- infection should wear surgical masks when being transported through hospital spaces or in rooms without negative pressure isolation. the transfer from the ward to the ot will be done by the ward nurses in full ppe including a well-fitting n mask, goggles or face shield, splash-resistant gown and boot covers. for patients coming from the icu, a dedicated transport ventilator is used to avoid aerosolisation, the gas flow is turned off and the endotracheal tube clamped with forceps during the switching of ventilators. the icu personnel should wear full ppe with a papr for the transfer. in the induction room, a papr is worn during induction and reversal of anaesthesia for all personnel within m of the patient. for operative airway procedures such as tracheostomy, all staff keep their papr on throughout the procedure. during the procedure, a runner is stationed outside the ot if additional drugs or equipment are needed. these are placed onto a trolley that will be left in the anteroom for the ot team to retrieve. this same process in reverse is used to send out specimens such as arterial blood gas samples and frozen section specimens. the runner wears ppe when entering the anteroom. personnel exiting the ot discard their used gowns and gloves in the anteroom and perform hand hygiene before leaving the anteroom. any papr will be removed outside the anteroom. patients who do not require icu care post-operatively are fully recovered in the ot itself. when the patient is ready for discharge, the route to the isolation ward or icu is again cleared by security (using an advance runner to clear the way). a minimum of h is planned between cases to allow ot staff to send the patient back to the ward, conduct thorough decontamination of all surfaces, screens, keyboard, cables, monitors and anaesthesia machine. surfaces in the ot should be thoroughly cleaned between cases including pulse oximeter probes, thermometers, blood pressure cuffs and other reusable materials ( % alcohol solution or . % chlorine solution). as part of minimising contamination in ot, in addition to surface cleaning, using clear plastic sheets (to be changed in between patients) to cover the anaesthesia machine, the monitors as well as the patient's face, especially during aerosol producing airway manoeuvres like intubation and extubation, is recommended. all unused items on the drug tray and airway trolley should be assumed to be contaminated and discarded. all staff must shower before resuming their regular duties. as an added precaution, after confirmed covid- cases, a hydrogen peroxide vaporiser will be used to decontaminate the ot. clear instructional posters for ppe donning/doffing should be prominently displayed. a taped off area just outside of the ot door should be clearly marked for donning and doffing activities. ( ) few steps must be emphasised to reduce the risk of contracting covid- among hcps. some precaution that needs to be taken note are: staff who are more at risks such as older adults (e.g. those over years), those with underlying medical conditions (e.g. heart disease, chronic respiratory diseases, cancer), those at risk due to an immunocompromised from a medical condition or treatment (e.g. chemotherapy) and pregnant staff should take care of the lower risk stream of non-covid- . ( ) ot is potentially a high exposure zones given manipulation of the airway and aerosolisation of respiratory particles, with anaesthesia providers at particularly high risk. it comes with the additional risk inherent in the presence of multiple staff members. the perioperative personnel are at an advantage given their familiarity with maintaining sterility. however, the ancillary staff such as ot cleaners, instrument reprocessing staff and laundry personnel may be at risk. hence, they should take appropriate precautions and wear ppe (goggles or face shield, surgical mask, heavy duty gloves, long sleeved gown, boots) to avoid exposure to contaminated materials. there are no special decontamination methods other than machine laundering with detergent are required for laundering linens; all surface areas should be disinfected with . % chlorine or % alcohol solutions. immediate surgical plan during pandemic ( ) a clear plan should be made to conduct essential operations. elective operations should be indefinitely postponed to preserve vital resources including hospital beds and ppe. exceptions are for cancer or highly symptomatic patients and as such the current guidance is not to postpone (table ) . each hospital must make a plan based on the current availability of resources. to facilitate decision making and avoid conflicts between patients and providers, a triage algorithm for identification of nonemergent conditions can be used. surgical emergencies still require prioritisation. funding must be adequate to support the hospital and staff with critical surgical services that will continue to be required despite the pandemic response. using a checklist to ensure appropriate precautions are taken for operations with suspected or known covid- infection is also important. simulation has been also helpful in establishing new routines in the ot. aerosolgenerating procedures that can be provided using other mechanisms should be avoided if at all possible (e.g. metered-dose inhaler instead of nebuliser treatment). further planning for the repurposing of ots to support critical care whilst not precluding the ability to provide lifesaving operative care is needed. surgical services are already underfunded and poorly prioritised in many health systems, so the commandeering of ots for use as icu, which has been proposed in many high-resource settings, must be done with extreme caution. emergency surgery will still be necessary for obstetrics and to save life (neurotrauma) and limb, and these capacities should not be compromised by taking up all available ot space and ventilators with covid+ patients. as the average reported time spent on mechanical ventilation has been up to days, critical resources and space will be occupied for many weeks and will be difficult to reclaim once repurposed. repurposing of staff for managing covid- cases should be taken into consideration as well. guidance and training should be provided to make the best use of the technical and clinical skills of all perioperative personnel while protecting them from exposure. hospitals, professional societies and ministries of health could also provide physician and nursing staff with basic icu and ventilator management refresher education to improve their capacity to care for covid- patients. up to date guidelines on covid- management should be provided as knowledge and evidence around best management evolves. it is also vital to maintain and support staff wellness. it is important to recognise that doctors, nurses, cleaners and other hospital support staff have significant fears and concerns (the fears of transmitting to family or becoming infected oneself, the increase in work hours and the need for childcare coverage) that must be acknowledged and managed. providers may also be understandably nervous about providing care outside of their normal scope of practice or working beyond their area of competence. leadership can help manage these by providing information in a transparent way, expressing gratitude for the commitment to patients and colleagues, and reassurances that the system will help protect them and support them and their family. national cprc mentioned that severity of the situation and the availability of resources may change on a daily basis. thus, communication is critical, and an effective communication plan both within and between facilities and health system planners, as well as between providers across the health system and even between countries, is essential and should be established immediately. the preparation of healthcare facilities at large for the safe triage, testing and management of patients with confirmed or suspected covid- , and managing surge conditions are needed. ethical considerations in resource management are also very important. in many places, the number of ventilators available for persons requiring ventilatory support will be inadequate. in some settings, it is common to reallocate resources from terminal patients or patients with brain death or very low likelihood of recovery (e.g. severe traumatic brain injury) to those with a higher likelihood of recovery. in settings where resources are severely limited and must be rationed, consider creating a committee or utilising standardised risk assessments to determine allocation decisions in advance. this avoids placing the burden of decision making on the frontline health care workers, as these decisions should be not be made ad hoc by the bedside clinician but through careful deliberations by the institution. cultural and medicolegal context should be taken into account to determine the most appropriate allocation and potential protocols for rationing medical resources and care in advance. critical testing, ppe, icu beds, therapeutics, and vaccines should go first to front line health care workers and others who keep critical infrastructure functioning; these workers should be given priority not because they are more worthy but due to their instrumental value in the pandemic response and difficulty of replacing (instrumental value). should the surgical instrument be reused? ( ). instruments and devices that have been used in procedures for patients with known or suspected covid- should be handled the same as other instruments. reprocessing should follow manufacturer's instructions for use (ifu) and be consistent with recommendations in the local infectious disease unit. covid- is an enveloped virus and is susceptible to the environmental protection agency (epa)registered disinfectants that are used in the health care setting ( ) . there are no additional recommendations by cdc for disinfection and sterilisation of these items used for covid- patients. instruments should be cleaned, decontaminated, dried and stored in a manner that reduces the risk of exposing patients and personnel to potentially pathogenic microorganisms ( ). high-level disinfect or sterilise them according to the manufacturer's written ifu. they should be packed and stored in individual packs that avoid contamination. ( ) patients should perform second pcr + rapid test prior to icu admission. if rapid test positive, then to discuss with covid- hospital. if accepted, then to transfer to covid- hospital. if not accepted, then send to negative pressure isolation room icu using designated walkway (only suspected covid- ) while awaiting second pcr results. if require urgent resuscitation, to transfer to negative pressure isolation room icu using specific walkway (only suspected covid- ). if rapid test is negative, then to send to negative pressure isolation room icu using designated walkway (only suspected covid- ) while awaiting second pcr. if two negative pcr results, then it is considered a non-covid- patient and to be admitted normal icu cubicle. if pcr is not done on admission or only rapid test is done on admission, then a critically ill patient should have pcr done h apart to rule out disease. there is an exception for planned elective admission to icu after elective surgery. for this group of patients, a negative first pcr is adequate, and the patient is to be admitted to a non-isolation cubicle in icu. ( , ) full ppe must be readily available in icu. prepacked full ppe sets including hazmat suit should be put into a bag, to ease donning in the case of emergency. two sets will be readily available in the emergency trolley with additional sets kept at specific storage area in the icu together with papr. two nurses to attend with full ppe first. one person to be exclusively in charge to help donning of ppe of medical staff to ensure that all are properly fitted, with hazmat suit and papr if required. papr and hazmat suit will be needed for procedures like intubation and bronchoscopy. donning and doffing of ppe instructions should be pasted on the wall. nurses and doctors to undergo training on where and how to don and doff in icu isolation room, as well as in other non-isolation cubicles. designated area to doff ppe in non-isolation icu cubicles/wards to be assigned. walkie talkie to be available in isolation room for outside communication (to get medications, additional materials). nurses outside will prepare required materials/medication and put on a trolley, leave it in the airlock to be collected by nurses in the isolation room. ( , , ) glidescope and ultrasound must be fully covered with plastic when in a room. ultrasound transducer to be covered with transducer cover if in use. cleaning should be per biomedic advice. person cleaning equipment should be made aware of the infectious component and be protected with full ppe. outside nurse to be fully protected when removing equipment outside isolation room for cleaning. the same ventilator should be used for negative pressure isolation room icu and should not with ventilator in the other rooms. ( ) the viral filter should be on both inspiratory and expiratory ends. once intubated, to clamp the ett, remove the viral filter for connection with ventilator tubing. etco monitor i.e. capnograph and closed suction catheter to be connected to patient immediately upon intubation. disconnection of ventilator should be reduced. ( ) nurses should be divided into covid- team and non-covid- team. the covid- team to take care of covid- suspect or covid- positive patients. the non-covid- team to take care of the non-covid- patients. the covid- team nurses should not be rotated to non-covid- patients. (e.g. patient a is managed by nurse x, y and z in three shifts. this team should take care of patient a until second pcr results are available) container for contaminated ppe for covid- suspect or positive should be clearly labelled for cleaners to take extra precautions. decontamination of the pathways and negative pressure isolation room icu used by these patients will be per hospital protocol. the whole icu need to be close and decontaminated in the presence of a covid- positive case in nonisolation icu cubicle with no other patients around. for the presence of a covid- positive case in non-isolation icu cubicle with existing non-covid- patients in icu, the whole icu must be closed and decontaminated plus to consider testing these patients (existing non-covid- patients) and transferring to other hospitals. potential covid- case in non-isolation room, to limit one visitor/patient. the covid- positive in non-isolation room, then no visitors allowed in icu. one staff member in front of icu is stationed to monitor visitor flow in and out of icu (get visitor's name and phone number in the case of contact tracing). in the event of a covid- positive case in non-isolation room in icu, contact tracing will include, ( ) existing non-covid- patients in icu during that period, ( ) all visitors who enter icu during that period, ( ) all icu staff entering icu during that period, and ( ) all doctors entering icu during that period. ( ) triage may not be implemented by a facility without clear sanction from appropriate public health authorities. systems for sharing information about the number and severity of cases, equipment availability, and staffing shortages could be activated throughout hospital groups and regional networks. patients are assessed on medical/ clinical factors alone, regardless of their work role. the ontario health plan for an influenza pandemic (ohpip) protocol and the sequential organ failure assessment (sofa) score should be used. candidates for extubation during a pandemic would include patients with the highest probability of mortality. initial assessment using the sofa scoring system (points based on objective measures of function in six domains: lungs, liver, brain, kidneys, blood clotting, and blood pressure) with best score of and worst score of . time trials assessment at intervals of h and h. those showing improvement would continue ventilator use until the next assessment, whereas those who no longer met the criteria would lose access to mechanical ventilation. chronic care facilities will have to provide more intensive care on-site as part of the general process of expanding care beyond standard locations. the proposed justification for such a strategy would be that more patients could ultimately survive if these ventilators were used by the previously healthy victims of a pandemic. setting aside the small number of ventilators in chronic care facilities for use by chronically ill people, who likely will have severely limited access to ventilators in acute care facilities. clinicians providing direct care will relay data to a supervising clinician serving as a triage officer, who will calculate the sofa score and make triage decisions but will not provide direct care. terminal weaning in response to patient preferences can include sedation so that the patient need not experience air hunger. patients who are extubated against their wishes should be offered appropriate palliative care based on their clinical conditions and preferences. because transparency is a crucial element of adherence to ethical standards, clinicians must document decisions regarding sedation with extubation. the guidelines do not support the use of manual ventilation devices for patients who do not meet criteria for ventilator access. daily retrospective review of all triage decisions should be made, to ensure consistency and justice. physicians will need to discuss altered standards of care in a disaster, especially for scarce resources such as ventilators. patients and families must be informed immediately that ventilator support represents a trial of therapy that may not improve the patient's condition sufficiently and that the ventilator will be removed if the patient does not meet specific criteria. elective surgeries and other elective procedures that could result in the use of mechanical ventilators should be cancelled ( ) . ventilators, supplies, and personnel from ambulatory surgery centres and other facilities not being utilised for covid- patients or not experiencing covid- outbreaks should be transferred. anaesthesia ventilation machines capable of providing controlled ventilation or assisted ventilation may be used outside of the traditional use for anaesthetic indication ( , ) . the asa and fda provide specific guidance on how to convert anaesthesia machines for use on covid- patients in respiratory failure ( ) . transport ventilators may be used for prolonged ventilation in certain patients. continuous ventilators labelled for home use may be used in a medical facility setting depending on the features of the ventilator and provided there is appropriate monitoring (as available) of the patient's condition. non-invasive ventilation (niv) patient interfaces capable of prescribed breath may be used for patients requiring such ventilator support, including niv patient interfaces labelled for sleep apnoea. channelling exhalation through a filter is recommended to prevent aerosolisation. continuous positive airway pressure (cpap), auto-cpap and bilevel positive airway pressure (bipap or bpap) machines typically used for treatment of sleep apnoea (either in the home or facility setting) may be used to support patients with respiratory insufficiency. bipap may be used for invasive ventilation. if all other alternatives are exhausted, care providers could consider ventilation of two patients on a single ventilator for short-term use, although there are significant limitations to this strategy. alternatively, manual bag-valve-mask ventilation done by ancillary providers can be considered as a bridging option to mechanical ventilation. the summary of head and neck examination and procedure recommendations can be viewed in table ( ) . ( ) in general, most tracheostomy procedures should be avoided or delayed (even beyond days) because of the high infectious risks of the procedure and subsequent care until such time as the acute phase of infection has passed, when the likelihood of recovery is high, and when ventilator weaning has become the primary goal of care. avoiding early tracheostomy in patients with covid- is suggested because of the higher viral load that may be present at this time. early tracheostomy was not found to be associated with improved mortality or reduced length of intensive care unit stays in a randomised clinical trial of patients on mechanical ventilation. select the patients carefully. if the tracheostomy is assessed as difficult because of anatomy, history, comorbidities or other factors, consider postponing the procedure. considerations may be given to percutaneous dilatational tracheostomy. allow it to be done safely with minimal or no bronchoscopy, endotracheal suctioning and disruption of the ventilator circuit. adequate sedation provided including paralysis to eliminate the risk of coughing during the procedure. ventilation should be paused (apnoea) at end-expiration when the trachea is entered and any time the ventilation circuit is disconnected. choose a non-fenestrated, cuffed, tracheostomy tube on the smaller side to make the tracheostomy hole smaller overall (shiley size for both men and women is adequate). keep the cuff inflated to limit the spread of virus through the upper airway. tracheostomy suctioning is performed using a closed suction system with a viral filter. heat moisture exchanger device is used instead of tracheostomy collar during weaning to prevent virus spread or reinfection of patients. changing the tracheostomy tube should be delayed until the viral load is as low as possible. case series of open tracheostomies performed during the severe acute respiratory syndrome (sars) outbreak can be viewed in table ( ) ( ) ( ) ( ) . making in times of covid- crisis: a proposal to safe and sustainable practice in times of crisis neurotrauma ( ) neurotrauma forms the bulk of emergency neurosurgical cases presenting or referred to neurosurgical centres, varying from cases of concussion to severe head injuries requiring urgent surgical intervention. in the current climate of a pandemic crisis, neurotrauma poses various management and logistics issues to the neurosurgical team in the following aspects as listed. time between injury to intervention determines outcome. urgency of intervention outlines management of patient. ongoing dynamic pathological process in trauma may alter clinical picture between referral to presentation. pre-emptive management plan is essential to ensure optimum outcome from intervention where feasible. pre-operative screening is vital, particularly those requiring surgical management ( ) . all cases undergoing surgery poses high risk to operative team due to potential aerosol generating procedure that may occur from intubation/extubation, positioning of patient to prone/park bench position, tracheostomy procedures and prolonged proximity of surgeon to the head region of patient ( , ) neurotrauma cases should be managed in a neurosurgical centre. most neurosurgical departments in malaysia are situated in major hospitals, often managing high volume of high risk or covid- cases. principle logistic consideration is to whether trauma cases referred from a non-covid- designated hospital should be managed in covid- designated hospital as this may increase risk of exposure to patients. alternative options should be taken into consideration where feasible, such as team deployment to manage patients in referring hospitals, training and privileging general surgeons in management of cases and transfer of patients back to referral hospitals for continuity of intensive care management postoperatively. resource availability ( ) neurotrauma patients require postoperative ventilation with icu care, often for prolonged duration which may limit availability in case of urgent needs. ventilators, ppe and icu are precious commodities in this current pandemic, and fluctuate with time depending on epidemiological dynamics. available resources are commonly and rightly so; prioritised to patients afflicted by the ongoing pandemic, health care workers (hcws) involved in their care. rational balance and anticipation of resource need is essential to optimise usage and sustainable availability in times of crisis. early prognostication ( , ) outcome from neurotrauma depends on various well-defined parameters. brain damage incurred in primary injury remains irreversible in majority of patients; compounded by secondary factors. early prognostication is essential in times of crisis for resource allocation. it is paramount to ensure that optimum patient care and outcome remains priority of intention to treat. determining long term outcome using available prognostic models for decision making in proceeding with active treatment or withdrawing treatment is essential; albeit exceptionally difficult to ensure continuous availability of limited resource. prognostication based decision is best made with team consensus using all available scientific evidence present. ( ) all brain trauma management is in accordance with the brain trauma foundation (btf) guidelines recommendations. all neurosurgical emergencies must be referred to the respective neurosurgical team for consultation and management plans (table ) ( ). brain trauma requiring urgent surgical intervention (decompression) with or without intensive care monitoring is best managed in hospitals with dedicated neurosurgical facilities or available neurosurgical services (level ii). brain trauma not requiring urgent decompressive surgical intervention, but which may require or benefit from intracranial pressure (icp) monitoring and intensive care management (level iib) is best managed in centres with available resources to provide objective assessment and management plan, reduce the duration of icu stay and intensive management and early weaning from intensive therapy. brain trauma not requiring urgent decompressive surgical intervention, but which may benefit from icp monitoring and intensive care management in situations where resource availability is limited may be managed with cerebral perfusion pressure (cpp) based target therapy (level iii) and serial ct scan at h- h intervals in an intensive care setting where feasible. brain trauma requiring surgical intervention but with limited resources available at dedicated neurosurgical facilities; the following may be considered (anecdotal evidence based on local/regional practice): brain trauma not requiring any surgical intervention but requiring close observation is best managed in dedicated neurosurgical centres or available neurosurgical services if the risk of potential deterioration is deemed to be high (e.g. burst temporal/frontal lobes) and duration and distance of transfer may result in a delay of treatment. brain trauma requiring multidisciplinary management is best transferred and managed in dedicated i) deployment of neurosurgical team to primary referral hospital where feasible to facilitate timely intervention ii) surgical intervention in neurosurgical facilities with subsequent transfer back to primary referring hospitals for continuity of intensive care management ( ) screening for traumatic brain injury cases is strongly recommended for safety of hcws. screening recommendations are in accordance with moh guidelines (figure ). risk of covid- /pui/severe acute respiratory infections (sari) should be ruled out as per moh guidelines and hospital protocols prior to transfer of cases for further management (figure ). secondary screening should be done by attending neurosurgical team on arrival. relatives must accompany for confirmation of history of potential exposure as per moh protocol and directives. confounding factors must be taken into consideration during screening, including: i) potential aspiration in patients with low glasgow coma scale (gcs); ii) metabolic response resulting in abnormal white blood cell count (wcc) and elevated temperature; iii) co-existing chest injuries; and iv) post-intubation changes on chest radiograph (cxr) common. note: all ventilated cases pose a high risk of aerosol exposure to hcws. it is vital to be meticulous and vigilant for potential risk: critical resources for optimum neurosurgical services remain limited and may continue to fluctuate in time of crisis. these include ventilators, ppe, icu availability and operative instruments. the rationale for early prognostication is recommended for optimum resource usage and allocation to ensure beneficial outcome and sustainable supply. prognostication is based on available scientific evidence to guide in management options and rationale of resource allocation. early triage is required for timely and appropriate treatment and enables surgeons to prioritise management according to available resources and the potential outcome. this will help in limiting the proportion of patients in a vegetative state and limiting burden to family and available resources at the time of crisis. in the end, it will help to prepare family with a realistic outlook on the potential outcome. prognostic factors include: i) age > ; ii) gcs post-resuscitation: motor score m -poor outcome; iii) pupils-bilateral fixed/ dilated pupils; iv) systolic blood pressure < mmhg -sustainable/multiple episodes; and v) marshall ct grade. age, gcs motor score and pupillary changes are the three main prognostic factors determining the outcome. the caveats to prognosticating outcome include: aneurysmal sah is a devastating clinical entity. the natural history of aneurysmal sah remains unfavourable with a cumulative rerupture rate at % at weeks after initial presentation and overall mortality of %. prognostication of aneurysmal sah is well defined according to the world federation of neurosurgery (wfns) grade system predictive of figure . proposed workflow of patients referred for sah outcome following aneurysmal rupture and hunt & hess grade which predicts mortality rate in patients. management of aneurysmal sah during times of crisis must be guided by expected prognosis as defined using these grading systems. this is essential in times of pandemic crisis as difficult decisions need to be made to preserve life and function in face of limited and precious resources essential to the management of patients ( ). the proposed recommendations can be viewed in figure . aneurysmal sah ( ) adequate resuscitation measures should be instituted on admission where required. these include the airway, breathing and circulation (abc) and mechanical ventilatory support as required with correction of fluid and electrolyte abnormalities if present at primary referral centres. the physician receiving the referral should get an accurate assessment of wfns, and hunt & hess grades on presentation. if hydrocephalus is present on ictus, urgent ventricular drainage should be performed at centres with neurosurgical facilities or trained and privileged surgeons at the designated non neurosurgical centres. a noncontrast ct brain and ct angiogram (cta) are the first line investigative parameter at the admitting hospital before transfer to a centre with neurosurgical facilities or services. when perimesencephalic sah is the likely diagnosis after confirmation by a neuroradiologist, then the patient should be managed expectantly. there will be no further imaging required. however, if aneurysmal rupture cannot be ruled out, then the recommendation is based on the wfns grading. for wfns - , a digital subtraction angiography (dsa) is recommended at the primary centre if available or transfer to centres with available facilities and neurosurgical services. for wfns and , the patient should stay at the primary centre if feasible with a repeat cta in week. a continuous neurological assessment should be documented and if whenever an improvement is noted, then the patient should be considered for transfer. poor grade aneurysm cases may benefit from continued neuroprotection. however, multiple factors should be taken into accounts such as age, comorbidities and available resources to sustain prolonged care in such patients. the decision to consider conservative management if no further improvement in wfns score is the prerogative of attending consultants. the quality of cta is important in determining the next treatment of care. for patients with wfns grade - , if cta deemed adequate by attending consultants for safe and effective definitive management by surgical clipping, then the recommendation is to proceed for surgical treatment as urgently possible at the centre with available neurosurgical services. if cta deemed inadequate for definitive management, then the patient should be transferred for dsa at centres with available radiological and neurosurgical services. the choice of treatment between surgical treatment and endovascular treatments should remain similar to current standards. however, interventional neurovascular services in malaysia are limited to a few major hospitals. transferring patients across states in times of limited resources may result in unnecessary delays and worsening outcomes from potential deterioration during the interim period. thus, various factors should be taken into consideration when deciding the best treatment options in times of crisis. they include: if dsa is required, the option of definitive management of endovascular coiling at the same setting should be considered. there are several reasons which include: i) minimising the risk of aerosol disbursement that is highest during intubation/extubation; ii) early definitive management can be achieved at the same setting with reduced risk of re-rupture; iii) treatment of vasospasm if present for applicable cases done at the same setting; and iv) reducing the risk of exposure to personnel from a second ga procedure. patients with wfns grade may benefit from neuroprotective measures. definitive management should be considered in selected cases such as: i) young age; ii) no morbidities/comorbidities; and iii) choice of treatment depends on available services and following discussion between attending consultant and family. for patients with wfns grade , conservative management should be considered if no further improvement achieved following a period of neuroprotection. the decision is made through a collective discussion between attending physician and family members. a thorough history should be elicited to determine any evidence of sentinel haemorrhage that may appear trivial to patients. an appropriate diagnostic modality is required to look for radiological evidence of recent i.e 'teat sign'. within an applicable timeframe, a lumbar puncture should be considered. an aneurysm with neurological symptoms and signs should be planned and treated in a timely manner as a semi-emergency case; an example is a patient with posterior communicating artery aneurysm presenting with ptosis, rather than a delayed surgery in this current pandemic of uncertain duration to avoid potential irreversible neurological compromise or worsening deterioration. in cases of multiple aneurysms, the treatment should be undertaken for ruptured aneurysm as well as aneurysm with increased risk of rupture, if deemed feasible at the same sitting. arteriovenous malformations (avms) are a heterogeneous group of neurovascular abnormalities with an incidence of . / population. anatomically avms are defined as a complex of abnormal arteries and veins that communicate directly without an intervening capillary bed. avm presents with haemorrhage in as many as % of cases. the natural history of avms is more favourable as compared to aneurysmal sah, with an annual rupture rate of %, and recurrent haemorrhage rate of %- % in the first year following a rupture ( ) . cases of avm presenting with haemorrhage may require urgent surgical management. the proposed recommendations are divided into three categories: i) avm rupture with mass effect; ii) avm rupture without mass effect; and iii) avms not presenting with haemorrhage ( ) ( ) ( ) . any ruptured avm with mass effect should be transferred to a centre with neurosurgical services or facilities. a cta should be performed on admission to confirm the diagnosis of ruptured avm and to determine the location of avm in relation to clot. this will aid a safe surgical access planning. following an urgent surgical evacuation of a clot, the patient should be managed in an intensive care setting for neuroprotection. a post-operative dsa/cta is warranted to look for potential high risk factors for haemorrhage, such as nidal aneurysm/varix and to consider an endovascular treatment if feasible and required. definitive treatment should be deferred safely to a later date if feasible. the patient should be transferred to a centre with neurosurgical facilities, particularly when avm presents with intraventricular haemorrhage (ivh) or cta shows evidence of nidal aneurysm or varix. if no ivh present and cta shows no high risk factors of haemorrhage, the patient may be managed at a non neurosurgical centre with early follow up scheduled in the clinic for review. the management is mainly medical treatment to optimise seizure control or headache. all definitive treatment should be deferred to a later date. ( ) these are rare conditions that comprise of fistulas connecting branches of dural arteries to dural veins or venous sinuses. dural arteriovenous fistulas (davfs) are typically stable lesions with a reported annual haemorrhage risk ranging between %- % ( ), and mortality rate ranges at %- %. endovascular modalities remain the diagnostic and therapeutic modality of choice. the recommendations are proposed for the management of ( ) ruptured cranial davf and ruptured spinal davf. patients who presented with ruptured cranial davf should be transferred to a neurosurgical centre with endovascular facilities for urgent surgical management of clot with mass effect, if present, and definitive endovascular management. patients who presented with ruptured spinal davf requires transfer to a neurosurgical centre with endovascular facilities for urgent treatment, especially when there is rapid neurological deterioration. some patients presented with spontaneous hypertensive haemorrhage that may or may not require surgical intervention. patients that are not a candidate for surgical interventions include: i) small, deep haemorrhage; ii) large haemorrhage without hydrocephalus, ivh or neurological deterioration; and iii) those with supratentorial haemorrhage with a gcs score below unless this is because of hydrocephalus ( ) . a poor prognosis is expected in the following conditions: ii) candidate with gcs score is or less; and ii) the haematoma is very large and death is expected ( ) . in this condition, a careful consideration should be taken and a family meeting should be done sooner. surgical interventions are recommended in the following categories: the diagnosis of middle cerebral artery (mca) infarction depends on the clinical presentation, neurological findings, followed by radiological imaging. patients with suspected transient ischaemic attack (tia) should be assessed by a specialist physician before a decision on brain imaging is made, except when haemorrhage requires exclusion in patients taking an anticoagulant or with a bleeding disorder when noncontrast ct should be performed urgently ( ) . further imaging, such as carotid imaging is essential for any patient presenting with symptoms suggesting of an anterior circulation cerebral ischaemia who might be suitable for intervention for carotid stenosis. patients with tia or acute non-disabling stroke with stable neurological symptoms who have symptomatic severe carotid stenosis of %- % (nascet method) should receive an urgent carotid endarterectomy (within days). the treatment tends to happen in a vascular surgical centre routinely participating in national audit ( ) . the indications for mechanical thrombectomy (mt) ( ) are when there are proximal large artery occlusion as an adjunct to intravenous thrombolysis (ivt), and for those patients with contraindications to ivt but not to mt. another indication is when major vessel occlusion is in the posterior circulation, up to h from known onset. the indications for decompressive hemicraniectomy are as follows ( ) ( ), ventriculostomy is recommended in the treatment of obstructive hydrocephalus. concomitant or subsequent decompressive craniectomy may or may not be necessary on the basis of factors such as: i) the size of the infarction; ii) neurological condition; iii) degree of brainstem compression; and iv) effectiveness of medical management. there are times when an emergency carotid endarterectomy (cea)/ carotid angioplasty and stenting will be useful as clinical indicators or brain imaging suggests ( ) . an example is when a small infarct core with large territory at risk (e.g. penumbra), compromised by inadequate flow from critical carotid stenosis or occlusion. however, in patients with unstable neurological status (e.g. stroke-in-evolution), the efficacy of emergency or urgent cea /carotid angioplasty and stenting is not well established. stroke complicated covid- infection in . % of patients at a median days after symptom onset. stroke mechanisms may vary and could include hypercoagulability from critical illness and cardioembolism from virusrelated cardiac injury. the clinical presentation in stroke patients typically manifested as cns involvements. the most common neurological manifestations in covid- patients were dizziness ( . %), headache ( . %) and encephalopathy ( . %). the most common peripheral signs and symptoms were anosmia ( . %), dysgeusia ( . %) and muscle injury ( . %, detected by elevated creatine kinase). patients with stroke were older, had more cardiovascular comorbidities, and more severe pneumonia. ideally, every stroke patient would be treated as potentially infected, hence the requirement of ppe. many teams have begun using telemedicine both within their own ed and regionally. this solution avoids the use of needed ppe, allows a reasonable stroke evaluation, avoids unnecessary interfacility transfers, and reduces exposure risk for the stroke team. in the setting of the pandemic, full compliance to clinical practice guidelines has become a goal, not an expectation. each team must use their judgement, guided by local realities, and continue to try to treat as many acute stroke patients as possible. patients with large intracerebral haemorrhages, sah or large ischemic strokes at risk for herniation must be monitored in an intensive care setting with appropriately trained personnel, where possible. appropriate resource should be allocated for critically ill stroke patients. appropriate intensive care of these seriously ill patients with haemorrhagic stroke, some of whom are also young and with an excellent long term outcome, should be maintained. however, in each locality, specialists from all intensive care specialities e.g. pulmonary, cardiology, neurology, neurosurgery must discuss the relative merits of prolonged icu care for any particular patient. ( ) the establishment of stroke networks and care systems can deliver a high quality emergency stroke care at all times, particularly at times of crisis. although there is a strong case for such centres to be the system of care, it is particularly important to have services that can continue to function. the hospital should inform the emergency medical system and the public that these centres will be protected and will remain fully operational even during crises. the hospital or stroke team should regularly update and educates the health professionals and the public, especially those who are at high risk of stroke to recognise a stroke and call emergency medical services immediately. those patients should be taken to one of the designated stroke centres to avoid significant delay in transferring patient from one hospital to the other. categorising elective neurosurgical cases at a time of covid- pandemic is adapted and as per guidelines (with minimal modification) -perioperative mortality review (pomr): prioritisation of cases for emergency and elective surgery ( nd revision) ( ) ( table ). the tier status of each case is according to the urgency and the decision will be based on: i) natural history of the disease; ii) patient's neurological status; and iii) availability of manpower and equipment's for surgery ( figure ). to summarised, all elective neurosurgery should be postponed ( , ) . in patients with suspected covid- , the surgery should be deferred for at least days, with an appropriate test taken to confirm the status ( , ) . the elective urgent inpatient diagnostic and surgical procedures should be shifted to outpatient settings, when feasible ( ). dangers during neurosurgical procedure ( , , , , , ) according to limited data from cdc, covid- has been detected in blood specimens and it is unknown whether the virus is viable or infectious in extrapulmonary (outside the lungs) specimens. there have been some reports that covid- is present in stool and maybe transmissible through the faecal-oral route. bronchoscopy, tracheostomy and thoracic cases may have a higher risk for airborne transmission of covid- because the nature of the procedures involves the respiratory tract, which could lead to aerosolisation of the virus. procedures that may aerosolise blood and body fluids during surgery include: i) electrocautery of blood or tissue; ii) laparoscopy; iii) endoscopy; iv) use of intraoperative debridement devices with irrigation (e.g. hydrosurgery, pulse lavage or low frequency ultrasonic debridement); and v) use of high speed powered equipment (e.g. saws and drills). surgical smoke represents another important issue to tackle during surgery. it is recommended for the evacuation of all surgical smoke as it contains hazardous chemicals, ultrafine particles, viruses, bacteria and cancer cells. the earliest detected case of covid- was in china on november . as such, there is currently no research on the transmission of the virus through surgical smoke. however, there is no indication or proof that covid- is not transmissible through surgical smoke. research studies have demonstrated the presence of viruses (e.g. human papillomavirus) in surgical smoke with documented transmission to health care providers. according to limited data from the cdc, sars-cov- rna has been detected in blood specimens and it is unknown whether the virus is viable or infectious in extrapulmonary (outside the lungs) specimens. in similar coronaviruses, viable and infectious sars-cov was isolated from blood specimens, although infectious mers-cov was only isolated from the respiratory tract. of importance to neurosurgeons, the use of high speed drills and also electrocautery during surgery will cause aerosolised blood and body fluid. thus, increasing exposure of neurosurgeons to the virus. however, the risk of transmission of covid- through aerosolised blood and body fluids is unknown. thus, extra precautionary measures must be taken during procedures for protection. proper ppe must be worn during any neurosurgical procedure to prevent transmission. ( , ) covid- was declared a pandemic by who on march because of its rapid worldwide spread. covid- has achieved effective and sustained human-to-human transmission via contact, droplet and likely airborne routes. as with previous outbreaks such as severe acute respiratory syndrome (sars), influenza a (h n ) infection and the middle east respiratory syndrome, this would require heightened precautions and tailoring our anaesthetic practice to reduce exposure to patients' respiratory secretions and the risk of perioperative viral transmission to healthcare workers and other patients. in particular, this should involve minimising the many aerosolgenerating procedures we perform during ga, such as bag mask ventilation, open airway suctioning and endotracheal intubation. during the sars outbreak, intubation was one of the independent risk factors for super-spreading nosocomial outbreaks affecting many healthcare workers in hong kong and guangzhou, china. nevertheless, to avoid any airway manipulation, the use of ra techniques (e.g. peripheral nerve blocks and/or central neuraxial blocks) may be consideration should be given to the available resources, facilities, equipment, consumable and real time logistic capability and feasibility. designated covid- hospitals may not be able to support all elective cases, in particular those that require post-operative intensive care or significant use of blood and blood products surgeons, in consultation with anaesthetist, nursing colleagues as well as patients (or legally accepted next of kin), should weigh the risks of proceeding (exposure, lack of resources) against those of deferment, (progression of disease, worse patients outcomes) including the expectation of delay of - months or more or until the covid- is less prevalent figure . availability of manpower and equipment for surgery preferred. thus, ra manipulation should be considered whenever surgery is planned for a suspected or confirmed covid- patient or any patient who poses an infection risk. ra has benefits of preservation of respiratory function, avoidance of aerosolisation and hence viral transmission. there is no proper guideline and recommendation as of today regarding the use of ra in covid- patients. however, general precautions and ppe should be applied for all the healthcare workers even though the patient is undergoing ra. this is because, in case of failed ra, ga must be used for the surgery. anaesthesia providers for these patients should be well-versed in both ga and ra techniques. for neurosurgery patients, ra such as scalp block must be considered in simple procedures such as borehole. for emergency neurosurgery cases, most of it would be involving patients with poor gcs thus making ra not as feasible as the patient would be already intubated. covid- is an infectious disease introduced to humans for the first time. individuals can be infected by breathing in the virus within metre of a person who has covid- , or by touching a contaminated surface and then touching their own mouth, nose, or possibly their eyes. on january , who declared the outbreak as a public health emergency of international concern (pheic), and by march , the outbreak has rapidly accelerated to become pandemic. until april , there were , confirmed cases, with , deaths, affecting countries, including malaysia ( ). following the pandemic of covid- , there is a major shift of practices among surgical departments in response to an unprecedented surge in reducing the transmission of disease. with pooling and outsourcing of more hcws to emergency room, public health care services and medical services, further in hospital resources are prioritised to those in need. along with slowing and breaking the transmission of covid- by social distancing, the neurosurgical outpatient clinic, elective and non-emergency surgery are delayed. this will reduce the face-toface contact with potential covid- cases, and shields patients and hcws from the virus. every neurosurgical team has to reevaluate the timing of operation in those patients with neurosurgical disease that are in need of treatment. the real risk of proceeding and the real risk of delay should be carefully assessed. when considering a delay in treatment to a time where covid- is less prevalent, the decision making process must always take into account each patient's courses of disease, social circumstances and needs. it is imperative to balance the requirements of caring for covid- patients with imminent risk of delay to others who need care ( ). currently, patient's screening process is crucial. the moh recommendations of screening involve questionnaires to identify suspected patients ( , ) . patients who meet certain criteria should be evaluated as a patient under investigation (pui). these general questions to all patients include: i) do you have any fever or acute respiratory infection (sudden onset of respiratory infection with at least one of: shortness of breath, cough or sore throat)? ii) do you have any history of travelling to or residing in affected countries in the past days? iii) did you have any contact with a confirmed covid- case within the past days? there are two laboratory tests that can be used to detect covid- ( , ): rt-pcr. the sample commonly taken is upper airway specimens (pharyngeal swabs, nasal swabs, nasopharyngeal secretions). among patients with confirmed positive in respiratory tract, ~ %- % of patients have detected viral load in faeces, ~ %- % in the blood, while the lowest positive rate is in urine samples. ii) rapid test kit (rtk) serology for serum antibody igm and/or igg. this can be used as diagnostic criteria for suspected patients with negative pcr detection. during follow-up monitoring, igm is detectable days after symptom onset and igg is detectable days after symptom onset. the viral load gradually decreases with the increase of serum antibody levels. urgent/emergent cases are previously defined as patients requiring access to surgical treatment within h of the decision to operate ( ) . however, with the current pandemic, access to surgical treatment may be delayed and some patients could face increasing morbidity/ mortality by the time surgery happens. other countries have now come up with guidelines for the triage, or ranking in order of priority, of surgical patients. the american college of surgeons (acs) describes the acuity scales based on tier classification, with most cancers and highly symptomatic patients considered tier a (do not postpone) ( ) . other than trauma and life threatening condition, other treatments are recommended to postpone, if possible. then what will happen to all elective cases that will be pushed back for a further few months? will that add to the mounting burden of long waiting lists that is already stretched? to delineate the current situation, we propose a few steps that will in future, limit and protect both patients and surgeons from the risk of transmission (figure ) . special consideration is given to pre-operative patients needing endoscopic transnasal surgery, even for asymptomatic patients ( , ) . the transmission of covid- is predominantly via respiratory droplets (e.g. coughing and sneezing) and contact with contaminated surfaces ( , , ) . however, earlier studies have shown the presence of the virus in conjunctival secretions and even stool ( ) . hence all body fluids except for sweat should be considered as potentially infectious ( ) . contamination of the surrounding environment may also occur following aerosol-generating procedures (agp) which include the use of high-speed devices or when splashing or spillage of bodily fluid is expected ( ) . appropriate steps especially in these environments need to be taken to disrupt the transmission of covid- and reduce risk of infection. these environments are considered as high-risk environments and include the icu, high-dependency unit (hdu) and ots. the emergency rhesus areas where suspected or confirmed cases of covid- are managed are also considered as high-risk areas ( ) . all highrisk areas require level iii ppe (table ) ( ) . ppe is only a part of the safe system of working ( ) . clinical staff must be trained and competent in the use of ppe in their respective hospitals. table shows the recommended ppe for clinical setting ( , , ) . ppe should be located close to the point of use and should be stored in a clean and dry area to prevent contamination. ideally, ppe is for single use and changed between patients unless in a situation of ppe shortage or when re-usable ppe is used. the used ppe must be disposed of in designated waste streams. the practice of donning (putting on) and doffing (taking off) of ppe must be done in designated areas safe for the respective procedures ( , ) . different hospitals may have different arrangements of clinical areas (ot, wards, clinics, etc.). hence, the physicians must make sure to be aware of the designated areas for donning and doffing prior to putting on ppe. ideally, each clinical staff donning must be supervised by another competent clinical staff especially to assist in donning and to make a final visual inspection of ppe. recommended ppe components: i) protective medical gown should be long in length, long sleeves, rear-fastening and fluid-resistant. also, include protective, fluid-resistant boots with disposable fluid-resistant covers when appropriate (high-risk procedures). for the gloves, the recommendation is to use disposable, non-sterile latex gloves for non-sterile procedures, whereas for sterile procedures is to use disposable sterile latex gloves. double gloving is essential in those procedures. ( ) ii) for the face/eye protector, ideally a disposable visor which covers the whole face including chin will give better protection than glasses and contact lenses. iii) for the respirator/mask, papr is recommended and preferred for high-risk procedures including agp. a minimum of n mask with face protector (i.e. visor) for agp ( , ( ) ( ) ( ) . for sars-cov, there is limited evidence (from observational studies) showing a protective effect of up to % of n masks (equivalent to ffp masks) used by healthcare workers. hence, although the cdc recommends n masks or higher level respirators for agp, n respirators are not recommended for agp in the uk ( , ) . the masks used should be fitted to the face without airleaks. in general clinical setting (other than aerosol-producing procedures), a fluidresistant mask is required. while fabric masks are widely available, this should not be used in any clinical setting. figure shows how to perform a particulate respirator seal check ( ) . i) essential to sanitise hand with alcohol gel before, in between each step and after donning of ppe ii) ppe must be put on in an order that ensures adequate placement of ppe equipment and prevents self-contamination and self-inoculation while using ppe and when taking off ppe ( , ) . figure shows levels of ppe. figure shows the recommended ppe to be used at the primary triage and non-sari area, while figure shows the recommended ppe in the ot, the ideal pressure system is a negative pressure room and if available, the recommended location is at the corner of the operating complex ( , ). the theatre should have a separate entrance. for intubation, the surgeons and personnel that are not involved in intubation should wait outside of the ot until anaesthetic induction and intubation are completed ( , , ) . during surgery (except for endoscopic endonasal procedures), procedures involving high speed devices are considered as aerosol-producing procedures and are high risk. the number of personnel in an ot should be minimised ( ) and full ppe should be applied. a n mask or masks that offer a higher level of protection should be used ( , , ) . endoscopic endonasal procedures are not safe and should be avoided ( , ) . if the surgery cannot be postponed, consider a craniotomy or microscope-based transsphenoidal procedure. during a shortage of ppe, the hospital or physicians are encouraged to minimise the use of ppe ( , ) . there are options available, such as considering telemedicine, where appropriate, to avoid direct contact with patients hence removing the necessity of ppe. the use of sterile gloves should be reserved only for procedures requiring sterility ( , , ) . all elective or non-urgent procedures, which usually require components of ppe should be delayed ( ) . certain areas should be monitored with restricted access, such as areas where suspected or confirmed covid- patients are being treated. some activities that require to be done at proximity to the patient (e.g. at bedside) must be planned early and bundle them together to minimise the number of times entering the room. visitors should not be allowed unless necessary, with restricted numbers and amount of time spent in the area. visitors must have clear instructions and guidance when donning and doffing with strict hand hygiene ( , ) . the use of appropriate ppe should be prioritised ( , ) and rationalised according to the risk of exposure and transmission dynamics of pathogens (air droplets, contact). overuse of ppe will further impact on supply shortages. (table ) the physician usually have to tailor the ppe usage based on the setting and activity being performed. below are some recommendations: extend the use of surgical gowns, masks and face protectors between patients with the same disease, who were confined in the same area without changing in between patients and whilst performing low risk procedures ( , , ) ii) consider re-usable face protectors (i.e. visors or googles) ( the ultraviolet (uv) spectrum is best known for uva, uvb and uvc (germicidal radiation). the spectral ranges for uva, uvb and uvc are nm- nm, nm- nm and nm- nm, respectively. uvc is the one with the strongest antimicrobial/antiviral properties ( , ) . with the rising healthcare awareness, some industry has demonstrated the effectiveness of radiation disinfection, especially uv light disinfection system on surface contamination, such as floors and equipment after the manual chemical disinfection process is completed ( ) . uv light disinfection is an implementation of 'no-touch' technology, is chemical free, does not require changes in the room's ventilation and will not leave a residue after treatment. in healthcare facilities such as icu and ot, this may be an adjunct to disinfection process ( ) . a laboratory study has shown that coronavirus could effectively be inactivated by uvc light ( , , ) . nevertheless, the uv light device is not a substitute for handwashing, mask-wearing and distancing. moreover, the international commission on non-ionizing radiation protection (icnirp) does not recommend the usage of lamps in the home. this is due to lack of adequate instructions of installation, duration of disinfection and increasing cases of skin and eye burns ( ) . who has come out with a fact that uv lamps should not be used to disinfect hands or other skin areas. furthermore, reiteration was made that 'cleaning your hands with alcohol-based hand rub or washing your hands with soap and water are the most effective ways to remove the virus' ( ) . the malaysian medical council has formed an advisory group to define and monitor virtual consultation (during the covid- pandemic). this advisory is guided by the medical act (amended ) which regulates the registration and practice of medicine in malaysia and the malaysian medical council's code of professional conduct. a virtual consultation is a form of telemedicine. telemedicine (teleconsultation, video conferencing, teleworkers, televideo) is a medical service provided remotely via information and communication technology. when the consultation is conducted without physical contact and does not necessarily involve long distances, then it is known as remote consultation. the role of the council is to regulate physicians, not technology. the council reminds physicians that the use of technology does not alter the ethical, professional and legal requirements in the provision of care. the malaysian medical council's jurisdiction is within this country only and physicians must ensure appropriate liability protection is in place to provide indemnity for malpractice. when the health care delivery is affected by any national epidemic or global pandemic, or any other movement restrictions imposed on the public by the government, the use of communication technology can improve the access to care. in this unprecedented time where the situation is seen to be very urgent, rapidly changing and where there is a fine balance between public safety and individual health, it is equally important for medical practitioners to have the virtues of accountability and truth telling. the code of professional conduct clearly says a physical examination is ethically mandatory. a non-physical contact virtual consultation makes a physical examination incomplete other than the visual and auditory observation. however, if a physician under current circumstances conducting such telemedicine virtual consultation feels this is so in good faith, then appropriate treatment can be initiated based on such, without the need for a physical examination in person. in providing medical care using telecommunications technologies, physicians are advised that they must possess adequate training and competency to manage patients through telemedicine. the ethical and legal requirements such obtaining valid informed consent from the patient should be taken, at the same time ensuring that the physician's identity, place of practice and registration status are made known to the patient, and the identity of the patient is confirmed at each consultation. the identities of all other participants involved in the telemedicine are disclosed and approved by the patient, and documented in the patient record. both the physician-site and the patient-site are using appropriate technology that complies with legal requirements regarding privacy and security and accreditation standards where required. considerations must be given to safety and maintaining a high standard of patient care. the physicians must consider whether the telemedicine medium affords adequate assessment of the presenting problem, and if it does not, an arrangement for a timely in-person assessment should be taken. the physician should be prepared to advise remote patients about how and where to arrange for necessary care when follow-up is indicated. with the limitation of telemedicine, the physicians should exercise caution when providing prescriptions or other treatment recommendations to patients whom they have not personally examined. when carrying out a diagnostic evaluation or prescribing medication, a physician conducting a remote interaction should: i) verify the patient's identity; ii) confirm that the remote interaction is appropriate to the patient's situation and medical needs; iii) write any prescriptions in keeping with best practice guidelines and formulary restrictions (and in keeping with ethics guidance on prudent stewardship); and iv) document the clinical evaluation and prescription, as well as any instructions given to the patient. a medical record of the consultation, in accordance with professional and legal requirements, are kept and available to other health care professionals for the provision of ongoing patient care. this is especially important when there is a followup and referral to other specialities. hence, the physician must ensure adherence to the same obligations for patient follow up in telemedicine as is expected with in-person consultation. many centres have implemented the telemedicine in neurosurgical consultation, specifically in patients with confirmed covid- , or recovered patients (pcr negative and beyond days incubation period) that may need comprehensive clinical assessment to be performed. throughout all levels, neurosurgeons are encouraged to convert meetings (with staff, colleagues and patients) to teleconsultation and/or video conferencing ( ) . teleconsultation minimises face-to-face clinic visits for all doctors and patients, including neurosurgeons and their patients ( ). staff and patients over the age of are encouraged to avoid coming to the hospital and clinic. the conversion of many clinic visits as medically appropriate to this new modality allow patients to stay safe at home and allows clinic nurses and staff to help care for covid- patients. another speciality that is using telemedicine is neurology, mainly for the assessment of patients with a suspected stroke. the telemedicine should enable the physician to discuss the case with the assessing clinician, talk to the patient and/or family/carers directly and review radiological investigations ( ) . hence, it is important that a high-quality video link is maintained to enable the remote physician to observe the clinical examination. the physician providing care (at both ends of the system) should be appropriately trained in the hyperacute assessment of people with suspected acute stroke, in the delivery of thrombolysis and the use of this approach and technology. the impact on the quality of care, efficacy of telemedicine and decision-making using telemedicine should be regularly audited ( ) in keeping with physician's fiduciary obligations to patients across that continuum ( ) . timely updates from trusted sources about the relative risk of contracting the novel disease versus a more common one are critical ( , ) . strategic social media use (e.g. hashtags) may be an effective way for agencies to communicate accurate information to the public during times of crisis. residents may be advised to connect with and follow local health agencies and service providers for the most geographically relevant information. researchers may use publicly available 'big data' (e.g. localised tweets) to gauge the risk of communication efforts of local agencies. ( ) ( ) ( ) in the emergency department, there is a surge control for 'forward triage', meaning utilisation of sorting the patients before they arrive in the emergency department. this allows patients to be efficiently screened, is both patient-centred and conducive to self-quarantine, and it protects patients, clinicians and the community from exposure. the physicians and patients are still able to communicate / , either by using smartphones or webcam-enabled computers. the respiratory symptoms (which may be early signs of covid- ) are among the conditions most commonly evaluated with this approach. telemedicine consultations for oncologic patients may not be suitable and individual clinicians must be able to make an appropriate judgment. however, patients will greatly benefit from such virtual clinic consultations over a cancellation. ( , ) the presence of virus within csf fluid and during autopsy can be tested via electron microscopy, immunohistochemistry and realtime reverse transcriptional. there are . % of patients had neurologic manifestations due to neurotropic potential in the covid- virus found in one study. during an early or later phase of the infection, the dissemination of covid- in the systemic circulation or across the cribriform plate of the ethmoid bone takes place. the ability to cross the blood brain barrier into the cerebral circulation is due to the properties of the covid- virus spike protein with angiotensin-converting enzyme (ace ) receptors expressed in the capillary endothelium. the receptor has been detected over glial cells and neurons. covid- virus exploits the ace receptors to gain entry inside the cells ( ) causing neuronal death in mice by invading the brain via the nose close to the olfactory epithelium. in an uncomplicated early stage, findings like an altered sense of smell or hyposmia can be found. once the virus caused respiratory manifestation, there will be neurological involvement with loss of involuntary control over breathing ( ) . tuberculosis ( ) the physician should maintain continuity of essential services for people affected with tuberculosis (tb) during the covid- pandemic. it is anticipated that ill patients with both tb and covid- may have poorer treatment outcomes, especially if tb treatment is interrupted. therefore, accurate diagnostic tests are essential for both tb and covid- . simultaneous testing of the same patient for both tb and covid- would generally be indicated for three main reasons (subject to the specific setting in the country): i) clinical features that are common to both diseases; or ii) simultaneous exposure to both diseases; or iii) presence of a risk factor for poor outcomes to either disease. in tuberculous meningitis with communicating hydrocephalus, the recommendation is to treat with furosemide with or without acetazolamide. some institutions favour daily lumbar punctures with icp monitoring through manometry ( ) . in tuberculous meningitis with noncommunicating hydrocephalus, this will involve invasive neurosurgical procedures such as an external ventricular drain (evd), ventriculoperitoneal shunting or endoscopic third ventriculostomy (etv) ( ) . acute necrotising encephalopathy is a condition that can be triggered by viral infections like influenza and herpes. a case report of a woman who tested positive for covid- developed acute necrotising encephalopathy ( ) . the patient presented altered mental status and a noncontrast head ct images demonstrated symmetric hypoattenuation within the bilateral medial thalami with a normal cta and ct venogram. brain mri demonstrated a haemorrhagic rim enhancing lesions within the bilateral thalami, medial temporal lobes, and subinsular regions. the patient was started on intravenous immunoglobulin. this is the first reported case of meningitis associated with sars-cov- who presented with convulsion followed by unconsciousness ( ) . the patient had transient generalised seizures that lasted about a minute. the specific sars-cov- rna was not detected in the nasopharyngeal swab but was detected in a csf. brain mri showed hyperintensity along the wall of right lateral ventricle and hyperintense signal changes in the right mesial temporal lobe and hippocampus, suggesting the possibility of sars-cov- meningitis. paediatric neurosurgery accounts for up to % of neurosurgical admissions. in this current crisis, covid- infection among children remains limited in numbers. however, paediatric patients are at risk of exposure from potential family members and caretakers that may harbour the virus and remain asymptomatic. the main consideration is therefore to be vigilant and screen caretakers and family of patients for risk of exposure based on current and updated guidelines provided by the moh ( ). the priority as for all cases in the pandemic crisis remains the protection of healthcare personnel and other non-infected patients as well as the working environment at healthcare facilities. the guidelines provided by moh ( ) applies equally for paediatric neurosurgery cases; principally in deciding for the need of surgical care and intensive management in times of reduced availability of resources. this guiding principle forms the core basis of decision making for paediatric neurosurgery in malaysia as the availability of specialised paediatric intensive care units and specialised instruments are typically present in major hospitals with dedicated neurosurgical units and facilities. with the ongoing pandemic crisis, these subspecialised resources are crucial for the treatment of patients afflicted by covid- . ( ) all non-essential outpatient cases should be postponed. some new cases with symptoms and signs of raised icp or neurological compromise should be reviewed urgently by a neurosurgeon. whereas, new cases with no symptoms or signs of raised icp or neurological compromise should be reviewed via teleconsultation. any pending surgeries should be reviewed with team and mdt to prioritise cases based on the urgency of surgical intervention, taking into account symptoms and signs, radiological evidence of mass effect or vital structure compression, expected radiological progression over time and expected histology along with the availability of vital specialised resources of intensive care, equipment requirements and ot availability. certain logistic factors, such as patient travel and family economic factor that requires one or both parents to be away from work should also be taken into account in the decision making process to ensure compliance of patient and caretakers to the management plan. paediatric neurotrauma ( ) all cases must be screened for risk of covid- as per hospital protocols. the management of paediatric neurotrauma is based on the brain trauma foundation (btf) guidelines. all cases undergoing emergency surgery must be performed under full ppe as per hospital/moh protocols ( , ) . the initial referral should be reviewed by the neurosurgical team or consulted via teleconferencing with the neurosurgical team on admission. the modified paediatric gcs score system (table ) must be applied and made available to referring or primary management team where applicable ( ) . cases of neurotrauma with surgical lesions must be transferred to a hospital with a neurosurgical facility and or services for management. frequent repeats of ct scan should be avoided where feasible and should be factored into the decision making process for applicable cases. there are certain cases of neurotrauma that has positive ct findings but with a nonsurgical lesion ( ) . if the treatment requires an icp monitoring, then the patient should be transferred to a centre with neurosurgical services or facilities. if the treatment does not require an icp monitoring but there is a potential risk of progression and deterioration, then the patient should also be transferred over. however, for patients who do not require intensive care with low risk of deterioration or progression, it is advisable to transfer to centres with available neurosurgical services. if it is not feasible, then the patient should be managed by attending paediatrician/surgeon at primary referral centres with regular consultations to the neurosurgical team. cases with no positive ct brain findings ( ) may be managed at primary referral centres if deemed suitable with a consultation to the neurosurgery team. in a non-traumatic paediatric neurosurgery case, the approach is the same; all cases must be screened for risk of covid- as per hospital protocols. suitable use of ppe must be adhered to for all cases undergoing surgery. the surgeon should: i) consider the option of fastest and simples access route to the lesion; ii) consider biopsy if deemed appropriate over surgical guidelines covid- management in malaysia covid- : recommendations for management of elective surgical procedures american association of neurological surgeons. covid- and neurosurgery cms adult elective surgery and procedures recommendations neurosurgery during the covid- pandemic: update from lombardy, northern italy letter: the coronavirus disease global pandemic: a neurosurgical treatment algorithm guidance for surgeons working during the covid- pandemic letter: precautions for endoscopic transnasal skull base surgery during the covid- pandemic just the facts: airway management during the coronavirus disease (covid- ) pandemic adoption of a safe or cautious approach towards surgery covid- preparedness within the surgical, obstetric, and anesthetic ecosystem in sub-saharan africa update: the use of personal protective equipment by anesthesia professionals during the covid- pandemic covid- among medical personnel in the operating room what we do when a covid- patient needs an operation: operating room preparation and guidance just the facts: protecting frontline clinicians during the covid- pandemic strategies for optimizing the supply of isolation gowns personal protective equipment: questions and answers managing icu surge during the covid- crisis: rapid guidelines us department of health and human services. personal protective equipment (ppe) coronavirus disease (covid- ): critical care and airway management issues operational considerations for personal protective equipment in the context of global supply shortages for coronavirus disease (covid- ) pandemic: non-us healthcare settings ministry of health malaysia. intensive care preparedness and management of covid- centers for disease control and prevention. contact tracing for covid- public health service commissed corps. strategies to optimize provision of mechanical ventilation safety recommendations for evaluation and surgery of the head and neck during the covid- pandemic surgical considerations for tracheostomy during the covid- pandemic: lessons learned from the severe acute respiratory syndrome outbreak safe tracheostomy for patients with severe acute respiratory syndrome clinical guide for the management of neuro trauma patients during the coronavirus pandemic preliminary recommendations for surgical practice of neurosurgery department in the central epidemic area of coronavirus infection guidelines on management of coronavirus disease (covid- ) in surgery response to covid- in chinese neurosurgery and beyond neurosurgery in the storm of covid- : suggestions from the lombardy region, italy (ex malo bonum) on pandemics: the impact of covid- on the practice of neurosurgery triage of scarce critical care resources in covid- . an implementation guide for regional allocation: an expert panel report of the task force for mass critical care and the american college of chest physicians society of british neurological surgeons. bnvg/ sbns guide for the neurosurgical management of neurovascular conditions during the covid- pandemic guidelines for the management of aneurysmal sah: a guideline for healthcare professionals from the american heart association/american stroke association arteriovenous malformation (avm) management of incidental cerebral avms in the post-aruba era arteriovenous malformations of the posterior fossa: a systematic review responses to aruba: a systematic review and critical analysis for the design of future arteriovenous malformation trials intracranial dural arteriovenous fistulas: a review the latest national clinical guideline for stroke guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the american heart association/american stroke association using the national institutes of health stroke scale: a cautionary tale guidelines for the early management of patients with acute ischemic stroke: update to the guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the temporary emergency guidance to us stroke centers during the coronavirus disease (covid- ) pandemic: on behalf of the american heart association/american stroke association stroke council leadership challenges and potential solutions of stroke care during the coronavirus disease (covid- ) outbreak ministry of health malaysia. perioperative mortality review (pomr): prioritisation of cases for emergency and elective surgery ( nd revision) [internet]. malaysia: medical development division society of american gastrointestinal and endoscopic surgeons. covid- statement and recommendations from the asociacion espanola de cirujanos practical considerations for performing regional anesthesia: lessons learned from the covid- pandemic preparing for a covid- pandemic: a review of operating room outbreak response measures in a large tertiary hospital in singapore handbook of covid- prevention and treatment ministry of health malaysia. garis panduan kementerian kesihatan malaysia protocol for urgent and emergent cases at a large academic level trauma center covid- : guidance for triage of non-emergent surgical procedures covid- -infection prevention and control measures covid- : infection prevention and control (ipc) guidelines for management of neurosurgical cases during covid- pandemic effectiveness of masks and respirators against respiratory infections in healthcare workers: a systematic review and meta-analysis infection prevention and control of epidemic and pandemic prone acute respiratory infections in health care letter: considerations for performing emergent neurointerventional procedures in a covid- environment minimizing sars-cov- exposure when performing surgical interventions during the covid- pandemic infectious diseases society of america guidelines on infection prevention in patients with suspected or known covid- ultraviolet irradiation doses for coronavirus inactivation -review and analysis of coronavirus photoinactivation studies far-uvc light ( nm) efficiently and safely inactivates airborne human coronaviruses covid- coronavirus ultraviolet susceptibility evaluation of an ultraviolet c (uvc) light-emitting device for disinfection of high touch surfaces in hospital critical areas susceptibility of sars-cov- to uv irradiation germany international commission on non-ionizing radiation protection. icnirp note on use of uvc lamps to kill/inactivate the coronavirus (sars-cov- ) world health organization. coronavirus disease (covid- ) advice for the public the impact of professional isolation on teleworker job performance and turnover intentions: does time spent teleworking, interacting face-toface, or having access to communicationenhancing technology matter? providing patient care remotely in a pandemic the novel coronavirus (covid- ) outbreak: amplification of public health consequences by media exposure telemedicine in neurosurgery: lessons learned and transformation of care during the covid- pandemic telehealth and telemedicine in the covid- era: a world of opportunities for the neurosurgeons malaysian medical council advisory on virtual consultation (during the covid- pandemic) vascular endothelial growth factor (vegf) as a vital target for brain inflammation during the covid- outbreak evidence of the covid- virus targeting the cns: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms fluorescence and electron microscopic localization of f-actin in the ependymocytes world health organization (who) information note: tuberculosis and covid- tuberculous meningitis in adults: a review of a decade of developments focusing on prognostic factors for outcome covid- -associated acute hemorrhagic necrotizing encephalopathy: ct and mri features a first case of meningitis/encephalitis associated with sarscoronavirus- impact of the coronavirus (covid- ) pandemic on surgical practice -part (surgical prioritisation) performance of the pediatric glasgow coma scale score in the evaluation of children with blunt head trauma the society of british neurological surgeons. clinical guide for the management of paediatric neurosurgery patients during the coronavirus pandemic early lessons in the management of covid- for the pediatric neurosurgical community from the leadership of the american society of pediatric neurosurgeons anaesthesia and sars infographic for principles of airway management in covid- world federation of societies of anesthesiologists this publication is not a proposed national guideline for the covid- management of covid- neurosurgical patients but a review of management and protocols from local and international peer reviewed and non-peer reviewed publications, web-based information and data until the month of august . we hope that this publication will be used to improve care of neurological or neurosurgical patients and their caregivers/frontlines globally especially in developing countries. none. none. appendix . principles of airway management in coronavirus covid- ( ) www.mjms.usm.my key: cord- - x cdul authors: díaz-guio, diego andrés; díaz-guio, yimmy; pinzón-rodas, valentina; díaz-gomez, ana sofía; guarín-medina, jorge andrés; chaparro-zúñiga, yesid; ricardo-zapata, alejandra; rodriguez-morales, alfonso j. title: covid- : biosafety in the intensive care unit date: - - journal: curr trop med rep doi: . /s - - -z sha: doc_id: cord_uid: x cdul purpose of review: covid- is a new, highly transmissible disease to which healthcare workers (hcws) are exposed, especially in the intensive care unit (icu). information related to protection mechanisms is heterogeneous, and the infected hcws’ number is increasing. this review intends to summarize the current knowledge and practices to protect icu personnel during the patient management process in the context of the current pandemic. recent findings: the transmission mechanisms of sars-cov- are mainly respiratory droplets, aerosols, and contact. the virus can last for a few hours suspended in the air and be viable on surfaces for several days. some procedures carried out in the icu can generate aerosols. the shortage of respirators, such as the n , has generated an increase in the demand for other protective equipment in critical care settings. summary: the probability of transmission depends on the characteristics of the pathogen, the availability of quality personal protective equipment, and the human factors associated with the performance of health workers. it is necessary to have knowledge of the virus and availability of the best possible personal protection equipment, develop skills for handling equipment, and develop non-technical skills during all intensive care process; this can be achieved through structured training. coronaviruses belong to the family coronaviridae, which comprise a great number of viruses common in humans and other animals [ ] . the severe acute respiratory syndrome coronavirus (sars-cov- ), a new betacoronavirus, is the etiological agent of the coronavirus disease [ , ] . sars-cov- is an rna virus, the seventh in a coronavirus family this article is part of the topical collection on emerging tropical diseases able to infect humans. it is - nm in diameter ( . - . μm) and has a lipid envelop. its target is angiotensinconverting enzyme (ace ) [ , ] . this new coronavirus has a high infecting capacity; its basic reproduction number (r ) is variable, possibly between and [ ] , twice the r of swine flu (h n ) [ ] , and similar to the pandemic influenza (spanish flu) [ ] . it has a global distribution; it is also a highly transmissible agent with potentially fatal outcomes. to date, july , , it has infected nearly . million people and caused the death of more than , patients, including health personnel [ ] . for a safe work environment, joint work between workers and employers is required. in the case of health services in the covid- pandemic, this premise is also pertinent. employers must guarantee resources for the protection of healthcare workers (hcws), and they must make judicious and rational use of the biosecurity elements available [ ] . covid- is a very transmissible disease; its transmission mechanisms are mainly respiratory droplets, aerosolized particles, and contact. however, in the intensive care unit (icu), some procedures are associated with aerosol production [ ] . most patients present mild symptoms, and - % need hospitalization in the icu [ , ] , which has exceeded the available resources, even in countries with robust healthcare systems [ ] . in low-income countries, the situation could become even worse [ ] . health systems must optimize their resources, prepare their icus, and guarantee the protection of those who face the pandemic on the front line [ ] . this article aims to show the different strategies to prevent the widespread of the disease to critical care healthcare workers based on the review of the recent literature and the author's experience with the personal protective equipment (ppe) in the care of patients with covid- and work on human factors in crisis management. covid- can be transmitted person to person through droplets emitted by infected patients when they speak, cough, sneeze, or when a person comes into contact with contaminated surfaces [ ] . most of the procedures that can generate aerosols are executed in the icu (orotracheal intubation, tracheostomy, cpr, among others), which exposes the personnel to a high risk of contagion [ ] . it is necessary to define some concepts of the dynamics of respiratory droplets (> μm) and aerosols (< μm) produced by the airways of patients with respiratory disease, and the interaction of these particles with the intensive care unit hospitalization environment. the flow acceleration achieved when coughing can be between and m/s, and when sneezing can reach up to m/s [ ] . the emitted gas forms a turbulent, multiphase cloud, which can go up to m [ ] ; the aerosolized virus may remain suspended for several hours and be active on surfaces for many days [ , ] . in china, . % of those infected correspond to health personnel [ ] ; in italy, - % [ , ] . in colombia, as of july , , , covid- infected healthcare workers have been reported, which corresponds to % of the total number of infected in the country; . % were associated with patient care. most infections have occurred in nursing assistants ( %), physicians ( . %), nurses ( . %), administrative staff ( . %), and clean and disinfection workers ( %). . % of infected health personnel have died [ ] . intensive care personnel is more habituated to biosafety protocols. nonetheless, in this pandemic, several limitations in adherence to infection control guidelines have been evidenced, including the shortage of ppe, poor quality of ppe, unavailability of rooms with antechamber, bathroom, negative pressure and air exchange, shortcomings in training in ppe donning and doffing, frequent changes on management guidelines, and ambiguity of the recommendations [ ] [ ] [ ] . the patient may disperse particles that have infectious contents. these particles experience changes with the dynamics of airflow in the room, which can be influenced by the high traffic in the place, the presence of air conditioning, negative pressure, door opening, among others. the droplets are heavy and usually fall on the patient and in his environment. despite that, they can be dried by air currents leaving the droplet nuclei exposed and able to persist suspended in the air. viral dose, exposure time, mucosal exposure, and tidal volume are determining factors in the possibility of contamination and hcws possible infection [ , ] . the infectious particles can be on the patient, in their environment (fomites), and possibly in the patient's room air. the virus can reach its target site through the eyes conjunctive, nose, and mouth mucosae. the fecal-oral route may be involved, but this has not been proven so far [ ] . if we understand these data, we may have an opportunity to prevent the spread of the disease to healthcare workers with specific physical barriers known as personal protective equipment (ppe) [ , ] . eye protection can be done by wearing goggles, facial shields, or full-face elastomeric respirators. mouth and nasal protection are conferred by n /kn /ffp (filtering face piece) or higher respirators. in the event of a shortage of disposable respirators, half-face or full-face elastomeric respirators with n or more top filters can be used. the inspiratory and expiratory seal verification is essential in all respirators before use (fig. ). the protection offered by masks and respirators against particles larger than . μm is a surgical mask: %, ffp : %, n : %, ffp : . %, n : . %. it is strongly recommended to verify the national institute for occupational safety and health (niosh) quality certification, it must be written on the front of the device. the who recommendations indicate the use of a surgical mask when health personnel is not exposed to aerosolgenerating procedures (agps) and n when performed [ ] . however, the european cdc in high-risk environments recommends the use of ffp or equivalent respirators, and for agps recommends ffp or equivalent [ , ] , we are aligned with the european recommendations. nonetheless, to date, there is no robust evidence that medical masks are inferior to n /ffp respirators for protecting healthcare workers against laboratory-confirmed covid- during patients care and non-agps [ ] . the elastomeric respirator is a valid and increasingly used option due to the shortage of n /ffp respirators [ ] . this device can be found in half-face and full-face versions. it is reusable and has different types of filters, although n or higher is recommended. it has been shown that short time is required to learn how to use them [ ] . in table , we describe the ppe with its use considerations. while personal protective equipment is an essential part of safety to prevent sars-cov- transmission, it must be employed appropriately, together with frequent hand hygiene, and mastering specific techniques and non-technical skills like awareness, closed-loop communication, leadership, team working, appropriate resource management, and cognitive aids [ , ] . below, we feature some safety recommendations from patient's admission to the icu until discharge. critically ill patients should be hospitalized in the intensive care unit after a triage process. the referring service (emergency room, operating room, general room, among others) must report the arrival [ ] . the hospital should have specific routes for infected patients' transfer [ ] . it is recommended that patients be hospitalized in individual rooms with antechamber, bathroom, and negative pressure systems with high-efficiency filters (hepa) and air changes per hour. non-intubated patients must wear a surgical mask [ , ] . the number of healthcare workers that meet the patient should be the minimum necessary, and all must use ppe appropriately, with donning and doffing assisted by an external verifier guided by a checklist (table ) [ ] . the most frequent covid- clinical manifestations are respiratory. most critically ill patients have respiratory distress and oxygenation disorder [ ] ; therefore, they need airway management and mechanical ventilatory support in the icu. airway management is considered a high-risk activity for aerosol production; this includes positive pressure mask ventilation, supraglottic device insertion, orotracheal intubation, open airway aspiration, bronchoscopy supported procedures, tracheostomy, and tracheal extubation [ , ] . for tracheal intubation of the patient with suspected or confirmed covid- , full and verified ppe must be available. that includes n /ffp , ffp , or equivalent respirators or paprs [ , ] , in addition to observing the following recommendations: for intubation and even for planned extubation, in places where negative pressure is not available, acrylic boxes and plastic devices have been used [ , ] . they can protect against splashes, possibly aerosols, but this is not clear. these devices can make intubation complex; therefore, the hcws must be trained in their use. before the pandemic, tracheostomies were performed between the th and th days of endotracheal intubation. however, the median time from intubation to death of covid- patients has been reported to be on the th day [ ] . due to the high risk of aerosol production during the tracheostomy, and hcws' risk of contagion, it seems reasonable to wait for establishing a life prognosis, which could avoid futile procedures if the tracheostomy were performed too early, thus, protecting healthcare personnel [ ] . all hcws participating in the procedure must wear full ppe, which includes paprs, n , or ffp respirators [ ] . the patient should be sedated and relaxed. regarding the technique, there is no apparent difference between open and percutaneous tracheostomy. if the percutaneous method is chosen, the one-step dilation technique is preferred [ ] . the consideration of thoracic compressions as an aerosolgenerating procedure has been controversial, due to the united kingdom's national healthcare system (nhs) not considering them agps [ ] ; however, the who and scientific societies put on inner gloves, "second skin". . gown / coverall gown: secure both ties at the back of the gown. coverall: fasten hat and arms of the suit to avoid contact with the ground. hold the cup with your hand, first raise the lower band, leave below the ears, then the upper band and leave it above the ears. fit the coupling plate over the nose dorsum and perform a fit check (forced exhalation -forced inspiration). put on your cap: no skin exposed. adapt the adjustable base to the size of the head in case of face shield. goggles or face shield must be worn over prescription glasses. . outer gloves put on the gloves making sure the suit cuffs are covered by the gloves. hand hygiene or alcohol gel application. remove one glove and squeeze it with the opposite hand, then remove the other glove from the inside and wrap the one that was initially removed. hand hygiene or alcohol gel application. remove the goggles by holding them from the temples. if it is a face shield, hold it from the posterior side of the adjustable base. . gown / coverall remove the gown by folding it and pulling it away from the body only by touching the inner part (disinfected side). include over shoes. hand hygiene or alcohol gel application. consider that they are [ , ] ; we agree with the latter. therefore, it is necessary to have all the aerosols precautions in addition to the following recommendations [ , ] : & define if the patient is a resuscitation candidate. & minimize the number of resuscitation personnel. & avoid the maneuver "listening and feeling" to determine to breathe. & perform early intubation along with a high-efficiency filter. & employ commercial chest compression systems. the mortality of patients admitted to the icu is elevated, even more so in those requiring mechanical ventilation [ , ] . there is no direct evidence on the risk of contagion of healthcare workers who have had contact with the bodies of covid- deceased persons. in a study related to the severe acute respiratory syndrome (sars) epidemic, there was a reported contagion of % of hcws that came into contact with corpses [ ] . it is recommended that icu healthcare workers who manage corpses use full ppe following the same recommendations that were described for performing icu procedures. tubes and venous and arterial lines should be removed; puncture sites should be disinfected. corpses should be packed in a double leak-proof bag; the exterior cover, surfaces, and environment must be adequately disinfected. it is also recommended to avoid direct contact with bodily fluids, contaminated surfaces, transporting stretchers, and make a timely transfer of corpses to the morgue or designated areas. for a recent systematic review on the management of bodies, we refer the reader to yaacoub et al. [ ] . one of the transmission mechanisms is the contact of hcws with contaminated surfaces; the presence of sars-cov- at different sites in the patient's room has been documented [ ] . the stability of the pathogen depends on several factors: inoculum size, viral resilience, surface ph, temperature, and humidity of the environment. persistence has been shown for up to days, depending on the material, being higher in plastic and steel [ ] . it is susceptible to heat and standard disinfection methods. the surface disinfection process should start with cleaning with soap and water or neutral detergents associated with mechanical measures, to remove dirt and reduce the load of pathogens. second, the use of disinfectants, the who recommends hydrogen peroxide, chlorine-based solutions, and alcohol. efficiency will depend on concentration and exposure time [ , ] . ethanol - % requires s- min to be effective, chlorine-based products (e.g., hypochlorite) at . % ( ppm) for general environmental disinfection or . % ( ppm) for blood and large body fluid spills require min, and hydrogen peroxide > . % at least min. cleaning and disinfection should start from the least contaminated to the most contaminated; the cleaning material must be labeled and frequently changed due to the risk of contamination. in general, it is recommended in the work areas with patients to clean two to three times a day; objects of everyday use (door handles, keyboards, tables, among others) must be cleaned with higher frequency. sanitation and disinfection workers are essential in this pandemic and should receive the best protection available against sars-cov- and the substances for disinfection use. it is not recommended to spray people or use disinfection chambers for personnel [ ] . at present, most of the people around world are at home protecting themselves with social distancing. meanwhile, the hcws must take care of the patients. anxiety, insomnia, depression, and cognitive overload have been reported in healthcare personnel. they are afraid of contagion, infecting their families, failing, and dying [ ] . the use of personal protective equipment, although it is an excellent measure of protection, also presents difficulties that can generate stress and discomfort. putting them on and removing them is not easy and time-consuming [ ] . in this crisis, performing procedures has become more difficult [ ] ; initially, a feeling of awkwardness is generated; the goggles become foggy; breathing with disposable or elastomeric respirators requires more effort; skin injuries occur; thirst, heat, dizziness, and headaches are felt. other difficulties are that most hcws dress similarly, which limits mutual recognition, added to that respirators significantly limit communication; this has increased the complexity of an already complex disease; the cognitive load of health personnel is already high. higher cognitive load increases the probability of failure [ ] , of becoming contaminated and infected. briefing and debriefing are strongly recommended on each shift and after each severe incident. possibly, the most efficient way to decrease cognitive load and improve performance is through training techniques and tasks such as donning and doffing, as well as human factors or non-technical skills such as leadership, communication, and situational awareness. an excellent way to do this is through structured clinical simulation; this includes clear learning objectives, plausibility between the simulated and real context, intentional reflection, usage of metacognitive strategies, and evaluation of learning results [ , ] . in low-and intermediate-income countries, the availability of adequate resources for the protection of hcws is possibly insufficient, which has led health care personnel to improvise their ppe, which puts their safety at risk; therefore, government and administrative levels must guarantee the workers of the icu the adequate resources. covid- is a highly contagious disease, and icu healthcare workers are very exposed. the main transmission mechanisms are droplets and contact. however, some procedures can generate aerosols. the virus enters the body through the mouth, eyes, and nose. therefore, biosafety should focus on aerosol precautions and the correct use of full personal protective equipment, surface decontamination, and frequent hand hygiene. the availability of full personal protective equipment does not indicate absolute safety; there are factors related to the pressure of critically ill care and human factors that are involved with non-safe performance, and that can be improved through training and teamwork. conflict of interest the authors declare that they have no conflict of interest. human and animal rights and informed consent not applicable. the species severe acute respiratory syndrome-related coronavirus: classifying -ncov and naming it sars-cov- a novel coronavirus from patients with pneumonia in china a new coronavirus associated with human respiratory disease in china the reproductive number of covid- is higher compared to sars coronavirus modeling influenza epidemics and pandemics: insights into the future of swine flu (h n ) transmissibility of pandemic influenza who. coronavirus disease -situation report - european centre for disease prevention and control. safe use of personal protective equipment in the treatment of infectious diseases of high consequence: a tutorial for trainers in healthcare settings staff safety during emergency airway management for covid- in hong kong clinical, laboratory and imaging features of covid- : a systematic review and meta-analysis at the epicenter of the covid- pandemic and humanitarian crises in italy: changing perspectives on preparation and mitigation. nejm catal innov care deliv will colombian intensive care units collapse due to the covid- pandemic the italian covid- outbreak: experiences and recommendations from clinical practice novel coronavirus: where we are and what we know airborne spread of infectious agents in the indoor environment turbulent gas clouds and respiratory pathogen emissions: potential implications for reducing transmission of covid- aerosol and surface stability of sars-cov- as compared with sars-cov- it is time to address airborne transmission of covid- characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention coronavirus disease (covid- ) in italy covid- and italy: what next? covid- colombia | reporte - - barriers and facilitators to healtcare workers' adherence with prevention and control (ipc) guidelines for respiratory infectious diseases : a rapid qualitative evidence synthesis ( review ) healthcare workers' and students' knowledge regarding the transmission, epidemiology and symptoms of covid- in cities of bolivia and colombia covid- : a crisis that requires urgent training measures airborne transmission of severe acute respiratory syndrome coronavirus- to healthcare workers: a narrative review who. transmission of sars-cov- : implications for infection prevention precautions. scientific briefing personal protective equipment (ppe) needs in healthcare settings for the care of patients with suspected or confirmed novel coronavirus ( -ncov) personal protective equipment for preventing highly infectious diseases due to exposure to contaminated body fluids in healthcare staff medical masks vs n respirators for preventing covid- in healthcare workers: a systematic review and meta-analysis of randomized trials. influenza other respir viruses storage and availability of elastomeric respirators in health care training and fit testing of health care personnel for reusable elastomeric half-mask respirators compared with disposable n respirators non-technical skills in the intensive care unit icu admission, discharge, and triage guidelines: a framework to enhance clinical operations, development of institutional policies, and further research preparing your intensive care unit for the covid- pandemic: practical considerations and strategies surviving sepsis campaign: guidelines on the management of critically ill adults intensive care medicine consensus guidelines for managing the airway in patients with covid- : guidelines from the difficult airway society, the association of anaesthetists the intensive care society, the faculty of intensive care medicine and the royal college of anaesthetist clear plastic drapes may be effective at limiting aerosolization and droplet spray during extubation: implications for covid- barrier enclosure during endotracheal intubation baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region recommendation of a practical guideline for safe tracheostomy during the covid- pandemic personal protective equipment (ppe) for surgeons during covid- pandemic: a systematic review of availability, usage, and rationing covid- : infection prevention and control guidance covid- in cardiac arrest and infection risk to rescuers: a systematic review covid- practical guidance for implementation risk factors for sars infection among hospital healthcare workers in beijing: a case control study safe management of bodies of deceased persons with suspected or confirmed covid- : a rapid systematic review protection and disinfection policies cleaning and disinfection of environmental surfaces in the context of covid- : interim guidance prevalence of depression, anxiety, and insomnia among healthcare workers during the covid- pandemic: a systematic review and meta-analysis human factors risk analyses of a doffing protocol for ebola-level personal protective equipment: mapping errors to contamination difficult airway in the critically ill patient: much more than technical skills evaluation of cognitive load and emotional states during multidisciplinary critical care simulation sessions relationship among mental models , theories of change , and metacognition : structured clinical simulation cognitive load and performance of health care professionals in donning and doffing ppe before and after a simulation key: cord- -u svwcpt authors: rauch, antoine; dupont, annabelle; goutay, julien; caplan, morgan; staessens, senna; moussa, mouhamed; jeanpierre, emmanuelle; corseaux, delphine; lefevre, guillaume; lassalle, fanny; faure, karine; lambert, marc; duhamel, alain; labreuche, julien; garrigue, delphine; de meyer, simon f.; staels, bart; van belle, eric; vincent, flavien; kipnis, eric; lenting, peter j.; poissy, julien; susen, sophie title: endotheliopathy is induced by plasma from critically ill patients and associated with organ failure in severe covid- date: - - journal: circulation doi: . /circulationaha. . sha: doc_id: cord_uid: u svwcpt nan l ung histological analyses revealed the presence of vascular inflammation and severe endothelial injury as a direct consequence of intracellular severe acute respiratory syndrome coronavirus (sars-cov- ) infection and ensuing host inflammatory response in coronavirus disease (covid- ). endothelial cells promote coagulation following injury, leading to widespread formation of microthrombi, provoking microcirculatory failure or large-vessel thrombosis. growing evidence suggests that microvascular thrombosis is a major pathophysiological event in covid- pathogenesis. damaged endothelial cells could be closely implicated in the prothrombotic state commonly reported in severe patients in the intensive care unit (icu). how sars-cov- exerts its cytopathic effects is still a matter of debate, and ultrastructural evidence of direct viral replication in endothelial cells remains to be demonstrated. although direct viral tissue damage is a plausible mechanism of injury, endothelial damage and thromboinflammation associated with dysregulated immune responses, inducing microvascular thrombosis, represent an attractive alternative hypothesis. using cultured human pulmonary microvascular endothelial cells (hpmvec), we assessed whether plasma collected from patients with covid- at different disease stages could trigger endothelial damage in vitro. the cytotoxicity of plasma samples on hpmvec was evaluated by assessing mitochondrial activity (wst- test) hour after incubation of cells with plasma as previously described. we further investigated the association of plasma-induced cytotoxicity with levels of circulating biomarkers related to organ dysfunction (pao [partial pressure of oxygen in arterial blood]/fio [fraction of inspired oxygen], widely used as an indicator of oxygenation requirements, lactate dehydrogenase, creatinine, and aspartate transaminase), endothelial damage (von willebrand factor antigen; adamts ; plasminogen activator inhibitor- ; syndecan- ), tissue injury (cell-free dna, a damage-associated molecular patterns marker), and levels of circulating cytokines related to the activation of innate (interleukin [il]- and tumor necrosis factor-α) and adaptative immune cell responses (soluble il- receptor). inclusion criteria were individuals aged years or older with a positive sars-cov- real-time reverse-transcriptase polymerase chain reaction on nasal or tracheal samples admitted to the lille university hospital. patients on treatment with direct oral anticoagulant or vitamin k antagonists were switched to therapeutic heparin therapy on admission. patients not in the icu received once daily thromboprophylaxis with enoxaparin according to their body weight. patients in the icu received enoxaparin or unfractionated heparin according to their renal status, their body weight, and the need for invasive procedures. this study was approved by the french institutional authority for personal data protection (commission nationale de l'informatique et des libertés no. dec - ) and the ethics committee (irb -a - ), and informed consent was obtained from all participants. hpmvec viability was assessed after coincubation with plasma sampled on admission from consecutive patients (non-icu, n= ; icu, n= ) hospitalized for circulation https://www.ahajournals.org/journal/circ correspondence covid- at the lille university hospital between march , , and april , , in convalescent patients with covid- (n= from the patients in the icu) sampled after icu discharge (mean±sd, ± days) and in control healthy donors (n= ). compared with healthy donor plasma, plasma from patients with covid- significantly decreased hpmvec viability, with plasma from patients in the icu inducing the greatest cytotoxicity (figure [a] ). it is interesting that hpmvec viability was partially restored to control when plasma from convalescent patients after icu discharge was tested and compared with plasma of the same patients at the time of icu admission. moreover, markers of organ dysfunction were correlated with plasma-induced cytotoxicity (figure [b] ). the cytotoxicity of platelet-poor plasma samples (obtained after a double centrifugation of citrate tubes at g for minutes at room temperature) from patients with covid- and controls on hpmvec was evaluated with a colorimetric assay using -[ -( -iodophenyl)- -( -nitrophenyl)- h- -tetrazolio]- . -benzene disulfonate (wst- ), which in viable cells is cleaved by mitochondrial dehydrogenases. after incubation, the cells were washed with phosphate buffered saline and incubated with wst- (roche, basel, switzerland) at a dilution of : ( µl) for h at °c. absorbance was measured using a multiwell plate reader (synergy htx multi-mode plate reader, biotek instruments, highland park, vt) at nm with a reference wavelength of nm. as a positive control for endothelial cell injury, shigatoxin (sigma-aldrich, saint quentin fallavier, france) was spiked in plasma from healthy adults ( µg/ml final concentration) and incubated at °c for minutes,before addition to hpmvecs. experiments were performed in triplicate for each patient sample. a, hpmvec viability after exposure to plasma sampled in healthy subjects (n= ), in non-icu november , correspondence hpmvec viability also correlated with most plasma markers related to endothelial damage or tissue injury ( figure [c] ). soluble il- receptor and tumor necrosis factor-α levels negatively correlated with hpmvec viability ( figure [d] ). overall, the degree of vascular endothelial cell injury induced by plasma sampled from patients with covid- correlated to both clinical illness severity at admission and the levels of biomarkers related to endothelial injury, tissue injury, and proinflammatory cytokines. our data shed new light on the pathophysiology of covid- by demonstrating the direct and rapid cytotoxic effect of plasma collected from critically ill patients on vascular endothelial cells. this rapid effect ( hour after plasma exposure) excludes a direct cytopathic effect of sars-cov- infection, as the progression of viral infection and visible cytopathogenic effects are in general only apparent to hours after infection. a higher cytotoxic effect of plasma on endothelial cells was associated with a more pronounced hypoxemia and organ dysfunction as reflected by the correlation with pao /fio , lactate dehydrogenase, creatinine, and aspartate transaminase. this cytotoxic effect also correlated with circulating markers of endothelial damage, indicating that this in vitro functional assay reflects microvascular endothelial damage in vivo. different pathways could be involved in endothelial cell injury during the course of covid- , ie, complement activation, cellular hypoxia, platelets, and direct cytotoxicity of cytokines such as il- , il- β, and tumor necrosis factor-α. we observed a relationship between this cytotoxic effect and the level of proinflammatory cytokines, suggesting that cytotoxicity could be related to overproduction of proinflammatory cytokines. however, this article does not provide the supportive evidence of convalescent plasma for treating severe patients with covid- . in conclusion, we provide for the first time the results of a functional assay demonstrating a direct effect of dysregulation of immune response on endothelial damage in covid- . endotheliopathy is an essential part of the pathological response on severe covid- , leading to respiratory failure, multiorgan dysfunction, and thrombosis. endothelial and microvascular damage are associated with immunopathology and may occur in parallel with intracellular sars-cov- infection. data sharing: the data that support the findings of this study are available from the corresponding author upon request. registration: url: https://www.clinicaltrials.gov; unique identifier: nct- . pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- extrapulmonary manifestations of covid- multiorgan and renal tropism of sars-cov- modified ham test for atypical hemolytic uremic syndrome proteomics of sars-cov- -infected host cells reveals therapy targets the authors thank all physicians and medical staff involved in patient care. special thanks are addressed to eric boulleaux, laureline bourgeois, aurélie jospin, catherine marichez, vincent dalibard, bénédicte pradines, sandrine vanderziepe, and all the biologists and technicians of the hemostasis department for their support during the covid- pandemic. a.r. and a. dupont collected clinical data, analyzed the data, and wrote the article. this study was supported by the french government through the program investissement d'avenir (i-site ulne/anr- -idex- ulne). none. key: cord- - csf z s authors: fernandez villalobos, n. v.; ott, j. j.; klett-tammen, c. j.; bockey, a.; vanella, p.; krause, g.; lange, b. title: quantification of the association between predisposing health conditions, demographic, and behavioural factors with hospitalisation, intensive care unit admission, and death from covid- : a systematic review and meta-analysis date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: csf z s background comprehensive evidence synthesis on the associations between comorbidities and behavioural factors with hospitalisation, intensive care unit (icu) admission, and death due to covid- is lacking leading to inconsistent national and international recommendations on who should be targeted for non-pharmaceutical interventions and vaccination strategies. methods we performed a systematic review and meta-analysis on studies and publicly available data to quantify the association between predisposing health conditions, demographics, and behavioural factors with hospitalisation, icu admission, and death from covid- . we provided ranges of reported and calculated effect estimates and pooled relative risks derived from a meta-analysis and meta-regression. results studies were included into qualitative and into quantitative synthesis, with study populations ranging from - , covid- cases. the risk of dying from covid- was significantly associated with cerebrovascular [pooled rr . ( % ci . - . )] and cardiovascular [rr . (ci . - . )] diseases, hypertension [rr . (ci . - . )], and renal disease [rr . (ci . - . )]. health care workers had lower risk for death and severe outcomes of disease (rr . (ci . - . ). our meta-regression showed a decrease of the effect of some comorbidities on severity of disease with higher median age of study populations. associations between comorbidities and hospitalisation and icu admission were less strong than for death. conclusions we obtained robust estimates on the magnitude of risk for covid- hospitalisation, icu admission, and death associated with comorbidities, demographic, and behavioural risk factors. we identified and confirmed population groups that are vulnerable and that require targeted prevention approaches. various factors have been identified to determine whether a higher risk of severe course of covid- disease and covid-related deaths exists. some of these identified factors are demographic in nature, such as age and sex, others have to do with having a diagnosed condition such as diabetes and hypertension ( - ). furthermore, behavioural and occupational risk factors have also been discussed ( ) ( ) ( ) ( ) . accordingly, during the pandemic, part of non-pharmaceutical interventions were aimed towards these corresponding population groups. for example, several affected countries worldwide have recommended to avoid visiting elderly relatives for recreational reasons ( ) . public health officials as well as national guidelines have been inconsistent and sometimes vague in defining exact target groups for health measures other than the elderly ( , ) . part of the reason for this is that many studies have reported some of these predisposing factors using incomparable data sources, indicators and calculations, and denominators. estimates are further challenged by the interrelation between factors such as age and comorbidities, which limits causal and relative attributions ( ) ( ) ( ) . several studies published have refrained from giving effect estimates for factors experienced by patients but have only described these data in the form of clinical case series ( ) ( ) ( ) . to inform national and international guidelines and policies on the actual impact of targeting different population groups with predisposing conditions or factors evidence synthesis is needed to quantify the risk of individual predisposing factors and conditions. this will inform both toward protection of potential risk groups, and on potential vaccination strategies in the case of not-optimal availability or efficacy of potential vaccination candidates. however, currently there is only fragmented evidence synthesis available on quantifiable information on the actual risk experienced by patients with these comorbidities for the most important outcomes. existing systematic reviews on that subject have been published either as pre-print or as peer reviewed publications to date ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . some of these focus on one association to a particular endpoint, e.g. cardiovascular morbidity and severity of course of disease ( ) ( ) ( ) . some assess several comorbidities as well ( , ) , but do not cover many studies yet. moreover, these do not investigate the interaction of age or do not account for those studies that do not report associations (this information is available in the supplement, table ). to our knowledge, no existing evidence synthesis provides comparative and exhaustive relative risk measures of the major predisposing conditions in most populations, using both data with and without reported relative risk measures, taking age structure of the respective study population into account. we conducted a meta-analysis on risk for covid-related hospitalisation, intensive care unit (icu) admission, and death and its association with comorbidities, behavioural factors, and death. we extracted and included crude study data to understand the magnitude of the effect of comorbidities and other factors on covid- health outcomes. by focussing on these outcomes, our objective was to generate evidence for prioritising health measures for vulnerable population groups. our results shall also establish baseline information to identify priority groups for covid- intervention strategies, e.g. vaccination. we performed a systematic review (registration number in prospero crd ), following prisma guidelines ( ) , in medline, biorxiv, and medrxiv, searching for publications on covid- and risk groups for severe or lethal disease outcomes (search terms "novel coronavirus", "covid- ", "sars-cov- "). we applied the snowball method to available systematic reviews to identify further evidence. the existing reviews are listed in the supplement, table . the literature search includes reports up to april . in addition to that search, we identified reports from other publicly available sources, namely national (public) health institutions, and data repositories, with a last search date of may . we included reports if: a) patients had covid- , either confirmed microbiologically or clinically (population); b) information on covid- outcome was reported as either death (hospital or after a defined follow-up time), icu admission (both icu and intermediate care), hospitalisation or aggravation of disease (clinical description) (outcome); and c) at least one comorbidity, risk factor or behavioural factor was described and if number of patients with/without outcome was reported according to the respective factor (exposure and comparison). eligible study designs were: cohort studies, cross-sectional studies, case series, and clinical trials. languages included were english, spanish, italian, french, or german. the data included from country-level reports focus on the seven countries with the highest officially reported absolute number of deaths due to covid- by april , according to numbers of the johns hopkins university ( ). we used data on age, sex, and comorbidities of reported cases. the outcomes were hospitalisations and death. we developed spreadsheets for crude data extraction. the template was developed and tested by the three extracting scientists (ck, nf, jo). we extracted relevant variables in the smallest reported unit and according to the main stratification variable, either comorbidity or behavioural risk factor, author and link, country, data source, age-range, study time-frame, baseline population group, outcome (mortality, severity, or other), number of individuals in the risk group, total sample, number of individuals among risk group with outcome, total number of individuals people with the outcome, and effect measures of association reported as well as relative risks computed automatically. the outcomes were severity/aggravation during the course of covid- disease in terms of hospitalisation/pneumonia, admission to icu, and death. "risk groups" were those with comorbidities, which we defined and grouped according to the international classification of diseases th revision (icd- ) (https://icd.who.int/browse /l-m/en). we extracted the five most common comorbidities or behavioural/occupational/demographic factors per included study. for data from research reports we did random plausibility checks and plotted relative risks with ranges. a researcher not involved in data extraction (ab) double-checked % of included studies and compared extracted numbers with original reports. for publicly available data we extracted data for all seven countries on: age of confirmed covid- cases, hospitalisations, icu admissions and deaths. for the us, spain, and france we additionally extracted mortality data, distinguished by comorbidities, which we used to estimate relative risk of death for cases, or in the case of france, for hospitalisations. we assessed risk of bias using an adapted version of the robins-i tool ( ) for nonrandomised studies. we analysed the studies in terms of bias due to confounding, selection of participants and follow-up, misclassification of exposure, missing data, measurement of outcome, or reporting. we measured the risk scales as low, moderate, and high. descriptive we display ranges of reported estimates of association [odds ratios (ors), hazard ratios (hrs), and relative risks (rrs)] for the health outcomes from included studies and calculate relative risks (rrs) for each risk group and for each outcome, based on crude and absolute data from the studies. strata of outcomes that reported "zero" were excluded from the analysis, as this gives an invalid statistical estimate of the underlying risks. for data from publicly available sources, we computed point estimates of the relative risks to severe health status, like hospitalisation or death; if possible, stratified by age groups and sex with % confidence intervals (cis). in addition, we estimated relative risks of death among three age groups and two sexes for cases in spain and hospitalised cases in france. we assessed heterogeneity visually in forest plots and by assessing the percentage of variance over studies i . due to the difference between populations and observed heterogeneity, we performed a random effects meta-analysis for pooled rrs. for those risk groups with considerable heterogeneity (> %), we performed subgroup analyses to investigate reasons for heterogeneity further according to the cochrane handbook for systematic reviews of interventions (https://training.cochrane.org/handbook/current). within meta-regression, we assessed effect modification by age on relative risks of included comorbidities or other risk factors. in order to include explanatory variables, we ran a series of mixed-effects meta-regressions to test the associations of case mortality of covid- with demographics and different comorbidities. we included of the studies presented in this paper ( , ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) that reported data on the variables of interest. our baseline modelling approach ( ) for this was: with being the ℎ moderator variable, being the homogeneity estimate among the studies and being an independent white noise process. the majority of studied individuals had comorbidities like cardiovascular disease, diabetes, or hypertension. we checked the correlation matrix among the variables median age, share of males, share of individuals with cardiovascular disease, share of individuals with diabetes, and share of individuals with hypertension. as correlations between cardiovascular disease and hypertension with diabetes were especially high, diabetes was ignored to avoid high multicollinearity among the regressors. to take collinearity between age and the comorbidities into account, we included interactions between the median age, the share of individuals with cardiovascular disease, and the share of individuals with hypertension in our full model. we iteratively omitted variables with lowest p-values and compared the models using the loglikelihoods, the corrected version of akaike's information criterion (aicc) and the bayesian information criterion (bic). model fit was performed in r using the rma.uni() command in the metafor package ( ). we identified a total of , records. we retrieved of them for full-text screening and studies met the inclusion criteria (supplement, figure ). all of them were used for our qualitative analysis, and for the quantitative analysis. the pre-print study "opensafely: factors associated with covid- -related hospital death in the linked electronic health records of million adult nhs patients" by williamson et al. was excluded because the actual number of confirmed covid- cases was not reported. the majority of reports (n= ) were from china, followed by the united states of america (usa, n= ). studies were based on medical or clinical records (n= ) or official reported data (n= ) and conducted between late december and april with follow-up of - days. endpoints were: hospitalisation/pneumonia (n= ), admission to icu (n= ), and death (n= ; mostly within days or in-hospital deaths). three studies had composite endpoints, three others reported multiple endpoints. the sample sizes were between and , confirmed covid- cases and individuals were aged between - years; and in seven studies children were included (supplement, table ). risk of bias assessment we assessed risk of bias due to a) confounding, b) selection, c) misclassification, d) missing data, and e) measurement of outcome. confounding was moderate in most studies as either adjusted estimates or age-information was provided. selection bias was mostly low to moderate as was misclassification. a high risk of bias was found for studies due to nonreporting or missing data. in several studies the source of data or definition of the outcome was unclear, and several reported results in selective subgroups. in general, studies had at all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august , . . https://doi.org/ . / . . . doi: medrxiv preprint least one moderate risk in terms of follow-up or adjusting for confounders and only few had overall low risk of bias in all categories (supplement, table ). reported and calculated associations fourteen studies reported odds ratios, nine studies reported hazards ratios, and one study reported relative risks for either one of the endpoints included. one study included cases reported from official data. we calculated rrs from crude study data for a) hospitalisation/pneumonia, b) admission to icu, and c) death (within days or within hospital) for all studies included in the quantitative analysis (table ) . three studies reported higher odds of being hospitalised due to covid- for patients with acute renal failure, cardiovascular disease, and diabetes [odds ratio . ( % ci . - . ); odds ratio . (ci . - . ); hazard ratio . (ci . - . ), respectively]. hypertension was reported as a factor that increased the odds of being hospitalised [odds ratio . (ci . - . ) - . (ci . - . ), hazard ratio . (ci . - . ), studies] (table ) . using crude data from all clinical case series that provided these numbers, we calculated that patients with acute renal failure, cerebrovascular disease, and copd had higher risk of hospitalisation [rr . ( % ci . (table ) . regarding the association of demographic, behavioural, and occupational factors and hospitalisation, four studies reported that male patients had higher odds and hazard of being hospitalised [or . ( %ci . - . ), hr . (ci . - . )], while two studies did not see evidence of association [or . (ci . - . ), hr . (ci . - . )] (table ) . using the crude data, we found that male patients [rr . ( % ci . - . (table ) . four studies reported on those patients that needed to be admitted at icu based on medical records. three studies reported cancer, diabetes, and hypertension as factors that increase the odds of being admitted at icu [or . ( % ci . - . ), hr . (ci . - . ), hr . (ci . - . ), respectively] (table ). using crude numbers of patients and events provided in studies, we calculated that patients with cancer [rr . ( % ci . - . ) - . (ci . - . ), studies] and copd [ . (ci . - . ) - . (ci . - . ), studies] had a high risk of being admitted at icu (table ) . regarding other risks, one study reported that male patients [or . ( %ci . - . )] had higher odds of being admitted at icu or having invasive mechanical ventilation (table ) . all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august , . studies] to be a risk factor for icu admission. other studies did not find associations between being male [ . (ci . - . ) - . (ci . - . ), studies] or smoking [ . (ci . - . ) - . (ci . - . ), studies] and icu admission (table ) . eight studies reported on patients deceased due to covid- , and one study included cases reported from official data (table ) (table ) . regarding demographic, behavioural, and occupational factors, two studies reported that male patients had higher odds of death [or . ( % ci . - . ), rr . (ci . - . )] (table ) . based on the calculated associations, we found that male patients [rr . ( % ci . - . (table ) . all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august , . . . - . ) ]. this study was not included in our meta-analysis as it did not provide absolute numbers of patients infected with covid- . we performed random-effects meta-analysis on the influence of comorbidities and other factors on three endpoints (hospitalisation, icu admission, and death) (figure ). to assess the influence of age on these associations we performed meta-regressions for those associations with more than studies available on the influence of age on these associations. we also performed a mixed-effects meta-regression on the main comorbidities adjusted for median/mean age and gender. the random-effects meta-analysis found patients with cardiovascular disease (rr . , % ci . - . ), cerebrovascular disease (rr . , % ci . - . ), and/or diabetes mellitus (rr . , . - . ) were at higher risk of hospitalisation. other comorbidities, including chronic renal disease, chronic respiratory disease, and copd, were correlated with higher hospitalisation rates as well. we found moderate to high heterogeneity for several of these risk factors (i - %) (figure .i.a.) . in pooled results from random effect meta-analysis obese individuals had . times the risk of being hospitalised compared to those without obesity (rr . , % ci . - . ). healthcare workers were less likely to be hospitalised (rr . , % ci . - . ), and males were % more likely to be hospitalised than females (rr . , % ci . - . ) (figure .i.b.) . the following comorbidities were associated with high risk for icu admission (figure .ii obesity and smoking moderately increased the risk to being admitted to icu (figure .ii.b.) . information on healthcare workers was insufficient to pool results. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august , . . https://doi.org/ . / . . . doi: medrxiv preprint the highest observed rr of death were found for cerebrovascular disease, cardiovascular disease, chronic renal disease, and hypertension (rr . %ci . - . ), ( . , ci . - . ), ( . , ci . - . ) , and ( . , ci . - . ), respectively (figure .iii.a.) . males had risk of death due to covid- . times that of females ( % ci . - . ), and healthcare professionals were at lower risk of death due to covid- , when compared to other population groups (rr . , ci . - . ) (figure .iii.b) . all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august , . . https://doi.org/ . / . . . doi: medrxiv preprint all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august , . the meta-regression revealed that the strength of the association between comorbidities and hospitalisation decreased with increased median or mean age of the study population [cardiovascular (beta-coefficient - . , %ci - . - . , p= . ) and diabetes (beta-coefficient - . , %ci - . -- . , p= . )], (figure .a). age was also modifying the association with diabetes; here, the rrs for icu admission decreased with increasing age (beta-coefficient - . , %ci - . -- . , p= . ) (figure .b). we did not find effect modification of age for other risk factors like gender, hypertension, or smoking. effect modification of mean/median age of population in study: a. modification of association between cardiovascular morbidity and hospitalisation, b. modification of age on the association of diabetes and icu admission risk. effect modification was found for the association of hypertension with dying from covid- with higher relative risks in those studies with lower median/mean ages (beta-coefficient - . , %ci - . -- . , p= . ). we did not find effect modification for diabetes or cardiovascular morbidity. in a meta-regression adjusted for gender and age ( table ) , results of model show the effect of age and comorbidities on mortality. the increase in mean mortality risk is more pronounced in older populations. for example, for a population with a median age of years, a %increase in prevalence of hypertension is associated with an increase in the overall mortality all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august , . . https://doi.org/ . / . . . doi: medrxiv preprint rate . % . for hypertension, this increase would result in a mortality rate of . % for a median age of years . ≈ ℎ * * Δℎ ≈ . * * . ≈ . * * . all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august , . . https://doi.org/ . / . . . doi: medrxiv preprint publicly available data we found publicly available data that allowed to assess the outcomes presented above for both effects of comorbidities and age for spain and france. based on this data, the rr varies by age and sex (table , a and b). individuals aged + years were at higher risk of death and hospitalisation than younger individuals (table , a) . for example, as of may in spain a - year-old male case of covid- had an estimated risk of dying . ( % ci . - . ) times that of a male below years of age. in terms of sex, men were at higher risk of dying or witnessing a severe course of the infection than women do (table , b) . for instance, in italy a male aged years or younger was estimated to have a . ( % ci . - . ) higher average risk of death after infection than a woman at the same age does. regarding comorbidities (table , c), the rr of diabetes ranged between . ( % ci . - . ) and . (ci . - . ). in terms of cardiac and cardiovascular disease, the rr of death was . (ci . - . )- . (ci . - . ). for pulmonary and respiratory disease, the risk of death were . (ci . - . ) - . (ci . - . ). all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august , . . results of our meta-analysis add to existing rather limited systematic reviews and metaanalyses ( , ( ) ( ) ( ) ( ) by providing a more comprehensive analysis of the magnitude of risk associated with both comorbidities and further risk factors to hospitalisation, icu admission, and death. we believe that the results have public health implications in four main fields. ( ). in addition to that, it has been documented that the angiotensin-converting enzyme (ace ) has a vital role in the cardiovascular and immune systems, and it is involved in the heart function and the development of hypertension and diabetes mellitus ( ) . moreover, zheng et al. considered that a disease severity in patients with cardiovascular disease can be associated with increased secretion of ace ( ) . there is evidence that hypertensive patients may experience a decreased expression of ace , and consequently, an elevation of the angiotensin ii levels that generates a severe manifestation of the disease ( ). the same protein and its poor regulation may also explain the link between copd and smoking in terms of covid severity and mortality ( , ) . additionally, exacerbations in copd cases are triggered by viral infections and environmental conditions ( ) . for diabetes, the increased rr is explainable by reduced pulmonary function and a thickening of the pulmonary basal lamina ( , ). other than for comorbidities, factors like sex determine the covid risk and women might be protected by hormonal factors ( ) . second, our analysis shows that association of these comorbidities with hospitalisation and icu admission are generally less strong for these same comorbidities and other risk factors and death. this also corresponds to public data from europe, where the proportion of infected people of older age or of other risk groups is relevantly higher in those who died compared to those who were hospitalised. in spain, for people infected and older than years old, regarding sex, the risk of dying was higher than the risk of hospitalisation [rr . ( % ci . other studies have also found that for patients with cerebrovascular disease and with diabetes the risk increase of icu admission was lower than the risk of dying compared to other population groups ( , ) . this finding is important in that implies that public health measures to protect healthcare surge capacities should not be equalled with measures to protect the vulnerable from death in the fight against covid- . even if -hypothetically -fully protecting all people vulnerable from death, the effect on healthcare surge capacities of these same measure, measured by hospital beds, critical care beds, healthcare workers, and healthcare expenditure ( ), will not be equally effective. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august , . . https://doi.org/ . / . . . doi: medrxiv preprint third, we provide evidence for previously discussed risk factors of covid- severity. similarly to others ( , ) , we observed low strength of association for obesity, and smoking. interestingly, our meta-analyses showed less risk of severe outcomes of covid- for healthcare professionals. this might be explained by a lower likelihood for underreporting in this population group but also by the healthy worker effect ( ) . therefore, comparative studies on this occupational group are needed. fourth, we confirm the results of previous meta-regressions on the effect of age on covid- outcomes and comorbidities ( ) . for several comorbidities (cardiovascular disease, hypertension, and diabetes) we showed weaker associations with deaths among study participants which were part of studies with a higher median age of patients. this implies that differentiation by specific predisposing conditions might be particularly effective in the lower age groups. this is also applicable as older patients suffer from multiple and coexisting medical conditions, reducing standalone effects of single conditions ( , , ) . the limitations of our work derive from the restricted search, which was a rapid approach in one main data base of medical literature. with this review type, we sought for contextualised evidence to inform decision makers in terms of vulnerable population groups. moreover, we did not include articles in chinese language into our search due to lack of interpreters, and that could have affected our included studies and findings. the nature of the included data were often based on hospital recording implying bias in a sense that more severely symptomatic patients are more likely included. although our assessment revealed high to moderate study quality, studies based on hospital records are highly selective regarding the population included. regarding our analyses, we did not consider age groups separately due to wide ranges and inconsistencies in reporting from the studies, which would have implied major assumptions for our meta-analyses. however, we approached this by assessing effect modification of age on different comorbidities and found effect modification for several comorbidities. the meta-analyses we conducted is univariate, and we did not adjust for comorbidities that appear in parallel. generalisability and country-comparisons of results from publicly available data are limited by different data sources used. also, our effect estimates for some countries only investigate subgroup of hospitalised cases (e.g. france), which may lead to a systematic underestimation of the effect estimates, since these individuals likely have an increased risk of severity. however the qualitative implications of our estimates seem to be robust across different geographic regions as well as different data sources. in conclusion, we provide evidence synthesis for the exact magnitudes of effects of comorbidities on severity of disease in covid- to help target public health measures more towards individual population groups at risk. most importantly, we show that the mortality risk from covid- is associated with the most prevalent existing comorbidities, such as cerebrovascular and cardiovascular diseases, hypertension, and renal disease and that there is a decrease of the effect of comorbidities on severity of disease with increasing age for some comorbidities, and that there is a generally higher strength of association in these comorbidities for death than for other severe course of disease. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august , . . https://doi.org/ . / . . . doi: medrxiv preprint clinical characteristics and outcomes of patients with severe covid- with diabetes clinical characteristics of patients with corona virus disease (covid- epidemiological and clinical features of hospitalized patients with covid- in clinical characteristics of cases of corona virus disease (covid- ) in changsha risk factors for severity and mortality in adult covid- inpatients in wuhan covid- in cardiac arrest and infection risk to rescuers: a systematic review the impact of copd and smoking history on the severity of covid- : a systemic review and meta-analysis risk factors of critical & mortal covid- cases: a systematic literature review and meta-analysis characteristics of emergency department patients with covid- at a single site in northern california: clinical observations and public health implications who regional office for europe. statement -older people are at highest risk from covid- , but all must act to prevent community spread european centre for disease prevention and control. rapid risk assessment: coronavirus disease (covid- ) in the eu/eea and the uk -eighth update people who are at higher risk for severe illness ageing and the epidemiology of multimorbidity change in comorbidity prevalence with advancing age among persons with heart failure the changing prevalence of comorbidity across the age spectrum clinical characteristics of noncritically ill patients with novel coronavirus infection (covid- ) in a fangcang hospital clinical characteristics of coronavirus disease in china clinical characteristics of deceased patients with coronavirus disease : retrospective study diabetic patients with covid- infection are at higher risk of icu admission and poor short-term outcome cardiac injury is associated with mortality and critically ill pneumonia in covid- : a meta-analysis the impact of novel coronavirus on heart injury: a systemic review and meta-analysis. prog cardiovasc dis diabetes mellitus is associated with increased mortality and severity of disease in covid- pneumonia -a systematic review, meta-analysis, and meta-regression prevalence and severity of corona virus disease (covid- ): a systematic review and meta-analysis arterial hypertension and risk of death in patients with covid- infection: systematic review and metaanalysis cerebrovascular disease is associated with an increased disease severity in patients with coronavirus disease (covid- ): a pooled analysis of published literature prevalence and impact of cardiovascular metabolic diseases on covid- in china preferred reporting items for systematic reviews and meta-analyses: the prisma statement robins-i: a tool for assessing risk of bias in non-randomized studies of interventions clinical features and short-term outcomes of patients with corona virus disease clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study low-density lipoprotein is a potential predictor of poor prognosis in patients with coronavirus disease clinical and transmission characteristics of covid- -a retrospective study of cases from a single thoracic surgery department epidemiological characteristics of coronavirus disease (covid- ) patients in iran: a single center study novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- ) -china, . china cdc wkly clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan coronavirus disease in elderly patients: characteristics and prognostic factors based on -week follow-up clinical course and outcomes of intensive care patients with covid- retrospective study of risk factors for severe sars-cov- infections in hospitalized adult patients. pol arch intern med conducting meta-analyses in r with the metafor package cdc. provisional covid- death counts by sex, age, and state informe sobre la situación de covid- en españa covid- : point épidémiologique hebdomaire du mai the weekly surveillance report in england. coronavirus covid- belgium epidemiological situation lagebericht des rki zur coronavirus-krankheit- (covid- ) clinical determinants for fatality of , patients with covid- does comorbidity increase the risk of patients with covid- : evidence from meta-analysis prevalence of underlying diseases in hospitalized patients with covid- : a systematic review and meta-analysis. arch acad emerg med the many faces of the anti-covid immune response ace : from vasopeptidase to sars virus receptor covid- and the cardiovascular system hypertension and its severity or mortality in coronavirus disease (covid- ): a pooled analysis ace- expression in the small airway epithelia of smokers and copd patients: implications for covid- cellular and structural bases of chronic obstructive pulmonary disease diabetes mellitus induces a thickening of the pulmonary basal lamina. respiration [internet impact of cerebrovascular and cardiovascular diseases on mortality and severity of covid- -systematic review, meta-analysis, and meta-regression indications for healthcare surge capacity in european countries facing an exponential increase in coronavirus disease (covid- ) cases standardized mortality ratios and the "healthy worker effect": scratching beneath the surface analysis of epidemiological and clinical features in older patients with coronavirus disease (covid- ) outside wuhan clinical impact of covid- on patients with cancer (ccc ): a cohort study key: cord- - b qfo authors: soriano, maría cruz; vaquero, concepción; ortiz-fernández, almudena; caballero, alvaro; blandino-ortiz, aaron; pablo, raúl de title: low incidence of co-infection, but high incidence of icu-acquired infections in critically ill patients with covid- date: - - journal: j infect doi: . /j.jinf. . . sha: doc_id: cord_uid: b qfo nan lansbury et al. recently reported in this journal that % of hospitalized covid- patients had a bacterial co-infection. this proportion increased to % in studies that only included patients who required admission to the intensive care unit (icu) . icu admission is a risk factor for hospital-acquired infections and nosocomial infections by multidrug-resistant (mdr) bacteria , . here, we report our findings of a retrospective cohort study to asses the incidence of co-infections, icu-acquired infections and their relation to mortality in patients with covid- . we retrospectively include all consecutive patients who were admitted to the intensive care department at hospital universitario ramón y cajal in madrid (spain), with the primary diagnosis of sars-cov- between march th and june th, . madrid was one of the pandemic epicenter cities in europe. all patients had a diagnosis of covid- confirmed by sars-cov- viral rna polymerase-chain-reaction (pcr) test from nasopharyngeal swabs or lower respiratory tract aspirates as well. we excluded patients in whom no positive pcr was detected despite the clinical diagnosis of covid- and patients with less than hours of admission at the icu admissions of less than h. clinical data were collected from institutional healthcare clinical database record and managed using redcap  (research electronic data capture) tool hosted at irycis (instituto ramón y cajal de investigación sanitaria). frequency measurements have been calculated using the incidence rates of each icu-acquired infections expressed in relation to the number of patients at risk or the number of days at risk. data were expressed as mean ± standard deviation (s.d) or percentages as appropriate. since most variables did not always fulfill the normality hypothesis, we compared continuous data by the mann-whitney u test and categorical data by chisquare or fisher's exact test as appropriate. study protocol was approved by the institutional ethics and clinical research committee. a total of patients were enrolled. clinical characteristics of critically ill patients are shown in table . overall mortality in the icu was . %. community-based bacteria and viruses were screened at hospital admission in . % ( / ) of patients. in our series, the incidence of bacterial coinfection at admission was only . % and no patient was diagnosed at admission with any other virus than sars-cov- . isolated bacteria were: s. pneumoniae n= , legionella pneumophila n= , pseudomonas aeruginosa n= , klebsiella oxytoca n= and methicilin-sensitive s. aureus n= . a low prevalence of bacterial co-infection might be underestimated having regard to the high proportion of patients who received empiric antibiotic therapy, such as azithromycin because its antiviral properties. these data are in agree lansbury et al. and with others reports , these findings support stopping empirical antibiotics in the vast majority of patients when covid- infection is confirmed. however, it is important to remark that mortality in the subgroup of patients with co-infection was very high, with a mortality rate of . % versus . % in patient without co-infection (p = . ). therefore, it is essential to suspect and look for the presence of bacterial co-infection to establish appropriate antibiotic therapy as soon as possible. conversely, the incidence of icu-acquired infection was as high as . % ( / ). in patients undergoing mechanical ventilation for more than days ( . %), microbiological surveillance samples were obtained during their icu stay. table shows incidence rate of icu-acquired infection. the respiratory tract was the most common site of infection, accounting for . %, followed by bloodstream ( . %), urinary tract infection ( . %), soft-tissue ( . %) and abdominal focus . %. icu mortality was significantly different for patients with or without icu-acquired infection ( / , . % versus / , . %; p= . ), respectively. there's controversy regarding to nosocomial infection and its relationship with mortality due to several confounding factors that converge in patients admitted to icu. in large european epidemiological studies of critically ill patients such as the epic ii study, among , patients, % were considered infected, the icu mortality rate of infected patients was more than twice than in non-infected patients . there is a lack of evidence related to superinfections acquired during covid- in patients who require hospitalization. a study conducted in wuhan, china shows a series of hospitalized covid- patients in whom the presence of secondary infection during hospital admission was one of the risk factors for increased mortality . a recent study found that frequency of hospital-acquired superinfections remained low and this finding was mainly related with icu admission . to the best of our knowledge, there are no previous data on the influence of nosocomial infection in the icu and its relationship with mortality. in conclusion, our results reveal that co-infections in patients diagnosed with covid- admitted to the icu is uncommon; however, the incidence of icu-acquired infections very high. when one of both types of infections comes out, this is associated with worse outcomes including higher mortality. assessment of necessary diagnostic workup could assist clinicians in decision-making to optimize antibiotic therapy in critically ill patients with covid- . co-infections in people with covid- : a systematic review and meta-analysis international study of the prevalence and outcomes of infection in intensive care units risk factors for multidrug-resistant gram-negative bacteria infection in intensive care units: a meta-analysis epidemiological and clinical characteristics of cases of china: a descriptive study clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china incidence of co-infections and superinfections in hospitalised patients with covid- : a retrospective cohort study key: cord- - vsvcza authors: jackson, craig t.; checchia, paul a. title: the ties that bind: a coronavirus disease journey date: - - journal: crit care explor doi: . /cce. sha: doc_id: cord_uid: vsvcza nan r elationships define our journey. the friendships that weave through each life draw depth and meaning from each shared experience. our current global circumstance, the coronavirus disease (covid- ) pandemic, has renewed some of these relationships, under frequently tragic circumstances. as covid- unexpectedly renewed our own friendship, it crystallized the stark realities of a patient experience for a seasoned physician. our friendship was forged during the shared toil of our undergraduate years. through academic rigor, fraternity life, and the postgraduate struggles of everyday life, we bonded as we lived our stories and overcame challenges. after graduation, we went our separate ways: one to software sales and one to medicine. we could not know that our paths would cross again when facing a common challenge. we certainly could not know that we would face that challenge in complementary roles-as patient and as critical care physician. the reconnection was catalyzed by the global health emergency. like so many other friends from distant pasts, we reconnected on social media, sharing advice and personal experiences during the current pandemic. critical care specialists have leveraged their knowledge and experience to help the public interpret data and extrapolate scientific reports into meaning and action in homes and communities worldwide. however, this advice exchanged over social media, whereas, gratefully received, it is necessarily general in nature and in audience. neither of us anticipated acting on the advice at an individual level. our personal-now-medical connection after one of us was exposed to a presymptomatic sibling during a parent's passing. a mother's death, even though not consequent to covid, increasingly serves as a common source for community spread. in a well-meaning attempt to maximize comfort for family members, mask-wearing requirements were briefly relaxed to fulfill the last wish of a dying parent to see the faces of her children once more. the virus found two new hosts. a higher risk older brother followed a somewhat benign course. the other, one of the authors of this report, had a vastly different experience: his infection led to shock, hyperinflammation, and prolonged ventilation. and yet, he was lucky-the severity of his illness also brought the other author back to him to face this challenge together. some describe covid critical care management as creating a "delirium factory. " although the critical care community is changing practice to improve outcomes ( - ), our shared experience of covid delirium-one as patient and the other as physicianfriend-offered a powerful lesson for both of us. the unfiltered delirium experience expressed between the trusted friends provided a rare perspective. for example, the unfettered sharing of a few, hazy "memories" of receptions on cruise ships with artists and the recently deceased mother came in states of half-consciousness. likewise, imparting strange images of care in the back of a muffler shop caused genuine fear while imagining an entire industry using every available resource to deal with healthcare overflow. there was even a period of enough cognition to "dream" that a fellow patient suffered a cardiac arrest, leading to attempts at selfharm through breath-holding to grasp at some semblance of selfdetermination. the genuine vulnerability in these conversations between the friends led to a deeper understanding of the delirium experience for both patient and physician. we learned from each other that providers can most easily affect the process of weaning sedation and "waking up" through simple attention. we saw that, as a patient, the confusion of total unknown-not even knowing why, or even if, the ventilator was functioning-raised doubt about the hope of survival. we brainstormed some simple, straightforward solutions to a few of those unknowns: a visible board with the name of each patient, their date of birth, a short explanation of history, goals for the day, and projected extubation day. we found this simple, yet consistent practice could positively influence sedated patients. we concluded that such an explanation of goals and milestones could at least alleviate the aforementioned self-extubation, easing its motivating discomfort, impatience, and the desire for control. we recognized that this overwhelming desire for control in the face of terrifying uncertainty represents an opportunity for teams to improve patient-centered care in our icu-and perhaps in every icu. each patient's ties to the outside serve as reminders of the importance of team-the care team and the patient's own team of partner, friends, and family-during the critical care journey. in an environment that forces isolation as a necessary protective strategy, we as a care community can create contact in different ways. partners isolated away from the bedside-in the waiting room or miles away-not only need information but also can actively provide an underutilized resource. in our case, text messages and phone calls from care providers to partner were rapidly interpreted, synthesized, and shared across a wide personal network. this became a method of self-control and engagement for those tied to the journey from outside the icu walls. thus, a partner can become a "project manager" to help share in the patient experience. as friends on a covid journey, we shared our appreciation of icu care as a team sport. through competency, compassion, diligence, and collaboration, icu teams can reimagine care partnerships to find what individual care-partner interactions will motivate best. as these partners-in-care, a relationship develops akin to coach and athlete. this pandemic illuminates the need to leverage that partner relationship in innovative ways, especially in the face of staffing limitations. this pandemic is transforming medicine. novel therapies, care approaches, and scientific discoveries have already made an impact on the trajectory of severe illness with severe acute respiratory syndrome coronavirus . for the patient, the encounter with this disease is an individual, unique, and deeply personal experienceone which can be deeply isolating. beyond each still-startling picture of masked caregivers, wearing personal protective equipment behind a linen or glass curtain lies a patient suddenly sentenced to solitary confinement. by capitalizing each patient's network of connections, the overwhelming solitude that invites delirium can be overcome. we are reminded-no matter our individual role on the covid journey-of the ties that bind us together. covid- : icu delirium management during sars-cov- pandemic covid- : what do we need to know about icu delirium during the sars-cov- pandemic? strategies to optimize icu liberation (a to f) bundle performance in critically ill adults with coronavirus disease the authors have disclosed that they do not have any potential conflicts of interest.for information regarding this article, e-mail: checchia@bcm.edu key: cord- -jtj v r authors: alharthy, abdulrahman; faqihi, fahad; abuhamdah, mohamed; noor, alfateh; naseem, nasir; balhamar, abdullah; al saud, ahad alhassan al saud bin abdulaziz; brindley, peter g.; memish, ziad a.; karakitsos, dimitrios; blaivas, michael title: prospective longitudinal evaluation of point‐of‐care lung ultrasound in critically ill patients with severe covid‐ pneumonia date: - - journal: j ultrasound med doi: . /jum. sha: doc_id: cord_uid: jtj v r objectives: to perform a prospective longitudinal analysis of lung ultrasound findings in critically ill patients with coronavirus disease (covid‐ ). methods: eighty‐nine intensive care unit (icu) patients with confirmed covid‐ were prospectively enrolled and tracked. point‐of‐care ultrasound (pocus) examinations were performed with phased array, convex, and linear transducers using portable machines. the thorax was scanned in lung areas: anterior, lateral, and posterior (superior/inferior) bilaterally. lower limbs were scanned for deep venous thrombosis and chest computed tomographic angiography was performed to exclude suspected pulmonary embolism (pe). follow‐up pocus was performed weekly and before hospital discharge. results: patients were predominantly male ( . %), with a median age of years. the median duration of mechanical ventilation was (interquartile range, – ) days; the icu length of stay was (interquartile range, . – . ) days; and the ‐day mortality rate was . %. on icu admission, pocus detected bilateral irregular pleural lines ( . %) with accompanying confluent and separate b‐lines ( %), variable consolidations ( . %), and pleural and cardiac effusions ( . % and . %, respectively). these findings appeared to signify a late stage of covid‐ pneumonia. deep venous thrombosis was identified in . % of patients, whereas chest computed tomographic angiography confirmed pe in . % of patients. five to six weeks after icu admission, follow‐up pocus examinations detected significantly lower rates (p < . ) of lung abnormalities in survivors. conclusions: point‐of‐care ultrasound depicted b‐lines, pleural line irregularities, and variable consolidations. lung ultrasound findings were significantly decreased by icu discharge, suggesting persistent but slow resolution of at least some covid‐ lung lesions. although pocus identified deep venous thrombosis in less than % of patients at the bedside, nearly one‐fourth of all patients were found to have computed tomography–proven pe. europe. [ ] [ ] [ ] [ ] [ ] [ ] lung us was suggested to be particularly useful during the covid- pandemic because of its ability to identify subtle lung parenchymal changes early in the course of disease, monitor the evolution of pulmonary lesions in hospitalized patients, and guide mechanical ventilation therapy in critically ill patients with acute respiratory failure and acute respiratory distress syndrome. [ ] [ ] [ ] [ ] although the role of traditional portable chest radiography, especially in this era of crisis and resource limitations, cannot be unheeded, lung us could represent a flexible diagnostic solution in covid- pneumonia. , unlike lung us, some reports indicate the sensitivity of chest radiography for covid- pneumonia to be as slow at %. lung us is a portable bedside imaging tool, which has been previously used in the diagnosis and monitoring of acute respiratory distress syndrome in the intensive care unit (icu). [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] chest computed tomography (ct) rapidly became the mainstream imaging method in the diagnosis and monitoring of covid- pneumonia by identifying the typical pattern of ground glass opacities with variable infiltrates and consolidations, while showing a high correlation with laboratory detection of the virus by real-time polymerase chain reaction (rt-pcr) assays. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] compared to ct, point-ofcare ultrasound (pocus) still has limited evidence supporting its diagnostic utility in covid- but could be helpful with proper expertise. since most lung parenchymal lesions in covid- are distributed peripherally, these lesions should theoretically be detected by pocus. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] hence, in this study, the primary end point was to analyze the lung us findings in critically ill patients with severe covid- pneumonia or admission to the icu longitudinally throughout their disease course. we prospectively enrolled consented patients with confirmed covid- pneumonia admitted to a polyvalent icu (king saud medical city) throughout may . inclusion criteria were age older than years, icu admission, and serious covid- pneumonia. the latter was defined as acute respiratory failure: dyspnea, a respiratory rate of breaths per minute or higher, blood oxygen saturation of % or less, a partial arterial pressure of oxygen-tofractional inspired concentration of oxygen ratio of less than , development of bilateral pulmonary infiltrates within to hours, or a combination thereof. [ ] [ ] [ ] [ ] [ ] [ ] severe acute respiratory syndrome coronavirus (sars-cov- ) infection was determined by rt-pcr assays on throat swab samples using a quantinova probe rt-pcr kit (qiagen, hilden, germany) in a light-cycler real-time pcr system (roche, basel, switzerland). [ ] [ ] [ ] [ ] [ ] [ ] [ ] exclusion criteria were patients with covid- who did not undergo a pocus examination (reasons included unavailability of operators on the patient's admission and transfer to other covid- -targeted hospitals per the saudi ministry of health surge plan) and consecutive negative rt-pcr test results for sars-cov- taken at least hours apart. the study was conducted according to the principles of the declaration of helsinki and approved by our institutional review board. written informed consent was obtained from patients or their legal representatives. on icu admission, a pocus examination was performed with phased array ( - -mhz), convex ( - -mhz), and linear ( - -mhz) transducers connected to portable us machines assigned exclusively to the study of patients with covid- , (figure ). the us examination was performed by a single operator with the assistance of a single icu nurse. both entered the icu isolation room wearing personal protective equipment adhering to preventive infection control measures for respiratory, droplet, and contact isolation in covid- as detailed elsewhere. [ ] [ ] [ ] all transducers were placed inside sterile sheaths, and us machines were dressed in sterile covers to perform each examination. at the end of the examination, machines and transducers were sterilized in a designated isolation room and were placed into new sterile covers. [ ] [ ] [ ] the thorax was scanned in lung areas in total: anterior-superior and anterior-inferior, lateral-superior and lateral-inferior, and posterior-superior and posterior-inferior bilaterally. [ ] [ ] [ ] [ ] [ ] [ ] , , ultrasound examinations targeted detection of b-lines, lung consolidations, and pleural line abnormalities in each lung ( figure ). [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] due to the high risk of thromboembolic disease in icu patients with covid- , during the pocus session, a vascular us examination of the lower limbs was performed in search of potential deep venous thrombosis (dvt). , , per hospital policy and regardless of pocus results, all patients with covid- who had a high suspicion of pulmonary embolism (pe; ie, elevated d-dimer levels or refractory hypoxia for > hours) underwent chest computed tomographic angiography (ccta) to exclude pe. [ ] [ ] [ ] [ ] [ ] [ ] [ ] the incidence of acute kidney injury, as defined per the "risk," "injury," and "failure" criteria, and the prevalence of comorbidities were documented. data regarding invasive mechanical ventilation and oxygen therapy by means of a high-flow nasal cannula (hfnc), which has shown promise in the management of serious covid- pneumonia, were tracked. outcome measures such as the duration of mechanical ventilation, icu length of stay, and raw (not adjusted for disease severity) mortality on day after icu admission were recorded. follow-up pocus examinations were performed weekly in all patients and once before hospital discharge in survivors. all pocus examinations were performed by experienced operators. point-of-care us images were electronically stored and analyzed. medical records were used to obtain demographic, clinical, and laboratory data for enrolled patients with covid- . continuous variables were expressed as medians with interquartile ranges (iqr). categorical variables were expressed as proportions. a power analysis suggested that a minimum sample size of patients would be required with a significance level of % to achieve power of %. the fisher exact test was used to compare differences between proportions. a -tailed significance level of . was regarded statistically significant. all data were stored on a spreadsheet (excel ; microsoft corporation, redmond, wa), and analyses were performed with a commercially available statistical package (spss version ; ibm corporation, armonk, ny). one hundred consecutive patients with covid- were admitted to the icu during the study period. eleven patients were excluded from study enrolment because of transfer to other covid- centers according to the saudi ministry of health surge plan. eighty-nine consented patients with covid- were finally enrolled. all patients had portable chest radiography, which was performed in the emergency department. ten of patients ( . %) had admission chest ct scans. all recruited patients underwent pocus examinations on study enrollment. table summarizes main baseline parameters and outcome measures of the study population. most of the patients with covid- were male ( . %) with a median age of (iqr, . - . ) years. table summarizes patient symptoms and comorbidities before hospital admission. the most common symptoms were cough ( %), fever ( . %), and dyspnea ( . %). on icu admission, . % of patients were intubated, and . % were receiving oxygen via an hfnc with median flow of l/min and a median fraction of inspired oxygen of %. however, after hours, all patients were intubated and mechanically ventilated. a high admission sequential organ function assessment score was documented ( . [iqr, . - . ]). venovenous extracorporeal membrane oxygenation was attempted in cases ( . %), of which patients died. all patients received acute respiratory distress syndrome net ventilation, prone positioning, lung recruitment, and empiric therapy for covid- with lopinavir/ritonavir, ribavirin, and interferon β b for days, dexamethasone for days, prophylactic anticoagulation, and icu supportive care per current recommendations for the treatment of severe covid- pneumonia. , , computed tomography, laboratory results, and illness severity twenty-five patients were screened for pe by ccta within the first hours of icu admission because of resistant hypoxemia. twenty-two of ( . %) patients were found to have positive results for pe by ccta (table ). acute kidney injury was documented in cases ( . %), of which received continuous renal replacement therapy, as they had anuria, values are medians (iqrs) where applicable. pao /fio ratio indicates partial arterial pressure of oxygen-to-fractional inspired concentration of oxygen ratio; sofa, sequential organ function assessment; and vv-ecmo, venovenous extracorporeal membrane oxygenation. table . on icu admission, all patients with covid- had an abnormal aeration pattern (b-lines). in most cases, coexistent confluent and separated b-lines were documented ( figure ). bilateral involvement and pleural line irregularities in more than lung areas were evident in most cases (table ) . however, the right lung ( %) was more frequently affected compared to the left lung ( . %). confluent b-lines originating from regular pleural lines, previously characterized as "beam line" or "waterfall" (figure ) artifacts and suggested to represent an early stage of actively spreading covid- pneumonia alternating with areas of normal lung parenchyma, were observed only in a minority of cases ( . %). , of note, the aforementioned sign was best visualized with the convex transducer because of its large scanning surface and low frequency (figure ). in contrast, confluent and separate b-lines originating from irregular pleural lines were evident in most cases ( . %), which may reflect a late stage of covid- pneumonia. variable consolidations, which were mainly identified in the posterior lung areas, were recorded (table ) . a "starry sky" pattern of consolidation (bright infiltrates) was evident in most cases ( . %; figures and ). less-prevalent consolidation patterns were subpleural consolidations ( . %) and lung parenchymal hepatization pattern ( . %). pleural and pericardial effusions were observed less frequently (table ) . small pneumothoraxes were detected by lung us in the first week of hospitalization in cases ( . %), although the median positive end-expiratory pressure used in this study was relatively low: (iqr, [ ] [ ] [ ] [ ] [ ] cm h o (figure ). on icu admission, dvt was detected in . % of cases compared to the confirmed rate of pe ( figure ) by ccta ( . %) in this study. the follow-up pocus examinations in the upcoming weeks (weeks - ) showed an initial increase of the incidence of lung us findings in weeks to , followed by a gradual decrease of these finding in weeks and after icu admission (table ). ten patients died in the first week, in the second week, in the third week, and in the fourth week of hospitalization. the survivors were examined again before hospital discharge, approximately (iqr, [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days after icu admission. at that time, lung abnormalities were still present (tables and ). however, the incidence of lung abnormalities on hospital discharge was significantly lower (p < . , -tailed fisher exact test) compared to baseline findings (table ). due to the sudden and rapid onset of the covid- pandemic with its disruptive effect on medical systems, prospective data regarding pocus use on critically ill patients has been slow to emerge. our study provides additional important data on the utility of pocus in the population of critically ill patients with covid- . we found that pocus effectively detected lung abnormalities such as b-lines, pleural line abnormalities, variable consolidations, and pleural effusions. additionally, our standardized pocus percentages were derived from the total numbers of patients examined at each point in time on admission, during follow-up, and on discharge. ten patients died in the first week, in the second week, in the third week, and in the fourth week of hospitalization. the total number of survivors who were examined in the fifth to sixth weeks before hospital discharge was . approach identified other critical conditions such as pericardial effusions and dvt in critically ill patients with covid- . early depictions of covid- lung us findings have suggested that the extent of lung involvement and typical appearances of patient lungs differ from one patient population to another. descriptions of lung us findings on emergency department presentation, including scattered areas of pleural involvement adjacent to normal lung, are less common among patients seen by icu providers and represent an earlier stage of covid- development. in our study, lung us examinations, performed on icu admission, identified bilateral lung abnormalities mainly in the posterior lung areas for most of the patients studied. [ ] [ ] [ ] [ ] [ ] [ ] in most of our patients, severe covid- pneumonia had already evolved, as their clinical picture and lung us findings suggested (figure ). the beam line artifact (integrating a pattern of regular pleural lines with accompanying confluent blines), which has been reported in publications focused on patient populations with early stages of active covid- pneumonia, was noted only in a minority of our cases, again supporting a steady progression of us findings as disease severity progresses. [ ] [ ] [ ] [ ] [ ] [ ] , our patient group showed rather extensive lung parenchymal involvement on pocus examinations on icu admission (table ) . depicting the natural course of the disease process in the icu population with lung us is an important task. our weekly follow-up scans of all patients showed that an increasing number of lung abnormalities were observed in weeks and after icu admission ( figure ) . a gradual improvement of the lung parenchymal abnormalities was then observed in weeks and after icu admission and before hospital discharge in survivors (> days after icu admission). these findings were consistent with a previous study, which used a similar but less-detailed lung us scanning protocol. we have documented pleural line irregularities (in > lung areas) with accompanying b-lines in most our patients ( figure ). - additionally, we found several consolidation patterns. the most prevalent one (starry sky pattern: bright infiltrates) could be a reflection of the severe lung parenchymal inflammation of covid- pneumonia (figure ) , which is also visualized on chest ct as ground glass opacities and infiltrates and was mainly distributed in peripheral and posterior lung zones. notably, on icu admission, clinical and laboratory data showed a high sequential organ function assessment admission score, as well as lymphocytopenia, with elevated levels of c-reactive protein, lactate dehydrogenase, d-dimers, and ferritin, which are predictors of severe covid- pneumonia, a cytokine storm, and death. [ ] [ ] [ ] [ ] [ ] [ ] our findings regarding the icu length of stay, days receiving mechanical ventilation, and the raw -day mortality were comparable to the published literature. [ ] [ ] [ ] , of particular interest was the low rate of dvt identified as part of our pocus evaluation: just . %. this was in contrast to ccta-confirmed pe in nearly one-fourth of our study population, at . %. these rates were much lower compared to findings reported by a previous study. the difference may be partially attributed to the fact that all of our patients received aggressive prophylactic anticoagulation per hospital policy. furthermore, we speculate that in covid- , pe may be due to predominantly local growth of microthrombi within the lung vasculature, which may not necessarily be linked to dvt formation and could be another reason for our findings related to dvt and pe frequencies. [ ] [ ] [ ] [ ] [ ] [ ] [ ] the pathophysiologic mechanisms of lung microthrombosis in serious covid- are highly complex and may be related to the development of cytokine release syndrome. [ ] [ ] [ ] [ ] [ ] notwithstanding, lung abnormalities were still present on hospital discharge in a minority of patients, suggesting that lung us findings correlate with resolution of severe covid- pneumonia in icu patients. however, the lack of clearance of lung findings in all patients, even on hospital discharge, suggests that the resolution of lung parenchymal abnormalities depicted by imaging techniques in covid- pneumonia requires considerable time. moreover, lung parenchymal damage and changes may persist for a long time (lung tissue scarring), highlighting potentially chronic issues for long-term rehabilitation of survivors. this prospective study had a number of limitations. the number of recruited patients was relatively small; hence, no meaningful subgroup analysis could be performed. we could not relate the us findings with pertinent laboratory findings and chest ct scans in all studied cases; however, that was not an end point of this study. although it is an operator-dependent modality, the advantages of pocus cannot be underestimated, even in contrast to ct scanning. point-ofcare us is a bedside diagnostic tool that could minimize the risk of cross-infection related to transport of patients with covid- . it is less resource intensive and delivers no ionizing radiation. more studies are clearly required to explore the role of pocus in the diagnosis and treatment of critically ill patients with covid- , bearing in mind that the absence of imaging signs cannot entirely rule out the infection. in conclusion, this study illustrated that pocus may be an alternative imaging modality in the diagnosis and monitoring of critically ill patients with covid- . lung us detected extensive lung involvement, featured by b-lines, pleural line irregularities, and variable consolidation patterns in patients with serious covid- pneumonia. lung involvement progression was successfully tracked with us as well as disease resolution on improvement. our rate of confirmed pe by ccta was high but could not be related to pocus-detected dvt. lung us confirmed the gradual improvement of covid- pneumonia in survivors approximately to weeks after icu admission. the putative correlation of pocus to ct and laboratory findings in covid- warrants further attention. chinese critical care ultrasound study group (ccusg). finding of lung ultrasonography of novel coronavirus pneumonia during the - epidemic a preliminary study on the ultrasonic manifestations of peripulmonary lesions of non-critical novel coronavirus pneumonia (covid- ). social science research network website point-of-care lung ultrasound findings in novel coronavirus disease- pnemoniae: a case report and potential applications during covid- outbreak lung ultrasound findings in a -year-old woman with covid- our italian experience of using lung ultrasound for identification, grading and serial follow-up of severity of lung involvement for management of patients with covid- lung ultrasound findings in patients with covid- pneumonia can lung us help critical care clinicians in the early diagnosis of novel coronavirus (covid- ) pneumonia? is there a role for lung ultrasound during the covid- pandemic? proposal for international standardization of the use of lung ultrasound for covid- patients; a simple, quantitative, reproducible method point-of-care lung ultrasound in patients with covid- : a narrative review it's not over until it's over: the chameleonic behavior of covid- over a six-day period covid- outbreak: less stethoscope, more ultrasound extension of coronavirus disease (covid- ) on chest ct and implications for chest radiograph interpretation relevance of lung ultrasound in the diagnosis of acute respiratory failure bedside ultrasound assessment of positive end-expiratory pressureinduced lung recruitment training for lung ultrasound score measurement in critically ill patients ultrasound of the lungs more than a room with a view ultrasonography for the assessment of lung recruitment maneuvers ultrasound assessment of lung aeration loss during a successful weaning trial predicts postextubation distress inter-rater reliability of quantifying pleural b-lines using multiple counting methods diagnostic accuracy of chest radiograph, and when concomitantly studied lung ultrasound, in critically ill patients with respiratory symptoms: a systematic review and meta-analysis lung ultrasound in the diagnosis and follow-up of community-acquired pneumonia: a prospective, multicenter, diagnostic accuracy study clinical and computed tomographic imaging features of novel coronavirus pneumonia caused by sars-cov- chest ct for typical -ncov pneumonia: relationship to negative rt-pcr testing correlation of chest ct and rt-pcr testing in coronavirus disease (covid- ) in china: a report of cases performance of radiologists in differentiating covid- from viral pneumonia on chest ct clinical and high-resolution ct features of the covid- infection: comparison of the initial and follow-up changes proposal of a low-dose, long-pitch, dual-source chest ct protocol on third-generation dual-source ct using a tin filter for spectral shaping at kvp for coronavirus disease (covid- ) patients: a feasibility study time course of lung changes on chest ct during recovery from novel coronavirus (covid- ) pneumonia radiological findings from patients with covid- pneumonia in wuhan, china: a descriptive study genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding china medical treatment expert group for covid- . clinical characteristics of coronavirus disease in china clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspectedinterim guidance coronavirus diseases (covid- ) guidelines (revised version . ). riyadh, saudi arabia: saudi ministry of health website comparative performance of sars-cov- detection assays using seven different primer/probe sets and one assay kit virological assessment of hospitalized patients with covid- detection of sars-cov- in different types of clinical specimens positive rate of rt-pcr detection of sars-cov- infection in cases from one hospital in improved molecular diagnosis of covid- by the novel, highly sensitive and specific covid- -rdrp/hel real-time reverse transcription-pcr assay validated in vitro and with clinical specimens detection of novel coronavirus ( -ncov) by real-time rt-pcr world medical association declaration of helsinki: ethical principles for medical research involving human subjects publicationsdetail/infection-prevention-and-controlduring-health-care-when-novel-coronavirus-(ncov)-infection-issuspected- air, surface, environmental, and personal protective equipment contamination by severe acute respiratory syndrome coronavirus (sars-cov- ) from a symptomatic patient world federation for ultrasound in medicine and biology safety committee. world federation for ultrasound in medicine and biology position statement: how to perform a safe ultrasound examination and clean equipment in the context of covid- lower-extremity doppler for deep venous thrombosis: can emergency physicians be accurate and fast? accuracy of ultrasonography performed by critical care physicians for the diagnosis of dvt incidence of thrombotic complications in critically ill icu patients with covid- isth interim guidance on recognition and management of coagulopathy in covid- abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia autopsy findings and venous thromboembolism in patients with covid- post-mortem examination of covid- patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction severe pulmonary embolism in covid- patients: a call for increased awareness thrombotic and hemorrhagic events in critically ill covid- patients: a french monocenter retrospective study acute kidney injury in the intensive care unit according to rifle characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of , cases from the chinese center for disease control and prevention a trial of lopinavir-ritonavir in adults hospitalized with severe covid- sonographic signs and patterns of covid- pneumonia. version what's new in lung ultrasound during the covid- pandemic immune response to sars-cov- and mechanisms of immunopathological changes in covid- can we use interleukin- (il- ) blockade for coronavirus disease (covid- )-induced cytokine release syndrome (crs)? tocilizumab treatment in covid- : a single center experience cytokine release syndrome in severe covid- immune mechanisms of pulmonary intravascular coagulopathy in covid- pneumonia key: cord- -wbwlfx q authors: gómez-rial, jose; currás-tuala, maria josé; rivero-calle, irene; gómez-carballa, alberto; cebey-lópez, miriam; rodríguez-tenreiro, carmen; dacosta-urbieta, ana; rivero-velasco, carmen; rodríguez-núñez, nuria; trastoy-pena, rocio; rodríguez-garcía, javier; salas, antonio; martinón-torres, federico title: increased serum levels of scd and scd indicate a preponderant role for monocytes in covid- immunopathology date: - - journal: front immunol doi: . /fimmu. . sha: doc_id: cord_uid: wbwlfx q background: emerging evidence indicates a potential role for monocytes in covid- immunopathology. we investigated two soluble markers of monocyte activation, scd and scd , in covid- patients, with the aim of characterizing their potential role in monocyte-macrophage disease immunopathology. to the best of our knowledge, this is the first study of its kind. methods: fifty-nine sars-cov- positive hospitalized patients, classified according to icu or non-icu admission requirement, were prospectively recruited and analyzed by elisa for levels of scd and scd , along with other laboratory parameters, and compared to a healthy control group. results: scd and scd levels were significantly higher among covid- patients, independently of icu admission requirement, compared to the control group. we found a significant correlation between scd levels and other inflammatory markers, particularly interleukin- , in the non-icu patients group. scd showed a moderate positive correlation with the time lapsed from admission to sampling, independently of severity group. treatment with corticoids showed an interference with scd levels, whereas hydroxychloroquine and tocilizumab did not. conclusions: monocyte-macrophage activation markers are increased and correlate with other inflammatory markers in sars-cov- infection, in association to hospital admission. these data suggest a preponderant role for monocyte-macrophage activation in the development of immunopathology of covid- patients. emerging evidence from sars-cov- infected patients suggests a key role for monocyte-macrophage in the immunopathology of covid- infection, with a predominant monocytederived macrophage infiltration observed in severely damaged lungs ( ) , and morphological and inflammation-related changes in peripheral blood monocytes that correlate with the patients' outcome ( ) . an overexuberant inflammatory immune response with production of a cytokine storm and t-cell immunosuppression are the main hallmarks of severity in these patients ( ) . this clinical course resembles viral-associated hemophagocytic syndrome (vahs), a rare severe complication of various viral infections mediated by proinflammatory cytokines, resulting in multiorgan failure and death ( ) . a chronic expansion of inflammatory monocytes and over-activation of macrophages have been extensively described in this syndrome ( ) ( ) ( ) . viral-associated hemophagocytic syndrome has been identified as a major contributor to death of patients in past pandemics caused by coronaviruses ( ) , including previous sars and mers outbreaks ( ) , and currently suggested for sars-cov- outbreak ( ) . cd and cd are both myeloid differentiation markers found primarily on monocytes and macrophages, and detection of soluble release of both in plasma is considered a good biomarker of monocyte-macrophage activation ( , ) . elevated plasma levels of soluble cd (scd ) are associated to poor prognosis in vih-infected patients, are a strong predictor of morbidity and mortality ( , ) , and associated with diminished cd +-t cell restoration ( ) . in addition, soluble cd (scd ) plasma levels are a good proxy for monocyte expansion and disease progression during hiv infection ( ) . in measles infection, a leading cause of death associated with increased susceptibility to secondary infections and immunosuppression, scd and scd levels have been found to be significantly higher, indicating an important and persistent monocyte-macrophage activation ( ) . we hypothesized that monocytes/macrophages may be an important component of immunopathology associated to sars-cov- infection. in this paper, we analyze serum levels of soluble monocyte activation markers in covid- patients and their correlation with severity and other inflammatory markers. we recruited patients with confirmed pcr-positive diagnosis of sars-cov- infection, classified according to icu admission requirement (n = patients), or non-icu requirement (n = ), and age-matched healthy individuals (n = ) as a control group. demographic data, main medication treatment and routine lab clinical parameters including inflammatory biomarkers were collected for all infected patients. leftover sera samples from routine analytical controls were employed for the analysis, after obtaining the corresponding informed consent. time elapsed from hospital admission to sample extraction was also recorded. to determine levels of soluble monocyte activation markers in serum specimens, appropriate sandwich elisa (quantikine, r&d systems, united kingdom) were used following manufacturer indications. briefly, diluted sera samples were incubated for h at room temperature in the corresponding microplate strips coated with capture antibody. after incubation, strips were washed and incubated with the corresponding human antibody conjugate for h. after washing, reactions were revealed and optical density at nm was determined in a microplate reader. concentration levels were interpolated from the standard curve using a four-parameter logistic ( -pl) curvefit in prism graphpad software. final values were corrected applying the corresponding dilution factor employed. data are expressed as median and interquartile range. all statistical analyses were performed using the statistical package r. mann-whitney tests were used for comparison between icu and non-icu groups versus healthy controls. pearson's correlation coefficients were used to quantify the association between scd and scd concentration and other lab parameters in non-icu patients. data outliers, falling outside the . interquartile range, were excluded from the statistical analysis. the nominal significance level considered was . . bonferroni adjustment was used to account for multiple testing. patients in the icu group showed significant differences when compared to non-icu group in several clinical laboratory parameters: lymphocytes, ferritin, d-dimer, lactate dehydrogenase (ldh), procalcitonin (pct), and interleukin- (il- ). the absolute value for circulating monocytes did not show significant differences between groups. however, these values may have been distorted by the use of tocilizumab, an il- blocking drug extensively employed in the icu group which interferes with monocyte function. age and time elapsed from admission to sample extraction did not show differences between groups. values are summarized in table . median levels for scd in sera from icu patients were . ( %ci: . - . ) ng/ml, compared to . ( %ci: . - . ) ng/ml in non-icu patients. the healthy control group median value was . ( %ci: . - . ) ng/ml. we observed significant statistical differences when comparing infected patients against controls (p-value < . ), however no significant differences were observed between icu and non-icu groups. median levels for scd in sera from icu patients were . ( %ci: . - . ) ng/ml, and . ( %ci: . - . ) ng/ml in non-icu patients. the healthy control group value was . ( %ci: . - . ) ng/ml. as with scd , we observed significant differences for values from infected patients compared to control group (p-value < ), but no differences between icu and non-icu infected patients. values are summarized in table and figure . we assessed the correlation between scd and scd levels and time elapsed from hospital admission to sample extraction (figure ) . we found a significant positive correlation between scd levels and time elapsed (r = . , p-value = . ) we did not observe a significant correlation between scd levels and time elapsed from hospital admission to sample extraction. we found significant correlations between scd and scd levels and several clinical laboratory parameters in infected patients (in these analysis, adjusted significance under bonferrori correction is . ), but only in the non-icu group, possibly reflecting an interference of the use of tocilizumab or corticoids in the icu group. levels of scd showed a negative correlation with the absolute value of lymphocytes (r = − . , p-value = . ) and a positive correlation with levels of ldh (r = . , p-value = . ), crp (r = . , p-value < . ); pct (r = . , p-value = . ), and ferritin (r = . , p-value = . ) (figure ) . no other significative associations were found with other lab parameters. levels of scd did not show significant correlation with clinical laboratory parameters (figure ) . particularly, il- also showed significant positive correlation with scd (r = . , p-value = . ) (figure ) . we analyzed possible interference of different treatments on scd and scd serum levels for all patients. we found an interference of corticoid treatment on scd , levels with median values of ( %ci: - ) ng/ml for treated group, and values of ( %ci: - ) ng/ml for nontreated group. values were significantly lower in corticoid-treated group (p-value = . ) (figure ) . no impact was found for corticoids on scd levels. likewise, hydroxychloroquine and/or tocilizumab were not found to have an impact on scd and scd serum levels. levels of scd and scd did not show association with length of hospital stay in both groups. also, these biomarkers did not show association with the number of days of onset of symptoms. we analyzed for possible age-dependence of scd and scd levels. values did not show association between these biomarker levels and the age of patients. our results show, for the first time, increased levels of scd and scd in sera from sars-cov- infected patients admitted to hospital. we did not observe statistical differences when comparing icu versus non-icu patients. this is probably due to the interference on monocyte function and scd levels produced by the use of corticoid treatment in icu patients, as shown here and previously by others ( , ) . however, levels of scd showed a strong correlation with clinical laboratory parameters, including acute phase reactants (ferritin, ldh, c-reactive protein, procalcitonin) and a strong correlation with il- levels in the non-icu patient group, where no corticoids treatments were used. hydroxychloroquine and tocilizumab treatment did not show interferences on scd and scd levels. furthermore, scd levels showed a correlation with the time elapsed from hospital admission to sample extraction, suggesting a potential indicator of disease progression. monocytes and macrophages constitute a key component of immune responses against viruses, acting as bridge between innate and adaptive immunity ( ) . activation of macrophages has been demonstrated to be pivotal in the pathogenesis of the immunosuppression associated to several viral infections (such as vih, measles), where expansion of specific subsets of monocytes and macrophages in peripheral blood are observed, and considered to be drivers of immunopathogenesis ( ) . our results support the hypothesis of a preponderant role for monocytes in sars-cov- immunopathology, associated to an overexuberant immune response. increased levels of monocytemacrophage activation markers, and their correlation with other inflammatory biomarkers (particularly il- ), indicate a close relationship between monocyte activation and immunopathology in these patients. inflammatory markers are closely related to severity in covid- pathology ( ) and selective blockade of il- has been demonstrated to be a good therapeutic strategy in covid- pathology ( ). our results thus suggest that monocyte-macrophage activation can act as driver cells of the cytokine storm and immunopathology associated to severe clinical course of covid- patients. further, monitorization of monocyte activity trough these soluble activation markers and/or follow-up of circulating inflammatory monocytes in peripheral blood, could be useful to assess disease progression in the same way as in other viral infections ( ) . in addition, our results identify monocyte-macrophage as a good target for the design of therapeutic intervention using drugs that inhibit monocyte-macrophage activation and differentiation. in this sense, anti-gm csf inhibitor drugs, currently under clinical trials for rheumatic and other auto-inflammatory diseases, might provide satisfactory results in covid- patients. other drugs targeting monocyte and/or macrophage could also be useful in covid- , as in other inflammatory diseases ( ) . the strategy of inhibiting monocyte differentiation has proved useful in avoiding cytokine storm syndrome after car-t cell immunotherapy ( ), suggesting a possible therapeutic application to covid- immunopathology ( , ) . the present study has several limitations, including a relatively low sample size and the interference of corticoids in icu patients' results. however, these preliminary results are strongly suggestive of an important implication of monocytemacrophage in covid- immunopathology, as highlighted by the correlations found between these biomarker levels and inflammatory parameters. further studies using broader series are needed to confirm our findings. in summary, our data underscore the preponderant role of monocyte and macrophage immune response in covid- immunopathology and provide pointers for future interventions in drug strategies and monitoring plans for these patients. the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. the studies involving human participants were reviewed and approved by comité de Ética de la investigación con medicamentos de galicia (fast-track approval -march- ). written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. the landscape of lung bronchoalveolar immune cells in covid- revealed by single-cell rna sequencing. medrxiv covid- infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of wich correlate with patient outcome. medrxiv speciality collaboration, covid- : consider cytokine storm syndromes and immunosuppression virus associated hemophagocytic syndrome cd (dim)/cd (bright) monocytes in hemophagocytic lymphohistiocytosis how viruses contribute to the pathogenesis of hemophagocytic lymphohistiocytosis. front immunol recommendations for the management of hemophagocytic lymphohistiocytosis in adults virus-associated hemophagocytic syndrome as a major contributor to death in patients with influenza a (h n ) infection is secondary hemophagocytic lymphohistiocytosis behind the high fatality rate in middle east respiratory syndrome corona virus? the pathogenesis and treatment of the 'cytokine storm' in covid- soluble cd is a nonspecific marker of monocyte activation differential expression of cd on monocyte subsets in healthy and hiv- infected individuals plasma levels of soluble cd independently predict mortality in hiv infection elevated levels of serum-soluble cd in human immunodeficiency virus type (hiv- ) infection: correlation to disease progression and clinical events immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory cd cells increased monocyte turnover from bone marrow correlates with severity of siv encephalitis and cd levels in plasma persistent high plasma levels of scd and scd in adult patients with measles virus infection modulation of human monocyte/macrophage activity by tocilizumab, abatacept and etanercept: an in vitro study effects of corticosteroids on human monocyte function co-ordinating innate and adaptive immunity to viral infection: mobility is the key soluble cd , a novel marker of activated macrophages, is elevated and associated with noncalcified coronary plaque in hiv-infected patients correlation analysis between disease severity and inflammation-related parameters in patients with covid- pneumonia. medrxiv the cytokine release syndrome (crs) of severe covid- and interleukin- receptor (il- r) antagonist tocilizumab may be the key to reduce the mortality gm-csf inhibition reduces cytokine release syndrome and neuroinflammation but enhances car-t cell function in xenografts a strategy targeting monocyte-macrophage differentiation to avoid pulmonary complications in sars-cov infection role of monocytes/ macrophages in covid- pathogenesis: implications for therapy the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © gómez-rial, currás-tuala, rivero-calle, gómez-carballa, cebey-lópez, rodríguez-tenreiro, dacosta-urbieta, rivero-velasco, rodríguez-núñez, trastoy-pena, rodríguez-garcía, salas and martinón-torres. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord- -ynel ore authors: momtazmanesh, sara; shobeiri, parnian; hanaei, sara; mahmoud-elsayed, hani; dalvi, bharat; malakan rad, elaheh title: cardiovascular disease in covid- : a systematic review and meta-analysis of , patients and proposal of a triage risk stratification tool date: - - journal: egypt heart j doi: . /s - - -z sha: doc_id: cord_uid: ynel ore background: coronavirus disease (covid- ) pandemic has drastically affected global health. despite several studies, there is yet a dearth of data regarding the mechanisms of cardiac injury, clinical presentation, risk factors, and treatment of covid- -associated cardiovascular disease. this systematic review and meta-analysis is aimed at defining the clinical, electrocardiographic, and pathologic spectrum of cardiovascular disease (cvd), frequency of elevated cardiac and inflammatory biomarkers, and their frequency and relationship with severity of the disease and mortality in covid- patients and to develop a triage risk stratification tool (trst) that can serve as a guide for the timely recognition of the high-risk patients and mechanism-targeted therapy. we conducted an online search in databases of pubmed and embase to identify relevant studies. data selection was in concordance with prisma guidelines. results were presented as pooled frequencies, odds ratio, standardized mean difference (smd), and forest and funnel plots. results: we gathered a total of studies and included of them in our meta-analysis. acute cardiac injury occurred in more than % of cases, mortality was times higher, and admission to intensive care unit increased by . times. hypertension was the most common pre-existing comorbidity with a frequency of . %, followed by diabetes mellitus ( . %). the deceased group of patients had higher cardiac and inflammatory biomarkers, with statistically significant smd, compared with survivors. pediatric patients were predominantly mildly affected. however, less frequently, the presentation was very similar to kawasaki disease or kawasaki shock syndrome. this latter presentation hass been called as multisystem inflammatory syndrome in children (mis-c). conclusions: there is a wide spectrum of cardiac involvement in covid- patients, and hence a triage risk stratification tool can serve as a guide for the timely recognition of the high-risk patients and mechanism-targeted therapy. coronavirus disease (covid- ) pandemic has drastically affected the global health and as of th may , resulted in , , million confirmed cases and a death toll of , worldwide [ ] . this disease has presented with a heterogeneous clinical course, ranging from asymptomatic carrier state to a lethal outcome with multi-organ failure and with a wide variety of case fatality rates ranging from . to % [ ] [ ] [ ] . although the respiratory tract is the most commonly involved organ system in this disease, other organs and particularly the heart are also affected with a negative impact on outcome [ ] . furthermore, pre-existing cardiovascular disease (cvd) can affect severity and mortality of these patients. despite myriads of studies investigating cardiovascular diseases in patients with covid- , there are still numerous unanswered questions, most importantly a triage risk stratification tool (trst) that allows timely recognition of high-risk patients and well-timed delivery of risk-levelappropriate, patient-tailored, and pathophysiologicaltargeted treatment [ ] . the aims of this systematic review and meta-analyses were ( ) to calculate pooled frequency of newly developed and pre-existing cvd, hypertension, diabetes mellitus, cardiac symptoms as the initial presentations of covid- , elevation of cardiac and inflammatory biomarkers, acute hepatic, and renal injury; ( ) to investigate association of newly developed and pre-existing cvd (including any acquired cardiac disease, encompassing ischemic and non-ischemic cardiomyopathies, or congenital heart disease) hypertension, and elevated cardiac and inflammatory biomarkers with severity of the disease and mortality; ( ) to define the clinical spectrum and mechanisms of the newly developed cardiovascular diseases in the pediatric and adult population, the spectrum of newly developed arrhythmias and electrocardiographic changes and the pathologic findings of cardiac autopsies; and ( ) to propose a trst for timely detection and appropriate pathophysiologically targeted treatment of high-risk covid- patients with associated cvd. we conducted an online search in databases of pubmed and embase on st april to identify relevant studies. the search terms included "covid- ," and "cardiovascular diseases," and other relevant or equivalent terms. we provided our search strategy in supplementary material (s ). to retrieve additional eligible studies, we also traced the reference list of the retrieved papers and relevant reviews. studies were included if ( ) they had reported associated cardiovascular diseases in covid- patients, ( ) assessed levels of cardiac biomarkers in covid- patients, and ( ) were original peer-reviewed studies (except for one study that we used in our qualitative analysis and was retrieved from medrxiv) [ ] . we did not apply any limitation on language or publication date. studies were included in our quantitative analysis if they had a sample size of equal to or larger than ten. the rest of the articles, including case reports, case series, and studies investigating pathological features of the heart tissue, were assessed in the qualitative analysis. we excluded review articles. data selection was in concordance with the preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines [ ] . two authors (sm and ps) independently assessed the eligibility of the retrieved references. in case of disagreement, emr made the final decision. three reviewers (sm, ps, and emr) extracted ( ) characteristics of the sample (age, gender, previous cardiovascular comorbidities, diabetes, and hypertension); ( ) incidence of cardiovascular diseases; ( ) levels of cardiac biomarkers, including troponins, n-terminal-pro b-type natriuretic peptide (nt-pro bnp), myoglobin, creatine kinase (ck), creatine kinase-mb (ck-mb), and lactate dehydrogenase (ldh) and inflammatory biomarkers including d-dimer, c-reactive protein (crp), erythrocyte sedimentation rate (esr), ferritin, interleukin- (il- ), and tumor necrosis factor-alpha (tnf-α); and ( ) frequency of acute hepatic injury and acute kidney damage. to critically appraise the included studies, we implemented the newcastle-ottawa scale (nos) [ ] . the possible scores of this scale range from to . studies with a score of seven to nine, four to six, and zero to three were classified as studies with low, moderate, and high risk of bias, respectively. we used openmeta analyst [ ] version . . and rev-man version . [ ] . using forest plots, we illustrated the results of the analyses. we used funnel plots to illustrate the publication bias. the odds ratio (or) were calculated to compare frequencies of acute cardiac injury, hypertension, and pre-existing cardiovascular diseases, between the "deceased" and the "recovered" patients and also between patients with "severe" and "non-severe" manifestations. we used standardized mean difference (smd) to compare levels of cardiac troponin, ck, ntpro bnp, myoglobin, ldh, crp, esr, ferritin, il- , and ldh between the "deceased" and "recovered" patients and levels of crp, ldh, ck, and ck-mb between the "severe" and "non-severe" cases. we used the i index to assess heterogeneity between studies. the i -indices of - %, - %, and - % represented low, moderate, and high degrees of heterogeneity, respectively [ ] . we utilized fixed effects models if the results were homogeneous (i < % and p > . ) and random effect models if these results were heterogeneous (i ≥ % or p ≤ . ) [ ] . to convert median and inter-quartile range (iqr) to mean and standard deviation (sd), we used statistical methods suggested by luo et al. [ ] and wan et al. [ ] . for one study which did not report the first and third quartiles of its data, we assumed the mean equal to the median and the standard deviation (sd) equal to iqr divided by [ ] . our analysis of the comparison of patients with severe to those with non-severe covid- included two types of categorization, namely "icu" versus "non-icu" groups and "severe" (defined as respiratory rate ≥ times/min, oxygen saturation at resting state ≤ %, partial pressure of arterial oxygen to fraction of inspired oxygen ratio < ) versus "non-severe" (presented as without pneumonia or with mild pneumonia) categories. we also calculated the overall effect of each parameter on both groups (severe or icu group and non-severe or non-icu group) as a whole. in the series of studies with "icu" versus "non-icu" groups, we did not include the study performed by du et al. [ ] , since they had clearly stated that all of their patients had an indication for icu admission, but they could not admit them into icu just because of a shortage of resources. regarding study of han et al. in which they had classified their patients into three subgroups as mild, severe, and critical, we merged the severe and critical groups. additionally, we did not include wan et al.'s [ ] study in our subgroup analysis comparing acute cardiac injury in patients with severe and non-severe disease because their definition of acute cardiac injury was not precisely defined. in the pooled frequency analysis of patients with higher levels of crp, esr, ferritin, il- , nt-pro bnp, d-dimer, ldh, cardiac troponins, myoglobin, ck, and ck-mb, we only included the studies which had indicated the number of patients with elevated levels of these biomarkers based on their laboratory cut-off values. we present our findings in two sections: "meta-analyses" and "systematic review" sections meta-analyses study selection figure depicts the detailed process of data selection. three-hundred and sixty-two ( ) studies were retrieved in our initial search of pubmed and embase, of which remained after removing duplicates. in title/abstract screening, papers did not meet our inclusion criteria and were excluded. five of the studies entering full-text screening had either wrong study design or study population and were excluded. we also added one pre-print study regarding cardiac pathological findings from medrvix [ ] . we included a total of studies in our qualitative synthesis, of which were contained in our meta-analysis [ , . of the selected studies for the review, records were case reports, case series, or pathological reports. among studies included in our meta-analysis, nine did not categorize their samples into subgroups, and the rest had a subgroup classification (tables and in the supplementary materials and (s and s ). five studies grouped their patients based on whether they survived or not, three depending on whether they had myocardial injury or high levels of cardiac biomarkers (troponin t or nt-pro bnp), four according to whether patients needed icu admission or not, and eight had divided their patients based on the severity of manifestations. three studies used a combination of these classifications and divided their patients into four or more subgroups. moreover, in three remaining studies, age, the time elapsed from the onset of symptom, or requirement of supplemental oxygen were used to stratify patients. of the studies we evaluated in the risk of bias assessment, studies had a low risk of bias, while five records had a moderate risk of bias. none of the included studies were assessed as a study with a high risk of bias. the table of risk of bias assessment is available in supplementary material (s ). table illustrates the summary of the results of the pooled analysis of the frequency of chest pain/chest tightness and palpitation as one of the initial manifestations, newly developed and pre-existing cardiovascular disease, and elevation of cardiac and inflammatory biomarkers. the forest plots are available in supplementary material (s ). newly developed cardiovascular diseases or related symptoms acute cardiac injury, with an estimated pooled frequency of . % ( % ci . - . %), was the most commonly reported cardiac complication of covid- . although the pooled estimated frequency of arrhythmia was slightly higher than acute cardiac injury ( . %), it was only reported in four studies, and the % confidence interval (ci) was equal to . - . %. notably, there was significant heterogeneity in the estimates of newly developed acute cardiac injury and arrhythmia (i = %). moreover, two studies with a total number of patients had assessed newly developed heart failure due to covid- infection, and the pooled frequency was calculated at . % (ci . - . %). among the cardiac manifestations as the initial presentation of covid- , frequency of chest pain or chest tightness and palpitation were investigated. a total of six studies had reported chest pain or chest tightness in covid- patients. our pooled frequency analysis showed that this presentation was observed as an initial manifestation in approximately one-fifth ( . %, % ci . - %) of patients. additionally, two other studies had reported palpitation as the initial presentation, the estimated pooled frequency of which equaled to . % ( % ci . - . %). pre-existing cardiovascular diseases, diabetes, and hypertension hypertension was the most common preexisting comorbidity among covid- patients with a pooled frequency of . % ( % ci . - . %), followed by diabetes with a pooled frequency of . % ( % ci . - . %). overall, fewer than one-fifth of patients had pre-existing cardiovascular diseases. the pooled frequency of cardiovascular diseases was estimated at . % ( % ci . - . %). additionally, our analysis on the pooled frequency of heart failure using data of five studies, which had reported pre-existing heart failure, showed a pooled frequency of . % ( % ci . - . %). there was significant heterogeneity in the estimates of pre-existing cardiovascular diseases and hypertension (i ≥ %). figure illustrates the pooled frequency of elevation of cardiac and inflammatory biomarkers. among the biomarkers we investigated, esr and crp were the most commonly elevated biomarkers. the estimated pooled frequencies of patients with elevated esr and crp were . % ( % ci . - . %) and . % ( % ci - %). similarly, higher levels of serum moreover, among cardiac biomarkers, increased levels of nt-pro bnp, d-dimer, and ldh were found in approximately % of patients. the estimated pooled frequencies of elevation of nt-pro bnp, d-dimer, and ldh were equal to . % ( % ci . - . %), . % ( % ci . - . %), and . % ( % ci . - . %), respectively. elevation of cardiac troponins was observed in approximately onequarter of patients ( . %, % ci . - . %). additionally, we identified and analyzed the findings of five studies that had investigated the number of patients with increased myoglobin levels. the estimated pooled frequency of elevated myoglobin was at near . % ( % ci . - . %). lastly, we found ten studies reporting the number of patients with elevated ck levels and two studies reporting the number of patients with elevated ck-mb levels. the estimated pooled frequency of elevation of ck and ck-mb were equaled to . % ( % ci . - . %) and . % ( % ci . - . %), respectively. of note, chen et al. reported reduction of ck levels in % of their patients [ ] . as the wide ci range and high heterogeneity score (i = %) show, the results of this analysis cannot be very reliable and additional original investigations are required in this regard. notably, there was significant heterogeneity in the estimates of the frequency of increased cardiac and inflammatory biomarkers ( % ≤ i ≤ %). table the summary of the pooled analysis of frequency of chest pain/chest tightness and palpitation as one of the initial manifestations, newly developed and pre-existing cardiovascular disease, and elevation of cardiac and inflammatory biomarkers in patients with covid- only two studies had measured the levels of tnf-α. pooled frequency of elevated levels of tnf-α was . % ( % ci . - . %) [ , ] . association of newly developed acute cardiac injury, pre-existing cardiovascular diseases, hypertension, and diabetes with disease severity and survival figure depicts the odds ratio for death and developing severe forms of covid- infection according to the presence of newly developed acute cardiac injury, hypertension, diabetes mellitus, and pre-existing cardiovascular diseases. the forest plots showing the odds ratio for death according to newly developed acute cardiac injury, pre-existing cardiovascular disease, hypertension, and diabetes mellitus are available in supplementary material (s ). newly developed acute cardiac injury: association with survival and severity the development of acute cardiac injury increased the risk of mortality by near times (or . , % ci . - . , p < . ). patients developing acute cardiac injury had a much higher risk of being admitted to icu (or . , % ci . - . , p < . ). studies included in the analysis of assessing the effect of acute cardiac injury on the risk of being admitted to icu were homogenous (i = %). when we added one study comparing the incidence of acute cardiac injury between severe and non-severe patients, we found that development of acute cardiac injury increased the occurrence of more severe presentation of the disease more than six times (or . , % ci . - . , p < . ) (fig. ) . pre-existing cardiovascular diseases: association with survival and severity pre-existing cardiovascular diseases pose a significant risk of mortality. patients with these conditions were near eight times more likely to have a fatal outcome (or . , % ci . - . , p = . ). studies comparing pre-existing cardiovascular diseases between deceased and survived patients were moderately heterogeneous (i = %, p = . ). similarly, patients with pre-existing cardiovascular diseases were about four times more likely to be categorized in the icu or severe groups (or . , % ci . - . , p < . ). patients with pre-existing cardiovascular diseases were approximately three times more likely to be admitted to the icu (or . , % ci . - . , p < . ) and four times more likely to develop severe forms of the disease (or . , % ci . - . , p < . ) (fig. ) . we included eight studies with low heterogeneity (i = %) to assess the role of hypertension in increasing the mortality rate and found that patients with hypertension were more than twice more likely to die from covid- compared to other patients (or . , % ci . - . , p < . ). likewise, patients with hypertension were about three times more likely to be categorized in the icu or severe groups (or . , % ci . - . , p < . ). patients with hypertension were approximately . times more likely to be admitted to the icu (or . , % ci . - . , p < . ) and . times more likely to develop severe forms of covid- infection (or . , % ci . , . , p < . ) (fig. ) . diabetes: association with survival and severity six studies with low heterogeneity (i = %) had reported number of patients with diabetes in deceased and survived groups. we found that patients with diabetes were fig. forest plots showing the odds ratio for severity according to the newly developed acute cardiac injury, pre-existing cardiovascular disease, hypertension and diabetes mellitus slightly more likely to die from covid- compared to other patients (or . , % ci . - . , p < . ). similarly, patients with diabetes were near three times more likely to be categorized in the icu or severe groups (or . , % ci . - . , p < . ). they were approximately . times more likely to be admitted to the icu ( % ci . - . , p = . ) and . times more likely to develop severe forms of covid- infection ( % ci . , . , p < . ) (fig. ) . elevated levels of cardiac and inflammatory biomarkers level: association with survival the levels of cardiac biomarkers, including cardiac troponin (smd = . , % ci . - . , p = . ), myoglobin (smd = . , % ci . - . , p < . ), ldh (smd = . , % ci . - . , p < . ), nt-pro bnp (smd = . , % ci . - . , p < . ), and ck (smd = . , % ci . - . , p < . ) were significantly higher in the deceased group (fig. ) . we included elevated levels of troponin i, t, and highsensitivity troponin (either i or t) as cardiac troponins. similarly, the levels of inflammatory markers, including il- (smd = . , % ci . - . , p < . ), ferritin (smd = . , % ci . - . , p < . ), crp (smd = . , % ci . - . , p < . ), and esr (smd = . , % ci . - . , p < . ), were significantly higher in the deceased group (fig. ) . overall, ck levels were higher in patients classified as the icu or severe groups (smd = . , % ci . - . , p < . ). additionally, the smd in icu or not icu subgroup (smd = . , % ci . - . , p < . ) was quite similar to the severe or non-severe subgroup (smd = . , % ci . - . , p = . ). two studies had assessed the difference between ck-mb levels between the severe and non-severe group of the patients. ck-mb levels were higher in the patients with severe forms of covid- (smd = . , % ci . - . , p < . ). when we added the only study which had compared the levels of ck-mb between icu and non-icu patients, the total smd was . ( % ci . - . , p = . ) (fig. ) . pooled frequencies of acute cardiac injury, acute hepatic injury, and acute kidney injury given the cardio-hepatic and cardio-renal interactions, we also analyzed the pooled frequency of acute liver injury and acute kidney injury in our selected studies [ ] [ ] [ ] [ ] [ ] . while acute cardiac injury was reported in . % ( % ci . - . %) of patients, acute liver injury was reported in . % ( % ci . - . %) and acute kidney injury was stated in . % of studies ( % ci . - . %). funnel plots showing publication bias of studies are shown in supplementary material (s ). a diverse range of cardiovascular disease has been reported in patients with covid- which encompasses acute myocarditis (including acute lymphocytic myocarditis) [ ] , fulminant myocarditis [ , , , [ ] [ ] [ ] , acute myocardial infarction type [ ] , acute myopericarditis [ ] , acute pulmonary embolism [ ] [ ] [ ] [ ] , cardiac tamponade [ ] , cardiogenic shock [ , ] , cardiomyopathy [ ] , heart failure, pericardial effusion, pulmonary hypertension, reverse takotsubo cardiomyopathy [ ] , and right ventricular dysfunction [ , ] . left ventricular failure was more commonly reported in covid- patients than right ventricular dysfunction. however, to date, the majority of cases with right ventricular failure were secondary to acute pulmonary embolism [ , ] . nevertheless, fried and his colleagues reported myopericarditis in a -yearold patient who developed biventricular failure and was successfully managed using an intra-aortic balloon pump (iabp) [ ] . in the pediatric population, there was a case of mild elevation of troponin i in a -day-infant with excellent outcome and discharge from the hospital [ ] . however, both kawasaki-like disease and kawasaki shock-like syndrome have been reported with covid- . jones et al. reported a -month-old female infant with the typical symptoms of kawasaki disease that was tested positive for covid- . her echocardiogram was normal [ ] . riphagen and her colleagues reported patients with shock, aged to years, who had initially presented with persistent fever, rash, inflammation of the conjunctiva, peripheral edema, and pain in the extremities. all except one had prominent gastrointestinal symptoms, and all except one weighed above th percentile. all had elevated levels of cardiac troponins and developed warm shock. none of them tested positive for covid- . however, a -year-old boy with kg weight and a bmi of kg/m , who underwent ecmo and died of cerebral infarction was tested positive postmortem, and another case was positive for covid- after discharge. antibody test was positive for covid- in all the eight patients. their echocardiographic findings included left ventricular and/or right ventricular dysfunction and increased brightness of walls of the coronary arteries. the authors suggested that covid- can produce a "hyper-inflammation syndrome" that involves multiple organs, mimicking kawasaki disease shock syndrome [ ] . the exact mechanisms of cardiac injury in patients with covid- are not confirmed. however, it is speculated that cardiac injury can occur through one or more of the putative mechanisms [ , , ] : direct invasion by the virus, indirect damage due to the systemic inflammatory syndrome and cytokine storm, dysregulation of renin-angiotensin-aldosterone system, hypoxia-induced cardiac injury, microvasculature damage of the heart, stress-induced cardiomyopathy, and cardiac damage secondary to multi-organ failure. timing of the appearance of the cardiac complications, early versus late stage, may serve as a hint to the diagnosis of the putative mechanism/s [ , ] . dynamic changes in ecg are of paramount importance during covid- and imply acute cardiac derangement. patients with covid- are at risk of arrhythmias and ecg changes due to the disease itself or because of the medications used for its prevention or treatment, such as chloroquine, hydroxychloroquine, and azithromycin. these three medications can prolong qt interval and predispose the patient to torsades de pointes [ ] . nevertheless, to date, no case of torsades de pointes due to qtc prolongation secondary to consumption of these drugs has been reported in these patients. sinus tachycardia is the most common rhythm disturbance reported in patients with covid- . moreover, a variety of other rhythm disorders and electrocardiographic alterations have been reported in patients with covid- such as supraventricular tachycardia [ , ] , ventricular tachycardia, first-degree atrioventricular block (avb), temporary second-degree avb, reversible complete heart block, generalized stelevation masquerading st-elevation myocardial infarction (stemi), triangular-type st-elevation myocardial infarction type , s q t pattern mimicking acute pulmonary embolism, non-specific st and t wave changes, diffuse u waves in the presence of a qtc of . ms, and pulseless electrical activity [ , ] . by rd of april , there are seven studies reporting the cardiac pathological findings [ , , , [ ] [ ] [ ] [ ] . the summary of these studies is tabulated in supplementary table in supplementary material (s ) . two of these have also performed electron microscopic examination [ , ] . only in one case with fulminant myocarditis and cardiogenic shock, virus was present in the pericytes [ ] . no obstruction or thrombosis of epicardial coronary arteries were reported. prominent infiltration of t lymphocytes was present in only one case which presented as reverse takutsubo cardiomyopathy [ ] . this study showed that compared to the liver and kidney, the heart was the second most commonly involved organ affected by covid- after the lungs. slightly more than one-fourth of the hospitalized patients with covid- develop cvd and arrhythmia, which increased the mortality by nearly times and the need for icu admission by . times. hypertension was present in slightly less than one-third of admitted patients and led to increased mortality and the need for icu admission by approximately . -and -folds, respectively. however, this association may be partly due to the fact that the incidence of hypertension increases with aging [ ] . it is already known that mortality is higher in older patients with covid- [ ] . the relationship among inflammation, oxidative stress, and vascular dysfunction, known as vascular health triad, is reported as a common mechanism between aging and hypertension [ ] . patients with pre-existing heart failure had -fold more death and nearly . -fold more need for the icu admission. in a systematic review and meta-analysis, santoso et al. studied patients, and by calculating the risk ratio showed that in patients with cardiac injury, mortality and need for icu admission were . times and . -fold more likely, respectively [ ] . not only do cardiovascular complications increase morbidity and mortality, but they also enhance the risk of sepsis and septic shock. this may be explained by the prolonged period of hospitalization and/or use of different invasive devices to support the circulatory failure [ , ] . even after discharge, patients with a history of myocarditis may develop myocardial scars, which predispose them to cardiac arrhythmia. follow-up investigation by cardiac magnetic resonance imaging is recommended in order to determine the risk of cardiac arrhythmias [ ] . another reason for the necessity of follow-up is to ensure that acute myocarditis of covid- does not evolve into dilated cardiomyopathy in later life [ ] . furthermore, cardiac magnetic resonance imaging can be of great help in the diagnosis of acute myocarditis in hospitalized patients; nevertheless, it was used scarcely [ ] . pulmonary embolism was frequently reported and should be considered in any patient with covid- who experience sudden deterioration of clinical condition associated with an acute drop in oxygen saturation or those with significantly elevated levels of d-dimer. covid- -associated coagulopathy (cac), the etiology of which is multifactorial and not yet completely understood, has been reported with a spectrum of manifestations ranging from hypercoagulability (in the vast majority of the reported cases) to less common reports of bleeding, particularly in patients treated with ecmo or anticoagulants [ ] . the triad of virchow, including endothelial damage, alterations in blood flow and presence of prothrombotic components in the circulation, appears to have a substantial role in the development of cac [ ] . the spectrum of presentation of hypercoagulability states in covid- encompasses a wide range that spans from localized microvascular thrombosis in the lungs or pulmonary intravascular coagulopathy (pic) to systemic venous and arterial thrombosis, including aortic thrombosis [ ] [ ] [ ] . development of covid- -associated coagulopathy is associated with a worse prognosis [ ] . hence, prophylactic treatment with low molecular weight heparin is recommended for all hospitalized covid- patients, unless there is a contraindication [ , ] . anticoagulant therapy has been shown to be associated with improved survival [ ] . our meta-analyses demonstrated that il- , which has a critical role in cytokine release syndrome, was elevated in approximately two-thirds of the hospitalized patients. coomes and his colleagues, in a recent systematic review and meta-analysis on the role of il- in patients with covid- , showed that il- was . times higher in patients with complicated covid- , compared with the non-complicated group. they also found that il- levels were . -fold higher in the patients who required icu admission in comparison with patients who did not need to be admitted in the icu [ ] . increased il- can also explain the speculative cardiac microvascular abnormalities in patients with covid- [ ] . zhang et al. highlighting the substantial role of il- , described the pathophysiology of cytokine release syndrome in patients with covid- and severe clinical course. they proposed that tocilizumab, a recombinant humanized monoclonal antibody against the receptor of il- , can serve as a potentially effective treatment for cases presenting as severe covid- [ ] . given the central role of il- in cytokine release syndrome and the safety of tocilizumab in children and adult patients, liu et al. also proposed tocilizumab as a treatment for patients with severe covid- [ ] . we observed higher levels of cardiac troponin, myoglobin, ldh, nt-probnp, ck, and il- , in the deceased patients in comparison with the survived. li and his colleagues showed that cardiac troponins and nt-probnp were higher in the deceased patients with covid- . they also reported that the dynamic rise in the latter biomarkers was only observed in the deceased group [ ] . likewise, guo et al. studied patients with covid- and observed that dynamic changes or rising levels of nt-probnp and cardiac troponin t were significantly higher in the deceased patients [ ] . we found a sharp contrast between frequency, severity, and outcome of cardiac involvement due to covid- in pediatric versus adult population [ ] . in a systematic review of children with covid- , ludvigsson et al. did not report even one case of covid- -induced cardiac injury in the pediatric age range. they cited the study of dong et al. as the largest study on children, the study in which only cases of the confirmed cases had the critical disease, none of them had cardiac injury [ , ] . shekerdemian et al. reported children with covid- who were admitted to icu and % of whom had significant underlying comorbidities, including congenital heart disease and cardiomyopathy in three cases. although they reported a fatality rate of %, they have not delineated whether the deceased patients were those with prior cardiac disease. furthermore, except the one patient with underlying cardiomyopathy who underwent veno-arterial ecmo for treatment of cardiogenic shock, no further information regarding acute cardiac injury is provided [ ] . given the fact that angiotensin-converting enzyme (ace ) functions as the receptor for the entry of sars-cov- into the cell, the answer may be partly hidden in the age-related differences in the renin-angiotensinaldosterone system (raas) [ ] . this hypothesis is supported by the evidence that shows the elderly are predisposed to severe forms of the covid- [ ] [ ] [ ] . furthermore, musso et al. reported that advancing age adversely affects the raas [ ] . similarly, senescence-related changes in the immune function may also be contributing [ ] . nevertheless, it seems that although mortality due to direct viral invasion to the heart is not reported in children, the catastrophic effects of hyper-inflammatory response with multi-organ involvement including the heart, the so-called covid- pediatric hyperinflammatory shock syndrome, can be life-threatening. in fact, both kawasaki-like disease and kawasaki shocklike syndrome have been reported with covid- . these findings may also potentially shed light on the role of viruses in the pathogenesis of kawasaki disease. time of presentation of the cardiac disorders (early stage versus late stage) and levels of various cardiac and inflammatory biomarkers can serve as clues to the putative underlying mechanism/s. to detect patients at the highest risk at the earliest, i.e., at triage, a simple and practical plan is necessary to guide the clinician on the minimal essential initial laboratory work-up as a guide for pathophysiologically targeted treatment. two considerations should be taken into account when using this tool. the first is that the laboratory investigations in this tool are in addition to the routine laboratory evaluations such as cbc, esr, crp, and blood glucose. secondly, it should be borne in mind that for consideration of mechanical circulatory support, the conventional indications and contraindications in patients with covid- , in addition to the precautions for prevention and treatment of infections, should be strictly followed [ ] [ ] [ ] . this study showed that pre-existing and newly developed cardiovascular disease are common in patients with covid- and are associated with increased severity and mortality in these patients. the frequency, clinical pattern, severity, and outcome of cardiovascular injury in pediatric patients with covid- is not only different from the adult population but also varies in the pediatric age range, ranging from no cardiac damage in the majority of cases to kawasaki shock-like syndrome in the minority. we proposed a triage risk stratification tool in patients with covid- and cvd for timely recognition of the high-risk patients and well-timed establishment of the pathophysiologically targeted treatment. this tool needs to be validated in future studies. lastly, covid- should be regarded as a disease that can affect multiple organs with multiple mechanisms, each of which may need therapy targeted at the mechanism of injury in order to be effective. there were significant inconsistencies in reporting cardiovascular derangements in patients with covid- . consistent terminology and definition of cardiac injury were not used in the studies. furthermore, the i index was high in some meta-analyses. certain studies had done intensive evaluation and had presented immense information, whereas there was a dearth of information regarding the patients in others. these limitations indicate the necessity of a standardized terminology to report cardiovascular complications and a standard diagnostic approach to patients with covid- worldwide. we did not include cardiac arrest in our analysis because the precise underlying pathophysiology of dying process (end-stage respiratory failure, cardiogenic shock, multiple organ failure, or cardiogenic shock) was not delineated in the majority of studies [ ] . we could not include obesity in our study because data in this regard was not provided in the majority of studies. another limitation of this study was that we did not search cochrane, cinahl, web of science, scopus, and google scholar database in our online search [ ] . lastly, the limitations due to the possible inherent biases in the non-randomized cohort data apply to this study. supplementary information accompanies this paper at https://doi.org/ . /s - - -z. figure . forest plot of the pooled frequency analysis of newly developed heart failure. figure . forest plot of the pooled frequency analysis of chest pain or chest tightness. figure . forest plot of the pooled frequency analysis of palpitation. figure . forest plot of the pooled frequency analysis of hypertension. figure . forest plot of the pooled frequency analysis of pre-existing cardiovascular diseases. figure . forest plot of the pooled frequency analysis of preexisting heart failure. figure . forest plot of the pooled frequency analysis of pre-existing diabetes. figure . forest plot of the pooled frequency analysis of patients with elevated nt-pro bnp levels. figure . forest plot of the pooled frequency analysis of patients with elevated cardiac troponins levels. figure . forest plot of the pooled frequency analysis of patients with elevated creatine kinase-mb levels. figure . forest plot of the pooled frequency analysis of patients with elevated creatine kinase levels. figure . forest plot of the pooled frequency analysis of patients with elevated d-dimer levels. figure . forest plot of the pooled frequency analysis of patients with elevated lactate dehydrogenase levels. figure . forest plot of the pooled frequency analysis of patients with elevated interleukin- levels. figure . forest plot of the pooled frequency analysis of patients with elevated c-reactive protein (crp) levels. figure . forest plot of the pooled frequency analysis of patients with elevated erythrocyte sedimentation rate (esr) levels. figure . forest plot of the pooled frequency analysis of patients with elevated ferritin levels). additional file : forest plots showing odds ratio for death according to newly developed acute cardiac injury, pre-existing cardiovascular disease, hypertension and diabetes mellitus. additional file : supplementary material (s ) figure . funnel plot of studies comparing frequency of acute cardiac injury between severe or icu group and non-severe or non-icu group showing publication bias. figure . funnel plot of studies comparing frequency of preexisting cardiovascular diseases between severe or icu group and nonsever or non-icu group showing publication bias. figure . funnel plot of studies comparing frequency of pre-existing cardiovascular disease between severe or icu group and non-severe or non-icu group showing publication bias. world health organization, coronavirus disease (covid- ) situation report - , data as received by who from national authorities by : cest asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus (sars-cov- ): facts and myths characteristics and outcomes of critically ill patients with covid- in washington state clinical features and treatment of covid- patients in northeast chongqing covid- and the cardiovascular system the impact of novel coronavirus on heart injury: a systemic review and meta-analysis vander heide rs. pulmonary and cardiac pathology in covid- : the first autopsy series from new orleans. medrxiv the newcastle-ottawa scale (nos) for assessing the quality of nonrandomized studies in meta-analyses closing the gap between methodologists and end-users: r as a computational back-end review manager (revman). . ed. copenhagen: the nordic cochrane centre: the cochrane collaboration assessing heterogeneity in meta-analysis: q statistic or i index? statistical primer: heterogeneity, random-or fixed-effects model analyses? interact cardiovasc thorac surg optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range hospitalization and critical care of decedents with covid- pneumonia in wuhan, china clinical features and treatment of covid- patients in northeast chongqing analysis of myocardial injury in patients with covid- and association between concomitant cardiovascular diseases and severity of covid- epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical characteristics of deceased patients with coronavirus disease : retrospective study clinical characteristics of fatal and recovered cases of coronavirus disease (covid- ) in wuhan, china: a retrospective study clinical characteristics of fatal and recovered cases of coronavirus disease (covid- ) in wuhan, china: a retrospective study predictors of mortality for patients with covid- pneumonia caused by sars-cov- : a prospective cohort study clinical features of fatal cases of covid- from wuhan: a retrospective observational study prognostic value of nt-probnp in patients with severe covid- hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease -covid-net, states baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region cardiovascular implications of fatal outcomes of patients with coronavirus disease (covid- ) analysis of heart injury laboratory parameters in covid- patients in one hospital in wuhan lancet, ) clinical features of patients infected with novel coronavirus in clinical characteristics and outcomes of patients undergoing surgeries during the incubation period of covid- infection clinical characteristics of patients with covid- in a tertiary hospital near wuhan risk factors for severity and mortality in adult covid- inpatients in wuhan analysis of epidemiological and clinical features in older patients with corona virus disease (covid- ) out of wuhan clinical characteristics of novel coronavirus cases in tertiary hospitals in hubei province clinical characteristics and outcomes of cardiovascular disease patients infected by -ncov clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan. china association of cardiac injury with mortality in hospitalized patients with covid- in wuhan clinical analysis of cases of novel coronavirus infection in nanyang city clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china imaging and clinical features of patients with novel coronavirus sars-cov- clinical findings in a group of patients infected with the novel coronavirus (sars-cov- ) outside of wuhan, china: retrospective case series epidemiologic features and clinical course of patients infected with sars-cov- in singapore clinical characteristics of patients infected with sars-cov- in wuhan association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin ii receptor blockers with mortality among patients with hypertension hospitalized with covid- clinical characteristics of cases of corona virus disease (covid- ) in changsha clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study heart failure and liver disease: cardiohepatic interactions cardiohepatic interactions in heart failure: an overview and clinical implications right heart failure and cardiorenal syndrome an update on the pathophysiology and treatment of cardiorenal syndrome cardiorenal syndrome: multi-organ dysfunction involving the heart, kidney and vasculature acute myocarditis presenting as a reverse tako-tsubo syndrome in a patient with sars-cov- respiratory infection coronavirus fulminant myocarditis treated with glucocorticoid and human immunoglobulin first case of covid- complicated with fulminant myocarditis: a case report and insights acute pulmonary embolism in covid- patients on ct angiography and relationship to ddimer levels covid- pneumonia with hemoptysis: acute segmental pulmonary emboli associated with novel coronavirus infection severe acute proximal pulmonary embolism and covid- : a word of caution acute pulmonary embolism in a patient with covid- pneumonia. diagn interv imaging myocardial localization of coronavirus in covid- cardiogenic shock the variety of cardiovascular presentations of covid- . circulation two cases of coronavirus -related cardiomyopathy in pregnancy acute myocarditis presenting as a reverse tako-tsubo syndrome in a patient with sars-cov- respiratory infection covid- complicated by acute pulmonary embolism and right-sided heart failure. jacc case rep acute pulmonary embolism and covid- pneumonia: a random association? a -day-old female infant infected with covid : presenting with pneumonia, liver injury, and heart damage covid- and kawasaki disease: novel virus and novel case hyperinflammatory shock in children during covid- pandemic the heart in covid : primary target or secondary bystander? the cardiovascular burden of coronavirus disease (covid- ) with a focus on congenital heart disease covid- illness and heart failure: a missing link? jacc: heart failure coronavirus disease (covid- ) and cardiovascular disease considerations for drug interactions on qtc in exploratory covid- (coronavirus disease ) treatment. heart rhythm characteristic electrocardiographic manifestations in patients with covid- pathological study of the novel coronavirus disease (covid- ) through postmortem core biopsies. modern pathology covid- autopsies pathological findings of covid- associated with acute respiratory distress syndrome a pathological report of three covid- cases by minimally invasive autopsies hypertension in the elderly case-fatality rate and characteristics of patients dying in relation to covid- in italy hypertension and aging cardiac injury is associated with mortality and critically ill pneumonia in covid- : a meta-analysis the role of cardiac mri in the management of ventricular arrhythmias in ischaemic and non-ischaemic dilated cardiomyopathy viral myocarditis and dilated cardiomyopathy: etiology and pathogenesis multiparametric cardiovascular magnetic resonance imaging in acute myocarditis: a comparison of different measurement approaches covid- update: covid- -associated coagulopathy covid coagulopathy in caucasian patients understanding the covid- coagulopathy spectrum covid- -related aortic thrombosis: a report of four cases abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia isth interim guidance on recognition and management of coagulopathy in covid- covid- and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy interleukin- in covid- : a systematic review and meta-analysis. medrxiv the cytokine release syndrome (crs) of severe covid- and interleukin- receptor (il- r) antagonist tocilizumab may be the key to reduce the mortality comparison of heart failure and novel coronavirus pneumonia in chest ct features and clinical characteristics cardiovascular implications of fatal outcomes of patients with coronavirus disease (covid- ) clinical and epidemiological features of children china: an observational cohort study epidemiological characteristics of pediatric patients with coronavirus disease in china systematic review of covid- in children shows milder cases and a better prognosis than adults characteristics and outcomes of children with coronavirus disease (covid- ) infection admitted to us and canadian pediatric intensive care units clinical implications of sars-cov interaction with renin angiotensin system clinical features of covid- in elderly patients: a comparison with young and middle-aged patients potential lethal outbreak of coronavirus disease (covid- ) among the elderly in retirement homes and long-term facilities renin-angiotensin-aldosterone system in the elderly: rational use of aliskiren in managing hypertension renin-angiotensin-aldosterone system and the aging kidney age-related changes in immune function: effect on airway inflammation utility of extracorporeal membrane oxygenation in covid- prevention and infection management in mechanical circulatory support device recipients cardiovascular collapse in covid- infection: the role of veno-arterial extracorporeal membrane oxygenation (va-ecmo). cjc open understanding pathways to death in patients with covid- optimal database combinations for literature searches in systematic reviews: a prospective exploratory study publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we are grateful to physicians, nurses, and the entire staff who serve the covid- patients across the world. authors' contributions sm co-developed the concept and design, collected the data, performed the statistical analysis, and had a major contribution in writing the manuscript. ps collected the data and had a major contribution in writing the manuscript. sh performed the statistical analysis. bd and hme critically revised the manuscript and had a major contribution in finalizing the manuscript. emr conceived the original idea, collected the data, had a major contribution in writing the manuscript, and supervised the project. all authors contributed to the final manuscript, read, and approved the final manuscript. no funding was received for this study. data is available on request.ethics approval and consent to participate this study was a review of the literature and obtaining the approval of the ethics committee was not applicable. consent to participate is not applicable. not applicable. the authors have no competing interest to declare. key: cord- -lmf h oc authors: light, r. bruce title: plagues in the icu: a brief history of community-acquired epidemic and endemic transmissible infections leading to intensive care admission date: - - journal: critical care clinics doi: . /j.ccc. . . sha: doc_id: cord_uid: lmf h oc the ability to diagnose and treat infectious diseases and handle infectious disease outbreaks continues to improve. for the most part, the major plagues of antiquity remain historical footnotes, yet, despite many advances, there is clear evidence that major pandemic illness is always just one outbreak away. in addition to the hiv pandemic, the smaller epidemic outbreaks of legionnaire's disease, hantavirus pulmonary syndrome, and severe acute respiratory syndrome, among many others, points out the potential risk associated with a lack of preplanning and preparedness. although pandemic influenza is at the top of the list when discussing possible future major infectious disease outbreaks, the truth is that the identity of the next major pandemic pathogen cannot be predicted with any accuracy. we can only hope that general preparedness and the lessons learned from previous outbreaks suffice. intensive care, the epitome of the application of modern technology to medicine, arguably began as a response to the increasing numbers of older children and young adults developing paralytic polio during the early s. severe paralytic polio itself turns out to have been among the products of increasing modernity in the western world. clinical recognition of the syndromes associated with the polio virus date back about years. the fact that the disease was caused by a transmissible viral particle was demonstrated by . until early in the twentieth century the virus was readily transmitted throughout the population almost continuously by personal contact and by the fecal-oral route via water. the result was that most people's first exposure to the virus occurred in infancy. at this age most infections resulted in a clinically unapparent infection, in part due to partial protection by maternal antibody, after which lifelong immunity was established. only a few suffered a paralytic episode with the infection, at the time termed ''infantile paralysis.'' as hygienic standards of the advanced economy nations rose throughout the first half of the century, early childhood exposure to the virus declined. an increasing fraction of the population had their first exposure in late childhood or during young adulthood. in these age groups the likelihood that the infection will cause a paralytic syndrome is greatly increased, so both the incidence of clinically recognized infection and that of paralysis rose. by the early s clinically recognized cases had reached - annually for every , people in the united states, making it a major public health concern and a source of a great deal of fear in the general populace. more than % of polio virus infections are asymptomatic. however, at the more severe end of the clinical spectrum are the paralytic syndromes which range from paralysis of one or more limbs (''spinal polio'') to syndromes with respiratory muscle or bulbar paralysis (''respiratory polio'' or ''bulbospinal polio'') with loss of respiratory or upper airway muscle function or both. these more severe outcomes rise in incidence from about . % in infants to more than % in older children and adults. in the early part of the century development of polio with bulbar involvement was associated with a death rate of greater than %, generally from respiratory failure. use of a mechanical respirator to try to avert death was first attempted at the children's hospital in boston in , using an ''iron lung.'' the machine was basically a sealed box with a hole at one end for the patient's head to protrude, attached to two vacuum cleaners. the motors were then cycled to alternately create vacuum inside the box, expanding the patient's chest and causing the patient to inhale through the mouth (outside the box), then allowing air back into the box to permit exhalation. the design was further improved in , and the machines came into increasingly broad use throughout north america and europe during the severe outbreaks of the s. adoption of this therapy resulted in a significant reduction in mortality during these years. iron lungs, however, were cumbersome, difficult to use when trying to provide nursing care, and expensive. a more cost-effective and user-friendly approach to providing respiratory support was clearly needed. this finally came by bringing the positive pressure ventilation (ppv) concept out of the operating room. ppv was first used for respiratory support for polio victims at blegdam hospital in copenhagen, denmark, an innovation attributable to danish anesthetist bjorn ibsen. during this large outbreak in , some medical students were put to work hand-ventilating dozens of patients through tracheostomies until the worst of the paralytic phase of the illness had passed, often several weeks. the concept quickly spread elsewhere and was widely adopted, yielding substantial reductions in mortality. for reasons of efficiency and convenience, patients needing respiratory support were often grouped in a single location where the necessary expertise and equipment were available. the introduction of ppv into a defined area of the hospital used to support respiratory failure was the genesis of the modern icu and represents a signal event in the development of the field of critical care medicine. the introduction of effective vaccines, the salk (inactivated) vaccine in and later the sabin (live attenuated oral) vaccine in , immediately and dramatically reduced the incidence of polio to less than one per , population by the early s and the incidence continued to fall thereafter. the last case of wild strain polio in north america was reported in , and since that time the only cases of paralytic polio have been rare instances of disease due to variants of the live oral vaccine strain. polio does, however, still contribute to illnesses that may require intensive care in the form of the ''post-polio syndrome.'' this occurs in patients who survived paralytic polio decades ago and who, over the years, develop a gradual decline in function in the originally affected nerves and muscles which can years later once again threaten them with disability and, in some cases, respiratory failure requiring intensive care. in july , american legion members attending a convention at a hotel in philadelphia suddenly began falling ill with an acute febrile illness with pneumonia, often associated with extrapulmonary symptoms such as myalgia or diarrhea. many developed acute respiratory failure requiring mechanical ventilatory support in icu. over were affected and died, an alarming mortality rate, especially since physicians caring for the patients had no idea what was causing the illness. conventional microbiologic investigations yielded no convincing pathogens despite intensive investigation for the usual bacteria and viruses and other potential pathogens. epidemiologic and various biologic investigations were quickly implemented by local health authorities and by the centers for disease control and prevention (cdc). these showed that the disease was likely airborne and that it occurred more frequently in older individuals who had underlying lung disease, smoked, or were relatively immunocompromised. analysis of the likelihood of death revealed that those who received tetracyclines or macrolide antibiotics were more likely to survive than those who received only betalactams. however, no causal agent was uncovered, though many potential causes were excluded-most known bacteria and viruses, many biologic toxins and many environmental agents such as toxic chemicals and metals. in , joseph mcdade and charles shepard of the cdc reported the isolation of a novel fastidious gram-negative bacillus from the available clinical specimens. they named it legionella pneumophila. this discovery was quickly followed by an explosion of knowledge about the organism and its ecology, antimicrobial susceptibility, and of other bacteria within the genus. over time, demonstration that it was a widely occurring colonizer of brackish water, particularly in air conditioners, cooling towers, and water heaters and pipes, led to the implication of these reservoirs in several hundred outbreaks of the disease worldwide, especially in hospitals and other public health institutions, and hotels. thus began widespread development of regulations and guidelines for limiting the degree of colonization of these water sources by legionella, resulting in a reduction in the size, number, and scope of subsequent outbreaks. since the initial description of the disease, legionella has, of course, been shown to be one of the major causes of community-acquired pneumonia (cap), particularly in the more severe subset requiring icu care; this fact underlies the major lesson from plagues in the icu the outbreak-the nearly universal recommendation for inclusion of antimicrobial therapy for legionell spp in any treatment regimen for severe cap without another obvious cause. although we now know that no amount of continuing effort can completely eliminate this organism from our environment, and that we will continue to see endemic cases, we also know that clusters of cases should trigger an investigation into finding the point source of the outbreak, a situation that continues to occur several times a year somewhere in the world. in addition, the philadelphia outbreak that defined ''legionnaire's disease'' was the first in the modern icu era to demonstrate that major unknown infectious disease syndromes of severe consequence still exist, presaging the new infectious disease syndromes to be discovered in the years that followed. in the late s, emergency rooms and icus throughout north america began to see an increasing number of young menstruating women presenting with a previously little-known syndrome characterized by sudden onset of a high fever, often associated with vomiting and diarrhea, quickly followed by severe hypotension. early in the course most patients developed a diffuse macular rash, often with mucous membrane inflammation, with subsequent desquamation during convalescence. patients frequently required massive fluid resuscitation because of systemic capillary leak, as well as vasopressor support, mechanical ventilation for adult respiratory distress syndrome, and even renal replacement therapy for acute renal failure, complicating the shock episode. one of the early clusters of observed cases was reported in , and the term ''toxic shock syndrome'' was coined based on the isolation of an exotoxin-producing staphylococcus aureus from mucosal surfaces or the site of a minor infection in the absence of bacteremia. as the case numbers rapidly increased case definitions for the syndrome were formulated and epidemiologic studies mounted. by , over cases had been formally reported to the cdc. the case fatality rate was reported to be as high as % in the more severe cases included in the earliest reports, falling to about %- % as recognition of the syndrome improved. by this time there were clear epidemiologic links between the syndrome and menstrual use of high-absorbency tampons which were often left in place longer than less absorbent products. colonization of the tampon with staphylococcus aureus was also implicated, consistent with the postulated toxin-mediated disease mechanism. within months of these revelations the main manufacturer of the implicated tampons withdrew them from the market and women began changing tampons with greater frequency or stopped using them at the urging of public health authorities. the incidence of the syndrome immediately began to fall and within a few years, with the changing of use patterns of tampons and changes in their manufacture, toxic shock syndrome disappeared, for the most part, but not entirely, from the icu. even at the height of tss incidence in the united states, about % of the cases reported were nonmenstrual and % were in males. subsequent development of the knowledge that the clinical syndrome was due to strains of staphylococcus aureus that secrete a particular toxin (toxic shock syndrome toxin , or tsst- ), which is both absorbable from mucosal surfaces and capable of producing a profound shock syndrome even in the absence of significant invasive infection, soon led to the more widespread recognition of the nonmenstrual toxic shock syndrome. this syndrome, which was almost certainly extant before but little-recognized, was perhaps the main lesson from the outbreak: even trivial staphylococcal skin or wound infections light or mucosal surface colonization in the presence of a foreign body such as a nasal pack for nosebleed can lead to a severe shock syndrome if the organism is present and produces this toxin or one of several related ones. the recognition of the staphylococcal toxic shock syndrome also led to increasing understanding of the role of ''superantigens'' as a mechanism of disease-bacterial toxins capable of activating a large fraction (up to %) of the total t-lymphocyte population. such superantigens have since been implicated in a number of other disease syndromes, among them the streptococcal toxic shock syndrome (see below). over the past two decades, the incidence of menstrual and nonmenstrual staphylococcal tss has been about one per , population in most areas. busy icus will, therefore, continue to see occasional cases. however, there is some recent evidence that case numbers may be on the rise again in at least some areas, possibly because of a resurgence in the prevalence of toxin-producing strains in the community. in , physicians working in infectious diseases and critical care medicine thought they knew all about pneumocystosis. the organism, then thought to be a protozoon, had been first described in by carlos chagas in brazil, and since then had been clearly implicated as a cause of interstitial pneumonia in debilitated and malnourished children (in the aftermath of world war ii) and, later, a cause of severe opportunistic pneumonia in immunocompromised patients, usually those being treated with highdose corticosteroids for connective tissue diseases or lymphoreticular neoplasms. in these patients it caused an impressively aggressive bilateral pneumonia leading to acute respiratory failure. this pneumonia was notoriously difficult to definitively diagnose, requiring bronchoscopy or open lung biopsy to demonstrate the small numbers of characteristic pneumocystis organisms on special silver stains of clinical specimens. the mainstay of treatment at that time was pentamidine, generally given intramuscularly, giving way to trimethoprim/sulfamethoxazole after the publication in of a randomized clinical trial showing that it was at least as effective and generally better tolerated. in the early s, a new form of the infection began to be seen with regularity. young men began to present to hospital with a rather more indolent diffuse bilateral pneumonia that nevertheless went on to cause respiratory failure and which, when investigated, proved to be due to pneumocystis. the course of the disease was quite different from what physicians had been used to up to then. it began more gradually, progressed at a slower pace and was associated with a much lesser systemic inflammatory response. microscopy of respiratory specimens revealed exponentially more organisms than previously seen, such that many patients could be diagnosed from sputum specimens rather than bronchoscopy, and biopsy was virtually never needed. nobody had any idea why this was happening, although it quickly became apparent that the underlying cause of the infection was a new form of severe deficiency of cell-mediated immunity. epidemiologic investigations were soon underway. patterns began to emerge. many of the young men were haitian or had been to haiti. many were homosexual, bisexual, or had worked in the sex trade; others had abused intravenous drugs. the many fewer women with the disease had similar exposures. theories proliferated. was it immunologic exhaustion from exposure to too many microbial stresses? toxins? drugs used in the sex trade? multiple and synergistic viral infections? through the early s, the case load grew. icus throughout north america and, later, in europe and elsewhere, saw increasing numbers of young people, mainly men, plagues in the icu with severe respiratory failure due to pneumocystis pneumonia. by they were being called patients with acquired immunodeficiency syndrome (aids) on the basis of demonstration of low numbers of cd lymphocytes in the blood, but the cause remained unclear. then, in , montagnier and barre-sinoussi at the pasteur institute in france isolated a viral pathogen that they named lymphadenopathy-associated virus (lav). at the national institutes of health in the united states, gallo demonstrated that the virus (which he referred to as human t-cell leukemia virus iii, based on an unproven relationship to other viruses he had previously discovered) definitively caused aids. the virus, now called human immunodeficiency virus (hiv)- was isolated and described and the first diagnostic kits devised, resolving the mystery of causation. montagnier and barre-sinoussi would eventually win the nobel prize in medicine in for their contribution. during the s, patients continued to present with severe pneumonia requiring respiratory support and intensive antimicrobial therapy, often with less than satisfactory results. as knowledge progressed, hiv-associated pneumocystis infection in the icu changed its face several times over the years. at the beginning of the epidemic, most patients presenting for care with hiv/aids and pneumocystosis were severely ill with diffuse pneumonia and hypoxemic respiratory failure and many died, %- % in most centers, prompting widespread debate about whether such patients should even be admitted to icu for mechanical ventilatory support. however, as experience with the disease developed it became clear that an early and aggressive approach could improve prognosis. it was found that in the aids population even minor respiratory symptoms with few or no abnormalities on chest radiograph could be due to pneumocystis infection in the earlier stages, and that even modest degrees of arterial oxygen desaturation signaled impending respiratory failure. earlier bronchoscopy for diagnosis followed by prompt antimicrobial therapy, with pentamidine predominantly in the early s and later primarily with trimethoprim/sulfamethoxazole, led to overall mortality rates falling to the %- % range by the middle of the decade. the advent of systemic corticosteroids therapy for early respiratory failure in aidsassociated pneumocystosis was then shown to further reduce the numbers of patients progressing to advanced respiratory failure, leading to reductions in the numbers of cases needing icu admission and further reducing overall mortality rates to the %- % range. but for patients requiring icu care mortality rates were as high as before the use of steroids and often higher, likely related to the fact that most patients developing respiratory failure had already failed to improve or had progressed despite intensive antimicrobial and corticosteroid therapy. along with these developments in management of the disease, progress was being made on hiv itself. following identification of the virus in , there soon followed increasingly reliable diagnostic tests for the infection, leading to earlier identification of cases and monitoring of cd lymphocyte counts. by the early s, studies supporting widespread use of chemoprophylaxis against pneumocystis in all patients with cd counts < /mm were available and became standard public health agency recommendations. pneumocystosis, which in the s and s was one of the principal causes of hypoxemic respiratory failure in many icus in north america and western europe, began to decline rapidly in incidence, becoming relatively uncommon even before the widespread adoption of highly active antiretroviral therapy, which has, since the mid- s, caused the disease to all but disappear from our icus. although many lessons can be drawn from the battle against aids-related pneumoncystis pneumonia during the s and s, for icu and infectious diseases practitioners one of the main ones comes from the sad fact that once patients had developed full-blown hypoxemic respiratory failure even the best intensive care could only deliver % survival rates. the really large gains in survival came not from better icu technology but from pre-empting the disease on multiple fronts, including earlier diagnosis of hiv infection, early diagnosis and antimicrobial treatment of pneumonia, steroid treatment of early respiratory failure, antimicrobial prophylactic regimens and, later, effective antiretroviral therapy. until , the only members of the bunyaviridae family of viruses known to cause disease in north america were members of the genus bunyavirus, all causing mosquito-borne viral encephalitis, mainly in children (california encephalitis). other members of the family were known to cause serious febrile illnesses, encephalitides and hemorrhagic-fevers in africa and asia (rift valley fever, crimean-congo hemorrhagic fever, hemorrhagic fever with renal syndrome). however, in the spring of wetter-than-usual conditions in the american southwest led to increased availability of food for deer mice, leading to a population explosion and increasing movement of rodents into human-occupied spaces, increasing the chance that humans might be exposed to the rodents and their excreta. in rapid succession, several previously healthy young people, mainly navajos, presented to health care institutions in the four corners area of the southwestern united states, all with fulminant illnesses leading to shock and acute respiratory failure requiring icu care. by early june that year, cases had been identified and had died. in most cases the illness had started with fever and widespread myalgia, soon followed by cough, then by cardiovascular collapse due to a severe systemic capillary leak syndrome and by acute respiratory failure due to low-pressure pulmonary edema. in some cases the time from onset to icu or death was as little as hours, in others a few days. remarkably, although no pathogen was initially identified from blood or tissues, in less than a month after the first report of a possible outbreak, serologic testing had demonstrated antibody cross-reactivity with a range of known pathogens of the hantavirus group, suggesting that the disease was due to a previously unknown member of this group. shortly thereafter exposure to deer mice and their excreta was implicated as the likely source of the infection. the mortality rate for the early cases of hantavirus pulmonary syndrome (hps) was extremely high- % in the initially reported group of patients-mostly due to intractable shock and unsupportable hypoxemic respiratory failure due to acute respiratory distress syndrome (ards). however, this improved with clinical experience as it became evident that administration of large amounts of intravenous fluids in the face of profound capillary leak only resulted in much worse generalized and pulmonary edema, with little improvement in the shock state and only worsening of the respiratory failure. management changed to an approach limiting the amount of fluid administered early in the course together with earlier institution of inotropic support, resulting in a much improved survival rate of about %, generally with minimal or no long-term sequelae in survivors. in subsequent years development of increasingly specific serologic and virologic testing has demonstrated that this disease had been present but unrecognized throughout north and south america long before this outbreak, and that there are several related viruses, each associated with a particular rodent, causing endemic disease and the occasional outbreak. by the mid- s, over cases were reported in states, mainly in the southwest, and cases have since been reported plagues in the icu in small numbers in most other states, canada, mexico, and south america, where several outbreaks have occurred. whereas occasional cases continue to be seen in icus in all these areas, no further major outbreaks have yet occurred in the united states or canada, though clearly remaining a threat under the right conditions; the only currently available preventive measure is avoiding rodent contact. steven simpson, md, one of the intensivists at the health sciences center in albuquerque, new mexico, who was closely involved in the initial four corners outbreak, points out that the event highlights several trends in subsequent disease outbreaks in north america. one is the extreme rapidity with which novel pathogens and potential pharmacotherapeutic agents can now be identified. whereas the pathogen in the legionnaire's outbreak took almost a year to identify, researchers identified the hps pathogen and its source in just months. computerized access to data and data analysis along with virtually instantaneous electronic transmission of information plays a central role in this development. the initial hps outbreak has several icu-related lessons to teach us. while the aforementioned treatment strategies effective in a systemic capillary leak syndrome have been absorbed by the critical care community, it appears that one lesson taken to heart by the local icu teams failed to disseminate to the broader icu community. the initial outbreak was accompanied by a marked element of fear and concern among health care workers, including those in the icu, and a significant level of panic in the local community; a combination of this fear, the requirement for rigorous quarantine precautions, and a marked increase in transfers to the icu of any severely ill patients with symptoms remotely compatible with hps resulted in some compromise of icu operations, due to being completely overwhelmed. this might potentially have been avoided by an awareness that for an effective epidemic response, it is essential to include both hospital and icu operations in each locale. the outbreak also reinforces the principle that nearly all old and most new epidemic infectious diseases have their origin in close contact between humans and other species of animal, both wild and domestic, and new kinds and quantities of such contact are likely to cause new, or newly recognized, disease syndromes. streptococcus pyogenes was one of the first bacteria ever to be conclusively linked to human disease (puerperal infection associated with childbirth). however, over the past years the nature of the diseases stemming from it has changed dramatically on several occasions. at the turn of the last century, it was well known as a cause of streptococcal pharyngitis, erysipelas, and wound infections. it also caused severe septicemic illnesses that frequently led to death. osler knew streptococcus pyogenes as a principal cause of thoracic empyema following pneumonia or severe cases of scarlet fever, and also as a major cause of primary bacteremia with sepsis. these more severe manifestations of streptococcal infection became increasingly uncommon as the twentieth century progressed, particularly after the arrival of antibiotics mid-century. notably, osler did not mention streptococcus as a cause of necrotizing fasciitis or being associated with soft tissue necrosis in wound infections. this syndrome was first described by meleney in ; at that time, it was characteristically a slowly evolving gangrenous infection, usually of surgical wounds, which often responded well to debridement and was associated with a mortality rate of only %. for over a generation after the advent of the modern antibiotic era, streptococcus pyogenes was seldom a problem that led to critical illness-soft tissue infections and light the occasional bacteremia were generally very amenable to treatment; extensive surgery or drainage was seldom required, and cases requiring icu support for shock or respiratory failure were rare. beginning in the mid- s, medical practitioners in centers across north america and europe began seeing previously unknown forms of severe streptococcal disease, soon labeled streptococcal necrotizing fasciitis and streptococcal toxic shock syndrome. streptococcal toxic shock syndrome (strep tss) is any infection with streptococcus pyogenes that is associated with a rapidly progressing systemic toxic response characterized by early onset of high fever and myalgia, often with prominent gastrointestinal symptoms, and by rapid progression to hypotension and multiple organ system failure. the illness usually requires icu support for massive fluid resuscitation, vasopressor and inotropic support and mechanical ventilation. although some cases have primary bacteremia, many others have a localized focus of infection, most often in soft tissues, that only becomes clinically apparent after the onset of shock. streptococcal necrotizing fasciitis is often associated with strep tss and, as mentioned, is often only correctly diagnosed after the onset of shock. the most characteristic story is presentation to a physician or an emergency room with abrupt onset of severe pain, often in an extremity with minimal or no evidence of cutaneous injury. at this stage severe systemic toxicity is usually not present and, since examination of the painful site is also at this stage quite unremarkable, patients are frequently sent home with analgesics and reassurance. over the next - hours pain at the site of infection continues to increase, soft tissue swelling and redness appear above the deeper tissues that are undergoing ongoing necrotizing infection, eventually resulting in full-thickness necrosis evidenced by ecchymosis, cutaneous necrosis, and bullae formation. early or later in this course strep tss frequently occurs. when these cases first began to appear, clinicians' approach to both the sepsis and the tissue necrosis was essentially the same as that used for apparently similar syndromes caused by other bacteria. a broad spectrum antimicrobial was started, fluid resuscitation begun and imaging studies ordered to better define the source of infection causing pain or localized swelling. imaging frequently demonstrated only soft tissue swelling consistent with cellulitis, so surgery was often deferred until superficial signs of tissue necrosis became obvious, and then when surgery was done it was often performed using the conventional approach of trying to conserve as much tissue as possible. the result was that treatment was often too little and too late, with mortality rates exceeding % in many reported series. with the realization that treatment, to be successful, must be swift and aggressive, approaches to therapy changed. emergency physicians were increasingly alerted to the fact that severe pain at any body site, even with relatively minimal localized physical findings and particularly if accompanied by signs of systemic inflammation, could represent necrotizing fasciitis. surgeons began to be consulted much earlier, and any localized pain with swelling more often led to diagnostic surgical exploration rather than imaging and waiting. antimicrobial strategies changed. addition of clindamycin to the usual penicillin or other beta-lactam therapy was advocated and widely adopted, based on results from animal models of the syndrome and on pharmacologic and physiologic considerations, including its ability to inhibit bacterial protein (ie, toxin) synthesis, penetrate necrotic tissues, and inhibit inflammatory cytokine synthesis. toxin neutralization using pooled intravenous gamma globulin was also advocated with the support of primarily historical case-control studies. in most centers, implementation of these approaches has led to dramatic reductions in mortality rates to about %- % although, in the absence of any adequate controlled trials, it remains unclear what the relative contribution of each of these measures has been to the improved outcome. unlike several of the other ''plagues'' discussed above, this is one that is still very much with us. the streptococcus pyogenes strains most strongly associated with severe invasive disease (m-protein types and ) have increasingly been supplanting those associated with less severe disease resulting in an endemic sporadic case-rate for severe disease of one to cases/ , population yearly, with intermittent larger-scale community outbreaks, both of which will continue to require vigilance and an aggressive therapeutic stance from the critical care community. the first case of this apparently novel severe viral respiratory infection occurred in guangdong province in southern china in november . the victim, a farmer, died of an undiagnosed ''atypical pneumonia.'' over the ensuing weeks several more cases of severe respiratory syndromes began to appear in the region, also undiagnosed. by the end of november there had been enough such cases to generate considerable alarm among the medical community in china, generating internet communications between institutions which were picked up by international monitoring agencies. this led to a request from the world health organization (who) for information about the outbreak, but no information was forthcoming from chinese authorities. the first official report about the outbreak was made to public health authorities in guangdong in early january , with a later report to the who in february that, in retrospect, did not fully make clear either the nature or the scale of the problem. transmission of the disease within china continued to occur, leading to rapidly increasing numbers of cases in south china, then throughout the country and to the capitol beijing (where one of the largest outbreaks occurred). exposure of chinese travelers and visitors to the country was inevitable, given the scale of the outbreak. one exposed individual was a physician from mainland china who, incubating the disease during his travel, stayed at the metropole hotel in hong kong in early march. later investigations showed that he transmitted the virus to at least other guests at the hotel, who then carried it by international air travel to taiwan, singapore, vietnam, and canada. one of these contact cases was an american businessman headed for singapore. becoming ill while in transit, he stopped in hanoi where he was admitted to hospital with a severe pneumonia, to which he eventually succumbed. soon after, a number of health care workers who had been in contact with him also became acutely ill. fortunately for the course of the outbreak, one of the consultants on the case was an italian physician working with the who in vietnam, dr. carlo urbani. he immediately recognized that this was a previously unknown severe atypical pneumonia that was relatively easily transmissible and reported it to the who; this led to immediate mobilization of investigative efforts and worldwide alerts about the threat. unfortunately, in the course of caring for the victims of the disease in hanoi, dr. urbani himself contracted the infection and died of it later. as information from china became more available, it became clear that by this time there had already been hundreds of cases and numerous deaths. the majority of the initial wave of cases were noted to have occurred primarily in farmers and food handlers, particularly those working in food markets where live wild animals were kept and sold for food. the second large wave of those affected were health care workers exposed in hospital to patients with the disease. the illness was characterized by fever and myalgia with gastrointestinal symptoms in the initial phase, occurring an average of days after exposure (range - days). many cases got no worse than this, but others went on to develop dyspnea associated with radiographic evidence of a diffuse, patchy pneumonitis which, in some, progressed to ards. an average of light % required mechanical ventilatory support, and when the data were all in from later phases of the outbreak, mortality rates averaged about % overall, worse in the aged and debilitated, lower in the young and healthy. the largest outbreak outside asia occurred in toronto, canada. the index case, a visitor to china, returned to canada and died of pneumonia at home, undiagnosed, in early march . shortly thereafter, one of his sons was admitted to hospital with a severe respiratory illness and died a few days later. by this time, four other family members had become ill and had been admitted to hospital; the first cases of affected health care workers appeared soon after among those who had cared for the dying son of the index case. within days, other instances of transmission from undiagnosed contacts of the initial cases in hospitals, doctors' offices, emergency rooms, and at social events were leading to admission of cases to several hospitals throughout toronto. the response of the public health authorities, beginning soon after the who global alert and coincident with the recognition of the first local cases, was quick and vigorous, including closure of the main affected hospital, intensive follow-up of probable contacts, quarantine of suspected cases based on a fairly inclusive case definition and strict institution of barrier contact protection for health care workers. by mid-april the number of new cases was rapidly declining, although there was one cluster of late cases related to exposure of a large number of health care workers during the resuscitation and difficult intubation of a critically ill patient. a later cluster of cases also occurred in a rehabilitation hospital, where it appeared that unrecognized contacts from the first phase of the outbreak had been transferred and transmitted the disease to other patients and staff. the worldwide outbreak was essentially over by july . there were a total of reported cases from countries, with deaths. intensive epidemiologic and laboratory study of the disease by investigators and laboratories worldwide led to unprecedented rapid growth in knowledge about the causative agent. the virus, more or less simultaneously characterized at a number of laboratories around the world, proved to be a previously unknown coronavirus (severe acute respiratory syndrome [sars]-cov) with capacity to infect and spread from a variety of wild animals to humans. epidemiologic, serologic, and virologic evidence was developed linking human cases to exposure to infected wild animals, including masked palm civets, raccoon dogs, ferrets and ferret badgers, all being sold for human consumption in markets in china. control of their transport and sale and exposures to humans by chinese health authorities was probably one of the major factors in bringing the first outbreak under control, the partial failure of which later led to a second, much smaller outbreak late in . although the initial speculation was that one or more of these wild animals were the reservoir in nature for the infection, it now appears more likely that the viral reservoir is actually bats, with crosstransmission of the virus between bats, food animals, and humans in crowded markets leading to development of strains with the capacity to transmit between humans. public health authorities worldwide learned much from sars about the importance of effective international communication in developing a rapid and effective response to outbreaks of novel viruses, and more about how to go about containing such infections within communities and hospitals. several intensivists involved in the outbreak credit e-mail communications from other international outbreak sites for effective advice on critical elements of disease protection (eg, powered air purifying respirators and full contact rather than droplet precautions) and therapy. for the critical care community, perhaps one main lesson was the importance of ''super-spreading incidents'' in propagating the disease in hospitals. many of these occurred in critically ill patients undergoing resuscitation with difficult or traumatic intubation, generating aerosols in closed spaces which contained many superfluous and inadequately protected health care workers. handling these situations safely depends crucially on identifying the potential risk and undertaking the resuscitation and intubation using the most experienced operators available, adequately protected with basic barrier precautions (eye protection, gloves and surgical face-masks), using sedation or paralysis as necessary to minimize trauma and aerosol generation, and with only essential and adequately protected staff in the room. this likely applies to many other situations with potential for disease transmission to health care workers. unfortunately, this epidemic again points out the primary lesson that was not absorbed from the earlier hps outbreak, namely, the need for detailed preplanning and preparation for a major infectious disease epidemic that is inclusive of hospital and icu operations in each locale. according to participants, the sars outbreak demonstrated many of the same early icu operational problems that plagued the hps outbreak albeit on a larger scale. in the icu era, there has yet to occur a true influenza pandemic with a high attack rate in all age groups and associated high hospitalization and mortality rates, as was seen in the great pandemic. in that worldwide disaster, it is estimated that % of all people became ill with the virus and an estimated - million died. minor recent pandemics in and had less than one twentieth of the impact of the influenza, not greatly different from the yearly interpandemic influenza the world has been experiencing in the years since. interpandemic influenza epidemics since have been caused primarily by h n and h n influenza viruses, to which most of the population has developed some degree of immunity from prior infection or vaccination. the result is what public health authorities have become used to seeing: each year a slightly different influenza a appears in asia with minor antigenic changes in the ha or na surface proteins (termed drift), making it infectious once again for humans whose immune systems have yet to be exposed to the new variant, and a new epidemic is launched. when the ''flu'' arrives in an area, cases begin to appear suddenly and there is rapid spread in the population, usually with %- % becoming infected over a -week period with a peak in case numbers at week two or three. about half of those infected will seek medical attention, many more than once, and one to about per thousand infected will be admitted to hospital with a respiratory syndrome such as pneumonia, chronic obstructive pulmonary disease exacerbation, asthmatic attack, or cardiac failure, the rate depending on age and underlying comorbidities. overall, about . % of those infected die, with mortality rates among those with major comorbidities up to %. these latter cases constitute most of the increase in the icu case load which most units experience every winter. the load is sometimes taxing but usually not overwhelming. a true pandemic is unlikely to play out this way. how different it would be depends on a number of factors: the antigenic difference in the new influenza virus compared with the old (ie, the antigenic ''shift'' to a different one of ha or na protein subtypes due to introduction of a variant from another influenza-susceptible species), how transmissible the new virus is, how virulent it is, how susceptible it is to antiviral drugs, and whether the world is prepared for it with drug availability and vaccines. the prototype severe pandemic was the spanish influenza of , an h n virus. the most recent circulating influenza virus just before that time was an h n that had arrived in . current evidence suggests that an avian influenza virus underwent a period of evolutionary adaptation, possibly in another susceptible species such as swine, fitting it for transmission to humans, which it then did. , this h n virus had not been previously experienced by any segment of the population except the very old, so nearly everyone, particularly non-elderly adults and children, was without immunity and was at risk of severe infection. attack rates, as noted earlier, were extremely high everywhere as were rates of primary influenza pneumonia, complicating bacterial pneumonia, and death. in the united states, death rates were more than -fold higher than in any influenza pandemic since. an outbreak of influenza on this scale, if unchecked by effective antiviral therapy or vaccines, would render icu care such as mechanical ventilatory support for respiratory failure irrelevant. even today, with maximal respiratory support, most patients with diffuse primary viral pneumonia complicated by respiratory failure cannot be saved, and the numbers presenting for such care in a short space of time, if comparable to the pandemic, would overwhelm our current icu capacity within days. currently the main apparent threat of a new pandemic comes in the form of the h n influenza virus. this virus is now present nearly worldwide in migratory and, intermittently, domestic bird populations. from time to time, transmission of the virus from birds to humans occurs, generally from close contact situations. who data indicate that there have been laboratory-confirmed cases of such transmission from to mid- . the mortality rate has exceeded %, although it is likely that many less severe cases do not come to medical attention and are therefore not counted as confirmed case survivors. to date no instances of transmission to humans by humans or other mammals has been documented. however, the threat remains that if this virus were to become capable of human-to-human transmission by adaptation in another susceptible mammalian host such as swine, a pandemic on the order of the event could occur. with no true pandemic for over years, including all of the icu era, health authorities worldwide are deeply engaged in trying to learn the lesson of this new ''plague'' before it actually occurs. it is clear that we will need excellent international communication, rapidly enactable containment and quarantine plans and, if possible, effective antivirals and vaccines to deal with the h n virus. if it evolves as feared and becomes easily transmissible while retaining its current virulence; modern life-sustaining technology alone will be no shield at all. the last years have seen remarkable advances in the ability to diagnose and treat infectious diseases and handle infectious disease outbreaks. for the most part, the major plagues of antiquity remain historical footnotes. however, despite these advances, there is clear evidence that major pandemic illness is always just one outbreak away. in addition to the hiv pandemic, the smaller epidemic outbreaks of legionnaire's disease, hantavirus pulmonary syndrome, and sars, among many others, points out the potential risk associated with a lack of preplanning and preparedness. although pandemic influenza is at the top of the list when discussing possible future major infectious disease outbreaks, the truth is that the identity of the next major pandemic pathogen cannot be predicted with any accuracy. we can only hope that general preparedness and the lessons learned from previous outbreaks suffice. a history of poliomyelitis polio: an american story an apparatus for the prolonged administration of artificial respiration the physiologic challenges of the copenhagen poliomyelitis epidemic and a renaissance in clinical respiratory physiology post-poliomyelitis syndrome legionnaire's disease: description of an epidemic of pneumonia legionnaire's disease: isolation of a bacterium and demonstration of its role in other respiratory diseases toxic-shock syndrome associated with phagegroup- staphylococci toxic-shock syndrome -united states toxic-shock syndrome in menstruating women: association with tampon use and staphylococcus aureus and clinical features in cases epidemiologic notes and reports, toxic-shock syndrome, united states reemergence of staphylococcal toxicshock syndrome in intensity of immunosuppression and the incidence of pneumocystis carinii pneumonia comparison of pentamadine isothionate and trimethoprim/sulfamethoxazole in the treatment of pneumocystis carinii pneumonia pneumocystis pneumonia -los angeles a controlled trial of early adjunctive treatment with corticosteroids for pcp in aids aids-related pneumonia in the era of adjunctive steroids outbreak of acute illness -southwestern united states hantavirus pulmonary syndrome: a clinical description of patients with a newly recognized disease cardiopulmonary manifestations of hantavirus pulmonary syndrome hantavirus pulmonary syndrome -united states: updated recommendations for risk reduction the principles and practice of medicine hemolytic streptococcus gangrene hemolytic streptococcal gangrene: the importance of early diagnosis and operation clinical and bacteriological observations of a toxic-shock-like syndrome due to streptococcus pyogenes streptococcal necrotizing fasciitis: comparison between histological and clinical features antibiotic effects on bacterial viability, toxin production and host response intravenous immunoglobulin therapy for streptococcal toxic-shock syndrome -a comparative observational study. the canadian streptococcal study group epidemiologic analysis of group a streptococcal serotypes associated with severe systemic infections, rheumatic fever, or uncomplicated pharyngitis who -epidemic and pandemic alert and response (epr) acute respiratory syndrome in hong kong special administrative region of china/vietnam public health measures to control the spread of the severe acute respiratory syndrome during the outbreak in toronto isolation and characterization of viruses related to the sars coronavirus from animals in southern china bats are natural reservoirs of sars-like coronaviruses critically ill patients with severe acute respiratory syndrome influenza: the mother of all pandemics molecular basis for the generation in pigs of influenza a viruses with pandemic potential who-epidemic and pandemic alert and response (epr) key: cord- - ba huwy authors: ansarin, khalil; tolouian, ramin; ardalan, mohammadreza; taghizadieh, ali; varshochi, mojtaba; teimouri, soheil; vaezi, tahere; valizadeh, hamed; saleh, parviz; safiri, saeid; chapman, kenneth r. title: effect of bromhexine on clinical outcomes and mortality in covid- patients: a randomized clinical trial date: - - journal: bioimpacts doi: . /bi. . sha: doc_id: cord_uid: ba huwy [image: see text] introduction: bromhexine is a potential therapeutic option in covid- , but no data from a randomized clinical trial has been available. the present study aimed to evaluate the efficacy of bromhexine in intensive care unit (icu) admission, mechanical ventilation, and mortality in patients with covid- . methods: an open-label randomized clinical trial study was performed in tabriz, north-west of iran. they were randomized to either the treatment with the bromhexine group or the control group, in a : ratio with patients in each arm. standard therapy was used in both groups and those patients in the treatment group received oral bromhexine mg three times a day additionally. the primary outcome was a decrease in the rate of icu admissions, intubation/mechanical ventilation, and mortality. results: a total of patients with similar demographic and disease characteristics were enrolled. there was a significant reduction in icu admissions ( out of vs. out of , p = . ), intubation ( out of vs. out of , p = . ) and death ( vs. , p = . ) in the bromhexine treated group compared to the standard group. no patients were withdrawn from the study because of adverse effects. conclusion: the early administration of oral bromhexine reduces the icu transfer, intubation, and the mortality rate in patients with covid- . this affordable medication can easily be administered everywhere with a huge positive impact(s) on public health and the world economy. altogether, the verification of our results on a larger scale and different medical centers is strongly recommended. trial registration: irct n ; https://irct.ir/trial/ . the severe acute respiratory syndrome coronavirus (sars-cov- ) disease has emerged as a multifaceted disease with varied pathologies involving multiple organs. the covid- infection can manifest in degrees from a predicted % asymptomatic illness, to % of cases having severe illness. according to johns hopkins university coronavirus resource center, the mortality rates vary between . - % in the top most affected countries. as of mid-june , the number of deaths patients were recruited in university hospital from april , , to may , . the study was completed on may , . written informed consent was obtained from all study participants. this clinical trial was an openlabel, randomized clinical study. eighty-nine patients with a diagnosis of covid- pneumonia were screened. eleven of the patients were excluded. [ not meeting inclusion criteria, declined]. a total of patients were enrolled. the diagnosis of covid- pneumonia was made by a board-certified pulmonologist based on clinical symptoms and signs, as well as chest ct findings compatible with the covid- pneumonia pattern. although pcr testing became available within a few weeks following the start of the outbreak, its use was not relied upon for entry into the trial given the lag period for the availability of results and a high number of false-negative results. the subjects, based on inclusion and exclusion criteria, were randomized ( : ) via balanced block randomization into treatment and non-treatment (standard) groups [ persons per each group] by epidemiologists of the study. clinicians and patients were not blind to treatment assignment. inclusion criteria were the following: hospital admission, years old or greater, chest imaging and clinical symptoms consistent with covid- pneumonia, willingness to participate in the study, signed informed consent, and no participation in other clinical trials. exclusion criteria were the following: pregnancy or lactation, patients with chronic respiratory disease that pre-existence symptoms or consolidations may interfere with an accurate diagnosis of covid- , and a history of allergy to bromhexine and patients with cancer. patients received treatment based on the iranian national covid- treatment protocol and best practice guidelines at that time and also the "hydroxychloroquine mg/d for two weeks" in addition to supportive and symptomatic therapy. the treatment arm received oral bromhexine hydrochloride mg three times a day for two weeks after randomization in addition to standard therapy. the primary outcomes were the improvement in the rate of icu admissions, intubation/mechanical ventilation, and -days mortality. the secondary clinical outcomes were as follows, clinical improvement of symptoms surpassed , individuals throughout the world. the virus can aggravate an inflammation cascade and cause a cytokine storm. this is one of the major mechanisms that can cause the deterioration of the general condition in patients with covid- infection. multiple different therapeutic options like antimalaria, hiv medications, antivirals, and steroids have been tried with limited results. the most notable was the compassionate use of remedisivir in the setting of covid- infection. the original data initially encouraged the fda to approve this medication for use in covid- infections, but further clinical trials have not been able to support significant clinical benefit. currently, no therapeutic agents have been proven to be effective in reducing the mortality and treatment of patients with covid- . [ ] [ ] [ ] sars-cov- attaches to the angiotensin-converting enzyme (ace ) receptor of the host cell via its spike protein. the virus has two pathways in which it can enter the cell, either endocytosis or non-endocytosis. today, the newer viruses tend to use the non-endocytosis pathway which is activated by transmembrane serine protease (tmprss ). blocking the tmprss and the nonendocytosis pathway would be an interesting therapeutic option in preventing virus entry into the cell and therefore, treating the disease. nafamostat and camostat mesylate, medications that are used to treat chronic pancreatitis are potential candidates for blocking virus entry by inhibiting tmprss . , there is some concern about the low distribution of these drugs in the respiratory system. as shown in fig. , another tmprss inhibitor with a greater distribution capacity into the lung tissue is bromhexine hydrochloride. , it is an old over-the-counter medication that has been used for several decades as a mucolytic agent. the current study, an open-label, randomized clinical trial, examined the efficacy of early start of oral bromhexine, in the intensive care unit (icu) admission, rate of mechanical ventilation, and mortality in patients with covid- pneumonia. including fever, dyspnea, and weakness, assessment of c-reactive protein (crp), lactate dehydrogenase (ldh), neutrophil/lymphocyte ratio (nlr), and length of stay in the hospital. the clinical improvement was defined as the improvement of the patient's symptoms to the point that we were able to discharge the subject home and complete treatment as an outpatient. clinical symptoms of the subjects included fever, cough, dyspnea, lassitude, myalgia, and gi symptoms, (nausea, vomiting, and diarrhea) which were ascertained by a physician blinded to the treatment allocation. a structured questionnaire for admission baseline and again at the end of the treatment period was used. in all patients, the nlr, crp, and ldh levels were measured and recorded before the treatment onset and again at the conclusion of treatment. oxygen saturation was monitored daily and chest x-rays were done as needed. clinical stability and oxygen saturation ≥ % in room air for hours were criteria for discharge home with isolation and all patients were followed for days total. the criteria for the icu admission were the worsening of respiratory distress assessed by the physician, hemodynamic instability requiring vasopressors, oxygen desaturation < % that was not responsive to low flow oxygen therapy. the apache score of all subjects was calculated. assuming % power, two-sided testing at α = . , the anticipated icu admission rate of % in the control arm and % in the treatment arm, a minimum sample size of subjects per group was calculated. the quantitative and qualitative variables were reported as mean ± standard deviation and number (%) respectively. the normally and non-normally distributed quantitative variables were compared between groups using the independent sample t-test and mann-whitney, respectively. besides, the qualitative variables were compared between two groups using the chi-square test, and fisher exact test was applied where the data sparsity was observed. all the statistical analysis was conducted using spss software (version , spss inc., chicago, il, usa) and p< . was considered significant. missing data for the secondary outcomes were not imputed. only observed values were used for data analysis and presentation. eighty-nine patients with proven covid- pneumonia were screened. eleven of the patients were excluded (i.e., not meeting the inclusion/exclusion criteria, declined). a total of patients were enrolled in this randomized clinical trial. they were assigned to either the treatment with the bromhexine group or the standard treatment group in a : ratio with patients in each arm. no attrition in either arm (fig. ) the demographic and disease characteristics of the treatment and standard groups were similar ( table ). the mean age was . ± . years among the treated arm and . ± . in the standard arm. in terms of gender, ( . %) were male, and the percentage of males in the treatment and standard groups was % and %, respectively. no significant difference was noted in the comorbid conditions of diabetes mellitus and hypertension between the treatment and control groups. there was no significant difference in the time-lag of symptom initiation to hospital admission in the treatment ( . ± . days) arm or the standard ( . ± . days) arm (p= . ). the body mass index (bmi) and apache score in both groups were almost identical. there was a significant difference in the -day mortality, no patient died ( %) in the treatment group, while five patients died ( . %) in the standard group; p= . (fig. ). among patients in the treatment arm with bromhexine, two patients were admitted to icu ( . %) while in the standard arm, eleven patients ( . %) were transferred to icu. there was a significant difference in the icu admission between the treatment and the standard group (p = . ). moreover, among patients in bromhexine arm, one patient received mechanical ventilation ( . %), while in the standard arm nine patients ( . %) were intubated and underwent mechanical ventilation. there was also a highly significant difference in the intubation and mechanical ventilation between the two groups (p = . ) as shown in table . there was also a significant difference in the secondary outcome of this study (fig. ) . improvement of cardinal respiratory symptoms such as cough and dyspnea within two weeks among the two groups were assessed: dyspnea remained in . % in the treatment group vs . % in the standard group p ≤ . and cough remained in the treatment group . % vs . % in the standard group, p = . ). similar results for lassitude between the two groups were observed ( . % vs . %, p = . ). at baseline, there was no significant difference in the frequency of fever, headache, and gastrointestinal symptoms between the two groups. (table ) . there was no significant difference in the length of stay in the hospital [from randomization to discharge] between the two groups (treatment . ± . days and standard . ± . days; p = . ). no major adverse events were found. bioimpacts, , ( ), - the data presented in this clinical trial confirmed that the early-onset treatment with oral bromhexine mg three times a day not only effectively mitigated the respiratory symptoms, but also significantly decreased the rate of icu admissions, intubation, mechanical ventilation, and mortality in covid- disease. this is a very significant finding that has a direct correlation with the outcome of the disease. the difference in the number of deaths in the bromhexine arm ( death) vs. the standard arm ( deaths, . %) is reflective of the efficacy of this medication in reducing mortality when started early in the course of the disease. covid- infection, like the original sars and mers diseases, has a strong affinity to the lung parenchyma. the clinical manifestations vary from a simple cough to fullblown acute respiratory disease (ards). hypoxemia and oxygen desaturation, which have often been unresponsive to the usual therapeutic measures have led the patients to icus which often includes initiation of ventilation support and death. hypercapnia due to neuromuscular involvement, thrombotic events despite anticoagulation, and cardiac involvement might be contributing factors in the deteriorating respiratory condition leading to icu admission and death. [ ] [ ] [ ] it has been observed that there is usually rapid deterioration of the general condition within the first hours of intubation and mechanical ventilation in patients with covid- infection, having a direct correlation with poor outcomes. , this observation might encourage intensivists to adopt a higher threshold for intubating patients with covid- infection. it is prudent to consider icu admission and intubation/ mechanical ventilation in this patient population as going into the danger zone rather than a bridge to recovery. therefore, any intervention that prevents icu admission, may have a high impact on mortality rates. the length of hospital stay in the treatment arm was . ± . days and in the standard group was . ± . days. the big margin between the minimum and maximum days of hospitalization in both groups could not provide a significant p-value. the data analysis of this clinical trial also showed that cardinal respiratory symptoms (cough, lassitude, and dyspnea) in patients with covid- disease who received bromhexine treatment was remarkably less than the standard group. these findings may reflect the lower intensity of pulmonary involvement in the group of patients who received bromhexine. sars-cov- activates several inflammatory and cytokine cascades in the human body. the crp is a marker of inflammation which is suggested to be used in the screening of the patients suspected of covid- disease. crp is an acute-phase reactant that is synthesized by the liver under the trigger of il- . the plasma halflife of crp is hours. higher crp has been linked to unfavorable aspects of covid- disease such as ards what is the current knowledge? √ starting from the emergence of the covid- disease in january an effective treatment was sought diligently and avidly all over the world to treat and decrease morbidity and mortality of this disease with no clear advancement and no remarkably effective drug detected at hand so far. what is new here? √ this study intended to verify for the first time the efficacy of the bromhexine hydrochloride as a tmprss inhibitor in various aspects of covid- disease. the trial revealed that the drug, if started relatively early in the course of the disease, is effective in providing clinical improvement of the patients with obviating icu admissions, intubation and mechanical ventilations, and also in reduction of the mortalities of the disease. another lab finding that predicts the severity of illness is the nlr. it has been shown that the nlr of > . is predictive of admission to icu. in our study, the nlr was higher than . in both groups before the treatment. in the bromhexine treated arm, by the end of the treatment, nlr was lower compared to the standard group but surprisingly, it was not statistically significant (p= . ). larger scale trials might be able to reveal the significant reduction of nlr with bromhexine. ldh is an intracellular enzyme and presents in all cells, including the lung. patients with covid- disease release high amounts of ldh into circulation due to cytokine release and lung damage. the ldh level increases in patients with covid- infection and returns to normal with the improvement of the disease. the ldh is a predictor of severity and mortality in hospitalized patients. in our study, the ldh levels in both groups were high on admission, but the ldh level was found to be lower in the patients in the bromhexine arm as compared to the standard group at the end of the therapy, however it was not statistically significant (p= . ). the low levels of ldh in the bromhexine group are indicative of the less cell damage and therefore, better outcomes during covid- pneumonia. this study revealed the efficacy of early oral administration of bromhexine hydrochloride in the reduction of mortality of patients with covid- disease. patients treated with bromhexine may experience a milder course of the disease, and thus, the need for icu transfer, intubation, and mechanical ventilation can be obviated. along the same line, decreasing crp after initiation of bromhexine is in favor of the efficacy of this medication in controlling inflammation and mitigating the disease. bromhexine is a very inexpensive, affordable, safe, and over-thecounter medication in most countries that can easily be clinical features of patients infected with novel coronavirus in wuhan, china sars-cov- : a storm is raging compassionate use of remdesivir in covid- . reply remdesivir for the treatment of covid- -preliminary report remdesivir in adults with severe covid- : a randomised, double-blind, placebo-controlled, multicentre trial protease inhibitors targeting coronavirus and filovirus entry sars-cov- cell entry depends on ace and tmprss and is blocked by a clinically proven protease inhibitor tmprss : a potential target for treatment of influenza virus and coronavirus infections potential new treatment strategies for covid- : is there a role for bromhexine as add-on therapy? the androgen-regulated protease tmprss activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis hypoxia in covid- : sign of severity or cause for poor outcomes management of covid- respiratory distress pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- covid- in critically ill patients in the seattle region -case series respiratory support for patients with covid- infection intubation and ventilation amid the covid- outbreak: wuhan's experience time-scale of interleukin- , myeloid related proteins (mrp), c reactive protein (crp), and endotoxin plasma levels during the postoperative acute phase reaction prognostic value of interleukin- , c-reactive protein, and procalcitonin in patients with covid- risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease the diagnostic and predictive role of nlr, d-nlr and plr in covid- patients lactate dehydrogenase levels predict coronavirus disease (covid- ) severity and mortality: a pooled analysis the authors would like to thank dr. sepideh zununi vahed for submitting the trial to irct. dr. majid sadigh and dr. ramin ahmadi for reviewing, dr. audrey tolouian for her contribution in editing the final version of the manuscript. this study was supported by tabriz university of medical sciences, tabriz, iran. the study was approved by the ethics committee of the tabriz university of medical sciences, tabriz, iran (ir.tbzmed.rec. . ). the authors declare no conflict of interest in publishing this paper. this study not supported by any grant money from a pharmaceutical company or for-profit organization. key: cord- - to xr authors: jansson, miia; rubio, juanjo; gavaldà, ricard; rello, jordi title: artificial intelligence for clinical decision support in critical care, required and accelerated by covid- date: - - journal: anaesth crit care pain med doi: . /j.accpm. . . sha: doc_id: cord_uid: to xr nan prior to covid- , up to million people annually required icu admission and mechanical ventilation (mv) [ ] . the burden for critical care services has risen exponentially in response to the covid- pandemic [ ] . facing this "new reality", icus and emergency departments (eds) need to be re-designed. for instance, creative ways of accommodating frequent ventilator adjustments while reducing the risk of exposure to health care workers need to be found (hcws) [ ] . ai, big data, and machine learning can help health care systems respond to these unprecedented challenges. if appropriately designed and deployed, ai can allow for early diagnosis (e.g. computer-aided methods to help radiologists identify covid- specific lesions in chest x-rays), distance monitoring, and can assist the clinical decision-making process, and improve efficiency. predictive analytics can be used to estimate the probability of either presenting (diagnostic models) or developing a particular disease or outcome (prognostic models) [ ] . diagnostic models have been proposed in a variety of clinical situations including early detection or stratification of sepsis [ ] , bacterial and viral infections (e.g., covid- ) [ ] , and delirium in the icu [ ] , as well as pulmonary embolism in primary care [ ] . prognostic models have focused on predicting icu-related mortality [ ] , infections (e.g., positive blood culture, mrsa) [ ] , responses to treatments [ ] , antibiotic resistance [ ] , asynchronies during assisted ventilation [ ] , prolonged mv [ ] , extubation failure [ ] , and death in influenza [ ] , covid- [ , ] , and community-acquired pneumonia [ ] . best performances were observed in models that rely on clinical, laboratory, and radiological variables [ ] . most of these studies, however, have not included continuous physiological signals (e.g., ventilator parameters, vital signals) for prediction [ ] . indeed, such information would substantially improve prediction performance [ ] . beyond predicting specific outcomes, one should expect advances in the direction of predicting the entire temporal evolution of a patient. techniques such as structured output prediction or latent embedding have been successfully used both in the icu and elsewhere [ , ] . this approach can be used for developing personalised patient management and treatment plans, based on the success on previous patients with similar prognosis. ai and machine learning (ml) have largely been applied to the data collected since the beginning of the covid- pandemic. traditional epidemic models have described the spreading of a contagious disease in a population using differential equations. most recently, ai has been used to predict covid- incidence and evaluate the impact of mitigating measures such as population confinement and social distancing [ ] . geolocated critical care demand prediction, optimal hospital resource planning, and intelligent patient flow management with decision support algorithms can also be achieved by integrating real time clinical data with population statistics and health interventions. computer-assisted detection systems can be used for early identification, grading, and monitoring of j o u r n a l p r e -p r o o f infectious and non-infectious lung diseases. interestingly, they can also be used to distinguish viral pneumonia from bacterial pneumonia [ ] . most recently, however, ml techniques have focused on detecting covid- infections in chest x-rays and ct scans [ , ] . overall, sensitivity of ct scan has ranged from %- % for symptomatic and %- % for asymptomatic covid- patients [ ] . the worldwide shortage of personal protective equipment has promoted the utilisation of robotic technologies to minimise human-to-human contacts and the workload of health care workers. a robotic telepresence is seen as a natural successor to telemedicine. robots have also been used to automate and scale up testing capabilities, with rapid prototyping, development, and validation of automated clinical diagnostic tests for covid- [ ] . robotassisted rehabilitation has been shown to be more effective than conventional therapy alone to improve functional recovery in critically ill patients, whereas the effectiveness of robot-assisted endovascular/intravenous catheterisation and tracheal intubation, for instance, are under investigation [ , , ] . novel sensor array techniques have been used in infectious and non-infectious lung diseases. for instance, exhaled breath biomarkers (e.g., volatile and non-volatile components) are promising alternatives to traditional microbiological diagnostics. commercially available electronic nose sensors have been developed to diagnose ventilator-associated pneumonia (with and without pseudomonas aeruginosa) [ ] . using several ml algorithms, a high diagnostic accuracy has been detected therein. in the future, detecting, tracing, and managing new viral outbreaks will require deploying inexpensive and ubiquitous sensor networks. intelligent biosensors may be become part of our smart cities and buildings, integrated in our environment, air, sewage, and waste management systems. wearable personal biosensors will monitor our bodies while synthetic molecular biosensors will be part of our tissues and cells. engineering biology capabilities are exponentially accelerating as dna/rna reading and writing costs rapidly approach zero. every mutation of covid- has been sequenced and synthesised in record time, and many regions in the world are beginning to integrate wgs human data with ehr systems for personalised medicine diagnostics and treatment [ ] ; research projects are now correlating genomic biomarkers with infection severity and prognostic treatment efficacy [ , ] . ml allows searching libraries of available drugs and known molecules, accelerates effective vaccine and treatment development, enables digital modelling and testing, and engineering antibodies. furthermore, by sharing information and using standards, synbio factories are able to locally manufacture physical biomolecules designed elsewhere. acterrea research group. big data and targeted machine learning in action to assist medical decision in the icu the patient needing prolonged mechanical ventilation: a narrative review the patient needing prolonged mechanical ventilation: a narrative review strengthening icu health security for a coronavirus epidemic remote control and monitoring of ge aisys anesthesia machines repurposed as intensive care unit ventilators machine learning for clinical decision support in infectious diseases: a narrative review of current applications diagnostic prediction models for suspected pulmonary embolism: systematic review and independent external validation in primary care predictors of -year mortality in patients on prolonged mechanical ventilation after surgery in intensive care unit: a multicenter, retrospective cohort study predictors of asynchronies during assisted ventilation and its impact on clinical outcomes: the episync cohort study prediction of prolonged ventilation after coronary artery bypass grafting: data from an artificial neural network predicting weaning difficulty for planned extubation patients with an artificial neural network using a machine learning approach to predict mortality in critically ill influenza patients: a cross-sectional retrospective multicentre study in taiwan artificial intelligence approach to predict the covid- patient´s recovery prediction models for diagnosis and prognosis of covid- infection: systematic review and critical appraisal risk prediction models for mortality in community-acquired pneumonia: a systematic review cardiorespiratory dynamics measured from continuous ecg monitoring improves detection of deterioration in acute care patients: a retrospective cohort study predicting sequences of clinical events by using a personalized temporal latent embedding model optimal intensive care outcome prediction over time using machine learning modified seir and ai prediction of the epidemics trend of covid- in china under public health interventions transfer learning with deep convolutional neural network (cnn) for pneumonia detection using chest x-ray automated detection of covid- cases using deep neural networks with x-ray images a systematic review of ct chest in covid- diagnosis and its potential application in a surgical setting a new role for biofoundries in rapid prototyping, development, and validation of automated clinical diagnostic tests for sars-cov- robot-assisted therapy using the motomed letto for the integrated early rehabilitation of stroke patients admitted to the intensive care unit current utilization and future directions of robotic-assisted endovascular surgery automated tracheal intubation in an airway manikin using a robotic endoscope: a proof of concept study diagnosis of ventilator-associated pneumonia using electronic nose sensor array signals: solutions to improve the application of machine learning in respiratory research + million genomes" initiative determinantes genéticos y biomarcadores genómicos de riesgo en pacientes con infección por coronavirus sars-cov- using whole genome sequencing to help combat covid- digi-hta: health technology assessment framework for digital healthcare services the clinical artificial intelligence department: a prerequisite for success key: cord- -bkan mwy authors: giannakoulis, vassilis g.; papoutsi, eleni; siempos, ilias i. title: effect of cancer on clinical outcomes of patients with covid- : a meta-analysis of patient data date: - - journal: jco glob oncol doi: . /go. . sha: doc_id: cord_uid: bkan mwy purpose: whether cancer is associated with worse prognosis among patients with covid- is unknown. we aimed to quantify the effect (if any) of the presence as opposed to absence of cancer on important clinical outcomes of patients with covid- by carrying out a systematic review and meta-analysis. methods: we systematically searched pubmed, medrxiv, covid- open research dataset (cord- ), and references of relevant articles up to april , , to identify observational studies comparing patients with versus without cancer infected with covid- and to report on mortality and/or need for admission to the intensive care unit (icu). we calculated pooled risk ratios (rr) and % cis with a random-effects model. the meta-analysis was registered with prospero (crd ). results: a total of studies involving , patients ( , patients with cancer) with covid- from asia, europe, and the united states were included. all-cause mortality was higher in patients with versus those without cancer ( , deaths; rr, . ; % ci, . to . ; p < . ; studies with , patients). the need for icu admission was also more likely in patients with versus without cancer ( , events; rr, . ; % ci, . to . ; p < . ; studies with , patients). however, in a prespecified subgroup analysis of patients > years of age, all-cause mortality was comparable between those with versus without cancer ( deaths; rr, . ; % ci, . to . ; p = . ; studies with , patients). conclusion: the synthesized evidence suggests that cancer is associated with worse clinical outcomes among patients with covid- . however, elderly patients with cancer may not be at increased risk of death when infected with covid- . these findings may inform discussions of clinicians with patients about prognosis and may guide health policies. an ever-increasing number of people in the global population are suffering from cancer. patients with cancer are therefore anticipated to be affected during the current epidemic of covid- . however, whether, when infected with covid- , patients with versus without cancer are at increased risk for unfavorable clinical outcomes is unknown. this was highlighted in a plenary session at the american association for cancer research virtual annual meeting held on april - , which subsequently issued a call for relevant research. we therefore aimed to quantify the effect (if any) of the presence as opposed to absence of cancer on important clinical outcomes, such as mortality and need for admission in the intensive care unit (icu), of patients with covid- by carrying out a systematic review and meta-analysis. we reported the current systematic review and metaanalysis in accordance with the preferred reporting items for systematic reviews and meta-analyses statement. we prespecified inclusion criteria, methods of data synthesis, and outcomes in a protocol registered in prospero (crd ) and available online we considered observational cohort studies of covid- , which reported on all-cause mortality and/or need for icu admission of patients with cancer versus patients without cancer. details on the assessment of need for icu admission are provided in the data supplement. both peer-reviewed papers and preprints were considered, because of the need for use of rapidly accumulated information during the current situation. reports on coronavirus-caused diseases other than covid- were excluded. we systematically searched pubmed, medrxiv, and cord- (covid- open research dataset). the latter is probably the most extensive machine-readable literature collection specially created for the covid- global crisis. we retrieved all relevant english literature from january , , up to april , . we also searched references of initially retrieved articles. we used boolean logic to create to quantify the effect (if any) of the presence as opposed to absence of cancer on important clinical outcomes of patients with covid- . knowledge generated cancer is associated with worse clinical outcomes among patients with covid- . however, elderly patients with cancer may not be at increased risk of death when infected with covid- . the findings of the meta-analysis may inform discussions of clinicians with patients about prognosis and may guide health policies. the search key phrase ("clinical characteristics" or comorbidities or cancer or malignancy) and (covid- or -ncov or sars-cov- ) and (mortality or morbidity or severity or icu or outcomes). when searching cord- , we replaced boolean operators "and" and "or" with the symbols "+" and "|", respectively. when searching medrxiv, we used "covid- cancer" as the main key phrase. two authors (v.g.g. and e.p.) independently conducted the literature search and uploaded their findings in an online file storage service (google drive) to double-check them. they subsequently discussed the possibility of duplicate patient populations with the third author (i.i.s.). two authors (v.g.g. and e.p.) independently extracted data in a prespecified worksheet and cross-checked their findings. we collected data on type of publication, author, type of study, total patient population, outcomes of patients with versus without cancer, age, sex, and comorbidities. authors of original contributions were contacted. six authors provided us with additional information, which was incorporated in the findings of the meta-analysis. we assessed the methodological quality of the retrieved observational cohort studies with the tool to assess risk of bias in cohort studies, developed by the clarity group at mcmaster university. the tool uses questions, with possible answers in each. clarifications on the risk-of-bias assessment are provided in the data supplement. two authors (v.g.g. and e.p.) independently assessed the studies. the results were discussed with the third author (i.i.s.). the primary outcomes of the meta-analysis were all-cause mortality and need for icu admission. the latter outcome included either actual admission to the icu or severe disease (such as application of invasive mechanical ventilation) that required admission to the icu, even if the original study did not specify whether such patients were indeed admitted in the icu (more details are provided in the data supplement). we did so because patients with severe disease might occasionally be unable to be admitted to the icu because of unavailability of enough beds. we performed prespecified sensitivity analyses by calculating the pooled risk ratio (rr) of studies with low risk of bias and by excluding each study and recalculating the rr. we attempted prespecified subgroup analyses by age, type of cancer (solid tumor v hematologic malignancy), and country, but we were not able to perform the last analyses because of unavailability of relevant data. we conducted data synthesis using review manager . (revman . ) by the cochrane collaboration. we expressed pooled dichotomous effect measures as rr with % ci. we used a random-effects (dersimonian and laird) model. we measured the presence of statistical heterogeneity with i , interpreted according to the cochrane handbook recommendations ; %- %: might not be important; %- %: may represent moderate heterogeneity; %- %: substantial heterogeneity; %- %: considerable heterogeneity. cancer and covid- figure shows the flow diagram for study selection. regarding mortality data from china, we excluded presumably duplicate publications with overlapping enrollment dates to include only overarching report from the chinese center for disease control and prevention (cdc). however, given that the latter report from the chinese cdc did not provide specific data on old patients, and studies from china provided such data, , we included these studies in our subgroup analysis by age. a total of studies ( peer-reviewed, preprints) involving , patients ( , patients with cancer) with covid- from asia, europe, and the united states were included in our meta-analysis. tables and list the summary characteristics and risk of bias assessment of the included studies, respectively. eight studies ( , total patients, , with cancer) provided data for all-cause mortality. , , , , , , , no statistically significant heterogeneity was detected (i = %). all-cause mortality was higher in patients with versus without cancer ( , deaths; rr, . ; % ci, . to . ; p , . ; fig ) . twenty-six studies ( , total patients, with cancer) provided data for need for icu admission. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] moderate significant heterogeneity was detected (i = %). patients with cancer were more likely to need icu admission than patients without cancer ( , events; rr, . ; % ci, . to . ; p , . ; fig ) . in the sensitivity analysis of studies with low risk of bias ( , total patients, with cancer), all-cause mortality was higher in patients with versus without cancer ( deaths; rr, . ; % ci, . to . ; p = . ). , , , this was also the case for the sensitivity analyses by excluding each study and recalculating the rr. in the prespecified subgroup analysis of studies ( , patients, with cancer), which provided data on mortality of patients . years old, all-cause mortality was comparable between those with versus without cancer ( deaths; rr, . ; % ci, . to . ; p = . ; fig ) . , , , , , , , discussion by performing the most comprehensive meta-analysis to date, which incorporated data from . , patients with covid- across almost all continents, we quantified the effect of cancer on all-cause mortality (rr, . ; % ci, . to . ) and need for icu admission (rr, . ; % ci, . to . ). also, by performing a prespecified subgroup analysis, we revealed the interesting finding that among patients . years of age, all-cause mortality was comparable between those with versus without cancer. it is important to quantify the effect of cancer on outcomes of patients with covid- , as there are conflicting reports in the literature. several studies indicated that patients with cancer are more likely to develop severe disease and are at increased risk for poor prognosis. [ ] [ ] [ ] they therefore encouraged clinicians to treat patients with cancer as an extremely vulnerable population. those studies might also raise issues as to whether it is futile to admit patients with cancer and covid- to the icu. on the other hand, other studies suggested that there was no evidence of elevated mortality rates among infected patients with cancer. , an interesting theory even suggested that immunocompromised patients, such as patients with cancer, may dampen the so-called "cytokine storm" because of downregulated immune response and thus have comparable or even better clinical outcomes. , the results of our meta-analysis might help to reveal the true effect of cancer on mortality and need for icu admission. an interesting finding of the meta-analysis was that, when data were collected from older patients, the increased mortality risk in the presence of cancer did not seem obvious. regardless of cancer presence, increased age is considered a factor of worse prognosis. , furthermore, older individuals are characterized by an increased prevalence of comorbidities, which variably contribute to overall worse outcomes. on considering the aforementioned, the observed absence of increased mortality risk in older individuals does not conflict with the main findings of the study; it rather implies that the presence of cancer may not further affect the already burdened prognosis among individuals age . years. our meta-analysis has limitations. first, there are concerns for duplicate publications, which might skew the results of any meta-analysis. in an attempt to minimize this risk, we excluded studies on mortality conducted in the same region with overlapping enrollment dates and we included only the results of the largest cohort. second, data were not available to perform meaningful subgroup analyses by type of cancer (including treatment and immunosuppressive status). however, through communications with authors of original studies, we were able to carry out an important subgroup analysis by age. in conclusion, by accumulating data from studies involving , patients ( , patients with cancer) with covid- from asia, europe, and the united states, we quantified the effect of cancer on important clinical outcomes, such as mortality and need for icu admission. we also found that elderly patients with cancer may not be at increased risk of death when infected with covid- . the findings of the meta-analysis are important to clinicians, because they can inform discussions with patients about prognosis. they may also guide health policies regarding protection of this vulnerable population. conception and design: all authors collection and assembly of data: vassilis g. giannakoulis, eleni papoutsi data analysis and interpretation: all authors manuscript writing: all authors final approval of manuscript: all authors accountable for all aspects of the work: all authors the following represents disclosure information provided by authors of this manuscript. all relationships are considered compensated unless otherwise noted. relationships are self-held unless noted. i = immediate family member, inst = my institution. relationships may not relate to the subject matter of this manuscript. for more information about asco's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs. org/go/site/misc/authors.html. open payments is a public database containing information reported by companies about payments made to us-licensed physicians (open payments). no potential conflicts of interest were reported. latest global cancer data: cancer burden rises to . million new cases and . million cancer deaths are cancer patients more vulnerable to covid- ? the prisma statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration editorial concern-possible reporting of the same patients with covid- in different reports tool to assess risk of bias in cohort studies. contributed by the clarity group at mcmaster university version . . copenhagen, the nordic cochrane centre, the cochrane collaboration cochrane handbook for systematic reviews of interventions version the novel coronavirus pneumonia emergency response epidemiology team: the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- ) -china clinical characteristics and outcomes of older patients with coronavirus disease (covid- ) in wuhan coronavirus disease in elderly patients: characteristics and prognostic factors based on -week follow-up characterization and clinical course of patients with covid- in new york: retrospective case series sars-cov- comorbidity network and outcome in hospitalized patients in covid- in a designated infectious diseases hospital outside hubei province clinical features of patients infected with the novel coronavirus (covid- epidemiological and clinical features of cases with coronavirus disease in areas adjacent to hubei, china: a doublecenter observational study clinical characteristics of coronavirus disease (covid- ) early findings from a teaching hospital in pavia covid- with different severity: a multi-center study of clinical features clinical characteristics of covid- in comorbidity and its impact on patients with covid- in china: a nationwide analysis clinical features of patients infected with novel coronavirus in wuhan clinical features and management of severe covid- : a retrospective study in wuxi outcomes of the novel coronavirus in patients with or without a history of cancer -a multi-centre north london experience risk factors for severity and mortality in adult covid- inpatients in wuhan do patients with cancer have a poorer prognosis of covid- ? an experience in characteristics of hospitalized adults with covid- in an integrated health care system in california epidemiological characteristics of coronavirus disease (covid- ) patients in iran: a single center study factors associated with hospitalization and critical illness among , patients with covid- disease in new york city covid- testing, hospital admission, and intensive care among , , united states veterans aged - years characteristics and outcomes of a cohort of sars-cov- patients in the province of reggio emilia clinical characteristics of imported and second-generation covid- cases outside wuhan, china: a multicenter retrospective study clinical features and treatment of covid- patients in northeast chongqing clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china clinical features of cases with coronavirus disease clinical characteristics of coronavirus disease in hainan retrospective study of risk factors for severe sars-cov- infections in hospitalized adult patients clinical features and outcomes of patients with covid- in wuhan risk factors for disease severity, unimprovement, and mortality in covid- patients in wuhan, china ct features of sars-cov- pneumonia according to clinical presentation: a retrospective analysis of consecutive patients from wuhan city clinical characteristics and durations of hospitalized patients with covid- in beijing: a retrospective cohort study a multicentre study of novel coronavirus disease outcomes of cancer patients in wuhan clinical characteristics of covid- -infected cancer patients: a retrospective case study in three hospitals within wuhan, china clinical characteristics and prognosis in cancer patients with covid- : a single center's retrospective study admission of critically ill patients with cancer to the icu: many uncertainties remain clinical factors predict deterioration among patients with cancer, covid- benign covid- in an immunocompromised cancer patient -the case of a married couple severe outcomes among patients with coronavirus disease (covid- ) -united states clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study we thank christopher t. rentsch key: cord- -xvauo d authors: hui, david s.; wong, ka t.; ko, fanny w.; tam, lai s.; chan, doris p.; woo, jean; sung, joseph j.y. title: the -year impact of severe acute respiratory syndrome on pulmonary function, exercise capacity, and quality of life in a cohort of survivors date: - - journal: chest doi: . /chest. . . sha: doc_id: cord_uid: xvauo d objective to examine pulmonary function, exercise capacity, and health-related quality of life (hrqol) among severe acute respiratory syndrome (sars) survivors. methods we evaluated survivors with confirmed sars at the prince of wales hospital, hong kong, at , , and months after symptom onset. our assessment included: lung volume (total lung capacity [tlc], vital capacity, residual volume, functional residual capacity), spirometry (fvc, fev ), diffusing capacity of the lung for carbon monoxide (dlco), inspiratory and expiratory respiratory muscle strength, -min walk distance ( mwd), chest radiographs (cxrs), and hrqol by medical outcomes study -item short-form general health survey questionnaire. results ninety-seven patients completed the serial assessments. there were male and female patients, and patients ( %) were health-care workers (mean age, . years [sd, . years]; body mass index, . kg/m [sd, . kg/m ]). at year, patients ( . %) had abnormal cxr findings. four patients ( . %), patients ( . %), and patients ( . %) had fvc, tlc, and dlco values < % of predicted values, respectively. the mwd at months was . m (sd, . m), which was higher than at months (mean difference, . m; % confidence interval [ci], . to . m; p < . ) but not different from months (mean difference, . m; % ci, − . to . m; p = . ). the mwd was lower than that for normal control subjects of the same age groups, and there was impairment of hrqol at months. patients who required icu admission (n = ) showed higher cxr scores ( . [sd, . ]; vs . [sd, . ]; p = . ) and lower percentage of predicted fvc, tlc, and dlco than those who did not, but there were no differences in mwd and health status. conclusion significant impairment in dlco was noted in . % of survivors year after illness onset. exercise capacity and health status of sars survivors were remarkably lower than those of a normal population. to maintain oxygen saturation Ͼ %. several studies [ ] [ ] [ ] have shown that to % of patients required icu admission, whereas to % progressed into ards, necessitating invasive ventilatory support. in a major outbreak of sars at our hospital in , over half of those with sars infection were previously healthy hcws. high-resolution ct (hrct) performed at weeks after hospital discharge selectively on outpatients with residual opacities revealed multiple patchy ground-glass appearance and interstitial thickening in patients ( %) and ct evidence of fibrotic changes in patients ( %). it is likely that ongoing active alveolitis, probably as a result of an uncontrolled host immune response triggered by the viral antigen, may lead to pulmonary fibrosis in some patients. previous studies on survivors of acute lung injury and ards [ ] [ ] [ ] [ ] unrelated to sars have shown variable degrees of residual abnormalities in pulmonary function, exercise capacity, and impairment in healthrelated quality of life (hrqol). we have recently reported that . % of our sars survivors (n ϭ ) had abnormal diffusing capacity of the lung for carbon monoxide (dlco) at months, whereas overall their exercise capacity and health status were lower than normal populations of the same age groups. we report herein the -year outcome of a prospective follow-up study of the same sars patient cohort, which was epidemiologically linked to a single index case during a major hospital outbreak in . , we examined serial lung function, exercise capacity, chest radiographs (cxrs), and hrqol at , , and months after the onset of illness. in addition, we compared sars survivors who required icu admissions to those who were treated on the medical wards with reference to the same outcome parameters. this is a prospective, longitudinal, follow-up study of patients with sars discharged from our hospital after surviving the major outbreak in . the patients came from our previously reported cohort recruited over a period of weeks from march to march , . the diagnosis of sars was based on the centers for disease control and prevention criteria at the time. all patients in this study had subsequent laboratory confirmation of sars. treatment and outcome of these patients during hospitalization have been reported in detail elsewhere. this prospective outcome study of sars survivors was approved by the ethics committee of the chinese university of hong kong. following discharge from the hospital, patients were evaluated in the lung function laboratory at the end of , , and months after disease onset. during the visit, subjects were interviewed and underwent a physical examination, pulmonary function testing, respiratory muscle strength measurement, posteroanterior cxr, resting oximetry, and a standardized -min walk test ( mwt). , in addition, they completed the medical outcomes study -item short-form general health survey (sf- ) to measure hrqol. mwt: the mwt provides a standardized, objective, integrated assessment of cardiopulmonary and musculoskeletal function that is relevant to daily activities. , the self-paced mwt assesses the submaximal level of functional capacity and has been applied in a long-term follow-up study of survivors of ards. the -min walk distances ( mwds) were compared to normative reference data collected from a population survey of normal healthy subjects in by the coordinating committee in physiotherapy, hong kong hospital authority, on separate days. the mwds of the control subjects (n ϭ ) on day and day of assessment were . m (sd, . m) and . m (sd, . m), respectively, with an intraclass correlation coefficient of . ( % confidence interval [ci], . to . ); se of measurement, . ; minimum detectable change, . m; and limit of agreement, . ( % ci, Ϫ . to . ). the mwd data stratified into different age groups are available for comparison with the sars patients, although we have no access to individual data of this population survey. sf- : the sf- includes eight multiple-item domains that assess physical functioning (pf), social functioning (sf), role limitation due to physical problems (rp), role limitation due to emotional problem (re), mental health (mh), bodily pain (bp), vitality (vt), and general health (gh). scores for each aspect can range from (worst) to (best) with higher scores indicating better hrqol. the validated chinese (hong kong [hk]) version of the sf- was applied for this study, and the results were compared to the hk normative data collected from a random telephone survey , and surface area for gas exchange (dlco adjusted for hemoglobin, and dlco adjusted for alveolar volume [kco]) were performed (vmax system; sensormedics; yorba linda, ca). dlco was determined by the single-breath technique using an infrared analyzer. we per-formed spirometry (fev and fvc) according to the standards of the american thoracic society. , the results were compared to the normative data, which have been widely adopted as the reference data in hk. measurement of the maximum static inspiratory pressure (pimax) that a subject can generate at the mouth or the maximum static expiratory pressure (pemax) is a simple way to gauge inspiratory and expiratory muscle strength. , since respiratory muscle weakness may lead to a restrictive pattern on lung function testing, pimax and pemax were assessed with a mouth pressure meter via a flanged mouthpiece after full lung function testing. in a study of normal subjects ( chinese and indian; mean age, . years) in singapore, the maximal static inspiratory effort from rv for the group was . cm h o (sd, . cm h o). a pimax of Ϫ cm h o and a pemax of ϩ cm h o generally exclude clinically significant weakness of the inspiratory and expiratory muscles, respectively. radiographic assessment: frontal cxrs were performed at , , and months using standardized techniques with computed radiography equipment as we have reported during the major hospital outbreak. the images were assessed using a picture archive communications system (magicview va e; siemens; erlangen, germany) and viewer (model k; siemens). each lung was divided into three zones (upper, middle, and lower) on frontal radiography. the observers assessed the presence, appearances (airspace opacities or reticular opacities), distribution, and size of lung parenchymal abnormalities on each cxr of all patients. the size of the lesion was assessed by visually estimating the percentage of area occupied in each zone on each side. the overall percentage of involvement was obtained by averaging the percentage of involvement of the six lung zones. the frontal cxr closest to the date of the lung function test was assessed by two radiologists, both of whom were blinded to the clinical information. the findings were reached by consensus. the assessment method was described in our previous study. statistical analysis was performed using statistical software (statistical package for social science, version . ; spss; chicago, il). cumulative steroid dosage during inpatient treatment and outpatient follow-up was converted into hydrocortisone in milligrams to facilitate analysis of this study. continuous variables were compared using independent-sample t test, whereas the mann-whitney u test was used for nonparametric data. categorical variables were compared using the test. all statistical tests were two tailed. statistical significance was taken as p Ͻ . . univariate analyses were performed to evaluate the potential determinants of exercise capacity expressed as the mwd. variables significant in univariate analysis (p Ͻ . ) were included in the multivariate analysis. age and sex were controlled in the analysis of the final multivariable models because they are independent determinants of the mwd. , repeated-measures analysis of variance (anova) was used to assess serial changes in mwt distance and cxr scores. of the first patients with sars infection in march , patients ( . %) died. among the survivors, patients ( . %) did not attend follow-up at months and months, whereas another patients ( . %) defaulted the -month assessment. of the defaulters at months, patients had normal lung function indexes, whereas the other patients had dlco of % and % of predicted normal values, respectively, at months. thus, there were only patients ( . %) who had completed the three assessments; among these, patients ( %) were hcws (doctors, nurses, ward assistants, and medical students) and patients ( %) were women. the mean age was . years (sd, . years) and body mass index (bmi) was . kg/m (sd, . kg/m ) during the visit at months from illness onset. the hospital length of stay (los) for the group was . days (sd, . days). there were only three smokers ( . %) among the whole group. there were patients with medical comorbidities, which included copd (n ϭ ; . %); ischemic heart disease (n ϭ ; . %); ischemic stroke (n ϭ ; . %); breast cancer (patient in stable clinical condition receiving tamoxifen) [n ϭ ; . %]; diabetes mellitus (n ϭ ; . %); cirrhosis (n ϭ ; . %), hypertension (n ϭ ; . %); and asymptomatic hepatitis b carrier (n ϭ ; . %). among the patients, patients ( %; men and women) required icu admission, with an icu los of . days (sd, . days; median, days; range, to days), whereas patients ( . %) required invasive mechanical ventilation. based on our icu admission criteria, all patients would have a pao /fraction of inspired oxygen ratio Ͻ mm hg, whereas the patients who were intubated had a pao /fraction of inspired oxygen ratio Ͻ mm hg. among these patients, patients had medical comorbidities, including ischemic heart disease (n ϭ ; . %), diabetes mellitus (n ϭ ; . %), hypertension (n ϭ ; . %), and asymptomatic hepatitis b carrier (n ϭ ; . %), but none had any history of smoking or pulmonary disease. an overview of the serial lung function tests and respiratory muscle strength results for the group are shown in table . overall, lung volume parameters and surface area for exchange were well preserved at , , and months. there was significant reduction in dlco, fef , and alveolar volume (va), whereas there was an increase in kco over the study period of months. pimax and pemax values Ͻ cm h o were noted in patients ( . %) and patients ( . %), respectively, at months. the frequency of sars survivors with lung function parameters Ͻ % of predicted values is as follows: months, fev (n ϭ ; . %), fvc (n ϭ ; . %), vc (n ϭ ; . %), tlc (n ϭ ; . %), dlco (n ϭ ; . %), and kco (n ϭ ; . %); months, fev (n ϭ ; . %), fvc (n ϭ ; . %), vc (n ϭ ; . %), tlc (n ϭ ; . %), dlco (n ϭ ; . %), and kco (n ϭ ; . %); and months, fev (n ϭ ; . %), fvc (n ϭ ; . %), vc (n ϭ ; . %), tlc (n ϭ ; . %), dlco (n ϭ ; . %), and kco (n ϭ ; %). thus, there were patients ( . %) with impaired dlco, whereas up to . % of patients had reduction in parameters of lung volume at months. the mean mwd increased significantly, from m (sd, m) at months to m (sd, m) and m (sd, m) at months and months, respectively (p value for trend Ͻ . ). when the subjects were stratified into different age groups and compared to the corresponding normative values, their exercise capacity was generally significantly lower than the normal subjects ( table ). the mwds of the sars survivors at , and months, in comparison with normative data, are shown in table . univariate followed by multivariate analyses, controlled for age and gender, were performed to look for factors associated with mwd (table ) . at months, there was no independent predictor identified, whereas percentage of predicted fvc was the only positive independent predictor for mwd at months. at months, the independent positive predictors for mwd were percentage of predicted fvc and percentage of predicted dlco. thirty-seven patients ( . %) were noted to have abnormal total cxr scores at months involving . % (sd, . %; range, . to %) of the total lung fields, whereas patients ( %) had abnormal cxr scores involving . % (sd, . %; range, . to %) of the lung fields at months. at year, patients ( . %) had abnormal cxr findings involving . % (sd, . %; range, . to %) of lung fields. by repeated-measures anova analysis of patients with abnormal cxr scores (n ϭ ), there was a significant trend for improvement from to months (p ϭ . ). correlations between the extent of cxr abnormality vs cumulative steroid dosage, lung function parameters, and mwd at months were examined. there was a significant positive correlation between the extent of radiographic abnormalities (percentage of lung fields) and the cumulative hydrocortisone dosage (r ϭ . , p Ͻ . ). there were significant negative correlations between the extent (percentage) of radiographic abnormalities and tlc (r ϭ Ϫ . , p ϭ . ) and dlco (r ϭ Ϫ . , p Ͻ . ). however, no significant correlations were noted between the extent of radiographic abnormalities vs mwd (r ϭ Ϫ . , p ϭ . ), fev (r ϭ Ϫ . , p ϭ . ), rv (r ϭ Ϫ . , *data are presented as mean (sd). †in comparison between months and months, the mean difference for fef was Ϫ . % ( % ci, Ϫ . to Ϫ . ; p Ͻ . ), whereas the mean difference was Ϫ . % ( % ci, Ϫ . to . ; p ϭ ) in comparison between months and months (p value for linear trend Ͻ . ). ‡in comparison between months and months, the mean difference for dlco was Ϫ . % ( % ci, Ϫ . to Ϫ . ; p ϭ . ), whereas the mean difference was Ϫ . % ( % ci, Ϫ . to Ϫ . ; p ϭ . ) in comparison between months and months (p value for linear trend . ). §in comparison between months and months, the mean difference for kco was . % ( % ci, . to . ; p Ͻ . ), whereas the mean difference was . % ( % ci, . to . %; p ϭ . ) in comparison between months and months (p value for linear trend Ͻ . ). ʈthere was a significant decrease in va from to months (mean difference, . ; % ci, . to . ; p Ͻ . ), and from to months (mean difference, . ; % ci, . to . ; p Ͻ . ) ͓p value for linear trend Ͻ . ͔. patients who had required icu admission (n ϭ ; men and women) had a higher peak lactate dehydrogenase (ldh) level, a higher peak c-reactive protein (crp) level, a longer hospital los, and received a significantly higher total steroid dose than those who did not require icu care ( table ). the lung function tests at months showed significantly lower percentage of predicted fvc, vc, tlc, rv, and dlco in survivors who required icu support than those who were treated on medical wards, although no significant difference was noted for mwd and respiratory muscle strength between the two groups ( table ) . sf- domain scores at , , and months after illness onset in patients who did and did not require icu support during the acute illness in comparison to normative data are shown in figure (more data are available only in on-line supplemental tables - ). there was significant impairment of health status among our sars survivors at months compared to control subjects of the same age groups. when directly comparing those who had required icu admission against those treated on the medical wards, there was no significant difference in all sf- domains between the two groups at months. when comparing the patients who did not require intubation in icu against those who had required intubation (n ϭ ), the latter had more severe lung injury, as reflected by a higher peak in addition, there were no significant differences between the two groups with regard to lung function indexes and sf- domain scores at months (data available only in on-line supplemental table ). this prospective cohort study has shown that . % and . % of sars survivors had impairment of dlco and abnormal cxr findings, respectively, at year after illness onset. overall, the serial assessments of mwd showed a significant improvement over months, but exercise capacity and health status were still significantly lower than those of normal control subjects of the same age groups. the -year lung function indexes (percentage of predicted fvc, vc, tlc, rv, and dlco) in survivors who required icu support were remarkably lower than those of patients who were treated on medical wards, although no significant differences were noted for mwd, respiratory muscle strength, and health status between the two groups. interestingly, there was no difference in lung function indexes, exercise capacity, and health status at year between the icu-intubated and the icu-nonintubated sars patients, although the former had more severe lung injury. based on the hrct appearance of bronchiolitis obliterans organizing pneumonia (boop) and the clinical suspicion that progression of the pulmonary disease might be mediated by the host inflammatory response, pulse methylprednisolone was administered during clinical progression of sars with a favorable response. , , [ ] [ ] [ ] lung histopathologic condition of fatal sars cases was dominated by diffuse alveolar damage and extensive consolidation, - but features of boop were indeed noted. at months after admission to hospital, residual abnormalities of pulmonary function were observed in three fourths of the queen elizabeth hospital cohort in hk (n ϭ ), mostly consisting of isolated reductions in dlco, whereas an abnormal hrct score was detected in . % of patients. in contrast, . % of our sars survivors had impaired dlco at months, whereas hrct performed on patients revealed ground-glass opacification and reticulation in patients ( . %) and patients ( . %), respectively. at year, . % of our patients had significant impairment of dlco with well-preserved kco. the serial results suggest an increase of the intra-alveolar diffusion pathway, which might be the result of diffuse alveolar damage and/or boop initially, - followed by postinflammatory changes such as atelectasis, ongoing alveolitis, and parenchymal fibrosis later in the course of the disease. our results are similar to a long-term follow-up study in beijing that reported that . % of their sars survivors ( of patients) had impaired dlco, whereas . % exhibited radiographic evidence of lung fibrotic changes at year. several studies - on ards survivors have shown that their pulmonary function generally returns to normal or near normal by to months, but dlco may remain abnormal in up to % of patients at year after recovery. the decreasing trend for va, discordant with tlc, observed in our study suggests there might be maldistribution of the inert gas during the single-breath dlco maneuver, such as in the setting of occult small airway obstruction in some patients. although expiratory hrct was not performed in adult patients, , a pediatric study of asymptomatic children at months from diagnosis of sars showed that patients ( %) had pulmonary abnormalities, whereas patients ( %) had evidence of air trapping on expiratory hrct. the self-paced mwt was performed to evaluate the global and integrated responses to exercise, although it did not provide specific information on the function of individual organs and systems. although showing considerable improvement over months, the mwd was markedly reduced for most age groups compared to normal control subjects. previous studies , have shown that mwd was substantially lower among ards survivors than control subjects to years after mechanical ventilation, whereas the absence of systemic steroid treatment, absence of illness acquired during icu stay, and rapid resolution of lung injury were important factors associated with a longer mwd at , , and months, respectively. after controlling for the known effects of age and gender, our analysis has shown that percentage of predicted fvc was the positive independent factor associated with higher mwd at months, whereas percentage of predicted fvc and percentage of predicted dlco were the positive independent predictors at months. given the relatively well-preserved lung function in the majority of our sars survivors, the poor performance in the mwt in most age groups could be due to additional factors such as muscle wasting, myopathy, and possibly cardiac diastolic dysfunction. lau et al noted that muscle strength and endurance were more impaired in proximal than in distal muscles among survivors in our sars cohort at months after illness onset. eighteen of sars survivors in singapore had reduced exercise capacity at months after hospital discharge that could not be accounted for by impairment of pulmonary function. these results suggest that the inability to exercise in recovered sars patients is primarily due to extrapulmonary causes such as physical deconditioning and possibly steroid myopathy. , in addition, % of sars survivors complained of some ) among sars survivors at , , and months after illness onset in comparison with hk normative data stratified into different age groups. the vertical axis represents sf- domain score in mean (sd) from (minimum) to (maximum), whereas the horizontal axis defines age groups in years. based on the study by lam et al, there were , normal subjects and normal subjects in the age groups of to years and to years, respectively. there were sars survivors and sars survivors who had required icu support in the age groups of to years and to years, whereas there were sars survivors and sars survivors who did not require icu support in the same age groups, respectively. *significant at p Ͻ . . **significant at p Ͻ . . #significant at p Ͻ . . mth ϭ month. degree of large-joint pain, although only patients ( . %, including patients in the current study) of sars survivors in our cluster of hospitals had evidence of osteonecrosis of the long bones on mri conducted at a median of . months from hospital admission. there are several possible causes for muscle weakness among sars survivors. more than % of our patients complained of myalgia with elevation of creatinine kinase in . % suggestive of viral-induced myositis at initial presentation. most of our patients required bed rest during hospitalization for an average of weeks. the long period of bed rest could lead to muscle wasting and deconditioning, whereas the use of systemic corticosteroid therapy to suppress immune-mediated lung injury , - , could contribute to myopathy. steroid myopathy has been reported in patients administered high-dose steroid for acute lung transplant rejection and status asthmaticus. critical illness-associated polyneuropathy/ myopathy has also been observed in sars survivors. a small proportion of our sars patients had evidence of respiratory muscle weakness. inspiratory muscle weakness may cause atelectasis, whereas expiratory muscle (abdominal and intercostal muscles) weakness may lead to air trapping. in addition, there was significant impairment of health status in most sf- domains among our patients at months. there were significant and positive correlations between lung function parameters (vc, fvc, fev , and dlco) and sf- domains such as pf, rp, gh, sf, and re. there were also significant positive correlations between mwd and all sf- domains except for mh. the results are not surprising as, in addition to the physical impairment, the long period of isolation and extreme uncertainty during the sars illness had created enormous psychological stress and mood distur-bances. in addition, steroid toxicity, personal vulnerability, and psychosocial stressors might have jointly contributed to the development of psychosis in some patients. other studies - on acute lung injury or ards survivors unrelated to sars have reported impaired health status at to years after recovery, whereas pulmonary function abnormalities, especially dlco, correlated with sf- domains. , twenty-seven patients ( . %) in this study still had abnormal radiographic scores at months, although their serial cxrs showed significant improvement. the positive correlation between the extent of residual radiographic abnormalities and the cumulative steroid dosage used for sars was expected, as the former was an indication on the treatment protocol for more systemic steroid during the outbreak. , , the negative correlation between residual radiographic abnormality and lung volume parameter (tlc) and parameter of surface area for gas exchange (dlco) reflected the physiologic effects of parenchymal inflammation and fibrosis. patients with more severe disease (as reflected by higher peak ldh level) , , who had required icu support during the acute illness had more residual opacities on cxrs at months. in addition, they had more extensive pulmonary injury and fibrosis, as reflected by a significantly lower lung volume parameter (tlc) and dlco at months than those treated on the general wards. there were, however, no significant differences in mwd and hrqol between the two groups at months. in addition, there were no differences in any functional parameters between icu patients receiving and not receiving mechanical ventilation. herridge et al reported that % of their ards survivors had minor abnormalities on cxrs at year. there are several limitations to this study. firstly, among the normal control subjects, , subjects and subjects were in the age groups to years and to years, whereas there were subjects and subjects who were sars survivors in the same age categories, respectively. see table for expansion of abbreviation. †significant at p Ͻ . . ‡significant at p Ͻ . . §significant at p Ͻ . . we did not perform cardiopulmonary exercise testing (cpet), as many patients complained of generalized muscle weakness on initial follow-up. cpet would also be too labor-intensive for a large cohort of sars survivors. nevertheless, reduced pulmonary gas exchange has been detected with cpet in some survivors of sars at months with normal dlco. secondly, only of survivors ( %) in the cohort had completed the serial assessments over months, and the results might not be representative of the entire cohort. thirdly, we assessed respiratory muscle strength with mouth pressure, but low pemax values do not always indicate expiratory muscle weakness and might result from technical difficulties such as mouth leakage. lastly, we could not measure the effects of extrapulmonary factors (such as muscle deconditioning, steroid or viralinduced myopathy, cardiac diastolic dysfunction, critical illness polyneuropathy and/or myopathy) in the poor performance of the mwt. it is difficult to determine the contribution by psychological and motivational factors, as many patients are seeking compensation for occupation-related sars. in summary, this study has shown significant impairment of dlco in . % of sars survivors, whereas their exercise capacity and health status were remarkably lower than the general population at months after illness onset. the functional disability appears to be out of proportion to the degree of lung function impairment and may be due to additional factors such as muscle deconditioning, steroid-related musculoskeletal complications, critical illness-related neuropathy/myopathy, and other psychological factors. further follow-up is needed to assess if these deficits are persistent. epidemiology and cause of severe acute respiratory syndrome in guangdong, people's republic of china the severe acute respiratory syndrome severe acute respiratory syndrome clinical progression and viral load in a community outbreak of coronavirusassociated sars pneumonia: a prospective study viral shedding patterns of coronavirus in patients with probable severe acute respiratory syndrome severe acute respiratory syndrome (sars): correlation of clinical outcome and radiological features a major outbreak of severe acute respiratory syndrome in hong kong short term outcome and risk factors for adverse clinical outcomes in adults with severe acute respiratory syndrome (sars) severe acute respiratory syndrome: clinical outcome and prognostic correlates thin-section ct in patients with severe acute respiratory syndrome following hospital discharge: preliminary experience health-related quality of life after acute lung injury one-year outcomes in survivors of the acute respiratory distress syndrome pulmonary function and health-related quality of life in a sample of long-term survivors of the acute respiratory distress syndrome pulmonary function and health-related quality of life in survivors of acute respiratory distress syndrome long-term assessment of lung function in survivors of severe ards the impact of severe acute respiratory syndrome (sars) on pulmonary function, functional capacity and quality of life in a cohort of survivors index patient and sars outbreak in hong kong severe acute respiratory syndrome (sars) updated interim u.s. case definition. available at: www.cdc.gov/ncidod/sars/casedefinition.htm severe acute respiratory syndrome: report of treatment and outcome after a major outbreak clinical exercise testing statement: guidelines for the six-minute walk test the mos -item short-form health survey (sf ): iii. tests of data quality, scaling assumptions, and reliability across diverse patient groups tests of scaling assumptions and construct validity of the chinese (hk) version of the sf health survey population based norming of the chinese (hk) version of the sf health survey standardization of spirometry, update lung function testing: selection of reference values and interpretative strategies pulmonary function studies in healthy chinese adults in singapore maximal respiratory pressures: normal values and relationships to age and sex statement on respiratory muscle testing comparison of two different mouthpieces for the measurement of pimax and pemax in normal and weak subjects transdiaphragmatic pressure in young adult singaporean subjects-normal values and a comparison between different respiratory manoeuvres respiratory muscles severe acute respiratory syndrome: radiographic appearances and pattern of progression in patients reference equations for the sixminute walk in healthy adults treatment of severe acute respiratory syndrome severe acute respiratory syndrome: epidemiology, diagnosis and treatment thin section ct of severe acute respiratory syndrome: evaluation of patients exposed to or with the disease lung pathology of fatal severe acute respiratory syndrome the clinical pathology of severe acute respiratory syndrome (sars): a report from china lung pathology of severe acute respiratory syndrome (sars): a study of autopsy cases from singapore pulmonary pathological features in coronavirus associated severe acute respiratory syndrome (sars) six month radiological and physiological outcomes in severe acute respiratory syndrome (sars) survivors severe acute respiratory syndrome: thin-section computed tomography features, temporal changes and clinico-radiological correlation during convalescent period dynamic changes of serum sars-coronavirus igg, pulmonary function and radiography in patients recovering from sars after hospital discharge long-term follow-up and bronchial reactivity testing in survivors of the adult respiratory distress syndrome pulmonary function following the adult respiratory distress syndrome clinical determinants of abnormalities in pulmonary functions in survivors of the adult respiratory distress syndrome radiological and pulmonary function outcomes of children with sars long-term follow-up of survivors of acute lung injury: lack of effect of a ventilation strategy to prevent barotraumas left ventricular performance in patients with severe acute respiratory syndrome: a day echocardiographic follow-up study the impact of severe acute respiratory syndrome on the physical profile and quality of life in a cohort of survivors pulmonary function and exercise capacity in survivors of severe acute respiratory syndrome osteonecrosis of hip and knee in patients with severe acute respiratory syndrome treated with steroids weakness of respiratory and skeletal muscles after a short course of steroids in patients with acute lung rejection acute steroidinduced tetraplegia following status asthmaticus neuromuscular disorders in severe acute respiratory syndrome stress and psychological impact on sars patients during the outbreak psychiatric complications in patients with severe acute respiratory syndrome (sars) during the acute treatment phase: a series of cases factors associated with psychosis among patients with severe acute respiratory syndrome: a case-control study acknowledgment: we thank the following colleagues who have provided help in this ongoing study: m. tong, rn; p.y. chan, rn; m.s. cheng, rn; t.y. cheong, rn; m.y. leung; en; e lee (clerk); and c ho (research assistant). we also acknowledge the coordinating committee in physiotherapy, hong kong hospital authority, for collecting the updated normative data on mwds. key: cord- -mw ec u authors: salton, francesco; confalonieri, paola; meduri, g umberto; santus, pierachille; harari, sergio; scala, raffaele; lanini, simone; vertui, valentina; oggionni, tiberio; caminati, antonella; patruno, vincenzo; tamburrini, mario; scartabellati, alessandro; parati, mara; villani, massimiliano; radovanovic, dejan; tomassetti, sara; ravaglia, claudia; poletti, venerino; vianello, andrea; gaccione, anna talia; guidelli, luca; raccanelli, rita; lucernoni, paolo; lacedonia, donato; foschino barbaro, maria pia; centanni, stefano; mondoni, michele; davì, matteo; fantin, alberto; cao, xueyuan; torelli, lucio; zucchetto, antonella; montico, marcella; casarin, annalisa; romagnoli, micaela; gasparini, stefano; bonifazi, martina; d’agaro, pierlanfranco; marcello, alessandro; licastro, danilo; ruaro, barbara; volpe, maria concetta; umberger, reba; confalonieri, marco title: prolonged low-dose methylprednisolone in patients with severe covid- pneumonia date: - - journal: open forum infect dis doi: . /ofid/ofaa sha: doc_id: cord_uid: mw ec u background: in hospitalized patients with covid- pneumonia, progression to acute respiratory failure requiring invasive mechanical ventilation (mv) is associated with significant morbidity and mortality. severe dysregulated systemic inflammation is the putative mechanism. we hypothesize that early prolonged methylprednisolone (mp) treatment could accelerate disease resolution, decreasing the need for icu and mortality. methods: we conducted a multicenter, observational study to explore the association between exposure to prolonged, low-dose, mp treatment and need for icu referral, intubation or death within days (composite primary endpoint) in patients with severe covid- pneumonia admitted to italian respiratory high-dependency units. secondary outcomes were invasive mv-free days and changes in c-reactive protein (crp) levels. results: findings are reported as mp (n= ) vs. control (n= ). the composite primary endpoint was met by vs. [adjusted hazard ratio (hr) . ; % confidence interval (ci): . - . ]. transfer to icu and need for invasive mv was necessary in vs. (p= . ) and vs. (p= . ), respectively. by day , the mp group had fewer deaths ( vs. , adjusted hr= . ; % ci: . - . ) and more days off invasive mv ( . ± . vs. . ± . ; p= . ). study treatment was associated with rapid improvement in pao( ):fio( ) and crp levels. the complication rate was similar for the two groups (p= . ). conclusion: in patients with severe covid- pneumonia, early administration of prolonged mp treatment was associated with a significantly lower hazard of death ( %) and decreased ventilator dependence. treatment was safe and did not impact viral clearance. a large rct (recovery trial) has been performed that validates these findings. clinical trial registration: clinicaltrials.gov nct italy was the first european country overwhelmed by the sars-cov- pandemic, experiencing an unsustainable burden on the healthcare system. the greatest impact was on intensive care units (icus) because % of hospitalized cases developed acute respiratory failure (arf) requiring icu admission. [ ] covid- patients with arf necessitate weeks of mechanical ventilation (mv) and have an unacceptably high mortality rate. [ ] this is an unprecedented global emergency where even countries with advanced health care systems rapidly reach icu saturation, and intensivists are forced to make difficult ethical decisions that are uncommon outside war zones. any intervention directed at decreasing dependence on ventilators and mortality in covid- patients is an ethical imperative and would have a significant global impact on public health. over the last few decades, italy has built-up a diffuse network of respiratory high dependency units (rhdus) which also treat patients with severe pneumonia-related arf requiring continuous monitoring and noninvasive positive pressure ventilation (nppv). [ ] patients with disease progression who require endotracheal intubation are transferred to the icu. during the pandemic, rhdus were pivotal in reducing icu referral. [ ] indeed, patients with severe covid- have exhausted antiviral defenses and massive tissue and systemic inflammatory response. corticosteroids are powerful anti-inflammatory drugs that could have a role in promoting the resolution of arf in patients with severe covid- infection. [ ] the rationale for prolonged, low-dose, corticosteroid treatment in severe covid- was recently reviewed. [ ] we hypothesized that early mp treatment in hypoxemic patients with severe sars-cov- pneumonia at higher risk for arf progression requiring invasive mv, may quicken disease resolution, reducing the need for icu support and mortality. we investigated the association between early intervention with prolonged mp treatment in this high-risk group and the risk for icu admission, the need for invasive mv or all-cause death by day . we conducted a multicenter, observational, longitudinal study to evaluate the association between mp treatment and outcome in consecutive patients with severe covid- pneumonia admitted to fourteen italian rhdus between february th and april th , . follow-up continued through may st , . the composite primary endpoint included admission to icu, need for invasive mv, or all-cause death by day , while secondary endpoints were mv c-reactive protein (crp) levels. the study was carried out in accordance with the declaration of helsinki. it was registered on a c c e p t e d m a n u s c r i p t clinicaltrials.gov (nct ) after approval by the referral ethics committee for the coordinating centre (university hospital of trieste, #ceur- -os- ). study baseline was defined as the time of inclusion criteria fulfillment after admission to rhdu. inclusion criteria were the followings: ) sars-cov- positive (on swab or bronchial wash); ) age > years and < years; ) pao :fio < mmhg; ) bilateral infiltrates; ) crp > mg/l; and/or ) diagnosis of acute respiratory distress syndrome (ards) according to the berlin definition [ ] as an alternative to criteria ) and ). exclusion criteria were: heart failure as main cause of arf, decompensated liver cirrhosis, immunosuppression (i.e. cancer on treatment, postorgan transplantation, hiv-positive, on immunosuppressant therapy), dialysis-dependence, on longterm oxygen or home mechanical ventilation, idiopathic pulmonary fibrosis, neuromuscular disorders, dementia or a decompensated psychiatric disorder, severe neurodegenerative conditions, on chronic steroid therapy, pregnancy, a do-not-resuscitate order, and use of tocilizumab or other experimental treatment. patients in both study groups received standard of care, comprising noninvasive respiratory support, antibiotics, antivirals, vasopressors, and renal replacement therapy as deemed suitable by the healthcare team. exposure to methylprednisolone (non-patented drug, atc code h ab ) complied with the following protocol: a loading dose of mg iv at study entry (baseline), followed by an infusion of mg/day in ml normal saline at ml/h for at least days, until achieving either a pao :fio > mmhg or a crp < mg/l. after which, oral administration at mg or mg iv twice daily until crp reached < % of normal range or a pao :fio > (alternative sathbo ≥ % on room air). the mp protocol was developed by the coordinating center in accordance with the "recommendation for covid- clinical management" by the national institute for the infectious diseases "l. spallanzani", rome. [ ] the decision to apply the protocol to covid- was left to the discretion of the treating team for each individual patient. unexposed patients (controls) were selected from concurrent consecutive covid- patients with the same inclusion and exclusion criteria. demographic details, laboratory, clinical and outcome variables were manually extracted from electronic medical records or charts and anonymously coded onto in a standardized data collection form. three independent physicians checked the data and two researchers adjudicated any difference in interpretation between the primary reviewers. serial measurements included: arterial blood gas, crp, d-dimer, white cell count with differential, hemoglobin, variables for the calculation of the sofa score, [ ] days free from invasive or noninvasive mv until study day . laboratory methodologies, including sars-cov- detection by reverse-transcriptase polymerase chain reaction (rt-pcr) and reference values were comparable a c c e p t e d m a n u s c r i p t between centers. other collected data included: date of death, admission to icu, dates of discharge from hospital and icu, intra-hospital medications, in-hospital adverse events and comorbidities. samples from seriated nasopharyngeal swabs were collected in each group to evaluate viral shedding. considering a study power ( -beta) of % and a probability of type error (alpha) of . , assuming that the proportion of treated patients having the primary endpoint was . under the null hypothesis (according to available information from fang et al. [ ] ) and . under the alternative hypothesis, and considering a % dropout rate, a minimum study sample of patients was established. data were described using absolute and relative frequencies (percentage) or position indices (mean or median) and relative dispersion indices (standard deviation or interquartile range), as appropriate according to the type and distribution of the variable analyzed. the differences between study groups (mp-treated and control) in the proportion of patients reaching the primary endpoint was evaluated by a two-sided chi-square test. the difference in numerical variables between groups was calculated using student's t-test or wilcoxon rank-sum test, depending on the distribution of the variables. differences between study groups concerning categorical or dichotomous variables were evaluated by means of the chi-square test or fisher's exact test, as appropriate. time-to-event analyses were performed for both the composite primary endpoint and death alone. time at risk for all-cause death was computed from the date of study enrollment up to the date of death, hospital discharge, or days, whichever came first. event-free probabilities were estimated by the kaplan-meier method and differences between groups were assessed by the log-rank test. multivariable cox proportional-hazard models estimated the hazard ratio (hr) of both the primary composite endpoint and all-cause death, with the corresponding % confidence intervals ( % ci), taking into account the confounding factors (i.e., sex, age, and baseline values of sofa score, pao :fio , crp levels) potentially associated with the outcome. these variables and others with baseline differences (e.g. smoke) were tested in univariate survival models and variables significant at p= . were tested in the multivariable models. proportional hazards assumption was assessed by visual inspection of the log(-log(survival)) plot. there were no missing data with regard neither to the composite primary endpoint and the adjustment factors included in the final cox models, nor to mv-free days. available case analysis was performed for time variation of c-reactive protein (crp) and pao :fio levels. all tests were two-sided and a p-value of < . was considered as statistically significant. sensitivity analyses were completed as recommended by strobe guidelines for reporting observational studies. [ ] although a protocol was used to standardize study measures, we conducted a sensitivity analysis to account for potential variance in medical decision making that a c c e p t e d m a n u s c r i p t could potentially impact the primary composite outcome. we examined hypothetical scenarios against the hypothesis by varying the number of subjects meeting the primary composite outcome by and subjects to account for potential bias in both groups. between february th and april th , , consecutive sars-cov- -positive patients who were admitted to one of rhdus with severe pneumonia, were assessed for study eligibility. a total of patients ( mp-treated exposed and untreated controls) were enrolled, while were excluded as detailed in figure . findings are reported as mp group vs. control group. rhdu admission days to study enrollment were comparable ( . ± . vs. . ± . , p= . ). table shows how the patients' baseline characteristics did not differ between groups. the mean duration of iv mp treatment was . ± . days, while the total duration of mp treatment was . ± . days. for the secondary endpoints ( table ) , we observed a significant increment in both mv-free days by day outcomes, combined invasive mv and nppv ( . ± . vs. . ± . , p= . ), and invasive-mv-free days alone ( ± vs. . ± . , p= . ). mp exposure was associated with a table and shown in figure . the hospital length of stay did not differ between the groups (p-value= . ). no tracheostomy was necessary in mp patients vs. controls (or . , % ci . to . , p-value < . ). concerning intra-hospital adverse events of any type (table s ) only the occurrence of hyperglycemia in non-diabetic patients, or severe glycemic decompensation in diabetic patients, and agitation was significantly higher in the mp group compared to control ( vs. , p= . and vs. , p= . respectively). no adverse event led to mp discontinuation. concomitant in-hospital treatments are summarized in table s . there were no relevant differences in viral genome sequencing in the two first recruited patients compared to the average sequences reported in open-source repositories (figure s ) . nor was any observed in viral shedding, determined as time lapse (days) between hospital admission and the first negative rt-pcr for sars-cov- nasopharyngeal swabs, in a sample of mp-treated patients compared to untreated ones ( . ± . vs. . ± . , p-value= . ). sensitivity analysis (table s ) show that the primary composite outcome still significantly differs between the mp and control group in scenarios biased against the original hypothesis. in our multicenter study, patients exposed to mp encountered the primary composite endpoint of icu referral, need for invasive mv or in-hospital all-cause death significantly less compared to the control group (adjusted hr . ). by day , mp treatment was associated with a significant reduction in mortality (adjusted hr . ) and an increase in mv-free days. among patients transferred to the icu, mp treated patients had a . days median reduction (p= . ) in the duration of invasive mv. in line with this data, fewer mp-treated patients required tracheotomy than controls ( vs. , p < . ). mp-treated patients had a higher reduction in crp levels than controls. this was statistically significant on days and from baseline and there was a quicker improvement in pao :fio ratio on day for mp-treated patients. there was no overall increase in adverse events between groups, except for an increase in hyperglycemia and mild agitation in the mp-treated patients; no adverse event necessitated mp discontinuation. no difference was observed in viral shedding, determined as the number of days between hospital referral and the first negative nasopharyngeal swab. early interventions aimed at down regulating the sars-cov- -associated hyper-immune response in severe covid- patients may well avoid disease progression and enhance pneumonia resolution. the cytokine profile reported for these patients [ ] is within the broad range of regulation provided by corticosteroids [ ] , particularly mp that is associated with an optimal lung penetration. [ ] our study protocol involved an initial iv bolus to achieve rapid, almost complete a c c e p t e d m a n u s c r i p t glucocorticoid receptor saturation, followed by an infusion to reach a total -milligram dose over the first hours and to maintain high levels of response throughout the treatment period. after day , treatment duration was guided by monitoring the anti-inflammatory response and oxygenation parameters. our study investigated a dose more than double the one investigated in the recovery rct and included tapering to minimize the risk of rebound inflammation. this might explain the rapid reduction observed in inflammatory markers. treatment duration was guided by monitoring the anti-inflammatory response and oxygenation after at least days. our mp treatment response is similar to that of randomized controlled studies (rcts) in covid- [ ] , non-viral ards [ ] and severe pneumonia [ ] , as well as of large-scale observational studies in severe pneumonia caused by sars-cov (n= ) [ ] [ ] [ ] and h n influenza (n= ). [ ] additional support for the use of methylprednisolone in covid- originates from transcriptomics data. after matching the expression changes induced by sars-cov in human lung tissue tissues and a lung cell line against the expression changes triggered by , fdaapproved drugs, methylprednisolone was found to be the drug with the greatest potential to revert the changes induced by covid- . [ ] this study has been carried out before the results of the recovery rct became available, as visible by clinicaltrials.gov posting records (results first posted june , ). in the recovery trial, patients were randomized to receive dexamethasone at a dose of mg/day or standard of care alone, providing evidence of a lower -day mortality in the dexamethasone group compared to the usual care group only among those who were receiving either invasive mechanical ventilation ( . % vs. . %) or oxygen alone ( . % vs. . %) at randomization, but not among those receiving no respiratory support. in our study, both mortality and mortality reduction in the mp group were better than reported in the recovery trial. apart from the different study design and setting, we speculate this difference is possibly due several reasons: first, the recovery trial uses a different drug (dexamethasone) at a lower dose, equivalent to approximately mg of methylprednisolone. [ ] second, it is likely that mp has pharmacokinetic and pharmacodynamic advantages over dexamethasone, despite lung penetration needs further comparison. [ ] third, in the recovery trial, the impact of the study treatment on survival seems to correlate with the need for respiratory support and therefore with illness severity. in this support, it was already noticed that glucocorticoids are not effective in patients without ards and/or sepsis. [ ] while permissive inclusion criteria are needed to recruit large populations in rcts, we have designed strict criteria that allowed us to include in the analyses only patients affected by severe pneumonia/ards with high levels of systemic inflammation and need for respiratory support. it is worth stressing that inflammatory organ injury with subsequent dysregulated host response is thought to be the main a c c e p t e d m a n u s c r i p t mechanism of damage in covid- ; as a consequence, the subgroup of patients having markedly elevated levels of inflammatory markers is the one supposed to benefit most from therapeutic interventions aimed at reducing inflammatory organ injury, including corticosteroids. the safety profile reported in our study is consistent with the findings of multiple rcts investigating prolonged corticosteroid treatment in thousands of patients with severe sepsis, septic shock and ards. [ ] in these rcts, hyperglycemia was transient in response to the initial loading bolus and did not impact negatively on outcome. [ ] viral shedding in both groups of our study was in agreement with international literature. [ , ] the who quotes a middle east respiratory syndrome coronavirus study to warn about the risk for reduction in viral clearance with corticosteroid treatment. in the arabi et al. study [ ] , however, those that received corticosteroid treatment for greater than seven days (similar to our study) had a fifty percent reduction in mortality [aor: . , % confidence interval (ci) . - . ; p= . ] and no impact on viral clearance (ahr: . , % ci . - . ; p= . ). moreover, there is no evidence linking delayed viral clearance to worsened outcome in critically ill covid- patients, and it is unlikely that it would have a greater negative impact than the host's own cytokine storm. [ ] the observational design of our study implies some obvious limitations, namely a possible restricted control over data collection and potential inclusion biases. however, internal validity was achieved by ( ) the comparability of concurrent groups at baseline, ( ) . accounting for potential confounders into the multivariable cox regression analyses, and ( ) conducting sensitivity analysis to assess for potential bias in outcome ascertainment potentially influenced by medical decision making. our study's strengths include a prospective evaluation of a pre-designed intervention protocol based on established pharmacological principles in patients at high risk of progression to arf and death. limitations of the study is that we did not control for center effects and site investigators were not blinded to treatment as with any observational study. despite these limitations, we believe that our findings represent valid and generalizable conclusions, that have been further strengthened by the recently published recovery rct. indeed, we observed benefits when mp treatment was started early and prolonged in the hospitalization of hypoxemic patients with covid- pneumonia at high risk of arf progression. mp treatment was demonstrated to be safe, and also allowed for a significant reduction in mortality and immediate improvements in systemic inflammation and oxygenation markers, as well as reducing invasive mv times. we believe our data support the evidence that early low-dose prolonged mp treatment can decrease icu burden and mortality, therefore contributing to reduce the concern surrounding this therapeutic approach in patients admitted with arf due to severe sars-cov- pneumonia in the current state of affairs. fs, pc, ps, sh, rs, sl, vv, to, ac, vp, mt, as, mp, mv, dr, st, cr, vp, av, atg, lg, rr, pl, dl, mpfb, sc, mm, md, af, ac, mr, sg, mb, failed to meet inclusion criteria (n= ): age > years old (n= ), criteria for pao :fio , c-reactive proteron level, or ards (n= ). met exclusion criteria (n= ): heart failure as main cause of arf (n= ), decompensated liver cirrhosis (n= ), on long-term oxygen therapy and/or home ventilation (n= ), dementia or severe neurodegenerative condition (n= ), active cancer (n= ), on chronic steroid therapy (n= ), use of tocilizumab or other experimental treatment (n= ). patients who reached the primary endpoint before admission to rhdu or within hours from admission to rhdu were excluded from the analysis; out of these patients did not start mp treatment. upper panel: time-course of c-reactive protein levels (mean ± standard error). the differences between groups were significant at days and . middle panel: time course of mean pao :fio . the differences between groups was significant at day . lower panel: time course of mean lymphocyte count showing no significant differences between groups. m a n u s c r i p t control m a n u s c r i p t critical care utilization for the covid- outbreak in lombardy, italy: early experience and forecast during an emergency response covid- in critically ill patients in the seattle region -case series respiratory intensive care units in italy: a national census and prospective cohort study early consensus management for non-icu arf sars-cov- emergency in italy: from ward to trenches complex immune dysregulation in covid- patients with severe respiratory failure rationale for prolonged corticosteroid treatment in the acute respiratory distress syndrome caused by coronavirus disease statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome acute respiratory distress syndrome: the berlin definition national institute for the infectious diseases "l recommendations for covid- clinical management use of the sofa score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study low-dose corticosteroid therapy does not delay viral clearance in patients with covid- the strengthening the reporting of observational studies in epidemiology (strobe) statement: guidelines for reporting observational studies hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease (covid- ): a meta-analysis general adaptation in critical illness: glucocorticoid receptoralpha master regulator of homeostatic corrections accessed penetration of corticosteroids into the lung: evidence for a difference between methylprednisolone and prednisolone dexamethasone in hospitalized patients with covid- -preliminary report prolonged glucocorticoid treatment is associated with improved ards outcomes: analysis of individual patients' data from four randomized trials and trial-level meta-analysis of the updated literature hydrocortisone infusion for severe communityacquired pneumonia: a preliminary randomized study clinical recommendations from an observational study on mers: glucocorticoids was benefit in treating sars patients treatment of severe acute respiratory syndrome with glucosteroids: the guangzhou experience corticosteroid treatment of severe acute respiratory syndrome in hong kong effect of low-to-moderate-dose corticosteroids on mortality of hospitalized adolescents and adults with influenza a(h n )pdm viral pneumonia covid- : disease pathways and gene expression changes predict methylprednisolone can improve out-come in severe cases pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids virological assessment of hospitalized patients with covid- re: low-dose corticosteroid therapy does not delay viral clearance in patients with covid- corticosteroid therapy for critically ill patients with middle east respiratory syndrome covid- : consider cytokine storm syndromes and immunosuppression pao :fio , mmhg, mean (sd) lymphocyte count, mean (sd) legend: sd, standard deviation; iqr inter-quartile range sofa, sequential organ failure assessment; pao :fio , ratio of partial pressure of arterial oxygen (pao in mmhg) to fractional inspired oxygen copd, chronic obstructive pulmonary disease obstructive sleep apnea syndrome/obesity-hypoventilation syndrome °p -value of the fisher's exact test for dichotomous variables, unpaired student's t-test or wilcoxon. rank-sum test for numerical variables, as appropriate pao :fio at day vs baseline, median (iqr) pao :fio at day vs baseline, median (iqr) the authors would like to thank barbara wade, contract professor at the university of torino, for her linguistic advice; amanda busby, university of hertfordshire, for her statistical suggestions; dr.valentina luzzi and dr. marco de martino for their help in data collection. all patients signed written consent for this study.the design of the study has been approved by the local ethical committee (#ceur- -os- ) and it conforms to the standards currently applied in italy. the authors have no conflicts of interest to disclose. ( to ) . legend: hr, hazard ratio; ci, confidence interval; sd, standard deviation; iqr, inter-quartile range; crp, c-reactive protein; pao :fio , ratio of partial pressure of arterial oxygen (pao in mmhg) to fractional inspired oxygen (fio ). * p-value of chi-square or fisher's exact test for dichotomous variables, unpaired t-test or wilcoxon rank-sum test for numerical variables as appropriate.°hr of event among methyprednisolone vs. control group, estimated using cox-regression model. the crude odds ratio and % ci for the composite outcomes is . ( . - . ). § cox-regression model was adjusted for sex, age, baseline sofa score, baseline pao :fio , and baseline crp. ¶ only ventilated patients ** both invasive and noninvasive a c c e p t e d m a n u s c r i p t a c c e p t e d m a n u s c r i p t key: cord- -p cab authors: kotfis, katarzyna; williams roberson, shawniqua; wilson, jo ellen; dabrowski, wojciech; pun, brenda t.; ely, e. wesley title: covid- : icu delirium management during sars-cov- pandemic date: - - journal: crit care doi: . /s - - -x sha: doc_id: cord_uid: p cab the novel coronavirus, sars-cov- -causing coronavirus disease (covid- ), emerged as a public health threat in december and was declared a pandemic by the world health organization in march . delirium, a dangerous untoward prognostic development, serves as a barometer of systemic injury in critical illness. the early reports of % encephalopathy from china are likely a gross underestimation, which we know occurs whenever delirium is not monitored with a valid tool. indeed, patients with covid- are at accelerated risk for delirium due to at least seven factors including ( ) direct central nervous system (cns) invasion, ( ) induction of cns inflammatory mediators, ( ) secondary effect of other organ system failure, ( ) effect of sedative strategies, ( ) prolonged mechanical ventilation time, ( ) immobilization, and ( ) other needed but unfortunate environmental factors including social isolation and quarantine without family. given early insights into the pathobiology of the virus, as well as the emerging interventions utilized to treat the critically ill patients, delirium prevention and management will prove exceedingly challenging, especially in the intensive care unit (icu). the main focus during the covid- pandemic lies within organizational issues, i.e., lack of ventilators, shortage of personal protection equipment, resource allocation, prioritization of limited mechanical ventilation options, and end-of-life care. however, the standard of care for icu patients, including delirium management, must remain the highest quality possible with an eye towards long-term survival and minimization of issues related to post-intensive care syndrome (pics). this article discusses how icu professionals (e.g., physicians, nurses, physiotherapists, pharmacologists) can use our knowledge and resources to limit the burden of delirium on patients by reducing modifiable risk factors despite the imposed heavy workload and difficult clinical challenges posed by the pandemic. the novel coronavirus, sars-cov- -causing coronavirus disease , emerged as a public health threat in december and was declared a pandemic by the world health organization in march [ ] . many hospitalized patients with covid- will develop delirium, and given early insights into the pathobiology of this virus indicating invasion into the brain stem, as well as the emerging interventions utilized to treat these critically ill patients, delirium prevention and management may prove exceedingly challenging, especially in the intensive care unit (icu). in addition to the neurobiology of covid- and typical deliriogenic factors omnipresent in the icu, this pandemic has created circumstances of extreme isolation and distancing from human contact whenever possible, including loved ones, plus the inability to freely ambulate, which essentially create a "delirium factory" that must be explicitly addressed to maximize human dignity and respect during care. in patients with covid- , delirium may be a manifestation of direct central nervous system (cns) invasion, induction of cns inflammatory mediators, a secondary effect of other organ system failure, an effect of sedative strategies, prolonged mechanical ventilation time, or environmental factors, including social isolation. drawing from experience with other closely related viruses from the coronaviridae family, direct cns invasion appears to occur rarely and late in the disease course but may be associated with seizures, impairments in consciousness or signs of increased intracranial pressure [ , ] . such symptoms may require specialized neuro-intensivist management. immunologic responses to coronaviridae appear to be mediated by acute cytolytic t cell activation [ ] . this response could, if dysregulated, cause an autoimmune encephalopathy [ ] . secondary effects include cerebral hypoxia or metabolic dysregulation in association with failure of pulmonary or other organ systems, such as can be seen in a variety of other types of delirium [ ] . environmental and iatrogenic factors such as prolonged mechanical ventilation, sedatives (especially benzodiazepines), and immobility also contribute heavily to the risk of icu delirium [ ] and can contribute to its development in the context of acute covid- infection. in an early retrospective report from wuhan, mao et al. reported that only . % had any chart documentation of "impaired consciousness," which was the only term approximating delirium [ ] . underreporting of delirium is extremely common in retrospective chart reviews, and under in with delirium is likely a gross underestimation. the literature is very consistent that % of occurrences of delirium are missed in patients unless objective delirium monitoring is being employed to detect this form of acute brain dysfunction [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in addition, in covid- , the risk of complications such as acquired dementia and icu-acquired weakness (icu-aw) as well as depression and ptsd, the defining illnesses of post-intensive care syndrome (pics), and pics in family members (pics-f) [ ] [ ] [ ] will be greatly exacerbated if we allow patients to suffer unmitigated delirium. this article will discuss how icu professionals (e.g., physicians, nurses, physiotherapists, pharmacologists) can use our knowledge and resources to limit the burden of delirium on patients by reducing modifiable risk factors despite the imposed heavy workload and difficult clinical challenges posed by the pandemic. for example, others have already stressed reasonable analgesia and sedation use with special attention to monitoring and mitigating delirium [ ] . delirium, the most frequent clinical expression of acute brain dysfunction [ ] , is especially important in the context of covid- . it may be regarded as an early symptom of infection, as previously described in septic patients [ ] . therefore, delirium should be actively screened for using dedicated psychometric tools, i.e., cam-icu [ ] or icdsc [ ] [ ] [ ] [ ] . it is also plausible that delirium severity, which could be measured with cam-icu- or drs-r- [ , ] , may be associated with covid- severity [ , , ] . the sars-cov- virus causes pneumonia, especially in elderly patients [ , ] . since advanced age is a well-described independent risk factor for delirium, it could be postulated that those who are at the greatest risk for severe pulmonary disease related to covid- are likely at the greatest risk for delirium as well. it has been reported that nearly % of covid- patients whose condition required admission to the intensive care unit need mechanical ventilation, either non-invasive (niv) ( %) or invasive requiring intubation ( %) [ ] . currently, due to the reports of increased aerosolization of the viral load, niv is not recommended yet still being used when icu resources become limited [ ] . the use of sedating medications in critically ill patients, especially sedative-hypnotics and anticholinergic agents is associated with the development of delirium [ , ] . despite advances in care bundles, such as the abcdef bundle [ ] [ ] [ ] , to reduce the incidence of delirium and improve the care of critically ill patients, recent reports from regions of the world hardest hit by covid- suggest that a flexible approach to management algorithms may be required, due to either a strained workforce or scarcity of resources [ ] . highlighting the importance of covid- -related morbidities it must be underlined that agitation associated with hyperactive delirium could theoretically be a source of intra-hospital disease spread in uncooperative patients in over-crowded settings with respiratory distress prior to intubation or awaiting admission to the icu. another potential factor contributing to the occurrence of icu delirium during the sars-cov- outbreak is social isolation created by "social distancing" strategies and quarantines, which may prove especially difficult in older adults, who have no or limited support from caregivers. in the age of covid- , in an attempt to "flatten the curve" and slow the spread of the virus, many hospitals have instituted no-visitation or very limited visitation policy, which may propagate a sense of isolation, ultimately contributing to disorientation and lack of awareness in the patient. what is needed now, is not only high-quality icu care, concentrated on providing adequate respiratory support to critically ill patients, but an identification of the source and degree of mental and spiritual suffering of patients as well as their families to provide the most ethical and person-centered care during this humanitarian crisis. many patients, coming from different religious backgrounds, will need the support of religious services that are likely to be unavailable for an extended period of time. implementation of policies that prevent visitors from coming into the hospital should be followed by additional efforts to support patient-family interaction. this must include dedicated time and effort for phone and video conversations during busy icu time. moreover, hospital management should provide all possible novel technological options for communication, including teleconferences or portable speakerphones. all of these concepts are summarized in fig. . this patient-centered approach is especially important for delirious patients, the majority of whom are elderly, may suffer from an evolving neurocognitive disorder, be hypoactive or aphasic and cannot express their emotional or spiritual needs, and would typically receive comfort from relatives, friends, and caregivers, during a medical crisis. during these strenuous and difficult times, an even deeper sense of humanity is required from healthcare professionals and hospital management to provide quality care to critically ill patients. the workload is already increased with the volume of new and deteriorating patients, but in order to provide maximum humanitarian care and preserve the sense of dignity, we must view the fulfillment of mental and spiritual needs as a medical intervention. yet it is obvious that during the covid- pandemic, the potential for nonpharmacological interventions encapsulated in the abc-def bundle (e.g., mobility outside the icu room, family engagement) may be extremely limited [ ] . all of these issues factor into the type of survivorship that our covid- patients and their families will experience the months and years ahead as they face the burdens of pics and pics-f [ ] [ ] [ ] . covid- : neuro-invasive potential of sars-ncov- as cause of delirium acute brain dysfunction, symptomatically presenting as delirium (also called encephalopathy), may be a feature of the neuro-invasive potential of sars-cov- . neurotropism of coronaviridae has been demonstrated during sars and mers epidemics [ ] [ ] [ ] . during the - sars epidemic older subjects presented not only with respiratory symptoms and typical febrile response, but also with decreased general well-being, poor feeding, and delirium [ ] . given the fact that sars-cov and sars-cov- are similar in terms of pathogenicity, it is quite likely that sars-cov- has a similar ability to cause delirium [ ] . most covs share a common viral structure, infection potential, and neurotropism [ , ] , covs are large, enveloped viruses with a large positive-sense, singlestranded rna genome [ ] . human pathogenic covs include those causing recent epidemics, severe acute respiratory syndrome cov (sars-cov and sars-cov- ), middle east respiratory syndrome cov (mers-cov) hcov- e, and other identified coronaviruses, i.e. hcov-oc , hcov-nl , and hcov-hku [ ] [ ] [ ] . covs have been associated with cns diseases such as acute viral encephalopathy, acute disseminated encephalomyelitis, and multiple sclerosis and are increasingly recognized as presenting a neurologic crisis [ , , ] . in one series of children hospitalized with acute encephalitis, % were associated with coronavirus infection [ ] . such propensity of covs has been documented for several of the beta-covs, including sars-cov and mers-cov [ , ] . acute necrotizing encephalitis has also been described in one case of sars-cov- . the patient presented with fever, cough, and altered mental status and was found to have hemorrhagic rim enhancing lesions in the deep gray matter of the cerebral cortex bilaterally [ ] . animal studies suggest coronaviruses are delivered through the peripheral nerves and may access the central nervous system through retrograde synaptic transmission [ , , ] . sars-cov spreads in the brains of intranasally inoculated mice primarily via the olfactory bulb with subsequent infection of the hypothalamus and brainstem [ ] . such neuro-invasive potential of sars-cov- has been postulated to contribute to respiratory failure observed in infected patients [ ] . the exact mechanism for neurotoxicity may depend on the brain entry route, which has not been fully elucidated [ ] . the sars-covs enter human host cells mainly via a cellular receptor angiotensin-converting enzyme (ace ), expressed not only in the entire respiratory tract (which it destroys resulting in the leading cause of death), but also in the upper esophagus or enterocytes and showing very low expression level in the brain under normal conditions [ ] . the virus entry route may be respiratory, via oro-fecal route, but also directly intranasal [ , , ] . the possible brain entry routes for covs, including sars-cov- , include either direct intranasal access to the brain via olfactory nerves (with anosmia as an early symptom) or indirect access to the brain by crossing the blood-brain barrier (bbb) via hematogenous or lymphatic spread [ , , ] . there are several mechanisms of coronavirus-related brain damage. one of them is connected with the dysfunction of renin-angiotensin system in the brain. ace is the major component of the cerebral renin-angiotensin system and is localized in the endothelia of cerebral vasculature [ ] . the use of ace inhibitors for treatment of blood hypertension reduces cognitive dysfunction through their anti-inflammatory actions [ ] . circulating reninangiotensin components do not affect the brain with airtight bbb. however, general inflammatory response to virus infection impairs bbb integrity leading to massive infiltration of renin-angiotensin components to the brain [ ] . uncontrolled infiltration of the brain with reninangiotensin components induces neuroinflammatory cascades resulting in extensive neurodegradation followed by cognitive dysfunction [ ] . the sars-covs can enter the brain via the bbb angiotensin-converting enzyme receptors and induce neurodegeneration, astrogliosis, and neuroinflammation. it is noteworthy that sars-cov particles have been found in the brain [ , ] . inflammatory response of the cns to viral infection seems to be another important reason for poor neurological outcome and occurrence of delirium. a few hours after infection, neutrophils and monocytes infiltrate cns, and neutrophils seem to be crucial in disruption of bbb permeability [ ] [ ] [ ] the postmortem study documented a massive infiltration of the brain by immune cells, which was associated with neuronal edema and the scattered red degeneration [ ] noteworthy, activated macrophages and microglia have been present in areas of demyelination and play a critical role in myelin destruction [ ] . the hypomyelinated axons were found in experimental animals with short-and long-term memory deficit, and the degree of myelin disorders was associated with memory dysfunction and short-and long-term cognitive dysfunction [ , ] . a large amount of damaged myelin following neuroinflammation is potentially immunogenic and activates macrophages again, which initiate a vicious cycle sustaining further inflammation. this prolonged inflammation may be responsible for the higher incidence of neuropsychological abnormalities in patients with severe infection and sepsis; however, this hypothesis should be confirmed in further studies. the median time from the onset of first symptoms to the diagnosis of respiratory compromise (dyspnea) is usually days and days from admission to the intensive care unit with severe respiratory failure requiring intubation and mechanical ventilation [ ] . the latency period indicates that there might be sufficient time for the coronavirus to enter and destroy cns neurons. previous studies have shown that some patients infected with sars-cov- present with neurological symptoms such as headache (about % of cases) or centrally mediated nausea and vomiting (about % of cases) [ , ] . a retrospective study performed by mao et al., reporting data from covid- patients, showed that neurological symptoms were present in % of severely ill patients, with symptoms including both acute cerebrovascular disease and impaired consciousness [ ] . possibly the neuro-invasive potential of sars-cov- may be associated with centrally mediated respiratory failure. as a hypothesis, early identification of patients with delirium, being an early symptom of cns involvement is critical in covid- patients, as it may indicate impending respiratory failure due to the neuro-invasive potential of sars-cov- . historically, delirium rates among mechanically ventilated icu populations were consistently - %, and the duration of delirium has consistently proven an independent predictor of longer lengths of stay, higher mortality, greater cost of care, and alarming rates of acquired dementia that lasts years following illness [ ] [ ] [ ] [ ] . given these facts, it is important to carry into the pandemic the knowledge that delirium in mechanically ventilated patients can be reduced dramatically to % using a culture of lighter sedation and mobilization via the implementation of the safety bundle called the abc-defs promoted by the society of critical care medicine (sccm) in their icu liberation collaborative [ , ] . limitations in the ability to conform to this approach are a major component of the burden of the isolation required to limit the spread of covid- , prompting us to discuss specifics related to bedside care that one might keep in mind in organizing busy triage units and routine icu care during the pandemic. delirium screening only takes s. as such, delirium screening and treatment should follow well-established international guidelines, such as the ecash concept [ ] and the sccm clinical practice guidelines [ ] . although routinely used in clinical practice, some sedation-and delirium-associated issues may be especially important when using limited resources. standard nonpharmacological measures to treat or prevent delirium may not be possible in isolation environments, and these environments may themselves worsen delirium. pain management remains a priority for all patients and requires the widespread implementation of behavioral pain scales (cpot or bps) for sedated and mechanically ventilated patients. after pain control is adequately assured, we must focus on the intersecting issues that lead a person's brain to fail in critical illness, chief among them including overuse of powerful sedatives and undue immobilization. these and other potential problems regarding icu delirium management during the sars-cov- pandemic are identified in table . during such harrowing times at the respiratory failure that is occurring with covid- , it would be easy to disregard patients' brains as not being an essential concern. if we follow the critical care literature, this would be a grave error. evidence indicates that delirium is not only a robust prognostic indicator of worse survival immediately, but also of the cost of care and quality of survival [ - , , ] . thus, healthcare professionals should follow local guidelines and policies regarding the monitoring and management of delirium. implementation of easy screening methods for delirium is necessary especially in light of heavy workload because without validated assessment tools % of delirium will be missed [ ] [ ] [ ] [ ] [ ] [ ] [ ] ] during the covid- crisis. it is necessary to reduce the icu delirium risks using standard management approaches towards adequate pain management, avoiding urinary retention and gastro-intestinal problems (constipation), identification and treatment of nosocomial sepsis, and maintaining adequate oxygenation. non-pharmacological interventions such as regular orientation despite social separation and lack of contact with family and caregivers are going to prove vitally important. regarding pharmacological interventions, no drugs can be recommended for the prevention or treatment of icu delirium other than avoidance of overuse of potent psychoactive agents like sedatives and neuromuscular blockers (nmb) unless patients absolutely require such management [ ] [ ] [ ] [ ] . this component of the conversation is especially important given the early anecdotal recommendations to treat patients with covid- in the prone position [ ] , which will be uncomfortable and thus likely be met with even higher than usual amounts of sedation, which could beget very high rates of delirium down the line in the management of these already high-risk patients. additionally, it is important to review previous medications to avoid withdrawal symptoms. the ease of covid- transmission and the risk of harm to others (healthcare workers, family, caregivers) may exceed risk of harm to the individual. this is an isolated example warranting earlier use of sedatives for hyperactively delirious patients who are proving harmful to self and others. icu beds and ventilators are valuable and needed resources so it will be important to consider ways to avoid unnecessary prolongation of ventilation time and icu length of stay that is associated with deeper sedation. table provides an overview of abcdef bundle adaptations to meet the needs of covid- . data regarding delirium in the sars-cov- pandemic era are thus far too limited. this virus destroys the respiratory tract and invades the cns, both of which will produce an extremely high-risk circumstance for both acute and long-term brain dysfunction in patients infected with the covid- virus. the further elements of human isolation, extended time away from family and other loved ones, and other elements of care all form what could be construed as a delirium factory that medical teams must address. in the patients with covid- , delirium can be a manifestation of direct cns invasion, induction of cns inflammatory mediators, secondary effects of other organ system failure, and untoward medical and environmental factors including heavy use of sedatives for prone positioning of the patient and quarantining and social isolation during care. the focus during the covid- pandemic obviously lies within the dire necessity of organizational issues, i.e., lack of ventilators, shortage of personal protection equipment, resource allocation, prioritization of limited mechanical ventilation options, end-of-life care. it is precisely during such times that standardization of safety concerns encapsulated in the abcdef bundle can provide a framework to help us accomplish "whole person" care that will help with acute management success as well as improvement of long-term survivorship and reductions of pics and pics-f burden on individuals and society as a whole. at the heart of this safety bundle lies the brain, the most vital organ of the human body, and it has been shown now in over , patients [ , , , ] that higher compliance yields better survival, less delirium and coma, shorter lengths of stay, less icu bounce-back, and lower cost of care. implementation at the bedside of excellent delirium prevention and management should be a priority during the covid- pandemic [ , ] . although regarded as a priority, in intubated, deeply sedated patients, assessment and management require the use of behavioral pain scales that may at first glance seem burdensome for strained healthcare workers but which will ultimately provide the most humane care and help reduce ptsd. regular pain assessment (nrs, cpot/bps)-especially in prone position. provide adequate pain management, identify uncommon sources of pain. consider development of peripheral neuropathies from viral invasion of peripheral nerves and picsrelated complications. stopping both sedation and the ventilator to conduct daily spontaneous awakening trials and spontaneous breathing trials is essential. these will not be possible during paralysis in proned patients, which creates a serious risk-benefit choice of this modality of patient positioning that argues for the shortest duration possible. precautions for early extubation must be used to lower the spread of aerosol for patients who need nmbd infusion (paralyzed patients)-monitor nmb depth and shorten duration whenever possible. regularly assess patients with both sbt and sat daily. sometimes, deep sedation may be necessary, especially when using nmbd, when providing high peep, and when prone positioning is implemented. gaba-agonist propofol is likely the best choice during proning, but this can be shortened via daily questioning of the necessity of this management approach assess with rass/sas regularly. adjust sedation to ventilation needs-priority lies in effective ventilation (rass- for prone position). as soon as possible, discontinue potent sedatives or use those agents that do not suppress the respiratory drive such as intermittent use of antipsychotics or alpha- agonists. remember prolonged ventilation is associated with poor outcomes. hyperactive delirium and agitation can be a source of intra-hospital cross-infection, especially in agitated patients or during non-invasive ventilation (if used, not recommended). hypoactive delirium is likely to be missed if not monitored for using a validated instrument routinely. thus, patients may not receive appropriate attention to delirium prevention mechanisms. provide regular delirium screening (cam-icu, icdsc). provide usual non-pharmacological interventions: ( ) orientation is a priority, because patients see healthcare wearing personal protective equipment; ( ) support for senses (hearing aids/glasses); ( ) monitor taste/ smell failure due to cov predilection to olfactory nerves (anosmia may be an early sign). limit the use of cns-active medications to agitated patients. when cam-icu or icdsc positive, use the dr. dre mnemonic to consider chief delirium risks: diseases (new nosocomial infections, acquired heart failure); drug removal, stop all unnecessary psychoactive medications, be on the lookout for withdrawal if the patient was on a prolonged course of sedatives; environment, maximize sleep, orientation to other humans, minimize sensory deprivation. e early mobility physiotherapy may be very limited due to heavy workload and epidemiologic precautions; infusion of nmbd may be necessary. physiotherapy must be adjusted to heavy workload and epidemiologic precautions. use passive physiotherapy interventions during the infusion of nmbd. limited or no family presence during the pandemic due to quarantine and social distancing. a major issue for elderly and as end-of-life problem. orientate both patients and family regularly, provide phone conversations and video conferences, use technology devices, headphones, and tele-medicine tools. provide visual and vocal contact with the family/ caregivers/friends, especially for all dying patients despite isolation, lack of time, and heavy workload. bps behavioral pain scale, cam-icu cognitive assessment method for intensive care unit, cns central nervous system, cov coronavirus, cpot critical pain observation tool, icdsc intensive care delirium screening checklist, nmbd neuromuscular blocking drugs, nrs numeric rating scale, peep positive end-expiratory pressure, pics post-intensive care syndrome, sat spontaneous awakening trial, sbt spontaneous breathing trial dg/speeches/detail/who-director-general-s-opening-remarks-at-themedia-briefing-on-covid detection of severe acute respiratory syndrome coronavirus in the brain: potential role of the chemokine mig in pathogenesis possible central nervous system infection by sars coronavirus coronavirus infection of the central nervous system: host-virus stand-off expanding role of t cells in human autoimmune diseases of the central nervous system delirium pathophysiology: an updated hypothesis of the etiology of acute brain failure validation of a modified sequential organ failure assessment (sofa) score incorporating the richmond agitation-sedation score (rass) to assess neurologic end-organ function neurologic manifestations of hospitalized patients with coronavirus disease a prospective study of delirium in hospitalized elderly prevalence and detection of delirium in elderly emergency department patients nurses' recognition of delirium and its symptoms: comparison of nurse and researcher ratings delirium in older emergency department patients: recognition, risk factors, and psychomotor subtypes comparison of delirium assessment tools in a mixed intensive care unit occurrence of delirium is severely underestimated in the icu during daily care screening, detection and management of delirium in the emergency department -a pilot study on the feasibility of a new algorithm for use in older emergency department patients: the modified confusion assessment method for the emergency department (mcam-ed) the burdens of survivorship: an approach to thinking about long-term outcomes after critical illness improving long-term outcomes after discharge from intensive care unit: report from a stakeholders' conference guidelines for family-centered care in the neonatal, pediatric, and adult icu the keypoints in treatment of the critical novel coronavirus pneumonia patient. zhonghua jie he he hu xi za zhi american psychiatric association. diagnostic and statistical manual of mental disorders a clinical perspective of sepsis-associated delirium delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (cam-icu) intensive care delirium screening checklist: evaluation of a new screening tool delirium monitoring: yes or no? that is the question the confusion assessment method for the intensive care unit (cam-icu) and intensive care delirium screening checklist (icdsc) for the diagnosis of delirium: a systematic review and meta-analysis of clinical studies clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit validation of the delirium rating scale-revised- : comparison with the delirium rating scale and the cognitive test for delirium the confusion assessment method for the icu- delirium severity scale: a novel delirium severity instrument for use in the icu evaluation of delirium in critically ill patients: validation of the confusion assessment method for the intensive care unit (cam-icu) the intensive care delirium screening checklist (icdsc)--translation and validation of intensive care delirium checklist in accordance with guidelines a novel coronavirus from patients with pneumonia in china early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia clinical features of patients infected with novel coronavirus in wuhan fair allocation of scarce medical resources in the time of covid- sedative and analgesic medications are independent risk factors in icu patients for transitioning into delirium use of medications with anticholinergic effect predicts clinical severity of delirium symptoms in older medical inpatients caring for critically ill patients with the abcdef bundle: results of the icu liberation collaborative in over , adults the abcdef bundle: science and philosophy of how icu liberation serves patients and families improving hospital survival and reducing brain dysfunction at seven california community hospitals: implementing pad guidelines via the abcdef bundle in , patients clinical and team management in the covid-icu: successful strategies from the first week organ distribution of severe acute respiratory syndrome (sars) associated coronavirus (sars-cov) in sars patients: implications for pathogenesis and virus transmission pathways multiple organ infection and the pathogenesis of sars neurotropic virus tracing suggests a membranous-coatingmediated mechanism for transsynaptic communication sars: clinical features and diagnosis the neuroinvasive potential of sars-cov may play a role in the respiratory failure of covid- patients mechanisms of host defense following severe acute respiratory syndrome-coronavirus (sars-cov) pulmonary infection of mice neuroinvasion by human respiratory coronaviruses middle east respiratory syndrome coronavirus causes multiple organ damage and lethal disease in mice transgenic for human dipeptidyl peptidase novel coronavirus is putting the whole world on alert neurotropism of human coronavirus e characteristics of a coronavirus (strain n) of pigs detection of coronavirus in the central nervous system of a child with acute disseminated encephalomyelitis neurologic complications of coronavirus infections coronavirus infections in the central nervous system and respiratory tract show distinct features in hospitalized children covid- -associated acute hemorrhagic necrotizing encephalopathy: ct and mri features. radiology. coronavirus infection of rat dorsal root ganglia: ultrastructural characterization of viral replication, transfer, and the early response of satellite cells severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ace covid- : gastrointestinal symptoms and potential sources of -ncov transmission evidence of the covid- virus targeting the cns: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms vascular aspects of cognitive impairment and dementia can angiotensin-converting enzyme inhibitors impact cognitive decline in early stages of alzheimer's disease? an overview of research evidence in the elderly patient population endothelin-converting enzyme- activity, endothelin- production, and free radical-dependent vasoconstriction in alzheimer's disease parp- involvement in neurodegeneration: a focus on alzheimer's and parkinson's diseases both spike and background genes contribute to murine coronavirus neurovirulence neutrophils promote mononuclear cell infiltration during viral-induced encephalitis maturation and localization of macrophages and microglia during infection with a neurotropic murine coronavirus. brain pathology hypomyelination, memory impairment, and blood-brain barrier permeability in a model of sleep apnea lingo- antibody ameliorates myelin impairment and spatial memory deficits in experimental autoimmune encephalomyelitis mice axonal transport enables neuron-to-neuron propagation of human coronavirus oc the impact of delirium in the intensive care unit on hospital length of stay delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit the cost of icu delirium and coma in the intensive care unit patient longterm cognitive impairment after critical illness comfort and patient-centred care without excessive sedation: the ecash concept clinical phenotypes of delirium during critical illness and severity of subsequent long-term cognitive impairment: a prospective cohort study critical illness brain injury prevalence and risk factors for development of delirium in surgical and trauma intensive care unit patients lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients effect of haloperidol on survival among critically ill adults with a high risk of delirium: the reduce randomized clinical trial intubation and ventilation amid the covid- outbreak: wuhan's experience safety and efficacy of the abcde bundle in critically-ill patients receiving mechanical ventilation staged implementation of awakening and breathing, coordination, delirium monitoring and management, and early mobilization bundle improves patient outcomes and reduces hospital costs improving health care for critically ill patients using an evidence-based collaborative approach to abcdef bundle dissemination and implementation icu delirium -a diagnostic and therapeutic challenge in the intensive care unit publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -pscw i authors: guo, zhen-dong; wang, zhong-yi; zhang, shou-feng; li, xiao; li, lin; li, chao; cui, yan; fu, rui-bin; dong, yun-zhu; chi, xiang-yang; zhang, meng-yao; liu, kun; cao, cheng; liu, bin; zhang, ke; gao, yu-wei; lu, bing; chen, wei title: aerosol and surface distribution of severe acute respiratory syndrome coronavirus in hospital wards, wuhan, china, date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: pscw i to determine distribution of severe acute respiratory syndrome coronavirus in hospital wards in wuhan, china, we tested air and surface samples. contamination was greater in intensive care units than general wards. virus was widely distributed on floors, computer mice, trash cans, and sickbed handrails and was detected in air ≈ m from patients. to determine distribution of severe acute respiratory syndrome coronavirus in hospital wards in wuhan, china, we tested air and surface samples. contamination was greater in intensive care units than general wards. virus was widely distributed on floors, computer mice, trash cans, and sickbed handrails and was detected in air ≈ m from patients. relatively high for floor swab samples (icu / , %; gw / , . %), perhaps because of gravity and air flow causing most virus droplets to float to the ground. in addition, as medical staff walk around the ward, the virus can be tracked all over the floor, as indicated by the % rate of positivity from the floor in the pharmacy, where there were no patients. furthermore, half of the samples from the soles of the icu medical staff shoes tested positive. therefore, the soles of medical staff shoes might function as carriers. the weak positive results from the floor of dressing room might also arise from these carriers. we highly recommend that persons disinfect shoe soles before walking out of wards containing covid- patients. the rate of positivity was also relatively high for the surface of the objects that were frequently touched by medical staff or patients (tables , ). the highest rates were for computer mice (icu / , %; gw / , %), followed by trash cans (icu / , %; gw / ), sickbed handrails (icu / , . %; gw / ), and doorknobs (gw / , . %). sporadic positive results were obtained from sleeve cuffs and gloves of medical staff. these results suggest that medical staff should perform hand hygiene practices immediately after patient contact. because patient masks contained exhaled droplets and oral secretions, the rate of positivity for those masks was also high (tables , ) . we recommend adequately disinfecting masks before discarding them. for the icu, the order of dressing is dressing room , dressing room , and dressing room ; the order of undressing is dressing room , dressing room , and dressing room . the isolation ward of icu is a large floor space with cubicles (each with a patient bed) along the opposite perimeters. each cubicle is open to the central open area without any partition. for the general ward, the order of dressing is dressing room , dressing room , and dressing room ; the order of undressing is dressing room , dressing room , and buffer room . the contaminated area of the general ward contains a patient corridor, and the -sided cubicles are all enclosed with door access to the corridor. we further assessed the risk for aerosol transmission of sars-cov- . first, we collected air in the isolation ward of the icu ( air supplies and air discharges per hour) and gw ( air supplies and air discharges per hour) and obtained positive test results for % ( samples positive/ samples tested) of icu samples and . % ( / ) of gw samples. air outlet swab samples also yielded positive test results, with positive rates of . % ( / ) for icus and . % ( / ) for gws. these results confirm that sars-cov- aerosol exposure poses risks. furthermore, we found that rates of positivity differed by air sampling site, which reflects the distribution of virus-laden aerosols in the wards ( figure , panel a). sampling sites were located near the air outlets (site ), in patients' rooms (site ), and (site ). sars-cov- aerosol was detected at all sampling sites; rates of positivity were . % ( / ) near air outlets, . % ( / ) in patients' rooms, and . % figure ( / ) in the doctors' office area. these findings indicate that virus-laden aerosols were mainly concentrated near and downstream from the patients. however, exposure risk was also present in the upstream area; on the basis of the positive detection result from site , the maximum transmission distance of sars-cov- aerosol might be m. according to the aerosol monitoring results, we divided icu workplaces into high-risk and low-risk areas (figure , panel b) . the high-risk area was the patient care and treatment area, where rate of positivity was . % ( / ). the low-risk area was the doctors' office area, where rate of positivity was . % ( / ). in the gw, site was located near the patients (figure , panel c). site was located ≈ . m up-stream of the air flow relative to the heads of patients. we also sampled the indoor air of the patient corridor. only air samples from site tested positive ( . %, / ). the workplaces in the gw were also divided into areas: a high-risk area inside the patient wards (rate of positivity . , / ) and a low-risk area outside the wards (rate of positivity ) (figure , panel d) . this study led to conclusions. first, sars-cov- was widely distributed in the air and on object surfaces in both the icu and gw, implying a potentially high infection risk for medical staff and other close contacts. second, the environmental figure contamination was greater in the icu than in the gw; thus, stricter protective measures should be taken by medical staff working in the icu. third, the sars-cov- aerosol distribution characteristics in the icu indicate that the transmission distance of sars-cov- might be m. as of march , no staff members at huoshenshan hospital had been infected with sars-cov- , indicating that appropriate precautions could effectively prevent infection. in addition, our findings suggest that home isolation of persons with suspected covid- might not be a good control strategy. family members usually do not have personal protective equipment and lack professional training, which easily leads to familial cluster infections ( ) . during the outbreak, the government of china strove to the fullest extent possible to isolate all patients with suspected covid- by actions such as constructing mobile cabin hospitals in wuhan ( ), which ensured that all patients with suspected disease were cared for by professional medical staff and that virus transmission was effectively cut off. as of the end of march, the sars-cov- epidemic in china had been well controlled. figure . spatial distribution of severe acute respiratory syndrome coronavirus aerosols in isolation wards of the intensive care unit (icu) and the general ward at huoshenshan hospital, wuhan, china. a) the air sampling sites in the icu were distributed in different regions: near the air outlet (site ), near the patients (site ), and around the doctors' office area (site ). orange circles represent sampling sites; blue arrows represent direction of the fresh air flow; and the graded orange arrow and scale bar indicate the horizontal distance from the patient's head. b) in terms of viral aerosol distribution, the space in the icu was divided into parts: a high-risk area with a . % rate of virus positivity and a low-risk area with a . % rate of virus positivity. c) the air sampling sites in the general ward were distributed in different regions around the patient (site ), under the air inlet (site ), and in the patient corridor. d) in terms of the viral aerosol distribution, the space in the general ward was divided into parts: a high-risk area with a . % rate of virus positivity and a low-risk area with a % rate of virus positivity. our study has limitations. first, the results of the nucleic acid test do not indicate the amount of viable virus. second, for the unknown minimal infectious dose, the aerosol transmission distance cannot be strictly determined. overall, we found that the air and object surfaces in covid- wards were widely contaminated by sars-cov- . these findings can be used to improve safety practices. world health organization. coronavirus disease (covid- ) situation report- covid- and italy: what next? lancet transmission routes of -ncov and controls in dental practice air, surface environmental, and personal protective equipment contamination by severe acute respiratory syndrome coronavirus (sars-cov- ) from a symptomatic patient rapid deployment of a mobile biosafety level- laboratory in sierra leone during the ebola virus epidemic a family cluster of sars-cov- infection involving patients in nanjing, china. lancet infect dis health protection guideline of mobile cabin hospitals during novel coronavirus pneumonia (npc) outbreak address for correspondence: wei chen beijing, china; email: cw @foxmail.com, lubing@nic.bmi.ac.cn, and gaoyuwei@gmail.com emerging infectious diseases • www baylisascaris procyonis, the common intestinal roundworm of raccoons, has increasingly been recognized as a source of severe, often fatal, neurologic disease in humans, particularly children. although this devastating disease is rare, lack of effective treatment and the widespread distribution of raccoons in close association with humans make baylisascariasis a disease that seriously affects public health. raccoons infected with b. procyonis roundworms can shed millions of eggs in their feces daily. given the habit of raccoons to defecate in and around houses, information about optimal methods to inactivate b. procyonis eggs are critical for the control of this disease. however, little information is available about survival of eggs and effective disinfection techniques. additional data provides infomation on thermal death point and determining the impact of desiccation and freezing on the viability of b. procyonis eggs to provide additional information for risk assessments of contamination and guide attempts at environmental decontamination. visit our website to listen: https://www c.cdc.gov/podcasts/ player.asp?f= key: cord- -nzxbogga authors: antinori, spinello; cossu, maria vittoria; ridolfo, anna lisa; rech, roberto; bonazzetti, cecilia; pagani, gabriele; gubertini, guido; coen, massimo; magni, carlo; castelli, antonio; borghi, beatrice; colombo, riccardo; giorgi, riccardo; angeli, elena; mileto, davide; milazzo, laura; vimercati, stefania; pellicciotta, martina; corbellino, mario; torre, alessandro; rusconi, stefano; oreni, letizia; gismondo, maria rita; giacomelli, andrea; meroni, luca; rizzardini, giuliano; galli, massimo title: compassionate remdesivir treatment of severe covid- pneumonia in intensive care unit (icu) and non-icu patients: clinical outcome and differences in post_treatment hospitalisation status date: - - journal: pharmacol res doi: . /j.phrs. . sha: doc_id: cord_uid: nzxbogga sars-cov- is causing an increasing number of deaths worldwide because no effective treatment is currently available. remdesivir has shown in vitro activity against coronaviruses and is a possible antiviral treatment for sars-cov- infection. this prospective (compassionate), open-label study of remdesivir, which was conducted at luigi sacco hospital, milan, italy, between february and march , , involved patients with sars-cov- pneumonia aged ≥ years undergoing mechanical ventilation or with an oxygen saturation level of ≤ % in air or a national early warning score of ≥ . the primary outcome was the change in clinical status based on a -category ordinal scale ( = not hospitalised, resuming normal daily activities; = deceased). the patients enrolled from february to march , , included in intensive care unit (icu), and in our infectious diseases ward (idw). the -day course of remdesivir was completed by patients ( %) and discontinued by , of whom eight ( . %) discontinued because of adverse events. the median follow-up was days (iqr - ). at day , ( . %) patients from idw were discharged, two were still hospitalized and one died ( . %), whereas in icu ( . %) were discharged, ( . %) patients died, three ( . %) were still mechanically ventilated and one ( . %) was improved but still hospitalized. hypertransaminasemia and acute kidney injury were the most frequent severe adverse events observed ( . % and . % of the cases, respectively). our data suggest that remdesivir can benefit patients with sars-cov- pneumonia hospitalised outside icu where clinical outcome was better and adverse events are less frequently observed. ongoing randomised controlled trials will clarify its real efficacy and safety, who to treat, and when. since the first reported outbreak in wuhan, china, in december , the world has witnessed the pandemic spread of the newly identified betacoronavirus sars-cov- (severe acute respiratory syndrome coronavirus ) that is responsible for coronavirus disease- [ ] [ ] [ ] . after a few sporadic cases in nine european countries, italy became one of the western countries with the highest number of diagnosed cases ( , as of april ), with the greatest outbreak occurring in the region of lombardy ( . cases) [ , ] . sars-cov- spreads from human to human transmission by means of respiratory droplets or direct contact, and has a median incubation period of . days and a basic reproduction number of . - . [ , ] . the clinical spectrum of covid- ranges from mild disease (i.e. the absence of pneumonia or mild pneumonia) in about % of cases to life-threatening pneumonia in the form of acute respiratory disease syndrome (ards) requiring intensive care in % [ ] [ ] [ ] [ ] . the case fatality rate (cfr) seems to vary and reported estimates range from % to %, but this should be more precisely known once surveillance studies have clarified the number of infected subjects [ ] [ ] . given the severity and expected high cfr of the pneumonia caused by sars-cov- , it is imperative to find an effective drug treatment because supportive care and oxygen supplementation is not always enough. remdesivir, a nucleoside pro-drug that is thought to act by inhibiting viral rna transcription, has shown in vitro antiviral activity against bat coronavirus and sars-cov- , and has been safely used in one patient with sars-cov- pneumonia in the usa [ ] [ ] [ ] [ ] . this study evolved in the context of the emergency caused by the large outbreak of covid- in lombardy, italy, that started on february . on february, the pharmaceutical company gilead sciences agreed to a request for the donation of remdesivir for compassionate use in individual patients seriously affected by sars-cov- pneumonia and hospitalised at luigi sacco hospital, milan, italy. a report containing the clinical information and laboratory test results of each eligible patient requiring oxygen supplementation was sent to gilead for approval. enrolment in the programme ended on march , as it was planned to start a randomised, controlled, double-j o u r n a l p r e -p r o o f blind clinical trial aimed at evaluating the efficacy and safety of remdesivir in hospitalised patients with mild to moderate covid- respiratory disease [ ] . pending the results of this trial, we report the outcomes of patients who received compassionate remdesivir treatment during the first days of the italian sars-cov- epidemic. patients were eligible to receive remdesivir for compassionate use if they were a male or non-pregnant female aged > years, had sars-cov- infection confirmed by a positive reverse-transcriptase polymerase chain reaction (rt-pcr) test of a respiratory tract sample and pneumonia confirmed by a chest x-ray or computed tomography (ct) scan, and were mechanically ventilated or had an oxygen saturation (sao ) level of < % in room air or a national early warning score (news) of  [ ] . patients were excluded if their alanine or aspartate aminotransferase level was > times the upper limit of the normal range and creatinine clearance was < ml/min. urgent approval for each eligible patient was obtained by our ethics committee and sent to gilead together with the patient's clinical history. written informed consent was obtained from all of the patients except those who were undergoing invasive mechanical ventilation, for whom the principle of urgency was applied. the patients were prospectively enrolled in the remdesivir treatment programme between february and march , (fig. ). the drug schedule was an intravenous loading dose of mg on day , followed by an intravenous dose of mg/day from day to day . the patients could continue their existing treatments including hydroxychloroquine (hcq), but had to discontinue lopinavir/ritonavir (lpv/r) in accordance with gilead's recommendations. the clinical and laboratory data of all of the patients who received at least one dose of remdesivir were collected on a daily basis from the date of enrolment to the date of discharge, death or censoring ( april ). in a subset of patients, a semi-quantitative rt-pcr test of a nasopharyngeal swab was carried out at baseline and during remdesivir treatment using an automated elite ingenius system and the genefinder covid- plus realamp kit (elitechgroup, france). the reaction mix was manually prepared in accordance with the manufacturer's instructions, and loaded on to the system with other reagents, and rna was extracted from l of sample and eluted in l; the final reaction volume consisted of l of rna plus l of reagent mix. the rt-pcr profile was °c for minutes, °c for five minutes plus cycles at °c for seconds and °c for seconds in accordance with the manufacturer's instructions. three target genes, rna-dependent rna polymerase (rdrp), nucleocapsid protein (n) and envelope membrane protein (e) were simultaneously amplified and tested. viral load was measured as the cycle threshold (ct) value. the primary outcome was the change in the patients' hospitalisation status on the th and th day of treatment. hospitalisation status was assessed using a -category ordinal scale previously used in influenza studies [ ], in which = not hospitalised, capable of resuming normal activities; = not hospitalised but unable to resume normal activities; = hospitalised, not requiring oxygen supplementation; = hospitalised and requiring oxygen therapy; = hospitalised an requiring highflow nasal oxygen therapy, non-invasive mechanical ventilation, or both; = intensive care unit (icu) hospitalisation, requiring invasive mechanical ventilation or extra corporeal membrane oxygenation (ecmo), or both; = deceased. the secondary outcome was safety, including adverse events leading to premature treatment discontinuation. adverse events were classified using the national cancer institute common terminology criteria for adverse events, version . . continuous variables are expressed as median values and their interquartile range (iqr), and were compared using the non-parametric mann-whitney test; categorical variables are expressed as j o u r n a l p r e -p r o o f absolute numbers and percentages, and were compared using fisher's exact test. friedman's test was used for paired samples. between february and march , consecutive patients (fully representative of all hospitalised covid- patients in italy) were evaluated for the compassionate use of remdesivir and were considered eligible for treatment. thirteen patients did not start the drug for the reasons given in figure . the remaining received at least one dose and were evaluated for the outcomes of interest. thirty-one of these patients had previously received lpv/r + hcq for a median of five days, but all discontinued lpv/r upon enrolment. eighteen patients started remdesivir in our icu and seventeen in our infectious disease ward (idw): most of icu patients were undergoing invasive mechanical ventilation, and most of the idw patients were undergoing high-flow oxygen therapy and/or non-invasive mechanical ventilation. table shows the main baseline characteristics of the icu and idw patients, who were prevalently males ( . % and . %) and had a median age of respectively . (iqr . - . ) and . years (iqr . - . ). the median time from symptom onset to hospital admission was seven days in both groups, whereas the median time from hospital admission to the start of remdesivir treatment was shorter in the icu than in the idw patients ( days, iqr . - . vs days, iqr - ). the median charlson co-morbidity index was in the icu group and in the idw group, and most frequent co-morbidity in both groups was hypertension ( . % and . %). the median news score was higher in the icu than in the idw patients ( vs ), and they also had a higher median white blood cell count ( /l vs /l) and d-dimer level ( . vs ), a lower absolute lymphocyte count ( /l vs /l), and higher c-reactive protein ( vs ) and ldh levels ( u/l vs u/l). twenty-two ( %) completed the scheduled course of remdesivir, whereas thirteen (nine in icu and four idw patients) had the treatment discontinued after a median of five doses (iqr - ) because of toxicities (n= , . %), death (n= , . %) and early discharge (n= , . %). as shown in figure , by day of rendesivir treatment, four ( . %) of the icu patients showed an improvement in their hospitalisation status (one was still hospitalized but not requiring supplemental oxygen and three had been weaned from invasive ventilation), ten ( . %) were still undergoing invasive ventilation, and four ( . %) had died; by the day of follow-up, the hospitalisation status of . % of the icu patients had improved (six had been discharged, one had been weaned from invasive ventilation), . % were still undergoing mechanical ventilation and the other . % had died. among the idw patients, the hospitalisation status of ( . %) had improved by day of remdesivir treatment (one had been discharged, three no longer required oxygen supplementation, and, two were still hospitalized but no longer required high-flow therapy and/or non-invasive mechanical ventilation); but still required high-flow therapy and/or non-invasive mechanical ventilation, and one had died. by day of follow-up, hospitalisation status had improved in . % of the idw patients ( had been discharged, one no longer required oxygen supplementation) but one still required high-flow therapy and/or non-invasive mechanical ventilation. the news and laboratory test results of fourteen icu and idw patients could be assessed on day of remdesivir treatment. there were no statistically significant changes from baseline in news in either group, but the idw patients (although not the icu patients) showed a statistically significant improvement in fio values (p= . ). moreover, there was a statistically significant increase in lymphocyte counts in both the icu and idw groups (p=< . and p= . ), and a statistically significant decrease in c-reactive protein levels (p= . and p< . ). twenty-one of the enrolled patients (seven icu and fourteen idw patients) were tested for sars-cov- viral load on a nasopharyngeal swab at baseline and during treatment. the overall median value at baseline was ct ( in the icu and in the idw patients), and had a negative viral load a median of days ) after the start of remdesivir treatment. table shows severe adverse events recorded during remdesivir treatment. the most frequent was hepatotoxicity, with a grade - increase in transaminases levels observed in . % of the patients. the most frequent adverse event leading to treatment discontinuation was acute kidney injury, which was observed in four patients, all in icu, three of whom eventually died. remdesevir was also discontinued in three patients showing a grade - increase in transaminase levels, and in one patients who developed a serious maculo-papular rash. the pandemic emergence of sars-cov- infection, which is characterised by progressively severe pneumonia and ards that leads to a high mortality rate among hospitalised patients, challenges the medical community to evaluate rapidly any possibly effective antiviral drug [ ] . on the basis of in vitro studies of different coronaviruses (including sars-cov- ), it seems that a number of drugs may be candidate treatment options, including lpv/r, chloroquine, hcq and remdesivir [ ] [ ] [ ] [ ] [ ] [ ] [ ] . one randomised, controlled trial of lpv/r involving hospitalised patients with severe covid- has failed to demonstrate any clinical benefit [ ] . - pneumonia [ , , ] . conversely, in a randomized, double-blind placebocontrolled study conducted in china, remdesivir was not associated with statistically significant beneficial clinical outcome with severe covid- pneumonia [ ] . this later study, however, has been stopped earlier due to the reduction of the number of covid- cases in china and it was therefore underpowered to provide conclusive information. we report, our experience of remdesivir compassionate use in patients treated at luigi sacco hospital in milan, italy, between february and march , of whom % completed the day course, and % discontinued it prematurely because of adverse events. the hospitalisation status of . % of our idw patients improved by the day from starting remdesivir treatment, the majority of whom had been discharged to resume their normal activities; however, there was a . % case fatality rate among the patients who started the treatment in our icu. given that the clinical condition of only one of our idw patients worsened, it is possible that remdesivir may be more efficacious in patients who present early in a non-critical condition. as has been shown in a previous study of the use of neuraminidase inhibitors against influenza [ ], a delay in beginning antiviral treatment can be crucial when evaluating the efficacy of drugs against an acute respiratory infection. interestingly, we were able to measure sars-cov- viral load in nasopharyngeal swabs of of our patients at baseline and during remdesivir treatment, and the rt-pcr showed that all of these patients became negative a median of days after the start of treatment. this is in line with with the rapid decline in viral load observed in a single patient treated with remdesivir in the usa [ ], and these may cautiously considered a positive virological response, given that a study conducted in wuhan showed that the median duration of viral shedding among patients surviving sars-cov- infection was days [ ]. one-third of the patients enrolled in our study were unable to complete the scheduled -day course of remdesivir because of aes. the most frequent severe ae was increase in liver enzymes, a finding in line with data of the multicenter compassionate study by grein et al. [ ] . moreover, four of our patients who started remdesivir treatment in the icu developed aki, and three of them eventually j o u r n a l p r e -p r o o f died; however, it is difficult to say whether the aki was caused by the infection itself, remdesivir, or any of the other administered medications. since lpv/r was discontinued hour before the administration of remdesivir we believe that the aes were likely independent of that previous treatment although it cannot fully excluded. we acknowledge that our study has a number of limitations. first, given the context in which it originated, it was impossible to include a control group so we cannot exclude the possibility that the patients whose hospitalisation status improved after remdesivir treatment may have improved regardless of any treatment. secondly, most of our patients had previously received lpv/r + hqc and this may represent a confounding factor when analysing the efficacy of remdesivir. finally, we could not predefine a virological follow-up which limits our finding of a possible virological effect of remdesivir in inducing the clearance of viral rna in the patients' respiratory samples. in conclusion, remdesivir treatment may have a beneficial effect on sars cov- pneumonia, especially in the case of non-critically ill patients. our decision to administer it for compassionate use was triggered by a state of emergency, but randomised controlled trials are now needed to determine the safety and efficacy of remdesivir and any other investigational agent in the treatment of patients with sars cov- infection. any ae leading to treatment discontinuation ( . % ) ( . %) ( . %) a novel coronavirus from patients with pneumonia in china a pneumonia outbreak associated with a new coronavirus of probable bat origin genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding first cases of coronavirus disease (covid- ) in the who european region   coronavirus: la situazione dei contagi in italia the incubation period of coronavirus disease covid- ) from publicly reported confirmed cases: estimation and application early phylogenetic estimate of the effective reproduction number of sars-cov- covid- -new insights on a rapidly changing epidemic clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study pathologic findings of covid- associated with acute respiratory distress syndrome care for critically ill patients with covid- clinical characteristics of hospitalized patients with -ncov infection novel coronavirus patients' clinical characteristics, discharge rate and fatality rate of meta-analysis remdesivir as a possible therapeutic option for the covid- coronavirus susceptibility to the antiviral remdesivir (gs- ) is mediated by the viral polymerase and the proofreading exoribonuclease remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus ( -ncov) in vitro first case of novel coronavirus in the united states arguments in favour of remdesivir for treating sars-cov- infections   royal college of physicians national early warning score (news) : standardising the assessment of acute illness severity in the nhs comparative effectiveness of combined favipiravir and oseltamivir therapy versus oseltamivir monotherapy in critically ill patients with influenza virus infection case-fatality rate and characteristics of patients dying in relation to covid- in italy comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against mers-cov broad-spectrum antiviral gs- inhibits both epidemic and zoonotic coronaviruses new insights on the antiviral effects of chloroquine against coronavirus: what to expect for covid- ? in vitro antiviral activity and projection of optimized dosing coronavirus (sars-cov- ) a trial of lopinavir-ritonavir in adults hospitalized with severe covid- delayed initiation of remdesivir in a covid- positive patient compassionate use of remdesivir for patients with severe covid- remdesivir in adults with severe covid- : a randomised, double-blind, placebo-controlled, multicentre trial alanine aminotransferase (u/l), median (iqr) intesive care unit; idw, infectious diseases ward; iqr, interquartile; fio , fraction of inspired oxygen wbc, white blood cells we are grateful to dr. adam dezure and all his colleagues at gilead science, inc (usa and italy), for granting the opportunity of a possible treatment for some of our severly ill covid- patients.the authors thank all patients enrolled in the study, their relatives, and all medical staff (nurses and physicians) engaged in the fight against covid- , some of whom eventually fell ill during the battle. we also thank dr. nadège fancy for the excellent help in writing the document.j o u r n a l p r e -p r o o f key: cord- - mg a c authors: liu, li; to, kelvin kai-wang; chan, kwok-hung; wong, yik-chun; zhou, runhong; kwan, ka-yi; fong, carol ho-yan; chen, lin-lei; choi, charlotte yee-ki; lu, lu; tsang, owen tak-yin; leung, wai-shing; to, wing-kin; hung, ivan fan-ngai; yuen, kwok-yung; chen, zhiwei title: high neutralizing antibody titer in intensive care unit patients with covid- date: - - journal: emerging microbes & infections doi: . / . . sha: doc_id: cord_uid: mg a c coronavirus disease (covid- ) has a wide spectrum of disease severity from mild upper respiratory symptoms to respiratory failure. the role of neutralizing antibody (nab) response in disease progression remains elusive. this study determined the seroprevalence of non-covid- individuals from april to february in the hong kong special administrative region and compared the neutralizing antibody (nab) responses of eight covid- patients admitted to the intensive care unit (icu) with those of patients not admitted to the icu. we found that nab against sars-cov- was not detectable in any of the anonymous serum specimens from the non-covid- individuals. the peak serum geometric mean nab titer was significantly higher among the eight icu patients than the non-icu patients ( [ % confidence interval (ci) - ]) vs ( [ % ci, - ]). furthermore, nab titer increased significantly at earlier infection stages among icu patients than among non-icu patients. the median number of days to reach the peak nab titers after symptoms onset was shorter among the icu patients ( . ) than that of the non-icu patients ( . ). multivariate analysis showed that oxygen requirement and fever during admission were the only clinical factors independently associated with higher nab titers. our data suggested that sars-cov- was unlikely to have silently spread before the covid- emergence in hong kong. icu patients had an accelerated and augmented nab response compared to non-icu patients, which was associated with disease severity. further studies are required to understand the relationship between high nab response and disease severity. since emerging in late , the coronavirus disease has rapidly spread across the world [ ] . the world health organization declared covid- a pandemic on march . as of th june , there are over million laboratory-confirmed cases worldwide with more than . million deaths. the severe acute respiratory syndrome coronavirus (sars-cov- ) predominantly causes respiratory tract infection. it also replicates to higher titers than sars-cov in ex vivo lung tissue explant cultures [ , ] . moreover, about % of patients experience gastrointestinal symptoms, and sars-cov- can infect and replicate in human intestinal cell line and organoid [ , ] . understanding the host immune response to sars-cov- is critical in deciphering the pathogenesis of covid- . we have previously shown that sars-cov- could stimulate inflammatory mediators in ex vivo lung tissues, though this stimulation is less than that of the sars-cov [ ] . in a hamster model, we have demonstrated there is marked cytokine activation and lymphoid atrophy [ ] . recovered hamsters showed a robust production of neutralizing antibody (nab) [ ] . using enzyme immunoassay, we and others have shown that igg against sars-cov- nucleoprotein (np) and spike protein receptor binding domain (rdb) started to increase during the second week of infection and that most patients had seroconversion by the third week [ , [ ] [ ] [ ] . nab response with a titer of at least : was identified in % of patients during the convalescent period [ ] . recent studies of vaccine in non-human primates and monoclonal neutralizing antibodies in ace transgenic mice suggested that neutralizing antibodies are effective for protection against sars-cov- [ ] [ ] [ ] [ ] . in this study, we analysed the temporal nab responses among patients with severe disease and compared this with the responses of patients with mild disease. this study consisted of anonymized archived serum samples collected from the biochemistry laboratory and microbiology laboratory as described previously [ ] . these specimens were randomly obtained between april and february (supplementary table s ), and some specimens have been used in our previous study [ ] . a total of patients with covid- were included. all patient cases were confirmed by reverse-transcription polymerase chain reaction (rt-pcr) as we described previously [ ] . patients were excluded if serum specimen was not available on or after day of symptom onset. eleven patients were described in our previous study [ ] , patients were included in our previous clinical trial [ ] , and patients were recruited additionally. clinical and laboratory findings were entered into a predesigned database. written informed consent was obtained from all patients, except for the patients for whom archived specimens were used [ ] . ethical approval was obtained from the hku/ha hkw institutional review board (uw - , uw - , uw - ) and kowloon west cluster research ethics committee (kw/ex- - ( - )). hek- t, huh and vero-e cells were cultured in dulbecco's modified eagle medium (dmem) with % inactivated fetal bovine serum (fbs) (invitrogen), units/ml penicillin, and μg/ml streptomycin sulfate (invitrogen). hek t-ace cells were cultured in dmem with % fbs, units/ml penicillin, μg/ml streptomycin sulfate, and μg/ml puromycin (sigma). the neutralizing activity of heat-inactivated patients' sera was determined using a pseudotype-based neutralization assay as previously described [ ] . the pseudotype virus was generated through cotransfection of t cells with plasmids, pvax- -s-covid and pnl - luc_env_vpr, carrying the optimized spike (s) gene (qhr ) and a human immunodeficiency virus type backbone, respectively as we previously described [ , ] (supplementary figure s ). viral supernatant was collected h post-transfection and was frozen at − °c. the serially diluted serum samples were incubated with tcid of pseudovirus at °c for h. the serum-virus mixtures were subsequently added into pre-seeded hek t-ace cells. after h, infected cells were lysed to measure luciferase activity using a commercial kit (promega, madison, wi). the nab titer is defined as the serum dilution that resulted in % inhibitory concentrations (ic ) as determined by log (inhibitor) vs. normalized response -variable slope model. this mn assay has been previously described by us [ ] . statistical analysis was performed using prism . or spss . . categorical and continuous variables were compared using fisher's exact test and mann-whitney u test, respectively. log-transformed nab titer was used for the comparison of geometric mean titer with the student's t test and to analyze the correlation between pseudovirus and mn assays by pearson correlation test. for the purpose of statistical analysis, a value of was assigned for nab titer < . nab titers above the median of all patients were considered to be of high titer, while nab titers below the median were considered to be of low titer. to determine independent factors associated with nab titer, backward stepwise regression analysis was used to control confounding factors. we first developed a single-cycle reporter pseudotyped virus containing a spike glycoprotein of sars-cov- . we examined the entry efficiency of pseudotyped viruses into the vero-e , huh and hek t-ace cells. we found that pseudotyped viruses were able to infect all target cells, with highest infection efficiency in hek t-ace cells ( figure ). we conducted parallel experiments with hek- t cells and found that the pseudotyped viruses did not infect these cells ( figure a ). furthermore, we sought to compare pseudotyped neutralization assay with the live sars-cov- based mn assay, which we have previously described [ ] . by testing the same set of patients sera, we found that there was a strong correlation between log-transformed nab titers measured by pseudotyped and mn assays by the pearson correlation test (p < . ) ( figure b ). we discovered that the pseudotyped assay was on average . -fold (range, . -to . -fold) more sensitive than the mn assay. to assess the starting point of covid- in hong kong special administrative region (hksar), we applied our assay to anonymized serum specimens. all specimens tested were negative at a dilution of : . our results, therefore, not only demonstrated the specificity of the pseudovirus nab assay, but also indicated that sars-cov- was unlikely to be circulating in hksar before its emergence in our patients. next, we determined the nab of covid- patients, including patients admitted to the intensive care unit (icu) and hospitalized patients who were not admitted to the icu ( , p = . ) were significantly lower for icu patients than those of non-icu patients. there was also a trend towards a lower platelet count for icu patients than for non-icu patients, almost reaching statistical significance (icu patients, × /l [iqr, - ] vs non-icu patients, × /l [iqr, - ], p = . ). overall, the peak geometric mean of nab titer was ( % confidence interval [ci], - ). out of these patients, ( %) had a nab titer of < and ( %) had nab titers of < ( figure a ). the nab titer increased from st to rd week ( figure b ). figure a ). icu patients also had significantly higher nab titer than non-icu cases as early as - days after symptoms onset ( figure b ). icu patients had higher positive rates of serum diagnosis than non-icu patients from st week onwards ( figure c ). furthermore, nab increased significantly earlier among icu patients than non-icu patients ( figure d ). the median number of days after symptoms onset to reach the peak nab titer was also shorter among icu patients ( . ) than non-icu patients ( . ). to determine the risk factors for high nab titer, we performed both univariate and multivariate analysis. in the univariate analysis, significantly more patients in the high titer group required oxygen supplement than those in the low titer group ( % [ / ] , p = . ) were significantly lower for high titer than low titer group. in the multivariate analysis, only fever (p = . ) and oxygen supplementation (p = . ) were independent factors associated with nab titer. comparison of geometric mean titers between icu and non-icu patients at weekly intervals after symptoms onset. the highest titer during each weekly period was presented. (c) comparison of seropositive rates between icu and non-icu patients. a serum specimen is considered to be seropositive if the defined % inhibitory concentration (ic ) value was above : . (d) comparison of nab titer change between icu and non-icu patients at weekly intervals after symptoms onset. fold change was calculated using the highest titer from each time period against the highest titer from prior week. the error bar indicates % confidence interval. unpaired student's t-test was used. *p < . , **p < . , ***p < . . knowledge regarding the nab response for covid- patients is critical for understanding the host humoral immune response towards sars-cov- and the pathogenesis of covid- . in this study, the absence of nab in the serum of over hksar residents indicates that sars-cov- is unlikely to have spread silently in hong kong before its emergence in covid- patients. furthermore, by comparing icu and non-icu patients, we have shown that nab response rose significantly earlier and to a much greater extent in severe patients than in mild patients. multivariate analysis showed that oxygen requirement and fever were the only factors associated with a higher nab response. the oxygen requirement signifies the extent of local lung damage due to the infection by sars-cov- , while the fever response indicates the systemic inflammatory reaction by the immune system of the host towards the virus. we have demonstrated that patients with severe disease developed a faster and higher level of nab response. previously, we and others showed that sars-cov patients who died also had a more rapid nab response [ , ] . there are several reasons why the faster nab response did not ameliorate the severe disease. first, there can be overwhelming virus-induced damage in the lungs, which exacerbates proinflammatory cytokine response [ , ] . since the antibody only neutralizes the virus, the inflammation triggered by virus-induced damage cannot be dampened by a nab response. in our hamster model, we have demonstrated that there is extensive diffuse alveolar damage and apoptosis in the lung, which was associated with significant cytokine activation [ ] . second, we reported that patients with covid- had the highest viral load near symptoms presentation and rapid antibody development could enhance macrophage-mediated acute lung injury [ , ] . high nab titer in icu patients might be due to higher viral/antigen loads during acute sars-cov- infection. third, we have previously shown that the anti-spike protein antibody, which contains potent receptor binding domainspecific nab [ ] , can worsen disease in a macaque model by skewing inflammation-resolving responses [ ] . several studies have evaluated the kinetics of antibodies against the sars-cov- np or spike protein. previous studies have shown that the antibody titer against these proteins were higher among patients with severe disease than those with mild disease [ ] . however, these antibodies that bind to np or spike protein may not be neutralizing. in a study by okba et al., it was shown that one patient with severe disease had a faster and more augmented nab response than two patients with mild disease [ ] . wang et al. has also shown that patients with severe disease had high titers of nab, but the number of patients were not shown [ ] . during our manuscript revision, a preprint paper indicated that sars-cov- neutralizing antibody responses are more robust in patients with severe disease [ ] . in a convalescent plasma transfusion study, out of severe patients (one unavailable) had actually self-developed nab responses before the treatment [ ] . since severe cases had the same high nab titer ( : ) even before and also after the transfusion, the therapeutic benefits of nab remains to be investigated. in our cohort, % of patients had a neutralizing titer below and % had a nab titer below . the inability to mount a high antibody titer corroborates with the results from a study by wu et al., which also showed that % of patients had undetectable pseudovirus nab levels [ ] . though the cell mediated immune response or cytotoxic lymphocyte response were not measured in these patients, the low level of nab suggests that some patients may be susceptible to re-infection in the future. these patients may also have a chance for longer period of viral shedding. currently, the protective nab titer has not been established. therefore, it would be important to followup patients to assess the protective nab titer level, which may have significant implication for vaccine development. we have used a pseudovirus neutralization assay. the main advantage of using pseudovirus assay is that the experiment can be performed in laboratories of biosafety level instead of biosafety level . furthermore, the pseudovirus neutralization assay is a high throughput assay and therefore a large number of serum specimens can be assessed simultaneously. results from pseudovirus neutralization assays are also highly reproducible [ ] . measuring nab is especially required for the screening of patients as convalescent plasma donors. it is also important to screen the collected convalescent plasma of patients who require passive immunization. the use of convalescent plasma has been reported for severe patients, which showed beneficial effect [ , ] . specially, there was better oxygenation, decreased inflammatory markers, and radiological improvement after patients were treated with infusion of convalescent plasma. further studies should be performed to understand the optimal timing of convalescent plasma administration, which may improve the outcome of severe covid- patients and minimize the risk of immunopathology. however, antibodies may also be as dangerous as they are helpful. although nab response is important in vaccine-induced immune response, as demonstrated in influenza vaccine trials, antibodies can also worsen disease cases, especially for dengue virus infection. therefore, the next step is to determine why patients still have worsened disease despite the rapid development of high titer of nab responses. understanding nab response is important clinically, especially for the use of convalescent plasma or hyperimmune globulin therapy. further studies on whether treatment with neutralizing antibodies is useful in earlier stages of disease remains to be carefully conducted. specifically, it is important to know whether such treatment should be started earlier, when the inflammatory damage to the lungs is still limited, or should be started later, when the amount of virus is already overwhelming, leading to further lung damage mediated by complement fixation due to excessive antibody-antigen complex formation. for example, a recent study has demonstrated that convalescent plasma or hyperimmune intravenous immunoglobulin against pandemic influenza h n is only useful within days of symptom onset [ ] . in addition, convalescent plasma or monoclonal antibodies especially derived from severe patients should be carefully studied for therapeutic use. there are several limitations to this study. first, all patients included in this study were adults. the nab response in children should be compared. second, this study assessed the nab response of patients during the acute and subacute phase of infection. their long term antibody response is still not known. our study has demonstrated the association between clinical severity and nab response. further studies are required to dissect the immunological events that lead to heightened nab response. in particular, whether or not neutralizing antibodies themselves can mediate disease severity remains to be investigated. manuscript. kk extracted plasmid dna and/or generated virus. liul and zc conducted the pseudoviral neutralization assay. kc and lul did the mn assay. kc, yw, rz, cf, lc, cc, ot, wl, wt and ih collected clinical samples. no potential conflict of interest was reported by the author(s). a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster comparative replication and immune activation profiles of sars-cov- and sars-cov in human lungs: an ex vivo study with implications for the pathogenesis of covid- temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by sars-cov- : an observational cohort study infection of bat and human intestinal organoids by sars-cov- gastrointestinal manifestations of sars-cov- infection and virus load in fecal samples from the hong kong cohort and systematic review and meta-analysis simulation of the clinical and pathological manifestations of coronavirus disease (covid- ) in golden syrian hamster model: implications for disease pathogenesis and transmissibility antibody responses to sars-cov- in patients with covid- antibody responses to sars-cov- in patients of novel coronavirus disease serological assays for severe acute respiratory syndrome coronavirus (sars-cov- ) seroprevalence of sars-cov- in hong kong and in residents evacuated from hubei province, china: a multicohort study potent neutralization of sars-cov- in vitro and in an animal model by a human monoclonal antibody potent binding of novel coronavirus spike protein by a sars coronavirus-specific human monoclonal antibody perspectives on therapeutic neutralizing antibodies against the novel coronavirus sars-cov- dna vaccine protection against sars-cov- in rhesus macaques assessment of population susceptibility to upcoming seasonal influenza epidemic strain using interepidemic emerging influenza virus strains triple combination of interferon beta- b, lopinavir/ritonavir, and ribavirin in the treatment of hospitalized covid- patients: a phase open-label randomized controlled trial anti-spike igg causes severe acute lung injury by skewing macrophage responses during acute sars-cov infection natural mutations in the receptor binding domain of spike glycoprotein determine the reactivity of cross-neutralization between palm civet coronavirus and severe acute respiratory syndrome coronavirus antibody responses against sars coronavirus are correlated with disease outcome of infected individuals neutralizing antibody response and sars severity cytokine release syndrome in severe covid- neutrophil extracellular traps in covid- recombinant modified vaccinia virus ankara expressing the spike glycoprotein of severe acute respiratory syndrome coronavirus induces protective neutralizing antibodies primarily targeting the receptor binding region severe acute respiratory syndrome coronavirus -specific antibody responses in coronavirus disease patients neutralizing antibodies responses to sars-cov- in covid- inpatients and convalescent patients. medrxiv preprint sars-cov- neutralizing antibody responses are more robust in patients with severe disease effectiveness of convalescent plasma therapy in severe covid- patients neutralizing antibody responses to sars-cov- in a covid- recovered patient cohort and their implications. medrxiv preprint establishment and validation of a pseudovirus neutralization assay for sars-cov- treatment of critically ill patients with covid- with convalescent plasma hyperimmune iv immunoglobulin treatment: a multicenter doubleblind randomized controlled trial for patients with severe influenza a(h n ) infection we thank serena j. chen for editorial inputs. authors' contribution: zc and ky contributed to study design and supervised two collaborative teams in the study, respectively. liul and kt analysed the data. kt, zc, liul and ky wrote the key: cord- -b exkw x authors: soh, mitsuhito; hifumi, toru; iwasaki, tsutomu; miura, yusuke; otani, norio; ishimatsu, shinichi title: impaired mental health status following icu care in a patient with covid‐ date: - - journal: acute med surg doi: . /ams . sha: doc_id: cord_uid: b exkw x background: severe respiratory failure patients with coronavirus disease (covid‐ ) sometimes do not receive post intensive care syndrome prevention bundles. no detailed report has been published on the practical observations of mental impairments in these patients. case presentation: a ‐year‐old man was admitted with covid‐ pneumonia. on day , he was admitted to the intensive care unit (icu). considering the risk of nosocomial infection, as per the hospital policy, early rehabilitation could not be initiated for covid‐ patients at that the time and family visits were not allowed. thereafter, his respiratory condition gradually improved; he was discharged on day . then, when the icu nurse called to assess his medical condition, the patient complained insomnia after icu discharge. therefore, we called him for an outpatient visit days after discharge and scored his mental health status. conclusion: careful follow‐up is required to treat mental impairment in patients with covid‐ . patients with coronavirus disease (covid- ) related severe respiratory failure are frequently treated with deep sedation, as well as using neuromuscular blockades (nmbs) use, and steroids administration ; these approaches can cause postintensive care syndrome (pics) . moreover, family visits are strictly restricted when patients are still at a high risk of causing contagion . early rehabilitation sometimes cannot be initiated due to the risk of nosocomial infections. thus, severe respiratory failure patients with covid- sometimes generally do not receive the pics prevention bundle, which is commonly applied in standard intensive care unit (icu) practice . several action/management plans for pics prevention in patients with covid- are proposed , ; however, details of mental impairment in practically observed cases have remained unreported. here, we report a covid- case that developed an impaired mental health status following intensive care unit icu care. we also emphasize the significance of follow-up in these patients. a -year-old male magazine editor was admitted because of covid- pneumonia. he had no past medical histories such as alcohol dependence or mental disorders, and he lives with his wife and a -year-old son. oxygen demand was not observed on the admission day, but the oxygen saturation level eventually dropped. on day , he had prominent tachypnea despite having a reservoir mask delivering l/min of oxygen. hence, he underwent emergency tracheal intubation and was admitted to the icu. weak sedation was maintained during icu management. no steroids or nmb was administered. considering the concern about nosocomial infection in the hospital policy, early rehabilitation in patients with covid- could not be initiated at that time. family visits were also prohibited for the same reasons. subsequently, his respiratory condition gradually improved, and he was extubated on day , left the icu on day , and finally discharged on day . before discharge, he was slightly worried about infecting his family. when the icu this article is protected by copyright. all rights reserved nurse examined his medical condition, the patient said, "when i try to sleep, i can't sleep because i remember icu stay," "the news that popular comedian died from a coronavirus made me feel anxious and scared," and "it's hard to see people die while playing games." therefore, in his outpatient visit days after discharge, we assessed his mental status. in posttraumatic stress diagnostic scale (pds), the patient met the ptsd criteria ( figure a) . thereafter, under psychiatric consultation, we evaluated the mental status by using the hospital anxiety and depression scale (hads) and the impact of event scale revised (ies-r). on the same day, the psychiatrist prescribed etizolam. although the psychiatric symptoms gradually improved, he was still diagnosed with ptsd because the symptoms based on the dsm- criteria continued for more than month. then, days after discharge, the scoring improved compared with the scoring days after discharge (figure b) . he remains to be an outpatient of our hospital. our patient with covid- who received icu care developed ptsd after discharge. through close observation with appropriate medication and frequent medical interview, his ptsd improved. to the best of our knowledge, mental impairment after icu care in patients with covid- has remained unreported. a recently published a systematic review and meta-analysis regarding psychiatric and neuropsychiatric presentations associated with severe coronavirus infections reported that the prevalence of depression, anxiety, ptsd, and fatigue might be high in the patients; however, to date, data on these diagnoses in patients with covid- are preliminary or unpublished . with regard to risk factors, in a systematic review by davydow et al., it was reported that the female sex is a significant predictor of ptsd after icu care . pre-existing depression, anxiety, ptsd, and alcohol abuse as well as lower education level increase the risk of icu-acquired mental illness . although these risks were not observed our patient, he still developed severe ptsd. regarding the mechanism of the development of impaired mental status, no deep sedation, steroid use, or nmb use was administered in our patient. however, both family visit and early this article is protected by copyright. all rights reserved rehabilitation were not provided because of the concern of covid- nosocomial infection containment reasons. moreover, undesirable tv news, such as the covid- -related death of celebrities, might have contributed to his ptsd. thus, early rehabilitation is mandatory to reduce pics , and any rehabilitation institutions are already involved in the acute care of patients with covid- . we carefully observed the mental status of our patient after discharge. after examination via telephone, we scheduled him for outpatient appointments. in the pics outpatient clinic, we discussed about the current mental state and evaluated the symptoms by using several scales. given that no outpatient practice is covered by any insurance in japan to follow-up on the progress of pics, we urged the patient to come to the hospital regularly during his examination via telephone for drug prescription and mental status evaluation. according to a national survey in japan, only % of the respondents said that a system exists for following up the long-term outcomes of patients after icu discharge . to actually follow-up patients' long-term outcomes at medical institutions, healthcare providers need to resolve various issues, such as securing costs and actual medical booths, in collaboration with other hospital departments (especially the psychiatry department, which is an important department for pics), and secure nurses and physicians for medical care. establishing a follow-up system for the long-term outcomes of patients after icu discharge enables the evaluation of long-term outcomes in current treatments. the limitation of the present study is that because both physical disabilities and cognitive impairment were not evaluated and that pics following covid- infection was not comprehensively described. careful follow-up is required to treat ptsd pics in patients with covid- . further actual condition evaluation, prevention, treatment, and follow-up activities for mental disorder pics should be systematically developed in actual clinical practice to improve the long-term prognosis of patients with covid- who underwent icu treatment. surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) improving long-term outcomes after discharge from intensive care unit: report from a stakeholders' conference effect of flexible family visitation on delirium among patients in the intensive care unit: the icu visits randomized clinical trial post-intensive care syndrome: its pathophysiology, prevention, and future directions covid- : icu delirium management during sars-cov- pandemic covid- and post intensive care syndrome: a call for action psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the covid- pandemic posttraumatic stress disorder in general intensive care unit survivors: a systematic review this article is protected by copyright. all rights reserved key: cord- -cqzfjg t authors: de lorenzo, antonino; tarsitano, maria grazia; falcone, carmela; di renzo, laura; romano, lorenzo; macheda, sebastiano; ferrarelli, anna; labate, demetrio; tescione, marco; bilotta, federico; gualtieri, paola title: fat mass affects nutritional status of icu covid- patients date: - - journal: j transl med doi: . /s - - -z sha: doc_id: cord_uid: cqzfjg t background: obesity and steatosis are associated with covid- severe pneumonia. elevated levels of pro-inflammatory cytokines and reduced immune response are typical of these patients. in particular, adipose tissue is the organ playing the crucial role. so, it is necessary to evaluate fat mass and not simpler body mass index (bmi), because bmi leaves a portion of the obese population unrecognized. the aim is to evaluate the relationship between percentage of fat mass (fm%) and immune-inflammatory response, after days in intensive care unit (icu). methods: prospective observational study of adult patients, affected by covid- pneumonia and admitted to the icu and classified in two sets: ( ) lean and ( ) obese, according to fm% and age (de lorenzo classification). patients were analyzed at admission in icu and at th day. results: obese have steatosis, impaired hepatic function, compromise immune response and higher inflammation. in addition, they have a reduced prognostic nutritional index (pni), nutritional survival index for icu patients. conclusion: this is the first study evaluating fm% in covid- patient. we underlined obese characteristic with likely poorly prognosis and an important misclassification of obesity. a not negligible number of patients with normal bmi could actually have an excess of adipose tissue and therefore have an unfavorable outcome such as an obese. is fundamental personalized patients nutrition basing on disease phases. obesity, measured as body mass index (bmi), is reported to associate with increase the risk of developing severe pneumonia in covid- [ ] . indeed, the risk correlated to obesity with covid- severity is greater in metabolic associated fatty liver patients [ ] . at the basis, we found altered mechanism of inflammation and immune response typic of obesity and correlated with alteration in the levels of circulating cytokines [ ] . in particular, obese patients have higher concentrations of tnf-alpha, mcp- and il- which are produced by visceral and subcutaneous adipose tissue and implicated in innate immunity [ , ] . furthermore, adipose tissue releases high levels of leptin, which creates an unfavorable inflammatory milieu that leads to dysregulation of the immune response [ ] . in , during h n pandemia, in obese patients it was characterized changing of differentiation of b cells [ , ] , predisposing to a greater risk of contracting influence, but also of being more contagious towards other people [ ] . however, they have impaired memory t cell response and vaccination efficacy [ ] . specifically, reduced response of virus-specific cd + lymphocytes and suboptimal macrophage functionality have been demonstrated, which could explain the low response to the vaccine stimulus [ ] . for covid- , in intensive care unit (icu), it was observed that the highest percentage are patients affects by severe obesity, with bmi > kg/m [ ] . the bmi does not reflect necessarily the fat mass (fm). there are evidence that suggest how fm% rather than bmi, predicts inflammatory (tnf-alpha, mcp- and il- ) and immune (leptin) response. these ultimate variables that relates with immune and inflammatory response in fm% [ ] . despite the relationship between fm% and severity of progression inflammatory response in patients admitted to icu for underlying infective disease, there are no available data on the relevance of fm% in covid- patients treated in icu. moreover, prognostic nutritional index (pni) can be used to evaluate the nutritional status and survival for icu patients [ ] . aim of this prospective observational study, in patients admitted to icu for covid- , is to evaluate the relationship between fm% and immune-inflammatory response, after days in icu. also, we want to investigate the metabolic associated fatty liver and pni and the comparison between fm% and bmi. after irb approval (regional ethic committee, section "area sud", th april, ) and having obtained the signed informed consent by the next of kin, clinical and anthropometric data of patients with covid- pneumonia admitted to the icu of the hospital "bianchi melacrino morelli" reggio calabria, italy between march and april , were recorded and analyzed. standard therapeutic protocol included, for all patients: low molecular weight heparin (lmwh), azithromycin, hydroxychloroquine, lopinavir/ritonavir. prospective observational study of adult patients affected by covid- pneumonia and admitted to the icu. patients with a history of neutropenia, acquired immunodeficiency, who underwent transplants or who received previous immunosuppressive therapies were excluded. rather than considering only the bmi, patients recruited in this study were categorized in two sets: "lean" or "obese" according to fm% and age, based on criteria presented by de lorenzo [ ] . computed tomography (ct) (ge medical systems, gamma optima, usa) without intravenous contrast was performed within h of admission to the emergency department. hepatic steatosis was evaluated on ct images in liver segments, independently, by qualified operators (lr and cf) [ ] . liver spleen ration (lrs) was calculated if reported difference between the measures were > %, a third operator was asked to repeat the evaluation of ct. from ct chest image, waist circumference was measured at the last rib with distance measurement tools. where part of the abdomen was outside the field of the image, waist circumference was estimated with a continuous arc [ ] . to estimate the fm% we used the siri eq. [ ] . the subcutaneous fat thickness was measured at ct, given the agreement between the ct and plicometry method [ ] . body density was obtained by the equation of durnin, using two subcutaneous fat thicknesses of the chest, suprascapular and suprailiac and the correction factors according to age, sex and folds used [ ] . all cts were performed with patients in the supine position with arms folded and hands positioned under neck. the subscapular fat thickness was measured in cross section starting from the origin of the scapular spine on the posterior medial edge up to the skin. the suprailiac fat thickness was measured in cross sect. cm from the last rib on the middle axillary line up to the skin. the subcutaneous fat thickness parameters were measured two times on ct. it was used the mean value for equation of durnin [ ] . only at baseline, ct was used to estimated fm% to stratificate the sample. the bmi was calculated as weight (kg) divided by height (m) squared and the patients were classified as follows: obese (ob) for bmi > . kg/ m , pre obese (po) for bmi between . kg/m and . kg/m , normal weight (nw) for bmi between . and . kg/m . prognostic nutritional index (pni) was calculated for each patient as a serum albumin (g/dl) × + total lymphocyte count (mm − ) × . [ ] . the following blood analysis were performed: c-reactive protein (mg/l), glycemia (mg/dl), creatinine (mg/ dl), albumin (g/dl), ast (u/l), alt (u/l), indirect bilirubin (mg/dl), total bilirubin (mg/dl), direct bilirubin (mg/dl), platelets ( /μl), white blood cells (wbc) ( / μl), neutrophils ( /μl), lymphocytes ( /μl), pni, fibrinogen (mg/dl), d-dimer (ng/ml). calculation of the sample size was based on a comparison between matched pairs, a power of %, a significance level of % (two-tails) and the detection of an effect size of . between the pairs. according to the study setting, necessary calculated sample size is patients and the g*power software (version . . . , germany) was used. [ ] since % of the sample may not have all the expected parameters, subjects were enrolled. all statistical analyzes were conducted with spss software (version . , ibm, armonk, ny, usa). the data collected before statistical evaluations were analyzed for the presence of outliners and for non-normally distribution with the kolmogorov-smirnov test. the categorical variables have been reported in percentage, while the continuous ones as median and interquartile range. before, the differences between lean and obese subjects were assessed at admission with the mann whitney test for independent samples. subsequently, the differences in lean and obese subjects were assessed between admission and th day with the wilcox test for matched pairs. cohen's kappa was used with binary data to measure the agreement between adiposity classification according to the fm% criterion and the bmi. according to landis and koch [ ] , cohen's kappa (κ) values could indicate an agreement: poor (κ < . ), light ( . ≤ κ ≤ . ), discrete ( . ≤ κ ≤ . ), moderate ( . ≤ κ ≤ . ), substantial ( . ≤ κ ≤ . ) or near-perfect (κ > . ). furthermore, the false-positive rate and false-negative rate were calculated for the different classification methods. correlation analysis was conducted with spearman's rho test. statistical significance was set to a value of p < . . all p values shown are two-tailed. a total of patients were evaluated for this prospective analytical observational study, subjects were excluded from the study because the following reasons: because covid- negative, died before th day; had incomplete data. finally, patients were included in the study (fig. ). mean age of enrolled patients was years (range - ), % were females and % males. patients were divided into two groups according to fm% and age: patients were "obese" and were "lean" ( table ) . the bmi-based classification, as compared to fm%, presents a discrete and significant cohen κ-value (κ = . p < . ). according to the bmi, % of the patients were categorized differently, in detail, % of the patients that presented a bmi within normal values were detected to have a fm% criteria for being considered "obese" according to fm% and age based on criteria presented by de lorenzo [ ] and % of the patients classified po were "obese". (table ) (fig. ) . the fm%-based categorization coincided to bmi-based categorization for the patients considered "lean" according the fm% and for patients considered "obese". lastly, for this sample the frequency of false negatives was %, while there were no false positives. baseline characteristics of "lean" vs. "obese" patients. no statistical differences were present for age and spleen attenuation between groups. liver and lsr attenuation were lower in "obese" than in "lean" ( table ). the alt and ast were significantly more elevated in "obese" than in "lean". no other statistical difference was found in blood chemistry parameters between the groups. at day th, the c-reactive protein, direct bilirubin, fibrinogen concentrations were lower in were lower than in "lean" (respectively p = . ; p = . ; p = . ), the lymphocytes concentration was increased in "lean" (p = . ) and not changed was observed in "obese". comparison of baseline to day th, concentrations of albumin and pni decreased in "obese" while remained unchanged in "lean" patients. no statistical difference was present in "lean" and "obese" groups between baseline and days (table ) . finally, an inversely proportional correlation was observed between fm% and liver attenuation (correlation coefficient = − . and p = . ). the distinctive feature of this prospective observational study, in patients admitted to the icu for covid- , is a persistent lymphocyte reaction at th day in fm%based "obese" patients that suggest a protract inflammatory reaction. in these patients, at the beginning of icu treatment, the metabolic associated fatty liver, pni and the immune-inflammatory response are severely compromised. furthermore, at baseline more patients evaluated according fm% result to be "obese" than using the bmi criteria. in covid- patients it is crucial to find risk factors associated with worse clinical course to allocate appropriate resources. however, population characteristics are fundamental for prognosis. in italy, covid- mortality is strongly influenced by different comorbidities [ ] and % of deaths are above years of age, unlike china, for which only % are above the same age threshold [ ] . in particular, pre-existing pathologies including obesity, cardiovascular co-morbidity, arterial hypertension and type diabetes mellitus are established risk factors [ ] [ ] [ ] . obesity also can be associated to insulin-resistance, that alters immune response [ ] . obese patients have greater infectivity correlated with exhalation, since they have higher ventilator volumes, due to a lower expansion capacity of the thoracic cavity, which consequently limits the lung expansion [ ] . this also results in increased aerosol production [ ] . in particularly, maier et al. [ ] showed that obese patients have a longer viral interaction. in the case of covid- , it has been observed that the infectious charge has an average duration of days, but it can last up to days after the infection table descriptive and compared between group at baseline differences among groups at baseline. all parameters are presented as median (interquartile range) and were compared by mann whitney test statistical significance was attributed as p < . iqr interquartile range, lsr liver spleen ratio ast aspartate aminotransferase, alt alanine aminotransferase, wbc white blood cell, pni prognostic nutritional index anthropometrics and body parameters [ ] . it remains to be shown the pathophysiological characteristics of patients who have a contagious duration of up to days. hence, the importance of assessing the inflammatory state, through circulating cytokines, has already been highlighted in patients suffering from acute respiratory distress syndrome. indeed, it was possible to identify two distinct phenotypes, with two different mortality risks. this is fundamental for indicating the patient future prognosis [ ] . in obese, lipid metabolism is already altered [ , ] and a covid- infection leads to an overexpression of the genes involved with a further increase in the production of pro-inflammatory cytokines and a reduced capability responding to infection. in our study, "lean" patients-according fm%, showed a significative reduction in c-protein reactive, direct bilirubin and fibrinogen and an important increase of lymphocytes at day th of icu. increased fm% is associated with a reduced icu treatment response. actually, our data showed that "obese" do not show the same improvement, based on biochemical-clinical parameters, respect to "lean" after the first th icu days. according to presented data, adipose tissue quantity acts on therapeutic goal achievement. increased adipose tissue leads to a lipid metabolism modification with increased storage of fat in liver and onset of steatosis in "obese". consequently, these patients suffer for high production of pro-inflammatory cytokines [ , ] and conduct to unfavorable condition, requiring defined protocols to counter malnutrition resulting [ ] . additionally, these patients are at higher risk for infection also because of covid- use angiotensin converting enzyme (ace ) receptors to enter the host cell [ ] . the ace is expressed in different tissues: kidney, lung, heart and adipose tissue [ ] . covid- infection leads to an upregulation of the genes associated with lipid metabolism, involved in the regulation of inflammation [ ] . thus, obese have a higher expression of ace and are therefore more susceptible to this infection [ ] . the complex picture is characterized by increased predisposition to infection and reduced ability to respond to it. in addition, these patients already present organ damage that induces worse response to treatments. according to the results, the main aim is a proper nutritional medical therapy, which takes into account the amount of fat, as a risk factor for complications in covid- . therefore, the therapeutic approach must be customized on the body composition. in addition, the loss of body protein content is a negative prognosis factor and it has been a constant observation in icu. a further aim, in the not-affected, affected and discharged covid- patients, is the saving and recovery of lean body mass, following an appropriate protein prescription. in pre-covid- patients, a personalized and balanced italian mediterranean reference diet characterized by anti-inflammatory and antioxidant properties [ ] , should be adopted as obesity preventive and therapeutic tool. the protein intake required is based on lean mass content ( g/kg of lean mass/day), a parameter that can be directly measured or calculated with prediction equations, accessible to all users [ ] . in covid- patients, a macronutrient balance calculated according to the clinical condition, a correct calorie intake based on the metabolic condition and all micronutrients must be guaranteed. in detail, respiratory failure requires hyperlipidic nutritional medical therapy, to counter hypercapnia and promoting metabolic flexibility [ , ] . the calorie prescription must be adjusted daily, following the catabolic and anabolic phases of hospitalization. similarly, the protein prescription must be modulated according to the metabolic phase. in the anabolic phase, the protein administrated should not be counted in the daily energy expenditure and the protein intake must be . g/kg of body weight/day [ ] . in post-covid- patients, keeping in mind that the fragility deriving from bedrest and inadequate nutrition, due to the ventilatory support, a specific nutritional and motor rehabilitation must be provided [ ] . for patients with comorbidity, nutrition support to anabolic and recovery stress represent a complex passage. diet therapy, personalized based on the body composition [ ] , must be hyperproteic, - . g/kg of lean mass/day, complete with all amino acids and enriched with branched amino acids, to promote anabolism. the meals consistency must be progressively personalized according to the subject ability to feed. our data, even if the sample size required by statistical tests is respected, nevertheless presents a limited number of patients. another limit was fm% estimate. at the same time, it is a strength, which has allowed an estimate of body composition, since other methods such as bioimpedance and anthroplicometry are difficult to apply in icu. it is hoped that from the covid- lesson, the public institutions will promote the prevention and treatment of obesity and sarcopenia, through healthy nutrition and a correct lifestyle. the comorbidities costs and the obstacle in the clinical treatment of an obese patient, in addition to the known health-care costs [ ] , has been paid with human lives. factors associated with hospitalization and critical illness among , patients with covid- disease in new york city obesity as a risk factor for greater severity of covid- in patients with metabolic associated fatty liver disease why primary obesity is a disease? individuals with obesity and type diabetes have additional immune dysfunction compared with obese individuals who are metabolically healthy obesity (silver spring) adipokines in inflammation and metabolic disease leptin mediates the pathogenesis of severe pandemic influenza a(h n ) infection associated with cytokine dysregulation in mice with diet-induced obesity the impact of obesity on the immune response to infection influenza and obesity: its odd relationship and the lessons for covid- pandemic role of the pyruvate dehydrogenase complex in metabolic remodeling: differential pyruvate dehydrogenase complex functions in metabolism impact of obesity on influenza a virus pathogenesis, immune response, and evolution high prevalence of obesity in severe acute respiratory syndrome coronavirus- (sars-cov- ) requiring invasive mechanical ventilation. obesity (silver spring) new obesity classification criteria as a tool for bariatric surgery indication association of "controlling nutritional status index" and "prognostic nutritional index" with intensive care unit survival in elderly patients developing and cross-validation of new equations to estimate fat mass in italian population computed tomography measurement of hepatic steatosis: prevalence of hepatic steatosis in a canadian population body composition from fluid spaces and density: analysis of methods accuracy of subcutaneous fat measurement: comparison of skinfold calipers, ultrasound, and computed tomography : • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold open access which fosters wider collaboration and increased citations maximum visibility for your research: over ready to submit your research ? choose bmc and benefit from body fat assessed from total body density and its estimation from skinfold thickness: measurements on men and women aged from to years clinical significance of the prognostic nutritional index for predicting short-and long-term surgical outcomes after gastrectomy: a retrospective analysis of gastric cancer patients. medicine (baltimore) power : a flexible statistical power analysis program for the social, behavioral, and biomedical sciences the measurement of observer agreement for categorical data case-fatality rate and characteristics of patients dying in relation to covid- in italy clinical characteristics and outcomes of cardiovascular disease patients infected by -ncov prevalence and impact of diabetes among people infected with sars-cov- an accumulation of muscle macrophages is accompanied by altered insulin sensitivity after reduced activity and recovery infectious virus in exhaled breath of symptomatic seasonal influenza cases from a college community obesity increases the duration of influenza a virus shedding in adults clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study identification and validation of distinct biological phenotypes in patients with acute respiratory distress syndrome by cluster analysis fto rs influence on adipose tissue localization in the italian population pathophysiological, molecular and therapeutic issues of nonalcoholic fatty liver disease: an overview endothelial dysfunction in obesityinduced inflammation: molecular mechanisms and clinical implications short report-medical nutrition therapy for critically ill patients with covid- assessing ace expression patterns in lung tissues in the pathogenesis of covid- single-cell rna-seq data analysis on the receptor ace expression reveals the potential risk of different human organs vulnerable to -ncov infection risk of covid- for patients with obesity role of personalized nutrition in chronic-degenerative diseases espen guideline on clinical nutrition in the intensive care unit editorial-epidemiological transition, crisis of the italian health system: ethical and logical economic choices adiposity rather than bmi determines metabolic risk springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors are in debt with pierpaolo correale for the english revision our data originally demonstrate that fm% and not only bmi correlates with the course of covid- patients admitted to icu. of note a not negligible number of patients with normal bmi could actually have an excess of adipose tissue and therefore have an unfavorable outcome such as an obese [ ] . since it is the actual representation of adipose tissue that is the driver of pro-inflammatory modulation the fm% might represent a better assessment tool than bmi. future studies are required to determine the relevance of fm% in predicting the clinical outcomes of covid- patients and might be a useful approach also for out of hospital surveillance. key: cord- - suu n authors: hetland, breanna; lindroth, heidi; guttormson, jill; chlan, linda l. title: - the year that needed the nurse: considerations for critical care nursing research and practice emerging in the midst of covid- date: - - journal: heart lung doi: . /j.hrtlng. . . sha: doc_id: cord_uid: suu n nan the daily disruption and toll of the global covid- pandemic is palpable. as the number of covid- cases and deaths continue to rise in the united states, there is no escaping the impact of this pandemic. critical care nurses are on the frontlines, shouldering the heavy burden of managing the 'sickest of the sick' patients who are in need of life-saving mechanical ventilatory support. now more than ever, icu nurses must rely on their tremendous knowledge base, impeccable technical skills, and compassion to ensure positive outcomes for critically ill patients in the covid- era. as experienced critical care nurse scientists conducting research studies in these dynamic settings, we provide our perspectives on the significant impact of the covid- pandemic in the icu and highlight implications for nursing practice and research. specifically, this editorial addresses the: ) need for agile, rapid innovation and implementation strategies; ) importance of research policies that ensure continuation of scientific discovery and dissemination amidst crises; and, ) necessity to develop creative strategies to promote a culture of patient and family engagement during critical situations. the dynamic nature of critical care demands rapid assessment and adaption of evidence to each patient's unique characteristics and health needs. this has never been truer than during the ongoing covid- pandemic. not only does the current healthcare crisis highlight the need to embrace an agile implementation model that mirrors our ever-changing clinical environment, it also emphasizes the value of applying adaptive research designs. the rapid identification and application of evidenced-based solutions within a dynamic infrastructure would allow clinicians and scientists to modify solutions to the local icu environment and to individualize care. in order to create a more agile critical care system, we must build an infrastructure capable of harnessing innovations while fostering the incubation of new ideas. doing so allows us to address research questions and integrate emerging evidence in real-time, applying clinically driven data that provides immediate feedback to the healthcare team and to the broader critical care community. future solutions should consider leveraging technology to integrate data across electronic health records and establish data extraction methods that equip the critical care team with an immediate, comprehensive, and dynamic clinical picture. additionally, in order to make meaningful progress towards an agile critical care system, we must engage a diverse team of frontline clinicians, patients, and family caregivers. this team approach is mandatory given the complex needs of critically ill patients, particularly in times of crises. lastly, this current global pandemic has emphasized transdisciplinary communication gaps. leaders among critical care professional societies should work collaboratively to develop cohesive communication, dissemination, and implementation channels across disciplines with the ultimate goal of helping providers adapt and tailor evidence to the right situation and the right patient at the right time. a majority of non-covid- clinical icu research around the country has been paused to conserve personal protective equipment, protect research staff's health, and limit non-essential staff on the icus. while this temporary interruption to non-essential icu-based clinical research is the appropriate solution, completely suspending these studies severely hampers progress to date and further impedes completion of clinical trials. promising therapies that would likely benefit covid- patients are now delayed further from efficacy testing and implementation. indeed, research that is focused on mitigating the potential complications of long-term mechanical ventilation and identifying supportive therapies to minimize isolation, fully engage patient and families in their care, and support recovery from icu-acquired disabilities is imperative. going forward, it is important that we develop critical care specific research policies and procedures that are adaptable to changing circumstances such as epidemic and pandemic situations. an example of such a policy would be the approval of two irb protocols for each study, one standard, and one with contingency plans for operation in crisis situations. another example is to consider adaptive clinical trial design principles. given that adaptive clinical trial designs support continual learning as data are accumulated, changes can be made to aspects of the protocol such as adding or dropping treatment arms depending on patient responses. for example, patients receiving mechanical ventilatory support due to suspected covid- hypoxemic respiratory failure placed initially on an experimental drug clinical trial, could be enrolled in a symptom management clinical trial and removed from the drug trial once laboratory testing reveals patients are covid- negative. cutting-edge scientific solutions that are relevant to our current and future crises urgently need to be developed and safely implemented through research focused on patients, families, and systems. these areas include symptom management, delirium mitigation, post-intensive care syndrome, icu-acquired weakness, and patient and family engagement along with many more opportunities for system-level and nurse-focused research. the high acuity of icu patients with covid- coupled with burgeoning unit census brought a common challenge faced by critical care nurses into sharp focus: the extreme difficulty in providing humanistic integrated patient and family centered care to our sickest icu patients. while the type of acute "crisis" of current interest is covid- , critical care nurses frequently encounter localized crises with all types of icu patients. we need to shift our culture towards one that embraces evidencebased practices for improving long term outcomes (e.g. holistic symptom assessment and management, sedation reduction, delirium prevention) once a patient has stabilized. the integration of dynamic measurements that capture current patient status such as symptom burden (e.g. anxiety, thirst, dyspnea), delirium severity, and immobility and mobility progress have immense potential to support evidence-based interventions and therapies that effectively manage symptoms and improve patient outcomes. visitation by family is restricted during covid- , perpetuating isolation among critically ill patients. patient social isolation is not unique to this crisis. in standard icu care, limited communication options for critically ill patients and a lack of integrated family engagement into routine critical care practice contribute to feelings of isolation. during the current covid- crises, nurses and physicians have needed to use technology ad hoc to allow family to see or interact remotely with patients, sometimes for the last time. these innovative clinicians are to be lauded, however, clinicians should not be burdened with inventing ways to support patients and families in the midst of the crises. many of these strategies and technologies existed prior to covid- , but were not fully implemented or consistently used in practice. going forward, we must embed mechanisms to ensure patient and family engagement are considered standard to support the delivery of high quality health care. practicing icu nurses can lead these efforts in partnership with nurse scientists. to conclude, the covid- pandemic is an unfortunate traumatic event that will shape critical care communities for many years to come. in this editorial, we've only scratched the surface by proposing selected considerations to positively emerge from this pandemic-harnessing what we have learned to date in order to improve our responses in the future. one thing is for certain, now more than ever, the holistic view and diverse expertise of critical care nurses are needed to provide a beacon of hope in this "year of the nurse". agile implementation a model for implementing evidence-based healthcare solutions into real-world practice to achieve sustainable key design considerations for adaptive clinical trials: a primer for clinicians delusions on the intensive care unit: what do patients think is going on? hospital preparedness for covid- : a practical guide from a critical care perspective key: cord- -i ygb z authors: deasy, jacob; rocheteau, emma; kohler, katharina; stubbs, daniel j.; barbiero, pietro; liò, pietro; ercole, ari title: forecasting ultra-early intensive care strain from covid- in england date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: i ygb z the covid- pandemic has led to unprecedented strain on intensive care unit (icu) admission in parts of the world. strategies to create surge icu capacity requires complex local and national service reconfiguration and reduction or cancellation of elective activity. theses measures require time to implement and have an inevitable lag before additional capacity comes on-line. an accurate short-range forecast would be helpful in guiding such difficult, costly and ethically challenging decisions. at the time this work began, cases in england were starting to increase. here we present an attempt at an agile short-range forecast based on published real-time covid- case data from the seven national health service commissioning regions in england (east of england, london, midlands, north east and yorkshire, north west, south east and south west). we use a monte carlo approach to model the likely impact of current diagnoses on regional icu capacity over a day horizon. our model is designed to be parsimonious and based on plausible epidemiological data from the literature available. on the basis of the modelling assumptions made, icu occupancy is likely to increase dramatically in the the days following the time of modelling. if the current exponential growth continues, out of commissioning regions will have more critically ill covid- patients than there are icu beds within two weekstodo{last thing to do}. despite variable growth in absolute patients, all commissioning regions are forecast to be heavily burdened under the assumptions used. whilst, like any forecast model, there remain uncertainties both in terms of model specification and robust epidemiological data in this early prospective phase, it would seem that surge capacity will be required in the very near future. we hope that our model will help policy decision makers with their preparations. the uncertainties in the data highlight the urgent need for ongoing real-time surveillance to allow forecasts to be constantly updated using high quality local patient-facing data as it emerges. the covid- pandemic has rapidly caused an enormous worldwide medical and socioeconomic impact since the first case emerged on november th [ ] . although a self-limiting illness for most, the percentage of covid- patients with hypoxaemic respiratory failure requiring icu admission for mechanical ventilation translates into large numbers which may challenge healtcare provision. in northern italy, an exponential increase in covid- admissions rapidly overwhelmed normal icu capacity [ ] and surge capacity had to be created quickly. the exact reason for the sudden need for icu surge capacity in italy, and whether this will generalise to other countries, is unclear, but both demographic factors and healthcare system structure are likely to be important. notably, uk availability of icu beds per capita compares poorly with other highincome countries-including italy [ ] . whilst standard acute wards may be re-purposed easily, creating icu capacity is constrained by the need for complex equipment and the delivery of highly specialised medical and nursing care. nevertheless, there are mechanisms by which icu capacity could be increased in an emergency, including facilitating icu discharge of recovering patients through liberating downstream beds by reducing elective work, by stopping elective work likely to require icu admission, or by changing referral policies. such changes are likely to be relatively quick to implement but have important repercussions for normal healthcare provision and ideally would not be instituted until absolutely necessary. furthermore, since icus in the uk typically undertake a high proportion of emergency work, much of which will continue despite the pandemic, and since occupancy is typically well above %, such strategies are likely to result in only a relatively modest increase in capacity. a greater increase in emergency physical capacity for mechanical ventilation could be achieved by opening new level beds with additional equipment (e.g. operating theatre ventilators). this requires significant changes to infrastructure, processes, or sta ng and is therefore logistically complex, expensive, and most importantly slow to implement. forecasting was therefore essential in guiding such di cult policy decisions in italy [ ] . the explosion of cases seen in italy means that an early warning of need for surge capacity is likely to be required in other countries including england. epidemiological simulation has previously been successful in predicting the need for surge h n icu capacity in [ , ] . in recent days, a similar simulation model for covid- has been described [ ] , which suggests an overwhelming demand for critical care, with a peak occurring between may and early june and lasting to months depending on non-pharmacological intervention (npi) assumptions. such models are very useful but do not incorporate up-to-date data. such projected timescales are unlikely to be reliable and are unsuitable for real-time surveillance and early warning. in this paper we use published covid- diagnosis data for england to generate the earliest possible estimates of additional icu demand due to infections in the coming days, based on cautious epidemiological data from the literature and under the assumption that the current increase in cases represents the exponential phase of an outbreak rather than a change in ascertainment. our emphasis is on making an updatable model from the little timeseries data that are available in this ultra-early period, with the understanding that assumptions are necessary where data are unavailable. our we used covid- diagnoses from england as reported by public health england (phe) and matched to nhs commissioning regions [ ] as our source data to obtain information on daily cases (reproduced in figure ). we started to extract this data feed on / / to give daily case data. figure : model timeline. our model relies on a n-day window for regression, beginning / with recent observed data. themodel predicts two weeks into the future from the time of writing. figure : regional demographics and expected critical care demand per case of covid- , stratified by region and compared to icu bed capacity per , people. population is divided into age categories and percentage of cases requiring icu is divided into expected percentage of survivors and non-survivors. the numerical data can be seen in table . we assumed that the daily incidence of covid- can be modelled as an exponential growth (in line with what was observed in italy [ ] ). therefore, we forecast the likely distributions of new covid- diagnoses over the next days by using an ordinary least squares fit to linearly extrapolate from the logarithm of the cumulative cases. we di↵erentiated the cumulative model to obtain a daily incidence model i.e. we multiply by the exponent ( d dx ⇥ ae bx ⇤ = bae bx ), which stabilises the exponent fitting (b). using early data from verity et al. [ ] (reproduced in table ), we estimated the icu admission rate by standardising to the local population in each nhs commissioning region in england (see figure , obtained from the clinical commissioning group population estimates for mid- [ ] ). we adjust by age and sex, which . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https://doi.org/ . / . . overall, figure shows predictions that will challenge icu capacity in all areas, particularly in populous regions. london and the midlands will gain a number of covid- patients equi-valent to % standard capacity within days for slightly di↵erent reasons. in london, despite the higher number of icu beds per capita, the higher case incidence per capita will overwhelm icu capacity. whereas in the midlands, due to an increased average age, a higher percentage of icu admissions is predicted (see table ), which combined with a higher number of cases than other regions will lead to exhausted capacity. as normal occupancy is often above %, even the additional minimum capacity due to covid- of % in other regions will prove to be di cult to . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint figure : projected regional covid- icu occupancy as a percentage of regional capacity in the seven national health service commissioning regions in england. the figure illustrates the large regional variation in projected icu occupancy, with london and the midlands reaching near % additional capacity due to covid- within days, whereas areas such as the south west and south east will only have approximately % of their beds occupied by covid- patients. in this study we demonstrate how publicly available data can be rapidly combined to dynamic- . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint ally model short-term icu requirements in light of the emerging covid- pandemic. our data suggests that traditional icu capacity could be rapidly consumed over a period of approximately days from the time of modelling/writing, such figures hide substantial regional heterogeneity, with london and the midlands demonstrating the most rapid growth. the key message from our paper varies with the temporal position of the reader. within the current acute stage of this pandemic, we hope our findings provide a framework to facilitate the rapid development and deployment of additional icu surge capacity as was required within days of the italian pandemic [ ] . in the future, we feel that our methodological approach (use of emerging epidemic curve data, monte carlo simulation, and population standardisation), as well as our simultaneous deployment of an interactive and dynamically updated web-tool have merit in modelling and communicating any future dynamically emerging event. however, we do recognise that as with all models our is subject to significant assumptions and limitations. both model and parameter uncertainties are inevitable, particularly when predicting the behaviour of a novel virus in a new population, and this may radically a↵ect our forecasts. nevertheless, we set out to provide the earliest possible data-driven forecast and therefore explicitly accept the limitations of the data that were available to us at the time. our approach has been to keep the model as parsimonious as possible, with parameter estimates from the existing literature, to give a rough guide to early surge needs. with the small amount of available data, there are some specific limitations which need to be discussed. our use of an updated, online resource we hope is a novel way of allowing interested parties to interact with the mathematical assumptions and formulate their own opinions. we have used phe published data for case ascertainment. we recognise that this data is potentially flawed and does not recognise all cases within the wider population. however, being as our explicit aim is to model the most severe cases, the e↵ect of any ascertainment bias on our findings should be minimised due to the roll-out of routine testing for all critical care patients as part of the "covid hospitalisation in england surveillance system-chess" [ ] . despite this, case ascertainment and delay between symptom onset and icu admission is unlikely to be uniform between populations, healthcare settings, or discrete time points. specifically, at the time of writing, test capacity for covid- in the uk has led to stringent requirements for testing with only cases requiring hospitalisation being routinely tested [ ] . by incorporating a 'delay to icu' parameter within our model, that can take on negative values (thus indicating a diagnosis after icu admission), we hope to have replicated the anecdotal experience of clinicians in these early phases of the pandemic; that a substantial proportion of patients are being con- forecast numbers as these data inform our standardised estimates of icu cases from within each population [ ] . similarly, as already intimated, uk case definition has evolved over time. if the upturn in covid- cases seen at the time of writing is largely driven by increased or altered ascertainment rather than a true rise in cases, . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . then this would render our model overly pessimistic. nevertheless, this will always be a limitation of any early modelling [ ] . although we have resolved icu admissions to the level of a commissioning region, this assumes that each region behaves as a homogeneously allocated 'pool' of icu beds, which is not necessarily true because inter-hospital icu-to-icu transfers may not be feasible for both operational and clinical reasons. we do not have more granular data available, but it is worth considering the likelihood that individual hospitals will reach critical capacity before the whole region. this has already been seen within the pandemic at certain london hospitals [ ] . in this sense our predictions represent a 'best case' scenario and cannot be used for decision making at the level of an individual unit. building on this theme, we forecast the percentage of covid- bed requirements in isolation, figures which do not reflect competing icu burden. since uk bed occupancy is typically greater than % and may frequently exceed % [ ] , clearly not all beds can simply be re-allocated for covid- patients. this may be especially true for specialist icus (e.g. neuroscience or cardiac) which may not be able to entirely reconfigure, or high-dependency beds which may not be able to provide mechanical ventilation routinely. furthermore, we assumed that all adult critical care bed spaces can be used for mechanically ventilated icu patients, which operationally may not be possible for a variety of reasons including equipment and sta↵ availability. thus, the precise percentage of additional covid- patients that will actually exhaust routine capacity will vary from unit to unit, particularly in icus with a substantial postoperative elective surgical workload. finally, front-line clinicians reviewing our results in these early days of the pandemic will highlight the disconnect between our estimated 'confirmed' cases and the substantial operational workload that is being created by treating all suspicious cases of respiratory failure as covid- until proven otherwise. at the time of writing, the potential challenge that faces the health system (including intensive care) is essentially without precedent and has resulted in social and political interventions that have never been seen in peacetime. as such, there is little relevant precedent to judge the utility of approaches such as ours against. we hope that regardless of the assumptions inherent within our model (which we feel are based on best available data) that the overarching message of the need for urgent surge capacity is timely. finally, we hope that our transparency in releasing our code, model assumptions, and results in a dynamic web format embodies a new paradigm in rapidly developed and reviewed science that persists beyond the current pandemic. early warning of an impending need for icu surge capacity is crucial if there is to be sufficient time to re-configure services. we have shown that ultra-early data can be used to make time-sensitive forecasts of icu occupancy. we show, subject to our assumptions, that it is credible that icu requirements may become challenging within weeks. there remains a significant degree of uncertainty in the predictions due both to limitations of the reporting data and modelling assumptions. this emphasises the need for the collection of real-time patient-facing local data by initiatives such as chess [ ] and a dynamic approach to improving models as new data becomes available. declarations of interest statement none declared. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint thank chris fryer for crowd-sourced peer review of the manuscript and code which have been invaluable. clinical characteristics of imported cases of covid- in jiangsu province: a multicenter descriptive study critical care utilization for the covid- outbreak in lombardy, italy: early experience and forecast during an emergency response the variability of critical care bed numbers in europe modelling the impact of an influenza a/h n pandemic on critical care demand from early pathogenicity data: the case for sentinel reporting modelling the impact of pandemic influenza a(h n ) on uk paediatric intensive care demand impact of non-pharmaceutical interventions (npis) to reduce covid- mortality and healthcare demand icu capacity snap-shot data public health england covid- online data matched to nhs commissioning region estimates of the severity of covid- disease. medrxiv clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study clinical features of patients infected with novel coronavirus in wuhan covid- : investigation and initial clinical management of possible cases) initial-investigationof-possible-cases/investigationand-initial-clinical-managementof-possible-cases-of-wuhan-novelcoronavirus-wn-cov-infection# interim-definition-possible-cases code available from github covid- hospitalisation in england surveillance system (chess) hospital's critical care unit overwhelmed by coronavirus patients the authors would like to thank ronan o'leary, isobel ramsay, david menon and tom borchert for useful discussions as well as mark cresham for rapidly procuring computer facilities for our online model. additionally we would like to key: cord- -t j leec authors: poeran, jashvant; zhong, haoyan; wilson, lauren; liu, jiabin; memtsoudis, stavros g. title: cancellation of elective surgery and intensive care unit capacity in new york state: a retrospective cohort analysis date: - - journal: anesth analg doi: . /ane. sha: doc_id: cord_uid: t j leec background: in response to the coronavirus disease (covid- ) pandemic, new york state ordered the suspension of all elective surgeries to increase intensive care unit (icu) bed capacity. yet the potential impact of suspending elective surgery on icu bed capacity is unclear. methods: we retrospectively reviewed years of new york state data on icu usage. descriptions of icu utilization and mechanical ventilation were stratified by admission type (elective surgery, emergent/urgent/trauma surgery, and medical admissions) and by geographic location (new york metropolitan region versus the rest of new york state). data are presented as absolute numbers and percentages and all adult and pediatric icu patients were included. results: overall, icu admissions in new york state were seen in . % of all hospitalizations (n = , , /n = , , ) and remained stable over a -year period from to . among n = , , icu stays, sources of icu admission included elective surgery ( . %, n = , ), emergent/urgent admissions/trauma surgery ( . %, n = , ), and medical admissions ( . %, n = , ). ventilator utilization was seen in . % (n = , /n = , ) of all icu patients of which . % (n = , ), . % (n = , ), and . % (n = , ) was for patients from elective, emergent, and medical admissions, respectively. new york city holds the majority of icu bed capacity ( . %; n = /n = ) in new york state. conclusions: patients undergoing elective surgery comprised a small fraction of icu bed and mechanical ventilation use in new york state. suspension of elective surgeries in response to the covid- pandemic may thus have a minor impact on icu capacity when compared to other sources of icu admission such as emergent/urgent admissions/trauma surgery and medical admissions. more study is needed to better understand how best to maximize icu capacity for pandemics requiring heavy use of critical care resources. icu bed and ventilator capacity, however, is not well studied. we reviewed new york statewide planning and research cooperative system (sparcs) data from to to estimate the effect of statewide suspension of elective surgeries on icu bed and ventilator usage. to assess the potential impact on new york city (nyc), we evaluated how nyc-the current epicenter of the covid- outbreak-related to the rest of nys with respect to changes in elective surgery and icu/ventilator capacity. this study was approved by the institutional review board of hospital for special surgery ( - ). the requirement for written informed consent was waived given the deidentified nature of the data. patient-level data were extracted from the new york sparcs dataset ( - ), which includes patient-level and billing data for all inpatient and outpatient visits in nys. we included all adult and pediatric icu admissions and excluded cases classified as "newborn" or "neonatal" icu admissions, those with missing date of admission, and patients with hiv infection or who had an abortion (due to withholding of data on these patients by nys). icu and mechanical ventilation were defined using icu-specific billing codes and international classification of diseases, ninth edition (icd- ) codes . x and . x. mechanical ventilation was further classified into invasive/noninvasive and duration (≥ and < hours of consecutive invasive ventilation). the source of icu admission was categorized as ( ) elective surgery, ( ) emergent/urgent/trauma surgery admissions, and ( ) medical admissions. surgical/medical cases were differentiated based on icd- -clinical modifications surgical flag software. type of admission (elective, emergent, trauma, and urgent) is a variable coded in the sparcs database. additional study variables included geographic region (nyc metropolitan area-defined as nyc, long island, and the mid-and lower hudson valley counties-compared to the rest of nys) and year. nys hospital-level data included the number of icu beds by hospital (categorized by small, - beds/medium, - beds/large, - beds/very large, > beds), and types of icu. overall, nys hospitals have a permanent icu representing a total number of icu beds ( reserved for neonates, pediatric, and adult icu beds). all analyses were conducted using sas version . (sas institute, cary, nc). results were reported as case number and percentage, stratified by year, source of icu admission, and geographic region. because sparcs does not provide icu length of stay data, we used the most recent estimate of an average of . days spent in the icu, as published by the society of critical care medicine, to estimate annual total icu days in this pre-covid- period (across pediatric and adult icus). as a sensitivity analysis, we also calculated a range of % shorter or longer average icu length of stay. number of total icu days was subgrouped by source of admission to allow for a theoretical estimation of the number of covid- related icu stays to be gained with the elimination of icu days related to elective surgery. an icu length of stay of . days was applied for this estimation based on data from california and washington state. a total of , , icu admissions were identified from to in nys. n = cases were excluded because of missing inpatient admission date, and newborn cases were excluded. for our analysis, , , cases were included, averaging , (n = , , / ) per year. this represented . % of total hospital admissions over the study period (n = , , /n = , , ) which remained stable over time (figure) . average icu occupancy rate was . % (with a range of . %- . % using a % variation in assumed average icu length of stay). overall, . % of icu admissions were attributed to elective surgery, versus . % for emergent/urgent/trauma surgery and . % for medical reasons (table ) among all icu admissions, . % (n = , / n = , , ) of patients required mechanical ventilation. the majority ( . %) of ventilated patients were medical icu admissions while . % represented patients admitted to the icu after elective surgery. emergent/urgent/trauma surgery-related icu admissions were most likely ( . %) to require prolonged (ie, ≥ hours) of invasive ventilation ( table ) . nyc had twice as many icu beds and admissions as the rest of nys (table ) . of all ventilated patients in nys, . % were located in the nyc metropolitan area. this imbalance in icu volume and use of mechanical ventilation was particularly evident for emergent/urgent/trauma surgery-related icu admissions (n = , in nyc compared to n = , admissions in nys) and the number of high icu volume hospitals. in nyc, , patients required an icu stay with mechanical ventilation (table ) ; , of those patients were admitted after elective surgery ( , / , = . %), versus emergent/urgent/trauma surgery (n = , ) and medical reasons (n= , ). in comparison, in nys, . % ( / , ) of patients required mechanical ventilation in the icu. in this -year retrospective review of the new york sparcs database, we found that only % of icu admissions represented an admission after elective surgery. in contrast, more than twice as many patients requiring an icu were admitted after emergent/ urgent/trauma surgery while the bulk of icu admissions were for medical reasons. elective surgeries played an even smaller role ( %) in terms of mechanical ventilation requirements while this was % and % for icu admissions related to emergent/urgent/ trauma surgery and medical reasons, respectively. the nyc metropolitan region holds the majority of critical care capacity in nys. our data are generally consistent with prior studies of icu resource use due to elective surgery. two studies of icu use after noncardiac surgery found that elective surgery cases only consumed . % of icu resources and . % of ventilator requirements. , figure. this assessment of a relatively minor impact is compounded by the relatively small share of patients after elective surgery that require prolonged ventilationthus suggesting a shorter icu length of stay-when compared to patients admitted to the icu for emergent/urgent/trauma surgery or medical etiologies. a study of surgical icus also observed that stays after elective surgery rarely were for extended periods while icu stays after emergency surgery were more likely to be prolonged. our data suggesting requirement of mechanical ventilation in . % of icu admissions is likewise consistent with previously reported rates ranging from . % to . %. results presented in the current study have potential implications for resource management in crises requiring heavy use of scarce icu resources. while suspending elective surgeries clearly increases hospital (non-icu) bed capacity, our analysis suggests a limited impact on icu resource allocation, especially in the context of the much larger share of icu admissions due to emergent/urgent/trauma surgery and medical etiologies. a surge in critical care demand requires an orderly deescalation of less essential services to prevent catastrophic failure of the health care system. unfortunately, unlike elective surgery, urgent/emergent/trauma surgery and medical icu admissions cannot be deescalated. suspending elective surgery is controllable, but may only free up limited critical care resources. in the context of covid- care, which often requires prolonged courses of mechanical ventilation, the relatively short duration of icu stays after elective surgery suggests that the impact of reducing elective surgery is likely even smaller. combined, these findings point toward greater use of critical care resources in icu admissions not linked to elective surgeries. of specific interest is critical care utilization among patients in the emergent/urgent/trauma surgery group as they represent a larger share of surgical admissions when compared to elective surgery. although data are lacking, we hypothesize that this category of icu utilization may also be impacted through policies such as stay-at-home orders. intended to contain the spread of covid- , statewide stay-at-home orders may also decrease automobile accidents due to less traffic. such an effect on traffic accidents , has been noted in california after statewide stay-at-home orders. reducing exposure to traffic is likely to lead to reduced trauma-related emergency department visits and subsequent critical care utilization. stay-at-home orders may also affect crime-related trauma activity that consumes icu resources, although existing data suggest mixed effects. effects of public health policies on icu resource availability represent an important knowledge gap in disaster planning policy. our data do not address other potential effects of suspending elective surgery. such a decision may only free up limited icu resources, but may also release non-icu hospital beds for covid- patients who do not need critical care. reallocating such patients may then preserve existing icu beds. health care workers previously involved in elective surgery may also be redirected to provide care to pandemic patients. reports of redirecting surgeons to perform invasive procedures, operation room (or) teams to position patients in prone position, and nurse anesthetists to manage ventilated icu patients suggest that health care system resource allocation is extremely complex. our study has limitations. first, data from to may not accurately represent current icu practice and capacity in new york. however, yearon-year data suggests that the icu capacity in nys and nyc has remained relatively constant during the study period. second, we do not estimate the effects of suspending elective surgery on non-icu beds. changes in these non-icu resources may have secondary effects on icu use. third, the balance of icu resource utilization due to different emergent or elective surgery or medical reasons may be seasonal, suggesting that the effect of elective surgery on icu admissions may vary by time of year. for example, better weather may increase the number of emergent/ urgent admissions/trauma surgery admissions which would further reduce the relative impact of suspension of elective surgeries in terms of icu capacity. in conclusion, we found that, over a -year period from to , icu admissions from patients after elective surgery in new york is likely to have only a small effect on icu bed availability. rather, icu admissions from urgent/emergent surgery and medical sources comprise the majority of icu admissions both in nys and nyc. our results may be valuable for hospital administrators and disaster planning policymakers to optimize the response to future diseases that require heavy use of critical care. e utilization of intensive care services healthcare cost and utilization project (hcup). surgery flags software for icd- -cm available at: https:// health.data.ny.gov/health/health-facility-certification-information/ g y- kqm the society of critical care medicine (sccm) incidence, clinical outcomes, and transmission dynamics of severe coronavirus disease in california and washington: prospective cohort study intensive care utilization following major noncardiac surgical procedures in ontario, canada: a population-based study european surgical outcomes study (eusos) in spain. intensive care admission and hospital mortality in the elderly after non-cardiac surgery analyzing the impact of long-term patients on icu bed utilization icu occupancy and mechanical ventilator use in the united states surge capacity principles: care of the critically ill and injured during pandemics and disasters: chest consensus statement respiratory pathophysiology of mechanically ventilated patients with covid- : a cohort study available at: https://data.lacity.org/ a-safe-city/traffic-collision-data-from- -to-present/ d tf-ez w special report: impact of covid on california traffic accidents initial evidence on the relationship between the coronavirus pandemic and crime in the united states innovative icu physician care models: covid- pandemic at newyork-presbyterian. nejm catalyst correlating weather and trauma admissions at a level i trauma center key: cord- - dm f l authors: huang, ian; pranata, raymond title: lymphopenia in severe coronavirus disease- (covid- ): systematic review and meta-analysis date: - - journal: j intensive care doi: . /s - - - sha: doc_id: cord_uid: dm f l objective: clinical and laboratory biomarkers to predict the severity of coronavirus disease (covid- ) are essential in this pandemic situation of which resource allocation must be urgently prepared especially in the context of respiratory support readiness. lymphocyte count has been a marker of interest since the first covid- publication. we conducted a systematic review and meta-analysis in order to investigate the association of lymphocyte count on admission and the severity of covid- . we would also like to analyze whether patient characteristics such as age and comorbidities affect the relationship between lymphocyte count and covid- . methods: comprehensive and systematic literature search was performed from pubmed, scopus, europepmc, proquest, cochrane central databases, and google scholar. research articles in adult patients diagnosed with covid- with information on lymphocyte count and several outcomes of interest, including mortality, acute respiratory distress syndrome (ards), intensive care unit (icu) care, and severe covid- , were included in the analysis. inverse variance method was used to obtain mean differences and its standard deviations. maentel-haenszel formula was used to calculate dichotomous variables to obtain odds ratios (ors) along with its % confidence intervals. random-effect models were used for meta-analysis regardless of heterogeneity. restricted-maximum likelihood random-effects meta-regression was performed for age, gender, cardiac comorbidity, hypertension, diabetes mellitus, copd, and smoking. results: there were a total of patients from studies. meta-analysis showed that patients with poor outcome have a lower lymphocyte count (mean difference − . μl [− . , − . ], p < . ; i( ) %) compared to those with good outcome. subgroup analysis showed lower lymphocyte count in patients who died (mean difference − . μl [− . , − . ], p < . ; i( ) %), experienced ards (mean difference − . μl [− . , − . ], p < . ; i( ) %), received icu care (mean difference − . μl [− . , − . ], p = . ; i( ) %), and have severe covid- (mean difference − . μl [− . , − . ], p < . ; i( ) %). lymphopenia was associated with severe covid- (or . [ . , . ], p < . ; i( ) %). meta-regression showed that the association between lymphocyte count and composite poor outcome was affected by age (p = . ). conclusion: this meta-analysis showed that lymphopenia on admission was associated with poor outcome in patients with covid- . coronavirus disease (covid - ) has been declared by the world health organization (who) as a global public health emergency due to its pandemicity [ ] . since its first emergence in wuhan, china, more than , cases and , deaths have been recorded globally due to covid- [ ] . while most patients with covid- have mild influenza-like illness and may be asymptomatic, a minority of patients will develop severe pneumonia, acute respiratory distress syndrome (ards), multi-organ failure (mof), and death [ ] . clinical and laboratory biomarkers [ ] to predict the mortality and severity of covid- are essential in this pandemic situation of which resource allocation must be urgently prepared especially in the context of respiratory support readiness. since the first descriptive study in china regarding the covid- infection [ ] , lymphocyte count has been a marker of interest. it has been associated with severe covid- [ , ] , and non-survivors of covid- were reported to have a significantly lower lymphocyte count than survivors [ ] . whether lower lymphocyte count and lymphopenia could really be predictor of severity of covid- was our main interest, since this laboratory tools are readily available even in the remote areas. therefore, in the present study, we conducted a systematic review and meta-analysis in order to investigate the association of lymphocyte count on admission and the severity of covid- . we would also like to analyze whether patient characteristics such as age and comorbidities affect the relationship between lymphocyte count and covid- . we included research articles concerning adult patients diagnosed with covid- that has information on lymphocyte count at admission, and clinical grouping or outcome of clinically validated definition of severe covid- , death, or icu care. we exclude review articles, non-research letters, commentaries, case reports, animal studies, original research with samples below or case reports and series, non-english language articles, and studies in pediatric populations (≤ years old). we systematically searched pubmed, scopus, eur-opepmc, proquest, cochrane central databases, and google scholar with the search terms "covid- " or "sars-cov- " and "lymphocyte" (table s ). after initial search, duplicates were excluded. two independent authors (ih and rp) screened title and abstracts for potentially relevant articles. the full-text of the potential articles was assessed by applying inclusion and exclusion criteria. the literature search was finalized on march , . the study was carried out in accordance with the declaration of helsinki and with the term of local protocol. this is a preferred reporting items for systematic reviews and meta-analyses (prisma)-compliant systematic review and meta-analysis data extraction was performed independently by two authors (ih and rp). we used standardized forms that included author, year, study design, age, gender, cardiac comorbidities, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, smoking, lymphocyte count, lymphopenia, mortality, ards, icu care, and severe covid- . the outcome of interest was composite poor outcome that comprised of mortality, ards, icu care, and severe covid- . mortality and icu care was defined as death and admittance to icu during inhospital care, respectively. ards was defined according to the criteria from the world health organization (who) interim guidance for severe acute respiratory infection (sari) in covid- , which includes the acuity of symptom onset, chest x-ray and origin of pulmonary infiltrates, and oxygenation impairment [ ] . severe covid- was defined as patients who had any of the following features at the time of, or after, admission: ( ) respiratory rate ≥ breaths per min, ( ) oxygen saturation ≤ % (at rest), ( ) ratio of partial pressure of arterial oxygen to fractional concentration of oxygen inspired air (pao to fio ratio) ≤ mmhg, or ( ) specific complications, such as septic shock, respiratory failure, and or multiple organ dysfunction [ ] . the meta-analysis of studies was performed using review manager . (cochrane collaboration) and stata version . to pool continuous variables, we used an inverse variance method to obtain mean differences (mds) and its standard deviations (sds). maentel-haenszel formula was used to calculate dichotomous variables to obtain odds ratios (ors) along with its % confidence intervals (cis). we used random-effects models for pooled analysis regardless of heterogeneity. all p values were two-tailed, and statistical significance was set at ≤ . . subgroup analysis was performed for lymphopenia cutoff point at ≤ cells/μl. sensitivity analysis using a leave-one-out method was performed to single out the cause of heterogeneity. regression-based egger's test was used to assess smallstudy effects for continuous variables and harbord's test for binary outcome. restricted maximum likelihood randomeffects meta-regression was performed for age, gender, cardiac comorbidity, hypertension, diabetes mellitus, chronic obstructive pulmonary disease (copd), and smoking. we found a total of records of which remained after the removal of duplicates. a total of records were excluded after screening the title/abstracts. after assessing articles for eligibility, we excluded in which lymphocyte count was unavailable. thereby, studies remained for qualitative synthesis and meta-analysis ( fig. ). there were a total of patients from studies [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . baseline characteristics are presented in table . the reported mean age of the patients on these studies was years old; % of the overall samples were men. most studies reported lymphocyte count on admission except for ruan sensitivity analysis showed that removal of one particular study [ ] reduced the heterogeneity for icu outcome, but lymphocyte count was still lower in those that received icu care (mean difference − . μl [− . , − . ], p < . ; i %, p = . ). removal of any single study did not significantly reduce heterogeneity for mortality, ards, and severe covid- . meta-analysis showed that lymphopenia was associated with severe covid- (or . [ . , . ], p < . ; i %, p = . ) (fig. b) . subgroup analysis was performed for lymphopenia with definition of lymphocyte count ≤ μl, showing that lymphopenia was associated with severe covid- (or . [ . , . ], p < . ; i %, p = . ) ( figure s ). random-effects meta-regression analysis showed that the association between lower lymphocyte count in patients with composite poor outcome was affected by age (p = . ) (fig. a) , but not by gender (p = . ), cardiac comorbidity (p = . ) (fig. b) , hypertension (p = . ) (fig. c) , diabetes mellitus (p = . ), copd (p = . ), and smoking (p = . ). since the composite poor outcome was affected by age, we performed subgroup analysis by using years old as cutoff point. funnel plot analysis showed asymmetrical shape for lymphocyte count and composite poor outcome (fig. ) . the funnel plot was symmetrical for lymphopenia and severe covid- . regression-based egger's test showed statistically significant small-study effects (p = . ) for the lymphocyte and composite poor outcome. trimand-fill method did not impute any study. regressionbased harbord's test showed no evidence of small-study effects (p = . ) for lymphopenia and severe covid- outcome. this meta-analysis showed that lower lymphocyte count was associated with increased mortality, ards, need for icu care, and severe covid- . the association seemed to be stronger in younger patients compared to older patients. although the definition of lymphopenia differed among studies, a subgroup analysis using ≤ cells/μl cut-off point has showed a consistent outcome in four studies [ ] [ ] [ ] ] . we set a cut-off point of ≤ μl because there were studies using it as a cutoff point. there were only studies for ≤ μl, and study for < μl and ≤ μl, respectively. this subgroup analysis aimed to determine the magnitude of odds ratio at a specific cutoff point (not because of its superiority over the other cutoff points). based on the meta-regression result, subgroup analysis of age group by using years old as the cutoff point was performed. by analyzing the bubble plot chart, the center of bubble plot is approximately to years old. hence, we chose as the cutoff point to ensure the number of studies is almost equal in the left side and the right side of the bubble plot. if the number of studies was too small, the pooled effect estimate will be less reliable. interestingly, we found that the association between lymphopenia and severe covid- was stronger in younger patients compared to older patients. this was a novel finding which, as far as we know, has not been discussed in previous literature. although changes in the number and composition of lymphocytes are considered as hallmark of immunosenescence [ ] , it could not fully explain this association. one possible hypothesis is that the aging of the immune system could contribute to a relatively "non-reactive" immune state, thereby causing a relatively stable reduced lymphocyte count, while in younger populations, the highly active lymphocyte kinetics may be influenced by a wide range of insults and comorbidities, thus contributing to a relatively higher mean difference between younger populations. this is further reflected by the sensitivity analysis which showed that upon removal of wang et al. study, heterogeneity can be reduced to % for the icu care outcome. this heterogeneity was attributed to the mean/median age; there were studies for the icu care outcome, cao et al. pre-existing cardiac disease has been shown to increase mortality in patients with covid- [ ] ; in this metaanalysis, cardiac comorbidity was not found to affect the association between lymphocyte count difference and composite poor outcome. angiotensin-converting enzyme (ace) inhibitor and angiotensin-receptor blocker (arb) have been hypothetically suggested to exacerbate covid- due to increase in angiotensin ii level [ ] . these drugs are frequently used in patients with diabetes and hypertension, which was associated with poor outcome [ , ] . although we did not have data on hypertensive medications in the present study, meta-regression showed that hypertension and diabetes did not significantly affect the lymphocyte count difference between poor and good outcome. our understanding of the pathogenesis of lymphocyte reduction in covid- might possibly be enlightened by studies of other similar beta-cov infection, including severe acute respiratory syndrome (sars)-cov and middle east respiratory syndrome (mers)-cov [ ] . peripheral t lymphocytes, both cd + and cd +, are rapidly reduced in acute sars-cov infection hypothetically due to lymphocyte sequestration in specific target organs [ ] . although mers-cov and sars-cov are structurally similar, they bind to different receptors to facilitate entry. sars-cov attaches to angiotensinconverting enzyme (ace ) to enter the host cells, while mers-cov attaches to a different receptor, namely dipeptidyl peptidase (dpp ) [ ] . although the mechanism of significant lymphocyte reduction in severe covid- remains unclear, there are hypothesis other than lymphocyte infiltration and sequestration in the lungs, gastrointestinal tracts, and or lymphoid tissues: ( ) lymphocytes express the ace receptor and may be a direct target of sars-cov- infection [ ] , and ( ) an increase of pro-inflammatory cytokines in covid- , especially il- , could induce further lymphocyte reduction [ ] . lymphopenia can be used as a marker for poor prognosis in covid- and in younger patients in particular. lymphopenia defined as lymphocyte count ≤ cells/μl is associated with threefold risk of poor outcome. the limitation of this systematic review and metaanalysis is the presence of publication bias. this is apparent in the lymphocyte count and composite poor outcome. most of the articles included in the study were published at preprint server of which are not yet peerreviewed. data curation from preprint server is crucial due to the novel and emergent nature of covid- ; most of the studies are not yet published in journals. most of the studies were exclusively from china; thus the possibility of the same patients reported more than once is high and may represent inaccurate scientific records. the included studies were also mostly retrospective in design. we encourage further studies to create prognostic model that include lymphopenia. this meta-analysis showed that lymphopenia on admission was associated with poor outcome in patients with covid- . supplementary information accompanies this paper at https://doi.org/ . /s - - - . additional file : table s . electronic search strategy. additional file : figure s . subgroup analysis performed for lymphopenia. world health organization. coronavirus disease (covid- ) outbreak world health organization. coronavirus disease (covid- ) situation report - . world heal epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study elevated n-terminal pro-brain natriuretic peptide is associated with increased mortality in patients with covid- -systematic review and meta-analysis clinical features of patients infected with novel coronavirus in wuhan clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a singlecentered, retrospective, observational study clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china. intensive care med clinical management of severe acute respiratory infection (sari) when covid- disease is suspected. ; - report of the who-china joint mission on coronavirus disease clinical features and outcomes of patients with covid- in wuhan clinical characteristics of patients infected with sars-cov- in wuhan, china clinical features and treatment of covid- patients in northeast chongqing platelet-to-lymphocyte ratio is associated with prognosis in patients with corona virus disease- dysregulation of immune response in patients with covid- in wuhan clinical characteristics of patients with severe pneumonia caused by the novel coronavirus in wuhan early prediction of disease progression in novel coronavirus pneumonia patients outside wuhan with ct and clinical characteristics clinical characteristics of patients discharged from hospital with covid- in chongqing longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of sars-cov- covid- in a designated infectious diseases hospital outside hubei province, china clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study neutrophil-to-lymphocyte ratio predicts severe illness patients with novel coronavirus in the early stage. medrxiv non-severe vs severe symptomatic covid- : cases from the outbreak on the cruise ship clinical characteristics and risk factors for fatal outcome in patients with -coronavirus infected disease (covid- ) in wuhan clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china clinical features of patients infected with the novel coronavirus (covid- risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease clinical features and progression of acute respiratory distress syndrome in coronavirus disease clinical characteristics of coronavirus disease in china analysis of factors associated with disease outcomes in hospitalized patients with novel coronavirus disease changes in blood lymphocyte numbers with age in vivo and their association with the levels of cytokines/cytokine receptors sars-cov : should inhibitors of the renin-angiotensin system be withdrawn in patients with covid- ? diabetes mellitus is associated with increased mortality and severity of disease in covid- pneumonia -a systematic review, meta-analysis, and meta-regression hypertension is associated with increased mortality and severity of disease meta-analysis, and meta-regression hypothesis for potential pathogenesis of sars-cov- infection--a review of immune changes in patients with viral pneumonia significant changes of peripheral t lymphocyte subsets in patients with severe acute respiratory syndrome dipeptidyl peptidase is a functional receptor for the emerging human coronavirus-emc high expression of ace receptor of -ncov on the epithelial cells of oral mucosa publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none authors' contributions ih and rp developed the concept and drafted the manuscript. ih and rp performed data acquisition, data analysis, and statistical analysis and approved the final version. availability of data and materials all data generated or analyzed during this study are included in this published article. corresponding author (r.p) can be contacted for more information.ethics approval and consent to participate not applicable the authors declare that they have no competing interests key: cord- -un s mr authors: levy, jonathan; léotard, antoine; lawrence, christine; paquereau, julie; bensmail, djamel; annane, djillali; delord, vincent; lofaso, frédéric; bessis, simon; prigent, hélène title: a model for a ventilator-weaning and early rehabilitation unit to deal with post-icu impairments with severe covid- date: - - journal: ann phys rehabil med doi: . /j.rehab. . . sha: doc_id: cord_uid: un s mr nan j o u r n a l p r e -p r o o f dear editor. the unprecedented outbreak of the novel coronavirus (ncov- or sars-cov- ) that emerged in wuhan, china, in and spread all over europe and the world has forced french hospitals to reorganize and admit a large number of critically ill patients in a short period of time. data from china reported up to % of patients overall ( ) and % with severe covid- ( ) requiring mechanical ventilation. median length of hospital stay was days ( ), but patients with severe disease may remain in intensive care units (icus) for to weeks, and survival time for non-survivors has been reported to be to weeks ( ). on march , in france, , of , confirmed cases of covid- needed intensive care ( ) . reports from italy warned of the risk of icu bed shortage ( ). new cases and especially severe ones are increasing exponentially following a similar evolution in italy ( ) , with a risk of icu saturation in many french regions. there is a growing need for ventilator weaning units that could help icus discharge ventilator-dependent patients with stable disease and no other organ failure but respiratory or neurological features. according to other physical medicine and rehabilitation societies worldwide, early evaluation and rehabilitation for these patients is mandatory ( , ) . here we describe our organization of this type of unit and our first feedback from its functioning, based on the experience in a french tertiary care university hospital. this weaning unit was set ex nihilo within days and was ready for the first patients by march , . the pavilion architecture of our hospital allowed us to secure buildings for covid- -free patients (from the conventional icu and infectious diseases and neurorehabilitation units) and isolate one building for covid- patients ( each bed is equipped with a level- life support ventilator astral ® (resmed, san diego, ca, usa) and non-invasive continuous monitoring (oxygen saturation, heart rate, noninvasive blood pressure). each ventilator has flow meters for perfusion and a nutrition pump for enteral feeding. we could not implement a full monitoring system in the nurses' office, but ventilator alarms are repeated by using "babyphones" or with an independent remote alarm system. finally, each room is equipped with a lift and harness for transfers (fig. ) . mean icu length of stay before admission in the weaning unit was ( . ) days (vs weeks in the chinese series ( )). mean length of stay in our unit was ( . ) days. for successfully weaned patients, mean total duration of mechanical ventilation was ( . ) days (range to days). six patients had a history of hypertension and none were active or previous smokers. three patients had post-icu-acquired weakness, progressively regressive, and had initial and transient brachiofacial paresis (intracerebral hemorrhage ruled out, but to date, mri could not be performed). all had moderate to severely low serum albumin levels (< g/l). all had mild to moderate post-icu delirium, and had persistent anxiety or post-traumatic stress. by the date of final acceptance of this article (april ), we counted , active cases of covid- in france; , patients were considered to have serious or critical disease and were in an icu. this indicates an exponential increase of severe cases and confirms the past hypotheses of icu-bed saturation (< , before the epidemic). the survivors (approximately %) will need invasive ventilation for weeks and early rehabilitation support. our preliminary feedback on our set-up attests to the appropriateness of our approach. the goal of the specific organization we describe is to allow for early patient discharge from the icu and increase icu admission capacity over time during the covid- crisis. it also allows for a physical medicine and rehabilitation holistic evaluation of post-critical covid- patients. hence, our first feedback strengthens the idea that our unit constitutes a possible intermediary stage between icu and either home discharge or inward rehabilitation for patients with pulmonary, nutritional, neurological and psychological covid- -related and/or post-icu impairments. clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study avis relatif aux recommandations thérapeutiques dans la prise en charge du covid- covid- and italy: what next? the lancet european centre for disease prevention and control (ecdc) public health emergency team. rapidly increasing cumulative incidence of coronavirus disease (covid- ) in the european union/european economic area and the united kingdom impact of covid- outbreak on rehabilitation services and physical and rehabilitation medicine (prm) physicians' activities in italy. an official document of the italian prm society (simfer) facing in real tim the challenge of the covid- epidemic for rehabilitation key: cord- -buq d k authors: jannes, g.; barreal, j. title: beta regression with spatio-temporal effects as a tool for hospital impact analysis of initial phase epidemics: the case of covid- in spain date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: buq d k covid- has put an extraordinary strain on medical staff around the world, but also on hospital facilities and the global capacity of national healthcare systems. in this paper, beta regression is introduced as a tool to analyze the rate of hospitalization and the proportion of intensive care unit admissions over both hospitalized and diagnosed patients, with the aim of explaining as well as predicting, and thus allowing to better anticipate, the impact on hospital resources during an early-phase epidemic. this is applied to the initial phase covid- pandemic in spain and its different regions from -feb to -apr of . spatial and temporal factors are included in the beta distribution through a precision factor. the model reveals the importance of the lagged data of hospital occupation, as well as the rate of recovered patients. excellent agreement is found for next-day predictions, while even for multiple-day predictions (up to days), robust results are obtained in most cases in spite of the limited reliability and consistency of the data covid- , the disease caused by the sars-cov- virus, has led to one of the largest pandemics known in recent times. it has caused an effective breakdown of many sectors of the economy and of most social activities, as well as an evidently tremendous concern for the health sector, from hospitals over pharmaceutical companies to scientific institutions. from a hospitalary point of view, three types of cases can be distinguished: asymptomatic and mild cases which do not require hospital treatment, hospitalized patients or inpatients, and patients that require admission to an intensive care unit (icu). the large number of patients in the third group is especially problematic for hospitals, because they lead to a sharp peak in the demand for hospital beds, equipment and medical attention, and thus to a saturation of the icus' available space and resources, both material and human. the current crisis has shown that the national and global healthcare and economic systems were insufficiently prepared to supply the demand for medical equipment and staff required to cope with this situation. these issues are ultimately related to the number of infected, and in particular those that will require hospitalization (regular or icu). many studies therefore focus on analysing absolute numbers and patterns of spread, see e.g. dong et al. ( ) , liu et al. ( ) , bi et al. ( ) ; while health management studies in the context of covid- focus mainly on qualitative aspects, such as the design of an emergency plan [cao et al. ( ) ], adaptation of hospital facilities and the importance of communication with staff [grange et al. ( ) ], or on analysing the risk for hospital personnel [cheung ( ) and yu et al. ( ) ] or for other hospital visitors, such as pregnant women ]. here, a complementary point of view is presented, allowing for a quantitative analysis and prediction of the ratio or proportion of patients that require hospital and/or icu admission. the main advantage of these ratios as compared to absolute numbers is that they are scaleindependent indicators of the strain put on the installations, amount of beds and other resources of hospitals of any size in regions with any amount of population. we mention two key applications here. first, this method allows to forecast which proportion of hospital resources and capacity should be reserved for icu purposes during such crises across all hospitals of a particular region. the scale-independence of the ratios means that it can be applied equally to hospitals of all sizes. second, several countries have made use of temporary hospitals created exclusively for covid- patients. the ratios that we will study, and in particular the uci/hosp ratio, provide a very simple and powerful way of planning the distribution of such temporary facilities. the purpose of this paper is thus to provide policymakers in the health sector with statistical and econometric tools to predict hospital occupation rates, both general and at the icu level, during the first phase of future pandemics with features similar to the current covid- pandemic. these predictions will relie on the identification of temporal patterns and spatial effects in the ratios of hospitalized patients over total cases, icu over hospitalized, and icu over total cases. at the heart of the methodology lies the well-known beta regression, which is ideally suited for modeling rates and proportions, and adds several elements of information to the more common predictions based on logistic distributions, such as villalobos-arias ( ), buizza ( ) , bliznashki ( ) , wu et al. ( ) and huang et al. ( ) , or the weibull distribution, as in zhang ( ) . beta distributions have been applied before to the health sector, in gange et al. ( ) , hunger et al. ( ) and moraes et al. ( ) , but for quite different purposes. a three-step methodology will be developed. first, a beta distribution will describe the probability function for all possible values of the ratios of interest; second, a logistic distribution will be used to estimate the time evolution of raw data of diagnosed, hospitalized, icu patients, and recovered patients; third and foremost, a beta regression will be used to develop a prediction method for the ratios described earlier based on their lagged values and on the proportion of recovered patients. to illustrate this methodology, it will be applied to spain during the early-phase covid- epidemic. there are several reasons why spain is an interesting example. first, spain has been one of the hardest hit countries so far, and thus provides a sample of a statistically interesting size. second, parts of the spanish hospital system have indeed been overwhelmed, which is precisely the focus of this research. third, spain's regional division in autonomous communities, each responsible for the collection and communication of the covid- data, means that spain naturally provides a relatively wide and diverse geographical sample. in this sense, spatial patterns will be essential to describe the evolution of the hospital ratios in the spanish health system. the paper therefore develops distribution models for both spain globally (in the main text) and for its regions separately (in the appendices). the methodology is robust and could be applied to other geographical areas. the paper is structured as follows. in the next section, a data description is given to visualize the early-phase spanish pandemic evolution, both temporal and spatial. the following section describes the statistical methods and the econometric models, with an emphasis on the beta regression with spatial and temporal components. some key results with regard to the current covid- data for spain are discussed next. additional information about the methods and the data, as well as detailed results for the spanish regions separately, are given in a series of appendices. the spanish ministry of health records and provides daily data about the pandemic evolution in each of the spanish regions [ministerio de sanidad ( ) ]. figure shows the mean number of newly recorded cases, hospitalized patients and fatalities per inhabitants per day in each of the spanish regions from -feb- to -apr- , counted from the first non-zero day. the plots clearly show the inhomogeneous character of the spatial distribution for all three variables. madrid (md), catalonia (ct), the basque country (bc) and la rioja (ri) are the areas with the highest impact in proportion to their number of inhabitants, while the south, the north-west and the spanish islands present lower values. note that for the first group ("cases") we take the data initially provided by the spanish ministry of health at face value, regardless of whether these cases have been effectively clinically diagnosed through a medical test, or are just based on a symptomatic analysis. this remark is important because the first category (positive medical test) could include asymptomatic patients, whereas the second category (symptomatic analysis) could include false negatives, for example due to influenza or other diseases. in fact, the uncertainty about the true number of people affected by covid- is one of the major current incognita. coma et al. ( ) suggest that several thousand covid- cases in catalonia alone may have been misdiagnosed as influenza. for italy, modi et al. ( ) estimate that the true number of covid- might be at least twice the official number, while vollmer & bommer ( ) estimate a factor of possibly to worldwide. an advanced mathematical model for undetected infections and their influence on the spread of the covid- virus has been developed in ivorra ( ) . figure shows the temporal evolution of cases, inpatients, icu patients, deaths, and recovered patients in absolute numbers for each spanish region, plotted from the day of the first official case recorded (which can differ by various days from region to region). while the number of cases follows a qualitatively similar evolution in all regions, there are some interesting differences in the evolution of the number of hospitalized patients. in particular, in cm (castilla-la-mancha) and madrid (md) these had already started to go down by april th, while the other regions were still in an increasing phase. as stated in the introduction, this paper aims to provide policymakers and hospital managers with some statistical methods to manage future similar situations, depending on the strain put on icus. we will from now on focus on the proportion of hospitalized patients to total cases ( a), the proportion of icu over total hospitalized patients ( b), and finally the proportion of icu patients over total cases ( c), since these are the variables crucial for the research goal. at the global (spanish) level, these variables are defined as where the summation is over the regions, and the index t indicates that these are calculated day by day. note that the third variable can in principle be obtained as the product of the previous two. as mentioned before, there is a large uncertainty about the real number of infected, so the description "cases" should be taken with caution, since this number can fluctuate a lot depending on whether one refers to "infected" (but not necessarily ill), "symptomatically diagnosed" or "clinically tested", and in the latter case: through pcr or antibody testing. current data on the number of cases is therefore rather unreliable and inconsistent, since different countries or regions use different methodologies. in any case, the methodology that we will present is independent of how the cases are counted. as we will show, it allows an accurate prediction of the three proportion variables just defined. figure shows the geographical distribution of the mean of these three variables over the period considered (starting from the first case recorded until april th). the first map shows . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . the ratio of hospitalized over total cases, and shows that regions such as madrid (md), castilla-león (cl), catalonia (ct) and the basque country (pv) present a higher rate of hospitalization than extremadura (ex), galicia (ga) or la rioja (ri). the second map shows the severity of the hospitalized cases, i.e. the ratio of icu patients over total hospitalized patients, with high recordings in murcia (mc) and the canary (cn) and balearic (bi) islands, and low values in center-north: castilla-león (cl), la rioja (ri) and the basque country (pv). the last plot involves icu cases over total cases, which is crucial to estimate hospital strains. catalonia (ct), aragon (ar) and the canary (cn) and balearic (bi) islands record the highest values; galicia (ga), extremadura (ex) and la rioja (ri) the lowest. the diversity in the recorded patterns is striking. with regard to the ratio of hospitalized over cases (red line), some regions present a relatively constant ratio, such as andalusia (an), aragon (ar) or navarra (nc). others show an increasing pattern, with saturation already achieved by -apr, as is the case in castilla-león (cl), catalonia (ct), or galicia (ga); or not yet, such as in asturias (as). madrid (md) and castilla-la-mancha (cm) had a strongly increasing initial phase, which transformed quite suddenly into a steadily decreasing phase. the ratio of icu over hospitalized (blue) and icu over cases (green) show less obviously striking variety, but can also be divided into roughly constant, increasing and (already) declining. we insist that these are ratios, and therefore do not directly reflect whether the absolute numbers are increasing more or less rapidly. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . in the remainder of this paper, we will use the data up to -apr to construct a model and make predictions, and verify this with the data from -apr to -apr, which is also provided by the ministerio de sanidad ( ). it should be noted that around -apr the criteria for a patient to be counted as a "case" has changed in several regions, which started including asymptomatic patients from this date on. as stated before, the accuracy of the predictions could be further improved by introducing more reliable data. but it is worth stressing that the model itself does not depend on this, and the predictions are reliable and accurate within the assumptions and limitations of each counting method. this paper uses a combination of statistical and econometric analysis in different steps. first, a beta distribution is used to estimate the density and distribution function of the study variables (the ratios defined in eqs. ) for both spain as a whole and the spanish regions separately. note that this distribution does not involve any time parameter. second, a logistic distribution is used to describe the time evolution of the cumulative raw data; in other words, the absolute number of diagnosed, hospitalized, and icu patients, as well as recoveries, is estimated through the use of a logistic functional form. these auxiliary results are used as input for the third and main step, namely the beta regression in which the ratios and their evolution is predicted, and which also includes an analysis of the temporal patterns and spatial effects in the variance of the modelization. we begin by briefly summarizing these different elements. the beta distribution b(α, β) is a family of two-parametric probability distributions limited to the interval y ∈ [ , ]. it therefore naturally applies to probabilities and proportions, such as the ratio of hospitalized over total cases, or of icu over hospitalized cases, that we are interested here. it is historically accredited to karl pearson, based on the beta integral studied by euler and legendre in the th century. the beta distribution is characterized by a probability density function where the parameters α, β > , and the normalization constant is precisely the beta integral mentioned above, with Γ(·) the gamma function. it can be shown that the beta distribution's expected value or mean µ and variance σ are respectively. these parameters allow an alternative definition of the beta distribution [ferrari & cribari-neto ( ) ] in terms of µ and a new parameter φ = α + β, such that b(µ, φ) is described by the equivalent probability density function note that . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . and therefore, for given mean µ, larger φ implies smaller variance. the parameter φ is therefore usually referred to as a precision parameter. this alternative parametrization forms the basis for the beta regression model discussed below. we insist that this distribution describes the probability distribution of all data points, but does not contain an explicit time variable. logistic distributions form the basis for many population models in general [richards ( ] , including epidemic outbreak models [chowell ( ) ], and have been applied to the covid- pandemic for example in wu et al. ( ) . one possible way of writing a logistic population model is where n t represents the population at time t, k * = log(k − n )/n , with n the initial population, r the growth rate, and k the carrying capacity (or asymptote). this is implemented in r through the parametrization asym = k, scal = /r and xmid = k * /r, see the table in fig. a below. note that eq. ( ) is obtained as a solution of the logistic or verhulst equation, which is a first-order differential equation of the form which describes a population (e.g., number of infected) whose size n grows in time proportionally with the existing population size, and with a quadratic saturation effect. this saturation can be due to competition for resources (food, space etc.) for a general population model, or to growing immunity, decrease of the non-infected population, or sanitary counter-measures in the case of an epidemic. we describe this in more detail in appendix a. since the dependent variables represent ratios or proportions, the final step consists of a beta regression [cribari-neto & zeileis ( )]. thus, for a random sample y = (y , , .., y n ) of proportions, where it is assumed that each y i ∼ b(µ i , φ i ), the beta regression model consists of two predictor functions. first, for the means µ i : where θ = (θ , ..., θ k ) τ and x i = (x i , ..., x ik ) τ are k × vectors representing the regression parameters θ j and the independent variables (or covariates) x ij , respectively, and g(.) is a so-called link function. the independent variables x ij could include pandemic features such as the lagged values of the same variables, as well as exogenous factors such as the proportion of recovered patients. to avoid problems of multicollinearity between variables, the correlation matrix and variance inflation factors (vifs) are calculated, see section . . the vector of regression parameters θ (as well as γ, see below) is determined through a numerical maximum likelihood procedure based on the sample y . the scalar product thus gives a linear prediction for the values of g(µ i ). in models with a non-zero intercept (such as we will encounter here), the x i can be taken x i = (∀i). the link function g(·) maps the restricted domain of the beta distribution (y ∈ [ , ]) to the range of the independent variables (in the most general case, r), and can in principle be chosen freely in order to provide an optimal fit. a usual choice, which is known to provide good results in a wide range of applications and moreover is conceptually indicated for the current model because of its relation to the logistic function, is the logit function. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . a second predictor function is developed for the precision parameters φ i : where γ = (γ , ..., γ p ) τ is the vector of regression coefficients and z i = (z i , ..., z p ) τ the set of independent variables. note that basic beta regression models use a constant parameter φ. however, we are interested in analysing the influence of temporal and spatial patterns, as well as cross effects, on the variance of the model, and these can ideally be studied by allowing for space and time-dependent precision parameters φ i , see eq. ( ). in order to select which effects should be included in determining the φ i , an akaike (aic) and bayesian information criteria (bic) are applied [akaike ( ) and schwarz ( ) ]. in these criteria, the following quantities are minimized, respectively, where Λ represents the maximum log-likelihood, n the sample size and k the number of parameters (spatial, temporal or mixed precision coefficients) to be estimated by the model. these criteria thus incorporate a penalty for overfitting, ensuring that only a limited number of relevant parameters are selected. to illustrate the previously developed methodology, it will now be applied to the early phase of the covid- epidemic in spain. we start by modelling the distribution of the dependent study variables defined in eqs. ( ) in spain according to a beta distribution. table shows the beta distribution coefficients (α; β) from eqs. ( ) and ( ) figure represents the density and cumulative distribution functions obtained from the parameters shown in table for the three ratios. the large difference between them is obvious from this figure. in particular, icu/hosp has a strong slope and faster cumulative progress in its probability distribution in comparison with the other two variables. this means that, according to the beta distribution model, all the values for this ratio icu/hosp lie in the narrow range ( − . ), whereas the other two ratios have a wider range. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . table . the graphical results of a statistical analysis showing that this beta distribution model fits the empirical data to excellent degree is given in appendix b. the density and distribution function of the study variables for each spanish region separately are shown in appendix c the table in fig. a records the estimated parameters of the logistic coefficients for the (absolute) cumulative number of covid- cases, hospitalized patients, icu patients, and recovered patients. all coefficients are highly significant, and a functional form is thus obtained to develop an estimation. figure b plots these functional forms, as well as the real data and a forecast for the next two weeks. since the fit between the functional forms and the real data is excellent, the forecast can be expected to be quite reliable, and this will be used to propagate the beta regression and make forecasts for the ratio variables defined in eq. ( ). nevertheless, it should be stressed that the logistic prediction is based on the simple logistic model that we have described in section . and calculated for each variable separately. this gives a rather smooth prediction, with the drawback that any sudden variation in, for example, the number of hospitalized patients will not be accomodated by the next-day forecast for the number of icu patients. in that sense, the beta regression that we will describe next is more powerful, since it incorporates cross effects between the variables. logistic descriptions and predictions can also be made for each spanish region separately. these are developed in appendix d. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . in this section, a beta regression model is developed for the ratios hosp/cases, icu/hosp and icu/cases defined in eqs. ( a), ( b) and ( c). as independent variables, we consider the lags of the two first variables (i.e., their values one day before) as well as the recovery ratio (recovered patients over number of infections). the modelization also includes spatial patterns, temporal trends, and their cross effect through the precision coefficients. to confirm that a meaningful regression model can be built with the independent variables just described, a twofold consistency analysis is performed previously. first, it is verified that the correlations between the independent variables are weak or at most moderate (|r| < . ). second, a multicollinearity analysis shows that the vifs or variance inflation factors are low (vif < ) in all models, so there is no risk of meaningless overfitting [fox & monette ( ) ]. for this reason, the model does not include the lag of the third ratio, icu/cases, since-as mentioned above-this can be obtained as the product between hosp/cases and icu/hosp, and it is thus easy to understand that it is strongly correlated with both, and thus leads to multicollinearity and high vif problems. further details are given in appendix e. a crucial element of the model is the precision parameter φ, defined in eq. ( ) and discussed in section . . this precision parameter determines the variance of the beta distribution, and thus the reliability of the forecast. it can be taken either as a global parameter (a single φ for the whole distribution), as dependent on temporal effects only (φ evolves with time from the onset of the epidemics), as dependent on spatial effects only (a separate φ i for each region i), or a mixed model which includes both temporal and spatial effects. both the aic and the bic criterion indicate that in two of the three cases the mixed model is by far the best, in spite of the fact that it has the highest number of parameters (and thus is the most penalized), i.e.: both spatial and temporal effects are sufficiently relevant and should be taken into account. in the third case (icu/hosp), the mixed-effect model is slightly outperformed by the spatial-effects-only model, but since the difference is tiny we also apply a mixed-effect model here. details of the aic and bic are given in appendix f. table shows the coefficients obtained for the beta regression model of the study variables. the precision coefficients are given in appendix c. the very high significance levels and pseudo-r values indicate that the obtained beta regressions provide excellent models for the empirical data. this is confirmed by the application of the model to the data for spain as a whole, as shown in fig. , as well as for the regions separately, see appendix g. the incidence of the factors considered is quite different. for the hosp/cases ratio, the lagged value of hosp/cases itself is much more important than the lagged value of icu/hosp, and vice versa, which seems reasonable. for the third ratio, icu/cases, the contribution of both lagged values is of the same order of magnitude. the recovery rate, finally, has a small but statistically significant influence on the various ratios. curiously, this influence is in fact positive on the icu/hosp ratio: an increment in the recovery rate leads to a (small) increase in the icu/hosp ratio. this can probably be understood as follows: patients who are considered "recovered" in the early phase of the epidemic are likely to come from the "light" (non-icu) category of patients. removing them from the pool of hospital patients therefore automatically increases the relative share of severe (icu) cases. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . the complete list of the precision coefficients φ i is given in appendix h. here, we limit ourselves to some general observations. the spatial patterns are highly significant for a majority of the spanish regions, for all three ratios. the temporal trends are highly significant for hosp/cases and icu/hosp, but not for icu/cases. the cross effects (spatial and time) are, again for all three ratios, highly significant for a majority of the spanish regions. with respect to their concrete incidence, it is striking that the cross effects for each single region are negative with respect to hosp/cases and positive (with one single exception) with respect to icu/cases. we don't have a straightforward interpretation for this phenomenon, but the main conclusion is that space-time cross effects are relevant for the determination of the precision parameter, and hence for the beta regression model in general and its dispersion in particular. figure plots the mixed beta regression models for the three ratios for the period until -apr. this mixed model (with space-time cross effects) is seen to adjust very closely to the real data, and so will be used next to make forecasts. figure represents the next-day prediction for the three ratios according to the beta regression results. the horizontal plane of this d plot represents all possible lagged values of the hosp/cases and icu/hosp ratios (on a scale from to ), i.e.: the previous values of . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint these variables (at a lag of day). the vertical axis then shows the beta regression prediction for the dependent variable day later, from left to right: hosp/cases, icu/hosp and icu/cases. in this prediction, for graphical convenience, a single constant recovery rate is assumed, namely %, which is the mean recorded by the study database. obviously, this prediction can be further improved numerically by adjusting this recovery rate. once this has been established, the main point of interest is to make predictions for the real data for each ratio. this is represented in fig. . two predictions are plotted here for the period -apr to -apr: the next-day predictions based on the real data, and a prediction based on the logistic forecast of the number of diagnosed, hospitalized, icu patients and recovered cases. in other words, to calculate the prediction for, for instance, -apr, the real-data next-day prediction is based on the beta regression prediction obtained from the recorded ratios -apr, whereas the logistic forecast uses the recorded data only up to -apr, propagates this into a logistic forecast up to -apr, which is then fed into the beta regression to obtain a prediction for the ratios on -apr. as can be seen, the next-day predictions are extremely close to the real data. the multipleday prediction obtained through the fitted values from the logistic expression of table a shows a stronger difference with respect to the real values. however, both in relative and in absolute terms this difference is still very reasonable (or said in other words, the scale of the graphs is strongly adjusted to the range of values, which might lead one to visually overestimate the error). figure : prediction of the three ratios hosp/cases, icu/hosp and icu/cases for spain as a whole based on the beta regression and comparison with real data for the period -apr to -apr. in all three figures, the y-axis range is strongly adjusted to the range of values. nevertheless, it is worth analysing the origin of these differences between the logistic-based beta regression and the real data. first, there is the intrinsic fact that this forecast is used for a prediction several days ahead, whereas the real-data prediction uses the empirical data . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . from the day before and so is much more cautious. however, the main reason for the differences lies in the poor quality of the data. two issues stand out here. first, the different regions have used different criteria and methods to count the number of cases. second, these criteria have even been changed precisely in the period that we use to make our prediction, which is particularly obvious from the jump in fig in the first few days of the prediction. obviously, this makes it highly complicated to make any accurate predictions, and makes it very difficult for hospital managers to make any reasonable planning. the simple logistic model that we have used (see also appendix a) is particularly vulnerable to this, since it does not adapt from one day to the next, which also contributes to the relatively large errors shown in fig . more advanced logistic models, see e.g. [wu et al. ( ) ] could be used to predict the absolute numbers of cases, and derive from it a beta prediction for the ratios that we have studied. finally, it should be stressed that the logistic-based forecast gets the slope essentially correct, and in fact even ascertains the correct value within an error margin of roughly % over the complete time range of prediction performed here (i.e., days). this illustrates the robustness and usefulness of the methodology. the predictions are further specified by region in appendix i. logistic models are the most commonly used statistical models for the study of epidemic evolution. in this article, we have discussed how these can be complemented through the use of beta distribution and regression models. beta models are useful for variables whose values are limited to the range [ , ] and are thus naturally suited to describe proportions. in particular, we have described how they can be used to describe the ratio between hospitalized patients and diagnosed cases (hosp/cases), between icu patients and hospitalized cases (icu/hosp), and between icu patients and diagnosed cases (icu/cases). these variables are particularly relevant for hospital management in the early phase of an epidemic crisis such as the one that we are currently experiencing due to the covid- virus. indeed, these ratios are indicators of the strain put on hospital resources in general, and of icu units in particular. moreover, they have the advantage of being scale-independent, and therefore adaptable to any hospital or region of any population size. they can thus help in planning contingency measures, making resource estimates, and reserving hospital capacity across all hospitals in a given region or country, independently of size. they also provide a robust way of planning the distribution of temporary facilities dedicated exclusively to the epidemic. the beta regression model developed here depends on the -day lagged value of the hosp/cases and icu/hosp ratios, as well as the patient recovery rate. the lagged value of the third ratio, icu/cases, was not used in the model as it would lead to dependency and multicollinearity issues. it was also shown that the most performant model includes mixed space-time effects in the precision coefficient of the beta distribution. these precision coefficients are indicators of (inverse) variance, and allowing them to vary across regions and along time thus allows to minimize the resulting variance. this model has been applied to the early-phase covid- epidemic in spain. it has been shown that next-day predictions for these ratios based on a beta regression model are extremely reliable. for longer-term predictions, the error was obviously larger. the main cause of this error was pinpointed to lie in the lack of consistency and reliability of data in this early phase of the epidemic. this became obvious even at the spanish level: different regions have used different criteria to count covid- cases, possibly also of counting covid-related hospitalized and icu patients, and have even changed their criteria during the crisis. this renders highly difficult a serious statistical analysis of the situation, and more importantly: makes it highly difficult to make serious hospital management predictions and provisions. in this sense, universal guidelines on how to collect, classify and publish data for such pandemics, for example issued by the who, might be useful. nevertheless, the methodology has been shown to be rather robust against these difficulties and to provide relatively reliable forecasts. in particular, for a -day prediction from -apr to -apr, . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . the logistic-based beta regression still gets the slope essentially correct, and the concrete values obtained for the three ratios that were analysed remain within an error margin of % compared to the real data. finally, it should be pointed out that the spanish ministry of health has in the meantime issued updated data. we plan to apply the method developed here on these updated data sets. in particular it would be interesting to see whether propagating the beta regression without the auxiliary logistic step leads to reliable and robust predictions of the ratios when applied to such updated and more realistic data. in this appendix, we briefly review basic mathematical population growth models and how these can be solved with differential equations, see e.g. [boyce & diprima ( ) ]. imagine a population n (e.g., number of infected) which increases with time t at a rate r proportional to the existing population (existing number of infected): the solution is n (t) = n e rt where n = n (t ) represents the initial population. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . taking the (natural) logarithm on both sizes, this can also be written as ln n n = rt or, for any time difference: the main drawback of this model is that it does not include saturation effects. as a population grows larger, competition for resources (such as food) come into play. if the considered model regards a subpopulation (e.g., number of infected), the growth rate could also decline because of the corresponding decrease in the pool of non-infected population members, or because of sanitary counter-measures and forced social distancing. such saturation effects can most simply be modelled as a negative quadratic influence, i.e.: this is structurally identical to the well-known logistic equation, whose solution is therefore the logistic or verhulst function, which in this case can be written as where c = n r−n b . in the long term the population tends to the (stable) value regardless of the initial population n . by defining k = r/b, the expression given in eq. ( ) is found. the function ( ) has the typical sigmoid (s-shaped) form seen in fig. b . finally, let us briefly look at the case in which one is interested in a proportion between two populations. assume that both are described by a simple exponential evolution as described above the ratio z ≡ n m then follows z(t) = z e (r −r )t where z = n /m . only if both populations grow at exactly the same rate (r = r ), a non-exponential result is found, namely the constant ratio likewise, it can be shown that the inclusion of saturation effects will still lead to a logistic function for the ratio of populations. b beta distribution for spain: comparison of model with data figure compares the beta distribution obtained as a fit for the three ratios, hosp/cases, icu/hosp and icu/cases. in each case, the top-left plot provides a comparison between the functional form of the proposed models and the empirical cumulative distribution. the top-right graphs show the corresponding histograms. the two bottom figures represent the q-q and p-p plot, i.e. a comparison between theoretical and empirical values in terms of . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . quantiles (left) and of probabilities (right). the agreement in all cases is excellent, with the exception of t the apparent discrepance in the q-q plots at high ranges is an artifact of this quantile representation, as can be seen from the other graphs. all in all, the agreement between the models and the empirical data is excellent. in each case, the solid line represents the theoretical beta distribution model, the dots (or bars, in the case of the histogram) the empirical data. section . contained the beta distribution analysis for spain as a whole. fig. similarly shows the beta distribution and cumulative density function for each region separately. there is a relatively large variety of slopes and patterns. this can be seen for the ratio hosp/cases, which is more extended in madrid, catalonia, or castilla-león than in other regions, and especially than in aragon (ar), murcia (mc) or navarra (nc). it is also true for the ratio icu/hosp, which has a rather large spread in extremadura (ex), canary islands (cn) or castilla-león (cl), and is much more peaked in madrid (ma), andalusia (an) or aragon (ar). the ratio icu/cases, finally, looks more homogeneous across the regions, with a sharp peak at low values. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , june , . . https://doi.org/ . june , / doi: medrxiv preprint figure a , of hospitalized patients in figure b , icu patients in figure c and recovered patients in figure d . in each figure, the red line represents the real data (as previously, obtained from [ministerio de salud ( )] up to -apr, and the blue line describes the values according obtained from the logistic functional form, region per region, which are extended to a prediction up to -apr. in most cases, the fit between the model and the real data is excellent, especially in the early period studied. in some regions, such as extremadura (ex), castilla-la mancha (cm) or valencia (vc), the empirical pattern changes rather abruptly towards the end of the recorded data, and this leads to larger differences between the model and the data. as mentioned in the main text, this is most likely due to a change in the counting methodology or classification criteria adopted by the regions during this period, which becomes particularly clear in the (temporary) decline in the empirical data in some of the regions, even though these represent cumulative numbers. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , june , . . https://doi.org/ . june , / doi: medrxiv preprint . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . when constructing a regression model, it is important to verify that the correlation between all possible pairs of variables are low, and that there are no multicollinearity problems. otherwise, this could lead to meaningless overfitting and spurious results. the correlation matrix in fig. a shows that all pairs of variables show adequate correlation values (r < . ) and can therefore be used in the regression model. the vif (variance inflation factor) for each model (no effects, temporal effects only, spatial effects only, mixed space-time effects) are shown in the table of fig. b . low values are obtained in every model (vif < ), so the models avoid the multicollinearity problem. note that the inclusion of the lagged value of icu/cases has also been considered, but since this presented high vif values as well as strong correlation with the other variables, it has not been withheld as an independent variable. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint g beta regression model per spanish region fig. g shows the beta regression model using mixed space-time effects and a comparison with the empirical data for each ratio and for each spanish region separately. it can be seen that there is a wide diversity of patterns across the regions. however, the beta model adjusts to all of them, in most cases to an excellent degree. because of the results of the aic and bic analysis, see appendix f, the beta regression model assumes that the precision parameter is not constant, but depends both on the evolution of time and on the concrete spanish region, as well as on space-time cross effects. these precision coefficients by time and region, as well as their cross effects, are listed in table . note that most coefficients are significant only for two (or exceptionally even only one) of the ratios. however, overall, each block is highly significant, at least for a majority of the regions. this is in agreement with the result of the aic and bic analysis just mentioned. to illustrate this, when looking at the temporal patterns, these are not significant for icu/cases, but they are highly significant for both hosp/cases and icu/hosp. an analogous observation applies to the spatial coefficients: for most regions, the spatial coefficient . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . is not significant for one of the ratios -for aragon (ar), cantabria (cb) and navarra (nc) even for two of the ratios. however, they are highly significant for the two other ratios -or the single remaining ratio for the three regions just mentioned. the significance of the cross effects could be detailed in a similar way. fig. shows forecasts per spanish region for the three ratios hosp/cases, icu/hosp and icu/cases. it shows similar strengths and weaknesses as fig. for spain as a whole. the next-day prediction based purely on the beta regression using the -day lagged ratios is excellent in almost all cases. the multiple-day prediction based on the logistic forecast is quite good for most variables in most regions, although there are some cases with a relatively wide difference. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . information theory and an extension of the maximum likelihood principle epidemiology and transmission of covid- in cases and of their close contacts in shenzhen, china: a retrospective cohort study a bayesian logistic growth model for the spread of covid- in new york elementary differential equations probabilistic prediction of covid- infections for china and italy, using an ensemble of stochastically-perturbed logistic curves maternal health care management during the outbreak of coronavirus disease (covid- ) staff safety during emergency airway management for covid- in hong kong fitting dynamic models to epidemic outbreaks with quantified uncertainty: a primer for parameter uncertainty, identifiability, and forecasts excess cases of influenza suggest an earlier start to the coronavirus epidemic in spain than official figures tell us: an analysis of primary care electronic medical records from over million people from catalonia beta regression in r an interactive web-based dashboard to track covid- in real time beta regression for modelling rates and proportions generalized collinearity diagnostics use of the beta-binomial distribution to model the effect of policy changes on appropriateness of hospital stays responding to covid- : the uw medicine information technology services experience spatial-temporal distribution of covid- in china and its prediction: a data-driven modeling analysis longitudinal beta regression models for analyzing health-related quality of life scores over time mathematical modeling of the spread of the coronavirus disease (covid- ) taking into account the undetected infections. the case of china. communications in nonlinear science & numerical simulation the reproductive number of covid- is higher compared to sars coronavirus evolución diaria de la pandemia de covid- en españa. spanish ministry of health, consumer affairs and social welfare total covid- mortality in italy: excess mortality and age dependence through time-series analysis. preprint from medrxiv intelligent assessment based on beta regression for realistic training on medical simulators. knowledge-based systems a flexible growth function for empirical use estimating the dimension of a model estimation of population infected by covid- using regression generalized logistics and optimization heuristics generalized logistic growth modeling of the covid- outbreak in provinces in china and in the rest of the world infection control against covid- in departments of radiology parametric regression model for survival data: weibull regression model as an example acknowledgments g.j. acknowledges project fis - -c - -p of the spanish micinn. key: cord- -d i m l authors: hashmi, madiha; taqi, arshad; memon, muhammad i.; ali, syed muneeb; khaskheli, saleh; sheharyar, muhammad; hayat, muhammad; shiekh, mohiuddin; kodippily, chamira; gamage, dilanthi; dondorp, arjen m.; haniffa, rashan; beane, abi title: a national survey of critical care services in hospitals accredited for training in a lower-middle income country: pakistan date: - - journal: j crit care doi: . /j.jcrc. . . sha: doc_id: cord_uid: d i m l purpose: to describe the extent and variation of critical care services in pakistan. materials and methods: a cross-sectional survey was conducted in all intensive care units (icus) recognised for postgraduate training to determine administration, infrastructure, equipment, staffing, and training. results: there were hospitals recognised for training, providing icu beds and ventilators. regional distribution of icu beds per , population ranged from . in sindh to none in gilgit baltistan (median . ). a senior clinician trained in critical care was available in ( . %) of units. one to one nurse to bed ratio during the day was available in ( . %) of units, dropping to ( . %) at night. availability of : nursing also varied between provinces, ranging from . % in punjab compared to % in azad jamu kashmir. similarly there was disparity in availability of ventilators between provinces. all icus had basic infrastructure (electricity, running water, piped oxygen) and basic equipment (electronic monitoring and infusion pumps). conclusion: pakistan, a lower middle-income country, has an established network of critical care facilities with access to basic equipment, but inequalities in its distribution. investment in critical care training for doctors and nurses is needed. baltistan (median . ). a senior clinician trained in critical care was available in ( . %) of units. one to one nurse to bed ratio during the day was available in ( . %) of units, dropping to ( . %) at night. availability of : nursing also varied between provinces, ranging from . % in punjab compared to % in azad jamu kashmir. similarly there was disparity in availability of ventilators between provinces. all icus had basic infrastructure (electricity, running water, piped oxygen) and basic equipment (electronic monitoring and infusion pumps). conclusion: pakistan, a lower middle-income country, has an established network of critical care facilities with access to basic equipment, but inequalities in its distribution. investment in critical care training for doctors and nurses is needed. keywords: critical care resources; critical care services; critical care staffing; lower middle-income country. demand for critical care services continues to grow internationally. resources remain limited, most notably in low and lower-middle income countries (llmics). in south asia, overall improved public health and primary healthcare services in the region, the growing burden of noncommunicable disease, and with it a demand for surgical and trauma care has resulted in a shift in health systems priorities [ , ] . there is thus an increasing demand for critical care services, and the associated human resources, infrastructure and equipment requirements in llmics. understanding the landscape of existing infrastructure, equipment and staffing both between and within countries provides valuable information for those seeking to strengthen critical care services and inform disaster and pandemic planning; including during the current global spread of covid- . furthermore, mapping critical care services to the clinical characteristics of the patient it serves is a fundamental step in evaluating quality of existing service provision and to identify priorities for research and quality improvement. sri lanka was the first country in south asia to undertake a comprehensive national survey of critical care services [ ] . since then, regional efforts to map critical care services in asia have contributed valuable information regarding intensive care unit (icu) bed availability in the region [ ] . however, information regarding skills, training and organisational processes (essential to developing strategies for improving the quality of care) remains absent. the pakistan registry of intensive care (price) [ ] , a cloud-based surveillance platform, currently supports a network of icus in pakistan recording over monthly critical care admissions. price provides near real-time reporting on the epidemiology, severity of illness, treatment, microbiology and outcomes of icu patients, alongside information regarding work force, unit occupancy, unit acuity, and resource utilisation. this information is used to drive local service evaluation and quality improvement interventions. price is a founding member of the recently established wellcome-moru-crit care asia (cca). this paper details a national survey of critical care services in pakistan including organisational structures, equipment, infrastructure and training capacity. an icu was defined as a clinical area (excluding operating theatres) which had the ability to provide organ support for in-patients, including mechanical ventilation. all hospitals recognised by the pakistan medical and dental council (pmdc) for internship training or the college of physicians and surgeons pakistan (cpsp) for postgraduate residency training in anaesthesia, internal medicine, general surgery, cardiac surgery, pulmonology, nephrology, cardiology or critical care medicine were contacted by telephone by mh. all such hospitals were invited to participate in the survey if they reported the presence of at least one adult icu. eligible hospitals were asked for the number of adult icus, number of ventilators and asked to nominate a senior icu doctor or sister in charge to respond to the survey questions. if a nominated contact was unavailable, at least one follow-up call was made for each icu. the surveys (supplementary file ) were administered by telephone or online between february and december . all responses were included in the analysis. the survey instrument including characteristics and organizational structure, infrastructure and human resources was based on the tool pioneered in south asia by our group [ ] . population per region was obtained from the government census up to january from publicly available sources [ ] . icus were defined as open, in which the primary specialty had primary responsibility for admission, treatment, and discharge decisions with optional consultative input from an intensivist, or closed, in which the intensivist had primary responsibility or there was a shared model of care between primary specialty and the intensive care team [ ] . one hundred and fifty-one hospitals were identified, of which did not have a icu and were therefore excluded. all eligible hospitals reported their icu bed and ventilatory capacity. two hundred and twenty icus were identified in these hospitals providing critical beds and ventilators. of these icus, ( . %) units containing a total of beds completed the full survey of organisational structure, infrastructure, equipment and human resources. of the remaining icus, icus had no designated in charge and a further were not available for interview ( figure ). table summarizes the main characteristics of the hospitals surveyed. the density and distribution of icu beds within teaching institutions (total and per population) by administrative regions is described in table access and organisational structure average beds within teaching institutions per , population was . (total number of icu beds in participating institutions divided by the total population of pakistan), ranging from in gilgit baltistan to . in sindh. the median number of critical care beds per unit was ( , ) . a total of ( . %) icus were managed directly by the government and ( . %) of units were managed by the private sector, with the remainder being administered by not-for-profit organisations ( . %). fifty-seven ( . %) of the icus surveyed reported a 'closed' model of care. unrestricted visiting for families was practiced in ( . %) of units (table ) . ventilator to bed ratio of : was observed in ( . %) of the icus (table ) , with punjab province having the greatest number ( . %) and azad jamu kashmir the lowest . all icus had a telephone line, however, only . % had access to the internet. table summarises the availability of equipment to monitor critically ill patients. almost all icus ( . %) had access to : non-invasive j o u r n a l p r e -p r o o f multiparameter monitoring. invasive arterial monitoring and capnography was available in ( . %) and ( . %) icus respectively. in addition, ( . %) and ( . %) units had access to point-of-care haemoglobin and lactate measurement respectively. isolation rooms essential for management of infectious diseases, including severe acute respiratory infections, were available in ( . %) icus, ( . %) of which were in private institutions. human resources, team structure and training opportunities table summarises the human resources, team structure and training opportunities. a senior clinician (in charge) trained in critical care was available in only ( . %) of units surveyed. the majority of units ( , . %) were overseen by a consultant anaesthetist (defined as an anaesthetist who has completed higher training in their speciality). in the remainder, . % were overseen by a consultant internal medicine physician and . % by a consultant surgeon. a non-consultant doctor was assigned to icu round-the-clock with no other work commitments in ( . %) of icus. of the institutions surveyed, ( . %) were recognised by the college of physicians and surgeons for speciality training (residency training). critical care medicine (ccm) fellowship training was offered by ( . %) of institutions. the majority of intensive care units were managed by registered nurses with general training ( . %), with the remaining ( . %) being managed by technicians trained in anaesthesia or critical care. one to one nurse to bed ratio during the day for ventilated patients was available in ( . %) of units, and in ( . %) of units for self-ventilated patients. at night this availability dropped to ( . %) and ( . %) respectively. availability of : nursing also varied between provinces, ranging from . % having a : availability in the punjab compared to % in azad jamu kashmir. similarly, availability of : nursing, already limited during the day, further reduced at night (table ). microbiologists and haematologists were accessible in ( . %) and ( . %) of units respectively. health care assistants or trained technicians were part of the care provision team in ( . %) of icus. radiology technicians were available in ( . %) units and a further ( . %) icus had access to physiotherapy services. this national survey from pakistan reports very limited critical care bed availability but where available icus are well resourced with basic equipment for invasive ventilation and monitoring. it further highlights the lack of critical care trained staff and the need for urgent investment in critical care services to address this gap in training capacity if care is to be improved. the number of critical care beds in llmics are known to be lower when compared to higher-income countries [ , ] , this disparity is pronounced in pakistan in comparison to neighbouring countries: at . per population, it is lower than sri lanka ( . critical care beds per , ), nepal ( . ) and india ( . ) [ ] . the survey further identified a wide disparity in access to critical care beds between the provinces (figure , lower panel) . punjab, whilst being the most densely populated province of the country, has lower availability of critical care beds than neighbouring sindh. similar disparity exists between major cities in each province ( table ) . as urbanisation and migration to cities for employment continues in pakistan, and as the burden of non-communicable disease rises -including road traffic j o u r n a l p r e -p r o o f accidents and multimorbidities, it is a national priority to address the disparity in access to critical care services [ ] . icus in both public and private sector institutions (including not-for-profit) had the basic infrastructure (electricity and a backup generator, piped oxygen, medical air and suction, infusion and syringe pumps), and basic monitoring (non-invasive multiparameter monitor, mercury thermometer, and manual cvp measurement). overall ventilator to bed ratio was : . , meaning out of every icu beds have the facility to mechanically ventilate. availability of these resources is reassuring, and suggests that the provision of the mainstays of critical care organ support-ventilation therapy, basic cardiovascular monitoring and support, and delivery of fluids is possible. however as with access to icu beds, availability of ventilators is not uniformly available within each region (supplementary file ) . the safe and effective delivery of these therapies, however, relies not only on the availability of equipment, but on specialist trained staff with the skills to instigate, titrate and troubleshoot treatment. in contrast to the specific resources of critical care described above, sinks for hand washing were absent in . % of icus and access to isolation rooms or cubicles to control cross infection with negative/positive air exchange mechanism was available in just . % of icus, the majority of which were private sector tertiary care hospitals in the major cities. addressing the absence of facilities for infection control is perhaps a key priority for those seeking to improve critical care services in the country, given the increasingly important role critical care plays in the preparation and management of seasonal epidemics (including severe acute respiratory infections-sari) and in the rising burden of drug resistant infections. furthermore, access to point-of-care (poc) measurements including lactate haemoglobin, and availability of invasive haemodynamic monitoring, which are increasingly seen as essential resources for the management of critical illness, is lacking [ , ] . only ( . %) of units had access to poc lactate and just ( . %) could invasively monitor haemodynamics. as pakistan seeks to improve diagnosis and management of critically ill patients with sari, sepsis and following trauma, better access to poc services and invasive monitoring, along with specially trained staff to interpret and respond to this information, is essential. just of the icus surveyed had trained intensivists. critical care has been a recognised speciality in pakistan with a structured training programme since , however, at the time of this survey, only six institutions out of teaching institutions (excluding military sites) were recognized by the college of physicians and surgeons of pakistan for critical care medicine training [ ] . these figures are much lower than estimates from south asia, latin and north america [ ] [ ] [ ] . to date, just twenty-seven fellows have obtained the fellowship from the college in critical care medicine [ ] . many currently practising intensivists in icus still have to travel outside of pakistan for their higher training fellowships. low intensivist to patient ratios (< : ) in academic medical icus have been cited as a barrier to delivery of quality of care and having a detrimental effect on staff well-being, specifically to the quality of professional mentorship available for rotating trainees, who may consider specialising in ccm [ ] . lack of specialist training opportunities may be perpetuating the low numbers of designated critical care doctors on-call in icus and the low percentage of icus which are led by a trained intensivist. lack of training opportunities extends beyond doctors, with only . % of nurses in charge of icus having j o u r n a l p r e -p r o o f received any formal training in intensive, critical or cardiac care. access to microbiologists, specialists who are increasingly considered fundamental to the interdisciplinary management of critically ill patients, was limited ( . %). whilst there is growing evidence to support that intensivist-led patient management is associated with better patient outcomes and greater compliance with broadly accepted indicators of critical care quality [ ] , a closed model was uncommon in the icus surveyed ( . %). furthermore of those icus reporting a closed structure, only had a trained intensivist as their clinical lead. investment in the reorganisation of critical care services to improve operational efficiency and patient outcomes (length of stay, duration of mechanical ventilation) in icus has resulted in a shift toward closed organisational structures whereby admission to and management of patients within the icu is coordinated by designated critical care clinicians [ ] . given the paucity of critical care services in pakistan, such a model of management may promote effective resource utilisation. however, such models require national level investment in specialist training, and institution level investment in hiring and retaining such a specialist workforce. other settings have demonstrated how investment in critical care trained clinician staff to lead units and investment in training for nurses working in critical care has positively impacted on safety within icus and outcomes for critical care patients. without this investment, efforts to strengthen specialist capacity and improve quality of critical care services through research and implementation will be hindered. this survey only approached institutions recognised for specialist teaching. consequently. the number of icu beds per , population is underestimated. a recent multicountry snapshot of critical care bed availability [ ] , to which pakistan contributed, reported a national average in pakistan of . beds per , population. however, such estimates included units which may have no recognised affiliation with critical care training and no support from critical care societies. whether considering the numbers reported here, or the estimates from those with broader inclusion, icu bed availability and trained, skilled staff is still lower than neighbouring countries. pakistan has no central register or standard definition for icus and as such units may be operating without the support of trained intensivists. this survey provides a detailed landscape of critical care resources and training institutions recognised by the pmdc and cpsp in pakistan. pakistan has an established network of critical care facilities with access to basic equipment but inequalities in access within and between provinces is prominent. investment in critical care training for doctors and nurses is a key priority for the country. investment in training for health care staff will likely enable efforts to improve safety within icus, accelerate opportunities for research and quality improvement. • critical care services are well established in pakistan. • all intensive care units have access to basic equipment for essential critical care. • inequity exists in access to critical care within and between regions. • investment in specialist training for doctors and nurses is an urgent priority. j o u r n a l p r e -p r o o f j o u r n a l p r e -p r o o f intensive care unit capacity in low-income countries: a systematic review health systems and services: the role of acute care pakistan registry of intensive care (price): expanding a lower middle-income, clinician-designed critical care registry in south asia a cross-sectional survey of critical care services in sri lanka: a lower middle-income country physician staffing pattern in intensive care units: have we cracked the code? the variability of critical care bed numbers in europe trends in critical care beds and use among population groups and medicare and medicaid beneficiaries in the united states critical care bed capacity in asian countries and regions sepsis and septic shock the european guideline on management of major bleeding and coagulopathy following trauma: fifth edition accredited institutions. college of physicians and surgeons pakistan n intensivists in u.s. acute care hospitals structure, organization, and delivery of critical care in asian icus organizational issues, structure, and processes of care in icus in latin america: a study from the latin america intensive care network list of good standing fellows. college of physicians and surgeons pakistan intensivist/patient ratios in closed icus: a statement from the society of critical care medicine taskforce on icu staffing a framework to enhance clinical operations, development of institutional policies, and further research the authors would like to thank all members of the critical care community in pakistan who contributed to this work with the shared goal of improving critical care services in the country. we would also like to thank dr t tolppa for his support with manuscript preparation, and mr t rashan for support with figures. the authors declare that they have no competing interests. key: cord- - qnymo authors: dos reis, helena lucia barroso; boldrini, neide aparecida tosato; caldas, joão victor jacomele; da paz, ana paula calazans; ferrugini, carolina loyola prest; miranda, angelica espinosa title: severe coronavirus infection in pregnancy: challenging cases report date: - - journal: revista do instituto de medicina tropical de sao paulo doi: . /s - sha: doc_id: cord_uid: qnymo there are few data on the impact of covid- in pregnancy, however, analyzing these data is important to guide the clinical practice, covering the early prevention, detection, patients’ isolation, epidemiological investigation, diagnosis and early treatment. this is a report of three cases of covid- confirmed by real-time reverse transcription – polymerase chain reaction (rt-pcr) of nasopharyngeal secretions collected in swabs from pregnant women in the city of vitoria, espirito santo state, brazil. in the three cases, all the patients presented with fever, one had shortness of breath, one had diarrhea, two of them reported abdominal pain and two of them had cough. the three patients progressed with a severe clinical evolution of covid- . the permanence in the intensive care unit (icu) was more than days. two of them recovered and one remained in the icu with irreversible refractory shock, multiple organ failure and died. the mode of delivery was individualized and based on the obstetric indication and severity of the maternal infection, and the cesarean section was indicated in the two severe maternal covid- cases that evolved favorably. these newborns were premature and tested negative for covid- by rt-pcr. a new coronavirus known as the severe acute respiratory syndrome coronavirus (sars-cov- ) was reported in and associated with pneumonia, causing a disease known as the coronavirus disease covid- . it is an emergent infectious disease that was first documented in wuhan, china, and the world health organization (who) has declared it a global public health emergency and a pandemia . studies on the effects of covid- during pregnancy are limited; however, owing to the high transmissibility of the virus and the possible development of severe acute respiratory symptoms, it is crucial that covid- is investigated in the routine clinical practice of obstetrics. pregnant women represent an important challenge in the course of the pandemic. these patients need to attend to at least monthly medical consultations throughout the course of their prenatal care visits and for the delivery . these appointments place them at a higher risk of contracting covid- at the hospital environment or in outpatient clinics, although at this moment, the impact of covid- on pregnancy and on newborn infants remains unclear. a chinese study which tested amniotic fluid, cord blood, neonatal throat swabs, and breast milk samples from covid- -infected mothers found that all the samples tested negative for the virus, and another study determined that three placentas of pregnant women infected by covid- tested negative for the virus , . however, the transmission rates from mothers to the newborns remain unknown. assessment of clinical data to better understand the effects of covid- in obstetrics will provide an opportunity to protect pregnant women, their offspring and the healthcare teams involved in their care. this study reports three cases of covid- comprising pregnant women with severe respiratory failure and evaluates the clinical management of covid- infection in obstetric clinics in vitoria, espirito santo state, brazil. a -year-old pregnant woman who worked as a nursing assistant, was a primigravida with weeks of gestation age who sought the emergency unit with fever and hyperemic lesions in the right lower limb, suggestive of a bacterial skin infection. the patient did not smoke or report a prior history of asthma, tuberculosis or pneumonia. treatment was initiated with intravenous ceftriaxone ( g) associated with iu per day of heparin, though after two days, the patient began to exhibit acute dyspnea. the room oxygen saturation was found to be %, and symptoms were accompanied by tachypnea and hypotension. fifteen liters of oxygen per minute were provided by mask, and the patient was transferred to the intensive care unit (icu) of another public institution. she was admitted in critical conditions requiring urgent intubation and mechanical ventilation. the lactate dehydrogenase (ldh) was u/l, d-dimer less than ng/ml (normal values below ng/ml) and , white blood cells (wbc). computed tomography (ct) scans revealed bilateral patchy ground glass opacities, and the patient was considered as a suspicious case of sars-cov- infection. considering the ct findings and the severe evolution in the third trimester of gestation, she was medicated with mg azithromycin per day, mg oseltamivir phosphate twice a day and mg hydroxychloroquine twice a day for five days, in addition to the ventilation support. pulmonary embolism was excluded by using specific diagnostic tests. she tested negative for coronavirus by the real-time reverse transcription polymerase chain reaction (rt-pcr) testing nasopharyngeal secretions swabs during the initial hospitalization. owing to the severe clinical conditions, a cesarean section (c-section) was performed. a healthy -week gestational age infant, weighting , g, was delivered and transferred to the neonatal care unit because of the prematurity, the apgar score was on the st minute of life and on the th minute and the preterm newborn was adequate for gestation age. the puerperal woman remained hospitalized for days in the intensive care unit (icu) due to her respiratory conditions, receiving supportive care. the patient tested positive for covid- by rt-pcr on the th day after hospitalization. the newborn tested negative for covid- by rt-pcr and was released after days. the puerperal woman evolved favorably and was discharged without sequelae after days. a -year-old puerperal woman who was a housewife in her second pregnancy, with one previous delivery, sought the emergency unit on the fifth day after delivery owing to an acute respiratory insufficiency. she did not report abnormalities during the antenatal care or during hospitalization for delivery. her medical record showed that she gave birth by c-section at weeks of gestational age and gave birth to a female newborn, weighing , g, with an apgar score of and in the st and th minutes, respectively. the mother reported severe dry cough and acute dyspnea associated with lower back pain and mild fever occurring hours before the hospitalization. the chest ct scan was suggestive of viral pneumonia with an acute inflammatory feature compromising to % of the pulmonary parenchyma, but the findings were not suggestive of covid- . the angiotomograpy of the thorax was negative for pulmonary embolism and the oxygen saturation was %. the ldh was u/l, d-dimer less than ng/ml and the initial leukogram showed , wbc. the patient was medicated with ceftriaxone ( g/day), azithromycin ( mg/day), oseltamivir ( mg twice a day), and enoxaparin (initially with mg daily, with increments up to mg/day). the rt-pcr for sars-cov- was positive three days after the delivery, and hydroxychloroquine ( mg twice a day) was administered initially, followed by mg daily for five subsequent days along with meropenem ( mg three times a day) and vancomycin ( g twice a day). ceftriaxone was discontinued. afterwards, the patient's respiratory condition worsened, she remained in the icu in critical conditions with a persistent high fever that last days, receiving supportive care covering oxygenation, ventilation, and vasoactive drugs. the patient no longer needed the icu hospitalization following this period and was transferred to the rehabilitation ward. her husband and the newborn tested negative for covid- . a -year-old pregnant woman, who was a housewife in her third pregnancy and two previous deliveries, was referred to the hospital at weeks and six days of gestational age with upper respiratory symptoms, fever, myalgia, and diarrhea for five days. thereafter, the patient's clinical condition worsened to a non-productive cough and intense fatigue. she did not report comorbidities, but her husband presented with fever in the previous hours and reported contact with two coworkers that had positive tests for covid- . she was transferred to the icu. corticosteroid therapy with g hydrocortisone was initiated to accelerate the fetal lung maturation along with oseltamivir, azithromycin, ceftriaxone, and enoxaparin in standardized doses. the patient also needed mechanical ventilation. d-dimer levels were normal ( ng/ml), and pulmonary embolism was excluded using specific diagnostic tests. the oxygen saturation was % and the initial leukogram showed , wbc and % of lymphocytes. the covid- serological tests resulted negative twice, while the rt-pcr on nasopharyngeal swab secretions was positive for sars-cov- . hydroxychloroquine was initiated ( mg twice a day), followed by mg daily for five subsequent days. a c-section was performed owing to the critical conditions of the mother, as well as severe oligohydramnios. a female infant weighing , g, adequate for gestational age was delivered. the apgar score was on the st minute and on the th minute. the newborn tested negative for covid- by rt-pcr, but was referred to the neonatal icu because of the extreme prematurity, where she underwent a systemic antibiotic therapy owing to a right hemi thorax atelectasis. the neonate was released after days in good conditions. the mother remained in the icu for days, where she was treated with meropenem ( mg three times a day) associated with vancomycin ( g twice a day) and polymyxin-b, requiring intubation and mechanical ventilation. the ldh result went from u/l to u/l during the hospitalization. . despite the icu stay and a continuous epinephrine drip, the patient's blood pressure decreased to / mmhg and her condition evolved to irreversible refractory shock, multiple organ failure and death. the blood cultures were all negative. there is not yet unequivocal scientific evidence of mother-to-child transmission (mtct) of covid- ; whether a cesarean section could prevent transmission, whether vaginal delivery is free of additional risks, or whether the time of delivery should be anticipated , . current recommendations are that cases should be individualized according to the instruction of the obstetrician and the degree of severity of the maternal conditions . however, it is consensual that infection by the sars-cov- virus during pregnancy may increase the risk of maternal and fetal health deterioration because covid- is an infectious disease that can evolve to severe pneumonia and admissions to the icu, potentially resulting in the anticipation of deliveries before the pregnancy full term . this situation occurred in two of the three cases reported, in all the cases, the patients presented with fever and the patients' clinical conditions worsen quickly. the patients' icu hospitalization were all more than days. two of them recovered, and one remained in the icu and developed refractory shock, progressing to death. the newborns were premature in two of the three cases due to the need to perform the c-section, but none of the newborns presented symptoms of infection, and all three tested negative for covid- using rt-pcr that tested nasopharyngeal secretions. two of the newborns were only admitted to the icu because of their prematurity. table summarizes the findings in the three cases. in brazil, there are other suggested cases of maternal mortality due to covid- . it can also be noted that the conditions of the women infected with sars-cov- during pregnancy progressed within a short period from the infection transmission and incubation period. case was admitted with a suggested bacterial skin infection, and her condition progressed to pneumonia in a few days. a previous study in china described . % cases of covid- presymptomatic patients; they have also reported a mean interval of . days between presymptoms and the diagnosis . it is important to be attentive and perform a good anamnesis and physical examination to identify these situations. according to another chinese study, the characteristics of pneumonia in pregnant women with covid- do not differ from pneumonia in non-pregnant women. in a small group of nine infected pregnant women, there was no evidence of vertical transmission of covid- in those who acquired the virus and developed pneumonia at the end of the pregnancy. all the patients underwent a cesarean section and all the newborns were tested for the virus and had negative results . another study including confirmed covid- pregnant women in new york city reported a . % rate of critical illness; these data were similar to the ones described for non-pregnant adults with covid- infections . similar findings were also observed in a study of pregnant chinese women infected with covid- in which there were no maternal deaths or confirmed cases of intrauterine transmission of the infection to the fetuses , . in the three cases examined here, all the patients initially presented with fever; one had shortness of breath, one had diarrhea, two reported abdominal pain, and two had cough. all three patients' clinical conditions progressed rapidly. there are still gaps regarding the mtct and newborn infection; a case report of a pregnant woman with coronavirus infection and a newborn infected with sars-cov- hours after delivery was identified; however, confirmation of mtct was not established . a possible case of mtct was also described elsewhere, but the newborn's rt-pcr result was negative . children with covid- seem not to be frequently recognized, and most of those identified had only mild symptoms . in addition, a morphological placental study of a series of three neonatal cases of mothers infected with covid- found no changes related to the infection . unfortunately, amniotic fluid and placenta were not tested by rt-pcr in our cases. in the patients examined here, two of the newborns were premature because of the urgency of the c-section, but they did not present symptoms of the sars-cov- infection, indicating there was no mtct. it is also uncertain whether our institution's empiric administration of hydroxychloroquine enabled the patients' recovery (cases and ). currently, there is no official recommendation of chloroquine or hydroxychloroquine for covid- treatment. the use of these drugs in pregnant women should only be considered if their benefits outweight the adverse effects . an interesting finding in this study was that case was a health professional; this highlights the extra concern about the security measures regarding the protection of front-line workers from contamination. in brazil, the only study on covid- during pregnancy to date has been a review of initial data on pregnancy and the implications for assisted reproductive treatments; this study recommended postponing pregnancies . as covid- is a new challenge for health professionals and its impact on mothers and children is unknown, new studies are needed to understand the impact on pregnant women to generate evidence for improving its clinical management, treatment, and prevention. there is still no clinical evidence regarding the timing of delivery, vertical transmission, or the safety of vaginal delivery in pregnant women with covid- . the mode of delivery must be individualized, based on the obstetric indication, the severity of the maternal infection, and cesarean sections should be indicated in severe cases. to our knowledge, this is one of the first published reports on the death of a brazilian pregnant women with confirmed covid- infection. a novel coronavirus from patients with pneumonia in china expert consensus for managing pregnant women and neonates born to mothers with suspected or confirmed novel coronavirus (covid- ) infection clinical characteristics and intrauterine vertical transmission potential of covid- infection in nine pregnant women: a retrospective review of medical records pregnant women with new coronavirus infection: a clinical characteristics and placental pathological analysis of three cases maternal deaths with coronavirus disease : a different outcome from lowto middle-resource countries? serial interval of covid- among publicly reported confirmed cases covid- infection among asymptomatic and symptomatic pregnant women: two weeks of confirmed presentations to an affiliated pair of new york city hospitals an analysis of pregnant women with covid- , their newborn infants, and maternal-fetal transmission of sars-cov- : maternal coronavirus infections and pregnancy outcomes clinical analysis of neonates born to mothers with -ncov pneumonia a case report of neonatal covid- infection in china possible vertical transmission of sars-cov- from an infected mother to her newborn diagnosis and treatment of novel coronavirus infection in children: a pressing issue chloroquine and hydroxychloroquine during pregnancy: what do we know? a review of initial data on pregnancy during the covid- outbreak: implications for assisted reproductive treatments the authors have no conflict of interests to declare. the women had not identified their identity compromised. the ethical review board of the university hospital approved the study. this research did not receive any specific grant from funding agencies in the public, commercial, or not-forprofit sectors. key: cord- -sax qc authors: rosas, i.; bräu, n.; waters, m.; go, r. c.; hunter, b. d.; bhagani, s.; skiest, d.; aziz, m. s.; cooper, n.; douglas, i. s.; savic, s.; youngstein, t.; del sorbo, l.; cubillo gracian, a.; de la zerda, d. j.; ustianowski, a.; bao, m.; dimonaco, s.; graham, e.; matharu, b.; spotswood, h.; tsai, l.; malhotra, a. title: tocilizumab in hospitalized patients with covid- pneumonia date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: sax qc background covid- is associated with immune dysregulation and hyperinflammation. tocilizumab is an anti-interleukin- receptor antibody. methods patients hospitalized with severe covid- pneumonia receiving standard care were randomized ( : ) to double-blinded intravenous tocilizumab mg/kg or placebo. the primary outcome measure was clinical status on a -category ordinal scale at day ( , discharged/ready for discharge; , death). results overall, patients were randomized; the modified-intention-to-treat population included tocilizumab-treated and placebo-treated patients. clinical status at day was not statistically significantly improved for tocilizumab versus placebo (p= . ). median ( % ci) ordinal scale values at day : . ( . to . ) for tocilizumab and . ( . to . ) for placebo (odds ratio, . [ . to . ]). there was no difference in mortality at day between tocilizumab ( . %) and placebo ( . %) (difference, . % [ % ci, - . to . ]; nominal p= . ). median time to hospital discharge was days shorter with tocilizumab than placebo ( . and . , respectively; nominal p= . ; hazard ratio . [ % ci . to . ]). median duration of icu stay was . days shorter with tocilizumab than placebo ( . and . , respectively; nominal p= . ). in the safety population, serious adverse events occurred in . % of patients in the tocilizumab arm and . % of in the placebo arm. conclusions in this randomized placebo-controlled trial in hospitalized covid- pneumonia patients, tocilizumab did not improve clinical status or mortality. potential benefits in time to hospital discharge and duration of icu stay are being investigated in ongoing clinical trials. coronavirus disease (covid- ) has rapidly developed into a global health threat since emerging in china in late . severe covid- pneumonia, occurring in approximately % of patients infected with severe acute respiratory syndrome coronavirus- (sars-cov- ), is associated with high mortality rates and places extensive burden on intensive care units to provide mechanical ventilation and other advanced forms of life support. , similar to middle eastern respiratory syndrome and sars-cov- , an initial phase of with high viral replication precedes a second disease phase that may be driven by the host immune response. this can lead to rapid increase in proinflammatory cytokines, an uncontrolled inflammatory response, acute respiratory distress syndrome (ards), and multiple organ failure. , interleukin- levels correlate with covid- severity, , suggesting that, in this setting, immune dysregulation and ards might be influenced by interleukin- . , accumulation of lymphocytes and inflammatory monocytes, endotheliitis, apoptosis, thrombosis, and angiogenesis in the pulmonary vasculature of patients with suggests that vascular inflammation and dysfunction contribute to the pathophysiology of severe covid- pneumonia. , interleukin- promotes endothelial dysfunction and development of vascular permeability and might play a role in the vascular dysfunction of this disease. the potential role of interleukin- in covid- pneumonia , provides rationale for investigation of interleukin- signaling inhibitors. tocilizumab is a monoclonal antiinterleukin- receptor-alpha blocking antibody used to treat certain inflammatory diseases. improvements in patients with severe covid- pneumonia who received tocilizumab were observed in case reports [ ] [ ] [ ] and supported by retrospective observational cohort studies that showed rapid reduction in fever, reduced need for oxygen support and mechanical ventilation, and improvement in lung manifestations. [ ] [ ] [ ] [ ] [ ] [ ] . cc-by-nc-nd . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint this is the first global, randomized, double-blind, placebo-controlled trial to investigate whether tocilizumab has clinical benefit in hospitalized patients with severe covid- pneumonia. covacta is a global, multicenter, randomized, double-blind, placebo-controlled, phase trial investigating the efficacy and safety of tocilizumab in patients with severe covid- pneumonia (clinicaltrials.gov, nct ). patients years or older with severe covid- pneumonia confirmed by positive polymerase chain reaction test in any body fluid and evidenced by bilateral chest infiltrates on chest x-ray or computed tomography were enrolled. eligible patients had blood oxygen saturation ≤ % or partial pressure of oxygen/fraction of inspired oxygen < mm/hg. patients were excluded if the treating physician determined that death was imminent and inevitable within hours or if they had active tuberculosis or bacterial, fungal, or viral infection other than sars-cov- . standard care per local practice (antiviral treatment, low-dose steroids, convalescent plasma, supportive care) was permitted; however, concomitant treatment with another investigational agent (except antivirals) or any immunomodulatory agent was prohibited. informed consent was obtained for all enrolled patients. the study was conducted in accordance with the international council for harmonization e guideline for good clinical practice and the declaration of helsinki or local regulations, whichever afforded greater patient protection. the protocol was reviewed by institutional review boards or ethics committees. eligible patients were randomized ( : ) to receive intravenous tocilizumab ( mg/kg infusion, maximum mg) or placebo plus standard care using an interactive voice or web-based . cc-by-nc-nd . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint response system and permuted-block randomization. randomization was stratified by geographic region (north america, europe) and mechanical ventilation (yes, no). if clinical signs or symptoms did not improve or worsened (defined as sustained fever or worsened ordinal scale clinical status), a second infusion could be administered to hours after the first. the primary analysis was performed at day , and the final study visit occurred at day . the primary efficacy outcome was clinical status assessed on a -category ordinal scale ( , discharged is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint were recorded according to medical dictionary for regulatory activities system organ class and preferred term. efficacy was assessed in the modified-intention-to-treat (mitt) population (any randomized patients who received study medication) for the primary and secondary endpoints according to treatment assigned at randomization. analyses were stratified by region and mechanical ventilation status at randomization except for some subgroup analyses, as specified. the primary endpoint compared distribution of the ordinal scale of clinical status between treatment groups using a nonparametric van elteren test. the ratio of the odds of being in a better clinical status category for tocilizumab versus placebo was determined using a proportional odds model to give odds ratios and % cis. data from the last available postbaseline assessment on the ordinal scale were used for patients who withdrew before day , and all deaths and hospital discharges were carried forward. differences in mortality were analyzed using the cochran-mantel-haenszel test, differences in the number of ventilatorfree days were assessed using the van elteren test, and time-to-event secondary endpoints were assessed using a log-rank test with kaplan-meier plots produced (deaths were rightcensored for all time-to-event endpoints assessing improvement). cumulative incidence plots were generated using the nonparametric aalen-johansen estimator, where death is a competing risk. safety was assessed in the safety-evaluable population (all patients who received any study medication) according to treatment first received. an estimated mitt population sample size of patients randomized to tocilizumab or placebo was determined to give % power for the primary endpoint using the van elteren test and an assumed distribution of the ordinal scale (appendix ). if significance was met, mortality at day would be tested at the % level, but no other adjustment for multiplicity was planned. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint overall, patients from countries (canada, denmark, france, germany, italy, netherlands, spain, united kingdom, united states) were screened, patients were randomized, and received study treatment ( figure ). the mitt population included patients randomized to tocilizumab and to placebo. the safety population included and patients, respectively, because patient randomized to placebo received tocilizumab. overall, of patients ( . %) randomized to tocilizumab and of patients ( . %) randomized to placebo completed the -day follow-up. excluding those who died, patients ( . %) from the tocilizumab arm and ( . %) from the placebo arm discontinued before day ; none discontinued because of safety reasons. baseline demographics and disease characteristics were generally balanced between treatment arms. approximately % of patients in each arm were men; patients ( . %) were white and ( . %) were black in the tocilizumab arm compared with ( . %) and ( . %), respectively, in the placebo arm. mean age was . ± . years in the tocilizumab arm and . ± . years in the placebo arm. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . figure s ). missing data were minimal for the primary endpoint of clinical status for the mitt population ( . % tocilizumab, . % placebo). all p values for secondary endpoints are nominal because the primary endpoint was not met. figure b ). median duration of icu stay was . days in the tocilizumab arm and . days in the placebo arm (difference, - . days [ % ci - . to . ]; van elteren p= . ) ( table ) . cumulative incidences of time to improvement in clinical status, time to hospital discharge/ready for discharge, and mortality are shown in figure s . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint in the safety population, adverse events were reported in . % of patients in the tocilizumab arm and . % of patients in the placebo arm through day (table ) (table s ). covacta, the first randomized, double-blind, placebo-controlled trial of tocilizumab in covid- pneumonia, included patients from countries. the primary endpoint was not met; there was no significant difference between tocilizumab plus standard care and placebo plus standard care in clinical status assessed using a -category ordinal scale at day , and no mortality benefit was demonstrated. however, tocilizumab appeared to be safe, and potentially clinically meaningful benefits were identified in time to hospital discharge/ready for discharge and duration of icu stay. among patients not mechanically ventilated at randomization, fewer treatment failures (progression to mechanical ventilation, icu admission, or death) occurred in tocilizumab-treated than placebo-treated patients. because the primary endpoint of the study was not met, these findings require validation in additional studies. adverse events, including those of special interest for tocilizumab (bleeding events, is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint hepatic events, cardiac events), were generally balanced between tocilizumab and placebo, and incidences of infections or serious infections were lower in the tocilizumab arm. the design and conduct of clinical trials in patients with covid- present unique challenges and limitations. the covacta study population was intentionally chosen to be heterogeneous with regard to patient characteristics, previous/concurrent treatments, and disease severity to allow assessment of potential benefit across a broad range of patients and to reflect real-world practice in the expanding pandemic. despite this heterogeneity, the proportion of patients discharged or ready for discharge by day was higher in the tocilizumab arm than the placebo arm across the baseline ordinal scale of clinical status categories, whereas no consistent pattern was observed for mortality. the lack of standardized treatment across study sites and countries is an important limitation of this study considering potential interactions with antivirals and steroids. more patients in the placebo arm than the tocilizumab arm received concomitant steroids, which might have created bias toward lower mortality in the placebo arm ; however, this imbalance is unlikely to have obscured a significant treatment effect because the mortality rate was similar between treatment arms regardless of steroid use and was higher in patients who received steroids in both treatment arms than in those who did not (table s ). since our study was initiated, standard care treatment and understanding of the natural history of covid- and its associated complications have evolved substantially. based on current knowledge, optimal endpoints for clinical trials and effective treatments are likely to be different for different stages of disease. future trials should be more narrowly focused or much larger to allow for further stratification based on disease severity and other baseline characteristics. results of this study must be interpreted in the context of therapies for severe covid- . among treatments for patients hospitalized with covid- investigated in randomized controlled trials, dexamethasone reduced mortality in patients receiving is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint mechanical ventilation or supplemental oxygen at randomization, but not in patients not receiving respiratory support. remdesivir shortened time to recovery, but there was no statistically significant difference in -day mortality. clinical trials investigating potential treatments-including other antivirals, anti-inflammatories, other targeted immunomodulators (sarilumab, anakinra, baricitinib, canakinumab), anticoagulants, and antifibrotics (tyrosine kinase inhibitors)-are underway, but the urgent need for effective treatments remains. in the absence of a more effective therapy, treatments such as tocilizumab, which this study suggests might hasten recovery and decrease the need for intensive care without increasing the risk for infections, serious infections, or other adverse events, might be clinically useful, even without a demonstrated mortality benefit. additional studies are ongoing and might expand the findings of covacta and address outstanding scientifically and medically relevant questions regarding the risk/benefit profile of tocilizumab in covid- in more narrowly defined patient populations and in conjunction with current treatments. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . * includes a patient who died on study day (baseline ordinal category ) but who was in category on day before death. † values below the lower limit of quantitation of . ng/l were set at this value. ‡ at randomization (for stratification). § counted from recorded intubation start date to the day before study day (inclusive). the earliest start date was used if multiple procedures were recorded. patients first intubated on study day were assigned zero days on mechanical ventilation before baseline. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint † defined as all events that occurred during or within hours of the infusion and were not assessed as "unrelated to study treatment" by the investigator, regardless of whether they were clinically consistent with hypersensitivity. ‡ alanine aminotransferase or aspartate aminotransferase levels > × upper limit of normal with either bilirubin level > × upper limit of normal. § reported by medical dictionary for regulatory activities preferred term. . cc-by-nc-nd . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint *one patient randomly assigned to the placebo arm was treated with tocilizumab; this patient was included in the tocilizumab group for the safety population and in the placebo group for the mitt population. mitt population, modified-intention-to-treat population, which included all randomized patients who received study treatment. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint -category ordinal scale: , discharged or ready for discharge; , non-icu hospital ward, not requiring supplemental oxygen; , non-icu hospital ward requiring supplemental oxygen; , icu or non-icu hospital ward, requiring noninvasive ventilation or high-flow oxygen; , icu, requiring intubation and mechanical ventilation; , icu, requiring ecmo or mechanical ventilation and additional organ support; , death. (a, b) data are plotted as one minus the kaplan-meier estimator. patients who discontinued or were lost to follow-up for any reason before the event were censored at their last ordinal scale assessment. patients who died were censored at day . (c) death or hospital discharge were carried forward, including deaths that occurred after withdrawal. any remaining missing data were imputed using the last postbaseline observation carried forward method. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint category includes a patient who died on study day (ordinal category ) but was in category on day before receiving study treatment; this patient was not included in the calculation of medians. ne, not evaluable. . cc-by-nc-nd . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . under these assumptions, the total modified intention-to-treat sample size of patients with a : randomization of tocilizumab to placebo provides approximately % power to detect a difference in distribution of the ordinal scale at week between the treatment arms using a -sided van elteren test at the % significance level. the sample size also provides % power to detect a ratio of (tocilizumab to placebo) for the odds of being in a category or a better category under the assumptions of the expected probability distribution of patients in the placebo arm using a proportional odds model with a -sided p value at the % significance level. assuming proportional odds and the assumed distribution in the placebo arm, the smallest odds ratio that could be statistically significant would be approximately . . finally, the sample size provides approximately % power to detect a % absolute difference in mortality rate assuming a mortality rate of % in the placebo arm. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint -category ordinal scale: , discharged or ready for discharge; , non-icu hospital ward, not requiring supplemental oxygen; , non-icu hospital ward requiring supplemental oxygen; , icu or non-icu hospital ward, requiring noninvasive ventilation or high-flow oxygen; , icu, requiring intubation and mechanical ventilation; , icu requiring extracorporeal membrane oxygenation or mechanical ventilation and additional organ support; , death. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint -category ordinal scale: , discharged or ready for discharge; , non-icu hospital ward, not requiring supplemental oxygen; , non-icu hospital ward, requiring supplemental oxygen; , icu or non-icu hospital ward, requiring noninvasive ventilation or high-flow oxygen; , icu, requiring intubation and mechanical ventilation; , icu, requiring extracorporeal membrane oxygenation or mechanical ventilation and additional organ support; , death. death or hospital discharge were carried forward, including deaths that occurred after withdrawal. any remaining missing data were imputed using the last postbaseline observation carried forward method. category includes a patient who died on study day (ordinal category ) but was in category on day before receiving study treatment; this patient was not included in the calculation of medians. ne, not evaluable. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint figure s . cumulative incidence function plot of (a) time to improvement in clinical status on the -category ordinal scale, (b) time to hospital discharge/ready for discharge, and (c) mortality to day . time to improvement in clinical status was defined as days from first dose of study drug to the time of at least a -category improvement in clinical status on the -category ordinal scale. time to hospital discharge (or ready for discharge) was defined as days from the first dose of study drug to hospital discharge (or ready for discharge), defined as normal body temperature and respiratory rate and stable oxygen saturation on ambient air or ≤ l supplemental oxygen. patients who discontinued or who were lost to follow-up before improvement in clinical status or before ready for discharge criteria were met were censored at their last ordinal scale assessment. cumulative incidence plots were produced using the nonparametric aalen-johansen estimator. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint -category ordinal scale: , discharged or ready for discharge; , non-icu hospital ward, not requiring supplemental oxygen; , non-icu hospital ward, requiring supplemental oxygen; , icu or non-icu hospital ward, requiring noninvasive ventilation or high-flow oxygen; , icu, requiring intubation and mechanical ventilation; , icu, requiring extracorporeal membrane oxygenation or mechanical ventilation and additional organ support; , death. last postbaseline observation carried forward was used for imputation of missing data for day analyses; observed data were used for over time analyses other than deaths and hospital discharge, which were imputed using last postbaseline observation carried forward. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint † defined as all events that occurred during or within hours of the infusion and were not assessed as "unrelated to study treatment" by the investigator, regardless of whether or not they were clinically consistent with hypersensitivity. ‡ alanine aminotransferase or aspartate aminotransferase levels > × upper limit of normal with either bilirubin levels > × upper limit of normal. § reported by medical dictionary for regulatory activities preferred term. . cc-by-nc-nd . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint -category ordinal scale: , discharged or ready for discharge; , non-icu hospital ward, not requiring supplemental oxygen; , non-icu hospital ward, requiring supplemental oxygen; , icu or non-icu hospital ward, requiring noninvasive ventilation or high-flow oxygen; , icu, requiring intubation and mechanical ventilation; , icu, requiring extracorporeal membrane oxygenation or mechanical ventilation and additional organ support; , death. death or hospital discharge were carried forward, including deaths after withdrawal with any remaining missing data imputed using the last postbaseline observation carried forward method. steroids included corticosteroids except topical, inhaled, or dermatologic applications. . cc-by-nc-nd . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint world health organization. coronavirus disease (covid- ) pandemic clinical characteristics of coronavirus disease in china clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study immunology of covid- : current state of the science complex immune dysregulation in covid- patients with severe respiratory failure elevated interleukin- and severe covid- : a metaanalysis endothelial cell infection and endotheliitis in covid- pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- the vascular endothelium: the cornerstone of organ dysfunction in severe sars-cov- infection a review of recent advances using tocilizumab in the treatment of rheumatic diseases favorable changes of ct findings in a patient with covid- pneumonia after treatment with tocilizumab tocilizumab, an anti-il receptor antibody, to treat covid- -related respiratory failure: a case report first case of covid- in a patient with multiple myeloma successfully treated with tocilizumab key: cord- -lgt rzob authors: moka, eleni; paladini, antonella; rekatsina, martina; urits, ivan; viswanath, omar; kaye, alan d.; yeam, cheng teng; varrassi, giustino title: best practice in cardiac anesthesia during the covid- pandemic: practical recommendations date: - - journal: best pract res clin anaesthesiol doi: . /j.bpa. . . sha: doc_id: cord_uid: lgt rzob the covid- outbreak has influenced the entire health care system, including cardiac surgery. in this review, the authors reveal practical aspects that are important during the covid- pandemic with regards to the safe delivery of cardiac anesthesia. timing for operations of the cardio-vascular system may be well programmed, in most cases. hence, the level of priorities must be defined for any single patient. the postponement of surgery may be convenient for most cases, if it is made in the best interest of the patient. the preanesthetic evaluation should keep attention to the respiratory history of the patient. cardiac anesthesia is always implying some respiratory monitoring; hence the existing clinical situation of the patient’s respiratory system should be clear. in case of emergency surgery, the patient should be treated as if they potentially have or are at risk for the virus. in the case of a covid- confirmed or suspected patient, attention must be made to preserve operating room and team integrity. the machineries are to be draped with plastic, in order to simplify the disinfection after the operation. perioperative management of suspected or confirmed covid- patients must strictly follow the most relevant international guidelines. this review article has synthesized the common aspect present in the most important of these. the outbreak of the novel coronavirus and coronavirus disease was labelled as a public health emergency of international concern, in january [ , ] . in march , the rapid and exponential increase in confirmed cases of infection and number of deaths globally obliged who to raise the alarm and declare covid- a pandemic, triggering upscaling of emergency response mechanisms worldwide. covid- control has been extremely critical and demanding, having unfolded serious challenges to disease prevention and public health protection [ , ] . although common clinical manifestations are mostly respiratory, some patients may develop severe cardiovascular damage and are consequently at higher mortality risk [ ] . patients with suspected or confirmed covid- infection, who undergo cardiac surgery procedures, represent numerous challenges for the cardiac anesthesia team. they necessitate an extremely careful approach during perioperative anesthetic care and may reflect higher risks of perioperative morbidity and mortality. it is emphasized that management of the infected covid- cardiovascular patients, as well as self-protection of involved personnel, are extremely challenging and of equal importance, mandating a meticulous handling in the perioperative setting [ , ] . cardiac surgery and related anesthesia practice might not be in the frontline of covid- patients' care, but coronavirus expansion resulted in an important impact in this surgical and anesthesia subspecialty. indeed, the pandemic has already affected cardiac surgery units in multiple ways: limited number of available icu beds and ventilation sites, necessity to postpone or cancel elective and/or complex cardiac interventional procedures, patients developing covid- post cardiac surgery, coronavirus patients necessitating urgent cardiac operations, cardiac anesthetists' in-hospital transfer to staff and support icus in front of the pandemic, infected health care providers with consequent shortage of medical and nursing practitioners, restrictions in clinical meetings, and cancelation of training and continuing medical education [ , ] . cardiac anesthesiologists have the responsibility to ensure that evidence-based anesthetic care, and only essential cardiac operations are provided to the general public. in this context, the wider burden of such procedures on the healthcare systems and health care workers needs to be minimized in the current coronavirus pandemic, by delaying elective cases, to sustain health care services [ , , ] . based on the current understanding of covid- pathophysiology and the clinical characteristics of cardiovascular surgical patients, in this review, the authors highlight related anesthesia concerns and provide practical recommendations in reference to perioperative planning and management of patients undergoing cardiac surgery, along with a focus on disease control and prevention in the times of covid- outbreak. while a conclusion to proceed with or postpone a cardiovascular operation seemed easy in the low and medium escalation phase, continued escalation related to restricted icu capacity made such decision very difficult [ , ] ; e.g. it is difficult to answer critical dilemmas such as offering surgery only to younger, or lower risk patients. cardiovascular surgical patients are usually characterized by a relatively progressive disease. the necessity for surgery for a given disease condition must be identified by an experienced surgeon, who will prioritize patients underlying problems and will recognize potential risks encountered delaying the operation, also taking into consideration the risks for health care providers. as such, moving on with a decision to postpone or perform a cardiac operation is not at all easy. indeed, it can be tricky and needs to be taken after careful evaluation of patient status and health care system capacity, rather than being exclusively based on covid- associated risks. in all cases, availability of medical staff (e.g., cardiac surgeon, cardiac anesthetist, icu bed, perfusionist), potential need for isolated icu bed, equipment (e.g., ventilators, pumps, extracorporeal membrane oxygenation, intra-aortic balloon pump, trans-esophageal echo), medical supplies, blood and blood products, should be balanced and taken into account prior to a definite conclusion. importantly, when such decisions are taken, both the decision process and the decision making should be well documented, for obvious medicolegal reasons [ - ] . a knowledgeable decision-making process is emphasized and has to be based on a classification of planned interventions or/and operations in levels of priority (lop), such as (a) elective (lop i), (b) urgent (lop ii), (c) emergency (lop iii), and (d) salvage (lop iv), as per international guidelines. in a progressively escalating situation, as it has happened in most european countries, routine elective cardiac surgery (lop i) should be postponed as much as possible. on the contrary, operations at lop ii-iv, should be further evaluated on an individual basis, by the whole cardiac surgery team, keeping in mind that pci or endovascular interventions are preferable and should be selected if applicable. on the contrary, in-house urgent cases (lop ii), at risk for adverse cardiac events if going home instead of remaining hospitalized, might still undergo cardiac surgery at this time point, with the application of all precautions and protective measures, as per recent recommendations. the same rule applies for lop iii & iv interventions [ , , - ] . however, one must seriously consider such patients exposure risk to a possible covid- infection, during hospitalization, and/or exposure of health care workers to patients with potential coronavirus infection. most covid- patients have mild or no symptoms and therefore, it might be difficult to identify them from the pool of in-hospital urgent cases. moreover, patients with acute coronary syndrome in case of severe coronary artery disease (e.g. severe lm trunk stenosis, severe triple vessel disease with high syntax score), who are not eligible candidates for conservative or interventional treatment may be operated on. this may be true also for younger patients with symptomatic severe aortic valve stenosis, left-sided endocarditis with a severe valve defect and/or large mobile vegetation, large ascending aortic aneurysm (> cm in diameter), and symptomatic severe mitral valve insufficiency. if the pandemic escalates into a crisis, characterized by an absolute shortage of icu beds and ventilation sites, cardiac procedures will need to be extremely limited to absolutely essential emergency surgeries, for example acute type a aortic dissection, acute heart failure due to severe coronary artery or valvular heart disease, and ventricular septal defect. under these circumstances, even such decisions obviously remain tough to be resolved, should be taken after examining available hospital resources and reserves, and must always be supported by an ethical and legal framework [ , , ] . in all cases, postponing elective cardiac surgery does not necessarily translate into a delay in or a neglection of patient care. it is fully understandable, as well as a realistic assumption that cardiac surgery units are responsible for their patients' best outcome, but also equally responsible towards the health care workers and the wider health care service in a region or country. therefore, in an escalating pandemic, patients normally scheduled for elective cardiac procedures are best managed by delaying their care until a few weeks or even months later. this is probably in the patients' best interest, to avoid their exposure to the hospital environment, and to eliminate chances of an incidental covid- development in their postoperative course. it is already documented that acs patients, infected by coronavirus usually end up with a poor prognosis. therefore, developing covid- post cardiac surgery might be associated with higher mortality rates. however, cardiac patients, whose operations are postponed, should be regularly re -evaluated and strictly followed -up, before their underlying conditions evolve further, and they arrive at a point of needing a cardiac surgery of lop ii or higher. finally, the cardiac surgery team should not only take decisions on postponing elective operations but should also discuss and plan regarding the timing of surgery in the future, based on the rapidly evolving covid- circumstances, and the continuously evolving regulations and restrictions [ ] [ ] [ ] [ ] [ ] . the coronavirus is highly contagious. its incubation period fluctuates between and days, although its latency period can extend up to days. most infected patients usually present with mild, flu-like symptoms, including low fever, dry cough and fatigue, or can be even asymptomatic. the mean age of a covid- case is reported to be years. worse outcomes are associated with geriatric populations and those with underlying diseases, such as obesity, cardiovascular comorbidities, pulmonary disorders, and/or diabetes. di erential diagnosis can appear extremely challenging, since common influenza is characterized by similar signs and symptoms. chest radiography or thoracic ct scan may be utilized, in identifying evidence of secondary pneumonia [ , , ] . taking into consideration that invasive or at least minimally invasive cardiorespiratory monitoring is usually required in most cardiac surgery procedures, all patients proceeding to or must be treated as confirmed covid- cases, not only if the disease is suspected, but until a test result becomes available. additionally, in an escalating pandemic, candidates for elective or semi-elective cardiac operations may be best managed by delaying their care until a few weeks or even months later, or in the worst case postponed until covid- virus detection results are negative, at least twice, with a minimum of hours between tests [ ] [ ] [ ] [ ] ] . it is known that patients with acute coronary syndrome, who are infected with coronavirus, often have a poorer prognosis compared to the general population. therefore, developing covid- after cardiac surgery might contribute to a complicated postoperative course and be associated with higher morbidity and mortality rates [ , ] . in the event of an emergency cardiac surgery operation, covid- status mandates immediate evaluation, in terms of patient recent epidemiologic and respiratory infection history, clinical manifestations, and laboratory and radiographic testing, including but not limited to temperature, respiratory pathogen testing, serum igg level, complete blood count, crp and procalcitonin levels, sars-cov- nucleic acid testing, and chest ct scanning. in case enough time is not available for a complete preoperative evaluation prior to surgery, preoperative hospitalization and preparation must strictly follow the already published guidelines for suspected/confirmed covid- cases. such patients should be admitted to an airborne isolation room (single room with negative pressure and frequent air exchange), with the quarantine necessity being evaluated and finally decided, according to sars-cov- nucleic acid testing and chest ct scanning examination results [ ] . a multidisciplinary team consisting of cardiac surgeons, cardiac anesthesiologists, respiratory infectious disease experts, perfusionists, and nursing staff should be involved in coordinating such patients care. for healthcare personnel involved in suspected or confirmed coronavirus cases, level infection control precautions (such as disposable hat, medical masks [n or above], powered air purifying respirators [papr], scrubs, disposable gloves, and disposable shoe covers) should be strictly applied throughout the whole perioperative period. personnel clinical observation and follow-up for signs and symptoms of covid- must not be forgotten and should be carried out closely after their clinical involvement in such patients care. in case of health care personnel exposure risks, an isolation period of at least days is mandatory [ ] [ ] [ ] ] . keeping in mind the ease of in-hospital coronavirus contaminating capability and expansion, and that all health care workers are among those at high risk of infection, they must all routinely apply protective and preventive measures, with attention to details, to avoid any nosocomial spread to patients and healthcare nursing and medical personnel. indeed, precautions in the care of all patients and in the interaction between health care personnel are of paramount importance, to limit infection spread, as much as possible. it is highly recommended that all health care providers focus on their personal protective equipment. in this context, all should wear a n mask, surgical cap, gown, protective eye googles, shoe covers, double gloves, and paprs or protective full-face shield, during very contact with suspected or confirmed covid- cardiac surgery candidates [ ] [ ] [ ] . a dedicated operating room for the suspected/confirmed cardiac surgery covid- patients must be readily available and in absolute isolation from the rest of operating theatres, with a warning sign posted outside and with predefined, dedicated preoperative and postoperative patient transportation pathways, which must be disinfected regularly. covid- or set up, workflow and organization are extremely critical. surgical devices and anesthetic equipment must be unique and dedicated only to the predefined covid- or, without any chance of being transferred to other operating sites. all non-essential surgical and anesthetic equipment needs to be removed outside this dedicated or. the operating room should also be converted to a negative pressure environment with airflow changes, with doors remaining shut at all times, to maintain an optimal negative pressure at all time points of the cardiac patient perioperative care [ , , [ ] [ ] [ ] . coordination of and collaboration between healthcare practitioners, workflow of the covid- or (inclusive of, but not restrictive to routine universal infection prevention practices, donning and doffing personal protective equipment [ppe] , and decontamination after the procedures), and designated personnel must be planned on a daily basis, also evaluated and adapted to circumstances dynamic alterations. cardiac surgery is a complex operative procedure that cannot be completed successfully without a group of health care practitioners. such operations must involve a dedicated team, limited to the minimum number of nursing and medical personnel (cardiac surgeon, anesthesiologist, anesthesia nurse/technician, cpb technician, perfusionist, scrub and circulating nurse). all team members should be assigned and allocated to their roles prior to covid- patient entrance in the or. irrelevant staff should not enter the covid- or to minimize unnecessary traffic. staff management can take appropriate measures to separate workers/anesthetists/surgeons into groups, so that possible necessary quarantines can be applied to groups within each unit, rather than the unit as a whole, which could lead to the closure of the entire cardiac surgery service, something that is especially true for smaller cardiac surgery units [ - , , ] . all equipment and devices required, for endotracheal intubation, arterial and central venous cannulation, syringes, gauzes, surgical drapes, surgical instruments, sutures, material for cannulation prior to cardiopulmonary bypass (cpb), oxygenator and circuit for cpb, prosthetic grafts and valves must be checked for adequacy prior to surgery and be set and positioned properly and definitely prior to patients arrival in the or. the aim is to have as minimal as possible traffic in circulation across the covid - or. additionally, high-touch surfaces of devices like anesthesia machines/workstation, infusion pumps, cpb machine, cell-saver device, iabp, heat exchangers and computerized devices for documentation should be wrapped with plastic sheets, to facilitate cleaning and decontamination after the end of surgery and following patients transportation to icu, as per international general guidelines. strict measures and precautions for infection control should be implanted and must definitely be applied in the case of suspected/ confirmed covid- cardiac surgery patients [ ] [ ] [ ] [ ] . first, in reference to staffing management, and based on the potential complexity of a cardiac operation, two experienced cardiac anesthesiologists and a cardiac anesthesia nurse are necessary to be present inside the cardiac surgery or, directly being responsible for the patient anesthetic care. a third cardiac anesthesiologist should be readily available outside the or, serving as backup and consultant, in case it becomes necessary [ , ] . or traffic should be limited to the minimum. only dedicated staff should be allocated for specimen collection and delivery (e.g. arterial blood samples analysis, act, thromboelastography, blood tests etc.). all healthcare providers involved should be covered by level iii protection and should wear in the following order: n mask, disposable surgical cap, disposable work uniform, disposable medical protective uniform, scrub, gown, anti-fog goggles, shoe covers, first layer disposable latex gloves, isolation gown, and full-face respiratory devices or powered air-purifying respirator (papr), if available. anesthesiologists must wear gloves before contacting the patient and eventually patient body fluids, such as blood, urine, mucus, or other potentially contaminated objects. in such case, vigilance is required to remove the outer gloves, followed by appropriate hand hygiene, with gloves repositioning being strongly advised afterwards. extreme care should be applied to avoid touching surfaces prior to contaminated gloves removal. also, contaminated, semi-contaminated, and clean zones should be clearly defined, and protective equipment must be removed consequently, and when necessary, according to the hospital guidelines and protocols [ , , , , ] . a specific note must be given to surgeons and scrub nurses preparation in terms of personal protection. they should put the surgical mask and cap above ppe, then get scrubbed in and move on with putting on the surgical coat with double gloves. gloves should be long-sleeve and fixed to sterile coat with adhesive tape or drapes. regarding equipment and devices preparation, anesthesia machines, monitors, toe probes, us machines, blood gas analyzers, act machines, and disposable or supplies must be prepared well in advance. the waste anesthetic gas disposal system should be checked for proper working provisionally and must be equipped with the necessary filtering and sterilizing functionalities. the centralized waste anesthetic gas disposal system should be avoided, to prevent the spread of coronavirus among operating rooms, in case standard negative pressure in the or cannot be achieved. an independent (preferentially portable) negative pressure suction device should be readily available in each or. a video laryngoscope (disposable laryngoscopes whenever possible) is strongly recommended and advised to be utilized, if available, to improve the success rate of endotracheal intubation, thus reducing exposure time. video laryngoscope must also be used even in case of unplanned emergency circumstances for securing airway [ - , , ] . cardiac surgery patients must always wear a n /surgical mask, and at all times, and should be transported to the or through a predesigned pathway. nasal oxygen supply /therapy can be offered underneath the surgical mask when needed. a venturi mask is advised to be avoided [ , ] . in patients with severe cardiac and pulmonary dysfunction, intra-aortic balloon pump, or extracorporeal membrane oxygenation (ecmo) might be considered [ - , , ] . general rules and principles: current guidelines . all non-essential or unnecessary equipment and devices must be kept outside the covid- or, during anesthesia induction and endotracheal intubation (eti). all anesthesia induction and resuscitation equipment must be prepared and ready for use, prior to patient transfer in the or. anesthesia and intubation protocols for covid- cases must be strictly followed [ - , , ]. . arterial and cv catheterization are recommended to be facilitated by ultrasound guidance, to improve success rates, reduce procedural times, and avoid multiple vessel punctures, that could contaminate surrounding personnel via blood [ , , , ] . . in general, regional anesthesia is preferred to ga in surgical procedures. however, in most cardiac surgery circumstances, a single ra technique cannot be applicable, although it may be combined to ga, based on the type of surgery, as an adjunct to a ga technique, for adequate perioperative pain management [ , , ] . electrostatic heat and moisture exchange filters (hmef) must always be used in the anesthesia circuit throughout the intubation process, as its virus filtration efficiency reaches . %. for suspected patients, lower respiratory tract secretions should be collected through the ett, and specimens should be sent for examination as soon as possible [ ] [ ] [ ] [ ] . patients covid- patients may suffer from severe viral myocardial damage. elevated cardiac injury biomarkers are commonly found in covid- patients. among other manifestations, hypertension, heart failure (with a high incidence in elderly), hypoxia-induced myocardial damage (especially after myocardial infarction, unstable angina, or in patients with a pci history), and stunned myocardium have been reported. multiple explanations have been described, all related with a high expression of ace receptors in the heart, blood vessels, and lungs, possibly being responsible for the virus induced activation of the raas system. patients receiving ace inhibitors prior to surgery might be in higher risk for complications and worse outcome [ , [ ] [ ] [ ] ] . in reference to cardiovascular monitoring, that is necessary in the covid- cardiac surgery patients, minimally or advanced invasive hemodynamic monitoring (picco, flotrac, pulmonary artery catheterization) and toe are mostly recommended to guide fluid therapy and inotropic/vasoactive drugs usage. patients with acute mi might need iabp insertion, ventricular assist device, or ecmo mechanical circulatory support, and these devices should be applied with extreme caution to avoid transmission of infection. intraoperative toe is the routine technique of choice for lv function monitoring, volume status optimization, and valvular diseases evaluation, and may serve as a useful guide during cardiac anesthetic management. concise and comprehensive toe examination represents the primary modality for the evaluation of every cardiac disease and of a covid- induced cardiac dysfunction. rv dysfunction, can be a manifestation of covid- cases, after cpb, related to increased pulmonary vascular resistance and pulmonary edema, lv dysfunction, and related stress cardiomyopathy [ ] [ ] [ ] . patients with sars, under mechanical ventilatory support, suffer a higher risk for developing pneumothorax, which contributes to increased mortality rates in this subgroup of patients. as such, it is recommended that pneumothorax is excluded by ct scanning during preoperative patient evaluation. a protective mechanical ventilation strategy must be applied in all suspected and confirmed cardiac surgery cases. pneumothorax should be suspected according to patient clinical picture (mostly decreased spo or sudden blood pressure decreases. lung ultrasound, as a basic part of pocus, can be useful for fast evaluation and diagnosis, and a chest tube should be placed if a pneumothorax is the final diagnosis. lung re-expansion should be verified prior to chest closure. lung ultrasound can also be useful in assessing the severity of pulmonary manifestations due to covid- , by easily identifying presence of b-lines, air bronchogram, and pleural effusion, thus helping in selecting proper lung protective ventilating strategies [ , , ] . critically ill covid- patients have a high incidence of acute kidney injury and severe acidbase imbalances, with electrolyte abnormalities commonly being encountered. continuous renal replacement therapy should be performed perioperatively when indicated. goal -directed fluid therapy is recommended to optimize fluid administration [ ] [ ] [ ] [ ] ] . blood conservation strategies should be applied, as such patients' coagulation profile is usually not normal. coagulation status should be checked routinely via measurements of platelet counts/ function, prothrombin time (pt), partial thromboplastin time (ptt), international normalized ratio (inr), and thrombo-elastography. antifibrinolytics, preoperative hemodilution, autologous platelet-rich plasma technology, mild hypothermia or normothermia during cpb, and intraoperative blood salvage must be used, as in non-covid cases, to minimize blood transfusion requirements and transfusion-related acute lung injury. coagulation factor concentrates are preferred over blood products when possible to reduce potential trali, which can worsen the already existing lung manifestations related to covid- [ - ] . major surgery and anesthesia produce well documented inflammatory and immune response in humans. in cardiac surgery procedures, extracorporeal circulation and cpb are further considered as an additional risk factor and the most important trigger for a massive perioperative inflammatory reaction, a problem that has been largely addressed in the past, because of its detrimental consequences and impact on perioperative morbidity and mortality. continuous blood exposure to non-endothelial surfaces (perfusion circuit) is responsible for a cascade of systemic inflammatory response, via activation of coagulation pathways, complement system, and production of tissue factor and cytokines, that can eventually result in ards, potentially being further complicated by blood transfusion, finally causing trali. the inflammatory response during cardiac surgery occurs due to not only cpb, but also surgical trauma, anesthesia, cardioplegia and myocardial ischemia, cardiac manipulation, heparin, and protamine. inflammatory response to cpb can be controlled and minimized by off-pump cardiac surgery, temperature maintenance and arrangement ( °- °c for operations requiring up to h of cpb), heparin coated-perfusion circuits, modified ultrafiltration, complement inhibitors, and glucocorticoids [ , ] . current covid- therapies are mainly supportive. development of novel therapies and effective prevention are an urgent need, particularly for life-threatening severe acute ards and hyper-inflammatory syndrome (characterized by a fulminant and fatal hypercytokinemia with multi-organ failure). several cytokines are involved in the disease pathogenesis. likewise, some of these cytokines induce increased vascular permeability and leakage, pulmonary edema, air exchange dysfunction, ards, acute cardiac injury, and multi-organ failure. novel therapies such as interleukin (il) antagonists (dupilumab), jak inhibitor (fetratinib), interferon blockers and stem cell and mesenchymal cell therapies have been applied to neutralize cytokine storm and offered some improvement. in the cardiac surgery setting, extracorporeal circulation and cellsaver application might reduce the systemic cytokine load, could in part eliminate immune and inflammatory response, and as such, might be reasonable options as alternatives and might be considered for covid- patients during cardiac surgery [ - , , , ] . at the end of each cardiac operation, specific attention must be given to patient transportation, medical waste management, or and equipment disinfection and patient and health care personnel follow up. a single dose of an antiemetic (e.g. -hydroxytryptamine receptor antagonist) should be administered to prevent postoperative nausea and vomiting (a common adverse effect due to high opioid doses that are provided intraoperatively), which may be responsible for an extensive coronavirus spread. prior to departure from or, all healthcare providers should take off the outer layer of their personal protective equipment, in the sequence guided by local hospital policy and international guidelines. the transportation of covid- patients should be performed by a personnel with ppe. this team should wear new personal protective equipment in the clean zone. in cases undergoing cardiovascular surgery, extubation should be planned in the or if possible and for the appropriate patients. patients to be admitted to the icu should be transferred in accordance with the infection prevention measures for covid- . if the patient transported to icu is intubated, ventilation can be performed by a disposable ambu bag, or an hmefequipped portable ventilator should be used. the positive pressure ventilation should be stopped prior to disconnection from ventilator, while placing the patient to ambu bag or the portable ventilator. if the transported patient is extubated, a n /should be applied to patient. regarding transportation, a pre-specified pathway must be followed, to transfer the patient to an airborne isolation intensive care unit room, specifically dedicated to covid- cases. personal protective equipment can be taken out only after leaving the isolation area. all disposable equipment and medical waste (breathing tubes, infusion tubing, disposable laryngoscopes, sutures, drapes etc.) should be discarded. these must be put in and sealed with double-layered medical waste bags and must be treated as highly contagious medical waste. anesthesia machine and their surfaces, other surfaces, equipment used in or, floor and operating table need to disinfect and decontaminate as per dictated procedures. it is advised they are wiped with % alcohol or chlorine-containing disinfectants. the inner circuit of the anesthesia machine should be removed and disinfected with % alcohol or hydrogen peroxide. mixed o and h o atomized gases or pasteurization can also be applied. or negative pressure must be maintained for at least minutes, after patient departure and transfer to icu. or ceiling filters of exhaust vent and or wall return vent must be definitely replaced. no operation should start in this or before or space has been thoroughly disinfected, as per the description provided above. plasma air purifiers can be used for air sterilization. alternatively, ultraviolet light can be used as well for one hour. the casing and monitor of ultrasound machines should be wiped with % alcohol. quaternary ammonium disinfectants should be avoided as they can damage the casing. however, ultrasound probes can be disinfected with quaternary ammonium or hydrogen peroxide. for disinfection of the toe probe, blood gas analyzer, and act machines, one should address to the manufacturer's instructions. reusable surgical instruments must be transferred to the nearest washstand (with a covid- warning sign above it) and decontaminated by personnel wearing ppe. reusable instruments disinfection via soaking must be carried out with a chlorine containing disinfectant for at least minutes [ , , , , , ] . postoperative care and intensive follow-up of covid- patients, necessitate establishment of a dedicated multidimensional cardiac covid- team, with a particular expertise in cardiac icu, mainly including, anesthesiologist, cardiovascular surgeons, respiratory medicine physicians, infectious diseases specialists, experienced nurses, physiotherapists, and social worker. team decisions should be taken jointly, as a multidisciplinary decision making among the covid- team can minimize specialty bias and prevent self-referral from interfering with the optimal patient care. in this context and to minimize/prevent infection, healthcare workers should follow the infection control policies and procedures already in place at their healthcare institutions. for the healthcare workers performing aerosol-generating procedures in patients with covid in the icu, it is advisable to use fitted respirator masks (i.e., n respirators, ffp , or equivalent), in addition to other ppe (i.e., gloves, gown, and eye protection, such as safety goggles) as described in the infection prevention measures for covid- . if possible, the shift of healthcare workers should be reduced to four hours. additionally, it is preferentially recommended that performing aerosolgenerating, nonaerosol-generating procedures in icu patients with covid- should be carried out in a negative-pressure room and a portable high-efficiency particulate air filter should be used in the room, if available. in patients who require endotracheal re-intubation, intubation should be performed by the healthcare worker who is the most experienced with airway management to minimize the number of attempts and risk for transmission and using videoguided laryngoscopy over direct laryngoscopy, if available. during icu follow-up of covid- patients, patients should be closely monitored for ards, systemic inflammatory response syndrome, and cytokine release syndrome. the preventive and treatment options (including antiviral treatment strategy which is subject to change) related to the diseases itself and subsequent serious clinical conditions (i.e., ards or shock) should be taken in accordance with the guideline recommendations [ , , , , , ] . finally, one other big problem is the feeling of fear of health care providers to be diseased or contagious for their families. therefore, they may need enormous support against burn-out during the covid- pandemic. cardiac anesthesia provision presents with many challenges in the coronavirus era, as presented in table . for the performance of cardiac operations in the covid- pandemic, it is important that a dedicated team decides on which cases to postpone for a later stage, based on an assessment of level of priority. the basic goal is to support the healthcare facilities and to protect patients from severe postoperative complications that contribute to high mortality rates, and health care workers from a potential contamination. the rest of operations that cannot be deferred should be performed with great caution, strictly following guidelines and health authorities' recommendations, that are readily available. personal protective equipment is the most crucial measure during pandemic, even if in this kind of working environment is challenging. support of health care cardiac anesthesia and surgery team is mandatory, taking into account that patients can only be treated if health care workers are healthy. the authors have no conflicts of interest to disclose. no funding was received for the completion of this manuscript. sars cov- is an appropriate name for the new coronavirus a pneumonia outbreak associated with a new coronavirus of probable bat origin who announces covid outbreak a pandemic world health organization. coronavirus disease (covid ) pandemic the current clinically relevant findings on covid- pandemic special article: chinese society of anaesthesiology expert consensus on anaesthetic management of cardiac surgical patients with suspected of confirmed coronavirus disease perioperative care provider's considerations in managing patients with covid - infection perioperative planning for cardiovascular operations in the covid - pandemic cardiac surgery in canada during the covid- pandemic: a guidance statement from the canadian society of cardiac surgeons american college of surgeons. covid- guidelines for triage of cardiac surgery patients ramping up the delivery of cardiac surgery during the covid- pandemic: a guidance statement from the canadian society of cardiac surgeons the society of thoracic surgeons covid- task force and the workforce for adult cardiac and vascular surgery. covid- guidance document: adult cardiac surgery during the covid- pandemic: a tiered patient triage guidance statement cardiac surgery in the time of the coronavirus novel coronavirus patients' clinical characteristics, discharge rate and fatality rate of meta-analysis covid- and cardiovascular disease covid - and the cardiovascular system practical recommendations for critical care and anaesthesiology teams caring for novel coronavirus ( -ncov) patients recommendations for endotracheal intubation of covid- patients cardiovascular surgery in the covid pandemic covid- and ecmo: the interplay between coagulation and inflammation-a narrative review anaesthesia and covid- : infection control covid- / coronavirus outbreak: how to establish a central venous access by placing a central venous catheter regional anaesthesia and covid- : first choice at last? regional anesthesia for cardiac surgery consensus guidelines for managing the airway in patients with covid- rational use of personal protective equipment for coronavirus disease (covid- ) recommendations for endotracheal intubation of covid- patients precautions for intubating patients with covid- the variety of cardiovascular presentations of covid- what we know so far: covid- current clinical knowledge and research covid- and kidney failure in the acute care setting: our experience from seattle the systemic inflammatory response to cardiac surgery: implications for the anesthesiologist inflammatory response and cardioprotection during open-heart surgery: the importance of anaesthetics extracorporeal oxygenation and coronavirus disease epidemic: is the membrane fail-safe to cross contamination? a case of postoperative covid- infection after cardiac surgery: lessons learned. the heart surgery forum ra preferable when applicable, combined with ga avoidance of aerosol generating processes (airway manipulation, face mask ventilation, suction awake eti -rapid sequence induction -video laryngoscope utilization -avoidance of circuit disconnection • cardiovascular considerations: hemodynamic monitoring, toe use, attention to possible rv dysfunction • respiratory considerations: protective mechanical ventilation strategy / lung ultrasound / pocus • renal dysfunction -role of renal replacement therapy postoperative care of suspected/confirmed cardiac surgery covid - patients • attention to patient transportation by personnel with ppe • antiemetics administration at end of surgery and prior to weaning • if possible, extubation in or -n mask applied to patient afterwards • proper disposable equipment and medical waste should be discarded as per guidelines and protocols key: cord- -syr av authors: piva, simone; filippini, matteo; turla, fabio; cattaneo, sergio; margola, alessio; de fulviis, silvia; nardiello, ida; beretta, alessandra; ferrari, laura; trotta, raffaella; erbici, gloria; focà, emanuele; castelli, francesco; rasulo, frank; lanspa, michael j.; latronico, nicola title: clinical presentation and initial management critically ill patients with severe acute respiratory syndrome coronavirus (sars-cov- ) infection in brescia, italy date: - - journal: j crit care doi: . /j.jcrc. . . sha: doc_id: cord_uid: syr av purpose: an ongoing pandemic of covid- that started in hubei, china has resulted in massive strain on the healthcare infrastructure in lombardy, italy. the management of these patients is still evolving. materials and methods: this is a single-center observational cohort study of critically ill patients infected with covid- . bedside clinicians abstracted daily patient data on history, treatment, and short-term course. we describe management and a proposed severity scale for treatment used in this hospital. results: patients were enrolled; with incomplete information on . of the studied patients, % were male, median age ; % were overweight or obese. % were hypertensive, % had been taking an ace-inhibitor. noninvasive ventilation was performed on % of patients for part or all or their icu stay with no provider infection. most patients received antibiotics for pneumonia. patients also received lopinivir/ritonavir ( %), hydroxychloroquine ( %), and tocilizumab ( %) according to this treatment algorithm. nine of patients survived their icu course and were transferred to the floor, with one dying in the icu. conclusions: icu patients with covid- frequently have hypertension. many could be managed with noninvasive ventilation, despite the risk of aerosolization. the use of a severity scale augmented clinician management. south korea, or complete lockdown and massive construction of hospitals and medical equipment, as in china. italy's crisis appears to foreshadow the sort of crisis expected in the rest of europe and the americas. in the lombardy region of italy, there have been massive shortages in equipment and personnel, with nonintensivists managing critically ill patients. this is the first reported cohort of icu patients with covid- from the lombardy region. in addition to describing the clinical management of such patients, this study details a proposed severity scale that was used to communicate with non-intensivists for management and triage, and for a step-up approach to drug therapy including antivirals, desamethasone and selective cytokine blockers. the covid- global epidemic will require hospitals to prepare for resource shortages and utilization of non-intensivist physicians. creation of a severity scale to assess patients with covid is of value to hospitals and physicians facing such shortages. the pandemic spread of severe acute respiratory syndrome coronavirus (sars-cov- ) and its disease, covid- , has resulted in massive strain in healthcare systems in several countries. recently, the lombardy region of northern italy has reported massive infection, overwhelming the region's capacity to care for such patients. at present, there are over intensive care patients in lombardy, and over deaths in italy attributed to this infection. as this infection is novel, there is no proven treatment for patients presently. the global tracking of spread suggests other countries are likely to have similar strains on their infrastructure in caring for these patients. china, where the sars-cov- originated, has slowed the progression of the pandemic with strict social distancing, while south korea has similarly impeded spread with widespread testing. europe and the united states appear poised for similar pandemics as italy in the absence of significant societal or governmental interventions. the experience of lombardy is interesting in that despite italy having the third most number of icu beds per capita, after the united states and germany, physicians have had to limit resources due to shortages [ ] . practicing physicians have previously not experienced massive triage based on resource limitations prior to this pandemic. these resource limitations have resulted in the creation of ethical guidelines on conserving resources at the expense of many human lives [ ] . clinicians have been overwhelmed and working beyond capacity. many non-intensivist physicians have had to manage critically ill patients with limited expertise or guidance. additionally, in the absence of proven therapies and overwhelming disease, many physicians have been attempting novel therapies in the hopes of mitigating the disease. part of the reason for attempting these novel therapies is the realization that rigorous study of therapies will likely be too late to be of benefit for many people who will otherwise die. in the absence of clinical trials, bedside clinicians need an instrument to assess disease progression or improvement in patients with covid- . we report the experience of the brescia spedali civili hospital, a large general regional university hospital serving an area of . million people in lombardy italy, in the hopes that this information might be informative for other hospitals in preparing for the pandemic. this is a prospective, observational cohort of critically ill patients with confirmed sars-cov- infection admitted to the intensive care units in brescia, italy between march and march , . this study was conducted in accordance with the declaration of helsinki and good clinical practice guidelines. this study was performed with waiver of informed consent by the brescia institutional review board and ethics board. viral infection was confirmed at a world health organization (who) reference laboratory. bedside clinicians recorded clinical data upon admission to the icu and daily thereafter. clinicians recorded medical history and outpatient medications and calculated the simplified acute physiology score (saps) and sequential organ failure assessment (sofa) score upon admission. clinicians also recorded daily clinical, ventilator, and laboratory data, diagnostic tests, and therapies administered. clinical outcomes were recorded but are incomplete at the time of this manuscript. data are reported using simple descriptive statistics. we report central tendencies of continuous variables as medians with interquartile ranges. all statistical analyses were performed using stata, v (statacorp, college station,texas, usa). during the management of these patients, intensivists had limited guidance on management. these intensivists created a management schema ( fig. ) to describe the clinical improvement or worsening of disease and used this schema to try to create replicable treatments among patients in icu and admitted to the ward. the aspiration of this schema was twofold: it allowed for consistent communication and decision-making among providers who were working beyond capacity, and it offered some bedside assessment of whether patients were clinically improving while receiving adjunctive therapies. the brcss was created by sharing experience between physicians of different specialties. since the onset of the lombardy covid- pandemic, a daily multidisciplinary meeting was held to coordinate patient care and transfer between units. participants of these meetings included intensivists, infectious disease physicians, chest physicians, immunologists, rheumatologists, and internists. the scale ( fig. ) was designed for rapid and common communication between clinicians, to achieve consistency on when to initiate therapies (antiretroviral therapy, corticosteroids, tocilizumab), and to help clinicians not familiar with ventilation to manage the outbreak. the study hospital had two ten-bed general intensive care units ( beds total), and one six-bed cardiac intensive care unit. at the time of drafting this paper, the hospital is actively managing covid- icu beds and general icu beds, for a total of icu beds. daily operating room surgical activity has ceased, and many covid- patients are managed with niv ventilation on the wards. despite these efforts, the hospital is still unable to sufficiently staff patients in need. non-intensivists staffing these beds relied on the brcss to communicate efficiently regarding the state of patients to other clinicians. the brcss uses clinical criteria to rate the non-intubated patient, assigning a score of to , relying on the four testing criteria: ) dyspnea or staccato speech, defined as being unable to count rapidly up to after a deep breath, at rest or during minimal activity, such as sitting up in bed, standing, talking, swallowing, coughing; ) respiratory rate n breaths/min; ) pao b mmhg or spo b % with supplemental oxygen; ) significant worsening of chest radiograph. among intubated patients, a threshold pao /fio b mmhg determined a score of or higher, and adjunctive therapies including prone positioning and neuromuscular blockade agents increased the score higher. we studied patients. at the time of this manuscript, data information concerning the outcome was incomplete on patients, making a study population of patients. patient characteristics are detailed in table . the study population was . % male, with a median age of years (interquartile range - ). the youngest was years old, and the oldest was years old. obesity was present in % of patients, with an additional % being overweight. almost half ( %) the patients had heart disease, with hypertension being most common. fifteen patients ( %) had hypertension, and four ( %) had been taking an angiotensin-converting enzyme (ace) inhibitor. most patients presented neurologically intact. many patients were euthermic their first day in the icu, with only one patient having fever n . °c, and one patient hypothermic b °c. the majority of the patients who presented to the icu had already been intubated prior to arrival or on the first day of icu admission. all but one patient ( %) required fio ≥ % at admission to the icu, with a median of %, although patients were able to oxygenate with adequate sao values. severe ards, with pao / fio b mmhg, was present in % of patients. half the patients were receiving neuromuscular blockade agents on their first day of icu care. although one third of the patients required vasoactive medications to maintain blood pressure, there was generally no difficulty in maintaining adequate mean arterial pressures at admission. initial laboratory data is also presented in table . of note, patients often presented with normal white blood count, with almost invariably reduces lymphocytes. troponin often was mildly to moderately elevated. procalcitonin was more often normal (median . ng/dl, iqr . - ), while c-reactive protein was often extremely elevated (median . mg/l, iqr . - ). one patient was found to have extended spectrum beta-lactamase e. coli in the blood. otherwise, blood culture data revealed no other infections. basic chemistry panels were often normal, as was arterial lactate. during hospitalization, echocardiography was performed in patients ( %), of which ( %) were abnormal. three patients ( %) developed pneumothorax during their icu stay. thirteen ( %) patients were managed with non-invasive positive pressure ventilation for part or all of their icu stay. patients who received invasive mechanical ventilation were ventilated with low tidal volume ventilation. the median tidal volume adjusted for predicted body weight, measured from mechanically ventilated patients over all icu days, was . ml/kg (interquartile range . - . ). patients adhered to a high peep strategy. median peep measured from mechanically ventilated patients over all icu days, was cm h o (iqr - ). patients receiving noninvasive ventilation had lower epap values ( cm h o, iqr [ ] [ ] [ ] [ ] [ ] most patients received targeted therapies for covid- . these therapies were administered according to the brcss. as a patient had increasing disease severity, more adjunctive therapies were administered (fig. ) . patients received combination lopinivir/ritonavir ( %), hydroxychloroquine ( %), dexamethasone ( %) and tocilizumab ( %). the decision to administer therapies was based upon the brssnine of patients survived their icu course and were transferred to the floor, with one dying in the icu. the remainder of the patients remain in the icu at the time of drafting this manuscript. the sars-cov- pandemic is perhaps the most devastating global event in modern medicine. physicians and scientists are struggling for therapies to mitigate this disease. lombardy has been affected heavily enough to require ethical triage that has not been seen in several generations. we report the clinical practice of intensive care physicians from one of the public hospitals in this region. the physicians practicing in this hospital are currently overwhelmed with staffing and resource shortages. many of the hospitals in the united states are currently drafting their own protocols. many such protocols have avoided the use of non-invasive positive pressure ventilation due to its risk of further aerosolizing the covid- virus. however, with the possibility of a crisis, such plans may need to be revised for the possibility of non-invasive ventilation. brescia hospital has managed a sizable proportion of its patients with non-invasive ventilation, without evidence of transmission to hospital staff who use appropriate personal protective equipment. the physicians at the study hospital have administered targeted therapies for covid- . sars-cov- is a betacoronavirus, as are sars and middle east respiratory syndrome (mers) coronoviridae. drugs such as lopinavir-ritonavir, interferon, chloroquine, and corticosteroids, have been used in patients with sars or mers, with controversial efficacy. the proteinase inhibitor lopinavir inhibits sars coronavirus, and ritonavir inhibits metabolism of lopinavir, thus increasing its concentration [ ] . the combination lopinavir/ritonavir is speculated as a possible therapy for covid- , as it has demonstrated some efficacy as a treatment for sars. chloroquine and hydroxychloroquine are anti-malarial drugs that have demonstrated in-vitro efficacy against covid- by an as yet not fully understood mechanism [ , ] . hydroxychloroquine might be preferred as it has fewer side effects than chloroquine, but have neither have yet demonstrated efficacy in infected patients. similarly, remdesivir is a potent inhibitor of rna-dependent rna polymerase from mers, and has also demonstrated in-vitro efficacy against covid- [ , ] . tocilizumab is an interleukin- inhibitor with a fairly good safety profile is being studied in china for treatment of covid- [ ] . at present, there are several trials underway in china to test these therapies [ ] , but the answers to such trials may be well after the sars-cov- virus has swept across the globe, killing millions. these therapies are not supported in the current who's interim guidance on managing covid- disease [ ] . there is no clear benefit of these interventions, and recommendations are that investigational therapies should only be conducted in the setting of randomized trials or monitored emergency use of unregistered interventions (meuri). our cohort is insufficiently powered to draw any useful inferences from these anti-covid- drugs. we describe these interventions to offer insight of how physicians treated critically ill patients suffering from a disease with no proven therapies. however, the value of adhering to a severity scale was that interventions could be applied consistently between patients. we believe an instrument, even unvalidated, to guide adjunctive therapies is extremely import for future studies that will attempt to make inferences on those therapy. at present, the numbers are insufficient to make any inferences on the efficacy of therapy. however, as more data accrue, the adherence to a treatment algorithm will improve the quality of such inferences. the ventilator management in this cohort adhered to the who guidelines on low tidal volume ventilation and higher peep. however, the interim guideline advocates for prone positioning in patients with severe ards, and avoidance of routine neuromuscular blockade. prone positioning was employed in only % of patients, and neuromuscular blockade was performed in over half. this practice is underscored by the proposed treatment schema from brescia, which employed neuromuscular blockade prior to prone positioning. many of our patients received antibiotics, which is also in accordance with the who interim guidelines to treat for possible bacterial infection. of note, despite the severity of disease in these patients with confirmed viral infection, procalcitonin was often normal, suggesting it was of low clinical utility in these patients. the severity scale proposed by the authors has not been clinically validated, and likely will warrant further revision as this sars-cov- pandemic progresses. in future iterations, the authors would move prone positioning as a therapy earlier in the scale, and consider omitting corticosteroid therapies based on newer evidence and guideline recommendations from the who [ ] . other drug therapies, such as hydroxycholoroquine, may appear earlier in the treatment plan, as additional data develops. additionally, the inclusion of non-invasive ventilation is a sub-optimal ventilation strategy for patients with covid- , but was chosen due to resource limitations [ ] . non-invasive ventilation may be obviated at other institutions with a surfeit of mechanical ventilators. however, clinicians believed this scale was useful for practicing clinicians to gauge clinical improvement or worsening of patients with sars-cov- . additionally, several patients in the study hospital were managed by non-intensivists out of necessity. these physicians needed guidance for management of patients and the creation of a scale allowed for consistent communication. we believe the value of the scale was to unify communication and management of such patients for intensivists working beyond their normal capacity. the scale also offered value in triage and assignment of resources, aspects of care that are foreign to most physicians. this scale may be of use in the united states, which appears to be on a trajectory for a comparable experience as italy. while the united states has nearly three times the number of icu beds per capita as italy, the staffing limitations may require a twotier model of physician management, as proposed by the society of critical care medicine [ ] . in such a model, use of the brcss or a similar severity scale may augment communication between non-intensivist physicians and nurses. we would recommend intensivists in europe and the americas to consider creating or adapting a similar scale to address the anticipated need for simple and consistent communication with non-intensivist physicians and nurses. our study is quite limited by the nature of the pandemic crisis. however, the need to promulgate the clinical information and management in lombardy required expediency over completion. consequently, clinical outcome data are incomplete. many of the treatments described in this manuscript are unproven. the brcss not been validated for clinical progression of covid- . data collection was limited to icu stay only and cannot inform on non-icu patients or recovery course outside the icu. we describe the early icu experience of patients with covid- in the lombardy region of italy. patients often received non-invasive ventilation as well as invasive, with several adjunctive therapies such as prone position ventilation and neuromuscular blockade. patients also received unproven targeted covid- therapies. the creation of a severity scale helped clinicians communicate and replicate their treatment plans. sp, nl conceived of and designed the study and data collection tools. sp, mf, ft, fr, sc, sdf, in, sb, lf, rt, ge, ef, fc, nl collected data and created the brescia covid severity scale. ml analyzed the data. sp, ml drafted the manuscript. nl, sp, revised the manuscript for important intellectual contribution. all authors read the final manuscript and approved submissions. no competing interests relevant to this study to disclose for all authors. full forms submitted and on file for all authors. in order to protect patient privacy and comply with relevant regulations, identified data are unavailable. requests for de-identified data from qualified researchers with appropriate ethics board approvals and relevant data use agreements may contact comitato.etico@asstspedalicivili.it united-states-resource-availability-for-covid- ?_zs= jxpjd &_zl=w pb raccomandazioni di etica clinica per l'ammissione a trattamenti intensivi e per la loro sospensione role of lopinavir/ritonavir in the treatment of sars: initial virological and clinical findings of chloroquine and covid- in vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus (sars-cov- ) remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus ( -ncov) in vitro the antiviral compound remdesivir potently inhibits rna-dependent rna polymerase from middle east respiratory syndrome coronavirus reducing mortality from -ncov: host-directed therapies should be an option more than clinical trials launch to test coronavirus treatments clinical management of severe acute respiratory infection (sari) when covid- disease is suspected. interim guidance recommendations for airway management in a patient with suspected coronavirus ( -ncov) infection. anesthesia patient safety foundation key: cord- -levsbye authors: almuabbadi, basel; mhawish, huda; marasigan, bobby; alcazar, alva; alfrdan, zahraa; nasim, nasir; alharthy, abdulrahman; memish, ziad a.; karakitsos, dimitrios title: novel transportation capsule technology could reduce the exposure risk to sars-cov- infection among healthcare workers: a feasibility study date: - - journal: infection control and hospital epidemiology doi: . /ice. . sha: doc_id: cord_uid: levsbye nan icu. all data were collected and retrospectively analyzed. of these transported patients, patients had been intubated and patients were on oxygen-supportive therapies. also, hcws were employed for the transportation of covid- patients: physicians, respiratory physiotherapists, icu nurses, and paramedics (fig. ) . apart from utilizing the capsule, all hcws used personal protective equipment according to the world health organization recommendations. none of the hcws became infected. moreover, all awake (ie, nonintubated) patients reported a high level of comfort during transportation. full treatment of icu patients via access ports, which facilitated emergency procedures (eg, intubation and insertion of central lines) has been possible. in conclusion, the insulated patient capsule has proven to be an efficient technology for the transportation of covid- patients. the capsule has shown good compatibility with ventilator circuits and full treatment of icu patients as well as ambulance stretchers. most importantly, none of our hcws was infected in the transportation process. large prospective studies are required to confirm or refute the present findings. strong associations and moderate predictive value of early symptoms for sars-cov- test positivity among healthcare workers, the netherlands covid- : protecting health-care workers escalating infection control response to the rapidly evolving epidemiology of the coronavirus disease (covid- ) due to sars-cov- in hong kong covid- and the risk to healthcare workers: a case report epiguard-medical isolation and transportation systems covid- ) outbreak: rights, roles and responsibilities of health workers, including key considerations for occupational safety and health interim guidance acknowledgments. none.financial support. no financial support was provided relevant to this article.conflicts of interest. all authors report no conflicts of interest relevant to this article. key: cord- - gh i authors: eimer, j.; vesterbacka, j.; svensson, a.-k.; stojanovic, b.; wagrell, c.; sonnerborg, a.; nowak, p. title: tocilizumab shortens time on mechanical ventilation and length of hospital stay in patients with severe covid- : a retrospective cohort study. date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: gh i background: hyperinflammation is a key feature of the pathogenesis of covid- with a central role of the interleukin- pathway. we aimed to study the impact of the il- receptor antagonist tocilizumab on the outcome of patients admitted to the intensive care unit (icu) with acute respiratory distress syndrome (ards) related to covid- . methods: eighty-seven patients with confirmed sars-cov- infection and moderate to severe ards were included (n tocilizumab = , n controls = ). a matched cohort was created using a propensity score. the primary endpoint was -day all-cause mortality, secondary endpoints included ventilation-free days and length of stay. results: no difference was found in -day all-cause mortality in patients treated with tocilizumab compared to controls ( . % vs. . %, p = . ; hr = . [ . - . ], p = . ). ventilator-free days were . (iqr . - . ) versus (iqr . - . ; p = . ), respectively. a higher rate of freedom from mechanical ventilation at days was achieved in patients receiving tocilizumab (hr . [ . - . ], p < . ). median length of stay in icu and total length of stay were reduced by and . days in patients treated with tocilizumab. similar results were obtained in the analysis of the propensity score matched cohort. conclusions: treatment of critically ill patients with ards due to covid- with tocilizumab was not associated with reduced -day all-cause mortality, but shorter duration on ventilatory support as well as shorter overall length of stay in hospital and in icu. dear editor, among patients with covid- who require treatment in intensive care for acute respiratory distress syndrome (ards), mortality rates have been reported between - % ( ). in patients who are discharged alive, an increased risk of sequelae from covid- is anticipated ( ) . the hyperinflammatory response induced by sars-cov- is pivotal in the pathogenesis of covid- and is accompanied by an upregulated expression of interleukin (il- ) that correlates with disease severity ( ) . tocilizumab, a monoclonal antibody against the il- receptor originally licensed for the use in rheumatoid arthritis, is also approved for treatment of chimeric antigen receptor t cell-related cytokine release syndromes and secondary hemophagocytic syndromes that share important features with the hyperinflammatory phase in covid- . several small studies from china and europe have reported promising results of the treatment with tocilizumab in patients with covid- , preventing the need for admission to an intensive care unit and improving clinical outcomes ( , ) . we aimed to evaluate the impact of treatment with tocilizumab compared to routine care on important clinical outcomes in critically ill patients admitted to an intensive care unit with ards due to covid- . we conducted a retrospective cohort study at karolinska university hospital huddinge between th march and th april (regional ethical approval: drn - ). patients over years with confirmed sars-cov- infection were eligible when admitted to the intensive care unit (icu) for severe ards and were followed for days from admission to icu until discharge from hospital or until death, whichever occurred first. all patients who received tocilizumab before admission to or on icu during the study period were included. consideration of treatment with a single dose of tocilizumab at mg/kg was at the discretion of the attending physician and required consultation of at least two members of an expert panel of infectious disease specialists as well as the fulfilment of specific criteria based on respiratory and inflammatory parameters. the control group consisted of consecutively admitted patients to the same icu receiving routine care only (see supplement for details). the primary outcome was -day all cause mortality after admission to icu (= day ). secondary outcomes were time to freedom from mechanical ventilation, number of ventilator-free days in survivors, length of stay in icu and in hospital. clinical endpoints were assessed in the native cohort and in a sub-cohort of patients matched by a propensity score (see supplement for detailed methodology). of patients in the cohort, received tocilizumab and patients received routine care only (control group). twenty-two patients (n= ) from each group were matched within a propensityscore matched sub-cohort. notable differences between groups in the native cohort included a higher proportion of male patients in the tocilizumab group and a lower body mass index. respiratory parameters were comparable upon admission to the hospital and upon admission to icu. in accordance with the prespecified treatment criteria, inflammatory biomarkers were higher in the tocilizumab group upon admission to icu. baseline comparability was improved in the propensity score matched sub-cohort (suppl. table ). as to the outcomes, the difference in all cause mortality at days was not statistically significant (hr = . , % ci . - . , p = . ) ( figure ). however, patients receiving tocilizumab had significantly more ventilator-free days (suppl. table ). freedom from mechanical ventilation was achieved earlier and in a higher proportion of patients (hr . , % ci = . - . , p = . ) (figure ). length of stay in icu and length of stay in hospital were both significantly shorter in patients treated with tocilizumab ( figure ). the rate of serious secondary bacterial infections upon treatment with tocilizumab was comparable to controls. no serious adverse events attributable to the intervention were recorded. analysis of the matched sub-cohort revealed consistent results across all outcomes (figure , suppl. table ). in this retrospective cohort study, the administration of tocilizumab did not reduce all cause mortality but was associated with a shorter time on mechanical ventilation and a shorter length of stay in hospital and in icu in critically ill patients with ards due to covid- . the treatment was well tolerated and not associated with an increased rate of serious adverse events during the study period. results were confirmed in a propensity-score matched sub-cohort. mortality in our study was low compared to previous reports ( ). this may be explained by a comparatively low prevalence of comorbidities and a low median age of years [iqr - ]. four out of five ( / , %) patients who died in icu following treatment with tocilizumab died within nine days from admission to the hospital from multiple organ failure. deaths occurred earlier than in the control group (median vs. days). all of these individuals presented with significant comorbidities. we hypothesize that the early deaths among patients in the intervention group represent a proportion of patients with a poor baseline prognosis and a potentially irreversible hyperinflammatory syndrome. patients receiving tocilizumab had significantly more ventilatorfree days compared to controls and achieved freedom from mechanical ventilation earlier. a pronounced divergence in respiratory recovery between groups was observed after day ( figure ). this may represent a lag time of clinical improvement following the rapid onset of action of tocilizumab. generally, time on the ventilator correlates with subsequent complications such as infections, cognitive impairment and critical illness neuro-myopathy ( ) . thus, our findings suggest a potential role of tocilizumab in the prevention of post-icu sequelae from severe covid- . if confirmed in a prospective randomized trial, the substantial reduction in length of stay in icu observed in our cohort would most likely render the intervention highly cost-efficient, with a single dose of tocilizumab ( mg/kg, adult patient of kg) being priced around . $ in the us according to recently published model ( ). we acknowledge several limitations. our study was designed as a retrospective cohort study at a single academic medical center with inherent limitations to generalizability of findings and potential biases. furthermore, the limited number of patients treated with tocilizumab restricted the power to detect a significant -day mortality difference. a strength of the study is the -day follow up exceeding previous reports on immunomodulatory treatment of covid- and adding further evidence to the course of disease in critically ill patients with covid- . in addition to that, the analysis after propensity score-based matching did not significantly alter the results, thus reducing the likelihood of measured confounders being the sole explanation of the differences in outcomes. in summary, our findings indicate that treatment with tocilizumab of critically ill patients with severe ards due to covid- may reduce time on mechanical ventilation and overall length of stay in icu and in hospital. treatment appears to be safe. data from randomized controlled trials are needed to confirm the results and establish causality. all authors: no reported conflicts of interest. baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region abnormal pulmonary function in covid- patients at time of hospital discharge imbalanced host response to sars-cov- drives development of covid- impact of low dose tocilizumab on mortality rate in patients with covid- related pneumonia effective treatment of severe covid- patients with tocilizumab long-term complications of critical care costs of providing infusion therapy for rheumatoid arthritis in a hospital-based infusion center setting alternate corresponding author / proof reader senior consultant in infectious diseases phone none. key: cord- -ej fx u authors: daunizeau, j.; moran, r. j.; mattout, j.; friston, k. title: on the reliability of model-based predictions in the context of the current covid epidemic event: impact of outbreak peak phase and data paucity date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: ej fx u the pandemic spread of the covid- virus has, as of th of april , reached most countries of the world. in an effort to design informed public health policies, many modelling studies have been performed to predict crucial outcomes of interest, including icu solicitation, cumulated death counts, etc... the corresponding data analyses however, mostly rely on restricted (openly available) data sources, which typically include daily death rates and confirmed covid cases time series. in addition, many of these predictions are derived before the peak of the outbreak has been observed yet (as is still currently the case for many countries). in this work, we show that peak phase and data paucity have a substantial impact on the reliability of model predictions. although we focus on a recent model of the covid pandemics, our conclusions most likely apply to most existing models, which are variants of the so-called 'susceptible-infected-removed' or sir framework. our results highlight the need for performing systematic reliability evaluations for all models that currently inform public health policies. they also motivate a plea for gathering and opening richer and more reliable data time series (e.g., icu occupancy, negative test rates, social distancing commitment reports, etc). as with the situation almost exactly one hundred years ago -with the spanish flu-the pandemic spread of the covid- virus has, as of th of april , reached most countries around the world (johnson and mueller, ) . the entire scientific community is now addressing the many issues that the virus poses, with an unprecedented collaborative spirit. one of these issues is of primary importance for guiding national and international decision makers: namely, predicting the health requirements and outcomes of the current epidemiologic event (siedner et al., ; wang, ) . over the past two months, about a thousand modelling papers have been deposited on preprint servers such as arxiv or medrxiv (nature, ) . this, if anything, demonstrates how fast and efficiently the scientific community can be set in motion towards a common goal. however, it is now apparent that models have not reached consensus, e.g., when it comes to predicting the population levels acquired immunity within the next months . this is unfortunate, since thisand related predictions-are critical for designing suppression or mitigation strategies that aim at limiting the human cost of the current pandemic (canabarro et al., ; james et al., ; rodriguez et al., ) . most models that attempt to furnish such predictions are variants of the sir framework (kermack et al., ) . in brief, these models assume that the population is divided into, e.g., 'susceptible', 'infected', and 'removed ' compartments, through which individuals transit at a pace that is characteristic of the time course of the infection and associated socio-medical measures. under mild assumptions, all sir models predict that the population dynamics will eventually reach so-called 'disease-free equilibria', which signal the end of the epidemic outbreak by exhaustion of the 'susceptible' compartment. this means that the signature of an epidemic lies in the transient dynamics of observable health reports such as confirmed case numbers and mortalities. these models have proven very useful in predicting, e.g., the prevalence or the duration of an epidemic. when properly adjusted to observable epidemiologic data, they also can serve to predict the impact of candidate health policies such as vaccination or social distancing (ganem et al., ; jeria et al., ; kissler et al., ; moghadas et al., ) . given the past success of these models, it may then come as a surprise that, despite relying on the same data sources, these models do not make the same predictions. in this note, we argue that this lack of consensus arises because modellers use the same dataset , which comprises cumulative counts of death and positive covid testing. the critical question here is: can these data sufficiently constrain estimates of sir cycles? if not, then subtle variants of sir models may make dramatically different predictions, despite showing almost no difference in terms of the fit accuracy on the available data so far (salomon, ) . also, model predictions may depend sensitively upon the current phase of the epidemic event: more precisely, whether the outbreak peak has been reached or not (lin et al., ) . this is because the ramping phase of the epidemic transient may not evince all the processes that are relevant for estimating unknown model parameters (and hence making reliable model-based predictions). in this note, we assess the impact of outbreak peak phase and data paucity on the reliability of predictions derived from sir-type models. in particular, we evaluate the prediction accuracy of a recent sir-type model that follows from augmenting the set of data to be explained (in particular, we focus on icu occupancy and negative testing rates , in addition to positive test results and death rates records), depending on whether the outbreak has already been observed or not. in what follows, we will focus on a specific sir model, namely: the so-called dynamic causal model of covid pandemics or dcm-covid moran et al., ) . in brief, the model considers four interacting factors describing location, infection status, test status and clinical status, respectively. within each factor people may probabilistically transition among four distinct states. given a set of model parameters (see below), the model describes the temporal dynamics of the marginal probabilities of belonging to each state within each factor. the location factor describes most modelling studies actually use the johns hopkins university center covid database, which gathers data from who and other national and international health organizations. it produces daily reports of deaths, positive tests and remission cases for most countries in the world (https://coronavirus.jhu.edu/map.html). these kinds of data are made openly available by some governmental organizations (e.g., santé publique france). if an individual is at home, at work , in an intensive care unit (icu) or in the morgue. the infection status is the closest to native sir models, and includes susceptible, infected, contagious or immune states. note that, at this point, the model assumes that the immune state is absorbing, i.e. people cannot get the disease twice. the clinical status factor comprises asymptomatic, symptomatic, acute respiratory distress syndrome (ards) or deceased. finally, the diagnostic status captures the fact that a given individual can be untested, waiting for the results of a test, or declared either positive or negative. model transitions amongst states are controlled by rate constants (inverse time constants) and probability constants (e.g., the probability of dying when in icu). the ensuing set of state probabilities can then be related to some specific observable epidemiologic outcomes, such as the number of deceased people per day or the number of people newly infected who have been tested positive. figure below summarizes the causal structure implicit in conditional transition probabilities. we refer the reader to friston et al. (friston et al., ) for a complete mathematical description of the model. in brief, this compartmental model generates timeseries data based on a mean field approximation to ensemble or population dynamics. the implicit probability distributions are over four latent factors, each with four levels or states (see main text). in particular, this model assumes that (i) there is a progression from a state of susceptibility to immunity, through a period of (pre-contagious) infection to an infectious (contagious) status, (ii) there is a progression from asymptomatic to ards, where people with ards can either recover to an asymptomatic state or not. with this setup, one can be in one of four places, with any infectious status, expressing symptoms or not and having test results or not. note that-in this construction-it is possible to be infected and yet be asymptomatic. crucially, the transitions within any factor depend upon the marginal distribution of other factors. for example, the probability of becoming infected, given that one is susceptible to infection, depends upon whether one is at home or at work. similarly, the probability of developing symptoms depends upon whether one is infected or not. the probability of being testing negative depends upon whether one is susceptible (or immune) to infection, and so on. finally, to complete the circular dependency, the probability of leaving home to go to work depends upon the number of infected people in the population, mediated by social distancing. at any point in time, the probability of being in any combination of the four states determines what would be observed at the population level. for example, the occupancy of the deceased level of the clinical factor determines the current number of people who have recorded deaths. similarly, the occupancy of the positive level of the testing factor determines the expected number of positive cases reported. from these expectations, the expected number of new cases per day can be generated. a more detailed description of the generative model can be found in friston et al . parameter estimation and model comparison relies on a variational bayesian approximation scheme (daunizeau, ; friston et al., ) which is adopted in established computational neuroscience toolboxes (ashburner, ) . in this particular work, we have chosen to implement the dcm-covid model from scratch, and make it available for another open academic model-based data analysis toolbox (daunizeau et al., ) . we did this to provide software validation for subsequent data analyses performed with the dcm-covid model. in addition to semi-informed prior distributions, model inversion -in the current implementation-places hard constraints on parameters to ensure that they stay within admissible ranges. more precisely, rate constants and probability constants are derived by passing unbounded parameters through an exponential mapping and sigmoid mapping, respectively . table below recapitulates the unknown model parameters, in terms of its prior mean and associated hard constraint. is the corresponding country astute readers will notice a few minor changes from the original model inversion scheme proposed by friston et al. . in particular, the hard sigmoid constraint on transition probability parameters ensures that these cannot be greater than one. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / we will pay particular attention to estimates of n  , i.e. the initial number of susceptible people among the country's population. this is because this parameter eventually controls the quantitative predictions regarding specific outcomes of interest, e.g. acquired immunity ratio at the end of this epidemiologic event. note that this type of prediction is critical, because it determines the likelihood of multiple rebounds (i.e. waves) of the covid pandemic are when or if confinement measures are relaxed . most modelling studies to date actually rely on daily who or ecdc data reports, which gathers cumulative death, positive test and remission counts across countries. these dataset are made openly available as part of a global collaborative effort to fight against the covid pandemic (see: https://github.com/cssegisanddata/covid- ). however, remission rates are typically considered unreliable, as is evident from established international worldwide data repositories that prefer to report consolidated death and confirmed positive test counts only (see: https://github.com/owid). this effectively reduces the available data to the death and positive test counts, on which most model predictions rely, including outcomes of interest that are only indirectly informed by these data (e.g., acquired population immunity at the end of the current epidemic outbreak). however, a few governmental agencies have recently made an effort to assemble and make openly available richer datasets, including, e.g., icu occupancy and confirmed negative test counts (see, e.g., for france: https://www.data.gouv.fr/fr/datasets/). this is particularly relevant in this modelling context, because recent sir models comprise multiple compartments that capture modern health care practices that are only partially observable (see, e.g.: https://ecosys.versailles-grignon.inra.fr/spatialagronomy/covid /). as with most modelling studies currently performed on the covid pandemic, previous applications of the dcm-covid model only fitted daily death (hereafter ( ) o ) and positive test ( ( ) o ) counts. however, the structure of the model and its associated inversion world health organization (https://www.who.int/). european centre for disease prevention and control (https://www.ecdc.europa.eu/en). . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint scheme makes it very easy to augment the generated outcome data with remission ( o ), and negative test ( ( ) o ) rates: ( ) ( ) ( ) , tp  is the current transition rate towards the location status 'home'. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / will happen over the next days, given what has happened during the past days. as we will see, the accuracy of the ensuing model predictions actually depends upon how far the country is with respect to the peak of its epidemic outbreak, in terms of the death rate. the accuracy of these predictions will also depend upon what type of data is actually provided to the model inversion. we thus simulated datasets with varying phases of the peak, which could emerge either before or after the first (available) data samples. we did this by randomly sampling the parameter set around the estimated parameters for the french gouv.fr dataset (up to the th of april, see below), which gathers the five outcomes of interest. for each parameter set, we simulated the dcm-covid model over a duration of days. this yielded realistic variations of epidemic outbreak dynamics. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / one can see that all generated outcome dynamics exhibit a simple transient, eventually reaching the disease-free equilibrium state (where inf susceptible p  ). in addition, one can see that simulations are collectively reminiscent of the variability observed across different countries. each simulated data time series was then truncated up to the th day, and then fitted using the dcm-covid vb inversion scheme. we considered two inversion variants:  vb : the full dataset (comprising the five observable outcomes) is provided (up to the th day) to the vb inversion scheme.  vb : remission, icu and negative test time series are omitted (this is the typical situation for most modelling studies so far). for each simulated dataset, we thus obtained two sets of estimated parameters, one from each vb inversion schemes. we derive the ensuing predictions by simulating the model for the remaining days, given each of those estimated parameter sets. we then estimated the following estimation/prediction accuracy metrics:  peak date estimation error, which we define as follows:  maximum icu occupancy: max max tt tt . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . we then analysed the impact of the time-to-peak ( peak  ) and data paucity (cf. the two vb variants) onto the four prediction/estimation error scores above. a. influence of date-to-peak and dataset availability on prediction/estimation accuracy one can see that this relationship is highly variable, i.e. estimation/prediction errors are clearly non-negligible. importantly, these errors are not due to model underfitting, . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint since the percentage of explained variance in fitted data (i.e. data up to days) is always greater than % (vb : mean r = %, vb : mean r = %). therefore, estimation/prediction errors are due to non-identifiability. the structure of these errors is most apparent for time-to-peak (cf. upper-left panel in figure ). when the simulated time-to-peak peak   , the correlation between simulated and estimated time-topeaks in the initial (observed) days is almost perfect. however, this correlation quickly falls as the simulated time-to-peak increases beyond the temporal window of observed data (and more so when fitted data is restricted to daily death counts and positive test rates: vb ). the structure of estimation/prediction errors is less explicit for outcomes of interest. we now evaluate the impact of simulated time-to-peak and data availability on estimation/prediction errors. first, we split the simulations according to whether the simulated death rate peak arose before the last observed sample (   , "early peak") or after (   , "late peak"). this enabled us to ask whether the prediction/estimation errors above were higher for late than for early peaks. figure below summarizes the simulation results, in terms of the influence of time-to-peak (early versus late peak) and dataset availability (vb versus vb ) onto prediction/estimation accuracy. is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . to begin with, note the typical error magnitude for the four outcomes of interest: timeto-peak error is of the order of days, cumulative death count error is about , people, the error on the initial number of susceptible people is millions, and the maximum icu occupancy error is around , . these errors are beyond acceptable limits, for most practical applications to public health policies. but, as we will see, error magnitudes depend sensitively upon time-to-peak and data paucity. one can see a clear influence of the time-to-peak onto all prediction/estimation error measures. in brief, it seems that both prediction and estimation are much less accurate when they are performed before the death rate peak has been observed (late peak). it transpires that, when the peak can be observed in the fitted data (early peaks), vb accuracy is significantly higher than vb accuracy for both icu occupancy (p< - ) and initial number of susceptible people (p< - ). in contrast, when the peak is yet to manifest (late peaks), only the accuracy on time-to-peak estimation is significantly worse for vb than for vb (p< - ). interestingly, the icu occupancy error is highest for vb when the peak has already been observed (cf. lower right panel). this counterintuitive result derives from the fact that default model explanations of death and positive test rates dynamics favour overestimated icu occupancy (which, for vb , is . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . not constrained by icu occupancy data). this will be clearer when analysing the french dataset below. in summary, the reliability of almost all predicted outcomes is severely impacted when the data analysis is performed before the epidemic peak has been observed. in addition, ignoring data such as icu occupancy and negative test rates strongly impairs the estimation of the initial number of susceptible people as well as the maximum icu occupancy, in particular when data is analysed > days before the epidemic peak has been observed. we will now illustrate our analysis of the reliability of the model's prediction/estimation using a single country's data. we focus on french data, because governmental agencies provide additional data , which are missing from who or ecdc databases (as of today). note that reported daily death rates are restricted to hospital data, i.e. it does not include those people who do not die in hospitals (c.f. e.g., retirement homes). we pre-processed the time series to correct data reports from various counting errors (see below). we also padded the governmental data with ecdc data from the st of january to the th of march (for both daily death and positive test rates) because these dates are not reported in the online available governmental data repositories. this means that there are missing data for both icu occupancy and total test rates. figure below shows the effect of data smoothing on the observed data. these data are made available online here: https://www.data.gouv.fr/en/datasets/donnees-hospitalieresrelatives-a-lepidemie-de-covid- / and here: https://www.data.gouv.fr/en/datasets/donnees-relatives-auxtests-de-depistage-de-covid- -realises-en-laboratoire-de-ville/. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . one can see that the native positive and total test rates exhibit strong periodic dips. inspection of the corresponding dates show that these dips correspond to data reports made on weekends. data pre-processing corrects most of these inconsistencies, without impacting on the corresponding cumulated counts (not shown). we conducted two analyses on these corrected datasets, by either fitting all reported data (vb ) or only daily death and positive test rates (vb ). figure below summarizes the ensuing data fits and their predicted dynamics days beyond the last reported date. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . recall that vb and vb both attempt to account for observed daily death rates and positive test rates. one can see that both succeed in explaining these time series with very high accuracy. in fact, vb explains these data better however, only vb tries to concurrently fit icu occupancy and negative test rates. here again, observed time series are very well explained (vb : r [icu occupancy]= %, r [total test rate]= %). in contrast, vb 's estimates of these time series are substantially overestimated. this is because vb has (unknowingly) overfitted the positive test rates, which has resulted in parameter estimation errors. the situation is quite different for vb , which had to find parameter estimates that yield a balanced trade-off between all concurrent data reports. this observation recapitulates the simulations results regarding icu occupancy error (although france is currently lying in between typical early or late peak phases). . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / although fit accuracies for common datasets are comparable, vb and vb make remarkably different predictions. this is illustrated on figure below. first, the estimated peak date is th of april for vb , whereas it is nd of april for vb (this can be seen in figure ). second, the predicted cumulated death counts after the current epidemic outbreak clearly differ. for vb , predicted cumulated death counts should be +/- ( , as of -apr- ), whereas for vb , predicted cumulated death counts should be +/- . in brief, ignoring icu occupancy and negative test rates yield epidemic outbreaks that terminate sooner and are less severe (in terms of casualties). third, recall that the model can be used to derive estimates of effective reproduction rates (r ), i.e. the expected number of people who are infected by a covid-carrier. this summary statistics of the infectiousness of the epidemics varies over time, depending upon the probability that people stay at home or not (this changes the . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / effective number of social contacts), and the probability of being susceptible to the disease. we refer the interested reader to equation . in friston et al . it turns out that model-based estimates of the effective reproduction rates' dynamics are clearly higher when accounting for icu occupancy and negative test rates (cf. upper-right panel on figure ). note that the effective reproduction rate starts to decrease roughly at the date of public lockdown (tuesday the th of march). this is interesting because the model is not informed about this public health event. more precisely, it defines social distancing in terms of the (hidden) behaviour of citizens, without assuming that everyone follows the governmental containment instructions. finally, accounting for icu occupancy and negative test rates produce more uncertain parameter estimates (cf. lower panels on figure ). this is most likely because vb overfits the observed data, effectively yielding underestimated (overconfident) evaluations of parameter estimation uncertainty. in this work, we have evaluated the reliability of model-based estimations/predictions for four outcomes of interest in the context of the current covid pandemics. we have shown that the reliability of these predictions depends sensitively upon whether they are derived before or after the epidemic outbreak peak. in addition, we have shown that data paucity (in particular, ignoring icu occupancy and negative test rates) can accentuate these prediction errors, even when the outbreak peak has already been observed. this is crucial when estimating the initial number of susceptible people, given that it determines the immunity ratio acquired by the population at the end of the epidemic event . we have also illustrated the impact of discounting icu occupancy and negative test rates on french data available to date. this is a timely analysis, since france is, in all likelihood, currently experiencing the peak of the current epidemic outbreak. the outbreak peak is a significant marker of the rise and fall of distinct transient epidemic dynamics (and its associated public health measures), the late phase of which is crucial to inform parameter estimation. this is reminiscent of what could be . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / observed in dcms for neural responses, where for instance, the key role of feedback connections between neuronal populations can only be evidenced once the first peak of the electrophysiological evoked response has been observed (garrido et al., ) . here, some key hidden biological processes (and their associated unknown parameters) can only be reliably inferred after the peak of the transient dynamics. having said this, the reliability of model-based predictions for countries that have not passed the peak yet (as is still the case now) could in fact be improved by informing the parameter estimation with data from countries where the outbreak peak has already been observed, using, e.g., hierarchical empirical bayes models kass and steffey, ) . at the european level in particular, this speaks to a common effort to gather and share data. from a statistical perspective, one may not be surprised that prediction/estimation errors decrease when augmenting the fitted data with icu occupancy and negative test rates. what is remarkable however, is the quantitative difference it makes for e.g., cumulative death counts or effective reproduction rates (see figures and ) . more remarkable is the interaction of data paucity and timing of predictions with respect to the outbreak peak. more generally, in those particular times where uncertainty is high and decisions have to be made as quickly as possible, it may be particularly important to complement models with quantitative assessments of their reliability and the limits of our predictive approaches. as a side point, we have not addressed the reliability of the data we have used in our analysis. daily death counts, for example, are potentially problematic for at least two reasons. first, different data repositories effectively give different numbers, e.g., people deceased in hospitals (as is the case for the french data we have presented here), or in hospitals and retirement homes. second, they may not account for "normal" seasonal mortality (goldstein et al., ) , though this is not the case here (because these hospital death counts are confirmed covid cases). testing procedures also have imperfect sensitivity and specificity (patel et al., ) , and icu occupancy actually depend upon heterogeneous clinical criteria (e.g., respiratory support versus reanimation). all these limitations are difficult (though not impossible) to account for, and further challenge even further the reliability of model-based predictions. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . . https://doi.org/ . / contrary to most papers that focus on model definition and extension, the approach here tackles this assessment which we believe will become more and more important as more alternative models are proposed, to account for, e.g., the influence of lockdown decisions. this applies to the dcm-covid model we evaluate here, which is currently being refined along these lines. the kind of data that may need to be acquired to inform the ensuing model predictions is an issue of primary practical importance if this or similar models are to guide public health decisions. performing this type of analysis for currently available models is beyond the scope of the current work. however, our results highlight the need for evaluating the reliability of model predictions that are currently used by national and international socio-political decision makers. they also motivate the gathering of multiple data time series and making them available to the modelling community. this requirement obviously extends beyond icu occupancy and negative test rates salomon, ) . in the near future for instance, data about the number of asymptomatic cases in the population, about how infectious are children or about individual immunity after recovery may prove critical. in order to validate model predictions, particularly those related to infected or clinical status, biological assays of these inferred measures are required. serological surveys for example are being rolled out to examine community infection rates. in a recent study in the santa clara region of california antibodies to sars-cov- were identified in . % of , people sampledwith an adjusted population prevalence of . % to . % of the population (bendavid et al., ) , with similar rates identified in an analysis of dutch blood samples in line with model estimates . larger 'serosurveys' will ultimately be required to more precisely define these measures with large populations being enrolled currently in germany and by the us national institute of health. in addition, reports from centres of recent outbreaks are providing further details that can inform model parameter priors. for example two hospitals in new york city have recently reported a mechanical ventilation requirement for . % of patients admitted for the treatment of covid- (goyal et al., ) . the impact of these and other kinds of data on the reliability of model-based predictions could be evaluated with the approach presented here, irrespective of the model used. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . . https://doi.org/ . / spm: a history covid- antibody seroprevalence in data-driven study of the covid- pandemic via age-structured modelling and prediction of the health system failure in brazil amid diverse intervention strategies mitigating covid- outbreak via high testing capacity and strong transmission-intervention in the united states the variational laplace approach to approximate bayesian inference vba: a probabilistic treatment of nonlinear models for neurobiological and behavioural data variational free energy and the laplace approximation dynamic causal modelling of covid- the impact of early social distancing at covid- outbreak in the largest metropolitan area of brazil evoked brain responses are generated by feedback loops improving the estimation of influenza-related mortality over a seasonal baseline clinical characteristics of covid- in suppression and mitigation strategies for control of covid- in new zealand chloroquine and hydroxychloroquine for the treatment of covid- : a living systematic review protocol updating the accounts: global mortality of the - "spanish" influenza pandemic approximate bayesian inference in conditionally independent hierarchical models (parametric empirical bayes models) a contribution to the mathematical theory of epidemics projecting the transmission dynamics of sars-cov- through the postpandemic period explaining the bomb-like dynamics of covid- with modeling and the implications for policy projecting hospital utilization during the covid- outbreaks in the united states estimating required lockdown cycles before immunity to sars-cov- : model-based analyses of susceptible population sizes, s , in seven european countries including the uk and ireland pick of the coronavirus papers : how hong kong stemmed viral spread without harsh restrictions report from the american society for microbiology covid- international summit a mechanistic population balance model to evaluate the impact of interventions on infectious disease outbreaks: case for covid defining high-value information for covid- decision-making key: cord- -fr uod authors: nan title: saem abstracts, plenary session date: - - journal: acad emerg med doi: . /j. - . . .x sha: doc_id: cord_uid: fr uod nan objectives: we sought to determine if the ocp policy resulted in a meaningful and sustained improvement in ed throughput and output metrics. methods: a prospective pre-post experimental study was conducted using administrative data from community and tertiary centers across the province. the study phases consisted of the months from february to september compared against the same months in . operational data for all centres were collected through the edis tracking systems used in the province. the ocp included main triggers: ed bed occupancy > %, at least % of ed stretchers blocked by patients awaiting inpatient bed or disposition decision, and no stretcher available for high acuity patients. when all criteria were met, selected boarded patients were moved to an inpatient unit (non-traditional care space if no bed available). the primary outcome was ed length of stay (los) for admitted patients. the ed load of boarded patients from - am was reported the editors of academic emergency medicine (aem) are honored to present these abstracts accepted for presentation at the annual meeting of the society for academic emergency medicine (saem), may to in chicago, illinois. these abstracts represent countless hours of labor, exciting intellectual discovery, and unending dedication by our specialty's academicians. we are grateful for their consistent enthusiasm, and are privileged to publish these brief summaries of their research. this year, saem received abstracts for consideration, and accepted . each abstract was independently reviewed by up to six dedicated topic experts blinded to the identity of the authors. final determinations for scientific presentation were made by the saem program scientific subcommittee co-chaired by ali s. raja, md, mba, mph and steven b. bird, md, and the saem program committee, chaired by michael l. hochberg, md. their decisions were based on the final review scores and the time and space available at the annual meeting for oral and poster presentations. there were also innovation in emergency medicine education (ieme) abstracts submitted, of which were accepted. the ieme subcommittee was co-chaired by joanna leuck, md and laurie thibodeau, md. we present these abstracts as they were received, with minimal proofreading and copy editing. any questions related to the content of the abstracts should be directed to the authors. presentation numbers precede the abstract titles; these match the listings for the various oral and poster sessions at the annual meeting in chicago, as well as the abstract numbers (not page numbers) shown in the key word and author indexes at the end of this supplement. all authors attested to institutional review board or animal care and use committee approval at the time of abstract submission, when relevant. abstracts marked as ''late-breakers'' are prospective research projects that were still in the process of data collection at the time of the december abstract deadline, but were deemed by the scientific subcommittee to be of exceptional interest. these projects will be completed by the time of the annual meeting; data shown here may be preliminary or interim. on behalf of the editors of aem, the membership of saem, and the leadership of our specialty, we sincerely thank our research colleagues for these contributions, and their continuing efforts to expand our knowledge base and allow us to better treat our patients. david background: two to ten percent of patients evaluated in the emergency departments (ed) present with altered mental status (ams). the prevalence of non-convulsive seizure (ncs) and other electroencephalographic (eeg) abnormalities in this population is not known. this information is needed to make recommendations regarding the routine use of emergent eeg in ams patients. objectives: to identify the prevalence of ncs and other eeg abnormalities in ed patients with ams. methods: an ongoing prospective study at two academic urban ed. inclusion: patients ‡ years old with ams. exclusion: an easily correctable cause of ams (e.g. hypoglycemia, opioid overdose). a -minute eeg with the standard electrodes was performed on each subject as soon as possible after presentation (usually within hour). outcome: the rate of eeg abnormalities based on blinded review of all eegs by two boardcertified epileptologists. descriptive statistics are used to report eeg findings. frequencies are reported as percentages with % confidence intervals (ci), and inter-rater variability is reported with kappa. results: the interim analysis was performed on consecutive patients (target sample size: ) enrolled from may to october (median age: , range - , % male). eegs for patients were reported uninterpretable by at least one rater ( by both raters). of the remaining , only ( %, %ci - %) were normal according to either rater (n = by both). the most common abnormality was background slowing (n = , %, %ci - %) by either rater (n = by both), indicating underlying encephalopathy. ncs was diagnosed in patients ( %, %ci, - %) by at least one rater (n = by both), including ( %, %ci - %) patients in non-convulsive status epilepticus (ncse). patients ( %, %ci - %) had interictal epileptiform discharges read by at least one rater (n = by both) indicating cortical irritability and an increased risk of spontaneous seizure. inter-rater reliability for eeg interpretations was modest (kappa: . , %ci . - . ). objectives: to define diagnostic sbi and non-bacterial (non-sbi) biosignatures using rna microarrays in febrile infants presenting to emergency departments (eds). methods: we prospectively collected blood for rna microarray analysis in addition to routine screening tests including white blood cell (wbc) counts, urinalyses, cultures of blood, urine, and cerebrospinal fluid, and viral studies in febrile infants days of age in eds . we defined sbi as bacteremia, urinary tract infection (uti), or bacterial meningitis. we used class comparisons (mann-whitney p < . , benjamini for mtc and . fold change filter), modular gene analysis, and k-nn algorithms to define and validate sbi and non-sbi biosignatures in a subset of samples. results: % ( / ) of febrile infants were evaluated for sbi. . % ( / ) had sbi ( ( . %) bac-teremia, ( . %) utis, and ( . %) bacterial meningitis). infants with sbis had higher mean temperatures, and higher wbc, neutrophil, and band counts. we analyzed rna biosignatures on febrile infants: sbis ( meningitis, bacteremia, uti), non-sbis ( influenza, enterovirus, undefined viral infections), and healthy controls. class comparisons identified , differentially expressed genes between sbis and non-sbis. modular analysis revealed overexpression of interferon related genes in non-sbis and inflammation related genes in sbis. genes were differently expressed (p < . ) in each of the three non-sbi groups vs sbi group. unsupervised cluster analysis of these genes correctly clustered % ( / ) of non-sbis and sbis. k-nn algorithm identified discriminatory genes in training set ( non-sbis vs sbis) which classified an independent test ( non-sbis vs sbis) with % accuracy. four misclassified sbis had over-expression of interferon-related genes, suggesting viral-bacterial co-infections, which was confirmed in one patient. background: improving maternal, newborn, and child health (mnch) is a leading priority worldwide. however, limited frontline health care capacity is a major barrier to improving mnch in developing countries. objectives: we sought to develop, implement, and evaluate an evidence-based maternal, newborn, and child survival (mncs) package for frontline health workers (fhws). we hypothesized that fhws could be trained and equipped to manage and refer the leading mnch emergencies. methods: setting -south sudan, which suffers from some of the world's worst mnch indices. assessment/intervention -a multi-modal needs assessment was conducted to develop a best-evidence package comprised of targeted trainings, pictorial checklists, and reusable equipment and commodities ( figure ). program implementation utilized a trainingof-trainers model. evalution - ) pre/post knowledge assessments, ) pre/post objective structured clinical examinations (osces), ) focus group discussions, and ) closed-response questionnaires. results: between nov to oct , local trainers and fhws were trained in of the states in south sudan. knowledge assessments among trainers (n = ) improved significantly from . % (sd . ) to . % (sd . ) (p < . ). mean scores a maternal osce and a newborn osce pre-training, immediately post-training, and upon - month follow-up are shown in the table. closed-response questionnaires with fhws revealed high levels of satisfaction, use, and confidence with mncs materials. participants reported an average of . referrals (range - ) to a higher level of care in the - months since training. furthermore, . % of fhws were more likely to refer patients as a result of the training program. during seven focus group discussions with trained fhws, respondents (n = ) reported high satisfaction with mncs trainings, commodities, and checklists, with few barriers to implementation or use. conclusion: these findings suggest mncs has led to improvements in south sudanese fhws' knowledge, skills, and referral practices with respect to appropriate management of mnch emergencies. no study has compared various lactate measurements to determine the optimal parameter to target. objectives: to compare the association of blood lactate kinetics with survival in patients with septic shock undergoing early quantitative resuscitation. methods: preplanned analysis of a multicenter edbased rct of early sepsis resuscitation targeting three physiological variables: cvp, map, and either central venous oxygen saturation or lactate clearance. inclusion criteria: suspected infection, two or more sirs criteria, and either sbp < mmhg after a fluid bolus or lactate > mmol/l. all patients had an initial lactate measured with repeat at two hours. normalization of lactate was defined a lactate decline to < . mmol/l in a patient with an intial lactate ‡ . . absolute lactate clearance (initial -delayed value), and relative ((absolute clearance)/(initial value)* ) were calculated if the initial lactate was ‡ . . the outcome was in-hospital survival. receiver operating characteristic curves were constructed and areas under the curve (auc) were calculated. difference in proportions of survival between the two groups at different lactate cutoffs were analyzed using % ci and fisher exact tests. results: of included patients, the median initial lactate was . mmol/l (iqr . , . ), and the median absolute and relative lactate clearance were mmol/l (iqr . , . ) and % (iqr , ). an initial lactate > . mmol/l was seen in / ( %), and / ( %) patients normalized their lactate. overall sutures on trunk and extremity lacerations that present in the ed. the use of absorbable sutures in the ed setting confers several advantages: patients do not need to return for suture removal which results in a reduction in ed crowding, ed wait times, missed work or school days, and stressful procedures (suture removal) for children. objectives: the primary objective of this study is to compare the cosmetic outcome of trunk and extremity lacerations repaired using absorbable versus nonabsorbable sutures in children and adults. a secondary objective is to compare complication rates between the two groups. methods: eligible patients with lacerations were randomly allocated to have their wounds repaired with vicryl rapide (absorbable) or prolene (nonabsorbable) sutures. at a day follow-up visit the wounds were evaluated for infection and dehiscence. after months, patients were asked to return to have a photograph of the wound taken. two blinded plastic surgeons using a previously validated mm visual analogue scale (vas) rated the cosmetic outcome of each wound. a vas score of mm or greater was considered to be a clinically significant difference. results: of the patients enrolled, have currently completed the study including in the vicryl rapide group and in the prolene group. there were no significant differences in the age, race, sex, length of wound, number of sutures, or layers of repair in the two groups. the observer's mean vas for the vicryl rapide group was . mm ) and that for the prolene group was . mm ( %ci . - . ), resulting in a mean difference of . mm ( %ci- . to . , p = . ). there were no significant differences in the rates of infection, dehiscence, or keloid formation between the two groups. conclusion: the use of vicryl rapide instead of nonabsorbable sutures for the repair of lacerations on the trunk and extremities should be considered by emergency physicians as it is an alternative that provides a similar cosmetic outcome. objectives: to determine the relationship between infection and time from injury to closure, and the characteristics of lacerations closed before and after hours of injury. methods: over an month period, a prospective multi-center cohort study was conducted at a teaching hospital, trauma center and community hospital. emergency physicians completed a structured data form when treating patients with lacerations. patients were followed to determine whether they had suffered a wound infection requiring treatment and to determine a cosmetic outcome rating. we compared infection rates and clinical characteristics of lacerations with chisquare and t-tests as appropriate. results: there were patients with lacerations; had documented times from injury to closure. the mean times from injury to repair for infected and noninfected wounds were . vs. . hrs (p = . ) with % of lacerations treated within hours and % ( ) treated hours after injury. there were no differences in the infection rates for lacerations closed before ( . %, %ci . - . ) or after ( . %, %ci . - . ) hours and before ( . %, % ci . %- . %) or after ( . %, % ci . %- . %) hours. the patients treated hours after injury tended to be older ( vs. yrs p = . ) and fewer were treated with primary closure ( % vs. % p < . ). comparing wounds or more hours after injury with more recent wounds, there was no effect of location on decision to close. wounds closed after hours did not differ from wounds closed before hours with respect to use of prophylactic antibiotics, type of repair, length of laceration, or cosmetic outcome. conclusion: closing older lacerations, even those greater than hours after injury, does not appear to be associated with any increased risk of infection or adverse outcomes. excellent irrigation and decontamination over the last years may have led to this change in outcome. background: deep burns may result in significant scarring leading to aesthetic disfigurement and functional disability. tgf-b is a growth factor that plays a significant role in wound healing and scar formation. objectives: the current study was designed to test the hypothesis that a novel tgf-b antagonist would reduce scar contracture compared with its vehicle in a porcine partial thickness burn model. methods: ninety-six mid-dermal contact burns were created on the backs and flanks of four anesthetized young swine using a gm aluminum bar preheated to °celsius for seconds. the burns were randomized to treatment with topical tgf-b antagonist at one of three concentrations ( , , and ll) in replicates of in each pig. dressing changes and reapplication of the topical therapy were performed every days for weeks then twice weekly for an additional weeks. burns were photographed and full thickness biopsies were obtained at , , , , and days to determine reepithelialization and scar formation grossly and microscopically. a sample of burns in each group had % power to detect a % difference in percentage scar contracture. results: a total of burns were created in each of the three study groups. burns treated with the high dose tgf-b antagonist healed with less scar contracture than those treated with the low dose and control ( ± %, ± %, and ± %; anova p = . ). additionally, burns treated with the higher, but not the lower dose of tgf-b antagonist healed with significantly fewer full thickness scars than controls ( . % vs. % vs. . % respectively; p < . ). there were no infections and no differences in the percentage wound reepithelialization among all study groups at any of the time points. conclusion: treatment of mid-dermal porcine contact burns with the higher dose tgf-b antagonist reduced scar contracture and rate of deep scars compared with the low dose and controls. background: diabetic ketoacidosis (dka) is a common and lethal complication of diabetes. the american diabetes association recommends treating adult patients with a bolus dose of regular insulin followed by a continuous insulin infusion. the ada also suggests a glucose correction rate of - mg/dl/hr to minimize complications. objectives: compare the effect of bolus dose insulin therapy with insulin infusion to insulin infusion alone on serum glucose, bicarbonate, and ph in the initial treatment of dka. methods: consecutive dka patients were screened in the ed between march ' and june ' . inclusion criteria were: age > years, glucose > mg/dl, serum bicarbonate or ketonemia or ketonuria. exclusion criteria were: congestive heart failure, current hemodialysis, pregnancy, or inability to consent. no patient was enrolled more than once. patients were randomized to receive either regular insulin . units/kg or the same volume of normal saline. patients, medical and research staff were blinded. baseline glucose, electrolytes, and venous blood gases were collected on arrival. bolus insulin or placebo was then administered and all enrolled patients received regular insulin at rate of . unit/kg/hr, as well as fluid and potassium repletion per the research protocol. glucose, electrolytes, and venous blood gases were drawn hourly for hours. data between two groups were compared using unpaired t-test. results: patients were enrolled, with being excluded. patients received bolus insulin; received placebo. no significant differences were noted in initial glucose, ph, bicarbonate, age, or weight between the two groups. after the first hour, glucose levels in the insulin group decreased by mg/dl compared to mg/dl in the placebo group (p = . , % ci . to . ). changes in mean glucose levels, ph, bicarbonate level, and ag were not statistically different between the two groups for the remainder of the hour study period. there was no difference in the incidence of hypoglycemia in the two groups. conclusion: administering a bolus dose of regular insulin decreased mean glucose levels more than placebo, although only for the first hour. there was no difference in the change in ph, serum bicarbonate or anion gap at any interval. this suggests that bolus dose insulin may not add significant benefit in the emergency management of dka. ihca; . return of spontaneous circulation (rsoc). traumatic cardiac arrests were excluded. we recorded baseline demographics, arrest event characteristics, follow-up vitals and laboratory data, and in-hospital mortality. apache ii scores were calculated at the time of rosc, and at hrs, hrs, and hrs. we used simple descriptive statistics to describe the study population. univariate logistic regression was used to predict mortality with apache ii as a continuous predictor variable. discrimination of apache ii scores was assessed using the area under the curve (auc) of the receiver operator characteristic (roc) curve. results: a total of patients were analyzed. the median age was years (iqr: - ) and % were female. apache ii score was a significant predictor of mortality for both ohca and ihca at baseline and at all follow-up time points (all p < . ). discrimination of the score increased over time and achieved very good discrimination after hrs (table, figure) . conclusion: the ability of apache ii score to predict mortality improves over time in the hours following cardiac arrest. these data suggest that after hours, apache ii scoring is a useful severity of illness score in all post-cardiac arrest patients. background: admission hyperglycemia has been described as a mortality risk factor for septic non-diabetics, but the known association of hyperglycemia with hyperlactatemia (a validated mortality risk factor in sepsis) has not previously been accounted for. objectives: to determine whether the association of hyperglycemia with mortality remains significant when adjusted for concurrent hyperlactatemia. methods: this was a post-hoc, nested analysis of a single-center cohort study. providers identified study subjects during their ed encounters; all data were collected from the electronic medical record. patients: nondiabetic adult ed patients with a provider-suspected infection, two or more systemic inflammatory response syndrome criteria, and concurrent lactate and glucose testing in the ed. setting: the ed of an urban teaching hospital; to . analysis: to evaluate the association of hyperglycemia (glucose > mg/dl) with hyperlactatemia (lactate ‡ . mmol/l), a logistic regression model was created; outcome-hyperlactatemia; primary variable of interest-hyperglycemia. a second model was created to determine if concurrent hyperlactatemia affects hyperglycemia's association with mortality; outcome- -day mortality; primary risk variablehyperglycemia with an interaction term for concurrent hyperlactatemia. both models were adjusted for demographics, comorbidities, presenting infectious syndrome, and objective evidence of renal, respiratory, hematologic, or cardiovascular dysfunction. results: ed patients were included; mean age ± years. ( %) subjects were hyperglycemic, ( %) hyperlactatemic, and ( %) died within days of the initial ed visit. after adjustment, hyperglycemia was significantly associated with simultaneous hyperlactatemia (or . , %ci . , . ). hyperglycemia with concurrent hyperlactatemia was associated with increased mortality risk (or . , %ci . , . ) , but hyperglycemia in the absence of simultaneous hyperlactatemia was not (or . , %ci . , . ) . conclusion: in this cohort of septic adult non-diabetic patients, mortality risk did not increase with hyperglycemia unless associated with simultaneous hyperlactatemia. the previously reported association of hyperglycemia with mortality in this population may be due to the association of hyperglycemia with hyperlactatemia. the background: near infrared spectroscopy (sto ) represents a measure of perfusion that provides the treating physician with an assessment of a patient's shock state and response to therapy. it has been shown to correlate with lactate and acid/base status. it is not known if using information from this monitor to guide resuscitation will result in improved patient outcomes. objectives: to compare the resuscitation of patients in shock when the sto monitor is or is not being used to guide resuscitation. methods: this was a prospective study of patients undergoing resuscitation in the ed for shock from any cause. during alternating day periods, physicians were blinded to the data from the monitor followed by days in which physicians were able to see the information from the sto monitor and were instructed to resuscitate patients to a target sto value of . adult patients (age> ) with a shock index (si) of > . (si = heart rate/systolic blood pressure) or a blood pressure < mmhg systolic who underwent resuscitation were enrolled. patients had a sto monitor placed on the thenar eminence of their least-injured hand. data from the sto monitor were recorded continuously and noted every minute along with blood pressure, heart rate, and oxygen saturation. all treatments were recorded. patients' charts were reviewed to determine the diagnosis, icu-free days in the days after enrollment, inpatient los, and -day mortality. data were compared using wilcoxon rank sum and chi-square tests. results: patients were enrolled, during blinded periods and during unblinded periods. the median presenting shock index was . (range . to . ) for the blinded group and . ( . - . ) for the unblinded group (p = . ). the median time in department was minutes (range - ) for the blinded and minutes (range - ) for the unblinded groups (p = . ). the median hospital los was day (range - ) for the blinded group, and days (range - ) in the unblinded group (p = . ). the mean icu-free days was ± for the blinded group and ± for the unblinded group (p = . ). among patients where the physician indicated using the sto monitor data to guide patient care, the icu-free days were . ± for the blinded group and . ± for the blinded group (p = . ). background: inducing therapeutic hypothermia (th) using °c iv fluids in resuscitated cardiac arrest patients has been shown to be feasible and effective. limited research exists assessing the efficiency of this cooling method. objectives: the objective was to determine an efficient infusion method for keeping fluid close to °c upon exiting an iv. it was hypothesized that colder temperatures would be associated with both higher flow rate and insulation of the fluid bag. methods: efficiency was studied by assessing change in fluid temperature ( c) during the infusion, under three laboratory conditions. each condition was performed four times using liter bags of normal saline. fluid was infused into a ml beaker through gtts tubing. flow rate was controlled using a tubing clamp and in-line transducer with a flowmeter, while temperature was continuously monitored in a side port at the terminal end of the iv tubing using a digital thermometer. the three conditions included infusing chilled fluid at a rate of ml/min, which is equivalent to ml/kg/hr for an kg patient, ml/min, and ml/min using a chilled and insulated pressure bag. descriptive statistics and analysis of variance was performed to assess changes in fluid temperature. results: the average fluid temperatures at time were . ( % ci . - . ) ( ml/min), . ( % ci . - . ) ( ml/min), and . ( % ci . - . ) ( ml/min + insulation). there was no significant difference in starting temperature between groups (p = . ). the average fluid temperatures after ml had been infused were . ( % ci . - . ) ( ml/min), . ( % ci . - . ) ( ml/min), and . ( % ci . - . ) ( ml/min + insulation). the higher flow rate groups had significantly lower temperature than the lower flow rate after ml of fluid had been infused (p < . ). the average fluid temperatures after ml had been infused were . ( % ci . - . ) ( ml/min), . ( % ci . - . ) ( ml/min), and . ( % ci . - . ) ( ml/min + insulation). there was a significant difference in temperature between all three groups after ml of fluid had been infused (p < . ). conclusion: in a laboratory setting, the most efficient method of infusing cold fluid appears to be a method that both keeps the bag of fluid insulated and is infused at a faster rate. fluid bolus. patients were categorized by presence of vasoplegic or tissue dysoxic shock. demographics and sequential organ failure assessment (sofa) scores were evaluated between the groups. the primary outcome was in-hospital mortality. data were analyzed using t-tests, chi-squared test, and proportion differences with % confidence intervals as appropriate. results: a total of patients were included: patients with vasoplegic shock and with tissue dysoxic shock. there were no significant differences in age ( vs. years), caucasian race ( % vs. %), or male sex ( % vs. %) between the dysoxic shock and vasoplegic shock groups, respectively. the group with vasoplegic shock had a lower initial sofa score than did the group with tissue dysoxic shock ( . vs. . points, p = . ). the primary outcome of in-hospital mortality occurred in / ( %) of patients with vasoplegic shock compared to / ( %) in the group with tissue dysoxic shock (proportion difference %, % ci - %, p < . ). conclusion: in this analysis of patients with septic shock, we found a significant difference in in-hospital mortality between patients with vasoplegic versus tissue dysoxic septic shock. these findings suggest a need to consider these differences when designing future studies of septic shock therapies. background: the pre-shock population, ed sepsis patients with tissue hypoperfusion (lactate of . - . mm), commonly deteriorates after admission and requires transfer to critical care. objectives: to determine the physiologic parameters and disease severity indices in the ed pre-shock sepsis population that predict clinical deterioration. we hypothesized that neither initial physiologic parameters nor organ function scores will be predictive. methods: design: retrospective analysis of a prospectively maintained registry of sepsis patients with lactate measurements. setting: an urban, academic medical center. participants: the pre-shock population, defined as adult ed sepsis patients with either elevated lactate ( . - . mm) or transient hypotension (any sbp < mmhg) receiving iv antibiotics and admitted to a medical floor. consecutive patients meeting pre-shock criteria were enrolled over a -year period. patients with overt shock in the ed, pregnancy, or acute trauma were excluded. outcome: primary patientcentered outcome of increased organ failure (sequential organ failure assessment [sofa] score increase > point, mechanical ventilation, or vasopressor utilization) within hours of admission or in-hospital mortality. results: we identified pre-shock patients from screened. the primary outcome was met in % of the cohort and % were transferred to the icu from a medical floor. patients meeting the outcome of increased organ failure had a greater shock index ( . vs . , p = . ) and heart rate ( vs , p < . ) with no difference in initial lactate, age, map, or exposure to hypotension (sbp < mmhg). there was no difference in the predisposition, infection, response, and organ dysfunction (piro) score between groups ( . vs . , p = . ). outcome patients had similar initial levels of organ dysfunction but had higher sofa scores at , , and hours, a higher icu transfer rate ( vs %, p < . ), and increased icu and hospital lengths of stay. conclusion: the pre-shock sepsis population has a high incidence of clinical deterioration, progressive organ failure, and icu transfer. physiologic data in the ed were unable to differentiate the pre-shock sepsis patients who developed increased organ failure. this study supports the need for an objective organ failure assessment in the emergency department to supplement clinical decision-making. background: lipopolysaccharide (lps) has long been recognized to initiate the host inflammatory response to infection with gram negative bacteria (gnb). large clinical trials of potentially very expensive therapies continue to have the objective of reducing circulating lps. previous studies have found varying prevalence of lps in blood of patients with severe sepsis. compared with sepsis trials conducted years ago, the frequency of gnb in culture specimens from emergency department (ed) patients enrolled in clinical trials of severe sepsis has decreased. objectives: test the hypothesis that prior to antibiotic administration, circulating lps can be detected in the plasma of fewer than % of ed patients with severe sepsis. methods: secondary analysis of a prospective edbased rct of early quantitative resuscitation for severe sepsis. blood specimens were drawn at the time severe sepsis was recognized, defined as two or more systemic inflammatory criteria and a serum lactate > mm or spb< mmhg after fluid challenge. blood was drawn in edta prior to antibiotic administration or within the first several hours, immediately centrifuged, and plasma frozen at ) °c. plasma lps was quantified using the limulus amebocyte lysate assay (lal) by a technician blinded to all clinical data. results: patients were enrolled with plasma samples available for testing. median age was ± years, % female, with overall mortality of %. forty of patients ( %) had any culture specimen positive for gnb including ( %) with blood cultures positive. only five specimens had detectable lps, including two with a gnb-positive culture specimen, and three were lps-positive without gnb in any culture. prevalence of detectable lps was . % (ci: . %- . %). the frequency of detectable lps in antibiotic-naive plasma is too low to serve as a useful diagnostic test or therapeutic target in ed patients with severe sepsis. the data raise the question of whether post-antibiotic plasma may have a higher frequency of detectable lps. background: egdt is known to reduce mortality in septic patients. there is no evidence to date that delineates the role of using a risk stratification tool, such as the mortality in emergency department sepsis (meds) score, to determine which subgroups of patients may have a greater benefit with egdt. objectives: our objective was to determine if our egdt protocol differentially affects mortality based on the severity of illness using meds score. methods: this study is a retrospective chart review of patients, conducted at an urban tertiary care center, after implementing an egdt protocol on july , (figure) . this study compares in-hospital mortality, length of stay (los) in icu, and los in ed between the control group ( patients from / / - / / ) and the postimplementation group ( patients from / / - / / ), using meds score as a risk stratification tool. inclusion criteria: patients who presented to our ed with a suspected infection, and two or more sirs criteria, a map< mmhg, a sbp< mmol/l. exclusion criteria: age< , death on arrival to ed, dnr or dni, emergent surgical intervention, or those with an acute myocardial infarction or chf exacerbation. a two-sample t-test was used to show that the mean age and number of comorbidities was similar between the control and study groups (p = . and . respectively). mortality was compared and adjusted for meds score using logistic regression. the odds ratios and predicted probabilities of death are generated using the fitted logistic regression model. ed and icu los were compared using mood's median test. results: when controlling for illness severity using meds score, the relative risk (rr) of death with egdt is about half that of the control group (rr = . , % ci [ . - . ], p= . ). also, by applying meds score to risk stratify patients into various groups of illness severity, we found no specific groups where egdt is more efficacious at reducing the predicted probability of death (table ) . without controlling for meds score, there is a trend in reduction of absolute mortality by . % when egdt is used (control = . %, study = . %, p = . ). egdt leads to a . % reduction in the median los in icu (control = hours, study = hours, p = . ), without increasing los in ed (control = hours, study = hours, p = . ). conclusion: egdt is beneficial in patients with severe sepsis or septic shock, regardless of their meds score. background: in patients experiencing acute coronary syndrome (acs), prompt diagnosis is critical in achieving the best health outcome. while ecg analysis is usually sufficient to diagnose acs in cases of st elevation, acs without st elevation is reliably diagnosed through serial testing of cardiac troponin i (ctni). pointof-care testing (poct) for ctni by venipuncture has been proven a more rapid means to diagnosis than central laboratory testing. implementing fingerstick testing for ctni in place of standard venipuncture methods would allow for faster and easier procurement of patients' ctni levels, as well as increase the likelihood of starting a rapid test for ctni in the prehospital setting, which could allow for even earlier diagnosis of acs. objectives: to determine if fingerstick blood samples yield accurate and reliable troponin measurements compared to conventional venous blood draws using the i-stat poc device. methods: this experimental study was performed in the ed of a quaternary care suburban medical center between june-august . fingerstick blood samples were obtained from adult ed patients for whom standard (venipuncture) poc troponin testing was ordered. the time between fingerstick and standard draws was kept as narrow as possible. ctni assays were performed at the bedside using the i-stat (abbott point of care). results: samples from patients were analyzed by both fingerstick and standard ed poct methods (see table) . four resulted in cartridge error. compared to ''gold standard'' ed poct, fingerstick testing has a positive predictive value of %, negative predictive value of %, sensitivity of %, and specificity of %. no significant difference in ctni level was found between the two methods, with a nonparametric intraclass correlation coefficient of . ( % ci . - . , p-value < . ). conclusion: whole blood fingerstick ctni testing using the i-stat device is suitable for rapid evaluation of ctni level in prehospital and ed settings. however, results must be interpreted with caution if they are within a narrow territory of the cutoff for normal vs. elevated levels. additional testing on a larger sample would be beneficial. the practicality and clinical benefit of using fingerstick ctni testing in the ems setting must still be assessed. background: adjudication of diagnosis of acute myocardial infarction (ami) in clinical studies typically occurs at each site of subject enrollment (local) or by experts at an independent site (central). from from - , the troponin (ctn) element of the diagnosis was predicated on the local laboratories, using a mix of the th percentile reference ctn and roc-determined cutpoints. in , the universal definition of ami (ud-ami) defined it by the th percentile reference alone. objectives: to compare the diagnosis rates of ami as determined by local adjudication vs. central adjudication using udami criteria. methods: retrospective analysis of data from the myeloperoxidase in the diagnosis of acute coronary syndromes (acs) study (midas), an -center prospective study with enrollment from / / to / / of patients with suspected acs presenting to the ed < hours after symptom onset and in whom serial ctn and objective cardiac perfusion testing was planned. adjudication of acs was done by single local principal investigators using clinical data and local ctn cutpoints from different ctn assays, and applying the definition. central adjudication was done after completion of the midas primary analysis using the same data and local ctn assay, but by experts at three different institutions, using the udami and the manufacturer's th percentile ctn cutpoint, and not blinded to local adjudications. discrepant dignoses were resolved by consensus. local vs. central ctn cutpoints differed for six assays, with central cutpoints lower in all. statistics were by chi-square and kappa. results: excluding cases deemed indeterminate by central adjudication, cases were successfully adjudicated. local adjudication resulted in ami ( . % of total) and non-ami; central adjudication resulted in ( . %) ami and non-ami. overall, local diagnoses ( %) were either changed from non-ami to ami or ami to non-ami (p < . ). interrater reliability across both methods was found to be kappa = . (p < . ). for acs diagnosis, local adjudication identified acs cases ( %) and non-acs, while central adjudication identified acs ( %) and non-acs. overall, local diagnoses ( %) were either changed from non-acs to acs or acs to non-acs (p < . ). interrater reliability found kappa = . (p < . ). conclusion: central and local adjudication resulted in significantly different rates of ami and acs diagnosis. however, overall agreement of the two methods across these two diagnoses was acceptable. occur four times more often in cocaine users. biomarkers myeloperoxidase (mpo) and c-reactive protein (crp) have potential in the diagnosis of acs. objectives: to evaluate the utility of mpo and crp in the diagnosis of acs in patients presenting to the ed with cocaine-associated chest pain and compare the predictive value to nonusers. we hypothesized that these markers may be more sensitive for acs in nonusers given the underlying pathophysiology of enhanced plaque inflammation. methods: a secondary analysis of a cohort study of enrolled ed patients who received evaluation for acs at an urban, tertiary care hospital. structured data collection at presentation included demographics, chest pain history, lab, and ecg data. subjects included those with self-reported or lab-confirmed cocaine use and chest pain. they were matched to controls based on age, sex, and race. our main outcome was diagnosis of acs at index visit. we determined median mpo and crp values, calculated maximal auc for roc curves, and found cut-points to maximize sensitivity and specificity. data are presented with % ci. results: overall, patients in the cocaine positivegroup and patients in the nonusers group had mpo and crp levels measured. patients had a median age of (iqr, ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) , % black or african american, and % male (p > . between groups). fifteen patients were diagnosed with acs: patients in the cocaine group and in the nonusers group. comparing cocaine users to nonusers, there was no difference in mpo (median [iqr, ] v ng/ml; p = . ) or crp ( [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] v [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] mg/l; p = . ). the auc for mpo was . ( % ci . - . ) v . ( % ci . - . ). the optimal cut-point to maximize sensitivity and specificity was ng/ml which gave a sensitivity of . and specificity of . . using this cutpoint, % v % of acs in cocaine users vs the nonusers would be identified. the auc for crp was . ( % ci . - . ) in cocaine users vs . ( % ci . - . ) in nonusers. the optimal cut point was . mg/l with a sensitivity of . and specificity of . . using this cutpoint, % v % of acs in cocaine users and nonusers would have been identified. conclusion: the diagnostic accuracy of mpo and crp is not different in cocaine users than nonusers and does not appear to have sufficient discriminatory ability in either cohort. results: hrs of moderate pe caused a significant decrease in rv heart function in rats treated with the solvent for bay - : peak systolic pressure (psp) decreased from ± . mmhg, control to ± . , pe, +dp/dt decreased from ± mmhg/sec to ± , -dp/dt decreased from ) ± mmhg/sec to ) ± . treatment of rats with bay - significantly improved all three indices of rv heart function (psp ± . , +dp/dt ± , -dp/dt ) ± ). hrs of severe pe also caused significant rv dysfunction (psp ± , -dp/dt ) ± ) and treatment with bay - produced protection of rv heart function (psp ± , -dp/dt ) ± ) similar to the hr moderate pe model. conclusion: experimental pe produced significant rv dysfunction, which was ameliorated by treatment of the animals with the soluble guanylate cyclase stimulator, bay - . hospital of the university of pennsylvania, philadelphia, pa; cooper university hospital, camden, nj background: patients who present to the ed with symptoms of potential acute coronary syndrome (acs) can be safely discharged home after a negative coronary computerized tomographic angiography (cta). however, the duration of time for which a negative coronary cta can be used to inform decision making when patients have recurrent symptoms is unknown. objectives: we examined patients who received more than one coronary cta for evaluation of acs to determine whether they had disease progression, as defined by crossing the threshold from noncritical (< % maximal stenosis) to potentially critical disease. methods: we performed a structured comprehensive record search of all coronary ctas performed from to at a tertiary care health system. low-tointermediate risk ed patients who received two or more coronary ctas, at least one from an ed evaluation for potential acs, were identified. patients who were revascularized between scans were excluded. we collected demographic data, clinical course, time between scans, and number of ed visits between scans. record review was structured and done by trained abstractors. our main outcome was progression of coronary stenosis between scans, specifically crossing the threshold from noncritical to potentially critical disease. results: overall, patients met study criteria (median age , interquartile range [iqr] ( . - ); % female; % black). the median time between studies was . months (iqr, . patients did not have stenosis in any vessel on either coronary cta, two studies showed increasing stenosis of < %, and the rest showed ''improvement,'' most due to better imaging quality. no patient initially below the % threshold subsequently exceeded it ( %; % ci, - . %). patients also had varying numbers of ed visits (median number of visits , range - ), and numbers of ed visits for potentially cardiac complaints (median , range - ); were re-admitted for potentially cardiac complaints (for example, chest pain or shortness of breath), and received further provocative cardiac testing, all of which had negative results. conclusion: we did not find clinically significant disease progression within a year time frame in patients who had a negative coronary cta, despite a high number of repeat visits. this suggests that prior negative coronary cta may be able to be used to inform decision making within this time period. . - . ) compared to non tro ct patients. there was no significant difference in image quality between tro ct images and those of dedicated ct scans in any studies performing this comparison. similarly, there was no significant difference between tro ct and other diagnostic modalities in regards to length of stay or admission rate. when compared to conventional coronary angiography as the gold standard for evaluation of cad, tro ct had the following pooled diagnostic accuracy estimates: sensitivity . conclusion: tro chest ct is comparable to dedicated pe, coronary, or ad ct in regard to image quality, length of stay, and admission rate and is highly accurate for detecting cad. the utility of tro ct depends on the relative pre-test probabilities of the conditions being assessed and its role is yet to be clearly defined. tro ct, however, involves increased radiation exposure and contrast volume and for this reason clinicians should be selective in its use. background: coronary computed tomographic angiography (ccta) has high sensitivity, specificity, accuracy, and prognostic value for coronary artery disease (cad) and acs. however, how a ccta informs subsequent use of prescription medication is unclear. objectives: to determine if detection of critical or noncritical cad on ccta is associated with initiation of aspirin and statins for patients who presented to the ed with chest pain. we hypothesized that aspirin and statins would be more likely to be prescribed to patients with noncritical disease relative to those without any cad. methods: prospective cohort study of patients who received ccta as part of evaluation of chest pain in the ed or observation unit. patients were contacted and medical records were reviewed to obtain clinical follow-up for up to the year after ccta. the main outcome was new prescription of aspirin or statin. cad severity on ccta was graded as absent, mild ( % to %), moderate ( % to %), or severe ( ‡ %) stenosis. logistic regression was used to assess the association of stenosis severity to new medication prescription; covariates were determined a priori. results: patients who had ccta performed consented to participate in this study or met waiver of consent for record review only (median age, , % female, % black). median follow-up time was days, iqr - days. at baseline, % of the total cohort was already prescribed aspirin and % on statin medication. two hundred seventy nine ( %) patients were found to have stenosis in at least one vessel. in patients with absent, mild, moderate, and severe cad on ccta, aspirin was initiated in %, %, %, and %; statins were initiated in %, %, %, and % of patients. after adjustment for age, race, sex, hypertension, diabetes, cholesterol, tobacco use, and admission to the hospital after ccta, higher grades of cad severity were independently associated with greater post-ccta use of aspirin (or . per grade, % ci . - . , p < . ) and statins (or . , % ci . - . , p < . ). conclusion: greater cad severity on ccta is associated with increased medication prescription for cad. patients with noncritical disease are more likely than patients without any disease to receive aspirin and statins. future studies should examine whether these changes lead to decreased hospitalizations and improved cardiovascular health. background: hess et al. developed a clinical decision rule for patients with acute chest pain consisting of the absence of five predictors: ischemic ecg changes not known to be old, elevated initial or -hour troponin level, known coronary disease, ''typical'' pain, and age over . patients less than required only a single troponin evaluation. objectives: to test the hypothesis that patients less than years old without these criteria are at < % risk for major adverse cardiovascular events (mace) including death, ami, pci, and cabg. methods: we performed a secondary analysis of several combined prospective cohort studies that enrolled ed patients who received an evaluation for acs in an urban ed from to . cocaine users and stemi patients were excluded. structured data collection at presentation included demographics, pain description, history, lab, and ecg data for all studies. hospital course was followed daily. thirty-day follow up was done by telephone. our main outcome was -day mace using objective criteria. the secondary outcome was potential change in ed disposition due to application of the rule. descriptive statistics and % cis were used. results: of visits for potential acs, patients had a mean age of . ± . yrs; % were black and % female. there were patients ( . %) with -day cv events ( dead, ami, pci). sequential removal of patients in order to meet the final rule for patients less than excluded patients based upon: ischemic ecg changes not old (n = , % mace rate), elevated initial troponin level (n = , % mace), known coronary disease (n = , % mace), ''typical'' pain (n = , % mace), and age over (n = , . % mace) leaving patients less than with . % mace [ % ci, . - . %]. of this cohort, % were discharged home from the ed by the treating physician without application of this rule. adding a second negative troponin in patients - years old identified a group of patients with a . % rate of mace [ . - . ] and a % discharge rate. the hess rule appears to identify a cohort of patients at approximately % risk of -day mace, and may enhance discharge of young patients. however, even without application of this rule, the % of young patients at low risk are already being discharged home based upon clinical judgment. background: a clinical decision support system (cdss) incorporates evidence-based medicine into clinical practice, but this technology is underutilized in the ed. a cdss can be integrated directly into an electronic medical record (emr) to improve physician efficiency and ease of use. the christopher study investigators validated a clinical decision rule for patients with suspected pulmonary embolism (pe). the rule stratifies patients using wells' criteria to undergo either d-dimer testing or a ct angiogram (ct). the effect of this decision rule, integrated as a cdss into the emr, on ordering cts has not been studied. objectives: to assess the effect of a mandatory cdss on the ordering of d-dimers and cts for patients with suspected pe. methods: we assessed the number of cts ordered for patients with suspected pe before and after integrating a mandatory cdss in an urban community ed. physicians were educated regarding cdss use prior to implementation. the cdss advised physicians as to whether a negative d-dimer alone excluded pe or if a ct was required based on wells' criteria. the emr required physicians to complete the cdss prior to ordering the ct. however, physicians maintained the ability to order a ct regardless of the cdss recommendation. patients ‡ years of age presenting to the ed with a chief complaint of chest pain, dyspnea, syncope, or palpitations were included in the data analysis. we compared the proportion of d-dimers and cts ordered during the -month periods immediately before and after implementing the cdss. all physicians who worked in the ed during both time periods were included in the analysis. patients with an allergy to intravenous contrast agents, renal insufficiency, or pregnancy were excluded. results were analyzed using a chi-square test. results: a total of , patients were included in the data analysis ( pre-and post-implementation). cts were ordered for patients ( . %) in the pre-implementation group and patients ( . %) in the post-implementation group; p = . . a d-dimer was ordered for patients ( . %) in the pre-implementation group and patients ( . %) in the post-implementation group; p = . . in this single-center study, emr integration of a mandatory cdss for evaluation of pe did not significantly alter ordering patterns of cts and d-dimers. identification of patients with low-risk pulmonary emboli suitable for discharge from the emergency department mike zimmer, keith e. kocher university of michigan, ann arbor, mi background: recent data, including a large, multicenter randomized controlled trial, suggest that a low-risk cohort of patients diagnosed with pulmonary embolism (pe) exists who can be safely discharged from the ed for outpatient treatment. objectives: to determine if there is a similar cohort at our institution who have a low rate of complications from pe suitable for outpatient treatment. methods: this was a retrospective chart review at a single academic tertiary referral center with an annual ed volume of , patients. all adult ed patients who were diagnosed with pe during a -month period from / / through / / were identified. the pulmonary embolism severity index (pesi) score, a previously validated clinical decision rule to risk stratify patients with pe, was calculated. patients with high pesi (> ) were excluded. additional exclusion criteria included patients who were at high risk of complications from initiation of therapeutic anticoagulation and those patients with other clear indications for admission to the hospital. the remaining cohort of patients with low risk pe (pesi £ ) was included in the final analysis. outcomes were measured at and days after pe diagnosis and included death, major bleeding, and objectively confirmed recurrent venous thromboembolism (vte). results: during the study period, total patients were diagnosed with pe. there were ( %) patients categorized as ''low risk'' (pesi £ ), with removed because of various pre-defined exclusion criteria. of the remaining ( %) patients suitable for outpatient treatment, patients ( . %; % ci, . % - . %) had one or more negative outcomes by days. this included ( . %; % ci, % - . %) major bleeding events, ( . %; % ci, % - . %) recurrent vte, and ( . %; % ci, % - . %) deaths. none of the deaths were attributable to pe or anticoagulation. one patient suffered both a recurrent vte and died within days. both patients who died within days were transitioned to hospice care because of worsening metastatic burden. at days, there was bleeding event ( . %; % ci, % - . %), no recurrent vte, and no deaths. the average hospital length of stay for these patients was . days (sd ± . ). conclusion: over % of our patients diagnosed with pe in the ed may have been suitable for outpatient treatment, with % suffering a negative outcome within days and . % suffering a negative outcome within days. in addition, the average hospital length of stay for these patients was . days, which may represent a potential cost savings if these patients had been managed as outpatients. our experience supports previous studies that suggest the safety of outpatient treatment of patients diagnosed with pe in the ed. given the potential savings related to a decreased need for hospitalization, these results have health policy implications and support the feasibility of creating protocols to facilitate this clinical practice change. background: chest x-rays (cxrs) are commonly obtained on ed chest pain patients presenting with suspected acute coronary syndrome (acs). a recently derived clinical decision rule (cdr) determined that patients who have no history of congestive heart failure, have never smoked, and have a normal lung examination do not require a cxr in the ed. objectives: to validate the diagnostic accuracy of the hess cxr cdr for ed chest pain patients with suspected acs. methods: this was a prospective observational study of a convenience sample of chest pain patients over years old with suspected acs who presented to a single urban academic ed. the primary outcome was the ability of the cdr to identify patients with abnormalities on cxr requiring acute ed intervention. data were collected by research associates using the chart and physician interviews. abnormalities on cxr and specific interventions were predetermined, with a positive cxr defined as one with abnormality requiring ed intervention, and a negative cxr defined as either normal or abnormal but not requiring ed intervention. the final radiologist report was used as a reference standard for cxr interpretation. a second radiologist, blinded to the initial radiologist's report, reviewed the cxrs of patients meeting the cdr criteria to calculate inter-observer agreement. patients were followed up by chart review and telephone interview days after presentation. results: between january and august , patients were enrolled, of whom ( %) were excluded and ( . %) did not receive cxrs in the ed. of the remaining patients, ( %) met the cdr. the cdr identified all patients with a positive cxr (sensitivity = %, %ci - %). the cdr identified of the patients with a negative cxr (specificity = %, %ci - %). the positive likelihood ratio was . ( %ci . - . ). inter-observer agreement between radiologists was substantial (kappa = . , %ci . - . ). telephone contact was made with % of patients and all patient charts were reviewed at days. none had any adverse events related to a background: increasing the threshold to define a positive d-dimer in low-risk patients could reduce unnecessary computed tomographic pulmonary angiography (ctpa) for suspected pe. this strategy might increase rates of missed pe and missed pneumonia, the most common non-thromboembolic finding on ctpa that might not otherwise be diagnosed. objectives: measure the effect of doubling the standard d-dimer threshold for ' 'pe unlikely'' revised geneva (rgs) or wells' scores on the exclusion rate, frequency, and size of missed pe and missed pneumonia. methods: prospective enrollment at four academic us hospitals. inclusion criteria required patients to have at least one symptom or sign and one risk factor for pe, and have -channel ctpa completed. pretest probability data were collected in real time and the d-dimer was measured in a central laboratory. criterion standard for pe or pneumonia consisted of cpta interpretation by two independent radiologists combined with necessary treatment plan. subsegmental pe was defined as total vascular obstruction < %. patients were followed for outcome at days. proportions were compared with % cis. results: of patients enrolled, ( %) were pe+ and ( %) had pneumonia. with rgs£ and standard threshold (< ng/ml), d-dimer was negative in / ( %, % ci: - %), and / were pe+ (posterior probability . %, % ci: - . %). with rgs£ and a threshold < ng/ml, d-dimer was negative in / ( %, - %) and / ( . %, . - . %) were pe+, but / missed pes were subsegmental, and none had concomitant dvt. the posterior probability for pneumonia among patients with rgs&# ; and d-dimer< was / ( . %, - %) which compares favorably to the posterior probability of / ( . %, - %) observed with rgs& # ; and d-dimer< ng/ml. of the ( %) patients who also had plain film cxr, radiologists found an infiltrate in only . use of wells£ produced similar results as the rgs&# ; for exclusion rate and posterior probability of both pe and pneumonia. conclusion: doubling the threshold for a positive d-dimer with a pe unlikely pretest probability can significantly reduce ctpa scanning with a slightly increased risk of missed isolated subsegmental pe, and no increase in rate of missed pneumonia. background: the limitations of developing world medical infrastructure require that patients are transferred from health clinics only when the patient care needs exceed the level of care at the clinic and the receiving hospital can provide definitive therapy. to determine what type of definitive care service was sought when patients were transferred from a general outpatient clinic operating monday through friday from : am to : pm in rural haiti to urban hospitals in port-au-prince. methods: design -prospective observational review of all patients for whom transfer to a hospital was requested or for whom a clinic ambulance was requested to an off-site location to assist with patient care. setting -weekday, daytime only clinic in titanyen, haiti. participants/subjects -consecutive series of all patients for whom transfer to another health care facility or for whom an ambulance was requested during the time period of / / - / / and / / - / / . results: between / / - / / and / / - / / patients were identified who needed to be transferred to a higher level of care. sixteen patients ( . %) presented with medical complaints, ( . %) were trauma patients, ( . %) were surgical, and ( . %) were in the obstetric category. within these categories, patients were pediatric and non-trauma patients required blood transfusion. conclusion: while trauma services are often focused on in rural developing world medicine, the need for obstetric care and blood transfusion constituted six ( . %) cases in our sample. these patients raise important public health, planning, and policy questions relating to access to prenatal care and the need to better understand transfusion medicine utilization among rural haitian patients with non-trauma related transfusion needs. the data set is limited by sample size and single location of collection. another limitation of understanding the needs is that many patients may not present to the clinic for their health care needs in certain situations if they have knowledge that the resources to provide definitive care are unavailable. background: the practice of emergency medicine in japan has been unique in that emergency physicians are mostly engaged in critical care and trauma with a multi-specialty model. for the last decade with progress in medicine, an aging population with complicated problems, and institution of postgraduate general clinical training, the us model emergency medicine with single-specialty model has been emerging throughout japan. however, the current status is unknown. objectives: the objective of this study was to investigate the current status of implementation of the us model emergency medicine at emergency medicine training institutions accredited by the japanese association for acute medicine (jaam). methods: the er committee of the jaam, the most prestigious professional organization in japanese emergency medicine, conducted the survey by sending questionnaires to accredited emergency medicine training institutions. results: valid responses obtained from facilities were analyzed. us model em was provided in facilities ( % of facilities), either in full time ( hours a day, seven days a week; facilities) or in part time (less than hours a day; facilities). among these us model facilities, % have a number of beds between - . the annual number of ed visits was less than , in %, and % have ambulance transfers between , - , per year. the number of emergency physicians was less than in % of the facilities. postgraduate general clinical training was offered at us model ed in facilities, and ninety hospitals adopted us model em after , when a -year period of postgraduate general clinical training became mandatory for all medical graduates. sixty-four facilities provided a residency program to be a us model emergency physician, and another institutions were planning to establish it. conclusion: us model em has emerged and become commonplace in japan. the background including advance in medicine, aging population, and mandatory postgraduate general clinical training system are considered to be contributing factors. erkan gunay, ersin aksay, ozge duman atilla, nilay zorbalar, savas sezik tepecik research and training hospital, izmir, turkey background: workplace safety and occupational health problems are increasing issues especially in developing countries as a result of the industrial automatisation and technologic improvements. occupational injuries are preventable but they can occasionally cause morbidity and mortality resulting in work day loss and financial problems. hand injuries are one-third of all traumatic injuries and are the most injured parts after occupational accidents. objectives: we aim to evaluate patients with occupational upper extremity injuries for demographic characteristics, injury types, and work day loss. methods: trauma patients over years old admitted to our emergency department with an occupational upper extremity injury were prospectively evaluated from . . to . . . patients with one or more of digit, hand, forearm, elbow, humerus, and shoulder injuries were included. exclusion criteria were multitrauma, patient refusal to participate, and insufficient data. patients were followed up from the hospital information system and by phone for work day loss and final diagnosis. results: during the study period there were patients with an occupational upper extremity injury. total of ( . %) patients were included. patients were . % male, . % between the age to , and mean age was calculated . ± . years. . % of the patients were from the metal and machinery sector, and primary education was the highest education level for the . % of the patients. most injured parts were fingers with the highest rate for index finger and thumb. crush injury was the most common injury type. . % (n = ) of the patients were discharged after treatment in the emergency department. tendon injuries, open fractures, and high degree burns were the reasons for admission to clinics. mean work day loss was . ± . days and this increases for the patients with laboratory or radiologic studies, consultant evaluation, or admission. the - age group had a significantly lower work day loss average. conclusion: evaluating occupational injury characteristics and risks is essential for identifying preventive measures and actions. with the guidance of this study preventive actions focusing on high-risk sectors and patients may be the key factor for avoiding occupational injuries and creating safer workplace environments in order to reduce financial and public health problems. background: as emergency medicine (em) gains increased recognition and interest in the international arena, a growing number of training programs for emergency health care workers have been implemented in the developing world through international partnerships. objectives: to evaluate the quality and appropriateness of an internationally implemented emergency physician training program in india. methods: physicians participating in an internationally implemented em training program in india were recruited to participate in a program evaluation. a mixed methods design was used including an online anonymous survey and semi-structured focus groups. the survey assessed the research, clinical, and didactic training provided by the program. demographics and information on past and future career paths were also collected. the focus group discussions centered around program successes and challenges. results: fifty of eligible trainees ( %) participated in the survey. of the respondents, the vast majority were indian; % were female, and all were between the ages of and years (mean age years). all but two trainees ( %) intend to practice em as a career. one-third listed a high-income country first for preferred practice location and half listed india first. respondents directly endorsed the program structure and content, and they demonstrated gains in self-rated knowledge and clinical confidence over their years of training. active challenges identified include: ( ) insufficient quantity and inconsistent quality of indian faculty, ( ) administrative barriers to academic priorities, and ( ) persistent threat of brain drain if local opportunities are inadequate. conclusion: implementing an international emergency physician training program with limited existing local capacity is a challenging endeavor. overall, this evaluation supports the appropriateness and quality of this partnership model for em training. one critical challenge is achieving a robust local faculty. early negotiations are recommended to set educational priorities, which includes assuring access to em journals. attrition of graduated trainees to high-income countries due to better compensation or limited in-country opportunities continues to be a threat to long-term local capacity building. background: with an increasing frequency and intensity of manmade and natural disasters, and a corresponding surge in interest in international emergency medicine (iem) and global health (gh), the number of iem and gh fellowships is constantly growing. there are currently iem and gh fellowships, each with a different curriculum. several articles have proposed the establishment of core curriculum elements for fellowship training. to the best of our knowledge, no study has examined whether iem and gh fellows are actually fulfilling these criteria. objectives: this study sought to examine whether current iem and gh fellowships are consistently meeting these core curricula. methods: an electronic survey was administered to current iem and gh fellowship directors, current fellows, and recent graduates of a total of programs. survey respondents stated their amount of exposure to previously published core curriculum components: em system development, humanitarian assistance, disaster response, and public health. a pooled analysis comparing overall responses of fellows to those of program directors was performed using two-sampled t-test. results: response rates were % (n = ) for program directors and % (n = ) for current and recent fellows. programs varied significantly in terms of their emphasis on and exposure to six proposed core curriculum areas: em system development, em education development, humanitarian aid, public health, ems, and disaster management. only % of programs reported having exposure to all four core areas. as many as % of fellows reported knowing their curriculum only somewhat or not at all prior to starting the program. conclusion: many fellows enter iem and gh fellowships without a clear sense of what they will get from their training. as each fellowship program has different areas of curriculum emphasis, we propose not to enforce any single core curriculum. rather, we suggest the development of a mechanism to allow each fellowship program to present its curriculum in a more transparent manner. this will allow prospective applicants to have a better understanding of the various programs' curricula and areas of emphasis. background: advance warning of probable intensive care unit (icu) admissions could allow the bed placement process to start earlier, decreasing ed length of stay and relieving overcrowding conditions. however, physicians and nurses poorly predict a patient's ultimate disposition from the emergency department at triage. a computerized algorithm can use commonly collected data at triage to accurately identify those who likely will need icu admission. objectives: to evaluate an automated computer algorithm at triage to predict icu admission and -day in-hospital mortality. methods: retrospective cohort study at a , visit/ year level i trauma center/tertiary academic teaching hospital. all patients presenting to the ed between / / and / / were included in the study. the primary outcome measure was icu admission from the emergency department. the secondary outcome measure was -day all-cause in-hospital mortality. patients discharged or transferred before days were considered to be alive at days. triage data includes age, sex, acuity (emergency severity index), blood pressure, heart rate, pain scale, respiratory rate, oxygen saturation, temperature, and a nurse's free text assessment. a latent dirichlet allocation algorithm was used to cluster words in triage nurses' free text assessments into topics. the triage assessment for each patient is then represented as a probability distribution over these topics. logistic regression was then used to determine the prediction function. results: a total of , patients were included in the study. . % were admitted to the icu and . % died within days. these patients were then randomly allocated to train (n = , ; %) and test (n = , ; %) data sets. the area under the receiver operating characteristic curve (auc) when predicting icu background: at the saem annual meeting, we presented the derivation of two hospital admission prediction models adding coded chief complaint (ccc) data from a published algorithm (thompson et al. acad emerg med ; : - ) to demographic, ed operational, and acuity (emergency severity index (esi)) data. objectives: we hypothesized that these models would be validated when applied to a separate retrospective cohort, justifying prospective evaluation. methods: we conducted a retrospective, observational validation cohort study of all adult ed visits to a single tertiary care center (census: , /yr) ( / / - / / ). we downloaded from the center's clinical tracking system demographic (age, sex, race), ed operational (time and day of arrival), esi, and chief complaint data on each visit. we applied the derived ccc hospital admission prediction models (all identified ccc categories and ccc categories with significant odds of admission from multivariable logistic regression in the derivation cohort) to the validation cohort to predict odds of admission and compared to prediction models that consisted of demographic, ed operational, and esi data, adding each category to subsequent models in a stepwise manner. model performance is reported by areaunder-the-curve (auc) data and %ci. signs, pain level, triage level, -hour return, number of past visits in the previous year, injury, and one of chief complaint codes (representing % of all visits in the database). outputs for training included ordering of a complete blood count, basic chemistry (electrolytes, blood urea nitrogen, creatinine), cardiac enzymes, liver function panel, urinalysis, electrocardiogram, x-ray, computed tomography, or ultrasound. once trained, it was used on the nhamcs-ed database, and predictions were generated. predictions were compared with documented physician orders. outcomes included the percent of total patients who were correctly pre-ordered, sensitivity (the percent of patients who had an order that were correctly predicted), and the percent over-ordered. waiting time for correctly pre-ordered patients was highlighted, to represent a potential reduction in length of stay achieved by preordering. los for patients overordered was highlighted to see if over-ordering may cause an increase in los for those patients. unit cost of the test was also highlighted, as taken from the medicare fee schedule. physician times. however, during peak ed census times, many patients with completed tests and treatment initiated by triage await discharge by the next assigned physician. objectives: determine if a physician-led discharge disposition (dd) team can reduce the ed length of stay (los) for patients of similar acuity who are ultimately discharged compared to standard physician team assignment. methods: this prospective observational study was performed from / to / at an urban tertiary referral academic hospital with an annual ed volume of , visits. only emergency severity index level patients were evaluated. the dd team was scheduled weekdays from : until : . several ed beds were allocated to this team. the team was comprised of one attending physician and either one nurse and a tech or two nurses. comparisons were made between los for discharged patients originally triaged to the main ed side who were seen by the dd team versus the main side teams. time from triage physician to team physician, team physician to discharge decision time, and patient age were compared by unpaired t-test. differences were studied for number of patients receiving x-rays, ct scan, labs, and medications. results: dd team mean los in hours for discharged patients was shorter at . ( % ci: . - . , n = ) compared to . ( % ci: . - . , n = ) on the main side, p < . . the mean time from triage physician to dd team physician was . hours ( % ci: . - . , n = ) versus to . hours ( % ci: . - . , n = ) to main side physician, p < . . the dd team physician mean time to discharge decision was . hour ( % ci: . - . , n = ) compared to . hours ( % ci: . - . , n = ) for main side physician, p < . . the dd team patients' mean age was . years ( % ci: . - . , n = ) compared to main side patients' mean age of . years ( % ci: . - . , n = .) the dd team patients (n = ) received fewer x-rays ( % vs. %), ct scans ( % vs. %), labs ( % vs. %), and medications ( % vs. %) than main side patients (n = ), p < . for all compared. conclusion: the dd team complements the advanced triage process to further reduce los for patients who do not require extended ed treatment or observation. the dd team was able to work more efficiently because its patients tended to be younger and had fewer lab and imaging tests ordered by the triage physician compared to patients who were later seen on the ed main side. ed objectives: to evaluate the association between ed boarding time and the risk of developing hapu. methods: we conducted a retrospective cohort study using administrative data from an academic medical center with an adult ed with , annual patient visits. all patients admitted into the hospital through the ed / / - / / were included. development of hapu was determined using the standardized, national protocol for cms reporting of hapu. ed boarding time was defined as the time between an order for inpatient admission and transport of the patient out of the ed to an in-patient unit. we used a multivariate logistic regression model with development of a hapu as the outcome variable, ed boarding time as the exposure variable, and the following variables as covariates: age, sex, initial braden score, and admission to an intensive care unit (icu) from the ed. the braden score is a scale used to determine a patient's risk for developing a hapu based on known risk factors. a braden score is calculated for each hospitalized patient at the time of admission. we included braden score as a covariate in our model to determine if ed boarding time was a predictor of hapu independent of braden score. results: of , patients admitted to the hospital through the ed during the study period, developed a hapu during their hospitalization. clinical characteristics are presented in the table. per hour of ed boarding time, the adjusted or of developing a hapu was . ( % ci . - . , p = . ). a median of patients per day were admitted through the ed, accumulating hours of ed boarding time per day, with each hour of boarding time increasing the risk of developing a hapu by %. conclusion: in this single-center, retrospective study, longer ed boarding time was associated with increased risk of developing a hapu. queried ed and inpatient nurses and compared their opinions toward inpatient boarding. it also assessed their preferred boarding location if they were patients. objectives: this study queried ed and inpatient nurses and compared their opinions toward inpatient boarding. methods: a survey was administered to a convenience sample of ed and ward nurses. it was performed in a -bed academic medical center ( , admissions/yr) with a -bed ed ( , visits/yr). nurses were identified as ed or ward and whether they had previously worked in the ed. the nurses were asked if there were any circumstances where admitted patients should be boarded in the ed or inpatient hallways. they were also asked their preferred location if they were admitted as a patient. six clinical scenarios were then presented and their opinions on boarding queried. results: ninety nurses completed the survey; ( %) were current ed nurses (ced), ( %) had previously worked in the ed (ped). for the entire group ( %) believed admitted patients should board in the ed. overall, ( %) were opposed to inpatient boarding, with % of ced versus % of current ward (cw) nurses (p < . ) and % of ped versus % of nurses never having worked in the ed (ned) opposed (p < . ). if admitted as patients themselves, overall ( %) preferred inpatient boarding, with % of ced versus % of cw nurses (p < . ) and % of ped versus % ned nurses (p = . ) preferring inpatient boarding. for the six clinical scenarios, significant differences in opinion regarding inpatient boarding existed in all but two cases: a patient with stable copd but requiring oxygen and an intubated, unstable sepsis patient. conclusion: ward nurses and those who have never worked in the ed are more opposed to inpatient boarding than ed nurses and nurses who have worked previously in the ed. nurses admitted as patients seemed to prefer not being boarded where they work. ed and ward nurses seemed to agree that unstable or potentially unstable patients should remain in the ed. weeks. staff satisfaction was evaluated through pre/ post-shift and study surveys; administrative data (physician initial assessment (pia), length of stay (los), patients leaving without being seen (lwbs) and against medical advice [lama] ) were collected from an electronic, real-time ed information system. data are presented as proportions and medians with interquartile ranges (iqr); bivariable analyses were performed. results: ed physicians and nurses expected the intervention to reduce the los of discharged patients only. pia decreased during the intervention period ( vs minutes; p < . ). no statistically/clinically significant differences were observed in the los; however, there was a significant reduction in the lwbs ( . % to . % p = . ) and lama ( . % to . % p = . ) rates. while there was a reduction of approximately patients seen per physician in the affected ed area, the total number of patients seen on that unit increased by approximately patients/day. overall, compared to days when there was no extra shift, % of emergency physicians stated their workload decreased and % felt their stress level at work decreased. conclusion: while this study didn't demonstrate a reduction in the overall los, it did reduce pia times and the proportion of lwbs/lama patients. while physicians saw fewer patients during the intervention study period, the overall patient volume increased and satisfaction among ed physicians was rated higher. provider-and hospital-level variation in admission rates and -hour return admission rates jameel abualenain , william frohna , robert shesser , ru ding , mark smith , jesse m. pines the george washington university, washington, dc; washington hospital center, washington, dc background: decisions for inpatient versus outpatient management of ed patients are the most important and costliest decision made by emergency physicians, but there is little published on the variation in the decision to admit among providers or whether there is a relationship between a provider's admission rate and the proportion of their patients who return within hours of the initial visit and are subsequently admitted ( h-ra). objectives: we explored the variation in provider-level admission rates and h-ra rates, and the relationship between the two. methods: a retrospective study using data from three eds with the same information system over varying time periods: washington hospital center (whc) ( - ), franklin square hospital center (fshc) , and union memorial hospital (umh) . patients were excluded if left without being seen, left against medical advice, fast-track, psychiatric patients, and aged < years. physicians with < ed encounters or an admission rate < % were excluded. logistic regression was used to assess the relationship between physician-level h-ra and admission rates, adjusting for patient age, sex, race, and hospital. results: , ed encounters were treated by physicians. mean patient age was years sd , % male, and % black. admission rates differed between hospitals (whc = %, umh = %, and fshc = %), as did the h-ra (whc = . %, umh = . %, and fshc = . %). across all hospitals, there was great variation in individual physician admission rates ( . %- . %). the h-ra rates were quite low, but demonstrated a similar magnitude of individual variation ( . %- . %). physicians with the highest admission rate quintile had lower odds of h-ra (or . % ci . - . ) compared to the lowest admission rate quintile, after adjusting for other factors. no intermediate admission rate quintiles ( nd, rd, or th) were significantly different from the lowest admission rate quintile with regard to h-ra. conclusion: there is more than three-fold variation in individual physician admission rates indicating great variation among physicians in hospital admission rates and h-ra. the highest admitters have the lowest h-ra; however, evaluating the causes and consequences of such significant variation needs further exploration, particularly in the context of health reform efforts aimed at reducing costs. background: ed scribes have become an effective means to assist emergency physicians (eps) with clinical documentation and improve physician productivity. scribes have been most often utilized in busy community eds and their utility and functional integration into an academic medical center with resident physicians is unknown. objectives: to evaluate resident perceptions of attending physician teaching and interaction after introduction of scribes at an em residency training program, measured through an online survey. residents in this study were not working with the scribes directly, but were interacting indirectly through attending physician use of scribes during ed shifts. methods: an online ten question survey was administered to residents of a midwest academic emergency medicine residency program (pgy -pgy program, annual residents), months after the introduction of scribes into the ed. scribes were introduced as emr documentation support (epic , epic systems inc.) for attending eps while evaluating primary patients and supervising resident physicians. questions investigated em resident demographics and perceptions of scribes (attending physician interaction and teaching, effect on resident learning, willingness to use scribes in the future), using likert scale responses ( minimal, maximum) and a graduated percentage scale used to quantify relative values, where applicable. data were analyzed using kruskal-wallis and mann-whitney u tests. results: twenty-one of em residents ( %) completed the survey ( % male; % pgy , % pgy , % pgy ). four residents had prior experience with scribes. scribes were felt to have no effect on attending eps direct resident interaction time (mean score . , sd . ), time spent bedside teaching ( . , sd . ), or quality of teaching ( . , sd . ), as well as no effect on residents' overall learning process ( . , sd . ). however, residents felt positive about utilizing scribes at their future occupation site ( . , sd . ). no response differences were noted for prior experience, training level, or sex. conclusion: when scribes are introduced at an em residency training site, residents of all training levels perceive it as a neutral interaction, when measured in terms of perceived time with attending eps and quality of the teaching when scribes are present. the effect of introduction of an electronic medical record on resident productivity in an academic emergency department shawn london, christopher sala university of connecticut school of medicine, farmington, ct background: there are little available data which describe the effect of implementation of an electronic medical record (emr) on provider productivity in the emergency department, and no studies which, to our knowledge, address this issue pertaining to housestaff in particular. objectives: we seek to quantify the changes in provider productivity pre-and post-emr implementation to support our hypothesis that resident clinical productivity based on patients seen per hour will be negatively affected by emr implementation. methods: the academic emergency department at hartford hospital, the principle clinical site in the university of connecticut emergency medicine residency, sees over , patients on an annual basis. this environment is unique in that pre-emr, patient tracking and orders were performed electronically using the sunrise system (eclipsys corp) for over years prior to conversion to the allscripts ed emr in october, for all aspects of ed care. the investigators completed a random sample of days/evening/night/weekend shift productivity to obtain monthly aggregate productivity data (patients seen per hour) by year of training. results: there was an initial . % decrease of in productivity for pgy- residents on average from . patients per hour on average in the three blocks preceding activation of the emr to . patients seen per hour compared in the subsequent three prior blocks. pgy performance returned to baseline in the subsequent three months to . patients per hour. there was no change noted in patients seen per hour of pgy- and pgy- residents. conclusion: while many physicians tend to assume that emrs pose a significant barrier to productivity in the ed, in our academic emergency department, there was no lasting change on resident productivity based on the patients seen per hour metric. the minor decrease which did occur in pgy- residents was transient and was not apparent months after the emr was implemented. our experience suggests that decrease in the rate of patients seen per hour in the resident population should not be considered justification to delay or avoid implementation of an emr in the emergency department. emory university, atlanta, ga; children's healthcare of atlanta, atlanta, ga background: variation in physician practice is widely prevalent and highlights an opportunity for quality improvement and cost containment. monitoring resources used in the management of common pediatric emergency department (ed) conditions has been suggested as an ed quality metric. objectives: to determine if providing ed physicians with severity-adjusted data on resource use and outcomes, relative to their peers, can influence practice patterns. methods: data on resource use by physicians were extracted from electronic medical records at a tertiary pediatric ed for four common conditions in mid-acuity (emergency severity index level ): fever, head injury, respiratory illness, and gastroenteritis. condition-relevant resource use was tracked for lab tests (blood count, chemistry, crp), imaging (chest x-ray, abdominal x-ray, head ct scan, abdominal ct scan), intravenous fluids, parenteral antibiotics, and intravenous ondansetron. outcome measures included admission to hospital and ed length of stay (los); -hr return to ed (rr) was used as a balancing measure. scorecards were constructed using box plots to show physicians their practice patterns relative to peers (the figure shows an example of the scorecard for gatroenteritis for one physician, showing resources use rates for iv fluids and labs). blinded scorecards were distributed quarterly for five quarters using rolling-year averages. a pre/post-intervention analysis was performed with sep , as the intervention date. fisher's exact and wilcoxon rank sum tests were used for analysis. results: we analyzed , patient visits across two hospitals ( , pre-and , post-intervention), comprising . % of the total ed volume during the study period. patients were seen by physicians (mean patients/physician). the table shows overall physician practice in the pre-and post-intervention periods. significant reduction in resource use was seen for abdominal/pelvic ct scans, head ct scan, chest x-rays, iv ondansetron, and admission to hospital. ed los decreased from min to min (p = . ). there was no significant change in -hr return rate during the study period ( . % pre-, . % post-intervention). conclusion: feedback on comprehensive practice patterns including resource use and quality metrics can influence physician practice on commonly used resources in the ed. billboards, via iphone application, twitter, and text messaging. there is a paucity of data describing the accuracy of publically posted ed wait times. objectives: to examine the accuracy of publicly posted wait times of four emergency departments within one hospital system. methods: a prospective analysis of four ed-posted wait times in comparison to the wait times for actual patients. the main hospital system calculated and posted ed wait times every twenty minutes for all four system eds. a consecutive sample of all patients who arrived / over a -week period during july and august was included. an electronic tracking system identified patient arrival date and the actual incurred wait time. data consisted of the arrival time, actual wait time, hospital census, budgeted hospital census, and the posted ed wait time. for each ed the difference was calculated between the publicly posted ed wait time at the time of patient's arrival and the patient's actual ed wait time. the average wait times and average wait time error between the ed sites were compared using a two-tailed student's t-test. the correlation coefficient between the differences in predicted/ actual wait times was also calculated for each ed. results: there were wait times within the four eds included in the analysis. the average wait time (in minutes) at each facility was: . (± . ) for the main ed, . (± . ) for freestanding ed (fed) # , . (± . ) for fed # , and . (± . ) for the small community ed. the average wait time error (in minutes) for each facility was (± . ) for the main ed, (± . ) for fed # , (± . ) for fed # , and (± . ) for the community hospital ed. the results from each ed were statistically significant for both average wait time and average wait time error (p < . ). there was a positive correlation between the average wait time and average wait time error, with r-values of . , . , . , and . for the main ed, fed # , fed # , and the small community hospital ed, respectively. each correlation was statistically significant; however, no correlation was found between the number of beds available (budgeted-actual census) and average wait times. conclusion: publically posted ed wait times are accurate for facilities with less than ed visits per month. they are not accurate for eds with greater than visits per month. reduction of pre-analytic laboratory errors in the emergency department using an incentive-based system benjamin katz, daniel pauze, karen moldveen albany medical center, albany, ny background: over the last decade, there has been an increased effort to reduce medical errors of all kinds. laboratory errors have a significant effect on patient care, yet they are usually avoidable. several studies suggest that up to % of laboratory errors occur during the pre-or post-analytic phase. in other words, errors occur during specimen collection and transport or reporting of results, rather than during laboratory analysis itself. objectives: in an effort to reduce pre-analytic laboratory errors, the ed instituted an incentive-based program for the clerical staff to recognize and prevent specimen labeling errors from reaching the patient. this study sought to demonstrate the benefit of this incentive-based program. methods: this study examined a prospective cohort of ed patients over a three year period in a tertiary care academic ed with annual census of , . as part of a continuing quality improvement process, laboratory specimen labeling errors are screened by clerical staff by reconciling laboratory specimen label with laboratory requisition labels. the number of ''near-misses'' or mismatched specimens captured by each clerk was then blinded to all patient identifiers and was collated by monthly intervals. due to poor performance in , an incentive program was introduced in early by which the clerk who captured the most mismatched specimens would be awarded a $ gift card on a quarterly basis. the total number of missed laboratory errors was then recorded on a monthly basis. investigational data were analyzed using bivariate statistics. background: most studies on operational research have been focused in academic medical centers, which typically have larger volumes of patients and are located in urban metropolitan areas. as cms core measures in begin to compare emergency departments (eds) on treatment time intervals, especially length of stay (los), it is important to explore if any differences exist inherent to patient volume. objectives: the objective of this study is to look at differences in operational metrics based on annual patient census. the hypothesis is that treatment time intervals and operational metrics differ amongst these different categories. methods: the ed benchmarking alliance has collected yearly operational metrics since . as of , there are eds providing data across the united states. eds are stratified by annual volume for comparison in the following categories: < k, - k, - k, and over k. in this study, metrics for eds with < k visits per year were compared to those of different volumes, averaged from - . mean values were compared to < k visits as a reference point for statistical difference using t-tests to compare means with a p-value < . considered significant. results: as seen in the table, a greater percentage of high acuity of patients was seen in higher volume eds than in < k eds. the percentage of patients transferred to another hospital was higher in < k eds. a higher percentage arrived by ems and a higher percentage were admitted in higher volume eds when compared to < k visits. in addition, the median los for both discharged and admitted patients and percentage who left before treatment was complete (lbtc) were higher in the higher volume eds. conclusion: lower volume eds have lower acuity when compared to higher volume eds. lower volume eds have shorter median los and left before treatment complete percentages. as cms core measures require hospitals to report these metrics, it will be important to compare them based on volume and not in aggregate. does the addition of a hands-free communication device improve ed interruption times? amy ernst, steven j. weiss, jeffrey a. reitsema university of new mexico, albuquerque, nm background: ed interruptions occur frequently. recently a hands-free communication device (vocera) was added to a cell phone and a pager in our ed. objectives: the purpose of the present study was to determine whether this addition improved interruption times. our hypothesis was that the device would significantly decrease length of time of interruptions. methods: this study was a prospective cohort study of attending ed physician calls and interruptions in a level i trauma center with em residency. interruptions included phone calls, ekg interpretations, pages to resuscitation, and other miscellaneous interruptions (including nursing issues, laboratory, ems, and radiology). we studied a convenience sampling intended to include mostly evening shifts, the busiest ed times. length of time the interruption lasted was recorded. data were collected for a comparison group pre-vocera. three investigators collected data including seven different addendings' interruptions. data were collected on a form, then entered into an excel file. data collectors' agreement was determined during two additional four hour shifts to calculate a kappa statistic. spss was used for data entry and statistical analysis. descriptive statistics were used for univariate data. chi-square and mann whitney u nonparametric test were used for comparisons. results: of the total interruptions, % were phone calls, % were ekgs to be read, % were pages to resuscitation, and % miscellaneous. there were no significant differences in types of interruptions pre-vs. post-vocera. pre-vocera we collected hours of data with interruptions with a mean . per hour. post-vocera, hours of data were collected with interruptions with a mean . per hour. there was a significant difference in length of time of interruptions with an average of minutes pre-vocera vs. minutes post-vocera (p = . , diff . , % ci . - . ). vocera calls were significantly shorter than non-vocera calls ( vs minutes, p < . ). comparing data collectors for type of interruption during the same -hour shift resulted in a kappa (agreement) of . . conclusion: the addition of a hands-free communication device may improve interruptions by shortening call length. '' talk background: analyses of patient flow through the ed typically focus on metrics such as wait time, total length of stay (los), or boarding time. however, little is known about how much interaction a patient has with clinicians after being placed in a room, or what proportion of the in-room visit is also spent ''waiting,'' rather than directly interacting with care providers. objectives: the objective was to assess the proportion of time, relative to the time in a patient care area, that a patient spends actively interacting with providers during an ed visit. methods: a secondary analysis of audiotaped encounters of patients with one of four diagnoses (ankle sprain, back pain, head injury, laceration) was performed. the setting was an urban, academic ed. ed visits of adult patients were recorded from the time of room placement to discharge. audiotapes were edited to remove all downtime and non-patient-provider conversations. los and door-to-doctor times were abstracted from the medical record. the proportion of time the patient spent in direct conversation with providers (''talk-time'') was calculated as the ratio of the edited audio recording time to the time spent in a patient care area (talk-time = [edited audio time/(los -door-to-doctor)]). multiple linear regression controlling for time spent in patient care area, age, and sex was performed. results: the sample was % male with a mean age of years. median los: minutes (iqr: - ), median door-to-doctor: minutes (iqr: - ), median time spent in patient care area: minutes (iqr: - ). median time spent in direct conversation with providers was minutes (iqr: - ), corresponding to a talk-time percentage of . % (iqr: . - . %). there were no significant differences based on diagnosis. regression analysis showed that those spending a longer time in a patient care area had a lower percentage of talk time (b = ) . , p = . ). conclusion: although limited by sample size, these results indicate that approximately % of a patients' time in a care area is spent not interacting with providers. while some of the time spent waiting is out of the providers' control (e.g. awaiting imaging studies), this significant ''downtime'' represents an opportunity for both process improvement efforts to decrease downtime as well as the development of innovative patient education efforts to make the best use of the remaining downtime. degradation of emergency department operational data quality during electronic health record implementation michael j. ward, craig froehle, christopher j. lindsell university of cincinnati, cincinnati, oh background: process improvement initiatives targeted at operational efficiency frequently use electronic timestamps to estimate task and process durations. errors in timestamps hamper the use of electronic data to improve a system and may result in inappropriate conclusions about performance. despite the fact that the number of electronic health record (ehr) implementations is expected to increase in the u.s., the magnitude of this ehr-induced error is not well established. objectives: to estimate the change in the magnitude of error in ed electronic timestamps before and after a hospital-wide ehr implementation. methods: time-and-motion observations were conducted in a suburban ed, annual census , , after receiving irb approval. observation was conducted weeks pre-and weeks post-ehr implementation. patients were identified on entering the ed and tracked until exiting. times were recorded to the nearest second using a calibrated stopwatch, and are reported in minutes. electronic data were extracted from the patient-tracking system in use pre-implementation, and from the ehr post-implementation. for comparison of means, independent t-tests were used. chi-square and fisher's t-tests were used for proportions, as appropriate. results: there were observations; before and after implementation. the differences between observed times and timestamps were computed and found to be normally distributed. post-implementation, mean physician seen times along with arrival to bed, bed to physician, and physician to disposition intervals occurred before observation. physician seen timestamps were frequently incorrect and did not improve postimplementation. significant discrepancies (ten minutes or greater) from observed values were identified in timestamps involving disposition decision and exit from the ed. calculating service time intervals resulted in every service interval (except arrival to bed) having at least % of the times with significant discrepancies. it is notable that missing values were more frequent post-ehr implementation. conclusion: ehr implementation results in reduced variability of timestamps but reduced accuracy and an increase in missing timestamps. using electronic timestamps for operational efficiency assessment should recognize the magnitude of error, and the compounding of error, when computing service times. background: procedural sedation and analgesia is used in the ed in order to efficiently and humanely perform necessary painful procedures. the opposing physiological effects of ketamine and propofol suggest the potential for synergy, and this has led to interest in their combined use, commonly termed ''ketofol'', to facilitate ed procedural sedation. objectives: to determine if a : mixture of ketamine and propofol (ketofol) for ed procedural sedation results in a % or more absolute reduction in adverse respiratory events compared to propofol alone. methods: participants were randomized to receive either ketofol or propofol in a double-blind fashion according to a weight-based dosing protocol. inclusion criteria were age years or greater, and asa class - status. the primary outcome was the number and proportion of patients experiencing an adverse respiratory event according to pre-defined criteria (the ''quebec criteria''). secondary outcomes were sedation consistency, sedation efficacy, induction time, sedation time, procedure time, and adverse events. results: a total of patients were enrolled, per group. forty-three ( %) patients experienced an adverse respiratory event in the ketofol group compared to ( %) in the propofol group (difference %; % ci ) % to %; p = . ). thirty-eight ( %) patients receiving ketofol and ( %) receiving propofol developed hypoxia, of whom three ( %) ketofol patients and ( %) propofol patient received bag-valve-mask ventilation. sixty-five ( %) patients receiving ketofol and ( %) receiving propofol required repeat medication dosing or lightened to a ramsay sedation score of or less during their procedure (difference %; % ci % to %; p = . ). procedural agitation occurred in patients ( . %) receiving ketofol compared to ( %) receiving propofol (difference . %, % ci % to %). recovery agitation requiring treatment occurred in six patients ( %, % ci . % to . %) receiving ketofol. other secondary outcomes were similar between the groups. patients and staff were highly satisfied with both agents. conclusion: ketofol for ed procedural sedation does not result in a reduced incidence of adverse respiratory events compared to propofol alone. induction time, efficacy, and sedation time were similar; however, sedation depth appeared to be more consistent with ketofol. with propofol and its safety is well established. however, in cms enacted guidelines defining propofol as deep sedation and requiring administration by a physician. common edps practice had been one physician performing both the sedation and procedure. edps has proven safe under this one-physician practice. however, the guidelines mandated separate physicians perform each. objectives: the study hypothesis was that one-physician propofol sedation complication rates are similar to two-physician. methods: before and after, observational study of patients > years of age consenting to edps with propofol. edps completed with one physician were compared to those completed with two (separate physicians performing the sedation and the procedure). all data were prospectively collected. the study was completed at an urban level i trauma center. standard monitoring and procedures for edps were followed with physicians blinded to the objectives of this research. the frequency and incremental dosing of medication was left to the discretion of the treating physicians. the study protocol required an ed nurse trained in data collection to be present to record vital signs and assess for any prospectively defined complications. we used chi-square tests to compare the binary outcomes and asa scores across the time periods, and two-sample t-tests to test for differences in age between the two time periods. results: during the -year study period we enrolled patients: one-physician edps sedations and (- to ) also received bag-valve-mask ( ) [ . to ) ( ) [ . to ] (- to ) two-physician. all patients meeting inclusion criteria were included in the study. total adverse event rates were . % and . %, respectively (p = . ). the most common complications were hypotension and oxygen desaturation, and they respectively showed one-physcian rates of . % and . % and two-physician rates of . % and . % (p = . and . .) the unsuccessful procedure rates were . % vs . % (p = . ). conclusion: this study demonstrated no significant difference in complication rates for propofol edps completed by one physician as compared to two. background: overdose patients are often monitored using pulse oximetry, which may not detect changes in patients on high-flow oxygen. objectives: to determine whether changes in end-tidal carbon dioxide (etco ) detected by capnographic monitoring are associated with clinical interventions due to respiratory depression (crd) in patients undergoing evaluation for a decreased level of consciousness after a presumed drug overdose. methods: this was a prospective, observational study of adult patients undergoing evaluation for a drug overdose in an urban county ed. all patients received supplemental oxygen. patients were continuously monitored by trained research associates. the level of consciousness was recorded using the observer's assessment of alertness/sedation scale (oaa/s). vital signs, pulse oximetry, and oaa/s were monitored and recorded every minutes and at the time of occurrence of any crd. respiratory rate and etco were measured at five second intervals using a capno-stream monitor. crd included an increase in supplemental oxygen, the use of bag-valve-mask ventilations, repositioning to improve ventilation, and physical or verbal stimulus to induce respiration, and were performed at the discretion of the treating physicians and nurses. changes from baseline in etco values and waveforms among patients who did or did have a clinical intervention were compared using wilcoxon rank sum tests. results: patients were enrolled in the study (age , range to , % male, median oaas , range to ). suspected overdoses were due to opioids in , benzodiazepines in , an antipsychotic in , and others in . the median time of evaluation was minutes (range to ). crd occurred in % of patients, including an increase in o in %, repositioning in %, and stimulation to induce respiration in %. % had an o saturation of < % (median , range to ) and % had a loss of etco waveform at some time, all of whom had a crd. the median change in etco from baseline was mmhg, range to . among patients with crd it was mmhg, range to , and among patients with no crd it was mmhg, range to (p = . ). conclusion: the change in etco from baseline was larger in patients who required clinical interventions than in those who did not. in patients on high-flow oxygen, capnographic monitoring may be sensitive to the need for airway support. how reliable are health care providers in reporting changes in etco waveform anas sawas , scott youngquist , troy madsen , matthew ahern , camille broadwater-hollifield , andrew syndergaard , jared phelps , bryson garbett , virgil davis university of utah, salt lake city, ut; midwestern university, glendale, az background: etco changes have been used in procedural sedation analgesia (psa) research to evaluate subclinical respiratory depression associated with sedation regiments. objectives: to evaluate the accuracy of bedside clinician reporting of changes in etco . methods: this was a prospective, randomized, singleblind study conducted in ed setting from june until the present time. this study took place at an academic adult ed of a -bed ( in the ed) and a level i trauma center. subjects were randomized to receive either ketamine-propofol or propofol according to a standardized protocol. loss of etco waveforms for ‡ sec were recorded. following sedation, questionnaires were completed by the sedating physicians. digitally recorded etco waveforms were also reviewed by an independent physician and a trained research assistant (ra). to ensure the reliability of trained research assistants, we compared their analyses with the analyses of an independent physician for the first recordings. the target enrollment was patients in each group (n = total). statistics were calculated using sas statistical software. results: patients were enrolled; ( . %) are males and ( . %) are females. mean age was . ± . years. most participants did not have major risk factors for apnea or for further complications ( . % were asa class or ). etco waveforms were reviewed by ( . %) sedating physicians and ( . %) nurses at the bedside. there were ( . %) etco waveforms recordings, ( . %) were reviewed by an independent physician and ( %) were reviewed by an ra. a kappa test for agreement between independent physicians and ras was conducted on recordings and there were no discordant pairs (kappa = ). compared to sedating physicians, the independent physician was more likely to report etco wave losses (or . , % ci . - . ). compared to sedating physicians, ras were more likely to report etco wave losses (or . , % ci . - . ). conclusion: compared to sedating physicians at the bedside, independent physicians and ras were more likely to note etco waveform losses. an independent review of recorded etco waveform changes will be more reliable for future sedation research. background: comprehensive studies evaluating current practices of ed airway management in japan are lacking. many emergency physicians in japan still experience resistance regarding rapid sequence intubation (rsi). objectives: we sought to describe the success and complication rate of rsi with non-rsi. methods: design and setting: we conducted a multicenter prospective observational study using the jean registry of eds at academic and community hospitals in japan during between and . data fields include ed characteristics, patient and operator demographics, method of airway management, number of attempts, and adverse events. we defined non-rsi as intubation with sedation only, neuromuscular blockade only, and without medication. participants: all patients undergoing emergency intubation in ed were eligible for inclusion. cardiac arrest encounters were excluded from the analysis. primary analysis: we described rsi with non-rsi in terms of success rate on first attempt, within three attempts, and complication rate. we present descriptive data as proportions with % confidence intervals (cis). we report odds ratios (or) with % ci via chi-square testing. results: the database recorded intubations (capture rate %) and met the inclusion criteria. rsi was the initial method chosen in ( %) and non-rsi in ( %). use of rsi varied among institutes from % to %. success cases of rsi on first and within three attempts are intubations ( %, %ci %- %) and intubations ( %, %ci %- %), respectively. the success cases of non-rsi on first and within three attempts are intubations ( %, %ci %- %) and intubations ( %, %ci %- %). success rates of rsi on first and within three attempts are higher than non-rsi (or . , %ci . - . and or . , % ci . - . , respectively). we recorded complications in rsi ( %) and in non-rsi ( %). there is no significant difference of complication rate between rsi and non-rsi (or . , % ci . - . ). conclusion: in this multi-center prospective study in japan, we demonstrated a high degree of variation in use of rsi for ed intubation. additionally we found that success rate of rsi on first and within three attempts were both higher than non-rsi. this study has the limitation of reporting bias and confounding by indication. (originally submitted as a ''late-breaker.'') methods: this was a prospective, randomized, singleblind study conducted in the ed setting from june until the present time. this study took place at an academic adult ed of a -bed ( in the ed) and a level i trauma center. subjects were randomized to receive either ketamine-propofol or propofol according to a standardized protocol. etco waveforms were digitally recorded. etco changes were evaluated by the sedating physicians at the bedside. recorded waveforms were reviewed by an independent physician and a trained research assistant (ra). to ensure the reliability of trained ras, we computed a kappa test for agreement between the analysis of independent physicians and ras for the first recordings. a post-hoc analysis of the association between any loss, the number of losses, and total duration of loss of etco waveform and crp was performed. on review we recorded the absence or presence of loss of etco and the total duration in seconds of all lost etco episodes ‡ seconds. ors were calculated using sas statistical software. results: patients were enrolled; ( . %) are males and are ( . %) females. . % participants were asa class or . waveforms were reviewed by ( . %) sedating physicians. there were ( . %) waveforms recordings, ( . %) were reviewed by an independent physician and ( %) were reviewed by ras, where there were no discordant pairs (kappa = ). there were ( . %) crp events. any loss of etco was associated with a non-significant or of . ( % ci . - . ) for crp. however, the duration of etco loss was significantly associated with crp with an or of . ( % ci . - . ) for each second interval of lost etco . the number of losses was significantly associated with the outcome (or . , % ci . - . ). conclusion: defining subclinical respiratory depression as present or absent may be less useful than quantitative measurements. this suggests that risk is cumulative over periods of loss of etco , and the duration of loss may be a better marker of sedation depth and risk of complications than classification of any loss. background: ed visits present an opportunity to deliver brief interventions (bis) to reduce violence and alcohol misuse among urban adolescents at risk for future injury. previous analyses demonstrated that a brief intervention resulted in reductions in violence and alcohol consequences up to months. objectives: this paper describes findings examining the efficacy of bis on peer violence and alcohol misuse at months. methods: patients ( - yrs) at an ed reporting past year alcohol use and aggression were enrolled in the rct, which included computerized assessment, and randomization to control group or bi delivered by a computer (cbi) or therapist assisted by a computer (tbi). baseline and months included violence (peer aggression, peer victimization, violence related consequences) and alcohol (alcohol misuse, binge drinking, alcohol-related consequences). results: adolescents were screened ( % participation). of those, screened positive for violence and alcohol use and were randomized; % completed -month follow-up. as compared to the control group, the tbi group showed significant reductions in peer aggression (p < . ) and peer victimization (p < . ) at months. bi and control groups did not differ on alcohol-related variables at months. conclusion: evaluation of the saferteens intervention one year following an ed visit provides support for the efficacy of computer-assisted therapist brief intervention for reducing peer violence. violence against ed health care workers: a -month experience terry kowalenko , donna gates , gordon gillespie , paul succop university of michigan, ann arbor, mi; university of cincinnati, cincinnati, oh background: health care (hc) support occupations have an injury rate nearly times that of the general sector due to assaults, with doctors and nurses nearly times greater. studies have shown that the ed is at greatest risk of such events compared to other hc settings. objectives: to describe the incidence of violence in ed hc workers over months. specific aims were to ) identify demographic, occupational, and perpetrator factors related to violent events; ) identify the predictors of acute stress response in victims; and ) identify predictors of loss of productivity after the event. methods: longitudinal, repeated methods design was used to collect monthly survey data from ed hc workers (w) at six hospitals in two states. surveys assessed the number and type of violent events, and feelings of safety and confidence. victims also completed specific violent event surveys. descriptive statistics and a repeated measure linear regression model were used. results: ed hcws completed monthly surveys, and violent events were reported. the average per person violent event rate per months was . . events were physical threats ( . per person in months). events were assaults ( . per person in months). violent event surveys were completed, describing physical threats and assaults with % resulting in injuries. % of the physical threats and % of the assaults were perpetrated by men. comparing occupational groups revealed significant differences between nurses and physicians for all reported events (p = . ), with the greatest difference in physical threats (p = . ). nurses felt less safe than physicians (p = . ). physicians felt more confident than nurses in dealing with the violent patient (p = . ). nurses were more likely to experience acute stress than physicians (p < . ). acute stress significantly reduced productivity in general (p < . ), with a significant negative effect on ''ability to handle/ manage workload'' (p < . ) and ''ability to handle/ manage cognitive demands'' (p < . ). conclusion: ed hcws are frequent victims of violence perpetrated by visitors and patients. this violence results in injuries, acute stress, and loss of productivity. acute stress has negative consequences on the workers' ability to perform their duties. this has serious potential consequences to the victim as well as the care they provide to their patients. a randomized controlled feasibility trial of vacant lot greening to reduce crime and increase perceptions of safety eugenia c. garvin, charles c. branas perelman school of medicine at the university of pennsylvania, philadelphia, pa background: vacant lots, often filled with trash and overgrown vegetation, have been associated with intentional injuries. a recent quasi-experimental study found a significant decrease in gun crimes around vacant lots that had been greened compared with control lots. objectives: to determine the feasibility of a randomized vacant lot greening intervention, and its effect on police-reported crime and perceptions of safety. methods: for this randomized controlled feasibility trial of vacant lot greening, we partnered with the pennsylvania horticulture society (phs) to perform the greening intervention (cleaning the lots, planting grass and trees, and building a wooden fence around the perimeter). we analyzed police crime data and interviewed people living around the study vacant lots (greened and control) about perceptions of safety before and after greening. results: a total of sq ft of randomly selected vacant lot space was successfully greened. we used a master database of , vacant lots to randomly select vacant lot clusters. we viewed each cluster with the phs to determine which were appropriate to send to the city of philadelphia for greening approval. the vacant lot cluster highest on the random list to be approved by the city of philadelphia was designated the intervention site, and the next highest was designated the control site. overall, participants completed baseline interviews, and completed follow-up interviews after months. % of participants were male, % were black or african american, and % had a household income less than $ , . unadjusted difference-in-differences estimates showed a decrease in gun assaults around greened vacant lots compared to control. regression-adjusted estimates showed that people living around greened vacant lots reported feeling safer after greening compared to those who lived around control vacant lots (p < . ). conclusion: conducting a randomized controlled trial of vacant lot greening is feasible. greening may reduce certain gun crimes and make people feel safer. however, larger prospective trials are needed to further investigate this link. screening for violence identifies young adults at risk for return ed visits for injury abigail hankin-wei, brittany meagley, debra houry emory university, atlanta, ga background: homicide is the second leading cause of death among youth ages - . prior studies, in nonhealth care settings, have shown associations between violent injury and risk factors including exposure to community violence, peer behavior, and delinquency. objectives: to assess whether self-reported exposure to violence risk factors can be used to predict future ed visits for injuries. methods: we conducted a prospective cohort study in the ed of a southeastern us level i trauma center. patients aged - presenting for any chief complaint were included unless they were critically ill, incarcerated, or could not read english. recruitment took place over six months, by a trained research assistant (ra). the ra was present in the ed for - days per week, with shifts scheduled such that they included weekends and weekdays, over the hours from am- pm. patients were offered a $ gift card for participation. at the time of initial contact in the ed, patients completed a written questionnaire which included validated measures of the following risk factors: a) aggression, b) perceived likelihood of violence, c) recent violent behavior, d) peer behavior, e) community exposure to violence, and f) positive future outlook. at months following the initial ed visit, the participants' medical records were reviewed to identify any subsequent ed visits for injury-related complaints. data were analyzed with chi-square and logistic regression analyses. results: patients were approached, of whom patients consented. participants' average age was . years, with % female, and % african american. return visits for injuries were significantly associated with hostile/aggressive feelings (rr . , ci . , ) , self-reported perceived likelihood of violence (rr . , ci . , . ) , recent violent behavior (rr . , ci . , . ) , and peer group violence (rr . , ci . , . ) . these findings remained significant when controlling for participant sex. conclusion: a brief survey of risk factors for violence is predictive of return visit to the ed for injury. these findings identify a potentially important tool for primary prevention of violent injuries among young adults visiting the ed for both injury and non-injury complaints. background: sepsis is a commonly encountered disease in ed, with high mortality. while several clinical prediction rules (cpr) including meds, sirs, and curb- exist to facilitate clinicians in early recognition of risk of mortality for sepsis, most are of suboptimal performance. objectives: to derive a novel cpr for mortality of sepsis utilizing clinically available and objective predictors in ed. methods: we retrospectively reviewed all adult septic patients who visited the ed at a tertiary hospital during the year with two sets of blood cultures ordered by physicians. basic demographics, ed vital signs, symptoms and signs, underlying illnesses, laboratory findings, microbiological results, and discharge status were collected. multivariate logistic regressions were used to obtain a novel cpr using predictors with < . p-value tested in univariate analyses. the existing cprs were compared with this novel cpr using auc. results: of included patients, . % died in hospital, % had diabetes, % were older than years of age, % had malignancy, and % had positive blood bacterial culture tests. predisposing factors including history of malignancy, liver disease, immunosuppressed status, chronic kidney disease, congestive heart failure, and older than years of age were found to be associated with mortality (all p < . ). patients who developed mortality tended to have lower body temperature, narrower pulse pressure, higher percentage of red cell distribution width (rdw) and bandemia, higher blood urea nitrogen (bun), ammonia, and c-reactive protein level, and longer prothrombin time and activated partial thromboplastin time (aptt) (all p < . ). the most parsimonious cpr incorporating history of malignancy (or . , % ci . - . ), prolonged aptt ( . , . - . ), presence of bandemia ( . , . - . results: there was poor agreement between the physician's unstructured assessment used in clinical practice and the guidelines put forth by the aha/acc/acep task force. ed physicians were more likely to assess a patient as low risk ( %), while aha guidelines were more likely to classify patients as intermediate ( %) or high ( %) risk. however, when comparing the patient's final acs diagnosis and the relation to the risk assessment value, ed physicians proved better predictors of high-risk patients who in fact had acs, while the aha/acc/acep guidelines proved better at correctly identifying low-risk patients who did not have acs. conclusion: in the ed, physicians are far more efficient at correctly placing patients with underlying acs into a high-risk category, while established criteria may be overly conservative when applied to an acute care population. further research is indicated to look at ed physicians' risk stratification and ensuing patient care to assess for appropriate decision making and ultimate outcomes. compartative conclusion: the amuse score was more specific, but the wells score was more sensitive for acute lower limb dvt in this cohort. there is no significant advantage in using the amuse over the wells score in ed patient with suspected dvt. background: the direct cost of medical care is not accurately reflected in charges or reimbursement. the cost of boarding admitted patients in the ed has been studied in terms of opportunity costs, which are indirect. the actual direct effect on hospital expenses has not been well defined. objectives: we calculate the difference to the hospital in the cost of caring for an admitted patient in the ed and in a non-critical care in-patient unit. methods: time-directed activity-based costing (tdabc) has recently been proposed as a method of determining the actual cost of providing medical services. tdabc was used to calculate the cost per patient bed-hour both in the ed and for an in-patient unit. the costs include nursing, nursing assistants, clerks, attending and resident physicians, supervisory salaries, and equipment maintenance. boarding hours were determined from placement of admission order to transfer to in-patient unit. a convenience sample of consecutive non-critical care admissions was assessed to find the degree of ed physician involvement with boarded patients. results: the overhead cost per patient bed-hour in the ed was $ . . the equivalent cost per bed-hour inpatient was $ . , a differential of $ . . there were , boarding hours for medical-surgical patients in , a differential of $ , , . for the year. for the short-stay unit (no residents), the cost per patient hour was $ . and the boarding hours were , . this resulted in a differential cost of $ , . , a total direct cost to the hospital of $ , , . . review of consecutive admissions showed no orders placed by the ed physician after decision-toadmit. conclusion: concentration of resources in the ed means considerably higher cost per unit of care as compared to an in-patient unit. keeping admitted patients boarding in the ed results in expensive underutilization. this is exclusive of significant opportunity costs of lost revenue from walk-out and diverted patients. this study includes the cost of teaching attendings and residents (ed and in-patient) . in a non-teaching setting, the differential would be less and the cost of boarding would be shared by a fee-for-service ed physician group as well as the hospital. improving identification of frequent emergency department users using a regional health information background: frequent ed users consume a disproportionate amount of health care resources. interventions are being designed to identify such patients and direct them to more appropriate treatment settings. because some frequent users visit more than one ed, a health information exchange (hie) may improve the ability to identify frequent ed users across sites of care. objectives: to demonstrate the extent to which a hie can identify the marginal increase in frequent ed users beyond that which can be detected with data from a single hospital. methods: data from / / to / / from the new york clinical information exchange (nyclix), a hie in new york city that includes ten hospitals, were analyzed to calculate the number of frequent ed users ( ‡ visits in days) at each site and across the hie. results: there were , ( % of total patients) frequent ed users, with , ( %) of frequent users having all their visits at a single ed, while , ( %) frequent users were identified only after counting visits to multiple eds (table ) . site-specific increases varied from % to % (sd . ). frequent ed users accounted for % of patients, but for % of visits, averaging . visits per year, versus . visits per year for all other patients. . % of frequent users visited two or more eds during the study period, compared to . % of all other patients. conclusion: frequent ed users commonly visited multiple nyclix eds during the study period. the use of a hie helped identify many additional frequent users, though the benefits were lower for hospitals not located in the relative vicinity of another nyclix hospital. measures that take a community, rather than a single institution, into account may be more reflective of the care that the patient experiences. indocyanine background: due to their complex nature and high associated morbidity, burn injuries must be handled quickly and efficiently. partial thickness burns are currently treated based upon visual judgment of burn depth by the clinician. however, such judgment is only % accurate and not expeditious. laser doppler imaging (ldi) is far more accurate -nearly % after days. however, it is too cumbersome for routine clinical use. laser assisted indocyanine green angiography (laicga) has been indicated as an alternative for diagnosing the depth of burn injuries, and possesses greater utility for clinical translation. as the preferred outcome of burn healing is aesthetic, it is of interest to determine if wound contracture can be predicted early in the course of a burn by laic-ga. objectives: determine the utility of early burn analysis using laicga in the prediction of -day wound contracture. methods: a prospective animal experiment was performed using six anesthetized pigs, each with standardized wounds. differences in burn depth were created by using a . · . cm aluminum bar at three exposure times and temperatures: degrees c for seconds, degrees c for seconds, and degrees c for seconds. we have shown in prior validation experiments that these burn temperatures and times create distinct burn depths. laicga scanning, using lifecell spy elite, took place at hour, hours, hours, hours, and week post burn. imaging was read by a blinded investigator, and perfusion trends were compared with day post-burn contraction outcomes measured using imagej software. biopsies were taken on day to measure scar tissue depth. results: deep burns were characterized by a blue center indicating poor perfusion while more superficial burns were characterized by a yellow-red center indicating perfusion that was close to that of the normal uninjured adjacent skin (see figure) . a linear relationship between contraction outcome and burn perfusion could be discerned as early as hour post burn, peaking in strength at - hours post-burn. burn intensity could be effectively identified at hours post-burn, although there was no relationship with scar tissue depth. conclusion: pilot data indicate that laicga using lifecell spy has the ability to determine the depth of injury and predict the degree of contraction of deep dermal burns within - days of injury with greater accuracy than clinical scoring. the objectives: we hypothesize that real-time monitoring of an integrated electronic medical records system and the subsequent firing of a ''sepsis alert'' icon on the electronic ed tracking board results in improved mortality for patients who present to the ed with severe sepsis or septic shock. methods: we retrospectively reviewed our hospital's sepsis registry and included all patients diagnosed with severe sepsis or septic shock presenting to an academic community ed with an annual census of , visits and who were admitted to a medical icu or stepdown icu bed between june and october . in may an algorithm was added to our integrated medical records system that identifies patients with two sirs criteria and evidence of endorgan damage or shock on lab data. when these criteria are met, a ''sepsis alert'' icon (prompt) appears next to that patient's name on the ed tracking board. the system also pages an in-house, specially trained icu nurse who can respond on a prn basis and assist in the patient's management. months of intervention data are compared with months of baseline data. statistical analysis was via z-test for proportions. results: for ed patients with severe sepsis, the preand post-alert mortality was of ( %) and of ( %), respectively (p = . ; n = ). in the septic shock group, the pre-and post-alert mortality was of ( %) and of ( %), respectively (p = . ). with ed and inpatient sepsis alerts combined, the severe sepsis subgroup mortality was reduced from % to % (p = . ; n = ). conclusion: real-time ed ehr screening for severe sepsis and septic shock patients did not improve mortality. a positive trend in the severe sepsis subgroup was noted, and the combined inpatient plus ed data suggests statistical significance may be reached as more patients enter the registry. limitations: retrospective study, potential increased data capture post intervention, and no ''gold standard'' to test the sepsis alert sensitivity and specificity. ) . descriptive statistics were calculated. principal component analysis was used to determine questions with continuous response formats that could be aggregated. aggregated outcomes were regressed onto predictor demographic variables using multiple linear regression. results: / physicians completed the survey. physicians had a mean of . ± . years experience in the ed. . % were female. eight physicians ( %) reported never having used the tool, while . % of users estimated having used it more than five times. % of users cited the ''p'' alert on the etb as the most common notification method. most felt the ''p'' alert did not help them identify patients with pneumonia earlier (mean = . ± . ), but found it moderately useful in reminding them to use the tool ( . ± . ). physicians found the tool helpful in making decisions regarding triage, diagnostic studies, and antibiotic selection for outpatients and inpatients ( . ± . , . ± . , . ± . , and . ± . , respectively). they did not feel it negatively affected their ability to perform other tasks ( . ± . ). using multiple linear regression, neither age, sex, years experience, nor tool use frequency significantly predicted responses to questions about triage and antibiotic selection, technical difficulties, or diagnostic ordering. conclusion: ed physicians perceived the tool to be helpful in managing patients with pneumonia without negatively affecting workflow. perceptions appear consistent across demographic variables and experience. objectives: we seek to examine whether use of the salt device can provide reliable tracheal intubation during ongoing cpr. the dynamic model tested the device with human powered cpr (manual) and with an automated chest compression device (physio control lucas ). the hypothesis is that the predictable movement of an automated chest compression device will make tracheal intubation easier than the random movement from manual cpr. methods: the project was an experimental controlled trial and took place in the ed at a tertiary referral center in peoria, illinois. this project was an expansion arm of a similarly structured study using traditional laryngoscopy. emergency medicine residents, attending physicians, paramedics, and other acls-trained staff were eligible for participation. in randomized order, each participant attempted intubation on a mannequin using the salt device with no cpr ongoing, during cpr with a manual compression, and during cpr with an automatic chest compression. participants were timed in their attempt and success was determined after each attempt. results: there were participants in the trial. the success rates in the control group and the automated cpr group were both % ( / ) and the success rate in the manual cpr group was % ( / objectives: our primary hypothesis was that in fasting, asymptomatic subjects, larger fluid boluses would lead to proportional aortic velocity changes. our secondary endpoints were to determine inter-and intra-subject variation in aortic velocity measurements. methods: the authors performed a prospective randomized double-blinded trial using healthy volunteers. we measured the velocity time integral (vti) and maximal velocity (vmax) with an estimated - °pulsed wave doppler interrogation of the left ventricular outflow in the apical- cardiac window. three physicians reviewed optimal sampling gate position, doppler angle and verified the presence of an aortic closure spike. angle correction technology was not used. subjects with no history of cardiac disease or hypertension fasted for hours and were then randomly assigned to receive a normal saline bolus of ml/kg, ml/kg or ml/kg over minutes. aortic velocity profiles were measured before and after each fluid bolus. results: forty-two subjects were enrolled. mean age was ± (range to ) and mean body mass index . ± . (range . to ). mean volume (in ml) for groups receiving ml/kg, ml/kg, and ml/kg were , , and , respectively. mean baseline vmax (in cm/s) of the subjects was . ± . (range to ). mean baseline vti (in cm) was . ± . (range . to . ). pre-and post-fluid mean differences for vmax were ) . (± . ) and for vti . (± . ). aortic velocity changes in groups receiving ml/kg, ml/kg, and ml/kg were not statistically significant (see table) . heart rate changes were not significant. background: clinicians recognize that septic shock is a highly prevalent, high mortality disease state. evidence supports early ed resuscitation, yet care delivery is often inconsistent and incomplete. the objective of this study was to discover latent critical barriers to successful ed resuscitation of septic shock. objectives: clinicians recognize that septic shock is a highly prevalent, high mortality disease state. evidence supports early ed resuscitation, yet care delivery is often inconsistent and incomplete. the objective of this study was to discover latent critical barriers to successful ed resuscitation of septic shock. methods: we conducted five -minute risk-informed in-situ simulations. ed physicians and nurses working in the real clinical environment cared for a standardized patient, introduced into their existing patient workload, with signs and symptoms of septic shock. immediately after case completion clinicians participated in a minute debriefing session. transcripts of these sessions were analyzed using grounded theory, a method of qualitative analysis, to identify critical barrier themes. results: fifteen clinicians participated in the debriefing sessions: four attending physicians, five residents, five nurses, and one nurse practitioner. the most prevalent critical barrier themes were: anchoring bias and difficulty with cognitive framework adaptation as the patient progressed to septic shock (n = ), difficult interactions between the ed and ancillary departments (n = ), difficulties with physician-nurse commu-nication and teamwork (n = ), and delays in placing the central venous catheter due to perceptions surrounding equipment availability and the desire to attend to other competing interests in the ed prior to initiation of the procedure (n = and ). each theme was represented in at least four of the five debriefing sessions. participants reported the in-situ simulations to be a realistic representation of ed sepsis care. conclusion: in-situ simulation and subsequent debriefing provides a method of identifying latent critical areas for improvement in a care process. improvement strategies for ed-based septic shock resuscitation will need to address the difficulties in shock recognition and cognitive framework adaptation, physician and nurse teamwork, and prioritization of team effort. the background: the association between blood glucose level and mortality in critically ill patients is highly debated. several studies have investigated the association between history of diabetes, blood sugar level, and mortality of septic patients; however, no consistent conclusion could be drawn so far. objectives: to investigate the association between diabetes and initial glucose level and in-hospital mortality in patients with suspected sepsis from the ed. methods: we conducted a retrospective cohort study that consisted of all adult septic patients who visited the ed at a tertiary hospital during the year with two sets of blood cultures ordered by physicians. basic demographics, ed vital signs, symptoms and signs, underlying illnesses, laboratory findings, microbiological results, and discharge status were collected. logistic regressions were used to evaluate the association between risk factors, initial blood sugar level, and history of diabetes and mortality, as well as the effect modification between initial blood sugar level and history of diabetes. results: a total of patients with available blood sugar levels were included, of whom % had diabetes, % were older than years of age, and % were male. the mortality was % ( % ci . - . %). patients with a history of diabetes tended to be older, female, and more likely to have chronic kidney disease, lower sepsis severity (meds score), and positive blood culture test results (all p < . ). patients with a history of diabetes tended to have lower in-hospital mortality after ed visits with sepsis, controlling for initial blood sugar level (aor . , % ci . - . , p = . ). initial normal blood sugar seemed to be beneficial compared to lower blood sugar level for in-hospital mortality, controlled history of diabetes, sex, severity of sepsis, and age (aor . , % ci . - . , p = . ). the effect modification of diabetes on blood sugar level and mortality, however, was found to be not statistically significant (p = . ). conclusion: normal initial blood sugar level in ed and history of diabetes might be protective for mortality of septic patients who visited the ed. further investigation is warranted to determine the mechanism for these effects. methods: this irb-approved retrospective chart review included all patients treated with therapeutic hypothermia after cardiac arrest during at an urban, academic teaching hospital. every patient undergoing therapeutic hypothermia is treated by neurocritical care specialists. patients were identified by review of neurocritical care consultation logs. clinical data were dually abstracted by trained clinical study assistants using a standardized data dictionary and case report form. medications reviewed during hypothermia were midazolam, lorazepam, propofol, fentanyl, cisatracurium, and vecuronium. results: there were patients in the cohort. median age was (range - years), % were white, % were male, and % had a history of coronary artery disease. seizures were documented by continuous eeg in / ( %), and / ( %) died during hospitalization. most, / ( %), received fentanyl, / ( %) received benzodiazepine pharmacotherapy, and / ( %) received propofol. paralytics were administered to / ( %) patients, / ( %) with cisatracurium and / ( %) with vecuronium. of note, one patient required pentobarbital for seizure management. conclusion: sedation and neuromuscular blockade are common during management of patients undergoing therapeutic hypothermia after cardiac arrest. patients in this cohort often received analgesia with fentanyl, and sedation with a benzodiazepine or propofol. given the frequent use of sedatives and paralytics in survivors of cardiac arrest undergoing hypothermia, future studies should investigate the potential effect of these drugs on prognostication and survival after cardiac arrest. background: the use of therapeutic hypothermia (th) is a burgeoning treatment modality for post-cardiac arrest patients. objectives: we performed a retrospective chart review of patients who underwent post cardiac arrest th at eight different institutions across the united states. our objective was to assess how th is currently being implemented in emergency departments and assess the feasibility of conducting more extensive th research using multi-institution retrospective data. methods: a total of charts with dates from - were sent for review by participating institutions of the peri-resuscitation consortium. of those reviewed, eight charts were excluded for missing data. two independent reviewers performed the review and the results were subsequently compared and discrepancies resolved by a third reviewer. we assessed patient demographics, initial presenting rhythm, time until th initiation, duration of th, cooling methods and temperature reached, survival to hospital discharge, and neurological status on discharge. results: the majority of cases of th had initial cardiac rhythms of asystole or pulseless electrical activity ( . %), followed by ventricular tachycardia or fibrillation ( . %), and in . % the inciting cardiac rhythm was unknown. time to initiation of th ranged from - minutes with a mean time of min (sd . ). length of th ranged from - minutes with a mean time of minutes (sd ). average minimum temperature achieved was . °c, with a range from . - . °c (sd . °c). of the charts reviewed, ( . %) of the patients survived to hospital discharge and ( . %) were discharged relatively neurologically intact. conclusion: research surrounding cardiac arrest has always been difficult given the time and location span from pre-hospital care to emergency department to intensive care unit. also, as witnessed cardiac arrest events are relatively rare with poor survival outcomes, very large sample sizes are needed to make any meaningful conclusions about th. our varied and inconsistent results show that a multi-center retrospective review is also unlikely to provide useful information. a prospective multi-center trial with a uniform th protocol is needed if we are ever to make any evidence-based conclusions on the utility of th for post-cardiac arrest patients. serum results: mean la was . , sd = . . mean age was . years old, sd = . . a statistically significant positive correlation was found between la and pulse, respiratory rate (rr), wbc, platelets, and los, while a significant negative correlation was seen with temperature and hco -. when two subjects were dropped as possible outliers with la > , it resulted in non-significant temperature correlation, but a significant negative correlation with age and bun was revealed. patients in the higher la group were more likely to be admitted (p = . ) and have longer los. of the discharged patients, there was no difference in mean la level between those who returned (n = , mean la of . , sd = . ) and those who did not (n = , mean la of . , sd = . ), p = . . furthermore, mean la levels for those with sepsis (n = , mean la of . , sd = . ) did not differ from those without sepsis (n = , mean la of . , sd = . ), p = . . conclusion: higher la in pediatric patients presenting to the ed with suspected infection correlated with increased pulse, rr, wbc, platelets, and decreased bun, hco -, and age. la may be predictive of hospitalization, but not of -day return rates or pediatric sepsis screening in the ed. background: mandibular fractures are one of the most frequently seen injuries in the trauma setting. in terms of facial trauma, madibular fractures account for - % of all facial bone fractures. prior studies have demonstrated that the use of a tongue blade to screen these patients to determine whether a mandibular fracture is present may be as sensitive as x-ray. one study showed the sensitivity and specificity of the test to be . % and . %, respectively. in the last ten years, high-resolution computed tomography (hct) has replaced panoramic tomography (pt) as the gold standard for imaging of patients with suspected mandibular fractures. this study determines if the tongue blade test (tbt) remains as sensitive a screening tool when compared to the new gold standard of ct. objectives: the purpose of the study was to determine the sensitivity and specificity of the tbt as compared to the new gold standard of radiologic imaging, hct. the question being asked: is the tbt still useful as a screening tool for patients with suspected mandibular fractures when compared to the new gold standard of hct? methods: design: prospective cohort study. setting: an urban tertiary care level i trauma center. subjects: this study took place from / / to / / in which any person suffering from facial trauma presented. intervention: a tbt was performed by the resident physician and confirmed by the supervising attending physician. ct facial bones were then obtained for the ultimate diagnosis. inter-rater reliability (kappa) was calculated, along with sensitivity, specificity, accuracy, ppv, npv, likelihood ratio (lr) (+), and likelihood ratio (lr) (-) based on a · contingency tables generated. results: over the study period patients were enrolled. inter-rater reliability was kappa = . (se + . ). the table demonstrates the outcomes of both the tbt and ct facial bones for mandibular fracture. the following parameters were then calculated based on the contingency table: sensitivity . (ci . - . ), specificity . (ci . - . ), ppv . (ci . - . ), npv . (ci . - . ), accuracy . , lr(+) . ), lr (-) . (ci . - . ). conclusion: the tbt is still a useful screening tool to rule out mandibular fractures in patients with facial trauma as compared to the current gold standard of hct. background: appendicitis is the most common surgical emergency occurring in children. the diagnosis of pediatric appendicitis is often difficult and computerized tomography (ct) scanning is utilized frequently. ct, although accurate, is expensive, time-consuming, and exposes children to ionizing radiation. radiologists utilize ultrasound for the diagnosis of appendicitis, but it may be less accurate than ct, and may not incorporate emergency physician (ep) clinical impression regarding degree of risk. objectives: the current study compared ep clinical diagnosis of pediatric appendicitis pre-and post-bedside ultrasonography (bus). methods: children - years of age were enrolled if their clinical attending physician planned to obtain a consultative ultrasound, ct scan, or surgical consult specific for appendicitis. most children in the study received narcotic analgesia to facilitate bus. subjects were initially graded for likelihood of appendicitis based on research physician-obtained history and physical using a visual analogue scale (vas). immediately subsequent to initial grading, research physicians performed a bus and recorded a second vas impression of appendicitis likelihood. two outcome measures were combined as the gold standard for statistical analysis. the post-operative pathology report served as the gold standard for subjects who underwent appendectomy, while post -week telephone follow-up was used for subjects who did not undergo surgery. various specific ultrasound measures used for the diagnosis of appendicitis were assessed as well. results: / subjects had pathology-proven appendicitis. one subject was pathology-negative post-appendectomy. of the subjects who did not undergo surgery, none had developed appendicitis at the post -week telephone follow-up. pre-bus sensitivity was % ( - %) while post-bus sensitivity was % ( - %). both pre-and post-bus specificity was % ( - %). pre-bus lr+ was ( - ), while post-bus lr+ was ( - ). pre-and post-bus lr-were . and . , respectively. bus changed the diagnosis for % of subjects ( - %). background: there are very little data on the normal distance between the glenoid rim and the posterior aspect of the humeral head in normal and dislocated shoulders. while shoulder x-rays are commonly used to detect shoulder dislocations, they may be inadequate, exacerbate pain in the acquisition of some views, and lead to delay in treatment, compared to bedside ultrasound evaluation. objectives: our objective was to compare the glenoid rim to humeral head distance in normal shoulders and in anteriorly dislocated shoulders. this is the first study proposing to set normal and abnormal limits. methods: subjects were enrolled in this prospective observation study if they had a chief complaint of shoulder pain or injury, and received a shoulder ultrasound as well as a shoulder x-ray. the sonographers were undergraduate students given ten hours of training to perform the shoulder ultrasound. they were blinded to the x-ray interpretation, which was used as the gold standard. we used a posterior-lateral approach, capturing an image with the glenoid rim, the humeral head, as well as the infraspinatus muscle. two parallel lines were applied to the most posterior aspect of the humeral head and the most posterior aspect of the glenoid rim. a line perpendicular to these lines was applied, and the distance measured. in anterior dislocations, a negative measurement was used to denote the fact that the glenoid rim is now posterior to the most posterior aspect of the humeral head. descriptive analysis was applied to estimate the mean and th to th interquartile range of normal and anteriorly dislocated shoulders. results: eighty subjects were enrolled in this study. there were six shoulder dislocations, however only four were anterior dislocations. the average distance between the posterior glenoid rim and the posterior humeral head in normal shoulders was . mm, with a th to th inter-quartile range of . mm to . mm. the distance in our four cases of anterior dislocation was ) mm, with a th to th interquartile range of ) mm to ) mm. conclusion: the distance between the posterior humeral head to posterior glenoid rim may be mm to mm in patients presenting to the ed with shoulder pain but no dislocation. in contrast, this distance in anterior dislocations was greater than ) mm. shoulder ultrasound may be a useful adjunct to x-ray for diagnosing anterior shoulder dislocations. conclusion: in this retrospective study, the presence of rv strain on focus significantly increases the likelihood of an adverse short term event from pulmonary embolism and its combination with hypotension performs similarly to other prognostic rules. background: burns are expensive and debilitating injuries, compromising both the structural integrity and vascular supply to skin. they exhibit a substantial potential to deteriorate if left untreated. jackson defined three ''zones'' to a burn. while the innermost coagulation zone and the outermost zone of hyperemia display generally predictable healing outcomes, the zone of stasis has been shown to be salvageable via clinical intervention. it has therefore been the focus of most acute therapies for burn injuries. while laser doppler imaging (ldi) -the current gold standard for burn analysis -has been % effective at predicting the need for second degree burn excision, its clinical translation is problematic, and there is little information regarding its ability to analyze the salvage of the stasis zone in acute injury. laser assisted indocyanine green dye angiography (laicga) also shows potential to predict such outcomes with greater clinical utility. objectives: to test the ability of ldi and laicga to predict interspace (zone of stasis) survival in a horizontal burn comb model. methods: a prospective animal experiment was performed using four pigs. each pig had a set of six dorsal burns created using a brass ''comb'' -creating four rectangular · mm full thickness burns separated by · mm interspaces. laicga and ldi scanning took place at hour, hours, hours, and week post burn using novadaq spy and moor ldi respectively. imaging was read by a blinded investigator, and perfusion trends were compared with interspace viability and contraction. burn outcomes were read clinically, evaluated via histopathology, and interspace contraction was measured using image j software. results: laicga data showed significant predictive potential for interspace survival. it was . % predictive at hours post burn, % predictive hours post burn, and % predictive days post burn using a standardized perfusion threshold. ldi imaging failed to predict outcome or contraction trends with any degree of reliability. the pattern of perfusion also appears to be correlated with the presence of significant interspace contraction at days, with an % adherence to a power trendline. ventions, isolation, testing, treatment, and ''other'' category intervention were identified. one intervention involving school closures was associated with a % decrease in pediatric ed visits for respiratory illness. conclusion: most interventions were not tested in isolation, so the effect of individual interventions was difficult to differentiate. interventions associated with statistically significant decreases in ed crowding were school closures, as well as interventions in all categories studied. further study and standardization of intervention input, process, and outcome measures may assist in identifying the most effective methods of mitigating ed crowding and improving surge capacity during an influenza or other respiratory disease outbreak. communication background: the link between extended shift lengths, sleepiness, and occupational injury or illness has been shown, in other health care populations, to be an important and preventable public health concern but heretofore has not been fully described in emergency medical services (ems objectives: to assess the effect of an ed-based computer screening and referral intervention for ipv victims and to determine what characteristics resulted in a positive change in their safety. we hypothesized that women who were experiencing severe ipv and/or were in contemplation or action stages would be more likely to endorse safety behaviors. methods: we conducted the intervention for female ipv victims at three urban eds using a computer kiosk to deliver targeted education about ipv and violence prevention as well as referrals to local resources. all adult english-speaking non-critically ill women triaged to the ed waiting room were eligible to participate. the validated universal violence prevention screening protocol was used for ipv screening. any who disclosed ipv further responded to validated questionnaires for alcohol and drug abuse, depression, and ipv severity. the women were assigned a baseline stage of change (precontemplation, contemplation, action, or maintenance) based on the urica scale for readiness to change behavior surrounding ipv. participants were contacted at week and months to assess a variety of pre-determined actions such as moving out, to prevent ipv during that period. statistical analysis (chi-square testing) was performed to compare participant characteristics to the stage of change and whether or not they took protective action. results: a total of , people were screened and disclosed ipv and participated in the full survey. . % of the ipv victims were in the precontemplative stage of change, and . % were in the contemplation stage. women returned at week of follow-up ( . %), and ( . %) women returned at months of followup. . % of those who returned at week, and % of those who returned at months took protective action against further ipv. there was no association between the various demographic characteristics and whether or not a woman took protective action. conclusion: ed-based kiosk screening and health information delivery is both a feasible and effective method of health information dissemination for women experiencing ipv. stage of change was not associated with actual ipv protective measures. objectives: we present a pilot, head-to-head comparison of x and x effectiveness in stopping a motivated person. the objective is to determine comparative injury prevention effectiveness of the newer cew. methods: four humans had metal cew probe pairs placed. each volunteer had two probe pairs placed (one pair each on the right and left of the abdomen/inguinal region). superior probes were at the costal margin, inches lateral of midline. inferior probes were vertically inferior at predetermined distances of , , , and inches apart. each volunteer was given the goal of slashing a target feet away with a rubber knife during cew exposure. as a means of motivation, they believed the exposure would continue until they reached the goal (in reality, the exposure was terminated once no further progress was made). each volunteer received one exposure from a x and a x cew. the exposure order was randomized with a -minute rest between them. exposures were recorded on a hi-speed, hi-resolution video. videos were reviewed and scored by six physician, kinesiology, and law officer experts using standardized criteria for effectiveness including degree of upper and lower extremity, and total body incapacitation, and degree of goal achievement. reviews were descriptively compared independently for probe spread distances and between devices. results: there were exposures ( pairs) for evaluation and no discernible, descriptive reviewer differences in effectiveness between the x and the x cews when compared. background: the trend towards higher gasoline prices over the past decade in the u.s. has been associated with higher rates of bicycle use for utilitarian trips. this shift towards non-motorized transportation should be encouraged from a physical activity promotion and sustainability perspective. however, gas price induced changes in travel behavior may be associated with higher rates of bicycle-related injury. increased consideration of injury prevention will be a critical component of developing healthy communities that help safely support more active lifestyles. objectives: the purpose of this analysis was to a) describe bicycle-related injuries treated in u.s. emergency departments between and and b) investigate the association between gas prices and both the incidence and severity of adult bicycle injuries. we hypothesized that as gas prices increase, adults are more likely to shift away from driving for utilitarian travel toward more economical non-motorized modes of transportation, resulting in increased risk exposure for bicycle injuries. methods: bicycle injury data for adults ( - years) were obtained from the national electronic injury surveillance system (neiss) database for emergency department visits between - . the relationship between national seasonally adjusted monthly rates of bicycle injuries, obtained by a seasonal decomposition of time series, and average national gasoline prices, reported by the energy information administration, was examined using a linear regression analysis. results: monthly rates of bicycle injuries requiring emergency care among adults increase significantly as gas prices rise (p < . , see figure) . an additional , adult injuries ( % ci - , ) can be predicted to occur each month in the u.s. (> , injuries annually) for each $ rise in average gasoline price. injury severity also increases during periods of high gas prices, with a higher percentage of injuries requiring admission. conclusion: increases in adult bicycle use in response to higher gas prices are accompanied by higher rates of significant bicycle-related injuries. supporting the use of non-motorized transportation will be imperative to address public health concerns such as obesity and climate change; however, resources must also be dedicated to improve bicycle-related injury care and prevention. background: this is a secondary analysis of data collected for a randomized trial of oral steroids in emergency department (ed) musculoskeletal back pain patients. we hypothesized that higher pain scores in the ed would be associated with more days out of work. objectives: to determine the degree to which days out of work for ed back pain patients are correlated with ed pain scores. methods: design: prospective cohort. setting: suburban ed with , annual visits. participants: patients aged - years with moderately severe musculoskeletal back pain from a bending or twisting injury £ days before presentation. exclusion criteria included nonmusculoskeletal etiology, direct trauma, motor deficits, and employer-initiated visits. observations: we captured initial and discharge ed visual analog pain scores (vas) on a - scale. patients were contacted approximately days after discharge and queried about the days out of work. we plotted days out of work versus initial vas, discharge vas, and change in vas and calculated correlation coefficients. using the bonferroni correction because of multiple comparisons, alpha was set at . . results: we analyzed patients for whom complete data were available. the mean age was ± years and % were female. the average initial and discharge ed pain scales were . ± . and . ± . , respectively. on follow-up, % of patients were back to work and % did not lose any days of work. for the plots of the days out of work versus the initial and discharge vas and the change in the vas, the correlation coefficients (r ) were . (p = . ), . (p = . ), and . (p = . ), respectively. conclusion: for ed patients with musculoskeletal back pain, we found no statistically significant correlation between days out of work and ed pain scores. background: conducted electrical weapons (cews) are common law enforcement tools used to subdue and repel violent subjects and, therefore, prevent further injury or violence from occurring in certain situations. the taser x is a new generation of cew that has the capability of firing two cartridges in a ''semi-automatic'' mode, and has a different electrical waveform and different output characteristics than older generation technology. there have been no data presented on the human physiologic effects of this new generation cew. objectives: the objective of this study was to evaluate the human physiologic effects of this new cew. methods: this was a prospective, observational study of human subjects. an instructor shot subjects in the abdomen and upper thigh with one cartridge, and subjects received a -second exposure from the device. measured variables included: vital signs, continuous spirometry, pre-and post-exposure ecg, intra-exposure echocardiography, venous ph, lactate, potassium, ck, and troponin. results: ten subjects completed the study (median age . , median bmi . , % male). there were no important changes in vital signs or in potassium. the median increase in lactate during the exposure was . , range . to . . the median change in ph was ) . , range ) . to . . no subject had a clinically relevant ecg change, evidence of cardiac capture, or positive troponin up to hours after exposure. the median change in creatine kinase (ck) at hours was , range ) to . there was no evidence of impairment of breathing by spirometry. baseline median minute ventilation was . , which increased to . during the exposure (p = . ), and remained elevated at . post-exposure (p = . ). conclusion: we detected a small increase in lactate and decrease in ph during the exposure, and an increase in ck hours after the exposure. the physiologic effects of the x device appear similar to previous reports for ecd devices. use background: public bicycle sharing (bikeshare) programs are becoming increasingly common in the us and around the world. these programs make bicycles easily accessible for hourly rental to the public. there are currently active bikeshare programs in cities in the us, and more than programs are being developed in cities including new york and chicago. despite the importance of helmet use, bikeshare programs do not provide the opportunity to purchase or rent helmets. while the programs encourage helmet use, no helmets are provided at the rental kiosks. objectives: we sought to describe the prevalence of helmet use among adult users of bikeshare programs and users of personal bicycles in two cities with recently introduced bicycle sharing programs (boston, ma and washington, dc). methods: we performed a prospective observational study of bicyclists in boston, ma and washington, dc. trained observers collected data during various times of the day and days of the week. observers recorded the sex of the bicycle operator, type of bicycle, and helmet use. all bicycles that passed a single stationary location in any direction for a period of between and minutes were recorded. data are presented as frequencies of helmet use by sex, type of bicycle (bikeshare or personal), time of the week (weekday or weekend), and city. logistic regression was used to estimate the odds ratio for helmet use controlling for type of bicycle, sex, day of week, and city. results: there were observation periods in two cities at locations. , bicyclists were observed. there were ( . %) bicylists riding bikeshare bicycles. overall helmet use was . %, although helmet use varied significantly with sex, day of use, and type of bicycle (see figure) . bikeshare users were helmeted at a lower rate compared to users of personal bicycles ( . % vs . %). logistic regression, controlling for type of bicycle, sex, day of week, and city demonstrate that bikeshare users had higher odds of riding unhelmeted (or . , % ci . - . ). women had lower odds of riding unhelmeted (or . , . - . ), while weekend riders were more likely to ride unhelmeted (or . , . - . ). conclusion: use of bicycle helmets by users of public bikeshare programs is low. as these programs become more popular and prevalent, efforts to increase helmet use among users should increase. background: abusive head trauma (aht) represents one of the most severe forms of traumatic brain injury (tbi) among abused infants with % mortality. young adult males account for % of the perpetrators. most aht prevention programs are hospital-based and reach a predominantly female audience. there are no published reports of school-based aht prevention programs to date. objectives: . to determine whether a high schoolbased aht educational program will improve students' knowledge of aht and parenting skills. . to evaluate the feasibility and acceptability of a school-based aht prevention program. methods: this program was based on an inexpensive commercially available program developed by the national center on shaken baby syndrome. the program was modified to include a -minute interactive presentation that teaches teenagers about aht, parenting skills, and caring for inconsolable crying infants. the program was administered in three high schools in flint, michigan during spring . student's knowledge was evaluated with a -item written test administered pre-intervention, post-intervention, and two months after program completion. program feasibility and acceptability were evaluated through interviews and surveys with flint area school social workers, parent educators, teachers, and administrators. results: in all, high school students ( % male) participated. of these, ( . %) completed the pretest and post-test with ( %) completing the twomonth follow-up test. the mean pre-intervention, postintervention, and two-month follow-up scores were %, %, and % respectively. from pre-test to posttest, mean score improved %, p < . . this improvement was even more profound in young males, whose mean post-test score improved by %, p < . . of the participating social workers, parent educators, teachers, and administrators, % ranked the program as feasible and acceptable. conclusion: students participating in our program showed an improvement in knowledge of aht and parenting skills which was retained after two months. teachers, social workers, parent educators, and school administrators supported the program. this local pilot program has the potential to be implemented on a larger scale in michigan with the ultimate goal of reducing aht amongst infants. will background: fear of litigation has been shown to affect physician practice patterns, and subsequently influence patient care. the likelihood of medical malpractice litigation has previously been linked with patient and provider characteristics. one common concern is that a patient may exaggerate symptoms in order to obtain monetary payouts; however, this has never been studied. objectives: we hypothesize that patients are willing to exaggerate injuries for cash settlements and that there are predictive patient characteristics including age, sex, income, education level, and previous litigation. methods: this prospective cross-sectional study spanned june to december , in a philadelphian urban tertiary care center. any patient medically stable enough to fill out a survey during study investigator availability was included. two closed-ended paper surveys were administered over the research period. standard descriptive statistics were utilized to report incidence of: patients who desired to file a lawsuit, patients previously having filed lawsuits, and patients willing to exaggerate the truth in a lawsuit for a cash settlement. chi-square analysis was performed to determine the relationship between patient characteristics and willingness to exaggerate injuries for a cash settlement. results: of surveys, were excluded due to incomplete data, leaving for analysis. the mean age was with a standard deviation of , and % were male. the incidence of patients who had the desire to sue at the time of treatment was %. the incidence of patients who had filed a lawsuit in the past was %. of those patients, % had filed multiple lawsuits. fifteen percent [ % ci - %] of all patients were willing to exaggerate injuries for cash settlement. sex and income were found to be statistically significant predictors of willingness to exaggerate symptoms: % of females vs. % of males were willing to exaggerate (p = . ), and % of people with income less than $ , /yr vs. % of those with income over $ , / yr were willing to exaggerate (p = . ). conclusion: patients at a philadelphian urban tertiary center admit to willingness to exaggerate symptoms for a cash settlement. willingness to exaggerate symptoms is associated with female sex and lower income. background: current data suggest that as many as % of patients presenting to the ed with syncope leave the hospital without a defined etiology. prior studies have suggested a prevalence of psychiatric disease as high as % in patients with syncope of unknown etiology. objectives: to determine whether psychiatric disease and substance abuse are associated with an increased incidence of syncope of unknown etiology. methods: prospective, observational, cohort study of consecutive ed patients ‡ presenting with syncope was conducted between / and / . patients were queried in the ed and charts reviewed about a history of psychiatric disease, use of psychiatric medication, substance abuse, and duration. data were analyzed using sas with chi-square and fisher's exact tests. results: we enrolled patients who presented to the ed after syncope, of whom did not have an identifiable etiology for their syncopal event. . % of those without an identifiable etiology were male. ( %) patients had a history of or current psychiatric disease ( % male), and patients ( %) had a history of or current substance abuse ( % male). among males with psychiatric disease, % had an unknown etiology of their syncopal event, compared to % of males without psychiatric disease (p = . ). similarly, among all males with a history of substance abuse, % had an unknown etiology, as compared to % of males without a history of substance abuse (p = . ). a similar trend was not identified in elderly females with psychiatric disease (p = . ) or substance abuse (p = . ). however, syncope of unknown etiology was more common among both men and women under age with a history of substance abuse ( %) compared to those without a history of substance abuse ( %; p = . ). conclusion: our results suggest that psychiatric disease and substance abuse are associated with increased incidence of syncope of unknown etiology. patients evaluated in the ed or even hospitalized with syncope of unknown etiology may benefit from psychiatric screening and possibly detoxification referral. this is particularly true in men. (originally submitted as a ''late-breaker.'') scope background: after discharge from an emergency department (ed), pain management often challenges parents, who significantly under-treat their children's pain. rapid patient turnover and anxiety make education about home pain treatment difficult in the ed. video education standardizes information and circumvents insufficient time and literacy. objectives: to evaluate the effectiveness of a -minute instructional video for parents that targets common misconceptions about home pain management. methods: we conducted a randomized, double-blinded clinical trial of parents of children ages - years who presented with a painful condition, were evaluated, and discharged home in june and july . parents were randomized to a pain management video or an injury prevention control video. primary outcome was the proportion of parents who gave pain medication at home. these data were recorded in a home pain diary and analyzed using a chi-square test. parents' knowledge about pain treatment was tested before, immediately following, and days after intervention. mcnemar's test statistic determined odds that knowledge correlated with the intervention group. results: parents were enrolled: watched the pain education video, and the control video. . % completed follow up, providing information about home pain education use. significantly more parents provided at least one dose of pain medication to their children after watching the educational video: % vs. % (difference %, % ci . %, . %). the odds the parent had correct knowledge about pain treatment significantly improved immediately following the educational video for knowledge about pain scores (p = . ), the effect of pain on function (p < . ), and pain medication misconceptions (p < . ). these significant differences in knowledge remained days after the video intervention. the educational video about home pain treatment viewed by parents significantly increased the proportion of children receiving pain medication at home and significantly improved knowledge about at-home pain management. videos are an efficient tool to provide medical advice to parents that improves outcomes for children. methods: this was a prospective, observational study of consecutive admitted cpu patients in a large-volume academic urban ed. cardiology attendings round on all patients and stress test utilization is driven by their recommendation. eligibility criteria include: age> , aha low/intermediate risk, nondynamic ecgs, and normal initial troponin i. patients > and with a history of cad or co-existing active medical problem were excluded. based on prior studies and our estimated cpu census and demographic distribution, we estimated a sample size of , patients in order to detect a difference in stress utilization of % ( -tailed, a = . , b = . ). we calculated a timi risk prediction score and a diamond & forrester (d&f) cad likelihood score on each patient. t-tests were used for univariate comparisons of demographics, cardiac comorbidities, and risk scores. logistic regression was used to estimate odds ratios (ors) for receiving testing based on race, controlling for insurance and either timi or d&f score. results: over months, , patients were enrolled. mean age was ± , and % ( % ci - ) were female. sixty percent ( % ci - ) were caucasian, % ( % ci - ) african american, and % ( % ci - ) hispanic. mean timi and d&f scores were . ( % ci . - . ) and % ( % ci - ). the overall stress testing rate was % ( % ci - ). after controlling for insurance status and timi or d&f scores, african american patients had significantly decreased odds of stress testing (or timi . ( % ci . - . ), or d&f . ( % ci . - . )). hispanics had significantly decreased odds of stress testing in the model controlling for d&f (or d&f . ( % ci . - . )). conclusion: this study confirms that disparities in the workup of african american patients in the cpu are similar to those found in the general ed and the outpatient setting. further investigation into the specific provider or patient level factors contributing to this bias is necessary. the outcomes for hf and copd were sae . %, . %; death . %, . %. we found univariate associations with sae for these walk test components: too ill to walk (both hf, copd p < . ); highest heart rate ‡ (hf p = . , copd p = . ); lowest sao < % (hf p = . , copd p = . ); borg score ‡ (hf p = . , copd p = . ); walk test duration £ minute (hf p = . . copd p = . ). after adjustment for multiple clinical covariates with logistic regression analyses, we found ''walk test heart rate ‡ '' had an odds ratio of . for hf patients and ''too ill to start the walk test'' had an odds ratio of . for copd patients. conclusion: we found the -minute walk test to be easy to administer in the ed and that maximum heart rate and inability to start the test were highly associated with adverse events in patients with exacerbations of hf and copd, respectively. we suggest that the -minute walk test be routinely incorporated into the assessment of hf and copd patients in order to estimate risk of poor outcomes. the objectives: the objective of this study was to investigate differences in consent rates between patients of different demographic groups who were invited to participate in minimal-risk clinical trials conducted in an academic emergency department. methods: this descriptive study analyzed prospectively collected data of all adult patients who were identified as qualified participants in ongoing minimal risk clinical trials. these trials were selected for this review because they presented minimal factors known to be associated background: increasing rates of patient exposure to computerized tomography (ct) raise questions about appropriateness of utilization, as well as patient awareness of radiation exposure. despite rapid increases in ct utilization and published risks, there is no national standard to employ informed consent prior to radiation exposure from diagnostic ct. use of written informed consent for ct (icct) in our ed has increased patient understanding of the risks, benefits, and alternatives to ct imaging. our team has developed an adjunct video educational module (vem) to further educate ed patients about the ct procedure. objectives: to assess patient knowledge and preferences regarding diagnostic radiation before and after viewing vem. methods: the vem was based on icct currently utilized at our tertiary care ed (census , patients/ year). icct is written at an th grade reading level. this fall, vem/icct materials were presented to a convenience sample of patients in the ed waiting room am- pm, monday-sunday. patients who were < years of age, critically ill, or with language barrier were excluded. to quantify the educational value of the vem, a six-question pretest was administered to assess baseline understanding of ct imaging. the patients then watched the vem via ipad (macintosh) and reviewed the consent form. an eight-question post-test was then completed by each subject. no phi were collected. pre-and post-test results were analyzed using mcnemar's test for individual questions and a paired t-test for the summed score (sas version . ). results: patients consented and completed the survey. the average pre-test score for subjects was poor, % correct. review of vem/icct materials increased patient understanding of medical radiation as evidenced by improved post-test score to %. mean improvement between tests was % (p < . ). % of subjects responded that they found the materials helpful, and that they would like to receive icct. conclusion: the addition of a video educational module improved patient knowledge regarding ct imaging and medical radiation as quantified by pre-and posttesting. patients in our study sample reported that they prefer to receive icct. by educating patients about the risks associated with ct imaging, we increase informed, shared decision making -an essential component of patient-centered care. does objectives: we sought to determine the relationship between patients' pain scores and their rate of consent to ed research. we hypothesized that patients with higher pain scores would be less likely to consent to ed research. methods: retrospective observational cohort study of potential research subjects in an urban academic hospital ed with an average annual census of approximately , visits. subjects were adults older than years with chief complaint of chest pain within the last hours, making them eligible for one of two cardiac biomarker research studies. the studies required only blood draws and did not offer compensation. two reviewers extracted data from research screening logs. patients were grouped according to pain score at triage, pain score at the time of approach, and improvement in pain score (triage score -approach score). the main outcome was consent to research. simple proportions for consent rates by pain score tertiles were calculated. two multivariate logistic regression analyses were performed with consent as outcome and age, race, sex, and triage or approach pain score as predictors. results: overall, potential subjects were approached for consent. patients were % caucasian, % female, and with an average age of years. six patients did not have pain scores recorded at all and did not have scores documented within hours of approach and were excluded from relevant analyses. overall, . % of patients consented. consent rates by tertiles at triage, at time of approach, and by pain score improvement are shown in tables and . after adjusting for age, race, and sex, neither triage (p = . ) nor approach (p = . ) pain scores predicted consent. conclusion: research enrollment is feasible even in ed patients reporting high levels of pain. patients with modest improvements in pain levels may be more likely to consent. future research should investigate which factors influence patients' decisions to participate in ed research. conclusion: in this multicenter study of children hospitalized with bronchiolitis neither specific viruses nor their viral load predicted the need for cpap or intubation, but young age, low birth weight, presence of apnea, severe retractions, and oxygen saturation < % did. we also identified that children requiring cpap or intubation were more likely to have mothers who smoked during pregnancy and a rapid respiratory worsening. mechanistic research in these high-risk children may yield important insights for the management of severe bronchiolitis. brigham & women's hospital, boston, ma background: siblings and children who share a home with a physically abused child are thought to be at high risk for abuse. however, rates of injury in these children are unknown. disagreements between medical and child protective services professionals are common and screening is highly variable. objectives: our objective was to measure the rates of occult abusive injuries detected in contacts of abused children using a common screening protocol. methods: this was a multi-center, observational cohort study of child abuse teams who shared a common screening protocol. data were collected between jan , and april , for all children < years undergoing evaluation for physical abuse and their contacts. for contacts of abused children, the protocol recommended physical examination for all children < years, skeletal survey and physical exam for children < months, and physical exam, skeletal survey, and neuroimaging for children < months old. results: among , children evaluated for abuse, met criteria as ''physically abused'' and these had contacts. for each screening modality, screening was completed as recommended by the protocol in approximately % of cases. of contacts who met criteria for skeletal survey, new injuries were identified in ( . %). none of these fractures had associated findings on physical examination. physical examination identified new injuries in . % of eligible contacts. neuroimaging failed to identify new injuries among eligible contacts less than months old. twins were at significantly increased risk of fracture relative to other nontwin contacts (or . ). conclusion: these results support routine skeletal survey for contacts of physically abused children < months old, regardless of physical examination findings. even for children where no injuries are identified, these results demonstrate that abuse is common among children who share a home with an abused child, and support including contacts in interventions (foster care, safety planning, social support) designed to protect physically abused children. methods: this was a retrospective study evaluating all children presenting to eight paediatric, universityaffiliated eds during one year in - . in each setting, information regarding triage and disposition were prospectively registered by clerks in the ed database. anonymized data were retrieved from the ed computerized database of each participating centre. in the absence of a gold standard for triage, hospitalisation, admission to intensive care unit (icu), length of stay in the ed, and proportion of patients who left without being seen by a physician (lwbs) were used as surrogate markers of severity. the primary outcome measure was the association between triage level (from to ) and hospitalisation. the association between triage level and dichotomous outcomes was evaluated by a chi-square test, while a student's t-test was used to evaluate the association between triage level and length of stay. it was estimated that the evaluation of all children visiting these eds for a one year period would provide a minimum of , patients in each triage level and at least events for outcomes having a proportion of % or more. results: a total of , children visited the eight eds during the study period. pooled data demonstrated hospitalisation proportions of %, %, %, %, and . % for patients triaged at level , , , , and respectively (p < . ). there was also a strong association between triage levels and admission to icu (p < . ), the proportion of children who lwbs (p < . ), and length of stay (p < . ). background: parents frequently leave the emergency department (ed) with incomplete understanding of the diagnosis and plan, but the relationship between comprehension and post-care outcomes has not been well described. objectives: to explore the relationship between comprehension and post-discharge medication safety. methods: we completed a planned secondary analysis of a prospective observational study of the ed discharge process for children aged - months. after discharge, parents completed a structured interview to assess comprehension of the child's condition, the medical team's advice, and the risk of medication error. limited understanding was defined as a score of - from (excellent) to (poor). risk of medication error was defined as a plan to use over-the-counter cough/cold medication and/or an incorrect dose of acetaminophen (measured by direct observation at discharge or reported dose at follow-up call). parents identified as at risk received further instructions from their provider. the primary outcome was persistent risk of medication error assessed at phone interview - days post-discharge. a major barrier to administering analgesics to children is the perceived discomfort of intravenous access. the delivery of intranasal analgesia may be a novel solution to this problem. objectives: we investigated whether the addition of the mucosal atomizer device (mad) as an alternative for fentanyl delivery would improve overall fentanyl administration rates in pediatric patients transported by a large urban ems system. we performed a historical control trial comparing the rate of pediatric fentanyl administration months before and months after the introduction of the mad. study subjects were pediatric trauma patients (age < years) transported by a large urban ems agency. the control group was composed of patients treated in the months before introduction of the mad. the experimental group included patients treated in the months after the addition of the mad. two physicians reviewed each chart and determined whether the patient met predetermined criteria for the administration of pain medication. a third reviewer resolved any discrepancies. fentanyl administration rates were measured and compared between the two groups. we used two-sample t-tests and chi-square tests to analyze our data. results: patients were included in the study: patients in the pre-mad group and in the post-mad group. there were no significant differences in the demographic and clinical characteristics of the two groups. ( . %) patients in the control arm received fentanyl. ( . %) of patients in the experimental arm received fentanyl with % of the patients receiving fentanyl via the intranasal route. the addition of the mad was not associated with a statistically significant increase in analgesic administration. age and mechanism of injury were statistically more predictive of analgesia administration. conclusion: while the addition of the mucosal atomizer device as an alternative delivery method for fentanyl shows a trend towards increased analgesic administration in a prehospital pediatric population, age and mechanism of injury are more predictive in who receives analgesia. further research is necessary to investigate the effect of the mad on pediatric analgesic delivery. methods: this was a prospective study evaluating php-se before (pre) and after (post) a ppp introduction and months later ( -mo). php groups received either ppp review and education or ppp review alone. the ppp included a pain assessment tool. the se tool, developed and piloted by pediatric ems experts, uses a ranked ordinal scale ranging from 'certain i cannot do it' ( ) to 'completely certain i can do it' ( ) for items: pain assessment ( items), medication administration ( ) and dosing ( ) , and reassessment ( ). all items and an averaged composite were evaluated for three age groups (adult, child, toddler). paired sample t-tests compared post-and -mo scores to pre-ppp scores. results: of phps who completed initial surveys, phps completed -mo surveys. ( %) received education and ppp review and ( %) review only. ppp education did not affect php-se (adult p = . , child p = . , toddler p = . ). the largest se increase was in pain assessment. this increase persisted for child and toddler groups at months. the immediate increase in composite se scores for all age groups persisted for the toddler group at months. conclusion: increases in composite and pain assessment php-se occur for all age groups immediately after ppp introduction. the increase in pain assessment se persisted at months for pediatric age groups. composite se increase persisted for the toddler age group alone. background: pediatric medications administered in the prehospital setting are given infrequently and dosage may be prone to error. calculation of dose based on known weight or with use of length-based tapes occurs even less frequently and may present a challenge in terms of proper dosing. objectives: to characterize dosing errors based on weight-based calculations in pediatric patients in two similar emergency medical service (ems) systems. methods: we studied the five most commonly administered medications given to pediatric patients weighing kg or less. drugs studied were morphine, midazolam, epinephrine : , , epinephrine : , and diphenhydramine. cases from the electronic record were studied for a total of months, from january to july . each drug was administered via intravenous, intramuscular, or intranasal routes. drugs that were permitted to be titrated were excluded. an error was defined as greater than % above or below the recommended mg/kg dosage. results: out of , total patients, , were pediatric patients. had documented weights of < kg and patients were given these medications. we excluded patients for weight above the %ile or below the %ile, or if the weight documentation was missing. of the patients and doses, errors were noted in ( %; % ci %, %). midazolam was the most common drug in errors ( of doses or %; % ci %, %), followed by diphenhydramine ( / or %; % ci %, %), epinephrine ( / or %; % ci %, %), and morphine sulfate ( / or %; % ci, %, %). underdosing was noted in of ( %; % ci %, %) of errors, while excessive dosing was noted in of ( %; % ci %, %). conclusion: weight-based dosing errors in pediatric patients are common. while the clinical consequences of drug dosing errors in these patients are unknown, a considerable amount of inaccuracy occurs. strategies beyond provision of reference materials are needed to prevent pediatric medication errors and reduce the potential for adverse outcomes. drivers background: homelessness affects up to . million people a year. the homeless present more frequently to eds, their ed visits are four times more likely to occur within days of a prior ed evaluation, and they are admitted up to five times more frequently than others. we evaluated the effect of a street outreach rapid response team (sorrt) on the health care utilization of a homeless population. a nonmedical outreach staff responds to the ed and intensely case manages the patient: arranges primary care follow-up, social services, temporary housing opportunities, and drug/ alcohol rehabilitation services. objectives: we hypothesized that this program would decrease the ed visits and hospital admissions of this cohort of patients. methods: before and after study at an urban teaching hospital from june, -december, in indianapolis, indiana. upon identification of homeless status, sorrt was immediately notified. eligibility for sorrt enrollment is determined by housing and urban development homeless criteria and the outreach staff attempted to enter all such identified patients into the program. the patients' health care utilization was evaluated in the months prior to program entry as compared to the months after enrollment by prospectively collecting data and a retrospective medical record query for any unreported visits. since the data were highly skewed, we used the nonparametric signed rank test to test for paired differences between periods. results: patients met criteria but two refused participation. the -patient cohort had total ed visits ( pre and post) with a mean of . (sd . ) and median of . (range - ) ed visits in months pre-sorrt as compared to a mean of . (sd . ) and median of . ( - ) in months post-sorrt (p = . ). there were total inpatient admissions pre-intervention and post-intervention, with a mean of . (sd . ) and median of . ( . ) per patient in the pre-intervention period as compared to . (sd . ) and . ( - ) in the post-intervention period (p = . ). in the pre-sorrt period . % had at least one inpatient admission as compared to . % post-sorrt (p = . ). there were no differences in icu days or overall length of stay between the two periods. conclusion: an aggressive case management program beginning immediately with homeless status recognition in the ed has not demonstrated success in decreasing utilization in our population. methods: this was a secondary analysis of a prospective randomized trial that included consenting patients discharged with outpatient antibiotics from an urban county ed with an annual census of , . patients unable to receive text messages or voice-mails were excluded. health literacy was assessed using a validated health literacy assessment, the newest vital sign (nvs). patients were randomized to a discharge instruction modality: ) standard care, typed and verbal medication and case-specific instructions; ) standard care plus text-messaged instructions sent to the patient's cell phone; or ) standard care plus voice-mailed instructions sent to the patient's cell. patients were called at days to determine preference for instruction delivery modality. preference for discharge instruction modality was analyzed using z-tests for proportions. results: patients were included ( % female, median age , range months to years); were excluded. % had an nvs score of - , % - , and % - . among the . % of participants reached at days, % preferred a modality other than written. there was a difference in the proportion of patients who preferred discharge instructions in written plus another modality (see table) . with the exception of written plus another modality, patient preference was similar across all nvs score groups. conclusion: in this sample of urban ed patients, more than one in four patients prefer non-traditional (text message, voice-mail) modalities of discharge instruction delivery to standard care (written) modality alone. additional research is needed to evaluate the effect of instructional modality on accessibility and patient compliance. figure) . conclusion: cumulative saps ii scoring fails to predict mortality in ohca. the risk scores assigned to age, gcs, and hco independently predict mortality and combined are good mortality predictors. these findings suggest that an alternative severity of illness score should be used in post-cardiac arrest patients. future studies should determine optimal risk scores of saps ii variables in a larger cohort of ohca. objectives: to determine the extent to which cpp recovers to pre-pause levels with seconds of cpr after a -second interruption in chest compressions for ecg rhythm analysis. methods: this was a secondary analysis of prospectively collected data from an iacuc-approved protocol. fortytwo yorkshire swine (weighing - kg) were instrumented under anesthesia. vf was electrically induced. after minutes of untreated vf, cpr was initiated and a standard dose of epinephrine (sde) ( . mg/kg) was given. after . minutes of cpr to circulate the vasopressor, compressions were interrupted for seconds to analyze the ecg rhythm. this was immediately followed by seconds of cpr to restore cpp before the first rs was delivered. if the rs failed, cpr resumed and additional vasopressors (sde, and vasopressin . mg/kg) were given and the sequence repeated. the cpp was defined as aortic diastolic pressure minus right atrial diastolic pressure. the cpp values were extracted at three time points: immediately after the . minutes of cpr, following the -second pause, and immediately before defibrillation for the first two rs attempts in each animal. eighty-three sets of measurements were logged from animals. descriptive statistics were used to analyze the data. in most cities, the proportion of patients who achieve prehospital return of spontaneous circulation (rosc) is less than %. the association between time of day and ohca outcomes in the prehospital setting is unknown. objectives: we sought to determine whether rates of prehospital rosc varied by time of day. we hypothesized that night ohcas would exhibit lower rates of rosc. methods: we performed a retrospective review of cardiac arrest data from a large, urban ems system. included were all ohcas occurring in individuals > years of age from / / to / / . excluded were traumatic arrests and cases where resuscitation measures were not performed. day was defined as : am- : pm, while night was : pm- : am. we examined the association between time of day and paramedic-perceived prehospital rosc in unadjusted and adjusted analyses. variables included age, sex, race, presenting rhythm, aed application by a bystander or first responder, defibrillation, and bystander cpr performance. analyses were performed using chisquare tests and logistic regression. objectives: determine whether a smei helps to improve physician compliance with ihi bundle and reduce patient mortality in ed patients with s&s. methods: we conducted a pre-smei retrospective review of four months of ed patients with s&s to determine baseline pre-smei physician compliance and patient mortality. we designed and completed a smei attended by of ed attending physicians and of ed resuscitation residents. finally, we conducted a twenty-month post-smei prospective study of ongoing physician compliance and patient mortality in ed patients with s&s. results: in the four month pre-smei retrospective review, we identified patients with s&s, with a % physician overall compliance and mortality rate of %. the average ed physician smei multiple-choice pre-test score was %, and showed a significant improvement in the post-test score of % (p = . ). additionally, % of ed physicians were able to describe three new clinical pearls learned and % agreed that the smei would improve compliance. in the twenty months of the post-smei prospective study, we identified patients with s&s, with a % physician overall compliance, and mortality rate of %. relative physician compliance improved % (p = . ) and relative patient mortality was reduced by % (p < . ) when comparing pre-and post-smei data. conclusion: our data suggest that a smei improves overall physician compliance with the six hour goals of the ihi bundle and reduces patient mortality in ed patients with s&s. conclusion: using a population-level, longitudinal, and multi-state analysis, the rate of return visits within days is higher than previously reported, with nearly in returning back to the ed. we also provide the first estimation of health care costs for ed revisits. background: the ability of patients to accurately determine their level of urgency is important in planning strategies that divert away from eds. in fact, an understanding of patient self-triage abilities is needed to inform health policies targeting how and where patients access acute care services within the health care system. objectives: to determine the accuracy of a patient's self-assessment of urgency compared against triage nurses. methods: setting: ed patients are assigned a score by trained nurses according to the canadian emergency department triage and acuity scale (ctas). we present a cross-sectional survey of a random patient sample from urban/regional eds conducted during the winters of and . this previously validated questionnaire, based on the british healthcare commission survey, was distributed according to a modified dillman protocol. exclusion criteria consisted of: age - years, left prior to being seen/treated, died during ed visit, no contact information, presented with a privacy-sensitive case. alberta health services provided linked non-survey administrative data. results: , surveys distributed with a response rate of %. patients rated health problems as life-threatening ( %), possibly life-threatening ( %), urgent ( %), somewhat urgent ( %), or not urgent ( %). triage nurses assigned the same patients ctas scores of i (< %), ii ( %), iii ( %), iv ( %) or v ( %). patients self-rated their condition as or points less urgent than the assigned ctas score (< % of the time), points less urgent ( %), point less urgent ( %), exactly as urgent ( %), point more urgent ( %), points more urgent ( %), or or points more urgent ( %, respectively). among ctas i or ii patients, % described their problem as life-threatening/possibly life-threatening, % as urgent (risk of permanent damage), % as urgent (needed to be seen that day), and % as not urgent (wanted to be but did not need to be seen that day). conclusion: the majority of ed patients are generally able to accurately assess the acuity of their problem. encouraging patients with low-urgency conditions to self-triage to lower-acuity sources of care may relieve stress on eds. however, physicians and patients must be aware that a small minority of patients are unable to self-triage safely. when the tourniquet was released, blood spurted from the injured artery as hydrostatic pressure decayed. pressure and flow were recorded in three animals (see table) . the concept was proof-tested in a single fresh frozen human cadaver with perfusion through the femoral artery and hemorrhage from the popliteal artery. the results were qualitatively and quantitatively similar to the swine carcass model. conclusion: a perfused swine carcass can simulate exsanguinating hemorrhage for training purposes and serves as a prototype for a fresh-frozen human cadaver model. additional research and development are required before the model can be widely applied. background: in the pediatric emergency department (ped), clinicians must work together to provide safe and effective care. crisis resource management (crm) principles have been used to improve team performance in high-risk clinical settings, while simulation allows practice and feedback of these behaviors. objectives: to develop a multidisciplinary educational program in a ped using simulation-enhanced teamwork training to standardize communication and behaviors and identify latent safety threats. methods: over months a workgroup of physicians and nurses with experience in team training and simulation developed an educational program for clinical staff of a tertiary ped. goals included: create a didactic curriculum to teach the principles of crm, incorporate principles of crm into simulation-enhanced team training in-situ and center-based exercises, and utilize assessment instruments to evaluate for teamwork, completion of critical actions, and presence of latent safety threats during in-situ sim resuscitations. results: during phase i, clinicians, divided into teams, participated in -minute pre-training assessments of pals-based in-situ simulations. in phase ii, staff participated in a -hour curriculum reviewing key crm concepts, including team training exercises utilizing simulation and expert debriefing. in phase iii, staff participated in post-training minute teamwork and clinical skills assessments in the ped. in all phases, critical action checklists (cac) were tabulated by simulation educators. in-situ simulations were recorded for later review using the assessment tools. after each simulation, educators facilitated discussion of perceptions of teamwork and identification of systems issues and latent hazards. overall, in-situ simulations were conducted capturing % of the physicians and % of the nurses. cac data were collected by an observer and compared to video recordings. over significant systems issues, latent hazards, and knowledge deficits were identified. all components of the program were rated highly by % of the staff. conclusion: a workgroup of pem, simulation, and team training experts developed a multidisciplinary team training program that used in-situ and centerbased simulation and a refined crm curriculum. unique features of this program include its multidisciplinary focus, the development of a variety of assessment tools, and use of in-situ simulation for evaluation of systems issues and latent hazards. this program was tested in a ped and findings will be used to refine care and develop a sustainment program while addressing issues identified. objectives: our hypothesis is that participants trained on high-fidelity mannequins will perform better than participants trained on low-fidelity mannequins on both the acls written exam and in performance of critical actions during megacode testing. the study was performed in the context of an acls initial provider course for new pgy residents at the penn medicine clinical simulation center and involved three training arms: ) low fidelity (low-fi): torso-rhythm generator; ) mid-fidelity (mid-fi): laerdal simmanÒ turned off; and ) high-fidelity (high-fi): laerdal simmanÒ turned on. training in each arm of the study followed standard aha protocol. educational outcomes were evaluated by written scores on the acls written examination and expert rater reviews of acls megacode videos performed by trainees during the course. a sample of subjects were randomized to one of the three training arms: low-fi (n = ), mid-fi (n = ), or high-fi (n = ). results: statistical significance across the groups was determined using analysis-of-variance (anova). the three groups had similar written pre-test scores [low-fi . ( . ), mid-fi . ( . ), and high-fi . ( . )] and written post-test scores [low-fi . ( . ), mid-fi . ( . ), and high-fi . ( . )]. similarly, test improvement was not significantly different. after completion of the course, high-fi subjects were more likely to report they felt comfortable in their simulator environment (p = . ). low-fi subjects were less likely to perceive a benefit in acls training from high-fi technology (p < . ). acls instructors were not rated significantly different by the subjects using the debriefing assessment for simulation in healthcareª (dash) student version except for element , where the high-fi group subjects reported lower scores ( . vs . and . in the other groups, p = . ). objectives: we sought to determine if stress associated with the performance of a complex procedural task can be affected by level of medical training. heart rate variability (hrv) is used as a measure of autonomic balance, and therefore an indicator of the level of stress. methods: twenty-one medical students and emergency medicine residents were enrolled. participants performed airway procedures on an airway management trainer. hrv data were collected using a continuous heart rate variability monitoring system. participant hrv was monitored at baseline, during the unassisted first attempt at endotracheal intubation, during supervised practice, and then during a simulated respiratory failure clinical scenario. standard deviation of beat to beat variability (sdnn), very low frequency (vlf), total power (tp), and low frequency (lf) was analyzed to determine the effect of practice and level of training on the level of stress. a cohen's d test was used to determine differences between study groups. results: sdnn data showed that second-year residents were less stressed during all stages than were fourthyear medical students (avg d = . ). vlf data showed third-year residents exhibited less sympathetic activity than did first-year residents (avg d = ) . ). the opportunity to practice resulted in less stress for all participants. tp data showed that residents had a greater degree of control over their autonomic nervous system (ans) than did medical students (avg d = . ). lf data showed that subjects were more engaged in the task at hand as the level of training increased indicating autonomic balance (avg d = . ). conclusion: our hrv data show that stress associated with the performance of a complex procedural task is reduced by increased training. hrv may provide a quantitative measure of physiologic stress during the learning process and thus serve as a marker of when a subject is adequately trained to perform a particular task. objectives: we seek to examine whether intubation during cpr can be done as efficiently as intubation without ongoing cpr. the hypothesis is that the predictable movement of an automated chest compression device will make intubation easier than the random movement from manual cpr. methods: the project was an experimental controlled trial and took place in the emergency department at a tertiary referral center in peoria, illinois. emergency medicine residents, attendings, paramedics, and other acls trained staff were eligible for participation. in randomized order, each participant attempted intubation on a mannequin with no cpr ongoing, during cpr with a human compressor, and during cpr with an automatic chest compression device (physio control lucas ). participants could use whichever style laryngoscope they felt most comfortable with and they were timed during the three attempts. success was determined after each attempt. results: there were participants in the trial. the success rate in the control group and the automated cpr group were both % ( / ) and the success rate in the manual cpr group was % ( / ). the differences in success rates were not statistically significant (p = . and p = . ). the automated cpr group had the fastest average time ( . sec; p = . ). the mean times for intubation with manual cpr and no cpr were not statistically different ( . sec, . sec; p = . ). conclusion: the success rate of tracheal intubation with ongoing chest compression was the same as the success rate of intubation without cpr. although intubation with automatic chest compression was faster than during other scenarios, all methods were close to the second timeframe recommended by acls. based on these findings, it may not always be necessary to hold cpr to place a definitive airway; however, further studies will be needed. background: after acute myocardial infarction, vascular remodeling in the peri-infarct area is essential to provide adequate perfusion, prevent additional myocyte loss, and aid in the repair process. we have previously shown that endogenous fibroblast growth factor (fgf ) is essential to the recovery of contractile function and limitation of infarct size after cardiac ischemia-reperfusion (ir) injury. the role of fgf in vascular remodeling in this setting is currently unknown. objectives: determine the role of endogenous fgf in vascular remodeling in a clinically relevant, closed-chest model of acute myocardial infarction. methods: mice with a targeted ablation of the fgf gene (fgf knockout) and wild type controls were subjected to a closed-chest model of regional cardiac ir injury. in this model, mice were subjected to minutes of occlusion of the left anterior descending artery followed by reperfusion for either or days. immunofluorescence was performed on multiple histological sections from these hearts to visualize capillaries (endothelium, anti-cd antibody), larger vessels (venules and arterioles, antismooth muscle actin antibody), and nuclei (dapi). digital images were captured, and multiple images from each heart were measured for vessel density and vessel size. results: sham-treated fgf knockout and wild type mice show no differences in capillary or vessel density suggesting no defect in vessel formation in the absence of endogenous fgf . when subjected to closed-chest regional cardiac ir injury, fgf knockout hearts had normal capillary and vessel number and size in the peri-infarct area after day of reperfusion compared to wild type controls. however, after days, fgf knockout hearts showed significantly decreased capillary and vessel number and increased vessel size compared to wild type controls (p < . ). conclusion: these data show the necessity of endogenous fgf in vascular remodeling in the peri-infarct zone in a clinically relevant animal model of acute myocardial infarction. these findings may suggest a potential role for modulation of fgf signaling as a therapeutic intervention to optimize vascular remodeling in the repair process after myocardial infarction. the diagnosis of aortic dissections by ed physicians is rare scott m. alter, barnet eskin, john r. allegra morristown medical center, morristown, nj background: aortic dissection is a rare event. the most common symptom of dissection is chest pain, but chest pain is a frequent emergency department (ed) chief complaint and other diseases that cause chest pain, such as acute coronary syndrome and pulmonary embolism, occur much more frequently. furthermore, % of dissections are without chest pain and % are painless. for all these reasons, diagnosing dissection can be difficult for the ed physician. we wished to quantify the magnitude of this problem in a large ed database. objectives: our goal was to determine the number of patients diagnosed by ed physicians with aortic dissections compared to total ed patients and to the total number of patients with a chest pain diagnosis. methods: design: retrospective cohort. setting: suburban, urban, and rural new york and new jersey eds with annual visits between , and , . participants: consecutive patients seen by ed physicians from january , through december , . observations: we identified aortic dissections using icd- codes and chest pain diagnoses by examining all icd- codes used over the period of the study and selecting those with a non-traumatic chest pain diagnosis. we then calculated the number of total ed patients and chest pain patients for every aortic dissection diagnosed by emergency physicians. we determined % confidence intervals (cis). results: from a database of . million ed visits, we identified ( . %) aortic dissections, or one for every , ( % ci , to , ) visits. the mean age of aortic dissection patients was ± years and % were female. of the total visits there were , ( %) with a chest pain diagnosis. thus there is one aortic dissection diagnosis for every ( % ci to , ) chest pain diagnoses. conclusion: the diagnosis of aortic dissections by ed physicians is rare. an ed physician seeing , to , patients a year would diagnose an aortic dissection approximately once every to years. an aortic dissection would be diagnosed once for approximately every , ed chest pain patients. patients were excluded if they suffered a cardiac arrest, were transferred from another hospital, or if the ccl was activated for an inpatient or from ems in the field. fp ccl activation was defined as ) a patient for whom activation was cancelled in the ed and ruled out for mi or ) a patient who went to catheterization but no culprit vessel was identified and mi was excluded. ecgs for fp patients were classified using standard criteria. demographic data, cardiac biomarkers, and all relevant time intervals were collected according to an on-going quality assurance protocol. results: a total of ccl activations were reviewed, with % male, average age , and % black. there were ( %) true stemis and ( %) fp activations. there were no significant differences between the fp patients who did and did not have catheterization. for those fp patients who had a catheterization ( %), ''door to page'' and ''door to lab'' times were significantly longer than the stemi patients (see table) , but there was substantial overlap. there was no difference in sex or age, but fp patients were more likely to be black (p = . ). a total of fp patients had ecgs available for review; findings included anterior elevation with convex ( %) or concave ( %) elevation, st elevation from prior anterior ( %) or inferior ( %) mi, pericarditis ( %), presumed new lbbb ( %), early repolarization ( %), and other ( %). conclusion: false ccl activation occurred in a minority of patients, most of whom had ecg findings warranting emergent catheterization. the rate of false ccl activation appears acceptable. background: atrial fibrillation (af) is the most common cardiac arrhythmia treated in the ed, leading to high rates of hospitalization and resource utilization. dedicated atrial fibrillation clinics offer the possibility of reducing the admission burden for af patients presenting to the ed. while the referral base for these af clinics is growing, it is unclear to what extent these clinics contribute to reducing the number of ed visits and hospitalizations related to af. objectives: to compare the number of ed visits and hospitalizations among discharged ed patients with a primary diagnosis of af who followed up with an af clinic and those who did not. methods: a retrospective cohort study and medical records review including three major tertiary centres in calgary, canada. a sample of patients was taken representing patients referred to the af clinic from the calgary zone eds and compared to matched control ed patients who were referred to other providers for follow-up. the controls were matched for age and sex. inclusion criteria included patients over years of age, discharged during the index visit, and seen by the af clinic between january , and october , . exclusion criteria included non-residents and patients hospitalized during the index visit. the number of cardiovascular-related ed visits and hospitalizations was measured. all data are categorical, and were compared using chi-square tests. results: patients in the control and af clinic cohorts were similar for all baseline characteristics except for a higher proportion of first episode patients in the intervention arm. in the six months following the index ed visit, study group patients ( . %) visited an ed on occasions, and ( %) were hospitalized on occasions. of the control group, patients ( . %) visited an ed on occasions, and ( %) were hospitalized on occasions. using a chi-square test we found no significant difference in ed visits (p = . ) or hospitalizations (p = . ) between the control and af clinic cohorts. conclusion: based on our results, referral from the ed to an af clinic is not associated with a significant reduction in subsequent cardiovascular related ed visits and hospitalizations. due to the possibility of residual confounding, randomized trials should be performed to evaluate the efficacy of af clinics. reported an income of less than $ , . there were no significant associations between sex, race, marital status, education level, income, insurance status, and subsequent -and- day readmission rates. hla score was not found to be significantly related to readmission rates. the mean hla score was . (sd = . ), equivalent to less than th grade literacy, meaning these patients may not be able to read prescription labels. for each unit increase in hfkt score, the odds of being readmitted within days decreased by . (p < . ) and for - days decreased by . (p < . ). for each unit increase in scbs score, the odds of being readmitted within days decreased by . (p = . ). conclusion: health care literacy in our patient population is not associated with readmission, likely related to the low literacy rate of our study population. better hf knowledge and self-care behaviors are associated with lower readmission rates. greater emphasis should be placed on patient education and self-care behaviors regarding hf as a mechanism to decrease readmission rates. comparison of door to balloon times in patients presenting directly or transferred to a regional heart center with stemi jennifer ehlers, adam v. wurstle, luis gruberg, adam j. singer stony brook university, stony brook, ny background: based on the evidence, a door-to-balloon-time (dtbt) of less than minutes is recommended by the aha/acc for patients with stemi. in many regions, patients with stemi are transferred to a regional heart center for percutaneous coronary intervention (pci). objectives: we compared dtbt for patients presenting directly to a regional heart center with those for patients transferred from other regional hospitals. we hypothesized that dtbt would be significantly longer for transferred patients. methods: study design-retrospective medical record review. setting-academic ed at a regional heart center with an annual census of , that includes a catchment area of hospitals up to miles away. patients-patients with acute stemi identified on ed -lead ecg. measures-demographic and clinical data including time from triage to ecg, from ecg to activation of regional catheterization lab, and from initial triage to pci (dtbt , and door to intravascular balloon deployment (d b). methods: the study was performed in an inner-city academic ed between / / and / / . every patient for whom ed activation of our stemi system occurred was included. all times data from a pre-existing quality assurance database were collected prospectively. patient language was determined retrospectively by chart review. results: there were patients between / / and / / . patients ( %) were deemed too sick or unable to provide history and were excluded, leaving patients for analysis. ( %) spoke english and ( %) did not. in the non-english group, chinese was the most common language, in ( %) background: syncope is a common, potentially highrisk ed presentation. hospitalization for syncope, although common, is rarely of benefit. no populationbased study has examined disparities in regional admission practices for syncope care in the ed. moreover, there are no population-based studies reporting prognostic factors for -and -day readmission of syncope. objectives: ) to identify factors associated with admission as well as prognostic factors for -and -day readmission to these hospitals; ) to evaluate variability in syncope admission practices across different sizes and types of hospitals. methods: design -multi-center retrospective cohort study using ed administrative data from albertan eds. participants/subjects -patients > years of age with syncope (icd : r ) as a primary or secondary diagnosis from to june . readmission was defined as return visits to the ed or admission < days or - days after the index visit (including against medical advice and left without being seen during the index visit). outcomes -factors associated with hospital admission at index presentation, and readmission following ed discharge, adjusted using multivariable logistic regression. results: overall, syncope visits occurred over years. increased age, increased length of stay (los), performance of cxr, transport by ground ambulance, and treatment at a low-volume hospital (non-teaching or non-large urban) were independently associated with index hospitalization. these same factors, as well as hospital admission itself, were associated with -day readmission. additionally, increased age, increased los, performance of a head ct, treatment at a low-volume hospital, hospital admission, and female sex were independently associated with - day readmission. arrival by ground ambulance was associated with a decreased likelihood of both -and - day readmission. conclusion: our data identify variations in practice as well as factors associated with hospitalization and readmission for syncope. the disparity in admission and readmission rates between centers may highlight a gap in quality of care or reflect inappropriate use of resources. further research to compare patient out-comes and quality of patient care among urban and non-urban centers is needed. background: change in dyspnea severity (ds) is a frequently used outcome measure in trials of acute heart failure (ahf). however, there is limited information concerning its validity. objectives: to assess the predictive validity of change in dyspnea severity. methods: this was a secondary analysis of a prospective observational study of a convenience sample of ahf patients presenting with dyspnea to the ed of an academic tertiary referral center with a mixed urban/ suburban catchment area. patients were enrolled weekdays, june through december . patients assessed their ds using a -cm visual analog scale at three times: the start of ed treatment (baseline) as well as at and hours after starting ed treatment. the difference between baseline and hour was the -hour ds change. the difference between baseline and hours was the -hour ds change. two clinical outcome measures were obtained: ) the number of days hospitalized or dead within days of the index visit ( -day outcome), and ) the number of days hospitalized or dead within days of the index visit ( -day outcome). results: data on patients were analyzed. the median -day outcome variable was days with an interquartile range (iqr) of to . the median -day outcome variable was days (iqr to . ). the median -hour ds change was . cm (iqr . to . ). the median -hour ds change was . cm (iqr . to . ). the -day and -day mortality rates were % and % respectively. the spearman rank correlations and % confidence intervals are presented in the table below. conclusion: while the point estimates for the correlations were below . , the % ci for two of the correlations extended above . . these pilot data support change in ds as a valid outcome measure for ahf when measured over hours. a larger prospective study is needed to obtain a more accurate point estimate of the correlations. background: the majority of volume-quality research has focused on surgical outcomes in the inpatient setting; very few studies have examined the effect of emergency department (ed) case volume on patient outcomes. objectives: to determine whether ed case volume of acute heart failure (ahf) is associated with short-term patient outcomes. methods: we analyzed the nationwide emergency department sample (neds) and nationwide inpatient sample (nis), the largest, all-payer, ed and inpatient databases in the us. ed visits for ahf were identified with a principal diagnosis of icd- -cm code .xx. eds were categorized into quartiles by ed case volume of ahf. the outcome measures were early inpatient mortality (within the first days of admission), overall inpatient mortality, and hospital length of stay (los). results: there were an estimated , visits for ahf from approximately , eds in ; % were hospitalized. of these, the overall inpatient mortality rate was . %, and the median hospital los was days. early inpatient mortality was lower in the highest-volume eds, compared with the lowest-volume eds ( . % vs. . %; p < . ). similar patterns were observed for overall inpatient mortality ( . % vs. . %; p < . ). in a multivariable analysis adjusting for patient and hospital characteristics, early inpatient mortality remained lower in patients admitted through the highest-volume eds (adjusted odds ratios [or], . ; % confidence interval [ci], . - . ), as compared with the lowest-volume eds. there was a trend towards lower overall inpatient mortality in the highest-volume eds; however, this was not statistically significant (adjusted or, . ; %ci, . - . ). by contrast, using the nis data including various sources of admissions, a higher case volume of inpatient ahf patients predicted lower overall inpatient mortality (adjusted or, . ; %ci, . - . ). the hospital los in patients admitted through the highest-volume eds was slightly longer (adjusted difference, . day; %ci, . - . ), compared with the lowest-volume eds. conclusion: ed patients who are hospitalized for ahf have an approximately % reduced early inpatient mortality if they were admitted from an ed that handles a large volume of ahf cases. the ''practice-makesperfect'' concept may hold in emergency management of ahf. emergency department disposition and charges for heart failure: regional variability alan b. storrow, cathy a. jenkins, sean p. collins, karen p. miller, candace mcnaughton, naftilan allen, benjamin s. heavrin vanderbilt university, nashville, tn background: high inpatient admission rates for ed patients with acute heart failure are felt partially responsible for the large economic burden of this most costly cardiovascular problem. objectives: we examined regional variability in ed disposition decisions and regional variability in total dollars spent on ed services for admitted patients with primary heart failure. methods: the nationwide emergency department sample (neds) was used to perform a retrospective, cohort analysis of patients with heart failure (icd- code of .x) listed as the primary ed diagnosis. demographics and disposition percentages (with se) were calculated for the overall sample and by region: northeast, south, midwest, and west. to account for the sample design and to obtain national and regional estimates, a weighted analysis was conducted. results: there were , weighted ed visits with heart failure listed as the primary diagnosis. overall, over eighty percent were admitted (see table) . fifty-two percent of these patients were female; mean age was . years (se . ). hospitalization rates were higher in the northeast ( . %) and south ( . %) than in the midwest ( . %) and west ( . %). total monies spent on ed services were highest in the south ($ , , ) followed by the northeast ($ , , ), west ($ , , ) and midwest ($ , , ) . conclusion: this large retrospective ed cohort suggests a very high national admission rate with significant regional variation in both disposition decisions as well as total monies spent on ed services for patients with a primary diagnosis of heart failure. examining these estimates and variations further may provide strategies to reduce the economic burden of heart failure. background: workplace violence in health care settings is a frequent occurrence. gunfire in hospitals is of particular concern. however, information regarding such workplace violence is limited. accordingly, we characterized u.s. hospital-based shootings from - . objectives: to determine extent of hospital-based shootings in the u.s. and involvement of emergency departments. methods: using lexisnexis, google, netscape, pub-med, and sciencedirect, we searched reports for acute care hospital shooting events from january through december , and those with at least one injured victim were analyzed. results: we identified hospital-related shootings ( inside the hospital, on hospital grounds), in states, with victims, of whom were perpetrators. in comparison to external shootings, shootings within the hospital have not increased over time (see figure) . perpetrators were from all age groups, including the elderly. most of the events involved a determined shooter: grudge ( %), suicide ( %), ''euthanizing'' an ill relative ( %), and prisoner escape ( %). ambient societal violence ( %) and mentally unstable patients ( %) were comparatively infrequent. the most common injured was the perpetrator ( %). hospital employees comprised only % of victims; physician ( %) and nurse ( %) victims were relatively infrequent. the emergency department was the most common site ( %), followed by patient rooms ( %) and the parking lot ( %). in % of shootings within hospitals, the weapon was a security officer's gun grabbed by the perpetrator. ''grudge'' motive was the only factor determinative of hospital staff victims (or = . , % ci . - . ). conclusion: although hospital-based shootings are relatively rare, emergency departments are the most likely site. the unpredictable nature of this type of event represents a significant challenge to hospital security and deterrence practices, as most perpetrators proved determined, and many hospital shootings occur outside the building. impact of emergency physician board certification on patient perceptions of ed care quality albert g. sledge iv , carl a. germann , tania d. strout , john southall maine medical center, portland, me; mercy hospital, portland, me background: the hospital value-based purchasing program mandated by the affordable care act is the latest example of how patients' perceptions of care will affect the future practice environment of all physicians. the type of training of medical providers in the emergency department (ed) is one possible factor affecting patient perceptions of care. a unique situation in a maine community ed led to the rapid transition from non-emergency medicine (em) residency trained physicians to all em residency trained and american board of emergency medicine (abem) certified providers. objectives: the purpose of this study was to evaluate the effect of the implementation of an all em-trained, abem-certified physician staff on patient perceptions of the quality of care they received in the ed. methods: we retrospectively evaluated press ganey data from surveys returned by patients receiving treatment in a single, rural ed. survey items addressed patient's perceptions of physician courtesy, time spent listening, concern for patient comfort, and informativeness. additional items evaluated overall perceptions of care and the likelihood that the respondent would recommend the ed to another. data were compared for the three years prior to and following implementation of the all trained, certified staff. we used the independent samples t-test to compare mean responses during the two time periods. bonferroni's correction was applied to adjust for multiple comparisons. results: during the study period, , patients provided surveys for analysis: , during the pre-certification phase and , during the post-certification phase. across all six survey items, mean responses increased following transition to the board-certified staff. these improvements were noted to be statistically significant in each case: courtesy p < . , time listening p < . , concern for comfort p < . , informativeness p < . , overall perception of care p < . , and likelihood to recommend p < . . conclusion: data from this community ed suggest that transition from a non-residency trained, abem certified staff to a fully trained and certified model has important implications for patient's perceptions of the care they receive. we observed significant improvement in rating scores provided by patients across all physicianoriented and general ed measures. background: transfer of care from the ed to the inpatient floor is a critical transition when miscommunication places patients at risk. the optimal form and content of handoff between providers has not been defined. in july , ed-to-floor signout for all admissions to the medicine and cardiology floors was changed at our urban, academic, tertiary care hospital. previously, signout was via an unstructured telephone conversation between ed resident and admitting housestaff. the new signout utilizes a web-based ed patient tracking system and includes: ) a templated description of ed course is completed by the ed resident; ) when a bed is assigned, an automated page is sent to the admitting housestaff; ) ed clinical information, including imaging, labs, medications, and nursing interventions (figure) is reviewed by admitting housestaff; ) if housestaff has specific questions about ed care, a telephone conversation between the ed resident and housestaff occurs; ) if there are no specific questions, it is indicated electronically and the patient is transferred to the floor. objectives: to describe the effects on patient safety (floor-to-icu transfer in hours) and ed throughput (ed length of stay (los) and time from bed assignment to ed departure) resulting from a change to an electronic, discussion-optional handoff system. conclusion: transition to a system in which signout of admitted patients is accomplished by accepting housestaff review of ed clinical information supplemented by verbal discussion when needed resulted in no significant change in rate of floor-to-icu transfer or ed los and reduced time from bed assignment to ed departure. background: emergency physicians may be biased against patients presenting with nonspecific complaints or those requiring more extensive work-ups. this may result in patients being seen less quickly than those with more straightforward presentations, despite equal triage scores or potential for more dangerous conditions. objectives: the goal of our study was to ascertain which patients, if any, were seen more quickly in the ed based on chief complaint. methods: a retrospective report was generated from the emr for all moderate acuity (esi ) adult patients who visited the ed from january through december at a large urban teaching hospital. the most common complaints were: abdominal pain, alcohol intoxication, back pain, chest pain, cough, dyspnea, dizziness, fall, fever, flank pain, headache, infection, pain (nonspecific), psychiatric evaluation, ''sent by md,'' vaginal bleeding, vomiting, and weakness. non-parametric independent sample tests assessed median time to be seen (ttbs) by a physician for each complaint. differences in the ttbs between genders and based on age were also calculated. chi-square testing compared percentages of patients in the ed per hour to assess for differences in the distribution of arrival times. results: we obtained data from , patients. patients with a chief complaint of weakness and dizziness waited the longest with a median time of minutes and patients with flank pain waited the shortest with minutes (p < . ) ( figure ). overall, males waited minutes and females waited minutes (p < . ). stratifying by gender and age, younger females between the ages of - waited significantly longer times when presenting with a chief complaint of abdominal pain (p < . ), chest pain (p < . ), or flank pain (p < . ) as compared to males in the same age group ( figure ). there was no difference in the distribution of arrival times for these complaints. conclusion: while the absolute time differences are not large, there is a significant bias toward seeing young male patients more quickly than women or older males despite the lower likelihood of dangerous conditions. triage systems should perhaps take age and gender better into account. patients might benefit from efforts to educate em physicians on the delays and potential quality issues associated with this bias in an attempt to move toward more egalitarian patient selection. background: detailed analysis of emergency department (ed) event data identified the time from completion of emergency physician evaluation (doc done) to the time patients leave the ed as a significant contributor to ed length of stay (los) and boarding at our institution. process flow mapping identified the time from doc done to the time inpatient beds were ordered (bo) as an interval amendable to specific process improvements. objectives: the purpose of this study was to evaluate the effect of ed holding orders for stable adult . ( . - . ) . ( . - . ) . ( . - . ) . ( . - . ) . ( . - . ) . ( . - . ) inpatient medicine (aim) patients on: a) the time to bo and b) ed los. methods: a prospective, observational design was used to evaluate the study questions. data regarding the time to bo and los outcomes were collected before and after implementation of the ed holding orders program. the intervention targeted stable aim patients being admitted to hospitalist, internal medicine, and family medicine services. ed holding orders were placed following the admission discussion with the accepting service and special attention was paid to proper bed type, completion of the emergent work-up and the expected immediate course of the patient's hospital stay. holding orders were of limited duration and expired hours after arrival to the inpatient unit. results: during the -month study period, patients were eligible for the ed holding orders intervention; ( . %) were cared for using the standard adult medicine order set and ( . %) received the intervention. the median time from doc done to bo was significantly shorter for patients in the ed holding orders group, min (iqr , ) vs. min (iqr , ) for the standard adult medicine group, p < . . similarly, the median ed los was significantly shorter for those in the ed holding orders group, min (iqr , ) vs. min (iqr , ) for the standard adult medicine group, p < . . no lapses in patient care were reported in the intervention group. conclusion: in this cohort of ed patients being admitted to an aim service, placing ed holding orders rather than waiting for a traditional inpatient team evaluation and set of admission orders significantly reduced the time from the completion of the ed workup to placement of a bo. as a result, ed los was also significantly shortened. while overall utilization of the intervention was low, it improved with each month. emergency department interruptions in the age of electronic health records matthew albrecht, john shabosky, jonathan de la cruz southern illinois university school of medicine, springfield, il background: interruptions of clinical care in the emergency department (ed) have been correlated with increased medical errors and decreased patient satisfaction. studies have also shown that most interruptions happen during physician documentation. with the advent of the electronic health record and computerized documentation, ed physicians now spend much of their clinical time in front of computers and are more susceptible to interruptions. voice recognition dictation adjuncts to computerized charting boast increased provider efficiency; however, little is known about how data input of computerized documentation affects physician interruptions. objectives: we present here observational interruptions data comparing two separate ed sites, one that uses computerized charting by conventional techniques and one assisted by voice recognition dictation technology. methods: a prospective observational quality initiative was conducted at two teaching hospital eds located less than mile from each other. one site primarily uses conventional computerized charting while the other uses voice recognition dictation computerized charting. four trained observers followed ed physicians for minutes during shifts. the tasks each ed physician performed were noted and logged in second intervals. tasks listed were selected from a predetermined standardized list presented at observer training. tasks were also noted as either completed or placed in queue after a change in task occurred. a total of minutes were logged. interruptions were noted when a change in task occurred with the previous task being placed in queue. data were then compared between sites. results: ed physicians averaged . interruptions/ hour with conventional computerized charting compared to . interruptions/hour with assisted voice recognition dictation (p = . ). conclusion: computerized charting assisted with voice recognition dictation significantly decreased total per hour interruptions when compared to conventional techniques. charting with voice recognition dictation has the potential to decrease interruptions in the ed allowing for more efficient workflow and improved patient care. background: using robot assistants in health care is an emerging strategy to improve efficiency and quality of care while optimizing the use of human work hours. robot prototypes capable of performing vital signs and assisting with ed triage are under development. however, ed users' attitudes toward robot assistants are not well studied. understanding of these attitudes is essential to design user-friendly robots and to prepare eds for the implementation of robot assistants. objectives: to evaluate the attitudes of ed patients and their accompanying family and friends toward the potential use of robot assistants in the ed. methods: we surveyed a convenience sample of adult ed patients and their accompanying adult family members and friends at a single, university-affiliated ed, / / - / / . the survey consisted of eight items from the negative attitudes towards robots scale (normura et al.) modified to address robot use in the ed. response options included a -point likert scale. a summary score was calculated by summing the responses for all items, with a potential range of (completely negative attitude) to (completely positive attitude). research assistants gave the written surveys to subjects during their ed visit. internal consistency was assessed using cronbach's alpha. bivariate analyses were performed to evaluate the association between the summary score and the following variables: participant type (patient or visitor), sex, race, time of day, and day of week. results: of potential subjects approached, ( %) completed the survey. participants were % patients, % family members or friends, % women, % white, and had a median age of . years (iqr - ). cronbach's alpha was . . the mean summary score was . (sd = . ), indicating subjects were between ''occasionally'' and ''sometimes'' comfortable with the idea of ed robot assistants (see table) . men were more positive toward robot use than women (summary score: . vs . ; p = . ). no differences in the summary score were detected based on participant type, race, time of day, or day of week. conclusion: ed users reported significant apprehension about the potential use of robot assistants in the ed. future research is needed to explore how robot designs and strategies to implement ed robots can help alleviate this apprehension. background: emergency department cardioversion (edc) of recent-onset atrial fibrillation or flutter (af) patients is an increasingly common management approach to this arrhythmia. patients who qualify for edc generally have few co-morbidities and are often discharged directly from the ed. this results in a shift towards a sicker population of patients admitted to the hospital with this diagnosis. objectives: to determine whether hospital charges and length of stay (los) profiles are affected by emergency department discharge of af patients. methods: patients receiving treatment at an urban teaching community hospital with a primary diagnosis of atrial fibrillation or flutter were identified through the hospital's billing data base. information collected on each patient included date of service, patient status, length of stay, and total charges. patient status was categorized as inpatient (admitted to the hospital), observation (transferred from the ed to an inpatient bed but placed in an observation status), or ed (discharged directly from the ed). the hospital billing system automatically defaults to a length of stay of for observation patients. ed patients were assigned a length of stay of . total hospital charges and mean los were determined for two different models: a standard model (sm) in which patients discharged from the ed were excluded from hospital statistics, and an inclusive model (im) in which discharged ed patients were included in the hospital statistics. statistical analysis was through anova. results: a total of patients were evaluated for af over an -month period. of these, ( %) were admitted, ( %) were placed in observation status, and ( %) were discharged from the ed. hospital charges and los in days are summarized in the table. all differences were statistically significant at (p < . ). conclusion: emergency department management can lead to a population of af patients discharged directly from the ed. exclusion of these patients from hospital statistics skews performance profiles effectively punishing institutions for progressive care. background: recent health care reform has placed an emphasis on the electronic health record (ehr). with the advent of the ehr it is common to see ed providers spending more time in front of computers documenting and away from patients. finding strategies to decrease provider interaction with computers and increase time with patients may lead to improved patient outcomes and satisfaction. computerized charting adjuncts, such as voice recognition software, have been marketed as ways to improve provider efficiency and patient contact. objectives: we present here observational data comparing two separate ed sites, one where computerized charting is done by conventional techniques and one that is assisted with voice recognition dictation, and their effects on physican charting and patient contact. methods: a prospective observational quality initiative was conducted at two teaching hospitals located less than mile from each other. one site primarily uses conventional computerized charting while the other uses voice recognition dictation. four trained quality assistants observed ed physicians for minutes during shifts. the tasks each physician performed were noted and logged in second intervals. tasks listed were identified from a predetermined standardized list presented at observer training. a total of minutes were logged. time allocated to charting and that allocated to direct patient care were then compared between sites. results: ed physicians spent . % of their time charting using conventional techniques vs . % using voice recognition dictation (p = . ). time allocated to direct patient care was found to be . % with conventional charting vs . % using dictation (p = ). in total, ed physicians using conventional charting techniques spent / minutes charting. ed physicians using voice recognition dictation spent / minutes dictating and an additional . / minutes reviewing or correcting their dictations. the use of voice recognition assisted dictation rather than conventional techniques did not significantly change the amount of time physicians spent charting or with direct patient care. although voice recognition dictation decreased initial input time of documenting data, a considerable amount of time was required to review and correct these dictations. objectives: for our primary objective, we studied whether emergency department triage temperatures detected fever adequately when compared to a rectal temperature. as secondary objectives, we examined the temperature differences when a rectal temperature was taken within an hour of non-invasive temperature, temperature site (oral, axillary, temporal), and also examined the patients that were initially afebrile but were found to be febrile by rectal temperature. methods: we performed an electronic chart review at our inner city, academic emergency department with an annual census of , patients. we identified all patients over the age of who received a non-invasive triage temperature and a subsequent rectal temperature while in the ed from january through february . specific data elements included many aspects of the patient's medical record (e.g. subject demographics, temperature, and source). we analyzed our data with standard descriptive statistics, t-tests for continuous variables, and pearson chi-square tests for proportions. results: a total of , patients met our inclusion criteria. the mean difference in temperatures between the initial temperature and the rectal temperature was . °f, with . % having higher rectal temperatures ‡ °f, and . % having higher rectal temperatures ‡ °f. the mean temperature difference among the , patients who an initial noninvasive temperature and a rectal temperature within one hour was . °f. the mean difference among patients that received oral, axillary, and temporal temperatures was . °f, . °f, and . °f respectively. approximately one in five patients ( . %) were initially afebrile and found to be febrile by rectal temperature, with an average temperature difference of . °f. these patients had a higher rate of admission, and were more likely to be admitted to the intensive care unit. conclusion: there are significant differences between rectal temperatures and non-invasive triage temperatures in this emergency department cohort. in almost one in five patients, fever was missed by triage temperature. background: pediatric emergency department (ped) overcrowding has become a national crisis, and has resulted in delays in treatment, and patients leaving without being seen. increased wait times have also been associated with decreased patient satisfaction. optimizing ped throughput is one means by which to handle the increased demands for services. various strategies have been proposed to increase efficiency and reduce length of stay (los). objectives: to measure the effect of direct bedding, bedside registration, and patient pooling on ped wait times, length of stay, and patient satisfaction. methods: data were extracted from a computerized ed tracking system in an urban tertiary care ped. comparisons were made between metrics for ( , patients) and the months following process change ( , patients). during , patients were triaged by one or two nurses, registered, and then sent either to a -bed ped or a physically separate -bed fast-track unit, where they were seen by a physician. following process change, patients were brought directly to a bed in the -bed ped, triaged and registered, then seen by a physician. the fast-track unit was only utilized to accommodate patient surges. results: anticipating improved efficiencies, attending physician coverage was decreased by %. after instituting process changes, improvements were noted immediately. although daily patient volume increased by %, median time to be seen by a physician decreased by %. additionally, median los for discharged patients decreased by %, and median time until the decisionto-admit decreased by %. press-ganey satisfaction scores during this time increased by greater than mean score points, which was reported to be a statistically significant increase. conclusion: direct bedding, bedside registration, and patient pooling were simple to implement process changes. these changes resulted in more efficient ped throughput, as evidenced by decreased times to be seen by a physician, los for discharged patients, and time until decision-to-admit. additionally, patient satisfaction scores improved, despite decreased attending physician coverage and a % decrease in room utilization. ) . during period , the ou was managed by the internal medicine department and staffed by primary care physicians and physician assistants. during periods and , the ou was managed and staffed by em physicians. data collected included ou patient volume, length of stay (los) for discharged and admitted patients, admission rates, and -day readmission rates for discharged patients. cost data collected included direct, indirect, and total cost per patient encounter. data were compared using chi-square and anova analysis followed by multiple pairwise comparisons using the bonferroni method of p-value adjustment. results: see table. the ou patient volume and percent of ed volume was greater in period compared to periods and . length of stay, admission rates, -day readmission rates, and costs were greater in period compared to periods and . conclusion: em physicians provide more cost-effective care for patients in this large ou compared to non-em physicians, resulting in shorter los for admitted and discharged patients, greater rates of patients discharged, and less -day readmission rates for discharged patients. this is not affected by an increase in ou volume and shows a trend towards improvement. background: emergency department (ed) crowding continues to be a problem, and new intake models may represent part of the solution. however, little data exist on the sustainability and long-term effects of physician triage and screening on standard ed performance metrics, as most studies are short-term. objectives: we examined the hypothesis that a physician screening program (start) sustainably improves standard ed performance metrics including patient length of stay (los) and patients who left without completing assessment (lwca). we also investigated the number of patients treated and dispositioned by start without using a monitored bed and the median patient door-to-room time. methods: design and setting: this study is a retrospective before-and-after analysis of start in a level i tertiary care urban academic medical center with approximately , annual patient visits. all adult patients from december until november are included, though only a subset was seen in start. start began at our institution in december . observations: our outcome measures were length of stay for ed patients, lwca rates, patients treated and dispositioned by start without using a monitored bed, and door-to-room time. statistics: simple descriptive statistics were used. p-values for los were calculated with wilcoxon test and p-value for lwca was calculated with chi-square. results: table shows median length of stay for ed patients was reduced by minutes/patient (p-value < . ) when comparing the most recent year to the year before start. patients who lwca were reduced from . % to . % (p-value < . ) during the same time period. we also found that in the first half-year of start, % of patients screened in the ed were treated and dispositioned without using a monitored bed and by the end of year , this number had grown to %. median door-to-room time decreased from . minutes to . minutes over the same period of time. conclusion: a start system can provide sustained improvements in ed performance metrics, including a significant reduction in ed los, lwca rate, and doorto-room time. additionally, start can decrease the need for monitored ed beds and thus increase ed capacity. . labs were obtained in %, ct in %, us in %, and consultation in %. % of the cohort was admitted to the hospital. the most commonly utilized source of translation was a layman ( %). a professional translator was used in % and translation service (language line, marty) in %. the examiner was fluent in the patient's language in %. both the patient and examiner were able to maintain basic communication in %. there were patients in the professional/ fluent translation group and patients in the lay translation group. there was no difference in ed los between groups vs min; p = . . there was no difference in the frequency of lab tests, computerized tomography, ultrasound, consultations, or hospital admission. frequencies did not differ by sex or age. conclusion: translation method was not associated with a difference in overall ed los, ancillary test use, or specialist consultation in spanish-speaking patients presenting to the ed for abdominal pain. emergency department patients on warfarin -how often is the visit due to the medication? jim killeen, edward castillo, theodore chan, gary vilke ucsd medical center, san diego, ca background: warfarin has important therapeutic value for many patients, but has been associated with signi-ficant bleeding complications, hypersensitivity reactions, and drug-drug interactions, which can result in patients seeking care in the emergency department (ed). objectives: to determine how often ed patients on warfarin present for care as a result of the medication itself. methods: a multi-center prospective survey study in two academic eds over months. patients who presented to the ed taking warfarin were identified, and ed providers were prospectively queried at the time of disposition regarding whether the visit was the result of a complication or side effect associated with warfarin. data were also collected on patient demographics, chief complaint, triage acuity, vital signs, disposition, ed evaluation time, and length of stay (los). patients identified with a warfarin-related cause for their ed visit were compared with those who were not. statistical analysis was performed using descriptive statistics. results: during the study period, , patients were cared for by ed staff, of whom were identified as taking warfarin as part of their medication regimen. of these, providers identified . % ( patients) who presented with a warfarin-related complication as their primary reason for the ed visit. . % ( ) each hours of daily boarding is associated with a drop of . raw score points in both pg metrics. these seemingly small drops in raw scores translate into major changes in rankings on press ganey national percentile scales (a difference of as much as percentile points). our institution commonly has hundreds of hours of daily boarding. it is possible that patient-level measurements of boarding impact would show stronger correlation with individual satisfaction scores, as opposed to the daily aggregate measures we describe here. our research suggests that reducing the burden of boarding on eds will improve patient satisfaction. background: prolonged emergency department (ed) boarding is a key contributor to ed crowding. the effect of output interventions (moving boarders out of the ed into an intermediate area prior to admission or adding additional capacity to an observation unit) has not been well studied. objectives: we studied the effect of a combined observation-transition (ot) unit, consisting of observation beds and an interim holding area for boarding ed patients, on the length of stay (los) for admitted patients, as well as secondary outcomes such as los for discharged patients, and left without being seen rates. methods: we conducted a retrospective review ( months pre-, months post-design) of an ot unit at an urban teaching ed with , annual visits (study ed). we compared outcomes to a nearby communitybased ed with , annual visits in the same health system (control ed) where no capacity interventions were performed. the ot had beds, full monitoring capacity, and was staffed hours per day. the number of beds allocated to transition and observation patients fluctuated throughout the course of the intervention, based on patient demands. all analyses were conducted at the level of the ed-day. wilcoxon rank-sum and analysis of covariance tests were used for comparisons; continuous variables were summarized with medians. results: in unadjusted analyses, median daily los of admitted patients at the study ed was minutes lower in the months after the ot opened, . to . hours (p < . ). control site daily los for admitted patients increased minutes from . to . hours (p < . ). results were similar after adjusting for other covariates (day of week, ed volume, and triage level). los of discharged patients at study ed decreased by minutes, from . hours to . hours (p < . ), while the control ed saw no significant changes in discharged patient los ( . hours to . hours, p = . ). left without being seen rates did not decrease at either site. conclusion: opening an ot unit was associated with a -minute reduction in average daily ed los for admitted patients and discharged patients in the study ed. given the large expense of opening an ot, future studies should compare capacity-dependent (e.g., ot) vs. capacity-independent (e.g, organizational) interventions to reduce ed crowding. fran balamuth, katie hayes, cynthia mollen, monika goyal children's hospital of philadelphia, philadelphia, pa background: lower abdominal pain and genitourinary problems are common chief complaints in adolescent females presenting to emergency departments. pelvic inflammatory disease (pid) is a potentially severe complication of lower genital tract infections, which involves inflammation of the female upper genital tract secondary to ascending stis. pid has been associated with severe sequelae including infertility, ectopic pregnancy, and chronic pelvic pain. we describe the prevalence and microbial patterns of pid in a cohort of adolescent females presenting to an urban emergency department with abdominal or genitourinary complaints. objectives: to describe the prevalence and microbial patterns of pid in a cohort of adolescent patients presenting to an ed with lower abdominal or genitourinary complaints. methods: this is a secondary analysis of a prospective study of females ages - years presenting to a pediatric ed with lower abdominal or genitourinary complaints. diagnosis of pid was per cdc guidelines. patients underwent chlamydia trachomatis (ct) and neisseria gonorrhea (gc) testing via urine aptima combo assay and trichomonas vaginalis (tv) testing using the vaginal osom trichomonas rapid test. descriptive statistics were performed using stata . . results: the prevalence of pid in this cohort of patients was . % ( % ci . %, . %), . % ( % ci . %, . %) of whom had positive sexually transmitted infection (sti) testing: % ( % ci . %, . %) with ct, . % ( % ci . , . %) with gc, and . % ( % ci . %, . %) with tv. . % ( % ci . , . %) of patients diagnosed with pid received antibiotics consistent with cdc recommendations. patients with lower abdominal pain as their chief complaint were more likely to have pid than patients with genitourinary complaints (or . , % ci . , . ). conclusion: a substantial number of adolescent females presenting to the emergency department with lower abdominal pain were diagnosed with pid, with microbial patterns similar to those previously reported in largely adult, outpatient samples. furthermore, appropriate treatment for pid was observed in the majority of patients diagnosed with pid. impact background: in resource-poor settings, maternal health care facilities are often underutilized, contributing to high maternal mortality. the effect of ultrasound in these settings on patients, health care providers, and communities is poorly understood. objectives: the purpose of this study was to assess the effect of the introduction of maternal ultrasound in a population not previously exposed to this intervention. methods: an ngo-led program trained nurses at four remote clinics outside koutiala, mali, who performed , maternal ultrasound scans over three years. our researchers conducted an independent assessment of this program, which involved log book review, sonographer skill assessment, referral follow-up, semi-structured interviews of clinic staff and patients, and focus groups of community members in surrounding villages. analyses included the effect of ultrasound on clinic function, job satisfaction, community utilization of prenatal care and maternity services, alterations in clinical decision making, sonographer skill, and referral frequency. we used qrs nvivo to organize qualitative findings, code data, and identify emergent themes, and graphpad software (la jolla, ca) and microsoft excel to tabulate quantitative findings results: -findings that triggered changes in clinical practice were noted in . % of ultrasounds, with a . % referral rate to comprehensive maternity care facilities. -skill retention and job satisfaction for ultrasound providers was high. -the number of patients coming for antenatal care increased, after introduction of ultrasound, in an area where the birth rate has been decreasing. -over time, women traveled from farther distances to access ultrasound and participate in antenatal care. -very high acceptance among staff, patients and community members. -ultrasound was perceived as most useful for finding fetal position, sex, due date, and well-being. -improved confidence in diagnosis and treatment plan for all cohorts. -improved compliance with referral recommendations. -no evidence of gender selection motivation for ultrasound use. conclusion: use of maternal ultrasound in rural and resource-limited settings draws women to an initial antenatal care visit, increases referral, and improves job satisfaction among health care workers. methods: a retrospective database analysis was conducted using the electronic medical record from a single, large academic hospital. ed patients who received a billing diagnosis of ''nausea and vomiting of pregnancy'' or ''hyperemesis gravidarum'' between / / and / / were selected. a manual chart review was conducted with demographic and treatment variables collected. statistical significance was determined using multiple regression analysis for a primary outcome of return visit to the emergency department for nausea and vomiting of pregnancy. results: patients were identified. the mean age was . years (sd± . ), mean gravidity . (sd± . ), and mean gestational age . weeks (sd± . ). the average length of ed evaluation was min (sd± ). of the patients, ( . %) had a return ed visit for nausea and vomiting of pregnancy, ( %) were admitted to the hospital, and ( %) were admitted to the ed observation protocol. multiple regression analysis showed that the presence of medical co-morbidity (p = . ), patient gravditity (p = . ), gestational age (p = . ), and admission to the hospital (p = . ) had small but significant effects on the primary outcome (return visits to the emergency department). no other variables were found to be predictive of return visits to the ed including admission to the ed observation unit or factors classically thought to be associated with severe forms of nausea and vomiting in pregnancy including ketonuria, electrolyte abnormalities, or vital sign abnormalities. conclusion: nausea and vomiting in pregnancy has a high rate of return ed visits that can be predicted by young patient age, low patient gravidity, early gestational age, and the presence of other comorbidities. these patients may benefit from obstetric consultation and/or optimization of symptom management after discharge in order to prevent recurrent utilization of the ed. prevalence conclusion: there is a high prevalence of ht in adult sa victims. although our study design and data do not allow us to make any inferences regarding causation, this first report of ht ed prevalence suggests the opportunity to clarify this relationship and the potential opportunity to intervene. background: sexually transmitted infections (sti) are a significant public health problem. because of the risks associated with stis including pid, ectopic pregnancy, and infertility the cdc recommends aggressive treatment with antibiotics in any patient with a suspected sti. objectives: to determine the rates of positive gonorrhea and chlamydia (g/c) screening and rates of empiric antibiotic use among patients of an urban academic ed with > , visits in boston, ma. methods: a retrospective study of all patients who had g/c cultures in the ed over months. chi-square was used in data analysis. sensitivity and specificity were also calculated. results: a positive rate of / ( . %) was seen for gonorrhea and / ( . %) for chlamydia. females had positive rates of / ( . %) and / ( . %) respectively. males had higher rates of / ( . %) (p =< . ) and / ( . %) (p = . ). patients with g/c sent received an alternative diagnosis, the most common being uti ( ), ovarian pathology ( ), vaginal bleeding ( ), and vaginal candidiasis ( ); were excluded. this left without definitive diagnosis. of these, . % ( / ) of females were treated empirically with antibiotics for g/c, and a greater percentage of males ( %, / ) were treated empirically (p < . ). of those empirically treated, / ( . %) had negative cultures. meanwhile / ( . %) who ultimately had positive cultures were not treated with antibiotics during their ed stay. sensitivity of the provider to predict presence of disease based on decision to give empiric antibiotics was . (ci . - . ). specificity was . (ci . - . ). conclusion: most patients screened in our ed for g/c did not have positive cultures and . % of those treated empirically were found not to have g/c. while early treatment is important to prevent complications, there are risks associated with antibiotic use such as allergic reaction, c difficile infection, and development of antibiotic resistance. our results suggest that at our institution we may be over-treating for g/c. furthermore, despite high rates of treatment, % of patients who ultimately had positive cultures did not receive antibiotics during their ed stay. further research into predictive factors or development of a clinical decision rule may be useful to help determine which patients are best treated empirically with antibiotics for presumed g/c. background: air travel may be associated with unmeasured neurophysiological changes in an injured brain that may affect post-concussion recovery. no study has compared the effect of commercial airtravel on concussion injuries despite rather obvious decreased oxygen tension and increased dehydration effect on acute mtbi. objectives: to determine if air travel within - hours of concussion is associated with increased recovery time in professional football and hockey players. methods: prospective cohort study of all active-roster national football league and national hockey league players during the - seasons. internet website review of league sties for injury identification of concussive injury and when player returned to play solely for mtbi. team schedules and flight times were also confirmed to include only players who flew immediately following game (within - hr). multiple injuries were excluded as were players who had injury around all-star break for nhl and scheduled off week in nfl. results: during the - nfl and nhl seasons, ( . %) and ( . %) players experienced a concussion (percent of total players), in the respective leagues. of these, nfl players ( %) and nhl players ( %) flew within hours of the incident injury. the mean distance flown was shorter for nfl ( miles, sd vs. nhl , sd ) miles and all were in a pressurized cabin. the mean number of games missed for nfl and nhl players who traveled by air immediately after concussion was increased by % and % (respectively) than for those who did not travel by air nfl: . (sd . ) vs. . games (sd . ) and nhl: . games (sd . ) vs. . (sd . ); p < . . conclusion: this is an initial report of an increased rate of recovery in terms of more games missed, for professional athletes flying commercial airlines post-mtbi compared to those that do not subject their recently injured brains to pressurized airflight. the obvious changes of decreased oxygen tension with altitude equivalent of , feet, decreased humidity with increased dehydration, and duress of travel accompanying pressurized airline cabins all likely increase the concussion penumbra in acute mtbi. early air travel post concussion should be further evaluated and likely postponed - hr. until initial symptoms subside. background: previous studies have shown better in-hospital stroke time targets for those who arrive by ambulance compared to other modes of transport. however, regional studies report that less than half of stroke patients arrive by ambulance. objectives: our objectives were to describe the proportion of stroke patients who arrive by ambulance nationwide, and to examine regional differences and factors associated with the mode of transport to the emergency department (ed). methods: this is a cross-sectional study of all patients with a primary discharge diagnosis of stroke based on previously validated icd- codes abstracted from the national hospital ambulatory medical care survey for - . we excluded subjects < years of age and those with missing data. the study related survey variables included patient demographics, community characteristics, mode of transport to the hospital, and hospital characteristics. results: patients met inclusion criteria, representing , , patient records nationally. of these, . % arrived by ambulance. after adjustment for potential confounders, patients residing in the west and south had lower odds of arriving by ambulance for stroke when compared to northeast (southern region, or . , % ci . - . , western region, or . , % ci . - . , midwest region, or . , % ci . - . ). compared to the medicare population, privately insured and self insured had lower odds of arriving by ambulance (or for private insurance . , % ci . - . and or for self payers . , % ci . - . ). age, sex, race, urban or rural location of ed, or safety net status were not independently associated with ambulance use. conclusion: patients with stroke arrive by ambulance more frequently in the northeast than in other regions of the us. identifying reasons for this regional difference may be useful in improving ambulance utilization and overall stroke care nationwide. objectives: we sought to determine whether there was a difference in type of stroke presentation based upon race. we further sought to determine whether there is an increase in hemorrhagic strokes among asian patients with limited english proficiency. methods: we performed a retrospective chart review of all stroke patients age and older for year of patients that were diagnosed with cerebral vascular accident (cva) or intracranial hemorrhage (ich). we collected data on patient demographics, and past medical history. we then stratified patients according to race (white, black, latino, asian, and other). we classified strokes as ischemic, intracranial hemorrhage (ich), subarachnoid hemorrhage (sah), subdural hemorrhage (sdh), and other (e.g., bleeding into metatstatic lesions). we used only the index visit. we present the data percentages, medians and interquartile ranges (iqr). we tested the association of the outcome of intracranial hemorrhage against demographic and clinical variables using chi-square and kruskal-wallis tests. we performed a logistic regression model to determine factors related to presentation with an intracranial hemorrhage (ich background: the practice of obtaining laboratory studies and routine ct scan of the brain on every child with a seizure has been called into question in the patient who is alert, interactive, and back to functional baseline. there is still no standard practice for the management of non-febrile seizure patients in the pediatric emergency department (ped). objectives: we sought to determine the proportion of patients in whom clinically significant laboratory studies and ct scans of the brain were obtained in children who presented to the ped with a first or recurrent non-febrile seizure. we hypothesize that the majority of these children do not have clinically significant laboratory or imaging studies. if clinically significant values were found, the history given would warrant further laboratory and imaging assessment despite seizure alone. methods: we performed a retrospective chart review of patients with first-time or recurrent non-febrile seizures at an urban, academic ped between july to june . exclusion criteria included children who presented to the ped with a fever and age less than months. we looked at specific values that included a complete blood count, basic metabolic panel, and liver function tests, and if the child was on antiepileptics along with a level for a known seizure disorder, and ct scan. abnormal laboratory and ct scan findings were classified as clinically significant or not. results: the median age of our study population is years with male to female ratio of . . % of patients had a generalized tonic-clonic seizure. laboratory studies and ct scans were obtained in % and % of patients, respectively. five patients had clinically significant abnormal labs; however, one had esrd, one developed urosepsis, one had eclampsia, and two others had hyponatremia, which was secondary to diluted formula and trileptal toxicity. three children had an abnormal head ct: two had a vp shunt and one had a chromosomal abnormality with developmental delay. conclusion: the majority of the children analyzed did not have clinically significant laboratory or imaging studies in the setting of a first or recurrent non-febrile seizure. of those with clinically significant results, the patient's history suggested a possible etiology for their seizure presentation and further workup was indicated. background: in patients with a negative ct scan for suspected subarachnoid hemorrhage (sah), ct angiography (cta) has emerged as a controversial alternative diagnostic strategy in place of lumbar puncture (lp). objectives: to determine the diagnostic accuracy for sah and aneurysm of lp alone, cta alone, and lp followed by cta if the lp is positive. methods: we developed a decision and bayesian analysis to evaluate ) lp, ) cta, and ) lp followed by cta if the lp is positive. data were obtained from the literature. the model considers probability of sah ( %), aneurysm ( % if sah), sensitivity and specificity of ct ( . % and % overall), of lp (based on rbc and xanthochromia), and of cta, traumatic tap and its influence on sah detection. analyses considered all patients and those presenting at less than hours or greater than hours from symptom onset by varying the sensitivity and specificity of ct and cta. results: using the reported ranges of ct scan sensitivity and the specificity, the revised likelihood of sah following a negative ct ranged from . - . %, and the likelihood of aneurysm ranged from . - . %. following any of the diagnostic strategies, the likelihood of missing sah ranged from - . %. either lp strategy diagnosed . % of sahs versus - % with cta alone because cta only detected sah in the presence of an aneurysm. false positive sah with lp ranged from . - . % due to traumatic taps and with cta ranged from . - . % due to aneurysms without sah. the positive predictive value for sah ranged from . - % with lp and from . - % with cta. for patients presenting within hours of symptom onset, the revised likelihood of sah following a negative ct became . %, and the likelihood of aneurysm ranged from . - . %. following any of the diagnostic strategies, the likelihood of missing sah ranged from . - . %. either lp strategy diagnosed . % of sah versus - % with cta alone. false positive sah with lp was . % and with cta ranged from . - . %. the positive predictive value for sah was . % with lp and from . - % with cta. cta following a positive lp diagnosed . - % of aneurysms. conclusion: lp strategies are more sensitive for detecting sah but less specific than cta because of traumatic taps, leading to lower predictive value positives for sah with lp than with cta. either diagnostic strategy results in a low likelihood of missing sah, particularly within hours of symptom onset. background: recent studies support perfusion imaging as a prognostic tool in ischemic stroke, but little data exist regarding its utility in transient ischemic attack (tia). ct perfusion (ctp), which is more available and less costly to perform than mri, has not been well studied. objectives: to characterize ctp findings in tia patients, and identify imaging predictors of outcome. methods: this retrospective cohort study evaluated tia patients at a single ed over months, who had ctp at initial evaluation. a neurologist blinded to ctp findings collected demographic and clinical data. ctp images were analyzed by a neuroradiologist blinded to clinical information. ctp maps were described as qualitatively normal, increased, or decreased in mean transit time (mtt), cerebral blood volume (cbv), and cerebral blood flow (cbf). quantitative analysis involved measurements of average mtt (seconds), cbv (cc/ g) and cbf (cc/[ g x min]) in standardized regions of interest within each vascular distribution. these were compared with values in the other hemisphere for relative measures of mtt difference, cbv ratio, and cbffratio. mtt difference of ‡ seconds, rcbv as £ . , and rcbf as £ . were defined as abnormal based on prior studies. clinical outcomes including stroke, tia, or hospitalization during follow-up were determined up to one year following the index event. dichotomous variables were compared using fisher's exact test. logistic regression was used to evaluate the association of ctp abnormalities with outcome in tia patients. results: of patients with validated tia, had ctp done. mean age was ± years, % were women, and % were caucasian. mean abcd score was . ± . , and % had an abcd ‡ . prolonged mtt was the most common abnormality ( , %), and ( . %) had decreased cbv in the same distribution. on quantitative analysis, ( %) had a significant abnormality. four patients ( . %) had prolonged mtt and decreased cbv in the same territory, while ( %) had mismatched abnormalities. when tested in a multivariate model, no significant associations between mismatch abnormalities on ctp and new stroke, tia, or hospitalizations were observed. conclusion: ctp abnormalities are common in tia patients. although no association between these abnormalities and clinical outcomes was observed in this small study, this needs to be studied further. objectives: we hypothesized that pre-thrombolytic anti-hypertensive treatment (aht) may prolong door to treatment time (dtt). methods: secondary data analysis of consecutive tpatreated patients at randomly selected michigan community hospitals in the instinct trial. dtt among stroke patients who received pre-thrombolytic aht were compared to those who did not receive pre-thrombolytic aht. we then calculated a propensity score for the probability of receiving pre-thrombolytic aht using a logistic regression model with covariates including demographics, stroke risk factors, antiplatelet or beta blocker as home medication, stroke severity (nihss), onset to door time, admission glucose, pretreatment systolic and diastolic blood pressure, ems usage, and location at time of stroke. a paired t-test was then performed to compare the dtt between the propensity-matched groups. a separate generalized estimating equations (gee) approach was also used to estimate the differences between patients receiving pre-thrombolytic aht and those who did not while accounting for within-hospital clustering. results: a total of patients were included in instinct; however, onset, arrival, or treatment times were not able to be determined in , leaving patients for this analysis. the unmatched cohort consisted of stroke patients who received pre-thrombolytic aht and stroke patients who did not receive aht from - (table) . in the unmatched cohort, patients who received pre-thrombolytic aht had a longer dtt (mean increase minutes; % confidence interval (ci) - minutes) than patients who did not receive pre-thrombolytic aht. after propensity matching (table) , patients who received pre-thrombolytic aht had a longer dtt (mean increase . minutes, % ci . - . ) than patients who did not receive pre-thrombolytic aht. this effect persisted and its magnitude was not altered by accounting for clustering within hospitals. conclusion: pre-thrombolytic aht is associated with modest delays in dtt. this represents a feasible target for physician educational interventions and quality improvement initiatives. further research evaluating optimum hypertension management pre-thrombolytic treatment is warranted. post-pds, % had only pre-pds, and % had both. the most common pds included failure to treat post-treatment hypertension ( , %), antiplatelet agent within hours of treatment ( , %), pre-treatment blood pressure over / ( , %), anticoagulant agent within hours of treatment ( , %), and treatment outside the time window ( , %). symptomatic intracranial hemorrhage (sich) was observed in . % of patients with pds and . % of patients without any pd. in-hospital case fatality was % with and % without a pd. in the fully adjusted model, older age was significantly associated with pre-pds (table) . when post-pds were evaluated with adjustment for pre-pds, age was not associated with pds; however, pre-pds were associated with post-pds. conclusion: older age was associated with increased odds of pre-pds in michigan community hospitals. pre-pds were associated with post-pds. sich and in-hospital case fatality were not associated with pds; however, the low number of such events limited our ability to detect a difference. ct background: mri has become the gold standard for the detection of cerebral ischemia and is a component of multiple imaging enhanced clinical risk prediction rules for the short-term risk of stroke in patients with transient ischemic attack (tia). however, it is not always available in the emergency department (ed) and is often contraindicated. leukoaraiosis (la) is a radiographic term for white matter ischemic changes, and has recently been shown to be independently predictive of disabling stroke. although it is easily detected by both ct and mri, their comparative ability is unknown. objectives: we sought to determine whether leukoaraiosis, when combined with evidence of acute or old infarction as detected by ct, achieved similar sensitivity to mri in patients presenting to the ed with tia. methods: we conducted a retrospective review of consecutive patients diagnosed with tia between june and july that underwent both ct and mri as part of routine care within calendar day of presentation to a single, academic ed. ct and mr images were reviewed by a single emergency physician who was blinded to the mr images at the time of ct interpretation. la was graded using the van sweiten scale (vss), a validated grading scale applicable to both ct and mri. anterior and posterior regions were graded independently from to . results: patients were diagnosed with tia during the study period. of these, had both ct and mri background: helping others is often a rewarding experience but can also come with a ''cost of caring'' also known as compassion fatigue (cf). cf can be defined as the emotional and physical toll suffered by those helping others in distress. it is affected by three major components: compassion satisfaction (cs), burnout (bo), and traumatic experiences (te). previous literature has recognized an increase in bo related to work hours and stress among resident physicians. objectives: to assess the state of cf among residents with regard to differences in specialty training, hours worked, number of overnights, and demands of child care. we aim to measure associations with the three components of cf (cs, bo, and te). methods: we used the previously validated survey, proqol . the survey was sent to the residents after approval from the irb and the program directors. results: a total of responses were received ( % of the surveyed). five were excluded due to incomplete questionnaires. we found that residents who worked more hours per week had significantly higher bo levels (median vs , p = . ) and higher te ( vs , p = . ) than those working less hours. there was no difference in cs ( vs , p = . ). eighteen percent of the residents worked a majority of the night shifts. these residents had higher levels of bo background: emergency department (ed) billing includes both facility and professional fees. an algorithm derived from the medical provider's chart generates the latter fee. many private hospitals encourage appropriate documentation by financially incentivizing providers. academic hospitals sometimes lag in this initiative, possibly resulting in less than optimal charting. past attempts to teach proper documentation using our electronic medical record (emr) were difficult in our urban, academic ed of providers (approximately attending physicians, residents, and physician assistants). objectives: we created a tutorial to teach documentation of ed charts, modified the emr to encourage appropriate documentation, and provided feedback from the coding department. this was combined with an incentive structure shared equally amongst all attendings based on increased collections. we hypothesized this instructional intervention would lead to more appropriate billing, improve chart content, decrease medical liability, and increase educational value of charting process. methods: documentation recommendations, divided into two-month phases of - proposals, were administered to all ed providers by e-mails, lectures, and reminders during sign-out rounds. charts were reviewed by coders who provided individual feedback if specific phase recommendations were not followed. our endpoints included change in total rvu, rvus/ patient, e/m level distribution, and subjective quality of chart improvement. we did not examine effects on procedure codes or facility fees. results: our base average rvu/patient in our ed from / / - / / was . with monthly variability of approximately %. implementation of phase one increased average rvu/patient within two weeks to . ( . % increase from baseline, p < . ). the second aggregate phase implemented weeks later increased average rvu/patient to . ( . % increase from baseline, p < . ). conclusion: using our teaching methods, chart reviews focused on - recommendations at a time, and emr adjustments, we were able to better reflect the complexity of care that we deliver every day in our medical charts. future phases will focus on appropriate documentation for procedures, critical care, fast track, and pediatric patients, as well as examining correlations between increase in rvus with charge capture. identifying mentoring ''best practices'' for medical school faculty julie l. welch, teresita bellido, cherri d. hobgood background: mentoring has been identified as an essential component for career success and satisfaction in academic medicine. many institutions and departments struggle with providing both basic and transformative mentoring for their faculty. objectives: we sought to identify and understand the essential practices of successful mentoring programs. methods: multidisciplinary institutional stakeholders in the school of medicine including tenured professors, deans, and faculty acknowledged as successful mentors were identified and participated in focused interviews between mar-nov . the major area of inquiry involved their experiences with mentoring relationships, practices, and structure within the school, department, or division. focused interview data were transcribed and grounded theory analysis was performed. additional data collected by a institutional mentoring taskforce were examined. key elements and themes were identified and organized for final review. results: results identified the mentoring practices for three categories: ) general themes for all faculty, ) specific practices for faculty groups: basic science researchers, clinician researchers, clinician educators, and ) national examples. additional mentoring strategies that failed were identified. the general themes were quite universal among faculty groups. these included: clarify the best type of mentoring for the mentee, allow the mentee to choose the mentor, establish a panel of mentors with complementary skills, schedule regular meetings, establish a clear mentoring plan with expectations and goals, offer training and resources for both the mentor and mentee at institutional and departmental levels, ensure ongoing mentoring evaluation, create a mechanism to identify and reward mentoring. national practice examples offered critical recommendations to address multi-generational attitudes and faculty diversity in terms of gender, race, and culture. conclusion: mentoring strategies can be identified to serve a diverse faculty in academic medicine. interventions to improve mentoring practices should be targeted at the level of the institution, department, and individual faculty members. it is imperative to adopt results such as these to design effective mentoring programs to enhance the success of emergency medicine faculty seeking robust academic careers. background: women comprise half of the talent pool from which the specialty of emergency medicine draws future leaders, researchers, and educators and yet only % of full professors in us emergency medicine are female. both research and interventions are aimed at reducing the gender gap, however, it will take decades for the benefits to be realized which creates a methodological challenge in assessing system's change. current techniques to measure disparities are insensitive to systems change as they are limited to percentages and trends over time. objectives: to determine if the use of relative rate index (rri) better predicts which stage in the system women are not advancing in the academic pipeline than traditional metrics. methods: rri is a method of analysis that assesses the percent of sub-populations in each stage relative to their representation in the stage directly prior. thus, there is a better notion of the advancement given the availability to advance. rri also standardizes data for ease of interpretation. this study was conducted on the total population of academic professors in all departments at yale school of medicine during the academic year of - . data were obtained from the yale university provost's office. results: n = . there were a total of full, associate, and assistant professors. males comprised %, %, and % respectively. rri for the department of emergency medicine (dem) is . , . , and . , for full, associate, and assistant professors, respectively while the percentages were %, %, and % respectively. conclusion: relying solely on percentages masks improvements to the system. women are most represented at the associate professor level in dem, highlighting the importance of systems change evidence. specifically, twice as many women are promoted to associate professor rank given the number who exists as assistant professors. within years, the dem should have an equal system as the numbers of associate professors have dramatically increased and will be eligible to promote to full professor. additionally, dem has a better record of retaining and promoting women than other yale departments of medicine at both associate and full professor ranks. objectives: we examine the payer mixes of community non-rehabilitation eds in metropolitan areas by region to identify the proportion of academic and nonacademic eds that could be considered safety net eds. we hypothesize that the proportion of safety net academic eds is greater than that for non-academic eds and is increasing over time. methods: this is an ecological study examining us ed visits from through . data were obtained from the nationwide emergency department sample (neds). we grouped each ed visit according to the unique hospital-based ed identifier, thus creating a payer mix for each ed. we define a ''safety net ed'' as any ed where the payer mix satisfied any one of the following three conditions: ) > % of all ed visits are medicaid patients; ) > % of all ed visits are self-pay patients; or ) > % of all ed visits are either medicaid or self-pay patients. neds tags each ed with a hospital-based variable to delineate metropolitan/non-metropolitan locations and academic affiliation. we chose to examine a subpopulation of eds tagged as either academic metropolitan or non-academic metropolitan, because the teaching status of non-metropolitan hospitals was not provided. we then measured the proportion of eds that met safety net criteria by academic status and region. results: we examined , , , , and , weighted metro eds in years - , respectively. table presents safety net proportions. the proportions of academic safety net eds increased across the study period. widespread regional variability in safety net proportions existed across all years. the proportions of safety net eds were highest in the south and lowest in the northeast and midwest. table describes these findings for . conclusion: these data suggest that the proportion of safety-net academic eds may be greater than that of non-academic eds, is increasing over time, and is objectives: to examine the effect of ma health reform implementation on ed and hospital utilization before and after health reform, using an approach that relies on differential changes in insurance rates across different areas of the state in order to make causal inferences as to the effect of health reform on ed visits and hospitalizations. our hypothesis was that health care reform (i.e. reducing rates of uninsurance) would result in increased rates of ed use and hospitalizations. methods: we used a novel difference-in-differences approach, with geographic variation (at the zip code level) in the percentage uninsured as our method of identifying changes resulting from health reform, to determine the specific effect of massachusetts' health care reform on ed utilization and hospitalizations. using administrative data available from the massachusetts division of health care finance and policy acute hospital case mix databases, we compared a one-year period before health reform with an identical period after reform. we fit linear regression models at the area-quarter level to estimate the effect of health reform and the changing uninsurance rate (defined as self-pay only) on ed visits and hospitalizations. results: there were , , ed visits and , hospitalizations pre-reform and , , ed visits and , hospitalizations post-reform. the rate of uninsurance decreased from . % to . % in the ed group and from . % to . % in the hospitalization group. a reduction in the rate of the uninsured was associated with a small but statistically significant increase in ed utilization (p = . ) and no change in hospitalizations (p = . ). conclusion: we find that increasing levels of insurance coverage in massachusetts were associated with small but statistically significant increases in ed visits, but no differences in rates of hospitalizations. these results should aid in planning for anticipated changes that might result from the implementation of health reform nationally. with high levels of co-morbidity when untreated in adolescents. despite broad cdc screening recommendations, many youth do not receive testing when indicated. the pediatric emergency department (ped) is a venue with a high volume of patients potentially in need of sti testing, but assessing risk in the ped is difficult given constraints on time and privacy. we hypothesized that patients visiting a ped would find an audio-enhanced computer-assisted self-interview (acasi) program to establish sti risk easy to use, and would report a preference for the acasi over other methods of disclosing this information. objectives: to assess acceptability, ease of use, and comfort level of an acasi designed to assess adolescents' risk for stis in the ped. methods: we developed a branch-logic questionnaire and acasi system to determine whether patients aged - visiting the ped need sti testing, regardless of chief complaint. we obtained consent from participants and guardians. patients completed the acasi in private on a laptop. they read a one-page computer introduction describing study details and completed the acasi. patients rated use of the acasi upon completion using five-point likert scales. results: eligible patients visited the ped during the study period. we approached ( %) and enrolled and analyzed data for / ( %). the median time to read the introduction and complete the acasi was . minutes (interquartile range . - . minutes). . % of patients rated the acasi ''very easy'' or ''easy'' to use, . % rated the wording as ''very easy'' or ''easy'' to understand, % rated the acasi ''very short'' or ''short'', . % rated the audio as ''very helpful'' or ''helpful,'' . % were ''very comfortable'' or ''comfortable'' with the system confidentiality, and . % said they would prefer a computer interface over in-person interviews or written surveys for collection of this type of information. conclusion: patients rated the computer interface of the acasi as easy and comfortable to use. a median of . minutes was needed to obtain meaningful clinical information. the acasi is a promising approach to enhance the collection of sensitive information in the ped. the participants were randomized to one of three conditions, bi delivered by a computer (cbi), bi delivered by a therapist assisted by a computer (tbi), or control, and completed , , and month follow-up. in addition to content on alcohol misuse and peer violence, adolescents reporting dating violence received a tailored module on dating violence. the main outcome for this analysis was frequency of moderate and severe dating victimization and aggression at the baseline assessment and , , and months post ed visit. results: among eligible adolescents, % (n = ) reported dating violence and were included in these analyses. compared to controls, after controlling for baseline dating victimization, participants in the cbi showed reductions in moderate dating victimization at months (or . ; ci . - . ; p < . , effect size . ) and months (or . ; ci . - . ; p < . , effect size . ); models examining interaction effects were significant for the cbi on moderate dating victimization at and months. significant interaction effects were found for the tbi on moderate dating victimization at and months and severe dating victimization at months. the computer-based intervention shows promise for delivering content that decreases moderate dating victimization over months. the therapist bi is promising for decreasing moderate dating victimization over months and severe dating victimization over months. ed-based bis delivered on a computer addressing multiple risk behaviors could have important public health effects. figure . the -only ordinance was associated with a significant reduction of ar visits. this ordinance was also associated with reduction in underage ar visits, ui student visits, and public intoxication bookings. these data suggest that other cities should consider similar ordinances to prevent unwanted consequences of alcohol. background: prehospital providers perform tracheal intubation in the prehospital environment, and failed attempts are of concern due to the danger of hypoxia and hypotension. some question the appropriateness of intubation in this setting due to the morbidity risk associated with intubation in the field. thus it is important to gain an understanding of the factors that predict the success of prehospital intubation attempts to inform this discussion. objectives: to determine the factors that affect success rates on first attempt of paramedic intubations in a rapid sequence intubation (rsi) capable critical care transport service. methods: we conducted a multivariate logistic analysis on a prospectively collected database of airway management from an air and land critical care transport service that provides scene responses and interfacility transport in the province of ontario. background: motor vehicle collisions (mvcs) are one of the most common types of trauma for which people seek ed care. the vast majority of these patients are discharged home after evaluation. acute psychological distress after trauma causes great suffering and is a known predictor of posttraumatic stress disorder (ptsd) development. however, the incidence and predictors of psychological distress among patients discharged to home from the ed after mvcs have not been reported. objectives: to examine the incidence and predictors of acute psychological distress among individuals seen in the ed after mvcs and discharged to home. methods: we analyzed data from a prospective observational study of adults - years of age presenting to one of eight ed study sites after mvc between / and / . english-speaking patients who were alert and oriented, stable, and without injuries requiring hospital admission were enrolled. patient interview included assessment of patient sociodemographic and psychological characteristics and mvc characteristics. level of psychological distress in the ed was assessed using the -item peritraumatic distress inventory (pdi). pdi scores > are associated with increased risk of ptsd and were used to define substantial psychological distress. descriptive statistics and logistic regression were performed using stata ic . (statacorp lp, college station, texas). results: mvc patients were screened, were eligible, and were enrolled. / ( %) participants had substantial psychological distress. after adjusting for crash severity (severity of vehicle damage, vehicle speed), substantial patient distress was predicted by sociodemographic factors, pre-mvc depressive symptoms, and arriving to the ed on a backboard (table) . conclusion: substantial psychological distress is common among individuals discharged from the ed after mvcs and is predicted by patient characteristics separate from mvc severity. a better under standing of the frequency and predictors of substantial psychological distress is an important first step in identifying these patients and developing effective interventions to reduce severe distress in the aftermath of trauma. such interventions have the potential to reduce both immediate patient suffering and the development of persistent psychological sequelae. figure) the predictive characteristics of pets, pesi, and spesi for -day mortality in emperor, including auc, negative predictive value, sensitivity, and specificity were calculated. results: the of patients ( . %; % ci . %- . %) classified as pets low had -day mortality of . % ( % ci . - . %), versus . % ( % ci . %- . %) in the pets high group, statistically similar to pesi and spesi. pets is significantly more specific for mortality than the spesi ( . % v . %; p < . ), classifying far more patients as low-risk while maintaining a sensitivity of % ( % ci . %- . %), not significantly different from spesi or pesi (p > . ). conclusion: with four variables, pets in this derivation cohort is as sensitive for -day mortality as the more complicated pesi and spesi, with significantly greater specificity than the spesi for mortality, placing % more patients in the low-risk group. external validation is necessary. nicole seleno, jody vogel, michael liao, emily hopkins, richard byyny, ernest moore, craig gravitz, jason haukoos denver health medical center, denver, co background: the sequential organ failure assessment (sofa) score, base excess, and lactate have been shown to be associated with mortality in critically ill trauma patients. the denver emergency department (ed) trauma organ failure (tof) score was recently derived and internally validated to predict multiple organ failure in trauma patients. the relationship between the denver tof score and mortality has not been assessed or compared to other conventional measures of mortality in trauma. objectives: to compare the prognostic accuracies of the denver ed tof score, ed sofa score, and ed base excess and lactate for mortality in a large heterogeneous trauma population. methods: a secondary analysis of data from the denver health trauma registry, a prospectively collected database. consecutive adult trauma patients from through were included in the study. data collected included demographics, injury characteristics, prehospital care characteristics, response to injury characteristics, ed diagnostic evaluation and interventions, and in-hospital mortality. the values of the four clinically relevant measures (denver ed tof score, ed sofa score, ed base excess, and ed lactate) were determined within four hours of patient arrival, and prognostic accuracies for in-hospital mortality for the four measures were evaluated with receiver operating characteristic (roc) curves. multiple imputation was used for missing values. results: of the , patients, the median age was (iqr - ) years, median injury severity score was (iqr - ), and % had blunt mechanisms. thirty-eight percent ( , patients) were admitted to the icu with a median icu length of stay of . (iqr - ) days, and % ( patients) died. in the non-survivors, the median values for the four measures were ed sofa . (iqr . - . ); denver ed tof . (iqr . - . ); ed base excess . (iqr . - . ) meq/l; and ed lactate . (iqr . - . ) mmol/l. the areas under the roc curves for these measures are demonstrated in the figure. conclusion: the denver ed tof score more accurately predicts in-hospital mortality in trauma patients as compared to the ed sofa score, ed base excess, or ed lactate. the denver ed tof score may help identify patients early who are at risk for mortality, allowing for targeted resuscitation and secondary triage to improve outcomes in these critically ill patients. the background: both animal and human studies suggest that early initiation of therapeutic hypothermia (th) and rapid cooling improve outcomes after cardiac arrest. objectives: the objective was to determine if administration of cold iv fluids in a prehospital setting decreased time-to-target-temperature (tt) with secondary analysis of effects on mortality and neurological outcome. methods: patients resuscitated after out-of-hospital cardiac arrest (oohca) who received an in-hospital post cardiac arrest bundle including th were prospectively enrolled into a quality assurance database from november to november . on april , a protocol for intra-arrest prehospital cooling with °c normal saline on patients experiencing oohca was initiated. we retrospectively compared tt for those receiving prehospital cold fluids and those not receiving cold fluids. tt was defined as °c measured via foley thermistor. secondary outcomes included mortality, good neurological outcome defined as cerebral performance category (cpc) score of or at discharge, and effects of pre-rosc cooling. results: there were patients who were included in this analysis with patients receiving prehospital cold iv fluids and who did not. initially, % of patients were in vf/vt and % asystole/pea. patients receiving prehospital cooling did not have a significant improvement in tt ( minutes vs minutes, p = . ). survival to discharge and good neurologic outcome were not associated with prehospital cooling ( % vs %, p = . ) and cpc of or in % vs %, (p = . ). initiating cold fluids prior to rosc showed both a nonsignificant decrease in survival ( % vs %, p = . ) and increase in poor neurologic outcomes ( % vs %, p = . ). % of patients received £ l of cooled ivf prior to hospital arrival. patients receiving prehospital cold ivf had a longer time from arrest to hospital arrival ( vs min, p =< . ) in addition to a prolonged rosc to hospital time ( vs min, p = . ). conclusion: at our urban hospital, patients achieving rosc following oohca did not demonstrate faster tt or outcome improvement with prehospital cooling compared to cooling initiated immediately upon ed arrival. further research is needed to assess the utility of prehospital cooling. assessment background: an estimated % of emergency department (ed) patients years of age and older have delirium, which is associated with short-and long-term risk of morbidity and mortality. early recognition could result in improved outcomes, but the reliability of delirium recognition in the continuum of emergency care is unknown. objectives: we tested whether delirium can be reliably detected during emergency care of elderly patients by measuring the agreement between prehospital providers, ed physicians, and trained research assistants using the confusion assessment method for the icu (cam-icu) to identify the presence of delirium. our hypothesis was that both ed physicians and prehospital providers would have poor ability to detect elements of delirium in an unstructured setting. methods: prehospital providers and ed physicians completed identical questionnaires regarding their clinical encounter with a convenience sample of elderly (age > years) patients who presented via ambulance to two urban, teaching eds over a three-month period. respondents noted the presence or absence of ( ) an acute change in mental status, ( ) inattention, ( ) disorganized thinking, and ( ) altered level of consciousness (using the richmond agitation sedation scale). these four components comprise the operational definition of delirium. a research assistant trained in the cam-icu rated each component for the same patients using a standard procedure. we calculated inter-rater reliability (kappa) between prehospital providers, ed physicians, and research assistants for each component. objectives: this study aimed to assess the association between age and ems use while controlling for potential confounders. we hypothesized that this association use would persist after controlling for confounders. methods: a cross-sectional survey study was conducted at an academic medical center's ed. an interview-based survey was administered and included questions regarding demographic and clinical characteristics, mode of ed arrival, health care use, and the perceived illness severity. age was modeled as an ordinal variable (< , - , and ‡ years). bivariate analyses were used to identify potential confounders and effect measure modifiers and a multivariable logistic regression model was constructed. odds ratios were calculated as measures of effect. results: a total of subjects were enrolled and had usable data for all covariates, ( %) of whom arrived via ems. the median age of the sample was years and % were female. there was a statistically significant linear trend in the proportion of subjects who arrived via ems by age (p < . ). compared to adults aged less than years, the unadjusted odds ratio associating age and ems use was . ( % ci: background: we previously derived a clinical decision rule (cdr) for chest radiography (cxr) in patients with chest pain and possible acute coronary syndrome (acs) consisting of the absence of three predictors: history of congestive heart failure, history of smoking, and abnormalities on lung auscultation. objectives: to prospectively validate and refine a cdr for cxr in an independent patient population. methods: we prospectively enrolled patients over years of age with a primary complaint of chest pain and possible acs from september to january at a tertiary care ed with , annual patient visits. physicians completed standardized data collection forms before ordering chest radiographs and were thus blinded to cxr findings at the time of data collection. two investigators, blinded to the predictor variables, independently classified cxrs as ''normal,'' ''abnormal not requiring intervention,'' and ''abnormal requiring intervention'' (e.g, heart failure, infiltrates) based on review of the radiology report and the medical record. analyses included descriptive statistics, inter-rater reliability assessment (kappa), and recursive partitioning. results: of visits for possible acs, mean age (sd) was . ( . ) and % were female. twenty-four percent had a history of acute myocardial infarction, % congestive heart failure, and % atrial fibrillation. seventy-one ( . %, % ci . - . ) patients had a radiographic abnormality requiring intervention. ing the likelihood of coronary artery disease (cad) could reduce the need for stress testing or coronary imaging. acyl-coa:cholesterol acyltransferase- (acat ) activity has been shown in monkey and murine models to correlate with atherosclerosis. objectives: to determine if a novel cardiac biomarker consisting of plasma cholesteryl ester levels (ce) typically derived from the activity of acat is predictive of cad in a clinical model. methods: a single center prospective observational cohort design enrolled a convenience sample of subjects from a tertiary care center with symptoms of acute coronary syndrome undergoing coronary ct angiography or invasive angiography. plasma samples were analyzed for ce composition with mass spectrometry. the primary endpoint was any cad determined at angiography. multivariable logistic regression analyses were used to estimate the relationship between the sum of the plasma concentrations from cholesteryl palmitoleate ( : ) and cholesteryl oleate ( : ) (defined as acat -ce) and the presence of cad. the added value of acat -ce to the model was analyzed comparing the c-statistics and integrated discrimination improvement (idi). results: the study cohort was comprised of participants enrolled over months with a mean age (± . ) years, % with cad at angiography. the median plasma concentration of acat -ce was lm ( , ) in patients with cad and lm ( , ) in patients without cad (p = . ) (figure) . when considered with age, sex, and the number of conventional cad risk factors, acat -ce were associated with a . % increased odds of having cad per lm increase in concentration. the addition of acat -ce significantly improved the c-statistic ( . vs . , p = . ) and idi ( . , p < . ) compared to the reduced model. in the subgroup of low-risk observation unit patients, the ce model had superior discrimination compared to the diamond forrester classification (idi . , p < . ). conclusion: plasma levels of acat -ce, considered in a clinical model, have strong potential to predict a patient's likelihood of having cad. in turn, this could reduce the need for cardiac imaging after the exclusion of mi. further study of acat -ce as biomarkers in patients with suspected acs is needed. background: outpatient studies have demonstrated a correlation between carotid intima-media thickness (cimt) on ultrasound and coronary artery disease (cad). there are no known published studies that investigate the role of cimt in the ed using cardiac ct or percutaneous cardiac intervention (pci) as a gold standard. objectives: we hypothesized that cimt can predict cardiovascular events and serve as a noninvasive tool in the ed. methods: this was a prospective study of adult patients who presented to the ed and required evaluation for chest pain. the study location was an urban ed with a census of , annual visits and -hour cardiac catheterization. patients who did not have ct or pci or had carotid surgery were excluded from the study. ultrasound cimt measurements of right and left common carotid arteries were taken with a mhz linear transducer (zonare, mountain view, ca). anterior, medial, and posterior views of the near and far wall were obtained ( cimt scores total). images were analyzed by carotid analyzer (mailing imaging application llc, coralville, iowa). patients were classified into two groups based on the results from ct or pci. a subject was classified as having significant cad if there was over % occlusion or multi-vessel disease. results: ninety of patients were included in the study; . % were males. mean age was . ± years. there were ( . %) subjects with significant cad and ( . %) with non-significant cad. the mean of all cimt measurements was significantly higher in the cad group than in the non-cad group ( . ± . vs. . ± . ; p < . ). a logistic regression analysis was carried out with significant cad as the event of interest and the following explanatory variables in the model: objectives: to determine the diagnostic yield of routine testing in-hospital or following ed discharge among patients presenting to an ed following syncope. methods: a prospective, observational, cohort study of consecutive ed patients ‡ years old presenting with syncope was conducted. the four most commonly utilized tests (echocardiography, telemetry, ambulatory electrocardiography monitoring, and cardiac markers) were studied. interobserver agreement as to whether tests results determined the etiology of the syncope was measured using kappa (k) values. results: of patients with syncope, ( %) had echocardiography with ( %) demonstrating a likely etiology of the syncopal event such as critical valvular disease or significantly depressed left ventricular function (k = . ). on hospitalization, ( %) patients were placed on telemetry, ( %) of these had worrisome dysrhythmias (k = . ). ( %) patients had troponin levels drawn of whom ( %) had positive results (k = ); ( %) patients were discharged with monitoring with significant findings in only ( . %) patients (k = . ). overall, ( %, % ci - %) studies were diagnostic. conclusion: although routine testing is prevalent in ed patients with syncope, the diagnostic yield is relatively low. nevertheless, some testing, particularly echocardiography, may yield critical findings in some cases. current efforts to reduce the cost of medical care by eliminating non-diagnostic medical testing and increasing emphasis on practicing evidence-based medicine argue for more discriminate testing when evaluating syncope. (originally submitted as a ''late-breaker.'') unusual fatigue was reported by . % (severe . %) and insomnia by . % (severe . %). these findings have led to risk management recommendations to consider these symptoms as predictive of acute coronary syndromes (acs) among women visiting the ed. objectives: to document the prevalence of these symptoms among all women visiting an ed. to analyze the potential effect of using these symptoms in the ed diagnostic process for acs. methods: a survey on fatigue and insomnia symptoms was administered to a convenience sample of all adult women visiting an urban academic ed (all arrival modes, acuity levels, all complaints). a sensitivity analysis was performed using published data and expert opinion for inputs. results: we approached women, with enrollments. see table. the top box shows prevalences of prodromal symptoms among all adult female ed patients. the bottom box shows outputs from sensitivity analysis on the diagnostic effect of initiating an acs workup for all female ed patients reporting prodromal symptoms. conclusion: prodromal symptoms of acs are highly prevalent among all adult women visiting the ed in this study. this likely limits their utility in ed settings. while screening or admitting women with prodromal symptoms in the ed would probably increase sensitivity, that increase would be accompanied by a dramatic reduction in specificity. such a reduction in specificity would translate to admitting, observing, or working up somewhere between % and % of all women visiting the ed, which is prohibitive in terms of personal costs, risks of hospitalization, and financial costs. while these symptoms may or may not have utility in other settings such as primary care, their prevalence, and the implied lack of specificity for acs suggest they will not be clinically useful in the ed. length methods: we examined a cohort of low-risk chest pain patients evaluated in an ed-based ou using prospective and retrospective ou registry data elements. cox proportional hazard modeling was performed to assess the effect of testing modality (stress testing vs. ccta) on the los in the cdu. as ccta is not available on weekends, only subjects presenting on weekdays were included. cox models were stratified on time of patient presentation to the ed, based on four hour blocks beginning at midnight. the primary independent variable was first test modality, either stress imaging (exercise echo, dobutamine echo, stress mri) or ccta. age, sex, and race were included as covariates. the proportional hazards assumption was tested using scaled schoenfield residuals, and the models were graphically examined for outliers and overly influential covariate patterns. test selection was a time varying covariate in the am strata, and therefore the interaction with ln (los) was included as a correction term. after correction for multiple comparisons, an alpha of . was held to be significant. results: over the study period, subjects (of , in the registry) presented on non-weekend days. the median los was . hours (iqr . - . hours), % were white, and % were female. the table shows the number of subjects in each time strata, the number tested, and the number undergoing stress testing vs. ccta. after adjusting all models for age, race, and sex, the hazard ratio (hr) for los is as shown. only those patients presenting between am and noon noted a significant improvement in los with ccta use (p < . ). objectives: determine the validity of a managementfocused em osce as a measure of clinical skills by determining the correlation between osce scores and faculty assessment of student performance in the ed. methods: medical students in a fourth year em clerkship were enrolled in the study. on the final day of the clerkship students participated in a five-station em osce. student performance on the osce was evaluated using a task-based evaluation system with - critical management tasks per case. task performance was evaluated using a three-point system: performed correctly/timely ( ), performed incorrectly/late ( ), or not performed ( ). descriptive anchors were used for performance criteria. communication skills were also graded on a three-point scale. student performance in the ed was based on traditional faculty assessment using our core-competency evaluation instrument. a pearson correlation coefficient was calculated for the relationship between osce score and ed performance score. case item analysis included determination of difficulty and discrimination. the acgme also requires that trainees are evaluated on these ccs during their residency. trainee evaluation in the ccs are frequently on a subjective rating scale. one of the recognized problems with a subjective scale is the rating stringency of the rater, commonly known as the hawk-dove effect. this has been seen in standardized clinical exam scoring. recent data have shown that score variance can be related to evaluator performance with a negative correlation. higher-scoring physicians were more likely to be a stringent or hawk type rater on the same evaluation. it is unclear if this pattern also occurs in the subjective ratings that are commonly used in assessments of the ccs. objectives: comparison of attending physician scores on the acgme ccs with attending ratings of residents for a negative correlation or hawk-dove effect. methods: residents are routinely evaluated on the ccs with a - numerical rating scale as part of their training. the evaluation database was retrospectively reviewed. residents anonymously scored attending physicians on the ccs with a cross-sectional survey that utilized the same rating scale, anchors, and prompts as the resident evaluations. average scores for and by each attending were calculated and a pearson correlation calculated by core competency and overall. results: in this irb-approved study, a total of attending physicians were scored on the ccs with evaluations by residents. attendings evaluated residents with a total of , evaluations completed over a -year period. attending mode score was ranging from to ; resident scores had a mode of with a range of to . there was no correlation between the rated performance of the attendings overall or in each ccs and the scores they gave (p = . - . ). conclusion: hawk-dove effects can be seen in some scoring systems and has the potential to affect trainee evaluation on the acgme core competencies. however, a negative correlation to support a hawk-dove scoring pattern was not found in em resident evaluations by attending physicians. this study is limited by being a single center study and utilizing grouped data to preserve resident anonymity. background: all acgme-accredited residency programs are required to provide competency-based education and evaluation. graduating residents must demonstrate competency in six key areas. multiple studies have outlined strategies for evaluating competency, but data regarding residents' self-assessments of these competencies as they progress through training and beyond is scarce. objectives: using data from longitudinal surveys by the american board of emergency medicine, the primary objective of this study was to evaluate if resident self-assessments of performance in required competencies improve over the course of graduate medical training and in the years following. additionally, resident self-assessment of competency in academic medicine was also analyzed. methods: this is a secondary data analysis of data gathered from two rounds of the abem longitudinal study of emergency medicine residents ( - and - ) and three rounds of the abem longitudinal study of emergency physicians ( , , ). in both surveys, physicians were asked to rate a list of items in response to the question, ''what is your current level of competence in each of the following aspects of work in em?'' the rated items were grouped according to the acgme required competencies of patient care, medical knowledge, practice-based learning and improvement, interpersonal and communication skills, and system-based practice. an additional category for academic medicine was also added. results: rankings improved in all categories during residency training. rankings in three of the six categories improved from the weak end of the scale to the strong end of the scale. there is a consistent decline in rankings one year after graduation from residency. the greatest drop is in medical knowledge. mean self-ranking in academic medicine competency is uniformly the lowest ranked category for each year. conclusion: while self-assessment is of uncertain value as an objective assessment, these increasing rankings suggest that emergency medicine residency programs are successful at improving residents' confidence in the required areas. residents do not feel as confident about academic medicine as they do about the acgme required competencies. the uniform decline in rankings the first year after residency is an area worthy of further inquiry. screening medical student rotators from outside institutions improves overall rotation performance shaneen doctor, troy madsen, susan stroud, megan l. fix university of utah, salt lake city, ut background: emergency medicine is a rapidly growing field. many student rotations are limited in their ability to accommodate all students and must limit the number of students they allow per rotation. we hypothesize that pre-screening visiting student rotators will improve overall student performance. objectives: to assess the effect of applicant screening on overall rotation grade and mean end of shift card scores. methods: we initiated a medical student screening process for all visiting students applying to our -week elective em rotation starting in . this consisted of reviewing board scores and requiring a letter of intent. students from our home institution were not screened. all end-of-shift evaluation cards and final rotation grades (honors, high pass, pass, fail) from to were analyzed. we identified two cohorts: home students (control) and visiting students. we compared pre-intervention ( ) ( ) ( ) ( ) ( ) and postintervention ( - ) scores and grades. end of shift performance scores are recorded using a fivepoint scale that assesses indicators such as fund of knowledge, judgment, and follow-through to disposition. mean ranks were compared and p-values were calculated using the armitage test of trend and confirmed using t-tests. results: we identified visiting students ( pre, post) and home students ( pre, post). ( . %) visiting students achieved honors pre-intervention while ( . %) achieved honors post-intervention (p = . ). no significant difference was seen in home student grades: ( . %) received honors pre- and ( . %) received honors post- conclusion: we found that implementation of a screening process for visiting medical students improved overall rotation scores and grades as compared to home students who did not receive screening. screening rotating students may improve the overall quality of applicants and thereby the residency program. background: there are many descriptions in the literature of computer-assisted instruction in medical education, but few studies that compare them to traditional teaching methods. objectives: we sought to compare the suturing skills and confidence of students receiving video preparation before a suturing workshop versus a traditional instructional lecture. methods: first and second year medical students were randomized into two groups. the control group was given a lecture followed by minutes of suturing time. the video group was provided with an online suturing video at home, no lecture, and given minutes of suturing time during the workshop. both groups were asked to rate their confidence before and after the workshop, and their belief in the workshop's effectiveness. each student was also videotaped suturing a pig's foot after the workshop and graded on a previously validated -point suturing checklist. videos were scored. results: there was no significant difference between the test scores of the lecture group (m = . , sd = . , n = ) and the video group (m = . , sd = . , n = ) using the two-sample independent ttest for equal variances (t( ) = ) . , p = . ). there was a statistically significant difference in the proportion of students scoring correctly for only one point: ''curvature of needle followed'': / in the lecture group and / in the video group (chi = . , df = , p = . ). students in the video group were found to be . times more likely to have a neutral or favorable feeling of suturing confidence before the workshop (p = . , ci . - . ) using a proportional odds model. no association was detected between group assignment and level of suturing confidence after the workshop (p = . ). there was also no association detected between group assignment and opinion of the suturing workshop (p = . ) using a logistic regression odds model. among those students who indicated a lack of confidence before training, there was no detected association (p = . ) between group assignment and having an improved confidence using a logistic regression odds model. conclusion: students in the video group and students in the control group achieved similar levels of suturing skill and confidence, and equal belief in the workshop's effectiveness. this study suggests that video instruction could be a reasonable substitute for lectures in procedural education. background: accurate interpretation of the ecg in the emergency department is not only clinically important but also critical to assess medical knowledge competency. with limitations to expansion of formal didactics, educational technology offers an innovative approach to improve the quality of medical education. objectives: the aim of this study was to assess an online multimedia-based ecg training module evaluating st elevation myocardial infarction (stemi) identification among medical students. methods: a convenience sample of fifty-two medical students on their em rotations at an academic medical center with an em residency program was evaluated in a before-after fashion during a -month period. one cardiologist and two ed attending physicians independently validated a standardized exam of ten ecgs: four were normal ecgs, three were classic stemis, and three were subtle stemis. the gold standard for diagnosis was confirmed acute coronary thrombus during cardiac catheterization. after evaluating the ecgs, students completed a pre-intervention test wherein they were asked to identify patients who required emergent cardiac catheterization based on the presence or absence of st segment elevation on ecg. students then completed an online interactive multimedia module containing minutes of stemi training based on american heart association/american college of cardiology guidelines on stemi. medical students were asked to complete a post-test of the ecgs after watching online multimedia. objectives: our objective was to quantify the number of pre-verbal pediatric head cts performed at our community hospital that could have been avoided by utilizing the pecarn criteria. methods: we conducted a standardized chart review of all children under the age of who presented to our community hospital and received a head ct between jan st, and dec st, . following recommended guidelines for conducting a chart review, we: ) utilized four blinded chart reviewers, ) provided specific training, ) created a standardized data extraction tool, and ) held periodic meetings to evaluate coding discrepancies. our primary outcome measure was the number of patients who were pecarn negative and received a head ct at our institution. our secondary outcome was to reevaluate the sensitivity and specificity of the pecarn criteria to detect citbi in our cohort. data were analyzed using descriptive statistics and % confidence intervals were calculated around proportions using the modified wald method. results: a total of patients under the age of received a head ct at our institution during the study period. patients were excluded from the final analysis because their head cts were not for trauma. the prevalence of a citbi in our cohort was . % ( % ci . %- . %) ( (dti) measures disruption of axonal integrity on the basis of anisotropic diffusion properties. findings on dti may relate to the injury, as well as the severity of postconcussion syndrome (pcs) following mtbi. objectives: to examine acute anisotropic diffusion properties based on dti in youth with mtbi relative to orthopedic controls and to examine associations between white matter (wm) integrity and pcs symptoms. methods: interim analysis of a prospective casecontrol cohort involving youth ages - years with mtbi and orthopedic controls requiring extremity radiographs. data collected in ed included demographics, clinical information, and pcs symptoms measured by the postconcussion symptom scale. within hours of injury, symptoms were re-assessed and a -direction, diffusion weighted, spin-echo imaging scan was performed on a t philips scanner. dti images were analyzed using tract-based spatial statistics. fractional anisotropy (fa), mean diffusivity (md), axial diffusivity (ad), and radial diffusivity were measured. results: there were no group demographic differences between mtbi cases and controls. presenting symptoms within the mtbi group included gcs = %, loss of consciousness %, amnesia %, post-traumatic seizure %, headache %, vomiting %, dizziness %, and confusion %. pcs symptoms were greater in mtbi cases than in the controls at ed visit ( . ± . vs. . ± . , p < . ) and at the time of scan ( . ± . vs. . ± . , p < . ). the mtbi group displayed decreased fa in cerebellum and increased md and ad in the cerebral wm relative to controls (uncorrected p < . ). increased fa in cerebral wm was also observed in mtbi patients but the group difference was not significant. pcs symptoms at the time of the scan were positively correlated with fa and inversely correlated with rd in extensive cerebral wm areas (p < . , uncorrected). in addition, pcs symptoms in mtbi patients were also found to be inversely correlated with md, ad, and rd in cerebellum (p < . ). conclusion: dti detected axonal damage in youth with mtbi which correlated with pcs symptoms. dti performed acutely after injury may augment detection of injury and help prediction of those with worse outcomes. background: sports-related concussion among professional, collegiate, and more recently high school athletes has received much attention from the media and medical community. to our knowledge, there is a paucity of research in regard to sports-related concussion in younger athletes. objectives: the aim of this study was to evaluate parental knowledge of concussion in young children who participate in recreational tackle football. methods: parents/legal guardians of children aged - years enrolled in recreational tackle football were asked to complete an anonymous questionnaire based on the cdc's heads up: concussion in youth sports quiz. parents were asked about their level of agreement in regard to statements that represent definition, symptoms, and treatment of concussion. results: a total of out of parents voluntarily completed the questionnaire ( % response rate). parent and child demographics are listed in table . ninety four percent of parents believed their child had never suffered a concussion. however, when asked to agree or disagree with statements addressing various aspects of concussion, only % (n = ) could correctly identify all seven statements. most did not identify that a concussion is considered a mild traumatic brain injury and can be achieved from something other than a direct blow to the head. race, sex, and zip code had no significant association with correctly answering statements. education ( . ; p < . ) and number of years the child played ( . ; p < . ) had a small effect. fifty-three percent of parents reported someone had discussed the definition of concussion with them and % the symptoms of concussion. see table for source of information to parents. no parent was able to classify all symptoms listed as correctly related or not related to concussion. however, identification of correct concussion definitions correlated with identification of correct symptoms ( . ; p < . ). conclusion: while most parents had received some education regarding concussion from a health care provider, important misconceptions remain among parents of young athletes regarding the definition, symptoms, and treatment of concussion. this study highlights the need for health care providers to increase educational efforts among parents of young athletes in regard to concussion. figure ). / ( %) of patients with baseline liver dysfunction were (oh)d deficient and / ( %) of deaths were patients who had insufficient levels of (oh)d. there was an inverse association between (oh)d level and tnf-a (p = . ; figure ) and il- (p = . ). background: fever is common in the emergency department (ed), and % of those diagnosed with severe sepsis present with fever. despite data suggesting that fever plays an important role in immunity, human data conflict on the effect of antipyretics on clinical outcomes in critically ill adults. objectives: to determine the effect of ed antipyretic administration on -day in-hospital mortality in patients with severe sepsis. methods: single-center, retrospective observational cohort study of febrile severe sepsis patients presenting to an urban academic , -visit ed between june and june . all ed patients meeting the following criteria were included: age ‡ , temperature ‡ . °c, suspected infection, and either systolic blood pressure £ mmhg after a ml/kg fluid bolus or lactate of ‡ . patients were excluded for a history of cirrhosis or acetaminophen allergy. antipyretics were defined as acetaminophen, ibuprofen, or ketorolac. results: one hundred-thirty five ( . %) patients were treated with an antipyretic medication ( . % acetaminophen). intubated patients were less likely to receive antipyretic therapy ( . % vs. . %, p < . ), but the groups were otherwise well matched. patients requiring ed intubation (n = ) had much higher in-hospital mortality ( . % vs. . %, p < . ). patients given an antipyretic in the ed had lower mortality ( . % vs. . %, p < . ). when multivariable logistic regression was used to account for apache-ii, intubation status, and fever magnitude, antipyretic therapy was not associated with mortality (adjusted or . , . - . , p = . ). conclusion: although patients treated with antipyretic therapy had lower -day in-hospital mortality, antipyretic therapy was not independently associated with mortality in multivariable regression analysis. these findings are hypothesis-generating for future clinical trials, as the role of fever control has been largely unexplored in severe sepsis (grant ul rr , nih-ncrr). , and caval index ) . ± . (ci ) . , ) . ) and all were statistically significant. the groups receiving ml/kg and ml/kg had statistically significant changes in caval index; however the ml/kg group had no significant change in mean ivc diameter. one-way anova differences between the means of all groups were not statistically different. conclusion: overall, there were statistically significant differences in mean ivc-us measurements before and after fluid loading, but not between groups. fasting asymptomatic subjects had a wide inter-subject variation in both baseline ivc-us measurements and fluid-related changes. the wide differences within our ml/kg group may limit conclusions regarding proportionality. there were significant differences in performance on ed measures by ownership (p < . ) and region (p = . ). scores on ed process measures were highest at for-profit hospitals ( % above average) and hospitals in the south ( % above average), and lowest at public hospitals ( % below average) and hospitals in the northeast ( % below average). conclusion: there was considerable variation in performance on the ed measures included in the vbp program by hospital ownership and region. ed directors may come under increasing pressure to improve scores in order to reduce potential financial losses under the program. our data provide early information on the types of hospitals with the greatest opportunity for improvement. methods: design/setting -an independent agency mandated by the government collected and analyzed ed patient experience data using a comprehensive, validated multidimensional instrument and a random periodic sampling methodology of all ed patients. a prospective pre-post experimental study design was employed in the eight community and tertiary care hospitals most affected by crowding. two . month study periods were evaluated (pre: / - / / ; post: / / - / / ). outcomes -the primary outcome was patient perception of wait times and crowding reported as a composite mean score ( - ) from six survey items with higher scores representing better ratings. the overall rating of care by ed patients (composite score) and other dimensions of care were collected as secondary outcomes. all outcomes were compared using chi-square and two-tailed student's t-tests. results: a total of surveys were completed in both the pre-ocp and post-ocp study periods representing a response rate of %. we compared in-patient mortality from ami for patients who lived in a community with either . miles or miles of a closure but did not need to travel farther to the nearest ed with those who did not. we used patient-level data from the california office of statewide health and planning development (oshpd) database patient discharge data, and locations of patient residence and hospitals were geo-coded to determine any changes in distance to the nearest ed. we applied a generalized linear mixed effects model framework to estimate a patient's likelihood to die in the hospital of ami as a function of being affected by a neighborhood closure event. results background: fragmentation of care has been recognized as a problem in the us health care system. however, little is known about ed utilization after hospitalization, a potential marker of poor outpatient care coordination after discharge, particularly for common inpatient-based procedures. objectives: to determine the frequency and variability in ed visits after common inpatient procedures, how often they result in readmission, and related payments. methods: using national medicare data for - , we examined ed visits within days of hospital discharge after six common inpatient procedures: percutaneous coronary intervention, coronary artery bypass grafting (cabg), elective abdominal aortic aneurysm repair, back surgery, hip fracture repair, and colectomy. we categorized hospitals into risk-adjusted quintiles based on the frequency of ed visits after the index hospitalization. we report visits by primary diagnosis icd- codes and rates of readmission. we also assessed payments related to these ed visits. results: overall, the highest quintile of hospitals had -day ed visit rates that ranged from a low of . % with an associated . % readmission rate (back surgery) to a high of . % with an associated . % readmission rate (cabg). the most variability was more than -fold and found among patients undergoing colectomy in which the worst-performing hospitals saw . % of their patients experienced an ed visit within days while the best-performing hospitals saw . %. average total payments for the -day window from initial discharge across all surgical cohorts varied from $ , for patients discharged without subsequent ed visit; $ , for those experiencing an ed visit(s); $ , for those readmitted through the ed; and $ , for those readmitted from another source. if all patients who did not require readmission also did not incur an ed visit within the -day window, this would represent a potential cost savings of $ million. conclusion: among elderly medicare recipients there was significant variability between hospitals for -day ed visits after six common inpatient procedures. the ed visit may be a marker of poor care coordination in the immediate discharge period. this presents an opportunity to improve post-procedure outpatient care coordination which may save costs related to preventable ed visits and subsequent readmissions. objectives: we sought to assess the effect of pharmacist medication review on ed patient care, in particular time from physician order to medication administration for the patient (order-to-med time). methods: we conducted a multi-center, before-after study in two eds (urban academic teaching hospital and suburban community hospital, combined census of , ) after implementation of the electronic prospective pharmacy review system (prs). the system allowed a pharmacist to review all ed medication orders electronically at the time of physician order and either approve or alter the order. we studied a -month time period before implementation of the system (pre-prs, / / - / / ) and after implementation (post-prs, / / - / / ). we collected data on all ed medication orders including dose, route, class, pharmacist review action, time of physician order, and time of medication administration. differences in order-to-medication between the pre-and post-prs study periods were compared using a results: ed metrics that were significantly associated with lbtcs varied across ed patient-volume categories (table) . for eds seeing less than k patients annually, the percentage of ems arrivals admitted to the hospital and ed square footage were both weakly associated with lbtcs (p = . ). for eds seeing at least k- k patients, median ed length of stay (los), percent of patients admitted to hospital through the ed, percent of ems arrivals admitted to hospital, and percent of pediatric patients were all positively associated, while percent of patients admitted to the hospital was negatively associated with lbtcs. for eds seeing k- k, median los and percent of x-rays performed were positively associated, while percent of ekgs performed was negatively associated with lbtcs. for eds seeing k- k, percent of patients admitted to the hospital through the ed was negatively associated and percent of ekgs performed was positively associated with lbtcs. for eds with volume greater than k, none of the selected variables were associated with lbtc. conclusion: ed factors that help explain high lbtc rates differ depending on the size of an ed. interventions attempting to improve lbtc rates by modifying ed structure or process will need to consider baseline ed volume as a potential moderating influence. objectives: our study sought to compare bacterial growth of samples taken from surfaces after use of a common approved quat compound and a virtually non-toxic, commercially available solution containing elemental silver ( . %), hydrogen peroxide ( %), and peroxyacetic acid ( %) (shp) in a working ed. we hypothesized that, based on controlled laboratory data available, shp compound would be more effective on surfaces in an active urban ed. methods: we cleaned and then sampled three types of surfaces in the ed (suture cart, wooden railing, and the floor) during midday hours one minute after application of tap water, quat, and shp and then again at hours without additional cleaning. conventional environmental surface surveillance rodac media plates were used for growth assessment. images of bacterial growth were quantified at and hours. standard cleaning procedures by hospital staff were maintained per usual. results: shp was superior to control and quat one minute after application on all three surfaces. quat and water had x and x more bacterial growth than the surface cleaned with shp, respectively. hours later, the shp area produced fewer colonies sampled from the wooden railing: x more bacteria for quat, and x for water when compared to shp. h cultures from the cart and floor had confluent growth and could not be quantified. conclusion: shp outperforms quat in sterilizing surfaces after one minute application. shp may be a superior agent as a non-toxic, non-corrosive, and effective agent for surfaces in the demanding ed setting. further studies should examine sporidical and virucidal properties in a similar environment. objectives: evaluate the effect on patient satisfaction of increasing waiting room times and physician evaluation times. methods: emergency department flow metrics were collected on a daily basis as well as average daily patient satisfaction scores. the data were from july through february , in a , census urban hospital. the data were divided into equal intervals. the arrival to room time was divided by minute intervals up to minutes with the last group being greater than minutes. the physician evaluation times were divided into minute intervals, up to , the last group greater than with days in the group. data were analyzed using means and standard deviations, and well as anova for comparison between groups. results: the overall satisfaction score for the outpatient emergency visit was higher when the patient was in a room within minutes of arrival ( . , std deviation . ), analysis of variation between the groups had a p = . , for the means of each interval (see table ). the total satisfaction with the visit as well as satisfaction with the provider dropped when the evaluation extended over minutes, but was not statistically significant on anova analysis (see table for means). conclusion: once a patient's time in the waiting room extends beyond minutes, you have lost a significant opportunity for patient satisfaction; once they have been in the waiting room for over minutes, you are also much more likely to receive a poor score. physician evaluation time scores are much more consistent but as longer evaluation times occurred beyond total of minutes we started to see a trend downward in the satisfaction score. results: in all three eds, pain medication rates (both in ed and rx) varied significantly by clinical factors including location of pain, discharge diagnosis, pain level, and acuity. we observed little to no variation in pain medication rates by patient factors such as age, sex, race, insurance, or prior ed visits. the table displays key pain management practices by site and provider. after adjusting for patient and clinical characteristics, significant differences in pain medication rates remained by provider and site (see figure) . conclusion: within this health system, the approach to pain management by both providers and sites is not standardized. investigation of the potential effect of this variability on patient outcomes is warranted. results: all measures showed significant differences, p < . . average pts/h decreased post-cpoe and did not recover post transitional period, . ± . vs . ± . , p < . . rvu/h also decreased post-cpoe and did not recover post transitional period, . ± . vs . ± . and . ± . , p < . . charges/h also decreased after cpoe implementation and did not recover after system optimization. there was a sustained significant decrease in charges/h of . % ± . % post cpoe and . % ± . % post optimization, p < . . sub-group analysis for each provider group was also evaluated and showed variability for different providers. conclusion: there was a significant decrease in all productivity metrics four months after the implementation of cpoe. the system did undergo optimization initiated by providers with customization for ease and speed of use. however, productivity measurements did not recover after these changes were implemented. these data show that with the implementation of a cpoe system there is a decrease in productivity that continues even after a transition period and system customization. background: procedural competency is a key component of emergency medicine residency training. residents are required to log procedures to document quantity of procedures and identify potential weaknesses in their training. as emergency medicine evolves, it is likely that the type and number of procedures change over time. also, exposure to certain rare procedures in residency is not guaranteed. objectives: we seek to delineate trends in type and volume of core em procedures over a decade of emergency medicine residents graduating from an accredited four-year training program. methods: deidentified procedure logs from - were analyzed to assess trends in type and quantity of procedures. procedure logs were self-reported by individual residents on a continuous basis during training onto a computer program. average numbers of procedures per resident in each graduating class were noted. statistical analysis was performed using spss and includes a simple linear regression to evaluate for significant changes in number of procedures over time and an independent samples two-tailed t-test of procedures performed before and after the required resident duty hours change. results: a total of procedure logs were analyzed and the frequency of different procedures was evaluated. a significant increase was seen in one procedure, the venous cutdown. significant decreases were seen in procedures including key procedures such as central venous catheters, tube thoracostomy, and procedural sedation. the frequency of five high-stakes/ resuscitative procedures, including thoracotomy and cricothyroidotomy, remained steady but very low (< per resident over years). of the remaining procedures, showed a trend toward decreased frequency, while only increased. conclusion: over the past years, em residents in our program have recorded significantly fewer opportunities to perform most procedures. certain procedures in our emergency medicine training program have remained stable but uncommon over the course of nearly a decade. to ensure competency in uncommon procedures, innovative ways to expose residents to these potentially life saving skills must be considered. these may include practice on high-fidelity simulators, increased exposure to procedures on patients during residency (possibly on off-service rotations), or practice in cadaver and animal labs. objectives: to study the effectiveness of a unique educational intervention using didactic and hands-on training in usgpiv. we hypothesized that senior medical students would improve performance and confidence with usgpiv after the simulation training. methods: fourth year medical students were enrolled in an experimental, prospective, before and after study conducted at a university medical school simulation center. baseline skills in participant's usgpiv on simulation vascular phantoms were graded by ultrasound expert faculty using standardized checklists. the primary outcome was time to cannulation, and secondary outcomes were ability to successfully cannulate, number of needle attempts, and needle-tip visualization. subjects then observed a -minute presentation on correct performance of usgpiv followed by a -minute hands-on practical session using the vascular simulators with a : to : ultrasound instructor to student ratio. an expert blinded to the participant's initial performance graded post-educational intervention usgpiv ability. pre-and post-intervention surveys were obtained to evaluate usgpiv confidence, previous experience with ultrasound, peripheral iv access, usg-piv, and satisfaction with the educational format. objectives: this study examines the grade distribution of resident evaluations when the identity of the evaluator was anonymous as compared to when the identity of the evaluator was known to the resident. we hypothesize that there will be no change in the grades assigned to residents. methods: we retrospectively reviewed all faculty evaluations of residents and grades assigned from july , through november , . prior to july , the identity of the faculty evaluators was anonymous, while after this date, the identity of the faculty evaluators was made known to the residents. throughout this time period, residents were graded on a five-point scale. each resident evaluation included grades in the six acgme core competencies as well as in select other abilities. specific abilities evaluated varied over the dates analyzed. evaluations of residents were assigned to two groups, based on whether the evaluator was anonymous or made known to the resident. grades were compared between the two groups. results: a total of , grades were assigned in the anonymous group, with an average grade of . ( ci . , . ). a total of , grades were assigned in the known group with an average grade of . ( ci . , . ). specific attention was paid to assignment of unsatisfactory grades ( or on the five-point scale). the anonymous group assigned grades in this category, comprising . % of all grades assigned. the known group assigned grades in this category, comprising . % of all grades assigned. unsatisfactory grades were assigned by the anonymous group . % ( ci . , . ) more often. additionally, . % ( ci . , . ) fewer exceptional grades ( or on the five-point scale) were assigned by the anonymous group. conclusion: the average grade assigned was closer to average ( on a five-point scale) when the identity of the evaluator was made known to the residents. additionally, fewer unsatisfactory and exceptional grades were assigned in this group. this decrease of both unsatisfactory and exceptional grades may make it more difficult for program directors to effectively identify struggling and strong residents respectively. testing to improve knowledge retention from traditional didactic presentations: a pilot study david saloum, amish aghera, brian gillett maimonides medical center, brooklyn, ny background: the acgme requires an average of at least hours of planned educational experiences each week for em residents, which traditionally consists of formal lecture based instruction. however, retention by adult learners is limited when presented material in a lecture format. more effective methods such as small group sessions, simulation, and other active learning modalities are time-and resource-intensive and therefore not practical as a primary method of instruction. thus, the traditional lecture format remains heavily relied upon. efficient strategies to improve the effectiveness of lectures are needed. testing utilized as a learning tool to force immediate recall of lecture material is an example of such a strategy. objectives: to evaluate the effect of immediate postlecture short answer quizzes on em residents' retention of lecture content. methods: in this prospective randomized controlled study, em residents from a community based -year training program were randomized into two groups. block randomization provided a similar distribution of postgraduate year training levels and performance on both us-mle and in-training examinations between the two groups. each group received two identical -minute lectures on ecg interpretation and aortic disease. one group of residents completed a five-question short answer quiz immediately following each lecture (n = ), while the other group received the lectures without subsequent quizzes (n = ). the quizzes were not scored or reviewed with the residents. two weeks later, retention was assessed by testing both groups with a -question multiple choice test (mct) derived in equal part from each lecture. mean and median test results were then compared between groups. statistical significance was determined using a paired t-test of median test scores from each group. results: residents who received immediate post-lecture quizzes demonstrated significantly higher mct scores (mean = %, median %, n = ) compared to those receiving lectures alone (mean = %, median = %, n = ); p = . . conclusion: short answer testing immediately after a traditional didactic lecture improves knowledge retention at a -week interval. limitations of the study are that it is a single center study and long term retention was not assessed. background: the task of educating the next generation of physicians is steadily becoming more difficult with the inherent obstacles that exist for faculty educators and the work hour restrictions that students must adhere to. the obstacles make developing curricula that not only cover important topics but also do so in a fashion that helps support and reinforce the clinical experiences very difficult. several areas of medical education are using more asynchronous techniques and self-directed online educational modules to overcome these obstacles. objectives: the aim of this study was to demonstrate that educational information pertaining to core pediatric emergency medicine topics could be as effectively disseminated to medical students via self-directed online educational modules as it could through traditional didactic lectures. methods: this was a prospective study conducted from august , through december , . students participating in the emergency medicine rotation at carolinas medical center were enrolled and received education in a total of eight core concepts. the students were divided into two groups which changed on a monthly basis. group was taught four concepts via self-directed online modules and four traditional didactic lectures. group was taught the same core concepts, but in opposite fashion to group . each student was given a pre-test, post-test, and survey at the conclusion of the rotation. results: a total of students participated in the study. students, regardless of which group assigned, performed similarly on the pre-test, with no statistical difference among scores. when looking at the summative total scores between online and traditional didactic lectures, there was a trend towards significance for more improvement among those taught online. the student's assessment of the online modules showed that the majority either felt neutral or preferred the online method. the majority thought the depth and length of the modules were perfect. most students thought having access to the online modules was valuable and all but one stated that they would use them again. conclusion: this study demonstrates that self-directed, online educational modules are able to convey important concepts in emergency medicine similar to traditional didactics. it is an effective learning technique that offers several advantages to both the educator and student. background: critical access hospitals (cah) provide crucial emergency care to rural populations that would otherwise be without ready access to health care. data show that many cah do not meet standard adult quality metrics. adults treated at cah often have inferior outcomes to comparable patients cared for at other community-based emergency departments (eds). similar data do not exist for pediatric patients. objectives: as part of a pilot project to improve pediatric emergency care at cah, we sought to determine whether these institutions stock the equipment and medications necessary to treat any ill or injured child who presents to the ed. methods: five north carolina cah volunteered to participate in an intensive educational program targeting pediatric emergency care. at the initial site visit to each hospital, an investigator, in conjunction with the ed nurse manager, completed a -item checklist of commonly required ed equipment and medications based on the acep ''guidelines for care of children in the emergency department''. the list was categorized into monitoring and respiratory equipment, vascular access supplies, fracture and trauma management devices, and specialized kits. if available, adult and pediatric sizes were listed. only hospitals stocking appropriate pediatric sizes of an item were counted as having that item. the pharmaceutical supply list included antibiotics, antidotes, antiemetics, antiepileptics, intubation and respiratory medications, iv fluids, and miscellaneous drugs not otherwise categorized. results: overall, the hospitals reported having % of the items listed (range - %). the two greatest deficiencies were fracture devices (range - %), with no hospital stocking infant-sized cervical collars, and antidotes, with no hospital stocking pralidoxime, / hospitals stocking fomepizole, and / hospitals stocking pyridoxine and methylene blue. only one of the five institutions had access to prostaglandin e. the hospitals stated cost and rarity of use as the reason for not stocking these medications. conclusion: the ability of cah to care for pediatric patients does not appear to be hampered by a lack of equipment. ready access to infrequently used, but potentially lifesaving, medications is a concern. tertiary care centers preparing to accept these patients should be aware of these potential limitations as transport decisions are made. background: while incision and drainage (i&d) alone has been the mainstay of management of uncomplicated abscesses for decades, some advocate for adjunct antibiotic use, arguing that available trials are underpowered and that antibiotics reduce treatment failures and recurrence. objectives: to investigate the role of antibiotics in addition to i&d in reducing treatment failure as compared to management with i&d alone. methods: we performed a search using medline, embase, web of knowledge, and google scholar databases (with a medical librarian) to include trials and observational studies analyzing the effect of antibiotics in human subjects with skin and soft-tissue abscesses. two investigators independently reviewed all the records. we performed three overlapping meta-analy-ses: . only randomized trials comparing antibiotics to placebo on improvement of the abscess during standard follow-up. . trials and observational studies comparing appropriate antibiotics to placebo, no antibiotics, or inappropriate antibiotics (as gauged by wound culture) on improvement during standard follow-up. . only trials, but broadened outcome to include recurrence or new lesions during a longer follow-up period as treatment failure. we report pooled risk ratios (rr) using a fixed-effects model for our point estimates with shore-adjusted % confidence intervals (ci). results: we screened , records, of which studies fit inclusion criteria, of which were meta-analyzed ( trials, observational studies) because they reported results that could be pooled. of the studies, enrolled subjects from the ed, from a soft-tissue infection clinic, and from a general hospital without definition of enrollment site. five studies enrolled primarily adults, pediatrics, and without specification of ages. after pooling results for all randomized trials only, the rr = . ( % ci: . - . ). exposure being ''appropriate'' antibiotics (using trials and observational studies) resulted in a pooled rr = . ( % ci: . - . ). when we broadened our treatment failure criteria to include recurrence or new lesions at longer lengths of follow-up (trials only), we noted a rr = . ( % ci: . - . ). conclusion: based on available literature pooled for this analysis, there is no evidence to suggest any benefit from antibiotics in addition to i&d in the treatment of skin and soft tissue abscesses. (originally submitted as a ''late-breaker.'') primary objectives: to compare wound healing and recurrence rates after primary vs. secondary closure of drained abscesses. we hypothesized the percentage of drained ed abscesses that would be completely healed at days would be higher after primary closure. methods: this randomized clinical trial was undertaken in two academic emergency departments. immunocompetent adult patients with simple, localized cutaneous abscesses were randomly assigned to i & d followed by primary or secondary closure. randomization was balanced by center, with an allocation sequence based on a block size of four, generated by a computer random number generator. the primary outcome was percentage of healed wounds seven days after drainage. a sample of patients had % power to detect an absolute difference of % in healing rates assuming a baseline rate of %. all analyses were by intention to treat. results: twenty-seven patients were allocated to primary and to secondary closure, of whom and , respectively, were followed to study completion. healing rates at seven days were similar between the primary and secondary closure groups ( we compared consecutive patients each scanned on the or slice ccta in - . measures and outcomes-data were prospectively collected using standardized data collection forms required prior to performing ccta. the main outcomes were cumulative radiation doses and volumes of intravenous contrast. data analysis-groups compared with t-, mann whitney u, and chi-square tests. results: the mean age of patients imaged with the and scanners were (sd ) vs. ( ) (p = . ). male:female ratios were also similar ( : vs. : respectively, p = . ). both mean (p < . ) and median (p = . ) effective radiation dose were significantly lower with the ( . and msv) vs. the -slice scanner ( . and msv) respectively. prospective gating was successful in % of the scans and only in % of the scans (p < . ). mean iv contrast volumes were also lower for the vs. the -slice scanner ( ± vs. ± ml; p < . ). the % non-diagnostic scans was similarly low in both scanners ( % each). there were no differences in use of beta-blockers or nitrates. conclusion: when compared with the -slice scanner, the -slice scanner reduces the effective radiation doses and iv contrast volumes in ed patients with cp undergoing ccta. need for beta-blockers and nitrates was similar and both scanners achieved excellent diagnostic image quality. background: a few studies have demonstrated that bedside ultrasound measurement of inferior vena cava to aorta (ivc-to-ao) ratio is associated with the level of dehydration in pediatric patients and a proposed cutoff of . has been suggested, below which a patient is considered dehydrated. objectives: we sought to externally validate the ability of ivc-to-ao ratio to discriminate dehydration and the proposed cutoff of . in an urban pediatric emergency department (ed). methods: this was a prospective observational study at an urban pediatric ed. we included patients aged to months with clinical suspicion of dehydration by the ed physician and an equal number of control patients with no clinical suspicion of dehydration. we excluded children who were hemodynamically unstable, had chronic malnutrition or failure to thrive, open abdominal wounds, or were unable to provide patient or parental consent. a validated clinical dehydration score (cds) (range to ) was used to measure initial dehydration status. an experienced sonographer blinded to the cds and not involved in the patient's care measured the ivc-to-ao ratio on the patient prior to any hydration. cds was collapsed into a binary outcome of no dehydration or any level of dehydration ( or higher). the ability of ivc-to-ao ratio to discriminate dehydration was assessed using area under the receiver operating characteristic curve (auc) and the sensitivity and specificity of ivc-to-ao ratio was calculated for three cutoffs ( . , . , . ). calculation of auc was repeated after adjusting for age and sex. results: patients were enrolled, ( %) of whom had a cds of or higher. median age was (interquartile range - ) months, and ( %) were female. the ivcto-ao ratio showed an unadjusted auc of . ( % ci . - . ) and adjusted auc of . ( % ci . - . ). for a cutoff of . sensitivity was % ( % ci %- %) and specificity % ( % ci %- %); for a cutoff of . sensitivity was % ( % ci %- %) and specificity % ( % ci %- %); for a cutoff of . sensitivity was % ( % ci %- %) and specificity % ( % ci %- %). conclusion: the ability of the ivc-to-ao ratio to discriminate dehydration in young pediatric ed patients was modest and the cutoff of . was neither sensitive nor specific. background: while early cardiac computed tomographic angiography (ccta) could be more effective to manage emergency department (ed) patients with acute chest pain and intermediate (> %) risk of acute coronary syndrome (acs) than current management strategies, it also could result in increased testing, cost, and radiation exposure. objectives: the purpose of the study was to determine whether incorporation of ccta early in the ed evaluation process leads to more efficient management and earlier discharge than usual care in patients with acute chest pain at intermediate risk for acs. methods: randomized comparative effectiveness trial enrolling patients between - years of age without known cad, presenting to the ed with chest pain but without ischemic ecg changes or elevated initial troponin and require further risk stratification for decision making, at nine us sites. patients are being randomized to either ccta as the first diagnostic test or to usual care, which could include no testing or functional testing such as exercise ecg, stress spect, and stress echo following serial biomarkers. test results were provided to physicians but management in neither arm was driven by a study protocol. data on time, diagnostic testing, and cost of index hospitalization, and the following days are being collected. the primary endpoint is length of hospital stay (los). the trial is powered to allow for detection of a difference in los of . hours between competing strategies with % power assuming that % of projected los values are true. secondary endpoints are cumulative radiation exposure, and cost of competing strategies. tertiary endpoints are institutional, caregiver, and patient characteristics associated with primary and secondary outcomes. rate of missed acs within days is the safety endpoint. results: as of november st, , of patients have been enrolled (mean age: ± , . % female, acs rate . %). the anticipated completion of the last patient visit is / / and the database will be locked in early march . we will present the results of the primary, secondary, and some tertiary endpoints for the entire cohort. conclusion: romicat ii will provide rigorous data on whether incorporation of ccta early in the ed evaluation process leads to more efficient management and triage than usual care in patients with acute chest pain at intermediate risk for acs. (originally submitted as a ''late-breaker.'') meta background: many studies have documented higher rates of advanced radiography utilization across u.s. emergency departments (eds) in recent years, with an associated decrease in diagnostic yield (positive tests / total tests). provider-to-provider variability in diagnostic yield has not been well studied, nor have the factors that may explain these differences in clinical practice. objectives: we assessed the physician-level predictors of diagnostic yield using advanced radiography to diagnose pulmonary embolus (pe) in the ed, including demographics and d-dimer ordering rates. methods: we conducted a retrospective chart review of all ed patients who had a ct chest or v/q scan ordered to rule out pe from / to / in four hospitals in the medstar health system. attending physicians were included in the study if they had ordered or more scans over the study period. the result of each ct and vq scan was recorded as positive, negative, or indeterminate, and the identity of the ordering physician was also recorded. data on provider sex, residency type (em or other), and year of residency completion were collected. each provider's positive diagnostic yield was calculated, and logistic regression analysis was done to assess correlation between positive scans and provider characteristics. results: during the study period, , scans ( , cts and , v/qs) were ordered by providers. the physicians were an average of . years from residency, % were female, and % were em-trained. diagnostic yield varied significantly among physicians (p < . ), and ranged from % to %. the median diagnostic yield was . % (iqr . %- . %). the use of d-dimer by provider also varied significantly from % to % (p < . ). the odds of a positive test were significantly lower among providers less than years out of residency graduation (or . , ci . - . ) after controlling for provider sex, type of residency training, d-dimer use, and total number of scans ordered. conclusion: we found significant provider variability in diagnostic yield for pe and use of d-dimer in this study population, with % of providers having diagnostic yield less than or equal to . %. providers who were more recently graduated from residency appear to have a lower diagnostic yield, suggesting a more conservative approach in this group. background: the literature reports that anticoagulation increases the risk of mortality in patients presenting to emergency departments (ed) with head trauma (ht). it has been suggested that such patients should be treated in a protocolized fashion, including ct within minutes, and anticipatory preparation of ffp before ct results are available. there are significant logistical and financial implications associated with implementation of such a protocol. objectives: our primary objective was to determine the effect of anticoagulant therapy on the risk of intracranial hemorrhage (ich) in elderly patients presenting to our urban community hospital following bunt head injury. methods: this was a retrospective chart review study of ht patients > years of age presenting to our ed over a -month period. charts reviewed were identified using our electronic medical record via chief complaints and icd- codes and cross referencing with written ct logs. research assistants underwent review of at least % of their contributing data to validate reliability. we collected information regarding use of warfarin, clopidogrel, and aspirin and ct findings of ich. using univariate logistic regression, we calculated odds ratios (or) for ich with % ci. results: we identified elderly ht patients. the mean age of our population was , ( . %) admitted to using anticoagulant therapy, and % were on antiplatelet drugs. ( . %) of the cohort had icb, patients required neurosurgical intervention, and had transfusion of blood products. of the non-anticoagulated patients, ( . %) were found to have ich, half of those ( ) , and mir- ) were measured using real-time quantitative pcr from serum drawn at enrollment. il- , il- , and tnf-a were measured using a bio-plex suspension system. baseline characteristics, il- , il- , tnf-a and micrornas were compared using one way anova or fisher exact test, as appropriate. correlations between mirnas and sofa scores, il- , il- , and tnf-a were determined using spearman's rank. a logistic regression model was constructed using in-hospital mortality as the dependent variable and mirnas as the independent variables of interest. bonferroni adjustments were made for multiple comparisons. results: of patients, were controls, had sepsis, and had septic shock. we found no difference in serum mir- a or mir- between cohorts, and found no association between these micrornas and either inflammatory markers or sofa score. mir- demonstrated a significant correlation with sofa score (q = . , p = . ), il- (q = . , p = . ), but not il- or tnf-a (p = . , p = . ). logistic regression demonstrated mir- to be associated with mortality, even after adjusting for sofa score (p = . ). conclusion: mir- a or mir- failed to demonstrate any diagnostic or prognostic ability in this cohort. mir- was associated with inflammation, increasing severity of illness, and mortality, and may represent a novel prognostic marker for diagnosis and prognosis of sepsis. objectives: to examine the association between emergency physician recognition of sirs and sepsis and subsequent treatment of septic patients. methods: a retrospective cohort study of all-age patient medical records with positive blood cultures drawn in the emergency department from / - / at a level i trauma center. patient parameters were reviewed including vital signs, mental status, imaging, and laboratory data. criteria for sirs, sepsis, severe sepsis, and septic shock were applied according to established guidelines for pediatrics and adults. these data were compared to physician differential diagnosis documentation. the mann-whitney test was used to compare time to antibiotic administration and total volume of fluid resuscitation between two groups of patients: those with recognized sepsis and those with unrecognized sepsis. results: sirs criteria were present in / reviewed cases. sepsis criteria were identified in / cases and considered in the differential diagnosis in / septic patients. severe sepsis was present in / cases and septic shock was present in / cases. the sepsis -hour resuscitation bundle was completed in the emergency department in cases of severe sepsis or septic shock. patients who met sepsis criteria and were recognized by the ed physician had a median time to antibiotics of minutes (iqr: - ) and a median ivf of ml (iqr: - ). the patients who met sepsis criteria but went unrecognized in the documentation had a median time to antibiotics of minutes (iqr: - ) and median volume of fluid resuscitation of ml (iqr: . median time to antibiotics and median volume of fluid resuscitation differed significantly between recognized and unrecognized septic patients (p = . and p = . , respectively). conclusion: emergency physicians correctly identify and treat infection in most cases, but frequently do not document sirs and sepsis. lack of documentation of sepsis in the differential diagnosis is associated with increased time to antibiotic delivery and a smaller total volume of fluid administration, which may explain poor sepsis bundle compliance in the emergency department. background: severe sepsis is a common clinical syndrome with substantial human and financial impact. in the first consensus definition of sepsis was published. subsequent epidemiologic estimates were collected using administrative data, but ongoing discrepancies in the definition of severe sepsis led to large differences in estimates. objectives: we seek to describe the variations in incidence and mortality of severe sepsis in the us using four methods of database abstraction. methods: using a nationally representative sample, four previously published methods (angus, martin, dombrovskiy, wang) were used to gather cases of severe sepsis over a -year period ( ) ( ) ( ) ( ) ( ) ( ) . in addition, the use of new icd- sepsis codes was compared to previous methods. our main outcome measure was annual national incidence and in-hospital mortality of severe sepsis. results: the average annual incidence varied by as much as . fold depending on method used and ranged from , ( / , population) to , , ( , / , ) using the methods of dombrovskiy and wang, respectively. average annual increase in the incidence of severe sepsis was similar ( . - . %) across all methods. total mortality mirrored the increase in incidence over the -year period ( background: radiation exposure from medical imaging has been the subject of many major journal articles, as well as the topic of mainstream media. some estimate that one-third of all ct scans are not medically justified. it is important for practitioners ordering these scans to be knowledgeable of currently discussed risks. objectives: to compare the knowledge, opinions, and practice patterns of three groups of providers in regards to cts in the ed. methods: an anonymous electronic survey was sent to all residents, physician assistants, and attending physicians in emergency medicine (em), surgery, and internal medicine (im) at a single academic tertiary care referral level i trauma center with an annual ed volume of over , visits. the survey was pilot tested and validated. all data were analyzed using the pearson's chi-square test. results: there was a response rate of % ( / ). data from surgery respondents were excluded due to a low response rate. in comparison to im, em respondents correctly equated one abdominal ct to between and chest x-rays, reported receiving formal training regarding the risks of radiation from cts, believe that excessive medical imaging is associated with an increased lifetime risk of cancer, and routinely discuss the risks of ct imaging with stable patients more often (see table ). particular patient factors influence whether radiation risks are discussed with patients by % in each specialty (see table ). before ordering an abdominal ct in a stable patient, im providers routinely review the patient's medical imaging history less often than em providers surveyed. overall, % of respondents felt that ordering an abdominal ct in a stable ed patient is a clinical decision that should be discussed with the patient, but should not require consent. conclusion: compared with im, em practitioners report greater awareness of the risks of radiation from cts and discuss risks with patients more often. they also review patients' imaging history more often and take this, as well as patients' age, into account when ordering cts. these results indicate a need for improved education for both em and im providers in regards to the risks of radiation from ct imaging. background: in nebraska, % of emergency departments have annual visits less than , , and the predominance are in rural settings. general practitioners working in rural emergency departments have reported low confidence in several emergency medicine skills. current staffing patterns include using midlevels as the primary provider with non-emergency medicine trained physicians as back-up. lightly-embalmed cadaver labs are used for resident's procedural training. objectives: to describe the effect of a lightlyembalmed cadaver workshop on physician assistants' (pa) reported level of confidence in selected emergency medicine procedures. methods: an emergency medicine procedure lab was offered at the nebraska association of physician assistants annual conference. each lab consisted of a -hour hands-on session teaching endotracheal intubation techniques, tube thoracostomy, intraosseous access, and arthrocentesis of the knee, shoulder, ankle, and wrist to pas. irb-approved surveys were distributed pre-lab and a post-lab survey was distributed after lab completion. baseline demographic experience was collected. pre-and post-lab procedural confidence was rated on a six-point likert scale ( - ) with representing no confidence. the wilcoxon signed-rank test was use to calculate p values. results: pas participated in the course. all completed a pre-and post-lab assessment. no pa had done any one procedure more than times in their career. pre-lab modes of confidence level were £ for each procedure. post-lab modes were > for each procedure except arthrocentesis of the ankle and wrist. however, post lab assessments of procedural confidence significantly improved for all procedures with p values < . . conclusion: midlevel providers' level of confidence improved for emergent procedures after completion of a procedure lab using lightly-embalmed cadavers. a mobile cadaver lab would be beneficial to train rural providers with minimal experience. background: use of automated external defibrillators (aed) improves survival in out-of-hospital cardiopulmonary arrest (ohca). since , the american heart association has recommended that individuals one year of age or older who sustain ohca have an aed applied. little is known about how often this occurs and what factors are associated with aed use in the pediatric population. objectives: our objective was to describe aed use in the pediatric population and to assess predictors of aed use when compared to adult patients. methods: we conducted a secondary analysis of prospectively collected data from u.s. cities that participate in the cardiac arrest registry to enhance survival (cares). patients were included if they had a documented resuscitation attempt from october , through december , and were ‡ year old. patients were considered pediatric if they were less than years old. aed use included application by laypersons and first responders. hierarchical multivariable logistic regression analysis was used to estimate the associations between age and aed use. results: there were , ohcas included in this analysis, of which ( . %) occurred in pediatric patients. overall aed use in the final sample was , , with , ( . %) total survivors. aeds were applied less often in pediatric patients ( . %, % ci: . %- . % vs . %, % ci: . %- . %). within the pediatric population, only . % of patients with a shockable rhythm had an aed used. in all pediatric patients, regardless of presenting rhythm, aed use demonstrated a statistically significant increase in return of spontaneous circulation (aed used . %, % ci: . - . vs aed not used . %, % ci: . - . , p < . ), although there was no significant increase in survival to hospital discharge (aed used . %; aed not used . %; p = . ). in the adjusted model, pediatric age was independently associated with failure to use an aed (or . , % ci: . - . ) as was female sex (or . , % ci: . - . ). patients who had a public arrest (or . , % ci: . - . ) or one that was witnessed by a bystander (or . . %: ci . - . ) were also predictive of aed use. conclusion: pediatric patients who experience ohca are less likely to have an aed used. continued education of first responders and the lay public to increase aed use in this population is necessary. does implementation of a therapeutic hypothermia protocol improve survival and neurologic outcomes in all comatose survivors of sudden cardiac arrest? ken will, michael nelson, abishek vedavalli, renaud gueret, john bailitz cook county (stroger), chicago, il background: the american heart association (aha) currently recommends therapeutic hypothermia (th) for out of hospital comatose survivors of sudden cardiac arrest (cssca) with an initial rhythm of ventricular fibrillation (vf). based on currently limited data, the aha further recommends that physicians consider th for cssca, from both the out and inpatient settings, with an initial non-vf rhythm. objectives: investigate whether a th protocol improves both survival and neurologic outcomes for cssca, for out and inpatients, with any initial rhythm, in comparison to outcomes previously reported in literature prior to th. methods: we conducted a prospective observational study of cssca between august and may whose care included th. the study enrolled eligible consecutive cssca survivors, from both out and inpatient settings with any initial arrest rhythm. primary endpoints included survival to hospital discharge and neurologic outcomes, stratified by sca location, and by initial arrest rhythm. results: overall, of eligible patients, ( %, % ci - %) survived to discharge, ( %, % ci - %) with at least a good neurologic outcome. twelve were out and were inpatients. among the outpatients, ( %, % ci - %) survived to discharge, ( %, % ci - %) with at least a good neurologic outcome. among the inpatients, ( %, % ci - ) survived to discharge, ( %, % ci - %) with at least a good neurologic outcome. by initial rhythm, patients had an initial rhythm of vf/t and non-vf/t. among the patients with an initial rhythm of vf/t, ( %, ci - %) survived to discharge, all with at least a good outcome, including out and inpatients. among the patients with an initial rhythm of non-vf/t, ( %, ci - %) survived to discharge, ( %, ci - %) with at least a good neurologic outcome, including out and inpatients. conclusion: our preliminary data initially suggest that local implementation of a th protocol improves survival and neurologic outcomes for cssca, for out and inpatients, with any initial rhythm, in comparison to outcomes previously reported in literature prior to th. subsequent research will include comparison to local historical controls, additional data from other regional th centers, as well as comparison of different cooling methods. protocolized background: therapeutic hypothermia (th) has been shown to improve the neurologic recovery of cardiac arrest patients who experience return of spontaneous circulation (rosc). it remains unclear as to how earlier cooling and treatment optimization influence outcomes. objectives: to evaluate the effects of a protocolized use of early sedation and paralysis on cooling optimization and clinical outcomes in survivors of cardiac arrest. methods: a -year ( - ), pre-post intervention study of patients with rosc after cardiac arrest treated with th was performed. those patients treated with a standardized order set which lacked a uniform sedation and paralytic order were included in the pre-intervention group, and those with a standardized order set which included a uniform sedation and paralytic order were included in the post-intervention group. patient demographics, initial and discharge glasgow coma scale (gcs) scores, resuscitation details, cooling time variables, severity of illness as measured by the apache ii score, discharge disposition, functional status, and days to death were collected and analyzed using student's t-tests, man-whitney u tests, and the log-rank test. results: patients treated with th after rosc were included, with patients in the pre-intervention group and in the post-intervention group. the average time to goal temperature ( °c) was minutes (pre-intervention) and minutes (post-intervention) (p = . ). a -hour time target was achieved in . % of the patients (post-intervention) compared to . % in the pre-group (p = . ). twenty-eight day mortality was similar between groups ( . % and . %) though hospital length of stay ( days pre-and days post-intervention) and discharge gcs ( preand -post-intervention) differed between cohorts. more post-intervention patients were discharged to home ( . %) compared to . % in the pre-intervention group. conclusion: protocolized use of sedation and paralysis improved time to goal temperature achievement. these improved th time targets were associated with improved neuroprotection, gcs recovery, and disposition outcome. standardized sedation and paralysis appears to be a useful adjunct in induced th. background: ct is increasingly used to assess children with signs and symptoms of acute appendicitis (aa) though concerns regarding long-term risk of exposure to ionizing radiation have generated interest in methods to identify children at low risk. objectives: we sought to derive a clinical decision rule (cdr) of a minimum set of commonly used signs and symptoms from prior studies to predict which children with acute abdominal pain have a low likelihood of aa and compared it to physician clinical impression (pci). methods: we prospectively analyzed subjects aged to years in u.s. emergency departments with abdominal pain plus signs and symptoms suspicious for aa within the prior hours. subjects were assessed by study staff unaware of their diagnosis for clinical attributes drawn from published appendicitis scoring systems and physicians responsible for physical examination estimated the probability of aa based on pci prior to their medical disposition. based on medical record entry rate, frequently used cdr attributes were evaluated using recursive partitioning and logistic regression to select the best minimum set capable of discriminating subjects with and without aa. subjects were followed to determine whether imaging was used and use was tabulated by both pci and the cdr to assess their ability to identify patients who did or did not benefit based on diagnosis. results: this cohort had a . % prevalence ( / subjects) of aa. we derived a cdr based on the absence of two out of three of the following attributes: abdominal tenderness, pain migration, and rigidity/ guarding had a sensitivity of . % ( % ci: . - . ), specificity of . % ( % ci: . - . ), npv of . % ( % ci: . - . ), and negative likelihood ratio of . ( % ci: . - . ). the pci set at aa < % pre-test probability had a sensitivity of . % ( % ci: . - . ), specificity of . % ( % ci: . - . ), npv of . % ( % ci: . - . ), and negative likelihood ratio of . ( % ci: . - . ). the methods each classified % of the patients as low risk for aa. our cdr identified . % ( / ) of low risk subjects who received ct but being aa (-), could have been spared ct, while the pci identified . % ( / ). conclusion: compared to physician clinical impression, our clinical decision rule can identify more children at low risk for appendicitis who could be managed more conservatively with careful observation and avoidance of ct. negative background: abdominal pain is the most common complaint in the ed and appendicitis is the most common indication for emergency surgery. a clinical decision rule (cdr) identifying abdominal pain patients at a low risk for appendicitis could lead to a significant reduction in ct scans and could have a significant public health impact. the alvarado score is one of the most widely applied cdrs for suspected appendicitis, and a low modified alvarado score (less than ) is sometimes used to rule out acute appendicitis. the modified alvarado score has not been prospectively validated in ed patients with suspected appendicitis. objectives: we sought to prospectively evaluate the negative predictive value of a low modified alvarado score (mas) in ed patients with suspected appendicitis. we hypothesized that a low mas (less than ) would have a sufficiently high npv (> %) to rule out acute appendicitis. methods: we enrolled patients greater than or equal to years old who were suspected of having appendicitis (listed as one of the top three diagnosis by the treating physician before ancillary testing) as part of a prospective cohort study in two urban academic eds from august to april . elements of the mas and the final diagnosis were recorded on a standard data form for each subject. the sensitivity, specificity, negative predictive value (npv), and positive predictive value (ppv) were calculated with % ci for a low mas and final diagnosis of appendicitis. background: evaluating children for appendicitis is difficult and strategies have been sought to improve the precision of the diagnosis. computed tomography is now widely used but remains controversial due to the large dose of ionizing radiation and risk of subsequent radiation-induced malignancy. objectives: we sought to identify a biomarker panel for use in ruling out pediatric acute appendicitis as a means of reducing exposure to ionizing radiation. methods: we prospectively enrolled subjects aged to years presenting in u.s. emergency departments with abdominal pain and other signs and symptoms suspicious for acute appendicitis within the prior hours. subjects were assessed by study staff unaware of their diagnosis for clinical attributes drawn from appendicitis scoring systems and blood samples were analyzed for cbc differential and candidate proteins. based on discharge diagnosis or post-surgical pathology, the cohort exhibited a . % prevalence ( / subjects) of appendicitis. clinical attributes and biomarker values were evaluated using principal component, recursive partitioning, and logistic regression to select the combination that best discriminated between those subjects with and without disease. mathematical combination of three inflammation-related markers in a panel comprised of myeloid-related protein / complex (mrp), c-reactive protein (crp), and white blood cell count (wbc) provided optimal discrimination. results: this panel exhibited a sensitivity of % ( % ci, - %), a specificity of % ( % ci, - %), and a negative predictive value of % ( % ci, - %) in this cohort. the observed performance was then verified by testing the panel against a pediatric subset drawn from an independent cohort of all ages enrolled in an earlier study. in this cohort, the panel exhibited a sensitivity of % ( % ci, - %), a specificity of % ( % ci, - %), and a negative predictive value of % ( % ci, - %). conclusion: appyscore is highly predictive of the absence of acute appendicitis in these two cohorts. if these results are confirmed by a prospective evaluation currently underway, the appyscore panel may be useful to classify pediatric patients presenting to the emergency department with signs and symptoms suggestive of, or consistent with, acute appendicitis and thereby sparing many patients ionizing radiation. background: there are no current studies on the tracking of emergency department (ed) patient dispersal when a major ed closes. this study demonstrates a novel way to track where patients sought emergency care following the closure of saint vincent's catholic medical center (svcmc) in manhattan by using de-identified data from a health information exchange, the new york clinical information exchange (nyclix). nyclix matches patients who have visited multiple sites using their demographic information. on april , , svcmc officially stopped providing emergency and outpatient services. we report the patterns in which patients from svcmc visited other sites within nyclix. objectives: we hypothesize that patients often seek emergency care based on geography when a hospital closes. methods: a retrospective pre-and post-closure analysis was performed of svcmc patients visiting other hospital sites. the pre-closure study dates were january , -march , . the post closure study dates were may , -july , . a svcmc patient was defined as a patient with any svcmc encounter prior to its closure. using de-identified aggregate count data, we calculated the average number of visits per week by svcmc patients at each site (hospital a-h). we ran a paired t-test to compare the pre-and post-closure averages by site. the following specifications were used to write the database queries: of patients who had one or more prior visits to svcmc for each day within the study return the following: a. eid: a unique and meaningless proprietary id generated within the nyclix master patient index (mpi). b. age: thru the age of . persons over were listed as '' + '' c. ethnicity/race d. type of visit: emergency e. location of visit: specific nyclix site. results: nearby hospitals within miles saw the highest number of increased ed visits after svcmc closed. this increase was seen until about miles. hospitals > miles away did not see any significant changes in ed visits. see table. conclusion: when a hospital and its ed close down, patients seem to seek emergency care at the nearest hospital based on geography. other factors may include the patient's primary doctor, availabilities of outpatient specialty clinics, insurance contracts, or preference of ambulance transports. this study is limited by the inclusion of data from only the eight hospitals participating in nyclix at the time of the svcmc closure. upstream methods: data were collected on all ed ems arrivals from the metro calgary (population . million) area to its three urban adult hospitals. the study phases consisted of the months from february to october (pre-ocp) compared against the same months in (post-ocp). data from the ems operational database and the regional emergency department information system (redis) database were linked. the primary analysis examined the change in ems offload delay defined as the time from ems triage arrival until patient transfer to an ed bed. a secondary analysis evaluated variability in ems offload delay between receiving eds. conclusion: implementation of a regional overcapacity protocol to reduce ed crowding was associated with an important reduction in ems offload delay, suggesting that policies that target hospital processes have bearing on ems operations. variability in offload delay improvements is likely due to site-specific issues, and the gains in efficiency correlate inversely with acuity. methods: a pre-post intervention study was conducted in the ed of an adult university teaching hospital in montreal (annual visits = ). the raz unit (intervention), created to offload the acu of the main ed, started operating in january, . using a split flow management strategy, patients were directed to the raz unit based on patient acuity level (ctas code and certain code ), likelihood to be discharged within hours, and not requiring an ed bed for continued care. data were collected weekdays from : to : for months (september -december ) (pre-raz) and for . months (february -march ) (post-raz). in the acu of the main ed, research assistants observed and recorded cubicle access time, and nurse and physician assessment times. databases were used to extract socio-demographics, ambulance arrival, triage code, chief complaint, triage and registration time, length of stay, and ed occupancy. background: telephone follow-up after discharge from the ed is useful for treatment and quality assurance purposes. ed follow-up studies frequently do not achieve high (i.e. ‡ %) completion rates. objectives: to determine the influence of different factors on the telephone follow-up rate of ed patients. we hypothesized that with a rigorous follow-up system we could achieve a high follow-up rate in a socioeconomically diverse study population. methods: research assistants (ras) prospectively enrolled adult ed patients discharged with a medication prescription between november , and september , from one of three eds affiliated with one health care system: (a) academic level i trauma center, (b) community teaching affiliate, and (c) community hospital. patients unable to provide informed consent, non-english speaking, or previously enrolled were excluded. ras interviewed subjects prior to ed discharge and conducted a telephone follow-up interview week later. follow-up procedures were standardized (e.g. number of calls per day, times to place calls, obtaining alternative numbers) and each subject's follow-up status was monitored and updated daily through a shared, web-based data system. subjects who completed follow-up were mailed a $ gift card. we examined the influence of patient (age, sex, race, insurance, income, marital status, usual major activity, education, literacy level, health status), clinical (acuity, discharge diagnosis, ed length of stay, site), and procedural factors (number and type of phone numbers received from subjects, offering two gift cards for difficult to reach subjects) on the odds of successful followup using multivariate logistic regression. results: of the , enrolled, % were white, % were covered by medicaid or uninsured, and % reported an annual household income of <$ , . % completed telephone follow-up with % completing on the first attempt. the table displays the factors associated with successful follow-up. in addition to patient demographics and lower acuity, obtaining a cell phone or multiple phone numbers as well as offering two gift cards to a small number of subjects increased the odds of successful follow-up. conclusion: with a rigorous follow-up system and a small monetary incentive, a high telephone follow-up rate is achievable one week after an ed visit. methods: an interrupted time-series design was used to evaluate the study question. data regarding adherence with the following pneumonia core measures were collected pre-and post-implementation of the enhanced decision-support tool: blood cultures prior to antibiotic, antibiotic within hours of arrival, appropriate antibiotic selection, and mean time to antibiotic administration. prescribing clinicians were educated on the use of the decision-support tool at departmental meetings and via direct feedback on their cases. results: during the -month study period, complete data were collected for patients diagnosed with cap: in the pre-implementation phase and post-implementation. the mean time to antibiotic administration decreased by approximately one minute from the pre-to post-implementation phase, a change that was not statistically significant (p = . ). the proportion of patients receiving blood cultures prior to antibiotics improved significantly (p < . ) as did the proportion of patients receiving antibiotics within hours of ed arrival (p = . ). a significant improvement in appropriate antibiotic selection was noted with % of patients experiencing appropriate selection in the post-phase, p = . . use of the available support tool increased throughout the study period, v = . , df = , p < . . all improvements were maintained months following the study intervention. conclusion: in this academic ed, introduction of an enhanced electronic clinical decision support tool significantly improved adherence to cms pneumonia core measures. the proportion of patients receiving blood cultures prior to antibiotics, antibiotics within hours, and appropriate antibiotics all improved significantly after the introduction of an enhanced electronic clinical decision support tool. background: emergency medicine (em) residency graduates need to pass both the written qualifying exam and oral certification exam as the final benchmark to achieve board certification. the purpose of this project is to obtain information about the exam preparation habits of recent em graduates to allow current residents to make informed decisions about their individual preparation for the abem written qualifying and oral certification exams. objectives: the study sought to determine the amount of residency and individual preparation, to determine the extent of the use of various board review products, and to elicit evaluations of the various board review products used for the abem qualifying and certification exams. methods: design: an online survey instrument was used to ask respondents questions about residency preparation and individual preparation habits, as well as the types of board review products used in preparing for the em boards. participants: as greater than % of all em graduates are emra members, an online survey was sent to all emra members who have graduated for the past three years. observations: descriptive statistics of types of preparation, types of resources, time, and quantitative and qualitative ratings for the various board preparation products were obtained from respondents. results: a total of respondents spent an average of . weeks and hours per week preparing for the written qualifying exam and spent an average of weeks and . hours per week preparing for the oral certification exam. in preparing for the written qualification exam, % used a preparation textbook with % using more than one textbook and % using a board preparation course. in preparing for the oral qualifying exam, % used a preparation textbook while % used a preparation course. sixty-seven percent of respondents reported that their residency programs had a formalized written qualifying exam preparation curriculum of which % was centered on the annual in-training exam. eight-five percent of residency programs had a formalized oral certification exam preparation. respondents reported spending on average $ preparing for the qualifying exam and $ for the certification exam. conclusion: em residents spend significant amounts of time and money and make use of a wide range of residency and commercially available resources in preparing for the abem qualifying and certification exams. background: communication and professionalism skills are essential for em residents but are not wellmeasured by selection processes. the multiple mini-interview (mmi) uses multiple, short structured contacts to measure these skills. it predicts medical school success better than the interview and application. its acceptability and utility in em residency selection is unknown. objectives: we theorized that the mmi would provide novel information and be acceptable to participants. methods: interns from three programs in the first month of training completed an eight-station mmi developed to focus on em topics. pre-and post-surveys assessed reactions using five-point scales. mmi scores were compared to application data. results: em grades correlated with mmi performance (f( . ) = : , p < . ) with honors students having higher mmi summary scores. higher third year clerkship grades trended to higher mmi performance means, although not significantly. mmi performance did not correlate with a match desirability rating and did not predict other individual components of the application including usmle step or usmle step . participants preferred a traditional interview (mean difference = . , p < . ). a mixed format was preferred over a pure mmi (mean difference = . , p < . ). preference for a mixed format was similar to a traditional interview. mmi performance did not significantly correlate with preference for the mmi; however, there was a trend for higher performance to associate with higher preference (r = . , t( ) = . , n.s.) performance was not associated with preference for a mix of interview methods (r = . , t( ) = . , n.s.). conclusion: while the mmi alone was viewed less favorably than a traditional interview, participants were receptive to a mixed methods interview. the mmi appears to measure skills important in successful completion of an em clerkship and thus likely em residency. future work will determine whether mmi performance correlates with clinical performance during residency. background: the annual american board of emergency medicine (abem) in-training exam is a tool to assess resident progress and knowledge. when the new york-presbyterian (nyp) em residency program started in , the exam was not emphasized and resident performance was lower than expected. a course was implemented to improve residency-wide scores despite previous em literature failing to exhibit improvements with residency-sponsored in-training exam interventions. objectives: to evaluate the effect of a comprehensive, multi-faceted course on residency-wide in-training exam performance. methods: the nyp em residency program, associated with cornell and columbia medical schools, has a year format with - residents per year. an intensive -week in-training exam preparation program was instituted outside of the required weekly residency conferences. the program included lectures, pre-tests, high-yield study sheets, and remediation programs. lectures were interactive, utilizing an audience response system, and consisted of core lectures ( - . hours) and three review sessions. residents with previous in-training exam difficulty were counseled on designing their own study programs. the effect on intraining exam scores was measured by comparing each resident's score to the national mean for their postgraduate year (pgy). scores before and after course implementation were evaluated by repeat measures regression modeling. overall residency performance was evaluated by comparing residency average to the national average each year and by tracking abem national written examination pass rates. results: resident performance improved following course implementation. following the course's introduction, the odds of a resident beating the national mean increased by . ( % ci . - . ) and the percentage of residents exceeding the national mean for their pgy year increased by % ( % ci %- %). following course introduction, the overall residency mean score has outperformed the national exam mean annually and the first-time abem written exam board pass rate has been %. conclusion: a multi-faceted in-training exam program centered around a -week course markedly improved overall residency performance on the in-training exam. limitations: this was a before and after evaluation as randomizing residents to receive the course was not logistically or ethically feasible. . years of practice. among the nonresidency trained, non-boarded em physicians, the percentage of individuals with board actions against them was significantly higher ( . % vs. . %, % ci for difference of . % = . to . %), but the incidence of actions was not significant ( . vs. . events/ years of practice, % ci for difference of . / = ) / to + / ), but the power to detect a difference was %. conclusion: in this study population, em-trained physicians had significantly fewer total state medical board disciplinary actions against them than non-em trained physicians, but when adjusted for years of practice (incidence), the difference was not significantly different at the % confidence level. the study was limited by low power to detect a difference in incidence. objectives: we chose pain documentation as a long term project for quality improvement in our ems system. our objectives were to enhance the quality of pain assessment, to reduce patient suffering and pain through improved pain management, to improve pain assessment documentation, to improve capture of initial and repeat pain scales, and to improve the rate of pain medication. this study addressed the aim of improving pain assessment documentation. methods: this was a quasi-experiment looking at paramedic documentation of the pqrst mnemonic and pain scales. our intervention consisted of mandatory training on the importance and necessity of pain assessment and treatment. in addition to classroom training, we used rapid cycle individual feedback and public posting of pain documentation rates (with unique ids) for individual feedback. the categories of chief complaint studied were abdominal pain, blunt injury, burn, chest pain, headache, non-traumatic body pain, and penetrating injury. we compared the pain documentation rates in the months prior to intervention, the months of intervention, and months post intervention. using repeated-measures anova, we compared rates of paramedic documentation over time. results: our ems system transported patients during the study period, of whom were for painful conditions in the defined chief complaint categories. there were paramedics studied, of whom had complete data. documentation increased from of painful cases ( . %) in qtr to of painful cases ( . %) in qtr . the trend toward increased rates of pain documentation over the three quarters was strongly significant (p < . ). paramedics were significantly more likely to document pain scales and pqrst assessments over the course of the study with the highest rates of documentation compliance in the final -month period. conclusion: a focused intervention of education and individual feedback through classroom training, one on one training, and public posting improves paramedic documentation rates of perceived patient pain. background: emergency medical services (ems) systems are vital in the identification, assessment, and treatment of trauma, stroke, myocardial infarction, and sepsis and improving early recognition, resuscitation, and transport to adequate medical facilities. ems personnel provide similar first-line care for patients with syncope, performing critical actions such as initial assessment and treatment as well as gathering key details of the event. objectives: to characterize emergency department patients with syncope receiving initial care by ems and their role as initial providers. methods: we prospectively enrolled patients over years of age who presented with syncope or near syncope to a tertiary care ed with , annual patient visits from june to june . we compared patient age, sex, comorbidities, and -day cardiopulmonary adverse outcomes (defined as myocardial infarction, pulmonary embolism, significant cardiac arrhythmia, and major cardiovascular procedure) between ems and non-ems patients. descriptive statistics, two-sided ttests, and chi-square testing were used as appropriate. results: of the patients enrolled, ( . %) arrived by ambulance. the most common complaint in patients transported by ems was fainting ( . %) or dizziness ( . %); syncope was reported in ( . %). compared to non-ems patients, those who arrived by ambulance were older (mean age (sd) . ( . ), vs. . ( . ) years, p = . ). there were no differences in the proportion of patients with hypertension ( . % vs . %, p = . ), coronary artery disease ( . % vs . %, p = . ), diabetes mellitus ( . % vs . %, p = . ), or congestive heart failure ( . % vs . %, p = . ). sixtynine ( . %) patients experienced a cardiopulmonary event within days. twenty-eight ( . %) patients who arrived by ambulance and ( . %) non-ems patients had a subsequent cardiopulmonary adverse event (rr . , %ci . - . ) within days. the table tabulates interventions provided by ems prior to ed arrival. conclusion: ems providers care for more than one third of ed syncope patients and often perform key interventions. ems systems offer opportunities for advancing diagnosis, treatment, and risk stratification in syncope patients. background: abdominal pain is the most common reason for visiting an emergency department (ed), and abdominopelvic computed tomography (apct) use has increased dramatically over the past decade. despite this, there has been no significant change in rates of admission or diagnosis of surgical conditions. objectives: to assess whether an electronic accountability tool affects apct ordering in ed patients with abdominal or flank pain. we hypothesized that implementation of an accountability tool would decrease apct ordering in these patients. methods: before and after study design using an electronic medical record at an urban academic ed from jul-nov , with the electronic accountability tool implemented in oct for any apct order. inclusion criteria: age >= years, non-pregnant, and chief complaint or triage pain location of abdominal or flank pain. starting oct th , , resident attempts to order apct triggered an electronic accountability tool which only allowed the order to proceed if approved by the ed attending physician. the attending was prompted to enter the primary and secondary diagnoses indicating apct, agreement with need for ct and, if no agreement, who was requesting this ct (admitting or consulting physician), and their pretest probability ( - ) of the primary diagnosis. patients were placed into two groups: those who presented prior to (pre) and after (post) the deployment of the accountability tool. background: there has been a paradigm shift in the diagnostic work-up for suspected appendicitis. edbased staged protocols call for the use of ultrasound prior to ct scanning because of its lack of radiation, and the morbidity related to contrast. a barrier to implementation is the lack of / availability of ultrasound. objectives: to evaluate the impact of the implementation of ed performed appendix ultrasounds (apus) on ct utilization in the staged workup for appendicitis in the emergency department. methods: we performed a quasi-experimental, before/ after study. we compared data from the first months of , before the availability of ed performed apus, with the same interval in after introduction of ed apus. we excluded patients who had appendectomies for reasons other than appendicitis or had been diagnosed prior to arrival. no patient identifiers were included in the analysis and the study was approved by the hospital irb. we report the following descriptive statistics (percentages, sensitivities, and absolute utilization changes conclusion: implementation of an ed apus in the staging work up of appendicitis was associated with a significant reduction in overall ct utilization in the ed. objectives: this study aims to evaluate ed patients' knowledge of radiation exposure from ct and mri scans as well as the long-term risk of developing cancer. we hypothesize that ed patients will have a poor understanding of the risks, and will not know the difference between ct and mri. methods: design -this was a cross-sectional survey study of adult, english-speaking patients at two eds from / / - / / . setting -one location was a tertiary care center with an annual ed census of , patient visits and the other was a community hospital with annual ed census of , patient visits. obser-vations -the survey consisted of six questions evaluating patients' understanding of radiation exposure from ct and mri as well as long-term consequences of radiation exposure. patients were then asked their age, sex, race, highest level of education, annual household income, and whether they considered themselves health care professionals. results: there were participants in this study, (of , total) from the academic center and (of , total) from the community hospital during the study period. overall, only % ( % ci - %) of participants understood the radiation risks associated with ct scanning. % ( % ci - %) of patients believed that an abdominal ct had the same or less radiation as a chest x-ray. % ( % ci - %) believed that there was an increased risk of developing cancer from repeated abdominal cts. only % ( % ci - %) of patients knew that mri scans had less radiation than ct. % ( % ci - %) either didn't know or believed that repeated mris were associated with an increased risk of developing cancer. higher educational level, household income, and identification as a health care professional all were associated with correct responses, but even within these groups, a majority gave incorrect responses. conclusion: in general, ed patients do not understand the radiation risks associated with advanced imaging modalities. we need to educate these patients so that they can make informed decisions about their own health care. background: homelessness has been associated with many poor health outcomes and frequent ed utilization. it has been shown that frequent use of the ed in any given year is not a strong predictor of subsequent use. identifying a group of patients who are chronic high users of the ed could help guide intervention. objectives: the purpose of this study is to identify if homelessness is associated with chronic ed utilization. methods: a retrospective chart review was accomplished looking at the records of the most frequently seen patients in the ed for each year from - at a large, urban academic hospital with an annual volume of , . patients' visit dates, chief complaints, dispositions, and housing status were reviewed. homelessness was defined by self-report at registration. patients were categorized according to their ed utilization with those seen > times in at least three of the five years of the study identified as chronic high utilizers; and those who visited the ed > times in at least three of the five years of the study were identified as chronic ultra-high utilizers. descriptive statistics with confidence intervals were calculated, and comparisons were made using non-parametric tests. results: during the -year study period, , unique patients were seen, of whom . % patients were homeless. patients were identified as frequent users. there were patients who presented on the top utilizer lists from multiple years. ( %, %ci - ) patients were identified as homeless. patients were seen > times in at least three of the years and ( %, - ) were homeless. patients were seen > times in at least three of the years and ( %, - ) were homeless. our facility has a % admission rate; however, non homeless chronic ultra-high utilizers had admission rates of % and homeless chronic ultra-high utilizers were admitted %. conclusion: chronic ultra-high utilizers of our ed are disproportionately homeless and present with lower severity of illness. these patients may prove to be a cost-effective group to house or otherwise involve with aggressive case management. the debate over homeless housing programs and case management solutions can be sharpened by better defining the groups who would most benefit and who represent the greatest potential saving for the health system. background: the prevalence of obese patients presenting to our emergency department (ed) is %: obese patients present in disproportionate number compared to the general population (us rate = %). in spite of this, there is a disconnect in patients' perceptions of weight and health: many patients underestimate their weight and report a key barrier to weight loss is patient-provider communications; such discussions have proven to be highly effective in smoking, drug, and alcohol cessation, an important initial step toward promoting wellness. information about patient provider communication is essential for designing and implementing emergency department (ed) based interventions to help increase patient awareness about weightrelated medical issues and provide counseling for weight reduction. objectives: we assessed patients' perceptions about obesity as disease and patient communication with their providers through two questions: do you believe your present weight is damaging to your health? has a doctor or other health professional every told you that you are overweight? methods: a descriptive cross-sectional study was performed in an academic tertiary care ed. a randomized sample of patients (every fifth) presenting to the ed (n = ) was enrolled. pregnant patients, patients who were medically unstable, cognitively impaired, or who were unable or unwilling to provide informed consent were excluded. percentages of ''yes'' and ''no'' are reported for each question based on patient bmi, ethnicity, sex, and the number of comorbid conditions. regression analysis was used to determine differences in responses between subgroups. results: among overweight/obese, white/black patients, . % do not feel their weight is damaging to their health and . % reported they have not been told by a doctor they are overweight. of individuals who have been told by a doctor they were overweight, . % still believe their present weight is not damaging to their health. of individuals who have not been told by a doctor they were overweight, . % believe their present weight is damaging to their health. differences in race and age were not found. p values < . for all results. conclusion: our data point toward a disconnect regarding patients' perceptions of health and weight. timely education about the burden of obesity may lead to a decrease in its overall prevalence. (originally submitted as a ''late-breaker.'') objectives: to examine the attitudes and expectations of patients admitted for inpatient care following an emergency department visit. methods: a descriptive study was done by surveying a voluntary sample of adult patients (n = ) admitted to the hospital from the emergency department in one urban teaching hospital in the midwest. a short, ninequestion survey was developed to assess patient attitudes and expectations towards hiv testing, consent, and requirements. analyses consisted of descriptive statistics, correlations, and chi-square analyses. results: the majority of patients report that hiv testing should be a routine part of health care screening ( . %) and that the hospital should routinely test admitted patients for hiv ( . %). despite these overall positive attitudes towards hiv testing, the data also suggest that patients have strong attitudes towards consent requirements with % acknowledging that hiv testing requires special consent and % reporting that separate consent should be required. the data also showed a statistically significant difference in the proportion of patients who believed that hiv testing is a part of routine health care screening by race (v = . , df = , p = . ). conclusion: patients attitudes and expectations towards routine hiv testing are consistent with the cdc recommendations. emergency departments are an ideal setting to initiate hiv testing and the findings suggest that patients expect hospital policies outline procedures for obtaining consent and screening all patients who are admitted to the hospital from the ed. results: the analysis revealed a ''hot spot'', a cluster of counties ( . %) with high ca rates adjacent to counties with high ca rates, located across the southeastern us (p < . ). within these counties, the average ca rate was % higher than the national average. a ''cool spot'', a cluster of counties ( . %) with low rates, was located across the midwest (p < . ). in this cool spot the average ca rate was % lower than the national average. figures and show us adjusted rates and spatial autocorrelation of ca deaths, respectively. conclusion: we identify geographic disparities in ca mortality and describe the cardiac arrest belt in the southeastern us. a limitation of this analysis was the use of icd- codes to identify cardiac arrest deaths; however, no other national data exist. an improved understanding of the drivers of this variability is essential to targeted prevention and treatment strategies, especially given the recent emphasis on development of cardiac resuscitation centers and cardiac arrest systems of care. an understanding of the relation between population density, cardiac arrest count, and cardiac arrest rate will be essential to the design of an optimized cardiac arrest system. we defined ed utilization during the past months as non-users ( visits), infrequent users ( - visits), frequent users ( - visits), and super-frequent users ( ‡ visits). we compared demographic data, socioeconomic status, health conditions, and access to care between these ed utilization groups. results: overall, super-frequent use was reported by . % of u.s. adults, frequent use by %, and infrequent ed use by %. higher ed utilization was associated with increased self-reported fair to poor health ( % for super-frequent, % for frequent, % for infrequent, % for non-ed users). frequent ed users were also more likely to be impoverished, with % of superfrequent, % of frequent, % of infrequent, and % of non-ed users reporting a poverty-income ratio < . adults with higher ed utilization were more likely to report the ed as the place they usually go when sick ( % for super-frequent, % for frequent, % for infrequent, . % for non-ed users). they also reported greater outpatient resource utilization, with % of super-frequent, % of frequent, % of infrequent, and % of non-ed users reporting ‡ outpatient visits/year. frequent ed users were also more likely than non-ed users to be covered by medicaid ( % for super-frequent, % for frequent, % for infrequent, % for non-ed users). conclusion: frequent ed users were a vulnerable population with lower socioeconomic status, poor overall health, and high outpatient resource utilization. interventions designed to divert frequent users from the ed should also focus on chronic disease management and access to outpatient services, rather than focusing solely on limiting ed utilization. objectives: we explored factors associated with specialty provider willingness to provide urgent appointments to children insured by medicaid/chip. methods: as part of a mixed method study of child access to specialty care by insurance status, we conducted semi-structured qualitative interviews with a purposive sample of specialists and primary care physicians (pcps) in cook county, il. interviews were conducted from april to september , until theme saturation was reached. resultant transcripts and notes were entered into atlas.ti and analyzed using an iterative coding process to identify patterns of responses in the data, ensure reliability, examine discrepancies, and achieve consensus through content analysis. results: themes that emerged indicate that pcps face considerable barriers getting publicly insured patients into specialty care and use the ed to facilitate this process. ''if i send them to the emergency room, i'm bypassing a number of problems. i'm fully aware that i'm crowding the emergency room.'' specialty physicians reported that decisions to refuse or limit the number of patients with medicaid/chip are due to economic strain or direct pressure from their institutions ''in the last budget revision, we were [told], 'you are losing money, so you need to improve your patient mix'''. in specialty practices with limited medicaid/chip appointment slots, factors associated with appointment success included: high acuity or complexity, personal request from or an informal economic relationship with the pcp, geography, and patient hardship. ''if it's a really desperate situation and they can't find anybody else, i will make an exception''. specialists also acknowledged that ''patients who can't get an appointment go to the er and then i am obligated to see them if they're in the system.'' conclusion: these exploratory findings suggest that a critical linkage exists between hospital eds and affiliated specialty clinics. as health systems restructure, there is an opportunity for eds to play a more explicit role in improving care coordination and access to specialty care. albert amini, erynne a. faucett, john m. watt, richard amini, john c. sakles, asad e. patanwala university of arizona, tucson, az background: trauma patients commonly receive etomidate and rocuronium for rapid sequence intubation (rsi) in the ed. due to the long duration of action of rocuronium and short duration of action of etomidate, these patients require prompt initiation of sedatives after rsi. this prevents the potential of patient awareness under pharmacological paralysis, which could be a terrifying experience. objectives: the purpose of this study was to evaluate the effect of the presence of a pharmacist during traumatic resuscitations in the ed on the initiation of sedatives and analgesics after rsi. we hypothesized that pharmacists would decrease the time to provision of sedation and analgesia. methods: this was an observational, retrospective cohort study conducted in a tertiary, academic ed that is a level i trauma center. consecutive adult trauma patients who received rocuronium in the ed for rsi were included during two time periods: / / to / / (pre-phase -no pharmacy services in the ed) and / / to / / (post-phase -pharmacy services in the ed). since the pharmacist could not respond to all traumas in the post-phase, this was further categorized based on whether the pharmacist was present or absent at the trauma resuscitation. data collected included patient demographics, baseline injury data, and medications used. the median time from rsi to initiation of sedatives and analgesics was compared between the pre-phase group (group ), post-phase pharmacist absent group (group ), and post-phase pharmacist present group (group ) using the kruskal-wallis test. results: a total of patients were included in the study (group = , group = , and group = ). median age was , . , and . years in groups , , and , respectively (p = . ). there were no other differences between groups with regard to demographics, mechanism of injury, presence of traumatic brain injury, glasgow coma scale score, vital signs, ed length of stay, or mortality. median time between rsi and post-intubation sedative use was , , and minutes in groups , and , respectively (p < . ). median time between rsi and post-intubation analgesia use was , , and minutes in groups , , and , respectively (p < . ). the presence of a pharmacist during trauma resuscitations decreases time to provision of sedation and analgesia after rsi. background: outpatient antibiotics are frequently prescribed from the ed, and limited health literacy may affect compliance with recommended treatments. objectives: among patients stratified by health literacy level, multimodality discharge instructions will improve compliance with outpatient antibiotic therapy and follow-up recommendations. methods: this was a prospective randomized trial that included consenting patients discharged with outpatient antibiotics from an urban county ed with an annual census of , . patients unable to receive text messages or voicemails were excluded. health literacy was assessed using a validated health literacy assessment, the newest vital sign (nvs). patients were randomized to a discharge instruction modality: ) usual care, typed and verbal medication and case-specific instructions; ) usual care plus text messaged instructions sent to the patient's cell phone; or ) usual care plus voicemailed instructions sent to the patient's cell phone. antibiotic pick-up was verified with the patient's pharmacy at hours. patients were called at days to determine antibiotic compliance. z-tests were used to compare -hour antibiotic pickup and patient-reported compliance across instructional modality and nvs score groups. results: patients were included ( % female, median age , range months to years); were excluded. % had an nvs score of - , % - , and % - . the proportion of prescriptions filled at hours varied significantly across nvs score groups; self-reported medication compliance at days revealed no difference across different instructional modalities nor nvs scores (table ) . conclusion: in this sample of urban ed patients, hour prescription pickup varied significantly by validated health literacy score, but not by instruction delivery modality. in this sample, patients with lower health literacy are at risk of not filling their outpatient antibiotics in a timely fashion. has been developed, validated, and utilized to study the processes of care involved in successful care transitions from inpatient to outpatient settings, but has not been utilized in the ed. objectives: we hypothesized that the ctm- could be successfully implemented in the ed without differential item difficulty by age, sex, education, or race; and would be associated with measures of quality of care and likelihood of following physician recommendations. methods: a descriptive study design based on exit surveys was used to measure ctm- scores and likelihood of following treatment recommendations. surveys were administered to a daily cross-sectional sample of all patients leaving the ed between a- a by research assistants in an urban academic ed setting for weeks in november . we report means and standard deviations, and analysis of variance to identify differences in ctm- scores for those who planned and did not plan to follow ed recommendations. results: surveys were completed; patients were ± years old, % black, % female, % with at least some college education, and % were admitted. average ctm- score was . ± . (range - ). scores were not associated with sex (p = . ), race (p = . ), or education level (p = . ). lower ctm scores were associated with increasing age (p = . ), patient perceptions that the ed team was less likely to use words that they understood, listen carefully to them, inspire their confidence and trust, or encourage them to ask questions (all p < . ). those who reported they were ''very likely'' to follow ed treatment had an average score of ± , while those who were ''unlikely'' or ''very unlikely'' to follow ed treatment plans had an average score ± (p = . ). conclusion: the ctm- performs well in the ed and exhibited only differential item difficulty by age; there was no significant difference by race, sex, or education level. furthermore, it is highly associated with likelihood of following physician recommendations. future studies will focus on ctm- scores ability to discriminate between patients who did or did not experience a subsequent ed visit or rehospitalization. age and race were found to be significant predictors of the race pathway. regression of the data by race revealed blacks (or . : ci . - . ; p < . ), hispanics (or . : ci . - . ; p = . ), and asians (or . : ci . - . ; p = . ), were more likely to enter the race cohort than were whites; however, much of this discrepancy is accounted for by age. the mean age of minority patients was years, while white patients were older at years (p = . ). conclusion: in a diverse demographic population we found that racial minorities were presenting at younger ages for chest pain and were more likely to receive cardiac testing at bedside than their white counterparts; and hence, were selected to a lower level of care (nonmonitored unit background: expanding insurance coverage is designed to improve access to primary care and reduce use of emergency services. whether expanding coverage achieves this is of paramount importance as the united states prepares for the affordable care act. objectives: we examined ed and outpatient department use after the state children's health insurance program (schip) coverage expansion, focusing on adolescents (a major target group for schip) versus young adults (not targeted). we hypothesized that coverage would increase use of outpatient services and emergency department services would decrease. methods: using the national ambulatory medical care survey and the national hospital ambulatory medical care survey, we analyzed years - as baseline and then compared use patterns in - after schip launch. primary outcomes were populationadjusted annual visits to ed versus non-emergency outpatient settings. interrupted time-series were performed on use rates to ed and outpatient departments between adolescents ( - years old) and young adults ( - years old) in the pre-schip and schip periods. outpatient-to-ed ratios were calculated and compared across time periods. results: the mean number of outpatient adolescent visits increased by visits per persons ( % ci, - ), while there was no statistically significant increase in young adult outpatient visits across time periods. there was no statistically significant change in the mean number of adolescent ed visits across time periods, while young adult ed use increased by visits per persons ( % ci, - ). the adolescent outpatient-to-ed ratio increased by . ( % ci, . - . ), while the young adults ratio decreased by . across time periods ( % ci, ) . to ) . ). conclusion: since schip, adolescent non-ed outpatient visits increased while ed visits remained unchanged. in comparison to young adults, expanding insurance coverage to adolescents improved access to health care services and suggests a shift to non-ed settings. as an observational study we are unable to control for secular trends during this time period. also as an ecological study we are unable to examine individual variation. expanding insurance through the affordable care act of will likely increase use of outpatient services but may not decrease emergency department volumes. background: cancer patients are receiving a greater proportion of their care on an outpatient basis. the effect of this change in oncology care patterns on ed utilization is poorly understood. objectives: to examine the characteristics of ed utilization by adult cancer patients. methods: between july and march , all new adult cancer patients referred to a tertiary care cancer centre were recruited into a study examining psychological distress. these patients were followed prospectively until september . the collected data were linked to administrative data from three tertiary care eds. variables evaluated in this study included basic we have previously shown that reducing non-value-added activities through the application of the lean process improvement methodology improves patient satisfaction, physician productivity and emergency department length of stay. objectives: in this investigation, we tested the hypothesis that non-value-added activities reduce physician job satisfaction. methods: to test this hypothesis, we conducted timemotion studies on attending emergency physicians working in an academic setting and categorized their activities into value-added (time in room with patient, time discussing cases and educating medical learners, time in room with patient and learner), necessary non-valueadded activities (charting, sign out, looking up labs), and unnecessary non-value-added activities (looking for things, looking for people, on the phone). the physicians were then surveyed using a -point likert scale to determine their relative satisfaction with each of the individual tasks ( worst part of day, best part of day). results: physicians spent % of their shift performing value-added work, % of their shift performing necessary non-value-added activities, and % of their shift performing unnecessary non-value-added activities (waste). weighted physician satisfaction (satisfaction x [percent time spent performing the activity / percent time engaged in activity category]) was highest when the physician was performing value-added work ( . ) compared to performing either necessary non-valueadded work ( . ) or waste ( . ). conclusion: the attending physicians we studied spent the majority of their time performing non-value-added activities, which were associated with lower satisfaction. application of process improvement techniques such as lean, which focus on reducing non-value-added work, may improve emergency physician job satisfaction. background: rocuronium and succinylcholine are the most commonly used paralytics for rapid sequence intubation (rsi) in the ed. after rsi, patients need sustained sedation while they are mechanically ventilated. however, the longer duration of action of rocuronium may influence subsequent sedation dosing, while the patient is therapeutically paralyzed. objectives: we hypothesized that patients who receive rocuronium would be more likely to receive lower doses of post-rsi sedation compared to patients who receive succinylcholine. methods: this was an observational, retrospective cohort study conducted in a tertiary, academic ed. consecutive adult patients, who received rsi using etomidate for induction of sedation between / / to / / , were included. patients were then categorized based on whether they received rocuronium or succinylcholine for paralysis. the dosing of post-rsi sedative infusions was compared at , , , and minutes after initiation between the two groups using the wilcoxon rank-sum test. results: a total of patients were included in the final analysis (rocuronium = , succinylcholine = ). mean age was and years in the rocuronium and succinylcholine groups, respectively (p = . ). there were no other baseline differences between groups with regard to demographics, reason for intubation, stroke, traumatic brain injury, glasgow coma scale score, pain scores, or vital signs. in the overall cohort, . % (n = ) of patients were given a sedative infusion or bolus in the ed. most patients were initiated on propofol (n = ) or midazolam (n = ) infusions. median propofol infusion rates at , , , and minutes were , , . , and mcg/kg/min in the rocuronium group and , , , and mcg/kg/ min in succinylcholine group, respectively. the difference was statistically significant at (p < . ) and (p = . ) minutes. median midazolam infusion rates at , , , and minutes were , , , and mg/hour in the rocuronium group and , , , and . mg/hour in succinylcholine group, respectively. the difference was statistically significant at (p = . ) and (p = . ) minutes. conclusion: patients who receive rocuronium are more likely to receive lower doses of sedative infusions post-rsi due to sustained therapeutic paralysis. this may put them at risk for being awake under paralysis. what is the impact of the implementation of an there was a difference in presenting pain (p < . ), stress (p < . ), and anxiety (p < . ) among patients that received an opioid in the ed. there was a difference in presenting pain (p < . ) for patients discharged with an opioid prescription, but not for stress (p = . ) or anxiety (p = . ). conclusion: patient-reported pain, stress, and anxiety are higher among patients who received an opiate in the ed than in those who did not, but only pain is higher among patients who received a discharge prescription for an opioid. methods: this was a prospective, randomized crossover study on the use of gvl and dl by incoming pediatric interns prior to advanced life support training. at the start of the study, the interns received a didactic session and expert modeling of the use of both devices for intubation. two scenarios were used: ( ) normal intubation with a standard airway and ( ) difficult intubation with tongue edema and pharyngeal swelling. interns then intubated laerdal simbaby in each scenario with both gvl and dl for a total of four randomized intubation scenarios. primary outcomes included time to successful intubation and the rate of successful intubation. the interns also rated their satisfaction with the devices using a visual analog scale ( - ) and chose their preferred device for their next intubation. results: interns were included in this study. in the normal airway scenario, there were no differences in the mean time for intubation with gvl or dl ( . ± . vs . ± . seconds, p = ns) or the number of interns who performed successful intubation ( vs , p = ns). in the difficult airway scenario, the interns took longer to intubate with gvl than dl ( . ± . vs . ± . seconds, p = . ), but there were no differences in the number of successful intubations ( vs , p = ns). interns rated their satisfaction higher for gvl than dl ( . ± . vs . ± . , p = . ) and gvl was chosen as the preferred device for their next intubation by a majority of the interns ( / , %). conclusion: for novice clinicians, gvl does not improve the time to intubation or intubation success objectives: to determine the time to intubation, the number of attempts, and the occurrence of hypoxia, in patients intubated with a c-mac device versus those intubated using a standard laryngoscope. methods: randomized controlled trial using exception from informed consent that included patients undergoing endotracheal intubation with a standard laryngoscope at an urban level i trauma center. eligible patients were randomized to undergo intubation using the c-mac or standard laryngoscopy. standard laryngoscopy was performed using a c-mac device laryngoscope with the video output obstructed to ensure equivalent laryngoscope blades in the two groups. data were collected by a trained research assistant at the patient's bedside and video review by the investigators. the number of attempts made, the initial and lowest oxygen saturation (spo ), and the total time until the intubation was successful was recorded. hypoxia was defined as an oxygen saturation < %. data were compared with wilcoxon rank sum and chi-square tests. results: thirty-eight patients were enrolled, ( % male, median age , range to , median spo %, range to ) in the standard laryngoscopy group and ( % male, median age , range to , median spo . %, range to ) in the c-mac group. the median number of attempts for standard laryngoscopy was , range to , and for c-mac was , range to (p = . ). the median time to intubation for the standard laryngoscopy group was seconds (range to ) and for the c-mac group was seconds (range to )(p = . ). hypoxia was detected in / ( %) in the standard laryngoscopy group and / ( %) in the c-mac group (p = . ). the median decrease in oxygen saturation during the attempt was . % (range % to %) for the standard laryngoscopy group and . % (range % to %) for the c-mac group. conclusion: we did not detect a difference in number of attempts, the occurrence of hypoxia, or the diagnosis of aspiration pneumonia between standard laryngoscopy and the c-mac. the time to successful intubation was shorter for patients intubated with the c-mac. the c-mac device appears to be superior to standard laryngoscopy for emergent endotracheal intubation. (originally submitted as a ''late-breaker.'') the background: aspiration pneumonia is a complication of endotracheal intubation that may be related to the difficulty of the airway procedure. objectives: to determine the association of the device used, the time to intubation, the number of attempts to intubate, and the occurrence of hypoxia with the subsequent development of aspiration pneumonia. methods: this was a prospective observational study of patients undergoing endotracheal intubation by emergency physicians at an urban level i trauma center conducted from / / until / / . the device used on the initial attempt to intubate was at the discretion of the treating physician. data were collected by a trained research assistant at the patient's bedside. the device used, the number of attempts made to intubate, the lowest oxygen saturation during the attempt, and the total time until intubation was successfully accomplished were recorded. patient's medical records were reviewed for the subsequent diagnosis of aspiration pneumonia. hypoxia was defined as an oxygen saturation < %. data were analyzed using multinomial logistic regression and odds ratios (or). results: patients were enrolled; ( %) subsequently developed aspiration pneumonia. were intubated with a standard laryngoscope (sl), using the c-mac, with an intubating laryngeal mask, and with nasotracheal intubation (ni) (or . , % ci = . - . ). comparison of individual devices versus sl did not show an association by device type. the median number of attempts for patients with aspiration pneumonia was , range to , and for those without was , range to (or . , %ci = . - . ). the median time to intubation for patients who developed aspiration pneumonia was seconds (range to ) and for those who did not was seconds (range to )(or . , %ci = . - . ). hypoxia during intubation was detected in / ( %) in the aspiration pneumonia group and / ( %) in the no aspiration pneumonia group (or . , % ci = . - . ). conclusion: there was not an association between the device used, the number of attempts, the time to intubation, or the occurrence of hypoxia during the intubation, and the subsequent occurrence of aspiration pneumonia. background: japanese census data estimate that million, or nearly % of the overall population, will be over age by the year . similar trends are apparent throughout the developed world. although increased patient age affects airway management, comprehensive information in emergency airway management for the elderly is lacking. objectives: we sought to characterize emergency department (ed) airway management for the elderly in japan including success rate, and major adverse events using a large multi-center registry. methods: design and setting: we conducted a multicenter prospective observational study using the japanese emergency airway network (jean) registry of eds at academic and community hospitals in japan between and inclusive. data fields included ed characteristics, patient and operator demographics, methods of airway management, number of attempts, success rate, and adverse events. participants: patient inclusion criteria were all adult patients who underwent emergent tracheal intubation in the ed. primary analysis: patients were divided to into two groups defined as follows: to years old and over years old. we describe primary success rates and major adverse events using simple descriptive statistics. categorical data are reported as proportions and % confidence intervals (cis). results: the database recorded patients (capture rate %) and met the inclusion criteria. of patients, patients were to years old ( %) and were over years old ( %). the older group had a significantly higher success rate at first attempt intubation ( / ; . %, % ci . - . %) compared with the younger group ( / ; . %, % ci . - . %). the older group had similar major adverse event rates ( / ; . %, % ci . - . %) compared with the younger group ( / ; . %, % ci . - . %). (see table ) background: the degree to which a patient's report of pain is associated with changes in blood pressure, heart rate, and respiratory rate is not known. objectives: to determine to what degree a standardized painful stimulus effects a change in systolic blood pressure (sbp), diastolic blood pressure (dbp), heart rate (hr), or respiratory rate (rr), and compare changes in vital signs between patients based on pain severity. methods: prospective observational study of healthy human volunteers. subjects had their sbp, dbp, hr, and rr measured prior to pain exposure, immediately after, and minutes after. pain exposure consisted of subjects placing their hand in a bath of degree water for seconds. the bath was divided into two sections; the larger half was the reservoir of cooled water monitored to be degrees, the other half filled from constant overflow over the divider. water drained from this section into the cooling unit and was then pumped up into the base of the reservoir through a diffusion grid. subjects completed a mm visual analog scale (vas) representing their perceived pain during the exposure and graded their pain as minimal, moderate or severe. data were compared using % confidence intervals. results: subjects were enrolled, mean pain vas mm, range to , reported mild pain, moderate pain, and severe pain. the percent change from baseline in vital signs during the exposure and minutes after are presented in the table. conclusion: there was a wide variety in reported pain among subjects exposed to a standard painful stimulus. there was a larger change in heart rate during the exposure among subjects who described a standardized painful exposure as moderate than in those who described it as severe. the small observed changes in blood pressure and respiratory rate seen during the exposure did not differ by pain report or persist after minutes. background: vital signs are often used to validate intensity of pain. however, few studies have looked at the capacity of vital signs to estimate pain intensity, particularly in patients with a diagnosis that a majority of physicians would agree produce significant pain in the ed. objectives: to determine the association between pain intensity and vital signs in consecutive ed patients and in a sub-group of patients with diagnosis known to cause significant pain. methods: we performed a post-hoc analysis of prospectively acquired data in a cohort study done in an urban teaching hospital with computerized triage and nurses records. we included all consecutive ed adult patients ( ‡ years old), who had any level of pain intensity measured during triage, from march to november . the primary outcome was the mean heart rate, systolic and diastolic blood pressure for every pain intensity level from to on a verbal numerical scale. our secondary outcomes where the same but limited to patients with the following diagnosis: fracture, dislocation, and renal colic. we performed descriptive statistics, one-way and two-way anovas when appropriate. results: during our study period, , patients ‡ years old where triaged with a pain intensity of at least / and had a diagnosis known to cause significant pain. . % of patients were female, with a mean pain intensity of . / , mean age of . years (± . ), and . % were ‡ years old. there was a statistically significant difference (p < . ) in mean heart rate, systolic and diastolic blood pressure for each level of pain intensity, ex: difference between / and / for mean heart rate was . beats per minutes, for systolic pressure was . mmhg and for diastolic . mmhg. results are similar for painful diagnosis: difference for mean heart rate was . beats per minutes, for systolic pressure was . mmhg and diastolic . mmhg. however, these differences are not clinically significant. conclusion: although our study is a post hoc analysis, pain intensity, heart rate, systolic and diastolic pressures during triage are usually reliable data and a prospective study would likely produce the same result. these vital signs cannot be used to estimate or validate pain intensity in the emergency department. % had a positive urine drug screen. logistic multivariate regressions analyses revealed the following factors to be significantly associated with the risk of having an abnormal head ct: association with seizure (p = . ); length of time of loss of consciousness, ranging from none to - min to > min (p = . ); alteration of consciousness (p = . ); post-traumatic amnesia (p = . ); alcohol intake prior to injury (p = , ); and initial ed gcs (p = . ). conclusion: in an emergency department cohort of patients with traumatic brain injury, symptoms including loss of or alteration in consciousness, seizure, post traumatic amnesia, and alcohol intake appear to be significantly associated with abnormal findings on head ct. these clinical findings on presentation may be useful in helping triage head injury patients in a busy emergency department, and can further define the need for urgent or emergent imaging in patients without clearly apparent injuries. background: the etiology of neurogenic shock is classically attributed to diminished peripheral vascular resistance (pvr) secondary to loss of sympathetic outflow to the peripheral vasculature. however, the sympathetic nervous system also controls other key elements of the cardiovascular system such as the heart and capacitance vessels and disruptions in their function could complicate the hemodynamic presentation. objectives: we sought to systematically examine the hemodynamic profiles of a series of trauma patients with neurogenic shock. methods: consecutive trauma patients with documented spinal cord injury complicated by clinical shock were enrolled. hemodynamic data including systolic and diastolic blood pressure, heart rate (hr), impedance-derived cardiac output, pre-ejection period (pep), left ventricular ejection time (lvet), and calculated systemic pvr were collected in the ed. data were normalized for body surface area and a validated integrated computer model of human physiology (guyton model) was used to analyze and categorize the hemodynamic profiles based on etiology of the hypotension using a systems analysis. correlation between markers of sympathetic outflow (hr, pep, lvet) and shock etiology category was examined. results: of patients with traumatic neurogenic shock, the etiology of shock was decrease in pvr in ( %; % ci to %), loss of vascular capacitance in ( %; to %), and mixed peripheral resistance and capacitance responsible in ( %; to %). the markers of sympathetic outflow had no correlation to any of the elements in the patients' hemodynamic profiles. conclusion: neurogenic shock is often considered to have a specific well-characterized pathophysiology. results from this study suggest that neurogenic shock can have multiple mechanistic etiologies and represents a spectrum of hemodynamic profiles. this understanding is important for the treatment decisions made in the management of these patients. -year ( - ) , pre-post intervention study of trauma patients requiring massive blood transfusion was performed. we divided the population into two cohorts: a pre-protocol group (pre) which included trauma patients receiving mbt not aided by a protocol, and a post-protocol group (post) who underwent mbt via the mbtp. patient demographics, hour blood component totals, timing of blood component delivery, trauma injury severity score (iss), initial glasgow coma scale (gcs) score, trauma mechanism, and patient mortality data were collected and analyzed using fisher's exact tests, student's t-tests, and mann-whitney u tests. results: fifty-two patients were included for study. median times to delivery of first products were reduced for prbcs ( minutes), ffp ( minutes), and platelets ( minutes) between the pre and post cohorts. median time to delivery of any subsequent blood product was significantly reduced ( minutes) in the post cohort (p = . ). the median number of blood products delivered was increased by . units for prbcs, units for ffp, . units for platelets, and unit for cryoprecipitate after implementation of mbtp. the percentage of patients receiving higher blood product ratios (> : ) was reduced between the pre and post cohorts for prbc to ffp ( % reduction) and prbc to platelet ratio groups ( % reduction). despite improved transfusion timing and ratios, we found no significant difference in mortality (p = . ) between pre and post cohorts when we adjusted for injury severity. conclusion: protocolized delivery of massive blood transfusion might reduce time to product availability and delivery, though it is unclear how this affects patient mortality in all us trauma centers. background: burns are common injuries that can result in significant scarring leading to poor function and disfigurement. unlike mechanical injuries, burns often progress both in depth and size over the first few days after injury, possibly due to inflammation and oxidative stress. a major gap in the field of burns is the lack of an effective therapy that reduces burn injury progression. objectives: since mesenchymal stem cells (msc) have been shown to improve healing in several injury models, we hypothesized that species-specific msc would reduce injury progression in a rat comb burn model. methods: using a gm brass comb preheated to degrees celsius, we created four rectangular burns, separated by three unburned interspaces on both sides of the backs of male sprague-dawley rats ( g). the interspaces represented the ischemic zones surround-ing the central necrotic core. left untreated, most of these interspaces become necrotic. in an attempt to reduce burn injury progression, rats were randomized to tail vein injections of ml rat-specific msc cells/ml (n = ) or normal saline (n = ) minutes after injury. tracking of the stem cells was attempted by injecting several rats with quantum dot-labeled msc. results: by four days post-injury, all of the interspaces in the control rats ( / , %) became necrotic while in the experimental group, / ( %) of the interspaces became necrotic (fisher's exact test; p < . ). at days, the percentage of the unburned interspaces that became necrotic in the msc treated group was significantly less than in the control group ( % vs. %, p < . ). we were unable to identify any quantum dot labeled msc in the injured skin. no adverse reactions or wound infections were noted in rats injected with msc. conclusion: intravenous injection of rat msc reduced burn injury progression in a rat comb burn model. although basic demographics of bicyclists in accidents have been described, there is a paucity of data describing the street surface involved in accidents, and whether designated bicycle roadways offer protection. this lack of information limits informed attempts to change infrastructure in a way that will decrease morbidity and/or mortality of cyclists. objectives: to identify road surface types involved in pedal cyclist injuries and determine the relationship between injury severity and the use of designated bicycle roadways (dbr) versus non-designated roadways (ndr). we hypothesized that more severe injuries would happen at intersections regardless of dbr versus ndr. methods: this retrospective cohort study reviewed the trauma database from a level i trauma center in tucson, az. we identified all bicyclists in the database injured in accidents involving a motor vehicle from january , , through december , . the patients were then linked to a local government database that documents location (latitude/longitude) and direction of travel of the cyclist. seventy-eight total incidents were identified and categorized as occurring on a dbr versus ndr and occurring at an intersection versus not at an intersection. results: only one patient who arrived at the trauma center died. fifty-one of the accidents ( %) occurred on dbrs; % of accidents occurring on dbrs took place in intersections. conversely, % of accidents on ndrs occurred outside of intersections. the odds of an injury occurring at an intersection versus not at an intersection were . times higher ( % ci: . - . ) for dbrs compared to ndrs. the odds of a trauma being severe (admitted) versus not severe (discharged home) were . times higher ( % ci: . - . ) when a collision occurred not at an intersection versus at an intersection. conclusion: contrary to our hypothesis, in this study group severe injuries were more likely outside of an intersection. however, intersections on dbrs were identified as problematic as cyclists on a dbr were more likely to be injured in an intersection. future city planning could target improved cyclist safety in intersections. background: minor thoracic injury (mti) is frequent and a significant proportion will still have moderate to severe pain at days. there is a lack of risk factors to orient specific treatment at ed discharge. objectives: to determine risk factors of having pain ( ‡ / , on a numerical intensity pain score from to ) at days in a population of minor thoracic injury patients discharged from the ed. methods: a prospective multi-center cohort study was conducted in four canadian eds, from november to january . all consecutive patients, years and older, with mti (with or without rib fracture), a normal chest x-ray, and discharged from the ed were eligible. a standardized clinical and radiological evaluation was done at and weeks. standardized phone interviews were done at and days. pain evaluation occurred at five time points (ed visit, and weeks, and days). using a pain trajectory model (sas), we planned to identify groups with different pain evolution at days. the final model was based on the importance of difference in pain evolution, confidence intervals, and number of patients in each group. to judge the adequacy of the final model, we examined whether the posteriori probabilities (i.e., a participant's probability of belonging to a certain trajectory group) averaged at least % for each trajectory group. then using logistic multinomial regression and the low risk group of having pain as the control group, we identified significant predictors of patients in the moderate and high risk groups having pain at days. results: in our cohort of , patients, , had an evaluation at days. we identified three groups at low ( %), moderate ( . %), and high risk ( . %) of having pain ‡ / at days. using risk factor identified by univariate analysis, we created a model to identify patients at risk containing the following predictors: age ‡ years old, women, current smoker, two or more rib fractures, complaint of dyspnea, and saturation < % at initial visit. posteriori probabilities for low, moderate, and high risk were %, %, and %. conclusion: to our knowledge, this is the first study to identify potential risk factor for having pain at days after minor thoracic injury. these risk factors should be validated in a prospective study to guide specific treatment plan. the use of ultrasound to evaluate traumatic optic neuropathy benjamin burt, lisa montgomery, cynthia garza meissner, sanja plavsic-kupesic, nadah zafar ttuhsc -paul l foster school of medicine, el paso, tx background: whenever head trauma occurs, there is the possibility for a patient to have an optic nerve injury. the current method to evaluate optical nerve swelling is to look for proptosis. however, by the time proptosis presents, significant damage has already occurred. therefore, there is a need to establish a method to evaluate nerve injury prior to the development of proptosis. objectives: fundamental to understanding the pathophysiology of optic nerve injury and repair is an understanding of the optic nerve's temporal response to trauma including blood flow changes and vascular reactivity. the aim of our study was to assess the dependability and reproducibility of ultrasound techniques to sequence optic nerve healing and monitor the vascular response of the ophthalmic artery following an optic nerve crush. methods: the rat's orbit was imaged prior to and following a direct injury to the optic nerve, at hours and at days. d, d, and color doppler techniques were used to detect blood flow and the course of the ophthalmic artery and vein, to evaluate the course and diameter of the optic nerve, and to assess the extent of optic nerve trauma and swelling. the parameters used to evaluate healing over time were pulsatility and resistance indices of the ophthalmic artery. results: we have established baseline ultrasound measurements of the optic nerve diameter, normal resistance and pulsatility indices of the ophthalmic artery, and morphological assessment of the optic nerve in a rat model. longitudinal assessment of d and d ultrasound parameters were used to evaluate vascular response of the ophthalmic artery to optic nerve crush injury. we have developed a rat model system to study traumatic optic nerve injury. the main advantages of ultrasound are low cost, non-invasiveness, lack of ionizing radiation, and the potential to perform longitudinal studies. our preliminary data indicate that d and d color doppler ultrasound may be used for the evaluation of ophthalmic artery and total orbital perfusion following trauma. once baseline ultrasound and doppler measurements are defined there is the opportunity to translate the rat model to evaluate patients with head trauma who are at risk for optic nerve swelling and to assess the usefulness of treatment interventions. background: alcoholism is a chronic disease that affects an estimated . million american adults. a common presentation to the emergency department (ed) is a trauma patient with altered sensorium who is presumed to be alcohol intoxicated by the physicians based on their olfactory sense. often ed physicians may leave patients suspected of alcohol intoxication aside until the effects wear off, potentially missing major trauma as the source of confusion or disorientation. this practice often results in delays in diagnosing acute potentially life-threatening injuries in the patients with presumed alcohol intoxication. objectives: this study will determine the accuracy of physicians' olfactory sense for diagnosing alcohol intoxication. methods: patients suspected of major trauma in the ed underwent an evaluation by the examining physician for the odor of alcohol as well as other signs of intoxication. each patient had determination of blood alcohol level. alcohol intoxication was defined as a serum ethanol level ‡ mg/dl. data were reported as means with % confidence intervals ( % ci) or proportions with inter-quartile ranges (iqr %- %). results: one hundred and fifty one patients ( % males) were enrolled in the study, median age years (iqr - ). the median score for glasgow coma scale was . the level of training of examining physician was a median of pgy (iqr pgy -attending). prevalence of alcohol intoxication was % ( % ci: % to %). operating characteristics: physician assessment of alcohol intoxication, sensitivity % ( % ci: % to %), specificity % ( % ci: % to %), positive likelihood ratio . ( % ci: . to . ), negative likelihood ratio . ( % ci: . to . ), and accuracy % ( % ci: % to %). patients who were falsely suspected of being intoxicated were . % ( % ci: % to %). conclusion: although the physicians had a high degree of accuracy in identifying patients with alcohol intoxication based on their olfactory sense, they still falsely overestimated intoxication in a significant number of non-intoxicated trauma patients. the background: optimal methods for education and assessment in emergency and critical care ultrasound training for residents are not known. methods of assessment often rely on surrogate endpoints which do not assess the ability of the learner to perform the imaging and integrate the imaging into diagnostic and therapeutic decisions. we designed an educational strategy that combines asynchronous learning to teach imaging skills and interpretation with a standardized assessment tool using a novel ultrasound simulator to assess the learner's ability to acquire and interpret images in the setting of a standardized patient scenario. objectives: to assess the ability of emergency medicine and surgical residents to integrate and apply information and skills acquired in an asynchronous learning environment in order to identify pathology and prioritize relevant diagnoses using an advanced cardiac ultrasound simulator. methods: em r residents and r surgical residents completed an online focused training program in cardiac ultrasonography (iccu elearning, https:// www.caeiccu.com/lms). this consisted of approximately hours of intensive training in cardiac ultrasound. residents were then given cases with a patient scenario that lacked significant details that would suggest a specific diagnosis. the resident was then given a list of possible diagnoses and asked to rank the top five diagnoses in order of most likely to least likely. each resident (blinded to the pathology displayed by the simulator) then imaged using an ultrasound simulator. after imaging, the residents were given the same list of potential diagnoses, and asked to rank them again from - . results: overall, residents ranked the correct diagnosis in the top five significantly more times post-ultrasound than pre-ultrasound. additionally, the residents made the correct diagnosis significantly more times postultrasound than pre-ultrasound. similar patterns occur for congestive heart failure, pericardial effusion with tamponade, and pleural effusion. there was no significant difference pre-and post-ultrasound for pulmonary embolism and anterior infarction. conclusion: an asynchronous online learning program significantly improves the ability of emergency medicine and surgical residents to correctly prioritize the correct diagnosis after imaging with a standardized pathology imaging simulator. mark favot, jacob manteuffel, david amponsah henry ford hospital, detroit, mi background: em clerkships are often the only opportunity medical students have to spend a significant amount of time caring for patients in the ed. it is imperative that students gain exposure to as many of the various fields within em as possible during this time. if the exposure of medical students to ultrasound is left to the discretion of the supervising physicians, we feel that many students would complete an em clerkship with limited skills and knowledge in ultrasound. the majority of medical students receive no formal training in ultrasound during medical school and we believe that the em clerkship is an excellent opportunity to fill this educational gap. objectives: evaluate the usefulness and effectiveness of a focused ultrasound curriculum for medical students in an em clerkship at a large, urban, academic medical center. methods: prospective cohort study of fourth year medical students doing an em clerkship. as part of the clerkship requirements, the students have a portion of the curriculum dedicated to the fast exam and ultrasound-guided vascular access. at the end of the month they take a written test, and month later they are given a survey via e-mail regarding their ultrasound experience. em residents also completed the test to serve as a comparison group. all data analysis was done using sas . . scores were integers ranging between and . descriptive statistics are given as count, mean, standard deviation, median, minimum, and maximum for each group. due to non-gaussian nature of the data and small group sizes, a wilcoxon two-sample test was used to compare the distributions of scores between the groups. results: in the table, the distribution of scores was compared between the residents (controls) and the students (subjects). the mean and median scores of the student group were higher than those of the resident group. the difference in scores between the two groups was statistically significant (p = . ). conclusion: our data reveal that after completing an em clerkship with time devoted to learning ultrasound for the fast exam and vascular access, fourth year medical students are able to perform better than em residents on a written test. what remains to be determined is if their skills in image acquisition and in performance of ultrasound-guided vascular access procedures also exceed those of em residents. results: there were respondents (total response rate . %). compared to non-em students, students pursuing em ( students, . %) were more drawn to their specialty for work hour control (p < . ) and shorter residency length (p < . ). em students were less likely than non-em students to be drawn to their chosen specialty for future academic opportunities (p < . ). em students formed their mentorships by referral significantly more than non-em students (p < . ), though there was no statistical difference in quality of existing mentorships amongst students. of the students not currently and never formerly interested in em, the most common response ( . %) for why they did not choose em was the lack of a strong mentor in the field. conclusion: the results confirmed previous findings of lifestyle factors drawing students to em. future academic opportunities were less likely to draw students to em than students pursuing other specialties. lack of mentorship in the field was the most common reason given for why students did not consider em. given the lack of direct em exposure until late in the curriculum of most medical schools, mentorship may be particularly important for em and future study should focus on this area. background: misdiagnosis is a major public health problem. dizziness leads to million visits annually in the us, including . million to the emergency department (ed). despite extensive ed workups, diagnostic accuracy remains poor, with at least % of strokes missed in those presenting with dizziness. ed physicians need and want support, particularly in the best method for diagnosis. strong evidence now indicates the bedside oculomotor exam is the best method of differentiating central from peripheral causes of dizziness. objectives: after a vertigo day that includes instruction in head impulse testing, emergency medicine residents will feel comfortable discharging a patient with signs of vestibular neuritis and a positive head impulse test without ordering a ct scan. methods: post graduate year - emergency medicine residents participated in a four hour vertigo day. we developed a mixed cognitive and systems intervention with three components: an online game that began and ended the day, a didactic taught by dr. newman-toker, and a series of small group exercises. the small group sessions included the following: a question and answer session with the lecturer; vertigo special tests (cerebellar assessment, dix hall-pike, epley maneuver); a head impulse hands-on tutorial using a mannequin; and a video lecture on other tests useful in vertigo evaluation (nystagmus, test of skew, vestibulocular reflex, ataxia). results: thirty emergency medicine residents were studied. before and after the intervention the residents were given a survey in which one question asked ''in a patient with acute vestibular syndrome and a history and exam compatible with vestibular neuritis, i would be willing to discharge the patient without neuroimaging based on an abnormal head impulse test result that i elicited''. resident answers were based on a sevenpoint likert scale from strongly agree to strongly disagree. twenty-five residents completed both surveys. of the seven residents who changed their responses pre to post,a significant proportion ( %) changed their answer from disagree/neutral to agree after a hour vertigo day (mcnemar's test, p value = . ). conclusion: in this single-center study, teaching headimpulse testing as part of a vertigo day increases resident comfort with discharging a patient with vestibular neuritis without a ct scan. background: previous studies have been inconsistent in determining the effect of increased ed census on resident workload and productivity. we examined resident workload and productivity after the closure of a large urban ed near our facility, which resulted in a rapid % increase in our census. objectives: we hypothesized that the closure of a nearby hospital closure with a resulting influx of ed patients to our facility would not change resident productivity. methods: this computer-assisted retrospective study compared new patient workups per hour and patient load before and after the closure of a large nearby hospital. specifically, new patient workups per hour and the pm patient census per resident were examined for a one-year period in the calendar year prior to the closing and also for one year after the closing. we did not include the four month period surrounding the closure in order to determine the long-term overall effect. background: emergency medicine residents use simulation for training due to multiple factors including the acuity of certain situations they are faced with, and the rarity of others. current training on highfidelity mannequin simulators is often critiqued by residents over the physical exam findings present, specifically the auscultatory findings. this detracts from the realism of the training, and may also lead a resident down a different diagnostic or therapeutic pathway. wireless remote programmed stethoscopes represent a new tool for simulation education which allows any sound to be wirelessly transmitted to a stethoscope receiver. objectives: our goal was to determine if a wireless remote programmed stethoscope was a useful adjunct in simulation-based cases using a high-fidelity mannequin. our hypothesis was that this would represent a useful adjunct in simulation education of emergency medicine residents. methods: starting june , pgy - emergency medicine residents were assessed in two simulation-based cases using pre-determined scoring anchors. an experimental randomized crossover design was used in which each resident performed a simulation case with and without a remote programmed stethoscope on a highfidelity mannequin. scoring anchors and surveys were used to collect data with differences of means calculated. results: fourteen residents participated in the study. residents noted most realistic physical exam findings associated with the case with the adjunct in / ( %) and that their preference was for the use of the adjunct in / ( %). based off of a five-point likert scale, with being the most realistic, the adjunct-associated case averaged . as compared to . without (difference of means . , p = . ). average scores of residents with the adjunct were . / with the use of the adjunct and . / without (difference of means . , p = . ). average total times were : with the adjunct as compared to : without. conclusion: a wireless remote programmed stethoscope is a useful adjunct in simulation training of emergency medicine residents. residents noted physical exam findings to be more realistic, preferred its use, and had approached significant improvement of scores when using the adjunct. background: prior studies predict an ongoing shortage of emergency physicians to staff the nation's eds, especially in rural areas. to address this, em organizations have discussed broadening access to acgme or aoa accredited em residency programs to physicians who previously trained in another specialty and focusing on physicians already practicing in rural areas. objectives: to investigate whether em program directors (pds) from allopathic and osteopathic residency programs would be willing to accept applicants previously trained in other specialties and whether this willingness is modified by applicants' current practice in rural areas. methods: a five-question web-based survey was sent to u.s. em pds asking questions about their policies on accepting residents with past training and from rural practices. questions included whether a pd would accept a resident with prior training in other specialties, how many years from this training would the applicant be still a competitive candidate and if a physician was practicing in a rural region would the likelihood of acceptance to the program be improved. different characteristics of the residency programs were recorded including length of program, years in existence, size, type, and location of program. we compared responses by program characteristics using chi-square test. results: of the ( %) pds responding to date, a large majority ( %) reported they do accept applicants with previous residency training, although directors of osteopathic programs were less likely to accept these applicants ( % vs % for allopathic; p < . ). overall, % of pds reported no limit on the length of time from prior training to when they are accepted at an em program. % reported it is very or possibly realistic they would accept a candidate who had completed training and was board certified in another specialty. a majority of all respondents ( %) felt a physician practicing in a rural setting might be viewed as a more favorable candidate, even if the resident would only be in the program for years after receiving training credit. directors of newer programs (< years of existence) were more likely to view these candidates favorably than older programs ( % vs %; p = . ). conclusion: there appear to be many em residency programs that would at least review the application and consider accepting a candidate who trained in another specialty. a qualitative assessment of emergency medicine self-reported strengths todd guth university of colorado, aurora, co background: self-reflection has been touted as a useful way to assess the acgme core competencies. objectives: the purpose of this study is to gain insight into resident physician professional development through analysis of self-perceived strengths. a secondary purpose is to discover potential topics for selfreflective narrative essays relating to the acgme core competencies. methods: design: a small qualitative study was performed to explore the self-reported strengths of emergency medicine (em) residents in a single four-year residency. participants: all residents regardless of year of training were also asked to report their selfperceived strengths. observations: residents were asked: ''what do you feel are your greatest strengths as a resident? provide a quick description.'' the author and another reviewer identified themes from within each year of residency with abraham maslow's conscious competence conceptual framework in mind. occurrences of each theme were counted by the reviewers and organized according to frequency. once the top ten themes for each year of residency were identified and exemplar quotes identified, the two reviewers identified trends. inter-rater agreements were calculated. results: representing unconscious incompetency, the first trend was the reported presence of ''enthusiasm and a positive attitude'' from residents early in their training that decreases further along in training. additionally, a ''willingness and motivation to improve and learn'' was reported as a strength throughout all the years of training but most frequently reported in the first two years of residency. entering into conscious incompetence, the second trend identified was ''recognition of limitations and openness to constructive feedback'' that was mentioned frequently in the second and third years of residency. demonstrating conscious competence, the third trend identified was the increase in identification of the strengths of ''educational leadership, teamwork skills and communication, and departmental patient flow and efficiency'' in the later years of residency. conclusion: self-reported strengths has helped to identify both themes within each year of residency and trends among the years of residency that can serve as areas to explore in self-reflective narratives relating to the acgme core competencies. training. pofu can also be used to assess the acgme core competency of practice-based learning. the exact form or frequency of pofu assessment among various em residencies, however, is not currently known. objectives: we aimed to survey em residencies across the country to determine how they fulfill the pofu requirement and whether certain program structure variables were associated with different pofu systems. we hypothesized that implementation of pofu systems among em residencies would be highly variable. methods: in this irb-approved study, all program directors of acgme allopathic em residencies were invited to complete a -question survey on their current approaches to pofu. respondents were asked to describe their current pofu system's characteristics and rate its ease of use, effectiveness, and efficiency. data were collected using surveymonkey(tm) and reported using descriptive statistics. results: of residencies surveyed, ( %) submitted complete data. . % were completed by program directors and over three-fourths ( . %) of em residencies require monthly completion of pofus. the mean total pofus required per year was ( % ci - ), with a median of and a range of - . almost / ( %) of residencies use an electronic pofu system. most ( %) -year em residencies use an electronic pofu system, compared with half ( %) of -year residencies (difference %, p = . , % ci . %- . %). seven commercially available electronic programs are used by % of the residencies, while % use a customized product. most respondents ( %) rated their pofu system as easy to use, but less than half ( %) felt it was an effective learning tool or an efficient one ( %). onethird ( %) would use a different pofu system if available, and almost half ( %) would be interested in using a multi-residency pofu system. conclusion: em residency programs use many different strategies to fulfill the rrc requirement for pofu. the number of required pofus and the method of documentation vary considerably. about two-thirds of respondents use an electronic pofu system. less than half feel that pofu logs are an effective or efficient learning tool. background: certification of procedural competency is requisite to graduate medical education. however, little is known regarding which platforms are best suited for competency assessment. simulators offer several advantages as an assessment modality, but evidence is lacking regarding their use in this domain. furthermore, perception of an assessment environment has important influence on the quality of learning outcomes, and procedural skill assessment is ideally conducted on a platform accepted by the learner. objectives: to ascertain if a simulator performs as well as an unembalmed cadaver with regard to residents' perception of their ability to demonstrate procedural competency during ultrasound (us) guided internal jugular vein (ij) catheterization. methods: in this cross-sectional study at an urban community hospital during july of , residents in their second or third year of training from a -year em residency program performed us guided catheterizations of the ij on both an unembalmed cadaver and a simulator manufactured by blue phantom. after the procedure, residents completed an anonymous survey ascertaining how adequately each platform permitted their demonstration of proficiency on predefined procedural steps. answers were provided on a likert scale of to , with being poor and being excellent. p values < . were considered educationally significant. results: the median overall rating of the simulator (s) to serve as an assessment platform was similar to that of the cadaver (c) with scores of . and . respectively, p = . . median ratings for permitting the demonstration of specific procedural steps were as follows: conclusion: senior em residents positively rate the blue phantom simulator as an assessment platform and similarly to that of a cadaver with regard to permitting their demonstration of procedural competency for us guided ij catheterization, but did prefer the cadaver to a greater degree when identifying and guiding the needle into the ij. methods: in fall , wcmc and wcmc-q students taking the course completed a question pre-and post-test. wcmc-q students also completed a postcourse single-station objective structured clinical examination (osce) that evaluated their ability to identify and perform eight actions critical for a first responder in an emergency situation (table ) . results: on both campuses, mean post-test scores were significantly higher than mean pre-test scores (p £ . ). on the pre-test, mean wcmc student scores were significantly higher than for wcmc-q students (p = . ); however, no difference was found in mean post-test scores (p = . ). there was no association between the scores on the osce (mean = . , sd = . ) and the post-test (p = . ) even after adjusting for a possible evaluators' effect (table ) . clinical skills course was effective in enhancing student knowledge in both qatar and new york as evidenced by the significant improvement in scores from the pre-to post-tests. the course was able to bring wcmc-q student scores and presumably knowledge up to the same level as wcmc students. students performed well on the osce, suggesting that the course was able to teach them the critical actions required of a first responder. the lack of association between the post-test and osce scores suggests that student knowledge does not independently predict ability to learn and demonstrate critical actions required of a first responder. future studies will evaluate whether the course affects the students' clinical practice. assess breathing assess circulation call ems call ems and assess abcs prior to other interventions immobilize localize and control bleeding splint fractured extremity and skills specific to wilderness medicine by incorporating simulated medical scenarios into a day-long adventure race. this event has gained acceptance nationally in wilderness medical circles as an excellent way to appreciate the challenges of wilderness medicine, however its effectiveness as a teaching tool has not yet been verified. objectives: the objective of this study was to determine if improvement in simulated clinical and didactic performance can be demonstrated by teams participating in a typical medwar event. methods: we developed a complex clinical scenario and written exam to test the basic tenets that are reinforced through the medwar curriculum. teams were administered the test and scored on a standardized scenario immediately before and after the midwest medwar race. teams were not given feedback on their pre-race performance. scenario performance was based on the number of critical actions correctly performed in the appropriate time frame. data from the scenario and written exams were analyzed using a standard paired difference t-test. results: a total of teams participated in both the pre-and post-event scenarios. the teams' pre-race scenario performance was . % (sd = . , n = ) of critical actions met compared to a post-race performance of . % (sd = . , n = ). the mean improvement was . % (sd = . , n = , % ci . , . ) with a significant paired two-tailed t-test (p £ . ). a total of individual subjects took the written pre-and posttests. the written scores averaged pre-race . % (sd = . , n = ) and post-race . % (sd = . , n = ). the mean improvement was . % (sd = . , n = , ci ) . , . ), with a significant paired twotailed t-test (p £ . ). conclusion: medwar participants demonstrated a significant improvement in both written exam scores and the management of a simulated complex wilderness medical scenario. this strongly suggests that medwar is an effective teaching platform for both wilderness medicine knowledge and skills. palliative methods: ed residents and faculty of an urban, tertiary care, level i trauma center were asked to complete an anonymous survey ( / - / ). participants ranked statements on a five-point likert scale ( = strongly disagree- = strongly agree). statements covered four main domains of barriers related to: ) education/training, ) communication, ) ed environment; ) personal beliefs. respondents were also asked if they would call pc consult for ed clinical scenarios (based on established triggers). results: / ( %) eligible participants completed the survey ( residents, faculty), average age was years, % ( / ) male, and % ( / ) caucasian. respondents identified two major barriers to ed-pc provision: lack of hour availability of pc team (mean score . ) and lack of access to complete medical records ( . ). listed domain barriers included: communication-related issues (mean . ) like access to family or primary providers, ed environment ( . ) for example chaotic setting with time-constraints, education/training ( . ) related to pain/pc, and personal beliefs regarding end-of-life ( . ). all respondents agreed that they would call pc consult for a 'hospice patient in respiratory distress', and a majority ( %) would consult pc for 'massive intracranial hemorrhage, traumatic arrest, and metastatic cancer'. however, traditional in-patient triggers like frequent re-admits for organ failure issues (dementia, congestive heart failure, and obstructive pulmonary disease exacerbations) were infrequently ( %) chosen for pc consult. conclusion: to enhance pc provision in the ed setting, two main ed physician perceived barriers will likely need to be addressed: lack of access to medical records and lack of - availability of pc team. ed physicians may not use the same criteria to initiate pc consults as compared to the traditionally established inpatient pc consult trigger models. percent of charts with an mse by ait prior to resident evaluation (a measure of reduced diagnostic uncertainty and decision-making), ( ) ed volume. results: there were no educationally significant differences in productivity or acuity between the pre-ait and post-ait groups. mse was recorded in the chart prior to resident evaluation in . % of cases. ed volume rose by . % between periods. conclusion: ait did not affect productivity or acuity of patients seen by em s. while some volume was directed away from residents by ait (patients treated-andreleased by ait only), overall volume increased and made up the difference. this is similar to previously reported rankings that program directors gave to the same criteria. although medical students agreed with program directors on the importance of most aspects of the nrmp application areas of discordance included higher medical student ranking for extracurricular activities and a lower relative ranking for aoa status than program directors. this can have implications for medical student mentoring and advising in the future. background: emergency care of older adults requires specialized knowledge of their unique physiology, atypical presentations, and care transitions. older adults often require distinctive assessment, treatment and disposition. emergency medicine (em) residents should develop expertise and efficiency in geriatric care. older adults represent over % of most emergency department (ed) volumes. yet many em residencies lack curricula or assessment tools for competent geriatric care. the geriatric emergency medicine competencies (gemc) are high-impact geriatric topics developed to help residencies meet this demand. objectives: to examine the effect of a brief gemc educational intervention on em resident knowledge. methods: a validated -question didactic test was administered at six em residencies before and after a gemc focused lecture delivered summer and fall of . scores were analyzed as individual questions and in defined topic domains using a paired student's t-test. results: a total of exams were included. the testing of didactic knowledge before and after the gemc educational intervention had high internal reliability ( . %). the intervention significantly improved scores in all domains (table ) . graded increase in geriatric knowledge occurred by pgy year with the greatest improvement seen at the pgy level (table ) . conclusion: even a brief gemc intervention had a significant effect on em resident knowledge of critical geriatric topics. a formal gemc curriculum should be considered in training em residents for the demands of an ageing population. the overall procedure experience of this incoming class was limited. most r s had never received formal education in time management, conflict of interest management, or safe patient trade-off. the majority lacked confidence in their acute and chronic pain management skills. these entry level residents lacked foundational skill levels in many knowledge areas and procedures important to the practice of em. ideally medical school curricular offerings should address these gaps; in the interim, residency curricula should incorporate some or all of these components essential to physician practice and patient safety. background: the american heart association and international liaison committee on resuscitation recommend patients with return of spontaneous circulation following cardiac arrest undergo post-resuscitation therapeutic hypothermia. in post-cardiac arrest patients presenting with a rhythm of vf/vt, therapeutic hypothermia has been shown to reduce neurologic sequelae and decrease overall mortality. objectives: to explore clinical practice regarding the use of therapeutic hypothermia and compare survival outcomes in post-cardiac arrest patients. a secondary outcome was to assess whether the initial presenting cardiac arrest rhythm (ventricular fibrillation/ventricular tachycardia (vf/vt) versus pulseless electrical activity (pea) or asystole) was associated with differences in outcomes. methods: a retrospective medical record review was conducted for all adult ( ‡ years) post-cardiac arrest patients admitted to the icu of an academic tertiary care centre (annual ed census , ) from - . data were extracted using a standardized data collection tool by trained research personnel. results: patients were enrolled. mean (sd) age was ( ) and . % were male. of ( . %) patients treated with hypothermia, ( . %) presented with an initial rhythm of vf/vt and ( . %) presented with pea or asystole. nine ( . %) patients with vf/vt were treated with therapeutic hypothermia and discharged from hospital compared to ( . %) patients with pea or asystole (d . %; % ci: . %, . %). of patients not treated with hypothermia, ( . %) presented with vf/vt, ( . %) presented with pea or asystole, and ( . %) initial rhythms were unknown. fifteen ( . %) patients with vf/vt, not treated with hypothermia, were discharged from hospital compared to ( . %) patients with pea or asystole (d . %; % ci: . %, . %). regardless of initial presenting rhythm or initiation of therapeutic hypothermia, ( . %) discharged patients had good neurological function as assessed by the cerebral performance category (cpc score - ). conclusion: although recommended, post-cardiac arrest therapeutic hypothermia was not routinely used. patients with vf/vt and treated with hypothermia had better outcomes than those with pea or asystole. further research is needed to assess whether cooling patients with presenting rhtyhms of pea or asystole is warranted. racial background: chronic obstructive pulmonary disease (copd) is a major public health problem in many countries.the course of the disease is characterised by episodes, known as acute exacerbations (ae), when symptoms of cough, sputum production, and breathlessness become much worse. the standard prehospital management of patients suffering from an aecopd includes oxygen therapy, nebulised bronchodilators, and corticosteroids. high flow oxygen is used routinely in prehospital areas for breathless patients with copd. there is little high quality evidence on the benefits or potential dangers in this setting but audits have shown increased mortality, acidosis, and hypercarbia in patients with aecopd treated with high flow oxygen. objectives: to compare standard high flow oxygen treatment with titrated oxygen treatment for patients with an aecopd in the prehospital setting. methods: cluster randomized controlled parallel group trial comparing high flow oxygen treatment with titrated oxygen treatment in the prehospital setting. in an intention to treat analysis (n = ), the risk of death was significantly lower in the titrated oxygen arm compared with the high flow oxygen arm for all patients and for the subgroup of patients with confirmed copd (n = ). overall mortality was % ( deaths) in the high flow oxygen arm compared with % ( deaths) in the titrated oxygen arm; mortality in the subgroup with confirmed copd was % ( deaths) in the high flow arm compared with % ( deaths) in the titrated oxygen arm. titrated oxygen treatment reduced mortality compared with high flow oxygen by % for all patients (p = . ) and by % for the patients with confirmed chronic obstructive pulmonary disease (p = . ). patients with copd who received titrated oxygen according to the protocol were significantly less likely to have respiratory acidosis or hypercapnia than were patients who received high flow oxygen. conclusion: titrated oxygen treatment significantly reduced mortality, hypercapnia, and respiratory acidosis compared with high flow oxygen in aecopd. these results provide strong evidence to recommend the routine use of titrated oxygen treatment in patients with breathlessness and a history or clinical likelihood of copd in the prehospital setting. (originally submitted as a ''late-breaker.'') trial registration australian new zealand clinical trials register actrn . background: toxic particulates and gases found in ambulance exhaust are associated with acute and chronic health risks. the presence of such materials in areas proximate to ed ambulance parking bays, where emergency services' vehicles are often left running, is potentially of significant concern to ed patients and staff. objectives: investigators aimed to determine whether the presence of ambulances correlated with ambient particulate matter concentrations and toxic gas levels at the study site ed. methods: the ambulance exhaust toxicity in healthcare-related exposure and risk [aether] program conducted a prospective observational study at an academic urban ed / level i trauma center. environmental ambient gas was sampled over a continuous five-week period from september to october . two sampling locations in the public triage area (public patient dropoff area without ambulances) and three sampling locations in the ambulance triage area were randomized for -hour monitoring windows with a temporal resolution of minutes to obtain days of non-contiguous data for each location. concentrations of particulate matter less than . microns in aerodynamic size (pm . ), oxygen, hydrogen sulfide (h s), and carbon monoxide (co) as well as lower explosive limit for methane (lel) were monitored with professionally calibrated devices. ambulance traffic was recorded through offline review of / security video footage of the site's ambulance bays. results: , measurements at the public triage nurse desk space revealed pm . concentrations with a mean of . ± . lg/m (median . lg/m ; maximum , . lg/m ). , ambulance triage nurse desk space pm . concentrations recorded a mean of . ± . lg/m (p < . , unpaired t test; median . lg/m ; maximum . lg/m ). oxygen levels remained steady throughout the study period; co, h s, and lel were not detected. ambulance activity levels had the highest correlations with pm . concentrations at the ambulance triage foyer (r = . ) and desk area (r = . ) where patients wait and ed staff work - hr shifts. conclusion: ed spaces proximate to ambulance parking bays had higher levels of pm . than areas without ambulance traffic. concentrations of ambient particulate matter in acute care environments may pose a significant health threat to patients and staff. an ems ''pit crew'' model improves ekg and stemi recognition times in simulated prehospital chest pain patients sara y. baker , salvatore silvestri , christopher d. vu , george a. ralls , christopher l. hunter , zack weagraff , linda papa orlando regional medical center, orlando, fl; florida state university college of medicine, orlando, fl background: prehospital teams must minimize time to ekg acquisition and stemi recognition to reduce overall time from first medical contact to reperfusion. auto-racing ''pit crews'' model rapid task completion by pre-assigning roles to team members. objectives: we compared time-to-completion of key tasks during chest pain evaluation in ems teams with and without pre-assigned roles. we hypothesized that ems teams using the ''pit crew'' model would improve time to recognition and treatment of stemi patients. methods: a randomized, controlled trial of paramedic students was conducted over months at orlando medical institute, a state-approved paramedic training center. we compared a standard ems chest pain management algorithm (control) with a pre-assigned tasks (''pit crew'') algorithm (intervention) in the evaluation of simulated chest pain patients. students were randomized into groups of three; intervention and control groups did not interact after randomization. all students reviewed basic prehospital chest pain management and either the standard or pre-assigned tasks algorithm. groups encountered three simulated patients. laerdal simmanÒ software was used track completion of tasks: taking vital signs, iv access, ekg acquisition and interpretation, asa administration, hospital stemi notification, and total time on scene. results: we conducted simulated-patient encounters ( control / intervention encounters). mean time-to-completion of each task was compared in the control and intervention groups respectively. time to obtain vital signs was : vs. : min (p = . ); time to asa administration was : vs : min (p < . ); time to ekg acquisition was : vs : min (p < . ); time to ekg interpretation was : vs : min (p < . ); time to iv access was : vs : min (p = . ); time to stemi notification was : vs : min (p < . ); and time to scene completion was : vs : min (p < . ). conclusion: paramedic student teams with pre-assigned roles (the ''pit crew'' model) were faster to obtain vital signs, administer asa, acquire and interpret the ekg, stemi notification, and overall time on scene during simulated patient encounters. further study with experienced ems teams in actual patient encounters is necessary to confirm the relevance of these findings. background: use of automated external defibrillators (aed) has remained low in the u.s. understanding the effect of neighborhoods on the probability of having an aed used in the setting of a public arrest may provide important insights for future placement of aeds. objectives: to determine associations between the racial and income composition of neighborhoods (as defined by u.s. census tracts), individual arrest characteristics, and whether bystanders or first responders initiate aed use. methods: cohort study using surveillance data prospectively submitted by emergency medical services systems and hospitals from u.s. sites to the cardiac arrest registry to enhance survival between october , and december , . neighborhoods were defined as high-income vs. low-income based on the median household income being above or below $ , and as white or black if > % of the census tract was of one race. neighborhoods without a predominant racial composition were defined as integrated. arrests that occurred within a public location (excluding medical facilities and airports) were eligible for inclusion. hierarchical multi-level modeling, using stata v . , was used to determine the association between individual and census tract characteristics on whether an aed was used. results: of , eligible cases, an aed was used in arrests ( . %) by a first responder (n = , , . %) or bystander (n = , . %). patients whose arrest was witnessed (odds ratio [or] . ; % confidence interval [ci] . - . ) were more likely to have an aed used (table) . when compared to high-income white neighborhoods, arrest victims in low-income black neighborhoods were least likely to have an aed used (or . ; % ci . - . ). arrest victims in lowincome white (or . ; % ci . - . ) and lowincome integrated (or . ; % ci . - . ) were also less likely to have an aed used. conclusion: arrest victims in black and low-income neighborhoods are least likely to have an aed used by a layperson or first responder. future research is needed to better understand the reasons for low rates of aed use for cardiac arrests in these neighborhoods. the impact of an educational intervention on the pre-shock pause interval among patients experiencing an out-of-hospital cardiac arrest jonathan studnek , eric hawkins , steven vandeventer carolinas medical center, charlotte, nc; mecklenburg ems agency, charlotte, nc background: pre-shock pause duration has been associated with survival to hospital discharge (std) among patients experiencing out-of-hospital cardiac arrest (oohca) resuscitation. recent research has demonstrated that for every -second increase in this interval there is an % decrease in std. objectives: determine if a decrease in the pre-shock pause interval for patients experiencing oohca could be realized after implementation of an educational intervention. methods: this was a retrospective analysis of data obtained from a single als urban ems system from / / to / / and / / to / / . in august , an educational intervention was designed and delivered to approximately paramedics emphasizing the importance of reducing the time off chest during cpr. specifically, the time period just prior to defibrillation was emphasized by having rescuers count every th compression and pre-charge the defibrillator on the th compression. in order to determine if this change resulted in process improvement, months of data were assessed before and months after the educational intervention. pre-shock pause was the outcome variable and was defined as the time period after compressions ceased until a shock was delivered. this interval was measured by a cpr feedback device connected to the defibrillator. inclusion criteria were adult patients who required at least one defibrillation and had the cpr feedback device connected during the defibrillation attempt. analysis was descriptive utilizing means and % ci as well as wilcoxon rank sum test to assess difference between the two time periods. results: in the pre-intervention period there were patients who received defibrillations compared to patients receiving defibrillations in the post-intervention phase. the mean duration of the pre-shock pause pre-intervention was seconds ( % ci - ) while the post-intervention duration was seconds ( % ci - ). the difference in pre-shock pause duration was statistically significant with p < . . conclusion: these data indicate that after a simple educational intervention emphasizing decreasing time off chest prior to defibrillation the pre-shock pause duration decreased. future research must describe the sustainability of this intervention as well as the effects this process measure may have on outcomes such as survival to hospital discharge. background: the broselow tape (bt) has been used as a tool for estimating medication dosing in the emergency setting. the obesity trend has demonstrated a tendency towards insufficient pediatric weight estimations from the bt, and thus potential under-dosing of resuscitation medications. objectives: this study compared drug dosing based on the bt with dosing from a novel electronic tool (et) that accounts for provider estimation of body habitus. methods: data were obtained from a prospective convenience sample of children ages to years arriving to a pediatric emergency department. a clinician performed an assessment of body habitus (average/underweight, overweight, or obese), blinded to the patient's actual weight and parental weight estimate. parental estimate of weight and measured length and weight were collected. epinephrine dosing was calculated from the measured weight, the bt measurement, as well as from a smart-phone tool based on the measured length and clinician's estimate of body habitus, and a modified tool (mt) incorporating the parent estimate of habitus. the wilcoxson rank-sum test was used to compare median percent differences in dosing. results: one hundred children (mean age years) were analyzed; % were overweight or obese. clinicians correctly identified children as overweight/obese % of time (ci . - . ). adding parent estimate of weight improved this to a sensitivity of % (ci . - . ). the median difference between the weight-based epinephrine dose and bt dose was %. for the et the median difference from the weight-based dose was % (p = . compared to the bt), and for the mt was . % (p < . compared to the bt). when a clinically significant difference was defined as ± % of the actual dose, bt was within that range % of the time, et was within range % of the time (p = . ), and mt was within range % of the time ( background: in most out-of-hospital cardiac arrest (ohca) events, a call to - - is the first action by bystanders. accurate diagnosis of cardiac arrest by the call taker depends on the caller's verbal description. if cardiac arrest is not suspected, then no telephone cpr instructions will be given. objectives: we measured the effect of a change in the ems call taker question sequence on the accuracy of diagnosis of cardiac arrest by - - call takers. methods: we retrospectively reviewed the cardiac arrest registry to enhance survival (cares) dataset for january , through june , from a city, population , , with a longstanding telephone cpr program (apco). we included ohca cases of any age who were in arrest prior to the arrival of ems and for whom resuscitation was attempted. in early , - - call takers were taught to follow a revised telephone script that emphasized focused questions, assertive control of the caller, and provision of hands-only cpr instructions. the medical director personally explained the reasons for the changes, emphasizing the importance of assertive control of the caller and the comparative safety of chest compressions in patients not in cardiac arrest. beginning in , call recordings were reviewed regularly with feedback to the call taker by the - - center leadership. the main outcome measure was sensitivity of the - - call taker in diagnosing cardiac arrest. bystander cpr was reported by ems crews attending the event. we compared with and using the v test and odds ratios (or). results: there were ohca cases in , cases in , and in the first half of ( / , population). the mean age was ± years, and % of the events were witnessed. before the revision, % of ohca cases were identified by - - dispatchers; and after the revised questioning sequence, % were identified (or . , % ci . - . ). the false positive rate changed little (from /month to /month). the mean time to question callers was unchanged ( vs seconds). bystander cpr was performed in . % of events in , . % in , and . % of events in (p < . ). conclusion: emphasis on scripted assessment improved sensitivity without loss of specificity in identifying ohca. with repeated feedback, it translated to an increase in victims receiving bystander cpr. in an out-of hospital cardiac arrest population confirmed by autopsy salvatore silvestri, christopher hunter, george ralls, linda papa orlando regional medical center, orlando, fl background: quantitative end-tidal carbon dioxide (etco ) measurements (capnography) have consistently been shown to be more sensitive than qualitative (colorimetric) ones, and the reliability of capnography for assessing airway placement in low perfusion states has sometimes been questioned in the literature. objectives: this study examined the rate of capnographic waveform presence of an intubated out-of-hospital cardiac arrest cohort and its correlation to endotracheal tube location confirmed by autopsy. our hypothesis is that capnography is % accurate in determining endotracheal tube location, even in low perfusion states. methods: this cross-sectional study reviewed a detailed prehospital cardiac arrest database that regularly records information using the utstein style. in addition, the ems department quality manager routinely logs the presence of an alveolar (four-phase) capnographic waveform in this database. the study population included all cardiac arrest patients from january , through december , managed by a single ems agency in orange county, florida. patients were included if they had endotracheal intubation performed, had capnographic measurement obtained, failed to regain return of spontaneous circulation (rosc), and had an autopsy performed. the main outcome was the correlation of the presence of an alveolar waveform and the location of the ett at autopsy. results: during the study period, cardiac arrests were recorded. of these, had an advanced airway placed (ett or laryngeal tube airway), and no rosc. of the advanced airway cases, were managed with an ett. autopsies were performed on of these patients and resulted in our study cohort. the location of the ett at autopsy was recorded on all of these cases. capnographic waveforms were recorded in the field in all of these study patients, and % of the tubes were located within the trachea at autopsy. the sensitivity of capnography in determining proper endotracheal tube location was % in this study. conclusion: in our study, the presence of a capnographic waveform was % reliable in confirming proper placement of endotracheal tubes placed in outof-hospital patients with poor perfusion states. results: over variables were presented to the ems medical directors responding ( % survey population captured). among the myriad of responses, ( %) initiate cardiopulmonary resuscitation (cpr) at compressions to ventilations consistent with il-cor/aha guidelines. seven ( %) initiate continuous chest compressions from the start of cpr with no pause and interposed ventilations. nine ( %) begin chest compressions only during the first - minutes, with either passive oxygenation by oxygen mask (six; %) or no oxygen (three; %). airway management following non-invasive oxygenation and ventilation by primary endotracheal intubation occurs in systems ( %), while six ( %) use supraglottic devices. fourteen ( %) allow paramedics to decide between endotracheal and supraglottic device placement. thirty systems ( %) utilize continuous waveform capnography. the initial approach to non-ems witnessed ventricular fibrillation is chest compression prior to first defibrillation in systems ( %). eighteen systems ( %) escalate defibrillation energy settings, with four systems ( %) utilizing dual sequential defibrillation. twenty ( %) initiate therapeutic hypothermia in the field. conclusion: wide variability in ca care standards exists in america's largest urban ems systems in mid- , with many current practices promoting more continuity in chest compressions than specified in the ilcor/aha guidelines. endotracheal intubation, a past mainstay of ca airway management, is deemphasized in many systems. immediate defibrillation of non-ems witnessed ventricular fibrillation is uncommon. objectives: determine the out-of-hospital cardiac arrest survival in this area of puerto rico using the utstein method. methods: prospective observational cohort study of adult patients presenting with an out-of-hospital cardiac arrest to the upr hospital ed. study endpoints will be survival and neurologically intact survival at hospital discharge, months, and months. results: a total of consecutive cardiac arrest events were analyzed for a period of years. one-hundred fifteen events met criteria for primary cardiac etiology ( . %). the average age for this group was . years. there were female ( . %) and male ( . %) participants. the average time to start cpr was . minutes. transportation to the ed was . % by ems and . % by private vehicle. a total of events were witnessed ( . %). the survival rate to hospital admission was . %. the overall cardiac arrest survival was . % and overall neurologically intact survival was . %. neurologically intact survival at and months was . %. the rate of bystander cpr in our population was . % with a survival rate of . %. conclusion: survival from out-of-hospital cardiac arrest in the area served by the upr hospital is low but comparable to other cities in the us as reported by the cdc cardiac arrest registry to enhance survival (cares). this low survival rate might be due to low bystander cpr rate and prolonged time to start cpr. background: hyperventilation has been directly correlated with increased mortality for out-of-hospital cpr. ems providers may hyperventilate patients at levels above national bls guidelines. real-time feedback devices, such as ventilation timers, have been shown to improve cpr ventilation rates towards bls standards. it remains unclear if the combination of a ventilation timer and pre-simulation instruction would influence overall ventilation rates and potentially reduce undesired hyperventilation. objectives: this study measured ventilation rates of standard cpr (and pre-instruction on effects of hyperventilation) compared to cpr with the use of a commercial ventilation timer (and pre-instruction on effects of hyperventilation). we propose that use of a ventilation timer, measuring and displaying to ems providers real-time ventilations delivered, will have no difference in ventilation rates when comparing these groups. methods: this prospective study placed ems providers into four groups: two controls measuring ventilation rates before ( a) and after instruction ( b) on the deleterious effects of hyperventilation, and a concurrent intervention pair with before ( a) and after instruction ( b), with the second pair measuring ventilation rates with a ventilation timer that provides immediate feedback on respirations given. ventilation rates were measured for a -second period after one minute of simulated cpr using mannequins. the control set without instruction ( a, n = ) averaged . breaths ( % ci = . - . ) and with instruction ( b, n = ) averaged . breaths ( % ci = . - . ). the intervention set without instruction ( a, n = ) averaged . breaths ( % ci = . - . ) and with instruction ( b, n = ) averaged . breaths ( % ci = . - . ). there was a significant improvement (p = . ) in ventilation rates with use of a ventilation timer (control group versus intervention group regardless of pre-instruction). there was no statistically significant difference between groups with respect to instruction alone (p = . ). conclusion: the use of a ventilation timer significantly reduced overall ventilation rates, providing care closer to bls guidelines. the addition of pre-simulation instruction added no significant benefit to reducing hyperventilation. background: in , the american heart association (aha) recommended a compression rate of (roc) / min and a depth of compressions (doc) at least inches for effective cpr. as an educational tool for lay rescuers, the aha as adopted the catch phrase ''push hard, push fast''. objectives: in this irb-exempt study, we sought to determine if persons without formal cpr training could perform non-ventilated cpr as well as those who have been trained in the past or those currently certified. methods: a convenience sample of patrons of the new york state fair was asked to perform minutes of hands-only cpr on a prestan pp-am- m adult cpr manikin. these devices provide visual indicators of acceptable rate and depth of compressions. each subject was video recorded on a dell latitude laptop computer with a logitech quick cam using logitech quick cam . . for windows software. results: a total of volunteers ( male, female) aged - years participated: were never certified (nc) in cpr, were previously certified (pc), and were currently certified (cc). there was no difference in age across the groups. the cc group had a higher proportion of females (chi-square = . , p < . ). cc volunteers sustained roc and doc for an average of . seconds as compared to an average of . seconds (pc) and . seconds (nc) respectively. (f = . , p < . ). the cc maintained roc of closer to / min (mean . /min) when compared to the pc (mean . /min) and nc (mean . /min) groups (f = . , p < . ). a higher proportion of volunteers of the cc group were able to perform adequate doc (chi-square = . , p < . ), and hand placement (chisquare = . , p < . ) when compared to the other two groups. conclusion: compared to the target roc and doc, none of the groups did well and only subjects met target roc/doc. increased out-of-hospital cardiac arrest survivability due to lay rescuer intervention is only assured if cpr is effectively administered. the effect and benefit of maintaining formal cpr training and certification is clear. background: more than , out-of-hospital cardiac arrests (ohcas) occur annually in the united states (us). automated external defibrillators (aeds) are life-saving devices in public locations that can significantly improve survival. an estimated million aeds have been sold in the us; however, little is known about whether locations of aeds match oh-cas. these data could help determine optimal placement of future aeds and targeted cpr/aed training to improve survival. objectives: we hypothesized that the majority (> %) of aeds are not located in close proximity ( feet) to the occurrence of cardiac arrests in a major metropolitan city. methods: this was a retrospective review of prospectively collected cardiac arrest data from philadelphia ems from january , until december , . included were ohcas of presumed cardiac etiology in individuals years of age or older. excluded were oh-cas of presumed traumatic etiology, cases where resuscitation was terminated at the scene, and those dead on arrival. aed locations in philadelphia were obtained from myheartmap, a database of installed and wallmounted aeds in pennsylvania. we used gis mapping software to visualize where ohcas occurred relative to where aeds were located and to determine the radius of ohcas to aeds. arrests within a , , and foot radius of aeds were identified using the attribute location selection option in arcgis. the lengths of radii were estimated based on the average time it would take for a person to walk to and from an aed ( feet minutes; feet minutes; feet minutes). results: we mapped , ohcas and , aeds in philadelphia county. ohcas occurred in males ( %; / ) and the mean age was . years. ventricular fibrillation occurred in % ( / ). aeds were primarily located in schools/universities ( %), office buildings ( %), and residential buildings ( %). aeds were not identified within feet in % ( , ) of ohcas, within feet of % ( , ) of ohcas, and within feet in % ( , ) of ohcas. the figure (large black circles) illustrates aed/ohca within feet on the left and feet on the right. conclusion: aeds were rarely close to the locations of ohcas, which may be a contributor to low cardiac arrest survival rates. innovative models to match aed availability with ohcas should be explored. (originally submitted as a ''late-breaker.'') potential background: early and frequent epinephrine administration is advocated by acls; however, epinephrine research has been conducted primarily with standard cpr (std). active compression-decompression cpr with an impedance threshold device (acd-cpr + itd) has become the standard of care for out of hospital cardiac arrest in our area. the hemodynamic effects of iv epinephrine under this technique are not known. objectives: to determine the hemodynamic effects of iv epinephrine in a swine model undergoing acd-cpr+itd. methods: six female swine ( ± kg) were anesthetized, intubated, and mechanically ventilated. intracranial, thoracic aorta, and right atrial pressures were recorded via indwelling catheters. carotid blood flow (cbf) was recorded via doppler. etc , sp , and ekg were monitored. ventricular fibrillation was induced and went untreated for minutes. three minutes each of standard cpr (std), std-cpr+itd, and acd-cpr+itd was preformed. at minute of the resuscitation, lg/kg of iv epinephrine was administered and acd-cpr+itd was continued for minute. statistical analysis was performed with a paired t-test. results: aortic pressure and calculated cerebral and carotid perfusion pressures increased from std < std+itd < acd-cpr+itd (p £ . ). epinepherine administered during acd-cpr+itd signficantly increased mean aortic ( ± vs ± , p = . ), cerebral ( ± vs ± , p = . ), and coronary perfusion pressures ( ± vs ± , p = . ); however, mean cbf and etco decreased (respectively ± vs ± . , p = . ; ± vs ± , p = . ). conclusion: the administration of epinepherine during acd-cpr+itd signficantly increased markers of macrocirculation, while significantly decreasing etco , a proxy for organ perfusion. while the calculated cerebral perfusion pressures increased, the directly measured cbf decreased. this calls into question the ability of calculated perfusion pressures to accurately reflect blood flow and oxygen delivery to end organs. hypoxia background: during cardiac arrest most patients are placed on % oxygen with assisted ventilations. after return of spontaneous circulation (rosc), % oxygen is typically continued for an extended time. animal data suggest that immediate post-arrest titration of oxygen by pulse oximetry produces better neurocognitive/ histologic outcomes. recent human data suggest that arterial hyperoxia is associated with worse outcomes. objectives: to assess the relationship between hypoxia, normoxia, and hyperoxia post-arrest and outcomes in post-cardiac arrest patients treated with therapeutic hypothermia. methods: we conducted a retrospective chart review of post-arrest patients admitted to an academic medical center between january, and december, who had arterial blood gases (abg) drawn after rosc. demographic variables were analyzed using anova and chi-square tests as appropriate. unadjusted logistic regression analyses were performed to assess the relationship between hypoxia (pao < mmhg), normoxia ( - mmhg), hyperoxia (> mmhg), and mortality. results: on first abg ( patients), ( . %) were hypoxic, ( . %) normoxic, and ( . %) hyperoxic. the average age of the cohort was . years (no difference for hypoxic, normoxic, and hyperoxic patients). overall mortality was . % ( / ). there were no significant differences between initial heart rate, systolic blood pressure, sex, race, or pre-arrest functional status. in-hospital mortality was significantly higher when the first abg demonstrated hypoxia ( . %; / ) than for normoxia ( . %; / ) or hyperoxia ( %; / ). in unadjusted logistic regression analysis of first pao values, hyperoxia was not associated with increased mortality (or . ; % ci . - . ) but hypoxia was associated with increased mortality (or . ; % ci . - . ). conclusion: hypoxia but not hyperoxia on first abg was associated with mortality in a cohort of post-arrest patients. background: there are over , deaths due to cardiac arrest per year in the us. the aha recommends monitoring the quality of cpr primarily through the use of end tidal co (etco ). the level of etco is significantly dependant on minute ventilation and altered by pressor and bicarbonate use. cerebral oximetry (cereox) uses near infrared spectroscopy to non-invasively measure oxygen saturation of the frontal lobes of the brain. cereox has been correlated with cerebral blood flow and jugular vein bulb saturations. objectives: the objective of this study is to compare the simultaneous measurement of etco and cereox to investigate which monitoring method provides the best measure of cpr quality as defined by return of spontaneous circulation (rosc). methods: a prospective cohort of a convenient sample of patients using out-of-hospital and ed cardiac arrest from two large eds. patients were monitored simultaneously by etco and cereox during cpr. patient demographics and arrest data were collected using the utstein criteria. all patients were monitored throughout the resuscitation efforts. rosc was defined as a palpable pulse and a measurable blood pressure for a minimum of thirty minutes. results: twenty two patients were enrolled with complete data sets; % of the subjects had rosc. average down time of rosc subjects was minutes (sd ± . ) and minutes (sd ± . ) for subjects without rosc. the inability to obtain a value of either for etco or cereox was % and % specific with an % and % npv respectively for predicting lack of rosc. obtaining a value of either for etco or cereox was % and % sensitive, respectively in identifying rosc. subjects with rosc had sustained values above for . mins on cereox and . mins on etco prior to rosc. the increase in values over a three minute period prior to rosc was . on cereox and . on etco . conclusion: the inability to obtain a value of on either the etco or cereox strongly predicted lack of rosc. cereox provides a larger magnitude and closer temporal increase prior to rosc than etco . attaining a value of on cereox was more predictive of rosc than etco . an discrepancies due to communicating information to multiple listeners in a short amount of time. this creates a communication barrier not always apparent to practitioners. we examine the perceptions of ems and ed personnel on the transfer of care and its correlation to missing patient data. objectives: evaluate provider perception of information transfer by ems and ed personnel and compare this to an external observer's objective assessment. methods: this is a retrospective quality improvement program at an academic level i trauma center. transfers of medical and trauma patients from ems to ed personnel were attended by trained external observers, research associates (ra). ra recorded the data communicated: name, age, past medical history (pmh), allergies, medications, events, active problems, vital signs (vs), level of consciousness (loc), iv access, and treatments given. then, ems and ed staff rated their perception of transfer on a - rating scale. results: ra evaluated patient transfers ( medical and trauma). transfer time did not differ, . minutes for medical ( % ci: . - . ), . minutes for trauma patients ( % ci: . - . )(p = . ). missing data between the two groups also did not differ, except loc and treatment were missed more in medical transfers, while pmh was missed more in the trauma transfers. comparing the transfers with all vs present ( %, / ) and all vs missing ( %, / ), with all vs missing, there was no difference in perception of transfer for ems ( . / vs present vs . / vs absent) or ed staff ( . / vs present, . / vs absent). when all vital signs were missing, ra rated . % of transfers as poor, whereas when all vs were present . % of transfers were considered good. conclusion: ems and ed staff felt transfers of care were professional, teams were attentive, and had similar amounts of interruptions for both medical and trauma cases. their perception of transfer of care was similar even when key information was missing, although external observers rated a significant amount of transfers poorly. thus, ems and ed staffs were not able to evaluate their own performance in a transfer of care and external observers were found to be better evaluators of transfers of care. swati singh, john brown, prasanthi ramanujam ucsf, san francisco, ca background: ems transports a large number of psychiatric emergencies to emergency departments (ed) across the us. research on paramedic education related to behavioral emergencies is sparse, but based on expert opinion we know that gaps in paramedic knowledge and training exist. in our system, paramedics triage patients to medical, detoxification, and purely psychiatric destinations, so a paramedic's understanding of these emergencies directly affects the flow of patients in our eds. objectives: our objectives were to understand the gaps in current training and develop a targeted curriculum for field providers with a long term goal of appropriately recognizing and triaging subjects to the ed. methods: data were collected using a survey that was distributed during a paramedic association meeting in october . subjects were excluded if they did not complete the survey. survey questions addressed demographics of paramedics, frequency of various psychiatric emergencies and their confidence in managing these emergencies. data were collated, analyzed, and presented as descriptive statistics. results: forty-nine surveys were distributed with a response rate of % (n = / ). of the respondents, % (n = ) were male and % (n = ) had at least five years experience. mood, thought, and cognitive disorders were the most frequently encountered presentations and % (n = ) of respondents came across psychiatric emergencies multiple times a week. many respondents did not feel confident managing agitated delirium (n = , %), acute psychosis (n = , %), and intimate partner or elder abuse (n = , %). a third to a half of the respondents felt they have little or no training in chemical sedation (n = , %), verbal de-escalation (n = , %), and triaging patients (n = , %). conclusion: we identified a need for a revised curriculum on management of psychiatric emergencies. future steps will focus on development of a curriculum and change in knowledge after implementation of this curriculum. background: prehospital endotracheal intubation has long been a cornerstone of resuscitative efforts for critically ill or injured patients. paramedic airway management training will need to be modified due to the acc/aha guidelines to ensure maintenance of competency in overall management of airway emergencies. how best to modify the training of paramedics requires an understanding of current experience. objectives: the purpose of this report is to characterize the airway management expertise of experienced and non-experienced paramedics in a single ems system. methods: we retrospectively reviewed all prehospital intubations from an urban/suburban ambulance service (professional ambulance, inc.) over a five-year period (january , to december , ). characteristics of airway management by paramedics with - years of experience (group ) were compared to those with greater than years of experience (group ). airway management was guided by massachusetts statewide treatment protocols governing direct laryngoscopy and all adjunctive approaches. attempts are characterized by laryngoscope blade passing the lips. difficult and failed airways were managed with extraglottic devices (egd) or needle cricothyroidotomy. we reviewed patient characteristics, intubation methods, rescue techniques, and adverse events. results: patients required airway management: ( %) were performed by group and ( %) were performed by group . group was both faster to intubate ( . vs . attempts, p = . ) and less likely to use a rescue device ( . % vs . %, p = . ). both are equally likely to go directly to a rescue device ( % vs %, p = . ). all patients were successfully oxygenated and ventilated with either an endotracheal tube or egd. no surgical airways were performed and no patients died as a result of a failed airway. conclusion: while intubation success rates of paramedics with less than and greater than five years of experience are similar, less experienced paramedics use fewer attempts and are less likely to use a rescue device. both recognize difficult airways and go directly to rescue devices equally. this highlights difficulties faced maintaining competence. education requirements must be evaluated and redesigned to allow paramedics to maintain competence and emphasize airway management according to the latest resuscitation guidelines. how well do ems - - protocols predict ed utilization for pediatric patients? stephanie j. fessler , harold k. simon , daniel a. hirsh , michael colman emory university, atlanta, ga; grady health systems, atlanta, ga background: the use of emergency medical services (ems) for low-acuity pediatric problems has been well documented. however, it is unclear how accurately general ems dispatch protocols predict the subsequent ed utilization for these patients. objectives: to determine the ed resource utilization rate of pediatric patients categorized as low acuity by - - dispatch protocols and then subsequently transferred to a children's hospital. methods: all transports for pediatric patients from the scene by a large urban general ems provider that were prioritized as low acuity by initial - - dispatch protocols were identified. protocols were based on the national academy of medical priority dispatch system, v . starting on jan , , consecutive cases of patients transported to three pediatric emergency departments (ped) of a large tertiary care pediatric health care system were reviewed. demographics, ped visit characteristics, resource utilization, and disposition were recorded. those patients who received meds other than po antipyretics, had labs other than a strep test, a radiology study, a procedure, or were not discharged home were categorized into the significant ed resource utilization group. results: % of the patients were african american and either had public insurance or self-pay ( %, % respectively). the median age was months ( d- yr). % were female. none of these low-acuity patients were upgraded by ems operators en route. upon arrival to the ped, % of transported patients were classified into the significant utilization group. six of the total patients were admitted, including a y/o requiring emergent intubation, an m/o old with a broken cvl, a y/o with sickle cell pain crisis, and a y/o with altered mental status. the remainder of the significant resource utilization group consisted of children needing procedures, anti-emetics, narcotic pain control, labs, and xrays. conclusion: in this general ems - - system, dispatch protocols for pediatric patients classified as low priority did poorly in predicting subsequent ed utilization with % requiring significant resources. further, ems operators did not recognize a critical child who needed emergent intervention. opportunity exists to refine general ems - - protocols for children in order to more accurately define an ems priority status that better correlates with ultimate needs and resource utilization. the objectives: determine if there is an association between a patient's impression of the overall quality of care and his or her satisfaction with provided pain management. it was hypothesized that satisfaction with pain management would be significantly associated with a patient's impression of the overall quality of care. methods: this was a retrospective review of patient satisfaction survey data initially collected by an urban als ems agency from / / to / / . participants were randomly selected from all patients transported proportional to their paramedic defined acuity; categorized as low, medium, or high with a goal of interviews per month. the proportions of patients sampled from each acuity level were % low, % medium, and % high. patients were excluded if there was no telephone number recorded in the prehospital patient record or they were pronounced dead on scene. all satisfaction questions used a five-point likert scale with ratings from excellent to poor that were dichotomized for analysis as excellent or other. the outcome variable of interest was the patient's perception of the overall quality of care. the main independent variable had patients rate the staff who treated them at the scene on their helping to control or reduce their pain. demographic variables were assessed for potential confounding. results: there were , patients with complete data for the outcome and main independent variable with . % male respondents and an average age of . (sd = . ). overall quality of care was rated excellent by . % of patients while . % rated their pain management as excellent. of patients who rated their pain management as excellent, . % rated overall quality of care as excellent while only . % of patients rated overall quality excellent if pain management was not excellent. when controlling for potential confounding variables, those patients who perceived their pain management to be excellent were . ( % ci . - . ) times more likely to rate their overall quality of care as excellent compared to those with non-excellent perceived pain management. conclusion: patients' perceptions of the overall quality of care were significantly associated with their perceptions of pain management. objectives: the purpose of this study is to determine whether ground-based paramedics could be taught and retain the skills necessary to successfully perform a cricothyrotomy. methods: this retrospective study was performed in a suburban county with a population of , and , ems calls per year. participants were groundbased paramedics in a local ems system who were taught wire-guided cricothyrotomy as part of a standardized paramedic educational update program. as part of the educational program, paramedics were taught wire-guided cricothyrotomy on a simulation model previously developed to train emergency medicine residents. after viewing an instructional video, the participants were allowed to practice using a step checklist. not all of these steps were automatic failures. each paramedic was individually supervised performing a cricothyrotomy on the simulator until successful; a minimum of five simulations was required. retention was assessed using the same -step checklist during annual skills testing, after a minimum of weeks to a maximum of months posttraining. results: a total of paramedics completed both the initial training and reassessment during the time period studied. during the initial training phase, % ( of ) of the paramedics were successful in performing all steps of the wire-guided cricothyrotomy. during the retention phase . % ( of ) retained the skills necessary to successfully perform the wire-guided cricothyrotomy. of the -step checklist, most steps were performed successfully by all the paramedics or missed by only of the paramedics. step # , which involved removing the needle prior to advancing the airway device over the guidewire, was missed by . % ( of ) of the participants. step # was not an automatic failure since most participants immediately self-corrected and completed the procedure successfully. conclusion: paramedics can be taught and can retain the skills necessary to successfully perform a wireguided cricothyrotomy on a simulator. future research is necessary to determine if paramedics can successfully transfer these skills to real patients. helicopter emergency medical services in background: netcare is one of the largest private providers of emergency air medical care in south africa. each hems (helicopter emergency medical service) crew is manned by a physician-paramedic team and is dispatched based on specific medical criteria, time to definitive care, and need for physician expertise. objectives: to describe the characteristics of net-care air medical evacuations in gauteng province and to analyze the role of physicians in patient care and effect on call times. methods: all patients transported by a netcare helicopter over a one year period from january -december were enrolled in the study. injury classifications, demographics, procedures, scene and flight times were collected retrospectively from run sheets. data were described by medians and interquartile intervals. results: a total of patients were transported on flights originating from the netcare gauteng helicopter base. ninety-two percent were traumarelated, with % resulting from motor vehicle accidents. physician expertise was listed % of the time as the indication for air medical response. a total of advanced procedures were performed by physicians on patients, including paralytic-assisted intubations, chest tube placement, and cardiac pacing. the median total call time was minutes with minutes spent on scene, compared with and minutes when advanced procedures were performed by hems (p < . ). conclusion: trauma accounts for an overwhelming majority of patients requiring emergency air medical transportation. advanced medical procedures were performed by physicians in nearly a quarter of the patients. there were significant differences in call times when advanced procedures were performed by hems. objectives: we sought to evaluate the level of awareness and adoption of the off-line protocol guidelines by utah ems agencies. methods: we surveyed all ems agencies in utah months after protocol guideline release. medical directors, ems captains, or training coordinators completed a short phone survey regarding their knowledge of the emsc protocol guidelines, and whether their agency had adopted them. in particular, participants were asked about the pain protocol guideline and their management of pediatric pain. results: of the agencies, participated in the survey ( %). of those participating, agencies ( %) were excluded from the analysis: ( %) who only treat adults and ( %) who do not participate in electronic data entry. of the remaining agencies ( %), ( %) were familiar with the utah emsc protocol guidelines; agencies ( %) have either partially or fully adopted the protocol guidelines. agencies ( %) were familiar with the pain treatment protocol guideline; ( %) had adopted it; ( %) planned to either partially or fully adopt the protocol. overall, agencies ( %) had offline protocols allowing the administration of narcotics to children. of those, ( %) had intranasal fentanyl as an available medication and delivery route. of the agencies with offline protocols for pain, ( %) reported familiarity with the emsc pain protocol guideline. conclusion: the creation and dissemination of statewide emsc protocol guidelines results in widespread awareness ( %) and to date % of agencies have adopted them. future investigation into factors associated with protocol adoption should be explored. background: intranasal (in) naloxone is safe and effective for the treatment of opioid overdose. while it has been extensively studied in the out-of-hospital environment in the hands of paramedics and lay people, we are unaware of any studies evaluating the safety and efficacy of in naloxone administration by bls providers. in recent years in naloxone has been added to the bls armamentarium; however, most services/states require an als unit be dispatched and attempt an intercept if in naloxone is administered by the bls providers. objectives: the purpose of this study is to evaluate the safety and effectiveness of bls-administered in naloxone in an urban environment. methods: retrospective cohort review as part of the ongoing qa process of all patients who had in naloxone administration by bls providers. the study was part of a special projects waiver by massachusetts oems from february through november in a busy urban tiered ems system in the metro-boston area. exclusion criteria: cardiac arrest. demographic information was collected, as well as vital signs, number of naloxone doses by bls, patient response to bls naloxone administration (clinical improvement in mental status and/or respiratory status), als intercept. descriptive statistics and confidence intervals are reported using microsoft excel and spss . . results: fifty-six cases of bls-administered in naloxone were identified, and were excluded as cardiac arrests. the included cases had a mean age of . years ± . (range - ), and % (ci - ) were male. of the included cases, % (ci - ) of patients responded to bls administration of naloxone. of the responders, % (ci - ) required two doses. there were protocol violations representing % (ci . - . ) of the total administrations, however in % of these protocol violations the patients had a positive response to the administration of in naloxone. seven of the protocol violations were patients who required a second mg dose of naloxone. eleven cases did not have an als intercept; only of these patients did not respond to bls administration of naloxone. there were no identified adverse events. conclusion: bls providers safely and successfuly administered in naloxone achieving a response rate consistent with studies of als providers' administration of in naloxone. given the success rate of bls providers, it may be feasible for bls to manage responders without the aid of an als intercept. background: an estimated % of patients arriving by ambulance to the ed are in moderate to severe pain. however, the management of pain in the prehospital setting has been shown to be inadequate, and untreated pain may have negative consequences for patients. objectives: to determine if focused education on pediatric pain management and implementation of a pain management protocol improved the prehospital assessment and treatment of pain in adult patients. specifically, this study aimed to determine if documentation of pain scores and administration of morphine by ems personnel improved. methods: this was a retrospective before and after study conducted by reviewing a county-wide prehospital patient care database. the study population included all adult patients transported by ems between february and february with a working assessment of trauma or burn. ems patient care records were searched for documentation of pain scores and morphine administration years before and years after an intensive pediatric focused pain management education program and implementation of a pain management protocol. frequencies and % cis were determined for all patients meeting the inclusion criteria in the before and after time period and chisquare was used to compare frequencies between time periods. a secondary analysis was conducted using only subjects documented as meeting the protocol's treatment guidelines. results: , ( %) of , adult patients transported by ems during the study period met the inclusion criteria: , in the before and , in the after period. subject demographics were similar between the two periods. documentation of pain score did not change between the time periods ( background: there is a presumption that ambulance response times affect patient outcome. we sought to determine if shorter response times really make a difference in hospital outcomes. objectives: to determine if ambulance response time makes a difference in the outcomes of patients transported for two major trauma (motor vehicle crash injuries, penetrating trauma) and two major medical (difficulty breathing and chest pain complaints) emergencies. methods: this study was conducted in a metropolitan ems system serving a population total of , including urban and rural areas. cases were included if the private ems service was the first medical provider on scene, the case was priority , and the patient was years and older. a -month time period was used for the data evaluation. four diagnoses were examined: motor vehicle crash injuries, penetrating trauma, difficulty breathing, and chest pain complaints. ambulance response times were assessed for each of the four different complaints. the patients' initial vital signs were assessed and the number of vital signs out of range was recorded. a sampling of all cases which went to the single major trauma center was selected for evaluation of hospital outcome. using this hospital sample, number of vital signs out of range were assessed as a surrogate marker indicating severity of hospital outcome. correlation coefficients were used to evaluate interactions between independent and outcome variables. results: of the cases we reviewed over the month period, we found that the ems service responded significantly faster to trauma complaints at . minutes (n = ) than medical complaints at . minutes (n = ) . in the hospital sample of cases, number of vital signs out of range were positively correlated with hospital days (r = . ), admits (r = . ), icu admits (r = . ), and deaths (r = . ), but not response times (r = (-) . ). in the entire sample, there was no correlation between vital signs out of range and response times for any diagnosis (see figure) . conclusion: conclusions: based on our hospital sample which showed that number of vital signs out of range was a surrogate marker of worse hospital outcomes, we find that hospital outcomes are not related to initial response times. adverse effects following prehospital use of ketamine by paramedics eric ardeel baylor college of medicine, houston, tx background: ketamine is widely used across specialties as a dissociative agent to achieve sedation and analgesia. emergency medical services (ems) use ketamine to facilitate intubation and pain control, as well as to sedate acutely agitated patients. published studies of ems ketamine practice and effects are scarce. objectives: describe the incidence of adverse effects occurring after ketamine administration by paramedics treating under a single prehospital protocol. methods: a retrospective analysis was conducted of consecutive patients receiving prehospital ketamine from paramedics in the suburban/rural ems system of montgomery county hospital district, texas between august , and october , . ketamine administration indications were: need for rapid control of violent/agitated patients requiring treatment and transport; sedation and analgesia after trauma; facilitation of intubation and mechanical ventilation. ketamine administration contraindications were: equivalent ends achieved by less invasive means; hypertensive crisis; angina; signs of significantly elevated intracranial pressure; anticipated inability to support or control airway. all patients were included, regardless of indication for ketamine administration. data were abstracted from electronic patient care records and available continuous physiologic monitoring data, and analyzed for the presence of adverse effects as defined a priori in ''clinical practice guidelines for emergency department ketamine dissociative sedation: update.'' results: no patients were identified as experiencing adverse effects as defined by the referenced literature. ketamine was utilized most often for patients with the following nemsis provider's primary impression: ( %) altered level of consciousness, ( %) behavioral/psychiatric, ( %) traumatic injury. overall, combativeness was associated with ( %) patients. the mean age was years (range - years) and ( %) were male. the mean ketamine dose was mg (range - mg) and twenty-four ( %) patients received multiple administrations. conclusion: in this patient population, our data indicate that prehospital ketamine use by ems paramedics, across all indications for administration, was safe. further study of ketamine's utility in ems is warranted. an background: rigorous evaluation of the effect of implementing nationally vetted evidence-based guidelines (ebgs) has been notoriously difficult in ems. specifically, human subjects issues and the health insurance portability and accountability act (hipaa) present major challenges to linking ems data with distal outcomes. objectives: to develop a model that addresses the human subjects and hipaa issues involved with evaluating the effect of implementing the traumatic brain injury (tbi) ebgs in a statewide ems system. methods: the excellence in prehospital injury care (epic) project is an nih-funded evaluation of the effect of implementing the ems tbi guidelines throughout arizona (ninds- r ns - a ). to accomplish this, a partnership was developed between the arizona department of health services (adhs), the university of arizona, and more than ems agencies that serve approximately % of the state's population. results: ebg implementation: implementation follows all routine regulatory processes for making changes in ems protocols. in arizona, the entire project must be carried out under the authority of the adhs director. evaluation: a before-after system design is used (randomization is not acceptable). hipaa: as an adhsapproved public health initiative, epic is exempt from hipaa, allowing sharing of protected health information between participating entities. for epic, the state attorney general provided official verification of hi-paa exemption, thus allowing direct linkage of ems and hospital data. irb: once epic was officially deemed a public health initiative, the university irb process was engaged. as an officially sanctioned public health project, epic was determined to not be human subjects research. this allows the project to implement and evaluate the effect of this initiative without requiring individual informed consent. conclusion: by utilizing an ems-public health-university partnership, the ethical and regulatory challenges related to evaluating implementation of new ebgs can be successfully overcome. the integration of the department of health, the attorney general, and the university irb can properly protect citizens while permitting efficient implementation and rigorous evaluation of the effect of ebgs. this novel approach may be useful as a model for evaluation of implementing ems ebgs in other states and large counties. ( . %- . % by age) were transported to non-trauma centers. the most common reasons cited by ems for hospital selection were: patient preference ( . %), closest facility ( . %), and specialty center ( . %). patient preference increased with age (p for trend . ) and paralleled under-triage ( figure ). iss ‡ patients transported to non-trauma hospitals by patient request had lower unadjusted mortality ( . %, %ci . - . ) than similar patients transported to trauma centers ( . %, %ci . - . ) or transported for other reasons ( . %, %ci . - . ) (figure ) . under-triage appears to be influenced by patient preference and age. self-selection for transport to non-trauma centers may result in under-triaged patients with inherently better prognosis than triagepositive patients. background: only % of all out-of-hospital cardiac arrest (ohca) patients receive bystander cpr (cardiopulmonary resuscitation). the neighborhood in which an ohca occurs has significant influence on the likelihood of receiving bystander cpr. objectives: to utilize geographic information systems to identify ''high-risk'' neighborhoods, defined as census tracts with high incidence of ohca and low cpr prevalence. methods: design: secondary analysis of the cardiac arrest registry to enhance survival (cares) dataset for denver county, colorado. population: all consecutive adults (> years old) with ohca due to cardiac etiology from january , through december , . data analysis: analyses were conducted in arc-gis. three spatial statistical methods were used: local morans i (lmi), getis-ord gi*(gi*), and spatial empirical bayes (seb) adjusted rates. census tracts with high incidence of ohca, as identified by all three spatial statistical methods, were then overlain with low bystander cpr census tracts, which were identified in at least two out of three statistical methods (lmi, gi*, or the lowest quartile of bystander cpr prevalence). overlapping census tracts identified with both high ohca incidence and low cpr prevalence were designated as ''highrisk''. results: a total of arrests in census tracts occurred during the study period, with arrests included in final sample. events were excluded if they were unable to be geocoded (n = ), outside denver county (n = ), or occurred in a jail (n = ), hospital/ physician's office (n = ), or nursing home (n = ). for high ohca incidence: lmi identified census tracts, gi* identified census tracts, and the seb method identified census tracts. twenty-five census tracts were identified by all three methods. for low bystander cpr prevalence: lmi identified census tracts, gi* identified census tracts, and census tracts were identified as being in the lowest quartile of cpr prevalence. twenty-four census tracts were identified by two of the three methods. two census tracts were identified as high-risk having both high ohca incidence and low cpr prevalence (figure) . high-risk census tract demographics as compared to denver county are shown in the table. conclusion: the two high-risk census tracts, comprised of minority and low-income populations, appear to be possible sites for targeted community-based cpr interventions. objectives: we sought to assess the accuracy and correlation of geographic information system (gis) derived transport time compared to actual ems transport time in ohca patients. methods: prospective, observational cohort analysis of ohca patients in vancouver, b.c., one of the sites of the resuscitation outcomes consortium (roc). a random sample from all of the ohca cases from / through / was selected for analysis from one site of the roc epistry. using gis, ems transport time was derived from reported latitude/longitude coordinates of the ohca event to the actual receiving hospital. this was calculated via the actual network distance using arcgis. this gis-derived time was then compared to the actual ems transport time (in minutes) using the wilcoxon signed rank test. scatter plot analysis of actual vs. gis times were created to evaluate the relationship between actual and calculated time. a linear regression model predicting actual ems transport time from the derived gis-time was also developed in order to examine the potential relationship between the two variables. differences in the relationship were also investigated based on time of the day to reflect varying traffic conditions. results: cases were randomly selected for analysis. the median actual transport time was significantly longer than the median gis derived transport time ( . minutes vs. . minutes). scatter plot analysis did not reveal any significant correlation between actual and gis-based time. additionally, there was poor approximation of gis-based time and actual ems time (r = . ) with no evidence of a significant linear relationship between the two. the poorest correlation of time was observed during the morning hours ( : - : ; r = . ) while the strongest correlation was during the overnight hours ( : - : ; r = . ). conclusion: gis derived time does not appear to correlate well with actual ems transport time of ohca patients. efforts should be made to accurately obtain actual ems transport times for ohca patients. objectives: we first sought to describe the incidence of ohca presenting to the ed. we then sought to determine the association between hospital characteristics and survival to hospital admission. methods: we identified patients with diagnoses of cardiac arrest or ventricular fibrillation (icd- . or . ) in the nationwide emergency department sample, a nationally representative estimate of all ed admissions in the us. eds reporting ‡ patient with ohca were included. our primary outcome was survival to hospital admission. we examined variability in hospital survival rate and also classified hospitals into high or low performers based on median survival rate. we used this dichotomous hospital level outcome to examine factors associated with survival to admission including hospital and patient demographics, ed volume, cardiac arrest volume, and cardiac catheterization availability. all unadjusted and adjusted analyses were performed using weighted statistics and logistic regressions. results: of the hospitals, ( . %) were included. in total, , cases of cardiac arrest were identified, representing an estimated , cases nationally. overall ed ohca survival to hospital admission was . % (iqr . %, . %) in adjusted analyses, increased survival to admission was seen in hospitals with teaching status (or . , % ci . - . , p < . ), annual ed visits ‡ , (or . , % ci . - . , p < . ), and pci capability (or . , % ci . - . , p = . ). in separate adjusted analyses including teaching status and pci capabilities, hospitals with > annual cardiac arrest cases (or . , % ci . - . , p < . ) were also shown to have improved survival (figure) . conclusion: ed volume, cardiac arrest volume, and pci capability were associated with improved survival to hospital admission in patients presenting to the ed after ohca. an improved understanding of the contribution of ed care to ohca survival may be useful in guiding the regionalization of cardiac arrest care. background: prior investigations have demonstrated regional differences in out-of-hospital cardiac arrest (ohca) outcomes, but none have evaluated survival variability by hospital within a single major us city. objectives: we hypothesized that -day survival from ohca would vary considerably among one city's receiving hospitals. methods: we performed a retrospective review of prospectively collected cardiac arrest data from a large, urban ems system. our population included all ohcas with a recorded social security number (which we used to determine -day survival through the social security death index) that were transported to a hospital between / / and / / . we excluded traumatic arrests, pediatric arrests, and hospitals receiving less than ohcas with social security numbers over the three-year study period. we examined the associa-tion between receiving hospital and -day survival. additional variables examined included: level i trauma center status, teaching hospital status, ohca volume, and whether post-arrest therapeutic hypothermia (th) protocols were in place in . statistics were performed using chi-square tests and logistic regression. results: our study population comprised arrest cases delivered to unique hospitals with an overall -day survival of . %. mean age was . (sd . ) years. males comprised . % of the cohort; . % of victims were black. thirty-day survival varied significantly among the hospitals, ranging from . % to . % (chi-square . , p = . ). ohcas delivered to level i trauma centers were significantly more likely to survive ( . % vs. . %, p = . ), as were those delivered to hospitals known to offer post-arrest th ( . % vs. . %, p = . ). hospital teaching status and ohca volume were not associated with survival. conclusion: there was significant variability in ohca survival by hospital. patients were significantly more likely to survive if transported to a level i trauma center or hospital with post-arrest th protocols, suggesting a potential role for regionalization of ohca care. limiting our population to ohcas with recorded social security numbers reduced our power and may have introduced selection bias. further work will include survival data on the complete set of ohcas transported to hospitals during the three-year study period. background: traumatic brain injury is a leading cause of death and disability. previous studies suggest that prehospital intubation in patients with tbi may be associated with mortality. limited data exist comparing prehospital (ph) nasotracheal (nt), prehospital orotracheal (ot), and ed ot intubation and mortality following tbi. objectives: to estimate the associations between ph nt, ph ot, and ed ot intubation and in-hospital mortality in patients with moderate to severe tbi, with hypotheses that ph nt and ph ot intubation would be associated with increased mortality when compared to ed ot or no intubation. methods: an analysis using the denver health trauma registry, a prospectively collected database. consecutive adult trauma patients from - with moderate to severe tbi defined as head abbreviated injury scale (ais) scores of - . structured chart abstraction by blinded physicians was used to collect demographics, injury and prehospital care characteristics, intubation status and timing, in-hospital mortality and survival time, and neurologic function at discharge. poor neurologic function was defined as cerebral performance category score of - . multivariable logistic regression and survival analyses were performed, using multiple imputation for missing data. results: of the , patients, the median age was (iqr - ) years. the median ph gcs was (iqr - ), median injury severity score was (iqr - ), and median head ais was (iqr - ). ph nt occurred in . %, ph ot in . %, and ed ot in . %, while mortality occurred in . %. the -, -, and -hour survival analyses are outlined in the table. survival curves for ph nt, ph ot, and ed ot are demonstrated in the figure (p < . ) . conclusion: prehospital intubation in patients with moderate to severe tbi is associated with increased mortality. contrary to our initial hypothesis, there was also a significant association between ed intubation and mortality. these associations persisted despite survival time, and while adjusting for injury severity. background: sbdp is a breakdown product of the cytoskeletal protein alpha-ii-spectrin found in neurons and has been detected in severe tbi. objectives: this study examined whether early serum levels of sbdp could distinguish: ) mild tbi from three control groups; ) those with and without traumatic intracranial lesions on ct (+ct vs -ct); and ) those having a neurosurgical intervention (+nsg vs -nsg) in mild and moderate tbi (mmtbi). methods: this prospective cohort study enrolled adult patients presenting to two level i trauma centers following mmtbi with blunt head trauma with loss of consciousness, amnesia, or disorientation and a gcs - . control groups included uninjured controls and trauma controls presenting to the ed with orthopedic injuries or an mvc without tbi. mild tbi was defined as gcs and moderate tbi as having a gcs < . blood samples were obtained in all patients within hours of injury and measured by elisa for sbdp (ng/ml). the main outcomes were: ) the ability of sbdp to distinguish mild tbi from three control groups; ) to distinguish +ct from -ct and; ) to distinguish +nsg from -nsg. data were expressed as means with %ci, and performance was tested by roc curves (auc and %ci). results: there were patients enrolled: tbi patients ( gcs , gcs - ), trauma controls ( mvc controls and orthopedic controls), and uninjured controls. the mean age of tbi patients was years (range - ) with % males. fourteen ( %) had a +ct and % had +nsg. mean serum sbdp levels were . ( %ci . - . ) in normal controls, . ( . - . ) in orthopedic controls, . ( . - . ) in mvc controls, . ( . - . ) in mild tbi with gcs , and . ( . - . ) in tbi with gcs - (p < . ). the auc for distinguishing mild tbi from both controls was . ( %ci . - . ). mean sbdp levels in patients with -ct versus +ct were . ( . - . ) and . ( . - . ) respectively (p < . ) with auc = . ( %ci . - . ). mean sbdp levels in patients with -nsg versus +nsg were . ( . - . ) and . ( . - . ) respectively (p < . ) with auc = . ( %ci . - . ). conclusion: serum sbdp levels were detectable in serum acutely after injury and were associated with measures of injury severity including ct lesions and neurosurgical intervention. further study is required to validate these findings before clinical application. utility of platelet background: pre-injury use of anti-platelet agents (e.g., clopidogrel and aspirin) is a risk factor for increased morbidity and mortality in patients with traumatic intracranial hemorrhage (tich). some investigators have recommended platelet transfusion to reverse the anti-platelet effects in tich. objectives: this evidence-based medicine review examines the evidence regarding the effect of platelet transfusion in emergency department (ed) patients with pre-injury anti-platelet use and tich on patientoriented outcomes. methods: the medline, embase, cochrane library, and other databases were searched. studies were selected for inclusion if they compared platelet transfusion to no platelet transfusion in the treatment of adult ed patients with pre-injury anti-platelet use and tich, and reported rates of mortality, neurocognitive function, or adverse effects as outcomes. we assessed the quality of the included studies using ''grading of recommendations assessment, development and evaluation'' (grade) criteria. categorical data are presented as percentages with % confidence interval (ci). relative risks (rr) are reported when clinically significant. results: five retrospective, registry-based studies were identified, which enrolled patients cumulatively. based on standard criteria, three studies were of ''low'' quality evidence and two studies had ''very low'' qualities. one study reported higher in-hospital mortality in patients with platelet transfusion (ohm et al), another showed a lower mortality rate in patients receiving platelet transfusion (wong et al). three studies did not show any statistical difference in comparing mortality rates between the groups (table) . no studies reported intermediate-or long-term neurocognitive outcomes or adverse events. conclusion: five retrospective registry studies with suboptimal methodologies provide inadequate evidence to support the routine use of platelet transfusion in adult ed patients with pre-injury anti-platelet use and tich. abnormal levels of end-tidal carbon dioxide (etco ) are associated with severity of injury in mild and moderate traumatic brain injury (mmtbi) linda papa , artur pawlowicz , carolina braga , suzanne peterson , salvatore silvestri orlando regional medical center, orlando, fl; university of central florida, orlando, fl background: capnography is a fast, non-invasive technique that is easily administered and accurately measures exhaled etco concentration. etco levels respond to changes in ventilation, perfusion, and metabolic state, all of which may be altered following tbi. objectives: this study examined the relationship between etco levels and severity of tbi as measured by clinical indicators including glasgow coma scale (gcs) score, computerized tomography (ct) findings, requirement of neurosurgical intervention, and levels of a serum biomarkers of glial damage. methods: this prospective cohort study enrolled adult patients presenting to a level i trauma center following a mmtbi defined by blunt head trauma followed by loss of consciousness, amnesia, or disorientation and a gcs - . etco measurements were recorded from the prehospital and emergency department records and compared to indicators of tbi severity. results: of the patients enrolled, ( %) had a normal etco level and ( %) had an abnormal etco level. the mean age of enrolled patients was (range - ) and ( %) were male. mechanisms of injury included motor vehicle collision in ( %), motor cycle collision in ( %), fall in ( %), bicycle/ pedestrian struck in ( %), and other in ( %). eight ( %) patients had a gcs - and ( %) had a gcs - . of the ( %) patients with intracranial lesions on ct, ( %) had an abnormal etco level (p = . ). of the ( %) patients who required a neurosurgical intervention, % had an abnormal etco level (p = . ). levels of a biomarker indicative of astrogliosis were significantly higher in those with abnormal etco compared to those with a normal etco (p = . ). conclusion: abnormal levels of etco were significantly associated with clinical measures of brain injury severity. further research with a larger sample of mmtbi patients will be required to better understand and validate these findings. background: acetaminophen (apap) poisoning is the most frequent cause of acute hepatic failure in the us. toxicity requires bioactivation of apap to toxic metabolites, primarily via cyp e . children are less susceptible to apap toxicity; one current theory is that children's conjugative pathway (sulfonation) is more active. liquid apap preparations contain propylene glycol (pg), a common excipient that inhibits apap bioactivation and reduces hepatocellular injury in vitro and in rodents. cyp e inhibition may decrease toxicity in children, who tend to ingest liquid apap preparations, and suggests a potential novel therapy. objectives: to compare phase i (toxic) and phase ii (conjugative) metabolism of liquid versus solid prepara-tions of apap. we hypothesize that ingestion of a liquid apap preparation results in decreased production of toxic metabolites relative to a solid preparation, likely due to the presence of pg in the liquid preparations. methods: design-pharmacokinetic cross-over study. setting-university hospital clinical research center. subjects-adults ages - taking no chronic medications. interventions-subjects were randomized to receive a mg/kg dose of a commercially available solid or liquid apap preparation. after a washout period of greater than week, subjects received the same dose of apap in the alternate preparation. apap, apap-glucuronide and apap-sulfate (phase metabolites), apap-cysteinate and apap-mercapturate (phase metabolites) were analyzed via lc/ms in plasma over hours. peak concentrations and measured auc were compared using paired-sample t-tests. plasma pg levels were measured. results: fifteen subjects completed the protocol. peak concentrations and aucs of the cyp e derived toxic metabolites were significantly lower following ingestion of the liquid preparation (table, figure) . the glucuronide and sulfate metabolites were not different. pg was present following ingestion of liquid but not solid preparations. conclusion: ingestion of liquid relative to solid preparations in therapeutic doses results in decreased plasma levels of toxic apap metabolites. this may be due to inhibition of cyp e by pg, and may explain the decreased susceptibility in children. a less hepatotoxic formulation of apap can potentially be developed if co-formulated with a cyp e inhibitor. background: pressure immobilization bandages have been shown to delay mortality for up to hours after coral snake envenomation, providing an inexpensive and effective treatment when antivenin is not readily available. however, long-term efficacy has not been established. objectives: determine if pressure immobilization bandages, consisting of an ace wrap and splint, can delay morbidity and mortality from coral snake envenomation, even in the absence of antivenin therapy. methods: institutional animal care and use committee approval was obtained. this was a randomized, observational pilot study using a porcine model. ten pigs ( . kg to . kg) were sedated and intubated for hours. pigs were injected subcutaneously in the left distal foreleg with mg of lyophilized m. fulvius venom resuspended in water, to a depth of mm. pigs were randomly assigned to either a control group (no compression bandage and splint) or a treatment group (compression bandage and splint) approximately minute after envenomation. pigs were monitored daily for days for signs of respiratory depression, decreased oxygen saturations, and paresis/paralysis. in case of respiratory depression, pigs were euthanized and time to death recorded. chi-square was used to compare rates of survival up to days and a kaplan-meier survival curve constructed. results: average survival time of control animals was ± minutes compared to , ± , minutes for treated animals. significantly more pigs in the treatment group survived to hours than in the control group (p = . ). two of the treatment pigs survived to the endpoint of days, but showed necrosis of the distal lower extremity. conclusion: long-term survival after coral snake envenomation is possible in the absence of antivenin with the use of pressure immobilization bandages. the applied pressure of the bandage is critical to allowing survival without secondary consequences (i.e. necrosis) of envenomation. future studies should be designed to accurately monitor the pressures applied. background: patients exposed to organophosphate (op) compounds demonstrate a central apnea. the kölliker-fuse nuclei (kf) are cholinergic nuclei in the brainstem involved in central respiratory control. objectives: we hypothesize that exposure of the kf is both necessary and sufficient for op-induced central apnea. methods: anesthetized and spontaneously breathing wistar rats (n = ) were exposed to a lethal dose of dichlorvos using three experimental models. experiment (n = ) involved systemic op poisoning using subcutaneous (sq) dichlorvos ( mg/kg or x ld ). experiment (n = ) involved isolated poisoning of the kf using stereotactic microinjections of dichlorvos ( micrograms in microliters) into the kf. experiment (n = ) involved systemic op poisoning with isolated protection of the kf using sq dichlorvos ( mg/kg) and stereotactic microinjections of organophosphatase a (opda), an enzyme that degrades dichlorvos. respiratory and cardiovascular parameters were recorded continuously. histological verification of injection site was performed using kmno injections. animals were followed post-poisoning for hour or death. betweengroup comparisons were performed using a repeated measured anova or student's t-test where appropriate. results: animals poisoned with sq dichlorvos demonstrated respiratory depression starting . min post exposure, progressing to apnea . min post exposure. there was no difference in respiratory depression between animals with sq dichlorvos and those with dichlorvos microinjected into the kf. despite differences in amount of dichlorvos ( mg/kg vs . mg/kg) and method of exposure (sq vs cns microinjection), min following dichlorvos both groups (sq vs microinjection respectively) demonstrated a similar percent decrease in respiratory rate ( . vs . , p = . ), minute ventilation ( background: patients sustaining rattlesnake envenomation often develop thrombocytopenia, the etiology of which is not clear. laboratory studies have demonstrated that venom from several species, including the mojave rattlesnake (crotalus scutulatus scutulatus), can inhibit platelet aggregation. in humans, administration of crotaline fab antivenom (av) has been shown to result in transient improvement of platelet levels; however, it is not known whether platelet aggregation also improves after av administration. objectives: to determine the effect of c. scutulatus venom on platelet aggregation in vitro in the presence and absence of crotaline fab antivenom. methods: blood was obtained from four healthy male adult volunteers not currently using aspirin, nsaids, or other platelet-inhibiting agents. c. scutulatus venom from a single snake with known type b (hemorrhagic) activity was obtained from the national natural toxins research center. measurement of platelet aggregation by an aggregometer was performed using five standard concentrations of epinephrine (a known platelet aggregator) on platelet-rich plasma over time, and a mean area under the curve (auc) was calculated. five different sample groups were measured: ) blood alone; ) blood + c. scutulatus venom ( . mg/ml); ) blood + crotaline fab av ( mg/ml); ) blood + venom + av ( mg/ ml); ) blood + venom + av ( mg/ml). standard errors of the mean (sem) were calculated for each group. results: antivenom administration by itself did not significantly affect platelet aggregation compared to baseline ( . ± . %, p = . ). administration of venom decreased platelet aggregation ( . ± . %, p < . ). concentrated av administration in the presence of venom normalized platelet aggregation ( . ± . %) and in the presence of diluted av significantly increased aggregation ( . ± . %); p < . for both groups when compared to the venom-only group. to control for the effects of the venom and av, each was run independently in platelet-rich plasma without epinephrine; neither was found to significantly alter platelet aggregation. conclusion: crotaline fab av improved platelet aggregation in an in vitro model of platelet dysfunction induced by venom from c. scutulatus. the mechanism of action remains unclear but may involve inhibition of venom binding to platelets or a direct action of the antivenom on platelets. background: routine use of both breathalyzers and hand sanitizers is common across emergency depart-ments. the most common hand sanitizer on the market, purell, contains % ethyl alcohol and a lesser amount of isopropyl alcohol. previous investigations have documented that risk is low to the health care worker who applies frequent hand sanitizers to themselves. however, it is unknown whether this alcohol mixture causes false readings on a breathalyzer machine being used to determine alcohol levels on others. objectives: to determine the effect on the measurement of breathalyzer readings in individuals who have not consumed alcohol after hand sanitizer is applied to the experimenter holding a breathalyzer machine. methods: after obtaining informed consent, a breathalyzer reading was obtained in participants who had not consumed any alcohol in the last hours. three different experiments were performed with different participants in each. in experiment , two pumps of hand sanitizer were applied to the experimenter. without allowing the sanitizer to dry, the experimenter then measured the breathalyzer reading of the participant. in experiment , one pump of sanitizer was applied to the experimenter. measurements of the participant were taken without allowing the sanitizer to dry. in experiment , one pump of sanitizer was placed on the experimenter and rubbed until dry according to the manufacturer's recommendations. readings were recorded and analyzed using paired t-tests. results: the initial breathalyzer reading for all participants was . after two pumps of hand sanitizer were applied without drying (experiment ), breathalyzers ranged from . to . , with a mean above the legalintoxication limit of . (t( ) = ) . , p < . ). after one pump of hand sanitizer was applied without drying (experiment ), breathalyzers ranged from . to . , with a mean of . (t( ) = ) . , p < . ). after one pump of hand sanitizer was applied according to manufacturer's directions (experiment ), breathalyzers ranged from . to . with a mean of . (t( ) = ) . , p < . ). conclusion: use of hand sanitizer according to the manufacturer's recommendations results in a small but significant increase in breathalyzer readings. however, the improper and overuse of common hand sanitizer elevates routine breathalyzer readings, and can mimic intoxication in individuals who have not consumed alcohol. stephanie carreiro, jared blum, francesca beaudoin, gregory jay, jason hack objectives: the primary aim of this study is to determine if pretreatment with ile affects the hemodynamic response to epinephrine in a rat model. hemodynamic response was measured by a change in heart rate (hr) and mean arterial pressure (map). we hypothesized that ile would limit the rise in map and hr that typically follow epinephrine administration. methods: twenty male sprague dawley rats (approximately - weeks of age) were sedated with isoflurane and pretreated with a ml/kg bolus of ile or normal saline, followed by a mcg/kg dose of epinephrine intravenously. intra-arterial blood pressure and hr were monitored continuously until both returned to baseline (biopaq). a multifactorial analysis of variance (manova) was performed to assess the difference in map and hr between the two groups. standardized t-tests were then used to compare the peak change in map, time to peak map, and time to return to baseline map in the two groups. results: overall, a significant difference was found between the two groups in map (p = . ) but not in hr (p = . ). there was a significant difference (p = . ) in time to peak map in the ile group ( sec, % ci - ) versus the saline group ( sec, % ci - ) and a significant difference (p = . ) in time to return to baseline map in ile group ( sec, % ci - ) versus the saline group ( sec, % ci - ). there was no significant difference (p = . ) in the peak change in map of the ile group ( . , mmhg, % ci - ) versus the saline group ( . mmhg, % ci - ). conclusion: our data show that in this rat model ile pretreatment leads to a significant difference in map response to epinephrine, but no difference in hr response. ile delayed the peak effect and prolonged the duration of effect on map but did not alter the peak increase in map. this suggests that the use of ile may delay the time to peak effect of epinephrine if the drugs are administered concomitantly to the same patient. further research is needed to explore the mechanism of this interaction. rasch analysis of the agitation severity scale when used with emergency department acute psychiatry patients tania d. strout, michael r. baumann maine medical center, portland, me background: agitation is a frequently observed and problematic phenomenon in mental health patients being treated in the emergency setting. the agitation severity scale (agss), a reliable and valid instrument, was developed using classical test theory to measure agitation in acute psychiatry patients. objectives: the aim of this study was to analyze the agss according to the rasch measurement model and use the results to determine whether improvements to the instrument could be made. methods: this prospective, observational study was irb-approved. adult ed patients with psychiatric chief complaints and dsm-iv-tr diagnoses were observed using the agss. the rasch rating scale model was employed to evaluate the items comprising the agss using winsteps statistical software. unidimensionality, item fit, response category performance, person and item separation reliability, and hierarchical ordering of items were all examined. a principle components analysis (pca) of the rasch residuals was also performed. results: variable maps revealed that all of the agss items were used to some degree and that the items were ordered in a way that makes clinical sense. several duplicative items, indicating the same degree of agitation, were identified. item ( . ) and person ( . ) separation statistics were adequate, indicating appropriate spread of items and subjects along the agitation continuum and providing support for the instrument's reliability. keymaps indicated that the agss items are functioning as intended. analysis of fit demonstrated no extreme misfitting items. pca of the rasch residuals revealed a small amount of residual variance, but provided support for the agss as being unidimensional, measuring the single construct of agitation. the results of this rasch analysis support the agss as a psychometrically robust instrument for use with acute psychiatry patients in the emergency setting. several duplicative items were identified that may be eliminated and re-evaluated in future research; this would result in a shorter, more clinically useful scale. in addition, a gap in items for patients with lower levels of agitation was identified. generation of additional items intended to measure low levels of agitation could improve clinician's ability to differentiate between these patients. background: attempted suicide is one of the strongest clinical predictors of subsequent suicide and occurs up to times more frequently than completed suicide. as a result, suicide prevention has become a central focus of mental health policy. in order to improve current treatment and intervention strategies for those presenting with suicide attempt and self-injury in the emergency department (ed), it is necessary to have a better understanding of the types of patients who present to the ed with these complaints. objectives: to describe the epidemiology of ed visits for attempted suicide and self-inflicted injury over a year period. methods: data were obtained from the national hospital ambulatory medical care survey (nhamcs). all visits for attempted suicide and self-inflicted injury (e -e ) during - were included. trend analyses were conducted using stata's nptrend (a nonparametric test for trends that is an extension of the wilcoxon rank-sum test) and regression analyses. a two-tailed p < . was considered statistically significant. results: over the -year period, there were an average of , annual ed visits for attempted suicide and self-inflicted injury ( . [ % confidence interval (ci) . - . ] visits per , us population). the overall mean patient age was years, with visits most common among ages - ( . ; %ci . - . ). the average annual number of ed visits for suicide attempt and self-inflicted injury more than doubled from , in - to , in - . during the same timeframe, ed visits for these injuries per , us population almost doubled for males ( . to . ), females ( . to . ), whites ( . to . ), and blacks ( . to . ). no temporal differences were found for method of injury or ed disposition; there was, however, a significant decrease in visits determined by the physician to be urgent/emergent from % in to % in . conclusion: ed visit volume for attempted suicide and self-inflicted injury has increased over the past two decades in all major demographic groups. awareness of these longitudinal trends may assist efforts to increase research on suicide prevention. in addition, this information may be used to inform current suicide and self-injury related ed interventions and treatment programs. benjamin l. bregman, janice c. blanchard, alyssa levin-scherz george washington university, washington, dc background: the emergency department (ed) has increasingly become a health care access point for individuals with mental health needs. recent studies have found that rates of major depression disorder (mdd) diagnosed in eds are far above the national average. we conducted a study assessing whether individuals with frequent ed visits had higher rates of mdd than those with fewer ed visits in order to help guide screening and treatment of depressed individuals encountered in the ed. objectives: this study evaluated potential risk factors associated with mdd. we hypothesized that patients who are frequent ed visitors will have higher rates of mdd. methods: this was a single center, prospective, crosssectional study. we used a convenience sample of noncritically ill, english speaking adult patients presenting with non-psychiatric complaints to an urban academic ed over months in . we oversampled patients presenting with ‡ visits over the previous days. subjects were surveyed about their demographic and other health and health care characteristics and were screened with the phq , a nine-item questionnaire that is a validated, reliable predictor of mdd. we conducted bivariate (chi-square) and multivariate analysis controlling for demographic characteristics using sta-ta v. . . our principal dependent variable of interest was a positive depression screen (phq score ‡ ). our principal independent variable of interest was ‡ visits over the previous days. results: our response rate was . % with a final sample size of . of our total sample, ( . %) had three or greater visits within the prior days. one hundred ( %) frequent visitors had a positive phq mdd screen as compared to ( . %) of subjects with fewer than three visits (p < . ). in our multivariate analysis, the odds for having three or more visits for subjects who had a positive depression screen was . ( . , . ). of subjects with three or more visits with a positive depression screen, only ( %) were actively being treated for mdd at the time of their visit. conclusion: our study found a high prevalence of untreated depression among frequent users of the ed. eds should consider routinely screening patients who are frequent consumers for mdd. in addition, further studies should evaluate the effect of early treatment and follow up for mdd on overall utilization of ed services. access to psychiatric care among patients with depression presenting to the emergency department janice c. blanchard, benjamin l. bregman, dana rosenfarb, qasem al jabr, eun kim george washington university, washington, dc background: literature suggests that there is a high rate of major depressive disorder (mdd) in emergency department (ed) users. however, access to outpatient mental health services is often limited due to lack of providers. as a result, many persons with mdd who are not in active treatment may be more likely to utilize the ed as compared to those who are currently undergoing outpatient treatment. objectives: our study evaluated utilization rates and demographic characteristics associated with patients with a prior diagnosis of mdd not in active treatment. we hypothesized that patients who present to the ed with untreated mdd will have more frequent ed visits. methods: this was a single center, prospective, crosssectional study. we used a convenience sample of noncritically ill, english speaking adult patients presenting with non-psychiatric complaints to an urban academic ed over months in . subjects were surveyed about their demographic and other health and health care characteristics and were screened with the phq , a nine-item questionnaire that is a validated, reliable predictor of mdd. we conducted bivariate (chi-square) and multivariate analysis controlling for demographic characteristics using stata v. . . our principal dependent variable of interest was a positive depression screen (phq ‡ ). our analysis focused on the subset of patients with a prior diagnosis of mdd with a positive screen for mdd during their ed visit. results: our response rate was . % with a final sample size of . ( . %) patients screened positive for mdd with a phq score ‡ . of the patients with a positive depression screen, . % reported a prior history of treatment for mdd (n = ). of these patients, only . % were currently actively receiving treatment. hispanics who screened positive for depression with a history of mdd were less likely to actively be undergoing treatment as compared to non-hispanics ( . % versus . %, p = . ). patients with incomes less than $ , were more likely to actively be receiving treatment as opposed to higher incomes ( . % versus . % p = . ). conclusion: patients presenting to our ed with untreated mdd are more likely to be hispanic and less likely to be low income. the emergency department may offer opportunities to provide antidepressant treatment for patients who screen positive for depression but who are not currently receiving treatment. evaluation of a two-question screening tool (phq- ) for detecting depression in emergency department patients jeffrey p. smith, benjamin bregman, janice blanchard, nasser hashim, mary pat mckay george washington university, washington, dc background: the literature suggests there is a high rate of undiagnosed depression in ed patients and that early intervention can reduce overall morbidity and health care costs. there are several well validated screening tools for depression including the nine-item patient health questionnaire (phq- ). a tool using a two-question subset, the phq- , has been shown to be an easily administered, reasonably sensitive screening tool for depression in primary care settings. objectives: to determine the sensitivity and specificity of the phq- in detecting major depressive disorders (mdd) among adult ed patients presenting to an urban teaching hospital. we hypothesize that the phq- is a rapid, effective screening tool for depression in a general ed population. methods: cross sectional survey of a convenience sample of adult, non-critically ill, english speaking patients with medical and not psychiatric complaints presenting to the ed between am and pm weekdays. patients were screened for mdd with the phq- . we used spss v . to analyze the specificity, sensitivity, positive predictive value (ppv), negative predictive value (npv), and kappa of phq- scores of and (out of possible total score of ) compared to a validated cut-off score of or higher of points on the phq- . the two questions on the phq- are: ''over the last two weeks, how often have you had little interest in doing things? how often have you felt down, depressed or hopeless?'' responses are scored from - based on ''never'',''several days'', ''more than half'', ''nearly every day''. results: subjects of approached agreed to participate ( . % response rate), and ( . %) completed the phq- . the phq- identified ( . %) subjects with mdd. table outlines the percent of subjects who were positive and the sensitivity, specificity, positive, and negative predictive values and kappa for each cut-off on the phq- . conclusion: the phq- is a sensitive and specific screening tool for mdd in the ed setting. moreover, the phq- is closely correlated with the phq- , especially if a score of or greater is used. given the simplicity and ease of using a two-item questionnaire and the high rates of undiagnosed depression in the ed, including this brief, self-administered screening tool to ed patients may allow for early awareness of possible mdd and appropriate evaluation and referral. patients. however, much of this self-harm behavior is not discovered clinically and very little is known about the prevalence and predictors of current ed screening practices. attention to this issue is increasing due to the joint commission's patient safety goal , which focuses on identification of suicide risk in patients. objectives: to describe the prevalence and predictors of screening for self-harm and of presence of current self-harm in eds. methods: data were obtained from the nimh-funded emergency department safety assessment and followup evaluation (ed-safe). eight u.s. eds reviewed charts in real time for - hours a week between / and / . all patients presenting during enrollment shifts were characterized as to whether a selfharm screening had been performed by ed clinicians. a subset of patients with a positive screening was asked about the presence of self-harm ideation, attempts, or both by trained research staff. we used multivariable logistic regression to identify predictors of screening and of current self-harm. data were clustered by site. in each model we examined day and time of presentation, age < years, sex, race, and ethnicity. results: of the , patients presenting during research shift, , ( %) were screened for self-harm. screening rates varied among sites and ranged from % to %, with one outlier at %. of those screened, , ( %) had current self-harm. among those with selfharm approached by study personnel (n = , ), ( %) had thoughts of self-harm (suicidal or non-suicidal), ( %) had thoughts of suicide, ( %) had self-harm behavior, and ( %) had suicide attempt(s) over the preceding week. predictors of being screened were: age < years, male sex, weekend presentation, and night shift presentation (table) . among those screened, predictors of current self-harm were: age < years, white race, and night shift presentation. conclusion: screening for self-harm is uncommon in ed settings, though practices vary dramatically by site. patients presenting at night and on weekends are more likely to be screened, as are those under age and males. current self-harm is more common among those presenting on night shift, those under age , and whites. results: there were out-of-hospital records reviewed, and hospital discharge data were available in non-cardiac arrest patients. of the patients, ( . %) patients survived to hospital discharge and ( . %) died during hospitalization. the mean age of those transported was years (sd ), ( %) were male, ( %) were trauma-related, and ( %) were admitted to the icu. average systolic blood pressure (sbp), pulse (p), respiratory rate (rr), oxygen saturation (o sat), and end-tidal carbon dioxide (etco ) were sbp = (sd ), p = (sd ), rr = (sd ), o sat = % (sd ), and etco = (sd conclusion: of all the initial vital signs recorded in the out-of-hospital setting, etco was the most predictive of mortality. these findings suggest that pre-hospital etco is a useful clinical tool for determining severity of illness and appropriate triage. background: the prehospital use of continuous positive airway pressure (cpap) ventilation is a relatively new management for acute cardiogenic pulmonary edema (acpe) and there is little high quality evidence on the benefits or potential dangers in this setting. objectives: the aim of this study was to determine whether patients in severe respiratory distress treated with cpap in the prehospital setting have a lower mortality than those treated with usual care. methods: randomized, controlled trial comparing usual care versus cpap (whisperflowÒ) in a prehospital setting, for adults experiencing severe respiratory distress, with falling respiratory efforts, due to a presumed acpe. patients were randomised to receive either usual care, including conventional medications (nitrates, furosemide, and oxygen) plus bag-valve-mask ventilation, versus conventional medications plus cpap. the primary outcome was prehospital or in-hospital mortality. secondary outcomes were need for tracheal intubation, length of hospital stay, change in vital signs, and arterial blood gas results. we calculated relative risk with % cis. results: fifty patients were enrolled with mean age ae (sd ae ), male ae %, mortality ae %. the risk of death was significantly reduced in the cpap arm with mortality ae % ( deaths) in the usual care arm compared to ae % ( death) in the cpap arm (rr, ae ; % ci ae to ae ; p = ae ). patients who received cpap were significantly less likely to have respiratory acidosis (mean difference in ph ae ; % ci ae to ae ; p = ae ; n = ) than patients receiving usual care. the length of hospital stay was significantly less in the patients who received cpap (mean difference ae days; % ci ) ae to ae , p = ae ). conclusion: we found that cpap significantly reduced mortality, respiratory acidosis, and length of hospital stay for patients in severe respiratory distress caused by acpe. this study shows the use of cpap for acpe improves patient outcomes in the prehospital setting. (originally submitted as a ''late-breaker.'') trial reg. anzctr actrn ; funding fisher and paykal suppliers of the whisperflowÒ cpap device. background: because emergency service utilization continues to climb, validated methods to safely identify and triage low-acuity patients to either alternate care destinations or a complaint-appropriate level of ems response is of keen interest to ems systems and potentially payers. though the literature generally supports the medical priority dispatch system (mpds) as a tool to predict low-acuity patients by various standards, correlation with initial patient physiologic data and patient age is novel. objectives: to determine whether the six mpds priority determinants for protocol (sick person) can be used to predict initial ems patient acuity assessment or severity of an aggregate physiologic score. our longterm goal is to determine whether mpds priority can be used to predict patient acuity and potentially send only a first responder to do an in-person assessment to confirm this acuity, while reserving als transport resources for higher acuity patients. methods: calls dispatched through the wichita-sedgwick county - - center between july , and october , using mpds protocol (sick person) were linked to the ems patient care record for all patients and older. the six mpds priority determinants were evaluated for correlation with initial ems acuity code, initial vital signs, rapid acute physiology score (raps), or patient age. the ems acuity code scores patients from low to severe acuity, based on initial ems assessment. results: there were calls dispatched using protocol for those years of age and older during the period, representing approximately % of all ems calls. there is a significant difference in the first encounter vital signs among different mpds priority levels. based on the logistic regression model, the mpds priority code alone had a sensitivity of % and specificity of % for identifying low-acuity patients with ems acuity score as the standard. the area under the curve (auc) for roc is . for mpds priority codes alone, while addition of age increases this value to . . if we use the raps score as the standard to the mpds priority code, auc is . . if we include both mpds and age in the model, the auc is . . conclusion: in our system, mpds priority codes on protocol (sick person) alone, or with age or raps score, are not useful either as predictors of patient acuity on ems arrival or to reconfigure system response or patient destination protocols. alternate ambulance destination program c. nee-kofi mould-millman , tim mcmahan , michael colman , leon h. haley , arthur h. yancey emory university, atlanta, ga; grady ems, atlanta, ga background: low-acuity patients calling - - are known to utilize a large proportion of ems and ed resources. the national association of ems physicians and acep jointly support ems alternate destination programs (adps) in which low-acuity patients are allocated alternative resources non-emergently. analysis of one year's adp data from our ems system revealed that only . % of eligible patients were transported to alternate destinations (ambulatory clinics). reasons for this low success rate need investigation. objectives: to survey emts and discover the most frequent reasons given by them for transportation of eligible patients to eds instead of to clinics. methods: this study was conducted within a large, urban, hospital-based ems system. upon conducting an adp for months, a paper-based survey was created and pre-tested. all medics with any adp-eligible patient contact were included. emts were asked about personal, patient, and system related factors contributing to ed transport during the last months of the adp. qualitative data were coded, collated, and descriptively reported. results: sixty-three respondents ( emt-intermediates and emt-paramedics) completed the survey, representing % of eligible emts. thirty-one emts ( %) responded that they did not attempt to recruit eligible patients into the adp in the last program months. of those emts, ( %) attributed their motive to multiple, prior, failed recruitment attempts. the emts who actively recruited adp patients were asked reasons given by patients for clinic transport refusals: ( %) cited that patients reported no prior experience of care at the participating clinics, and ( %) reported patients had a strong preference for care in an ed. regarding system-related factors contributing to non-clinic transport, of the emts ( %) reported that clinic-consenting patients were denied clinic visits, mostly because of non-availability of same-day clinic appointments. conclusion: respondents indicated that poor emt enrollment of eligible patients, lack of available clinic time slots, and patient preference for ed care were among the most frequent reasons contributing to the low success rate of the adp. this information can be used to enhance the success of this, and potentially other adp programs, through modifications to adp operations and improved patient education. the effect of a standardized offline pain treatment protocol in the prehospital setting on pediatric pain treatment brent kaziny , maija holsti , nanette dudley , peter taillac , hsin-yi weng , kathleen adelgais university of utah, school of medicine, salt lake city, ut; university of colorado, school of medicine, aurora, co background: pain is often under treated in children. barriers include need for iv access, fear of delayed transport, and possible complications. protocols to treat pain in the prehospital setting improve rates of pain treatment in adults. the utah ems for children (emsc) program developed offline pediatric protocol guidelines for ems providers, including one protocol that allows intranasal analgesia delivery to children in the prehospital setting. objectives: to compare the proportion of pediatric patients receiving analgesia for orthopedic injury by prehospital providers before and after implementation of an offline pediatric pain treatment protocol. methods: we conducted a retrospective study of patients entered into the utah prehospital on-line active reporting information system (polaris, a database of statewide ems cases) both before and after initiation of the pain protocol. patients were included if they were age - years, with a gcs of - , an isolated extremity injury, and were transported by an ems agency that had adopted the protocol. pain treatment was compared for years before and months after protocol implementation with a wash-out period of months for agency training. the difference in treatment proportions between the two groups was analyzed and % cis were calculated. results: during the two study periods, patients met inclusion criteria. patient demographics are outlined in the table. / ( . %) patients were treated for pain before compared to / ( . %) patients treated after the pain protocol was implemented; a difference of . % ( % ci: . %- . %). patients were more likely to receive pain medication if they had a pain score documented (or: . ; % ci: . - . ) and if they were treated after the implementation of a pain protocol (or: . ; % ci: . - . ). factors not associated with the treatment of pain include age, sex, and mechanism of injury. conclusion: the creation and adoption of statewide emsc pediatric offline protocol guideline for pain management is associated with a significant increase in use of analgesia for pediatric patients in the prehospital setting. background: evidence-based guidelines are needed to determine the appropriate use of air medical transport, as few criteria currently used predict the need for air transport to a trauma center. we previously developed a clinical decision rule (cdr) to predict mortality in injured, helicopter-transported patients. objectives: this study is a prospective validation of the cdr in a new population. methods: a prospective, observational cohort analysis of injured patients ( ‡ y.o.) transported by helicopter from the scene to one of two level i trauma centers. variables analyzed included patient demographics, diagnoses, and clinical outcomes (in-hospital mortality, emergent surgery w/in hrs, blood transfusion w/in hrs, icu admit greater than hrs, combined outcome of all). prehospital variables were prospectively obtained from air medical providers at the time of transport and included past medical history, mechanism of injury, and clinical factors. descriptive statistics compared those with and without the outcomes of interest. the previous cdr (age ‡ , gcs £ , sbp < , flail chest) was prospectively applied to the new population to determine its accuracy and discriminatory ability. results: patients were transported from october -august . the majority of patients were male ( %), white ( %), with an injury occurring in a rural location ( %). most injuries were blunt ( %) with a median iss of . overall mortality was %. the most common reasons for air transport were: mvc with high risk mechanism ( %), gcs £ ( %), loc > minutes ( %), and mvc > mph ( %). of these, only gcs £ was significantly associated with any of the clinical outcomes. when applying the cdr, the model had a sensitivity of % ( . %- %), a specificity of . % ( . %- . %), a npv of % ( . %- %), and a ppv of . % ( . %- . %) for mortality. the area under the curve for this model was . , suggesting excellent discriminatory ability. conclusion: the air transport decision rule in this study performed with high sensitivity and acceptable specificity in this validation cohort. further external validation in other systems and with ground transported patients are needed in order to improve decision making for the use of helicopter transport of injured patients. background: acute non-variceal upper gastrointestinal (gi) bleeding is a common indication for hospital admission. to appropriately risk-stratify such patients, endoscopy is recommended within hours. given the possibility to safely manage patients as outpatients after endoscopy, risk stratification as part of an emergency department (ed) observation unit (ou) protocol is proposed. objectives: our objective was to determine the ability of an ou upper gi bleeding protocol to identify a lowrisk population, and to expeditiously obtain endoscopy and disposition patients. we also identified rates of outcomes including changes in hemoglobin, abnormal endoscopy findings, admission, and revisits. background: acute uncomplicated pyelonephritis (pyelo) requires no imaging but a ct flank pain protocol (ctfpp) may be ordered to determine if patients with pyelo and flank pain also have an obstructing stone. the prevalence of kidney stone and the characteristics predictive of kidney stone in pyelo patients is unknown. objectives: to determine elements on presentation that predict ureteral stone, as well as prevalence of stone and interventions in patients undergoing ct for pyelo. methods: retrospective study of patients at an academic ed who received a ctfpp scan between / and / . ctfpps were identified and randomly selected for review. pyelo was defined as: positive urine dip for infection and > wbc/hpf on formal urinalysis in addition to flank pain/cva tenderness, chills, fever, nausea, or vomiting. patients were excluded for age < y.o., renal disease, pregnancy, urological anomaly, or recent trauma. clinical data ( elements) were gathered blinded to ct findings; ct results were abstracted separately and blinded to clinical elements. ct findings of hydronephrosis and hyrdroureter (hydro) were used as a proxy for hydro that could be determined by ultrasound prior to ct. patients were categorized into three groups: ureteral stone, no significant findings, and intervention or follow-up required. classification and regression tree analysis was used to determine which variables could identify ureteral stone in this population of pyelo patients. results: out of the patients, ( . %) met criteria for pyelo; subjects had a mean age of ± . and % (n = ) were female. ct revealed ( %, % ci = . - . ) symptomatic stones, and ( %, % ci = . - . ) exams with no significant findings. two patients needed intervention/ follow-up ( %, % ci = . - . ), one for perinephric hemorrhage and the other for pancreatitis. hydro was predictive for ureteral stone with an or = . ( % ci = . - , p < . ). eleven ( %) ureteral stone patients were admitted and ( %) of them had procedures. of these patients, % had ct signs of obstruction, ( %) had hydronephrosis, and ( %) had hydroureter. conclusion: hydronephrosis was predictive of ureteral stone and in-house procedures. prospective study is needed to determine whether ct scan is warranted in patients with pyelonephritis but without hydronephrosis or hydroureter. curative objectives: the specific aim of this analysis was to describe characteristics of patients presenting to the emergency department (ed) at their index diagnosis, and to determine whether emergency presentation precludes treatment with curative intent. methods: we performed a retrospective cohort analysis on a prospectively maintained institutional tumor registry to identify patients diagnosed with crc from - . emrs were reviewed to identify which patients presented to the ed with acute symptoms of crc as the initial sign of their illness. the primary outcome variable was treatment plan (curative vs. palliative). secondary outcome variables included demographics, tumor type and location. descriptive statistics were conducted for major variables. chi-squre and fisher's exact tests were used to detect the association between categorical variables. two-sample t-test was used to identify the association between continuous and categorical variables. results: between jan and dec , patients were identified at our institution with crc. ( %) were male and ( %) were female, with mean age . ; sd: . . thirty-three patients ( . %) initially presented to the ed, of whom ( . %) received palliation. of patients who initially presented elsewhere, ( . %) received palliation. acute ed presentation with crc symptoms did not preclude treatment with curative intent (p = . ). patients who presented emergently were more likely to be female ( % vs male %; p = . ) and older ( vs. ; p = . ). there was no statistically significant relationship between age, sex, tumor location, or type and treatment approach. conclusion: patients with crc may present to the ed with acute symptoms, which ultimately leads to the diagnosis. emergent presentation of crc does not preclude patients from receiving therapy with curative intent. cannabinoid (or . , , and white blood cell (wbc) count ‡ , /mm (or . , % ci . - . ). conclusion: age ‡ years is not associated with need for admission from an ed observation unit. older adults can successfully be cared for in these units. initial temperature, respiratory rate, and pulse were not predictive of admission, but extremely elevated blood pressure was predictive. other relevant predictor variables included comorbidities and elevated wbc count. advanced age should not be a disqualifying criterion for disposition to an ed observation unit. older adult fallers in the emergency department luna ragsdale, cathleen colon-emeric duke university, durham, nc background: approximately / of community-dwelling older adults experience a fall each year, and . million are treated in u.s. emergency departments (ed) annually. the ed offers a potential location for identification of high-risk individuals and initiation of fall-prevention services that may decrease both fall rates and resource utilization. objectives: the goal of this study was to: ) validate an approach to identifying older adults presenting with falls to the ed using administrative data; and ) characterize the older adult who falls and presents to the ed and determine the rate of repeat ed visits, both fall-related and all visits, after an index fall-related visit. methods: we identified all older adults presenting to either of the two hospitals serving durham county residents during a six month period. manual chart review was completed for all encounters with icd codes that may be fall-related. charts were reviewed months prior and months post index visit. descriptive statistics were used to describe the cohort. results: a total of older adults were evaluated in the ed during this time period; ( . %) had an icd code for a potentially fall-related injury. of these, record review identified ( %) with a fall from standing height or less. of the fallers, . % of the patients were discharged, % were admitted, and % were admitted under observation. of those who fell, . % had an ed visit within the previous year. approximately / ( . %) of these were fall related. over half ( . %) of the patients who fell returned to the ed within one year of their index visit. a large proportion ( . %) of the return visits was fall-related. follow-up with a primary care provider or specialist was recommended in % of the patients who were discharged. overall mortality rate for fallers over the year following the index visit was %. conclusion: greater than fifty percent of fallers will return to the ed after an index fall, with a large proportion of the visits related to a fall. a large number of these fallers are discharged home with less than fifty percent having recommended follow-up. the ed represents an important location to identify high-risk older adults to prevent subsequent injuries and resource utilization. objectives: we studied whether falls from a standing position resulted in an increased risk for intracranial or cervical injury verses falling from a seated or lying position. methods: this is a prospective observational study of patients over the age of who presented with a chief complaint of fall to a tertiary care teaching facility. patients were eligible for the study if they were over age , were considered to be at baseline mental status, and were not triaged to the trauma bay. at presentation, a questionnaire was filled out by the treating physician regarding mechanism and position of fall, with responses chosen from a closed list of possibilities. radiographic imaging was obtained at the discretion of the treating physician. charts of enrolled patients were subsequently reviewed to determine imaging results, repeat studies done, or recurrent visits. all patients were called in follow-up at days to assess for delayed complications related to the fall. data were entered into a standardized collection sheet by trained abstractors. data were analyzed with fisher's exact test and descriptive statistics. this study was reviewed and approved by the institutional review board. results: two-hundred sixty two patients were enrolled during the study period. one-hundred ninety eight of these had fallen from standing and fell from either sitting or lying positions. the mean age for patients was (sd . ) for those who fell from standing and (sd . ) for those who fell from sitting or lying. there were patients with injuries who fell from standing: three with subdural hematomas, one with a cerebral contusion, one with an osteophyte fracture at c , and one with an occipital condyle fracture with a chip fracture of c . there were patients with injuries who fell from a seated or lying position: one with a traumatic subarachnoid hemorrhage and one with a type ii dens fracture. the overall rate of traumatic intracranial or cervical injury in elders who fell was %. no patients required surgical intervention. there was no difference in rate of injury between elders who fell from standing versus those who fell from sitting or lying (p = ). (table) . conclusion: both instruments identify the majority of patients as high-risk which will not be helpful in allocating scarce resources. neither the isar nor the trst can distinguish geriatric ed patients at high or low risk for or -month adverse outcomes. these prognostic instruments are not more accurate in dementia or lower literacy subsets. future instruments will need to incorporate different domains related to short-term adverse outcomes. background: for older adults, both inpatient and outpatient care involves not only the patient and physician, but often a family member or informal caregiver. they can assist in medical decision making and in performing the patient's activities of daily living. to date, multiple outpatient studies have examined the positive roles family members play during the physician visit. however, there is very limited information on the involvement of the caregiver in the ed and their relationship with the health outcomes of the patient. objectives: to assess whether the presence of a caregiver influences the overall satisfaction, disposition, and outpatient follow-up of elderly patients. we performed a three-step inquiry of patients over years old who arrived to the upenn ed. patients and care partners were initially given a questionnaire to understand basic demographic data. at the end of the ed stay, patients were given a satisfaction survey and followed through days to assess time to disposition, whether the patient was admitted or discharged, outpatient follow-up, and ed revisit rates. chi-square and t-tests were used to examine the strength of differences in the elderly patients' sociodemographics, self-rated health, receiving aid with their instrumental activities of daily living, and number of health problems by accompaniment status. multivariate regression models were constructed to examine whether the presence or absence of caregivers affected satisfaction, disposition, and follow-up. results: overall satisfaction was higher among patients who had caregivers ( . points), among patients who felt they were respected by their physician ( . points), and had lower lengths of stay ( hours). patients with caregivers were also more likely to be discharged home (or . ) and to follow-up with their regular physician (or . ). there was no evidence to suggest caregivers affected the overall rates of revisits back to an ed. conclusion: for older adults, medical care involves not only the patient and physician, but often a family member or an informal care companion. these results demonstrate the positive influence of caregivers on the patients they accompany, and emergency physicians should define ways to engage these caregivers during their ed stay. this will also allow caregivers to participate when needed and can help to facilitate transitions across care settings. background: shared decision making has been shown to improve patient satisfaction and clinical outcomes for chronic disease management. given the presence of individual variations in the effectiveness and side effects of commonly used analgesics in older adults, shared decision making might also improve clinical outcomes in this setting. objectives: we sought to characterize shared decision making regarding the selection of an outpatient analgesic for older ed patients with acute musculoskeletal pain and to examine associations with outcomes. methods: we conducted a prospective observational study with consecutive enrollment of patients age or older discharged from the ed following evaluation for moderate or severe musculoskeletal pain. two essential components of shared decision making, ) information provided to the patient and ) patient participation in the decision, were assessed via patient interview at one week using four-level likert scales. results: of eligible patients, were reached by phone and completed the survey. only % ( / ) of patients reported receiving 'a lot' of information about the analgesic, and only % ( / ) reported participating 'a lot' in the selection of the analgesic. there were trends towards white patients (p = . ) and patients with higher educational attainment (p = . ) reporting more participation in the decision. after adjusting for sex, race, education, and initial pain severity, patients who reported receiving 'a lot' of information were more likely to report optimal satisfaction with the analgesic than those receiving less information ( % vs. %, p < . ). after the same adjustments, patients who reported participating 'a lot' in the decision were also more likely to report optimal satisfaction with the analgesic ( % vs. %, p < . ) and greater reductions in pain scores (mean reduction in pain . vs. . , p < . ) at one week than those who participated less. background: quality of life (qol) measurements have become increasingly important in outcomes-based research and cost-utility analyses. dementia is a prevalent, often unrecognized, geriatric syndrome that may limit the accuracy of patient self-report in a subset of patients. the relationship between caregiver and geriatric patient qol in the emergency department (ed) is not well understood. objectives: to qualify the relationship between caregiver and geriatric patient qol ratings in ed patients with and without cognitive dysfunction. methods: this was a prospective, consecutive patient, cross-sectional study over two months at one urban academic medical center. trained research assistants screened for cognitive dysfunction using the short blessed test and evaluated health impairment using the quality of life-alzheimer's disease (qol-ad) test. when available in the ed, caregivers were asked to independently complete the qol-ad. consenting subjects were non-critically ill, english-speaking, community-dwelling adults over years of age. responses were compared using wilcoxon signed ranks test to assess the relationships between patient and caregiver scores from the qol-ad stratified by normal or abnormal cognitive screening results. significance was defined by p < . . results: patient qol ratings were obtained from patient-caregiver pairs. patients were % female, % african-american, with a mean age of -years, and % had abnormal cognitive screening tests. compared with caregivers, cognitively normal patients had no significant qol assessment differences except for questions of energy level and overall mood. on the other hand, cognitively impaired patients differed significantly on questions of energy level and ability to perform household chores with a trend towards significant differences for living setting (p = . ) and financial situation (p = . ). in each category, the differences reflected a caregiver underestimation of quality compared with the patient's self-rating. conclusion: discrepancies between qol domains and total scores for patients with cognitive dysfunction and their caregivers highlights the importance of identifying cognitive dysfunction in ed-based outcomes research and cost-utility analyses. further research is needed to quantify the clinical importance of the patient-and caregiver-assessed quality of life. background: age is often a predictor for increased morbidity and mortality. however, it is unclear whether old age is a predictor of adverse outcome in syncope. objectives: to determine whether old age is an independent predictor of adverse outcome in patients presenting to the emergency department following a syncopal episode. methods: a prospective observational study was conducted from june to july enrolling consecutive adult ed patients (> years) presenting with syncope. syncope was defined as an episode of transient loss of consciousness. adverse outcome or critical intervention were defined as gastrointestinal bleeding or other hemorrhage, myocardial infarction/percutaneous coronary intervention, dysrhythmia, alteration in antidysrhythmics, pacemaker/defibrillator placement, sepsis, stroke, death, pulmonary embolus, or carotid stenosis. outcomes were identified by chart review and -day follow-up phone calls. results: of patients who met inclusion criteria, an adverse event occurred in % of patients. overall, % of patients with risk factors had adverse outcomes compared to . % of patients with no risk factors. in particular, / ( %; % ci - %) of patients < with risk factors had adverse outcomes, while / ( %; % ci - %) of the elderly with risk factors had adverse outcomes. in contrast, among young people / ( %; % ci . - . %) of patients without risk factors had adverse outcomes while / ( . %; % ci . - %) of patients ‡ without risk factors had adverse outcomes. conclusion: although the elderly are at greater risk for adverse outcomes in syncope, age ‡ or older alone does not appear to be a predictor of adverse outcome following a syncopal event. based on these data, it should be safe to discharge home from the ed patients with syncope, but without risk factors, regardless of age. (originally submitted as a ''late-breaker.'') antibiotics background: adherence to national guidelines for hiv and syphilis screening in eds is not routine. in our ed, hiv and syphilis screening rates among patients tested for gonorrhea and chlamydia (gc/ct) have been reported to be % and %, respectively. objectives: to determine the effect of a sexually transmitted infection (sti) laboratory order set on hiv and syphilis screening among ed patients tested for gc/ct. we hypothesized that a sti order set would increase screening rates by at least %. methods: a -month, quasi-experimental study in an urban ed comparing hiv and syphilis screening rates of gc/ct-tested patients before (control phase) and after the implementation of a sti laboratory order set (intervention phase). the order set linked blood-based rapid hiv and syphilis screening with gc/ct testing. consecutive patients completing gc/ct testing were included. the primary outcome was the absolute difference in hiv and syphilis screening rates among gc/ ct-tested patients between phases. we estimated that subjects per phase were needed to provide % power (p-value of £ . ) to detect an absolute difference in screening rates of %, assuming a baseline hiv screening rate of %. results: the ed census was , . characteristics of patients tested for gc/ct were similar between phases: the mean age was years (sd = ) and most were female ( %), black ( %), hispanic ( %), and unmarried ( % services have recommended the use of immunization programs against influenza disease within hospitals since the s. the emergency department (ed) being the ''safety net'' for most non-insured people is an ideal setting to intervene and provide primary prevention from influenza. objectives: the purpose of this study is to assess whether a pharmacist-based influenza immunization program is feasible in the ed, and successful in increasing the percentage of adult patients receiving the influenza vaccine. methods: implementation of pharmacist-based immunization program was developed in coordination with ed physicians and nursing staff in . the nursing staff, using an embedded electronic questionnaire within their triage activity, screened patients for eligibility for the influenza vaccine. the pharmacist using an electronic alert system within the electronic medical record identified patients who we deemed eligible and if agreed the pharmacist vaccinated the patient. patients who refused to be vaccinated were surveyed to ascertain their perception concerning immunization offered by a pharmacist in the ed. feasibility and safety data for vaccinating patient in the ed were recorded. results: patients were approached and enrolled into the study. of the , % agreed to receive the influenza vaccine from a pharmacist in the ed. the median screening time was minutes and median vaccination time was minutes for a total of minutes from screening time to vaccination time. % were willing to receive the influenza vaccine from a pharmacist, and % were willing to receive the vaccine in the ed. the main reason given for refusing to receive the influenza vaccine was ''patient does not feel at risk of getting the disease''; only . % stated they were vaccinated recently. conclusion: a pharmacist-based influenza immunization program is feasible in the ed, and has the potential to successfully increase the percentage of adult patients receiving the vaccine. . ± . , p < . ). ed visits by hiv-infected patients also had longer lengths of ed stay ( ± . minutes vs. . ± . minutes, p < . ) and were more likely to be admitted ( % vs. %, p < . ), than their non-hiv infected counterparts. conclusion: although ed visits by hiv-infected individuals in the u.s. are relatively infrequent, they occur at rates higher than the general population, and consume significantly more ed resources than the general population. the background: the influence of wound age on the risk of infection in simple lacerations repaired in the emergency department (ed) has not been well studied. it has traditionally been taught that there is a ''golden period'' beyond which lacerations are at higher risk of infection and therefore should not be closed primarily. the proposed cutoff for this golden period has been highly variable ( - hours in surgical textbooks). objectives: to answer the following research question: are wounds closed via primary repair after the golden period at increased risk for infection? methods: we searched medline, embase, and other databases as well as bibliographies of relevant articles. we included studies that enrolled ed patients with lacerations repaired by primary closure. exclusion: . intentional delayed primary repair or secondary closure, . wounds requiring intra-operative repair, skin graft, drains, or extensive debridement, and . grossly contaminated or infected at presentation. we compared the outcome of wound infection in two groups of early versus delayed presentations (based on the cut-offs selected by the original articles). we used ''grading of recommendations assessment, development and evaluation'' (grade) criteria to assess the quality of the included trials. frequencies are presented as percentages with % confidence intervals. relative risk (rr) of infection is reported when clinically significant. results: studies were identified. four trials enrolling patients in aggregate met our inclusion/exclusion criteria. two studies used a -hour cut-off and the other two used a -hour cut-off for defining delayed wounds. the overall quality of evidence was low. the infection rate in the wounds that presented with delay ranged from . % to %. one study with the smallest sample size (morgan et al), which only enrolled lacerations to the hand and forearm, showed higher rates of infection in patients with delayed wounds (table). the infection rates in delayed wound groups in the remaining three studies were not significantly different from the early wounds. conclusion: the evidence does not support the existence of a golden period, nor does it support the role of wound age on infection rate in simple lacerations. background: although clinical studies in children have shown that temperature elevation is an independent and significant predictor of bacteremia in children, the relationship in adults is largely unknown or equivocal. objectives: review the incidence of positive blood cultures on critically ill adult septic patients presenting to an emergency department (ed) and determine the association of initial temperature with bacteremia. methods: july to july retrospective chart review on all patients admitted from the ed to an urban community hospital with sepsis and subsequently expiring within days of admission. fever was defined as a temperature ‡ °c. sirs criteria were defined as: ) temperature ‡ °c or £ °c, ) heart rate ‡ beats/ minute, ) respiratory rate ‡ or mechanical ventilation, ) wbc ‡ , /mm or < , or bands ‡ %. objectives: we examined the utility of limited genetic sequencing of bacterial isolates using multilocus sequence typing (mlst) to discriminate between known pathogenic blood culture isolates of s. epidermidis and isolates recovered from skin. methods: ten blood culture isolates from patients meeting the centers for disease control and prevention (cdc) criteria for clinically significant s. epidermidis bacteremia and ten isolates from the skin of healthy volunteers were studied. mlst was performed by sequencing bp regions of seven genes (arc, aroe, gtr, muts, pyr, tpia, and yqil) . genetic variability at these sites was compared to an international database (www.sepidermidis.mlst.net) and each strain was then categorized into a genotype on the basis of known genetic variation. the ability of the gene sequences to correctly classify strains was quantified using the support vector machine function in the statistical package r. , bootstrap resamples were performed to generate confidence bounds around the accuracy estimates. results: between-strain variability was considerable, with yqil being most variable ( alleles) and tpia being least ( allele). the muts gene, responsible for dna repair in s. epidermidis, showed almost complete separation between pathogenic and commensal strains. when the seven genes were used in a joint model, they correctly predicted bacterial strain type with % accuracy (iqr , %). conclusion: multilocus sequence typing shows excellent early promise as a means of distinguishing contaminant versus truly pathogenic isolates of s. epidermidis from clinical samples. near-term future goals will involve developing more rapid means of sequencing and enrolling a larger cohort to verify assay performance. conference are presented by influenza scenario in table and background: antiviral medications are recommended for patients with influenza who are hospitalized or at high risk for complications. however, timely diagnosis of influenza in the ed remains challenging. influenza rapid antigen tests have short turn-around times, making them potentially useful in the ed setting, but their sensitivities may be too low to assist with treatment decisions. objectives: to evaluate the test characteristics of the binaxnow influenza a&b rapid antigen test (rat) in ed patients. methods: we prospectively enrolled a systematic sample of patients of all ages presenting to two eds with acute respiratory symptoms or fever during three consecutive influenza seasons ( ) ( ) ( ) ( ) . research personnel collected nasal and throat swabs, which were combined and tested for influenza with rt-pcr using cdc-provided primers and probes. ed clinicians independently decided whether to obtain a rat during clinical care. rats were performed in the clinical laboratory using the binaxnow influenza a&b test on nasal swabs collected by ed staff. the study cohort included subjects who underwent both a research pcr and clinical rat. rat test characteristics were evaluated using pcr as the criterion standard with stratified sub-analyses for age group and influenza subtype (pandemic h n (ph n ), non-pandemic influenza a, influenza b). results: subjects were enrolled; subjects were pcr positive for influenza ( ph n , non-pandemic influenza a, and influenza b). for all age groups, rat sensitivities were low and specificities were high ( hiv infection with cd < ; and among nursing home residents, inability to independently perform activities of daily living. sources for bacterial cultures included blood, sputum (adults only), bronchoalveolar lavage (bal), tracheal aspirate, and pleural fluid. only sputum specimens with a bartlett score ‡ + were considered adequate for culturing. results: among children enrolled, ( %) had s. aureus cultured from ‡ specimen, including with methicillin-resistant s. aureus (mrsa) and with methicillin-susceptible s. aureus (mssa). specimens positive for s. aureus included pleural fluid, blood, tracheal aspirates, and bal. two children with s. aureus had evidence of co-infection: influenza a, and streptococcus pneumoniae. among adults enrolled, ( %) grew s. aureus from ‡ specimen, including with mrsa and with mssa. specimens positive for s. aureus included blood, sputum, and bal. five adults with s. aureus had evidence of co-infections: coronavirus, respiratory syncytial virus, s. pneumoniae, and pseudomonas aeruginosa. presenting clinical characteristics and outcomes of subjects with staphylococcal cap are summarized in tables - . conclusion: these preliminary findings suggest s. aureus is an uncommon cause of cap. although the small number of staphylococcal cases limits conclusions that can be drawn, in our analysis staphylococcal cap appears to be associated with co-infections, pleural effusions, and severe disease. future work will focus on continued enrollment and developing clinical prediction models to aid in diagnosing staphylococcal cap in the ed. background: emergency care has been a neglected public health challenge in sub-saharan africa. the goal of global emergency care collaborative (gecc) is to develop a sustainable model for emergency care delivery in low-resource settings. gecc is developing a training program for emergency care practitioners (ecps). objectives: to analyze the first patient visits at karoli lwanga ''nyakibale'' hospital ed in rural uganda to determine the knowledge and skills needed in training ecps. methods: a descriptive cross-sectional analysis of the first consecutive patient visits in the ed's patient care log was reviewed by an unblinded abstractor. data on demographics, procedures, laboratory testing, bedside ultrasounds (us) performed, radiographs (xrs) ordered, and diagnoses were collated. all authors discussed uncertainties and formed a consensus. descriptive statistics were performed. results: of the first patient visits, procedures were performed in ( . %) patients, including ( . %) who had ivs placed, ( . %) who received wound care, and ( . %) who received sutures. complex procedures, such as procedural sedations, lumbar punctures, orthopedic reductions, nerve blocks, and tube thoracostomies, occurred in ( . %) patients. laboratory testing, xrs, and uss were performed in ,( . %), ( . %), and ( %) patients, respectively. infectious diseases were diagnosed in ( . %) patients; ( . %) with malaria and ( . %) with pneumonia. traumatic injuries were present in ( %) patients; ( . %) needing wound care and ( . %) with fractures. gastrointestinal and neurological diagnoses affected ( . %) and ( . %) patients, respectively. conclusion: ecps providing emergency care in sub-saharan africa will be required to treat a wide variety of patient complaints and effectively use laboratory testing, xrs, and uss. this demands training in a broad range of clinical, diagnostic, and procedural skills, specifically in infectious disease and trauma, the two most prevalent conditions seen in this rural sub-saharan africa ed. assessment of point-of-care ultrasound in tanzania background: current chinese ems is faced with many challenges due to a lack of systematic planning, national standards in training, and standardized protocols for prehospital patient evaluation and management. objectives: to estimate the frequency with which prehospital care providers perform critical actions for selected chief complaints in a county-level ems system in hunan province, china. methods: in collaboration with xiangya hospital (xyh), central south university in hunan, china, we collected data pertaining to prehospital evaluation of patients on ems dispatches from a '' - - '' call center over a -month period. this call center services an area of just under km with a total population of . million. each ems team consists of a driver, a nurse, and a physician. this was a cross-sectional study where a single trained observer accompanied ems teams on transports of patients with a chief complaint of chest pain, dyspnea, trauma, or altered mental status. in this convenience sample, data were collected daily between am and pm. critical actions were pre-determined by a panel of emergency medicine faculty from xyh and the university of maryland school of medicine. simple statistical analysis was performed to determine the frequency of critical actions performed by ems providers. results: during the study period, patients were transported, of whom met the inclusion criteria. ( . %) evaluations were observed directly for critical actions. the table shows the frequency of critical actions performed by chief complaint. none of the patients with chest pain received an ecg even though the equipment was available. rapid glucose was checked in only . % of patients presenting with altered mental status. a lung exam was performed in . % of patients with dyspnea, and the respiratory rate was measured in . %. among patients transported for trauma, blood pressure, and heart rate were only measured in % and . %, respectively. conclusion: in this observation study of prehospital patient assessments in a county-level ems system, critical actions were performed infrequently for the chief complaints of interest. performance frequencies for critical actions ranged from to . %, depending on the chief complaint. standardized prehospital patient care protocols should be established in china and further training is needed to optimize patient assessment. trends little is known about the comparative effectiveness of noninvasive ventilation (niv) versus invasive mechanical ventilation (imv) in chronic obstructive pulmonary disease (copd) patients with acute respiratory failure. objectives: to characterize the use of niv and imv in copd patients presenting to the emergency department (ed) with acute respiratory failure and to compare the effectiveness of niv vs. imv. methods: we analyzed the - nationwide emergency department sample (neds), the largest, all-payer, us ed and inpatient database. ed visits for copd with acute respiratory failure were identified with a combination of copd exacerbation and respiratory failure icd- -cm codes. patients were divided into three treatment groups: niv use, imv use, and combined use of niv and imv. the outcome measures were inpatient mortality, hospital length of stay (los), hospital charges, and complications. propensity score analysis was performed using patient and hospital characteristics and selected interaction terms. results: there were an estimated , visits annually for copd exacerbation and respiratory failure from approximately , eds. ninety-six percent were admitted to the hospital. of these, niv use increased slightly from % in to % in (p = . ), while imv use decreased from % in to % in (p < . ); the combined use remained stable ( %). inpatient mortality decreased from % in to % in (p < . ). niv use varied widely between hospitals, ranging from % to % with median of %. in a propensity score analysis, niv use (compared to imv) significantly reduced inpatient mortality (risk ratio . ; % confidence interval [ci] . - . ), shortened hospital los (difference ) days; %ci ) to ) ), and reduced hospital charges ; ) . niv use was associated with a lower rate of iatrogenic pneumothorax compared with imv use ( . % vs. . %, p < . ). an instrumental analysis confirmed the benefits of niv use, with a % reduction in inpatient mortality in the niv-preferring hospitals. conclusion: niv use is increasing in us hospitals for copd with acute respiratory failure; however, its adoption remains low and varies widely between hospitals. niv appears to be more effective and safer than imv in the real-world setting. background: dyspnea is a common ed complaint with a broad differential diagnosis and disease-specific treatment. bronchospasm alters capnographic waveforms, but the effect of other causes of dyspnea on waveform morphology is unclear. objectives: we evaluated the utility of capnographic waveforms in distinguishing dyspnea caused by reactive airway disease (rad) from non-rad in adult ed patients. methods: this was a prospective, observational, pilot study of a convenience sample of adult patients presenting to the ed with dyspnea. waveforms, demographics, past medical history, and visit data were collected. waveforms were independently interpreted by two blinded reviewers. when the interpreters disagreed, the waveform was re-reviewed by both reviewers and an agreement was reached. treating physician diagnosis was considered the criterion standard. descriptive statistics were used to characterize the study population. diagnostic test characteristics and inter-rater reliability are given. results: fifty subjects were enrolled. median age was years (range - ), % were female, % were caucasian. / ( %) had a history of asthma or chronic obstructive pulmonary disease. rad was diagnosed by the treating physician in / ( %) and / ( %) had received treatment for dyspnea prior to waveform acquisition. the interpreters agreed on waveform analysis in / ( %) cases (kappa = . ). test characteristics for presence of acute rad, including %ci, were: overall accuracy % ( . %- . %), sensitivity % ( . %- . %), specificity % ( . %- . %), positive predictive value % ( . %- . %), negative predictive value % ( . %- . %), positive likelihood ratio . ( . - . ) , negative likelihood ratio . ( . - . ). conclusion: inter-rater agreement is high for capnographic waveform interpretation, and shows promise for helping to distinguish between dyspnea caused by rad and dyspnea from other causes in the ed. treatments received prior to waveform acquisition may affect agreement between waveform interpretation and physician diagnosis, affecting the observed test characteristics. asthma background: asthma and chronic obstructive pulmonary disease (copd) patients who present to the emergency department (ed) usually lack adequate ambulatory disease control. while evidence-based care in the ed is now well defined, there is limited inform-ation regarding the pharmacologic or non-pharmacologic needs of these patients at discharge. objectives: this study evaluated patients' needs with regard to the ambulatory management of their respiratory conditions after ed treatment and discharge. methods: over months, adult patients with acute asthma or copd, presenting to a tertiary care alberta hospital ed and discharged after being treated for exacerbations, were enrolled. using results from standardized in-person questionnaires, charts were reviewed by respiratory researchers to identify care gaps. results: overall, asthmatic and copd patients were enrolled. more patients with asthma required education on spacer devices ( % vs %). few asthma ( %) and no copd patients had written action plans; asthma patients were more likely to need adherence counseling ( % vs %) for preventer medications. more patients with asthma required influenza vaccination ( % vs %; p = . ); pneumococcal immunization was low ( %) in copd patients. only % of asthmatics reported ever being referred to an asthma education program and % of the copd patients reported ever being referred to pulmonary rehabilitation. at ed presentation, % of the asthmatics required the addition of inhaled corticosteroids (ics) and % required the addition of ics/long acting beta-agonist (ics/laba) combination agents. on the other hand, % of copd patients required the addition of long-acting anticholinergics while most ( %) were receiving preventer medications. finally, % of copd and % of asthma patients who smoked required smoking cessation counseling. conclusion: overall, we identified various care gaps for patients presenting to the ed with asthma and copd. there is an urgent need for high-quality research on interventions to reduce these gaps. methods: this is an interim, sub-analysis of an interventional, double-blinded study performed in an academic urban-based adult ed. subjects with acute exacerbation of asthma with fev < % predicted within minutes following initiation of ''standard care'' (including a minimum of mg nebulized albuterol, . mg nebulized ipratropium, and mg corticosteroid) who consented to be in a trial were included. all treatment was administered by emergency physicians unaware of the study objectives. patients were randomly assigned to treatment with placebo or an intravenous beta agonist. all subjects had fev and ds obtained at baseline, , , and hours after treatment. fev was measured using a bedside nspire spirometer, and ds was calculated using a modified borg dyspnea score. results: thirty-eight patients were included for analysis. spearman's rho test (rho) was used to measure correlations between fev and ds at , , and hours post study entry and subsequent hospitalization. rho is negative for fev (higher fev correlates to lower rate of hospitalization) and positive for ds (higher ds correlates to higher rate of hospitalization). at each time point, ds were more highly correlated to hospitalization than were fev (see table) . conclusion: dyspnea score at , , and hours were significantly correlated with hospital admission, whereas fev was not. in this set of subjects with moderate to severe asthma exacerbations, a standardized subjective tool was superior to fev for predicting subsequent hospitalization. methods: this is an interim, subgroup analysis of a prospective, interventional, double-blind study performed in an academic urban ed. subjects who were consented for this trial presented with acute asthma exacerbations with fev £ % predicted within minutes following initiation of ''standard care'' (includes a minimum of . mg nebulized albuterol, . mg nebulized ipratropium, and mg of a corticosteroid). ed physicians who were unaware of the study objectives administered all treatments. subjects were randomized in a : ratio to either placebo or investigational intravenous beta agonist arms. blood was obtained at and . hours after the start of the hour long infusion. blood was centrifuged and serum stored at ) °c, and then shipped on dry ice for albuterol and lactate measurements at a central lab. the treatment lactate and d lactate were correlated with hr serum albuterol concentrations and hospital admission using partial pearson correlations to adjust for ds. results: subjects were enrolled to date, with complete data. the mean baseline serum lactate level was . mg/dl (sd ± . ). this increased to . mg/ dl (sd ± . ) at . hrs. the mean hr ds was . (sd ± . ). the correlations between treatment lactate, d lactate, hr serum albuterol concentrations (r, s and total) and admission to hospital are shown (see table) . both treatment and d lactate were highly conrrelated with total serum albuterol, r albuterol, and s albuterol. there was no correlation between treatment lactate or d lactate and hospital admission. conclusion: lactate and d lactate concentrations correlate with albuterol concentrations in patients presenting had asthma. fifty one percent were < years old and % were female. we found a decline of % ( % ci: %- %, p < . ; r = . , p < . ) in the overall yearly asthma visits to total ed visits from to . when we analyzed sex and age groups separately, we found no statistically significant changes for females or for males < years old (r £ . , p ‡ . ). for females and males > years old, yearly asthma visits to total ed visits from to decreased % ( % ci: %- %, p < . ; r = . , p < . ) and % ( % ci: %- %, p < . ; r = . , p < . ), respectively. conclusion: we found an overall decrease in yearly asthma visits to total ed visits from to . we speculate that this decrease is due to greater corticosteroid use despite the increasing prevalence of asthma. it is unclear why this decrease was seen in adults and not in children and why it was greater for adult females than males. objectives: our objectives were to describe the use of a unique data collection system that leveraged emr technology and to compare its data entry error rate to traditional paper data collection. methods: this is a retrospective review of data collection methods during the first months of a multicenter study of ed, anti-coagulated, head injury patients. on-shift ed physicians at five centers enrolled eligible patients and prospectively completed a data form. enrolling ed physicians had the option of completing a one-page paper data form or an electronic ''dotphrase'' (dp) data form. our hospital system uses an epicÒbased emr. a feature of this system is the ability to use dps to assist in medical information entry. a dp is a preset template that may be inserted into the emr when the physician types a period followed by a code phrase (in this case ''.ichstudy''). once the study dp was inserted at the bottom of the electronic ed note, it prompted enrolling physicians to answer study questions. investigators then extracted data directly from the emr. our primary outcomes of interest were the prevalence of dp data form use and rates of data entry errors. results: from / through / , patients were enrolled. dp data forms were used in ( . %; % ci . , . %) cases and paper data forms in ( . %; % ci . , . %). the prevalence of dp data form use at the respective study centers was %, %, %, %, and %. sixty-six ( . %; % ci . , . %) of physicians enrolling patients used dp data entry at least once. using multivariate analysis, we found no significant association between physician age, sex, or tenure and dp use. data entry errors were more likely on paper forms ( / , . %; % ci . , . %) than dp data forms ( / , . %; % ci . , . %), difference in error rates . % ( % ci . , . %, p < . ). conclusion: dp data collection is a feasible means of study data collection. dp data forms maintain all study data within the secure emr environment obviating the need to maintain and collect paper data forms. this innovation was embraced by many of our emergency physicians. we found lower data entry error rates with dp data forms compared to paper forms. background: inadequate randomization, allocation concealment, and blinding can inflate effect sizes in both human and animal studies. these methodological limitations might in part explain some of the discrepancy between promising results in animal models and non-significant results in human trials. whereas blinding is not always possible, in clinical or animal studies, true randomization with allocation concealment is always possible, and may be as important in minimizing bias. objectives: to determine the frequency with which published emergency medicine (em) animal research studies report randomization, specific randomization methods, allocation concealment, and blinding of interventions and measurements, and to estimate whether these have changed over time. methods: all em animal research publications from / through / in ann emerg med and acad emerg med were reviewed by two trained investigators for a statement regarding randomization, and specific descriptions of randomization methods, allocation concealment, blinding of intervention, and blinding of measurements, when possible. raw initial agreement was calculated and differences were settled by consensus. the first (period = - ) and second (period = - ) -year periods were compared with % confidence intervals. results: of em animal research studies, were appropriate for review because they involved intervention in at least two groups. blinding of interventions and measurements were not considered possible in % and %, respectively. significant differences between period and were absent, although there was a trend towards less blinding of interventions and more blinding of measurements. raw agreement was %. conclusion: although randomization is mentioned in the majority of studies, allocation concealment and blinding remain underutilized in em animal research. we did not compare outcomes between blinded and non-blinded, randomized and non-randomized studies, because of small sample size. this review fails to demonstrate significant improvement over time in these methodological limitations in em animal research publications. journals might consider requiring authors to explicitly describe their randomization, allocation, and blinding methods. background: cluster randomized trials (crts) are increasingly utilized to evaluate quality improvement interventions aimed at health care providers. in trials testing ed interventions, migration of eps between hospitals is an important concern, as contamination may affect both internal and external validity. objectives: we hypothesized geographically isolating emergency departments would prevent migratory contamination in a crt designed to increase ed delivery of tpa in stroke (the instinct trial). methods: instinct was a prospective, cluster-randomized, controlled trial. twenty-four michigan community hospitals were randomly selected in matched pairs for study. following selection of a single hospital, all hospitals within miles were excluded from the sample pool. individual emergency physicians staffing each site were identified at baseline ( ) and months later. contamination was defined at the cluster level, with substantial contamination defined a priori as > % of eps affected. non-adherence, total crossover (contamination + non-adherence), migration distance and characteristics were determined. results: emergency physicians were identified at all sites. overall, ( . %) changed study sites. one moved between control sites, leaving ( . %) total crossovers. of these, ( . %) moved from intervention to control (contamination) and ( . %) moved from control to intervention (non-adherence). contamination was observed in of sites, with % and % contamination of the total site ep workforce at follow-up, respectively. two of crossovers occurred between hospitals within the same health system. average migration distance was miles for all eps in the study and miles for eps moving from intervention to control sites. conclusion: the mobile nature of emergency physicians should be considered in the design of quality improvement crts. use of a -mile exclusion zone in hospital selection for this crt was associated with very low levels of substantial cluster contamination ( of ) and total crossover. assignment of hospitals from a single health system to a single study group and/or an exclusion zone of miles would have further reduced crossovers. increased reporting of contamination in cluster randomized controlled trials is encouraged to clarify thresholds and facilitate crt design. objectives: an extension of the lr, the average absolute likelihood ratio (aalr), was developed to assess the average change in the odds of disease that can be expected from a test, or series of tests, and an example of its use to diagnose wide qrs complex tachycardia (wct) is provided. methods: results from two retrospective multicenter case series were used to assess the utility of qrs duration and axis to assess for ventricular tachycardia (vt) in patients with undifferentiated regular sustained wct. serial patients with heart rate (hr) > beats per minute and qrs duration > milliseconds (msec) were included. the final tachydysrhythmia diagnosis was determined by a number of methods independent of the ecg. the aalr is defined as: aalr = /n total [r (n i *lr i ) (for lr > ) + r (n k /lr k ) (for lr < )], where lr i and lr k are the interval lrs, and n i and n k are the number of patients with test results within the corresponding intervals. roc curves were constructed, and interval lrs and aalrs were calculated for the qrs duration and axis tests individually, and when applied together. confidence intervals were bootstrapped with , replications using the r boot package. results: patients were included: with supraventricular tachycardia (svt) and with vt. optimal qrs intervals (msec) for distinguishing vt from svt were: qrs £ , < qrs < , and qrs ‡ . qrs axis results were dichotomized to upward right axis ( - degrees) or not () to degrees). results are listed in the table. conclusion: application of the qrs interval and axis tests together for patients with wide qrs complex tachycardia changes the odds of ventricular tachycardia, on average, by a factor of . ( % ci . to . ), and this is mildly improved over the qrs duration test alone. both a strength and weakness of the aalr is its dependence on the pretest probability of disease. the aalr may be helpful for clinicians and researchers to evaluate and compare diagnostic testing approaches, particularly when strategies with serial non-independent tests are considered. consultation for adults with metastatic solid tumors at an urban, academic ed located within a tertiary care referral center. field notes were grouped into barrier categories and then quantified when possible. patient demographics for those who did and did not enroll were extracted from the medical record and quantified. patients who did not meet inclusion criteria for the study (e.g., cognitive impairment) were excluded from the analysis. results: attempts were made to enroll eligible patients in the study, and were successfully enrolled ( % enrollment rate). barriers to enrollment were deduced from the field notes and placed into the following categories from most to least common: patient refusal ( ); diagnostic uncertainty regarding cancer stage ( ); severity of symptoms preclude participation ( ); patient unaware of illness or stage ( ); and family refusal ( ). conclusion: patients, families, and diagnostic uncertainty are barriers to enrolling ed patients with advanced illness in clinical trials. it is unclear whether these barriers are generalizable to other study sites and disease processes other than cancer. objectives: the purpose of this study was to evaluate the use of a high-fidelity mannequin bedside simulation scenario followed by a debriefing session as a tool to improve medical student knowledge of palliative care techniques. methods: third year medical students participating in a -week simulation curriculum during a surgery/ emergency medicine/anesthesia clerkship were eligible for the study. all students were administered a pretest to evaluate their baseline knowledge of palliative care and randomized to a control or intervention group. during week or , students in the intervention group participated in and observed two end-of-life scenarios. following the scenarios, a faculty debriefer trained in palliative care addressed critical actions in each scenario. during week , all students received a posttest to evaluate for improvement in knowledge. the pre-test and post-test consisted of questions addressing prognostication, symptom control, and the medicare hospice benefit. students were de-identified and pre-and post-tests were graded by a blinded scorer. results: from jan-dec , students were included in the study and were excluded due to incomplete data. the mean score on the pre-test for the intervention group was . , and for the control group was . (p = . the results indicate that educators identify the most important scenarios as protocol-based simulations. respondents also suggested that scenarios of very common emergency department presentations bear a great deal of importance. emergency medicine educators assign priority to simulations involving professionalism and communication. finally, many respondents noted that they use simulation to teach the presentation and management of rare or less frequent, but important disease processes. the identification of these scenarios would suggest that educators find simulation useful for filling in ''gaps'' in resident education. background: prescription drug misuse is a growing problem among adolescent and young adult populations. objectives: to determine factors associated with past year prescription drug misuse defined as using prescription sedatives, stimulants, or opioids to get high, taking them when they were prescribed to someone else or taking more than was prescribed among patients seeking care in an academic ed. methods: adolescents and young adults ( - ) presenting for ed care at a large, academic teaching hospital were approached to complete a computerized screening questionnaire regarding demographics, prescription drug misuse, illicit drug use, alcohol use, and violence in the past months. logistic regression was used to predict past year prescription drug misuse. results: over the study time period, there were participants ( % response rate) of whom ( . %) endorsed past year prescription drug misuse. specifically, rates of past year misuse for opioids was . %, sedatives was . %, and stimulants was . %. significant overlap exists among classes with over % misusing more than one class of medications. in the multivariate analysis significant predictors of past year prescription drug misuse included female gender (or conclusion: approximately one in seven adolescents or young adults seeking ed care have misused prescription drugs in the past year. while opioids are the most common drug misused, significant overlap exists among this population. given the correlation of prescription drug misuse with the use and misuse of other substances (i.e. alcohol, cough medicine, marijuana) more research is needed to further understand these relationships and inform interventions. additionally, future research should focus on understanding the differences in demographics and risk factors associated with misuse of each separate class of prescription drugs. prospective objectives: this study aims to examine the association of depression with high ed utilization in patients with non-specific abdominal pain. methods: this single-center, prospective, cross-sectional study was conducted in an urban academic ed located in washington, dc as part of a larger study to evaluate the interaction between depression and frequency of ed visits and chronic pain. as part of this study, we screened patients using the phq- , a nineitem questionnaire that is a validated, reliable predictor of major depressive disorder. we analyzed the subset of respondents with a non-specific abdominal pain diagnosis (icd- code of .xx). our principal outcome of interest was the rate of a positive depression screen in patients with non-specific abdominal pain. we analyzed the prevalence of a positive depression screen among this group and also conducted a chi-square analysis to compare high ed use among abdominal pain patients with a positive depression screen versus those without a positive depression screen. we defined high ed utilization as > visits in a -day period prior to the enrollment visit. background: numerous studies have found high rates of co-morbid mental illness and chronic pain in emergent care settings. one psychiatric diagnosis frequently associated with chronic pain is major depressive disorder (mdd). objectives: we conducted a study to characterize the relationship between mdd and chronic pain in the emergency department (ed) population. we hypothesized that patients who present to the ed with selfreported chronic pain will have higher rates of mdd. methods: this was a single-center, prospective, crosssectional study. we used a convenience sample of noncritically ill, english speaking adult patients presenting with non-psychiatric complaints to an urban academic ed over months in . we oversampled patients presenting with pain-related complaints (musculoskeletal pain or headache). subjects were surveyed about their demographic and other health and health care characteristics and were screened with the phq , a nine-item questionnaire that is a validated, reliable predictor of mdd. we conducted bivariate (chi-square) and multivariate analysis controlling for demographic characteristics (race, income, sex, age) using stata v. . . our principal dependent variable of interest was a positive depression screen (phq score ‡ ). our principal independent variable of interest was the presence of self-reported chronic pain (greater than months). results: of patients enrolled, did not meet all inclusion criteria. had two or more assessments for comparison. their average age was (range - ), % were male, and % were in police custody. % used methadone alone; % heroin alone; % oxycodone alone; and the rest used multiple opioids. the average dose of im methadone was . mg (range - mg); all but patients received mg. the mean cows score before receiving im methadone was . (range - ), compared to . (range - ) minutes after methadone (p < . ; mean difference = ) . ; % ci = ) . to ) . ). the mean wss before and after methadone was ) . (range ) to ) ) and ) . (range ) to ), respectively (p < . ; % ci = ) . to ) . ). the mean physician-assessed wss was significantly lower than the patient's own assessment by . (p < . ). adverse events included an asthmatic patient with bronchospasm whose oxygen saturation decreased from % to % after receiving methadone, a patient whose oxygen saturation decreased from % to %, and two patients whose amss decreased from ) to ) (indicating moderate sedation). background: as the us population ages, the coexistence of copd and acute coronary syndrome (acs) is expected to be more frequent. very few studies have examined the effect of copd on outcomes in acs patients, and, to our knowledge, there has been no report on biomarkers that possibly mediate between copd and long-term acs patient outcomes. objectives: to determine the effect of copd on longterm outcomes in patients presenting to the emergency department (ed) with acs and to identify prognostic inflammatory biomarkers. methods: we performed a prospective cohort study enrolling acs patients from a single large tertiary center. hospitalized patients aged years or older with acs were interviewed and their blood samples were obtained. seven inflammatory biomarkers were measured, including interleukin- (il- ), c-reactive protein (crp), tumor necrosis factor-alpha (tnf-alpha), vascular cell adhesion molecule (vcam), e-selectin, lipoprotein-a (lp-a), and monocyte chemoattractant protein- (mcp- ). the diagnoses of acs and copd were verified by medical record review. annual telephone follow-up was conducted to assess health status and major adverse cardiovascular events (mace) outcomes, a composite endpoint including myocardial infarction, revascularization procedure, stroke, and death. background: aortic dissection (ad) is an uncommon life-threatening condition requiring prompt diagnosis and management. thirty-eight percent of cases are missed upon initial evaluation. the cornerstone of accurate diagnosis hinges on maintaining a high index of clinical suspicion for the various patterns of presentation. quality documentation that reflects consideration for ad in the history, exam, and radiographic interpretation is essential for both securing the diagnosis and for protecting the clinician in missed cases. objectives: we sought to evaluate the quality of documentation in patients presenting to the emergency department with subsequently diagnosed acute ad. methods: irb-approved, structured, retrospective review of consecutive patients with newly diagnosed non-traumatic ad from to . inclusion criteria: new ad diagnosis via ed. exclusion criteria: ad diagnosed at another facility; chronic, traumatic, or iatrogenic ad. trained/monitored abstractors used a standardized data tool to review ed and hospital medical records. descriptive statistics were calculated as appropriate. inter-rater reliability was measured. our primary performance measure was the prevalence of a composite of all three key historical elements ( . any back pain, . neurologic symptoms including syncope, and . sudden onset of pain.) in the attending emergency physician's documentation. secondary outcomes included documentation of: ad risk factors, pain quality, back pain at multiple locations, presence/absence of pulse symmetry, mediastinal widening on chest radiograph, and migratory nature of the pain. results: / met our inclusion/exclusion criteria. the mean age was . years; % were male, ( . %) were stanford a. ( %) presented with a chief complaint of chest pain. primary outcome measure: / ( . %; %ci = . , . ) documented the presence/ absence of all three key historical elements. [back pain = / ; . % ( . , . ); neuro symptoms = / ; % ( . , . ); sudden onset = / ; . % ( . , . ).] limitations: small number of confirmed ad cases. conclusion: in our cohort, emergency physician documentation of key historical, physical exam, and radiographic clues of ad is suboptimal. although our ed miss rate is lower than that which has been reported by previous authors, there is an opportunity to improve documentation of these pivotal elements at our institution. objectives: this study assessed the opinions of iem and gh fellowship program directors, in addition to recent and current fellows regarding streamlining the application process and timeline in an attempt to implement change and improve this process for program directors and fellows alike. methods: a total of current iem and gh fellowship programs were found through an internet search. an electronic survey was administered to current iem and gh fellowship directors, current fellows, and recent graduates of these programs. results: response rates were % (n = ) for program directors and % (n = ) for current and recent fellows. the great majority of current and recent fellows ( %) and program directors ( %) support transitioning to a common application service. similarly, % of current and recent fellows and % of program directors support instituting a uniform deadline date for applications. however, only % of recent/current fellows and % of program directors would support a formalized match process like nrmp. conclusion: the majority of fellows and program directors support streamlining the application for all iem and gh fellowship programs. this could improve the application process for both fellows and program directors, and ensure the best fit for the candidates and for the fellowship programs. in order to establish effective emergency care in rural sub-saharan africa, the unique practice demographics and patient dispositions must be understood. objectives: the objectives of this study are to determine the demographics of the first patients seen at nyakibale hospital's ed and assess the feasibility of treating patients in a rural district hospital ed in sub-saharan africa. methods: a descriptive cross-sectional analysis of the first consecutive patient visits in the ed's patient care log was reviewed by an unblinded abstractor. data collected included age, sex, condition upon discharge, and disposition. all authors discussed uncertainties and formed a consensus. descriptive statistics were performed. results: of the first patient visits, ( . %) occurred when the outpatient clinic was open. there were ( %) male visits. the average age was . years (sd ± . ). pediatric visits accounted for ( . %) patients, and ( . %) visits were for children under five years old. only one patient expired in the ed, and ( . %) were in good condition after treatment, as subjectively defined by the ed physicians. one person was transferred to another hospital. after treatment, ( %) patients were discharged home. of those admitted to an inpatient ward, ( . %) patients were admitted to medical wards, ( . %) to pediatrics, and ( %) to surgical. only six ( . %) patients went directly to the operating theatre. conclusion: this consecutive sample of patient visits from a novel rural district hospital ed in sub-saharan africa included a broad demographic range. after treatment, most patients were judged to be in ''good condition'', and over one third of patients could be discharged after ed management. this sample suggests that it is possible to treat patients in an ed in rural sub-saharan africa, even in cases where surgical backup and transfers to higher level of care are limited or unavailable. background: communication failures in clinical handoffs have been identified as a major preventable cause of patient harm. in italy, advanced prehospital care is provided predominantly by physicians who work on ambulances in teams with either nurses or basic rescuers. the hand-offs from prehospital physicians to hospital emergency physicians (eps) is especially susceptible to error with serious consequences. there are no studies in italy evaluating the communication at this transition in patient care. studying this, however, requires a tool that measures the quality of this communication. objectives: the purpose of this study is to develop and validate a tool for the evaluation of communication during the clinical handoff from prehospital to emergency physicians in critically ill patients. methods: several previously validated tools for evaluating communication in hand-offs were identified through a literature search. these were reviewed by a focus group consisting of eps, nurses, and rescuers, who then adapted and translated the australian isbar (identification, situation, background, assessment, recommendation), the tool most relevant to local practice. the italian isbar tool consists of the following elements: patient and provider identification; patient's chief complaint; patient's past medical history, medications, and allergies; prehospital clinical assessment (primary survey, illness severity, vital signs, diagnosis); treatment initiated and anticipated treatment plan. we conducted and video-taped the hand-offs of care from the prehospital physicians to the eps in pediatric critical care simulations. four physician raters were trained in the italian isbar tool and used it to independently assess communication in each simulation. to assess agreement we calculated the proportion of agreement among raters for each isbar question, fleiss' kappas for each simulation, as well as mean agreement and mean kappas with standard deviations. results: there was % agreement among the four physicians on % of the items. the mean level of agreement was % (sd . ). the overall mean kappa was . (sd . ). conclusion: the standardized tool resulted in good agreement by physician raters. this validated tool may be helpful in studying and improving hand-offs in the prehospital to emergency department setting. objectives: we hypothesized that residents who were provided with vps prior to hfs would perform more thoroughly and efficiently than residents who had not been exposed to the online simulation. methods: we randomized a group of residents from an academic, pgy - emergency medicine program to complete an online vps case, either prior to (vps group, n = residents) or after (n = ) their hfs case. the vps group had access to the online case (which reviewed asthma management) days prior to the hfs session. all residents individually participated in their regularly scheduled hfs and were blinded to the content of the case -a patient in moderate asthma exacerbation. the authors developed a dichotomous checklist consisting of items recorded as done/not done along with time completed. a two sample proportion test was used to evaluate differences in the individual items completed between groups. a wilcoxon rank sum test was used to determine the differences in overall and subcategory performance between the two groups. median time to completion was analyzed using the log-rank test. results: the vps group had better overall checklist performance than the control group (p-value . ). in addition, the vps group was more thorough in obtaining an hpi (p-value . ). specific actions (related to asthma management) were performed better by the vps group: inquiring about last/prior ed visits ( . ), total number of hospitalizations in the prior year ( . ), prior intubations ( . ), and obtaining peak flow measurements ( . ). overall there was no difference in time to event completion between the two groups. conclusion: we found that when hfs is primed with educational modalities such as vps there was an improvement in performance by trainees. however, the improved completeness of the vps group may have served as a barrier to efficiency, inhibiting our ability to identify a statistical significant efficiency overall. vps may aid in priming the learners and maximize the efficiency of training using high-fidelity simulations. training using an animal model helped develop residents' skills and confidence in performing ptv. retention was found to be good at months post-training. this study underscores the need for hands-on training in rare but critical procedures in emergency medicine. methods: in this cross-sectional study at an urban community hospital, residents in their second or third year of training from a -year em residency program performed us-guided catheterizations of the ij on a simulator manufactured by blue phantom. two board-certified em physicians observed for the completion of pre-defined procedural steps using a checklist and rated the residents' overall performance of the procedure. overall performance ratings were provided on a likert scale of to , with being poor and being excellent. residents were given credit for performing a procedural step if at least one rater marked its completion. agreement between raters was calculated using intraclass correlation coefficients for domain and summary scores. the same protocol was then repeated on an unembalmed cadaver using two different board-certified em physician raters. criterion validity of the residents' proficiency on the simulator was evaluated by comparing their median overall performance rating on the simulator to that on the cadaver and by comparing the proportion of residents completing each procedural step between modalities with descriptive statistics. results: em residents' overall performance rating on the simulator was . ( % ci: . to . ) and on the cadaver was . ( % ci: . to . ). the results for each procedural step are summarized in the attached figure. inter-rater agreement was high for assessments on both the simulator and cadaver with overall kappa scores of . and . respectively. background: the environment in the emergency department (ed) is chaotic. physicians must learn how to multi-task effectively and manage interruptions. noise becomes an inherent byproduct of this environment. previous studies in the surgical and anesthesiology literature examined the effect of noise levels and cognitive interruptions on resident performance during simulated procedures; however, the effect of noise distraction on resident performance during an ed procedure has not yet been studied. objectives: our aim was to prospectively determine the effects of various levels of noise distraction on the time to successful intubation of a high-fidelity simulator. methods: a total of emergency medicine, emergency medicine/internal medicine, and emergency medicine/family medicine residents were studied in a background noise environments of less than decibels (noise level ), - decibels (noise level ), and of greater than decibels (noise level ). noise levels were standardized by a dosimeter (ex tech instruments, heavy duty ). each resident was randomized to the order in which he or she was exposed to the various noise levels and had a total of minutes to complete each of the intubation attempts, which were performed in succession. time, in seconds, to successful intubation was measured in each of these scenarios with the start time defined as the time the resident picked up the storz c-mac video laryngoscope blade and the finish time defined as the time the tube passed through the vocal cords as visualized by an observer on the storz c-mac video screen. analytic methods included analysis of variance, student's t-test, and pearson's chi-square. results: no significant differences were found between time to intubation and noise level nor did the order of noise level exposure affect the time to intubation (see table) . there were no significant differences in success rate between the three noise levels (p = . ). a significant difference in time to intubation was found between the residents' second and third intubation attempts with decreased time to intubation for the third attempt (p = . ). conclusion: noise level did not have an effect on time to intubation or intubation success rate. time to intubation decreased between the second and third intubations regardless of noise level. background: growing use of the emergency department (ed) is cited as a cause of rising health care costs and a target of health care reform. eds provide approximately one quarter of all acute care outpatient visits in the us. eds are a diagnostic center and a portal for rapid inpatient admission. the changing role of eds in hospital admissions has not been described. objectives: to compare if admission through the ed has increased compared to direct hospital admission. we hypothesized that the use of the ed as the admitting portal increased for all frequently admitted conditions. methods: we analyzed the nationwide inpatient sample (nis), the largest us all-payer inpatient care database, from - . nis contains data from approximately million hospital stays each year, and is weighted to produce national estimates. we used an interactive, webbased data tool (hcupnet) to query the nis. clinical classification software (ccs) was used to group discharge diagnoses into clinically meaningful categories. we calculated the number of annual admissions and proportion admitted from the ed for the most frequently admitted conditions. we excluded ccs codes that are rarely admitted through the ed (< %) as well as obstet- background: the optimal dose of opioids for patients in acute pain is not well defined, although . mg/kg of iv morphine is commonly recommended. patient-controlled analgesia (pca) provides an opportunity to assess the adequacy of this recommendation as use of the pca pump is a behavioral indication of insufficient analgesia. objectives: to assess the need for additional analgesia following a . mg/kg dose of iv morphine by measuring additional self-dosing via a pca pump. methods: a three-arm randomized controlled trial was performed in an urban ed with , annual adult visits. a convenience sample of ed patients ages to with abdominal pain of < days duration requiring iv opioids was enrolled between / and / . all patients received an initial dose of . mg/kg iv morphine. patients in the pca arms could request additional doses of mg or . mg iv morphine by pressing a button attached to the pump with a -minute lock-out period. for this analysis, data from both pca arms were combined. software on the pump recorded times when the patient pressed the button (activation) and when he/she received a dose of morphine (successful activation). results: patients were enrolled in the pca arms. median baseline nrs pain score was . mean amount of supplementary morphine self-administered over the hour study period subsequent to the loading dose was . mg and . mg for the and . mg pca groups respectively. patients activated the pump at least once ( %, % ci: to %). figure shows the frequency distribution of the number of times the pump was activated. of those who activated the pump, the median number of activations per person was (iqr: to ). there were activations of the pump. % of activations were successful (followed by administration of morphine), while % were unsuccessful as they occurred during the -minute lock-out periods. % of the activations occurred in the first minutes, % in the second minutes, % in the third minutes, and % in the last minutes after the initial loading dose. conclusion: almost all patients requested supplementary doses of pca morphine, half of whom activated the pump five times or more over a course of hours. this frequency of pca activations suggests that the commonly recommended dose of . mg/kg morphine may constitute initial oligoanalgesia in most patients. marie-pier desjardins, benoit bailey, fanny alie-cusson, serge gouin, jocelyn gravel chu sainte-justine, montreal, qc, canada background: administration of corticosteroid at triage has been suggested to decrease the time to corticosteroid administration in the ed. objectives: to compare the time between arrival and corticosteroid administration in patients treated with an asthma pathway (ap) or with standard management (sm) in a pediatric ed. methods: chart review of children aged to years diagnosed with asthma, bronchospasm, or reactive airways disease seen in the ed of a tertiary care pediatric hospital. for a one year period, % of all visits were randomly selected for review. from these, we reviewed patients who were eligible to be treated with the ap ( ‡ months with previous history of asthma and no other pulmonary condition) and who had received at least one inhaled bronchodilator treatment. charts were evaluated by a data abstractor blinded to the study hypothesis using a standardized datasheet. various variables were evaluated such as age, respiratory rate and saturation at triage, type of physician who saw patient first, treatment prior to visit, in ed, and at discharge, time between arrival and corticosteroid administration, and length of stay (los background: return visits comprise . % of pediatric emergency department (ped) visits, at a cost of >$ million/year nationally. these visits are typically triaged with higher acuity and admission rates and raise concern for lapses in quality of care and patient education during the first visit. objectives: the aim of this qualitative study was to describe parents' reasons for return visits to the ped. methods: we prospectively recruited a convenience sample of parents of patients under the age of years who returned to the ped within hours of their previous visit. we excluded patients who were instructed to return, had previously left without being seen, arrived without a parent, were wards of the state, or did not speak english. after obtaining consent, the principal investigator (ce) conducted confidential, in-person, tape-recorded interviews with parents during ped return visits. parents answered open-ended questions and closed-ended questions using a five-point likert scale. responses to open-ended questions were analyzed using thematic analysis techniques. the scaled responses were grouped into three categories of agree, disagree, or neutral. results: from the closed-ended responses, % of parents agreed that their children were getting sicker, and % agreed that their children were not getting better. % agreed that they were unsure how to treat the illness, however only % agreed they did not feel figure : frequency distribution of number of pca activations comfortable taking care of the illness. only % agreed that the medical condition and/or the instructions were not clearly explained in the first visit. some common themes from the open-ended questions included worsening or lack of improvement of symptoms. many parents reported having unanswered questions about the cause of the illness and hoped to find out the cause during the return visit. conclusion: most parents brought their children back to the ped because they believed the symptoms had worsened or were not improving. although a large proportion of parents believed that the medical condition was clearly explained at the first visit, many parents still had unanswered questions about the cause of their child's illness. while worsening symptoms seemed to drive most return visits, it is possible that some visits related to failure to improve might be prevented during the first ped visit through a more detailed discussion of disease prognosis and expected time to recover. pediatric background: experience indicates that it is difficult to effectively quell many parents' anxiety toward pediatric fevers, making this a common emergency department (ed) complaint. the question remains as to whether athome treatment has any effect on the course of emergency department treatment or length of stay in this population. objectives: to determine whether anti-pyretic treatment prior to arrival in the emergency department affects the evaluation or emergency department length of stay of febrile pediatric patients. methods: a convenience sample of children, ages - years, who presented to a tertiary care ed with chief complaint of fever were enrolled. parents were asked to participate in an eight-question survey. questions related to demographic information, pre-treatment of the fever, contact with primary care providers prior to ed arrival, and immunization status. upon admission or discharge, investigators recorded information regarding length of stay, laboratory tests and imaging ordered, and medications given. results: eighty-one patients were enrolled in the study. seventy-six percent of the patients were pre-treated with some form of anti-pyretic by the caregiver prior to ed arrival. there was no significant effect of pre-treatment on whether laboratory tests or medications were ordered in the ed or whether the patient was admitted or discharged. the length of ed stay was found to be significantly shorter among those who received anti-pyretics prior to arrival ( ± vs. ± minutes; p = . ). conclusion: among febrile children, those who receive anti-pyretics prior to their ed visit had statistically significant shorter length of stays. this also supports implementation of triage or nursing protocols to administer an anti-pyretic as soon as possible in the hope of decreasing ed throughput times. background: during the past two decades, the prevalence of overweight (bmi percentile > ) in children has more than doubled, reaching epidemic proportions both nationally and globally. the public health burden is enormous given the increased risk of adult obesity as well as the adverse consequences on cardiovascular, metabolic, and psychological health. despite the overwhelming prevalence, the effect of obesity on emergency care has received little attention. objectives: the goal of this study is to determine the relation of weight on reported emergency department visits in children from a nationally representative sample. methods: weight (as reported by parents) and height along with frequency of and reason for emergency department (ed) use in the last months were obtained from children aged - y (n = , ) in the cross-sectional, telephone-administered, national survey of children's health (nsch). bmi percentiles were calculated using sex-specific bmi for age growth charts from the cdc ( ). children were categorized as: underweight (bmi percentile£ ), normal weight (> to < ), at-risk for overweight ( to < ), and overweight ( ‡ ). prevalence of ed use was estimated and compared across bmi percentile categories using chisquare analysis and multivariable logistic regression. taylor-series expansion was used for variance estimation of the complex survey design. results: the prevalence of at least one ed use in the past months increased with increasing bmi percentiles (figure , p < . ). additionally, overweight children were more likely to have more than one visit. overweight children were also less likely to report an injury, poisoning, or accident as the reason for ed visit compared to other bmi categories ( , , , % in overweight, at-risk, normal, and underweight respectively, p < . ). conclusion: as rates of childhood obesity continue to grow in the u.s., we can expect greater demands on the ed. this will likely translate into an increased emphasis on the care of chronic conditions rather than injuries and accidents in the pediatric ed setting. results: mean pediatric satisfaction score was . (sd . ) compared with . ( . ) for adult patients (p < . ); monthly sample sizes ranged from - and from - for the two populations, respectively. both populations showed an increase in satisfaction after opening of the ped-ed. for both populations there was no significant trend in patient satisfaction from the beginning of the study period to the opening of the ped-ed, but after the opening the models of the populations differed. the pediatric satisfaction model was an interrupted two-slope model, with an immediate jump of . points in november and an increase of . points per month thereafter. in contrast, adult satisfaction scores did not show a jump but increased linearly (two slope model) after / at a rate of . per month. prior to the opening of the ped-ed, mean monthly pediatric and adult satisfaction scores were . ( . ) and . ( . ), respectively (difference . % ci . - . , p = . ). after the opening the mean scores were . ( . ) and . ( . ), respectively (difference . , % ci . - . , p < . ). conclusion: opening of a dedicated ped-ed was associated with a significant increase in patient satisfaction scores both for children and adults. patient satisfaction for children, as compared to adults, was higher before and after opening a ped-ed. the background: there are racial disparities in outcomes among injured children. in particular, black race appears to be an independent predictor of mortality. objectives: to evaluate disparities among ed visits for unintentional injuries among children ages - . methods: five years of data ( ) ( ) ( ) ( ) ( ) from the national hospital ambulatory cares survey were combined. inclusion criteria were defined as unintentional injury visits (e-code . to . or . to . ) and age - years. visit rates per population (defined by the us census) were calculated by race and age group. weighted multivariate logistic regression analysis was performed to describe associations between race and specific outcome variables and related covariates. primary statistical analyses were performed using sas version . . . results: , , of , , weighted ed visits met our inclusion criteria ( . %). per persons, black children had . times as many ed visits for unintentional injuries as whites (table) . there were no racial differences in the sex ratio ( . boy visits: girl), proportion of visits by age, ed disposition, immediacy with which they needed to be seen, whether or not they were evaluated by an attending physician, metropolitan vs. rural hospital, admission length of stay, mode of transportation for ed arrival, number of procedures, diagnostic services, or ed medications. background: sudden cardiac arrests in schools are infrequent, but emotionally charged events. little data exist that describes aed use in these events. objectives: the purpose of our study was to ) describe characteristics and outcomes of school cardiac arrests (ca), and ) assess the feasibility of conducting bystander interviews to describe the events surrounding school ca. methods: we performed a telephone survey of bystanders to ca occurring in k- schools in communities participating in the cardiac arrest registry to enhance survival (cares) database. the study period was from / - / and continued in one community through . utstein style data and outcomes were collected from the cares database. a structured telephone interview of a bystander or administrative personnel was conducted for each ca. a descriptive summary was used to assess for the presence of an aed, provision of bystander cpr (bcpr), and information regarding aed deployment, training, and use and perceived barriers to aed use. descriptive data are reported. results: during the study period there were , ca identified at cares communities, of which were identified as educational institutions. of these, ( . %) events were at k- schools with ( . %) being high schools. of the arrests, a minority were children ( ( . %) < age ), most ( , . %) were witnessed, a majority ( , . %) received bcpr, and ( . %) were initially in ventricular fibrillation (vf). most arrests / ( %) occurred during the school day ( a- p). overall, ( . %) survived to hospital discharge. interviews were completed for of ( . %) k- events. eighteen schools had an aed on site. most schools ( . %) with aeds reported that they had a training program and personnel identified for its use. an aed was applied in of patients, and of these were in vf and survived to hospital discharge. multiple reasons for aed non-use (n = ) were identified. conclusion: cardiac arrests in schools are rare events; most patients are adults and received bcpr. aed use was infrequent, even when available, but resulted in excellent ( / ) survival. further work is needed to understand aed non-use. post-event interviews are feasible and provide useful information regarding cardiac arrest care. physician background: gastroenteritis is a common childhood disease accounting for - million annual pediatric emergency visits. current literature supports the use of anti-emetics reporting improved oral re-hydration, cessation of vomiting, and reduced need for iv re-hydration. however, there remains concern that using these agents may mask alternative diagnoses. objectives: to assess outcomes associated with use of a discharge action plan using ed-dispensed ondansetron at home in the treatment of gastroenteritis. methods: a prospective, controlled, observational trial of patients presenting to an urban pediatric emergency department (census , ) over a -month period for acute gastroenteritis. fifty patients received ondansetron in the ed. twenty-nine patients were enrolled in the pediatric emergency department discharge action plan (ped-dap) where ondansetron for home use was dispensed by the treating clinician. twenty-one patients were controls. control patients did not receive home ondansetron. ped-dap patients were given instructions to administer the ondansetron for ongoing symptoms any time hours post ed discharge. all patients were followed by phone at - days to assess for the following: time of emesis resolution, alternative diagnoses, unscheduled visits, and adverse events. results: all patients were followed by phone. / ped-dap patients received home ondansetron. / patients had resolution of emesis in the ed. / had resolution of their emesis between time of discharge and hours. / of ped-dap patients reported emesis after hours from ed discharge. five patients reported an unscheduled visit. all five return visits returned to the ed ( / returned for emesis, / for diarrhea). / controls reported resolution of symptoms within the ed. / of controls had resolution between time of discharge and hours. / of the control patients had resolution with between and hours post discharge. / had an unscheduled appointment with the pmd at hours post-discharge for ongoing fever and nausea. in follow-up there were no alternative diagnoses identified. the effect of the ped-dap on resolution of emesis between discharge and hours appears to be statistically significant (p value < . ). conclusion: ondansetron given in schedule with a discharge action plan appears to provide a modest benefit in resolution of symptoms relative to a control population. objectives: to determine the repeatability coefficient of a mm vas in children aged to years in different circumstances: assessments done either at or minute interval, when asked to recall their score or to reproduce it. methods: a prospective cohort study was conducted using a convenience sample of patients aged to years presenting to a pediatric ed. patients were asked to indicate, on a mm paper vas, how much they liked a variety of food with four different sets of three questions: (set ) questions at minute interval with no specific instruction other than how to complete the vas and no access to previous scores, (set ) same format as set except for questions at minute interval, (set ) same as set except patients were asked to remember their answers, and (set ) same as set except patients were shown their previous answers. for each set, the repeatability coefficient of the vas was determined according to the bland-altman method for measuring agreement using repeated measures: . x Ö x s w where s w is the within-subject standard deviation by anova. the sample size required to estimate s w to % of the fraction value as recommended was patients if we obtained three measurements for each patient. results: a total of patients aged . ± . years were enrolled. the repeatability coefficient for the questions asked at minute intervals was mm, and mm when asked at minute interval. when asked to remember their previous answers or to reproduce them, the repeatability coefficient for the questions was mm and mm, respectively. conclusion: the condition of the assessments (variation in intervals or patients asked to remember or to reproduce their previous answers) influence the testretest reliability of the vas. depending on circumstances, the theoretical test-retest reliability in children aged to years varies from to mm on a mm paper vas. background: skull radiographs are a useful tool in the evaluation of pediatric head trauma patients. however, there is no consensus on the ideal number of views that should be obtained as part of a standard skull series in the evaluation of pediatric head trauma patients. objectives: to compare the sensitivity and specificity of a two-and four-film x-ray series in the diagnosis of skull fracture in children, when interpreted by pediatric emergency medicine physicians. methods: a prospective, crossover experimental study was performed in a tertiary care pediatric hospital. the skull radiographs of children were reviewed. these were composed of the most recent cases of skull fracture for which a four-film radiography series was available at the primary setting and controls, matched for age. two modules, containing a random sequence of two-and four-film series of each child, were constructed in order to have all children evaluated twice (once with two films and once with four films). board-certified or -eligible pediatric emergency physicians evaluated both modules two to four weeks apart. the interpretation of the four-film series by a radiologist, or when available, the findings on ct scan, served as the gold standard. accuracy of interpretation was evaluated for each patient. the sensitivity and specificity of the two-film versus the four-film skull xray series, in the identification of fracture, were compared. this was a non-inferiority cross-over study evaluating the null hypothesis that a series with two views would have a sensitivity (specificity) that is inferior by no more than . compared to a series with four views. a total of controls and cases were needed to establish non-inferiority of the two-film series versus the four-film series, with a power of % and a significance level of %. results: ten pediatric emergency physicians participated in the study. for each radiological series, the proportion of accurate interpretation varied between . to . . the four-film series was found to be more sensitive in the detection of skull fracture than a two-film series (difference: . , %ci . to . ). however, there was no difference in the specificity (difference: . , %ci ) . to . ). conclusion: for children sustaining a head trauma, a four-film skull radiography series is more sensitive than a two-film series, when interpreted by pediatric emergency physicians. the objectives: we developed a free online video-based instrument to identify knowledge and clinical reasoning deficits of medical students and residents for pediatric respiratory emergencies. we hypothesized that it would be a feasible and valid method of differentiating educational needs of different levels of learners. methods: this was an observational study of a free, web-based needs assessment instrument that was tested on third and fourth year medical students (ms - ) and pediatric and emergency medicine residents (r - ). the instrument uses youtube video triggers of children in respiratory distress. a series of cased-based questions then prompts learners to distinguish between upper and lower airway obstruction, classify disease severity, and manage uncomplicated croup and bronchiolitis. face validity of the instrument was established by piloting and revision among a group of experienced educators and small groups of targeted learners. final scores were compared across groups using t-tests to determine the ability of the instrument to differentiate between different levels of learners (concurrent validity). cronbach's alpha was calculated as a measure of internal consistency. results: response rates were % among medical students and % among residents. the instrument was able to differentiate between junior (ms , ms , and r ) and senior (r , r ) learners for both overall mean score ( % vs. %, p < . ) and mean video portion score ( vs. %, p = . ). table compares results of several management questions between junior and senior learners. cronbach's alpha for the test questions was . . conclusion: this free online video-based needs assessment instrument is feasible to implement and able to identify knowledge gaps in trainees' recognition and management of pediatric respiratory emergencies. it demonstrates a significant performance difference between the junior and senior learners, preliminary evidence of concurrent validity, and identifies target groups of trainees for educational interventions. future revisions will aim to improve internal consistency. results: the survey response rate was % ( / ). among responding programs, ( %) reside within a children's hospital (vs. general ed); ( %) are designated level i pediatric trauma centers. forty-three ( %) programs accept - pem fellows per year; ( %) provided at least some eus training to fellows, and ( %) offer a formal eus rotation. on average this training has existed for ± years and the mean duration of eus rotations is ± weeks. twenty-eight ( %) programs with eus rotations provide fellow training in both a general ed and a pediatric ed. there were no hospital or program level factors associated with having a structured training program for pem fellows. conclusion: as of , the majority of pem fellowship programs provide eus training to their fellows, with a structured rotation being offered by most of these programs. background: ed visits are an opportunity for clinicians to identify children with poor asthma control and intervene. children with asthma who use eds are more likely than other children to have poor control, not be using controller medications, and have less access to traditional sources of primary care. one significant barrier to ed-based interventions is recognizing which children have uncontrolled asthma. objectives: to determine whether the pacci, a item parent-administered questionnaire, can help ed clinicians better recognize patients with the most uncontrolled asthma and differentiate between intermittent and persistent asthma. methods: this was a randomized controlled trial performed at an urban pediatric ed. parents were asked to answer questions about their child's asthma including drug adherence and history of exacerbations, as well as answer demographic questions. using a convenience sample of children - years presenting with an asthma exacerbation, attending physicians in the study were asked to complete an assessment of asthma control. physicians were randomized to receive a completed pacci (intervention) or not (control group). using an intent-to-treat approach, clinicians' ability to accurately identify ) four categories of control used by the national heart, lung, and blood institute (nhlbi) asthma guidelines, ) intermittent vs. persistent level asthma, and ) controlled / mildly uncontrolled vs. moderate/severely uncontrolled asthma were compared for both groups using chi-square analysis. results: between january and august , patients were enrolled. there were no statistically significant differences between the intervention and control groups for child's sex, age, race and parents' education. conclusion: the pacci improves ed clinicians' ability to categorize children's asthma control according to nhlbi guidelines, and the ability to determine when a child's control has been worsening. ed clinicians may use the pacci to identify those children in greatest need for intervention, to guide prescription of controller medications, and communicate with primary care providers about those children failing to meet the goals of asthma therapy. figure) . fewer than half of physicians reported the parent of a -year-old being discharged from their ed following an mvc-related visit would receive either child passenger safety information or referrals (table) . conclusion: emergency physician report of child passenger safety resource availability is associated with trauma center designation. even when resources are available, referrals from the ed are infrequent. efforts to increase referrals to community child passenger safety resources must extend to the community ed settings where the majority of children receive injury care. background: pediatric subspecialists are often difficult to access following ed care especially for patients living far from providers. telemedicine (tm) can potentially eliminate barriers to access related to distance, and cost. objectives: to evaluate the overall resource savings and access that a tm program brings to patients and families. methods: this study took place at a large, tertiary care regional pediatric health care system. data were collected from / - / . metrics included travel distance saved (round trip between tm presenting sites and the location of the receiving sites), time savings, direct cost savings (based on $ . /mile) and potential work and school days saved. indirect costs were calculated as travel hrs saved/encounter (based on an average speed of miles/hr). demographics and services provided were included. results: tm consults were completed by separate pediatric subspecialty services. most patients were school aged ( % >/= yrs old objectives: to analyze test characteristics of the pathway and its effects on ed length of stay, imaging rates, and admission rate before versus after implementation. methods: children ages - presenting to one academic pediatric ed with suspicion for appendicitis from october -august were prospectively enrolled to a pathway using previously validated lowand high-risk scoring systems. the attending physician recorded his or her suspicion of appendicitis and then used one of two scoring systems incorporating history, physical exam, and cbc. low-risk patients were to be discharged or observed in the ed. high-risk patients were to be admitted to pediatric surgery. those meeting neither low-nor high-risk criteria were evaluated in the ed by pediatric surgery, with imaging at their discretion. chart review and telephone follow-up were conducted two weeks after the visit. charts of a random sample of patients with diagnoses of acute appendicitis or chief complaint of abdominal pain and undergoing a workup for appendicitis in the eight months before and after institution of the pathway were retrospectively reviewed by one or two trained abstractors. results: appendicitis was diagnosed in of patients prospectively enrolled to the pathway ( %). mean age was . years. of those with appendicitis, were not low-risk (sensitivity . %, specificity . %). the high-risk criteria had a sensitivity of . % and specificity of . %. a priori attending physician assessment of low risk had a sensitivity of % and specificity of . %. a priori assessment of high risk had a sensitivity of . % and specificity of . %. we reviewed visits prior to the pathway and after. mean ed length of stay was similar ( minutes before versus after). ct was used in . % of visits before and . % after (p = . ). use of ultrasound increased ( . % before versus . % after, p < . ). admission rates were not significantly different ( . % before versus . % after, p = . ). conclusion: the low-risk criteria had good sensitivity in ruling out appendicitis and can be used to guide physician judgment. institution of this pathway was not associated with significant changes in length of stay, utilization of ct, or admission rate in an academic pediatric ed. computer-delivered alcohol and driver safety behavior screening and intervention program initiated during an emergency department visit mary k. murphy , lucia l. smith , anton palma , david w. lounsbury , polly e. bijur , paul chambers yale university, new haven, ct; albert einstein college of medicine, bronx, ny background: alcohol use is involved in percent of all fatal motor vehicle crashes and recent estimates show that at least , people were injured due to distracted driving last year. patients who visit the emergency department (ed) are not routinely screened for driver safety behavior; however, large numbers of patients are treated in the ed every day creating an opportunity for screening and intervention on important public health behaviors. objectives: to evaluate patient acceptance and response to a computer-based traffic safety educational intervention during an ed visit and one month follow-up. methods: design. pre /post educational intervention. setting. large urban academic ed serving over , patients annually. participants. medically stable adult ed patients. intervention. patients completed a self-administered, computer-based program that queried patients on alcohol use and risky driving behaviors (texting, talking, and other forms of distracted driving). the computer provided patients with educational information on the dangers of these behaviors and collected data on patient satisfaction with the program. staff called patients one month post ed visit for a repeat query. results: patients participated; average age ( - ), % hispanic, % male. % of patients reported the program was easy to use and were comfortable receiving this education via computer during their ed visit. self-reported driver safety behaviors pre, post intervention (% change): driving while talking on the phone %, % () %, p = . ), aggressive driving %, % () %, p = . ), texting while driving %, % () %, p = . ), driving while drowsy %, % () %, p = . ), drinking in excess of nih safe drinking guidelines %,% () %, p = . ), drinking and driving %, % () %, p = . ). conclusion: we found a high prevalence of selfreported risky driving behaviors in our ed population. at month follow-up, patients reported a significant decrease in these behaviors. overall patients were very satisfied receiving educational information about these behaviors via computer during their ed visit. this study indicates that a low-intensity, computer-based educational intervention during an ed visit may be a useful approach to educate patients about safe driving behaviors and promote behavior change. prevalence of depression among emergency department visitors with chronic illness janice c. blanchard, benjamin l. bregman, jeffrey smith, mohammad salimian, qasem al jabr george washington university, washington, dc background: persons with chronic illnesses have been shown to have higher rates of depression than the general population. the effect of depression on frequent emergency department (ed) use among this population has not been studied. objectives: this study evaluated the prevalence of major depressive disorder (mdd) among persons presenting with depression to the george washington university ed. we hypothesized that patients with chronic illnesses would be more likely to have mdd than those without. methods: this was a single center, prospective, crosssectional study. we used a convenience sample of noncritically ill, english-speaking adult patients presenting with non-psychiatric complaints to an urban academic ed over months in . subjects were screened with the phq , a nine-item questionnaire that is a validated, reliable predictor of mdd. we also queried respondents about demographic characteristics as well as the presence of at least one chronic disease (heart disease, hypertension, asthma, diabetes, hiv, cancer, kidney disease, or cerebrovascular disease). we evaluated the association between mdd and chronic illnesses with both bivariate analysis and multivariate logistic regression controlling for demographic characteristics (age, race, sex, income, and insurance coverage). results: our response rate was . % with a final sample size of . of our total sample, ( . %) had at least one of the chronic illnesses defined above. of this group, ( . %) screened positive for mdd as compared to ( . %) of the group without chronic illnesses (p < . ). in multivariate analysis, persons with chronic illnesses had an odds ratio for a positive depression screen of . ( . , . ) as compared to persons without illness. among the subset of persons with chronic illnesses (n = ), . % had ‡ visits in the prior days as compared to . % of persons with chronic illnesses without mdd (p = . ). conclusion: our study found a high prevalence of untreated mdd among persons with chronic illnesses who present to the ed. depression is associated with more frequent emergency department use among this population. initial blood alcohol level aids ciwa in predicting admission for alcohol withdrawal craig hullett, douglas rappaport, mary teeple, daniel butler, arthur sanders university of arizona, tucson, az background: assessment of alcohol withdrawal symptoms is difficult in the emergency department. the clinical institute withdrawal assessment (ciwa) is commonly used, but other factors may also be important predictors of withdrawal symptom severity. objectives: the purpose of this study is to determine whether ciwa score at presentation to triage was predictive of later admission to the hospital. methods: a retrospective study of patients presenting to an acute alcohol and drug detoxification hospital was performed from july through january . patients were excluded if other drug withdrawal was present in addition to alcohol. initial assessment included age, sex, vital signs, and blood alcohol level (bal) in addition to hourly ciwa score. admission is indicated for a ciwa score of or higher. data were analyzed by selecting all patients not immediately admitted at initial presentation. logistic regression using wald's criteria for stepwise inclusion was used to determine the utility of the initially gathered ciwa, bal, longest sobriety, liver cirrhosis, and vital signs in predicting subsequent admission. results: there were patients who fit the inclusion criteria, with admitted for treatment at initial intake and another admitted during the following hours. logistic regression indicated that presenting bal was a strong predictor (p = . ) of admission for treatment after initial presentation, as was presenting ciwa (p = . ). thus, presenting bal provided a substantial addition above initial ciwa in predicting later admission. no other variables added significantly to the prediction of later admission. to determine the interaction between presenting bal and ciwa scores, we ran a repeated measures analysis of the first five ciwa scores (from presentation to hours later), using bal split into low (bal < . ) and high (bal > . ) groups (see figure) . their interaction was significant, f ( , ) = . , p < . , g = . . those presenting with higher initial bal had suppressed ciwa scores that rose precipitously as the alcohol cleared. those with low presenting bal showed a decline in ciwa over time conclusion: initial assessment using the common assessment tool ciwa is aided significantly by bal assessment. patients with higher presenting bal are at higher risk for progression to serious alcohol withdrawal symptom. objectives: to describe patient and visitor characteristics and perspectives on the role of visitors in the ed and determine the effect of visitors on ed and hospital outcome measures. methods: this cross-sectional study was done in an , -visit urban ed, and data were attempted to be collected from all patients over a consecutive -hour period from august to , . trained data collectors were assigned to the ed continuously for the study period. patients assigned to a rapid care section of the ed ( %) were excluded. a visitor was defined as a person other than a health care provider (hcp) or hospital staff present in a patient's room at any time. patient perspectives on visitors were assessed in the following domains: transportation, emotional support, physical care, communication, and advocating for the patient. ed and hospital outcome measures pertaining to ed length of stay (los) and charges, hospital admission rate, hospital los and charges were obtained from patient medical records and hospital billing. data analyses included frequencies, student's t-tests for continuous variables, and chi-square tests of association for categorical variables. all tests for significance were two-sided. objectives: to examine the effect of sunday alcohol availability on ethanol-related visits and alcohol withdrawal visits to the ed. methods: study design was a retrospective beforeafter study using electronically archived hospital data at an urban, safety net hospital. all adult non-prisoner ed visits from / / to / / were analyzed. an ethanol-related ed visit was defined by icd- codes related to alcohol ( .x, .x, . , . ). an alcohol withdrawal visit was defined by icd- codes of delirium tremens ( . ), alcohol psychosis with hallucination ( . ), and ethanol withdrawal ( . ). we generated a ratio of ethanol-related ed visits to total ed visits (ethanol/total) and ratio of alcohol withdrawal ed visits to total ed visits (withdrawal/total). a day was redefined as am to am. the ratios were averaged within the four seasons to account for seasonal variations. data from summer were dropped as it spanned the law change. we stratified data into sunday and non-sunday days prior to analysis to isolate the effects of the law change. we used multivariable linear regression to estimate the association of the ratio with the law change while adjusting for time and the seasons. each ratio was modeled separately. the interaction between time and the law change was assessed using p < . . results: during the study there were a total of , ed visits including , ( % of total) ethanol-related visits and , ( % of total) alcohol withdrawal visits. unadjusted ratios in seasonal blocks are plotted in the figure with associated % ci and best fit regression line for before and after law change, respectively. after adjusting for time and season in the multivariable linear regression, we found no significant association of either ethanol/total or withdrawal/total with the law change. this remained true for both sunday and non-sunday data. all interactions assessed were not significant. conclusion: the change in colorado law to allow the sale of full-strength alcoholic beverages on sundays did not significantly affect ethanol-related or alcohol withdrawal ed visits. background: olanzapine is a second-generation antipsychotic (sga) with actions at the serotonin/histamine receptors. post-marketing reports and a case report have documented dangerous lowering of blood pressure when this antipsychotic is paired with benzodiazepines, but a recent small study found no bigger decreases in blood pressure compared to another antipsychotic like haloperidol. decreases in oxygen saturations, however, were larger when olanzapine was combined with benzodiazepines in alcohol-intoxicated patients. it is unclear whether these vital sign changes are associated with the intramuscular (im) route only. objectives: the assessment of vital signs following administration of either oral (po) or im olanzapine, either with or without benzodiazepines (benzos) and with or without concurrent alcohol intoxication. methods: this is a structured retrospective chart review of all patients who received olanzapine in an academic medical center ed from - who had vital signs documented both before medication administration and within four hours afterwards. vital signs were calculated as pre-dose minus lowest post-dose vital sign within hours, and were analyzed in an anova with route (im/po), benzo use (+/)), and alcohol use (+/)) as factors. significance level was set to < . . results: there were patients who received olanzapine over the study period. a total of patients ( po, im) met inclusion criteria. systolic blood pressures decreased across all groups as patients reduced their agitation. neither the route of administration, concurrent use of benzos, nor the use of alcohol were associated with significant changes in systolic bp (p = ns for all comparisons; see figure ). decreases in oxygen saturations, however, were significantly larger for alcoholintoxicated patients who subsequently received im olanzapine + benzos compared to other groups (route: p < . ; alcohol: p < . ; route x alcohol: p < . ; route x benzos x alcohol: p < . ; see figure ). conclusion: alcohol and benzos are not associated with significant decreases in blood pressure after po olanzapine, but im olanzapine + benzos is associated with potentially significant oxygen desaturations in patients who are intoxicated. intoxicated patients may have differential effects with the use of im sgas such as olanzapine when combined with benzos, and should be studied separately in drug trials. patients with a psychiatric diagnosis rasha buhumaid, jessica riley, janice blanchard george washington university, washington, dc background: literature suggests that frequent emergency department (ed) use is common among persons with a mental health diagnosis. few studies have documented risk factors associated with increased utilization among this population. objectives: to understand demographic characteristics of frequent users of the emergency department and describe characteristics associated with their visits. it was hypothesized that frequent visitors would have a higher rate of medical comorbidities than infrequent visitors. methods: this was a retrospective study of patients presenting to an urban, academic emergency department in . a cohort of all patients with a mental health-related final icd- coded diagnosis (axis i or axis ii) was extracted from the electronic medical record. using a standard abstraction form, a medical chart review collected information about medical comorbidities, substance abuse, race, age, sex, and insurance coverage, as well as diagnosis, disposition, and time of each visit. results: our sample consisted of frequent users ( ‡ visits in a day period) and infrequent users (£ visits in a day period). frequent users were more likely to be male ( % vs. . % p = . ), black ( % vs. % p < . ), and had a higher average number of comorbid conditions ( . , %ci . , . ) as compared to infrequent users ( . , %ci . , . ). a higher percentage of visits in the infrequent user group occurred during the day ( % vs. . % p < . ) while a higher number of visits in the frequent users occurred after midnight ( . % vs. . % p = . ). visits in the frequent user group were less likely to be for a psychiatric complaint ( . % vs. . %) and less likely to result in a psychiatric admission ( . % versus . %) as compared to the infrequent user group (p < . ). conclusion: our data indicate that among patients with psychiatric diagnoses, those who make frequent ed visits have a higher rate of comorbid conditions than infrequent visitors. despite their increased use of the ed, frequent visitors have a significantly lower psychiatric admission rate. many of the visits by frequent users are for non-psychiatric complaints and may reflect poor access to outpatient medical and mental health services. emergency departments should consider interventions to help address social and medical issues among mental health patients who frequently use ed services. background: the world health organization estimates that one million people die annually by suicide. in the u.s., suicide is the fourth leading cause of death between the ages of and . many of these patients are seen in ed, while outpatient visits for depression are also high. no recent analysis has compared these groups in the recent years. objectives: to determine if there is a relationship between the incidence of suicidal and depressed patients presenting to emergency departments and the incidence of depressed patients presenting to outpatient clinics from - . the secondary objective is to analyze trends in suicidal patients in the ed. methods: we used nhamcs (national hospital ambulatory medical care survey) and namcs (national ambulatory medical care survey), national surveys completed by the centers for disease control, which provide a sampling of emergency department and outpatient visits respectively. for both groups, we used mental-health-related icd- -cm, e codes and reasons for visit. we compared suicidal and depressed patients who presented to the ed, to those who presented to outpatient clinics. our subgroup analyses included age, sex, race/ethnicity, method of payment, regional variation, and urban verses rural distribution. results: ed visits for depression ( . %) and suicide attempts ( . %) remained stable over the years, with no significant linear trend. however, office visits for depression significantly decreased from . % of visits in to . % of visits in . non-latino whites had a higher percentage of ed visits for depression ( . %) and suicide attempt ( . %) (p < . ), and a higher percentage of office visits for depression than all other groups. among patients age - years, ed visits for suicide attempt significantly increased from . % in to . % in . homeless patients had a higher percent of ed visits for depression ( . %) and suicide attempt ( background: for potentially high-risk ed patients with psychiatric complaints, efficient ed throughput is key to delivering high-quality care and minimizing time spent in an unsecured waiting room. objectives: we hypothesized that adding a physician in triage would improve ed throughput for psychiatric patients. we evaluated the relationship between the presence of an ed triage physician and waiting room (wr) time, time to first physician order, time to ed bed assignment, and time spent in an ed bed. methods: the study was conducted from / - / at an academic ed with annual visits and a dedicated on-site emergency psychiatric unit. we performed a pre/post retrospective observational cohort study using administrative data, including weekend visits from noon- pm, months pre and post addition of weekend triage physicians. after adjusting for patient age, sex, insurance status, emergency severity index score, mode of arrival, ed occupancy rate, wr count, boarding count, and average wr los, multiple linear regression evaluated the relationship between the presence of a triage physician and four ed throughput outcomes: time spent in the wr, time to first order, time spent in an ed bed, and the total ed los. results: visits met inclusion criteria, in the months before and in the months after physicians were assigned to triage on weekends. table reports demographic data; multivariate analysis results are found in table . the presence of a triage physician was associated with an ( % ci . - . ) minute increase in wr time and no associated change in time to first order, time spent in an ed bed, or in the overall ed los. conclusion: use of triage physicians has been reported to decrease the time patients spend in an ed bed and improve ed throughput. however, for patients with psychiatric complaints, our analysis revealed a slight increase in wr time without evident change in the time to first order, time spent in an ed bed, or total ed los. improvements in ed throughput for psychiatric patients will likely require system-level changes, such as reducing ed boarding and improving lab efficiency to speed the process of medical clearance and reduce time spent in the unsecured wr. these findings may not be generalizable to eds without a dedicated ed psychiatric unit with full-time social workers to assist with disposition. initial assessment included ciwa scoring, repeated hourly, as well as other variables (see table ). treatment and admission to the inpatient hospital was indicated for a ciwa score of or higher. statistical analysis was performed utilizing repeated measures general linear modeling for ciwa scores and anova for all other variables. results: there were patients who fit the inclusion criteria, with admitted for treatment at initial intake and another admitted during the following hours. the table below compares the three most prevalent ethnic populations seen at our hospital. native americans presented at a significantly younger age (p < . ) than the other two ethnicities. initial ciwa scores taken on admission were significantly lower in the native american group than the other two groups (p < . ) and at hour a difference existed but failed to reach significance. repeated measures analysis indicate that ciwa scores progressed in a u-shaped curvilinear fashion (see figure ) conclusion: initial assessment utilizing ciwa scores appears to be affected by ethnicity. care must be taken when assessing and making decisions on a single initial ciwa score. further research is needed in this area as our numbers are small and differences might be seen in subsequent scoring. in addition, our study consists of primarily male patients and does not include african-american patients. background: age is a risk factor for adverse outcomes in trauma, yet evidence supporting the use of specific age cut-points to identify seriously injured patients for field triage is limited. objectives: to evaluate under-triage by age, empirically examine the association between age and serious injury for field triage, and assess the potential effect of mandatory age criteria. methods: this was a retrospective cohort study of injured children and adults transported by ems agencies to hospitals in regions of the western u.s. from - . hospital records were probabilistically linked to ems records using trauma registries, emergency department data, and state discharge databases. serious injury was defined as an injury severity score (iss) ‡ (the primary outcome). we assessed under-triage (triage-negative patients with iss ‡ ) by age decile, different mandatory age criteria, and used multivariable logistic regression models to test the association (linear and non-linear) between age and iss ‡ , adjusted for important confounders. results: , injured patients were evaluated and transported by ems over the -year period. under-triage increased markedly for patients over years, reaching % for those over years ( figure ). mandatory age triage criteria decreased under-triage, while substantially increasing over-triage: one iss ‡ patient identified for every additional patients triaged to major trauma centers. among patients not identified by other criteria, age had a strong non-linear association with iss ‡ (p < . ); the probability of serious injury steadily increased after years, becoming more notable after years ( figure ). conclusion: under-triage in trauma increases in patients over years, which may be reduced with mandatory age criteria at the expense of system efficiency. among patients not identified by other criteria, serious injury steadily increased after years, though there was no age at which risk abruptly increased. background: although limited resuscitation with hemoglobin-based oxygen carriers (hbocs) improves survival in several polytrauma models, including those of traumatic brain injury (tbi) with uncontrolled hemorrhage (uh) via liver injury, their use remains controversial. objectives: we examine the effect of hboc resuscitation in a swine polytrauma model with uh by aortic tear +/) tbi. we hypothesize that limited resuscitation with hboc would offer no survival benefit and would have similar effects in a model of uh via aortic tear +/) tbi. methods: anesthetized swine subjected to uh inflicted via aortic tear +/) fluid percussion tbi underwent equivalent limited resuscitation with hboc, lr, or hboc+nitroglycerin (ntg) (vasoattenuated hboc) and were observed for hours. comparisons were between tbi and no-tbi groups with adjustment for resuscitation fluid type using two-way anova with interaction and tukey kramer adjustment for individual comparisons. results: there was no independent effect of tbi on survival time after adjustment for fluid type (anova, tbi term p = . ) and there was no interaction between tbi and resuscitation fluid type (anova interaction term p = . ). there was a significant independent effect of fluid type on survival time (anova p = . background: intracranial hemorrhage (ich) after a head trauma is a problem frequently encountered in the ed. an elevated inr is recognized as a risk of bleeding. however, in a patient with an inr in normal range, a level associated with a lower risk of ich is not known. objectives: the aim of this study was to identify an inr threshold that could predict a decreased risk of an ich after a head trauma in patients with a normal inr. it is hypothesized that there is a threshold at which the likelihood of bleeding decreases significantly. methods: we did a study using data from a registry of patients with mild to severe head trauma (n = ) evaluated in a level i trauma center in canada between march and february . all the patients with a documented scan interpreted by a radiologist and a normal inr, defined as a value less then . , were included. we determined the correlation between inr value binned by . and the proportion of patients with an ich. threshold was defined by consensus as an abrupt change of more than % in the percentage of patients with ich. univariate frequency distribution was tested with pearson's chisquare test. logistic regression analysis was then used to study the effects of inr on ich with the following confounding factors: age, sex, and intake of warfarin, clopidogrel, or aspirin. results are presented with % confidence intervals. results: patients met the inclusion criteria. the mean age was . years ± . and % were men. patients ( . %) had an ich on brain scan. we found a significantly lower risk of ich at a threshold of inr less than . (p < . , univariate or = . , %ci . - . ) and a strong correlation between the risk of bleeding for every increase of the inr (r = . ). in fact, after adjustment for confounding variables, every . inr increase was associated with an increased risk of having an ich (or . ; % ci . - . ). conclusion: we were able to demonstrate an inr threshold under which the probability of ich was significantly lower. we also found a strong association between the risk of bleeding and the increase in inr within a normal range, suggesting that clinicians should not be falsely reassured by a normal inr. our results are limited by the fact that this is a retrospective study and a small proportion of traumatic brain injured patients in our database had no scan or inr at their ed visit. a prospective cohort study would be needed to confirm our results. background: increasingly, patients with tbi are being seen and managed in the emergency neurology setting. knowing which early signs are associated with prognosis can be helpful in directing the acute management. objectives: to determine whether any factors early in the course of head trauma are associated with shortterm outcomes including inpatient admission, in-hospital mortality, and return to the hospital within days. methods: this irb-approved study is a retrospective review of patients head injury presenting to our tertiary care academic medical center during a -month period. the dataset was created using redcap, a data management solution hosted by our medical school's center for translational science institute. results: the median age of the cohort (n = ) was , iqr = - yrs, with % being male. % had a gcs of - (mild tbi), % - (moderate tbi), and % gcs < (severe tbi). % of patients were admitted to the hospital. the median length of hospital stay was days, with an iqr of - days. of those admitted, % had an icu stay as well. the median icu los was also days, with an iqr of - days. twenty nine ( %) patients died during their hospital stay. lower gcs was predictive of inpatient admission (p = . ) as well as icu days (p < . ). significant predictors of re-admission to the hospital within days included hypotension (p = . ) upon initial presentation. the prehospital and ed gcs scores were not statistically significant. significant predictors of in-hospital death in a model controlling for age included bradycardia (p = . ), hyperglycemia (p = . ), and lower gcs (p = . ). the incidence of bradycardia (hr < ) was . %. conclusion: early hypotension, hyperglycemia, and bradycardia along with lower initial gcs are associated with significantly higher likelihood of hospital admission, including icu admission, as well as intrahospital death and re-admission. background: over , people per day require treatment for ankle sprains, resulting in lost workdays and training for athletes. platelet rich plasma (prp) is an autologous concentration of platelets which, when injected into the site of injury, is thought to improve healing by promoting inflammation through growth factor and cytokine release. studies to date have shown mixed results, with few randomized or placebo-controlled trials. the lower extremity functional scale (lefs) is a previously validated objective measure of lower extremity function. objectives: is prp helpful in acute ankle sprains in the the emergency department? methods: prospective, randomized, double-blinded, placebo-controlled trial. patients with severe ankle sprains and negative x-rays were randomized to trial or placebo. severe was defined as marked swelling and ecchymosis and inability to bear weight. both groups had cc of blood drawn. trial group blood was centrifuged with a magellan autologous platelet separator (arteriocyte, cleveland) to yield - cc of prp. prp along with . cc of % lidocaine and . cc of . % bupivicaine was injected at the point of maximum tenderness by a blinded physician under ultrasound guidance. control group blood was discarded and participants were injected in a similar fashion substituting sterile . % saline for prp. both groups had visual analog scale (vas) pain scores and lefs on days , , , and . all participants had a posterior splint and were made non weight bearing for days after which they were reexamined, had their splint removed, and were asked to bear weight as tolerated. participants were instructed not to use nsaids during the trial. results: patients were screened and were enrolled. four withdrew before prp injection was complete. eighteen were randomized to prp and to placebo. see tables for results. vas and lefs are presented as means with sd in parentheses. demographics were not statistically different between groups. conclusion: in this small study, prp did not appear to offer benefit in either pain control or healing. both groups had improvement in their pain and functionality and did not differ significantly during the study period. limitations include small study size and large number of participant refusals. methods: a structured chart review of all icd- radius fracture coded charts spanning march , to july , was conducted. specific variable data were collected and categorized as follows: age, moi, body mass index, and fracture location. the charts were reviewed by two medical students, with % of the charts reviewed by both students to confirm inter-rater reliability. frequencies and inter-quartile ranges were determined. comparisons were made with fisher's exact test and multiple logistic regression. results: charts met inclusion criteria. charts were excluded due to one of the following reasons: no fracture or no x-ray ( ), isolated ulnar fracture ( ), or undocumented or penetrating moi ( ). of the analyzed patients (n = ), distal radius fractures were most common ( %), followed by proximal ( %) and midshaft ( %). chart reviewers were found to be reliable (j = ). age and moi were significantly associated with fracture location (see table) . ages - and bike accidents were more strongly associated with proximal radius fractures (odds ratio: [ - ] and [ - ], respectively). conclusion: patients presenting to our inner city ed with a radius fracture are more likely to have a distal fracture. adults - and bike accidents had a significantly higher incidence of proximal fractures than other ages or mois. background: trauma centers use guidelines to determine the need for a trauma surgeon in the ed on patient arrival. a decision rule from loma linda university that includes penetrating injury and tachycardia was developed to predict which pediatric trauma patients require emergent intervention, and thus are most likely to benefit from surgical presence in the ed. objectives: our goal was to validate the loma linda rule (llr) in a heterogeneous pediatric trauma population and to compare it to the american college of surgeons' major resuscitation criteria (mrc). we hypothesized that the llr would be more sensitive than the mrc for identifying the need for emergent operative or procedural intervention. methods: we performed a secondary analysis of prospectively collected trauma registry data from two urban level i pediatric trauma centers with a combined annual census of approximately , visits. consecutive patients < years old with blunt or penetrating trauma from through were included. patient demographics, injury severity scores (iss), times of ed arrival and surgical intervention, and all variables of both rules were obtained. the outcome (emergent operative intervention within hour of ed arrival or ed cricothyroidotomy or thoracotomy) was confirmed by trained, blinded abstractors. sensitivities, specificities, and % confidence intervals (cis) were calculated for both rules. results: , patients were included with a median age of . years and a median iss of . emergent intervention was required in patients ( . %). the llr had a sensitivity ranging from . %- . % ( % ci: . %- . %) and specificity ranging from . %- . % ( % ci: . %- . %) between both institutions. the mrc had a sensitivity ranging from . %- . % ( % ci: . %- . %) and specificity ranging from . %- . % ( % ci: . %- . %) between institutions. conclusion: emergent intervention is rare in pediatric trauma patients. the mrc was more sensitive for predicting the need for emergent intervention than the llr. neither set of criteria was sufficiently accurate to recommend their routine use for pediatric trauma patients. droperidol for sedation of acute behavioural disturbance leonie a. calver , colin page , michael downes , betty chan , geoffrey k. isbister calvary mater newcastle and university of newcastle, newcastle, australia; princess alexandra hospital, brisbane, australia; calvary mater newcastle, newcastle, australia; prince of wales hospital, sydney, australia background: acute behavioural disturbance (abd) is a common occurrence in the emergency department (ed) and is a risk to staff and patients. there remains little consensus on the most effective drug for sedation of violent and aggressive patients. prior to the food and drug administration's black box warning, droperidol was commonly used and was considered safe and effective. objectives: this study aimed to investigate the effectiveness of parenteral droperidol for sedation of abd. methods: as part of a prospective observational study, a standardised protocol using droperidol for the seda-acute and delayed behavioral deficits were demonstrated in this rat model of co toxicity, which parallels the neurocognitive deficit pattern observed in humans (see figure) . similar to prior studies, pathologic analysis of brain tissue demonstrated the highest percentage of necrotic cells in the cortex, pyramidal cells, and cerebellum. the collected data are summarized in the table. we have developed an animal model of severe co toxicity evidenced by behavioral deficits and neuronal necrosis. future efforts will compare neurologic outcomes in severely co poisoned rats treated with hypothermia and % inspired o versus hbo to normothermic controls treated with % inspired o . increasing in popularity, attracting more than , annual participants worldwide. prior studies have consistently documented renal function impairment, but only after race completion. the incidence of renal injury during these multi-day ultramarathons is currently unknown. this is the first prospective cohort study to evaluate the incidence of acute kidney injury (aki) in runners during a multi-day ultramarathon foot race. objectives: to assess the effect of inter-stage recovery versus cumulative damage on resulting renal function during a multi-day ultramarathon. methods: demographic and biochemical data gathered via phlebotomy and analyzed by istatÒ (abbott, nj) were collected at the start and finish of day ( miles), ( miles), and ( miles) during racing the planet'sÒ -mile, -day self-supported desert ultramarathons. pre-established rifle criteria using creatinine (cr) and glomerular filtration rate (gfr) defined aki as ''no injury'' (cr < . x normal, decrease of gfr < %), ''risk'' (cr . x normal, decrease of gfr by - %), and ''injury'' (cr x normal, decrease of gfr by - %). results: thirty racers ( % male) with a mean (+/) sd) age of + /- years were studied during the sahara (n = , . %), gobi (n = , %), and namibia (n = , . %) events. the average decrease in gfr from day start to day finish was + /- (p < . , % ci . - . ); day start to day finish was . + /- . (p < . , % ci . - . ); and day start to day finish was . ± . (p < . , % ci . - ). runners categorized as risk and injury for aki after stage was . % and %; after stage was % and %, and after stage was . % and . % conclusion: the majority of participants developed significant levels of renal impairment despite recovery intervals. given the changes in renal function, potentially harmful non-steroidal anti-inflammatory drugs should be minimized to prevent exacerbating acute kidney injury. background: more than % of the elderly abuse prescription drugs, and emergency medicine providers frequently struggle to identify features of opioid addiction in this population. the prescription drug use questionnaire (pduqp) is a validated, -item, patient-administered tool developed to help health care providers better identify problematic opioid use, or dependence, in patients who receive opioids for the treatment of chronic pain. objectives: to identify the prevalence of prescription drug misuse features in elderly ed patients. methods: this cross-sectional, observational study was conducted between / and / in the ed of an urban, university-affiliated community hospi-tal that serves a large geriatric population. all patients aged to inclusive were eligible, and were recruited on a convenience basis. exclusion criteria included known dementia, and critical illness. outcomes of interest included self-reported history of prior prescription opioid use, substance abuse history, aberrant medication-taking behaviors, and pduqp results. results: one hundred patients were approached for participation. two were excluded for inability to read english, three were receiving analgesia for metastatic cancer, had never taken a prescription opioid, and seven refused to participate beyond pre-screening. sixty patients completed the study (see table ). of those, . % reported four or more visits within months; chronic pain was reported by . %; debilitating pain by . %; prior pain management referral by . %; and storing opioids for future use by %. seventeen patients reported current prescription opioid use, and were administered the pduqp (see figure) . in this population, . % thought their pain was not adequately being treated; . % reported having to increase the amount of pain medication they were taking over the prior months; . % saved up future pain medication; . % had doctors refuse to give them pain medication for fear that the patient would abuse the prescription opioids; and . % reported having a previous drug or alcohol problem. conclusion: screening instruments, such as the pduqp, facilitate identification of geriatric patients with features of opioid misuse. a high proportion of patients in this study save opioids for further use. interventions for safe medication disposal may decrease access to opioids and subsequent morbidity. age extremes, male sex, and several chronic health conditions were associated with increased odds of heat stroke, hospital admission, and death in the ed by a factor of - . chronic hematologic disease (e.g. anemia) was associated with a - fold increase in adjusted odds of each of these outcomes. conclusion: hri imposes a substantial public health burden, and a wider range of chronic conditions confer susceptibility than previously thought. males, older adults, and patients with chronic conditions, particularly anemia, are likely to have more severe hri, be admitted, or die in the ed. background: carbon monoxide (co) poisoning is a remarkable cause of death worldwide. co, produced by the incomplete combustion of hydrocarbons, has many toxic effects on especially the heart and brain. co binds strongly to cytochrome oxidase, hemoglobin, and myoglobin causing hypoxia of organs and issues. co converts hemoglobin to carboxyhemoglobin and makes transport of oxygen through the body impossible and causes severe hypoxia. objectives: the aim of this study is to investigate the levels of s b and neuron specific enolase (nse) measured both during admittance and at the sixth hour of hyperbaric and normobaric oxygen therapy carried out on patients with a diagnosis of co poisoning. methods: the study is designed as a prospective observational laboratory study. forty patients were enrolled in the study: underwent normobaric oxygen therapy (nbot) and the other underwent hyperbaric oxygen therapy (hbot). levels of s b and nse were measured both during admittance and at the sixth hour of admittance of all patients. demographic data, clinical characteristics, and outcome measures were recorded. all data were statistically analyzed. results: in both treatment groups, mean levels of nse after therapy were significantly lower than admittance levels. although levels of nse measured before and hours after treatment in hbot group were high, the difference between groups was not statistically significant (p > . ). in both treatment groups, mean levels of s b after therapy were significantly lower than admittance levels; likewise nse. although levels of s b measured before and hours after treatment in hbot group were high, the difference between groups was not statistically significant (p > . ). additionally, while levels of s b measured after treatment in the hbot group were lower compared to the nbot group, the difference between groups was also not statistically significant (p > . ). conclusion: levels of s b and nse as evidence for brain injury elevation in case of co poisoining and decrease by therapy according to our study as well as previous studies. decrease in levels of s b is more significant. according to our results, s b and nse may be useful markers in case of co poisoning; however, we did not meet any data providing more value in determining hbot indications and determining levels of cohb in the management of patients with a diagnosis of co poisoining. neurons objectives: this study was conducted to determine if neurons in the dmh, and its neighbor the paraventricular hypothalamus (pvn), were likewise involved in mdma-mediated neuroendocrine responses, and if serotonin a receptors ( -ht a) play a role in this regional response. methods: in both experiments, male sprague dawley rats (n = - /group) were implanted with bilateral cannulas targeting specific regions of the brain, i.v. catheters for drug delivery, and i.a. catheters for blood withdrawal. experiments were conducted in raturn cages, which allow blood withdrawal and drug administration in free moving animals while recording their locomotion. in the first experiment, rats were microinjected into the dmh, the pvn, or a region between, with the gabaa agonist muscimol ( pmol/ nl/side) or pbs ( nl) and min later were injected with either mdma ( . mg/kg i.v.) or an equal volume of saline. blood was withdrawn prior to microinjections and minutes after mdma for ria measurement of plasma acth. locomotion was recorded throughout the experiment. in a separate experiment of identical design, either the -ht a antagonist way (way, nmol/ nl/side) or saline was microinjected followed by i.v. injection of mdma or saline. in both experiments, increases in acth and distance traveled were compared between groups using an anova analysis. results: when compared to controls, microinjections of muscimol into the dmh, pvn, or the area in between attenuated plasma increases in acth and locomotion evoked by mdma. when microinjected into the dmh or pvn, way had no effect on acth, but when injected into the region of the dmh it significantly increased locomotion. background: poor hand-offs between physicians when admitting patients have been shown to be a major source of medical errors. objectives: we propose that training in a standardized admissions protocol by emergency medicine (em) to internal medicine (im) residents would improve the quality of and quantity of communication of vital patient information. methods: em and im residents at a large academic center developed an evidence-based admission handover protocol termed the ' ps' (table ) . em and im residents received ' ps' protocol training. im residents recorded prospectively how well each of the seven ps were communicated during each admission pre-and post-intervention. im residents also assessed the overall quality of the handover using a likert scale. the primary outcome was the change in the number of 'ps' conveyed by the em resident to the accepting im resident. data were collected for six weeks before and then for six weeks starting two weeks after the educational intervention. results: there were observations recorded in the preintervention (control) group and observations in the post-intervention group. for each of the seven 'ps' the percentage of observation where all of the information was communicated is shown in table . the communication of 'ps' increased following the intervention. this rise was statistically significant for patient information and pending tests. in the control group the mean of total communicated ps was and in the intervention group, the mean increased to (p < . ). the quality of the handover communication had a mean rating of . in the control group and . in the intervention group (p < . ). conclusion: this educational intervention in a cohort of em and im residents improved the quality and quantity of vital information communicated during patient handovers. the intervention was statistically significant for patient information transfer and tests pending. the results are limited by study size. based on our preliminary data, an agreed-upon handover protocol with training improved the amount and quality of communication during patients' hospital admission on simple items that were likely had been taken for granted as routinely transmitted. we recruited a convenience sample of residents and students rotating in the pediatric emergency department. a two-sided form had the same seven clinical decisions on each side: whether to perform blood, urine, spinal fluid tests, imaging, iv fluids, antibiotics, or a consult. the rating choices were: definitely not, probably not, probably would, and definitely would. trainees rated each decision after seeing a patient, but before presenting to the preceptor, who, after evaluating the patient, rated the same seven decisions on the second side of the form. the preceptor also indicated the most relevant decision (mrd) for that patient. we examined the validity of the technique using hypothesis testing; we posited that residents would have a higher degree of concordance with the preceptor than would medical students. this was tested using dichotomized analyses (accuracy, kappa) and roc curves with the preceptor decision as the gold standard. results: thirty-one students completed forms (median forms; iqr , ) and residents completed ( ; iqr , ). preceptors included attending physicians and fellows ( ; iqr , ). students were concordant with preceptors in % (k = . ) of mrd while residents agreed in . % (p = . ), k = . . roc analysis revealed significant differences between students and residents in the auc for the mrd ( . vs . ; p = . ). conclusion: this measure of trainee-preceptor concordance requires further research but may eventually allow for assessment of trainee clinical decision-making. it also has the pedagogical advantage of promoting independent trainee decision-making. background: basic life support (bls) and advanced cardiac life support (acls) are integral parts of emergency cardiac care. this training is usually reserved in most institutions for residents and faculty. the argument can be made to introduce bls and acls training earlier in the medical student curriculum to enhance acquisition of these skills. objectives: the goal of the survey was to characterize the perceptions and needs of graduating medical students in regards to bls and acls training. methods: this was a survey-based study of graduating fourth year medical students at a u.s. medical school. the students were surveyed before voluntarily participating in a student-led acls course in march of their final year. the surveys were distributed before starting the training course. both bls and acls training, comfort levels, and perceptions were assessed in the survey. results: of the students in the graduating class, participated in the training class with ( %) completing the survey. % of students entered medical school without any prior training and % started clinics without training. . % of students reported witnessing an average of . in-hospital cardiac arrests during training (range of - ). overall, students rated their preparedness . (sd . ) for adult resuscitations on a - likert scale with being the unprepared. % and % of students believe that bls and acls should be included in the medical student curriculum respectively with a preference for teaching before starting clerkships. % of students avoided participating in resuscitations due to lack of training. of those, % said they would have participated had they been trained. conclusion: to our knowledge, this is one of the first studies to address the perceptions and needs for bls and acls training in u.s. medical schools. students feel that bls and acls training is needed in their curriculum and would possibly enhance perceived comfort levels and willingness to participate in resuscitations. background: professionalism is one of six core competency requirements of the acgme, yet defining and teaching its principles remains a challenge. the ''social contract'' between physician and community is clearly central to professionalism so determining the patient's understanding of the physician's role in the relationship is important. because specialization has created more narrowly focused and often quite different interactions in different medical environments, the patient concept of professionalism in different settings may vary as well. objectives: we hoped to determine if patients have different conceptions of professionalism when considering physicians in different clinical environments. methods: patients were surveyed in the waiting room of an emergency department, an outpatient internal medicine clinic, and a pre-operative/anesthesia clinic. the survey contained examples of attributes, derived from the american board of internal medicine's eight characteristics of professionalism. participants were asked to rate, on a -point scale, the importance that a physician possess each attribute. an anova analysis was used to compare the sites for each question. results: of who took the survey, were in the emergency department, were in the medicine clinic, and were in the pre-operative clinic. females comprised % of the study group and the average age was with a range from to . there was a significant difference on the attribute of ''providing a portion of work for those who cannot pay;'' this was rated higher in the emergency department (p = . ). there was near-significance (p = . ) on the attribute of ''being able to make difficult decisions under pressure,'' which was rated higher in the pre-op clinic. there was no difference for any of the other questions. the top four professional attributes at each clinical site were the same -''honesty,'' ''excellence in communication and listening,'' ''taking full responsibility for mistakes,'' and ''technical competence/ skill;'' the bottom two were ''being an active leader in the community'' and ''patient concerns should come before a doctor's family commitments.'' conclusion: very few differences between clinical sites were found when surveying patient perception of the important elements of medical professionalism. this may suggests a core set of values desired by patients for physicians across specialties. emergency medicine faculty knowledge of and confidence in giving feedback on the acgme core competencies todd guth, jeff druck, jason hoppe, britney anderson university of colorado, aurora, co background: the acgme mandates that residency programs assess residents based upon six core competencies. although the core competencies have been in place for a number of years, many faculty are not familiar with the intricacies of the competencies and have difficulty giving competency-specific feedback to residents. objectives: the purpose of the study is to determine the extent to which emergency medicine (em) faculty can identify the acgme core competencies correctly and to determine faculty confidence with giving general feedback and core competency focused feedback to em residents. methods: design and participants: at a single department of em, a survey of twenty-eight faculty members, their knowledge of the acgme core competencies, and their confidence in providing feedback to residents was conducted. confidence levels in giving feedback were scored on a likert scale from to . observations: descriptive statistics of faculty confidence in giving feedback, identification of professional areas of interest, and identification of the acgme core competencies were determined. mann-whitney u tests were used to make comparisons between groups of faculty given the small sample size of the respondents. results: there was a % response rate of the faculty members surveyed. eight faculty members identified themselves as primarily focused on education. although those faculty members identifying themselves as focused on education scored higher than non-education focused faculty for all type of feedback (general feedback, constructive feedback, negative feedback), there was only a statistical difference in confidence levels . versus . (p < . ) for acgme core competency specific feedback when compared to noneducation focused faculty. while education focused faculty correctly identified all six of acgme core competencies % of the time, not one of the non-education focused faculty identified all six of the core competencies correctly. non-education focused faculty only correctly identified three or more competencies % of the time. conclusion: if residency programs are to assess residents using the six acgme core competencies, additional faculty development specific to the core competencies will be needed to train all faculty on the core competencies and on how to give core competency specific feedback to em residents. there is no clear consensus as to the most effective tool to measure resident competency in emergency ultrasound. objectives: to determine the relationship between the number of scans and scores on image recognition, image acquisition, and cognitive skills as measured by an objective structured clinical exam (osce) and written exam. secondarily, to determine whether image acquisition, image recognition, and cognitive knowledge require separate evaluation methodologies. methods: this was a prospective observational study in an urban level i ed with a -year acgme-accredited residency program. all residents underwent an ultrasound introductory course and a one-month ultrasound rotation during their first and second years. each resident received a written exam and osce to assess psychomotor and cognitive skills. the osce had two components: ( ) recognition of images, and ( ) acquisition of images. a registered diagnostic medical sonographer (rdms)-certified physician observed each bedside examination. a pre-existing residency ultrasound database was used to collect data about number of scans. pearson correlation coefficients were calculated for number of scans, written exam score, image recognition, and image acquisition scores on the osce. results: twenty-nine residents were enrolled from march to february who performed an average of scans (range - ). there was no significant correlation between number of scans and written exam scores. an analysis of the number of scans and the ocse found a moderate correlation with image acquisition (r = . , p = . ) and image recognition (r = . , p = < . )). pearson correlation analysis between the image acquisition score and image recognition score found that there was no correlation (r = . , p = . ). there was a moderate correlation with image acquisition scores to written scores (r = . , p = . ) and image recognition scores to written scores (r = . , p = . ). conclusion: the number of scans does not correlate with written tests but has a moderate correlation with image acquisition and image recognition. this suggests that resident education should include cognitive instruction in addition to scan numbers. we conclude that multiple methods are necessary to examine resident ultrasound competency. background: although emergency physicians must often make rapid decisions that incorporate their interpretation of an ecg, there is no evidence-based description of ecg interpretation competencies for emergency medicine (em) trainees. the first step in defining these competencies is to develop a prioritized list of ecg findings relevant to em contexts. objectives: the purpose of this study was to categorize the importance of various ecg diagnoses and/or findings for the em trainee. methods: we developed an extensive list of potentially important ecg diagnoses identified through a detailed review of the cardiology and em literature. we then conducted a three-round delphi expert opinion-soliciting process where participants used a five-point likert scale to rate the importance of each diagnosis for em trainees. consensus was defined as a minimum of percent agreement on any particular diagnosis at the second round or later. in the absence of consensus, stability was defined as a shift of percent or less after successive rounds. results: twenty-two em experts participated in the delphi process, sixteen ( %) of whom completed the process. of those, fifteen were experts from eleven different em training programs across canada and one was a recognized expert in em electrocardiography. overall, diagnoses reached consensus, achieved stability, and one diagnosis achieved neither consensus nor stability. out of potentially important ecg diagnoses, ( %) were considered ''must know'' diagnoses, ( %) ''should know'' diagnoses, and ( %) ''nice to know'' diagnoses. conclusion: we have categorized ecg diagnoses within an em training context, knowledge of which may allow clinical em teachers to establish educational priorities. this categorization will also facilitate the development of an educational framework to establish em trainee competency in ecg interpretation. ''rolling refreshers background: cardiac arrest survival rates are low despite advances in cardiopulmonary resuscitation. high quality cpr has been shown to impart greater cardiac arrest survival; however, retention of basic cpr skills by health care providers has been shown to be poor. objectives: to evaluate practitioner acceptance of an in-service cpr skills refresher program, and to assess for operator response to real-time feedback during refreshers. methods: we prospectively evaluated a ''rolling refresher'' in-service program at an academic medical center. this program is a proctored cpr practice session using a mannequin and cpr-sensing defibrillator that provides real-time cpr quality feedback. subjects were basic life support-trained providers who were engaged in clinical care at the time of enrollment. subjects were asked to perform two minutes of chest compressions (ccs) using the feedback system. ccs could be terminated when the subject had completed approximately seconds of compressions with < corrective prompts. a survey was then completed by to obtain feedback regarding the perceived efficacy of this training model. cpr quality was then evaluated using custom analysis software to determine the percent of cc adequacy in -second intervals. results: enrollment included subjects from the emergency department and critical care units ( nurses, physicians, students and allied health professionals). all participants completed a survey and cpr performance data logs were obtained. positive impressions of the in-service program were registered by % ( / ) and % ( / ) reported a self-perceived improvement in skills confidence. eighty-three percent ( / ) of respondents felt comfortable performing this refresher during a clinical shift. thirtynine percent ( / ) of episodes exhibited adequate cc performance with approximately seconds of cc. of the remaining episodes, . ± . % of cc were adequate in the first seconds with . ± . % of cc adequate during the last second interval (p = . ). of these individuals, improved or had no change in their cpr skills, and individuals skills declined during cc performance (p = . ). conclusion: implementation of a bedside cpr skill refresher program is feasible and is well received by hospital staff. real time cpr feedback improved upon cpr skill performance during the in-service session. teaching emergency medicine skills: is a self-directed, independent, online curriculum the way of the future? tighe crombie, jason r. frank, stephen noseworthy, richard gerein, a. curtis lee university of ottawa, ottawa, on, canada background: procedural competence is critical to emergency medicine, but the ideal instructional method to acquire these skills is not clear. previous studies have demonstrated that online tutorials have the potential to be as effective as didactic sessions at teaching specific procedural skills. objectives: we studied whether a novel online curriculum teaching pediatric intraosseus (io) line insertion to novice learners is as effective as a traditional classroom curriculum in imparting procedural competence. methods: we conducted a randomized controlled educational trial of two methods of teaching io skills. preclinical medical students with no past io experience completed a written test and were randomized to either an online or classroom curriculum. the online group (og) were given password-protected access to a website and instructed to spend minutes with the material while the didactic group (dg) attended a lecture of similar duration. participants then attended a -minute unsupervised manikin practice session on a separate day without any further instruction. a videotaped objective structured clinical examination (osce) and post-course written test were completed immediately following this practice session. finally, participants were crossed over into the alternate curriculum and were asked to complete a satisfaction survey that compared the two curricula. results were compared with a paired t-test for written scores and an independent t-test for osce scores. results: sixteen students completed the study. pre-course test scores of the two groups were not significantly different prior to accessing their respective curricula (mean scores of % for og and % for dg, respectively; p > . ). post-course written scores were also not significantly different (both with means of %; p > . ); however, for the post-treatment osce scores, the og group scored significantly higher than the dg group (mean scores of . % and . %; t( ) = . , p < . .) conclusion: this novel online curriculum was superior to a traditional didactic approach to teaching pediatric io line insertion. novice learners assigned to a selfdirected online curriculum were able to perform an emergency procedural skill to a high level of performance. em educators should consider adopting online teaching of procedural skills. background: applicants to em residency programs obtain information largely from the internet. curricular information is available from a program's website (pw) or the saem residency directory (sd). we hypothesize that there is variation between these key sources. objectives: to identify discrepancies between each pw and sd. to describe components of pgy - em residency programs' curricula as advertised on the internet. methods: pgy - residencies were identified through the sd. data were abstracted from individual sd and pw pages identifying pre-determined elements of interest regarding rotations in icu, pediatrics, inpatient (medicine, pediatrics, general surgery), electives, orthopedics, toxicology, and anesthesia. agreement between the sd and pw was calculated using a cohen's unweighted kappa calculation. curricula posted on pws were considered the gold standard for the programs' current curricula. results: a total of pgy - programs were identified through the sd and confirmed on the pw. ninetyone of programs ( %) had complete curricular information on both sites. only these programs were included in the kappa analysis for sd and pw comparisons. of programs with complete listings, of programs ( %) had at least one discrepancy. the agreement of information between pw and sd revealed a kappa value of . ( % ci . - . ). analysis of pw revealed that pgy - programs have an average of . (range, - ), . (range, - ), . (range, - ), and . (range, - ) blocks of icu, pediatrics, elective, and inpatient, respectively. common but not rrc-mandated rotations in orthopedics, toxicology, and anesthesiology are present in , , and percent of programs, respectively. conclusion: publicly accessible curricular information through the sd and pw for pgy - em programs only has fair agreement (using commonly accepted kappa value guides). applicants may be confused by the variability of data and draw inaccurate conclusions about program curricula. from the gravid uterus and improves cardiac output; however, this theory has never been proven. objectives: we set out to determine the difference in inferior vena cava (ivc) filling when third trimester patients were placed in supine, llt, and right lateral tilt (rlt) positions using ivc ultrasound. methods: healthy pregnant women in their third trimester presenting to the labor and delivery suite were enrolled. patients were placed in three different positions (supine, rlt, and llt) and ivc maximum (max) and minimum (min) measurements were obtained using the intercostal window in short axis approximately two centimeters below the entry of the hepatic veins. ivc collapse index (ci) was calculated for each measurement using the formula (max-min)/max. in addition, blood pressure, heart rate, and fetal heart rate were monitored. patients stayed in each position for at least minutes prior to taking measurements. we compared ivc measurements using a one-way analysis of variance for repeated measures. results: twenty patients were enrolled. the average age was years (sd . ) with a mean estimated gestational age of . weeks (sd . ). there were no significant differences seen in ivc filling in each of the positions (see table ). in addition, there were no differences in hemodynamic parameters between positions.ten ( %) patients had the largest ivc measurement in the llt position, ( %) patients in the rlt position, and ( %) in the supine position. conclusion: there were no significant differences in ivc filling between patient positions. for some third trimester patients llt may not be the optimal position for ivc filling. background: although the acgme and rrc require competency assessment in ed bedside ultrasound (us), there are no standardized assessment tools for us training in em. objectives: using published us guidelines, we developed four observed structured competency evalua-tions (osce) for four common em us exams: fast, aortic, cardiac, and pelvic. inter-rater reliability was calculated for overall performance and for the individual components of each osce. methods: this prospective observational study derived four osces that evaluated overall study competency, image quality for each required view, technical factors (probe placement, orientation, angle, gain, and depth), and identification of key anatomic structures. em residents with varying levels of training completed an osce under direct observation of two em-trained us experts. each expert was blinded to the other's assessment. overall study competency and image quality of each required views were rated on a five-point scale ( poor, -fair, -adequate, -good, -excellent), with explicit definitions for each rating. each study had technical factors (correct/incorrect) and anatomic structures (identified/not identified) assessed as binary variables. data were analyzed using cohen's and weighted k, descriptive statistics, and % ci. results: a total of us exams were observed, including fast, cardiac, aorta, and pelvic. total assessments included ratings of overall study competency, ratings of required view image quality, ratings of technical factors, and ratings of anatomic structures. inter-rater assessment of overall study competency showed excellent agreement, raw agreement . ( . , . ), weighted k . ( . , . ). ratings of required view image quality showed excellent agreement: raw agreement . ( . , . ), weighted k . ( . , . ). inter-rater assessment of technical factors showed substantial agreement: raw agreement . ( . , . ), cohen's k . ( . , . ). ratings of identification of anatomic structures showed substantial agreement: raw agreement . ( . , . ), cohen's k . ( . , . ). conclusion: inter-rater reliability is substantial to excellent using the derived ultrasound osces to rate em resident competency in fast, aortic, cardiac, and pelvic ultrasound. validation of this tool is ongoing. a objectives: the objective of this study was to identify which transducer orientation, longitudinal or transverse, is the best method of imaging the axillary vein with ultrasound, as defined by successful placement in the vein with one needle stick, no redirections, and no complications. methods: emergency medicine resident and attending physicians at an academic medical center were asked to cannulate the axillary vein in a torso phantom model. the participants were randomized to start with either the longitudinal or transverse approach and completed both sequentially, after viewing a teaching presentation. participants completed pre-and post-attempt questionnaires. measurements of each attempt were taken regarding time to completion, success, skin punctures, needle redirections, and complications. we compared proportions using a normal binomial approximation and continuous data using the t-distribution, as appropriate. a sample size of was chosen based on the following assumptions: power, . ; significance, . ; effect size, % versus %. results: fifty-seven operators with a median experience of prior ultrasounds ( to iqr) participated. first-attempt success frequency was / ( . ) for the longitudinal method and / ( . ) for the transverse method (difference . , % ci . - . ); this difference was similar regardless of operator experience. the longitudinal method had fewer redirections (mean difference . , % ci . - . ) and skin punctures (mean difference . , % ci ) to . ). arterial puncture occurred in / longitudinal attempts and / transverse attempts, with no pleural punctures in either group. among successful attempts, the time spent was seconds less for longitudinal method ( % ci - ). though % of participants had more experience with the transverse method prior to the training session, % indicated after the session that they preferred the longitudinal method. methods: a prospective single-center study was conducted to assess the compressibility of the basilic vein with ultrasound. healthy study participants were recruited. the compressibility was assessed at baseline, and then further assessed with one proximal tourniquet, two tourniquets (one distal and one proximal), and a proximal blood pressure cuff inflated to mmhg. compressibility was defined as the vessel's resistance to collapse to external pressure and rated as completely compressible, moderately compressible, or mildly compressible after mild pressure was applied with the ultrasound probe. results: one-hundred patients were recruited into the study. ninety-eight subjects were found to have a completely compressible basilic vein at baseline. when one tourniquet and two tourniquets were applied and participants, respectively, continued to have completely compressible veins. a fisher's exact test comparing one versus two tourniquets revealed no difference between these two techniques (p = . ). only two participants continued to have completely compressible veins following application of the blood pressure cuff. the compressibility of this group was found to be statistically significant by fisher's exact test compared to both tourniquet groups (p < . ). furthermore, participants with the blood pressure cuff applied were found to have moderately compressible veins and participants were found to have mildly compressible veins. conclusion: tourniquets and blood pressure cuffs can both decrease the compressibility of peripheral veins. while there was no difference identified between using one and two tourniquets, utilization of a blood pressure cuff was significantly more effective to decrease compressibility. the findings of this study may be utilized in the emergency department when attempting to obtain peripheral venous access, specifically supporting the use of blood pressure cuffs to decrease compressibility. background: electroencephalography (eeg) is an underused test that can provide valuable information in the evaluation of emergency department (ed) patients with altered mental status (ams). in ams patients with nonconvulsive seizure (ncs), eeg is necessary to make the diagnosis and to initiate proper treatment. yet, most cases of ncs are diagnosed > h after ed presentation. obstacles to routine use of eeg in the ed include space limitations, absence of / availability of eeg technologists and interpreters, and the electrically hostile ed environment. a novel miniature portable wireless device (microeeg) is designed to overcome these obstacles. objectives: to examine the diagnostic utility of micro-eeg in identifying eeg abnormalities in ed patients with ams. methods: an ongoing prospective study conducted at two academic urban eds. inclusion: patients ‡ years old with ams. exclusion: an easily correctable cause of ams (e.g. hypoglycemia, opioid overdose). three -minute eegs were obtained in random order from each subject beginning within one hour of presentation: ) a standard eeg, ) a microeeg obtained simultaneously with conventional cup electrodes using a signal splitter, and ) a microeeg using an electrocap. outcome: operative characteristics of micro-eeg in identifying any eeg abnormality. all eegs were interpreted in a blinded fashion by two board-certified epileptologists. within each reader-patient pairing, the accuracy of eegs and were each assessed relative to eeg . sensitivity, specificity, and likelihood ratios (lr) are reported for microeeg by standard electrodes and electrocap (eegs and ). inter-rater variability for eeg interpretations is reported with kappa. results: the interim analysis was performed on consecutive patients (target sample size: ) enrolled from may to october (median age: , range: - , % male). overall, % ( % confidence interval [ci], - %) of interpretations were abnormal (based on eeg ). kappa values representing the agreement of neurologists in interpretation of eeg - were . ( . - . ), . ( . - . ), and . ( . - . ), respectively. conclusion: the diagnostic accuracy and concordance of microeeg are comparable to those of standard eeg but the unique ed-friendly characteristics of the device could help overcome the existing barriers for more frequent use of eeg in the ed. (originally submitted as a ''late-breaker.'') a background: patients who use an ed for acute migraine are characterized by higher migraine disability scores, lower socio-economic status, and are unlikely to have used a migraine-specific medication prior to ed presentation. objectives: to determine if a comprehensive migraine intervention, delivered just prior to ed discharge, could improve migraine impact scores one month after the ed visit. methods: this was a randomized controlled trial of a comprehensive migraine intervention versus typical care among patients who presented to an ed for management of acute migraine. at the time of discharge, for patients randomized to comprehensive care, we reinforced their diagnosis, shared a migraine education presentation from the national library of medicine, provided them with six tablets of sumatriptan mg and tablets of naproxen mg, and if they wished, provided them with an expedited free appointment to our institution's headache clinic. patients randomized to typical care received the care their attending emergency physician felt was appropriate. the primary outcome was a between-group comparison of the hit score, a validated headache assessment instrument, one month after ed discharge. secondary outcomes included an assessment of satisfaction with headache care and frequency of use of migraine-specific medication within that one month period. the outcome assessor was blinded to assignment. results: over a month period, migraine patients were enrolled. one month follow-up was successfully obtained in % of patients. baseline characteristics were comparable. one month hit scores in the two groups were nearly identical ( vs , %ci for difference of : ) , ), as was dissatisfaction with overall headache care ( % versus %, %ci for difference of %: ) , %). not surprisingly, patients randomized to the comprehensive intervention were more likely to be using triptans or migraine-preventive therapy ( % versus %, %ci for difference of %: , %) one month later. conclusion: a comprehensive migraine intervention, when compared to typical care, did not improve hit scores one month after ed discharge. future work is needed to define a migraine intervention that is practical and useful in an ed. background: lumbar puncture (lp) is the standard of care for excluding non-traumatic subarachnoid hemorrhage (sah), and is usually performed following head ct (hct). however, in the setting of a non-diagnostic hct, lp demonstrates a low overall diagnostic yield for sah (< % positive rate). objectives: to describe a series of ed patients diagnosed with sah by lp following a non-diagnostic hct, and, when compared to a set of matched controls, determine if clinical variables can reliably identify these ''ct-negative/lp-positive'' patients. methods: retrospective case-control chart review of ed patients in an integrated health system between the years - (estimated - million visits among eds). patients with a final diagnosis of non-traumatic sah were screened for case inclusion, defined as an initial hct without sah by final radiologist interpretation and a lp with > red blood cells/mm , along with either ) xanthochromic cerebrospinal fluid, ) angiographic evidence of cerebral aneurysm or arteriovenous malformation, or ) head imaging showing sah within hours following lp. control patients were randomly selected among ed patients diagnosed with headache following a negative sah evaluation with hct and lp. controls were matched to cases by year and presenting ed in a : ratio. stepwise logistic regression and classification and regression tree analysis (cart) were employed to identify predictive variables. inter-rater reliability (kappa) was determined by independent chart review. results: fifty-five cases were identified. all cases were hunt-hess grade or . demographics are shown in table . thirty-four cases ( %) had angiographic evidence of sah. five variables were identified that positively predicted sah following a normal hct with % sensitivity ( % ci, - %) and % specificity ( % ci, - %): age > years, neck pain or stiffness, onset of headache with exertion, vomiting with headache, or loss of consciousness at headache onset. kappa values for selected variables ranged from . - . ( % sample). the c-statistic (auc) and hosmer-lemeshow test p-value for the logistic regression model are . and . , respectively (table ) . conclusion: several clinical variables can help safely limit the amount of invasive testing for sah following a non-diagnostic hct. prospective validation of this model is needed prior to practice implementation. background: post-thrombolysis intracerebral hemorrhage (ich) is associated with poor outcomes. previous investigations have attempted to determine the relationship between pre-existing anti-platelet (ap) use and the safety of intravenous thrombolysis, but have been limited by low event rates thus decreasing the precision of estimates. objectives: our objective was to determine whether pre-existing ap therapy increases the risk of ich following thrombolysis. methods: consecutive cases of ed-treated thrombolysis patients were identified using multiple methods, including active and passive surveillance. retrospective data were collected from four hospitals from - , and distinct hospitals from - as part of a cluster randomized trial. the same chart abstraction tool was used during both time periods and data were subjected to numerous quality control checks. hemorrhages were classified using a pre-specified methodology: ich was defined as presence of hemorrhage in radiographic interpretations of follow up imaging (primary outcome). symptomatic ich (secondary outcome) was defined as radiographic ich with associated clinical worsening. a multivariable logistic regression model was constructed to adjust for clinical factors previously identified to be related to postthrombolysis ich. as there were fewer sich events, the multivariable model was constructed similarly, except that variables divided into quartiles in the primary analysis were dichotomized at the median. results: there were patients included, with % having documented pre-existing ap treatment. the mean age was years, the cohort was % male, and the median nihss was . the unadjusted proportion of patients with any ich was . % without ap and . % with ap (difference . %, % ci ) . % to . %); for sich this was . % without ap and % with ap (difference . %, %ci ) to . %). no significant association between pre-existing ap treatment with radiographic or symptomatic ich was observed (table) . conclusion: we did not find that ap treatment was associated with post-thrombolysis ich or sich in this cohort of community treated patients. pre-existing tobacco use, younger age, and lower severity were associated with lower odds of sich. an association between ap therapy and sich may still exist -further research with larger sample sizes is warranted in order to detect smaller effect sizes. background: post-cardiac arrest therapeutic hypothermia (th) improves survival and neurologic outcome after cardiac arrest, but the parameters required for optimal neuroprotection remain uncertain. our laboratory recently reported that -hour th was superior to -hour th in protecting hippocampal ca pyramidal neurons after asphyxial cardiac arrest in rats. cerebellar purkinje cells are also highly sensitive to ischemic injury caused by cardiac arrest, but the effect of th on this neuron population has not been previously studied. objectives: we examined the effect of post-cardiac arrest th onset time and duration on purkinje neuron survival in cerebella collected during our previous study. methods: adult male long evans rats were subjected to -minute asphyxial cardiac arrest followed by cpr. rats that achieved return of spontaneous circulation (rosc) were block randomized to normothermia ( . deg c) or th ( . deg c) initiated , , , or hours after rosc and maintained for or hours (n = per group). sham injured rats underwent anesthesia and instrumentation only. seven days post-cardiac arrest or sham injury, rats were euthanized and brain tissue was processed for histology. surviving purkinje cells with normal morphology were quantified in the primary fissure in nissl stained sagittal sections of the cerebellar vermis. purkinje cell density was calculated for each rat, and group means were compared by anova with bonferroni analysis. results: purkinje cell density averaged (+/) sd) . ( . ) cells/mm in sham-injured rats. neuronal survival in normothermic post-cardiac arrest rats was significantly reduced compared to sham ( . % ( . %)). overall, th resulted in significant neuroprotection compared to normothermia ( . % ( . %) of sham). purkinje cell density with -hour duration th was . % ( . %) of sham and -hour duration th was . % ( . %), both significantly improved from sham (p = . between durations). th initiated , , , and hours post-rosc provided similar benefit: . % ( . %), . % ( . %), . % ( . %), and . % ( . %) of sham, respectively. conclusion: overall, these results indicate that postcardiac arrest th protects cerebellar purkinje cells with a broad therapeutic window. our results underscore the importance of considering multiple brain regions when optimizing the neuroprotective effect of post-cardiac arrest th. the effect of compressor-administered defibrillation on peri-shock pauses in a simulated cardiac arrest scenario joshua glick, evan leibner, thomas terndrup penn state hershey medical center, hershey, pa background: longer pauses in chest compressions during cardiac arrest are associated with a decreased probability of successful defibrillation and patient survival. having multiple personnel share the tasks of performing chest compressions and shock delivery can lead to communication complications that may prolong time spent off the chest. objectives: the purpose of this study was to determine whether compressor-administered defibrillation led to a decrease in pre-shock and peri-shock pauses as compared to bystander-administered defibrillation in a simulated in-hospital cardiac arrest scenario. we hypothesized that combining the responsibilities of shock delivery and chest-compression performance may lower no-flow periods. methods: this was a randomized, controlled study measuring pauses in chest compressions for defibrillation in a simulated cardiac arrest. medical students and ed personnel with current cpr certification were surveyed for participation between july and october . participants were randomized to either a control (facilitator-administered shock) or variable (participantadministered shock) group. all participants completed one minute of chest compressions on a mannequin in a shockable rhythm prior to initiation of prompt and safe defibrillation. pauses for defibrillation were measured and compared in both study groups. results: out of total enrollments, the data from defibrillations were analyzed. subject-initiated defibrillation resulted in a significantly lower pre-shock handsoff time ( . s; % ci: . - . ) compared to facilitator-initiated defibrillation ( . s; % ci: . - . ). furthermore, subject-initiated defibrillation resulted in a significantly lower peri-shock hands-off time ( . s; % ci: . - . ) compared to facilitator-initiated defibrillation ( . s; % ci: . - . ). conclusion: assigning the responsibility for shock delivery to the provider performing compressions encourages continuous compressions throughout the charging period and decreases total time spent off the chest. this modification may also decrease the risk of accidental shock and improve patient survival. however, as this was a simulation-based study, clinical implementation is necessary to further evaluate these potential benefits. objectives: to determine the sensitivity and specificity of peripheral venous oxygen (po ) to predict abnormal central venous oxygen saturation in septic shock patients in the ed. methods: secondary analysis of an ed-based randomized controlled trial of early sepsis resuscitation targeting three physiological variables: cvp, map, and either scvo or lactate clearance. inclusion criteria: suspected infection, two or more sirs criteria, and either systolic blood pressure < mmhg after a fluid bolus or lactate > mm. peripheral venous po was measured prior to enrollment as part of routine care, and scvo was measured as part of the protocol. we analyzed for agreement between venous po and scvo using spearman's rank. sensitivity and specificity to predict an abnormal scvo (< %) were calculated for each incremental value of po . results: a total of were analyzed. median po was mmhg (iqr , ). median initial scvo was % (iqr , ). thirty-nine patients ( %) had an initial scvo < %. spearman's rank demonstrated fair correlation between initial po and scvo (q = . ). a cutoff of venous po < was % sensitive and % specific for detecting an initial scvo < %. twenty-seven patients ( %) demonstrated an initial po of > . conclusion: in ed septic shock patients, venous po demonstrated only fair correlation with scvo , though a cutoff value of was sensitive for predicting an abnormal scvo . twenty percent of patients demonstrated an initial value above the cutoff, potentially representing a group in whom scvo measurement could be avoided. future studies aiming to decrease central line utilization could consider the use of peripheral o measurements in these patients. sessions. ninety-two percent were rns, median clinical experience was - years, and % were from an intensive care unit. provider confidence increased significantly with a single session despite the highly experienced sample (figure ). there was a trend for further increased confidence with an additional session and the increased confidence was maintained for at least - months given the normal sensitivity analysis. conclusion: high fidelity simulation significantly increases provider confidence even among experienced providers. this study was limited by its small sample size and recent changes in acls guidelines. background: recent data suggest alarming delays and deviations in major components of pediatric resuscitation during simulated scenarios by pediatric housestaff. objectives: to identify the most common errors of pediatric residents during multiple simulated pediatric resuscitation scenarios. methods: a retrospective observational study conducted in an academic tertiary care hospital. pediatric residents (pgy and pgy ) were videotaped performing a series of five pediatric resuscitation scenarios using a high-fidelity simulator (simbaby, laerdal): pulseless non-shockable arrest, pulseless shockable arrest, dysrhythmia, respiratory arrest, and shock. the primary outcome was the presence of significant errors prospectively defined using a validated scoring instrument designed to assess sequence, timing, and quality of specific actions during resuscitations based on the aha pals guidelines. residents' clinical performances were measured by a single video reviewer. the primary analysis was the proportion of errors for each critical task for each scenario. we estimated that the evaluation of each resident would provide a confidence interval less than . for the proportion of errors. results: twenty-four of residents completed the study. across all scenarios, pulse check was delayed by more than seconds in % ( %ci: %- %). for non-shockable arrest, cpr was started more than seconds after recognizing arrest in % ( %ci - %) and inappropriate defibrillation was performed in % ( %ci - %). for shockable arrest, participants failed to identify the rhythm in % ( %ci - %), cpr was not performed in % ( %ci - %), while defibrillation was delayed by more than seconds in % ( %ci - %) and not performed in one case. for shock, participants failed to ask for a dextrose check in % ( %ci - %), and it was delayed by more than seconds for all others. conclusion: the most common error across all scenarios was delay in pulse check. delays in starting cpr and inappropriate defibrillation were common errors in non-shockable arrests, while failure to identify rhythm, cpr omission, and delaying defibrillation were noted for shockable arrests. for shock, omission of rapid dextrose check was the most common error, while delaying the test when ordered was also significant. future training in pediatric resuscitation should target these errors. background: many scoring instruments have been described to measure clinical performance during resuscitation; however, the validity of these tools has yet to be proven in pediatric resuscitation. objectives: to determine the external validity of published scoring instruments to evaluate clinical performance during simulated pediatric resuscitations using pals algorithms and to determine if inter-rater reliability could be assessed. methods: this was a prospective quasi-experimental design performed in a simulation lab of a pediatric tertiary care facility. participants were residents from a single pediatric program distinct from where the instrument was originally developed. a total of pgy s and pgy s were videotaped during five simulated pediatric resuscitation scenarios. pediatric emergency physicians rated resident performances before and after a pals course using standardized scoring. each video recording was viewed and scored by two raters blinded to one another. a priori, it was determined that, for the scoring instrument to be valid, participants should improve their scores after participating in the pals course. differences in means between pre-pals and post-pals and pgy and pgy were compared using an anova test. to investigate differences in the scores of the two groups over the five scenarios, a two-factor anova was used. reliability was assessed by calculating an interclass correlation coefficient for each scenario. results: following the pals course, scores improved by . % ( . to . ), . % ( . to . ), . % () . to . ), . % ( . to ), and . % () . to . ) for the pulseless non-shockable arrest, pulseless shockable arrest, dysrhythmia, respiratory, and shock scenarios respectively. there were no differences in scores between pgy s and pgy s before and after the pals course. there was an excellent reliability for each scoring instrument with iccs varying between . and . . conclusion: the scoring instrument was able to demonstrate significant improvements in scores following a pals course for pgy and pgy pediatric residents for the pulseless non-shockable arrest, pulseless shockable, and respiratory arrest scenarios only. however, it was unable to discriminate between pgy s and pgy s both before and after the pals course for any scenarios. the scoring instrument showed excellent inter-reliability for all scenarios. a background: medical simulation is a common and frequently studied component of emergency medicine (em) residency curricula. its utility in the context of em medical student clerkships is not well defined. objectives: the objective was to measure the effect of simulation instruction on medical students' em clerkship oral exam performance. we hypothesized that students randomized to the simulation group would score higher. we predicted that simulation instruction would promote better clinical reasoning skills and knowledge expression. methods: this was a randomized observational study conducted from / to / . participants were fourth year medical students in their em clerkship. students were randomly assigned on their first day to one of two groups. the study group received simulation instruction in place of one of the lectures, while the control group was assigned to the standard curriculum. the standard clerkship curriculum includes lectures, case studies, procedure labs, and clinical shifts without simulation. at the end of the clerkship, all students participated in written and oral exams. graders were not blinded to group allocation. grades were assigned based on a pre-defined set of criteria. the final course composite score was computed based on clinical evaluations and the results of both written and oral exams. oral exam scores between the groups were compared using a two-sample t-test. we used the spearman rank correlation to measure the association between group assignment and the overall course grade. the study was approved by our institutional irb. results: sixty-one students participated in the study and were randomly assigned to one of two groups. twenty-nine ( . %) were assigned to simulation and the remaining ( . %) students were assigned to the standard curriculum. students assigned to the simulation group scored . % ( % ci . - . %) higher on the oral exam than the non-simulation group. additionally, simulation was associated with a higher final course grade (p < . ). limitations of this pilot study include lack of blinding and interexaminer variability. conclusion: simulation training as part of an em clerkship is associated with higher oral exam scores and higher overall course grade compared to the standard curriculum. the results from this pilot study are encouraging and support a larger, more rigorous study. initial approaches to common complaints are taught using a standard curriculum of lecture and small group case-based discussion. we added a simulation exercise to the traditional altered mental status (ams) curriculum with the hypothesis that this would positively affect student knowledge, attitudes, and level of clinical confidence caring for patients with ams. methods: ams simulation sessions were conducted in june and ; student participation was voluntary. the simulation exercises included two ams cases using a full-body simulator and a faculty debriefing after each case. both students who did and did not participate in the simulations completed a written post-test and a survey related to confidence in their approach to ams. results: students completed the post-test and survey. ( %) attended the simulation session. ( %) attended all three sessions. ( %) participated in the lecture and small group. ( %) did not attend any session. post-test scores were higher in students who attended the simulations versus those who did not: (iqr, - ) vs. (iqr, - ); p < . . students who attended the simulations felt more confident about assessing an ams patient ( % vs. %; p = . ), articulating a differential diagnosis ( % vs. %; p = . ), and knowing initial diagnostic tests ( % vs. %; p = . ) and initial interventions ( % vs. %; p = . ) for an ams patient. students who attended the simulations were more likely to rate the overall ams curriculum as useful ( % vs. %; p < . ). conclusion: addition of a simulation session to a standard ams curriculum had a positive effect on student performance on a knowledge-based exam and increased confidence in clinical approach. the study's major limitations were that student participation in the simulation exercise was voluntary and that effect on applied skills was not measured. future research will determine whether simulation is effective for other chief complaints and if it improves actual clinical performance. background: the acgme has defined six core competencies for residents including ''professionalism'' and ''interpersonal and communication skills.'' integral to these two competencies is empathy. prior studies suggest that self-reported empathy declines during medical training; no reported study has yet integrated simulation into the evaluation of empathy in medical training. objectives: to determine if there is a relation between level of training and empathy in patient interactions as rated during simulation. methods: this is a prospective observational study at a tertiary care center comparing participants at four different levels of training: first (ms ) and third year (ms ) medical students, incoming em interns (pgy ), and em senior residents (pgy / ). trainees participated in two simulation scenarios (ectopic pregnancy and status asthmaticus) in which they were responsible for clinical management (cm) and patient interactions (pi). this was the first simulation exposure during an established simulation curriculum for ms , ms , and pgy . two independent raters reviewed videotaped simulation scenarios using checklists of critical actions for clinical management (cm: - points) and patient interactions (pi: - points). inter-rater reliability was assessed by intra-class correlation coefficients (iccs objectives: we explored attitudes and beliefs about the handoff, using qualitative methods, from a diverse group of stakeholders within the ems community. we also characterized perceptions of barriers to high-quality handoffs and identified strategies for optimizing this process. methods: we conducted seven focus groups at three separate gatherings of ems professionals (one local, two national) in / . snowball sampling was used to recruit participants with diverse professional, experiential, geographic, and demographic characteristics. focus groups, lasting - minutes, were moderated by investigators trained in qualitative methods, using an interview guide to elicit conversation. recordings of each group were transcribed. three reviewers analyzed the text in a multi-stage iterative process to code the data, describe the main categories, and identify unifying themes. results: participants included emts, paramedics, physicians, and nurses. clinical experience ranged from months to years. recurrent thematic domains when discussing attitudes and beliefs were: perceptions of respect and competence, professionalism, teamwork, value assigned to the process, and professional duty. modifiers of these domains were: hierarchy, skill/training level, severity/type of patient illness, and system/ regulatory factors. strategies to improving barriers to the handoff included: fostering familiarity and personal connections between ems and ed staff, encouraging two-way conversations, feedback, and direct interactions between ems providers and ed physicians, and optimizing ways for ems providers to share subjective impressions (beyond standardized data elements) with hospital-based care teams. conclusion: ems professionals assign high value to the ed handoff. variations in patient acuity, familiarity with other handoff participants, and perceptions of respect and professionalism appear to influence the perceived quality of this transition. regulatory strategies to standardize the contents of the handoff may not alone overcome barriers to this process. miology, public health) then developed an approach to assign ems records to one of symptom-based illness categories (gastrointestinal illness, respiratory, etc). ems encounter records were characterized into these illness categories using a novel text analytic program. event alerts were identified across the state and local regions in illness categories using either change detection from baseline with (cusum) analysis (three standard deviations) and a novel text-proportion (tap) analysis approach (sas institute, cary, nc). results: . million ems encounter records over a year period were analyzed. the initial analysis focused upon gastrointestinal illness (gi) given the potential relationship of gi distress to infectious outbreaks, food contamination and intentional poisonings (ricin). after accounting for seasonality, a significant gi event was detected in feb (see red circle on graph). this event coincided with a confirmed norovirus outbreak. the use of cusum approach (yellow circle on graph) detected the alert event on jan , . the novel tap approach on a regional basis detected the alert on dec , . conclusion: ems has the advantage of being an early point of contact with patients and providing information on the location of insult or injury. surveillance based on ems information system data can detect emergent outbreaks of illness of interest to public health. a novel text proportion analytic technique shows promise as an early event detection method. assessing chronic stress in the emergency medical services elizabeth a. donnelly , jill chonody university of windsor, windsor, on, canada; university of south australia, adelaide, australia background: attention has been paid to the effect of critical incident stress in the emergency medical services (ems); however, less attention has been given to the effect of chronic stress (e.g., conflict with administration or colleagues, risk of injury, fatigue, interference in non-work activities) in ems. a number of extant instruments assess for workplace stress; however, none address the idiosyncratic aspects of work in ems. objectives: the purpose of this study was to validate an instrument, adapted from mccreary and thompson ( ) , that assesses levels of both organizational and operational work-related chronic stress in ems personnel. methods: to validate this instrument, a cross-sectional, observational web-based survey was used. the instrument was distributed to a systematic probability sample of emts and paramedics (n = , ). the survey also included the perceived stress scale (cohen, ) to assess for convergent construct validity. results: the survey attained a . % usable response rate (n = ); respondent characteristics were consistent across demographic characteristics with other studies of emts and paramedics. the sample was split in order to allow for exploratory and confirmatory fac-tor analyses (n = /n = ). in the exploratory factor analysis, principal axis factoring with an oblique rotation revealed a two-factor, -item solution (kmo = . , v = . , df = , p £. ). confirmatory factor analysis suggested a more parsimonious, two-factor, -item solution (v = . , df = , p £ . , rmsea = . , cfi = . , tli = . , srmr = . ). the factors demonstrated good internal reliability (operational stress a = . , organizational stress a = . ). both factors were significantly correlated (p £ . ) with the hypothesized convergent validity measure. conclusion: theory and empirical research indicate that exposure to chronic workplace stress may play an important part in the development of psychological distress, including burnout, depression, and posttraumatic stress disorder (ptsd). workplace stress and stress reactions may potentially interfere with job performance. as no extant measure assesses for chronic workplace stress in ems, the validation of this chronic stress measure enhances the tools ems leaders and researchers have in assessing the health and well-being of ems providers. effect of naltrexone background: survivors of sarin and other organophosphate poisoning can develop delayed encephalopathy that is not prevented by standard antidotal therapy with atropine and pralidoxime. a rat model of poisoning with the sarin analogue diisoprophylfluorophosphate (dfp) demonstrated impairment of spatial memory despite antidotal therapy with atropine and pralidoxime. additional antidotes are needed after acute poisonings that will prevent the development of encephalopathy. objectives: to determine the efficacy of naltrexone in preventing delayed encephalopathy after poisoning with the sarin analogue dfp in a rat model. the hypothesis is that naltrexone would improve performance on spatial memory after acute dfp poisoning. the sarin analogue dfp was used because it has similar toxicity to sarin while being less dangerous to handle. methods: a randomized controlled experiment at a university animal research laboratory of the effects of naltrexone on spatial memory after dfp poisoning was conducted. long evans rats weighing - grams were randomized to dfp group (n = , rats received a single intraperitoneal (ip) injection of dfp mg/kg) or dfp+naltrexone group (n = , rats received a single ip injection of dfp ( mg/kg) followed by naltrexone mg/kg/day). after injection, rats were monitored for signs and symptoms of cholinesterase toxicity. if toxicity developed, antidotal therapy was initiated with atro-background: one of the primary goals of management of patients presenting with known or suspected acetaminophen (apap) ingestion is to identify the risk for apap-induced hepatotoxicity. current practice is to measure apap level at a minimum of hours post ingestion and plot this value on the rumack-matthew nomogram. one retrospective study of apap levels drawn less than hours post-ingestion found a level less than mcg/ml to be sufficient to exclude toxic ingestion. objectives: the aim of this study was to prospectively determine the negative predictive value (npv) for toxicity of an apap level of less than mcg/ml obtained less than hours post-ingestion. methods: this was a multicenter prospective cohort study of patients presenting to one of five tertiary care hospitals that are part of the toxicology investigator's consortium (toxic). eligible patients presented to the emergency department less than hours after known or suspected ingestion and had the initial apap level obtained at greater than but less than hours post ingestion. a second apap level was obtained at hours or more post-ingestion and plotted on the rumack-matthew nomogram to determine risk of toxicity. the outcome of interest was the npv of an initial apap level less than mcg/ml. a power analysis based on an alpha = . and power of . yielded the requirement of subjects. results: data were collected on patients over a month period from may to nov . patients excluded from npv analysis consisted of: initial apap level greater than mcg/ml ( ), negligible apap level on both the initial and confirmatory apap level ( ), initial apap level drawn less than one hour after ingestion ( ), or an unknown time of ingestion ( ). ninety-three patients met the eligibility criteria. two patients ( . %) with an initial apap level less than mcg/ml ( mcg/ml at min, mcg/ml at min) were determined to be at risk for toxicity based on oh s saem annual meeting abstracts implementation of an emergency department sign-out checklist improves patient hand-offs at change of shift nicole m ma computer-assisted self-interviews improve testing for chlamydia and gonorrhea in the pediatric emergency department is the australian triage system a better indicator of psychiatric patients' needs for intervention than the ena emergency severity index triage system? patients were given an initial dose of mg droperidol intramuscularly followed by an additional dose of mg after min if required. inclusion criteria were patients requiring physical restraint and parenteral sedation. the primary outcome was the time to sedation. secondary outcomes were the proportion of patients requiring additional sedation within the first hour, over-sedation measured as - on the sedation assessment tool, and respiratory compromise measured as oxygen saturation < %. results: droperidol was administered to patients and of these had sedation scores documented. presentations included % with alcohol intoxication. dose ranged from . mg to mg, median mg (interquartile range conclusion: droperidol is effective for rapid sedation for abd and rarely causes over-sedation serum creatinine (scr) is widely used to predict risk; however, gfr is a better assessment of kidney function. objectives: to compare the ability of gfr and scr to predict the development of cin among ed patients receiving cects. we hypothesized that gfr would be the best available predictor of cin. methods: this was a retrospective chart review of ed patients ‡ years old who had a chest or abdomen/pelvis cect between / / and / / . baseline and follow-up scr levels were recorded. patients with initial scr > . mg/dl were excluded, as per hospital radiology department protocol. cin was defined as a scr increase of either %, . mg/dl, or a gfr decrease of % within hours of contrast exposure. gfr was calculated using the ckd epi and mdrd formulae, and analyzed in original units and categorized form (< , ‡ ) with each additional unit decrease in ckd epi, subjects were % more likely to develop cin (or = . ) (p < . ). additionally, subjects with ckd epi < were . (or) times more likely to have cin than subjects with ckd epi ‡ in original units, ckd epi (p < . ) and mdrd (p < . ) both had a significantly higher auc than scr. conclusion: age, as an independent variable, is the best predictor of cin, when compared with scr and gfr. due to a small number of cases with cin, the confidence intervals associated with the odds ratios are wide. future research should focus on patient risk stratification and establishing ed interventions to prevent cin. a rat model of carbon monoxide induced neurotoxicity heather ellsworth non-traumatic subarachnoid hemorrhage diagnosed by lumbar puncture following non-diagnostic head ct: a retrospective case-control study and decision a dass score of > has been previously defined as an indicator of increased stress levels. multivariable logistic regression was utilized to identify demographic and work-life characteristics significantly associated with stress. results: . % of individuals responded to the survey ( , / , ) and prevalence of stress was estimated at . %. the following work-life characteristics were associated with stress: certification level, work experience, and service type. the odds of stress in paramedics was % higher when compared to emt-basics (or = . , % ci = . - . ). when compared to £ years of experience - . ) were more likely to be stressed. ems professionals working in county (or = ci = . - . ) and private services (or = ) were more likely than those working in fire-based services to be stressed. the following demographic characteristics were associated with stress: general health and smoking status finally, former smokers (or = . , % ci = . - . ) and current smokers (or = . , % ci = . - . ) were more likely to be stressed than non-smokers literature suggests this is within the range of stress among nurses, and lower than physicians. while the current study was able to identify demographic and work-life characteristics associated with stress, the long-term effects are largely unknown methods: design: prospective randomized controlled trial. subjects: female sus scrofa swine weighing - kg were infused with amitriptyline . mg/kg/minute until the map fell to % of baseline values. subjects were then randomized to experimental group (ife ml/kg followed by an infusion of . ml/kg/minute) or control group (sb meq/kg plus equal volume of normal saline). interventions: we measured continuous heart rate (hr), sbp, map, cardiac output (co), systemic vascular resistance (svr), and venous oxygen saturation (svo ). laboratory values monitored included ph, pco , bicarbonate, lactate, and amitriptyline levels. descriptive statistics including means, standard deviations, standard errors of measurement, and confidence limits were calculated. results: of swine, seven each were allocated to ife and sb groups. there was no difference at baseline for each group regarding hr, sbp, map, co, svr, or svo . ife and sb groups required similar mean amounts of tca to reach hypotension one ife and two sb pigs survived. conclusion: in this interim data analysis of amitriptyline-induced hypotensive swine, we found no difference in mitigating hypotension between ife and sb lipid rescue : a survey of poison center medical directors regarding intravenous fat emulsion therapy michael r. christian , erin m. pallasch cook county hospital (stroger), chicago, il reliability of non-toxic acetaminophen concentrations obtained less than hours after ingestion evaluating age in the field triage of injured background: hiv screening in eds is advocated to achieve the goal of comprehensive population screening. yet, hiv testing in the ed is sometimes thwarted by a patient's condition (e.g. intoxication) or environmental factors (e.g. other care activities). whether it is possible to test these patients at a later time is unknown. objectives: we aimed to determine if ed patients who were initially unable to receive an hiv testing offer might be tested in the ed at a later time. we hypothesized that factors preventing testing are transient and that there are subsequent opportunities to repeat testing offers. methods: we reviewed medical records for patients presenting to an urban, academic ed who were approached consecutively to offer hiv testing during randomly selected periods from january to january . patients for whom the initial attempted offer could not be completed were reviewed in detail with standardized abstraction forms, duplicate abstraction, and third-party discrepancy adjudication. primary outcomes included repeat hiv testing offers during that ed visit, and whether a testing offer might eventually have been possible either during the initial visit or at a later visit within months. outcomes are described as proportions with confidence intervals. results: of patients approached, initial testing offers could not be completed for ( %). these were % male, % white, and had a median age of ( - ). a repeat offer of testing during the initial visit would have been possible for / ( %), and / ( %) were actually offered testing on repeat approach. of the for whom a testing offer would not have been possible on the initial visit, ( %) had at least one additional visit within months, and / ( %) could have been offered testing on at least one visit. overall, a repeat testing offer would have been possible for / ( %, % ci - %). conclusion: factors preventing an initial offer of hiv testing in the ed are generally transient. opportunities for repeat approach during initial or later ed encounters suggest that, given sufficient resources, the ed could succeed in comprehensively screening the population presenting for care. ed screening personnel who are initially unable to offer testing should repeat their attempt. hiv adopt an ''opt-out'' rapid hiv screening model in order to identify hiv infected patients. previous studies nationwide have shown acceptance rates for hiv screening of - % in emergency departments. however, it is unknown how acceptance rates will vary in a culturally and ethnically diverse urban emergency department.objectives: to determine the characteristics of patients who accept or refuse ''opt-out'' hiv screening in an urban emergency department.methods: a self-administered, anonymous survey is administered to ed patients who are to years of age. the questionnaire is administered in english, russian, mandarin, and spanish. questions include demographic characteristics, hiv risk factors, perception of hiv risk, and acceptance of rapid hiv screening in the emergency department. results: to date patients responded to our survey. of the , ( . %) did not accept an hiv test (group ) in their current ed visit and ( . %) accepted an hiv test (group ). the major two reasons given for opting out (i.e., group ) was ''i do not feel that i am at risk'' ( . %) and ''i have been tested for hiv before'' ( . %). there was no difference between the groups in regards to sex (p = . ), age (p = . ), religious affiliation (p = . ), marital status (p = . ), language spoken at home (p = . ), and whether they had been hiv tested before ( . % in group and . % in group ; p = . ). however, there was a statistically significant difference with regards to educational level and income. more patients in group ( . %) and . % in group had less than a college level education (p < . ). similarly, more patients in group ( . %) and only . % in group had an annual household income of £$ , (p < . ). conclusion: in a culturally and ethnically diverse urban emergency department, patients with a lower socioeconomic status and educational level tend to opt out of hiv screening test offered in the ed. no significant difference in acceptance of ed hiv testing was found to date based on primary language spoken at home or religious affiliation background: antimicrobial resistance is a problem that affects all emergency departments. objectives: our goal was to examine all urinary pathogens and their resistance patterns from urine cultures collected in the emergency department (ed).methods: this study was performed at an urban/suburban community-teaching hospital with an annual volume of , visits. using electronic records, all cases of urine cultures received in were reviewed for data including type of bacteria, antibiotic resistance, and health care exposure (hcx). hcx was defined as no prior hospitalization within the previous six months, hospitalization within the previous three months, hospitalization within the previous six months, nursing home resident (nh), and presence of an indwelling urinary catheter (uc). an investigator abstracted all data with a second re-abstracting a random % for kappa statistics between . and . . group background: approximately - % of patients treated with epinephrine for anaphylaxis receive a second dose but the risk factors associated with repeat epinephrine use remain poorly defined. objectives: to determine whether obesity is a risk factor for requiring + epinephrine doses for patients who present to the emergency department (ed) with anaphylaxis due to food allergy or stinging insect hypersensitivity. methods: we performed a retrospective chart review at four tertiary care hospitals that care for adults and children in new england between the following time periods: massachusetts general hospital ( / / - / / ), brigham and women's hospital ( / / - / / ), children's hospital boston ( / / - / / ), hasbro children's hospital ( / / - / / ). we reviewed the medical records of all patients presenting to the ed for food allergy or stinging insect hypersensitivity using icd cm codes. we focused on anthropomorphic data and number of epinephrine treatments given before and during the ed visit. among children, calculated bmis were classified according to cdc growth indicators as underweight, healthy, overweight, or obese. all patients who presented on or after their th birthday were considered adults.background: transitions of care are ubiquitous in the emergency department (ed) and inevitably introduce the opportunity for errors. despite recommendations in the literature, few emergency medicine (em) residency programs provide formal training or standard process for patient hand-offs. checklists have been shown to be effective quality improvement measures in inpatient settings and may be a feasible method to improve ed hand-offs. objectives: to determine if the use of a sign-out checklist improves the accuracy and efficiency of resident sign-out in the ed as measured by reduced omission of key information, communication behaviors, and time to sign-out each patient. methods: a prospective study of first-and second-year em and non-em residents rotating in the ed at an urban academic medical center with an annual ed volume of , . trained clinical research assistants observed resident sign-out during shift change over a two-week period and completed a -point binary observable behavior data collection tool to indicate whether or not key components of sign-out occurred. time to sign out each patient was recorded. we then created and implemented a computerized sign-out checklist consisting of key elements that should be addressed during transitions of care, and instructed residents to use this during hand-offs. a two-week post-intervention observation phase was conducted using the same data collection tool. proportions, means, and non-parametric comparison tests were calculated using stata. results: one hundred fifteen sign-outs were observed prior to checklist implementation and after; one sign-out was excluded for incompleteness. significant improvements were seen in four of the measured signout components: inclusion of history of present illness increased by % (p < . ), likely diagnosis increased by % (p = . ), disposition status increased by % (p < . ), and patient/care team awareness of plan increased by % (p < . ). (figure ) time data for sign-outs pre-implementation and post-implementation were available. seven sign-outs were excluded for incompleteness or spurious values. mean length of sign out was s ( % ci to ) and . s ( % ci to ) per patient. conclusion: implementation of a checklist improved the transfer of information but did not affect the overall length of time for the sign-out. the objectives: to determine risk factors associated with adult patients presenting to the ed with cellulitis who fail initial antibiotic therapy and require a change of antibiotics or admission to hospital. methods: this was a prospective cohort study of patients ‡ years presenting with cellulitis to one of two tertiary care eds (combined annual census , ). patients were excluded if they had been treated with antibiotics for the cellulitis prior to presenting to the ed, if they were admitted to hospital, or had an abscess only. trained research personnel administered a questionnaire at the initial ed visit with telephone follow-up weeks later. patient characteristics were summarized using descriptive statistics and % confidence intervals (cis) were estimated using standard equations. backwards stepwise multivariable logistic regression models determined predictor variables independently associated with treatment failure (failed initial antibiotic therapy and required a change of antibiotics or admission to hospital). results: patients were enrolled, were excluded, and were lost to follow-up. the mean (sd) age was . ( . ) and . % were male. ( . %) patients were given antibiotics in the ed. ( . %) were given oral, ( . %) were given iv, and ( . %) patients were given both oral and iv antibiotics. ( . %) patients had a treatment failure. fever (temp > °c) at triage (or: . , % ci: . , . ), leg ulcers (or: . , % ci: . , . ), edema or lymphedema (or: . , % ci: . , . ), and prior cellulitis in the same area (or: . , % ci: . , . ) were independently associated with treatment failure. conclusion: this analysis found four risk factors associated with treatment failure in patients presenting to the ed with cellulitis. these risk factors should be considered when initiating empiric outpatient antibiotic therapy for patients with uncomplicated cellulitis. use background: children presenting for care to a pediatric emergency department (ped) commonly require intravenous catheter (iv) placement. prior studies report that the average number of sticks to successfully place an iv in children is . . successfully placing an iv requires identification of appropriate venous access targets. the veinviewer visionÒ (vvv) assists with iv placement by projecting a map of subcutaneous veins on the surface of the skin using near infrared light. objectives: to compare the effectiveness of the vvv versus standard approaches: sight (s) and sight plus palpation (s+p) for identifying peripheral veins for intravenous catheter placement in children treated in a ped. methods: experienced pediatric emergency nurses and physicians identified peripheral venous access targets appropriate for intravenous cannulation of a cross-sectional convenience sample of english speaking children aged - years presenting for treatment of sub-critical injury or illness whose parents provided consent. the clinicians marked the veins with different colored washable marker and counted them on the dorsum of the hand and in the antecubital fossa using the three approaches: s, s+p, and vvv. a trained research assistant photographed each site for independent counting after each marking and recorded demographics and bmi. counts were validated using independent photographic analyses. data were entered into sas . and analyzed using paired t-tests. results: patients completed the study. clinicians were able to identify significantly more veins on the dorsum of the hand using vvv than s alone or s+p, . (p < . , ci . - . ) and . (p < . , ci . - . ), respectively, as well as significantly more veins in the antecubital fossa using vvv than s alone or s+p, . (p < . , ci . - . ) and . (p < . , ci . - . ), respectively. the differences in numbers of veins identified remained significant at p < . level across all ages, races, and bmis of children and across clinicians and validating independent photographic analyses. conclusion: experienced emergency nurses and physicians were able to identify significantly more venous access targets appropriate for intravenous cannulation in the dorsum of the hand and antecubital fossa of children presenting for treatment in a ped using vvv than the standard approaches of sight or sight plus palpation. an background: mental health emergencies have increased over the past two decades, and contribute to the ongoing rise in u.s. ed visit volumes. although data are limited, there is a general perception that the availability of in-person psychiatric consultation in the ed and of inpatient psychiatric beds is inadequate. objectives: to examine the availability of in-person psychiatry consultation in a heterogeneous sample of u.s. eds, and typical delays in transfer of ed patients to an inpatient psychiatric bed. methods: during - , we mailed a survey to all ed directors in a convenience sample of nine us states (ar, co, ga, hi, ma, mn, or, vt, and wy). all sites were asked: ''are psychiatric consults available in-person to the ed?'' (yes/no), with affirmative respondents asked about the typical delay. sites also were asked about typical ed boarding time between a request for patient transfer and actual patient departure from the ed to an inpatient psychiatric bed. ed characteristics included rural/urban location, visit volume (visits/hour), admission rate, ed staffing, and the proportion of patients without insurance. data analysis used chi-square tests and multivariable logistic regression. results: surveys were collected from ( %) of the eds, with > % response rate in every state. overall, only % responded that psychiatric consults were available in-person to the ed. in multivariable logistic regression, ed characteristics independently associated with lack of in-person psychiatric consultation were: location within specific states (eg, ar, ga), rural location, lower visit volume, and lower admission rate. among the subset of eds with psychiatric consults available, % reported a typical wait time of at least hour. overall, % of eds reported that the typical time from request to actual patient transfer to an inpatient psychiatric bed was > hours, and % reported a maximum time in past year of > day (median days, iqr - ). in a multivariable model, location in ma and higher visit volume were associated with greater odds of a maximum wait time of > day. conclusion: among surveyed eds in nine states, only % have in-person psychiatric consultants available. moreover, approximately half of eds report boarding times of > h from request for transfer to actual departure to an inpatient psychiatric bed.background: many emergency departments (ed) in the united states use a five tiered triage protocol that has a limited evaluation of psychiatric patients. the australian triage scale (ats), a psychiatric triage system, has been used throughout australia and new zealand since the early s. objectives: the objective of the study is to compare the current triage system, emergency nurses association (ena) esi -tier, to the ats for the evaluation of the psychiatric patients presenting to the ed. methods: a convenience sample of patients, years of age and older, presenting with psychiatric complaints at triage were given the ena triage assessment by the triage nurse. a second triage assessment, performed by a research fellow, included all observed and reported elements using the ats protocol, a self-assessment survey and an agitation assessment using the richmond agitation sedation scale (rass). the study was performed at an inner city level i trauma center with , visits per year. the ed was a catchment facility for the police department for psychiatric patients in the area. patients were excluded if they were unstable, unable to communicate, or had a non-psychiatric complaint. results were analyzed in spss v . the analysis of data used frequencies, descriptive and anova. results: a total of patients were enrolled in the study: % were african american, % caucasian, % hispanic, % asian, and % indian; % of subjects enrolled were male. the patients' level of agitation using rass showed % were alert and calm, % were restless and anxious, % were agitated, and % combative, violent, or dangerous to self. the only significant correlation found was among the ats and several self assessment questions: ''i feel agitated on a to scale'' (p = . ) and ''i feel violent on a to scale'' (p = . ). there were no significant correlations found among the ena triage, rass scores, and throughput times. conclusion: the ats test was more sensitive to the patient declaring that he or she was agitated or felt violent. this shows that this system might be a more useful system in determining the severity of need of psychiatric patients presenting to the ed. variations background: hemoglobin-based oxygen carriers (hbocs) have been evaluated for small-volume resuscitation of hemorrhagic shock due to their oxygen carrying capability, but have found limited utility due to vasoactive side-effects from nitric oxide (no) scavenging. objectives: to define an optimal hboc dosing strategy and evaluate the effect of an added no donor, we use a prehospital swine polytrauma model to compare the effect of low-vs. moderate-volume hboc resuscitation with and without nitroglycerin (ntg) co-infusion as an no donor. we hypothesize that survival time will improve with moderate resuscitation and that an no donor will add additional benefit. methods: survival time was compared in groups (n = ) of anesthetized swine subjected to simultaneous traumatic brain injury and uncontrolled hemorrhagic shock by aortic tear. animals received one of three different resuscitation fluids: lactated ringers (lr), hboc, or vasoattenuated hboc with ntg co-infusion. for comparison, these fluids were given in a severely limited fashion (sl) as one bolus every minutes up to four total, or a moderately limited fashion (ml) as one bolus every minutes up to seven total, to maintain mean arterial pressure ‡ mmhg. comparison of resuscitation regimen and fluid type on survival time was made using two-way anova with interaction and tukey kramer adjustment for individual comparisons. results: there was a significant interaction between fluid regimen and resuscitation fluid type (anova, p = . ) indicating that the response to sl or ml resuscitation was fluid type-dependent. within the lr and hboc+ntg groups, survival time (mean, %ci) was longer for sl, . min ( injuries are common and result from many different mechanisms of injury (moi). knowing common fracture locations may help in diagnosis and treatment, especially in patients presenting with distracting injuries that may mask the pain of a radius fracture.objectives: we set out to determine the incidence of radius fracture locations among patients presenting to an urban emergency department (ed).background: carbon monoxide (co) is the leading cause of poisoning morbidity and mortality in the united states. standard treatment includes supplemental oxygen and supportive care. the utility of hyperbaric oxygen (hbo) therapy has been challenged by a recent cochrane review. hypothermia may mitigate delayed neurotoxic effects after co poisoning as it is effective in cardiac arrest patients with similar neuropathology. objectives: to develop a rat model of acute and delayed severe co toxicity as measured by behavioral deficits and cell necrosis in post-sacrifice brain tissue.methods: a total of rats were used for model development; variable concentrations of co and exposure times were compared to achieve severe toxicity. for the protocol, six senescent long evans rats were exposed to , ppm of co for minutes then , ppm for minutes, followed by three successive dives at , ppm with an endpoint of apnea or seizure; there was a brief interlude between dives for recovery. a modified katz assessment tool was used to assess behavior at baseline and hours, day, and , , , , , and weeks post-exposure. following this, the brains were transcardially fixed with formalin, and lm sagittal slices were embedded in paraffin and stained with hematoxylin and eosin. a pathologist quantified the percentage of necrotic cells in the cortex, hippocampus (pyramidal cells), caudoputamen, cerebellum (purkinje cells), dentate gyrus, and thalamus of each brain to the nearest % from randomly selected high power fields ( x background: there remains controversy about the cardiotoxic effects of droperidol, and in particular the risk of qt prolongation and torsades des pointes (tdp).objectives: this study aimed to investigate the cardiac and haemodynamic effects of high-dose parenteral droperidol for sedation of acute behavioural disturbance (abd) in the emergency department (ed). methods: a standardised intramuscular (im) protocol for the sedation of ed patients with abd was instituted as part of a prospective observational safety study in four regional and metropolitan eds. patients with abd were given an initial dose of mg droperidol followed by an additional dose of mg after min if required. inclusion criteria were patients requiring physical restraint and parenteral sedation. the primary outcome was the proportion of patients who have a prolonged qt interval on ecg. the qt interval was plotted against the heart rate (hr) on the qt nomogram to determine if the qt was abnormal. secondary outcomes were frequency of hypotension and cardiac arrhythmias. results: ecgs were available from of patients with abd given droperidol. the median dose was mg (iqr - mg; range: to mg). the median age was years (rnge: to ) and were males ( %). a total of four ( %) qt-hr pairs were above the ''at-risk'' line on the qt nomogram. transient hypotension occurred in ( %), and no arrhythmias were detected.conclusion: droperidol appears to be safe when used for rapid sedation in the dose range of to mg. it rarely causes hypotension or qt prolongation. blood background: soldiers and law enforcement agents are repeatedly exposed to blast events in the course of carrying out their duties during training and combat operations. little data exist on the effect of this exposure on the physiological function of the human body. both military and law enforcement dynamic entry personnel, ''breachers'', began expressing sensitivity to the risk of injury as a result of multiple blast exposures. breachers apply explosives as a means of gaining access to barricaded or hardened structures. these specialists can be exposed to as many as a dozen lead-encased charges per day during training exercises.objectives: this observational study was performed by the breacher injury consortium to determine the effect of short-term exposure to blasts by breachers on whole blood lead levels (blls) and zinc protoporphyrin levels (zppls). methods: two -week basic breaching training classes were conducted by the united states marine corps' weapons training battalion dynamic entry school. each class included students and up to three instructors, with six non-breaching marines serving as a control group. to evaluate for lead exposure, venous blood samples were acquired from study participants on the weekend prior and following training in the first training class, whereas the second training class had an additional level performed mid-training. blls and zppls were measured in a whole-blood sample using the furnace atomic absorption method and hematofuorimeter method, respectively. results: analysis of these blast injury data indicated students demonstrated significantly increased blls post-explosion (mean = mcg/dl, sd . , p < . ) compared to pre-training (mean = mcg/dl, sd . ) and control subjects (mean = mcg/dl, sd . , p < . ). instructors also demonstrated significantly increased blls post explosion (mean = mcg/dl, sd . , p < . ) compared to pre-training (mean = mcg/ dl, sd . ) and control subjects (mean = mcg/dl, sd . , p < . ). student and instructor zppls were not significantly different in post-training compared to pretraining or control groups. conclusion: the observation from this study that breachers are at risk of mild increases in blls support the need for further investigation into the role of lead following repeated blast exposure with munitions encased in lead. direct observation of the background: notification of a patient's death to family members represents a challenging and stressful task for emergency physicians. complex communication skills such as those required for breaking bad news (bbn) are conventionally taught with small-group and other interactive learning formats. we developed a de novo multi-media web-based learning (wbl) module of curriculum content for a standardized patient interaction (spi) for senior medical students during their emergency medicine rotation.objectives: we proposed that use of an asynchronous wbl module would result in students' skill acquisition for breaking bad news. methods: we tracked module utilization and performance on the spi to determine whether students accessed the materials and if they were able to demonstrate proficiency in its application. performance on the spi was assessed utilizing a bbn-specific content instrument developed from the griev_ing mnemonic as well as a previously validated instrument for assessing communication skills.results: three hundred seventy-two students were enrolled in the bbn curriculum. there was a % completion rate of the wbl module despite students being given the option to utilize review articles alone for preparation. students interacted with the activities within the module as evidenced by a mean number of mouse clicks of . (sd . ). overall spi scores were . %, (sd . ) with content checklist scores of . % (sd . ) and interpersonal communication scores . % (sd . ). five students had failing content scores (< %) on the spi and had a mean number of clicks of . (sd . ), which is not significantly lower than those passing (p = . ). students in the first year of wbl deployment completed self-confidence assessments which showed significant increases in confidence ( . tobackground: pelvis ultrasonography (us) is a useful bedside tool for the evaluation of women with suspected pelvic pathology. while pelvic us is often performed by the radiology department, it often lacks clinical correlation and takes more time than bedside us in the ed. this was a prospective observational study comparing the ed length of stay (los) of patients receiving ed us versus those receiving radiology us. objectives: the primary objective was to measure the difference in ed los. the secondary objectives were to ) assess the role of pregnancy status, ob/gyn consult in the ed, and disposition, in influencing the ed los; and ) to assess the safety of ed us by looking at patient return to the ed within weeks and whether that led to an alternative diagnosis.methods: subjects were women over years old presenting with a gi or gu complaint, and who received either an ed or radiology us. a t-test was used for the primary objective, and linear regression to test the secondary objective. odds ratios were performed to assess for interaction between these factors and type of ultrasound. subgroup analyses were performed if significant interaction was detected. results: forty-eight patients received an ed us and patients received a radiology us. subjects receiving an ed us spent minutes less in the ed (p < . ). in multivariate analysis, even when controlling for pregnancy status, ob/gyn consult, and disposition, patients who received an ed us had a los reduction of minutes (p < . ). in odds ratio analysis, patients who were pregnant were times more likely to have received an ed us (p < . ). patients who received an ob/gyn consult in the ed were five times more likely to receive a radiology us (p < . ). there was no association between type of us and disposition. in subgroup analyses, pregnant and non-pregnant patients who received an ed us still had a los reduction of minutes (p < . ) and minutes (p < . ), respectively. sample sizes were inadequate for subgroup analysis for subjects who had ob/gyn consults. in patients who did not receive an ob/gyn consult, those who received an ed us had a los reduction of minutes (p < . ). finally, % of subjects returned within two weeks, but none led to an alternative diagnosis. conclusion: even when controlling for disposition, ob/gyn consultation, and pregnancy status, patients who received an ed us had a statistically and clinically significant reduction in their ed los. in addition, ed us is safe and accurate. background: although early surface cooling of burns reduces pain and depth of injury, there are concerns that cooling of large burns may result in hypothermia and worse outcomes. in contrast, controlled mild hypothermia improves outcomes after cardiac arrest and traumatic burn injury. objectives: the authors hypothesized that controlled mild hypothermia would prolong survival in a fluidresuscitated rat model of large scald burns. methods: forty sprague-dawley rats ( - g) were anesthetized with mg/kg intramuscular ketamine and mg/kg xylazine, with supplemental inhalational isoflurane as needed. a single full-thickness scald burn covering % of the total body surface area was created per rat using a mason-walker template placed in boiling water ( deg c) for a period of seconds. the rats were randomized to hypothermia (n = ) and nonhypothermia (n = ). core body temperature was continuously monitored with a rectal temperature probe. hypothermia was induced through intraperitoneal injection of cooled ( deg c) saline. the core temperature was reduced by deg c and maintained for a period of hours, applying an ice or heat pack when necessary. the rats were then rewarmed back to baseline temperature. in the control group, room temperature saline was injected into the intraperitoneal cavity and core temperature was maintained using a heating pad as needed. the rats were monitored until death or for a period of days, whichever was greater. the primary outcome was death. the difference in survival was determined using a kaplan-meier analysis or log rank test. results: the mean core temperatures were . deg c for the hypothermic group and . deg c for the normothermic group. the mean survival times were hours for the hypothermic group ( % confidence interval [ci] = to ) and hours for the normothermic group ( % ci = to ). the seven-day survival rates in the hypothermic and non-hypothermic groups were % and %. these differences were not significant, p = . for both comparisons. conclusion: induction of brief mild hypothermia increases but does not significantly prolong survival in a resuscitated rat model of large scald burns. serum objectives: we sought to determine levels of serum mtdna in ed patients with sepsis compared to controls and the association between mtdna and both inflammation and severity of illness among patients with sepsis. methods: prospective observational study of patients presenting to one of three large, urban, tertiary care eds. inclusion criteria: ) septic shock: suspected infection, two or more systemic inflammatory response (sirs) criteria, and systolic blood pressure (sbp) < mmhg despite a fluid bolus; ) sepsis: suspected infection, two or more sirs criteria, and sbp > mmhg; and ) control: ed patients without suspected infection, no sirs criteria, and sbp > mmhg. three mtdnas (cox-iii, cytochrome b, and nadh) were measured using real-time quantitative pcr from serum drawn at enrollment. il- and il- were measured using a bio-plex suspension array system. baseline characteristics, il- , il- , and mtdnas were compared using one way anova or fisher exact test, as appropriate. correlations between mtdnas and il- /il- were determined using spearman's rank. linear regression models were constructed using sofa score as the dependent variable, and each mtdna as the variable of interest in an independent model. a bonferroni adjustment was made for multiple comparisons.results: of patients, were controls, had sepsis, and had septic shock. we found no significant difference in any serum mtdnas among the cohorts (p = . to . ). all mtdnas showed a small but significant negative correlation with il- and il- (q = ) . to ) . ). among patients with sepsis or septic shock (n = ), we found a small but significant negative association between mtdna and sofa score, most clearly with cytochrome b (p = . ). conclusion: we found no difference in serum mtdnas between patients with sepsis, septic shock, and controls. serum mtdnas were negatively associated with inflammation and severity of illness, suggesting that as opposed to trauma, serum mtdna does not significantly contribute to the pathophysiology of the sepsis syndromes. methods: we consecutively enrolled ed patients ‡ years of age who met anaphylaxis diagnostic criteria from april to july at a tertiary center with , annual visits. we collected data on antihypertensive medications, suspected causes, signs and symptoms, ed management, and disposition. markers of severe anaphylaxis were defined as ) intubation, ) hospitalization (icu or floor), and ) signs and symptoms involving ‡ organ systems. antihypertensive medications evaluated included beta-blockers, angiotensin converting enzyme (ace) inhibitors, and calcium channel blockers (ccb). we conducted univariate and multivariate analyses to measure the association between antihypertensive medications and markers of severe anaphylaxis. because previous studies demonstrated an association between age and the suspected cause of the reaction with anaphylaxis severity, we adjusted for these known confounders in multivariate analyses. we report associations as odds ratios (ors) and corresponding % cis with p-values. results: among patients with anaphylaxis, median age (iqr) was ( - ) and ( . %) were female. eight ( . %) patients were intubated, ( %) required hospitalization, and ( %) had ‡ system involvement. forty-nine ( %) were on beta-blockers, ( %) on ace inhibitors, and ( . %) on ccb. in univariate analysis, ace inhibitors were associated with intubation and ‡ system involvement and ccb were associated with hospital admission. in multivariate analysis, after adjusting for age and suspected cause, ace inhibitors remained associated with hospital admission and beta-blockers remained associated with both hospital admission and ‡ system involvement. conclusion: in ed patients, beta-blocker and ace inhibitor use may predict increased anaphylaxis severity independent of age and suspected cause of the anaphylactic reaction. background: advanced cardiac life support (acls) resuscitation requires rapid assessment and intervention. some skills like patient assessment, quality cpr, defibrillation, and medication administration require provider confidence to be performed quickly and correctly. it is unclear, however, whether high-fidelity simulation can improve confidence with a multidisciplinary group of providers with high levels of clinical experience. objectives: the purpose of the study was to test the hypothesis that providers undergoing high-fidelity simulation of cardiopulmonary arrest scenarios will express greater confidence. methods: this was a prospective cohort study conducted at an urban level i trauma center from january to october with a convenience sample of registered (rn) and license practical nurses, nurse practitioners, resident physicians, and physician assistants who agreed to participate in / high-fidelity simulation (laerdal g) sessions of cardiopulmonary arrest scenarios about months apart. demographics were recorded. providers completed a validated preand post-test five-point likert scale confidence measurement tool before and after each session that ranged from not at all confident ( ) to very confident ( ) in recognizing signs and symptoms of, appropriately intervening in, and evaluating intervention effectiveness in cardiac and respiratory arrests. descriptive statistics, paired t-tests, and anova were used for data analysis. sensitivity testing evaluated subjects who completed their second session at months rather than months. results: sixty-five subjects completed consent, completed one session, and completed at least two background: prehospital studies have focused on the effect of health care provider gender on patient satisfaction. we know of no study that has assessed patient satisfication with patient and prehospital provider gender. some studies have shown higher patient satisfaction rates when cared for by a female health care provider.objectives: to determine the effect of ems provider gender on patient satisfaction with prehospital care. methods: a convenience sampling of all adult patients brought in to our ed, an urban level i trauma center by ambulance. a trained research associate (ra) stationed at triage conducted a survey using press ganey ems patient satisfaction questions. there were thirteen questions evaluating prehospital provider skills such as driving, courtesy, listening, medical care, and communication. each skill was assigned a point value between one and five; the higher the value the better the skill was performed. the patient's ambulance care report was copied for additional data extraction.results: a total of surveys were done. average patient age was , and % were female. scores for all questions totaled (mean . ± . ). prehospital providers pairings were: male-male (n = ), male-female (n = ), and female-female (n = ). there were no statistically significant differences in scores between our pairings (mean scores for male:male . , male:female . , and female:female . ; p = . ). we found nonstatistical differences in satisfaction scores based on the gender of the emt in the back of the ambulance: males had a mean score of . and females had a mean score of . (p = . ). we examined gender concordance by comparing gender of the patient to the gender of the prehospital provider and found that male-male had a mean score of . , female-female . , and when the patient and prehospital provider gender did not match, . (p = . ). conclusion: we found no effect of gender difference on patient satisfaction with prehospital care. we also found that overall, patients are very satisfied with their prehospital care. objectives: we set out to determine the sensitivity and specificity of eps in determining the presence of recently ingested tablets or tablet fragments.methods: this was a prospective volunteer study at an academic emergency department. healthy volunteers were enrolled and kept npo for hours prior to tablet ingestion. over minutes subjects ingested ml of water and tablets. ultrasounds video clips were performed prior to any tablet ingestion, after drinking ml of water, after tablets, after tablets, after tablets, and minutes after the final tablet ingestion yielding six clips per volunteer. all video clips were randomized and shown to three eps who were fellowship-trained in emergency ultrasound. eps recorded the presence or absence of tablets.results: ten volunteers underwent the pill ingestion protocol and sixty clips were collected. results for all cases and each rater are reported in the table. overall there was moderate agreement between raters (kappa = . ). sub-group analysis of , , or pills did not show any significant improvement in sensitivity and specificity.conclusion: ultrasound has moderate specificity but poor sensitivity for identification of tablet ingestion. these results imply that point-of-care ultrasound has limited utility in diagnosing large tablet ingestion. background: intravenous fat emulsion (ife) therapy is a novel treatment that has been used to reverse the acute toxicity of some xenobiotics with varied success. us poison control centers (pcc) are recommending this therapy for clinical use, but data regarding these recommendations are lacking.objectives: to determine how us pcc have incorporated ife as a treatment strategy for poisoning. methods: a closed-format multiple-choice survey instrument was developed, piloted, revised, and then sent electronically to every medical director of an accredited us pcc using surveymonkey in march ; addresses were obtained from the aapcc listserv, participation was voluntary and remained anonymous; three reminder invitations were sent during the study period. data were analyzed using descriptive statistics.results: forty-five of ( %) pcc medical directors completed the survey. all respondents felt that ife therapy played a role in the acute overdose setting. thirty ( %) pcc have a protocol for ife therapy: ( %) recommend an initial bolus of . ml/kg of a % lipid emulsion, ( %) pcc recommend an infusion of lipids, and / pcc recommend an initial infusion rate of . ml/kg of a % lipid emulsion. thirty-three ( %) felt that ife had no clinically significant side effects at a bolus dose of . ml/kg ( % emulsion). forty-four directors ( %) felt that the ''lipid sink'' mechanism contributed to the clinical effects of ife therapy, but ( %) felt that there was a yet undiscovered mechanism that likely contributed as well. in a scenario with cardiac arrest due to a single xenobiotic, directors stated that their center would always or often recommend ife after overdose of bupivicaine ( ; %), verapamil ( ; %), amitriptyline ( ; %), or an unknown xenobiotic ( ; %). in a scenario with significant hemodynamic instability due to a single xenobiotic, directors stated that their pcc would always or often recommend ife after overdose of bupivicaine ( ; %), verapamil ( ; %), amitriptyline ( ; %), or an unknown xenobiotic ( ; %).conclusion: ife therapy is being recommended by us pcc. protocols and dosing regimens are nearly uniform. most directors feel that ife is safe but are more likely to recommend ife in patients with cardiac arrest than in patients with severe hemodynamic compromise. further research is warranted. levels drawn at hours or more ( mcg/ml at hours, mcg ⁄ ml at hours, respectively). npv for toxic ingestion of an initial apap level less than mcg/ml was . % ( % ci . - . %).conclusion: an apap level of less than mcg/ml drawn less than hours after ingestion had a high npv for excluding toxic ingestion. however, the authors would not recommend reliance on levels obtained under hours to exclude toxicity as the potential for up to . % false negative results is considered unacceptable. background: genetic variations in the mu-opioid receptor gene (oprm ) mediate individual differences in response to pain and addiction.objectives: to study whether the common a g (rs ) mu-opioid receptor single nucleotide polymorphism (snp) or the alternative splicing snp of oprm (rs ) was associated with overdose severity, we assessed allele frequencies of each including associations with clinical severity in patients presenting to the emergency department (ed) with acute drug overdose. methods: in an observational cohort study at an urban teaching hospital, we evaluated consecutive adult ed patients presenting with suspected acute drug overdose over a -month period for whom discarded blood samples were available for analysis. specimens were linked with clinical variables (demographics, urine toxicology screens, clinical outcomes) then de-identified prior to genetic snp analysis. in-hospital severe outcomes were defined as either respiratory arrest (ra, defined by mechanical ventilation) or cardiac arrest (ca, defined by loss of pulse). blinded taqman genotyping (applied biosystems) of the snps were performed after standard dna purification (qiagen) and whole genome amplification (qiagen repli-g). the plink . genetic association analysis program was used to verify snp data quality, test for departure from hardy-weinberg equilibrium, and test individual snps for statistical association. results: we evaluated patients ( % female, mean age . ) who overall suffered ras and cas (of whom died). urine toxicology was positive in %, of which there were positives for benzodiazepines, cocaine, opiates, methadone, and barbiturates. all genotypes examined conformed to hardy-weinberg equilibrium. the g allele was associated with . fold increased odds of ca/ra (or . , p < . ). the rs mutant allele was not associated with ca/ ra. conclusion: these data suggest that the g mutant allele of the oprm gene is associated with worse clinical severity in patients with acute drug overdose. the findings add to the growing body of evidence linking the a g snp with clinical outcome and raise the question as to whether the a g snp may be a potential target for personalized medical prescribing practices with regard to behavioral/physiologic overdose vulnerability. key: cord- -nkaow h authors: sim, starling a.; leung, vivian k.y.; ritchie, david; slavin, monica a.; sullivan, sheena g.; teh, benjamin w. title: viral respiratory tract infections in allogeneic hematopoietic stem cell transplantation recipients in the era of molecular testing date: - - journal: biol blood marrow transplant doi: . /j.bbmt. . . sha: doc_id: cord_uid: nkaow h viral respiratory tract infection (vrti) is a significant cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-hsct). this study aimed to assess the epidemiologic characteristics, risk factors, and outcomes of vrti occurring in the period from conditioning to days after allo-hsct in the era of molecular testing. this study was a retrospective record review of patients who underwent allo-hsct at royal melbourne hospital between january and december . symptomatic patients were tested using respiratory multiplex polymerase chain reaction (pcr). logistic regression and kaplan-meier analysis were used to identify risk factors for vrti and the risk of death or intensive care unit (icu) admission, respectively. a total of patients were reviewed, and episodes of vrti were identified in patients ( . %). rhinovirus accounted for the majority of infections ( . %). the majority of episodes presented initially with upper respiratory tract infection ( . %), with . % of them progressing to lower respiratory tract infection. eleven episodes ( . %) were associated with icu admission. there were no deaths directly due to vrti. previous autologous hsct was associated with an increased risk of vrti (odds ratio, . ; % confidence interval, . to . ). the risks of death (p = . ) or icu admission (p = . ) were not significantly different by vrti status. vrti is common in the first days after allo-hsct and is associated with icu admission. respiratory viruses (rvs), including influenza virus, parainfluenza virus, respiratory syncytial virus (rsv), rhinovirus, coronavirus, adenovirus, and human metapneumovirus (hmpv), are common causes of viral respiratory tract infection (vrti) [ ] [ ] [ ] . previous studies have shown that rvs cause significant morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (hsct), in particular allogeneic hsct (allo-hsct) [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the diagnosis of rvs, especially in older studies, has been dependent mainly on nonmolecular diagnostic methods, including direct antigen detection or cell culture, which are limited by poor sensitivity [ ] . molecular testing using polymerase chain reaction (pcr) allows rapid detection of rvs with high sensitivity and specificity. moreover, multiplex assays enable the detection of multiple rvs in a single test, and these are now the current standard of care in many clinical settings. the purpose of this study was to assess the epidemiologic characteristics, risk factors, and outcomes of vrti in allo-hsct recipients in the era of molecular testing. melbourne hospital (rmh) between january and december . only the first allo-hsct was considered in patients who underwent multiple transplantations during the study period. patient records for the first days following allo-hsct were reviewed. demographic and clinical data were collected from hospital clinical records using a case report form and included age, sex, underlying disease, previous therapy, stem cell source, conditioning therapy, graft-versus-host disease (gvhd), and outcomes (ie intensive care unit [icu] admission and death). baseline measurements of lymphocyte and neutrophil levels and cytomegalovirus (cmv) seropositivity were collected. data on respiratory viral pcr testing and results from symptomatic patients were extracted from the rmh pathology database. for patients with rv infection, the number of vrtis, type of rvs, clinical presentation, antiviral therapy, and outcomes (ie, icu admission, death, use of mechanical ventilation, and progression to lower respiratory tract infection [lrti]) were also obtained during the -day period. during the review period, treatment of rsv with i.v. ribavirin was recommended in the setting of radiologic changes in patients within days of allo-hsct. all specimens, including nasal and throat swabs, nasopharyngeal aspirates, and sputum or bronchoalveolar lavage specimens, were examined by real-time pcr at the melbourne health shared pathology service according to previously published protocols [ , ] . rvs included in the multiplex pcr panel were rsv, influenza type a and b, and rhinovirus. the testing of copathogens was not part of routine assessment and was performed at the discretion of treating physician. these tests included conventional culture for bacteria and fungi; pcr for legionella, pneumocystis jirovecii, and aspergillus [ ] ; viral pcr for herpes simplex virus (hsv)- , hsv- , cmv, varicella zoster virus, human herpesvirus (hhv)- , hhv- , hmpv, and adenovirus; and bacterial pcr for mycoplasma pneumoniae, chlamydophila pneumoniae, and chlamydia psittaci. baseline measurements of lymphocytes and neutrophils were defined as measurements obtained on the day of admission ± days. lymphopenia was defined as an absolute lymphocyte count below . × /l, and neutropenia was defined as absolute neutrophil count below . × /l. conditioning intensity was defined in accordance with center for international blood and marrow transplant research guidelines [ ] . upper respiratory tract infection (urti) was defined as an rv detected in an upper respiratory tract fluid specimen together with symptoms and/or signs, with the exclusion of other possible causes. lrti was defined as detection of rv in respiratory secretions, preferentially in samples obtained from sites of involvement together with pathological sputum production, hypoxia, or pulmonary infiltrates [ ] . progression to lrti was defined as the onset of lrti in patients with a previous urti. an episode of infection was defined as evidence of rv, urti, or lrti detected during the conditioning period and for up to days following allo-hsct. an infection was considered subsequent if the rv detected was nonidentical or if it was identified at least days following the previous episode with the identical rv [ ] . the presence of a copathogen was defined as a bacterial, fungal, or nonrespiratory virus pathogen isolated from a respiratory tract sample during an episode of infection. overall mortality was defined as death due to any cause within days of vrti diagnosis or allo-hsct. death attributable to vrti was defined as death resulting from respiratory failure with other causes excluded. the risk of vrti was calculated as the number of patients testing positive for any rv among all allo-hsct recipients. patients' baseline characteristics were compared by vrti status using the chi-square test or fisher exact test for categorical variables and the student t test or wilcoxon rank-sum test for continuous variables. only the first episode of vrti was considered for risk factor analysis. univariable and multivariable analyses of risk factors for vrti were performed using logistic regression models. variables with a p value <. were included in the multivariable testing, along with variables previously identified as important risk factors for vrti, including lymphopenia, gvhd, and donor relation [ , , ] . patients with vrti had their records reviewed for days following infection. in patients without vrti, the review was censored to the date of death/icu admission or days following transplantation, whichever was sooner. survival (to death or icu admission) within days following transplantation was assessed using kaplan-meier plots, stratified by vrti status. the log-rank test was used to assess differences in survival among groups. all statistical analyses were performed using r version . . , with statistical significance defined at α = . . approval to conduct the study was granted by the melbourne health human research ethics committee (reference qa ). a total of patients were identified during the review period (january to december ). medical records could not be obtained for patients, including patient with vrti ( figure ). the patients reviewed included slightly more males (n = ; . %) than females (n = ; . %), and the median patient age was years (interquartile range [iqr], to years). the median age of patients with vrti was significantly lower than patients without (p = . ). other patient demographic data and characteristics were not significantly different by vrti status ( table ) . out of patients, were tested for vrti ( . %) within days following allo-hsct and episodes of vrti were identified in patients ( . %). eight patients had multiple episodes, with episodes and with episodes. the median time to onset of the first infection from the date of allo-hsct was days (iqr, . to . days). among the patients identified with vrti, their first episode was identified during the first days following transplantation in ( . %). the clinical characteristics of vrti episodes are summarized in table . rhinovirus accounted for the majority of infection episodes ( of ; . %), followed by rsv ( of ; . %), and there was episode of coinfection with these pathogens. most of the cases initially presented with urti ( of ; . %), and this was most pronounced for rsv ( of ; . %). progression to lrti was observed in . % ( of ) of all patients with an initial presentation of urti and was most common for rhinovirus ( of ; . %). the most common symptom observed was cough (n = ; . %), followed by fever ( ; . %), coryza ( ; . %), and sputum production ( ; . %). the rates of cough ( % versus . %), sputum production ( . % versus %), and fever ( . % versus . %) were significantly higher in the patients with lrti compared with those with urti (all p < . ). antiviral therapy was administered in cases ( . %). among the patients with rsv, ( . %; urti and lrti) received ribavirin, and ( . %; urti) received either placebo or gs- as part of a clinical trial. all patients who had either influenza a or b received oseltamivir, and patient with an lrti with rhinovirus infection (n = / , . %) received i.v. immunoglobulin. antiviral therapy was initiated within a median of . days (iqr, . to . days) after the detection of rv. the median duration of antiviral therapy was . days (iqr, . to . days). sixteen copathogens were identified from vrti episodes ( . %). one episode had copathogens ( bacterial and fungal), and episodes had copathogens ( episodes with fungal pathogens and episode with a bacterial and a fungal pathogen). bacterial copathogens were found in out of episodes ( . %) and accounted for one-half the copathogens detected ( of ; . %). these included staphylococcus spp. (n = ), enterococcus faecium (n = ), haemophilus influenzae (n = ), chlamydophila pneumoniae (n = ), and pseudomonas aeruginosa (n = ). of note, fungal and nonrespiratory virus copathogens were only found concomitantly with rhinovirus infection. fungal copathogens identified include aspergillus (n = ), candida albicans (n = ), cladosporium sp. (n = ), saccharomyces cervisiae (n = ), and p. jirovecii (n = ). no episodes met the european organization for research and treatment of cancer/mycoses study group criteria for invasive fungal disease. the nonrespiratory viruses isolated were cmv and hhv- . in univariate and multivariable analyses, only previous autologous hsct was associated with increased risk of vrti (odds ratio, . ; % confidence interval, . to . ). other variables, including age, sex, underlying disease, cmv seropositivity, donor relation, stem cell source, conditioning regimen and intensity, acute gvhd, lymphopenia, and neutropenia were not statistically significant (table ). in addition, no variables were significantly associated with the risk for vrti for fixed periods following hsct (< days, to days, or to days following transplantation). there were a total of episodes of vrti in our study cohort. during the study period, episodes ( . %) were associated with icu admission within days of vrti, with episodes ( . %) necessitating the use of mechanical ventilation. of the episodes, episodes of vrti ( rhinovirus, rsv, and influenza a) had lrti as the initial presentation and respiratory symptoms that precipitated the icu admission. patients were admitted to icu within a median of . days (iqr, to . days) after vrti and for a median duration of days (iqr, . to . days). the risk of icu admission within days following transplantation between patients with vrti ( of ; . %) and those without vrti ( of ; . %) was not significantly different (p = . ) ( figure ). five patients died within days of vrti, all of whom had rhinovirus infection and prior icu admission. three patients were admitted to the icu day before the detection of rhinovirus, whereas the other patients had icu admission on day and day following the detection of rhinovirus. of the patients who died, ( . %) had lrti as the initial site of infection and ( . %) had copathogens detected. however, none of these deaths was directly attributable to vrti. causes of death included multiorgan failure (n = ), pneumonitis (n = ), acute pulmonary edema (n = ), and aspiration pneumonia, gvhd, and fluid overload (n = ). the risk of mortality within days following transplantation between patients with vrti ( of ; . %) and those without vrti ( of ; . %) was not significantly different (p = . ) ( figure ). all vrti patients who died within days following transplantation developed vrti during the first days following transplantation. in this study, vrti was prevalent among allo-hsct recipients during the first days following transplantation. the frequency of vrti among allo-hsct recipients was . %, which is consistent with the rates of . % to % reported elsewhere [ , , , ] . however, differences between our study and previous studies include a shorter duration of review ( days), inclusion of symptomatic patients only, and the range of pathogens tested [ , , , , ]. outcomes (icu admission or death) days following transplant. rhinovirus accounted for the majority of infections, as has been reported previously, albeit among symptomatic and asymptomatic patients [ , ] . copathogens were identified in % of the episodes and were most common in patients with rhinovirus infection. ison et al. [ ] hypothesized that rhinovirus might predispose patients to additional infection. respiratory colonization with potentially pathogenic bacteria also may increase the risk of subsequent vrti [ ] . however, we note that in both that study and our present study, the number of patients was small, and further investigation of a potential link is warranted. in our cohort, patients who had undergone previous auto-hsct were at increased risk of developing vrti independent of gvhd, donor relation, and lymphopenia. auto-hsct has been identified as an important risk factor for progression to lrti [ ] . previous auto-hsct may reflect advanced disease status and thus the susceptibility of patients to vrti. in addition, cumulative immune suppression from multiple lines of previous therapy may increase the risk of vrti, as has been seen in patients with multiple myeloma [ ] . delays in immune recovery following auto-hsct also could explain the increased risk of vrti in this patient population [ , ] . a key findings of the present study was the low number of deaths in patients with vrti, with no mortality directly attributable to vrti. this finding was consistent with rates reported in previous studies ( % to . %) [ , , , ] . we were unable to directly assess factors contributing to reduced mortality, but postulate that it may be attributable to high standards of supportive care. in addition, antiviral therapy was initiated in some rsv cases and in all episodes of influenza type a and b infection early in the course of infection. among the patients with vrti, all deaths occurred in patients who acquired the infection within days of transplantation. this high risk and poor prognosis subgroup supports the need for strict infection prevention measures for staff and patients in the early days after transplantation [ , [ ] [ ] [ ] [ ] [ ] , along with careful assessment of patients presenting for allo-hsct with respiratory symptoms. our study demonstrates that vrti is an important cause of morbidity in allo-hsct recipients. up to % of vrti episodes necessitated icu admission and % required the use of mechanical ventilation, percentages consistent with previous reports [ ] [ ] [ ] . overall, close to % of patients had lrti on initial presentation. progression to lrti occurred in % of infections, most commonly involving rhinovirus. progression to lrti was also observed in % of rsv urti episodes, a higher rate than reported previously [ ] . both the innate and adaptive arms of the immune system, particularly neutrophils and cytotoxic t cells, play integral roles in the defense against vrti [ ] . th -dominant responses, * includes episode in which both rsv and rhinovirus were detected concurrently. † percentages do not sum to because episodes of rhinovirus infection were identified as neither urti nor lrti, because there was insufficient information available for classification. ‡ nonattributable death was calculated using the number of patients. mediated by ifn-γ, appear to have a protective role in rsv infections, whereas th responses may be associated with more severe disease manifestations [ ] . the profound immune depletion and impaired immune responses seen in the acute period following transplantation could account for the rates of initial lrti and progression seen even with respiratory viruses considered less pathogenic, such as rhinoviruses. in addition, our cohort had a lower rate of antiviral therapy for rsv. because we did not evaluate pulmonary function test results, the risk for vrti and later complications, such as airway disease, as shown previously by erard et al. [ ] , could not be assessed. a limitation of this study was the number of rvs included in the multiplex pcr panel. other rvs, such as parainfluenza virus, adenovirus, coronavirus, and hmpv, were not routinely tested but might be important causes of morbidity in these patients. as such, rhinovirus as a cause of vrti and its burden in the study may be overestimated. furthermore, because in this study we examined only prevalence, risk factors, and outcomes of vrti within days following transplantation our results might be not translatable beyond this time frame. however, because this is a known high-risk period [ , ] , our study focused on this time frame to highlight the importance of early preventive measures and infection control measures among patients as well as healthcare workers following transplantation. in conclusion, vrti was prevalent among our allo-hsct recipients. although its impact on mortality appears limited, it led to a number of icu admissions and necessitated the use of mechanical ventilation in several cases. our findings indicate that an association between previous auto-hsct and an increased risk of vrti. outcomes were poorest for patients diagnosed within days following transplantation, a group of patients at high risk and with a poor prognosis for whom early preventive and infection control measures should be targeted. the authors thank ms. jenny collins for her assistance with the transplantation-related data and the staff of melbourne health shared pathology service for the pathology information. aspergillus pcr testing was performed by the department of microbiology at westmead hospital. financial disclosure: the world health organization collaborating centre for reference and research on influenza is supported by the australian government department of conflict of interest statement: there are no conflicts of interest to report. respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center respiratory viral infections after bone marrow/peripheral stem-cell transplantation: the christie hospital experience respiratory virus infections after stem cell transplantation: a prospective study from the infectious diseases working party of the european group for blood and marrow transplantation respiratory virus infections in adults with hematologic malignancies: a prospective study community respiratory virus infections among hospitalized adult bone marrow transplant recipients community respiratory virus infections in bone marrow transplant recipients: the m.d. anderson cancer center experience respiratory virus infections in bone marrow transplant recipients: the european perspective prospective study of the incidence, clinical features, and outcome of symptomatic upper and lower respiratory tract infections by respiratory viruses in adult recipients of hematopoietic stem cell transplants for hematologic malignancies comparison of conventional and molecular detection of respiratory viruses in hematopoietic cell transplant recipients real-time rt-pcr detection of respiratory viral infections in four triplex reactions rapid and sensitive method using multiplex real-time pcr for diagnosis of infections by influenza a and influenza b viruses, respiratory syncytial virus, and parainfluenza viruses , , , and the evolution and evaluation of a whole blood polymerase chain reaction assay for the detection of invasive aspergillosis in hematology patients in a routine clinical setting centre for international blood and marrow transplant research. form instruction manual ecil- ): guidelines for diagnosis and treatment of human respiratory syncytial virus, parainfluenza virus, metapneumovirus, rhinovirus, and coronavirus risks and burden of viral respiratory tract infections in patients with multiple myeloma in the era of immunomodulatory drugs and bortezomib: experience at an australian cancer hospital outcome of pandemic h n infections in hematopoietic stem cell transplant recipients viral respiratory infections diagnosed by multiplex pcr after allogeneic hematopoietic stem cell transplantation: long-term incidence and outcome rhinovirus infections in hematopoietic stem cell transplant recipients with pneumonia respiratory syncytial virus: infection, detection, and new options for prevention and treatment cd + t lymphocyte counts after autologous transplantation in multiple myeloma: a retrospective study immune parameters in multiple myeloma patients: influence of treatment and correlation with opportunistic infections prospective study of respiratory viral infections in pediatric hemopoietic stem cell transplantation patients respiratory virus infections in transplant recipients after reduced-intensity conditioning with campath- h: high incidence but low mortality symptomatic parainfluenza virus infections in children undergoing hematopoietic stem cell transplantation the clinical features and outcome of h n influenza infection in allo-sct patients: a british society of blood and marrow transplantation study outcome of influenza infections in outpatients after allogeneic hematopoietic stem cell transplantation infections with the h n influenza virus among hematopoietic sct recipients: a single center experience respiratory syncytial virus infection in recipients of allogeneic stem-cell transplantation: a retrospective study of the incidence, clinical features, and outcome the human immune response to respiratory syncytial virus infection airflow decline after myeloablative allogeneic hematopoietic cell transplantation: the role of community respiratory viruses rhinovirus infections in myelosuppressed adult blood and marrow transplant recipients key: cord- -ykcd d authors: cheung, carmen ka man; law, man fai; lui, grace chung yan; wong, sunny hei; wong, raymond siu ming title: coronavirus disease (covid- ): a haematologist's perspective date: - - journal: acta haematol doi: . / sha: doc_id: cord_uid: ykcd d coronavirus disease (covid- ) is affecting millions of patients worldwide. it is caused by the severe acute respiratory syndrome coronavirus (sars-cov- ), which belongs to the family coronaviridae, with % genomic similarities to sars-cov. lymphopenia was commonly seen in infected patients and has a correlation to disease severity. thrombocytopenia, coagulation abnormalities, and disseminated intravascular coagulation were observed in covid- patients, especially those with critical illness and non-survivors. this pandemic has caused disruption in communities and hospital services, as well as straining blood product supply, affecting chemotherapy treatment and haematopoietic stem cell transplantation schedule. in this article, we review the haematological manifestations of the disease and its implication on the management of patients with haematological disorders. coronavirus disease is caused by the severe acute respiratory syndrome coronavirus (sars-cov- ), a positive-strand rna virus belonging to the family coronaviridae with about % genomic similarities with sars-cov [ ] [ ] [ ] . the virus is highly contagious, with over million confirmed cases causing more than , deaths worldwide, reported to the who by the end of april [ ] [ ] [ ] [ ] [ ] . viral infection is well known to be associated with abnormal haematological parameters. autopsy of patients who died of covid- showed markedly shrunken spleen with reduced lymphocyte, macrophage proliferation, and phagocytosis [ ] . lymphocytes were also depleted in lymph nodes, and all haematopoietic cell lineages were reduced in the bone marrow. the battle against covid- is likely to be a marathon and the pandemic has a major impact on health care systems in many countries [ ] . the virus will continue to pose a risk to people without immunity to it. in this article, we review the haematological manifestations of covid- and its implications on the management of patients with haematological disorders. lymphopenia is a common finding in viral infection. in a multicentre study including , patients from sites in china, lymphopenia was present in . % of patients on admission [ ] . many other studies in china reported rates of lymphopenia ranging from % to % (table ) [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in a large us series that included , patients, lymphopenia was present in around % ( , ) of patients on initial laboratory tests [ ] . lymphopenia was observed on admission in . and % of cov-id- patients reported in singapore and korea, respectively [ , ] . lymphopenia has been consistently found to correlate with the severity of covid- infection and might have a predictive value in the clinical setting. zhou et al. [ ] evaluated risk factors for mortality in a retrospective cohort study involving patients and showed that baseline lymphocyte count was significantly higher in survivors than non-survivors ( . × /l versus . × /l, p < . ). in survivors, lymphocyte count was lowest on day after onset of illness and improved during hospitalization, whereas severe lymphopenia was observed until death in non-survivors. in another retrospective analysis of cases, zhang et al. [ ] demonstrated that the level of lowest lymphocyte count correlated with disease severity and a composite endpoint including intensive care unit (icu) admission, mechanical ventilation, or death. among patients with lymphocyte counts < . × /l, . % were classified as severe cases and all of them reached the composite endpoint, while in patients with lymphocyte counts > . × /l, only . % were severe cases and . % reached the composite end point. in a retrospective cohort including patients, lymphopenia during the disease course was also reported to be associated with the development of acute respiratory distress syndrome (ards) [ ] . a significantly higher number of patients requiring treatment in icu had low lymphocyte counts on presentation [ , , ] . fan et al. [ ] also found that on serial monitoring, the median nadir absolute lymphocyte count in the icu group was . × /l compared to . × /l in the non-icu group. wang et al. [ ] analysed dynamic changes in the haematological parameters of patients from day to day after onset of disease and showed that non-survivors developed more severe lymphopenia over time. lymphopenia was frequently encountered in patients requiring icu care, ranging from % to % in various case series [ ] [ ] [ ] . however, there was no significant difference in median lymphocyte counts between survivors and non-survivors in a retrospective observational study involving critically ill patients in wuhan [ ] . depletion of t cells and nk cells was seen in patients suffering from covid- [ , [ ] [ ] [ ] . lymphopenia on presentation correlated with a high viral load, as reflected by the low cycle threshold value in respiratory samples [ ] . liu et al. [ ] analysed the correlation between dynamic changes in the nasopharyngeal viral load and the lymphocyte count. it was found that the higher the rna load in the nasopharynx, the lower the cd + and cd + t lymphocyte count and these changes were closely related to the severity of covid- . jiang et al. [ ] evaluated lymphocyte subsets in patients, which revealed that cd +, cd +, and cd + t cells and nk cells were significantly decreased in covid- patients with a more severe decrease in cd + t cells compared with cd + t cells. in addition, severe covid- patients showed significant decreases in lymphocyte subset counts compared to mild to moderate patients, especially in cd +, cd +, and cd + t cells [ ] . another study analysed lymphocyte subsets of patients at presentation and found that both cd + and cd + t cells were below normal levels in patients with covid- infection, but the decline in cd + cells was more pronounced in severe cases [ ] . the percentage of naïve helper t cells (cd +, cd +, cd ra+) increased and memory helper t cells (cd +, cd +, cd ro+) decreased in severe cases when compared with non-severe cases [ ] . wan et al. [ ] analysed lymphocyte subsets in patients on the first day of hospital admission and - days before discharge. although there was a greater reduction of cd + and cd + t cells in the severe group, both cd + and cd + t cells improved before discharge, suggesting that the cellular immunity had been restored. liu et al. [ ] reported that the decrease of t cells, especially cd + t cells, in the severe patient group reached its lowest within the first week during the course of the disease, and then t cell numbers gradually increased during the second week with recovery to a level comparable to that of the mild patient group in the third week. all the severe patients survived the disease in the study [ ] . another study which compared lymphocyte subsets before and after treatment showed that post-treatment decrease of cd + t cells and b cells and increase of cd +/cd + ratio were independent predictors of poor treatment efficacy [ ] . lower cd t lymphocyte counts may predict a longer persistence of sars-cov- rna in stool, where viral clearance may be further delayed by corticosteroid [ ] . hence, lymphocyte subset may serve as a biomarker for disease evolution, and its monitoring may help to predict disease outcome. sars-cov- could trigger necrosis or apoptosis of lymphocytes resulting in lymphopenia. the virus induced nkg a expression and possibly correlated with functional exhaustion of nk and cd + t cells at an early stage, resulting in disease progression [ ] . a dysregulated/exuberant innate response also contributed to sars-cov-mediated pathology [ ] . cytokine storm with elevation of interleukin (il)- r, il- , il- β, il- , il- , granulocyte colony-stimulating factor (g-csf), tumour necrosis factor-α (tnf-α), ip , mcp , and mip α was seen in covid- patients and may also lead to lymphopenia [ ] . compared to lymphopenia, thrombocytopenia is less commonly seen in patients suffering from covid- . the reported rates of thrombocytopenia varied from less than % to about . % (table ) [ , , , , , , , , , ] . platelet count has been evaluated as a biomarker to predict the severity of covid- in multiple studies, but the results were confounded by heterogeneity regarding definitions of thrombocytopenia and endpoints used. two meta-analyses showed that a lower platelet count is associated with an increased risk of severe disease and mortality in patients with covid- and may serve as a marker for progression of illness [ , ] . in the multicentre study by guan et al. [ ] , thrombocytopenia (platelet count < × /l) on admission was more commonly seen in severe ( . %) than nonsevere ( . %) patients [ , ] . zhou et al. [ ] reported that % of non-survivors had platelet counts less than × /l on admission compared to only % in survivors (p < . ). in contrast, no difference in platelet count on admission was observed between patients requiring icu care compared with those that did not in other studies [ , ] . a study that monitored the sequential changes in platelet count in the first weeks after admission found that there was a gradual drop in platelet counts with a lower nadir among non-survivors compared to survivors ( vs. [ - ], p < . ) [ ] . dynamic changes of platelets were also reported to be closely related to mortality [ ] . an increment in platelets was associated with decrease in mortality, suggesting the role of monitoring platelets in predicting prognosis during hospitalization [ ] . a case series including hospitalized covid- patients evaluated the prognostic value of dynamic changes in platelet count and found that a higher platelet-to-lym-phocyte ratio (plr) at peak platelet count was associated with longer hospital stay and the change in plr was more prominent in severe patients, which may be caused by cytokine storm provoking inflammation resulting in the stimulation and release of platelet [ ] . yang et al. [ ] analysed the predictive role of plr and showed that a higher plr was seen in severe patients ( . ± . ) compared to non-severe patients ( . ± . ; p < . ). elevated plr showed a trend of association with disease progression (hazard ratio [hr] . , % ci . - . by multivariate cox regression), but the statistical significance was lost after adjustment of gender and age, limiting its clinical utility [ ] . experience from previous sars patients, caused by sars-cov- , suggested that coronavirus could cause thrombocytopenia by direct viral infection of bone marrow haematopoietic stem cells via cd or cd a, formation of auto-antibodies and immune complexes, disseminated intravascular coagulopathy (dic), and consumption of platelet in lung epithelium [ , ] . higher soluble vascular cell adhesion molecule- (svcam- ) level was found in sars patients, which enhanced vascular sequestration resulting in thrombocytopenia [ ] . several mechanisms by which covid- causes thrombocytopenia have been proposed, including (a) reduction in platelet production due to direct infection of bone marrow cells by the virus, destruction of bone marrow progenitor cells by cytokine storm, and indirect effect of lung injury; (b) increased platelet destruction by autoantibodies and immune complex; and (c) platelet aggregation in the lungs, resulting in microthrombi and platelet consumption [ ] . cytokine storm of severe disease may lead to secondary haemophagocytic lymphohistiocytosis, which can also result in thrombocytopenia [ ] . thrombocytopenia-associated bleeding is uncommon in covid- . platelet transfusion is recommended in patients with active bleeding and a platelet count less than × /l. for patients at high risk but without active bleeding, platelet transfusion may be considered if the platelet count is less than - × /l [ ] . anaemia is not a major problem in patients suffering from covid- [ , , , , , , , ] . in a cohort of patients with covid- , only . % of them required blood transfusion, while the transfusion requirement was higher in those admitted to icu [ ] . been reported, including blood loss during continuous renal replacement therapy and gastrointestinal bleeding with or without anticoagulant use [ ] . autoimmune haemolytic anaemia was also reported in patients with covid- within a timeframe compatible with the development of cytokine storm [ ] . sars-cov- can enter epithelial cells of the gastrointestinal tract via the angiotensin-converting enzyme (ace ) receptor [ ] . endoscopy revealed oesophageal bleeding caused by erosions and ulcers with detection of sars-cov- in a patient with severe infection [ ] . sars-cov- was demonstrated in gastric, duodenal, and rectal epithelial cells by rna detection and intracellular staining of viral nucleocapsid protein [ ] . the direct viral invasion into the gastrointestinal tract may result in mucosal damage resulting in bleeding and subsequent need of blood transfusion. ribavirin has been used as treatment for covid- [ , ] . haemolytic anaemia is one of the major side effects of ribavirin, but most patients did not require transfusion according to previous sars experience [ ] . a randomized controlled trial on the safety and efficacy of its use in covid- patients is ongoing [ ] . adequate haemoglobin level is important to ensure sufficient tissue oxygenation. phlebotomy by small-volume blood tubes may help to reduce iatrogenic blood loss [ ] . iron replacement should be given to patients with pre-existing iron deficiency anaemia. use of erythropoiesis-stimulating agents in critically ill patients should be cautious if thromboembolic event is a concern [ ] . decision on allogeneic red cell transfusion should be individualized. a single-unit policy should be followed whenever possible [ ] . diverse coagulation abnormalities in covid- infection have been described [ , , , , , , , ] . a study in chongqing showed that the majority of the patients had normal coagulation indexes, probably explained by the fact that % of the included patients had mild disease [ ] . dic is characterized by activation of coagulation and generation and deposition of fibrin, leading to microvascular thrombi deposition in various organs and subsequently multiple organ dysfunction, which predicts mortality in septic patients [ ] . tang et al. [ ] studied coagulation parameters in patients suffering from covid- and found that . % of non-survivors devel-oped overt dic compared to only . % among survivors. patients who died had significantly higher d-dimer, fibrin degradation product levels, and longer pt on admission [ ] . the study by guan et al. [ ] showed that . % patients who reached the primary composite endpoint (icu admission, mechanical ventilation, or death) had elevated d-dimer level (≥ . mg/l) on admission compared to . % not reaching the primary endpoint. wu et al. [ ] showed that significant prolongation of pt (median . s) and higher d-dimer level ( . μg/ml) at presentation were observed in patients with ards compared to those without (median pt . vs. . s, median d-dimer level . vs. . μg/ml, p < . for both comparisons). elevated d-dimer level has been shown to be associated with higher mortality rates in various studies [ , , , ] . in a retrospective study including patients in wuhan, patients with d-dimer levels ≥ μg/ ml on admission had higher mortality compared to those with d-dimer level < μg/ml (hr . , % ci . - . ) [ ] . a d-dimer cut-off value of ≥ μg/ml on admission could predict in-patient mortality with a sensitivity of . % and a specificity of . % [ ] . prolongation of pt and markedly elevated d-dimer on admission were associated with poor prognosis and were more commonly seen in patients requiring icu care [ , ] . in addition to coagulation parameters on presentation, dynamic change in coagulation profile could predict disease severity and progression. tang et al. [ ] reported dynamic changes in coagulation parameters from day to day after admission. non-survivors demonstrated significant increase in d-dimer and fibrin degradation product as well as prolongation of pt by day - , while fibrinogen and antithrombin activity were significantly lower when compared with survivors [ ] . other studies also showed similar findings of a gradual increase in d-dimer levels among non-survivors [ , ] . pooled results in a metaanalysis including studies revealed that pt and d-dimer levels were significantly higher in patients with severe covid- [ ] . dynamic change in fibrinogen concentration has also been shown to correlate with an increased risk of death [ ] . covid- patients with acute respiratory failure presented with severe hypercoagulability due to hyperfibrinogenaemia resulting in increased fibrin formation and polymerization that may predispose to thrombosis [ ] . the systemic inflammatory response triggered by viral infection results in an imbalance in homeostatic procoagulant and anticoagulant. cytokine storm, endothelial dysfunction, von willebrand factor elevation, tolllike receptor activation, and tissue-factor pathway activa- doi: . / tion may contribute to hypercoagulability [ ] . overactivation of nadph oxidase- (nox ), resulting in increased reactive oxidant species, is implicated in arterial vasoconstriction, clotting, and platelet activation [ ] . tang et al. [ ] provided data in a retrospective study on patients and showed that anticoagulant with unfractionated heparin ( , - , u/day) or low-molecular-weight heparin (lmwh, enoxaparin - mg/ day) reduced mortality in patients with sepsis-induced coagulopathy score (a scoring system including platelet count, pt, and major organ failure assessment) of ≥ (from . % to . %, p = . ) [ , ] . a % reduction in mortality was also seen in patients with d-dimer level -fold the upper limit of normal who received anticoagulant [ ] . interestingly, no improvement in mortality was seen in anticoagulation therapy for patients with severe pneumonia caused by pathogens other than sars-cov- even with high d-dimer level [ ] . a brief report showed that % of patients with severe covid- requiring icu care developed venous thromboembolism (vte) [ ] , which may explain the promising results of anticoagulation. in a cohort of patients admitted to the icu who received at least standard doses of thromboprophylaxis, the cumulative incidence of vte and arterial thrombosis was % [ ] . coagulopathy, defined as spontaneous prolongation of pt > s or aptt > s, was an independent predictor of thrombotic complications (adjusted hr . , % ci . - . ). in another multicentre prospective cohort of patients with ards admitted to icu, ( . %) of them developed pulmonary embolisms and ( %) developed deep vein thrombosis despite prophylactic or therapeutic anticoagulation [ ] . since diagnostic tests were only performed based on clinical suspicion, the actual incidence of thrombosis could have been underestimated. llitjos et al. [ ] conducted a retrospective study on patients admitted to icu with systematic screening of vte using complete duplex ultrasound performed on days - of icu admission, followed by a second scan on day if the first one was negative. the incidence of vte was % in the group of patients who received anticoagulation [ ] . autopsy of consecutive covid- deaths revealed deep vein thrombosis in patients ( %) in whom vte was not suspected before death. pulmonary embolism was the direct cause of death in patients [ ] . histologic analysis of pulmonary vessels in patients who died from covid- showed widespread thrombosis with microangiopathy and a much higher prevalence of alveolar capillary microthrombi when compared with those who died from influenza-associated respiratory failure [ ] . in addition to vte, arterial thromboses such as acute myocardial infarction have been reported [ ] . large vessel stroke can be a presenting feature in young patients [ ] . in a retrospective study of hospitalized patients from wuhan, . % of the severe patients suffered from acute cerebrovascular disease [ ] . hypercoagulability was also demonstrated in icu patients with respiratory failure by thromboelastography [ ] . all these findings suggested a pro-coagulant tendency in covid- patients, especially if critically ill. middeldorp et al. [ ] administered thromboprophylaxis to all patients admitted for covid- . patients admitted to the general ward received nadroparin , iu once daily or , iu for patients with a body weight of ≥ kg. from april onwards, the dose of anticoagulation in icu patients was doubled. symptomatic vte was detected in out of ( %) icu patients and out of ( . %) ward patients (sub-distribution hazard ratios . ; % ci . - ) [ ] . lodigiani et al. [ ] studied venous and arterial thromboembolic complications in hospitalized patients. thromboprophylaxis was used in all icu patients and % of those on the general ward. eight events occurred in icu patients ( . %; % ci . - . %), while events occurred in patients on the general ward ( . %; % ci . - . %), corresponding to cumulative rates of . and . %, respectively. importantly, events in the general ward occurred in patients with cancer, highlighting that additional risk factors might further increase the risks of vte [ ] . racial difference on thrombotic risk should also be taken into consideration [ ] . the international society on thrombosis and haemostasis (isth) suggested all patients (including non-critically ill) who require hospital admission for covid- infection should receive a prophylactic dose of lmwh unless contraindicated (table ) [ ] . lmwh was the preferred drug of choice due to a high instability of international normalized ratio for vitamin k antagonists and drug-drug interaction between direct oral anticoagulants and anti-viral agents [ ] . the american society of hematology (ash) recommended all hospitalized patients with covid- should receive pharmacological thromboprophylaxis. if it is contraindicated or unavailable, mechanical prophylaxis should be implemented [ ] . however, the recommendations of pharmacological thromboprophylaxis on non-critically ill patients are still controversial [ , ] . we recommend physicians stay vigilant to thrombotic complication. decision on thromboprophylaxis should also be based on clinical judgement and other risk factors, such as prolonged immobilization, active malignancy, obesity, previous history of vte, and ethnicity. the efficacy, safety, and optimal dosage of anticoagulation in non-critically ill covid- patients need to be confirmed by prospective studies. a more recent consensus statement recommended vte risk assessment for non-critically ill patients, and only to consider pharmacological thromboprophylaxis in patients with a moderate to high risk of vte [ ] . a significant reduction of blood donations has been reported after the outbreak [ ] . possible reasons include lockdown, stay-at-home order, anxiety for volunteer donors to attend blood donation centres, and additional deferral policy on travel history. the number of eligible donors may further decrease if the outbreak continues to evolve. establishment of a crisis system to reduce usage (e.g., deferring elective surgery), coordination of blood products delivery to areas with a shortage, use of social media to promote blood donation, etc. might help to overcome the crisis of paucity in blood supply [ ] . if the supply of blood product is limited, there may be a need to adopt a more restrictive blood transfusion approach. transfusion alternatives such as use of iron supplement in iron deficiency anaemia and erythropoiesisstimulating agents should be encouraged. currently there is no reported case of transmission of the coronavirus from donor to recipient through blood product transfusion or cellular therapies, but given that sars-cov- rna was detected in the serum of covid- patients [ ] , the actual risk of transfusion transmission of sars-cov- remains unknown [ ] . there is no additional screening test for blood donors recommended by the american association of blood banks (aabb) at the moment [ ] . use of riboflavin and ultraviolet light-based photochemical treatment to plasma and platelet products may be effective in reducing the theoretical risk of transfusion-transmitted sars-cov- [ ] . the covid- pandemic poses a big challenge for the medical community, with a great impact on management of patients with haematological conditions. in a cohort study of hospitalized subjects with haematological cancers at two centres in wuhan, they have a similar rate of covid- compared with normal health care providers but have more severe disease and a higher case fatality rate [ , ] . non-hospitalized patients with haematological cancers may also have a higher chance of developing symptomatic covid- . in a study using a questionnaire to evaluate subjects with chronic myeloid leukaemia in hubei, prevalence of covid- in chronic myeloid leukaemia patients was -fold higher than the . % reported in normal [ , ] . chemotherapy and transplant schedules have been affected during the outbreak when hospitals are overwhelmed by confirmed covid- cases. the huge demand in isolation facilities compromises the care of patients who have received myelosuppressive therapy complicated with profound neutropenia requiring isolation rooms and prolonged hospitalization. treatment may also be deferred due to lockdown, quarantine order, disrupted medical health care service, shortage of isolation bed and blood product, and phobia towards attending hospital. delay in treatment may have a negative impact on the clinical conditions and outcomes of patients, especially those with more aggressive diseases. their need for timely treatment should not be neglected. in general, less essential service should be postponed [ ] in order to reduce the number of patients requiring hospital care so as to minimise risk of nosocomial covid- infection, to conserve personal protective equipment for high-risk clinical activities, and to maintain the capacity of the health care system. monitor d-dimers, pt, platelet count, and fibrinogen can help to stratify patients who may need admission and close monitoring prophylactic dose lmwh should be given to all patients (including non-critically ill) who require hospital admission unless contraindicated (active bleeding and platelet count < × /l) transfuse and aim platelet count above × /l; fibrinogen above . g/l; pt < . lmwh, low-molecular-weight heparin; pt, prothrombin time. cheung/law/lui/wong/wong acta haematol doi: . / table . suggested strategies in the management of haematological malignancies under covid- pandemic [ , [ ] [ ] [ ] disease management recommendation aml induction and consolidation -all patients should be tested for covid- prior to initiation of intensive chemotherapy -delay treatment if possible for patients positive for covid- -standard induction therapy should be offered to eligible patients -intermediate-dose cytarabine ( . g/m ) or decreasing the number of consolidation cycles can be considered in patients who achieve complete remission salvage therapy -intensive re-inductions should be performed according to the algorithms of the individual centre -for patients without proliferative disease or significant transfusion dependence, therapy may be temporarily postponed hsct -consider cryopreservation of donor cells prior to the start of conditioning apl -standard regime including atra and ato should be given -prophylactic dexamethasone should be considered for patients at high risk of differentiation syndrome all induction and consolidation -all patients should be tested for covid- prior to initiation of intensive chemotherapy -delay treatment if possible for patients positive for covid- ; intrathecal chemotherapy may be given if cns symptoms are present -philadelphia chromosome negative -proceed with standard curative induction therapy -dose reduction may be considered for patients at high risk for complications -philadelphia chromosome positive -consider tki with minimal steroid exposure as initial treatment salvage therapy -treatment that can be administered at outpatient setting such as inotuzumab or blinatumomab should be considered for b-all hsct -allogeneic hsct should be considered for patient who achieved cr despite the pandemic aggressive lymphoma -standard regime such as r-chop for diffuse large b-cell lymphoma and da-epoch-r for double-hit and primary mediastinal b-cell lymphomas should be offered -dose reduction or limiting treatment cycle can be considered for elderly or early stage disease -consider subcutaneous rituximab to reduce patient's time spent in clinical area -for relapse/refractory disease, admission for asct may be delayed if another cycle of outpatient chemotherapy can be administered indolent lymphoma -treatment deferral with close monitoring is recommended for asymptomatic patients -when treatment is indicated, consider rituximab monotherapy rather than chemoimmunotherapy -treatment options that minimize clinic or chemotherapy unit visits are preferred hl initial therapy -strategies to reduce the risk of bleomycin pneumonitis should be prioritized especially during the pandemic -standard treatment such as abvd, aavd, and radiotherapy should be given general recommendation -patients should be tested for covid- before hospital admission, starting a new treatment, cell apheresis, or asct in countries with high spread of sars-cov- -treatment re-schedule and de-intensification can be considered for responding patients -patients receiving bisphosphonates should reduce frequency of drug infusion to every months or temporarily withheld transplant eligible -bortezomib, lenalidomide, or daratumumab-based triplet therapy for - cycles should be offered -for patients with standard risk disease, delay asct by additional induction cycles and/or lenalidomide maintenance -patients with high-risk disease may proceed with asct after exclusion of covid- infection transplant ineligible -dexamethasone should be reduced to mg weekly -all-oral drug combinations, e.g., lenalidomide with dexamethasone, are preferred -addition of bortezomib or daratumumab can be considered for patients with high-risk disease relapsed/refractory -watchful waiting may be considered for biochemical relapses -orally administered agents (such as ixazomib, lenalidomide, pomalidomide, and panobinostat) should be considered -modify treatment regime to minimize clinic/hospital visit, such as once weekly instead of twice weekly bortezomib/ carfilzomib and monthly daratumumab infusions are recommended confirmed covid- -if anti-myeloma treatment has been started, therapy might be continued for asymptomatic covid- infection, although pausing of treatment is also an option; steroids and drugs inducing lymphopenia should be de-intensified -for symptomatic infection, treatment should be interrupted and steroids should be tapered to zero until full recovery from covid- aavd, brentuximab vedotin, adriamycin, vinblastine, dacarbazine; abvd, adriamycin, bleomycin, vinblastine, dacarbazine; all, acute lymphoblastic leukaemia; aml, acute myeloid leukaemia; apl, acute promyelocytic leukaemia; asct, autologous stem cell transplantation; atra, all-trans-retinoic acid; ato, arsenic trioxide; bcr, b-cell receptor; cll, chronic lymphocytic leukaemia; cml, chronic myeloid leukaemia; cns, central nervous system; cr, complete remission; da-epoch-r, dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin-rituximab; hl, hodgkin lymphoma; hsct, haematopoietic stem cell transplantation; mm, multiple myeloma; nhl, non-hodgkin lymphoma; pd- , programmed cell death protein ; r-chop, rituximabcyclophosphamide, doxorubicin, vincristine, prednisolone; tfr, treatment-free remission; tki, tyrosine kinase inhibitor. life-saving chemotherapy for conditions such as acute leukaemia or aggressive lymphoma should not be delayed. watchful waiting approach may be considered for patients with indolent diseases if the risk of severe co-vid- infection outweighs treatment benefit, while single-agent monoclonal antibody instead of combination chemoimmunotherapy can be considered in patients who require treatment. oral formulation is preferred to intravenous injection to minimize hospital visit. prioritization and triage of anti-cancer therapy should be based on disease-and patient-specific considerations through communication with specialists and patients [ ] . recommendations on induction, consolidation, and salvage therapies on haematological malignancy during the pandemic by the ash, european hematology association (eha), and international myeloma society are summarized in table [ , [ ] [ ] [ ] . primary prophylaxis using g-csf in patients receiving intensive chemotherapy reduces the risk of febrile neutropenia and the risk of hospitalization and thus should be considered [ , ] . effective non-immunosuppressive treatments, such as intravenous immunoglobulin and thrombopoietin receptor agonists, may be considered in lieu of high-dose steroid for patients with immune thrombocytopenia purpura and severe thrombocytopenia. if patients are stable on low doses of immunosuppressive drugs, no modification of drug regimen is needed. infection prevention measures such as hand hygiene in ambulatory chemotherapy centres or clinics should be implemented. screening procedures, including questionnaire on respiratory symptoms, travel and contact history, and measuring of body temperature, should be performed for patients and hospital visitors [ ] . patients may benefit from increased surveillance of sars-cov- infection and protective isolation [ ] [ ] [ ] . psychosocial support should be provided where possible, when measures of social distancing might have affected the well-being of patients with haematological malignancies. great obstacles on allogeneic haematopoietic stem cell transplantation have been encountered during the co-vid- outbreak. closure of international borders, travel restriction, and shutdown of air travel has affected international donor travel and the shipping of cellular products. cryopreserved stem cell transplantation during the pandemic can be considered if alternative cellular products or donors are not available and does not appear to have a negative impact on the long-term outcome [ , ] . appropriate measures such as home quarantine and screening of donors for covid- prior to donation should be implemented in areas with a high frequency of sars-cov- infection [ ] . all transplant recipients should also be tested negative for sars-cov- irrespective of respiratory symptoms before initiating conditioning chemotherapy [ ] . treatment cycles may be increased to achieve a deeper remission before proceeding to allogeneic haematopoietic stem cell transplantation. the european society for blood and marrow transplantation (ebmt) proposed suggestions on haematopoietic stem cell transplantation during the covid- pandemic, which is shown in table [ ] . in summary, the covid- disease has had notable haematological manifestations. lymphopenia, thrombocytopenia, and coagulation abnormalities on presentation and during the disease courses have been associated with poor outcomes, and serial monitoring is recommended. physicians should stay vigilant against vte and for transplant candidate ---for confirmed covid- patients with high-risk malignancy, hsct should be deferred for a minimum of days until the patient is asymptomatic and has two negative virus pcr swabs taken at least h apart in patients infected with covid- with low-risk malignancy, a -month hsct deferral is recommended for patients who had close contact with a person diagnosed with covid- , any transplant procedures (pbsc mobilization, bm harvest, conditioning) shall not be performed within at least days from the last contact for donor ---donors should have been asymptomatic for at least days before donation and a negative test for covid- is recommended in case of diagnosis of covid- , donor should be excluded from donation. stem cell collection should be deferred for at least days after recovery. if the recipient's need for transplant is urgent and the donor is completely well and there are no suitable alternative donors, an earlier collection may be considered if local public health requirements permit, subject to careful risk assessment in case of close contact with a person diagnosed with sars-cov- , the donor shall be excluded from donation for at least days; if the patient's need for transplant is urgent, the donor is completely well, a test is negative for sars-cov- , and there are no suitable alternative donors, earlier collection may be considered subject to careful risk assessment bm, bone marrow; hsct, haematopoietic stem cell transplantation; pbsc, peripheral blood stem cell; pcr, polymerase chain reaction. consider pharmacological thromboprophylaxis in highrisk patients. changes in clinical practice are unavoidable in the current pandemic. treatment decision should be tailored on an individual basis to minimize risk of infection without jeopardizing the disease outcome. coronavirus infections and immune responses a new coronavirus associated with human respiratory disease in china. nature a pneumonia outbreak associated with a new coronavirus of probable bat origin who health emergency dashboard coronavirus (covid- ): world health organization (who) early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia nowcasting and forecasting the potential domestic and international spread of the -ncov outbreak originating in wuhan, china: a modelling study estimation of the reproductive number of novel coronavirus (covid- ) and the probable outbreak size on the diamond princess cruise ship: a data-driven analysis preliminary estimation of the basic reproduction number of novel coronavirus ( -ncov) in china, from to : a data-driven analysis in the early phase of the outbreak chinese clinical guidance for covid- pneumonia diagnosis and treatment the untold toll -the pandemic's effects on patients without covid- china medical treatment expert group for covid- . clinical characteristics of coronavirus disease in china epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan. china: jama initial clinical features of suspected coronavirus disease in two emergency departments outside of hubei clinical characteristics of patients infected with sars-cov- in wuhan clinical characteristics and imaging manifestations of the novel coronavirus disease (covid- ): a multi-center study in wenzhou city clinical features and treatment of co-vid- patients in northeast chongqing early clinical and ct manifestations of coronavirus disease (cov-id- ) pneumonia clinical characteristics of novel coronavirus cases in tertiary hospitals in hubei province clinical features of covid- in elderly patients: a comparison with young and middle-aged patients clinical characteristics of medical workers ct features of coronavirus disease (covid- ) pneumonia in patients in wuhan, china clinical and computed tomographic imaging features of novel coronavirus pneumonia caused by sars-cov- chest ct findings in patients with coronavirus disease and its relationship with clinical features novel coronavirus ( -ncov) pneumonia. radiology clinical findings in a group of patients infected with the novel coronavirus (sars-cov- ) outside of wuhan, china: retrospective case series clinical characteristics of cases of corona virus disease (covid- ) in changsha differences between covid- and suspected then confirmed sars-cov- -negative pneumonia: a retrospective study from a single center clinical features of patients infected with novel coronavirus in wuhan and the northwell covid- research consortium. presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the hematologic parameters in patients with covid- infection korea national committee for clinical management of covid- . clinical course and outcomes of patients with severe acute respiratory syndrome coronavirus infection: a preliminary report of the first patients from the korean cohort study on covid- clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study. lancet analysis of clinical characteristics and laboratory findings of cases of novel coronavirus pneumonia in wuhan, china: a retrospective analysis risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china characteristics and outcomes of critically ill patients with covid- in washington state covid- in critically ill patients in the seattle region -case series clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study dysregulation of immune response in patients with covid- in wuhan, china clinical and immunological features of severe and moderate coronavirus disease lymphocyte subset (cd +, cd +) counts reflect the severity of infection and predict the clinical outcomes in patients with covid- clinical and biochemical indexes from -ncov infected patients linked to viral loads and lung injury correlation between relative nasopharyngeal virus rna load and lymphocyte count disease severity in patients with covid- t cell subset counts in peripheral blood can be used as discriminatory biomarkers for diagnosis and severity prediction of covid- relationships among lymphocyte subsets, cytokines, and the pulmonary inflammation index in coronavirus (covid- ) infected patients longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of sars-cov- infected patients characteristics of peripheral lymphocyte subset alteration in covid- pneumonia persistence and clearance of viral rna in novel coronavirus disease rehabilitation patients functional exhaustion of antiviral lymphocytes in covid- patients t cellmediated immune response to respiratory coronaviruses covid- : immunopathology and its implications for therapy hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease (covid- ): a meta-analysis thrombocytopenia is associated with severe coronavirus disease (covid- ) infections: a metaanalysis diagnosis and treatment of adults with community-acquired pneumonia. an official clinical practice guideline of the american thoracic society and infectious diseases society of america thrombocytopenia and its association with mortality in patients with covid- hematological features of persons with covid- . leukemia association between platelet parameters and mortality in coronavirus disease : retrospective cohort study platelet-to-lymphocyte ratio is associated with prognosis in patients with coronavirus disease- the diagnostic and predictive role of nlr, d-nlr and plr in covid- patients. int immunopharmacol the effect of sars coronavirus on blood system: its clinical findings and the pathophysiologic hypothesis. zhongguo shi yan xue ye xue za zhi thrombocytopenia in patients with severe acute respiratory syndrome (review) role of vascular cell adhesion molecules and leukocyte apoptosis in the lymphopenia and thrombocytopenia of patients with severe acute respiratory syndrome (sars). microbes infect mechanism of thrombocytopenia in covid- patients. ann hematol hlh across speciality collaboration, uk. covid- : consider cytokine storm syndromes and immunosuppression the scientific standardization committee on dic of the international society on thrombosis haemostasis. guidance for diagnosis and treatment of dic from harmonization of the recommendations from three guidelines covid- ): a haematologist's perspective blood and blood product use during covid- infection autoimmune haemolytic anaemia associated with covid- infection evidence for gastrointestinal infection of sars-cov- gastrointestinal symptoms of cases with sars-cov- infection novel coronavirus treatment with ribavirin: groundwork for an evaluation concerning covid- potential therapeutic agents against covid- : what we know so far haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis comparative effectiveness and safety of ribavirin plus interferon-alpha, lopinavir/ritonavir plus interferon-alpha, and ribavirin plus lopinavir/ritonavir plus interferon-alpha in patients with mild to moderate novel coronavirus disease : study protocol a cohort study assessing the impact of small volume blood tubes on diagnostic test quality and iatrogenic blood loss in a cohort of adult haematology patients safety and efficacy of erythropoiesis-stimulating agents in critically ill patients admitted to the intensive care unit: a systematic review and meta-analysis patient blood management during the covid- pandemic: a narrative review prominent changes in blood coagulation of patients with sars-cov- infection abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia international society on thrombosis and haemostasis score for overt disseminated intravascular coagulation predicts organ dysfunction and fatality in sepsis patients d-dimer levels on admission to predict in-hospital mortality in patients with covid- changes in blood coagulation in patients with severe coronavirus disease (covid- ): a meta-analysis covid- -related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure coagulation disorders in coronavirus infected patients: covid- , sars-cov- , mers-cov and lessons from the past hypercoagulation and antithrombotic treatment in coronavirus : a new challenge anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy scientific and standardization committee on dic, and the scientific and standardization committee on perioperative and critical care of the international society on thrombosis and haemostasis. diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation difference of coagulation features between severe pneumonia induced by sars-cov and non-sars-cov prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia incidence of thrombotic complications in critically ill icu patients with covid- high risk of thrombosis in patients with severe sars-cov- infection: a multicenter prospective cohort study. intensive care med high incidence of venous thromboembolic events in anticoagulated severe covid- patients autopsy findings and venous thromboembolism in patients with covid- pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- virus disease (covid- ) presenting as acute st elevation myocardial infarction large-vessel stroke as a presenting feature of covid- in the young neurologic manifestations of hospitalized patients with coronavirus disease hypercoagulability of covid- patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis incidence of venous thromboembolism in hospitalized patients with covid- humanitas covid- task force. venous and arterial thromboembolic complications in covid- patients admitted to an academic hospital in more on covid- coagulopathy in caucasian patients isth interim guidance on recognition and management of coagulopathy in covid- . j thromb haemost switch from oral anticoagulants to parenteral heparin in sars-cov- hospitalized patients ash) recommendations on coronavirus disease and covid- re: isth interim guidance to recognition and management of coagulopathy in covid- isth interim guidance on recognition and management of coagulopathy in cov-id- : a comment prevention treatment of vte associated with covid- infection consensus statement group. prevention and treatment of venous thromboembolism associated with coronavirus disease infection: a consensus statement before guidelines prepare to adapt: blood supply and transfusion support during the first weeks of the novel coronavirus (covid- ) pandemic affecting washington state coronavirus disease (covid- ) and decrease in blood donation: experience of iranian blood transfusion organization (ibto) coronavirus disease : coronaviruses and blood safety american association of blood bank (aabb)'s coronavirus resources inactivation of severe acute respiratory syndrome coronavirus in plasma and platelet products using a riboflavin and ultraviolet light-based photochemical treatment covid- in persons with haematological cancers perspective: sars-cov- , cov-id- and haematologists hubei anti-cancer association. covid- in persons with chronic myeloid leukaemia health impact of hospital restrictions on seriously ill hospitalized patients: lessons from the toronto sars outbreak cancer, covid- and the precautionary principle: prioritizing treatment during a global pandemic management of patients with multiple myeloma in the era of covid- pandemic: a consensus paper from the european myeloma network (emn). leukemia international myeloma society recommendations for the management of myeloma patients during the covid- pandemic eha) covid- hematology hub granulocyte colony-stimulating factor in combination with intensive chemotherapy in the treatment of acute myeloid leukemia barron r. the impact of primary prophylaxis with granulocyte colony-stimulating factors on febrile neutropenia during chemotherapy: a systematic review and meta-analysis of randomized controlled trials. support care cancer managing oncology services during a major coronavirus outbreak: lessons from the saudi arabia experience cryopreservation of allogeneic pbsc from related and unrelated donors is associated with delayed platelet engraftment but has no impact on survival long-term follow-up of leukaemia patients after related cryopreserved allogeneic bone marrow transplantation coronavirus and haematopoietic stem cell transplantation. worldwide network for blood & marrow transplantation. wbmt coronavirus disease covid- : european society for blood and marrow transplantation (ebmt) recommendations update the authors have no relevant conflict of interest to disclose. carmen k.m. cheung: acquisition, analysis, and interpretation of data/references; drafting and approving the manuscript. man fai law: acquisition, analysis, and interpretation of data/references; drafting and approving the manuscript. grace c.y. lui: analysis, interpretation of data/references; revising critically and approving the manuscript. sunny hei wong: analysis, interpretation of data/references; revising critically and approving the manuscript. raymond s.m. wong: analysis, interpretation of data/references; drafting, revising critically, and approving the manuscript. key: cord- -zccd mq authors: christian, michael d.; loutfy, mona; mcdonald, l. clifford; martinez, kenneth f.; ofner, mariana; wong, tom; wallington, tamara; gold, wayne l.; mederski, barbara; green, karen; low, donald e. title: possible sars coronavirus transmission during cardiopulmonary resuscitation date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: zccd mq infection of healthcare workers with the severe acute respiratory syndrome–associated coronavirus (sars-cov) is thought to occur primarily by either contact or large respiratory droplet transmission. however, infrequent healthcare worker infections occurred despite the use of contact and droplet precautions, particularly during certain aerosol-generating medical procedures. we investigated a possible cluster of sars-cov infections in healthcare workers who used contact and droplet precautions during attempted cardiopulmonary resuscitation of a sars patient. unlike previously reported instances of transmission during aerosol-generating procedures, the index case-patient was unresponsive, and the intubation procedure was performed quickly and without difficulty. however, before intubation, the patient was ventilated with a bag-valve-mask that may have contributed to aerosolization of sars-cov. on the basis of the results of this investigation and previous reports of sars transmission during aerosol-generating procedures, a systematic approach to the problem is outlined, including the use of the following: ) administrative controls, ) environmental engineering controls, ) personal protective equipment, and ) quality control. d uring the global spread of severe acute respiratory syndrome (sars) ( - ), a great deal was discovered about the illness and the sars-associated coronavirus (sars-cov) ( , ) . sars-cov infection is thought to occur primarily by either contact or large respiratory droplet transmission ( , ) . however, despite the use of infection control precautions and personal protective equipment designed to prevent contact and droplet transmission, episodes of sars-cov transmission to health-care workers have continued to occur under certain circumstances. of particular concern are procedures performed on sars patients that may aerosolize sars-cov and lead to limited airborne transmission or enhanced contact and droplet transmission ( ) . such procedures include noninvasive positive pressure ventilation (bipap), intubation, and high-frequency oscillatory ventilation. as a result, special infection control procedures have been recommended for aerosol-generating procedures ( , ) . we present the results of an investigation of the first reported transmission of sars-cov to healthcare workers that occurred during attempted cardiopulmonary resuscitation of a completely unresponsive sars patient. on the basis of the results of this investigation, as well as previous reports of sars transmission during aerosol-generating procedures, we used the continuous quality improvement framework ( ) to suggest interventions for preventing future episodes of transmission. data were collected through interviews of healthcare workers present during the attempted cardiopulmonary resuscitation where transmission of sars-cov was thought to have occurred. interviews included a structured questionnaire component. hospital and provincial policies in place at the time of the resuscitation were reviewed. the hospital patient-care environment was inspected by a team of environmental engineers and industrial hygienists. laboratory specimens, collected with nasopharyngeal swabs, were obtained from healthcare workers with symptoms that fulfilled the sars clinical case definition after exposure during the attempted cardiopulmonary resuscitation. these were tested by reverse transcriptase-polymerase chain reaction (rt-pcr) with primers specific for sars-cov ( ) . after participants gave informed consent, convalescent-phase serum was collected from all consenting healthcare workers exposed to the attempted resuscitation event as part of a larger seroprevalence study of hospital staff. for this, samples were analyzed with a commercially available indirect immunofluorescent assay (euroimmune, lübeck, germany) according to the directions of the manufacturer. in addition, a limited evaluation of the stryker t personal protection system (stryker instruments, kalamazoo, mi), worn by some of the healthcare workers involved in the resuscitation attempt, was conducted to estimate the operating parameters, including particle removal efficiency and air-flow rate. a met one model b hand-held particle counter (met one, inc., grants pass, or) was used to count ambient particles outside and inside the hood; five replicates were collected for each condition over a -minute sampling period. all information was obtained as part of an ongoing joint investigation into the cause of the second phase of the toronto sars outbreak conducted by toronto public health, health canada, and the centers for disease control and prevention ( ) . a -year-old woman with a history of asthma was admitted to hospital a on may , , with a day history of fever, cough, malaise, headache, and myalgias. the patient's mother had recently been admitted to the same hospital and died of a nosocomial pneumonia after orthopedic surgery for a fractured hip. on the basis of clinical findings and the identification of secondary infections in exposed persons, the mother's death was retrospectively determined to be due to sars. on admission, the patient was febrile and her chest radiograph showed left lower lobe and lingular infiltrates. both acute-phase serologic tests and serum rt-pcr were positive for sars-cov (national microbiology laboratory, health canada, toronto). she was admitted to the hospital and placed in respiratory isolation on the sars unit. progressive respiratory failure later developed in the patient, and within hours of admission, she required % supplemental oxygen. on may , , she was found to have no vital signs and cardiopulmonary resuscitation was attempted. nine healthcare workers participated in the resuscitation attempt. three ward nurses (rn - ) were the initial responders (table) . rn performed chest compressions while rn and rn prepared suction, oxygen, and intubation equipment. three intensive care unit nurses (icu-rn - ), two respiratory therapists (rt and ), and a physician (md) also participated in the resuscitation. icu-rn took over chest compressions from ward-rn . icu-rn inserted a peripheral intravenous catheter (iv) in the left foot of the patient and administered medications via the iv during the resuscitation attempt. icu-rn ventilated the patient with a bag-valve-mask, without a bacterial/viral filter. rt performed the endotracheal intubation, which was completed in < seconds. no suctioning was required during or after the intubation and no respiratory secretions or other bodily substances were observed in the environment. a bacterial/viral filter was placed on the bag-valve-mask after the intubation. all nurses in the room during the resuscitation were wearing protection equipment that was considered standard for routine sars patient care at this hospital. this equipment consisted of two gowns, two sets of gloves, goggles, a full-face shield (with the exception of rn and rn ), shoe covers, hair cover, and niosh-approved n disposable respirators that were not fit-tested. in addition, all nurses involved in the resuscitation were experienced in working on sars units and thus familiar with the recommended infection control policies and procedures. in contrast to the nurses, both rts and the md were wearing t personal protection systems during the resuscitation. all nurses left the room immediately after the intubation and removed their protection equipment following the standard hospital protocol. approximate exposure times are outlined in the table. on the may , , both icu-rn and icu-rn had a temperature > . °c, myalgia, and malaise. in addition, icu-rn complained of headache and nausea, and icu-rn reported dyspnea. icu-rn had a normal chest radiograph results, but the radiograph of icu-rn showed a left lower lobe infiltrate that persisted for several days. both rns were admitted to the hospital for observation; their condition remained stable. rn reported a headache and myalgia on june , , but her maximum temperature reached only . °c. she remained in home quarantine, and her symptoms resolved without further progression. results of rt-pcr performed on nasopharyngeal swabs from icu-rn and icu-rn were negative ( ) . at present, only one case (icu-rn ) meets the world health organization criteria for probable sars, one case (icu-rn ) is under investigation, and the third (rn ) does not meet the case definition as her temperature remained < . °c ( ) . a review of the -hour period before the resuscitation did not show any other likely transmission episodes. in particular, icu-rn was the charge nurse in the icu and had little or no direct patient contact in the hours before the resuscitation. five of the nine healthcare workers involved in the resuscitation agreed to participate in serologic testing. all convalescent-phase samples were collected > days after the event (table) . evaluation of the stryker t personal protection system indicated an average removal efficiency of % for particles > . µm in diameter and % for particles > µm. this equates to a reduction factor (i.e., particles outside of the hood would be reduced in number by this factor) of . and . , respectively. this report describes the apparent transmission of sars-cov from a patient to healthcare workers during an attempted resuscitation. the similar symptom onset dates suggest a point source of exposure. in this case, sars-cov was transmitted despite healthcare workers' wearing protection equipment designed to protect against contact and droplet transmission; no breaches in droplet protection equipment were identified, and exposure times were fairly brief. although sars transmission that involved intubation and bipap ( ) have been reported, this episode is unique in that the patient was neither conscious nor breathing at the time of the intubation, and the intubation procedure was performed quickly and without difficulty. these factors make it less likely that transmission occurred as a direct result of the intubation procedure. instead, it is more likely that transmission was related to events leading up to the intubation. in this case, just as in previous cases, either contact, droplet, or airborne transmission might have occurred. direct and indirect contact are the most common forms of transmission for most nosocomial pathogens; transmission between patients or from patient to healthcare worker usually follows contamination of the healthcare workers' hands after touching either the patient or a fomite that came into direct contact with the patient. large aerosol droplets (i.e., > µm) can, in addition to contaminating both animate and inanimate surfaces in close range of the patient, travel short distances through the air and make direct contact with the exposed mucous membranes of healthcare workers or other patients. in contrast, airborne transmission is mediated by respiratory aerosols. these aerosols of infectious organisms contain droplet nuclei < µm in size and, depending upon their size within this range as well as ambient environmental conditions, can float on air currents and remain airborne for many hours ( ) ( ) ( ) ( ) . a large variety of viruses ( , ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) are transmissible through both contact and airborne modes. often, investigation of the epidemiology of nosocomial viral infections, establishes the occurrence of airborne transmission ( ) . two explanations may account for the transmission observed in this case: ) an unrecognized breach in contact and droplet precautions occurred, or ) an airborne viral load was great enough to overwhelm the protection offered by droplet precautions, including non-fit-tested n disposable respirators. if the last form of transmission was responsible, airborne virus may have been generated by the coughing patient ( ) before her cardiopulmonary arrest or due to a "cough-like" force produced by the airway pressures created during asynchronous chest compressions and ventilations using the bag-valve-mask ( ) . regardless of the exact mode of transmission in this case, several lessons were learned through our investigation that may help reduce the risk of transmission to healthcare workers. a systematic approach to this problem is outlined considering the following framework: ) administrative controls, ) environmental engineering, ) protection equipment, and ) quality control. policies and protocols for emergency resuscitation involving patients known to have or suspected of having sars should include ) description of the roles and responsibilities of healthcare workers responding to the emergency, ) mechanisms to alert responders that the emergency involves a potentially contagious patient (e.g., announcing the code as an "isolation code blue"), ) steps to limit the number of healthcare workers involved to minimize potential exposures, ) plans for having auxiliary staff staged in a safe area where they can be easily called on if needed but otherwise preventing unnecessary exposure, ) plans for safe disposal and cleaning of equipment used during the emergency response, and ) procedures for disposition of the patient after the emergency, either to the icu if resuscitation is successful or the morgue if unsuccessful. policies must be developed that consider all high-risk exposures or emergency situations and not just individual procedures. policies that are too focused are of little value in dealing with the hundreds of unforeseeable possible situations that may arise. conversely, policies that educate healthcare workers to assess the risks of a task and empower them to take appropriate protective action will be more effective. these policies should be crafted at each healthcare facility by a team that involves key stakeholders, including persons involved in the clinical response along with infection control practitioners and infectious disease experts. it is also important to minimize the chance that a patient will suffer unwitnessed cardiopulmonary arrest or require emergency intubation on a sars unit. prevention of these events will involve two changes in policy. the first is to recognize that isolation wards cannot be staffed with the same nurse-to-patient ratio as a regular ward. care of patients in isolation is more time intensive due to both the physical barriers (e.g., anterooms, doors kept closed at all times) and the required use of protection equipment. the nurse-to-patient ratio on the sars ward at the time of the arrest was between : and : ; a more ideal ratio might be : or : . it is also necessary to have a lower threshold for transferring patients to a higher acuity setting (i.e., icu or stepdown unit) when they first begin to show signs of a clinical deterioration. to enable this, all patients on a sars unit should have measurement of vital signs along with pulse oximetry at a minimum of every hours. should their oxygen saturation drop below % on room air one should administer oxygen through nasal prongs - l per minute to maintain saturation > %, and increase vital signs/pulse oximetry to every hours. if the patient subsequently requires oxygen through nasal prongs at > l per minute the responsible physician should be notified and increase vital signs or pulse oximetry to every hour. finally, if the patient requires supplemental oxygen of > % to maintain saturation > %, the patient should be transferred to the intensive care unit and undergo elective intubation in a controlled manner. this later policy has worked well in other sars units, as well as in hospital a after it was implemented by one of the authors (m.l.) after this cluster. finally, policies should be developed to address the appropriateness and application of advanced cardiac life support for patients suffering cardiopulmonary arrest on a sars ward. many considerations must enter into any such discussion, including the usefulness and outcome of resuscitation efforts, particularly in unwitnessed arrests ( ) ( ) ( ) . despite even the most well-planned and wellwritten policies, if healthcare workers are not trained in proper infection control practices, sars will continue to be transmitted. staff must be trained in both the application of policies as well as the use of protection equipment. in addition to education, practice is also important; for example, consideration should be given to staging one or more "mock sars code blue" events. the second line of defense against the transmission of sars is environmental engineering controls. these consist of physical engineering elements such as negative pressure rooms, dilution ventilation, high-efficiency particulate air filtration, ultraviolet lights, and scavenging devices. the primary goal of environmental engineering processes is to contain the infectious agent in a limited area and to minimize or rapidly decrease the viral load in the environment so that in the event of a breach in infection control process or protection equipment, the chance of healthcare workers or other patients becoming infected is minimized. in this case, a breach occurred in source control; the initial bag-valve-mask used in the resuscitation did not have a viral/bacterial filter on the exhaust. this breach may have resulted in "uncontrolled" release of aerosolized virus into the environment. however, previous studies with coxsackie virus showed that little or no virus is detectable in expired air, only in respiratory aerosols and droplets from coughing or sneezing ( , ) . the final line of protection against occupational exposure is protection equipment. the use of n respirators offers a level of protection against airborne transmission of sars. however, for any form of respiratory protection to perform at the level of its full potential, it must be properly fitted to provide an adequate seal. the n disposable respirators used by healthcare workers in this instance were not fit-tested to ensure an adequate seal. thus the exact level of protection afforded by the n respirators for each person in this case is unknown. nonetheless, a higher level of respiratory protection should be considered in environments with a potentially very high sars-cov load, such as that associated with aerosol-generating procedures as a result of the transmission of sars co-v during aerosol-generating procedures, some hospitals in ontario, canada, have adopted use of the t personal protective system (stryker instruments) ( figure ). this system was originally designed to maintain a highly sterile field during surgery to prevent operative site infections. as a form of protection equipment, this system has both advantages and disadvantages. the primary advantage is that the entire body of the healthcare worker is covered, providing a high level of droplet protection. the primary disadvantage of the t is the length of time required to put one on during an emergency. in the emergency resuscitation described in this report, the delay in certain rescuers responding was due to the time required to put on the t . this resulted in the need for a second code blue to be announced for the same patient, which drew additional personnel to the code and thus increased the number of healthcare workers exposed to sars. the healthcare worker must also be attentive to avoid contamination when removing the t . moreover, the airborne reduction factors of . , for particles > . µm in diameter, and . for particles > µm were less than the protection factor of that is assigned (i.e., minimum expected in practice) for a fit-tested, disposable n respirator. however, a disposable n is commonly worn under the t used in ontario hospitals, suggesting the respiratory protection afforded healthcare workers using the t would be greater. the powered air-purifying respirators (paprs) most commonly used in healthcare settings have a disposable full hood with face shield covering the healthcare worker's upper body (figure ) . this device provides a higher level of protection against airborne infectious agents (any papr equipped with a hood or helmet with any type of particulate air filter has an assigned protection factor of [ ] ), and it may be faster and easier to apply in an emergency situation. finally, ensuring that a hospital has adequate protection against airborne diseases, even if not absolutely required for sars, will ensure that staff are prepared to deal with future emerging infectious diseases or bioterrorism events that could involve airborne agents. regardless of what device (t versus papr) is used in an institution for potentially aerosol generating procedures, it is essential that they are distributed throughout the hospital in areas where they are most likely to be required by primary responders in an emergency situation as opposed to a central area where teams must wait for them to be brought to the emergency. in addition, extra protection equipment should be included as part of any "crash cart" used by the responding code team. although there is a tendency to focus only on hightech forms of protection equipment, it is important not to forget the basics of infection control procedures such as glove changing and hand hygiene. healthcare workers must remain vigilant about not only protecting themselves from sars transmission but also protecting against patient-to-patient transmission. as was found in the second phase of the sars outbreak in toronto ( ), one of the best ways to prevent healthcare worker infections is to ensure that no sustained transmission of sars occurs within the patient population, which may act as a reservoir of infection. after developing good policies and training staff who are rehearsed for emergencies and provided with appropriate protection equipment, the last step is to ensure ongoing adherence to the standards set. this adherence is achieved through quality control. without an effective quality control program in place, lapses in infection control procedures will occur, particularly as healthcare workers become fatigued during a prolonged outbreak. a variety of quality control methods can be implemented, including administrative checks to ensure equipment is in good repair, policies are current, and training materials are up to date. another quality control practice often used by emergency services personnel dealing with hazardous situations is the "buddy system." in this system, healthcare workers always work in teams on sars units with each person being responsible for double checking to make sure that their partner is wearing appropriate equipment and following correct infection control practices before entering a patient's room. finally, a process should be in place to review responses to emergencies after they have occurred to learn from the experience and facilitate continuous quality improvement. sars has increased the medical community's awareness of issues related to occupational health and safety. it has also highlighted the importance of infection control programs and practices. a systematic approach, including administrative controls, environmental engineering, protection equipment, and quality control, is advocated to prevent future sars-cov transmission to healthcare workers. emerging infectious diseases • www.cdc.gov/eid • vol. a cluster of cases of severe acute respiratory syndrome in hong kong a major outbreak of severe acute respiratory syndrome in hong kong identification of severe acute respiratory syndrome in canada clinical features and short-term outcomes of patients with sars in the greater toronto area cumulative number of reported cases of severe acute respiratory syndrome (sars) identification of a novel coronavirus in patients with severe acute respiratory syndrome a novel coronavirus associated with severe acute respiratory syndrome effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (sars) cluster of severe acute respiratory syndrome cases among protected health care workers-toronto directive to all ontario acute care hospitals for high-risk procedures involving sars patients critical care areas. directive - (r) interim domestic infection control precautions for aerosol-generating procedures on patients with severe acute respiratory syndrome (sars) the pdsa cycle at the core of learning in health professions education update: severe acute respiratory syndrome-toronto world health organization. sars case definition airborne nosocomial infection: a contemporary perspective effect of route of inoculation on experimental respiratory viral disease in volunteers and evidence for airborne transmission airborne transmission of respiratory diseases occupationally acquired infections in health care workers. part i small round structured viruses: airborne transmission and hospital control airborne transmission of a small round structured virus airborne transmission of respiratory infection with coxsackievirus a type airborne transmission of nosocomial varicella from localized zoster airborne transmission of varicella-zoster virus in hospitals an outbreak of influenza aboard a commercial airliner airborne transmission of measles in a physician's office -to -nm virus particle associated with a hospital outbreak of acute gastroenteritis with evidence for airborne transmission an airborne outbreak of smallpox in a german hospital and its significance with respect to other recent outbreaks in europe regional blood flow during cardiopulmonary resuscitation in dogs using simultaneous and nonsimultaneous compression and ventilation the problem with futility when to let go survival after cardiopulmonary resuscitation in the hospital national institute for occupational safety and health. niosh guide to industrial respiratory protection. dhhs (niosh) publication no. - we thank randy wax and laurie mazurik for taking the figure photos.dr. christian is a consultant practicing general internal medicine, including critical care, in both academic and community hospitals. he will soon begin a combined fellowship in infectious diseases and critical care. key: cord- - fpmatkb authors: garbey, m.; joerger, g.; furr, s.; fikfak, v. title: a model of workflow in the hospital during a pandemic to assist management date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: fpmatkb we present a computational model of workflow in the hospital during a pandemic. the objective is to assist management in anticipating the load of each care unit, such as the icu, or ordering supplies, such as personal protective equipment, but also to retrieve key parameters that measure the performance of the health system facing a new crisis. the model was fitted with good accuracy to france's data set that gives information on hospitalized patients and is provided online by the french government. the goal of this work is both practical in offering hospital management a tool to deal with the present crisis of covid- and offering a conceptual illustration of the benefit of computational science during a pandemic. care unit (icu) are or are going to be be severely strained. healthcare professionals are often times forced to make difficult decisions in patient care and resource allocation. patient profiles might be out of the ordinary routine of the hospital and workflow must be different. end-to-end on demand visibility with identification of real constraints is needed for the senior management. a manager may have simple but essential questions such as: how many beds do i need on the floor, how many beds are available in the critical care unit, how much supplies should be ordered to take care of our patients and protect our staff from infection, how long will the facility have to work at maximum capacity, is there enough staff to hold this workload long enough, are we doing well with patient outcomes, etc. people who are going to be symptomatic enough to require hospitalization. this approach has been quickly applied to covid- with success [ , ] . in the case of the covid- pandemic, it is particularly difficult because large bodies of infected people are asymptomatic. consequently, the basic reproduction number r factor of covid- is still under active debate. on the hospital workflow side, while there is a large amount of work on this topic [ ] , one of the difficulties is to asses the death rate of patients hospitalized at the beginning of the pandemic because the length of stay (los) is rather long and the disease is still not well understood [ , , ] . every hospital has to adapt to the new crisis as it arrives, so clinical practice may vary greatly from one institution to another. a number of guidelines and great reports have been quickly edited to support the heath community, but it takes time to standardize the healthcare process [ , , , ] . our goal in the paper was to come up with a simple and robust mathematical framework that is easy to use and that supports the management of the patient workflow during a pandemic. such a model should operate on a relatively limited data set that reports daily on the number of patients admitted for hospitalization, patient acquisition. much more can be done with the patient electronic records that detail patient comorbidities and chronic conditions, provided that the disease of the pandemic is well understood. we have used a markov process description of the workflow's graph with probability governing the patient transition from one care unit to another, as well as a simple statistical model of patient los at each stage. we will show that with a minimum number of parameters used to fit on the time series listed above for a period of a few weeks, one may start to assemble the information needed to assist the senior management in getting answers and identifying real constraints to reduce speculation or misallocation of resources. this work is our first iteration to achieve a very ambitious goal: as data becomes available, the quality and level of detail of modeling should keep improving to achieve better results. it is our hope that such an effort, among many others, will once again prove how much digital health can benefit from computational science to improve patient care. the paper is organized as follows: section describes our method to construct the model and details the choices we made to work with the data set on hand; section gives the main results and solution to our initial goal in supporting management; section discusses the benefit and limitation of our method and concludes with further potential development. because of the sparsity of data available to construct a predictive model during a pandemic crisis, we are going to use a very simple model that reproduces the workflow of table . let's start with a brief description of standard patient workflow -see figure -with respect to disease progression -see figure . the patient moves from one care unit to another according to his/her condition. the first two steps are registration and diagnostics, which in principle should be a relatively quick process. for the patients who stay in the hospital because their health condition justifies a longer stay, they are first put in a ward unit for further assessment and treatment. this step is where a number of medical imaging steps start involving work flow transition table . probability of transition for the patient in reference to the workflow of either a chest ct scan in the imaging center or a chest x-ray with a mobile unit. meanwhile, significant biological lab work starts to grade the patient's condition more precisely and continues during the patient's stay. these resources, i.e. imaging and lab work, are typically shared by all patients in the hospital and therefore may slow down the process. for simplicity and in the absence of adequate data set for validation, we neglect these constraints. some of the patients who receive medical attention do well with conservative management only and can be discharged home after a few days. but for others, their health condition may deteriorate and those patients will need to be moved to the imu for higher level of care and/or to transfer to the icu for ongoing monitoring and mechanical ventilation. the imu and icu require extensive supplies and resources. it is often mentioned that the number of available ventilators is critical to icu functions. however, it is not the only limiting factor: patients under mechanical ventilation need sedation and might be connected to a number of additional systems to deal with organ failures. once again for simplicity and because of the lack of input data, our model will not take into account these bottlenecks. there are no technical difficulties required to add those constraints in the mathematical model with our bottom up description of the workflow as in [ , ] . additional steps can be recovery for patient being well or unfortunately palliative care when the patient is not responsive to treatment. there are many exceptions and singularities to these standard paths: for example, a patient may go directly from admission to the icu when their condition is too unstable. in some hospitals, the floor might be shared by patients who are recovering from covid- and palliative care patients.despite this, we will separate these functional units in our model to clarify the workflow process according to what each patient stage requires in terms of resources and time to deliver adequate care. to summarize, a simple workflow graph is created and the main requirement is to know (i) the probability that a patient goes from one care unit to another and (ii) a statistical estimate of how long the patient should stay in each care unit before moving on. [ , ] . our model follows a markov process for (i): there is a probability associated with each branch of the graph summarized in table . with respect to (ii), we use a lognormal distribution that can be reconstructed from the parameters listed in table and table . this simple framework allows us to construct a generic model that resource allocation, as well as the number of patient outputs, such as the number of patient healed and discharged per day, or the number of death(s). these time series can be fitted to existing data the hospital obtains during a period of a few weeks prior to retrieving the performance parameters of table . once the model is calibrated, it can be used to extrapolate the load of each care unit in the next few days and anticipate the need of staff and supplies -see table . figure this discrete model is stochastic, so one needs to run many simulations to build a statistical estimate of such quantities. it is appropriate to retrieve the unknown parameters of the model using a form of stochastic optimization method, such as genetic algorithm, since the model workflow process, like the one in the hospital, is discrete, noisy, and nonlinear. floor imu icu recovery palliative nurse beds beds beds beds beds md beds beds beds beds beds table . number of staff required at each care unit per beds in reference to the workflow of figure let us describe the data set we are using to construct our model. the french government has kindly decided to release the records of most public hospitals around the country during the covid crisis. from this excel file, we can easily recover the number of patients staying in hospitals, the number of patients in icu, the number of patients healed and discharged, and the number of patients dying in a medical institution. those numbers are updated daily and go back to march , [ ] . we will extensively use this french data set (fds) to identify the missing parameters of our model. the number of parameters of our model is relatively large: about one parameter for each branch of the graph minus the number of nodes for (i) and two parameters for the log distribution of (ii) in each care unit. to avoid over-fitting, one should come up with a strategy that lowers the number of unknown based either on literature or hypothesis that can be validated otherwise. we are going to describe thereafter the rationale for our choices to the best of our knowledge and further discuss some of the limitations of our model in section . first of all, a lognormal distribution of the duration of each step of the process might be justified as follows. biological process, such as incubation and recovery, are often described as such [ , ] . first, the patient's condition is indeed dominated by his/her biological time. second, medical procedures with their associated time lag and delay are also often best described as lognormal processes [ , ] with a long tail. this is not in contradiction with the fact that patient los in the hospital may not ideally be described by a simple exponential distribution or similar. overall, los adds up the time distribution of each step in a markov process and might be described at the convolution of the probability distribution of each step [ ] . now let's review the parameters of table that gives the probability transition from one unit to another, in order to rationalize the construction of our generic model. one can first list the following constraints assuming that all possible paths are exhaustively april , / . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint listed in the workflow of figure , so we have: α + α + α = , α + α + α = , α + α = , α + α = , α + α = . ( ) overall, the death rate and recovery rate of patients who are staying in the hospital should be within an acceptable limit. technically, the death rate of hospitalized patients is: similarly, the recovery rate of hospitalized patients β h = − β d is: β d is difficult to asses with a pandemic that just started. as a matter of fact, most infected patients are still in the hospital and their outcome may not be clear. we look thereafter for some lower and upper bounds of β d that limits our search. in france, as of april , , the number of deaths in hospitals was , patients and recovered was , patients [ ] . assuming that the proportion of death versus recovery will be about the same for the patients who are still ill, the death rate of hospitalized patients should be around %. finally, according to [ ] , an early estimate of the death rate for hospitalized patients in wuhan, china based on a case series of patients was / = %. we restrict ourselves to the model matching the fds to a [ %, %] death rate interval, that is: according to several reports including the icnarc one mentioned above, it is expected that the number of patients dying in icu is about %. [ ] provides much further details on the probability of survival of patients with ards under mechanical ventilator as a function of the day of the start. it shows that about % of the patients in icu die during the first few days from severe complications. we will introduce an artificial two phases icu decomposition of the patient stay in the icu to bypass the limitation of a single lognormal distribution that may not represent an adequate model of los in this unit according to [ ] clinical studies: a short phase one with mortality driven by α and a longer phase with mortality driven by α . consequently, we will assume that: there are also few parameters in table that should have near to no limited effect on statistics when matching our model to fds. fds is based on hospitalized patients, so α cannot be recovered from this data set. according to fds, about % of patients who show up at the emergency room (er) are returning home [ ] . we will choose α = . . april , / . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint according to dr. m. mueller [ ] , % of the patients who are not responsive to treatment may leave palliative care alive and are discharged home. this may vary depending on each country or hospital policy. because patients with covid- in palliative care are still very contagious, we will assume they stay in the hospital until the end. we will choose α = ., for all our calculations. to sum up, our model essentially needs the calibration of parameters, namely a = (α , α , α , α , α , α ) under the set of constraints ( ), ( ), ( ). let us denote f admission (jd) the number of patients admitted per day jd ∈ ..n in the hospital who have a positive diagnosis and must stay in the hospital. we will use we find a as the solution of the minimization problem of the weighted norm: where f s is the mean of a large number of runs of the model. this number of runs is set large enough to let the solution of the optimization problem be independent of it. as mentioned above, we will use a genetic algorithm to solve that minimization problem. the weight factor (γ , γ , γ ) in ( ) can be set equal or unequal to favor the quality of the fitting for one of the variables, such as the number of patients in the icu that is critical to management. table and give the time window we used for each transient stage. we construct a lognormal distribution of duration for the patient stay in such a way that about % of the patients' stay will be within a coarse approximation [p, q] listed in these tables. the choice of the parameters in table and table might be easier to come up with. one of the most remarkable features is that patients with covid- who stay in the icu can be longer than usual [ ] . the los in palliative care was set according to dr. m. mueller's data [ ] . we have used extensively [ , ] , as well as the feedback from clinicians in the field to estimate the interval of variation for the parameters [p, q] the best we could. we used a fairly large interval since it can be observed that the standard deviation for los in each care unit is large as described in this report from the imperial college london covid- response team [ ] . one may fine tune the interval value [p, q] if needed in the fitting process of the model to the data set of time series available. to distinguish those unknown parameters that are important from those who are less significant, we run linear sensitivity analysis for each of our results. this method is used to confirm that the time window parameters of table and table have a secondary effect on the quality of the model fitting. finally, we derive from our model some predictions on staffing and supplies for the next week or so, as well as the load foreseen for each care unit. the nature of the stochastic simulation automatically gives an uncertainty estimate on these predictions that increases as time grows. to compute supplies such as personal protection kits, we can use some adaptation of the reference of the cdc web site [ ] that was constructed for ebola. our software can then be used to feed the stock management scheme implemented by cdc for covid- [ ] . in this paper, we use a growth estimate of two personal protective equipment (ppe) per shift and per staff member for simplicity. april , / . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . table a gross approximation of the number of nurses and staff per bed site in each unit. those figures are depending on the crisis situation and might differ depending on the country [ ] . in order to take into account the fact that staff and supplies are limited and require hard management choices during a pandemic crisis, we tested the model further against the scenario of a shortage on nurses who are essential in intensive care units. to introduce a risk factor due to the shortage of nurses, we have extrapolated from [ ] to get a continuous approximation, we assume that the shortage of nurses has a linear effect, and use linear interpolation for shortages from % to % maximum. this is certainly a gross approximation, but we felt that it was important to bring awareness to those effects with a simulation tool. we will present in the next section our results. let us first report on the model fitting with the fds. we sum up the number of admissions, patients in icu, number of recoveries and deaths for the whole country of france in order to get a robust data set that averages the noise of the data. we calibrated the model to this largest data set that covers the period / / to / / and found a death rate of about %. this result is in agreement with the estimate we did in section , as of april , [ ] . table to . all numbers have been scaled by a factor to represent an average hospital size. the sensitivity analysis on the alpha unknown vector a is reported in figure . april , / . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . we observed that the number of patient admissions is not a smooth curve. typically, sunday's have less activity with less patients discharged than weekdays. however, the model fitting seems adequate and robust to a small variation of parameters. the logic on the influence of parameters is simple, α being the one who is most important for all output. each of the six parameters seems to have some significant influence for at least april , / . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . in order to compare the results obtained with designated subset of the fds that corresponds to the hospital in paris and the hospitals in alsace, we used the simulation with the exact same set of parameters found for the data set with the whole country. alsace has been the busiest cluster at the beginning of the pandemic, followed later on by paris and ile de france. the results for alsace are reported in figure and figure . we observed a fairly large difference of the model's prediction on the number of patients under mechanical ventilation. it seems that at the peak of the pandemic in alsace, the number of patients under mechanical ventilation was less in reality than in the model. one possible factor would be the shortage of available beds in the icu. on the other hand, the number of deaths did not go higher than significantly expected. a better explanation might be the fact that a fairly large number of patients in critical condition were transferred to hospitals in different parts of the country or neighboring countries: according to local newspaper more than patients from alsace have been transferred [ ] . this seems coherent with our results: the scaling factor for the alsace data set to get a maximum hospitalization rate of about patients per day is ; the overshoot on the icu prediction is about in figure ; the total maximum overshoot is therefore about ; considering that the average los in icu (see table ) is roughly days, our model still seems to give an adequate approximation. but unfortunately, we do not have enough information to add this new patient path in the workflow of figure . this phenomena is less present in the results for the data set with paris but are still there -see figure and figure . one can indeed refine the parameter fitting to be specific for alsace and paris in order to reflect that the clinical decision process in the workflow, i.e parameters of table to , might be sensitive to how much the local system is under stress, but we should then take into account those number of transferred patients that are not negligible. next, let us describe the use of our model to assist daily management in the hospital during the pandemic. one key factor is to anticipate the load of each care unit and required resources, either to match the increase in number of patients or to reallocate resources to other patients who have seen their surgery postponed. we choose a hypothetical scenario that might occur if confinement conditions to contain the pandemic are lifted too early. we assume that the hospital has a nominal low flux of patients from week to , and a recurrence with a daily % increase of new patients coming in occurs in week . figure shows the dynamic of the load of each care unit, in particular the large delay in the number of patients in the icu that becomes saturated the latest. the black curves are a simulation of the previous week's load (week ), while red curves are the prediction for the following week (week ). the april , / . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . as an illustration of the capability of the model, figure and figure provide an estimate of the growth of resources needed to face the new patient wave. a number of decisions should be made in regards to patient care. figure compares the patient april , / . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . output with or without shortage of nurses. those results are speculative since it is difficult to quantify the risk for patients beyond the nice publication results of [ ] and [ ] . it is our hope that data accumulated during crises such as the present episode of covid- will give the mathematical modeling the base to do this estimate rigorously in future work. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . mathematical models available, even for the present crisis, see [ ] and [ ] . it might be difficult to assess the basic reproduction number r factor, which is under active debate. it is probably even more difficult to assess the exact impact of global confinement or targeted confinement on those parameters that characterized the pandemic model. we should however be able to use our model to test if the effect on the most critical resource, such as icu beds and delay in care, are linearly or nonlinearly related to those parameters. let us use the most simplistic ordinary differential equation epidemiology model: the function i(t) is used as the input of our workflow model, and represents the number of patients admitted to the hospital. we test the influence of the transmission rate on the number of icu beds over a -week period. figure shows that the maximum number of icu beds required during the epidemic is significantly higher when april , / . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . admission goes up to patients per day. this is a significant load for any hospital system because all patients suffer from the same disease and cannot be triaged using the existing departmental structure. the hospital system needs to recruit resources quickly enough to deliver quality patient care while keeping the staff safe from infection. there are many ways of developing such a mathematical model. we chose a markov process that can augment a workflow graph provided by the clinicians and used a simple statistical model for the los of the patient at each stage corresponding to a graph node. a number of variations in the model construction are available: for example, changing the probability distribution of los for specific stages with a more sophisticated model than lognormal or decomposing the graph nodes into subgraphs of the workflow with more details. in particular, the icu supports different paths of medical care depending on patient conditions. because of the sparsity of data on hand, we kept the model as simple as possible and we were able to fit the french data set with good accuracy. using this approach, we could: • recover important parameters that are characteristics of the workflow such as the probability for a patient to transition from one unit to another, and important patient outcomes such as healing rate or death rate. april , / . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint • on a pragmatic side, we use the model to assist the senior manager in answering his/her questions as listed in our introduction: how many beds do i need on the floor, how is this affecting patient outcomes, do we need to transfer patients to a different facility, etc.? there are a number of limitations to our approach. the smaller the hospital, the less predictable the outcome will be. with time, the characteristics of the population of patients who show up to the er may change and the pandemic management by the governing organizations would evolve. one can think, for example, that systematic testing would provide early diagnostics and impact the performance of the health system as shown by the statistics of countries who were early adopters of that strategy. due to the heterogeneity of the patient population and disease patterns that depend heavily on patient characteristics, our next step in improving this model would be to include patients' medical history listed in the electronic medical record. above all, any model of workflow especially during a pandemic should be aware of the human factor. staff can get sick or burnout during a pandemic and there should be a number of strategies to compute that risk and enter this into the constraints imposed on the health care system [ , , , ] . further, human behavior and decision process changes under stress: it can be for economical or psychological reasons. the covid- in critically ill patients in the seattle region -case series timsit severe sars-cov- infections: practical considerations and management strategy for intensivists centers for disease control and prevention: novel coronavirus overcrowding and understaffing in modern health-care systems: key determinants in meticillin-resistant staphylococcus aureus transmission dod covid- practice management guide characteristics and outcomes in adult patients receiving mechanical ventilation jama impact of non-pharmaceutical interventions (npis) to reduce covid- mortality and healthcare demand temime management of nurse shortage and its impact on pathogen dissemination in the intensive care unit epidemics the returns to nursing: evidence from a parental leave program working paper multiscale modeling of surgical flow in a large operating room suite: understanding the mechanism of accumulation of delays in clinical practice an agent-based and spatially explicit model of pathogen dissemination in the intensive care unit the effect of workload on infection riskin critically ill patients modelling hospital length of stay using convolutive mixtures distributions a cyber-physical system to improve the management of a large suite of operating rooms a predictive model for the early identification of patients at risk for a prolonged intensive care unit length of stay the incubation period of coronavirus disease (covid- ) from publicly reported confirmed cases: estimation and application markus abbt log-normal distributions across the sciences: keys and clues bioscience early efforts in modeling the incubation period of infectious diseases with an acute course of illness multi-city modeling of epidemics using spatial networks: application to -ncov (covid- ) coronavirus in india understaffing, overcrowding,inappropriate nurse:ventilated patient ratio and nosocomial infections: which parameter is the best reflection of deficits? modeling the uncertainty of surgical procedure times: comparison of log-normal and normal models traversing the many paths of workflow research: developing a conceptual framework of workflow terminology through a systematic literature review -ncov) situation reports a mathematical model for the novel coronavirus epidemic in discovery of a novel coronavirus associated with the recent pneumonia outbreak in humans and its potential bat origin, biorxiv . icnarc report on covid- in critical care palliative and end of life care for patients with respiratory diseases symptom progression of covid- estimated personal protective equipment (ppe) needed for healthcare facilities personal protective equipment (ppe) burn rate calculator où les patients alsaciens atteints du covid- ont-ilsété transférés we would like to thank patrick doolan for sharing his view with us on management and risk evaluation from his great experience acquired from the energy sector. declarations of interest: none key: cord- -egy rgtl authors: barrasa, helena; rello, jordi; tejada, sofia; martín, alejandro; balziskueta, goiatz; vinuesa, cristina; fernández-miret, borja; villagra, ana; vallejo, ana; sebastián, ana san; cabañes, sara; iribarren, sebastián; fonseca, fernando; maynar, javier title: sars-cov- in spanish intensive care: early experience with -day survival in vitoria date: - - journal: anaesth crit care pain med doi: . /j.accpm. . . sha: doc_id: cord_uid: egy rgtl abstract purpose: community transmission of sars-cov- was detected in spain in february , with % intensive care unit (icu) capacity expanded in vitoria by march th, . methods: we identified patients from the two public hospitals in vitoria who were admitted to icu with confirmed infection by sars-cov- . data reported here were available in march th, . mortality was assessed in those who completed -days of icu stay. results: we identified patients ( males) with confirmed sars-cov- . median [interquartile range (iqr)] age of patients was [ - ] years. symptoms began a median of [ - ] days before icu admission. the most common comorbidities identified were obesity (n = %), arterial hypertension (n = %) and chronic lung disease (n = %). all patients were admitted by hypoxemic respiratory failure and none received non-invasive mechanical ventilation. forty-five ( %) underwent intubation, hfnt, ( %) extracorporeal membrane oxygenation (ecmo) and ( %) required prone position. after days, / ( %) intubated patients died ( % within one week), ( %) were extubated, and / ( %) underwent mechanical ventilation. six patients had documented co-infection. procalcitonin plasma above . µg/l was associated with % vs. % (p = . ) risk of death after days. conclusion: this early experience with sars-cov- in spain suggests that a strategy of right oxygenation avoiding non-invasive mechanical ventilation was life-saving. seven-day mortality in sars-cov- requiring intubation was lower than %, with % of patients still requiring mechanical ventilation. after days of icu admission, half of patients remained intubated, whereas one third died. since the initial identification of sars-cov- infections in wuhan, it has been important to identify characteristics beyond china with implications in management [ , ] . reports describing icu patients with sars-cov- out of china are still limited [ , ] . the clinical course of adult inpatients in wuhan has been reported [ ] with a high mortality rate and a risk of death above % in presence of high ( . ng/ml) procalcitonin (pct) plasma [ ] . because most patients in china and italy received non-invasive ventilation, information is needed on patients following a strategy of early intubation without inducing potential ventilator-induced lung injury. moreover, in view of the limitation of resources, it is also important to improve insight on -day mortality and identify different phenotypes for personalised management [ ] . in the capital of alava, a city in the basque country which experienced the acceleration curve before other spanish provinces (in relation to a massive contagion in a funeral) with % icu capacity being already in wuhan and usa. because of mortality reports in wuhan [ ] suggesting a close association, we assessed correlation between plasma procalcitonin at icu admission and -day mortality. j o u r n a l p r e -p r o o f all consecutive sars-cov- adult patients (≥ years old) from the university hospital araba (vitoria, spain) between march , and march th , were included. all patients that required hospitalisation with a covid- diagnosis according to who interim guidance [ ] were included. patients were followed until icu discharge or death from march , (first patient admission) to march , . all clinical data were collected prospectively by the investigators. pct plasma levels samples were obtained within icu admissions. non-invasive ventilation was not indicated in this cohort. intubation was clinically indicated in presence of respiratory alkalosis with progressive hyperventilation when delivering high oxygen concentrations. basic epidemiological, clinical, laboratory, microbiology, treatment, and outcome data were extracted (hb) and standardised in a crf, modified from the isaric crf. the study protocol was approved by the irb and informed consent was waived (ref. - ). patient data were censored at days of follow up, on april th, and survival data were estimated at -day and -day after icu admission. clinical specimens for sars-cov- identification were obtained in accordance with centres of disease control guidelines. methods for laboratory confirmation of sars-cov- pcr were performed at the hospital laboratory. page of j o u r n a l p r e -p r o o f a confirmed case was defined by a positive result on a reverse-transcriptase-chain-reaction (rt-pcr) assay of a nasopharyngeal swab or respiratory specimen. comorbidities were identified from hospital charts. definitions used in this article have been reported elsewhere [ ] . procalcitonin plasma levels were determined with the assay, alinity i ®, abbott, eeuu. the assay has a detection limit of . ng/ml with a probability of %, sensitivity of . μg/l (upperreference-range . μg/l in healthy subjects). determination of pct plasma levels was performed within hours after icu admission. considering the rapid spread of the covid- pandemic, the aim of the study was to report a fast overview of the situation in one of the first cities to be impacted by the outbreak. therefore, no sample size was calculated. continuous variables were described as medians, and interquartile range (iqr) or mean with standard deviation (sd), and categorical variables were presented as counts and percentages. pairwise comparisons for categorical variables were performed by using the pearson's χ test. comparisons between continuous variables used student's t-test and mann-whitney test according to their distribution. statistical significance was considered if the p-value was less than . . statistical analyses were performed with spss statistics version . software (ibm). association between survival and pct plasma levels was estimated using kaplan-meier curves. hazard ratios (hr) and % confidence intervals (ci) were computed using the long rank test. statistical significance was considered if the p-value was less than . . statistical analyses were performed with graphpad prism software. the most common symptoms at icu admission were fever ( %), dyspnoea ( %), cough ( %) and malaise ( %). myalgias were very uncommon ( %). ninety-four percent of patients received antiviral treatment with lopinavir/ritonavir and hydroxychloroquine, plus interferon beta ( %). empirical antibiotic agents were administrated to patients, whereas co-infection was identified in patients. chest-x ray findings are reported in table . this study describes critically ill patients with covid and severe acute respiratory failure in vitoria, spain, from march , to march , . patients received hfnt or intubation, but non-invasive mechanical ventilation was not applied. two weeks after icu admission, three out of ten intubated patients have died, and half of the patient cohort required prolonged ventilatory support. two out of ten intubated patients were extubated (and discharged), most at the second week of ventilation. plasma procalcitonin (threshold . µg/l) failed to predict mortality. our findings suggest that an oxygenation strategy emphasising optimisation of oxygenation, intubation based on clinical criteria of hyperventilation and avoiding ventilator-induced lung injury associated with non-invasive mechanical ventilation would be life-saving in a significant proportion of patients. table compares current findings with first series of sars-cov in the icu in china, usa, and pandemic influenza in spain. clinical presentation is consistent with a recent systematic review [ ] , lymphocytopenia and coagulation alterations being common at hospital admission, with some important differences documented when compared with pandemic influenza in (table ) , as reported elsewhere [ ] , and also with the first icu series reported from wuhan [ ] . obesity was the most common comorbidity in our report, suggesting differences in western countries regarding wuhan reports ( ), followed by hypertension and chronic respiratory j o u r n a l p r e -p r o o f diseases. the low prevalence of immunocompromised (solid organ transplants or hiv) and pregnant patients compared with severe influenza-infected patients may be associated with the interaction of coronavirus with innate immunity. fei zhou et al. [ ] reported a risk of death above % in patients with high procalcitonin, which is not consistent with our findings. this can be due to different laboratory techniques, co-infection rates or degree of acute lung injury (no niv was applied in our cohort). although more information on procalcitonin is required [ ] , our findings suggest that no prognostic information can be inferred. this early report of characteristics of sars-cov- influenza in spain is of interest, as most information currently available is coming from large cohorts in china, or short case series from italy or usa ( , , , ) . an important characteristic is that in the current cohort, no patients were exposed to prior non-invasive ventilation, which was commonly performed using a facial mask in wuhan or a helmet in italy, with a protocol of earlier intubation based on hyperventilation unable to maintain satv above %. patients in this cohort were intubated a median of days after onset, which is later than in pandemic influenza but earlier than in to ) days. although -day mortality was not available due to the early report, day mortality was estimated to be lower than % in our cohort and patients were extubated within the second week, which means that the prognosis is better with different strategies of oxygenation. in contrast with reports from china or seattle suggesting a severe ards, a strategy of early intubation disclosed that sars-cov- does not lead to a typical ards. in our experience, two thirds of our patients have initial lung compliance > ml/cm h postintubation being consistent with a preliminary report with patients by gattinoni et al. ( ) , suggesting that ards is a consequence of acute lung injury associated with delayed intubation or super-infection. thus, non-invasive ventilation seems not recommended and early high peep (above cm h is probably not the right ventilatory strategy) may be harmful. our experience suggests avoiding spontaneous ventilation early in the ed or ward may be harmful. thus, sars-cov- patients can be maintained with high-flow oxygen nasal therapy (hfnt) or high-concentration oxygen reservoir if they do not present extreme hyperventilation. early on this disease, non-intubated patients may benefit from prone position before intubation. three of our patients were managed like this without intubation and were discharged early. recruitment manoeuvres should be contraindicated and the benefit of prone position in intubated patients and protective ventilation should be restricted to those developing acute lung injury. these findings suggest that hypoxemic vasoconstriction is the main early mechanism and patients can benefit of inhaled prostacyclin or nitric oxide (before developing tachyphylaxis). lastly, although we did not document pulmonary embolisms in our cohort (autopsies were not allowed), laboratory tests are consistent with endothelial injury and micro-thrombosis. zhou et al. ( ) reported serum ferritin with a median above ng/l among non-survivors in a context of hyperinflammatory states. these patients should receive scd measurements and a bone marrow aspirate to rule out systemic haemophagocytic lymphocytosis, which should be treated with mg/kg gamma globulins/day and dexamethasone mg/ h for days. the same authors also reported d-dimer above ug/ml among % of non-survivors and our j o u r n a l p r e -p r o o f findings are consistent with these observations. although no difference on overall -day mortality was found between heparin users and non-users ( . % vs. . %, p = . ) in a report among patients with severe sars-cov- infection in china ( ) , the -day mortality was significantly reduced in those receiving low molecular weight heparin with a d-dimer > fold the upper limit of normal ( % vs. %, p = . ) or a sic score ( ) > ( % vs. %, p = . ). our study has several limitations. more than half of the cohort remained in the icu at the time of censoring on april th , and further outcomes assessment have to be performed. our sample size is small, because we focused on critically ill, and data cannot be extrapolated to patients hospitalised in medical wards. however, it is an early report illustrative of the epidemiology in south europe, which can be compared with wuhan and initial reports of pandemic influenza a h n pdm in spain (table ). we already expanded the icu capacity above two-fold in march th and data cannot be generalisable to patients with another acceleration phase or with different available resources, but may serve to develop contingency plans in other geographical regions. procalcitonin technique of determination may influence values and data may not be comparable when using other methods, such as kriptor® to determine plasma values. similarly, the strategy of early intubation, without prior non-invasive ventilation trial would means that data cannot be extrapolated to sites with other management strategies. lastly, pulmonary compliance and driving pressure was not recorded in the study protocol, limiting identification of phenotypes and extrapolation to other sites. this early experience with sars-cov- in spain suggests that the right oxygenation is life-saving. seven-day mortality in sars-cov- requiring intubation was lower than %, with % of patients still requiring prolonged mechanical ventilation. pct plasma levels do not predict survival. after days of icu admission, half of patients remained intubated, whereas one third were non-survivors. our clinical observations provide useful insights that can help to improve management and outcomes. authors declare no conflict of interest regarding this manuscript this work was funded in part by ciberes, instituto salud carlos iii, madrid, spain (cb - - and fondos feder). the study was approved by the clinical research ethics committee of araba hospital ( - ) and consent was waived due to the observational nature of the study. not applicable. the datasets generated and/or analysed during the current study are not publicly available due to privacy (patients' data) but are available from the corresponding author on reasonable request. the study was designed by jr. hb enrolled patients and it is responsible for the integrity of data. an analysis of data was performed by st, hb and jm. jr and st wrote the first draft of the manuscript. all authors contributed scientifically in the subsequent versions. all authors read and approved the final manuscript. - - ( %) ( %) ( %) ( %) pseudomonas strengthening icu health security for a coronavirus epidemic coronavirus disease (covid- ): a critical care perspective beyond china potential legal liability for withdrawing or withholding ventilators during covid- : assessing the risks and identifying needed reforms covid- in critically ill patients in the seattle region -case series clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study covid- does not lead to a "typical" acute respiratory distress syndrome clinical management of severe acute respiratory infection (sari) when covid- disease is suspected: interim guidance v . . world health organ intensive care adult patients with severe respiratory failure caused by influenza a (h n )v in spain clinical, laboratory and imaging features of covid- : a systematic review and meta-analysis clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study procalcitonin in patients with severe coronavirus disease (covid- ): a meta-analysis characteristics and outcomes of critically ill patients with covid- in washington state anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation . ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( - ) sofa score, mean (sd) key: cord- -h lwzpl authors: zhang, john j y; lee, keng siang; ang, li wei; leo, yee sin; young, barnaby edward title: risk factors of severe disease and efficacy of treatment in patients infected with covid- : a systematic review, meta-analysis and meta-regression analysis date: - - journal: clin infect dis doi: . /cid/ciaa sha: doc_id: cord_uid: h lwzpl the coronavirus disease (covid- ) pandemic spread globally in the beginning of . at present, predictors of severe disease and the efficacy of different treatments are not well-understood. we conducted a systematic review and meta-analysis of all published studies up to march , which reported covid- clinical features and/or treatment outcomes. studies reporting patients were included. pooled rates of intensive care unit (icu) admission, mortality and acute respiratory distress syndrome (ards) were . %, . % and . %, respectively. on meta-regression, icu admission was predicted by raised leukocyte count (p< . ), raised alanine aminotransferase (p= . ), raised aspartate transaminase (p= . ), elevated lactate dehydrogenase (ldh) (p< . ) and increased procalcitonin (p< . ). ards was predicted by elevated ldh (p< . ), while mortality was predicted by raised leukocyte count (p= . ) and elevated ldh (p< . ). treatment with lopinavir-ritonavir showed no significant benefit in mortality and ards rates. corticosteroids were associated with a higher rate of ards (p= . ). a pandemic of coronavirus disease caused by the novel severe acute respiratory syndrome coronavirus (sars-cov- ) spread from asia to the rest of the world in the first three months of . the consequences for human health, the global economy and normal functioning of society have been unprecedented. covid- causes infection in any age group, though severe disease is more common in older adults [ ] . the clinical spectrum of disease ranges from asymptomatic or subclinical infections to organ dysfunctionshock, acute respiratory distress syndrome (ards), acute cardiac injury, and acute kidney injury (aki)and death [ ] . as of may , , there was a total of , , confirmed cases globally. of the , , cases that had an outcome reached, , had resulted in mortality [ ] . the growth curve of covid- academic literature since the first report of this outbreak from wuhan, hubei province, china in december has been exponential [ , publications found on the national institutes of health covid- portfolio and publications found on pubmed on may , using the search string 'coronavirus disease or sars-cov- ']. however, systematic reviews which consolidate these findings remain scarce, with none focused on understanding the predictors for severe disease including the effects of different experimental antiviral and immune-modulatory treatments [ ] . to address this gap in the literature, we conducted a systematic review, meta-analysis and meta-regression to ) investigate the predictive value of laboratory investigations for severe disease and adverse outcomes, and ) evaluate the efficacy of antivirals and corticosteroids for covid- . m a n u s c r i p t reviews and meta-analyses (prisma) guidelines [ ] . all titles and abstracts were screened independently by two reviewers (jjyz and ksl) against a set of pre-defined eligibility criteria. potentially eligible studies were selected for full-text analysis. disagreements were resolved by consensus or appeal to a third senior reviewer (bey). agreement among the reviewers on study inclusion was evaluated using cohen's kappa [ ] . all original studies reporting the clinical characteristics (symptoms and signs, laboratory investigations and radiological findings) and treatment outcomes of patients with covid- were included in our meta-analysis. case reports and series with a sample size of < were excluded per recommendations by the cochrane statistical methods group and in accordance with methodologies of previously published meta-analyses [ ] [ ] [ ] . other exclusion a c c e p t e d m a n u s c r i p t criteria included non-english articles, non-original research papers, laboratory-based and epidemiological studies with no clinical characteristics reported, as well as non-human research subjects [see supplementary table ] . the quality of included studies was assessed using the joanna briggs institute (jbi) checklist for prevalence studies and the jbi checklist for case series [ ] . full details are in supplementary tables and . in summary, these tools rated the quality of selection, measurement and comparability for all studies and gave a score for prevalence studies (maximum of ) and case series (maximum of ). two researchers (jjyz and ksl) assessed the quality of all included studies and discussed discrepancies until consensus was reached. data were extracted on the following variables: study details, sample size of study, method of diagnosis, age, gender, coexisting medical conditions, clinical symptoms, laboratory investigations, radiological findings, treatment details and patient outcomes. primary outcome measures were intensive care unit (icu) admission rate, mortality rate and the event rate of ards. icu admission was used as a surrogate marker for severe infection. secondary outcome measures included other morbidities such as respiratory failure, septic shock, coagulopathy, acute cardiac injury, aki and secondary infection, as well as length of hospital stay (los) and discharge rate at the point of study completion. a c c e p t e d m a n u s c r i p t to account for intra-study and inter-study variance, random effects models were used for meta-analyses of variables and end points [ ] . pooled proportions were computed with the inverse variance method using the variance-stabilizing freeman-tukey double arcsine transformation [ ] . confidence intervals (ci) for individual studies were calculated using the wilson score confidence interval method with continuity correction. the i statistic was used to present between-study heterogeneity, where i ≤ %, between % and %, between % and %, and ≥ % were considered to indicate low, moderate, substantial, and considerable heterogeneity, respectively [ ] . p values for the i statistic were derived from the chi-square distribution of cochran q test. for pooling of means of numerical variables, we computed missing means and standard deviations (sds) from medians, ranges (minimum to maximum) and interquartile ranges (iqrs) using the methods proposed by hozo et al. and wan et al [ , ] . summary-level meta-regression was performed using the mixed-effects model after computation of the sd of freeman-tukey double arcsine transformed proportions. publication bias of studies was assessed using funnel plots, where an asymmetrical distribution of studies was suggestive of bias [ ] . quantitative analysis of funnel plot asymmetry was done using egger's regression test, based on a weighted linear regression of the treatment effect (expressed as a freeman-tukey double arcsine transformed proportion) on its standard error [ ] . the grade approach was used to evaluate the quality of evidence for each outcome [ ] . all statistical analyses were performed using r software version . . (r foundation for statistical computing, ), with the package meta [ ] . p-values less than . were considered statistically significant. all included studies were non-randomized, retrospective observational studies. studies reported data from china, with one each from singapore, south korea and hong kong. details of included studies are reported in supplementary table . of the prevalence studies, studies attained a full score of on the jbi checklist for prevalence studies, two studies attained a score of and one study attained a score of [see supplementary table ]. of the nine case series, studies attained a full score of , one study attained a score of and one study attained a score of [see supplementary table ]. of the total patients, were male ( . %) and were female ( . %). a c c e p t e d m a n u s c r i p t the most common blood abnormalities observed were elevated c-reactive protein (crp) ( . %), decreased albumin ( . %), elevated lactate dehydrogenase (ldh) ( . %) and lymphopenia ( . %). the most common radiological abnormalities seen on chest computed tomography (ct) scan were bilateral infiltrates ( . %), ground glass opacities ( . %), interlobular septal thickening ( . %), subpleural lines ( . %) and consolidation ( . %). in terms of treatment, type of antivirals used included combinations of oseltamivir, ganciclovir, lopinavir, ritonavir, ribavirin and arbidol. type of antibiotics used comprised moxifloxacin, ceftriaxone and azithromycin. table funnel plots and egger's regression test were done to assess for publication bias for icu admission, mortality and ards rates. there was no evidence of publication bias for icu admission (p = . ), mortality (p = . ) and ards (p = . ) [see supplementary figure ]. at baseline, the quality of evidence derived from a review of covid- studies was assessed as low, owing to their observational nature. the quality of evidence for respiratory failure was rated down to very low for imprecision, due to the large confidence interval range and the relatively small sample size analyzed. despite considerable study heterogeneity demonstrated by the i values for most outcome measures, there was no rating down due to inconsistency, as the heterogeneity could likely be explained by differences in patient demographics, diagnostic criteria, treatment methods and management protocols given that covid- is a newly emergent disease. meta-regression was performed to identify risk factors of icu admission, ards and mortality [ table ]. fourteen studies with a total of patients reported icu admission rates. subgroup analysis was performed for studies with the use of corticosteroids reported. sixteen studies with a total of patients reported the use of corticosteroids. pooled mortality rate in these patients was . % ( % ci: . - . ) and pooled ards rate was . % ( % ci: . - . ). meta-regression demonstrated a significant association between corticosteroids use and higher rate of ards (p = . ) [fig. a c c e p t e d m a n u s c r i p t our meta-analysis provides an in-depth analysis of the key epidemiological features, clinical characteristics, laboratory investigations, radiological findings, treatment details and outcomes of covid- from published literature. we identified elevated ldh as a significant predictive marker of ards, and found that both elevated leukocyte count and elevated ldh predict mortality. treatment with the anti-retroviral drug lopinavir-ritonavir was not associated with significant benefit, while corticosteroids were associated with possible harm. early recognition of severe infection may allow early intervention with supportive measures and therapeutics and improve outcomes [ ] . our meta-regression identified five significant markers of icu admission: raised leukocyte count, raised alt and ast, in addition to elevated ldh and finally increased procalcitonin. while . % of patients had a raised leukocyte count in our meta-analysis, the degree of leukocytosis was modest (pooled mean leukocyte count was . x /l). raised alt and ast in severe covid- disease may be a result of liver damage caused by the direct binding of sars-cov- to angiotensinconverting enzyme positive cholangiocytes [ ] . in our analysis, ldh was the only marker that significantly predicted all three measured outcomes: icu admission, ards and mortality. ldh is released from cells upon damage to their cytoplasmic membrane, and is not only a metabolic but also an immune surveillance prognostic biomarker [ , ] . ldh increases the production of lactate, which leads to enhancement of immune-suppressive cells and inhibition of cytolytic cells [ ] . these changes could weaken the immune response mounted against the viral infection, resulting in more severe disease in patients with elevated ldh. increased procalcitonin may have been a marker of bacterial co-infection, thereby resulting in complications of covid- disease and hence a higher rate of icu admission in these patients [ ] . interestingly, lymphopenia was not found to be a significant predictor of icu admission, mortality and ards in our meta-analysis. a possible explanation may be that we analyzed lymphopenia as a dichotomous variable without taking into account a c c e p t e d m a n u s c r i p t the degree of lymphopenia i.e. the numerical value of lymphocyte count, which lies on a spectrum and could affect disease severity among patients with lymphopenia. the results of randomized clinical trials of covid- interventions are of critical importance as only weak evidence supports the currently available repurposed and novel antivirals [ ] . among the patients with antiviral use reported in our meta-analysis, overall rates of mortality, icu admission and ards were . %, . % and . %, respectively. we found no overall benefit from treatment with lopinavir-ritonavir, in line with a recent randomized controlled trial however, this trial demonstrated that lopinavir-ritonavir treatment granted a significant reduction in icu length of stay in survivors. further trials (nct and nct ) are in progress to assess the efficacy of both lopinavir and ritonavir in reducing the covid- viral load, and we look forward to future developments to provide recommendations on the use of antiviral therapy [ , ] . severe covid- is associated with a dysregulated host inflammatory response, suggesting immune modulators as an attractive treatment modality [ ] . corticosteroids were used during the sars-cov outbreak, however, in a meta-analysis only four studies provided conclusive data, and all four indicated possible harm [ , ] . these harms included risks of prolonged viremia, corticosteroid-induced diabetes, avascular necrosis and psychosis [ , , ] . our meta-analysis suggested that the use of corticosteroids is associated with disease severity (icu admission) and higher ards rates. it is not clear if this effect is a consequence of corticosteroid treatment, or confounding by indication bias where sicker patients are more likely to receive corticosteroids. an rct of corticosteroids in severe respiratory viral infections has long been called for, and at least one clinical trial in covid- (nct ) is ongoing [ ] . a c c e p t e d m a n u s c r i p t sars-cov- -induced pneumonia is marked by a cytokine stormhyperactivation of effector t cells and excessive production of inflammatory cytokines, particularly interleukin- (il- ) [ ] . blockade of il- function using tocilizumab, a specific monoclonal antibody against its receptor appears to be useful in alleviating hyperinflammation symptoms in severe cases [ , ] . selective janus kinase-signal transducer and activator of transcription (jak-stat) inhibitors such as baricitinib may also be beneficial, though clinical trials are required and any benefit is likely to be greatest in combination with an effective antiviral [ ] . to the best of our knowledge, this is the first systematic review and meta-analysis of covid- to describe specific laboratory predictors of severe disease and adverse outcomes. our study is also the first meta-analysis to evaluate the efficacy of antivirals and corticosteroids. careful attention should be given to the management of patients with raised leukocyte count, raised alt and ast, elevated ldh, increased procalcitonin and raised leukocyte count as these factors predict icu admission, mortality and ards. in terms of treatment efficacy, the use of corticosteroids in covid- patients is significantly associated with higher rates of ards. compared to other antivirals, the use of lopinavir and ritonavir is non-superior in terms of lowering mortality rate. further prospective studies are vital to clarify our findings. a c c e p t e d m a n u s c r i p t no funding was used for the production of this work. all authors have no potential conflicts of interest to disclose. m a n u s c r i p t a c c e p t e d m a n u s c r i p t figure sw epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical features of patients infected with novel coronavirus in wuhan prevalence of comorbidities in the novel wuhan coronavirus (covid- ) infection: a systematic review and metaanalysis preferred reporting items for systematic reviews and meta-analyses: the prisma statement a coefficient of agreement for nominal scales extracorporeal membrane oxygenation in pregnant and postpartum women with h n -related acute respiratory distress syndrome: a systematic review and meta-analysis extracorporeal membrane oxygenation in pregnant and postpartum women: a systematic review and meta-regression analysis excluding small studies from a systematic review or metaanalysis the methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review a basic introduction to fixed-effect and random-effects models for meta-analysis metaprop: a stata command to perform metaanalysis of binomial data cochrane handbook for systematic reviews of interventions version . . . the cochrane collaboration estimating the mean and variance from the median, range, and the size of a sample estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials bias in meta-analysis detected by a simple, graphical test grade: an emerging consensus on rating quality of evidence and strength of recommendations how to perform a meta-analysis with r: a practical tutorial clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study specific ace expression in cholangiocytes may cause liver damage after -ncov infection lactate dehydrogenase, a risk factor of severe clinical characteristics and prognosis of community-acquired pneumonia in autoimmune disease-induced immunocompromised host: a retrospective observational study elevated lactate dehydrogenase (ldh) can be a marker of immune suppression in cancer: interplay between hematologic and solid neoplastic clones and their microenvironments. cancer biomarkers : section a of disease markers procalcitonin in patients with severe coronavirus disease (covid- ): a meta-analysis pharmacologic treatments for coronavirus disease (covid- ): a review a trial of lopinavir-ritonavir in adults hospitalized with severe covid- the efficacy of lopinavir plus ritonavir and arbidol against novel coronavirus infection (elacoi) comparison of lopinavir/ritonavir or hydroxychloroquine in patients with mild coronavirus disease (covid- ) the trinity of covid- : immunity, inflammation and intervention sars: systematic review of treatment effects corticosteroid therapy for critically ill patients with middle east respiratory syndrome factors associated with psychosis among patients with severe acute respiratory syndrome: a case-control study effects of early corticosteroid treatment on plasma sars-associated coronavirus rna concentrations in adult patients glucocorticoid therapy for novel coronaviruscritically ill patients with severe acute respiratory failure (steroids-sari) clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china covid- : consider cytokine storm syndromes and immunosuppression tocilizumab treatment in covid- : a single center experience covid- : combining antiviral and antiinflammatory treatments a c c e p t e d m a n u s c r i p t a c c e p t e d m a n u s c r i p t a c c e p t e d m a n u s c r i p t key: cord- -w aa elj authors: tonetti, tommaso; grasselli, giacomo; zanella, alberto; pizzilli, giacinto; fumagalli, roberto; piva, simone; lorini, luca; iotti, giorgio; foti, giuseppe; colombo, sergio; vivona, luigi; rossi, sandra; girardis, massimo; agnoletti, vanni; campagna, anselmo; gordini, giovanni; navalesi, paolo; boscolo, annalisa; graziano, alessandro; valeri, ilaria; vianello, andrea; cereda, danilo; filippini, claudia; cecconi, maurizio; locatelli, franco; bartoletti, michele; giannella, maddalena; viale, pierluigi; antonelli, massimo; nava, stefano; pesenti, antonio; ranieri, v. marco title: use of critical care resources during the first weeks (february –march , ) of the covid- outbreak in italy date: - - journal: ann intensive care doi: . /s - - -z sha: doc_id: cord_uid: w aa elj background: a covid- outbreak developed in lombardy, veneto and emilia-romagna (italy) at the end of february . fear of an imminent saturation of available icu beds generated the notion that rationing of intensive care resources could have been necessary. results: in order to evaluate the impact of covid- on the icu capacity to manage critically ill patients, we performed a retrospective analysis of the first weeks of the outbreak (february –march ). data were collected from regional registries and from a case report form sent to participating sites. icu beds increased from to ( . %), and patients receiving respiratory support outside the icu increased from ( . %) to ( . %). patients receiving respiratory support outside the icu were significantly older [ vs. years], had more cerebrovascular ( . vs. . %) and renal ( . vs. . %) comorbidities and less obesity ( . vs. . %) than patients admitted to the icu. pao( )/fio( ) ratio, respiratory rate and arterial ph were higher [ vs. ; vs. breath/min; . vs. . ] and paco( ) and base excess were lower [ vs. mmhg; . vs. . ] in patients receiving respiratory support outside the icu than in patients admitted to the icu, respectively. conclusions: increase in icu beds and use of out-of-icu respiratory support allowed effective management of the first days of the covid- outbreak, avoiding resource rationing. data regarding the impact of covid- outbreak on the capacity of the health-care system to accomplish the need for icu care are limited. the estimated need for intensive care unit (icu) admission is variable, ranging between . [ ] , . [ ] and . % [ ] . reported icu mortality ranges between [ ] , [ ] [ ] , and % [ ] . this extreme variability has been attributed to differences in terms of beds availability, staff and organization of intensive care units [ ] . on thursday, th february , the first cases of positivity for sars-cov- were recorded in lombardy region, northern italy. since then, the number of patients with corona virus and acute hypoxemic respiratory failure in three regions of northern italy (lombardy, veneto and emilia-romagna) dramatically increased, subsequently leading to the call of a national emergency status [ ] . a mathematical model of the occupation of intensive care resources in italy predicted the saturation of the theoretical availability of beds on the national territory by mid-april [ ] . in order to respond to such predicted growing need for icu resources, on march st the italian government published a notice, ordering to increase the number of icu beds (https ://www.salut e.gov.it/porta le/homem obile .jsp) and approved a law decree that allocated million euros to the public health service to bring the number of icu beds for invasive mechanical ventilation to the % of the total hospital beds (https :// www.gazze ttauf ficia le.it/eli/id/ / / / g / sg). since the spread of the sars-cov- virus is growing and critical care resources of public health systems are dramatically challenged [ ] , we reasoned that a better understanding of clinical management and icu requirements for patients with severe covid- at the very beginning of the outbreak may support resources planning and may help to set effective organizational and clinical interventions for the most seriously affected patients. the objective of the study was therefore to ( ) describe the process of expansion of the icu capacity in response to the covid- outbreak during the first weeks of the pandemics; ( ) describe settings and modalities of care of acutely ill covid- patients; ( ) compare outcomes between critically ill patients with covid- receiving care in or outside the icu. we retrospectively studied consecutive critically ill patients with confirmed covid- who were referred to the hospitals of the lombardy, veneto and emilia-romagna regions during the first weeks of the italian outbreak (february - march , ) . a confirmed case of covid- was defined as a patient with a positive result on high-throughput sequencing or real-time reverse transcriptase-polymerase chain reaction assay of nasal and pharyngeal swab specimens [ ] . in total, hospitals ( in lombardy, in emilia-romagna and in veneto) participated in the study. institutional review boards reviewed the protocol and authorized data collection. data on icu beds expansion and on total hospital and icu admissions were gathered from registries of the regional icus coordinators of lombardy (ap), veneto (pn) and emilia-romagna (vmr) [ ] . moreover, a data collection form was circulated among participating icus and de-identified data on patients admitted in the icu and receiving respiratory support outside the icu were recorded h after admission. in particular, demographics, comorbidities and basic physiological data were collected. in the initial days of the epidemics in northern italy, icu beds and personnel were made available by closing elective surgical admissions and centralizing to a limited number of single non-covid- hub hospitals all neuro-and cardiac-surgical admissions. moreover, ordinary availability of icu beds in the three regions was increased from to ( . %); in particular, icu capacity increased by . % (from to ), . % (from to ) and . % (from to ) in lombardy, emilia-romagna and veneto, respectively. this was achieved by converting operating rooms, coronary units, step-down units and recovery rooms to fully equipped covid- icus. furthermore, the use of outof-icu respiratory support in the form of cpap or niv [ ] [ ] [ ] was extended to many different wards, although initial reports suggested caution in the use of non-invasive respiratory support in covid- patients due to the risk of transmission of infection [ ] . all patients included in the study underwent evaluation by a senior intensivist, who decided according to her/ his clinical judgment and to local protocols whether to treat the patient in a ward under supervision of the icu team or to admit the patient to the icu. the criteria for icu admission were: (a) failure of noninvasive respiratory support, defined as persistent hypoxemia, tachypnea and respiratory distress or development of hypercapnia despite the application of cpap/niv; (b) expected imminent need for invasive mechanical ventilation; (c) absence of a do-not-intubate order, as discussed collegially by the intensivist and the ward staff physicians caring for the patient. at all sites out-of-icu respiratory support was provided by care teams that included at least (i) a senior clinical staff with certified experience in intensive care medicine available around the clock; (ii) nurse support provided with a nurse/patients ratio ranging from : to : ; (iii) continuous monitoring of electrocardiogram trace, non-invasive blood pressure, oxygen saturation, and respiratory rate. conventional oxygen therapy was referred as applied through venturi or no-rebreathing masks. helmets were the interface systematically used to deliver cpap. niv was equally delivered through mask and helmets. highflow oxygen therapy was adopted in some units as an alternative to cpap. classification into oxygen therapy and non-invasive respiratory support followed the rule of the highest degree of support; accordingly, a patient receiving oxygen therapy at first and then escalating to non-invasive support was classified as receiving non-invasive support. continuous variables were expressed as medians and interquartile ranges (iqr). categorical variables were summarized as counts and percentages. no imputation was made for missing data. statistical analyses were descriptive. comparisons between groups were made using wilcoxon rank-sum and pearson's chi-square. all tests were -tailed and were considered significant if p < . . twenty-eight-day mortality of patients admitted in the icu through the period february -march , and of patients receiving respiratory support outside the icu through the same period was evaluated using the method of kaplan-meier. cumulative incidence of patients extubated and disconnected from mechanical ventilation was calculated and death was considered a competing event. patients were followed up until april th. all the analyses were performed with the use of sas software, version . (sas institute inc., cary, nc). in the period february th-march th, registries of the coordinating centers of lombardy, emilia-romagna and veneto showed that a total of patients were hospitalized for covid- and a total of were admitted and treated in the icu ( . %). data collection forms collected from the participating centers provided information on patients treated in the icu and on patients who received respiratory support outside the icu ( patients in total). notably, the number of patients receiving respiratory support outside the icu increased from ( . %) on february to ( . %) on march (fig. , top) , and the proportion of patients admitted to the icu declined from the . % of hospitalized covid- patients on february to the . % of hospitalized covid- patients on march (fig. , bottom) . compared to patients admitted to the icu, patients receiving respiratory support outside the icu were significantly older, had more cerebrovascular and renal comorbidities and fewer of them were obese. the attending intensivists deemed patients ( . % of the patients treated outside the icu) as non-eligible for further escalation of respiratory support (i.e., for invasive mechanical ventilation). in patients treated outside the icu, conventional o therapy was applied in the . % of the cases and non-invasive respiratory support (including niv, cpap and high-flow o therapy) in the . %, while . % of icu patients were intubated. pao /fio ratio, respiratory rate and arterial ph were higher and paco and base excess were lower in patients receiving respiratory support outside the icu than in patients admitted to the icu. (table ). the infectious disease and the pneumology wards were the most more common locations where out-of-icu respiratory support was delivered ( . % and . %, respectively) ( table ). patients receiving conventional o therapy outside the icu had less cerebrovascular comorbidities and obesity and had significantly higher values of pao /fio and arterial ph than patients receiving noninvasive ventilatory support outside the icu (including niv, cpap and high-flow o therapy). mortality did not differ between patients receiving conventional o therapy and non-invasive respiratory support ( . % vs. . %, respectively; table ). analysis of -day mortality showed a proportion of deaths of . % ( out of ) in patients treated in the icu and of . % ( out of ), in patients receiving respiratory support outside the icu (p = . ). nonsurvivors treated in the icu died within ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) days while in non-survivors receiving respiratory support outside the icu death occurred within ( - ) days. fortyfour patients in the icu group ( . %) and patients ( . %) in the out-of-icu group were still hospitalized through april th (last day of follow-up). the present study describes how the italian health-care system of three northern italian regions responded to the increasing need for clinical resources for critically ill patients during the first days of the covid- outbreak through the . % increase in icu beds and the increasing use of non-invasive respiratory support outside the icu. data to evaluate the impact of covid- outbreak on the capacity of the health-care system to accomplish the need for icu resources are limited. xie and coworkers reported that in wuhan as of feb , , there were about patients requiring ventilatory support with new patients every day. however, since only icu beds were available, three general hospitals were rapidly converted to critical care hospitals with a total of about beds dedicated to covid- critically ill patients [ ] . griffin and coworkers described the process to implement an icu surge capacity at the greater new york presbyterian system. in their experience, new covid- icus had to be rapidly assembled after the first weeks from the admission of the first critically ill covid- patients [ ] . concomitantly to the increase in icu bed capacity, there was a progressive increase in the number of patients who received respiratory support outside the icu (from . to . %) under the daily supervision of an intensivist. this allowed to reduce the percentage of patients admitted to the icu from . % on february th to . % on march th. the response between the italian and the greater new york presbyterian systems was similar, despite the different icu capacity ( . % of the total hospital beds in the usa [ ] vs. . % in italy (https ://www.salut e.gov.it/imgs/c_ _pubbl icazi oni_ _alleg ato.pdf ). this might be explained by the extensive use of out-of-icu respiratory support we adopted in italy [ ] [ ] [ ] . our data show that, compared to patients admitted to the icu, patients receiving respiratory support outside the icu were significantly older, had more comorbidities and had a higher pao /fio ratio and a lower paco . among patients treated outside the icu, proportions of patients treated with conventional o therapy and noninvasive respiratory support were comparable ( . vs. . %, respectively). the median age of our icu population [ years ( - )] is consistent with the one reported at national level in pre-pandemic times [ ] and, although it is difficult to draw conclusion from these data, it is probable that the same age criteria were adopted during the first weeks of the covid- epidemics in northern italy. patients receiving conventional o therapy outside the icu showed a pao /fio ratio higher than those receiving non-invasive support outside the icu, without differences in age and mortality. although a crude comparison of mortality is not very informative because of the baseline differences between the icu and outof-icu populations, we show here that the difference in survival at days in patients treated in the icu and those receiving respiratory support outside the icu was small ( . vs. . %, respectively). altogether these data seem to suggest that treatment outside the icu has been offered as a therapeutic setting proportional to patient's conditions and not as a 'limited' standard of care, always remaining within the ethical perimeter of standard clinical practice [ , ] . nevertheless, is unlikely that all eligible patients were transferred to an icu, and we cannot exclude that at least some patients who matched criteria for icu admission did not survive long enough to be transferred to icu or comorbid disease or goals of care precluded escalation to icu level care. non-invasive ventilation was suggested to be avoided in covid- patients due to the risk of transmission of infection [ ] . in our hospitals, the risk might have been reduced for the following reasons: (a) helmets equipped with high-efficiency particulate air filters at the peep port were the interface of choice for delivering non-invasive respiratory support in almost / of patients treated outside the icu; this interface might have avoided the dispersion of the multiphase turbulent gas cloud from coughing and sneezing on part of the patients, possibly reducing the transmission of covid- [ ] ; (b) about % of the patients receiving respiratory support outside the icu were treated in infectious disease wards that are commonly equipped with negative pressure rooms [ ] . moreover, there is growing evidence that niv can be safely performed outside the icu in covid- patients, and even advanced maneuvers such as prone positioning have been successfully tested in these patients [ ] . these data have may important implications for the reorganization required by health-care systems necessary to manage the covid- outbreak. the italian society of anesthesia, analgesia, resuscitation, and intensive care (siaarti) recommended an approach for resource allocation based on "clinical appropriateness" and "distributive justice" in case of significant mismatch between the number of patients requiring icu admission and the available resources and acknowledged that: "it is not about making choices on value, but to reserve possibly scarce resources first to who has higher probability of survival and second to who can have higher saved years of life, with the purpose of maximizing benefits for the highest possible number of people" [ ] . our data show that increasing the icu capacity by . % obtained through the reorganization of available facilities (conversion of operating rooms, coronary units, closure of all scheduled surgical activity) and use of out-of-icu respiratory support [ ] [ ] [ ] , the healthcare system was able to accomplish the clinical needs for respiratory support in covid- patients and may suggest that end-of-life practices might have remained within the ethical perimeter of standard clinical practice [ , ] . the retrospective nature represents the major weakness of this study. although data have been collected by personnel with experience in clinical research and strongly motivated to share their experience, the enormous clinical load and the risk of contagion have certainly influenced the quality of the data and limited the number of information that has been possible to collect. moreover, further analysis is needed to provide information regarding use of resources, allocation of beds, staffing choices, timing of opening up of new beds, and what resources were most stretched in the first weeks. moreover, the expected heterogeneity in hospital capacity and care practices between study hospitals may limit the practical utility of the description for clinicians facing an imminent surge of patients with covid- disease. despite these limitations, this study represents the first and most detailed description of the clinical reality of the first western country overwhelmed by the covid- epidemic. in conclusion, although our analysis confirms the grave concerns regarding the capacity of health-care systems to effectively respond to the covid- outbreak, these data show that the rapid increase in beds obtained through the reversal of already available resources into intensive care facilities and the use of out-of-icu respiratory support allowed to manage the first terrible days of the covid- outbreak. the present analysis shows that only rapid acquisition of new intensive care facilities with appropriate equipment and personnel and use of out-of-icu respiratory support [ ] [ ] [ ] may avoid the rationing of health-care resources that may be acceptable for "battlefield medicine", but should be incompatible with health-care systems founded on the principles of universality, solidarity and distributive justice (article of the constitution of the italian republic and law number december rd, ). manerbio (italy), benvenuto.antonini@asst-garda.it; nicolangela belgiorno, istituto clinico san rocco ), massimo_borelli@asst-bgovest.it; luca cabrini, ospedale di circolo e fondazione macchi, varese (italy), luca.cabrini@uninsubria.it; livio carnevale busto arsizio (italy), daniel.covello@asst-valleolona.it; gianluca de filippi, asst rhodense-presidio ospedaliero g milan (italy), deipolimd@gmail.com; paolo dughi, asst franciacorta -presidio ospedaliero di iseo vimercate (italy), giorgio.gallioli@asst-vimercate.it; paolo gnesin saronno (italy), stefano.greco@asst-valleolona.it; luca guatteri, ospedale "sacra famiglia" fatebenefratelli seriate (italy), roberto.keim@asst-bergamoest.it; giovanni landoni melegnano (italy), giovanni.marino@asst-melegnanomartesana.it; guido merli, asst crema-ospedale maggiore di crema, crema (italy), guido.merli@asst-crema.it; dario merlo fondazione poliambulanza istituto ospedaliero, brescia (italy), giuseppe.natalini@gmail. com; nicola petrucci, asst garda-ospedale di desenzano d/g, desenzano del garda (italy), nicola.petrucci@asst-garda legnano (italy), danilo.radrizzani@asst-ovestmi.it; maurizio raimondi, asst pavia-ospedale civile di voghera ), enrico.storti@asst-lodi.it; mario tavola zingonia (italy), giovanni.vitale@ grupposandonato.it mirano (italy), mauroantonio.calo@aulss .veneto.it; vinicio danzi, u.o.c anestesia e rianimazione ospedale cà foncello, treviso (italy), antonio.farnia@aulss .veneto.it; francesco lazzari, u.o.c. anestesia e rianimazione, ospedale dell azienda zero del veneto, padova (italy), mario.saia@azero.veneto.it; nicolò sella, u.o.c. istituto di anestesia e rianimazione, azienda ospedale università padova, nico.sella@hotmail.it; eugenio serra, u.o.c. istituto di anestesia e rianimazione, azienda ospedale università di padova, padova, eugenio.serra@ aopd.veneto.it; ivo tiberio, u.o.c. anestesia e rianimazione, azienda ospedale università padova, ivo.tiberio@aulss .veneto.it (italy), martina.bordini @studio.unibo.it; fabio caramelli, policlinico sant'orsola malpighi (italy), guido.frascaroli@aosp.bo.it; maurizio fusari, ospedale "santa maria delle croci (italy), costanza.martino@auslromagna.it; raffaele merola, policlinico sant'orsola-malpighi (italy), mrofrc@ unife.it; giuseppe nardi, ospedale "infermi rimini (italy), antonella.potalivo@auslromagna.it; francesca repetti, ausl piacenza, piacenza (italy), francesca.repetti@hotmail.it; pierpaolo salsi, azienda ospedaliera santa maria nuova, reggio emilia (italy), salsi.pierpaolo@ausl.re.it; marina terzitta modena (italy), tosimartina@gmail.com; sergio venturi, emergency commissioner for emilia-romagna region, sergio arcispedale sant' anna clinical characteristics of coronavirus disease , in china clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a singlecentered, retrospective, observational study clinical characteristics of hospitalized patients with, novel coronavirus-infected pneumonia in wuhan china baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region italy characteristics and outcomes of critically ill patients with covid- in washington state critical care crisis and some recommendations during the covid- epidemic in china critical care utilization for the covid- outbreak in lombardy, italy: early experience and forecast during an emergency response covid- and italy: what next? lancet facing covid- in italy-ethics, logistics, and therapeutics on the epidemic's front line clinical features of patients infected with novel coronavirus in wuhan china early cpap prevents evolution of acute lung injury in patients with hematologic malignancy introducing critical care outreach: a ward-randomised trial of phased introduction in a general hospital effect of the critical care outreach team on patient survival to discharge from hospital and readmission to critical care: non-randomised population based study aerosol and surface stability of sars-cov- as compared with sars-cov- hospital preparedness for covid- : a practical guide from a critical care perspective critical care bed growth in the united states: a comparison of regional and national trends the influence of gender on the epidemiology of and outcome from severe sepsis changes in end-of-life practices in european intensive care units from to withholding or withdrawing of life-sustaining therapy in older adults (>/= years) admitted to the intensive care unit turbulent gas clouds and respiratory pathogen emissions: potential implications for reducing transmission of covid- protecting healthcare workers from sars-cov- infection: practical indications respiratory parameters in patients with covid- after using noninvasive ventilation in the prone position outside the intensive care unit it/sitea ssets /news/covid % -% d ocume nti% s iaart i/siaar ti% -% c ovid- % -% c linic al% e thics % r eccom endat ions members of the covid- northern italian icu network: lombardy: giovanni albano, humanitas gavazzeni, bergamo (italy), giovanni.albano@gavazzeni.it; armando alborghetti, policlinico san pietro-ponte san pietro (italy), armando.alborghetti@grupposandonato.it; giorgio aldegheri, irccs tt, gg, az, pn, mc, fl, pv, ma, sn were responsible for study design, data acquisition, analysis, interpretation, and preparing the first draft of the manuscript. gp, rf, sp, ll, gi, gf, sc, lv, sr, mg, va, ac, gg, ab, ag, av, iv, dc, cf, mb mg, were responsible for data acquisition and data interpretation. ap and vmr were responsible for study design, data acquisition, analysis, interpretation, finalize the manuscript and study data integrity. all authors had an opportunity to review the manuscript and approved its final submitted version. no funding was provided. the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. the study was approved by the coordinating center's irb (comitato etico avec, bologna, italy) with approval number / /oss/aoubo; participant centers obtained approval from their respective irbs; consent to participate was waived for unresponsive, uncommunicative or deceased patients, in accordance to rule / of the italian privacy authority. key: cord- -j sqs q authors: koetsier, antonie; van asten, liselotte; dijkstra, frederika; van der hoek, wim; snijders, bianca e.; van den wijngaard, cees c.; boshuizen, hendriek c.; donker, gé a.; de lange, dylan w.; de keizer, nicolette f.; peek, niels title: do intensive care data on respiratory infections reflect influenza epidemics? date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: j sqs q objectives: severe influenza can lead to intensive care unit (icu) admission. we explored whether icu data reflect influenza like illness (ili) activity in the general population, and whether icu respiratory infections can predict influenza epidemics. methods: we calculated the time lag and correlation between ili incidence (from ili sentinel surveillance, based on general practitioners (gp) consultations) and percentages of icu admissions with a respiratory infection (from the dutch national intensive care registry) over the years – . in addition, icu data of the first three years was used to build three regression models to predict the start and end of influenza epidemics in the years thereafter, one to three weeks ahead. the predicted start and end of influenza epidemics were compared with observed start and end of such epidemics according to the incidence of ili. results: peaks in respiratory icu admissions lasted longer than peaks in ili incidence rates. increases in icu admissions occurred on average two days earlier compared to ili. predicting influenza epidemics one, two, or three weeks ahead yielded positive predictive values ranging from . to . , and sensitivities from . to . . conclusions: icu data was associated with ili activity, with increases in icu data often occurring earlier and for a longer time period. however, in the netherlands, predicting influenza epidemics in the general population using icu data was imprecise, with low positive predictive values and sensitivities. a limitation of current influenza surveillance systems is that timely information on severe influenza illness requiring hospital admission is not available. influenza surveillance in most countries is based upon sentinel general practitioners (gp) networks and the collected information on influenza like illness (ili) is dependent on the health care seeking behavior of the general population, which can fluctuate with for example media attention. the implementation of a hospital based surveillance system for severe acute respiratory infection (sari) is now promoted by the world health organization (who) and european centre for disease prevention and control (ecdc) as a public health priority worldwide, both for routine surveillance and for preparedness [ , ] , such as in the case of the middle east respiratory syndrome coronavirus (mers-cov). sari surveillance can focus on admissions for respiratory infections in general hospital wards or in intensive care units (icu) . during the pandemic period, hospitalization for laboratory confirmed influenza a(h n )pdm infection was notifiable in the netherlands. in the season / as well as in the season / , ili incidence as measured by gp sentinel practices, reached the epidemic threshold of . consultations per . enlisted patients at a time when already more than patients had been hospitalized, with several icu admissions and deaths from laboratory confirmed influenza (national institute for public health and the environment, unpublished surveillance data). hospital admission for influenza is not notifiable anymore and in the netherlands sari cases are not routinely collected. an alternative source of information could be the dutch national intensive care evaluation registry (nice) [ ], wherein diagnostic, and physiologic information from the first hours of adult icu admissions, as well as length of stay and in-hospital mortality of all icu patients are registered. patients are admitted to the icu if they have a high severity of illness, and require constant monitoring of their vital functions, regardless of their expected outcome. respiratory infections, such as pneumonia, are among the most common conditions for which patients are admitted to the icu. in the early onset of an influenza epidemic, patients with multiple comorbidities are more likely to develop more severe influenza related diseases like pneumonia. they possibly get submitted to the icu before there is an epidemic in the general population [ ] . therefore, increases in the number of admissions at the icu with a respiratory infection can possibly occur before a detectable increase in ili incidence in the gp sentinel network. in this study we explore whether icu data on respiratory infections reflect ili activity in the general population, and which relevant time lag exists between both data sources. additionally we assessed whether icu data can predict ili defined influenza epidemics (further referred to as influenza epidemics). in the netherlands, patients that consult the gps with symptoms of ili are reported on a weekly basis to the continuous morbidity registration sentinel general practice network (further referred to as sentinel gp registry), covering . % of the dutch population being nationally representative by age, gender, regional distribution, and population density [ ] . the sentinel gp data consists of the weekly number of patients presenting with ili at the gp. in , the registry had participating gp practices with gps covering a population of approximately , patients [ ] . ili was defined according to the criteria of pel [ ] , by ( ) acute onset, with prodromal stadium of three to four days, ( ) a temperature increase to at least degrees celsius, and ( ) at least one of the following symptoms: cough, nasal congestion, raw throat, frontal headache, retrosternal pain, and body aches. incidence of ili is calculated on a weekly basis, using number of patients registered at the reporting gp practices as the denominator. this is acceptable as almost every person in the netherlands is registered with a gp. in the netherlands, an influenza epidemic is defined as more than . patients with ili per , inhabitants per week consulting the gp for at least two consecutive weeks [ ] , combined with influenza a virus isolation from laboratory samples. data quality is assured by training of gps for data entry, and a pop-up appearing in the system when an ili diagnosis is entered reminding the gp to register the ili case in the sentinel gp registry. the nice registry was founded in , with initially six participating icus. in this number had grown to and in icus participated covering approximately % of the dutch adult icus. for each admission, among other items, the acute physiology and chronic health evaluation ii (apache ii) [ ] reason for icu admission diagnosis is registered and sent to the nice registry on a monthly basis. upon receipt, the data is usually entered into the nice registry database and available for participants within one day. there is currently no distinct variable describing whether an icu patient has influenza like illness or was diagnosed with an influenza virus infection, or receives antiviral drugs. therefore, we defined an icu admission with a possible sari (further referred to as icu admission with respiratory infection) when the following four criteria were met: ( ) the patient was admitted to the hospital less than two days before icu admission, ( ) there was a medical (non-surgical) reason for admittance, ( ) the icu admission was not a readmission to the icu within the hospitalized period, and ( ) the apache ii reason for admission was 'respiratory infection. we used the percentage of icu admissions with a respiratory infection (relative to the total number of medical icu admissions), instead of the absolute number of icu admissions to adjust for the growing number of nice registry participants throughout the study period. thus our study dataset included study year, week number, number of patients with ili, population size of reporting gps, number of icu admissions with respiratory infection, and number of medical icu admissions. data quality is assured by regular on site visits of the icus [ ] . in this study, we used weekly time series of patients presenting with ili from the sentinel gp registry and icu admissions of respiratory nature from the nice registry. in the nice registry, few icus were participating in the years until , leading to large variations in the percentage of icu admissions with respiratory infections. therefore, from both registries, we used data from through . as influenza generally occurs between week and week of the subsequent year [ ] , we defined an influenza year (i.e. season) from july st until june th the next year, thereby having ten influenza years in our dataset. to explore the association between the weekly incidence of ili patients and the percentage of icu admissions with a respiratory infection, we plotted per week the percentage of icu admissions with a respiratory infection and the incidence of ili over the period january , , through december , . in addition, we performed a generalized estimating equations (gee) [ ] additive poisson regression analysis [ ] using an autoregressive working correlation matrix over this time period. the dependent variable was weekly incidence of patients with ili, and the independent variables were chronological week number, percentage of icu admissions with respiratory infection in the current week, and one to five weeks before the current week and one to five weeks after the current week, and sine and cosine terms to adjust for seasonality [ ] . the sine term was sin(k pt/t) and the cosine was cos(k pt/t), where k is a constant with values (yearly seasonality) or (half year seasonality), t is current week number, and t is total number of weeks in the specific influenza year, e.g. weeks (years and had weeks, and the cases were added to week ). we adjusted for autocorrelation in the residuals, where the unit of clustering was influenza year. we calculated the average time lag between the sentinel gp and icu data by computing the weighted average of the time lag in weeks ( , …, , …, + ), using the corresponding regression coefficients as weighting factors. the r-squared (r ) value based on the deviance residuals [ ] was also calculated. to assess the possibility of using icu data for predicting influenza epidemics, we used a subset of three years of training data to develop three gee models with the same characteristics as the aforementioned model, to predict the incidence of ili patients one to three weeks ahead. in each of these models, independent variables were removed by pseudo stepwise selection [ ] , using a fixed scheme for removal. we first considered the time trend (chronological week number) for removal, then seasonal terms, and finally time lagged percentage of icu admissions with respiratory infection. in order for the final models to be useful in surveillance, the following restrictions also applied: ( ) the percentages of icu admissions with respiratory infection one to five weeks after the current week were not included as they are unavailable and useless for prospective surveillance, ( ) the percentage of icu admissions with respiratory infection in the current week cannot be removed from the model, ( ) additional variables of lagged icu admissions should correspond to a range of subsequent weeks (e.g., one and two weeks before the current week, not one and three weeks before the current week), and ( ) a seasonal term is always a combination of a sine and cosine function. we used data of the first three influenza years (january , , , through june , to generate the final model for predicting the incidence of ili one week ahead. to accomplish this, we varied the decay factor l of the full model, giving weeks further back in time exponentially lower weights, from . to . with increments of . , resulting in seven candidate models. variable selection for these seven models was performed with pseudo stepwise selection, with the quasi-likelihood information criterion (qic) [ ] as performance measure. to determine the optimal value of l, -fold cross validation [ ] was performed for the seven candidate models using the same three influenza years that they were built with. the model with the best r value was selected as final model. the above steps were repeated for variable selection of the models predicting ili two and three weeks ahead. using the final models based on the training years of data we started predicting the incidence of ili patients week by week starting from the fourth influenza year in our dataset (july , ) onward. before predicting each successive week, the model parameters were recalculated with an updated dataset that included the data of the previous week to make the model dynamic. we continued updating the model parameters week by week, until all remaining seven influenza years were predicted. from the fourth influenza year onward, the predicted incidence of ili patients was plotted together with the observed incidence of ili patients. we used the same threshold as the ili sentinel surveillance to define an influenza epidemic in the predicted ili numbers (incidence . = . ili patients per , inhabitants for at least two consecutive weeks). we compared the predicted epidemic weeks using icu data with observed epidemic weeks based on ili data. accordingly, we calculated the positive predictive value (ppv), and sensitivity of the predicted epidemic weeks on a weekly basis. for comparison, we also predicted the weekly incidence of ili with models that used only seasonal terms and auto-regressive ili variables, but excluded icu data. these models were also created with pseudo stepwise selection. the resulting ppv and sensitivity were also calculated. the statistical analyses were performed using the statistical package r, version . . (http://www.r-project.org/; vienna, austria). in the period january , , through december , there were a total of , icu admissions, of which , ( . %) had a medical (non-surgical) reason for admittance. of the medical icu admissions, , ( . %) were for a respiratory infection ( table ). the incidence of ili was on average . per , , with a standard deviation of . , and a minimum of . per , and a maximum of . per , . there were nine epidemics, consisting of weeks in total, and an average length of eight weeks. on average, gps supplied data on ili. both the incidence in ili and percentage of icu admissions with a respiratory infection show a similar timing of seasonal peaks (figure ). the amplitude of the yearly peaks in the icu data were relatively lower than ili peaks, and often lasted for a longer time period. increases in the incidence of ili showed a yearly pattern and increased in a smoother pattern compared to icu data. while trends were roughly comparable, they differed in some instances since peaks in icu data occasionally occurred when ili increases were absent in the general population. the association between the different lags of icu admissions and ili incidence is shown in table (assessed using gee additive poisson regression analysis). the r value of the full model was . . of each variable, the contribution to the r of the full model is also shown, which is the r value of the full model minus the r of the model with the corresponding variable omitted. figure also shows the predicted ili incidence (black line) according to the full model. statistically significant time lags were percentage of icu admissions with respiratory infection were one week before, current week, one week after, two weeks after, and four weeks after current ili incidence. the time lags mostly associated with increases in ili incidence one week before and in the current week, with coefficients of . and . . for example, if the percentage of icu admissions with a respiratory infection in the current week increased by one percent, then the incidence of ili in the general population increased by . per , population. according to the contribution to r , also icu admissions one week later was strongly associated with current ili (coefficient of . ). there is no linear time trend present, but seasonality exists in the data reflected by a half year sine function (sine term with k = ) with a p-value of , . and a large contribution to r . looking at figure , a yearly time trend would be expected but is now partly reflected in the different icu time lagged variables. using the coefficients of the time lags in table , the average of the weighted relative week numbers was . weeks implying that the increase in percentage of icu admissions with a respiratory infection was on average . days earlier than the increase in ili incidence. for our second research question, whether icu data can predict ili incidence ahead in time, we generated three gee models predicting the incidence of ili patients one to three weeks ahead using icu data. table shows these three different gee models, and their ppv and sensitivity. predicting two weeks ahead yields the largest sensitivity of . and predicting one week ahead has the largest ppv of . . for comparison, models using only auto-regressive ili variables and seasonal terms, showed the sensitivity to range between . - . and the ppv between . - . . figure shows three figures plotting the predicted incidence of ili patients one to three weeks ahead versus the actually observed ili incidence. the epidemic threshold of . patients (or more) with ili per , population is plotted and the weeks in which an influenza epidemic occurred according to the predicted versus the actual data is shown. predicting one week ahead detected three of the six epidemics, of which two were longer and one shorter according to the icubased predictions. one epidemic was predicted earlier, one at the same time and one later. using icu data to predict two weeks ahead resulted in five of the six epidemics detected, one is missed, and one false epidemic is predicted in the autumn of (which was not present in the ili data). according to the icu data, the predicted epidemics were longer in time except one. besides, most predictions were shifted in time compared to the actual occurrence: two epidemics were predicted earlier and three later. when predicting three weeks ahead all six epidemics were detected, however four were shorter in length, one longer, and one had the same length, again shifted in time: two epidemics were predicted earlier, three later, and one at the same time with icu data. the study showed that the percentage of medical icu admissions for respiratory infection was associated with weekly incidence of ili in the current week, and with one week positive and negative time lag. an increase in the percentage of icu admissions for respiratory infections on average preceded the increase in the incidence of ili (gp data) by . days, implying that before an epidemic the severely ill influenza cases get admitted to the icu. despite this precedence, our analyses showed that with the current models icu data do not accurately predict influenza epidemics in the general population, but including icu data showed an improvement in sensitivity and ppv compared to only including auto-regressive ili variables and seasonal terms. in our study we built three additive poisson gee regression models with icu data to predict the incidence of ili patients, thereby detecting influenza epidemics and aimed at detecting opportunities for enhancing the current national surveillance method. previous studies also aimed at enhancing their current surveillance of influenza epidemics, using laboratory or hospital data. steiner et al. [ ] used an exponentially weighted moving average control chart to enhance and automate influenza epidemic detection. weekly laboratory notifications data of seven years were used instead of the ili data that we studied. the predicted influenza epidemics were compared to retrospective inspection of the same notification data by epidemiologists. the predictions were, just like our study, not the same as their reference data. however in their study there was a maximum of one week difference only, except for one year where there was a difference of eight weeks. a study by closas et al. [ ] used a kolmogorov-smirnov test with virologic laboratory data of five years to detect influenza epidemics. the test provides a binary signal indicating epidemic activity and a quantitative measure of its confidence. they sequentially updated the test as new data became available. the results differed one to nine weeks with the retrospective data of the sentinel network, which is comparable to our results. google flu trends also aimed to detect influenza epidemics, but overestimated peak influenza levels [ ] whilst our study underestimates peak influenza levels. these methods complement the current surveillance networks, but cannot replace them. a study by van den wijngaard et al. [ ] did not aim to predict influenza epidemics, but instead explored whether excesses in influenza severity per season can be detected by combining gp, hospital, laboratory, and mortality data ( years of data). their finding was that combining these data sources is of added value, allowing for better understanding of increases in severe morbidity and mortality due to influenza infections. also from our data we see that trends in icu related sari differ from the trends of ili in the general population and may thus be of value in offering additional information on severity of influenza seasons which need to be explored further. however, both respiratory icu admissions and ili in the general population are not necessarily caused by influenza alone. microbiological laboratory results would provide better insight but to date, these data are not available at the icu patient level. the major strength of our study is that we had access to two large historical datasets from the nice registry and the sentinel gp registry. this allowed us to retrospectively analyze ten influenza years of data, which, to our knowledge, is a longer time period than in comparable studies. a second strength of our study is that we used gee in our additive poisson model, thereby correcting for correlations between weeks. the last strength of our method is that for each additional week we sequentially updated the coefficients of the covariates in the model used for prediction of ili, adding a decay factor giving historic data less weight, and adjusted our models for seasonal changes. with these adjustments, our models always incorporated the most recent information on icu and ili trends. a limitation of the nice registry data is that there is no distinct variable describing whether a patient has an influenza like illness or whether an patients has been diagnosed with an influenza virus infection. furthermore it only contains adult patients thus representing an older population compared to the ili surveillance which also includes children. we extracted admissions with a medical respiratory infection, admitted to the icu within two days after hospital admission, and excluding readmissions. these admissions represent community-acquired respiratory infections and, therefore, included influenza virus infections. additionally, the data of the sentinel gp registry is weekly updated, whereas the nice registry is updated on a monthly basis. this frequency is developed because outcome data, e.g. mortality, is measured at hospital discharge. for sentinel purposes this delay is too long and more frequent updates are needed. however our results can give incentives to set up an additional registry of near real-time surveillance of sari cases at the icu. our statistical analysis also has some limitations. due to the weekly scope of the ili data, we aggregated the icu data on a weekly basis, losing detail as they are available on a daily basis. with regard to our chosen models to predict ili, in the ideal situation stepwise variable selection is combined with -fold cross validation. since automating this process is not possible in gee, we first performed stepwise selection and then -fold cross validation on the seven remaining candidate models. additionally, we used three years of data as training set to determine the best models, whereas a longer period would also have been an option but not necessarily better, since we continuously added data to the baseline data. another limitation is that during the - pandemic, the ili peaks were not detected or later. this means that our models were not sensitive to large or unexpected changes. apparently the association between icu admissions and ili in the general population can change greatly from season to season. icu related sari might occur at a very different rate (compared to symptoms in the general population) during a pandemic or unexpected seasons [ ] . a probable explanation is that the influenza pandemic caused by the a(h n )pmd virus targeted another patient population than the previous epidemics with severe illness in younger patients, and fewer elderly with a severe infection. this could explain why increases in icu admissions during the pandemic were later than usual. additionally, the icu data reflects only sari cases. therefore, we do not know if the icu data reflect an influenza epidemic in the general population or possibly very different influenza dynamics in the icu population alone. icu data on respiratory infections was associated with ili incidence, with highest association in the same week and in the week before and the week after. increases in icu data on average occur two days sooner and for a longer time period than increases in ili. icu data thus contains additional information on icu related sari cases during a specific influenza epidemic. predicting influenza epidemics one, two or three weeks ahead in the general population using icu data was imprecise, reflected by the low ppvs and sensitivities. thus, icu data cannot improve the current surveillance method to detect influenza epidemics. due to the association between both data sources, a next step is to investigate the possibility of using icu data in combination with microbiological laboratory results for surveillance of severity of illness, and icu capacity prediction when an (severe) influenza epidemic is present. the performance of the gee models in predicting the start, end and length of an influenza epidemic is expressed by the positive predictive value (ppv), and sensitivity (n = weeks) based on comparing the signals for an epidemic predicted with intensive care unit (icu) data with the reference standard from the observed influenza like illness data. doi: . /journal.pone. .t surveillance trends of the influenza a(h n ) pandemic in europe responding to new severe diseases-the case for routine hospital surveillance and clinical networks in europe continuous morbidity registration sentinels: netherlands proefonderzoek naar de frequentie en de aetiologie van griepachtige ziekten in de winter - modelling influenza epidemics: can we detect the beginning and predict the intensity and duration? apache ii: a severity of disease classification system defining and improving data quality in medical registries: a literature review, case study, and generic framework comparing pandemic to seasonal influenza mortality: moderate impact overall but high mortality in young children longitudinal data analysis using generalized linear models fitting additive poisson models studying seasonality by using sine and cosine functions in regression analysis r-squared measures for count data regression models with applications to health-care utilization a biometrics invited paper. the analysis and selection of variables in linear regression akaike's information criterion in generalized estimating equations how biased is the apparent error rate of a prediction rule detecting the start of an influenza outbreak using exponentially weighted moving average charts sequential detection of influenza epidemics by the kolmogorov-smirnov test detection of excess influenza severity: associating respiratory hospitalization and mortality data with reports of influenza-like illness by primary care physicians key: cord- -e h tmy authors: lopez, alexandre; duclos, gary; pastene, bruno; bezulier, karine; guilhaumou, romain; solas, caroline; zieleskiewicz, laurent; leone, marc title: effects of hydroxychloroquine on covid- in intensive care unit patients: preliminary results date: - - journal: int j antimicrob agents doi: . /j.ijantimicag. . sha: doc_id: cord_uid: e h tmy during the covid- pandemic, a large number of intensive care unit (icu) patients received hydroxychloroquine. the primary objective of our study was to assess the effects of hydroxychloroquine according to its plasma concentration in icu patients. to this purpose, a single-center retrospective study was performed from march to april in an icu of a university hospital. all patients admitted to our icu with a confirmed covid- pneumonia and treated by hydroxychloroquine were included. we compared patients in whom the hydroxychloroquine plasma concentration was in the therapeutic target (on-target) and patients in whom the plasma concentration was below the target (off-target). the follow-up of patients was days. no association was found between hydroxychloroquine plasma concentration and viral load evolution (p = . ). there was no significant difference between the two groups for the duration of mechanical ventilation, length of icu stay, in-hospital mortality, and -days mortality. this finding suggests that hydroxychloroquine administration for covid- patients hospitalized in icu is not associated with improved outcomes. these results need confirmation by larger multicenter studies. in march , the world health organization announced the severe acute respiratory syndrome coronavirus (sars-cov- ) outbreak [ ] . a large number of patients was admitted to intensive care units (icus) for acute respiratory failure in the context of the covid- [ ] . the usefulness of antiviral and other drugs used in these patients does not rely on strong evidence. hydroxychloroquine, a drug mainly used to prevent and treat malaria [ ] , stops the viral entering inside the cells by inhibiting glycosylation of host receptors, proteolytic process and endosomal acidification, and has immunomodulatory effects by decreasing the cytokine storm [ ] . in vitro, hydroxychloroquine has an antiviral activity for sars-cov- [ ] . gautret et al. reported that hydroxychloroquine and azithromycin was associated with viral load reduction in nasopharyngeal samples in patients after six days of treatment [ ] . however, icu patients were not included in this study. the surviving sepsis campaign guidelines on the management of covid- patients concluded there was insufficient evidence to recommend the use of antiviral drugs and hydroxychloroquine in icu patients [ ] . in addition, the use of two different dosing regimens of this drug did not affect the outcomes of critically ill patients [ ] . our study aimed to determine the effects of hydroxychloroquine in icu patients by measuring plasma concentrations of hydroxychloroquine within the therapeutic target (on-target) and comparing them to patients with concentrations below the therapeutic target (off-target). this single-center, retrospective, observational study was performed in icu at north hospital of marseille from th march to th april . the study was approved by the committee for research ethics of french society of anesthesia & intensive care medicine (cerar no. irb - - ). patients were informed regarding the use of their data. strategies were considered standard care; consent was not required. confirmed covid- patients with acute respiratory failure were included in the study if they completed the criteria: i) age of or older and; ii) polymerase chain reaction (pcr) documented sars-cov- in nasopharyngeal samples upon icu admission. the exclusion criteria were patients with a known allergy to hydroxychloroquine; a contraindication to treatment like retinopathy, glucose- -phosphate dehydrogenase deficiency or qt prolongation; preexisting treatment that might interact with hydroxychloroquine and patients treated by another drug. we identified two groups: i) the patients with hydroxychloroquine plasma concentration above the target concentration range of . μg/ml and a full treatment ("on-target group") between [ ] ; ii) the patients with hydroxychloroquine plasma concentration below the target or treatment discontinuation ("off-target group"). upon icu admission, each patient's demographic, clinical and biological data were collected, and the simplified acute physiology score ii (saps ii) and the sepsis-related organ failure assessment (sofa) score were calculated. the covid- features, the onset of disease, and respiratory and systemic symptoms were reported. the use of catecholamines and the duration of mechanical ventilation were also recorded. all patient underwent an electrocardiogram for the detection of qt prolongation. the virus load was determined from nasopharyngeal swab samples collected every hours. recovery was defined as two consecutive negative nasopharyngeal swab samples [ ] . the follow-up for each patient was days. the treatment consisted of an -mg loading dose of hydroxychloroquine and maintenance dose of mg for days. plasma concentration of hydroxychloroquine was measured every hours; to adjust dose; in the laboratory of pharmacokinetics and toxicology (timone hospital -marseille). analytical method was previously validated according to european medicine agency guidelines and was linear in the . - . μg/ml range [ ] . an additional treatment consisted of a -mg loading dose of azithromycin and -mg maintenance dose and cefotaxime ( g continuous infusion) for days. early treatment discontinuation and side effects were recorded. the first endpoint was the reduction/disappearance of sars-cov- in the patient samples at day . the secondary endpoints were the number of days before obtaining a negative pcr, the length of icu and hospital stays, the length of mechanical ventilation, the use of vasopressor and -days mortality. no statistical samples were performed a priori, and sample size was equal to the number of treated patients during the period. the x², fisher's exact test, t test and mann whitney test were used to compare variables between ontarget and off-target groups, as appropriate. for the viral load, the data were analyzed in order to confirm whether or not our first endpoint was reached at day . statistical significance was defined as p < . . analyses were performed using prism (graphpad software, san diego, ca, usa). from th march to th april , covid- confirmed cases were referred to our icu, of whom patients were excluded ( patients received other antiviral drugs and patient had missing data). finally, patients ( in the ontarget group and in the off-target group) received hydroxychloroquine and azithromycin according to our protocol ( figure a) . upon icu admission, no significant differences in demographic characteristics, severity scores and clinical symptoms were observed between the groups ( table ). the plasma concentrations of hydroxychloroquine in the groups are shown in figure b . hydroxychloroquine was discontinued in % in the off-target group and % of cases in the on-target group (p < . ). side effects, notably cardiac conduction disorders, were reported in ( %) patients in the on-target group and ( %) patients in the offtarget group (p = . ). on day after icu admission, the nasopharyngeal swab pcr results were negative in ( %) patients in the off- table ). the duration of mechanical ventilation and the use of vasopressors were also similar (p = . and p = . , respectively). no statistical difference was found in the -day mortality rate ( ( %) patient in the ontarget group and ( %) patients in the off-target group, p = . ) ( table ). our study compared patients in whom the hydroxychloroquine plasma concentration reached the therapeutic target to those in whom it did not. we showed that the viral load at day , viral clearance and the clinical endpoints did not differ significantly between the groups. the benefits of hydroxychloroquine for covid- patients are still debated. due to potential side effects, its indication should be carefully balanced. in icu patients, the use of antiviral drugs is also discussed. oseltamivir, used to treat or prevent influenza, appears to have no benefits for critically ill patients [ ] . in our study, the mean duration between symptom onset and treatment initiation was seven days, which probably made this treatment ineffective [ ] . in fact, antiviral drugs seem to be effective at the onset of the infection, and their beneficial effects diminish as the disease progresses [ ] . in this study, patients in whom hydroxychloroquine did not reach the therapeutic concentration were used as controls. the pharmacokinetics of hydroxychloroquine has been previously described [ ] . the clinical and viral courses of the disease were similar regardless of the plasma concentration of hydroxychloroquine, suggesting a low probability of efficacy in these patients [ ] . moreover, an -mg bolus dose followed by daily -mg dose did not reach a plasma therapeutic concentration in ( %) patients between days and . furthermore, we noted a significant number of side effects. these side effects may have been related to the patients' medical histories and comorbidities and to interactions with other drugs [ ] . they resulted in a treatment discontinuation in cases and were not associated with plasma concentrations. our study has several limitations. it is a retrospective series with a small sample without a placebo group. we did not clearly consider the effects of azithromycin, which also prolongs qt interval, as an accompanying factor. moreover, although the groups were similar in most demographic and clinical variables, undetermined variables may have resulted in differences between them. the negative results of pcr were meaningful, but the comparison of viral load is controversial because of the limitation of the technical problem to collect samples. finally, we arbitrarily determined that the plasma concentration should reach the therapeutic value between days and , which seems reasonable if an effect is to be expected by day . the choice was based on in vitro data and is debatable [ ] . in conclusion, our results showed that there was no association between the plasma concentration of hydroxychloroquine and the viral and clinical evolution of icu patients admitted for covid- . this finding suggests that the use of this drug at this stage of the disease could be not useful. randomized controlled trials are required to show whether this drug may be useful in icu patients admitted for covid- [ ] . we did not represent patients which were a treatment discontinuation. the viral load (in cycle threshold (ct) of pcr assay) between on-target group and off-target groups (p = . ). who director-general's opening remarks at the media briefing on covid- - critical care utilization for the covid- outbreak in lombardy, italy: early experience and forecast during an emergency response chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases pharmacologic treatments for coronavirus disease (covid- ): a review in vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus (sars-cov- ) hydroxychloroquine and azithromycin as a treatment of covid- : results of an open-label non-randomized clinical trial surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus (sars-cov- ) infection: a randomized clinical trial novel coronavirus (sars-cov- ) -discharge criteria for confirmed covid- cases. european centre for disease prevention and control bioanalytical method validation early oseltamivir after hospital admission is associated with shortened hospitalization: a -year analysis of oseltamivir timing and clinical outcomes severe sars-cov- infections: practical considerations and management strategy for intensivists towards optimization of hydroxychloroquine dosing in intensive care unit covid- patients assessment of qt intervals in a case series of patients with coronavirus disease (covid- ) infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit comparison of hydroxychloroquine, lopinavir/ritonavir, and standard of care in critically ill patients with sars-cov- pneumonia: an opportunistic retrospective analysis the authors thank emmanuelle hammad, md; chatelon jeanne; md and piclet jules, md (department of anesthesiology and intensive care, aphm, marseille) for participating to patient management. key: cord- -bkydu authors: luis silva, l.; dutra, a. c.; iora, p. h.; ramajo, g. l. r.; messias, g. a. f.; gualda, i. a. p.; scheidt, j. f. h. c.; amaral, p. v. m. d.; staton, c.; rocha, t. a. h.; andrade, l.; vissoci, j. r. n. title: brazil health care system preparation against covid- date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: bkydu background: the coronavirus disease outbreak from (covid- ) is associated with a severe acute respiratory syndrome coronavirus (sars-cov- ), a highly contagious virus that claimed thousands of lives around the world and disrupted the health system in many countries. the assessment of emergency capacity in every country is a necessary part of the covid- response efforts. thus, it is extremely recommended to evaluate the health care system to prepare the country to tackle covid- challenges. methods and findings: a retrospective and ecological study was performed with data retrieved from the public national healthcare database (datasus). numbers of intensive care unit and infirmary beds, general or intensivists physicians, nurses, nursing technicians, and ventilators from each regional health unity were extracted, and the beds per health professionals and ventilators per population rates were assessed. the accessibility to health services was also performed using a spatial overlay approach to verify regions that lack assistance. it was found that brazil lacks equity, integrity, and may struggle to assist with high complexity for the covid- patients in many regions of the country. conclusions: brazilian health system is insufficient to tackle the covid- in some regions of the country where the coronavirus may be responsible for high rates of morbidity and mortality. the coronavirus disease is associated with the novel severe acute respiratory syndrome coronavirus- (sars-cov- ) identified in december ( ) . as of may , , covid- has globally infected , , people resulting in , deaths ( ) [report ]. the who declared covid- a public health emergency of international concern (pheic) by the end of january under the international health regulations (ihr) ( ) . few weeks after the pheic declaration, the covid- outbreak was declared to be a pandemic, drawing attention worldwide ( ) . the pandemic led to the adoption of several non-pharmacological interventions ranging from social distancing guidelines to national-level lockdowns by different countries ( ) . these stringent interventions have severely impacted the way of living of many people and disrupted the already precarious health system in many countries ( ) . in response to the covid- pandemic, several countries undertook analyses for the necessary health system strengthening efforts. according to studies dedicated to characterizing the clinical evolution of the disease, % of the cases demand emergency care, with a subset of % needing icu and . % demanding ventilator support to sustain life ( ) . in the u.s., the percentage of patients needing ventilator support was even higher, reaching up to , %. the response effort to tackle the covid- requires a strong organization of the emergency network ( ) . the lack of beds, iniquities in the distribution of hospitals, and inadequate availability of ventilators could hamper the actions aiming to decrease the negative consequences of the covid- ( ) . unfortunately, usually, the distribution of the health resources within the countries are characterized by inequities ( ) . due to the covid- consequences, the scenario faced by low and medium-income countries is even more staggering ( ) . the historic challenges regarding an insufficient number of health professionals, iniquities in the distribution of human resources ( ) , low accessibility to emergency care services ( ) , and economic issues create additional pressures to be addressed, aiming is to achieve an adequate covid- response. as the covid- spreads around the world, the hospital systems lack measures against the virus ( ) , and many countries are experiencing shortages of hospital supplies ( ) . for example, as of march , in italy, where there were , cases of covid- and deaths, , of , beds in intensive care units (icu) are occupied. a few days later, there were no more icu beds available ( ). in the united states of america, it is estimated that the disease will stress bed capacity, equipment, and health care personnel, as never seen before ( ) . the brazilian case is not an exception ( ) . in order to reduce the burden of covid- , the hospital administrators, governments, policy-makers, and researchers must be prepared for a surge in the healthcare system ( ) . brazil is characterized by severe social disparities and health inequities. on may , cases were confirmed and , deaths ( ) (https://covid.saude.gov.br/). however, this number is under-reported, and the real number is estimated to be nine times greater, . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint according to some simulations ( ) . to further the concern, the imperial college estimates that up to million people will fall ill due to covid- in brazil ( ) . during the last decade, brazil is struggling to increase the funding of the public unified system (sus). despite the efforts performed in , the constitution amendment (e.c. acronym in portuguese) reduced the budget of the ministry of health by almost seven billion reais by year ( ) . before the ec , the brazilian health system was already underfunded ( ) . two years after the ec , the consequences regarding the lack of funding were aggravated by the covid- pandemic. additionally, brazil is also facing a political crisis contributing to divergences between the administrative levels in the country. the consequences of all these elements combined could hamper the response actions to tackle the covid- . the availability of information during a crisis is essential to support the decision-making process based on evidence. taking this point into consideration the present work addresses critical aspects regarding the organization of the emergency network system in brazil, jointly with the spatial expansion of covid- cases within the country, and to highlight where the efforts currently performed in brazil were capable of coping with the lack of access to emergency care needed to cope covid- consequences. the present paper is an ecological, observational, and cross-sectional study using a spatial analysis approach. the data sources are based on secondary data from the unified health system (sus) ( ) . to fulfill the defined objective, the adequacy parameters in terms of human resources, health care structure, and accessibility to emergency care services were analyzed in comparison with the reported incidence of covid- . according to data from the brazilian institute of geography and statistics (ibge), brazil is located in south america with a territorial area of . . , km and has a total of , , inhabitants, with human development index (hdi) of . with diversified values for the municipalities ranging from . to . (figure ) ( ). for the assessment of methodological quality, we followed the guideline strengthening the reporting of observational studies in epidemiology (strobe). to characterize the brazilian emergency care services network, three sources were used: national register of health facilities (cnes acronym in portuguese), population data from the ibge, and covid- cases reported by secretariat of surveillance of the ministry of health (https://covid.saude.gov.br/). data regarding hospitals, professionals (nurses, nursing technicians, doctors, and physiotherapists), and equipment (ventilators, icu, and infirmary beds) were obtained from . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint the cnes website using r through the microdatasus package ( ) . the population data and thematic maps were fetched from the ibge ( ). the match between the number of health professionals and the recommended suitability parameters were compared using the guidelines from the national health surveillance agency (anvisa) resolution of the collegiate board of directors (rdc). the anvisa rdc number provides the minimum requirements for the operation of intensive care units, in which ten icu beds are required for each one intensive care physician and one physiotherapist, one intensive care nurse for every eight beds, and two nursing assistants for each bed ( ) the building of thematic maps was carried out by grouping the municipalities by health regions unity (h.r.) using software qgis . . the (h.r.) is a continuous geographic space constituted by a group of bordering municipalities delimited by cultural, economic, and social identities, created by the ministry of health in order to mitigate the disparities in the country ( ) . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . to identify regions with a high incidence of covid- , simultaneously presenting a lack of emergency network was used as a spatial overlay approach. the first step comprised the development of an emergency infrastructure index (eii). the eii was obtained computing the number of beds registered, by the ratio of professionals and equipment according to the last competence of february from cnes. to evaluate the geographical accessibility to emergency care service care was used the two-step floating catchment area ( sfca) technique. with this approach, it was possible to assess the accessibility to emergency care services by the interaction of two geographic characteristics: (a) the volume of available hospital beds weighted by population within hours of travel distance, and (b) the proximity of hospitals within a hours displacement from . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint each municipality ( ) . the sfca method generated two accessibility indexes for each municipality in brazil, one regarding the network available in february , and a secondary one highlighting where the covid- new exclusive beds increased the access to emergency services. both indexes created the conditions to identify regions with a lack of access to emergency care, as well as the regions being benefited by the expansion of the icu beds dedicated to the codvid- response. to highlight regions with a high incidence of covid- and a lack of emergency structure, an overlap analysis was conducted to select the municipalities concurrently, showing a pattern of high incidence, jointly with a lack of access to emergency services. once the eii was computed, and the municipalities with high incidence within regions with low access to emergency care services care were identified, a getis-ord-gi analysis was performed. thus, it was possible to point out three spatial clusters: ( ) emergency care services accessibility on february ; ( ) municipalities with low access to emergency care services and high covid- incidence, ( ) accessibility to icu beds exclusively dedicated to covid- response in march . following the resolution no. / of the national health council and considering that we used secondary sources which are available in governmental and online databases, the dispensation of the consent form was requested to the ethics committee. covid- has shown a fast growth rate in brazil. the total number of confirmed deaths in the country initially increased at a similar pace as germany and iran. however, differently than these countries, it has not yet shown a decrease in its growth rate ( figure a) . subnationally, the growth rate of confirmed deaths shows an unequal pattern. likely due to different state-level isolation policies, the states of são paulo, rio de janeiro, ceará, and amazonas have shown a much faster growth rate than the rest of the country ( figure b) . nonetheless, the country as a whole seems to be still far from its peak number of new deaths by covid- . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . february ) . in terms of professionals and beds per , inhabitants, the southern region had the highest rates for icu beds, ventilators, physicians, nurses, and technicians. in contrast, the northern region had the lowest ones (table ). figure shows the rates of beds and professionals per health regions. the icu beds per intensivist varied from zero to , zero to . per intensive care nurse, zero to . per technician, and zero to per physiotherapist. in addition, hospital beds per physician varied from . to . , . to . per nurse, . to . per technician, and . to . per physiotherapist. figure shows the distribution of professionals, beds, and ventilators throughout the territory, and classifies this distribution according to rdc number . in a, most h.r. is by the rdc, which determines up to intensivists for each icu bed. however, hr do not have icu beds and / or have no intensivist. in b, only h.r. are working according to the recommended amount of critical care nurse for each icu beds. c and d show that hr are working correctly with the capacity of nursing assistant and one physiotherapist for every and beds, respectively. in the second row of figure , f, g, and h show that there are nurses, nursing technicians and physiotherapists working above the limit of nurse per infirmary bed, one nursing technician for each two-infirmary bed and one physiotherapist per infirmary bed. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . panel a in figure depicts the covid- incidence by the brazilian municipality up to / / . it is possible to observe that all states and regions currently are presenting covid- cases with a highlight to the states of amazonas, amapá, espírito santo, and santa catarina, where it is already noted areas with hot colors. the hot colors indicate higher levels of incidence. in terms of deaths, all state capitals of the north, northeast, and southeast regions are presenting high levels of mortality when compared with the rest of the country. figure presents three maps characterizing the brazilian situation in terms of emergency services and the covid- incidence. panel a exhibits the accessibility index to icu beds by population. the map highlights a higher accessibility index close to the state capitals of the brazilian states. the map b emphasizes the municipalities presenting a covid- incidence higher than the national average of . , simultaneously with an accessibility index lower than the national mean per , inhabitants thus, every municipality in the map b is facing challenges in terms of emergency care services and a high covid- incidence for the brazilian standards. map c presents the accessibility index of the new beds created exclusively to offer intensive care to covid- patients. few beds with this specific purpose were open in the states of the north and midwest region of the country. figure shows the result of spatial clustering analysis to identify trends in access, as well as in the covid- incidence. panel a exhibits a hot spot covering the southeast, midwest, and south regions of the country. the states covered by the red layer presents the spatially significant group of municipalities with higher levels of access to icu beds by population. on the opposite side, the blue layer highlights the regions facing geographical barriers to grant access to icu beds to the population. to build the map b, the same approach was used, but this time only applied to the municipalities with high covid- incidence and a low index of accessibility to icu beds. the red color characterized a group of municipalities in the south and midwest regions. despite the higher availability of beds in these regions, it was possible to observe a statistically significant group of municipalities within these regions with barriers to access icu beds. map c illustrates the cluster of accessibility regarding the icu beds created to tackle the covid- . the lack of overlay between the red color of maps b and c is pointing out a mismatch of the response efforts dedicated to addressing the covid- challenge. the regions in map b characterized as hotspots were considered cold spots regarding the creation of icu beds dedicated to covid- . the result suggests that the use of scarce resources needed to put in order icu beds are not being directed to municipalities lacking access to emergency care services, despite their high levels of covid- incidence. the ongoing covid- pandemic has caused nearly million confirmed cases and claimed over , lives worldwide as of may , ( ) [report ]. it is noteworthy to mention that the covid- outbreak is a challenge to the health systems worldwide ( ) , and although the outcome for the crisis caused by this disease is uncertain, sars-cov- will overwhelm health care infrastructure for months ( ) . in this study, the brazilian health system was evaluated to verify its capacity to tackle the covid- challenge. according to the who, it is recommended one doctor and one nurse per , inhabitants as a parameter of health care for the population ( ). to strengthen the who recommendations, the brazilian health governments has established in the resolution of the collegiate board of directors number / , the quantities of icu and infirmary beds per intensivists, general physicians, nurses, nursing technician and physiotherapists ( ) . although table shows that in brazil, there is a sufficient number of physicians in the country, figure shows that these professionals are not evenly distributed to accomplish the who recommendations and cbr. in addition, the number of nurses does not meet the criteria in the north and midwest. to illustrate the problem, figure shows that brazil has desert zones of icu assistance and regions where these professionals have to take care of beds far beyond the quantities stipulated by the rdc. bahtt et al., verified that professionals in critical care that were caring for more patients per shift were more likely to experience burnout ( ). halpern et al., informed that intensivists are also in shortage in the united states of america, and this situation may be attributed to burnout ( ) . therefore, the combat against the covid- may be a difficult task in these regions, since providing access and affordable care for the large urban populations is already a challenge for many countries ( ). experience from lombardia has shown that % of patients with covid- were admitted in the icu treatment, whereas this number varied from to % in some cities in china ( ) . on the other hand, in brazil, there are no available large data of icu patients at the moment, and supposing that those numbers might appear in the country as well, only out of health regionals could manage this number of patients. in terms of nursing care in icu accessibility, figure shows that there are large regions of care voids, probably because there are low amounts of icu nurses in brazil ( ) . besides that, it's possible to visualize that there are regions where icu and generalist nurses are responsible for more than eight icu and infirmary beds, which may represent a risk of unfavorable outcome for the covid- treatment since that high amount of patients per nurse are associated with a range of negative patient outcomes ( , ) . the pandemic has led to severe shortages of many essential supplies, such as icu beds and ventilators ( ) . based on italy's numbers that to % of hospitalized patients will require ventilation, the centers for disease control and prevention estimates that in the usa, there will be between . to patients per ventilator this period ( , ). brazil, on the other hand, . to . million people will require hospitalization, according to the imperial . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . college of london ( ) , which represents to patients per ventilator if distributed equally. the numbers may represent a satisfactory amount of equipment. however, figure shows that there are no ventilators in some h.r. that are potential places to have a high number of deaths. the most staggering result was obtained through the spatial cluster analysis. brazil is currently facing a double crisis. the political positioning of the president is going against the technical recommendations of the ministry of health and who. consequently, there is a disagreement between the federal administration, and the states and municipalities. on account of that situation, each administrative level is conducting several response actions against covid- without country-level coordination. the spatial clusters analysis highlighted that new beds created to tackle the covid- were misplaced. the hot spot clusters of municipalities with high incidence and lack of access are not overlapping with the hot spot cluster of new beds dedicated to the covid- . this situation calls attention for the misplacement of scarce resources during a pandemic. the scenario depicted is the result of a lack of coordination at the national level. the consequence of misplacing the new covid- icu beds is an increase in the chance of deaths due to a lack of emergency care services for municipalities currently presenting a covid- incidence above the national average. from now on, brazil has several difficulties in treating patients in critical care. this paper shows that there is an insufficient number of icu beds, ventilators, and a huge lack of professionals in healthcare. additionally, the misplacement of the new beds aiming to fight the covid- pandemic contributes to worsening the situation observed through the other indicators assessed. developed countries like italy and the united states demonstrate that covid- can overwhelm the healthcare capacities of well-resourced nations very fast ( , ) . therefore, the sars-cov- epidemic in middle-income countries, such as brazil ( ), may be devastating. our findings suggest that strong leadership is needed to coordinate the response efforts against the covid- . the limitations of this work rely on the complex data available. health data from health information systems, including health-facility records, surveys, or vital statistics, may not be representative of the entire population of a country and, in some cases, may not even be accurate ( ). the cnes database presents some limitations well known by the brazilian scientific community ( ) . despite this, the information regarding the availability of covid- beds was published just a month ago, calling attention to the occurrence of efforts aiming to improve the quality of the data available to policymakers. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint a" iv to "z" ikv: attacks from emerging and re-emerging pathogens covid- ): situation report clinical characteristics of coronavirus disease in china world health organization declares global emergency: a review of the covid- : extending or relaxing distancing control measures. lancet public health deep impact of covid- in the healthcare of latin america: the case of brazil communication, collaboration and cooperation can stop the coronavirus intensive care management of coronavirus disease (covid- ): challenges and recommendations global surgery : evidence and solutions for achieving health, welfare, and economic development addressing inequalities in medical workforce distribution: evidence from a quasiexperimental study in brazil addressing geographic access barriers to emergency care services: a national ecologic study of hospitals in brazil universal masking in hospitals in the covid- era fangcang shelter hospitals: a novel concept for responding to public health emergencies how should u.s. hospitals prepare for coronavirus disease (covid- )? covid- ): update for anesthesiologists and intensivists the immune escape mechanisms of mycobacterium tuberculosis comparison of the microwave-heated ziehl-neelsen stain and conventional ziehl-neelsen method in the detection of acid-fast bacilli in lymph node biopsies. open access maced the global impact of covid- and strategies for mitigation and suppression. imperial college covid- response team emenda constitucional / e o teto dos gastos públicos: brasil de volta ao estado de exceção econômico e ao capitalismo do desastre implicações de decisões e discussões recentes para o financiamento do sistema Único de saúde. saúde em debate regulamenta a lei no . , de de setembro de , para dispor sobre a organização do sistema Único de saúde-sus, o planejamento da saúde, a assistência à saúde ea articulação interfederativa, e dá outras providências microdatasus: pacote para download e préprocessamento de microdados do departamento de informática do sus (datasus). cadernos de saúde pública dispõe sobre os requisitos mínimos para funcionamento de unidades de terapia intensiva e dá outras providências brasília região de saúde e suas redes de atenção: modelo organizativo-sistêmico do sus. ciência & saúde coletiva covid- : operational guidance for maintaining essential health services during an outbreak: interim guidance world health o. health workforce requirements for universal health coverage and the sustainable development goals.(human resources for health observer, ). . critical care medicine in the united states: addressing the intensivist shortage and image of the specialty organizational characteristics, outcomes, and resource use in brazilian intensive care units: the orchestra study baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region profile of an intensive care nurse in different regions of brazil ratios and nurse staffing: the vexed case of emergency departments workloads in australian emergency departments a descriptive study the toughest triage -allocating ventilators in a pandemic hospital surge capacity in a tertiary emergency referral centre during the covid- outbreak in italy factors potentially associated with the decision of admission to the intensive care unit in a middle-income country: a survey of brazilian physicians. rev bras ter intensiva cadastro nacional de estabelecimentos de saúde: evidências sobre a confiabilidade dos dados. ciênc. saúde coletiva [internet] we would like to thank the coordination for the improvement of higher education personnel (capes). the authors declare no conflicts of interest. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , key: cord- -qraq aho authors: mirouse, adrien; vignon, philippe; piron, prescillia; robert, rené; papazian, laurent; géri, guillaume; blanc, pascal; guitton, christophe; guérin, claude; bigé, naïke; rabbat, antoine; lefebvre, aurélie; razazi, keyvan; fartoukh, muriel; mariotte, eric; bouadma, lila; ricard, jean-damien; seguin, amélie; souweine, bertrand; moreau, anne-sophie; faguer, stanislas; mari, arnaud; mayaux, julien; schneider, francis; stoclin, annabelle; perez, pierre; maizel, julien; lafon, charles; ganster, frédérique; argaud, laurent; girault, christophe; barbier, françois; lecuyer, lucien; lambert, jérôme; canet, emmanuel title: severe varicella-zoster virus pneumonia: a multicenter cohort study date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: qraq aho background: pneumonia is a dreaded complication of varicella-zoster virus (vzv) infection in adults; however, the data are limited. our objective was to investigate the clinical features, management, and outcomes of critically ill patients with vzv-related community-acquired pneumonia (vzv-cap). methods: this was an observational study of patients with vzv-cap admitted to intensive care units (icus) from january to january . results: one hundred and two patients with vzv-cap were included. patients were young (age years (interquartile range – )) and ( %) were immunocompromised. time since respiratory symptom onset was ( – ) days. there was a seasonal distribution of the disease, with more cases during spring and winter time. all but four patients presented with typical skin rash on icu admission. half the patients received mechanical ventilation within ( – ) day following icu admission (the ratio of arterial oxygen partial pressure to fractional inspired oxygen (pao( )/fio( )) = ( – ), % with acute respiratory distress syndrome (ards)). sequential organ failure assessment (sofa) score on day (odds ratio (or) . ( . – . ); p < . ), oxygen flow at icu admission (or . ( . – . ); p = . ), and early bacterial co-infection (or . ( . – . ); p = . ) were independently associated with the need for mechanical ventilation. duration of mechanical ventilation was ( – ) days. icu and hospital mortality rates were % and %, respectively. all patients were treated with aciclovir and received adjunctive therapy with steroids. compared to matched steroid-free controls, patients treated with steroids had a longer mechanical ventilation duration, icu length of stay, and a similar hospital mortality, but experienced more icu-acquired infections. conclusions: severe vzv-cap is responsible for an acute pulmonary involvement associated with a significant morbidity and mortality. steroid therapy did not influence mortality, but increased the risk of superinfection. electronic supplementary material: the online version of this article (doi: . /s - - - ) contains supplementary material, which is available to authorized users. pneumonia is associated with significant morbidity and mortality worldwide [ ] . the importance of viruses as pathogens responsible for community-acquired pneumonia (cap) has been emphasized by several epidemic outbreaks over the last decade: severe acute respiratory syndrome (sars), avian influenza a (h n ) virus, and the pandemic influenza a (h n ) [ ] [ ] [ ] [ ] . it is estimated that about million cases of viral cap occur annually, accounting for to % of cap [ ] [ ] [ ] [ ] [ ] . in the intensive care unit (icu) setting, viruses have been reported to account for up to one-third of patients with severe cap, with a similar mortality to that observed with bacterial pneumonia [ ] . the availability of new molecular techniques (such as polymerase chain reaction (pcr)) has greatly increased our ability to detect a wide range of viruses in respiratory secretions [ ] [ ] [ ] [ ] . nevertheless, although convincing data are available for agents such as influenza virus or respiratory syncytial virus and their role in severe pneumonia, the role of other recently discovered viruses (bocavirus, coronavirus nl ) remains debated and requires further research [ ] [ ] [ ] [ ] . varicella-zoster virus (vzv) is one of eight herpes viruses known to cause human infection and is distributed worldwide. varicella or chickenpox is defined as the vzv primo-infection. in adults, vzv infection is associated with a greater number of complications, of which pneumonia is the most common and serious. since its initial description in , vzv-related communityacquired pneumonia (vzv-cap) has become increasingly recognized as a serious and potentially lethal complication of what was once considered a relatively benign and self-limited viral infection [ ] . a study with systematic chest x-ray showed an incidence of . % of vzv-cap in adult patients [ ] . autopsy findings have demonstrated the role of vzv in fatal cases of pneumonia. microscopic findings included pulmonary edema, extensive alveolar hemorrhage, and mononuclear cell infiltration with histological evidence of intranuclear inclusion bodies [ , ] . data on critically ill adult patients with vzv-cap are limited to case reports and small case series. the purpose of this study was to describe the clinical, biological, and radiological features and the outcome of severe forms of vzv-cap (i.e., requiring icu admission) in a large cohort and to report its implication for icu management. this retrospective study was conducted in french adult icus (see additional file : table s ). this study has been approved by the french intensive care society ethics committee (n° - ) and an authorization to use patient data from the french data protection agency (n° ). according to french law, a waiver of informed consent was obtained. all adult patients (≥ years old) admitted for vzv-cap in the participating icus between january and january were included. patients were identified from the icu databases using codes j and b from the international classification of diseases system (icd- ) system. all the medical records of patients were reviewed by two investigators (am and ec). the data reported in tables , , and were abstracted from medical charts. chickenpox features at icu admission were collected including skin rash, pulmonary involvement, neurological impairment, or abdominal symptoms. patients were defined as immunosuppressed if they met one of the following criteria: hematopoietic stem cell or solid organ transplantation, hematological malignancy, solid tumor progressing or in remission less than years, steroid treatment for more than months, and other immunosuppressive drugs. physiological variables, laboratory data, and radiographic findings (chest x-ray and computed tomography (ct) when available) on icu admission were also reported. thrombocytopenia was defined as platelet count < g/l and hepatitis as alanine aminotransferase and/or aspartate aminotransferase ≥ n. disease severity was assessed using the sequential organ failure assessment (sofa) on day after icu admission [ ] . patients were classified as having acute respiratory failure (arf) if they met the following criteria: severe dyspnea at rest; a respiratory rate greater than breaths/min or clinical signs of respiratory distress; and oxygen saturation less than % or arterial oxygen partial pressure (pao ) less than mmhg on room air. hypoxemia severity was assessed using the pao /fraction of inspired oxygen (fio ) ratio [ ] . the decision to perform fiberoptic bronchoscopy and bronchoalveolar lavage (fo-bal) and the use of life-sustaining treatments (i.e., noninvasive or invasive mechanical ventilation, renal replacement therapy, and vasopressors) was left at the discretion of the attending physicians. acute respiratory distress syndrome (ards) was defined according to the berlin definition [ ] . therapeutic regimens were reported including antiviral therapy (molecule, dose, and length of treatment) and the use of steroids. high-dose steroids was defined as > mg per day of prednisone [ ] . patients receiving steroids were matched in a : ratio to a control group of patients within this cohort who did not receive steroids. the four matching criteria were: age, year of icu admission, sofa score on day , and ards criteria according to the berlin definition. icu-acquired infections were recorded. the diagnosis of infection was confirmed if patients met both the following criteria: microbiological identification of a pathogen and administration of related antibiotic treatment. icu and hospital length of stays, and vital status at icu and hospital discharge were obtained in all patients. patient characteristics at baseline and during icu stay were described using medians and interquartile ranges for quantitative variables and counts and percentages for qualitative variables. characteristics of patients requiring mechanical ventilation during their icu stay were compared to those of patients without mechanical ventilation using either wilcoxon rank sum test or fisher's exact test. to assess variables independently associated with the requirement for mechanical ventilation, baseline characteristics significantly associated with the requirement for mechanical ventilation were included in a multivariable logistic regression model. due to the small sample size, a forward stepwise p value-based variable selection was performed, and, when several highly correlated variables were associated with the requirement for mechanical ventilation, only one was included in the multivariable analysis based on clinical relevance. missing covariates were handled using multivariate imputation by chained equations. baseline and icu management characteristics were also compared between deceased patients and those discharged alive. cumulative incidence of death in the icu and death in hospital were estimated considering discharge alive from icu/hospital as competing events. to assess the prognostic effect of steroid therapy in the context of an observational cohort, a matched comparison of patients receiving and not receiving steroids was performed. patients receiving steroids were matched in a : ratio to a control group of patients within this cohort who did not receive steroids. the four matching criteria were: age, year of icu admission, sofa score on day , and ards criteria according to the berlin definition. during the study period, we identified adult patients admitted to the icu for the management of vzv-cap. there was a seasonal distribution over the study period, with the highest incidence observed during winter and spring (additional file : figure s ). the median age was ( - ) years and ( %) patients were immunocompromised. six ( %) cases of vzv pneumonia occurred in pregnant women (table ) . a typical chickenpox skin rash was reported in all but four ( %) patients and occurred ( - ) days before the onset of respiratory symptoms. the median time from onset of respiratory symptoms to icu admission was ( - ) days. on admission, patients were severely hypoxemic with a pao /fio ratio of ( - ) mmhg and ( - ) l/min oxygen flow. respiratory symptoms included a cough in ( %) patients, chest pain in ( %) patients, and hemoptysis in ( %) patients. arf was noted in ( %) patients (table ). in addition to skin and respiratory symptoms, ( %) patients had encephalitis. laboratory findings indicated thrombocytopenia in ( %) patients and hepatitis in ( %) patients. blood pcr to amplify vzv dna was always positive when performed (n = , . %). the median sofa score on day was ( - ). a chest ct was performed in ( %) patients and was never normal. common abnormalities were diffuse bilateral centrolobular nodules with tree-in-bud appearance (n = , %) and diffuse ground glass opacities (n = , %) ( fig. ) . alveolar consolidations were also reported (n = , %). fiberoptic bronchoscopy was performed in ( %) patients and demonstrated vesicular lesions or ulcerations on bronchial mucosa in ( %) cases. pcr for vzv in the bronchoalveolar lavage was tested in patients and yielded a positive result in % of cases. noninvasive mechanical ventilation was implemented in ( %) patients, failing in ( %) who were subsequently intubated. invasive mechanical ventilation was used in ( %) patients overall, of whom ( . %) fulfilled the ards criteria according to the berlin definition (table ) . patients were intubated ( - ) day after icu admission. three factors were independently associated with the need for invasive mechanical ventilation: sofa score on day (odds ratio (or) . ( . - . ); p < . ), oxygen flow at icu admission (or . ( . - . ); p = . ), and early bacterial co-infection (or . ( . - . ); p = . ) ( table and fig. ). vasopressors were required in ( %) patients and renal replacement therapy in ( %). among the patients, ( %) patients had documented bacterial co-infection with ( %) early infections (documented within h after icu admission) and ( %) late infections. the primary sources of co-infections were the lungs (n = , %), bloodstream (n = , %), and skin (n = , %), with staphylococcus aureus being the most often recovered pathogen (n = , %). the median icu and hospital length of stay were ( - . ) days and ( - ) days, respectively. duration of mechanical ventilation was ( - ) days. all patients were treated with aciclovir mg/kg/ h during ( . - ) days. one ( %) patient received a treatment with a varicella-zoster immune globulin preparation. high-dose adjunctive steroid therapy, in addition to antiviral therapy, was reported in patients. patients treated with high-dose steroids were no different compared to steroid-free patients regarding demographics, respiratory parameters on icu admission, and icu management ( table ). compared to steroid-free patients, steroid treatment was associated with a longer duration of mechanical ventilation, and prolonged icu and hospital stays. icu mortality was similar in the two groups ( % vs. %; p = . ). icu-acquired bacterial infections were more frequently reported in steroid-treated patients ( % vs. %; p = . ) ( table ) . overall icu and hospital mortality were % and %, respectively, without significant variation over the study period (additional file : table s ). the main causes of death were: multi-organ failure in patients ( %), refractory ards in patients ( %), and septic shock in fig. imaging characteristics from lung ct. a -year-old woman was admitted to the icu for acute respiratory failure. she underwent kidney transplantation years ago. she reported fever and a typical chickenpox skin rash days before admission. the onset of respiratory symptoms started days before icu admission and invasive mechanical ventilation was implemented at day . she developed a severe ards requiring prone positioning, neuromuscular blockers, and days of invasive mechanical ventilation. lung ct scan demonstrated diffuse bilateral nodules, patchy ground glass opacities, and interlobular septal thickening. a fiber bronchoscopy with bronchoalveolar lavage documented a staphylococcus aureus co-infection. she received intravenous aciclovir mg/kg/ h during days associated with days of oxacilline and was discharge alive from the icu days after admission patients ( %). one ( %) patient died from fulminant hepatic failure attributed to vzv infection and ( %) patient died from brain edema. the cause of death was missing for patients. by univariate analysis, factors associated with hospital mortality were: age ( ( - . ) vs. ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ; p < . ), underlying immunosuppression ( % vs. %; p < . ), sofa score on day ( ( - . ) vs. ( - . ) ; p = . ), disseminated intravascular coagulation ( % vs. %; p = . ), and empiric antibiotic treatment on icu admission ( % vs. %; p < . ) (additional file : table s , additional file : figure s , and additional file : figure s ). we identified patients with severe forms of vzv-cap who were admitted to french icus. underlying immunosuppression accounted for half of the patients we evaluated, mainly related to impaired cellular immune response (lymphoproliferative disorders, immunosuppressive drugs for solid-organ transplant recipients, and/or steroid exposure). nevertheless, we identified severe illness from vzv-cap among ( %) young and healthy patients. more than half of the patients required invasive mechanical ventilation, of which % met ards criteria. risk factors for intubation were related to the severity of the respiratory failure, the presence of an early bacterial co-infection, and the onset of other organ failures. in addition to antiviral therapy, high doses of steroids were used in ( %) patients without benefit either on improvement of respiratory parameters or on mortality, and were associated with an increased number of superinfections. there was a ( - )-day period of illness prior icu admission, which is similar to influenza virus infection and other causes of viral pneumonia [ , , ] . all patients but four presented with a typical chickenpox skin rash, suggesting that vzv-cap is mostly a dreaded complication of primary vzv infection rather than recurrent vzv infection. the four patients without rash were all immunocompromised (solid cancer or hematological malignancy). atypical cases of recurrent vzv infection with pulmonary involvement have been reported, almost exclusively in immunocompromised patients, and cannot be excluded in our study [ ] [ ] [ ] [ ] . in addition, exogenous clinical reinfection by vzv has also been demonstrated and is thought to occur more likely in immunocompromised patients [ ] . the illness course was characterized by a short period of acute and severe respiratory deterioration, requiring invasive mechanical ventilation in half of the cases, shortly after icu admission. we identified that risk factors for intubation were related to the presence of a bacterial coinfection, the severity of the respiratory failure, and the onset of other organ failures. neither comorbidities nor underlying immunosuppression were independent predictors of invasive mechanical ventilation. these results are in agreement with previous studies suggesting that the underlying medical context was no longer significantly associated with the risk for intubation after adjustment for the severity of the acute disease [ ] [ ] [ ] . the factors we identified are easy to assess at the bedside and may contribute to recognizing hospital admission patients who may benefit from early icu admission. results are presented for the imputed data candidate predictors were: age, any comorbidity, underlying immunosuppression, sofa score at day , oxygen flow at icu admission, alveolar consolidation on chest x-ray, antibiotics at icu admission, and early bacterial co-infection ci confidence interval, icu intensive care unit, or odds ratio, sofa sequential organ failure assessment in our study, the overall mortality was % and reached % in patients who received invasive mechanical ventilation. viruses have been increasingly recognized as pathogens responsible for both severe community-acquired and healthcare-associated pneumonia [ , ] . choi et al. recently demonstrated in a prospective study that, in the icu setting, the mortality rate of patients with viral pneumonia was similar to that of patients with bacterial pneumonia [ ] . nevertheless, most of our knowledge on severe forms of viral pneumonia is related to the influenza virus. we report that patients with vzv-cap who required intubation experienced a long period of invasive mechanical ventilation ( ( - ) days) and a high rate of bacterial coinfections ( %). these findings might be explained by the extent of skin and mucosal vesicular lesions. indeed, previous clinical and autopsy studies have demonstrated that these lesions are responsible for necrotic and hemorrhagic foci distributed both in the upper airways and in the lower respiratory tract that may promote bacterial co-infection [ , ] . in our study, % of the patients who underwent fiberoptic bronchoscopy had vesicular lesions on bronchial mucosa. in addition to antiviral therapy, the use of steroids has been reported by observational studies in the treatment of vzv pneumonia [ ] [ ] [ ] . the role of steroids in the management of pneumonia remains controversial. on the one hand, steroids might have the potential to decrease intrapulmonary inflammation and thus to reduce some ards-related pulmonary lesions. but, on the other hand, steroids might increase immunosuppression, favor persistent viral replication, and promote superinfection. based on the results of two randomized controlled trials, the benefit-to-risk ratio argues for its use patients who received steroids were matched in a : ratio to a control group of patients who did not receive steroids. matched controls were screened from the current cohort with the following four matching criteria: age, year of icu admission, sofa score at day , and ards criteria according to the berlin definition ards acute respiratory distress syndrome, icu intensive care unit, pao :fio ratio of arterial oxygen partial pressure to fractional inspired oxygen, sofa sequential organ failure assessment in severe pneumocystis jirovecii pneumonia in the acquired immunodeficiency syndrome [ , ] . a recent meta-analysis reported that it may decrease the risk of ards as adjunctive therapy in community-acquired pneumonia [ ] . on the other hand, no benefit has been demonstrated with the use of steroids in influenza pneumonia [ ] . in , mer and richards [ ] reported on adult patients treated for vzv-cap, six of whom received steroids in addition to antiviral therapy and supportive care. these six patients experienced clinical improvement, a significantly shorter icu and hospital length of stay, and no mortality when compared to those who did not receive steroids. however, the study design precluded any robust conclusion. another study from saudi arabia reported improvement in oxygenation parameters in adult patients treated for vzv-cap with steroids as adjunctive therapy [ ] . this was not our experience in the present study. ten patients received steroids . ( - ) days after icu admission. we compared these patients to matched controls who did not receive steroids. there was no difference between the steroid group and the nonsteroid group in icu and hospital mortality. however, patients treated with steroids had a longer duration of invasive mechanical ventilation, more bacterial superinfection, and an increased icu and hospital length of stay than control patients not treated with steroids. thus, our data did not report any benefit associated with the use of steroids as adjunctive therapy in severe vzv-cap. our study has several limitations. first, given the retrospective design over a long period of time, supportive care practices may have changed throughout the study period and influenced the results. however, we report the largest study on the severe forms of vzv-cap and we believe that it adds valuable data to the current knowledge. second, we had no biological identification of vzv for all patients included our study. nevertheless, clinical signs and symptoms of chickenpox are obvious in most cases and laboratory diagnosis is restricted to unusual cases. thus, we can reasonably assume that the patients included in the present study had vzv-cap. third, due to the limited number of death we were unable to identify independent predictors of hospital mortality. however, we report predictors of invasive mechanical ventilation that conceivably may be related to mortality. fourth, for the diagnosis of vzv-cap we used a database encoded by physicians at patient icu discharge and we cannot exclude that some patients with vzv-cap had been missed. in conclusion, severe vzv-cap in adults is an acute respiratory disease that requires invasive mechanical ventilation in more than half of the cases. although underlying medical conditions or immunosuppression are common, healthy young individuals may be involved. we identified that respiratory disease severity, early bacterial co-infection, and other organ failures on icu admission were independent risk factors for invasive mechanical ventilation. early recognition of these factors may help to identify patients that may benefit from close monitoring to ensure that no treatment delay occurs when intubation is required. adjunctive steroid therapy did not influence mortality and increased the risk of superinfection. limoges, france. inserm u service de réanimation médicale service de réanimation médico-chirurgicale service de réanimation médicale département de néphrologie et transplantation d'organes service de réanimation médicale service de réanimation médicale, hôpital brabois service de réanimation médicale, hôpital e. herriot, hospices civils de lyon, lyon, france. medical intensive care unit a novel coronavirus associated with severe acute respiratory syndrome avian influenza a (h n ) infection in humans pneumonia and respiratory failure from swine-origin influenza a (h n ) in mexico critical care services and h n influenza in australia and new zealand viral pneumonia viral infection in adults hospitalized with community-acquired pneumonia: prevalence, pathogens, and presentation etiology of communityacquired pneumonia: increased microbiological yield with new diagnostic methods rates of hospitalizations for respiratory syncytial virus, human metapneumovirus, and influenza virus in older adults incidence of respiratory viruses in patients with community-acquired pneumonia admitted to the intensive care unit: results from the severe influenza pneumonia surveillance (sips) project viral infection in patients with severe pneumonia requiring intensive care unit admission incidence and characteristics of viral community-acquired pneumonia in adults human metapneumovirus as a major cause of human respiratory tract disease human bocavirus: prevalence and clinical spectrum at a children's hospital human coronavirus nl , a new respiratory virus severe pneumonia and human bocavirus in adult human bocavirus: passenger or pathogen in acute respiratory tract infections? characterization of human coronavirus oc and human coronavirus nl infections among hospitalized children < years of age coronavirus nl -induced adult respiratory distress syndrome severe forms of chickenpox in adults: with autopsy observations in a case with associated pneumonia and encephalitis varicella pneumonia: study of prevalence in adult men primary varicella pneumonia disseminated varicella at autopsy in children with cancer the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine international study of the prevalence and outcomes of infection in intensive care units acute respiratory distress syndrome: the berlin definition standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology critically ill patients with influenza a(h n ) in mexico viruses associated with pneumonia in adults clinical reinfection with varicella-zoster virus recurrent varicella-zoster virus infections in apparently immunocompetent children reinfection with varicella-zoster virus in immunocompromised patients varicella-zoster virus antibody avidity and igg-subclass patterns in children with recurrent chickenpox identifying cancer subjects with acute respiratory failure at high risk for intubation and mechanical ventilation predictors of noninvasive ventilation failure in patients with hematologic malignancy and acute respiratory failure predictors of failure of noninvasive positive pressure ventilation in patients with acute hypoxemic respiratory failure: a multi-center study varicella-zoster virus pneumonitis bacterial complications of primary varicella in children corticosteroids in life-threatening varicella pneumonia effect of corticosteroids on adult varicella pneumonia: cohort study and literature review combining corticosteroids and acyclovir in the management of varicella pneumonia: a prospective study corticosteroids as adjunctive therapy for severe pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. a double-blind, placebo-controlled trial a controlled trial of early adjunctive treatment with corticosteroids for pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. california collaborative treatment group efficacy and safety of corticosteroids for community-acquired pneumonia: a systematic review and meta-analysis the influence of corticosteroid treatment on the outcome of influenza a(h n pdm )-related critical illness none. none. the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.authors' contributions am, jl, ppi, and ec made substantial contributions to the conception of the work, the acquisition, analysis, and interpretation of data for the work. they drafted the work and revised it critically for important intellectual content. they gave final approval of the version to be published. they agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. pv, rr, lp, gg, pb, cgui, cgué, nb, ar, al, kr, mf, jdr, ase, bs, asm, sf, am, jmay, fs, ast, ppe, jmai, ds, fg, la, gb, fb, and gc made substantial contributions to the acquisition of data for the work. they revised the work critically for important intellectual content. they gave final approval of the version to be published. they agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. additional file : table s . participating centers (n = ) with the number of cases of vzv pneumonia during the study period . the authors declare that they have no competing interests. ethics approval and consent to participate this study has been approved by the french intensive care society ethics committee (n° - ) and an authorization to use patient data from the french data protection agency (n° ). according to french law, a waiver of informed consent was obtained. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. submit your next manuscript to biomed central and we will help you at every step: key: cord- - bi pobg authors: ganem, fabiana; mendes, fabio macedo; oliveira, silvano barbosa; porto, victor bertolo gomes; araujo, wildo; nakaya, helder; diaz-quijano, fredi a; croda, julio title: the impact of early social distancing at covid- outbreak in the largest metropolitan area of brazil. date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: bi pobg we evaluated the impact of early social distancing on the covid- transmission in the sao paulo metropolitan area. using an age-stratified seir model, we determined the time-dependent reproductive number, and forecasted the icu beds necessary to tackle this epidemic. within days, these measures might prevent , deaths. the covid- pandemic has led to the collapse of healthcare systems in several countries ( ) . the virus has a higher basic reproduction number (r ) (i.e., the average number of secondary cases generated by a primary case) and case fatality rate (cfr) when compared to influenza (r : , - , and cfr: , - , % versus r : , and cfr: , %- , %, respectively) ( ) ( ) ( ) ( ) . to tackle the spread of disease, a range of interventions have been implemented in china, including increasing test capacity, rapid isolation of suspected and confirmed cases and their contacts, social distancing measures, as well as restricting mobility ( ) . the first confirmed case of covid- in brazil was on february th in the city of são paulo and, since march th, the state of são paulo has recommended a series of social distancing measures. these include recommending that older adults and individuals with chronic medical conditions stay at home as much as possible; cancelling mass events; reducing public transportation; closing schools, universities and workplaces; and maintaining only essential services. the collapse of health care systems is the major concern for most countries hit by the pandemic. among the confirmed cases in china, . % were considered severe and . % of those required intensive care ( ) . the são paulo metropolitan area (spma) has , icu beds available, , of which belong registered in the national council of health establishments (cadastro nacional de estabelecimentos de saúde, cnes: http://cnes.datasus.gov.br). considering the significant expected burden of the covid- pandemic, nonpharmacological interventions are necessary to flatten the epidemic curve and prepare the public response to the shortage of icu beds and healthcare workers needed to treat critically ill patients ( ). we evaluated the impact of early social distancing measures in the transmission of covid- in the spma, and projected the number of icu beds necessary for covid- patients in brazil. during the epidemic, the brazilian ministry of health (moh) implemented an electronic form for reporting suspected cases of respiratory syndrome. we retrieved all . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . confirmed covid- cases between th february and th march. the form includes several different information, such as exposure and travel information, the contact names of people that could be infected (primary cases), the date of onset of symptoms, and laboratory results. using only locally acquired cases, we linked the reported contacts with the original dataset of confirmed cases in order to create a set of infection pairs. we then compared the dates of onset of symptoms to establish the set of serial intervals. in addition, we used the daily number of covid- confirmed patients from a são paulo state to calculate time dependent reproductive number r(t). in , the moh established a mandatory notification of any hospitalized case of severe acute respiratory illness (sari) into the national disease notification system (sivep-gripe). we retrieved all sari cases notified on the sivep-gripe system between th february and th march ( ). those cases were included regardless of covid confirmation as a proxy of covid infections. this proxy was used to validate r(t) of confirmed covid cases and was chosen in order to minimize the impact on shortage of rt-pcr tests. we calculated the r(t) during one month period for confirmed cases of covid , as well as sari in the spma, and estimated the expected number of covid cases requiring an icu bed. the reproductive number at the beginning of the epidemic (r ) and during the epidemic (rt) were calculated using the package r r studio ( ). the expected icu demand was calculated using an age stratified seir model ( ), which includes compartments for individuals requiring hospitalization and intensive care. the parameters are described in table . considering only the confirmed cases reported by são paulo state, the r (i.e. previously to the introduction of social distancing measures) was close to . during the interventions, the r(t) dropped to values close to and had a subsequent increase ( figure a ). underreporting and the shortage of confirmatory tests for covid could directly affect these r(t) estimations. to deal with this, we analyzed the number of sari available in the epidemiological surveillance of influenza system (sivep-gripe) and showed that the social distancing measures reduced the r(t) below to with a more accurate confidence interval (figure b) . the r(t) of sari cases was used in the seir model to forecasted the icu beds necessary and the number of deaths. . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint in the absence of social distancing measures, the model predicts that in the end of days, covid patients would demand , icu beds, which corresponds to % of the icu capacity and exceed times the icu capacity in the second month. overall, this would result in , deaths in the first month and , in the second month. with maintenance of social distancing measures, the model predicts deaths in the first month and a total of in the second. this scenario does not overburden the healthcare system and requires a maximum of % icu beds capacity. the impact of the social distancing measures must be monitored daily based on the number of hospitalized sari, especially during the shortage of the covid- confirmation tests. using the severe cases notification systems, we identified that the social distance measures implemented in the spma reduced the covid r(t) to below . in april and may, during influenza seasonality, with the maintenance of this level of social distance, the spma will need no additional icu beds for covid patients. we realized that the downward trend seems to have started before the intervention. this could be explained by a decrease in mobility documented since the first days of march in places like national parks, public beaches, marinas, dog parks, plazas, and public gardens. according to a covid- community mobility report performed by google this reduction was intensified and spread to other settings since the local government declared a state of emergency ( ) . this report suggested that intervention was effectively applied, and it is consistent with the transmissibility reduction observed. the baseline scenario shows that completely relaxing social distancing produces thousands of additional deaths. figure shows that the rate of fatalities per day increases dramatically when icu capacity is overloaded. the simulation shows that the number of deaths per day in this scenario quickly spikes from , a week prior the system is overloaded, to a peak of , deaths per day in less than a month. several factors may impact our predictions. to minimize the impact on our estimations caused by the delay between the patient's onset of symptoms are reported we censored the last week of data. another potential limitation is that outbreaks of covid in nearby cities could lead to an overburden in the spma healthcare system, . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . which is a reference for the state of são paulo, even if the epidemic is controlled in the spma. despite the limitations, we reported through sari electronic notification systems as a proxy for severe cases of covid an important decrease on the r(t) after two week of the implementation of social distance measures in the spma. these measures are expected to avoid , deaths in days even without any increase in total icu bed capacity. . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia novel coronavirus pneumonia emergency response epidemiology team transmission parameters of the a/h n ( ) influenza virus pandemic: a review. influenza other respir viruses the a (h n ) influenza virus pandemic: a review the reproductive number of covid- is higher compared to sars coronavirus real-time forecasts of the covid- epidemic in china from impact of non-pharmaceutical interventions (npis) to reduce covid mortality and healthcare demand expected impact of covid- outbreak in a major metropolitan area in brazil | medrxiv covid- community mobility report covid- community mobility report fadq and jc were granted a fellowship for research productivity from the brazilian national council for scientific and technological development -cnpq, process/contract identification: / - and / - , respectively. key: cord- - e umbpi authors: fort, daniel; seoane, leonardo; unis, graham d.; price-haywood, eboni g. title: locally informed modeling to predict hospital and intensive care unit capacity during the covid- epidemic date: journal: ochsner j doi: . /toj. . sha: doc_id: cord_uid: e umbpi background: in the early phases of the novel coronavirus (covid- ) pandemic, health system leaders faced the urgent task of translating the unknown into forecasting models for hospital capacity. our study objective was to demonstrate the application of a practical, locally informed model to estimate the hospital capacity needed even though the community covid- caseload was unknown. methods: we developed a susceptible-infected-recovered (sir) model that was adopted from the university of pennsylvania covid- hospital impact model for epidemics and employed at hospitals within ochsner health, the largest integrated delivery system in louisiana, between march and april , . intensive care unit (icu) admissions of cases in the new orleans area were used to estimate the community case load when testing was delayed. results: initially, the observed icu census trended near r( )= . , whereas the ventilator census trended between r( )= . and . . after implementing social distancing, both the icu and ventilator capacity trended toward r( )= . , while non-icu medical/surgical beds trended toward r( )= . . the model accurately predicted peak icu (n= ) and hospital bed (n= ) usage by april , . in response to model trends, ochsner added icu beds across its hospitals by opening a new icu and converting operating rooms and parts of emergency departments to icu beds. conclusion: when disease testing is limited or results are delayed, icu admissions data can inform sir models of the rate of spread of covid- in a community. our model used various r( ) plots to demonstrate an array of scenarios to guide planning for hospital and political leaders. during the uncertainty of the early phase of the novel coronavirus (covid- ) pandemic, hospitals and health system leaders faced the urgent task of translating the unknown into forecasting models of acute care, critical care, and ventilator capacity. a number of models emerged, with the university of washington institute for health metrics and evaluation covid- forecasting model garnering the attention of the federal government. a compilation of models was subsequently made available for quick access via the american hospital association. all of the models are based on assumptions about the current state of the disease, how quickly it spreads, and the degree to which interventions such as social distancing have been employed to slow the spread of infection. many of the models are web-based tools that require local data entry and display outputs generated from background advanced statistical modeling. the pri-mary challenge for many nonstatisticians and nonepidemiologists who must make key decisions for health systems, cities, or states is how to comprehend concepts of exponential growth and lag times and then to overlay these concepts with concrete bed or ventilator counts to predict future resource utilization. ochsner health, the largest integrated delivery health system in louisiana, usa, based in new orleans, became one of the epicenters for the covid- pandemic in early march following the annual mardi gras celebration. to help system leaders make operational decisions, we searched for a practical forecasting model that would be easy to translate locally without complex statistical modeling. we selected susceptible-infected-recovered (sir) modeling given its ease of implementation. sir models, however, can be challenging to use in the moment because they rely on known cases. in the early stages of the pandemic in the united states, testing was limited, turnover time for test results widely varied, and efforts toward standardized reporting of covid- cases were delayed. in particular, standardized reporting for diagnosis codes and laboratory result codes had not yet been published, leaving healthcare systems with variable methods of manual case tracking. notwithstanding these limitations, ochsner leadership deemed the university of pennsylvania covid- hospital impact model for epidemics (chime) - the most conceptually practical and informative tool. this report describes the development of a simplified covid- forecasting tool that was derived from the chime concepts, demonstrates the validity of our early modeling using real-world hospital census data, and shows how the tool was used to make operational decisions for a large health system in one of the covid- epicenters. ochsner health is the largest integrated delivery health system in the state of louisiana, usa, and is headquartered in new orleans. ochsner owns or manages hospitals and more than health centers and urgent care centers, has almost , employees, and employs more than , physicians in more than medical specialties and subspecialties. ochsner uses epic systems electronic health records, and data for approximately . million patients from across the system are stored in the same epic instance, allowing for robust, integrated reporting. this report is based on data collected from patients hospitalized between march , and april , . the ochsner institutional review board approved this study. the first presumptive case of covid- in louisiana was identified on march , in new orleans. during the fol-lowing week, patients with complications of covid- infections began to be admitted to ochsner hospitals and other area hospitals at a rate that would overwhelm system bed capacity in a few weeks. on march , , the mayor of the city of new orleans issued a social distancing proclamation. the governor of louisiana issued a stay-at-home order on march , , involving the closure of all nonessential businesses and educational institutions. throughout this time, state officials worked closely with hospital executive leadership to estimate capacities for hospital beds, critical care units, and mechanical ventilation. the sir model compartmentalizes the population into the categories susceptible, infected, and recovered. on average, individuals develop symptoms of covid- days after becoming infected. to estimate covid- hospital utilization on any given day, we initially made several practical assumptions: ( ) newly hospitalized patients represent % of the population, and a proportion of these patients require the intensive care unit (icu) or the icu with mechanical ventilation ( % and %, respectively); ( ) hospital discharges reflect a range of patient care-from noncritical care to icu care to icu care with mechanical ventilation-with different average lengths of stay ( , , and days, respectively); and ( ) the hospital census for each level of care is a combination of carryover patients and newly admitted patients after adjusting the daily count for patients discharged. refer to table for a summary of model parameters and table for the variables and formulas used to estimate the number of hospitalized patients according to the maximum required level of care. using the latest new orleans census track population data (n= , , ) and a random assumption of initial cases, we calculated imputations of the number of susceptible, infected, and recovered individuals in the community fort, d table were embedded to allow for rapid visual-ization and investigation of parameter changes. we initially assumed an r = . (doubling time of days, based on the chime model specifications) on march , , the last date prior to the original model publication on march , with the days of initially observed data starting march . two major changes had to be incorporated during the first weeks of model observation: the mayor's social distancing proclamation and the governor's stay-at-home order. each of these social interventions was assumed to effectively reduce infectivity to an r = . on march and to r = . or . on march , with full effects of those changes trailing by approximately days. branching forecasts were carried forward until enough icu census data were available to determine the true observed course. these branching forecasts allowed hospital executives to make operational plans based on multiple possible scenarios. the march version of the model also reflected expanded interest in bed utilization beyond icu beds. forecasting medical/surgical (medsurg) noncritical care demand began after an initial internal observation of a : medsurg to icu admission rate. the imputed non-icu hospitalization rate was %, assuming a % icu hospitalization rate. subsequent observations demonstrated : med-surg:icu census. starting march , , staff of the ochsner pulmonary critical care department began collecting census data on manually identified covid- -confirmed cases and persons under investigation for each icu and emergency department-boarded admission across the entire ochsner system. the homogenous presentation of critically ill patients with covid- allowed us to reliably identify patients with covid- infection at a time when the lack of testing did not allow the accurate calculation of spread in the community. patients were also categorized as to whether they received mechanical ventilation. on march , , we used days of manually compiled census data to fit an initial sir epidemic model that we then tracked to evaluate model fidelity during the following weeks. to better understand the arrival and flow of patients with covid- , a report was created to capture covid- confirmed patients by site, unit, and ventilation status. each unit was mapped to a level of care: emergency department, icu, medsurg, or other. the other designation included departments such as labor and delivery, psychiatry, and behavioral health where care was assumed to be unrelated to covid- status; those data were not modeled. patients on mechanical ventilation were identified with the additional status of vent. by tracking patients across each daily census file in which they appeared, the number of days at each level of care were compiled for each admission, as well as key care transitions such as initiation of mechanical ventilation, care upgrade to icu, or stepdown to medsurg. the model was started with an initial infected individuals and run forward. a starting point in terms of a known calendar date was identified by matching a modeled number of total icu patients to the observed manual census. the model was deemed qualitatively valid and useful if the days of subsequently observed census continued to track the model forecast, thereby allowing adequate time for initial expansion of icu bed capacity. we constructed sets of model forecasts. the first was the original -week forecast (march to march , ) based on the initial days of observed census data paired with the subsequently observed icu census data and expanded icu capacity. the second model forecast was an updated -week forecast (march to april , ) that accounted for expanded social interventions. figure displays the initial forecast and subsequent observed icu/ventilator census and expanded bed capacity. the observed covid- icu census appeared to trend near an r = . , whereas the covid- ventilator census trended between r = . and . . figure displays the follow-up forecast and subsequent observed icu/ventilator census and expanded bed capacity after real-time hospital data were acquired. figure displays the prediction curve for medsurg noncritical care and the observed subsequent census. by the end of the observation period, both the covid- icu and ventilator capacity appeared to be trending toward an r = . , while medsurg trended toward r = . subsequent to implementation of social distancing interventions. ochsner health used data modeling to quantify and determine the time frame needed to expand capacity for icu beds and redeploy staff. overall, ochsner added icu beds at its main tertiary facility in the first weeks after new orleans became an epicenter for covid- . icu bed capacity was also increased by beds at community hospitals by opening a new icu and converting operating rooms and parts of emergency departments to icu beds. the model provided support for physician and administrative leaders' decisions around canceling elective surgeries; not accepting transfers from outside the region; and redeploying surgeons, anesthesiologists, and nurses to covid- -related clinical duties. the model accurately predicted peak icu (n= ) and medsurg (n= ) bed needs by april , . the model also helped the health system leaders make workforce decisions, such as how many agency nurses would be needed, and supply chain decisions regarding the purchase of pharmaceuticals, ventilators, and other supplies. finally, longterm modeling led to the decision to expand the critical care tower at the main tertiary hospital by building new icu beds by the end of june . numerous mathematical models have emerged to predict the future of the covid- pandemic in the united states and globally. the most effective use of these models is to estimate the effect of various interventions for reducing overall disease burden. , [ ] [ ] early in the pandemic, uncertainty about the actual number of cases, availability and/or accuracy of diagnostic testing, differences in the reported reproductive number, heterogeneity of subpopulations, and the yet-to-be-seen effects of social distancing generated a high level of urgency to find a practical model that could be used on the frontlines of healthcare. we developed a modified version of the university of pennsylvania chime model [ ] [ ] that can be used by hospital executives and political leaders to make short-and long-term operational decisions about capacity, supply chain, and ventilator needs. on the gulf coast of the united states, leaders are accustomed to emergency planning because of experience with hurricane-related natural disasters. hurricane forecasts use spaghetti plots to show potential hurricane paths. likewise, our model used various r plots to demonstrate an array of utilization scenarios in a manner familiar to our healthcare and political leaders. because we were also plotting realtime hospital bed and icu bed use along different infection rates, we were able to provide timely evidence of the impact of our regional nonpharmacologic mitigation measures on the local r . our model provided a means for regional hospitals in the new orleans area to come together to assess medsurg bed capacity, icu bed capacity, and ventilator needs. area health systems agreed to provide daily data to our modelers and to regularly meet to coordinate emergency response. the health systems agreed to not have any one hospital go on diversion. instead, admissions were coordinated to transfer patients and resources within and between the health systems to prevent any one hospital from being overwhelmed. the model helped inform the utilization and resource needs for the entire region. as mitigation measures are eased, our model will provide valuable data for our leaders to make decisions. we will continue to track our r after mitigation measures are relaxed and can advise local leaders if it demonstrates a concerning rise over time. our study has several limitations. our use of icu census as the single source of truth for documented cases of covid- when we did not have reliable testing was one of the innovations of the model and proved to be very reliable. however, icu admissions may not represent the true number of patients needing icu care when icu units reach capacity and patients are admitted to nontraditional icu areas or transferred to hospitals outside the region. we accounted for this limitation by manually evaluating every admission and communicating daily with critical care physicians across our hospitals to account for all icu patients. during peak local covid- infectivity-late march and early april -patients were transferred between hospitals but always within the region. ochsner is the principal referral hospital for the region; therefore, some covid- admissions were transferred in and may have resulted in an overestimation of community spread. however, the fort, d number of these patients was limited because ochsner stopped accepting transfers from outside the region during this time frame. our study is also limited by changes in management of the disease over time. initially, the critical care teams intubated patients with respiratory failure early to close the circuit and protect healthcare workers from droplets. as understanding of the treatment of covid- evolved, our critical care teams adopted evidence-based practices used for other forms of hypoxemic respiratory failure, including high-flow nasal cannula, continuous positive airway pressure, and bilevel positive airway pressure with good success in keeping patients off the ventilator and as an adjunct to removing patients from the ventilator. as a result, our models soon demonstrated a much lower need for mechanical ventilators. finally, our model represents the epidemiology of covid- spread in the new orleans area where we had a large inoculating event (mardi gras) and may not be representative of other regions. our simplified sir model offers leaders a practical approach to epidemic modeling that assesses utilization needs based on service areas of a given hospital. when testing is limited or results are lagging, icu admissions data can be used to inform sir models of the rate of spread of covid- in a community. forecasting the impact of the first wave of the covid- pandemic on hospital demand and deaths for the usa and european economic area countries. ihme covid- health service utilization forecasting team a compendium of models that predict the spread of covid- american hospital association locally informed simulation to predict hospital capacity needs during the covid- pandemic university of pennsylvania. penn-chime.phl.io mathematical models to characterize early epidemic growth: a review the incubation period of coronavirus disease (covid- ) from publicly reported confirmed cases: estimation and application influenza forecasting in human populations: a scoping review predictive mathematical models of the covid- pandemic: underlying principles and value of projections key: cord- -mvsdrxzf authors: canavera, kristin; elliott, andrew title: mental health care during and after the icu: a call to action date: - - journal: chest doi: . /j.chest. . . sha: doc_id: cord_uid: mvsdrxzf nan critical illness is associated with high rates of significant, negative psychological and psychiatric sequelae that are commonly associated with post-intensive care syndrome (pics). pics refers to the cognitive, physical, and psychological impairments that many patients experience post-icu. the primary mental health impairments that critical illness survivors experience are long-term cognitive impairments, depression (approximately % of survivors), anxiety (up to approximately %), and post-traumatic stress disorder (ptsd; - %). , delirium during critical illness, sometimes referred to as "icu psychosis," is also common and has been associated with ptsd. despite this data, patients often do not receive mental health care during or after their icu admission in our country. few u.s. hospitals have comprehensive psychological or psychiatric care available either during or after an icu admission. europe seems to be doing better in terms of prioritizing the mental health needs of this population. they have pioneered research in reporting psychological/psychiatric outcomes and treatments for icu patients. , we hear growing concerns about a potential mental health crisis due to covid- , including that difficulties in coping with this illness and associated stressors (i.e., isolation, financial stressors) could potentially lead to higher suicide rates, drug overdoses, trauma, and mood disorders. these concerns are likely to be more prominent in the icu population given both their more severe physical illness and the higher rate of mental health concerns already noted in this population, , in response, we must be prepared for the possibility that covid- icu patients and survivors may require intensified mental health care interventions to address pics. even prior to the covid- pandemic, our country had an unmet yet important need to improve our provision of mental health care for critically ill patients and icu survivors. filling this gap in mental health care could protect against some of the negative outcomes of critical illness. during this era of covid- , the need to address these negative psychological outcomes will likely become increasingly important. we urge public health experts, hospital administrators, and clinicians to prioritize actions developed to address these mental health care needs both during and after critical illness. to start, icu clinicians should regularly screen for delirium. in pediatrics, for example, some hospitals have trained their bedside nurses to use a delirium screener each and every shift. hospitals can devote resources to train staff, particularly nurses, to better recognize and manage delirium, including not only screening and assessment, but also implementation of nonpharmacological interventions (e.g., improving sleep/wake cycles and orienting patients). early mobilization/rehabilitation is another initiative that more and more icus are implementing to improve the long-term outcomes for icu patients and should be considered. preventative measures to mitigate pics are increasingly being implemented in icus. one such tool is the abcdef bundle, an evidence-based guide for multidisciplinary critical care coordination. adjustments to the abcdef bundle due to covid- restrictions and challenges (socially isolated patients) have recently been proposed to lessen the burden of delirium among covid- patients. hospital administrators should consider allocating resources to creating or increasing use of consultation/liaison services for both psychiatric and psychological care. ideally, icus will have either part-time or embedded psychologists and psychiatrists for critical care patients, both during and after the icu admissions. likewise, there is a need to develop and implement systems to screen for anxiety, depression, ptsd/trauma, and cognitive disturbances surrounding icu admission efforts to both treat and prevent these outcomes. hospitals and clinicians must also consider post-icu follow-up care. hospitals can consider developing and creating post-icu care clinics to better monitor and manage pics. europe has led the way in establishing these clinics, but they are still scarce in the u.s. as a broader public health issue, we also need to train our mental health care workforce in these unique icu issues and outcomes. while a select few mental health care clinicians are specialized in rehabilitation psychology or critical illness, most are not. amidst this global pandemic we are facing and the unprecedented surge in icu admissions, it is likely that mental health clinicians may be providing services to patients or families negatively impacted by critical care during this era of covid- . as such, more mental health care clinicians should familiarize themselves with the psychological outcomes of critical illness and receive additional training and education in this realm and/or mentorship. the evidence is growing and convincing -critical care is associated with substantial mental health needs and cognitive impairments negatively impacting the overall quality of life of patients. public health experts, hospitals, and clinicians need to prioritize mental health care both during and after icu admissions. now more than ever, mental health care for icu patients and survivors is critical, particularly in light of the global pandemic we are facing today. as a nation and global community, we have turned to public health experts for guidance in increasing the capacity for covid- patients by increasing the availability of icu beds and associated medical needs. but we cannot forget about the equally important psychological outcomes of our critical care patients. we have an obligation to also increase capacity to meet the mental health care needs of icu survivors, minimize issues related to pics, and consider the provision of mental health care and screening as a psychosocial standard of care for critically ill patients. post-intensive care syndrome: its pathophysiology, prevention, and future directions psychological impact of critical illness assessment of pediatric delirium: a valid, rapid, observational tool for screening delirium in the picu* the abcdef bundle: science and philosophy of how icu liberation serves patients and families covid- : icu delirium management during sars-cov- pandemic key: cord- -pol qm authors: nan title: third international congress on the immune consequences of trauma, shock and sepsis —mechanisms and therapeutic approaches date: journal: intensive care med doi: . /bf sha: doc_id: cord_uid: pol qm nan this issue of the journal contains the abstracts for the third international congress on the immune consequences of trauma, shock and sepsis -mechanisms and therapeutic approaches. we hope that the information contained in this special issue will stimulate you to participate in the congress, to contribute to the knowledge being developed in this field and to use this information to help you in providing better care for your patients. we thank the editors and the editorial board and publishers of the journal for their interest and support in preparation of this special issue. we also, on behalf of the scientific committee, welcome you to the third international congress in munich on - march . when, in the mid- s, we thought of having a worldwide congress, we hoped to bring together investigators to discuss this theme. the explosion of knowledge occurring around that time provided an excellent background against which the first conference in provided stateof-the-art information and consensus on factors involved in injury and sepsis. in , the second congress was held at the time of another resurgence of research, study and information on injured and operated patients. it seemed then that there would be a lull in the development of new information and therapy, and that another state-of-the art conference might not be necessary until or . however, the explosion in molecular biology has continued. the wonderful world of cytokines has gone from ill to il- to il- , il- and il- and beyond. the vast amount of information about mediators and their importance in disease is impressive. this has all suggested a magic bullet that might be used to alter or block inflammatory responses. this has not happened, however, and the question is "why not"? our science is powerful, but our therapy is still weak. what are the issues, then, in , to be dealt with at this symposium and congress? ( ) proposals for new terminology. there have been a number of proposals for new terminology and new classifications of injury, sepsis, inflammation and various other problems related to human illness. the question is whether this is the way to go. will this contribute to better clinical trials, information basis and better research? the pros and cons of this development will be reviewed by those making the proposals and those questioning the need for and wisdom of this effort. ( ) magic bullets: the prospect of a magic bullet to deal with inflammation in injury and infection seemed highly promising earlier. many preclinical trials and a lot of animal research suggested the possibility of a great breakthrough in clinical care. what has become, then, of all the expensive and extensive multi-institution randomized, placebo-controlled, double-blind clinical trials of agents that block mediators and endotoxin. many such studies have yielded equivocal, marginal or negative results. the reasons for this and the future of clinical research will be the subject of presentations and discussions to set the stage for further work. ( ) should future clinical trials be based on new classifications of illness such as mods, sirs, apache iii, sap ii, mrm, etc., or should trials be dedicated to specific diseases -urinary tract infections, pneumonia, trauma patients, cardiac surgery and other specific problems, rather than generalized problems of sepsis, the sepsis syndrome and other classifications? in other words, should we now begin to have clinical trials on specific diseases with causes that are known and can be attacked? the causality of disease becomes an important consideration in this regard. ( ) a multitude of potential therapeutic agents has been proposed on the basis of animal studies. how should we decide which of them should be brought to clinical trial? the possibilities are endless as we develop new clinical information about the mechanisms and pathogenesis of human disease. ( ) information on the pathogenic mechanism of disease states and of injury continued to emerge in an explosive fashion, and in light of our gathering knowledge we can look forward to working out a cohesive system of response to injury. ( ) additional information will be provided in plenary sections, many symposia and free communication sessions and posters, which will update the participants on a variety of relevant topics presented by many of the leading in-iv vestigators in these fields. topics will range from molecular mechanisms, such as signal transduction, through the explosive growth of information on the role of cytokines and pathophysiology, to practical considerations in the design of immunomodulatory therapeutic regimens. these merely touch on a few areas, from the basic to the clinical, which will be the subjects of those symposia. all this information will fit into the jigsaw of this exciting area and its stimulus to further research study. this promises to provide an exciting, educational programme with experts and participants from all over the world. we hope it will set the stage for many years to come and will increase our understanding of trauma, shock and sepsis and help us to provide better therapy for those of our patients who are affected by such problems. a. the clinical syndrome of mods versus mof will be reviewed in detail by those who have made these proposals. b. an extensive review of the design and interpretation of clinical trials in patients with shock and injury will be provided. the reasons why so many clinical studies in the recent past have been negative will be reviewed. the therapeutic strategies that are being developed for the treatment or prevention of mods or mof will be the subject of another panel discussion by experts who have been involved in and contributed to this area. a consensus conference or controversy conference will be presented about various aspects of mods or mof, including the benefits of supernormal oxygen delivery, bacterial translocation, parenteral nutrition, the immune response and other aspects. the successes and failures of completed clinical trials will be presented by those who are involved in these clinical trials, with a refreshing review of the problems related to that injury. there will be late news about studies just being completed at present or after the beginning of and where they stand. c. the mechanisms and biochemical profiles of specific organ dysfunction or failure will be reviewed. what are the definitions? what are the mechanisms? how can organ dysfunction and/or failure be defined? an extensive review of the biological mechanisms involved in production of injury by mediators will be presented. a session will be devoted to how future ongoing trials might be better designed and what can be done about the studies recently completed, many of which are negative. d. the immunological or inflammatory pathways resulting in organ injury will be reviewed in detail in presentations and a panel discussion. we look forward to welcoming you to an exciting and rewarding conference, which undoubtedly possesses the potential to become a landmark event and major reference point for any scientific discussion about the complex of host defense dysfunctions following trauma, shock and sepsis. studies over the past years have established that the contact system, which forms bradykin/~, is gax important mediator in hypotensive septicemia. in addition to hradyk{nln, another product of the contact system, kailikrein, can mediate inflammation by virtue of its chemotaetic mad neutrophj/activating properties. using functional and immunochemical tech~ ques, we have demonstrated activation of the contact system in the adult respiratory distress syndrome in typhoid fever and clin/cal sepsis. we have also been able to inhibit the hypotension but not the disseminated intravaseular coagulation in a model of primate sepsis by the use of a monoclonal antibody directed agsi~st factor xii, the initiating protein of the contact system, in volunteers given e. coil endotoxin, who did not develop hypotension, we were also able to demonstrate activation of the contact system with a rise of alpha- macrogiebulin-kalllkrein complex. we have also examined, j~ an i~tensive care situation, patients with sirs. we found that serial measuremezzts of the contact system were useful in eva~u~ting prognosis+ these studies suggest that inhibition of kalllkrein a~d l e r bradykinin actions might be useful i~ obviating many .of the features seen in sepsis and septic shock. dextran sulfate (dxs) activates the contact system and, in vivo, produces transient hypotension. in order to better define the mechanisms underlying the dxs-induced hypotension, we investigated the effects of either the plasma kallikrein inhibitor, des-pro -iarg] ]aprotinin (bay ) or the b kinin antagonist, hoe on the hypotensive response to dxs. in the first study, anesthetized miniature pigs ( pigs/group, randomly assigned) were given one of the following treatment protocols: ) dxs ( mg/kg), - ) dxs plus bay ( , , , or rag), or ) saline. dxs alone produced a profound but transient systemic arterial hypotension with a corresponding reduction in plasma kinin-containing kininogen. circulating kinin levels, complement fragment c adesarg and fibrin mom)mer were all increased. bay produced a dose-dependent delay or attenuation in these effects with the highest dose completely blocking dxs-induced hypotension and elevations of kinin, c adesarg and fibrin monomer levels. thus, the effects of dxs are solely dependent on contact system activation and this activation is sensitive to bay . llowev~:r, contact system activation is known to produce changes in a variety of vasoactive mediators, all of which can affect blood pressure. in a second study, two groups of pigs ( /group) were given either dxs alone ( mg/kg) or dxs minutes after a bolus injection of hoe ( #g/kg). dxs alone produced transient hypotenmon. this response was completely blocked by hoe pretreatment. both groups had identical reductions in kinin-containing kininogen. we conclude that dxs-induced hypotension is produced by activation of the contact system which results in the production of bradykinin. liberation of bradykinin is both necessary and sufficient to produce all of the hemodynamic changes observed. dr. matthias siebeck, department of surgery, university of munich, klinikum lnnenstadt, nussbaumstrasse , d- munich, germany in experimental animals exposed to i.v. injection of endotoxin accumulation of leukocytes in various organs as lungs and the liver is a prominent feature. as a part of these morphological changes damages of endothelial ceils are regularly seen. this process, which is a part of endothelial-cellular interaction, leeds to exposure of the sub-endothelial basement membran. the basement membran is known f r its capacity to activate the contact system of plasma. during this cascade activation, coagulation factor xii is converted to the active factor xii. this activation might produce increased plasma kallikrein activities and thereby give release of the vasoactive substance bradykinin. using a porcine model we have noticed that endotoxin infusion ( , mg/kg) induces elevated plasma kailikrein activities within two hours after the start of the infusion. this enzyme activity remained increased during the next hours and reached value of up to u/ . in patients with sepsis we also have observed elevated plasma kallikrein activities with enzyme activities up to u/ . in order to further elucidate the significance of these elevated enzyme activities, we prepared human plasma kallikrein and injected it intravenously in anaesthetized pigs ( ). when very small plasma kailikrein activities ( , u/kg bodyweight) were given intravenously a % decrease in arterial blood pressure was seen in the animals. in the patients with sepsis also decreases in prekallikrein values and functional plasma kallikrein inhibition are frequently seen. furthermore, degradation of high molecular weight kioinogen is found in these patients indicating formation of bradykinin. these experimental and clinical studies underline that contact activation in sepsis might results in the release of very powerful mediator substances which can be of pathophysiological importance in this disease. a number of pathological disorders as reperfusion injury, bone marrow transplantation, polytrauma and septic shock are associated with capillary leakage. as the activation of the complement system and the contact phase play a major role in these diseases we investigated whether cl-lnhibitor (c -inh), which inactivates cl-esterase, kallikrein and clotting factors xii and xl, could abolish vascular leakage. a capillary leakage was induced in rats by the administration of interleukin- ( x iu/kg). the increased vascular permeability was monitored for one hour as the extravasation of fitc marked rat serum albumin from a mesenterial vessel by a video-image processing system. ci-inh (berinert®, behringwerke) given as a single i.v. bolus in concentrations of , or u/kg dose-dependently prevented the capillary leakage. carrageenaninduced inflammation in the rat leads to vascutar leakage and to edematous swelling of the paw. ci-inh in this model leads to a dose-dependent decrease in paw edema formation. finally, we investigated the effect of ci-inh (infusion ( - u/kg x h) on a lps-induced shock in the rat by combination therapy with the antithrombotlc agents antithrombin ill (kybernin®) or rec. hirudin (both substances from behringwerke). in this animal model mortality was % in the untreated control. both antithrombotic agents decreased mortality rates by inhibiting formation of dic; a further significant improvement of survival was achieved by the treatment with ci-inh. thus+ it could be concluded that c -inh has a beneficial effect in diseases associated with a vascular leakage. iclb and laboratory for experimental and clinical immunology, university of amsterdam, the netherlands; thrombosis research center, temple university, penn., usa; oklahoma medical research foundation,. ok. city, usa. to evaluate the contribution of the contact system to activation of other mediator systems in an experimental model of sepsis, we investigated the effect of mab c b which inhibits activation of factor xli, on activation of complement and fibrinolytic cascades and activation of neutrophils in baboons suffering from a lethal sepsis. activation of the complement system was assessed by measuring circulating levels of c b/c and c b/c, and a significant reduction was observed in animals that had received a lethal dose of e. coli together with mab c (treatment group), compared to animals that had received a lethal dose of e. coil only (control group). activation of the fibrinolytic system as reflected by circulating plasmin-= antiplasmin complexes and tissue plasminogen activator, and activation of neutrophils, assessed by measuring circulating elastase-=l-antitrypsin complexes, was also significantly less in the treatment group. we conclude that activation of the contact system protein factor xll during the inflammatory response to a lethal dose of e. coil in this baboon model, modulates directly or indirectly activation of the complement and fibrinolytic systems and that of neutrophils. in a prospective study, plasma levels of c a, c , and c a were measured in patients from an internal intensive care unit. patients were clinically septic defined by the criteria of bone et al.(l) . the remaining patients were critically ill but didn't fulfill the clinical criteria of sepsis. from both groups of patients blood samples were taken over a l days period. during the first days blood samples were drawn every h, on day - every h and the last days once daily. mean plasma concentrations of c a within the first h after clinical onset of sepsis were + pg/ml, whereas non-septic-patients exhibited mean values of only +_ p_g/m/. c levels were lower for septic-patients ( + lag/ml) than for non-septic-patients ( _+ lag/ml). the most profound difference between both groups was found, when the c a/c ratio was compared ( . + . for septic-patients and . _+_ . for the control group). no significant differences between both patient groups were observed in c a plasma levels ( . + . ng/ml in septic-patients vs. . _+ . ng/ml in control patients). in of cases of clinically defined sepsis causative organisms like bacteria, protozoa or fungi could be cultured from blood, bronchoalveolar lavages and/or section materials. application of the complement parameters to survivors (n= ) and non-survivors (n=l ) within the septic-group revealed, that the c a/c ratio could also be used as a prognostic parameter for clinical outcome. the possibility of rapid and easy measurement of c a and c in only - minutes ( ) and the significant difference of the c ajc ratio between the septic and non-septic group renders this parameter a good candidate for early diagnosis of sepsis in the intensive care unit. hirudin, a single polypeptide chain composed of amino acids with cysteine residues (mr daitons), is the most potent and specific thrombin inhibitor, which is now available as a genetically engineered product (rec. hirudin -hbw , behringwerke; marburg). the aim of our study was to establish a rabbit model of tissue factor (tf) induced activation of the extrinsic pathway of coagulation and to evaluate the therapeutic efficacy of rec. hirudin. coagulation was induced in female nzw rabbits by infusion of . p.g/kgxh thromboplastin for hours. development of disseminated clotting was manifested by a decrease of fibrinogen and platelets to . % and , % respectively, and by an increase of fibrin monomers from . to > . ~tg/ml. we administered rec. hirudin to rabbits in different concentrations ( . , . and . mg/kg); treatment started simultaneously with the infusion as an i.v. bolus. rec. hirudin significantly prevented the decrease of fibrinogen, platelets and the increase of fibrin monomers. this effect was dose dependent and long lasting, even hours after the administration of rec. hirudin, clotting was still significantly reduced. as could be drawn from the plasma levels, rec. hirudin had been cleared from plasma at this time. in a post-treatment study we administered rec. hirudin ( . , . and . mg/kg i.v. bolus) as late as hours after the start of tf infusion. at this time there was already a prominent activation of coagulation. even in this post-treatment regimen rec. hirudin significantly prevented disseminated clotting. hence, it was concluded, that rec. hirudin by inkihiting thrombin could be effective in the prevention of coagulation disorders including disseminated intravascular clotting (dic) induced by a septic disease. research laboratories of behringwerke ag, marburg, germany $ novel protease inhibitory activities of the second domain of urinary trypsin inhibitor (r- ) and its effect on sepns-lnduced organ injury in rat atsuo murata , hitoshi toda , ken'ichi uda , hidewaki nakagawa , takesada mori , hideaki morishita , tom yamakawa , jiro hirese , atsushi ni~ , nariaki matsuura osaka university medical school, osaka, mochida pharmaceutical co. ltd. tokyo, wakayama medical schoof, wakayama, japan inhibitory-activities of the second kuntz-type inhibitor domain of human urinary trypsin inhibitor (uti) and its effect on sepsis-induced organ injury in rat were investigated by using the recombinant protein. uti is a glycoprotein with a structure in which kunitz-type inhibitor domains are linked in a row. we isolated the gene encoding the second kunitz-type inhibitor domain of uti, and then constructed expression plasmids by ligating it to the e. coli phoa signal peptide gene. these plasmids expressed the second domain in e. coil strain je which lacks the membrane lipoprotein. the recombinant second domain (r- ) innb[ted trypsin, plasmin, neutrophil elastase and chymotrypsin. in addition it inhibited blood coagulation factor xa and plasma kallikrein in a concentration dependent and competitive manner. the in vivo effect of the recombinant r- was investigated in a rat model of septic shock induced by cecal ligation and puncture. the administration of r- significantly improved the survival rate of the rats and attenuated the pathological changes of lung and iiver. we found out the novel protease inhibitory activities of the second domain of uti and its protective effects on sepsis-induced organ injury. macrophages are known to secrete lysosomal proteinases,mainly cathepsin b and cathepsin l, and also ~-proteinase inhibitor (pi),related to acute phase proteins.disturbances of proteinases/ proteinase inhibitors correlates with inflammatory process,leading sometimes to noncontrol "pathglogical" proteolysis (jochum et ai., ) . the cathepsin l-like and cathepsin b-like activity were measured in serum of patients with chronic bronchitis ( -with obstructive, -with nonobstructive bronchitis),acute bronchitis ( ) and healthy persons.simultaneously the level of~pi was determined in the same groups.cysteine proteinases were measured with help of fluorogenic substrates,as was presented earlier (korolenko et ai., ) , ~pi with help of immune enzyme method. it was shown increase of cathepsin l-like and cathepsin b-like activities during aggravation of chronic bronchitis comparatively to the controls ( - fold) .after treatment there was a tendency to normalization of indices,but the increase was about - % more than the control values.~pi level in this group was also increased (two-fold),in patients with acute bronchitis - - -times more comparatively to the control.it is possible to conclude that chronic bronchitis induced increased secretion both cysteine proteinases and d{pi into blood. some peculiarities of ratio were noted in patients with emphysema. endotoxins are microbial products derived from the outer cell membrane of gram negative bacteria. the active component of endotoxin is lipopolysaccharide (lps), a complex macromolecule consisting of polysaccharide covalently bound to a unique lipid, termed lipid a. now recognized to embody the endotoxic principle of lps, lipid a consists of a/ - diglucosamine backbone, both ester and amide linked fatty acids, some of which are acyloxyacylated, and charged constituents such as phosphate, phosphorylethanolamine and amino arbinose lps, exerts its biological effects in vivo by noncytotoxic interactions with a variety of host inflammatory mediator cells, primarily the mononuclear phagocyte and the endothelial cell, although other host cells also participate. these interactions are modulated by lps-specific binding proteins found in plasma, including lps-binding protein (lbp) scd and perhaps other proteins as well. specific receptors for lps have been identified on mammalian cells which mediate signal transduction via multiple pathways. lps-activated host cells are stimulated to secrete or express multiple proinflammatory mediators, including tnf-a, illa, il- / , ifn-a, il- , il- , il- , paf, pge, ltb and procoagulant activity. the overproduction of these proinfiammatory mediators results in the manifestations of endotoxemia, observed experimentally as fever, hypotension, disseminated intravascular coagulation and death. modulation of activity of these mediators protects animals against lethality. similar pathways are thought to be operative in gram negative sepsis, and control studies with human volunteers support such conclusions. immunotherapeutic approaches in clinical gram negative sepsis have, to date, been less successful. in vitro experiments and studies in animal models have recently shown that several proteinaceous bacterial exotoxins can evoke cytotoxic effects that ultimately lead to cardiovascular collapse and shock. since the possible relevance of bacterial exotoxins in the pathogenesis of septic shock has received very little attention in the past, an attempt will be made here to provide a brief overview of this generaily neglected topic. protein toxins act intracellularly or they dz~nage the integrity and function of the plasma membrane. major representatives of the former group are the adenosine diphosphate (adp)-ribosylating toxins, e.g. cholera and cholera-like toxins, diphtheria toxin), and the neurotoxins. most medically relevant toxins of this category have been studied in great detail. although often responsible for severe and sometimes fatal disease, their association with septic shock is rare. in contrast, experimental evidence is accumulating for a role of membrane<lamaging toxins in the pathogenesis of inflammatory lesions. formation of transmembrane pores is probably the most widespread mechanism via which such physical membrane perturbation can occur ( , ), the present discussion will be restricted to this category of toxins. the author shall first discuss basic properties of pore-forming proteins, and consider the factors that direct their attack to specific targets. thereafter, attention will be drawn to diverse functional consequences that may follow membrane damage so that a general concept of how pore-forming toxins may contribute towards the development of shock will evolve. i. bhakdi, s. and tranum-jensen. j. gram positive bacteria produce exotoxins that, at least in part, exhibit the unusual properties of superantigens. superantigens (sag) activate v/ selectively t cells to produce lymphokines including i - and tnf/lymphotoxin. systemic application of the sag staphylococcal enterotoxin b (seb) to d-galactosamine sensitized mice causes lethal shock within hours. seb reactive v/ + t cells accumulate within - min mrna for the ii- , i - , tnfai~ and ifn- ,. parallel in time high concentrations of bloodborne i - and tnf are noted. anti tnf t~// neutralizing mab protect mice against seb induced t cell dependent lethal shock thus indicating a key role of tnf in effecting lethal toxicity. within - h distinct levels of tolerance to seb become discernable on ligand reactive v/ t ceils, dependent of the dose of seb used. these levels include anergy, t cell receptor downregulation, loss of cd , cd , cd accessory molecules and programmed cell death. m.freudenberg, y.yaegashi, p.nielsen, c.galanos. the sensitivity towards endotoxin (lps) is genetically determined, however it may be increased under different experimental conditions. these include treatment with hepatotoxic agents such as d-galactosamine, and with live (infection) or killed bacteria. it is well established now that d-galactosamine sensitizes to lps by increasing the susceptibility of the host to toxic activity of lps-induced tnf~. sensitization by bacteria, especially by gram-negative once is of especial interest because it implies that infecting microorganisms not only produce lps, but als sensitize the host to its lethal activity. sensitization to lps by bacteria proceeds in all lps-sensitive (lps n) mouse strains that have been investigated so far. it also proceeds in lps-resistant (lps d) c h/hej mice. the absence of sensitization to lps in lps d c bl/ sccr mice was identified as being due to their inability to produce interferon- (ifn?). administration of exogenous ifn? to these mice conferred sensitivity to lps. conversely, administration of anti-ifn? to lpsn; mice inhibited the development of sensitization'by bacteria. it may be concluded therefore that ifn is the mediator of sensitization to lps by bacterial infection. the ifn? defect of c bl/ sccr mice concerns only the ifn response to bacteria, since the response to the t-cell mitogen con a and to cd monoclonal antibodies was not impaired. the ifn?producing cells themselves were shown to be intact. on closer investigation the impaired ifn? response was identified as the result of a defective accessory function of macrophages. macrophages of c bl/ sccr mice are incapable of producing interferon-~ (ifn~) which we could show to be obligatory for the production of ifn? in response to bacteria. although antibiotics are required to clear bacteremia, they do not reverse evolving shock, because endotoxin free in the bloodstream or exposed on the surface of circulating bacteria continues to activate the production of inflammatory mediators, furthermore, antibiotics have been shown to induce release of endotoxin from gram-negative bacteria during the treatment of severe infection. in an in-vitro study, using live escherichia coil, we have observed the release of endotoxin upon treatment with several antibiotics like cefuroxim, imipenem, ceftazidime and aztreonam. incubation with imipenem or ceftazidime induced an early lyeis and a mild rise in endotoxin levels, whereas incubation with cefuroxime or aztreonam resulted in the formation of filaments with a late but dramatic rise in endotoxin levels. in a second study we studied the influence of different antibiotics on the tnf-= production of e.coli stimulated human monocytes. we found again great differences in the production of this important cytokine among the different antibiotics according to their capacity to induce liberation of endotoxin. these differences in the amount of endotoxin release are probably caused by penicillin-binding-proteins (pbp) specificities of the antibiotics with resultant differential morphological changes, in a rat sepsis model treatment with imipenem or ceftazidime resulted in a transient increase in il- levels, whereas treatment with aztreonam resulted in progressively increasing levels of il- and a significant increase in mortality. the increased mortality in pbp- specific aztreonam treated rats might have been the result of filament formation in the abdominal cavity of the septic rats. the endotoxin sequestered at local sites may account for the precipitation of gram-negative shock. finally, we've also demonstrated that in patients under treatment for septic shock endotoxin release can be related to the administration of antibiotics. carbapenem-and cephalosporin-lnduced release of lps from smooth and rough pseudomonas aeruginosa: in-vivo relevance j. jackson and h. kropp, merck research laboratories, rahway, nj b-lactam (cell-wall active) antibiotics are generally deemed the class of antibiotics most responsible for the release of free endotoxin (lps) from gram-negative bacteria due to their cell lytic actions although all antibiotic classes studied thus far induce release of endotoxin. we have recently shown in-vitro that antibiotics within the b-lactam class (i.e. imipenem , meropenem and ceftazidime , with equivalent mics) differ in their propensities to release excessive amounts of lps from both smooth-(s-) and rough-(r-) lps laboratory and clinical and antibiotic-sensitive and -resistant p. aeruginosa isolates and that lps release is independent of cell lysis. additionally, variations in the induction of endotoxin release is antibiotic concentration dependant and correlate with antibiotic penicillin-binding protein (pbp) affinities which result in morphological changes. these studies also show that lps differences measured via chromogenic lps (c-lal) assay correlate with lps lethality in lps-sensitive mice. release of lps was compared to changes in cfus, cell mass, morphology and antibiotic pbp-specificity. corresponding in-vivo studies in cd mice against s-lps p. aeruginosa isolates show that, despite equivalent in-vitro protection, antibiotic efficacy in mice differ as much as -to lo -fold. to establish a possible in-vivo role for antibiotic-induced release of free lps we compared antibiotic efficacy results in mice challenged with virulent parent s-lps and its relatively avirulent r-lps mutant (lacking only its side chain) p. aeruginosa isolates. results show the relevance of quantity and physiochemical composition (bioreactivity) of free lps to virulence and in-vivo antibiotic efficacy. in other in-vivo studies chemical agents that destroy cells (m~) which mediate lps lethality in-vivo were used to pretreat mice prior to antibiotic therapy and bacterial challenge with wild type pseudomonas. we conclude that circumstances in which antibiotic-induced filamentation occurs are also conditions that yield excessive lps release, the in-vivo effects of which are shown through the requirement of larger amounts of antibiotic to afford equivalent protection. bacterial endotoxins have been reported to play a significant role in the pathogenesis of gram negative sepsis by their interaction with, and stimulation of, host inflammatory mediator cells to produce cytokines, biologically active lipid intermediates, and procoagulant activity (tfa). although both microbe-associated and free endotoxin are capable of stimulating mediator production, studies from our laboratory suggest that free endotoxin may be the more potent stimulus for tnf and tfa. further, our studies suggest that the majority of the proinflammatory activity released from antibiotictreated e. coli coisolates with lps by two different fractionation techniques. to assess whether actions of endotoxin directly contribute to lethality in gram negative sepsis, an experimental model was developed in which mice were made hypersusceptihle to the lethal effects of endotoxin by treatment with d-galactosamine (dgaln). challenge of cf- dgaln-treated mice with e. coli olll:b resulted in an lds of approximately . x cfu. resolution of the peritonitis and bacteremia by treatment with cell wall-active antibiotics resulted in an increase in the ldso. ceftazidime and imipenem, which differ in their mechanism of action and in their capacity to effect endotoxin release in vitro, also differed in their in vivo capacity to provide chemotherapeutic protection ( fold vs fold respectively, p< . ). parallel studies with endotoxin hyporesponsive c h/hej mice indicate significantly greater levels of protection with imipenem (> fold vs saline controls). collectively these data suggest that endotoxin may contribute directly to the pathogenesis of experimental gram negative sepsis. bacterial lipopolysaccharides (lps) are the endotoxins of gram-negative bacteria and represent their major surface antigens. lps is made up of three chemically, biologically and genetically disctinct regions, i.e, the o-chain, the core region and the lipid a moiety whereby the latter represents the endotoxic center. it is our current understanding that lps is responsible for many of the pathophysiological events observed during gramnegative infections and that one of the major mechanisms leading to shock and death is the lps-induced activation of macrophages resulting in the production and release of lipid and peptide mediators, among which tumor necrosis factor seems to be the most important. therefore, in the fight against the lethal outcome of gram-negative infections, modern strategies, in addition to antibiotic treatment, aim at i) the neutralization of tumor necrosis factor, ii) the inhibition of the production of tumor necrosis factor or iii) the neutralization of the activation potential of lps for macrophages by monoclonal, preferably human antibodies. the latter approach, to be effective against a broad spectrum of gram-negatives, must be directed against common structures of lps (lipid a and core region). the molecular basis of this approach and the controversy in this field will be discussed. passive immunotherapy has been used since , when von behring described the administration of immune horse serum to treat a patient with diphteria infection. even if this therapy was sometimes successful in bacterial infections, it has been largely replaced by antibiotics. however, antibiotics have their limitations, especially in critically-ill patients. to improve outcome, adjunctive therapies such as immunotherapy with polyclonal and monoclonal antibodies particularly against endotoxin are again considered. the role of humoral immunity in host defenses against bacterial infections is weu known. for instance, tile importance of antibodies in the defense against gramnegative infections has been established clinically by studies relating the outcome of patients with gram-negative bacteremia to tilers of antibodies directed at the offending pathogens at the onset ofbacteremia (mccabe ; pollack ) . ever since we know the role of endotoxins in the pathophysiology of sepsis, antibodies against the s-and r-lps have also been detected in sepsis patients. the aim of the administration of iv/g to the sepsis patient is as follows: ) enhancing of opsonization and phagocytosis(antibactericidai activity) ) synergistic effects with [ - actam antibiotics ) neutralization of endotoxin, the main pathogenic mediator of gram-negative sepsis ) modulation and/or inhibition of cytokine release the enhancement of opsonic-and phagocytic-activity especially with igg via fc and c receptors has been well documented. monoclonal antiendotoxin antibodies, proven in clinical studies, do not appear to neutralize endotoxin in vitro and are not reproducibly protective in animal models of sepsis. also they can not suppress endotoxin-induced tnf-~, il- release in mice (baumgartner , corriveau and danner ) . in conlrast, recent studies of a polyclonal immunoglobulin preparation, containing high levels of antibodies against gram-negative bacteria and their o-antigen of lps in igg, igm and iga classes (pentaglobin®) provide evidence to neutralize endotoxin. this effect is demonstrated in vitro (berger (berger , , in animal models (stephan , berger and also in prospective, randomized, controlled clinical trials (schedel , poynton , behre . furthermore mortali b' was reduced statistically in patients with septic shock and endotoxemia by using this preparation, as has been demonstrated by sehedel. anti-core lps monoolonal antibodies: binding specificity and biological properties f.e. di padova, r. barclay, e.th. rietschel. bacterial lps and cytokines are responsible for the pathological processes of gram-sepsis and are suitable targets for therapeutic interventions. chemical characterization and structural analysis of different lps have revealed common features. the inner core region of lps shows a high degree of similarity among e. coli, salmonella and shigella. among a large number of broadly cross-reactive murine anti-core lps mab one of these igg ak) has been selected and chimerized into a human igglk (sdz - ). in elisa and in immunoblots on purified lps both sdz - and wni - show a strong reactivity with all smooth lps from e. coli and salmonella. reactivity with all the known complete core structures from e. coli and salmonella (ra) is evident. reactivity with re structures or free lipid a is not observed. this mab cressreacts with all clinical e. coli isolates from blood, urine and feces and with other enterobacteriaceae. sdz - and wni - have biological activity as they inhibit the lal assay and the secretion of monokines (il- and tnf) by mouse and human macrophages. moreover, sdz - and wni - inhibit the release of il- and tnf in vivo. in vivo sdz - as well as wni - neutralize the pyrogenic activity of e. coli lps and protect mice from lethality in d-gain-sensitized mice. the possibility to use wni - as a capture antibodies in the immunolimulus assay opens the possibility to differentiate the origin of the lps in patients with endotoxemia. franco di padova, sandoz pharma ag, ch basel, $chweiz $ presentation of lps to cd by lps binding protein peter s. tobias, julie gegner, katrin soldau, lois kline, loren hatlen, douglas mintz, and richard j. ulevitch. the activation of myeloid cells by lipopolysaccharides (lps) has been shown to require the serum glycoprotein lps binding protein (lbp) and binding of lps to membrane bound cd (mcd ). other cells such as human umbilical vein endothelial cells (huvec), smooth muscle cells, and some epithelial cells, which do not express mcd but nevertheless respond to lps in the presence of serum, have receptors for complexes of lps with the soluble form of cd (scd ). these complexes of lps with scd are only formed efficiently in the presence of lbp. we have begun to characterise the mechanisms by which lbp enables lps to bind to cd , either soluble or membrane bound. with the use of fluorophore and radiolabelled reagents we have developed procedures for quantitative measurement of the association of lps with lbp and of lps-lbp complexes with cd . these results show that the delivery of lps to scd is catalysed by lbp, i.e., lbp is not included with the lps-scd complex. in contrast, on the surface of cells, lbp does not dissociate from the cells after lps binds to mcd . the kinetics, equilibria and stoichiometry of these reactions will be discussed in the context of models for cellular activation by lps and cellular uptake of lps. supported by nltt grants gm , ai , ai , gm , and assistance from the pharmaceutical research institute of johnson and johnson. the scripps research institute, imm- , n. torrey pines rd. la jolla, ca usa . modulation of endotoxin-induced cytokine production by lps partial structures h.-d. flad, h. loppnow, t. mattern, and a.j. ulmer department of immunology and cell biology, forschungsinstitut borstel, d- borstel lipid a constitutes the active moiety of endotoxin (lps) of gramnegative bacteria. it activates mononuclear phagocytes to produce cytokines, such as tnf, i _- , and il- , which are the major mediators of the endotoxic effect of lps in vivo. lipid a precursor la (synthetic compound ) does not induce cytokines, but is able to specifically antagonize lps-or lipid a-induced mediator production in human mononuclear cells, vascular endothelial cells, and smooth muscle cells. furthermore, we present evidence for the first time that t-lymphocytes proliferate in response to lps and express mrna for interleukin- and interferon-~ and that these responses are also antagonized by synthetic lipid a precursor la. when comparing the agonistic and antagonistic activity of lipid a and different partial structures at the functional and binding level, the number and length of the fatty acids and the number of phosphoryl groups were pound to be of crucial importance. unexpectedly, lipid a precursor la, although biologically inactive, turned out to be both the most potent antagonist and competitor in inhibiting the binding of lps. taken together, our results provide evidence for a model in which lipid a partial structures compete with lps for specific cell surface receptor(s). in this sense, biologically inactive lipid a analogues may be good candidates as therapeutic agents for the prevention of gram-negative septic shock. two mammalian lipid a-binding proteins have been identified that are believed to have important roles in mediating the host response to endotoxin: lipopolysaccharide-binding protein (lbp) and bactericidal/ permeability-increasing protein (bpi). human lbp shares a % amino acid sequence identity with human bpi. despite the sequence homology, the two lipid a-binding proteins have very different functional activities. lbp is an acute phase serum protein that markedly potentiates the proinfiammatory host response to gram-negative infection by a mechanism which involves binding of the lbp-lps complex to cd receptors on monocytes, neutrophils and endothelial cells. in contrast, bpi is a neutrophil granule protein with potent bactericidal and lps-neutralizing activities. the divergent functional properties of these two lps-bindlng proteins can be explained by the inability of bpi-lps complexes to bind to cell-surface cd receptors. a recombinant protein (rbpi ), corresponding to the amino terminal kd fragment of human bpi, has been shown to retain the potent biological activities of the hdlo protein and may represent a novel therapeutic agent for the treatment of gram-negative infections, sepsis and endotoxemia. for therapeutic effectiveness in many clinical situations, rbpi will have to successfully compete with relatively high serum levels of lbp ( - ~g/mi) for binding to endotoxin and gram-negative bacteria. to evaluate this issue, experiments were conducted to compare the relative binding affinities of rbpi and human recombinant lbp (rlbp) for lipid a. the binding of both proteins to iipid a was specific and saturable with apparent kd's of . nm for rbpi and nm for rlbp. in a competition assay format rbpi was approximately -fold more potent than rlbp in inhibiting the binding of nsi-rlbp to lipid a. these results demonstrate that rbpi has a significantly higher affinity for endotoxin than does rlbp and may explain the potent inhibitory activity of low concentrations of rbpi in a variety of in vitro functional assays for lps activation of cells despite the presence of high lbp levels. for example, rbpi at . ~tg/mi was able to totally inhibit lps-induced tnf release from monocytes despite a -fold weight excess of rlbp over rbpi . and for heparin binding. three separate domains which inhibit the lal reaction to lps and bind to heparin were identified in amino acid regions - , - and - . a single synthetic peptide ( - ) was bactericidal. these results suggest that rbpi contains three separate functional domains which may contribute to its high affmity interaction with gram-negative bacteria and heparin. the individual activity of each domain and the cooperative interaction among domains provide the basis for developing rbpi analogues with increased biologic efficacy. a considerable body of experimental data has accumulated implicating tumour necrosis factor (tnf) as a principal mediator of the pathophysiological features of septic shock. these data prompted the development of clinical strategies designed to limit excess (inappropriate) tnf production. monoclonoal antibodies (mobs) were developed and a phase ii dose escalation trial in patients confirmed that the mab was safe, and suggested that it was having a beneficial effect on certain parameters. preliminary results of a large phase iii study indicated that (a) the mob was safe; (b) that it was of no discernible benefit in non-shocked patients; (c) that it reduced mortality in shocked patients, especially during the first days. an alternative strategy was to take advantage of the high binding affinity of soluble receptors for tnf (stnfr). stnfr-iggfc constructs were made for both the p and p receptors. both were effective in animal models of lps challenge, but when a clinical trial was done with the p stnfr-fc there was unexpected mortality in the treated arm. using an animal model of live e.coli sepsis, we have shown that this may have been due to the release of bound tnf from the construct. plasma enhances while bpi inhibits lps-induced cytokine production from peripheral blood mononuclear cells (pbmc). pseudomonas species produce cytokine-inducing substances which are different from lps as indicated by the fact that polymyxin b blocks only % of the cytokine-inducing activity of these pyrogens. we now tested the effect of plasma and bpi on the il- [ -inducing activity of pseudomonas maltophilia -derived pyrogens (pmp). bacteria were cultured to the log phase and filtered ( kd) to obtain prop. dilutions of pmp or lps were added to pbmc alone or to pbmc in % plasma +/-bpi ( ng/ml). pbmc were incubated for hours at °c and total il-i~ was measured by ria. results: il-i[~ in ng/ml (n= , mear~+sem, *p< . vs control). control . _+ + bpi . + % plas. . _+ + bpi . _+ pmp (ng/ml) lps (ng/ml) . _+ . _+ . _+ . _+. . +. . _+. . _+. " _+ " . _+ " . _+ " . _+. . + _+ _+. * _+ " . +. " . + -+ . -+ " . _+. " cba, c bl/ , balb/c, akr, dba, swiss mice, guinea pigs, rabbits have been used in research work. the toxicity, immunogenicity, mitogenic and immunomodulating activity of lps have been studied. the possibility of reduction of the toxic activity of lps on macroorganism by bioglycansimmunomodulators obtained from sea invertebrates anymals (crenomytilus grayanus, stromhus gigas) have been investigated too. lps has been shown to induce specific antibody response of laboratory animals. cba mice are high responsive to lps. lps stimulates humoral immune response of mice to tdependent and t-independent antigens and suppresses intensity of the delayed hypersensitivity. the small doses of lps stimulate functional activity of macrophages, the large doses of lps -decrease one and show the cytotoxic effect. the bioglycans enhance the resistance of mice to the lethal effect of lads and provide protection - % of mice. one opens possibility to use of bioglicans for reduction of toxinemia in generalizated forms of pseudotuberculosis. thus, lps from y.pseudotuberculosis is immunogen and immunomodulator wich has influence on humoral and cellular factors of immunity and plays the important role in immunopathogenesis of infection. endotoxaemia is implicated in the pathophysiology of obstructive jaundice. the lirnulus lysate (lal) assay is the gold standard method for measuring endotoxin concentrations, but inherent biochemical and technical problems limit the usefulness of this assay. the endocab elisa is a novel assay which measures endogenous antibody (igg) to the inner core region of circulating endotoxins (acga). objectives we evaluated the significance of endotoxaemia in biliary obstruction using the endocab assay and subsequently the specificity of the humoral response to endotoxin compared with an exogenous antigenic challenge [tetamls toxoid (tt) ]. materials and methods in experiment i three groups of male wistar rats ( - g) were studied [no operation (n= ) , sham operation (n= ), and bile duct ligation for days (bdl)(n= )]. plasma was collected and assayed for bilirubin, endntoxin(lal) and acga(endocab). in experiment ii rats were actively immunised with tetanus toxoid ('it) and then randomised to have no op(n= ), sham op(n= ) or bdl(n=i ). blood was taken at this time (to) and days later(t at sacrifice for acga concentrationslendocab] and igg produced to tt(ttab) [elisa] . antibody concentrations are expressed as % increase from control values.results in bdl rats, acga concentrations were significantly increased compared with controlslp< . , mann-whitney]. endotoxin concentrations were sporadically elevated in the jaundiced rats but the rise was not significant. in experiment [i there was no difference between the acga or ttab concentrations in the fllree groups at to, bdl rats had a significant rise in acga concentrations by t [p< , ,paired t-test] and humoral response to tt was significantly impaired in bdl rats compared with control groupslp< . , paired ttest data plasma endotoxin was measured by means of an endotoxinspecific endospecy test after pretreatment of the plasma with a new perchloric acid method that we developed. the normal value of plasma endotoxin is less than . pglml. polymyxin b was administered at a dose of , u every hours. plasma endotoxin rapidly decreased to the normal range in of the patients. body temperature fall significantly. apache ii scores were also significantly improved. tumor necrosis factor-o~ and interleukin decreased in survivors, while in high values tended to persist in patients died. no side effects were observed in any of the patients. in conclusion, intramuscular injection of minute of polymyxin b was useful in the treatment of endotoxemia. - uchimaru, morioka , japan. l e v a n t g r a m n e g a t i v organisms. m e t h o d s : u n d e r general anesthesia, n o r w e g i a n b r e d landrace pigs ( - kg) of either sex, pr group, u n d e r w e n t t r a c h e o s t o m y a n d w e r e v e n t i l a t e d on a / air a n d o x y g e n m i x t u r e a i m e d at m a i n t a i n i n g a n o r m a l p h a n d a isocapnic level. ventilation w a s not readjusted d u r i n g the observation period. the anesthesia w a s k e t a m i n e . m g / k g h a n d d i a z e p a m . m g / k g h i n t r a v e n o u s l y . h e m o d y n a m i c m o n i t o r i n g of m e a n aorta, p u l m o n a r y artery, central v e n o u s a n d p u l m o n a r y capillary w e d g e pressures w a s p e r f o r m e d w i t h a f s w a n -g a n z catheter a n d an aorta catheter. a continous infusion of r i n g e r ' s acetate ( m l / k g h ) w a s g i v e n intravenously. w h e n stabilised, the a n i m a l s w e r e g i v e n . x l cfu of e colt intraperitoneally as a bolus in ml saline, the a n t i b o d y g r o u p received in a d d i t i o n m g / k g e a n t i e n d o t o x i n i n t r a v e n o u s l y over h o u r via a n infusion p u m p at the start of the observation period. the a n i m a l s w e r e observed for hours. results : a t a n d hours, the o x y g e n c o n s u m p t i o n increased by % in the a n t i b o d y treated g r o u p w h e r e a s there w a s a significant fall of % in the sepsis group. in the a n t i b o d y group, the arterial p h a n d the cardiac index were also significantly h i g h e r at the s a m e p o i n t s in time. there w a s no significant difference in arterial po . in severe bacterial infections it would be beneficial to neutralize the plasma endotoxin content with complex forming compounds. the phenothiazines are able to form complexes with endoto×in and the existence of these complexes were already shown in differential speetrophotometry and animal experiments, however, the mechanism of partial neutralization was not clarified. therefore some representative phenothiazines and structurally related compounds were tested for anti-endotoxin activity. the endotoxin neutralizinb effects of several benzophenothiazines were investigated in differential speotrophotemetry, tnf induction and in the conventional limulus test. in animal experiments some beneficial effect of complex forming compounds was found. the benzophenothiazines were not able to inactivate the biological effect of endotoxin in the limulus test. the recent findings indicates that a multifocal effect can be responsible for "anti-endotoxin action in vivo". effects of tnf inducing effect of endotoxin in leukocytes and bypotensiv action in experimental animals were reduced by some phenothiazine derivatives. monophosphoril lipid a was without effect. of microbiology, albert szemt-gydrbyi medical university, odm t~r lo, h- szeged~ hunbary involvement of streptococcus pyogenes erythrogenic toxins in the induction oflstreptococcal toxic shock syndrome heide mgller-alou~* , joseph e. alouf , die [er gerlach , ~atherine fitting., and jean-marc ca~aillon . unit des toxines microbiennes and "unit d'immuno-allergie, institut pasteur, , rue du docteur roux - paris (france) ; institut f~r experimentelle mikrobiologie, jena (germany). superantigen erythrogenic toxin a (eta) is thought to be involved in toxic shock syndrome in humans by inducing massive release of cytokines by patient immune cells. the cytokineinducing capacity of eta w~:s £:ompa~ed to that of lps, a gram-negative bacterial cell wall component. eta elicited weak production of il- d and ~, tnf ~ and il- in purified human monocytes whereas lps stimulated the production of high amounts of these cytokines. in the presence of t cells, eta elicited the production of significant amounts of il-i~, il-i~, il- and il- . however, the most preponderant cytokine was tnf~, which peaked at i ng/ml after stimulation with i ~g eta. comparable amounts of tnfd (ca ng) were induced by .i ~g eta and .i ~g lp$. in contrast to lps, eta was a strong inducer of tnf~ which was produced only in marginal amounts by lps. these results suggest that the septic shock induced by gramnegative bacteria (lps) and by gram-positive bacteria {extracellular superantigens) follows different pathogenic pathways. lps-induced shock is mainly mediated by monocytes and monocyte-produced cytokines (il-i and tnf). the eta-induced shock is mediated by t-cells or depends on t cell help for the production of monocyte-liberated cytokines. production of t cell cytokines such as tnf~ and interferon in addition to the other cytokines contribute very likely to the severity of the toxic-shock resulting from s. auzeus and s. pyogenes infections in humans. the present study was utidertakc~l to cvalu~tlc the effect of soluble chemically modified giucan during septic shock. carboxylnethyl-b-i, -glucan (ram ) was injected twice and h before the shock i.v. in a dose of ing/kg. shock was induced in u~?esthetizcd (sodikm~. l)mntobarbital) rats by i.v. injection of endotoxin of escherichia colli bs, mg/kg. aiiofcmg pretreated ruts survived during first haher ¢ndotoxine, while in controi shock group the lethality was %. the concentration of ~col)terin in serum was significantly elevated hafterthc second cmginjection (appare~tly % if compare with the control rats), but didu't chartged rain and s rain after endotoxin injectjom cardiac output in cmogroup was higher a* the i and min after endotoxine onset ( i % trod ~, respectively of initial level) than in the control shock group ( % and % at the same time). pretreatment of rals with soh~ble giucan w~ts associated with beneficial effects o~ the hepatic c~ergy $ia[tls after h after challenge of endotoxiae: the tissue level of lactale was ahnost twice lower than in the control ruts, me~mthne the tissue atf in cmg pretreated group was higher at %. twice injected macrophage stimuhttor soluble glucan can prevent the endotoxic shock, and extremely ir~creased survival rate after endotoxine injection. the national committee of surgical infections of the spanish association of surgeons have produced a computer program for the collection and analysis of information on surgical infections. the program is suitable for ibm compatible hard disk personal computers and works through the ms-dos system. the main menu is called up on the screen when the operating disk has been installed; it reads as follows: i. new record; . modify records; . erase records; . searches; . reports; . configure; o. ouit. if you ask fdr a new record the screen will prompt you to enter the number of case, record number, hospital, age and sex. the next screen will come up and the words "topographic diagnosis" will flash. a menu of areas or organs will be displayed. then, the words "type of pathology" (inflammatory, neoplastic, traumatic and other). days of postoperative period. type of surgery (programmed and emergency). type of operation (clean, clean contaminated, contaminated and dirty). duration of surgery. this is followed by "order of operation" and the "type of anaesthesia (general, regional or local). you are then required to supply the "diagnostic code of who" (icd ) and the "procedure code of who. analytic and concurrent illnesses (total proteins, albumin, haemoglobin, haematocrit, leucocytes, red corpuscles, glucose and bilirubin). the next screen asks for "risk factors" (obesity, uraemia, neoplasia, malnutrition, urinary catheter, distant infection, artificial valve, immunosuppressive drugs, over years and anergy. this is followed by a screen headed "postoperative complications". "evolution" (the questions asked are drainage, systemic antibiotics, and on each ocasion a choice of antibiotics is displayed), local antiseptics, reoperation, etc. under "microhiology" is a choice of organisms and the chance of identifyin organisms. finally, "sepsis score". our recent work had shown that renshen-fuzi-chaihu mixture could increase the survival rate in experimented study. the purpose of this study was to determine the effect of combined administration of renshen-fuzi-chaihu mixtuer and antibitics (sa) in patients with septic shock. the result showed that, in sa group ( cases), the total effective rate was , %, in the contral group (combined administration of gentamycin and dexamethasone, cases) the total effective rate was %. however the obviously effective rate in sa group % was significantly higher than in contral group % (p<o.os). sa group appeared to be more obvious than the contral group in raising arterial pressure, recovering consciousness and pulse, improving cold lilmbs and reducing fever (p<o.o ). it was found that sa could inhibit the pathogeneses changes of septic shock such as the decreases of superotide dismutase (sod) and glutathione peroxidase (gsh-px) in erythrocytes and the increases of plasma free hemoglobin (phb), plasma malondialdehyde (mda) and -glucuronidase ( -gc) occured in septic shock. sa had stronger effect than gd in inhibiting the changes mentioned above. hence, these results suggest that sa has beneficial effect in the treatment of septic shock. sa could diminish the decrease of the antioxdase activities and inhibit lipid peroxidization and stabilize cellmembrance. this may be one of the principal mechanisms of the beneficial effect of sa in the treatment of septic shock. donna l. lehman, heather a. childers, irshad h. chaudry and alfred ayala. the thymus is thought to be a privileged sight for tcell generation. here the t-lymphocytes are either selected for their potential to recognize and react competently to foreign antigens or de-selected, due to their potential to react to auto-antigens, de-selected. tcells with this latter capacity are thought to be deselected through a process referred to as programmed cell death or apoptosis. while it is known that thymic apoptosis is elevated by a variety of stressers associated with infection and inflammation, little or no information is available concerning its presence in polymicrobial sepsis. it was, therefore, the aim of this study to determine whether thymocytes exhibit increased apoptosis during sepsis. to assess this, thymocytes were harvested from c h/hen mice at i and h following cecal ligation and puncture (clp; to induce sepsis) or sham-clp (sham). thymic yields were assessed and the extent of apetosis determined by staining the cells with propidium iodide (a dna intercalating dye) for facs analysis or by examining the extracted dna electrophoretically for the endogenous endonuclease activity the results (n= /grp) indicate that at i h post-clp there was no marked changes in any of these parameters. however, at h the thymic cell yield from clp mice was significantly decreased (sham: . ! . x l vs clp: . i . x * cells; *,p< . ), the % of cells apoptotic by facs analysis increased from . i . % in sham to . ± . %* in clp, and the septic mouse genomic dna exhibited dna degradation these results indicate that clp, but not simple laparotomy, induces marked thymic apetosis, which may contribute to the lymphocytic immune deficiency seen in these mice the purpose of this retrospective study was to evaluate effectiveness of irrigation to treat septic knee joints from longterm results. from to patients with septic knee joints have been treated. treatment in acute cases started with asp#at[on of the effusion to evaluate for cultures. without awaiting the result treatment was continued with immediate joint irrigation under arthroscopic control. three redon tubes ( ch ) were introduced for continuous irrigation and for intermittent distention of the joint cavity. in case of chronic joint infection additionally all foreign and synthetic material was removed. systemic antibiotics were given. patients could be re -examined with a mean follow-up of years. re-examination showed that immediate arthroscopic lavage started at the onset of septic sings had best results (less signs of osteoarthr[tis, less synovitis, less pain while loading and less range of motion loss ). patients ( %) out of patients with s tre_=.tsd acute se.~tic knee joint had excellent functional recovery, whereas all patients with chronic septic knee joints showed poor results. additionally, in of these patients with chronic septic knee joint after irrigation a further procedure was necessary due to recurrent septic knee joint. the concept that bacteria can translocate across the intestinal mucosa under a variety of circumstances is well established. however, due to the inherent limitations of in vivo studies, the cellular mechanisms underlying the process of bacterial translocation (bt) across the epithelial barrier are poorly understood. this is especially true in those circumstances in which there is no merphologic evidence of mucosal injury. consequently, we have utilized an in vitro cell culture model system to investigate the cellular events involved in the translocation process. in this model system, a polarized monolayer of intestinal cells (caco- cell line) is grown on a micron filter in a two compartment system. after tight junction integrity is established, bacteria are placed in the apical surface chamber and bt across the caco- monolayer is measured by culturing the basal chamber. the results of our studies utilizing the caco- system indicates that; l) several strains of non-pathogenic bacteria will translocate across the caco- monolayer in a time-dependent and dose-dependent fashion. however, the incidence and magnitude of bt are highest for those strains of bacteria (gram-negative enterics) that are most commonly cultured in vivo. ) caco- cells are actively involved in the transcellular passage of bacteria across the caco- monolayer, since inhibition of caco- microtubule or microfilament function decreases the magnitude of st. ) lectin but not integrin receptors are involved in bacterial translocation of e. col~ across the caco- cell monolayer. ) caco- cells have the ability to ingest and kill certain strains of bacteria. the mechanisms involved in caco- bactericidal activity appear similar to that of pmns to the extent that both are oxidant but not nitric oxide mediated. these in vitro studies suggest that caco- cells can function as "nonprofessional" phagocytes and that both bacteria and enterocytes are involved in the translecation phenomenon. bacterial translocation due to gut barrier dysfunction is considered to be a major cause of septic complications and multiple organ failure following trauma, burn injury, hypoxia, shock and shock-like states. the invasion of bacteria into the circulation from the gastrointestinal tract or even from other sources, however, should not necessarily result in systemic infection or organ cohinisation, as long as the humoral and cellular defense mechanisms are not impaired. thus, a reduced res clearance capacity and hepatic clearance function of bacteria and toxins can be observed under the same conditions which enable bacterial translocation from the gut. in order to evaluate the influence of circulatory, metabolic and humorul disorders on the elimination of bacteria out of the blood circulation, a series of experiments were performed in anesthetized and ventilated rabbits which received defined numbers ( . x colony-furming units) of escherichia coli as a bolus injection. in unaffected control animals the intravenously injected bacteria are eliminated about . % within the first minutes and are totaiy cleared within minutes. % offue total cfu counted in the cultures of the organ homogenates were found in liver and spleen, whereas only very low numbers could be detected in the lungs and kidneys. systemic injury of the animals by hemorrhagic shock, endotoxinemia, hypoxia, coagulation disorder, systemic vasoconstriction by norepinephrine and other types of injury reduced the elimination rate of bacteria and changed the pattern and degree of their dissemination and tissue distribution. the bacterial clearance was delayed mostly in rabbits subjected to hypoxemic hypoxia in which about cfu of viable e.eoli per ml blood could still be counted hours following their injection. the number of viable bacteria was some ten powers higher in organs of hypoxic rabbits in comparison to control ardmais, and an excessive colonisation of the lungs and kidneys with % respectively % of the total cfu of the cultared organ homoganates was observed. unilateral iscbemia of the kidney prior to the intravenous injection of e.coli only moderately delayed the bacterial clearance, bowever, caused an intense eohinisation of the affected reperfused organ. in contrast to this, inhalation injury did not promote the accumulation of bacteria in the lungs. conclusion: shock, systemic and local affections reduce the clearance of bacteria from the blood circulation and enable their dissemination and accumulation in vital organs. the degree of this reduction and the organ pattern of the bacterial distribution varies with the type of injury. thus, these factors seem to be essentially involved whether or not bacterial translocation and multiple organ failure will follow the invasion of bacteria into the circulation as in the ease of gut barrier dysfunction. movement of enteric baaterla from gut to extralumeaal sites (bacterial tra~sloeation) m~y play a role ~. nraltipl~ orga~ failure. traumatic stress (shock, hffectiort, and im~lammation) and severe illness are common alateeedents. tnt~st~aal lleus is e common proximme causal factor. we have exanlined the hypothesis that bacterial ttanslecation from the gut in expe~me~tal paaerestitis is due to bacterial overgrowth as a cuas~ucnee of a deere~ae in intestinal transit. ne~rotit_.~g pancreatitls fbliowlng bile duct iigation in the opossum is associated with colonization of the pa,se ~re, aa by gut derived organisms or salmonella of biljary origin in infected animals (previously reported). to ti~rther define the mechanism of transloemdon in panereati* inflammation, pancteatitis was induced hy iigatlon of t~e lower bile duet distal to the pancreatic duets m the rat. intestinal transit, enteric bacteriology, and tromsloeatien of bacteria to mesanterie lymph nodes, blood stream and splanelmie organs wen deletmhaed at (n~ ), g (n ~ ), and (n~ ) hours with the fallowing results: ly~testinai,..transfi". geometric mean of fluorescent marker - % at hour~ with return to % of gut leugth (similar to ~m) at hour~. bacterial overgrowt_hff -increase in total bsctetia ~ad gram negative rod.~ at ,; hours with return to sham control at hours ( log cfu/g veraus log cfu/g ia ileum). translocation to mesenteric nodes - , , and percent at , , and fi hours compared to b in sham controls (n=l of ). conclusion -bacterial translocation following panetoatieobiliary duct ljgation induced panereatitls ha the rat is tighlly linked to intestinal trausit and bacterial overgrowth within the gut lumen. speclrjlation -the ilens in in/~arm~ation may be related to activation of eytokiaes and mediated by nitric oxide. preliminary evidence for this notion will be discussed. in a series of studies we investigated: a) the time course of bacterial translocation (bt), b) the kinetics of lps and cytokine appearance (tnf, il- , soluble tnf receptor [stnf-r] ) in the circulation, and c) the role of lps and/or tnf with regard to haemorrhagic shock (hs) related pathophysiologie alterations and mortality in baboons and/or rats. method: baboons were subjected to femur fracture, soft tissue trauma (acute experiment), and hs ( mmhg mean arterial pressure: map for - h terminated at an accumulated oxygen debt of - ml/kg followed by resuscitation). a chronic model of hs was set up by administration of zymosan activated plasma (zap) before and after hs but without trauma. hs was induced in rats by bleeding the animals to map of - mmhg - rain followed by resuscitation. results and conclusion: in rats, lps increased in the systemic circulation, plasma tnf levels were found to be significantly elevated at min and were still markedly increased at rain postshock. plasma tnf, il- , and stnf-r levels increased already during the shock period in baboons, while tnf was not detectable. our data suggest that haemorrhagic shock may lead to early bt in the intestinal wall (at min following resuscitation in rats subjected to hs for min, similarly at h after the end of oxygen debt period in baboons ) and transient access of gut-derived lps into the circulation (levels became significant at min, while in baboons higher levels up to pg/ml were found at the end of shock and h after reinfusion, partially accompanied by bacteremia). in addition, since the treatment of rats with anti lps measures or anti tnf therapy significantly improved the -hour survival rate it can be assumed that endogenous lps and lps-induced mediator(s), in particular tnf, may lead to organ injury and mortality following haemorrhagic shock. alteration of the mesenteric blood flow and the consequent ischemia / reperfusion injury to the intestine appear to be one of the earliest events in the systemic inflammatory response following severe thermal injuries. the causative relationship between the subsequent disruption of the intestinal integrity and the potentiation of the translocation of indigenous bacteria and/or endotoxins to remote body organs and the systemic circulation has been deeumented in several studies. among other effects, endotoxemia solely or acting synergistically with thermal injuries has been shown to promote bacterial translocation. as these sequences continue without adequate intervention, multiple organ failure and eventually death may become inevitable. hence, the crucial need of treatment modalities with the capacity of modulating the intestinal blood flow and preventing the manifestations of these pathological incidents. although the underlying mechanisms of this process have not yet been fully elucidated, there is accumulating evidence that various interacting vasomediators are involved. the actions of these mediators can probably be modulated by either nonspecific or selective agents. among the nonspecific agents, the composition, volume and timing of the resuscitation fluids appear to play an important role in this process. nitropmsside, a nonspecific vasodilator, has been shown to prevent the decrease of the postbum mesentefic blood flow when selectively infused in the mesenteric artery. the nonspecificity of various vasodialators with their possible undesirable systemic effects emphasizes the importance of the identification and modulation of selective vasomniiators. thromboxane a (txa ) and angiotensin ii (a-ii) appear to be the primary mediators of the postburn vasoconstriction. both mediators were found to be elevated following thermal injuries. in a previous study, pretreatment with oky- , a thromboxane synthetese inhibitor was found to attenuate the postbarn mesenteric vasoconstriction. in a bum/sepsis porcine model the efficacy of dup , an a- receptor antagonist as a posthum treatment modality was evaluated. treatment with dup prevented the early posthum and the late posteodotoxin elevation in the mesenteric vascular resistance and subsequently abrogated the fall in the mesenteric blood flow. the incidence of burn & endotoxin induced bacterial translocation was significantly reduced by dup from % to % (p< . , fisher's exact test). the indigenous flora of the gastrointestinal tract exerts a potent influence on the developmental maturation of normal systemic immunologic responsiveness. moreover, both oral and intraportal administration of experimental antigen is associated with a systemic state of immunologic hyporesponsiveness, known as oral tolerance. since trauma and critical illness are associated with changes in the flora of the gut and with altered systemic immune reactivity, we have hypothesized that the interactions of an altered gut flora with immune tissues in the gut and liver play a role in the pathogenesis of the immunologic derangements of critical illness. prolonged feeding of two clinically relevant killed organisms-pseudomonas and candida-to a rat results in significant impairment of cutaneous delayed hypersensitivity (dh) reactivity. conversely, measures directed against gram negative bacterial overgrowth in experimental peritonitis result in partial restoration of impaired dh reactivity. to ascertain the role of the liver in the pathogenesis of these alterations, we studied the differential immunologic sequelae of portal versus systemic (ivc) infusion of killed bacteria. experimental infusion of live or killed gram negative organisms into the portal vein produces dh suppression in rive, and profound suppression of mitogen-driven lymphocyte proliferation in vitro; systemic administration of the same organism has no effect on these phenomena. suppression is tgf -dependent, and mediated by a soluble factor released by fixed tissue macrophages of the lung and spleen. the suppressive influence appears to be mediated at the level of interactions between il- and its high affinity receptor. release of this factor can be induced by a second circulating factor present in the plasma of portally-, but not systemically-infused animals two hours after bacterial administration. these studies suggest that the release of inducible immunoregulatory factors from the liver, and possibly from the gut, may play a role in the pathogenesis of the profound derangements of systemic immune homeostasis that accompany trauma and critical illness. acad.hospital st. radboud,postbus , lib nijmegen introduction. the central question being tested in this study was whether liposome encapsulated dichloromethylene-diphosphonate (ci mdp) mediated elimination of liver and splenic maorophages would influence zymosan induced systemic toxicity (st) and bacterial lranslocation (bt). materia|s and methods. male swiss (icr) mice were used weighing - g elimination of liver and spleen macrophages was accomplished by intravenous injection of / suspension of ci mdp-liposome suspension. control mice received an i.v. injection with pt phosphate-buffered saline (pbs) . two days later all mice were challenged with an i.p. injection of zymosan suspended in paraffin (z) at a dosage of either mg/g, . mg/g or . mg/g body weight (n= in each group), signs of st and bacterial translocation bt were measured hours later the st was assessed by blindly grading the degree of lethargy, conjunctivitis, diarrhea, and ruffled fur of each mouse on a four point scale. bt to the mesenteric lymph nodes (mln) and systemic organs (liver, spleen, lung and blood) was tested by culturing on blood and macconkey's agar at the time of sacrifice sections of the distal ileum were taken for histology. an additional two control groups (n= in each group) were tested to verify that neither paraffin nor pbs or ci mdpqiposome suspension alone induced bt or st. furthermore survival over a -day period was assessed in a control and macrophage-depleted group with a dose of d mg/g z. results. neither the paraffin nor ci mdp-tiposome suspension induced bt or st the incidence of bacterial translocation to the mln was similar between macrophage depleted and control groups. however, macrophage depletion was associated with a significantly higher incidence of systemic spread of bacteria. data expressed as positive tissues/total tissues tested: / vs. / at . mg/g zymosan (p~o. ); vs. at mg/g zymosan (p~q ); / vs. / st . mg/g zymosan (p~o.o ).the magnitude of bt however did not show any differences. although systemic bt was greater in the macrophage depleted groups, the systemic toxic response was significantly less at doses of . mg/g zymosan ( . -+ . vs. . -+ , p~o. ) and . mg/g zymosan ( . -+ . vs. . -+ . , p<_.o. ) . the day mortality after . mg/g zymosan was % in the control group and % in the macrophage depleted group (p=o. ). histology did not show any differences between the control and macrophage depleted groups. conclusion. the lethal and toxic effects of zymosan in this model appear to be more related to the excessive activation of macrophages than to the systemic spread of bacteria. bacterial translocation (bt) in hemorrhagic shock was studied using a porcine model. in this study three groups were randomized: one control (n= ) and two experimental (n= each). a portal vein catheter was placed and remained in situ hrs. a femoral artery and vein catheter were in place hrs. the arterial eaanula was used for monitoring mean arterial pressure (map) in all animals and to bleed the experimental animals and the venous cannula to repelfuse with ringer's lactate (rl) or autologous blood (ab). baseline samples and values were taken in this period. control animals were observed for a sham shock period of . hrs., given more hours of anesthesia, and studied for further hrs. % of the estimated blood volume was withdrawn from each experimental animal over min. these animals were kept in shock for . hrs. at the end of the shock one group was perfused with rl and the other with ab. two hours later they were extubated and further studied for hrs. samples from portal blood for cultures and measurement of leukotriene b (ltb ), prostaglandin e (pge ), and nitric oxide (no) metabolites were taken from all animals at intervals beyond baseline up to hrs. after hrs. under general anesthesia a second laparotomy was performed and samples for culture from mesenteric lymph nodes (min), liver and spleen were taken; as well as samples for histologic study with light and scanning electron microscopy were taken from jejunum, ileum, and colon. animals were then euthanized. results: significant shock was induced as indicated by map and arterial blood gases. significant bt to min was observed in all groups. no significant bt was observed in cultures from liver and spleen in any of the groups. increased values for ltb , pge and no metabolites were found during the period of shock. these results suggest that the isehemic phenomenon triggers a significant inflammatory response, and that bt to min may be an epiphenomenon without apparent significant influence on the inflammatory response. objective: to study the potential effects and mechanisms of action of systemic administration of monoclonal antibodies anti-endotoxin (ha- a) in a animal model of gut-origin sepsis. materials and methods: exoeriment a. balb/c mice were transfused with allogeneic blood (from c hb-iej mice). five days post-transfusion the animals were gavaged with lxl viable escherichia coil and randomized into groups (n= /group) to receive a sham burn (sb group) or a % thermal injury immediately followed by the systemic administration, via a tail vein, of monoclonal antibodies ( mg/kg) (ha- a group) or a % burn injury and administration of equal volume of sterile saline (c group). all groups were resuscitated by intraperitoneal injection of . ml of saline. the animal survival rate was observed for days post-burn. experiment b, transfusion and burn procedures were identical to experiment a but the mice (n= /group) were gavaged with viable e.coli labeled with mmndium oxine. four hours after burn the mesenteric lymph nodes (mln), liver, lungs and blood were harvested to determine plasma endotoxin levels and the magnitude of transtocation of labeled bacteria as measured by the residual radioactivity (dpm) in the organs. circulating endotoxin levels were determined by limulus colorimetric assay. diamine xidae(dao) is an enzyme existing in the mucosa of small intestines, but its activity is low in the plasma. it is evoked in the blood with the intravenous injection of much heparin. it is well known that da declines under the chronic mueosal injury when the small intestines are cut off or the mucosae become atrophied. aim of this paper is to confirm that da goes up to the measureable level by the intravenous injection of a small amounts of low molecular heparin(lmh objectives: the aims of this study is to investigate the inhibitor" effect of the prolease inhibitor, urinastatin, on endotoxin induced bacterial transleeation in mice. materials and methods:lcr mice were divided in six groups as the fotlows, group i: control mice receiving intraperitoneal injections (ip) of saline . and hr prior to sacrifice, group ih treated mice receiving ip of utinastatin . hr and endotoxin ( mg/kg) hr prior to sacrifice,group ilk sham reated mice receiving ip of saline . hr and endotoxin ( mg/kg) hr prior to sacrifice,group iv: saline control mice receiving ip twice during rain intervals,group v: mice received ip of utinasmtin, and min later they were received ip of endotoxin ( mg/kg), group vi: mice received ip of saline,and min later they received ip of endotoxin ( mg/kg). in group l,ii and ill ,the mice were killed by cervical dislocation.using stetile techniques,a middle-line incision was made and the mesenteric lymph nodes were harvested in order to culture on selective agars for quantitation of bacterial trauslocation. in group iv, v and vi, survival was recorded for days. unnastatin pretreatment could rednce mortality significantly. first surgey, shiga university of medical science, seta ,ohtsu - ,japan increased gut permeability correlates with inflammatory response in multiple trauma aptients. pape, h.-c. dwenger, a. grotz, m. regel, g. purpose: disturbances of intestinal permeability have been advocated as a pathogenetic factor of posttranmatic multisystem organ failure (mof). a close relationship with impairment of the stationary reticulocndothelial system (res) and a systemic inflammatory response (sir) was discussed. these tactors were investigated prospectively in patients with multiple trauma showing posttraumatie complications (multiple organ failure, mof). methods: polytranmatized patients were studied prospectively. according to a mof-score (goris) those with posttrattmatic complications were selected (> points at days), others were excluded. every second day gut permeability according to the ratio of urine concentrations of lactulose and mannitol (l/m) was evaluated (enteral application). at parallel time points res clearance capacity (k-value, invasion constant, normal range . - . mind) was studied after i.v. injection of mbq rotehuman albumin. liver perfusion was calculated from these data, total serum bilirubin (/zmol/l) was documented. serum elastase (#g/l) levels were determined enzymatieally. results . + + liver perfusion did not ehangu, bilirubin showed progressive worsening indicating mof. a positive correlation was present between l/m and k (r= . ) and between l/m and ela (r= . ). conclusions: there is a positive correlation between the time pattern of intestinal permeability dysfunction and res hyperactivity as well as between intestinal permeability and the systemic intlammatory response (elastase levels). the results speak in favor of an interaction between intestinal and extraintestinal inflammatory systems, which in eombiuation are likely to be responsible for post~anmafic complications. endotoxemia, il- release and consecutive acute phase reaction are observed as a host response to surgical trauma. as well vasodilative prostaglandins (pg) and thromboxane (tx) are released after abdominal meaenteric traction (mt). the following hypotension and acute hypoxeraja are duo to prostacyelin (pgiz) arm can be avoided by perioperative cyclooxygenase inhibition. we therefore focused on the effect of pg and tx liberated following mt on the induction of endotoxemia. methods: in a prospective, randomized double-blinded protocol patients, who were scheduled for major abdominal surgery (pancreatic or infrarenal abdominal surgery), were studied. ibuprofen ( mg i.v.) or a placebo equivalent was administered minutes before skin incision. mt was applied in a uniform fashion. baseline values were obtained before induction of anesthesia. further measurements followed before the incision of the peri[onenm (tl) and , , , min, . the plasma concentrations (,pc) of -keto-pgft,, txb: and-ki- -pgf ~ (stable metabolites of pgi , txa and pge~) were determined by ria. we measured endotoxin pc by limulus-amoebocyte-lysate test and il- levels by elisa. data are given as mean+sem (* p< . placebo vs. [ibuprofen] ). results: endotoxin plasma levels increased before incision of the peritoneum tl both in the ibuprofen pretreated and in the placebo group. peak pc were observed minutes after mt. endotoxin pc were significantly higher in the ibuprufen treated group (t . + . e[ . + . ] eu/ml). il- pc demonstrated an increase continuously from t to t (t + [ + ] ng/l) in both groups. after intentional abdominal mesenteric traction we observed a marked increase of -keto-pgf~,, pc up to h after mt in untreated patients with a peak of *[ ] ng/ at tl. also txb: and kh pge pc showed a considerabe increase up to h after mt in the placebo group. in ibuprofen pretreated patients the pg and tx pc remained within the normal range. discussion: our data clearly indicate a significant endotoxemia and il- release following major surgical trauma which is not initiated either by prostaglandin or thromboxane release. moreover endotoxemia is accentuated by ibuprofen pretreatment. therefore we hypothesize that in major abdominal surgery prostacyclin release-after mt may play a crucial physiological role in maintaining splanclmic microcirculation and thus preserving gut mucosal barrier function. objectives of the study it has been shown recently that parenteral and certain euteral diets promote the translocation of gut flora to the mesenteric lymph nodes (mln) and systemic organs, a process termed bacterial translocation (bt). in chow fed rats bt usually does not occur without further promoting factors. the goals of the present study were to determine whether the provision of defined amounts of standard lab chow during iv-tpn administration wotfld redane the incidence of bt, materials und methods male spf spragnle-dawley rats were divided into groups. group received standard laboratory chow feeding ad lib. in group a central venous catheter was placed, ligated and secured by a spring coil tether attached to a swivel allowing free movement in the housing cage and chow was fed ad lib. in group % of the calculated daily required calory intake (drci) ( /kcal/kg) was given by iv-tpn ( % glucose, , % amino acids) and % by limited chow administration. groups and received % and % of the drci by i.v. tpn and % and % respectively by chow feeding. group received iv-tpn only. after days the rats were sacrificed and the mln, liver, spleen and cecum removed aseptically, homogenized and cultured for bt samples of distal ileum were taken for light microscopy. the group with the least amount of chow shown to be protective against bt received the amount of non-fermentable fiber of that chow regimen during iv-tpn feeding and bt was studied. , + , , - , , / + ~ " , -+ , , -+ ~ - , / +~ + _+ , + , , - , -+ + , ~ , , -+ ~ conclusions: the administration of % of drci by chow feeding during iv-tpn significantly reduced the incidence of bt and maintained gut barrier function. the addition of the respective amount of dietary fiber of this group did not prevent iv-tpn-indueed bt. dr. med. m naruhn., dep. of general surgery, eberhard-karls-university, hoppe-seyler-str. previous experimental studies have suggested that a disturbed ecology of the enteric bacterial population might contribute to the development of bacterial translocation from the gut in acute liver failure (alf). in the present study, the effect of oral administration of lactobacillus reuteri r lc and oat fiber on bacterial overgrowth and translocation was investigated in rats with acute liver failure induced by subtotal ( %) liver resection. the oatmeal soup base was anaerobically inoculated with lactobacillae and fermented for hours, after which the animals were fed with either fermented or unfermented oatmeal or saline daily for days prior to the operation. bacterial translocation to mesenteric lymph nodes (mln) and the systemic circulation was determined, as well as the intestinal bacterial flora and enterocyte protein content. the incidence of bacterial translocstion to the systemic circulation was nit in rats subjected to sham operation and saline treatment and % in animals subjected to % bepatectomy and lreatment with fermented oatmeal, while - % and - %, respectively, in rats subjected to hepatectomy and treatment with either saline or unfermented oatmeal. only one rat with fermented oatmeal demonstrated bacterial growth in mln (p < . vs hepatectomy and treatment with saline or unfermented oatmeal). the enterocyte protein content significantly decreased (p < . ) in salinetreated animals following % hepatectomy, while there was no significant difference between bepatectomized animals with oral administration of fermented or unfermented oatmeal. the number of anaerobic bacteria, gram-negative anaerobes and lactobacillus significantly decreased and the number of e.cnli increased in the distal small intestine and colon in hepatectomized animals with enteral saline or unfermented oatmeal as compared with animals subjected to sham operation or bepatectomy with fermented oatmeal. our results thus show that the occurrence of bacterial translocatiou from the gut in % hepatectomy-induced alf could be prevented by enteral administration of fermented oatmeal, maybe partly due to a positive effect on the enteric bacterial ecology. _+ " +_ " . " data=mean_+sd, * stats anova p< . vs control. l+air and lap groups, both exposed to exogenous i.ps shnwm:t m significant increase (p<. ) in lps gut translocation compared to control and l+co . this correlated with a significant increase in peritoneal inflammatory responses (o -,tnf) above that of the control and l+co groups, while mac- and cr opsonized phagocytosis were significantly impaired. the absence of significant differences between l+air and lap groups indicates that lps rather than wound factors is the principle mediator. thus, lps plays a significant role in regulating peritoneal responses in the early post-operative period dept of surgery, rcsi, beaumont hospital, dublin , ireland brlke e, berger d, staneseu a, buttenschsn k, vasilescu c, seidelmann m, beger hg in patients undergoing a colonoscopy, endotoxin, endotoxin neutralizing capacity (enc), thromboxane b o (stabile metabolite of tbmomboxane ~), -keto-prostaglansin, leueotriene c , interleukin and the incidence of bacteremia were determined before and then every five minutes during the procedure. twenty-one of patients showed a significant increase of endotoxin plasma levels during colonoscopy (p= . ), whereas only one patient had a positive blood culture with bacteria obviously derived from the gastro-intestinal tract. the enc decreased significantly five minutes after the beginning of eolonoscopy and was diminished further thereafter. the baseline values were reached after hours. ~hromboxane b o levels also increased after five min. from to pgyml peaking at min. with pg/ml. -keto-prostaglandin,leucotriene c , ii- and crp remained unchanged. a control group of i volunteers who were not subjected to endoscopy, were prepared for eolonoscopy by orthograde lavage. the blood sampling procedure remained identical. no differences were seen in all described parameters for the controls. these data show that the gut barrier can be compromised by mininml invasive procedures, at least, concerning bacterial products. living bacteria, on the contrary, do not pass the gastro-intestinal wall. endotoxin, when determined by enc, is more sensitive than the conventional limulus-amebocyte-lysate test. no acute-phase reaction was induceri by the observed endotoxin translocation. it can be speculated from the dramatically enhanced thromboxane b levels, together with its hemodynamie effects, that the thromboxane release may support translocation of bacterial products. sepsis is common after hemorrhagic shock. this study aims to demonstrate that hemorrhagic shock alone can promote translocation of gut bacteria from intestinal tract to its regional nodes and subsequently to blood. one hundred twenty mice, divided into groups were subjected to , and minutes of %, % and % of hemorrhagic shock. on the specified time, blood cultures were taken and mice were sacrificed. the intestinal tract were histologically examined for any changes which allows translocation and its regional nodes were quantitatively cultured for translocated bacteria. there was a direct relationship between duration and degree of hemorrhagic shock and incidence of translocation (p . ). there was a high incidence of gut bacterial translocation to the mesenteric and mesocolic nodes in all degrees of shock (p . ). bacterial growth in the regional intestinal nodes increased and blood cultures were positive in direct proportion to degree and duration of shock. histologic evaluation of segments of git showed submucosal congestion to allow bacteria normally contained within the gut to cause systemic infections. translocation of gut bacteria in untreated hemorrhagic shock is clearly shown in this study on animal models. in this study, guotobiotic rats with known species of bacteria were subjected to total parenteral nutrition(tpn) and subsequent hemorrhagic shock. the purpose of the study was to observe the impairment of gut barrier function following tpn and hemorrhagic shock and to study the mechanism of enterogenic infection induced by tpn and shock.the results were as follows: .long term( - days) tpn induced impairment of gut barrier function, evidenced by atrophy of intestinal mucosa, significant decrease in diamine oxidase activity of intestinal mucosa and blood, and marked microecologic imbalance of the intestinal mucosa flora with dorminant growth of aerobes and relative decrease in anaerobes. the degree of mucosal damage were proportional to the duration of tpn. .in tpn+shock groups, failure of gut barrier function was found. ri,~ere were further damage in the mucosa, with a large number of gramnegative organisms invading mucosa and submucosa and a significant decrease in dao activity as compared with each relative tpn groups. these changes were significantly correlated with enhanced bacterial translocation, elevation of lps and mda levels in the plasma. these findings suggested that long term standard tpn impaired the gut barrier function, precipitating posttraumatic gut barrier failure. thus infec. fion following shock might be oi'iginated from the gut and it was obviously related to the impaired gut defence resulted from antecedent tpn. the determination of plasma dao activity might provide a valuable tool for the ear. ly diagnosis of gut injut;y during tpn and after trauma. in our earlier studies we have investigated the dynamics of granuloayte infiltration of the ischemic/reperfused s~all intestine (g. illy~s, j. hamar int. j. exp. athol. . . .) . there was a increasing infiltration of the mucosa c m~nating at the d to th hours of reperfusion. in the present series we have studied sc~e of the conseqn/ences and the possible role of this cellular reaction. ~in isehemia was followed by a hour reperfusion in the anesthetized rat. arterial ~/ad mesenteric venous blood samples were collected at m_in, i, ~ , and hours of reperfusion. elastase and lactate concentrations were determined and hamoculture was carried out from the blood samples, and tissue pieces from the heart, lung, liver and kidney were collected for histological analyses at the above mentioned times of reperfusion. all blood samples were free of cell bacteria. staphylococci appeared only occasionally at the th hour in the arterial blood .and at the d and th hours in the venous blood, respectively. arterial and venous elastase activities were high throughout the reperfusion, venous concentrations being higher at all times. lactate concentrations of the arterial and mesenteric venous blood samples increased during shock. ~ranuloeyte infiltration of all organs studied appeared during the d hour and it increased at later times of reperfusion. it is concluded that heavy infiltration of the intestinal mucosa can block bacterial translocation in most of the cases during reperfusion. granulocytes activated either by the reperfused area or by the released cytokines infiltrate other organs contributing by this way to the mesenteric shock s!rndrc~e. intestinal motility plays an important role for maintaining nutrient transport and absorption and for balancing the enteric bacterial population. disturbances of intestinal motility may be one of the earliest notable changes in intestinal function. in the present study, we aimed at determining early alterations in intestinal transit time following ischemia-reperfusion injury induced by occlusion of the superior mesenteric artery in the rat. intestinal ischemia was induced for and minutes by applying a microvascular clip on the superior mesenteric artery followed by reperfusion , and hours after clip removal. intestinal transit time was measured by the propulsion of a radiolabelled solution (cr ). light microscopy was performed on intestinal samples. macroscopical pathological changes were not observed. however, microscopically, mucosal epithelial oedema, degeneration or slight ulceration occurred in rats hours after reperfusion in ischemia- rain group and and hours after reperfusion in the ischemia- rain group. delayed small intestinal transit time was seen from hours and on after intestinal ischemia for both and rain ischemia followed by reperfusion. the distribution of radioactivity demonstrated that most radioactivity was accumulated in the first two segments following intestinal ischemia and reperfusion, significantly differing from what was seen in animals subjected to sham operation (p < . ). the distribution of radioactivity in segments and in the group with repeffusion hours after intestinal iscbemia for rain was significantly higher than that noted in the group with repeffusion hours after intestinal ischemia for min (p < . ). q'he results indicate that a delayed intestinal transit time may be one of the earliest pathophysiological alterations noted, associated with duration of gut ischemia, and a potential factor for the development of bacterial overgrowth, gut barrier failure and bacterial translocation, in hypovolemic conditions. bacterial infections still constitute a major cause of morbidity and mortality in patients with acute liver failure. the present study aimed at evaluating the effect of ethylhydroxyethyl cellulose (ehec) on bacterial translocation following surgically induced acute liver failure. acute liver failure was induced by subtotal hepatectomy ( %) in the rat. water-soluble ehec was administered orally and hours prior to hepatectomy. the incidence of bacterial translocation from the gut to mesenteric lymph nodes (mlns) and systemic and portal circulation was evaluated and the number of isolated bacteria from these samples and from intestinal content were determined. intestinal transit time, bacterial adherence onto the intestinal surface, intestinal mucosal mass, bacterial growth and dna synthesis, bacterial surface characteristics (hydrobiology: hydrophobicity, hydrophilicity and neutrality; surface charges: positive, negative and neutral) were also determined. hepatectomized animals showed a - % translocation rate to mlns or blood and hours after operation, while only - % of rats subjected to sham operation or animals with % hepatectomy and pre-treatment with ehec (p < . ). bacterial overgrowth, increased bacterial adherence onto the intestinal surface as well as decreased intestinal mucosal masses were observed in animals with subtotal liver resection alone, alterations that were prevented by enteral ehec treatment. a delay in intestinal -hour transit time occurred in both groups with subtotal liver resection, with or without enteral ehec. ehec inhibited bacterial growth and dna synthesis, and altered bacterial surface properties following hour incubation with bacteria. in conclusion, the findings in the present study imply that ehec alters enterobacterial capacities for metabolism, proliferation and invasion by effects on e.g. bacterial surface characteristics. furthermore, ehec seems to possess a trophic action on the intestine, rather than exerting its effect by enhancing intestinal motility. department of surgery, lund university hospital, s- lund, sweden disturbances in intracellular calcium signalling can potentially result in impairments of cellular responses vital to the functional integrity of both immune and non-immune cells, and thus contribute to a decrease in host resistance against infection and to multiple organ system failure during sepsis. studies in our laboratory have focused on assessments of intracellular ca ÷ regulation and ca~+-depended cellular responses in the liver, skeletal muscle and splenic tlymphocytes harvested from rats subjected to gram-negative intraabdominal sepsis. cytosolic ca + concentration, [ca *]i, and ca + fluxes were measured by the use of fluorescent ca + chelating dyes (fura- or indo- ) and ca respectively. to assess sepsis-related changes in ca + dependent cellular responses, we measured the acute phase protein response in the liver, the regulation of protein and sugar metabolism in the skeletal muscle, and the proliferation response in the splenic tlymphocytes. altered ca + i signalling with sepsis was correlated with an exaggerated inappropriate acute phase protein response ( % ¢) in the liver, and a blunted insulin mediated sugar utilization ( % ) and increased proteolysis ( % ~) in the skeletal muscle. in t-lymphocytes, a decrease in mitogen induced elevation of [ca +]i by - % was correlated with a significant depression in their proliferative capacity. these studies clearly suggest that altered calcium signalling is correlated with disturbances in cellular responses in both immune and non-immune cells during sepsis. the altered cellular responses adversely effect the outcome of the septic injury. (supported by nih grant gm ). alfred ayala, ping wang and irshad h. chaudry. changes in macrophage capacity to respond to foreign pathogens are thought to be central to the developing immunosuppression associated with traumatic injury. in this respect, the suppression seen in m~ functions following hen (a common component of traumatic injury) may be mediated by the direct or indirect inhibition of their capacity to perceive external stimuli (e.g., opsonized & non-opsonized bacteria, and their cellular components, etc.} due to the breakdown of the receptormediated signal transduction system. results of a number of studies by our laboratory and others indicate that this inability to respond to external stimuli is in part due to the loss of cell surface receptors. decreases have been documented for not only la antigen, but also c b, fc, and tnf receptors following hem in mice. furthermore, studies which have examined second messenger generation in these cells indicate that m~ derived from the peritoneum and spleen exhibit a decreased capacity to mobilize ca + from intracellular stores. this protein kinase dependent process of [ca+ ] i mobilization appears to be linked to the inability to synthesize inositol triphosphate. of interest, the depression in ca + signal generation appears to be inversely related to presence of elevated levels of camp in m~ from hen mice. we have reported that m~ priming agents, such as ifn- (which exhibits salutary effects on m~ function following hem), appear to restore cell signal transductive capacity while reducing the levels of camp. nonetheless, the extent to which depressed receptor signal transduction in hem, is due to receptor loss~dysfunction or elevated antagonistic second messenger levels remains to be determined. conclusions: significant impairment of calcium signaling occurs at all time-points prior to and following pha stimulation in trauma patients. tcell activation failure can, in part, be explained by the inadequacy of this essential intracellular second messenger system. restoration of immunocompetence following trauma will have to address strategies to better assess and restore this vital step in the activation sequence leading to proliferation during the antigen recognition process. patrick a. bseuerle institute biochemistry, albert-ludwigs-university, hermann-herder-str. , d- freiburg, germany the active form of the transcriptional activator nf-~b is a heteredimer composed of a and kda polypeptide. in this form, nf-'<b can bind with high affinity to decameric sequence motifs (consensus: "-gggpunnf'ypycc- ") found in enhancers and promoters of many genes activated upon a wide variety of pathogenic conditions, including viral and bactedai infections, acute phase response, oxidative stress and uv and gamma irradation. clinically important target genes for nf-k:b encode inflammatory cytokines (il- b, tnf, [l- , il- , gm-csf etc), cell adhesion molecules (icam- , elam- , vcam- ), acute phase proteins and immunoregulatory ceil surface receptors. in most cell types, nf-~:b is sequestered in the cytoplasm and, therefore, unable to initiate transcription of these genes. the cytoplasmic form of nf-~:b contains one additionai subunit, referred to as h,;:b. i~b can reversibly suppress dna binding and nuclear uptake of nf-~b by virtue of its association with p . upon stimulation of cells, ikb is proteolytically destroyed, allowing nf-kb to enter the nucleus and activate genes upon binding to transcriptional enhancers. we have demonstrated that various antioxidative compounds inhibit the activation of nf-~b in response to many inducers. moreover, nf-~:b was shown to be activated upon treatment of cell cultures with p.m-amounts of hydrogen peroxide. these data suggested that nf-~b prinicipaliy is an oxidative stress-responsive transcnption factor. the notion is supported by numerous reports on the induction of oxidative stress by many nf-nb-inducing agents. nf-~b activition can likewise be suppressed by protease inhibitors. these drugs apparently inhibit a yet unidentified protease responsible for the inducible decay of inb. we propose to use nf-nb inhibifors as novel drugs with a very broad application under acute phases el inflammation, injury and infection. northern blot experiments revealed that expression of the recently discovered lipopolysaccharide binding protein (lbp), a / kd glycoprotein, in the liver rises substantially during the acute phase response. experiments with an in-vivo acute phase model using new-zealand-white rabbits and also in-vitro experiments employing stimulated hep-g cells showed that lbp transcripts could be induced to ford within hours after induction with cytokines. by using a newly established nonradioactive nuclear run-on technique we show that induction of lbp during the acute phase is transcriptionally regulated. furthermore we screened a human genomic library and were able to clone the lbp gone, containing the promoter . kb upstream. several liver-specific and "acute-phase-typical" potential binding sites were found fn the promoter region and reporter gone assays were set up. several caat-boxes, the il- responsive elements hstf-hsp . and h-apf- rs as well as the transcription factor hnf- and the glucocrticoid-responsive elements oct- -d and gcre were found, which correlates with the induction pattern of lbp mrna in hep-g cells by il- , il- and dexamethasone. pcr-based analysis of the exon-intron pattern of the lbp gene revealed similarities with the genes of two other lps binding proteins, namely bpi and cetp. further analysis of this novel acute phase protein, that also has an important role in endotoxin recognition and immunomodulation will help in understanding the complex acute phase mechanism and potentially lead the way to new therapeutic strategies. lps activation of nucle?/r fa-ctor:~b " (nf:~bj"in cd .transfected fi'broblasts does not appear to require tyrosine kinase activity d. t. golenbock, r. delude, r. savedra, s. vogel and m. j. fenton lipopolysaccharide (lps) is the major constituent of the outer leaflet of gram-negative bacteria. during the course of serious infection, shock may occur as a result of the interaction of lps with macrophage lps receptors. cd , a kda glycosyl phosphatidylinositol (gpi)-linked protein, functions as an lps receptor. a critical issue in lps activation concerns the mechanism by which cd , which has no transmernbrane domain, transduces a sig,nal after lps binding. evidence exists which suggests that cd may signal cells after lps binding by interacting with an lps signal transducer with tyrosine kinase (tk) activity. wild-type chinese hamster ovary fibroblasts (cho) normally do not respond to lps, but can be activated following transfection with cd (cho/cd ). stimulation of cho/cdi with as little as ng of lps/ml resulted in the release of h-arachidonic acid ( h- : ) into the culture supernatant. in addition to h- : release, we examined lps-imiuced activation (transl cation) of the transcription factor nf-~b. similar to lps-induced h- : release, these responses were observed only in cho cells lransfected with cd closely resembling the same response in the marine macrophage cell line raw . . maximum nf-~cb expression occurred at minutes. in contrast to lps-induced h- : release, dexamethasone, cycloheximide, and actinomycin d had no effect on activation of nf-r,.b in cho/cd , suggesting that nf-r,b activation begins early after lps binding to cd and does not require transcription or translation. we then examined cells for lps-induced tk activity by western blotting cellular ly~ates with anti-phcsphot-'rosin:~ anl',bodie~" although tk activity was seen in lps-stimulated raw cells and phorbol ester stimulated cho/cd , lps-induced tk activity in cho/cd was not observed. although the tk inhibitor herbimycin inhibited the release of h- : in cho/cd and raw cells, neither herbimycin nor genestein effectively blocked nf-r,b activation in either cell type. these results suggest that tk activity is involved in a portion of the signaling pathway that is distal to initial signal transduction. the absence of observable lps-induced phosphotyrosine residues in cho/cd cells as well as the failure of tk antagonists to inhibit lps-induced nf-~cb activation suggest that the proposed cd -related lps signal transducer in cho/cd is not a tymsine ldnase. dimished cardiac inotropic function and response to -adrenergic receptor ( -ar) stimulation are frequently seen in septic patients, these cardiac defects are also seen in animal models of entoxemia. to determine the characteristics of the decreased transmembrane signal associated with the decreased beta adrenergic response we measured the force and rate of contraction of atria harvested from sprague-dawley rats exposed to endotoxin ( : gm/kg). to stimulate various components of the transmembrane signal cascade of -ar was isoproterenol (i -ar), acetylcholine (m ach receptor), naf(gs and gi proteins), forskolin (adenylate cyclase), and calcium (intracellular contracttile signal) were used. to eliminate the transmembrane control of calcium and test the intrinsic contractile response, hypothermia ( °c) was used the results showed alterations in the inotropic function with no significant difference in chronotropic response. the inotropic reponse for the endotoxin exposed atria and controls is shown below these results show that there is a transmembrane signal defect both for the i~-ar signal and for ca +. these data indicate that the level of the defect appears to be at the g proteins. ischemia-reperfusion of the rat intestine produces an injmry both to the intestine and to distal organs, notably the lungs and liver. prior studies have shown that h of intestinal ischemia leads to a nemtrophil independent reperfusion injury of the gut. thus, rats rendered neutropenic by pl~l antiserum have been shown to express a severe local gut injury when subjected to ischemia and reperfusion. this gut injury is postulated to he mediated at least in part by the complement system. the soluble (s) cri receptor which binds to c b and cdb was given to rats at a dose of mg/kg by intravenous bolus, min before reperfusion of the ischemic gut. a control group was given pbs buffer. at h of rmperfmsion the animals were sacrificed. pbs treatment led to a significant activation of both classical and alternate complement pathways while scri inhibited both pathways (fall to zero of chbo ). intestinal mucosal injury score, assessed by histological grading was reduced by scri ( . ± . to . _+ . ,p< . ) . intestinal neutrophil sequestration estimated by assay of myeleperoxidase was also reduced ( . ± . to . ± . u/g). c was detected in the gut hy i~unohistochemistry. remote organ injury was modified that is lung permeability (ration of concentration of radiolabelled albumin in broncho-alveolar lavage fluid to that in blood) was reduced ( . ± . x i to . ± . x , p<o. ). however, neutrophil sequestration by the lungs was unaffected. this remote protection is thougth to be related to prevention of ic b deposition on imng andotheli~ which activates adherent neutrophils. these findings support the hypothesis of complement mediated local and remote injury. we postulate that complement fragments may be deposited either as a result of the ischemia induced loss of membrane bound complement regulatory proteins, such as decay accelerating factor or membrane cofactor protein, which allow complement fragments to accumulate on the endothelial cell surface. alternatively, increased expression of p-selectin on the endothelial cell surface may, by means of its complement binding domains, act as a lattice for complement deposition. indeed, p-selectin has been detected on the surface of endothelial cells ans platelet-neutrophil aggregates recovered from the intestine of these animals. ischemia ( hr) followed by reperfusion (dhr) of rat hind limbs resuits in local (muscle) injury as well as in remote (lung) injury, which is characterized by increased vascular permeability (leakage of j sl labeled albumin) and neutrophil accumulation (tissue content of myeloperoxidase, mpo). within minutes of reperfusion following ischemia, tumor necrosis factor-o~ (tnfc , interleukin-i ( l-i) and il- plasma levels increased significantly, reaching maximum levels after hours ofreperfusion. polyclonal antibodies to tnfet and l-i provided significant protection against muscle and lung injury. muscle and lung vascular permeability decreased in anti-tnfct treated rats by % and % respectively and mpo was reduced by % and %. antml- yielded a protection in muscle and lung vascular permeability of . °, and . % respectively whereas muscle mpo was reduced by . % and lung mpo by . °, . these results were confirmed by the use of soluble tnf~ receptor and il-i receptor antagonist (il-ira). when icam-i expression in vivo was examined using mabeled antmcam-i, constititive expression of icam- was evident only in lung but not in muscle. during reperfusion icam- expression increased by . %. treatment with anti-tnfcx or il-ira reduced icam-i upregulation by . °, and . % respectively. frozen sections of normal rat lung revealed no evidence of e-selectin expression, whereas lung sections obtained after ischemia and reperfusion immunhistochemically demonstrated expression of e-sdectin. lungs from rats pretreated with anti-tnfct were negative for e-selectin staining. our data indicate a role for cytokines in the upregulation of adhesion molecules in ischemia/reperfusion injury. adherence of neutrophils to the coronary endothelium is associated with significant myocardial injury following min of ischemia (mi) and . h of reperfusion (r). p-selectin is expressed by activated endothelial ceils and platelets within min and tethers polymorphonuclear leukocytes (pmns) to the endothelium. we examined the cardioprotective effects of a monoclonal antibody (mab) designated pb . to p-selectin in a feline model of mi+r. pb . ( mg/kg) administered rain post-occlusion ( min prior to reperfusion) significantly attenuated myocardial necrosis compared to a non-blocking mab (nbp . ) for p-selectin ( + vs + % of area-at-risk, p< . ). endothelial dependent relaxation to acetylcholine was also significantly preserved in ischemic-reperfused coronary arteries isolated from cats treated with pb . compared to nbp . ( + vs + , p< . ). furthermore, pmn adherence to ischemic-reperfused coronary endothelium was significantly attenuated in pb . treated cats ( + vs + pmns/mm z, p< . ). also, normal coronary endothelium activated with thrombin ( u/mt) had increased pmn adherence under conditions of shear stress, an effect which was significantly (p< . ) blocked by pb . , but not by nbp . . furthermore, p-selectin is markedly upregulated - min post-reperfusion in coronary arterial and venous endothelinm. similar results were obtained in a rat model of mesenteric ischemia/reperfusion, including upregulation of p-selectin on mesenteric vascular endothelium. these results demonstrate that tethering of neutrophils to endethelium by p-selectin is an important early consequence of reperfusien injury, and a specific monoclonal antibody to p-selectin exerts significant endothelial preservation and cardioprotection in ischemia and reperfusion states. as recent interest has increased in the role of extracellular matrix proteins in inflammation, we examined the role and relationship of laminin and fibronectin to the processes of cell infiltration in a rat model of heart isografts. changes occurring in this system are on a nonimmunological basis and may be an effect of the initial surgical manipulation and the warm and cold ischemic times of transplantation. lewis (lew) donor hearts were transplanted into lew recipients, naive lew acted as naive controls (nc). grafts were harvested , , , , , , , and h after transplantation (n= /time point) . snap frozen sections of organs were stained for cd- (w / ), cd- (ox ), t-lymphecytes (tl) (ox- ), macrophages (ed , ed ), neutrophils (pmn) (mom), icam-i (iap ), laminin and fibrinogen. results were evaluated visually by counting cells/field of view (cf) for w / , ox , ox , ed , ed and mom, staining for icam , lain and fib was assessed visually using a scale (ve= - ). as early as h after transplantation, fibrinogen and laminin expression increased in i, peaking h after transplantation (ve= . ; nc: ve=i. ) . at and h in i, on both vessels and interstitial cells laminin and fibrinogen expression had declined to baseline (ve=i. ) but rose again at h, peaking at h (ve= ) and remaining elevated thereafter (ve= ). the high expression at h correlated well with the maximal pmn infiltration at that time (cf= ) in i returning to baseline at h (cf= . ) and thereafter. the second peak at h correlated with the onset of macrophage and t-lymphocyte infiltration. thus, laminin and fibrinogen seem to guide leucocyte infiltration following graft ischemia during the time of reperfusion. background. reperfusion of ischemic kidneys with xenogeneic blood leads to activation of endothelial cells and circulating leucocytes with the final consequence of microvascular thrombosis. in concordant systems, the mechanisms of rejection can be studied due to cross-reactivity of mediators with anti-human monoclona~ antibodies. aim of the study. to obtain information about the kinetics of proinflammatory cytokines and production of soluble adhesion molecules in the acute phase of reperfusion, eight kidneys from rhesus monkeys were perfused ex-vivo with human blood (group b/o) for one hour in a closed system. blood levels of il-lb, il- , tnf-a, soluble icam and e-selectin were measured in elisa-technique under steady-state conditions. results. cytokine levels rose significantly within the minute interval (il-lb: , __+ , to , __+ , pg/ml; il- : . - , to , __+ , pg/ml; tnf-a: , __+ , to , + , pg/ml; p< . ). immediately after the beginning of reperfusion, soluble icam- and selectin levels were abnormally high and constantly rising throughout the observation period, reaching significance at minutes. discussion. high levels of proinflammatory cytokines may lead to an induction of adhesion molecules, thus upregulating the leukocyte-endothelial interaction in an complement-independent mechanism. specific pretreatment with monoclonal antibodies against icam- , lfa- or other soluble mediators may be useful in downregulating hyperacute rejection in transspecies transplantation. prolonged ischemia has been associated with later dysfunction of solid organs as it may cause upregulation of adhesion molecules, production of cytokines on vascular endothelium and migration of host cells into the graft. these early events may lead to irreversible organ injury. this study evaluates the effects of global ischemia on early immunohistological changes in cardiac grafts transplanted in rats. isografted hearts (lewis->lewis) were were divided into ischemic and non-ischemic groups (n= /group). all donor hearts were flushed immediately with cold saline. non-ischemic hearts were then transplanted within rain, ischemic hearts were stored in cold ringer's solution for hours before revascularization. representative grafts were removed after . , hrs, and days, and evaluated immunohistologically (cells/field of view=c/f). restitution of ventricular activity was significantly delayed in ischemic grafts ( vs rain). after hrs, all ischemic grafts exhibited an extensive interstitial edema, declining slowly thereafter. at the same time, numbers of pmn peaked ( vs c/f in non-ischemic grafts), whereas edl+macrophages ( vs c/f) and tnfe expression peaked by hrs. by hrs t-lymphocytes began to enter ischemic myocardium and icam- was moderately increased. after days cellular infiltration had returned to baseline, and no differences were seen among both groups after days. global myocardial ischemia inhibits initial graft function, and engenders a brisk inflammatory reponse, primarily pmn and macrophages, with increased mhc class ii and cytokine expression. leukocyte -endothelial interactions are the result of endothelial activation, leukocyte activation or combination of both, which are accompanied by nee-expression, upregulation or shedding of adhesion molecules (selectins, inlegrins). such interactions differ with regard to the stimulus (e.g. thrombin or histamine for p-selectin, endotoxin or tnf/il- for e-selectin), the time course of response (minutes versus hours) and the localisation in different organs. recently assays are available for circulating soluble fragments of the cell bound adhesion molecules e.g. se-seleetin was found to be increased in plasma concurrent with high circulating endoloxin and cytokine levels. the importance of adhesion molecules for the sepsis event is evident, while effectiveness of anti-adhesion inolecu]e therapy is controversial e.g. beneficial anti-e-selectin therapy in baboon bacleremia but deleterious effects of amti-cd treatment in the same model. in other species similar controversial results with anti-cd therapy in sepsis were reported. steven l. kunkel,theodore standiford* and robert m. stricter. the migration of leukocytes to the lung during endotoxemia is dependent upon the coordinated expression of lung vascular adhesion molecules and the subsequent production of appropriate leukocyte chemotactic proteins. in experimental animals, neutrophils accumulate within the lung soon after the administration of endotoxin, while mononuclear cell infiltration occurs in a more distal manner. a kinetic analysis of lung leukocyte levels revealed a -fold increase in neutrophil numbers associated with dispersed lullg tissues hours after lps treatment, while macrophage levels increased by -fold at the hour time point. thus, the recruitment of different leukocyte populations to the lungs during endotoxemia is likely directed by different mechanisms. recent studies have identified a supergene family of small inducible chemotactic cytokines (chemukines) which possesses chemotactic and activating properties for neutrophils. the prototype of this family is interleukin- (il- ). interestingly, a related supergene family has been identified which possesses activity for recruiting mononuclear cells. examples of this group of inflammatory chemukines are monocyte chemotactic protein-i (mcp-i) and macrophage inflammatory protein-i alpha (mip-i). in initial in viva studies we examined whether mip-i was expressed systemically or in a compartmentalized fashion post lps challenge. assessment of plasma cytokine levels revealed maximal tnf levels occurred i hour post lps administration, returning to baseline by hours, while mip-i levels were maximal at hours ( , ng/ml), with a second peak at hours after lps challenge. interestingly, aqueous extracts of liver homogenates from lps treated animals demonstrated no mip-i levels, while aqueous extracts of lung revealed a -fold increase in mip-i levels over control lungs. immunohistochemical analysis of the lungs from hour lps treated animals demonstrated the alveolar macrophage was a rich source of mip-i protein. cell-associated mip-i was also expressed by blood monocytes adherent to the pulmonary vascular endotheliun, however the expression of monocyte-mip-i was observed by hours post lps administration. immunohistochemical analysis also demonstrated that mip-i antigen is associated with the extracellular matrix on the interstitial side of the endothelium. this suggests that the extracellular matrix, which is produced during inflammation, can bind mip-i and this may serve as a depot for the prolonged presence of nip- . in additional studies we have demonstrated that the intratracheal instillation of rmui [ip-l(loong) activation of polymorphonuclear leukocytes by inflammatory stimuli may contribute to the development of multiple organ failure in septic patients. thereby pmnl are proposed to avidly adhere to vascular endothelium causing damage by the subsequent release of toxic agents. as cellular adhesion is primarily mediated by -integrins and lselectins, the present study compares the expression of these adhesionmolecules on pmnl in septic patients and healthy volunteers. methods: expression of -integrins and l-selectins on pmnl was measured in whole blood by flow cytometry using the monoclonal antibodies ib and dreg , baseline values were determined immediatley after drawing blood. in addition cells were incubated min at °c to allow for spontaneous regulation of adhesion molecules. blood specimens from septic patients were obtained during the course of their illness. control values were determined in healthy volunteers. results: baseline expression of -integrins and l-selectins was not signifcantly different in septic and in healthy subjects. in contrast, there was a significant upregulation of g -integrins and shedding of l-selectins of pmnl in septic patients (sp) compared to healthy volunteers (hv). the local or systemic production of inflammatory cytokines, such as tumor necrosis factor alpha (tnfc~), can serve to modulate multiple aspects of neutrophil function. the ability of neutrophils to leave the circulation and migrate to areas of infection is one essential component of host defense. l-selectin, a leucocyte-associated adhesion molecule, is responsible for the initial reversible contact between neutrophils and endothelium and the subsequent roiling action of neutrophils along the vessel wall. in contrast to other adhesion molecules, l-selectin expression is rapidly down-regulated after neutrophil activation. the loss of l-seleclin may thus be a critical determinant of how neutrophils become unbound from their endothelial attachments and enabled to proceed towards an underlying extravascular area of infection. we hypothesize that the shedding of l-selectin is a strictly controlled process, occurring primarily at localized sites of inflammation, which may be modulated by tnf~, a flow cytometric method of staining neutrophhs by monoclonal antibodies in whole blood is described whereby the kinetics of l-selectin shedding may be followed in real time. the dose response and time course of in-vitro l-selectin shedding by neutrophils from normal human subjects was assayed after exposure to n-formyl-methionylleucyl-phenylalanine (fmlp) and tnfc~. either singly or in combination, our results show that l-selectin shedding can be reliably followed over time. a significant percentage of cells shed l-selectin after exposure to pg/ml tnfc~ or nm fmlp (but not at pg/ml tnfc~ or nm fmlp). greater numbers of cells were able to shed their l-selectin when fmlp and tnf~x were presented in combination rather than alone. high levels of tnfc~ did not appear to alter the threshold concentration of fmlp required to induce shedding, we conclude that the extent and rapidity of l-selectin shedding may be modified by different combinations of ligands and that shedding, by vidue of the high concentrations of cytokines or chemotactic factors required, is a process localized to sites of infection or inflammation. we prospectively studied patients with severe sepsis syndrome; group a : septic shock with or without adult respiratory distress syndrome lards) (n = , bacteremia = ); group b : sepsis syndrome without septic shock (n = , bacteremia = ). serial plasma samples obtained on day , , , , and , were assayed using elisas method (british biotechnology), normal control levels of soluble icam- and e-selectin, obtained from healthy volunteers, were respectively ± . ng/ml and ± . ng/ml (mean _+ se), acute lung injury was quantified dally on a tour-point score system (murray, am rev respir dis, ) . compared to control mean values, initial levels of groups a and b were significantly higher for icam- (p < - ) and e-selectin (p < - ). comparisons of group a and [] (* = p< . ; ** = p< . t) soluble icam- levels of group a enhanced significantly (p< . ) during the first hours, and a sustained high levels was of bad prognosis ( % of survivors at day ). the evolution of soluble icam- and e-selectin levels were significantly correlated with murray's score (spearman test : p < . ). conclusion: these results suggest that endothelial adhesion molecules are released into the plasma of patients with severe sepsis syndrome. soluble icam- and e-selectin are correlated with endothelial lung damage, and loam- seems to be a better indicator of the severity of endothelial injury. introductory remarks to anti-adhesion molecule strategies as a therapeutic modality ch wortel, repligen corporation, one kendall square, building , cambridge, ma , usa. the development of antimicrobial therapy represented a major breakthrough in the struggle against disease. it strengthened the notion that disease could be overcome by eliminating foreign invaders threatening the host. this paradigm has proven to be very successful, the threat of many infectious diseases has significantly changed, some have even been eradicated. nevertheless, sepsis has remained a severe condition, increasing in incidence while mortality remained very high. more recently, it has become increasingly clear that besides the nature and treatment of an exogenous agent, the reaction of the host defense itself plays a pivotal role in the outcome of the event. endogenous mediators, such as tnf, il-i, il- and il- , govem many of the actions of the host defense system. while the expression of these cytokines more often than not benefit the host, (over)-expression can cause severe damage. based on this hypothesis,anticytokine strategies, such as those targeted against tnf or il- , have been evaluated for the treatment of sepsis. results of these early studies have not yet indicated success in improving the outcome of the disease. it has been difficult to define a patient population where a benefit could be reproducibly shown. furthermore, it has been documented that synergy between cytokines occurs, but detailed knowledge of the cytokine network is not yet available. it is conceivable, that neutralization of one cytokine prompts the induction of another which will evoke the intended response in the host. recent data obtained in human endotoxemic volunteer models seem to confirm this. if this turns out to be the case, neutralizing a single cytokine may not be a successful approach. cytokines in tum, induce various adhesion molecules, such as icam- . such molecules regulate for instance the neutrophil-endothelial cell interactions, which are thought to play an important role in the pathogenesis of systemic organ injury. the potential for monoclonal antibodies to adhesion proteins to reduce vascular and tissue damage has been studied in a large number of experimental models. protective effects have been observed in a wide variety of inflammatory, immune, and ischemia-reperfusion injuries. thus, altering the host response by modulating the function of adhesion molecules may attenuate the inadvertent injury caused by inappropriate behavior of host defense cells. targeting cellular surface interactions has been added to the efforts to change the outcome of disease. modulation oftheseprocesses seems very promising, but may temporarily leave the host without effective defense mechanism. great care therefore, must be exerted when studying this powerful two-edged sword in a clinical setting. our knowledge of the role of adhesion molecules in the intlammatory response has increased rapidly due to the availability of new reagents and mice geneticly deficient in adhesion molecules. these molecules are important in interactions of leukocytes with endothelial cells, other leukocytes, platelets, and epithelial cells. when these molecules are engaged, they can also play a role in activating leukocytes and their effector functions. in the venules of the systemic circulation, adhesion often occurs through a series of sequential interactions. initial interactions are mediated by members of the selectin family to loosely associate the leukocytes with the endothelium and are followed by firm adhesion requiring members of the integrin and immunoglobulin family. later interactions with endothelium may require pecam. adhesion molecules are usually required for leukocyte emigration in response to extravascular stimuli and for neutrophil-mediated endothelial cell injury. they are critical for host response in many diseases including infections. however, when the inflammatory response results in damage to host tissues, patients may benefit from blocking the leukocyte response. anti-adhesion molecule agents are an important potential antiinflammatory therapy. the focus of anti-adhesion therapy may be at any step of the sequence. diseases where anti-adhesion molecule therapy may benefit patients include ischemia/reperfusion injury in many organs, ards and mof, and transplantation, both to protect the donor organ from ischemia/reperfusion injury and to inhibit graft vs host disease. many strategies have been considered and include: ) blocking the ability of adhesion molecules to recognize their ligand using antibodies that have been humanized or soluble receptors linked to igg to prolong their circulating halflife, ) blocking the ligands for adhesion molecules using soluble adhesion molecules, peptide analogues, or oligosaccharides, and ) blocking the production of the adhesion molecule using anti-sense oligonucleotides. because the synthesis of adhesion molecules is usually regulated by cytokines, inhibiting the action of cytokines is another potential site for interrupting the adhesion process. although important issues of safety must be evaluated, the potential for modulating the inflammatory response make this an exciting area of improvement in health care delivery. claire m. doerschuk, m.d.; riley hospital for children, room ; barnhill drive; indianapolis, in usa. modulation of neutrophil-endothelial cell adhesion with anti-cdl i/cd monoclonal antibodies as a therapeutic modality. ch wortel, repligen corporation, one kendall square, building , cambridge, ma , usa. the central role of inflammatory cells in the pathogenesis of lung and systemic organ injury is well recognized. binding of neutrophils to endothelial cells and migration into the parenchyma are largely regulated by complementary adhesion molecules. the leukocyte integrins are glycoproteins expressed on the neutrophil surface and in the cytoplasmic granules. integrins consist of a common beta or cluster differentiation (cd) chain covalently linked to one of three different alpha chains (cdlla, cdllb, cdilc) and exist on the cell surface as three distinct heterodimers. cdlla/cd is expressed on all leukocytes, whereas cd b/cd and cd c/cd . are restricted to cells of myeloid origin. cd i / cd interacts with intracellular adhesion molecule- (icam-i), its ligand on endothelial cells. the potential for monoclonal antibodies to adhesion proteins to reduce vascular and tissue damage has been studied in a large number of experimental models. protective effects with anti-cd antibodies have been observed in a wide variety of inflammatory, immune, and isehemia-reperfusion injuries, such as arthritis, burns, endotoxic shock, bacterial meningitis, autoimmune diabetes, nerve degenemrion, allograft rejection, allergic asthma, acute lung inflammation, skin lesions, and ischemia-reperfusion models of the intestine, myocardium, lung, skeletal muscle, and central nervous system. protective effects have also been observed in animals resuscitated following hemorrhagic shock. blockage of cd , however, would affect all leukocytes, as would antibodies to cdlla/cdi . targeting cdllb/cd would affect cells of the myeloid lineage only, which could prove to be beneficial. cd b/cd is not only involved in transendothelial migration, but is also implicated in adherencedependent formation of reactive oxygen species. blocking cd lb/cd may therefore not only reduce the numbe r of leukocytes accumulating in the tissue, but also attenuate the oxidant stress of infiltrated neutrophils. anti-cd b treatment has been used effectively to reduce tissue injury initiated by ischemia-reperfusion, complement activation and endotoxemia. altering the host response by modulating the function of adhesion molecules may attenuate the inadvertent injury caused by leukocytes, but may also temporarily leave the host without effective defense machinery. overall, animal studies suggest that it may be safe to inhibit neutrophil adhesion for a limited period of rime. these observations will have to be confirmed in carefully designed clinical trials. c, arbobydrams are ubiquizom constir~uts of cell sv.rfaees, and possess many c~xssfies ttm~ m~,e ~em ide~. canaidates for r~ognifioa mole~ule& in m~y systems whe,~ cer udhesioa ~lays a critical ro~ car~hydram l:~dtag ~otegas have been shown to b~ad tocell surfa~ earbohydzaxes ~nd pzrl~pate in cell-ceil lumtaefion& such sys,.ems include ~rti~za~io=, deveaopmeat, l~thoge~-hcet reeog--ition ~d i~zmmadon_ in particular, tb.z recent di%~ve~ of lhe selec~ and th~ impo.~a~c~ in teukccy~udo~lelium adh~ion has -~f~m av.c~on ok l~in m~ted cell adhe~on. s~vere/poten~s/cs.rbohydr~ l~ga~s hrve ~e~l ~u~ilied for ~he s~lcc~ins. the,~ c~u be broadly di,,sded la~o ~wo m'oups -sibyl l~wis x m~ mh~.~l oligo~chadd~s, ~d sf/~ ca~ohydmma, all ~:~ ~l~dns bind m siflyl l~wis x (sie$ o!igos~ccb.e.rkms, zlthou~ w~ differing avi~re~. 'we have i~¢n~ed the functional g~oups a s~ex ~n~ med/a~ ~he b~u ~di~g of ~h~ c~b hydmm = e-se/sedm we have used ~hat iv.formation to sya~esize sle ~ '~mt gs r.he, t focus on replacing slslic ~sd ~nd fuc s¢ wi~ simpler, more stable strunt~es. a[~ou~a ~ proeer~ is ongoing, we hve been ~ucee,.~ful a~ rep~aein t.ke si~ic a~id. residue wi~ std.fzte. ~ce~ or la~c amd groupa we t'we ex aninad &e ten, bunion of ezed~ hydroxyl group of the fizeose residue ~ billding of e-, l-~nd p-selees..u. we have also found m~fi~fio~ of the reducing end ~¢.cha'i~ ~z increase mtagovsst activity. the, m¢ond. group of figs,rids a.r eontzin su~a~ u a ea.rbohydr~t¢ support,, und seem to bi~.d to t~e sele~ti~s wi~ dlf:ferem characteristics c .an does sle:, s=h compounds are m ogniz~d by l-selects. md p-selectia, bur., in genera/, not e, selecti~ these dam may mdicam r.hat l-and p-s~ ¢at~ h~d via o, second ~te thaz operates lu~.ead of, or in conjunction with ~tc sle" b~ding ~iite. dam rela~&~g to ±e, se two types of ,ml~ liga~ds have beam t~ed to desig~ potential the ~peutics for i~fi~anmat ry disease. lr:rng maimai models of acute lung lu ury we can demo~trate that eompmmds that inhibit seleetiu birding ~ ~i~o hzve ber~ficial effects when uc~d in rive. progressive microvascular damage in the tissue adjacent to a cutaneous burn injury results in extension of burn size. the role of leukocytes in the pathogenesis of microvascular injury was investigated by inhibition of their adherence to the microvascular endothelium using monoclonal antibodies directed to leukocyte cdi or its endothelial ligaud, intercellular adhesion molecule- (icam- , cd ). a model of thermal injury was developed using new zealand white rabbits. two sets of three full-thickness burns separated by two x -mm zones were produced by applying brass probes heated to °c to the animals' backs for sec. cutaneous blood flow determinations carried out with a laser doppler blood flowmeter were obtained for hours. there were five experimental groups: controls given saline alone; animals given monoelonal antibody to the cd r . prior to burn injury (pre-r . ); animals given r . min after burn injury (post-r . ); animals given a monoclonal antibody to icam-i, r . prior to burn (pre-r . ); and animals given the r . min postburn injury (post-r . ). blood flow in the marginal "zone of stasis" between burn contact sites was significantly higher in the antibody-treated animals. administration of the antibodies min after injury was as effective as preburn administration in preserving blood flow. at hr post-burn all antibody -treated animals had blood flow in the areas at risk for progression (i.e., the zone of stasis) at or above baseline levels while the control animals had levels equal to . _+ % of baseline (p < . by analysis of variance and mann-whitney u test). these results indicate that leukocytes play an important role in the pathogenesis of burn wound progression, and that this progression can be attenuated by moduiating adherence to endothelial cells. a wealth of information now supports the hypothesis that inhibition of cell adhesive mechanisms will nter the course of immunologicand inflammatory processes. what remains unclear is whether inhibition of specific mechanisms wfl[ be of therapeutic benefit in any specific human disease. current data derived from animal models are not inconsistent with the hope of therapeutic benefit, but techniques for inhibition (e.g., antibodies, antisense oligonucleotides, inhibitory peptides, inhibitory carbohydrates, smaii synthetic inhibitors, etc), tissue and species differences in the relative contributions of adhesion molecules to the inflammatory process, and the cascade model of adhesive interactions are all confounding issues, making predictions of therapeutic benefit in any specific human disease process very difficult. additional concerns involve the potential roles of adhesive mechanisms in host resistance to infection. as human therapeutictdals are initiated, more exact information on the roles qf specific adhesion molecules in human disease should emerge. inhibition of leukocyte adherence to endothelial cells can represent a novel therapeutic approach to septic shock. we performed a pilot study to evaluate the safety and tolerability to cy- , a monoclonal antibody against human e-selectin, in patients with septic shock. septic shock was defined by clinical signs of sepsis, a documented source of infection, and fluid-resistant hypotension requiring the use of vasopressors. eleven patients entered the study, but patients who died during the first hours were excluded, as this was part of the protocol. cy- was administered as a single intravenous bolus of . mg/kg (n= ), . mg/kg (n= ) or i mg/kg (n= ) mg/kg. the antibody was well tolerated. none of the patients died during the day follow-up period. organ failure was assessed for organs (cns, lungs, liver, kidneys and coagulation). the mean number of organs failing, which was initially . ± . , decreased to . ± . at the end of the study (p<o.o ). these results are therefore encouraging. administration of an antibody to e-selectin in patients with septic shock requires further study. the importance of cytotoxic t lymphocytes (ctl) in the host defense mechanism against viral as well as parasitic and bacterial diseases is becoming increasingly appreciated. the design of vaccines to generate cytotoxic t ceils from nonviable or subunit constructs, however, poses challenges due to the unique characteristics of antigen processing and presentation by class i major histocompatibility complex (mhc) molecules. since the final antigen recognized by ctl are short peptides capable of high affinity binding to class i mhc molecules, we have designed strategies: a) to define the structural characteristics of peptides that are required for their high affinity binding to mhc; and b) to formulate these peptides into immunogenic vaccines that are capable of generating cytotoxic t lymphocytes. the strategy and results to accomplish these two goals will be discussed. amnon altman and erich gulbins ras proteins represent essential intermediates in receptor-mediated growth and differentiation pathways. they couple signals initiated by receptor or nonreceptor protein tyrosine kinases (ptks) at the cell surface to cytoplasmic targets which coordinate signal transduciion to the nucleus. ras also participates in t lymphocyte activation initiated by the antigen-specific t cell receptor (tcr)/cd complex, which leads to lymphokine production and proliferation. receptor ligation causes activation of associated ptks of the src and syk families as the earliest identifiable event in this pathway. the importance of ras in t cell activation is indicated by the findings that an oncogenic ras protein activates the interleukin- (il- ) gene promoter; conversely, a transdominant inhibitory ras mutant inhibits this event and the activation of map kinases. the rate-limiting step in ras activation is the exchange of bound gdp for gtp, which is catalysed by guanine nucleotide exchange factors (gefs). we identified the sh /sh domain-containing vav protein, which is selectively expressed in hematopoietic cells, as a ras-specific gef coupled to several hematopoietic receptors. vav can be activated by two pathways, i.e., by ptk-mediated phosphorylation or by binding of diglyceride second messengers to a cysteine-rich, protein kinase c (pkc)homologous vav domain. these pathways are independent as demonstrated by structure/function analysis and the use of pharmacological inhibitors. the two activation pathways may enable vav to integrate signals from distinct hematopoietic cell receptors, and couple them to ras. t cells express another, ubiquitous ras gef, i.e., sos, which is known to be coupled to activated tpk receptors. t cell activation leads to membrane association of a signaling complex consisting of sos and two other signaling proteins, grb- and shc, via direct binding of the shc sh domain to the tyrosine-phosphorylated chain of the tcr/cd complex. thus, multiple receptors, ptks and ras activators participate in signaling pathways that lead to hematopoieitc cell growth and differentiation. the interactions and function of these various signal transducers will be reviewed. phagocytes. immunity is mediated by specific t lymphocytes, cytokines produced by these specific t cells activate antimicrobial capacities in mononuclear phagocytes, thus contributing to protection. other immune mechanisms also participate in the acquisition of resistance. on the other hand, t cells are also crucial for many pathologic sequelae of intracellular bacterial infections. although ifn-y is central to macrophage activation, synergistic and antagonistic effects with other cytokines occur. the cd/ t cells, representing the major t cell population in experimental mice, are the main mediators of antibacterial immunity; an auxiliary role for y/~ t cells appears likely. the c~// t cell population further segregates into cd t cells which recognize microbial peptides in the context of gene products of the major histocompatibility complex (mhc) and cd t cells which see their peptide in the context of mhc class i. the -y/~ t cells are generally double-negative. knock-out mice in which the genes for various t cell receptor chains, for mhc class i or mhc class ii molecules, for cytokines or cytokine receptors had been deleted, have provided extremely helpful tools for analyzing the role of t cell subsets and cytokines in antimicrobial immunity. using these mutant mice, the role of distinct t cell subsets and cytokines in bacterial elimination and granuloma formation was analyzed in detail. these studies underline the central role of a// t cells and ifn-y in antibacterial immunity and, furthermore, show a distinct function of /$ t cells. moreover, these studies show that the relative contribution of cd or cd t cells to antimicrobial immunity varies in response to different pathogens. apoptosis is an active form of cell death in which the cell participates in its own demise, providing the biochemical pathways that trigger and mediate the complex events of the process. although this phenomenon has been studied for many years, it is only recently that significant progress has been made towards the elucidation of the molecular mechanisms that control apoptosis. once such mechanism came as something of a surprise: in a number of eases, apoptosis can be promoted by the action of the c-myc protein, a protooncogene product that had previously been associated only with cell proliferation (and presumably, survival) . expression of c.myc in cells can cause them to enter an apoptotic pathway or proliferate, mad this "decision" depends upon additional signals, such as growth factors that inhibit apoptosis and allow the ceils to proliferate. thus, c-myc directs cells out of rest and the choice of proliferation or death depends upon the presence or absence of survival signals. other survival signals are generated by oncogene products that can cooperate with my¢, including bcl- and abl there are implications of this interplay between apoptotie and anti-apoptorlc signals in cell iransformation and the resistance of some tumor ceils to therapeutic agents capable of inducing apoptosis. oncogene interactions therefore control the life or death of transformed ceils but also have important roles in normal, development processes. in the immune system, developing t ceils are "screened" for potential self-reactivity by a process of negative selection, in which activation via the t cell receptor (tcr) induces apoptosis. this process can be mimicked in t cell hybridomas, and appears to depend upon the expression of the c-mye protein. evidence that this represents a requirement for the myc/max heterodimer will be presented. as above, these cells are presented with the "choice" to proliferate or die and this depends not only upon myc but also other signals. thus, expression of functional v-an kinase in these ceils can render them resistant to the activation of apoptosis via tcr ligation, surprisingly, bcl- does not appear to be capable of blocking this form of apoptosis, and the reasons for this will provide new insights into the development of the immune system and the process of apoptosis. although the oncogene products discussed here probably do not directly participate in the biochemical process of apoptosis, they represent molecular controls on this complex mechanism. as such, they gave us new ways to look at the life and death of a cell recent attention has focused on macrophage release of cytokines, such as il- , il- and tnf as important mediators of septic shock. however, serum cytokine levels have correlated poorly with outcome of septic shock. the purpose of this study was to compare the functional status of macrophages to serum cytokine levels in early sepsis by an analysis of splenic macrophage protein synthesis during abdominal sepsis. macrophage total protein distribution and biosynthetic activity was assessed by large format -d page, autoradiography of s-labeled proteins and computer assisted densitometric analysis. sepsis was induced in sprague dawley mts by cecal ligation and puncture (clp). untreated and sham operated rats served as controls. splenic macrophages were harvested at and hrs. following clp. serum il- levels were determined at , , and hours by the tdi bioassay. by hrs. % of the clp mls exhibited multi-microbiaj bacteremia. control or sham operated rats did not show bacteremia. clp resulted in a significant % elevation (p < . ) in serum il- levels at hrs. there was no difference in il- at and hrs. when compared to the control groups. d page studies examined splenic macrophage total protein distribution and biosynthetic activity at and hrs. post-clp. at hrs. macrophages from clp rats showed a substantial decrease in total protein pattern ( protein spots vs protein spots) when compared to non-septic control macrophages. a decrease in the number of lower molecular weight proteins (< kd) was observed. at hrs. post-clp, splenic macrophages from clp rats showed a substantial increase in the synthesis of low molecular weight (< kd) proteins, when compared to non-septic controls. we conclude that: l) fulminate abdominal sepsis induces an early ( hrs.) staining with cd and cd mabs will identify two monocyte subpopulations in human blood: a major population of regular monocytes, which strongly expresses the cd antigen (cd ++) and a minor population with weak expression of cd and expression of the cd antigen lcd +/ cd + cells). in healthy control donors(n= ) the latter cells account for + cells/mm and %+ % of the monocytes. in sepsis patients, the cd] +/cd + cells can become a major population with more than % of all monocytes in of patients and with more than cells/mm in of cases. there was no correlation of cd +/ cd + cells to any clinical parameter except for cd +/cd + percentage and body temperature (p= . ). the cd ++ monocytes showed a substanttial decrease in cd antigen density in of patients. three-color-if shows that the cd +/ cd + cells in sepsis patients when compared with the cd ++ monocytes exhibit a higher level of class ii antigen and a lower level of cdiib and cd antigens, consistent with a more mature nature of the cd +/cd + cells. levels of il- were increased in sepsis patients: of patients with high numbers of cdi +/cd + cells ( /mm ) had high levels of il- ( u/ml). these data suggest that septicemia may lead to substantial changes in blood monocyte composition and this may be related to elevated levels of cytokines such as il- . human peritoneal macrophages were exposed to increasing doses of lipopolysaccharide (lps) or a synthetic lipid a analogue (mrl ) and production of the cytokines il-lb, il- , tnf-a and g-csf was assessed at the protein-and mrnalevel. cells were also stimulated with low doses of lps and mrl to study their "adaptation" to a secondary challenge with high doses of lps. tnf-a production after stimulation with lps could be almost completely relieved by preincubation of cells with low doses of lps and similarly, il- production was suppressed. surprisingly, however, "adapted" cells were able to synthesize even larger quantities of of g-csf and il-lb when exposed to a secondary lps challenge. the changes in tnf-a, il- and g-csf protein synthesis could a/so be detected on the mrna level, whereas transcript levels for il-lb remained unaltered as assessed by northern blot analysis. high doses of the synthetic lipid a analogue mrl were also able to "adapt" macrophages for a secondary lps challenge by downregulating tnfa-and il- -production, while priming secretion of g-csfand il-lb as well. taken together, here we describe for the first time the discordant adaptation of human peritoneal macrophages to a secondary lps stimulus in vitro. these findings appear to bear ramifications for the in-vivo endotoxin response during inflammation and gramnegative septicemia. shock states with inadequate cellular oxygen delivery may contribute to macrophage (mo) activation or dysregulation. in this study we compared the effect of transient hypoxia and endotoxin pretreatment (lps ) on mo mediator release with a second endotoxin stimulus (lps ). methods: in vitro cultures of marine peritoneal exudate mo were exposed to hr. of hypoxic or normoxic conditions, then incubated hr under identical normoxic conditions _+ ng/ml of lps pretreatment. during the final hours all m~l were exposed to a range of lps concentrations. m~i supernatants were assayed for tnf, il- , il- , pge , nitric oxide (no), and superoxide release. results: lps markedly inhibited mo tnf release by lps but hypoxia had no effect on lps -triggered tnf release. hypoxia increased mo il- production in the absence of lps , but inhibited lps augmentation seen under normoxic conditions. pretreatment with lps increased no production from lps under normoxic conditions, but bypoxiainhibited this effect. pretreatment with lps signifcantly augmented mo release of il-i and pge , but hypoxia had no significant effect (data not shown) superoxide production was increased by lps under normoxic conditions, but hypoxia significantly inhibited superoxide release (not shown a. lepape, c. docile, f. arpin, m. c. gutowski, v. banssillon and j. bienvenu. i aim of the study. increased levels of tnf are inconsistently correlated with the severity of sepsis. one possible explanation is a decrease ability of ceils to produce eytokines. the objectives of this study were m compare at different levels of of clinical severity the responsiveness of cytokine producing cells. this was evaluated by the response to a stimulation by lps as well as to the inhibitory effect of ptx. the technic used is a whole blood ex-vivo model, as described by desch et al. ( ) . h materials and methods. different groups of icu patients, postoperative (n= ), sepsis (n= ), septick shock (n= ), and healthy control (n= ), were studied. blood was drawn in endotoxio free heparinized robes. stimulation was achieved by addition nf pl oflps ( ng/ml) to id of whole blood in presence of various concentrations of ptx ( , " , - , " , i " m). after hrs incubation at °c, the tubes were centrifuged and supematants frozen at - °c. tnfa and/l were measured by elisa (medgenix r and immunotech r respectively). monocytes were quantified on a technicon h . the results are expressed as median values. non parametric tests are used for testing differences between groups. hi results, tnftx and , , corrected for monocytes count, are given as % of their initial value, the baseline before stimulation or inhibition being %, ) stimulation by lps. the control group is much more stimulated (> % for il , > % for tnfa). blood samples taken postoperatively and in patients with simple sepsis are significantly less stimulated (> % for il , > % for tnfa ). the lowest stimulation was observed in patients with septic shock (median = %), some patients being not stimulated at all. )effects of ptx.the inhibitory effect of ptx on tnftx production is effective in all groups at - m (reduction to less than '¼ of the median values), and is almost complete at " m. the septic shock group has a decreased sensitivity to ptx. il production exhibits a lesser reduction at - m (~ 'a to ½ of the median values), further increased at - m. the septic shock group is again less sensitive to ptx. iv conclusion: the reduced ability of circulating monocytes to produce cytokines during severe infections is confirmed here. ptx is able to reduce significantly tnfc~ at - m and the inhibition is nearly complete at - m. surprisingly, there is a lesser, but significant suppressive action of ptx on il , not found in experiments using purified monocytes. one possible explination could be the interplay between cytokines production. ( ) lymphokine research ( ) cdna sequencing constitutes a powerful method of measuring steady-state mrna levels for all genes transcribed in a given cell or tissue at a particular stage of differentiation. by comparing transcript abundance both prior to and following differentiation, individual genes can be identified whose transcription is regulated both positively and negatively. in order to examine monocyte activation, the human monocyte line thp- was induced with phorbol ester ( h) and activated for h with lipopolysaccharide (lps) after which polya + rna was purified. the rna from control and lps-treated cells were each used to construct a cdna library under identical conditions, and all resulting clones were selected for cdna sequence analysis. each clone sequence was evaluated by matching with both genbank and our own gene databases. very different patterns of gene expression were seen in the two libraries, the latter reflecting very high levels of known inflammatory mediators such as il- and tnf. a second set of libraries were made from umbilical vein endothelial cells (huvec), both with and without lps stimulation, and were analyzed in a similar fashion. the effects of lps induction on specific gene transcription in both cell types will be discussed. t. tadros, md, th wobbes, me) phd, rja goris, md phd to investigate whether the preactivation of regional macrophuges by liposomes containing muramyl tripeptide (mtp-pe) can counteract the detrimental effect of blood transfusions on both anastomotic repair and host susceptibility to infections. methods eighty lewis rats received lmg/kg of either empty or mtp-pe encapsulated liposomes, intraperitoneally (ip). twenty-four hours thereafter, the animals underwent resection and anastomosis of both ileum and colon, and received ml of either saline or blood from brown norway donors,iv. the animals were killed or days after surgery and examined for septic complications and anastomotic repair. the average anastomotic strength, as assessed by bursting pressure (+sd), was significantly diminished in the transfused animals, as compared to the non-transfused animals (ileum;day ; -+ vs + , p< . ). transfused animals pretreated with mtp-pe encapsulated liposomes showed a significant improvement of their anastomotic bursting pressure ( + , p< . vs transfusion). pretreatment with mtp-pe encapsulated liposomes decreased significantly the incidence of anastomotic abscesses in transfused animals ( from % in ileum on day to %, p< . ). conclusions preactivation of regional macrophges by intraperitoneal administration of mtp-pe encapsulated liposomes prevents the detrimental effects of transfusions on anastomotic repair and reduces the incidence of intraabdominal sepsis. academic hospital nijmegen, dept of general surgery, pb i, hb nijmegen, the netherlands. leukemia cell line, teip- . robin s. wa, gner*, perry v. halushka "~, and james a. cook*, departments of physiology , pharmacology "l" and medicine "t, medical university of south carolina, charleston, s.c. . adherence of monoeytes to endothelium and extracella/ar matrix proteins is essential for accumulation at sites of inflammation. txa , an arachidonic acid metabolite, inhibits human monocyte chemotactic responses suggesting that txa may alter monocyte adhesiveness. we selected the thp- cell line, a human monocytic leukemia cell line to further investigate the effect of txa on adhesion. we tested the hypothesis that txa alters lpsinduced adhesion of thp- cells and that txa exerts its effect on adhesion via a camp dependent mechanism. thp-i cells were exposed to s. enteritidis endotoxin (lp.g/ml) _+ the cyelooxygenase inhibitor lndomethacin (in), the txa mimetic i-bop ( . .tm,) or txa receptor antagonists bms and l ( ~m). cells were allowed to adhere for hours and adherent protein/well was determined. lps-induced a significant (p< . ;n= ) increase in adherence of thp- cells (basal, . + . gg protein/well; lps, . +_ . p.g protein/well). the amino acid glutamine is an essential compound for synthesis of purine and pyrimidine basis and therefore necessary for rna-and dna synthesis. in human plasma the concentration of glutamine is between . - . mm, and is reduced in septic patients up to % ( . - . mm). monocytes play a central part in the inunune system and it was of interest, whether glutamine is involved in the modulation of cell surface markers and phagocytosis of these cells. human peripheral blood mononuclear ceils were obtained from ml heparinized blood of apparently healthy donors by ficoll-paque density gradient and isolated by counterflow elutriation. the puritiy was more than %. subsequently cells were cultured in phenolred-free rpmi medium with various concentrations of glutamine ( . , . , . , . , . , , mm) in teflon-fluorinated ethylene propylene bottles to exclude cell adhesion and possible cell activation. aider seven days culture, cell viabilty was determined by trepan blue exclusion and varied between and %, independent of glutamine concentrations. cell surface markers were detected by flow cytometry, noaspecifie phagoeytosis was measured with latex beads and specific phagocytosis with opsonizied e.eoli using a facscan. lower concentrations of glutamine decreased the expression of hla-dr and icam- /cd on monocytes in a dose-dependent manner. the receptor for fc'/rucd as well as the receptors for complement cr /cdllb and cr /cdllc were down-regulated. cr /cd which is only slightly expressed on monocytes was not influenced. furthermore, no effects on the expression of cdi , the receptor for transferrin cd and fc'friii/cd were seen. our data indicate, that lower concentrations of glutamme influence the phenotype of monocytes. we are now interested to study whether glutmnine influences non-specific phagocytosis, or whether specific phagocytosis correlates with the decreased expression of fc'/r and complement receptors. we investigated immunologically more than patients who were admitted to icu because septic syndrom during the last four years. patients were immunologically followed up - times per week until release from icu. the expression of hla-dr antigen on monocytes turned out to be the best prognostic parameter. the persistence (> days) of low hla-dr expression (< %) predicts fatal outcome (mortality > %). the altered phenotype was associated with a functional deactivation of monocytes (diminished apc, ros formation, cytokine secretion). we called this phenomenon "immunoparalysis". ifn-gamma and gm-csf were able to restore the altered phenotype and function in vitro. however, addition of autologous plasma from septic patients with "immunoparalysis" to these cultures prevented the cytokine-induced restitution. the inhibitory activity could not be removed by dialysis. therefore, we started a study to prove the therapeutic efficacy of plasmapheresis. indeed, [ of patients recovered from "immunoparalysis" following repeated plasmapheres; of them survived ( %). patients recovered temporarely and patients did not respond (all died). the survival rate in the control group of septic patients with persistent "immunoparalysis" was of ( %; p< , ). in summary, plasmapheresis in association with immune monitoring may be an alternative strategy to improve survival rate in severe sepsis. taurolidine, a synthetic taurine-formaldehyde derivative has antiadherent, bactericidal and anti-lps properties functioning primarily through binding of the lipid a region of the lps molecule. the active derivative of taurolidine, taurine, modulates calcium channel activity, critical to the initiation of a number of immunostimulatory pathways. we hypothesised that taurolidine may have direct immunostimulatory activity. the aim of this study was to investigate the immune effects of taurolidine on peritoneal macrophage (pmo) function and then determine the role of taurine in this response. study : in vivo stimulation:cd- mice (n= ) were randomized to receive taurolidine ( mg/kg bw/i.p.) or saline cor~trol. peritoneai cells were harvested after hours and were assessed for pm function [superoxide anion generation (o -), nitric oxide (no), tumor necrosis factor (tnf), fc/cr -mediated phagocytic function (phago) study : control pm were harvested and cultured in vitro with taurine ( . mg/ml for hrs), after which time they were assayed for -and tnf release. in vivo stimulation with taurolidine taurolidine has specific immunological effects on m . release of the inflammatory mediators -and tnf, and fc/cr -mediated phagocytosis were significantly increased, while release of the endothelial relaxing factor no was significantly reduced. in addition, the amino acid taurine, which is released as a byproduct of taurolidines breakdown has an immunostimulatory effect on pmo and may be the active moeity of the compound tanrolidine. in sepsis, a number of mediators which affect vasomotor tone and cardiovascular function are produced. inasmuch as sepsis causes decrease in systemic vascular resistance (svr), attention is usually focussed on vasodilators such as lactate, tumor necrosis factor, interleukin-i & , and nitric oxide. but injury and inflammation als cause production of several vasoconstrictors whose effect may not be evident in changed svr, but may significantly affect organ blood flow or function in the paracrine environment. endothelin (et) is a amino acid peptide vasoconstrictor produced by ischemic or injured endothelial cells (ec's). et is also a potent constrictor for renal mesangial and coronary vessels, an endocrine regulator, and a negative cardiac inotrope. systemic et levels increase significantly in hypoperfusion and ischemia. while et is principally produced by ec's, we asked if human monocytes might also produce et and thereby regulate vasomotor tone in areas of inflammation. monocytes from healthy donors were separated on ficoll, resuspended in rpmi + % fetal calf serum and stimulated with i ug/ml endotoxin (lps). et was measured by radioimmunoassay. lps-stimulated monocytes produced ! fm of et/ cells (vs. unstimulated controls of < ). this calculates to - % of the amount of et observed in patients with low cardiac output, sepsis or ischemia. we conclude that et is a cytokine produced by both ec's and monocytes with potent effects on numerous cells and organs in the critically ill. wuppertal , germany we and other authors showed that fatal outcome in septic disease is associated with a decreased capacity of peripheral blood monocytes for the in vitro production of proinflammatory cytokines, especially tnf-alpha. we found that this monocytic deactivation is completed by a persistent and marked decrease of hla-dr expression on monocytes (< % hla-dr+ monocytes) and a diminished antigen presenting activity whereas the capacity to form the antiinflammatory il- receptor antagonist remains high. in order to evaluate the in vivo situation and to determine at which level tnfproduction/secretion is altered we assessed the tnf-alpha mrna expression in freshly isolated peripheral blood mononuclear cells (pbmnc) from septic patients. tnf-mrna was onty rarely detected by semiqaantitative polymerase chain reaction in pbmnc's from septic patients with monocyte deactivation. meanwhile, it was found in almost all pbmncs from septic patients without monocytic deactivation. we wondered, whether il-i , which ,is known to depress monocytic proinflammatoly response and mhc class ii expression, could be one of the mediators in fatal sepsis. in fact, we found that il- message in pbmncs of septic patients peaked in the beginning phase of monocytic deactivation. in further investigations we found that tnf-administration can induce monocytic deactivation in a murine model/n vivo and provoke il- message in human pbmncs in vitro. these results support our hypothesis that an excessive delivery of proinflammatory cytokines in a first phase can induce an overwheiming inhibitory feedback, mediated by immuninhibitory mediators like il-l , which leads to often fatal monocytic deactivation in a second phase. interferon-gamma which is known to counteract il- production and the effects of il- on monocytes restores the function and phenotype of monocytes from septic patients with monoq, te deactivation in vitro and could be a possible therapeutic agent in otherwise fatal sepsis. our laboratory previously reported that lps dependent macrophagederived tnf-a production can be enhanced by pretreatment with lps at substimulatory lps priming doses coincident with a suppression of lps dependent nitric oxide (no) production (zhang and morrison, j. exp. med : , ) . in order to extend the characterization of these lps priming effects in mouse macrophages, we examined the capacity of substimulatory lps to modify lps dependent il- production. macrophages were obtained from peritoneal exudate of thioglycollate treated c heb/fej mice and cultured in rpmi medium containing % fetal bovine serum. macrophages were pretreated with various subthreshold stimulatory concentrations of lps (olll:b ) for hours, washed three times, and then stimulated with the effective stimulatory concentration of lps for hours. the amount of il- in the supernatant was measured by il- dependent cell line (b and td ) proliferation assay. il- was produced by macrophages at lower threshold doses of lps than those required for tnf-o~ or no production. subthreshold doses of lps modulated il- production in a biphasic manner characterized by an initial suppression and then potentiation. higher doses resulted in secretion of il- during the initial incubation with lps and subsequent desensitization. il- , like tnf-~ and no, is, therefore, also affected by lps pretreatment. moreover, tnf-a and il- shared the similar potentiational pathway, but differed by the fact that only il- was inhibited. (supported by r ai and po a .) department of microbiology, molecular genetics and immunology and the cancer center, wahl east, university of kansas medical center, kansas city, ks - . korolenko t.,urazgaliev k.,and arkhipov s. the role of macrophage (mph) stimulation in mechanism of protective effect of new immunomodulators yeast polysaccharides -heteropolysaccharide cryelan and homopolysaccharide mannan rhodexman (both produced by petersburg chem.-pharm. inst.) was studied. in vitro according to nst test incubation of murine peritoneal mphs with cryelan or rhodexman, ~g/ml, min was followed by increase of potencial microbicidic activity of mphs. in vivo mph stimulation by immunomodulators studied included increase rate of carbon particles phagocytosis during single i.v. or i.p. mode of administration to mice - days after (peak at nd day for i.v. and th day for i.p. mode of administration of the same dose of mg/ g b.w.).the preliminary injection of cryelan ( mg/ g, or h before) to mice with acute cold stress (- ° c, h) revealed protective effect restorating the value of depressed phagocytosis up to the normal level;the positive effect on ultrastructure of hepatocytes was noted also.there was no changes of plasma corticosterone level between group with acute cold stress and mice with cryelan + acute cold stress (several fold increase comparatively to the control mice).as was suggested, the mechanism of protection can include mph stimulation and secretion of some acute phase proteins responsible for positive effect of immunomodulators. new yeast polysaccharides cryelan and rhodexman can be used for macrophage stimulation,especially in pathological states. immunomodulators were shown to increase production and secretion of lysosomal enzymes (like zymosan). secreted enzymes,especially cysteine proteinasescathepsins b and l -involve in the process of inflammation;however, excessive release of these enzymes may lead to noncontrolled proteolysis followed by tissue degradation (assfalg-machleidt et al., ) .the effect of zymosan,bcg and new immunomodulator carboxymethylglucan (cmg), second fraction on secretion of lysosomal enzymes by murine peritoneal macrophages was studied. zymosan increased the secretion of n-acetyl-~-d-glucosaminidase and ~-galactosidase into the culture medium ( - fold); bcg possessed similar effect.cmg in the same concentrations ( /~g/ml) increased release of these enzymes only saightly ( . times).it's known that zymosan-induced secretion reflects the enzyme release from formed lysosomes (warren, ) .it was suggested that cmg activated macrophages via interaction with scavenger-receptors,followed by weak secretion of lysosomal enzymes and as a result decrease of tissue damage. in vivo zymosan induced stimulation of mononuclear system of phagocytes followed by increase of cysteine proteinases activity in liver at the th day. in the same time in blood n-acetyl-~-d-glucosaminidase and n-acetyl-~-d-galactosidase activity increased - fold. it was concluded that in drug design it's possible to select such immunomodulators,e.g. cmg,which can activate mononuclear system of phagocytes and do not damage tissue. endothelin-i (et-i) is produced by injured/ ischemic endothelium, mobilizes intracellular ca ++ and is a potent vasoconstrictor. it is also a ca ++ agonist for anterior pituitary or renal mesangial cells and monocytes. et-i causes monocytes to produce interleukin-l, , , prostaglandin e , and substances which trigger neutrophil superoxide production. et-i levels increase in shock and et may play a role in activating leukocytes post shock causing reperfusion injury. but blood flow experiments suggest splanchnic circulation changes more profoundly in shock than peripheral circulation. we therefore asked if et- (or vic), the et which predominates in splanchnic vessels, had any effect on monocyte cytokine production. human monocytes from health~ blood donors were separated on ficoll. . x ucells/ ml in rpmi + % fcs were incubated i min., & hrs. with - m et-i, - m vic or i ug/ml of lps. supernatants were assayed by elisa. we have shown that low dose endotoxin pretreatment (lps ) for hrs markedly inhibits the macrophage (mo) release of tumor necrosis factor (tnf) and increases interleukin- (il-i) in response to a subsequent endotoxin stimulus (lps ). in this study we examined the kinetics of lps inhibition of tnf and augmentation ofil- . methods: murine peritoneal exudate mo from balbc mice were exposed in vitro to medium or ng/ml of lps for intervals of to hours. culture medium was then replaced with , or ng/ml of lps for hrs. tnf and il- in mo supernatants were measured by specific bioassays. during sepsis endotoxin (lps) activates macrophages (mo) to release mediators such as tumor necrosis factor (tnf), interleukin- (il- ), interleukin-i (il-i) and prostaglandin e (pge ). we showed that preexposure to lps (lps ) alters the response of murine m~i to subsequent lps stimulation (lps ). we hypothesized that in vitro cytokine release by lps in human monocytes (mo) is also be altered by preexposure to lpsi. methods: human peripheral blood mo were obtained from healthy volunteers (n= ), cultured in vitro hrs, then pretreated hr _+ lps -cultures were then stimulated with lps and mediators in mo supernatant measured: tnf, il-i, and il- by specific bioassays, pge by immunoassay kit. serum cytokine levels (specific elisa kits) were compared to in vitro supernatant levels. data is expressed as % control_+sem, lps = ng/mh the table shows that all mediators were increased, in the absence of lps . pretreatment with lps resulted in complete inhibition of lps -triggered tnf release. in contrast, lps significantly increased mo secretion of il- , il- and pge (data not shown). serum cytokine levels were as follows: tnf _+ , il-i + , and il- . -+ . ng/ml. these serum levels were low, showed an extremely wide variation, and did not correlate with in vitro lps -triggered mediator production. conclusion: human monoeyte mediator production is differentially regulated by preexposure to lps . provocative in vitro testing of monocytes may ultimately be clinically useful to identify prior in vivo lps exposure or mo macrophages release numerous secretory products involved in host defense and inflammation. activated macrophages with cytokines produced have been implicated in tissue damage in sepsis and multiple organ dysfunction. aimed to elucidate the organ-association phenomena,this study is to compare peritoneal macrophage(pm),alveolar macrophage(am), and kupffer cells(kc) during sepsis in terms of cellular protein contents as symbol of activation by flow cytometry analysis. sepsis were produced by cecal ligatien and perforation (clp) in wistar rats weighing - g.pm were obtained by peritoneal lavage,am by bronchial lavage and kc by incubating the collegenase digested liver with pronase-e. leukocytes have been implicated as a mediator of the microvascular dysfunction associated with reperfasion of ischemic tissues. a role for ieukocytes is largely based on observations that rendering animals anutropenic with anti-neutrophil serum or preventing leukocyte adhesion with monoclonal antibodies attenuates the increased fluid and protein leakage from the vaseulature that is normally observed in postischemic tissues. we have recently undertaken studies designed to determine the relationship between leukocyte-endothelial cell adhesion and albumin leakage ia rat mesenterlc venules exposed ~o ischemia-reperfusion (i/r). leukocyte adherence and emigration as well as albumin extravasafion were monitored in single postcapillary venules using iatravital fluorescence microscopy, lschemia was induced by complete occ!usion of the superior mesenteric artery and ~dl parameters were monitored at various intervals following reperfusion. the magnitude of the leukocyte adherence and emigration, and albumin leakage elicited by i/r was positively con-elated with the duration of ischemia. the albumin leakage response was also highly correlated with the number of adherent and emigrated leukocytes. monoclonal antibodies against the adhesion glycoproteins cd , cdllb, icam- and l-selectin, but not p-or e-selecdn, reduced i/r-induced leukocyte adherence and emigration as well as albumin leakage. phauoidln, an f-aetin stabilizer, largely prevented the emigration (but not adherence) of leukocytes and greatly reduced, the raicrovascular protein leakage. plateletleukocyte aggregates were formed in postischemic vemdes; the number of aggregates was reduced by antibodies against p-selecdh, cdilb, cd , and icam- , but not e-selectin or lselectin. a significant fraction of the mast ceils surrounding the posteapillary venules degranulated in response to ischemia/repeffusion, but mast cell stabilizers did not afford protection against the albumin leakage elicited by i/r. these results indicate that reperfusloninduced albumin leakage is tightly coupled to the adherence and emigration of leukocytes in posteapillary venules. this adhesiomdependent injury response is primarily mediated by cdllb/cdi on activated neutrophils and icam- on venular endothellum, and appears to require l-selecda dependent leukocyte rolling. mast cell degranulation does not appear to conwibate to the vascular pathology associated with i/r. m.d. rod=iek, boston, ma, usa the polymorphonuclear neutrophil (pmn) has long been known to pa~tlcipats in the inflammatory rebpons~ as a phagocyte and killer of invading organisms, but little attention has been given to its potential as a participant in the in~une interaction of lymphocytes and macrophages. we and others have shown that the pmn may have i~m~/nomcdulatory effects both in vitro and in vlvo. more recently it has been proven that the pmn can make mrna for and secrete the proinflammatory oytokines illa, il-ib, tnfs, il- and il- as does the other major circulating phagocyte, the monocyte/macrophags. furthermore it has been shown to make the potentially autoregulatory oytokines gcsf and gmcsf. these functional capabilities suggest that the pmn is not an wend cell ~, but one which has a potential role in regulation cf ~he immune response and that this potential ~cle should no longer be ignored when considering the immune abnormalities existing in patients following majo~ injury or surgery. we have investigated the proinflaznmatory oytokine secretion patter~ by pmn in patients following major ~hermal or tra~matic injury and in volunteers fellowinq endotoxemia. ?ollowing major injury there is variable pmn secretion of these cytokines when stimulated in vlero. following endotoxemia in a group of human volunteers pmn showed a hypo=esponsivenesa to lps hrs following endotoxin infusion followed at hre by an overshoot. pretreatment with steroids modulated this overshoot phenomenon, suggesting that receptors for steroids are involved in the regulation of cytokin® secretlon by fmn. these results sugges~ that the pmn, the most numerous cell in the circulation and the first to respond to an ins~l~ may be a so~rce of the prolnflammatory cytokine cascade following injury that has been recognized as significant in the process which often leads to multiple o;gan failure, the immunosuppresslon which occurs following major thermal injury may predispose these individuals to infection and sepsis, which remain a significant cause of morbidity and mortality. included among the many immune aheratlons are the p integrln (cdlla, b,c/cd ) dependent activities of adhesion, chemotaxls, diapodesls, and phagocytosls. our investigations indicate that, following major thermal injuries, the expression of the [~ integrlns, but not cd , is significantly decreased on neutrophlls (pmns). it remains unclear if pmns from thermally injured patients respond normally to lps, the effects of treatment in vitro with lps and f-met-leu-phe (fmlp) on the expression of cdtlb was examlned on pmns from the peripheral blood of healthy volunteers and non-septic burn patients (> ~; total body surface area, >ls~ full thickness), the pmns were incubated with lps (]ng- p.g/ml) or f'mlp ( " to " m) et oc for mln, in ~; human ab serum, the expression of the ]ntegrins was detected using monoclonat antibodies and flow cytometry. lps and f'mlp resulted in a slight increase ( fold) in the expression of cd b on pmns from burned patients compared to an and fold increase, respectively, on pmns from healthy individuals. this inability of lps or fmlp to increase cd b expression was not due to the amount of lps bound to the two cell populations. because the same defect is seen after either lps or fmlp stimulation, it is speculated that the defect must be in the amount of preformed cd ] b or its transport to the plasma membrane. platelet-activating factor (paf) and neutrophils have been implicated in the patbophysiology of ischemia-repeffusion injury, in addition, paf stimulates neutrophi[ (pmn) oxidative metabolism in vitro. the present study examined the potential role of paf in repeffusion injury in an in viva rabbit model. eight anesthetized rabbi~s underwent retroperitoneal exposure of the infrarenal abdominal aorta after percutaneous insertion of a catheter through the jugular vein into the infrahepatic inferior vena cava. doppler flow probes were placed around the abdominal aorta and the right common femoral artery to assess flow through these vessels. an occlusive ligature was placed around the abdominal aorta (superior to the flow probe) at t = and total occlusion of blood flow to the lower extremities was maintained for g mins., after which the ligature was released allowing for reperfusion of the ischemic lower limbs. effluent blood from the ischemic hind-limbs was collected through the ivc catheter at the times indicated below and assayed for paf by a direct radioimmunoassay. in addition, neutrophil h production was determined by a previously described ' '-dichlorofluorescein flowcytametric assay. _+ amean _+ s.e.m, pg/ml blood; brelative fluoresenee (% of baseline); caortic and femoral artery flow (% of baseline); *p < . vs. baseline; "p < . vs. baseline. a significant elevation of paf was observed in ischemic hind-limb effluent blood at min. after release of the aortic ligature during the repeffusion phase, as compared to baseline levels. in addition, pmn h production was increased by . -fold above baseline values by hour after ligature release during the reperfusion phase. both of these elevations were transient and returned toward baseline by hours post-isehemia. tatar occlusion of hind-limb flow was achieved as evidenced by the absence of aortic or femorat flow at rain. post-ischemia, however after release the ligature a significant reactive hyperemia was observed by mln. into the rapeffusion phase. histolog[c examination of reper[used gastrocnemius muscle revealed moderate pmn infiltration into the interstitium. in conclusion, these data indicate that paf is released into the circulation during repeffusion, and is likely involved as a mediator in the observed pmn oxidative burst activity, thereby contributing to reperfusien injury. following thermal injury and infection granulocyte function ts abnormal. to elucidate the mechanism by which thermal injury and infection affect the granulocyte's ability to polymerize and depolymedze actin, we serially measured f-actin levels in granulocytes from burned patients (mean age , +_ . years, mean burn size . % _+ . %) during the first s weeks post injury. six of the patients had infections during the course of the study, (septicemia, wound invasion and pneumonia). actin levels in granulocytes from eleven healthy volunteers (mean age years) were measured repeatedly and served as controls. lysecl white blood cell preparations were brought to c and incubated with n-formyl-met-leu-phe (stim) or with dulbecco's phosphate unbuffered sellne (unstim). the cells were concomitantly stained and fixed with formaldehyde, lysoleclthln and fiuoresceln phafioidin. actin depolymedzation (depol) was measured by incubating stimulated cells at °c before the stain-fixative was added. baseline (base) f-actln levels were assessed by adding stsln-fixatlve to icecold unstimulated cells. fluorescence was estimated in a facscan and expressed as ilnesr mean channel fluorescence_+ sem (mcf). figure displays granulecyle fectln levels in infected and uninfected patients as compared to controls. f-actln levels were consistently lower in control cells than in those from burned or burn-infected patients under all measured conditions. granulocytes from infected burned patients demonstrated a significant decrement in their ability to depofymerlze f.actin compared to both uninfected burned patients and controls, while there were no significant differences between infected and ,~ uninfected patients in the baseline, unstlmuleted and stimulated conditions. those results indicate la that grsnulocytas from burned and bum-infected patients contain higher levels of polymerized actln than ~ , s control cells. in order to study tumor necrosis factor (tnf) receptor sensitivity in septic critically ill patients we investigated blood samples of such people in reaction of leucocyte migration inhibition. migration of their polymorphonuclear leucocytes (pmns) was studied with stimulation with human recombinant tnf in concentration of . u/ml (recommended by manufacturer is the range of - o/ml) and without such. ten healthy blood donors formed control group. the results obtained showed diminished pmn reactivity to tnf in patients (migration inhibition was absent) oscaring with significantly increased migration ability of their pmns ( . % of that in control group). at the same time normal pmns in control group did show migration changes upon tnf stimulation. considering all the above we come to a conclusion that externally added tnf fails to activate pmns in critically ill patients more than they are by their endogenous tnf. moreover, this tnf no longer serves a positive chemotactic factor for such pmns. these findings may suggest that in critically ill septic patients reactivity of pmns to tnf is deeply altered. tnf receptors of pmns are either exhausted as such by excessive stimulation with endogenous tnf or further transmission of their message is impossible due to "fatigue" of the cell's activation mechanisms. we express our gratitude to reanal factory of laboratory chemicals for generously providing us with a tnf com~rcial sample. ~-sanguis medical, ekaterineburg russia; s-urals med.lnst. activated neutrophils infiltrating the local site of inflammation following trauma release high amounts of destructive lysosomal enzymes into the extracellular space. cytokines were discussed to be involved in regulation of this early process. the task of this investigation was to evaluate the possible regulatory role of interleukin- (il- ) and its potential immunosupressive opponent, the transforming growth factor-&, in regulation of neutrophil degranulation. we analysed the concentration of the al-proteinase-inhibitor complex of the lysosomal elastase as marker for the degranulation of neutrophils as well as the levels of il- and tgf- in the plasma probes of patients undergoing multiple trauma and severe surgeries. the time courses of il- and elastase were found to be highly correlated, wheras the concentrations of the cytokine tgf-e~ were found to be not significantly altered in comparison to the control group. this close temporal correlationship was confirmed by investigation of fluids derived from sites of inflammation. interstingly, the inhibitory potential (~zcproteinase inhibitor, antithrombin iii) was dramatically reduced in the early inflammatory phase. to prove this in vivo findings, the effects of il- and tgf-i~ on the degranulation of isolated human neutrophils of healthy donors was investigated in vitro. pathological high concentrations of rhll- up to u/ml (as detected in fluids derived from local inflammatory site) were found to be capable to induce a significant release of lysosomal elastase in a concentration-dependent manner, whereas the degranulation of neutrophils was uneffected by tgf- . in conclusion, these data suggest a contribution of il- in regulation of neutrophil activation at sides of inflammation. the immunosuppressive cytokine tgf-i&~ seems to have no direct regulatory effect beside its described chemotactic function on neutrephils. postirradiation chan~es of adhesive properties arid supercoiled nucleoid dna structure of blood leukocytes were studied in macaca nemestrina andrats. the dynamics of membrane chan~es after nonlethal irradiation of rats demonstrated the temporary increase of the leukocyte adherence at h followed by return of this parameter to normal levels at h. after lethal irradiation of both animal species the increase in adhesive leukooytes fraction was detected as early as at h. this hi~her index persisted until the end of experiments ( days). the early ( - h) temporary loosin~ of supercoiled dna structure was demonstrated in the leukocytes of nonlethally irradiated animals. this phenomenon seems to be connected with the lymphocyte fraction chan~es. this process was not dependent on altered adhesive properties of leukocyte membranes. the membrane chan~es of leukocytes preceded decondensation of supercoiled dna after lethal irradiation of animals, in this case loosin~ of supercoiled dna pro-~ressively increased at h and at the later terms of postirradiation period. the systemic inflammatory response syndrome (sirs) involves many inanunological reactions of the host including acfivatinn of inflammatory mediator cascades and depression of cellular reactivity in t-lymphecytes ( ). there are reports of nentrophil dysfunction in inflammatory disorders of the skin ( ), are there dysfunctions concerning the unspecific host defense in sirs, as well? in this study, we examined the reactivity of neutrophil granolocytes from patients suffering from sirs. twenty-one patients (apache ii-score ± ) with diagnosis of sirs entered the study. granulocytes were prepared as reported previously ( ) . in parallel, granulocytes from healthy individuals were tested. two granulocyte functians were studied in vitro: . migration of the ceils in a boyden chamber through a filter matrix following stimulation with different receptor dependent stimuli (c a, intefleukin- , platelet-activating-factor, leukotrien b , fmlp). . release of glucuronidase following stimulation with the aforementioned activators. the results demonstrate, that the release of -glucuronidase in patients suffering from sirs was comparable to the enzyme release of granulocytes prepared from healthy individuals. each stimulant induced release of p-glucuronidase in a characteristic dose dependent fashion. all granulocyte preparations from the healthy donors showed a positive chemotaxis response in the migration-assay. in contrast, only ten out of twenty-one patients had granulocytes migrating after stimulation. the two groups of patients displaying reactive or non-reactive granulocytes differed clinically: the nonreactive group consisted of patients with multiple organ failure ( / ) and nonsurvivors ( / ), whereas / patients in the reactive group survived. thus, the in vitro chemotaxis of granulocytes is impaired in a subgroup of patients with sirs. this defect of the non-specific host defense may contribute to poor prognosis and outcome of these patients. dermatol. : - , klinik ffir an~isthesiologie und operative intensivmedizin der cau kiel, schwanenweg , kiel, germany. objectives of the study: major emphasis has been given to the analysis of interactions of antibiotics with microorganisms. effects of antibiotics on cells of primary host defense mechanisms, such as the neutrophils, are less well known. therefore, attention has been focused on clindamycin, a member of the lincoseamide family. materials and methods: the effect of clindamycin (i -i ~g/ml) on granulocyte functions (healthy volunteers) such as random migration, chemotaxis (agarose method), ingestion (radiometric assay), superoxide (cytochrom c reduction) and hydrogen peroxide production (phenol red oxidation), lucigenin-and luminol-amplified chemiluminescence (luminometry) and degranulation (turbidometry with micrococcus lysodeicticus) were investigated in vitro. results: motility and degranulation were inhibited, ingestion of saccharomyces cerevisiae, zymosan-induced lucigenin-and luminol-amplified chemiluminescence, superoxide and hydrogen peroxide production were stimulated in a dose dependent fashion. conclusion: clindamycin has granulocyte function modulating properties. recognition of immunomodulating effects of antibiotics may have therapeutic significance, especially in patients with long-term antibiotic therapy or immune deficiencies. the intense muscle activity (ea) of rats resulted in increase of neutrophil influx in muscles during the recovery. we investigated neutrophil proteinases involvement in neutral proteinases balance of skeletal muscles by na. the rats were submited to swim with the load ( % of body mass) till exhaustion. immediately after na the neutrophil antiserum was injected i.p. to rats of experimental group. saline was injected to control animals° injections were repeated in h of the recovery and cytosol proteolytic activity (ph . ; fitc-casein) was determined. isolated soleus muscles were incubated also in vitro and proteolytic activity of incubation media was measured. it was found that there was - -fold proteinases activity increase in cytosols of all investigated muscles (soleus, white and red portions of quadriceps) of control animals by h of the recovery (the comparison was done with the sedentary rats). in h cytosol proteolytic activity decreased and then increased again by h of the fast. antiserum injections resulted in relible decrease of the proteolytic activities at every investigated time. when incubating m. soleus in vitro the activities of proteinases in incubation media turned out reliably less if soleus muscles were isolated from the animals to which antiserum was injected. the conclusion is that neutrophil proteinases can be involved in the balance of rat skeletal muscle neutral proteinases after ~a. a lot and new clinical problems complicating the outcome of polytrauma, burn and septic patients in surgical intensive care units, have arisen as the care improvement prolonged the patient's survival: a progressive degradation of organ and system functions often develops, usually making its first clinical appearance by ards, followed by the other organ failure (mof) and sepsis symptoms. the clinical picture is polymorphic, the end result of a complex systemic pathophysiological reaction trigg~ed off by trauma consequences (tissues disruption, hypo~xygenatiun and necrosis). nowadays there is not a preventi~ or specific therapy to lower the mortality rate ( - %) and-'mdy-a~ early, aggressive surgical approach .-evacuating haematomas, stopping bleeding, toileting all septic, necrotic foci and restoring anatomic continuity-, seems to be of some help this complex clinical entity has not an univocal denomination yet. the proper labelling of an illness should come from the full understanding of its pathopysiology and suggest the proper treatment choice. clinical and experimental studies demonstrated that pathophysiologic mechanisms involved in the past-traumatic illness, share the same anatomo-pathological elemem: the interstitial edema, due to a generalised endothelial micro circulatory injury. this alteration, as constantly seen in polytrauma patients, develops in a few hours after trauma as a consequence of the deregulation of the homoeostatic and immune mechanisms. in fact the overproduced oxygen free radicals and r~ombinam cytokines (il ,tnf), together with the complement degradation fragments, the proteolytic enzymes and many other mediators are all strongly h~l ~ ,_he e,,j,yheha! ceils. our~osect, atim~,-bnsed on examination of autopsical specimens from polytraanm patients, showed that such endothelial damage, supporting the interstitial edema, is widely and simultaneensly distributed, ensues shortly arer trauma and shows its effects in different organs at different times, only because each apparatus has different fimctienal reserves: the lung is the first organ to fail just because its ah, celocapillary membrane is one of the most delicate bodily structure, and its function is irroplace~le. we think it will be of a great help, in planning a preventive therapy, to chose a denomination focusing the physician's attention on the earl)" generalized endothelial injury and its effects, as in trauma patients it is present -even if latenflysince the first few hours. we would like to see the generalised endothelial microcircolatory injury properly highlighted when considering the best definition and the optimal nomenclature for the post-traumatic s mdrome. the presence of interleukin (il)- in bronchoalveolar lavage fluid of critically ill patients correlates clinically with the development of the adult respiratory distress syndrome lards), and inhibition of il- in animal models can attenuate lung injury. collectively, evidence to date suggests that il- attracts and activates neutrophiis (pmn), which are then responsible for the capillary leak of ards. however, an alternative explanation is that il- is directly toxic to the endothelial cell (ec). in this study, we have hypothesized that il- can disrupt endothelial integrity independent of pmn. meth ods: human umbilical vein (huv) ec monolayers were cultured to confluency on collagen-coated micropore filters. to assess ec integrity, .albumi n leak was quantitated by measuring the counts which crossed the monolayer, using a gamma counter. il- (lpg/ml) was incubated in the culture medium with .albumi n for hrs. the il- dose was not cytotoxic. to determine the involvement of protein synthesis in this process, selected monolayers were pretreated with cycloheximide (ch) prior to .- addition. statistical analysis was performed using anovmfisher plsd. we have previously shown that platelet activating factor (paf) enhances cdt expression and primes pmn's for subsequent generation. both are important steps in pmn mediated injury and are assumed to occur in concert. following major trauma non-specific pmn inflammation is activated, however, unbridled systemic pmn activity needs to be minimized. since circulating catecholamines are high early post-injury, we hypothesised that they downregu/ate cd expression and pmn priming via the [ adrenergic signal transduction pathway. methods: normal human pmns were primed with paf ( ng/ml for min) or pre-treated with - m of isoproterenol (i) or forskoklin (f) for rain and then primed with paf. cd expression was measured by flow cytometry (fig.l) and -generation in response to -rm fmlp was determined as sod inhibitable reduction of cytochrome c ( fig. holler** and georg w. bornkamm* lymphocyte-endothelial interactions are crucial for various immune responses, including cytokine driven inflammatory processes. protein kinase c (pkc)-inhibitors on the other hand are discussed as potential cytokine antagonists. in the present study we investigated the influence of the pkc-inhibitor gf x on cytokine-and endotoxin induced expression of intercellular adhesion molecule (icam- ) and on adhesion of lymphocytes to cytokine activated endothelial cells. we found that tumor necrosis factor alpha (tnfo -and lipopolysaccharide (lps)-induced icam- expression on human endothelioma celts (eahy ) were unaffected by the pkc-inhibitor and thus appeared to be independent of pkc activation. in contrast, gf x significantly reduced icam- expression induced by interferon-y (ifn-?) and interleukin- (il- ). the functional relevance of these findings was evaluated in an adhesion assay using human umbilical vene endothelial cells (huvec) and peripheral blood mononuclear cells (pbmc). in fact, the ifn-? and il- induced adhesion of pbmc to cytokine treated huvec could be downregulated by the pkc-inhibitor, whereas tnfc~-and lps-mediated adhesion was not influenced. additionally, the il- driven icam- expression on eahy cells as well as the il- induced adhesion of pbmc to huvec was found to be tnf-dependent, since both effects could be inhibited by an anti-tnf monoclonal antibody ( f) . these in vitro data further support the idea of examining pkc-inhibitors, such as gf x, for their biological relevance in cytokine related dysregulations. seiffge, d., bissinger, t., laux, v., during inflammation there are some key processes, which occur in the microcirculation: the release of mediators from various cell types, the migration of inflammatory cells towards a chemotactic stimulus in the tissue, the expression of adhesion molecules on different cells, and the extravasation of plasma proteins. the aim of the present study was to elucidate the mediator induced interaction of leukocyte adhesion and plasma leakage in postcapillary venules. using an analogous video-image analysing system we have studied the effect of different mediators on leukocyte adhesion and macromolecular permeability in the mesentery of the rat. the increase in permeability was measured as changes in optical density. we found that topical administration of leneotriene b (ltb , x " tool/l) or intravenous injection of interleuldn- (il- , - iu/kg b.w.) and lipopolysaccharide (lps, mg/kg b.w.) resulted in a significant extravasation of fitc-labelled rat serum albumin (fitc-rsa) in venules but not in arterioles. we could correlate the changes in vascular permeability with a locally increased number of rolling and sticking leukocytes in venules. both effects were dose dependently inhibited by different drugs. pentoxlfylline inhibits lps-indueed fitc-rsa extravasation and leukocyte adhesion at a dose of mg/kg b.w., superoxid-dismutase (sod, . iu/kg b.w.) was able to decrease the ltb effect, and the immuumodulating drug leflunomide (hwa ) exerted inhibitory effects on il- -induced permeability at a dose of mg/kg b.w.i.v. the obtained results demonstrate that lps, ltb or il- induced extravasation of fitc-rsa is mediated by activated leukocytes and can be deminished following administration of different drugs. platelet-endothelial cell adhesion molecule-i (pecam-i), a member of the immunoglobulin superfamily, is constitutively expressed at high levels on the endothelial cell surface. in vitro data have suggested that pecam-i functions as a vascular adhesion molecule, specifically in neutrophil transmigration across the endothelium. this current work is the first demonstrating the in vivo role of pecam- in neutrophil migration. blocking antibodies to human pecam- , in which the antibodies are crossreactive with rat pecam- , were able to block the movement of neutrophils into the rat lungs after igg immune complex deposition. furthermore, when human foreskin was transplanted into mice with severe combined immunodeficiency and the site injected with tnf-alpha, anti-pecam-i blocked neutrophil emigration into the dermal interstitium. it has already been established that neutrophil recruitment is dependent upon selectin mediated rolling, followed by firm adherence that is icam- / integrin mediated. these data suggest, for the first time, that a third endothelial adhesion molecule (pecam-i) is involved in the coordinated recruitment of neutrophils in vivo. to test whether trauma causes generalized activation or priming of pmns, cdi adherence receptors were measured with iinmunomonitoring in whole blood after lps stimulation ex vivo. anesthetized (fentanyl) mongrel pigs ( - kg) were subjected to % arterial hemorrhage + soft tissue injury and after liar, resuscitated with all the shed blood + supplemental fluid. blood was collected at hr intervals from unanesthetized animals with indwelling catheters, pmns were counted, and lps was added ( , , , i.tg/ml) ex vivo. after hr incubation at - °c, %cd (+) pmns were determined with fitc-ib and flow cytometry from mean channel fluorescence histograms. ± # p< . vs baseline * p< . vs sham $p< . vs no anesthesia these observations provide direct evidence for time-dependent changes in pmn priming following major injury because cd expression was depressed for at ]east hr after trauma relative to sham but by hr, was enhanced, relative to sham, and because fentanyl anesthesia at hr had a greater effect on cd expression in trauma vs sham. neutrophil (pmn) adhesion to vascular endothelial cells (•c) is a key element in the inflammatory response and tissue injury. inflammatory mediators such as lps (exogenous) and tnf (endogenous) can promote pmn-ec interaction which is believed to be responsible for capillary leakage and subsequent organ injury. however, the mechanism of this injury remains unclear.we hypothesised that the mechanism of tissue injury is due to ec necrosis with release of toxic products and that activated pmn are responsible. human pmn were obtained from healthy donors, separated by density gradient, and activated with lps ( ng/ml), tnf( ng/ml), and lps/tnf( ng/ ng/ml). cultures of the human ec tine(ecv- ) were used as surrogates of the microvasculature, were exposed to either lps, tnf, lps/tnf and pmn activated with lps, tnf, lps/tnf and incubated for , , , and hrs. ec necrosis was assessed by a cr release cytotoxicity assay. pmn activation was assessed by cd lb receptor expression and respiratory burst activity hr _+ . -+ -+ . _+ _+ . _+ _+ . _+ . hr + . _ _+ . _+ _+ _+ " +_ +-- . " lghr - . _+ +_ - " o:fo , " ~ +- . * hr _+ . - -+ +_ * _+ _+ * _+ _+ " data = ec % necrosis mean_+sd stats: student's t-test with significance (*) set at p< . vs control. ( our previous studies have indicated that despite the increased cardiac output and maintenance of tissue perfusion, hepatoceliular dysfunction occurs during early sepsis. nonetheless, it remains unknown whether vascular endothelial cell function (i.e., the release of endothelium-derived relaxing factor/nitric oxide) is depressed under such conditions and, if so, whether endothelial cell dysfunction also occurs at the microcirculatory level. to determine this, rats were subjected to sepsis by cecal ligation and puncture (clp), following which these and corresponding shams received ml/ g bw normal saline. at hr after clp (hyperdynamic sepsis) or sham operation, the thoracic aorta was isolated, cut into rings, and placed in organ chambers. norepinephrine (ne, xi - m) was used to achieve near-maximal contraction. responses for an endothelium-dependeut vasodilator, acetylcholine (ach, via nitric oxide), were determined. in additional studies, the small gut was isolated at hr post-clp. after pre-contraction of blood vessels in the isolated gut with xl m ne, vascular responses to ach ( x m) and an endotheliumindependent vasodiiator, nitroglycerine (ntg, xl - m), were determined. total vascular resistance (tvr, mmhg/mi/min/ g) was then calculated as pressure/ perfusinn rate. ach-induced relaxation (%, n= /group) in the aortic rings were: ach lxl i~s, st-in ~ ~ significantly at hr post-clp (i.e., increased *p(o vs. sham; n- per group. tvr) in the absence of any changes in ntginduced relaxation (fig. a) . thus, the vascular endothelial cell dysfunction observed in the aorta in early sepsis also occurs at the microcirculatory level. introduction: the cytokine-mediated adherence of leulcooytes to vascular endothelium is considered as an early step in the cascade of pathologic reactions culminating in the "systemic inflammatory response syndrome" (sirs); the purpose of this study was to evaluate the influence of interleakin- on leukooyteendothelial cell-interactions and microoirculation in the liver after hemorrhagic shock by means of intravital microscopy. methods: in anesthetized female sprdrats co.w. - g) shook was induced by fractionated withdrawl of arterial blood within rain and maintained for h (map at mm hg, cardiac output % of baseline). rats were adequately resuscitated with % of shed blood and twice the volume in ringer's solution additionally. following h of reperfusinn (map > mm hg, co > % of baseline) the microcirculation in liver lobules was examined by intravital fluorescence microscopy after labelling of leukocytes. continuous administration of il-lra (synergen, boulder, colorado, mg/kg/h) was started at different time points in a randomized and blinded manner. the animals in group p (n= ) received the il-lra as pretreatment beginning min prior to shock induction. in the group t (n= ) the application of il-lm started at the beginning of the reperfusion period with a bolus injection of mg/kg and was followed by continuons administration of mg/kg/h. the control group c (n= ) received equal volumes in nac , %, the sham-operated group s (n= ) was not exposed to shock. results: macrohemodynamics were comparable in all shook groups. the increased percentage of permanendy adherent leukocytes after hemorrhagic shook (s: , % + , %; c: , % _+ , %) was significantly reduced by pretreatment or treatment with il-lra (p: , % -+ , %; p< . , t: , % -+ , %, p< . , anova). temporary adhesion of leukocytes was unaffected by application of il-lra. liver microcirculation measured by volumetric blood flow in liver sinusoids and sinusoidal diameters was impaired after hemorrhagic shock in all groups and was not affected (c: iam /s + um /s, p: llm /s + }am /s, t: ams/s -+ lam /s, s: am /s -+ am /s). di.seu~sinn: the results demonstrate that permanent adherence of leukocytes to endothelium is in part regulated by il- . pathological adherence could be reduced by application of illra, even given at die time of resuscitation. the effect of ll-lm on permanent adhesion is a specific event and might be caused by reduced expression of specific receptors on sinusoidal endothelial cens and leukocytes. objectives of the study. the adhesion of activated neutrophils (pmn) to endothelial ceils (ec) and the concomitant production of reactive oxygen metabolites (rom) initiates organ damage after trauma, sepsis, shock and organ reperfusion. aien of this study was to investigate the effect on adhesion and rom production of the highly water-soluble, membrane-permeable and physiological ascorbic acid (asc). materials and methods. adhesion of pmn to nylon fiber (cell count) and simultaneous rom production (chemiluminescence-cl-response) were measured up to retool/ asc as well as adhesion, rom production and ec damage (lllln-release from labeled ec) of endotoxin-activated pmn to cultered ec moanlayers. in an in vivo animal model (sheep with lung lymph fistulas) the effect of asc ( g/kg bw bolus, followed by . g/ kg-h infusion) on the endotoxin-induced ( . ixg/kg bw) neutropenia (cell count), lung capillary permeability damage (lung lymph protein clearance) and rom production of neutrophils (zymosan-induced cl response) was measured. results. asc scavenged rom dose-dependently during adhesion of pmn to nylon fiber (p< . at mmol/l asc), adhesion itself was unchanged. during the activated pmn/ec interaction asc scavenged rom (p< . at mmol/l asc) and reduced the adhesion dose-dependently (p< . at mmol/l asc); ec damage was also reduced (p< . at retool/ asc). in the in rive model asc increased the endotoxin-induced blood pmn decrease (p< . ), decreased the protein clearance (p< . ) as well as the zymosan-induced rom production (p< . ), indicating the asc-mediated reduction of adhesion, rom production and lung tissue damage processes. conclusions. by in vitro and in rive experiments ascorbic acid reduced the adhesion-and rom production-initiated tissue damage. therefore, i.v. administration of ascorbic acid is recommended for oxidative stress-associated states after trauma, sepsis, shock and organ reperfusion. for neut rophi l-accumulat ion and activation. we investigated the influence of or to the activation and the expression of lecam-i and cdiib,cdi on neutrophils and lymphocytes. methods: from blood samples (n= ) all white blood cells (wbc) and neutrophils (nc) were isolated and cultured. or were produced via the xanthine oxidase/hypoxanthine system. after , , , , and minutes a giemsa-staining to determine the granulation of neutrophils (n: normal, r : reduced ) and a facs-analysis with monoclonal antibodies detecting cdiib,cdi and lecam-i was performed. results: under the influence of or a degranulation of neutrophils starting at min was observed in wbc-cultures (n/r: min / , min / , min / , min / , min / ). these data were confirmed in the dot-plots of facs-analysis. only in wbc-cultures or induced a significant increase of lecam-i expression on neutrophils up to min followed by a decrease to normal values at min. lecam-i on lymphocytes disappeared totally during the observed period. cdllb,cdl -expression was not altered. conclusion:increased lecam-i expression on neutrophils due to or could enhance the 'rolling' of neutrophils along the endothelium which is a prerequisite for neutrophil sticking and migration. further or are able to activate neutrophils without endothelium. these changes seem to be mediated by other wbc. introduction. multiple organ failure (mof) has been hypothesized to be the result of an excessive uncontrolled autedestructive inflammatory response. since the complement system is an important mediator and initiator of the inflammatory response, interruption of this cascade could theoretically lead to an attenuation of mof. in order to test this hypothesis we evaluated the response of c -delicient mice in a model of zymesan indt~ed mof. materials and methods. c -deficient b d /oid and c -sufficient b d /new mice were used in this study. on day all mice received an intraperitoneal injection with zymosan suspended in paraffin in a dose of mg/g body weight. between day and , biological parameters (temperature, body weight and clinical condition) were measured daily and mortality was monitored. clinical condition was assessed by blindly grading the degree of lethargy, conjunctivitis, diarrhea, and ruffled fur of each mouse on a two point scale (maximum score= ). on day all surviving mice were sacrificed and relative organ weights of lungs, liver, spleen and kidneys (relative organ weight= (organ weight/body weight)x ) wore calculated. earlier experiments with our model have shown a good correlation between histological organ damage and relative organ weights. statistical analysis of biological parameter was performed using the koziol curve analysis. analysis was divided in an acute phase (day - ) and a late phase (day - ). relative organ weights were analyzed using wilcoxon's test and mortality rate using fischor's exact test. results. all zymosan injected mice showed a typical triphesic illness. deterioration of the clinical condition as indicated by the symptom score and the decrease in temperature and body weight in the acute phase were all significantly lass severe in c deficient mice (all p< . ). in the late phase no differences could be noticed in the courses of biological parameters. overall mortality was / ( %) in c deficient mice and / ( %) jn c sufficient mice (p= . ), a difference mainly due to a difference in the acute phase. organ damage assessed as the relative organ weights did not show any statistical differences for any organ between both strains. conclusion. complement factor c appears to play an important role in the acute hyperdynamic septic response in this model but deficiency of c could not prevent organ damage in the late mof phase. this suggests that other factors could be more important in the development of the inflammatory response leading to mof. proinflammatory cytokines are thought to play a critical role in the pathophysiology of multiple organ failure (mof). in mice, zymosan-lnduced generalized inflammation (ztgi) leads to mof. therefore we performed a sequential study into plasma levels of, and macrophage production capacity for, four cytokines during the development of mof in the zigi model. male young-adult c bl/ mice received zymosan ( mg/g body weight) intraperitoneally. groups of animals were killed after , , , and h and subsequently at each day until day . plasma was collected and peritoneal macrophages were isolated and cultured overnight with or without lipopolysaccharide (lps). interleukin -ct, and - (il-lc~,~,), and tumour necrosis factor-o~ (tnf-c were measured in plasma and culture fluid by means of a ria (detection limit . ng/ml). interleukin- (il~) levels were assayed using the b hybddoma cell proliferation assay. zymosan induces a three-phase disease in mice. after an acute phase the animals recover. around day , they start to develop clinical signs which resemble mof. plasma tnf-~ peaked within h after zymosan injection and disappeared within h. from day onwards, tnf levels started to rise again. plasma il- behaved almost similarly in the acute phase, but in the mof phase plasma il- remained low. no circulating il- could be detected at any time point. macrophage lps-stimulated production of il-lcq il- ~ and tnf--c~ was suppressed immediately after zymosan injection. production of il- and tnf-~ was normalized within h, while production of il-lc~ remained lower than that in macrophages from untreated control mice. only at day did production of il-i~ reach control values. il- production was higher than control values from day onwards. il production was similar to that of ili-il the production of tnf-ct was strongly elevated between days and and again during days to . the development of mof-like symptoms during zlgi in mice is accompanied by increased plasma levels of tnf-ct without enhanced il- or il- . also, the ability of macrophages to produce excessive amounts of il- and tnf--~, as well as the suppressed capacity to produce il-lcq could be important mechanisms in the pathophysiology of mof. when conjugated to an asialoglycoprotein, dna and oligonucleotides are specifically taken up by the hepatocytes via the asialoglyccprotein receptor which is unique to the liver. human asialoglycoprotein (~ -acid, asgp) was derivatized with low molecular weight poly(l)lysine(pll) and complexed with antisense dna's (as) complementary to the ' region of the il- gpl receptor. the antisense were '-agtttagggatgagg- ' (asl), '-atcttcatcttctgaat- ' (as ), '-aagtgaatgattaaaacact- ' (as ), '-aaacctttataggcg- ' (as ), and '-cgttctacaactgcaacgt- ' (as ). using hepg , the biological effects of these antisense complexes on the high affinity il- receptor were evaluated by scatchard analysis, cellular proliferation, and acute phase protein expression by radioimmunoprecipitation and two dimensional gel electrophoresis. scatchard analysis demonstrated that high affinity receptor expression was inhibited by incubation of cells with asgp-pll-asi for h. underivatized asl was less effective and the complex, asgp-pll-as , had minimal effects on high affinity binding. when the cells were treated with the conjugates and stimulated with il- (i units) asgp-pll-asi alone showed a dose dependent ( .i- . ~m) inhibition of ss fibrinogen synthesis. two dimensional gel electrophoresis showed that expression of other acute phase proteins was also blocked. these results indicate that the targeted delivery of antisense molecules via conjugates recognized by the asialoglycoprotein receptor can block the cytokine stimulated acute phase protein response in hepatocytes, this approach may be relevant to the therapeutic management of patients with severe injury and sepsis. it has been established that immune cells are able to express neuropeptide genes and to release products that were considered to be of neuroendocrine origin. we have shown that proenkephalin (penk), a neuropeptide encoding gene, is expressed in lymphoid cells in culture. to study the physiological significance of these observations we have used the model of experimental endotoxemia. in this model, a disease state is induced by bacterial lipopolysaccharide (lps), that activates the immune system, the adrenocortical axis and the nervous system. we found that the expression of penkmrna is markedly enhanced in vivo immediately after lps injection both in the adrenal glands and in the lymph nodes. in situ hybridization analysis combined with immunohisto-chemistry indicated that the induced penk expression is confined to macrephages within the lymph nodes and chromaffin cells in the adrenal medulla. furthermore, this expression in lymph nodes is modulated by ligands of the adrenergic system. our results strongly support the notion that immune derived opioids participate in the bidirectional communication between the nervous and immune systems. of neurology hadassah university hospital, jerusalem , israel. objectives of the study: multiple-organ-failure is recognized as the most severe, and often lethal, complication after multiple trauma. however there is no adeqate animal model available. our goal was to develop an animal model, in which reproducable irreversible failure of parenchymal organs is achieved in the late phase after insults in the early phase (trauma). materials and methods: l female merino-sheep were included (mean weight: kg). day : hemorrhagic shock (mean arterial pressure (map) mmhg for hrs.), closed femoral nailing (ao-technique), day - : bolusinjection of endotoxin (et) ( , ~tg/kgbw) und zymosan-activated plasma (zap) ( ml) every hrs., day - : observation. bronchoalveolar lavage (bal): day , , . the course of representative parameters of organ function was documented: cocardiac output (i/min), svr -systemic vascular resistence (dyn ~ s cm- ), pap -putm.art.pressure (mmhg), pap -arterial oxygen pressure (mmhg), bill -bilirubin (;xmov ), crci -creatinin clearence (ml/min) statistics: data as means+sem, *significant from baseline (wileoxon test; p< ) results: baseline day day day day heart: co , _+ , , _+ , , _+ , , _+ , * , _+ , * svr _+ + _+ +_ " +- " lung: pap , _- , , _+ , " , +- , " , + , " , +- , ' pap , + , , +- , , _+ , , +- , , +_ , * liver: bill , _+ , , _+ , ' , _+ , ' , _+ , " , _+ , " kidney:crcl , +_ , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , _+ , , + , , + , histologic specimens showed all signs of fulminant mof. combination of hemorrhagic shock, femoral nailing, et und zap (insults in the early phase) lead to an irreversible organ failure in the late phase. prostaglandin e (pge) levels are elevated by trauma, shock or sepsis and can profoundly affect the immune response. pge is produced by many cell types including fibroblasts, macrophages, monoeytes, follicular dendritic cells, and epithelial cells and is induced by il-i, bacterial lps, components of the complement cascade, tnf, il- and crosslinking of surface fc receptors for igg, iga and ige. our research has shown that pge inhibits b cell activation (specifically enlargement, class ii ~c and fc~ rii expression), proliferation, igm and igg responses, t cell proliferation, and il- synthesis in the mouse model. in contrast, pge greatly promotes class switching to ige,the isotype responsible for type i allergic hypersensitivity. thus, our model mirrors th~ general immunosuppression and elevated ige titers of the trauma or sepsis patient. pge increases the number of cells secreting ige and iggl, acts on surface igm positive b cells, synergizes with il- and lp$ to induce preswitch germline transcripts, and induces more rapid expression of mature vdj~ mp~a than in eontro~ pge intracellular signalling occurs through cyclic adenosine monophosphate (camp) levels and can be mimicked by camp-inducing agents and blocl~ed by an inhibitor of campdependent protein kinase a. pge action requires de novo protein synthesis and candidate pge-inducible regulatory proteins have been identified by d gel eleetrophoresis. thus, pge inhibits a number of immune mechanisms while promoting ige production. a deeper understanding of pge immune regulation may lead to more effective treatment of immune perturbations as sequelae of trauma, shock or sepsis. during infrarenai aortic surgery mesetueric traction (re.t.) results in prostacyclin (pgi:) release and consecutively in hemodynamic disturbances (decreased systemic vascular resisteace, mean arterial pressure; increased cardiac output, heartrate). these symptomes are bypassed by cyclooxygenase inhibition. hemodynamic symptoms vanish after - rain even without cyclooxygenase inhibition although pgi levels remain elevated. to study the endocrine vasopressor system in a prospective double blinded protocol, we investigated patients undergoing major abdominal surgery as compared to ibuprofen ( rag, i.v.) pretreated (ibu) patients. the surgeon applied m.t. in a uniform fashion. we chose a general anesthesia combined with a supplemental thoracic epidural anesthesia. at the points in time , , , , , , , rain after and before (to) mesentzrie traction we determined the plasma concentrations (pc) of -keto-pgf~o~pr~, epinephrine, norepinephrine, dopamine, renin, aldosterone, adh and cortisol. pc of -k-pgf~,tp~, peaked minutes after m.t. ( _+ , ibu: _+ , to: +i ng/l) and declined monotonously over h ( +_ , ibu: _+ ng/ ). catecholamine pc "s did not exceed the reference range during the observation period. reninpc peaked after rain ( _+ , ibu: + , to: -+ /~u/ml); aldosteronc also presented a maximum after rain ( + , ibu: -+ , to: +- pg/ml), whereas cortisol demonstrated irrespectively of circadian rhythms a maximum h after m.t. ( +_ , ibu: -+ , to: +_ ~g/ ). adh pc peaked min after m.t. ( + , ibu: -+ , to: +_ pg/ml) and showed analogously to -k-pgft~j~ pc a monotone decline over the observation period. our data demonstrate a counteractive reaction to pgiz mediated vasodilation via adh secretion. the second regulative is the renin-angiotensin-aldosterone system (raas), which is activated min after m.t., the aldosterone pc does not paratlel the cortisol pc, which peaked post operafionem in both groups, probably due to the end of anaesthesia. a regulative release of catecholamines could not be documented. the activation of adh and raas after mt is not a hormonal response primaryly related to surgical trauma and/or stress but a counterregulation to systemic vasoditafion induced by prostacyclin. although adh and raas support systemic circulation, angiotensin and vasopressin may compromise local organ blood flow (e.g. splancimic vascular bed). insfitut f. klin. chemic, anaesthesiologie ~, chirurgie l*, univ. ulm, elm, expression of c-fos protein in rat brain following occlusion of superior mesenterie artery. takanobu there is general agreement that neurologic abnormalities are seen in sepsis. the aim of this study is to examine what effect does the brain receive in case of sma occlusion by immunohistochemistry using antibody to c-fos, an immediate early gene, which is recently recognized as a genetic marker of activated neurons. moreover, we investigated the correlation between c-fos induction in the brain and plasma endotoxiu level. rats of them received sma clipping and others wee used as control. control and treated rats at , , , hours were perfused and fixed. the brain were sectioned at pm and stained by abc method using c-fos antibody. plasma endotoxin level of rats were measured at , , , , hours after the treatment by chromogenic limulus method. immunohistochemical study showed scarcely no immunoreactivity in control rat brain. in treated rat brain, the significant expression of c-los was detected in specific nuclei including the habenula, some hypothalamie nuclei, amygdala, locus ceruleus and nucleus tractus solitarii. such immunoreactivities were increased in time curse, which well corresponded plasma endotoxin levels. the mean plasma endotoxin level of , , , , hours after the treatment were . ± . , . _- - . , . _+ . , . ± . and . ± . pg/ml, respectively. the results indicate that limbic and hypothalamic-brainstem systems are involved in sma occlusion, and suggest that such neuronal actival.jon may precede the elevation of plasma endotoxin icy.el. systemic vascular resistance and increased cardiac output accompanied presumingly by a increased pulmonary shunt (qs/qt). this response is induced by prostacyclin (pgi ). we examined oxygen transport after traction on the mesentery root and the transpulmonary prostacyclin levels in a prospective placebo controlled study with intravenous ibuprofen. methods: with approval of the human [nvestigadon review board we studied patients in a prospective, randomized double-blinded protocol who were scheduled for major abdominal surgery. ibuprofen ( mg i.v.) or a placebo equivalent was administered minutes before skin incision. pulmonary artery thermodilution and radial artery catheters were placed after induction of anesthesia. mt was applied in a uniform fashion. baseline values preceded the incision of the peritoneum (to). fulther assessments followed , , , , . tile plasma concentrations (pc) of -keto-pgft, (stable metabolite of pgi ) were determined in arterial and mixed venous blood by radioimmunoassay. at all points in time we measured arterial and mixed venous blood gases. qs/qt was calculated by standard formula. data are given as median (p < . placebo vs. [ibuprofen] [ ] mmhg (*p< . i). these changes were accompanied by a marked increase of -keto-pgf~ pc up to rain after mt in arterial and mixed venous blood of untreated patients with a peak of *[ ] ng/l tl (*p< . ol). there was no difference between arterial and mixed venous pc. ibuprofen pretreated patients (n=zr) demonstrated stabile qs/qt and pao while -keto-pgf~ pc remained within the normal range. discussion: our data clearly indicate that mesenteric traction response includes a critical rise in qs/qt followed by significant decrease of paov stable oxygen transport determinants following cyclooxygenase inhibition signify an action mediated by prostacyclin. an indicative transpulmonary gradient for -keto-pgft~ was not detectable. a splanchnic vascular source for pgi release seems to be likely, but could not be proved by our current data. department of anesthesiology, cliu. chemistry * and surgery*; university clinics uim, prittwitzstral]e , ulm, germany it is unclear whether injuries like bums, in general, directly result in alterations of cell-mediated immunity that, in turn, promote endotoxic and bacterial translocation or, alternatively, whether these conditions allow increased bacterial invasion that, in turn, inhibits cmi. aim: to determine whether infectious challenge, as clp alone or combined with ti causes further immune abnormalities in the days following clp. study plan: on day , two groups of n= week old aj mice were subjected to either a % scold burn (ti), or were untreated (c) n= . on day , mice (ti+clp) and mice (clp) were subjected to clp. the two other groups (ti and c) were untreated. at days , and after thermal injury splenocytes (sp) were harvested and cultured with cona for an assay of il- and adherent splenocytes (as) were cultured with lps for il- , tnf, il- and pge . results: either ti + clp or clp alone result in significantly decreased secretion of all cytokines tested. in the ti group almost every cytokine production determined was elevated in comparison to ti + clp and prosmcyclin (pgi ) has been implicated in the pathophysiology of septic shock. however, pgi~'s role in the inflammatory response to sepsis is not well-defined. the purpose of this study was to identify which acute septic events are mediated by pgi during graded bacteremia. methods: eleven ~nesrhetized, hemodynamically monitored adult swine were infused iv with aeromonas h. ( /ml) at rates increased incrementally from . to . mi/kg/hr over hours. animals were studied in two groups: septic control (sc), graded bacteremia only (n= ); pga (n= ), graded bacteremta plus anti-pgiz antibody, ml/hr iv, beginning at hours. mean systemic (map) and pulmonary arterial (pap) pressures and arterial po , mmhg, cardiac index (ci), l/min/m , oxygen delivery index (do i) and consumption index (vozi), ml/min/m , and oxygen extraction (er), %, )latelet aggregometry (plt), %max., plasma pg -keto f alpha ; in the first instance~ peak values of lt ~ after i~ hrs post infarction were times higher than in the controls and excess leucocyte infiltration was noted at the infarction zone. in second instance two levels of lt b led to weak infiltration of the infarction zone by leucocytes. a. mo~e~o, in~.~p~siolo~,d~t.e~.cardiolo~,bogotsolets , ~ev , ukrmne systemic lesion$of erythron in traumatic disease and possibilities of their regulation by opioid peptides. redkin y. v., fominih s. g. using clinical ( patients) and experimental material( rats and dogs) we revealed general regularities of erythron lesions after hard mechanical trauma of various genesis as well as some mechanisms of development of posttraumatic anemia and possibilities of its correction with preparations of opioid peptides. the condition of central and peripheral compartments of erythron was studied with unified morphologic, immunogematological, biochemical and radiological methods. it was revealed that irrespective of the experimental animal species (dogs, rats) or in clinical experiments (patients) and irrespective of the injuring factor type (skeletal trauma, craniocerebral trauma, loss of blood) in erythron can be observed one-directed unspecific reaction realized by the considerable lowering of hemoglobin concentration, erythrocytes number and hematocrit. in the initial period ( - days) in the system of erythron prevail processes of distraction and elimination of er~zthrocytes relatively to the general production of stimulated erythropoiesis. the primary alterating factor is the prolonged intensification of peroxydation of membrane iipids of erythrocytes with simultaneous lowering of reserves of reduced glutathione. the distraction of erythrocytes is supported by the developing phenomena of autoallergization of organism that becomes apparent by the appearance of sensitized t cells and antierythrocyte antibodies. the intensified production of erythropoietin rules to the realization of he program of fetal and terminal (reserved) erythropoiesis. failure of erythropoiesis function is supported by disturbances of the processes of the injuring of cell metabolic apparatus. using of dalargin ( microgram per kilogram of body mass intrap'eritoneally within days after the trauma) showed the precise pharmacotherapeutic effect revealed by the diminishing of anemia of experimental rats, more . fiberbronohoscopic procedures are known to produce "peep-like" effects and to increase pulmonary artery (pa) resistance [ ] . peep can affect rv function by reducing preload and ejection fraction (ef) [ ] . since changes of rv function during bronchoscopy in septic patients are not reported, we measured rv parameters before, during and after fiberoptic bronchoalveolar lavage (bal). method: this -year-old patient (apache-ii: ) developed a hyperdynanlic septic state due to staphylococcus aureus (blood culture). we inserted a "fast response" thermistor pa-catheter (baxter-edwards) to evaluate rv performance [ ] . the therapeutic procedure included volume replacement, vasopressors (dopamine , dobutamine gg/kg/min. iv) and analgosedatior/. before bronchoscopy (olympus bf- , od= mm) the patient received pancmonium for muscle relaxation. ventilation was not changed during the procedure (endotracheal tube: id= ram, bennett a, pressure controlled mode, pm~x= mbar, peep= mbar, i:e=i:i, fio = . ). we measured rv enddiastolic volume (edv), stroke volume (sv), ef, heart rate (hr), cardiac index (ci) and mean pa pressure (mpap gerlach h, gerlach m, clauss m, falke kj renal hypoxia and/or ischemia initiates the development of a deteriorated medullary perfusion based on fibrin deposition in the peritubular capillaries, vasoconstriction, and perivascular edema, which is followed by a swelling of the tubular epithelial ceils, intraluminal tubular obstruction, and a backleak of fluid through the injured tubules into the renal interstitium, finally leading to an acute tubular necrosis (atn) [ ], clinically diagnosed as acute renal failure (arf). one important pathway for induction of enhanced vascular procoagulant activity and permeability is based on the synthesis and expression of macrophage-derived cytokines, which bind to specific endothelial cell surface receptors. we recently described the identification and purification .of a new , dalton polypeptide, which is synthesized and expressed by murine macrophages after stimulation with lipopolysaccharide, and exerts procoagulant activity on cultured endothelial cells [ ] . in the presented study, we demonstrate that the new polypeptid is also synthesized by macrophages under hypoxic conditions. the protein binds to specific receptors, which are expressed by endothelial cells dependent on the environmental oxygen tension. animal studies were performed after approval by the local committee for animal safety; the animals were anesthetized, treated and supervised in accordance with the guidelines of this committee. in contrast to other authors, who performed long-term hypoxia experiments in awake animals, we preferred to implement the studies under anesthesia for ethical reasons, although regulatory functions for ventilation might be influenced. animal studies demonstrated that the intravenous injection of the polypeptide initiates fibrin formation in the peritubular vessels. keeping the animals under hypoxic conditions induces similar effects, which are reduced by a rabbit-antiserum against the new protein. in conclusion, the new polypeptide obviously contributes to the pathogenesis of acute renal failure by tubular necrosis during and after hypoxic events. the use of verapamil as cardioprotective agents for management of patients with acute ischemic/reperfused heart is based on the assumption that the increased intracellular ca+ level is a key factor in causing cell death. our in vitro study was designed to focus on effects of verapamil on the metabolic potential of cardiac slices after reversible ischemia in rats. the material consisted of two main groups : group a (non ischemia/reperfusion group) and group b (ischemia/reperfusion group), each is subdivided into two subgroups (a and b). each subgroup included rat hearts. group aa is the control group, group ab is verapami] added group. group ba is ischemia group without verapamil. group bb is verapamil added group. ischemic cardiac slices were obtained from rats subjected to min. haemorrhage to induce reversible global ischemia. both nonischemic and ischemic cardiac slices were placed in well oxygenated krebs ringer phosphate buffer containing mg% glucose & gm% bovine albumin and incubated in dubnoff shaking water bath for min at °c the results revealed that there was an enhancement in release of free fatty acids (ffa) ( %) and lactate ( %) and in glucose uptake ( %) in group ba as compared with group aa. these metabolic alternations produced by ischemic cardiac slices were reversed by verapamil addition ( ml%) but in group ab verpamil did not alter the release of ffa & lactate from non-ischemic cardiac slices, whereas it inhibited glucose uptake from these slices by %. the improvement of the metabolic intervention of ischemic myocardium indicates that verapamil may be of importance in reducing the extent and severity of acute myocardial ischemic injury in acute haemorrhage. severe endothelial dysfunction occurs following injury to carotid arteries which is characterized by a decreased ability of these arteries to dilate when challenged with ach or a , but not with a direct vasodilator (nano ). this failure to relax to ach and a reflects an inability of endothelium to generate edrf, but relaxation recovers gradually to control values by weeks. exogenous no donors (e.g., c - or spm- ), accelerate the recovery of the injured endothelium in rat carotid arteries. intravenous infusion of an no donor ( p.g/day) with an implanted osmotic pump significantly accelerated the recovery of regenerated endothelium to produce edrf at days. rat carotid artery rings relaxed only + % and + % to gm ach in vehicle treated rats and in inactive no donor treated rats respectively days following injury compared with + % in no donor rats (p< . ). relaxation to gm nan was normal in all groups indicating that the differences in relaxation were not the result of damage to vascular smooth muscle. contraction to l-name ( mm) was markedly reduced by injury, but was protected by no donors (p< . ). thus, exogenous no donors enhance the ability of the endothelium to regenerate and to release edrf in response to endothelium-dependent vasodilators. this may be due to an anti-proliferative and anti-mitogenic effect of no on vascular smooth muscle cells, allowing the endothelium to regenerate without intimal thickening. no also has been shown to inhibit platelet aggregation, and to attenuate neutrophil adherence and activation. the superoxide scavenging effect of no is not the basis for these effects since hsod is inactive in preserving endothelial function in injured arteries. thus, no exerts a variety of cytoprotective effects which may be of importance in protecting against vascular injury. much evidence has now accumulated to show that the excess production of the vasodilator nitric oxide (no) in sepsis is an important contributor to the hypotension and multiorgan failure characteristic of this condition. various cytokines play an important role in this process through their ability to induce the production of one of the enzymes responsible for no synthesis, the inducible no synthase (inos). we have studied the effects of cytokines on the induction of this enzyme both in vitro using vascular smooth muscle cells, and in a murine model of gram-negative sepsis. tn smooth muscle ceils, the cytokines il- , ifnq', and tnf-oc show strong synergy with one another in the production of inos. in order to define the molecular basis for this synergic effect, we have linked the promoter of the inos gene to a "reporter" gene, chloramphenicol acetyl transferase (cat), and transfected these constructs into vascular smooth muscle cells. assays of cat activity reflect the activity of the promoter in this system, and by generating sets of deletion mutants of the promoter sequence we have been able to define the area within the promoter which mediates the synergic effect of these cytokines. in addition to stimufatory effects on inos production, certain cytokines are able to down-regulate the production of inos in vascular smooth muscle cells, and the effects of these counterregulatory cytokines will be discussed. the interaction of these cytokine effects in the whole organism has been studied in a murine model of gramnegative sepsis. widespread induction of inos occurs in this model as assayed by enzyme activity and through use of specific antisera to inos. neutralizing antibodies to tnf-~ and tfn-y are both able to prevent death in this model, but it is only the anti-ifn-y which attenuates the induction of inos assayed in the liver. clearly there is some redundancy in the effects of cytokines on the production of inos in sepsis, and greater understanding of the most important factors in inos production is required in order to target anti-cytokine therapy most appropriately. effects of nitric oxide on hepatocyte metabolism in inflammation. j. stadler, department of surgery, tu mqnchen, frg hepatocellular nitric oxide (no) synthesis is induced by proinflammatory mediators such as tumor necrosis factor, interleukin- and interferon gamma or by bacterial toxins such as lipopolysaccharide. stimulation of the hepatocytes (hc) with a combination of these agents leads to an output of no in quantities which are not seen in any other celltype. it has been demonstrated by various investigators that important effects of these cytokines and bacterial toxins on hc metabolism can be attributed to the action of no. in contrast to other celltypes hc seem to be relatively resistant to suppression of basic metabolic functions such as energy metabolism by no. therefore, cell damage has not been described to a significant extent following exposure to no. however, no does inhibit total protein synthesis. the exact biochemical mechanism of this phenomenon has not been uncovered yet, but it has been demonstrated for some specific proteins that their production is inhibited at a posttransscriptional level. as in many other celltypes cgmp generation is elevated in hc by no through activation of the soluble guanylate cyclase. cyclic gmp may possibly exert a plethora of metabolic functions, but it is interesting to note that most of the cgmp seems to be transported out of the cell. some very specific effects of no on hc metabolism include the inhibition of the glyceraldehyde- -phosphate dehydrogenase (gapdh) and the cytochrome p (cyp) enzymes. inhibition of gapdh activity is mediated through nitrosylation of critical domains of the enzymes by no which enhances auto-adpribosylation. this effect on gapdh activity might be responsible for the inhibition of gluconeogenesis by no, which has been described recently. finally, no-mediated inhibition of cyps may help to explain the suppression of hiotransformation processes which is a characteristic featur,'~ r ~ "~flamed liver. nitric oxide (no) is an endogenous inhibitor of polymorphonuclear leukocyte (pmn) adhesion which limits pmn-endothelial cell interactions under normal conditions. we have previously demonstrated that following ischemia, no production by the vascular endothelinm is dramatically reduced. accordingly, we investigated the effects of no-donors on pmn accumulation and tissue injury following hemorrhagic shock and ischemia. hemorrhagic shock was induced in anesthetized rats by bleeding to mmhg for hours followed by reperfusion. segments of superior mesenteric artery (sma) were isolated and suspended in organ baths. in rats receiving saline sma relaxation to acetylcholine (ach, nm) was reduced by % compared to control sma segments (p< . ) while relaxation to sodium nitrite ( gm) was unaffected. in addition, mesenteric tissue pmn accumulation as determined by myeloperoxidase (mpo) activity was significantly elevated compared to controls (p< . l). interestingly, treatment with the no-donating agent, s-nitroso-n-acetylpenicillamine (snap) significantly preserved sma relaxation (p< . ), attenuated mesenteric mpo (p< . ) activity, and significantly improved survival compared to saline vehicle. in anesthetized, open-chest dogs we investigated the cardioprotective actions of a novel no-donor, spm- (schwarz pharma), following regional myocardial ischemia ( hour) and reperfusion ( . hours) . treatment with spm- ( rim) significantly reduced myocardial necrosis by % (p< . ) compared to an no-deficient analog of spm- , spm- . furthermore, mpo activity within the ischemic-reperfused zone was also significantly (p< . ) reduced following treatment with spm- compared to spm- ( . + . vs. . + . u/ mg tissue). these data strongly suggest that no is a potent inhibitor of pmn-mediated tissue injury following hemorrhagic shock as well as in acute myocardial ischemia-reperfusion injury. overproduction of nitdc oxide (no') may contribute to sepsis-induced hypotension. during septic shock, excess no" is produced by an isoform of nitric oxide synthase (nos) which is induced by inflammatory mediators. nonselective nos inhibitors have been proposed as a new therapeutic approach to treating hypotension in septic shock. we studied the differential hemodynamic effects of n~-methyi-l-arginine (l-nma), a nos inhibitor, in normal canines versus those challenged with endotexin (lps) and compared the activity of this drug across the venous, pulmonary and systemic vascular beds. awake canines were challenged with lps ( mg/kg, n= : mg/kg, n= ; or mg/kg, n= ) and treated with l-nma ( , , , , mg/kg/hr) for hours following a , , or mg/kg loading dose. animals were resuscitated with iv ringers solution ( ml/kg/hr). hemodynamic data were collected at , , , , , and hours using intravascular catheters and radionuclide heart scans and analyzed by anova. in both normal and endotoxemic animals, l-nma at all doses studied similarly increased mean arterial pressure (p= . ), and systemic vascular resistance index (p= .ol) and decreased cardiac index (p= . ) and oxygen delivery index (p= . ). in contrast, the effect of l-nma on mean pulmonary artery pressure, central venous pressure, pulmonary capillary wedge pressure, and pulmonary vascular resistance index was greater in lps-challenged canines compared to normal animals (p< . ), but this differential effect on the venous and pulmonary circulation occurred, > hours after lps challenge. l-nma did not significantly increase survival rates or times at any of the doses studied ( , , , or mg/kg/h) in either the low ( mg/kg) or high dose ( mg/kg) lps-challenge groups. a nonsignificant (p> . ) trend toward a beneficial effect on survival ol low dose l-nma ( mg/kg/h) in animals given the mg/kg lps-cha[lenge was not enhanced by increasing the lethality of the model or by administering higher l-nma doses. at the highest l-nma dose used in this study ( mg/kg/h), survival time decreased significantly for both the low and high dose lps-challenge animals (p< . ). this increased mortality was not explained by changes in plasma concentrations of either lps or tnfc~. thus, l-nma did not have a greater effect on the systemic arterial circulation in endotoxemic compared to normal canines. however, in the venous and pulmonary vascular beds, the effect of l-nma increased with time after endotoxin-challenge these data suggest the induction of nos activity by endotoxin in canines may be relatively greater in venous and pulmonary vessels compared to systernic arteries. l-nma, a nonselective nos inhibitor, did not decrease mortality in endoloxemic canines and the highest dose studied was harmful. pulmonary hypertension (ph) and arterial hypoxemia are characteristic features of the adult respiratory distress syndrome (ards). reducing pulmonary vascular pressures may promote the resolution of pulmonary edema. intravenously infused vasodilators lower ph in ards, but, as a result of their general vasodilatatory effects, systemic mean arterial pressure may also decrease. furthermore, blood flow may be increased to non-ventilated or poorly ventilated lung areas resulting in a rise of intrapulmonary shunt, thus causing a further fall in pad . recently, short term inhalation of low concentrations of the gas nitric oxide (no), an endogenous endothelium derived relaxing factor, which is rapidly inactivated in blood by hemoglobin, was reported to decrease ph without causing systemic vasodilation in sheep [ ]. similar changes have been observed in patients with severe ards during repeated short term inhalation of no ( and ppm), which rapidly and selectively decreased the mean pulmonary artery pressure (pap) and, in contrast to intravenously infused prostacyclin, induced a remarkable increase of pad [ ] . this improvement in oxygenation was caused by a redistribution in blood flow away from intrapulmonary shunt areas to normal ventilated lung regions. continuous no inhalation ( - ppm) consistently lowered the pap and augmented the pao /f.o for up to days. no negative side effects were observed during the whole time span examined. in particular methemoglobin levels always remained below . %. following these investigations, it could be shown that these effects may also occur using concentrations in the parts per billion range [ ] , which may reduce possible toxic side effects. however, in the same study it was demonstrated that the dose-response curves for pa and pap have different patterns. whereas pap presented a continuous dose-dependent downward tendency with an eds o of approximately - ppm, the improvement of oxygenation had a maximum at ppm and, at higher doses, drifted back towards the baseline data. the ed~o was estimated at approximately ppb, i.e. more than ten times lower than for the reduction of pap. in conclusion, inhalation of no by patients with severe ards may result in persistent and reproducible decreases in pap associated with an evident improvement in pad , thus allowing reduction of the f.o . no inhalation should be performed using low concentrations which are less toxic, although any possible risks still have to be considered carefully. dose-response studies for the individual patients are recommended urgently. finally, controlled randomized studies are required to demonstrate that additional no inhalation is able to reduce mortality of ards. inhibition of the activity of glyceraldehyd- -phosphate dehydrogenase (gapdh), an enzyme of the glycolysis/gluconeogenetic pathway, through adp-ribosylation is promoted by nitric oxide (no). since no is produced in the septic liver and hypoglycemia is a major problem of late sepsis, it was investigated whether no interferes with gluconeogenesis of hepatocytes. hepatocytes (hc) were isolated from sprague-dawley rats using a collagenase perfusion technique and differential centrifugation. exogenous no was applied by incubation with the no-donors s-nitrosyl-acetylpenicillamine and sodium-nitroprusside. endogenous no synthesis was induced by incubation with cytokines (tnfcq il- , ifnj and lipopolysacchafide (lps). hrs later the incubation medium was changed to a solution containing lactate, ornithine, lysine, ammoniumchloride and glucagon for optimal conditions of gluconeogenesis. after more hrs glucose and nitrite levels were determined spectrophotometrically. gapdh activity was measured by the nadh-dependent conversion of , -diphosphoglycerate to glyceraldehyde- -phosphate. incubation of hc with no-donors led to a concentrationdependent inhibition of gluconeogenesis and gapdh activity. however, gapdh activity was about times more sensitive to the inhibitory effect of exogenous no. incubation of hc with cytokines and lps induced nq synthesis as measured by an increase in nitrite concentrations. endogenously produced no suppressed gluconeogenesis by _+ %. in contrast to exogenously applied no, the effect of endogenous no synthesis was less on gapdh activity resulting in an inhibition of only _+ %. in conclusion, exogenous and endogenous no inhibited gluconeogenesis as well as gapdh activity. however, there was no correlation between the extent of inhibition of these two parameters of hepatocellular glucose metabolism. we have shown that inhibition of hepatocyte (hep) synthesis of nitric oxide (no) potentiates cell injury in a model of acetaminopheninduced oxidative stress and the extent of damage was paralleled by depletion of reduced glutathione (gsh) stores. to clarify the role of no in modulating the redox state of hep, we studied the effect of inhibition of cytokine-mediated no production on hep gsh stores, in a system of isolated rat hep in primary culture, no synthesis was induced (stim) by exposure to il- , tnf, ifn, and lps for hours. , , and ~m of n-monomethyi-l-arginine (nmma), a specific inhibitor of no synthesis, was added. cells incubated in media alone served as controls (cont). the no metabolite (no ); aspartate aminotransferase (ast), an indicator of cell injury; and gsh were assayed. (data presented as mean + sem; n= .) gsh (nmovma orotein) ..~ (nmol/ma orotein) cont . + . + . # stim . + . + stim+ o tzm nmma . + . + . # stim+ ~m nmma . _..+ . * + . # stim+ pm nmma . + . * + . # stim+ )lm nmma . + . * + . # anova , . (* p < . versus stim, # p < . versus stim; anova with neuman-keuls) gsh in cont+ i~m l-nmma was equivalent to that of cont ( . vs. . ). ast release was equivalent in all treatment groups. these data show that inhibition of hep synthesis of no depletes intracellular stores of reduced gsh. we conclude that hepatocyte no production modulates cellular gsh homeostasis and as a result, may be hepatoprotective in oxidative injury. nitric oxide (no) is a modulator of immune response and may be involved in the changes in immune reactivity after major trauma and operations. we investigated no-generation in rat and mice spleen cells (sc) after partial hepatectomy (ph). c bl/ mice and lew rats underwent a % and % ph, respectively. sc were prepared - days after ph and plated at to x ecells per well. after h incubation at °c, no-production was measured as nitrite levels (griess reagent). normal mouse sc did not produce no, neither basal nor in response to lps or con a starting at the second day after ph, we found a substantial production of no. in rats, also sc from control animals were able to generate no; both basal and stimulated no-generation were further enhanced after ph (table, values expressed as mean --se). after shame operation, there was only a modest elevation of noproduction in rat and mouse sc. in first experiments we could demonstrate no-production also in phagocytes from a patient days aider liver partial resection ( . nmol nitrite/ cells) enhanced no-production in macrophages may contribute to the changes of immune reactivity after partial hepatectomy. nitric oxide (no) is recognized as an important mediator in endotoxemia and sepsis. increased synthesis of no has been demonstrated in septic humans and animals, and no inhibitors have been used in the treatment of septic shock. recent reports have, however, suggested that this form of therapy may cause serious organ damage. in the present investigation circulatory and metabolic changes in the liver were studied during treatment with the no-synthase inhibitor n-nitro-l-arginine-methyl ester (l-name) in endotoxemia. methods: juvenile pigs were randomized to one of the following treatment groups: ) encletoxin and l-name, ) endotoxin, ) naci and l-name, ) nach preliminary results from groups (n= ) and (n= ) are presented. catheters for pressure measurement were introduced into the aorta, hepatic and portal veins and ultrasonic transit time flow probes were placed on the hepatic artery and portal vein. a catheter was introduced into the pulmonary artery. endotoxin ( . gg/kg/h) was given as a continous portal infusion over the entire observation period of hrs. l-name ( mg/kg) was given as a bolus after hrs. of endotoxemia. results: endotoxin transiently reduced portal vein flow (pvf) by %* and hepatic artery flow (hal e) by %*, while l-name caused a further and lasting reduction in flow (pvf %, haf %)*. transhepatic (portal-hepatic vein) vascular resistance increased to times baseline value during endotoxemia while l-name caused a further marked increase in resistance to times initial value. portal oxygen saturation (so ) decreased by %* during endotoxemia. l-name caused a reduction in portal so by %*. arterial so was unchanged in both groups. hepatic oxygen uptake was not changed by endotoxin, but was markedly reduced after addition of l-name. endotoxin caused a % reduction in cardiac output (co). the addition of l-name reduced co by a total of %*. *: p < . . conclusion: is the present model of endotoxemia treatment with the nitric oxide synthase inhibitor l-name markedly reduced liver perfusion and portal oxygen supply. this might explain the increased liver damage reported in previous studies using no-inhibitors. the increase in transhepatic resistance found after l-name treatment will tend to cause pooling of blood in the splanchnic veins, resulting in reduced filling of the heart and thus contribute to the observed reduction in cardiac output. institute for surgical research, rikshospitalet, the national hospital, university of oslo, oslo, norway. we have investigated the role of tumour necrosis factor (tnf) and interleukin-i (il-i) in the induction of nitric oxide synthase (nos) by bacterial endotoxin (lipopolysaccharide; lps; mg kg -i i.v.) in vivo. in anaesthetized rats, pretreatment with a monoclonal antibody for tnf (tnfab; mg kg -i s.c., at h prior to lps) or with an il-i receptor antagonist (il-ira; mg/kg bolus and . mg/kg/h infusion) ameliorated the fall in mean arterial blood pressure (map) at - min after lps. for instance, endotoxaemia for min resulted in a fall in map from -+ (control) to -+ mmhg (p< . ; n= ). in contrast, animals pretreated with tnfab or il-ira prior to lps injection maintained significantly higher map at min when compared to lps-control: -+ mmeg (n= ) and -+ mmhg (n= ), respectively (p< . ). three hours of endotoxaemia significantly reduced the contractile effects of noradrenaline (na) in the thoracic aorta ex vivo. the hyporeactivity to na was partially restored by in vitro treatment of the vessels with ng-nitro-l-arginine methyl ester (l-name, min, x - m). pretreatment of rats with tnfab or il-ira significantly (p< . ) prevented the lps-induced hyporeactivity of rat aortic rings ex vivo. l-name did not alter or only slightly enhanced the contractions of aortic rings obtained from tnfab or il-ira treated lps-rats, respectively. at min after lps there was an induction of calcium-independent nos activity in the lung ( . -+ . pmol citrulline/mg/min, n= ), which was attenuated by tnfab and !l-ira by -+ % and -+ %, respectively (n= ; p< . ). thus, the production of both tnf and il-i contributes to the induction of nos by lps in vivo. the protective effect of agents which inhibit the release or action of tnf or il-i in shock may be, in part, due to inhibition of nos induction. neal garrison, md objective: sepsis is often accompanied by organ dysfunction, in part due to impaired microvascular perfusion. recently, nitric oxide (no) has been described as an important mediator of the hemodynamic changes of sepsis, and no synthase (no-s) inhibitors have been advocated for treatment of septic shock, but their visceral microcirculatory effects are inadequately characterized. we postulated that no-s inhibition would exacerbate the impaired organ perfusion of sepsis. methods: six groups ofdecerebrate rats were studied. bacteremia was induced with live e. coli, which consistently increased cardiac output - % above baseline (bl). the no-s inhibitor nm-nitro-larginine methyl ester (l-name, mg/kg iv), prevented this increase and elevated map by - %. in the first groups, total hepatic blood flow (thbf, ml/min by time transit flowmetry) and microvascular perfusion (mi-ibf, ¼ bl by laser doppler flux) were measured. in the other groups, in vivo videomicroscopy was used to observe renal microvascular responses (ila=interlobular artery, aff=afferent arteriole, eff=efferent arteriole; % bl for all). results: data are rains after e. cob. n= - /group. * p< . vs bl by remanova and § p< . vs e. coli alone by anova. ec+l-name -+ - _+ " § - _+ * § - _+ * § - + * - + * § conclusions: l-name administration in controls decreased renal blood flow, indicating no contributes to basal renal tone. bacteremia decreased mtlbf but not thbf, and mi-ibf was further impaired by no-s inhibition. e. coli caused renal preglomemlar, but not postglomerular constriction and reduced flow. l-name exacerbated these e. coli-induced alterations and caused eff constriction. these data indicate that no-s inhibition exacerbates bacteremia-induced impairment of renal and hepatic blood flow, suggesting that no is an importam compensatory dilator mechanism in these organs during sepsis. irf (iron responsive factor) is the central regulatory protein of intracellular iron metabolism able to bind to responsive rna elements (ires) present atthe 'untranslated region (utr) of ferritin mrna and 'utr of transferrin receptor mrna. binding of irf to ires results in repression of ferritin mrna translation and increased stability of transferrin receptor mrna leading to enhancement of transferrin receptor translation. we describe here that either tetrahydrobiopterin dependent stimulation as well as cytokine (ifn-~)/lipopolysaccharidemediated induction of nitric oxide synthase activates irf, which is due to direct interaction of nitric oxide with the iron-sulphur-cluster of irf. this was shown by gene expression studies using a plasmid containing a ferritin ire and a cat indicator box which was transfected into k myelomonocytic cells, which were shown to have a constitutive form of nitric oxide synthase (nos). furthermore, the increased binding of re to irf due to irf activation of irf by nitric oxide was demonstrated by gel shift assays. irf activity was much more increased in cellular extracts from murine macrophages (j ) where a cytokine inducible form of nos has been characterized earlier as compared with irf activity in k cells, where nos was stimulated by increasing the availability of the essential nos cofactor , , , -tetrahydrobiopterin. we then demonstrated that activation of irf by nitric oxide is accompanied by alterations in ferritin translation as checked by metabolic labeling and immunoprecipitation. these results suggest a reasonable mechanism for the regulation of iron disturbances under chronic inflammatory disorders, characterized by increased concentration of immune activation parameters like ifn- or neopterin and low serum iron and hemoglobin concentrations. taken nitric oxide, no, the putative endothelial derived relaxant factor, edrf, has been shown to be a potent inhibitor ofplatelet aggregation in vitro. in vivo evidence however, is scarce. accumulation of platelets in the lungs has been shown to occur during extracorporeal circulation. the aim of the present study was to investigate the effect of inhaled no on this reaction. materials and methods: the animals were divided into two groups, each consisting of pigs. platelets were selectively labelled with luln-oxine. dialysis was instituted via catheters in the femoral vessels. in group , no, ppm, was added to the inhaled gas from the start of dialysis. in group no was not given. the activity over the lungs was followed dynamically with a gamma camera. central hemodynamics was monitored via a swan -ganz catheter. results: the activity was significantly lower in group , from minutes after start of dialysis and onwards, indicating diminished accumulation of platelets in the lungs. parallel to this the hemodynamic response in terms of increased pulmonary artery pressure and pulmonary vascular resistance was blunted in this group conclusion: inhaled no in this model seems to affect pulmonary platelet sequestration. an associated attenuation of the changes in central hemodynamics was also seen. previous studies from our laboratory have demonstrated that vascular contractility decreased in endothelium-intact blood vessel rings in early and late stages of sepsis. although endothelium removal in early sepsis restored vascular contraction, the depressed smooth muscle contractility observed in late sepsis was not restored by endothelium removal. this indicates that impairment of smooth muscleper se may be responsible for such dysfunction in late sepsis. the aim of this study, therefore, was to determine whether or not smooth muscle-derived nitric oxide (no) plays a role in producing vascular smooth muscle dysfunction during late stages of sepsis. to study this, rats ( - g, n= - /group) were subjected to sepsis by cecal ligation and puncture (clp). septic and shamoperated rats then received rrd/ g bw normal saline. the animals were killed at , , or h post-clp ( h post-clp=early sepsis; - h post-clp=late sepsis), and thoracic aortic rings were prepared for contraction studies using organ chambers. the complete removal of endothelial cells was tested by the absence of any significant acetylcholine-induced vascular relaxation. contractile responses to norepinephrine (ne, to - m) were determined in the aortic rings without intact endothelium. ng-monomethyl-l-arginine (l-nmma, /~m, an inhibitor of no synthase) was then added to the organ chamber and ne-induced peak contraction was determined before and after the addition of l-nmma. the peak contraction (rag/rag tissue, mean_+sem) is shown below: the results indicate that the addition of l-nmma did not significantly affect ne-lnduced peak contraction in endothelium-denuded vessel rings at and h after clp. in contrast, l-nmma administration produces an % increase (p< . ) in peak contraction during late sepsis. therefore, the vascular smooth muscle contractile dysfunction observed at h post-clp is partially due to smooth muscle-derived no over-production. thus, unlike macrophages in which inducible nitric oxide synthase (inos) is observed in early sepsis, the inos in vascular smooth muscle appears prominent only in the late stages of sepsis. in three cases of human septic shock in which ng-monomethyi-l-arginine, (l-nmma) a nitric-oxide-synthase-inhibitor was applied, we isolated three completely different types of pathogens: candida, pseudomonas aeruginose and multiresistant coagulase-negative staphylococci. this observation suggests that endotoxin alone is not the main factor triggering hypotension in septic shock by the nitric oxide pathway. in a -years-old woman in severe septic shock due to a candida and pseudomonas aeruginosa infection complicated by adult-respiratorydistress-syndrome conditions deteriorated despite adequate conventional therapy. in this trial, effects of l-nmma on cytokin-levels were investigated. the study-protocol was approved by the ethical committee of the department of surgery. after two boll of mg of l-nmma, a continuous infusion was installed ( . mg/minute and kg body weight l-nmma). as expected mean arterial blood pressure rose ( to mmhg}, heart rate stayed stable ( + b/rain), systemic vascular resistance increased ( to dyne.sec/cm ), cardiac output decreased ( to . l/rain), and cardiac index declined ( . to . l/min/m }. before and after minutes while the infusion of l-nmma, blood samples for immunological measurements were taken and processed together. pulmonary-shunt-volume was observed before the application of l-nmma, after one hour and after matutes. neopterine increased from . to . ng/ml, tumour-necrosis-factor-a increased from . to . pg/ml and intedeukin- increased from . to . pg/ml. immunoglobulines a, g, and m ( . to . , . to . , . to . g/i), complement factor c- c and c- ( . to . , . to . g/i), alpha-l-antitrypsine ( . to . g/i), c-reactive-protein ( . to . rag/i), interleukin- ( pg/ml) and soluble interleukin- ( to units/ml) did not change significantly. pulmonary-shuntvolume decreased from . % to . % within one hour and to . % after minutes. in septic shock blocking nitric oxide as an intervention at the end of a not ~,et ful!y understood cascade might have important influences on pulmonary-shunt-volume and inter-cell-communication. department of surgery, pharmacy* and immunology**, university hospital of zurich, r~imistrasse , zurich, switzerland we previously reported that hypoferremic cba mice had an increased resistance to salmonella infection, and that injection of ammonium ferric citrate (afc) to these mice led to enhanced infection (ganthier et at. . microbiol.immuno : ) . because nitric oxide (no) is involved in the antimicrobial activity of routine macmphages towards various inttacellular pathogens, we investigated the influence of iron on the bactericidal activity of cba mouse macrophages towards s.typhimurium and on the production and activity of reactive nitrogen intermediates (rni). peritoneal macrophages hum cba mice were cultured in the presence (or not) of afc ,um, ifn-,/ u/ml, lps fig/m/, ngmonomethyl-l--arginine (mmla) ram. nitrite (no -) content of the supematants was determined by a standard griess reaction, and h release was measured by the peroxidese dependant oxidation of phenol red. for intracellular killing, macrophages monolayers were infected, and, at various intervals, lysed by triton x- , and surviving bacteria enumerated by colony counting on agar. for in vivo experiments, mice were infected ip with . ml of a suspension of . ~" s.typhimurium, strain c , and injected with aminoguanidine (ag) mg/ml in saline. our results show that the rn[ inhibitor ag strongly accelerates the mortality of infected mice, the survival rate decreasing from % in the control group to % in the treated group, days after challenge. correlatively the rni inhibitor mmla induces in vitro a decrease in the rate of bacterial killing, fxom % to %, in macrophages triggered with ifn-? + lps. the cultivation of macrophages in the presence of afc leads to a decreased no -accumulation, . nmole/well v.s. nmole/well. conversely h production is enhanced from nmole/well up to , nmole/well. nevertheless, macrophages cultivated in the presence of afc exhibit an increased tale of intracellular killing, % in iron exposed macrophages v.s, % in control macrophages. when triggered with ifn-~, alone, macrophages have a reduced antibacterial activity ( % v.s. %) whereas the addition of afc to these macrophagas restores an elevated ( %) rate of killing. in conclusion, the results show that bactericidal activity of cba macrophages towards s.typhimurium depends on the production of no by these macrophages ; but they also demonstrate that no is not the only reactive species involved in the intracellular kil/ing of s.thyphimurium ; indeed afc which strongly inhibits rni production, stimulates h release by these macrophages and increase their bactericidal activity in vitro. nevertheless afc may promote bacterial growth in vivo. crssa. unit de microbiologie. bp . la tronche cedex france. henning jahr, ulrike noack, karin braun the large amounts of no produced by the inducible no synthase in rat macrophages have direct antimicrobial effects, but inhibit the activation of the lymphocyte-dependent host defense system. the aim of this study was to investigate if complement activation influences no-generation. spleen cells from lew rats were incubated at °in tcm- / % fcs, with or without additional rat serum. after h, nitrite (end product from no metabolism) was measured by oriess reagent. in rat spleen cell preparations, most of the no is produced by macrophages. complement activation in vivo was carried out by i.v. injections of u cobra venom factor/kg b.w. at days and . significantly higher (p<o.o ) lps-stimulated no-generation was found in spleen cells prepared at day ( . - . nmol nitrite/ cells, n= ) compared to spleen cells from non-treated animals ( . ± . nmol, n= ) complement activation was effective also in vitro. when incubated in % zymosan-activated rat serum, both basal and lps-stimulated noproduction were enhanced in spleen cells (table, values increased production of nitric oxide (no) is associated with sepsis, however, the effect of no inhibition on survival during sepsis is unclear. we examined the effect of no inhibition on host's ability to eliminate bacteria and survival in mice sepsis model. sixty female balb/c mice were injected with e.coli ( qbody) into peritoneal cavity. the treated group received n-ultro-l-arginine-methyl-ester (l-name), an inhibitor of nos, one hour before bacterial challenge. thirty mice were observed for survival after e.coli challenge and the other mice were sacrificed at hours. blood was obtained by cardiac puncture and peritoneal lavage fluid (plf), liver and lung were harvested. the number of peritoneal exudative cell (pec) was counted and colony forming units (cfld of bacteria in the tissues, blood, and plf were also determined. in addition, pec was cultured in vitro with or without lipopolysaecharide (lps). tnf levels in the blood, plf, and supematants of cultured pec were measured by l bioassay. survival rate (%) qrql/,p n hr hr dav control (normal saline . ml/body i.p.) n (l-name mg/kg i. administration of l-name before e.coli injection increased the number of bacteria in plf and tnf level in plasma, the result suggests that nos inhibitor may depress the host's ability to kill the injected bacteria and that it may induce greater systemic tnf production. we conclude that nos inhibitor is detrimental to animals in sepsis. the hypothesis that sod prevents reperfusion injury to the liver by protecting the endogenous endothelium derived vascular relaxing factor (no) from being inactivated by oxygen free radicals should be investigated. male wistar rats were subjected to min of partial liver ischemia ( %) and min of consecutive reperfusion in situ. some rats were pretreated with the no synthase inhibitor nitro-l-arginin (nla: i mg/kg). sod, when used, was given as mn-containing preparation at a dose of u. i.v. i min prior to ischemia. results (sod/ nla+sod/ ni~,, respectively): bile flow (~i/g/min) : . ± . "#/ . ± . / . ± . . alt (u/ ) • ± ~#/ ± / ± . gldh (u/l): . ± . e#/ . ± . #/ . ± . . in absence of nla, sod enhanced postischemic bile flow and reduced leakage of alt and gldh into the plasma, while the effects of sod disappeared, when endogenous ~synthesis was inhibited by nla. nla had no ~ffect on untreated animals submitted to the same protocol. these results may suggest, that oxygen free radicals interfe~:e with the endogenous vasodilator no and that the benefit of sod can be attribuated in large part to a protection of no during reperfusion. nitric oxide (no) reduces pulmonary vascular resistance and increases oxygenation by inhalation in ards patients [ ] . animal studies on the endogeneous no production proved that no is exhaled after synthesis in the respiratory tract [ ] . with approval by the hospital ethics committee, we studied healthy volunteers and ventilated patients by measurement of inand exhaled no by no/no -chemiluminescence in segments of the upper respiratory tract. we found that no is synthesized predominantly in the nose and in the upper nasopharynx, leading to inspiratory tracheal no concentrations of . - . parts per million in non-smoking volunteers; data during mask ventilation per nose were as follows: non . . . . , parts per million (ppm) no, mean, n = ; ~ p < . (t-test) between smokers and non-smokers; p < . (t-test) between in-and expiration. about % of no is resorbe.d by the lung, and the exhaled no -in contrast to former presumptions -is the remaining part of the autoinhaled no. intubated and ventilated patients are deprived of no autoinhalation, and the exhaled no in the trachea decreases more than % {o. ppm before intubation vs. . ppm after intubation, ~, < . ), whereas the nasal no concentration increases by cumulation. hence, low-dose no inhalation in ards patients might be considered as a no replacement, especially since the tracheal no concentrations we measured in volunteers are similar to those which could be demonstrated to be effective for ards in former studies [ ] . the data demonstrate that no is synthesized in the nose, and inhaled and resorbed by the lung. this phenomenon of no autoinhalation, which is reduced in smokers and in ventilated patients, does possibly contribute to the regulation of the ventilation-perfusion ratio in the lung. kikuchi , yoshihiro inoue , masao yoshida critical care and emergency center, and department of bacteriology, iwate medical university. nitric oxide (no) is produced by macrophages and vascular endothelial cells. it is thought to be the true form of endotheliumderived relaxing factor, and to be involved in the fall of blood pressure during septic shock. we have reported previously that endotoxin (lps), tnf-c~ and il- contribute to the occurrence of septic shock (circ shock : ; . the present study investigated the in vitro effects of lps, tnf-o~, il- and ifn-'i on the production of no by macrophages. peritoneal macrophages were cultured with lps, il- , tnf-~ and ifn-¥. in culture with lps, no was produced in a dose-dependent manner, and the production was suppressed by a no production inhibitor, l-nmma. ifn-y, il- and tnf-c~ used alone did not promote the production of no, but helped lps to facilitate no production. a combination of il- and tnf-c( enhanced lps-facilitated no production to a greater extent than il- or tnf-c~ alone. the above results suggest that these cytokines are involved in endotoxin shock through the mechanisms that facilitate no production. - uchimaru, morioka . japan. t. yolk , , i. ioannidis , w.j. kox and h. de groot objectives: nitric oxide (no.) is known to play an important role in neurotransmission, vasoregulation, and bactericidal as well as tumoricidal cellular defense systems. by means of no-donating agents we studied the mechanism of no-mediated cytotoxicity against rat liver microvascular endothelial cells. materials and methods: -morphoiinosydnonimine-n-ethylcarbamide (sin-l) and sodium nitroprusside (snp) were used as no. donators, ldh release and trypan blue exclusion were applied to indicate cell viability. results: sin- ( mm), which releases both no. and o -., caused a time-dependent cytoreduction of % and % after and hrs, respectively. this effect was not inhibited by superoxide dismutase (sod), which removes --to form h and . in contrast, the addition of catalase (cat), which removes h to form h and , diminished the cytotoxic effect ot sin- to %, equivalent to high concentrations of snp ( mm), which solely releases no.. in addition, the amount of h formed by mm sin- equaled the amount ot enzymaticany produced h by mu/l glucose oxidase (god). whereas god in this concentration and snp in low concentration ( mm) alone were not toxic to endothelial cells, the combination caused an % reduction of viability, comparable to the effect observed with sin- ( mm) alone. moreover, toxicity mediated by high concentrations of snp ( mm and ram) was reduced by % under hypoxic conditions indicating synergism with no-and . conclusions: we conclude, that no.-induced toxicity against endothelial cells is enhanced slightly in the presence of oxygen and is not due to an interaction with -. however, toxicity increases dramatically in the presence of h . this may possibly occur either by a chemical formation of more potent reactive hydroxyl radicals or by independent actions on different cellular targets. although it is becoming increasingly clear that nitric oxide (no) is associated with otxan dysfunctions in septic patients, little is known as to die kinetics of no production in these patients to clarify these kinetics, we have investegated serum arid monocyte associated no in septic patients. five patients who had undergone gastrointestinal surgeries mid were complicated postoperatively with severe sepsis served as the subjects in this study (sgroup), using twelve healthy volunteers as a control group (c group). serum no and no levels were measul*d sliectrophotometricallymonocyte cultures were done for itrs with or without lps+ifn-t stimulation mid no and no levels in the supernat,'utts were also measured spectrophotometrically. furthermore,using an no selective electrode,time course of the lps+ifn-t induced no production by monocytes was studied. l) serum no levels in s group were slightly lfigher than dmse in c group,bnt there were no significoatt differences between the two. )both no levels in the supematmlts of monocytes cultured with lps+ifn-t mid no , no levels ill lhe supernatants of monocytes cultured without lps+ifn-y were significantly higher in s group. further,the time required for the no production by enltnred monoeytes was siglfificantly shorter also in s groap. conclusions l)in severe septic patients, monocyte no productions wei~ not only primed, but also activated concomitantly, suggesting that these monocyte activations m'e strongly associated with organ dysfunctions in sepsis. )based on the restdts of serum no nteasuremeuts, it can be deduced that no p~'oduced by monocytes in septic patients affects tissues and org~s ioeoregiomflly. objectives of the study: nitric oxide (no) is an important messenger which accounts for a wide spectrum of physiological and pathophysiological processes, e.g. mediating vasodilation in endoloxin shock investigating the signal lransducfion pathways involved in the regulation of the inducible nitric oxide synthase (inos), we report the involvement of phosphatidylcholinespecific phospholipase c (pc-plc) and proteinkinase c (pkc). materials and methods: no-production was induced in the murine macrophage cell line j with lipopolysaccharide (lps) [lljg/ml] and interferon ;f (ifny) [ u/ml]. after hours of incubation no-release was determined as nitrite (no ) by using a colorimetric assay based on the griess-reaetion. results: preincubation of cells with the pkc-inhibitors staurosporine (stp), chelerythrine, bisindolylmaleimide (bim) and d , that recently has been identified as a selective inhibitor of pc-plc, diminished significantly lpsand ]fnt-induced no -production (p<o, ). although we observed no toxic effect on cell viability, no -production was related to protein concentrations to exclude any inhibitory effect on celt growth. celts preincubated with stp [lo nm] released % less no in response to lps and ifn,[ compared to control cells cultured without inhibitor. chelerythrine [ }jm] and bim [ioijm] reduced the no -formation by % and %, respectively. interestingly, the most potent inhibitor of no-production turned out to be the xanthate d cells pretreated with d [ ~g/mt] released % less no than stimulated controls the inhibitory effect on no production decreased the later the inhibitore were added after stimulation; e.g. bim added and hours after stimulation reduced no -production only by % and %, respectively. accordingly, inqs activity present in stimulated cell lysates supplemented with l-arginine and co-factors was not suppressed by the inhibitors tested. conclusions: our findings suggest, that the induction of inos but not its activity is a pkc and particularly pc-plc dependent process. dr. k tschaikowsky, institut for anaesthesiologie, universital erlangen--nqrnberg, krankenhausstr , erlangen interleukin- (il- ) affects nearly every cell type by increasing the expression of a variety of genes associated with the promotion of inflammatory processes. these include upregulation of cyclooxygenase and nitric acid synthases. the il- ri transmits a signal(s) through the cytoplasmic domain which is structurally related to the fruit fly toll protein. we have recently cloned the promotor most proximal to the ' utr of the human il- ri gene. the genomic sequences reveal a lack of tata and caat boxes but rather a considerable ( %) gc rich region. the translation of the type i il- r appears under a significant suppression and may limit the biological activities of il- by low level of expression. on the other hand, the type ii il- r, lacking a significant cytoplasmic domain, does not transmit a signal and acts as a decoy receptor preventing the binding to the type i receptor. there are several approaches to reducing il- activity; inhibition of il- converting enzyme which cleaves pro-il-l[ , anti-il- ri, the il-i receptor antagonist (il- ra) and soluble (extracellular) il- ri and il- rii. il- ra is structurally related to il- and binds at °c to the il- ri with near equal affinity as that of bona fide il-i; however, il- ra does not transduce a signal. il- ra has been given to humans in pharmacologic levels (mean plasma levels of gg/ml) without evidence of agonist activity. in addition, there has been no affect on normal homeostatic parameters, suggesting that il-i does not play a role in health. in healthy humans given intravenous endotoxin, il-ira reduced endotoxin-associated neutrophilia by % and completely reversed endoloxin-iuduced immunosuppression, il-tra is produced naturally and is elevated in the circulation in several diseases. in a variety of diseases, plasma levels of il- ra are in -fold molar excess to those of il-i [ . it is unclear whether these endogenous levels of il- ra are sufficient to block il- activity in disease. a single injection of ]l- or ifna in humans does not induce il- but rather high levels of il- ra ( ng/ml). prof.dr.l.a. aarden interleukin (il ) is a multifunctionai cytokine with a central role in host defense mechanisms and consequently in inflammation. il is thought to be involved in the pathogenesis of various diseases. therefore, specific inhibitors could have therapeutic value. a human-mouse chimeric monoclonal antibody to il has been applied in a phasei clinical trial in patients with multiple myeloma and in primate models of sepsis. no toxicity was observed and the most remarkable outcome of this study was the build up in the circulation of il -anti-il complexes, suggesting that plasma il measurements represent a gross underestimation of il production in the patient. until now no natural antagonists of il have been described. the biological activities of il results from binding to a lowaffinity il -receptor (il r). the il /il r complex induces disulfide-linked homodimerization of the signal transducing receptor component, gp . studies on the structure-function relation of il revealed that disruption of the gpl -interaction site on il gives rise to a mutant il that, by virtue of its intact binding to the il r, acts as a potent antagonist on human hepatocytes and on human b cells. in vivo studies using this molecule will be initiated in the near future. the evolution of infla~ation involves a dynamic series of cellular events controlled by specific signals which are important to the initiation, maintenance, and final resolution of the inflammatory response. the various phases of inflammation are influenced via the expression and subsequent regulation of a number of key mediators which play a predominant role during each particular stage of the developing lesion. for example, the initial elicitation of blood born leukocytes to on inflamed area is a complex system that is dependent upon the expression of early response cytokineso these proximal mediators, including both interleukin-i (il-i) and tumor necroisis factor (tnf), are important in the initiation phase by activating both immune and non-immune cells and establishing a series of cytokine networks, thus, the above proximal mediators can stimulate endothelial cells, epithelial cells, smooth muscle cells, and fibroblasts to generate more distal cytokines. these latter cytokines include interleukin- (il- ), macrophage inflammatory protein-i (mip-i), and monocyte cbemoattractant protein-i (mcp-i). the importance of the above chemukines can be found in the role they play in leukocyte elicitation, as well as wound repair. numerous investigations have shown the diverse cellular sources of il- and the ability of il- to elicit neutrophils in vitro at pm to nm concentrations, however, recent studies have sho%~ an additional role for il- during the resolution phase of the inflammatory process. using corneal pocket animal models of angiogenesis/neovascularization, il- was found to be a potent angiogenic factor at concentrations ranging from - ng/ml. sequential fluorescein angiograms demonstrated that il- induced neovascularization by days, which regressed by weeks. in further analyses, both conditioned media recovered from either inflamed human heumatoid synovial tissue macrophages or lps-stimulated peripheral blood monocytes were found to possess potent angiogenic activity, which was effectively blocked by neutralizing antibodies directed against human il- . in addition, an il- antisense nligomunclentide blocked the expression of a functionally active angiogenic factor from lps treated monocytes. the above data demonstrate that il- has multifumctional activities during the initiation, maintenance, and resolution of a local inflammatory response. inhibits specific t-cell responses to soluble protein antigens and alloantigens. the proliferative responses of th , thl and th cd ÷ t-cell clones and cytokine production by these t-cell subsets are equally well inhibited. the inhibitory effects of il- are indirect and related to inhibition of antigen-presenting capacity and accessory function of the antigen-presenting cells (apc). however, il- also directly inhibits t-cell proli/eration induced by cross]inked anti-cd or anti-cd mabs (e.g. in the absence of professional apc), by specifically inhibiting il- gene transcription and il- protein production. il- also inhibits the production of the pro-inflammatory cytokines il-l-a, ~, il- , and tnf-a and the chemokines il- and mip-i-u, which are strong chemo attractants for neutrophils and macrophage, respectively. in contrast, il- enhances the production of the il- receptor antagonist, a cytokine with anti-inflammatory activity. il-l produced by monocytes downregulates class ii mhc expression and il- production by these cells in an autoregulatory fashion. collectively, these in vitro data indicate that il- is a powerful suppressor factor for immune-and inflammatory responses and therefore may have potential clinical utility as an anti-inflammatory agent. this notion is supported by recent studies which indicated that il- also prevents lethal lps-induced toxic shock in mice. five of the chamekines (hip-i~,era~tes. ip-io and il ) also chemoattraet t lymphocytes, while others act on mast cells. we have studied the effaces of these chemokines on t cell subsets. il preferentially chemoattracts uns~imulated t cells. raises ~ttracte resting as well as activated cd and cd memory t cells. ip- chemoattracts only preactivated (not resting) cd or cd t cells. hip-l~ preferentially chemoattracts gd t calla, while hip- more readily attracts the cd t call subset. the chemoklnes and ip-io were also sho~rn to promote the adherence of ~he same subsets of anti-cd activated t cells to ili activated human umbilical vein endothelial cells (hitvec). this was not associated with a~y i~crease in the number of lymphocyte adhesion molecules, bu~ could be inhibited by neutralizing monoclonal antibodies re lfa-i and vla- . these chemokines also rapidly increased ~ha adhesion of resting t l~phoeytes to plates coated wi~h integrlns (i-cam or v-cam) or matrix proteins such as f~bronectln. this induction of adhesion began wiehln ', peaked by hr and was completed in hr. this suggests that chemoklnee rapldly increase the binding affinity of adhesion prote~ns on t cells. we also recently observed ~hat mcaf/mcpi and rantes chemoattract unatimulated mast calls. furthermore, igs actlvared mast calls were chemoattraeted by mcaf, ra~tes, pf and mip.i~. however. ~he chemoklnee did not induce mast cells ~o release histamines. presumably, chemokines as regulators of the adhesion, migration and homing of all kinds of leukocytes participate in many types of inflammatory diseases. natural killer cell stimulatory factor or interleukin- (il- ) is an heterodimerie cytokine formed by two covalently linked glycosylated chains of kd and kd. il- was originally purified from the supermatant fluids of ebv-transformed human b ly~phobiastoid cell lines. however, in addition to b cells, phagocytic cells, i.e. monocytes, macrophages, and neutrophils, have been identified as the major physiological producers of il- . phagocytic cells produce il- in response to bacteria, bacterial products such as lps, and intracellular parasites. the cell types on which il- exert biological activity are t and nk cells. the major direct biological function of il- on these cell types are the induction of cytokine production, primarily ifn-y, the enhancement of a generation of cytotoxic cells, and a mitogenic effect on antlgen-activated lymphocytes. in part thromgh its ability to induce ifn-y production, il- , produced in response to infections, represents an important functional link between effector cells of innate resistance, phagocytic cells and nk cells, and effector cells of adaptiye resistance, t and b lymphocytes. the ability of il- to induce ifn-y production from circulating. nk cells and at least a proportion of t cells determines a rapid, antigen-independet production of ifn-y during infections. ifn-y acts as a potent enhancer of phagocytic and bacteriocidal activity of phagocytic cells, participating early in infection to activate some of the inflammatory mechanisms that represent the first innate resistance against infection. this antigem-independet activation of phagocytic cells that involves, in addition to il- , other monocyte derived cytokines such as tnf and il-l, has been shown to be important in experimental animals for the resistance against infection by microorganisms such as limteria monocytogens and toxoplasma gondii. in addition to this role, early in infection in the antigen-independet phagocytic cell activation, il- has a major effect in the ensuing antigenspecific admptive immune response by facilitating the generation of t helper type (th-i) response and suppressing a th- response. the presence of il- during antigen stimulation in vitro using human peripheral blood lymphocytes, or both in vivo and in vitro in experimental animals, induces generation of th-i cells producing ifn-y and il- , and inhibits the generation of th- cells producing il- . il- induces a direct differentiative effect on th-cells, priming them for high ifn-y production. ~is priming effect is stable and maintained even when t cell clones are cultured for extended periods in the absence of il- , however, il- needs to be present during the first few days after stimulation with antigen or mitogen and established th clones are resistant to the priming effect of ifn-y. unlike the generation of high ifn-y producing clones, the il- -mediated inhibition of il- producing cells in probably due to selective mechanisms, which may include a selective mitegenic effect of il- for thl cells and an inhibitory effect of ifn-y on th cell proliferation. in several experimental systems, it has been shown that the enhancing effect of il- on th-i responses is dependent on production of if~-y and on the presence of nk cells, possibly needed for the early production of ifn-y. the importance of phagocytic cells and nk cells in determining the characteristics of the th response during antigenic stimulation indicated that the mechanisms of innate resistance have a determining influence on the subsequent antigen-specific immune response: il- appears to have a key role in mediating the interaction between phagocytic cells. nk cells, and t lympocytes in these proccessem. trinchieri, g. , interleukin- and its role in the generation of t e cells, imm~ol. on peripheral blood monocyte/macrophages, il- behaves like il- in a variety of assays, and shows both similar and contrasting, activties with either il- or ifn-y. il- reduces inflammatory monokine and il- production. it reduces the pyrogen-induced expression of tissue factor (herbert et el, , febs lett. , ) . it mpregulates manmose receptor and ~c class ii expression, while reducing cdi expression. il- produces morphological changes (extensive cell processes, aggregation, giant cell formation) which have previously been observed with il- . it inhibits niv-i production (montaner et el, , i. exp. mad. , ) , and interferes with hiv-induced cell fusion. the activities of il- and il- differ on t-ly•ocyte and large granular lymphocyte population. in particular il- does not exhibit the suppressive effects of il- on thl-type-helper functions (ifny production) and cytotoxic functions (perforin production). data will be presented showing that il- and il-l share a common receptor on a nu~er of cell types, but not on t-lympocytes (see also zmrawski st el. , embo j. . - ), explaining both thai common and divergent activities. the levels of il- ~a in activated peripheral blood lymphocytes are greater than or equivalent to those of il- mp~ja and the two ml{nas are expressed by different t lympocyte population: in particular, t cytotoxic lymphocytes express markedly higher levels of il- ~rna. in vivo, il- may thus be contributing, significantly to some of the activites previously ascribed to il- il- . recently, we cloned the human cdna encoding interleukin- (il- ). human il- is a non-glycosylated protein of aa with a molecular mass (mr) of kd and has biological activities on monocytes and b cells, il- , like il- , strongly enhanced the expression of class ii mhc antigens on monocytes and induced expression of cd (fc~rii). furthermore, il- , like il- and il~ , inhibited the production of pro-inflammatory cytokines il- , ]l- , tnfo~ and chemokines miplc~ and tl- by lps activated monocytes. both il- and il- enhanced the production of il-lra by monocytes. in contrast, il- lacked the t cell stimulating activities of il- . the responses of monocytes to il- and il- were not additive or synergistic, supporting the hypothesis that il- and il- receptors are complex and share a common component which is important for signal transduction, taken together, these data indicate that il- , il~ and il- have important anti-inflammatory activities on human monocytes. in addition, these results indicate that il- is unique in that it can modify inflammatory reactions without stimulating (as does il- ) or inhibiting (as does il- ) t cell responses. transforming growth factor beta i (tgf-fll) belongs to a family of proteins that have potent immunoregulatory properties ranging ftom effects on the growth and dfflerentiafion of primitive stem cells to the differentiated functions of immune system effector cells. tgf-i~i is synthesized as a large secretory precursor polypeptide of amino acids that is inactive until processed to a disulfide linked homodimeric molecule of t amino acids each. recently it has been found that tgf-[~i can have autocrine as well as paracrine effects on the immune system indicating that immune cells can activate the inactive secreted form of tgi~-~i. in addition, tgf-i~i has differential intraceuular effects on cell surface receptor modulation, tyrosine phosphorylation and cytokine gene transcription as well as cell mediated cytotoxicity. the systemic administration of tgf- has proven beneficial in a variety of animal models such as septic shock, allograft rejection and experimental forms of autoimmunity including collagen induced arthritis and experimental autoimmune encephalomyelitis. moreover the increased levels of tgf-ill and other tgf- isoforms found in several disease states associated with immunosuppression such as different forms of malignancy, chronic degenerative diseases and aids implicate the involvement of tgt~-i~ in the pathogenesis of some diseases. hopefully, well designed clinical trials will define the potential roles of the tgf-[ family of proteins in the treatment of diseases of man. patient development of systemic inflammatory response syndrome (sis) after severe trauma is accompanied by a wide range of immune aberrations and altered cytokine production. in particular, t lymphocyte proliferation and ifn, t production is suppressed while monocyte (mo) tnfc~, il- , pge and tgf~ production is massively increased concomitant to decreased antigen presenting capacity. recently, two new cytokines, il- and il- , have been characterized as critical in regulation of mo tnfa and il- , as well as in induction of t lymphocyte proliferation and ifn production. in this study, peripheral blood leukocytes (pbl) from severe trauma patients (injury severity score > ) were analyzed for their il- levels, their in vitro proliferation to mitogen (pha) and their response after il- addition. since il- produced either by mo or by t lymphocytes can depress m~ antigen presenting capacity, inhibit t cell ifn,/production and directly diminish t cell proliferation, it might be suggested that immunosuppressed patients' mo and/or t lymphocytes would have increased il- levels. increased patient il- production might also be resulting from the high levels of tnfa a known stimulator of il- . conversely, since il- augments mo antigenpresenting capacity, thl induction and proliferation, post-trauma leukocytes might be il- deficient. pbl of trauma patients were compared to normals' pbl, either unstimulated or ptta induced, and their levels of il- found to be dramatically and significantly reduced. patients' isolated m~, either stimulated with the bacterial cell wall analogue, mdp, or unstimulated, also had depressed il- production concomitant to elevated tnfa production when compared to normals' mo. mechanisms for the depressed patients' mo il- were explored. increases in tgf[ may have partially contributed to the patients' depressed il- level, but elevated pge had no effect. addition of il- to patients' pbl significantly increased their mitogen responses. these data imply that sis is characterized by disruption in the interactions between mci and t lymphocytes so that patients' m~i produce excesses of some mediators (tnfa, il- , pge ) and a dearth of other monokines (il- , il-io). t lymphocytes are not activated and, therefore, unable to function in both immune defense and monocyte regulation. it is known that lge receptor-mediated or ca-ionophore-induced activation of mouse bone marrow-derived mast cells ( mmc) may result in the production of different cytokines including the interleukins (il) , , , and as well as gm-csf and tnf-a. in the present study we analyzed the effects of exogeneously applied pro-inflammatory cytokines (il- , l- , tnf-c as well as various mast cell growth factors (il- , il- , il- , il- , ngf, kl (kit ligand)) on cytokine production in primary mouse bmmc using a standard activation protocol (lxl bmmc/ml; ll.um ionomycin; - h). the actixdties of bmmc supernatants were assessed in specific biological (il- , il- il- , l- ) and/or elisa assays (il- , il- ). here we show that homogeneous populations of bmmc (> %alcian blue+/safranln-; in vitro age: weeks) generated in the presence of recombinant (r) rail- from normal balb/c mice produced modest amounts of l- and low or undetectable levels of il- , - , and - after induction with lp.m ionomycin only. however, a dramatic increase ( -to -fold) of these cytokine activities was noted, when in addition to ionomycin also human ( ) rll-la was provided during the induction period. this il- effect was dose dependent with a maximgm at - u/ml hrll-la and specific, as pre-incubation (lh) of bmmc with ng/ml hrll- receptor antagonist abolished the action of u/ml hrll-lcc similar effects were noted with hrll-lg or rurll-lb (lng/ml, respectively), but not with rhll- or rmtnf-~. both mrll- and hrll- substantially enhanced ionomycin-induced l- production of bmmc in the absence or presence of il- . il- significantly enhanced il- and il- production while decreasing il- activities to abont - % of control levels, when il-i was provided in the presence of il-l/ionomycin. a monoclonal anti-nfil-t antibody (ascites : ) abrogated the effects of mrll- . other mast cell-active cy~okines (] ,- , il- , l- , ngf, or kl) added to ionomycia-or l- /ionomycin-treated bmmc had no major effects on cytokine production. il- and il-i did not induce significant cytokine release in the absence of ionomycin suggesting tlmt cadependent signalling was required. at doses of " m, dexamethasone, corticosterone, or hydrocortisone almost completely abolished ionomycin/il- /ll- induced cytokine production. the inducer cocktails per se did not interfere with the cytokine bio-assays. in case of il- inducibility of this cytokine in bmmc was confirmed at the mrna level by northern blot analysis. hence our data show that activated mast cells are a source of il- previously recognized as a product of th type lymphocytes only. moreover, our study reveals novel functional roles for i-l-i, il- , and ghicecorticoids in the regulation of cytoldne production in mast ceils. accumulating data suggests that cytokines, peptides involved in regulation of both physiological and pathological immunological responses, predominantly are produced at the local site of antigen stimulation. a new method was used to detect cytokine-producing cells in haman tissue at the protein level. single-cell production of different httman cytokines, ilia, ill [ , illra, il , il , il , il , il , ils, ill , gm-csf, tnfa, ifn and tgf[ . , was identified by indirect immunohistochemical staining procedures and use of carefully selected cytokine-specific mab's. frozen sections were fixed with % paraformaldehyde and permeabilized by . % saponin treatment, eluting cholesterol from the membranes. the intracellular presence of all cytokines except ill, illra (late) and tfg[ _ , could be demonstrated by a characteristic perinuclear configuration in producer cells. in addition, the immunoreactivity extended over a large extracellular area encompassing the producer cell. a localization of the cytokine to the golgi-organelle was established by use of two culour staining including a haman golgi complex specific mab. this staining pattern was only evident in producer cells because injection of recombinant human cytgkines into the tissue caused a membraneous and extracellular staining pattern. both the extra-and the intracellular types of staining reaction could, however, be blocked by preincubating the cytokine specific mab with pure human interleukins. oxygen radicals (or) directly induce lipid peroxidation, indirectly they trigger adhesion and activation of pmn leukocytes. we investigated whether or also lead to a release of acute-phase response cytokins such as tnf-alpha, il-i beta or il- in whole blood cultures to maintain the induced inflammatory reaction. methods: blood samples from healthy volunteers (n= ) were incubated at °c. or were produced by the xanthine oxidase (xo)/ hypoxanthine (hx) system. after , , , , and minutes plasma levels of tnf-alpha, il-i beta and il- were determined with elisa kits. results: under the influence of or tnf-alpha plasma levels increased from , pg/ml at min to pg/ml, pg/ml, pg/ml after , and min. il-ibeta ( , pg/ml, , pg/ml, , pg/ml, pg/ml and pg/ml after , , , and min) and il- ( , pg/ml, l,lpg/ml, , pg/ml, pg/ml and , pg/ml after , , , and min) plasma levels were increased min later than tnf-alpha. summary: these data suggest that or do not only play an important role in initial accumulation and activation of pmn leukocytes but also lead to a stimulation of monocytes to produce the acute phase reaction cytokins tnf-alpha, il-i beta and il- to maintain and strengthen the inflammatory reaction. department of general surgery, steinhsvelstr. , ulm, germany jan k. horn md, greg a. hamon md, robert h. mulloy md, greg chen bs, rebecca chow bs, and christof birkenmaier md. transforming growth factor-i~l (tgf- ) is released from inflammatory ceils following injury and in sepsis. in vitro experiments have confirmed that low concentrations of tgf- ( . - . ng/ml) are chemoattractive for monocytes, whereas higher levels of tgf- (> . ng/ml) potentiate production of the immunedepressive prostaglandin e . other investigators have shown that tgf-] can cause the appearance of cd (fc immunoglobulin receptor) on monocytes exposed to ng/ml of tgf-[~i for hours. monocytes also express on their surface a glycoprotein that binds complexes of lipopolysaceharide (lps) and lpsbinding protein (lbp). such binding is associated with generation of proinflammatory cytokines such as tumor necrosis factor alpha. we have shown that cd is depressed in septic patients and therefore we hypothesized that tgf- could account for the down-regulation of cd observed in these individuals. we incubated normal human monocytes with platelet-derived tgf-[ for and hours at °c and examined ceils for cd and cd expression using flow cytometry after immunnfluoreseent staining with appropriate monoclonal antibodies. monocytes were selected on the by usual criteria for size and granularity. non-viable ceils were excluded with the use of propidium iodide. two populations of monocytes could be found afcer incubation at °c alone. one displaying high density of cd had increased fluorescence over the homogeneous expression of cd in cells maintained at °c (baseline). the other population displayed decreased cd expression relative to the baseline cells. tgf-i~i ( - ng/ml) caused a shift of ceils from the high density into the low density cd population. this trend was observed within hours of incubation and was complete by hours. we observed a net decrease in cd expression f % for all subjects studied (p< . vs controls). phorbol myristate acetate ( ng/ml) also caused down-regulation of cd to a similar degree as tfg-i~i. we also confirmed that monocytes could be induced to express cd after incubation with tgf- ( ng/ml) for hours. these studies demonstrate that monocytes incubated with immunodepressive levels of regulation of cd by tgf- deplete their surface expression of cd while generating cd . this down-regulation of cd by tgf- correlates with our clinical observations of lower cd expression on monocytes obtained from septic patients. for over years, activated t lymphocytes have been considered to be the cellular source of mif. we recently isolated and cloned the murine homolog of mif after identifying the specific secretion of this protein by lpsstimulated pituitary cells in vitro and in vivo. however, further experiments showed that mif protein is detectable both in t-cell deficient (nude) and hypophyseetomized mice, suggesting that yet additional cell types may produce mif in vivo. since monocytes/macrophages are a major source of the cytokines that appear in response to lps administration, we examined the possibility that mif also is expressed in cells of the monocyte/macrophage lineage. we found that mif is expressed constitutively in the murine macrophage-line raw . and in thioglycollate-elicited peritoneal macrophages. significant amounts of mif mrna (rt-pcr) and protein (western blotting) were observed in cell lysates. in raw . cells, mif secretion was induced by as little as pg/ml of lps (e.coli l:b ), peaked at ng/ml, but was not detectable at lps concentrations > txg/ml. similar data were obtained with elicited macrophages, but higher lps concentrations were required, unless the cells had been preincubated with ifn . production of mif by lps-stimulated (l ng/ml) macrophages peaked at hr. expression ofmif mrna and tnf mrna by lps-stimulated raw . macrophages was investigated by rt-pcr. as expected tnf mrna expression increased over the range of lps concentrations ( pg/ml to p_g/ml). in contrast, levels of mif mrna correlated inversely with lps concentration. by competitive pcr, mif mrna was observed to increase approximately -fold after lps induction ( pg/ml). mif secretion also was induced by tnfoc ( ng/ml) and ifn? ( iu/ml), but not by il- and il- (up to ng/ml). lps and ifn had additive effects in inducing mif secretion. in separate experiments, macrophages stimulated with recombinant mouse mif ( gg/ml) were found to secrete bioactive tnf~ (> pg/ml by l cytotoxicity). we conclude that the macrophage is an important albeit overlooked cellular source of mif in vivo. mif secretion is induced by lps, tnfc~ and ifn?. mif also stimulates macrophages to secrete tnf. taken together with previous observations that anti-mif antibody protects against lethal endotoxemia, these data implicate mif as a critical mediator of inflammation and septic shock. inflammation is characterized by an exacerbation of proinflammatory cytokine production. cytokines such as il- , il- , and tgf , have been identified as anti-inflammatory mediators thanks to their ability to down regulate the production of il- , il- , il- , tnfc~ by activated monocytes / macrophages. however, other cells, including polymorphonuclear cells (pmn) do contribute to the release of pro-inflammatory cytokines. we investigated the capacity of the so-called anti-inflammatory cytokines to control the release of il- by activated neutrophils. human pmn were purified following glucose-dextran sedimentation and ficoli-hypaque centrifugation. the cells were cultured at °c for h in the absence or presence of lipopolysaccharide (lps) or tnfa. il- release was measured in the supernatants using a specific elisa. among tested cytokines, il- was the most efficient inhibitor of il- production by lps-activated pmn. il- was also active, whereas no down regulation was noticed with tgfp~i. when tnfa was used as a triggering agent, none of the cytokine could prevent il- production. northern analysis are under investigation to precise the level of the il- -and il- -induced inhibition of il- production by pmn. our data illustrate that il- and il- possess the capacity to down regulate the production of il- by both monocytes and pmn, whereas tgfb has a more limited inhibitory activity. ciliary neurotrophic factor (cntf), a member of the il- superfamily, has recently been shown to promote axonal growth and neuronal healing. cntf production is also increased during neuronal and muscle damage, associated with soft tissue injury or trauma. we postulated that production of cntf may explain the loss of skeletal muscm protein that occurs in inflammation. female, wistar ( - gm) rats received either or pg/kg bw s.c. injections of recombinant rat cntf for seven days, or received sham injections and were freely-fed. additional animals were pretreated with mg/kg ibuprofen lp prior to pg/kg bw cntf. rats treated with ,ug/kg bw cntf lost . _+ . gms bw as compared to freely-fed controls which gained . _+ . gms (p<o. by anova and lsd), and ibuprofen treatment had no effect on cntf-induced weight loss (- . _+ . ). animals pair fed to the high dose cntf gained body weight ( . -+ . ), although weight gain was less than seen in freely-fed controls. rats treated with pg/kg bw had reduced body weight gain (+ . +_ . gin). food intake was also reduced by % in pg/kg cntf (from . +_ . gm/day to . _+ . gm/day; p<o. ) and was also unaffected by prior ibuprofen treatment ( . +- . gm/day). despite the loss in body weight noted in the high dose cntf animals, there was no appreciable hepatic acute phase response, since liver weight ( . + , gms vs. . _+ . gins), total protein ( . +- . gms/l vs . +- . gins/l) and albumin ( . + . gms/l vs. . +_ . gms/l) were not different between cntf and freely fed animals. we conclude that cntf causes anorexia, and increases body weight loss in excess of the associated anorexia. unlike the cachexia associated with il- and tnf infusions, which is associated with an acute phase response, cntf acts predominantly on food intake and carcass weight through a prostaglandin-independent mechanism and has only minimal acute phase inducing properties, n. joseph espat, md. university of florida, department of surgery, j-box , gainesville, fl. . of cytokines by neurotrophic factors, the neuroendocrine system and phenotiazines. cytokines, including tnf and il- , have a pathogenetic role in various diseases related to infection and inflammation. the action and/or production of cytokines can be regulated by drugs or endogenous mechanisms that involve the cetral nervous system (cns) we found that the antipsychotic chlorpromazine (cpz) potently inhibits tnf production and protects mice against endotoxic shock. cpz also inhibits brain tnf production in mice intracerebrally injected with endotoxin, whereas cpz analogs that do not cross the blood-brain barrier inhibit only perypheral, not brain, tnf. tnf production and susceptibility to the toxicity of endotoxin, tnf and il- are increased in adrenalectomized mice, indicating that endogenous corticosterone (cs) controls cytokine production and toxicity, in a feedback fashion since endotoxin and cytokines increase serum cs. increased tnf production was also observed in mice where the hypothalamus-pituitary-adrenal axis was blocked by chronic administration of dexamethasone, following a two-day washout. administration of cytokines acting through the gp signal transd,uction protein, including il- and ciliary neurotrophic factor, cntf potentiated il-l-induced elevation of cs. il- and cntf also induced hepatic acute-phase proteins. thus il- and cntf might have antiinflammatory activity, by potentiating the feedback responses of the neuroendocrine axis. these data indicate how complex can be the interregulatory relationships between the brain and the immune system, how they can be used to pharmacomodulate cytokine action and how their disregulation might exacerbate il- -and tnf-mediated pathologies. lipopolysaccharide (lps) constitutes a well established activator of monocytes/ macrophages (mizi) and murine b lymphocytes. the hydrophobic part of lps, termed lipid a, represents the endotoxic principle of lps. we now demonstrate that lps is also capable of inducing proliferation of human t cells at a dose of to pg/ml. the specificity of this stimulation was analysed by the following experiments: i) the synthetic hexaacyl escherichia coiltype lipid a (compound ) also stimulated human t cells; ii) the synthetic tetraacyl lipid a precursor (compound ) or the phosphono-oxyethyl analogue pe- , structures known to antagonize lps-induced monokine production in human mz, also inhibited lpsinduced t-cell proliferation. the t-cell proliferation expressed the following features: i) cd ÷-as welt as cd ÷ t cells proliferate in response to lps, ii) limiting dilution analyses reveal that the frequency of responding cells was between / to / cells; iii) purified t cells alone cannot be stimulated by lps, but need the help of monocytes. this help cannot be replaced by b cells or fixed monocytes. furthermore, for activation a direct cell-to-cell contact between t cells and monocyte is neccessary; iv) t cells stimulated with lps express mrna for il- and ifnf, but not for il- or il- (determined by pcr). in supernatants, ifnf was detectable (elisa); v) lps-activated cd ÷ as well as cd + t cells express cd , the high affinity il- receptor. our results indicate that in contrast to previous reports human t cells respond to lps with il- receptor expression, lymphokine production, and proliferation. the reactive cells appear to belong to the t, cell type, the finding that human t cells can be activated by lps is of important relevance for the understanding of the pathomechanisms of infections by gramnegative bacteria. this may lead to new strategies for the therapy of sepsis. we have recently shown that human eosinophils produce mrna for interleukin (il)- when stimulated with calcium ionophore (eur. j. immunol. ( ), ). we now present evidence that human eosinophils contain preformed il- protein although they do not express mrna for il- as measured by rt-pcr. il- protein expression was determined using specific anti-human il- monoclonal antibodies by western blotting, facs analysis and immunohistochemistry. moreover, preformed il- was re/eased into supernatant by % pure eosinophils after priming with gm-csf or il- and subsequent -min stimulation with paf, rantes, ionomycin or pma, however not with il- or il- , as measured by elisa. this observation implies that activation of protein kinase c and/or intracellular calcium mobilization are necessary events for il- release in human eosinophils. the determined amounts of preformed il- protein was higher in patients with asthma compared to normal individuals suggesting a role for eosinonhi! derived il- in asthma. since the eosinopnit is the ,,r~:=z~mmant cell in the asthmatic airways, we determined il- concentrations in bronchoaiveolar lavage (bal. ~ids from normal !i~.~ijvtduals and asthmatic patients. indeed, il- concentrations in bals from both groups were similar to those seen in the supernatants released by activated eosinophils. the role for il- in asthma remains to be determined. based on a well established rat model named activity-induced ulceration (asu) or activity based anorexia (aba), we have developed a rat model for chronic stress. male rats were exposed to a feeding schedule in order to reduce body weight by - % within days. while one group of rats was kept sedentary, the other had access to a running wheel. food restricted rats allowed to exercise developed highly increased activity as compared to ad libitum fed rats in wheels (ca. versus kin/day). they developed elevated plasma corticosterone levels ( _+ gg/dl) at their circadian peak, increased adrenal weight and decreased thymus and spleen weight as compared to control rats and weight matched sedentary rats, establishing this paradigm as a model of chronic stress. no differences in plasma acth were seen among the various groups, suggesting increased sensitivity of the adrenal glands to acth. the effect of chronic stress accompanied by hypercorticism on baseline and endotoxin-induced cytokine levels was studied in this model. under baseline conditions,splenic il- a was suppressed in both food-restricted groups. this was more pronounced in rats with access to a running wheel. il- and tnf activity in plasma was not affected. after administration of .tg/kg lipopolysaccharide (lps), tnf activity in plasma was suppressed by food restriction but there were no differences between sedentary or exercising rats. in addition, no differences were found among groups for corticosterone, spleen il-lc~ and plasma il- activity. we conclude, that the food restriction-induced hyperactive rat model is a useful model for studies on the effects of chronic stress. in this model, under basal conditions il-le~ in tissues may be subject to downregulation by glucocorticoids, whereas after lps-stimulation of cytokine production only tnf activity is regulated by fast acting feedback loop between cytokines and the hypothalamo-pituitary-adrenal axis (hpa-axis). this is supported by strong correlations between plasma tnf activity and corticosterone in stressed rats. cytokine antagonists modulate cytokine actions and it appears that a balance between production of cytokines and cytokine antagonists is important to control of host responses. recent observations show that during myocardial infarction there is an increase in circulating cytokines such as tumor necrosis factor (tnf) and interleukin (il- ). we tested the idea that compensatory increases in cytokine antagonists likewise occur and investigated changes in plasma concentrations of tnf and interleukin i (il- ) and those of their specific antagonists interleukin- receptor antagonist (il- ra) and soluble tumor necrosis factor receptor type i (s tnf r-i). we also measured plasma concentrations of ~-melanocyte-stimulating hormone (~-msh), an endogenous neuropeptide that occurs in pituitary, brain, skin, gut and other tissues. when administered to laboratory animals, this peptide has potent antiinflammatory and antipyretic activity, perhaps by mimicking an endogenous modulatory influence on cytokine actions. samples were obtained from patients with acute myocardial infarction at presentation in the coronary unit, every three hours for hours, and daily thereafter until discharge. we found elevations in the plasma cytokines il- and tnf only in a proportion of subjects whereas cytokine antagonists c~-msh, il-lra, and stnfr were elevated in all patients, o~-msh was elevated at presentation but it decreased progressively in successive tests, reaching normal values within hr whereas stnfr and l-lra peaked at - hr or later. there were significant correlations between plasma concentrations of cytokine antagonists and enzymes released from injured myocardium, including creatine kinase (ck), aspartate serum transferase (ast), and lactate dehydrogenase (ldh). the data show that cytokine antagonists increase in the circulation of patients with acute myocardial infarction likely to modulate prninflammatory effects of cytokines. objects of the study: interleukin- (il- ) is a multifunctionai cytokine known to be involved in important homeostatic processes. il- levels are increased in many pathological situations, and correlates with disease activity and patient outcome. to exert its effect il- binds to its receptor on the membrane of its target cell. this receptor is also present in a soluble form in plasma and in urine. in this study we quantitatively measured the availability of soluble il- receptor (sll- r) in biological fluids in healthy volunteers. materials and methods: blood, urine, cerebrospinal fluid (csf), and synovial fluid (sf) are obtained from healthy volunteers, sil- r and il- are measured using elisa's. both elisa's are tested for interference of sil- r mid il- . the effect of sll- r in the il- bio-assay (b ) is tested. results: baseline levels are (mean + sd): . -+ . ng/ml in serum, . -+ . ng/ml in urine, . _+ . ng/ml in csf and . + . ng/ml in sf. there is no interference of sll- r in the il- elisa or bio-assay and no interference of l- in the sil- r elisa. conclusions: in all investigated biological fluids sll- r can be found. these data provide baseline values for investigations concerning pathological situations. both elisa's described are useful tools to do these investigations. trauma-associated immune aberrations coincide with augmented release of immunoregulatory and proinflammatory cytokines. the present study examines the effect of thermal trauma on the capacity for specific (receptormediated) response of lymphoid cells to interleukin (il ) and to turnout necrosis factor ~x (tnfc . methods. bum patients (n= , -> % total body surface area) were studied weekly up to days post-injury. the limulus amoebocyte lysate (lal) test was used to measure plasma endotoxin levels. the percentage of il ~-and tnfcz-binding t(cd ) lymphocytes was assessed by flow cytometry analysis. levels of il receptor antagonist (il lra) in patients' plasma and cultures of peripheral blood ceils (pbc) were determined by immunoassay. results. plasma endotoxin concentrations were significantly (p< . ) increased up to weeks post-bum (means . + in non-surviving and . + . u/ml in surviving patients vs < u/ml in the control). within weeks of bum, the percentage oft ceils expressing receptors for tnfa and il [~ constitutively was elevated (by - fold). in contrast, the capacity for de novo receptor expression by activated pbc was reduced. serum levels of il ira were significantly increased (range . - x j pg/ml vs < . x j pg/ml in the control). in all patients, high concentrations of il lm were released spontaneously in unstimulated cultures of adherent ceils (range - x - pg/ml vs - x j pg/ml in the control). however, its secretion was decreased in lps-stimulated parallel preparations. conclusions. in the bum patient, susceptibility to the immunoregulatory effect of tnfcz and tl ~ may be modulated by infection-related products. alterations in the capacity for receptor expression and secretion of l lra may affect il -regulated biological responses including specific immune reactions. while studies suggest that il- is an important lymphokine involved in cell-mediated immunity, little is known about this mediator's role in hem-induced immunesuppression. our aims, therefore, were to determine: i) if il- contributes to depressed t-cell responses seen following hem; and ) how other agents, known to play a role in hem, effect il- release. to study this, c h/hen mice were bled to and maintained at a map of mmhg for h and then adequately resuscitated. mice were killed h post-hem to obtain splenic t-cells (nylon-wool purified). il- 's immunosuppressant role was demonstrated by the ability of monoclenal antibody (mab) to il- to markedly improve the t-cell proliferative response [ . #g the marked increase in capacity of t-cells from hem mice to produce il- was significantly reduced by treatment with either ibu or mabs. since ibu, tgf-~, as well as il- are all reported to directly/indirectly influence prostanoid synthesis, this implies that eicosanoids play a major role in inducing il- release by t-cells following hem which depresses t-cell function. the mechanisms underlying immunosuppression induced by thermal injury and alcohol ingestion are in part due to cytokine dysregulatinn. il- down-regulates production of eytokines by maerophages and may be an important regulator of the initiation of the immune response. il- has also been demonstrated to inhibit the production of no by macrophages. this study examined the alterations in eytokine production and effect of inhibition of no production on immunologic function in a routine thermal injury model. methods: balb/c mice (n= ) were randomized to groups: saline-sham(ns-sham), alcohol-sham(etoh-sham), ns-bum, etoh-bum. animals received % etoh or ns daily for days by gavage. a % full thickness bum was induced hrs after the last dose of etoh or ns. animals were resuscitated, then sacrificed days post bum. splenic lymphocytes were cultured for days with lps, and lps with two concentrations of n-monomethyl-l-arginine, a nitric oxide inhibitor (l-nmma . ug/ml, ug/ml). splenocyte production of il- , interferon-gamma, il- , pge were measured, and lymphocyte proliferative response examined. results: il- production was significantly suppressed in thermal injury. exogenous l-nmma normalized the suppression of .- in a dose-dependent manner, indicating nitric oxide may modulate il- and interferon-gamma production in thermal injury. il- production is normal in etoh-burn animals. conclusion: il- and interferon-gamma production is altered in this murine thermal injury model, and may contribute to this injury-induced immunosuppression. inhibition of no synthesis normalizes il- production and should be investigated further as an immanomodalator in thermal injury. surgery, infection and inflammation results in the production of pro-inflammatory cytokines which mediate metabolic and immunologic host responses. the aim of this study was to characterise the elaboration of cytokine release following a variety of surgical procedures. twenty one patients undergoing elective intermediate, hip, knee and major gastrointestinal surgery were studied. levels of interleukin- (i - ), interleukin- (i - ), the interleukin- receptor antagonist (i - ra) and the acute phase c-reactive protein (crp) were measured in bloods drawn , , , , , , and hours following operation. a portion of the results are shown (mean -+ sem). + -+ _+ one and two factor anova; *p< . , #p< . , §p< . , ¶p< . , for differences between groups i - was not detected at any time point. both ii-ira and i - increased after surgery. maximum responses occurred following major git and hip surgery, minimal responses were seen after intermediate and knee surgery. ii-ira levels increased within two hours and remained elevated for hours; the b-ira increase was a thousand fold greater than the rise in i - levels. i - levels increased up to hours after surgery. crp levels reflected maximum ii-ira and i - levels (r =. , p< . and r =. , p< . respectively). high ii- ra and i - levels reflect major surgery, however the ii-ira response is more rapid and of greater magnitude. the strong i - ra correlation with crp may indicate that this regulatory cytokine is itself a mediator of host responses to surgery. dept. of surgery, meath/adelaide hospitals, heytesbury st., dublin , ireland. change of il- and soluble il- receptor levels after surgery s. hisano, k. sakamoto, s. mita, t. ishiko, m. ogawa [objectives] under surgical stress, il- plays a main role in producing acute phase proteins and contributes to host defense mechanism. soluble il- receptor (sll- r) is considered to be agonistic to il- , unlike other soluble type receptors of cytokines. here we measured il- and sll- r levels in the serum and drain fluid from surgical field in order to investigate the changes of il- and sll- r after surgery and their origins. [materials and methods] serum and drain fluid samples from cases ( of esophagectomy and of gastrectomy ) were serially collected before and after surgery. il- and sll- r levels were measured by elisa. [results] ( ) serum il- : all cases reached the maximum level on pod-l, more precisely - hours after operation. ( ) il- in the drain : maximal il- levels in the drain were recognized - hours after operation, at almost the same time as serum il- . furthermore the il- values in the drain were much higher, about times, than those in serum. ( ) sll- r in the serum : all cases reached minimum levels - hours after operation and recovered to the preoperative levels a few days later (decrease ratio : . + . ~,, range : - ~'). ( ) sll- r in the drain : sll- r levels in the drain showed almost the same value and change as serum sll- r. [conclusions] ( ) il- is produced from the cells gathering around operative fields whereas sll- r is considered to be produced in the cells which do not gather around the operative fields. ( ) there may be a mechanism that down-regulates sll- r in the early stage of surgery. [objectives] il- plays an important role in host defense in the early stage after surgery. in the present study, we examined changes in il- concentration after major thoracoabdominal surgery and elucidated the effect of surgical trauma and factors influencing postoperative elevation of serum il- . [materials and methods] thirty-eight patients undergoing elective surgery of the thoracoabdomen were classified into groups according to the location of the operation. bloods and drain fluids were serially obtained and samples were frozen until measured, keukocytes were simultaneously collected for northern blot analysis. concentration of il- was measured by elisa and il- mrna was detected by northern blotting after total rna was extracted by the acid guanidium phenol chloroform method. [results] ( ) serum il- levels reached the maximum concentration on the st postoperative day in all patients. ( ) the il- peak was significantly correlated with surgical trauma as defined by the operation length and the volume of blood loss during operation (r= . , p< . , r= . , p< . , respectively). ( ) the peak concentration of serum il- in patients undergoing esophagectomy was significantly higher than in those undergoing pancreaticoduodenectomy (p< . ), despite a similar degree of surgical trauma. ( ) peak l- concentration observed in a patient who underwent esophagectomy was about fold greater in the drain fluid of thorax than in the peripheral blood. ( ) il- mrna was demonstrated in leukocytes from thoracic and abdominal exudate at , and hours after surgery. in contrast, il- mrna could not be detected in leukocytes from the peripheral blood. [conclusion] il- is mainly produced in the operative field and subsequently enter the peripheral blood to induce cytokinemia. the operation length, volume of blood loss and thoracotomy are factors influencing the concentration of cytokine in the blood. zaragoza spain age may be an important factor influencing the function of immunocompeteut cells releasing cytokines after both accidental and surgical trauma the aim of the present paper is to ascertain if patients (pts) over years old show a different serum level cytokine pattern than pts under after a standard surgical procedure considered as a "medium strength trauma". patients and methods: pts( females males)with gallstone disease were perspectively studied, pts were allotted in two groups: gr.a: pts under years(mean age: . +- )gr.b: pts over years(mean age: . _+ ). all pts underwent cholecystectomy and cholangiography. pts in gr.a and pts in gr. b underwent common duct exploration. spbintercctomy was performed in each group. on the day of surgery (pre) and on the st and th postoperative day(leo, po) : percentages of cd , cd , cd , cd and cd cells we measured by means of flow cytometry using moab. and levels of il- , il- , il- and tnf "in vivo" by elisa using moab. results: ere: cd % was . _+ in gr.a and . objectives of the study. after surgery for esophageal cancer multiple organ damage has been reported to be caused by polymorphonuclear leukocyte (pmn)-mediated injury. we measured serum granulocyte colony-stimulating factor (g-csf) and interleukin (il- ) levels to determine a role of g-csf and il- in pmn function after surgery for esophageal cancer. materials and methods. peripheral pmn counts, peripheral pmn chemiluminescence, serum g-csf levels, and serum il- levels were measured before and after surgery in patients with esophageal cancer (ec), and patients of gastric cancer (gc). esophagectomy with thoracotomy and laparotomy were performed for patients with ec, while subtotal gastrectomy with laparotomy were performed for patients with gc. results. peripheral pmn counts (p< . ) and peripheral pmn chemiluminescence (p< . ) of patients with ec were significantly decreased compared to those of patients with gc at and hours after surgery. serum g-csf levels of patients with ec were significantly (p< . ) increased compared to those of patients with gc at and hours after surgery. serum il- levels of patients with ec were significantly (p< . ) increased compared to those of patients with gc at , and hours after surgery. significant inverse correlations (p< . l) between peripheral pmn count and serum g-csf and il- levels were seen at hours after surgery. conclusion. these results suggest that many circulating pmns, which are excessively activated by g-csf and il- , may adhere to the endotherial cells and then migrate into the tissues, and cause multiple organ damage after surgery for esophageal cancer. immunnogical changes in patients with severe brain trauma receive increasing attention since morbidity and mortality ere still high. interleukin- (il- ) was previously detected in the cerebrospinal fluid (csf) during different pathologies of the nervous system ( , , ). in our study we monitored il- and nerve growth factor (ngf) production in the csf after human brain trauma. since astrocytes within the brain constitute one of the major cell type contributing to the inflammatory response through the release of cytokines and other factors after injury, we investigated the functional relationship of il- and ngf on a single cell niveau using cultured astrocytes. methods csf was obtained from patients with severe brain injury (glasgow coma score (gcs) < and ct abnormatities or gcs < over hours) after implantation of intraventricular icp monitoring device for therapeutic purpose and collected over hours csf and serum. il- and ngf were assayed by elisa. astrocytes were isolated from neonatal mouse brain as described ( ) . ngf production by cultured astrocytes was measured by elisa in the presence of csf, il- and il- antibody. astrocyte migration was tested in a chemstaxis chamber. results head trauma patients were included in this study (approved by the university hospital medical ethics board) and the csf was obtained through intraventricular catheters. high levels of il- were detected in the csf of these patients when compared to serum during the first days after brain trauma. furthermore ngf could be found inside the intracerebral compartment. csf containing high levels of il- could stimulate ngf production in cultured astrocytes. this effect could be [nhibited partially by il- antibodies, purified il- exposed to cultured astrocytes in vitro, stimulated the migratory activity of these cells in a dose response fashion. il- was found in the csf of brain injured patients, suggesting a role for this cytokine in the pathophysiology of brain injury. since astrocytes are involved in maintaining the homeostasis of the brain, we further investigated the possible role o il- on astrocyte functions, il- promoted ngf production in vivo and in vitro, thus contributing to neuronal cell survival and regeneration. furthermore il- stimulated astrocyte migration in a dose response fashion, potentially contributing to astrocytosis following brain injury and inflammation, these results show that il- represents a key cytokine in traumatic human brain injury with possible systemic effects, which are at preserlt under investigation. we studied a) the role of tnf and b) the therapeutic effect of a mab to tnf with regard to haemorrhagic shock (hs) related ,pathophysiologic alterations and mortality in rats. method: a prolonged hs was induced by bleeding to a blood pressure of - mmhg for pin followed by reinfusion of shed blood (sb) and resuscitation with two times of sb volume of ringer's lactate over rain. animals received a bolus dose ( mg/kg) of tnf mab (celltech, berkshire, uk) at min after resuscitation (tn ). the control group (n = ) was treated similar to the tn group but received ringer's lactate (con). results: at min the prolonged hs resulted in a metabolic acidosis indicated by a significant decrease of blood ph ( . + . ), hco -( . ___ . mm), and base excess (- . + . ram) values with pco ( . + . mmhg) and po ( . + . mmhg) in the tn with no difference to the con group. immediately after resuscitation ( min) plasma endotoxin levels were found to be increased in both groups ( . + . in tn vs . _ . pg/ml in con group) . prior to the treatment with tnf mab ( min) there was also no difference between plasma tnf levels of the two groups ( . + . in tn vs + . pg/ml in con group). treatment with the tnf mab at rain post-hs improved the hour survival rate to . % as compared to . % in the control group. macropathologic evaluations revealed frequency of intestinal bleeding in oniy animals in the tn vs in the con group. no bleeding in the kidneys was found in the tn but in rats in the con group. the significant increase in lung wet weight observed in non-survivors in the con (n = ) was prevented in animals which died in the tn (n = ) group (( . +_ . vs . +_ . g/kg). conclusion: our data suggest that tnf formation induced by hs in rats is an important mediator for pathophysiologic alterations leading to multi organ failure and lethality. antibodies to tnf might be a useful agent in the treatment of haemorrhagic shock related disorders. -+ n=ll*$ -+ n= _+ n= * * p< . vs baseline :~p< . no anesthesia vs anesthesia thus ) tnf production increased - fold by - hrs following trauma in unstimulated blood, but was reduced or not changed after lps stimulation, so circulating leukocytes are probably not an important source of tnf post trauma; ) anticd had no obvious effect on tnf production in unstimulated or lps stimulated blood, relative to vehicle, which suggests that the protective mechanism of anticd does not involve tnf suppression; ) fentanyl anesthesia at hrs following trauma unexpectedly decreased lps-evoked tnf production, which suggests that anesthesia alone can influence an inflammatory response. proinflamrnato~ cytokines have been shown to play a signific~t role in the pathogenesis of sepsis, which is a very common occurrence in born injury. tnfa is infrequently detected in the blood of burned patients, the ability to detect the shed receptors of stnfg has not been determined. serial serum mmples from burn patients were collected from the time of admission until death from septic shock. these samples were analyzed using an enzyme-linked immunosorbent assay (elisa) for stnfr, l-ira, tnf-a, and il-ib. the patients ranged in age from to yeas of age. the percentages of bum ranged from % - %. cytokine concenlrntions vmled from patient to padent irrespective of bum size. tnfa levels were consistentiy in the range of pgjml - pg/ml. peaks in the tnfa values were above pg/ml and were also associated with a peak in the stnfr levels. these levels began at < , pghnl within the in,st ins of injury and gradually increased with time. clinically. ti~ appearance of eytoklnes was independent of positive wound, blood, or respiratory cultures however peak values in tnfa and stnfr were ~ialed with a fluid requirnmenl levels of il-i ra were also elevated independent of clinical findings as well as extent of injury. in pl there is a significant corresponding peak in il-trn (> ~ /ml) at the same time as t/~:a and stnfr levels. we aimed to characterise the pattern of secretion of interleukin- beta l-ii ), intefleukin- (il- ) and tumour necrosis factor alpha (tnfa) in multiply injured patients and to relate these results to their clinical condition and outcome. two hourly blood samples were taken from ten patients from the time of injury until hours. cytokine levels were measured using sandwich enzyme-linked immunosorbent assays (elisas). injury severity scores (iss) were calculated and haemorrhage was assessed from the blood transfusion requirement over the hours. patients' ages ranged from to years. iss varied from to and transfusion requirement from to units. five patients died after the study period. ] ,- was raised in / patients (max level , pg/ml) but was unrelated to condition or outcome. / showed a rise in il- b (max level pg/ml) which was negatively correlated to iss (i=- . , p< . ). tnfa was raised in / (max level pg/ml). peak tnfc~ was positively correlated with iss ( = . , p< . ) and haemorrhage (i= . but p< . ). il-ib and tnfa production was mutually exclusive. there was no common cytokine profile for these patients. unlike elective surgery there was no correlation between peak ,- and severity of injury: tissue damage may not be the stimulus for the cytokine response to multiple injury. periods of ischemia or hypoxia produce endothelial damage in peripheral organs. tumor necrosis factor-alpha (tnf) plays a central role for regulation of endothelial physiology during septic events, taking influence on vascular permeability and coagulant activity [ ] . animal experiments demonstrated a synergism between hypoxia and septic shock on letality, leading to the hypothesis that low oxygen tension leads to enhanced sensitivity of target cells for tnf [ ] . radioligand binding studies with ~ odid-tnf on cultured human endothelial cells were performed after incubation in several environmental oxygen tensions (pc ) for hours. data were achieved by nonlinear regression of an idealized saturation curve according to the equation: b = n " k./( + k,); b = totally bound tnf; k,: association constant (concentration for half-maximal binding); n: number of binding sites per cell. p_o o (mm h¢i): _k, (nm}: n (molecules/cell): - . ± . _+ - . ± . + - , ± . -+ - . + . -+ presented are calculated values on the idealized curve + % percentiles. hypoxia induces enhanced binding of tnf to specific receptors on the endothelial cell surface in a time-and dose-dependent manner by a mechanism, which is not dependent on oxygen radicals, as shown by additional protocols with radical-scavenging drugs. with respect to former findings about a correlation between growth and tnf receptor affinity [ ] , these data lead to the hypothesis that enhanced tnf binding during hypoxia is due to a biochemical conversion of the receptor protein from the low affinity to the high affinity state, possibly by posttranslational phosphorylation of the binding protein by intracel)ular kinases. the proposed involvement of tnf-dependent pathways in pathogenesis of organ dysfunction and multiple organ failure after hypoxia/ischemia may provide a basis for understanding the initiation of hypoxic vascular injury, as manifested by increased permeability and prothrombotic tendency, and, thus, merits further attention. the levels of activity of circulating cytokines (ill, il- and tnf-alpha) which are believed to play important regulatory role in response to trauma are determined (by hioassays and respective anti-cytokine antibodies) in mice and rats subjected to scald injury ion c, see, ° v bsa, ld ) and ( c, see, ~ b ~^)~ , respectively. biphasic increase of cytokine activity was noted in mice: initial increase of il-i and il- , - hr following injury and of try activity hr after scald, followed by elevated levels of il-i and il- at hr, with tendency of decrease of activity at later time points. increased activity of tnf was noted hr following injury, in rats, initial, short-lived increase of il-i and tnf activity was detected lhr following injury, folowed by increase on days i and postburn. il- increase peaked - hr after scalding and levels remained elevated - days following injury. similar kinetics of appearance of proinflammatory cytokines (il-i and tnf-alpha) both in lethal and ncnlethal injury concomitant with differential profile of circulating il- activity (early,short-lived increase and later slow decrease of activity in lethal burn injury) with late persistent high levels of activity in nonlethai injury demonstrated in the present study highlight the need for investigation the relationship of these cytokines in burn-injury induced inflammation. zikica jovicic,lnstitute for medical research, mma,crnotravska , belgrade~yu. asadullah k ( ), woiciechowsky c ( ), liebenthai c ( ), doecke wd ( ), volk hd ( ), vogel s ( ), v. baehr r ( ); depts. of med. immunology ( ) and neurosurgery ( ) , medical school (char#d), humboldt university berlin, frg in patients after polytrauma or major abdominal surgery a hyperinflammatory phase seems to be followed by the development of a phase of monocyte inactivation. the latter is charaeterised by a decrease of monocytic hla-dr expression and a shift to anti-inflammatory cytokine production. as shown, by us and others, this phenomenon indicates severe immunodepression with a high risk of infection. however, the mechanisms leading to monocyte inactivation in the above mentioned syndromes may be multiple. to elucidate the influence of a selective, sterile trauma to the central nervous system (cns) on immune reactivity the neurosurgieal patient is an interesting model. initially, patients who developed a systemic inflammatory response syndrome following neurosurgery were analysed. in all of them a marked decrease of monocytic hla-dr expression was observed soon after the operation. these results suggest that neurosurgery alone can induce immunodepression and lead us to conduct a prospective study, in which we closely monitored l patients undergoing neurosurgery from the first preoperative day until at least day after the operation. hla-dr expression was decreased hi all patients to various extent only hours after surgery. in one patient only we found a persistently reduced hla-dr expression and this was the only patient to develop sepsis syndrome. this suggests that a prolonged, postoperatively decreased hla-dr expression is predictive of infection following cns trauma. in order to assess, whether a decrease of hla-dr expression was associated with a preceding inflammatory response, local cytokine release in the cns was compared with systemic cytokine release. for this purpose, paired samples of earebrospinal fluid (csf) from a vantricle drainage and peripheral blood plasma were obtained. in the csf extremely elevated futerleakin (il)- levels, peaking already a few hours after the operation were found. in plasma, by eontrast, il- ( and tnf-alpha) was detectable not until days later and only if infection was present. the antiinflammatory ili-ra, on the other hand, was also present in csf but peaked after il- and was detectable in peripheral plasma too. we believe there is an association between the inflammatory response in the cns and the following depression of hla-dr expression on peripheral blood monocytes. our results suggest that even a sterile cns-trauma by itself may contribute to general immunodepressinn leading to septic complications. the aim of this study was to evaluate the effect of haemorrhagic shock (hs) a) on total capacity of the host, and b) the circulating blood cells to produce tnf immediately after bleeding. in vivo studies: baboons were subjected to a limited oxygen deficit ( - ml/kg) hypotension phase (mean arterial pressure = map of - mmhg for - hours followed by adequate resuscitation). rats subjected to hs (map of - mmhg for rain followed by reinfusion of shed blood and fluid resuscitation) were challenged with endotoxin ( ~g/kg i.v.) at the end of shock (rhs group). the control group (rco) received the same dose of endotoxin as rhs group but without prior bleeding. in vitro studies: whole blood (wb) obtained from both baboons and rats before and at the end of hs were incubated with endotoxin ( ng/ml) for hrs at °c. results: at min post-lps challenge we found significantly higher plasma tnf levels in rats that were subjected to hs prior to the endotoxin challenge as compared to the control group ( _+ vs + pg/ml) . after hs the tpc was significantly decreased in in vitro stimulated cbc of both rats ( + post-hs vs + ng tnf/ml pre-hs) and baboons ( ± post-hs vs ± pg tnf/ml pre-hs). in contrast, the il- productive capacity was increased in baboons cbc (not yet analysed in rats) stimulated at the end of hs ( ± pre-vs ±_ pg il- /ml post-hs). conclusion: from our data we suggest that despite of down regulation of the cbc to produce tnf the overall tpc is enhanced at the early stage of i-is. with regard to the related literature (chaudry's group) it can be assumed that among the macrophage/monocyte populations, as the main source only the kupffer cells (kc) exhibit enhanced tnf production capacity following haemorrhage. the mechanisms of down/up regulation of cytokine response of cbc and/or kc following hs remain to be examined. d. eg~er, s. geuenich °, c. dertzlin~er °, e. schmitt*, r. mailhammer, h ehrenreich #, p. drrmer, and l. h mer gsf-instimt fox experimentelle h~znatologie, °medizinische kliulk iii, klinikum groghadern, munich, *institut for immunologic, johannes gutenberg universit/it, malnz, and #psychiatrische k/in& der georg-aagust-universi~t, grttingen, germany. it has been shown previously (ehranreich et al., , new biol. : ) that mouse bone marrow-derived mast cells (bmmc) synthesize and secrete endothelin- (et-i) and express eta-type endothelin receptors (eta). so far, however, no functions of et- /et a in bmmc have been described. in the present study we investigated the effect of exogeneously administered et- on the release of histamine, serotonin, and leukotriene c (ltc ) by primary mouse bmmc (in vitro age: weeks) caltured with different recombinant mttrine cytokines (interleukin (il- ) and/or kit ligand (kl) in the presence or absence of il ) for two weeks prior to activation. et- ( x - to lxl - m) induced an extremely rapid (_<lmin) and dose-dependent release of histamine and serotonin (up to % and % of total mediator content, respectively, comparable to ige/ag-indueed mediator release) from bmmc cultured with il- and il- . only when cultured in the additional presence of il- rather than in medium containing kl or kl plus il- alone, bmmc released histamine and serotoaln upon challenge with et- .furthermore, et- stimulated ltc biosynthesis up to -fold in bmmc cultured in the presence of il- . in contrast, the peptide was without major effect on ltc biosynthesis in bmmc culturd without il- . the release of histamine and sereotonin was not altered if bmmc were preincubated for i h with il- prior to activation with et-i, suggesting that a differentiation process rather than a functional priming effect had been initiated by ]l- . et- ( " m) -induced histamine and serotouln release from bmmc was inhibited by an eta-specific antagonist (cyclic id-asp-pro-d-val-leu-d-tel ) in a dose-dependent manner, with a complete inhibition observed at an antagonist concentration of - m. crude peritoneal cells (containing - % serosal mast cells) obtained from normal balb/c-mice released % histamine upon challenge with et- ( - m; rain). taken together, these resu/ts demonstrate that et- can directly function as a histamine and serotohin secretagogue and as a stimulator of ltc production in mast cells. il- appears to be involved in the differentiation of immature mast cell prec~trsors towards an et-l-reactive functional phenotype. when inflammatory reactions are advanced, type ii phospholipase a (type ii pla ) is produced in high levels by various cells at the site of inflammation. cytokines such as tnf-a and il-i activate type ii pla and promote the production of eicosanoid, which is one of the mechanisms by which they enhance the inflammatory reaction. in the present study, the blood levels of type ii pea , endotoxin, tnf-c~, il- and il- were determined in patients with sepsis to examine the relationship between these levels and the patients' pathological conditions. the levels of type ii pla and tnf-a in these patients were . ± . ng/ml and . ± . pg/ml, respectively, the two parameters being significantly correlated (r = . , p = . ). there were also a significant correlation between the level of type ii pla an il- (r = . , p = . ). there was no significant correlation between the level of type ii pla and il- . these in vivo findings suggest that tnf-a may be involved in the production of type ii pla . a. filzmaver, g. reisbach, e. schmitt °, r. mailhammer, and l. hiittner. gsf-iustitut ff~r experimentelle h~imatologie, munich, and °iustitut fttr immunelone , johannes gutenberg universit~t, mainz, germany the product of c-kit, a transmembrane tyrosin ldnase receptor, and a corresponding kit ligand (kl) are critically involved in the control of different hemopoietic cell lineages including the proliferation, maturation, migration, and function of mast cells. it has been reported previously that interleukin (il)- down-regulates kit receptors in human primary myeloid leukemic cells and in a human mast celt line (sinaber et al. , j. immunol. : ) . transforming growth factor (tgf) gl, was also found to down-modulate c-kit mrna and kit receptor proteins in human aml blasts, a mechanism probabely contributing to the anti-proliferative effect of tgfih on kl-stimulated aml ceils in vitro (de vos et at. , cancer res. : ) . in porcine endothelial cells transfected with a retroviral construct carrying the human (hu) e-kit gena, exogenous hu kl transiently down-regulated kit receptors (blume-jeusen et al. , embo j : ) . in the light of these previous findings we analyzed the effects of these exogenously applied cytokines (il- , tgfgl, kl) on kit receptor expression and kl-mediated proliferation and chemotactic migration of primary mouse bone marrow-derived mast cells (bmmc) (in vitro age: weeks). our results show that in bmmc cultures initiated with recombinant (r) marine (mu) il- the additional presence of rmull- for or days did not change the expression of kit protein (assessed by facs analysis with the anti-mouse c-kit antibody ack- ) nor kl-mediated proliferation or chemotaxis. in contrast, il- syeergistically increased kl-stimulated growth of bmmc in a short-term proliferation assay (mtt-tes . pre-incubation of bmmc with rhutgfl~ ( . , . , or . ng/ml) for h had no effect on kit receptor expression, although tgffil at concentrations of . - . ng/ml completely suppressed the proliferative action of kl on these ceils. similar anti-proliferative effects of tgfg were observed in various factor-dependent mast cell lines stimulated with different mast cell growth factors (il- , i,- , il- , and/or il- ). moreover, pre-incuhation ( h) of bmmc with tgf-gl (> pg/ml) significantly enhanced spontaneous undirected cell movement (chemokinesis) and synergistically increased il- -or kl-induced chemetaxis. when bmmc were preancuhated with rmukl ( ng/ml) for , . or days, a transient down-modulation of kit receptors with a maximum effect on day was demonstrated by facs analysis and correlated well with a decreased chemotactic response of these cells. in conclusion our results show that neither il- nor tgfi affect expression of kit receptors in primary murine bmmc. it is reasonable to suggest that c-kit expression is controlled in a cell type-specific manner.interestingly, tgfgl is obviously able to dissect the proliferative from the migrational signal transducted by kl in these cells. objectives of the study: antisense strategies using dna-otigonucleofides (odn) to modulate the cytokine response are presently under investigation. odn are thought to act very specifically with little or no relevant negative side effects. we now report that odn unspeeifically protect wehi cells from tnf-mediated cytolysis. material and methods: wehi subclone ceils ( x ), that are highly sensitive to the cytolytic activity of tnf, were grown on -well culture plates in rpm medium. after hours, phosphorothioate(ps)and partially ps-modified-odn as well as phesphodiester-odn ( - bp) were added ( . , and pm). four hours after incubation with odn, ce(i lysis was induced by recombinant murina tnf. after hours the plates were washed and stained with crystal violet cell lysis was determined by reading the absorbance (abs) at nm. results: wehi ceils incubated with tnf ( - ng/ml) were completely lysed after hours ( % abs). interestingly, wehi cells incubated with tnf and odn resisted complete lysis, eg cells incubated with . ng/ml tnf and jm odn showed still % of the absorbance observed in control ceils without tnf ( % abs). the protective effect of odn started at . pm, reached a maximum at ,um, and diminished at jm. with increasing amounts of tnf the protective effect of qdn decreased and no protection was detectable at ng tnf per ml conclusions: dna-oligonucleotides were found to unspecifically inhibit tnf-induced cytolysis. we hypothesize, that this protective effect of qdn results from an inhibition of the binding of tnf to its receptor, or from interference of odn with the subsequent signal transduction mechanisms. as a consequence, to discriminate the specific effect of odn in biologic systems, several control odn should be used. secondly, whether dna released by degradation of tumor cells or leukocytes can significantly impair tumor-and immune-defense mechanisms merits further investigation dr. med. michael meisner, institut for anaesthesiologie der universitat erlangen-nqmberg, krankenhausstral~e , d- erlangen. in this study we investigated the involvement of serine protease and free radical generation in the systemic release of tumor necrosis factor-alpha (tnf) and interieukin i(il- ), in the sepsis model of lipopolysaccharide (lps, mg/kg i.p.) induced hepatitis in galactosamine (gain, rag/mouse, i.p.) sensitized mice. treatment of gain-sensitized mice with lps (gain/lps) led to dramatic increase in serum cytokine (tnf and il-i) ievels and transaminase activity at hr and hr respectively. pretreatment of serine protease inhibitor, c~jantitrypsin (a j-at, mg/kg i.p.), rains prior to gain/lps treatment, fully protected the animals against the hepatotoxic challenge with significantly reduced serum tnf and il- levels. in order to block and scavenge superoxide generation, the mice were pretreated with xanthine oxidase inhibitor, allopurinol (al, x mg/kg i.p.) and pyran polymer-conjugated superoxide dismutase (sod, x unit/mouse i.v) r spectively. pretreatment with al and sod ( and hr prior to gain/lps) prevented gain/lps hepatitis and blocked lps induced released of tnf and il- into serum of the mice. the protective agents like cq-at or al/sod did not protect the mice against th~ hpp~totoxi£ ch~llpn-e indllee b'~ th~ recombinant mmlse tnf-o' ( . ~/rno~e j.p.) ~d oi~lps ~ caln-.~dlfa%aed mlce. it-l cett~aged la tnf (x/gain treated mjde was not detectable in animals pretreated with oq-at or al/sod. our study suggests that a serine protease sensitive to cq-antitrypsin is responsible in regulating tnf release, possibly by proteolytic cleavage of a tnf-precursor or membrane bound tnf. in addition our evidence suggest that the balance of extracellular protease/antiprotease activity may be regulated by free radical generation, possible superoxide anion, resulting in inactivation of the antiprotease. il- release may be subsequent to tnf release. objective: during sepsis one can observe a dramatically impaired production of proinflammatory cytokines like the tumor necrosis factor alpha (tnf-a), interleukin i-alpha (il-la), intedeukin i-beta (il-i&) and interferon gamma (if~) upon in vitro stimulation of circulating cells. however there is also evidence of a decreased ability to produce cytokines in other immuno-deficient states. in this study we compared the capacity to secrete proinflammatory cytokines upon in vitro stimulation of patients in severe sepsis and patients with malignant tumors. methods: heparinized blood samples of ten patients ( + years) in severe sepsis (sepsis score > according to e}ebute and stoner) were drawn at onset of disease, from fifteen patients with solid growing carcinoma ( + years) blood was drawn at diagnosis prior to any therapy. controls were obtained from fifteen healthy volunteers. pl of whole blood were incubated either with / of a standard medium or with pl of a standard medium and pl of phytohemagglutinin (pha) a potent mitogen. after an incubation period of hours plasma concentrations of tnf-a, il-la, il- and if-~ were determined by elisa. comments: our results suggest that down-regulation of cytokine secretion or of cell responsiveness to non-specific mitogens during sepsis has occurred. we observe a similar phenomenon for the group of carcinoma patients vs control significant for stimulated tnf-a and stimulated if-t. sustained immunological interactions between tumorcells and cytokine producing cells could effect responsiveness of the latter, a general increased immuno-tolerant state in patients with carcinoma has to be discussed. however we found significant differences between sepsis and cancer concerning the in vitro capacity of responsable cells to produce il-la and il-i#. the dramatically decrease of the ability to produce il-i upon in vitro stimulation could be more sensitive for a septic state than stimulated tnf-a or if- ,. objective: tumor necrosis factor alpha (tnf-a) has been implicated as a central mediator of sepsis and its sequelae. increased systemic levels of this cytoklne seem to be correlated with severity of sepsis and outcome. however mechanism of action and metabolism of tnf-g are not fully understood. in most studies blood samples for tnf-a determinations are obtained either by peripheral venipuncture, a central venous catheter or by an indwelling arterial catheter. very often blood samples are taken in different manners within the same study. in this study we measured circulating tnf-a and the amount of tnf-a released upon in vitro stimulation in arterial and central venous blood. methods: heparlnized arterial and central venous blood samples of ten patients ( males, females, mean age +_ ) with severe sepsis (sepsis score > , elebute and stoner} were drawn on day , , , , and of disease. blood was immediately placed on ice and processed within hour. pl of whole blood were incubated with pl rpmi-medium supplemented with antibiotics and l-glutamlne or with pl of rpmi-medium and pl phytohemagglutinin (pha) a potent mitogen. after an incubation period of hours samples were centrifuged and plasma was harvested and stored at - ° celsius before assessment of tnf-a concentration by elisa. statistical analysis was performed with the paired student-t-test. results: we found a significant difference (p < , ) for circulating mean arterial tnf-a concentration ( pg/ml _+ sem} and central venous tnf-a ( pg/ml +_ sem). upon in vitro stimulation there was also a significant difference (p < , ) between released arterial tnf-~' { pg/ml _+ sem) and venous tnf-a ( pg/ml +_ semi. conclusions: these results are difficult to interprete but could reflect the influence of pao and sao on tnf a release. it could also be the result of different concentrations of tnf-o release influencing factors like for example endotoxin, interferon-f or prostaglandin. a possible pulmonary and/or a hepatic metabolism of tnf-n and tnf-a producing cells cannot be ruled out. however for better interpretations of tnf-a release in septic states it is necessary to use either arterial or venous blood samples. early inflammatory processes following trauma and/or infections were found to be associated with the secretion of high amounts of proinflammatory cytokines. besides intedeukin-t (il- ), tumor necrosis factor-a (tnf-c and interleukin- (il- ) the multifunctional cytokine intedeukin- (il- ) was described to be a central regulatory element of the primary cellular and humeral defence reaction. the previously described close temporal correlation of pathologically elevated il- -concentrations and the extracellulary release of lysosomal enzymes from activated pelymorphnuclear neutrophils suggests, that il- may be a potential substrate of these preteases. the serine preteases elastase (ec . . . ) and cathepsin g (ec . . . ) derived from the azurophilic granules were assumed to be mainly involved in unspecific proteolysis at sites of inflammation by cleavage of structural as well as soluble proteins at random sites, if the inhibitory potential is decreased. the possible proteolytic activity of elastase and cathepsin g toward the proinflammatory cytokine interleukin- (il- ) was investigated. the addition of purified neutrephil elastase and cathepsin g to recombinant human il- leads to a rapid sequential degradation in vitro. at least two intermediate products could be detected by silver staining and western blotting following protein separation under reducing conditions. the serine protease inhibitor g-anitrypsin was shown to prevent the proteolytical degradation of intedeukin- . furthermore the loss of the biological activity of both, recombinant and natural human il- , was demonstrated by determination of the capacity of protease-treated il- to stimulate hybddoma growth ( td bioassay). these data suggest a possible downregulation of pathologically elevated il- levels by proteolytic activity of extracellulary released enzymes at sites of inflammation. the aim of the study was to compare circulating levels of three cytokines -il- , il- , _- -between critically ill subjects who developed gram-negative sepsis and who did not. materials and methods: the patient population consisted of patients admitted to an intensive cars unit, with different underlying diseases. sepsis diagnosis was given according to pre-estabilished cdteda. nineteen cases were enrolled in sepsis group, twenty in control group. serum sampling was collected in sterile tubes at study entry and every three days until study dismissal. serum concentrations of il- , _- and il- were measured using commercially available test kits, based on the dual immunometric sandwich principle. results: the causative patogens of sepsis were: pseudomonas aeruginosa, acinetobacter, eseherichia co~i, serratia marceseens, proteus mirobilis and citrobacter freundl the time of observation was equal to days, for a total of four tests performed (to, tl, t , t ). i .- was not detected in any samples. the serological profiles of the two cytokines .- and _- were similar; augmented levels were found at study entry and throughout the observation period, peaking at t and decreasing at t . however, in patients with sepsis, il- and _- concentrations were significantly higher in respect to control group. conclusion: our observations shown that in icu patients increased il- and il- release may be induced by cdtical illness; however, in subjects in which sepsis occurred, il- and il- production appears more significantly elevated, suggesting a role of il- and _- in the pathophysiology of sepsis. the fact that ii. objective: to check whether continuous veno-venous haemofiltration (cvvh) could remove the cytokines, namely tumour necrosis factor alpha (tnfc and interleukin (il- ) from the circulation of critically ill patients with sepsis ad multiple organ failure (mof). setting: the intensive therapy unit of the medical school teaching hospital. patients: nine critically ill patients with sepsis and mof treated with cvvh. methods: blood samples were collected before the cvvh had been started. then, blood and ultrafiltrate samples were collected simultaneously after hours and every hour. tnfct and il- levels were measured using the bioassays with cell lines wehi- ci and td , respectively. other data were recorded from the patient notes and intensive therapy unit charts. results: no measurable concentrations of tnfct were detected in either blood or ultrafiltrate samples. il- was found in all the patients' plasma samples and five patients' ( . %) ultrafiltrate samples. the il- blood level ranged from . to . u/ml (mean . , sd . ). the il- level in positive ultrafiltrate samples ranged from . to . u/ml (mean . , sd . ). conclusions: our preliminary results suggest that il- is present in bloodstream of septic patients. we assume we could not detect tnfa in any sample because we usually started observations when septic state had developed. cvvh could extract cytokines from the circulating blood. it remains under discussion, whether that extraction may be beneficial to patients with mof. the pattern of some significant cytokines tnf, il- and il- and their pharmacomodulation were evaluated in an experimental model of polimicrobial sepsis induced in cd- mice by cecal ligation and puncture (clp) in order to understand their roles. this model of sepsis, which resembles the clinical situation of bowel perforation, was also compared with that induced by administration of pure endotoxin (lps). tnf was detectable in serum and tissues during the first h with a peak h after clp at a significantly lower level than after lps. il- was measurable in serum only after h, significantly increased in spleen and liver after and h and in mesenteric lymphonodes from to h after clp compared with shammice. il- was significantly increased in serum throughout the first h after clp. pretreatment with dexamethasone (dex), ibuprofen (ibu) and nitro-l-arginine (n-arg) significantly reduced the survival time while chlorpromazine (cpz) and tnf did not affect it. only the antibiotics and pentoxifylline (ptx) significantly increased the survival in clp. however cpz and dex protected from lps-mor~ality. in conclusion, by inhibiting tnf with dex, cpz, ptx a reduced, unchanged and increased survival time was observed and by increasing tnf with ibu and tnf administration the survival was decreased or unchanged respectively suggesting that the modulation of this cytokine does not seem to play a significant role in clp unlike lps_ moreover the negative effects of ibu and n-arg suggest an important and protective role by prostaglandins and no in clp. to gain more insigths on the contribution of tnf~, il-i~ and if to lps toxicity, we explored the time-course of the cytokine production in ealb/c mice given different doses, from the lethal (= ld ) to the sublethal (= / ld ) of three different lps (e.coli oiii:b and :b ; p.aeruginosa r ) endowed with different degree of toxicity cytokines were measured in serum and organs with specific elisas up to i h after lps administration. results demonstrate that i) circulating and organ levels of tnf~ do not reflect lps toxicity. in fact, the lethal dose of lps :b induced as much tnf~ as the sublethal dose of lps :b ; furthermore, lps r , whose cytokine inducing capability is far lower than that of lps from e.coli, induced higher tnf~ levels at the sublethal than at the lethal dose. in addition, policlonal anti tnf ab, that were able to protect mice from e.coli lps induced mortality, failed in mice treated with lps r ) circulating il-i~ levels are generally low and increase significantly only in muribond animals. on the contrary, in spleen and lung very high levels of il-i~ are persistent from i to h post lps administration moreover, the treatment with mgr of neutralizing policlonal anti il-i~ ab, did not modify survival in lps challenged mice. ) circulating and organ levels of if are proportional to the dose and degree of toxicity of all the administered lps even if lps r was again a less efficient cytokine inducer than lps from e.coli. csa is an immunos~ppressive drug, able to inhibit gene expression for many cytokines, including if . to study the effect of cytokines modulation on lps toxicity, csa was administered to mice twice at the oral dose of i mg/kg before the challenge with lps. mice were monitored in terms of mortality and tnf~, il-i~ and if production. together with the total ablation of if , the strong reduction of tnfu and unmodified il-i~ levels, a significant increase of lps toxicity was also observed. these results suggest the hypothesis that the numerous factors that jointly mediate lps toxic effects, can also be protective, the final outcome depending on their relative ratio rather than on the absolute amount interleukin- (il- ) mediates the septic shock syndrome and affects intestinal secretion in vitro. we studied the intestinal production of il-t and its effects on diarrhea during endotoxic shock. cd- mice were randomized to mg/kg e.coli :b lps or saline infusion (i.p. or i.v.). diarrhea invariably occurred following lps infusion. mice were sacrificed at , ', lh, . h, h, h, h, and h ( mice/group/time-point). the small bowel was compressed and the intestinal contents were weighed and expressed per g sb weight. the small (sb) and large bowels (lb) were eventually frozen, weighed, and homogenized for either cytosolic protein or total rna. il-i~ (cell-associated agonist) was measured with a radioimmunoassay specific for mouse il-l~ (detection limit pg/ml) and expressed as ng/g weight + sem (lowest detectable amount ng/gwt). northern analysis of total rna and in sfu hybridization of paraformaldehyde-fixed frozen tissue were done with [ ~- p]-iabeled mouse il-lc~ cdna probes. only sb had il-i~ constitutively present ( . + . ng/gwt). lps i.p. or i.v. induced elevation of il-lc¢ in both organs in a biphasic pattern; lps i.v. induced -fold more il-i~ than lps i.p. following lps i.p., il-i~ in sb was . + . ng/gwt at lh, reached maximal levels at . h ( . -+ . ng/gw-i) and returned to baseline at h. saline controls maintained their constitutive il-i~ levels. sb had fold more il- ¢ than lb and identical kinetics, but lb showed a clearer doseresponse. northern analysis of sb-total rna showed induction of il-i~ mrna by lps in correlation with il-lc¢ kinetics. il-i~ mrna producing cells were mononuclear cells in the lamina propda and epithelial cells at the bottom of the crypts of ueberkuhn. mucus and fluid were increased in the small bowel post-lps in correlation with intestinal il-lc~ kinetics (r = . ). separate mice were pretreated with saline i.p. orthe il- receptor antagonist (irap, mg/kg bolus i.p.) and were challenged rain later with . mg/kg lps i.p. or saline i.p. specific blockade of il- by irap decreased intestinal secretion at h and h post-lps challenge (p<_. . , student's-t-test). these data indicate that local (intrinsic) intestinal il-i~ mediates sepsis-induced intestinal changes. inflammatory cytokines initiate the host response to endotoxemia, causing severe physiological and hemodynamic changes which may lead to septic shock. among the regulatory systems that play an important rote in controlling host inflammatory responses is the pituitary. it has been known for many years for example, that hypophysectomized animals are extremely sensitive to lps lethality. while investigating the possibility that protective, pituitary mediators might explain this phenomenon, we identified the cytoldne mif to be a specific secretory product produced by pituitary cells in vitro and in vivo after lps challenge. analysis of serum mif levels in control, t-cell deficient (nude), and hypophysectomized mice revealed that pituitary-derived mif contributes significantly to the rise in serum mif that occurs after lps administration. of note, pituitary mif content ( . % of total pituitary protein) and peak serum mif levels ( - ng/ml) were determined to be within the range observed for other pituitary hormones that are released after pituitary stimulation. to investigate a possible beneficial role for mif in septic shock, we co-injected mice with purified, recombinant murine mif (rmif) together with lps ( mg/kg). surprisingly, rmif markedly potentiated lps lethality compared to control mice that were injected with lps alone ( % vs. %, p = . ). to confirm these results, mice were treated with anti-rmif antibody prior to injection of a high dose of lps ( . mg/kg). anti-rmif antibody fully protected mice against lps lethality, increasing survival from % to % (p = . ). serum levels of tnf,~, the first cytokinc that appears in the circulation after lps challenge, were reduced by . _+ . % in anti-rmif-treated mice. we conclude that pituitary derived mif contributes significantly to circulating mif in the post-acute response in endotoxemia and may act in concert with other pituitary mediators to regulate both pro-and antiinflammatory effects. moreover, mif may play a critical regulatory role in the systemic host response in septic shock. our results suggest that anti-rmif antibody might be of potential therapeutic use in the treatment of septic shock. although anti-interleukin- (il- ) antibodies and il- receptor antagonist have been shown to improve survival in animal models of endotoxemia and abrogate the lethal effects of tnf, the presence of il- in the serum does not correlate well with outcome. we hypothesized that this may be because il- acts mainly in a paracrine fashion and is metabolized before it diffuses into the circulation. methods: we measured the il-i~ mrna expression with the differential reverse transcription polymerase chain reaction (rt-pcr) using g-actin as internal standard in the peritoneal macrophages and lung tissue in normal controls and mice after cecal ligation and puncture (clp). clp resembles human intra-abdominal sepsis in that it is characterized by very slight elevations of serum il- levels. results: il-lg mrna levels after clp are expressed as % of normal (mean+sem, n= in several experimental models of infection exacerbation of disease was observed, when infected animals were depleted of tuajor necrosis factor (tnf). after sublethal cecal ligation and puncture (clp) leading to peritonitis and sepsis the survival of mice also critically depends on tnf as demonstrated in earlier studies, when clp-treated mice injected with anti-tnf antibody died, whereas mice injected with a control antibody survived after clp (echtenacher et al. , j. inununol. : ) . from a panel of different cell types (macrophages, neutrophils, t lymphocytes, natural killer cells, mast cells) able to produce tnf upon activation~ the mast cell is apparantly the only one capable of storing in cytoplasmic granules preformed tnf-ct which is rapidly released following challenge. in the present study-we analyzed serum tnf after lps injections as well as the outcome of clp in severely mast cell deficient mutant mice (wav v) as compared to syngeaeic wild-type littermates (+/+). we proposed that concentrations and/or kinetics of serum tnf should be different between wavv mutants and wild-type mice, if mast cell-derived tnf significantly contributes to the rise in serum tnf levels following systemic stimulation with endotoxin. although similar levels of increased tnf were detected in the sera of both genotypes after and hours of lps injection ( btg/ . ml / mouse i. p.), mast ceil-deficient mice indeed showed decreased serum tnf levels iron after injection amounting to only to % of the concentrations observed in the corresponding sera of normal wildtype mice. in the clp model of septic peritonitis we found that mast celldeficient mutant mice were dramatically more sensitive to clp than syngeneic normal mice resulting in % mortality in w/w v versus % mortality in +/+ mice . days after initiation of clp. further experiments with w/w v mutants selectively reconstituted with cultured bone marrow-derived mast cells from normal syngeneic wild-type mice and the use of an antibody specifically blocking the action of tnf tn vivo should clarify a potential protective function of mast cells in this model of septic peritonitis. interleukin- (il- ) inhibits cytokine production, including tumor necrosis factor (tnf), by lipopolysaccharide (lps)-aetivated maerophages. we recently observed that lps injection (e.coli :b , gg ip) into balb/c mice induces the rapid release of circulating il- ( ± u/ml at min). blocking endogenous il- using monocional antibody (jes - a , mg, h before lps) resulted in a massive increase in tnf production ( ± in lps+anti-il- treated mice vs ± ng/ml in lps alone, p< . , n= to mice per group) and an enhanced lps-induccd lethality ( % vs % in anti-il- +lps or lps alone respectively, p= . , n= mice per group). irrelevant igg rat monoclonal antibody (lo-dnp) did not influence neither tnf production nor lethality associated with endotoxin shock. this led us to study the production of il- during human septicemia. plasma samples were obtained from patients with gramnegative (gns, n= ) or gram-positive septicemia (gps, n= ) and from healthy volunteers. among these patients, suffered from septic shock at the time of sampling. il- levels were measured by elisa (detection limit: i pghrd). we found that patients ( %) had increased il- plasma levels (range to pg/nd). patients with gps had il- levels similar to the ones observed in gns (median: vs . pg/m, respectively). patients with septic shock had higher il- values (median: pg/ml) than septicemic patients without shock ( pg/ml, p= . ). no il- was detected in plasma from healthy volunteers. we conclude that il- is produced daring human septicemia. our experimental data suggest that il- might be involved in the control of the inflammatory response induced by bacterial products. dr arnand marchant, immunology department, hopital erasme, route de lennik, brussels, belgium. to provide information about the role of tnf in sepsis and mods we measured tnf and stnfr-i levels in septic patients and investigated if there is a relation between plasma concentration of these molecules and the severity of sepsis evaluated by two scores (apache i and sss). patients and melhods: septic patients fullfilling sepsis criteria of american college of chest physician and society of critical care medicine were studied. tnf-cc and stnfr-i ( kda) were measured by enzyme immuneassays (norms values = + pg/ml and . _+ a ng/ml respectively). results: the mean tnf and stnfr-i values for each patient (mean+sd) were + pg/ml and . + . ng/ml respectively. these values are approximately seven and ten times greater than those observed in normal healthy volunteers (p< . ). mean tnf concentrations for each patient were significantly greater in non survivors ( + vs _+ pg/ml p< . ); stnfr-i levels also were greater in this group, but the difference was not statistically significant ( . + . vs . _+ . ng/ml). plasma tnf and stnfr-i concentrations were significantly correlated (r = . p< . ). mean tnf levels were significantly correlated with apache ii (r = . p< . ) and sss (r = . p<o. ); stnfr-i levels were likewise correlated with both scores (r = . p< . and r = . p< . respectively). tnf and stnfqgi levels increase with the number of dysfuctional organs; in particular tnf and stnfr-i increase when hemodynamics deteriorate and kidney failure ensues. conclusions: the correlations between tnf and stnfr-i levels and sepsis severity scores suggests that tnf is involved in sepsis and may influence the occurrence of mods and finally clinical outcome. tnf and stnfr-i are in fact especially increased when mods occurs. in particular their concentrations are elevated when cardiovascular system and kidney failure ensue, suggesting that tnf can have a direct role in hemodynamic derangements caused by sepsis and that kidneys are involved in tnf and stnfr-i excretion. lif is a pleiotropic cytokine that has been implicated in the pathogenesis of sepsis in animal models. we conducted a prospective study in septic patients to correlate lif plasma levels with patient's clinical and biological data (among them il- ). plasma was drawn daily from day one to .ten and lif presence was determined with a specific elisa and with the dai,a bioassay (sensitivity of pg/ml and ngml respectively). risk factor associated wftt~ with elevated lif plasma level was determined by an univariate analysis. a multivariate stepwise logistic regression analysis was subsequently performed with a bmdp statistical software. lif was detected with the elisa and with the bioassay in and out of the patients, respectively. lif peak plasma levels were statistically associated with high creatmin levels, temperature and il- . multivariate regression analysis showed that high serum creatinin level was the major independent risk factor associated with elevated lifplasma levels. this correlation was also found for il- . peak plasma levels of both lif and il- correlated inversely with patients survival duration. cox's analysis for plasma levels of lif > pg/ml yelded a hazard ratio of [exp ( . )= . ]. our study indicates that lif levels were associated with clinical and biological parameters of illness severity and significantly increased (cut-off value pg/mi) in patients with fatal outcome. current consensus exists about the central role of tumor necrosis factor (tnf) alpha in initiating the systemic inflammatory response syndrome (sirs). a correlation with sirs has inconsistently been found. tnf effects its pleiotropic reactions upon two distinct cellular receptors. soluble extracel]ular fragments of the human kda tnf receptor (stnfri) and the kda receptor (stnfrii) are detectable in the circulation. the kinetics of these endogenously produced tnf-inhibitors were measured to evaluate their role in patients with sirs. fourteen patients of an operative icu were included with the diagnossis of sirs (mean apache ii score: points). serial blood samples were obtained within h after diagnosis of sirs, every hrs for the first hrs and every hrs thereafter until patients died or recovered. soluble tnfri and stnfrii were assayed by an enzymed-linked immunological binding assay. soluble tnfri and ii could be detected in all samples with a significantly higher level (p<o,o ) compared to healthy controls (normal value: tnfrh , ng/ml; tnfrii: , ng/ml). the serum concentration of tnfri ( , ng/ml) as well as tnfrii ( , ng/ml) were significantly higher in nonsurvivors (n= ) compared to survivors ( , and , ng/ml; n= ) at the onset of sirs and during the course of the inflammation response (p< , ). a positive correlation exists between both receptors (r- , ; p < , ). increasing levels and maximal values of stnfri ( ng/ml) and i ( ng/mi) were detected only in patients who died. the serum concentrations of patients who recovered did not change and are remaining at the initial level. tnf alpha bioactivity was detected in out of patients. no significant correlation exists between the concentration of both receptors and tnf alpha as well as the apache ii score at the onset of sirs. elevated serum concentration of stnfri and are found in patients with sirs. these naturally occuring antagonists reflect the inflammatory process. the measurement of soluble tnf receptor levels may be useful in monitorina sirs and in the prediction of outcome. - is given to patients with advanced melanoma or renal carcinoma. however, this therapy is accompanied by severe side effects, including the vascular leak syndrome (vls) that closely resembles septic shock. to investigate the involvement of cytokines and phospholipase a z in the pathogenesis of the vls we collected serial plasma samples from patients during the first hours after administration of il- . in these patients we monitored temperature, blood pressure and heart rate and assessed levels of the cytokines tnf, il- and il- using immuno assays. in these plasma samples we also measured phospholipase a activity using an enzyme activity assay, since this enzyme is beleived to play a major role in the generation of lipid mediators. we demonstrate that during il- therapy the cytokines tnf, il- , and il- are produced and that the release of these cytokines is followed by an induction of phospholipase az activity in the plasma of these patients, we further discuss the role of these mediators in the development of the vascular leak syndrome observed in patients receiving il- . objectives of the study: sepsis caused by candida albicans (ca) is no longer a clinical rarity but a common consequence of immunosuppression and surgery, and is associated with high mortality. tumor necrosis faetor-c¢ (tnf-<~), interlcukin-lg (il-lg) and interleukin- (il- ) are thought to play an important role in the pathogenesis of the sepsis syndrome. we therefore studied the in vitro production of tnf-<x, il-ib and il- by human peripheral blood mononuclear cells (pbmc) stimulated by ca compared to stimulation by bacterial lipopolysaccharide (lps). materials and methods: pbmc were isolated from venous blood of healthy volunteers and cultured at a concentration of . • ~ eells/ml in culture medium with a dose-range of either heat-killed ca or lps. supernatants were harvested after hours. using elisa, tnf-c~, il-ib and il- concentrations were measured. ca was isolated from a patient with ca sepsis and cultured under sterile conditions. results: ca and lps stimulate the production of tnf-~t, il- ] and il- by human pbmc. we observed a dose-dependent synthesis of these three cytokines in human pbmc. tnf-c¢, il-ib and il- in ng/ml as mean _+ standard error. ca/ml . . ( ) we constructed a single-chain fv-fragment (sc-fv) from the variable domains of a neutralizing antibody to human tumornecrosisfactor-alpha (tnf) because sc-fv should have some advantages in vivo. the sc-fv has a similar affinity ( , x - m) as the fab-fragment ( , x - m) but bind the antigen with a eightfold lower avidity compared to the parental mab ( , x - ). the parental mab as well as its fragments can compete the binding of rhutnf to both tnf-receptors. this was shown by competitive binding to the cell line hl- and to immobilized rtnf-receptors. in the nutralization assay on the cell line, l , the sc-fv can neutralize tnf but in comparison to the mab or its fabfragment, the capacity was three-fold lower as expected from the molar ratio of the dissociation constants. the in rive-neutralizing capacity was tested in a mice receiving toxic dose of rhutnf. the sc-fv showed a -fold lower neutralizing capacity in comparison with the fab-fragment. this could be explained in different manners: i) partial instability of scfv at c, ii) shorter half-life because sc-fv but not fab-fragments are eliminated via kidney, iii) elimination of tnf-immunocomplexes may be improved by opsonization mechanisms which requires some structures of the constant region (as in fab or mab). in summary, despite the encouraging in vitro experiments, the in vivo data suggest that sc-fv are not the right strategy for neutralizing tnf in vivo. tnf production in endotoxin non-responder mice, effect of a glucocorticoid antagonist g. iazgtr jr, e. duda, j. ol~th, e. husztik, g. iazar glucocorticoids inhibit lipopolysaccharide (lps)-induced tnf production and tnf can stimulate pituitary adrenocorticotropin secretion, resulting in the release of corticosterone. earlier studies ( ) reveales that the glucocorticoid antagonist ru , nufepristone, sensitizes both endotoxin responder and nonresponder, c h/hej, mice to endotoxin lethality. we have also shown that the glucocorticoid antagonist ru sensitizes endotoxin-tolerant (endotoxin-pretreated) and normal mice to the lethal effect of septic and endotoxin shock. on this basis, we set out to study the influence of ru on tnf production induced by endotoxin in endotoxin responder and non-responder mice. one and hrs following lps injection, ru significantly increased the tnf concentration in the serum, liver and spleen of treated animals as compared with the control and methylprednisolonetreated groups. in tissue cultures, ru induced the tnf synthesis of myeloid cells and increased the tnf production of genetically modified hela cells, which synthesize tnf constitutively. normal and tumor cell cultures exhibited an increased sensitivity toward tnf in the presence of ru . however, the same dose of lps did not induce tnf production in the serum, liver and spleen of endotoxin non-responder mice and this was not influenced by concomitant ru treatment. these studies suggest that ru aggravates lps lethality via factors other than tnf in endotoxin non-responder, c h/hej mice. the cytokine response to a novel exnacellular mitogenic factor, mf, produced by the group a streptococci (gas), and to the streptococcal pyrogenic exotoxins (spe) a and b, was determined by in vitro stimulation of peripheral blood mononuclear cells (pbmc) obtained from healthy blood donors. the induction and kinetics of different cytokines was studied at single-cell level using cytokine specific monoclonal antibodies and intracellular immunofluorescent staining. all three mitogens induced a massive ifny and tnfi response in - % of the pbmc after - hours of cell stimulation. in contrast, il and tnfc~ containing cells was only detected in - % of the pbmc. the induction ofil , il , il , and ill , was weak or completely absent. thus, the response indicates activation of th cells. however, illc~, illl , illra and il , were consistently found and gradually produced, peaking at hems in approximately - % of the pbmc. mf induced an equally extensive cytokine as well as proliferative inducing capacity, as did spea and speb, which suggests that also mf is a superantigen. a marked inter-individual variation could be noted between lymphocytes isolated from different individuals, both in the toxin induced proliferation and cytokine induction. this may be one explanation for the varying clinical severity noted in patients after infection with clonal gas strains. introduction -tumour necrosis factor (tnf) is released by mononuclear cells in response to inflammation and sepsis. it has been implicated as a possible mediator in inflammatory bowel disease (ibd) but its pathogenic role remains uncertain. this study assessed the relationship between tnfct and disease activity by measuring plasma and faecal tnf concelnmtions in an experimcntai model of ibd. methodologo' -colitis was induced in male wistar rats by intmcolonic instillation of rag , , -trinitrobenzenesulphunic acid in . ml % ethanol (n= ). control animals received an isovohlmetric instillation of normal saline (n= ). faecal pellets were collected before induction of colitis (day ) and throughout the experiment. after days the colon was excised, ueighed and the colon macroscopic score (cms) assessed plasma tnf (ptnf) samples were assayed by bioassay and elisa. faecal samples were vortcxed in water and the supernatant removed for estimation of protein and faecal tnf (itnf) content (elisa). there is a significant increase in itnf on day -#p= alld the total ftnf measured during the study correlatcs with the cms oll day -p= . there is no correlation between ftnf and ptnf. conclusions -therc is evidence of coloific tnf excretion by macroscopically normal animals and following induction of colitis there is increased faecal tnf which correlates with disease actmty. there is no significant elevation in bioactive or imnmnoreactive plasma tnf in colitie animals this data would suggest that faecal tnf is a marker of colonic inflamrnatiort and serial tnf assessment inay be useful as an indicator &severity in ibd. to study the effect of in-vivo hypoxia/reoxygenation on cytokine elaboration by routine peritoneal macrophages. materials and methods: adult male cba mice ( - g) were primed intraperitoneauy with either lipopolysaccharide (lps) ug]anlmal or saline. five days later, the animals were subjected to hypoxia ( % ) for , followed by of normoxia. harvested peritoneal macrophages were plated in-vitro, culture supernatants were collected at , , and and assayed for tumor necrosis factor (tnf), prostaglandin e (pge ) and nitric oxide (no). control animals underwent the same procedures, but were maintained in normoxia ( %o disease , berlin, germany the precise mechanisms of reactivation of latent human cytomegalovirus (cmv) infection are still unknown. apart from the permissive effect of diminished cellular immunity there is evidence of a cytokine mediated cmv reactivation as it is known for other systemic virus infections (e.g. hiv). we found that tumor necrosis factor-alpha (tnf) -in contrast to all other cytokines tested -can stimulate the activity of the cmv-ie-enhancer/promoter region in the human monocytic cell line, hl . we wondered whether our in vitro results were actually reflected by the incidence of cmv reactivation in diseases which go together with high tnfalpha levels. cellular immunodeficiency as well as at least temporarily increased tnf levels are known to occur in septic disease. we tested for the presence of cmv infection in peripheral blood mononuclear cells (pbmnc) by means of h centrifugation culture, immunocytological detection of different cmv antigens (apaap-technique), and pcr technique (cmv-ie dna). in striking contrast to healthy controls almost all examined septic patients were positive, irrespective of the method for cmv-ddtection applied, including the less sensitive immunocytology. follow-up studies showed that cmv-antigen positive pbmnc ceased to be detectable in patients with good outcome once septicaemia had been overcome. to further back up our hypothesis, we looked for a coincidence of enhanced tnf-alpha serum levels and cmv antigenaemia (immunocytology) in some other diseases which are known to have either enhanced tnf serum levels or increased incidence of active cmv infection and found the majority of patients with b-cell chronic lymphocytic leukemia, liver cirrhosis, and common variable immunodeficiency to be positive for these two parameters. we now wondered whether, apart from cmv reactivation, tnf-alpha could also cause cellular immunodeficiency this way promoting cmv replication and spreading and eventually causing cmv disease. in summary, we were able to show that a diminished cellular immune response results from/n vitro or in vivo methylprednisolone (mps) is used to suppress both inflammatory and immune responses. il- receptor antagonist (il-lra) and tnf binding protein (tnfbp) are naturally occuring anti-cytokine proteins, possibly modulating inflammatory and immunological responses. to define mps modulation of cytokine and anticytokine responses, we examined effects of mps on il-lra production and tnfbp generation as well as il-i~ and tnfa production by human peripheral blood mononuclear cells (pbmc) stimulated with lipopolysaccharide (lps). pbmc were purified from the blood of healthy volunteers, then incubated with lps ( ng/ml) supplemented with different concentrations of mps ( , pg/ml, mg/ml). after hrs incubation, the supernatants were collected for rias of secreted cytokines. the cell lysates obtained by cycles of freeze-thaw, were also collected for r ias of cell-associated cytokines. both the supernatant for secreted cytokines and the cell lysates for the cell-associated cytokines were subjected to rias for il-i~, tnfa, il- ra, and tnfbp-i (tnfsrp ). il-la, il- ra, and tnfbp were produced mainly as cell-associated forms in response to lps, whereas most tnfa was secreted into the supernatant of lps-stimulated pbmc. mps supplement resulted in reduction of il-la, il-lra, and tnfa production. il-la production was reduced up to . + . %( mg/ml) by mps in a dose dependent fashion, whereas about % decrease in tnfc, and il-lra production was observed at both high and low dose mps supplement. however, total tnfbp generation was not reduced significantly by mps supplement. furthermore, tnfbp secretion was increased times more in the supernatant of lps-stimulated pbmc with gg/ml of mps. these data suggest that mps could effectively block tnf activity by both reducing its production and up-regulating tnfbp generation and that mps works as an anti-inflammatory drug as well as an immunosuppressant by modulating cytokine and anticytokine responses. in severe gram-negative sepsis, excess of proinflammatory cytokines is associated with increased morbidity and the mortality. we have found that immunocytes possess functional -adrenergic receptors (~-ar) which, when activated, down regulate the lipopolysaccharide (lps) induced gene expression and subsequent secretion of tnf-~ in vitro. in the present study, we used a lethal endotoxic model in mice to test the hypothesis that -ar stimulation will down regulate the gene expression thus decreasing the circulatory levels of proinftammatory cytokines and improve the survivals in severe endotoxicosis. the animals (iso group) were injected times with ! -ar agohist isoproterenol ( . mg/kg i.m. and . mg/kg s.c.) , and hours prior to a lethal dose of lps injection ( mg/kg i.p.). control group (ctl) received same volume of saline at the same times before the lps insult. at the appropriate time points after lps injection animals were sacrificed and venous blood was collected from the inferior vena cava. the plasma levels of tnf-cc and il-loc were determined by elisa. in the mortality study, each grou the data showed that isoproterenol significantly decreased the mortality and the circulatory levels of tnf-c~ and il-lcc (fig. ) . these data suggest that -ar activation of immunocytes down regulates cytokine gene expression, decreasing circulatory eytokine levels thus reducing endotoxicosis mortality. these results provide a new pharmacological approach to reduce the excess of proinflammatory cytokines and mortality in sepsis. introduction: cytokines released from monocytic cells are thought to play an important role in the pathophysiology of sepsis. during the last few years several investigations have been performed aimed at modulating this mediator response. in the present investigation using a full blood model we have studied the effect of a standard immune globulin and an antitipopolysaccharide (lps) immune globulin preparation and a monoclonal anti-lps antibody in modulating the endotoxin induced cytokine response. methods: citrated blood from healthy human donors was incubated at °c in rotating polystyrene tubes. samples were taken before addition of x ng/l e. col± endotoxin and after hours. plasma was assayed for the cytokines minor necrosis factor alpha (tnf-~) and interleukin- (il- ) using elisa methods. the eodotoxin concentration was assayed by lal and end-point chromogenic substrate technique. the blood was preincubated with standard immune globuline (human igg from pooled plasma, gammagardr, baxter) or with an anti-lps immune glubuline (human anti-lps igg obtained by screening of blood donors, novo nordisk) in the concentrations of mg/ml or mg/ml or with the monoclonal lipid a igm antibody ha- a for ten minutes before the endotoxin was added. results: two hours after endotoxin addition markedly elevated tnf-~ and il- values were found.in the plasma. cytokine values at hours: tnf-ec pg/ml (mean) and l- pg/ml (mean). preincubalion with mg/ml standard immune globulins reduced il- values by % (mean) while there were no effects on tnf-c~ values at hours. a slight reduction in il- values was also found with the lower concentration, mg/ml, but this was not statistically significant. preincubation with anti-lps immune globulins had no effect on il- nor on tnf-cc values. preincubation with the monoclottal lipid a igm antibody ha- a in variable concentrations had no effect on cytokine release in this model. in this full blood in vitro model standard immune globuline reduced endotoxin induced l- release while tnf-cc values were unchanged.the anti-lps immune glubuline preparation and the monoclonal lipid a igm antibody ha- a had no effect on the il- or tnf-ct release. the effect of anti-tnf treatment in severe haemorrhagic/traumatic shock was investigated in a conscious rabbit model. the jugular vein (for administration of substances and blood withdrawal) and right femoral artery (for measurement of bp) were cannulated and an aortic thermistor probe inserted into the left; femoral artery for the measurement of cardiac output (co). the following day, upto % of the estimated blood volume was withdrawn over - rain, to reduce bp to - mmttg and co by / mad withheld for rain. shed blood ( %) was then reinfused followed by lactate solution to give a total potential dreulat%ag fluid volume of %. zymoeen activated plasma ( , gg/ml) was given rain prior to haemorrhage and during blood r~n%eion, all ~,~ir, ak were killed at h and o~gane removed for histology. rabbita received either monoclonal antirabbit tnf (r , rat igg , mgkg i.e. n= ) or emine (nffi ), rain prior to haemorrhage. the cardiovascular and biochemical changes during the haemorrhage and hypotensive phase (is. haemorrhagic stimulus) were similar in both groups. upon reinfusion, haematccrit and white cell count remained sigutfia~utly (p< . ) higher in saline compared to r -treated animals, indicating a relative haemoconcentration (i,e. reduced circulating volume) in saline animals. the lettkocytosis persisted in the saline animals upto h. plasma glucose, lactate and asparteto .m~-o transferase all rose similarly in both gorups but plasma ¢rea~!~+-e levels were markedly (p< . ) higher in ealine ve r animals at and h indicative of kidney damage, using a macro and micro. pathological scoring system, major organ damage was seen in the lung, liver and kidney which was significantly (p< . ) attenuated in r treated animals. in the hmg and liver, this was primarily due to a reduced bleeding and pmn infiltrate and to an additional maintenance of tubular integri~:y in the kidney. hence, in tlais model anti-tnf treatment markedly reduced the biochemical and histological indices of severe ,, ~gan damage during liaemorrhage and ranerfn~ion. thermal injuries and systemic bacterial sepsis produce a wasting diathesis with anorexia and marked loss of lean tissue and body fat. endogenously produced cytokines, including interleukin- (il- ), are thought to mediate many beneficial as well as pathologic host changes that occur during burn injury and infection. to evaluate whether bluckade of il- in vivo would affect survival and attenuate the anorexia and cachex[a associated with a thermal injury and chronic fulminant gram negative infection, sprague-dawley rats were studied. anesthetized rats were divided in groups, implanted with alzet r minipumps and randomized to receive the following treatment for days:i: gg/kgbw/min of il-lcc; ii: ~tg/kgbw/min of il- receptor antagonist (il-ira); iii: buffered vehicle. the animals were subjected to a % bsa, full thickness scald burn and the wounds then infected with + cfu/ml pseudomonas aeruginosa. eight additional rats were anesthetized, but were not burned, and served as healthy controls. . il-hx reduced food intake transiently but was otherwise without effect however, il-lra significantly attenuated weight loss over the first days and improved food intake between days and . we conclude that blockade of il- after a thermal injury with superimposed infection does not adversly affect the progression of the disease, but does attenuate the anorexia and weight loss associated with this model. these data indicate that il-i receptor blockade may offer a means to minimize the morbidity associated with catabolic illness. tumor necrosis factor (tnf) and its downstream induced mediators have pivotal roles in the pathogenesis of sepsis and septic shock. the suppressive effect of pentoxyfillin (ptx) on tnf production may be of clinical importance. when peripheral white blood ceils were stimulated with either lps or staphylococcus aureus, pentoxyfillin inhibited tnf production. in contrast, no inhibitory effect was observed on the induction of il- . ptx inhibited not only the tnf production of monocytes but also the tnf secretion of both granulocytes, and unseparated whole blood. the facs analysis revealed that the expression of cd antigen on monocytes was not influenced by pentoxyfillin. the in vitro tnf and il- producing capacity in septic patients were higher than in the control group, but decreased on subsequent days especially in fatal cases. administration of ptx ( mg/day) in septic patients resulted in tnf and il- productions similar to those found in control donors. it also subsequently led to an improvement of the clinical status. a further improvement in apache score could be achieved by administration of pentaglobin ° (biotest)( ml/kg/day ). the prevention of lpsinduced in vitro tnf and il- production by pentaglobin ° could be demonstrated in in vitro experiments involving the use of whole blood rather than purified lymphocytes, very probably because of the presence of lps binding protein in the plasma. the level of soluble icam- in sera of septic patients was significantly higher ( - ng/ml) than in normal individuals ( - ng/ml), but it decreased following the ptx and pentaglobin ° therapy. it is presumed that ptx and pentaglobin ° can antagonize eytokine production at different levels, resulting synergistic action being beneficial in the treatment of sepsis. albert szent-gy rgyi medical university, institute of microbiology, szeged, hungary h- ddm t. . e~i~im~/tii, septic sh ~ '. tnf alfa/pge, and somatostatln lands ji., alvarez j., gram m., llanos k., alcalde j., sanchez ja., balibr~d jl. taurine, a semi-essential sulphur-containing t:~-amian acid, promotes neutrophil phagocytic activit ' against yeasts and enhances intracellular killing of e.coli. paradoxically it protects against hypochlorous acidmediated biomembmne oxidatio~ and abrogates the pyrogenic effects of intracerebral endotoxin. it is therefore possible that taurine mediates some of these effects by modulating the cytokine cascade. aim to assess the cytekine responses in a rat model of intraperitoneal sepsis, pretreated with supplenmntary taurine, by measuring tnf and il- concentrations. methodology female wistar rats (wt - g) (n- per group) were prefed with % tanrine, . % glyciuc ( in tap water) or tap water (tw) for days prior to caecal ligation aud puncture (clp). normothermia was maintained intraoperatively and the animals received . % saline subcutaneously ( mls/ g) post-procedure. animals were venosected by direct cardiac puncture at or hours post-operation and the blood placed in endotoxin-free tubes. centrifilgation and storage of plasma at - °c was completed within hours. tnf and il- were measured using wehi and b bioassays respectively. results (means ± sem) bioactivc tnf concentrations were not significantly different between clp or sham groups. however plasma il- estimation revealed a statistically significant reduction at hours in tanrine-treated animals compared to glycino and tw controls ( objective: to evaluate the effects of allogeneic blood transfusion, thermal injury and bacterial garage on interteukin (il- ), tumor necrosis factor alpha (tnf) production and host mortality and to study if the administration of thymopentth (thy) could affect these events. materials and methods: balb/c mice were transfused with allogeneic blood (from c h/hej mice) and treated daily with thy (i mg/kg)(t+thy) . control animals were transfused but not treated (t). after days systemic blood was harvested to determine the circulating levels of il and tnf. a second group was treated with thy for days and then received a gavage wide lxl escherichia coli and a % burn injury (bg+thy). one hour post-bum, blood was collected to measure cytokins. control animals received the same treatment but thy (bg). a third group was transfused, treated with thy for days and then received gavage and burn (tbg+thy). one hour post-burn, blood was collected to measure cytokins. control animals received the same treatment but thy (tbg). all treated and control groups had mice/group. in separate groups (n= /group), receiving the same treatments, mortality was observed for days post-burn or transfusion. the production and release of oxygen radicals by phagocytic leukomytee is one of the most relevant and important functions of these substances in biology. when neutrophilic granulocytes or certain macrophages phagocytize they produce super oxide and hydrogen peroxide and form secondary products of these activated species. all of these substances are released in to the phagosome. it has been appreciated since that the amount of oxygen consumed by phagocytes in producing free radicals is prodigious. what has not been totally appreciated is the significant contribution this consumption contributes to total body oxygen consumption. our understanding of increased oxygen consumption following sepsis is compounded by a paradox of increased cardiac index and a narrow av difference. it was mclean in a study reported in that showed an increase in cardiac index and a narrowing of the avo z difference in humans following sepsis. other studies documented similar changes in humans and it has recently been speculated that increasing o~ delivery might have a favorable impact on outcome. at least three different explanations have been put forward as to why there are possible alterations in energy metabolism during sepsis. these include decreases in oxygen supply, peripheral shunts and direct action o~ cellular mediators on o~ delivery, a provocative review by hodgkiss and nark in shewed that in experimental animals sepsis did not cause any evidence of bioenergatic failure in muscle i liver, heart or brain tissue. they further showed that the increase in serum lactate is mot necessarily due to cellular hypoxia. they conclude that cellular hypoxia and defects in energy producing metabolites are not the cause of metabolic abnormalities in sepsis. we set out on a series of experiments to try to explain the paradox in cellular metabolism and whether or not white cells might contribute to total body oxygen consumption during sepsis. the first set of experiments involved growing rat cardiac myocytes on tissue culture. pyruvate was added to the medium as substrata and physiologic levels of peroxide were also added simultaneously, carbon labeled co~ production was measured as was nucleotides and degradation products from the cell. the peroxide induced a significant inhibition of pyruvate dehydrogenase. in addition, there was a loss of cellular atp and a corresponding rise in the release of inosine and adenine from the cell. we concluded from this first sst of experiments that physiologic levels of peroxide are a potent inhibitor of pyruvate dehydrogenase in isolated cardiac mitochendria as well as the cultured myocyte. we further showed that pyruvate dehydrogenase inhibition blocks the aerobic oxidation of glucose and leads te adenine nucleotide metabolism with adenosine and inosine release from the cell. other enzymes within the tca cycle did not appear to be specifically blocked by peroxide. this would explain the increase in lactate and the ability of the cell to continue to make high energy phosphate by entry of metabolites in to other entry points of the tca cycle, the second set of experimbnts was designed to estimate the magnitude of whole body reactive oxygen generation via nadph oxidase following granuloeyte activation invivo. using a guinea pig model baseline oxygen consumption was determined. ~iaphenyl iodinium (dpi) was used as a specific inhibitor of granulocyte nadph oxidase. animals were divided into two groups; those that received dpi and those that served as control, all animals were then injected with phorbcl myristate acetate (pma) intravenously. pma is a potent stimulus for granulocyte activation and subsequent reactive oxygen generation. whole body oxygen consumption measurements were then repeated after the p~la injection. in addition, arterial blood gas amalysis was performed, circulating neutrophils were collected and assayed for their ability to generate hydrogen peroxide and the r~ght lung was removed for wet and dry weight measurement. total body oxygen consumption increased by percent after pma injection. arterial oxygen tension fell significantly in the control animal. neutrophil hydrogen peroxide generation rate doubled and lung water in the untreated animals increased by percent. in this animal model we could show that granulocyte activation substantially increases whole body oxygen consumption to approximately percent of control values. the nadph oxidase inhibitor, dpi, decreases granulocyte hydrogen peroxide generation invivo and prevents the pulmonary injury induced by pma. using this animal modal it is possible to transpose this to the human septic state. if we assume there are , neutrophils per cubic millimeter of blood, a kg man would have ~ . xi u circulating neutrophils. when activated ixl ~ neutrophils generate one nanemole of hydrogen peroxide per minute. t~erefore, the circulating neutrophil pool could generate - . xi nanomoles of hydrogen peroxide per minute. this corresponds to an oxygen consumption of - . ml/ojmin by the circulating neutrophil pool alone. this does not take into account the production of oxygen by macrophages or the amount of oxygen consumed to produce nitric oxide. manipulation of oxygen delivery in human sepsis may or may not be beneficial. irshad h. chaudry, ping wang, and alfred ayala life threatening blood loss, due to soft tissue and bony injuries, is a frequent complication in trauma victims. although numerous organs and cells are adversely affected by hemorrhage, the focus here will be to discuss whether or not there are any differential alterations in splenic and hepatic immune functions. in particular, m~ antigen presentation (ap) and associated processes will be described since one of the important functions of the m is to activate resting t-cell lymphocytes by processing and presenting foreign antigens in a mhc class ii-restricted fashion. studies have shown that splenic m and kupffer cell (kc) ap was significantly depressed following hemorrhagic shock and remained so for at least h alter resuscitation. the presentation of antigenic fragments associated with mhc class ii antigen itself was not decreased following hemorrhage, but the catabolism of antigens in antigen-presenting cells was decreased. this is likely due to a significant loss of cellular atp. although m ap was depressed in splenic, as well as kc, only kc showed an enhanced capacity to produce inflammatory cytokines, il- , il- , and tnf. this difference in response between kc and splenic md may be due to differences in the microenvironment in which these cell populations are found, as well as potential differences in the effects that hemorrhage has on the environment from which these cells are obtained. splenic m from hemorrhage-resuscitated mice exhibited a significantly reduced cytotoxic response, whereas kc showed an enhanced cytotuxic capacity. the increased kc cytotoxicity is probably mediated through the increased expression of cell-associated tnf and the release of reactive nitrogen. the enhanced production of reactive nitrogen may play an important role in the clearance of microbes translocated from the gut following hemorrhage. however, excessive release of reactive nitrogen by kc may have deleterious effects on the adjacent hepatncytes. such an effect could, in part, explain the reduction in active hepatocellular function, which is seen following hemorrhage-resuscitation. thus, hemorrhage induces differential effects on splenic and kc m populations; it decreases splenic m but increases kc capacity to mount a cytotoxic response. the depressed splenic md and kc ap was, however, significantly improved by posttreatment of animals with atp-mgcia, chloroquine, diltiazem or interferon-'/. these agents also decreased the susceptibility to sepsis following hemorrhage. thus, the use of atp-mgci~, dfltiazem, chloroquine or interferon- offers new therapeutic modalities in the treatment of immunosuppression and for decreasing the susceptibility to sepsis, which is observed following severe blood loss. the production of macrophages from bone marrow precursor cells is a dynamic and highly regulated process. the differentiation of myeloid lineage-restricted progenitor cells is initially controlled by interleukin- , which drives the progenitors along a maturation pathway that leads to their response to specific lineagerestricted colony-stimulating factors(csfs) we have previously hypothesized that thermal injury can initiate a self perpetuating cycle of production of defective immune cells: thermal injury can initially affect circulating immune cells. then these cells, by unbalanced production of colony stimulating factors and other mediators, can cause a derangement of hematopoiesis resulting in an abnormal production profile of tnf, il-i, and il- and cytotoxic activity of bone marrow derived cells. the results of our studies so far have supported parts of this hypothesis. il- and il- +m-csf treatments increased the production of tnf in burn day macrophages and progenitor cells compared to normal cells. il- +m-csf+il- increased the production of il- by burn progenitor cells compared to normal macrophagee. preliminary results for the ratios of tnf/~ actin mrna indicate that il- +m-csf increased the mrna for tnf in the -day macrophages derived from burned animals compared to macrophages derived from normal animals. ratios of il- /~ actin mrna indicated that il- , il- +m-csf, and m-csf increased the il- ~rna in progenitor cells from burn animals compared to progenitor cells from normal animals. these preliminary results support our hypothesis that bone marrow derived macrophages and progenitor cells from burned animals act differently compared to cells from unburned animals regarding the production of inflanunatory cytokines. more specifically, the results suggest that the different cell types are regulated in different ways by cytokines, and cells from burned animals are regulated differently than cells from unburned animals. it i,~ to ~ssume that the translneatinn is due to a ixx~h,v functioning ~astroiutestlnal surface pro|ection system, which leads to an unacceptably high load ¢ln the imrsunc dcfcncc system, partlcul~ly the local system in the gastrointestinal wall, leading tu exh~ustiou of ihi~ system. tlae g&~lrointesliual i]'ac( can be regal'deal a.s a t~ servojf of appr m ~ separating i~ eucayotic ceils of the hosl ttom l ~ bacterial culls. in the human body the the myriad of cndngan¢nts micrix)rganistns, exogenous itl,~ttdittg micro~ganisms altd taxies m-'e sepia"areal li'otll lhe rest of the body by a simple epithclhd layer. the barrier function is heavily tlcpcnding tm =~ proleclive layer cmtsisting ie. surl~:emts, nluclts, probiotic bacteria, and ,~ub~tances with strong antioxid~lt, antipfotease al~d other i~rotective eft'ecru, the surfaet~ml htycr consists at tile besl if i(.) bimolecular layers, fl is thus very iltil~, the epilhelial layer is renewed every hours , and tile tanuwer of the mucus is ~so fa,~t, all attdphy of die epithelial layei induced by g&sttointestinal st~'vation does also include the mu~usprndocing cells, gnhlet cells, which leaduhg lu slmnage aad luwer quality of gi mucus, altered viscoelas,jc properties and reduced protection, ]~'obioiic bactcrla keeps the ppm's low, produce nutrients for the intestinal mllcosa, eliminates tuxia~ and stimulates the local immune system, the gl surface is conslanlly under hc wv wearing by ingested bacteria and their enzymes, ingested substaucas, chefftie,'ds at~d toxins. 'll~e n~tective flora is reduced in disease, by stress and by cm'clcss antibiotic therapy. wc have made attempts tn recondition the i,,.astroiniesli!l~d. tnucosa by rcstlpply of surfactants or sttrfactanfliko glyc~lipids, gels with pseudomuein [until.oil, and probiotl¢ laetobaeilli. by supply of glycolipids we have bt:cn able m prevent and heal intlammatory and tlleerallve injuries (and io p)'cveut microbe transhteatkln) in uppe~' and lower (. u'acl, this c~al be fu~'ther augmentented by shnultaueos supply el' a p.~uedomucin,likc gel like pectin. ()at contain~ one hundred times more ot membrane lipid$ th~a =nay other food, much of fiber, ~spceially watcrsnlnhlc betaglucaal~, at~d has an close to ideal amino acid cornpo~ition, <')at, termented by species-specific lactobacilli, has a strol~ ability to prevent local inflammatory and ulcerative chunges,transh)cadnn and sepsis in experimeut~d attimals mid to pl~ven~ revert mof in ba,nan.~.lt seems us, that it the mucos~lnucus/probiotic bacterial filnclinns cat'= %' restated by mucosa reconditioning, even in severely sick iudividuals) the hx:~d iuuuuue ~y,~teme will be capable tu pr~)tec! the ix~y ag~lls~ sepsis ~nd mof. the impaired immune response associated with multiple system organ failure (msof) has been most widely studied following surgery for inflammatory disease and trauma. the majority of late deaths following trauma are due to infection and msof. not all patients with multiple organ failure have concomitant infection present, yet most have been septic at some time in their hospital course. their generalized inflammatory condition often persists whether or not organisms have been recovered. immune failure probably precedes msof with or without overt infection and indeed may perpetuate such widespread sepsis. macrophage tumor necrosis factor-alpha (tnf) production is thought to represent an important pathogenic mechanism by which this is mediated. cecal ligation and puncture (clp) is a clinically relevant murine model of intra-abdominal infection and sepsis. serum tnf and endotoxin levels, and peritoneal macrophage tnf production are only slightly elevated in this model even in endotoxin sensitive animals. mortality in this model, therefore, does not appear to be attributed to overwhelming endotoxemia and/or tnf production. it has therefore been postulated that tnf and other cytokines may act in a paracrine fashion to cause local injury. tnf messenger rna (mrna) expression was therefore measured and found to be increased in the lung and liver following clp. a different pattern of expression was seen after endotoxin administration, characterized by a more rapid rise and fall, and enhanced tnf mrna expression in the spleen as well. route of spread of infection as well as the type of stimulus may determine the organ specific cytokine response. these data support the concept of locally produced tnf as a contributing factor in tissue damage and multiple organ failure during sepsis. the estimation of histamine's role in sirs changed over the years based on increased knowledge in shock pathogenesis, evidence later found to be faulty, and the discovery of other, more fashionable mediators. over the decades, the prevailing view has been that histamine is a noxious mediator contributing to the fatal outcome of shock. the analysis of experimental data on exogenously administered, endogenously released and/or newly formed histamine in septic/endotoxic shock suggests that histamine contributes to the early cardiovascular changes via hi-receptor vasoconstriction thus excerbating (directly and indirectly) the effects of catecholamines. in the later phase of septic shock (low out-put, high resistance states), however, it can be assumed that histamine exerts strong vasodilator and positive inotropic effects via h -receptors. these effects are considered beneficial in counteracting or attenuating the effects of sympathetic responses of catecholamines and other mediators. thus, a blockade of the early reaction with hi-antagonists and a stimulation of the h -receptors by h -agonists are worthwhile therapeutic approaches. shock produc~s ~ij alterations, an encrgy crisis and eventual c~ll damage, however, shock in itse|f do~ not lead freqoenfly to r~mote organ damage. in animal ~xpcrhnents and clinical expariez:ces in korea and vietnam, shock i~r s¢ was not associated with lung damage, renal failure or ards. the same is true with g.l bleeding. however, when shock is due to trauma or associated with tlssus injmy, then organ malfunction m~d damage is frequent. shock is bclleved to increase the frequency of infection, but clinical evidcnc~ for this is scant. hemonhsgio shock akme is an unusual o~orrenee dinica[ly. immune dysfolletion dons occur witl~ experhnental hypovolemic shock and in pailcnts with hypotcnsion or after receiving blood ~ansfosions. tbc most significant factor affecting reoorrcnce of resented ca,lorectal liver mclastasis was hypotensivc episodes during operation. blood transfosions depress immune function, improve transplant ~raft survival and increase ttll'rmr rec~r'tcnos ill co[eli and head and nc~k cancers. in experimental hemorrhagic shock, we found decreased response of [ymphocytes to mitogens, el:clad mixed lymphocyte reactilln and i[,- decreased. othe~.x hsvc found decreased macrophage and t and b ¢¢lt function, deci~ased re,ease of/l~i, increased poe v depressed macrophagc antigen presanlatiota, increased ien y, decreased il- , and , and shared mscrophags funclion with loss nr f and c b r~ccpto~s. this is inhibited by chlornqoine, ibuprofen, dihiazem, and atp. shock may activate ncutrophils contributing to ilappitlg in cspillarics, no refluw, increased adhesion, cytotoxicity and organ damage. this may be related to decreased clearance of bacteria after shock. t~lls shock, hypotcnsion and decreased microcirculatory blued flow initiate or set the stage for immune dysfmtction. they, along with tissue injury trigger inflammatory cascades. this also contributes to immunologic dysfonctitm, which is associated with increased lufoction. thus altered bh,od flow and mediator cascades are bolh involved, the question now is can wc rapidly improve microcirculatory blood flow, and dg'masa inflsrmnatory fosponss, which is also necessary for survival the effe~ of ~nterferon ~amma @n wour~ healing was ewaluated ~n a routine mo~el. ~mma ~n~erferon we g~ven in doses of ~ . to ~ , u~%$ synchronous with ereatio~ of a pa~splnal woumd then daily for is ~lays. ~mteet~on ~amma impaired tensile strength a% all ~oses relative to control. m zphology suggested ~reas~ ¢oll~gen deposition and r~du~-~ neovag~ulaeit¥ ~n t~eat~ animals, interferon ~amma was a so ~valuated in a murine mo~el of cecal llgatlon and punneure. one hundred to ,s uni~ vere ~iv.n following ~nju~ an~ than daily. interferon qamma was associated with inco:ea~ed mortalit~ and earlier death a~/a~n ~n a dose dependant manner (p< , ). afmlnistra~ion the proinfiammatory cytokines tumor necrosis factor-c~ (tnf-c , interleukin- (il-ii ), interleukin- (il- ), and interleukin- (il- ) have been implicated in the pathogenesis of the multiple organ dysfunction syndrome (mods) following shock and trauma. these mediators which are released in high concentrations by activated macrophages, endothelial cells, and connective tissue cells cause a systemic inflammatory response syndrome (sirs), thus leading to a shock-like state and tissue destruction. recently, a number of proteins have been characterized in in vitro and in vivo studies demonstrating potent anti-inflammatory properties. these latter cytokines include interleukin- (il- ), interleukin- (il= ), transforming growth factor- (tgf-j ), and the newly sequenced interleukin- (il-i ). they are considered antiinflammatory, since in vitro studies using purified macrophage cultures or whole blood assays revealed an inhibitory effect of these antmnfiammatory cytokines on ~he synthesis and release of tnf-cl and il-u . in addition, they reduced the severity of disease and reduce plasma levels of tnf-c~ and il-ii when administered to animals with infection or inflammation. furthermore, naturally occurring substances have been described that specifically neutralize the bioactivity of il- b and tnf-a. the il- receptor antagonist (il-i ra) is related structurally to il-i and binds to the same cell-surface receptors, but does not stimulate the cell. in animal models ore. cob-induced shock, inflammatory bowel disease, and peritonitis, injection of il-lra significantly reduced the severity of disease. the cytotoxicity of tnf-c~ can be inhibited through two types of soluble tnf receptors (stnfr) type i (p ) and type ii (p ). these stnfrs are proteolytic cleavage products of the cell-bound tnfreceptors. when given to baboons to combat e. coil-induced shock, soluble receptm's to the tnf type [ receptor decreased the severi~ of the shock-like state. it has been well accepted that shock and severe injury result in an increased release of proinflammatory cytokines with a high incidence of sirs and mods. our studies investigating plasma levels of anti-inflammatory mediators (il- , il-lra, stnfrs) in patients after severe injury further suggest that shock and injury lead to an activation of anti-inflammatory processes with altered plasma levels of these mediators. however, while plasma levels of il- and l-lra were significantly increased in trauma patients compared to healthy volunteers, stnfrs did not differ from control samples. thus, shock and severe injury result in different activation patterns of anti-inflammatory processes. m,l. rodrick, boston, b~usa following severe thermal injury significant suppression of the immune response has been demonstrsfed. these changes are associated with increased susceptibility not only to co,on human pathogens, but to organisms not normally pathogenic in the uncompromlsed host. early observations included prolonged graft rejection and skin test anergy in patients following burn injury. work from our laboratory and that of numerous others has shown that the~e is a profound £mmunoeuppresslon following severe thermal injury. i~mune deficiency has been identified in these patients hyz ii lack cf t nell responses to mitogens, ) early decreases in total t and helper t cells in the peripheral bloo~ } lack of response to tetanus toxoid i~uniza~io~ in spite of increased non-speoifi~ i~k~unoglobulin praduction and ) severe and prolongei deficiency of interleukin- (il- ) prcductlon by peripheral blood mononuclear cells (pbmo). this il- deficiency could be an underlyin~ cause of all the afo~ementloned immune defects by failing to activate both helper and suppressor t cell functions. mo~a recent work has focused on the molecular mechanisms of this il- deficiency end shown that the defect lies post-transcrlptionally since mrna for il- is also depressed following thermal injury. we have also investigated the potential of a defect in ii- receptor status on peripheral blood mononuclear uolls from patients fqllowing burn injury and in a murine model. in both oases no decrease in il- r was found either by phenotypic markers or by funational assays. another hallmark of thermal injury is hyperao~ivatlon of proinflammatory ~ytok~ne secretion, which may play a significant role in multiple organ failure following burn injury. therapy o~ major burn injury may reasonably be aimed, therefore, at up-regulating t cell ~unction and down-regulating hyperactive secretion of proieflaam~ntory cytokines. the majority of patients dying of bums succumb to sepsis which coincides with dysfunction in the specific and non-specific host defences. generally, concepts relating to the mechanism(s) of specific immune failure in thermal trauma imply that inhibition of t (cd +) cell responses is imposed by the injury or infection-related factors. however, the same factors elicit strong biological reactions within the lymphoid compartment. recent evidence indicates that systemic activation is inherent in the burn patient. to establish the relation of molecular and cellular events to the development of post-bum anergy we examined the state of and the capacity for t cell activation with regard to: ) occurrence of activation-induced cell death (aicd), ) activation-related phenotypic and functional_ diversity in the pool of peripheral cd + t cells. initially, (up to days post-bum), peripheral blood lympliocytes from severely injured (> % total body surface area) patients exhibited high levels of constitutive expression of surface receptor for ]l (cd ) and spontaneous blastogenesis. the presence of activation-related t cellproducts in bum plasma was also apparent. subsequent impairment of the t cell receptor (tcr)-regulated t cell responses in vitro was accompanied by significantly increased dna fragmentation that is associated with cell death by the mode of apoptosis. using molecular markers we established that flesh peripheral blood ceils from immunosuppressed patients also contain large numbers of apoptotic cells. fluctuations in the number of viable (pi-) peripheral blood lymphocytes involved primarily cd +/cd ro+ (memory) subset of t ceils. the above observations suggest that thermal trauma-associated t cell anergy develops through aicd, a phenomenon commonly associated with the tolerogenic activity of bacterial superantigens. persistence of staphylococcal infections in the burn patient may support this assumption. response following trauma jane shelby, ph.d. the immune system is integrated with other physiologic systems, and is exquisitely sensitive to changes in nervous and endocrine systems changes following traumatic stress challenge. the immune, nervous and endocrine systems interact via both direct and indirect pathways which utilize neuro and endocrine hormones, neurotransmitters, neurepeptides and immune cell products. it is now known that the immune system may be affected by all of the neuroendocrine products produced during a stress response, with evidence for innervation of iymphoid organs, lymphoid cell receptors for neuroendocdne products, and leukocyte production of chemicals which are virtually identical to certain neuroendocdne peptides (acth, endorphins). trauma induced alterations in the equilibrium of various neuropeptides and neuroendocdne hormones have a significant impact on immune response potential, affecting control of proliferation, differentiation and function of immune cells. for example, the neurohormone melatonin is thought to be a natural antagonist to counteract glucocorticeid associated immunosuppression resulting from stressful challenges, such as surgery and trauma, plasma melatonin levels are known to be significantly reduced in burn patients. the administration of exogenous me[atonin improved cellular immune response following burn injury in an animal model. melatonin was also shown to have in vivo cytokine regulatory activity, increasing the potential for il- secretion and downregulating excessive il- and ifn~ in burn injured, stress susceptible mice. the regulatory interactions between the immune, nervous and endocrine systems provide mechanistic pathways for trauma associated immune dysfunction. increased knowledge of these interactions will enhance the potential for the design of novei clinical interventions to improve immune response and decrease the risk for infection in trauma and surgical patients. . animals receiving e were given a single dose daily of either . g/kg of e in a % solution by garage (ge), or . g/kg of sterile ive in saline. four hours following the last dose, bum animals were subjected to a % body surface area bum injury to their dorsum. twentyfour hours following injury, the animals were sacrificed and spleen cells were harvested for assessment of lymphocyte function. splenocytes were prepared by mincing the spleen, followed by incubation on glass petri dishes to remove adherent macrophages. non-adherent cells were then tested for proliferative response to t-cell mitogen concanavalin a (con a) and b-cell mitogen lipopolysaccharide (lps). data were analyzed by anova. results: chronic alcohol exposure and burn injury independently inhibit lymphocyte response to con a but not to lps. the combination of e plus bum injury, however, pmfouedly decreases this response to both con a and lps as outlined in the this data clearly identifies the synergistic impairment of immune function produced by ethanol and bum injury. it is furthermore apparent that ibis effect is gut mediated and that gastrointestinal exposure to alcohol is necessary to produce this effect. further studies will work to identify cellular and subcellular mechanisms to explain this effect. in experimental animal studies and investigations on human volunteers endotoxin infusion is mgulary accompanied by the release of the cytokine tumor necrosis factor a (tnf-~) determined by elisa technique. in patients with menigococcal sepsis also elevated tnf-a values have been found using a functional assay. we have studied the role of tnf-et in surgical icu patients with sepsis. using functional technique, we were not able to detect tnf-~ activities in the patient plasmas. when this cytokine, however, was determined by immunochemicai technique (el sa) elevated tnf-e~ values where frequently oberserved. in order to further elucidate these observations, we studied shedding of tnf receptors in the patients. in these studies, we noticed that shedding of tnf receptors oecured regulary in the patients. at the time of diagnosis, soluble tnf receptor p and p were both - fold higher than values found in plasma samples obtained prior to die diagnosis of sepsis. we also observed that the sepsis patients revealed higher maximum values of p and p during the icu stay compared to values found in surgical icu patients without sepsis. these observations indicate that soluble tnf receptors are available in sufficient amounts to bind tnf-ot which is released in surgical patients developing sepsis. this mechanism may explain why functional tnf-c~ was not detected in the patients. institute for surgical research, rikshospitalet, the national hospital, university of oslo, oslo, norway. decker, d., sch ndorf, m., bidlingrnaier, f., hirner, a., yon rfcker, a. the advantage oflaparoscopic cholecystectomy over conventional open surgical approaches in the treatment of symptomatic cholelithiasis has been shown convincingly by clinical studies. in order to facilitate comparisons of different surgical approaches, we evaluated the cell biological characteristics of tissue trauma by measuring changes in various cell surface markers on leukocytes and eytokines in plasma as a possible means to assess tissue trauma in choleeystectomy. patients recruited into our study had experienced at least one typical bifiary colic, had ultrasound-proven cholelithiasis (stages -ii according to me sherry), were - years old, and presented for elective choleeysteetomy. patients could choose between laparoscopic and conventional eholeeystectomy after being informed about the advantages and disadvantages of each procedure. cell surface markers on leukoeytes were determined using whole blood techniques with the help of commercially available fluorescent monocloml antibodies and flow cytometry. shed cell surface markers in plasma and cytoldnes were measured with the help of sandwich-elisa kits. blood samples were drawn h before surgery, immediately before incision (after anaesthesia), h and h after incision. seventeen cell surface markers were examined on different cell populations and cellular subsets in laparoscopic and open-surgery patients. three soluble cell surface markers and six cytokines were monitored. by statistical analyses (multivariate regression analysis, student's t test, wilcoxommann-whituey's rank sum test) the six markers/cytekines that best distinguished open surgical from laparoscopic procedurea were determined. these were . the interleuldn- receptor and im soluble form (cd /scd ); . the activation antigen fd- and its soluble form (cd /scd ), a member of the nerve-growth-factor receptor family; . the cd ro epitope which characterizes t memory ceils; . the trausferrin receptor cd ; . the soluble adhesion molecule icam- ; and . the cytokines interieukin- and interleuldn- . on the basis of these results, a tissue trauma activation (tta) index was calculated by combining the marker/cytoldne measurements by simple multiplication. anaesthesia and pre-ineision maneuvers did not significantly change cell marker or cytokine levels in either surgical approach as compared to h before surgery. h after incision the tra index in open cholecystectomy showed a distinct - fold increase, whereas in laparoseopic surgery a mere - fold increase was noted. h after incision, the tra-index returned to near pre-surgery levels. in conclusion, our results demonstrate that changes in cell surface markers and cytokines can help evaluate the magnitude of tissue trauma in diffei'ent surgical approaches. the relationship between lymphocyte subpopulation changes after thermal injury and the increased susceptibility of burned patients to infection is unclear. in this study, we have attempted to correlate such subpopulation changes with the presence of infection in burned patients. peripberal blood from patients was monitored for lymphocyte subpopulation changes three times weekly for three weeks postburn and weekly thereafter for three additional weeks. mean bum size was . % (range %- %) of total body surface and mean age was years. infection was diagnosed by carefully defined clinical and laboratory criteria and its presence or absence noted each time blood was drawn. samples taken when patients had wound infection, bacteremia, or pneumonia were compared with samples taken in the absence of systemic infection. whole blood samples were stained with four monoclonal antibodies, the red blood cells lysed and the leukocytes fixed and analyzed by flow cytometry. for each patient sample, the proportion of lymphocytes falling within the light scatter gates was determined as the percentage of cells negative for cd and most strongly positive for cd . this percentage was used to correct each sample for the presence of debris or nonlymphocytic cells. the proportion of cd and cd positive cells was slightly greatc~ in the samples from infected patients, while the proportion of b cells (cd +) was unchanged and nk (cd +) cells were decreased by ahnos[ % compared to sampie~ li'om uuiuleclcd patients. the percentage of cells positive for cdilb (c~ integrin) decreased sharply and cd ro (memory cells) decreased slightly in samples from infected patients while the expression of the lymphocyte homing receptor and cd were unchanged. cd (il receptor) and cd (early activation marker) were significantly increased in the samples from the infected patients while hladr was unchanged. these changes in lymphocyte phenotype correlate with the presence of infection. if they closely precede or occur during the early development of infection they may be valuable clues to the mechanism of susceptibility following thermal injury. trauma patients are subjected to an immediate massive impact on their host defense integrity due to the combined effect of tissue trauma, shock and endotoxemia. cytoldnes are playing a crucial role within the course of an impaired cell mediated immune response (cmi) resulting from a disruption of intact m%/tcell interaction. the current study was undertaken to further elucidate the mechanisms of dysfimctional cmi following major burn and mechanical trauma -via comparative analysis of mrna expression and protein release. the major regulatory levels for different cytokines were determined in mitogen, respectively lps stimulated peripheral blood mononuclear cell (pbmc) cultures of trauma patients on consecutive days ( ) t, , , and post injury. we analyzed the cumulative data for interleukin- beta (il-i[ ), il- , il- as well as tumor necrosis factor alpha (tnf-~) and saw a considerable impairment of the protein release in the stimulated pbmc cultures until d post-trauma and recovery thereafter. *p < . , ** p < . vs control comparing the autoradiographies of the specific cytokine mrna expression with the protein release in the supernatants, we saw a good correlation between mrna signal intensity and protein synthesis for il- and ,- , suggesting that for these cytokines the main regulatory mechanisms are located at the pre-/transcriptional level. for the other cytokines investigated one has to suppose posttranseriptional mechanisms. the analysis of our data clearly indicates a severe impairment of forward regulatory immune mechanisms following trauma. most likely the regulatory mechanisms, that are involved are greatly different among the cytokines investigated. it may be concluded, that depressed cmi responses post-trauma are partly due to an impaired pro-inflammatory cytokine production. the severity of the injury (iss) correlated with the development at multiple organ failure (mof-score; r= . ). the levels of mediators and markers of the inflammatory response were generally higher in the more severely injured group (iss> , n= ). i - , - , g-csf, fpa, and c a -levels differed significantly (p< . ) between the iss-groups (>-< iss ) at the time of admission, whereas on day tnfa, c a, - , and ealpi showed significant differences. beyond the first week, major differences were restricted to pge and c a. the formation of two groups with respect to later multiple organ failure (mof < ; mof > n= ) yielded similar results. leukocyte-facs analysis revealed significant differences mainly in the cd (monocytes), cd /cd (i - r + t-cells), and cd /cd (th calls) populations. summarizing our findings we were able to detect some alterations in the surface antigens of immunocompetent cells. the inflammato d response, however, seemed to be more pronounced and correlates wi~ the further clinical course. using an experimental bum model in rodents, we have demonstrated that administration of a full thickness, scald burn involving % or more of the total body surface area (tbsa) elicits systemic responses which are characterized by numerous alterations in t-ceu function (i.e., lymphokine production and contact hypersensitivity (ch) responses) plus an enhanced susceptibility to bacterial infection. in the present study we questioned whether the apparent systemic effects mediated by large burns would be elicited as site-specific alterations in immune function following administration of small area burn trauma ( % tbsa). following a % tbsa burn, ch responses to contact sensitizing antigens were found to be altered. the depression in ch responses could be induced independent of the site used for topical skin sensitization. following a % tbsa thermal injury, development of ch responses were affected in a site-specific manner. immunization of % tbsa thermally injured mice in a site near the position of the burn resulted in depressed responsiveness, whereas immunization through a contralateral site resulted in responses that displayed both the intensity and kinetics of a ch response equivalent to sham-bumed mice. similar systemic and site-limited changes in lymphokine production were observed with % and % tbsa thermal injuries, respectively. a % tbsa injury affected the lymphokine producing potential of all cells regardless of which lymphoid tissue the cells were isolated from. the effect of a % tbsa burn was significant but site-specific. thus, ceils from lymph nodes receiving drainage from thermally injured tissue were specifically affected, whereas lymphokine production by cells from lymphoid organs receiving drainage from unaffected skin was normal. it was concluded that modulation of lymphokine production and cellular immune responses may be a normal consequence of burntrauma regardless of the size of the burn. changes in immune competence can be mediated either regionally or systemically in direct proportion to the area of skin exposed to the burn injury. this work is supported by phs grant gm and the office of navy research n - -j- . division of cell biology and immunology, department of pathology, university of utah school of medicine, salt lake city, ut . post spleneetomy septic sequelae may be fatal, but the mechanisms remain unclear. the objectives ef this study were to assess the mortality from concomitant splen-'etomy and ]~eritoneal bacterial challenge and to elucidate the local cetkdar responses. cd- mice were randomised to receive laparotomy and sham splenectomy (l) or splenectomy (s) with simultaneous ca'-cal ligation and "):mcture and the survival patterns assessed. subsequently, cd- mice were randomised into control (c), l or s groups and peritoneal cells studied at hours for bacterial phagocytosis and killi:~g, superoxide ( -) and tumour necrosis factor (tnf) production and macrophage activation vsing mac-i(cd- b) receptor in~.ensity expressed es mean channel of fluorescence (mcf). these resides indicate that sf!enectomy predisposes to nrortal~ty from bacterial sepsis ia the early pos~ operative period compared to sham operated animals. failure ~f p'.acrophages to kill bacteria in the splenectomv group '~:cured in t?~e absence of impairment of oxygen freeradical or tnf pred:~ctien. the macrovh~ge ac!ivotion marker mac- was significantly reduced in both l and s groups and impaired phagocytosis of bacteria oceured in both operative groups compared to controls. laparotomy a!one reduces macrophage activity in terms of surface re:eptor mac- expression and !ingestive capacity. splenectomy however s~gnificantiy ~mpairs r-acrophage-wediated l~,acterial killing and this qefect rttav co~tribut~ sig~ifjcav'ly to th-~ dissemination of local infection and to n':ortalit). depts of haem~ tology & surgery, beaumont hosoital, dub!in ,eire. introduction: loss of cell membrane integrity appears to be a common pathway of injury to tissues subjected to high-voltage electrical shock. the cell membrane is the most heat labile structure in the cell, and is also the most vulnerable to externally-imposed electrical forces. skeletal muscle and nerve cells are particularly susceptible to electroporation by clinically relevant electric fields. restoration of membrane integrity is essential for cell survival in victims of electrical shock. we have studied the effect of non-ionic triblock copolymers ( poloxamer class) on the transport properties of isolated rat skeletal muscle cells following electroporation-induced membrane disruption. - mm long adult skeletal muscle fibers were isolated by enzymatic digestion from the rat flexor digitorium brevus and maintained under standard culture conditions. they were loaded with the calcein-am dye and placed in a ,c chamber for recording by real-time video confocal microscopy. the cells were subjected to msec, v/era, a field pulses with a low duty cycle to allow thermal relaxation. peak temperature rise was , .c. the uye content of the cell was monitored in real time. experiments were carried out in calcium-free phosphate buffered saline, with mm mg%. experiments were repeated with mm neutral dextran ( the aim of the present paper is to ascertain if thuracotomy induces a different pattern of variations of cytokines, immunocompetent cells and antibodies from laparotomy in the early postoperative period. patients ( males females,mean age: . _+ ) with gallstone disease and with non neoplastic pulmonary disease were studied. none of these patients received blood transfusion, biological response modifiers, radiotherapy or surgery for at least months before being included in our study. anaesthetic procedures were similar in all patients and none were matnourished. on the day of surgery and on the st and th postoperative days (pre, lpo, po) percentages of cd , cd , cd , cds, cdi were measured by means of flow cytometry using moab., and levels of ig a, lgg, igm, ige. by nephelometry cytokine levels in peripheral blood(il- , il- , il- , il- , tnf) were measured in pts. of each group by means of elisa using moab. _r. esults:variations of il- and il- were not s.s.. il- increased but differences between groups were not statistically significant (s.s). il-i decreased on po and increased on po in both groups but were only s.s. in the th.g., and therefore, the differences between groups were s.s (p< . ).tnf decreased in the l.g. and increased in the th.g. on the po, the difference was s.s(p< . ); on po, tnf decreased in the l.g. and decreased in the th.g. but these variations were not s.s. cell percentages decreased an lpo and increased on po, except for %cd cell that increased on lpo and decreased on po ,in both groups of pts. differences were not s.s. ig a, igm decreased and ige increased in both groups (p< . i), but differences between them were not s.s. in contrast, igg decreased on po (p< . ) and increased on po in both groups, but the decrease iu the th.g. was greater than in the l.g. twenty male children,aged from six months to years,admitted for elective inguinal operation were studied. the operations were performed under balanced combined anaesthesia (fentanyl,thiopemtone,vecuronium, % nitrous oxide in oxygen) and blood samples were collected before flunitrazepam premedication,after anaesthesia, and hours after anaesthesia. cells from the wound were collected with cellstick sponge which was removed from the wound or hours after anaesthesia. the study was approved by the local ethical committee. the percentage of neutrophils was increased and that of lymphocytes was decreased in perpheral blood after the operation.the values in the wound were close to the values found in peripheral blood. the percentage of t-lymphocytes (cd ) and helper-t-cells (cd ) decreased in peripheral blood being lower in the wound than in peripheral blood after the operation. the percentage of t-eytotoxic cells (cd ) also decreased in peripheral blood and was similar to that in the wound. b-lymphocyte (cd ) percentage was increased in pe~pheral blood after the operation and was higher than in the wound. the percentage of activated t-cells (cd +hla-dr-positive cells) in peripheral blood increased while that of natural killer cells (cd +cd +leu -pos) was increased just after anaesthesia being decreased at g and hours after the operation. spontaneous lymphocyte proliferative responses didn't change while phytohemagglutinin a and concavalin a induced responses were decreased in peripheral blood samples hours after the operation with recovery at hours.pokeweed mitogen induced lymphocyte proliferative responses were decreased at hours (p<o. ) and hours after the operation we previously reported that plasma ige increased after traumatic injury. in this study, we measured plasma ige ievels in trauma patients on hospital admission and x weekly in the intensive care unit to evaluate ige kinetics. patient characteristics were: mean age -+ years ( m, f), mean injury severity score (iss) + , sepsis ( patients), sepsis syndrome ( patients), ards ( patients), renal failure ( patients). ige increased in patients ( %). the mean increase was ng/ml (range to ng/ml; % ci was to ng/ml). increase in plasma ige was significantly greater in patients with sepsis syndrome (p= . ) and renal failure (p< . ). although mean plasma ige was higher with ards, pneumonia, hepatic dysfunction, and shock, these differences were not significant (p> . ). plasma ige increase was not related to severity of injury by iss score (p = . ). the mean day to highest ige was . -+ . . the day sepsis was first observed preceded the day of highest ige by . + . days. there was a significant association between the day of sepsis onset and the day of highest ige (p= . ). eight of nine patients with sepsis syndrome had > % increase in plasma ige from admission. one patient's ige levels were normal ( - ng/ml) for days and then increased to ng/ml over the next days, after onset of sepsis syndrome. changes in ige plasma levels may reflect the action of cytokines, such as il- , which concurrently regulate production of ige and il- receptor antagonist in a response to sepsis. sepsis remains a leading cause of late mortality in trauma and hs. although hs-induced bacterial translocation is supposed to be the major cause of sepsis and mof, depression of the res increases susceptibility to infection after injury. the purposes of this study were: a) to evaluate the res in the lung, spleen and liver after hs and subsequent hypertonic saline (hsl) treatment, and b) to document the patterns of phagocytic activity in these organs during hrs. adult male wistar rats ( +_ gin) were submitted to hs (sbp tort) and after t hr (shock i hr) and hrs (shock hrs) hsl (nac . %, . ml/kg) treatment, e. coli (i ) was injected into the portal vein ~tci (n_> ). twenty minutes later, the lungs, spleen and liver were harvested and scintilographic counts obtained. data is depicted as mean_%+sem * p< . , ~" p< . and statistical analysis was performed by analysis of variance and wilcoxon tests. one hr after treatment, lung uptake was increased and liver and spleen uptake were reduced compared to sham. twenty four hrs after treatment, all organs, except lung uptake, returned to normal values. radioautographic histological analysis revealed radiolabeled particles inside phagocytic cells of all organs. we conclude that pulmonary phagocytic activity increases after hr of hs hsl reatment, diminishing by hrs although still above normal values. in contrast, res suppression occurs in liver and spleen after hr hs hsl treatment, returning to normal values by hrs. these results may explain lung complications and immunosuppression after trauma. infusion of endotoxin as well as major surgery is followed by lymphopenia in peripheral blood. the purpose of this study was to investigate to which tissues the lymphocytes are redistributed in response to endotoxaemia and major surgery. in addition changes in lymphocyte subpopulations and expression of mecii was measured. lymphocytes were isolated from peripheral blood of rabbits, labelled with indium-tropolene and reinjected intravenously into the rabbits, i rabbits received an infusion of escherichia coli endotoxin ~g/kg, while i rabbits were subjected to a major sham operation and i rabbits served as a control group. the redistribution of lymphocytes were imaged with af gamma camera, and calculated with an interfaces computer before, and , and hours after major surgery or infusion of endotoxin or saline. interleukin-l~ and serum cortisol were measured. in addition we followed cd , cd , cdlla/b, cdis, cd , cd , mhcii and cd /cd ratio. following endotoxaemia interleukin-lf~ increased significantly, following endotoxaemia as well as major surgery serum cortisol increased significantly. following major surgery as well as endotoxaemia there was significant lomphocytepenia in peripheral blood with a decreased cd /cd ratio while the cd positive subpopulation increased. in addition there was a decrease in the expression of mhcii on the lymphocytes peripheral blood. the radioactivity of the lymphatic tissue in and around the intestine increased to % of initial values following endotoxaemia and to % following major surgery. the results indicate that endotoxaemia as well as major surgery induces redistribution of lymphocytes from peripheral blood to lymphatic tissue. among the lymphocytes staying in peripheral blood there was a decreased expression of mhcii and a relative decrease in cd cells compared to cd positive lymphocytes. in order to analyze the effects of immune suppressive substances on expression of mrna of interleukin- (il- ) and interleukin- reeeptor(il- r), this study was carried out. twenty male rabbits with comminuted fracture were used in the study. ten ml blood were taken at , i, , , days after injury. the sera were tested for the effects on lymphocyte blastogenesis and induction of il- stimulated by concanavalin a(con a): the sera from the rabbits days after injury were analyzed with sds-page gel eleetrophoresis, and divided into three groups by ultrafiltration (ufpi ttk, kd,milipore; centricon- , kd,amicon), that are less than kd, between i and kd, and more than kd. each group of the substances also was tested for the expression of il- and il- r by the dot blot hybridization. the results showed that: i) all sera from the rabbits after injury had significant suppression on lymphocyte proliferation and secretion of il- by the con a-stimulated splenocyte in mice; ) the sera from the rabbits days after injury had more profound suppression than other injured sera; ) there was a marked band at about kd in sera from the rabbits days after injury, but nothing at the same position in normal sera analyzed with electrophoresis; ) the substance with molecular weight of about iokd had more obvious suppressive action on expression of mrna of il- and il- r than other groups substances, of which molecular weights are more than kd. it is concluded that: i) the sera from the injured rabbits can reduce immune response; ) there is kind of substance, of which molecular weight is about kd, it is probable the main factor involved in the pathogenesie of postinjury suppression immune; } the substance can depress the expression of mrna of both il- and il- r. research institute of surgery daping, chongqing, p. r. china acute ethanol uptake prior to injury modulates monocyte tnfo~, production and mononuclear cell apoptosis. g. szabo, b. verma, p. mandrekar, d. catalano monocytes (mo) have been shown to contribute to immunosuppression after both major injury and alcohol consumption. we reported that acute ethanol exposure of m( results in decreased antigen presentation, induces tgf- and pge while inhibiting inflammatory monokine production. we also showed that post-trauma immunosuppression is mediated by hyper-elevated mo tnfc~ and il- . consequently, here we investigated rnonokine production in trauma patients (n= ) who had elevated (>o.lmg/dl) or had no blood alcohol level (n=t ) at the time of emergency room admission. none of the patients had chronic alcohol use history. met tnfc~ production from trauma patients with prior alcohol uptake was undetectable during days - post-injury in contrast to patients without alcohol exposure. furthermore, decreased tnf~x levels were found in alcoholic patients' mci after mdp or ifny + mdp induction. however, mcl tnfc~ levels during the - days post injury period became higher in alcoholic trauma patients. furthermore, over days post-injury, alcoholic trauma patients showed significantly elevated mci tnfo~ production after adherence isolation, mdp, or ifn+mdp stimulation compared to patients without alcohol. these results suggest that acute ethanol uptake prior to injury decreases tnf(x inducibility in the early post-trauma period, but these patients' mo produce hyper-elevated tnfa levels later post-injury, thereby prolonging their cytokine shock risk. tnf ng/ml - days post-injury days post injury stimulus ale. pt. pt . . . . immunosuppression might also be increased by the elevated apoptotic activity found in trauma patients' mononuclear ceils, which was even greater in alcoholic trauma patients' cells. in non-alcoholic trauma patients' preactivated mo, in vitro acute ethanol ( - mm) exposure resulted in a significant down-regulation of tnfc~ (p< . ) and il- (p< . ) production. in contrast, in vitro ethanol exposure increased the production of inhibitory monokine, tgfi]. these results provide both in vivo and in vitro evidence for the effect of acute ethanol exposure increasing immunosuppression and cytokine shock. the 'systemic inflammatory response syndrome' (sirs) with consecutive septic multi-organ dysfunction represents the major cause of late death following major mechanical and burn trauma. systemic hyperinflammation and concurrent depression of cell mediated immune response (cmi) render the traumatized host anergic, resulting in profound susceptibility to opportunistic infection. monooytes/macrophages (mo) play a central role within the host defense system in developing and manifesting states of injury, shock and sepsis. the mechanistic scrutiny of the synthesis patterns of crucial cccytokines appears to be a helpful tool to further analyse mo behaviour in the compromised individual. the objective of this study was to further dissect the characteristics of cytokine regulation in pbmc under stressful conditions, via analysis of the expression of cd + receptor, the proinflammatory mediator il- , the macrophage activating factor ifn- ,, and neopterin (npt) a metabolite of activated mo. we investigated pbmc's on consecutive days , , , and after mechanical trauma of and after bum trauma of patients (mean age ~ years; mean iss ± pts). in trauma patients we saw a massive increase of pha induced neopterin synthesis compared to controls. however, when discriminating the npt levels in the supernatants for the amount of mo stimulated, the npt output of the individual cell was lower compared to mo of nontraumatized individuals. interestingly there was a contrary coarse in the cumulative protein release patterns of il- and ifn- in mechanical versus burn trauma patients. wheras in burn patients ifn-y was decreased significantly ( + u/ml) compared to controls ( + u/ml) as well as mechanical trauma ( + u/ml). il- showed a significant suppression following mechanical trauma ( + u/ml) vs control ( + u/ml) and bum patients. the rt~,na signal intensity for beth eytokines was in concurrence with the protein release in more than % of the individual patients investigated. from these data we can conclude that the inadequate low npt synthesis predominantly in bum patients appears to be a sign of cellular immaturity and is probably partly due to low t-cell ifno t signals. in addition we could state that the quality of trauma is apparently responsible for the different synthesis patterns of ]l- and ifn-q,. it has been postulated that bacterial invasion or endotoxemia are necessary for cytokine production following burn injury. we studied the organ distribution and kinetics pattern of il-fc~ (cell-associated il- agonist) in eutrophic rats subjected to either % tbsa cutaneous scald injury (bi), muscle scald injury of equivalent % tbsa (mbi), sham muscle bum (resection of skin only, up to % tbsa) (smbi), and sham cutaneous burn (sbi), followed by saline resuscitation ( mukg i.p.). separate rats were infused with mg/kg e.coli :b lps or saline lv. unmanipulated rats were baseline normal controls. liver, lung, spleen, ileum, thymus, kidney, skin, and plasma were harvested at various time-points within the first h. tissues were frozen, weighed, homogenized, the homogenates centrifuged and the supernates assayed with a radioimmunoassay specific for rat il-l(z (detection limit pg/rnl). il-lc~ was expressed as ng/g weight + sem (lowest detectable amount . ng/gwt). il-lo~ was constitutively present only in the skin ( + . ng/gwt). cutaneous burn and sham cutaneous bum induced biphasic elevations of il-lcc in the liver and lung only, with maximal levels at . h (in the liver, bi = . _+ . ng/gwt, sbi = . + . ng/gwt, p _< . ; in the lung, bi = . + . ng/gwt, sbi = . + . ng/gwt, p -< . ). of note, both bi and sbi rats had detectable il-i~ in the liver at timepoint already ( min real-time). these levels increased in parallel until min and became eventually different by log at - . h. all other organs as well as plasma were below detection limits. muscle burn injury and sham muscle burn (skin resection) induced similar elevations of il- ~ in the liver at lh, indistinguishable from each other and from cutaneous burn. in contrast, lps challenge induced dramatic elevation of il-t~ in all organs tested except for the kidney; the spleen was the most responsive organ to lps-induced il-lo~ production. these data indicate that thermal or mechanical injuries induce very early and organ specific production of il- c~ in vivo by mechanisms other than endotoxemia. injury-induced complement and platelet activation may be involved as well as the neuro-endocrine axis, which may explain the low levels of il-lo~ induction observed in all rats at the very early time-points. trauma services, massachusetts general hospital, and department of surgery, harvard medical school. fruit, st, boston, ma . j. f. schmand *#, a. ayala* and i. h. chaudry* studies indicate that i.v. infusion of the colloid hes in normal animals does not adversely affect non-specific immunity. it remains unknown, however, if lies affects cell mediated, specific immune functions after trauma and hemorrhage (hem). to study this, non-heparinized c h/hen mice underwent midline laparotomy to induce trauma and were then bled to and maintained at a bp of mmi-ig for rain. the animals were then resuscitated with either times (x) the shed blood vohune as lactated ringer's solution (lrs) or x lrs + lx % lies. sham mice were neither hemorrhaged nor resuscitated. at or hours post hem serum, peritoneal (pm~) and splenic macrophages (sm~) were obtained. bioassayes were employed to assess the levels of ii-l, il- ( alternatively pmqb showed no differences in il- release between all groups at and h, while sm~ from the lrs + hen group showed a depression at h. tnf production by pm~ was depressed in all groups at h and remained so in the lrs + hes group at h. sm~b showed decreased tnf release values in both hem groups at and h. in summary, the levels of inflammatory cytokines (particularly the values of circulating il- ) after trauma/hem are positively influenced by the administration of hes. this might be due to a protective effect on pmqb and sm~, but also on other cytokine producing cells, e.g. kupffer ceils. we conclude that hes is not only a safe, but also beneficial agent in the resuscitation of patients atler trauma/bemorrhagic shock. this study investigated endotoxemia and consecutlve immune response in patients with multiple trauma (median injury severity score = , ). blood samples.were collected shortly after injury and after , , , , s and l days. endotoxin was measured with limulus-amebocyte lysate test and the specific antibody content (sac) against endotoxins of the classes igg, igm and lga by elisa-technique. five antigens were used: lipopolysaccaride (lps) of e.coli (ec), lipid a of e.coli (la), lps of pseudomonas aerog. (pa), lps of vibrin cholerae (vc) and cx-hemolysin of staphylococcus anreus (oth). a nephelometer indicated the total concentrations of igg, igm and iga. differences were checked with wilcoxon-test and p< , s was considered significant. cross-reactivity was calculated with rank correlation coefficients. results: endotoxemia peaked shortly after injury ( - h) at , eki/ml (median), decreased thereafter to , eh/ml at day s and remained on this level. sac oflgmclass increased to all endotoxins and peaked at day revealing the lfighest level to la followed by pa (= % of la-sac), ec (= % of la-sac) and vc (= % of la-sac). lga antibodies increased as well but only slightly and not significant (exception: sac to la was elevated significantly at day ). igg antibodies increased similar to iga class only slightly and again only sac to la was significantly higher at day and . however sac to (xh of all ig-classes remained continuously on the same level troughout the observation time. correlation analysis revealed strong cross-reactivity (r> , ; p< , ) most often between antibodies of igm-elass ( %) followed by igaclass ( %) and lgg class ( %]. conclusions: multiple trauma is associated with temporary endotoxemia. endotoxins probably translocated from the gut cause specific increase of anti endotoxin antibodies in blood of the igm-class. endotoxins cause no increase of antibodies to gramposilave bacteria. igm antibodies are most unspecific. during cardio-pulmonary bypass, as well as postoperatively, high levels of endotoxin, interleukin- (ii- ) and c-reactive protein (crp) were measured in patients. i female and male, ageing from to with a median age of . blood sampling was done preoperatively, immediately after induction of anaesthesia, after thoracotomy, after cannulation of the aorta and right atrium after the first half of the reperfusion phase, after closure of the thorax, and hours after the operation and then every morning until the th postoperative day. blood was drawn into heparinized tubes (i iu/ml) which were free of endotoxin. crp levels were determined through the use of the behring nephelometer. - levels were measured by using commercially-available elisa test. the endotoxin level was determined by a chromogenic modification of the limulus amebocyte test. the statistical analysis was done using the wilcoxon ranks test and correlation analysis. a significant increase {p . ) in endotoxin plasma occurred during surgery, culminating in a peak (median value of . eu/m!) during reperfusicn. plasma levels of endotoxin continued to be slightly raised till the th day after surgery, whereas those of interleukin- rose at the end of the operation and were at their highest hours later (median value of . pg/ml). crp levels were also high postoperatively with a median value of mg/l, and were markedly raised on day ( mg/l). a definite, statistically significant correlation between the plasma levels of endotoxin and - during the operation was establisthed (p . ), leading us to conclude that the endotoxin liberated during cardiac surgery acts as the main trigger in the releasing of - , and thus induces the postoperative acute phase reaction. there was no evidence of a correlation between crp and endotoxin or - plasma levels. impaired immune function is well described following trauma and hemorrhagic shock (hs). prior studies have utilized peripheral blood or spleen cells to index immune function following hs. however, changes in mucosal immunity are not weii characterized in this setting. gut origin sepsis is thought to be an important cause of organ failure and death following trauma. a rodent model was utilized to allow comparison of mucosal-associated immune function vs, systemic compartments after hs. fischer rates underwent hs (map ± mm hg) for minutes followed by resuscitation with shed blood and lr. sham animals were instrumented only. rat tears were collected at and hours following hs for quantitation of slga by ria. animals were sacrificed at hours and spleen (spl), peripheral lymph nodes (pln), and mesenteric lymph nodes (mln) harvested for cell population analysis using flow cytometry and mitogen stimulation analysis. cell marker expression analysis revealed no changes in t or b ceil populations following hs. mitogen mucosal immune function appears relatively spared following hs. the mechanism(s) for this variability in immune function requires further investigation. we have found that transplantation of bone marrow in a hind-limb graft to syngeneic lethally irradiated recipient is followed not only by rapid repopulafion but also overpopulation of bone marrow cavities. the question arises whether this unexpected phenomenon could be the result of stimulation of stem cells by factors (cytokines) released from surgical wound at the site of anastomosis of graft with recipient. aim of the study was to investigate which tissues damaged during the procedure of limb transplantation may be a potential source of humoral factors accelerating in vivo bone marrow proliferation. methods. experiments were carried out on lew rats in groups. in group i, the hind limb was transplanted orthotopically to a syngeneic recipient; in group ii, sham operation was performed; in group iii, a four-cm long cutaneous wound was made on the dorsum; in group iv, limb skin was harvested, fragmented and implanted into peritoneal cavity; in group v, bm from femur and tibia was implanted intraperitoneally. bm, lymphoid tissues and blood were sampled and days later for cell concentration and phenotype evaluation. results. the yield of nucleated cells from tibia was on day in the control . + . , in group . + . , in group ii . + . , in group iii . + . , in group iv . _+ . , in group v . _+ . x ( ). the evident increase in bmc yield in all groups continued until day . increase in weight and total cell count of spleen and mesenteric lymph nodes in all but group iii was also found. no differences in percentage of maturing erythroid cells, but higher of mature myeloid cells and lower of lymphocytes were observed. conclusions. trauma of skin, muscles, and bone brought about an increase in bone marrow cellularity and acceleration of maturation of myeloid lineage. transplantation of bm ceils alone did not produce this effect. transplantation of bm in limb graft is a good model for studies of natural factors reaulatin~ bm hemormesis. this study sought to determine a relationship, if any, between the degree of hypochclesterolemia upon trauma patients' admission and their subsequent outcome. all blunt and penetrating trauma patients admitted to a level i facility from through , and who had serum cholesterol assayed during the first hrs were retrospectively studied for development of death or significant organ dysfunction. the mantel-kaenzel chisquared test was used to determine significance of data at the p< . level. results: trauma patients were admitted during the four-year period who had serum cholesterol assays performed in the first hrs. patients had cholesterol levels less than mg/dl; of these ( . %) died, ( . %) developed ards, ( . %) developed acute renal failure, and ( . %) developed multisystem organ dysfunction; hypocholesterolemia in these patients was not due to liver injury or massive fluid administration. the risk of death was times greater and risk of multi-organ failure times greater in this group than in those with a normal serum cholesterol (>if mg/dl; patients; p< . ). conclusions: admission serum cholesterol level in the trauma patient serves as a powerful marker for those at risk of subsequent organ failure or death. hypocholesterolemia in this setting may result from organ hypoperfusion and humeral mediator release. lung tissue contains many immunocompetent cells. resection, therefore, is expected to activate extensively inflammatory mediators such as pmn-elastase, pmstanoids and pteridines. in a prospective clinical study we compared patients (pts) undergoing either thomcotomy with or without lung tissue msectioh and tboracoscopic lung resection concerning activation of inflammatory response. material & methods: group a pts (n= ) had thoraantomy but no lung tissue injury; group b pts (n=ls) had thoracotomy and lung tissue resection due to benign diseases; group c (n= ) represents group b tissue resection but using a thomcoscopic procedure. the following parameters were determined pre-, peri-, and postoperatively: elastase and crp as indicators of activation of pmn-leukocytes and injury severity; prostacyclin (pgi ) and thromboxane (txa~) as parameters of lung endothelial response; prostaglandin f ~ (pgf~) and pgm representing pulmonaly metabolic activity; pge a and neopterin as proof of macmphage activation. statistics were performed using analysis of variance for repeated measures. results: group b pts revealed postoperatively an increase in crp (p< . ) indicating a higher injury severity in comparison to the thoracoscopic procedure (c). both, controls (a) and group c pts did not show pmn-activation, whereas group b demonstrated a reversible increase in elastase. surgical trauma caused in all groups a release of pgi z and txa which was more pronounced in c (p< . ) and most in b (p< . ). similar results were found for pge~ and pgf =. there was no activation of maerophages since neopterin did not increase. apparently, metabolic lung function was not impaired because there was no marked rise in pgm except in b (p< . vs. c). discussion: our results demonstrate that lung tissue injury aggravates the mediator release induced by thoracic traum. these mediators among others are able to increase capillary pressure and hence lung edema formation. impairment of lung function, however, seems dependent on the extent of the liberation. therefore, the maximal release reactions occured in group b and c after lung tissue resection, whereas the controls showed the highest levels immediately after the incision. we conclude that thoracoscopic procedures are superior in reducing the resection trauma per se and hence might prevent severe mediamr-induced (pulmonary/systemic) sequelae. in a prospective study we investigated patients using radiochemical method according to sch~dlich (s) and photometric method according to hoffmann (h). serum of severly traumatized patients was withdrawn directly after admission at our emergency room and in narrow time intervals during first hours after trauma. follow up control samples were taken daily until day ten. whereas no elevated pla-ca was found during first hours, a peak was regularly observed around day four. there was high correlation between pla-ca and iss (r= . , p<o.o ) except patients suffering from thoracic trauma, thoracic trauma {tt) provoked similar gons-score-and pla-ca-values compared to multiple trauma (mt) despite significantly lower iss: pla-ca (h) mt . + . tt , +_ , n.s. pla-ca(s) mt . +_ . tt . _+ . n.s. goris mt . - . tt . _+ . n.s. iss mt - tt - p< . we found delayed elevation of pla-ca after severe trauma, however detection of delayed pla-ca in the serum of traumatized patients cannot give reliable information about the exact role of pla in the inflammatory reaction after trauma as latest results show that pla is secreted early but bound at lipophilic sites of vascular membranes. hern~mdez m j, amiguet ja, monreal ji, vid~n jr, jim nez f j, l pez-vivanco g acute phase reactant proteins increment in serum of patients with traumatisms and inflammation has been previously reported. alpha- antitrypsin (aat), alpha- macroglobulin (amg) and ceruloplasmin (cp) are evaluated in the following of patients, males and females (mean age: years), with compound fractures. % of them were located in tibia and fibula. intercurrent infection developed in patients and internal fixation rejection in one. measurements were made by radial immunodiffusion on days , , , , , and . a control group of healthy volunteers was also evaluated. aat and cp showed increased values from day which kept elevated untill the end of the study. amg elevated from day . when infection developed, aat and cp values were even higher whereas amg values decreased. fixation rejection caused aat, amg and cp increment. aat and cp increment in non complicated fractures might be due to accompanying inflamation, by means of cytokines release and aprps hepatic synthesis induction. therefore, increment is higher when infection or rejection develop. amg behaviour at early stages of evolution is secondary to hiperconsumption, considering mean life shortening after proteases ligation. amg modifications in fixation rejection remain obscure. aprps increment modulates inflammation and bony callus formation by means their antyprotease and antioxidant properties. clinically, aprps might be useful parameters in determining complications onset in fractures evolution. hemorrhagic shock (hs) is a common complication of trauma, as well as some major surgical procedures. the alteration of the immune system by hs is thought to contribute to the increased septic morbidity and mortality seen in these patients. multiple mediators are released following hs. il- , il- , tnf, pge and tgf-b have all been implicated in these immune system changes. in vitro, pge causes many of the immune system changes following hs, yet the time course of pge release has not been well deliniated. the aim of this study was to determine the time course of pge release by peritoneal and splenic macrophages following hs. c h/hen mice were bled to a mean bp of + mm hg for minutes. the animals were resuscitated with the shed blood and normal saline. control animals were cannalated, but blood was not withdrawn. the animals were sacrificed at , , , , and hours following hs. peritoneal and splenic macrophages were harvested from each animal and cultured with lps for hours. the supernatants were collected and frozen until assayed. pge was assayed using an elisa (cayman chemical). results are shown below for the peritoneal macrophages: pge release by peritoneal macrophages was significantly elevated at , and hours over control. it was maximal at hours, but by hours it had started to decline. splenic macrophage pge release was much more variable. (data not shown.) there was less consistency between time points and no clear trend was seen. in conclusion, pge is significantly elevated at hours following hs, and reaches a peak at hours. pge release may be responsible for the immune system changes seen in the first few days following hs. splenic and peritoneal macrophages respond differently in their release of pge following hs; which may be due to differences in their milieu. there is an obvious association between the altered immunocompetence of patients following traumatic injury of various types and the increased riskto develop complications. the present investigation was undertaken in order to analyze the value of both neopterin (n) and c-reactive protein (crp) in monitoring disease course in patients with multiple trauma. we were interested to compare nconcentrations as marker of t-cell/macrophage activation with crp levels as indicator of the inflammatory acute-phase response daily serum concentrations(n and crp) were measured in patients ( male, female, mean age . ), admitted to our icu following serious trauma (mean iss= ) and in control subjects. the clinical course of each patient was evaluated with apacheii score according to knaus. mean stay in icu was . (range - ). patients didn't develop organ failure(nof-group), patients survived, developing mof (s,mof-group), patients died with mof (ns, mofgroup). three patients(one s and two ns) showed signs of septicemia and septic shock. the serum samples were measured for neopterin (immu-test-ria, henning-berlin) and for crp (immunoturbidimetric method) -at the university hospital for internal medicine, innsbruck, austria. the highest crp levels were measured h after trauma, but they were not accompanied by significant increase in n-values. we found significantly elevated n-concentrations from the days - . n and crp levels showed a parallel release peaks on the days - and the values discriminated significantly among the three outcome groups(the second crp peak is lower in comparison to the first posttrauma peak). by the ns-group we found constant and parallel increasing crp and n levels, reaching extremly high values - h and preceding clinical signs of mof and sepsis. the values increased dramatically before death. the serum levels by all control subjects were upper the normal limit for n and crp.. the parallel occured peak changes in n and crp concentrations showed a significant correlation with clinical status, using a disease activity score (apac h eli). our findings suggest that both-cellular and humoral mediated immune mechanisms are activated after multiple trauma and that simultaneous determination of n-crp may be of advantage as diagnostic and prognostic parameter in polytrauma-patient monitoring panel. it is apparent, that measurement of very high levels may be of value as a srong indicator in developing of mof or septic complications and thus offer the possibility for earlier therapeutic intervention. the modification of t-cell/macrophage and acute-phase responses may be potentially useful in the treatment of icu patients, resuscitated after severe trauma, and suggest that n-crp may be relevant indicator for testing experimental immunomodulating therapies. although several in vitro studies suggested the catalytic action of iron in oxygen free radical generation, few data are available concerning iron-metabolism following ischemia-reperfusion injury and hemorrhage in vivo. aim of the present studies was to evaluate iron metabolism following mild and severe hemorrhage in the presence and absence of intraperituneal hematoma. methods. male lewis rats ( g) divided in groups (observation time hrs): a: mild hemorrhage by sequential blood sampling ( . ml each)( , , , , , , , , hrs). b: a with hemoperitoneum (hp)( ml/ g), c: hemorrhagic shock: blood withdrawal of ml/ g over min and resuscitation with ringer's lactate ( x shed blood) and isogenic donor blood; d: c with hp. parameters: serum iron ([g/dl], ferrozin-method); fe labeling of erythrocytas (application of ci fe i.a. into a donor rat, days later bleeding of the rat and injection intraperitoneally in experimental rat; plasma transferrin ([g/ml], ria). t-tests and mann whitney. data are expressed as mean + sem. results. compared to baseline, mild and severe hemorrhage caused a significant increase in serum iron at and hrs, respectively ( + vs. + ; +_ vs. +_ ). hp reduced this increase ( +_ vs. + ; + vs. +- , p<. ). i-ip significantly increased hemoglobin between to hrs in mild ( . +_. vs. . +. ) and severe hemorrhage ( . +. vs. . +. ). in mild and severe hemorrhage comparable maximal resorption ( fe labeled erythrocytes in circulating blood) of intraperitoneal hematoma occured at hrs (mild: +_ vs. severe: +- counts/rain). hp increased survival-rate following hemorrhagic shock (no hp: / ; hp: / ). in mild hemorrhage no alterations of plasma transferrin concentrations. in shock group without hp, there was at hrs a significant higher transferrin level than with hp alone ( . +_. vs. . + . ). in conclusion, hemoperitoneum with hemorrhage prevents increase in plasma iron levels by increasing hemoglobin through resorption of erythrocytes and thereby suppressing iron mobilization from endogenous iron resources, e.g. liver. this suggests that intraperitoneal hematoma not necessarily promotes iron-mediated oxygen free radical production, especially since survival in these groups was improved. increased transfarrin levels in group c at the end of the experiment suggest increased iron turnover which was not observed in shock groups associated with hemoperitoneum. primary immune response to thymus-dependent (srbc) and thymus-independent (vi-polysaccharide) antigens was determined during days after cct. antigenic challenge was made on day i, , or . number of spleen plaque forming cells (pfc) and serum haemagglutinin (ha) titre were studied on day after immunization. cct stimulated immune response to t-dependent, but not to t-independent antigen. enhanced response was noted when srbs were given in posttraumatic day i, it was higher than preceding one after injection on day and reached a maximum when antigen was presented on day after trauma (pfc number . times exceeded the level of immunized, but nontraumatized rats). the rise of pfc number in spleen correlated with increased ha level. thymectomy had been performed days before cct completely abolished posttraumatio stimulation of immune response to t-dependent antigen. standard thoracotomy also enhanced humoral response when srbc were administered on day after the operation. thymus trauma modeled by pincett squeezing of its right lobe and performed at the same time with thoracotomy fully abrogated as well as thymectomy stimulation of immune reaction. thus, different experimental chest traumas are able to increase antibody production via thymus-dependent mechanisms. endothelin is a amino acid peptide produced by ischemic or injured endothelial cells. in vitro and in animal studies, et is also a potent constrictor for renal mesangial and coronary vessels, a negative cardiac inotrope and an endocrine regulator. our lab has shown that et is an agonist for monocyte production of interleukins i, & , prostaglandin e (pge ) , and substances which trigger superoxide production. systemic et levels increase in hypoperfused and septic patients, and et may be yet another important cytokine in critical illness. but while et has been shown to be a potent vasoconstrictor in healthy dogs, systemic vascular resistance does not increase in critically ill patients with high et levels. (we hypothesize that this might be due to pgez-mediated vasodilation predominating over et-mediated vasoconstriction.) we next asked what happened to systemic et levels in patients with major burns (> %.) ten hemodynamically stable patients resuscitated by a modified parkland formula to a urine output > cc's per hour had et levels drawn on admission, at i, , , and hrs. et levels were measured by radioimmunoassay. mean levels were elevated at ± pg/ml at all time points versus levels in healthy controls of ± . in summary, systemic et levels increase significantly in patients with major burns. et may be yet another cytokine playing a significant role in the immune, inflammatory and multiorgan dysfunction observed with major burns. restoration processes in an organism after ischemic damage are realized through ~n~lammatory mechanisms~ the intensity of which is significantly defined by blood levels of neuropeptides. myocardial infarction (mi) was chosen for studyin these processes since it eradicates the influence of infectious factc~rs. dogs~ in whom mi underwent different forms o¢ healer, g; bhn~ed ~h~t during the acute phase of the disease there was a characteristic rise of ne!~ropeptides in the blood. these neuropeptides had nociceptive and antinociceptive effects. particularly substance p and -endorphins triggered off the development of compensatory and adaptive mechanisms and defined the intensity of inflammatory reaction at the zone of ischem~t: damage-notable fall in substance p levels after an ~nitial increase, while the ~-endorphins stayed high was an important condition for non complicated healing of mi. on the other hand high levels of substance p with low ~-endorphin concentrations lead to increased infiltration o~ neutrophils into the infarction zone and weakened the activity of synthetic processes~ thereby leading to left ventricular aneurysm. at the same time low intitial levels of substance p slowed down the development of necrotic processes which lead to delay in refunctioning of the heart and complicated the healing process. thus, regulation of the levels of neuropeptides in the blood in trauma forms a perspective method of its treatment. of laparascopic versus open choleocystectomy c. schinkel, s. zimmer, v. lange, d. fuchs, e. faist the impairment of immune function due to surgical trauma may be followed by deleterious septic sequelae. compared to open abdominal surgical procedures (lap), laparaseopic surgery (lsc) is associated with a decrease in hospital stay and in accelerated patient recover. the aim of the study was to evaluate the sensitivity of the immune sermn parameters of il- , saa and neopterin, the percentage of cd + cells, the in-vitro il- synthesis after mitogen stimulation and lymphocyte proliferation, in order to purposefully discriminate differences in the severity of trauma. we investigated the blood of patients with cholecystolithiasis undergoing either laparascopic ( ) or open (i ) cholecystectomy on consecutive perioperative days - , , and . there was no significant difference between the two groups concerning age and sex. patients with clinical signs of acute cholecystitis were excluded from the study. operation time and hospital stay were obviously longer in lap patients ( versus minutes, versus days) compared to the lsc group. concerning the unspecific acute phase reaction we could show no difference in the increment of senun amyoid a (saa) synthesis in the lsc group (d-i + lng/ml, d + ng/ml) versus lap group (d- + ng/ml, d + ng/ml), while in serum il- levels we saw a less steep increment in the lsc group ( -fold from d- to d ) compared to the lap group ( -fold from d- to d ). the analysis of cd + receptor expression and serum neopterin did not reveal any difference between the groups. lymphocyte function showed an impairment of proliferation to antigen stimulation in lap (d - : . + . cpm, d : . + . cpm) compared to the lsc group (d -h . + . cpm, d h . + . cpm). in both groups il- synthesis was decreased post-operatively. our data indicate that laparascopic cholecystectomy reusults in a less distinct unspecific acute phase reaction post-trauma compared to that following lap. neopterin serum levels and cd receptor expression show that these parameters apparently are less useful markers to detect differences of surgical trauma severity while it appears that the impact of lap is reflected most impressively on the lymphocyte compartment. trauma alters the host resistance of organism and is accompained by appearence of excgenic and endogenic proteins in the body. to understand the molecular mechanisms of host resistans disorders in trauma, as a first step, the genetic regulatory mechanisms of immune response after antigen injection has been studed. the appearence of specific protein factors ( - and kda), in the nucleus of rat splenic and brain cells, accordingly, was shown after immunization with sheep erythrocytes. the stimulatory effect of these factors on the il- mrna and il- production was detected. the nucleotide sequences of the human il- gene regulatory region bounding by the splenic nuclear proteins were determined between + - b.p. the il- trans-factors shows the affinity to splenic and thymic lymphocytes in vitro. thus, the antigen causes the appearence of specific protein factors in the cells,which act on the gene level,stimulate il- production and the host resistance. these results cause the next step of experiments using the same model, but after trauma. these investigations will let us verify the hypothesis that the protein il- gene trans-factors may play a definite role in the decrease of the cell immune responce after trauma. confronted with the routine procedure of prophylactic treatment of candidates for surgery in a rural african hospital, we initiated studies on the fre'quency of post-surgical malaria. in tanzania non-pregnant patients from rural areas were followed. of preoperative patients % had a parasitaemia and those maintaining it showed no increase or complaints. nine percent of patients without detectable parasitaemia before surgery came down afterwards and one-third had malaria-like complaints. spinal and general anaesthesia were equally applied in these last patients. in burkina faso we studied patients of which % had a parasitaemia on admission and % had postoperative malaria. half of the surgical patients came from rural areas, whilst only % of those with malaria lived in the city (with much less exposure and immunity). % underwent major surgery and % minor. bloodtransfusions ( % with parasites) never evoked a parasitaemia in recipients. post-surgical malaria is thus a reality in about % of the adult cases, both in east and west africa. surgery evokes a cascade of factors, varying from cortison to interleukines and acute phase proteins; immune responses may temporarily be suppressed. clinical attacks of malaria in otherwise immunes could be evoked by one of these factors. though malaria can easily be cured, the differential diagnosis is difficult because of post-surgery fevers; we found that % was treated without justified indication. the involvement of "student-doctors" a. this study examines glucose uptake and hexose monophosphate (i~ip) shunt activity in normal human peripheral lymphocytes and polymorphonuclear leukocytes (pmn). glucose uptake was determined by measurir,g the uptake of tritiated deoxyglucose, a non-metabolized glucose analogue. adsorption of co derived from [i- c] glucose was used to determine knp shunt activity. in vitro assays were carried out in hormone concentrations approximating normal and elevated trauma blood levels. (normal -cortisol . ~g/ml, glucagon #g/m , epinephrine ~g/ml, insulin t~u/ml; traumaeortisol . ~g/ml, glucagon /*g/ml, epinephrine ~g/ml, insulin ~ij/ml. analysis of twenty subjects showed a reduction of ° ~mp shunt activity by lymphoeytes and a ] % reduction in glucose uptake by p~n in normal vs. trauma hontc,nes p < . . lymphocyte glucose uptake was also reduced by trauma hormones p~ . . it ha~ be.ea~ suggested thgt idiopatno pulmonary fibrous (y.pf) [s a consequence of severe alveolar epithelial injury and is associated with an nveolar irnammamry reactio~ and the presence f.neutr phils. there~bre, neutr pk~ chemoattra~ant~ are probably important in the genegs oft.he infial lesions of ipf. the obse,"wson that stimulated macrophages are or~n histologically promin~t in fibmfio [-~gs ~.nd am capable of p~oducmg a v~dery f flbrogenic pep'ides also a~gues for their role ~n the pathogenic prc~e~ oflpf. the observation that stimume~ maerophages ere often histologica[iy prominent in fibrotio lungs and ~re ~pable of producing a varie~, offibroge.~e peptide~ also argues for tkek role in the pathogenic process, therefore, we ha-~e tested the potentn for iater!eukln- (i ..- ) and mo~tocyte chemotacde pop, de (x¢cp- ) to induce neutro~hil ~d mononuclear phagocyte accumuhdon in lungs of pafient~ with pulmonary .~r~idosis and i~f. brenet~o.alveolar lavabo (bal) fluids from ipf and sar~qidosis patient were conexntratea by reversed-phase chromatography, ~d ii. arid mcp-i asso.~ed by ells& ehemotaxis mad enzyme-reieasing ~ssas's on msnocyte~ and neatrophiis. elisa revealed significenfly elevated b al-eoneentrations o£mcp-i ( . ng]mg aibumm) in purisms with p~monary sarcoidodis artd in ipf ( . ng!mg) in comparises to . normal individuals ( . ng/mg) and to patients w~th obreic bronentis (cb) (~, rig/rag). similarly, chemota*dc ac~a~' for monocles (mcp- e.qu/va]ent) was strongly increased in sareoidosis ( . ngjmg) as well as ~n f pag,nts ( . ng/mg). norra.al indlvidu~s and cb patiants hzd a . or -fold lower ~cn%i~y, re~peefively. patients with ipf and sarcoidosi~ also h~l eievated il- ievei~ ( . and . rig/rag, respe~veiy; nomzls: . rig/rag; cb: . ng/mg) mad nvatropmi ohemotax~ ( . ~'~d . nnmg, res!z~ztiveiy; aormals: . ng,'mg; cb: l ngmg). these data suggest that increased ievels of born mcp. ~d il- may be oharacted~tie for ~arcoidosis or ipf_ it appears iikely that both ehernoattraetants ~ontribute to the influx ofmonocytes and neutrophils into the pulmonary alveoius and interstit~um in these dlsea~es. we have recently shown that the combined administration of noninjurious doses of lps and paf in the rat produce ards-like lung injury characterized by neutrophil adhesion to lung capillary venules, neutrophil accumulation in lung parenchyma, pulmonary edema, and increased protein and neutrophil count in bal fluid. this new paradigm of lung injury was associated with elevated serum tnfc~ and pretreatment with anti tnfa mab dose-dependently prevented these responses. also, the combined administration of lps and paf induced lung mrna levels of tnfe~ ( fold vs. lps or paf alone), ll-lg ( fold), kc ( fold) and il- . taken together, these data suggest that this new paradigm of lung injury is cytokinemediated and that lps/paf in vivo can functionally couple to the activation of gone expression of a multi-cytokine network system, all of which may be involved in the pathogenesis of ards. materials and methods. the sheep model included hemorrhagic shock and closed femoral nailing at day , hourly injections of e. coli endotoxin and zymosan-activated autologous plasma at clays - and further observation and measurements at days - . from venous blood and bronchoalveolar lavage(bal)fluid of ten merino sheep (mean weight kg) neutrophil counts ( e pmn/ml blood or epithelial lining fluid-elf-), the elf/ plasma ratio of albumin (r), and the zymosan-induced (stim) and non-induced (spont) chemiluminescence response (cl) of blood ( e cpm/ , pmn), and of blood-and bal-isolated pmn ( e cpm/ , pmn) were measured. for statistical calculations the wilcoxon test was used. data of the changes in polymorphonucleur leukocyte (pivinl) metabolism have been suggested to play a pivotal part in the post-traumatic systemic inflammatory response syndrome. the underlying cellular mechanisms which control this response are not yet completely understood. since the 'ca + second messenger'-system has been shown to be involved in regulation of pmnl-'respiratory burst', we investigated changes in pmnl-ca z÷ regulation in relation to oxygen free radical mediated injury. methods. in polytranmatized patients (mean injury severity score = ) arterial and venous blood samples during days. daily evaluation of horowitz-quotiant (po /fio ), plasma lactate (mg/dl) and body temperature ( results. body temperature peaked at day and (day : +. ; day : . +. ). plasma lactate was significantly increased at day l ( + ) and day ( . + ). hurowitz-quotient (day : + ) was low at day ( + ) and day to ( + )(p<. ). at day a substantial rise in venous pmnl-superoxide production (day : . +_. , day : . +. , day : . +_. ), oecured with significant increase in plasma lipid peroxidation (day : . + . ; day : . + . ). pivin~-myeloperoxidase activity was high at day ( . +--. ) and then continuously declined (day : . +. ). plasma antiexidant activity (glutathione pemxidase) was reduced by % at day (day : . +. ; day : . +_. ; day : . +. ). whereas basal ca + concentration remained unchanged (day : +_ , day : +_ ), fmlp-stimulated cytosolic ca + mobilization increased at day (day : + , day : , day : + ). conclusion. the present study in polytraumatized patients shows, that seven days after injury the agonist-induced pmnl ca + mobilization is significantly enhanced. at the same time, pmnl-oxygen free radical release and phagocytotic activity, systemic fever response and lactate concentrations were maximal. these observations were accompanied by post-tranmatic respiratory failure and in some patients by clinical signs of multiple organ failure. preliminary data from an ongoing study using hes-and dextran-infusions in these patients show attenuation of this inflammatory response. stefan rose, m.d., trauma surgery, univ. of saarland, homburg/saar donnelly sc, haslett c, dransfield i, robertson ce, grant is, carter c, ross ja, tedder tf. dept's of respiratory medicine, accident & emergency, intensive care, surgery, university of edinburgh, scotland and dept. tumor immunology, dana farber cancer institute, boston. the selectins are a family of adhesion molecules (l-selectin, e-selectin, pselectin), all of whom are implicated in inflammatory cell transendothelial migration. they, as a family can be proteolytieally cleaved from their parent cell and exist in a soluble form within the circulation. ards is a disease state in whic neutrophils and neutrophil transendotheliat migration have been implicated. in this study we wished to investigate whether the levels of these circulating soluble receptors from patients at-risk of ards at initial hospital presentation, correlated with subsequent ards progression. eighty-two patients were enrolled (pancreatitis (n= ), perforated bowel (n= ), and multiple trauma (n= )), of whom progressed to ards. assays for soluble l,p & e-selectin were performed on collected plasma samples via a sandwich elisa. (ns = not significant, **** = p<o. ) we have found a highly significant inverse correlation between a low circulating soluble l-selectin (and not soluble e & p-selectin) and subsequent ards. these results further our understanding of neutrophilendothelial interactions in the early stages of ards pathogenesis and offer the promise of sl-selectin in combination with other markers of inflammatory events being used to identify individuals at particularly high risk of ards progression on initial hospital presentation. it has been suggested that polymorphonuclear leukocytes aggregate in the lung capillaries of patients developing the adult respiratory distress syndrome (ards) and account for the endothelial damage while releasing toxic metabo-iites such as o.a. free oxygen radicals. among many antioxidants which have been investigated in in vitro systems and in animal models, n-acetylcysteine (nac) has been established to be useful as a free radical scavenger in vivo. to assess the influence of n-acetylcysteine (nac) on the activation of neutrophils in patients undergoing cardiopulmonary bypass (cpb) surgery with extracorporeal circulation (ecc), we evaluated the plasma levels of elastase and myeloperoxidase (mpo) throughout the operation and up to hours after surgery. four hours after surgery also a bronchoalveolar lavage was performed. a spectrophotometric method was used for the detection of plasma elastase activity and mpo levels were measured using a radioimmunoassay. we found that pretreatment with intravenous nac prevented the increase in elastase activity ( _+ pmol/i vs _+ ; p - . ), but not the release of neutrophil related mediators ( . _+ . ng/i vs . _+ . ; p= . ). besides, nac had the capability to prevent the enhancement of neutrophil numbers in lavage fluid as is normally seen during cpb ( . + . % vs . _+ . ; p = . ). although not significant, nac prevented also the increase in elastase levels in lavage fluid ( . + . pmol/i vs . + . ; p = . ). it is concluded that nac is able to protect against the inactivation of a -proteinase inhibitor, the main inhibitor of elastase activity, and that nac interferes with adhesion and migration of neutrophils. therefore nac may be useful in the prevention of tissue damage. this study is supported by inpharzam belgium. sodium nitroprnsside (snp) has previously been shown to attenuate the neutrophil induced lung injury associated with limb ischaemia and repeffusion. glyceryl trinitrate (gtn), already widely used in aortic surgery, also increases nitric oxide but has a less marked splanchnic "steal" effect. we examined the effect of gtn on lung injury, neutrophil infiltration and activation in a model of aortic occlusion ( rain) and repeffusion ( min). sprague dawley rats were randomized into: control (n=i ); ischaemia repeffusion (ir) (n= ); and ir treated with gtn ( ug/kg/min) during repeffusion (n= ). myeloperoxidase activity (mpo) measured pulmonary neutrophil influx. pulmonary endothelial permeability was measured by wet to dry weight ratio (w/d), broncboalveolar lavage protein (bal) and neutrophil counts (bal pmn). neutrophil superoxide release (mean channel fluorescence mcf) was measured by flow cytometry in a further ir v gtn experiment (n= per group). control _+t "* _+ _+ ** bal pmn/mm l+- " + # _~ *p< . , #p< . v control/gtn;**p< . v ir. students t test the significant increase in mpo activity produced by ir was attenuated by gtn. the increase in pulmonary microvascular leakage after reperfusion was also prevented by gtn. neutrophil superoxide release increased significantly from . + . to . _+ . mcf after minutes repeffusion (p<. ). this increase in superoxide was prevented in the gtn treated group. these results indicate that gtn inhibits neutropbil superoxide release during limb reperfusion, thus preventing pulmonary vascular leakage and neutrophil infiltration. these data suggest that the beneficial effects of gtn in aortic surgery may be due in part to a protective effect onpulmonary microvasculature. department of surgery, beaumont hospital, dublin , ireland. lipton adult respiratory distress syndrome (ards) is marked by increased vascular permeability of the lung to white blood ceils (wbc). indeed, influx of wbc into the lung is believed to be the central mechanism in acute lung injury of ards. evidence is developing that the neuropeptide c~-melanocyte stimulating hormone (c~-msh), a proopiomelanocortin derivative, inhibits inflammatory reactions in animai models of inflammatory responses in humans. to test the influence of a-msh on experimental ards, the peptide was administered to rats after intratraeheal infusion of endotoxin (s. typhosa, #g in . ml saline). three groups (n= each) received: intratracheai infusion of endotoxin plus ip injections of o~-msh ( ~tg in . ml saline) at , , and hr post-endotoxin treatment; intratracheal endotoxin infusion plus saline injections; control intratracheal saline infusion plus saline injections. the bal data showed overall differences among groups (f , = . , p<. ), o~-msh treatment inhibited endotoxin-induced wbc migration into the pulmonary tree (p<. ). circulating wbc counts were markedly lower in both groups given endoroxin than in the control group (p<. ), but there was no difference in wbc count between these two endotoxin-treated groups. the results indicate that c~-msh can reduce wbc migration in experimental lung injury. in further experiments we tested the hypothesis that c~-msh, administered alone or in combination with an inhibitor of gram-negative bacterial growth, increases survival in a model of peritonitis/endotoxemia/septie shock. cecal ligation and puncture were performed under sodium pemobarbital anesthesia ( mg/kg, i.p.) in female balb/c mice ( - g) that were then randomly assigned ( - mice per group) to receive at time and hr later: control saline thjectioas (i.p.), injections of ~-msh ( ~tg), gentamicin sulfate (i mg/kg), or both ~-msh and gentamicin. one ml of normal saline was given s.c. to each animal for fluid replacement. both ix-msh and gentamicin treatments administered singly improved survival; when given in combination survival was even greater these findings suggest that the anticytokine ot -msh molecule might be useful for treatment of systemic inflammation, perhaps particularly when used in combination with agents that inhibit bacterial growth. previous studies showed a close relationship between xanthine oxidase activation, membrane damage and postischemic cardio-respiratory failure following aortic clamping and reperfusion. aim of the present study was to evaluate alterations of polymorphonuclear leukocyte (pmnl)-metabolism and signal lransduction systems during ischemia/reperfusion induced by aortic clamping in man. methods, in patients ( female, + years) with elective reconstruction of infrarenal aortic anearysms, arterial (a) and venous (v) blood samples were obtained before clamping and declamping, and min after declamping. arterial pla concentrations were higher than venous ( + vs. + ). while cytosolic basal pmnl ca + concenlxation was not altered at the end of ischemia (v: . + ; a: _+ ) and during reperfusion (v: + ; a: + ), fmlp-stimulated cytosolic ca + mobilization showed a significant arterial increase as compared to venous ( _+ vs. + , p < . ). these presented data indicate that the reperfusion syndrome after infrarenal aortic clamping is characterized by ) pulmonary membrane damage possibly due to pmnl-degranulation, ) activation of pmnl-superoxide radical production with release of activated pmnl in arterial circulation, and ) a significant arterial increase of pmnl cytosolic ca + mobilization after fmlp-stimulation parallel to pmnl-activation. in conclusion, ischemia/reperfusion in man induces pulmonary damage and activation of pmnl superoxide production possibly due to an altered pmnl-ca + messenger system by inflammatory mediators (e,g. ii- , tnf, paf). the septic lung diseases (i.e. ards) generally show distinct alveolar damage and surfactant disturbances. it is thought that alveolar macrophages are involved in specific release products like h and cytokines like tnf. in this pathway the type ii alveolar epithelial cell (p cell) is not only an important target, but as recently shown it is also capable of producing h . the aim of this study was to investigate the influence of endotoxin on h release of p cells. we obtained p cells from lungs of female wistar rats and investigated the effect of lipopolysaccharid (lps) on h release of fresh isolated cells and on cells cultured for days in a fibronectin matrix. furthermore we conditioned isolated alveolar macrophages for hours with p.g/ml lps and tested the conditioned medium (mcm) on cultured p cells. p cells h ex vivo were _> % pure, _> % vital and had an basal h release of . _+ . nmol h per hour and million cells. adding p.g/ml lps to the incubation medium the h release decreases slightly but significantly to . _+ . nmol. adding . p.g/ml phorbol myristate acetate (pma) to the basal incubation medium the h release increased -fold to . _+ nmol. pma induced h release decreased to . + . nmol after addition of p.g/ml lps. after culture days the p cells were _> % pure and showed a pma inducible h release of . _+ . nmol addition of p.g/ml lps had the inverse effect as on freshly isolated cells as it increased the h release up to . _+ . nmol. addition of mcm to cultured p cells increases pma-stimulated h release to . +_ . nmol. the release decreased to . _+ . nmol when an murine anti-tnf-alpha antibody was added. vitality of cultured cells was > % in all experiments. the results show that lps has an direct effect on p cells cultured on fibronectin. we conclude that the observed additional stimulatory effects of mcm seems to depend on tnf-alpha. the induction of h release of p cells could be important for generating internal oxidative stress in p cells before external oxygen radicals exceed. the produced h did not necessarily damage p ceils, but it can effect surfactant metabolism, especially when extracellular h release of alveolar macrophages following an immune response is increasing. introduction: primary stabilization of femoral shaft fractures in patients with multiple trauma is beneficial. however, in patients with associated lung contusion we have found an increased incidence of ards, apparently associated with primary reamed femnral nailing (rfn). previous animal studies revealed, that perioperative disturbances of lung ftmetion appear to be related to the reaming procedure, ix~ssibly due to pulmonary embolizafion of bone marrow fat. in a prospective clinical analysis we compared effects of intrameduuary nailing with and withont reaming on parameters known to be related to ards-pathoganesis. in order to gain further insight into the role of endotoxin and cytokines in the pathogenesis of the adult respiratory distress syndrome (ards), we enrolled patients with severe lung injury after sepsis ( ) or polytrauma ( ) and obtained multiple blood samples ( days) for endotoxin, tumor necrosis factor e (tnfa), interleukin (il- ) and interleukin (il- ) determination. to evaluate the cytokine releasing capacity of the blood, plasma concentrations of tnfe, il-l and il- were also determined after the "in vitro" stimulation of the whole blood samples with lipopolysaccharide (lps, . ng/ml) for hours at c (stimulated values). the difference among stimulated cytokines levels and the basal plasma concentrations were defined as "delta values", an expression of the cytokine releasing capacity of the blood. the pao /fiao quotient was used as an index of the severity of lung injury (sli). the endotoxin plasma level was significantly higher in patients with sli < ( . ± . eu/ml, mean values ± sem) versus the patients with a sli > ( . ± . eu/ml, p<o. ). the basal plasma concentration of ll- also correlates with the sli index (p<o.o ). the delta tnfe and delta il- values were s~gnificantly decreased in patients with a severe lung injury. compared with the survivors (n: ), the deceased patients (n= ) showed higher endotoxin level, a reduced tnfa and il- releasing capacity of the blood and higher basal il- levels. we can conclude that endotoxemia, high il- plasma level and a decreased capacity of the blood to release tnfa an il- under endotoxin stimulation associates with the severity of lung injury. [objectives] experimental and clinical findings implicate the involvement of inflammatory cytokines in the pathogenesis of the decreased oxygenation in the lung after major surgery, though the mechanism remains unclear. in the present study, we elucidated the involvement of il- in the pathogenesis of lung injury defined by deterioration of pulmonary oxygenation after esophagectomy. [materials and methods] seventeen patients underwent subtotal esophagectomy through a right thoracotomy. in all patients, tbe alveolar-arterial oxygen tension difference (aado ) was measured everyday and bronchoalveolar lavage fluid (balf) samples were obtained from a single segment ($ or $ ) of the right and left lung through a bronchoscope on days l, , and days after surgery. they were then examined for cell analysis, measurement of cytokines by elisa, and measurement of neutrnphil elastase (ne) by elisa. [results] aado unexceptionally deteriorated postoperatively and the mean aado in patients reached the maximum (mean ± sem; _+ mmhg) on the rd postoperative day. the mean concentrations of il- , ne and neutrophil count in balf also increased postoperatively and reached their maximum level ( + pg/ml, -+ gg/l, and ± x cells/ml, respectively) on the rd postoperative day. these increases in balf were recognized in both the right and left lung. a highly significant correlation was observed between il- and ne levels in balf (r= . , p= . ). also, significant correlations between aado and the neutropbil count, and the concentration of ne or l- were observed. in contrast to il- , neither il- , il- nor tnfa was detected in balf. [conclusion] major surgical trauma such as esophagectomy may induce recruitment of neutrophils to the lung and cause lung injury. il- increased in the lung is an important mediator of neutrophil recruitment and activation in the lung. phorbol myristate acetate (pma) is commonly used to cause edema and other tissue damages in the lung. lung injuries induced by the administration of pma has been shown to be mediated mainly by neutrophils. neutrophils recruited to the lower respiratory tract may damage lung tissues by releasing reactive oxygen species, neutral proteases and lysosomal enzymes. the present study was conducted to investigate whether c~tocopherol, entrapped in dipalmitoylphosphatidylcholine liposomes and delivered directly to the lung, could counteract some of the pma-induced lung injuries. plain liposomes or c~tocopherol-containing liposomes ( mg c~-tocopherol/kgbody wt.) were instilled into the lungs of rats h prior to pma exposure ( pg/kg, intratracheally) and treated rats were killed h later. lungs of control animals exposed to pma developed increases in lung weight and lipid peroxidation as well as decreases in lung angiotensin converting enzyme (ace) and alkaline phosphatase (akp) activities. pma treatment also caused an increase in myeloperoxidase (mpo) activity in the lung, suggestive of neutrophi] infiltration. pretreatment of pma-treated rats with plain liposomes had no effect on pma-induced injuries. in contrast, pretreatment of rats with liposomal c~-tocopherol, h prior to pma administration, resulted in a significant elevation of pulmonary a-tocopherol concentration, accompanied by a concomitant reduction in mpo activity and reversal of pmainduced changes in lung edema, lipid peroxidation, ace and akp activities. these results appear to demonstrate that the intratracheal administration of a liposome-associated lipophilic antioxidant, such as a-tocopherol, can significantly ameliorate the toxic effects of reactive oxygen species, released from pmastimulated pulmonary target cells and infiltrating neutrophils. jk wojcik, g palasiewicz, w roszkowski immunology department,institute of tuberculosis and lung diseases~ warszawa, poland, m~larhospital, eskilstuna, sweden. introduction:the critical point in neutrophil migration to the alveolar space in the course of ards is the attachment between giyeoproteins of neotrophil membranes(sialyl lewis x carbohydrate epitope containing u-l-fucose) and lectin domains of endothelial p and e selectins (gmp- ,elam-i). a potential beneficial therapeutic strategy may be designep to suppress neutrophil recruitment to the lungs by preventing their rolling and attachment to the pulmonary endothelial cells. objeclive:to investigate if tz-l-fueose prevent experiments pulmonary hypertension in ards as effective as metylpredniselone. methods:only healthy rabbits (n- ) weighing .d- . kg oaselinepao> kpa and mean pulmonary arterial pressure (mpap)<i. kpa were included in this study. anaesthesia was induced with thiopental - mg/kg bw and "blind" jntubation was performed. a f swan ganz catheter was introduced via the left jugular vein into the pulmonary artery. pma, as was used in our experiments activates neutrophils and produces acute respiratory failure with pulmonary hypertension and pulmonary edema. eight rabbits serving as control animals received pma ug/kg bw iv only. sixteen other animals were divided into two groups receiving either ~-l-fucose mg iv or metylprednisolone mg iv min before pma admininstration. results:after pma administration notable physiological changes including marked increase in mpap( . -+o.~ kpe ..lere found. the increase of npap was observed to be completely blocked in both groups of animals which received ~-l-fucose or metylprednisolone. conclusion:in aur rabbit model ards cz-l-fucose pretreatment prevents pulmonary hypertension after pma administration. the effect is comparable with high dose metylprednisolone. the possible explanation is that g-l-fueose molecules block iectin domains of gnp- or elam-i preventing the adhesion of the neutrophils to the pulmonary endotheliom. bartens c, elmadfa i, steltzer h, fischer m, druml w introduction: various micronutrients and vitamins are particulary effective in modulating immune functions and host defense. the nutritive ant±oxidants vitamin c, e and b-carotene, as well as selenium lower the burden of reactive free radicals and protect the structural integrity of cells and tissues of the immune system, as well as other systems in the body. certain cells of the immune system like polymorphonuclear leucocytes (pmn's) use free radicals as a weapon to destroy invading pathogens. these reactive molecules, when released into the surrounding area, mediate lipid peroxidation and tissue injury. there is growing evidence that pmn's are activated in vivo by complement or immune complexes in disorders such as ards. the respiratory host defense mechanisms of patients with adult respiratory distress syndrome (ards) may be defective. the aim of this study was ta evaluate the status of the free radical scavengers and their activity in ards and to investigate the respiratory burst of ards patients. methods: seven ards patients ( sepsis, trauma) with an fie of . + .( , a peep of . ± . , and a murray score of . ± . were included in this study. healthy adults served as controls. superoxide anion production in granulocytes was measured photometrically, and the hydrogen peroxides by fluorimetric assay. vitamin a, e, and g-carotene concentrations were assessed by hplc, and plasma vitamin c photometrically. plasma selenium was determined by dectrothermal aas. plasma lipid peroxidation pruducts, expressed as malondialdehyde (mda), were determined by thiobarbituric acid assay and hplc. results: mda-plasma (/xmol/l) . ~: . * . ± . *= < . , **=p< . condusion: ards patients showed significantly decreased plasma concentrations of vitamin c, e and g-carotene, as well as selenium. these nutritive ant±oxidants are consumed during increased oxidative stress. mda, a final product of lipid peroxidation, is increased. however, a difference in rates of release of hydrogen peroxides and superoxide-anion of pmn could not be detected. therefore, oxygen radical accumulation is more likely a result of excessive inspiratory oxygen concentrations (f.io ), pro-oxidant drugs, and a high settlement of pmn in the lungs, and not an increased release of free radicals of the single pmn. kd glycoprotein secreted by the alveolar type ii cells. recent study showed that sp-a exists in the sera from normal healthy adults and that the significantly elevated serum sp-a levels were observed in the patients with interstitial pneumonia and pulmonary alveolar proteinosis. these findings means there may be a mechanism that the sp-a produced in the alveoli escapes into the bloodstream. here we examined the serum sp-a levels in the patients with critical illness including sepsis and ards. ]clinical subjects & methods] a total of serum samples were collected from patients hospitalized in the division of critical care medicine(icu), sappom medical college hospital. serum sp-a levels were measured by an enzyme-linked immunosorbent assay using monoclonal antibodies to human sp-a. ]results] there was no significant difference between the septic (n= ) and non-septic (n= ) patients. patients with ards (n= , . + . ng/ml) and with respiratory disease other than ards (n= , . +- . ng/ml) showed significantly higher levels of serum sp-a than those with non-respiratory disease (n= , . _+ . ng/ml). as to the ards patients, it was likely that the serum sp-a levels were getting higher in their clinical courses. however, there was no significant correlation between the serum sp-a levels and the pa%/fio ratio. ]discussion] at the present time, the exact mechanism of the escape of sp-a into the bloodstream remain to be unclear. our results may suggested that there was some relation between this leakage of sp-a and the alveolar-capillary permeability because of the higher sp-a levels observed in the ards patients. however it is also likely that higher serum sp-a level represents the proliferation of alveolar type ii cells as the regeneration of damaged lung. further studies are now being done. neutrophils contain a number of enzymes within intracellular granules,potentially damagingto lung tissue.release of these enzymes into the lung tissue from the sequestred activated neutrophils is felt to play significant role in lung injury in the course of aros. using -hours acute animal model of aros the activity of cathepsins,beta-glucuronidase and acid phosphatase was determined in the lung tissue. results of this research were compared with neutrophil proteases activity in serum and broncho-alveolar lavage.also hemodynamic,respiratory and biochemical investigations were performed before beginning of experiment,and in a two-hours time intervals of its duration.after hours was determined total and free activity of cathepsins,beta-glucuronidase and acid phosphatase in full homogenate of the lung tissue,mitochondriallysosomal fraction and the final supernatant. in the course of our experiment we observed an increase ( .i- . %) both total and free activity of neutrophil proteases in all fractions of the lung tissue.generally accepted current pharmacological treatment of aros only attenuated this increase but never caused reversion to the level before beginning of our investigations. the presence of aros was histologically proved.an activity of acid phosphatase in serum and the lung tissue fractions was compared with histochemical pictures of the lung. results of our research indicate that neutrophil proteases are a very important mediators in aros and they are a cause of the lung injury. in addition neutrophil-derived proteases can amplify the inflamatory process by enzymatitally activating of many other mediators and they also may to increase an oxidant induced injury by imparing of antioxidant defenses. oepartment of general surgery, sk~odowskiej a - ~ia~ystok, poland, tel/fax + . in vitro studies demonstrated that paf activates polymorplionuclear leukocyte (pmn) - ipoxygenase, but the generation of leukotrienes (lts) is critically dependent on exogenous arachidunic acid (aa) disposal (f. grimminger et at., mol. pharmacol. : , ) . we investigated the features of paf-evoked lt synthesis in a model of pulmonary microvascular leukostasis, in the presence and absence of intravascular n- -and n- -prescursor fatty acid supply. human neutrophils were infused into isolated, ventilated and perfused rabbit lungs to achieve microvascular sequestration of ligand-responsive leukecytes. leukotrienes (lt) and hydroxyeicosatetra(penta)enoic acids (het(p)e) were quantified by itplc techniques. intravascular application of paf ( um) or arachidonic acid (aa;ioum) provoked the generation of limited quantities of -series lts and -hete (total sum of - ipoxygenade products rd. and rd. pmol/ml.; both in pmn-preloaded and non-preloaded lungs). combined administration of pat r and aa caused amplification of - ipoxygenase product formation with predominance of cysteinyl-lt synthesis both in lungs without (total sum rd. pmol/ml) and, much more strikingly, with pro-application of neutrophils (total sum rd. pmofml). eicosapentaeooic acid ( um) elicited exclusive generation of -series lts and -hepe (total sum rd. pmol/mi). dual stimulation with paf and epa provoked amplification of epa-derived - ipoxygenase product formation, again with predominance of cysteinyl-lts, in lungs without (total sum rd. pmul/ml) and in particular in those with preceding microvascular pmn entrapment (total sum rd. pmol/ml). we conclude that the paf-evoked - ipoxygenase product formation in the neutrophil-harbouring lung capillary bed is critically dependent on intravascular precursor fatty acid supply, with epa representing the preferred substrate as compared to aa. pmn-related transcellular eicosanoid synthesis is suggested to underly the predominant generation of cysteinyl-lts. these findings may be relevant for lipid mediator profiles provoked by infusion of n- -versus n- enriched lipid emulsions in diseases with pmn-related inflammators events. adult respiratory distress syndrome (ards) involves damage to the alveolar epithelium and microvascular endothelium. products released from neutrophils (pmn) are thought to be among the chief causes of this damage, while the role of mononuclear cells (mnc) is uncertain. we studied patients at risk of or with acute ards. we measured the concentration of myeloperoxidase (mpo) and elastase (el) within circulating pmn as an index of pmn activation, elastin degradation products (edp) in the plasma as an index of tissue damage, as well as the cytotoxici~y of pmn and mnc to endothelial cells (ec) in vitro. cells and plasma were prepared from venous blood of healthy controls; or systemic arterial blood of patients on ventilators in intensive care but not at risk of ards; at risk of ards because of sepsis; at risk because of multiple transfusion/major trauma; or with acute ards. lung injury, multi-organ failure and apache h scores were recorded. to measure cytotoxicity, human umbilical vein ec were labelled with cr- , incubated with either pmn or mnc for hours, and the supernatant counted. the adherence of the pmn and the mnc to the ec was also measured. standard assays were used to measure mpo and el in the pmn, mad edp in the plasma. the mnc cytotoxicity did not differ between the groups. the pmn cytotoxicity was higher in the transfusion/trauma patients compared to each other group, which did not differ from each other. there was no correlation between cytotoxicity and adherence for any group. the mpo and the el concentrations were significantly decreased in the pmn from each of the patient groups, including the patient controls, compared to healthy controls. the edp were only increased in patients at risk of or with ards. thus pmn degrannlation occurred in patients not at risk of ards, but tissue damage as measured by increased edp only occurred in patients with or at risk of ards, suggesting that factors additional to pmn activation and degranulation are required for the progression to ards. there was no correlation between the parameters measured and the indices of disease activity, or outcome. these measures of pmn and mnc activation and function are not of value as prognostic indicators in patients with or at risk of ards. the liver is made up of several different cell types which subserve distinct functions in vivo. in addition to the different functions of the distinct cell types, it is now evident that even within the population of hepatocytes substantial functional heterogeneity exists. this heterogeneity occurs in a very organized fashion in the normal liver based upon the position of the hepatocyte in the acinus. although it has been proposed that the acinar heterogeneity of hepatocytes arises from migration of immature hepatocytes from the periportal region to the perivenous region where they become senescent and die, many of the heterogeneous responses can be accutely reversed by reversal of the oxygen gradient via retrograde perfusion. under normal conditions in which the acinus is exposed to unidirectional flow, the periportal hepatocytes are exposed to relatively high levels of oxygen, substrates and hormones. as these substances are extracted along the aeinus their concentration decreases leaving relatively low concentrations for the perivenous hepatocytes. in the normal liver, the heterogeneity of response is attenuated by extensive communication via gap junctions. the major liver gap junctions are made up of hexamers of connexin (cx ) which forms channels between cells capable of pas.~ing any molecule smaller than d. coupling is sufficient to allow diffusion of molecules such as atp or camp from one hepatocyte into > adjacent hepatocytes within seconds. during stress conditions such as endotoxemia or zymozan inflammation, expression of cx is markedly decreased while the secondary gap junction protein cx is either unchanged or even increased. while cx readily effects electrical coupling, molecules > d pass only very slowly. this would result in restriciton of transmission of moecules the size of atp or camp. since inhibition of gap junctions also attentuates metabolic response to hormone or nerve stimulation, it is evident that modulation of hepatocyte hetereogeneity by gap junctions must be considered in determining the mechanisms of metabolic alterations during stress. already minor haemorrhage decreases portal venous blood supply to the fiver and the reduction in portal blood flow becomes more pronounced with more profound btood loss. severe hacmorrhagic hypovolemia also reduces hepatic arterial blood supply which, however, is maintained over a vide range of haemorthage. the net effect of blood loss is a reduction in liver oxygee supply and this reduction is in proportion to the vulume iossed. however, oxygen supply to the liver exceeds the demands of the normal liver and this is the ca~ stilt following reduction of % of blood volume. the situation in sepsis is more complicated. po~l venous supply to the liver is redur.~i fairly early following normovolemic sepsis while hepatic arterial blood supply is maintained at le,~t initialiy, oxygen saturation might be maintained in arterial blood but may also be slightly reduced during sepsis, oxygen saturation of portal venous blood is significantly reduced during sepsis due to increased extraction of the intestines. therefore oxygea delivery to the liver during sepsis becomes sigalfkzntly reduced. at the s,~ne time and for mai.v.ly unknown reasons the need for oxygen becomes significantly increased in the ~-~ptic liver. as a consequence liver oxygen consumption becomes flow dependent and the liver is likely to suffer from ischemia during septic conditions. $ although liver failure is well recognized in sepsis, it is generally thought to be a late complication following pulmonary and renal failure. jaundice, hypoglycemia, encephalopathy and bleeding secondary to low levels of liver-synthesizing clotting factors are, however, signs of rather severe end-stage hepatic failure. furthermore, elevated liver enzymes (sgot and sgpt) represent hepatucyte damage and not hepatocellular dysfunction. in view of this, a more sensitive indicator of hepatic function is desirable in order to detect early hepatic abnormality. in this respect, indocyanine green (icg) is a tricarbocyanine dye that possesses several properties which makes it particularly valuable inthe assessment ofhepatic function. this dye is bound m albumin and is cleared exclusively by the liver through an energydependent membrane transport process and is nontoxic at lower doses. we propose that maximal velocity (vm~,) of icg clearance is a valuable measure of active hepatocellular function, since the total concentration of functioning receptors is directly proportional to vm~. we have utilized a fiber optic catheter and an in vivo hemoreflectometar to continuously measure the administered icg in vivo and consequently determine its clearance without the need of blood sampling. using this technique, we have found that in the early stages of sepsis (i.e., and h following cecal ligation and puncture), the vm~ and kinetic constant (k=) of icg clearance was significantly depressed. it should be noted that at this stage of sepsis, there was no elevation in serum enzyme levels. furthermore, hepatic blood flow and cardiac output increased at the above mentioned time points. thus, the extremely early depression in active hepatocellular function in sepsis, despite the increased hepatic blood flow and cardiac output, may form the basis for cellular dysfunctions leading to multiple organ failure during sepsis. additional studies indicated that following hemorrhage, active hepatocellular function was markedly depressed. this returned to prehemorrhage levels after ringers lactate resuscitation, however, this function was not maintained and decreased significantly after fluid resuscitation. nevertheless, the depressed active hepatocelinlar function following hemorrhage was markedly improved by post-treatment of animals with either atp-mgci , peutoxifylline or diltiazem. thus, the use of icg clearance provides an early sensitive indicator of hepatic abnormality during sepsis and following hemorrhage and this method should be used, not only experimentally, but also in the clinical arena for the early detection of hepatocellular abnormality. although multiple organ dysfunction syndrome (mods) remains a major cause of mortality and morbidity in intensive care units, very little is known about the mechanisms that precipitate its development. since an episode of inadequate tissue oxygenation is considered to be the trigger for mods, we have proposed that a primary localized injury such as ischemia/reperfusion may be sufficient to cause a change of gene expression of remote and apparently unaffected organs. such modulation of remote organ gene expression may decrease the organ's tolerance to a subsequent stress contributing to the development of mofs. to test this hypothesis, rats were subjected to hepatic regional ischemia by clamping the blood flow (hepatic artery and portal venous inflow) of the left and median liver lobes. intestinal congestion was prevented by allowing flow through the smaller right and caudate lobes. after minutes of ischemia, the clamp was removed and the blood flow restored. the animals were allowed to recover for , and hours. kidneys were removed, total rna was isolated and poly(a) ÷ selected by affinity chromatography on oligo(dt) columns. message was in vitro translated using rabbit reticulocyte iysates in the presence of radioactive amino acids. the gene products (radiolabeled polypeptides) were fractionated by two dimensional gel electrophoresis, and visualized by fluorography. analyses of the two dimensional fluorograms indicate that there is a dramatic change in the electrophoretic pattern of in vitro translated products in samples corresponding to kidneys obtained after minutes of hepatic ischemia and hours of reperfusion with respect to kidney samples obtained after sham operation or from control rats. the latter were not subjected to any surgical manipulation. these studies suggest that the gene expression of the kidneys is specifically modified after a remote organ injury (hepatic ischemia/reperfusion). we speculate that this change of gene expression in kidneys after an indirect injury may be part of the early events leading to the development of mods. a priming event, e.g. local ischemia, in combination with a second insult, e.g. sepsis, may amplify a host's response and lead to multiple organ failure. to better understand the mechanisms involved in the pathophysiology, male fischer rats were subjected to min of hepatic ischemia followed by reperfusion (rp) and injection of . mg/kg salmonella enteritidis endotoxin (et) at min of rp. et injection potentiated the postischemic liver injury as indicated by histopathology and an increase of plasma alt activities from + u/l (i/rp only) to + u/l at h rp. inhibition of kupffer cells (kc) with gadolinium chloride ( mg/kg) attenuated liver injury in this model by %, however, monoclonal antibodies (cl , wt ) directed against adhesion molecules ( integrins, cd ) on neutrophils had no effect on the injury despite the substantial accumulation of neutrophils in the liver at that time ( + pmns/ hpf; baseline: + ). isolation of kc and neutrophils from the postischemic liver indicated a -fold increase of the spontaneous superoxide formation only in the kc fractions [ . + . nmol o -/h/ %elts (kc ); . _+ . (kca) ] at h rp compared to control cells. in addition, stimulation with phorbol ester or opsonized zymosan revealed a substantial priming of kc for reactive oxygen formation. in contrast to the short-term experiments ( h), the antibody wt ( mg/kg) attenuated liver injury by % at h of rp and improved survival. conclusion: liver injury during the early rp phase is mediated mainly by kc generating excessive amounts of reactive oxygen while neutrophils are primarily responsible for organ damage during the later rp period. (es- and gm- ) tumor necrosis factors (tnf) are cytokines which are cytotoxic towards some tumors in vivo and certain tumor lines in vitro. moreover, these polypeptides are powerful immunomodulators and have been found to be distal mediators in several models of septic shock and septic organ failure. one of the best-characterized experimental systems is the hepatitis caused by lps or tnf in galactosamine (galn)-sensitized mice. here we describe a cell culture system, in which the direct toxicity of tnf towards mouse hepatocytes was examined. the toxicity of tnf, as determined by ldh-release or formazan-formation, was dose-and time-dependent. the threshold of toxicity was ng/ml, which corresponds to serum concentrations found in mice after lpsinjection. toxicity was only observed in hepatocytes sensitized with transcriptional inhibiters such as galn, actinomycin d (actd) or cxamanitin. sensitization was neither observed with different translational inhibitors nor with various other metabolic inlaibitors or toxins. inhibitors of protein synthesis or protein processing such as cycloheximide, puromycin, tunicamycin and ricin protected actdsensitized hepatocytes from tnf-induced cytotoxicity. tnf induced apoptotic changes and dna-fragmentation in sensitized hepatocytes which is in line with the above findings that cell death is dependent on protein synthesis. thus tnf may be a trigger of programmed cell death during inflammatory organ damage. with the purpose of studying the role of complement activation in tissue injury after ischaemia and reperfusion we blocked the complement cascade in a model of rat liver isehaemia and reperfusion, either by administration of soluble human complement receptor type (scri), mg/kg iv after vascular occlusion (n= ) or by depleting the complement system using cobra venom factor (cvf), . mg im, and hours before ischaemia (n= ). non-ischaemic rats (n= ) and ischaemic non-treated rats (n= ) were used as controls. the experimental procedure consists of the temporary interruption of arterial and portal blood flow to the left lateral and medial lobes of the liver during minutes, followed by reperfusion, recording the liver blood flow and haemoglobin saturation with a laser doppler flowmeter and photometer during one hour after declamping; alt levels were assayed and immunoperoxidase stainings for c and c were performed. there were statistically significant differences between the experimental ~roups and the untreated ischaemic control group in terms of post-isehaemic blood flow (p< . ) and haemoglobin saturation (p< . ). c and c were present in the endothelium of the ischaemic control group. no deposits of c or c were found in the cvf group. few c and no c were found in scri treated rats. these results show that the effect of reperfusion injury in the rat liver is ameliorated either by depleting complement with cvf or by regulating complement activation with scri. hepatic dysfunction, a major cause of mortality following hemorrhagic shock, has not yet been well characterized. the present study was designed to assess the effects of liver blood flow and cytokine levels on hepatic function following resuscitation from severe hemorrhagic shock in normal and cin-hotic rats. methods: aftor pentobarbltal anesthesia, control and cirrhotic sprague-dawley rats were subjected to severe hemorrhage to reduce their systolic blood pressure to + mm hg. this level of hypotension was maintained until the skeletal muscle transmembrane potential (era) depolarized by %.; the animals were then resuscitated with ringer's lactate solution in three times the volume of the shed blood. serial blood samples for tumor necrosis factor (tnf) determination (a modified flow-cytomeuic wehi cell bioassay) were obtained at baseline, during hemorrhage and following resuscitation. liver blood flow measurements by low dose galactose clearance (glc) and functional bepatocyte mass (fhm; defared as galactose elimination capacity [gec] from the zero order portion of the plasma disappearance curve following an intravenous galactose bolus [ mg/kg], divided by liver weight) were measured before shock and after resuscitation. results: higher survival rates (p < . ) were observed in control as compared with cirrhotic rats. shock produced a significant reduction in gec (to < . ); fhm ( < . ); and liver blood flow (p < . ) in normal and cirrhotic rats. decreases in gec and fi-im were greater (p < . ) in cirrhotic rots. tnf levels were higher (p < . ) in cirrhotic rats at baseline and during induction of shock. pre gap junctions provide pathways for metabolic signals between cells. in the liver, the majority of gap junctions are composed of connexin (cx ) polypeptide subunits, and are regulated by gluconeogenic hormones. since sepsis and other inflammatory states alter hepatic glucoregulatory control, we have evaluated the contribution of gap junctional conductance to the metabolic dysregulation in the liver. an acute inflammation was induced in rats by injection with e. coli endotoxin (lps lmg/kg). northern blot/hybridization analysis of total rna isolated from livers after endotoxin injection show a decrease in the steady state transcript levels of cx to % of sham controls. immunostaining of liver sections using anti-cx revealed punctate fluorescent staining on the plasma membrane at regions of call-cell contact in saline injected animals, whereas, staining was only observed in cytoplasmic vesicles hrs after animals were treated with lps, suggesting the internalization of cx without replacement on the cell surface. the staining was quantitated and expressed as % of pixels above threshold. at hr post injection . % ofpixels exceeded threshold, compared to . % in sham controls. functional gap junctional communication was assessed by dye coupling using lucifer yellow in an isolated perfused liver under intravital fluorescence microscopy. dye diffusion was markedly decreased hr after endotoxin injection. this suggests that decreased metabolic coupling after lps injection results from decreased gap junction abundance. the present data suggest that metabolic dysregulation during sepsis may arise in part from changes in intercellular communication caused by a decrease in gap junctional expression and communication. given the marked metabolic heterogeneity of hepatocytes with respect to acinar location, metabolic signaling via gap junctions most likely serves to moderate this heterogeneity, contributing to a coordinated metabolic response. altered cellular ca ÷ regulation might be a critical step in organ dysfunction during sepsis and ischemia/reperfusion events. the aim of the present study was to evaluate hepato-ceuular ca ÷ regulation in isehemiah'eperfusion after hemorrhage and to assess effectiveness of tnfc~-monoclonal antibody (tnfo~-moab). methods. male sprague-dawley rats ( g, n>_ /group; pentobarbital mg/kg) with hemorrhage for rain at mm hg. reperfusion by ringer's lactate ( x maximal bleed out/ min) and % of citrated shed blood. tnfcz-moab (tn , ceutech, mg/kg in . % nac ) infused during flrst min of reperfusion. at baseline, end of ischemia and min of reperfusion, hepatecyte isolation by liver collagenase perfusion. " hepatocyte incubation ( mg w.w./ml) with caci ( . + + + mbq/ml) for rain (ca influx [slope, /mini; ca uptake [nmol ca /mg protein]) w/ and w/o epinephrine (epi, nm). hepatecyte resuspension in radioisotope-free medium and farther incubation (exchangeable ca + (ca +ex) [nmol ca +/mg protein]; ca + membrane flux [nmol ca +/mg protein'min]). during incubation, aliquots ( ~tl) were centrifuged through oil/lanthanum gradient and acivity measured by scintillation counting. statistics: anova. mean + sem. results. hepatocyte ca +ex and membrane ca + flux were significantly increased at both, the end of ischemia ( . +. ; . +. ) and reperfusion ( . +. ; . +. ), as compared to sham-operated animals ( . +_. ; . +. )( <. ). tnfc~-moab treatment significantly prevented reperfusion-induced increase of ca +ex ( +. ) and membrane ca + flux ( . +. )(p<. ). fast ca + influx was significantly increased by epinephrine in hepatecytes from sham-operated rats ( . +. vs. epi: . +. , p< . ). this hormone effect was not observed in isehemia ( . +. , epi: . !-_. ) or reperfusion (untreated: . +. , epi: . +. ; tnft~-moab: . _+. , epi: . +. ). conclusion. the present study clearly demonstrated hepato-cellular ca + overload in ischemia and reperfusion as a result of hemorrhagic shock. analysis of membrane ca + fluxes and hormone ca + mobilization suggests disturbances of membrane ca + transport mechanisms, e.g. through ca +-atpases. reperfusion-induced oxygen free radical generation which affect exchange kinetics of cellular ca + buffering compartments might also be operative. prevention by tnfct-moab indicates the pivotal role of tnf as an early inflammatory mediator of hepatocellular alterations in signal transduetion mechanisms and cellular homeostasis. although the precise mechanism has not yet been elucidated, bacterial translocation and endotoxin absorption have been frequently shown after burn, and have been postulated to be one of the underlying processes of sepsis. the purpose of the current study is to define the hemodynamic response of the liver to endotoxin release in burns, in correlation to bacterial translocation. twelve female minipigs, weighing - kg, underwent a laparotomy & transition time ultrasonic flow probes were positioned on the portal vein, the common hepatic artery, and the superior mesenteric artery. . fr catheters were inserted in the superior mesenteric vein and the left hepatic vein. a jejunostomy was also performed. after five days all animals were anaesthetized and randomized to receive % of tbs a third degree burn. eighteen hours after burn. gg/kg e. coli lps was intravenously administered over rain. ali animals were studied for additional hours and then sacrificed. several recent data suggest that in severe injuries, such as shock state, the gradual activation of kupffer cells and the excessive release of destructive and immunosuppresive products from macrophages may contribute to the development of "multiple organ failure". in in vivo experiments in mice, the effect of kupffer cell phagocytosis blockade on the correlation between the tissue distribution of lps, endotoxin sensitivity and lps-induced tnf production was investigated. to depress the activity of the kupffer cells, gadolinium chloride (gdc ) or carrageenan was used. th~e studies indicate the dissociation of tissue localisation of cr jllabelled endotoxin and endotoxin lethalithy. both gdc and carrageenan depressed kupffer cell activity, but endotoxin sensitivity was enhanced only by carragenan treatment. however, there was a close correlation between the sensitivity to lps and lps-induced tnf production as measured in the serum, since lpsinduced tnf production was enhanced only by carrageenan treatment. on the other hand, gdc pretreatment significantly increased tnf production in the spleen. these results support our earlier findings that gdc -indueed kupffer cell phagocytosis blockade leads to activation of the spleen, and may explain some of the immunological effects of gdc . inositol(l, , ) triphosphate (ip ) has been proposed as a second messenger for calcium mobilization. the addition of ip at low concentration has been shown to cause calcium release from intracellular microsomal store in rat hepatocytes. the effects of sepsis on the ip binding from microsomal fraction of rat hepatocytes during sepsis were investigated. sepsis was induced by cecal ligation & puncture (clp). control rats were sham-operated. three microsomal fractions (rough, intermediate and smooth) were isolated from rat liver. study of ip receptor binding was performed with tridium label ip . the results shewed that the ip binding was significantly depressed by - % (p< . ) during late sepsis ( hrs after clp), but not in early sepsis ( hrs after clp). the ip binding depression during late sepsis was most significant on rough and intermediate endoplasmic reticulum (p< . ), but not on smooth subfraction. since ip binding plays an important role in the regulation of intracellular calcium homeostasis in hepatocytes, an impairment in the calcium release due to depressed ip binding on smooth and intermediate endoplasmic reticulum during late sepsis may have a pathophysiological significance in contributing to the development of altered hepatic metabolism during septic shock. septic organ failure is currently recognized as an overactivation of the nonspecific immune system by bacterial stimuli giving rise to proinflammatory mediators. little is known about the mechanisms of the resulting cellular injury. here, a synergism is described between tnf as a major mediator of septic organ injury released by macrophages and hydrogen peroxide (h ) as a representative of reactive oxygen species as formed by e.g. neutrophils. rat hepatocytes are only slightly sensitive to either agent alone. when treated with a conbination of tnf and h# a stronq synergistic toxicity was found, especially w~e~ tnf-treatment preceeded challenge with h~o~. we have recently described a coculture model bfzrat liver macrophaqes and hepatocytes where lps induces hepatocyte cell death partially mediated by macrophage tnf release. when h was also employed in fhis more complex cellular system a similar synergism was found: the ecc~ of lps was consecutive patients with liver cirrhosis admitted to the department of surgery over a year period from january to december were studied for their complement profiles in relation to other parameters of liver function, the aim of the study was to determine if a direct correlation existed between low complement levels and end stage liver cirrhosis. cirrhotic patients were divided into child's a, b and c categories using child's classification. complement levels (c , c ) were measured and functional assay for complement (ch ) were performed in each of these groupings in addition to normal blood donor controls. these results show that the qualitative c , c and the functional chs complement assays have good predictive values in assessing deteriorating liver function• in particular, the functional assay for complement (ch ) showed marked impairment in child's c patients (p< . ) confirming the impaired immunological status of these patients. sera from this group of patients (child's c) were titrated with pig red blood cells (rbcs) in a haemolytic assay. the results showed that there were significantly less haemolysis of pig rbcs in these patients (p= . ) as compared to the controls. this findings strongly support an impaired immunological status in child's c liver cirrhosis and may explain the high incidence of sepsis as a terminal event in these patients. aim:kupffer cells(kc) have an importamt play to cause hepatocellular injury in sepsis, because these cells release many kinds of substances. we reported that oxygem radicals released by kcs stimulated by lipopolysaccharide (lps) caused hepatocellular injury. aim of this study is to investigate the relationship between imtracellmlar calcium(ca) concentration of cultured rat kcs stimulated by lps and release of oxygen radicals, and effect of prostaglandin e~ (pge~) on imtracellular ca concentration. production of acute phase proteins (c-reactive protein, crp, transferrin, tf) and £erritin (f) in rat hepatocytes (hps) and its dependence on extracellular matrix components were studied. hps isolated from the liver by collagenase perfusion were cultured at ~o per . ml medium fi +dmem ( : ) with % fetal calf serum for days on uncoated or type i collagen coated plastic surface or in the presence of dextrane sulphate in the medium. hps were stimulated by conditioned medium (gm) from i~ia-p or e. coli lps preineubated human blood mononuclear cells. production of crp, tf and f by hps was detected by elisa. it was found that both cms decreased tf synthesis in hps by - % (p<o.os). the level of f synthesis didn't change or only slightly decreased. the addition of cms led to the enhancement of crp synthesis more than . times. the most reproducible results were obtained when plastics had been coated with collagen. dextran sulphate markedly increased crp synthesis. thus using this model of an acute phase reaction in vitro we found the enhancement of crp synthesis and the decrease of tf synthesis. our data correspond with nublished materials on the acute phase in vivo and point to relevance of the proposed model. metabolism of hepatocytes under traumatic illness has not been sufficiently investigated. therefore we have applied absorption and fluorescent cytophotometry techniques to study the content of rna, glycogen and its fractions in hepatocytes of patients with severe mechanical trauma, both with and without endointoxication at various stages. for these purposes slides were prepared from the repeated aspiration biopsy material according to special techniques (kudryavtseva et al., ) . slides were stained by gallocyanin-chromalum to measure rna or underwent fluorescent pas-reaction to measure glycogen and its fractions (kudryavtseva et al., (kudryavtseva et al., , the ability of metabolites derived from the xanthine-xanthine oxidase system to inhibit mitochondrial function was examined using freshly isolated rat liver mitochondria. under uncoupled conditions, mitochondria exposed to free radicals exhibited a significant decrease in consumption supported by nad+-iinked substrates, but showed almost no change in consumption in the presence of succinate and ascorbate. the activity of electron transfer complex i (nadh oxidase and nadh-cytochrome c oxidoreductase) and the energy-dependent reduction of nad+ by succinate were unaltered by oxidative stress. exposure to free radicals also had an uncoupling effect at all three coupling sites. the degree of mitochondrial swelling was closely correlated with the inhibition of state oxidation of site i substrates and with the increase in state oxidation of succinate. the immunosuppressive agent cyclosporin a (cya) completely prevented the mitochondrial damage induced by oxygen free radicals (swelling, ca + release, sucrose trapping, uncoupling, and selective inhibition of the mitochondrial respiration of site i substrates). the same protective effect was found when ca + cycling was prevented, either by chelating ca + with egta or by inhibiting ca + re-uptake with ruthenium red. these findings suggest that the deleterious effect of free radicals on mitochondria in the present experimental system was triggered by the cya-sensitive and ca ÷-dependent membrane transition, and not by direct impairment of the mitochondrial inner membrane enzymes. correspondence should be addressed to: naoshi takeyama the aim of this study was to clarify the critical role of reduced glutathione (gsh) on the progression of lipopolysaccharide (lps)induced liver damage of mouse. the conditions of gsh-depletion and -richness were produced by intraperitoneal administration of buthionine sulfoximine (bso), a specific inhibitor of gsh synthetase, and of gsh-monoethyl ester (gsh-me), respectively. gsh-me, which was esterified the caboxyl group of the glycine residue, is readily transported into cells and is hydrolyzed intracellularly; this leads to greatly increased the cytosolic and mitochondrial levels of gsh. bso and gsh-me were administered intraperitoneally mmol/kg and mmollkg, respectively, and lps ( mg/kg) given h later. hepatocytes were isolated by in situ perfusion of the liver with collagenase h after lps injection. the degree of hydrogen peroxide (h ) synthesis and mitochondrial membrane potential were measured by flow cytometry using fluorescence probe dichrolofluorescein diacetate and tetrametyl rhodamine ethyl ester, respectively. the degree of mitochondria membrane permeability transition (mmp) was assessed by [ ]sucrose entrapment. we found that lps treatment results in a decrease in hepatic gsh level and mitochondrial membrane potential, and an increase in h synthesis and mmp. lps administration to bsq-pretreated mouse worsened at[ these parameters. in contrast, gsh-me pretreatment ameliorates. all together, gsh may acts an important role in cellular defence against lps-mediated liver damage, and mmp may result in the decrease in mitochondrial membrane potential. it has been shown, up to now, that disturbances of enzymatic processes in the cell organella are the basic factor of the changes taking place during endotoxin shock it has been observed that lysosomes are biochemically changed as result of the effect of lipopotysacharides of gram negative endotoxic bacteria. the purpose of the experiment was: .evaluation nfthe course of the ees due to the biochemic changes .determination of the influence of the ees on the activity of lysosomal enzymes in liver cell .deterrmnatian of the influence of h and d on the activity of some lysosomal enzymes in liver cell during ees material and method: examinations ware carried out on dogs. the shock was evoked by i.v. administration of endotoxin e.coli. the dogs were divided into groups: icontrols, i[ -dogs with untreated shock, iii-dogs in shock treated with h, ivdogs in shock treated with d, v -dogs in shock treated with h and d. the following parameters were determined: .activity of acid phosphatase in the venous blood serum. - .total and free activity of acid phosphatase and catepsins in the full liver cell homogenate, in mitochondrial-and-lysosomal fraction, and in the superuatunt (all after hours of the experiment). conclusions . essential increase of activity of lysosomal enzymes was observed in the ees. . increased activity of lysosomal hydrolases in the liver cell homogenate corresponds, as a result of the endotoxin effect, with increased enzymatic activity in the peripherial blood. extensive investigations from our laboratory of the pathophysiology of hepatic no-flow ischemia ( min) -reperfusion injury demonstrated substantial kupffer cell activation with reactive oxygen formation during the first few hours of reperfusion as indicated by increases in plasma glutathione disulfide (gssg) levels in vivo (am. j. physiol. : g , ) and enhanced superoxide formation by kupffer cells (kc) isolated from the postischemic livers (free radic. res. commun. : , ) . the early kc-induced injury initiated the later, primarily neutrophilmediated reperfusion injury (faseb j. : , ). to test whether or not similar mechanisms are operative during hepatic ischemia induced by hemorrhagic shock, male fischer rats ( - g) were subjected to rain of hemorrhage (mean arterial pressure mm hg) followed by resuscitation (rs) (reinfusion of shed blood). hepatic atp levels declined from . + . txmol/g to . _+ . ( min shock) indicating severe ischemia, and recovered to . -- . at min rs. to test for potential oxidant stress during rs, plasma gssg conc. were measured. although gssg levels increased by % compared to baseline levels ( . !-_ . i.tm), there was no significant difference to shamoperated controls. spontaneous superoxide formation of isolated kc was . + . nmol o -/min/ ecells (kc ) and . + . (kc ) in controls and did not change significantly after shock and rain rs. addition of phorbol ester or opsonized zymosan to isolated kc did not indicate a priming of these cells. conclusion: in striking contrast to our previous findings with hepatic no-flow ischemia, there is no evidence for a significant kc activation after min of hemorrhagic shock and up to rain of resuscitation. objectives-this study investigates morphometric changes in kc nltrastmcture which might account for this diminution in phagacytosis. materials and methods -three groups of wistar rats were studied: control, sham-operated [sham] and bile duct ligated [edl] . after weeks animals were sacrificed and livers were "perfusion fixed" with % glntaraldehyde and processed for transmission electron microscopy and image analysis. results -in the the bdl group kupffer cell numbers were greatly increased. biliary ductular proliferation was evident and sinusoidal spaces were compromised. eleven nuclear and cytoplasmic parameters were measured and statistically significant results are summarised in the results: ascorbic acid levels were slightly elevated after the hs and returned to basal values after rain. glutathione concentrations were increased significantly after the hs and the gsh levels kept rising continuously to as much as -fold of basal levels at the end of min. mda showed no significant variation before and after the hemorrhagic shock. plasma concentrations of ratine, teucine, isoleucine, phenylalanine, proline, threonine and serine showed significant increase over basal levels during the whole ischemic period. glutamic acid was slightly elevated at the onset of hs and remained the same for the rest of ischemic period. hydroxyproline was significantly below the basal value at the mid-point of ischemic period. alanine, glycine, histidine and aspartate did not change significantly throughout experimental time course. conclusions: ( ) oxidative stress might not be severe in the systemic hemorrhagic shock for pigs since no significant variations were observed for ascorbic acid and mda ( ) the increase of gsh might be that it was released from hepatocytes when the animal was under systemic ischemia. ( ) celzain amino acids might be acting as transmitters in the event of ischemia. however, fm"lher investigations are needed to clarify the detailed mechanism in regard with antioxidants and amino acids. dr. fang-ku p'eng taichung veterans general hospital talchung, taiwan , r.o.c. jia shi yong, huang zhi oiang and men xian jun. in patients underi~ent major hepatic surgery,obstructive jaundice has been implicated with fnoreased susceptibility to sepsis and liver failure. jaundice was said to he associated with derangement of iamune function and result in expression of pr,:.inflar...aatory cytoki~es that cause hepatooellular damage. this study is ~.o investigate the effects ,.,t lip,~polysaccharide(lps)rats. jaundice were produced in healthy ~istar rats of either sex weighing - m~ by common hi l~ duet l igation(bl)l).seven days post l igation, rats were given lps( .gg. ) . rag/kg intraperitoneally. at the end ,:,f l,gand hours after lp$ ehanllenge, liver were removed and prepared for forzen sections immediately. i)emonstration of inf in liver parenchyna were performed by method of abu i~munohistochemistry using r~onoolonal antibody against tnf, leve of mrna for tnf ~ere measured by in-situ hybridization using biotin-labeled edna probe. results sho'~ed that tnf stained granules appeared in kup~'fer eell~ and polymorphonuclear leukocytes(pnnl,but not in hepatoeytes nor endothelial eel is. they ~'ere located within cytoplasms and peaked at - hours after lps ohal lenge. there was vocomitant tnfmrna expression but peaked earlier hour post lps challenge. tnfmrna vcere detected notably in necrotic area and barely in bdl rats ~ithout lps challenge. it is therefore postulated that production of tnf by inflammatory effeetor cells-kupffer cell and phn in site, in the obstructive jaundice rats during sepsis may atribute to the hepatocellular damage. it also provide evidence for the beneficial effects of early release of biliary obstruction. in the present study, an animal model of a c in wlstar rats was developed by tigatlng the common bite duct and injecting d. mt solution of e. goli % b, (g× ' efm/mt) into the bite duct. the mortality rate was ~ at h after aoc. at , , , h after aoc, kcs were isotated and cultured atone or cocuttured with hepatocytes to evaluate the modulation effect of kgs on hepatoeyte protein synthesis. the results showed that tactodehydrogenase leakage was increased progressively as the injured k~ function and structure developed. tnf and il-i tn the supernatant were detected with the peak values at h after aoc. at h after aoc, ~-teueine incorporation was obviousty decreased in the normal hepatocytes eocuttured with stimulated kcs compared to the uormai hepatocyte cultured group (p< . ), but it was slgnificantiy increased in the group cocultured with normal kcs. in the a c group, 'h-teuclne ineorporatien was decreased progressively in the injured hepatoeytes cocuttured with stimulatedkgs and it was markedly elevated when cocuttured wlthnormat kcs at h after a c (p< . og). it is concluded that the impaired hepatocyte proterin synthesis was directly mediated hy the stimulated kc function during aoc. such a mechanism possibly may be involved in the patho ensis of hepatic dysfunction and m f following h . " the project supported by nsfc. in the past few years it has become evident that cytokines are implicated in various pathophysiological mechanisms. therefore measurement of cytokines and their potential inhibitors in biological fluids may be helpful in diagnosing and monitoring of diseases. however, dependent on the type of assay used investigations performed in different laboratories have often yielded conflicting results. in order to assess reliability and reproducibility of cytokine measurements two comparative studies for the determination of cytokines in biological fluids were launched by several investigators interested in this field: one national austrian ~tudy and one european study in the context of the european workshop for rheumatnlogy research. serum and synovial fluid samples were distributed by the organisers, and participants had to measure one or several of the following cytokines in all samples: il- , il- , l- , i , tnf-alpha, ifn-gamma, gm-csf, and the soluble receptors for il- and tnf; both commercially available immunoassays and home-made assays were allowed. so far, the main conclusions emerging from these preliminary studies are: ( ) the same immurzoassay (elisa) yielded comparable results in different laboratories; ( ) immunoassays from different manufactureres usually measured the highest concentrations in the same samples, yielded similar relative values but disparate absolute values; ( ) assays for soluble receptors yielded less discrepant results; ( ) some assays seem to be more suitable for measuring cytokines in biological fluids than others. the mean retrieval of exogenous recombinant human cytokines was approximately % for most cytokines tested. however, it must be borne in mind that natural and recombinant cytokines may behave differently in immunoassays. this raises the question as to the necessity of setting up international standards for all cytokines. possible interferences by serum components such as (lipo)proteins, complement, rheumatoid factors, etc., which may either decrease assay sensitivity or yield false positive results, must also be considered. in addition, natural cytokine binding proteins (e.g. soluble receptors) might interfere with cytokine determination in immunoassays. the problem of immunoassays versus bioassays has not yet been approached, but is without any doubt worth indepth investigation. thus, these studies are a promising first approach to deal with the difficulties of cytokine analysis in biological samples, and it is hoped that they will help to overcome some of the major methodological problems in the near future. tumor necrosis factor (tnf) is a pleiotropic cytokine which plays a key role in a number of immunologically mediated disorders like septicemia or cachexia. tnf receptors are found on the surface of a variety of cells, where they provide molecular signals for the cytokine effect. there exist two types of soluble tnf receptors (stnf-rs), tnf-r p and tnf-r p . these stnf-rs can compete with the cell surface receptors and block their activity. the expression on and shedding from the cell surface of stnf-rs is enhanced by interferon gamma. increased concentrations of stnf-rs can be found in patients with infectious as well as malignant disorders. in patients undergoing immune stimulatory therapy with interleukin- and interferon alpha a simultaneous increase of tnf and its soluble receptors can be seen. in patients with hiv infection a strong correlation exists between the levels of stnf-rs and markers of immune activation like neopterin or beta- -microglobulin. likewise patients with hematological disorders show elevated stnf-r levels. patients with weight loss have higher concentrations than patients with stable weight. the final value of stnf-rs within the complex network of cytokines is not yet clear. however, there exist striking parallels between infectious and malignant disorders pointing to a key role of endogenous immune activation. biochemicatly, d-erythro-neopterin derives from guanosine triphosphate. in vitro studies show that large amounts of neopterin are produced by human monocytes/macrophages stimulated with interferon-j (ifn-j). neopterin is biologically stable, and its halflife in the blood seems to solely depend on renal excretion. specimen for neopterin determination can be stored without special precautions. increased concentrations of neopterin have been described in body fluids of patients suffering from diseases which are apparently associated with an activated cellular immune response and with enhanced endogenous formation of ifn-~', e.g,, ) increasing neopterin levels predict rejection episodes in allograft recipients ) virus infections induce increased neopterin concentrations, and the degree of neopterin elevation predicts prognosis in these patients which is particularly true in hiv- infection ) in autoimmune disorders such as systemic lupus erythematosus or rheumatoid arthritis neopterin levels reflect activity of the disease ) increased neopterin concentrations in patients suffering from certain types of cancer indicate poor prognosis. significant associations between changes of neopterin and decrease of hemoglobin as well as the development of weight loss and cachexia, e.g., in cancer patients and in patients with hiv- infection, support the concept that endogenously formed cytokines such as ifn-~" and tumor necrosis factor-~( are involved in the pathogenesis of such symptoms. in conclusion, neopterin monitoring is a sensitive tool to detect the activation status of the cell-mediated immune system in vivo. repair and healing or perpetuation of acute inflammation is characterized by a complex network of interacting cellular and humoral defence mechanisms. of the numerous inflammatory mediators/effectors investigated hitherto, the proteolydc lysosomal enzyme pmn elastase has turned out to be highly destructive when released extracellularly thus contributing considm:ably to organ dysfunctions in severe posttraumatic and postoperative courses. besides various cytokines, elastase in complex with its main antagonist c¢ -proteinase inhibitor (a pi) is also supposed to induce the shedding of intercellular adhesion molecules from inflammatory cells (pmns, monocytes/macrophages, endothelial cells). these soluble adhesion molecules may modulate the inflammatory process in many different ways, e.g. via acting as chemotaxins, blocking neutrophil activation or competing with the membrane-bound forms in cell-cell adhesion. thus, measuring circulating or local levels of elastase-a pi and soluble adhesion molecules (icam, e-selectin,-pselectin, l-selectin) may be a helpful tool in judging the severity of an acute inflammatory process. in several clinical studies on surgical patients suffering from multiple trauma and/or sepsis we could demonstrate that the measurement of these parameters in consecutive plasma samples and local body fluids was highly valuable for early diagnosis and prognosis of multiple organ failure. prof. dr. m./ochum, institut fdr klinischechemie und biochemie, lmu miinchen, nufibaumstrage , m nchen, germany procalaitonin (proct) a aa peptide is dramatically increased in the blood of patients with various sepsis and infections. the increase begins as soon as hours after the andoto:edn release and readied maximal level with a to b-fold increase h after li~ edrmrdstration. prcc, alcitorfin response was temporally different from these of tnf~ and ii- , that reached peak levels at h and h respectively. at the opposite of eytokine (tnfcz, ild, j, is), proct is a very stable molecule. the half iife of proct in ~he blood is surprising if we consider the half llfe (about nine mirtute) of mature ¢alcitonin (co. we have found that it is due to the binding of proct with a protein on the n-termktal part. thin complex of about daltons is unable to cross the kidney and the c_n barriers and the half life is at least elghteen hours. this long half llfe is very useful in the evaluation of a sepsis. a very sensitive and specific sandwich in'ununoassay has been developped. the results cart be delivered in two hours. at time, we know that in the healthy adults, the values are less thau . ng/ml. it is also clear that proct is not increased ~n patients wlth inflammatory dleeasea without lnfectlon. for instance, proct is not signlffcat vely increased in purpura rhumatom, arthritis, crohn's disease, rectocolitis, also in various cancer patients with inflammatory components. am other interesting finding, is the absence of increase or a very low increase in the viral infections. at the opp site, in all the patients with bacterial sepsis or in the malaria pat/ants, progt was dramatically increased, from i to fold. p~oct can be useful to the follow up of patients with sepsis. actually, we don't know the origin of this proct production, in the united states, will also be discussed. the septest portion of this study will eventually enroll over patients tentatively diagnosed as septic. the results of septest will be compared with commonly accepted symptoms and criteria associated with sepsis in order to determine the clinical utility of this endotoxin assay. preclinical results of patients and normals be presented as well as data on the time course of endotoxemia and clinical outcome of selected septic patients. preparation of dna libraries clifford w. schweinfest, ph.d. a fundamental tool of the molecular biologist today is the ability to work with purified dnas representing genes of interest with respect to the investigator's field of study. originally applied almost years ago to the genetic dissection of simple organisms such as viruses and bacteria, molecfllar cloning was rapidly applied to study the more complex genetics of the mammalian cell. today, virtually any study of cell physiology which depends upon specific gene expression is approachable using the tools of the molecular biologist. therefore, stress induced gene expression (such as the heat shock gene, hsp ) or the regulation of the nitric oxide synthetase gene or the induction of cytokines and growth factors as a result of trauma or injury lend themselves to investigation at the level of the gene. during these workshops, we will discuss the means by which cdnas and genes are isolated, amplified and identified. we will discuss the strategies and methods for cloning cdnas and genomic dnas, for organizing such cloned libraries, for finding specific genes and for characterizing those genes. this speaker will focus on the techniques and considerations involved in the synthesis of cdna libraries. topics include rna isolation, mrna quality, reverse transcription, choice of cloning vectors and library quality. genomic dna library synthesis will also be discussed with respect to the vector/host systems available and applications which are specific to genomic dna. finally, polymerase chain reaction (pcr) will be discussed briefly with regard to its impact on dna cloning. the identification of the genes or gene products that have a role in cellular processes is fundamental to our understanding of genetic control and methodologies to achieve this aim are currently available. all levels of the various signal transduction pathways can b~ molecularly analyzed to define the mechanism by which critical steps in each pathway are achieved. the questions that are unresolved in each area of investigation serve to direct the scientist towards analyses of gene products or gene regulation of the gene itself. thus, selection of the type of library (genomic or cdna) to be used is dependent upon the specific goals of each investigator. to facilitate resolution of this question, an overview of the uses for the different types of libraries will be presented. at least four methodologies are currently available for screening a library, which are dependent upon specific interaction between nucleic acids, nucleic acids and proteins, antibodies and antigens or between different proteins. the use and advantages of each of these methodologies will be discussed along with a description of probe preparation. sequence methodologies required to begin characterization of gene clones will be presented. hopefully, the participants in the workshop will help define areas of emphasis and allow time for directed interaction to discuss specific applications based upon their own experimental systems. alterations of physiological conditions, such as those occurring after shock and sepsis, induce changes in gene expression of cells composing the major organ systems. the challenge is to detect and characterize these changes in geae expression and relate them to the injury. the development of cloning techniques has emerged as the methodology of choice. changes in gene expression are usually characterized by variations in the concentration of cellular messages because synthesis of the final product "the polypoptide" is usually proportional to the concentration of mrna. due to the rapid regulation of gene expression the cellular concentration of messages changes very quickly. this is commonly referred to as steady-state levels, a balance between transcription and degradation. steady-state levels of mrna can be detected in a single cell (in situ hybridization) or in total rna isolated from cells or organs and separated in agarose gels (northern blots). although analysis of mrna steady-state levels are very useful, they do not provide information about the mechanisms that regulate gene expression. changes in gene expression primarily occur at the level of transcription; characterization of the rna species being synthesized at a given time is performed by the nuclear run-off technique. when there is no a priori information about the gene that may be regulated after a particular situation such as sepsis, the total pool of messages present in cells at given time can be characterized by a combination of in vitro translation of the cellular messages and fractionation of the in vitro translated products by two dimensional gel electrophoresis. such approach permits the visualization of the general pattern of gene expression, a "finger print", of the physiologic state. in summary, researchers now have access to a great variety of techniques to identify and characterize genes expressed in response to a physiological condition that may be utilized as "molecular tools" to study the organism's responses to shock and sepsis. the acute phase proteins are a set of plasma proteins with greatly increased plasma concentrations during acute inflammations and after tissue trauma, e.g. after major surgery. the proteins counteract the source of injury, facilitate clearance of infectious particles by phagocytes, assist immune responses and initiate wound healing. the corresponding genes are expressed in liver hepatocytes and regulated by the inflammatory mediators interleukin and interleukin (ill, il ). class acute phase genes are mainly controlled by ill and by combinations of ill plus il ; class genes mainly by ii, . the human c-reactive protein(crp), serum amyloid a(saa) and complement c genes will be discussed as examples of class genes, and rat c~ macroglobulin as a prototypical class gene. both classes of genes use different types of ¢ytokine response elements in their promoter-proximal transcription control regions; class genes use the transcription factor nf-il or c/ebp as the key factor to mediate cytokine responsiveness; class genes use a different, so far unidentified factor to achieve responsiveness to il . ongoing efforts to purify this factor, called the il -response factor (il -rf), from rat liver nuclear protein extracts will be described. the il -rf apparently mediates the effects of il in a broad range of cell types, including b lymphocytes and other hematopoietic cells. it is therefore likely to be of equal general importance for gene regulation by il as nf-il . the importance of transcription factors as potential targets for novel bioactive substances and possibly therapeutic agents will be discussed with the help of several recent examples. new methods for altering the germ lines of mice provide powerful tools for understanding the roles of individual genes in normal and pathological processes, and for reproducing specific genetic mutations that result in congenital disease. three approaches will be discussed. conventional transgeulc mice are frequently constructed using artificial transgenes that express genes from a promoter other than the normal gene promoter. this paradigm is used to produce very high levels of a gene product, for example, with a viral promoter, or to attempt to regulate gene expression using an inducible promoter. alternatively, normal promoter sequences can be hooked to a gene whose expression is lethal to the cell (e.g., diptheria toxin a chain) to ablate all cells expressing that gene. another approach uses an intact gene with its normal regulatory sequences. here, an elevated level of the gene product is delivered from the correct cells in the correct tissues at the correct developmental stages or in response to natural signals. this approach has been refered to as "genetic pharmacology," and provides a precise delivery of the gene product to the target. however, to be most effective, the transgene should contain arl regulatory sequences as welt as the entire genomic segment containing gene coding regions. the introduction of conventional transgenes is limited to roughly kilobases, while genes containing all regulatory sequences frequently stretch over dozens or even hundreds of kilobases. to overcome this problem, procedures have been developed recently to introduce yeast artificial chromosomes (yacs) into mouse embryonic stem (es) cells. yacs can include over mb of human dna, large enough to encompass the largest known human genes. es cells are also useful for targeted gene deletions and mutations. homologous recombination can be targeted to any known gene in es cells. when these modified cells are injected into a mouse blastocyst, they can be incorporated into all tissues of the resulting mouse, including germ cells, so subsequent generations will pass the genetic modification as an inherited trait. assessment of the effects of a null allele on development can provide valuable insights into its normal role. ultimately, these technologies may be adapted to human cells -not for embryonic intervention, but to provide modified stem cells for various tissues (e.g., gut, eye, hematopoietic system) which could then be applied to somatic therapies. with major illness/injury that respirswy faihne fi'equently followed sepsis, tilney el al nse, d the term "soqueutial syste~ failure" for patients with renal failure after solmir of ruptured abdominal aortic ~aeurysms, i then reviewed our experiences after inju~ and oporstion and suggested that multiple, progsesslve or sequential systems or organ failure was a syndrome to be reckoned with in the, 's. eiseman et al then wrote about "multiple organ failure", especially with liver failure. polk el m found that renmte orgau failure often signalled occult anita-abdominal infection. fry et al ampbasized the role of uncontrolled infection in organ failure, border et ai described metabolic alterations with mof and used the term multiplesystems organ feilmo (msof). other early conltibutots to our knowledge of mof include faist, trunkey and miller, marshall and dimic&, cassone, catlleo, meakins and marshall, (}otis et at., mater and many others. mof or msof were used eommoifly. cerra coined the terms "post-trsumatic septic sfndromc" and "hyper metabolism otgau failure complex", and border et al, used lhe ex ~ression "gut origin seplic states" to illdioate important eurrem aspects of abe gt.'nerlc problem of organ failure and death, other terms include acute organ-system failure, multiple organ injury syndrome, post-traumatic multi-system organ failure nod post-~aumatic organ system infection s~dmmc (fi~sis), i bdieve the latin "maltiple organ failure" is clean, neat and says it all, now there is a proposal for a new set of torminolugios -mods and sirs. will they be helpful in the study and esro of patients? our speakers in this session will review thcsa proposals and the evidence as we strlvo for eoasensns. it has been well demonstrated that the administration of pro-inflammatory cytokines, and especially tumor necrosis factor (tnf) can result in a picture similar to septic shock with secondary multiple organ failure. it is also clear that tissue hypoxia can lead to organ damage. we believe that it is the interaction between the two phenomenons that can lead to mof. on the one hand, the inflammatory response is amplified in the presence of hypoxia. on the other hand, the release of the mediators of sepsis can increase tbe oxygen demand ef the tissues, alter their oxygen extraction and decrease myocardial contractility, and the combination of these elements accounts for the development of septic shock. this hypothesis is supported by two lines of evidence. first, mof is usually preceded by an episode of acute circulatory failure (even though frank circulatory shock may not be evident). second, recent experimental and clinical studies indicated that immunotherapy (especially antibodies to tnf) is particularly effective in the most severe forms of sepsis, associated with circulatory shock. hence, an effective way to prevent mof may be a combination of aggressive cardiovascular management and immunotherapy. development of the multiple organ dysfunction syndrome (mods) in the critically ill follows an heterogeneous group of stimuli including infection, sterile inflammmion, extensive tissue injury, ischemia, intoxication with a variety of substances, and immune system activation. whether the resulting physiologic abnormalities reflect a common pathologic process, or are simply a non-specific manifestation of tissue injury is unknown. moreover, the lack of clearly-defined functional criteria for the characterization of the syndrome on the one hand, and of reliable biochemical markers of its evolution on the other, has made attempts to define its epidemiology and natural history difficult. using a numeric scoring system to quanfimte the clinical severity of mods, we demonstrated that, although mods is more common in patients who have significant infection at the time of icu admission, a much stronger correlation is evident between the severity of mods and the subsequent development of nosocomial icu-acquired infection. furthermore the severity of mods correlates strongly with the severity of the clinical septic response, and with the degree of immunologic compromise evident on delayed type hypersensitivity skin testing. to determine the relative importance of the initial stimulus, and the host response to that stimulus, to the subsequent emergence of mods, we undertook a matched cohort study of critically ill patients admitted to the icu with infection, matched by age, sex, and apache ii score to uninfected controls. organ dysfunction scores were higher in patients admitted with infection, but were also significantly associated with the expression of a septic response at the time of icu admission, independent of the presence of infection. by stepwise regression analysis, the magnitude of the septic response was the most powerful predictor of the severity of mods in both infected and uninfected patients. these data suggest a model of mods in which a stimulus (eg infection) and the host response to that stimulus (eg the septic response) result in a state of altered systemic homeostasis (manifested in this example by immunologic dysfunction). moreover they suggest that the principle determinant of the emergence of mods is the response of the host, rather than the nature of the stimulus, and are consistent with the hypothesis that a stereotypie systemic response to an heterogeneous group of injurious stimuli underlies the pathogenesis of mods. arthur e. baue, m.d, ever since the attorapt build the tower ef babel, as desclibcd in the old testament of the biblc, it has been difficult to got agreement o;x common definitions or language, although mof has served well, there will always he now classifications proposed with good reasons for them, thus mods and sirs are not the final oxpressinns in the lexico~aphic sweepstakes. attcmpts to develop standard animal shock and scpsis models (hemorrhage, endotoxin, foes[ pellets, cecal ligation and puncture, e. colt hlf sioi to evaluate therapy have net been suoca.ssf~. clinical syndromes of mof, sepsis, sepsis syndrome and athers have not been aeacpte.d by all. our problem is that we arc tryittg tu d¢ffino a non-emily. mof or mods or sirs is net a disease or oven a syndrome. it is a series of complications of injury, disease and intensiva care which loads to death for many patients in intensive care units, it is not a fixed entity, but an ewilving picture. we have lumped (ugethet for therapy and definition a number of diseases and problems according to clinical manifestatieos rather than the eause of ihe problem, the search for unified mechanisms has not bean successful. will we benefit oleo from a more precise classification and definition of a non-outjty, a hodgu-podge of human disorders which have charsmeristic.s and manifestations of tissue injury, inflammation and infactian? re.hi clinical trials of potential "magle ballets" suggest that we should go in a different direction--instead of lumpors, we should be splitters, to seek effective therapy, we must fucus on specific disorders such as trauma, specific infections, inflammatory disease and chronic or acute organ damage (copd -renal failure, etc.), i will say more aboet this later ha the me.ethag. thcre is cue potentially important pert of the mods proposal, and that would be do~mcntation of organ dysfunction before fsiiure occurs and before tile need for external supporl dovelope. this could lead to hatter methods of preventing organ failure. preveution is ultimately the only answer to organ failure, m mof, mods and sirs. have wo reached a consensus?--only that we arc dealing wilh a diffl~x:lt probtolr looking for solutlons. acute lung injury (ali) and its most severe form, acute respiratory distress syndrome (ards) characterized by severe hypoxemia, diffuse infiltration of both lungs, a reduction of compliance and a wedgepresure lower than mm hare related to direct or indirect injury. when aliresults from direct injury (toxic agents, lung contusion, pneumonia), the lesions of epithelial barrier and the activation of lung macrophages are the first events leading to the release of inflammatory mediators wh:ch are responsible for alteration of the membranar permeability and for invasion of the alveoli by fluids, proteins and cells. an inflammatory reaction develops, with injury to endothelial cells, adhesion of polymorpbonuclear leucocytes (pmn) and the release in blood stream of intlammatory mediators dispersing the inflammatory reaction to other organs and tissues. the failure of lung function also results into hypoxia in other organs, leading to tissular ischemia, triggering an inflammatory reaction leading to organ dysfunction. frequent complications of direct lung injury are septic pneumonia with endotoxin release, phagocytes activation and cytokine production disseminating inflammation. by this way, direct lung injury can be at the origin of the multiple organ dysfunction syndrome (mods), the frequence of which having been estimated to % and is increased when all has occured in patients alreadypresenting an organ dysfunction (immunodepresslon, cancer...). when ali results from redirect or extrathoraclc injury (trauma, infections, hypovolemic shock, acute pancreatitis...), inflammatory mediators and micro-aggregates released in particular organs or tissues reach the lung via the blood and lymph streams, are filtered in the organ or trapped in the lung capillaries, and are responsible for a local inflammatory reactaon (endothelial cell activation, pmn trapping and adhesion, platelet aggregation, release of mediators). sepsis acts by the way of endotoxiu and sequential eytokines release (tnf, ill,...) while trauma with important blood loss acts especially by the way of hypoperfusionreperfusion phenomena leading to a disseminatedinflammatory reaction and to a possible bacterial transloeation when intestinal hypopeffnsion is present. in these conditions of indirect injury, all (or ards) is a iocal early (often the first) manifestation of a general phenomenon of altered membrane permeability and inflammatory reaction, easily and rapidly recognized by its clin~cai signs. the iung is one of the numerous organs participating to the mods, in these conditions, the mortality rate is high, reaching more than % when sepsis is present or when at least organs are implicated in mods. by direct or redirect injury, lung is so a target organ for mods and injured lung can be the cause of mods or simply a participant to this syndrome. jorge cervts-navarro main determinants for brain dysfunction are breakdown of the blood-brainbarrier and raise of intracranial pressure (icp), in second place decrease of systemic blood pressure, disorders of blood coagulation and respiratory function. the blood-brain-barrier of cerebral blood vessels can be opened by stroke, cerebral trauma, inflammation, convulsions, acute hypertension and changes in the blood osmolarity. the consequence is brain oedema, increase of lop and decrease of the perfusion pressure. a close correlation between intraventricular pressure and the fate of patients with severe brain injuries has been established. regional cbf values of to ml/ g/min are reflected in isoelectric eeg, and values about t ml/ g/min, result in loss of somatosensory evoked potentials. for ionic pump failure the threshold has been determined by values of about ml/ g/min and is reflected in massive release of intracellular potassium. in stroke and in brain trauma when the oedematogenous condition is initially localized the tissue pressure variance within and between the hemispheres lead to tentorial and falciform herniations are the common cause of death even before the critical threshold of intracranial pressure is reached. the increase of the icp over the level of the perfusion pressure leads to the arrest of the cbf. if this persists {or periods exceeding seconds of global brain ischemia loss of conciousness and developing seizures appear. if it exceeds min irreversible injuries of the brain appear. following cerebral ischemia and after severe head injury a tendency to increased coagulation can be detected. vascular occlusion may develop either as a result of local thrombus formation or from emboli caused by circulating platelet aggregates. the formation of microthrombi is triggered by the plateletactivating factor a mediator in central nervous injury also responsible for aggravation of posttraumatic brain edema. acute hemorrhagic leucoencephalitis and brain purpura are known to arise as complications of acute viral infections and following gram-negative septicaemia. institute of neuropathology, free university of berlin, hindenburgdamm , berlin, germany undoubtedly, attempts to quantify as objectively as possible the degree of dysfunction of the various organs is very valuable. however, cardiovascular failure has a peculiar place in the context of sepsis. the development of acute circulatory failure (shock) is of paramount importance as a cause rather than as a consequence of organ failure. it is therefore essential to clearly separate patients with and without circulatory failure. once this has been done, attempts to list the cardiovascular system among the other systems have been unconvincing. in a number of studies, cardiovascular complications are assimilated to a low systemic vascular resistance (svr), but since svr is basically the ratio of blood pressure over cardiac output, and since hypotension is already included in the definition of shock, then a low svr is basically equivalent to a high cardiac output, which is a characteristic rather than an ominous complication of severe sepsis. development of a low cardiac output unresponsive to fluids is usually a terminal event. it is not advisable to list other problems such as severe arrhythmias, myocardial infarction or tamponade as complications of severe sepsis. host defense dysfunction following trauma, shock and sepsis e. faist, g. f. babcock * major accidental, burn and operative injury often precipitates a profound multicentric immunologic depression that is believed to predispose patients to become anergic and thus to develop towards a higb probability of infection. anergy or a lack of immunologic reactivity stands for a total elimination of skin test reactivity and recall antigen responses in the inununocompromised patient. anergy following overwhelming trauma or major septic conditions results from a massive impairment of cell mediated immunity (cmi) together with a whole body malignant inflammationiike state. we and others have demonstrated clearly that the skeration of cmi following trauma is mainly due to the disruption of intact monocyte (moo) / t-cell interaction. within this phenomenon we see a shift of the cell ratio in the compartment of peripheral blood mononuclear cells (pbmc) with a considerable increase of prostaglandin e synthesizing m~ and a simultaneous decrease of functionally competent cd + and cd + lymphocytes. t-cell dysfunction in states of profound stress is characterized by impaired synthesis of two crucial lymphokines -interleukin- (il- ) and gamma-interferon (y-ifn). the inability to produce adequate amounts of il- , most likely attributable to alterations in the transmission of signals from the cell membrane to the nucleus, results in incomplete proliferative t-cell responses to antigenic stimuli, while a lack of ?-ifn results in inadequate m~ antigen processing and presentation. the role of the two functionally distinct t-helper subsets, t-helper- (thl) secreting principally il- and ?-ifn and t-helper- (th ) acting principally in inducing antibody formation with a secretion of il- , il- , il- and tnf-[ has still to be established within the context of major trauma. antibody formation to common protein antigens is impaired, the predominant finding is a shift from igm to igg synthesis. although excessive secretion of prninflammatory cytokines (il-u , tnf-c~, il- , il- ) has been considered to be deleterious for the host in states of major inflammation and infection, in-vitro and whole blood investigation of me function has clearly revealed that there is initially a marked suppression of moo from septic patients to synthesize and secrete proinflammatory cytokines to endotoxin. this probably will result in immunodeficiency of traumatized as well as septic patients, since these cytokines in low concentrations are involved in the upregulation of the essential humoral and cellular immune functions. abnormalities of pmn function noted after serious injury have been interpreted by some investigators as signs of unresponsiveness of this cell population, others have demonstrated signs of pmn byperactivation. latest findings revealed that there is a clear pmn dysfunction in circulating blood: % of all pmn's in this compartment show downregulated or non existent ~-integrins within hours posttrauma -these cells do not phagocytose, have a reduced respiratory burst and appear to be completely degranulated. restoration of these cell functions within days post-trauma is significantly correlated to survival of traumatized patients. other reports however stress increased expression of cr + receptors (cdll/cd complex) on circulating pmn's, increasing the ability of these cells to adhere to intercellular adhesion molecules, thus contributing to play a major role in inducing the pulmonary capillary leakage. our knowledge about the perturbation of host defenses associated with serious injury and sepsis is continuously increasing and represents the precondition for the design of effective therapeutic measures to prevent and counteract the resistance to invading microorganisms. dept. of surgery, klinikum grosshadern, ludwig-maximilians-university, munich, germany. * dept. of surgery, university of cincinnati, cincinnati, ohio, usa lg thijs~ ce n~ck sepsis is the most common cause of acute disseminated intravascular coagulation (dic) and coagulation disorders as well as abnormalities of fibrinolysis are common in septic patients. some clinical and experimental studies indicate that dic is a pathogenetic factor for the development of multiple organ failure. endotoxin and various mediators (tnf, il-i) enhance tissue factor and decrease expression of thrombomodulin on endothelial cells in vitro. also, tpa activity is suppressed and release of pai-i is stimulated. in such a way the endothelial surface becomes procoagulant whereas fibrinolysis is inhibited. following administration of endotoxin to normal volunteers levels of prothrombin fragments (fi+ ) and thrombin-antithrombin (tat) complexes increase, indicating thrombin generation. also the fibrinolytic system is activated as evidenced by a rise of levels of tpa and plasmin-antiplasmin (pap) complexes but this is counteracted by a subsequent release of pai-i. in severely ill septic patients levels of tat complexes are increased and concentrations of the natural inhibitors of coagulation (at iii, protein c) are usually decreased. also, tpa levels snd pap complexes as well as concentrations of pai-i are elevated. the severity of many of these alterations is related to mortality. thus, both coagulation and fibrinolysis are activated in sepsis, but not in a balanced way, thereby promoting coagulation. one of the hallmsxk pathological alterations associated with sepsis is the development of microvascular thrombosis, an entity ~lmre~erizod by microvas~tlar plugbing with leukoeyies (predominately nentrophils) and fibrin deposits. preranably, ischemia remlt~g fibm ve~-'ttlac ow,.luwion contributes sisni.ficantly to end orgen darnaje and consequent dysfatlctlon. p, er~t srldies haw focused pmdominately on the role of adhesion molecules in the pathogenesis of neu~ophil sequestration during infection and s~sis. this preparation will review the mechanisms underlying intravak-'v.ler i~brin deposition and its contribution to organ injury. the normal endothelial cell sure is generally conddered o be anticos~am. this state is maintained by two major anticoag~lam molecules on the cell so,ace: hepax'an su,lfale and thmmbomodulin. studies performed over the past decade have do~mentod a general shii~ towards a procoa~qtlant staw during gram negative hffeodon, aft e~| mediated mainly by changes in the endothalial cell surface. antt-tf antibodies have been shown to be pro~ective during l~'ml endotexemia. in summary, ~erova~'~ler fibrin deposition, in ~rt mediated by ~rcgulation of cellular tf, is a consistemt patholo~cal flndin~ during sepsis and contributes to organ injury. strategies designed to abrogate this event may n~nimjze the magnitude of erg~ dysftm~on. n, v, christou md phd, department of surgery, megill university, montreal, quebec, canada interactions between immune calls and the endothelium vie adhesion molecules serve to modulate immune cell traffic between the blood strum and the extrmvascular space, these families of molecules acting in a cascade and closely integrated with the oytoklna network, blood coagulation and the complement system, are responsible for the homing of leukocytes to areas of inflammation and the realrculatlon of tymphocytes. there are three types of immune ceils that must exit the blood stream into the extravascular space: lymphocytes ; polymorphonuclear leukocytes; and non-lymphocyta mononuclaar cells (monooytes, basophlls, aoslncphils). b lymphocytes exit the blood stream and recircu}ate mostly via the high endothelial venule (hev) in lymphatic tissue, rarely, in chronic }nfectlon=, they may recirqulate vie hev in non-lymphoi:t tissue. t-lymphocyte recircutation on the other hand can occur via hev in lymphoid tissue, as well as, the endothalium of the skin, returning to peripheral lymph nodes via the lymphatic channels. lymphocyte recirculation is the mechanism which allows ¢ontaot between the immune repertoire and pathogens, and homing delivers these cells to the appropriate environment for activation and for effeotor function, pmns exit the blood stream through endotbelium in close proximity to the site of inflammation after appropriate endothelial membrane receptor expression. they must reach the site of pathogen tnveslon quickly in order to be effective. their exudation to the inflammatory site can be modulated by their intravascular pdmlng, which results from appropriate receptor expression. because endotoxin leak from the gut has been postulated as an important trigger mechanism for the systemic inflammatory response syndrome seen after serious injury, the immunologic and metabolic effects of bacterial endotoxin infusion into normal volunteers can be expected to shed considerable light on the validity of this hypothesis. we and ethers have used tbis model to show that endotoxin causes a temporary paralysis in the ability of circulating monocytes to prudce the proinflammatory cytokines interleukin-i (il-i) and tnf-a. endotoxin, however, causes increased production of pge by the same cell population. endotoxin infusion causes significant suppression of circulating t-cell numbers and a profound suppression in the ability of the circulating t-cell population to proliferate and to produce interle~in- (il- ) upon in vitro stimulation. after endotoxin circulating t-cells are also more sensitive to the inhibitory action of exogenous pge . administration of cyclooxygenase inhibitors at the time of endotoxin infusion largely abrogates the effect of endetexin on t-cell proliferation and il- production. endotoxin infusion also causes the release of increased levels of circulating catabolic hormones including cortisol. administration of cortisol alone or cortisol along with endetowin to volunteers has allowed dissection of cortisol effects from those of endotoxin itself. cortisol infusion alone causes a diminution in the circulating t-cell population but the remaining ceils continue to produce il- after appropriate stimulation. cortisol infused along with endotoxin blocks the overshoot in monocyte proinflammatory cytokine production seen - hours after endetoxin infusion. at present, one may conclude that administration of sublethal doses of bacterial endetoxin to human volusteers produces alterations in cytokime production and tlymphocyte activation which are both similar and dissimilar to those seen following serious injury. hemodynamic support is based first on intravenous fluids and second on vasoactive agents. colloids are usually preferred to crystalloids, for their more rapid hemodynamic effects and their lesser passage in the interstitial space. in the presence of hypotension, the pharmacological profile of dopamine makes it the first agent of choice. it is only when high doses of dopamine are insufficient to restore a sufficient tissue perfusion pressure that norepinephrine should be added. even when cardiac output is not decreased, a dobutamine infusion is often indicated to counteract the myocardial depression, prevent vasoconstriction, and increase oxygen delivery to the tissues. the benefit derived from the administration of "renal" doses of dopamine is doubtful, but stimulation of dopaminergic receptors may increase blood flow also to the gut. in any case, none of these catecholamines has been shown to significantly improve the oxygen extraction capabilities of the tissues. agents with antiinflammatory properties but also with some vasodilating properties, such as n-acetylcysteine, prostaglandin el or pentoxifylline represent more attractive options to increase oxygen extraction. cardiovascular support should aim not only at the restoration of a sufficient arterial pressure but also at the maintenance of an optimal oxygen delivery to the cells. it should thus be guided also by measurements of cardiac output, mixed venous oxygen saturation and oxygen extraction, and indexes of cellular hypoxia, such as blood lactate levels, gastric intramucosal ph or vanearterial pc gradients. supranorma[ delivery contributes to the prevention of tissue hypoxia tissue hypoxia is considered to be the common final pathway in the pathogenesis of multipte systems organ failure. it may directly contribute to cellular injury and organ dysfunction as well as enhance further mediator activation and release by a positive feed back mechanism. prevention of tissue hypoxia, is therefore, one of the most important aims in the supportive therapy of critically ill patients, especially in those with sepsis and septic shock. mismatch of cellular o= supply and demand in these patients may resuit from the impairment of the cardiocircu[atory system on all levels. . myocardial depression with a drop in delivery (do~) . redistribution of blood flow between the different organ systems . inadequate nutritive blood flow due to tissue edema and endothelial damage (gic, leucocyte swelling etc.) these pathological changes may go along with increased metabolic needs. cellular and organ supply may therefore be inadequately matched with cellular needs in patients with normal and even supral normal doz. hyperdynamic circulation is often present in adequately volume resusucitated patients. it is most likely that one of the bodys main compensatory mechanisms would maintain cellular o= supply in the face of increased metabolic needs and impaired oz extraction capabillities. this pathophysiology may explain the findings in several clinical investigations that patients with normal or even supranormal doz can have signs of inadequate regional tissue oxygenation. it is also consistent with the results of different studies which demonstrated that the achievement of supranormal doz levels, either spontanuously or due to adequate supportive therapy, resuits in better patient outcome. any attempt to prevent or treat tissue hypoxia in these patients, however, has to take into account the effects of therapy not only on global dgz but especially on regional and microcirculatory blood flow. r. rossaint, d. pappert, k. lewandowski, h. gedach, k. slama, k.j. falke klinik for anaesthesiologie und operative intensivmedizin, ukrv, freie universit §t berlin, germany important contributory factors to the high mortality of severe acute respiratory distress syndrome lards) are the aggressive therapies required, such as mechanical ventilation with high inspiratory oxygen concentrations and airway pressures. as specific therapies for reducing or preventing the general inflammatory reaction of the lung resulting in severe hypoxemia is unknown, today's therapy is limited to procedures which predominantly support or maintain pulmonary function, i.e. pressure limited ventilation with peep and permissive hypercapnea, avoiding or treatment of fluid overloading, and positional maneuvers. extracorporeal lung assist combined with low frequency positive pressure ventilation has been recommended, when conventional therapy fails. today, extracorporeal gas exchange may be carried out using a system internally coated with covalently bound heparin. this allows for a lower level of systemic heparinzation reducing the risk of severe hemorrhagic complications of extracorporeal respiratory support. from april to august patients, aged from months to years, were transferred to our intensive care unit (icu) for treatment of severe ards. all fulfilled at least the slow entry criteria of the u.s. national ecmo study. due to hypoxemia patients required veno-venous extracorporeal membrane oxygenation (ecmo) immediately after transfer to our icu. the other patients were first treated with pressure controlled mechanical ventilation, permissive hypercapnea, prone position, and dehydration, if necessary. in out of these patients, in which the gas exchange did not improve in the following days, veno-venous ecmo with heparin-coated systems was additionally performed. heparin was given to achieve a partial thrombin time between - s and an activated clotting time between - s. if surgery was performed during ecmo, heparin infusion was interrupted. no severe bleeding complications related to anticoagulation for the extracorporeal bypass could be observed, however, in some patients, after three weeks of ecmo thrombi in the drainage cannula were observed. a problem of of membrane leakage shortened the life span of the membrane lungs to a mean of about four days. in the conventionally treated group % survived and in the additionally with ecmo treated group % survived, representing a % survival rate in patients whose risk of death is considered more than %. on the basis of these experiences, we conclude that the described strategy, including veno-venous ecmo with heparin-coeted systems, may improve the survival in patients suffering from severe ards. abnormally high skeletal muscle po in septic patients and its normalization during recovery: evidence against tissue hypoxia but for impaired oxygen metabolism of skeletal muscle? p. boekstegers, k. werdan department of medicine i, gro hadern university hospital, munich, germany a pathological oxygen uptake supply dependence was suggested to indicate tissue hypoxia in sepsis-a hypothesis which is discussed controversially. because the detection of reduced oxygen transport to tissue and &tissue hypoxia would have important implications for therapy, skeletal muscle oxygenation was studied in patients with sepsis. intermittent and continuous determination of skeletal muscle po by polarographic needle or catheter probes provided no evidence for skeletal muscle hypoxia even in severe stage of sepsis (boekstegers et al., crit care med ) . in contrast, mean skeletal muscle po was found to be abnormally high in patients with sepsis ( _+ , mmhg, n= ) compared to patients with limited infection ( , + , mmhg, p< . , n= ) , to patients with cardiogenic shock ( , + , mmhg, p< . , n=ls) and to healthy subjects ( , _+ , mmhg, p< . , n= ). furthermore, serial measurements in patients with sepsis showed that skeletal muscle po was higher ( , _+ , mmhg) on days with severe sepsis than on days with intermediate state ( , _+ mmhg) and than on days without sepsis ( , _+ , i mmhg) . thus, a decrease of abnormally high skeletal muscle po was related to improvement of sepsis. this was also demonstrated by comparing the decrease of abnormally high skeletal muscle po with the decrease of apache ii score or elebute score as well as interleukin- serum levels in a separate study (boekstegers et el., shock, in press). in summary, our data provide no evidence for skeletal muscle hypoxia in patients with sepsis but support the assumption &impaired oxygen metabolism in severe sepsis. neutropnlic emigration from the vascular space into the extracellular matrix is important for the response to tissue injury or contamination by providing a large recruitable pool of tissue-based phagocytes. the consequences of neutrophil exposure to intravaseular chemoattractants, likely relevant for il- and c a in sepsis, trauma, and in burn injury, are suppression of neutrophil attachment to endothelial cells and matrix proteins. it is probable that proteoglycan-bound attractants are of considerable biologic relevance, and may result in enhancement of responses to subsequently encountered cytokines. in the presence of connective tissue proteins expressing integrin-specific binding ligands, neutrophils respond to tnf-cq gm-csf and other cytokines by producing large amounts of hydrogen peroxide. this response is likely important in the digestion of contaminated or injured tissue by facilitating activity of neutrnphil granular proteases and inactivating plasma anti-proteases. this matrix-dependent oxidative response is important in defining potential novel targets for therapeutic intervention. the response appears to involve signalling by integrin-linked tyrosine kinases. the net effect of matrix protein injury through this mechanism is enhancement of the fibrotic response which underlies much of the prolonged ventilator dependence of patients with the adult respiratory distress syndrome. this adherence dependent response has also been implicated in direct hepatocyte injury, and may represent an early component of the syndrome of multisystem organ failure. study purpose: in this patient (pat.) population with a considerable sepsis morbidity and mortality, parameters proposed for sepsis assessment (elebute sepsis score [ele], sirs) were investigated with regard to their use in the early classification of pop. pat. at risk for developing sepsis. patients and methods: in a previous observational study on consecutive pat. after elective open-heart surgery, we had determined ele daily for at least pop. days (in pat. with a longer stay: until icu discharge). after publication of the newly proposed sirs definition, these criteria were retrospectively calculated and compared to ele. results: on the total of n = patient-days, both ele and sirs showed significant (p< . ) correlations with parameters reflecting the general and sepsis-related severity of the pop. clinical course. compared to sirs, the ele correlations were better (icu mortality: . vs. . ; icu treatment days: , vs. . ; days on mechanical ventilation: , vs. . ; days with vasopressor requirement: . vs. . ; number of microbiological findings: . vs. . ), the optimal classification criteria for the mainly sepsis-related outcome gave maximal youden indices of . for ele (ele >_ on >_ days, accuracy: %) compared to . for sirs (sirs present on > days, accuracy: %). accordingly, ele roc curve areas for both overall ( . ) as well as sepsis-related prognostic evaluation ( . ) were significantly (p< , ) larger compared to sirs ( . and . , resp.), this higher overall accuracy of the ele criterion was primary due to a more valid assessment already on the first and second pop. day, where sirs still had a high false positive classification rate ( % and %, compared to % and %, resp.). conclusion: in the early postoperative course after cardiac surgery, the sirs definition displayed a high false-positive classification rate (low specificity) for subsequent sepsis-related mortality compared to better classification results obtained by the elebute sepsis score. from the departments of medicine i and of "cardiac surgery, grosshadern university hospital, marchioninistr. , d- munich, frg. correlation between physiological and immunological parameters in critically ill septic patients. ma rogy, h oldenburg, r trousdale, s coyle, l moldawer, sf lowry a relationship between physiological parameters of severe sepsis and immunological function has not been established. in an effort to assess such a relationship we prospectively evaluated nine severely ill septic patients. physiological risk was assessed by the apache iii score , while one component of immunologic function was evaluated by peripheral blood mononuclear cells (pbmc) eytokine production after in vitro lps stimulation . four of the nine patients died. apache iii scores at h were lower in survivors (s) than in non-survivors (ns), ( -+ vs -+ p< . ), while apache iii scores at admission were not significant different between s and ns ( -+ vs -+ ). down regulation of cytokine production by pbmc upon lps stimulation was a transient event in s. while s demonstrated an fold increase of tnf-a bioactivity with[r~ hours, ns did not demonstrate any increase at all. a similar pattern was demonstrated for il- [ and il- immunoactivity. tnf was measured by wehi bioactivity, il- [~ and il- immunoactivity were determined by elisa. the sensitivity was pg/ml for tnf, pg/ml for il-ll and pg/ml for il- , respectively. in conclusion, both physiological as well as immunological functions of severe critically ill septic patients demonstrate predictive value for ultimate survival. while patients biological status seems to be more predictable by apache iii at day , p< . , the pattern of cytokine production by pbmc upon lps stimulation over the first h might be a reliable predictor as well. introduction: therapy of sepsis and its sequelae depends largely on its early recognition. many studies have investigated the change of certain mediators during sepsis and their potential to predict multiple organ failure and outcome. it was the objective of this study to investigate whether the onset of sepsis can be predicted by alterations of levels of interleukin- (il- ), tumour-necrosis-factor (tnf), pmn-elastase and c-reactive protein (crp). materials and methods: over a one year period, polytraumatized patients were prospectively studied (mean age y, % male, iss ). serum and edta-plasma samples were taken in h intervalls until the patient left the icu. il- , tnf, elastase, and crp were determined immunologically. sepsis was defined according to the criteria of 'systemic sepsis' (veterans" administration study, ) with at least of clinical signs: ( ) tachycar-dia> /min, ( ) temperature > , °c, ( ) blood pressure < mmhg, ( ) mechanical ventilation, ( ) leukocytosis > . /ml, ( ) thrombocytopenia < . /ml and ( ) presence of an obvious septic focus. clinical parameters, sepsis severity and serum levels were documented on a daily basis, beginning on day after trauma. results: of patients developed a systemic sepsis ( . %), and died. all mediator levels were elevated under septic conditions. the clinical severity of sepsis correlated well with the respective levels of mediators. in patients, who developed a sepsis the following day, il- ( vs. ng/l; p= . ), crp ( vs. mg/l; p= . ) and tnf ( vs. ng/l; p= . ) were significantly increased as compared to those patients who remained non-septic. elastase levels were considerably elevated but did not reach the level of significance. we conclude that il- , tnf and crp appear to be sensitive markers for prediction of septic complications in polytraumatized patients. objectives of the study: the assessment of liver function in polytraumatized patients who are at risk of developing mof is too inaccurate and late by using conventional biochemical parameters. methats: the injury severity of the patients (n= ) was determined by the injury severity score (iss). lidocaine is given at a dose of mg/kgbw over rain. i.v. and is metabolized in the liver by a cytochrome p- mechanism to monoethylglycinexylidide (megx). the metabolite is measured by a fluorescence polarization immunoassay. serial determinations of the test were performed between the ~t and the ~ day after trauma and were compared with other liver function tests (bilimbin, gldh, alt, ast). the systemic inflammatory response syndrome (sirs) is still a challenge concerning early diagnosis, therapy and prognosis. therefore, evaluation of inflammatory and disease activity becomes more important. c-reactive protein (crp) is a well established acute phase protein in chronic inflammatory diseases. recent reports suggest an induction of crp by interteukin- (il- ), a cytokine involved in the mediator cascade of sirs. on the other hand, tumornecmsisfactor alpha (tnfcx) is a very early released mediator in sirs removed very rapidly from circulation. in addition, soluble tnf receptors (stnfr~ , stnfr ) are released into circulation in the acute phase response. this study examines the kinetics of five acute phase proteins (crp, il- , tnfot, stnfr , stnfr ) in patients suffering from sirs. eighteen patients entered the study after diagnosis of sirs. blood samples were drawn every six hours during the first two days and every twelve hours thereafter. crp was measured in an routine turbimetric assay. il- was detected in an biological assay using the/l- dependent -cell line / . detection of tnfc~ was performed in an elisa system using a monoclonal antibody" for tnfo~. soluble tnf receptors were also measured by elisa. crp levels were elevated (> mg/l) in all patients and at all time points. crp values did neither differ significantly in patients with ( ± mg/l) or without ( a: ) multiple organ failure (mof) nor in survivors ( ± ) or non-survivors ( :t: ). in contrast, l- was elevated in patients wilh mof (mean pg/ml, range - pg/ml). il- levels correlated especially with lung dysfunction. tnf(x levels were consistently elevated in patients with mof. crp, il- and tnfoc did not correlate with each other. in contrast, levels for both stnfr showed a positive correlation (r= . ). patients could be divided into two groups by values for stnfr~ and stnfr : the group with higher soluble tnf receptor levels showed increasing values combined with a poor prognosis. the group with lower levels of soluble tnf receptor consisted of patients surviving mof or without mof. in conclusion, crp does not monitor the course of sirs adequately. in contrast, il- correlates with mof and episodes of high disease activity. high stnfr levels may indicate poor prognosis. klinik f r an/isthesiologie and operative intensivmedizin der cau kiel, schwanenweg , kiei, germany. ch. waydhas, md; d. nast-kolb, ivid; m. jochum, phi); l. schweiberer, mi) objective: to evaluate the irfflarranatory response after different types of orthopedic operations and compare them with the systemic effects of accidental trauma of varying severity. patients: in consecutive patients with multiple injuries (iss . ) the inflammatory response to trauma was prospectively studied. the patients were divided into groups according to their iss points. additionally, the alterations after secondary operations (> hr) were determined (msteosynthesis of the femur (n= ), pelvic girdle (n=ll) and spine (n= ), facial reconstruction (n= ), smaller osteosynthesis (n= ) and others (n= )). methods: specific and unspecific parameters of the inflammatory response were determined in the trauma patients every h, beginning on admission of the patient to the emergency room for a period of hr, and in the operative patients on the morning of the operation, at the end of the procedure and every hr during the first two days. results: lactate, neutrophil elastase, heart rate, po /fio -ratio, and other parameters discriminated significantly between the injury severity groups during the first hr (kruskal-wallis-test, p<. ). the degree of postoperative changes differed significantly (kmskal-wallis-test, p<. ) between the types of operations for lactate, heart rate, po /fio -ratio, nitrogen excretion and showed a strong discriminating tendency for neutrophil elastase and c-reactive protein. the extent of changes were highest after operations of the pelvic girdle, followed by procedures on the femur, spine, smaller bones, and the facial region. the postoperative changes after osteosynthesis of the femur or pelvis were comparable to the alterations noticed after smaller (iss to ) or moderate (iss to ) accidental trauma for neutrophil elastuse, heart rate, po /fio -ratio and parameters of the coagulation system. conclusions: there is a considerable inflammatory response to operative procedures that varies with the type of surgery. large operations cause changes in the body homeostasis that resemble those after multiple injuries. it remains to be established whether the inflammatory sequelae of surgical trauma are additive to the changes caused by accidental trauma. objective of the study: we retrospectively compared characteristics of elderly patients (~ years) and yeunger patients admitted to a surgical {sicu) and a medical intensive care unit (micu). we further studied the relations between advancing age, chronic disease, sepsis, organ system failure (osf) and mortality in the elderly group. material and methods: during a -year period, patients were consecutively admitted into the icu; and during a -year period, patients were consecutively admitted to t~mich. criteria for chronic disease, sepsis, osfsi.e. cardiovascular (cf), pulmonary (pf), renal (rf), neurological (nf), haematological (hf), hepatic (lf), and gastrointestinal failure (gf)-were derived from the literature. results: patients from the sicu and~cu were similar in age, number of osf, and length of stay. however, when compared to sicu patients, micu patients had more cf (p<o.o ), sepsis (p<o.o ), and mortality rate ( % vs. ii~, p<o.ool). in contrast, sicu patients had more hp and nf, and prior chronic disease (all, p<o.o ). of the total group of , patients, there were ( %) patients years of age or older. elderly and younger patients had comparable length of stay in the icj, but elderly patients had significantly more chronic disease, sepsis, and number of osf (all, p<o.o ). all osfs, except hf and nf, were more ~o~mon i~ mdeljl, eompard to you-ger patients. ~he mortality is also higher in elderly patients ( % vs. % in younger patients). after multiple logistic regression, only number of osf increased mortality by a factor of . ( % confidence limits, . - . ), age did not increased [odds ratio . (i. i.i )], while admission to the sicu reduced risk of death by a factor of . ( . - . ). conclusions: based on these results, we conclude that age does not have any impact on icu outcome in the elderly. the only prognostic factor is the extent of acute disease, as measured by the number of osf. hence, prevention of oaf may influence outcome in elderly patients with critical illness. the lower risk of death in sicupatients may be explained by the large proportion of postoperative elective patients with relative mild chronic disease, and the lower incidence of sepsis. department of surgery, free university hospital, de boelelaan , ~v amsterdam, the netherlands. septic shock and low output syndrome h.miyakawa, t.noguchi, s.hattori, a. mizutani, m. mori and n.honda objectives: cytckines are thought to cause the acute phase reactions under several critical conditions. we had investigated the relationships between cytokines network which included il- , l- ,acth and cortisol,and the outcome of the patients with septic shock or low output syndrome (los). materials and methods: in the septic group and los group,nine and four patients were enrolled respectively. furthermore, the patients in the septic group were divided into two groups,survival (n= ) and non-survival group (n= ).tn these patients,ll- , l- ,acth and cortisol had been measured every day after diagnosis of septic shock or los.the total number of measurements were points in survival septic group, l l points in non-survival septic group and points in los group.statistical analysis was used student's t-test to compare the mean of each group,and the changes were reported as clinicat significant if p< . . results: il- levels in non-survival septic group were higher than in both survival septic and los group.ll- levels in non-survival septic group were more significant than in both survival and los group.otherwise,there were no differences with respect to acth and cortisol among three groups. conclusions: we assumed that los would make several organs dysfunction as well as septic shock. but our results showed septic shock, especially non-survival,had different cytokins network mechanism for organs failure from los. lasson ,~, g/ ransson j, jijnsson k. eady diagnosis of complications after trauma is imperative to decrease morbidity and mortality. for this purpose an easy, cheap and fast diagnostic method is needed. the aim of this study was to analyse if complications after surgical trauma of various extent could be diagnosed earlier using preoperative or daily postoperative measurements of various plasma proteins than by using climcal signs of complications. material and methods: two acute phase proteins (c-reactive protein and antichymotrypsin), lbur main plasma protease inhibitors (alpha- -maeroglobulin, c estemse inhibitor, antithrombin ill and alpha- -antiplasmin) and one collagen precursor (procollagen iii peptide) were measured preoperatively and then once dally for days postoperatively. for the plasma protease inhibitors immunorcactive as well as functional levels were measured. haemoglbin, albumin and the white blood cell count were also measured. measurements were done preoperatively in patients and continued postoperatively in patients, % of the patients were operated on for malignancy. resulls: preoperative plasma c-reactive protein levels were higher in patients developing postoperative complications. this discrimination increased when plasma was sequentially analysed postoperatively, when a remaining high level ora second increase in plasma levels depicted a complication - days earlier than clinical signs. high levels were seen both in patients developing local as well as in patients developing general complications. there was no clear correlation between plasma protease inhibitory levels and complications, neither pre-nor postoperatively. procollagen iii paptide levels were slightly (but not significantly) higher postoperatively in patients developing complications. contusions: the acute phase response, especially concerning c-reactive protein, predicts postoperative complications better than both plasma protease inhibitors or collagen precursors. preoperative plasma c-reactive protein levels indicate the risk of postoperative complications, while daily postoperative measurements more readily depicts a complication, usually preceeding the clinical signs of complication by - days. dept. of surgery m'alm general hospital, s- i malmr, sweden. mof is a major threat to the extensive burned patients and associated with a high mortality rate. the role of endotoxemia in the pathogenesis of mof in burned patients remains controversial. in this study, we examined the relationship of plasma endotoxin levels to development of mof, and outcome in patients with thermal injury. methods: a prospective cohort study of patients admitted with burns covering more than per cent of body surface area was undertaken. circulating endotoxin concentrations were measured by modified limulus amebocyte lysate assay in serial samples of plasma. results: out of burned patients developed mof according to multiple criteria. the plasma endotoxin concentrations of patients with mof were . -- . eu/ml, significantly higher than that of patients without mof ( . - . eu/ml) on , , and days postburn (p< . -- . ). significantly more incidence of positive endotoxin test (>_ . eu/ml) was found in patients who developed mof as compared to that of non-mof during the observation period (p< . ). as the mean endotoxin levels increased, the prevalence of mof and death also increased (see table below), persistent endotoxemia carried a poor prognosis. conclusions: the present investigation provide further evidence that endotoxemia in severely burned patients commonly occur. cimulating endotoxin has also been found to be strongly associated with development of mof and mortality following major burn injury. multiple hemostatic changes occur in sepsis mad multiple organ failure (mof). to evaluate the role of platelcts in patients with sepsis and mof, we examined changes in surface glyeoproteins on circulating platelets of t patients with suspected sepsis and mof. the severity of sepsis and mof was assessed by eiebute and apache i scoring system, respectively.using flow cytometric techniques and platelets specific monoclonal antibodies, platelet surface expression of fibrinogen receptor on gpiib-iiia, ofvon willebrand receptor gpib, and of granula glycoproteins (thrombospondin, gmp- , and gp ) was measured. receptor density of gpiib-illa mad gpib on circulating platelets was not affected by sepsis or mof. in septic patients surface expression of activated fibrinogen receptor (libs expression) was significantly elevated (p< . ) and correlated well with severity of disease (f . ). no significant change in surface expression ofthrombospondin, gmp- or gp was noted in septic patients. in contrast, degranulation ofgraanle glycoproteins was significantly elevated in mof (! < . ) that correlated well with severity of mof (gmp- , r= . ; thrombospondin, r= . ).we speculate, that platelets in sepsis circulate in a hyperaggregable (fibrinogen receptor activation ) but still reversible state that results in increased risk of microthrombotic events. in the course of the disease, irreversible platelet degranulation might occur and may play an important role in development of mof. abdominal sepsis is still associated with high morbidity and mortality. the present study aimed at evaluating patients with abdominal sepsis treated at our surgical intensive care unit during a -year period with the aim of identifying potential prognostic factors, bacteriological cultures, diagnostic procedures, treatment and outcome. during the period - i patients with abdominal sepsis were treated at the icu at our university hospital. patients were women and men with a mean age of ( - ) years. in cases, the abdominal sepsis occurred as a postoperative complication. the patients were scored according to apache ii and bacteriological cultures and the occurrence of organ failure were noted. the patients were hospitalized in median for (- ) days out of which (- ) in the intensive care unit. out of patients ( %) died in median after ( - ) days. the primary cause of mortality was multiple organ failure ( / ; %). apache ii scoring could not predict a fatal outcome. abdominal bacterial cultures were dominated by bacteria of enteric origin ( %) and in % cultures grew multiple bacteria. patients bad organ failure and multiple organ failure. / patients ( %) had abdominal sepsis due to diffuse peritonitis despite a morphologically intact gastrointestinal tract and the absence of localized abscess formation. mortality in this group was significantly higher as was the percentage of positive blood cultures and the occurrence of multiple organ failure. abdominal sepsis is still associated with a high mortality, predominantly caused by multiple organ failure. abdominal culture findings are dominated by bacteria of enteric origin. in about / of patients with severe abdominal sepsis a diffuse peritonitis with intact gastrointestinal tract without localized abscess formation was found. in this group the mortality was increased as well as the risk of developing multiple organ failure. during the period from january to september patients, mean age + years were referred to our department of resuscitologywith the diagnosis of eclampsia. all the patients were delivered by cesarian section and were mechanically ventilated for . _+ . days. diagnosis of sepsis was confirmed in cases by clinical and microbiological methods. patients were divided in two groups: lnon septic patients, -patients with sepsis, the control group consisted of patients after cesarian section without symptoms of eclampsia or infection. we determined plasma concentrations of immunoglobulins a,g,m(a,g,m), complement factors (c ,c ), alphal-antitrypsin (aat), trausferrin (trf) and albumin (alb) using beckman (usa) analyzer,protein concentration, using kone (finland) analyzer. a(mg/dl) g(mg/dl) m(mg/dl) c (mg/dl) c (mg/dl) k +- + _+ + +- -+ " -+ * _+ " -+ ' _+ " +_ '* -+ ** -+ "* -+ "* _+ " in a prospective study we investigated serum of severly traumatized patients withdrawn directly after admission at our hospital (tr i). follow up controls were taken daily until day ten after trauma (tr ii). two control groups were performed: serum of healthy volunteers (co, n = ) was investigated as. well as serum of patients undergoing elective herniotomy (n= ) hours before (op i) and hours after operation (op ii). serum bactericidal index (sbi) was determined using a hemolytic e.coli strain :k :h . / suspension with a final concentration of - cfu were incubated with l oopl serum. after overnight incubation sbi was calculated according a special formula. results: co . _+ . opi . _+ . opii . _+ . * tri . _+ . "* trii . + . ** (*:p< . ; **:p<o. ) sbi represents a simple and reproducible method to detect immunobiological alterations after trauma and elective surgery. patients undergoing elective surgery showed slight but significant diminuation of sbi h after operation. deterioration of sbi was observed in serum of traumatized patients directly withdrawn after admission at our hospital. ten days after trauma significant improvement of sbi was found. further investigations have to be done to proof sensitivity and prospectivity of this simple but reliable test. a sepsis like syndrome (sls) occurs in i % of our patients following cardiac surgery. sls is characterized by a severe decrease in systemic vascular resistance requiring the use of vasopressors to maintain adequate hemodynamics in the presence of negative blood cultures. in order to determine whether preoperative factors predict the occurrence sls we retrospectively studied patients with sls (group i: age . ~ . years); they were compared to control patients (group : age ± . years). treatment of sls consisted of aggressive fluid replacement and norepinephrine infusion. rydrocortisone ( mg/ hrs) was given on the first day. antibiotics were switched prophylactic to cover gramnegative bacteria in pts. preoperatively pts in group revealed a significantly lower cardiac index ( . ± i/min/m ) compared to group ( . ± . i/min/m ; p < . ) higher left atrial pressure (group i: . ~ . mmhg; group : . ~ . mmhg; p < . ) and lower ejection fraction (group i: . z . %; group . ± . %; p < . ). bypass time, minimum and mean blood pressure on bypass and aortic clamp time were not different between the groups. immediately postoperatively (pop), the white blood count was elevated (group i: , ± , /ui; group : , ~ , /ui; p < . ) and core temperature hours pop was higher (group i: . . °c; group : . ~ . °c; p < . ). serum lactate was already elevated on arrival on the icu pop (group i: , z . mmol/l, group : . ~ . mmol/l) but dropped within hours (p < . ). icu stay (group i: . ! . ; group : . ± . days; p < . ) and mortality over months (group i: . %; group : . %; p < . ) were significant higher in group i. sls is observed more frequently in patients with preoperative cardiac congestion and results in longer icu stay and higher mortality. although intraoperative hemodynamics are similar in both groups, the white blood count and serum lactate levels suggest an intraoperative cause for sls. further investigations will focus on possible intraoperative causes of sls. the objectives of the study were to estimate the problem of stress ulcers in critically ill patients and to compare ranitidine and omeprazole to determine their efficacy in the prophylaxis of stress ulcers. patients who were admitted to the intensive care units between january and july ' with polytrauma, sepsis or those requiring ventilatory support for more than hours were selected for the study. the patients were randomized into groups to receive ranitidine, omeprazole or a placebo. the changes in gastric ph were monitored hourly and the patients underwent an upper gi endoscopy hours after the start of the study to look for stress ulcers and hemorrhage. the drugs were withdrawn one week after the start of the study. of the patients selected for the study, had undergone cardiac surgery, had polytrauma and had sepsis. the change in average pre and post drug gastric ph was + . in the omeprazole group, + . in the ranitidine group and -). in the placebo group (p < . ). endoscopic evidence of stress ulcers was seen in % of patients not on prophylaxis, . % of those on omeprazole and . % of those on ranitidine. while all the patients in the placebo group who had stress ulcers showed endoscopic evidence of hemorrhage, % of the patients with ulcers in the ranitidine group and none of the patients with ulcers in the omeprazole group showed hemorrhage (p < . ). in critically ill patients the incidence of stress ulceration is high. an alkaline gastric ph is protective against stress ulcers. omeprazole when used for prophylaxis against stress ulcers in critically ill patients or those on short term ventilation will reduce the incidence of formation and hemorrhage from stress ulcers. the early and accurate diagnosis of sepsis is of key importance for critically ill patients survival. many studies have shown that tumor necrosis factor ~x (tnf ~) and interleukin- (il- ) are mediators of the inflammatory response in sepsis. bacterial antigens interact also with antigen specific t cell receptors and the activation of t ceils takes place. activated t cells release soluble interteuldn- receptors (sil- r). the aim of this study was to evaluate: the significance oftnf c~, il- and sll- r in the diagnosis of bacterial sepsis and to evaluate the correlation of clinical and laboratory parameters with serum levels of tnf ~x, il- and sll- r. we examined patients with clinical signs of sepsis treated in the intensive care units of university medical centre ljubljana. venous blood was drawn from each patient within hours after the first clinical signs of sepsis. clinical data (body temperature, blood pressure), laboratory dam (peripheral white blood cell count with differential, platelet count, c-reactive protein), and quantitative blood cultures were recorded. serum levels of tnf c~, ,- and sil- r were measured in septic patients and in adult healthy controls. tnf ct, il- and sil- r serum levels were measured by commercially available ria and elisa (amersharn and eurogenetics) kits. the differences in serttm levels of tnf ~, il- and sil- r between healthy control and patients and correlation between clinical and laboratory parameters were calculated. we found that only sll- r serum levels were significantly (p< . , student t test) increased in patients in comparison with healthy controls. of all indicators of sepsis that we compared, only hypotension was significantly correlated with tnf ~x levels and leukocytosis with ] ,- levels. we conclude that only the increased serum sil- r levels were predictive of bacterial sepsis within hours after the first septic signs. tnf c~ and il- levels were not significantly increased at that time in lifts small group of patients. in order to create high precision prognostic system for patients with sepsis and septic shock we have made prospective and retrospective analis of cases of sepsis. patients were included in this analis according bone's criterions of sepsis. comparing with apache-h, we have excluded such phisiologic variables as:temperature,na+ ,k+ ,}it, ph,which had a little influence on prognos of illness. we have added the other, more important variables: biilirubin, plateles,pti. we took into account: the seat arrangement, methods of respiratory support, comorbid conditions as: caneer, diabets,obersity. in general new score has headings: -physiologic variables, -age, -seat arrangement, -chronic comorbid conditions, -methods of respiratory support. roc -analis have showed a greater precision of our score, compared with apache-ii score. there is significant difference between the roc-curve of apache-ii scare. the k.p.tit~v.,i.e.gurmanchuk. objectives of the study. sepsis is a severe complication of the local infection, th e fever and the systemic inflammatory response syndrome may take place in such a case as manifistations of the inflammation induced by bacteria. the systemic fever observed in infection is known to develop due to the action of certain cytoldnes. other systemic manffistation of inflammation are the production of acute phase reactants, acute phase proteins, the activation of the complement system. ivratertals and methods. we observed children with light and children with severe course(l- class of serionuess) of the sepsis. the ftmetional activity of the complement system (ch , level of c -c , factors b told d, c a), level of c-reactive protein (crp} and tumor necrosis factor (tnf) were investigated, results. the level of crp was increased in the children with more severe class of the septic process in both group ( %- st and ioo%- nd}( with light and hard eours of disese) of patients. parameters of the complement system -the activity of cl, c , c components, activity of b and d factors-were increased in the seram of children with light course of sepsis. in children with severe course of sepsis these parameters were signffieantty decreased, especially in the group of chiidrellwith higer level of crp. we found the negative correlation of the tnp-alfa concentration with the functional activity of classical pathway components (cl~ ) and the positive onewith the funfional activity of the alternative pathway factors b-and d of the complement system. conclusions. thus, in children with different course of sepsis certain changes in levels and functional activity of an acute phase o[ inflammation proteins -crp and the complement system ones -&ire characteristic. the relationship between the tnf-alfa level and the activity of classical and alternative pathways proteins indicates on its role in the complement proteins genes expression. schr der j, braun j, rennekampff ha, schr der dw various alterations of the immune response are known in trauma, but the course will not be complicated by multiple organ dysfunction syndrome (mods) in all patients. phenotyping of cells offers a rapid system of evaluation certain aspects of the immune response. different subsets of lymphocytes and neutrophils were determined to evaluate their prognostic role in developement of mods. in trauma patients with an injury severity score (iss) > (mean iss = ; mean age years) lymphocyte and neutrophil phenotypes cd (t-cells), cd (t-helper cells), cd (t-suppressor cells), ratio cd /cd , cd b (receptor for cr ) and cd (fcriii) were measured on day , , , , and post trauma. the expression of class ii histocompatibility antigen (hladr) on monocytes (hladr+ cd ) and il -receptors on t-helper cells (cd /cd were determined as well. the percentage of cells was monitored by immunofluorescence using monoclonal antibodies and three color cytometry. the percentage of hladr+ cd were significantly lower an day , , and in patients who developed mods (p< , ) compared to patients without mods and a healthy control (p<o,o ). the expression of il receptors on cd was significantly different only on day . no differences could be measured in lymphocyte phenotypes cd , , and cd /cd -ratio as well as in expression of cd b and cd on neutrophils. class ii histocompatibility antigen (hladr) on monocytes offers the best ability to reflect cellular immunosuppression in trauma. this parameter allows the best differentiation of patients with and without mods. we retrospectively studied the relative importance of age, prior chronic disease, sepsis and organ system failure (osf) to determine outcome in critically ill patients with acute renal failure (arf). arf was defined as serum creatinine > /zmol/i, a twofold creatinine rise in prior renal insufficiency or the need of acute renal replacement therapy. definitions for prior chronic disease and other osfs -i.e. cardiovascular (cf), pulmonary (pf), neurological (nf), haematological (hf), hepatic (lf), and gastrointestinal failure (gf)-were derived from the literature and described previously. of the consecutively admitted patients to a surgical and a medical intensive care unit during -ye r period, ( %) had arf. arf mortality was %. ninety-eight percent had other osf. overall, cf, pf, gf, and nf was significantly more common in nonsurvivors than in survivors (all, p<o, ). although both the number of osf before and after arf was higher in nonsurvivors than in survivors (p< . ), the number of osf before was higher compared to after arf in both groups of patients (p< . ). furthermore, age, cf and pf before the ontset of arf, nf thereafter, and renal replacement therapy were related to mortality (all, p< . ). however, prior chronic disease was not related to mortality and chronic renal insufficiency was inversely related to outcome (p< . ). after multiple logistic regression, advancing age, cardiopulrnonary failure and sepsis before arf, and nf after arf remained significant. these results show the high prevalence of arf in critically ill patients and that arf rarely occurs alone. the prognosis of arf in critically ill patients is poor, especially if associated with advancing age, additional osf, particularly cardiopulmonary failure and sepsis before arf, and nf after arf. hence, prevention of cardiopulmonary and sepsis before the outset of arf may influence outcome in arf in patients with critical illness. the search cominnes for a magic bullet ta help critically ill petienta, bat recent elini ',.ml rials of agents that showed ixomise in animal studies raise questions about such trials. expcrlmemai uvidan~ :in anlmats and human volanteet~ for concepts, mechanisms and treatment of inju~ ur illness can be substentlal, l~rauasive and exciting but the positive effects of potential therapy suggested by such animal and ctinieal research may be difficult to prove in sick patients. efficacy of a new txeatment can be difficult to prove became elinie.al situations, hi spi~e of important biologic phenomena, are v~iable and conrplex. there is redundancy and overlap of mediators ~d problems of timing of therapy. a majt~r cause of this dilemtns is not with the trials or hypotheses, but rather the promem of the cause or the causability of the human dise~.se that is trebled. this is/hu "causa nets" or '*specific cause" as described by stehbens, when prevention or tre.atmcnt is based em the sauna nero, extinetiem of the disease is ix~ssible as with saul/ pox. only elimination of the cause wl cure the disease. careful animal studit~s evaluate single pcrturbmiuns for survival or other changes. an ldso preparation may be infiuancad aignificantly by a ~mall clangs which may be insignific~lt ht pstiants, most human experiments ate carried out in normal volunleers with a single porlurbation, such as a low-level, non-lethal dose of a substance. such studies are huportant in defining mechanisms attd mediators of disease, in our world of injm'ed, operated, infected and inflslned patients, there are many diseases, mof is not one of lhem. it isn't even a syndrume, it is the final pathway for a number of diseaaes~ each of which has a cause. mecormock believes thal a "multi-causal" etiology is a euphemism for ignoranc# or a synonym fo~ unknown etiology. admission iv sn icu, a high apache seer% the sepsis syndrome, mof, muds, or sirs and having predictors indicating potential mortality, are not diseases. the inmpors are getting negative results in trials of agents on eiek or septic icu patients and aru now becoming splitters, dafining subgaoups at higher risk for death. such an approach may produce positive results if the diseases are identified and the treatmeul is specific for them, a major challenge in deterraintng the efficacy of new therapies for sepsis nnd shock is identifying patients whose e#temtc inflammatory response is appropriate from those in whom the mediator| are contributing to end organ system damage end death, traditional and recently revised categorical patient descriptions such as sepsis syndrome, sepsis syndrome with shock, multiple organ system failure, or the recently proposed systemic inflammatory response syndrome (sirs) may not be sufilcient since they identify individuals at varying levels of risk for short term mortality, the efficacy of new lmmunotherapy may be directly related to the patient's severity end risk of mortality at entry to the study. we recently reported (jama ; : z - ~ ) a comprehensive risk assessment approach for patients with sepsis syndrome, a common eategarlcal description used as an entry eriterlon for many trials. by screening s database of , recent admissions to hospitals in the united states and western europe, we identified , patients who met sepsis syndrome criteria but were not enrolled tn clinical trinh, we then developed a survival model end severlty assessment method to estimate their g.day mortality risk. k..ente physiologic abnormalities were the most important prognostic factors ( % of total chl square) influencing outcome. the specific disease resulting in ice admission and the days the patient spent in the hospital and icu before qualification were independent risks, as were age and a clinical history of cirrhosis. the predictive model was cross-validated within the original , patients with a receiver d_perator characteristics (roc) area of . and in two independent databases, the first independent database contained hospitalized patients with gram-negative infection meeting criteria for sepsis syndrome (roc= . ); in the second, the placebo patients withtn the recently completed phase ill e~aluatlan of il- ra (rocffi . ). in all databases the risk model was able to accurately risk stratify patients throughout the range of risks that varled from a very low % to a very hlglt %. by drawing on the ready avatlabillty of large clinically aeuurate, current databases and using the power of modern statistical techniques to model the bodfs response to sepsis, we are able to produce very aeettrate pre-treatment risk estimates, these prospectively defined and continuous risk estimates reduce reliance on multiple subgroups and data dredging that can compromise a stady's integrity. they cart provide a nnlform method for patient description across clinical trials of different attempts at immmlotherapy. risk calculations can also be useful in developing entry criteria for phase ii evaluations in order to initially test efficacy on a limited number of high risk patients, fonowing sueeessinl completion of a definitive trial, the risk estimates can be used to develop specific |ndlcattons for s drug's use and can monitor the impact of both new and multiple compounds on patient outrome, when dealing with therapeutic trials for the treatment of sepsis, there are ways of checking the comparability of the groups (placebo and treated groups) -to use several description items such as age, sex, preexisting disease, number and nature of organ failures, physiology score, such as saps il ( ) -to use a model for risk of death either from a score (apache ii, lii, ( ) saps ii) or directly (mpm ii system ( )) before using the model for risk of death in septic patients, is it mandatory to validate it (by calibration, i.e. goodness of fit, and discrin'dnation, i.e., roc curves) first on a data base using the same definition for sepsis as in the trial and secondly on the placebo group of the trial ? or is it better to use a specific model for each trial ? the general models usually do uot fit for septic patients. there are methods to make them fit : either to add variables to the original score (model for sepsis using the apache iii system ( )) or to customize the model. for saps ii the customization is applied to the equation regression, using the same saps ii score. for mpm i each component of the model can be customized. several remarks : only one model is published to be applied at the icu entry ( mpm ii ) before any therapy. -most of the published scores are calculated from the lsl icu day. applying these scores to the let day of sepsis could have a very different significance. -is the accp classification of sepsis useful at the bedside to select oatients ? ( the pathophysiology of sepsis involves a dynamic interaction between the host and the infecting microorganism(s). a multitude of biochemical and hemodynamic interactions occur which function in concert to determine the ultimate outcome of the septic episode. the complexities of the septic process preclude outcome analysis by in vitro systems or computer models, animal studies have become indispensable in evaluating new therapeutic agents in the treatment of sepsis. these studies provide valuable information on safety, pharmacokinetics, relative efficacy and dosing strategies for potential therapeutic agents in the treatment of sepsis. there are three basic types of animal models: ( ) toxicity models with injection of bacterial endotoxin or exotoxins; ( ) live or killed bacterial challenge models; ( ) actual infection models. all models employ some form of external manipulation under controlled conditions to induce sepsis and to analyze potential therapeutic efficacy. these experimental requirements may limit the ability of animal models to accurately predict the clinical value of new agents in human sepsis. four major end points are analyzed in the various animal models: ( ) hemodynamic parameters; ( ) modulation of host-derived inflammatory mediators; ( ) resolution of end organ injury; or ( ) lethality. each animal model has certain advantages and limitations. species-specific differences in physiologic and immunologic features make it difficult to directly extrapolate the results of animal experiments into clinical medicine. while no ideal animal model exists, consistent benefit of a new immunotherapeutic agent in multiple animal systems provides the most compelling preclinical evidence of its therapeutic potential in septic patients. consensus-assisted development of a study protocol on sepsis: an important difference from previous randomized trials there have been several, and perhaps too many metaanalyses of cliuical trials on surgical infections, but their results have only rarely been incorporated into the design of new randomized trials in sepsis. metaanalysis is retrospective. it seems more important to analyse and to criticize the design of tria/s before they are ongoing. incorporation of that into development of a study protocol is the aim of the following procedure: the time-schedule of about two years should include further cell culture and animal experiments after the first successful studies showing effectiveness. exhaustive evidence for a dose-dependent cost-banefit and near complete explanations of the pathomechanism should not be awaited for development of the protocol of the clinical study. however, a discussion forum of experts should be performed in a recently published, almost perfect trial in order to see the frontiers of the present research in cell and molecular biology, clinical pharmacology, statistics and decision making. this should be followed by a metaanalysis of at least study designs on sepsis with methods of formalized medical decision making (decision tree). clinical algorithms -developed by objective methods including nominal group processes -should be developed to standardize any concomitant treatment in the centers considered for a multinentre trial. the latter is usually necessary in the field of sepsis. finally, a pilot study should be performed to demonstrate not only feasability, but to learn about all possible types of interventions which modify endpoints as response variables. especially mortality is not free from such effects. the time for the individual phases of this consensus-assisted process of protocol development have to be shortened by their temporal hiterloeldug. due to the fast discovery of new chemical factors in sirs it wilt otherwise be impossible to come up with results of randomized trials which are fascinating enough to be incorporated in daily routine treatment. severity scoring systems are intended to provide a population-based estimate for the risk of an unwanted outcome resulting from some disease process. in the area of infections and the "septic" response, this has routinely been defined as death. for anti-infective trials, there has been a reasonable correlation of severity (apache ll) with outcome measured as persistent or recurrent infection, but this is not as robust as the association with mortality. it is expected that non-lethal failure would not immediately correlate with disturbed physiology: the basis for antiinfective failure depends on a variety of factors not measured in severity scoring, such as type of infecting organisms, density and susceptibility to administered antimicrobia[s, and anatomic features of infection (e.g., pancreatic). severity scoring is important in differentiating these "categorical" variables from continuous (physiologic) variables. there are, additionally, a series of problems related to the cause of death in relation to severity scoring. in those tdals in which cause of death is analyzed, high severity scores did not routinely predict death as an immediate sequelae of sepsis/septic shock. many of the predicted deaths occurred remotely of progressive background diseases. other important problems with severity scoring have to do with lead-time bias: hew long patients were ill before entry into the study. statistical techniques for condensing various categorical and continuous variables, as well as factoring in information requiring the pharmacodynamics of agents which affect outcome, are being developed to further refine deviation from predictive equations as an outcome measure. stepwise logistic regression analysis has identified the presence of shock, intm-abdominal or unknown source of infection, hospital acquired infection, age greater than years, neutropenia and inappropriate antimicmbial therapy as independent variables associated with increased mortality in sepsis. maldistribution or" these variables is a concern in targe randomized clinical studies. it should be noted that only the selection of antimicrobiai therapy could be addre.~'sed and altered at the time of enrollment in a sepsis clinics] trial. inappropriate antimicrobial therapy has been noted in %- % of septic patients. well designed, randomized sepsis trials do not assure the absence of imbalance between treatment and control groups with regard to inappropriate antibiotic therapy, especially with subgroup analysis. statistical manipulation to correct for any imbalance is appropriate but avoiding imbalance is ideal. selection of antibiotics in septic patients requires such considerations as clinical setting (history, physical examination and underlying disease), appropriate laboratory tests (such as gram stain), identification of source and associated bacterial flora, antibiotic susceptibility patterns for that hospital and likelihood of resistant organisms. determination of inappropriate antibiotic therapy is made retrospectively after culture results are available. in some circunmtances the organism and antibiotic sensitivities cannot be predicted, while in others it can. leibovici et al identified hospital acquired infection, antibiotic treatment before a bacteremic episode, endotracheal intubetion and thermal trauma as independent variables which predicted isolation of a multiresistant organism. the same authors developed a predictive index for resistant organisms, which when compared to prescriptions of attending physicians, improved antibiotic selection in critically ill patients. including a standard antibiotic regimen for all septic patients in a clinical trial is impractical. there is too much interhopsital variability in flora and antibiotic susceptibility. in addition, the aggressive broad spectrum coverage necessary for some patients is inappropriate for others. a protocol which guides a prescribing physician through a logical chain of reasoning might improve antibiotic selection in critically ill patients and could be included in the design of a clinical trial in sepsis. although this approach might minimize potential for maldistribution of inappropriate antimierobial therapy, it would likely create multiple problem areas. will the patient's physicians agree to the protocol choice? what is the availability of speciftc antibiotics at a participating hospital? what is the aplpiieability of study results in typical clinical situations? if there is agreement that thin is an appropriate antibiotic protocol, should it not be used in all seriously ill septic patients in the hospital? in other conditions such as ards, the success of protocol therapy is dependent upon measurable goals such as pao and highest plateau pressure, while measurable goals are not as clear in choosing antibiotics. based on the above confounding issues, a complex and extensive algorithm covering many potential possibilities of error and specific antibiotics seems impractical; however, an algorithm focusing on three to four major common errors in antibiotic selection and dealing with classes of antibiotics is plausible for inclusion in sepsis clinical trials. in this session we will attempt to outline the methodology of such a future study, emphasizing the immense difficulties involved in its proper conduction including: design, selection of patients, surgical considerations, supportive treatment, the "human factor" and ~nd points. only a close cooperation between a few dedicated surgeons, obsessively studying a large number of well selected and stratified patients over years, could make such a study possible. algorithmis have frequently been mistaken for the graphic format in which they are presented. however, an algorithm is neither a flow chart nor a list of instructions; it is a step-by-step approach to solving a problem. likewise, a clinical algorithm is a step-by-step approach to solving a clinical problem. cas are deterministic, which does not mean that they are rigid. they are practical rather than mathematical algorithms, that tan be used only with clinical judgment, and must be tailored to each patient. there are a number of types of, or uses for, cas that can improve sepsis management, including: diagnostic or severity scorm cas, a management ca for managing sepsis constructed according to recently published standards for use in teaching research protocol algorithms that must be used to collect data or guide implementation of a clinical trial aimed at validating one or more dicisions in the management ca; finally, protocol-style cas drawn from the management ca and should be validated using matching outcome studies. organisational problems peculiar to multicentre trials the organisation of any randomised clinical trial is fraught with difficulties, and that of a multicentre trial particularly so. there are problems associated not only with the principles on which the investigation is based but also with the detailed organisation and analysis. are all the participants truly unbiased about the relative merits of the regimens being studied? is like being compared with like -are all the end points and the standards for measuring them clearly defined so that they cannot be misunderstood? are all eligible patients being studied, and their results reported? is truly informed consent being sought that will satisfy not only the patient's right to choose what happens to him, but also the law of the land? and, finally, how can the participants be sure that the trial will be stopped at the right time, to ensure that no treatment is given to any patient that might be harmful? these questions may seem insoluble, but until we tackle them we shall never be certain. dr.m. ev~s, scar~mu~ hospital, scarborough, nonhyo~s~ y ql, u.k. increasing knowledge of the pathogenesis of sepsis and septic shock has led to the development of many new therapies and technologies capable of preventing, blocking or even reversing the deleterious cycle of events. recent results of subsequent multicenter trials testing some novel therapeutic drugs, however, did not confirm the promising sometimes overwhelming effects obtained experimentally. it is postulated that this is largely due to inappropriate design and conduct of multicenter trials as currently performed. one of the shortcomings emphasized in this paper is the "treatment mix" problem. multicenter trials in sepsis are performed because no single center is able to recruit the necessary number of eligible subjects within a reasonable time. each single center (icu) has its own individual policy which cannot be standardized for the trial (treatment mix). even if we ascribe that each icu did the "best" for their patients, it is highly probable that the outcome differs between the icus. this translates to the effect of the new therapy under investigation. ]t is therefore worthwhile to consider that icus must first demonstrate a certain standard based on the patients' outcome (audit) before becoming accepted as a participating center. this prerequisite ensures comparable quality between participating centers, led to the reduction of "noise level" and increases the probability of positive study results. the riyadh-icu program based on standard mortality ratios is recommended as an audit instrument. during the last decade most clinical trials of potential therapeutic agents in systemic sepsis have failed to demonstrate benefit from the drug under study. although in many instances it is entirely possible that the agent in question does not have clinical efficacy, an equally plausible explanation for the multitude of negative results is that the studies were improperly designed and thus could not show therapeutic benefit, if it existed. problems which have been identified in these various trials include inappropriate or unrealistic definitions of response to the drug; inadequate sample size, with attendant insufficient statistical power to demonstrate a difference, if it existed; insufficient standardization of customary therapeutic maneuvers in septic patients; imprecise criteria for patient entry into the study, which creates unacceptable inhomogeneity between control and treatment groups and invites unjustified post-study subgroup analysis; the lack of a formal sequential monitoring procedure for interim data analysis, which could potentially affect patient safety; and a primary analysis of study results that excludes protocol deviants and is not according to intent-to-treat. these and other problems have impacted upon the validity of the various trials conducted to date and may well have prevented the resolution of controversies surrounding the use of certain agents in the treatment of septic patients. the complexity of bacterially-induced septic shock involves a cascade of events that evolve over time, beginning with the proliferation of offending organisms and followed by the release of toxic mediators from the bacteria. endotoxins [e.g. lipopolysaccharides) from gram-negative bacteria initiate septic shock by precipitating a systemic inflammatory response syndrome (sirs) through release of a broad spectrum of hostderived mediators. over the last century, hundreds of these endogenous mediators have been proposed to serve as pathophysiological substances in this "alphabet soup" of cytokines, eieosanoids, biogenic amines, kinins, peptides, ions and hormones. an evaluation of the literature on septic shock leaves the investigator with a sense that, although many pieces of the septic shock puzzle have been presented, no clue was provided to indicate how these pieces fit together, in an attempt to assess objectively the causal role of individual mediators, we recently completed a collective meta-analysis of mediators that were individually reviewed and subjected to koch-dale analysis of causality by distinguished authorities in the field ( ). in summary, our attempt analyze available evidence to support a cause-and-effect relationship for putative mediators of septic shock revealed that only eight of the mediators analyzed could be strongly inferred as playing a causal role in septic shock. evidence supported the involvement of endotoxln, endorphins, complement, interleukins, tumor necrosis factor, eieosanoids, platelet activating factor and calcium. other mediators either lacked adequate supportive evidence or were not conclusively involved. posttraumatic outcome may be reduced by an amplified stress response mediated by neural and humoral stimuli. the classical hormonal catabolic response is predominantly mediated directly or indirectly by neural stimuli, while most changes in inflammatory responses such as leukocytosis, acute phase proteins and changes immunofunction are mediated by humoral mediators. clinical experience from controlled studies suggest afferent neural blockade and modification of stress response to improve organ function and postoperative outcome, and limited experimental studies also suggest neural blockade to be of beneficial value in shock states. of special value may be the improved gastro-intestinal motility after neural (visceral) blockade. no outcome studies are available from patients with major truma, multiple organ failure or sepsis, conditions where humorai mediators may be more important to modify than neurally mediated responses. future studies should investigate the clinical outcome effect of combined neural and humoral mediated blockade, as well as the potential role of an initial neural blockade in elective trauma (first hit) to improve the metabolic scene and outcome if a postoperative complication (second hit) should occur. neutrophil elastase is the predominant protease of the human neutrophil. this enzyme, and a variety of other enzymes, including neutrophil collagenase, are released by activated neutrophils in the setting of high concentrations of reactive oxygen metabolites. in addition, in this extracellular environment, the normal antiprotease defense mechanisms of the organism may have been severely inactivated oxidatively especially along capillary endothelial cells. accordingly, release of neutrophil elastase which mediates inflammation and degrades most extracellular matrix proteins, including elastin, fibronectin and many forms of collagen, may contribute to tissue injury and organ failure in a variety of diseases ranging in severity and acuity from pulmonary emphysema to the adult respiratory distress syndrome (ards). as a result, significant efforts by the pharmaceutical industry have been directed not only toward the development of human neutrophil elastase inhibitors, but also toward their characterization in a variety of animal models of neutrophil mediated diseases, and their evaluation as potential therapeutics for the treatment of a variety of human clinical conditions. data from animal models of organ injury and failure along with data collected from a series of patients at risk for ards and with ards will be presented and discussed as a rationale for inhibition of neutrophil elastase. parameters that need to be monitored to obtain success in future clinical studies will also be presented in this context. have turned out to initiate and maintain organ dysfunctions in severe posttraumatic and postoperative courses. such proteolysis-induced disorders are especially rendered possible by the concurrently arising consumption of inhibitory regulators (e.g. a vproteinase inhibitor=a pi, antithrombin iii=at iii) via cofnplex formation and/of proteolytic/oxidative inactivation. besides the well-known destructive potency against protein substrates, proteinases such as elastase or thrombin (active or in complex with the serpin inhibitors ~ pi or at iii) are also supposed to increase the inflammatory reaction by inducing cytokine release or shedding of soiuble adhesion molecules from various inflammatory cells (pmns, monocytes/macrophages, endothelial cells). those cell-derived mediators may provoke further cell activation through an autocrine/paracrine loop thus increasing significantly the proteinase burden at the inflammatory focus. therefore, this noxious circle might be interrupted by a convenient proteinase inhibitor therapy to ameliorate the inflammatory process. to verify this hypothesis, high dosis of at iii (mean plasma levels up to %) were applied in first controlled randomized studies on surgical patients suffering from multiple trauma or severe sepsis. in control patients we could clearly demonstrate the sequential appearance of proteinase/serpin-complexes (fa pi, tat), cytokines (il- , il- ), and soluble intercellular adh sion molecules (icam, elan, p-selectin) in the circulation. these factors turned out to be a helpful tool for early diagnosis and prognosis of forthcoming organ dysfunctions. interestingly, m at iii-treated patients a significantly reduced release/production of inflammatory mediators became obvious concomitant with the improved clinical course in comparision to an increasing deterioration in control patients. soluble mediators of inflammation are cytokines (e.g. il- , il- and tnfe) as well as breakdown products of complement proteins (e.g. c a and terminal complement complex). therefore, attenuation of both, release and generation of these synergistically functioning mediators together with stimulation of release of antagonists including soluble forms of receptors are potentially beneficial in all kind of inflammatory diseases. intravenous immunoglobulins (ivigs) are known to have an anti-inflammatory effect in humans (nih consensus conference on wig, ) . the mechanism of action becomes more and more clear. in single cells stimulated by anti-cd mab wig was able to down-regulate production of il- , il- , ifn% and tnfj~ significantly. igg coated solid-phase stimulates release from monocytes of interleukin- receptor antagonist (il-lra) but not of il- ; this observation is very much in contrast to the effect of endotoxin in the same in vitro system. furthermore, naturally occurring anti-cytokine antibodies can be demonstrated in apparently healthy individuals and in wig prepared from plasma pools. some of these antibodies can be detected by antigen/antibody reactions in fluid phase (anti-ll-le, anti-il- ), some only by solid-phase detection systems (anti-ll- , anti-ifn% anti-tnfc . infusion of wig to patients suffering from inflammatory disorders have resulted in a decrease in il- in circulation. during infusion wig might induce an acute but transient rise of tnfo~, il- , and il- . self limitiation of this process might be due to demonstrable instant release of il- ra and soluble tnfo~ receptors. in vitro ivig has also been shown to attenuate complement activation via the classical pathway. furthermore, acid haemolysis of erythrocytes in paroxysmal nocturnal haemoglobinuria could partially be prevented by ivig. ivig was able to attenuate forssman shock in guinea pigs. we have seen a patient with congenitally elevated turnover of alternative pathway of complement who repeatedly showed an increase of haemolytic titres after administration of ivig. thus, wigs apparently have multiple potencies including attenuation of soluble mediators of inflammation and might therefore be of benefit in trauma, shock, and sepsis. significance of sinusoidal liuing cells and of humoral factors on hepatic function following sepsis and major surgery hirata k, katsuramaki t, yamaguchi h, mukaiya m, yamashiro k. regeneration of the liver after hepatic necrosis or partial removal has been extensively studied, but uncontrolled mechanisms to irreversible hepatic failure following sepsis or major surgery of liver or with hepatic dysfunction have so far not been well documented. we suggested the importance of the intrasinusoidal aggregation between sinusoidal lining cells and intrasinusoidal running ceils in the mechanisms of hepatocyte dysfunction. thus, the purposes of this study was to investigate the changes in each sinusoidal lining cell during this process and the effect of cytokine on hepatocyte under various oxygenation. [ materials and methods ] ( ) clinical study : thirty two patients with histologically proved malignant tumor underwent major hepatectomy were devided in two groups, i_e. the cirrhotic liver group and the non-cirrhotic [aver group. most of the former were the patients with hepatocellular carcinoma and most of the latter were the patients with metastatic carcinoma of colorectal cancer. five patients were complicated septic conditions with hepatic failure. following operation in each patient, a verous blood sample was taken for measurement of serum il- , il- , tnf and c-reactive protein concentration. and hepatic biopsies were sometimes undergone in patients with anomalous hepatic function. ( ) experimental study : kupffer ceils, sinsoidal endothelial cells and hepatocytes were separated from mouse ( c hhen ) liver. and also polymorphonuclear cells and platelets were purified from blood and peritoneal macrophages were from peritoneal cavity of mouse. co-cultures between or among these cells with iipopolysaccharide were performed. cytokine concentrations in media and hepatocytic function were compared. [ results and conclusion ] our findings in above experiments demonstrated the cleanly different concept for the mechanism of hepatocyte dysfunction following sepsis or major surgery. namely, the effect of hepatoeytie function by cytokines or superioxide were significantly affected under low oxygenation, but not significant under good oxygenation. hirata m.d.,nishi ,hokkaido,japan $ immune complexes as .mediators of sepsis and immune dyafumcffon laa k horn, chxistof birkenmaier, and greg h mon departmen~ of surgery, san frandsco general hospital, urdversr , of calif(~rrda, san frandsco. immune complexes (ic) a;:e commonly found circulating in parians during infection and sepsis; and following traumm, bums, and massive l~ensfusion. clearance of c occurs by phago~'tmsis of esll-bou_nd or opsonized p~tlcles. monocyte activation du~jng phmgocytos/s could lead ~o release of cytokilies ieletexiot~ to the hosh to examine tb/s phenomenon, we formed insoluble ic by precipitating iow-endotoxin bovine serun~ albumin (bsa) with rabbit ant/-bsa igg. we have ~town that these ic are ingested by monocytes and concomitantly stimv/ate re~pizatory bu~t activity measuxed by assay of in%racellul~ peroxldaffon. we have shown that ic ingesffon produces signlqcant el,era,lore in the monoey~e phenotype. spedacally, cdi is down-regu/ated, along wl~ cd and cd . thus responsiveness to lipopolysacchmdde ( ) a~xd i=m~unoglobulin fe st~mu/mtlon is reduced. in cert,+rest, the complement rote.p tot cdc is u~-regulamd, indicaling mcremsed re~ponalx=~ness to opsonized pat,rotes, we examined monocyte superna~n~s for production of hzmor necrosis factor alpha (tnfg) following ic stimulation and showed that ic are capable of provoking ~elaase of hrmaunl)reac~ve tni~. j[c also increase mono=yte produchon of prnstaglandin e . in summary, ~/~ese results demonstrate lhmt ic are capable of indudng production of ¢ytokines and the imrau-nosuppressive prostaglandin pge . ic also allez ~he surface expression of important receptors involved in actlvaffon by lp~ and phagocyiosis. thus, ic aze competent for indud/on of the mepl/e s! otlse. by examining m n cyte phenotypms, it may be possible to d~mrmkne extent ohn'u~u~e complex activation and predict immune depression iu criffcally ill pa~ents. a great deal of experimental work has focused on preventing and/or treating sepsis and organ failure following injury. many of these strategies have tried to attack mediator substances released during the systemic inflammatory response following injury. sugermann has demonstrated the improvement of pulmonary function, but not eappillary leak using [buprofen in the porcine model. in a clinical trial, faist demonstrated the effectiveness of indomethacine in amelierating the post trauma of cellular amenity using in vitro parameters. morbidity and mortality, however, were not different between control and treatment groups. baue und chaudry have suggested that atp magnesium chloride may have protective effect in renal failure um kupfer cell dysfunction seen after shock. pentoxiphyllin has been found to be effective in improving tissue oxygenation and oxygen consumption following hemorrhage, and there may be promise for this drug in the ischemia reperfusion injury. monoclonal antibodies against endothxin and inflammatory mediators seemed promising at first glance; however, preliminiary clinical data of the treatment of sepsis with either ha-ia or e monoelonoal antibodies against bacterial cell wall have been disappointing. initial studies with il-i receptor antagonist also appeared encouraging, but no difference was seen in the most recent trial. currently studies are ongoing with monoclonal antibodies to tumor necrosis factor which may have more efficacy given the fact that it is a macrophage mediator released by endotoxin. although we seem closer to understanding and preventing the problems of sepsis and organg failure after trauma, we must continue to appreciate the complex interrelationships and delicate balances inherent in the host defense system. overzealous attempts at restoring immunity in the absence of understanding pathophysiology may be just as dangerous at post-traumatic immlmospremsion. severe acute pancreatitis was caused by different etiologic factors, but once pancreatic tissues were infected, patients show a similar pattern of aggravation and develop organ failure. remarkable elevation of serum il- was unexceptionally observed in patients with severe acute pancreatitis. the serum levels were more than pg/ml (normal: less than pg/ml) during the first one or two days after onset. there was a significant correlation between the peak serum il- level and the number of organs showing failure (r= . ). tnf-a production by isolated peritoneal macrophages following lipopolysaccharide (lps) stimulation was significantly increased in cerulein-induced pancreatitis rats. serum tnf-a activity was elevated following intraperitoneal administration of lps as the septic challenge both in pancreatitis rats and in control rats, being significantly higher in the former (p< . ). histological findings and liver function tests revealed that lps induced more severe liver damage in pancreatitis rats than in control rats. these results indicate that increased tnf-a production by peritoneal macrophages in acute pancreatitis augmented lps-induced liver injury. organ failure in severe acute pancreatitis could be caused, at least in part, by increased cytokine production. it is clear now, that in mods, organ injury is not directly due to exogenous factors, such as bacteria or toxins, but instead is largely a consequence of the host's own endogenously produced mediators. there is an extensive body of literature on the inhibition of mediator production, release and action in different cascade systems by glucocorticoids. they can serve as a host protection against overactive defense reactions if used adequately. a new understanding of the regulation of cytokine synthesis, especially tnf, may lead to an insight of the conflicting findings between the benefits of glucocorticoid therapy in animals and its current failure in recent clinical trials. glucocorticoid shares its role with other novel therapeutic approaches also shown to be successful only in experimental settings. a mete-analysis of steroids in sepsis, however, revealed a beneficial effect in the subgroup of patients with gram-negative infections. there is now a series of arguments to reevaluate the indication for steroid thera-py and/or prophylaxis in mods and sepsis. honjo i- - , kumamoto , japan in septic shock j. briegel, m. halter, h. forst, w. kellermaun, m. bittl, k. peter imrodnetlea and methods: hydrocortisone (hc) at an infusion rate similar to the maximal secretory rate of cortisol in man improves hemodynamics in human septic shock ( ). we hypothesized that the hc-induced hypercortisolemia prevents a harmful overshoot of immune reactions. to test this hypothesis we prospectively investigated patients admitted to the icu in refractory septic shock. after resuscitation (mechanical ventilation, fluid resuscitation, titration of vasopressors, and initiation of antimicrobial therapy) hc was started with a loading dose of mg/ rain, followed by a continuous infusion ( mggh). with hemodynamic improvement (dopamine < gg/kg/min) the infusion rate nfhc was tapered over a period of days. phospbolipase a (pla ), c-reactive protein (crp), and elastase-proteinase inhibitor complex (e-pi) were deierminated daily. results: according to our previous results hemodynamics improved during hc infusien. after days dopamine requirements decreased to less than gg&g/min in all patients. this corresponded to an attenuation of the systemic inflammatory response syndrome (sirs) indicated by the abrogation of fever and the decrease in heart rate and inflammatory mediators. pla activity and e-pi concentrations decreased to near normal values and crp concentrations decreased as well. after cessation of hc infusion (between day and ) a reinforcement nfthe sirs was observed despite cortisol levels within the normal range. this was first indicated by e-pi, followed by fever, increases in heart rate, crp, pla , and finally by the relapse of septic shock in four patients on days , , and o. a second infusion of hc again resulted in shock reversal and in a decrease in pla , crp, and e-pi in the patients under study. discussion: there is growing evidence that the endogenous steroid hc and proinflammatory cytokines integrate a complex immunoregulatory feec~ack circuit. the elaboration of tnf, il- , il- , and il- is attenuated by- rag hc prior to endotoxin challenge in humans ( , ) . cytokines like tnf, il- , il- , and il- are potent proinflammatory signals for acute reactants (--, clip), neutrophil degranulation (--, e-pi), and pla synthesis and secretion. our data provide evidence that hc at an infusion rate similar to the maximal secretory rate of cortisol in man attenuates the systemic inflammatory response in human septic shock. to evaluate the feasibility of a nigh-dose regimen of antithrombin iii (at iii) treatment in patients with multiple injuries regarding blood levels of antithrombin iii and undesired side effcts and to analyse effects of the initibitortherapy on the systemic inflammatory response. patients and methods: patients with an iss nf more than points who could be treated with at iii administration within rain after trauma were randomized to receive either at iii or placebo. at iii was given to reach an antithrombin iii inhibitory capacity in plasma of % by using the following calculation: at iii to administer = ( % -at iii measured) x body weight. at iii was given every six hours for a period nf hours and on the th day. patients were followed up throughout their stay in the icu but at least days. in this abstract the data of the first patients are included. results: the patients' median injury severity score was points with a median age of years. the patients were equally distributed between verum and placebo groups with respact to age , iss, prehospital treatment, blood pressure, hemoglobin and at nmevel on admission, and time from the accident until the test solution was given. the patients of the at iii group received , units of the inhibitor on average during the first days. with our regimen, the at iii levels could be kept between % and % of normal, whereas control patients an at hi concentration of % to % was observed. patients with at ni treatment required less red blood cells bur received the same amount of ffp and fluids. there were no differences with respect to platelet count, partial thromboplastin time, l~rothrombin time and prothrombim. we did not observe bleeding disorders or any other side effect with peak concetrations of up to % of normal. white blood count, pmn--elastase, interleukin and and c-reactive protein tended to be lower in the at iii group. there were no differences with respect to renal and hepatic function parameters but the duration od mechanical ventilation was shorter in the at ii group ( . vs. . days) conclusions: we conclude that our treatment protocol (a) was able to restore at iil levels to the desired range of %, (b) did not lead to coagulation disorders, (c) did not increase transfusion requirements, (d) did not reveal other undesired side effects, and (e) showed a tendency towards reduced posttranmatic inflammation and mechanical ventilation requirements department of trauma surgery, essen, germany antithrombin-lll (at-ill) acts as an inhibitor of thrombin, further proteases and the alternative pathway of the complement system. inhibiting thrombin, at-ill works as a functional antagonist of paf~ therefore, in state of hypevolemic-traumatic shock, continuous supranormal serum -and tissue -concentrations of at-ill may be efficient to reduce the local posttraumatic reactions resulting from complement and pmn-activation. patients with severe multiple trauma ( treatment [at-ill] -- controls [c]) were investigated. study cdteda were age > and < years, injury severity (iss) > points and glasgow-coma-scale > points; randomization and treatment has to be started within hours after trauma. permission for the clinical study was given by the local ethic committee. bradykinin (bk) and related kinins are potent inflammatory peptides which possess the ability to induce, vasodilation, increased vascular permeability and hyperalgesia. cp- , a novel homodimer bk antagonist has previously been shown to increase survival in rat and rabbit models of lethal endotoxin shock and is now in clinical trials for sepsis. we have now evaluated the effect of cp- in other models of inflammation. male rats were precannulated with a catheter in the carotid artery. h later bk was injected ia and the pain score ranked from (no responses) to (vocalization). cp- at . umoles/kg completely inhibited the pain responses for a period of . - h. cp- at . umoles/kg s.c. was also found to inhibit the increase in paw volume and hyperalgesia induced in rats over a - h period by an intraplantar injection of . % carrageenan. the abdominal constriction response o an intraperitoneal injection of kaolin was inhibited in a dose-dependent manner by cp- . when ul of . % formalin was injected into the paw of a mouse a characteristic licking response was observed which was biphasic in nature. cp- significantly inhibited both the first ( - min) and second ( - min) phase responses. ]n a rat burn model, where the hind paw is immersed in water at °c for sec the increase in paw volume was significantly reduced by pretreatment with cp- , . umoles/kg s.c. finally cerebrai edema was induced in rats by applying cold (- °c for sec) to the dural surface following a craniectomy. cp- at . umoles/kg s.c. produced a significant reduction in the amount of edema compared with sham controls h later. these data suggest that bk is an important mediator of inflammation and hyperalgesia and that the bradykinin antagonist, cp- , may be useful in the treatment of such inflammatory, hyperalgesic disorders. partial hepatectomy in humans is associated with a considerable morbidity due to hemodynamic and metabolic derangements, which increase the risk for organ failure and mortality. we hypothesized that endotoxemia may play a pivotal role in these complications. we therefore, investigated whether peri-operative infusion of rbpi , a recombinant protein of the human neutrophil bpi with bactericidal and endotoxin-binding capacity, could prevent postoperative derangements following partial hepatectomy. male wistar rats ( - g.) received a % liver resection (phx) or a sham operation (sh), and a continuous intravenous infusion of either . mg/kg/hr rbpi (phx-bpi, n= ; sh-bpi, n= ) or the (iso-electric, iso-kd) control protein thaumatin (phx-con, n= ; sh-con, n- ). various parameters were measured h after the resection or sham operation. mean arterial pressure, cardiac output and heart rate were significantly decreased in phx-con rats compared with sh rats, which effects were not observed in phx rats treated with rbpi . blood ph was significantly decreased in the phx-eon group, whereas the leucocyte count, hematocrite and il- levels were significantly increased compared to sham levels. in the phx-bpi group, these parameters were restored to near sham levels. in vitro experiments with rat plasma and human mononuclear cells (mncs) revealed that plasma of phx-con rats is highly capable of activating mncs, accompanied by the release of cytokines. this activation is attenuated with phx-bpi plasma. in vitro added acd or polymyxin b was able to reduce the activation by phx-con rat plasma to the levels of phx-bpi rats thus, these data suggest that systemic endctoxemia, possibly of gut origin, is a major cause of postoperative hemodynamic and metabolic derangements following phx and that rbpizz can prevent these changes. more recently we reported a transient appearance of both endotoxin and tnf in the circulation of rats subjected to the haemorrhagic shock (hs) already at - rain. similar to bpi, recombinant bpi was found to bind lps and inhibit tnf formation in vitro. the aim of this study was to investigate the effects of rbpi (kindly provided by xoma corporation, berkeley, ca) against haemorrhage related endotoxemia and mortality in rats. method: a prolonged hs was induced by blood withdrawal to a mean arterial pressure of - mmhg for rain followed by reinfusion of shed blood (sb) and resuscitation with two times of sb volume of ringer's lactate over rain. rbplg. was administered at a total dose of mg/kg i.v. ( . mg/kg at the -eginning followed by two doses of . mg/kg each at end of shock and the end of resuscitation). the control group was treated similar to the bpi group but received thaumatin as a protein control preparation at the same dose as rbpi . results: imrffe?diately after resuscitation ( min) the detected plasma endotoxin levels in the control group (mean = , range = - pg/ml) were almost neutralized by rbpi treatment (mean = , range = - pg/ml) . plasma tnf levyis were not significantly influenced by rbpi treatment at the two time points and min of experiment (means: and in bpi vs , pg/ml in the control group). the -hour survival rate was improved from / ( . %) in the control to / ( %). conclusion: these data suggest that haemorrhagic shock may lead to bacterial translocation and/or transient endotoxemia with concomitant cytokine formation that may play an important role in the pathogenesis after shock and trauma, rbpi might be a useful therapeutic agent against endogenous bacterfal/endotoxin related disorders in hemorrhagic shock. morbidity and mortality after hypoxia of the vital organs had been correlated to the production of oxygen radicle which is mediated by xanthine oxidase activity, in this study we have evaluated the survival rate after allopurinol. rabbits weighed + grams divided into two groups. group i included tabbits were treated with allopurinol mg/kg for seven days before induction of haemorrhage. group ii as a control included rabbits. all rabbits were subjected to % arterial blood loss through the central ear artery for one hour then resusciatation was done by the heparinized withdrawn blood through a marginal ear vein. during the experiment blood pressure and heart rate were monitored through the central ear artery. also uric acid, lactic acid, glutathione activity were estimated. animal survival was followed for days. postmortem vital organ histochemistry and histopathology examinations were done. in group i the survival after three days was out of while in group ii it was two out of . our conc|usion, allopurinol had increased the survival in aiiopurinol pretreated rabbits which may indicate the value of allopurinol premedication for patient prepared for elective bloody surgical intervention . h receptor antagonists are commonly used for stress ulcer prophylaxis, but their actions on the septic response are largely unknown, in an experimental model, pigs were first anesthetized, then injured with joules of energy to the posterior thigh, then hemorrhaged - % of their blood volume. after i hr of shock, all the shed blood plus x the hemorrhage volume as lactated ringers was infused. following resuscitation, ranitidine ( . mg/kg iv twice daily) or saline placebo was begun. the treatment group was randomly assigned in a blinded fashion. after hrs, a septic challenge was administered ( bg/kg of e. coil endotoxin (lps)). serial gastroscopy, gastric ph, hemodynamics, abg's, physiologic dead space ventilation, leukocyte counts, and tumor necrosis factor (tnf) levels were recorded for min. baseline values and units were cardiac index _+ ml/min/kg (ci), arterial po + mmhg(pao ), base excess . -+ meq (be), physiologic dead space fraction +_ % (pds), and tnf . + . units/ml. baseline gastric ph was . -+ . and . _+ . in the placebo and ranitidine groups, respectively. the gastritis following hemorrhage was marginally attenuated in the ranitidine group. following lps infusion the following were obtained: ci pao * be* gastric* pds* peak* rain rain rain ph min tnf ranitidine _+ _+ - . ± . bum injury results in hypermetabolism, fever and nitrogen wasting. endotoxin (lps) has been proposed to mediate these effects, either directly or via activation of macrophages to produce cytokines such as interleukin- (ii- ). this study was designed to clarify the role of lps and - in the metabolic response to bum injury. twenty-five burn patients ( -+ %; + % ft bsa burn; _+ years old) were studied serially for three weeks post bum. patients underwent partitional calorimetry to assess metabolic rate and compartmented heat loss. nitrogen was assayed using chemiluminescence. lps and i - were measured with limulus amebocyte lysate assay and elisa. patients were excluded if they suffered smoke inhalation, showed any sign of sepsis or failed to rapidly meet their nutritional needs via the enteral route. ten patients received intravenous polymixin b ( , u/kg/day to bind lps). these patients did not differ for the remainder. all patients were hypermetabolic and febrile in proportion to the size of their bum wound but were not endotoxemic ( . +_ . pg/ml; normal < pg/ml). i - did demonstrate a significant correlation with cole temperature (tr~ = . + . ogi - , p= . ) and with nitrogen excretion (nou t = - . - . ogi - + . tr, p= . ). administration of polymixin b had no effect on metabolic rate, temperature or i - levels but did reduce nitrogen excretion resulting in more positive nitrogen balance ( .t grn/day vs. - . gm/day, p= . ). although bum injury does not produce an obligatory endotoxemia, i - does appear to play a role in the fever and nitrogen wasting seen with such injuries. the effect ofpolymixin b on nitrogen excretion suggests that lps may play a role either locally or in the portal system. introduction: there is substantial evidence that release of inflammatory mediators by activated kupffer cells contribute to the course of a systemic inflammatory process, e.g. after shock or lrauma. besides the systemic effects of mediators such as tnf, paf or interleukines, local actions on hepatic microvasculature and hepatic inflammatory response have to be considered. our aim was to assess the role of tnf and paf by blocking their effects using anti-tnf monoclonal antibody, pentoxifylline and a paf antagonist. methnds: in anesthetized sprd-rats, hemorrhagic shock was induced by withdrawl of arterial blood within rain and shock state was hold for h at a map of mm hg (cardiac output of %). following adequate resuscitation with % of shed blood and twice of this volume as ringer's solntion, animals recovered to map > mm hg and co > %. hepatic microcirculation and sinusoidal leukocyte-endothelium interactions were examined by intravital epi-fluorescence microscopy at , , or hours after resuscitation. in a blinded fashion, a rat-specific monoclonal anti-tnf antibody [ mg/kg, celltech, uk) , pentoxffylline (ptx, mg/kg, hoechst, d), and a paf antagonist (web , boehringer, ingh., d) were given either as pretreatment or at the time of resuscitation (n= - group bolla. k*., duchateau, j., hajos, gy., mbzes, t., hern~di, f. prevention of temporary/secondary immune deficiencies or reduction of their severity and/or duration as well as the reduction of the perifocal inflammatory processes belong to the rational targets of posttraumatic/pedsurgical medication. such a targeted medication can result in less frequently occurring nosocomial infections, and in reducing the duration of the intensive care and convalescence period. the results of in vitro studies performed with the amino acid sequence - of thymopoietin, i.e., with thymocartin in whole blood and peripheral mono-nuclear celi(pbnc) cultures clearly show some characteristic effects of this immunomodulator. preincubation with the tetrapeptide significantly (p<o.ol) and concentration-dependent reduced the endotoxin(lps)-induced tnfalfa production from , to about pglml, but did not abolish it. the inhibition of the lps( . ug/ml)-induced tnf production occured already in presence of , pg peptide/ml and peaked at the concentration of , ng/ml. higher concentrations did not increase this effect. in contrast to the other two small thymic peptides (tp- and tp- ), thymocartin did not enhanced the pwm-induced pge production in pbmc cultures up to a concentration of ng/ml, inclusive. the selection of thymocartin (tp- ) for perisurgical medication and/or for treatment of trauma-induced temporary immune depression has been strongly supported also by targeted animal experiments. thus, mortality of about % registered in mice infected with pseudomonas aeruginosa after bum injury could be reduced with the tetrapeptide treatment to a level which did not differ significantly from that of the infected non-burned controls. moreover, observations gathered first of all with the inflammatory model of air poach/croton oil grenuloma (selye) clearly showed, that a very definite, antiexudative effect can be achieved with this thymic peptide. as to this effect, thymocartin has been confirmed, e.g., to be equipotent with locally administered fluocinolone acetonide and/or s.c. injected prednisolone. the interim results of two explorative double-blind clinical studies (involving more than patients after polytrauma and hip-fracture untill now, respectively) correspond to the expectations. the treatment significantly reduced the occurence of nosocomial infections, the days spend in intensive care and on antibiotics as well as it shortened the bed-out time and reduced the additional medication. objective of this prospective randomized study was to further delineate the mechanisms leading to these alterations and to investigate the effects of immunomodulatory intervention. patients and methods: patients (pts) formed control group a. group b pts received x mg indomethacin (indo) from the first (dl) to the fourth postoperative day (d ) intravenously to block prostaglandin e induced suppression of cmi response as well as mg thymopentin (tp- ) subcutaneously preop., on d and d to augment cmi reactivity. in vitro investigations preoperatively, on dl and d included measurements of the percentage of cd + t-helper (th) cells, pbytohemagglutinin (pha)induced synthesis of interleukin (il)- as one cytokine primarily produced by thl-cells, and pha-induced synthesis of il- as one cytokine primarily produced by th -cells. delayed type hypersensitivity (dth) skin response to an antigen skin test battery and specific antibody (ab) production following tetanus vaccination preoperatively and on d were used as in vivo tests for thl-and th -induced immune response respectively. results: postoperatively, group a pts showed a persistent significant reduction of cd + th cells, il- /il- ratio, and dth skin response as compared to baseline values (bl), while ab production increased (p< . vs.bl). in group b pts no change in cd + th cells, il- /il- ratio, or dth skin response was observed (p< . vs.group a), and postoperative ab production increased significantly (n.s. vs. group a). conclusions: .these results clearly indicate a significant suppression of th induced cmi response, while th induced response remains normal following ohs. .these alterations may gain clinical significance whenever a postoperative infection requires a th response and may explain the susceptibility to opportunistic microorganisms observed in pts after ohs. the aim of this study was to find out whether the establishment of administration of thymostimulin (tp-i) in jaundiced and anergic rats would return the rats to the state of immunocompetence. material and methods. male wistar rats weighing - g were injected with haemocyanin (klh). all rats with a positive response were included in the study and we evalu ated the t cell subpopulations and il- . they underwent laparotomy and the common duct was ligated and divided. those rats whic become jaundiced and anergic one week after the operation, were divided in two groups: control group ( objective of study. the goal of this study was to prove the necessity of thymus derived immunomodulators treatment in acute period of infantine sepsis, materials and methods. immune status was investigated in o infants. clinical conditions of children were defined by syndrome of multiple polyorgan]c insufficiency. the heaviness nf condition was estimated as the sum of points according to efforts needed to restore of basic living functions -respiration, hemodynamjcs, hemocoagulatlon, metabolism, functions of liver and kidneys. it was expressed in form of clinic condition classes from to . results.it was found that in % of infants with - classes of heaviness immunode[iciency took place simultaneously with ii and iii stages of hemocoagulattve syndrome. amounts of t cells and t helpers were decreased more then times, ratio th/ts was reduced to . or lower. concentration of lgg and igawas reduced almost a hull in comparison to control. phagocytic and metabolic activities nf neutrophils were depressed. complement system state was changed: the functional activity of the alternative pathway factors b, d and the level or c a subcomponent were increased but the level of c , c ,, c and c components of the classic pathway were decreased. during the development of coagnlopathy the direct correlation between chso, levels of plasminogen and antithrombine iii was found. in greater extent the function of immune system was disodered in accordance with point metabolic violations and hemocoagulative disturbances considered as disseminated inmtravaseular clotting syndrome on ii or ili stages. conclusions. the rehabilitation of the immune system functions was promoted by taetivine and thymaline in doses of i- mcg/kg per day and mg/kg per day accordingly during a week in children with - classes el heaviness. aiter - days tactivine had advantage. when eoagulopathy took place thynaaljne promoted restoration of ( - )-~-d-glucan (bgc) is a major cell wall compornent of pathogenic fungi and shows many immunopharmacological activities on experimental animals. lps is also derived from gram-negative bacteria and have in~ttnomodulating activities on immune systems positively or negatively. because of difficulty to cure contaminating lps from bgc preparations, it is very hard to evaluate the exact activities of bgc. in this study, we compared the immunological activities of lps ans highly purified bgc on murine system. materials and methods: c h/hen or c h/hej mice, to wkolds of both sexes were used through experiments. highly purified ( - )-{ -d-glucan (gurdran; bgc)was courteous gift from seikagaku kogyo co. tokyo, japan and resolved in endotoxin-free ultra-pure water. escherichia cell lps was purchased from sigma chemicals, usa. mitogenic activities of bgc or lps on splenic cells were measured by mit dye assay. in vitro activation of peritoneal exudate macrophage (pen) have moniotored by phagocytosis and intraphagocytic killing of pseudomonas aeruginosa (z~b- . induction of cytokine productions from pem or spleen cells induced by bgc or lps were detected by cytotoxic assay. results and (bnclnsions: i ) in vitro cultures of pem with bgc have induced enhanced phagocytic and bactecidal activities in c h/hen and c h/hej mice, whereas lps only induced such activities in c h/hen mice. most effective dose of bgc was ug/ml. ) bgc-dependent proliferative response of c h/hen splenic cells was not detected under the culture condition used. ) induction of tnf~ prodction was apparently observed in bgc-stimulated c h/hej pd cultures, but not in lps stimulated one. these findings indicate that activation mechanisms of pr and splenic cells by bgc are different from that by lps. to investigate the bsc-induced p~ activation, intracellular signaling pathways of p~ by bgc-stimulation are under consideration. yamagami k, uedono y, kawakami k, kitazawa y and tanaka t according to the latest reports of use of il- in a burned-sepsis model, the dose was too high to adjust for human therapy. adoptive transfer of l~ymphokine-activated killer (lak) cells has been demonstrated as a means of enhancing therapy in malignant tumors. we therefore attempt to use lak therapy on burned-infected mice instead of il- . under anesthesia, -weekold male c h-hej mice were subjected to a % scald or sham burn and then resuscitated. sham burned mice served as controls. scald burn mice were subjected to peritonitis by intraperitoneal innoculation of organisms of p. aeruginosa hr after burn. burned-infected-mice were divided into two groups. one group had no further treatment, and the other group received lak cells ( x ) intraperitonelly after septic challenge. the mice were scored for survival daily. on day after burn, using moabs dual-color flow cytometry, we studied lymphocyte expression in mice with use of blood and spleen. simultaneousely we studied the alteration of il- and il- in their serum using immunoassy kits. sham burned animals had no mortality. the mortality of the lak-treated mice was significantly reduced when compared with that of the burned-infected mice. the most consistent changes observed were depressions in percentages of thyl, positive cells and a remarkable depression of nk cells in spleen. after lak cell treatment, those two percentages of cells significantly increased. all the data of assay of ill and [l were not detected on sham burn mice serum. due to burn and septic challenge the levels of illand il (n= ) were raised to . _+ . and _+ pg/ml, while the levels in lak treated mice were reduced to . _+ . and _+ pg/ml, respectively. the results reported here demonstrate that lak therapy is able to improve cell-mediated immunity in burned-infected mice. this is associated with a significantly improved survival rate, since ill has been demonstrated to mediate immune and inflammatory responses. also a cause effect relationship between elevated endetoxin levels and increases of [l has been recently established. the aim of our present study was to investigate the effect of parenteral indomethacin on the immune system of patients under major operations. our study included operated patients, of which received mg indomethacin before and , and days after surgery (group a) and patients received no antiinflammatory therapy (group b). we measured total t-cells helper (cd ), suppressor (cd ), nk-cells and interleukin- and tnf production by pha or endodoxin (lps) stimulated peripheral blood mononuclear cells at day and , and days after operation. in group a we detected a significant (p< . ) increase in cd /cd ratio on day while no differences were ~oted in nk-cells or cytokine production in both groups (table ) . it seems, therefore, that parenterai indomethacin may have a benefitial effect on the immune system of patients under major operations by increasing the t-helper /t-suppressor cell ratio while having no effect on the production of cytokines by peripheral blood mononuclear cells. this study was undertaken td dete~nnine the role of prostaglandin synthesis inhibitor on survival post traulna sepsis. analysis of the effects of prostaglandin synthesis inhibitor on survival of four groups of mice each were made after laparatomy and intravenous administration of live e.coli. post trauma sepsis, group a received no treatment; group b received antibiotics im; group c received prostaglandin synthesis inhibitor im and group d received both antibiotics and prostaglandin synthesis inhibitor im. survival time was longest in group treated with prostaglandin synthesis inhibitor and antibiotics post trauma sepsis. the singular use of either antibiotic or prostaglandin synthesis inhibitor did not alter the outcome on survival. mortality rate was lowest in the group treated with combined prostaglandin synthesis inhibitor and antibiotics. use of this combination showed a reduction in bacterial growth in peritoneal and blood samples, mild morphologic changes secondary to sepsis in the heart, lungs, liver, kidney and stomach and marked enhancement of mean level of activity. the study indicates that addition of prostaglandin synthesis inhibitor in treatment of trauma-sepsis has clear beneficial effects. interferon-? (ifn-y) is a potent immunostimulant which has been shown to be detrimental when administered during septic shock. blockade of this cytokine however is beneficial during the acute septic response. the aim of this study was to evaluate the cellular effects of this cytokine and its blocking monoclonal antibody (moab) in lethal sepsis following injury. female cd- mice were randomized into two groups: septic=lps vs injury=hind limb amputation (hla vs igg. nstats= anova=p< . vs lgg ifn-y was detrimental when given to control septic animals. however its blocking moab was protective (p< . ). conversely ifn-y was proteetive in injured septic animals compared with anti-ifn-? (p< . ). these findings demonstrate that the immune stimulant ifn-? has therapeutic potential in the immunosuppressed injured host predisposed to sepsis, while blockade of this cytokine is required for protection in the septic host with a normal immune response. dept of surgery, rcsi, beaumont hospital, dublin , ireland. oxidants play a role in physiology. the potential noxious oxidant biochemistry is restrained by chemically distinct antioxidants. these antioxidants, which may reside in different cellular compartments, can act synergistically. in normal physiology an oxidant/antioxidant bai&nce exists. unbalance in favour of the oxidants is called oxidative stress. oxidative stress has been implicated in many pathologies including lung diseases(e.g, doxorubicin induced cardiotoxicity), ischemia/reperfnsion damage and central nervous system trauma. transition metals such as iron are involved in the early events leading to oxidative damage in these pathologies. this has been underlined by the finding that postischemic cns pathology closely resembles that caused by a chemical oxidative insult (e.g. iron microinjection). moreover, a protective effect of oxygen-radical scavening agents or compounds that inhibit lipid peroxidation (antioxidants) in brain ischemia/trauma is apparent. some known drugs (e.g. anti-arrhythmics or histamine h -antagonists may act as non-specific antioxidants. howe~er, recently, interesting new membrancespecific antioxidants (e.g. -aminosterdids) have been designed. subt&e effects on iron redox chemistry contributes to the potent antioxidant activity of these aminosteroids. since a few years, one area that greeted enthusimastlcally in clinical medicine is that of reoxygenatlon injury or ischemia-repeffusion, a phenomenon accepted to make a majo:" contribution to organ dysfunction in trauma, shock and sepsis through the formation o( oxygenated free radical species. however, thei detection in vivo always remains a difficult challenge. efforts have been made recently to directly establish the formation of free radicals in biological samples as complex as blood, plasma or tissue with the use of electron spin resonance (esr) spectroscopy. using spin trapping agents, the presence of reactive carbon-and oxygen-centered radicals has been demonstrated in animals blood submitted to heart, renal and intestinal ischemia-repeffusion or to liver transplantation. recently, the in vivo formation of free radicals in the cerebra; extracellnlar fluid during cerebral isehemia-repeffusion has been assessed by the spin trapping technique coupled to brain microdialysis. esr investigations have also been conducted to detect endotoxin-induced free radical generation in rat or baboon liver and oxygen free radicals (ofr), produced both at intra-and extra-cellular levels, seem to play a major role in the pathophysiology of tissue injury and organ dysfunction in sepsis, through induction of lipid pemxidation in cell membranes. oxidative damage can result both to an ofr-overpmduction or to a depletion of endogenous antioxidant defenses, which are represented by scavenger enzymes (e.g. sod), hydrosoluble and liposoluble antioxidants (e.g. ascorbate, vitamin e), and other mechanisms such as metal-ion sequestration. in animal models, oxidative damage has been proved by detection of increased levels of lipoperoxidative products, and a depletion of antioxidant defenses was found both in plasma and tissues. in the few clinical studies a similar results have been reported, and oxidative damage appears to correlate with dic, with organ dysfunction and with red blood cell deformability. in a group of critically ill septic patients we found increased levels of conjugated dienes (cd) (bioproducts of lipoperoxidation) and decreased plasma levels of alpha-tocopherol and coenzyme qlo (coqi )(endogenous liposoluble antioxidants). a relationship between cd and uric acid (p< . ) was found, may be related to xantine-dehydmgenase to xantine-oxidase conversion. antioxidant depletion is due both to overconsumption and to a nutritional deficiency, even if a reduced synthesis can also be present. in fact one more relationship between coqi and plasma cholesterol (p< . ) demonstrates the commun hepatic biosynthetic defect. is there any role for antioxidative therapy in sepsis? can it achives a significant improvement in the septic course, organ dysfunction, and final outcome? several antioxidant drugs, have been evaluated in experimental and clinical sepsis: scavenger enzymes, natural antioxidants, alloporinol, -aminosteroids or lazaroids, have been proved to reduce lipopemxidative damage, to protect organ dysfunction, and in some cases to improve survival. several questions must be addressed in evaluating safety and utility of antioxidative therapy. more specific and standardized methods must be applied to detect and quantify the lipoperoxidative damage. antioxidant drags must act selectively on ofr-production, without interference with other than that are beneficial for the organism. antioxidants must be able to achive in adequate amount the tissue or cellular compartment where their action is required. many antioxidants have also a pro-oxidative effect which can he detrimental in some conditions. the timing of administration, the dosage used and the association wih others antioxidant drugs must be defined. nutrition plays an important role as antioxidative therapy, since it supplies all compounds needed to maintain adequately levels of endogenous antioxidant or to support their synthesis. thiobarbituric acid reactive substances (tbars) concentration in serum has been determined in a large population of healthy subjects and in patients suffering acute hepatitis and chronic cases of hepatitis c, as well as several other processes. the correlation with different physiological and clinical parameters in these populations is also presented. treatment with interferon of the chronic active hepatitis c patients, x u three times a week during two months, led in those patients whose sgpt activity normalized in serum, to a concomitant decrease in serum tbars content. the possible theoretical involvement of peroxidation and antioxidants in this beneficial effect of i~terferon in hepatitis c patients is discussed. the results presented confirm the value of tbars as laboratory test in the management of disease and as a useful tool for the study of pathogenic and/or therapeutic mechanisms. -hydroxyalkenals are among the different substances measured by the tbars assay. these compounds show several biological effects that have been demonstrated mainly in different experimental models. we have studied the capacity of different tissues to conjugate these compounds patients surviving the initial subarachnoid hemorrhage (sah) from a ruptured in~raeranial aneurysm are prone to develop cerebra] ischemia from vasospasm which is associated with significant morbidity and mortality. among the many treatments that have been prol~osed to treat this condition, none has been shown to be satisfactorily effective. recently, a new drug, namely the -aminosteroid tirilazadmesylats, has been studied in a large, prospective, multicentor trial for its effectiveness to improve the outcome of patients with aneurysma! said. the study was conducted in europe and australia in neurosurgical centers and included patients. all patients received presently accepted standard treatment, including nimodipine. patients were randomized to four different groups: placebo and groups of tirilazad in escalating dosage ( . - mg/kg/day). the clinical outcome was compared for these groups and cerebral a~giography was performed in % of patients on day - follovang sah, to study the effect f'the dflf~ off cerebral vasospasm. the study reached its planned endpoint months ago. preliminary results ~how a significant improvement with regardto mortality in those patients receiving the highest tirilazad dose as compared to placebo and the two lower dose groups. additional beneficial effects were seen in the rag/day groups with regard to the occurence of symptomatic vasospasm and good clinical outcome. although the final analysis of all data is still pending, these results suggest that tirilazad-mesylate could represent a major improvement for the treatment of patients with sail. experimentally lipidperoxidation products (lpo) are increased in acute pancreatitis (ap) due to oxygen radicals (or). the purpose of this clinical study was to determine the antioxidant status and lpo in patients suffering from ap and to evaluate the effect of antioxidant treatment with sodium selenite (se) thus improving the function of the se dependant glutathione peroxidase which is the major detoxifying system for or. materials and methods: in z patients sufferin s from severe ap (c-reactlve protein > me/l) we determined on day and day after admission the lpo ma!ondialdehyd (mda), conjugated dishes (cd), reduced (gsr) and oxidized (gssg) glutathione, the vitamins a,c,e and se. moreover the patients were evaluated clinically using the ranson and the apache ii score. i patients were randomly treated with ug/day of se for days. results: all patients suffered from a severe depletion of antioxidants,especially a low concentration of se (only / of normal). thereby the increase in lpo correlated with the clinical course. during se treatment lpo decreased and the levels of antioxidant vitamins improved. se had no influence on leth-slity the lenl or the chan in rs or ap ii. background: since reperfusion injury occurs when oxygen is reintroduced into ischemic tissue, the ideal timing for administration of therapeutic compounds aimed at ameliorating oxygen radical mediated injury is at the time of initial fluid resuscitation. currently used colloid or crystalloid preparations do not provide optimal, or even significant, anti-oxidant protection. systemic iron chelation affords protection against the iron catalyzed components of oxygen and lipid radical mediated tissue injury. the conjugate resulting from chemical attachment of the clinically approved iron chelator, deferoxamine (dfo, desferal ®, ciba), to hydroxyethyl starch (hes) represents a novel approach to colloid based fluid resuscitation. hes-dfo contains % hes and % chemically bound dfo. the polymer-drug conjugate has a lower molecular weight than that of hes in order to allow more rapid excretion. results: preclinical and initial clinical trials indicate that hes-dfo is well tolerated, even at high doses. in animal studies, fluid resuscitation with hes-dfo does not significantly improve central hemodynamic recovery beyond that observed with hes, but hes-dfo seems to afford better protection of microcirculation in organs at risk (lung, liver and gut), possibly by decreasing neutrophil sequestration. in a burn model, total fluid requirements are lower and oxygen utilization higher in hes-dfo treated animals compared to hes controls, suggesting decreased vascular leak and improved tissue perfusion. conclusion: hes-dfo represents a means by which potent antioxidant protection can be administered at resuscitation. iron has been suggested to play a pivotal role in oxygen flee radical mediated tissue injury. in vitro experiments indicated its critical role as a katalyst in hydroxyl free radical generation fenton-reaction). since iron chelator deferoxamine administered in shock alone demonstrated severe side effects, a hydroxyethylstarch (hes)daferoxamine (dfo)-conjugute was used to modulate oxygen free radical injury during the ischemia/reperfi~ion syndrome induced by hemorrhagic shock. methods. female lewis rats ( - g, n> ; pentobarbital anesthesia mgjkg), in hemorrhagic shock ( the aim of the study was to elucidate ( ) whether the generation of or would affect lung and kidneys as primary shock organs in the very early phase of sepsis and ( ) whether dfo-hes could prevent this tissue damage. methods: in rats sepsis was induced by cecal ligation puncture (clp) peritonitis. the animals were randomly assessed to groups: one group was treated with ml dfo-hes ( mg/kg iv), the other rats received solely ml of the carrier starch solution. , , , and min after induction of sepsis respectively, the animals were sacrificed, the organs collected, and tissue contents of glutathione (gsh), malondialdehyde (mda), myeloperoxidase (mpo) and conjugated dienes (cd) determined. plasma samples were obtained for analyses of endotoxin (chromogenic lal test). blood pressure (map) was measured via a carotid artery catheter. results: clp caused sepsis with high (> . eu/ml) endotoxin levels. map in both groups decreased slightly but significantly during sepsis regardless any treatment. in the lungs mpo concentration was increased (p< . ) in the lies group already min after sepsis induction. concomitantly, tissue gsh level decreased and lipid peroxidation was pronounced as shown by elevated mda and cd levels. dfo-hes diminished tissue pmn accumulation and mpo concentration. moreover, at each time point lung mda and cd levels were lower (p< . ). histomorphological examination showed marked micro-atelectases, destruction of the alveolar septa, and splicing of the basal membranes in the lies group. in contrast, in dfo-hes treated rats the alveoli remained well-ventiiated and only some enlarged reticular fibers without splicing were observed. almost similar results were found for the kidneys. mpo levels differed neither within nor between both groups. the slight decrease in gsh levels seen after min in the dfo-hes group seems to demonstrate an oxidative stress to a lesser degree. the most impressive effect of iron chelation, however, was revealed by the lipid peroxidation products. at each time point, mda and cd levels were lower (p< . ) compared to the hes group. light and electron microscopic examination disclosed tubulotoxic and mitochondriat damages while dfo-hes lxeatment prevented that alterations. conclusion: both the biochemical and histological results of this study reveal an early and remarkable generation of or in peritonitis-induced sepsis. thereby, these or obviously cause pulmonary and renal tissue damages, intravenous application of dfo-hes may, however, benefit by preventing early lipid peroxidation of the tissue. the proteolytic irreversible conversion of xanthine dehydrogenase (xd) to xanthine oxidase (xo) is triggered by calcium flux. the aim of our study is to clarify ~he link between intracellular ca + levels and xo activity determined by uric acid release, and to evaluate the efficacy of verapamil, on the generation of hydrogen peroxide associated with reperfusion by assaying lactate & pyruva~e release and the levels of cytosolic free nad /nadh ratio. experimental protocol consisted of :(a) non ischemic/reperfused experiment in which normal cardiac slices of rats were perfusated with oxygenated kreb's ringer phosphate buffer containing glucose ( mg%) and bovine albumine ( gm%) for min at °c.it composed of groups, group aa (control group), and groups ab & ac (perfusate supplemented with verapamil in the dose of loo& mi% respectively). (b) ischemic reperfused experiment in which ischemic cardiac slices were obtained from rats subjected to min ~aemorrhage.lt was also divided into two groups; group ba and bb (verapam~/ mi% added to perfusate}. verapamil stimulated uric acid release from normal rat cardiac slices were % in group ab and % in group ac(dose related). rates of uric acid release is enhanced by verapamil in group bb. moreover, rates of uric acid release in groups ac & bb are insignificant. in verapmil added groups (group ab, ac & bb), increase uric acid release is associated with an enhancement in pyrurate release and with increase levels of cytosolic free nad+/nadh ratio, although it is not evident ~ ischemic group (group ba).it is concluded that the conversion of xd to xo is calcium independent. eicosanoids like thromboxane a , leukotriene b and leukotriene c are known as promoters of initial inflammatory reactions. we investigated whether oxygen radicals (or) are able to induce a release of these eicosanoids in whole blood. blood from healthy volunteers was incubated with xanthine oxidase/hypoxanthine to generate oxygen radicals. after , , , and minutes plasma levels of thromboxane b (txb ), leukotriene b (ltb ) and leukotriene c (ltc ) were determined via elisa technique. another volunteer had taken mg aspirin one day before taking the blood sample (no ). results: txb plasma levels increased from pg/ml at min to pg/ml, pg/ml, pg/ml and pg/ml at , , and min (p< , ) . ltb and ltc plasma levels showed an increase during the first few minutes (ltb : min: llpg/ml, min: pg/ml; ltc : min: pg/ml, min: pg/ml (p< , )) followed by a decrease to normal values at min. in the sample no the cyclooxigenase-pathway was completely inhibited, the txb plasma-levels did not alter at all, whereas ltb and ltc -plasma levels weren't affected. opallogeneic blood transfusion jane shelby, ph.d., and edward w, nelson, m.d, there have been numerous investigations dudng the last two decades examining the effect of surgery, anesthesia, blood loss and transfusion on vadous immune parameters in humans and animal models. there appears to be concurrence among several well controlled studies that transfusion of whole blood (containing leukocytes), has regulatory effects on immune ceil function which include decreased cell mediated immune response, and inhibition of il- secretion. these effects occur following transfusion alone and in con.cart with the distinct immune effects of surgery, trauma and anesthesla, the clinical consequences of this immune modulation by transfusion include decreased allogeneic response to transplanted organs, which has been exploited clinicelly in renal transplant patients. additionally, there is evidence for a strong association with increased risk for infection in transfused patients following surgical procedures. aiiogeneio blood transfusions have been shown to inhibit cellular anti.bacterial mechanisms, causing increased susceptibility to bacterial pathogens, in humans and in animal models. there is also concern that allog~neic transfusion may adversely affect cancer patients, resulting in decreased disease-free survival. several stategies have been proposed to minimize the adverse effects of blood transfusion. there is evidence that the risk of immune mediated infectious complications associated with transfusion may be greatly minimized wlth the use of autologous blood and leukocyte free allogeneic blood.products in surgical and trauma patients, it also appears that the inhibition of cellular immune response and il- productiorl following atlogeneic blood transfusion may be mediated by increased prostaglandin e secretion, and that immune response may be preserved in allogeneio whole blood transfused subjects receiving c lc~oxygenase inhibitors such as ibuprofen. among these are various alterations in immune function. efforts have therefore been made to utilize alternatives to homologous transfusions. these include the use of autologous predonation, supplemental iron therapy, and recombinant human erythropoietin. although initially considered innocuous, these therapies are now recognized to have potential deliterious immune sequelae. erythropoietin, by its ability to lower serum iron levels, can impair both lymphocyte and nk cell activity. autologous donation impairs nk cell function. finally, supplemental iron therapy can stimulate bacterial growth and increase the rate of infectious complications. this talk will present a discussion of these factors as well as a weighting of their importance. r.l rutan, rn;bsn, shriners burns institute and the university of texas medical branch, galveston tx, usa the serious sequelae of homologous blood transfusions have resulted in vigorous efforts at identifying alternate therapies for correcting red blood cell (rbc) deficits. erythropoietin (epo) was hypothesized to exist in the early th century, however the protein was not isolaled until . the human gene was identified and cloned in , which permitted the production of epo through recombinant techniques. the earliest clinical trials were performed in anemic end-stage renal failure palients on hemodialysis. treated patients experienced increases in erythropoiesis with normalization of hematocrit and hemoglobin levels, cessation of lrans-fusion requirements and improvement in general wellbeing. these studies, however, identified side effects of epo treatment such as hypertension, seizures and ee deficiency. volunteer trials have established that the hypertension is not a direct pressor effect but rather the result of abnormally rapid increases in red cell mass in the face of the incompetent volume-controlling mechanisms of the end stage renal failure patient. lower doses of epo and the subsequent gradual increases in red cell mass are associated with significantly lower incidences of hypertensive complications of epo therapy. likewise, seizure activity is not the result of a direct epileptogenie effect but parallels the incidence of hyper-tensive-related sequelae during high.dose epo treatment. in cross-over designed studies, pre-existing iron deficiency has been demonstrated to decrease or negate stimulated erythropoiesis but effective-hess can be restored with appropriate fe supplementation. exogenous epo is effective whether given by iv or sq routes and dose response curves do not vary with route of administration. increases in rbc mass are directly related to the dose of epo, both in amount and frequency of administration although there is a - day time lag between the first epo dose and laboratory indications of its action (i.e. increase in the number of reticulceytes in peripheral wood). epo is currently labelled for use in the treatment of anemias associated with end-stage renal disease and aids. however, its use in the surgical population has been explored because of its unique direct dose-response, epo has been used to effectively increase the blood harvest amounls in autologous pre-donation, significantly increase hematocrils in children following thermal trauma and successfully increase red blood cell mass following essential surgical procedures in patients with religious aversion to transfusion. by blood transfusion in colorectal cancer surgery mm heiss md, ch delanoff md, r stets md, j hofinann, e faist md, kw jauch md, fw schildberg md allogeneic blood transfusions are associated with an increased risk for postoperative infections in colorectal surgery when compared with autologous blood transfusions. attribution of this effect to immunomodulation was suspected in our previous study (lancet ; : - ) . task of the recent investigations was to analyze which specific effector systems were affected in-vivo by this transfusion-associated modulation. for global in-viva assessment of cell-mediated immunity (cmi) multiple recall skin-reactions were applied prior and post-operative. the specific humoral immune mechanisms were investigated by applying tetanus-toxoid one day preoperatively and deterimnating the quantitative igg-response. for indication of macrophage stimulation in-vivo tnf-levels were determinated by bioassay. dth-responses were significantly suppressed (p< . ) in patients receiving allogeneic blood (n= ) or operated without blood transfusions (n= ). dthresponses were not suppressed and tendentiously increased in patients with autologous blood transfusions (n= ). in contrast, specific igg-levels increased sigmficantly (p< . ) in patients receiving allogeneie blood (from . + . to . _+ . ie/ml) whereas in patients receiving autologous blood a smaller increase (from . + . to . + . ; p= . ) was observed. tnflevels demonstrated a similar pattern with a higher increase in patients receiving allogeneic transfusions (l . + . to . + . u/ml) compared to those patients with autologous blood ( . + . to . + . ). in conclusion these data indicate that allogeneic blood transfusions lead to a remarkable macrophage/rhs stimulation. this is corroborated by the boostered humoral igg-response which was initiated before onset of surgical trauma and blood transfusion. concerning cmi this caused a substancial suppression probably due to a stimulated secretion of immunosuppressive monokines. objective: firstly, to analyse the concentrations of the cytokines tumor necrosis factor (tnc), interleukin- (il-i), interleukin- (il- ) and coagulatioo/fibrinolysis parameters in postoperatively retrieved blood from a surgical area, secondly to characterize the correspanding cytokine patters in the patients and thirdly to study cytokine concentrations in the initial portion of drainage blood from a surgical area. materials and methods: blood retrieval was performed in a closed-loop system without anticoagulant during - hours after surgery in patients undergoing arthroplasty ( hips and knee). kf, il- , it- , thrembin-antithrombin complexes (tac) and antithrombin (at) ~ere determined in shed blood. patient plasma tn v, il-i and il- concentrations ~ere analysed at the beginnlqg and end of the - hour blood retrieval period. in a separate study ( hip arthroplasties) f~f, il-i and il- ~ere determined in the initial portion of drainage blood. cytekine analyses ~re performed usiog ipmuooassays. an omidolytic method was used for at determinaf.ion and tac was analysed by elisa. n~n-poram~tric tests was used for the statistical comparison. results: the patient plasma il- coocemtratiems rose from a median value of to pg/ml, p<o. , during the blood ret.rieval period. in c was detectable in patients, range: - pg/ml. il-i was not detectable in the patients. in retrieved blood tag was > mg/ml in all samples (ref:< . mg/ml) and at was . - . units/ml (ref:o. - . ) . the il- concentrations in retrieved blood was > pg/ml in all samples. tn v or il-i was not detectable. in the separate study, (n= ), characterlzing eytokine content in the initial portiere of drainage blood, in= (range: - pg/ml) and il-i (range: - pg/ml) ~re present in all samples but ii- (range:o- pg/ml) was detectable in o.qly one semple. conclusion: theses findings indicate that hypereoagulability and hic~ ccrcentratioos are present in retrieved blood. the cytokine pattern in the initial portion of blood from a surgical area differed from these observed in retrieved blood and in the systemic circulation. to identify the role of both autologous and homologous blood on postoperative infections in elective cancer surgery. materials and methods: patients with colo-rectal cancer submitted to curative elective surgery were prospectively studied. on hospital admission the following nutritional measurements were assessed: serum level of albumin, cholinesterase, delayed hypersensivity response , total lymphocyte count and weight loss, as were age and sex, duration of operation , operative blood loss, amount and type of blood given, pathological dukes' stage of the disease and the attending surgeon were also recorded. results : eighty-four patients ( . %) were perioperatively transfused. thirty-six ( . %) patients were given autologous blood , while ( . %) received homologous blood. no patients received both autologous and homologous blood. twenty eight ( . %) patients developed postoperative infections. non transfused patients had a . % infection rate , those receiving autologous blood had a . % infection rate, whi]e in the homologous blood group the infection rate was . % (p < . ). univariate analysis showed that infections were significantly related to operative blood loss (p< . ), length of operation (p< . ) blood transfusion (p< . ) and attending surgeon (p< . ) . multivariate analysis identified homologous blood transfusion as the only variable related to the occurrence of postoperative infections , while the other variables failed to reach statistical significance. blood transfusion (bt) remains an essential life-saving treatment for surgical patients. however, besides the beneficial short-term impacts, negative longer-term effects are observed, which include various alterations in the immune responsiveness. in surgical patients these alterations may contribute to the increased risk for infections and cancer recurrence. since relatively few data demonstrate immunologic changes occurring in other lymphoid compartments than blood after bt, we studied the effect of et on the frequency and responsiveness of immune cells in bone marrow (bm), spleen (spl) and blood (b) in a rat model. normovalemic, month old rats were transfused intravenously with syngeneic heparinized venous blood ( x ml, every other day), and , and days after the last transfusion bm cells ( leh is an experimental oxygen-carrying resuscitation fluid. since leh is cleared from the circulation primarily by the mps, its effect on the development of sepsis and the nature of its relationship with the mps remain a major concern. preliminary in vivo data from our laboratory failed to show any leh effect on the hemodynamic and hematologic responses to endotoxin lipopolysaccharide (lps) in the rat. in contrast, leh exacerbated the lps-induced tnfa production and early mortality. the exacerbation of early mortality by leh was attenuated by pretreatment with the tnfu synthesis inhibitor rolipram. ex vivo, peritoneal macrophages from rats treated with leh and lps have shown increased il-lg mrna signal as compared to lps alone. also, leh increased tnftx production by peritoneal macrophages in response to lps stimulation in vitro. additionally, recent pilot studies indicate that leh attenuates pma-induced superoxide production from rat peritoneal macrophages and that leh augments fmlp-induced migration of human monocytes. taken together, these data strongly support possible interactions of leh with the mps and therefore the nature of such interactions should be further explored. over the last decade, we have developed liposome encapsulated hemoglobin (leh) as an artificial oxygen carrying fluid, or blood substitute. our efforts have focused on studies to define the safety and efficacy of this resuscitative solutions. leh consists of distearoyl phosphatidylcholine, cholesterol, dimyristoyl phosphatidylglyeerol, and alpha tocopherol in a : : . : . mole ratio and can encapsulate hemoglobins of different origin (bovine, human, recombinant human). leh is fabricated using hydrodynamic shear to create an average particle size of . microns. leh can be lyophilized using disaccharides and stabilized in the dry state and easily reconstituted before administration. histopathology and clinical chemistries indicate that leh rapidly accumulates in tissue resident macrophages in small animals injected in the tail vein, principai y in the liver and spleen. the consequences of accumulation in the reticuloendothelial system are manifest by transient increases in liver transaminases (ast, alt), bilirubin, and bun over - hours with no change in biliary function (ggt, ap) . clearance through the liver and spleen is observed over the course of - -weeks. more recent attention has been focused on secondary consequences of leh administration especially with regard to inflammatory eytokines. leh does not elicit expression of tumor necrosis factor in vivo and in isolated macrophage cultures, but does result in a transient increase in serum il- . we have also examined the interaction of leh with lps in vitro macrophage culture to further understand how this blood substitute may effect the immune system. we have labeled leh with technetium- m ( mtc) to study the biodistribution of leh non-invasively in anesthetized rabbits. rabbits were infused with a % topload of leh ( mg of phospholipid, . g of hemoglobin per kg of body weight) and imaged continuously with a gamma camera. at hours, images were again acquired. animals were then sacrificed and tissue counts obtained, images revealed an initial rapid uptake bythe liver, % at minutes and % by hours. the spleen accumulated activity at a slower rate, % at minutes and % at hours. at hours, autopsy biodistribution studies revealed that approximately . % of the dose is in the blood pool, . % in liver, . % in spleen, . % in lungs, . % in muscle and . % in urine, with trace levels in kidney, brain and heart (< °/o). in a hypovolemic model, rats were % or % exchange transfused with mtc-leh. in the % exchange model, mtc-leh was rapidly taken up by the liver and spleen with minimal activity in the circulation at hours. with the % exchange, % of the leh was in circulation at hours. the interaction of leh with platelets labeled with indium- was also studied. after infusion of leh, the labeled platelets rapidly moved from the circulation to the lungs and liver. over the next minutes, the platelets gradually returned to circulation. this effect was not seen with iiposomes of the same lipid composition but containing no hemoglobin. non-invasive imaging is proving to be a very useful tool for the investigation of leh. the need for a safe, efficacious and commercially viable blood substitute is unequivocal. of the several strategies pursued to invent an adequate blood substitute, liposome entrapped hemoglobin (leh) has been already established as a leading possibility. major advances in liposome technology have already resulted in liposome preparations compatible with clinical use for drug delivery. recent technological advances made by the u.s. naval research laboratories resulted in the capacity to entrap hemoglobin into liposomes in a way which secludes hemoglobin from interacting freely with biological systems. the leh produced has already been tested in in vivo systems and was foun.d to be well tolerated. moreover, the leh originally produced as a solution can be transformed into a lyophilized form which can be reconstituted and delivered as a fresh solution. while important milestones in leh development for a practical blood substitute have been achieved, several issues remain to be explored. most notably, the long term consequences of leh on host defense mechanisms and, in particular, immune cell function. in addition, it is important to understand more fully the metabolic fate and repercussions of leh delivered at clinically relevant dose/schedule regimens. finally, while leh is a highly promising strategy for a blood substitute, the present formulations consist of human hemoglobin derived from human blood, to improve the safety profile, a recombinant preparation for liposome entrapment will be much desired, aa-ginine, a semi-essendai dietary amino acid, possesses several unique and potentially pharmacologic properties. argirdun is a potent secretagogue for pituitary growth hormone and prolacfin and for pancreatic insulin and glueagon; it modulates host protein metabolism by increasing nkmgen retention and enhancing wound collagen synthesis. it also is a potent t call function regulator. ait of these effects coupled with its relative lack of toxicity and safety make it an a~antive nulritionai pharmacologic agem (t). rodents fed supplemeutal arginine exhibit increased thymsc weight which is due to increased numbers of thymic lymphocytes present in the gland. thymic lymphocytes from animals fed supplemental ar~e demonstrate increased blastogenesis in response to coma. and pha ( ) . peripheral blood lymphocytes from humans given supplemental arginine also have heightened mitogunic responses to mitogen or antigens ( ) . in postsurgery padents supplemental arginine abrogates or diminishes the deleterious effects of trauma on lymphocyte responsiveness and restores peripheral blood lymphocyte responses much faster than observed in controls. overall host immunity is also enhanced by arginine. allograft rejection is enhanced and septic animals survive longer when given supplemental arginine ( ) . tumor bearing urginine-supplemented animals have decreased tumor growth and enhanced survival (i). lastly, asgmine can induce t cell maturation and t cell mediated responses in athyrnic nude mice. arginine also has remarkable effects on host nitrogen metabolism post-injury. in increases nitrogen retention in healthy human volunteers and in surgical patients. this beneficial effect on overall nitrogen metabolism is accompanied by a unique effect on the healing wound. supp]emental arginine increases wound collagen synthesis which also translates into increased wound breaking strength ( ) . arginine has no effect ou epithelialization. douglas w. wilmom, m.d. boston, ma gintamine is the most abundant amino acid in the body, but it has long been considered a nonessential amino aeid because it is synthesized in many tissues. fohov~g st,~'vation~ injury or infection, skeletal muscle pmteln inoresses its net tale of degradation and releases amino acids into the blunds~mm at an aocelerared rate. app~o)~mately one-third of the amino nitmgea is ghitamine, which is metabolized by the kidney where it parth:~pates in acid-base homeostasis, is the primly ~ for lymphocytes, mac~optmgcs and untexocyms, and contm'butcs to the synthesis of giumth~une. olmamine degrades slowly while in ~olu~ou, especially at usual room teml~mtums. because giulamine was considered nonessential, it has beer absent r'om nil intravenous and most gluts.mine should be considered a cendittona]ly essential nutrient for individuals with serious ilinesses, uspccially those confoanded by infcctinn and inflammation. over the uc~:t - years, glutamine will be incorgorated into most feeding formulas designed for patients with critical illness. o]~ga- pufa there continues to much interest in the application of the mega- pufa in clinical nutrition. the basic principle has been that the mega- pufa will displace arachidunic acid and result in a decrease in eic san id production. in addition these changes in pufa will after the physical characteristics of the membrane including flujdity, receptor function and transmembrane signals. animal studies have shown that there is omega- incorporation with continuou~ enteral feeding both in control and endotoxic animals within days. this includes the liver, spleen, circulating and alveolar marc phages and the lung. this incorporation resuls in significant changes in the eicosan id production including pgf and ket -pgflalpha. there is improvement in the cardio-vascular reep nse of these animals with ~ecreamed lactic acidosis and improved cardiac contractility. as well there is improved immune function with improved t cell response to mit gens. the ~ of a mumber of pharmacological agents blocking cicosanoid production can enhance the cell effects of mega- pufa. clinical studies using short term entsral nutrition with mega- either alone or with other enteral supplements in a number of clinical settings have shown significant mesa- incorporation and decreased eicosan id production. these positive results must be discussed with the additional evidence that long term omega- supplementation decrease eic san id production but als induce a state of immune suppression that is capable of increasing transplant sunvival. these ng te~ inune effects may benefit clinical conditions including rheumatoid arthritis and cr hn' disease early enteral nutrition instituted i~mediately afte~ injury will decrease the entry of bacteria into the intestinal wall and decrease the number of bacteria that translocate into the portal blood. these reductions are associated with & decreased catabolic response, decreased plasma cortisnl levels, end decreased vma excretion in the urine and prevention of mueosal atrophy. sdecific nutrients also affect the transloeation process. addition of arginlne to the diet significantly improves the ability to kill translocated organisms. however. translooetion across the gastrointestinal barrier is not affected. in contrast, glutamine diminishes the rate of translooation across the imtestinal barrier and also improves killing of the beetarla that do translooate. the omega fatty acids in the form of fish oil slightly decrease the rate of translocation but more significantly increase the ability of the animal to kill translo~ated organisms, all three dietary additives, i.e. argini~e, glu=amine and fish nil. significantly improve survival, hut adding glyoine or medium chain triglyeeridem do not, combinations of srginine and glutamlns, glutamine and fish oil, and fish ell end arginine each improve survival, and to a greater degree than a combination of all three. these studies add further evidence that translocation is an important determinant of survival after injury, early feeding with immunonutrlent enriched dices will improve survival and dsarease transloeation to varying degrees, depending upon the nutrients provided. objectives: we studied effects of supplementing a commercial enteral diet, impact r (imp, sander nutr lnc), with fiber (imp/fib) or alanyl-glutamine (imp/ag, exogenous glutamine (gln) gms/l) on influencing the incidence of bt to mesenteric lymph nodes (mln) in burned mice. fiber has been shown to improve gi integrity under certain stress/treatment conditions. the dipeptide ag is a water-stable source of gln, which is a specific fuel for many cells including enterocytes. traumacal (trcal), a high-protein, high-fat enteral diet (mead johnson iuc), was also studied, as well as rodent chow (harlan teklad inc), which contains very high protein & fiber. methods: anesthetized cf- mice aged - wks received % tbsa fullthickness dorsal burns & were resuscitated with cc ip saline. diets were allowed ad lib; caloric intakes were comparable in all gps except fasted gp (fast hrs, chow hrs). at hrs postburn mln were sterily removed, homogenized and plated on heart brain infusion agar; cfu/g mln tissue were determined. bt was analyzed by fishers exact test, cfu/g by anova-bonferroni. * p< . , ** p< . compared to imp and burn-fast gps. background. infectious complications following trauma, major operation, or critical illness adversely affect hospital cost and length of stay (los). some key nutrients have been shown to possess immune enhancing properties. this multicenter trial was conducted to determine if early administration of an enteral formula supplemented with arginine, dietary nucleotides and fish oil can decrease los and infectious complications in icu patients. methods. this was a prospective, randomized, double-blind study of adult icu patients who required enteral feeding for > days. patients entered the study within hr of the event, were stratified by age and disease, and were randomized to receive either the supplemented formula (impact®) or the conventional formula (osmolite ® hn). feedings were initiated at full strength and advanced to at least ml/hr by hr after event. results. both groups tolerated administration of formula well. for patients fed > days, the median los was % shorter (p=o.ol) for the--supplemented group ( days) compared to the conventional group ( days). the incidence of most infectious complications was lower in the supplemented group, but this difference reached significance only for urinary tract infections (p=o.o ). the supplemented group had a significantly shorter los from onset of infectious complication until discharge for patients with pneumonia ( vs. days) and skin/soft tissue infection ( vs. days). conclusions. administration of the supplemented formula was safe and well tolerated. when fed > days, it reduced the incidence of most infectious complications, and significantly reduced los. materials and methods: twenty-seven patients were randomised into groups ( n= each) to receive either a standard enteral formula, the same formula enriched with arginine, rna and omega fatty acids (enriched group) or isonitrogen, isocaloric parenteral nutrition. early enteral nutrition was started within hours following surgery ( ml/hour). it was progressively increased reaching a full regimen on day . on hospital admission and on post-operative day and , the following parameters were assessed: serum level of transferrin , albumin , prealbumin, retiool binding protein (rbp), cholinesterase. delayed hypersensitivity response, igg, igm, iga, lymphocyte subsets and monocyte phagocytosis ability were evaluated on admission and on post-operative day , , . the three groups were comparable for sex, age, cancer stage, type and duration of surgery, intra-operative blood loss and amount of blood transfused . in all groups a significant drop in all the nutritional and immunological parameters was observed on postoperative day . comparing post-operative day versus day a significant increase of prealbumin (p< . ) and rbp (p< . ) was found only in the enriched group. with respect to immunological variables an increased phagocytosis ability (p< . ) and a significant recovery in delayed hypersensitivity response (p< . ) was observed only in the enriched group. conclusions : these data are suggestive for a more effective post-operative recovery of both. nutritional and immunological status in cancer patients fed with enriched enteral formula. gastrointestinal intolerance was equivalent ( % in each group) and laboratory screening confirmed that both diets were safe. when analyzing clinical outcome for all patients, there were no significant differences in septic complications (immun-aid = % vs vivonex ten = %), mean mof score (immun-aid = l.b vs vivonex ten = . ), or mortality (immun-aid % vs vivonex ten = %) . kowever, when analyzing the subgroup of patients with severe injury (iss or ati _> ), patients receiving immun-aid appeared to have fewer septic complications ( % vs %) and their mean mof was significantly lower ( . _+ . vs . + . , p = . , student's t-test) . these preliminary data indicate that immun-aid is tolerated well when aggressively delivered immediately postinjury. the ultimate affect on clinical outcome appears ~avorable for immun-aid, but needs to be confirmed in larger patient groups. kemp?n, m., neumann, h.a., he i[michh b: as both increased, normal and reduced phagocytic capabilities of polymorphonuclear leukocytes (pmn) and monocytes in acute batterial infections have been reported, the role of phagocytes in patients with severe sepsis is less clear.we examined pmn and monocytes from patients in septic shock and heailhy votunteers for phagocytic function. phagocytosis was determined by flow cytometry (facscan) and was measured by the ability of pmn and monocytes to phagocytose e.coli marked with fluorescent antibodies. a septic shock was defined by the presence of a ~ource of i, nfoctiqn with a known bacteriology, distinct signs of a systemic response and defined minimum scores in icu scoring systems indicating the presence of a multiple organ failure. additionally we examined how phagocytosis is influenced when a new enteral diet formulation containing substrates suggested to improve immune function or arginine, one of its major compononts, is added in vitro in defined concentrations and incubated for minutes. pmn (p{o, ) and monocytes (p<o, ) of the septic patients showed a significantly enhanced phagocytosis compared tolhe phagocytes of the healthy group. the incubation with the enteral diet in vitro was followed by a higher dose-related rate of phagocytosis, especially in the healthy group, that was not statistically significant. after addition of l-argintne we atso observed an iqcrease in phagocytosis, that was lower than in the group with the complete diet. using a modern immunefluorescence-cytometric essay we founfl an improved phagocytic function in septic shosk. there are signs for an influence of nutrient substrates on phagocytosis which seems to be complex and should be further investigated. arg and gln were lower in the %-bcaa vs %-bcaa group; arg was related directly to arg dose and inversely to bcaa dose (p<o.o for all). clearances of bcaa increased with increasing bcaa dose (p<o.o ); arg and gln clearances were directly related to the bcaa clearances (rz=o. , p<o.o i). relationships between arg, gln and other aa seem to be ruled by patterns involving specific intracellular aa transport systems. regulation of arg and gln clearances through bcaa administration may be related to an increased flux of aa into synthetic processes. intestinal segments from rats immunized by infection with the nematode trichinella spiruus undergo intestinal anaphylaxis or type i hypersensitivity when challenged in vitro with parasite antigen. immunized rats exposed to t-radiation ( gy) and sustained on rat chow,fail to fully express type i hypersensitivity up to days post irradiation (dpi). we hypothesized that enteral nutritional support immediately following irradiation may be effective in preserving mucosal immune responsiveness or in reducing the recovery time after radiation-induced injury. rats were infected with x t.spiralis larvae. thirty to fifty days later rats received gy t-radiation from a co source as total abdominal irradiation (tai). immediately following tai, rats were fed an elemental amino acid diet (eaad) and at various dpi sacrificed and tested in ussing chambers for local anaphylaxis, expressed as antigen-induced ci secretion. the normal ci secretory response to antigenic challenge which is suppressed after irradiation,was restored by dpi when rats were placed on the eaad. antigen-induced c[ secretion is dependent on the interaction o~ antigen with specific ige antibodies on the surface o mucosal mast cells and their subsequent degranulation. mast cell-derived -ht,histamine and pg, together effect ci secretion.in irradiated rats on rat chow,the failure to respond to antigenic challenge appears to be associated with the destruction of mast cells. they are undetectable with standard staining procedures and mucosal histamine levels are drastically reduced. also,el secretion can be induced by direct stimulation of epithelium with cr secrctagogues and circulating ige levels are normal. despite a more rapid recovery of immune responsiveness in irradiated rats receiving eaad,mast cells were not restored. we conclude that the eaad contributes to an adaptation that supports the expression of local anaphylaxis in the absence of mast cells. total parenteral nutrition (pn) and bowel rest may influence the host response to infection. this study examined the different host response to infection in parenterally and enterally fed animals. forty-three rats were divided into pn group and total enteral nutrition (en) group. they received identically constituted isocaloric isonitxogenous diets for seven days. animals were then challenged intraperitoneauy with xl(y escherichia coli and survival were observed. in other experiments, they were sacrificed before and two hours after bacterial challenge. peritoneal cavity was lavaged with ml saline and peritoneal exudative cells (pec) were harvested and cultured in vitro for hours with and without lipopolysaccharide (lps). colony f(m, ning units of bacteria (cfu-b) in the peritoncal lavaged fluid (plf) were determined and tnf in the plf, serum and pec culture supernal,ants were measured by l bioassay. twenty-fonr hour survival rate in en group was significantly greater than that in pn group ( % vs %). the data suggest that local immune responses of pn-treated animals may be depressed with consequent disturbance in the clearance of bacteria. this may lead to a greater systemic cytokine response and resulting in a poor survival after bacterial challenge in pn group. the effects of intragastfic tube feeding of diets enriched with m- polyunsaturated fatty acids (pufa) from safflower oil (so) or (o- pufa from menhaden oil (mo) on eicosanoid production, and onthe membrane phospholipid fatty acid composition were investigated in a severe acute septic shock model. the percent calories from fat maintained at % in the diets was adjusted to provide % each of saturated, monounsaturated, and pufa using olive oil and palm oil as filler fats. after feeding for days, lipopolysaccharide (lps, mg/ g) was injected through the tail vein. the percent of animals surviving in the mo group was % ( / ), and did not differ significantly compared to % ( / ) in the so group. the plasma concentrations of tnf ct for the groups of animals fed so ( . + . ng/ml) and those fed mo ( . + . ) did not differ significantly. the levels of prostaglandin(pg)e , -keto-pgflc~ and tumor necrosis factor-ct (tnf-c were determined min after lps injection. the fatty composition (relative mole%) of the liver was determined before (lps-) and h after the lps administration (lps+). the data (mean_+sd; n= ) are as follows. group these data indicate that a marked reduction in the plasma levels of poe and -keto-pgflct for rats fed mo diet was associated with a reduction in aa which was displaced by epa in the membrane phospholipids. further, in these rats, we observed that there was a . % reduction in the percent of epa following lps challenge compared to the basal levels. however, for the group of rats maintained on so diet, the liver membrane phospholipid fatty acid composition before and after lps administration was unaltered. these finding suggest that although a reduction in aa was associated with a decrease in the production of pro inflammatory eicosanoids after days of continuous mo feeding, there was no marked effect on the survival following lps challenge. animal models have been used to examine the effects of various nutrients and nutrient combinations upon the immune system. we studied the effects of standard and specialized enteral formulations on the response of mice to infectious challenge with listeria monocytogenes, influenza a or candida albicans in order to test the efficacy of specialized ingredients. cf- outhred female mice ( - g) were fed purina # chow, commercially available osmolite hn ®, perative ® or impact*. mortality and tissue burden of pathogen were examined during the d period following induced infection. the results indicate that there were no differences between the groups fed the liquid formulas with regards to mean survival time or % survivors in these models of infection. examination of spleens in the groups challenged with l. monocytogenes and kidneys in the groups challenged with c. albicans revealed no differences in tissue burden of pathogenic organisms. alterations in the length of pre-feeding from to days prior to infection did not affect these results. these data demonstrate that, contrary to previous reports, the use of specialized nutrients did not improve resistance to disease in mice challenged with l. monocytogenese, influenza a or c. albicans as compared with mice fed osmolite hn. animals fed standard chow tended to be more resistant to infectious disease than those fed the liquid formulas perhaps due to the form of diet or complexity of ingredients. the results indicate that these animal models of infectious challenge may be of limited use to distinguish effects of modified nutrient composition of enteral formulas. laboratories the beneficial effects of sesame oil (ses) have been attributed to the presence ofsesamin, a non-fat constituent which is claimed to iultibit a- desaturase activity. we investigated the effects of ad libidum feeding of ses enriched diet on fatty acid composition of phospholipids from plasma, liver, on eicosanoid production, and on the protective effects in mice after cecal ligation and puncture (clp) and compared with safflower oil (so) diets. olive and palm otis were added as filler fats to the so diet to maintain the ratios of saturated, and unsaturated fatty acids similar to ses diet. thus, while the total fat remained at wt%, the only difference between the two diets is the presence ofsesamin in ses diet. the animals were fed for weeks. the incorporation of dihomo-y-linolealc acid (dgla: : o)- ) in the phospholipids from plasma and from the liver for the group of mice fed so diet ranged between - % compared to the undetectable levels for those fed so diet. there were no significant differences in the incorporation of other fatty acids either in plasma or in the cell membranes between the two groups. following an intraperitoneal administration oflps ( p.g/kg body wt), the plasma levels of both pge , and txb , were significantly decreased (p< . ) by nearly % for the group of animals maintained on ses diet compared to those maintained on so diet. these findings suggest that sesamin inhibited the release of arachidonic acid (aa) which upon accumulation is retroconverted to dgla which could reflect a modest increase in the content of dgla. failure to decrease the formation of aa could mean that the effects of sesamin on chain elongation process may be after aa is formed, and that sesamin may not inhibit a- desaturase activity. on the other hand, our data suggest that sesamin present in sesame oil inhibited the activity of cyclooxygenase which converts aa to its metabolites), or alternatively could block the activity of phosphalipase a (pla ) (which releases aa from membrane phospholipids) as is evident from a marked decrease in eicosanoid production. the percentage of animals surviving after cecal ligation and puncture in rite group of mice fed ses diet was % ( / ) which was markedly higher (p< . ) compared to only % ( / ) for the so group. increase in survival in the group of mice fed ses diet was associated with nearly % reduction in the production of tnf in response to lps i.p. challenge, for ses group compared to so fed animals. our data suggest that sesamin, present in sesame oil, decreased the production tnf~, inhibited the activity ofpla and consequently offered a significant protection against clp. thus sesamin or sesame oil appear to be novel antiinflammatory agents which are present naturally in many edible products. [dept. surgery, ~e. deasoness hosp.,harvard medical school, boston, usa] stress causes alterations in the homeostasis of an organism with major changes in various organs, lifespans of cells, protein turnovers, metabolic pathways of activation or stimulation, energy mobilization, etc. punctual changes have been described in several organs and various cell types of the nervous, endocrine and immune systems. many stored or newly synthesized proteins are released to the bloodstream to be transported to target organs or to be disposed of. as stress alters protein synthesis and requirements in the targets, the bloodstream is a useful system for monitoring the relevant changes. we present here the pattern of newly synthesized or released serum proteins in c bl/ mice that have been stressed by immobilization. the proteins have been labelled with ssmethionine in vivo and the study was performed by two dimensional gel electrophoresis based on the method originally described by o'farrel. the electrophoretic run was carried out in an isodalt apparatus. a molecular dynamics laser scanner and the kepler image analysis system (lsb, rockville, usa) were used for modelling the radiofluorographic images. the radiofluorographic images of the gels from serum samples obtained from mice injected with i mci of ss-methionine reveal about protein spots, from which a small fraction -about are altered in both qualitative and quantitative manner. the major changes are in the range of to . d. the analysis displays a highly reproducible pattern, where clear differences between stressed and non-stressed conditions are shown. differences between patterns attributed to chronic vs. acute stress will be presented. patients with severe trauma or major surgery are known to acquire alterations in neutrophil functions which contribute to their enhanced susceptibility towards microbial infections. we analyzed neutrophil functions from fourty patients admitted for major surgery days and days preoperatively and on the ist and th postoperative days (study-days i, , , and ) in a randomized placebo-controlled double-blind study. patients were divided into two groups, one ~eceived days preoperatively an enteral nutrition enriched with omega- fatty acids, arginiee, and rna (impact), the other an isocaloric, not enriched control nutrition (placebo). meutrophils were isolated from the peripheral blood and stimulated with the ca-ionophor a ( . pm). the capacity of the respective neutrophils to generate leukotrienes was analyzed by rp-hplc. neutrophils from impact group generated significantly higher amounts of ltb (mean values . ng/l x i~ cells) compared to the placebo group ( . ng) at study-day [p, . ). in contrast, the capacity of neutrophils to produce ltb was not significantly different in both patients populations at study-days and . the omega-oxidation of ltb to its biologically less active metabolites oh-ltb and cooh-ltb was not significantly different in both groups. however, neutrophils from group f patients generate more ltc at study-day (p( / ). the capacity of the patients'neutrophils to generate reactive oxygen radicals upon stimulation with fmlp, pma or the caionopbore a exhibited patient dependent differences but no correlations to the repective nutritional supplementation as was measured by luminol dependent ohemiluminescense= these data indicate that an enteral nutrition enriched in omega- fatty acids lead to alterations in distinct parameters of neutrophil functions. clinical patient characteristics and mean caloric intake were similar between the two groups. both formula were tolerated well and the incidence of diarrhea was low. the number of infectious and wound complications as well as the apache ii score was evaluated for the two study groups. although the number of complications in the group supplemented with arginine, rna and omega- fatty acids was lower no significant difference in the occurance of infectious and wound complications has been observed between the two groups. however, the apache ii score indicated a significantly improved clinical outcome in patients with supplemented diet. in conclusion, early enteral nutrition with an arginine, omega- fatty acids and rna supplemented diet helps to recover more rapidly after surgical total parenteral nutrition (tpn} is associated with intestinal atrophy and dysfunction attributed to the absence of the non-essential amino acid glutamine in current parenteral nutrition solutions. in this animal study with male wistar-rats we tested the hypothesis that glutamine-dipeptide supplementation during tpn for days would restore small bowel atrophy and tpn induced dysfunction. a conventional tpn solution ( kcai/kg bw) was compared to an isocaloric and isonitrogenous tpn ( , g n/animal/d) supplemented with alanin-glutamin (ala-gin) dipeptide ( , g n derived from ala-gin = % gin-n). an enteral fed cqntrol group was included. mucosal thickness, villous height and architecture, absorption of water and glucose as well as dissacharidase activity of maltase and alkaline phosphatase were evaluated. total parenteral nutrition in rats causes villous atrophy, a significantly reduced absorption rate and a decreased activity of villous enzymes compared to an enteral fed control (p<o, ). addition of ala-gin to parenteral nutrition solutions prevents intestinal atrophy and restores functional alterations with a significantly increased rate of water and glucose absorption as well as a higher dissacharidase activity compared to the standard tpn group (p< , ). there was no significant difference found between the enteral fed control and the dipeptide supplemented animals concerning intestinal structure and absorption, the enzyme activity was significantly decreased in the ala-gin supplemented group compared to the enteral fed control (p< , ). in this rat model supplementation of parentera] nutrition solutions with ala-gin dipeptide restores tpn induced intestinal atrophy and dysfunction. boston. ~ usa injury, infection and major o ~'ations s~nulate a variety of factors whi~ initiate the body's response to th~ st~..sses. 'i"hese reactions are m~liated by a cbmage ia the neta'al hormonal, eac.ranmemt, by the elaboration of eytokines and tl~ougb the stimu/ation of other inflammatory mediators. this eatabolio setting zesulis in body protein loss, which g-taduai y erodes both fimetianal and stm~ tissue. wiu _b the normally nom'ished individual can withslzod "d~ response for a brief period of time, ircolonged eatabollsm l~ associated with ~,nmunosuppmssion, poor wound healing, and proioagcd convalescence. surgeons have rej ed on intraveaous or eater~ feedings to ~everse this process. a va~ety of data now indicates that it is extremely di~edt to replete protein-containing tissue d~g the eataholie state of illness; the umutt response to hypercaloise feedings in this setting is the incxeased accretion of body fat md water. administration of gxow~ ho~moae ~cesults i.a n shift of the body's oxidative machinery to fat rather than eazbohydmte utiq~afic~; ¢oncomitaatiy, protein synthesis is stimulated. this metabolic state may have clinical utility in p~e.n.ts who need to heal large wotmds, in those who need to gain strength in order to be w~ed ore veatilatory support, or those patients who ~ve mulfiorgan failure and nee~ to ealaaace protein syatsesis to in.suze recovery. als are now in progress to dcterm~e the benefit of growth hormone in these and other disease state.s, rn the fature, the increased use of growth hormone, will occur;, this and other growth factors will serve to su~ po~ the host and shorten convalesceace following catabolic diseases. our objective was to study effects of pre-trauma growth hormone (gh) treatment on liver and skeletal muscle metabolism in a trauma model in piglets. twenty-four piglets were randomized to three treatment groups; one group was pretreated with gh iu daily three days before the experiment (gh- ), another group treated with gh ie at the start of the surgical procedure (gh- ) and one group served as untreated controls (con). they underwent a standardized surgical procedure to place sampling cathethers in the portal, hepatic and femoral veins and doppler flow probes around the portal vein, the hepatic and the femoral arteries. all pigs recieved a primed constant infusion of u- c-glutamine. substrate fluxes were measured one (lh) and five ( b) hours after termination of the surgery. nitrogen excretion was significantly decreased in the gh treated animals (gh- : . + . mg/kg, gh-i: . +_. . mg/kg, con: . +- . mg/kg, p= . ). in the hindieg, there was reduced net glutamine efflux due to decreased absolute glutamine release (gh- : . + . gmol/min at lh and - . + . in.tool/rain at h, gh-i: - . + . i.tmol/min at lh and - . + . pmol/min at h, con: - . +_ . g mol/min at lh and - . + . /amol/min at h, p= . , p= . ), whereas the absolute uptake of glutamine in hindleg was unchanged (p= . ). glucose uptake in the hindleg was decreased (p= . ). net glutamine uptake in liver was attenuated (p= . at h), whereas net glutamate release from liver was increased (p= . ). thus, pre-trauma treatment with gh improved nitrogen economy, attenuated net glutamine loss from hindieg due to decreased absolute release, and attenuated hindleg glucose uptake. liver net glutanaine uptake was decerased and net glutamate release increased. patients with major abdominal surgery exhibit a considerable catabolic response with negative nitrogen balance and protein breakdown, which may have detrimental effects on outcome. we investigated the effects recombinant human growth hormone on substrate metabolism in parenterally fed patients. metabolic healthy patients were randomized to receive either placebo or hgh in a dosage of , ; , or , i.u. per kg bw. substrate oxidation rate, energy expenditure as well as short life proteins were measured daily. six patients were excluded from analysis as drop outs, due to surgical complications. we could find a dose-dependend effect of growth hormone on resting energy expenditure, carbohydrate oxidation, fat and proteine oxidation. with increasing growth hormone resting energy expenditure increased from . calories per kg body weight to . calories. this was mainly due to an increased carbohydrate and fat oxidation, while proteine oxidation decreased. this was in accordance with a decreased urea.production rate and an improvement in cumulative nitrogene balance, which increased from minus . to plus . g n / days. in consequence short life proteins were also increased. the only negative side effect was an increased blood glucose concentration in some of the patients, making insuline administration mandatory in patients. our results are in accordance with other studies showing improvement of nitrogen balance, maintainance of lean body mass and muscular strength. if growth hormone administration may have any impact on morbidity, mortality and length of hospital stay in these patients it should be evaluated in a larger number of patients. in patient after liver transplantation (oltx) the effect of recombinant human growth hormone (rhgh) on protein metabolism and hormonal changes was studied. patients and methods: the underlying disease in all patients was end stage liver cirrhosis, non of the patients included in the study was suffering from malignancies. the patients were randomly allocated to receive either u of rhgh bid (sc) or no alternative medication. the study period lasted days. from daily hrs udne collection urinary nitrogen loss and daily loss of urea were determined. body compostion analysis (bca, bioimpedance, akern-ltaly) was performed preoperativly and at the postoperative days and to evaluate changes in body water and body cell mass (bcm). the effect on resting energy expenditure (ree) was analysed using indirekt calorimetry wrhin the same intervalls (metabolic monitor, datex). blood levels of gh, igf and igf , igfbp were measured daily during the study period, on day a hour profile of gh was.performed. samples were collected each minutes. results: cumulative udnary nitrogen and urea loss were not signifcantly different for the whole study period but for the first study days. bia indicated for the rhgh-group a loss of bcm to a lesser extent than for the controls (n.s.), changes in bodywater where similar for both groups. ree changes (kcal/kg bcm) were not significantly different for the two groups. blood levels of gh and igf differed significantly between the groups for the whole study period, but not igf and igfbp- . the circadian rhythm of endogenous gh-excretion had not been altered by gh, but absolute levels of gh were increased. conclusion: during the first days after oltx we could proof the protein sparing effect of gh treatment. although the differences between the two groups were not significantly different for the whole study period the results showed on all days a less catabolic situation for the rhgh treated patients. to possibly improve protein balance after major abdominal surgery we studied the effects of gh on protein metabolism after ltx. excluding malignant diseases, candidates for ltx were randomized to either postoperatively receive the usual treatment (co=control group, n= , age range - yr, bmi . + . kg/m ) or for days additional gh ( x i.u.s.c.) (gh group, n= , - yr, . + . kg/m ). metabolic studies (calorimetry and lsc-leucine infusion) were performed (test a) and days (test b) after surgery. tracer analysis was done by gas chromatography-mass spectrometry. during the -week study clinical parameters did not differ significantly between groups; however, there was a tendency for increased glucose levels, insulin need, and energy expenditure at the time of test b in the gh group. leucine oxidation (x+se) during test a;b was + ; + (co) and + ; ± (gh) pmol/kg ffm/h (n.s.). protein breakdown was ± ; + (co) and + ; + (gh) pmol/kg ffm/h (n.s.). nonoxidative-leuine disposal was ± ; + (co) and ± ; + (gh) pmol/kg ffm/h (p< . for the rise in the gh group). tracer data were supported by cumulative urea nitrogen excretion (days - : gh + vs co ± g; p< . ). we conclude that after major abdominal surgery gh lowers nitrogen excretion by increasing total body protein synthesis. it is not known which organs contribute to this effect. in several investigations it has been shown that the protein saving effect of recombinant human growth hormone (rhgh) in the postoperative state is accompanied by raised igf- levels in plasma. it was concluded that the anabolic effects of rhgh were probably, at least in part, mediated by igf- . this study was aimed at detecting the efficacy of igf-i on modulation of the protein metabolism in the catabolic state. patients and methodes: patients (both sexes, age: - years, bmi - kg/m ) with major upper gastrointestinal surgery (gastrectomy or partial gastrectomy) received ug rhlgf- /kg body weight/twice daily or placebo during treatment days beginning on the first postoperative day in a double-blind, randomized study. all patients received hypocaloric and hyponitrogenous total parenteral nutrition ( g chng, o. g aa/kg) troughout the whole study period. cumulated nitrogen balance, -methyl-histidin exretion in urine as well as serum-igf- levels have been determined. the two tailed wilcoxon test was used for statistical analysis results: first results will be presented previous studies have suggested that growth hormone (gh) potentiates various activities of leukecytes. however, it is not clear whether gh can improve survival of animals with gram-negative sepsis. we investigated the effects of gh on host response to infection in septic mice model. methods balb]c mice were randomized to groups (n= /gronp): gh-high ( + mg/kg/day), gh-iow ( a mg/kg/day) or control (saline). following subcutaneous treatment (every hours for days) with gh or saline, mice were challenged i.p. with e.coli (lxl /body). survival rate was recorded every hours. in the next experiment, gh-high and control animals were sacrificed hours after bacterial challenge. peritoneal cavity was lavaged with ml saline and the peritoneal exudative cells (pec) were harvested and counted. colony forming units (cfu) of bacteria in the peritoneal lavaged fluid (plf), liver, lung and blood were determined. pec were cultured in vitro for hours with lipopolymccharide ( p.g/ml in normotensive adults growth hormone (gh) rises when clonidine challenge is performed. recently evidence was shown for gh to accelerate wound healing. while gh secretion patterns are inconstant the gh-dependant insulin like growth factor (igf- ) and the insulin like growth factor binding protein (igfbp- ) reflect the integrated gh secretion over days. since we administer clonidine to patients with acute alcohol abuse we determined plasma levels of igf- and igfbp- . materials and methods: patients sheduled for esophagus resection were investigated once they had given written informed consent. patients showed acute alcohol abuse and were treated with clonidine postoperatively• patients with no history of acute alcohol abuse served as controls. besides liver enzymes igf- and igfbp- were determined. results: both groups had a comparable hepatic capacity of synthesis with decreased cholinesterase levels as to be expected after a major operation. regression analysis of igf- and igfbp- levels showed no differences between the groups. discussion: igf- and igfbp- plasma levels are not increased in normotensive patients who are treated with clonidine for prevention of postoperative alcohol withdrawl syndrom. further studies are required to discriminate whether our results are due to impaired postoperative liver function or if clonidine has not any impact on the gh-igf-axis in patients with alcohol abuse. recent studies have revealed that igf-i has several immanoregulatory roles. however, little is known about its effects on septic animals. we tested whether igf-i could increase the survival o f mice challenged intraperitoneally (i.p.) with e. coli. m~thqd$ balb/c mice received either high dose igf-i (n= , mg/kg/day), low dose igf-i (n= , . mg/kg/day) or saline ( = ) every eight hours subcutaneously for six days. animals were then challenged i.p. with lx e. coli. survival was observed every two hours. in the other experiment, mice that received high dose igf-i or saline were sacrificed four hours after bacterial challenge. peritoneal cavity was lavaged with ml saline and the peritoneal exudative ceils (pec) were harvested and counted. colony forming units (cfu) of bacteria in the peritoneal lavaged fluid (plf), liver, lung and blood were determined. in addition, pec were cultured/n vitro for hours with lipopolysaccharide ( ).tg/ml). tumor necrosis factor (tnf) in the supernatants of pec culture, plf and serum were measured by l bioassay. results igf-i improved the survival rate at a dose of mg/kg/day. severe chronic neutropenia (scn) is a disorder characterized by severe neutropenia secondary to either a maturational arrest of myelopoiesis at the level of promyelocytes (kostmann-syndrome; scn) or regular cyclic fluctuations in the number of blood neutrophils with a median absolute neutrophil count (anc) of less than /~tl (cyclic neutropenia). patients suffering from scn have an impaired acute inflammatory response to injury and an increased susceptibility to infections, i.e. bacterial or fungal infections, resulting in chronic oral inflammation, severe pneumonia, abscess formation and bacteraemia. we have treated patients ( scn, cyclic neutropenia) with r-methug-csf (filgrastim). thirty of patients with scn and all cyclic neutropenia patients responded to this treatment with an increase of the median anc to greater than /~tl. the dose of r-methug-csf needed to achieve and maintain the response varied between . and ~tg/kg/d. long-term treatment did not exhaust myelopoiesis: the anc remained stable after up to years of treatment and antibodies to r-methug-csf were not detected. the increase of anc was associated with dramatic clinical responses: significant reduction of severe bacterial infections, reduction of intravenous antibiotic treatment, and reduction of hospitalizations. no severe bacterial infections occurred in any of the r-rnethug-csf responders during longterm treatment. severe adverse events, most likely due to the underlying disease, included the development of mds/leukemia in two patients, and osteopenia/osteoporosis in patients. these results demonstrate the beneficial effects of r-methug-csf treatment in severe chronic neutropenia patients. the newborn is predisposed to mortality during infections due in large part to developmentally immature host defenses. recently cytokines have been identified that regulate the development of these defenses. one such cytokine is specific for neutrophils and is termed granulocyte colony stimulating factor (g-csf). in the studies to be discussed, we have attempted to impact hematopoiesis in the fetus using exogenous rhg-csf delivered through the pregnant dam. our rationale was that an enhanced myeloid system may result from such in utero treatment leading to, perhaps, enhanced protection to microbial insult. rhg-csf crossed the placenta and reached peak fetal serum concentrations hours after administration. these levels were -fold lower than the levels detected in the adult dams serum. white blood cell counts were elevated approximately - -fold over control newborn blood. this increase was due to circulating numbers of neutrophils. the marrows from these pups were hyperplastic consisting of predominately immature and mature neutrophilic cells. no changes were seen in the thymus or livers. pups born to mothers treated with rhg-csf since day of gestation (parturition in rodents occurs on approximately day ) survived a lethal challenge of group b- hemolytic streptococcus. in contrast their untreated yet infected counterparts did not survive. recent clinical developments have led to trials of rhg-csf in certain neutropenic states including cyclic and chronic neutropenia. we have identified several of these patients who were pregnant during treatment with rhg-csf. biologically and anfigenically identifiable rhg-csf was detected at increased levels in the cord serum of these neonates. we will discuss our findings with these patients in light of our animal model of neonatal myeloid development. we have previously demonstrated decreased g-csf production and g-csf mrna expression from activated mononuclear cells from newboms compared to adults (cairo, pediatr res : , ) . we have also recently observed that administration of a single dose of rhg-cse to one-day-old newborn rats induced significant neatrophilia, while administration for days induced neulrophilia and increased the bone marrow (bm) neutrophil storage and progenitor pools (cairo, blood : , cairo, pediatr res : , ) . we embarked on a phase i trial exploring the safety, pharmacokinetics, and biological efficacy of g-csf in newborns with presumed sepsis. infants < hrs old with a diagnosis of presumed sepsis were stratified into three groups: very preterm ( - wk), preterm ( - wk), and term (> wk) and randomized to receive either a placebo or , , and gg/kg/qd or and p.g/kg/bid of rhg-csf infused by pump over hour for consecutive days. cbcs were obtained at , , , , and hrs. tibial bone marrow aspirations were performed hrs after study entry and differential counts and cfu-gm pools were determined. c bi expression was determined at and hrs after rhg-csf, and g-csf pharmacokinetics were performed after the first dose of rhg-csf utilizing a sandwich elisa. a significant increase in the anc was observed at , and hrs following administration of both and ~tg/kg/d of rhg-csf. the maximum increase in the anc occurred hrs after and ~tg/kg/d ( - %) (p< . ) and ( % -+ %) (p< . ), respectively. there was a significant dose-dapendeat increase in the bm neutrophil storage pool ( _+ % vs. + %) (p< . ) (placebo vs. ~tg/kg/d). there was no significant difference in the nantrophil proliferative pool. an increase in cfu-gm and cfu-gemm was seen at all doses tested, compared to placebo ( . _+ . vs. -+ ) (colonies/l(p cells/plate). c bi expression was significantly increased hrs after bg/kg/d of rhg-csf ( + % vs. +- %) (p< . ). peak serum g-csf levels occurred at hrs and were dosedependent. the half-life of rhg-cse was . + . hrs. most importantly, there was no observed toxicity from g-csf in all patients studied. of patients were on ventilators prior to administration of rhg-csf and there was no increase in pulmonary toxicity. these preliminary data suggest that rhg-csf is well tolerated at all gestational ages in newborns with presumed sepsis. a multi-center phase ii/iii randomized double-blindad placebo controlled trial is required to determine the efficacy of rhg-csf in this clinical setting. we investigated the effects of recombinant canine granulocyte-colony stimulating factor (g-csf) on survival, cardiopulmonary function, serum endotoxin levels and tumor necrosis factor (tnf) levels in a canine model of lethal bacterial septic shock (clinical research. : , ) . methods: awake ylo beagles had serial cardiopulmonary and laboratory studies before and for up to days after intraperitoneal placement of an e. celi infected clot. nine days before and daily until days after clot placement, animals received high (n= ) or low dose (n= ) g-csf or protein control (n= ) subcutaneously. results: survival in high dose g-csf animals ( / ) was significantly improved compared to low dose ( ) and controls ( ) (p< . wilcoxon). high dose g-csf also improved cardiovascular function evidenced by a higher mean left ventricular ejection fraction (day after clot, p< . ) and mean arterial pressure (day , p< , ) compared to low dose and controls. high dose rcg-csf increased (p< . ) peripheral neutrophil numbers both before and after clot implantation ( hours to days) compared to low dose and controls. in addition, high dose rcg-csf produced a more rapid (p< . ) rise (day ) and fall (day ) in alveolar neutrophils determined by bronchoalveolar lavage compared to low dose and controls. lastly, high dose rcg-csf decreased serum endotoxin ( to h, p< . ) and tumor necrosis factor (tnf, h, p< . ) levels compared to low dose and controls. discussion: these data suggest that therapy with g-csf sufficient to increase peripheral neutrophil numbers during peritonitis and septic shock may augment host defense and endotoxin clearance, reduce cytokine levels (tnf) and improve cardiovascular function and survival. the use of g-csf in sepsis prophylaxis in neutropenic patients is well established and has been ascribed to accelerated recovery in granulccyte counts. here, an additional sepsis-prophylactic property could be demonstrated in healthy volunteers: eleven volunteers were employed in a sinqle-btind, controlled study and were given uq g-csf or saline placebo via subcutaneous injection. blood was withdrawn immediately before and or hours later. lps-inducible tnf, il- , stnf-r p and il-lra were assessed in the supernatant of whole blood incubations stimulated with ug/ml lps from salmonella abortus equi. similarly to previous animal studies, lps-inducible tnf was attenuated by about % hrs. after treatment. the same was true of il-lb. in contrast, lps-inducible stnf-r p which was indetectable in blood incubations from untreated donors increased dramatically hrs. after g-csf treatment. il-lra found after lps challenge was increased tenfold by g-csf treatment. it is concluded that g-csf treatment switches peripheral leukocytes to an antiinflammatery state characterized by an attenuation of il-i and tnf releasing capacity and an augmentation of the release of cytokine antagonists. this findinq minht offer a novel concept in septic shock prophylaxis. objective.the aim of the study was to investigate the effect of recombinant human g-csf (rhg-csf) on survival, bone marrow neutrophil myelopoiesis, neutrophil counts, levels of bacteria and some important sepsis mediators in a model of rat abdominal sepsis. lethal peritonitis was induced with a mm coecal perforation (cp) in male wistar rats. rhg-csf was administered as /.tg/kg iv every h, first dose at sepsis induction. bone marrow neutrophi] progenitors were determined as blast colonies, cfu-gm and cfu-g. neutrophils and bacteria were determined in peripheral blood and peritoneal fluid. lps, tnf, endothelin and lactate were measured in blood from femoral vein. mortality rates were registered with g-csf treatment starting either or days before or hours after cp. results. mortality was reduced from % to about % with rhg-csf intervention and there was no difference between the pretreatment and treatment groups. bone marrow blast colonies were not influenced while neutrophil myelopoiesis was augmented at the stages of cfu-gm and cfu-g. neutrophils in blood and peritoneal cavity were enhanced and numbers of bacteria in the same compartments were substantially reduced. circulating lps, tnf, endothelin and lactate were attenuated the first hours after cp. neutrophil myelopoiesis is augmented with increased number of neutrophils in blood and peritoneal cavity, resulting in enhanced clearance of pathogens. lps, tnf, endothelin and lactate are suppressed the first hours during sepsis course. a. wendel, j. barsig, g. tiegs gm-csf stimulates the proliferation and differentiation of granulocytic and monocytic progenitor cells. in addition the hemopoietic cytokine activates the inflammatory response in mature leukocytes. the priming effect of gm-csf towards lipopolysaccharide (lps)-induced cytokine production in vitro has been described, but little is known about proinflammatory gm-csf effects in vivo. we detected gm-csf in plasma of lps-challenged mice with kinetics similar to tnf, reaching peak levels h after lps administration. gm-csf pretreatment ( ~tg/kg i.v.) enhanced mortality in mice challenged by a sublethal dose of lps. plasma levels of tumor necrosis factor (tnf) and interleukin- (il- ) were significantly enhanced. a monoclonal antibody, which neutralizes gm-csf bioactivity, rendered mice less sensitive towards lethal lps-challenge. tnf-and il- -tevels were reduced in these mice compared to control animals without antibody treatment. in addition, severalfold potentiation of lps-induced cytokine release by gm-csf was observed in vitro in murine bone marrow cell cultures. these data demonstrate the proinflammatory capacity of gm-csf and suggest that the hemopoietic cytokine plays also a role as an endogenous modulator of lps toxicity. immune dysfunction, developing in the wake of multiple trauma, overwhelming infection and other forms of critical surgical illnes% is associated with increased infections, morbidity and mortality. the mechanisms responsible for alterations in immune regulation are incompletely understood but monocyte appear to play a central role. polymorphonuclear leukocytes (pmn) are known to play a central role in the inflammatory response of the host toward invading microrganisms. reports of defects in all the aspeots of pmn function have been accumulated in recent years. the possible role of gm-csf in modifing the state of immuno suppression detected in severe intraabdominal infected pt~. inspite of surgical appropriate procedures and in reducing the expected mortality is investigated. the safety of rh-gm-csf administration in sepsis is also evaluated. a double blind randomized study is proposed. this study include icu patients who do not exhibit signs of shock and/or ards, with clinical signs and symptoms of abdominal infection. immunodepressed patients-aids, chronic chemotherapy or chronic steroid administration do not partecipate to the study. patients will receive rgm-csf (l~g/kg/day) or placebo in hs. continuous infusion for days. safetyandefyieacy will be assessed till to day . the apache ii score is adopted for risk stratification of patients because it is reliable and validated, objective and composed of information that is indipendent of diagnostic criteria. patient's entry criteria is apache ii > (score corresponds to expected mortality rate of %).in this protocol the surgeons report the judgement of the efficacy of surgical procedure to remove or not the focus of infection. objectives: infections and subsequent septic responses remain the leading cause of death among surgical intensive care (sicu) patients despite tmprovetaunts in supportive care and brond-epectrum antibiotics. usually invading bacteria are efficiently cleared by neutrophil granulocytes. however, during sepsis various neatrophil dysfunctions have been demonstrated, leading to impaired host defense. granulocyte colony-stimulating factor (g-csf) induces a sustained increase in circulating neutrophils and enhances various noutrophil functions. it was the purpose of the present study, to evaluate the safety and efficacy of g-csf (filgrastim) in sicu patients at risk of sepsis. materiel a.d methods: the study was designed as an open-label phase-ll study of filgrastim. ten consecutive slcu patients, with a therapeutic interveotion score greater than , were included in the study. filgrastim was given by daily continuous intravenous infusion for days or discharge from the sicu. apache ll-score, multiple-organ-failure (mof) score, definitions of infections, sepsis, systemic inflammatory response syndrome (sirs), and acute respiratory failure were applied daily. a response to filgrastinl th_erapy was defined as an improvement in disease severity quantified by a decrease of > apache i score points on day after onset of treatment. results: none of the patients developed a sepsis or mof later on and no patient died during hospitalization. specific postoperative complications occured in one patient ~jth a leekage of the oesophagou-gastric anastomosis after oesophageus resection. at study entry the leucocytes amounted to . + . /~tl (mean + sem) and reached a level of . +_ . /tal at day after onset offilgrastim therapy. the apache ii score initally was + . (mean + sem) and as an indicator of filgrastim response a decrease of points ~dthin days oceured in out ot patients. filgrastim was well tolerated, side effects were not noted. growth of solid tumors might be modulated by the activity of inflammatory and/or immune effector cells of undefined specificity. in this study patients undergoing surgical treatment for gastric (n= ) or colorectal (n= ) cancers were evaluated for endogenous serum levels of granulocyte colony-stimulatingfactor (g-csf) during a pre-and postoperative time period. from the same blood specimens mononuelcar cells (mnc) were prepared. the release of ifn-%, and il- , which are secreted by thl cells, were stimulated in vitro by pha during a cell culture period up to hours. the patients were further classified for their immunreactivity by responses in dth skin testing to seven different antigens (e.g. tetanus toxoid, ppd, diphtheria toxin, trichophyton, streptococcus, candida and proteus antigens). dth testing has been repeated in each patient two remarkable results were obtained. the serum levels of endogenous g-cse showed a biphasic increase with maximum values of pg/ml (preoperative < pg/ml) on day and day to after surgical treatment. similar patterns of g-csf production were found in both groups of patients with gastric or colorectal cancers. high serum levels of g-csf were significantly (p < , ) correlated with infectious complications in patients whh gastric cancer (n= / ). secondly patients could be arranged into two groups according to an anergic (n= ) or normergi¢ (n = ) responsiveness in dth testing. the frequency of anergi¢ responsiveness was similar in both patients with gastric (n= / ) or colorectal (n= / ) cancers. interestingly we found a significant correlation (p < , ) between low serum levels of g-csf and anergy during the postoperative period in both groups. stimulation of mncs from anergic patients (n= ) within the pre-and postoperative period resulted in reduced mean values (about %) for ifn-ff release (preoperative means llo pg/nfl), if compared to patients with normergic dth (n= , preoperative means pg/ml). similar, but less significant results were obtained for il- secretion. our results confirm a correlation between infectious complications and g-csf in the postoperative period, however elevated levels were also found in some patients without any signs of infections. more interestingly there might be an association between cytokine (c~csf, ifn-% and il- ) release and dth, which is known to be mediated by activated thl calls. to recognize anergic dth as a possible higher risk in the postoperative outcome of cancer patients extended periods of observation are needed. objectives of the study effects of recombinant huraan granulocyte colony-stimulating factor(rhc-csf)a galnst severe septic infections were investigated by its single use or by its corn b{nation with cephera antibiotlcs.we examined its effects on the mortality,and circulating blood neutrophyis counts and functlons,such as phagocytic activity and h production using the rat severe septic model. rats were subcutaneously administsrd rhc~csf(s orl o ~ g/k~ body wt)after on set of peritonitis brought about by cecal ]igation and one puncture withe -gaug e needle once a day for three days.in addjtlon,cefmetazol na(cmz)( m$/k bo dy wt)was injected intrarnustularly to the rats tv~ce a day for three days. cirehlatlng blood neutrophyls counts were determoned electronically with a hem ocytometer,and blood smears stained with may~runwaldm.qlemsa~taln. neutrophyls functions in vltro,such as phagocytic activity and h producti on using the rat severe septic model was analyzvd by automated flow cytometri c single cell-analysis methods. the reortallty rate after weeks was significantly decreased by administratlon of rh~-csf(p< , ).ln addjtion,a combination therapy of rhg-csf wlte cephern ant~biotics(cmz)showed a significantly survive] advantage and the rate had b een reached . %. nextly,treatn%ent wlth rhg-csf(s ~ $/k body wt)increased the nuzaber of the peripheral blood neutrophjls slgn[fieantly(p< . ). iv~oreover,functions of neutrophlis which were phagocytic activity and h p roduction were remarkably enhanced by admlnlstratlon of rhg-cs~( ~ /ks b ody wt) (p< .( ). these findings suggest that combination therapy of rhcrcsf with cephern antib iotlcs(cmz)is an efficient regime against severe infectlons.and the increased ne utrophils counts and enhanced neutrophiis functions were played a important ro le about the survival advantage. granulocyte macrophage colony-stimulating factor (gm-csf) is a haematopoietic growth factor active on neutrophils and macrophages. leukopenia often occurs following renal transplantation and can be associated with infection and/or the myelosuppressive effect of azathioprine. aim: we report the use of gm-csf in renal allograft recipients with leukopenia. nonglycosylated recombinant gm-csf was obtained from e. coli transvected by human gm-csf gene. m~terial ~,nd methods : written informed consent was obtained from all patients. patients were suffering from toxic neutropenia (neutrophils < /mm ) with medullar hypocellularity on bone marrow aspiration, or leukopenia (neutrophils < /ram ) with cytomegalovirus infection requiring ganciclovir administtation. gm-csf was given subcutaneously at a dally dose of to mcg/kg/day, according to renal function. results : in all cases, neutrophil counts returned to normal levels within to days. in most of them, spectacular correction was observed within hours, with a single injection. adverse events due to gm-csf at this dose were mild and easily managed ( cases of bone pain treated with paracetamol). one acute rejection episode was observed after correction of leukopenia. conclusion : on the basis of this study, it appears that gm-csf at a dose below mcg/kg/day is an effective treatment for renal transplant recipients with leukopenia associated with cmv infection or toxic neutropenia. department of nephrology, , rue de s~vres, hopital necker, paris, france. changes in serum g-csf and il- after surgical intervention hitoshi toda , atsuo murata , hidewaki nakagawa , takesada mori , nariaki matsuura osaka university medical school, osaka, wakayama medical school, wakayama, japan we measured serum immunoreactive interleukin (il- ) and granulocyte colony-stimulating factor (g-csf) levels of the patients undergoing major thoraco-abdominal surgery for esophageal cancer. serum samples were collected from eight patients on the day before surgery, at the time of operation, and thereafter at suitable intervals for one week. il- and g-csf were measured by means of enzyme linked immunoassay. the normal range of serum ]l- was less than pg/ml and g-csf less than pg/ml. values between groups were compared with linear regression analysis. both serum g-csf and il- levels reached their maximal levels at the first postoperative day and decreased thereafter. the correlation between g-csf (y) and il- (x) was y= . x+ . (r= . , n= , p< . ), showing a significant correlation. in the case who suffered from aspiration pneumonia and ards at the second postoperative day, the peak level of il- was pg/ml and g-csf pg/ml respectively. the estimated value of g-csf was pg/mi by the regression equation. this means the real g-cse level was less than half of the estimated value. it suggests that low responsiveness of g-csf is one of the reason of immunodeficient state after the major surgery, neutrophils from injured patients ingest and kill bacteria less efficiently as compared to those of healthy individuals, probably reflecting the suppression in respiratoly burst which occurs after severe trauma. one of the main mechanisms of killing bacteria by neutrophil granulocytes is production of oxygen radicals (respiratory burst). granulocyte colony-stimulating factor (g-csf), a kilodalton cytokine, leads to a sustained, dose-dependent increase in circulating neutrophils. thus, it was investigated whether filgrastim (recombinant human granulocyte colony-stimulating factor, rhg-csf) therapy fits for prophylaxis of sepsis in postoperative/posttraumatic patients, and whether, besides an expected increase in neutrophil count, filgrastim would also augment neutrophil function. material and methods: this study was designed as an open label, prospective phase ii study of filgrastim and performed in a surgical intensive care unit (sicu) (university hospital). postoperative/post-traumatic patients with a therapeutic intervention scoring system (tiss) score greater than were treated with filgrastim ( . - l.tg/kg/day) for prophylaxis of sepsis on days or until discharge from the sicu. production of oxygen radicals can be quantified by analysis of fmlp-and zymosan-induced chemiluminescence. neutrophil oxygen radical production was tested by fmlp-and zymosan-induced chemiluminescence by the polymorphonuclear cells (pmn) of these patients in multiple blood samples over a period of up to days. results: none of the patients treated with filgrastim for prophylaxis of sepsis developed sepsis. in vitro fmlp-induced ( - reel/l) neutrophil oxygen radical production was significantly increased under therapy with filgrastim by a maximum of % +- % ( % - %) compared to pretreatment values of %. tapering of filgrastim resulted in a reduction of fmlp-induced neutrophil oxygen radical production within hours. in contrast, zymosan-induced neutrophil oxygen radical production was not affected by filgrastim treatment. conclusions: besides its quantitative effect on neutrophil counts enhanced neutrophil function, documented here as increased fmlp-induced oxygen radical production, may account for the beneficial effect of filgrastim for prophylaxis of sepsis in posttraumatic/post-operative patients. granulocyte colony stimulating factor (g-csf) and granulocytemacrophage colony stimulating factor (gm-csf) have been recently introduced in the treatment of chemotherapy-induced neutropenia. effects of these csfs on cellular immune system were evaluated in neutropenic gynecological cancer patients during chemotherapy. g-csf and gm-csf were equally able to induce a rapid recovery of white cell count within one or two days. g-csf treatment resulted in a significantly higher concentration of leukocytes measured in the peripheral blood although by gm-csf a sufficient effect was achieved (p< . ). before initiation of csf treatment urinary neopterin was similar in both groups of patients ( +/- and +/- lamol/mol creatinine for gm-csf and g-csf respectively expressed as mean +/-one sd). in g-csf treated patient only a marginal induction of neopterin was observed. on day the mean value was about % above the basal level (p< . ). on the other hand gm-csf treated patients were characterized by a pronounced increase in urinary neopterin levels. in comparison with the basal level a more than fold induction was noted and the difference between g-csf and gm-csf was highly significant (p< . ). this effect was confirmed in vitro by investigating the effects of these csfs on interferon-gamma mediated pathways in thp- human myelomonocytic cells. results suggest activation of immune effector cells by gm-csf which may help the organism to overcome infections. however, activated macrophages produce several growth factors which may increase malignant proliferation, and augmented neopterin production as sign of macrophage activation has also been associated with poor prognosis m several malignancies. more data are therefore necessary to clarify whether csf mediated immune activation is beneficial or deleterious for cancer patients but considering our results caution in applying csfs in oncology seems advised. from a historical perspective, the development of humoral immunity to bacterial endotoxin has assumed a prominent position in the spectrum of therapeutic approaches which have been explored for the treatment of gram negative septic shock. predicated upon the fact that rough strains of bacteria manifest lps containing exclusively conserved structural features common to lps from all gram negatives, specific antibodies were elicited which conveyed cross protective immunity in experimental models of bacteremia and endotoxemia. such studies culminated in a well-conducted, randomized, double-blind placebo-controlled clinical trial using passively administered human polyclonal antiserum to treat patients with suspected gram negative sepsis. the efficacy of treatment established in that trial spurred efforts to develop monoclonai reagents which, to date, have not been uniformly successful in reproducing those earlier studies with polyclonai antibodies. nevertheless, the numerous successes which have been documented in experimental models of endotoxemia continue to foster promise for this immunotherapeutie approach. several recent studies with human polyclonalimrnunoglobulin preparations containing antibodies reactive with lps and lipid a have yielded promising results in treatment of patients with sepsis. in addition, the recent development of an antiidiotypic monoclonal antibody which reflects an internal image of a kdo specific monoclonal antibody has provided an alternative experimental approach to generate anti-lps antibody. immunization of mice with the antiidiotype provides significant protection against subsequent lps lethality consistent with the development of circulating immunoglobulin specific for lps. thus, the use of polyclonal immunoglobulins contrives to provide an alternative and potentially cost effective method for the treatment of endotoxin shock. supported by r a and pot ca . john holaday, anne fortier, shawn green, glenn swartz, john madsen, carol naey, and jan dijkstra entremed, inc.. rockville, md, . at the time of diagnosis, the signs and symptoms of septic shock are an indication that the systemic inflammatory response is well underway; thus, it has been argued that the endotoxin "cat is out of the bag", and that subsequent passive immunization may be too late to achieve therapeutic benefit. our approach has been to evaluate active immunization as a prophylax~s against sepsis. mice were inoculated twice (two weeks apart) with liposomes containing dmpc[i. ], dmpg[ . ], cholesterol [ . ] , and monophosphoryl lipid a [ - gg/txmole phospholipid] by several routes (i.p., i.m.), and serum was collected - days after each inoculation. after a single injection, highest tilers of ab were produced in mice inoculated i.p., but mice inoculated by all routes produced anti-lipid a ab. following the second injection. ab levels were roughly equivalent in mice inoculated by all routes, regardless of lipid a concentration. mice vaccinated i.p. with liposomes containing , or gg lipid a were treated with cyclophosphamide to produce neutroperda and then challenged with e. cole in an infection model of gram negative sepsis. the lds for control (liposomes with no lipid a) mice was x bacteria; ld for mice vaccinated with p.g was x ( -fold increase in resistance) and with ~tg was x bacteria ( -laid increase in resistance). mice vaccinated as before were also treated with actinomyein d to increase sensitivity to lps (salmonella minnesota) challenge in an endotoxemia model of grain negative sepsis. the ld for control (liposomes with no lipid a) mice was ng lps; the ld for gg lipid a was rig lps ( -fold increase in resistance) and for xg was ng lps ( -fold increase in resistance). mice were similarly vaccinated and challenged with an aggressive gram negative pathogen, francfsella tularensis. the ld of franciseua in normal mice or mice inoculated with liposomes without lipid a was - bacteria. in contrast, mice vaccinated with liposomal lipid a ( ggl survived challenges as high as , bacteria, ( logs of protection). the impressive protective capacity of this vaccine did not correlate with ab liter in any of the sepsis models, nor did it correlate with classic nonspeeific events, such as macrophage activation. maerophages harvested from the peritoneum of mice vaccinated and protected against sequelae of gram negative infections did not spontaneously kill the bacteria in vitro, but could be activated by ifn-y for antimicrobial activity equivalent to that of macrophages from unt#eated mice. research is underway to defme the protective mechanism(s) activated by this liposomal-lipid a vaccine. intervention by monophosphoryl lipid a in septic shock jon a. rudbach, ribi immunochem research, inc., hamilton, montana, usa monophosphoryl lipid a (mla), the clinical form of which is called mpl®-immunostimulant, has been tested extensively as an intervenient material in septic shock. mla is protective when given to experimental animals prior to a live microbial challenge or challenge with lethal doses of microbial products or certain cytokines. this is shown with gram negative and gram positive bacteria, gram negative bacterial endotoxins, and gram positive bacterial exotoxins. furthermore, animals treated with a regimen of mla which results in a refractory state to a lethal dose of gram negative bacterial endotoxin concomitantly display increased resistance to a live bacterial challenge. thus, both endotoxin tolerance and nonspeciflc resistance to infection can be manifested simultaneously. also, prophylactic doses of mla do not interfere with other therapies given subsequently; an additive or a synergistic protective effect can be demonstrated with certain combinatorial treatment regimens, such as mla followed by antiendotoxin monoclonal antibodies. the preclinical studies were extended to human trials wherein the safety of agonistic doses of mla was verified. furthermore, when mla was administered to human volunteers hr before challenge with a pharmacologically active dose of reference endotoxin, febrile, cardiac, tnf, il- , and il- responses were all decreased significantly as compared with the responses of subjects pretreated with a control solution and challenged with endotoxin. human trials with mla are being extended into patient cohorts which have high probabilities of developing septic shock; this will expand the safety base and establish clinical efficacy for mpl®-immunostimulant. a considerable body of in vitro evidence supports the concept that the effects of lps on cells of the immune/inflammatory systems are controlled by interactions of lps with cd . to evaluate if blocking lps-cd interactions has potential as a therapeutic in septic shock we have evaluated the effect of anti-cdi monoclonal antibody (mab) on lps-induced cytokine production and physiologic changes in an experimental model of endotoxin shock performed in cynomolgus monkeys. a novel model has been established where animals were treated with interferongamma for three days prior to infusion of highly purified lps over an eight hour period. in this model lps challenge resulted in marked release of eytokines in the blood, substantial hemodynamic changes, release of liver enzymes and alteration in lung permeability observed over a hour period. to evaluate the effect of treatment with anti-cd mab, animals were given either nothing, an isotype control or anti-cd mab ( mg/kg) rains, prior to the beginning of the lps infusion. evaluation of physiologic changes including mean arterial blood pressure and cardiac output, quantitative analysis of eytoldne levels including tnfct, il- , i,- , il- and il- , and liver enzymes during a hour period revealed that treatment with anti-cd mab markedly attenuated all parameters of injury including decreased mean arterial blood pressure, increased cytnkine levels and the release of liver enzymes observed in animals given the isotype control mab or those not treated. administration of anti-cd mab to interferon-gamma treated animals not challenged with lps did not induce any detectable physiologic changes or increases in cytoldnes. these studies suggest that strategies to block lps-cd interactions will have utility in diseases such as septic shock or ards where lps plays a central role in initiating injury. preclinical studies with recombinant bactericidal/permeability increasing proteins (rbpi and rbpi ). p.w. "frown, dept. of preclinical science, xoma corporation, berkeley, california, usa. bactericidal/permeability increasing protein (bpi), from neutrophils, binds to and neutralizes lipopolysaccharide (lps); it also specifically kills gram-negative bacteria (gnb). these properties, which reside in the n-terminal half of the molecule, indicate potential therapeutic application in the treatment of gram-negative sepsis. the gene for human bpi has been cloned and recombinant holoprotein (rbpi) and a kd n-terminal fragment (rbpi; ) have been produced in sufficient quantities for preclinical studies. both rbpi and rbpi bind to lipid a and neutralize the biological activities of lps derived from a variety of organisms, rbpi has equivalent antibacterial activity to bpi against rough gnb but is up to x more potent than bpi vs. serum-resistant and smooth gnb. rbpi and rbpi compete with lps-binding protein (lbp) for binding to lps under physiological conditions. consequently, both rbpi and rbpi block the cd -dependent lpsinduced synthesis of the cytokines tnf, il- , el- and il- in vitro. rbpi has also been shown to inhibit the lps-induced synthesis of reactive metabolites, endothelial adhesion molecules and the procoagulant molecule tissue factor. in animals, rbpi has been reported to increase survival of endotoxin-challenged rats and mice, to inhibit the dermal schwartzman reaction in rabbits and to increase survival of neutropenic rats with pseudomonas bacteremia, rbpi increases survival and decreases cytokine production in endotoxin challenged mice and rats. it normalizes lps-induced changes in hemodynamic, pulmonary and/or metabolic parameters in lps-induced rats, rabbits and pigs. treatment with rbpi also increases survival and decreases cytokine production in bacterial challenge models in rats and mice. rbpi was not toxic to rats after daily consecutive i.v. doses of mg/kg. this combination of properties indicate that recombinant bpi may be useful in the treatment of sepsis. phase i/ii clinical trials of rbpi have begun. the discovery of lps binding protein (lbp) and subsequent identification of cd as a receptor for lps or lps-lbp complexes has resulted in a new understanding o£ how lps responsive ceils are stimulated. cd is found either as a glycosylphosphatidyl-inositol (gpi)-anehored membrane glycoprotein (mcd ) of myeloid cells or as a soluble serum protein (scd ) lacking the gpi-anchor. binding of lps to mcd triggers cell activation while binding of lps-scd complexes to cells such as endothelial or epithelial cells that normally do not express mcd activates these cells. these pathways are shown in schematic form below. ~di mcd plays a crucial role in presentation of lps to additional membrane components that make up a functional lps receptor. an immediate consequence of engagement of this functional receptor is protein tyrosine phosphorylation. the molecular mechanisms leading to these events will be discussed. understanding of these pathways will lead to the development of new therapeutic approaches to controlling host responses to lps. pretreatmen t posttreatment (before or after tnf peak) d) with different antibody dosages: mg/kg --- . mg/kg pretreatment with anti-tnfab prevented death in most model situations (except peritonitis), but also posttreatment up to h after sepsis induction was successful in the few studies performed. there is additional evidence that low-dose tnfab is partially effective. especially baboon anti-tnfab studies provided many insights into the pathophysiological sequences of sepsis induction, due to crossreactivity with human reagents. those events include the cytokine sequence with tnf-dependent il-i, il- , or il- , but also il-lra or stnf receptor release. granulocyte as well as endothelial cell activation were shown to be partly tnf related, and the procoagulatory response was influenced by anti-tnf treatment. from many animal studies the concept that tnf plays a pivotal role in sepsis is clearly evident and therefore anti-tnf therapy is a major candidate tbr clinical studies. the beneficial or harmful effects of tnf-mediated inflammatory responses depend on the clinical context. decreasing exaggerated tnf-mediated inflammatory responses may be useful in some patients with organ failure. tnfr:fc (immunex, seattle, wa) is a recombinant human protein composed of two identical extracellular p tnf receptors linked by the fc region of iggl. it neutralizes tnf with an affinity for tnf<z of - m and has a t / of • h in normal humans. methods: normal volunteers were randomized to receive either tnfr:fc vehicle (n= ), or low dose (ld) tnfr:fc ( mg/m iv, n= ), or high dose (hd) tnfr:fc ( mg/m iv, n= ) infused over rain prior to endotoxin (e) (escherichia coil : ; ng/kg iv) administration. plasma cytokines were measured using elisa and tnf bioactiv'dy. systemic hemodynamics were evaluated with indwelling arterial and pulmonary artery catheters and radionuclide heart scans and compared before and after fluid loading in subjects given vehicle with hd tnfr:fc. results: endotoxin-related symptoms were unchanged after ld or hd. peak temperature occurred at a later time point ( - h) in subjects given tnfr:fc compared to vehicle ( h) (p=. ). at h, h (post fluid load ), and h, subjects given vehicle developed increased cardiac index and heart rate and decreased systemic vascular resistance index (all p=. ). hd tnfr:fc did not alter this hyperdynamic cardiovascular response. ld and hd inhibited the e-induced teukopenta at i h post endotoxin (p<. ) and later leukocytosis (p< . ). peak tnf bioactivity in subjects given vehicle was + pg/ml and < pg/ml in the ld or hd tnfr:fc groups (p<. ). two immunoassays for tnf were performed because the detection of receptor bound tnf varies with elisa. tnf (biosource) was decreased in ld vs vehicle or hd (p=. ) whereas tnf (r&d systems) was increased after hd or ld vs vehicle (p<. ). decreased levels of il- (p=. t), granulocyte colony stimulating factor (p=. ), and il- receptor antagonist (p=. ) were found after ld or hd vs vehicle. il- levels were lower after ld vs vehicle or hd (p=. ). il- levels were similar among subjects given vehicle, ld, and hd tnfr:fc. conclusions: ld and hd tnfr:fc delayed the febrile response to e but did not alter the early hyperdynamic cardiac response. this suggests that mediators other than tnf play an important role in the initial cardiovascular response to e in humans. tnfr:fc attenuated the release of some e and tnf-induced cytokines. ti~e antiinflammatory responses of tnfr:fc may be useful in some patients with disease processes resulting from excessive tnf-mediated inflammatory responses. the biosynthesis of tnf within macrophages is regulated both at the transcriptional and the translational levels. the ' flanking region of the tnf gene contains several transcriptional control elements, including two kb enhancers similar to those of immunoglobulin genes and a "y box" similar to that of the mhc class ii promoter. these elements are critical for the enhancement of transcription noted after stimulation of macrophages with lps. despite these and other elements, transcriptional regulation alone accounts neither for the absence of tnf protein during normal homeostasis nor the profound increasein tnf production following stimulation with lps or other secretagogues. the translation of tnf mrna into protein is also tightly regulated via mechanisms involving the octameric "ttatttat" motif present in the 'untranslated region of tnf, human inducible no synthase, and several other cytokine genes. this region not only destabilizes mrna, but also confers a translational blockade so that tnf protein is not normally synthesized despite leaky basal transcription. lps stimulation releases translational blockade and, together with enhanced trancriptional rate, accounts for significantly increased tnf secretion. opportunities for inhibition of tnf production are available at each of these two levels. agents which increase intracellular camp (pentoxif¥ ine, amrinone) inhibit accumulation of tnf mrna; in contrast, corticosteroids act primarily at the level of translation, inhibiting lps induced translational activation. understanding the regulation of tnf biosynthesis may assist in clinical strategies designed to regulate tnf secretion. the serine protease thrombin is formed by enzymatic conversion from its proenzyme form after coagulation activation and may enhance the inflammatory response in various ways. in the last step of the coagulation cascade, thrombin cleaves its substrate fibrinogen, thus forming fibrin. the fibrin clot may prevent phagocytosis of bacteria and promote local bacterial growth. thrombin can also stimulate a specific th.rombin receptor that exists on a variety of cells. for example, minute amounts of thrombin ma), stimulate platelets to develop tissue factor and boost the activation of more thrombin, thus initiating a positive feedback loop. other cellular effects of thrombin receptor stimulation include increase in intracellular calcium of platelets and monocytes, contraction of smooth muscle cells, increase in endothelial permeability, thromboxane generation by neutrophils and lymphocytes, pulmonary vasoconstriction, and enhanced cytokine production. animal experiments have been conducted with a variety of thrombin inhibitors including heparin, antithrombin ili, hiradin, and hirudin-like peptides. an alternative approach is the inhibition of the coagulation cascade at an earlier point in the cascades, or administration of the anticoagulant enzyme protein c work from our own group in a porcine model of lipopolysaccharide-(lps)-induced shock with disseminated intravascular coagulation has shown that prelreatment with recombinant desulfatohirudin (r-h) or with a preformed complex of human donor antithrombin iii with heparin or post treatment with r-h are able to block the degradation of fibrinogen and the formation of fibrin monomer. in addition, after pretreatment with r-h it was found that lps-induced lung injury was reduced. since both natural hirudin as well as r-h were well tolerated by healthy volunteers, adminislration of r-h may be a promising therapeutic approach in patients with sepsis and sirs. corticosteroids have been used in the management of various shock syndroms including sepsis. the data concerning the effects of this therapy is, however, conflicting and in large prospective studies, the use of early administration of high doses of corticosteroids have been found to give no beneficial effects in patients with sepsis. we have particularly been engaged in studies on possible effects of corticosteroids on the plasma cascade systems and on the mediator release from leukocytes. in in vitro studies, high doses of methylprednisolone were found to facilitate endotoxin induced generation of plasma kallikrein. furthermore, plasma prekallikrein and kallikrein inhibitor values decreased together with formation of kallikrein-c inhibitor complexes ( ). in this in vitro plasma model we also found that methylpredoisolone alone in doses of mg/ml induced contact activation with the formation of kallikrein-c inhibitor complexes. methylprednisolone was also found to have an additive effect on endotoxine induced decreases in kallikrein inhibitor functions. in the same experimental model on endotoxemia methylprednisoione was found to give an additive effect on activation of the initial part of the complement cascade ( ) . activation of the terminal part of complement, however, was inhibited by the same dose of methylprednisolone. addition of methylprednisolone alone to plasma was also found to activate the initial part of complement. using a full blood model, we studied the effect of methylpredoisolone in modulating the endotoxin induced cytokine response. when ng/l e. coli endotoxin was added to citrated blood from healthy human donors preinkubation with gg/ml methylprednisolone significantly reduced the release of tumor necrosis factor et ( %) and interleukin- ( % ) at two hours after exposure to endotoxin. in conclusion, these studies show that corticosteroids might facilitate contact activation of plasma and reduce the function of major protease inhibitors. furthermore, we also observed that this drag in in vitro conditions facilitated activation of complement. on the other hand, corticosteroids were found to reduce endotoxin induced cytokine release from leukocytes in whole blood. these studies also showed a dose dependence of the effects of corticosteroids on endotoxin induced cellular and cascade system activation. different predisposing conditions like extensive trauma, infection or pancreatitis result in a remarkably similar inflammatory response. although thls inflammatory response primarily aims at the removal of devitalized tissues, destruction of bacteria and reestablishment of the integrity of host tissues, it may potentially become unregulated and generalized and thereby producing deleterious effects to vital organs or the body" as a whole. cytokines play an important role in the development of the systemic inflammatory response. most of their biological effects, however, are not directly mediated but exerted through other mediator systems. when the inflammatory response results in the formation of capillary leak syndrome and refractory hypotension, the unregulated activation of complement and contact systems appears to be the cause. both systems are almost exclusively regulated by c - nhibitor. am unbalanced degradation of the inhibitor protein was found to be associated with the onset of capillary leakage in various conditions such as bone marrow transplantation, severe burns, and septic shock. these observations suggest a relative deficiency of biologically active c - nhibitor in these septic shock like syndromes. therapeutic intervention studies were initiated using high doses of c - nhibitor concentrate. first results are promising, as in most patients the administration of the drug was followed by a quick and marked improvement of the patient's hemodynamics. whether the administration of c - nhibitor alone or in combination with other drugs is also sufficient to improve long-time survival has to be investigated in double-blind, placebocontrolled studies. salutary effect of human soluble complement receptor type- in models of adult respiratory distress syndrome g. feuerstein, m. dimartino, and *r. rabinovici, smithkline beecham pharmaceuticals, king of prussia, pa, usa, and *jefferson medical college, philadelphia, pa, usa adult respiratory distress syndrome (ards) is a severe pulmonary insufficiency syndrome associated with diverse diseases and injuries. ards is believed to be the consequence of a massive acute inflammatory reaction consisting of activated neutrophils infiltration into the lung. neutrophil activation is likely the result of multiple factors of which complement is believed to play a major role. a potent complement regulatory system in the form of the complement receptor type- (cr- ) exists on many cells where protection against complement injury is provided by inhibition of both the alternative and classical pathways for c /c convertase formation. we have recently purified the human recombinant cr- in a truncated form (brl , tp-io, scr- ) and tested this soluble protein for protective effects in several models of ards. specifically, we have used the following rat models: ) endotoxin-induced ards in paf primed animals; ) .- induced ards; ) thermal injury ( % body surface)-induced ards; ) acid aspiration-induced ards. ards-like features included edema (increase in lung wet weight and water content), neutrophil accumulation (histological inspection and myeloperoxidase assay) and increase in cells and protein in the bronchoalveolar lavage (bad. scr- , - mg/kg, i,v., given as prophylactic (and in some cases, therapeutic) treatment significantly inhibited edema formation and leukocyte infiltration and, in some cases (e.g., endotoxin/paf or il- ), virtually completely. these comprehensive studies strongly support the therapeutic potential of scr- in ards due to diverse injuries. the xanthine derivative pentoxifylline (ptx) and several analogs of ptx have been evaluated for their protective effect in various animal models of septic shock. data from these in vivo studies demonstrate that ( ) ptx suppresses lps-induced tnf release from activated macrophages; ( ) ptx prevents tnf-induced pmn activation; ( ) ptx attenuates lps-or tnfinduced acute lung injury as evidenced by prevention of increased pulmonary vascular permeability and detoriation of gas exchange; ( ) ptx exerts its .protective effects even when administered following initiation of sepsis. the sum of these actions suggest that administration of ptx in sepsis may have therapeutic potential. hans hoffmann md, dept. of surgery, klinikum grosshadern, ludwig-maximilians-universit~.t, marchioninjstrasse , d- m nchen, germany. pentoxifylline [pof] and related xanthins are drugs of known haemorrheologieal activity and widely used clinically. recently, new pharmacological aspects of these established drugs could be demonstrated. it was found that pof selectively inhibits the formation of tnf but not il- most likely by causing accumulation of intraceliular camp via inhibiting phosphodiestersse activity, and, secondly, by inducing prostacyclin in different cell types. furthermore, pof is able to counteract tnf-mediated adherence of neutrophils to vascular endothelium and to inhibit fmlp-indueed respiratory burst in neutrophils. we and others have, therefore, studied its effect in different animal models. it was found that pof protected from increased pulmonary vascular permeability and sequestration of neutrophils into the lung in different animal models of acute lung injury. moreover, in pigs with induced faecal peritonitis the drug improved haemodyrmmle variables as well as pulmonary compliance and reduced the number of pulmonary neutrophila and lymphocytes. consequently, as a general outcome, pof could be found to improve survival in different models of haemorrhagie and endotoxie shock. the protective effect of pof was dose-dependent and observed even when pof was given up to hours after endotoxin. in order to evaluate these pharmacological effects of pof in humans, we studied pof under controlled conditions of endotoxlnemia in volunteers. we found that pof selectively inhibits the lps-indueed endogenous formation of tnf without affecting il- and il- . moreover, pof counteracts the lps-indueed initial leukocytopenia by interfering with the adherence of neutrophils in the microvasculature. meanwhile the inhibition of endogenous formation of tnf by pof could be demonstrated under different clinical conditions of acute and chronic cytokine release syndromes, {okt first-dose reaction, cancer-or tuberculosis-induced cachexla}. it appears worthwile and promising to investigate wether pof exhibits beneficial effects also in septic patients. objectives: to determine the specific role of paf in both lethal primate bacteremia and nonlethal human endotoxemia. materials and methods: two double-blinded placebo controlled studies were performed. first, ten baboons ( . +. kg), were randomized to a control group receiving ° cfu/kg of intravenously administered e. co/i (n= ) and a treatment group (n = ), pretreated with . mg/kg of paf receptor antagonist ro - two hours prior to e. co/i infusion. in a second study, ten healthy male volunteers were randomized to a control group receiving ng/kg of intravenously administered endotoxin (lps) (n= ) and a treatment group (n= ) pretreated with mg of ro - eighteen hours prior to lps administration. physiologic parameters and cytokine levels were measured continuously in both studies for hours. results: baboons pretreated with the paf antagonist had improved oxygenation ( + mm hg v -+ in controls, p < . ) and creatinine clearance hours post e.coli ( . + . ml/min v . _+ . in controls, p < . ). similarly, volunteers pretreated with the paf antagonist experienced fewer symptoms, including rigors and myalgias at hour post lps. this was in concert with a diminished peak cortisol ( +_ mmot/l v +- mmol/l in controls, p < . ), epinephrine secretion ( + nmol/l v + nmol/l in controls, p < . ). hemodynamics and circulating tnfa levels (data not shown) were unaffected in either study by prior paf antagonism. concluslons: paf influences some components of the multi-organ failure syndrome in lethal gram negative sepsis and the counter-regulatory hormonal system in human endotoxemia through tnf-independent mechanisms. paf antagonists may serve as adjuncts to cytokine blockade in the treatment of gram negative sepsis. the mediator role of platelet-activating factor in gramnegative septic shock pierre g. braquet, david hosford and matyas koltai institut henri beaufour, le plessis robinson, france considerable evidence has been accumulated to support the concept that a paf/cytokine autogenerated feedback network is responsible for priming and amplification of inflammatory mediator release in septic shock. cytokines, such as tnf~x, il- and other interleukins interact with paf which then amplifies cytokine production, therefore, paf may be the principle mediator in endotoxin shock. a single factor identified as tnf is suggested to play a pivotal role in the fatal phase of septic shock. presumably excess tnf release is the result of amplification process primarily triggered by paf. one may assume that the high tnf concentration in the blood of 'non survivors' is the consequence rather than the cause of cell death. the dubious results of clinical trials with anti-tnf antibodies and il- ra, a naturally occurring il- antagonist protein, have risen debate around the exceptional role of cytokines in the pathomechanism of septic shock or systemic inflammatory response syndrome (sirs) induced by gramnegative microorganisms. there are similar problems with the interpretation of the results obtained in clinical trials of monoclonal igm antibodies against e. coli endotoxin, ha- a and e . future studies will answer the question as to the effectivity of inefficiency of this treatment. perhaps when the plasma concentrations of lps and cytokines exceed a critical level, treatment fails to save the patients life. with regard the causal role of lps in septic shock, the putative role of bacterial porins may have to be taken into consideration. the marked release of paf induced by endotoxin leading to excess txa production may be responsible for the microvascular failure and death in septic shock. antagonists of paf markedly protect against the release of txa , and may interrupt the vicious circle of amplification process. no produced by the inducible no synthase plays a pivotal role in causing vascular paralysis in lps-induced sirs. to explore the relationship of paf to no synthesis will provide better understanding of the pathomechanism of septic shock. several paf antagonists, including bn , have undergone phase ii and phase iii clinical trials. the strategy in the treatment of sirs, however, remains multifactorial, since little is known about the sirs caused by microorganisms other than gram-negative bacteria. evidence has begun to accumulate which suggests that in sepsis excess production of lps and cytokines can lead to uncontrolled production of inos and that this might in part explain the severe unresponsive hypotension seen in some septic patients. a number of strategies have been explored in an attempt to limit excess no production. a favourite target has been competitive inhibition of nos by arginine analogues such as l-nmma. in animals, some investigators have shown that the haemodynamic effects of lps challenge can be attenuated by l-nmma, but there is a narrow toxic-therapeutic ratio. in a model of live e. cell sepsis, we have been unable to reproduce these findings. localisation of no production by immunohistochemistry suggests that no production is compartmentalised, and more subtle methods of regulation may be required if this approach is to have clinical valuc. anti-adhesion molecule strategies ch wortel, repligen corporation, one kendall square, building , cambridge, ma , usa. the neutrophil has been implicated as a pivotal player in the pathogenesis of multiple organ dysfunction. an important first step in the process of neutrophilmediated organ injury involves the binding of neutrophils to endothelial ceils. this process is largely regulated by complementary adhesion molecules, some of which are present constitutively on the cell surface and others that can be upregulated in response to chemotactic and pro-inflammatory stimuli. several different adhesion molecules have been described. l-selec tin is expressed on the plasma membrane of neutrophils and is shed from the surface early in the inflammatory process. it is therefore thought to mediate the initial interactions with endothelial cells. e-selectin and p-selectin are endothelial adhesion molecules. e-selectin is not constitutively expressed but is upregulated by inflammatory mediators, particularly il- and tnf. p-selectin is present in the weibel-palade bodies within the endothelial cytoplasm and can be upregulated rapidly in response to thrombin, histamine, and oxidants. all selectins recognize oligosaccharides, particularly sialylated lewis x antigen. this carbohydrate moiety is expressed on many proteins, including the selectins themselves. the leukocyte integrins are glycoproteins expressed on the neutrophil surface and in the cytoplasmic granules. integrins consist of a common beta or cluster differentiation (cd)i chain covalently linked to one of three different alpha chains (cd a, cd lb, cd lc) and exist on the cell surface as three distinct heterodimers. cd l a/cdi is expressed on all leukocytes, whereas cd l b/ cd and cd lc/cd are restricted to cells of myeloid origin. cd i/cd interacts with intracellular adhesion molecule- (icam- ), its ligand on endothelial cells. icam- is a member of the immunoglobulin family of adhesion molecules. it is constitutively expressed on endothelial cells and can be upregulated by cytokines. the potential for monoclonal antibodies to adhesion proteins to reduce vascular and tissue damage has been studied in alarge number of experimental models. protective effects have been observed in a wide variety of inflammatory, immune, and ischemia-reperfusion injuries such as arthritis, bums, endotoxic shock, bacterial meningitis, autoimmune diabetes, nerve degeneration, allograft rejection, allergic asthma, acute lung inflammation, skin lesions, and ischemia-reperfusion models of the intestine, myocardium, lung, skeletal muscle, and central nervous system. protective effects have also been observed in animals resuscitated following hemorrhagic shock. since modulating the function of adhesion molecules may temporarily leave the host without effective defense machinery, safety evaluations are of utmost importance in evaluating this therapeutic approach. treatment of gram-negative septic shock with an immunoglobulin preparation: a prospective, randomized clinical trial ingolf schedel, ursula dreikhausen; birgit nentwig; marion hockenschnteder, dirk rauthmann, salim balikcioglu, rolf coldewey, helmuth deicher, md endotoxin may play a major role in the pathogenesls of muitiorgan failure in the context of the toxic process in septicemia induced by gram-negative pathogens. the hypothesis which has led to a prospective clinical study consisted in the idea of inhibiting the biological effects ofendotoxin during the early phase of septic process, and thereby attampting to attain a positive effect on the clinical course of the disease. -objecave: to evaluate the effectiveness ofa polyclonal immunoglobulln (ig) preparation containing igg, lgm, and iga as an adjunctive therapy for septic shock. -desigru prospective, randomized clinical trial. patients: fifty-five patients w~th septic shock were randomly allocated to two groups according to criteria of septic shock. -intervention: one group of patients (n = ) received a commercially available immunoglobulin preparation (containing high titers of antibodies specific for determinants to bacteria endotoxin) during the first days after inciosion in the study. the other randomized group (n = ) did not receive any immunogiobulin preparation. -measuremems and main resmts: during the period of < wks after the beginning of clinically apparent septic shock, death related to the septic process occurred in one ( %) of patients who received immunoglobulln. by comparison, nine ( %) of control group patients died during this period (p <. ). within the first hrs after onset of the clinically apparent septie process, significaptly increased activity of circulating endotoxin and simultaneously decreased specifie igg serum titers to lipid a were detected in the group of nonsurvivors. the rationale for the use of polyvalent intravenous immunogiobulins (ivig) to treat severe infections stems from in vitro and animal studies documenting that high-dose igg enhance opsonization and phagocytosis of pathogenic bacteria. moreover, recent clinical studies have shown that in septic patients the phagocytic function of circulating polymorphonuclear neutrophils (pmn) is defective; the degree of such impairment correlates to the severity of the septic state, the beneficial effect of administering high dose igo in septic patients can be two-fold: i) ivig provides large quantities of antibodies against invading pathogens; the igg bound to the pathogens can opsonize their phagocytosis; ) the opsonization of phagocytosis by exogenously administred polyvalent igo would be of special importance in those patients who present a significant defect of their phagocytic function, when they are challanged by a large bacterial invasion. a prospective, randomized, double-blind study was carried out comparing the administration of ivig (sandoglobulin@) vs, paeebo (human albumin) in severely septic surgical patients, only patients with gepis score >_ (meaning a mortality risk > %) were accepted into this protocol. patients were randomized to receive . g/kg of ivig or placebo on day (when they reached sepsis score> ), repeated on day + and + . at the beginning of icu treatment, the two groups of patients were similar for severity of sepsis, age, concomitant disease, type of surgical procedures, antra and perioperative procedures, antibiotic administration. the results of the study indicated a significantly reduced mortality in patients with severe surgical sepsis treated with ivig as compared to placebo control patients (mortality: % vs, % respectively; p< , ). in conclusion, the results of our study in patients with severe surgical sepsis were the following: ) ivig plus multimodal treatment of sepsis, including antibiotics, reduce mortality significantly', ) the reduction of mortality seems to be due to a decreased incidence of lethal septic shock. despite substantial clinical research, the avallable data regarding the effectiveness of supplemental immunoglobulin (ig) treatment in sepsis in adult patients do not yet allow definitive conclusions. in view of the persistently high sepsis mortality there is a need to continue clinical investxqations regarding supplemental sepsis treatmen~ in general, as well as concerning ig administration in particular. we present and discuss the protocol of the ongoing ,,score-based-immuneglobulin therapy of sepsis (sbits)" study. the protocol (theoret surg ( ) - ) of this multicenter, randomized, prospective and double-blind trfal relies on the results of an observational trial on i.v. igg treatment in patients with sepsis and septic shock (infection ~ ) - ), carried out as a prerequisite for the present trial. using microcomputer-based bedside routine score monitoring, we regard quantitative measures of severity of disease and sepsis: only patients with a certain degree of both severity of disease (apache ii score - ) and severity of sepsis (elebute sepsis score - ) will be included. by observing these previously validated inclusion criteria, this trial snould iqentify a priori and include patients with potentially optimal response to therapy, consisting o~ either placebo ( .i % albumin) or polyglobin n" - ml ( . g)/kg on day and ml ( . g)/kg on day i. with an anticipatedpopulation size of patients the study should comply with the statlstical requirements (estimated mortality: %, with a % reduction in -day mortality in the treatment groupl to prove or disprove the question of igg effectiveness in sepsis in terms of improved prognosis. up to november , more than patients had been included; patient enrollment will be finished in . previous studies have demonstrated rhll-i ra, a naturally occurring antagonist of il- , increases survival in animal models of andotoxemia and eschehchia coli bacteremia and attenuates the decrease in mean arterial pressure resulting from challenge with both gram-negative and gram-positive bacteria. previously, in patients, rhll-lra was demonstrated to increase survival in patients with sepsis syndrome and septic shock in a dose-dependent manner. methods: a randomized, double-blind, placebo-controlled, malticenter, clinical trial enrolled patients at academic medical centers in europe aad north america. eligible patients received either placebo (vehicle) or rhil-lra (anakinra) . or . mg/kg/hr by continuous intravenous infusion for hours. the presence of organ dysfunction (i.e., ards, dic, renal, and hepatic) at study entry was determined prospectively by a clinical evaluation committee using definitions which were developed a-priori. survival time was evaluated over days utilizing a linear dose-response model, assuming a log-normal distribution. results: patients had one or more sepsis-induced organ dysfunction(s) at study entry. a dose-related increase in survival time was observed with rhll-lra compared to placebo in patients with ards, dic, and renal dysfunction (p --< . endotoxin infusion releases platelet-activating factor (paf), a potent phospholipid mediator which leads to an autocatalytic amplification of cytokine release. bn (ginkgolide b), a natural paf receptor antagonist, has provided significant protection against sepsis in different animal models• a randomized, placebo-controlled, double blind, multicenter trial on efficacy (mortality at d ) and tolerance of bn ( iv infusion of mg x /day over days) in severe sepsis has enrolled pts. the day mortality rate was % for the placebo group and % for the bn group (p = . ). the efficacy of bn was greater in pts with gram-negative sepsis: the -day mortality rate was % for the placebo group and % for the bn group (p = . ). bn also reduced mortality among pts with gram-negative septic shock (mortality was % for placebo vs % for bn ; p = . ). using statistical adjusments for pronostic factors, the relative risk of death of the bn group was . ( . - . , % confidence interval; p = . ). this risk corresponds to an adjusted reduction in mortality of % for pts receiving bn . no differences in mortality rates were found between the placebo and the bn groups in the absence of gram-negative sepsis• there were no differences in adverse events between the placebo and the bn groups. bn is a safe and promising treatment for patients with severe gram-negative sepsis. a confirming study, focused on gram negative sepsis, is in progress. v~ lliam a. kanus m.d. and the rhll-lra it has been traditional within the field of infection and sepsis to think in terms of specific indications for drugs based on the type of infecting organisms, advances in antibiotic therapy now control or ltnflt the growth of bacteria. the majority of deaths are now caused by either an initial overwhelming response to infection or subsequent multiple organ system failure attributed, in part, to the effects of intrinsic biologic responses of the host. type of organism, therefore, may not be as critical as determining the exact severity of the host's severity or risk of death from infection. we also know that both the relative benefit of a new treatment across groups and its absolute benefit for an individual patient will vary with their risk in a predictable fashion. we recently iuve~iguted the relationship between one measure of host response, the acute risk of death as prospectively estimated by u comprehensive risk mode[ for -day mortality (jamb. ; : , - ) , by its retrospective application to the results from the phase in evaluation of recombinant human intcrlenkin- receptor antagonist (rhll. ira). we found that there was a significant interaction between the patient's predicted risk of mortality at the time of entry to the study and the ability of rhil-lra to prolong survival time (x = . , p [] . , log.normal) for all patients in the trial• survival benefit began st approximately % baseline risk of -day mortality. for the $ patients with a predicted risk > %, there was a % reduction (p= , $ log normal). when we examined the variation in patients above and below the % risk level with hazard functions, i.e., their daily risk of death during the study period, we found that placebo patients with < % risk had lltile acute daffy risk during the hlltial two days follawh~g study entry and this risk was little affected by rhil-lra, in contrast, patients with > % risk had high daily mortality risks during the tuttlal two days that high dose rhtl-lro substantially reduced. these results are compatible with our current understanding of outcome from sepsis and the proposed mechanism of action o£ immunotherapy, the earliest deaths from sop sis are secondary to an immediate inflammatory response followed closely by deaths secondary to multiple organ system failure, later deaths (after days) are not as closely related to the acute effeete of the inflammatory cascade. because of the timing and action of most proposed tmmunotherapy, they may be capable of preventing mortality primarily in these initial two phases. in this study, an independent predicted risk of mortality reflected this mortality pattern ned illustrated the potential benefit of immtmotherapy. use of a predicted risk of mortality in the design and analysis of clinical trials could improve our understanding of the clinical benefit of these new therapeutic approaches. the systemic inflammatory response syndrome (sirs) is a term recently proposed to describe patients with systemic inflammatory responses to insults such as infections (sepsis), trauma, burns, pancreatitis, and other initiating events. patients with sirs may have similar activation of inflammatory mediators and similar outcomes independent of the initiating event. these outcomes include organ dysfunction and failure, shock, and death. challenges to the successful conduct of clinical trials in sirs include the complexity of illness in these patients and the important--but limited--clinical benefits of novel compounds that may be limited to selected patient subsets. addressing these challenges will require new tools and approaches. these will include more sensitive and appropriate endpoints, and the use of methods such as baseline risk adjustment, to allow detection of drug risk interactions not captured adequately by categorical definitions, such as sepsis syndrome. on the basis of supportive preclinical and phase i safety studies, we have initiated phase ii clinical trials of a novel bradykinin antagonist, cp- , in four sirs subcategofies: sepsis, multiple trauma, burns, and pancreatitis. each of these studies is designed to measure the effect of cp- on mortality, organ dysfunction and failure, and activation of mediators. in addition to investigating rates of organ failure using standard definitions--a new endpoint--a continuous summary measure of organ dysfunction (the acute physiology score of apache tm iii) is being used to quantify the degree of organ dysfunction and the speed and pattern of recovery of physiologic stability. in the sepsis study, another new approach--a study specific risk model based on the apache ill database--has been developed which will be used to assign a pre-treatment baseline risk to each patient enrolled. the primary outcome variable will be risk adjusted survival time to days. this type of risk-adjusted analysis may allow for more efficient and powerful trials and more accurate and useful indications for use. study purpose: in post-cardiac surgical patients (pat.) at risk for sepsis, the efficacy of early i.v. immunoglobulin (ig) treatment was compared to a matching historical control (con.) population. postoperative risk assessment: using apache ii scores lap) (first postoperative [pop.] day) in a pilot study phase, we were able to differentiate between the large population ( . %) of pop. low-risk pat. (ap< ; mortality: %) and the small groups of pop. pat. at risk lap= - ) and high risk lap_ ) with a significantly higher mortality ( % and %, mainly due to sepsis). subsequently, among consecutive pop. pat. we prospectively identified and treated these pat. iq treatment reqimens: first study period (n = ): (gg (psomaglobin n a, tropon biologische pr~parate, cologne, frg, day : ml/kg, day : ml/kg). second study period (n= ): iggma (pentaglobin r, biotest, dreieich, frg, ml/kg on days to ). results: ig pat. and con. were comparable in demographic data, operation characteristics and baseline disease severity lap and elebute sepsis scores). in contrast to con. (risk: n= , high-risk: n- ), the ig pat. showed a marked improvement in disease severity (fall in ap), especially in the high-risk group (igg, n= : p<o. ; iggma, n= : p: . ). in this group, ig led to higher (p< . ) response rates, defined as an ap score decrease -> within four days (igg: %, iggma: %; con.: %), and reduction in mortality (igg: %, iggma: %; con.: %), statistically significant (p< . ) for ig treatment as a whole (igg and iggma). conclusion: given the good comparability of the study groups, our results indicate, despite the non-randomized design, that early supplemental ig treatment can improve disease severity and may improve prognosis in prospectively apache ii score-identified high-risk patients after cardiac surgery. objective. elevated plasma levels of endothelin (et) have been demonstrated in both experimental and human sepsis. et has been proposed as a sepsis mediator leading to vasoconstriction with tissue hypoperfusion and organ failure. the aim of the study was to determine the effects of sepsis treatment with volume resuscitation, antibiotics and the anti-lps monoclonal antibody es® on big et and active, aminoacids et (et ) in rat abdominal sepsis. methods. lethal peritonitis was induced with a mm coecal perforation (cp) in male wistar rats. plasma levels of big et and et were determined with amersham tm endothelin rias , and h after sepsis induction. experimental groups: . cp control, . volume replacement (vr); , % saline ml/kg/h continous iv infusion started after h, . antibiotic; imipenem mg/kg iv after h, . e ®; mg/kg iv after h, . vr + imipenem + es® after h. results. high concentrations of both big et and et could be demonstrated after h and lasting for h after cp. neither volume replacement nor imipenem did influence the elevated plasma et. e ® significantly reduced et both , and h after sepsis induction, but did not reduce big et. when es® was combined with vr and imipenem, reduction of et was the same as for e ® alone. these results strongly suggest that bacteria and hypovolemia per se are not decisive stimuli for et production during sepsis. e ® reduces circulating lps and tnf which is the probable mechanism of the suppressed et synthesis. the unaltered big et fraction after e ® treatment indicates conversion of big et to et as the site of action responsible for reduced et . conclusion. lethal peritonitis in the rat is followed by elevated plasma levels of big et and et . e ® anti-lps antibody significantly reduces plasma et while volume resuscitation and antibiotics failed to do the same. es® did not reduce plasma big et. pmx treatment on severe endotoxemia with multiple organ failure was safety and effect in prognosis, and sepsis related parameters. it was certified that reduction of plasma endotoxin was effective in severe endotoxemia. a. lechleuthner,s. aymaz, g. grass, c. stosch, s. dimmeler, m. nagelschmidt, e. neugebauer. ii. dept. surgery, university of cologne, germany. introduction: the cardiovascular therapy of hypodynarnic shock states is a challenging problem. in clinical as well as experimental studies beneficial functions of a new hg-agonist bu-e- in congestive heart failure has been demonstrated aumann, ). therefore, we investigated the effect of bu-e- in hypodynamic shock in pigs. materials and methods: pigs (deutsches hausschwein, pitrain, [ ] [ ] [ ] [ ] [ ] [ ] were anesthesized with fentanyl/dormicum, ventilated (n :o = : ) and cardiovascular parameters were monitored with a complete icu-eqnipment. the hypodynamic model was established in a pilot study ( animals) to evaluate the effective concentration of bue- in healthy and endotoxin (lps)-treated animals. endotoxic shock was induced by continous infusion of ~g lps/kgkg/h ( :b , fa. difco). the hypodynamic state was defined as a decrease of cardiac output by % of steady state levels. a wedge pressure of - mmhg was kept constant by volume resucitation during the experiment. in a subsequent randomized controlled trial (rtc) groups with animals per group were studied. the groups were treated as follows: group i, lps and , % nac ; group ii, lps and bu-e- ( #g/kgkg/h); group iii, famotidine (h -blocker) pretreatment ( mg/kgkg), lps and bu-e- . results: the pilot study in healthy pigs revealed, that bu-e- had positive inotropic effects. these effects were inhibited by the h antagonist famotidin. bu-e- however had no beneficial effects in the hypodynamic phase of endotoxic shock in the rct. cardiac index (ci) and the oxygen delivery (do ) were not significantly influenced by bu-e- application (group i versus group ii). bu-e- did not ameliorate the negative inotropic effect measuring left ventricular stroke work (lvsw) in hypodynamic shock phases. on the contrary, bu-e- led to a further significant decrease of lvsw (p < , ). famotidin pretreatment did not affect the response (group iii versus group ii). conclusion: in hypodynamic shock states the h -agonism seemed to have no beneficial effect under these experimental conditions. receptor down regulation or changes of signal transduction under septic conditions may be responsible. cellular studies may help to identify these mechanisms. objectives. antithrombin iii inactivation of proccagulant proteases is so far the only inhibitory therapeutic approach to disseminated intravascutar coagulation (dic). we therefore set out to investigate whether cll substitution reduces coagulation activation in an endotoxin induced rabbit dic model. materials and methods. male rabbits chbb:hm(spf) were randomty assigned to one of the following groups. group k : naci . % (control without endotoxin, n= ). group e : endotoxin tjg kg " bolus i.v. + naci . % (control with endotoxin, n= ). group c : endotoxin pg kg - bolus i.v. + cll u kg - bolus + u kg " h "~ i,v. (treatment group, n= ). all animals were anesthetized and mechanically ventilated. blood samples were drawn prior to endotoxin administration (m ) and after (m ) and rain. (m ). thereafter, lung and liver tissue samples were taken intravitatly in a standardized fashion for h&e microscopic fibrin quantification using a triple score (fibs). from all blood samples the prothrombin time (pt), activated partial thromboplastin time (aptt), fibrin monomers (fm), and d-dimers (dd) were measured. for statistical significance of differences between the groups anovas and the wilcoxon test (fibs) were performed. results. fibs for lung/liver were significantly different (p< . ) between group e (lung , liver ) and c (lung , liver ) (group k : lung , liver ). , a synthetic serine proteinase inhibitor, has an anticoagulant activity in the absence of" antithrobim iii. gabexate has been reported to be useful in the treatment of disseminated intravascular coaguiation due to neoplastic diseases. in this study, we investigated gabexate therapy for the treatment of dic due to sepsis in the postoperative critical patients. materials and methods: from july to june , patients in the surgical intensive care unit met the criteria of dic or pre-dic. eleven were male and four were female with the mean age of . years. all these patients suffered from some complication of operations which led to the development of sepsis. foy was administered at the rate of mg/kg/hr untii the coagulation profile retumed to normal or the patient died. the coagulation parameters were monitored before and on the st, rd, th and th day. results: fourteen of these fifteen patients died despite transient improvement of the coagulation parameters in five patients. these patients suffered from sepsis resulting from surgical complications which could not be well controlled. the only survival was a case of recurrent intrahepatic duct stone with biliary tract infection complicated with sepsis and dic. after choledocholithotomy and the use of foy, the patient recovered gradually. conclusion: dic is a late manifestation of sepsis in the critical surgical patients. the most important thing is to eradicate the cause of sepsis. if the underlying septic focus cannot be controlled, dic will persist despite the use of gabexate mesilate. emergency surgery, taipei veterans general hospital, taipei, taiwan. there are main types of bradykinin (bk) receptor, namely bk~ and bk z. the bk receptor is constitutive. the bk receptor is also constitutive but in the majority of cases is inducible and involved in chronic inflammatory syndromes such as sepsis, hyperalgesia and airways hyperreactivty in animals. the mechanism(s) involved in the upregulation of the bk receptor is unclear, however a variety of agents including lps, e coil and ill are particularly efficacious in vitro and in vivo. ill and bradykinin acting at their respective receptors are believed to be involved in sirs/sepsis. we have investigated the effect of antagonists at ill (antril), bk (bradycor [cp- ]),bk~ (cp- ) and bkz/bk (cp- ) receptors on the de novo generation of bk~ receptors (reflected by hypotensive responses to a bk agonist) in the lps-treated ( ug iv) rabbit. in lps treated rabbits hypotensive responses to bk~ but not bk agonists increased with time and at time min appeared maximally induced. constant iv infusions of cp- blocked bk but not bk~ and cp- bk~ but not bk responses. cp- ,cp- +cp- and antril+cp- blocked both bk and bk~ responses. antril alone had no effect on bk or bk~ responses. within - min after stopping the infusions of antagonists the responses to bk~ and bk z agonists were the same as those in nonantagonist infused rabbits. these results indicate, at least in the lps-treated rabbit, that neither bk ,bk ~ or ill receptors alone or in combination, are involved in the de novo generation of bk receptors. in vitro studies demonstrated that beth bradycor and cp- (but not antril) were antagonists at both bk z and bk~ receptors. if both bk z and bk receptors are significantly involved in chronic inflammatory situations in man such as sirs/sepsis then the rationale for the use of compounds such as bradycor or cp- is clear. infection is a major cause of or contributor for morbidity and mortality in liver transplant recipients. effectiveness of prophylactic and therapeutic protocols is important for the success of liver transplantation ( olt ). sdd is used as prophylaxis for reduction of infection caused by gram negative or fungal microorganisms. between september and july olt's in patients were performed at our department. the actuarial -year patient survival is %. infection prophylaxis is started with sdd and ciprofloxacin once the patient is accepted as an olt candidate. perioperatively metronidazol, tobramycin and cefotaxim, postoperatively cotrimoxazol are prescribed additionally. the table shows pneumonia, peritonitis, major wound and urinary tract infection are common nosocomial infections following severe injury. in a series of severely injured patients from the university of louisville hospital, pneumonia was the most common infection followed by peritonitis, intra-abdominal abscess formation and burn wound infection. pneumonia is actually the leading cause of death from nosocomial infection. these are defined as occurring from to hours after hospital admission. this definition has important implications for antibiotic therapy because the likely pathogens and their respective sensitivities are different for community acquired pneumonia. the diagnosis of nosocomial pneumonia is difficult following major injury as many patients will have pre-existing fever, leukocytosis, tachypnea, and chest x-ray changes. reliance on sputum gram stain and culture is important and best obtained by a bronchoalveolar lavage or protected specimen brush during bronchoscopy. predisposing risk factors include severe head injury, emergent intubation and shock, and such patients have been shown to benefit by early tracheostomy. staph aureus has been the most common pathogen isolated from the sputum and the remainder gram-negative organisms with pseudomonas aeruginosa, and klebsiella pneumonia predominating. bacteria recovered by site as well as by intensive care unit is published in the six month antibiogram which also includes recent antibiotic sensitivities. this aids in empiric antibiotic selection against such nosocomial organisms. in a series of severely injured patients (iss - ), mean temp. was . f, leukocytosis was k, pan was , fin was . , and peep was . at the time of diagnosis (ards excluded). there was marked reduction in class ii histocompatibility antigen (hla-dr) density on peripheral and bal monocyte/macrophages which recovered over time with resolution of pneumonia. immune suppression occurred prior to development of pneumonia, was especially localized to the infected tissue, but recovered with clinical improvement. specific immune modulation targeted to pulmonary white cells may hasten clinical recovery and minimize pulmonary dysfunction. -clinical experience j. tnllemar amphntericin b remains the drug of choice for many systemic fungal infections. its advantages include a broad spectrum of activity and intravenous administration. the major disadvantages of amphoterlcin b is its severe side-effects, especially the nephrotoxicity. to decrease the toxic side..cffccts various liposomal amphoteficin b formulations have been produced. it was found that these liposemal formulations were as effective as amphotericin b but in contrast had a low incidence of toxicity. at present there are three ~different variations of lipid formulations under assessment: amphotericin b lipid complex (ablc), amphotericin b coloidal dispersion (abcd) or true liposomes. the ablc has a ribbon like structure. it has been shown to have a reduced toxicity and an efficacy ranging from being as effective to four times less effective that conventional amphotericin b. regarding abcd the particles have a disk-like structure with a diameter of around t am and a thickness of nm. the ami-fungal efficacy is - times less than that of conventional amphotedcin b. both ablc and abcd are presently investigated in phase ii/iii studies in the us. ambiseme is currently the only commefieally available true lipesome. ambiseme is a spherical small unilamellar lipesome with a diameter less than nm with a mutina ld of > mg/kg. it has been used in dosages up to mg/kg/day in compassionate based studies with good tolerability. the mycological efficacy range from a % response rate for invasive candida infections to % response rate for aspergillosis. ambisomc have been evaluated as anti-fungal prophylaxis in randomized trials in bone marrow (bmt) and liver transplant (ltx) recipients. it was well tolerated. in bmt recipients the incidence of proven fungal infections was % among placebo treated patients compared to % for the ambisome treated patients (ns). in ltx recipients ambisome prophylaxis was effective, significantly reducing the incidence of deep fungal infections from % to % ill placebo and ambisome treated patients respectively (p< . ). prospective randomized trials comparing these various amphotericin b preparations with conventional amphotericin b is needed to determine their future place in the therapeutical arsenal. two patlentgroups ere particularly at risk to develop serious cmv disease: cmv seronegative transplant recipients of seroposltlva donors and those patlants treated for rejection with anti t-ceil preparations, we have evaluated the value of prophylactic anti-cmv immunoglobulin (cytotect", biotest pbarma gmbh, dreieich, frg) administration in high risk heart and kidney transplant recipients, in a double blind placebo controlled study kidney transplant recipients, treated for biopsy proved re)action with rabbit atg, received globullntplacebo infusions. the preparatlons were given i,v, in a dose of mg/kg at day , , , , and after the initiation of anti = rejection therapy, passive immunization completely prevented cmv related death, although it did not reduce th~ incidence of cmv isolation, viraemia or disease, this effect was mainly observed in cmv saronegativa recipients of a serop sitive donorktdney. seroposltive recipients did not benefit from treatment and seronegatlve recipients of a seronegetlye donor were not et risk for cmv infection at e!l. in a open study the incidence of cmv infection and disease was evaluated in consecutive i~eart sllograft recipients. sixty-five patients were cmv seronagatlve and they all received passive immunlzation according to the dosage schedule used in the kidney patients, but starting on the day of transplantation, this scheme resulted in median snti-cmv igg titers of elisa units during months. cmv infection occurred in / ~eronegetlve and in / seropositive recipients (n,s,), in ssronegetive donor-recipients pairs the incidence was significantly lower ( / ] , the passively immunized seronegstive recipients of e seroposltlve donorheart showed comparable incidence of cmv infection f t ) vs the seropositive recipients. primary infection more often resulted in disease than secondary infection ( v / ), but no difference in incidence of disease ( vs / ) or severity in symptoms was noted between the immunoglobulln treated serone(]ative patients and the seropositiva recipients. apparently passive immunization induces anti-cmv immunity which crossly resembles naturally acquired resistance. abdulkadirov k.,chebotkevich v., moiseev s. the incidence of infection is still high in patients underwent bmt. this complication is the major cause of mortality if it is not recognized and treated promptly and properly. our data showed that from patients with different types of leucemia after autologous and allogenzc bmt had the episodes of fever. in the ma i ority of these episodes the bacterial etiolog$ gram negative bacflli and gram positive cocci) can be proved. on the other hand, in % of the fever cases we detected also viral respiratory (corona-, adeno-, rs-and other) infection. our previous investigations showed that even in healthy persons the viral infection has influence on antibacterial immunity, in the cases of model experimental reaction in volunteers we found the decrease of delayed hypersensitivity - days after intranasal inoculation of influenza virus a (h n - ) to bacterial (staphylococcal, streptococcal and pneumococcal) and ~iycoplasma pneumoniae antigens in the leucocyte migration inhibition test. these results showed that respiratory viruses may be the important pathogenic factor in the development of bacterial infection in posttransplanted period. we consider the constant control of latent and visual respiratory viral infection in bmt patients to be very important. ficcb the ~ter£~li of the nation~l institute of trad/~atoloqy in budapest . consecutive cases of revision hip grafting were carried out arthroplasties wlth hemoloquous bone between the years and . in the same period of time pri~ total hlp replacen~nts were performed under i entieal technical conditions. the average septic rate for the 'total hip althroplasties was less than %. in the selected i cases the septic rate was % indicating the role of bone grafting° homografts were prepared by deep freezing~ it .is recognized that the cells of the hl~grafts become destroyed by the ium~unological, response of the host~ and the patients develop ~ti-hl~, ar~tib'o~ies. the dead ~trix, however, has a bone-inducing capacity that stimulates host osteoblasts to recolonize the *i~/trix which serves as scaffolding. the sequence of events favours the infections. for this reason, beside preventive perioperative systemic ant/biotic treatment, local ~ntibioties were also applied in the form of antibiotic-//npregnated cement. the role of age and the .immune status of the patients .is discussed.. the purpose of this study is to evaluate the rate of toxemia in patients with acute panereatitis and to find this coudition to the activation of cascade systems that are encountered in the subsequent complications of the disease. we studied a series of patients with acute pancreatitis, the severeness of which was evaluated by the ranson's criteria and the apach-ii scoring system. all of them were considered to have severe acute puncreatitis. the determination of toxemia was made using the limulus test (lal test). we also determined the levels of the third (c ) and fourth (c ) complement components as weu as the coagulation factors, iibrinolysis faeters and kimns by serial measurements. the severity of the disease was serially determined by the apach-ii scoring system. it was found that complement activation ( which was also assessed using a graphically illustrated method by a aggregometer ) was followed by an increase of morbitity and mortality .we also detected that toxemia (positive lal-test) was closely correlated with complement activation and more of the ranson's criteria. a clear relation existed between the number of ranson's signs and the enmplieations' rate ( "= - . , p < . ). the documentation of toxemia and the complement activation cannot predict the kind and the severity of complications. the study of coagulation, fibrinolysis and kinms systems didn't reveal any results with statistical significance. necrotizing pancreatitis still represents a life-threatenthg disease. infectious complications dominate among the causes of death. differences in the individual immune response could possibly explain different clinical courses even in patients with comparable pancreatic morphology. to explore the inflammatory response in acute pancreatitis, the following investigation was performed. methods: peripheral-venous blood was withdrawn on admission and furthermore twice weekly in as yet patients with acute pancreatitis and tested for the parameters mentioned below. in parallel, polymorphounciear granaiocytes were isolated using density gradient centrifugation and assessed for superoxide anion and hydroxyl radical producing capacity using electron spin resonance techniques. results: total leukocyte cotmt and total lymphocyte count did neither reflect the clinical course nor predict complications. this comes tree also for serum igg, igm, iga, c , c , crp, alpha-l-antitrypsin and neopterth as well as for plasma il-la, il-ib, il- ra, il- , il- r, il- r, tnf-ct, tnf-~r (p ) and icam- . in contrast, pmn-elastase, il- and il- closely correlated to the clinical course. isolated pmn's in vitro capacity to produce oxygen radicals depended on the respective radical species and was slightly elevated (superoxide anions) or decreased (hydroxyl radicals), respectively. patients with a cd +/cd + ratio below i were seen at risk of developing septic complications. in contrast, a percentage of monocytes of % or more among total mononuclear cells indicated an uncomplicated course, in general. conclusions: the immune status of the individual patient may significantly influence the course of acute pancreatitis. the cytokine pattern in peripheral blood is very complex and most parameters are of little use for the clinician. the pmn-elastase, il- and il- , however, closely correlate to the clinical course and may prove valuable for follow-up. the cd +/cd + ratio was found the best predictor of septic complications, but it failed in non-septic patients. a percentage of % or more of monocytes among total mononuclear ceils indicated a rather mild course. the reduced ability of the pmns to produce hydroxyl radicals may help to explain the frequent development of septic complications in severe necmtizing pancreatitis. peroxidation of membrane lipids contributes to ceil injury in pancreatitis. overwhelming release of toxic metabolites by infiltrating neutrophils is regarded a major pathogenetic factor, too. as yet little is known about the mechanisms by which oxidative stress and leukocytes damage pancreatic cells. the present study examines (i) the susceptibility of pancreatic acinar cells to attacks by oxidants and leukocytes and ( ) the potential of antioxidants to prevent such damage in order to better understand the cellular mechanisms of pancreatic injury in inflammatory states. methods: freshly isolated rat pancreatic acinar ceils were exposed to a model system of oxidative stress consisting of mu/ml xanthine oxidase (xod), mm hypoxanthine (hx), mm fec and mm edta. in a second set of experiments, acinar cells were exposed to excess autologous neutrophils or neutrophils obtained from patients with acute pancreatitis. neutrophils were stimulated by zymosan a, pma, and il- . cell viability was assessed by both cellular uptake of trypan blue (tb) and by release of ldh. results: the xod/hx system caused a time-dependent acinar cell injury. this injury was effectively prevented by catalase (cat) and gfutathione peroxidase (gpx). in comrast, superoxide dismutase (sod) enhanced cell injury. addition of both sod and cat abolished the damage seen with sod alone. the non-enzymatic scavengers mannitol, dmso, dmtu and the iron chelator deferoxamine were not protective and at a higher concentration even accelerated cell decline. the newly developed antioxidants of the lazaroid type effectively prevented oxidative acinar cell damage. stimulated neutrophils, both autologous and heterologous, did not damage healthy acinar cells but had even protective effects. conclusion: pancreatic acinar ceils are very susceptible to oxidative injury. a combination of catalase and sod prevented cell damage effectively. sod when given alone may rather damage than protect aelnar cells when h is generated in concentrations overwhelming the capacity of endogenous catalase. therapeutic approaches to pancreatic disease using antioxidants should, therefore, include combinations of protective substances. the lazaroids seem to be candidates for clinical use as antioxidants in pancreatitis. the results argue against direct toxic effects of stimulated neutrophils to pancreatic acinar cells. are ch~act~z~ by the presence of a polymicrobial flora, the pmtotyi~ cffthese inf~ons is secend~,y bacterial pedtonitlw, whereby a pathololoeal process in the ~trointesfimd tract r~ful~ in tim disrup~on ofi~ inteffrlty and ¢ollseqtlent sptl]nge of inte~.i,o~.l gontents into the peritoneal c~iry. the ensuing infection invariably contains a mixtm~ of gt~m negative enteric bacilli, gram positive b~eria and anaerobe& experimental and clinical =t~ies have de~ed the eantrlbution of each of th¢~ components to ti~ ovemu virulence of these in~ons, gram negative enteri~ such as f.veher~chla coil ere endowed with a virulent l~l~x~lyse~haride ptill~ly t~sponsible for lethality, by contrast, bacteroldes sl~cles, which rarely c~se death, prornot~ abscess fonllation, a uniqm~ capsul~ polyseccluu'ide, particularly on b.j~ogiljs slrai~, oontributes to tjtis erect, several mecltanims have bccn pml~ed whereby or~ microorganism mi~t interact with its microbial ~net to augment the overall virulence of a r~xed im~edan. these include: l) provision of nutrients by one apexes which stimulates the growth of its ~opathoge& ) inhibition of host deletes by one of the migroorganisms so that the other microbes might persist and exert their virulence, ) the trant~ of vim.©n~e traits between ~renr~a.,dsms and ) the ~.mizatian d the mi~oe~vironmental con~tion$ by one d the baetez'isl pa#, so that the other might persist. exampl~ for each of these m~banisms imv~ been provided by experimental ttudies i~stigating e.co!l-b.p~flls synergistic in~ra~ons. byproducts ofg.coli metabolim l~¢ovide essential short ebath fatty acids £~ optimal b,frosili~ ga'owth. fm-ther, oxygen ¢ons~tmption by kcelt lowers oxygen tension end redox potantial to levels eomlucive to b#a#lts gro~h. coawr~ely, b,~agtlis rolea~s proteases and fatty acids wl~¢h impair pl'tsgocy~¢ ~lt rmctlon tnd permit f-..¢oli proliferation and expression of its intrinsic virulent. in summaxy, interactions among the separate microbial cemponents of mixed infections heighten the overall virttienee of these lafectiot~, this knowledge provides ~r rationale for targetting of antibiotic therapy against the knowa eantributors of these synergistic pro~¢sses, intraabdominal abscess formation and the macrophage william g. cheadle, m.d., department of surgery, university of louisville school of medicine, louisville, ky inflammation of the peritoneal cavity following bacterial contamination has been classified into primary, secondary and tertiary, the last two relating to bacteria originating from the gastrointestinal lumen. the natural history of such infection is either resolution without clinical sequelae, which is uncommon, abscess formation, or generalized peritonitis, which occurs as a result of failure of peritoneal host defenses. early clearance of microorganisms by peritoneal fluid circulation and filtration througti subdiaphragmatic lymphatics into the thoracic duct and systemic circulation occurs as well. simultaneously peritoneal macrophages and the omentum approach the area of inflammation and lead to neutrophil influx and abscess formation adjacent to the affected viscus. we have found a shift in peritoneal macrophage function from antigen presentation to proinflarnmatory cytokine production that occurs early after experimental peritonitis produced by cecal ligation and puncture. this is also reflected by reduced class ii histocompatibility antigen expression on peripheral blood mononuclear cells and peritoneal macrophages. this is accempauied by an influx of both neutrophils and macrophages into the peritoneum and subsequent abscess formation. interestingly, there is little serum endotoxin or tnf seen in this model despite tnf mrna expression in peritoneal macrophages. we believe this model is more clinically relevant than other models of endotoxemia or bacteremia in which different patterns of cytokine expression are seen. newer agents aimed at reduction of systemic manifestations of sepsis originating from intra-abdominal infection such as monoclonal antibodies against cytokines or il- receptor antagonists may need to be directed against remote organ macrophage populations while preserving peritoneal macrophage function. inflammation is a complex process involving microcirculatory changes, extravasation of fluid and a cellular influx in the affected body area. in our communication, we will only consider the regulation of the cellular infiltrate which plays a major role in the defense of the peritoneum against microbial invasion. until recently, it was thought that the influx of leukocytes in the abdomen was induced by bacterial products, local humeral factors and secretions of resident macrophages. there is now increasing evidence that this view is too simplistic. many other cell types present in the abdominal cavity or composing the peritoneal membrane (mast-cells, mesothelial cells, fibroblasts) are able to release or secrete vasoactive or chemotactic substances such as histamine, prostagtandines, or cytokines. they are most likely to play a role in the regulation of intraperitoneal inflammatory reactions. the emigration of leukocytes towards the abdominal cavity is also modulated by a previous contact with gram negative bacteria. in the rat, this intriguing phenomenon is long lasting, cannot be transferred by serum and seems independent from t lymphocytes. the clinical relevance of these various regulating mechanisms has still to be determined. kinnaert paul, h pital erasme, route de lennik , bruxelles belgium generalized response in secondary peritonitis the clinical course of an intraabdominal infection may depend on a variety of variables including the capacity of host defense mechanisms and the degree of the inflammatory response. if local defense mechanisms fail to restrict the inflammation to the abdominal cavity a generalized inflammatory reponse will result. in a first stage generalized signs of a local inflammation become detectable whereas the second stage comprises the overwhelming systemic inflammatory response. the extent of this systemic response determines the outcome. sometimes it may appear to be unrelated to the severity of the intraperitoneal findings. the activation of plasma systems and cellular elements leads to a fast release of cytokines, inflammatory mediators and other substances. these parameters precisely reflect the degree of the generalized response. inflammation of the peritoneum causes significant morbidity. objektives: to test the hypothesis that peritoneal mesothelial cells play a role in regulating inflammatory responses within the peritoneal cavity, we examined neutrophil-chemotactic activity (interleukin ) and monocyte-chemotactic cytokine (mcp) release by sytokine-etimulated mesothelial cells. confluent human peritoneal mesothelial cells were exposed to varying concentrations of phorbolmyristate-acetate (pma) and the cytokines tumorneerosis factor a (tnf a) and interleukin i~ (il-i~). the supernatant was examined for il- by elisa and for mcp by investigating the ehemotactic activity for isolated human monocytes. mesothelial cells express low levels of il and monocyte chemotactic activity when cultured. these activies were significantly increased ( -fold) after stimulation with either tnf a or il-i~. additionally macrophage inflammatory protein was detected. these observations provide a probably important mechanism whereby peritoneal mesothelial cells respond to imflammatory stimuli released during peritonitis and how leucocyte recruitment by liberation of chemotactic cytokines is regulated. the perioperative course of lps, tnfa and il- in patients with bacteriologic proven abdominal infection (intraabdominal abscess , diffuse peritonitis , pancreatic necrosis , pancreatic abscess ) was followed prospectively and evaluated for possible correlation with septic state and organ function. methods: patients were studied in a to hours period during their first surgical intervention because of intraabdominal infection. all were monitored for their cardiovascular, respiratory, hepatic and renal function. plasma samples for lps. tnfa and il- determination were drawn preoperatively, intraoperatively, and until h postoperatively in regular intervals (min /pat), results: preoperative apache ii was in median (rain , max ). patients fulfilled the criteria of sirs. of them were in septic shock.there was a significant correlation between preoperative tnfa and apache ii (p= , i, spearman coefficient). preoperative cardiovascular (systol. rr< mmhg) and respiratory (pao < mm hg) dysfunction were associated with significantly elevated tnfa (cardial: p= , i, wilcoxon; pulmonal: p= , ) and il- (cardial: p= , ; pulmonal: p= . ) overall, lps, tnfa and il- values varied considerably during the observation period. however, tnfa was markedly higher in patients with sirs and septic shock (group a: n= i , mean pg/ml) than in those who did not fulfill these criteria (group b; n= , mean pg/ml; p= , i, wilcoxon). il- was significantly higher in group a (mean pg/ml) than in group b (mean pg/ml; p= , o i wilcoxon). conclusion: perioperative tnfa and il- were shown to correlate significantly with preoperative organ function, apache ii and the severity of sepsis. these results could help to define patients that might benefit from further therapeutic strategies, e.g. antibody administration. department of surgery, university vienna, akh wien, wahringer gurtel - , wien. aim of the study: the purpose of this pilot study was to establish and to prove a standardized reproducible animal model of intraperitoneal sepsis induced by e.coli-endotoxinaemia in lew.lw-rats in order to investigate early immunoserological responses to find a mediator based evaluating system of peritonitis sepsis. materials and methods: in lew. lw-rats, diffuse peritonitis was induced by intraperitoneal injection of a mixture of e.coli (khu +) and autogenous haemoglobin solution. in the control animal group (n= ) an intraperitoneally injection of physiological saline solution was done. blood samples were obtained by heart puncture after hours. stastistieal calculations were performed on a personal computer with the spss programm vers. . (correlation with pearson's r, mann-whitney-u-test, descriptives statistics, discriminant analysis). results: in contrast to the sham treated rats, the peritonitis animals showed significant differences in the concentrations of endotoxin, interferon-gamma (wn-y), the pteridin derivate biopterin and serum pla -activities [endotoxin range from . eu/i, sd= . to . eu/ , sd- . (p < ), ifn-¥ levels, range from . pg/ml, sd- . , to pg/ml, sd= (p < . ), circulating pla -activities range from . , sd= . to . u/ , sd= . (p < . ) and biopterin range from . nmol/l sd= . to . nmol/l, sd= . (p < . )]. for the peritonitis group we found strong correlations between the degree of endotoxinaemia to elevated levels of ifn-'~ (rp = . , p < . ) and bioptefin synthesis (rv= . , p < . ). the increase of ifn-t levels was correlated to the regulatory synthesis of biopterin (r = p < . .. p • , . . ) and to the pla -actwtues (rp = . , p < . ). the biopterin synthes~s correlates slightly with the pla -actn,ities (rp= : . ; p < . ). using the para, meters of endotoxin, ifn-y levels, biopterin and the pla~ -activities only, the statistical procedure of the linear discriminant analysis makes it possible, to distinguish between non-septic animals and septic animals correctly at a rate of %. anaerobes were found in . %, anaerobes were isolated in . %. there were aerobic and anaerobic associations in . % and microflora was not found in . % of the cases. express method of anaerobes discovering let to receive information on - days early than in generally accepted nethods. intraaotal transfusion of oxygenate blood and laser irradiation of blood reduces the duration of anaerobic sow, disminishes intoxication and accelerate the patients recovery. patients with abdominal sepsis are subject to long periods of hospitalization and high associated morbidity and mortality rates. this category of patients is thus consuming extensive facilities and costs. as the age-related outcome of abdominal sepsis is not fully known, the aim of the present study was to investigate abdominal sepsis in the elderly. out of patients with abdominal sepsis treated at the surgical intensive care unit during a -year period, ( %) had an age of years or more. were women and were men, a sex distribution not differing with patients younger than years. the patients were scored according to apache ii and septic severity score (sss) upon arrival to the intensive care unit. bacterial cultures, the occurrence of organ failure, hospitalization and outcome was noted. in median two operations were performed for both "younger and elderly" patients. the median time of hospitalization in the elderly was (- ) days including in median days in the icu. figures in patients less than years of age were comparable ( (- ) days out of which in median days in the icu). apache ii and sss-scores did not significantly differ ( . vs and . vs . , respectively), between the groups. neither did the incidence of organ failure differ ( / vs / ). however, the incidence of multiple organ failure was significantly lower in elderly patients ( / vs / (p < . )). the mortality rate, however, did not differ between the groups ( / vs / ). in conclusion, severe abdominal sepsis in the elderly was not associated with an increase in mortality, incidence of organ failure or hospital stay. with the help of light transmissional scanning electron microscopy morphology of erythrosytes of peripheric blood was studied in patients with different stages of diffuse peritonitis before and after intravascu!ar irradiation of blood with heliun-neon laser. peritoneal morphology was investigated in patients who died from peritonitis, it was established that in all phases of peritonitis occured stomatocytoric and echinocytoric transformation of erythrocytes which progressed simultaneously with increase of intoxication. it combined with strongly pronounced vessels variability of microcirculatory peritoneal bed which displaied by erythrocytes aggregation, stasis and microtrombogenesis. in intravascular laser irradiation of blood number of erythrocytes which underwent to stomatocytoric and echinooytorie transformation was lower than in patients without laser irradiation. it indicated that the intravascular irradiation of blood with helium-neon laser can prevent development of severe alterations of rheological property of blood and consequently variability of microcirlatory peritoneal bed in patients with diffuse peritonitis. abdominal sepsis is still associated with high morbidity and mortality rates, frequenfly caused by multiple organ failure. it has been reported that changes in capillary permeability play a role in the pathogenesis of multiple organ failure. the present study aimed at evaluating the influence of intraabdominal sepsis induced by cekal ligation and puncture on capillary permeability in multiple organs and tissues. adult male sprague-dawley rats were subjected to laparotomy with separation of the cekum (sham operation) or induction of intraabdominal sepsis by cekal ligation and puneatre (n-- in each group). at , , , , and hours (n= /timepoint), the animals were evaluated concerning mortality and capillary permeability as determined by the passage of : i-labelled albumin from capillaries to the peritoneum, the proximal and distal small intestine, cekum, colon, spleen, kidneys, lungs. the mortality rate in rats with intraabdominal sepsis was % both at and hours. capillary permeability in the peritoneum, cekum, colon and kidneys significantly increased from hours and on in rats with intraabdominal sepsis. in septic animals, capillary permeability in the lungs and spleen increased from hours and on and in the proximal and distal small intestine from hours and on. different types of alterations in capillary permeability seem to appear: ) a temporary short increase e.g. in the proximal small intestine and spleen; ) a temporary longer increase e.g. in the colon and kidneys; ) a persisting increase e.g. in the peritoneum, cekum, distal small intestine and lungs. we conclude that experimentally induced intraabdominal sepsis induces early alterations in capillary permeability in multiple organs and tissues. such changes may contribute to explain the development of sepsis-induced multiple organ failure. despite a number of significant advances in the care of burn and non-burn traumatic injury, infection and sepsis remain major causes of morbidity and mortality. the severe immunosuppresslon often seen in patients with severe trauma or large burns may predispose these patients to life threatening infections. included among the many immune alterations are changes in the functional capabilities of neutrophlls (pmns). we have examined the expression of the p integrins (cd l a, b,c/cd ), and the fc'?r (cd , cd , and cd ), as well as several functional parameters, on pmns from thermal and non-thermal traumatic injury, pmns were obtained from patients sustaining severe trauma (initial apache ii score > ) or thermal injury (> ~ total body surface area, % full thickness), and healthy controls. the expression of cd b and c and to a lesser degree cdi a was significantly reduced on pmns. the expression of cd and cd but not cd was also significantly reduced. pmns displaying this reduction in receptor expression have a significantly reduced ability to phagocytose bacteria and undergo the oxidative metabolic burst response. thermal and traumatic injury result in global reduction in the expression of integrins and for which may lead to decreased functional capabilities, these abnormalities may in turn account at least in part for the increased rate of infection in these patlems, institute, dept. of surgery, ~ ethesda ave, cincinnalt, oh, usa, - s b, antibiotic-phagocytic cell interactions: their effect on endotoxin release. c g c-emmet , dep[baeteriolog.z, univer_sitv of glasgow, scotlan~_d increasingly it is recognised that pathogenic bacteria are capable of surviving intracellularly within phagocytic cells in addition to their capacity to produce disease whilst in the extracellular milieu. as well as providing protection from certain antibiotics which fail to penetrate the phagocyte, such intraceltular bacteria may be transported from the initial site of infection to a distant more vulnerable body site wherein they may proliferate. it is also known that some antibiotics are capable of becoming concentrated within phagocytic cells mid displaying bioactivity therein. such bioactivity might be responsible for the release of endotoxia #orn gram-negative bacteria which when liberated from the celt could ~gger the cytokine cascade. anfib,.'otic-induced damage to the ultrastructure of bacteria can also occur when the target bacteria are exposed to low (sub-mic) concentrations of certain drugs. such bacteria may present quite altered surface components m host-defense cells as well as releasing biologically active ceil wall components such as endotoxin. the nature of these interactions at the cellular level as well as the consequences for the host will be discussed. new jersey medical school: umd, newark, nj a technique of physiologic state classification has been developed based on the m~itlvariable analysis of patient derived data sets of seventeen physiologic variables. these multivariable data sets obtained from critically ill patients requiring intensive care, were aormallsed by the mean and the standard deviation of recoverin~ trauma patients who were not critically ill, the resulting normalized seventeen variable sets were then clustered. seven independent data groupings were developed. the normal stress response hyperdynamic state seen post-trauma and in compensated sepsis (a stets)/ metabolic insufficiency seen in septic decompsnsation (b stste}; early (c,) and late (e ) respiratory insufficiency associated with ards; cardlogenlc dscompensation (n state); post-trauma hyvolemla without shock (r stats). the stats closest to a new patient's values allows patient classifi atlon with regard to his previous physiologic state. classifying observations f~om patients who lived or died who fell into these physiologic states enables a probability of death (p death) to be obtalned. utilizing this criteria for the staging of severity in recent trauma patients the physiologic states accurately and significantly predicted the likelihood that the patient had an increased circulating level of the eytoklnes tnf and il- . the probability of death (p death) as well as the cytoklne levels appear to be a function of the physiologic b state with the highest levels being seen in the b state of metabolic insufficiency and the c~ state of oombined respiratory and metabolic insqffioienoy characteristic of septlc ards. the increase in the magnltude of metabolic abnormalities associated with the transition from non-sepsls to septic a, septic b, or septic c z states was associated with an increasing probability of death (p denth)(mean a state =. , mean b state = . , mean ~ state = . ). the accuraay of this estimate was prospectively analyzed in this group of m~itlple patients of whom % had sepsis and % had ssptlo ards. the survivors had a mean p death of . and the deaths had a mean p death of . . the severity of post-trauma sepsis can be quantified by probability analysis and stra~ifie~ by physiologic state. serologic tests have not been extensively tes'~ed in surgical patients but seem to be of limited value. we use nystatin as the main form of chemoprophyhxis. patients "~'ith signs of infection who do not rapidly improve with antibacterial therapy are candidates for anti-funsal therapy, amphoteradn b remains the first llne of therapy although combination therapy '~'ith flueonazole is use;l with increasing freque~;c)', the recovery of c~dida from an antra-abdominal site represents a challenging problem, anti~ngal therapy in such patients depends on the underlying disease, the nature of the infected material and overall patient risk. role of neural stimuli and pain principles and practice of anesthesiology effect of combined prednisolone, epidural analgesia and indomethacin on the systemic response after colonic surgery arginine: biochemistry, physiology and therapeutic irnplications immunosfimulatory effects of arginine in normal and injured rats arginine stimulates lymphocyte immune response in heahhy humans rote of arginine in trauma, sepsis and immunity arginine enhances wound healing in humans if labrecque t, gv campion t, and the rhll-lra phase i//sepsis syndrome study group the cleveland clinic foundation a murine-anti-human tnf-monoclonal antibody known as cb was the first anti-tnf mab which was studied in a phase ii multinational trial in the treatment of patients with severe sepsis.this was an open-label, dose-escalation trial consisting of patients who were enrolled into one of four treatment groups: ( ) . mg/kg of anti-tnf mab, ( ) . mg/kg, ( ) mg/kg or ( ) . mg/kg at study entry and the second dose hours later. the small sample size in each group (n= ) precludes detailed statistical inference in this study. nonetheless, a considerable amount of useful information was obtained from this investigation. irst, this study demonstrated the clinical feasibility of specific anticytoldne therapy in septic patients. second, the measurement systemic levels of tnf proved to be an elusive target; interleukin- may prove to be a more useful indicator of cytokine activation. third, immunologic reactions including tnf: anti-tnf mab immune complexes and human anti-routine antibodies were frequently found in these patients. despite their apparent lack of overt toxicity in this study, these immunologic reactions may complicate this form of anticytokine therapy. additionally, the potential benefits of anti-tnf mab therapy occur within the first hours of therapeutic administration in these septic patients. infecting organisms differ in their potential to induce tnf in vitro and these differences correlate with circulating tnf levels observed in septic patients. rapid methods to define those patients most likely to respond to anticytokine therapy are needed to determine the ultimate therapeutic potential of these agents in clinical medicine. wherry, j., abraham e., wunderink r., silverman h., perl t., nasraway s., levy h., bone r., wenzel r., balk r., allred r., pennington j. and the tnfa mab sepsis study group.tnfa mab (bay x ) is a murine monoclonal antibody raised against human tumor necrosis factor. tnf~ mab has been shown to reduce morbidity and mortality in animal models of septic shock and has been safely administered to septic and non septic patients.to evaluate the efficacy and safety of tnf~ mab in patients with sepsis syndrome, a prospective, multicentered, double-blind, placebo-controlled trial was conducted in hospitals in north america. patients were prospectively stratified into shock or nonshock groups and then randomized to receive a single intravenous infusion either of mg/kg tnf~ mab, . mg/kg tnf~ mab or placebo ( . % human albumin).patients received standard aggressive medical/surgical care during the day post dosing period.the three treatment arms were well balanced with respect to demographics, apache ii score and other parameters. for all infused sepsis syndrome patients, those who received tnf~ mab had slightly reduced day all cause mortality compared to placebo. among shock patients there was a more pronounced trend towards efficacy at day post dosing with lower mortality rates in both active treatment arms. among nonshock patients tn~ mab did not appear beneficial. the initial clinical experience with a chimeric anti-tnf monoclonal antibody, ca , was undertaken in septic patients. the objectives of the study were to determine the safety, pharmacokinetics and effects on cytokine levels of ca . as a single infusion or in combination with ha- a in septic patients. the study was conducted with the intent to progress to an efficacy trial based on the information collected.the trial was conducted in three stages. stage was an open label trial in which groups of patients each with the clinical diagnosis of sepsis received ascending doses of ca ( . , , , mg/kg). stage was a randomized, double blind study in which patients received a single dose of ha- a ( mg) and placebo or one of doses of ca ( , , mg/kg). stage was a randomized, double blind study in which patients received a single dose of placebo or one of doses of ca ( . , , mg/kg). in addition to usual laboratory tests, the following assays were performed: chimeric anti-tnf concentration, anti-chimeric antibody, endotoxin, tnf, il- , and il- levels.a total of patients were enrolled from clinical sites ( in stage , in stage and in stage ). primary analyses were performed on patients in stage and . there were patients who received ca exclusively and patients received placebo. administration of ca was well tolerated at doses up to mg/kg. no patient discontinued treatment due to adverse events. human anti-chimeric antibody responses were positive in % ( / ) of evaluated patients. mean cma × and auc increased proportionally with increasing doses of ca . the mean half-life was - hrs ( - hrs). a dose related decrease in tnf concentration was observed hr post infusion of ca . tnf is considered to be one of the central endogenous mediators for the inili'ation of the pathophysiological changes in patients with sepsis and septic shock. high tnf levels were demonstrated to correlate with patient outcome. blocking or neutralising tnf with specific antibodies was effective in preventing death in some animal modets of sepsis. in a placebo controlled prospective randomized study we tested the mur~ne derived antibody mak f. it is a f(ab') fragment. the fragment rather the complete antibody was selected in order to reduce the potential immunogenicity and to facilitate tissue penetration. patients with severe sepsis or septic shdck were enrolied in the study, three different doses of mak f or placebo were administered ( , ; , and i mg/kg) over a perid of hours in random order. the patients were evaluated for side effects, hemodynamics, organ dysfunction, cytokines (il , il and tnf), and outcome. at this time only an interim analysis of patients is available i indicating that mak f in all dosage groups resulted in a decrease in il . this contrasted to a further in crease of il in the placebo patients. no serious side effects have been reported so far. a more detailed analysis on all patients in the study will be presented and discussed.$ s staubach,k.h., otto, v., kooistra,a,, rosenfeid,j.a., bruch, h.p., univ. lfibeek, germany once endotoxinemia occurs in sepsis a vieieus cycle with translocation of et can be established. increasing the clearance capacity for et would therapeutically be the ulimate aim. we developed a new et on-line adsorption (ad) system in whole blood by means of polymyxin b (pb) coupled eovalently to a matrix (acrylic particles) via a atom-chain spacer. the detoxification capacity was ug[et/ml column material. the biocompatbility resulted in ~ platelet recovery. the column contained ml of admaterial and was sterilized by high steam autoclave, anticoagulation was achieved by heparine . iu/h in the inflowline after bolus injection of . iu. hp was performed on pigs at a rate of ml/min by means of a roller-pump until the animals succumbed (h). animals served as controls (c). serum et levels rose from . pg/ml to , pg/ml after hours in the c and from . pg/ml only to pg/ml in the h group after hours whieh was highly significant. survival time could be extrended from to min. results are listed in the following l. blinzler, p. zaar, m. leier, r. b( rger, d. heuser clinic of anaesthesiology , city hospital nuremberg, germany sepsis and multiple organ failure (mof) are still related with poor prognosis inspire of pharmacological and technical progress. impressed by revealing reports about blood purification the continuous veno-venous hemofiltration (cvvh) was used as supporting treatment beside the critical cam basic therapy of mof. from to consecutive patients were treated by cwh. mof was caused by hemolrhagic-traumatic noxa in °, and by septic-toxic event in %. all patients required mechanical ventilation (fio > , ) . ° showed hyperdynamic shock. % had renal and % hepatic failure. medium appache ii score amounted to , points. cvvh was performed in postdilution mode with a polyamide membrane (fh ) and high volume exchange ( l/die). anticoagulation was done with heparin. hemofiltration in mof was installed, when critical cam basic therapy including adequate respiratory and hemodynamic management, pamnteral nutrition, antibiotic treatment, etc., failed to stabilize organ functions. during consequent application of cvvh most of these patients showed improvement of their clinical course. pulmonary stabilization was seen in %, hemodynamic in % and renal in % of the cases. % of the patients survived and were discharged from hospital. of non-survivors ( %) died because of fatal mof within h after admission to icu. patients with early application of cvvh in mof showed a better survival rate.mediators of mof, i.e. products of the complement cascade measured in blood and nitrafiltrate by elisa, were partially removed by cvvh. the testing ultrafiltrate by hplc demonstrated decreasing spikes ofpolypeptides during hemofiltration. mof seems to be generated by cascade-activation of immune competent cells and plasmatic mediators (e.g. bmdykinin, eicosanoides, cytokines, anaphylatoxins, etc.). therapeutic approaches aim to inactivate or eliminate single substances. cwh with high-flux membranes in combination with high-volume exchange allows elimination of many mediators with different molecular weight and therefore may contribute to improve the prognosis of mof. other significant advantages of this teqalnique like adequate nutrition, optimized fluid balance and control of body temperature should not be negicctod. introductioni pseudomonas (p) aeruginosa has to be considered an important pathogen of nosocomial pneumonia and septic organ failure. the lung seems to be the predominant target organ for the pore-forming p. aeruginosa cytotoxin, thus inducing microvascular injury. with respect to therapeutical consequences, the potential protective effects of paf-antagonist (web ), cyelooxygenase inhibitor (diclofenac) and specific and unspecific antibodies on cytotoxin-induced pulmonary vascular reaction and mediator release were studied in the isolated perfused rabbit lung. methods: cytotoxin ( p_g/ml) was administered into the perfusion fluid in all groups, either in the absence of inhibitors (n= ), or after pretreatment with web ( xl -gm, n= ), or diclofenac ( #g/ml, n- ). furthermore, the application of specific antitoxin (mg/ml, n= ) was tested in comparison with the unspecific immunoglobulins (venimmun®, behring, . mg/ml) (n= ) and the combination of immunogiobulins, web and diclofenac (n= ). six experiments without toxin served as controls. the arterial pressure mad the weight gain as an indicator of edema formation were continuously monitored during the three hour peffusion phase. arachidonic-ucid metabolites, as well as lactate dehydrogenase (ldh) and k + concentrations were determined at rain intervals. results: cytotoxin caused a gradual increase in pulmonary arterial pressure, reaching a maximum value of . times higher than the control, starting after min and a delayed onset of edema formation resulting in a mean weight gain of g after min. this was paralleled by a significant increase in prostacyclin generation and a continuous release of k + and ldh. thromboxane synthesis exceeded about times that of controls in the toxin treated lungs. pretreatment with web or diclofenac significantly attenuated the pressure response and edema formation evoked by cytotoxin. the addition of the unspecific immunognbulin preparation alone induced a transient pressure increase within the first minutes, but mean values remained below those of the cytotoxin group in the continuing observation period. mmost complete inhibition of the pressure reaction, the edema formation and the metabolic alterations was achieved mainly by the combination of immunoglobulin, web and diclofenac and to lesser extend by the specific toxin antibody. conclusion: the current results point towards the crucial role of paf and aa-metabolites as mediators of cytotoxin induced microvascular injury. the systemic or local application of cytotoxin antibodies or even unspecific immunoglobolins in combination with paf-antagonist and diclofenac appears to be a promising therapeutic approach in the case of infection with cytotoxin-preducing strains. cytokines have long been shown to be of particular importance in the metabolic derangements occurring in lps-induced shock. recent studies strongly imply the involvement of platelet aggregating factor (paf) in the pathogenesis of gram-negative bacterial sepsis. an autocatalytic feedback network has been postulated to exist between paf and tumor necrosis factor (tnf), a key cytokine involved in septic metabolic cascade, leading to an uncontrolled amplification of inflammatory mediator release. we have previously shown that st ( -n,n,n trimethylammonium-(r)- -isovaleroyloxy-butanoic acid z- -( -chlorphtalidiliden) ethyl ester bromide) was quite effective in inhibiting the "in vitro" binding of h-paf (ki= . x - m) to rabbit platelets. the present study shows that pretreatment of c bl/ mice with st , administered by different routes, dose-dependently and significantly reduces the lethality induced by endotoxin (e.coli :b injected at mg/kg intraperitoneally). very interestingly, st administered at the same doses as above (i.e. . , . , and mg/kg body weight) results to be significantly effective in reducing the endotoxin-induced release of serum tnf. the reported dual activity of st (i.e. paf antagonism and decreased circulating tnf levels) may turn out to be greatly beneficial, in combination with current therapies, in the treatment of diseases that involve overproduction of tnf and paf such as septic shock. introduction: recently, we reported that prophylactic whole body hyperthermia ( . °c) induces heat shock protein ('asp) and increases smvival - fold in a mouse endotoxin model (am. j. physiol. in press). other investigators reported that prophylactic pharmacologic induction of hsp- by sodium arsenite improves survival in a rat sepsis model (abstract a am. rev. resp. dis. vol. , ) . the effects of heat are complex and in addition to formation of lisp- include release of cytokines, changes in cellular ph etc. thus, the protective mechanisms of heat may differ from those due to pharmacologically induced . the purpose of this study was to compare the protection of heat vs the protection of pharmacologically induced hsp- in a mouse endotoxin model to determine if different protective mechanisms were likely to be involved.. i%'lethods: both sodium arsenite ( mg/kg) and ethanol ( ~ of % ethanol) caused marked induction of hsp- in lung, gut, kidney, and liver, which was comparable to heat-induced hsp- . female nd mice weighing - gms were pretreated with arsenite or alcohol hours prior to challenge with escherichia coli endotoxin (-ld ) and survival was compared to control mice. results: survival at hrs. for arsenite treated and alcohol treated mice was % and % respectively and was statistically different from the % survival for control mice. (p< . ) (n= mice per group). however, at days post endotoxin, there were no differences in survival in the groups, i.e., ~ % survival for all groups. in contrast, the protective effect of hyperthermia remains present at days, i.e., ~ % survival vs % survival control. conclusion: the protective effect of heat is probably due to other factors such as the effect of hyperthermia to release il-lc~ and is not due solely to hsp- formation. it was the aim of the study to examine whether bacteria play a causative role in the pathogenesis of anastomotic insufficiency following gastrectomy in man.the study was carried out in form of a prospective, randemised, double-blind, multicenter trial. primary endpoints were the rate of anastomotic insufficiencies, infectious-and uncomplicated postoperative courses. all pat. received a periop, i.v. prophylaxis with cefotaxim. identical numbered vial either contained placebo or polymyxin b, tobramycin, vancomycin and amphotericin b . the vials were administered x per day from the day be ~ fore the operation until the th postop, day. insufficiencies were detected by gastrographin swallow and recorded by x-ray on day postop.. evaluation was carried out on an "intention to treat'basis. statistical analysis was done with the pearson's chi square and fisher's exact tests~ results: interim analysis was carried out in / after pat. had been recruited. along with a significant reduction of s.aureus and enterobacteria there was a reduction in the rate of anastomotic insufficiency of the esophago-jejunostomy from . % in the placebo-group to . % in the treatment group. the difference was not yet significant. the rate of nosocomial infections (e.g. respiratory tract infection and uti) were significantly reduced from . % in the placebo-group to . % in the treatment-group (p ~ . ;fisher's exact test). in march final results with more than patients will be presented for the first time. (= po < mm hg, b s-creatinin > mg%). respiratory insufficiency was the most frequent systemic complication followed by sepsis and respiratory insufficiency. etiology of pancreatitis and initial serum increase of pancreatic enzymes predicted neither complications nor outcome. only of deaths occurred during the st week, all other deaths occurred late (after - weeks), generally as the consequence of septic complications and multi-organ failure. high levels of crp were correlated with a compliacted course and a fatal outcome. although same cytokines (e.g. -- ) were found increased in severe disease, the predictive value of these markers was not better than the combination of ctinical scores (ranson, imrie, apache ii) with gt or crp. conclusions: intensive care medicine can often control the inital shock situation in severe pancreatitis. thus. only % of deaths today occur eady in the course of the disease, whereas this percentage varied between - % just years ago. nowadays, most deaths are caused by late septic complications and multi-organ failure. ranson-and ct-scores as well as serum crp predict a course with systemic complications; they are less helpful for prediction of sepsis and late mortality. it is doubtful whether measurements of cytokines will help to better predict the late outcome. as yet, only careful and continuous monitoring of patients (e.g. by apache scores) may help to early identify those who develop septic complications and multi-organ failure. the classic description of severe acute pancreatitis has hinged upon the release of large volumes of activated enzymes into the peritoneal cavity and thertce the lymphatics and blood stream. these activated enzymes escape from the pancreas due to disruption of cells with associated ischaemia and occasional infarction of tissue. for to years it has been postulated that the bocly's defence system to activated pancreatic enzymes required supplementation iu the form of anti-protease support either in the vascular space or in the peritoneal cavity. all controlled studies have shown that this is either impracftcal or unnecessary.hore recently release of a large number of cytokines from monocytes, macrophages and neutrophils have been considered to be harmful to the body and various agent~ which oppose the action of tnf alpha, paf and similar cytokines are being examined in experimental anim~is and certain clinical trials, it has clearly been shown that higher levels of cytokines are released in the patients with objectively graded severe acute pancreatitis than in those with milder disease. we now seem to be moving into an exciting phase of potentially beneficial therapy in acute pancreatitis which has had no specific effective therapy through studies utilising aprotinin, gabexate mesilate and fresh frozen plasma. inflammation cascades may play a role in the pathogenesis of acute pancreatitis. to evaluate the status of the cellular immune system we examined serum concentrations of immune activation markers in patients with acute pancreatitis ( males, females; median age: years, range: - years). concentrations of neopterin, serum soluble tumor necrosis factor receptor (stnf-r) and serum soluble intercellular adhesion molecule type (slcam- ) were determined using immunoassays (henning, bender, t cell sciences). / had increased concentrations of stnf-r compared to the th percentile obtained in healthy controls (> . ng/ml), and / patients had increased neopterin (> . nmol/i), / presented with elevated slcam- (> u/i). all patients with increased neopterin also had increased stnf-r, patients had concentrations of all three markers outside the normal range. there existed a significant correlation between neopterin and stnf-r (rs = . , p < . ). weak associations between age and stnf-r (rs= . , p=o. ) or neopterin (rs= . , p = . ) were also found. our results demonstrate activation of the cell-mediated immune system taking place in a sub-group of patients with acute pancreatitis. the finding of increased neopterin and stnf-r levels implies that activated monocytes/macrophages are involved in the pathogenesis of the disease. further data are necessary to evaluate potential associations between changes of marker concent-rations and the course of the disease. pancreatic injury after heart surgery was reported as soon as ( , ) and characterized by increased serum or urine amylase levels (in about % of patients) in the fi~t postoperafi.'ve days. this pancreatic injury, which sometimes led to acute pancreatitis, was atreaay at~buted to inappropriate perfusion of this organ. in the ffs, studies were published dealing with pancreatic suffering alter heart surgery, in large series of patients, concluding ~n~at panc~a~c injury (with a low incidence of pancreatifis) is more common than previously recognized and is a potential source of complication after camliac surgery ( , , ) . in a recent study ( ), evidence of pancreatic cellular injury was found in out of patients undergoing cardiac surgery, with out of these patients presenting abdominal signs or symptoms and developing severe pancreafitis. this injury was associated w~th preoperative renal insufficiency, valve surgery, ~..stoperalive hytxxension, calcium administered periopuratively and length of bypass. we studied patients submitted to cardiopulmunary bypass (cpb) for heart surgery and used the measurement of un:~sin, pancreatic iso-amylase and lipase in plasma for biochemical characterization of pancreatic cellular injury. blood samples were obtained before surgery, directly aller surgery (return to inte~ve care unit), hours alter surgery and in the folfowing days alter surgery (days , , , and ). computed tomography scan of pancreas was performed in patients presenting hi~ levels of amylase on day . we measured abnormal levels of trypsin and pancteatic iso-amylase in % of patients and observed simultaneous releases of these enzymes, the fi,'st one in the hours after surgery and the second more intense from day and pa~icularly on day after smgery. this second release was concomitant with abnormal levels of llpase. these biochemical observations were accompanied by radiological and clinical signs of pancreatic injury in about % of our patients : pancrealic abnormalities were revealed by scan in patients and acute pancreatitis in i patient. more pronounced pancreatic suffering was observed in patients undergoing valve replacement than in patients undergoing coronam-anrtic bypass grafm~g. analysis of trypsin and pare're, tic so-amylase are sw.cific of pancreatic cellular injury and their simultaneous ir~rease in plasma alter cpb in our padents confirms the presence of an exocrine pancreatic injury. the presence of a simultaneous peak of lipase mcaezse~ the specificity of overt pancreatic injtu diagnosis. the precise cause of th/s injury could he related to hypoperfnsion leading to ischemic injury of foe splancbnic area, pancreas being largely sensible to hypoperfnsion ( ). this hypoperfosion could he responsible for the ftmt release of pancrealac enzymes observed in our patients and would contribute to the deterioration of other organs leading to an inflammatory reaction developing in the following days and responsible for the second release of pancreatic enzymes observed in our patients. patients with necrotizing pancreatitis show a heigh rate of pulmonary, renal and septic complications, whereas the course in acute interstitial pancreatitis is generally very mild. we have prospectively analysed the value of endotoxin, interleukin- (il- ) and transferrin in compare with c-reactive protein(crp) for the early assessment of the severity of acute pancreatitis. patients aud methods: the values of endotoxin(measured by limulus-lysate-test), ii- (elisa), transferrin and crp (nephelometry) were analysed daily along the first i days of hospitalisation by patients with acute pancreatitis admitted to our hospital from / to / . it was judged whether the patients have either interstitial (aip) (n= ) or necrotizing (anp) (n=lg) pancreatitis. patients with anp have died during the course of pancreatitis (mortality= . %). results: -severity o~ pancreatitis: signifcant differences (p<o. , mann-whitney test) could be calculated between aip and anp for endotoxin, il- , transferrin and crp during the i days of monitoring. -mortality: except of il- on days , , and after ad-mission there were no significant differences between the values of analysed parameters in patients who survived and those values in patients who died. -organ failure: the patients with pulmonary, renal or multiorgan failure have significantly heigher values of endotoxin, il- and crp along the i days of monitoring in compare with those patients without an organ failure. conclusions: endotoxin, il- and transferrin, an important endotoxin carrier, are promising parameters to differentiate between the severe and mild form of pancreatitis comparable with crp. this parameters may be helpfull in the early clinical assessment of patients with acute panereatitis. the determination of cytokines may elucidate the pathophysiologic mechanisms that produce early systemic complications in acute interstitial (i) or necrotizing (n) pancreatitis (ap). the appearence of respiratory insufficiency (ri) is used to appraise the early systemic complications and is compared to the results of cytokine blood levels. in a prospective clinical trial from / - / , patients with ap were recruited and blood samples taken for cytokine determination with commercial elisa-kits. the differentiation between i (n= ) and n (n=l ) ap was made through ct-scan in all and laparotomy for drainage and necrosectomy in patients. the etiology of ap was gallstones in , alcohol abuse in , hyperlipidemia in and other or unknown causes in patients.five of patients with nap died early (n=l) or of late septic complications. none died of iap.the peak of cytnkine level in the first three days of hospitalisation was used for calculation. ri was diagnosed in the first week of hospitalisation, if oxygenmask or iutubation for at least days was nescessary to treat arterial hypoxemia. for statistical analysis u-test of wilcoxon, mann and whitney was applicated.the il- concentration in blood reached up to pg/ml in the first days depending on the severity of ap and dropped to almost zero in the next days, independently of the clinical course. the differentiation of i-versus nap, using a cutoff-line of pg/ml was correct in patients ( %, sensitivity (se): %= specificity (sp): %, (z: , ). high levels of il- over pg/ml correlated well with the prognosis ifri in the first week (accuracy: %, se: %, sp: %, c~: , ). the blood levels of il- reached a maximum of pg/ml in the first days, depending on the severity of ap, and showed a correlation to the clinical course in the following days. the peak of l,- blood levels indicated correctly the severity of ap in out of patients using a cut offtevel of pglml (accuracy: %, se: %, sp: %, ~: , ). there was no correlation between cytokine blood levels and mortality, also there seemed to be no correlation between the levels of il- and il- . in the bloodsamples of five patients with i-or nap no c~-tnf was detectable.the blood levels of il- , and to a lesser extent of [l- , can predict the severity and early systemic complications of ap in men. the excessive rise of cytokines can be explained by the stimulation of immunological cells ( macrophages, lymphocytes and endothelial cells) in the course of ap. objectives: in an opossum model, ligation of the sphincter of oddi or separate ligation of the bile and the pancreatic duct together leads to severe haemorrhagic pancreatffis while single ligation of the pancreatic duct causes only an exocdne atrophy. since bo has been discussed to be a contdbutor t¢, res dysfunction, this may depdve the organism of a potent defensive mechanism thus promoting the course of pancreatitis. the present study wa,,; carded out tc develop a new method for measuring dynamic liver res func.. tion and to test the hypothesis that bo causes a res dysfunction. material & methods: opossums were randomly placed in three groups. all received a central venous line. after midline laparotomy, a specially designe tourniquet was placed around the common hepatic duct above its junction with the pancreatic duct (group a, n= ), around the pancreatic duct (group b, n= ) or around both ducts (group c, n= ). after one week, the tourniquets were closed. using a scintillation camera, the liver uptake of nanocoll, a mtcalbumin colloid with a diameter of nm, was measured before, , and days after the obstruction. the curves were analysed by a computer and two parameters (r, s) were calculated using natural logarithmic regression. as a common measure for res function, the corrected granulopexic index (a) wa,,; determined, after day , the pancreas of each opossum was searched for necrosis by morphometdc methods. results: all animals survived till day . the opossums in groups a & had a macro-and microscopic normal pancreas, while those in group c showed a severe hemorrhagic pancreatitis. the granuinpexic index showed a significan~ change to the worse starting at day in group a & b (p<o, ) and at day it~ group c (p< ,ol). at day , res function in group c was significantly worse than that in group a & b (p< , ). the regression parameter r showed no significant change in groups a & b, but a highly significant decrease in group c starting at day (p< . ), thus showing a dysfunction of the hepatic res. conclusions: obstruction of the hepatic or pancreatic duct alone does no{ result in immediate dysfunction of the hepatic res, while obstruction of beth ducts does. because only ligation of both ducts is followed by a severe hereof.. rhagic pancreatitis, res dysfunction could be an important factor in the pathogenesis of pancreatitis and resulting organ failure.logarithmic regressinrl has proven to be a valuable tool to analyse dynamic hepatic res function. (b ) in lewis rats weighing - g. there were five groups: group a (n= ) were untreated controls; group b (n= ) were given isotonic saline intraperitoneally and observed for hours; group c (n= ) ml x e. coli intraperitoneally and observed for hours; group d (n= ) were given ml x e. coli and observed for hours; group e (n= ) ml x i e. coli and observed for hours, the rats were than killed, the spleens were removed and heparinised blood taken for immunological tests. total t-ceils, helper t-ceils, suppressor t-cells, monocytes, and the interleukin receptor were determined by monoclonal antibodies, indirect immunfluorescence, and flow cytometry (facs analyser ). statistical analysis was by the t test on rank transformed data.in group b (isotonic saline) the total t-ceils increased in the blood (p= , ) and spleen (p= , )com pared with the untreated rats (group a), in the groups with peritonitis (c, d, and e) we found highly significant rises in suppressor t-cells in the blood and spleen (both p< , ) compared with the non-infected control groups a and b. this increase was significantly higher in group d than in groups c and e. as well as other alterations, we found a uniform increase in the number of t suppressor ceils in our model of acute peritonitis that was both time and dose dependent, department of surgery, university vienna, akh wien, w~hringer gurtel - , wien. d~'na~'aics of som~ l~mnunologic indices in children with abdo;~tinal shock v.z.i~ioskalenko, s.f.vesiol$,t.v.p~bina serum (iga,:~i,g, circulating imaune co!~plexes, co:apleaentary serum activity, antimesothelialvisceral and parietal antibodies) and cellular (i-l~q~hocytes, ~s/th,b-lyaphoeytes,i nlaunoleukosis to aesothelial allergens; spontaneous blast cell transformation to phytohemaaglutinin and .nesoth<-~lial ~,togen; phagooftic neutrophil activity) im:~une indices v.'ere studied in children operated v:ith symi~to'as of abdo~ainal shock. ,'~!-~ of them had appendicnlar( - ocalized jo-diffuse, -~eneralized) and -hemoperitoni-~is (dull abdominal trau;na with injayy of 'the spleen- , the spleen and liver-q), flo patients tjere operated on for co~iplete iieus (~-intussnsc.sption, -com:lissural ileus). he follo~'~ing serum factors: cireula:;ing im~aune complexes and ~).esothelial antibodies are the aost i~portant ~ar~ers of the abdominal shock course. :yith the progress of the process the indices increase irresponsive of t.l~e cha±.aeter of pathology. in case of ileus regress and hemoperitonotis an abrupt drop in ~he titer of anti~aesothelial antibodies is noted. in bacterial peritonitis a high ~iter of anti:aesothelial parietal antibodies in great dilutions ("+++","++++"-q ; ) persisted even in the period of clinical recovery. cellular factors cham'acterize dfnaaics of the abdominal shock coulees less specifically llast cell transfor~aation and phagocyue neut~ophil activit can inderectly characterize transition of shock f~orn reversible into irreversible phases. the past so years have brought a number of major advances in burn care. the initial advance was the discovery that burn victims required large volumes of resuscitation fluid in the initial hours to maintain hsmodynamic stability, this was followed hy the dsvelopmsnt of topical antimicrohlal agents to prevent end treat infections. next, was the reporting that early excision of burn wounds, with autografting of the excised wounds was possible.finally, was the identification of the importance of aggrsssive nutritional support for the hypermstabolic burn patient.these advances have markedly increaesd survival rates for given burn mimes, s~ch that burns which would previously have been considered to be aniformly fetal, are now readily survivable.thsre remain two unsolved problems in burn care, which are limiting survivability cf burn patients.the first ie ths treatment of inhalation injury. ths sscond is how to obtain coverage of ths maaaivsly burned patient, who has limited skin graft donor sites available.this ssssion will focus on the new treatments being developed to obtain permanent coverage of burn wounds.these include the use of various tcplcal growth £aotore which can speed the rate of reepithelialization of wounds, both the beneficial and dstrimental effects of using cultured karatinooyte preparations, to obtain in excess of one squats meter of a pseudoskin from a single fifteen square centimeter biopsy of unburned skin, will be discussed, finally, the used for artificlal dermal preparations will be discussed. integumentary wound healing consists of simultaneous epithelializalion and contraction. not long ago, it was thought that healing proceeds at an optimum fixed rate and could only be delayed. the recent explosion in molecular biology and recombinant gene techniques have produced information on the biological activity of compounds previously believed to be biologically inert. many current attempts to modulate the rate of wound healing center on the topical application of various growth factors produced by integumentary cells or agents designed to modulate growth factor expression or response. epidermal growth factor (egf), plateiet derived growth factor (pdgf), transforming growth factor (tgf) and fibroblast growth factor (fgf) have been demonstrated, both in vitro and in vivo, to stimulate the proliferation and diferentiation of their designated cells types. egf and pdgf have been clearly demonstraled to increase the rate of wound closure in partial and full thickness wounds. pdgf also has demonstrated efficacy in the closure of recalcitrant pressure sores, whereas tgf increases the tensile strength of incisiona[ wounds and fgf stimulates angiogenesis. it appears that epidermal keratinocyte migration during wound healing depends on integrin-mediated interactions with compounds and ceils extracellular matrix. additionally, the activities of extracellular glycoproteins such as fibronectin, fibrinogen, laminin and thrombospondin are coordinated by multiple integrins with specific distributions and binding affinities. currently, agents which incorporate specific protein sequences essential for the interaction of the glycoproteins with the cells of the extracellular matrix are being investigated. it is has been clearly established that the rate and nature of wound healing can be influenced by the application of various agents and that sufficient quantities of these agents can be manufactured. the future challenge is to develop techniques to now the objective evaluation of the clinical efficacy of these various agents and to employ the appropriate agents in a cost-effective manner. transplantation; and ) the immune status/manipulation of the host.multiple interactive variables will determine the effect of employing allogeneic cells and tissue in wound coverage design and a batter understanding of the dynamics of the wound-graft microenvironment will facilitate the dove opment of clinicauy beneficial graft composites. cadaver allograft skin (cas) is the "gold standard" for wound coverage, but has limitations including varied availability & quality, immunogenicity leading to rejection, & potential for disease transmission. our development of a temporary living skin replacement (tlsr) addresses these issues; the tlsr consists of highly screened human neonatal fibroblasts (hf) cultured in biobrane a, a bilayer dressing consisting of nylon mesh laminated to a thin silicone membrane which controls water-vapor transmission. studies in our lab indicated that "fresw ~ tlsr grafts reproducibly close full-thickness wounds in mice & perform better than bb controls. we studied wound adherence & structural/molecular properties of fresh & cryopreserved (cryo) tlsr. methods: tlsrs were prepared by seeding /co hf in bb nylon mesh in dmem. hf quickly attached to the nylon mesh & were allowed to proliferate - wks. fibroblast mitochondrial activity was assayed by mtt assay. matrix proteins were identified by immunostaining, mrnas for specific growth factors were identified by reverse-transcription polymerase chain reaction amplification, & quantitated by gel scans. bb structure was studied by scanning electron microscopy & stretching measurements pro/post cryo. grafts were cryo'd in % dmso, quick-thawed & sutured onto x cm excised full-thickness dorsal wounds on athymic mice. "fresh" grafts were similarly placed. controls grafts were cas and aeellular bb. adherence was quantitated by a device which peeled grafts from wounds at intervals following placement, using a serve motor and a strain gauge. results: postcryo, storage and subsequent thawing tile tlsrs maintained > % cell viability by the mtt assay, indicating continued mitochondrial activity, and bb structure & stretchability were maintained. multiple matrix proteins secreted and deposited in the bb nylon mesh (types l/iii collagen, decorin, fibroneetin) were identified by specific immunostaining. growth factor mrnas in the tlsrs (afgf, bfgf, kgf, tgf~,p~,) were present in - , x higher levels in fresh/cryo tlsrs than in adult hcs. grafts adhered to wounds on mice through days of followup. histologic exams on days - showed excellent vascular ingrowth and minimal inflammation. adherence of tlsrs to wounds was >cas adherence. burn wound coverage in the massively burned patient remains a difficult problem. although cultured keratinocytes have been utilized for burn wound coverage, their impact on the patient with burns greater than % total body surface area has not been spectacular, with poor graft take and unstable epithelium.current investigations have been directed toward dermal replacement beneath either very thin split-thickness autografts (stag) or utilizing cultured keratinocytes. current products include: collagen dermal replacement with thin stag (burke, et al). collagen dermal replacement with cultured keratinocytes and fibroblasts (boyce, et ai). allograft dermis with cultured keratinocytes (cnno, et al). allograft dermis with thin stag (life cell). polyglactin acid mesh and neonatal human fibroblasts with thin stag (hansbrnngh, et al).investigations regarding culture media, use of growth factors, topical nutrients and antibiotics, and melanocytes for pigmentation as well as safety and efficacy are needed before any of the current products become viable options for coverage of the massively burned patient. the~ is a growing world-wide problem with the ujc of cadaver tissues and ocgans bae, au~ of the tren~m~s~km of dilemma such a; cmutzfeldt.jukob disease and iiiv as we ] as ready availability of urdform lis~ue~. on dec~mt~r , , the fda assumed control of as tissue bar~s in the uldtod st=tea in an attempt to bflng ~s difficult problem of dise~s~ transmission under ¢onlrol. in europe, ~om¢ of the governments are consldofll~ a c~mplcte bat) on the use of cadaverlc fissu~s such as ddn, 'this |ncroam in regulation of cadavefle ~s,quct will incmar¢ the difficulty of obtain~g and dlslflbulmg them. however, thc nc~ for these tissues contlnue~ m incrcaso, we will discuss ~'l¢ solulion to this important pmbl~n: tissue engineering. tlssu~ engineering is an in~rdisdpllnary field that applies pdnclplc~ of angin~edng and die life sclcnce~ reward the development of ~olok~¢al sub~dtute,~ ih= mslom, maintain, or improve tissue function, " ssuc ongln~cdng can provide ~ho nccassary tlssuoa for wound repair ~d ibe assuranoe fl'~t the lissuos are d.ls¢~¢ free. in addition, a ds~uo-cng~ne~n~l wound covering will bo u~lvemally acceptable and evntlublc as "off g~o shell", consis~t products, them are several approaches to restating thls function in a large wound, 'l'nosc i~elud~ tmmcdiete long term coverage, short t=nn coverage, uandtl~el coverage and compost= dssu¢ coverage, "flssuo onglncrcd wound coverings that meet those vaflous ne,.cds will he r~vlowod.cllni~:sl and experimental d~la in venous ulcer, dlabctl¢ ulcers, prossur~ ulcers and bum wounds wgj be mvlcw~, a~ welt as new approacl~s u~ csrtilag¢, bone, liver and bone marrow it~suos. c oomplon, k nadirs, w press, g wetland, j fallen iv, shrtners burns institute and massachusetts general hospital, boston, ma~schusetts, usa the clinical "take" rate o? cultured epithelial autografts (cea) has been observed to increase with transplantation to allodermls, but the reasons for the improved clinical performance have not yet been defined. the aim of this study was to determine the biological impact of normal human dermis on cea differentiation and maturation, biopsies of cea transplanted to engrafted and de-opldermlzed human homograft dermis have been compared to nopsles of cea transplanted to granulation tissue in tullthickness burn wound beds on the same patient, each patient serving as hls or her own control. paired test and control biopstes from six patients have acquired from as early as one week postgrafting to as late as years postgrafting (one patient) and analyzed histopathologlcally, ultrastructurally and immunoh[stochemloally, results demonstrate more rapid normalization of differentiation markers (e,g., involucfln, fllaggrln, cytokeratln profiles) in the cea transplanted to allodermls compared to their corresponding controls by in all patients, the proliferation rate within the basal layer ot the epidermis as determined by ki- (proliferation-associated antigen) is seen to norh~altze more quickly in the cea transplanted to allodermls in every case, persistence of allodermal matrix can be dooumented in all patients by elastic tlssue-trichrome stain, allowing visualization of the dermal elastin network. the popu;atlon densities ot intraepldarmal langerhans cells are conslstently and signlflcantly higher in cea transplanted to ,allodermls, possibly reflectlng an immunologlcal reaction to the underlying allogenlc tissue. overall, these preliminary results indicate that transplantation to a normal human dermal matrix accelerates the maturation of cea-deflved epidermis, wound closure continues to be a major problem in patients who have sustained a major thermal injury, cultured epidermal autografts (cea) have been utilized extensively since when galllco et el reported theh'use in two brothers with greater than % total body surface area burn. unfortunately, cea take rate varies widely and the resultant skin coverage is often fragile and the cosmetic results are less than optimal however the overall take rate and durability of the coverase can be markedly improved by using nn allodermls base as the recipient bed. a review of cea applications performed by physicians using cultured outologens epithelium obtained from blusurfaoe teclmology, inc. shows a marked discrepancy in the results obtained utilizing different methods of wound bed preparation. tgf-b is an important modulator coordinating complex physiological events associated with growth and development. it is assumed that tgf-b is also involved in the well-coordinated process of cutaneous wound healing by regulating proliferation, differentiation, chemotaxis and matrix deposition. the purpose of our study was to analyze the spatial and temporal pattern of tgf-b expression during granulation tissue formation in patients with accidanutl surgical trauma (monotraumata mid polytraumata) and bum wounds. after debridement (day ), the full thickness wounds were covered with epigard, a synthetic dressing until day . after this time the granulated wounds were closed by transplantation of mesh graft. biopsies of the wound center were taken from patients at the beginning of surgical treatment (day ) and after , , and days. cryosections were stained with antibodies against tgf-fi s using the apaap technique and -for standard histology -with hematoxylin-eosin. for identification of the cell type expressing tgf- , double staining immunofluorescence experiments were conducted using antibodies specific for monocytes/macrophages, polymorphoanclear neutropkils and fibroblasts. the results showed a characteristic pattern of tgf-t~ distribution during wound development. tgf-fi appearence was mainly cell-associated znd the absolute and relative number of cells that were positive increased with lime. infiltrating cells and developing blood vessels were most prominently stained; epithelial and t-cells showed no immuno-reactivity. a delay of emergence for tgf-b during the time course could be seen in one patient group. this might reflect various regulation patterns depending on the type and severity of injury.( ) pharmatec gmbh, frankfurt ( ) institut fiir immonologie and serologic, heidelberg ( immune cells extravasating specifically in skin recognize and eliminate the invading antigens (bacteria, viruses, etc.) either in situ or transport them to regional lymph nodes. they also participate in the process of skin wound healing. cells which traffic through the skin can be harvested from efferent lymph drained from a given area of skin. the type of migrating cells changes after trauma, heating and infection. we have developed a method for collection of human afferent lymph in lower limbs. the method allows obtaining immune cells from normal and injured skin and their characterization. aim of the study was to characterize skin immune cells in situ and in skin lymph with use of immunohistological methods (staining, facs). results. group , cells migrating through skin: + % t lymphocytes (cd ), + % langerhans and dendritic cells (cdla, hla dr, s ), + % cd , + % cd , no b cells (cd , ), % cd r (memory cells), + % il r. approximately % cells possessed cdlla and antigens. cd lc was expressed only on large cells. the frequency of all phenotypes was different from the blood populations. group , cells in skin: langerhans cells were found only in epidermis, cd , and , cd r , rb, ila/ cells around venules, cd (macrophages) uniformly dispersed, no il r and b cells. hla dr positive were endothelial and some dispersed mononuclear cells. group , one, three and thirty days after surgical wound (simple varicous vein extirpation): high density of epidermal langerhans cells, hla dr positive keratinocytes and all endothelial ceils, few il r cells, perivenular infiltrates of cd , r but less cd cells, high density of cdlla/ cells. classic staining of isolated and in situ located ccl!s with mgg or he did not allow to follow kinetics of changes. conclusions. this study presents the first in the literature quantitative data of immune cell traffic through normal and injured human skin. in the controlled release of biological response modifiers for soft tissue regeneration. alan s. rudolph, helmut speilberg, mariam monshipouri, and florence rollwagen, and barry j. spargo. we have employed lipid microstructures as controlled release vehicles for the delivery of growth factors in wound repair. traditional liposomes as well as novel lipid based microcylinders have been examined for their in vitro kinetics of the release of transforming growth factor beta (tgf-b). in vitro reiease has been examined by setting up models with examine the physical release of iodinated tgf-b as well as a cell based bioassay (based on the ht bioassay). the hollow lipid microcylinders ( microns in length and i micron in diameter) show an initial burst ( - ng) followed be zero order kinetics which result in the release of approximately i ng tgf/day. this release behavior can be modified by temperature based on the phase behavior of the lipid bilayer which comprises the microcylinder.we have also examined the cellular response to lipid microcylinders applied in vivo. the lipid microcylinders are mixed in agarose and implanted as a composite hydrogel block under the flank of a mouse. the blocks are removed , , and days following implant and the cells analyzed by facs sorter analysis. the observed pattern of ceil recruitment to the blocks mimics that seen in a local inflammatory response. cell surface phenotype studies included the determination of cd and cd , mac-l, and ig bearing cells. we have also begun to examine the change in cell surface phenotype and kinetics of recruitment following the inclusion of tgf-beta in the lipid microcylinders.center for biomolecular science and engineering, code , naval research laboratory, washington, dc. - . expression pattern of heat shock proteins in acute, good healing and chronic human wound tissue. abstract: wound healing is a complex biologic process that is well characterized at the histological level, but its molecular regulation is poorly understood. after clot formation, inflammatory cells are rapidly drawn into the wound, followed by migration of fibroblasts and epithelial cells that divide and repopulate the wound area. during the last decade peptide growth factors and cytokine are thought to play a key role in initiating and sustaining the phase of tissue repair. these factors which are released from different cells appear to initiate the cascade of events that lead to healing. different studys described the rapid activation of a family of proteins,named heat shock proteins (hsp) in differnt tissue that were exposed to various forms of stress (heat, toxic agents, mechanical). in this context hsp's have the ability to regulate protein folding and assembly, to transport proteins across cytoplasm and membranes, to disrupt protein complexes, to stabilize, degrade and regulate the synthesis of proteins and to take part in dna replication and repair. we now attempted to find out if hsp-gene activation is also involved in injury and wound healing, which likewise resemble a stress situation for cells. therefore we collected tissue samples during operation and single biopsies from chronic wounds (decubitus for example) and granulation tissue. after rna preparation from these samples we used rna-pcr and nothern analysis to study the expression of objectives of the study chronic, non-healing cutaneous tflcers are a challenging clinical and socioeconomic problem. several animal studies have shown that cytukines (e.g. egf, pdgf, fgf, tgfb) accelerate the healing process and tissue repair in general. results from first clinical trials indicate a promising value of cytokines in the treatment of chronic non-healing diabetic and venous ulcers. recent reports in the literature indicate that the biological activity of the solution of platlet derived wound healing formula (pdwt~) released from c~-granules (mainly pdgf & tgfi~) is greater than the activity of the recombiant single factors like e.g. pdgf-bb (robson, lancet ) . the aim of our study was to determine whether a correlation exits between the concentration of tgfi~ & pdgf and the time course of wound healing. materials and methods pdwhf was prepared from ml of auto]ogous patient blood and diluted with a special buffer to a final concentration of ng/ml g-thromboglobulin. the concentrations of pdgf and tgfg were determined by elisa-tests developed in our laboratory. patients with chronic non-healing ulcers have been evaluated alter treatment by topical application of pdwhf. pdfg and tgff~ concentrations of the topical solution were measured and two patient groups formed for analysis the time course of wound healing was regularly and meticulously documented and evaluated by photography and casting. the time from initiation of treatment instil o wound volume reduction to go of the origional size (t %) was noted• results: healing of extensive burn wounds can be accelerated by grafting cultured autologous or allogeneic keratinocytes. the stimulation of granulation tissue formation and reepithelialization is presumably based on growth factors and cytokines released by keratinocytes. we wanted to prove this hypothesis by investigating the bfgf expression during wound development, bfgf is mainly described as an angiogenic protein with mitogenic activity on various mesodermal and ectodermal cell types pointing to its stimulating potential in wound heating. in the present study we compared the pattern of human bfgf m-rna expression and the localization of bfgf protein during the first days of wound healing. biopsies were taken from juvenile human bum patients, immediately after wound debridemerit mad on day after transplantation of cultured allografts. biopsies were snap frozen and cryosected. the pattern of bfgf expression was assessed by in situ hybridization of the bfgf m-rna with a digoxigenin-labelled antisense-rna and the parallel detection of the mature protein with an anfi-bfgf monoclonal antibody. our study revealed typical patterns of bfgf-m-rna-expression and intense bfgfprotein deposition during granulation tissue formation and reepithelialjzation of healing bum wounds. 'it, is known that major thermal injuries cause early impairment of wound healing followed by decreased influx of granuiocytes st. the site of injury. the role of granuiocytes in the process of wound healing is not ~"~ "" elucidated, it is now assumed that they are not merely phagocytic cells but active participants in ~n~*' ~.,.,a+~o~: processes secreting_ a number of various cvt-;kines, in order to investigate the effect of there is accumulating evidence that neuropeptides could be involved in the pathogenesis of several inflammatory reactions. vasocactive intestinal polypeptide (vip) and substance p (sp) have been detected by immunohistochemistry in normal as well as inflammed skin mostly in perivascular and periglandular location. both vip and sp are involved in vasodilatation, mast cell degranulation and irnmunomodulation.we determined the influence of sp and vip on the proliferation of lymphocytes in patients with psoriasis and healthy individuals. peripheral blood t-lymphocytes of psoriatics and healthy controls were isolated by density gradient centrifugation and passage over nylon wool. cell enrichment was controlled by facs analysis, lx t-lymphocytes were then incubated alone or in coculture with x irradiated autologous lymphocytes in culture medium containing - mol/i sp or vip. cell proliferation was measured semiquanfitatively by tdr uptake in a betacounter. significance was tested by the wilcoxon signed-rank test.our results show that sp and vip exert only an effect on unstirnulated t-cells. in healthy individuals but not in patients with psoriasis sp increases significantly proliferation of t-cells. vip, however stimulates significantly the blastogenesis of t-lymphocytes only in psoriatics.our results confirm the psychoneuroimmunologic component in inflammatory reactions and vip and sp could be partially implicated in their pathogenetic mechanisms. moreover psoriatic lymphocytes show an altered reaction to sp and vip. this might be due to a preexisting (genetic?) or more likely to an epiphenomenal receptor defect. the adhesive interactions between endothelial cells and circulating ~enkocytes in shock and innammatory vondltions is mediated by several distinct families of ce -surface determinants. of particular importance are the leukocyte integrins cdib / cdlla-c. in this study monoclonal antibodies to two of the u chains (cdlla & cdiib) and the common [~ chain (cdib) have been used to investigate leukocyte-dependent and leukocyte-independent plasma leakage in tee skin of rabbite. plasma leakage was measured as the local accumulation of t si-hsa over a rain period, the chemotac~c peptide imlp ( . . ng) and bradykinin were used to induce cell.dependent and cell- ndependent leakage respectively, the antibodies used were . e (cdis), nri (cdlla) and antibody (cdllb). ]ntradermal in~ections of bradyklnin and ~dlp both caused a dose dependent increase in plasma extravasatien ( .~. ffi . p.l to . z b.bttl and . ,- . ~ to . z . d respectively. . e ( . - . mf,/k~ iv) caused a dose dependent inhibition of imlp-induced but not bradyldnin.inducecl plasma exudation. at . mk/kg, the plasma leakage was completely inhibited, antibody nr produced similar results, treatment with antibody did not cause inhibition o£ plasma leakage due to either tnedi~tor. in vitro, the irmnune system ex~nination in persons with bone, chest and abdominal traumatic injury (i group . patients without infectious coz~lications and group - patients with wound infections development) was carried out. to restore found immunity disorders and host defense to infection patients of the group were treated with thymalin-the biologically active peptides prepared from bovine thymus. the examination on t~e i- days after injury revealed a considerable decrease of lymphocytes, ed ",$d ~ and cd cells amo~it in the blood, cd /cd ratio and indexes of let~ocyte migration inhibition test in both groups of patients. the imm~lity disorders recovered to norm on the - days in pateents of+the i group. but stable ~eple$ion of cd and cd cells amount, lower cd /cd ratio and indexes of leukocyte migration inhibition test in patients of the group were observed~ besides that, these persons showed higher cd cells amount and ig level in the blood. after thymalin therapy valid ii~rovement of inun~e status was discovered. also good clinical effect of immunotherapy and best wo~id healing observed in % of cases. these results allow us to propose that the thymus involution and the reduction of cell-mediated immunity responsiveness with disturbances of immu_uoregulatio~ on the level of restriction of activated cd tho cells play the most important role in the pathogenesis of wound infections development in persons with traumatic injury.dept. of immunology, military-nedical academy, lebedeva str. , , st.petersburg, russia a severe impairment of neutrophil (pmn) function often occurs following severe thermal or non-thermal traumatic injury. our laboratory has previously reported that following severe burn or non-burn traumatic injury the expression of the p integrlns (cd a,b,c/cd ) and the fw receptors (cd , and cd ) were significantly decreased on pmns, in this study, the effects of gm and g-csf on the expression of the f~ r and the ~ integrln family on pmns were examined, pmns were obtained from severe trauma (initial apache ii score ;z ) or thermal injury (> ~; total body surface area, > ~ full thickness) and incubated /n v/tro with gm or g-csf. the j integrins or fcyr were detected with monoclonal antibodies and flow cytometry. gm end g-csf induced a sllght increase in the percentage of pmns expressing cd lb, cd , and cd while gm bur not c-csf induced an increase in the percentage expressing cdi a, cd lc, and cd , gm-csf and to a lesser extent g-csf induced an increase in the density ( , fold) of the ~ integrlns on pmns from normal, burn, and trauma patients, these data suggest that cytoklne modulation with csfs could have a role clinically in certain situations. institute, dept. of surgery, bethesda ave, cincinnati, oh, usa, - . funl~al infections after solid organ transplantatlon(sot) lewis flint, md and ed,~-afd e. etheredge, me) dept. of surgery tullrte univ. school of medicine new orleans. louisiana infections contribute to increased gra loss and mortaliw following sot. pr~isposing facton include diabetes, hepatitis, leukopenia, cc.¢xistem infection, and intense, especially triple drug, immunosuppression. funga] infections occur ~s isolated conditions in % and in association with bacterial infection(l %), viral infection( */.), and combined infections(it%), candida sp. is the most common fungus recovered but aspecgillus, coccidiodies, cryptococcus, histoplasma, mueor~ ghizopus, tinea, and toruiop~is s?. also are pathogens. clinical syndromes vary among orga.aizms or may be variable with a single p~tthogen, for ~ample, with aggressive immunosuppression, candlda my be localized esophagitis or cystitis or systemically iavaslve with an associated high mortality. aspergilius presents ~ a diffuse pneumonia while cryptococcus causes pulmonary and centrad nervons sy'stem infection, clinical examination, ct scanning and aggressive sampling for c'ultures a.s wall as serologic tests contribute to diagnosis. empiric the~py is ind',cated where there is a high level of suspicion. preventlon of ca.adlda izfection is ~ci~itated by early remov-a. of central }ants, ca~hetess and stents as well as by the use of oral nystatin. amphotericin ]~ remains the drug of choice for treatment of in.save fungd infection, surgical resection of infectious loci in the lung and brain is indicated in selected patients. the main problems of diagnosis in lower respirator-), tract infection are the differentation of infection from colonization or contamination, and the isolation of a reliable and true pathogen. expectorated sputum may be unreliable in pneumonia, because of contamination by oropharyngeal flora. although blood cultures may be negative, they provide a precise diagnosis and should be obtained in all pneumonias. other more invasive procedures are transtracheal needle aspiration, fibrobronchoscopic techniques including protected specimen brush and bronchoalveolar lavage with quantitative culturing and cytological analysis, transthoracic needle aspiration, thoracoscopy -guided biopsy and open lung biopsy. recently m. e -ebiary, a. torres et al, reported quantitative cultures of endotracheal aspirates for the diagnosis of ventilator-associated pneumonia offering reliable results in these patients and should be further investigated. any invasive procedure in a severely ill patient should be carefully directed weighing the risks as well as the benefits, whilst taking the underlying diseases and expected survival into consideration. -current therapeutic approach is based mainly on monotherapy with broad spectrum antibiotics. combination therapy is apparently indicated only in p. aeruginosa infections and severe s. aureus pneumonia. graft infection can lead to fulminant graft failure or rapid progressive cirrhosis. for prevention of graft infection immunoprophylaxis, i,e. administration of human polyclonal anti hbs hypedmmunoglobutin (hig), starting in the anhepatic phase during operation, has proved to be at least partially succesful when performed on a long term basis.from a total of olt in adult patients olt were performed for hbsag positive liver disease (cirrhosis n= , fulminant liver failure n= , retransplantation n= ) in pat. all pat. received . u hig in the anhepatic phase and . u/per day for the first week. a small group of pat. received hig only for i week (short term immunoprophylaxis), in all other pat. hig is administered on a long term basis to keep anti hbs serum levels above uii or until graft infection occurs (long term immunoprophylaxis);one-year survival rates are % in pat. who were transplanted for fulminant hepatitis, % in pat. with cirrhosis and long term prophylaxis, and % ir~ pat. with short term prophylaxis. all fatalities were related to hbv graft infection. the total rate of graft infection was % under short term prophylaxis and was independent from preoperative hbv dna status, under long term prophylaxis graft infection occurad in % in pat, negative for hbv dna. in hbv dna positive pat. infection rate was %, the total rate of reinfection for all pat. with long term prophylaxis was %the results of liver transplantation in hbsag positive pat. are comparable to other indications, graft infection with hepatitis b virus ist the major risk factor for these patients. under long term therapy with hig the rate of graft infection can be significantly reduced. the crucial cellular element for mods-mof: monocyi'f_./m acrophaoe ronald v. meier, m,d., f.a,c,s. the severely :injured or crldcally ill surgical patient is at high risk for immune dysfunction. a major consequence of this immune dysfunction is multiple organ dysfunction and failure leading to death, the underlying etiology is now recognized to be an uncontrolled, unfocused, disseminated activation of the host normally protective inflammatory. ,, cascades.. the resultant "mahgnant' systemic" inflan'a'natlon produces d~ffuso multiple organ bystander injury !eading to progressive organ dysfunction and failure. systemic malignant inflammation involves diffuse actlvatton of all components of the humoral and cellular inflammatory host response. of these various components, the macropha~e is the crucial central cellular element. the tissue fixed macrophage is ideally located diffusely throughout the various organs injured to orchestrate the inflammatory process. the macrophage is long-lived and highly metabolic, the macrophage regulates both the extent and the dissemination of the inflammatory processes. the macrophage is an exu'emely active c¢ capable of producing and releasing not only directly eytotoxlc agents, s irnil~, to the neutrophil, including oxidants and numerous proteases out also the multitude of other cytokines and initiators of the interacting inflammatory cascades. the macrophage is the central source for ehemotactic agents (il- , ltb , c a) for neutrophils and other inflammatory cells, production of vasoaetive arachidonie acid metabolites (tx, pgi , poe, lt's), complement components (c a, csa), thrombotic agents (pca, tx), metabolic and physiologic modulators (il, , il- or tnf), and immunosuppressivc agents (poe , il- ). these products of the macrophage are highly effective in enhancing and augmenting the inflammatory response. disseminated activation otthe macrophage is critical to the induction of the long-term diffuse activation of inflammation necessary to induce multiple organ injury and failure. our ability to elucidate the molecular mechanisms that control the macrophage will lead to our ability to conu'ol the maerophage response and prevent mods-mof.flarborview medical center, - th ave za- , seattle, wa usa key: cord- - ftu b q authors: martinez-sanz, j.; muriel, a.; ron, r.; herrera, s.; perez-molina, j. a.; moreno, s.; serrano-villar, s. title: effects of tocilizumab on mortality in hospitalized patients with covid- : a multicenter cohort study date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: ftu b q background while there are no treatments with proven efficacy for patients with severe coronavirus disease (covid ), tocilizumab has been proposed as a candidate therapy, especially among patients with higher systemic inflammation. methods we conducted a cohort study of patients hospitalized with covid in spain. the primary outcome was time to death and the secondary outcome time to intensive care unit admission (icu) or death. we used inverse probability weighting to fit marginal structural models adjusted for time varying covariates to determine the causal relationship between tocilizumab use and the outcomes. results a total of , and , person/days were analyzed. in the adjusted marginal structural models, a significant interaction between tocilizumab use and high c reactive protein (crp) levels was detected. tocilizumab was associated with decreased risk of death (ahr . , % ci . to . , p= . ) and icu admission or death (ahr . , % ci . to . , p= . ) among patients with baseline crp > mg/l, but not among those with crp [≤] mg/l. exploratory subgroup analyses yielded point estimates that were consistent with these findings. conclusions in this large observational study, tocilizumab was associated with a lower risk of death or icu or death in patients with higher crp levels. while the results of ongoing clinical trials of tocilizumab in patients with covid will be important to establish its safety and efficacy, our findings have implications for the design of future clinical trials and support the use of tocilizumab among subjects with higher crp levels. there are still no treatments with proven efficacy to prevent mortality in patients with severe coronavirus disease (covid- ) pneumonia. however, various medications such as hydroxychloroquine, azithromycin, and lopinavir/ritonavir have been used off-label worldwide to minimize the impact of the current sars-cov- pandemic. tocilizumab is an fda-approved humanized monoclonal antibody against the soluble interleukin- (il- ) receptor. it is widely used in the treatment of autoimmune disorders such as rheumatoid arthritis or cytokine release syndrome. , tocilizumab has been suggested as an effective treatment for severe covid- pneumonia due to the increased interleukin (il- ) blood levels in patients with covid- and its correlation with a more severe lung damage. tocilizumab is not currently approved for use by the fda in covid- patients. no efficacy results from observational studies or clinical trials in this disease have been published, and the available data comes from small studies with surrogate endpoints that are underpowered to detect significant clinical effects or lack a control group. [ ] [ ] [ ] [ ] [ ] despite this absence of information, tocilizumab has been widely used due to its potential effect in the treatment of sars-cov- -induced cytokine release syndrome in which il- plays an important role. , , il- determination is rarely available in clinical settings. however, c-reactive protein (crp)-an inflammatory biomarker upstream in the il- pathway-, is commonly used to monitor the activity of inflammatory diseases. in attempt to recruit the population with covid with a higher probability to respond, some ongoing clinical trials of tocilizumab have considered heightened high crp levels as an inclusion criterion (clinicaltrials.gov: nct and nct ). given the urgent need to respond to the covid- pandemic, observational studies are important to evaluate clinical outcomes associated with the medications empirically used to treat covid- . however, critical analytical issues, including the risk of immortal time bias and indication bias from time-varying confounding , challenge the validity of observational data in this setting. here, we investigate the association between tocilizumab use and mortality in a large cohort of hospitalized covid- patients in spain. we hypothesized that tocilizumab use would be associated with a lower risk of death and influenced by baseline systemic inflammation levels. we used marginal structural modeling to account for baseline and time-varying confounders. we analyzed data from , subjects included in the hm hospitales cohort-a multicenter cohort of patients admitted to any of the hospitals in the hm group in madrid and diagnosed with covid- from january st to april rd , . hm hospitales made their anonymous dataset freely accessible to the international medical and scientific community. the dataset includes all available clinical information on patients diagnosed with covid- , confirmed by polymerase chain reaction in nasopharyngeal swabs or another valid respiratory sample. the dataset collects the different interactions in the covid- treatment process including detailed information on diagnoses, treatments, admissions, intensive care unit (icu) admissions, diagnostic imaging tests, laboratory results, discharge or death, and diagnostic and procedural records coded according to the international statistical classification of disease and related health problems (icd- ) classification. we excluded patients younger than years and those who died or were transferred to another facility within hours after admission to the emergency department. this study was approved by the ethics committee at university hospital ramón y cajal (ceic.hrc@salud.madrid.org, approval number / ). . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint the primary end point was the time from study baseline to death. the secondary outcome was a composite event including admission to the icu or death (hereafter icu/death). study baseline was defined as the first day of hospitalization. we tested the associations among the preadmission variables with treatment variable by chi-square tests for categorical variables and wilcoxon rank sum tests for continuous variables. we calculated the incidence rates of death and icu/death and compared the time of death or the composite endpoint according to tocilizumab using kaplan-meier methods and log-rank tests. we fitted marginal structural models to estimate discrete time hazards of death according to tocilizumab use via an inverse probability treatment weight (iptw) estimation to account for the non-randomized treatment administration of tocilizumab, baseline confounding, and time-varying confounders. , we assumed that once a patient received tocilizumab, they remained on it until the end of follow-up. this assumption helped obtain a conservative estimate of the treatment hazard ratio analogous to intention-to-treat analysis in an unblinded randomized controlled trial. we structured the data set to allow for exposure, outcomes, right-censoring, and time-dependent covariates to change daily after admission. propensity score logistic models predicted exposure at baseline and censoring over time as a result of recognized confounders of severe covid- , including age, gender, comorbidities (hypertension, diabetes, ischemic heart disease, kidney disease, congestive heart failure, lung disease), oxygen blood saturation and need for oxygen therapy at baseline, and time-varying parameters of clinical severity (blood pressure, heart rate, total lymphocyte and neutrophil count, lactate dehydrogenase, alanine aminotransferase, urea, d-dimers, and crp). there were , subjects in the dataset with the information needed to fit marginal structural models. the characteristics of the individuals not included due to missing data in the information required for the statistical modelling strategy are shown in table s in the supplement. the main differences between groups in the analyzed population were comparable to those found in the population with missing . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint information. iptw were stabilized and truncated below the first percentile and above the th percentile. the models included a main term for the exposure and a flexible functional form of time, that is, restricted cubic splines with knots set at the first, th , th , th , and th percentiles of the subjects' day of follow-up, and the interaction term between tocilizumab and elevated crp levels (> mg/l, cutoff selected based on the th percentile value, mg/l). the interaction term between tocilizumab and crp was significant, and thus we report the adjusted (weighted) hazard ratios (hrs) derived from marginal structural models for the primary and secondary outcomes segregated by crp levels. we planned exploratory sensitivity analyses restricted to subjects who received specific concomitant treatments against sars-cov- (corticosteroids, hydroxychloroquine, azithromycin, lopinavir/ritonavir). due to the recognized prognostic value of lymphocyte counts and d-dimer levels, we also performed sensitivity analysis to explore the possible confounding effect of d-dimer > ng/ml (upper limit of the normal range in the reference laboratory) or absolute lymphocyte count < /ul (lower limit of the normal range in our reference laboratory). statistical analyses were performed using stata v. we analyzed , subjects accounting for , observations and , person-days of follow-up who were diagnosed with covid- in hm hospitals between january st and april rd , and have the information needed for iptw estimation. we excluded patients because they died, were discharged, or were transferred to a different hospital within hours after admission to the emergency department. a total of subjects ( . %) died, ( . %) were admitted to the icu, and had a composite outcome of death or icu admission ( . %). the median time to censoring date was (iqr - ) days. of the , patients, ( %) received a median total dose of mg (iqr - mg) of tocilizumab. the first dose was administered at a median time of (iqr - ) days . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint from inpatient admission. the distribution of the patient's characteristics according to tocilizumab use is shown in table . compared to the control group, there was a higher frequency of men and previous lung disease in the tocilizumab group while controls were significantly older and had a higher prevalence of diabetes. as expected, there were small differences between both groups in some of the baseline vital signs and laboratory parameters that were indicative of greater disease severity in the tocilizumab group than in the control group. the , subjects accounted for , observations, and the crude incidence rate of death was we used kaplan-meier estimates as a first approach to visualize the cumulative probabilities of death and icu/death. we did not observe differences in the estimates of death or icu/death in the pooled analysis ( figure a-b) . however, we found a significantly lower cumulative probabilities of both outcomes among patients with baseline crp levels above > mg/l (figure c-d) but not among those with crp ≤ mg/l (figure e-f) . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . (figure ) . weighted hazard ratios derived from marginal structural models adjusted for sex, age, comorbidities (hypertension, diabetes, ischemic heart disease, chronic kidney disease, congestive heart failure, lung disease), need for oxygen therapy at baseline, oxygen blood saturation, and time-varying parameters of severity (blood pressure, heart rate, total lymphocyte and neutrophil count, ldh, alt, urea, d-dimer, and crp). abbreviations: alt, alanine aminotransferase; ci, confidence interval; icu, intensive care unit; ldh, lactate dehydrogenase. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint figure and table s show the adjusted hazard ratios for exploratory sensitivity analyses restricted to patients with baseline lymphocyte count < cell/µl and baseline d-dimer > ng/ml segregated by crp levels. the results are consistent with the principal analysis. individuals with baseline crp levels higher than mg/dl maintained a lower risk of death and icu/death, but no significant effects of tocilizumab were found among those with low crp levels. weighted hazard ratios derived from marginal structural models adjusted for sex, age, comorbidities (hypertension, diabetes, ischemic heart disease, chronic kidney disease, congestive heart failure, lung disease), need for oxygen therapy at baseline, oxygen blood saturation, and time-varying parameters of severity (blood pressure, heart rate, total lymphocyte and neutrophil count, ldh, alt, urea, d-dimer, and crp). abbreviations: alt, alanine aminotransferase; ci, confidence interval; icu, intensive care unit; ldh, lactate dehydrogenase. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint we also explored the effects of concomitant therapies against sars-cov- in sensitivity analyses restricted to subjects who received corticosteroids (n= ), hydroxychloroquine (n= , ), azithromycin (n= ), or lopinavir/ritonavir (n= ) ( table s ). the effect sizes among subjects with baseline crp > mg/l were very similar to those observed in the principal analyses for both the primary and secondary outcomes (all p-values < . except azithromycin and lopinavir/ritonavir, with p= . in the primary and p= . in the secondary outcome, respectively). this is the first study to evaluate the effects of tocilizumab on the mortality of hospitalized patients with covid- . while the overall risk of death or icu admission did not differ among patients who received tocilizumab to those who did not and had crp levels ≤ mg/l, we found a % reduction in the risk of is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint the ct scan after days. in a single-arm study of patients with a proinflammatory and pro-thrombotic state due to severe covid- , treatment with tocilizumab was associated with a decrease in crp, d-dimer, and ferritin levels. thus, tocilizumab and other repurposed medications have been widely used offlabel to treat covid- in an attempt to mitigate the dramatic clinical consequences of sars-cov- pandemic, despite the lack of information on the effects of tocilizumab on robust clinical outcomes. the first confirmed case of covid- in spain occurred on january of , and , cases had been identified by may th , . due to the impact of the disease at a time when randomized trials were lacking, many protocols were developed, and the use of - doses of tocilizumab adjusted by weight was allowed by the spanish national guidelines as a possible treatment for covid- . shortly after the release of this document, the number of doses was restricted to a single dose adjusted by weight ( mg or mg) to avoid a tocilizumab shortage. in this multicenter cohort, we could compare subjects who received tocilizumab with who did not. these subjects accounted for deaths, icu admissions, and combined events of icu admission or mortality. we selected an analytical approach capable of dealing with the potential confounders inherent to observational studies in which subjects receiving tocilizumab were expected to have more risk factors for clinical progression and greater disease severity at baseline. in our cohort, controls were significantly older and had a higher prevalence of hypertension, which are the risk factors that have been more robustly associated with severe covid- and death. , , , however, subjects who received tocilizumab tended to have a greater prevalence of other potential risk factors for disease severity such as lung disease, as well as differences in baseline vital signs and laboratory parameters indicative of greater disease severity. all of these factors were included as covariates, and the estimates were consistent across the two endpoints analyzed. we found a strong and consistent protective effect of tocilizumab among patients with crp levels above mg/l (ahr . , % ci . - . ). the selection of the modeling strategy was a critical decision. longitudinal studies in which exposures, confounders, and outcomes are measured repeatedly over time . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint can facilitate causal inferences about the effects of exposure on outcome. however, there are key analytical issues in this setting, including the risk of immortal time bias (i.e., the requirement for patients to survive long enough to receive the intervention of interest, which can lead to a potentially incorrect estimation of a positive treatment effect), and indication bias from time-varying confounding (e.g., the use of tocilizumab following elevations of crp). standard regression models for the analysis of cohort studies with time-updated measurements may result in biased estimates of treatment effects if time-dependent confounders affected by prior treatment are present. , marginal structural models are a powerful method for confounding control in longitudinal study designs that collect time-varying information on exposure, outcome, and other covariates, such as the present one. , our study has a number of limitations. as with any observational study, there is still a risk of unmeasured confounding. tocilizumab targets the il- receptor, and thus using baseline il- levels instead of crp in the interaction term with tocilizumab use could have helped to better discriminate the population benefiting most from tocilizumab treatment. although il- measurements are rarely available in clinical settings, crp is widely accessible and is an inflammatory biomarker upstream of the il- pathway. hence, we doubt that the use of crp instead of il- limited the scope of the results. ongoing trials of tocilizumab in covid- have also considered heightened crp instead of il- to identify patients with heightened inflammation and, therefore, potential greater benefit with this treatment (clinicaltrials.gov: nct and nct ). in addition, the results should be interpreted cautiously and must not be taken as confirmatory of tocilizumab efficacy because of the relatively wide confidence intervals in the principal analysis. the sensitivity analyses suggested that patients with high crp and high d-dimer levels or lymphopenia may also be target populations for tocilizumab use. however, despite the fact that the size effects observed here were consistent with those obtained in the principal analyses, the sub-analyses must only be interpreted as exploratory and hypothesis-generating. the main strengths of the study include the large sample size and multicenter contribution that is representative of a real-life setting. this can allow . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint generalizability of the results. the availability of daily information on covariates defining treatments and laboratory parameters allowed us to control confounding issues using marginal structural models. finally, the high number of outcomes powered the statistical analysis, and the results are novel and biologically plausible. in summary, we analyzed a large number of consecutive patients hospitalized with covid- and found that tocilizumab was associated with a lower risk of mortality or icu admission/mortality among patients with crp > mg/l, but not among those with lower crp levels. although the results of ongoing clinical trials of tocilizumab in patients with covid- are mandatory to establish its safety and efficacy, our findings have implications for the design of future clinical trials and support the use of tocilizumab among subjects with higher levels of inflammatory markers. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint absolute lymphocyte count (cells/µl), median (iqr) treating covid- -off-label drug use, compassionate use, and randomized clinical trials during pandemics tocilizumab in rheumatoid arthritis: a meta-analysis of efficacy and selected clinical conundrums therapeutic efficacy of humanized recombinant anti-interleukin- receptor antibody in children with systemiconset juvenile idiopathic arthritis clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study the cytokine release syndrome (crs) of severe covid- and interleukin- receptor tocilizumab may be the key to reduce the mortality pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe covid- effective treatment of severe covid- patients with tocilizumab use of tocilizumab for covid- -induced cytokine release syndrome: a cautionary case report tocilizumab treatment in covid- : a single center experience tocilizumab for the treatment of severe covid- pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of patients in supportive treatment with tocilizumab for covid- : a systematic review general office of the national health committee of china, china traditional chinese medicine administration office from c-reactive protein to interleukin- to interleukin- : moving upstream to identify novel targets for atheroprotection controlling for time-dependent confounding using marginal structural models who | who family of international classifications (who-fic) marginal structural models to estimate the causal effect of zidovudine on the survival of hiv-positive men development and validation of a clinical risk score to predict the occurrence of critical illness in hospitalized patients with covid- baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region sars-cov- cell entry depends on ace and tmprss and is blocked by a clinically proven protease inhibitor a crucial role of angiotensin converting enzyme (ace ) in sars coronavirus-induced lung injury the cytokine release syndrome (crs) of severe covid- and interleukin- receptor tocilizumab may be the key to reduce the mortality autopsy findings and venous thromboembolism in patients with covid- : a prospective cohort study absolute neutrophil count (cells/µl) alt (u/l), median (iqr) urea (mg/dl), median (iqr) c-reactive protein (mg/l), median (iqr) /ml), median (iqr) interleukin (pg/ml), median (iqr) outcome non-icu length of stay (days), median (iqr) all variables were available in the , subjects, with exception of il- , which was measured only in individuals we acknowledge all study participants who made this research possible. we thank hm hospitales group for releasing the dataset used to perform this research to the scientific community. outside the submitted work, s. s.-v. reports personal fees from viiv healthcare, janssen cilag, gilead sciences, and msd as well as non-financial support from viiv healthcare and gilead sciences and research grants from msd and gilead sciences. j.m.-s. reports non-financial support from viiv healthcare, non-financial support from jannsen cilag, non-financial support from gilead sciences. ja.p. reports grants, personal fees and nonfinancial support from viiv healthcare, and grants from msd, outside the submitted work.s.m. reports grants, personal fees and non-financial support from viiv healthcare, personal fees and non-financial support from janssen, grants, personal fees and non-financial support from msd, grants, personal fees and non-financial support from gilead, outside the submitted work. there are no potential conflicts of interest. key: cord- -a kgo ct authors: gavriilaki, eleni; anyfanti, panagiota; gavriilaki, maria; lazaridis, antonios; douma, stella; gkaliagkousi, eugenia title: endothelial dysfunction in covid- : lessons learned from coronaviruses date: - - journal: curr hypertens rep doi: . /s - - - sha: doc_id: cord_uid: a kgo ct purpose of review: to review current literature on endothelial dysfunction with previous coronaviruses, and present available data on the role of endothelial dysfunction in coronavirus disease- (covid- ) infection in terms of pathophysiology and clinical phenotype recent findings: recent evidence suggests that signs and symptoms of severe covid- infection resemble the clinical phenotype of endothelial dysfunction, implicating mutual pathophysiological pathways. dysfunction of endothelial cells is believed to mediate a variety of viral infections, including those caused by previous coronaviruses. experience from previous coronaviruses has triggered hypotheses on the role of endothelial dysfunction in the pathophysiology of sars-cov- (severe acute respiratory syndrome coronavirus ), which are currently being tested in preclinical and clinical studies. summary: endothelial dysfunction is the common denominator of multiple clinical aspects of severe covid- infection that have been problematic for treating physicians. given the global impact of this pandemic, better understanding of the pathophysiology could significantly affect management of patients. recent evidence suggests that signs and symptoms of severe coronavirus disease- (covid- ) infection resemble the clinical phenotype of endothelial dysfunction and share mutual pathophysiological mechanisms [ ] . importantly, endothelial dysfunction has been suggested as a main pathophysiological process in several viral infections, including previous coronaviruses [ , ] . experience from previous coronaviruses has triggered studies testing hypotheses on the role of the endothelial dysfunction in patients with sars-cov- (severe acute respiratory syndrome coronavirus ). as a result, recent lines of evidence implicate endothelial dysfunction in the pathophysiology of this systemic infection. endothelial dysfunction appears to be the common denominator of multiple clinical aspects of severe covid- that have been problematic for treating physicians. given the global impact of this pandemic, better understanding of the pathophysiology could significantly affect management of patients. therefore, we systematically reviewed current literature on the pathophysiology of endothelial dysfunction, evidence of endothelial dysfunction in coronaviruses, and particularly in covid- focusing on the clinical phenotype. large endocrine organ are critical to maintain hemostatic balance. well-described functions of the endothelium include restoration of vascular integrity upon vascular injury and inhibition of excessive thrombosis and clot formation through multiple anticoagulant pathways, including the protein c/protein s pathway [ ] . endothelial cells interact with platelets and leucocytes, prompting their recruitment, adhesion, and interaction on thrombogenic surfaces, at sites of vascular injury driven by inflammation or infection, or at lesion-prone sites such as the carotid bifurcation [ , ] . in addition, endothelium plays an important role in the regulation of vascular tone and growth by synthesizing and releasing a variety of vasoactive substances, both vasodilatory, such as nictric oxide (no), prostaglandins, and endothelium-dependent hyperpolarization (edh) factors, as well as endothelium-derived contracting factors, such as endothelin and angiotensin ii [ , ] . no biosynthesis by endothelial cells is the most important for the maintenance of vascular homeostasis. the main source of circulating no is endothelial nitric oxide synthase- (enos ), expressed in endothelial cells and platelets [ ] . nos activity is regulated by the ca + /calmodulin (cam) complex, and can also be activated by phosphorylation, which can be ca + /cam-independent as most of the stimuli, such as shear stress applied on the vessel wall, do not require the presence of ca + /cam [ , ] . increased oxidative stress promotes oxidation of tetrahydrobiopterin (bh ), which is essential for the formation and stability of nos [ ] . when the supply of bh is reduced, nos becomes uncoupled and generates superoxide instead of no [ ] . based on the above, it becomes apparent that conditions characterized by increased oxidative stress are associated with diminished biosynthesis and availability of no. therefore, an imbalance between excessive formation of reactive oxygen species with inadequate antioxidant defense capacity is considered the hallmark of endothelial dysfunction [ ] . under such conditions, the protective properties of the endothelium are lost, with a shift toward impaired vasodilation and the expression of a pro-inflammatory, pro-atherosclerotic, and pro-thrombotic phenotype in the vasculature which is directly associated with the pathogenesis, the progression, and the complications of cardiovascular diseases (cvds) [ ] . endothelial dysfunction has been documented early in the course of cvd by use of several vascular markers, such as the gold standard flow-mediated vasodilation (fmd), or by measurement of circulating biomarkers, including asymmetrical dimethylarginine (adma), oxidized ldl, and endothelial microvesicles (emvs) [ , ] . endothelial dysfunction triggers coagulation disorders in severe infectious diseases, including viral infections. in such cases, free radicals damage the endothelium and disrupt the endothelial barrier by quenching no, thus allowing toxins to pass into underlying tissues. vascular leakage is a key feature of endothelial dysfunction in viral infections and can be caused either directly by the viral attack or indirectly by excessive endothelial activation mediated by maladaptive immunological responses [ ] . disruption of the endothelium, either directly through signaling effects or indirectly through increased pro-inflammatory mediator production and subsequent deregulation of the coagulation cascade, has been described in the pathophysiology of previous coronavirus infections [ , ] . sars-cov was confirmed to be the causative agent for a sars epidemic associated with severe respiratory failure two decades ago. sars-cov infection primarily targets pneumocytes and enterocytes due to their abundant expression of angiotensin-converting enzyme (ace ), the main functional sars-cov receptor, followed by immune system deregulation. although endothelial cells express ace in the vasculature of several organs, direct evidence regarding endothelial cell infection and dysfunction in sars patients is limited [ , ] . in a study that included sars patients, yang et al. showed the development of autoantibodies against human umbilical venous and pulmonary endothelial cells in the convalescent phase that could mediate complementdependent cytotoxicity, thus suggesting a possible pathogenic mechanism [ ] . in addition, vasculitis and evidence of endothelial cell inflammation have been documented in postmortem analyses of individual sars patients, but their role in the pathogenesis of the disease is unknown [ ] [ ] [ ] . coronavirus-infected patients (sars-cov and middle east respiratory syndrome/mers-cov) have an enhanced thrombotic tendency that has been documented both in vitro and in vivo [ ] . studies in mice showed that sars-cov infection is associated with dysregulation of the urokinase pathway, leading to inflammatory vascular damage and activation of the coagulation cascade, culminating in thrombosis [ , ] . similarly, in vitro studies showed that sars-covinfected human cells significantly upregulate the expression of genes implicated in inflammation and coagulation and their related proteins [ ] [ ] [ ] , thus contributing to a pro-coagulant profile that mimics the thrombotic alterations observed in sars patients. in this context, data have shown that sars patients exhibit abnormal coagulation parameters and thromboembolic events. in a retrospective study including sars patients, % of them presented reactive thrombocytosis and % presented prolonged activated partial thromboplastin time (aptt) during the course of their illness with no evidence of thromboembolism or other coagulation abnormalities, whereas . % developed disseminated intravascular coagulation [ ] . in another study of sars patients, almost % of the study population had a prolonged aptt and increased levels of d-dimers, while % showed increased levels of lactate dehydrogenase, a significant predictor of intensive care unit admission and death [ ] . an abnormal coagulation profile, including increased levels of thrombopoietin, von willebrand factor (vwf), and plasminogen activator inhibitor- (pai- ), has also been documented in sars patients [ , ] . in a study of critically ill sars patients, an increased frequency of thromboembolic complications, including pulmonary embolism and deep vein thrombosis, was observed [ ] . in another study, a uniform pattern of large-vessel ischemic strokes was observed in out of sars patients with relatively few vascular risk factors, while approximately % of those who were critically ill had venous thromboembolism [ ] . of note, increased levels of anticardiolipin antibodies have been found in post-sars patients [ ] . despite relatively limited reports of confirmed clinical thromboembolic events, evidence of enhanced coagulation in sars patients has been firmly established in histopathological analyses, with fibrin clots in the pulmonary vasculature being a prominent feature [ ] . further, postmortem findings of individual sars cases were consistent with microvascular thrombi formation in the pulmonary veins and evidence of systemic vasculitis in multiple organs, associated with endothelial cell inflammation, proliferation, swelling, and apoptosis [ ] . in a case-series study of sars patients by chong et al., autopsy findings included pulmonary thromboemboli in the main and segmental pulmonary arteries as well as deep vein thrombosis and widespread multi-organ infarctions associated with intravascular thrombi [ ] . in addition, a larger study including autopsies from sars patients by hwang et al. revealed vascular endothelial damage of both small-and medium-sized pulmonary vessels and multiple intravascular fibrin thrombi and thromboemboli associated with pulmonary infarctions [ ] . another postmortem analysis of an individual sars patient revealed evidence of endothelial cell inflammation and thromboemboli in the veins and microcirculation of multiple organs, thereby highlighting the thrombogenic potential of sars-cov in a wider spectrum, including the systemic vasculature [ ] . the first step in understanding new complex pathophysiological mechanisms is to combine experimental and translational research and apply a bench-to-bedside approach. figure summarizes our understanding of the pathophysiology of endothelial dysfunction in covid- . taking into account previous experience from other coronaviruses, several recent studies have implicated complement activation as part of the vicious cycle of endothelial dysfunction in covid- [ ] . complement is a major regulator of endothelial injury syndromes, such as thrombotic microangiopathies [ , ] . severe covid- appears to resemble complementmediated thrombotic microangiopathies in both pathophysiology and clinical phenotype [ ] . this resemblance could be also important for management [ ] , since complement inhibitors have shown safety and efficacy in covid- [ , ] . as mentioned above for other coronaviruses, pericytes with high expression of ace are target cells of covid- , resulting in endothelial cell and microvascular dysfunction. since ace is highly expressed on cardiac myocytes, cardiac injury is expected in covid- [ ] . similarly, a recent study has suggested a coronaviral tropism for the kidney, since ace is highly expressed on podocytes and tubular epithelial cells of the kidney [ ] . a puzzling question is the neuroinvasive potential of sars-cov- that has been suggested by the clinical observation of neurological signs in infected patients. animal models of structurally similar coronavirus infections point to direct nervous system invasion by coronaviruses. another hint is that ace is also expressed in in the vasculature of the brain [ ] . potential routes of central nervous system entry, including hematogenic spread, olfactory bulbs, synapse-connected routes, and peripheral nerves, have been suggested. it has been proposed that even before neuronal damage occurs, endothelial injury leads to rupture of cerebral capillaries and eventually to fatal intracerebral hemorrhage in patients with covid- [ ] . further research is needed to explore how such invasiveness could cause direct neurological tissue damage through endothelial dysfunction and the probable variable interaction of the virus with different hosts leading to fluctuating clinical manifestations and severity [ ] . the most critical step in unraveling the neuroinvasive propensity of the new coronavirus is to study human neuropathological findings. the first evidence of sars-cov- presence in brain tissue from postmortem examination strongly supported the hypothesis of endothelial injury and hematogenous dissemination as the primary route of central nervous system (cns) invasion as viral particles were found in brain capillary endothelium [ ] . in a prospective cohort study, sars-cov- rna was detected at low titers in autopsied brains of ( %) patients [ ] . these data appear to confirm the predominant theory of hematogenous dissemination, leading to endothelial damage. attempts to isolate sars-cov- from csf have been made but were not always successful [ , ] . the latter study described the first case of meningitis/ encephalitis associated with sars-cov- virus in which rna was detected in csf but not in the nasopharyngeal swab [ ] . another case report of acute disseminated encephalomyelitis supported an immune-mediated cns involvement that could occur after covid- infection [ ] . hence, alternative routes of direct nervous system invasion or an indirect immune-mediated involvement of cns cannot be ruled out. -clinical phenotype thromboembolic events the interplay between endothelial injury, complement activation, hypercoagulable state, and thrombin production seems to be a common denominator of covid- clinical features such as deep vein thrombosis (dvt), pulmonary embolism (pe), microvascular thrombosis, cerebrovascular, and cardiac disease [ , ] . table summarizes clinical features of endothelial dysfunction and microvascular thrombosis in covid- . microvascular thrombosis autopsy findings in sars-cov- patients have demonstrated extensive microvascular injury mediated by complement activation and an associated hypercoagulability [ •] . another postmortem examination of covid- -affected lungs revealed that pulmonary vascular endotheliitis, thrombosis, and angiogenesis are distinctive pulmonary vascular pathophysiologic features of covid- infection not seen in influenza a (h n ) infection or in uninfected controls [ ] . in this context, use of term microclots (microvascular covid- lung vessels obstructive thromboinflammatory syndrome) has been proposed [ ] . venous thromboembolism venous thromboembolism (vte) manifested as dvt or pe is encountered commonly in critically ill covid- patients despite prophylactic anticoagulant treatment. autopsy studies revealed generalized thrombotic microangiopathy and endothelial dysfunction together with pe and dvt in covid- -infected patients [ , ] . in the first study, pe was found in of specimens while receiving anticoagulation [ ••] . in the other autopsy study of consecutive covid- patients, only four of which were receiving anticoagulation; dvt was revealed in ( %), but in no case was dvt suspected clinically [ ] . pe was identified and was the primary cause of death in patients. both studies reported high body mass index and high prevalence of cardiovascular disease, hypertension, and diabetes mellitus history in the afflicted patients. in parallel with autopsy findings, high rates of vte ( to %, especially pe) have been clinically diagnosed in covid- patients in intensive care units (icus) [ , ] . a multicenter dutch study in covid- icu patients confirmed vte in %. pe was the most frequently encountered thrombotic complication ( %) [ ] . a chinese icu study identified a % incidence of vte in patients, of which were fatal ( %) [ ] . furthermore, in a series of icu patients with severe covid- , pe was observed in ( %) and dvt in case [ ] . pe incidence rate was % in another series of icu patients despite prophylactic or therapeutic anticoagulation [ ] . in contrast, in another cohort, the incidence of vte was % overall, but no vte events were observed in patients receiving therapeutic level anticoagulation on admission [ ] . Α high rate of vte ( %, mainly pe) overall was reported in another series of icu patients in which patients with covid- associated acute respiratory distress syndrome (ards) had higher rates of thrombotic complications compared with non-covid- -ards [ ] . in a small series of individuals with covid- , in whom screening leg ultrasounds were performed in the icu, vte was found in ( %) cases [ ] . all patients were receiving either prophylactic or therapeutic anticoagulation, and some had additional vte risk factors. non-icu covid- patients had lower rates ( % to %) of vte during hospitalization [ , , ] . data on thrombotic events in patients with covid- infections who were not hospitalized are insufficient for analysis. the repeated reports of high rates of vte in covid- have led to the development of a guidance document recommending more aggressive thromboprophylaxis dosing intensities, extended-duration post-discharge thromboprophylaxis, and an individualized approach, taking into account average body mass index, severe thrombocytopenia, and drug-to-drug interactions [ , ] . acute limb ischemia acute upper or lower extremity ischemia has been identified as a covid- arterial thrombotic complication, in some cases requiring surgical embolectomy [ , ] . in one case series, two young patients who had no comorbidities developed acute limb ischemia despite low molecular weight heparin prophylaxis [ ] . a case report linked acute covid- -associated limb thrombosis with a probable diagnosis of antiphospholipid syndrome [ ] . the largest single-center, observational cohort study assessed covid- patients who presented with and were treated for acute limb ischemia over a -month period [ ] . an increased incidence rate of acute limb ischemia was observed in compared with the same months in , and successful revascularization was achieved in of the ( . %) patients. cardiovascular events acute myocardial injury, evidenced by elevated cardiac biomarkers (cardiac troponins, ecg changes, or echocardiographic abnormalities) is the most commonly reported cardiovascular complication of covid- infection [ ] . the frequency of myocardial injury varies among hospitalized patients, with reported incidence of to % [ •, - ] . acute cardiac injury occurred in five out of the first covid- patients in wuhan, four of whom were admitted to icu, suggesting that cardiac involvement was a predictor of disease severity [ ••] . some studies identified an association of troponin elevation in hospitalized patients with a more severe clinical course and worse outcomes [ , , ] . in one of the aforementioned cohorts of covid- hospitalized patients in wuhan, one out of five patients had extremely elevated high-sensitivity troponin i (hs-tni) on admission [ •] . similarly, in another study from wuhan, elevation of hs-tni on admission was identified in half of nonsurvivors compared with % of survivors [ ] . in contrast, in a study carried out in the usa, troponin levels on icu admission were elevated in only of critically ill covid- patients, with a % mortality rate in the group as a whole [ ] . heart failure has been proposed as another predictor of covid- outcome. in a study from wuhan of hospitalized patients, heart failure was found in half of the fatal cases and in only % of survivors [ ] . these observations were confirmed in a second chinese cohort of hospitalized covid- patients [ ] . apart from myocardial injury and heart failure, evidence of other forms of cardiovascular disease and risk factors in covid- is limited. both tachyarrhythmia and bradyarrhythmia have been described. the incidence was higher in patients requiring icu admission ( . % versus . %) but the exact type of arrhythmia is unknown [ ] . according to the report from national health commission of china (nhc), cardiovascular symptoms, e.g., palpitations and chest pain, were the first manifestation of covid- infection for some patients [ ] . importantly, pre-existing cardiovascular risk factors and/or development of acute cardiac injury have been consistently found to be associated with significantly poorer prognosis in covid- patients [ ] . furthermore, a significantly increased prevalence of pre-existing cardiovascular disease/cardiac risk factors has been reported in covid- patients with evidence of myocardial injury [ •] . however, there is not yet sufficient evidence to conclude that cardiac involvement is a surrogate biomarker of covid- severity rather than just a confounding factor. cerebrovascular events acute ischemic stroke is a recognized extra-pulmonary thromboembolic clinical feature of covid- . there are reports of stroke as the presenting clinical feature of polymerase chain reaction (pcr)-confirmed covid- infection, not simply a complication of inhospital stay [ ] . in one case series, four elderly patients with cardiovascular disease histories presented with fever and neurologic deficits related to acute infarction in the middle cerebral artery territory but were deemed unsuitable candidates for thrombolysis or any acute neurointervention. another report of five patients younger than years of age identified large-vessel stroke as a presenting feature of covid- [ ] . two of these had unremarkable medical histories; four out of five received acute treatment; and only one was hospitalized in icu. a large study that examined the neurologic signs and symptoms of consecutively hospitalized covid- patients in wuhan reported six acute cerebrovascular events and found that neurologic symptoms were present in severely affected covid- patients [ ] . in a nationwide, multidisciplinary study from the uk, ( %) covid- patients had a cerebrovascular event, of whom had acute ischemic strokes [ ] . in contrast, in a spanish registry, ischemic stroke was recorded in only ( . %) cases, and in an icu cohort of patients, only three cases were found [ , ] . another three strokes were reported in a similar french icu cohort of covid- patients [ ] . a uk report confirmed the observation of covid- association with large-vessel occlusion, - days after covid- symptom onset in six cases (aged - years, with cardiovascular medical history) [ ] . five of six patients had a positive lupus anticoagulant, one with coexisting low-medium titer of antiphospholipid antibodies (apl). the theory that covid- might stimulate the production of apl has been put forward [ ] . however, apl are usually transient in the postinfection period and their clinical significance is ambiguous [ ] . the most likely mechanism of early cerebrovascular accidents during the course of covid- infection appears to be hypercoagulability and vascular endothelial dysfunction mediated by pro-inflammatory cytokines. an italian retrospective study reported significantly increased rates of cerebrovascular disease in covid- patients with neurological manifestations compared with hospitalized neurological patients without covid- ( . % vs . %, respectively) [ ] . in that study, covid- patients with cerebrovascular disease presented with a hypercoagulability state characterized by longer prothrombin times, higher fibrinogen levels and inflammatory indices, and statistically significantly worse outcomes (covid- patients with a good outcome . % vs non-covid- . %). yet, further investigation is needed to assess the risk factors, causative relationship, mechanisms, and stroke phenotype, especially in young patients with covid- . increased awareness is needed to recognize the coexistence of covid- with stroke and promptly treat a covid- patient presenting with an acute neurologic symptom with thrombolysis or mechanical thrombectomy when appropriate [ ] . the other side of cerebrovascular disease, intracerebral hemorrhage (ich), has also been also linked with covid- , but occurs less frequently. nine intracerebral hemorrhages were reported in the uk-wide cohort and three in a spanish registry [ , ] . in a case report, evaluation of acute loss of consciousness in a febrile -year-old patient with an unremarkable medical history revealed covid- infection and a massive intracerebral hemorrhage together with intraventricular and subarachnoid hemorrhage [ ] . moreover, in an icu cohort of covid- patients receiving anticoagulation, one patient presented with both ich and ischemic lesions [ ] . cerebral vein and dural sinus thrombosis (cvt) and cns vasculitis are less common types of cerebrovascular disease. a rare case of cvt was observed in a cohort of covid- icu patients [ ] . small-vessel cns vasculitis was present as a result of presumably direct viral infection of endothelial cells based on a radiological finding of gadolinium-enhanced white matter lesions. similar findings occurred in one case in the uk-wide cohort [ , ] . neurologic invasion and phenotypes in addition to cerebrovascular accidents, sars-cov- can affect the central and peripheral nervous systems, causing a variety of neurologic disease phenotypes [ , ] . many neurological symptoms, such as headache, dizziness, myalgia, loss of smell and taste, ophthalmoparesis, pseudoexacerbations of multiple sclerosis and altered level of consciousness have been reported in covid- patients and have been attributed to the coronavirus [ ] [ ] [ ] [ ] [ ] [ ] . severe cases may manifest as impaired level of consciousness, encephalopathy, or encephalitis [ , , ] . in this context, the idea of covid- disease classification according to the presence or absence of neurological involvement of covid- neurological complications has been supported. reports of covid- neurological complications have described a - % incidence of secondary neurological events [ ] . of note, a large spanish registry revealed that . % of hospitalized covid- patients developed some type of neurological symptom [ ] . the most common was altered level of consciousness. however, neurological complications were considered the primary cause of death only in . % of total deaths. some patients may present with nonspecific neurological symptoms, as reported in one of the first retrospective cohorts from wuhan with patients. muscle ache occurred in %,confusion in % and headache in % of the patients [ ] . this large study from wuhan reported an incidence of . % involving cns, peripheral, and skeletal muscles [ •] . they observed an association of severe infection with the development of neurologic symptoms. in a french retrospective cohort of inhospital patients, encephalopathy with consistent electroencephalography findings and also prominent agitation and corticospinal tract signs were observed in the majority of icu patients [ •] . the coronavirus could not be isolated from csf, but mri showed lesions that included leptomeningeal enhancement, bilateral frontotemporal hypoperfusion and ischemic strokes. neurologic sequelae in icu-survivors of covid- also included critical illness neuropathy or myopathy and neuropsychiatric manifestations [ , ] . acute de novo psychotic and neuropsychiatric symptoms, hyperkinetic movements, generalized myoclonus, and status epilepticus have also been reported in association with covid- infection [ , [ ] [ ] [ ] . a multicenter retrospective study that investigated the risk of seizures or status epilepticus during covid- infection did not record any event, although of patients enrolled had a severe infection [ ] . this contrasts with previous reports of frequent neurological complications in covid- patients [ , ] . furthermore, an increasing number of case reports support the causative role of covid- in postinfectious neurologic complications such as miller fisher and guillain-barré syndrome (gbs) [ ] [ ] [ ] [ ] [ ] [ ] . however, in some cases no sars-cov- pcr assay was performed to confirm the diagnosis of infection before the hospitalization for gbs [ , ] . hence, it is important to note that the evidence of nervous system involvement in covid- disease is mainly based on case reports and retrospective data. in the middle of the pandemic, the research community is trying to understand the new virus, but publication bias lies in wait. our review summarizes for the first time available evidence of endothelial dysfunction caused by coronaviruses, focusing on covid- . our data confirm previous and recently acquired knowledge that endothelial dysfunction plays a key role in these infections. these data are important in order to understand the multisystemic attack of these viruses, and could also be helpful in patient management. although there is no direct therapeutic target for endothelial dysfunction, several agents have shown beneficial effects. a promising new strategy for treating severe covid- is complement inhibition. given the global impact of the pandemic, further well-designed, mechanistic, and clinical studies are urgently needed to translate this knowledge into clinical practice. author contributions e.g., p.a., m.g., and a.l. drafted the manuscript, tables, and figures. eu.g. edited the manuscript. funding information e.g., p.a., and eu.g. are co-financed by greece and the european union (european social fund-esf) through the operational programme "human resources development, education and lifelong learning - ", in the context of the project "evaluation of novel markers of endothelial dysfunction and thrombotic microenvironment in patients with rheumatoid arthritis: association with markers of subclinical inflammation and cardiovascular damage (mis )". conflict of interest the authors declare no conflicts of interest relevant to this manuscript. human and animal rights and informed consent this article does not contain any studies with human or animal subjects performed by any of the authors. endothelial cell infection and endotheliitis in covid- do viral infections mimic bacterial sepsis? the role of microvascular permeability: a review of mechanisms and methods review: viral infections and mechanisms of thrombosis and bleeding the vascular endothelium and human diseases endothelial cell functions Εndothelial functions in health and disease are summarized in this well-written informative report platelet-derived nitric oxide signaling and regulation calcium-dependent and calcium-independent activation of the endothelial no synthase nitric oxide dysfunction in vascular endothelium and platelets: role in essential hypertension characterization of bovine endothelial nitric oxide synthase as a homodimer with down-regulated uncoupled nadph oxidase activity: tetrahydrobiopterin binding kinetics and role of haem in dimerization tetrahydrobiopterin, but not l-arginine, decreases no synthase uncoupling in cells expressing high levels of endothelial no synthase oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases clinical significance of endothelial dysfunction in essential hypertension endothelial microvesicles circulating in peripheral and coronary circulation are associated with central blood pressure in coronary artery disease asymmetric dimethylarginine levels are associated with augmentation index across naive untreated patients with different hypertension phenotypes pathogenetic mechanisms of severe acute respiratory syndrome tissue distribution of ace protein, the functional receptor for sars coronavirus. a first step in understanding sars pathogenesis autoantibodies against human epithelial cells and endothelial cells after severe acute respiratory syndrome (sars)-associated coronavirus infection the clinical pathology of severe acute respiratory syndrome (sars): a report from china pulmonary pathology of severe acute respiratory syndrome in toronto. modern pathol: an official journal of the united states and canadian academy of pathology severe acute respiratory syndrome and venous thromboembolism in multiple organs coagulation disorders in coronavirus infected patients: covid- , sars-cov- , mers-cov and lessons from the past molecular pathology of emerging coronavirus infections mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury comparative host gene transcription by microarray analysis early after infection of the huh cell line by severe acute respiratory syndrome coronavirus and human coronavirus e the nucleocapsid protein of sars-cov induces transcription of hfgl prothrombinase gene dependent on c/ebp alpha a human in vitro model system for investigating genome-wide host responses to sars coronavirus infection haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis nejmoa a report of clinical, laboratory, and radiologic features of severe acute respiratory syndrome (sars) outbreak in hong kong thrombopoietin levels increased in patients with severe acute respiratory syndrome analysis of thrombotic factors in severe acute respiratory syndrome (sars) patients acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome large artery ischaemic stroke in severe acute respiratory syndrome (sars) osteonecrosis in patients after severe acute respiratory syndrome (sars): possible role of anticardiolipin antibodies lung pathology of fatal severe acute respiratory syndrome analysis of deaths during the severe acute respiratory syndrome (sars) epidemic in singapore: challenges in determining a sars diagnosis complement as a target in covid- ? pretransplant genetic susceptibility: clinical relevance in transplant-associated thrombotic microangiopathy linking complement activation, coagulation, and neutrophils in transplant-associated thrombotic microangiopathy complement activity and complement regulatory gene mutations are associated with thrombosis in aps and caps complementopathies and precision medicine eculizumab treatment in patients with covid- : preliminary results from real life asl napoli nord experience the first case of covid- treated with the complement c inhibitor amy- the ace expression in human heart indicates new potential mechanism of heart injury among patients infected with sars-cov- receptor recognition by the novel coronavirus from wuhan: an analysis based on decade-long structural studies of sars coronavirus severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ace evidence of the covid- virus targeting the cns: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms does sars-cov- invade the brain? translational lessons from animal models central nervous system involvement by severe acute respiratory syndrome coronavirus- (sars-cov- ) clin microbiol infect: the official publication of the european society of clinical microbiology and infectious diseases covid- -associated acute hemorrhagic necrotizing encephalopathy: ct and mri features a first case of meningitis/encephalitis associated with sars-coronavirus- acute disseminated encephalomyelitis after sars-cov- infection severe covid- infection and thrombotic microangiopathy: success does not come easily a case-series study describing a possible pathophysiologic mechanism of severe covid- infection unravelled the catastrophic microvascular injury syndrome mediated by complement cascade pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- microvascular covid- lung vessels obstructive thromboinflammatory syndrome (microclots): an atypical acute respiratory distress syndrome working hypothesis post-mortem examination of covid patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction autopsy findings and venous thromboembolism in patients with covid- incidence of thrombotic complications in critically ill icu patients with covid- prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy pulmonary embolism in covid- patients: awareness of an increased prevalence incidence of venous thromboembolism in hospitalized patients with covid- high risk of thrombosis in patients with severe sars-cov- infection: a multicenter prospective cohort study high incidence of venous thromboembolic events in anticoagulated severe covid- patients venous and arterial thromboembolic complications in covid- patients admitted to an academic hospital in milan systematic assessment of venous thromboembolism in covid- patients receiving thromboprophylaxis: incidence and role of d-dimer as predictive factors thromboembolism and anticoagulant therapy during the covid- pandemic: interim clinical guidance from the anticoagulation forum scientific and standardization committee communication: clinical guidance on the diagnosis, prevention and treatment of venous thromboembolism in hospitalized patients with covid this consensus provides practical guidance for the diagnosis, thromboprophylaxis strategies, and treatment of venous thromboembolism in hospitalized patients with suspected or confirmed covid- infection unheralded lower limb threatening ischemia in a covid- patient acute upper limb ischemia in a patient with covid- acute limb ischaemia in two young, non-atherosclerotic patients with covid- global haemostatic tests in rapid diagnosis and management of covid- associated coagulopathy in acute limb ischaemia acute limb ischemia in patients with covid- pneumonia cardiovascular disease and covid- association of cardiac injury with mortality in hospitalized patients with covid- in wuhan, china cardiac troponin i in patients with coronavirus disease (covid- ): evidence from a meta-analysis. prog cardiovasc dis covid- and cardiovascular disease covid- in critically ill patients in the seattle region-case series cardiovascular implications of fatal outcomes of patients with coronavirus disease (covid- ) clinical features of patients infected with novel coronavirus in wuhan clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan china clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study clinical characteristics of deceased patients with coronavirus disease : retrospective study covid- and the cardiovascular system covid- presenting as stroke large-vessel stroke as a presenting feature of covid- in the young neurologic manifestations of hospitalized patients with coronavirus disease uk-wide surveillance of neurological and neuropsychiatric complications of covid- : the first patients neurologic manifestations in hospitalized patients with covid- : the albacovid registry characteristics of ischaemic stroke associated with covid- coagulopathy and antiphospholipid antibodies in patients with covid- risk of developing antiphospholipid antibodies following viral infection: a systematic review and meta-analysis clinical characteristics and outcomes of inpatients with neurologic disease and covid- in brescia interventional stroke management in a covid- patient covid- and intracerebral haemorrhage: causative or coincidental? new microbes new infect kocer n brain mri findings in patients in the intensive care unit with covid- infection covid- -white matter and globus pallidum lesions. demyelination or small-vessel vasculitis? epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical characteristics of coronavirus disease in china covid- infection in a patient with multiple sclerosis treated with fingolimod covid- presenting with ophthalmoparesis from cranial nerve palsy rhabdomyolysis as potential late complication associated with covid- concomitant neurological symptoms observed in a patient diagnosed with coronavirus disease pearls and oy-sters: facial nerve palsy as a neurological manifestation of covid- infection neurological complications of coronavirus disease (covid- ): encephalopathy scoping review of prevalence of neurologic comorbidities in patients hospitalized for covid- nejmc the first european observational series on neurologic features of covid- patients admitted to intensive care units are we facing a crashing wave of neuropsychiatric sequelae of covid- ? neuropsychiatric symptoms and potential immunologic mechanisms covid- : icu delirium management during sars-cov- pandemic two patients with acute meningoencephalitis concomitant to sars-cov- infection generalized myoclonus in covid- de novo status epilepticus in patients with covid- new onset acute symptomatic seizure and risk factors in coronavirus disease : a retrospective multicenter study frequent convulsive seizures in an adult patient with covid- : a case report miller fisher syndrome and polyneuritis cranialis in covid- guillain-barre syndrome related to covid- infection fatal guillain-barre syndrome after infection with sars-cov- guillain-barre syndrome following covid- : new infection, old complication? guillain-barré syndrome associated with the coronavirus disease (covid- ). neurology: clinical practice a case series of guillain-barré syndrome following covid- infection in new york guillain-barré syndrome related to sars-cov- infection guillain-barre syndrome associated with sars-cov- infection: causality or coincidence? publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -otr authors: wax, randy s. title: preparing the intensive care unit for disaster date: - - journal: crit care clin doi: . /j.ccc. . . sha: doc_id: cord_uid: otr critical care teams can face a dramatic surge in demand for icu beds and organ support during a disaster. through effective preparedness, teams can enable a more effective response and hasten recovery back to normal operations. disaster preparedness needs to balance an all-hazards approach with focused hazard-specific preparation guided by a critical care-specific hazard-vulnerability analysis. broad stakeholder input from within and outside the critical care team is necessary to avoid gaps in planning. evaluation of critical care disaster plans require frequent exercises, with a mechanism in place to ensure lessons learned effectively prompt improvements in the plan. the hazard-specific approach creates a plan that is tailored to a specific type of event. advantages and disadvantages of both approaches are summarized in table . an all-hazards approach has the advantage of being potentially applicable to all possible events; however, it may create a less effective response due to lack of planning for specific challenges (eg, dialysis resources for crush injury-related renal failure after a major earthquake). a hazard-specific approach works well for the disaster events considered during planning; however, an unexpected type of event may result in a challenging response in the early stages of the disaster until the response can be recalibrated. disaster preparedness efforts should include a hazard-vulnerability analysis (hva), which evaluates risk by taking into account the likelihood of an event occurring, the severity of impact should such an event occur, the current state of preparedness, and internal/external capability to respond (risk probability  severity). for health care organizations, the kaiser permanente model provides an excellent example of such a framework and provides some online tools (such as their hazard and vulnerability assessment tool) to help hospitals prepare an hva. generating risk scores or rankings for different types of disaster events can help prioritize preparedness efforts by focusing on the most likely or most severe types of events, keeping in mind the need to maintain some level of all-hazards preparedness in case the hva proves inaccurate or that a highly unlikely event occurs. an hva may be conducted from different perspectives, with different results. federal, state/province, county/region, and local hospitals may note different probabilities, potential impact, and levels of preparedness creating different risk profiles. for example, a nuclear power plant disaster may be much less likely than natural disasters from a federal or state perspective; however, a hospital system located in close proximity to nuclear power plants (such as the one in which this author practices) should likely take such events much more seriously in their planning efforts. even within a hospital, the results of an hva may be more or less generalizable to different areas/programs within the hospital. the emergency department (ed) and operating room would typically experience a huge impact in a sudden onset trauma surge (such as a mass casualty shooting), whereas a bioterrorism or pandemic event with a prolonged incubation period may have a greater effect on the intensive care unit (icu) because of the prolonged need for mechanical ventilation and icu support for disaster-related patients. hence the importance of involving critical care in table characteristics of all-hazards versus hazard-specific approaches to disaster preparedness hospital-wide disaster planning, but also ensuring that the critical care team conducts independent disaster preparedness activities to consider issues specific to the icu. given that critical care is by nature an interprofessional health care effort, the need for interprofessional involvement in critical care disaster planning should be obvious. understanding the potential roles for usual members of the critical care team in disaster planning should help guide expectations and accountabilities in the planning process. in addition, clarity of the nature of the ideal -way interaction with noncritical care stakeholders inside and outside the hospital is essential, thus encouraging the sharing of critical care expertise with others to help with their planning efforts and improving critical care planning with expert internal input. table highlights potential contributions of different stakeholders toward critical care disaster planning, with further details discussed below. critical care physicians possess key understanding of the nature of organ failure and support, and have day-to-day experience with patient prioritization and triage activities. strong critical care physician presence and leadership in disaster planning is essential for developing an adequate and sustainable critical care physician resource plan for disaster events. as part of disaster planning, critical care physicians can help design an education strategy to prepare noncritical care physicians to assist in a disaster event as icu physician extenders, often deployed using a just-in-time approach at the time of a disaster. critical care physicians can also work with physicians in other areas of the hospital likely to provide critical care outside the icu during a disaster, such as the ed, to ensure their planning takes into account critical care capacity. as essential frontline care providers for any critically ill patient, critical care nursing must be involved in icu disaster planning. key factors for consideration include appropriate and sustainable nursing staffing (including potentially modified nurse:patient ratios), modifications to care standards if required, and documentation requirements. planning for use of icu nursing extenders with non-icu nurses requires advance clarification of the scope of non-icu nurses in caring for critically ill patients and creation of just-in-time education support to allow non-icu nurses to augment their ability to contribute during a disaster. critical care nursing leadership involvement will ensure adequate planning for the required interfaces between the icu and other areas of the hospital from a patient safety and administrative perspective, including strategies for bed management and patient flow into and out of the icu. advanced nursing providers, such as nurse practitioners and nurse anesthetists, and other providers, such as physician assistants and critical care paramedics, may provide helpful input during the planning process. in particular, these providers can help others understand how leveraging their enhanced scopes of practice may provide additional support during a severe critical care surge. respiratory therapist expertise is required to ensure appropriate planning for availability of medical gas (especially oxygen) in icu and non-icu clinical spaces, adequate access to airway equipment and mechanical ventilators, and planning for provision of respiratory support in non-icu areas of the hospital. strategies for enhancing capacity for mechanical ventilation may rely on use of unfamiliar ventilators from an external stockpile, or use of modified ventilators (such as transport ventilators or anesthesia gas machines). respiratory therapists may also help with other aspects of hazard-specific preparedness, such as strategies for monitoring of carbon monoxide in mass casualty exposures or delivery of bronchodilators for patients exposed to pulmonary irritants. in many jurisdictions, respiratory therapists with maximized scope of practice can also provide support for nonrespiratory issues, such as intravenous insertion or medication delivery, that can be incorporated into planning for provider oversight of patients during a major surge event. pharmacists appropriate stockpiling of medications is an essential component of critical care disaster preparedness, for which pharmacist input is invaluable. from an all-hazards perspective, generic medication requirements for management of icu patients can be modeled, such as need for sedation and analgesia for ventilated patients, or preventative therapy such as deep venous thrombosis prophylaxis. hazard-specific planning can include medications specific to address the hazard, such as antidotes for organophosphate poisoning, cyanide exposure treatment, or antiviral medications for pandemic influenza. the icu-specific hva can help pharmacists prioritize medication planning during disaster preparedness activities. knowledge of factors such as shelf life of medications, need for special storage such as refrigeration, and costing helps pharmacists provide essential advice for procurement. ideally, stockpiling strategies will avoid unnecessary availability of multiple drugs that can provide the same effect, such as having morphine and fentanyl and hydromorphone available as multiple narcotics. pharmacy input for creation of preprinted order sets to be used during a disaster can help align prescribing by providers with the available drugs stockpiled. finally, given that funds used for disaster preparedness take away from funds required for usual hospital expenses, pharmacy input on cost:benefit ratios of different medication options can help with a fiscally responsible approach to disaster planning and logistics. maintaining appropriate nutrition, early mobilization, and encouraging improved recovery to baseline functional state are essential adjuncts to life-support efforts. encouraging the involvement of relevant interprofessional team members in critical care disaster planning can help determine potential limitations in services during a disaster, suggest mitigation strategies to minimize the impact of a surge in demand for their expertise, and propose educational strategies to use other health care staff and even family members to assist as extenders with less frequent available input from these health care professionals. critical care disaster planning should take into account the tremendous stress of such events on patients, families and clinical staff. more detailed discussion of these issues can be found in other articles in this issue. although prehospital and ed triage strategies should identify and support disaster victims with isolated psychological/mental health issues, nothing precludes the copresence of mental health injuries (novel or exacerbations of existing mental health diagnoses) with critical illness from physical causes. planning for availability of psychiatry and other mental health consultationliaison services should be considered to support patients requiring critical care after a disaster. similarly, family members of critically ill patients will require ongoing support throughout the hospitalization of their loved ones, which may include need for social work and chaplaincy. strategies to ensure effective communication and support of family members when patients require transfer out of the hospital for higher level of care or capacity reasons should be considered in planning efforts. withdrawal of active life support may be required when patients are not benefiting from critical care support and/or if triage decision making requires shifting of resources to patients more likely to benefit, and the involvement of clinical ethicists to support patients, families, and staff members can be very helpful thus requiring consideration during planning. an emerging concept in disaster planning incorporates the concept of mental health/stress inoculation for hospital staff, which may include advance and just-intime deployment to increase performance during the disaster and prevent long-term psychological effects. , trauma, emergency department, and perioperative services during events that cause a sudden and rapid surge of patients to the hospital with mass casualty medical issues, trauma/burns, or other injuries requiring surgical support, impact on the icu can be delayed but substantial as the disaster unfolds. in such circumstances, the ed is usually on the frontline as first receivers of critically ill patients. the ed and icu teams must collaborate during disaster planning to ensure that critically ill patients receive optimal care regardless of their geographic location within the hospital. in the early stages of a disaster, icu planning may need to include a time-limited option to have critical care clinicians support patient care and triage activities in the ed. many patients will require resuscitation and stabilization in the ed before being safe to transport to the icu, and may also require transfer to the operating room for damage control or definitive surgery before transfer to the icu. planning for the orderly and safe transfer of patients from the ed or the operating room to the icu should include strategies for efficient transfer of clinical information and accountability of care. in the event of a nonsurgical disaster creating severe patient surge within the icu and hospital as a whole, disaster planning should include procedures for decision making regarding the cancellation of elective surgery to augment availability of space, staff and, supplies for disaster-related patients. plans for using surgical resources to support critically ill patients in the postoperative recovery room area (as an extended icu) or operating rooms (using anesthetic gas machine ventilators) should be discussed collaboratively. pediatric specialty hospitals that have a distinct pediatric critical care unit often provide regional support for critically ill and injured children. in a disaster event, the dedicated pediatric critical care center may be overwhelmed with patients, or the nature of the disaster may preclude immediate transfer of pediatric patients. therefore, nonpediatric hospitals should plan for management of pediatric patients. this would require potential stockpiling of equipment and supplies appropriate for pediatric patients. advance or just-in-time education for nonpediatric critical care providers to manage critically ill children should be considered ( course currently recommended for this purpose in some jurisdictions is the pediatric fundamental critical care support course offered by the society of critical care medicine , ) , as well as planned partnership with pediatricians to comanage critically ill children with adult intensivists. a disaster may force hospitals to care for obstetric patients beyond their usual complexity case mix or with gestational age earlier than usual, resulting in neonatal patients requiring more support than usually provided at the facility. these patients may have issues related to the disaster, or may be unable to be transferred because of the overwhelming surge in the usual tertiary care facility or because of the disrupted patient transport resources. from a critical care perspective, collaboration with obstetric teams will be required for management of critically ill pregnant patients. neonatal icus may need to work with adult critical care teams to gain access to additional neonatalcapable mechanical ventilators and monitoring equipment for their patients, or may face requests to share their ventilators to support an adult critical care surge. for these special groups of potentially critically ill patients, the critical care team and hospital at large should take account of space, equipment, supplies, and staff to help manage surges for those groups. in the absence of expertise to manage these patient populations, hospitals should consider planning to leverage telemedicine technology [ ] [ ] [ ] to gain assistance from clinical experts at a remote site (which may be different than their usual partners who may be also affected by the disaster and unable to assist). from an all-hazards perspective, a disaster can change the need for laboratory and diagnostic imaging support because of the increased demand for tests and the need for rapid, point-of-care results to minimize delay in clinical decision making and triage decisions during mass casualty events. from a laboratory perspective, disaster planning should incorporate strategies for triaging of laboratory study requests to maximize time-sensitive results impacting on critical clinical decision making. use of existing or stockpiled portable point-of-care laboratory equipment that can be operated by frontline clinical staff can be considered to reduce burden on the laboratory team. bedside clinical monitoring may be used as a laboratory test mitigation strategy in some cases, such as the use of pulse oximetry and quantitative capnography for ventilated patients instead of arterial blood gas testing, or advanced pulse oximeters that can measure carbon monoxide levels as a screening strategy in mass casualty carbon monoxide exposure. certain high-priority threats identified by the icu-specific hva may warrant specific discussion with laboratory services to ensure availability of necessary hazard-specific testing if possible. blood bank services in particular will need to coordinate with critical care and other hospital services to prepare for mass casualty events placing excessive demands for blood products, including a strategy to triage blood product requests in extreme cases. during a disaster, demand for diagnostic imaging studies may outstrip capacity of available equipment and technologists, and availability of radiologists to interpret the studies. use of portable radiographic equipment with an integrated monitor to allow immediate review of images by frontline clinicians may reduce delay in detection of critical clinically important findings. planning for enhanced availability of point-of-care ultrasound can be helpful as a substitute for other diagnostic imaging modalities, or to help triage cases when resources are limited, such as prioritizing computed tomography scan requests for possible abdominal injuries or ruling out of a pneumothorax and avoiding need for portable radiographic equipment. other newer point-of-care technology may help identify patients at higher risk for neurosurgical intervention and again help prioritize patients for access to limited diagnostic resources. an essential element of critical care disaster planning assumes the high likelihood of having to manage critically ill patients outside of the usual icu space. ensuring that appropriate physical plant and space is available, along with information technology support, will reduce some challenges with regard to working in non-icu space. understanding of space capabilities, with the input of facilities engineers, can help with the appropriate planning choices for icu surge space within the hospital and help avoid unpleasant surprises, such as lack of emergency backup power outlets, sufficient medical gas supply, or other limitations. a particular concern is the availability of negative-pressure airborne isolation rooms in the event of a serious airborne-spread biohazard disaster. most hospitals have limited airborne isolation capacity during usual operations. during hospital surge experiences during the worldwide to severe acute respiratory syndrome (sars) outbreak, some facilities were able to modify airflow and erect barriers to create large negative-pressure isolation wards, including icus. planning for various scenarios identified in the icu-specific hva should identify potential physical facility gaps and prompt mitigation strategies. intensive care units are technology-dependent areas of care that rely on sophisticated information technology services for networking of patient care monitors and equipment, electronic drug dispensing modules, and computer access to support icu-specific electronic medical records. in disaster situations, initial receipt of patients in the ed will often shift to a paper-based triage and registration strategy. planning for the transition from the initial crisis phase of a disaster with mass casualties to integration of patients within the electronic medical record will help ensure timely and accurate access and creation of health provider notes, laboratory results, and diagnostic imaging reports. information technology services should also plan for additional need of mobile computers and sufficient wireless network access to manage critically ill patients outside of the usual icu space. the potential need for use of telemedicine services to support management of special populations of patients, as mentioned above, should prompt planning and testing of telemedicine capacity including equipment and network bandwidth in advance to prevent service gaps during a disaster. hospitals typically spend considerable effort and resources on controlling external access to the facility during disaster events to ensure patient and staff safety, deter premature entry of persons requiring decontamination, maintain control of limited resources and supplies, and prevent unauthorized members of the media or other members of the public from compromising patient and family privacy. in the event of strict hospital visitor restrictions, attempts to circumvent security controls can be expected. specific consideration of the security needs of the critical care areas wax (traditional and makeshift) is occasionally overlooked. intense emotional reactions of family and friends of critically ill patients can occur and be compounded in a stressful disaster situation. in the event of implementation of triage activities and a shift from usual standards of care, decisions to withdraw life support from those patients not benefiting from scarce resources can be met with violent objection. physical measures to limit access to the critical care areas may need enhancement, and there may also be a need for greater visible presence of security staff as a deterrent to unacceptable treatment of hospital staff. liaison with security staff should be included as part of the critical care disaster planning process to avoid gaps in security capability. disaster preparedness requires an investment of resources in terms of staff time to commit to planning, equipment, and supplies earmarked for disaster stockpiling, and development of relationships and agreements with external entities. for preparedness to be effective, hospital administration must appreciate the need for planning and endorse recommendations. although the finance elements within a hospital are usually prepared to capture costs incurred while a disaster is in progress to facilitate reimbursement, advance efforts to secure funding support for disaster preparedness through government and other agency grants can mitigate opposition to diversion of funds away from frontline clinical activities. increasingly, hospitals are appointing a lead for disaster preparedness who can act as a liaison between clinicians and administration. given the high costs that can be associated with provision of critical care, particularly in surge situations, clear articulation of the needs for critical care disaster planning may enable the necessary allocation of resources to ensure the planning vision is realized. certainly, lessons can be learned after each disaster event that can lead to identification of problems or gaps in a critical care disaster plan. fortunately, those disaster events are uncommon, but, unfortunately, we cannot rely only on actual disaster events to test plans and maintain disaster competency among hospital staff. frequent disaster exercises can help educate staff on how to function during an actual event, and provide feedback to disaster planners allowing plan improvement before a disaster. disaster exercises may vary in scale and fidelity (fig. ) . the scale of a disaster exercise may be limited to a single critical care unit, involve multiple hospital services, or be expanded to a regional, state, or even national scale. the fidelity of a disaster exercise may be tabletop-based, using patient cards and virtual clinical spaces; may take into account current actual clinical volumes and bed availability; or may use hundreds of actors playing the role of patients, combined with highfidelity patient simulators, scattered throughout actual areas of the hospital for an in-situ exercise. exercises of greater fidelity and greater scale consume more resources to conduct, and may be more likely to interfere with routine hospital operations. however, the greater the fidelity and the greater the scale, the more likely it will be to identify opportunities for improvement in disaster planning. thus, a balance of these factors must take into account local resources, support for disaster preparedness by hospital leadership, and mandatory activities required for hospital accreditation or government funding. beyond generic disaster exercise activities, certain aspects of disaster planning specific to critical care should be specifically addressed in exercise design. critical care leaders and staff should understand the hospital incident command system (hics) preparing the icu for disaster as organized in their hospital, and know how they interface with the hics. critical care would normally fit within the operations branch, under control of the operations chief. in some cases, leadership roles within the hics may be filled by critical care leaders given their broad clinical understanding of the hospital as a whole; however, their responsibilities would be guided by the hics role rather than keeping a narrow focus on critical care. depending on the nature of the disaster event, critical care leaders and clinicians may be asked to assist the hics leadership team as subject matter experts, or participate in task forces or strike groups designed to handle specific problems. certain principles of the hics can be useful in disaster planning on a smaller scale specific to critical care. the concept of span of control, having everyone report to only person, and each person only having to people reporting to them, may be helpful in organizing clinical teams including non-icu staff supervised by icu clinicians. also, the concept of job action sheets that provide guidance for key actions given a particular role can be helpful in reminding staff of key tasks during a stressful disaster event, and can be a valuable teaching tool during an exercise. hospital exercises often emphasize infrequent but important tasks, such as decontamination of patients before entry to hospital, which are important but potentially less relevant to critical care staff. patients should never enter a critical care area without decontamination if required. for biological infectious events, there may be no ability to perform the equivalent of decontamination, because the patients remain infectious and put staff and other patients at risk. exercise and evaluation of advanced infection control strategies (such as conversion to negative-pressure clinical areas, use of infection control coaches), or advanced personal protective equipment (such as powered air-purifying respirator use, safe donning and doffing of equipment) may be of special significance for critical care team preparedness. exercises should also encourage familiarity with stockpile equipment, such as monitoring equipment or unfamiliar ventilators, so that there is some retention of competency in the event of the need to use such equipment in a disaster event. just-in-time education strategies to augment clinical care for special populations (eg, pediatrics) or hazard-specific care (eg, radiation sickness) can be practiced and evaluated for future revision. much of the learning from a disaster exercise takes place during the debriefing phases after the event. a "hotwash" debriefing immediately after the event can capture important lessons; however, another opportunity to capture additional lessons after some time to reflect can also provide further guidance on disaster plan revisions. preparing an after-action report after simulated and real disasters can ensure that lessons learned are captured; however, development of a list of actions including accountabilities and timelines, with a process for follow-up to ensure completion, should reduce the rediscovery of the same recommendations at the next real or simulated disaster. the preparedness phase of disaster management can make or break the response to an actual disaster. teams should aim for an optimal balance between flexible all-hazards preparedness and hazard-specific preparedness guided by the hazardvulnerability assessment. one of the best strategies for ensuring ongoing support for disaster preparedness activities is to identify potential flaws in the current disaster plan through frequent disaster exercises. despite the temptation to divert resources to routine clinical budget demands, an upfront investment in preparedness will hopefully lead to a more efficient disaster response and more rapid recovery to normal operations should a disaster occur. disaster preparedness: are we ready yet? hospital news reassessing the effectiveness of all-hazards planning in emergency management emergency preparedness: california hospital association clinical review: the role of the intensive care physician in mass casualty incidents: planning, organisation, and leadership nurses' competencies in disaster nursing: implications for curriculum development and public health guidelines regarding the role of the certified registered nurse anesthetist in mass casualty incident preparedness and response creating a disaster plan for rt departments pharmacy leader's role in hospital emergency preparedness planning ethical considerations: care of the critically ill and injured during pandemics and disasters: chest consensus statement computer-assisted resilience training to prepare healthcare workers for pandemic influenza: a randomized trial of the optimal dose of training resilience training for hospital workers in anticipation of an influenza pandemic emergency preparedness: manual for anesthesia department organization and management wny hospital pediatric disaster preparedness presentation - recommendations for increasing nyc pediatric critical care surge capacity (draft) the impact of telemedicine on pediatric critical care triage the role of telemedicine in pediatric critical care the use of telemedicine to address disparities in access to specialist care for neonates emergency department management of suspected carbon monoxide poisoning: role of pulse co-oximetry test characteristics of ultrasonography for the detection of pneumothorax: a systematic review and meta-analysis the infrascanner, a handheld device for screening in situ for the presence of brain haematomas hospital preparedness and sars lessons healthcare security professionals learned from hurricane harvey. security management world health organization. hospital and health facility emergency exercises: guidance materials hospital incident command system guidebook key: cord- -pep opiq authors: remy, kenneth e.; verhoef, philip a.; malone, jay r.; ruppe, michael d.; kaselitz, timothy b.; lodeserto, frank; hirshberg, eliotte l.; slonim, anthony; dezfulian, cameron title: caring for critically ill adults with coronavirus disease in a picu: recommendations by dual trained intensivists* date: - - journal: pediatr crit care med doi: . /pcc. sha: doc_id: cord_uid: pep opiq in the midst of the severe acute respiratory syndrome coronavirus pandemic, which causes coronavirus disease , there is a recognized need to expand critical care services and beds beyond the traditional boundaries. there is considerable concern that widespread infection will result in a surge of critically ill patients that will overwhelm our present adult icu capacity. in this setting, one proposal to add “surge capacity” has been the use of picu beds and physicians to care for these critically ill adults. design: narrative review/perspective. setting: not applicable. patients: not applicable. interventions: none. measurements and main results: the virus’s high infectivity and prolonged asymptomatic shedding have resulted in an exponential growth in the number of cases in the united states within the past weeks with many (up to %) developing acute respiratory distress syndrome mandating critical care services. coronavirus disease critical illness appears to be primarily occurring in adults. although pediatric intensivists are well versed in the care of acute respiratory distress syndrome from viral pneumonia, the care of differing aged adult populations presents some unique challenges. in this statement, a team of adult and pediatric-trained critical care physicians provides guidance on common “adult” issues that may be encountered in the care of these patients and how they can best be managed in a picu. conclusions: this concise scientific statement includes references to the most recent and relevant guidelines and clinical trials that shape management decisions. the intention is to assist picus and intensivists in rapidly preparing for care of adult coronavirus disease patients should the need arise. t he worldwide pandemic of coronavirus disease (covid- ) caused by severe acute respiratory syndrome coronavirus has already resulted in critical care demands overwhelming resources in nations such as italy ( ) . this has stressed local healthcare systems requiring new approaches for triage and acute care. with significant resource limitations, especially in differing geographic locales, this pandemic may exhaust existing capacity making it difficult to maintain adequate critical care necessitating adaptations. fortunately, covid- disease has been uncommon in children with a reported mean age for most icu patients between and years ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . many of these patients have comorbidities such as hypertension, type diabetes, coronary vascular disease, cerebrovascular events, and chronic obstructive pulmonary disease (copd). patients commonly present on day - of illness with acute hypoxemic respiratory failure ( , , , , ) and the frequent icu complications include shock differences between adults and pediatric advanced life support cardiopulmonary resuscitation (cpr) and life support algorithms for adults are deliberately similar to pediatric patients. identical approaches should be taken toward both ventricular fibrillation/pulseless ventricular tachycardia and asystole/ pulseless electrical activity ( ) . the advanced cardiac life support algorithm for symptomatic bradycardia does not include cpr and uses atropine iv ( . mg every - min, maximum mg) as a first-line agent followed by early consideration of epinephrine or dopamine infusions and transcutaneous pacing ( ) . tachycardia with hemodynamic instability due to regular rhythms (e.g., atrial flutter) requires synchronized cardioversion with - j while irregular rhythms (e.g., atrial fibrillation [af]) require - j. cpr on adults is similar to pediatrics: push hard (although deeper, > inches), fast ( - per min), and allow complete recoil ( ) . advanced directives and patient prognosis in determining code status should be considered at picu admission in every patient and in some cases, the team may determine to limit resuscitation. picu epidemiology favors smaller sizes/heights thus deficits in supplies tend to occur when dealing with taller (> cm) and heavier (> kg) adults. table provides a list of commonly used supplies to consider for these larger individuals. central venous catheters for vascular access or dialysis placed in the right internal jugular or subclavian often require ~ - cm length which most picus stock. we recommend adding cm catheters that are better for adult left sided upper body and femoral approaches. as the covid pandemic has driven use of telecommunications in lieu of in person meetings, it is our anticipation that most picus will have access to a full suite of adult physician consult services. in table , we outline the most likely needed consultations for acute covid- issues. we include procedures which may be performed in the acute setting by the consultant (table ) , purposely omitting those which do not offer therapeutic potential and thus may be deferred. likewise, we omit consultative services where pediatric specialists can provide support, or the entire consultation may be performed by telecommunication. for procedures, the consulting physicians and picu team will need to determine whether the services can be safely rendered within the pediatric facility or require transport to an adult hospital. many procedures are now feasible at the bedside in adult hospitals such that a similar approach would appear to be less problematic than transport of a highly infectious and critically ill covid patient across centers. - . mm-cuffed tube. morbidly obese adults are often best preoxygenated in a reverse trendelenburg position with the head of bed elevated to drop abdominal weight off the chest. with covid- , we recommend the use of video laryngoscopy for rapid sequence intubation (rsi) by the most experienced operator ( ) to maximize success and prevent aerosols. central venous catheters are placed infrequently in the femoral position due to heightened risk of deep venous thrombosis and infection ( ) . arterial catheters are used more frequently than in the picu and often employ a preloaded needle/wire introducer kit. thoracentesis and lumbar puncture (lp) in a cooperative adult may have more success with the patient sitting upright and from behind with ultrasound guidance. obese patients often require longer needle lengths than the standard . cm ( . in) for lp ( ) with various lengths up to cm available. the length needed can be estimated in cm as . × body mass index + . ( ) . table provides a list of commonly prescribed medications for adults which may not be commonly stocked in pediatric centers (at least not in large supply) as well as recommendations on whether continuation is critical and whether substitutions can be made with agents more often found in a pediatric formulary. escalation of respiratory support in adults generally includes nonrebreather mask, venturi or oxymask, high-flow nasal cannula (hfnc), or noninvasive positive pressure ventilation (nippv) ( ) ( ) ( ) ( ) ( ) . with covid- , there is concern for generating infectious aerosols in when using hfnc and nippv such that some institutions are avoiding greater than l flow ( ) , although recent society of critical care medicine/european society of intensive care medicine guidelines include both modalities ( ) . this risk is minimal with good cannula or mask fit on the patient ( , ) and with use of protective filters ( ) . negative pressure isolation rooms mitigate this concern. oxymask allows titration of oxygen flow but not titration of the fio , whereas hfnc and nippv allow fio titration and use with inhaled pulmonary vasodilators ( , ( ) ( ) ( ) . commonly used settings are listed in table . for covid- patients we recommend rsi in a negative pressure room ( , , , ) . in rsi, bag-valve-masking is minimized and patients receive an induction agent (propofol at . - . mg/ kg, or etomidate . mg/kg) "immediately" followed by a neuromuscular blocker (succinylcholine at . mg/kg, rocuronium at . mg/kg, or cisatracurium at . mg/kg) and intubation within a minute. succinylcholine and propofol use in adults is common and offers the advantage of rapid and favorable intubation conditions with less safety concerns compared with other agents ( ) . mechanically ventilated adults are mostly managed with assist-control ventilation, rather than synchronized intermittent mandatory ventilation based on studies showing improved work of breathing, synchrony, and extubation rates ( ) . volume modes, such as volume control (vc) or pressure regulated vc (vc+), permit maintenance of lower tidal volumes ( - ml/ kg) based on predicted body weight and lower plateau pressures (< cm h o) in acute respiratory distress syndrome (ards) ( , ) . in the absence of ards, ml/kg is safe ( ) . positive end-expiratory pressure (peep) is titrated based on fio using validated protocols ( , ) to levels higher ( - cm h o at fio = ) than encountered in pediatrics ( ) . our experience and that of many centers is that covid- hypoxemia responds well to peep increases. however, notable exceptions have been found where lower peep is preferred ( ) . these cases may be the result of pulmonary microthrombi reducing blood flow ( ) as covid- patients are recently reported to develop coagulation abnormalities ( ) . in these cases, higher peep may be deleterious by increasing pulmonary vascular resistance. highfrequency oscillation is not used in adults due to randomized trials showing increased mortality ( ) and greater need for sedation ( , ) . assessment for extubation readiness is typically done using a combined spontaneous awakening-spontaneous breathing trial ( ) in which all sedation is lifted and the patient is placed on a continuous positive airway pressure (table on dosing) opioid, benzodiazepine, and dexmedetomidine iv infusions and/or boluses are used for sedation in adults and pediatrics in similar dose ranges despite the common practice in adults of using absolute doses (e.g., mg/hr) as opposed to weight-based dosing (e.g., mg/kg/hr). propofol use is common in adults due to few reports of propofol infusion syndrome ( , ) with dose range of - µg/kg/min employed for continuous prolonged sedation or up to µg/kg/min for brief procedures. multiple randomized trials have failed to demonstrate any optimal adult sedative ( ) ( ) ( ) ( ) ( ) . propofol or dexmedetomidine produces more hypotension than midazolam and opioids but are metabolized more rapidly. sedation interruptions or closely titrated sedation based on clinical scores (i.e., richmond agitation-sedation scale) are superior to both or minimal sedation in producing patient comfort and hemodynamic stability ( ) ( ) ( ) . prone positioning for at least hours daily in adults with severe ards may increase ventilator-free days, reduce in-hospital mortality, and reduce the need for rescue therapies like inhaled nitric oxide and extracorporeal membrane oxygenation (ecmo) ( , ( ) ( ) ( ) ( ) . the surviving sepsis guidelines for covid- for moderate to severe ards recommend proning within hours of presentation ( ) . our collective experience supports impressive responses in oxygenation following proning in covid- . prone patients typically require additional staff for patient manipulation, deep sedation, and often neuromuscular blockade. care should be taken to minimize complications such as endotracheal tube obstruction, pressure sores, facial edema, and ocular injury ( - ). copd is a common chronic illness worldwide and leading cause of both morbidity and mortality ( ) . patients with copd are at high risk to develop acute exacerbation of copd (aecopd) during the covid- pandemic and early recognition and treatment is essential. the mainstay of treatment for aecopd are short-acting bronchodilators, short courses of steroids, oxygen therapy to target oxygen saturations of - %, and short courses of antibiotics ( - d [ ] ). inhaled bronchodilators (short-acting β agonists and muscarinic antagonists) are effective in the treatment of acute exacerbations. nebulization should be avoided due to risk of viral aerosolization rather these medications should be administered via meter-dose inhalers. prednisone or iv methylprednisolone ( - mg daily) for - days is recommended ( ) . nippv is the standard of care especially for aecopd as it has been demonstrated to decrease intubation rates, and overall mortality due to respiratory failure ( , ) . akin to intubated asthmatics, intubated aecopd with covid may require lower respiratory rates and higher tidal volumes to avoid autopeep and increased intrathoracic pressure, decreased venous return, and hemodynamic compromise. adults with ards may receive a survival and disability benefit from venovenous ecmo when offered within days of initiation of mechanical ventilation ( ) ( ) ( ) . venovenous ecmo has been found to be safe and effective, especially in ards patients during the h n influenza pandemic ( ) ( ) ( ) . evidence from adults with covid- in japan and south korea suggest that carefully selected patients with severe ards failing conventional treatment can be successfully supported with venovenous ecmo ( , , ) . venovenous ecmo flow rates needed to support oxygenation in adults are generally - ml/kg/min ( ) . "lung rest" ventilation should target fio less than or equal to %, peep ~ , and plateau pressure ~ - ( ) . covid- appears to cause myocardial injury with increased mortality in these patients ( ). selected adults progressing to cardiovascular failure may benefit from venoarterial ecmo, although this is associated with a higher risk of stroke, bleeding, and renal failure and should only be considered only in experienced, resourced centers ( ). cerebrovascular accident (cva) is a leading cause of death in the united sates with an overall prevalence of . % in those greater than years old ( ) ( table ) . most cva ( %) is ischemic. immediate evaluation to stabilize hemodynamics, decipher if intracranial hemorrhage or ischemia is present, and then decide on reperfusion therapy is temporally critical. sudden loss of focal brain function is a core feature of ischemic stroke onset. management of cva includes stabilizing the patient's airway, breathing, and circulation (abcs), reversing contributing issues, determining the etiology (for ischemic strokes, consider thrombolysis or endovascular thrombectomy), and preparation for post intervention surveillance/management. pediatric intensivists should calculate a national institutes of health stroke scale score, obtain immediate acute imaging to exclude hemorrhage, assess the degree of brain injury, and identify the vascular lesion responsible for the deficit. imaging may be difficult given isolation for covid- ; however, these studies are time critical as thrombolysis must occur in less than . hours from symptoms ( ) ( ) ( ) ( ) ( ) ( ) ( ) . imaging includes hyperacute mri, noncontrast ct, or ct angiography. reperfusion is the most effective maneuver for salvaging ischemic brain that is not already infarcted and is time sensitive as the benefits of reperfusion for ischemic stroke diminish over time. recent guidelines for early stroke management are published ( ) . consultation with a stroke team (telestroke) is recommended. mounting evidence demonstrates that up to % of covid- patients have direct cardiac injury with increases in arrhythmia, myocardial infarction (mi), myocarditis, and acute heart failure ( , , , , ) . thus, we provide considerations for these common complications with guidance on management. acute or new onset atrial fibrillation. af is the most common cardiac arrhythmia in adults, more prevalent in men, and prevalence increases with age ( , ) . af presents as an irregularly irregular pulse which on electrocardiogram (ecg) has rr intervals without repetitive pattern and often absent p waves. af and resultant tachycardia may compromise cardiac output and result in atrial thrombus formation with potential for embolic stroke. understanding the immediate etiology for af is important, as some causes are reversible (i.e., mi, active infection, electrolyte disturbance). management of af centers on rate and rhythm control. rate control to slow the ventricular rate is best achieved via use of beta-blockers (metoprolol or esmolol) or calcium channel blockers (diltiazem). a transesophageal echocardiogram is recommended to evaluate for signs of acute heart failure or left atrial appendage thrombus. to immediately restore normal sinus rhythm direct electric cardioversion within hours of onset is warranted if af is causing hemodynamic embarrassment. direct current cardioversion may be more successful with use of amiodarone infusion for hours. in the setting of persistent af with lower blood pressures, digoxin and amiodarone may be considered for rate control. management of af is the subject of a recent guideline update ( ) . acute coronary syndromes (including demand ischemia). assessment of chest pain and acute coronary syndrome (acs) must be undertaken immediately. if a patient experiences chest pain, arm pain, dizziness, or new onset arrhythmia a stat ecg should be ordered to determine if there is st elevation. patients experiencing an acute st elevation myocardial infarction (stemi) require immediate interventional cardiology consultation to consider percutaneous intervention within minutes. if angiography is deemed unacceptable due to covid- infection risk, thrombolysis is an option ( ) . in the absence of stemi, these symptoms with troponin elevation mark unstable angina (usa) or non-stemi. treatment of usa/non-st elevation myocardial infarction (nstemi) consists of anticoagulation, aspirin ( - mg), β blockade and if needed, oxygen ( ). these same treatments applied for usa/nstemi are often employed initially in the setting of stemi until reperfusion occurs. persistent chest pain may be treated with . mg sublingual nitroglycerin every minutes or a nitroglycerin drip assuming blood pressure is adequate. severe critical illness in adults with limited coronary perfusion may result in troponin elevation due to demand-mediated myocardial ischemia (dmmi). management of dmmi is to minimize myocardial oxygen demands and patient stress (e.g., β blockade, sedation/paralysis); however, there is no role for aspirin or anticoagulation ( ) . bedside echocardiogram or point of care ultrasound to evaluate for focal wall motion abnormality can help distinguish infarction from dmmi. laboratory evaluation of acs should include electrolytes (with correction of abnormalities), serial troponins, platelets, and coagulation indices. mi should be treated with high dose statin therapy (e.g., mg atorvastatin daily). recommendations from suggest nstemi patients should also receive p y inhibitor ( ). typically, before administering additional antiplatelet therapy, a cardiology consult is warranted to discuss the timing of angiography. congestive heart failure. acute decompensated heart failure (adhf) is one of the main causes of respiratory distress in adult patients requiring the icu ( ) . heart failure with preserved ejection fraction (hfpef) or reduced ejection fraction (hfref) have similarities and differences in management. hfref shares similarities to the congestive heart failure (chf) seen in the picu. respiratory distress is typically a result of elevated left ventricular end-diastolic pressure (lvedp) resulting in pulmonary congestion. diuresis is helpful in both clinical presentations, although patients in hfref generally are more hypervolemic. in general, icu patients in adhf do not require maintenance iv fluids. hfpef patients have diastolic dysfunction and often present with tachycardia and hypertension; subsequently elevating lvedp. these respond well to vasodilators and β blockade directed at restoring "normal" range heart rates and blood pressures ( ) . af should be rate controlled immediately as it can exacerbate hfpef. point of care cardiac ultrasound can assist in identifying patients with reduced ejection fraction ( - ). hypertensive patients with hfref require afterload reduction to optimize cardiac output and may require low-dose inotropic support. home medications (angiotensin blockade and β blockers) should be discontinued at admission to the icu and assessed for continuation after the patient has reached clinical stability. in patients with significant hypervolemia, high venous pressures may contribute to poor renal perfusion and poor diuretic response ("cardiorenal syndrome"). aggressive diuresis (occasionally dialysis) with inotropic or vasodilator support may be needed to improve oxygenation. weighing the patient daily may assist in targeting appropriate fluid balance. myocardial ischemia should be considered as a cause of adhf and ruled out with serial troponins. acute pulmonary embolism and deep vein thrombosis prophylaxis. acute pulmonary embolism (pe) is a common and fatal complication of hospitalization that account for over , deaths in the united states annually. the diagnosis and management of pe is summarized ( ) ( ) ( ) ( ) . pe in the icu may present as hemodynamic stability or increased hypoxia not explained by new chest radiograph findings. this diagnosis is rarely seen in the picu and a high index of suspicion should be maintained when caring for adults. definitive imaging includes ct pulmonary angiography and less commonly ventilation/perfusion scan ( , ) . treatment is identical to pe for presence on ultrasound of deep vein thrombosis (dvt) in the setting of pe symptoms. the mainstay of therapy is systemic anticoagulation ( ) with unfractionated heparin or low molecular weight heparin that should not be withheld due to delay in obtaining imaging especially due to quarantine for covid- . hemodynamic instability including right heart strain should warrant consideration for thrombolysis or acute thrombectomy ( , , ) . to prevent dvt, especially given immobility with covid- in the icu, the use of sequential compression devices and, if not contraindicated, prophylactic anticoagulation ( , ) is recommended. the common adult conditions causing acute gastrointestinal bleeding (gib) are distinguished based on whether their origin is in the upper or lower gastrointestinal tract. the most common etiologies of upper gastrointestinal bleeding are peptic ulcer disease, variceal bleeding, mallory-weiss tears, and carcinoma ( ) . the most common cause of lower gastrointestinal bleeding are diverticular disease, angiodysplasia, neoplasms, colitis, and anal lesions like hemorrhoids and fissures ( ) . in critically ill intubated adults stress ulcer prophylaxis with a proton pump inhibitor (ppi) has a small benefit in preventing gib ( ) . as with pediatric patients experiencing acute gib, the initial priorities are managing the abcs particularly hemorrhagic shock. to facilitate transfusion, two large bore ( gauge) iv catheters should be established and hypotension managed aggressively with iv fluids and the transfusion of blood and blood products as necessary. a ppi should be administered for upper gib. we recommend pantoprazole mg iv bid as an initial approach with an immediate gastrointestinal consult. upper endoscopy can be both diagnostic and therapeutic in upper gib, whereas colonoscopy is primarily diagnostic. a nasogastric tube may be helpful to differentiate the source of bleeding or remove stomach contents and blood prior to endoscopy. this helps to identify a source and allow specific treatments to be provided. if no source is found on the initial endoscopy and the patient remains unstable, additional diagnostic testing including computerized tomography and/or angiography can be pursued while resuscitation continues. surgery remains an option for those in whom the source remains elusive. hyperosmolar hyperglycemic state (hhs) is an acute metabolic emergency classically affecting type diabetics. it is distinct from diabetic ketoacidosis (dka) in that it typically presents with higher levels of hyperglycemia (plasma glucose > mg/dl), a greater degree of dehydration, minimal acidosis (ph > . ) and ketosis ( , ) . treatment principles of hhs are insulin infusion titrated to decrease blood glucose to less than mg/dl (which is the threshold of glucosuria which drives dehydration/electrolyte abnormalities) and aggressive hydration. total fluid resuscitation requirements are usually much greater than in dka ( ) , although in covid- this must be balanced against the risks of volume overload and chf. resolution of hhs is indicated by improvement in osmolality, dehydration, and altered mental state ( ) . disease aki is the most common organ dysfunction in critically ill adults ( %) and is associated with high in-hospital mortality ( %) ( ) . patients with advanced chronic kidney disease or end-stage renal disease may already be on intermittent hemodialysis (ihd) through a tunneled percutaneous hemodialysis catheter or a matured arteriovenous fistula. temporary catheters can be used for ihd or continuous renal replacement therapy, but an arteriovenous fistula is reserved for ihd. the prevalence of aki in covid- is low ( %) similar to that seen in the severe acute respiratory syndrome (sars) epidemic ( . %) ( , ) . like sars, covid- may cause an acute tubular necrosis ( ) . patient in the sars epidemic who developed aki had a higher overall mortality compared with those without renal impairment ( . % vs . %) ( ) . management should include avoidance of nephrotoxic agents and use of ph balanced crystalloids ( ) . delirium is common among adult icu patients (prevalence: - %) ( ) and caused by an underlying medical condition, intoxication, or medication effect. it is a significant contributor to both morbidity and mortality, including worse long-term cognitive outcomes ( ) ( ) ( ) . delirium can occur in agitated, hypoactive, and mixed subtypes, with the overwhelming majority of patients falling into the latter two categories. there are several validated scales for delirium assessment in the icu, with the confusion assessment method for the icu being the most widely used ( , ) . many of the risk factors are modifiable and include exposure to psychoactive or centrally-acting medications, sleep-wake cycle disruption, immobility, polypharmacy, and unmanaged pain ( ) ( ) ( ) . nonpharmacologic approaches to these modifiable risk factors include frequent environmental reorientation, cognitive stimulation, minimizing sleep interruptions, engaging familiar visitors, limiting use of sedative medications, and scheduled sedation "holidays." these strategies have consistently shown improved clinical outcomes in critically ill patients and are now considered standard of care ( ) . although there is some evidence suggesting the prophylactic use of certain pharmacologic agents (antipsychotics, dexmedetomidine, ketamine, etc.), this is currently not recommended due to the inconsistency and lower quality of most of the studies and lack of benefit in other patientcentered outcomes ( ) . for severe agitation posing risk of self-harm or interruption of care, a trial of short-term lowdose antipsychotics (haloperidol, quetiapine, and olanzapine) may be helpful ( ) . although children can develop pressure-related injury (pi), it affects a higher frequency (~ - %) of critically ill adults ( ) . severity ranges from nonblanchable skin erythema (stage ) to full-thickness destruction of dermis and subcutaneous tissue (stage ) ( ) . some of the healthcare burden from pi's is preventable with good risk assessment and implementation of skin care protocols ( ) . distinct icu risk factors include prolonged mechanical ventilation and bedbound status which is often exacerbated by higher prevalences of neuromuscular weakness in adults ( ) ( ) ( ) , hypotension and vasopressor administration ( ) and should be considered along with general risk factors (age, comorbidities, obesity, mobility, and nutrition) when utilizing risk assessment tools like the braden scale ( ) . pi preventative strategies include use of protective silicone foam dressings, frequent repositioning, use of support surfaces, and nutritional optimization. although the use of silicone foam dressings has proven effective, evidence for the other strategies remains limited ( ) . early consultation of a wound care team (if available), coverage with a transparent film for stage injuries, maintaining a moist wound environment with occlusive dressings for stage injuries, and possible debridement for stage and injuries form the basis for preventing pi progression ( ) . efforts should be made to efficiently incorporate these strategies into the overall care of the patient in a way that limits patient staff interactions. about - % of adult icu patients have an alcohol use disorder and are at risk for developing alcohol withdrawal syndrome (aws) ( , ) . aws carries significant morbidity and mortality in hospitalized patients and requires careful management. without treatment, symptoms begin within - hours after cessation of drinking and may include anxiety, agitation, tremors, diaphoresis, headache, hallucinosis, withdrawal seizures, and delirium (i.e., delirium tremens). symptoms may be measured using the clinical institutes withdrawal assessment scale for alcohol and management tailored based on severity of symptoms. a high index of suspicion and preemptive treatment with folate ( mg daily) and thiamin ( mg iv daily) is important to avoid wernicke-korsakoff syndrome. withdrawal symptoms are managed first line using titrated doses of benzodiazepines with potential benefit from other therapies such as dexmedetomidine, ketamine, phenobarbital, and antipsychotics ( ) ( ) ( ) . propofol may be added in agitated intubated patients. critically ill adults typically require surrogate decision-making while incapacitated ( ) and many have a prepared advanced care document (i.e., durable powers of attorney for healthcare www.pccmjournal.org july • volume • number (dpahc) and living wills) to express healthcare wishes ( , ) . dpahcs authorize particular person(s) as legally recognized medical decision-makers if the patient lacks capacity. living wills summarize medical care that a patient would or would not want under specific circumstances such as serious illness or hospitalization. particularly in a setting of critical resource limitation, an ethical duty to plan compels physicians to identify these advanced directives or identify a surrogate decision-maker, as misapplication of these resources may detract from other patients. do-not-resuscitate (dnr) orders should be entered in the medical record for patients who do not desire cpr. public health ethics, which focuses on overall community good, differs from clinical ethics, which focuses on the good of the individual patient ( , ) . crisis resource allocation and rationing strategies, often designed to save the most possible lives and the most possible life years, deserve early institutional articulation ( ) . such policies may create tension during the care of adults in pediatric settings, as many allocation guidelines give preference to younger patients. palliative care consultation should be engaged early, which may reduce icu resource utilization by increasing transition to dnr status without increasing overall mortality ( ) . additionally, if crisis resource allocation is used, patients (and/or surrogates) should be proactively informed and palliative care should be provided to those who do not receive icu resources. consultation with adult practitioners in cases where limitation of life sustaining therapy is being considered would be prudent. finally, adults receiving medical treatment in a pediatric facility will certainly recognize differences in the typical standard of care and should receive transparent communication about these deviations. hospitals should clearly define and document their triggers for adopting altered standards of care. this approach creates a helpful framework for physicians and also engenders discussions with patients about the care they can expect to receive. with significant resource limitations, the covid- pandemic may challenge picus to adapt to the care of adult patients after existing capacity is exhausted. surprisingly, the majority of care delivered to these "big children" will be familiar to the pediatric intensivist. understanding and preparing for the differences and anticipating complications is important to optimize care in the setting of covid- or other situations where adults may be cared for in a picu (e.g., adult congenital heart disease). facing covid- in italy -ethics, logistics, and therapeutics on the epidemic's front line clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study clinical characteristics of children with coronavirus disease in hubei, china the clinical dynamics of cases of covid- outside of wuhan, china clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china care for critically ill patients with covid- clinical features of patients infected with novel coronavirus in wuhan, china clinical characteristics of novel coronavirus disease (covid- ) in newborns, infants and children clinical characteristics of coronavirus disease in china epidemiology of covid- among children in china case-fatality rate and characteristics of patients dying in relation to covid- in italy task force for mass critical care; task force for mass critical care: ethical considerations: care of the critically ill and injured during pandemics and disasters: chest consensus statement task force for mass critical care; task force for mass critical care: triage: care of the critically ill and injured during pandemics and disasters: chest consensus statement task force for mass critical care: special populations: care of the critically ill and injured during pandemics and disasters: chest consensus statement task force for mass critical care: surge capacity logistics: care of the critically ill and injured during pandemics and disasters: chest consensus statement european society of intensive care medicine, and society of critical care medicine: an official american thoracic society/european society of intensive care medicine/society of critical care medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome intensivists in u.s. acute care hospitals united-states-resource-availability-for-covid- association of cardiac injury with mortality in hospitalized patients with covid- in wuhan, china quality measures for children's health care american heart association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) sites study group: intravascular complications of central venous catheterization by insertion site does obesity preclude lumbar puncture with a standard spinal needle? the use of computed tomography to measure the skin to lumbar subarachnoid space distance in the general hospital population using body mass index to predict needle length in fluoroscopy-guided lumbar punctures aerosol delivery through adult high flow nasal cannula with heliox and oxygen non-invasive ventilation or high-flow oxygen therapy: when to choose one over the other? florali- study group; reva network: non-invasive ventilation versus high-flow nasal cannula oxygen therapy with apnoeic oxygenation for preoxygenation before intubation of patients with acute hypoxaemic respiratory failure: a randomised, multicentre, open-label trial florali study group; reva network: high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure high-flow nasal cannula: mechanisms of action and adult and pediatric indications staff safety during emergency airway management for covid- in hong kong exhaled air dispersion during high-flow nasal cannula therapy versus cpap via different masks difficult tracheal intubation in critically ill southmedic oxymask™ compared with the hudson rci(®) non-rebreather mask™: safety and performance comparison epoprostenol delivered via high flow nasal cannula for icu subjects with severe hypoxemia comorbid with pulmonary hypertension or right heart dysfunction expert recommendations for tracheal intubation in critically ill patients with noval coronavirus disease rocuronium versus succinylcholine for rapid sequence induction intubation should intermittent mandatory ventilation be abolished? acute respiratory distress syndrome: advances in diagnosis and treatment writing group for the prevent investigators: effect of a low vs intermediate tidal volume strategy on ventilator-free days in intensive care unit patients without ards: a randomized clinical trial a cluster-randomized trial of bloodpressure reduction in black barbershops epvent- study group: effect of titrating positive end-expiratory pressure (peep) with an esophageal pressure-guided strategy vs an empirical high peep-fio strategy on death and days free from mechanical ventilation among patients with acute respiratory distress syndrome: a randomized clinical trial bayes to the rescue: continuous positive airway pressure has less mortality than high-flow oxygen covid- does not lead to a "typical" acute respiratory distress syndrome coagulopathy and antiphospholipid antibodies in patients with covid- oscar study group: highfrequency oscillation for acute respiratory distress syndrome oscillate trial investigators; canadian critical care trials group: high-frequency oscillation in early acute respiratory distress syndrome efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (awakening and breathing controlled trial): a randomised controlled trial liberation from mechanical ventilation in critically ill adults: executive summary of an official effect of pressure support vs t-piece ventilation strategies during spontaneous breathing trials on successful extubation among patients receiving mechanical ventilation: a randomized clinical trial a prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation predictors of mortality in patients with suspected propofol infusion syndrome propofol infusion syndrome dexmedetomidine for long-term sedation investigators: dexmedetomidine vs midazolam www.pccmjournal.org or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials dexmedetomidine for sepsis in intensive care unit randomized evaluation (desire) trial investigators: effect of dexmedetomidine on mortality and ventilatorfree days in patients requiring mechanical ventilation with sepsis: a randomized clinical trial effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the mends randomized controlled trial sedcom (safety and efficacy of dexmedetomidine compared with midazolam) study group: dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial group and the spice iii investigators: early sedation with dexmedetomidine in critically ill patients daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation sleap investigators; canadian critical care trials group: daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol: a randomized controlled trial nonsedation or light sedation in critically ill, mechanically ventilated patients prone position in acute respiratory distress syndrome. rationale, indications, and limits proseva study group: prone positioning in severe acute respiratory distress syndrome prone position for acute respiratory distress syndrome. a systematic review and meta-analysis prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis bold collaborative research group: international variation in the prevalence of copd (the bold study): a population-based prevalence study global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease report. gold executive summary non-invasive positive pressure ventilation for treatment of respiratory failure due to exacerbations of chronic obstructive pulmonary disease extracorporeal membrane oxygenation for severe acute respiratory distress syndrome cesar: conventional ventilatory support vs extracorporeal membrane oxygenation for severe adult respiratory failure cesar trial collaboration: efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar): a multicentre randomised controlled trial australia and new zealand extracorporeal membrane oxygenation (anz ecmo) influenza investigators: extracorporeal membrane oxygenation for influenza a(h n ) acute respiratory distress syndrome referral to an extracorporeal membrane oxygenation center and mortality among patients with severe influenza a(h n ) adult venovenous extracorporeal membrane oxygenation for severe respiratory failure: current status and future perspectives covid- , ecmo, and lymphopenia: a word of caution planning and provision of ecmo services for severe ards during the covid- pandemic and other outbreaks of emerging infectious diseases cannulation strategies in adult veno-arterial and veno-venous extracorporeal membrane oxygenation: techniques, limitations, and special considerations association of cardiac injury with mortality in hospitalized patients with covid- in wuhan, china venovenous versus venoarterial extracorporeal membrane oxygenation for adult patients with acute respiratory distress syndrome requiring precannulation hemodynamic support: a review of the elso registry american heart association council on epidemiology and prevention statistics committee and stroke statistics subcommittee: heart disease and stroke statistics- update: a report from the american heart association epidemiology, aetiology, and management of ischaemic stroke in young adults thrombolytic therapy in acute ischemic stroke the stroke : a daily checklist for inpatient stroke management update in the management of acute ischemic stroke acute stroke treatment in the community: improving our performance and expanding our options isar-react trial investigators: ticagrelor or prasugrel in patients with acute coronary syndromes guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the sanchis-gomar f: cardiac troponin i in patients with coronavirus disease (covid- ): evidence from a metaanalysis impact of coronavirus disease (covid- ) outbreak on st-segment-elevation myocardial infarction care in hong kong the state of the art: atrial fibrillation epidemiology, prevention, and treatment new-onset atrial fibrillation: an update aha/acc/hrs focused update of the aha/acc/hrs guideline for the management of patients with atrial fibrillation: a report of the american college of cardiology/american heart association task force on clinical practice guidelines and the heart rhythm society in collaboration with the society of thoracic surgeons accf/aha guideline for the management of st-elevation myocardial infarction: a report of the american college of cardiology foundation/american heart association task force on practice guidelines aha/acc guideline for the management of patients with non-st-elevation acute coronary syndromes: a report of the american college of cardiology/american heart association task force on practice guidelines assessment and treatment of patients with type myocardial infarction and acute nonischemic myocardial injury clinical practice. acute pulmonary edema acc/aha/hfsa focused update of the accf/aha guideline for the management of heart failure: a report of the american college of cardiology/ american heart association task force on clinical practice guidelines and the heart failure society of america how to diagnose heart failure with preserved ejection fraction: the hfa-peff diagnostic algorithm: a consensus recommendation from the heart failure association (hfa) of the european society of cardiology acute pulmonary embolism. part : epidemiology and diagnosis pulmonary embolism acute pulmonary embolism. part : treatment antithrombotic therapy for vte disease: chest guideline and expert panel report treatment of acute pulmonary embolism: update on newer pharmacologic and interventional strategies guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients clinical guidelines committee of the american college of physicians: venous thromboembolism prophylaxis in hospitalized patients: a clinical practice guideline from the american college of physicians diagnosis of gastrointestinal bleeding: a practical guide for clinicians peptic investigators for the australian and new zealand intensive care society clinical trials group, alberta health services critical care strategic clinical network, and the irish critical care trials group: effect of stress ulcer prophylaxis with proton pump inhibitors vs histamine- receptor blockers on in-hospital mortality among icu patients receiving invasive mechanical ventilation: the peptic randomized clinical trial hyperglycemic crises in adult patients with diabetes hyperosmolar hyperglycemic state: a historic review of the clinical presentation, diagnosis, and treatment acute kidney injury enhances outcome prediction ability of sequential organ failure assessment score in critically ill patients acute renal impairment in coronavirus-associated severe acute respiratory syndrome smart investigators and the pragmatic critical care research group: balanced crystalloids versus saline in critically ill adults delirium in the critically ill patient clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the icu icu delirium -a diagnostic and therapeutic challenge in the intensive care unit sedation and delirium in the intensive care unit incidence and prevalence of pressure injuries in adult intensive care patients: a systematic review and meta-analysis risk factors for pressure injury development in critically ill patients in the intensive care unit: a systematic review protocol icu-acquired weakness and recovery from critical illness critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis critical illness myopathy and neuropathy pressure injury risk factors in adult critical care patients: a review of the literature effectiveness of pressure ulcer prevention strategies for adult patients in intensive care units: a systematic review treatment of pressure ulcers: a systematic review management of acute alcohol withdrawal syndrome in critically ill patients approach to the complicated alcohol withdrawal patient the use of dexmedetomidine as an adjuvant to benzodiazepine-based therapy to decrease the severity of delirium in alcohol withdrawal in adult intensive care unit patients: a systematic review proxy decision making for incompetent patients. an ethical and empirical analysis advance directives and outcomes of surrogate decision making before death approximately one in three us adults completes any type of advance directive for end-of-life care allocating scarce life support in a public health emergency who should receive life support during a public health emergency? using ethical principles to improve allocation decisions fair allocation of scarce medical resources in the time of covid- early palliative care consultation in the medical icu: a cluster randomized crossover trial the authors would like to offer support and expertise to our pediatric critical care colleagues caring for adult patients during this pandemic. as such, we have provided the emails of the combined adult and pediatric critical care medicine authors and will do our best to respond promptly to questions: dr. verhoef's institution received funding from national institutes of health national heart, lung, and blood institute k award. dr. dezfulian's institution received funding from mallinckrodt pharmaceuticals. the remaining authors have disclosed that they do not have any potential conflicts of interest.for information regarding this article, e-mail: dezfulianc@upmc.edu; kremy@wustl.edu key: cord- -pmn ll q authors: mulet bayona, juan v.; tormo palop, nuria; salvador garcía, carme; herrero rodríguez, paz; abril lópez de medrano, vicente; ferrer gómez, carolina; gimeno cardona, concepción title: characteristics and management of candidaemia episodes in an established candida auris outbreak date: - - journal: antibiotics (basel) doi: . /antibiotics sha: doc_id: cord_uid: pmn ll q the multi-resistant yeast candida auris has become a global public health threat because of its ease to persist and spread in clinical environments, especially in intensive care units. one of the most severe manifestations of invasive candidiasis is candidaemia, whose epidemiology has evolved to more resistant non-albicans candida species, such as c. auris. it is crucial to establish infection control policies in order to control an outbreak due to nosocomial pathogens, including the implementation of screening colonisation studies. we describe here our experience in managing a c. auris outbreak lasting more than two and a half years which, despite our efforts in establishing control measures and surveillance, is still ongoing. a total of colonised patients and blood stream infections (candidaemia) have been detected to date. the epidemiology of those patients with candidaemia and the susceptibility of c. auris isolates are also reported. thirty-five patients with candidaemia ( . %) were also previously colonised. forty-three patients ( . %) were hospitalised ( . %) or had been hospitalised ( . %) in the icu before developing candidaemia. antifungal therapy for candidaemia consisted of echinocandins in monotherapy or in combination with amphotericin b or isavuconazole. the most common underlying disease was abdominal surgery ( . %). the thirty-day mortality rate was . % and two cases of endophtalmitis due to c. auris were found. all isolates were resistant to fluconazole and susceptible to echinocandins and amphotericin b. one isolate became resistant to echinocandins two months after the first isolate. although there are no established clinical breakpoints, minimum inhibitory concentrations for isavuconazole were low (≤ μg/ml). an increase in the prevalence of candida bloodstream infections (candidaemia) and a shift in the epidemiology have been observed in recent years, especially since the emergence of the multidrug-resistant yeast candida auris [ ] . c. auris was first identified in , from the auditory canal of a japanese patient [ ] and, since then, it has been reported in a large variety of body parts and in the six continents of the world [ ] . this yeast is considered a growing menace to global health for several reasons, which include its resistance to multiple commonly used antifungals, its problematic identification in the laboratory and its facility to spread among patients, causing nosocomial outbreaks, especially in intensive care units (icu) [ ] . different organisations, such as centers for disease control and prevention (cdc) or the european centre for disease prevention and control (ecdc), claim that there is an emergency in using reliable methods to identify candida spp. isolates to the species level and encourage hospitals to do screening colonisation studies in order to control the outbreaks caused by c. auris [ , ] . in our setting, there is an ongoing c. auris outbreak since october [ ] , and, despite the implementation of different control measures (e.g., periodic screening for c. auris surveillance), we still report cases, showing the difficulty in eradicating this nosocomial pathogen. the aim of this study is, first, to describe the c. auris outbreak that is currently ongoing in our setting and the measures established in order to control it. secondly, we analyse the evolution in the candida species distribution causing candidaemia in our setting since and the clinical and epidemiological characteristics of all patients diagnosed with c. auris candidaemia, as well as the antifungal susceptibility of the isolates. in september , c. auris was detected for the first time in our hospital in the urine culture of a patient. one month later, in october , a second case was detected in a blood culture of another patient, being therefore the first case of candidaemia. since then, screening for c. auris colonisation is part of the infection control practices in the icu, where the outbreak is located. screening is performed before a patient is admitted in the icu and once a week until hospital discharge. when a colonised or infected patient is discharged to a general ward, surveillance is also performed, and when a case is detected outside the icu, surveillance cultures are performed to contacts in the ward. together with the screening of patients, other measures were implemented, such as the isolation of cases, patient cohorting, the reduction of health workers in contact with colonised patients, the decolonisation of patients with clorhexidine solutions and environmental cleaning with hydrogen peroxide solutions (oxivir ® ). environmental surveillance is also performed in the icu once a year or when an increase in the number of cases is produced, and c. auris has been isolated from mattresses. tables, computers and an emergency button. the entire icu was also cleaned with a more concentrated hydrogen peroxide solution following the environmental cultures. a total of colonised patients and candidaemia episodes ( of them were also previously colonised) have been detected since the beginning of the outbreak ( figure ). our icu includes beds and it is divided in two sections: a general icu and a cardiac icu. due to the large amount of cases and the long evolution of the outbreak, the c. auris outbreak already affects the entire icu. in july , despite the implementation of infection control practices and surveillance cultures, an increase was observed with four new patients with candidaemia ( figure ). after that, new episodes of candidaemia continued to be detected but at a lower frequency. however, in april , the incidence of colonisation and candidaemia increased again, coinciding with the novel coronavirus sars-cov- pandemic in spain ( figure ). recently, a pcr assay has been introduced in our laboratory for the detection of c. auris in surveillance samples, which is expected to reduce the response time from - h to h, compared to conventional culture (unpublished data). the evolution of species distribution causing candidaemia since in our setting is shown in figure . although c. albicans has always been the most isolated species, a high proportion of more resistant candida species (e.g., c. glabrata, c. parapsilosis) are also usually isolated in all studied years. in , when c. auris emerged, this pathogen rapidly spread and caused several episodes of candidaemia. especially remarkable is the large increase in candidaemia in , the first year since the outbreak was established, becoming the year with most candidaemia episodes reported. in the first half of , a large number of candidaemia episodes have also been produced, especially due to c. auris. the evolution of species distribution causing candidaemia since in our setting is shown in figure . although c. albicans has always been the most isolated species, a high proportion of more resistant candida species (e.g., c. glabrata, c. parapsilosis) are also usually isolated in all studied years. in , when c. auris emerged, this pathogen rapidly spread and caused several episodes of candidaemia. especially remarkable is the large increase in candidaemia in , the first year since the outbreak was established, becoming the year with most candidaemia episodes reported. in the first half of , a large number of candidaemia episodes have also been produced, especially due to c. auris. the evolution of species distribution causing candidaemia since in our setting is shown in figure . although c. albicans has always been the most isolated species, a high proportion of more resistant candida species (e.g., c. glabrata, c. parapsilosis) are also usually isolated in all studied years. in , when c. auris emerged, this pathogen rapidly spread and caused several episodes of candidaemia. especially remarkable is the large increase in candidaemia in , the first year since the outbreak was established, becoming the year with most candidaemia episodes reported. in the first half of , a large number of candidaemia episodes have also been produced, especially due to c. auris. the median length of hospital stay before the candidaemia episode was days (iqr . - . ). the median total length of hospital stay was days (iqr . - ). a total of . % of patients ( / ) were hospitalised or had been hospitalised in the icu before developing candidaemia. in patients ( . %), candidaemia was detected when the patient was in the icu, while in patients ( . %), candidaemia was detected once the patient was discharged from the icu, to a general ward. four patients admitted to a general ward ( . %) were never hospitalised in the icu but developed c. auris candidaemia. however, those cases could not be related to other cases produced in a general ward. the median length of icu stay before the candidaemia episode was days (iqr: . - . ) and the median total length of the icu stay was days (iqr: - . ) . only one patient developed candidaemia in the first week of stay in the icu, five patients in the second week and nine patients in the third week. the remaining patients took four or more weeks since admission to the icu until the candidaemia episode. epidemiological and clinical characteristics, antifungal treatment and outcome of patients with c. auris candidaemia are summarised in table . in seven patients, c. auris was isolated along with another candida species: three were mixed with candida albicans, two with candida tropicalis, one with candida krusei, and one with c. albicans and candida parapsilosis. antifungal treatment was administered until two weeks after a negative blood culture, and it consisted of echinocandins in monotherapy ( . %) or in combination with amphotericin b ( . %) or isavuconazole ( . %), when this most recent azole was available in our hospital. the median duration of the antifungal treatment was days (iqr: - ). surveillance cultures were conducted in all patients except four: the first case and three patients because they were not hospitalised in the icu. from the performed cultures, were positive ( . %), for both axillary-rectal and pharyngeal samples ( . %), only for the axillary-rectal sample ( . %) and two only for the pharyngeal sample ( . %). the median time since admittance to the icu to a positive colonisation sample was days (iqr . - . ). six patients had a positive colonisation sample in the first week since they were admitted to the icu ( . %), one of which was already hospitalised in a general ward. thirteen patients were positive to colonisation in the second week after they were admitted to the icu ( . %), two of which were already hospitalised in a general ward. eight patients were positive to colonisation in the third week ( . %) and the remaining eight patients were positive in the fourth or more weeks after their admittance to the icu ( . %), most of which were already hospitalised in a general ward. one patient was positive at the admission screening in the icu, but this patient had a prior stay in the icu registered from a month before. the median time since a positive colonisation sample to the candidaemia episode was days (iqr - ). antifungal susceptibility of c. auris isolates is reported in table . only the first isolate of every patient was included in the table, as susceptibility did not differ greatly. however, it is noteworthy that an isolate that was resistant to echinocandins was isolated from a patient from whom a susceptible strain was isolated two months earlier. this patient presented a first episode of candidaemia associated with a permanent central venous catheter and was treated with anidulafungin for days and antifungal lock of the catheter with anidulafungin until the catheter was replaced, but a second episode of candidaemia with the resistant strain was produced. c. auris is a global public health threat because of its ease to persist and spread in a clinical environment, among other reasons. during an outbreak, patients are colonised with c. auris at several body sites, including axilla, groin, nostrils, ears and rectum, and it also has been detected in beds, tables, floors, walls, equipment and monitors [ ] [ ] [ ] [ ] [ ] . several measures were established in order to control the outbreak, following the recommendations of the ecdc [ ] , the cdc [ ] and the previous experience of other established outbreaks, as the first european outbreak described in a london cardio-thoracic centre [ ] or the first spanish outbreak described in [ ] . these infection control practices include the strict isolation/cohorting of cases, decolonisation with chlorhexidine, regular environmental cleaning and the implementation of screening colonisation studies in the high-risk hospital environments such as the icu. axilla and groin swabs are usually recommended for screening, although other body parts can be sampled if it is clinically relevant [ ] . in our setting, axillary-rectal and pharyngeal swabs were selected for the screening and showed good performances, especially axillary-rectal swab ( . % of tested patients with candidaemia were previously positive for this sample). all these measures allowed a reduction in the frequency of the isolation of c. auris in both clinical samples and colonisation samples. however, two years after the outbreak started, and despite our efforts at establishing control measures and epidemiological surveillance, c. auris is still being isolated from colonisation samples and, what is most worrying, from blood cultures, showing that this nosocomial pathogen is very difficult to eradicate and can cause important infections. two peaks are observed in the evolution of the outbreak. the first one was in , corresponding to the first months of the outbreak, and it could be in part because the control measures were not strictly followed by all health workers, especially in the holiday period, with some replacement staff. the second peak was in april and may , coinciding with the peak of the sars-cov- pandemic in spain. hospitalisation rooms had to be reorganised in order to isolate patients affected by and that forced ignoring other nosocomial pathogens. relaxing the control measures for c. auris could explain the increase in the cases (both colonisation and candidaemia) in those two periods, reinforcing the importance of infection control practices. it is important to note that the higher peak in candidaemia (july ) overlaps the lower peak in colonisations. this is because the patients are first colonised and approximately two weeks after develop candidaemia (the median time since icu admittance to colonisation is days and since admittance to the candidaemia episode is days); therefore, a peak in colonisations is expected to produce an increase in candidaemia later. candidaemia is a life-threating condition in critically ill patients, which makes it crucial to understand local epidemiologic trends and the antifungal susceptibility of etiological agents. multiple studies have shown an increase in the incidence of candidaemia and a shift to uncommon candida species in recent years [ , [ ] [ ] [ ] , including multidrug-resistant species such as c. auris, which has further complicated their management. in our setting, c. albicans is usually the predominant species, causing between a third and a half of candidaemia, followed by c. glabrata and c. parapsilosis alternating in second place until , similar to other data reported in spanish hospitals [ ] . although a clear tendency in species distribution over the years cannot be observed, what is clear is that candidaemia increased greatly in the first year of the outbreak, and c. auris has displaced c. glabrata and c. parapsilosis in our hospital, becoming the most isolated species in , equal to c. albicans, and even exceeding c. albicans in the first half of . it is noteworthy that in seven patients, c. auris was isolated along with another candida species, which is a higher proportion than mixed non-c. auris candidaemia in the same period, which totalled five cases. most mixed candidaemia was produced in , when the larger increase in c. auris candidaemia was produced. several known risk factors for developing candidaemia [ , ] were present in a high number of our patients affected with c. auris candidaemia, like prior antibiotic exposure ( . %), central venous catheter ( . %), mechanical ventilation ( . %), previous surgery ( . %), previous colonisation with c. auris ( . %) and icu stay more than two weeks ( . %). gastrointestinal disease, both surgical and non-surgical, was the most common underlying disease ( . %), which is also common for other candida species candidaemia. a total of patients with prophylactic antifungal treatment, of them with echinocandins, developed candidaemia. previous exposure to fluconazole or echinocandins has been associated with a higher incidence in c. auris candidaemia, which could be due to a selective pressure for c. auris [ ] . interestingly, age, apache ii and charlson comorbidity index were relatively low in the patients affected by c. auris candidaemia, which is also reported in a study from india comparing c. auris with non-auris candida candidaemia [ ] . this could be attributed to the profiles of patients that are usually admitted in the icu, where the outbreak is established. as a complication of candidaemia, and despite the antifungal treatment, we detected two cases of endophtalmitis, which is less common than for other candida species [ ] . the crude mortality rate of c. auris candidaemia at days in our series was . %, similar to that reported by other recent studies [ ] [ ] [ ] . however, this is lower than the mortality rates reported in initial studies of c. auris candidaemia [ ] [ ] [ ] , ranging - % approximately, although c. auris-attributable mortality cannot be calculated from those series. the attributable mortality rate for c. auris candidaemia is difficult to evaluate because it affects critically ill patients with multiple comorbidities, though it should be analysed in futures studies. c. auris is a multidrug-resistant yeast, and levels of resistance can vary between isolates, so antifungal susceptibility testing must be performed. there are no established susceptibility breakpoints, although cdc reported tentative breakpoints [ ] . according to those breakpoints, all isolates were resistant to fluconazole and susceptible to echinocandins and amphotericin b. however, an isolate that was resistant to echinocandins was detected in one patient two months after the initial isolation of a sensitive strain. this might be due to a prolonged treatment with anidulafungin in the treatment of the first candidaemia episode, which exerted antimicrobial pressure. resistance to echinocandins, amphotericin b and even pan-resistant isolates have been reported, in some cases after a prolonged treatment with these antifungals [ , ] . this demonstrates the need for continued surveillance, even in serial isolates from the same patient, and encourages being cautious when prescribing antifungal drugs. however, in our series, despite the intensive use of echinocandins, either in monotherapy or in combination, and also as an empirical treatment, no other strain developed resistance. mics for posaconazole and voriconazole were variable, although the high resistance to fluconazole and to other azoles reported in the literature makes them not recommended to treat c. auris infections [ ] . all tested isolates showed low mics for isavuconazole (≤ µg/ml), although there is limited evidence of the effectiveness. the reported outbreak in our setting is one of the most important globally, with prolonged transmission over two and a half years. although genotypic typing of the strains is still ongoing, epidemiological tracing is highly consistent with the existence of an outbreak (same hospital ward). preliminary results with some strains suggest they belong to the south african clade, the same as other spanish isolates [ ] . consorcio hospital general universitario de valencia (chguv) is a -bed tertiary hospital which provides medical assistance to a population of around , people in valencia, spain. the evolution of the c. auris outbreak which started in october in our setting is described, as well as the infection control practices established. a screening colonisation study is performed in patients admitted to the icu and periodically once a week. for this purpose, a pharyngeal and an axillary-rectal sample are collected and cultured in chromagar tm candida (becton, dickinson and company, franklin lakes, nj, usa). plates are incubated at • c for h, and lectures are done at and h. all patients with positive blood cultures for c. auris since october , when the first episode was detected, to june were included. blood samples were processed according to our routine laboratory procedure. briefly, blood samples are incubated in bd bactec tm fx (becton, dickinson and company, franklin lakes, nj, usa) for days or days if fungi blood infection was suspected. when the sample flags positive, and the gram stain reveals the presence of yeasts, subculture is performed in sabouraud-chloramphenicol and chromagar tm candida. in this medium, c. auris grows in a non-specific colour of white, beige or pink, and these colonies are further identified. candida isolates from both blood samples and surveillance samples are further identified by matrix-assisted laser desorption/ionisation (maldi-tof; bruker, billerica, ma, usa). susceptibility testing is carried out for candidaemia isolates by broth microdilution through sensititre tm yestone yo (thermo fisher scientic, waltham, ma, usa) for antifungals micafungin, caspofungin, anidulafungin, flucytosine, voriconazole, itraconazole, fluconazole and amphotericin b. lastly, isolates were tested through the new version of sensititre tm (sensititre tm yeastone itamyucc), which replaces flucytosine with isavuconazole. tentative breakpoints from cdc were used to describe the susceptibility of the isolates to fluconazole (≥ µg/ml), anidulafungin (≥ µg/ml), caspofungin (≥ µg/ml), micafungin (≥ µg/ml) and amphotericin b (≥ µg/ml) [ ] . only anidulafungin, micafungin, caspofungin and amphotericin b were reported in all isolates because the other antifungals were not routinely used in the treatment of c. auris infections. isavuconazole was tested since it was available for use in the hospital. fluconazole is also tested as a complementary method for identification since all isolates are resistant to it. only the first isolate from every patient is included in the analysis. demographic and relevant clinical data were retrospectively collected via chart review, including comorbidities, underlying diseases, risk factors, duration of hospitalisation, duration of stay in the icu before the candidaemia episode, previous antibiotic treatment, previous antifungal treatment, therapeutic measures and clinical outcome. recurrence of candidaemia was defined as the case when a positive blood culture was obtained after a negative one. persistence of candidaemia was defined as the case when a positive culture was obtained after days of adequate antifungal treatment. the reported outbreak in our setting is one of the most important globally, with prolonged transmission over two and a half years. our experience, as well as the experience of other hospitals reported in the literature, show that c. auris can persist and efficiently spread in hospital environments, being difficult to eradicate. instauration of infection control policies and periodic screening for colonisation are essential to control an outbreak caused by c. auris. candidaemia is one of the most worrisome conditions caused by this multidrug-resistant yeast because it usually affects critical patients. its multidrug resistance makes it even more difficult to manage these infections, especially since c. auris has potential to become more resistant in the course of a treatment with antifungal drugs. therefore, patients with antifungal treatment for c. auris should be monitored closely and susceptibility testing should always be performed. epidemiologic shift in candidemia driven by candida auris candida auris sp. nov., a novel ascomycetous yeast isolated from the external ear canal of an inpatient in a japanese hospital tracking candida auris the recent emergence of a multidrug-resistant fungal pathogen information for laboratorians and health professionals european centre for disease prevention and control. candida auris in healthcare settings-europe; first update candida auris: descripción de un brote candida auris: a global fungal public health threat environmental contamination with candida species in multiple hospitals including a tertiary care hospital with a candida auris outbreak environmental surfaces in healthcare facilities are a potential source for transmission of candida auris and other candida species an outbreak due to candida auris with prolonged colonisation and candidaemia in a tertiary care european hospital candida auris: a review of the literature first hospital outbreak of the globally emerging candida auris in a european hospital fungemia surveillance in denmark demonstrates emergence of non-albicans candida species and higher antifungal usage and resistance rates than in other nations epidemiology and outcomes of candidemia in patients: data from the prospective antifungal therapy alliance registry changes in the epidemiological landscape of invasive candidiasis epidemiology and predictive factors for early and late mortality in candida bloodstream infections: a population-based surveillance in spain epidemiology and risk factors for invasive candidiasis high incidence of candidaemia in a nationwide cohort: underlying diseases, risk factors and mortality candida auris candidaemia in indian icus: analysis of risk factors candida auris and endogenous panophthalmitis: clinical and histopathological features candida auris outbreak: mortality, interventions and cost of sustaining control clinical spectrum and factors impacting outcome of candida auris: a single center study from pakistan first report of candida auris in america: clinical and microbiological aspects of episodes of candidemia candidemia caused by amphotericin b and fluconazole resistant candida auris first three reported cases of nosocomial fungemia caused by candida auris investigation of the first seven reported cases of candida auris, a globally emerging invasive, multidrug-resistant fungus-united states antifungal susceptibility testing and interpretation candida auris isolates resistant to three classes of antifungal medications candida auris: from multidrug resistance to pan-resistant strains candida auris: a systematic review and meta-analysis of current updates on an emerging multidrug-resistant pathogen the apc was funded by fundación de investigación del hospital general universitario de valencia, spain. the authors declare no conflict of interest. key: cord- -o uwryp authors: amit, moran; sorkin, alex; chen, jacob; cohen, barak; karol, dana; tsur, avishai m; lev, shaul; rozenblat, tal; dvir, ayana; landau, geva; fridrich, lidar; glassberg, elon; kesari, shani; sviri, sigal; gelman, ram; miller, asaf; epstein, danny; ben-avi, ronny; matan, moshe; jakobson, daniel j.; bader, tarif; dahan, david; king, daniel a.; ben-ari, anat; soroksky, arie; bar, alon; fink, noam; singer, pierre; benov, avi title: clinical course and outcomes of severe covid- : a national scale study date: - - journal: j clin med doi: . /jcm sha: doc_id: cord_uid: o uwryp knowledge of the outcomes of critically ill patients is crucial for health and government officials who are planning how to address local outbreaks. the factors associated with outcomes of critically ill patients with coronavirus disease (covid- ) who required treatment in an intensive care unit (icu) are yet to be determined. methods: this was a retrospective registry-based case series of patients with laboratory-confirmed sars-cov- who were referred for icu admission and treated in the icus of the participating centers in israel between march and april . demographic and clinical data including clinical management were collected and subjected to a multivariable analysis; primary outcome was mortality. results: this study included patients (median age = years (range = – years)); % ( of ) were male. eighty-nine percent ( of ) of patients had at least one comorbidity. one hundred three patients ( %) required invasive mechanical ventilation. as of may , the median length of stay in the icu was days (range = – days). the overall mortality rate was %; a multivariable regression model revealed that increasing age (or = . for each year of age, %ci = . – . ), the presence of sepsis (or = . for each year of age, %ci = . – . ), and a shorter icu stay(or = . for each day, % ci = . – . ) were independent prognostic factors. conclusions: in our case series, we found lower mortality rates than those in exhausted health systems. the results of our multivariable model suggest that further evaluation is needed of antiviral and antibacterial agents in the treatment of sepsis and secondary infection. coronavirus disease is caused by severe acute respiratory syndrome coronavirus (sars-cov- ). this novel coronavirus was identified as the cause of a pandemic that originated in wuhan, china, in december . as of may , more than . million people had been diagnosed with the disease in over countries, with more than , deaths. [ ] the magnitude of this pandemic has overwhelmed health care systems worldwide. hospitals have been overcrowded with covid- patients, and medical providers have been challenged by shortages of intensive care unit (icu) beds, ventilators, and essential medical personnel [ ] [ ] [ ] . differences in resource availability among countries, an absence of data on covid- 's clinical course, and the rapid development of the spread of the pandemic, with insufficient follow-up time, have not allowed informed and balanced decision making. for instance, accurate data on clinical outcomes (death versus discharge or transfer from icu) of ventilated patients would allow better planning of ventilator distribution and use. in addition, data are lacking on the effectiveness of novel therapies, such as antivirals, and existing therapies, such as glucocorticoids and antibiotics. as of may , israel had , covid- cases, with deaths. israel has designated over icu beds for severely ill covid- patients. however, the country has had no more than severely ill patients at a time [ ] . analyzing data from a non-overwhelmed health system of the developed world may shed light on the "natural history" of this disease. in addition, focusing on patients with established outcomes provides a better understanding of the role of different interventions. in this report, we comprehensively assessed the clinical characteristics, interventions, and outcomes of severely ill patients who were treated in israel. we also identified factors that were associated with mortality. this retrospective registry study was performed at the medical corps-israel defense forces, israel, which is the national coordinating center for the israel covid- icu registry. we enrolled all consecutive patients with laboratory-confirmed sars-cov- infection who were admitted to one of the icus among participating hospitals between march and april . because of the crisis status declared in israel and the nature of this retrospective chart review, with minimal-risk research using data collected for routine clinical practice, the israel ministry of health (jerusalem, israel) waived the need for an individual institutional ethics board and the need for informed consent from individual patients. according to the world health organization (who) guidelines [ ] , laboratory confirmation of sars-cov- was defined as a positive result on a real-time reverse transcriptase-polymerase chain reaction assay of nasal and pharyngeal swabs. this guidance was implemented locally with the adjunct of using reverse transcriptase-polymerase chain reaction assay from lower respiratory tract aspirates. after being de-identified, patients' data were recorded daily on an online questionnaire-based electronic worksheet (surveymonkey) that was accessible online to registry associates. this study included critically ill patients admitted to icu. criteria for icu admission were either acute respiratory distress syndrome (ards), sepsis or acute organ failure [ , ] . ards was defined as pao /fio a ≤ mmhg with positive end-expiratory pressure (peep) or continuous positive airway pressure (cpap) ≥ cm h o or non-ventilated; if pao was not available, spo /fio ≤ . sepsis was defined as life-threatening organ dysfunction caused by a dysregulated host response to a suspected or proven infection and a sepsis-related sequential organ failure assessment (sofa) score of ≥ points. acute organ dysfunction was defined as respiratory (hypoxemia defined by low pao /fio ), coagulation (low platelets), liver (high bilirubin), cardiovascular (hypotension), central nervous system (low level of consciousness defined by glasgow coma scale), or kidneys (low urine output or high creatinine). patients who died prior to icu admission and patients without outcome data were excluded. clinical data reported in this study were collected within the first - h following icu discharge or death. the recorded data included the following: age, sex, medical comorbidities (i.e., smoking status, hypertension, diabetes, ischemic heart disease, chronic heart failure, cancer, chronic kidney disease, immunosuppression, cirrhosis, and dementia), medication history, vital signs, chest x-rays, laboratory studies on admission to the icu, anti-covid- pharmacological therapy in the icu (antimalarials, antivirals, anti-inflammatories, and plasma from recovered patients), respiratory support method (invasive or noninvasive mechanical ventilation and oxygen mask), renal replacement therapy, nutrition methods (enteral and total parenteral nutrition), the use of extracorporeal membrane oxygenation (ecmo), complications, and outcome. the number of patients who had died, been discharged, and been transferred to a lower level of care as of may , were recorded; icu length of stay was also determined. no statistical sample size calculation was performed a priori, and the sample size was equal to the number of patients treated during the study period. the primary outcome was patient status on discharge from the icu (i.e., dead vs. alive). continuous variables are presented as the median and interquartile range (iqr) with % confidence intervals (cis). categorical variables were expressed as the number of patients (percentage). differences in the distributions of patient characteristics by median age subgroups and the presence or absence of hypertension were reported using differences with % cis. the distribution of data over the age subgroups was based on the available data for that variable, and the other percentages were calculated using the available data for that subgroup. the mann-whitney rank sum test was used to compare nonparametric continuous variables. χ or fisher exact test was used for categorical variables as appropriate. the first step was to study the correlation between death and each covariate via a univariable analysis; this was followed by a preliminary multivariable logistic regression model and a wald test. thus, covariates with a univariable p < . were included in a preliminary multivariable wald regression model. variables that remained statistically significant (p < . ) were included in the final multivariable model. all statistical tests were two-tailed, and statistical significance was defined as p < . . analyses were performed using jmp pro . . the analyses were not adjusted for multiple comparisons, and given the possibility of a type i error, the findings should be interpreted as exploratory and descriptive. from march to april , patients with suspected or confirmed covid- were hospitalized at one of the participating centers in israel. table shows patients' demographic and clinical characteristics. positive sars-cov- status was confirmed prior to hospitalization in patients ( %); in these patients, the median time from laboratory-confirmed sars-cov- - to presentation was days (range = to days). the remaining patients had pending test results for sars-cov- , and their positive sars-cov- status was confirmed during hospitalization. patients' median age was years (iqr = - years; range = - years); patients ( %) were aged years and older, and ( %) were younger than years. overall, % ( of ) of patients were male, with a similar sex distribution among patients younger than years. among patients older than years, % ( of ) were female. there was no significant variance in age distribution (p = . , leven's test) between centers; at one center, % of patients ( of ) were male, resulting in a significant variance in sex distribution between centers (p = . , pearson test). eighty-nine percent ( of ) of patients had at least one comorbidity (table ) . hypertension was the most common, affecting ( %) patients, followed by diabetes ( patients ( %)) and ischemic heart disease ( patients ( %)). only patients ( %) had a history of chronic obstructive pulmonary disease, eight of whom ( %) were treated for cancer and five of whom ( %) had immunosuppression (i.e., as a result of organ transplant or chronic treatment with systemic corticosteroids). only one ( . %) patient older than years presented without preexisting comorbidities; and % ( of patients) presented with multiple comorbidities. body mass index (bmi) data were available for patients: % ( of ) of patients were overweight (i.e., bmi between and ) and % ( of ) were obese (i.e., body mass index, bmi > ). supplementary table s presents patients' medication histories. table presents patients' vital signs, chest x-rays, and laboratory findings on admission. acute organ failure was the most common critical illness-defining condition ( of patients ( %)), followed by ards ( of ( %)) and sepsis ( of ( %)) ( table ). deterioration in inpatients who were initially not classified as critically ill occurred in % of patients ( of ); in these patients, the median time to deterioration and icu admission was days (iqr = - days, range = - days). hydroxychloroquine and chloroquine were the most commonly used anti-covid- pharmacological agents administered in the icu ( of ( %)), followed by corticosteroids ( %) and antiviral agents ( %) ( table ) . of note, fresh plasma from patients who had recovered from covid- was administered in seven patients ( %). table presents the icu interventions and organ replacement therapies used. among patients who were admitted to the icu, ( %) required endotracheal intubation and mechanical ventilation, and patients ( %) were treated with noninvasive ventilation. there were no differences in mechanical ventilation rates among different age groups ( % of patients younger than years, % of patients older than years, and % of patients between and years; p = . , likelihood ratio); however, noninvasive ventilation was used more frequently in patients younger than years ( of ( %)) than in patients older than years ( of ( %)) and patients between and years old ( of ( %)), p < . , likelihood ratio). tracheostomies were placed in % ( of ) of ventilated patients. ecmo and renal replacement therapy were used in % ( of ) and % ( of ) of patients with acute respiratory and renal failure, respectively. seventy-four ( %) patients required tube feeding via a nasogastric tube, and ( %) were fed with total parenteral nutrition. a secondary infection was diagnosed in ( %) patients, and ( %) developed sepsis. an acute kidney injury developed in ( %) patients, and an acute cardiac injury developed in eight ( %) ( table ) . as of may , the median (iqr) length of stay in the icu was days (iqr = - days; range = - days). among patients who were intubated (n = ), the median (iqr) ventilation time was days (range = - days) compared to days (range = - days) in non-intubated patients (p < . , analysis of variance-anova). we also found a significant correlation between patients' age and length of stay: the median (iqr) length of stay in the icu was days ( - days) in patients younger than years and days ( - days) (p = . , correlation coefficient = − . ) in patients older than years. with a total of deaths, the overall mortality rate was %; ( %) patients were discharged home, and ( %) experienced clinical improvement and were transferred to a lower level of care (i.e., rehabilitation or covid- internal medicine departments). we found a significant difference in the length of icu stay between patients who died (median = days; iqr = - days) and those who experienced improvement and were discharged from the icu (median = days; iqr = - days). a univariate analysis revealed that patients' age, sex, comorbidity status, sepsis, white blood cell count, antiviral therapy, antimalarial therapy, and length of icu stay were all statistically significant predictors of outcome (table ). we included the significant variables in a multivariable regression model. this analysis revealed that older age (or = . for each year of age; % ci = . - . ), the presence of sepsis (or = . for each year of age; % ci = . - . ), and short length of icu stay (or = . for each day; % ci = . - . ) were the only independent prognostic factors. in this multicenter case series, we evaluated critically ill patients who were admitted to icus in israel with laboratory-confirmed sars-cov- from march to may . while the pandemic has been subsiding in some parts of the world, there is still a stable plateau in the western world and north america. covid- adversely impacts health systems, mostly due to major uncertainties regarding the outcomes of this disease. these uncertainties explain the aggressive responses of policy makers that have detrimentally affected societies and economies around the globe [ ] . here, we focused on critically ill patients because ( ) they are at the highest risk, ( ) their clinical course and management are poorly defined, and ( ) they demand the most resources and care [ ] . most of the recently published data were collected during or near the peak of the outbreak, and careful evaluation revealed that outcome data were available for only a minority of patients and were not available for many hospitalized patients. we focused on survival data in our analysis of critically ill covid- patients. the israeli health system has not reached its maximal treatment capacity (supplementary figure s ) , which has allowed us to provide the best possible care, with minimal to no resource constraints for each patient. this unique report provides a clear understanding of the course of the disease at its extreme and sheds light on its clinical course in a non-overwhelmed health system. in israel, the disease course is unique as the health system was underutilized; and most, if not all patients received best possible care with minimal resource constraints. this, might also explain the relatively low mortality compared to reports from other regions. the patient population in our cohort was similar to those reported elsewhere in the world. the majority of patients were older men, and a large proportion presented with multiple comorbidities. most of our patients were admitted with ards and respiratory failure and required respiratory support, similar to the patients described in reports from china [ ] . approximately two-thirds of the patients required invasive mechanical ventilation, mostly in older patients. despite these similarities, we found a difference in outcomes. the following mortality rates have been found for covid- patients in the icu for whom outcome data are available (i.e., excluding patients who were still being treated in the icu at the time of the report): % (lombardy, italy [ ] ), % (new york city, ny, usa [ ] ), % (wuhan, china [ ] ), % (seattle, wa, usa [ ] ), % (washington state, usa [ ] ), and % (china [ ] )) the mortality rate in our series was % at the time of data cut-off. there are several possible reasons why our rate was lower. first, use of the health system for covid- in israel never reached its maximal capacity, allowing longer icu stays. the median icu length of stay in our cohort was days, with an even longer stay in patients who survived (median, days). in the above-mentioned studies, the median length of icu stay ranged between . and days [ , , , ] . a longer icu stay allows patients to be weaned more slowly from the ventilator and allows longer follow-up to monitor response to novel therapies that, in turn, might affect patients' outcomes and prevent relapses and readmission or subsequent death. second, the lag between the outbreak in china, italy, and spain and israel allowed israel's health system to adjust and implement some of the lessons learned in regions that had been severely impacted by the virus; these included the need for an isolation regimen, personal protective equipment, and "capsules" that allow complete separation between providers who treat sars-cov- -infected patients and those who do not. lastly, novel and advanced therapies, such as plasma derived from patients who have recovered from covid- and ecmo, were readily available for these patients. ecmo was performed in six patients in our study who were younger (median age = years, iqr = - years) than the mean of the cohort, and only one patient treated with ecmo died. although the differences in survival rates between patients who were and were not treated with ecmo were statistically significant, we have refrained from making a conclusive statement about the therapeutic yield of ecmo; however, we recommend its consideration in younger critically ill patients. by evaluating patient and outcome data, we were able to assess the effects of various patient and disease factors on outcome. while multiple factors were associated with death, our multivariable regression model indicated that only older age, longer length of icu stay, and the presence of sepsis were independent predictors of outcome. similar to our data, some studies have reported the presence of comorbidities, such as hypertension, in severely ill patients [ , , ] . hypertension and associated therapies (e.g., angiotensin-converting enzyme and angiotensin receptor blockers) have been found to be associated with mortality [ ] . the results of our multivariable analysis suggest that these factors (i.e., comorbidities and related medication used) are associated with patients' age rather than with actual outcome; thus, the mortality rate is also associated with age. we were able to include novel therapies in our analysis, some of which were considered compassionate (e.g., remdesivir). as a retrospective cohort, we suspect that our study was not designed to evaluate the efficacy of different anti-covid therapies and was underpowered. our data support the prospective evaluation of antiviral and antimalarial agents in critically ill patients. our data showed no difference in the outcomes of patients treated with glucocorticoids. however, the results of a recent study suggested that glucocorticoids are associated with better clinical outcomes in patients with covid- and ards [ ] . on the basis of the results of previous studies that investigated phylogenetically similar viruses (sars-cov- ( ) and middle east respiratory syndrome coronavirus (mers-cov)), we hypothesize that glucocorticoid treatment was associated with a higher subsequent plasma viral load, a longer viremia duration, and worse clinical outcomes in our cohort [ ] [ ] [ ] [ ] . this hypothesis is also in agreement with the better overall outcomes in patients who were treated longer in the icu. a large proportion of patients in this series presented shock that required vasopressor support. many of these patients presented sepsis or developed secondary infection and septic shock. unlike other reports that have demonstrated no bacterial or viral coinfection, we found the presence of sepsis in some patients; this finding suggests that, similar to seasonal influenza, covid- is associated with bacterial coinfection due to pathogens that colonize the nasopharynx, such as staphylococcus and streptococcus, in critically ill patients [ ] . this might also explain the lack of efficacy of glucocorticoid treatment that might be hindered. of note, most of our patients were treated with antibiotics for over hours. we recommend the prospective evaluation of the role of antimicrobial therapy in critically ill patients. this study has several limitations. first, it was a retrospective study. as such, some variables were not available for assessment. for example, computed tomography scans were not done routinely in all cases, and in the few cases when it was performed, it was done in a single time point. these considerations precluded the utilization of computed tomography (ct) scan as a marker for disease severity or prognosis in our cohort. however, the data were collected no longer than days after outcomes were achieved for each patient. second, although our data are comprehensive and complete, we could not include all of the collected variables in the regression model because of our considerably underpowered number of events. that said, considering the population size in israel (nearly million citizens), the reported numbers of cases and deaths reflect the relative numbers of events in other countries affected by covid- . third, while the post-discharge follow-up was short, the follow-up time in the hospital was considerably long compared with the course of the disease, and more data were available with regard to the reported mortality data and length of stay data reported in other studies. in this nation-based registry study of critically ill patients with covid- who were admitted to icus in israel, the majority of patients were years and older men, and a large proportion required mechanical ventilation. the overall mortality rate was %; increasing age, shorter icu stay (median, days versus days), and the presence of sepsis were independently associated with death. we found no association between coexisting conditions and outcome. our findings also highlight the importance of novel therapies, antibiotics use, and the availability of resources such as icu beds and ventilatory support in the treatment of patients with covid- . these data will inform quality improvement efforts and counseling of high-risk covid- patients. supplementary materials: the following are available online at http://www.mdpi.com/ - / / / /s . figure s : covid- burden in israel. a, overall number of cases (orange) and deaths (blue). logarithmic scale. b, number of available icu beds dedicated to sars-cov- -positive patients (orange) and number of icu beds occupied by critically ill covid- patients. clinical features of patients infected with novel coronavirus in baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region clinical characteristics of coronavirus disease in china presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the country & technical guidance-coronavirus disease (covid- ) who clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspected: interim guidance jpj surviving sepsis campaign-society of critical care medicine care of the critically ill and injured during pandemics and disasters task force for mass critical care. introduction and executive summary: care of the critically ill and injured during pandemics and disasters: chest consensus statement clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study covid- in critically ill patients in the seattle region-case series characteristics and outcomes of critically ill patients with covid- in washington state clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in renin-angiotensin-aldosterone system inhibitors in patients with covid- risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study effects of early corticosteroid treatment on plasma sars-associated coronavirus rna concentrations in adult patients corticosteroids as adjunctive therapy in the treatment of influenza corticosteroid therapy for critically ill patients with middle east respiratory syndrome bacterial coinfection in influenza we thank ann sutton of the department of scientific publications at the university of texas md anderson cancer center for editing the manuscript. the authors declare no conflicts of interest. key: cord- -ak pq authors: nan title: th european congress of intensive care medicine athens - greece, october – , abstracts date: journal: intensive care med doi: . /bf sha: doc_id: cord_uid: ak pq nan objectives: evaluate the levels of tnf, il- and pai-i in different moments of the ards and the possible relationships among them. methods: septic patients with ards were studied. also significant differences for: tnf, pai-i and il- in septic patients and both evaluations of ards with control gropup; pai- between septics and nd evaluation in ards, and between the ist and nd evaluation in ards; il- between septics and both evaluations in ards; and il-~ in both evaluations in ards patients in relation to mortality. conclusions: i) elevations of tnf, pai-i and il- , with clinical signs, are suggestive of infection; ) the persistent and progressive elevation of pai-i with any clinical criteria may suggest evolution to ards; ) due to its own kynetics, il- takes part later in the acute phase, its levels being related to the magnitude of the injury in the tissues. objectives: the influence of long-term volume therapy with different solutions on plasma levels of circulating adhesion molecules was studied. methods: according to a randomized sequence, patients with sepsis secondary to major surgery exclusively received either hydroxyethylstarch solution ( % hes, mean molecular weight (mw) , daltons, degree of substitution (ds) . ) or human albumin % (ha) for volume therapy for days. plasma levels of circulating (soluble) adhesion molecules (endothelial leukocyte adhesion melecule- [selam -i] , intercellular adhesion molecule- [sicam -i] , vascular cell adhesion molecule- [svcam -i] , and p-selectin ) were serially measured on the day of admission to the intensive care unit (='baseline ' value) and during the next days. results: selam-i, sicam-i, and svcam-i plasma levels were markedly higher than normal at baseline in both groups. in the hes-patients, selam-j decreased to normal range, whereas it further increased in the ha-group (from • to • during the study period, sicam-i and svcam-i plasma levels remained unchanged in the hes-patients, but further increased in the ha-group (from • to , • sgmp- increased significatly only in the ha-group ( • to • only pao /fio was significantly correlated to plasma levels of adhesion molecules. conclusions: sepsis is associated with markedly elevated plasma levels of adhesion molecules indicating endothelial activation or damage. by long-term volume therapy with hes, these levels remained unchanged or even decreased, whereas volume therapy with human albumin did not have any beneficial effects on soluble adhesion. central venous catheters are frequently used in the care of the critically ill patient. the incidence of catheter related sepsis varies in the literature. we investigated the occurrence of contamination and sepsis compared to results of the epic study as part of quality assesment in our intensive care unit. from january until august all removed central venous catheters were examined for microbiological culture. the patients who showed signs of sepsis were also registered. the results of the contaminated catheters and septic patients were compared with results from the epic study. during the month period , patients were hospitalized on our intensive care unit. central venous catheters were examined for microbiological culture. specimens appeared to be possitive ( %). patients showed clinical signs of sepsis. the incidence of sepsis due to contaminated central venous catheters was / ( %). the incidence of sepsis due to the presence of all central venous lines was / ( %). the microorganisms responsible for the sepsis syndrom were : stapylococcus aureus (n= ), escherichia colt (n= ), others (n= ). in the epic study the percentage for sepsis on the icu was . % for the netherlands and . % for europe. despite a high number of positive culture from removed intravascular lines, a low percentage of sepsis was seen compared to results of the epic study. we recommend routine bacteriological culture of all removed central venous lines and recommend to look at colonization and sepsis due to intravascular lines as a measure of quality control in the intensive care unit. objectives: prognostic assessment of simplified acute physiology score (saps) in granulocytopenie patients with septic shock (ss). methods: the medical records of admissions to an intensive care unit (icu) of granuloeytopenic patients with ss are reviewed. fiftytwo patients had haematological malignancies. seven patients had aplastie anaemia. patients were categorised as survivors (discharged from icl and non-survivors (died in the icu). saps index was calculated for patients daily during their stay in icu. all patients were severe granulocytopenic (total white cell count less than , ] ] ). results: five patients ( , %) were discharged from icu. fifty-four patients died in icu. non-survivors had saps on admission higher than survivors ( . + . and . + . , respectively, p< , , mann-whitney u test). no patient with a saps greater than survived. mortality among the patients with saps from to was , %o. the evolution of ss was rapid. the mean stay in icu among non-survivors was only hours. an analysis of the saps index on admission of non-survivors showed an inverse correlation with the duration of their stay in icu (r=- , , p= . ). all survivors recovered from granulocytopenia. they had normal white cell counts at the time of discharge from icu. there was inverse correlation in survivors between saps and white cell counts, when these parameters were evaluated daily. however, the saps index alone cannot be considered to be on individual predictor factor of mortality. patients who had failure of the malignancy to respond to chemotherapy and who had persistent granuloeytopenia died in icu despite saps index on admission and recovery from ss. conclusion: saps index greater than , failure of the malignancy to respond to chemotherapy and persistent leueopenia all point to a poor outcome of granulocytopenie patients with ss. introduction: antipyretics sometimes are used for fever control in febrile neutropenic patients with hematological malignancies(hm). we observed a dramatic fall of blood pressure(bp) and development of septic shock(ss) in some of the patients who received antipyretics. aim: to clarify can antipyretics provoke ss in neutropenic patients with infection. methods: retrospective review of medicat records of neutropenic(wbc < , / )patients with hm, admitted to the intensive care unit for ss, was performed. there was selected group of patients receiving antipyretics shortly before a fall of bp. results: there was a definite causal relationship between receiving antipyretics and fall of bp in from patients. all patients had fever due to infection and had normal level of bp before receiving antipyretics. hypotension developed within minutes up to , hours after administration of antipyretics. three patients received , g of metamisol and one , g ofparacetamol per os. in all cases we observed dramatic diaphoresis and the temperature fall to subnormal level ( . + . ~ accompanied'by hypotension. but in - hours the fever was coming back without blood pressure elevation. the fluid replacement was controlled by central venous or wedge pressures. there were required + ml colloid and cristalloid solutions for volume loading. in spite of fluid administration the hypotension persisted and all patients required inotropic therapy. only one patient survived and is alive now. conclusion: it seems to us that our data offer to state that antipyretics administration can initiate ss in febrile neutropeuic patients with infection. objectives: to assess the agreement between cardiac output (co) measured by odm t and by other methods used in icu patients. methods: we prospectively studied adu t patients requiring hemodynamic monitoring with a pulmonary artery catheter. an esophageal doppler monitor provided measurements of co (odm), stroke volume and flow time (ft) used as an indirect evaluation of patient's volume status. patient hemodynamic status was evaluated by a modified fast response pulmonary artery catheter (baxter health care corporation, santa ana, ca), allowing co measurements by thermodilution "d) and an evaluation of right ventricular ejection fraction and end diastolic volume (rvef and rv-edv). in the last six patients co was measured by transthoracic echocardiography (echo) and oxygen consumption was measured by a deltatrack ii metabolic monitor (datex) allowing co calculation according to the fick formula (fick). the agreement between methods measuring co and their reproducibility, were evaluated by bland and altman analysis. results: agreement between co measurements is expressed as bias (d) and % limits of agreement (l of a = d_+ sd . td-fick - . - . to . fick-echo . - . to . there was no correlation between ft and rv-edv. conclusions: although co measurements by odmil had the best reproducibility, the limits of agreement between the four methods tested were unacceptable for clinical purposes. further investigation is required in order to improve the accuracy of co measurement in the icu. phd, a. paltzev, v.bajbikov, b.dobryakov d.sc., a.ostanin phd, o.leplifia phd, h.chernykh phd munieip. hosp. n l, n ; inst. of clin. immunol., novosibirsk, russia objectivies: efficiency of native cytokines used in the treatment of patients with severe surgical infections has been studied. methods: for two years patients were treated with cytokine mixture (ssp) obtained by arterio-venous perfusion of swine spleen and contained the following cytokines: il- , il- , il- , tnfa, ifny, gm-csf. results: ssp intravenous infusions were shown to accompany with mortality decrease from . % to . % in patients with abscessed pneumonia and lung abscesses and from % to % if disease course was complicated with sepsis. in patients with purulent peritonitis and sepsis efficiency of ssp was decreased due to endotoxieosis. thus, we used adoptive immunotherapy with mnc activated in vitro with ssp or recombinant il- . intravenous infusions of such cells resulted in transformation of a pathologic process from destructive into productive one. moreover, clinical manifestations of sepsis were controlled in % and mortality was decreased from % to %. conclusions: the use of eytokines themselves as well as cytokine-treated lymphoeytes permits to control the disease and leads to the mortnlity decrease owing to stimulation of host defence mechanisms. background: although red blood cell transfusions (rbct) are used to increase oxygen availability in septic patients, several lines of evidence suggest that rbct may actually worsen tissue hypoxia. thus, rbct may negatively influence outcome of septic patients. objectives: to determine the association of ) rbct ; ) number of units transfused; and ) mean age of the units transfused on the first day of transfusion with mortality of critically ill septic patients. methods: we prospectively identified patients who met strict criteria for sepsis syndrome (ss) seen in the icu of st. paul's hospital from to and excluded patients who died in the first days after the onset of sepsis. we recorded clinical characteristics, multiple system organ failure score, and apache ii at onset of sepsis. then, we retrospectively recorded the total number and age of rbc units transfused during the first days after onset of sepsis. overall -day mortality was %. results: the main results are shown in the table. the mortality of patients who received rbct was nearly double the mortality of those who did not receive rbct even after adjusting for severity of illness using apache ii. objectives: gastric mucosal acidosis is frequently observed in patients with sepsis. the aim of this study was to determine whether volume infusion using pentaspan| decreases abnormal gastric mucosal pco (pico ) in patients who have sepsis syndrome (ss) who have already been resuscitated using clinical endpoints. methods: we prospectively identified patients who met strict criteria for ss, had a pulmonary artery catheter and a gastric tonometer in place, and pico > mmhg. pentaspan| ( ml) was infused in rain. measurements of hemodynamics, hemoglobin, arterial lactate, blood gas analysis, and pico were performed before and repeated miff and hr after pentaspun| infusion. we calculated the pico -arterial pco' difference (pico -paco ) and phi (using henderson-hasselbach equation). anova was used to assess statistical significance. results: all patients werereceiving adrenergie drugs. map was : : mmhg and lactate . : : . mmol/l. pentaspan| increased ci by % (p< . ) but did not change pico ( and increase m oxygen o* wery were simimny achieved in both groups. nevertheless, epinephrine was associated with a lactic acidosis and increased laetate/pyruvatemia ratio (l/p) that evoke a dysoxia rather than a metabolic effect. an higher gastric mucosal pco in the ep group compared to nor-rob suggests the hypothesis of an anaerobic production of co in favor of a splanchnic hypoxia. in both group, arterial ketone body ratio that reflects hepatic mitochondrial redox state, compared to a control group without shock was decreased but increased between and hours after restoration of arterial pressure. the association norepinephrine-dobutamine seems to be better for splanehnic circulation than epinephrine and should be used for dopamine resistant septic shock. moreover, the increase in arterial pressure with nor-dob improved gastric mueosal ph and hepatic mitochondrial redox state and argue to reconsider arterial pressure as a significant goal for resuscitation in septic shock. conclusion: significantly higher malondialdehyde and ghitathione levels and glutathione-peroxidase activity in group ns at the end of icu stay were related to mortality these findings indicate an increased generation of free oxygen radicals together with increased anfioxidant activity in this group and sapport the employment of antioxidant interventions in critically ill patients. oblecfives: to determine the role of nitric oxide (no) in the mechanism of septic shock induced by isolated limb perfuslen with recombinant tnfcr methods: we have measured tnfr~ and metebo~ites of no in patients with signs ot septic shock following treatment with isolated limb perfusion for nonresectable soft tissue tumors and melanomas of a limb. perfuslen was carried out with melphalan (burroughs wellcome) and recombinant tnfcr (boehringer). tnfc~ was determined by specific radiometric assay (medgenix diagnostics), nitrate and nitrite were measured with a modification of the guess reaction ~. results: results are shown in the table. conclusions: during isolated limb pedusion with recombinant tnf~ very high levels of tnfcr were measured in arterial blood in patients. they all showed signs of severe sepsis syndrome with shock from vasodilafion, probably due to leak of recombinant tnft~ from the peduslen circuit to the systemic circulation. tnfc~-induced vasodilation was not accompanied by a rise in serum no-metsbolites. our findings do not confirm the widely accepted theory, mainly based on animal experiments, that genera• of no is the key pathogenefic mechanism in septic vasodilafion , nor that tnfrt invariably induces forreafion of no. the precise mechanism of shock in these patients remains to be elucidated. references: . moshage h, kok b, huizenga jr, jansen plm nitrite and nitrate determinaiions in plasma: a critical evaluation. clin chem : / . . moncada s, higgs a. the l-argioine-nitrio oxide pathway. n engl j med ; : - ec is a commonly used for prolonged, stable animal anesthesia. noting that the hypotension after iv lps was attenuated by ec, we hypothesized ec also protects against lps toxicity. sprague-dawley rats received ip saline (s), thiobutabarbita mg/kg (tb), or varied doses of ec, followed hours later by bolus mg/kg iv lps. -day survival is shown below: group: s tb ec( . gmikgi ec( .sgm/kg) ec(i. gm/kg) alive (n) t ~ total (n) s s "signiflcant;y different from all other groups, p< . s / rats given lps followed hours later by ec ( . gm/kg) also died. additional rats were treated with s (n= ) or gm/kg ec (n= ) followed by mg/kg lps, then sacrificed at hours. blood glucose (bg, mg/dl),.hematocrit (hct), leukocyte count (wsc/mm~ platelet count (pltxl ~/mm ), bicarbonate (hco, mg/dl), gross bowel hemorrhage (bh, - scale) and lung myeioperoxidase activity (mpo, ~vmirvgm wet lung) are shown below ( we conclude that ec reduces the lethality and multiple organ toxit;~ty of lps. its diverse effects suggest asite of activity upstream from the cytokine cascade. these results are important for studies of lps which may use ec anesthesia and may have potential in the therapy of septic shock. [zo = hz impedance (z; {dyn.sec.cm " }); zl = first harmonic z; zc = characteristic z; z ph. = t'trst harmonic phase angle {radians}; f, #, * at least p < . between fio . and . , fio . and fio . &no - . _+ . - . _+ . # - . + . m - . + . * - . + . * - . + . * - . _+ . * in hyperoxia, compared to dogs at the same q, minipigs had a higher ppa ( + rnmhg versus + mmhg; p < . ). hypoxia increased (ppa-ppao) at all levels of q by an average of mmi-ig in minipigs and mmhg in dogs. inhaled no inhibited hypoxia-induced (ppao-ppa)/q changes in both species. conclusions: we conclude ~ that the minipig is an animal model of elevated pulmonary vascular resistance and impedance, and ~ that hypoxia-induced alterations in pvz spectrum are due to changes of resistance in small arteries. objectives: ) to determine the toxicity of ng-monomethyi-larginine (nma) administered by intravenous bolus to patients with refractory septic shock. ) to investigate the biologic activity of nitric oxide synthase inhibitors in septic shock. methods: from august to january , thirteen patients with vasopressor refractory septic shock received nma intravenously in escalating doses from to mg/kg. results: no hepatic, renal, gastrointestinal, or hematologic toxicity was observed at doses of nma as high as mg/kg. significant biological activity was observed at all dose levels consisting of increased blood pressure (systolic blood pressure from . mm hg + . to . _+ . s.e.m., p= . , systemic vascular resistance ( + to + dyne.sec/ cm s, p=. ), and a decrease in vasopressor requirements. the magnitude and duration of these effect were dose dependent. decreased cardiac output ( . _+ . to . _+ . i/min p=. ) and increased pulmonary artery pressure ( . _+ . to . _+ . mm hg; p=. ) were also observed. no significant effects on heart rate, pulmonary capillary wedge pressure, or central venous pressure were observed. four of patients survived for more than days, patients died of cancer complications (all patients had maintained blood pressure for h on nma) and patients died of complication attributable to septic shock (mods, ards, dic, refractory hypotension), and patient was unevaluable. conclusions: no adverse clinical effects have been observed in patients receiving bolus doses of nma as high as mg/kg. the increased pulmonary artery pressures observed in septic shock patients is further augmented by nma and may limit the dose which can be administered by intravenous bolus. other schedules of drug dosing may attenuate this effect. glucose-insulin-potassium (gik) solutions have been shown to improve cardiac contractility and increase oxygen availability in experimental and clinical settings of septic shock. several mechanisms have been proposed to explain these effects including a direct improvemeut of the energy balance by glucose, a direct influence of insulin on cardiac performance or an increase in intravascular volume due to the hyperosmolarity of the solution. to explore the role of hyperosmolapity, we compared the effects of gik to those of a isoosmolar hypertonic saliue solutiou in endotoxin shock in dogs. methods : the study included mongrel dogs ( • pentobarbitalanesthetized aud mechanically ventilated with air. thirty minutes after the intravenotls administration of mg/kg of e. coli endotoxin, the dogs were randomized to receive a ml/kg infusion in rain of a hypertonic ( mosm]l) solution iucludiug either a mixture of glucose % with u insulin and meq kcl/l (glk-group ) or hydroxyethyl starch . % in naci . % (hes-group ). in each dog, a . % saline infi~sion was continued to maintain the puhnonary arlery occluded pressure at baseline level. hemodynamic, blood gas aualysis and laboratory data were collecled at baseline and miu, rain, rain, and nunutes later.. results : eudotoxin administration was followed by a fall in mean arterial pressure (map) aud cardiac index (ci) and a rise in blood lactate levels. resuscitation with either gik or hes hypertoaic solutions resulted in similm increases in map, ci, oxygen delivery and left ventricular stroke index (table ) . we conclude that during resuscitation from endotoxic shock the use of gik solutions is not superior to hypertouic hes solutions. the higher blood lactate levels observed in the dogs receiving gik can be attributed to the glucose metabolism. , for group , for group ) were drawn and immediately analysed at ~ using the abl radiometer for po , pco and ph, and the osm radiometer for hbo %, hbco% and methb%. psost (i.e. the ps at ph= . , pco = mmhg and temperature at ~ c) was calculated automatically by the instruments on mixed venous blood, as was the ps "in vivo" (i.e. the ps at the patient's value of ph, pcoz and temperature), using siggaard-andersen's algorithm. the data were compared by the one-way anova test and by the t-test for paired and unpaired samples. results: the mean resulting values (in mmhg) with the statistical differences are shown in table i. in addition, the time series analysis shows the mean ps~st values as statistically below the psin vivo" in the septic patients while the opposite is shown for the cardiac patients. no differences in the time analysis are demonstrated for the second group. a possible clinical significance may be drawn from these different behaviours. objectives:toxemia degree and humoral immunity condition have been studied in patients aged from to with progressive course of sepsis and polyorganic insufficience. methods: such toxemia and humoral immunity findings as lencositlcindex of toxication (lii), level of oligopeptides of the middle molecular mass registered at the wave length of nm(mmi) & nm (mm ), distribution index (id), immunoglobulins a,m,g, concentration of circulating immunocomplexes (cici & cic ) and also some clinical and biochemical findings on the , , day after the operation serve as criteria for treatment effect. results: it was founded that in intensive therapy and detoxication, level of lii is successively decreased from . ~ . to . +. on the -th day after the operation. true decrease of the level mm from . ~. to . +. un & optimal density and increase of distribution index from . to . are argued. conclusions: in studlng the dynamics of the immunoglobulin's spectrum and the true increase of immunoglobulin g level from . +. g/i to i . +. g/i on the -th day after the operation simultaneously with the decrease of cic from . ~ to . ~ . (p . ) were founded. some stages of the investigation true increase of lymphocytes from . + . % to . + . % was noted and it appeared to be a favourable prognosis finding for disease outcome. high correlation dependence between bacillus-and segmentonuclear neutrophils and immunoglobullns g & m (r=. -. in p<. ) was discovered and it also showed positive dynamics of the course of the disease. a year old male patient was admitted to the icu with severe paraquat poisoning. treatment consisted of gastic lavage and oral administration of fullers earth. because of very high plasma levels hemodialysis together with charcoal hemoperfusion was started within one hour after admission. this treatment was further continued by continuous veno-venous hemofiltration in order to remove the circulating paraquat and also circulating cytokines. nevertheless patient s condition worsened necessitating artificial. ventilation and hemodynamic support. patient died hours after admission of acute multiple organ failure due to paraquat poisoning. serum levels of paraquat were determined by colorimetric method (table) . levels of interleukin (il ) and (il ), tumor necrosis factor (tnf-alpha), interleukin i receptor antagonist (il ra) were determined both in plasma and ultrafiltrate ( q~!ectives : evaluate in critically ill patients the effects of tow-dose dopamine on gastric mucosal blood flow (gmbf) using laser-doppler flowmetry, a continuous non invasive method of assessing microcirculation. methods : patients requiring both mechanical ventilation and pulmonary artery catheterization for multiple trauma (n= ), ards (n= ) and pancreatitis (n=l) were included. in each patient, the laser-doppler (ld) probe was inserted through a naso-gastric tube. the ld signal is proportional to the number of red blood cells moving in the measuring volume and the mean velocity of these cells. when the ld signal was satisfactory, an aspiration was created into a catheter which was fixed in parallel to the ld probe, to maintain the tip of the probe against the gastric wall at the site of measurement. data (systemic hemodynamic parameters and gmbf) were obtained at the end of a rain resting period (baseline), then min after dopamine ( mcg/kg/min) infusion, and finally rain after the end of dopamine infusion (recovery gmbf _+ (perfusion units) gmbf ~a% vs baseline) * p < . vs "baseline" and "recovery". conclusions : ) despite a slight increase in co (+ %), the dramatical increase in gmbf (+ %) with dopamine, strongly suggests a selective vasodilator effect of low-dose dopamine on gasaic mucosal perfusion. ) laser-doppler flowmetry appears a promising method to assess gastric microcircalation in critically ill patients. increasing evidence suggests that the activation of inos is the final common pathway for vasodilation in human sepsis associated with endotoxic shock. activation of the cellular immune system induces the excessive release of the pteridines neopterin (n) and , -dihydroneopterin (nh ) by human macrophages/monocytes. besides the well established diagnostic value of pteridines in several inflammatory diseases, it is speculated that these substances per se exhibit biochemical functions. thus we hypothesize that pteridines can modulate inos gene expression in vascular smooth muscle cells (vsmc) in vilro. cdtured rat aortic vsmc from female wistar kyoto rats were incubated with n ( pm), nh ( ilm), lipopolysaccharide (lps, ~g/ml), and interferone-~/(ifn-~/, u/ml) for h, respectively, inos gene expression was measured by competitive reverse transcription polymerase chain reaction. the results are summarized in the table. the present study demonstxates a neopterin induced increase in inos mrna expression at the transcriptional level in vsmc. while coincuhation of cells with n + lps resulted in an additive effect on inos gene expression, n + ifn- seem to have a more than additive effect nh did not alter inos mrna synthesis, but it suppresses the lps as well as the ifn-yinduced augmentation of inos gene expression. we speculate that this pteridine-mediated modulation of inos gene expression is involved in the regulation of the vascular tone in endotoxic septic shock. the relationship of sepsis and coagulation abnormalities is well known, mainly in severe sepsis and septic shock. still farther, the extreme expression of hemostasis abnormalities (disseminated intravascular coagulation) in sepsis, has been extensively described. we studied the changes in several coagulation and fibrinolysis markers in septic patients, trying to correlate them with the evolution of the sepsis phenomenon, with an emphasis in its early stages, where therapeutic intervention might be more drastic. in patients, with sepsis, with severe sepsis and with septic shock, as well as in healthy volunteers (control group) we measured : platelet (ptl), coagulation markers [fxii, fvii, fviii, fvw, fibrinogen (fibr) we conclude that all parts of the coagulation system are gradually changed during the evolution of sepsis phenomenon , even in the earliest stage of sepsis. the expression of an inducible nitric oxide (no) synthase (inos) plays a major role in the pathophysiology of septic shock (ss). inhibition of inos could therefore be of therapeutic value. however, such an inhibition has been shown to be detrimental, increasing tissue anoxia (and end-organ damage), possibly through the simultaneous blockade of constitutive nos (cnos). thus, selective inhibition of inos might be more suitable. we evaluated the effects of l-canavanine (can), a more potent inhibitor of inos than cnos, in an animal model of ss. method: in anesthetized rats, catheters were placed in the femoral vein and artery. rats were given an iv bolus of lipopolysaccharide (lps, mg/kg), at baseline (to). after h (t ), rats received at random an infusion of either can ( mg/kg/h; can group, n=l ) or an equivalent volume of . % naci ( cc/kg/h; nac group, n= ), giyen over h (t -t ). a third group (sham group, n= ) received . % nac in place of lps, and then was treated like the nac group. mean blood pressure (mbp), blood lactate and nitrates (no ) were measured each h. glucose, creatinine and asat were also measured in rats (n= in each group). the can _+ * + "t . + . "~ . +_ . "t + " + " *p< . can vs naci ?p< . vs sham can suppressed the hypotension, reduced the hypoglycemia and hyperlactatemia, and attenuated the biological signs of renal and hepatic dysfunction induced by endotoxemia. these effects were associated with a lesser elevation of blood no , confirming a partial inhibition of inos. conclusion: l-canavanine attenuates the hemodynamic and metabolic consequences of endotoxemia in the rat. these effects may be related to a partial inhibition of inos. they contrast with the deleterious effects described with non selective inhibitors of nos. l-canavanine could become a new tool for the treatment of septic shock. rocalc tonin :marker of sepsis, ii~flammaiiur% t~ boifi .cheval*~ jf.timsit*, m.assicot**, b.misset*,/.carlet*, c.bohuon** saint joseph heap, paris**biochemistry institut g roussy, villejuif, ce bi~)l~i~ttectives_: high serum levels of procalcitoaln (proct) have been shown to be ~ss-ocinted with bacterial infection. however, few data exist about the ability of proct to differenciate septic shock and shock from other origin in which an activation of intlmmamtory mediators has been also demonstrated. methods: thirteen patients with bacterial septic shock (ss), patients with non septic shock (nss), patients with bacterial infection without shock ( nf) and icu patients without shock and without infection (control) were compared for proct levels at dayl, , , , . patients were classified blindly and independently fi'om proct results. twelve patients were excluded because any classification was impossible due to mixed pathology. proct was measured with ebemoluminescenee (brahms diagnostica-berlin). results: dayl, proct levels are significantly different between the four groups. dayl proct levels are correlated with saps (p= . ), infection ( . +_ vs _+ ,p= . ), shock ( _+ vs +.- ,p= . ), death at day ( _+ vs _+ ,p= . ). when shock and infection are introduced in multifactor &nov& only infection remains correlated with day proct levels ( = . ) in patients with shock, dayl proct levels are correlated with saps, infection and death at day , but not with arterial lactate levels (p= . ), white blood calls (p= . ) or fever (p= . ). proct levels remain higher i~i septic shock patients at day , and ( figure) . i c edpsion: procalcitonin levels in the first three days of shock are differen[" between septic and non septic shock patients. in patients with diseases known to induce acute an inflammatory process, procaldtonin seems to be a marker o~ infection. obiectives-to evaluate the effect of endotoxic shock on the distribution of blood flow between the mucosal and the muscular layer of the intestinal wall. methods: in fasted pigs, mean aortic pressure (map, mm hg), cardiac output (co, ml/min-kg),superior mesenteric artery flow (q sma, ml/min.kg), and phi, where measured before (control) and after i.v. endotoxin ( gg/kg). the blood flow to the mucosal and the muscular layer was measured in regions (proximal jejunum (pj), mid-small intestine (mi) and terminal ileum (ti)) by colored microspheres, using adjacent samples in each region. the muscular layer was separated from the mucosa by blunt dissection, and the flow determined independently in each layer. results: endotoxin with fluid resuscitation induced the expected decrease in map ( . _+ . vs . -+ . , p< . ), and phi ( . !-_ . vs . _+ . , p< . ), with a constant co ( _+ vs _+ , p= . ) and qst, aa ( . _+ . vs . _+ . , p= . ). the results of regional pertusion are presented in the table. (flow in ml/rain g of tissue; mean _+ sem ; * p< . vs control by two-way anova) conclusions-these data indicate that the mucosal flow increased during septic shock. they suggest that a decrease in phi may be due to hypoper~usion of the muscular layer or to metabolic alterations within the mucosa, despite a % increase in flow. acute increase in wbc count (from a mean of lo.oo mm a to o /mm~), between the rd and the th day of therapy. there was a decline of the wbc count to an average of about . mm a after decreasing the daily dose of the medication to mcg there was no increase in tile absolute number of the eosinophils during the whole course of the medication. there was a slight decrease in the c complement between . to . g/i. normal values . to . g/i there was no change in c values. conclusions : an early increase in wbc count was observed ( rd day) without subsequent increase in the number of immature types from bone marrow, probably due to the mobilization of wbc from the periphery and this increase was dose dependent. there was a slight decrease in c fraction of complement, probably due to the consumption of this fraction in the process of opsonization. no adverse effects of the medication were observed, during the treatment with the above dose. these data sugest that cm csf may be a useful complement to tile main antimlcrobial treat,nent ~ of septic [cu patients. objectives: as part of a large multicentric, placebo-controlled, randomized clinical trial investigating the effects of interleukin- receptor antagonist (ii-lra) in the treatment of severe sepsis and septic shock, this substudy evaluated in dem.il the acute hemodynamic effects of ii-lra in patients who were invasively monitored. methods: in a total of evaluable patients in whom vasoactive support was little altered, hemodynamic measurements were performed at baseline (twice), and i hour, h, h, h, h, and h after the administration of mg/kg (n= ) or mg/kg (n= ) of i - ra or the corresponding placebo (n = ). / patients ( %) were treated with adrenergie agents and / ( %) with mechanical ventilation. data were analyzed by a kruskal-wallis test. results: during the study, there was no significant difference with time or between groups in arterial pressure, cardiac filling pressures, cardiac index or left ventricular stroke work (figure). burmester, "~ man and h. djonlagic medical university (internal medicine, "cardiology, *'microbiology) and "**southern city hospital, lfibeck, germany obiectives: evaluation of the incidence of bacteremia and sepsis in patients with nontyphoidal salmonella (s.) infections, specification of risk factors, need of icu treatment, clinical course, and mortality in the group of the patients who developed septic complications. methods: data of all patients with microbiologically proven s. infections hospitalized in the medical university of lobeck and in the southern city hospital of l beck from to . results: within the observation period s. was isolated from the stool cultures of patients. in patients (g m, f, median age yrs) s. could be detected in blood cultures ( s. enteritidis, s. typhimurium). in addition, in of these patients s. was also isolated from other specimens (urine, liquor, and tissue fluids derived from abscess punctures). in all patients with positive blood cultures the clinical course of s, infection was complicated: ? patients developed mof (acute renal failure, ards, hemodynamic instability, dic) and required icu treatment for at least up to days, of the patients died. the predisposing disorders in the patients with s. bacteremia were (n=): aids ( ), immunosuppressive drugs ( ), chronic alcoholism ( ), malignancies ( ), none ( ). septic complications in patients with nontyphoidal s, infections are relatively rare (in this study < % of all hospitalized patients with microbiologically proven salmonellosis) but severe (mortality of approx. %). patients at risk for a complicated clinical course are predominantly those with predisposing disorders but occasionally also patients without evidence for an underlying disease. age (yr) + + death (n) duration of shock (h) + + noradrenaline (rag/h) , _+ + temperature (~ , + , + pvr (dynxsecxcm - ) + + co (ljmin) , _+ , , + , lactate (mmol/l) + , , + interleukin- (pg/ml) _+ + interleukin- (pg/ml) , _+ , , + , tnf-alpha (pg/ml) , + , + neopterin (nmol/l) , + , + crp (rag/l) _+ +_ pro-ct (ng/ml) , + , , + there was no positive correlation between serum lactate levels, degree of shock, hypoxemia and pro-ct positivity. pts with septic shock of bacterial origin entirely developed hyperprocalcitoninemia, whereas pts with cardiogenic shock, who expired within h did not. however, in late cardiogenic shock (> h) all pts developed fever of unknown origin and consecutive hyperprocalcitoninemia. these data suggest bacterial inflammation and/or mucosal translocation of bacterial products in pts with prolonged cardiogenic shock. the use of a loading dose of quinine ( . mg/kg base in h) is recommended in previously untreated patients (pts) with sfm, particularly in multi-drug resistance areas. this protocol is difficult to validate, since the viability of microorganisms is not assessed routinely in parasitology laboratories. objectives: to examine the evolution of parasite viability during the early phase of therapy of sfm. methods: from / to / , pts with sfm (who ) treated with iv quinine for less than h were included prospectively. blood samples were collected at o, , , , , and h viability was assessed by culturing parasitized red blood cells in the presence of h-hypoxanthine, and radioactivity was determined at h by scintillation counting. viability was expressed as the percentage of radioactivity compared to the initial sample. plasma quinine was determined by liquid chromatography. tile ratio plasma quinine (pmol/ )xlo /icso for quinine (nmo]/]) was called the parasiticida/ index. results: pts were included, • saps . -+ . . the initial parasitemia was t. + . %. complications of malaria were coma ( pts), shock ( pts), renal failure ( pts) and acute lung injury ( pts). all strains were sensitive to quinine (icso -- nmol/ ). in pts who were not given a loading dose, parasite viability increased by and %, with concomitantly low quinine levels ( and #mow] at h); pt died. in pts that received a loading dose (serum quinine at h = . -- . ~mol/]) a marked decrease of parasite viability (by +_ % at h) was shown. viability was inversely correlated with plasma quinine (r=. , p-.o ) and parasiticidal index (r=. , p-.o ). conclusions: even with fully sensitive strains, the use of a loading dose of quinine seems warranted in severe falciparum malaria in order to reach rapidly adequate plasma quinine ]evels, necessary to inhibit significantly parasite viability. l nkka, e ruokonell j takala. critical care research program, department of intensive care, kuopio univ hospital, finland objective: to determine the incidence of positive blood cultures, their microbial subgroups and to evaluate the outcome of icu patients with different bacleremias. material and methods: we analysed all positive blood cultures in consecutive admission to a university hospital icu in - and the icu and hospital survival of the bacteremia patients. during these years patients had positive blood cultures that were considered as clinically relevant, excluding colonizations or contanfinations. results: patients with positive blood cultures had an icu survival of . % (vs. , % in all icu patients) and six month survival of . % (vs. . % in all icu patients). the most common bacteria were enterobacteriaceae ( , %), staphylococcus aureus ( , %) , coagulase negative staphylococci ( . %), pseudomonas ( . %) and slieptococci ( . %). obiectives: to evaluate prognostic factors and mortality in consecutive patients (pts) with hiv infection and septic shock. methods: from - to - , records of consecutivepts with septic shock (crit care med , : - ) admitted to the icu were reviewed retrospectively. results: among pts with septic shock admitted during the study period, had hiv infection- of whom had aids-(gr. i) and were hiv-negative (gr. ill. ten gr. ii pts ( %) were irnmunosuppressed because of neoplastic or immune dlsease. mechanica] ventilation was required in % gr. i and % gr. ii pts in gr . i pts ( %) a multivariate analysis demonstrated that hiv infection and sap i were independently predictive of death in pts with septic shock. ~onclusions: evidence of increased mortality, number of organ failures and higher severity scores (saps i does not take into account immunosuppression) is demonstrated in hi v-positive pts, infection with hiv appears to be an independent prognostic factor in pts with septic shock. the frequency of opportunistic infections (often responsible for delayed diagnosis and treatment) may contribute to the poor prognosis in this population. obiectives: to determine interleukin (il)-i levels in plasma of patients with sepsis and septic shock. to analyze the relationship between plasma il- and the proinflammatory mediators, tumor necrosis factor-aifa (tnf) and il- , the underlying severity of the disease and the evolution of patients with sepsis. methods: we studied critically ill patients ( men, women; - years old) in three diferents groups. group i: patients without evidence of infection, group i : patients with sepsis and with septic shock (group iii). we measured plasma il-lo, tnf and il- levels in the first hours of diagnosis. severity of illness was estimated with the acute physiology and chronic health evaluation (apache ii) scoring sytem. results: plasma levels of il- were higher in group iii (median, pg/ml; range, - pg/ml) than in group ii (median, pg/ml; range, - pg/ml; p <. ) and group i (median, pg/ml; range, - pg/ml; p <. ). median il- concentrations did not differ among patients who survived (median pg/ml; range, - pg/ml) and those who died during the overall follow-up period ( days) (median, ; range, - pg/ml); but patients who died in short-term (< hours) with catecholamine-refractory hypotension showed the highest concentrations of il-io (median, pg/ml; range, - pg/ml). in patients with bacteriemia ( %), levels of il- were higher (median, pg/ml; range, - pg/ml) than in those with negative blood culture (median, , pg/ml; range - . pg/ml; p< . ). there was a good correlation between plasma il-io concentration and levels of tnf (r= . ; p < . ) and il- (r= . ; p < . ). the correlation between levels of il- and the apache ii score was significant only in the septic shock group (r= . ; p <. ). conclusions: in septic shock, il-io and proinflammatory citokines are released in high concentrations. the significant correlation observed in patients with septic shock between il- levels and apache ii, short-term death and bacteriemia can possibly be explained by the massive inflammatory response in septic shock with fulminant course. intensive care department -calmette hospital - lille -france. in septic shock, inadequate splanchnic blood flow may play a prominent role in the pathogenesis of multiple organ failure. measurement of gastric phi has been propose to evaluate tissue oxygenation in splanchnic organs. objectives: to compare gastric phi values with hepatic icg clearance, an index of liver blood flow and function ; to determine if one of these two methods could be proposed to assess the entire splanctmic peffusion in septic shock. methods : patients (age : • years ; saps ii : • were prospectively investigated (septic shock : bone criteria). following parameters were collected during hours : systemic hemodynamic parameters (swan ganz catheter a h -ref computer -baxter lab.), calculated systemic oxygen transport (do ), oxygen consumption (vo ) by indirect calorimetry (deltatrac datex lab.), gastric intramucosal pco (pco ss) and phi (trip -ngs catheter -tonometrics lab.) and plasma disappearance rate of icg (pdr dye) (femoral artery fiberoptic/thermistor catheter , cold z computer -pulsian medizintechnik, germany). correlations were performed using a linear regression. elevated in all days with the highest value in second and third days of treatment. nonsurvivors had higher values of these parameters than survivors but differences did not reach statistical significance. another trend of changes were observed in selectin p (gmp- ) concentration. in all patients concentrations measured were elevated but in survivors after not significant decrease this parameter in second day another one had simmilar values. in patients who died we noted significant decrease in third day (p < . ) whereafter prominent increase, significant after seventh day, in comparison to third day value and value in survivors group. icam- concentrations in all patients reached high levels and in nonsurvivors after four day of treatment significant increase in comparison to survivors we found. conclusions: multiple trauma complicated with sepsis induce rapid elevation of concentrations of il- , il- and increased expressior of adhession molecules (selectin e, p, icam- ) measure of icam- and selectin p concentration determine lung injury severity and prognosis as to health and life. (clp) .pathophysiology of cip is unclear, but changes in regional bloodflow may be a ~ignificant factor. nerve blood flow (nbf)is reduced in rat models of hemorrhagic shock (g),but no information is available in sepsis. we studied the comparative effect of acute endotoxemic shock {etx)& h on perfusion of rat sciatic nerve. methods: male sprague-dawley rats were anesthetized with pentobarbital (ip), instrumented with a tracheostomy, carotid arterial & venous catheters and mechanically ventilated (fi = . ). the left sciatic nerve was surgically exposed. monitored variables included: a) mean arterial pressure (map,mmhg) ,b) nbf (ml/ o g/min) by laser doppler flow meter,c) nerve internal arterial diameter (id ~ m) by video image shearing and splitting method. after stable baseline measurements were obtained, acute hypotension was induced by randomly assigning the rats to etx ( . b , difco) in saline at mg/kg or h. both interventions produced % reduction in map within min., which recovered to baseline values spontaneously in etx group, & by reinfusion of heparinized withdrawn blood in m. data were analyzed by linear regression, two-way repeated measures analysis of variance followed by bonferroni-t method. experimental stages were:( )baseline, ( ) mid-point of map reduction; ( ) nadir of hypotension, ( )midpoint of map recovery, & ( ) after stable recovery of map. both etx & h induced shock result in similar reduction in nbf consistent with lack of autoregulation in peripheral nerve vessels independent of etiology. since cip is primarily associated with sepsis, it is not likely that acute reduction in nbf alone causes cip. direct & indirect neurotoxic effects of mediators of sepsis need to be evaluated. .':_.~::::o o:oc ., objectives : evaluate the relationship between il- , a cytokine which inhibits tnf, production and protects mice from endotoxin toxicity, and the other proinflammatory cylokines, tnf~, il and ils in severe sepsis and septic shock. methods : twenty-eight icu patients ( m, f, mean age + y) were studied as soon as they developped a severe sepsis (n = ) or a septic shock episode (n= ) as defined by a conference consensus in ( ). tnf~, il , il s and il- plasma levels were measured by immuno-radiometrie assays from medgenix (fleurus, belgium). lc mean and range. results : the comparisons between cytokine levels in severe sepsis versus septic shock were made using the logarithm of the value in order to normalize the distribution of data, and student test. il- plasma levels were higher in patients with septic shock than in patients in severe sepsis. there was a significant correlation (p < . ) between il- and tnf a (r= . ), il- and il~ (r = . ) and il- and il s (r = . ) as well as between il- and apache n score (r= . ). patients who died (n = ) had il- levels higher than patients who survived but this difference was not statistically significant ( pg/ml vs . pg/ml; p> . ). conclusions : during severe sepsis and sepsis shock, il- seems at least to follow the same evolution (increase in plasmatic level) with the severity of sepsis as the other cytokines. reference : ( ) crit care med ; : - . objectives: to evaluate the effects of steroids on hemodynamics and mortality in septic patients with konwn levels of cortisol concentration. methods: retrospectively we analyzed data ofpatients with documented septic shock who received steroids after assessment of adrenal function. in all patients hemodynamic parameters as well as the necessary vasoactive medication were assessed, before and hours after corticosteroid medication. immediately before administration of corticosteroids adrenal function was evaluated with cortisol levels before and after synthetic corticotropin ( . mg). finally we studied mortality. we defined a positive respons on corticosteroids as an elevation of map of at least mmhg and/or a decrease in the necessary vasoactive medication of at least % within hours. adrenal insufficiency was defined as a cortisol level after stimulation of less than nmol/l. results: of patients were found to respond to steroid medication, did not. mean cortisol levels before and after corticotropin were • and • nmol/l in the responder group (rg) and • and • nmol/l in the non responder group (nrg). in the rg out of ( %) were found to have an adrenal insufficiency, in the nrg out of ( %). in the rg -weeks mortality was . % (l out of ), the overall mortality % ( out of ). mortality in the nrg was % ( out of ) (p < . ) and % ( out of ) (p < . ) respectively. conclusions: in patients in septic shock there is a beneficial effect of steroids in case of adrenal insufficiency, but also in a subgroup with normal adrenal f{unction. obiectives: intercellular adhesion is a critical step in the accumulation of leukocytes. postischemic cardiac lymph has the capacity to stimulate icam-i. in the coronary microcirculation neutrophils can be trapped and in many cases obstruct capillaries, previously we found that troponin t (s-tnt) a marker for myocardial iechemia, was increased in septic patients. the aim of the study was to follow slcam- and s-tnt levels continuously starting at the beginning of sepsis. methods: patients were ingluded in this institutionally approved study after relatives had given their informed consent. all patients were included within hrs following the beginning of sepsis. blood was drawn every hrs in the first ;~ hrs, after hrs, followed once per day for days. s-tnt, icam- , elam (elisa's, boehringer mannheim inc, r&d systems ltd.) arterial and venous blood gases were determined, an ecg and a complete hemedynamir measurement including cardiac output were obtained. all patients received adequate volume and catecholamine therapy (norepinephrine, dopamine, dobutamine; median (range) . ( . - . ), . ( . - ), . ( . - . ) pg/kg/min, respectively). statistical analysis: wileoxon signed rank-sum test. . ( . - . ) . patients had s-tnt levels > . pg/l. of these died, whereas only of patients died with s-tnt values < . pg/l (p= . ). all patients that died had elevated sjcam- levels ( ilg/l:cut-off ) whereas in the survivor group only % had elevated icam- levels (p= , ). conclusions: increased slcam- and s-tnt levels were found during early sepsis in the majority of patients, a high sicam- and s-tnt value was associated with a higher mortality. the research of the noninvasive haemodynamic monitoring accelerated recently all over the world. the aim of our study was to test whether the changes of the haemodynamk parameters measured by impedance cardiography (icg) were corresponded to clinical changes in septic patients. investigations were performed on critically ill postoperative septic patients (their multiple organ failure score was - /with icg monitor. in cases the investigation~ were performed in septic shock. the measured parameters were: heart rate (hr), mean arterial pressure (map), cardiac output (co), peripherial resistance (svr),preejection period (pep), and ventricular ejection time (vet). these parameters were measured during - hours in every minutes, depending on the patients cl~tnical condition. results: at the septic patients the hr and the co ]~reased. in septic shock the co was significantly higher the svr lower than in the septic group. in the hr there was no difference between the two groups. in septic shock noradrenalin influenced more effectively the measured parameters than dobutamin. conclusion: the trend of the measured icg parameters correlated with the clinical changes of septic patient's state. the noninvasive haemodynamic monitoring by impedance cardiography helps the planning and leading the adequate intensive therapy of these critically ill septic patients. to evaluate the development of sirs, sepsis and septic shock in hospitalized patients with fever, a prospective study was performed on patients using previously defined criteria. methods: normotensive patients with fever (temperature > . ~ axillary), admitted to the department of internal medicine were evaluated for the existence of sirs during the first three days of the study and sepsis at inclusion. during a follow-up period of days the patients were daily evaluated for the development of sepsis or septic shock. results: most patients ( %) had or developed sirs within the first three days, patients ( %) did not. sepsis was present in % at inclusion. in patients with sirs, % did not progress to sepsis or septic shock, % progressed to sepsis (mean interval . • . days), and patient (< %) directly progressed from sirs to septic shock. in patients with sepsis, % progressed to septic shock (mean interval . • . days). sepsis was preceded by sirs in %. septic shock was preceded by sepsis in % and by sirs in %. conclusions: % of patients with fever in an internal medicine department develop sirs, or sepsis. furthermore, progression from sirs to sepsis or septic shock is poorly predicted by fever or sirs. nevertheless, all patients with septic shock were preceded bysirs or sepsis. taken together, this may indicate a severity hierarchy of the syndromes. however, fever, sirs and sepsis are relatively poor indicators of development of septic shock. this supports further research on additional predictors of septic shock. b. m.manuylov, v.b.skobelsky (moscow) in recent years sodium hypochlorite (sh) has been successfully used to eliminate pyo-septic complications. moreover, the mechanism of the sh effect on the immune system has not been sufficiently studied. the aim of the present investigation was to study the mechanism of sh effect in inflammatory pulmonary diseases. patients with double pneumonia were subjected to the evaluation. sh in the concentration of mg/l in the volume of - m / hours was administered by drop infusion into the central vein. to evaluate one of the defence systems the leukocytes activity by the chemoluminescence technique was studied. in all the patients baseline secondary immunodeficiency which was indicated by the decrease in the luminescence level was established. even hour after the sh administration the leukocytes activation exp-ressed by the enhancement of their chemoluminescence . - times was observed. this supports the available findings that accumulation and liberation of the oxygen active forms (ol'oh, ' , h ) are accompanied by the increased phagocytosis, i,e. the signs of "the oxydation explosion" testify to the favourable sh effect on the course of inflammation processes. the use of sh permitted to decrease the percentage of lethality in double pneumonia by % in the intensive care unit over the year. at the same time, excessive activation of free radical oxygen may be a damaging factor. therefore, precise individual control over the choice of concentration, dosage and the preparation administration rate is required. prospective, double-blind, placebo-controlled, trial of atiii substitution in sepsis r. a. balk objective: pilot study to evaluate the efficacy and safety of atiii substimtion therapy in patients with sepsis. efficacy assessed using change in mortality or organ failure/dysfunction. adult patients meeting a definition of sepsis and cared for in a tertiary care academic medical center in chicago were identified and prospectively randomied to receive either atiii (kybernin p) or placebo in a double-blind treatment protocol. all other therapy and patient management were under the direction of the patient's attending physician. all patient's were followed for days and the organ dysfunction/failure were scored using published scoring systems (jordan et al crit. care med. , goris et al arch. surg. , kuaus et al ann. surg. colldusions:wha~ we met the shomaeker objectiv% the mortality and the pro~os[s were i~ttc*. those criteria were obtained with file tradititmal t~ctor likr doht~mme, hut c.~vh ~,as ca in~aertam measure. they ac~s smxergically in the optimizatic~l of the fell vmtrictdar work index, tad fimdameatally cavh seox~s to have an impo.aat role in the better respiratory ev-altmtioa, leaving yet the possibility to coltrol the flui& r althou~l eomproved it's not aec~pt~xl file importmlce h* the diminution, of the sepsis modiat~lrs llke fnt and il- with h~wmotiltrafi(al, stopphlg the evolution to nmltiorganic failure mid de~easethe mortality. with ours clhlicals results, we could saythat cavii in multiol~atlie disfut~oa septic patieats, se~r~ to be an c xilna] supoa or troatmeat maesure. of anaesthesia and intensive therapy, medical university of prcs, p~csf hungary. objectives: since some biological effects of bacterial endotoxin require an interaction between the lps molecule and a serum factor(s), we hypothesized that lps-induced no production and cgmp accumulation in vascular smooth muscle cells (vsmc), a mechanism ~thought to underlie cardiovascular collapse associated with septic shock, is modulated by serum factor(s). methods: cultured vsmc from rat aorta were challenged with e. coli lps for - hours either in the presence or absence of fetal calf serum (fbs), and no production was monitored by radioimmunoassay determination of cgmp content of hci extracts. results: in the absence of serum, o ng/ml lps was required to increase cgmp levels, whereas the presence of % fbs shifted the lps concentration curve i times to the left. similarly to fbs, human serum also potentiated lps-induced cgmp accumulation. in contrast to lps, serum had no effect on cgmp accumulation elicited by sodium nitroprusside, a no releasing agent, suggesting that the sensitivity of vsmc to generate cgmp in response to exogenous no is not modulated by serum. heat inactivation (> ~ min) but not removal of small molecules (< , d) from the serum by dialysis, reduced the potentiation of cgmp accumulation by serum. time course studied indicated that serum is required within the first min of lps exposure to increase cgmp levels. to investigate whether the effect of serum is specific for lps, we treated the cells with increasing concentration of interleukin -~ (il-i). % fbs shifted the il-iinduced cgmp responses five times to the left. conclusions: our study suggests that lower concentrations of e. cell lps and il-i require a heat labile macromolecule in the serum in order to elicit no production. this factor is present in the human serum and it may play a potentially important role during no synthesis induction in vsmc. objective: to evaluate the factors of acquisition and the outcome of methicillin resistant staphylococcus aureus (mrsa) bacteremia in an intensive care unit (icu). methods: all patients in which bacterermia due to staphylococcus aureus developed > hours following admission to our icu, during a year period ( january through january ) were reviewed. patients (pts) were included, mean age , y (sd , ), saps , (sd , ), mac cabe ( and ) %, mortality directly due to sepsis %. pts had mrsa bacteremia and methicillin susceptible staph. aureus (mssa) . both groups were compared using the chi square (with correction of yates), fisher's exact, student's t or wilcoxon test. results: there was no statistically significant difference between mrssa and mssa regarding at age ( , + , vs , + , ) , saps ( , + , vs , + , ), use of vancomycin ( % vs %), mechanical ventilation ( % vs %), number of days (d) before the drawing of the first positive blood culture (median d, range - d vs median d, range - d). more mrsa than mssa pts had previous use of nonsteroidal anti-inflammatory drugs (nsaid) ( % vs % p< , ), central venous catheter infection due to staph.aureus ( , % vs % p< , ), but previous use of antibiotics was not significantly different ( , % vs %). the outcome of the bacteremic pts was not statistically different: saps at the first day of bacteremia ( , +_. , vs , + , ), severe sepsis and septic shock ( % vs %), persistence of the bacteremia ( % vs %), mortality directly due to bacteremia ( % vs %). conclusion: previous use of nsaid, infection of venous central catheter are more frequently associated with mrsa bacteremia. thus, similar to others studies (hershow infect control hosp epidemio ; : - ) , these results do not indicate that mrsa is associated with increased virulence. objectives: to closer definition of mosf formation mechanismes in nosocomial sepsis (ns) the complex clinicobiochemical, microbiological, immunological, functional exaroination of cases with ns had been done. methods: examination of cellular and humoral immunity, nonspecific immunologic reactivity, systemic and hepatic circulation, microbiological examination of blood,electro-and echocardiography, sonography and computer tomography of chest and abdomen organs were obligatory. autopsy findings of dead cases had been analized. results: in cases ( , %) opportunistic pathogen microscopic flora ( staphylococcus anreus,staphylococcus epidermidis, staphylococcus saprophyticus) had been found out in blood inoculations. in cases ( %) side by side with destructive process in lungs the bacterial endo-and myocarditis with blood circulation failure had been determined.in cases ( %) simultanious lesion of three organs (heart,lungs,liver) had been found. morphologic examinations of dead cases ( %) internal revealed involvement of them in mosf-syndrome.hyperplasia of adenohypophysis;sclerosis of adrenal glands cortical layer;perivascular brain oedema,paralysis of brain capillaries and plasmorrhagia, cerebral thrombosis and cerebral abscess,necrobiosis of epithelium tubules of the kidney,pletora of hepar, fatty and granular degeneration of hepatocytes had been found.atrophy of white pulp and hyperplasia of red pulp, supress of lymphoid tissue, plethora and formation of infarctious had been found in spleen. mentioned changes in spleen were indispensable in ns. conclusion: in ns spleen can not secure it functions to support and appropriate detoxication potencial of organism,elimination of microbes,toxines,antoallergenes. insolvency of immunological link of antimicrobic defence is the starting mechanism of mosf developmentin ns. %neviere, jl. chagnon, b. vallet, d. mathieu, n lebleu, f. wattel ] ept of intensive care, hop calmette, lille, france ~everal studies have described tiypoperfusion of intestine during sepsis. owever, it is unknow whether the mesenteric blood flow is associated with nucosal hypoperfusion. additionally, the effects of resuscitation on the ntestinal microcirculation remain controversial. bjectives : to describe the effects of endotoxin in a porcine model during ~hock and resuscitation. ~ethods : ten pigs ( kg) were anesthetized and instrumented for "neasurement of cardiovascular variables. gastric and gut oxygenation vere assessed by intra-mucosal ph and microvascular laser doppler lowmetry. after baseline data collection, a minute intravenous infusion )f escherichia colt (serotype h , sigma, st. louis, mo) was begun ~t a rate of pg/kg. an infusion of either saline at . ml/kg/min (group ; n= ) or saline and dobutamine at a rate of pg/kg/min (group ii; n= ) vas begun mn after the end of the endotoxin infusion. tesults : to td t ~ fl w fluid ioadin,q alone sfyras d, k perreas, e douzinas, k spanou, m pitaridis and c roussos critical care dpt, evangelismos hosp., athens univ, school of medicine. obiectives: much controversy exists concerning the beneficial effects of cvvh on sepsis. we studied the effects of cvvh application on septic patients with reference to the following parameters: i) survival rate ii) cytokines' removal and iii) timing of cwh onset. methods: patients with sepsis (criteria according to accp/sccm, ) underwent cvvh as soon as they developed renal failure or dysfunction (urinary output< ml/ h, cr> . mg/dl and bun> mgd'dl ). specimens were collected: blood samples before cvvh and therafter both blood and ultrafiltrate (uf) samples on , and hours. cytokines tnfa, i - and ii- were measured by the immunoassay method in all specimens (uf and plasma -p) and sieving coefficient ([uf]/[p]) and h solute mass transfer of tnf and i - were calculated (v h x [uf] ). the apache ii score before cvvh onset, the duration of icu stay and the timing of cwh application related to the sepsis onset in days (ta) were recorded.with respect the mortality two groups were formed, i.e. group a (survivors) and group b (non-survivors) . the morbidity period in days of those septic patients who died in the past year and were not subjected to cwh (group c) was compared to that of group b. results: group a included pts and group b pts with mean+sd age ( _+ vs _+ , ns) and apache scores( _+ vs -+ . , ns). the mean ta-+ sd was . + vs -+ , p< . . the mean_+se morbidity period of group b vs group c was _+ vs _+ . p< . . the mean values of cytokines are presented in the following figures. the sieving coefficient for tnf was . and for i - was . . the solute mass tranfer was -fold the actual plasma content at a given time. . o conclusions: i) early application of cvvh seems to favourably affect the outcome of septic patients, ii) cytokine plasma levels do not decrease although cytokine removal is substantial, iii) it seems that cwh application in sepsis of any stage helps to buy time for further treatment. the most commonly monitored variables in shock stages idclude : arterial pressure, heart rate, central venous pressure, pulmonary artery wedge pressure and cardiac index. with vigorous therapy it is possible to bring these values back into the normal range in both survivors and nonsurvivors. therapeutic goal in septic shock stages is to maximize the values of cardiac index, delivery (do ) and consumption (c ). objectives: the main purpose of this article is to determine the relationship betwee~ delivery an consumption as a sign of hypoxia. fifteen patitents with septic shock were treated with intention to maximize the value of ci,d and v . we compared the levels of these parameters between the survivors and nonsurvivors and found no significant differences after hours. high levels of do and v may not guarantee against tissue hypoxia in early stage of septic shock. zjar~iic, dj janjic, lj. gvozdenovic, a.komareevic. t.petrovic, &marjanovic, institute of surgery, novi sad, yugoslavia objectives: evaluation and mutual comparison of clinical signs, laboratory data and microbiological monitoring in the patients with burn sepsis. method: retrospective analysis of the recorded data of all burn patients treated in our department between january and december . specially attentions were given to data considering wound infection, positive haemocultures, positive urinocultures and characteristics of septic state. results: out of patient there were ( , ~) adults and ( , ( ~) children. almost two thirds of the patients ( - , ~) were males. the predominantly cause ( , ~) of children's burns was scalding b~y hot liquids and flame burns ~ , ~) in adult patients. the most frequdntly species isolated from surface swat~ were pseudomonas aeruginosa ( " in adult patients) and staphyloccocus epidermidis ( , % in children). in only five patients ( , ~ the haenmcultures were positive -pseudomonas aeruginosa was isolated in three and staphyloccocus aureus in two patients. urine infection was diagnosed in , % of all patients. the treatment protocol included use of imipenem and polyvalent pseudomonas vaccine again~ pseudomonas aeruginosa and vancomycin and aminoglycosides against staphylococcus aureus. total mortality rate in this group of burned patients was , ~, but the mortality rate caused of sepsis was low (i %) . conclusions: early detection of any signs of wound infection and symptoms of septic state is a foundation for prevention and treatment of burn sepsis. the burn sepsis could be reliable detected by continuously monitoring the patient's status and by systematic microbacteriological monitoring of the burned patients. hyperdynamic vasoplegic septic shock p.f. laterre, p. goffette, j. roeseler, j.p, fauville, a. poncelet, p. lonneux, m.s. l~eynaert. dept. of intensive care, st. luc univ. hospital, brussels, belgium. splanchnic ischemia is described as a common feature of septic shock and could determine the development of msof. therapy such as noradrenaline (na) aiming at improving blood pressure is expected to worsen splanchnic ischemia by its vasoconstrictive effect and subsequent reduction in intestinal blood flow. ob[ective: evaluate the effect of na on splanchnic blood flow. material and method : in a patient admitted for variceal bleeding, ards and sepsis with positive blood culture, a fiberoptie catheter was positionned in the portal vein after recanalisation of its portosystemic stent shunt. blood pressure (bp-mmhg) , ci, svr, do (vigilance ~ baxter), v (indirect colorimetry), arterial, mixed venous and portal vein blood gases, phi were determined before (to) and during (t ) na infusion ( , to , hcg/kg/min.) . changes in splanchnic flow were assessed by changes in portal oxygen saturation (sp ) and arterio-portal oxygen saturation gradient (sao, -spoe laterre, ,lp. pedgrim, th. dugernier, v. delrue, ph. hantson, p. mahieu, m.s. reynaert. dept. of intensive care, st. luc univ. hospital, brussels, belgium. aim of the study : prospective determination of plasma levels of in patients with ss and their correlation with the type of microorganism and outcome. material and methods : in patients (pts) with ss and severe sepsis, plasma levels of tnfti, ill-b, il and il were determined every hours for days and on day after fulfilling the criteria of ss and severe sepsis. results : in pts, sepsis was caused by a gram (-) microorganism, in pts by a gram (+) and in pts no microorganism was identified. there were survivors ( %) (s) and non-survivors ( %) (ns) . cytokines profiles and levels were not different between gram (+) and gram (-) sepsis. ill-b levels were seldom elevated whatever the group studied. tnfot and il- were significantly higher in ns than in s ( objective: to evaluate the effects on the nitric oxide synthase inhibitor l-n~ hcl ( c ) on myocardial performance in human septic shock. method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map< mmhg) or the requirement for a noradrenaline (na) infusion >_ .i ]tg/kg/min with a map _< mmhg. cardiovascular support was limited to na _+ dobutamine (db), c was administered for up to h at a fixed dose-rate of either , . , , or mg/kg/h iv. during c infusion, na was to be reduced and if possible withdrawn, whilst maintaining map above mmhg and the cardiac index (ci) as clinically appropriate. assessments were made at baseline (t = ); at i h from the start of treatment (t = ); and at the end of treatment (t = ) with c . conclusions: c can restore systemic vascular tone in patients with septic shock enabling na therapy to be reduced and/or removed. the ci tends to fall whilst lv performance is sustained over time. c is a novel vasoacfive agent for the treatment of septic shock, which is undergoing further clinical evaluation. laterre, f. thys, e. danse, j.p. pelgrim, e. florence, z roeseler, m.s. r eynaert. dept, of intensive care, st. luc univ, hospital, brussels, belgium. therapy aiming at improving blood pressure and cardiac index in septic shock (ss) might have deleterious effects on regional blood flow. objectives : compare the influence of volume loading (vl), dobutamine (dobu) and noradrenaline (na) on sushepatic oxygen saturation (shoe) and svoe-sho, gradient in treated ss. material and methods : in patients with ss, ci (thermodilution) , doe, svo,. sho,, svoe-sho e gradient and lactate (l) were determined before (to) and after (t ); vl, dobu and na. results: in patients with treated ss, tests were performed (vl n= ; dobu n= ; na n= method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map< mmhg) or the requirement for a noradrenaline (na) infusion ~> . ~g/kg/min with a map _< mmhg. cardiovascular support was limited to na + dobutamine (db), c was administered for up to h at a fixed dose-rate of either i, . , , or mg/kg/h iv. during c infusion, na was to be reduced and if possible withdrawn, whilst maintaining map above mmhg and the cardiac index (ci) as clinically appropriate. assessments were made at baseline (t = ); at h from the start of treatment (t = ); and at the end of treatment (t - ) with c . conclusions: c is a novel vasoactive agent that can sustain map in patients with septic shock, enabling na support to he reduced and/or removed. there is a tendency for the ci to fall during treatment, which may be reflex in response to the increase in systemic vascular tone. c is a promising new therapy for septic shock, which will now be evaluated in a randomised, placebo-controlled safety and efficacy study. k. guntupalli objective: to evaluate the acute effects of the nitric oxide synthase inhibitor l-n~ hc ( c ) on selected indices of organ function in patients with septic shock. method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map < mmhg) or the requirement for a noradrenaline (na) infusion --> . [xg/kg/ min with a map _< mmirlg. cardiovascular support was limited to na + dobutamine. c was given for up to h at a fixed dose-rate of either , . , , or mg/kg/h iv. during c infusion, na was to be reduced and if possible withdrawn, whilst maintaining map above mmhg and the cardiac index (ci) as clinically appropriate. indices of organ function were assessed at baseline (t = ); at the end of treatment (t = ); and h after treatment (t = ) with c . results. -median values (* assessment made at h or when c discontinued). conclusions: there was no appareut dose-dependent adverse effect on these indices of organ function either during or after exposure to c . the plmelet count tended to fall whilst creadnine appeared to increase over time in all dose cohorts. this novel and promising therapy for septic shock will now be evaluated in a randomised, placebo-controlled safety and efficacy sludy. pharmacokinetics of c in patients with septic shock preliminary results z. hussein, b. jordan, c. fook-sheung, k. guntupalli objective: to evaluate the pharmacokinetics of the nitric oxide synthase inhibitor l-n~ hc ( cg ) given by continuous infusion for h in patients with septic shock. method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map < mmhg) or the requirement for a noradrenaline (na) infusion --> . ~tg/kg/min with a map _< mmhg. cardiovascular support was limited to na • dobutamine. c was administered for up to h at a fixed dose-rate of either , . , , or mg/kg/h iv. plasma was collected from each patient over a h period and analysed for c . pharmacokinetic parameters were derived from plasma concentration-time profiles using non-compartmental pharmacokinetic analysis. results: the (cm~ -maximum plasma concentration; auc -area under curve; cl -plasma clearance; v,, s -steady state volume of distribution; t'/ -plasma elimination halflife). conclusion: the pharmacokinetics of c in patients with septic shock are dose-independent at infusion rates up to . mg/kg/h. at higher rates, clearance of c decreases without any marked change in volume of distribution. c metabolism may be partially saturable at dose-rates above . mg/kg/h. obiectives: investigate the effect of the no synthase inhibitor, l-nt-methylarginine hc ( c ) on the haemodynamics and survival rate in a conscious mouse model of endotoxin shock. methods: female cd- mice ( - g) were instrumented under gaseous anaesthesia (isofluorane, %) and connected to a swivel tether system for continuous monitoring of blood pressure and drug administration. results: after h recovery, endotoxin administration (e. col• :b , - . mgkg - i.v.) elevated the plasma concentration of nitrite/nitrate (nox) and caused a progressive fall in mean arterial pressure (map) from + to + mmhg (n= , p< . ) at h, with a survival rate at h, h and h of %, % and % respectively. c administered as a h continuous infusion ( mgkg-th -t i.v., n= ), h after endotoxin, inhibited the elevation of plasma nox and attenuated the fall in map from + to + mmhg (n= ) at h, with an improved survival rate at h, h and h of %, % and % respectively. conclusions: this study suggests that overproduction of no is involved in the hypotension and mortality characteristic of septic shock. inhibition of no synthase using c represents a novel and promising treatment for septic shock. cultures of e.coli ( , %) and candida( , %) were olso received from autopsy material of children;p.aeruginosa,unspored anaerobes,proteus sp.,s.aureus,b.pneumonia were found in the few cases. in adults the spectrum of bacterioflora was mo~ re limited speaking about the number of species and cultures. in generalized forms of bacterial pyo-septic pathology a wider specific spectrum of causative agents was revealed usua fly with associations. e.coli and k.pneumonia played the leading role in children as well as in adults. in general,k.pneumonia ( , %cultures) and common e.coli( , %)prevailed according to the date of microbiological investigations of authopsy material in pyo-septfc pathology in . objectives: .in spite of all clinical exertion sepsis is still the reason for high clinica! lethality. this study is characterizing the group of patients which survived a septi~ shock. methods: during a period of months all surgical patients on icu were registrated prospectively, more than parameters for each of them were documented'daily in a paradox file. results (see table ): of patients fulfilled the criterion of a septic shock (r. bone, ) , of them died at the lth day, while the surviving group of patients stayed almost days at icu. obiectives: to compare the effects of and % pentastarch solutions to a human albumin solution on oxygen delivery (do ) in septic patients. methods: this stud}, included septic patients with fever (t > ~ tachycardia flqr > /rain), tachypnea (rr > /min) or mechanical ventilation, leukocytosis (wbc> /mm ) or leukopcnla (wbc< ()/mm ) and a clinical source of infection, who required a fluid challenge. in each patient the pulmonary arterial occlusion pressure (paop) was < mmhg. patients were randomized to receive ml of % albunun (n:i ), hydroxyethyl starch (hes -mw /d.s. . ) % (n: ) or t % (n=i ); patients were also treated with adrenergic agents. results cardiac index (c ) increased significantly only in % lies (table) hemoglobin (hb) decreased significantly at min in the same group. there was not significant change in oxygen delivery ( do ). baseline ci alb . :: . (l'min/m ) hes % . = . hes % . polyneuropathy of the critically ill (pci ) is a well recognized complication, acquired in the course of severe illness. we undertook a prospective study, to estimate the severity, extension and time of onset of pci in a selected group of patient with established septic shock ( bone's criteria ). all patients received inotropic circulatory support and were mechanically ventilated. none received relaxants or aminoglycosides. pci was diagnose<by clinical investigation and by emg, and repeated weekly ( axonal degeneration ). after days ( day = onset of septic shock ) in % of the patients pci was demonstrable. after days % of the patients had pci. there was a strong correlation between pci and other mof and between pci and encephalopathy ( eeg ). we conclude that i. pci is a common complication after septic shock. . pci develops early in the course of illness ( % after days ). . pci can be considered as a part of mof, suggesting a common pathogenesis. objectives: we addressed two questions: ) can serial measurements of vapco and avph also reflect the onset of tissue hypoxia during endotoxemia? ) are whole body changes in vapco and avph associated with parallel changes in regional circulation? methods: in anesthetized, mechanically ventilated dogs exhaled gases were sampled for determination of oxygen consumption (vo ). a catheter was positioned into the pericardial cavity to induce cardiac tamponade. ultrasonic flow probes were placed around superior mesenteric, left renal and left femoral arteries, and the corresponding veins were cannulated. group l served as control (n= ), group (n-- ) received mg/kg of endotoxin. thirty min later, tamponade was induced to gradually reduce do . results: systemic do crit was higher ( . _+ . vs . + . ml/kg.min, p < . ) and critical oxygen extraction ratio (o ererit) was lower ( . +_ . vs . +_ . %, p< . ) in the endotoxie than in the control group. meslenteric and femoral do crit were higher in the endotoxic than in the control group ( . _+ . vs . _+ . mlll g tissue.min and . _+ . vs . _+ . ml/min, respectively, both p< . ). regional o ercrit were lower in we endotoxic than in the control group (mesenteric: . _+ . vs .i_+ . %, renal: . + . vs . -+ . % and femorah . -+ . vs . _+ . %, all p< . ). vapco and avph followed a similar pattern in both groups, increasing slightly before do crit was reached, but dramatically wh,en do fell below do crit. in the presence like in the absence of endotoxin, systemic and regional do crit calculated from vo , from vapco , or from avph were similar; do crit was also significantly higher in the mesenteric and the femoral beds of the endotoxic than the control dogs. systemic and regional do crit could be calculated from the blood lactate levels only in the control group. conclusions: during an acute reduction in blood flow i) vapco and avph can reflect hypoxic threshold in the presence like in the absence of endotoxemia. ) alterations in organ oxygen extraction capabilities induced by endotoxin can be reflected by regional changes in vapco and avph. objectives: enhanced nitric oxide (no) release has been incriminated in the vasodilation and myocardial depression characterizing septic shock, but the administration of no blockers has yielded equivocal results. the present study explored the systemic and regional effects of a no donor linsidomine (sin-i) during endotoxic shock. methods: anesthetized dogs received endotoxin ( mg/kg iv), followed min later by a saline infusion to keep cardiac filling pressures constant. oxygen uptake (vo ) was derived from the expired gas analysis. regional blood flow was measured by an ultrasonic flowmeter (transonic). results: the control endotoxie group (n= ) maintained low arterial pressure and systemic vascular resistance. the dogs receiving a continuous infusion of , , ~ug/kg.min of sin- starting min following initial fluid resuscitation (each dose for h), had a higher cardiac index ( . -+ . vs . _+ . l/min.kg, p< . ) and lower systemic and pulmonary vascular resistance than the control group ( -+ vs -+ and -+ vs -+ dyne.sec/cm , respectively, both p< . ). arterial pressure and pulmonary artery pressure were not influenced. sin- significantly increased the mesenteric blood flow from -+ to + % of baseline levels and renal blood flow from -+ to -+ % (both p< . ) but did not influence femoral blood flow. the relative blood flow was increased in the mesenteric bed (at all doses), and reduced in the femoral bed (at highest dose). systemic oxygen delivery, vo , oxygen extraction and blood lactate levels had similar course in the two groups. conclusions: in fluid-resuscitated endotoxic shock dogs, the no donor sin- increased cardiac index without deleterious effects on arterial pressure, and increased splanchnic blood fl w. objectives: sepsis syndrome is associated with the release of a variety of inflammatory mediators, such as interleukins, tumor necrosis factor and platelet-activating factor (paf). administration of paf, a naturally occuring phospolipid, to laboratory animals has been demonstrated to resullt in pathological changes that closely resemble those found in sepsis. in addition, paf antagonists of various origins have been demonstrated to attenuate cardiovascular collaps and to protect against lethality in endotoxemia. in the present study the efficacy and safety of the paf-antagonist tcv- g was investigated in sepsis syndrome patients. in addition, the putative inflammatory parameters tumor necrosis factor (tnf), interleukin il) - il- , and soluble (s) e-selectin were measured in both tcv- and placebo treated patients. metho.~a randomized, double-biind, multi-center study was undertaken to compare the safety and efficacy of intravenously administered tcv versus placebo (takeda chemical industries ltd., osaka, japan). tcv- was used as add-on to conventional therapy in the treatment of patients with severe sepsis and septic shock ( . mg/kg body weight intravenously over hrs, twice a day for one week). day mortality was registered, as well as vital signs, laboratory parameters, hemodynamic parameters, apache ii score and mof score. plasma samples for the determination of inflammatory parameters were collected twice a day for one week. the study was approved by each institutional review board and written informed consent was obtained for each patient. results: a total of patients were included in the study. one patient had to be excluded as a result of protocol violation of the remaining patients patients were randomised to receive tcv- and to be treated with placebo. there were no significant differences between the treatment group with respect to age. gender, and apache i~ score on admission. however, admission levels of il- and il- , considered to reflect severity of disease, tended to be higher in tcv treated patients: . . vs . ng/ml for il- (p. ) and . vs . ng/ml for il- (p. ) in tcv- and placebo treated patients, respectively. a remarkable difference in survival, however not significant, was observed at day i.e. the end of tcv treatment (mortality: out of in the tcv group and out of patients in the placebo group). the inc;dence ui ~-,~verse events, 'n both treatment groups were comparable. plasma il- and plasma il- levels tended to decrease more rapidly in tcv treated patients compared to controls (p=. and p=. , for il- and /l- respectively) conclusions: tcv- is safe as add-on treatment in sepsis syndrome patients. the data presented indicate that tcv- may enhance survival of sepsis syndrome which will be assessed in a phase ill study. objective: oxidation of lipids by free oxygen radicals playes an important role in sepsis. an important source of oxygen radicals is the respiratory burst of phagocytic leukocytes, especially~ polymorphonuclear leukocytes. clinically the hallmark of sepsis is the capillary leak, which is mediated in part by oxyradicals. the adult respiratory distress syndrom (ands} represents the most studied capillary leak phenomenon in sepsis. methods: in ii patients (df,~m, aged - y.) with verified septicemia had been included in this study. beginning from day oxidisable lipidautoantibodies (club), ~opterin and crp were determined in the patients serum and compared against the apache ii score during the days - . patients, f and m died @u= ring their stay at the icu, of them in less than h~urs: after admission. at the begin surviving patients showed olab values between - %, non-survivors between - %, com= pared to neopterin values of - m~ol/l in survivors and - ~mol/l in non-survivors. apache ii score didn t show any difference. during the following days olab sbowed an in= crease in survivors, while in non-survivors olab stayed equal or showed a decrease. no difference between both groups was found in neopterin, crp and apache ii score. as result we conclude, tbat lipidperoxidation playes an important role during septicemia. olab as a marker of this process are predictive for the outcome of patients. obiectives : to evaluate the influence of cardiopulmonary bypass ongastrointestinal transit. meth~xls; gastrocoecal transit time (gtt) in consecutive children on day after uncomplicated open heart surgery was compared to gtt in children after closed heart thoracic surgery and to healthy controls. gtt was measured by hydrogen breath testing, using lactulose (o, g/kg in a % aequous solution) as nonabsorbable marker. exspiratory hydrogen content was measured using a electrochemical system (stimotron). patients in both groups had continuous infusion of morphine and midazolam and were comparable in respect to catecholamine dose. children with a history of toddler's diarrhoea and children with elevated central venous pressure were excluded. results: gastrocoecal transit was delayed in all patients after cpb, no transit was achieved within minutes in / . after closed heart surgery gtt was delayed (+- ) min vs. (+- ) compared to controls, but transit was achieved in all aptients within rain. mean dopamine dose was , mcg/kgmin after cpb and , meg after closed heart surgery.. conclusions: after uncomplicated cpb gastmcoecal transit is extremely delayed. the degree of delay is not explained neither by the use of analgetic and sedative drugs neither by the use of catecholamines. factors directly related to cpb (e.g. low flow perfusion, hypothe,mia) may be responsible. these findings are of limited clinical relevance in ancomplicated cases. in critically ill patients delayed enteral feeding may contribute to infectious complications. studies of therapentic measures to accelerate gastrointestinal transit therefore are warranted. neonatal ecmo -czech experience. nekvasil r., penkova z, vasek l., plier p., bobula a novotna e., pavlicek v., hnilicka m. nicu and ecmo center brno and dept. pediatric surge ', children's hospital brno, czech republic. introduction. in spite of the fact that neonatal ecmo has been gradually considered a standard method of solving uncontrollable respiratol t failure in newborns in most countries of the western europe, the introduction of this sophisticated method in countries of the former communist block meets a lot of problem. material methods. in the course of two years, only newborns, b.w. - g, were reffered to neonatal ecmo because of uncontrollable respiratow failure. at the admission the average values of oxygenation index were + , and aado , -+ , kpa. results. newborns ( %) died shortly alter" admission or during transport without possibity to further is newborns ( , %) were treated using high-frequency ventilation (hfo or hfjv), one for conspicuous airway resistance paradoxically with low-frequency ippb. all ventilated newborns survived. ecmo was applied in newborns ( , %) and of them survived the mortality rate of group mentioned was %. conclusion. the fact that in the czech republic ( mil. population with natality rate of about . newborns/year) only small part of patients was reffered to neonatal ecmo has a number of causes. the most important are: unacquaintance of prognostic and indication criteria at forwarding workplaces and the aversion of neonatologist to all new.therapeutic interventions. last but not least, a negative role is also played by current change of health service systems when, under the influence of health-service insurance companies a newborn in serious condition given only a standard intensive care in primary and secondary nicu is literally "the golden calf", and therefore these workplaces either do not send him or send him too iate ~o an ecmo center. stndy aim: urfactant, which is being applied into the lungs for treatment of respiratory distress syndrome, can reach the circulatory blood system by absorption. it refinances local fimctiun of macrophages and lymphocytes and increases the accumulation of nentrophils into the hmgs this eunld influence the local acute phase reactiml in the hmgs after surfactant application. "ilia aim of the stud), was to investigate the influence of oatural and artificial surfactaat onto the acute phase reaction and the blood elottiog system. material :and methods: a) measurement of tnf-a, - , ltb and thromboxane b release in whole blood: each of . ml hepariaised blood of healthy adult volunteers was iucubated lbr hears with eillier ill ug/ml lps, mg/ml b&,ine smfactant (alveulhct/themae), rag/nil artificial surfactant (exosurf/wellcome), og lps + i mg/ml bovine surfactant or i ug lps + i mghal artificial sorfactant, tleparinised bhx-,d without additions was used for controls. ' e concentration of e)lokines and eicosanoids ".van measured semiquantilatively by eijsa or eia (dimmva/hamburg) after ceatrifagalion, b) measurement of platelet aggregation: each of . ml haparinised hltxxl of healthy adult vohmteers was inculmled lbr hours with eilher aghnl i,ps, i mg/ml bovine surfactant (alveafact/thomae), i mg/ml artificial snrlhctant (exosurf/wellcotne), it} ug lps + i mghnl bovine snrfactant or ug lps + i mg/ml artificial surfaetant, tlepminised blood withont additions was nsed for controls. platelet aggregation in whole blood was measured by impedance in the aggregometer (g~nstaedt). c) measurement of the dotting activity: citrated bleed of healthy adult w~lunlccrs was mixed with difl'ereul couccalrations of imvine or artificial snrfactant fad then prolhrombiu tiaras and imrlial thrmnlx~plaslia filues were ineasnrcd. for measurement of the prokoagulatioo acfivily the reagent in the qnick test was replaced by surfaclant. results: dependmlt on the dose both surfactants stimulated the release of - but not or tnf-a io wlmle blood. "illere was no suppression of the lps-indaeed eytokine-release. both surfaclants did not directly influence the extrinsic blood coagulation system, while both activated the inniasie activity dependant on the dose. platelat aggregatiun was slightly stimulated by bovine snrfactunt and strongly inhibited by by artificial surthctant. in comhinafion with . ~ both factors showed no difft.'renca to lps ahme.'fhe reltu.tse of eiconasnid~." was stimolated more by artificial surfactant then by bovine surfilctant with regard to the cyehmxygelmse (thromboxsne b ) and the lipooxygenase (lencotrieae b ) pathways. conclusion: we cooclude: ) i:lovine as well as artificial surfaelant stimulate the cellular inmnn]e response. ) bovine as well as artificial surfnctant activate the intrinsic ctmgnlation cascade. ) bovine surlilctant stimulates platelet aggregation, artificial sar-fijctant inhibits platelet aggregation.. introduction: although the use of modem noninvasive methods like measurement of tope , tcpco or san leeds to an carly infonnation about pathologic alterations of the gas exdmage of ventilated patients, these methods cannot replace invasive bloodgas analysis. a new noninvasive method to monitor the capillary gas exchange is the reflection spectrophotometry. to record reflection spectra with a ldgh sensitivity on the surface of tissue we eonstnmted a special mierolightgnide photospectronmter (empito). this spectrometer enables the investigation of local helerogenities of llbo and lb content, capillary flow rate and oxygen uptake rate. aim of the study: ) to compare the sousitivity and specifity ofthe empilo with other non-invasive method~ of monitoring the gas exchange in neonatal intensive care patients. ) to investigate the possibility of obtainiug infonnations about the local nptake and the venous as well as arterial satnration. patients and methods:we investigaled non-selected patients of oar pediatric intensive care unit. for coulinnons monitoring we conslracted a special sappert to fix file end nf the microlightguide+ during the investigation tope , tcpco and san were measured by standard methods. "fo investigate the local tisslm oxygen uptake we recorded spectres within minutes by moving the lightgnide over an described area of the skin of the patient. 'lhe reselting i(gx) l ibo vahms were sorted by a software package. on the assumption that the low values correspond to the tibo value of the veaons ends of the capillaries and the high values to those of the arterial ends we ) it is possible to gel infonnations about the local o -uptake and arterial saturation ia the peripheral tissue by photoslg'ctroscopy. ) in combination with noninvasive pl i-measorement it seems possible to reduce withdrawal of blood for invasivn bhmd gas analysis. objectives:improve ventilation,tissue oxygenation and acid base balance among extremly low birth weightand premature infants. methods: fourteen cases were s~udied,their gestational age ranged from( - )ws.continnous positive air way pressure was applied to six cases at peep level from ( - )cm h o through nasal pronge,(group i),the other cases were managed as routine,(group ii).blood gases, tcpo ,tcco ,resp.rate,depth and pattern were monitored for assessment of tissue oxygenation and ventilation, results: our rasults showed that early application of cpap improve ventilation among ( . %)of cases,while ( . %)of cases need imv.the cases of group ii need imv among ( %)of the studied cases during the second or the third day of life. conclusions:-this preliminary study showed the import-............ ance of early application of cpap before the onset of respiratory distress syndrom to improve spontaneous ve ventilation,tissue oxygenation and to gecrease the risk of intubation. comparative assessment of pediatric intensive care; a national multicenfre siudy. reinoud j.b.j. gemkc, gouke j. bonsel , the dutch picasso (pediatric intensive care assessment of outcome) study group. twilbelmina children's hospital and utrecht university, utrecht department of clinical epidemiology, academic medical center, : amsterdam, the netherlands the performance of all ( ) pediatric intensive care units (icus) in the netherlands ( tertairy and non-tertiary) was analyzed in an open prospective muiticenter study. effectiveness of care was defined as the ratio of observed to prism-score derived expected mortality aenee, standardized mortality rate). efficiency was determined by objective criteria (mortality risk > % or administration of at least icu-dependent therapy)'. consecutive admissions aged < years old were included. overall, observed and expected mortality were in good agreement (p > . ). between hospitals, crude mortality showed wide variations (mean . %, range - %). however, in each center, observed and expected mortality were similar (mean ratio . , range . - . ). in tertiary care centres, severity of illness corrected mortality in high-risk patients was less than in non-tertiary care centres; paradoxically, in low-risk patients the opposite was found. probably the large proportion of low-risk tertiary care patients suffering from severe, incurable chronic disease, explains the higher mortality in this group. this indicates that simultaneous assessment of circumstances of dying and of long term morbidity in similar future studies is imperative. the average proportion of efficient icu days was %, however large variations between units were found (range: - %). in conclusion differences in mortality rates among pediatric icus were explained by differences in severity of illness. high efficiency rates in combination with adequate effectiveness, found in several centres suggest that admission and discharge decisions might be improved by a better selection of high risk patients requiring icu-dependent therapies, especially in less efficient centres. objectives: previously published studies showed that serum lactate levels correlated with outcome of severe ill adult, 'we hypothesized that critically ill newborns are often incurred hypopeffusion manifested by elevated lactate levels. these initial blood lactate levels should be related to nicu outcome. design: prospective study with ethical comfnittee approval. setting: the -bed neonatal intensive care unit of a university hospital material and method: a total of consecutive outbem newborns admitted to nlod from , . to ., . were enrolled to the study. babies who died or were discharged from the unit within hours of treatment were excluded from the study, mean birth weight was g (+/- r), mean gestatational age was weeks (+/- . wks), mean age at the admission was h (+/- hi. multiple (~_ j organ system failure occurred jn . % of babies at the admission./~tertal lactates were measure/at the admission, among - hour and - hour of n[c'lj therapy. outcome was defined as a mortality and length of nicu stay. results" survival rate was . %, mean length of nicu stay for survivors was . days (+/- . day). we found high lactate levels at the admission in . % babies (~ . % with levels above . retool/i). the mean arterial lactate concentrations for nonsurvivors were signiftcahtly higher than for survivors durin~ consecutive da~ as follows: objectives: the purpose of our research was to analyze the frequency of bronchial asthma (b.a.) exacerbations in pregnant women and health status of infants. methods: the research was based on the epidemiological investigation and prolonged observation of pregnant women with b.a. during the gestation period. remission of b.a. before the pregnancy in excess of years was recorded in patients ( . %), patients ( . %) reported a - year remission and patients ( . %) had a remission lasting less than months before they became pregnant. results: seven patients ( . %) developed medium attacks in the second half of pregnancy, four patients ( . %) experienced light attacks of b.a. asthma attacks were most frequently caused by acute respiratory diseases and stress factors. in two cases with grave manifestation of b.a., the pregnancy ended in abortion within the first - weeks due to the frequent and heavy choking attacks. to fight b.a. attacks, five patients used adrenomimetics (salbutamol, becotid) in sprays, six women were administered theophyllinum and salbutamol in the form of tablets during - weeks. a significant portion of pregnant women with b.a. ( %) exhibited frequent complications during pregnancy (toxemia, late gestosis, threat of miscarriage). our findings prove that babies born from women with b.a. of domestic and pollen origin had a low body weight ( - gr), functional immaturity and chronic antenatal and intranatal hypoxia twice as often as the infants born from healthy women without allergic background. conclusions: preventive treatment of women with b.a. prior to pregnancy is required to maintain a stable remission of the disease, which is a key to having healthy children delivered by mothers suffering from b.a. introduction. intracerebral hemorrhage (ich) is a common event in human prematudty, affecting about % of newborns weighing below g who are born before weeks of gestation, however, little is known about the pathogenesis of ich with exception of the prematurity of the brain itself, (birth) trauma, and asphyxia. the postischemic production of oxygen free radicals (ofr) dudng reoxygenation as a cause of brain damage has been demonstrated in animal research. since almost all preventive antioxidant activity of plasma is associated with ceruloplasmin and transferdn we investigated the association of such iron-oxidizing resp. iron-binding proteins and ich. we could demonstrate significantly reduced levels of both, iron-oxidizing and iron-binding proteins, in premature asphyxiated newboms pdor to development of ich. an increase of suparoxide after hypoxia in the presence of iron ions facilitates the formation ofthe highly reactive hydroxyl radicals. our data support the theory that ich may be caused by ofr, which can damage any sensitive tissue including growing endothelial cells. the estimation of transferrin-saturation and measurement of ceruleplesmin levels might help to identify an infant at dsk before the onset of ich. with the new medos | hia-vad | cardiac assist system the missing tool in the armamentarium of cardiac surgeons is available in two pediatric sizes: i -ml and -ml pump volume. the right sided pumps are % smaller for biventricular use. between february and may we implanted this assist system in children. the indications and demographics are indicated in the following table (left ventricular assist device-lvad, right vad-rvad univentricular vad-uvad, post cardiotomy cardiac failure-pcf, dilated cardiomyopathy-cmr bland white garland syndrome-bwg, tetralogy of fallot-tof, hypoplastic left heart syndrome-hlhs). objectives: evaluate tile effeci'of inhaled nitric oxide (no) as puhnona] t vasodilating agent ill tile posloperalivc period after correclion of congenital heart defects in infant. patient n.l: kg, lnonlhs, down syndrome undenvcnl rep~fir of atrioventricular septal defect (avsd). after surgery the puhnonary arlcry pressure (pap) slowly rose to tile syslemic dcspilc tnaximal eonvcnlional fllerapy (fentanyl mcg/kg/h, hypocapnia of mmhg and metabolic alcalinization). no was delivered into tile inspiratory branch of!be breathing circuit at ppm, and the gas aoalyser for no and no (polylron dmger) were situated at the espiratory branch, a rapid dccrcasc of pap io i/ of systemic was obtained with a dramalic improvement. no was continued at ppm for six days and the baby was exlnbated if! days after surgery and discharged from the icu days after. patient n. : . kg, monlhs, onderwen! repair of avsd. the day after surgery the systemic oxygen salnralion was % wilh a pap at % of systemic. two hours of c wenlional therapy failed o improve ihc patient and no administration was slarled at ppm. so dramatically incrcased to %, but the pap dropped only to % of syslemic. nevertheless ihe clinical conditions improved and the no administration could be reduced at ppm in the following days. she was extubaled days after surgery and discharged from the icu days after. patient n. : kg, 'ears. underwen| hearl tral~splantalion for congenital heart disease with moderate hypoplasia of pulmonary arlcrics. at the end of cardiopulmonary bypass the transpnlnlonary al~erio-venoas gradient yeas higher than mnfflg and we speculaled !hat w'ls due to a degree of puhnonary vasocostrictiont. the nsnal dose of no was otilised, however no significant modilicalion of pulmonary pressure or systemic oxygen saluralion was noled, and after h no was discontinned. tile palienl was carried io the icu with maximal inotropic support, extubated after d;b's and disclmrged from the icu after days. in all patient no major adverse effect relaled to no admilfistration ",','as holed. conclusion: in our experience no ms a pulmonary vasodilaling agent is effective and easily adjustable to tile palienls requiemenls, however its use remains limited ill those palienl ill whoin tile alnonll! of fixed inlllllojliify vascular resistance is predominanl. we report the use of ecmo support in two unusual cases of severe tracheal disruption in which it had become impossible to achieve adequate ventilation. case : severe tracheal laceration due to aspiration of a share forelan bodv: a previously healthy month old toddler was referred for ecmo following aspiration of a porcelain foreign body (with razor sharp edges) which had become embedded in the right mainstem bronchus with massive extrusion of air. this was removed on veno-arteda[ ecmo support, as the patient was unventilatable prior to bronchoscopy due to ongoing airieak. ecmg was continued after bronchoscopy to permit airway healing without the presence of an endotracheal tube. unfortunately, an extensive pulmonary haemorrhage on day of ecmo necessited re-exploration of the airway. this revealed a posterior tracheal tear from the cricoid to the middle of the right lower lobe. following repair the patient was left on ecmo support together with high frequency oscillation ventilation (hfov), the latter being used to minimise potential aideak and maximise alveoli recruitment. ecmo was weaned after days ( hours) -the patient was extubated weeks later. case : tracheal wound dehiscence due to seosls -tracheal transelant on ecmo: a month old infant with a c[inically significant congenital long segment tracheal stenosis and left pulmonary artery sling underwent resection of the stenosis, followed by primary reanastomosis. this was complicated, days later, by severe mediastinitis and complete dehiscence of the anastomosis. an autologous pericardial patch was used to repair this, however, the tracheal wound again dehisced days later making mechanical ventilation impossible. in view of ongoing sepsis and a severely disrupted trachea ecmo was the only possible form of support. following resolution of the local sepsis ( days) a definitive procedure in the form of a tracheal homograft (transplant) was undertaken on ecmo. the patient was managed on ecmo and hfov for a further days, the hfov being used to optimize rapid lung inflation. unfortunately this patient died months after weaning from ecmo due to complete disintegration of the homograft, which was not deemed reparable. conclusions: ) ecmo can be used in the acute management of oxygenation when there is major airway disruption making mechanical ventilation impossible. ) hfov was a useful adjunct in aiding recruitment of lung volume on ecmo in these two patients. backoreund: persistent pulmonary hypertension of the newborn (pphn) consists of a heterogenous group of diseases ranging from transient reversibte pulmonary hypertension to fixed primary malformations of the lung (primary pulmonary dyspfasia-ppd). inhaled nitric oxide (ino), a selective pulmonary vasodilator, has been proposed as a treatment for severe pphn. obiective and methods: ino was administered to near term neonates with severe persistent pphn, oxygenation index > and echocardiogrephic evidence of pulmonary hypertension, in order to further determine the clinical role of ino in the treatment of pphn. the response to ino was also analysed retrospectively to examine whether this could be of diagnostic value in differentiating at an early stage patients with reversible from fixed causes of pphn results: twenty one of the patients studied responded to the initial trial of no ( ppm x minutes), as defined by a greater than percent improvement in pad as well as a fall in the el to < . these patients were continued on ino therapy, with patterns of response emerging: pattern babies (n= ) continued to show a sustained response to ino and were successfully weaned from it within days -all survived. pattern babies (n= ) failed to sustain their response to ino over hours, as definded by a rise in the el > . six survived, five with ecmo. pattern babies (n= ) had a sustained dependence on ino for - weeks. all three died and lung histology revealed severe primary pulmonary dysplasia (ppd). patients with ppd (pattern ) not only required ino for longer periods of time than did the sustained responders (pattern ), but also required significantly higher doses of ino we report on the air transport of paediatric intensive care patients. these transports fall into three categories: ) retrieval of critically ill neonates and paediatdc patients referred for either ecmo or inhaled nitric oxide (ino) (n = ). one patient was transferred on ind. mean transfer time . hours (se + . hrs). ) long distance international transport using chartered aircraft (n = ). the indications for these transfers included both urgent retrievals for cardiac surgery and semi-elective transfer of stable patients back to their referring unit following treatment in tertiary centres. mean transfer time . hours (se + . hrs) ) long distance international transport using commercial aircraft (n = ). indications for transfer were either semi-elective retrieval for tertiary treatment or the return of stable chronically ventilated patients to their referring hospitals. mean transfer time hours (se _+ .fhrs, longest hrs). the transport team consisted of a paediatric intensive care doctor of at least registrar grade and a registered sick chidrens nurse with intensive care experience. the administrative components of the transfer (ambulances, airlines, customs) were managed in collaboration with companies specializing in air ambulance transfers. outcome: all the patients were safely transported to their destination without mortality or morbidity. complications durino transfer ir~lv~; ) patient complications -semielective endotracheal tube change and central access needed in the only patient brought to the commercial aircraft by the referring hospital (all others retrieved directly from referral hospital), seizure in patient with known encephalopathy, severe cyanotic spells in patient with fallots tetralogy who was retrieved for urgent surgery for this indication ) mechanical compfications -ventilator failure, incubator battery failure, oxygen regulator failure -all occurred with equipment sent from referral hospital, this was unfamiliar and unchecked by our transport team -it was not the decision of the transfer team to use this equipment on this single occassion. ) administrative complications -confiscation of incubator battery by airport security police, excessive delay by custom officials ( hours) in the airport. the incidence of such problems were felt to be low and unpredictable. in conclusion: mechanically ventilated paediatric patients can be safely transported on both chartered and commercial airlines. these transports are best accomplished by trained intensive care medical and nursing staff with the backing of an air ambulance organization competent in arranging the necessary administrative details. it is essential to use your own equipment and to retrieve the patient _directly from the referrin(] hospital to minimise ootential complications. our experience with anaesthesia for paediatric electromyography _w_._pla_ti_k_a_n_o_v, r.eousseff, k.pavlova, d.marinova dpts. of anaesthesiology and int. care and clinika] neurophysiology, med. university, pleven, bulgaria ~)_b_j#~ti_v~. to t~st a " heavv sedation " regimen of anaest-es~a for the purpose of paediatric electromyography d#s~gil~ non-randomized,non-blinded human trial in the seting of an uriiversity hospetal. _m_a_t_eri_a_is_a_nd_ m_e_th_od_s_. children,asa i-if,median age years,range - who undervent eleetrcmyography required anaesthesia. they recieved low-dose ketamine + i~iazepam or midazolam via musculary route( children,age - yrs,ketamine , mg/kg, diazepam - mg total dose ) or per os ( children,ketamine - mg/kg,diazepam , mg/kg or midazclam , - , mg/kg ) _resu_l_t_s. - minutes after medication a state of heavy sedation with weak spontaneos and stimuli-provoked movements was achieved in all children, that lasted - minutes and allowed adequate needle emg and nerve conduction investigation. children recieved additional , - , vol.% halothane during the placement of the needle. non -invasive blood pressure , breath and heart sounds and hb sad by pulse oxymetry were monitored.none of the older children disclosed memories of pain when asked after they regained adequate verbal contact.no complicationes were observed. antenatal maternal steroids reduce the risk of periventricular-intraventricular hemorrhage in very premature neonates treated with natural surfactants. i.apostolidou, c.papagaroufalis, g.touloumi, m.xanthou, n.kalpoyannis a' and b" neonatal icu "ag. sophia" children" s hosp. athens, greece. dept of hygiene and epidemiology, athens university, greece. obiectives: the aim of the study was to evaluate the association of periventricular-intraventricular hemorrhage (p-ivh) in surfactanl treated premature neonates with pre-and postnatal variables. methods: the population of the study was neonates admitted during the years to , with gestational age _< weeks and severe respiratory distress syndrome (rds) (mechanical ventilation and arterialalveolar oxygen tension ratio (ajapo ) < . ), who received rescue therapy of at least two doses of natural surfactants (alveofact or curosurf) and examined with ultrasound and/or autopsy for the presence of p-ivh (papile's classification). the examined factors in each neonate were the following: gestational age, birth weight, sex, multiple pregnancy, antenatal maternal steroids (complete and incomplete course of betamethasone), a/apo before the administration of the st dose of surfeclant, delivery, apgar score at min, type of surfactant, pneumothorax and patent ductus arteriosus. the statistical methods used were x and one-way analyses of variance followed by logistic regression medels, results: the incidence ot p-ivh was . %. three factors were found to have an independent relation to p-ivh (final logistic regression model): gestalional age, a/apo before surfactant administration, and antenatal administration of maternal steroids (complete and incomplete courses). for every weeks of lower gestational age the neonates had an almost doubled associated risk of p-ivh (or: . , % c : . , . ). for every . on average decrease of a/apo before surfactant administration the risk of p-ivh in the neonates was . times higher ( % ci: . , . ). the neonates whose mothers received antenatally steroids had only one tenth of the risk of p-ivh of the neonates whose mothers had not (or: . , % ci: . , . ). conclusions: our results suggest that the antenatal administration of maternal steroids, even less than hours before delivery, reduce the risk of pqvh in very premature neonates treated with natural surfactants, whereas the small gestational age and the lung immaturity still remain the main risk factors tor the development of p-ivh. we analysed retrospectively the management of ( boys, girls) accidental ingestions of foreign bodies in children (mean age : . years, range : months- years). no child had ingested more than foreign object. the majority of the ingested foreign bodies were : coins (n : ), toy parts (n : ), jewellery (n : ), batteries (n : ), "sharp" materials such as needles and pins (n : ), "large" amounts of food (n : ). impaction of food occurs more frequently in children after oesophageal reconstruction in cases of oesophageal atresia. although according to literature "coca-cola" is reported to be effective, this was not seen in our experience. / patients had minor transient symptoms at the moment of ingestion, such as retrosternal pain. only children experienced severe manifestations (cyanosis, dysphagia). in these children, endoscopy revealed oesophageal and gastric erosions. children were seen at the emergency ward within a few hours after the accident ( mean : hours, range min. - hours). chest and/or abdominal x-ray was performed as first-line investigation ( / objects were radio-opaque), and revealed an (unexpected) oeeophageal impaction in children. in / the foreign body was in the stomach. batteries, sharp objects and objects trapped in the oesophagus were removed, either by endoscopy or by magnet-extraction whenever possible. the outcome of the patients was excellent. no complications were observed. extraction is recommended in symptomatic patients, and whenever the foreign body is trapped in the oesophagus, or if the foreign object is "sharp" or a battery. objectives: two strategies were used for management of malignant diphtheria in children aged from . to years. methods: protocol n consisted of intravenous administration of diphtheria antitoxic serum, prednisolone ( mg/kg bw/day), plasmapheresis and supportive care. protocol n included the use of antitoxic serum against the background of high-dose dexasone ( - mg/kg bw/day), hemocarioperfusion and a preventive use (before the clinical manifestation of myocardial damage) of inotropic medications, inhibitors of angiotensin-converting enzyme and pentoxyphylline. each of protocols included the monitoring of serum toxin (diphtherin) levels. results: the group of patients treated according to the protocol n consisted of children with malignant diphtheria, of them with severe malignant diphtheria (grade and ). all patients exhibited the circulation of toxin during at least three days after the start of treatment. all patients with severe grade of disease demonstrated heavy cardiovascular disturbances associated with malignant diphtheria. of the children in the group died seven. the children of the second group were treated according to the protocol n . out of total of patients of this group. patients had severe malignant diphtheria. in all children a significant reduction in serum toxin level was revealed after hemocarboperfusion. in all but one case the satisfactory control of cardiovascular function on was achieved. of children admitted to the trial survived, one child with malignant diphtheria of grade and congenital filbroelastosys of the left ventriculum died. the severity of neurological complications was similar in each of groups. conclusions: the use of hemocarboperfusion, high-dose dexasone and early prevention of heart failure as a adjunct to the standart treatment has been shown to be of benefit in the management of malignant diphtheria. t. schaible, i. reiss, j. m er, l. gortner med. university of lqbeck, children's hospital, kahlhorststr. - , l~beck, germany surfactant therapy seems a promising approach for the treatment of the biochemical and biophysical abnormalities of the pulmonary surfactant system in severe ards. patients and methods: over a months period non-neonatal pediatric ards patients (age - months) in a "pre-ecmo"-situation (oi over h) were treated with bovine surfactant (alveofact| the underlying conditions-of ards were pneumonia ( ), sepsis ( ), immunosuppression ( ), near drowning ( ), neurogenous ards ( ). a total of - mg/kg b.w. was applied in several fractions. before surfactant therapy, we first tried different ventilation (best peep-finding, inversed i/e-ratio, hfo-ventilation) while monitoring the pulmonary mechanics. for hemodynamic stabilisation both norepinephrine and epoprostenol were used to optimize pulmonary perfusion for max. hrs. if there was no improvement of the oi by at least , further treatment with surfactant was initiated. in addition to surfactant all patients received a treatment with dexamethasone of mg/kg in doses. patients with no benefit (oi remained unchanged or increased within the max. - hrs) were taken on ecmo. results: nine patients improved within hours after surfactant therapy: the oi decreased from a level of (mean, range - ) before our treatment to a level of (mean, range - ) thereafter. in patients we were able to continue the positive effects of our treatment and they could be weaned of the respirator within - days. the other patients got worse despite respiratory improvement, they suffered of multiorgan failure of more than organ systems. the last patient did not benefit from surfactant, he had to be put on ecmo, but died because of a complication (hemopericard)after days. the autopsy of the ecmo-patient showed a pulmonary fibrosis, but the other death were not due to pulmonary failure. conclusion: a different sequential ards treatment integrating surfactant therapy can reduce the number of patients requiring ecmo. but ecmo as a therapeutic tool should be available in centers involved in ards treatment. l.blindl, t.p.le, h.weinzheimer, centre for paediatrics, university of bonn, germany selective reduction of elevated pulmonary vascular resistance by inhaled prostacycliu (pgi) has been reported in adults with acute lung injury, neonates with persistent pulmonary hypertension and in one infant with idiopathic pulmonary hypertension. we report on the effect of aerosolized prostacyclin in two children with secondary pulmonary hypertension. patient : in a boy with down's syndrome an avsd had been surgically corrected at month of age. at , yr of age a catheter examination revealed a pulmonary vascular resistance of % of systemic vascular resistance in room air and at an fin of . . prostacyclin ( . mcg/ml) was administered with a jet nebulizer at an fin of . . pvr declined to . systemic vascular resistance and returned to baseline after stopping pgi-inhalation. subsequent intravenous infusion ( ng/kg rain) had to be stopped after minutes because of systemic arterial hypotension. patient : a month old male infant with bronchopulmonary dysplasia developed suprasystemic right ventricular pressure inspire of therapy with oxygen and nifedipin. while he was spontaneously breathing % oxygen via face mask pao was mmhg, arterial ph was . . systolic arterial pressure was mmhg, a rv-ra gradient of mmhg was measured by cw-doppler. while fio was maintained aerosolized prostacyclin was administered over minutes. rv-ra gradient was mmhg, systemic blood pressure mmhg, pao mmhg. two hours later nitric oxide ( ppm) was inhaled at an fio of ( , . rv-ra gradient declined from to mmhg, systemic systolic blood pressure remained stable at mlnhg. discussion: sporadic experience shows that aerosolized prostacyclin selectively reduces elevated pulmonary vascular resistance in some patients. in patient the poor response to inhaled pgi compared to inhaled nitric oxide may be explained by the fact that the action of pgi is not independent from endothelial function, limiting it's effect in severe vascular disease. during the last two years ( - ), infants weighing less than gr. admitted to our referral unit. thirty four of them ( %) survived, ( % of infants weighing - g and % of infants weighing - gr survived) for the years - - the survival of these infants was % and for the years - - , % (p< . ). we analyzed the perinatal and neonatal factors influencing the outcome of these infants. the comparison among neonatal survivors ( ) to neonatal deaths ( ) shows: gestational age: . w ( ) to . w ( ) (s). birth weight: . g ( ) to . ( ) (s). apgar score: , ( ) to . ( ) (ns). presentation and mode of delivery: breech presentation is associated with higher incidence of neonatal deaths. i.v.h. (at the age of weeks): no one of the survival infants had evidence of i.v.h. respiratory problems: intubation, at the admittance of the infants . ",,( ) to % ( ) (s) use of surfactant: % ( ) to % ( ). bpd observed in % of the babies and only one was dependent on oxygen at home. antenatal betamethasone was given in % of the mothers. in conclusion: ) a great improvement in the survival rate observed in these infants the last years in our unit. ) factors with positive effect are increasing gestational age and birth weight, the absence of i.v.h. and the use of surfactant. the breech presentation and the severe respiratory problems increase the incidence of death. animal experiments demonstrated, that brain temperature determines the amount of neuronal damage caused by hypoxia and that mild hypothermia may have a protective effect. until now there is no method described and evaluated to measure brain temperature in neonatal intensive care units. we non-invasively measured brain temperature analogues, nasopharyngeal (tnasoph) and zero-heat-flux temperature (zht) at the temple whereby under zero heat flux surface temperature represents deep head and thus brain temperature. the aim of our study was to investigate the practicability of the method, the relationship of the two brain temperature analogues to rectal temperature (trect) and their dependence on insulation, thermal environment, body activity and time course. we investigated healthy preterms less then weeks postnatal age (gestational age +_ . wks; x + sd, weight +_ g) in an incubator. tnasoph was measured by a thermistor within a feeding tube, advanced to the nasopharynx, zht temple by a thermistor and a heat flux transducers both covered by an insulating pad, and trect thermal environment was characterised by operant temperature (tair . . + twall . ). body activity was video taped. measurements were performed during the following interventions: i/ insulation increased by turning the temple with sensors onto the mattress ( rain). ii) insulation increased by a cap ( min), iii) min after its removal, iiii) increased operant temperature by . + . ~ ( min). results: seven children with ea had a gasless abdomen, the endoscopic procedure excluded ( ) or diagnosticated an upper pouch fistula ( ). in patients who suspected "h" fistula ( ) broncoscopy has strong advocated method to make diagnosis and established cervical approach. from july newborns with ea and lower pouch tef received a selective transtracheal incannulation. we were not able to proceed just in case with congenital subglottie stenosis. in these patients we provided gastric drainage by radiopaque and flexible - french catheter. the knowledge of the precise anatomic position of tef consent to adjust the tip of the endotracheal tube in order to achieve best ventilation. the presence of the catheter through the fistula helps the surgeon to identify, it quickly. no complications were correlated to the procedure and no babies had early pneumonia. alimentary continuity was achieved in all patients ( primary anastomosis, resections of tef, oesophagocoloplasty and died with gastrooesofagostomy). the late mortality . % ( ) was only directly related to the severity of associated malformations. conclusion: the advantages of this technical approach are unquestionable for the anaesthesiologist and the surgeon. in our experienc e the procedure improves perioperative management of babies and appears to be safe. relation between cytokines, prethrombotic markers and endotelial injury markers in children with septic shock objectives: to establish the relationship between cytokines (tnf, il- , il- ) prethrombotic markers (d.d., pcam) and endothelial injury markers (tm, uwf) in pediatric patients with sepsis and bacteriemia without shock, and patients with septic shock. design and methods: prospective study, children ( months- years) were admitted in our picu in with the following diagnosis: bacteriemia ( ) sepsis ( ) and septic shock ( ) according to jacob's r f criteria. measurements: il- , il- , tnf, tm, vnf, d.d. pcam and routine laboratory data on admision, , , hours and on discharge. the prism (pediatric risk of mortality score) was also recorded. results and conclusions: two patients in the septic shock group died. significant differences were found between non-shock and septic shock patients in relation to tm, dd, pcam, il- , il- and tne high levels of tnf and il- are closely associated with the severity of septic shock with purpura in children. low levels of pcam on admission were associated with severe shock. who underwent open hea~nt surgery, hypervotaemia with or without oliguria was the most frequent reason to start pd ( %). in patients pd lasted less then one week and there were no complications; in patients it lasted - days (one child had a peritonitis). instillation of dialysis fluid into the peritoneal cavity was associated with a significant increase in central venous pressure. there were no significant changes in cardiac output or arterial oxygeu saturation. in all patients pd dhnjnished fluid overload or improved the metabolic status. patients ( %) survived the postoperative course and all had complete reintegration of renal function. conclusion: pd is a useful method to treat the fluid overload and acute renal failure in paediatric patients following open heart surgery with file effects of little importance on the cardiovascular fimction. obieetives: with the marketing of computerised systems for lung function testing in newborns, there has been an increasing interest in clinical approaches. percentile curves of pulmonary parameters permit an appropriate and clinically useful interpretation. however, the manual evaluation of the results using different curves is an impractical technique. therefoi'e a computer programme was developed. methods: the percentiles ( %, %, ~ %, %) of the most important pulmonary parameters were determined non-parametrically in weight-classes. for the calculation we have taken results of our own as well as other laboratories using a meta-analysis of reference studies. in all, individual data of - healthy newborns ageing between - days were collated. using these percentiles, for every parameter in relation to the body-weight the cumulative distribution was calculated approximately using piecewise linear and exponential functions. as shown in the figure the results of computing are represented numerically as well as graphically and can be included in the patient report. conelusions: clinic~d experiences with the programme have shown that representation of all measured parameters on standardised % scales allows an easy interpretation at first sight and improves the detection of pathologic patterns in the parameters. ")supported by bmft, fp "risikoneugeborene" prism (pediatric risk of mortality) score is a well known, already validated scoring system that quantifies severity of illness based on routinely clinical and laboratory variables measuring physiological instability. once computed the score by summing up the weights corresponding to the most abnormal value recorded during the first hours, the overall risk of mortality can be predicted by using the coefficients estimated by a logistic regression where prism score is the main independent variable. (pollack mm et al, -pediatric risk of mortality (prism) score. crit. care med. ; : - . to assess the applicability and validity of prism in the italian setting we launched out a prospective data collection in a sample of pediatric icus. measures of calibration (goodness of fit statistics) and discrimination (receiver operating characteristics and area under the roc curve) are planned to be adopted in the cohort of patients recruited during year period. as the validation study started on july , data collection is still on going and validation analyses will be carried out on july . up to now centers recruited cases. at present, characteristics of the sample recruited are the following: most of the patients were male ( %); the mean age is years with % of patiens having less than days; more than half were medical cases ( %) admitted from emergency room or from hospital floor ( %); % cases were admitted with an organ failure while % to be intensively monitored. icu-mortality was l %. the paper will present final results of calibration and discrimination analyses that will be carried out in the whole sample and across subgroups known to differ in terms of clinical relevance and prognosis. if calibration and discrimination assessment will produce not satisfactoty findings, a customization of the current coefficients will be made allowing a formal comparision of previous and new parameters. jf riera-faneao, m wells, j lipman. baragwanath intensive care unit, university of the witwatarsrand, south africa. [background the prism score is designed to assess the likelihood of death in ipaediatdc icu patients, using only acute physiological disturbances, age and [operative status to predict mortality. there is no evaluation of chronic health status, [including malnutrition. this may significantly affect its ability to accurately predict outcome in a population where malnutdtion is common. aim to determine the influence of nutritional insufficiency, as indicated by a low weight-for-age on outcome prediction by prism. patients & methods we analysed prism, weight and demographic data co ected prospectively from consecutive paediatdc icu admissions over a year pedod. a proportional weight (pwt) was calculated as a percentage from the th centile of the who weight-for-age growth charts. the pwt was compared for survivors and nonsurvivors, and mortality compared for pwt categodes nho wellcome classification). multivariate statistical techniques were used to identity associations with non-survival and to develop a modified logistic regression equation including a measure of i nutdtional status. receiver operating characteristic (roc) analysis was performed including and excluding patients with low pwt for the odginal and modified equations. results non-survivors had a lower weight than survivors ( . kg and . kg medians p = ) a lower pwt ( % and % medians p = . " . the incidence of malnutdtion , in our icu population was %. the mortality of manoudshed patients was' significantly increased (p = . ), with a good correlation with the degree of malnutrition. the accuracy of prism was significantly improved when malnourished patients were excluded from the analysis (roc value increased from . to . ). ! logistic regression and discriminant analysis identified a significant association between prism, pwt and outcome; age and operative status were not significantly related to mortality. the use of a modified equation including the raw prism score, pwt category and age can significantly improve the discriminatory power (az dm/elopmental sample . , az validation sample . ). the modified formula is: legit = - . + . *prism score - . *age + . *weight category, where the probability of mortality is exp(iog/t)/ + exp(iogio. discussion although we can improve the prediction of mortality by a modified or recelibrated formula, this still does not compare with the reference prism population. the need for validation of the score itself, in the association with outcome of the acute physiological variables themselves, is thus apparent. we conclude that while the odginal prism formula can be improved significantly, a modification of the basic variables in this and other third wodd populations may be essential. a high incidence of malnutrition is an independent risk factor of mortality, and an important cause of the poor discriminatory performance of prism. in order to improve the accuracy of prism, nutritional status should be taken into account. objectives: to assess the value of inhaled no to differentiate between pulmonary vascular constriction or fixed anatomical obstruction. methods: we assessed the response to ppm inhaled no in patients( m, f, median age . months, range day to years) with signs of increased pulmonary vascular resistance, there were pre and postoperative patients. patients were divided into responders(+) or non-responders(-). a positive response was defined as a % reduction in pulmonary arterial pressure and pulmonary vascular resistance(pvr) or in the presence of a left to right shunt, a fall in pvr accompanied by increasing pulmonary blood flow. left atrioventricular valve atresia + mustard pat: pulmonary atresia vsd: ventricular septal defect asd: atrial septal defect pda: patent ductus arteriosus tapvc: total anomalous pulmonary venous connection the responders( / ) were characterised by left to right shunts or pulmonary venous hypertension( / ). patient# was weaned from ecmo with inhaled no. patient# , without congenital heart disease, underwent a lung biopsy which confirmed reversible pulmonary vascular changes. patient# had a pulmonary hypertensive crisis which responded to no. all non-responders( / ) had evidence of anatomic obstruction to pulmonary blood flow (# , , )or a low pvr(# ) on subsequent cardiac catheterisation. in patient # , lung biopsy confirmed severe obliterative vascular disease. conclusions: inhaled no appears to be an effective pulmonary vasodilator. a failed response may be evidence of either irreversible pulmonary vascular disease or a residual anatomical obstruction which may be surgically remediable in the postoperative cardiac patient. therefore, inhalation of no may be a useful diagnostic test to differentiate between fixed anatomical obstruction and reversible vasoconstriction. results: during these years, the incidence of sdra was . % of the total of admissions. the most common etiology was meningococcic septic shock. since , there is a decrease of its incidence. (from % to %) and an increase of pneumonia and immtmodeficiencies. mean age of our patients was , years ( % males, % females), total mortality by sdra was % and there is an increase up to % since mean time of stay of the dead was , days and , days those who survived. although during the late years we offer in the picu a better attendance quality to the patients with sdra and the mean stay is longer, both for those who die and for those who survive, mortality of patients with sdra have increased. the incidence of sdra secondary to the septic shock of a meningococcic etiology have decreased. on the contrary, the sdra secondary to infections by opportunistic germs in patients with congenital inmmunodeficiencies or acquired immuodeficiencies have a tendency to increase. in our series, this change of aetiology is the responsible for the increase in mortality. hospital infantil unlversitario "virgen de roclo". sevilla. espalqa aims:to assess the incidence, etiology, clinical course, sequelae and mortality of the patients admitted to a paedfiatic intensive care unit with the diagnosis of severe traumatism. material and method: cases of severe traumatism in children admitted to our icu in the period from january to june were reviewed. age of patient ranged from months to years, % were males. in our series, % of cases suffered traumatism due to a traffic collision and % had a fall from a considerable height. only in one case was traumatism due to violence to the child. we assessed the first assistance received in % of cases: where was it performed, interval of time since the accident, and steps taken. these data were also studied in relation to the latter evolution. results: % of our patients suffered cranioencephalic traumadsm (ct); in % it was an isolated picture and in % of cases was associated to other lesions. there was participation of thoracic and/or abdominal organs in % of cases. % of cases presented important maxillofacial involvement. only one case presented serious cervical medullar lesion. mortality in our series was . %. in . % important sequelae remained. all of these patients presented tepas on admission equal or lower than . % of those with traumatises had slight sequelae. . % of the total evolve towards healing. a polytraumatized child is a patient that benefits considerably of it admission in a paedriatic !cu. the rapidity in receiving first aid and its quality are essential to avoid sequelae and to make mortality decrease. after unilateral lungtransplantation % of the patients develop a lung failure with decrease of perfusion and increase of pulmonary blood pressure in the transplantated lung. the improvement of perfusion is an importent task in the postoperative period. case report: a year old girl with idiopathic pulmonary fibrosis received a left sided single lung transplantation. during the early postoperative period occured a higtter demand of oxygen and an increasment of the pulmonary vascular resistence in the left lung. the pulmonary ventilation and perfusion scintigraphy indicated in comparison with the right lung a reduced perfusion of only % in spite of a ventilation of % of the transplanted lung. to improve the perfusion of the transplant we administrated per inhalation prostacyclin in a maximal dose of ng/kg/min. the arterial blood pressure decreased but the perfusion continued nearly at the same level. during the following administration of ppm no in the respiratory air we achieved a significant reduction of the respiration pressure f~m to nun h and of the pulmonary arterial pressure. the perfusion in the transplanted lung increased to ca/of the total pulmonary perfusion. after days of administration with no we were able to withdraw the axtifical respiration without any following complications. conclusions: the perfusion of transplanted lungs is a major proble_r~ in the postoperative period. this case demonstrated the advantage of no towards the inhalativ application of prostacyclin. no showed a significant improvement of perfusion in the transplanted lung of a year old girl. results: a total of children with ards were treated with bovine surfactant (alveofact| cases were evalable. the median age was . years (range weeks to , years). in six cases ards was associated with pneumonia, in two cases with lung hemorrhage; in one case isolated ards followed hemihepatectomy. the first surfactant application was performed with a median latency of clays (range - days) after first symptoms of ards witha median doseof mg/ kg (range - mg/kg). in patients doses of surfactant were applied. during the hour before therapy, the median pao / fio -ratio was - . within min. after application of exogenous surfactant the pao / fio -ratio increased to with successive decrease over a period of hours to . accordingly, an increase in pao and oxygen saturation and (less significant) a decrease in ventilation parameters could be observed. analysis of broncho-alveolar lavage before surfactant application in children receiving repeated doses revealed in most examined cases either clear surfactant deficiency or pathological function. of treated patients survived ( of the , respectively). of the surfactant doses were applied in the surviving patients.conclusions: the application of exogenous surfactant in children with ards caused a significant increase in oxygenation, which declined over a period of - hours. the effect often could repeatedly reproduced, in one case after applications. the increase in oxygenation often allowed the reduction of fio and/or the inspiratory pressure. no side effects were observed after exogenous surfactant application.in many cases the application of surfactant wag too late after first symptoms of disease (median latency days). ards mostly due to pneumonia seemed to respond to surfactant therapy less well or not at all. permanent junctional reciprocating tachycardia (pjrt) is the most common incesant supraventricular tachycardia (svt) in children. it is usually drug resistant and its onset in early life has been associated with dilated eardiomyopathy. we report our clinical experience with patients detected antenatally and another diagnosed at months of age. method.diagnosis: negative p waves were detected in leads ii,iii and f, p'r > rp" and there was not warm-up at tachycardia onset.clinical records, ekg,x-rays, echo and holter were reviewed. ep studies were undertaken only with therapeutic purposes. results. in a year period patients under y of age fullfilled diagnostic criteria; were detected prenatally ( - weeks) and one was diagnosed at age mo. the fetuses had intermitent svt during gestation. all of them had pjrt in the first month of life at rates between and bpm. they were admitted to the icu but did not develop signs of heart failure. they were controlled with digoxine (d); d and quinidine; d and propafenone in to days. one was in sinus rhytm until age y; he then showed persistent pjrt over % of the day on repeated holters and underwent successful radiofrecuency catheter ablation (rfca).the other two patients showed initially a lowering of tachycardia rate followed by sinus rhytm for over % of the day (follow-up ran and y). the mo. old infant was admitted to the icu in severe cardiac failure. echocardiogram showed marked systolic dysfunction (shortening fraction %) treatment with digoxine, amiodarone and propafenone were unsuccessful despite lowering heart rate to ; rfca was performed at m. of age with restoration of sinus rhytm and rapid recovery of contractility. all patients were given atp at admission with transient ( to see) recovery of sinus rhytm. ff,s clinical course of pjrt is variable. atp is useful only as a diagnostic tool. initial treatment with digoxine + amiodarone or propafenone is adviced. rfca is a very useful therapeutic modality and can also be performed in young infants twelve patients ( %) died. these were meningitis, head injury, sub-arachnoid bleeds, status epileptieus, leukaemie, drowning, and multiple trauma. calculated from the a admission day p edialric risk of mortality score (prism), the probability of death (p) ranged from - %. of the deaths, i were predicted by prism analysis except for the leukaemie patient (p i%) who died from haematological complications following chemotherapy. two children predicted to die (p % & %) survived. the median length of stay was days (range - days). patlents( %) received ventilatn~ support and patienta( %) were transferred to specialist units ( neurosciences, liver, cardiac, bums). this data supports the view that many paediatric patients are being adequately treated in a dgh icu. meningitis and other neurological illness caused the majority of deaths and respiratory problems caused most admissions. most deaths ( of ) occurred within a few hours of admission. ectopic junctional tachycardia (ejt) is one of the most dangerous arrhythmias in the postoperative setting of congenital heart defects since it does not respond to antiarrhythmics or defibrilation. the object of this presentation is to report on two patients who presented f_jt in the early postoperative period and developed intense congestive heart failure which could be controlled after treatment with moderate topical hypothermia. two patients, m and y, diagnosed of atdoventficular septal defect and tetralogy of fallot developed intense heart failure in the early postoperative period. taehyeardia rate was and bpm. medical drug therapy included weaning from vasoactive drugs, iv digitalization and iv amiodarone treatment. there was not response. they were both surfaced cooled by placing plastic bags filled with cold water over the patient's chest and abdomen. temperature was monitored to obtain a central temperature of ~ there was a gradual decrease in heart rate in the following hours ( - bpm) paralel to the degree of surface cooling and clinical course estabilized.both recovered normal sinus rhytm in to hours. there were not significant arrhytmias after the procedure and postop, was uneventful. conclusions. moderate hypothermia is a very useful manuever for the treatment of drug resistant ejt. since it lacks side effects of other antiarrthymics we beleave it should be the treatment of choice for the treatment of ejt in the postoperative patient. present understanding of the pathogenesis of sepsis, based on the theory of systemic inflammatory reaction, has risen new interest in the more invasive methods of treatment, like plasmapheresis, leucapheresis and exchange transfusion (et). obiectives: evaluate the effect of et in the treatment of neonatal sepsis. material and methods: from september to december , a prospective study was carried out, where the severest cases of bacteriologically proven neonatal sepsis (n= ) were treated with et. in total newborns were treated for culture positive sepsis in the intensive care unit during this study period. diagnosis of sepsis was based on the clinical criteria of suspected neonatal sepsis, used by mc harris et al., laboratory data and positive blood culture. newborns with severe congenital malformations were excluded. et was carried out with fresh (less than hours old) adsol-conserved erythrocytes, from which buffy coat had been removed, and same donors plasma, using a slow continuous two-site technique. the mean volume of et was . ml/kg. the effect of et was assessed as a change in the score for acute neonatal physiology (snap), general treatment results were compared with a historical control group of newborns, treated for culture-positive sepsis in the same icu during the first eight months in . students ttest and chi-square test were used in statistical analysis of the data. results: with the use of el a significant decrease in mortality was achieved: death of cases during the study period, compared to deaths among the controls (p< . ). no baby, receiving et, died. the incidence of severe complications did not differ in the two groups. the snap-score showed quick improvement by the first post-transfusion day (p<o. ) and the effect persisted during the five following days. conclusions: we conclude, that the use of et in the treatment of critical cases may help to lower the mortality of neonatal sepsis. it provides a quick improvement in the clinical condition of septic neonates. the granulocyte-colony stimulating factor (g-csf) is largely employed in granulocytopenic patients. experimental studies have' demonstrated the effectiveness and safety of the therapeutic use, nevertheless the human employ is reported almost exclusively in neoplastic patients submitted to chemotherapy and in patients with fungal or pseudomona~ spp infections. the authors report the data concerning three non granulocytopenic children: in the first, o girl years old, affected by pseudomomm aerug/n~a pyeionephritis, the antibiotic therapy was not tolerated in consequence of renal and hepatic failure. the second patient, an infant months old, has been treated with salbactam-ampiciilin, ceftriaxone and chioramphenicol because of haemepldlw iafluem~ meningitis; a late neurological aggravation required the antibiotic therapy recommencement the last, a years old insulin dependent diabetic boy, was affected by cared/do spp systemic infection; the antifungnl therapy w~ not practicable in consequence of renal and hepatic involvement in all the g-csf was administred subcutaneously at the'dose of $ u for days. a significant increase of granulocytes was ever noted already after the second administration until hours after the last dose. clinical signs, fever and biochemical values are promptly influenced positively and all patients are restored to health. no side affects were noted. the granulocyte colony stimulating factor, at indicated doses, can prove of great help in critical patients, in who the antibiotic or antifangal therapies can result toxye or cannot be tolerated. the ~reptococcas p~, among the gram pmltlve~ represents the main causative organism of bacterial meningitis in children, with the majority of deaths occurring within hours of admission, the third generation cepohlosporim were indicated as antibiotic of first choice, and some literature reports have demonstrated no significant dlffereuces in dinical course of patients treated with ce~rlaxoae and of those treated with ampieibin and chlornmphenicol. the authors report the ease of on infant, male, months old, submitted to a neurosurgical interventiol after days the infant became febrile and lethargic and a bacterial meningitis by ~trepmcecctz ~ was diagnosed, in spite of he was given the eoftriaxone therapy.. an amelioration was found only when a systemic treatment with vaucomyein was added. after days an intrathecal administration of vancomyein m~day was started: the norbmlization of the spinal fluid profile was uoted two days later and the infant receve~d progressively. the follow-up after eight months doem't evidentiate motosensorini sequelae-the individuation' of ~cscc~ pmmmsm/ae strains heta-loctam antibiotics resistant requires alternative therapeutic regimens: the k~terity quead vitam and quoad valetudinem of these infections justifies an intrathecal therapy, especially failing o prompt answer to the systemic treatment objectives: to evaluate the incidence of the burnout (bo) of the staff in a picu in a university hospital. the bo is a syndrome charactedzed by many factors like emotional stress, lack of personality and reduced work ability. this syndrome represents a kind of abnormal response in the working habitat, above all, where psychological and personal characters are mostly involved. the symptoms of bo are represented by demoralisation, demotivation, incapability, boredom, isolation up to organic disturbances, like migraine, insomnia, dizziness and gastrointestinal disturbances. the major incidence of this syndrome was found in the hospital staff, especially among the nurses, working in an atmospher of high emotional dsk, just like in an intensive care unit. methods: from january ' till april ' , all the staff of the picu of the a. gemelli hospital of rome, underwent a test to evaluate the bo. the test used was taken from the book "bumout: from tedium to personal growth", by pines and aronson. twenty seven people were studied ( females, males)i out of which doctors, residents and nurses. it was considered sign!ficant as mild bo, a score between - and as severe, the score of bo >. . results: subjects ( %) resulted positive for bo, out of which were females ( %) and were males ( %). the subjects with mild bo were / : was a doctor, residents and nurses. the subjects with severe bo were / , out of which resident and nurses. conclusion: the results obtained show that bo is a condition well represented in the staff of our picu. the category most at dsk seem to be the nurses ( subjects), as well as residents ( subjects), as in literature, which shows a major incidence of the syndrome in younger subjects and having a limited partecipation of functional decision. the results obtained obliged us to start a programme of serial controls so that the subjects most exposed can have a necessary psychological support to react adequately to this condition. the term systemic inflammatory response syndrome (sirs) was adopted by the consensus conference to denote a type of systemic response to severe infection or otherinsults in critically ill patients. when sirs occurs from infection it is called sepsis. sepsis occurs more frequently in persons with perexisting illness or severe trauma. there has been tremendous advances in prophylaxis, diagnosis, and treatment of sepsis. a comprehensive model of the disease progression from sirs to mods should be developed giving priority to severity of illness scoring system and other predictive methods. some recommendations for future clinical trials include: trials should not start with humans. before proceeding to human trials, animal studies should indicate an acceptable risk/benefit ratio. appropriate patient populations must be defined and treatment protocols should be standardized. full and rapid reporting of all results should be mandatory and a central repository of published and unpublished study results could be helpful. accrual at each center should be of sufficient size, and should include the number of patients accrued, mortality rates, and patient characteristics. pivotal trial should be preceded by sufficient pilot or phase ii studies. correct drug dosage and usage should be delineated in pilot studies. large, multicenter, trials should be used to enhance the unversality of trial results. analyses should be planned a priori. definitions for the target population should be explicit, reproducible, and include illness severity scores. outcomes should be relevant reproducible and include both measures of benefit and harm. mods and its reversal should be considered as an endpoint. quality of life should also be considered as an endpoint. the estimators of overall treatment effects should be controlled for base-line prognostic factors and subgroup anaiysis should only be used for hypothesis generation and not to modify the conclusoin of the trial. economic analysis should be included as part of clinical design. evaluatin of source control should be a critical component of any study. standardized clinical mediator assays should be pursued. placebo patients in clinical trials should be studied for a better understanding of the pathogenesis and epidemiology of sirs, evidence based medicine should be used to evaluate the validity of clinical. introduction: use of inhaled nitric oxide (no) as a modulator for optimizing ventilation-perfusion or lowering pulmonary artery pressure is becoming increasingly common. no is a free radical but little toxicological research has been published. clearance of nebulized mtc-dtpa is known to be, a sensitive indicator for early function impaimaent of the alveolocapillary barrier. we investigated whether exposure to no increased clearance of ~tc-dtpa from the lung. methods: three groups of white sealand rabbits (bw . kg) were anesthetized, tracheotomized and paralyzed. groups were ventilated for six hours at pressure regulated volume control, set to deliver ml/kg with a frequency of /rain, i/e ratio = : and peep = cm hzo using a modified servo ventilator (siemens, solna, sweden) with computerized no delivery system. gas mixture per group was either / or / [no (ppm) / fioz]. after six hours of ventilation in these groups and immediately after anesthesia in group (control), ~tc-dtpa was nebulized into the inspiratory line of the breathing circuit and administered as a fine aerosol. gamma counting was measured for minutes, monoexponential curves were fitted to the data and the clearance half-time (t was calculated. the t~/ mean • sd of the different groups were: t~a (mean -sd) h"e,i witl~ arf : di.ff:erent kinds, aged .q-ore mon't.hes to [ gears o : (bodi weight .~rom ., to kg), is presen .... "ed ( i,,~u::trl:e i:ibstraclive d:lse~se... ~ .ards'- ; :~,;,,arf o~ ::entral genes:i s .- , ,~ :inc lud ing men ingeenceph it :is- ~ reye ' s ~yrtdro~e-..#~,bri~:ln pes~.re~nimatior~ disease.." ). int:lrl~]. pa-. "iiulle'i,~s ariel regymes o+ l;mv,l;i"t"v were cle'l'.ermllled by ba- 'i~ier was. about . tuber,, dopamin tiara-:. t.io; was ~.".,,'.r:~r~led. cmv,cppv d~.!"~tion raniled -~rom f to dayns.,~ < .-:in , "t -irl lo;and> davs'-in 'l~atierr~{s i'i"ai s:ltiol~ o ; patterers to imv, simv modee was per.r:)rmed, ~herl pif:' decrease.d to - ml~ar, fi ~ecreased to , . lind less with a = /,,. i:lesq.lts:{ in pat:i.ents e{ group :l, who were tre,~d.ed w&th f'f'v, teoph :i. : . l:i.r~ (is- .mg/kg/day), g lucecdr t icostei~oids ( .... :~;mg/kg/day), when r exceeded in , -.];, times normal va i tea the e aqes/,'!:l"oln ~j,, ite :i.~;::.!;, ~ml"lrj), it was possible 't'(' ce 'e~ e aad]t:..~rom ! . '.' i', to !..'; , - , mml-lg in ~}.. :~.[~ houi,!; ~d'l(:i to ru:}l",g'd!~l:i. e i::h,:~e,'~c['el';i.stil obieetives : this chapter will describe what is knovca of the psychlogical responses of infant and children to hospiuiisation and attendant procedures. the factors which may modify these responses will he discussed and important considemtiorts will be outlined for optimal anaesthetic management and postoperative period of infants and children which will minimised the rise of emotional upset. methods : in this paper the autors will discttssed the probl of: . health children (asa i, ii) facing single uncomplicated surgical elective procedures . various abnormal situations including neurotic children, children facing repeted operations, chronically ill, buaaes and tsaumatically impired ones . unfortunate young patient facing and often expoclting fatal outcome from le "ul'ukaemia, tumors, cystic fibroses or otheq" disease. : management of each child must vary greatly, ifi general the phases of emotional conditioning include home and preadmissiun preparation, admitiun preoperated and operative care and postoperative period. the authors would be happy if the child passes all stages without any trauma which could be prolonged in the future life. introduction ino is used to selectively reduce pulmonary vascular resistan(~e. we applied ino in the postoperative intensive care of patients with pulmonary hypertension and the risk of right ventricular failure after surgical correction of a congenital cardiac defect. methods - ppm no were added to the ventilatory gas mixture using a specially designed equipment (messer-griesheim, germany/austria). indications for application included pulmonary artery pressure > % systemic pressure, critically depressed right, ventricular function or an oxygenation index > . assessment of n oefficiacy consisted of on-off-on measurements according to the clinical stability of the patient including hemodynamic parameters, pulmonary gas exchange, continuous monitoring of ventitatory function and transesophageal echocardiography of the right heart. results in situations ( patients, age days- , years), ino was applied - h postoperatively. oxygenation was improved in situations from _+ to + mmhg pc ; pulmonary pressure was reduced in situations from -* % to _+ % of systemic pressure. in situations, no reduction of pulmonary pressure was present, but measurement of cardiac output or echocardiographic analysis indicated an improvement of right ventricular function (right ventricular stroke volume + -* %, cardiac output + -* %). in situations (immediately postoperativ with suprasystemic pulmonary artery pressures [n= ], multi-organ-failure [n= ]), no response to ino could be determined. conclusions for a special group of patients, the selective reduction of pulmonary vascular resistance by ino has become an important part of postoperative therapy. using this selective afterload reduction, postoperatively depressed right ventricular function can be improved. this effect of ino seems to be the most important one in the postoperative period. thus, ino appears justified to be appfleo when impaired right ventdcular function could be improved even when pulmonary artery pressure is not raised or remains unchanged. obiectives : premature infant are exposed to danger of apaea due to anaesthesia during their tirst months of life. it is yet unknown whether prematurity is corelated to any other kind of reslgratory disorder due to anaesthesia within the tirst year of life. methods : we theretbre researched retrospectively for respiratory disorders in all infants under months of life belonging to asa group . they all had been anaesthetised in . in our clinic for the following surgical reasons: ingvinal haemia, umbilical haemia, hydrocelae testis and phymosis. results : in cases we tbund: lafingospasm during induction in anaesthesia ( , %), bronchospasm during induction in anaesthesia ( , %), impaired intubation ( , ~ postanaesthetic laringospasm ( , %), supposed aspiration ( , %),postanaesthetic inspiratory stridor ( , %), postinductional inngoedema ( , %), death after months in consequative of infection pneumonie ( , %), none of these disorders was correlated the prematurity, infants suffered of post anaesthetic apnea, of them had premature medical history. concludions : prematurity does not enhance the risk of respiratory disorders due to anaesthesia within the first year of life, except the danger of postanaesthetic almea needs spetial cosideration. it could be demonstrated that aepgi lowers pulmonary vascular resistance and indirectly improves cardiac function. this effect seemed to be selective, and was comparable to ino in the doses we have examined. therefore, aepgi could represent a clinically useful alternate to inc. however, further research is necessary to work up the benefits of either therapeutic strategy. objectives: heat and moisture exchange filtem (hme) are used as artificial noses for intubated patients to prevent tracheo-bronchial or pulmonary damage resulting from dry and cold inspired gases. furthermore they are used for the prevention of bacterial contamination of the anesthetic apparatus by the patient's exspired air. so they are considered as a time-and money-saving device in anesthesia. filters are mounted directly on the tracheal tube, where they collect a large fraction of the heat and moisture of the exspired air, adding this to the subsequent inspired breath. the effective performance depends on the water-and bacteria-retention capacity of the filter. this study evaluates the efficiency of four different filters under clinical conditions. methods: four different types of filters ( dar hygrobac, gibeck humidvent, medisize hygrevent and pall bb ) were investigated dudng mechanical ventilation over a pedod of hours. minipigs with hemorrhagic shock were intubated and ventilated for days in an animal intensive care unit (icu). after hours of mechanical ventilation the filter was randomly replaced maintaining the individual ventilatory conditions. the weight of the filter was determined before use and after removal after hours. the airway pressure was monitored online to record changes during use. tracheal secretions and both sides of the filter were microbiolologically tested to see whether bacteria of the animal's respiratory system could be found on the patient's side of the filter or if they even would have penetrated the barrier. results and discussion: over a pedod of hours of types of filters showed an increase in weight of + % and airway pressure. bactedal celonisation ccured in nearly all fillers ( of ) on the patient's side, whereas only three of four types of filters showed identical bacterial colonisation on both sides. the only filter that did not show bacterial penetration, increase in weight or airway pressure was the pall-hme, a condensation humidifier without hygroscopic salts for moisture retention. with respect to our data one should use a condensation humidifier if airway conditions should remain stable dudng mechanical ventilation and desinfection of the anesthetic apparatus should be avoided after each patient. aim: to assess the clinical uses of, and experiences with, the hayek oscillator. this is a non-invasive device capable ef delivering not only continuous negative pressure (cnp) but also external oscillatory ventilation around a negative baseline (eov-nb) using an external cuirass. this type of ventilation avoids the need for intubation and intermittent positive pressure ventilation (ippv) and facilitates weaning in ventilator dependent patients. patients and methods: patients in respiratory failure, age range weeks to years in a total of patient episodes were treated using either cnp or eov-nb mode. duration of treatment varied from hours to days. indications for use ef the device were: ) to facilitate weaning from ippv ) prevent reintubation of patients following unsuccessful extubation, and ) avoid intubation and ippv altogether using the hayek oscillator as the on[y means of respiratory support. results: there was an increase in pao :fio ratio after cnp and eov-nb (p < . , and p= . respectively, wilcoxon signed rank test). patients who were in respiratory failure with hypercapnia showed a statistically significant reduction in paco both with eov-nb and cnp (p= . and p= . respectively) but the magnitude of change was individually greater in the patients who were treated with eov-nb. all patients, however, showed a fall in respiratory rate (p< . ) after the application of the cuirass in cnp mode. there was no physiological deterioration related to the application of external extrathoracic negative pressure in either cnp or eov-nb modes. conclusion: the improvement in pao :fio , the fall in paco and respiratory rate were indicators of an improvement in ventilation. the proposed mechanisms include improvement in frc, recruitment of additional alveolar units, and improvement in secretion clearance resulting in reduction in the work of breathing. meek to ~ month of the lifo,the bemodyuanicfacls were defined uitb the help of tetropolar reography method!. the excretion of !he catbocholauines fcfi] mith the urine gas detertend by taylor ll,laoorsy ~ iacg/dayl. hsaltl in the hypercuagulation stage of bic we deflorteeed the acliuutiun of the tbrubio and plasiin syaet~ mitb the increase of the inhihitnrs, in this case we registered in full uahe dot this process coabined uitb the dayl~ excreliou with lho urine epinopbr ne e], nor~pinopbr no tel and dophanine io], lbat shod the inlensificatiou of the s~nthosis prnoe-s~es and the release of ea in blood fron hissue deport the actffat on of the svnpathadrenui systen ]sfisl assisted to furl the b?perd~nanical rosins of the eircuidion and increase the ,icrocirculatinn, the klinicai sings of the insufissieutly of the circulalion have not defined,that has been associated the conpensatury character uf the ehan~es of ~ and heludy~enic status, t~e uun~u|p-lion ceugulupatby bus been donoustraled in the hypocougulatien stage ~bat man xauifosted b the exhaust of lhe confulalion nod oessel-platel heuostasis, the consuxptton of cnnpononts tbronbln ,plnstin, kallek~eiu-kinln s~slots and the forniration eat in fell canoe clot uas accoqaued bs docrea,e of fl,nfl,o, the products of the xotabolisx of c~ and the activation of xonoaninoxydasu. the decrease of the extoll'on g and the exhaust deport co indicahd about t!e ]ou fund/anal reserve of ~fl~. it was one of the lain reason of ~bo heiod~uanic disbroed iheat insnfissient]~] and the uicrncireulaflion lintestinal codeme with the low effectife periferal flow] and nul[iplay organ failure,the distrued deport of sos mitb throubocytupenin no; be one of the nechanisn the dislrood of uessej-plalol heioshasis, the correlation bolueeo changes of boiostosis c~ and circulation ore reguired aduinistration nedidns, thai reslore the love s of c~ in the blood, prevent uulliplay organ failure and hetorrnge in children with sepsis, ~b~ectives: multi-measured correlative analysis of the most number of non-invasive indices of the cardiorespiratory system function was made to determine the structure of their interrelation and the ways of their adequate and effective correction. hethods: spiremetry, capno~raphy, oxygenography, indirect fick method at recurrent respiration, plethysmography, integral rheography -in all indices were used. the received data were processed on a computer by a standard package of statistical bmdp programs. results: women with ~h-gestosis (i group) and somatically healthy pregnant women (ii group) were studied. cluster analysis has shown that the rate of the mean correlation connection between ventilation indices was % in the ist group and % in the iind group; gaseous metabolism - % and %, respectively; central hemodynamics was ~ in both groups. conclusion: cluster interpretation allowed to suggest that an increase of the rate of the mean correlation connection between the indices was characteristic of effective adaptation as the system was multi-component and well-regulated. on the contrary, the increase of the rate of strong correlation connection between the indices reveals the rigidity of the system and the tensity of adaptation mschaniams, i.e. the proximity to decompensation. it follows from this that in cases of eph-gestgsis, the reliability of regulating ventilation and gaseous metabolism decreases. seve/e hypoxemia in non intubated patients represents a major contraindicafion to fiberoptic bronehoscopy (fob) and bronehoalveolar levage (bal), but these procedures are often required for a correct diagnosis of the causative agent of pneumonia. aim of this investigation was to veaify the safety and efficacy of bronehoseopic procedures during pressure support ventilation administered through facial mask (fm-psv). five intensive care patients, all immunoeompromised, ( males and females; mean age . • were enrolled in the study. all patients presented criteria for pneumonia with pao /fio ratio ~ and were responders to fm-psv. fob and bal were performed afte~ topical anesthesia with fm-psv ( ps = em h ; peep = emh ; trigger = -lemh ) continuously admires" tered ( ' before fob fio = . ; during fob, fio = and for ' alter fob, fio = . ). pao /fio ratio as well as saturation (sat) did not show signifteative changes during the procodure (fig.l) . no complication was observed and hemodynamic conditions were stable for all patients. cmv, pnenmoeystiis ( ), legionella and mycobaetermm tuberculosis were identified from bal allowmg a prompt and targeted therapy. we concluded that mask psv can represent an excellea~ technique to pexform fob and bal in severely hypoxemic patients without deterioration of gas exchanges and avoiding endotraoheal intubation. intensive care unit, hospital general of albacete, albacet~ spain. objective: to analyze the current incidence and epidemiology of total parenteral nutrition (tpn) among critically ill patients placed on mechanical ventilation. design: prospective observational study. setting: medical intensive care unit in a tertiary hospital. patients: a total of consecutive l'ritically ill patients with non-coronary related disease needing mechanical ventilation admitted in our icu during a months period. measurements: data of sex, age, diagnosis, and outcome were recorded. severity of illness and therapeutic effort in the first hours were measured using acute physiology score and chronic health evaluation (apache ii) and therapeutic intervention scoring system (ties). r~ults: mechanically ventilated patients, male and female, were studied. only ten patients needed tpn and their main diagnoses were: five cases of multiple organ failure secondary to pneumonia ( ), ards ( ) and septic shock ( ); two eases of acute panereatitis; and one mesenteric throngmsis, one status epilepticas, and one ,prolonged cholinergic crisis b~ suicidal organophnsphate insecticide subcutaneous injection. no statistically significant differences between both tpn and non-tpn groups were found: objectives: evaluate the efficacy of prone position in ards and determine its importance in the therapeutic algorithm. methods: consecutive patients with severe ards (murray-score > , ; pao / fit < mmhg; male, female, mean age years) were conventionally ventilated (pcv, peep - mbar, i:e=i:i, ppeak < mbar). if after hours pulmonary function did not improve patients were placed in prone position. change from prone to supine position was done every hours. beside ultimate survival, parameters investigated were aado , pao /fio , and venous admixture (qs/qt). results: during the first hours in prone position of patients showed a significant decrease in qs/qt ( . % vs. . %) and aado ( vs. mmhg), and an increase in pao /fio ( vs. mmttg). changes were most pronounced in patients with high qs/qt, and in patients with an onset of ards less than hours before first application of prone position. after an average of position changes ( to ) of patients could be weaned from the ventilator. patient could leave tile hospital. i the later course letality was primarily determined by additional organ failures and by the severity of the underlying disease. negative side effects were minor, including slight cardio-vascular depression and increase in p~co , and never posed a limitation to continuation of prone position. especially in patients with septic shock skin lesions in exposed areas could not always be prevented, prone position could easily be combined with all ventilation modes and with all intensive care interventions. also immediately after major surgery and in patients with open packing prone position was possible. conclusions: in this investigation prone position proved to be an efficient and safe method in the treatment of severe ards. patients with a pronounced ventilation/ perfusion mismatch and patients in the early stages of ards appear to profit most from prone position. though the immediate effect on oxygenation is striking, still more the % of all patients die from multi organ failure and underlying diseases. a proposed therapeutic algorithm for ards is as follows: if under conservative ventilation (pcv, peep < mbar, ppeak < mbar) pulmonary function does not improve within - hours prone position should be applied. when after - position changes no lasting effect can be achieved further ventilation modes (e.g. pc-irv, aprv, no, etc.) should be used in addition to prone position. standard intensive care principles, such as fluid restriction and optimization of circulation, apply also to patients in prone position. objectives: nitric oxide reacts with superoxide to form peroxynitrite, an extremely reactive and toxic species. we quantified the presence nitrotyrosine, the stable product of the interaction ' of peroxynitrite with tyrosine residues in the lungs of pediatric patients that died with respiratory distress syndrome (rds). methods: paraffin embedded lung sections, obtained at autopsy, were incubated with a polyclonal antibody raised against nitretyrosine, followed by a secondary fluorescent antibody. alveolar structure-associated fluorescence was quantified using existing methods. results: tissue sections from patients who died with rds exhibited significant specific immunostaining which was uniformly distributed across the blood-gas barrier. in contrast only background levels of fluorescence were seen in the lungs of patients who died from non-pulmonary causes. intense staining was also seen in the lungs of rats that breathed % for h, a condition known to result in rds-type illness; no immunostaining was observed in air-breathing rats. conclusions: significant levels of peroxynitrite may be formed in the lungs of patients with acute lung injury. peroxynitrite may be contributing to the pathology of rds by damaging key components of the alveolar epithelium including the pulmonary surfactant system. mechanical ventilation time was prolonged ,g • days in patients with ardsvs , _+ l, days in control . mean staylcuwas lg _+ ,g days in the ards group vs , • , days in control group postoperative mortality rate was % in ards patients vs , % in those without respiratory failure. -ards incidence in liver transplantation is low ( , % in our sene) but it causes high mortality ( %) page, gas ventilation of the perfluorocarbon-f'dled lung, supports gas exchange and circulation in small animals (< kg) with lung disease. we hypothesized that large animals could be supported by page without adverse effects on bemodynamics. we first elucidated the determinants of gas exchange in normal sheep, and applied them to a model of adult respkatory distress syndrome (ards). methods: using the ventilator settings determined to be optimal in our pilot study (fio of . , peep of cm h , imv of bpm, it of %, and tv of ml/kg), sheep weighing . ~ . ) kg had lung injury induced by instilling ml/kg of . n hc into the trachea. ten minutes after injury, sheep with pao < ton" were randomized to continue gas ventilation (control, n= ) or to institute page (n= ). page was instituted by instilling . l of unoxygenated pefflubron into the trachea and resuming gas ventilation at the previous settings. abg's were drawn at baseline, minutes after injury, minutes after injury, and then every minutes for hours. objectives: inhaled nitric oxide (no) can improve oxygenation and decrease mean pulmonary artery pressure (papm) in hypoxemic patients with ards. in severe hypoxemic copd patients, it is not known whether inhaled no can exert a similar effect on hemodynamics and gas exchange. therefore, we investigated die response of inhaled no in hypoxemic copd patients and the results compared with those obtained in a group of ards patients. methods: ten copd patients (age _+ y;fev~ . _+ . l) and ards patients (age _+ ; lis . _+ . ) mechanically ventilated were studied. hemodynamic parameters were measured using a swan ganz catheter. arterial and mixed venous blood gas determinations, sao , svo , hb and methb were measured (abl ,osm ). mean intratracheal concentrations of no and no were continuously monitored using a chemiluminescence analyzer (nox ) . during the study the ventilatory pattern and fioz were kept constant. the protocol was for ards group: basalt, no loppm, basal~; copd group: basalz, no lo ppm, no ppm, no ppm and basal . after a steady state of rain hemodynamic and gas exchange measurements were performed. a positive noresponse was defined as a % increment in pao . results: papm was similar in both groups and decreased significantly after no (ards, basal . _+ . mmhg, no . + . mmhg, p < . ) (copd, basal . _+ . mmhg, no- . _+ . nrmhg, p< . ). all other hemodynamic variables remained unchanged after no. basal oxygenation was higher in copd group (paojfio _+ mmhg) vs ards group (paojfio _+ mmhg)(p< . ). after no- , pao increased ( _+ mmhg to _+ mmhg, p< . ) and qs/qt decreased ( + % to _+ %, p< . ) only in ards group. in both groups, significant correlations between basal papm and inhaled no-induced decrease in papm were found. inhaled no-induced increase in pao /fio was not correlated with basal paoflfio . no responders were / ( %) in ards group and / ( %) in copd group (p< . ). conclusions. in hypoxemic ards and copd patients, inhaled no decreased mean pulmonary artery pressure. however, oxygenation only ameliorated in ards group because die number of responders to inhaled no were higher in ards group and this effect seems not to be related to the basal hypoxemia. these results might be explained by the v/q abnormalities present in copd patients. grant fis / . objectives: it has been recently reported that expired con slope as a function of time is modulated by total respiratory system resistance (rrs) in critically ill patients (chest ; : - ) . in this study, we analyze the relative contribution of disease (dis), endotracheal tube resistance (rtube), airway resistance (rmin), additional resistance (~rrs), autopeep (peepi) and dylmmic/static elastance (ed/es) to the co elimination in different clinical conditions. methods: we have studied adult patients ( controls, acute respiratory failure, severe ards and copd) mechalfically ventilated (servo and c, siemens) without peep. we recorded tracheal pressure, airflow and capnograms. signals were analogic to digital converted for posterior data analysis. objectives: alveolar ejection volume (van) can be defined as the fraction of tidal volume (vt) with minimal dead space (vd) contamination. according to the classical paradigm: limvd_~ [vco /vt] =facoz, vco vs vt relationship tends asyntotically to a constant slope when approaches end-tidal volume. we have defined van as the volume that defines this relationship until a limit of % variation. methods: six subjects with normal respiratory mechanics were studied during anesthesia for minor surgery. two subjects, otherwise normals but having high values of total resistance and dynamic compliance, were also studied. capnograms were recorded in steady-state at levels of vt ( . , . and . l) and four levels of peep ( , , and cmh objectives: patients with ards presented lung abnormalities which originate an increase in airway resistance (rmin), in additional resistance (~rrs) and in static elastance (ers). application of peep further increases ~rrs. capnographic indexes reflect lung ventilation]per fusion inhomogeneities. in these conditions, the effects of peep on lung mechanics could be better understood by simultaneous measurement of capnographic indexes. methods: we studied groups of subjects. n: normal subjects scheduled for minor surgery; arf: critically ill patients with mild acute respiratory failure; ards: patients with early ards (< h). we recorded tracheal pressure, airflow and capnograms. signals were analogic to digital converted for posterior data analysis. respiratory system mechanics was assessed by constant end-inspiratory and end-expiratory occlusions technique. at equal tidal volmne ( . l) a peep level of , , and cmh was applied in all patients. we calculated ers (cmh /l), rmin, c~rrs (cmh /l/s) and autopeep. capnographic indexes were alveolar ejection volume (vae)/vt ratio and expired co slope beyond vae (sipco in contrast to synthetic surfactant natural suffactants (alveofact| are able to inhibit pmn-activation. after incubation of activated neutrophils with surfactant, l-selectin expression is decreased. these effects depends on which preparation is used. we conclude, that natural surfactant (aveofact| can perhaps influence early recruitment (,,rolling") of pmn in patients with respiratory failure like ards. with ards hormann cb, baum m, putensen c, knapp r, lingnau w, putz g . clinic for anesthesia and general lntensiv care medicine, university of lnnsbruck, anichstrabe , innsbruck objectives: in thoracic ct scans of patients with severe ards atelectasis and pleural effusion can be found in the dependent lung regions. by rotating these patients from left lateral position to right lateral position a redistribution of the ct densities, a recruitment of atelectasis and therefore an improvement of gasexchange is possible within a few days ( , ). the objective of this study was to find out the mechanism of alveolar recruitment during lateral positioning by ct scanning in left and right lateral position. methodes: after approvel by the local institutional reviewboard we investigated ventilated patients with severe ards (entry criterias: murray score > , ) in the ct scann of the university hospital. after a stabilisation period of minutes in supine position a thoracic ct scan slice cm above diaphragm was taken. then two different positions of the patients were studied in a randomized order: a) degree of left lateral position, b) degree of right lateral position. each lateral position was held for minutes. at the end of each of these periods a thoracic ct scan slice cm above diaphragm was taken. quantitative analysis of ct scan data was based on the frequency distribution of the ct numbers. to quantify the alveolar recruitment during lateral positioning by means of ct scan we defined compartments within the lungs: a) normaly inflated lung, b) poorly inflated lung, c) noninflated lung ( = atelectases) ( ). results: independant of the side of lateral positioning (l) in the non-dependent upper lung a significant increase of the normaly inflated compartment (s: %; l: %) as well as a significant decrease of the noninflated compartment (s: %, l: %) was observed in comparison to supine position (s). in the dependant lower lung the normaly inflated compartment decreased significantly (s: %, l: %) whereas the noninflated compartment increased significantly (s: %, l: %). throughout the whole studyperiode we did not observe any significant change regarding gasexchange and hemodynamic parameters. conclusions: in lateral position the non-dependent upper lung is decompressed. therefore a significant recruitment of atelectases is observed in the upper lung within minutes. on the other hand the dependent lung is compressed by the weight of the upper lung and the mediastinum. a great amount of the alveoli of the dependant lung collapse in this short time intervall. therefore the net effect of recruitment of one positioning maneuver is very small. when positioning patients one should be aware, that the patient is kept in each lateral position long enough to clean up the atelectases in the non-dependant lung and short enough to compress less lung tissue in the dependant lung. objective: to analyze effects of low-dose no inhalation ia patients with severe aeut~ respiratory distress syndrome (ards) over five days. methods: we prospectively studied patients ( men, woman) with severe ards admitted to our icu between may and may who required no inhalation with a dose of ppm for at least days. entry criteria for no injaalafioa were murray score >i . aud pat/fie < nun hg with peep >~ em i~o for at least hours. all patients were sedated, intubated and mechanicauy vantil~ed with volume assist-control ventilation, and had indwelling arterial catheters (pulmonary artery, and radial or femoral artery) to measure cardiac output (by thermodilufion) and relevant intravaseular pressures, and to calculate derived parameters. no was administered between y piece of the ventilator and endotraeheal tube and flow was adjusted to obtain ppm no in the inhaled gas. the no, no and no x concentrations were continuously measured at the distal end of the endouacheal tube by the chemiluminiscence method (nox , see-seres, france). metahemoglobinemia levels were mesured daily. no inhalation was manteined if paojfio ~ improved at least % and was stopped when the change in pao /fio ~ was below % or when the patient presented a paojf > mm hg a~er minutes without no inhalation. every day we made an on-off test to determine if no inhalation improved pao /fio ~. statistics: analysis of vmiance. data: mean + standard deviation. results: the mean age was . +_ . years and mean lung injury score was . • . . mortality was % ( / ), metahemoglobinemia . • . %, and no concentrations zero. paojf~o always improved significantly al~er ppm no inhalation (see :~ conclusions: reintubation in salf-extubated patients strongly depends on the type of meehamcal venfilatory support: the probability of needing a reintabation ff ese occurs during fult vontilatory support is higher than ff ese occurs during weaning. these data suggest that some patients may remain under weaning from mechanical ventilation for unnecessarily prolonged periods of time. objective: the aim of this study was to evaluate the acute effects on gas exehonge and hemodynamics due to positional changes from supine (sp) to prone (pp) in patients with severe acute respiratory distress syndrome (ards). methods: nine intubated, sedated, paralyzed and mechanically ventilated patients with severe ards were prospectively studied. all had a murray score > . , and a pao /f~o < with peep ~ cm h for at least h. all patients had indwelling arterial catheters in the pulmonary artery as well as in the radial or femoral artery in order to measure cardiac output (by thermodilution) mad relevont pressures, and to withdraw blood samples. arterial blood gases and hemodynamie parameters were measured first in sp, and then in pp after minutes of stabilization. vontilatoly parameters remaing unchanged during all the study. statistical analysis was done by the non parametric wdeoxon test. data are expressed as mean ~= sd. results: there were men and women with a mean age of . years ( - ) and mortality was % ( / ). main results are shown below: objective: to describe and compare a new method for obtaining p-v loops (p-vcv) by using a two-way collins valve (twv) with thosu obtained by the supersyringe method (p-vss). methodology: we prospectively studied patients who had an aeute lung injury and were intubated, sedated and paralyzed, and mechanieany ventilated. we performed the p-vev loops and p-vss loops in random order, and the static inflation pressure was limited to emh with both methods. pressure (p) was measured at the airway opening by means of a differential p transducer, and volume was obtained from flow (measured with a pneumotacograph) integration. the p-vse method has already been described (h~trf a,et al.bepr ; : - ) . the p-vev method consists in the following: the inlet of a twv is connected to the ventilator's y-piece, and both outlets are couneeted to the endotraeheal tube by means of an additional y-piece; one of this outlets has a one-way rudolph valve in order to allow inspiration but not expiration during the inflation maneuver. changing the twv tap position allows basal ventilation or progressiveinflation of the respiratory system. this maneuver is as follows: during an end-expiratory occlusion, the ventilatory settings are adjusted to deliver a ml v r with a respiratory rate of /min and i/e ratio : ; at the same time the twv tap is ehonged in order to divert flow through the one-way valve. inflation then begins alter releasing the expiratory oonlusion. pressure and flow signals were digitized and acquired by a computer for subsequent data analysis. we analyzed the following parameters: inflation compllonee ( objective: to analyze the variables which eventually may differentiate ards patients who do and do not respond to low doses of inhaled no. we prospectively studied patients ( men, woman) with severe ards admitted to our icu between may and may who were treated with no ( ppm). the onta'y criteria for no inhalation were murray score >/ . and paojfo z < mm fig and peep >/ cm i~o for at least hours. all patients were sedated, intubated and mechanically ventilated with volume assist-control ventilation. tidal volume was between and ml&g, with constant inspiratory flow, respiratory rate was - /rain, and i/e ratio between : to : . all patients had indwelling arterial catheters (pulmonary artery, and radial or femoral artery) in order to measure cardiac output (by thermodiintion) and relevant intravascular pressures, and to calculate derived parameters. no was administered between y piece of the ventilator and ondotracheal tube, and flow was adjusted to obi~a ppm no in the inhaled gas. the no, no and no x concentrations were continuously measured at the distal end of the endotracheal tube by the chemilumiinscenee method (nox , see-seres, france). metahemogtobinemia levels were measured daily. we considered a response to no inhalation when an improvement in paoz/fo above % was observed after the inhalation of ppm no (group r) . when the cha~age in paojfi z was below % it was considered a lack of response (group non-r small airways functional abnormalities have been recognized as a common feature of lung pathology. however peripheral airways contribute relatively little (~ %) resistance to flow and there disturbances can not be adequately estimated by conventional measurements of respiratory mechanics. the purpose of the study was to evaluate the relationship between raw and small airways conductance following weaning from ventilator methods. patients (age: - years; males) with no serious complications al~er mitral or multiple valves replacements and with more than hrs on mechanical ventilation have been enrolled in this study. the modified flow interrupter technique (ptg "gould" with fleish head # ; differential pressure transducer pm- -tc "statham" w amplifier "kistler ") and flow-volume recording of forced expiration (fleish head # ) have been applied before surgery and following operation on mechanical ventilation (my), after extubation (t:xtijb), on ( nay) and ( day) days. airways specific conductance (sg aw) has been calculated as a mean of - consequent measurements in each patient at each stage. the sac was estimated by max expiratory flow at and % of vc on - f-v curves (mef .~ , mef ) all the data were statistically analyzed with t-test introduction : noninvasive ventilation (niv) reduces the need for endotracheal intubation, the length of stay in icu and the mortality rate in acute exacerbation of copd. however, some patients failed to be ventilated with niv. .objectives...; to further delineate patients who failed to be ventilated with niv and to obtain predicted factors of failure. patients : a cohort of patients ( • years) presenting with acute exacerbation of copd (fevi: • ml, paco : • , ph: . • . ) and nonmvasively ventilated (pressure support through a full-face mask) between april and may twenty-seven ( %) were successfully ventilated with niv (discharged alive without the need for endotracheal intubation) while ( %) failed, requiring endotracheal intubation. .methods : patients successfully ventilated and those who failed were compared according to respiratory and nonrespiratory variables univariate analysis (wilcoxon rank-sum test and fisher-exact test) was performed to select variables included in a multivariate analysis by stepwise logistic regression. results : underlying disease assessed by the simplified acute physiologic score ( • vs • , p = . ), creatinine serum concentration ( • vs • gm/l, p = . ), blood urea nitrogen (bun : • vs mm/l, p = . ), age ( • vs • , p = . ) were higher and encephalopathy ( vs %, p = . ) more frequent in patients who failed. multivariate analysis showed that encephalopathic patients (or (odd ratio) = , p = . ) older than years (or = , p = . ) and presenting with bun >_ mmyl (or = , p = . ) failed to be ventilated with niv. variables related to the respiratory" status (i.e. paco , pao , fev ) were unable to predict tile failure of niv. conclusion : copd patients older than years, presenting with acute exacerbation, encephalopathy and bun > ram/l, should be carefully monitored because of high probability of failure with niv. methods:from february to december we studied pa_ timnts, males and females(mean age +/- ); of the se had emphysema,lo chronic bronchitis, dilatative car diomyopatia,with tracheostomy and emphysema.mean pac at admission in icu was +/- mmhg,while when weaningbegan, +/- .mean autopeep was cmh ( - ).all patients were ventilated in crpv as long as four hours to calculate st tic and dynamic cmpliance and autopeep.then the ventila tion was continued with psv+cpap(peep cmh objectives: analysis of the incidence of neurogenic pulmonary edema (npe) in a population of headtrauma patients with acute respiratory failure (arf). npe can occur after a central nervous system insult. differential diagnosis: cardiogenic pulmonary edema and other forms of non eardiogenic pulmonary edema. true incidence and pathophysiohigy remain poorly defined, however the role of catecholamines seems undeniable. early onset npe (within h after trauma) is characterised by hypoxemia, transient pulmonary hypertension and bilateral central fluffy infiltrates on chestx-ray. characteristics of cardiogenic edema or pneumonia are absent. late onset npe, (beyond hours after trauma), is more insidious. the clinical and radiographic picture has to clear within to hours. ( ) methods: all headtrauma patients admitted from january to december , in a nearotrauma icu setting were retrospectively analyzed for arf with as sole criterinm a pao -fio ratio < . results: neurotrauma patients were admitted during . patients ( %) presented with severe head injury (gcs< ), patients ( . %) with moderate (gcs - ) and patients ( . %) with minor head injury (gcs - ). overall mortulity was . % early (within h. after trauma) and delayed onset respiratory incidents were distinguished, counting for ( . %), respectively patients ( . %), patients ( . %) had early and late respiratory complications. early respiratory insufficiency was caused in patients ( . %) by aspiration, in patients ( . %) by lung contusion, in patient ( . %) by fat embolism and in patients ( %) by npe. in the late onset group patients ( . %) presented with pneumonia, ( . %) with fat embolism and ( . %) with npe. the npe group, patients, presented as follows: patients ( . %) developed early npe, and ( . %) delayed onset npe. patients ( %) died within the first days after admission, showing high mortality. gcs was less than in patients ( . %), indicating severity of head injuries. conclusions: high incidence of arf with various etiology ( , ~ was found in this population. in about % of all admitted hcadtrauma patients ( , % of arf) npe was causing attetial hypoxemia. occurrence of npe seems to be related to the severity of the brain injury and thus to outcome. these data call for extreme vigilance in respect of the insidious occurrence of npe. were included if recovering from respiratory failure and if in the opinion of the primary physician were ready for extubation. patients were excluded if undergoing compassionate withdrawal of support or had tracheostomies. the attending physicians were blinded to the measurements. included patients were placed on pressure support (ps) of em h with demand-flow continuous positive airway pressure (cpap) cm h . after a minimum of minutes on the above sehiogs: gastric intramucosai pc'o , abg, and a p . were measured. the padents were then disconnected from the ventilator for a period of one minute and the patients" respiratory rate and minute ventilation were measured using a wrights respirometer to calculate the frequency to tidal volume ratio (f/vt). patients were then extubated. extubafion failure was defined as the inability to maintain spontaneous ventilation for hours for any reason. results: twenty patients met criteria and were studied over one month period in october . six of the twenty patients ( %) failed weaning. the mean and standard deviation is outlined in failure . +/- . . +/- . . +/- . . +/- . comparison between roc areas shows phi and p . to each show a statistically significant difference from an area of . (p<o. ). the area at which the test has no discriminative value. this is not the case for either the integrative index or the f/vt ratio. the differences between areas for each curve is not statistically significant. the area's for each roc curve is shown in table #' . results. of the newborns referred to us for ecmo-therapy developed barotrauma, of the required ecmo and one of the three other patients who did not recieve ecmo-therapy died. to determine the correlation between the risk factor barotrauma and the severity of the pulmonary situation, we determined the oxygenation index of each patient referred to us for ecmo-therapy . the table demonstrates , d- giessen, frg. inhalation of nitric oxide (no) and aerosulizatiun of prostaglandin (pg) i: have been suggested to achieve selective pulmonary vasodilation and improvement of arterial oxygenation in patients with acute respiratory distress syndrome (ards). we directly compared these two modes of transbronchial vasodilator therapy in ards patients mechanically ventilated for - h (mean murray lung injury score [ ] . + . ). patients were randomized to receive either first no and then pgi (n= ), or vice versa (n= ), with an intermediate baseline period. each drug was titrated individually to find the lowest effective dose for maximum improvement of arterial oxygenation. gas exchange variables, including data from the multiple inert gas elimination technique (miget), and hemodymmaics under application of no/pgi were compared to pro-and past-challenge values. no (mean dose . + . ppm) increased the mean oxygenation index (pao /fio ) from + to + mmi-ig (p < . ) and reduced the shunt-flow from . + . to . : . % (p < . ). aernselized pgi (mean dose . + . " ng/kg rain) augmented pao /fio from + to + mmhg (p < . ), and decreased shunt from . + . to . + . % (p < . ). the miget analysis showed predominant redistribution of blood-flow from shunt areas to regions with normal ventilation-perfusion ratios in response to both agents. in patients, both no and pgi caused an increase in pao /fio by at least rnmhg. two further patients displayed a corresponding improvement of arterial oxygenation in response to either no or pgiz. the mean pulmonary artery pressure decreased from . : . to . : . mmhg in response to no, and from . : . to . : . mmhg (p < . ) in response to pgi . cardiac output, systemic arterial pressure, and right and left heart filling pressures were not affected by either agent. we r that individually titrated doses of inhaled no and aerosolized pgi~ effect selective pulmonary vasodilation and redistribute blood-flow from shunt-areas to weu-ventilated regions with nearly identical efficacy profiles. obieetives: the use of extraeorporeal bypass systems for oxygenation and co -removal is performed in patients with acute respiratory distress syndrome (ards) to reduce mortality and to improve restitution of pulmonary functions. high-dose heparin -commonly used in such patients to prevent thrombotic complications -might cause incurable bleadings as a major risk. this lead to the development of heparinized bypass systems; results of animal and first clinical studies proposed that such systems might run with low-dose heparin or even without any systemic anticoagulation. methods: since , patients with severe ards were treated with extracorporeal lung assist (ela) using heparin-coated systems (type maxima, medtronic, carmeda coating) in our icu. they received a moderate systemic heparinization. standard clotting assays (act, aptt, tt, ptt, at-ill, fbg, fsp) as well as special tests (tat, r~-tg, pf , pal-l, d-dimers, protein c, cl-inhibitor) were performed. results: covalent heparin-eoating of the ela-systems combined with lowdose heparinization could not prevent major changes in coagulation: ) in mean, platelets dropped from /nl to /nl within h after onset of ela. ) tat levels were already elevated before ela start ( ug/]) and demonstrated an additional peak h after onset of ela (up to ug/[). ) in parallel, there was a transient peak of pai-i levels (from to au/ml} h after onset of ela. ) in mean, fibrinogen levels dropped from to mg/ ml within h after onset of ela. ) in mean, cl-inhibitor levels dropped significantly from % to % after onset of ela and reached the initial levels within h. ) after membrane change, there were significant changes for c -inhibitor, fibrin-d-dimers and tt. ) global clotting tests such as aptt, ptt and tt were within normal range. conclusions: patients with severe ards develop a prethrombotic state already before they get connected to the ela bypass system. after onset of ela, they experience additional involvement of procoagulant, anticoagulant, fibrinolytic, and complement systems. in parallel to laboratory findings, clinical data suggest that the use of heparin-coated systems with accompanying systemic low-dose heparinization does not avoid thrombembolic and hemorrhagic complications in tong-term ela patients. thus, at the present, higher dosed individually adjusted heparin treatment has to be recommended. thereby, standard clotting monitoring is not sufficient. objective: poor muscle performance contributes to prolonged dependence on mechanical ventilation. longitudinal data on muscle function in icu patients is scarce. we evaluated changes in inspiratory and peripheral muscle performance during prolonged intensive care in patients with acute respiratory failure. methods: patients requiring intensive care for more than one week were studied. maximum inspiratory pressure (pimax) was measured twice a week for a maximum of three weeks. handgrip power (dynamometer) and subjective fatigue (keldet score) were obtained in survivors only. one measurement was done on the date of extubation. pimax pressure was obtained by occluding the airway for seconds or at least five inspiratory breath attempts. obiectives -measurement of peep-induced changes in lung volume helps to assess respiratory mechanics in acute lung injury (ali). we evaluated the accuracy and stability of a new respiratory inductive plethysmograph (rip), in the measurement of peep induced changes in end-expiratory lung volume (eelv) and tidal volume (vt) against volume reference, pneumotachograph (pnt), methods -two hours periods of basal ventilation and stepwise increases and reductions of peep ( - - - - cm h ) were recorded in patients with all. in addition, the new rip device (respitrace plus tm) was compared to an older rip (respigraph tm, nims, fl, usa) to determine its thermal stability using cold and warm devices and a ventilated lung model. results -the difference between the new rip and pnt in the measurement of vt was - _+ mi (x _+ se) or a - . _+ . % error. increasing peep from to cm h induced a + ml change in eelv. a difference of + ml ( . % of max. eelv change) (ns) was found between rip and pnt eelv readings. during controlled ventilation with constant settings the mean change in eelv was _+ ml/ min (fig.i) . validation of calibration showed a mean error of -+ . % after rain. the new rip had a higher drift when cold (cold + ml/ min vs warm _+ ml/ min), whereas the old rip was thermally stable (cold - + ml/ rain vs warm i + ml/ min). trauma icu, hospital traumatologia y rehabilitacidn. vall d'rebron. barcelona. spain. recent data suggest that the proportion of patients with relevant discrepancies between two jugular bulb (jb) oxygen saturation (sjo ) values is higher than suspected. objectives: determine the incidence, the significance and the pro nosis value of those differences,if they exist,in severe head injured-patients. material and methods: severe head-injured patients, coma glasgow scale (gcs) , with diffuse brain injury according to marshall criteria in the first ct scan, icp recorded, with an interval from accident-double jb monitoring < than hours, were studied. data from bilateral sjo were obtained simultaneously, every hours. discrepancies were considered significant, when differences in sjo were > %. no chan es in treatment protocol (hyperventilation, man• etc) were carried out due to this study. results: men and women were studied, aged • yrs. at arrival at hospital, gcs were < in and ) in to. the incidence of high icp() mmhg) were sz at the entry. the mean therapy index level required to control lop was ~l all patients required vasopressor therapy to maintain upp over ds mmhg. in patients a s.s f swan-ganz fiberoptic catheter was used to obtain a continuous recording of sjo . in the others , sj were intermittently controhed.the mean time of monitoring were d. • days. ten patients died within this period. a total of . blood samples were analized. at arrival, sjo discrepancies were found in patients, b %. at hours, the incidence were lower, / , . %. at th day, were h/ , z and at day , when the catheters were retired, ii[ , z showed discrepancies. the ct showed new injuries in g z of patients with differences > ~ in sd values throughout treatment period. none of those were considered for neurosurgical treatment. no correlation was found between iop and sjo values and sjo differences. conclusions: the incidence of discrepancies between sjo was higher than expected in severe head-injured patients. these situation could reflect disturbances between demands. when differences are known, and those lend to change, the ct scan, nearly always, will show new injuries. platelet-activating factor (paf) is an inflamatory mediator implicated in the pathogenesis of bronchial asthma and acute respiratory distress syndrome (ards). its inhalation in healthy subjects produces transient bronchoconstriction and mild ventilation-perfusion mismatch, together with peripheral leukopenia as a result of intrapulmonary neutrophil (pmn) sequestration. likewise our group has shown in healthy subjects and asthmatic patients that aaibutamol (s) inhibits both pulmonary and systemic effects of paf, suggesting that s may inhibit paf-induced venoconstriction in pulmonary microoirculation. the aim of the present study was to investigate if s inhalation decreases pmn by lung sequestration induced by paf. we studied healthy, non-atop• nonsmoking subjects ( m/ f, + yr), which were pre-treated with s ( ,ug) or placebo, with a randomized, double-blind, crossover, design, before paf ( ,ug) inhalation. we measured the respiratory system resistance (rrs) by forced oscillation, arterial btood gases and both total white cell and pmn count every min over a min. period. simultaneously, we recorded continuously the lung dynamics of inm-neutrophil and tc m-erythrocytes activity, with a gammacamara. after placebo, paf inhalation decreased white cells (from to x /l), and pmn(from to _+ x /l), and increased aapo (from . _+ . to . + . mmhg, p<o. ) and rrs(from . . to . . cmh .s.i q ) (p < . each). the fall in total white cell count correlated with the intrapulmonary pmn retention (r = . , p < . ). by contrast, after s, paf did not induce any change in white ceil count (from to + x /i), pmn count (from to x /i), aapo (from . to . + . mmhg), and rrs (from . . to . . cmh .s.i ). compared with placebo, after s there was a lower ~lln-pmn lung activity ( . . vs . . cts/mci/pixel, p<o. ), lower intrapulmonary pmn retention ( . . vs . . %, p=o, ), and a faster washout ( . . vs . . s ~, p= , ). our results indicate that s inhibits paf-induced intrapulmonary pmn sequestration, being consistent with the hypothesis that s may offset the venoconstriction of pulmonary microcirculadon caused by this mediator. supported inpiratory muscle fatigue with failure of force generation as def'med by a tensiontime index (tti)> . - . has been shown to occur in normal volunteers and in stable copd patients with a specific imposed breathing pattern. its role, however, in hypercapnic respiratory failure is less certain. we studied failed weaning trials in copd patients in which breathing pattern, tension-time index (tti) of inspimtory muscles, dynamic peepi, dynamic lung elastance, lung resistance, and arterial paco and ph were measured at the beginning and end of a t-piece weaning trial. in addition, the change in esophageal pressure during a mueller maneuver (apes max) was measured. a weaning trail has been prospectively defined to have failed if one of the following criteria was met: a rise in pco > mmhg from baseline accompanied by a fall in ph< . ; a respiratory frequency (f) > /min; excessive accessory inspiratory muscle recruitment; and a marked increase in dyspnea. values are expressed as mean • se. weaning failure was characterized by a more rapid, shallow breathing pattern, worsened mechanics, hypercapnia and respiratory acidemia despite an unchanged tri and pes max. we conclude that in this setting hypercapnic respiratory failure is not a consequence of inspiratory muscle fatigue. rather the adopted breathing strategy and resultant hypercapnia may represent an adaptation to forestall the onset of muscle fatigue. concerning the investigated elf-par~eters, no stadstically signhqcant differences were detected between the pgi and the control group. histopathologlcal changes occured in both groups and consisted in rare focal flaaaning f tracheal epithelium with loss of cilia and slight inflammatory cell infiltration, as well as slight swelling of alveolar typo pneumoeytes. sections of generation , and from bronchial tree were free of pathological changes. conclusion: alter h inhalation of p~ji no signs of respiratory-lract tissue damage caused by the aerosol could be detected. the minor pathological findings in the trachea are most likely due to mechanical irritation by bronchoscopy, changes of the alveolar epithelium are known for long-term mechanical ventilation . objectives: the aim of this study was to evaluate of efficiacy of ganglion stetlate blockade in patients with respiratory failure. methods: two groups of patients were investigated: group i (n = ) trauma patients with acute lung injury (ali), group if (n = ) patients with asthmatic status. in all cases continuous mandatory ventilation (cmv) was used with bennett ae. in both groups bilateral ganglion stellate blockade with antero-lateral approach was performed, using . % marcain. the following parameters were analysed: pao , sao , paco~, pip and c~t~t. results: in trauma patients with aij after bilateral ganglion stellate blockade short -lived and slight improvement of pao and sao , decrease of pacoz and pir and increase of static compliance of respiratory system were found. in second group bilateral ganglion stellate blockade interrupted the asthmatic status and significant statistical improvement of parameters of oxygenation, ventilation and respiratory system mechanics were observed. conclusions: we suggest that the bilateral ganglion stellate blockade is a very useful method in treatment of patients with obstructive respiratory insufficiency. the aim of the study was to analyse whether there exists serum and urine electrolyte disorder in patients(pts.) with acute respiratory insufficiency(ari). the study included t pts. with ari (pao : , @ , kpa. paco : , i- , kpa, ph: ~: , , hco : , :~ , mmol/ , sao : , ~- , %) who were hospitally treated due to pneumonia( pts.),emboly of the pulmonary artery( pts.) and severe attack of bronchial asthma ( pts). among tham there were ( , %) males and ( , %) females, average age , ~: , years, otherwise previously healthy. electrolyte concentracions were measured at the onset of the disease in serum and urine collected during hours (sodium-na,potassium-k, chlorine-c , calcium-ca,magnesium-mgand phosphorus-p). the measured serum and urine electrolyte concentrations were compared with respective referent values (rv). by serum electrolyte analysis, the following average velues were obtained: na:l o, the object of our investigation was a group of pts with massive pneumonias, males ( . %), females ( . %),mean age yrs.thirteen ( %) of them were smokers, ( %) nonsmokers. only pt ( . %) had pre-existing chronic respiratory disease, and ( . %) were admitted for the first lime,with no previous respiratory anamnesis. diagnose was based on anamnestic data of productive cough in pts( . %),physicaly ~onchial breathing in i~s ( . %),white cell count onder x /l in pts( . %). radiographicly, bilateral massive homogeneous shadows were found in pts ( . %), onilateral in pts( . %),pleural effusion in pts ( . %). abnormal renal function was found in pts ( . %). sputum culture was positive in pts ( %): slr.pneumoniae, str.pyogenes, pse'udomonas aerug, in , , cases respectively. all patients had remarcable hypoxernia (pao range from , to , kpa) without hypercalmea. all patients needed oxygenotherapy together with antibiotics and other .symptomatic therapy. nineteen pts had anaelioration of general condition and normalization of blood gas analyses, while pts with the lowest hypoxcmia died.in conclusion, massive pneumonias are frequently followed by respiratory insufficiency which is one of the markers of pneumonia severity. as existing hypoxemia complicates the course of the disease,prolonges the recovery, makes therapy more complexe and may be cause of death , frequent blood gas measurement is recomanded. we studied the effects of bosentan (bos), an eta and etb receptor antagonist, to examine if endogenous et mediates pulmonary hypertension in anesthetized and ventilated dogs with acute lung injury due to oleic acid (oa). the gradient between pulmonary artery pressure (ppa) and occluded ppa (ppao), and gas exchange (evaluated by arterial blood gases and sf intrapulmonary shunt) were measured at controlled flow. in dogs (treatment), data were collected at baseline, during long injury (obtained rain after intravenous administration of oa . ml/kg), and again after bos ( mg/kg intravenously). in dogs (pretreatment), data were obtained at baseline, after bos and then after oa. in treated dogs, oa increased (ppa-ppao, mmhg, table, means + sem, * p < . vs base) and deteriorated gas exchange. after oa, bos did not affect pulmonary vascular tone nor gas exchange. in pretreated dogs, bos had no effect on baseline pulmonary vascular tone but prevented the increase in (ppa-ppao) after oa. the deterioration in gas exchange after oa was not influenced by bos pretreatment. objectives: the alveolar tension is measured by the application of the alveolar air equation in which the arterial pco is used or by the simplified form of this equation in which the respiratory exchange ratio is taken at the value of . . the purpose of this study was to estimate the effective alveolar tension (pao eff) during spontaneous breathing with a new bedside technique which is simple non-invasive in normal subjects and patients with chronic bronchitis-emphysema. we also compared these values with the ideal alveolar po (pao (i)), measured from the alveolar air equation in which paco was substituted by the effective alveolar pco (paco eff) and with the alveolar po measured from the simplified alveolar air equation (pa ). this study is complemantary to previous work for the estimation of paco eff. methods: the subjects breathed quietly through the equipment assembly (mouthpiece monitoring ring, fleisch transducer head) connected to a pneumotachograph and a fast response and co analyzer. the method is a computerised calculation of the effective alveolar po quite similar to that of paco eff, obtained from the simultaneously recorded at the mouth expiratory flow, and co concentration versus time curves. results: the results showed a mean difference (pao eff-pa (i)) of - . kpa in normal subjects and - , in patients. the mean of the difference (pao eff-paq ) and (pad (i]-pao z) was much greater than . in all subjects. the limits of agreement for the difference (paozeff-pa (i))were - . to . kpa in normal subjects and - . to . in patients, while those for the differences (pao eff-pad ) and (pao (i)-pad ) were very large ( > - . to > . ) in all subjects. conclusions: the effective alveolar po is very close to the ideal one in normal subjects, tn patients pao eff may excessively deviate from pa (i) due to the observed significant difference between the alveolar/tidal volume ratio for o and that for co . the alveolar po measured from the simplified alveolar air equation (pao ) differed substantially from pao eff and pad (i) in all subjects. the essential role of glucoprotein hormone erythropoietin is to control red cell production. hypoxemia, reduced blood -carrying capacity and increased affinity of hemoglobin for are the primary stimuli for erythropoietin production. both anemia and hypoxemia induce rapidly erythropoietin secretion. kidney erythropoietin rna levels correlate inversely with hematocrit and directly with plasma erythropoietin level. similarly, hypoxemia increases kidney erythropoietin rna and plasma erythropoietin. the effect of hyperoxemia (pa >lo mmhg) on erythropoietin secretion isn't very well understood. the purpose of this study was first to evaluate the erythropoietin secretion in patients with acute respiratory failure and second to determine the effect of hyperoxemia on erythropoietin secretion in patients with and without anemia. sixteen patients with acute or acute on chronic respiratory failure needed mechanical ventilation were included in this study. these patient were divided in two groups. the patient who developed anemia were included in group i and the patients without anemia in group i . erythropoietin was estimated in venous blood in three stages. the first sample was taken during hypoxemia, the second during hyperoxemia and third during normoxemia. all the patients had high erythropoietin level during the hypoxemia period (mean value • mu/ml). during hyperoxemia etythropoietin levels were reduced in both groups ( mean value . + . mu/ml in group i, . • mu/ml in group ii). in normoxemia stage, erythropoietin increased again in anemic patients, and decreased more in the patients of group i . we conclude that hyperroxemia inhibit erythropoietin secretion in spite of anemia and tow arterial oxygen content. hyperoxemia may be a factor of the insisted anemia in with oxygen treated icu patients. the purpose of this study was to determine the relationship between clinical features of acute lung injury (all) and parameters like total proteins, total and individual phospholipids, the presence of paf, and acetylhydrolase activity in bal of mechanically ventillated patients. acetylhydrolase catalyses the cleavage of acetyl-group from the second position of the glycerylether backbone of paf, leading to its inactivation. mechanically ventillated patients were divided to three groups. group i includes patients without all; group ii, comprisespatients with moderate degree all, ( . <g-i < . ); and group iii comprises patients with severe ards (all score > . ). broncoalveolar lavage (bal) was obtained after infusion of normal saline at ~ to intubated patients and cooled immediately. cells were removed after mild centrifugation ( x g, min, oc). aliquots from the supernatant were used for total protein, phospholipid and paf analysis and determination. acetylhydrolase activity was assessed after incubation of bal with h-paf labelled on the acetyl group. released label was measured by liquid scintillation counter in the supernatant after trichloroacetic acid precipitation of the non-reacted substrate. kinetic characteristics of the enzymes were also studied. total phospholipids appear reduced in bal of patients with all, while total proteins increase. these factors appear to correlate with the severity of all. paf was not present in bal samples pretreatad with equal volume of % acetic acid to denaturate acetylhydrolase. detection limit for paf under our experimental conditions: pg paf/ml bal. instead, acetylhydrolase activity was detected in amounts increasing with the total protein content. background: intubated patients without lung injury or impaired breathing control normally display an inspiratory peak flow of below l/s. the aim of our study was to investigate the inspiratory peak flow generated by patients with acute respiratory insufficiency (ari). we had to take into account that both an inspiratory pressure support (ips) and the resistance of the endotracheal tube considerably influence the flow pattern generated by the patient. patients and methods: to investigate the non-influenced flow pattern we developed a new ventilatory mode which automatically compensates for the flow-dependent resistance of the endotracheal tube (automatic tube compensation, atc). furthermore, the mode maintains a constant tracheal pressure in inspiration and expiratio n . consequently, the measured flow pattern exactly corresponds to the flow pattern generated by the patient except that the ventilator modified for this mode (evita, driiger liibeck, germany) was not able to deliver a gas flow of more than l]s. we have investigated patients with ari arising from different reasons. results: the inspiratory peak flow measured in the atc-mode was . l/s _+ . l/s. the maximal deliverable flow of l/s was obtained in of patients. the figure shows the flow pattern under atc and ips in [~s] oi:) one of these patients. conclusions: patients with ari display a highly increased inspiratory peak flow. ventilators used for spontaneous breathing should therefore be able to deliver a gas flow of more than l/s. an overproduction of no and reactive oxygen species (ros) has been demonstratred in septic shock. ros and nitric oxide (.no) are free radicals which are known to react together leading to peroxynitrite anions that can decompose to form nitrogen dioxide (no ) and hydroxyl radical (oh~ thus, no has been reported to have a dual effect on lipid peroxidation (prooxydant via the peroxinitrite or antioxidant via the chelation of ros). in the present study we have investigated in different models the in vitro and in vivo action of no on lipid peroxidation. copper-induced ldl oxidation was used as an in vitro model of lipid peroxidation. ldl ( ~g apob/ml) was incubated with cu + ( , ~tm) in presence or absence of no donor (sodium nitroprussiate or glutathione-no) from to ~m. oxidation of ldl was monitored continuously with conjugated diene formation ( nm) and hydroxy nonenal accumulation (hne). exogenous no prevents in a dose dependent maner the progress of copperinduced oxidation. ischaemia-reperfusion injury (i/r), characterized by an overproduction of ros, is used as an in vivo model. anaesthetized rats were submitted to hour renal isehaemia following by hours of reperfusion. sham operated rats (sop) were used as control. lipid peroxidation was evaluated by measuring the hne accumulated in rat kidneys in presence or absence of l-arginine or d-arginine infusion. l-arginine, but not darginine, enhances hne accumulation in i/r but not in sop (< . nmol/g tissue in sop versus . nmol/g tissue in i/r), showing that in this experimental conditions, no produced from l-arginine, enhances the toxicity of ros. this study shows that the pro-or antioxydant effects of no are different in vivo and in vitro and could be driven by environemental conditions such as ph, relative concentration of no and ros, ferryl species...these conditions are impaired in circulatory shock. methods:" the diagnostic and therapeutic approach was standardized so that data collected over a -year period were comparable. a progressive deterioration of clinical conditions and/or pulmonary gas exchanges was considered as indication for my. variables potentially predicting the need for hv were derived from clinical and arterial gas data, extrapulmonary diseases, use of drugs, chest x-ray and ecg abnormalities. results: rv, performed with external and/or internal ventilators, was necessary in patients ( %). at the hospital admission, pac was higher and ph was lower in patients requiring rv ( pneumomediastinum, pneumothorax, ateleetasis and myocardial infarction are rarely seen in bronchial asthma. these complications occur as a result of the severe asthma.the aim of our retrospective study was to analyse the complications seen in acute asthma attacks. during the years through , patients were admitted to hospital in acute asthma episode. there were ( , %) pts with complications; mean age of yrs; females ( %). clinical history, ecg and chest radiogr~hs were analysed. the mean duration of bronchial asthma was yrs (range from months to yrs), all patients were atopics. there were four ex-smokem and one smoker. the worsening of asthma symptoms begun two days before the admission (range from to days). on ecg all patients had tschycardia. rightward shift of the qrs axis and st-t changes indicative of right ventrieutur strain were found in three pts. these were the transient fmdings that improved after curing the acute asthma attack. non-q myocardial infarction oeeured in one patlent and resulted from the hypoxaemia of asthma. hyperinfl~ion was the usual finding on the chest radiograpk pneumomediastinum and subcutaneous emphysema were apparent in five pts and required no additional treatment unilateral pneumothoraccs were present in two pts and needed eontimous intrapleural drainage; one of these patienst died in eardiorespiratory insufficiency. ateleetasis of right upper lobe was present in one patient. it oceured due to inspissated secretions and needed no additional treatment all these patients, except one who died, improved on lreaanent with oxygcr~ steroids, beta-two agonists, theophylline and antibiotics. in conclusion, complications occur in acute asthma episodes as a result of the severe asthma mediastir,*l emphysema and atelectasis are not serious complications. pneumothorax and myocardial infarction are very serious life-treatening complications and always have to i:m considered in taati~ts with sev~ asthma. acute bronchial asthmatic episodes represent one of the most common respiratory mnergendes, its maximmum expression "status asthmatiens" is one entity of low incidence, still it is a risk to the physical integrity of the patient. during a total of patients with diagnosis of status asthmabcas were hospitalized. out of these palients six had a near-fatsl asthma and they were subjected to a complex examination. near-fatal asthma was defined as either respiratory arrest or acute asttuua with paco greater than , kpa and/or an altered state of consciousness. mean age was , -d: , yrs, four male and two female sex. at presentation two patients suffered from coma, others were confused. they exh'bited severe dystmoes, diffieul~ speaking, used accessory muscles of respiration, increased whee~tg while two cases had silent chest on auscultation. cyanosis indicated a very severe asthma attack in all six patients. mean respiratory rate was ~ /min and puts rate .d: bts/imn. arterial blood gases revealed a pao of , ~ , kpa, paco of , • kpa and ph of , -+- , . area-careful evaluation they received conventional therapy (immediately continuous oxygen, impelled nebulization with high doses of betatwo agonists and ipmtropium bromide, intmvanous st~oids and theophylline). in two eases signs and symptoms of deteriorating airflow and respiratory muscle fatigue determined the need for mechanical ventilation. out of six near-fatal attacks aggressive lrealanent was suscessfull in four patients and fatal in two eases. one patient admittcxl in coma died in severe hypoxae~a upon one hour and one mechanicaly ventilated died from cardiac arrhythmia. life-threatening attacks in asthmatics in our group developed gradual worsening despite neatment which r symptoms in most other patients. one patient had "brittle asthma", other long-standing acute episodes ireated with systemic steroids. conclusions: idantitiechon of fatality prone subjects may lead to fttrther muetion of seveze episodes. respiratory affest and coma upon admission, severe dyspnoca with silent chest on ausouhation, oyanusis and use of accessory muscles of respiration constitute the basic cfinieal picture. hypoxasmia must be immediately eon'ected.the patients and physicians should be able to assess the severity of asthma, a major factor in near-fatal and fatal asthma attacks. objectives :our purpose was to asses if the evolution of patients with a adult respiratory distress syndrome (ards) ,shows any relation to the pulmonary or systemic origin of the disease and whether or not there were differences in the frequency of the syndrome in both groups. methods : randomized prospective study in multidisciplinary icu. one hundred and sixteen patients with a high risk developing ards were distributed into two groups. one was named systemic origin group(so) and the other pulmonary origth group (po).ai patients only showed one cause (pulmonary or systemic) with potential risk of ards.the patient's hemodynamic and respiratory status was evaluated every hours the first day and every hours the second and third day. at the end of hours the patients were diagnosed as ards or non-ards. measurements and main results : of the total patients, were finally included in the so group and in the po group.patients in so group and po group had comparable ages (p<. ).peep in both groups was comparable (=. ) at the mmnent of admission to the study. there were no statistically significant differences for cardiac index and systemic vascular resistances. the pulmonary vascular resistances (pvr) showed significant differences at h.(p<. ) and h. (p<. ).the oxygen comsumption (vo) in patients of the so group showed statistically significant differences at h. (p<. ) with respect to initial values.fifteen cases of ards ( . %) in the so group and twenty five cases ( . %) in the po group were identified. the time of onset of ards was _+ hours in the so group and + b hours in the po group.the final outcome was very similar th both groups : mortality of % in the so group versus % in the pc group. conclusions : the pathogenesis of ards depends on whether the lesion is originated at or outside the lung. the po group showed a sborter thne of onset of ards, a faster and more severe increase of pulmonary shunt and a higher percentage of patients developing ards compared with patients of the so group.the so group showed a higher and faster increase in puhnonary resitances tbat po group and a decrease th oxygen comsumption earlier and more severe than in the po group. these data thus seem to show that there could be two mechanisms involved in the genesis of ards depending on the cause. the fact that the ards genesis is shorter in the cases of pulmonary etiology with faster impairment of pulmonary shunt, and a slower increase in pulmonary resistances in this pulmonary group, would indicate that the underlying mechanisms responsible for the hypoxemia are different to those which thitiate the increase in pulmonary resistances. finally, the exclusive inapairinent of oxygen consumption, which appears earlier than the onset of ards in the systemic origth group, could show the generalized character of the process in this group. perfusion of prostacyclin (pgi ) to treat pulmonary hypertension in adult respiratory distress syndrome (ards) worse pulmonary gas exchange due to a marked impairement of ventilation/perfusion mismatch. recently has been shown that if prostacyclin is given by aerosol instead of intravenous the net effect is an improvement of arterial oxigenation due to a redistribution of blood flow to well ventilated areas. objectives: to asses the effects of inhaled proatacyclin on pulmonary haemodynamics and gas exchange in patients with severe ards. methods : two patients with severe ards (murray score > ) recived inhaled pgi at - ng.kg.min " using an ultrasonic nebulizer. haemodynamic measurements, arterial and mixed venous blood gas analysis were performed before and after rain of pgi inhalation. results: short-terro p~i inhalation improved pulmonary g-~ e-'~hange in both patients. arterial oxygen partial pressure (pao ) increased from to mmhg in patient and from to in patient , the ratio pao to the fraction of inspired oxygen increased from to (patient ) and from to (patient ). venous admixture decreased from % to % and from % to % in patient and respectively. mean pulmonary artery pressure decreased slightly from to mmhg in patient and from to mmhg in patient . no effects on systemic haemodynamics were observed in any patient. conclusions: pgi inhalation improves gas exchange and produces selective pulmonary vaaodilation, thus can be an alternative therapy for the treatment of pulmonary hypertension and hypexemia in patients with severe respiratory falllure. methods: we treated ards-patients (age yr ( - ) mean, range) during - . the lowest pao /fio -ratio was ( - ), the worst murray score . ( . - . ), icu-stay ( - ) days and hospital mortality %. the costs of intensive care were calculated according to intensivity of patient care as assessed by tiss-scoring (therapeutic intervention scoring system). the more intensive the care, the higher are the costs. costs per year of life saved (=life-year" in us $) were compaired by other medical treatments ( - ). it is assumed that the mean expected length of remaining life in ards-survivors after intensive care is years. treatment life-year ($) ' bone marrow transplantation (acute leukemia) lowering cholesterol using iovastatin treating hypertension using nifedipine heart transplantation intensive care of ards-patients conclusions: intensive care of patients with severe ards is highly more cost-effective as compared with many other routinely used medical treatment strategies, the usually good recovery and the reasonable quality of life in survivors justifies investments to care of these patients ( ). there is a close correlation between these two methods of measuring evlw. however there is an underestimation of . % in this kind of pulmonary edema ( oleie acid induced ) with the double dilution method. although the size of the sample is small, in normal lungs there appear not to be this underestimation. the effect of peep on evlw has been studied with contradictory results, probably as a consequence oft differences in methods of measuring evlw, variations in the type and severity of lung injury, and different timings of peep application. objective= ) to analyse the effect of different levels of peep ( , and omh ) on evlw during hpe; ) to establish whether increases in intrathoracic pressure due to high peep levels can obstruct lymphatic drainage. material and methodet hpe was provoked in groups of dogs by inflating a foley catheter in left auricular to a pressure of - r~uhg. peep levels of , i or m~hg were applied. resultst objective: to assess the effect on extravascular lung water (evlw) of the application of peep and the reduction of vt in an oleic acid pulmonary edema model in pigs, using three ventila~ary strategies. material and methods: twelve adolescent pigs (weighing over kg) were randomly divided in three gmups immediately alter infusing via a central vein . ml/kg of oleic acid to produce a permeability pulmonary edema. the ventilatory parameters for each group were as follows: group i (n= ) : vt: - ml/kg; zeep. group :(n= ) : vt: - ml/kg; peep: cm h . group :(n= ) : vt: - ml/kg; peep: emil . (resulting in permissive hypereapnla) after a four-hour period of ventilation the animals were killed and the lungs excised to calculate gravimetrically the extravascular lung water using a standardized procedure ( hemoglobin content method ). ill evlw (ml/kg) group obiective: in the postoperative period, maintenance of adeguate arterial oxygen tension is a major problem in morbidly obese patients probably because of a large reduction in functional residual capacity (frc). the aim of this study was to evaluate the effects of peep on respiratory mechamcs and gas exchange in this kind of patients. methods: in nine postoperative mechanically ventilated morbidly obese patients (bmi> kg/m ) we partitioned the total respiratory system mechanics into its lung ( ) and chest wall (w) components using the airway occlusion technique associated with the esophageal balloon, during constant flow inflation (jap ; : ) . at three different levels of peep ( , , cmh ) we measured: compliance (cst), airway (rim) and "additional" (dr) resistance, frc and gas exchange. obiectives. to describe the use of prone position in our icu we analyzed the clinical records of all patients admitted in - , selecting adult patients with arf defined as: intubation and pao /fio < mmhg plus an fio > . or peep> cm i . results. patients met the arf criteria: of them ( . %) underwent prone positioning (p+). prone position use began in the early phase of arf ( . • days from the beginning, range - , median ). out of p+ pts were treated with controlled ventilation (cppv or pcv), while were on assisted ventilation (simv+ps) and on spontaneous breathing (cpap). only pts were awake when turned prone, while pts required adjuncts of sedation to tolerate the change of position. the duration of prone positioning was variable (average lenght . • h, range . - h). only minor side effects were observed (eyelids and facial edema, chest and facial pressure bruises). we consider responders (r+) those patients presenting at least . mmhg increase in pao /fio : / patients ( . %.) were responders when first pruned. the pao /fio changes induced by prone position are reported in the figure. pao /fio increased when patients were pruned (*p< . ) and remained higher than baseline values when returning supine(*p< . ). paco remained unchanged. prone positioning was used at least twice in / ( conclusions. this retrospective analysis confirms that prone positioning improves oxtgenation in the majorib' of arf patients. altough we have no available criteria to discriminate in advance r+ from r-pts, we now routinely consider the use of prone position in the treatment of severe arf. palo a, otivei m*, galbusera c, veronesi r, sala gallini g, zanierato m, iotti g, braschi a.servizio anest. e rianim. i, *laboratorio biotecnologie e tecnologie biomediche irccs s. matteo, pavia, italy inhaled no can improve arterial oxygenation and reduce pulmonary hypertension in ards patients; little information is, however, available about the dose-response curves. methods seven ards patients (lis . +. ) submitted to mechanical ventilation randomly received inhaled no doses in increasing or decreasing sequence: . , , , , , and ppm. reference measurements were obtained before and after the entire period of no inhalation. hemodynamic parameters and blood gases were measured after min in each condition. cmv was administered under sedation and paralysis, with constant ventilation, peep (lol-_ cmh ) and fit (. +. ). the changes in vt and fit due to the no ( ppm in n ) injection in the ventilator external circuit were compensated for. results . the dose of . ppm, ineffective on papm, significantly improved oxygenation. the increase of pat and the decrease of q'va/q' and papm were nearly maximal at - ppm. no deterioration of arterial oxygenation was observed at no doses as high as ppm. co exchange was not influenced by no inhalation. systemic hemodynamic variables did not change throughout the study. these results suggest that a concentration around ppm is adequate for obtaining maximum effects on hypoxemia and pulmonary hypertension in patients with ards. low-dose inhaled nitric oxide (no) induces redistribution of pulmonary perfusion in patients with severe ards and causes improvement of oxygenation [ ] . however, addition of exogenous lowdose no in the inspiratory gas mixture might be only a replacement of missing atmospheric no ( - ppb) in hospital central-supplied medical air. [ ] we have realised nitric oxide measurements in ten healthy volunteers, ( smokers and non-smokers) breathing with a mouthpiece and occluded nostrils through a ventilator circuit, with separation of inhaled and exhaled gases by a valve. no concentration was measured with a double-chamber chemiluminometer (environnement sa, france) and with charcoal/silicate purified compressed air. there was no nitric oxide detectable in the inspirat ry limb of the ventilator. unfiltered central supply medical air contained : - ppb of no and - ppb of no , whereas central supplied oxygen was no/no free. samples were taken after equilibration periods of minutes, with increasing fit levels of . , . and . for subsequent minutes periods; paired values were recorded every s. the mean no value was . ppb (sd . ) and n o significant differences were found for different fit levels both in smokers and non-smokers. these data suggest that the no concentration of pulmonary origin in the exhaled air of' healthy volunteers is probably lower than that reported by other authors [ ] and that, previously reported, differences between smokers and non-smokers are not always striking [ ] . we suggest the use of activated charcoal/silicate filters for clinical trials in order to achieve standard conditions. [ objective: to compare efficacy and safety of two doses of salbutamol. methods: sixteen adults who had severe acute a~hma were randomly assigned to receive either rag (n= ) or rag (n= ) of nebulized sulbutamol. both groups were similar with respect to age, duration of a~hma, duration of attack before arrival at the hospital and severity of a~hma according to baseline measurements (table) . evaluation was performed , , and rain after the start of nebulization. results: compared with mg regimen, mg regimen resulted in the same improvement in peak-flow and fischl index (figure). the changes in heart rate, respiratory rate and pace did not differ significantly between both groups. the incidence of side effects, which included tremor, palpitations, cardiac arrythmlas and other symptoms, was not sj~ificanfly different in the two populations. conclusion:the results of this study suggest that nebulization of ng of salbutamol is not more effective than rag in the initial treatment of acute severe asthma in adult patients. the prognostic factors of neutropenic patients admitted to the icu remain poorly known. the aim of this study was to determine the respective weight of underlying malignancy and organ system failures on the outcome of these patients. patients and methods: the charts of neutropenic patients (wbc < /mm and/or pmn < /ram ), admitted to the icu between and , were retrospectively reviewed. the characteristics of the neoplastic disease (h~emopathy or solid tumor, tumoral evolution, duration of cancer disease and of neutropenia), the mac cabe's score, the organ system (respiratory, hemodynamic, renal, neurologic, hepatic) failures and the severity scores (saps, saps ii ,osf) were registred within the st day in the icu. when discharged from the icu, the patients were classified as alive or dead. results: fifty-seven patients ( . %) had a h~ematologic malignancy, and ( . %) a solid tumor. fifty-nine of the patients died ( . %); the mortality rate did not differ between both groups ( . and % respectively, p = . ). with univariate analysis, none of the tumoral features is linked to the prognosis; only the respiratory (p < - ) and cardiovascular (p < - ) failures, and the number of organ system failures (p < - ) are associated to the risk of death. the saps (p < - ) and saps ii scores (p < - ) were higher in patients who died. with multivariate analysis (logistic regression), only the respiratory failure is correlated to the risk of death (p = - ); neither the features of the underlying malignancy (p > . ), nor the duration of neutropenia before admission in icu (p = . ), nor the severity scores figs ii: p = . ) are linked to the outcome. conclusions: the tumoral characteristics do not modify the prognosis after admission to the icu. they should not influence the decision to admit or refuse a cancer patient in the icu. respiratory failure at icu admission has the predominent weight on the risk of death in the icu. patients with respiratory acidosis due to asthma occasionally require levels of mechanical ventilation that place them at risk for barotrauma. a few case reports have described the use of an extra-corporeal membrane oxygenator(ecmo) circuit as an alternative means of co removal. generally, this has been used for short periods of time (< h) without serious complications and with low blood flows through the extra-corporeal circuit. we report a case of refractory asthma who could not tolerate even small-volume breaths from a mechanical ventilator due to severe bilateral airleak. ecmo therapy was initiated at the referring hospital prior to helicoptor transport. high blood flows were used ( % of the patient's cardiac output), sufficient to achieve both co removal and oxygenation. satisfactory gas-exchanged was accomplished (pco = - mmhg) with nearly total lung rest for a prolonged period ( h). however, the long ecmo duration was associated with two severe complica-ti ns: ) bilateral hemothoraces due to anticoagu!ation in the extra-corporeal circuit, and ) prolonged weakness as a result of neuromuscular blockade for six days. the patient was discharged from the hospital in good condition. we present the respiratory and hemodynamic features of this case aw well as the potential complications of ecmo therapy in asthma. objectives: parameters derived from tidal expiratory flow ~e) and volume (vt) can be used to detect airflow obstruction in copd patients who might be unable to perform forced spirometry (e.g., icu). however, indices such as ave/v t and at/re are highly variable (thorax, : ; ) . methods: we investigated whether the standardized for v m effective time (teff~) of a tidal breath, which is derived by asimple mathematical procedure (teff,= j'vdt/vt ), is a more reproducible and sensitive detector of airways obstruction, we studied nine normal subjects ( male, -+ yr) and copd patients ( male, -+ yr) in the seated position, with a noseclip on. they breathed quietly, through a pneumotashograph to measure flow (v). volume was obtained by numerical integration of thellow signal. each subject had an initial - min trial run, in order to become accustomed to the apparatus and procedure. when regular breathing had been achieved, all breaths over a min time interval were recorded. the mean value of six consecutive breaths (ers criteria) for each subject was used for analysis under the condition that within session variation of tidal volume (vt) was < %. lung function tests were: in normals (mean-sd), fevl%pred = • fevl/fvc%= -+ % , and in copd patients, fev~%pred= __. and fevi/fvc%= --. %. results: values are shown as mean-..+-sd in the following a su~ve~ os literature sources p~oves that t~aditlona], i.e. medicinal medication and physiothe~apeutic methods os t~eatment often p~ove to be insufficientl~ effective both currently and in the ~emote future. the goal of this study was to investigate the efficacy os t~eatment of b~onchial asti~ma patients by means os speleo-and artificial sp~ay therapy. speleotherapy t~eatment was conducted in the conditions os mic~oclimate os salt mine in solotvino hospital. a~tis sp~ay the-~apy was conducted by means os a self-made device. ou~ method is based on the p~inci-~ le os using the majo~ facto~ of speleo-he~apy -highly dispe~sed sp~ay s sodium chloride. the obtained ~esults ~e~e analyzed in five g~adations. at the end os the speleothe~apy improvement and considerable improvement was observed in , ~ os patients; inconsiderable improvement -in , ~ os patients. having evaluated the e~s os t~eatment using a~tis sp~ay therapy the indices a~e , h and , ~ ~espectively. remote ~esults of t~eatment a~e an important index os t~eatment, the ~esult os ~hich ~e~e studied by means s a ~uestionnaive-method. patients ~ho had been t~eated by speleothe~apy mo~e f~eguently ~e-po~ted a ~elapse in disease ust afte~ the course o~ t~eatment ( , h). ho~eve~, in a ]ate~ phase the ~emission ~ould last ]on-~e~ (s months in , ~ os patients, till one yea~ in ~ ~). in , ~ os patients who passed the co~se os a~tificial sp~ay therapy a ~elapse was ~egiste~ed immediately as the co~se os t~eatment. then thei~ condition stabilized ~hile in , ~ os patients a period os ~emission lasted s ha]s a yea~. , ~ of patients dida't ~epo~t a ~elapse of the disease du~in~ one yea~. evangelismos hospital, critical care department, athens, greece method#: mechanically ventilated patients ( copd, ards, other pulmonary diseases) were studied in two phases: ) during the acute phase of respiratory failure; ) during recovery - days later. we measured mip and monitored the pattern of breathing while the patients were breathing spontaneously through the respirator (pressure support mode with - cmh ) until either the point they were unable to sustain spontaneous breathing (sb) any longer (phase ) or for two hours when they could sustain sb indefinitely (phase ). subsequently the patients were sedated, paralyzed and mechanically ventilated. then we simulated the pattern of sb at the end of the sb trial by manipulating the variables of the ventilator and assessed respiratory mechanics b y the end-inspiratory and end-expiratory occlusion technique. . during recovery, a combination of reduced inspiratory load and increased venfilatory capability makes a patient previously unable to sustain sb to breathe spontaneously. . inspiratory load is reduced during recovery, mainly because both intrinsic peep and breathing frequency are diminished. obiectives: although elevated concentrations of a few cytokines have been shown to be present in the bronchoalveolar lavage (bal) fluid (balf) of patients with the adult (acute) respiratory distress syndrome (ards), the pethogenesis of ards is largely unknown. leukemia inhibitory factor (lif), a growth factor recently recognised as a polyfunctional cytokine integrated in cytokine networks was measured in unconcentrated balf of patients from different patient groups. methods: lif was measured in balf by means of a specific and sensitive elisa (detection limit pg/ml)in balf (lavage of x ml in the right middle lobe). results: lif was not detected in the balf of healthy control patients and in only one ( pg/ml) out of patients at risk for ards (after cadiopulmonary bypass surgery) who underwent bal h after the end of the extracorporeal circulation. high and detectable levels were found in the unconcentrated balf of out of patients with full-blown ards ( + , mean + sem, range - pg/ml). there was a good correlation between the level of lif in the balf and a number of markers of inflammation: neutrophils/ml (r: . , p= . ), albumin ( r: . , p= . ) and protein level (r: . , p= . ). conclusions:the biological role of lif in these balfs is not readily explained by its currently known actions and it is unkwon whether lif contributes to or is a response to local tissue damage. our results indicate that this cytokine with lots of interesting _functions is a pert of the inflammatory cytokine cascade in ards. background and obiective : we recently demonstrated that cisapride -a new prokinetic drug -enhanced enteral feeding in a heter genoas group of ventilated icu patients by significantly accelerating their gastric clearance (crit care meal, ; : - ) . it remains unknown, however, whether certain subgroups of patients might benefit more from adding cisapfide to their enteral nutrition regimen than others. patients with chronic obstructive pulmonary disease (copd) might represent such a subgroup since their illness and its specific treatment put them at risk for gastric emptying disorders. design and setting : prospective, consecutive sample study in an adult medical intensive care unit in a university hospital. patients : mechanically ventilated and hemodynamically stable copd patients. interventions : gastric emptying was evaluated by bedside scintigraphy and expressed as the time at which % of a tcg~-labelled test meal was eliminated from the stomach (t / ). baseline data (do) were recorded after enteral nutrition reached to ml daily. scintigraphic measurements were repeated days after cisapride ( ml orally, q.i.d) had been added to this regimen (d ). patients were considered cisapride responders when gastric clearance improved by more than % from baseline. results : normal values for the test meal and for scintigraphic acquisitions obtained in the supine position were found to be + min. in healthy volunteers (crit care med, ; : - ) . five patients responded to cisapride (t / : + rain vs. + min at do and d , respectively) and five did not (t / : + min vs. _+ rain at do and d , respectively). in contrast with non-responders, all five responders had clinically significant maldigestion at baseline (excessive (> ml) gastric residues, vomiting (> times/day and abdominal distension) which disappeared in of them after the administration of cisapride. conclusion : copd patients who tolerate enteral nutrition well have basal gastric emptying times which are comparable with those of healthy volunteers and are not influenced by cisapride. however, cisapride treatment provides both scintigraphic and clinical improvement in those copd patients who exhibit clinically obvious gastric emptying disorders. cernv v., dostal p., zivny p., zabka l. dept. of anesth. and critical care, charles university, faculty hospital, i-irade~ kralove , czech republic objective: the aim of the study was to evaluate the effect of early entera nutrition started within hours of injury on the incidence of multiple orgar failure (mof) in trauma patients requiring vantilatory support. methods: after institutional approval patients were enrolled in the study enteral feeding was begun within hours of injury in trauma patients (en group) admitted to icu. nasuenteric tube was placed as soon as possible after admission into the distal duodenum under endoscopy. additional parenteral nutrition was used to meet patients energy and protein requirements. the control group (pn) consisted of patients fed during this period paretuerally. severity score apache ii, trauma score, cumulative balance of nitrogen (g), incidence of mof (three and more organs) and length of ventilatury support (days) were calculated. values are expressed as mean + sd. results: tab introduction : parenteral nutrition (pn) is an important aspect in the optimal treatment of patients on gastroenterology or intensive care. the aim of this bi-center study in patients has been to assess tolerence and efficacy of a new protein-lipid mixture for pn from a simple preparation. patients and m~hods : patients were selected in two hospitals (tenon and saint-lazare, paris) and were divided into two groups : group a (gastroenterology~ l short bowel syndrome) and group b (intensive care, surgical patients). all patients likely to require pig for a period of days (group a) or days (group b) were studied. the pn regimens administered were the following : combination with g of mct/lct fat emulsion end , g of nitrogen, in liter end glucose requirements were met by imfizsion of l liter of glucose - % via a "y " connection. lipid thus provided % of the non introgen calories. total daily calorie intake was to ] kced. this study monitored, before and at the end of infusions, the sennn albumin (alb), preaiburtun (prealb), triglycendes (tg), cholesterol (cs), and the serum ammotransferases (sgot and sgpt) end alkaline phosphatase (alp) activities. statistical significances were calculated using the wilcoxon-tost. introduction: many cu patients present a catabolic illness in response to inflammation and infection, characterized by a rapid loss in skeletal-muscle mass despite optimal nutritional support. growth hormone (gh) is responsible for a rise of lipolysis, enhancing the energetic balance, and of protein synthesis. recombinant human gh (rhgh) is nowaday available for clinical use, but its cost is very high. therefore, rhgh should only be prescribed to icu patients when its efficacy can reasonably be anticipated (ie. when the patients are catabolic or stressed, but in order to avoid overprescription for unstressed patients and for those who are overly catabolic). hence, we, as others, recently demonstrated that rhgh had no favorable effect in highly stressed icu patients. objective: to detect on a clinical basis, low (ls), mild (ms) and severe stress (ss) states in icu patients and validate this clinical judgement by objective metabolic mesurements, in order to select early those icu patients potentially able to benefit from rhgh therapy. methods: consecutive icu patients were prospectively stratified as ls, ms and ss by two experienced icu senior consultants (temperature; agitation; heart rate; arterial blood pressure; presence of an infection; respiratory rate; exogenous catecholamines). anabolic (insulin, igf- , gh) and catabolic (cortisol, ghicagon) hormones, and nitrogen balance were determined for each patient within hours after admission in the icu. metabolic and clinical data were then compared. the clinical stress states determined by icu physicians correlate with an objective metabolic assessment. therefore, the patients who will more likely benefit from adjuvant rhgh therapy can be detected simply and early. a prospective study on rhgh therapy in ms icu patients is in progress. berger mm md , chiolero r md , pannatier a phd , berger l , cayeux c , voirol p , hurni m md . surgical icu, pharmacy, and cardiac surgery, chu vaudois, ch-iotl lausanne, switzerland objective. nutrition of the compromised cardiac surgical patient is challenging. numerous factors influence the gastrointestinal (gi) absorption function, among which gut perfusion, which depends largely on the systemic hemodynamic status. patients in hemodynamic failure are prone to organ failure, and may benefit from an early jejunal feeding. the study was designed to assess the absorption function after cardiac surgery in patients with adequate and altered hemodynamic status, using paracetamol as tracer of gi absorption. methods. after cardiac surgery, patients, aged _+ years (mean_+sd) were assigned to groups (anaesthesia: fentanyl gg/kg + midazolam): group (n= ): reference group, with normal hemodynamic status, easy recovery. group ('n= ): patients in low output syndrome, cardiac index < . i/m on day (d ) after surgery, requiring prolonged intensive care, mechanical ventilation + nutritional support. paracetamol g, was given intragastrically on d + d : plasma levels measured (h.p.l.c), at administration (to), t - - - - - and rain. hemodynamic status assessed with pulmonary artery catheter. healthy subjects served as controls. results. compared to healthy controls, absorption was strongly reduced on d in all patients (no difference between groups). on d , peak paracetamol level was significantly lower in group (low cardiac output): in group the area under the curve on d and d were similar. there was a large inter-patient variability, reflecting the hemodynamic status. conclusion. gi absorption was decreased on d in all patients, and reverted to normal between d and d in case of normal cardiac function, but not in case of low output syndrome. the decrease on d can be attributed to fentanyl, known to slow down the gi transit. in patients with cardiac failure, correction of altered absorption was correlated with the hemodynamic status, suggesting that gi absorption is dependent on adequate splanchnic perfusion. the aim of the work was to define specific significance and evaluate efficiency of enteral component of infusion therapy in the intensive care of gastroenterotogic patients of surgical profile with pyo-septic complecations. there were used the methods of radial diagnostics and polyelectrography; the laboratory control on oxygen-transporting function, volumetric and hemodynamic state, changes in metabolic, hormonal and immunologic status was conducted. from january, [ till november, there was carried out the randomized study of patients with general purulent peritonitis; among them persons constituted the control group and -the main one. in the main g~oup the intestinal lavage, enterosorption, enteral introduction of nutrient solutions with gradual turn to enteral nutrition by equalized mixture "ovolaet" were started from the first hours after operation. the data obtained allowed to define the specifity of the program of artificial medical nutrition in the group of examined patients, based on necessity of individual selection of media for enteral introduction depending on the stages of intestinal insufficiency syndrome. it was shown that inclusion of enteral component into the program of infusion therapy during early periods stabilized circulation in the regime of moderate hyperdynamia, considerably decreases the deficiency of circulating blood volume, normalizes the values of oxygen transport, consumption an}d extraction, provides the optimal level of mycardial adaptive possibilities without tension of its compensatory functions and pulmonary circulation overload. due to combined application of parenteral and enteral nutrition the metabolic processes are shifted towards anabolism. this is supported by decrease to normal values in the contents of blood aggresive hormones (acth,hydrocortisone) and increase in somatotrophic hormone. the complete parenteral-andenteral nutrition influences positively on restoration of cellular and tumoral immunity, activates the factors of organism nonspecific protection and recovery from immunodepression, prevents the development of immunodeficiency. impact tm vs control. s atkinson, n maynard, r grover, e sieffert, r mason, m smithies, d bihari departments of surgery and intensive care, guy's hospital, london, u.k objectives: comparison of the effect of an immunonutrient enteral feed versus a control on the outcome of a mixed intensive care unit (icu) population. methods: admissions to this multidisciplinary adu)t icu thought likely to stay more than three days and with tube access to the gi tract ~r randomised to receive either impact tm, a feed with supplemental arginine, dietary nucleotides and omega- fatty acids, or an isocaloric and isonitrogenous control feed. study end points included mortality and icu stay. approval was obtained from the hospital ethics committee. rosults: patients were entered into the trial. the two groups were well matched for age, sex, and admission apache ii with an overall mean admission risk of death of . (std. dev. -+ . ). on an intention to treat basis, there was a no significant difference in icu mortality, icu stay or standardised mortality ratio (s.m.r.) between the two groups (see table) . similarly, there were no differences after stratification for patients receiving or more litres of feed. conclusion: there is no evidence of an effect of impact@, an enteral immunonutrient feed, on pre-determined end-points (icu mortality, icu stay or standardised mortality ratio) in a mixed intensive care unit population over that of an isocaloric, isonitrogenous control feed. objeeflves: evaluate changes of blood laatate levels according to patient medical status after cvvhd initj,~ion using dialysate solution containing lactate. method: review of medioal records of consecutive patients ~eated by cvvhd (dialysate solution hmnosol lg , hospal,uk, lactate concentration retool/l). date obtained hr before and - hrs at~er cvvhd initiation were analysed. results: all data are presented as mean + sem. in one patient, pre end post filter lactate levds were measured during standard cvvhd setting (blood flow ml/mlu, dialysate solution flow i /hr), and approximate daily lactate flux into the patient was calculated to be as high as mmol/d. lactate leveh measured after cvvhd initiation increased significenfly compared to baseline levels ( . + . axtd . + . ,respectively; p< . ,paired t-test). when patiente with increased basal lactete (~- ) were compared to paliente with normal basal values (n= ), no difference in laotete increase was fmmd (p= . , manova). patiente with severe liver dysfunction ( points in mop scomlg, n= ) had higher basal laotate levels than patiente with normal or slightly abnormal liver teste ( or point in mof scoring, n=ll), rite values being . + . and . + . , respectively (p< . , student t-test). increase in blood lactate did not differ between these two groups after cvvhd was stetted (p= . , manova). in pafiente with invasive hemedynamio mo~, no oorrelation batween changes in lactate levels and eitlm" changes in oxygen ddivery (t =o.ol; p--o. ) or oxygen consumption (reversed fie, k) (r -q).o ;p-- . ) were found after cvvhd initiation. conclusion: blood lactate increases on cvvhd with dialysate soh~on rich in lactate. this increase is predominantly caused by influx of lactate into the blood via the filter end does not seem to depend on the liver fimotion and/or oxygen metabolism changes. objectives: the study was designed in order to determine the effect on plasmatic proteins, of two types of aminoacids solutions of parenteral nutrition (pn) adapted to stress, having different concentration of branched chain aminoacids (bcaa), when applying to politraumatized critical patients. methods: a prospective study was performed using a randomized double blind design of polytraumafized patients, split in two groups of ten patients each, with mean ages of _+ an -+ years. due to their condition, all patients required p.n. for at least days. both groups were subjected to isocalorie and isonitrogenous solutions ( ci/kg/ day and . g of nitrogen/ks/day), varying only in the concentration of bcaa; solution a having a % concentration and solution b %. blood samples determinations during days , , , after the beginning of treatment with p.n. were total proteins., albumin, trandferrine, protein binding retinol; prealbumine and fibronectine. the anova test (one and two way) was used to compare the values between the two groups. results: the administration of solution a, showed statistically significant increases in the determinations of the values of protein binding retino] (p < . ) and prealbumin (p < . ). no significant increases were observed in the values of total protein, albumin, transferrine and fibronectin. solution b produced statistically significant increases only in the values of total proteins (p < . ). the remaining proteins did not changed from their control values during the whole period of pn administration. comparing both groups, no statistically significant differences were observed related to the type of diet. nevertheless, differences were found in total proteins, albumin, protein binding retinoi, fibronectin (p< . ) and prealbumin (p < . ) in relation to the time course of pn therapy. only the albumin values showed significant differences (p < . ) when considering the interaction of both the type of diet and the time course of pn. conclusions: . solutions of pn adapted to stress, can maintain the control values of slow turnover proteins and improve the values of rapid turnover proteins. . no significant differences on plasma proteins were found between the two solutions having % or % concentration of branched chain aminoaeids. &determination of rapid turnover proteins does not seems useful for discriminating different solutions of bcaa during pn. obiectives; the hormonal changes in the post-traumatic situation often leads to an elevated blood glucose and a negative nitrogen balance. to reduce the elevated glucose production by aminoacids the apprication of xylitol may be an alternative energy source. in a double-blind randomized study we investigated the effects of a xylitol/glucose solution (group a: aminoacids g/i; glucose/xylito g/ g/l) on metabolism and particularly on pancreatic and liver enzymes compared to a glucose based nutrition solution regimen (group b: aminoacids g/i; glucose g/i). methods: the clinical trial was carried out after the approval by the local ethical committee on patients with severe brain injury. there was no difference in body mass index bmi (group a: . +/- . kg/m and group b: . +/- . kg/m=), age, and sex. daily individual energy expenditure was measured by indirect calorimetry (deltetrac "~). nutrition was started - hours after trauma or surgery with carbohydrates and aminoacids. fat was added h after nutrition had started. to analyze the effects on pancreatic and liver enzymes we investigated the following parameters for days: blood gtucose, serum lipase, serum amylase, asat, alat, ~gt, ap, and serum cholinesterase (che). results: due to the daily indirect calorimetric measurements energy requirements were satisfied. there was no difference in blood glucose concentration and cumulative nitrogen balance between the two groups. neither were there any significant changes in asat, alat, ap, and che for days in both groups. serum tipase steadily rose to lull in group a and . lull in group b, respectively. conclusions: there was no measurable influence of either nutrition solution on liver enzymes. the xylitol/glucose nutrition regimen does not have any advantage over the glucose based nutrition solution concerning blood glucose level or nitrogen balance. the elevation of serum lipase to a -fold level in either group needs further investigation on trauma patients. the effects of fat emulsions in lung function, particularly in lungdamaged patients, have been attributed to alterations in pulmonary vascular tone caused by eicosanoid production modificatione. as the eicosanoid production may depend on the fatty acid profiles of the intravenous fat emulsion, haemodynamic, pulmonary gas exchange and plasma levels of prostanoids were investigated in acute respiratory distress syndrome (ards) patients, during different intravenous lipid emulsions (providing different prostanoid precursors). we studied in a randomized double-blind design groups (n= each) with ards. group i (lct) received a fat emulsion with long chain triglycerids (lct- %), group ii (mct) an emulsion containing a mixture of medium and long chain triglycerids (mct/lct / - %) and group iii placebo (control), during h ( mg/kg/min each). we measured before, at the end of h infusion, and h after the end of the infusion: lipaemia, arterial and venous blood gases, pulmonary and systemic haemodynamics, and plasmatic levels (arterial and in mixed venous sample) of eicosanoids (txb=, -keto pgf~,, and ltb ). at the end of the fat emulsion, groups (i and il) to , • to , • mmol/i), the paoz/fio z remained unchanged in the three groups; no changes in intrapulmonary shunt (qs/qt) were shown; neither in the mean pulmonary artery pressure. in contrast, only in the lct group: cardiac output and oxygen consumption increased significantly ( . % and %) (p< . ). eicosanoids were increased at baseline compared to reference values (p< , ). a decrease (p<o, l in the arterio-venous difference of the vasodilatador prostanoid ( -keto pgf~=) was shown in lct group. our results indicate that fat emulsions in ards patient do not influence pulmonary gas exchange, provided that the perfusion rate were keept at mg/kg/min. the present study was designed to evaluate the metabolic changes of a carbohydrate-based diet versus a fat-based diet on oxidation rate of substrates and energy muscle metabolism in patients with an acute exacerbation of chronic obstructive lung disease. patients were mechanically ventilated with a volume-cycled respirator. after an overnight fast, patients were randomnly treated with a continuous enteral feeding over a nasogastrie tube with a carbohydrate/fat ratio of / in group i (n= ) , and a carbohydrate/fat ratio of / in group i] (n = ) during consecutive days. indirect calorimetry was set at baseline and hours later the enteral feeding was started. muscular quadriceps biopsy was performed on baseline and on day of enteral feeding. urine was collected during hours and was used to measure h urea nitrogen production. the caloric intake was set according to the measured resting energy expenditure. respiratory gas exchange rate were measured using a computerized open-circuit indirect calorimeter. quadficeps femoral muscle samples were obtained by muscular biopsy after local anesthesia. analyses of glycogen, glucose -phosphate, lactate, phosphocreatine and adenosine triphosphate (atp) and enzymes (glycogen synthase and glycogen phosphorylase) were determined. after h of nutrition patients in group i showed an increase in carbohydrate oxidation (from . % to . %, p= . ), and in group ii a decrease in protein oxidation (from % to %, p= . ). after days of enteral feeding a tendency to increase in glycogen concentration (group i, p= . ; and group ii,p= . ) was observed. while patients in group i showed a tendency (p= . ) to decrease glycogen phosphorylase, patients in group ii maintained these enzymatic levels. the increased in glycogen was correlated in group li with degradation enzyme (p = . ). in group i, the pao /fio ratio increased after days of treatment (from . to . ; p= . ), but no changes in days of mechanically ventilation, length of stay in icu, or mortality rate was evidenced between groups. it is concluded that the oxidation rate of substrates used for energy production varies according to the caloric sources administered. with nutritional therapy muscle glycogen concentration increases in both diets, with different enzymatic influence. more studies are warranted to further assess the clinical implications of the different pathophysiologic behavior of the two diets. under certain experimental and human conditions (radiation and/or thermal injury) the gi mucosa is unable to perform this protective function and could play an important role in the pathophysiology of the syndrome of multiple organ failure (smof). the objective of the present multicenter study was to know the gi mucosal permeability in critically ill patients and the relationship with their outcome. the method used to assess the integrity of the gi mucosal barrier measured mucosal permeability to various hydrophilic compounds. specifically, we measured the urinary excretion ratio (uer) of two sugars (lactulose and mannitol) that had been previously administered through a nasogastric tube. urinary excretion rate was measured in healthy humans (control) and in patients admitted to the intensive care unit (icu) at days , and . the apache ii of the patients studied was _+ . there was an increase of uer in the critically ill patients compared with controls (o. _+ . vs . _+ . ) (p< . ). in contrast, no changes in uer between days , and were observed ( . -+ . . significant changes were also established in the different groups: major and minor surgery, general and epidural anaesthesia , transfused and non transfused patients except for iron and ferritin plasma levels which didn't change significantly in patients who had received blood. a positive significant correlation was established between crp and ferritin (r= . ) for patients under general anaesthesia, but not on epidural, regardless of the type of surgery. conclusions: iron and transferrin plasma levels fell acutely in surgical patients while ferritin and crp rose. transfusion implied an acute iron load.the established correlation between cpr and ferritin in patients on general anaesthesia suggests that ferritin behave as an acute phase reactant in that setting, while epidural anaesthesia may ameliorate the inflammatory response. objectives: to analize the effect of gastrointestinal complicacions (gic) related to the enteral nutrition (en) in the real volume of diet administered to icu adult patients. a prospective multicenter study was designed (comgine study) in wich en application, gic definition and his management were defined by collaborative consensus.patients treated with en in one month pedod were included. in each case, daily volume of diet prescribed (pv) and administered (av) was recorded and the volume ratio calculated (vr=pvxl /av). patients were divided for days of en according to the presence (group ) or absence (group ) of gic (abdominal distension, increase of gastdc residuals,vomits or regurgitation, diarrhea,constipation and bronchoaspiration). differences between groups were analized by anova and mann-whitney u test with p< . for statistical significance. (vr%) group (vr%) tolerance to the enteral nutrition (en) has been related to the severity of illness in icu patients. the aim of this study was to evaluate this relationship. methods. a prospective, multicenter, study was performed (comgine study) in wich en application and related gastrointestinal complications (gic) were defined by collaborative consensus. adult icu patients treated with en in one month pedod were included. gic were classified as: ) abdominal distension (abd), ) increase of gastdc residuals (igr), ) vomits (vom), ) diet regurgitation (reg), ) diarrhea (dia) and ) constipation (con). patients were divided in two groups: group a: patients with gic dudng their evolution. group b: patients without gic. differences between groups were analized for apache ii admission score or evolutive variables ( carbon dioxide production is a major determent of work of breathing. increase in co production during nutritional support may precipitate ventilatory failure and difficulty in weaning from mechanical ventilation. in the present study, co output was calculated while passive mechanically ventilated patient were fed with different amount of calories and different proportion of protein, carbohydrate and fat. four clinical stable and mechanically ventilated patients were studied. carbon dioxide was calculated while patients were paralyzed, sedated and mechanically ventilated. six nutritional regimens were used: a) no calories, b) t gr glucose/ h, c) calories equal to rest energy expenditure in special formula with low carbohydrates and high fat (pulmocare) d) calories equal to rest energy expenditure in standard formula (nutdson) e) calories double to rest energy expenditure in standard formula (nutrison) and f) calories equal to rest energy expenditure parenterel (tpn). carbon dioxide output was low while no calories and/or only gr/ h glucose was provided, the mean values of vco output were _+_ and !-_ ml/min respectively. there was no difference in vco output between with low carbohydrates and high fat regimen and standard regimen, mean values were t . -+ and _+ respectively.the high calories regimen and tpn resulted in higher vco output, mean values _+ and • respectively. we conclude that the special with low carbohydrates and high fat regimen did not reduce vco output, in the contrary, high calories intake as well as tpn increased vco output under tested conditions. klouche k., cristol j.p., vela c., canaud b., b raud j.j. m tabolic intensive care unit and nephrology department. lapeyronie hospital. montpeuier france. predictive factors for rhabdomyolysis (rh) -induced acute renal failure (arf) were studied in a retrospective study from january to january . patients (pts) (male: , female:lo; mean age: + y.o.) were admitted with rh defined as cpk> iu/ . etiologies were: traumatic and ischaemic , infectious , toxic , excess activity . factors studied were: simplified acute physiologic score (saps: . + . ), organ systemic failure (osf: . _-!- . ), diagnosis delay (d: +_ h), clinical parameters (sepsis, dehydration), blood chemistry data (cpk, bun, creatinine, potassium, phosphorus, calcium, proteins, hematocrit) and urinary ph. severity of rh was estimated by ward score determined according to phosphorus, albumin, potassium, cpk, dehydration and sepsis. urea appearance rate (uar) and creatinine index (ci*) were determined over a hours period. arf was observed in pts. in non-arf and arf groups respectively, saps ( . _+ . vs . + . ), deshydratation ( vs ), sepsis ( vs ), phosphorus ( . + . vs . -+ . ), calcium ( . + . vs . _+ . ), ward score ( _+ . vs . + . ) were significantly different. however, no significance was observed in uar ( -+ vs -+ ) and ci ( _+ vs _+ ). patients required hemodialysis (hd) ( : sessions) and remained dialysis free. only osf ( . _+ . vs . -+ . ), ward score ( . _-/- . vs . _+ . ) and ci ( +_ vs -+ ) appeared significantly higher in pts requiring hd. pts died from associated disease. all patients suffering from arf recovered a normal renal function. we confwmed that an elevated ward score (over ) is a good predictive index of arf. in addition we found that ci is a severity factor for arf requiring hd. thus, patients suffering for rh with elevated ward score and ci, have a fair chance of dialysis and should be treated more intensively. * ci (expressed in mg/kg) = (car + feces creatinine) / weight. where car: creatinine appearance rate; feces cr~t..= mean plasmatic creatinine x . . tr~er k., cetin t.e., tugtekin i., georgieff m., ensinger h. universit~tsklinik flir an~sthesiologie, uim, germany introduction: endogenous as well as exogenous adrenergic agonists have a profound effect on carbohydrate metabolism in human critical illness. in this study the effects of noradrenaline (nor) and dobutamine (dob) on carbohydrate metabolism during a hr infusion were investigated. methods: after approval by the local ethic committee healthy volunteers were studied. hepatic glucose production (hgp [mg/kg/min]), using , -d glucose as stable isotope tracer, as well as plasma concentrations of glucose (glc [mmol/i]) and lactate (lac [mmol/i]) were measured prior and during infusion of nor ( . pg/kg/min) and dob ( pg/kg/min). blood samples were drawn before and during the agonist infusion. results: no major changes in insulin and gtucagon plasma concentrations could be found during the study period. ::i:::: :iiiii~ ~ i ::i: ~:: : :: i:ii. mean-+sd are shown. # p< . , anova for repeated measurments. conclusions: the effect of nor on hgp and glc were smaller as compared to adrenaline (i) with a similar time course. in contrast to the effects of adrenaline and nor, dob had a different effect on carbohydrate metabolism: a decrease in hcp and glc, which is uncommon for a / -adrenoceptor agonist. since hgp is an energy consuming process that might deteriorate hepatic oxygen balance in critical illness, the differential effects of adrenergic agonists may be of importance and need further clarification. the nutritional insufficiency often accompanies post-operative hypercaloric states, inanition, serious infections and weakening chronic illnesses. that is why the early nutritional support, sufficient and appropriate for each individual base, is a fundamental component of intensive care unit as an indispensable factor for recovery. per this reason, our unit, developed a software for the implementation and nutritional control of t~e assisted patients. this software is incorporated is an expert system called ~i~su, designed and developed by the computational division of our unit. this system arrives to inferred diagnoses such as : respiratory, hepatic, renal(with and without dialysis) dysfunctions, pancreatitis, ards, decrease of consciousness, diabetes. according to these data objectives: to compare the effect of short term enteral feeding versus parenteral nutrition, when a isonitrogenous and isocaloric feeding solution is administered by either mute. methods: in a prospective controlled clinical trial patients were studied; all exhibited moderate degree of malnutrition, normal liver and kidneys, and a functi ning gastrointestinal tract. the patients were randomized to receive a free amino acid and small peptide diet ( patients) or an isonitrogenous isocaloric parenteral support (tpn) ( patients) (total energy: kcal, nitrogen: . g, carbohydrates: g, fat: g, n/non protein calories: / ) at least for days. results: there were no significant changes in anthropometric parameters within either group. nitrogen equilibrium was aqhieved by day in the tpn group and by day in the enteral group ( . % of the enterally fed patients and % of the tpn patients maintained in positive balance the day of the study). there were no significant changes in serum albumin within either group. serum level of transferrin reached a significant increase in both groups (p= . ). thyroxine-binding prealbnmin rose significantly in both groups as well (p= . and . respectively). statistically significant rises in lymphocyte counts (p= . and . respectively), in levels of c (p= . and . ) respectively), iga (p= . ), igg (p= . and . respectively) and igm (p= . ) occurred in either treatment group. there was a high incidence of negative skin tests at the start of the study in the enteral group ( . %) and the tpn group ( %). by the end of the study the incidence of negative responsiveness was . % and . % respectively. despite maintenance of similar glucose levels in both groups, tpn led to significantly higher serum insulin levels. the serum insulin increased almost linearly over the study period and eventually prevented fat mobilization and lipolysis, so that free fatty acid levels had fallen significantly. a significant elevation of the liver enzymes over the study period occurred in . % of the tpn group, but not in the enterany fed patients. conclusions: the present findings provide no evidence that enteral diets containing free amino acids and small peptides, as their nitrogen sources, are in any way inferior to isonitrogenous isoealoric regimes parenterally given. aim: the aim of this study is to describe and explore the expectations of the functions of the critical care nurse to enable the formulation of guidelines for the scope of practice for the critical care nurse with a south african context, methods: phase i was to determine the expectations of the critical care nurse, the nursing service managers and the doctors with regard to the functions of the critical care nurse. a focus group interview was held with a group of experts in the field of critical care. the results were used to compile a questionnaire. this questionnaire was sent to the critical care nurses, the nursing service managers and the doctors in south africa for completion. from these results the functions of the critical care nurse were determined. phase ii was to formulate guidelines for the scope of practice for the critical care nurse within a south african context. through usage of the date (phase i) the scope of practice was formulated. guidelines were formulated for the practise, education and research regarding the limitations of the professional-ethical authoration and the implementation of the scope of practice for the critical care nurse. objectives : high output gastric aspirates arc occasionally observed during fasting in critically ill paticnts, preventing any attempt of feeding via the enteral route. although these patients are often said to suffer from "gastroparesia", the motor correlates of this condition arc lurgcly unknown. in this stud?', wc recorded the gastrointestinal motility of critically ill patients with abundant (> ml/ hours) fasting gastric aspirates. methods : antral ( sites separated each other from . cm), duodenal ( site) and jejunal ( site) contractions were recorded simultaneously by ~eans of a multihimen tube assembly positioned trader fluoroscopic control (perfused catheter technique). tracings from prolonged recordings were obtained on a multichannel recorder ( a recorder, hewlett-packard) then anal) ,ed visually, with a special attention for the following abnormalities which are characteristic of intcstinal pseudoobstmctiou: l) absence or aberrant propagation of the migrating motor complex (mmc), ) presence of bursts (> min) of nonpropagated phasic pressure and ) presence of sustained (> min) uncnardinate pressure activity. patients with a volume of gastric aspirates of • (sd) [median ml/ hrs were investigated for - [median minutes. results : only one patient had no detectable motor abnormality. mmcs were either absent (n= ) or migrated abnormally (retrograde propagation : n= ; retrograde and stationnary : n= ) in pts. bursts of nonpropagated phasic pressure activity were present in the duodenum in pts and sustained uncoordinate pressure activity was found in pts. additional abnormalities included episodes of prominent pyloric activity. (n=l) and sustained antral pressure activity (n= }. conclusion : critically ill patients with large volume of gastric aspirates have manometric evidence of intestinal pseudoobstruction. prokinetic therapy in these patients should thus focus not only on enhancing gastric motility, but also on restoring a normal propagative contractile activity in the intestine. this prospective, open-label, randomized placebo-controlled study included patients with hypokalemia in whom rapid potassium replacement ( meq kci in h) was performed: patients received mg sulfate ( g in hours) and patients received a corresponding saline infusion. measurements were made at time , + , + and + hours results: k levels increased more in mg treated patients than in the patients who received saline infusion at time and h (p < . -students-newman-keuls). (table ). introduction. dual lumen uaso-gastrojcjunal tubes are a major ads'ance in nutritional therapy of mechanically ventilated critically ill patients since the " authorizc jejunal feeding with concurrent gastric decompression, there,, reducing the risk for aspiration. unfortunately, placcmem of these tubes in the jejunum regularly dictates to resort to endoscopy in order to facilitate pyloric intubation. recently, the remarkable gastrokinetic properties of the well known macrolide antibiotic er}lhromycin have been demonstrated in gastroparetic critically ill patients . aim. in the presem stu~,, we evaluated the feasibility of placing dual lumen naso-gastrojcjunal feeding tubes at the bedside without endoscopy, using edthromycin to help iranspy'loric migration of the tube under fluoroscopic control. methnd each patient admitted in our icu during a months period and requiring artificial ventilation and enteral nutrition for a period of at least days was included in the study.. after inserting the tube (stayput| sandoz, usa) in the gastric anmnn, e.rythromycin ( rag) was aduunistored intravenously, to help fluoroscopic positioning of the tube into the jejunum. the total duration of the procedure (from nasal intabatiun to jejunal placement), as well as the duration of ftuoroscopy were recorded in each patient. results. patients (male/female : / : mean age : . + . years; mean apacbell score : .t • . ) wore enrolled into the study.the procedure was performed within the dab,s following institution of mechanical ventilation. jejunal access was obtained in all patients without resort to enduscopy in , • . min.(total duration of the procedure). mean duration of fluoroscopy was . + . rain. conclusion. we conclude that placement of dual lmnen naso-gastrojejunal tubes can be obtained in mechanically ventilated critically ill patients without resort to endoscopy., provided that e rythromycin is used as gastrokinetic agent to help pyloric intubation. the following ad and dis parameters were considered in all patients: -mid arm circumference, triceps skinfold thickness, serum transferrin, albumine and lymphoeites and urinary creatinine/height index. patients whose results were bellow % of normal values in or more of the above criteria were considered undernourished (und).statistical analysis was performed using % analysis.statistical significance was established at p<o.o . results: a total of patients( female, male) -with a mortality rate (~) of , % -were studied, aged -+ years and a median ]enght of stay of days. -nourished (nou) at ad and at dis - ; ~ %; -nou at ad and und at dis - ; ) , % ; -und at ad and und at dis - ; ~ . %; -und at ad and nou at dis - ; ~ , %. we observed a p< . when we compared groups and (p= . ), and groups and (p= . ). variation in nutritional status and longht of stay: -nou at ad and nou at dis = > median lenght of stay days; und at ad and und at dis = > median lengbt of stay days; nutritional status and age at admission: -age > = years : nou ( ) , und ( ) -age < years: nou ( ), und ( ) nutritional status and age at discharge: -age > = years : nou ( ) , und ( ) -age < years: nou ( ), und ( ) we observed a p<o. when we compared groups and (p=o. ) and groups and (p = . ) conclusion: such study permits to conclude that most of our patients ( . %), staying in icu for more than days, were und, namely the elder. we observed that this kind ef patient had a longer median length of stay in icu, associated with higher mortality rate. in conclusion, the nutritional management is an essential element in suportive care of critical)y ill patients. ohiectives: sirs is associated with hypercataholisnl and resistance to nutritional support, despite raised circu&ting levels of growth hormone and insulin. serum igf- levels however are low; thercti~re rhigf-i administration might produce nsefnl anabolic effects. the pharmacokinetics of exogenously administration rhlge-i in such patients are likely to differ from that seen in the less seriously ill due to changes in circulating blood volume, increased capillary permeability, poor nutritional stares, and alterations in binding proteins. the ol jective of this study was to determine the clearance, apparent vohnne (if distribution (vd), time to peak concentration (tmax) and elimination half-like (tia) of a single subctkaneous il~ieetion of rhlgf-i in patients with sirs on the intensive care unit (icu). methods: icu patients with sirs were entered into the study, which had been approved by the ethics comjnittee. in each patient baseline hlood samples for circulating gf-i were obtained over a hour period, prior to il!iection of p.g/kg of rhlgf- subcutaneously. a further l samples were taken fi'om each subject over the next hours. circulating ige-i was measured in serum at each time point by radioimmtme assay, and the area under the curve tbllowing administration of rhlgf-i was derived tbr individual patients fixm~ baseline a~!justed igf-i levels. clearance values were caietdated by dividing the administered dose of rh[ge-[ by the total area under the etnve. vd and tv were calculated by regression analysis of the terminal part nf the log sertnn concentration time profiles. results: results are expressed as median (range). age ( - ) years, apache ii score ( - ), and length of icu stay ( - ) days. baseiine circulating igf- levels were low ( < - ) ng/ml reaching a peak of only ( < - ) ng/ml. of the patients had basal levels predmnhaantly below the inwel-limit of detection of the assay, and showed no appreciable rise in serum igf-[ levels tbllowing rhigf-i injection. parmacokinetic variables could not therefi)re be determined in these two patients. following rhlgf-i injection in the remaining patients tmax was at ( - ) hours, clearance was ( - ) ml/min, vd was . ( . - . ) l/kg, and tia . ( . - . ) honrs. conchlsions: there was marked patient wu-iability in response to rhlgf-i administration. vd was similar to that seen in poshq~erative maior surgery patients ( . vs . l/kg), but clearance was greater ( vs ml/min), tmax earlier ( vs hours) and t~a shorter ( . vs i . homts). if riaigp-i is to be administered to dtically ill patients the dose should he nlodified m the light of these findings. baekgronnd: acute bacterial endoearditis continues to be a condition with high morbidity and mortality. the majority of patients are treated with high dose antibiotics, but a patient group requires surgical treatment. methods and results: from january to march , patients underwent surgery for acute bacterial endocarditis: had native valve endocarditis and had prosthetic valve endocarditis. there were men and women. streptococcus viridans was the predominant infecting agent in native ~alve endocarditis and staphylococcus epidermidis in prosthetic valve endocarditis. progressive congestive failure, uncontrolled sepsis and peripheral emboli were the most common indication for surgery. although the mitral valve is more commonly involved in acute bacterial endocarditis, the aortic valve most often requires surgical inlervetion. the postoperative bleeding in the no-aprotinin group was + cc and in the aprotinin was :t: (p < , ). the mortality in icu was , %, the staphyloccocical endoearditis mortality was , % and the no-staphyloccocical endocarditis mortality was , % (p< , ). conclusions: the early surgery is indicated if endocarditis has no response with medical treatment. the mortality of staphyloceocical endoearditis involving left valves was higher than caused by other infecting agents. aprotinin treatment improved prosta#andin metabolism and preserved pletelet function during open heart surgery and could be useful in this type of interventions. urgent surgery had a high mortality ( %). selective digestive decontamination (sdd) has increasingly become the subject of critical discussion sine~ the development of multiresistant organisms has become an issue. moreover, a selection of gram-positive pathogens must also be taken into account when using the sdd regimen, which is primarily directed at the gramnegative bacterial specumn, with the methicillin-resistant staphylococcus aureus strains (mrsa) being of particular importance. the objective of our study was to determine the extent to which colonization with mrsa strains is promoted by sdd. method: patients (ventilation period > days) were randomized and allocated to the sdd group (n= ) or the control group (n= ). in their general intensive care theraw, there were no differences between the groups. the sdd regimen consisted of the four times daily administration of rag polymi~ mg tobramycin and mg amphotericin b in the nesc, mnoth and stomach. systemic prophylactic ~dmini~/rution of antibiotics was not part of the sdd regimen. smears were taken from the nose and the rectum twice wceldy and from the pharynx and trachea once wceldy, and tested for mrsa. further samples were taken as clinically reqnircr results: smears were examined in the sdd group. mrsa strains were detected in samples ( . %) from patients, and in patients they were detected for a period of up to weeks. the positive smears were districted as follows: tracheal / ( . %), nasal / ( . %), pharyngeal / ( . %) and rectal ( . %). severe mrsa-induced infections were observed in patients (infection rate . % of the colonized sdd patients). smears were examined in the control group. ivlrsa swains were r in samples ( . %) from patients, but only repeatedly over a period of up to days in patients. the po~tive snmars were distributed as follows: traclmal / ( . %), nasal / ( . %), pharyngeal / ( . %) and rectal / ( . %). there were no mrsa infections in the control group. conclusion: the data collected support the view that the use of sdd promotes a selection and persistence of mrsa strains. longer-term colonization with mrsa and sovere systemic inf~ons were only found in the sdd group. although the clinical and epidemiological impact of resistance develol~ng when sdd is applied ~maine unclear, this question should be given close scrutiny. tazobactam/piperacillin (taz/p p) is a new broad spectrum antibiotic, in which the acylaminopenicillin piperaeillin is protected by the betatactamase inhibitor tazobactam from hydrolization by bacterial enzymes. taz/pip has shown to possess a high antibacterial activity against almost all clinically relevant bacteria and is a registered drug in germany. obiectives: purpose of this investigation was to evaluate, whether faz/pip . g is suited for efficient antibacterial monotherapy of severe infections and what influence dosage frequency reveals on clinical efficacy. methods: hospitalized patients have been documented in this multicenter trial during a year period. as this investigation should reflect the usual clinical treatment, the only criteria for enrolment were the typical signs of infection as e.g. temperature > ~ leucocytosis or an isolated pathogen. exclusion criteria did not exist and the patients were treated in accordance to the severeness of infection, underlying diseases, risk factors etc. with taz/pip . g t.i.d, or b.i.d. results: patients suffered in most cases from infections of the lower respiratory tract (n= ), followed by intraabdominal (n= ) and skin and soft tissue infections (n= ). % of the lrtis wvre nosocomial acquired and in % the treatment was conducted as monotherapy. in % the lrti was treated with taz/pip b.i.d, and in % t.i.d. pseudomonas spp. (n= ) and staph..aureus (n= ) were the most isolated pathogens pretrcatment. the clinical response rates (cured/improved) after treatment with taz/pip . g b.i.d, and t.i.d, were % and % respectively. results for intraabdominal-and skin and soft tissue infections will be presented. conclusions: in hospitalized patients with severe infections successful treatment with taz/pip in monotherapy is possible. in this population a reduction of the dosage frequency to . g b.i.d, revealed equivalent clinical response rates. objectives. retrospective evaluation of cases of severe generalized tetanus (sgt), treated in our icu the last years. we review cases of sgt ( m, f), mean age . years. in eases the entry site of c.tetanus was a skin laceration, in case it proved to be the external genitalia, while in the rest no portal of entry could be determined. in the first cases incubation period was short ( - days) and so was the period of onset ( - days). all patients needed mechanical ventilation (range - days), initally through an orotracheal tube,and later through a tracheostomy, performed • days after admission. clinical manifestations of sgt included muscle rigidity and i generalized spasms, persisting for up to weeks in the most severe cases. significant autonomic nervous system dysfunction was present in cases occurring - days after the admission and following the time course of generalized spasm. besides general supportive measures, specific treatment included passive +active immunization, penicillin g, magnesium sulphate and sedation in a variety of regimens. neuromuscular blockade was required in cases. nosocomial infections occurred in eases, with sepsis and mof in one. average stay in the icu was - days. one patient died with severe septic complications and one was discharged with severe disability due to anoxaemie ancephalopathy, after a cardiac arrest on admission. ~ disinfectant in suspension test, without presence of organic load, disinfectants showed efficacy on lm. in the carrier test, in the presence of organic load, out of examined disinfectants did not exposed efficacy on lm. the results of examinations clearly showed that evaluation of disinfectant's efficacy partly depend on the used test method. antun basi , intensive care unit, kb firule split spin~ideva ! jugoslavia bacteremia and sepsis are frequent complications encouuntered in severe icu patients.microorganism identification with hemoculture presents the basis for adequate and successful antibiotic treatment.in many patients damage and vulnerability of the peripheral veins presents an obstacle for obtaining the blood culture from the central venous (cv) catheter sample could be also used. material and methods blood cultures were perfomed in lo patients on blood samples simultaneously obtained from the peripheral vein and cv catheter three times in a -hour period.criteria for the suspected bacteremia were body temperature above c and leucocytosis above ioooo leucocytes/dl. the site for venipuncture and the cv catheter stopcock port were cleansed with povidon iodine.after the initial ml of blood were discarded,lo ml were used for the blood culture.standard laboratory technique for blood cultures was used. results and discussion in ( %) patients hemocultures was negative at both sites,whereas in the remaining ( %) they were positive.for twentyone ( ~ of the positive patients the same results were obtained at both sites (peripheral vein and cv catheter),whereas in ( . %) patients the blood culture were positive only for the cv catheter samples.the cv catheters were in place for less than days in patients and for more than days in patients.from patients with positive blood culture from the cv catheter,one patient had the catheter for three days,whereas the other had the catheter from - o days. we neither found significant differences in hemodynamic dates : objectives: , to count and evaluate bacteria isolated from endotracheal (et) suctiori samples (with and without saline). . to establish the exogenous source(s) of pathogens isolated from carer's hands and the equipment involved in sampling in order to reduce the incidence of contamination and infection. method~: this prospective study included consecutive ventilated patients ( male and female, _ + yr; apache ii score -+ ) over a period of months. et aspirated samples with and without saline were taken daily from day of intubation until pathogen~ were presented in counts of _> per ml. at the same time, samples from both carer's hands were taken before and after et suction and a swab from the ventilator tube. results: the overall length of intubation varied between to days. bacterial transfer between staff and patients was noted in % of patients until day of intubation. there was no significant correlation between severity score and appearance of colonization. the incidence of pneumonia in studied patients was % with an overall mortality rate of %. acinetobacter anitratas (no ), staphylococcus aureus (no. ), klebsiella pna~moniae (no. ) and pscudomonas aeruginosa (no. ) isolates predominated in all our specimens. we noticed increased resistance to most antibiotics with the exception of imipenem for gram (-) bacteria and vancornycin for gram (+) bacteria. conclusions: i. tracheobronchial colonization appears directly in the maiority of intubated patients. . there is a close relationship between the microflora of personnel, patients and equipment. . bacteria transfer was noted both to and from patients. . strict hand disinfection policy remains an important measure for the proper care of mechanically ventilated patients to reduce respiratory infections. nnseeomial pneumonia is the most common nnsocomiai infection in the icu-settiag, reported in up to % of patients admitted to the icu following surgery. it is associated with significant mortality that ranges from ~ to %. enteric gram-negative bacilli have been implicated in % to % of ventilntor-associated pneumonias and pseudomonas aeruginosa accounts for % to % of these pneumonias. importantly, epidemics of/ - actamnse-pruducing enterobacter spp or klebsiella spp that are resistant to extended spectrum cephalosporins or penicillins, pose serious obstacles to effective antibiotic choices. carbapenems provide in ~tro activity against a wide range of enterobacteriaceaeand other gramnegative aerobic bacteria, except steaotrophomonns maltophilia. in vitro meropcnem is more active against pseudomonas spp than imipanem (especially p. aeruginosa and p. cepacia), imipenem and meropenem are effective against more than % of strains responsible for nnsocomial infections. all major pathogens associated with lrti are usually covered by the carbapenems, exceptions are pathogens involved in so-called atypical pneuomouia like mycoplasma, chlamydia and legionella. carbapenems are highly stable in the presence of most chromsomal and plasmid-mediated blactumases and usually offer a postantibiotie effect lasting for three hours against most of the enterubacteriaceae. reeent studies comparing imipenem/cilastatin with other ~-lactams and fluoroquinolones in severe lrti in icu patients resulted in favourable clinical cure rates and good tolerance, but development of resistance in p. aeruginosa and ;. aureus during treatment were of some concern. meropenem offers the advantage of greater stability against enzymatic degradation, so no concomitant administration of an enzyme inhibitor is necessary, and meropenem appears to be associated with a lower risk of seizures, particularly when used at high doses. results from studies with meropenem in lrti, especially in critically ill patients with acute exacerbations of chronic bronchitis, demonstrated excellent cure rates and better gastrointestinal tolerance of this new carbapenem. both earbapenems are effective candidates for use as empiric monotherapy in nosucominl infections of critically ill patients. qbl~ctives a favourable effect of iv immunoglobulins in septic surgical patients has been reported, but not sufficiently validated. we conducted this study on trauma patients to: i) investigate the effect of ivig on septic complications and il) quantify this effect by means of serum bactericidai activity (sba) assessment and iii) to explore the effect of temperature increase (from to ~ c) on the sba methods: twenty trauma patierits matched on admission for age, sex, inju~ severity score and glasgow coma scale, were allocated to receive either wig (ivig group; i patients) or equal volumes of human albumin % (control group; patients). wig (sandoglobulin) was administered in a total dose of g/kg divided in a four time regimen on days , , and post-admission. three blood collections were performe& before the first dose (day ) and hours after the third and the fourth dose (days and respectively). complement, lgg fractions, the sba at ~ and at o c and clinical parameters were recorded. results-similar lgg and igg] serum levels were found in groups ivig and control on day ( +_ vs • ns and + vs + , ns), whereas they were significantly higher (p< ) in the v g group on days ( _+_ vs + , p< ) and ( _+ vs +i , p< . ). the various complement-fractions increased in both groups without inter-group differences the mean (• sbas ( ~ c) at rain in ivig group vs control group were: - _+ vs - • ns for day , _+ vs - _+ p< for day and _+ vs - + p< for day . the mean (+sd) sbas ( ~ c) at rain presented a significant improvement over those of ~ c but for the control group remained negative a~d were respectively as following: -~ • vs - + , ns for day , +_ vs - _+ , p< . for day and _+ vs - _+ , p< . for day . the increase of temperature induced a -fold improvement of sba in iv g group and -fold ofcontrol-~oup positive blood cultures, and the product of the infectious episodes number multiplied by days of occurence, were significantly lower (p< ) in the ivig group than in the control ( vs , and vs , respectively). conclusions: our study shows a significantly favourable effect of ivig administration on septic complications and on sba of trauma patients. the increase of temperature results in a significant improvement of sba of patients that received ivig, which theoretically means a farther prevention of infection in the febrile state. pharmaceutical microbiology, university of bonn, meckanheimer aune , d- bonn, germany infectious diseases in intensive care patients are common in comparison to patients on other wards and out-patients. the main difference is that intensive care patients are much more sensitive even to less virulent bacteria. thus, the spectrum of infecting organisms is different. strains often regarded as pathogens with low virulence cause serious infections in these patients. strains such as serratia, however, have intrinsic resistance to most commonly used agents such as rd generation eephalosporins. furthermore, the common pathogens like staphylococci, psoudomonas aeruginosu, enterocneei and gram-negative bacteria, enterobacteriaeceae as well as the non-fermenters are less sensitive if isolated from intensive care patients. it is difficult to generalize on intensive care units as different patient groups are in different icus aud there are great changes from one hospital to another and from one country to another. if we take s. aurens strains from one study from the'overall resistance in intensive care units towards oftoxacin was %, whereas in other hospital wards the percentage of resistance was . %, in out-patients, however, only .$ %. the same trend was true for entercnecus faecnlis, coagulase-negntive staphylococci, and other bacteria as well as other drugs. one most striking difference was found with klebsialla pneumoniae and gantamycin resistance, which was $ times higher in intensive care units as compared with outpatients, whereas in the same species no difference was to be seen with the resistance towards carbapenems. however, differences between countries seem to be even more striking, as example gantamycin resistance and staph. anrens is given. the extreme difference is more than fold. thus, it is evident that there is a general trend towards higher resistance in intensive care units, but no generalizatiouis possible. therefore, surveillance studies in intensive care units are needed and the antibiotic policy has to be adapted to the specific needs of the unit. in the icu setting the most potent antimicrobial agents are required to address problem organisms including those resistant to penicillins, cephalosporins and aminoglycosides. carbapanems would appear to present a useful option in this setting. objectives of this study was the evaluation of systemic candid• in postoperative cardiac surgery patients (pts) with prolonged icu stay. methods: out of postoperative adults pts of mean age . + . years old, with a mean icu stay of . _+ . days, following an open heart surgery from july to april , pts ( %) remained in icu for more than days because of severe perioperative complications. patients were included in the protocol if they had clinical signs of infection or sepsis, and fungi isolated in blood culture or in culture from at least three different sites. the patients who developed systemic candidiasis received iv fluconazole ( mg/day) ( patients) or amphotericin-b for at least four weeks, and then they were closely monitored. results: out of postoperative pts with prolonged jcu stay, pts ( . %) developed systemic candid• usually after the th postoperative day. they were males and females of mean age +_ . years old. this group of pts had prolonged bypass and aortic cross-clamp time compared to control group ( min vs , and vs min). all these pts received inotropes per• (mean value= . ). during their icu stay, pts developed sepsis of bacterial origin, while the other two severe infection, and received antibiotic regimens for prolonged period. the patients were submitted to mechanical ventilation for a median period of days. the median icu and hospital stay was and days respectively. all pts have been improved and finally negative cultures were obtained. conclusions: . a significant percentage of patients who remained in the postoperative icu for more than days developed systemic candidiasis. . all patients who developed systemic candidiasis had received antibiotics because of sepsis or severe infection, for prolonged period. . fluconazole seems to be a very good alternative to amphotericin-b. . fluconazole is a safe antifungal agent with few side effects. botulism is the most severe and an odd food poisoning. although it is more commonly related to preserved meat derivatives, preserved fish and vegetables are also responsible for a number of cases. obiectives: to evaluate four familiar outbreaks of botulism . methods: we study the patients that were admitted in our hospital because of botulism from may to february . results: the thirteen pacients involved had a previous history of home preserved beans ingestion. after a -hours incubation period, gastrointestinal symptoms (abdominal pain, vomits, constipation) appeared and lead them to hospital consultation in the th to th day after ingestion. two patients died (acute respiratory failure before admission), seven were admitted in icu, two in ward and two of them were discharged from emergency room. clinical symptoms and the previous history of the ingestion established the diagnosis, that was emg confirmed. in all cases, symptoms were consistent with b-toxin botulism. b-toxin was isolated in serum and food proceeding from the third outbreak, and the serum was negative in the other ones. neurological symptoms were predominant: midriasis ( %), dry mouth ( %), dysfagia ( %), asthenia ( %), palpebral ptosis ( %), accomodation paralisis ( %) and urinary retention ( %). muscle weakness lead to acute respiratory failure in three patients (one of them required mechanical ventilation). four patiens developed infections (respiratory, urinary and phlebitis). both died patients and one another presented severe hypertension. all admitted patients were treated with polivalent anti-toxin. the two patients who underwent a more severe muscle weakness received also guanidine hydrochloride, with no answer in one case and provoquing a cholinergic crisis in the other one. icu length of stay was days. at hospital discharge, patients continued symptomatic, mainly with dry mouth, disfagia and impaired vision. conclusions: although botulism is a serious illness, the pronostic seems favorable if treatment and support measures are avaible. usually neurological symptoms we predominant and at discharge some of them could still persist. the arrow "hands-off" (aho) thermodilution catheter (tc) is completely shielded during balloon testing, preparation, and the insertion procedure. in order to assess the value of the aho thermodilution catheter in the prevention of systemic infections associated with pulmonary artery catheterization (siapa), we conducted a randomized prospective study over an -month period. methods : the patients (pts) were randomly assigned to two groups : group i for a standard tc customarily used in the department, versus group for the aho thermodilution catheter. the diagnosis of siapa was determined on the basis of a positive culture of tc and bacteremia with the same organism, with out any other nearby focus, in association with regression or disappearance of the clinical signs of infection after removal of the thermodilution catheter. results ( objectives: the mortality rate (mr) of tb requiring mechanical ventilation (mv) is high ( - %). the aim of the study was to evaluate mr, associated factors, and prognostic significance of mv and hemodynamic disorders from tb in icu in patients with tb. methods: clinical parameters on admission, and complications in icu were related by univariate analysis to icu, hospital, and month outcome. patients required mv; were immunocompromised (ic) including hiv. tb was pleuropulmonary in , disseminated in and meningeal in . results: mr was % in icu, % in hospital and % at month. / ( %) < . mortality was associated with a high saps score, initial shock, mv and nosocomial septicemia. the mr dramatically increased when ards occurred during illness, despite the lack of correlation between mr and initial po /fio ratio or initial murray score. the site of infection did not influence the mr. surprisingly, the mean therapy delay was shorter for non survivors. mr was not related to ic status, nor hivstatus, but was only related to previous steroid therapy. conclusion: mr of tb requiring icu is high ( % at month). need for mv increased mortality ( % vs %). general severity and respiratory dysfunction seem to be major prognostic factors in icu rather than tb per se or than therapy delay. in spite of the improvement in the prognosis of pneumococcal meningitis (pm) with third generation cephalosporins (tgc), this infection still presents a great mortality which could be increased with the appearance of antibiotic resistant streptococcus pneumoniae. objectives: to asses intensive care mortality and morbidity of pm and to define patients (pts) at risk of complicated evolution. patients and methods: a retrospective evaluation of pm cases (all diagnosed by csf culture) admitted in our icu from january tit march . in all pts we analized: demographic data, underlying disease, apache ii score, clinical symtomps, treatment, complications and outcome. statistical analysis was done using bmdp sofware package. results:a total f pts were studied, males; mean age , _+ ( - ); apache ii score , + , ; glasgow coma scale (gcs) at admission , _+ , ; ( %) pts suffer from cronic pathology; ( %) pts diabetes mellitus (dm), ( , %) pts had had a previous cranial traumatism. in cases the source of infection was otic and also in ( %) episodes of pm there were bacteriemia. in out of ( %) pts that ct was performed no radiologic abnormalities were shown, of them presented cerebral oedema and pts a cerebral abscess. twenty-eight percent presented seixures, % hemiparesia, , % respiratory failure, , % shock, i % renal failure, , % multiple organ failure (mof). as for treatment refers , % pts recieved only penicillin, , % pts only tcg, , % pts tcg followed by penicillin and , % pts tcg+vancomycin. seventy-five percelat of pts recieved corticosteroids and , % vasoaetive drugs. the mean icu stay was , : days ( - ). twelve ( , %) pts died, two of them presented pm relapse (resistant streptococcus pneumoniae) and another two pts developed neurological sequelae. factors associated statistically with bad prognosis were dm, the use of vasoactive drugs, shock, mof, the apache ii score at admission, the gcs at the and hours from admission in the icu but not the gcs at admission. didn't resulted statistiealy signifcative age, previous eronie pathology, seizures, baeteriemia, renal failure and coagulation disorders. conclusions: mortality was high and associated to apache ii score at admission, to gcs at and hours after admission, shock, vasoaetive drugs and mof. objectives:the aim of the study was to analyse some of significant immunologycai changes in surgical patients,requiring intensive health care,and to determinate the possibility for evaluation,dynamical examination and importance of immunologycal problems for treatment. methodes:the study concerns a number of patients with expanded surgical intervention or serious postoperative complications.the results has been carried out with fiowcytometryc analyses of lymphocytic suhpopulations and routins methods for investigation of humeral immunity.the"panel" for evaluation of (} immunologycal parameters has been offered:t-calls total/cd +/;t-helper/cd +/;t-supressor/cd +/ th/ts ratio;b-cells/cd +/;naturai kilier/nk/cells;skin test for cellular immune function;phagocytic and oxidative activity;serum levels of immunogiobulins-g ,a,m;protease inhibitors;c-reactive protein.all patients have been studied during suffering and after surgical procedures dynamicaly. results:there have been estimated significant changes in immunologycal parameters especially:decrease of t-cells: cd +mean= . %/ . %- . %/and cd +mean= . %/ % - . %/;inverted th/ts ratio ,mean=o. / . - , /;reduced or negative skin teste;reduced phagocytic and oxidative activity before septic complications. conclusions:dynamical examination of immunologycal parameters shows,that the prolonged t-total,t-helper lymphocytopenia with functional deficience of ceils-mediated immunity correlates with the stage of clinical condition of the patients and has prognostic importance.it's clear,that immunologycal monitoring gives a possibility for immunecorrection. patients (pts) with the human tmunodeficiency virus (hiv) infection have a decreased immune response and are particularly susceptible to infectious endocarditis (ie). the aim of our study was to analyze the prevalence of ie, its clinical and therapeutic implications in a hiv population we prospectively studied pts, . % ( / -group ie+) with ie during the clinical course of this disease. we analyzed the following parameters: age, gender, race, type of hiv, cdc classification, number of t and t type cell population and its ratio, therapeutic with azt, type and number of opportunist infections (inf, mycobacteriosis (mb), neoplasm's (nee) the echocardiographic parameters were lv internal diastolic and systolic diameters, lv percentage of fractional shortening, interventricular and posterior wall thickness, the degree of valvular regurgitations and the presence of pericardial effusion. el was located at the mv in . %, tv in . %, av in % and pv in . ~ and was multiple in . %. hiv el+ pts had larger lv diameters and more frequent significant valvular regurgitations ( % tr, pe %, mortality %). these two groups differed significantly in the following clinical parameters: the typical symptoms were watery diarrhea, high fever, tachycardia,luekocytopenia and oligouria within th postoperative days. the patients with mrsa enterocolitis had positive mrsa culture from the many materials except feces.mesa strains frequently had coagulase type ,enterotoxin a and toxic shock syndrome toxin- .eight of patients had postoperative organ failure.most of the mrsa strains in japan were similar in coagulase type to our hospital and our department.all of mesa strains were susceptible to vancomycin and arbekacin,tbough most of them showed resistant to many other antibiotics.we have employed guidelines for therapies such as oral or enteral administration of vancomycin and correction of the hemodynamics for dehydration and circulatory failure due to diarrhea from .futhermore we have placed colonized or infected patients in private room,worn gown and mask,and carefully washed our hands from . these countermeasures for prevention of nosocomial infections after significantly reduced the incidence of mrsa enterocolitis. conclusions:earlier diagnosis and treatment, and distric prophylactic measureres against mrsa infections are very important. -- cdo ivda leptespiresls affects all the organs with widespread hemorrhage that is more prominent in skin, mucosa, skeletat muscles, liver and kidneys. lung involvement is usually mild and less common. suli, it is very uncommon acute respiratory failure to be the pr sontirlg symptom. a case with leptosplrosl..,s which was presenting with acute respiratory failure is described. a year-old man admitted to icu becauso of fever, myaigla, aevere c~, hemopty~s. his blood gases showed: pao : mmhg with fio : . , pco : mmhg, ph: . , hco : mecl chest x-ray film demonstrated diffuse bilateral alveolar pattern occupying beth lung / ). trarmamlnase, bllllrubln, ~ and esr were elevated, wbc was . mm , platelet: . ram , hematesrlt: %, hemoglobin: .sgrldl=. there was no clinical or ecttlographlc evidence of left heart failure.patient fulfilled the criteria for diagnosis ards he was found to have an ~lutinatlon tlter for leptoq~lral antigens(indirect he~lutlnatlon atomy, ilia} very high ( / , negative<ill ) and iglm antibodies also very high (elisa, a= . , negative< . ) strongly suggesting leptospirosls. treatment with tetracycline and non-tnvaslve mechanical ventilation by nasal mask were started. pre~jre support mode and cpap was usod. the following days the clinical picture,the oxygenation and the chest x-ray of the patients were improved, and patient dl~herged from the icu. the control of leptosplremlc phase as well as his good cooperation during nipsv contributed to rapid recovery and excellent outcome in hiv infections, pneumonias (pnm), mainly due to pne~ mocystis carinii (pc) have an outstanding place in pu ! monary complications. the aim of this work was to compare two group> of patients admitted with pnm in our icu during the same period ( - ): group a, patients hiv+, and group b, patients hiv-. apache ii was identical in the groups (p=ns). group a required more often mechanical ventilation (p= ,o ), had a higher p(a-a)o (p= , ) and metabolic acidosis was more frequent (p= , ). regarding laboratorial parameters group a had a lower no. of linfocytes (p= , ), a higher ldh (p= , ) and a more marked hypoalbuminemia (p=o, ). mortality was higer in group a ( , %) than in group b ( , %), (p= , ). analysing the a group patients, we found no significant differences between alive and deceased patients, with exception for albuminemia, which was lower in the deceased patients (p= , ). in conclusion, the hiv+ patient's pnm have a more agres sive behavior when compared with community acquired hiv-patient's pnm. the prognosis was not influenced by the apache ii. perhaps other parameters such as p(a-a)o , metabolic acidosis, linfocytes, ldh and albumin shoud be more evaluated as possible predictive indices. some prognostic factors, usually accepted as predictive in the analysis of hiv+ patients do not seem to be worth in the late stages of aids, mainly when they reqquire intensive care. intensive care unit, onassis cardiac surgery center, athens, greece. objectives of this study was the comparison of two different antibiotic regimens as prophylaxis in cardiac surgery patients. methods: in a prospective randomised comparative study, two different forms of antibiotic regimens were investigated : a single dose of cefuroxime (zinacef, gr) (group a) given during the induction of anaesthesia, versus a four days combination of amoxiculine (amoxil, gr tid) plus netilmicin (netromycin, mg bid) (group b). a total of patients (pts) ( males and females, of mean age . + . years old) were included in the study over a period of one year; in group a and in the group b. patients were checked for the occurrence of infection during the first postoperative month. results: the total rate of infection in cardiac surgery pts was . %; . % in group a and . % in group b (p=ns). pts ( . %) developed infection following cabg, pts ( . %) following valve replacement and pts ( . %) after other cardiac surgery. they were males ( . %) and females ( . %). endocarditis has occurred . % in group a and . % in group b. severe wound infection was recorded in . % in group a and in . % in group b. one case of sepsis ( . %) in group a and in group b ( . %). respiratory infection occurred in pts of group a ( . %) and in pts of group b ( . %). two cases of urinary tract infection was in group a and one in group b. catheterrelated infection was occurred in ( . %) in group a and ( . %) pts in group b. pts ( . %) had fever of unclear aetiology in group b. conclusions: there was no statistically significant difference regarding the rate of infection in both groups. a single dose administration of cefuroxime is accordingly just as effective as a four days regimen of amoxicilline plus netiimicin. legionella pneumophila is a common bacteria of the environment, and it is an agent responsible for severe community acquired pneumonia (cap). we analyzed the patients with lpp admitted in our icu during the last years ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . they represented . % of cap. seven patients were males and female, with mean age . + . years. tiss was . + . and apache ii . + . . all, but patient, were under mechanical yen tilation (mv) during a mean period of . • (min-l, max- ) days. two pneumonias occurred beyond the season, while patients had an epidemiological history. only patient had no risk factor. in all the others tobacco smoking and alcohol abuse was quite frequent. diagnosis was based on serologic test and culture or direct fluorescent antibody staining of bronchial secretions. seven patients had a multisystemic disease with hepatic dysfunction in , renal failure in (due to rhabdomy~ lysis in ). one patient had a prosthetic valve endocarditis and another developped ards. nosocomial septicaemie occurred in patients. mortality rate was %. deceased patients had initially higher apache ii, (a-a) , and lower natriemia. comparing lpp with the other cap (n= ), both submitted to mv, mortality rate was similar ( , % versus . %). in conclusion lpp can occur all over the year. there was a high incidence of severe complications and outcome was similar to the other cap when requiring mv. prospective specimen brash (psb) with culture > cfu cfu/ml. broncho-alv~lat lavage (bal) ~= c'fu/rnl or positive blood culture. were excluded for rapture of treatment ; were analysed (shift with oral antibiotic : ; prohibited antibiotics associations : ; resistant germ : ). clinical data : age , • , ; saps • , ; mac cabe i : , % -ii : , % -iii : , . , % of the patients were intubated and under mechanical ventilation. the pneumoaiae were : primitive in ( , %), copd ( , %), aspiration pneumonia ( , %). germs were isolated (psb , bal , blood culture ) : s. pneumoniac ( , %), h. influeazae ( , %), sttep~:occns ( , %), saar ns ( , %), enterobaetdrindr ( , %), mosexella catarrhalis ( , %), othem . / ( , %) were sensitive to freatment. the ltentment was mg/kg/d of ampiclllin and mg/kg/d of sulbactam in continuous iv adminisu'ation during at least days. clinical eff~ienev : success ( %), failures ( %) with superinfeetion , worsening or relapse , dead , side effects . there was no difference between etiologies : primiti~;e~ , %, copd , %, aspiration pneamoniae , %. the bacteriological effieieacy was evaluated only for patients with eradication ( , %), eradication but super~ection ( , %) : with pseadomoaas a&ogiuosa , eater~ac~ ; beeteriological failure ( , %). in conclusion, the aasor ampicillin -sulbactam is effective for the i~eatment of severe acquired community pneumonise. objectives : to assess the efficacy of chlorhexidine (cl) gel or suspension applied in the nose and in the op for the prevention of the tmcheobronchial colonization. methods : thirty-seven patients expected to be intubated for > h were randomized to received topical application oga cl suspension ( %) qshrs, a cl gel ( %) q hrs or a placebo. in addition all vpts received a nasal and a op spray ( %) of either cl or placebo administrated according to the same schedule. semi-quantitative cultures of the anterior nares, the oropharynx (op) and the trachea were obtained on admission and once a day until extubation (just before the next application). the results were assessed according to the following criteria: success = no acquisition of gnb in the trachea ; failure = acquisition of gnb in the trachea. acquisition was defined by a follow-up culture positive for a gnb not present in the trachea on admission. results : success failure nosocomialpneumonia overall morality clsusp. placebo clgel placebo n= n= n= n= / / / * / / / / * / / / / / / / / / i *p = , byfisher'sexacttest conclusions : these results suggest that topical cl gel administered q hrs may prevent tracheal colonization by gnb. f. daumal*, m. daumal**, c. plot**, v. vurmmen ~ e.colpurt**, b. manonry** * hygiene hospitali&e, ** service de r enmmtion, * service des admissiens-urgeuces centre hospitalier g- ndral - saint-quentin -france obiectives: evaluate the nosocemial risk due to peripheral venous inserted short catheters, and the quality of care. patients-methods: the intensive tare unit (i.c.u.) is a beds unit. the prospective study includes all the patients comn~ in from / / to / / . the recruitemont uses an evaluation schedule of local clinical signs. the nurses aimed to create this evaluation data which includes the place of entry site, the duration of catheterization and the cause ot withdrawal. only patients staying longer than days in the i.c.u. are accounted for. the diagnosis of uosoenmial infection is assured by the physician taking care of the patient and by the hospital epidemiologist on the next signs: evident pus at the catheter entry site, positive culture of the strain, with or without the same pathogen in the blood sla'uam,the patient having no other distant source of infection. analyses were performed on epi/nfo. results: the occurrence of nosoeomjal inthrtions: i abcess and bacteremia during the first part of the study lent the medical staff to modify the protocol of insertion end survey of the device. so we analysed different periods: period ( / / to / / ) and period ( / / to / / ) for all .e peripheral catheters inserted in the i.c.u. period , % , % en infection due to peripheral venous device is a daily threat. the severity of some clinical situations requiring admission in icu proves it. the motivation of nurses for rigid adherence to established protocol, the daily survey of the entry site, the withdrawal of the peripheral catheter every hours aimed to reduce significantly the local signs of inflammation end infection of peripheral catheters inserted inside the i.c.u. objectives: to investigate the use of a new metabolic monitoring device for different ips levels by comparing oxygen consumption (vo ) to measurements of the mechanical work of breathing (web) and p . . methods: the study was approved by the institutiotml ethics committee. eight patients were investigated during weaning after prolonged mechanical ventilation ( - days) for various diagnoses when the clinical physician judged the patient to be ready fur weainag. ips was setto , , , mbar far rain periods each. all patients had a peep between - mbar.. respiratory frequency (f), tidal volume (tv), minute ventilation (ve) were read from the ventilator display ( ae, puritan bennett, carlsbad, usa). flow and airway pressure were measured at the endotracheal tube site. esophageal pressure was measured using an esophageal balloon catheter (fa. ruesch, frg). web was determined as the area subtended by the pleural-pressure-vohime curve. p . was determined by using standard occlusion technique and graphical analysis of the airway pressure tracing. vo and vco were measured using the pb metabolic monitor (puritan bennett, carlsbad, usa) connected to the pb ae ventilator. all data are given as mean• deviation for each ips level. comparison between the different ips levels was performed using anova for repeated measurements. significance was considered at p< . , compared to ips mbar. results: the values for breathing pattern, web, p . , vo and vco are given in the table for the different ips levels; significance is indicated by ~. objectives: fluidized beds are often used in the management of critically ill mechanically ventilated patients. critically ill patients are increasingly colonized with resistent pathogens [ie: p. aeruginosa, methicillinresistent s. aureus (mrsa), extended spectrum i~-iactamase producing enterobacteriaceae ] that can ultimately cause nosocomial infection. methods: we prospectively monitored bacterial colonization of mechanically ventilated patients and of the fluidized bed (clinitron) inwhich they were treated. multiple samples for quantitative bacterial cultures were taken from oropharynx, trachea, feces and bedsores. samples of ceramic beads from the bed were also taken both during and after patient stay (after bed operation in the absence of patient). re,~ults: episodes in consecutive patients (mean age: . years) were analyzed. all had bedsores and/or urinary catheters and fecal incontinence, patients had nosocomial pneumonia, had urinary tract infection [ with extended spectrum imactamase producing k/ebsie//a pneumoniae (ki~lse)], one had positive blood cultures with mrsa, and one patient had a ki~lse found in high concentrations ( - s cfu/ml) in occasions in feces. patients were heavily colonized: the , samples from ceramic beads showed no growth or became sterile without any sterilisation procedure (even in one case of presence of kf~lse) during the patient stay. conclusions: fluidized beds do not put patients at high risk of acquiring nosocomin pathogens, and cross-contamination between patients seems unlikely, even when multiple resistent organisms were initially present. the recommandation from some manufacturers to undergo extensive sterilization of fluidized beds after use does not seem warranted, at least with the bed used in this study. ant. koutsoukou, a, tahmitzi, p. kithreotis, m. koutonlidou, k. stavrakaki, kainis e, g. vlahogiorgos and e. eliopoulos icu-centre for respiratory failure -chest diseases hospital of athens. the cost-effectiveness issue is becoming vital in modern medicine and may lead to moral dilemmas since sometimes certain groups of patients may not have access to highly specialised modalifies. objective: our study compared the mean daily cost for antimicrobial medication in copd patients treated in icu versus all other patients in the context of relevant epidemiological, prognostic and outcome data. methods: age, sex apache ii score, length of icu stay (los) and in -icu fatality were retrieved from the files of all icu admissions over . mean daily cost for antimicrobial therapy per patient (dcat) was estimated. these variables were statistically compared between copd and non-copd patients. significance was assumed at p< . results: of the total admissions were fully evaluable. of them ( %) were copd patients. data (m---sd) results for statistical test are given in table i . copd patients were significantly older spent more time in the icu and presented with significantly higher apache ii scores. outcome and dcat were comparable in the two groups. objectives: the use of heat and moisture exchangers (hmes) during long term mechanical ventilation (mv) is increasing. in icu patients, they are routinely changed every day, according to the recommendations of the manufacturers, but the clinical basis for such a daily practice is lacking. we therefore prospectively assessed whether changing hmes (dar hygrobac, spa, mirandola, italy) every h only would affect their clinical and bacteriological efficiency. methods: two consecutive groups of patients requiring mv for > h were compared: group = hme replaced every day, n= episodes of mv in patients; group = hme changed every h, n= episodes in patients. tubings were not changed in the same patient during the whole length of ventilatory support. diagnosis of nosocomial pneumonia (np) was based on a positive quantitative culture (~ cfu/ml) of a protected specimen brush in patients with clinical signs of pneumonia. quantitative cultures of pharynx, trachea and y-cannector were performed every h. results: the groups were similar in terms of age, indication for and overall duration of mv ( +_ . vs +_ days, p= . ), and severity of illness (saps: --- . vs . +_ . , p= . ). the maximal values for peak airway pressure were identical in both groups ( . -+ . vs . • cmh , p= . ). obstruction of the tracheal tube was observed in only one instance in a group patient who had tracheal bleeding. circuit colonization was very rare, and of low grade in both groups. the level of patient colonization and the type of organisms were identical in both groups. more importantly, the incidence of np was the same ( / vs / , p= . ), as was duration of mv before the occurence of pneumonia ( • vs . +_ . , p= . ) and overall mortality rate ( vs , p= . ). conclusions: the clinical efficiency of this hme does not seem altered after days of use. indeed, replacing this hme every h only neither affect circuit and patient bacterial colonization nor the incidence of np. therefore, substantial savings could be obtained changing hmes every other day only. obiectives: to evaluate the usefulness of different paraclinical investigations for the diagnosis and prognosis of acute viral encephalitis in icu patients. methods: we reviewed patients (pts) admitted to our icu from july to december with the diagnosis of acute viral encephalitis. all were in coma and were initially treated as presumed herpes simplex virus (hsv) encephalitis. the causative agents were: hsv ( cases), herpes zoster varicellae ( ), measle ( ), rabies ( ), unidentified ( ). eleven pts survived and three presented neurologic sequelae. twelve pts were investigated by mri, and eleven also by spect and multi-modality eps. including brainstem auditory eps (baeps). these investigations were obtained as soon as possible following admission and were repeated during icu stay when possible. the clinical outcome was noted. results: six pts ( / ) had an abnormal mri. among them, pts made a complete recovery, in comparison with / pts with a normal mri. in one hsv infected patient, mri remained normal despite clinical deterioration and bad outcome. when repeated, mri became abnormal in cases (with poor outcome in one) and was improved in one. spect was found abnormal in / pts (among them, pts had thus a normal mr/). the correlation regarding the topography of brain lesions was poor between mri and spect. the findings of spect could not be correlated with a poor outcome. the baeps confmned in % of the pts the clinical diagnosis of brainstem involvement. changes in visual and somatosensory eps were mild in all the pts and were not helpful for the prognosis. eps were otherwise interesting for the follow-up of the coma in these sedated and ventilated pts. conclusions: the value of mri and eps for the diagnosis of acute viral encephalitis is of limited interest. spect seems to show early modifications, even in pts with a normal mri, but this test is poorly specific and does not correlate with mri changes when present. concerning the prognosis, larger studies should probably confmn that a normal mri could usually result in a good outcome. this serie illustrates also that hsv encephalitis could be demonstrated only in a small number of cases and that the prognosis of non hsv encephalitis is not easily assessed. objectives: to study the influence of gram (-) bacterial lung infections on liver function i~ mv icu pts. pts and methods: we studied pts, # ( , %), ( , %). hean age: , • years ( - ). mean stay in icu: , • days ( - ). they were divided in groups: a( pts) who did not suffer from pneumonia and b ( pts) who developed a gram(-) bacterial pneumonia. both groups were consisted of pts with same age, sex and disease distribution and same systemic failures. we measured sgot, sgpt, total bilirubin(tb), direct bilirubin (db), alk.phosphatase (al.ph.), v-gt and albumin (alb.) times: on days o, and of the pneumonia for group b and respectively for g~oup a. conclusions: ) in elderly intubated pts of an icu, kp is isolated more frequently than in icu pts< years (p<o, ). ) the frequency of isolation of kp in icu pts during - was - %, but now ( - ) kp becomes more and more rare ( - %) and is isolated especially in elderly pts. ) its sensibility to antibiotics remains always the same. ) the prognosis of np in our study was independent from age (p<o, ), sex, presence of bacteremia (p< , ) and type of invading microorganism. gram neg bacteria and renal failure (rf) from aminoglycoside toxicity are common and serious complications in critically ill patients. the aim of this prospective, pilot study was to compare the safety and adequancy of the endotrecheal (et) vs the intravenous (iv) administration of aminoglycosides. were measured in the plasma and the bronchial secretions at and hours after the iv (bolus) or the et (nebulized) administration of mg of gm in seven criticcally ill patients ( with established renal failure). safety was defined as peak and trough plasma gm levels _< than and ijg/ml respectively and adequancy as gm levels in bronchial secretions _> , ijg/ml. results: gentamicin was administered by the et and iv routes in and separate sessions respectively. a total of samples were assayed, in bronchial secretions (bs) and in serum. the et route resulted in higher gm levels in the bronchial secretions compared to the iv route ( , + , vs , _+ , pg/ml respectively, p = ns ). adequate bronchial gm levels were achieved in % of patients after et administration, compared to % after iv aaministretion. the blood levels of gm were significahtly lower after the et vs the iv route ( , + , vs , • , pg/ml respectively, p _< . ). the et administration resulted in toxic bronchia~ gm levels in % of the specimens. % of these samples were from patients with renal failure, however toxic blood levels were reached in only % of these. gentamicin seems to be a safe and adequate alternative route of treatment for the lrti. however, in patients with renal failure the et administration of the aminoglycosides should also be modified and continuously monitored. in order to evaluate the pathogenic role of anaerobes in nosocomial pneumonia (np), we investigated the systemic humoral response in patients who developed a np with anaerobic bacteria, especially prevotella species. methods: blood samples from groups of patients were tested. group i: patients with a np in which prevotella spp. was isolated from protected specimen brush (psb), group ih a control group of patients with a np without anaerobic bacteria, group ill: a control group of patients with dental stumps but without pulmonary infection, group iv: a control group of healthy voluntary people with prevotella spp. isolated from the dental plaque. an elisa was used to evaluate the total antibodies level against a mixture of four prevotella strains and a western-blot method was done to identify the antigenic proteins. results: data are expressed as means .+ sd. the antibody levels in patients of group i ( • was statistically higher (p=o.o ) than in the control groups (respectively: + , _+ , _+ ). using western-blot method, the intensity of the response was roughly superposable to levels obtained by elisa and the profiles were different according to the prevotella species. the occurence of a np with anaerobic bacteria (prevotella species) isolated from psb leads to an antibody response which seems specific of the prevotella species isolated. fever is common in the intensive care unit, but is not always related to an infection. we sought to define the epidemiology of febrile patients in a general medical/surgical icu. methods: we prospectively analysed the source of fever (t > . ~ c) in all adult patients admitted for >- hours in the icu during a two month period. these patients were studied for consecutive days. and werc classified in groups according to the evidence of infection (center for disease control criteria) after complete evaluation: documented infection: cdc criteria + isolation of pathogen (d); possible infectron: cdc criteria without isolation of pathogen (p); unlikely infection: patients who did nol meet the cdc criteria (u). results: of a total of patients studied, dec'eloped fever ( %). including (after complete evaluation) d, p and u palients. both the highest temperature in tile first day of fever and the maximal temperature were higher in d than in u ( . • versus . • and . -~ . ~ versus . - . , respectively p= . and p= . ). most common sources of infection in d were the lungs in patients ( %) and urina .ry tract in ( %). of these patients had positive blood cultures ( %). the overall mortality was % ( % in d, % in p and % in u. differences ns). antibiotics were given in % of d, % of p and % of u ( patients). in p there was a non significant lower mortality." in patients who received antibiotics ( / ( %) versus / ( %) patients, respectively). conclusions: in febrile icu patients both the highest first day" temperaturc and maximal temperature are significantly higher in infected than in non infected patients, but the differences are too small to be useful clinicall). mortality rate is not significantly influenced either by the presence of an infection or by the administration of antibiotics, obiective: retrospective study to determine the influence of candida infection on icu outcome. methods: patieet with a stay of more than days in inteaasive care were screened for candida infection. patients were treated with antifungal therapy due to either an increased antigen titre of -> : or clinical evidence of candida colonization. serological candida-antigens (ramco, pastorex) and antibody titres (hemagglutination, lgg-, igm-elisa) were examined routinely. seroconversion was defined as a threefold increase of antibody titre or a titre of : or higher. results: the median length of stay was (ranging from to ) days, the mean apache ii score on admission was (+_ . sd) points. of patients patients died ( . %). in the group treated with antifungnls ( patients) patients died ( . %). although of the patients only ( . %) developed a candida infection as defined above the mortality in the group that showed signs of infection was significantly higher ( . % vs. . %, p < . [chi-square-test]). in patients an antigen concentration-> : was measured. seroconversion was found in patients. the most common fungus was candida albicans ( . %). furtberm re, candida glabrata was found in . %. most of the patients were treated with x mg fluconazole ( patients). in patients therapy was changed to amphotericin b/flucytosine. in patients therapy was started with amphotericine b and flucytosine. in patients a threefold decrease of candida antigen titre was found. patients showed a decrease of candida antibody titre. conclusions: meticulous screening for eandida infection seems to be necessary since the number of patients with fatal outcome is significantly higher in the group with signs of fungal infections and thus requires immediate antifungal treatment. objective: early diagnosis of patients with ventilator-associated pneumonia (vap), and subsequent identification of causative microorganism, and selection of the appropriate therapy are critical important points that affect morbidity and mortality. the results of the quantitative bacterial cultures are not available for at least hours, while a two hours period, since the specimen are obtained is enough to know the gram stain results. the aim of this study is to determine the usefulness of gram stain in specimens obtained by bronchoaiveelar lavage (bal), through the bronchoscope. material and methods: we studied patients ( males and females, age + ) with suspected ventilator-associated pneumonia. the bal gram stain was considered positive when the specimen after a centrifugation at rpm for min revealed: i) more than leukocytes per optic field, ii) squamous epithelial cell less than percent and iii) one or more microorganisms per optic field on magnification. all patients had been receiving antibiotics, with no change during the last days, prior to bronchoscopy. results: patients had vap and patients did not. in cases the bal specimens (quantitative bacterial cultures) established the diagnosis of vap in the remaining three patients the vap diagnosis was established by other procedures (blood or pleural fluid culture, clinical outcome, autopsy). apache fl score in patients with vap was , -+ , , while in patients without vap was , + , . there was a significantly higher incidence of vap in patients who had i) coma (gcs < ) and ii) been receiving neuromuscular blockade (p< . ) . the sensitivity of the gram stain for vap diagnosis was %, the specificity , %, the positive predictive value %, and the negative predictive value , %. conclusion: our data indicate that the gram stain of bal specimens is useful for the early diagnosis of vap and the subsequent administration of the appropriate treatment. the role of anaerobes in mechanically ventilated patients with pneumonia (mvp) have been poorly investigated aim of the study : analyse the prevalence of anaerobic isolation in mvp. methods : between october and february all suspected mvp were investigated using protected specimen brush (psb) technique. brushes were rapidly transported in shaedler broth to laboratory. a special care was tooken for anaerobic isolation. results : among the psb performed for suspected mvp ( nosocomial and community-acquired pneumonia), yielded at least one micro-organism (positive psb : %). of positive psb demonstrated only aerobic bacteria and ( %) yielded with anaerobes. in out patients, anaerobes were associated with aerobic bacteria. anaerobes were mostly isolated in nosocomial pneumonia ( / positive psb). strains of anaerobes were isolated. prevotella species represent out these strains ( %) the most frequent anaerobic species were prevotella oralis ( ) p. intermedia ( ) and p. buccae ( ). comments:using adequate methods, anaerobic bacteria are frequently isolated in mvp. it could be off importance to take in account anaerobes in the choice of empirical antibiotic therapy in mvp. objectives: the majority of patients with multiple trauma are considered immunocompromised. the aim of this study was to identify risk factors of pneumonia in mechanically ventilated patients with multiple trauma or after surgery. methods: in this prospective study we studied multi-trauma patients (mean age + years, apache ii . + ), admitted to a general intensive care unit (icu). all patients were intubated and mechanically ventilated. we were considered that a patient had ventilator associated pneumonia (vap) when the specimens of bronchoalveolar lavage (bal) or protected specimen brush (psi?,), ebb'ned through the bronchoscope, had one or more microorganisms in concentrations greater than and cfu/ml respectively. all patients had been receiving antibiotics, with no change during the last days, prior to bronchoscopy. results: patients had vap, and patients didn't. in the bivariate analysis, the glasgow coma scale (gcs)< (x = . , p< . ), the administration of neuromuscular blockade (x = . , p< . ), the duration of mechanical ventilation to be greater than days (x = . , p< . ), the flail chest (x = . , p< . ), the parenteral nutrition (x = . , p< . ), the ards (x = . , p< . ), the abbreviated injury scale (ais) of more than for thorax (:,: = . , p< . ), the pneumothorax (x = . , p< . ) were statistically significant related to development of vap. in multivariate regression analysis, using the stepwise technique, three of the seventeen studied factors showed to have an indepantent association with the development of vap:the administration of neuromuscular blockade (f: . , p< . ), flail chest (f: . , p= . ), and gcs (< ) (f: . , p= . ). conclusions: in patients admitted to icu for multiple trauma or major surgery, the administration of neuromuscular blockade, the flail chest, and the gcs (< ), in the population under study, were the indepedent risk factors for vap. mof is a sereous complication of differem states: infection, sterile inflamation, extensive fissure injure, intoxication, ets. there is close correlation between extension of mof and death, developement of nasocomial infection. immunologic disfunction. in order to prgnose probability of risk of mof development among the patients with sepsis and septic shock, we achived an eqation, allowing to recive a coeficient, closely connected with this probabiliti. we have used retrospective analisis of cases of sepsis. diagnosis of sepsis was based according to bone's criterions of sepsis. mof was assessed as disfunction of or more systems according to bone's classification of mof. having used correlation analisis we have estimated factors which have had high correlation coeficient with the probability of development of mof. there were: apache-ii score points, evidenceof septic shock, endocrinopathy. with the help of multyple regression analisis we acheved next equation: y= , + , x~ + , x + , x , were x i-apache-ii score points, x -evidence of septic shock, x -endocrinopathy. the explanatory power of this quation was evidenced by roc of . , se (v - . introduction: the presence of liver dysfunction in the process of multiple organ failure is associated with an adverse outcome, particularly when it becomes progressive to liver failure. disturbances of liver function may occur early and their detection may be of significant importance for the further development of organ failure. routinely used liver function tests appear to be inconsistent indicators of hepatic damage. in this study, we used p_lasma disappearance rate (pdr) of indocyanin-green dye (icg) as an early estimate of liver function. methods: we serially evaluated pdr and routine liver function tests (serum bilirubin, sgot, sgpt), as well as acute phase and non-acute phase proteins (crp, transferrin) in patients during the first week after trauma or the onset of sepsis. patients: group : (n = ) multiple trauma iss > , group : (n = ): abdominal sepsis, acute necrotizing pancreatitis (anp) grade iii. patients were selected on the basis of clin cal estimates that these patients would require continued icu observation. pdr was determined by means of a fiberoptic catheter and a computerized system (cold z- , pulsion), which permits repeated bedside measurements. the initial values of pdr, serum bilirubin and transaminases were not significantly different in trauma, sepsis and anp. in trauma patients pdr improved during the first week. in patients with sepsis and anp pdr remained low and worsened with time. the decrease in pdr preceeded an increase in biochemical liver function tests in these patients. + . &-_ ( - ) discussion: routinely available blood tests of liver function are usually altered several days after injury. however, they are generally non-specific indicators and they are influenced by extrahepatic factors. pdr seems to be useful to evaluate impaired liver function early after the onset of sepsis and trauma. objectives: to study frequency of organ system failure (osf) and it's influence on outcome in granulocytopenic patients with hematological malignancies and septic shock(ss). materials and method: retrospective review of medical records of granulocytopenie(wbc< , xl ) patients with hematological malignancies and ss, who were admitted to the intensive care unit (icu). frequency of osf before and after ss was analysed. the patisnts were categorised on survival and non-survival. results: signs of osf were observed in . % of patients before ss and in all patients after ss. only patients presented with hypotension refractory to inotropic therapy. nevertheless there was a significant increase of frequency of acute respiratory failure (arf), acute renal failure (arenf) and liver injury (li) after ss occurred(showed on the figure). only frequency of organ failure before and after objectives: statusmetria allows to define the effective level of oxygen status and accordance to it means of carbon dioxide and elec-trolyte in critical care. the conception of syndrome int~ive care (sic) is exhausted itself and invariable outcomes of sic of multiergan system failure (mosf) confirms that. therefore, an alternative to sic should be advanced. methods: efficlenoy of treatment has been asscsaed in patients with mosf using value of metabolic rate and ability of an organism to cover it by oxygen and substrate supply. oxygen pulse (op) and index of efficacy of oxygen transport (ieto ) was monitored. ~lt~.lntenaive care is considered to be homeostasis-securing therapy (hst) if energostructure deficit is eliminated and necessary for recovery regeneration rate is .restored. op in patients with mosf was . mt-m " , and le,~ and ie'i~ w~ . units in sic. we managed to maintain op of . - . ml.m " and ieto of . - . units in hst. patients from with mosf survived in sic and patients from survived in hst. efficiency of hst appeared to be two times as much as efficiency of sic. cr of homeostasia-se-'uring therapy is advancing. the conception provides restoration of regeneration rate due to effective then in sic elimination of en=gostructure deficit. the conception may be a basis of new technology for treatment of mosf. helen f goode phd, nigel r webster phd. anaesthesia & intensive care, university of aberdeen, ab zd, uk. objectives: xanthine dehydmgenase is converted under conditions of ischemia, reperfusion and endothelial damage to xanthine oxidase, with superoxide anion as a co-product of its catalytic activity. multiorgan dysfunction syndrome is associated with splanchnic vasoconstriction resulting in significant and prolonged gut ischaemia. aggressive volume resuscitation with prompt restoration of blood flow results in reperfusion of the tissue and is likely to cause xanthine oxidase-mediated release of oxygen-derived radicals. this study investigates xanthine oxidase activation and oxygen-derived free radical-mediated damage in such patients. methods: fourteen consecutive patients on itu who met established criteria for septic shock and secondary organ dysfunction were studied. serum xanthine oxidase activity was measured using oxidation of a chromagen in a dual enzyme system and plasma malondialdehyde was measured using a specific spectrephctometdc assay. apache ii scores, blood pressure, svr, cardiac output and day survival were also recorded. biochemical data were compared with results from healthy subjects. results: xanthine oxidase activity was . + . units/i in patients (mean :t: sem) and . + . units/i in controls (p<o. , mann whitney u test), and was highest in the patients who survived (p< . ). malondialdehyde concentrations were elevated ( . • . prnol/i compared with . • . pmol/i in controls, p< . ). xanthine oxidase activity did not relate to apache score or any of the cardiovascular parameters recorded, and was not influenced by the degree of organ dysfunction. conclusions: patients with sepsis and secondary organ dysfunction have xanthine oxidase activation and evidence of free radical damage. the finding that activity was highest in those patients who survived suggests that reperfusion was incomplete in patients who died, with decreased tissue xanthine oxidase ~tash out' into the circulation. influence objective : evaluation of the feasibility of measuring the intragastrie partial pr~sure of carbon dioxide (pco ) using a chemilumin~nt optode and fibre~ptics originally developed for intrav~cular blood gas monitorlng(p ) methods the pco electrode w~ calibrated i~-vitro according to the m~ufaeturers instructions the sensor w~ then stripped of its outer c~ing and threaded down the pile tube of a g~ c enema e (gt) so ha he ens ng portion sat well within the balloon. the modified gt was inserted n~og~trically after induction of anesthesia in ten patients undergoing c~diopuimonary byp~s throughout results: according to the datas of integral rheography % of patients were revealed to have hypodynamic type of blood circulation (cardiac output was decreased on - % and general peripheral resistance increased on - %). it was effective to use complamin (xantinoli nicotinas) in the complex therapy of su~h patients. the dosage was - mg/kg during - days. as a result of such therapy was also the oliguric stage shortening (ac n ).in , % of the cases unsatisfactory datas of central hemodynamic,combined with high (more than cm h ) venous pressure,lung oedema.then nanipruss ( , - , mkg/kg/min) was succesfutly used in complex with routine therapy.in the patients with low cardiac output and low general peripheral resistance mesaton ( , - , mg/kg) and dopamine ( - mkg/kg/min) were effective.change for the worse in the hemodynamics datas, inspire of therapy during - days,was prognostically unfavourable. conclusions:we consider early diagnostic of hemodynamic disorders and adequate correction of them is one of the most important factors, determined the outcome and prognosis in arf patients. obiective: to evaluate the results of renal replacement therapy (rrt) in surgical icu patients with acute renal failure (arf). arf in icu patients is associated with high mortality rates. we investigated the relation between mortality and organ failure in different categories of surgical icu patients receiving renal replacement therapy (rrt) for arf. methods: the records of surgical icu patients with arf requiring rri-(haemodialysis or cavhd) were examined. five different patient categories were defined; .ruptured aneurysm of the abdominal aorta (raaa) n = .elective vascular surgery (evs) n = .abdominal sepsis n - .trauma n = .others ( e.g. malignancy, obstetric emergencies) n- seven organ systems (cns,circulatory,respiratory,hepatic,renal,digestive,haematologic) were scored for possible failure using the mof score. results: mortality was as follows: all patients % , group % , group % , group % , group % , group % . mortality increased with the number of failing organ systems; mortality for all patients with > failing organsysterns was % the only exception being the subgroup of trauma patients where mortality under these circumstances was o% conclusions: mortality in surgical icu patients receiving rrt for arf is high. no significant difference in mortality is found between raaa and evs. mortality increases with the number of failing organ systems. the subgroup trauma patients shows a lower mortality compared to the group as a whole, even with > failing organ systems. to look for the most accurate scoring system to measure the severity of the complications occuring in the early phase ( first day) of kidney transplantation and to asses their prognostic value. methods: in our retrospective study we applied the apache li and the goris scoring system for the kidney recipients who developed multiple organ failure (mof) as a consequence of their pulmonary and. cardiovascular complications following kidney transplantation. we evaluated the recipients the distribution of the women and men ( % ~ % ) was the same as in the kidney recipients. applying the apache ii system most of the patients had their score between and , and the function of , or organs were affected at the time of the onset of mof. the apache ii system gave adequeate information about the disturbance of the function of other organs beside the kidney failure even at the time of the transplantation. the scores and the number of the affected organs correlated with the condition of the patients in the goris scoring system but not as sensitively as in the apache ii scoring system. conclusions: both the goris and the apache ii scoring system can be applied to measure the severity of the multiple organ failure occuring during the early phase of kidney transplantation. however the apache ii system is more suitable to follow not only the stateof the patients at the time of the admission but also the changes occuring in their condition during the complication. v.v.erofeev, v.v.ivleva scientific research institute for general reanimatulogy russian amsci, moscow, russia objectives: the analysis of ssc and results of their treatment in patients following critical states showed the necessity of developing a combined antibacterial therapy. methods: according to the protocol patients ( - years old) with combined trauma and massive hemorrhagy following vast aml traumatic operations were examined. microflora's composition and resistence to up-to-date antibiotics was studied using the anaiyser iems reader by "labsisteme"(finland). general clinical, bacteriological, immunological indices, as weil as the duration of the treatment and recovering rate served as criteria of the combined antibacterial therapy effectiveness. results: it was proved expedient to administer antibiotics in staphylococcus infection in the following combinations: riphampizin with fluoroquinolones; i-ii degeneration, cephalosporins with aminoglycosides; cephalosporins with fluoroquinolones. in case of singling out the exciters of the euterobacteriaceae family, including the pseudomonas aereginosa, -fluoroquinolones combined with modern amynoglycosides; fluuroquinolones with ureidopenicillines; ureidopenicillines with amynoglycosides; amynoglycosides with the ii-iii generation cephalosporins; cephalosporins with fluoroquinolones. in severe ssc caused by combined infection (including anaerobes) clindamicin with modern amynoglycosides was prescribed. conclusion: the combined antibacterial therapy allows: ) to increase the effect on microbic agents and the efficacy of treatment in combined infections; ) to lessen the possibility of the exciters'resistence to antibiotics; ) to prevent the development of superinfection: ) to decrease the doses of medicine and its toxic effect. objectives: two methods of blood volume measurement in a group of critically ill patients were compared to investigate the practical possibilities of a new easy to use method based on carbon monoxide (co) uptake. methods: all patients had multi-organ failure and haemodynamic monitoring with a swan-ganz catheter. mean apache ii score was ( - ). when indicated, patients had blood volume measurements simultaneously based on the techniques of, i) dilution of ~cr labelled red cells, and ii) inhalation of carbon monoxide gas with measurement of the rise of carboxyhaemoglobin produced. the co was administered via a newly designed, ventilator driven, fully closed circle system ensuring co retention and co removal with automatic addition of oxygen to m}ttch patient uptake. a portable computer performed all necessary calculations. results: volumes obtained by co uptake were compared with the "gold standard" radiolabelling method. mean blood volume determined by the co method was ml ( - ml) compared with ml( - ml) with slcr labelled red cells (r= . ). regression analysis produced an intercept at ml. the slope of the regression line was . ( . - . , % confidence limits). discussion: the co method produces volumes in excess of the radiolabelling method. there appears to be a systematic error, and one possible explanation is co binding to substances other than haemoglobin. conclusion: the co method is easier to use than radiolabelling and of the lower cost, since cohb measurement only is required. aceuraey is sufficient for clinical use and our preliminary findings suggest this system will meet the requirements. objectives: this study was conducted to determine the role of nitric oxide (no) in the pathophysiologic alterations and multiple organ damage, and the possible effects of " " " (l-n -monomethyl-l-arglnlne nmma) on hemodynamics and mortality in rats caused by a prolonged hypovolemic insult. methods: a prolonged hemorrhagic shock ( - mmhg for rain) was induced in anesthetized rats followed by adequate resuscitation. l-nmma was administered intravenously at doses of . mg/kg or . mg/kg at the end of resuscitation. results: infusion of . mg/kg l-nmma diminished the fall in mean arterial pressure, significantly increased the cardiac index (ci) and stroke volume (sv), together with remarkable protection from multiple organ damage compared to the controls. the h survival rate was significantly improved from . % in the control group to . % in the treatment group (p< . ). in contrast, the high dose of . mg/kg l-nmma resulted in a strong blood pressure response but a marked reduction in ci and sv concomitant with an increased total peripheral resistance index within the observation period, and caused severe damage to various organs at h after treatment. in addition, marked elevation in both endotoxin and tnf levels were observed in animals subjected to shock insult. conclusions: these results suggest that no induced by hemorrhagic shock in rats is an important mediator for pathophysiologic alterations associating with cardiovascular abnormalities, multiple organ dysfunction, and even lethality. thus, regulation of no generation and use of no inhibitors might provide new aspects in the treatment of hemorrhage related disorders, and the use of l-nmma would be either deleterious or salutary in a dose dependent manner. (hebert, chest- ) . the purpose of this study was to assess the risk factors for hepatic dysfunction in mosf. methods: patients have been hospitalized in our icu from january to may . , ( %) with mosf. among mosf pati~ts, ( %) have had hepatic dysfunction defined according to hebert (bilirubin ~ ttmop , chest ). thirty six of these patients acquired hepatic dysfunction after admission in the icu. these patients were compared with mosf patients without hepatic dysfunction selected blindly. chrorfic diseases, severity scores, eanse of admission, clinico-biologieal and hemodyunrrfic parameters, use of vesopressors, use of hepaiotoxic drugs, use of nutritional support and mortality were compared for hepatic failare and non hepatic failure groups.twenty nine patients had postmortem hepatic histologic examination, results: univaciate analysis: only parameters with p _< . are pre~nted. including these paramet~'rs in a multivariate analysis, anly c~hosis and vascular surgery remain independent risk factors for hepatic dysfunction. in particular, pao /fio , arterial lactate, do were not different between the two groups, some de~'ee of histological abnormalities was found in all liver samples, despite a normal bilirubin level in % of the cases conclusions: in our patients, conu'ary to previous studies, hypoxic and hemody~anfic parameters were not independent risk factors for hepatic dysfantion. this might be due to the inadequacy of the usual biologic definition of hepatic dysfunction as well as to the poor sensitivity of general hamodynamic parameters. critical states of various origin are complicated with the mldtiorgan farm (moi~ oceuzr~ce. due to their and functional features the lungs become the primmy damage target in various critical.states. ard that occurs in such states is associated with pulmonary edema development because of capillary permeability increase mediated by humeral and cenular responses to amag/~ factors exposure. r nmst be emphasized that mediators and effecto~rs of this respo~e affect not only puknonary capillaries, but other organs capiu~es as wellenhancing their permeability. orsans edema is a conmm~ finding at the autopsy of patients died from mof.clinical and radiolosial findings allow to have a diagnosis of pulmonmy edema before ~mi!ar lesions in other organs occm. additionally, there are some techniques that permit quantitative assessment of pulmonary edema flv.id (evlw) volume. in conclusion, we suggest that evlw changes in .dyn~rmcs in patients with mof are considered as a critical state severity measure which reflects indirectly the edema in other organs. objectives: we compared three different dialysis membranes to find out whether or not there were differences between their clearance characteristics on substances such as inuline, creatinine, urea, and phosphate to be eliminated in acute renal failure (arf). moreover, if a loss of clearance did occur we were interested in whether this was due to heparinization and a high production of the thrombine-anti-thrombine-complex (tat). methods: we carried out a randomized controlled study on consecutive critically ill patients presenting with arf, most of them in association with multi-organ failure, to be treated by continuous pump-driven arterio-venous renal replacement therapy on continuous low-dose heparinization. three different types of high-flux filter membranes (f tm [fresenius] , ct tm [baxter] , and filtra tm [hospal]) were assessed. each filter was changed intentionally after a hours" use. together the data of filters were evaluated, each at three different times (immediately after its onset [ hi, after h, and after h). the clearances of creatinine, urea, phosphate, and inuline were measured. results: there were some significant differences in clearance characteristics of inuline, creatinine, urea and phosphate between the filters (p< , ) showing the f tm membrane excelling filtra mand ct tm the more. the loss of inuline clearance ( mi/min/m ) after h, however, was insignificant for all filter types. a continuous low-dose heparinization scheme was applied without any relevant prolongation of the aptt. even lower losses were noted for the clearances of creatinine, urea, and phosphate. we found the tat-producfion increased after h (p< , ), but it did not rise any further. conclusions: as we could demonstrate in our study the clearance data of different types of filter membranes applied during continuous renal replacement therapy do show significant differences. on the other side, no relevant loss of clearance occurs during a hours" period indicating a high efficiency over time. to consider commercial aspects as well it shows that inexpensive conventional filter membranes can successfully be applied even for a longer renal replacement period, if needed. a retrospective study was performed on patients with acute renal failure (arf). we analysed survival in continuous (cd) and intermittent dialysis (hi)). mean age of the patients was years (y), patients ( % ) were < y, patients ( %) were >= y. the incidence of dialysed arf in our mixed intensive care departement is %/admission/y. statistics: fischer's exact test, mann-whitney-u test. efioloev: the contribution sepsis, cardiac failure and aminnglycosidcs was respectively %, % and %. treatment: cavh (cd) or cvvh (cd) was used in patients ( %), hemedialysis (hd) was used in patients ( %). data: mean apache scores were the same for cd and hd ( for both groups), patients treated with continuous dialysis techniques had significantly (p<o, ) more need for ventilation ( % vs %), elevated bilirubin ( % vs %) and a higher vasopresser need ( % vs %@ than patients treated with hemedialysis. there was a trend towards more sepsis ( % vs %; p= . ) mad coaguiation disorders ( % vs %; p= . ) in cd. taere were sign/ficantly more younger patients (< y) treated with cd ( % vs %, p< .os). mean apache score was significantly lower in patiants< y than as patienta>= y ( vs ; p< . ). patients< y had significantly (i}< . ) more coagulation disorders ( % vs %) and elevated bilirabin ( % vs %). there was no significant difference in vasopressur need and ventihatio~ between age groups. outcome:. hi) had a better sr compared to cd ( % vs ~ p< . ). patiants>= y had a comparable sr vs patients< y ( ") */e vs %; p----a.s.). tha global survival rate (sr) was % ( patients). conclusions : diaiysed arf has a well known lowsurvival rate ( %): hc~raedialysed patients had a better survival rate than patients treated with continuous dialysis. this can be explained by the fact that the latter were in a worse condition considering organ failure (more vantilatian, elevated bflirubin and need for vasepressurs), apache score couldn't illustrate that. patient~ y with arf have the same survival rate as patients< y: although patients >=- y have a higher apache score they have less organ faille. the avacbe score is not a good oredictor of survival in p with organ failure. departments of surgery and intensive care, guy's hospital, london, u.g-obiectives: a randomised controlled trial of a management protocol utilising the regular measurement of gastric intramucosal ph (phim) to control the administration of dopexamine. methods: patients admitted to a multidisciplinary teaching hospital intensive care unit (icu) undergoing insertion of a pulmonary artery catheter were managed according to a resuscitation protocol. randomisation was to either the protocol alone or to insertion of a nasogastric tonometer and subsequent management guided by phim. phim < . initiated volume and inotrope resuscitation and, if unsuccessful in elevating phim, dopexamine was commenced. approval was obtained from the hospital ethics committee. results: patients were considered for analysis and the two groups were well matched for age and sex. overall, there was a high hospital mortality of . %. there was no difference in icu or hospital mortality between the two groups (see table) . objectives: to compare cardiac output (co) measurements between continuous termodilution (cco) by thermal wire on pulmonary artery catheter (cco/svo vigilance. baxter critical care), and co measurement using a trans-esophageal doppler (dco) ultrasound system (odm ii, abbott laboratories), in the immediate postoperative period of cardiac surgery. methods: patients undergoing myocardial revascularization were monitored with cco by a swan-ganz catheter and an intra-esophageal dco probe, after induction of anesthesia. exclusion criteria were: aortic valve disfunction, previous valvular surgery esophageal disease, absense of sinus cardiac rhythm, and need of ventricular or intraaortic assistance. hemodynamic parameters, co by both cco and dco, svo . sao , diuresis, pha, and hemoglobin were repeatedly registered during the first hours after surgery, as the patients were kept under sedation and mechanical ventilation. results were compared using the method described by bland and altman. results: measurements of co were obtained, ranging . objectives: a decreased tissue oxygen delivery is responsible for a higher morbi-mortality rate among surgical patients; this diminished oxygen delivery/consumption rate (dojvo ) may origin the lactic acidosis observed in the gastrointestinal tract, reported in patients undergoing hypothermic cardiopulmonary extra corporeal surgery, and can be registered by tonometry as result of the gastric mucose ph. the purpose of this study is to evaluate the reliability of the intramucosal ph (phi) measurement by a nasogastric catheter as indicator of the do /vo > its co> relation to other parameters of do /vo disturbance, and with postoperative complications and clinical course. methods: patients ( male, female) undergoing cardiac surgical procedures were included ( myocardiai revascularizations, valvular substitutions, constrictive pericarditis). mean age was + years, mean weight _+ kg. a nasogastric probe (trie tonometrics) was placed after anesthesia induction; phi values were registered in the postoperative period ( ', ', ", ' and h after surgery end). the corresponding hemodynamic parameters, venous oxygen saturation (svo ), diuresis and arterial ph (pha) were also recorded. results: phi values ranged . to . (mean . ( . ); the mean values of clinical evolution were: extubation time, _+ hr.; discharge from postoperative care unit, - hr.; and hospital total postoperative time, _+ . days. complications registered were: perioperative acute myocardial infarctions, cases of respiratory insufficiency, occlusion of coronary bypass, an ease of hyperamilasemia. all patients with severe complications needing specific treatment showed either a low phi value, or a considerable descent in comparison with the initial register. statistic correlation between low phi and presence of complications was found; the low significance (p > . ) degree may be due to the low population size. conclusions: phi measurement in cardiac surgery patients is a non invasive, uncomplicated method for prediction of doz/vo disturbances, thus reflecting risk of increased major complications, and may precede changes in other usual indicators (svo , pha, cardiac output, ...). work-in-progress with a greater population size may offer more significant results. references: ( ) gutidrrez g: lancet ; : - . ( ) landow i: acta anaesthesiol scand ; : - . the haemoglobin-level (hb) is besides the arterial oxygen saturation and the cardiac index one of the relevant parameters of oxygen supply to the tissue. in contrast to otherwise healthy patients, there is no agreement on tile so-called transfusion-trigger in critically ill patients. in i?ont of this background the question arises, whether and to what extent blood transfusion in critically ill patients improves oxygen supply io tile tissue. this study was performed in critically ill/septic patients in the postoperative period alier an inlcclive/scptie revision operation of the hip or knee joint. on cardiac/seplic reasons monitoring consisted beside other measures of a pulmonary arlery catheter and of an indwelling arterial line li~r measurering/calculating standard haem~dynamic as well as systentic oxygen parameters. the indication for blood transfusion was given by hb together with the cliuical slatus of thc patienl (asa-scorc and multiple organ dysfunction (moi))). statistical analysis w~ks performed by mann-whitney-u-test. by fisher's exact-test and by wii.coxon-test: statistical significance was set with p< . . according tu the pretransfusion value of hb and of lactate (lac) palicnts ;,,'ere divided into groups as follows: a: hb< and b: >sg/dl: i: ac< . and ii: > .smm. in either group blood transfusion results in zt significant increase in hb (a: . _+ . to . + . g/dl; b: .(~ . tt, . + . g/dl; i: . -+ . to . -+ . jdl; i : . -+ . to . + . g/dl). wlailc, however, haemodynamic parameters do not difl)r significantly from each other before and alter blood transfusion, oxygen delivery (do, -ml/min x m-') increases significantly hi either group studied (a: -+ to -+ ; b: + to + ; : -+ to -+ ; i : -+ to -+ ), in contrast oxygen consumption (vo~ -ml/min x m e) does not change significantly in either group (a: i -+ to -+ ; b: -+ to -+ ; i: -+ tu -+ ; : -+ to +_ ); oxygen exlraction ratio decreases. this study in critically ill/septic patients demonstrates, that in this group of patients studied blood transfusion at a base-line-value of > . -+ . g/dl expectedly rises do~, however, it does not improve vo=; even not in septic patients with elevated lac-values. paclitaxel in a new anticancer agent, extract from the bark of the yew tree (taxus brevifolia), employed against breast and ovarian cancers resistant to chemotherapy. it promotes the polymerization of tubuline, and disrupts the normal microtubule dynamics. hematologic toxicity, hypersensitivity reactions (bronchospasm, urticaria and hypotension), and peripheral neuropathy are the main reported toxic effects. cardiac side effects are rare: atrioventricular blocks of higher degree are reported in . % of patients; congestive cardiotoxicity was discussed only in one trial in patients treated with paclitaxel and doxorubicin. we describe the history of a -years-old worn an with a breast cancer, diagnosed in , initial staging t nim , treated with mastectomy, axillary lymphadenectomy, andchemotherapy with a cumulative dose of anthracyclines of mg/m until august . the patient complained of dyspnea and severe hypotension immediately after an intravenous infusion of mg paclitaxel, given over hour for the treatment of bilateral, malignant pleural effusion. at echocardiography die left ventricular ejection fraction was reduced to %. she died days later because of a severe cardiac low output with hepatic and renal failure; an impressive hepatic cytolysis was observed. the post mortem examination confirmed the dilatation of the cardiac cavities, especially of the right ventricle, bilateral pleural fluid, and ascites. the histology was suggestive for a cardiomyopathy secondary to anthracyclines. the electron microscopy revealed a deposition of an unusual pathological pigment in the myocytes; subsarcolemmal deposition or membranous were absent. we hypothesize that paclitaxel was the cause of a major hypersensitivity reaction with shock and severe hepatic cytolysis, worsening the myocardial damage induced by anthracyclines. the possibility that a low doge of paclitaxel could directly increase anthracyclines cardiotoxicity -as decribed in the medical literature -will be discussed. objectives: activated endothelial cells release soluble intercellular adhesion molecule- (sicam- ), vascular cell adhesion molecule- (svcam- ), and e-selectin (selam- ). sicam- , svcam- , selam- , and inflammatory cytokines were determined. methods: sicam- , svcam- , and selam- were determined by elisa. tnf-a, il- , and il- were also measured by elisa. endotoxin was measured by an endotoxin-specific endospecy test after pretreatment of new pea method. results: the sicam- and s vcam-i levels were significantly higher in the septic multiple organ failure (mof) and sepsis groups than in the non-septic mof group. the selam- level was slightly higher in the septic mof group than in the sepsis withut mof group and non-septic mof group. the increases of soluble adhesion molecules were not in agreement with changes of plasma endotoxin level. levels of soluble adhesion molecules were correlated with the levels of plasma tnf-a and il- , but the level of il- . discussion and conclusion: the slcam- and svcam- levels in septic patients closely reflected the severity of the pathophysiological conditon. it was possible that the release of sluble adhesion molecules were not stimulated by plasma endotoxin, but endotoxin in the local infectious region. tnf-c~ and il- also were suggested to be involved in the release of these soluble adhesion molecules. obiectives: cardiopulmonary bypass (cpb) surgery is associated with a systemic inflammatory response attributable to the release of various inflammatory mediators and the activation of complement or coagulofibrinolytic system. in addition, adhesion molecules, such as icam- , elam- , and vcam- , appear to be of central importance in the inflammatory process following cpb surgery. we previously reported the effects of a synthetic protease inhibitor, fut- , reduced release of inflammatory cytokines (tnf, il-lg, il- ), activation of complement (c a, c a) or coagulofibrinolytic system (tat, pic, fpa) and protected platelet function (gpib, gpiib/llla) following cpb surgery. methods: in this study, we analyzed fut- on soluble adhesion molecules following cpb surgery. patients undergoing cpb surgery were divided into two groups, group a consisted of patients who received omg of fut- in priming solution, followed by a continuous infusion at mg/kg/hr during cpb in addition to initial heparin dose of mg/kg. group b, a control group, included patients who were injected with heparin only. the plasma slcam- , selam- , and svcam- concentration was measured by elisa. results: every soluble adhesion molecules decreased during cpb in both groups, and rose after cpb. selam- and slcam- reached their peaks on hours after cpb and on pod respectively in both groups, but they remained lower in group a (selam-i: . + . vs. . • ng/ml, p< . , slcam-i: • vs. • ng/ml, p< . ), svcam- , in both groups, remained lower than preoperative levels, but did much lower in group a. conclusions: fut- reduced adhesion molecules and suggested to be the effect on postoperative organ dysfunction. in the last few :,'ears the conditions of treatment in continuous hemofiltration/hemodiafiltration were discussed controversially. a significant removal of tnf-alpha and il-i could be demonstrated in cvvhd. the aim of our study was to investigate the elimination of tnf-alpha, l- , il- , il- , s-cd- and ifn-gamma in cvvh by measurement in plasma and hemofiltrate of critically ill patients with an acute renal failure. the patients of our study were treated with a continuous veno-venous-hemofiltration (polysulfone-filter, blood flow: - ml/h, filtration rate ml/h). the samples, hemofiltrate and plasma, were taken one hour after the start of treatment. the patients suffered from septic shock ( ), the so called hepatorenal s~aldrome ( ) and a severe pancreatitis ( ). the cytokine concentrations were measured with elisa-method. in contrast to elevated concentrations in plasma for tnf-alpha ( cases), scd ( cases), il- (l case) and il- ( cases), hemofiltrates contained no activities. only il- was removed in significant amounts with even higher levels in hemofiltrate than in plasma. this phenomenon was described so far for tnf-alpha and il- and may be due to the absence of metabolic properties (possibily enz~natic) in hemofiltrate. it can be shown, that tnfalpha, il- , il- could not be eliminated in cvvh with a filtration rate to ml/h. in contrast to findings of other investigators with a higher filtration rate (> ml/h), we found no significant concentrations of tnf-alpha and il in hemofiltrate. we conclude, that for a significant removal of important cytokines higher filtration rates (> ml/h) are necessary. objectives: multiple organ dysfunction syndrome including liver and renal impairment is a fatal complication in patients with the diagnosis of sever sepsis. this study focused to the effects of removing toxic substances from inflamnatory tissue by hemodiafiltration. ~ ethods: eleven patients were admitted to the icu in emergency center and met the criteria of systemic inflammatory response syndrome in association with infection. all patients developed liver and renal dysfunction and were treated by hemodiafiltration with high flux membranes (fb-u:nipro). the hemodiafiltration were performed times using nafamostat mesilate as an anticoagulant in hours with l of substitution fluid (hf-b:fuso). the serdm levels of endotoxin, cytokines, endothelin-i (et-]), human neutrophil elastase ~ -proteinase inhibitor complex (hne-pi), fibronectin (fn), lactate, and amino acids were measured before and after the hemodiafiltration. the hemodiafiltration would be effective to renal dysfunction by reducing endothelin and beneficial to tissue metabolism represented in fisher's ratio, but might be harmful to respiratory function by activating neutropila in patients of severe sepsss. background : intermittent hd may be poorly tolerated in the early phase of arf in hemodynamically unstable patients (pts). this technic may fail to achieve steady state urea low levels in hypercatabolic pts. method : nt = consecutive pts treated with hd; n = consecutive pts treated with cvvhf. hemodynamic unstability is defined by arterial hypotension and requirement of inotropie support despite adequate filling. rate of change in urea (u), ereatinin (cr), k + , ph were computed from a linear regression .analysis of data vs time in each treatment group during the first days of application of the two technics (anova). dally worst values were recorded. results : hd-group : apach% score = _+ ; mean number of organ system failure (osf) = . -+ ; mean blood pressure (mbp) = • mmhg (first day of application of hd). cvvhf-group : apachen score : + ; osf = -+ ; mbp = + mmhg (first day of application of cwhf discussion : during the first days of application of hd/cvvhf, u and cr decreased much more rapidly in the cwhf-group. k* and ph were maintained within normal range in the two groups. initial mbp which was much lower in the cwhf-group significantly improved during the application of cvvhf while mbp remained unchanged in the hd-group. conclusion : despite higher severity of disease in cvvhf group (apachen score, osf, lower initial mbp), we obtained a better performanco with cvvhf regarding the decrease of u and cr and the improvement of mbp. in relation to the different and continuous renal replacement techniques, the continuous venovenous one is the alternative method to continuous arteriovenous for critical patients with acute renal failure (arf). we present you our experience with cvvh in patients with mof. in our intensive care unit (icu) patients with mof were treated with cvvh in the period between january in to march in . the mean (• age of our patient population was , • years, being % male and % female the whole patient population was with mof iust at the moment the technique was accomplished; % was in mechanical ventilation, % needed vasopressor support and % required both of them (mechanical ventilation and vasopressor support) apache ii score mean of the patient population was , ~: , (range - ) and ati of them were with arf oligoanudc. technique: cvvh was accomplished using a single-d~al iumen catheter, ptaced in either a temoral or subclavian vein by the stand ard seld{nger technique. pol{sultone hemofitiers were also used, and the extracerporeal circuit used standard arterial-venous blcod tubing. blood flow and hence oltrafiltration pressure, within the circuit was generated by a roller blood pump. the modulus has a roller pump, a pressure transducer connected in an arterious and venous line, such as an air-transducer which is adapted to a drip-chamber in the return way. the replacement used was a peritoneal dialysis solution. medicine , st. george's hospital medical school, london. england. hepatic sinusoidal endothelium shows a major inflammatory response in porcine sepsis that can be attenuated by the administration of dopexamine hydrochloride. dopexamine is a beta and dopaminergic receptor agonist. the specific beta adrenoceptor antagonist ici has been shown to reduce the protective effects of dopexamine. we investigated the effect of this antagonist on hepatic ultrastructure in porcine sepsis. six pigs ( - kg) divided into groups were anaesthetised and intubated. cardiac output and portal blood flow were measured using standard techniques. the groups were; placebo, (peritonitis induced); blocker, (peritonitis induced and pg/kg ici bolus infused then given hourly). caecal content was aspirated and peritonitis induced. colloid was infused to maintain pawp at - mm hg for eight hours the animals culled, hepatic tissue removed and prepared for electron microscopy. in the placebo group hepatic endothelium was swollen and the sinusoids occluded by wbc. but in the ici blocker group, much of the sinusoidal endothelium was absent and there where large extra sinusoidal spaces among the hepatocytes. an assessment of the two groups showed worse hepatic architecture in the blocker group. the b antagonist blocked any protective effect of endogenous beta adrenoceptor agonist (adrenaline) on hepatic endothelium in porcine sepsis. george's hospital medical school, london. england. dopexamine hydr chloride, a beta and dopaminergic receptor agonist reduces hepatic damage in porcine sepsis. we tested dopexamine's effect on cerebral oedema. the beta adrenoceptor antagonist ici was infused to block any protective effect of dopexamine. nine anaesthetised pigs ( - kg) were randomised into groups; placebo, (peritonitis induced); dopexamine, (peritonitis induced and ~tg/kgdar of dopexamine infused); blocker, (as in dopexamine group but in addition pg/kg ici bolus given then infused at that rate hourly). caecal peritoneum was induced and colloid infused to maintain pawp at - mmhg for eight hours when the animals were culled, cerebral tissue removed, prepared for electron microscopy and digitisation. digitisation of the area of oedema surrounding the blood vessel and expressed as a percentage of the micrograph. . _+ . , dopexamine . + . ", blocker . + . . data expressed as mean + sd. significance p< . . * dopexamine compared to placebo and blocker. in the dopexamine group the area of tissue oedema was significantly lower than either the placebo or blocker groups. there were no significant differences between the placebo or blocker groups. the antagonist completely blocked the protective effect of the drug on cerebral oedema in porcine sepsis. beta adrenoceptor stimulation is protective of cerebral oedema in porcine sepsis. objectives: the hemodynamie~ of hepatic circulation during multiple organ failure (mof) have not been suffleienly studied. we investigated liver hemodynamics in two subgroups of patients with mof, those with either liver or lungs as the main organ of involvement. methods: three groups of patients were created: i) mof-hepatic involvement (mof-hi) ( patients) with bilirubin > . mg/dl and lung injury score < . , it) mof-ards ( patients) with respective values < . and > , iii) patients with head injury with respective values < and < , served as group control. all patients were in haemodynamieally stable state with an oxygen delivery index > ml/min/m prior to measurements. two swan-ganz catheters 'were inserted, one in the hepatic veins and one in pulmonary artery and the following measurements were determined: the hepatic vein free pressure (hvfp), the hepatic vein wedge pressure (hvwp), cvp, paop and co. the gradient of hvwp-hvfp represents liver perfusion pressures. by injecting contrast media at dose of iml/lokg with the balloon inflated to achieve sinusoidai image, the hepatic blood flow (hbf) was concluded by the time in seconds of media removal after balloon deflation. results: the co, cwp and cvp were comparable to all three groups. namely, for mof-hi, mof-ards and control groups the mean (+sd) value of co was . _+ . vs . _+ . (ns) and . _+ . respectively, of the paop was . +_ . vs +: (ns) and . + . respectively and of the cvp was .+. . vs . + . (ns) and . respectively. in contrast the two mof groups were different after the cut-offinclusion criteria ie the mean (+sd) value for bilirubin was . + . vs . + . ( < . ) and . _+ . respectively and lung injury score was . objectives: oxygen delivery (do ) and oxygen consumption (vo ) are increasingly monitored parameters in the icu. there still remain controversies about an oxygen supply dependency in critical illness particularly with respect to vo determination by either indirect calorimetry (vo m) or tick calculation (vo c). the purpose of this study was to investigate the changes in vo m and vo c following do increase. methods: the relatives of critically ill patients (mean age years, mean apache ii , mean mof-score ) gave their written informed consent to participate in this institutionally approved, prospective study. do was increased by fluid loading (hydroxyethylstarch %: mean volmne ml, mean duration of infusion min) and catecholamine support (dobutamine: mean dose , ~g/kg/min). changes in vo m and v c were recorded sinmltaneously before, during and following interventions. calorimetry was obtained with the metabolic monitor integrated in the ventilator (puritan bennett, carlsbad, ca adaptive endocrine response of organism to septic shock consisting in activation of the production of adrenal hormons, renin -angiotensin -aldosterone system (raas) and other hormonal systems has an influence over microvascular changes in these states and for development of multiple organ failure (mof). in patients with peritonitis of different origins ( nonsurvivors and survivors) were followed the changes in cortisol level and raas by radioimmunological methods and many variables for evaluation of respiratory, renal, hepatic function, coagulation etc. as a signs of mof. it was observed significant increase of the level of cortisol ( +_ , nmol/ i), aldosterone ( , • , nmol/i). by factorial statistical analysis we found significantly high correlations between hormonal changes and respiratory function (for example r=- , , p < , between cortisol and pao ; r = , , p < , between cortisol and d (a-v) ; olso renin -cao r=- , , p < , , renin d ~,vl o r = , , p < , ). such significant correlations was found and for raas with respiratory, renal function, byproducts of arachidonic acid thromboxan b and p fla, soluble fibrine degradation products etc. these correlations between the degree of endocrine changes and multiple organ failure in patients with septic shock produced by peritonitis suggest that their effects upon peripheral vascular resistance and constriction of the splanchnic, splenic, renal and other organ vasculatures are not always with physiologic expediency and there are perhaps the possibilities of therapeutic influence. intredu~on : dopexamlne has previously been shown to control hyperkalaemia ia patients with acdto renal failure (arf), however effects on the subsequent course of art are undomunente~ ob_iectlv~ : to evaluate clinical progress in patients with acute renal failure (arf) in an intensive care unit (icu) with regard to biochemical control, need for -and time to -dialysis, and outcome in patients receiving dopexamine. m~ods : consecutive patients meeting standard criteria for diagnosis of arf were included in the study. full cardiovas~dar, biechemical and intervention/outcome details were recorded. dopex.~min~ was infilsed at a dose of pg/kg/min in conjunction with a regimen of inotropir support and blood volume optimization. resn]~ : following the intzoduetion of dopc',~mine ilrinr vohlmes increased slightly over the next hrs fzom + ml/ hrs to + ml/ hrs (ns). data expres,uxl as mean + sem. three patients ( %) became polyuric with urine output > ml/hr within days and did not need dialysis. in the remaining patients the time to dialysis (to correct acid-base deficits or volume overload) was . + . days. serum potassium levels were well controlled. day or immediate pre-dialysis levels were . + . mmol/l compared with pre-lreatment . + . mmol/l overall mortality in this series was / ( %). duration of acute dialysis in survivors with renal recovery was . +_ . days. patients ( %) progressed into chronic renal failure and needed continuing renal replacement therapy. no adverse cardiovascular altects were seen at this low dopoxami~ dose although its competitive inhibition to adrenergic reuptake mechanisms meant that doses of pressor agents could often be reduced. : dopcx:~minr nsed in conjunction with inotropic support and blood volume oplimitntion, can safely postpone, or even avoid, the necessity for acute haemodialysis in icu patients. no evidence of tachyphylaxis to the effect on serum potassium levels was seen over the duration of the study. hen'era m., suarez g., dagn d., varela a., ramos j., garoia jm, aragdm c, jurado l, medina a. icu. hospital regional. malaga. spain. objective: to evaluate the haemodinamic tolerance to the veno-venous continuous hemefiltration (vvchf) system in patients with systemic inflammatory response sindrome (sirs), and the possible beneficial effect of this technique on the haemodinamics in these patients. material: patient admitted to the icu, with diagnosis of sirs and monitored with a pulmonary artery catheter at the beginning of wchf. we performed a complete haemodinamic study to all these patients (cardiac output, vascular resistanoss, ph and co in arterial and mixed venous blood samples, saturation of pulmonary mixed venous blood, do and vo calculations and temperature) and determined the respiratory mechanics (compliance and pao /fie relatinship) before starting the procedure, after minutes operating with the ultraflltrate branch closed (without filtered fluid production), afler and minutes of zero fluid balance bemofiltration and after minutes of filtration with negative balanos adjusted to the patients conditions. for the statistical analisis we have performed the anova test over the mentioned variables. results: we have not detected statisticaly significant differences of the analyzed variables before the beginning after operating the pun'@ for minutes without filtered fluid production and after minutes of zero fluid balance hf. only temperature shows a meaningful decrease in time. objectives: among many organs, playing the important role in pathogenesis of multiple organ failure, the particular place is taken by the intestine. ~ethods: the study was carried out in dogs !~n"~h pi was modelled by severe operative trauma (ot). the dcm was estimated by the indices values of work time (wt), contraction frequency (cf), mean amplitude of contractions (~ac) and motility index (mi) measured by method of tensography. "sl", created on the basis of sorbit and sodium lactate ( mosm/l), was injected in the dose of .o ml/ kg into v. cephalica antebrachii after hrs of ot. the results of the present study are the evidence of "sl" stimulative action on dcm and are experimental ground for "sl" using in complex therapy of pi in clinic. with splanchnic venous blood pc p.f. laterre p. goffette, j.p. fauville, a. poncelet, p. loneux, m.s. reynaert. intensive care unit, st. luc univ. hospital, brussels, belgium. determination of gastric intramucosal ph (phi) by gastric tonometry using the henderson-hasselback equation is expected to allow the detection of splanchnic ischemia in critically ill patients. because of bicarbonate concentration and acidbase balance influences on the calculation of phi, it has been proposed to use arterio-gastric pco,_ gradient [p(gast-a)co,] to assess splanchnic perfusion. htpothesis : pcoz in the gastric mucosa is in equilibrium with intraluminal co z and with co, in the blood leaving the stomach (mesenteric and portal blood). objective: mesure pco; and ph in portal vein blood and compare its value with pco and phi obtained simultaneously by gastric tonometry. material and method : in a patient ( y.), a fiberoptic catheter (baxter r) was positionned in the portal vein after transhepatic stent shunt repermeabilisation. hemodynamic parameters, do, (vigilance n baxter), gastric co and phi (tonometrics baxter) and portal blood gas were determined at regular intervals. results : sets of data were obtained and are expressed in mean + sd. gastric pco z was , + compared to , + . mmhg for portal pco . phi was . +._ , vs . +._o, for portal ph. no correlation was found for these parameters. p (gast-a) c was . + mm hg vs + . mm hg for p (portal-a) coz (no correlation). there was a good correlation between do e and p (portal-a) co z (r = , ) [figure] but no correlation with p (gast-a) c . obiectives: desaturation is a common finding during haemodialysis (hd). pulmonary oedema might be one cause for impaired gas exchange ( ). the aim of this study was to quantitate the amount of extravascular lung water (evlw) and gasexchange in chronic renal failure patients during and after a regular hemodialysis session. methods: chronic renal failure patients without symptoms or diagnosis of cardiac or respiratory disease were studied at the start (i), at the end (ii) and two hours after (iii) a regular bicarbonate hemodialysis session. the double-indicator dilution method, with indocyanine green and the stable isotope h as tracers, was used to measure evlw ( ). arterial bloodgases and endtidal co were registered. evlw data was compared to a group of renal healthy patients ( ). dcp n evlw, ml -pao , mmhg h~o +, nmol/l control group - -- l _+ "* -+ _+ crfgroup ii -+ ~ +- ns -+ "(" iii +- t _+ ns -+ t ** p < . dcp i from dcp , t p < . dcp li or i from dcp i, :~ p < . dcp ii from dcp i the evlw at the start of dialysis was larger in the crf group than in the control group. the evlw decreased significantly to a level not different from the control group in response to the reduction in weight after hd. pao~ was normal at the start of hd and showed a nun-signficant reduction after hd. paco ( . + . kpa) and etco ( . + . kpa) were unchanged while h o+ decreased and bicarbonate increased significantly. conclusions: the elevated level of evlw at the start of hd did not impair gasexchange. the decrease in evlw did not inhibit the decrease in pao . the reduction in h + followed by a fall in alveolar vantilation is the most plausible cause for the decrease in pao in bicarbonate dialysis. . prezant lung ; : - . . wallin j appl physio ; : - . a. dona~ d. battis& l col~ r danieli, d. achill~ l viglienz;~ c. giov-anaini, p. piaropao~ oblectives: to verify if intraoperative modifications of mtramucosal gastric ph (phi) below the normal lowest value . , can be predictive for important complications, as perforation, sepsis, mof or death. methocls: we have considered patients who andenvent major abdominal surgery. all patients received the same drugs in pre-anaesthasia, the same type of anaesthesia (balanced anaesthesia) and the same treatment with h -bloekers. after the induction of anaesthesia a gastric tonometer was positioned and a catheter was positioned in the radial artery. during the operation, every minutes, the following parameters were measured at the same time: phi, arterial ph (pha), blood lactate, mean arterial pressure. in follow up we considered death and complications happened during the hospital stay, in relation to intraoperative phi falls below . . results: among the patients, had a drop of phi below . during surgery. in three of them this fall was a single episode and happened within the first hour after the begiluting of the operation. after that phi rose to nomml values until the end of the operation these patients had a normal post-operative period, without complications, the other patients had a fall of phi during the demolitive manoeuvres. two paticots of them died. the first had a lowest phi= . and the second . . the first one ~zs operated on for hepatic istiecitoma, suffered a complete del'dseenco of the surgical wound on the th day after operation and died on the th day, the second one was operated on for a hepatic carcinoma had an intraoperative haemorrhage and died ~vo hours after the end of the operation. the other patients with a fall of phi had a lowest phi= . . . . . . . respectively.the first patient,operated onfor sigmoid carcinoma, underwent on a second operation for a transmural necrosis of the colic segment on the th day; the second one, operated for carcinoma of the right colon, had a cardiac ischelnia on the th pest-operative day and a dehiscence of the surgical wound on the th day: the third one, operated on for a sigmoid carcinoma, had melena in h post~ operative da b, and finally the fonrth patient, operated on for carcinoma of the tight colon, suffered a fistula of the surgical enteral anastomosis.all these patients were discharged alive from the hospital. the other patients, who had not reductions of phi ditring the operation, had a normal pest-operative period, without complications. conclusion: phi was able to predict the arising of some complications, probably due to intraoperative ischemic events. we can say that gastric tenometry, for its low invasivi.ty, can be included among the intraoperative monitoring in patients that tmdenvent on major abdominal surgery. (ttd),t"ea~rrerj.~ of hours duraticn. all l:atients nm.'-~ms_(~lly va~ ated in eantrol wcde ard_ la':'ad a a,~m--ganz catheter, with optic fibers for contirums mmsuremmt of svo mic studies were performed, c~e before the hegir~ of hd, c~e rain after the ~, ~ne at the middle, ~ne rain before lhe erd ard one rain after the erd of hd. paired t test ~as used far slatistical eval~ti~n. results: daring i~d there was a significant'reductton (p<o.~) of: c~tr~ venc~s eres~.re ( ve)emm to . ~ ~, ) ~arn'~w capil~ ~f~e pressure (i<~p) fr~n to ~mg hg, ) i~ from to . mmg hg. ~here was also a less pmnameed bat also-slatistics/ly significant r~ucticn (p<o. ) of: i) s~o~ from to patients undergoing surgical reconstruction of the aorta due to anenrysms of its abdominal part may develop transient and sometimes sustained episodes of dysoxia despite the conventional appeoreneas of being adequately resuscitated. indirect masurement of gastric mussel ph (phi) is being widely evaluated as a minimally invasive and sensitive means of assessing the adequaey of tissue oxygenation in these circumstances. the duration end degree of gastric intramucosal acidosis are related to the risk developing injured gastrointestinal tract end its putative consequences, i.e. translceation, cytokine release, organ dysfunction end failure, sepsis end death. measurement of phi is obtained indirectly by measuring pc in the lumen of the stomach with a silicone balloon tonometer (tonometrics, inc., worcester, ma, usa) and the bicarbonate concentration in arlz,,rial blood, end substituting these two values in the henderson-hasselbalch equation. objectives: to evaluate whether perioperative phi changes are predictive of complications end outcome end how they compare to standard haemodyuamic and oxygen trensport parameters. methods: patients ( males and female) urtderwent surgical replacement of abdominal aortic anonrysm with the aortic simple or bifurcated grail. patients were operated on eleetively, had an emergency surgery for raptured enentysm. haemodynamic, arterial ph and bicarbonate concentration measurements were taken before and after induction of anaesthesia, after cross-clamping and declamping of the aorta end at admission to itu. phi calculations ware done at the sime time except before induction, as tonometers were inserted after patient had been asleep. we used pulmonary utilizing a computer billing survey as well as hospital service transfer data from a month period ( / - / ), all obstetric patients that were transferred to the med/surg icu were identified, as well as their diagnoses and procedures. twenty-eight obstetric patients were transferred to the med/surg icu, compared to , deliveries occurring during that time period for a . % rate. the following procedural indications for icu transfer occured: insertions of endotracheal tubes, arterial catheterizations, temporary tracheostumy, and venous catheter. the following medical diagnoses were found: hypertensive/eclamptic episodes, hypotensive episodes, pulmonary embolism, mitral stenosis, and coagulation deficiency. there were four episodes of respiratory failure ( %). the historical rates of respiratory failure from the medical literature seen at a university hospital ore higher than those at our community hospital despite comparable icu transfer rates for critically ill ob patients. objectives: to evaluate the usefulness of several isss used in order to predict risk of death (rd). design: prospective data collection for months in a multidisciplinary -bed icu. methods: data from consecutive patients admitted to the icu from / / to / / were studied. all the necessary informations were stored in a computer using special software for every day computation of three isss (saps, saps ii, apache ii) and of the rd predicted by saps ii, mpm , mpm and odin. data from days of hospitalisation were used for comparative evaluation of isss and rd, while sensitivity and specificity in death prediction (cut off point of rd = %) were evaluated from data collected during the day of admission (saps ii, rpm , odin) or after hrs (mpm ). agreement between rd predictions was evaluated by bland and altman analysis. results:our results were the following: objectives: a) to create and validate software specially designed for the collection of demographic data and estimation of illness severity and predicted rd and b) to provide data necessary for the evaluation of the effectiveness and the efficiency of our icu. design: prospective data collection in a multidisciplinary -bed icu. methods: prospective data on specific physiological variables, selected demographic characteristics, comorbidity and the reason for icu admission were recorded every day for consecutive patients admitted to the icu from / / to / / . data were entered into a portable computer using specially designed software allowing the calculation of usual illness severity scoring systems (isss) and the corresponding predicted rd. results: we studied men and women, with a mean age of years. we conclude that, although observed mortality was higher than predicted rd, this difference was not statistically significant. the fact that the sd of predicted rd was too large, limits the usefulness of isss predictions for a comparative evaluation of different icus. objectives :the importance of objective evaluation of patients prognosis at their admission to an emergency department is clear. the aim of this study was to appreciate the prognosis of patients with the simplified acute physiology score ii (saps ii), and correlate this score to the prognosis and orientations of patients. methods : the score which is a reduced form of saps ii was calculated from clinical variables and laboratory items for patients. sensibili}y (se), specificity (sp) and accuracy (ac) were calculated to evaluate the performances of saps i . thresholds were calculated with the youden's test (se+sp- ). results : patients were admitted in the intensive care unit (icu)and patients in medical units; patients died. the saps ii was higher in patients which died than the survivors ( , + , vs. , + , , p< , ; respectively), the best threshold was , se was de %, sp was %, the ac was / . thus for patients admitted in icu than in medical unit ( , : : , vs. , + , , p< , ; respectively); the best threshold was , se was %, the sp was %, the ac was %. conclusions : these preliminary results suggest that saps ii can be used to determine the short term prognosis and the destination of patients seen in an emergency department. design: data was collected on all admissions over a six month period. all patients had a screening hiv elisa test. confirmatory ifa tests, western blot and flow cytometry were performed on hiv positive patients. the institutional ethics committee considered the major clinical impact of the study sufficient cause to waive the patient's right to informed consent, icu staff and patients were blinded to hiv results. following discharge patients were given the option of being advised of their hiv status. setting: the study was conducted in a bedded surgical icu at a tertiary care teaching hospital. patients, participants: all patients admitted during the period in question were included. interventions: "all patients were treated according to standard icu protocols. there were no interventions. results: most patients were admitted following trauma. there were no patients with aids, hiv positive and hiv negative patients. with respect to the latter two groups, the mean age and sex distribution was similar, there was a significant difference in organ failure ( % versus %, p < . ) and septic shock ( % versus %, p , : ) but no difference in icu/hosp[tal mortality or duration of icu/hospital stay. flow cytometry changes in hiv positive patients were consistent with the quiescent phase of hiv infection. conclusion: while morbidity is higher in hiv positive patients, there is no difference in mortality. hiv status should, therefore, not be an exclusion criterion for icu admission in this patient population. , n= ) and january-march (period , n= ) were studied. interventions: a resident micu team led by a trained intensivist took over the medical care from the primary physicians when the patients were admitted to the micu. the intensivist also vetted micu admissions and decided on micu discharge. in addition, there was a resident respiratory therapist to attend to vendlatory care during office hours. after office hours, the care of the micu was delegated to the on-call team on a rotational basis among the medical departments. results: the patients in the two groups were similar with respect to age, sex, race, source of admission and apache scores. the icu and hospital mortalities decreased from . % to . % (p=ns) and . % and . % (p=ns) respectively in period . the mean icu and hospital stay was also decreased from . __+ . to . + . days (p=ns) and . __+ to . • . days (p=ns) respectively. the improved micu length of stay for survivors in period was statistically significant ( . • . days vs . • . days = . ). there was no significant differences in the vse of peritoneal dialysis ( . % vs . %) and mechanical ventilation ( . % vs . %). however, utilisation of intra-arterial lines and pulmonary artery catheters increased from % in both to . % and . % respectively in period . conclusion: the duration of critical illness was reduced in period . hence, we believe that the closed |cu which was staffed by an intensivist and had the services of a respiratory therapist was beneficial for the care of the critically ill. the intensivist, was also more likely to utilise invasive monitoring. in the absence of liver transplantation, intensive care for patients with acute hepatic decompensation arising from alcoholic liver disease (ald) is indicated only for those who are likely to benefit from conventional means of organ support. we have attempted to elucidate potential risk factors and the efficacy of organ support in relation both to hospital outcome and icu costs so as to allow the earlier identification of relatively futile intensive care in this group of patients. methods: over a period of one year, ald patients ( males; females; median age years, median apache ii score ; hospital mortality %)with severe complications ( [ %] with bleeding oesophageal varices, [ %] with hepatorenel failure, [ %] with respiratory failure, [ %] with septic shock, and [ %] others) were studied in our liver icu. organ system failure, daily therapeutic interventions and icu costs were assessed using a patient management system (riyadh intensive care program). results: whilst survivors had a significantly lower admission apache ii score compared with non survivors (medians and , p< . ), or more organ systems in failure in the first hours of icu admission was associated with a % ( ) mortality. mortality was also related to child's grading and the numbers of organs supported. of the patients who received more than one form of organ support only one survived. organs supported mortality a (n= ) % none / ; % b (n= ) . % one / ; % c (n= ) . % two or more / ; % the icu costs for the patients were only s but s ( %, patient days) was utilised by the patients who died, giving an effective cost per survivor (ecps) of s . although the cost of treating the patients with or more organ systems in failure on the day of admission was s ( % of the budget) the ecps was s . conclusion patients with ald who have or more organ systems in failure early in their icu course have a poor prognosis and in the absence of liver transplantation, traditional strategies of organ support are ineffective. this begs the question whether such costly care is appropriate as although the ecps in this sub group is comparable with other patient groups with multiple organ failure, their outcome is considerably worse. objectives: to evaluate the economic impact to the healthcare sector of using dopexamine hydrochloride infusions to deliberately increase perioperative oxygen delivery in high-risk patients. methods: effectiveness data were obtained from a controlled clinical trial in which surgical patients were randomly assigned to either a control group (n = to receive best standard optimal fluid resuscitation perioperatively, or a protocol group (n = ) to receive, in addition, an infusion of dopexamine hydrochloride to increase the perioperative oxygen delivery index to greater than ml/min per square metre. resources consumed by patients during treatment were recorded prospectively and costs of resources at / prices were obtained retrospectively. cost-effectiveness ratios were estimated by dividing the total cost for each treatment group by the total number of patients in each group and by the clinical outcome of mortality days postoperatively. results: in the protocol group, there was a % reduction in mortality days postoperatively (p = . ), a significant reduction in the number of complications (p = . ) and a reduction in length of stay in the icu and surgical ward. the average cost per protocol patient to achieve a . % survival rate days postoperatively was s , , resulting in an average cost of s , per surviving protocol patient. the average cost of a control patient was s , to achieve a . % survival rate days postoperatively, resulting in an average cost of s , per surviving control patient. the use of dopexamine to deliberately increase oxygen delivery perioperatively generated a cost saving to the nhs of s , per patient together with a % reduction in mortality at days postoperatively. hence, the cost per surviving protocol patient was s . less than the cost of a surviving control patient. conclusion: the additional cost of dopexamine in protocol patients was offset by a lower incidence of complications and a shorter stay in the icu and on the surgical ward. hence, increasing oxygen delivery perioperatively in high-risk surgical patients saves both money and lives. objective: although king's college criteria are widely used, indication and timing for liver transplantation in acute liver failure is still far from certain. long-latency sensory evoked potentials -a proven measure of metabolic brain dysfunction (grimm et al. lancet ; : - ; madl et al. lancet ; : - ) -are markedly affected in patients with acute liver failure. serial sensory evoked potential recording should provide very useful information for the management of patients with acute liver failure. methods: recordings of standard bilateral sensory evoked potentials were performed in patients with acute liver failure. findings were focused on cortical n peak -a stable negative deflection occuring • ms after median nerve stimulation in healthy subjects, which can be recorded by skull electrodes over the sensory cortex. results: nine patients recovered spontaneously, patients were referred to emergency liver transplantation, and patients died. in all patients who recovered spontaneously, n peak was detectable between and ms. all patients who were referred to liver transplantation and of patients who died, developed a loss of a prior detectable n peak during the course of acute liver failure. objective: to determine high risk arid low risk patient groups in a medical intensive care unit regarding short term and long term outcome. methods: data on all admissions of the year were collected prospectively. according to their mode of admission patients were classified as admissions by the physician staffed ambulance service (as), admissions through the emergency department (ed)i referrals from non-intensive care wards (ni), and secondary referrals from other hospitals (oth). outcome was assessed in terms of in-unit mortality, in-hospital mortality, and long time mortality. patient groups were compared using the \ -test. life table analysis were per{ormed by kaplan-meier method comparing patient groups by log-rank test. the software spss for windows . . was used for statistical calculations. results: in-unit mortality: / patients ( . %) --oth . % > as . %> ni . % > ed . %; p = . . in-hospital mortality: / patients ( . %) --oth . % > ni . % > as . % > ed . %; p = , . mean survival time in days after discharge: as < ni < oth < ed ; p = . . conclusions: despite an excess in-unit mortality of secondary referrals from other hospitals the iongtime course of this special patient group is not different to others. solsuam, j, marrugat*, g, mirs, j, nolla, a, vazqu~z-sanchez, l alvamz, ~ioio s xndioina i~siw. ir~itate l(~icipal da l~sti~isn l~di~*, ~ospits dal objective: to study the influence of modifiable variables (complications derived from therapeutic activities) on the prognosis of ~atients admitted to the icu indapemently on thn severity of illnsss. patients am methods: between january asd ]lay data from , patients over years of aqe who retained in the icu for mare than hours ~ere pr~pectively regiatered. a cohort st~ly with follo~-~ nf patients durin~ ~eir stey in the hospital was deni~.el in all patients, reasons for a~issien, principal diagnosis sad severity of illn~s moasared by the saps scare vare recorded. fastens affecting patients' outcome that my be proventsd or modified included technical :omplisafioss, heapital-acqnired infections and in~pro~riate therapeutic decisions. a logistic regression model was used to assess the relative risk (l~} for in-heapital mortality adjusted for each variable. results: ic~ mortality ~s . % and in-hospitul mortality . %. patients who died showed a higher spas score then survivors ( , ~ i ,i). after adjusting hy severity of illness, co~;licetices that statistically increased the risk of in-hospital death were septic shock secomery to hoapitul-acqdired infection ( ~ . ; % el, . to . ), pmo~othor~x related to mocasnical ventilation (@ . ; % cl, . to . ) and delay in the insertion of a fln~-quidod catheter (ii~ . ; % ic, i.i to . ). col~lusien: registration of complicaticas derived from therapeutic activities is a valuable tool far quality central in the icu. g, ~i~ , j.l mle~ma, j, ~amqat*, j..~lla, a, vazquez-saltemz, f, alvamz , servioia de nndicina l~siu. i~stitutu ~icipal de ln~sti~acidn ~ i:a*, hospital dsl objective: to dstsr~ine the incidence of self-extebatien and its effect on ~ortality. patients and ]~etheds: betveen january and april , all i~tiente in whom selfextubatien w~s registered were inclnded in a prospective study. patients were divided into @nee who needed r~intabatinn within hoers and those who did not. in all patients, dsmoqraphie and ciinical data were recorded as well as icii mortality, in-hoapital mrtality and severity of illness according to saps score. eta were analyzed usi~ the cbj-square test for cathgorical verinbls, the analysis of varianc~ (anva) for aontinuc~ ~ria~les and a leqi tic regression anal~is to estimate the relative risk (iiii) for mortality as result of celt-nxtt~ation after adjusting for severity of illness. results: a total of intnmtsd patients amre stndied. self-extu~atien occurred in ( . %) patients and . % required reintuhot~pn. when a co,arise was made between patients who did not required reint@atinn and patien~.s who did, statistically significant differences in eqe ( . v_s . years, p = .~ ), ~verity of illness ( . ~ . spas score, p = . ), dia~isstia category ( s. % v_s . % of patients with res~iratury conditiono, p = , } and mean length of stay ( , ~ , days~ p = . ) were fo~m, a~ter ad~sti~ for severity, patients with self-ext@atinn who did not reqnired reintalatien showed a . iir for mortality ( % ci, .i to . ) as co~arod with patients in when self-ext@ation did mot occur. conclnsien: self-~extamtice that does not require reint@ation is associated with a isamr in-hospital natality probably dt~ to a prolonged period of weaming. patients' admissions to ices am often delayed doe to the shortage of beds available. @ile amaltieq icu admission, these patients are treated in observation nits of @e emergency services which bare ,either tile structure nor the trained ~reomenl that are available in leb~. objective: to daterdno the effect on the patient's proqusis of a delay in tile admission to the icu when criteria for icij admission are fulfilled. ~terials and methods: between jme am l?ece~ber all patients who fulfilled criteria to be almittod to the ic who for waste~r reason retained in tile observation unit for more than hours were included in a prospective stedy. in all patients, des~raphic end clinical dabs amre recorded as well as severity of illness aencrdi~j to saps score. a cesucontrol dasi~ was eend with a total ss~ln of , patients who suffered no delay is admission to icii over a period of years. data wen analyzed using the chl.-squ~re test (to aeons the association hetwenn in-patienty mortality end categorical vari~lns) and a maltipln logistic reqression model to sstimta odds ratio for) for in-hospital mortality as result of delay in icy admission as compared with early ad~issi| after adjusting for severity of illness end use of assisted mchenical ventilation. ~ &ults: a total of patients remained in the observation nit for more than hours with a del w in igd admission of . _+ . hoers. assisted mechanical ventilation was requited in % of patients and only monitericatien in %. itsse patients were cspared with ntients from the tet~l sample ratchod by age, sp~ score and rennoss of admission. in-hospital mortality for cases warn % as compared with . % for controls (p = s). after adjamtilg fen spas, age and mobamioal ventihtien, no statistically significant differences between both ~renpa were foam, altho~b there was a tendency towards a higher mortality amen@ patients with delay in icu admission (or = . ; % ci, , to , ). conclnnien: ~se findings suggest that prognosis of critically-ill patients is no worse as a result of admission to the loll being deln~d for borers. all data appropriate for the calculation of the apache ii score (aps) together wi'th other specific cardiac details relevant to these .patients were collected daily, verified and enter~ into a computer database. results: patients were studied. six patients died and five of thee underwent cardiac surgery. the mean aps was for survivors and t for non-survivors (p < . ). the mortality ratio was . and the major markers of mortality were apache ![ score, presence of chronic ill health, mean duration of ventiiation, mean length of icu stay and need for emergen~ surgery. sixteen percent ( ) of icu bed days were occupied by % of patients (non-sarvivors) which resulted in cancellation of cardiac sot#cat sessions in momhs. conclusions: this study concludes that apache t could be used as an audit tool in a cardiac surgical icu and demonstrates the severe compromis~don of cardiac surgical throughput by a few non-survivors, organ to determine the number of organ failure free days (offd) in a cohort of survivors and non-survivors with sepsis syndrome followed over a day period. ) to determine sample size requirements for clinical trials utilizing a increase in the number of organ failure free days as the primary outcome as opposed to mortality. methods: beginning december through to april , patients who met inclusion criteria of the "cardiopulmonary effects of ibuprofen in sepsis syndrome" and who did not have hiv/aids. brain death or moribund state were prospectively identified. presence or absence of failure of organ systems (pulmonary, cvs, renal, hepatic, gi, hematologic, & cns) was recorded daily until death or until days. a score of one was assigned to each organ system free of organ failure in patients still alive, ie, maximum daily off score= , maximum day off scorn= , sample size estimations were performed for variable detectable differences in off scores (delta). alpha was set at . (two-sided), with n/group = [(z a +z b ) o conclusions: a clinically relevant increase in off days may be detected with as small a sample size as to patients per group. this represents a significantly smaller sample size than needed to detect a change in mortality from % to % ( % relative risk reduction) where the n/group= . scoring patients in this manner prevents a lethal inte~entien from providing an improved organ failure score. in addition, an intervention that prolongs survival must also provide greater organ failure free days in order to be counted by this scoring method. survival as an outcome provides no information about the quality of that survival. off days provides a measurement of burden of illness. interventions which lessens this burden may be just as valuable as those that decrease mortality by providing a measure of the quality of survival and by decreasing costs of care. they may also prove to be an accurate surrogate marker of mortality. the advantage of this approach is that the event rote is much higher and sample size requirements are subsequently smaller. this would mean that clinical trials can be completed faster and at lower cost. outcomes such as mortality could then be assessed at a later date utilizing recta-analysis. we suggest that the use of off days is a valid outcome measure that may be utilized in clihieal trials of sepsis syndrome. the icu is perceived by many as being a stressful environment for both patients and staff. stress has been defined in three ways: a stimulus producing a particular response; the physiological and psychological response to a stimulus; an interaction butwom an individual and their environment. stress is currently thought to be a dynamic system of stimulus and. response which takes into account the individual's perception of the stimulus and their ability to respond effectively. stress may, therefore, be positive and allow personal development but an individual unable to respond effectively to a stimulus will experience negative effects or strain. critical illness is an intense stimulus to which the body needs to respond effectively. physiological responses are vital and most of intensive care involves supporting these. alternatively, blocking them, for instance with atom(date, increases mortality. psyehological responses are also vital but often poorly appreciated because of communication problems. many of the problems patients experience in an icu are evidence of psychological strain. this can be exhibited in various ways, for instance, anxiety, depression, passivity and confusion. dealing with critically ill patients is perceived as stressful. we recently studied occupational stress in our icu. most aspects of intensive care were not generally perceived as stressful indicating a self-selectien of icu staff. the most stressful aspects of icu work for nursing staff were the structure of the organization and career opportunities. medical and nursing staff had different stressors and different coping strategies. support for occupational stress, therefore, should focus on the individual and concentrate on information and communication. atmosphere, and especially at intensive care units, we face up to daily decision making. in most cases these are taken on the basis of personal opinion and the processing of a very limited amount of information. rising need to optimize the results of medical attendance becomes necessary to set structured system of d@cision making in which ethical basis have a sp@dial significance in view of next considerations: -we live into a pluralist society in which the importance of values is different. -most persons consider health as the first value only in the event of illness. -medical resources available are limited, whereas medical, attendance demand from population increases in a way many people consider it unlimited. in consequence, it becomes necessary to set up priorities in patients treatment. ehtical basis that rule decision making are essentially these ones: i. beneficence: to provide the patient that is being treated the highest profit. . non maleficence: it is our first duty to avoid hurting or damaging the patient."primum non nocere" . autonomy: in every particular medical attendance, the patient has ability to decide by himself. . justice: as equity: to provide the same treatment for those who have the same pathology, ignoring another factors such as age, sex or race. severe application of these principles can cause difficulty, which resolution requires a systematization of decision making. ( - ) . the lenght of stay between survivors and non survivors didn "t show statistical significance (p = . ). the mean aiii score when considering all admissions was , ( - ) . the initial score between survivors and non survivors showed ststistical difference ( . vs . ) respectively (p < . ). univariate logistic regresion analysis demostrated a % increment in death probability for every points augmentation in the aiii score with a sensitlbity of . % and specificity of . %, the roc curve showed that the best cut off point for death prediction was points with a sensitivity of . % and specificity of . %. if a patient is classified as high risk (> ) the bayesian analysis showed a . probability of death and for one class(fed as low risk (< ) a death probability < %. conclusions: the first day aiii score in this population showed to be a good discriminator between survivors and non survivors, and the risk of death augments as the aiii does. in this population an aiii score > points is asociated with a greater risk of death. using the aiii score in conjuntion with the clinical judgement will help clinicians reducing uncertainty in the every day decision making and better predict outcome, the results from this study should been taken with caution because the data were obtained from a small sample. objective: the quality of life has been considered a "uniquely personal perception" resulting from a mixture of health related factors and social circumstances [t. m. gill, jama , : ] . the aim of this study was to evaluate two measures of pqol in intensive care unit (icu) admitted patients. patients and methods: during icu stay and six-months after hospital discharge, co-operative icu admitted patients were directly interviewed about their pqol. we administered ftrstly the uniscale (pqolu) [sage et al crit. care med. , : - ] and then a step verbal scale (pqolv): best, good, fair, poor, worst. of the studied patients, at the first interview, were able to use both scales, but ( . %) understood only the verbal one. at the second interview, patients were not able to answer, used both scales and only pqolv. statistical analysis was performed using wilcoxon signed ranks, spearman rank correlation, student's t and chi square tests. results: of all cardiac surgery pts, pts ( . %) died in icu. they were males ( . %) and females ( . %). their mean age was (+ ) years and mean ef was . (+ . ). nineteen pts ( %) had low (< . ) preoperative ef. mortality was . % in the coronary artery bypass grafting (cabg) group (n= ) and . % in the valve replacement (vr) group (n= ). in the cabg +vr group, mortality was . % (n= ), and . % in the remaining pts (n= ). cardiogenic shock was the sole cause of death in pts ( %), septic shock in pts, whereas sepsis in combination with ards in pts, sepsis and stroke in two pts. in addition, pts died from cerebrovascular accidents, one from ards and one from pulmonary embolism. the pts who died in the icu had a significantly longer bypass and aortic cross clamp time and received more blood transfusions (p< . ) than a matched control group that survived to icu discharge. the duration of mechanical ventilation and length of icu stay were greater in the pts who died in the icu than in the control group. conclusions: . although cardiogenic shock is the main cause of death ( %)in cardiac surgery pts, sepsis and cerebrovascular accident are relatively frequent causes. . patients who died in the icu had longer bypass and aortic cross clamp time and received more transfusions, compared with the control group. . although renal or hepatic failure contributed to death in some pts, they were not the primary cause of death in any patient. objectives: evaluate the acute and follow-up outcome of patients (pts) treated with primary ptca (without prior thrombolysis) in acute myocardial infarction (ami) after and up to hours after onset of typical thoracic pain ("late" primary-ptca). methods and patients characteristics: from / to / consecutive pts with ami were treated by primary ptca in the wuppertal heart center pts ( , %) were admitted to our hospital > hours and < hours after symptom onset with ongoing chest pain and typical ecg-changes.mean age was years ( - ). pts were male, four female. % had an anterior wall myocardial infarction, % suffered an inferior/postero-lateral wall myocardial infarction.two pts were in cardiogenic shock at admission. singlevessel-disease was documented in . %, multi-vessel-disease in . %. average time of onset of pain to recanalisation was min ( - ). angiography revealed timi-flow in . % of the pts, timi-flow i in . %, timi-flow ii in . %. average follow-up (fu) period was months ( - months). timi iii lv-ef ~ -day major late re-late flow p.i.* aeute/fu mortality bleeds infarction mortality . % %/ % . % . % . % % early mortality occured in the two pts, who were in cardiogenic shock at admission no pt required emergency coronary artery bypass grafting.restenosis > % was seen in % of the pts. conclusions: "late" primary ptca achieves a favourable high recanalisation rate of about % (timi ill-flow) in our study group. additionally, there seems to be a trend for lv-ef improvement in follow-up. early high mortality is influenced by the patients admitted in cardiogenic shock. there might be a trend for increased major bleeding complications. objective: to assess the validity of saps ii (new simplified acute physiology score), comparing it with the previous version, (saps), in a sample of patients recruited by giviti, a network of icu's representative of the italian icu system methods: measures of calibration (goodness-of-fit statistics) and discrimination (receiver operating characteristics curve and area under the curve) were adopted in the whole sample and across subgroups differing in relevant prognostic characteristics. of the patients recruited during one month period, a total of patients were included in this study. for the purpose of the comparison of the two scores, patients with less than years, or having cardiac surgery or staying in the icu less than hours were excluded. vital status at icu discharge in the whole sample and at hospital discharge in half cases wher adopted as outcome measure. re$ ~: saps ii fits the data equally well compared to the older version (goodness-of-fit p= . and in the new and old versions, respectively) but its performance is somewhat better in terms of capability to distinguish patients who live from patients who die (areas under the curve . and . , respectively). furthermore, saps ii is better in terms of uniformity of fit across relevant subgroups, although substantial over prediction of mortality was observed in trauma patients and in patients admitted without organ failure to be intensively monitored. saps ii performed very wet] also in the subsample where hospital mortality was the dependent variable.satisfactory measures of calibration (goodness-of-fit p-- . ) and discrimination (receiver operating characteristics area= . ) were observed. c nr saps ii, a multipurpose scoring system developed in an international study, retains its validity in this independent sample of patients recruited in a large network of italian icus. although it has shown a good performance when adopted to predict icu and hospital mortality in the entire sample, further investigations are warranted. the observed over prediction of mortality in a few subgroups indeed call for a through assessment of the impact of confounders and biases on model performance when saps ii is adopted in samples that do not reflect the "average" icu patient. objectives: ) assess the effectiveness in a group of intensive care units by means of a quality performance index (qpi); ) assess the efficiency by means of a resource use index (rui); ) evaluate the performance of individual icus with respect to both indices (clinical and economical) while controlling for severity of illness. critical from ucis in catalonia patients alearic islands have been included in the study. inhospital mortality and weighted hospital lenght-of-stay (los) have been considered the outcome variables. severity of illness has been measured with the mpm ii at admission. in each icu, expected mortality has been obtained adding the probabilities of dying for its patients. expected los has been estimated adjusting a second order polynomial to the severity of illness. performance indices have been obtained by dividing the observed by the expected outcomes. re~ult~: the overall qpi was . and it ranged from . to . in the icus. the overall rui was and it ranged l~ont . to . . there was not a trade-offpattern between clinical performance and resource use. objectives: teaching hospitals often provide [cu care across a variety of specialized services. overall, this approach appears to result in the best risk adjusted survival rates, but at the highest cost (critical care medicine ; : - ): recently, there has been increasing focus on markers of overall hospital performance. however, in large teaching institutions, such markers may fail to detect intra-institntional variation at a large tertiary care medical center. methods: first intensive care unit (icu) day, acute physiology and chronic health evaluation iii (apache iii) and active therapeutic intervention scoring system (tiss) data were collected on random admissions to specialty icus with beds (range - ) between february i and december l, . post-operative solid organ transplant recipients were excluded. units included general medical, general surgical, and trauma, neurosurgery, cardio-thoracic surgery, and coronary care units. data were analyzed for risk adjusted outcomes: icu and hospital mortality and length ef stay (los); risk of requiring active cu treatment; and icu readmissinn using apache iii risk prediction models. results: the study icus cared for a diverse group of patients. mean apache iii scores ranged from . - . ; predicted risk of hospital death ranged from . - . %. standardized mortality ratios ranged from . to . with icus performing significantly better and performing worse than predicted (p< , ). los ratios and icu readmission rates ranged from . to . (ns) and . to . % respectively. patients predicted at low risk of requiring active icu treatment ranged from , to . % conclusions: there was wide variation in the mean level of patient severity between icus. after controlling for this severity, outcomes also varied widely. no clear pattern of overall institutional performance was evident. these data suggest that efforts to assess performance, improve quality, and maximize efficiency must be focused within individual units. programmatic evaluation of outcome allows for focused review of the processes of care contributing to good outcome (best practices) and where to focus ongoing quality improvement and cost reduction activities. background and method : we compared icu mortality in different age groups presenting with the same severity of disease. we assessed severity of illness by the physiological day -apache~ (physio-aa) score (thus excluding the age related points). for each of the following physio-a n score intervals ( - ; - ; - ; - ; > ) , we compared tcu mortality within age intervals (< ; - ; - ; - ; - ; > years - , - , - ) . in these groups mortality may be twice higher in the > years patients than in the _< years. mortality does not vary with age in low (physio a n = - ) and high (physio a n = > ) risk groups. in the low risk group, mortality is low in all the age intervals because of the begninity of illness. in the high risk group, extreme severity of disease probably blunts the impact of age and leads to high mortality rates in all age intervals. introduction: to access the actual social/clinical outcome of the patients who undenvent intensive care therapy oct) is rather difficult, quality of lilr is not easih.' defined and ohserver subjectivity is a prime factor in the evaluation. mortality ratio after discharge must be established and its causes understood. obieetives: the propose of this stud)-is to look into the mortality ratio that occurred on a series of patients that undorwent ict at our unit from of the ~iew point of severity of the original illness and the diagnostic groups. material and methods: during the period of one )-ear ( ), patients were treated at the unit, of them died, and ~ere not matched in our series because os incumpletc records. thirteen patients died in hospital after their reference to other departments, twelve patients were lost after discharge. thus. at the end. only patients were evaluated on the fu. the, were classified into the follov ng three groups: acute medical, elective surge d and acute and emergency postoperative. the patients were seen at , and months after discharge. the, were evaluated in accordance to their abili~, to being self supported in their daily life and capecity to fully return and hold to their pre~ ous jobs. apache scores were evaluated for each of the three groups and correlated to the icu dead, hospital dead, and mortality after hospital discharge, spss package was used for statistical analysis. remlts/conclasions: data shows that / patients died after discharge from the hospital, of ~itch nine died in the first three months. seventy-eight per cent of the patients were fully self supported in their daily life and % showed some kind of handicap. fosty-nine per cent of the patients wore on retirement either due to age or some form of chronic disease, when admilled to our unit. thirty-two peg cent had not been able to return to work, because the" were incapacitated on discharge. only % had return to their fully jobs but the period of the stu~, is not enough for all of them to be fully physically recovered. preliminmy statistical analysis shows us significant differences among groups. the aim of the present study is to compare the prognostic performance of five general severity indices ou coronary patienta and to find out if a proper ntatistical hundling of these indices could provide better results in these patients. methods: saps ii, mpm ii (mpm ii i mpmp ii ), apach ii end gaprik were evaluated o~ patients with acute myocardial infurction admitted to intensive care units from catulunye. calibration and discrimination were calculated for each index. calibration was calculated by th bosmer-lemeshow test. discrimination was evaluated by the area under the relative operating characteristic (roc)curve. if a model did not show a good performance it was customized using multiple logistic regression. finally, tworeduced models were developed, one fro~ the mpm series (mpm ii cor) and one from the group apache-saps (sapsiicor).their performances were again evaluated. results: discrimination was high enough for all models. neverthelees, oelibration of apache ii, saps ii and mpm was not satisfactory. thus,mpm ii , saps ii and gaprik were customized for coronary patients using the logits of both models, and obtaining good calibrations. mpm ii , and apache-saps were adapted and reduced to (mpm ii cor) end to variables (sapsiicor), respectively . both models showed better oalibrutions end discriminations than the original models. conolusion| models developed for multidisciplinary patients show a good discrimination when applied on aoronar i patients, but some needed customization in order to improve calibration. the number of variables of the principal model can be reduced (even to or variables) without loosing prognostic accuracy. objective: to compare the ability of two methods to predict outcome for intensive care patients. methods: we included consecutive intensive therapy unit (itu) admissions with an itu stay> hrs in a month prospective study (exclusion criteria: burn injury and age < yrs). data were couectsd applying the criteria described by the developers [ , ] . the definition of coma (mpm ii) was modified and the best assessment within in's, rather than the admission score, was used. statistical analysis included classification tables and receiver operaung characteristics (roc) curves to assess discriminative power, and lemeshaw-hosmer statistics and calibration curves to test accuracy of prediction. results~ average abe was yrs (ranse: - ) with a male:female ratio of . : . the actual hospital mortality was . %, mean predicted death rates were . % (mpmz ii) and . % (ap hi). non-survivors had siguitlcanfly higher predicted risks than survivors applying both methods (p< . l, t-test). the total correct classification rates (tccr) for apache iii were bett~r for all decision criteria applied (tccr, decision criterion %: apache ]/i . %, mpm ii . %). the area under the roc curve was . (ap iii) and . (mpm ii) confirming the better discrimination of apache ill. accuracy of risk prediction was similar for both models (ap nl ~ - , mpm b ;( - , lemeslmw-hosmer). showing some fluctuation, calibration curves lay close to the ideal line for predicted risks -< % with increasing deviation for higher risk groups (s. figure) . apache iii underestimated the risks of hospital death for almost all risk groups (curve above diagonal), whereas considerable overestimation for predicted risks > % ceenred with mpm~ii. objective: to assess the goodness-of-fit of the apache iii model for british itu patients. methods: we prospectively studied a cohort of adult patients consecutively admitted to a medical-surgical itu over a period of months. patients with burn injury, age < yrs and itu stay < hrs were excluded. using a eomputerlsed database, we routinely recorded hrs apache ill scores. predicted risks of hospital death were computed by critical audit ltd, london. accuracy of risk prediefion was assessed by hosmer-lemeshaw chi square (;( ) statistics and calibration curves [ ]. discrimination was tested employing classification tables and receiver operating characteristics curves (roc). restths: the mean age of the male and female patients was yrs (range: - yrs). of these patients, % were medical admissions, % were admired after emergency and % after elective surgery. the observed hospital mortality was . %, the overall mean predicted death rate was . %. mean predicted risks were siguifieanfiy greater for nonsurvivors ( . %o) than for survivors ( . %, p< . l, t-test). apache iii showed good calibration (z -~ , lemeshaw-hosmer). however, the calibration curve lay above the diagonal for almost all risk groups reflecting the tendency to underestimate actual mortality (s. figure) . the best total correct classification rate (tccr) was . % (decision criterion: %). the area under the roc curve was . % confirming the good discriminative ability of the model. objectives: the aim of this study is to point out the discrepancies between needs and actual treatment of less severely ili patients admitted in italian intensive cam units (icus) requiring only intensive monitoring, and verify the substantial likelihood of data comparing those collected from a national short term study with a regional long ternl use. ~: less severely ill patients ("observed patients") were only monitored; they did not require intubation, even if for a short period (less than houm) or major cardioeiranlatory supports, and were neurologically normal. epidemiologieal national data were obtained from giviti group (gruppo italiano valutazione interventi in terapia intensiva); this cohort study, collected patients, in two months in summer in all over italy. regional data were echieved in a three years entlection ( -i ) in lombardia' icus from archidia group (arehivio diagnostieo), including patients. mortality, severity score, diagnostic category and some typical intensive procedures were analysed and compared in both studies. patients' disgunstie categories were defined as surgical, medical and trauma, according to the main diagnosis and the presence/absence of surgical procedures. rr observed patients account for . % and % of all icu's patients respectively in national and regional data. very tow mortality rate was found in national data ( . %) and extremely low mortality in regional data ( . %). in both studies mortality, s.a.p.s. and length of stay were much lowor in "observed patients" than in general icu's population (mortality: . % and . %; .a.p.s. score: . and ; iength of stay: % and ). homologous distribution of patients in the two studies was noted for what concern their diagnostic category, aside from a slight prevalence of tranmatised patients in the giviti study. in the two groups the surgical patients were respectively % vs. %, medical patients were % vs. % and traumatised were % vs. %. % of "observed patients" in national study and % in the regional did not received any intensive procedure. only a minority of these patients availed haemodynamie eonu'ol with swan-ganz or renal haemofiltration. conclusions: these results underline that about one fourth patients admitted in italian icus benefit an oversized slructure i, relation to the real needs of their pathology. in hot more than % did non received any advanced treatment and mortality and s.a.p.s. score were substantially lower respect to general population. the results obtained from these two studies are similar, suggesting an uniform distribution of the case mix in italy, even if a different recruitment period and a different gengraphieal distribution were used. some discrepancies in the two studies were found in the diagnostic categories moreover regarding the tranmatised patients ( % vs. %); this can be explained from the seasonal (summer) characteristic of the national study. mutuality, yet very low, is different in the two groups, but these data do not allow any definite explanation. finally these epidemiologieal survey suggest need of further studies settling more strict criteria of admission in icu. this study aims to evaluate patients outcome, quality of care and effectivity of therapy in our intensive care unit. the main goal was to indentify factors that the most influence that outcome. during . the authors collected data of patients outcome and predictor variables. overall mortality rate was , %. the most common causes of death were infection. the diagnosis of sistemic inflammatory response syndrome (sirs) and multiple organ dysfunction syndrome (muds) significantly correlate with death ( %). average length of stay was . days ~. % patients died in the first ten hosiptal days and only % after days. age was directly correlated with death % of dead were older then sixty years. an analysis of physiological variables showed that serum levels of gl~cose ( %) and natrium ( %) were in optimal physiological values. serum proteins ( %) and haemoglobin ( %) levels were inversely related to death. multivariate showed that alveolo-arterio difference in content was the most informative of all mortality predictors (mean value , mmhg in % patients io>mrnhg). factor that most influence the patients outcome was infection (sepsis) and muds. use of predictive indicators of outcome in critically ill patients may help to assess treatment regimens and to compare patient groups. acute physiology and chronic health evaluation (apache if) score (crit. care had. ; : - ) and the sepsis score of elebute and stoner (br. h surg. ; : - ) have been used, objectives: to compare sepsis score and apache ii score in predicting outcome of critically ill patients. methods: overall survival during the past years for patients in our icu was calculated = % (prior probability). the outcome of patients who were admitted to our icu for > hours was observed. apache ii score on admission, patient predicted risk of death (apache ii risk) and the sepsis score on the first day of antibiotic course were prospectively recorded. discriminant function analysis of the scores in relation to outcome was performed. results: apache ii and sepsis scores in the survivors were significantly lower than in those who died ( . i . v~s . • . and . • v's . • . respectively p < . ). correct prediction of outcome by each score is shown in discussion and conclusions: although both scores have been previously evaluated in predicting outcome of icu patients, studies of the sepsis score were conducted in small numbers of patients or involved additional measurements not routinely available. this study demonstrates that the sepsis score alone or in combination with apache ii score is more effective than apache ii score in predicting outcome. objective to test the hypothesis that resuscitation titrated against gastric intramucosal ph (phi) improves survival in critically ill patients as suggested by gutierrez et al~. method emergency admissions to the intensive care unit were randomized into control and intervention groups. in the control group phi was measured at , and h while in the intervention group phi measurements were made hourly for h. both groups were managed according to the same guidelines to achieve the following targets: mean arterial pressure > mmhg, systolic arterial pressure > mmhg, urine output > . /ml/kg, haemoglobin > g/dl, blood glucose < mmol/ , arterial oxygen saturation > % and correction of uncompensated respiratory acidosis. if the phi was < . after achieving these targets, or after maximal therapy to achieve the targets, patients in the intervention group were given fluid to ensure an adequate cardiac preload and then dobutamine at then mcg/kg/h, titrated against phi. this additional therapy was continued until h after entry into the study. in each year patients were subdivided in two series with random selection, so that the st series contained abeat / and the nd / of the patients. the st series of all the years constituted the devdoping data set and the nd series the validation data set. with data of the st series ( patients), we created the predictive model, using stepwise logistic regression (bmdp, usa). each patient has been evaluated in die st, th, th and th day, calculating for each lime the apache ii score (for a total of records), independent variables were, besides time and apache ii of the time ( michaloudia g,, melissaki a., alexias g., gogafi c., kolotoura a., krimpeni g., pamouktaoglou f, filias n. objectives: to determine the medical staff's attitude towards various ethical issues methods : between january and february , anonymous questionnaires were sent to intensive care units, all over greece. results : questionnaires ( , %) were replied and returned back. of them , % were answered by male and , % by female. the doctors replied in the following rate : , % aged up to , % aged between and , % aged over . questions were answered and were divided into main topics, as following: . admission criteria: limited bed availability was the main cause for refusing admission in , % of icu's. , % evaluated each case's viability and only , % used some prognostic score system. , % of icu's accepted all cases and a significant percentage ( %) gave in to pressure coming from their colleagues ( , % female and , % male). . informing the patient/relatives: only , % was willing to tell the whole truth, while , % had given selective information.. in the case of iatrogenic incident, , % withheld it, because either they feared legal implications ( , %), or lost of trust ( , %). doctors are asking consent from the patient and/or his family, in order to include him/her in research protocols, in a rate of , %, while only , % found informed consent necessary for the proposed treatment procedure. . withdrawal of therapy/dnr orders/organ donation: , % were willing to withdraw complex treatment in patients with short life expectancy, except of administi'ating intravenous fluids, feeding and analgesics. in , % such a decis~n was unanimous, while the percentage of those carrying it out was , % ( , % female, , % male). in case of brain stem death , % ( , % female, , % male) withdrew any life support. , % would like therapy withdrawal to be legally established, while only , % would perform euthanasia, if there was substantial legal cover. for these cases, relatives' consent was considered to be necessary from a percentage of only , %. , % considered organ donation to be a necessary proposal, while , % refused to ask the patients' relatives for an organ donation, either because they didn't have the psychological strength for it ( , %), or because they doubted the procedures' objectivity ( , %). note: in greece, icu beds are less than % from the total number of hospital beds available. only a percentage of - % of these admissions comes from the same hospital, with a potentially direct evaluation. usually an icu doctor has to be informed through the telephone. finally, employment conditions in greece are such that any changes of the medical and nursing staffare limited. conclusions: the mathematical model we found has been validated also in the second series and the discrimination capability increases with time. using this model we can evaluate the probability of survive at every, time. its application at different times permits a better evaluation of haemodinamically instable patient trend. introduction: the feasibility to assess pulmonary capillary pressure (pcap) offers the opportunity to determine the longitudinal distribution of pulmonary vascular resistance (pvr). the purpose of this study was to measure pcap and to calculate pvr to determine whether relevant shifts in the distribution of pvr could be expected after routine cardiac surgery. methods: the study population consisted of consecutively admitted patients after cardiac surgery. surgical procedures included coronary artery bypass graft (cabg) (n= ) and mitral valve replacement (mvr) (n=t ). pcap was estimated by analysis of the pressure decay tracing after pulmonary artery occlusion. after estimation of pcap precapillary (ra) and postcapillary resistance (rv) was calculated. a complete set of hemodynamic variables was obtained at hour and at hours after operation. results: there were no significant hemodynamic changes during the first hours after surgery. the mvr group maintained pulmonary hypertension and higher levels of pcap. ra/rv, reflecting the longitudinal distribution of resistances, remained unchanged. however, rv predominated ra during the postoperative period in both groups. objectives: evaluation of the influence of long-term continuous i.v. administration of the ace-inhibitor enalaprilat on regulators of circulatory homeostasis. methods: t trauma and sepsis patients randomly received either . mg/h (group i, n= ) or . mg/h (group , n= ) of enalaprilat i.v. or saline solution (control, n= ) as placebo for days. plasma levels of endothelin- (et), atrial natriuretic peptide (anp), renin, vasopressin, angiotensin-ii, and catecholamines were measured before injection of enalaprilat (='baseline' values) and during the next days. results: except for et, plasma levels of all vasoactive substances exceeded normal range at baseline. angiotensin-ii significantly decreased during enalaprilat infusion ( . mg/h: from . • to . • pg/ml; . mg/h: . • to . • whereas it remained significantly elevated in the untreated control patients. vasopressin increased only in the control group (p< . ) and decreased after . mg/h of enalaprilat. et remained almostunchanged in group , whereas et increased significantly in the control patients (from . • to .t• on the th day). catecholamine plasma levels (epinephrine, norepinephrine) markedly increased in the control group (p< . ), but they did not change significantly throughout the study period in both enalaprilat groups. conclusions: continuous i.v. administration of the angiotensin-converting enzyme inhibitor enalaprilat beneficially influenced systemic and local vasoactive regulators of the circulation, which are normally increased in the critically ill. thus patients at risk of (micro-) circulatory abnormalities may profit from enalaprilat infusion. objectives: to determine the time taken for hemodynamic and gas exchange variables to a reach stady-state after a change from supine to trendelenburg position (trp). methods: we prospectively studied adult patients with severe sepsis or septic shock requiring hemodynamic monitoring. usual cardiorespiratory parameters were measured at baseline, min after the patient was placed in a trp and again min after the return to a supine position. a fiberoptic pulmonary artery catheter (svo~ oximetrix, abbott) allowing continuous svo monitoring wa~used. during the protocol we also continuously measured sao~ by pulse oximetry and vco~ and vo by monitoring partial concentration of o and co ir~ inspiratory and expiratory gases (deltatrac metabolic monitor, datex). therefore, we were able to monitor cardiac output variations by dividing vo~ with arteriovenous difference according to the fick equation (co-fick). results: no significant difference in hemodynamic status was observed min after the patients were placed in trp. despite the fact that no significant change was observed in co and vo~ estimated by thermodilution, co-fick had a tendency to dedrease continuously in trp and then to return to its initial value when patients regained supine position. respiratory gas analysis showed a small but persistent continuous increase in vco without a similar trend in vo values. conclusions: we conclude that no significant hemodynamic effect was detected in our patients after min in trp. evaluation of vo from respiratory gases analysis after a change in body's position should be interpreted with caution, since the patient may not yet have reached a stady-state after rain. since vo did not change, vco~ increase was probably due to position related changes in-pulmonary gas exchange and not to a change in patient's metabolic status. objectives: to determine whether changes in svo and/or other hemodynamic parameters during weaning trials could be used to predict successful weaning. methods: we prospectively studied adult patients with a history or clinical evidence of cardiovascular dysfunction, who were unable to tolerate spontaneous breathing (sb) for hours. for all these patients right heart catheterisation was considered necessary in order to detect hemodynamic alterations during weaning. a fiberoptic pulmonary artery catheter (svo ximetrix, abbott) allowing continuous svo monitoring was sod. hemodynamic status was evaluated ~t baseline and after one hour of spontaneous breathing through a t-piece. patients were assigned to one of two groups depending on whether they tolerated sb for hours. data were analysed by analysis of variance and unpaired student's t-test we also used multiple linear regression analysis to determine which hemodynamic variables were correlated with the magnitude of svo~ change and multiple discriminant analysis to determine if asy of the above variables were associated with toleration of sb for hours and/or successful weaning (s-w). (j physiol ; ." - ) . we tested the hypothesis that the ventilatory stimulation by dead space (vd) loading and % co inhalation is accompanied by a proportionate cardiovascular change. methods: six healthy subjects, mean age, year, performed three incremental exercise tests in a randomized order: ) inspiring air without vd (air control, ac); ) inspiring air with vd of ml (avd); ) inspiring % co ; % oxygen, balance nitrogen. the ventilatory responses were examined at matched heart rate (hr) equivalent to % peak hr. results: ventilation (vi) was significantly greater (p< . ) during the avd and co tests than during the ac test at the same work rates. end-tidal co (petco ) and estimated arterial co (paco ) were significantly greater (p< . ) at w and w. oxygen saturation was significantly lower (p< . ) during the avd test than during the ac and % co exerdse. at matched hrequivalent to % peak hr, vi was significantly greater (p< . ) during the avd and % co tests than during the ac exerdse ( l, l, and /). conclusion: we conclude that the increase in xri and petco due to vd loading and % co inhalation is not associated with an acceleration in hr. sup.ported by mrc (canada). objeetlve: the production of large amounts of oxygen radicals from the onset of ~en may be responsible, st least in part, for peroxidative damage to myocardial tissue. the aim of this study was to evaluate the time dependence of plasma tbars in patients with am] receiving thrombolytie therapy (tt). patients and m~hods: filiy eight patients admitted in icu ( men and women; mean age . - . years) rec~ving systemic tt for possible am] were ~died. all patients received recorabinant haman tissue-type plasminogen activator (r-tpa). the mean time fi'om the onset of symptoms and the be~nning of tt was . - . hours. peripheral veao~s blood samples were obtained fi'om each patient before and serially after tt ( , , and hours). tbars levels woe determined by using a spectrophotometrie technique. rq~r fusion was identified by the timing of ereatine phosphate kkmse (cpk) peak (< hours). table i list the variation of plasma eoneenlrations of tbars (mean -sd) in groups (a,b, and c) as a function of time from the beginning of tr. co,arisen oftbe time cuncentzatiens reveal a difference p<o. between group ami (a and b) versus group c. the between-groups (a-c) comparison showed significant differences (p<~). ) at , and hours fi-om de begin~g of'it. comparison ofthe , and hours eonocnlratiens did not reveafl any difference becween n~ (group b) and angor (group c). condmien: we have observed a maintenance of high level of tbars in reperfused patients enly. these results suggest that the increase of tbars levels may be due to phospholipid derangament of reperfused myocytes. objective: to detemline if tbars levels may be an early index reflecting peroxidative damage in ami patients. patients and methods: by using a spectrophotometric teclmiqtm, based on a modificatien oftbe buege and aust method, tbars levels ware determined in healthy subjects (group i) , patients with several risk factors of ischaemic cardiopathy (group if) and icu patients with possible aim ( were confirmed ami (group ma) and were angor (group iiib)). peripheral blood was obtained at the time of the icu admission in the group i . electrecardiographic data and eehocardiographic wall motion were used to identify ami location (anterior, inferoposterinr and indeterminate). statistical analysis was made with a standard statistical package (rsigma, horus hardware). , h , s, , h statistically significative increase of ' ix~e/ea.ee x~* tbars levels (p< . ) only in pstients with con/tuned ami (group ilia) . no differences were found between the rest of the groups. the figure shows the relationship between the tbars values and the time from the onset of the aim's symptoms. conclusion: we have found that in am/patients the tbars levels can be used as an early index reflecting peroxidative damage occurring to ischemie tissues. perioperative risk in patients with ischemic heart disease. the protective role of diltiazem. lg. hatziantoniou, p. tassiopoulos, c. fakiolas, ! g. foussas~ m. lycourinas perioperatlve morbidity and mortality are mainly of cardiac origin, particularly among elderly patients (pts) ~ith ischemic heart disease. we performed a randomized trial, in order to investigate the possible protective activity of diltiazem (d). methods: pts (aged zo• with a history of coronary insufficiency were subjected to major urological operations. they were randomized to two groups: group i ( pts) -p:ithout d and group ii ( pts) -d ~as administered . mg/kg iv bolus hours prior to anesthesia and . mg/kg/h upon the end of operation and for at least hours post-operatively. iv was substituted by oval administration of x mg starting the next day and for the rest of hospital stay. all pts underwent daily clinical, electrocardiographic and laboratory (ck-mb) control. results: are shown in the following interactions between the heart-lung unit and a cardiac assist device are the crucial issues for successful outcome of patients under mechanical circulatory support. several factors have been indicated and we can diffrentiate between anatomical and hemodynamic interactions. especially right heart failure and pulmonary hypertension have been proven to limit left ventricutar assist device (lvad) performance. in order to study the effects of right heart failure (rhf) and pulmonary hypertension (pht) on mechanical circulatory support, we designed an experimental study in dogs and combined in six groups left heart failure (lhf) and rhf and pht, respectively. in the control group we induced lhf with subsequent occlusions of lad and cx followed by reperfusion: in the next group we supported with an lvad during minutes starting minutes after cx occlusion (group if). in the next group we added right ventricular ischemia by occluding the rca simultaneously to the cx (group iii). these both groups we repeated only with pre-existing acute pht induced by the injection of o fm glass beads (groups vi and v). a last group was similar to group v (lhf and rhf and pht), but instead of a lvad, we used bvad support. in i and v no animal survived the second perfusion period ( hours). in ii and iii (no pht), all dogs survived in stable conditions. in iv (lvf, pht), % survived, the remainder died of incomplete recovery. in vi with bvad, only % survived. in iii and v, during occlusion of the rca, the right ventricle stopped contracting and right atrial pressure and mean pulmonary pressure equalized. this lead to a significant drop in inflow on the left heart side, which still provided sufficient lvad performance in case of absent pht (iii) and lead to death due to "low lvad output" syndrome in v. this "low lvad output" snydrome could be partly overcome by bvad support. we conclude that heart-lung interactions play a major role in lvad performance. by optimizing the perioperative management, they all can be overcome, except the occurrence of alveolar leakage syndrome. obiectives : we propose a new approach of transmural pulmtmary artery occlusion pressure (paoptm), in presence ef peep, from the folluwing hypothesis : if respiratory swings of paop are compared to those of alveolar pressure (apalv = plateau pressure -total peep), an index of transmission of airway pressures to pulmonary vessels is obtained (i t = apaop/apalv). the value of the product of it by peep can be substracted from end-expiratery paop (paopee) to obtain a calculated paoptm (paoptrnc). thus paoftmc = paopee -(apaop/apalv x peep). methods : we tested this hypothesis in patients by comparing paopee, paoptmc, and paopnadir obtained within the first seconds after disconnection from the ventilator, value of reference of paoptm in absence of intrinsic peep (peepi). at zeep, peepi was absent in patients (group a) but present in others (group b). patients were studied under the peep level chosen by the attending physician-(gr a : +_ ; gr b : _+ cmh ). results : l. gr a : paopee ( _+ mmhg) differed (p < - ) from paopnadir ( • mmhg) and paoptmc ( _+ mrahg). gr b : paopee, paopnadir, paoptmc differed between themselves ( " - , + , + mmhg respectively). . good correlatkm (r - (i. ) and agreement between paopnadir and paoptm were found in gr a, while there was no agreement in gr b (bland and altman analysis). . lung compliance (v t/bpah,) correlated well with i t in both groups (r - . ), suggesting that our hypt)thesis was strtmg even in patients with peepi. conclusions : paoptm under peep ventilation can be obtained, even in patients with peepi, from parameters easily measured at the bedside. introduction: cardiopulmonary bypass (cpb) may cause ischemia in several organ systems like the heart, brain and kidneys. reactive oxygen species (ros) are formed by subsequent reperfusion and stimulation of neutrophils by cpb. ros are harmful to biological systems e.g. cellular membranes, enzymes~ dna. many natural antioxidant systems protect against the effect of ros. in patients undergoing cabg we evaluated the production of ros by total plasma antioxidant status (tas) and lipid peroxidation measured by lipofuscin flip). methods: tas (randox, uk) and concentrations ofllp (tsuchida et al.) were measured in consecutive patients undergoing cabg. all the patients had a normal serum creatinine clearance (> ml/min). serum samples were obtained a) before operation, b) after removal of the aortic crossclamp, c) at admission to the icu, d) hours after operation, e) hours after operation. results: tas was significantly decreased after removal of the aortic crosselamp ( b, c and d lower than a), followed by a subsequent significant increase of lip ( c and d higher than b). the levels of tas and lip returned to baseline hours after operation. methods: patients with preoperative lvef< % undergoing coronary artery bypass grafting were studied. after surgery, a f femoral artery catheter was inserted and connoted to a fiberoptic monitoring system (cold z- t; pulsion medizintechnik, germany); this allows, with a double-indicator dilution technique, the calculation of cardiac index (ci,l/min/m ), intrathoracic bood volume (itbv,ml/m ), pulmonary blood volume (pbv,ml/m ) and extravascular lung water (evlw,ml/kg). with a f pulmonary artery catheter, wedge (w,nunhg) and central venous pressure (cvp,mmhg) were measured, while extraction ratio (o exr,%) and oxygen delivery (do ,ml/min/m ) was calculed. peak inspiratory pressure (pawp,cmh ) and mean airway pressure (mawp,cmh ) were measured with a varflex flow transducer (bicore,sensormedics,us). the patients were studied after minutes (to) of volume controlled standard ratio ventilation (vc), and after minutes (ti) of stabilisation period of pcirv ( % inspiratory time, % pause). vt,ve and total peep were held constant in every mode of ventilation. +_ . " *'p < , versus to conclusions: these data show that pcirv : is a safe ventilatory support also in cardiac patients with impaired ventricular function, and monitoring of itbv is more reliable to measure and optimise circulatory volume status, than w and cvp. c.ledeki-,g.rldisis,s.karotzai,c.micheilidis,m.agioutantb, g.beltapaulos. objeolivee:to evaluate the influence of lvswl on the well known correlation of sr and svo . paw eight patients ( melee end females) were included in this study regerdlen of the icu ~h"niseion couse. all paints were ,'~theta~ with e fiboroptir pulmonary artery catheter connected with an oxymetfir (r)~ so /co abbot computer.for any pulmonary artery catheter insertion, two pain= of sr and svo were obtained, one dudng inserlion and one during taking the catheter out. for any pair obtained, we eleo collected the deta concemig with the pedient's hemodynamir and oxygenation end we calculated the lvswi. were significantly (p<o. ) higher in group i. conclusion: breathing room air, the less hypoxemic patients had a rather satidactory do and tissue oxygenation (pro ) because they had properly adapted their ci. the absence of this mechanism (right heart impairement ?) in the hypoxemic patients, in spite of higher blood ne and e, was responsible for the poor do and pro . objectives: acute massive pulmonary embolism (pe) increases pulmonary artery pressure (pap) and dght ventdcular aftedoad, which may lead to dght ventdcular failure. inhaled nitdc oxide (no) selectively dilates pulmonary vessels. thus, inhaled no may be of potential therapeutic value in the management of the acute phase of pe. methods: following institutional approval, ten piglets (body weight + kg) were anaesthetised (midazolam/piritramide) and ventilated using a modified servo ventilator (siemens elema, sweden; fio . ). the following variables were obtained: systolic pap (spap), mean pap (mpap), diastolic pap (dpap), mean artedal pressure (map), central venous pressure (cvp), pulmonary capillary wedge pressure (pcwp), cardiac output (co), and artedal (pao ) and mixed venous (pvo ) oxygen saturation. pulmonary vascular resistance (pvr) was calculated. to induce pe, pm microspheres (sephadex g coarse, pharmacia biotech, freiburg, germany) were injected in an amount sufficient to increase mpap to mmhg initially. rain after embolisation when haemodynamics were in a steady state (control ), inhaled no was administered. further measurements were taken min after ppm no (no ), min after ppm no (no ), and min after discontinuation of no administration (control ). the administration of inhaled no resulted in a significant decrease in spap, mpap, and pvr. the cessation of no inhalation led to a complete return to pretreatment control values (table) . co, map, cvp, pcwp, pao?, and pv~ remained unchan no administration. objectivss:evsluate the yield of recombinant tissue plasminogen activater(rt-pa, actiiyse ~ oehringer ingelheim) as a thrombolytic agent ie pulmonary embolism ie .kr~auma patients. methods: in five patients with diagnosed pulmonary embolism(blood gases, chest x-ray, echocardiography, perlesion lung scans) were given rag of actij.yse as ~ hrs infusion, followed by heparin~single j. ihjaction snd iefusion ie doses - j./kg/day).the effectiveness of rt-pg thrembo].ytic sctier~ was svaluated im . . hrs(blood gases) amd on the third dayafter t~eat-,ment(~chocardiography and lung scan). results: three hrs after actilyse was given we observed significant clinical imprevemeet,confirmed by elevation of pao and sao in dlood.echocardiegr~m on the third day showed regression of pulmonary hypertension and lung scans showed % improvement in total lung perfusien. except slight bleeding from the site of injection nc~ more thromboiytic complicatioos were observed. conclusiens: actilyse used in five hrauma patients with pulmonary embol.ism was a very effsctive and safe thrombolytic agerlt, inducing rapid and evident clinical improvement. intermittent positive pressure ventilation ( ppv) by increasing pleural pressure, decreases the pressure gradients for systemic venous return and left ventricular (lv) ejection. we have previously shown that when inspiration is synchronized with systole using synchfjv in patients with severe cardiomyopathy, that cardiac output (co) was increased relative to both ippv and non-synchronized hfjv ( ). however, it is not known if similar effects could be realized in ventilatordependent patients with lesser degrees of lv dysfunction and fluid overload. we thus compared synci-ifjv to ippv in stable patients following coronary artery bypas grafting. methods: normothermic who were stable (< % variance/h.) were studied following admission to the sicu. heart rate (hr), mean arterial (pa), pulmonary artery occlusion pressure(ppao), co by continuous thermodilutiun (vigilance, baxter, usa), mixed venous saturation (svoz) and arterial blood gases (abg) were measured after rain. of each step. ippv was simv adjusted for a rate, tidal volume and fit to insure both normal abg and a peak airway pressure < cm h,o. syncfifjv was delivered by a hfjv ventilator (acutronic) during systole with ventilator parameters adjusted to optimize abg. protocol: patients received three ippv runs (ippvi. , ) with synchfjv runs interposed (hfjvz ). statistics: anova for repeat measures and paired t-test were used to compareruns and demonstrate variability. results:no significant difference in any of the measured hemodynamic variables were seen among the ippv and synchfjv runs (table) . post hoc separation of patients by preoperative ejection fraction (ef; ef > % ; n= and < %; n= ) did not alter these results. back~ound: in man, vascular endothelium-bound ace is expressed in concentrations greater than x that in serum and is believed to be the site of synthesis of circulating angioteusin il it is unclear whether ace inlubitors interact similarly with ace in different vascular beds. coronary vessels possess all the components of the renin-angiotensin system, including ace which may be involved in normalcardiac homeostasis, as well as in the pathogenesis of various cardiomyopathies. obiecfive: to develop a method for assaying the interaction of ace inkibitors with coronary endothelium-bunnd ace in man, methods: ace a~aty was meas~ed in five patients undergoing cabg surgery, from the transeuronary hydrolysis of the synthetic ace substrate h-bpap. trace mnou~ of ~fi-bpap ( gci) were injec~d as a bolus in the root of the aorta and simultaneously blood was withdrawn from a coronary sinus catheter into a syringe containing protease inhibitors which prevented the convession of umeaet~ ai-i-bpap by blood ace. the sample was later centrifuged to separate cells from plasma and the radioactivities due to formed product (~rl-bphe) and total sh were astimated in a [b-counter. two additional such determinations of ace activity were perform~ the second in the presence of . pg/kg e (coinjected with ~-i-bpap) and the third ten minutes after e. results: all subjects were hemodynamically stable throughout the course of the there were no noticeable hemodynamic effects of e. control transcorunary metabolism of~-bpap averaged g -a: %, in agreement with previously reported data. in the presence of e, % metabolism of ~-bpap was reduced to • reflecting a • inhibition of normal ace activity. ten minutes after e, ~ri-bfap metabolism had partially recovered to :l: %, representing a -a: % inhibition of control ace activity. from this data, the dissociation constant of e for coronary ace in vivo was estimated as . x " sec "l. conclusions: we have demonstrated the feasibility of repeated, reproducible measures of coronary endothelium-bound ace activity and of its inhibition by e. this procedure is safe and can be used to study the role of ace in normal cardiac function and in card pathologies. objectives. primary pulmonary hypertension (pph) is a progressive fatal disease of unlmown origin, with median life expectancy of less than three years after diagnosis. the responsiveness of pulmonary hypertension to a variety of vasodilator agents led to the speculation that, concomitant with vascular renmdelling processes, persistent vasoconstriction is an important feature of the disease. long term use of ca-channel blockers and intravenous pgiz may improve mortality in certain populations of pph patients, but both of these treatments lack selectivity for tire lung vasculature. the aim of this study was to test the efficacy of aerosolised prostacyclin and its stable analogue, [loprost for selective pulmonary vasodilatation in pph. methods: in three patients with pph, we compared aerosolisation of prostaglandin iz (pgi ) and iloprost to a battery of vasodilatory agents (diltiazem, nifedipin, inhaled nitric oxide, intravenous pgiz). results: nebulisation of pgi and iloprost tumed out to be most favourable for achieving effective and selective pulmonary vasodilatation. pulmonary vascular resistance decreased from + to -+ dyn*s*cm (p< . ) and pulmonary artery pressure from . + . to + . mmhg (p < . ), cardiac output increased from . + . to . _+ . i/rain (p < . ), mixed venous oxygen saturation from . _+ . to . + . % (p < . ) and arterial oxygen saturation from . + . to . _+ . % (mean _+ sem of trials in patients). -month iloprost nebulisation in one patient ( gg/day in six aerosol doses) demonstrated sustained efficacy of the vasodilator r~men. conclusion: aerosolation of pgi or its stable analogue may offer as new strategy for selective pulmonary vasodilatation in pph. endothelial adhesion molecules may play an important role in the pathogenesis of myocardial cell damage, and may contribute to the progression of heart failure. we measured the plasma soluble intercellular adhesion molecule- (sicam- ), vascular cell adhesion molecule- (svcam- ), and e-selecfin (selam- ) levels in patients with acute myocardial infarction admitted within hours after onset. peripheral venous plasma-samples were collected at the time of admission, , , , , and hours after onset. plasma soluble adhesion molecule concentrations were determined by elisa. patients were divided into groups as follows: group ; killip's class (k) and without thrombolytie therapy, group ; k and with thrombolytic therapy and group ; k and . both plasma sicam- and svcam- concentrations in group and were elevated rapidly and significantly and maintained at a high level during the first days. plasma selam- level did not change in any of the groups. these results suggest that the adhesion molecules icam- and vcam- may play a role in the pathogenesis of myocardial reperfusion injury and may indicate its severity in myocardial infarction. objectives: nitric oxide (no) is known to exert cytotoxic and negative inotropic effects on cardiomyocytes. no synthase activity has been reported to be increased in infarcted area in animal model of myocardial infarction. these findings suggest that no may be an important regulator for myocardial damage and cardiac function after myocardial infarction. we measured plasma no no -(nox) levels and estimated serial changes in acute phase of myocardial infarction. methods: subjects were patients admitted within hours after onset. venous blood samples were collected at -hour intervals on the first day, -bour intervals on the nd day and -hour intervals on the rd day and th days after onset. plasma nox concentrations were determined by griess method. results: the time course of the plasma nox levels (mea~+sem) displayed a tendency to gradually increase and to make a biphasic pattern with two peaks about hours and - days after onset (basal level; . _+ . , first peak; . !-_ . , second peak; . + . ram/l). plasma nox concentration was not influenced by the thrombolytic therapy, and nox values at the time of hours after onset were significantly correlated with maximal plasma creatine kinase level (r= . , p< . ). the levels of plasma nox in the early stage of myocardial infarction (from admission to the th day after onset) did not correlate significantly with the hemodynamic parameters (left ventricular ejection fraction, pulmonary capillary wedge pressure). conclusion: the early and late increase in no production after myocardial infarction may be implicated in the deterioration of myocardial contractility and induction of myocardial damage in the early phase of myocardial infarction. range - ) fullfilling the high risk criteria of shoemaker (colectomy , gastrectomy , pancreaticoduodenectomy , others ). patients were admitted to the icu preoperatively. arterial and pulmonary artery catheters were inserted and hemodynamics and oxygen transport were measured at admission and after stabilization to predetermined physiological end points. patients were considered stable when ci > . l/min/m , pcwp > mmhg, hb > g/l, sat >. . objectives: evaluate the acute effects of , mg ipratropium bromide and , mg fenoterol (ibf) inhaled dose on pulmonary function in nonsmocers (nb:m) and smocers (s) with sever (new york heart association class ii-iii), stabile congestive heart failure(chf) and healthy subjects. methods: pulmonary function tests were performed < h postprandial. the tests consisted el arterial blood gas aspiration followed by routine spirometry and pletismography, and single-breath gas analysis. after performance of these maneuvers, the patients was administred puffs-ipratropium bromide ( , rag) and fenoterol ( , rag). for , h, spirometry was repeated. results: in resting, pulmonary abnormalities observer in the s group were more severe then abnormalities observere in the nsm group. after treatment with ibf the improvement in pulmonary function was even more marked in patients who had smoked. the mean changes by forced expiratory volume in second(eevt) was , % (p< , t) improvement and , % (p< ,ob), forced expiratory flow betwen % and % of the forced vital capacity (fef . ) was , % (p< , ) and , % (p< , ) and maxamal voluntary ventilation (mw) was , % (p< , ) and , % (p<o, ) improvement. the mean changes in normal subjects were mild (fev increased by , %,fef - by , % and mvv by , %). we observed no adverse heamodinamie conseevence and no arrthytmogenicity. conclusion." in patients with chf the airway response to ibf is highly significant. further study is needed to determine whether therapy with ibf will load to improvement quality of life in patients with chf with dearly documented venti/atory defects. compared with unilateral ima grafts, usage of bilateral ima grafts in cabg patients causes greater thoracic trauma and further reduces blood supply to the sternum and intercostal muscles. these effects may be associated with increased postoperative respiratory complications obiectives: to study the effects of bilateral ima grafts on postoperative respiratory morbidity in cabg patients. methods: two groups of patients undergoing cabg were prospectively studied: group (n= ) received both imas as grafts and group (n= ) received only the left ima. the two groups were matched for age, smoking habits, total number of grafts and preoperative ejection fraction. pao /fio ratio was measured in all patients in the icu, at , , minutes on mechanical ventilation (mv), at , , minutes after extubation (ex) and on postoperative day (pod) . in addition, radiografic scores of atelectasis and pleural effusion were assessed postoperatively. results: group had significantly longer bypass ( _+ vs + . p< , ) and aortic cross clamp time ( +- vs + , p= , ). pao /fi ratio was significantly higher in group only at minutes after extubation (table) . there was no difference in the incidence or severity of atelectasis or pleural effusion between the two groups. the duration of mv was longer in group ( +_ vs _+ , p= , ), but the length of icu stay and hospitalization were similar. there was one case of pneumothorax in group and one case of pulmonary infection in each group. after extubation m[n min min min* rain min pod ' _+ _+ + -+ - -+ _+ _+ _+ _+ -+ _+ _+ -+ mean_+sd, *p=o, o conclusions: compared with unilateral ima grafts, the usage of bilateral ima grafts in cabg patients is not associated with increased postoperative respiratory morbidity. the diagnosis of rv ischaemia is difficult in the critical care setting. the purpose of this study was to determine the ability of rv endomyocardial and interstitial ph electrodes to detect rv ischaemia in an animal model of rv infarction produced by fight coronary artery ligation. we hypothesized that changes in transmural and interstitial ph would accompany the induced tissue hypoperfusion. rv interstitial (phint) and transmural endomyocardial ph (phendo) were measured in adult anaesthetized pigs before and serially after coronary ligation. phendo and phint fell progressively and significantly following coronary occlusion. this was accompanied by ischaemic ekg changes. the absolute and relative rates of change were greater for phendo compared to phint, particularly after minutes of ischaemia, ph was unchanged in control experiments when the electrode was placed within the fight atrial or ventricular chambers, as well as when coronary ligation was not performed. these data suggest that rv myocardial ph measurements reflect coronary ligation induced rv ischaemia, ph recorded from an electrode placed against the rv endomyocardial wall via a central vein was as useful as an interstitial measurement that required a thoracotomy. this newly described technique may be helpful in clinical settings where differentiation between ischaemic and nonisehaemic causes of rv dysfunction is important. centre. depts of cardiac surgery and anesthesiology, university of bari, italy. lung injury secondary to cardiopulmonary bypass (cpb) is well recognized. nevertheless, mechanical respiratory changes after cpb have been poorly investigated. aim of the study was to evaluate the effects of cpb on respiratory mechanics. elastance of the lung (est l), chest wall (est cw), and total respiratory system (est rs) were measured in patients without previous pulmonary disease undergoing elective cardiac surgery. there were males and females; no pleurotomy was done. cpb was carried out with membrane oxygenator. mean cpb and cross clamping times were _. and • min. flow (pneumothacograph), airway opening and esophageal pressures (pressure transducers and esophageal balloon) were measured on patients sedated and paralysed. measurements were obtained before sternotomy, at the end of cpb after chest closure, four and seven hours later. est rs, est l and est cw, were measured by occluding the airways and the end of a tidal breath. before end cpb- h after h after stemotomy closed chest cpb cpb estrs (cmh /l) . + . . - . " . _+ . * . - . * est cw " . _+ . . • . + . . -+ . est l " . -- . . - . " . -_ . " . _+ . " x + sd. * p < . : anova vs "before sternotomy". our data show that cpb induces increase in est l, whereas est cw remains unchanged despite sternotomy. impairment in est l after cpb evolves within the first hours and stabilizes hours later. during the clinical course of human imunodeficiency virus infection (hiv), patients (lots) can develop congestive and dilated cardiomyopathy syndrome (dcm). the aim of our study was to analyze the prevalence of dcm among an hiv population, its clinical and echocardiographic changes under a long term follow-up and therapy with an ace-inhibitor agent (captopril). we prospectively studied pts, % ( / ) developed dcm during the follow-up study. among this group % ( / pts) were in class i and ii and % ( / pts) in class iii and iv of the nyha classification. we divided this population in a acei+ ( pts) and acei-( pts), according to the administration of captopril. we analyzed the following parameters: age, gender, race, ivda, type of hiv, cdc classification, number of t and t type cell population and its t /t ratio, therapeutic with acei, type and number of opportunist infections, mycobacteriosis and neoplasm's. we analyzed several echocardiographic parameters, which included the initial (i), final (f) and variation (a) of the lv internal diastolic (lvdd/mm) and systolic (lvsdimm) diameters, lv % of fractional shortening (lv%fs/%), ivs and posterior wall thickness and lv mass (lvm/g). the two groups differed significantly in the following parameters: left ventricular functional indices of patients (pts) with iscjhemic dilated cardiomyopathy (idcm) have a critical value in terms of clinical prognosis of this disease. three-dimensional echocardiography ( -de) is a recently developed method that gives a better evaluation of lv morphology and function. the purpose of our prospective study was to assess the clinical applicability of this new -de method in a population with ischemic dcm diagnosis and calculate its lv indices of global and regional function. we studied a group of idcm pts, mean age _+ yrs, % male gender, using a combined -de tee approach. all pts were in class ill/iv of the nyha classification. first, ekg gated images were acquired through a mechanical pullback of the tee probe, and each set of data was transferred to a conventional ibm-pc system using a dedicated -de software. computer processing and analysis of the tee images led to a -de reconstruction matrix and off-line calculation of several lv global and regional indices. in all idcm lots the lv cavity was clearly reconstructed and end-systole and diastole in several orthogonat projections, out in multiple planes and its function quantitated using -de derived indices. mean values of -de lvesv= -+ ml, lvedv= _+ ml, lvstv= _+ ml and lvef= -+ % were obtained. for all these -de parameters, good correlations were observed with -de lv measurements obtained through biplane tee analysis of the lv cavity (r>. ; p<. ) as well as regional analysis of sequential -de cut planes. conclusion: in our group of patients with the diagnosis of ischemic dilated cardiomyopathy, this new -de method could be applied. our results show that this method allows a better assessment of the lv morphology and spatial geometry, with the calculation of global and regional indices with critical clinical and prognostic value in this particular cardiovascular pathology. simultaneous left atrial (la) and left ventricle (lv) inflow analysis assessed by pulsed doppler tee illustrate the loading conditions and reflect the hemodynamics of the left heart. we performed a prospective tee pulsed doppler study with recordings of the transmitral lv filling and pulmonary venous (pv) flow drainage in a group of patients with dilated cardiomyopathy (dcm). a group of dcm patients, mean age _+ yrs, % male were studied. this population was divided according to tee severe lv dysfunction (group slvd+ % pts; group slvd- % pts) in each pt we measured the peak velocities (vel/m/sec) and time velocity integrals (vti/m) of the transmitral early (e) and late (a) filing waves, the vel and vti of the pv systolic (s), diastolic (d) and atrial contraction (c) reversal flows. -de tee evaluation of the lved, lves, lvst volumes and lvef were obtained. we calculated other parameters, such as e/a, s/d and a/c ratios and the sum of c+a vel, that refelect la systolic function and lv compliance. + -_ . simultaneous and quantitative analytical approach of the pulmonary venous and transmitral flows and ventricular volumes improve the non invasive assessment and understanding of left ventricular diastolic function and cardiac performance in dilated cardiomyopathy patients. objectives : to assess the hemodynamic effects of fluid loading (fl) in acute circulatory failure (acf) due to acute massive pulmonary embolism. methods : hemodynamic measurements (fast-response thermistor pulmonary artery catheter) were performed at baseline (baseline) and after a rapid fluid loading with (fl ) and (fl ) ml of dextl'an (rhemacrodex| in patients free of previous cardiopulmonary disease ( • yrs) with acf (ci < . l/rain/m ) due to angiographicalty proven mpe (miller score > ) . results : are expressed as mean _+ sem and compared by anova. a significant negative correlation (r = . ) was observed between baseline rvedv[ and the effects of fl on ci. such correlation was not observed between baseline rap and the fl induced increased in ci. conclusion : fusibmificantly increases ci in acf due to mpe. however, the simultaneous decrease of arterial content due to hemodilution, limits the benefits expected from improved ci on peripheral oxygenation. obiective: to examine the hemodynamic effects of external positive endexpiratory pressure (peep) on right ventricular (rv) function in acute respiratory failure (arf) patients. methods: incremental levels of peep ( - - - cmh ) were applied and rv hemodynamics were studied by a swan-ganz catheter with a fast response thermistor for right ventrieular ejection fraction (rvef) measurement in mechanically ventilated arf patients (lis = . ~- . sd). according to the response to peep , two groups of patients were defined: group a ( pts.) with unchanged or increased rv end diastolic volume index (rvedvi) and group b (h pts) with decreased rvedvi. results: in the whole sample cardiac index (ci) and stroke index (sj) decreased at all levels of peep, while rvedvi , rv end systolic volume index (rvesvi) and rvef remained anchange d. at zeep the hemodynamic parameters of the two groups did not differ. in group a, ci decreased at peep , rvef decreased at peep (~ . %)~ rvesvi increased only at peep (+ . %) and rvedv[ reded unchanged. in group b, ci and rvedvi started to decrease at peep , 'rvesvi decreased only at peep (- . %), anf rvef was unchanged. individual behaviors of the hemodynamic parameters at the levels& peep were studied. rvedvi and ci were significantly correlated in out of:l patients in group b, and in no patient of group a. on the contrary, mpap and rvesvi were significantly correlated in out of patients in group a, and in no patient of group b. the slope of the relationship between rvedvi and rv stroke work index (rvswi) expresses rv myocardial performance. this relationship was significant (no change in rv contractitity)in patients of group b and in patients of group a. in some patients of group a, increments of peep shifted the rvswi/rvedvi ratio rightward inthe plot (rv function decrease). conclusions: in arf patients peep causes more often a preload decrease with unclmnged rv conctraetility. on the contrary, the finding of increased rv volumes during the application of peep is related to a decrease in rv myocardial performance. thus, these data suggest that application of peep might be considered as a stress test to assess rv function. right introduction: after heart transplant (ht), the right ventricle can be subject to an acute pressure overload, especially in cases where there is a preexisting severe pulmonary hypertension. this provokes right ventricular failure and, occasionally, circulatory collapse in intensive care unit. desire the advances that have been made in systems for preserving the donor heart and in post-surgical management, we have failed in our attempts to totally avoid this problem. the right ventricular function, although it usually remains within tolerable limits in these patients during the post surgery period, represents a factor which limits the results achievable in clinical transplant programmes. objectives: to determine the maximum tolerance of the right ventricle (mxtrv) when faced with acute pressure overload. to study the function of both ventricles of the healthy heart (donor) when faced with different degrees of pulmonary hypertension. to detect possible interactions between the ventricles in the absence of the pericardium to approximate the experimental model to the clinical model of ht. materials and methods: the pulmonary artery is progressively constrained in an experimental model until biventricniar failure is detected. this experiment is performed in two diffferent situations: with and without pericardial integrity. results: when pericardial integrity is maintained the mxtrv faced with a pressure overload is . + . nun hg. when this pressure is exceeded there is a circulatory collapse with a sharp fall in the cardiac output and in the aortic pressure. however, when pericardectomy is performed (model similar to ht), only • . nun hg is tolerated (p < . ). conclusions: with the pericardium open, as in heart transplant, the maximum pressure that the right ventricle can support is significantly less than with the pericardium closed. the pericardium has a positive effect in protecting the systolic ventricular interaction. it is, therefore, advisable to close the pericardium after heart transplant. jb prrez-bernal, a ordrfiez, a. heroandez, jm borrego, map camacho, c cruz, mac s~nchez, j monterrubio, c garcia, e. gonz~lez. hospital uulversitario " virgen del rocio ". sevilla. espaiqa. introduction: nowadays cardiomyoplasty isused incases of cardiac insufficiency as an alternative to cardiac transplant. after surgery the patients show a noteable improvement with the aid of this "biological circulatory assistance". some researchers suspect that the improvement could also be due to the formation of new blood vessels from the muscle that wraps the heart, nourishing the ischemic myocardium. objectives: our cardiovascular research group has proposed as an objective, the detection of any possible myocardial neovascularization through the muscle used for cardiomyoplasty. in the case that there are new blood vessels to the diseased myocardium through the wide dorsal muscle in which it is wrapped and which aids it mechanically, it would be possible to confirm the worldng hypothesis that cardiomyoplasty not only improves the cardiocirculatory funcfinn mechanically but also by facilitating a better blood flow to the ischemic myocardium. materials and methods: the cardiomyoplasty technique is described using an experimental model of myocardial ischemia. the vascular cast is achieved by injecting methacrylate simulataneously into both the coronary tree and the wide dorsal muscle, in five experiments the connections between the coronary vascular system and the vascular structure of the wide dorsal muscle are demonstrated, conclusions: we have demonstrated that cardiomyoplasty, as well as improving ventricular function, favours the revascularization of the myocardium. cardiomyoplasty could be indicated for cases of ischemic cardiopathy in patients in whom it is not possible to perform direct revacularization using conventional methods. a the therapeutic cardiological manouevres necessary in cases of ischeima reperfusion have increased considerably: fibrinolysis, transluminal angioplasty, coronary revascnlarization surgery and cardiac transplant. the appearance of a specific pathology ht acute reperfusion has been related to free oxygen radicals (for) generated by oxidative damage. objectives: to evaluate the appearance of for during a conti-olled process of ischemia-reperfusion in an experimental biological model and compare it with that in clinical cases. materials and methods: transitory cardiac ischemia was performed in five rabbits by reversible surgical ligation of the descending anterior coronary artery. after minutes coronary reperfusion was performed. blood samples were taken in the basal situation, at the end of ischemia and at , and minutes after the start of reperfusion. malondialdehyde (mda) was measured to evaluate the degree of lipid peroxidation (oxidative damage to the membrane). in ten patients undergoing conventional cardiac surgery the production of for was measured after aortic clamping. results: we observed that after minutes of reperfusion there was a highly significant increase (p < . ) in the mda values (mean = . /zmols/l). these returned to basal levels after and minutes of reperfusion. conclusions: an "explosion" of oxygen free radicals was detected very quicldy, just a few minutes after post-ischemia reperfusion. thus, if antioxidant agents are to be used to reduce the toxic effects of the for, these will ordy have a therapeutic effect if they are administered in the early phases of reperfusion. introduction: aortic connterpulsation is a ventricular assistance widely used in intensive care units in patients with cardiogenic shock as a provisional ventricular assistance. paraaortic or external aortic counterpnlsation is been investigated as a definitive veutricular assistance in those cases of terminal congestive heart failure and when heart transplantation is counterindicated. aims: to assess the haemodynamic effects of an aortomyoplasty in a biological model of congestive heart failure. material and method: as specimens, we used "large white" pigs. mean weight was kg. after the administration of conventional anaesthesia, dissection of the ladssimns dorsi muscle was performed on the samples at the laboratory of experimental surgery of our hospital. then we performed a thoracotomy at the level of the fourth intercostal space to reach the thoracic aorta. the aorta is dissecated centimetres from the exit of the subclavia and it is wrapped by the dissecated muscle. a cardiomyostimulator is provided in order to allow the synchronization between the diastole and the muscle contraction. the model of heart failure was provoked using verapamil plus propanolol i.v.. results: a significant increase of the aortic diastolic pressures and a significant decrease of the left ventricle telediastolic pressures were observed. this improvement in the parameters (dpti/tti) implies an increase of the coronary perfusion in a model of heart failure. conclusions: using the external aortic counterpulsation, the aortomyoplasty improves the coronary perfnsion and the heart efficiency in patients with heart failure in whom no conventional therapeutic action is possible. the permanent character of the paraaortic counterpulsation is it main advantage. the appearance of specific pathologies as a resuk of myocardial reperfasion has been related to the oxidative damage secondary to the release of oxygen derived free radicals (ofr). during the myocardial ischemia induced during heart surgery with extraeorporeal circulation, severalsubproducts of the oxygen are produced that shall cause toxic effects after the reperfusion which could be counteracted by the physiological antioxidant systems and/or provided by the medication. aims: to asses the ofr during heart surgery. to check whether an antioxidant treatment administered in the preoperative period make decrease the levels of ofr before and after the myocardial reperfusion and to verify whether its administration have any beneficial effect on the intra and extraoperative management. material and method: the study comprehends patients studied as two groups of individuals each (a and b). all patients underwent conventional heart surgery of valvniar substitmion or myocardial revaseularization. group a patients were administered rag/ hours of vitamin e (tocopherol acetate) hours prior to the intervention as antioxidant treatment. group b patient were not administered vitamin e. we assessed the quantity of malondialdehido (mda) to assess the degree of lipidic peroxidation or oxidative damage of the membrane during the myocardial ischemia and nm after the reperfusion. conclusion: patients who underwent heart surgery and were treated with tecopherol acetate in the preoperative period presented levels of rlo significantly lower than those who were not administered the drug, both during the intraoperative period and after myocardial reperfusion. we detected in these patients a need for antiarrhythmicals and pharmacoiogical support with catecholaminas, although not significant, both in the introaperative period and the immediate postoperative period. recommendations for the treatment of pulmonary embolism (pe) in the presence of right atrial thrombus (at) are conflicting. because of a significantly higher mortality rate due to fulminam or recurrent pe, there is a necessity to treat patients (pts) with mobile type a thrombi compared to pts with adherent type b thrombi. therapeutic strategies include anticoagulation, thrombolysis (t) or surgical thrombembolectomy. combination thrombolysis (cot), predominantly used for the treatment of acute myocardial infarction proved to prevent reocclusion of the infarct related artery at a comparable rate of hemorrhagia. benefit has been related to the alteration of hemostatic proteins by non-fibrinspecific thrombolytic s. administration of cot in pe has been performed sporadically. in the present case, a -year old male with no history of prior cardiovascular disease developed acute dyspnea which was related to pe in the presence of deep vein thrombosis of the left femoral vein. therapeutic anticoagulation was installed for a couple of days until there were several bouts of deterioration. biplane transesophageal echocardiography (tee) was performed and revealed a large, wormlike, hypermobile thrombus within the right atrium. computer tomography (ct) of the chest detected a saddle embolus in the bifurcation of the pulmonary tmnk almost occluding the entire left pulmonary artery (pa) and parts of the right pat consisted of mg frontloaded rt-pa and the subsequent continuous administration of urokinase in a dosis of . u/hr for hrs followed by therapeutic anticoagulation. symptoms, blood gases and ecg improved steadily during infusion, no adverse effects, i.e. minor or major hemorragia were registered. follow-up ct promptly after termination of t showed almost complete resolution of the saddle embelus, whereas tee showed complete dissolution of the at. ' finally, the patient was switched to oral anticoagulants and had an uneventful clinical course until he was discharged. conclusion: in the present case, cot was effective for the treatment of a complicated pe without any adverse effect. introduction: nowadays we can assist hearts with problems of insufficiency by techniques other than transplant. many researchers believe that the best way of assisting insufficient heart muscle is with another muscle from the patient. this technique of ventficular assistance is known as cardiomyoplasty. we describe the surgical technique of cardiomyoplasty using a biological model. the transformed skeletal muscle is transferred to the thoracic cavity where it wraps the heart and assists it. the choice and preparation of this muscle is currently under investigation. our group has focussed on the development of protocols for electrical stimulation to transform a skeletal muscle into a muscle which resists fatigue and which is functionally similar to the myocardium. we detect the optimum time at which this muscle has been transformed, by studying the transmembrane action potentials using intracellular electrodes. when the action potential of the trained muscle behaves like cardiac muscle we consider it ready for cardiomyoplasty. conclusions: cardiomyoplasty is an alternative surgical technique to cardiac transplant, which has a great future in the treatment of patients with advanced cardiac insufficiency. we describe methodology which, by intracellular techniques, allows selection of the optimum moment of transformation of a skeletal muscle trained to perform,like cardiac muscle, without suffering fatigue. purulent pericarditis is a rare disease. its treatment associate systemic antibiotics and drainage of the pericardium. we report a ease of purulent constrictive pericarditis in which intraperieardial fibrinolysis was use. a years old patient admitted in our icu for a constrictive pericarditis as a complication of a purulent pericarditis diagnosed seventeen days before. he had also an aehalasia and the o'esogastric endoscopy had found an oesophageal neoplasm. a fistula was not seen, indeed pericardial of flora was the same that oropharyngeal. hemodynamie and echographic study had confirmed a constrictive pericarditis. because of the poor state of the patient an intraperieardial fibrinolysis was prescribed ( . ui of streptokinase on days , , , ). fluid drainage was improved and cardiac output was also improved (day : . .min "i, day : . l.min'l). no change ofhemostasis was noted. a pericardeetomy and an oesophagectomy were performed after days of evolution. eighteen months latter the patient was still alive. intraperieardial fibrinolysis seems an interesting therapeutic way if rapidly prescribed in the purulent pericarditis course. the decrease in the systolic pressure following a mechanical breath, termed ddown (delta down), has been shown to be a sensitive indicator of preload ( , ) . however, the clinical use of this method necessitates the introduction of a short apnea. we have therefore developed a respiratory systolic variation test (rsvt) which obviates the need for apnea. the test is based on the delivery of successive breaths of increasing magnitude ( , , , and ml/kg). a line of best fit is drawn between the minimal systolic values (one after each breath) and the downslope calculated as the decrease in blond pressure for each increase in airway pressure ( mmhg / cmh ). in mechanically ventilated patients the rsvt was performed during controlled mechanical ventilation under sedation. the test was repeated after the administration of ml/kg of plasma expander. the initial mean downslope of the rsvt was -. + . mmhg/cmh . following volume loading the downslope decreased to -. + . (ns). at the same time, cardiac output (co) increased by . + . l/min (p<. ), end-diastolic area (determined by tee) increased from . + . to . + . cm (ns), and paop increased from + to + mmhg ( p < . ). the preinfusion downslope value of the rsvt correlated significantly with the increase in the co (r = . ) and the eda (r = . ). methods: an expert system has been constructed running on a multimedia computer with the two objectives in mind, viz training of inexperienced staff, and protocol guidance with treatment regimes for all staff. the system is based on experience gained from two previous systems, the one for dealing with acid-base and electrolyte problems in icu patients; the second for stabilisation of patients with heart rate and blood pressure abnormalities. the training section takes the form of a stage-by-stage account of the insertion of the pac and displays of correct waveforms, coupled with indications of possible incorrect placements, and guidance when failing to achieve the perfect positioning. the treatment protocol section extends an existing protocol for correcting abnormalities in heart-rate and blood-pressure, and now takes account of all the indices as measured by the pac. the system will suggest treatment to correct such things as abnormal wedge pressures concomitant with parameter values throughout the rest of the cardiovascular system. the type of patient eg post-operative cardiothoracic or i. c. u. trauma, will be taken into account when recognising abnormal parameter values and when prescribing treatment. results: a working system which will be improved by the finetuning being carried out. the results and lessons learnt will be presented at the conference. method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map < mmhg) or the requirement for a noradrenaline (na) infusion ~ . g/kg/ rain with a map --< mmhg. cardiovascular support was limited to na + dobutamine (db). c was given for up to h at a fixed dose-rate of either , . , , or mg/kg/h iv. during c infusion, na was to be reduced and if possible withdrawn, whilst maintaining map above mmhg and the cardiac index (ci) as clinically appropriate. assessments were made at baseline (t = ); at i h from the start of treatment (t - ); and at the end of treatment (t - ) with c . conclusions: c does not appear to increase mpap or worsen pulmonary gas exchange in patients with septic shock, when given by infusion for up to h. c is a novel vasoactive agent for the treatment of septic shock which will now he evaluated in a randomised, placebo-controlled safety and efficacy study. objectives : to compare cardiac output (q) data obtained for thermal indicators in pulmonary artery (qtpa) and aorta (qtao) and for the stable isotope hzo in aorta (q v~ o) with indocyanine green (icg) in aorta (qicg) as reference. methods : an indicator solution of ice cold h ( . ml), h ( . ml) and icg ( mg) was injected as bolus via the injection port of a swan-ganz catheter. qlco and qzmo was measured using a dual optical system (penn lab instruments, philadephia, pa, usa). qtpa and qtao was measured using a in contrast to the recoveries of thermal indicator in pa and h in aorta the :~covery of thermal indicator in aorta was significantly increased in group ii (n= boluses) over group i (n= boluses) ( . <- . vs. . +- . , p= . ). conclusions: the "overrecovery" of thermal indicator in aorta is in agreement with " biscks deconvolution study (i) and results in erroneous values for q. the most pausible explanation is the distortion of the thermal curve caused by the slow response time of the thermal detection instrument as shown by ganz ( ) objectives: to compare data obtained with the double indicator dilution method using indocyanine green (icg) and the stable isotope h for the estimation of extravascular lung water (evlw hzo) to gravimetriu lungwater data (evlwg~). methods: an indicator solution oflcg ( rag) and h ( . ml) was injected as bolus via the injection port of a swan-ganz catheter. dilution curves for icg and zh was registered in aorta with a dual optical system (penn lab instruments, philadephia, pa, usa). cardiac output and mean tranist time was measured for both tracers (qico, tlco, q n o, t o) ( ). data analysis: evlwg~av was reference for evlwzhzo calculated as q hzo times the difference in mean transit time between t nzo and rico (atm n). as reference for atzn o evlwg~,v was divided by q~cg to obtain atg~,. a reference distribution volume for h was calculated as the sum of central blood volume and evlwg=v. boluses were administrated in a group (i) of anaesthetized pulmonary healthy sheep while q was altered. another boluses were administrated in a group (ii) of anaesthetized sheep with stable oleic acid induced pulmonary oedema. evlwg~v measurement was performed postmortem. results: for boluses h parameters were not significantly different from their respective reference parameter: at vao . +_ . s vs. atg~, . + . s, evlwzh o -+ ml vs. evlwg~,~ + ml. in group i the ratio between hzo parameters and respective reference parameters (n= ) were independent of qlco from . to . l/min. obiectives: to assess the thermo dye method using indocyanine green (icg) and thermal indicator for the estimation of lung water (evlwt). methods: ice cold indicator solution of icg ( mg) in water ( ml the aim of the study was to assess left and right ventricular function in the early postoperative period after orthotopic heart transplantation to elaborate therapeutic approaches of heart function abnormalities correction. mathefial and methods. haemodynamic monitoring data of twenty one patients ( men, women ) age from to were studied. cardiac output, pulmonary artery, right atrium and pulmonary wedged pressure were measured with swan-gans catheter. central haemodynamic indices were calculated with the help of computer-based monitoring system. relations of ventricular stroke work index to it's end-diastolic pressure were used for ventficular function assessment. results. in most cases right ventricular disfunction was the main problem. isolated fight ventficular failure with high pulmonary vascular resistance (pvr) was observed in % ( pts), without high pvr-in % opts) and with left ventricular failure-in % ( pts). one of the most important reasons for fight ventricular failure was the time of heart ischemia more than min, which is of great importance in the ease of distance harvesting. the most effective treatment for cardiac failure was combination of dobutamine with i oprotherenol, atrial pacing and vasodilatators in case of right ventfieular disfunction. all cases with isolated right ventricular failure were treated sucsessfully. biventricular heart failure was a sighn of bad prognosis and the reason of death in cases. conclusion. right ventfieular disfunetion is the main problem during transplanted heart adaptation in the early postoperative period. optimal therapeutic management of cardiac disfunction includes infusion of dobutamine in combination with isoprotherenol, atrial pacing and vasodilatators. cardiology-department of clinical centre-kragujevac institution for occupational health "zastava"-kragujevac, sr yugoslavia the aim of the investigate is analisis five years survives patients with a.i.m.in dependence of locality and risk-factors. we ana~sed- ~-pat~e~ts ( males and woman), average , years. for statistic evaluation we used life-table slstem in oder to estimate prognostic determinants. patients with respkatory muscle paralysis may benefit from respiratory assistance by abdomino-diaphragmatie pneumatic belt. we used a non invasive technique, m-mode sonography, to assess the effect of this device on diaphragmatic excursion. we measured the amplitude of right diaphragm motion in seven patients with duehenne muscular dysl~ophy in supine position with various thoracic posture ( ~ ~ ~ without and during pneumatic belt respiratory assistance. without respiratory assistance, the thoracic posture had no significant consequence on the amplitude of diapttragm motion, either in quiet or deep breathing. the pneumatic belt increased the diaphragm motion amplitude from . +__ . mm to . +_ . ram (p = . ) at ~ tilt angle, and from . + . mm to . + . mm (p = . ) at " tilt angle. the tidal volume increased from + to + rut a * tilt angle, and from + to + ml at * tilt angle (p = . ). two patients could not bear the horizontal position ( ' tilt). in the five other patients, the pneumatic belt increased but not significantly the amplitude of diaphragm motion ( . + . mm to . + . ram). after an overnight respiratory assistance, pao increased from . +_. . to + . mmhg ( = . ), sao increased from . + . % to . +_. % (p = . ), and paco decreased from + . to . +_. mmhg (p = . ) according to the ventilatory pattern result, m-mode sonography allows to measure non invasively the improvement of diaphragm kinetics obtained by pneumatic belt respiratory assistance, and may be helpful for its adjustment. objective: to study the effect of flow triggering (flow sensitivity and l/min) vs pressure triggering (-lcmh ) on inspiratory effort during pressure support ventilation (psv) and assited/controlled mode (a/c) in stable copd patients non-invasively ventilated with a full face mask. methods: the patients were studied during randomized min. runs using a bird st ventilator at zero peep (zeep). trigger values for pressure (-lcmh ) and flow ( l/rain) were the lowest allowed by this ventilator. the transdiaphragmatic pressure time product per breath (ptpdi), dynamic intrinsic peep (peepi,dyn), maximal airway pressure drop during inspiration (apaw) andl ventilatory variables (ti,te,ttot,rr,vt and minute ventilation) were measured. results: no major problems due to airleaks or to auto-triggeriffg phenomena were observed in the patients, so that all of them were able to perform all the protocol runs. minute ventilation and respiratory pattern were not different using the two triggering systems. the ptpdi was significantly higher during both psv ( . + . cmh: x sec) and a/c ( . + . ) with pressure triggering, as respect to psv ( . + . , p< . ) and a/c ( . + . , p< . ) with flow triggering ( l!m). no differences were observed between and l/min flow triggers. apaw was also significantly larger during pressure triggering; peepi,dyn was reduced during flow triggering being . + . cmh (psv flow trigger) vs . + . (psv pressure trigger) and . +_ . (a/c flow trigger) vs'f~ +l (atc pressure trigger). conclusions: in stable copd patients non-invasively ventilated, flow triggering reduces the respiratory effort during both psv and aic mode as compared to pressure triggering. this may be partly due to a decrease in peepi,dyn using a flow-by system. objective. cardiac output is higher during alternating ventilation (av) (i.e. differential ventilation of the lungs with a phase shift of half a ventilatory cycle) than during synchronous ventilation (sv) of both lungs . we verified the hypothesis that the higher cardiac output depended on a lower central venous pressure and intrathoracic pressure, due to a lower mean lung volume, which we attributed to part of the expansion of the inflated lung at the expense of the expiring, opposite lung . we studied this interaction between the lungs during one-sided inflation, which we called cross-talk. method. in anaesthetized and paralyzed piglets we applied short periods ( s) of one-sided ventilation ( breaths per rain, bpm), while the other lung was open to the ambient air. the air flow into the non-ventilated lung during expiration of the ventilated lung was integrated to volume. we studied -to-r and r-to-i cross-talk at ventilatory rates of , and bpm. the amount of cross-talk was the volume displacement in the non-ventilated lung. results. during bpm the r-to-i crosstalk was _+ . % (mean +__ sd) of the tidal volume to the right lung and the -to-r crosstalk _ . % of the left tidal volume. both values increased at bpm to _ . % (p < . ) and _ . % (p < . ) respectively. the values at bpm were in between., conclusion. we concluded that the lower mean lung volume and lower thoracic expansion during av compared to sv depends on partial expansion of the inflated lung into the non-inflated lung, resulting in a lower mean intrathoracic pressure as the main reason for the higher cardiac output during av. obiective: natural surfactant given for rds in premature infants leads to a rapid improvement in oxygenation, but lung compliance did not improve in most studies. however, acute effects on lung mechanics during and immediately after surfactant administration have not been studied before. methods: a total of administrations of bovine surfactant in recommended doses was given via a small catheter into the distal endotracheal tube either as a bolus (n = ) or as a slow infusion (n = ) in infants with established rds. static compliance (c), resistance (r) and time constant (tc = cxr) of the lung were measured every minutes with a lung function cart (sensormedics ) without interrupting ventilation. infants receiving synthetic surfactant were studied as controls. results: after surfactant as a bolus or during infusion c first decreased but then increased, whereas r increased immediately with great fluctuations but did not return to baseline. this pattern was more pronounced in infusion than in bolus administration. change of c and r varied greatly in the individual case, maximum c was > %, maximum r > % of baseline value. retreatment was followed by an increase in r in all patients, but c increased only in the one who was responder. patients receiving synthetic surfactant had no change of c or r and were non-responders. ob~i ctives= acute lung injury (ali} sometimes induces severe hypoxernla which may be refractory to conventional modes of mechanical ventilation (mv). the elm of this study was to observe some cardio-pulmonary effects of an alternative method of ventilatory management of severe ali. five patients with severe ali (murray scores > ) requiring mv were studied. protocol inclusion was considered when a control-mode of mv (with a pzo~=l. and a peep level < cme=o} was not able to get either a p.ojf=o= ratio > or a s.o= > %. patients were sedated, paralyzed, and a ventilator (serve c) was used for pressuz'e-control ventilation (pcv). fio= was maintained at . and peep removed. continuous gas flow ( • ml/kg] was humidified and jet delivered through a tube ( ram id, ml capacity, . ml/cm h=o compllancel ended in a nozzle ( . mm is) attached to the endotracheal tube connector. a thermodilution flcw-dlrected catheter was inserted in pulmonary artery. following variables were recorded minutes before and after protocol started: tidal volume (vt), minute ventilation (vz), intratracheal pressures (p~w), wedge pulmonary artery pressure (wp), central venous pressure (cvp), mean arterial pressure (map), cardiac index (ci), arterial and mixed venous oxyhemoglobin saturation (sao=, svoa) , oxygen delivery (do~) , oxygen consumption (vo ) , intrapulmonary shunting (q./qt) , and oxygen extraction ratio (ero). this observation suggests that hfpv could allow to ventilate at lower fin and improve blood oxygenation during the acute phase after inhalation injury reducing toxicity risk related to high fin . further studies are necessary to confima these results and evaluate the possible implications on mortality alter smoke inhalation and for other icu pts. objectives: to design a system for volume controlled high frequency ventilation (hfv) and to estimate the dependence of the tidal volume (vt) on frequency (f) in normocapnic ventilation in rats at frequencies - hz. methods: a new system for volume controlled hfv was devised consisting of the generator of the constant flow during inspirium and the constant pressure during expirium. the ventilator allows ventilation at frequencies - hz with the relative inspiratory time (ti) . - . . the airway pressure was measured at the proximal port of tracheostomic cannula , at the same site inspiratory and expiratory flow was measured using modified lilly-type of pressure-differential flow sensor. non-linearity of flow sensor was compensated on line by derived equation based on calibration at static and dynamic conditions. flow and pressure data were evaluated on line using original software. value of the positive end expiratory pressure (peep) was serve-regulated by analogous feed-back. in animal experiments white wistar rats ( - g) narcotized with ketamine/xylazine with cannulated carotid and femoral arteries were kept at the rectal temperature ~ the arterial pressure was monitored. after traeheotomy the metal cannula ( mm [.d.) was inserted, animals were curarized and ventilated at the following condition: peep = . kpa, ti = . . the dead space of ventilator including canula was . ml. the initial frequency was hz and rain after each change of the ventitatory regimen the blood gases analysis was performed. the frequency was changed according to the following schedule : hz--> hz--> hz--> hz--> hz--> hz--~ hz--> hz. vt for each frequency was regulated to maintain normocapnie ventilation with arterial pco = + mm hg. the arterial po was always above mm hg. results: for normocapnie ventilation in rats the following tidal volumes vt [ ml/kg] were found : vt = . --+ . ml/kg for ft = hz, vt = . + . mukg for fz = hz, vt = . +_ . ml/kg forf = hz, vm = . + . ml/kg forf = hz andvmt= . + . mukg for fs = hz (presented as mean values _+ s.d., n = ). the regression analysis using the mean values resulted in the equation for normocapnic vt in rats in our experiments : vtn = . * f-e. . conclusions: the described system allowing ventilation in a wide frequency range - hz with accurate measurements of airway pressures and vt might be useful for optimisation of artificial ventilation in new-barns with different lung pathologies. supported by grants iga mz cr nr - and gacr nr . s intensive care unit. university. hospital of south manchester, uk. methods: measurements were conducted on ventilated patients (puritan bennett ac with metabolic monitor pb set to measure end tidal co ). all measurements were repeated with the patient stabilised at cm. cm and cm peep. inclusion criteria were: ) haemedynamic stab(l( .ty for hr; ) pulmonad" anon" flotation catheter in situ: ) volume control ventilation with plateau of . s: ) fio ~ > . to maintain pao~. > kpa with em peep: ) qs/ot > %; ) pao /fio ratio < . measured variab!es included: r minute volume: plateau ainvay pressure: applied and intrinsic peep: fractional end tidal co ; arterial and mixed venous blood gases and hacmod).ttamic variables. results: statistical analysis was performed using repeated measures anova. significant decreases in cardiac index (ch p< . ), compliance (p<t). ) and o,'gcn deliver, index (do , p< . ) occurred with increasing peep (table ) . no other variable showed any significant change. methods : all consecutive patients orally intubated in the micu between january to april were studied. etts were positioned according to the reference marks mentioned above (measurements from upper incisors). the position of the ett tip in relation to the carina was measured on the chest radiograph done with the patient's head in neutral position. results : a total of men and women were studied (n= ). the mean distance of ett tip to carina was . cm. using the reference markings, cases ( . %) had the ett tip < cm from the carina and cases ( . %) > cm. one case resulted in an endobronchial intubation. the mean height of all patients were cm ( - ) for males and cm ( - ) for females. of the patients with ett tip < cm from carina, the mean height was cm and cm respectively. ~ onclusion : adopting the above quoted reference marks did not result in ideal positioning of the ett in a significant proportion of cases ( . %). we postulate that [s because our asian population is generally shorter than those in previous studies. objectives: to measure the changes of pulmonary mechanics before and after tracheostomy in patients with prolonged mechanical ventilation and to determine factors that predict the outcome of liberation from mechanical ventilation. design: prospective. setting: respiratory intensive care unit (ricu) in a tertiary hospital. patients: twenty patients with chronic lung disease requiring long-term mechanical ventilation. tracheostomy is indicated for further care. intervention: tracheostomy. measurements and results: pulmonary mechanics including respiratory rate (rr), tidal volume (vt), peak inspiratory pressure (pip), intrinsic positive end ex~ piratory pressure (peepi), lung compliance (cld), mean airway resistance (rawm), work of breathing (wob), pressure time product (ptp) by bicore cp- pulmonary monitor were recorded hours before and after tracheotomy. ventilator setting parameters remained the same during surgical intervention and were also recorded for comparison. generally, the mechanics including pir wob, raw~x and ptp showed improvment after tracheostomy. but only pip was significantly reduced (pre . _+ . to post . _+ . , p < . ). changes of wobp showed significant correlation with pre-operation rr, minute volume (mv), wobp, and peep(. changes of raw m were also significantly correlated with pre-operation peep, vt, and raw m. the patients were divided into two groups according to their outcome after two week follow-up. group included eight patients who were completely weaned from ventilator; group included twelve patients who still remained ventilator-dependent or were mortality. there was no difference in age, duration of mechanical ventilation, pro, post or changes of several lung mechanics between the groups of patients. pre-tracheostomy peep i and cld showed significant difference between these two groups ( . _+ . vs . + . in peepi; . _+ . vs . _+ . in cld, p < . ). pre-tracheostomy ventilator setting in mode of assist/control also showed significant higher percentage in group ( % % in group vs . % in group ). conclusion: in prolonged mechanical ventilation patients with chronic lung disease, tracheostomy will significantly improve pip and slightly reduce wobp, raw m and ptr patients who used pressure support mode before tracheostomy had better underlying lung conditions (lower lung compliance and auto-peep) will have better chance to wean from mechanical ventilation. forty-eight infants with congenital diaphragmatic hernia presenting within the first hours of life, who underwent surgical rapair,were analysed prospectively in order to produce a reliable inde x of severity of disease that would reliably predict eventual outcome. there were survivors and deaths in this series (mortality %).using arterialpco values measured hours after surgical repairand correlating them with an index of mechanical ventilation,we have been able to clearly define two groups of diaphragmatic hernia based on their response to hyperventilation. the first group, with co retention and severe preductal shunting,was unresponsive to hyperventilation with high rates and pressures the mortality was %. the second group responded well to hyperventilation and demonstrated reversable ductal shunting only. survival in this group was %. arterial co accurately reflects the degree of lung development in this disease and separates those patients with severe pulmonary hypoplasia where the outcome is invariably fatal, from those with a well developed contralateral lung where there is excellent potential for survival. respiratory failure unit, dpt medicine, univ. thessaloniki, thessaloniki, greece the variability of arterial blood gases (po , pc ) and the ph (abg) was examined in stable icu patients, few hours before a successful weaning from the ventilator. all patients were lightly sedated and the ventgatory conti~ons were pressure support (ps) for and ps plus intermitted mantatory ventilation in ii. [n each patient, speciments of abg were measured at min intervals during a - study period. at the same time with abg the arterial blood pressure (bp), the heart rate (cf), the tidal volume (tv) and the respiratory rate (n r were measured. for all the patients, the mean coefficient of variation (c) was . percent for po , . percent for pco and . percent for hco . the average sd for ph was . , the corresponding c for systolic bp, diastolic bp, cf, tv, rf were . , . , . , . , . percent. we conclude that the spontaneous variability of arterial blood gases in icu patients is not substantial ~hen they have stable the heamodynamic and the ventilatory parameters. deptx?fa'aaesthesioiogy and reanimation, rhe sechenov medical academy, moscow, russia objective: ~he prevention and treatment of hypoxia in the critical patiems. methods: i~fusions of perphtoran -a blood substitute with gas-transporting fimclion based on perphtorhydrocarbon -in patients with acute hypovolemia, microcirculatory distnrbance~ tissue gas exchange and metabolism; pulmonary iavage in ; iongterm extrapulmonary oxigenation with tleoroearboa oxygenator in combination whb ~trafiltra!ion, hemosorption and hemodialysis -in patients. results: pe~htoran increases blood volume, co,sv, decreases svr, improves capillary blood flow, increases the blood oxygen capacity, tissue oxygen tension, del, vo by improving the rheologic properties of blood and plasma, normalizes ext., prevents and eliminates fat embolisation and ards. decreases the need for blood transfusions and infusions of plasma expanders by . - . limes. alveolar venti!ation-perfusion ratio remains unchanged with its increased effective utilization. there was no surfactant destruction during lavage. extrapulmonary oxygenation of small volumes of venous blood eliminates venous destruction and then arterial hypoxia and increases pulmonary oxygenation. the use of lluorocarbon cxygenators during hemosorption and hcmodialysis provides the atraumatic and iongterm oxygenation of arterial blood and increases elimination of co which prevents the development of hypoxic complications. conclusions: perphtoran and fluorocarb~n oxygenators are effective in the correction of hypoxia in the criticat patients. objeqtives: to determine if there are differences in oxygen consumption (vo ) during weaning from mechanical ventilation (during total ventilatory support and spontaneous ventilation with cpap), and to compare different predictive parameters of weaning in predicting success of weaning. methods; prospective study in critically ill patients treated with mechanical ventilation for at least h, who fulfilled at least of standard weaning criteria (vt> ml/kg; respiratory frecuency (f) < ; pimax > cm h ; pao /fio > ). baseline measurements: t, vt, p . , pimax, f/vt, p . *(f/vt), p . /pimax. study protocol: measurement of vo , vco (medgraphics), vt, f, ve, and arterial blood gases during total ventilatory support (cmv), and after and minutes of spontaneous ventilation with cpap cm h . the weaning trial was stopped, failure to wean diagnosed, and mv resumed it a patient presented significant tachypnea, tachycardia, bradycardia, cardiac rythm disturbances, hypertension, hypotension, hypoxemia or hypercapnia. results: four patients did not complete the weaning trial, were extubatad, and of them had to be reintubated before h, being considered also weaning failures. during cmv, vo /kg was . + . ml/kg/min, and . _+ . mlo- /kg/min after ' on cpap cm h (p < , ). of patients ( %) with standard criteria were extubated, while only of ( %) with criteria (p< , ). next objectives: compare the extent and distribution of lung injury in dogs preinjured with oleic acid (oa) and ventilated with high tpp and adequate peep in the prone and supine position. methods: lung injury was induced with oa ( . - . ml/kg) in anesthetized, paralyzed, and intubated dogs (n= ) during volume controlled ventilation: rate= /min, peep= cmh , ti/ttot= . , fio = . , vt= ml/kg. animals were rotated during the oa infusion and the following minute stabilization period to assure uniform injury. in the supine position, peep was set - cmh above the lower inflection point (as determined by the pressure-volume curve), and vt was set to obtain a tpp of cmh : animals were ventilated in either the prone (n= ) or supine (n= ) position for four hours. pulmonary artery occlusion pressure was maintained constant ( - mmhg) with saline infusion. at the end of the protocol the lungs were removed and divided by template into dependent (d) and nondependent (nd) sections for wet weight/dry weight (v~n/dw) and grading of nstologic lung injury (hli; scale - ). oseillatron | is a pneumatic device that generates high frequency, oscillation by means of a reciprocating system in the form of a membrane. it generates sinusoidai wave form at ( to ( cycles/rain. the system does not deliver gas but must be adapted to the proximal respiratory, circuit of a conventional ventilator, resulting in ci-ifo. it was developed to enhance intrapnlmona~ diffusion during mechanical ventilation and to mobilise endebronchial secretions. methods. we measured arterial blood gases and haemedynamics during a first period of conventional ventilation (cppv) followed by. two rain periods of chfo (sequences : ( and ) c/rain : group l, n = l: and c/rain : group , n = ). measurements were made at the end of each period. cardiac output was measured using thermedilution method: flu and peep were kept unchanged throughout the study. intrinsic peep was also evaluated by, means of an occlusive valve. results. pa is not significantly modified during chfo at or c/rain. paco is slightly decreased at c/rain (p = .( ). however, intrinsic peep remains unchanged. there is no sequential effect (gr. l vs gr. ). there is no more effect of chfo for patieets who are at a flu higher than . (n = ). no changes in haemodynurmcs are observed except a slight increase in central venous pressure (cvp) during ci-ifo (p < .ol). obiectives: to examine the effects of inspiratory muscles unloading on neuromuscular output at controlled levels of chemical stimuli. methods: the ventilatory response to co was examined in ten normal subjects using rebreathing method. ventilation ~) and respiratory muscle pressure output (pmus) at the same end-tidal partial pressure of co (petco~) were compared with and without combined flow and volumeproportional pressure assist in two protocols (a and b). protocol a (n = ): two levels of assist were studied; flow assist (fa) of cmh /i/sec and volume assist (va) of cmh /i (assist ), and fa of cmh /i/sec and va of cmh /i (assist ). all conditions were applied randomly. v~, tidal volume (vt) and breathing frequency (f) were measured breath by breath and plotted as a function of petco~. protocol b: in subjects, in addition to above measurements, esophageal (pes) and gastric (pg) pressures were measured and the time courses of transdiaphragmatic pressure (pdi) and pmus were calculated. one level of assist (assist ) was studied in this protocol. results: in both protocols inspiratory muscle unloading did not change the f response to c%. compared to control, with assist v t response was displaced upwards; at petco of mmhg v t was increased significantly by . + . i and . + . i in protocol a with assist end , respectively, and by . _+ . i in protocol b with assist (p< . ). ~/~ responses showed similar changes as vtresponses. in both protocols the slope of v~ response (s did not change significantly with unloading. at low petco~ ( mmhg), pdi and pmus waveforms did not differ with and without assist. with unloading, at high petco ( mmhg), pdi and pmus at the end of neural inspiration decreased by . -+ . % and . + . %, respectively, from control values. neither change was significant (p> . ). by theoretical analysis we estimated the expected changes in vt and ~/~ when the levels of assist used in both protocols were applied in the absence of : any change in neural output response to co z. the predicted response was similar to that observed, indicating that the small difference in pdi and pmus between control and unloading runs was due to intrinsic properties of respiratory muscles end respiratory system. conclusions: these results suggest that when chemical stimulus is controlled, respiratory motor output is not downregulated with unloading. the determinants of the response of the respiratory output to inspiratory flow rates (v~) were examined in awake normal subjects. subjects were connected to a volume-cycle ventilator in the assist/control mode and v~ was increased in steps from to i/min and then back to i/min. v~ pattern was square, and all breaths were subject-triggered. in six subjects the effects of breathing route (nasal or mouth) and temperature and volume of inspired gas (protocol a) and in subjects the effects of airway anesthesia (upper and lower airways, protocol b) on the response of respiratory output to varying v~ were studied. in protocol b, in order to calculate muscle pressure during inspiration (pmus), respiratory system mechanics were measured using the interrupter method at end-inspiration. independent of conditions studied breathing frequency increased . significantly and end-tidal concentration of c% decreased as v~ increased. the response was graded and reversible and not affected by breathing route, temperature and volume of inspired gas and airway anesthesia. with and without airway anesthesia (protocol ) neural inspiratory and expiratory time and neural duty cycle, estimated from pmus waveform, decreased significantly as v~ increased. at all conditions studied the rate of change in airway pressure prior to triggering the ventilator tended to increase as v~ increased. the changes in timing and drive were nearly complete within the first two breaths after transition with no evidence of adaptation during a given ~/~ period. we conclude that v~ exerts an excitatory effect on respiratory output which is independent of breathing route, temperature and volume of inspirate and airway anesthesia. the response most likely is neu~'al in origin, mediated through receptors not accessible to anesthesia such as those located in chest wall or below the airway mucosa. it has been shown, in mechanically ventilated awake normal humans, that increasing inspiratory flow rate (~/~) exerts an excitatory effect on respiratory output. it is not known if this effect persists during sleep. to test this seven normal adults were studied during wakefulness and nrem sleep. subjects were connected through a nose-mask to a volume-cycled ventilator in the assist/control mode and ~/t was increased in steps ( - breaths each) from to i/min and then back to i/min. v~ pattern was square, and all breaths were subject-triggered. forty-one trials during nrem sleep and during wakefulness were analyzed. both during sleep and wakefulness minute ventilation increased and total breath duration (ttot) decreased significantly in a graded and reversible manner as ~' increased. these changes were complete in the first breath after v{ transition. the response was significantly less during sleep than during wakefulness (p< . ); at i/min ttot, expressed as % of that at i/rain, was . +_ . % during sleep and . +_ . % during wakefulness. during wakefulness, at i/min, the rate of change in airway pressure prior to triggering the ventilator, an index of respiratory drive, was % of that at i/min (p< . ). the corresponding value during sleep, was % (p> . ). in four sleeping subjects the increase in v~ was sustained for . - min. there was no evidence for adaptation of the response; tro t, averaged over the last three breaths, did not differ from that obtained when vj was sustained for only - breaths. we conclude that ) vt exerts an excitatory effect on respiratory output, mediated by a reflex neural mechanism and ) the gain of this reflex is attenuated by sleep. chest radiographs is a common complementary technique for patients in critical care units, with a low cost and easily available. however, it has certain well-known limits in diagnosis, the most important derived from the low quality of some pictures. in this paper we make a general review of some new technical approaches developed for improving the quality of the images, and so incrensing the diagnostic value of conventional radiology. we begin deaeng with the correct positioning of the patient, trough the filtering techniques, the synchronization of radiology and ventilation, and we make reference to the new computerized systems for digital image processing. conclusions: the portable radiographic system is a device that probably with maintain for many years in critical care units as a basic non-invasive diagnostic tool. but we need an increase in the efficiency of it, applying means as simple as a correct positioning of the patient, or the use of fitlers or synchronizers. thus we should improve the general standards of portable radiography. "are circular circuits safe? quantifying undelivered tidal volume in pediatrics patients". objectives: to evaluate the overall influence of internal compliance of circular circuits on delivered tidad volume (vt). methods: we studied prospectively asa i pediatrics patients ( to yr. old) scheduled for elective general surgery. mechanical ventilation was supplied by an ohmeda excel (circular circuit). the internal compliance of the circuit (cc)-anesthesia machine plus external circuit-was determined by the supersyringe method: corrugated dar tubes of mm. id and . m. long (children < kg), and a corrugated dar set of mm. id and . m. long (children > kg) were respectively used for ccl an cc values of . and . ml/cm h . a vtof mlg/kg and respiratory frequency was adjusted for an end-tidal co (etpco ) between mmhg. tidal volumes (measured by spirometry) and airway pressure (paw) data were recorded every ten minutes. volumes and thorax-lung compliances were calculated as follows: (vt delivered = vtadjusted-vol compressible, being vol. compressible = co x ppeak (aw). apparent compliance (ca) = vt adjusted/pplateau(aw), and true compliance (ct) = =vt delivered/pplatean(aw)). comparative statistics were separately designed between calculated compliance data and tidal volumes on a paired sample ~test basis. results: calculated values for volumes and thorax-lung compliances were: conclusions: due to the elevated internal compliance of the circular circuit there is a remarkable dilference between adjusted and delivered vt: mean undelivered vt was . % and reached as high as . %. teere is also a significative error in calculating true thorax-lung compliance: its overestimation can be as high as . %. circular circuits are considered safe and cost-saving for anesthetical practice. nevertheless we conclude that anesthetists should bearin mind vt losses when using circular circuits, due to compressible volume. tracheal stenosis is one of the most serious complications of patients submitted to prolonged endotracheal intubation, in which the decrease in inner diameter of upper airway makes it very difficult to achieve a correct ventilation. objectives: compare the results of applying high frequency jet ventilation (hfjv) to some of these patients with conventional controlled ventilation (cmv). methods: we used a prototype of high frequency jet ventilator (santiago- ) developed in our university, and we developed a tracheal tube in wich we modified the distal tip (conic tip). we applied this system to two patients which were initially ventilated in the operating room with usuai controlled mecanical ventilation (cmv) following the standards of our department, and then intubated with the special endotracheal tube and ventilated with hfjv. results: we could verify a proper ventilation of both patients with cmv and hfjv. during hfjv, the airway pressures were lower than those recorded during cmv. a lower airway pressure prevents lesions due to high pressures. conclusions: hfjv is a good method of ventilation for patients with significative stenosis of the trachea, not only during surgical procedures, but also during ventilation for long periods in critically patients. the ventilatory setting is pressure support mode. the pressure level and fit were kept constant during h/d. arterial blood gas, wbc count, and mean bp was checked according to the schedule: '(immediately before h/d), ', ', ', ', ', '. respiratory drive (represented by poa), tidal volume(ti) and minute ventilation(ve) were continuously recorded by pulmonary mechanics monitor (bicore cp- ). the mean value of the breaths minutes before blood sampling were used to represent the ventilatory status of that period. anova test is used for comparison between groups. for poa, hierarchical cluster method is applied to divide the cases into two groups of similar change. conclusions: our data suggest that pl is very useful, non invasive and low-expensive emergenc e support for arf, expecially in the elderly with severe chronic pulmonary disease and relative controindications to eti. pl seems to be an effective alternative when it is not immediatly possible to perform etl. the multiple inert gas elimination technique (miget) can be used to assess the effects of any given mode of mechanical ventilation on the pulmonary and systemic factors determining arterial po and pco> however, a potential problem in mechanically ventilated patients is that the l mixing box (mb- l) placed in series in the expiratory side of the circuit of the ventilator to sample mixed expired gas may provoke substantial discrepancies between the tidal votume set in the ventilator and the effective tidal volume delivered to the patient, due to the increase in the compression volume (vc) of the circuit. the effects of the mb- l on the v c were compared with those produced by a new l mixing box (mb- l) specifically designed to produce adequate gas mixing and to prevent loss of the two most soluble gases (ether and acetone) used in the miget. at any given peak cycling pressure (p~ak, cm h~o), the v c (ml) provoked by the mb- l was substantially higher (vc= . *ppeak) than that provoked by the new mb- l (vc= . *ppeak). at a ppeak = cm h ~ the v c were ml (mb- l) and m{ (mb- l), respectively (p< . ). in a group of subjects ( m/ f, _+ years), for each of six the gases used in the miget, the regression line between the mixed expired partial pressures simultaneously obtained from mb- l and mb- l fell on the identity line. it is concluded that the new mb- l allows adequate assessment of the effect of different modalities of mechanical ventilatory support on pulmonary gas exchange, with less potential for gas compression and thus hypoventilation. objectives evaluate the influence of different pressure support ventilation (psv) levels on cardiovascular and respiratory funcion in icu polytrauma patients. metbed&we studied polytrauma icu patients , who were in weaning process , after long term mechanical ventilation for acute respiratory failure . mean age ( - ) yrs . they all were connected to servo ventilators siemens c , and all were in stable condition , without sedation , inotropes or diuretics. the hemodynamic studies were done with continuous svo , swan ganz catheter (oximetrix, abbott). they all were in spontanuous mode (spent) with cm h cpap for at least one hour. we turned them to psv with inspiratory assistance (psv cm h ) and after rain we applied psv cm h , and after min psv cm h . hemodynamlo and respiratory measurements were done before and after the application of insiratory assistance. the results were statistically analyzed with anova. resets . respiratory variables . no significant changes in minute volume (ve). tidal volume (vt) and mean airway pressure (mpaw) increased statistically significant (p< . ) . respiratory rate (rr) decreased significantly (p< . ) . blood gase showed no difference . cardiovascular variables. cardiac output (co) decreased ns , heart rate (hr) had no change , central venous pressure (cvp) , mean pulmonary artery pressure (mpap) , pulmonary capillary wedge pressure (pcwp) , increased ns , oxygen delivery (do ) decreased ns, oxygen consumption (vo ) decreased ns. conclusions. psv is a very useful respiratory mode helping patients to be weaned from long term mechanical ventilation . it has beneficial effects on respiratory function and oxygen consumption without affecting seriously the hemodynamic parameters, possibly due to a decrease of the work of breathing. a. michalopoulos, a. anthi, k. rellos, j. kriaras, s. geroulanos intensive care unit, onassis cardiac center, athens. objectives of this study was to examine the effect of different levels of peep on postoperative svo and pvo values in a group of patients, following open heart surgery. methods: upon transfer to icu, patients ( males and females) of mean age _-+ years, were randomly assigned to receive (n= ), (n= ), or cm of peep (n= ). there were no statistically significant differences in demographic data or preoperative respiratory status among the three groups. all patients were ventilated on the assist control mode with a tidal volume of ml/kg. the fraction of inspired oxygen (fio ) was adjusted to keep a pao around mmhg. mixed venous po and svo were measured at min, and hours after application of mechanical ventilation in the icu, just before extubation (be), half hour after extubation (ae), and at hours post-extubation. differences at each study time were analysed by anova. results: mean svo and pvo values among the three groups, for all study intervals, are presented in the table. conclusion: we found no differences (p=ns) in tissue oxygenation (expressed by svo and pvo ) among the three groups, at any study interval, in the early postoperative course of patients following open heart surgery. intrinsic peep (peepi), and high elastance and resistance increase inspiratory work load in copd. cpap reduces work of breathing by counterbalancing peepi. pav provides flow (fa) and volume (va) assistance proportionally to patient resistance and elastance and inspiratory effort. we studied the effects of partitioned support (cpap-fa-va) on breathing pattern and inspiratory effort in five copd patients on pav compared to spontaneous ventilation (sv) and full support (fs: cpap+fa+va). flow, volume, minute ventilation (ve) respiratory rate (rr), inspiratory swing in esophageal pressure (apes), and its integral per breath (pti/b) and per minute (pti/m) were measured. objectives: to evaluate airway pressure fluctuation (apf) during spontaneous breathing in a high compliance cpap system. methods: the cpap system consisted of two l weighted balloons in a wedge shaped holder. ventilating gas flowed from one balloon through a low resistance one way valve into a tracheal tube (ett) provided with a pycor co sensor to monitor rebreathing. the ett was connected to a piston drive mechanical lung. expired gas flowed through a low resistance valve into a second weighted balloon, from where it was exhausted through a peep valve connected in parallel with the second weighted balloon. we evaluated system performance at v r from to ml, at rr from to bpm, while closely monitoring cpap airway pressure swings. at v v of and ml the rr was limited to bpm. for comparison we explored aps of a one l balloon cpap system, the cpap mode of the puritan bennett , and siemens ventilators, when connected to a healthy adult volunteer breathing through an ett. results: the compliance (cpl.) of one l balloon system was linear over a range from . to . l, with a cpl. of . l/em h .the cpl. of the l balloon ( . l/em h ) was linear between a volume of and . l. apf of the weighted balloon system was under em h at all v r (except at a v r of ml aps was . em h ), while the apf in the l balloon was up to em h . apf witli human volunteers with the two commercially available ventilators in the cpap mode was about cm h ; while under identical conditions apf in the l balloon system was . emhzo; and in the two l balloon system was below lcm h . conelusions: cpap using the two balloon system exhibits lower airway pressure fluctuations than a single balloon system; and is substantially lower than found in the two commercially available ventilators when used in the cpap mode. objective: to perform independent lung ventilation (ilv) with individual tidal volume (vt) set at a value generating a plateau airway pressure (pplat) < crnh~o and to evaluate the usefulness of the continuous monitoring of endtidal co (etco ) as a guide to titrate individual lung vt during ilv and for the weaning from ilv. methods: in seven patients, ilv was performed with ttvo ventilators set with the same fio: and respiratory rate. each lung was ventilated with a vt that developed a pplat < cmh~o. this setting led to a lower vt on pathological lung (pl). vt was increased in pl following etco~ and paco -etco variations. ilv was discontinuated when etco~., vt and statical compliance (cst) were similar in both lungs. results: one hour after starting ilv (ti), pl mean vt was significantly lower than in normal lungs (nl) ( + ml vs + ml, p< ) two individual behaviours were observed on tl in pl: four patients presented low etco: (range - mmhg)and normal pacoz (range - mmhg), while three patients had normal etco (range - mmhg) with high pac (range - mmhg). one hour before stopping ilv (t ), vt, etc and paco were the same in each lung. the pao /fio: ratio improved in all patients from the beginning ofllv cst of pl was + % of the normal lungs' cst on ti and improved to . + % ofnl's cst on t (p< . vs conclusions: setting vt of pl to a value not overcoming a pplat threshold does not impair oxygenation and is helpful in avoiding barotraumatism. measurements of differential etco and of the differential paco -etco gradient can be used to titrate vt allocation during ilv and as a guide for the weaning from ilv. total respiratory resistance in mechanically ventilated patients exceeds values obtained in normal subjects, due to the added and highly flow dependent resistance of the endotracheal tube (rett). this can adversely effect the efficacy of pressure regulated modes of assisted ventilation, such as pressure support (psv) and proportional assist ventilation (pav). recent work demonstrates that the influence of rett during psv can be overcome by using tracheal (ptr) rather than airway opening (pao) pressure to regulate the pressure applied (intensive care med :$ , ) . the purpose of this study was to see if this approach would also be effective during pav. flow, volume, pao, ptr, and transdiaphragmatic pressure (pdi) were measured in intubated patients in which either pao or ptt were used to regulate the pressure applied during pav where volume assistance was varied from to % of respiratory elastance. representative results (mean + se) are shown below. compared to spontaneous breathing (pav %), pav increased tidal volume (vt) while reducing respiratory rate (rr) so that minute ventilation ('~e) also rose. this was associated with a reduction in inspiratory effort, as reflected by a decrease in the pressure-time integral ( [ p) of pes and pdi both per minute and per liter ~re. the effects on breathing pattern were similar for pao and ptr regulated pav. in contrast, the reduction in inspiratory effort was always greater for ptr regulated pav. in conclusion, the volume assistance provided by pav is more effective when ptr rather than pao is used to regulate the pressure applied. pav methods: retrospective data analysis of adult patients with normal pulmonary function before operation and uneventful course following coronary artery bypass graft surgery over an month period. we compared assist/controlled mandatory ventilation (s-cmv, patients), synchronized intermittent mandatory ventilation with inspiratory pressure support (s-imv/psv, patients) and biphasic positive airway pressure ventilation (bipap, patients). results: patients ventilated with bipap had a significantly shorter mean duration of intubation ( . h, p< . ) than patients treated with s-imv/-psv ( . h) and s-cmv ( . hi. with s-cmv . % of the patients required single or multiple doses of midazolam but only . % in the s-imv-/psv group and . % in the btpap group. the mean total amount of midazolam of these patients was significantly higher in the s-cmv group ( . mg) than in the s-imv/psv group ( . mg, p< . ) and in the bipap group ( . mg, p< . ). the consumption of pethidine and piritramide did not differ between s-cmv and s-imv/psv but was significantly lower during bipap (p< . ). after extubation the paco patients was highest in the s-cmv group. conclusion: ventilatory support with bipap reduces the consumption of analgesics and sedatives and duration of intubation. unrestricted spontaneous breathing as well as fully ventilatory support allow adequate adaptation to the patients requirements. bipap seems to be an alternative to s-cmv and sqmv/psv ventilation not only in patients with severe ards but also in short term ventilated patients. _objectitives: after end-inspiratory airway occlusion we examined the ensuing gradual decrease in tracheal pressure (ptr) with the following equations proposed by bates et al. and hildebrandt: pv = p'v e'~cccl~ +pst, rs (bates) [ ] where p'tr is tracheal pressure immediately after occlusion, to= is occlusion time, "r is viscoelastic time constant of respiratory system, and p t is static elastic recoil pressure of respiratory system. p~(t) = h -h log t (hildebrandt) [ ] where h~ and h are parameters depending on lung volume, and initial time is s for analytical reasons. materials & methods: we studied healthy patients intubated, anestethized with propofol, paralyzed with vecuronium, and mechanically ventilated with constant flow ( . i/s) at zeep for minor surgery. pressure was measured in the trachea. flow was measured with a pneumotachograph and volume was obtained by numerical integration. the rapid occlusions were produced by an external valve. the signals were sampled at a frequency of hz and processed on a pc. the influence of the cardiac artifacts during the occlusion time ( s) was reduced by a software low-pass filter kaiser finite duration impulse response of elevated order. results: the mean (+ sd) coefficient of correlation using eq. was , -+ . , and using eq. was . + . . the values ofz~ (eq. ), however, decreased with increasing the tidal volume (vt) according to the following equation: "~ = . - . v t, similary, the values of h~ and h increased with increasing v t according to the following functions: h~ = . + v i and h = . + . v t. conclusions: the behaviour of "% of eq. suggests that the linear viscoelastic model is not sufficient to further describe the mechanical properties of the respiratory system over the vt range ( - ml/kg) in ventilated patients. infect this model predicts that "c is constant and independent of tidal volume. on the other hand the plastoelastic model is not sufficient to further describe the mechanical properties of the respiratory system. in fact "r obtained by fitting an exponential for data of eq. , is determined by the time of endinspiratory airway occlusion. obiectives: according to the viscoelastic model, the viscoelastic pressure of the respiratory system pv=rs during lung inflation with constant flow e~ is t/ r wh t lsms ira tlmeand r given by:pv~c.~ = d~( -'e-~ )[ ] ere " ' p" tory " and "r are resistance and time constant of viscoelastic unit. in the past, the viscoaletic constants were determinated by performing a series of occlusions at different lung volumes, or a sedes of occlusions at a fixed lung volume achieved with various inflation flows. in the present study we have developed a new method for determining "c and r which requires a single constant flow inflation. our method is based on determination of pv~r, during a single breath constant flow inflation, and of z during the ensuing end-inspiratory airway occiusion. dudng the occlusion the tracheal pressure p~, declines according the following function: ptr = p'lr e " too= " z + e~t.r= [ ] where p'~r is tracheal pressure immediately after occlusion, toc c is occlusion time, p,i.rs is static elastic recoil pressure of respiratory system, and ~ is viscoelastic time constant. we first determinated "~ by analyzing the time-course of ptr according to eq and next determining r according to eq. , using the expedmental values of p,i=~, ~ and ti, as well as "~ obtained with eq. . materials & methods: we studied healthy patients intubated, anestethized with propofol, paralyzed with vecurenium, and mechanically ventilated with constant flow ( . i/s) at zeep for minor surgery. pres-sure was measured in the trachea. flow was measured with a pneumniachograph and volume was obtained by numerical integration. the rapid occlusions were produced by an external valve. the signals were sampled at a fi'equency of hz and processed on a pc. the influence of the cardiac artifacts dudng the occlusion time ( s) was reduced by a software low-pass filter kaiser finite duration impulse response of elevated order. results: the mean coefficient of correlation with eq. was . . with v t of ml/kg, the mean values (+ sd) of ': and r of the subjects amounted to . • . s and . • . cmh i "~ s. with the traditional multi breath method the corresponding values were . + . s and . _+ . cmh i " s, respectively. with the t-test the difference between new and traditional "~ was statistically significant, between new and traditional r was not significant. conclusions: with the single breath method it is possible to compute ': and r . the mean values of r with v t of nd/kg, however, was slighuy different than those obtained with the traditional multi breath method. the application of modem principles of respiratory care and mechanical ventilation in icus has resulted in increased survival of critically ill individuals with neuromuscular, skeletal and irrevers~le pulmonary diseases. in these chronically ill individunts mechanical ventilation, long term therapy (ltot) and continuous home care is considered a chronic life supporltng technique that can not be withdrawn after their discharge from an icu. the aim of this study was to present the results of a rehabilitation programme and home care that runs in our ward. twenw three patients were referred to our clinic f~om icus during - . a specific rehabilitation programme designed according to individual's needs was performed. patients that benefitted from this programme were grouped into the following disorders. ) post tb respiratow failure ( %) ) neuromuscular diseases, ( %) } undiagnosed sas { %) ) cope) ( %) ( patients had a overlap syndrom). the programme consists of : ) assessment and mechanical support ff needed of the respiratonj system with non invasive methods (nasal or via tracheostomy). ) group and individual respiratory therapy ) mobilization ) nutritional support ) educational classes for the members of the family. three from the patients passed away (during the year), are under nippv during night with or without supply, pts recieve ltot. conclusion: the development of a programme for chronically ill individuals in especially designed wards in hospitals and the overall care at home is considered necessary at least in hospitals with icus. a rehabilitation programme and home care permits the fast but safe discharge of these patients from units of acute medicine that the cost of treatment is high and besides permits beds that are invaluable. we considered that the rehabilitation prod'amine and home care in our ward is the first performed in greek chronically ill pts and even though there is no special administxative support we think that the results are quite saltsfactory. objective: we postulated that the product of the respiratory frequency (f) and the ratio of inspiratory pressure (ip) to maximal inspiratory pressure (mip) would predict the weaning outcome in deeompensated copd patients better than either variable alone or other indices previously proposed. methods: in decompensated copd patients with difficult weaning, we measured, daily, respiratory mechanics data both during mechanical ventilation and after ten minutes of spontaneous breathing. then we calculated weaning indices reported in literature and some new integrated indices. according to the results of the discriminant analysis, we considered the integrative index crop (acronym of compliance, rate, oxygenation and pressure), the rapid shallow breathing index f/vt, the load/capacity ratio ip/mip, and the following new index: f x ip/mip. we used receiver-operatingcharacteristic (roc) analysis by calculating the area under the curve considered as the overall probability of correct classification. results: main results are reported in the following objective: to evaluate the reliability of some indices of endurance in predicting the weaning outcome of decompensated copd patients. methods: in decompensated copd patients with difficult weaning from mechanical ventilation (mv) we measured, daily, blood gas analysis, ventilatory and airway pressure pattern during mv, breathing pattern (frequency (f) and tidal, volume (v~)), inspiratory pressure (ip), and maximal ip (mip) during spontaneous breathing (sb). thereafter we calculated the following weaning indices: crop (compliance * mip * (pao /pao ) / f), flvt, ip/mip. data obtained the day at which the patient was considered ready for a trial of sb on clinical grounds but weaning failed (wf) and those obtained the day of the successful weaning (ws) were compared statistically through the wilcoxon rank-sum pair analysis. in order to quantify the predictive accuracy for each index with respect to successful weaning we calculated sensitivity, specificity, and diagnostic accuracy according with the standard formulas. methods : five patients ( + yrs) suffering from ards (lung injury score > . ) for hours or less entered into the study. irv (volume controlled, decelerating flow, % inspiratory pause, lie = / ) was compared to conventional ventilation (cv) (volume controlled, constant flow, no inspiratory pause, iie= / ). these two modes were applied for hours in a randomized order, with the same levels of total peep (peept = peep + peepi), tidal volume ( . • . ml/kg), respiratory rate ( • "bpm) mad fit ( • %). measurements (respiratory mechanics, hemodynamics, arterial and mixed venous blood gases) were performed after , , and hours of application of each mode. rvsuils : are expressed as mean + sem and compared by anova. backeround and methods: periodic breathing (pb) is characterized by repetitive cyclic variation in minute ventilation. pb is considewxl to be provoked by an instability in the respiratory control. inintubated, spontaneously breathing patients conventional modes of pressure support ventilation, i.e., triggered inspiratory pressure support ps), do not allow patients to breathe with theirinherent breathing pattern. therefore, pb, if existing, will appear mainiy after extubation. since our new mode of pressure support ventilation" automatic tube compensation" (atc) continuonsly corrects for the flow-dependent tube resistance during insnmdon and expiration ("electronic" extubatim), it pemaits patients to maintain their own inherent breathing pattern. then, ff necessary, tracheal pressure can be additionally supported by volume-proportioead and/or by flow-proportional pressure support (proportional assist ventilation, pav). (~as~: we report the case of a -year-old male patient who was intubated due to acute respiratory insufficiency after acute myocardial infarction with left ventricular dysfunction. during ips of mbar the patient showed a regular breathing pattem which became periodic during atc. in addition, proportional assist ventilation of mbar/l increased periodic breathing in such a way that the typical cheyne-stokes breathing pattem occurred (see figure) . baqkground: the hering-breuer reflex (hbr) is characterized by an inhibition of inspiration during lung inflation. this response has been recognized as an important vagally mediated mechanism for regulating the rate and depth of respiration in newborn mammals. in adult man the hbr is considered to be active only at lung volumes well above functional residual capacity, i.e., at tidal volumes above ml. assessment of the hbr requires specialized methods such as single breath or multiple occlusion technique. methods; in the presence of desynchronization between ventilator and patient, which frequently occurs during triggered inspiratory pressure support ventilation (ips)(see figure) , prolongation of the interval between inspiratory efforts (indicated by negative deflection of the esophageal pressure) due to lung inflation exposes an active hbr. we examined the occurrence of hbr in intubated critically ill patients. strength of hbr was assessed by the formula: prolongation [%] = ((inspiratory interval of interest -preceding inspiratory interval)/preceding inspiratory interval) * ( . rr of patients examined showed moderate to severe desynchronization. in of these patients a (re)activation of the hbr was found. the strength of hbr amounted to + %. there was a significant correlation between tidal volume and strength of hbr. in contrast to previous reports, an active hbr was shown during lung inflation well below ml. b pck~round: triggered inspiratory pressure support ventilation (ips) is commonly used to support inspiration in intubated spontaneously breathing patients. despite its usefulness ips shows some disadvantages which can be deleterious in crificauy ill patients: -additional work of breathing to be performed by the patient due to the flow-dependent tube resistance -desynchronization between patient and ventilator due to inherent triggering failures of the ips mode suppression of the patient's inherent breathing pattern -inability to predict successful extubation in difficult-to-wean patients methods: based on the known flow-dependent tube resistance our new mode "automatic tube compensation" (atc) compensates for the pressure drop across the endotracheal tube ("electronic" extubation). then, if necessary, tracheal pressure can be supported by volume-proportional pressure support (vpps) and/or by flow-proportional pressure support (fpps). results: hitherto, we have examined patients after open-heart surgery and patients with acute respiratory insufficiency (ari) or ards using atc with/without vpps/fpps. preliminary results suggest that the new mode avoids additional work of breathing due to accurate compensation of the pressure drop across the endotracheal tube during in-/expiration prevents desynchronization between patient and ventilator allows patients to breathe with their inherent breathing pattern accurately predicts the outcome of extubation even in difficult-to-wean patients due to "electronic" extubation conclusions: the new mode atc with/without vpps/fpps allows to support ventilation in a more physiologic manner and overcomes the disadvantages of conventional modes of pressure support in intubated patients. backgound: cheyne-stokes respiration (cs) is characterized by regula]; recurring periods of hyperpnea and apnea. in normal subjects, cs may occur after hyperventilation, after arrival in high altitude, or during sleep. it has also been observed in patients with prolonged circulation time due to congestive heart failure, as well as in some neurological patients. there is no report about the influence of sedative drugs on periodic breathing (pb) and cs. methods: in intubated patients conventional modes of pressure support do not allow patients to breathe with their inherent breathing pattem. therefore, periodic breathing and cs are rarely seen. since our new mode of pressure support ventilation "automatic tube compensation" (atc) continuously corrects for the flow-dependent tube resistance during inspiration and expiration ("electronic" extubation) it permits patients to maintain their own inherent breathing pattem even if pathological, e.g., periodic. results: using this new mode of pressure support ventilation, periodic breathing was unmasked in of intubated patients, of which showed cs. in of these patients the occurrence of cs was linked to impaired left ventricular function with increased circulation time. normal left ventricular and neurologic function was found in the remaining patients. in of these patients cs disappeared after intravenous administration of the benzo-diazepine antagonist flumazenil (figure). consequently, in this patient cs was induced by benzodiazepine sedation. objecti',~s: in contrast to conventional rhodes for pressure supported spontaneous breathing, our newly developed ventilatow mode ,,automatic tube compensation" (atc) completely compensates for the flow-depandant pressure drop tlpm-r across endotracheal ttlbe (ett). in the atc mode, the ventilator supplies a flow v' in order to maintain a constant tracheal pressure p~,,~. to this end, pk,,= has to be oontinuousiy determined. since continued measurement of p,,~ by introducing a catheter via the ett is not reliable, we opted for its continuous calculation socordng to the following equation: p~ = p,,, -aperr, pw being the continuously measured airway pressure. this also requires the continual measurement .of flow v' to calculata apm-r using the non-fineer approximation: aport = kvv' + k .w. the constant tube coefficients k~ and k are mathematically determined by mesns of a least-squares-fit procadum based on laboratory investigations. tracheal secretions, however, reduca the omss-saction of the ett. consequently, ~ values of ki end k are changed rendering the p~,ch calculations inaccurate. therefore, k and ~ have to be pedodcally updated to ensure an a~urete monitoring of pn,~ and a complete tube compensation under atc at any time. background: one of the first steps in weaning patients from controlled mechanical ventilation is to stop muscle relaxation and to reduce sedation. it can take several hours, however, until the patient is able to trigger the ventilator and to breathe spontaneously. during this period, many patients display a sudden increase in peak airway pressure of up to %. patients and methods: to investigate the reason for this potentially dangerous effect, we continuously measured lung and chest wall mechanics in post-operatively ventilated patients. lung mechanics (airway resistance and lung compliance) was measured using the esophageal balloon technique as described in [ ] . chest wall mechanics (tissue resistance and chest wall compliance) was calculated from lung mechanics and total respiratory system mechanics as described in [ ] . results: we found a decrease of chest wall compliance (cw) to be the main reason for episodes of sudden airway pressure increase while lung compliance (cl) remained unchanged. the decrease of c w can be inter- gil cano a, san pedro jm ~, sandar d, herntndez . , carrizosa f, , herrero a. emergency and intensive care department, hospital of jerez, spain objective: ) to determine the incidence of hypoteasion (h) associated with emergency intabatian of mechanical ventilation, and ) to establish its relauonship with respiratory mechanics (rm) and arterial blood gases. mechanical ventilation performed in the emergency room, in a prospective eans~eative manner, were evaluated. data collected included patient demographics, diagnoses, blood pressure and arterial blood gas levels before and at~er intabatian, and p_m, including calculated pulmonary end-inspiratory volume above functional residual capacity (veic) and calculated dynamic hypetinflatien (dhc). all patients received midazolen and awaanrinm to facilitate tracheal intubatien and rm measurement. hypotension was defined as a decrease in systolic pressure higher than mmhg or an absolute decrease in systolic blood pressure below to mhg within hour of intabatian. patients were excluded because met at least one of the following exclusion criteria: preexisting shock or h ( ), cardiac arrest ( ) . there weren't any association between peepi or other airway pressures (paw) and h, but calculated pulmonary volitmes had tendency to be larger in patients with h (p < . ). high paco before lrasheal intubatian ( . - mmhg) with a quickly decrease alter starting mechanical ventilation was a usual finding (p < . ) in patients who developed h. paw. ) thexe was a good relatienship between h and high arterial paco before traqueal intahatian and its fast "washing" with mechanical ventilation. ) because cao patients had the highest incidence of h, controned mechanicel hypoventilatien driven by paco changes and pulmonary volumes monitoring instead paw, should be attempted in these patients to avoid this cemplication after tracheal intubatiert. introduction: the endotracheal tube (ett) and demand valve devices cause an added work of breathing (wobadd), which is the work necessary to overcome the resistive load of the ett and the breathing circuit ( ). application of ips has been shown to partly compensate this added work ( ). since tbe amount of wobadd is flow dependent, a fixed ips is not adequate to completly compensate the wobadd ( ). therefore, atc has been developed as a new form of assisted spontaneous breathing ( ), which provides a flow-dependent pressure support. thereby, it theoretically should compensate all the wobadd due to the tube. the purpose of this study was to evaluate the reduction of wobadd with ips and atc for different ett. methods: a mechanical lung model (ls , dr*alger, liibeck, frg) was used to generate a constant spontaneous breathing pattern. the ls was connected to an artificial trachea (at, cm long, mm id). the at was intubated with three different tubes of . , . , . mm id and connected to an evita ventilator modified to provide atc as an option (dfager, liibeck, frg). flow and airway pressure were measured between the y-piece and the ett for four different modes of ventilation: cpap, ips of and cm i and atc all with a peep of cm h . the tracheal pressure (ptrach) was measured in the at. total wobadd was calculated as the area subtended by the ptrach-volume curve below peep. results: the results for total wobadd in nd/ are shown in the figure for the three different ett: breath/mln, s=success, f=failur% *~p<. , **-p< , ns = non significant, f versus s neveltheless, in / patients, invasive ventilation was necessary in mean . _+ hours after beginning of fmpsv. there was no significant difference between the two groups (success, failure) in following parameters : sex, age, previous histoly, medical treatment, saps & , clinical signs (rr, spo , heart rate, blood pressure, glasgow score...), radiological and echocardiographic findings and standard biological parameters. only two parameters were related with failure : .a low value of pac on admission until the patients were intubated. . an increased level of cpk in relation with an acute myocardial infarction ( / cases in the failure group, vs / cases in the success group, x~(with continuity correction) : p<. ). conclusion : fmpsv is a noninvasive, safe, rapidly effective method of treatment in acpe, which may avoid tracheal intubation. further studies are necessary to precise if association of arf and low paco (< mmhg) and/er acute myocardial infarction represents an indication of immediate invasive ventilation. introduction: since the added work of breathing (wobadd) imposed by the endotracheal tube (ets and the breathing circuit is regarded as an important contribution to the total work of breathing, considerable effort has been tmdettaken to compensate for this added work. ips has been fotmd to decrease the wobadd imposed by different ventilators ( , ). because of the flow dependent pressure drop across the etf the tracheal pressure (ptr) should be measured to estimate the total imposed wobadd (wobtut) ( , ). the aim of this study was to assess the circuit imposed work (wobcirc) and wobtot (including ett) for different demand valve ventilators during cpap and/ps. methods: a mechanical lung model (ls , driiger, lfibeck, frg) generated a constant spontaneuus breathing pattern. the ls was connected to an artificial trachea (at), intubated with an . nun et]', end connected to one of four ventilators (servo c and servo , siemens,-elema, sweden; evita , driiges, liibeck, frg; pb ae, puritan bennett, carlsbad, usa). three different modes of ventilator settings were tested (cpap, ips and mbar; trigger set at maximal sensitivity, peep always mbar). flow and airway pressure (paw) were measured between the y-piece and the etr; tracheal pressure (ptr) was measured in the at. wobtot was calculated as the area under the ptr-volume curve below peep, wobcirc was calculated as the area under the paw-volume curve below peep. results: in the foti g., patroniti n., cereda m., sparacino me., giacemini m., pesenti a. inst.of anesth.and intensive care-univ.of milan -sgh monza i aim of the study was to assess cpl,rs measurement obtained by the airway occlusion method during psv. we therefore studied paralyzed cppv ventilated ali patients (lung injury score = . • that were weaned to psv. we performed end inspiratory and end expiratory airway occlusions using the hold function of the ventilator (siemens serve c), first during cppv and then within the th psv hour. airway pressure and flow signals were recorded (cpi bicore) for subsequent analysis. an airway pressure plateau was defined as a flow tracing in which airway pressure was stable for at least . sec. end inspiratory (pel,rsi) and end expiratory (pel,rse) recoil pressures were then measured as the mean airway pressure during plateaus. cpl,rs was computed as tv/ (pel,rsi-pel,rse i) cpl,rs can be adequately estimated during psv using the airway occlusion method; ) during psv inspiratory plateaus are longer than the expiratory ones; ) the length of plateaus is negatively affected by the respiratory drive. foti g., de marchi l., *tagliabue m., gilardi p., giacomini m., sparacino me., pesenti a. inst.of anesth.and intensive care,-univ.of milan *dept.of radiology-sgh monza i we retrospectively compared ct scan and gas exchange findings between a group of patients successfully weaned from vcv to psv (group s = ii patients) and a group who failed the weaning (group f = patients). we selected ali patients (lis= . • in vcv mode who had available a chest ct scan performed within days from the weaning trial. a psv trial was began as soon as the patient reached hemodynamic stability and a pao > mmhg, irrespective of fie (peep < cmh ). maximum psv level was < (pel,rs-peep) measured during vcv, where pel,rs was the respiratory system elastic recoil pressure at end inspiration. psv ventilation was considered successful if a respiratory rate < bpm, an increase in fie lower than . compared to vcv, a pace increase < % of vcv value and hemodynamic stability were maintained during the next hours of psv. if any of these conditions was not met the trial was declared a failure. interdisciplinary critical care unit, regional hospital lugano-ch *surgical critical care unit, university hospital, geneva-ch objective: to assess the degree of correlation of cardiac output measured by thoracic electrical bioimpedance and thermodilution in mechanically ventilated patients with different levels of positive end-expiratory pressure (peep). methods: prospective study with ventilated patients, after head injury and with postoperative sepsis, with normal cardiac output: simultaneous determination of cardiac output by thermodilution and thoracic electrical bioimpedance performed with different levels of peep ( - - cm h ). results: cardiac output measured by thermodilution during sequential increment of peep did not vary: . + . for peep , . + . for peep and . + . l/rain for peep . simultaneously the bioimpedance device recorded a significant increase in cardiac output from . + . for peep to . + . l/mi for peep . (p < , ). conclusion: cardiac output measured by bioimpedance cannot replace the invasive thermodilution methods of cardiac measurement output during mechanical ventilation with peep. we also isolated a subset (h) of patients who had been hypercapnic (paco > mmhg) for at least days (range to days) before the end of cv. the psv trial was started as soon as pao was > mmhg, irrespective of fie and with peep < cmh and the psv level had to be < (pplateau-peep) as measured during cv. pace , pha, base excess (be) were collected before discontinuation of cv and on the ist day of psv: ) . ) weaning is more difficult in pts with head injury(p<o, ) and iss> (p<o,ol), in elderly(p<o, ) and in pts who need fi > , (p<o, ) and peep>io cm h (p<o, ). ) pts with iss> need longer duration of mv (p<o,ol). ) the mortality rate is higher in pts with iss> (p<o,o ), with head injury (p<o,ol) and in elderly (p<o, ). ) paradoxally, compliance was found to be higher in pts> years than in pts< years (p<o, ). s. crotti, p.pelosi, d.mascheroni, m.cerisara, a.lissoni, l.gattinoni. istituto di anestesia e rianimazione -irccs, milano, italia. obiectives. we investigated by ct scan the effects of extrinsic peep (peepe) on lung inflation, tidal volume distribution and regional compliance in sedated, paralyzed chronic obstructive pulmonary disease (copd) patients with dynamic hyperinflation (peep• methods. two ct section (end expiration, end inspiration) were obtained at lung base level in patients (individual analysis for each of the eight lungs) at peepe levels: peepe = cmh (zeep) and peepe amounting to %, % and % of the peep• at zeep ( . • cmh ). tidal volume was kept constant ( • . ml/kg). each lung section was divided into zones equally spaced along the vertical axis: upper (the most ventral), middle and lower (the most dorsal) zone. for each zone we computed: gas volume at end expiration (gase) and at end inspiration (gas• tidal volume (dgas=gasi-gase) and compliance (cpl=dgas/dp;.dp=plateau pressureactual peep• we also computed the lung inflation as the entire ct section gas volume at end expiration (total gase). results. at each peep level both gase and gas• were higher in the upper than in the lower zone ( we cone!ude that in copd patients with dynamic hyperinflation only the application of peepe higher than peepi produces a further increase of lung inflation, decreasing cpl of the upper zone (the more expanded one) probably by stretching phenomena, and causing dgas redistribution from the non dependent to the dependent lung zones. i. ravagnan, p. vicardi, f. valenza, d. tubiolo. p. pelosi l. gattinoni. st . anestesia e rianimazione, universita' di milano, ospedale maggiore -irccs, italy objectives: to investigate the effects of peep and ps on respiratory. pattern and inspiratory effort during ps ventilation in patients with acute lung injury or acute exacerbation of chronic lung disease. methods: pts with acute (a) (paco = • mmhg, pao /pao = . • and pts with chronic (c)(paco = • mmhg, pao /pao = . : . ) lung disease were studied in ps ventilation during the weaning phase. measuring airway pressure, esophageal pressure and gas flow we computed respiratory rate (ril bpm), tidal volume (tv, ml) and pressure time product (ptp, cmh *s/min), which is an index of oxygen muscle consumption. measurements were collected, after rain of stabilization, at and cmh ps and at two different peep levels ( and cndd conclusions: during psv: ) breathing pattern and ptp are different between a and c; ) in both groups peep does not modify breathing pattern; ) peep reduces ptp in c but not in a; ) ps modifies breathing pattern and reduces ptp in c but not in a. to test the performance of a new heat and moisture exchanger (hme): twistair, baxter. this is a hydrophobic-hydrophilic hme without hygroscopic salts. method: we evaluated the hme performance with a previously described method (i); it consists of a "lung simulator" connected to a mechanical ventilator and a flow divider, with a dry and a wet thermal probe inserted into inspiratory and expiratory limbs. on average ps level changes were associate( with opposed changes in both p . and rr. changes in p . were remarkable, homogeneous and highly significant (p<. ), while changes in rr were less pronounced, inhomogeneous and less significant (p<. ). it seems therefore that p . is a better index than rr for estimating a change in load for the respiratory muscles. recently, the lsf method has been described as an interesitng alternative to conventional tecniques used to measure total respiratory mechanics, providing, over these latter, advantages such as no need for hold maneuvers and no need for particular flow patterns. data on the reliability of the lsf method, however, are still few. methods. sets of measurements were obtained in each of ards patients, paralyzed and ventilated in cmv with constant inspiratory flow and an end-inspiratory pause equal to % of ttot. the lsf method provided data for total compliance (ctotlsf) and total resistance (rtotlsf) by multiple linear regression analysis of airway pressure, flow and volume change, applied over the entire breath. the lsf measurements were automatic and continuous, and each value used for analysis was the average of consecutive cycles. conventional measurements of dynamic.compliance (cdyn), quasistatic compliance (cqs), minimum inspiratory resistance (rmin) and maximum inspiratory resistance (rmax) were obtained by the constant flow, end-inspiratory occlusion method, each value being the average of measuremts. ctotlsf was compared with cdyn and cqs, while rtotlsf was compared with rmin and rmax. results. ctotlsf showed a high correlation both with cdyn (cdyn=. .ctotlsf+l. , r =. ), and with cqs (cqs =. .ctotlsf + . , r =. ). the average difference between ctotlsf and cqs, yet, was much lower (+. + . ml/cmh ) than the one between ctotlsf and cdyn (+ . + . ml/cmh ). rtotlsf correlated much better with rmax (rmax=. *rtotlso+. , r =. ) than with rmin (rmin =. .rtotlsf +. . , r =. ). the average difference between rtotlsf and rmin was + . + . cmh / /s, while the one between rtotlsf and rmax was +. + . , confirming the better agreement between rtotlsf and rrnax. conclusion.the agreement between rtotlsf and rmax suggests that rtotlsf takes into account both the airway and the tissue components of resistance, unlike rmin which only expresses airway resistance. the agreement between ctotlsf and cqs indicates that ctotlsf expresses the pure elastic components of the respiratory system. in the paralyzed patient, the expiratory time constant (rce) of the unit represented by total respiratory system and ventilator can be calculated from the slope of the expiratory flow-volume curve. recently it has been suggested that an estimate of this slope is provided by the ve/v'epeak ratio, ve being the exaled tidal volume and v'epeak the peak expiratory flow.the reliability of this method is still little known. methods. sets of measurements were obtained in mechanically ventilated ards patients during paralysis and cmv. measurements of ventilator expiratory resistance (rext) and of total respiratory mechanics were performed in order to calculate these reference measurements for ve/v'epeak: rcdyn=(rmin+rext)ocdyn, rcstat=(rmax+rext)ocqs, rclsf=(rlsf+rext)~ cdyn (dynamic compliance), cqs (quasistatic compliance), rmin (minimum inspiratory resistance), rmax (maximum inspiratory resistance) were obtained by the constant flow, end-inspiratory occlusion method. clsf and rlsf respectively corresponded to measurements of total respiratory system compliance and resistance by the least squares fitting method. ve/v'epeak showed a high correlation with all reference measurements, rcdyn (ve/v'epeak= . orcdyn-. , r =. ), rcstat (ve/v'epeak = . rcstat -. , r = . ), and especially rclsf (see fig the static pressure volume curve of the respiratory system (p/vst) provides valuable information, but the extensive data analysis prevents its use in clinical routine. dynamic p/vcurves are simpler to record. the objective of this study was to develop an automated method to obtain quasi-static p/v-curves (p/vqs) during low flow inflation as well as to measure resistance. preliminary tests were done in normal subjects and subjects with varying degree of lung disease. methods: a computer/ventilator interface (cvl) was constructed for control of a servo ventilator c during an automatic sequence: a) a normal breath, b) a prolonged expiration at zero peep, c) a low flow inflation of a predetermined volume, d) analysis of ventilator pressure and flow. pressure was corrected for tube resistance. airway resistance was calculated from a) and used to derive p/vqs from c). as reference, p/vst was obtained by the occlusion method. results: in non-obstructive diseases the method performed well at volume and pressure controlled ventilation. static and quasistatic compliance were virtually identical. p/vqs clearly reflected the lower inflection point and, when present, the upper inflection point (uip). in some patients uip was more evident in p/vqs, especially at an increased inflation flow rate. in obstructive diseases, the method for subtraction of resistive pressure was inadequate. conclusions: the system for automated computer controlled studies of lung mechanics based on a standard ventilator provides comprehensive information. differences between p/vst and p/vqs imply that the latter reflects also other factors than p/vst that contribute to impedance at hyperdistension. the clinical significance of the two curves remains to be shown. obiective: to evaluate the effect of combined high frequency jet ventilation (chfjv) in patients with severe respiratory insufficiency (sri). methods: in a retrospective study of the period - we analyzed patients suffering from sri who were refractory to conventional mechanical ventilation and were treated with combined high-frequency jet ventilation (chfjv). refractory to conventional mechanical ventilation was defined as a pao /fio < , despite maximal ventilator settings: peep > cm hz , fit > . . a total of patients matched these criteria, males and females with a median age of ( - ) years. seventeen suffered from severe trauma. chfjv was started following a median period of ( - ) days of conventional mechanical ventilation. prior to chfjv ventilation parameters expressed as median were the following: fit . , pao /fio , peep cm h peak airway pressure (pap) cm h . chfjv consisted of high frequency jet ventilation with a frequency of to breaths/minute, driving pressure of . to . arm, and inspiration time of to percent, superimposed on the whole cycle of conventional mechanical ventilation with a frequency of l to breaths/minute and tidal volumes of to ml. results: following two days of chfjv of patients showed an improvement of ventilatory parameters; peep could be reduced to < cm h in patients, the pap was decreased with > cm h:o in patients, fio could be reduced to < . in patients and finally the median pao /fio ratio changed from to . during chfjv patients died, of respiratory failure and due to multiple organ failure, died within two days of chfjv. the median duration of chfjv in survivors and nonsurvivors was days in both groups. conclusions: our data show that with chfjv in the majority of patients with sri who are refractory to conventional mechanical ventilatior" the ventilatory parameters can be improved. backeround and obiectives: although ventilation with peep above the inflection point (pinf) has been shown to reduce lung injury by recruiting previously closed alveolar regions, it carries the risk of hyperinflating the lungs. in the present study we set out to develop a new strategy to recruit the lung during ventilation with small vt, while maintaining peep levels as low as possible. we hypothesized that if the lung was recruited with a sustained inflation (si) to total lung capacity, recruitment would be maintained as long as the peep level was higher than the critical closing pressure of the lung, as observed on the deflation limb of the pv curve (ajrccm ; ( ) :a ). the purpose of this study was to examine the hypothesis that a strategy using si and a peep<pinf would induce less lung injury during small tidal ventilation than ventilation at the same low peep level without using a recmitment strategy in a model of respiratory distress syndrome. methods: we used a randomized protocol with groups to ventilate nonperfused, lavaged rat lungs with small vt ( to ml/kg) for hours and studied the effect on compliance and lung injury. group : peep>ping group : peep<pin f with an si, inflation to on h over sec, to recruit volume; group : peep<pinf without si; group : control group, lungs were inflated at peep<pin f, but not ventilated. results: in group and group static compliance did not change after ventilation (table) . in group static compliance fell significantly. group showed significant changes in the pv curve, which were less severe than in group . results from morphological examination are pending but preliminary results showed less lung injury in group , compared to group . conclusions: small tidal ventilation following a recruitment manoeuvre in a model of respiratory distress syndrome allows ventilation on the deflation limb of the pv curve at a peep below pinf. this strategy ( ) minimizes lung injury as well as, or better than using peep above pint" and ( ) ensures a lower peep to minimize the detrimental consequences of high lung volume ventilation. i~peep>pin~ _objectives-this report is presenting the results of the clinical study for using eeg examination as a method of the evaluation of patients ability for weaning. methods: the study inclljqles eeg examinations with fourier spectral analysis' of patients ~vith respiratory insufficiency and prolonged control mechanical ventilation (cmv). all patients have had a-rhythm of eeg before weaning. we have followed respiratory rate, tidal volume, respiratory pa{tern, end-tidal co and blood gases during weaning. results: patients had invariable eeg activity or short -waves period (till one hour). the weaning of this patients was fast arid sucsessful. other patients have had a decreasing of a-activity, an appearence of -waves for an hour and more, a short episodes of a-and e-activity. after that this patients had gas exchange and respiratory disorders with regression of the weaning right up to cmv. conclusion: eeg could be used as a method of the evaluation of patients ability for weaning from cmv. some eeg signs shows the overstrain of compensatory systems before the change to the worse of gas exchange and respiratory pattern. s. elatrous, p. aslanian, d. touchard, d. corsi, h. lorino, l. brochard. medical intensive care unit, inserm u , hopital henri mender, cr~teil, france. in vitro comparison of flow triggering (ft) systems demonstrated advantages compared to pressure triggering (pt) systems for some ventilators (puritan bennett ) but not others (siemens serve ). we studied the two types of systems in two groups of patients mechanically assisted with pressure support ventilation ( + cmh ). in the first group (pb ) the effort of breathing, assessed by the esophageal pressure time index, was significantly lower with the ft than with the pt ( + cmh .s/min - vs + , p< . ). by contrast no significant difference appeared in the second group (serve ), as predicted by the bench study despite marked interindividual differences ( + cmh .s/min - vs + , p = . ). we conclude that ) rigorously performed bench studies can predict in vivo effects, ) mild advantages can be found for the new triggering systems on some ventilators. objectives: pressore-volume curves (pv) of the respiratory system is of interest for the determination static compliance (cs , lower (lip) and upper (uip) inflection points which indicate zones of airway recruitment and overdistension. this study aimed to compare an "automated low flow inflation" method (alfi) to the reference occlusion (oc) method. the ability of the former method to identify cst, lip and uip was tested in icu patients. me,otis: ( arf and ards) sedated paralysed patients were studied using a serve c ventilator linked to a computer which automatically forced the ventilator to insufflate at a low constant flow a velum up to - ml or a maximum paw of cm h (alfi). the quasistatic elastic pressure (pel,qs was obtained by subtraction of the resistive pressure of tubing and patient and related to volume for calculation of compliance cqst. for oc tidal volumes (v from up to - ml were followed by a s post-inspiratury pause for determination of static pal (pel,st) in relation to volume. compliance was defined from the linear part of the p/v curves. lip and uip were defined from the consistent deviation of p/v data from extrapolated the linear part. ~,~ i~: in ards, mean cst was . + . and cqst . + . ml/cm h (us), lipst . + . and lipqst . + . cm h (us), uipst . + . and uipqst . + ~ cm h (us). nosocomial pneumonias (np) are frequent and often unsuspected during ards (bell, ! ). in the present study, we evaluated prospectively the onset of np during severe ards (group b of the european study). patients and methods: the charts of patients with severe ards have been prospectively recorded. a plugged telescopic catheter (ptc) specimen has been systematically performed every hours, for quantitative bacteriological analysis. the diagnosis of np was defined by a number > colony forming units / ml. results: for the patients studied, the mean saps score (+ sd) was +_ , the initial pao /fio ratio was -&-_ , the duration of mechanical ventilation (mv) was + days. the mean delay before the onset of the first np was . + . days ( - ), and the mean pao /fio ratio was +- . respiratory symptoms (purulent aspirates, new pulmonary infiltrates, or gazometric changes) were present in % of the patients studied. alteration of gas exchange was present in of the patients ( np) . a new pulmonary infiltrate was present in only np ( %). an increase of fever was noted in patients, an increase of leukocytosis > % in patients, an increase of volume and purulence of sputum in of the patients with np. the degree ofgazometric worsening (pao /fio before np minus pao /fio during np) during the first episode of np was + mmhg. excluding the bacteriological criteria of np, the number of criterias of np present was in / patients, ( / ), ( / ) or ( / ). two patients only had a pulmonary colonization (ptc: < cfu / ml) before the first episode of np. the incidence of np is high ( %) during severe ards. the first episode occurs in average:at the th day, and is the cause of a severe hypoxemia (pao /fio ) . the onset of a np may contribute to the high mortality rate observed in our patients ( %). each worsening of hypoxemia during severe ards should induce to suspect a np. respiratory system during mechanical ventilation. the me~hod quantifies the dissipative energy consumption of the respiratory system in terms of energy loss aek, inefficiency ~k~ and respiratory dissipative resistance rk~ over a given partition of the tidal volume. the method can be applied in intensive care units with no interference to ventilatory support. it allows for monitoring the combined effects of inhomogeneities, non-linearities and visco-elastic effects, that are subject to change in the respiratory system. the method is studied on pigs~ in the presence of a log-dose response curve of methacholine (mch) induced disease. in healthy pigs~ we find a mean value of energy loss, ae, of . • j/l, a mean value of inefflency, ~ of . ~= . and a mean value of resistance, ~, of . • cm h s/ . the respiratory resistance, rk, shows a variation over the partition of tidal volume with armax ---- . • . cm h s/l. during methacholine provocation~ ae rises more than five-fold up to . • j/l~ doubles to . • and t~ increases to a maximum of • cm h s/l, with armax : . • . cm h s/ . the variation in rk becomes more pronounced with higher doses of methacholine. methods: ards patients were prospectively studied. initially they were ventilated in the amv (assist mechanical ventilation) mode with the settings prescribed by their primary physician. after stabilization, ventilatory gas exchange and hemodynamic variables were determined. patients were then ventilated in the mrv (mandatory rate ventilation) mode with breaths as the target rate. in mrv the target rate is set and the ventilator autoregulates the pressure support level delivered ~o achieve this rate. after stabilization, the measurements done on amv were repeated. finally, patients were sedated and paralyzed and ventilated in cmv (control mechanical ventilation) with the ventilatory variables they had during mrv. measurements done in amv and mrv were repeated and respiratory mechanics were assessed with the constant flow end inspiratory occlusion method. results: two groups were recognized based on their response to mrv. tn group patients responded to mrv by decreasing their v and increasing the t/t t ratio. ve, vo , and aado decreased while paco increased and tda vo ume and co remained unchanged. on the contrary, in group v, vr and ve increased; ppeak and trr t remained unchanged, paco~ decreased while vo and aado increased with constant co, the pressure support level needed to achieve the target rate was much lower in group than in group ( , -+ . vs . _+ . ). obiectives : in the newly developed mode of ventilatory support ,,automatic tube compensation" (atc) the ventilator compensates for the flow-dependent pressure drop across the endetracheat tube (ett) thus allowing ,,e]ectronic extubation". the aim of the study is to investigate whether healthy subjects perceive atc in inspiration (atc-in) and in expiration (atc-in-ex) and whether atc provides an increase in subjective comfort compared with the conventional assisted spontaneous breathing mode (asb). methods : healthy volunteers (no preceding lung disease, non-smokers, male, - years)breathed spontaneously through an uncut ett of . mm id via a mouthpiece. the ett was connected with a prototype ventilator evita modified by the manufacturer (drfiger, lebeck) for atc. flow and airway pressure were measured at the outer end of the ett. three ventilatory modes, ( ) asb ( mbarover mbar peep), ( ) atcin, ( ) atc-in-ex were selected in random order. immediately following the transition from one mode to another the volunteers answered by hand sign how they perceived the new mode compared with the preceding mode: ,,better" (+ ), ,,equal" ( ) or ,,worse" (- ). inspiration and expiration were investigated separately by presenting mode transitions (in total; including ,,placebo" transitions). results : the difference between atc and conventional asb is perceived in inspiration and in expiration. atc is positively judged; asb is nega ively judged. the diagrams show mean values _+ sd of five volunteers investigated up to now. the new mode atc is perceived as an increase in subjective comfort. our explanation is that atc preserves the natural breathing pattern better than conventional asb. objectives: to determine the role of cerebral vasoconstriction in the delayed hypoperfusion phase in comatose patients after cardiac arrest. to correlate the results with indices of cerebral oxygenation and the levels of several vasoactive hormones in the jugular bulb. methods: in comatose patients after cardiac arrest we measured the pulsatility index (pi) of the medial cerebral artery by transcranial doppler sonography. the pi is a reliable indicator of cerebral vascular resistance. we also sampled blood from the jugular bulb and measured cerebral oxygen extraction ratio and jugular bulb levels of endothelin, nitrate and cgmp. the first measurement was done within hours after cardiac arrest and repeated , , , , and hours later. results: we studied patients, females, mean age , + , years. the pi decreased s!gnificantly between th~ first and the last measurement from . _+ . to . + . (p = . ). cerebral oxygen extraction ratio decreased also from . + . to . + . (.p = . ). endothelin levels were high, but didn't change during the studied period. nitrate levels varied in a wide range, but didn't change significantly. however, cgmp levels increased significantly from very low levels in the first measurement to very high levels hours later, rasp. . pmol/ml (median; th . - th . ) and . pmol/ml (median; th . - th . ) (p = . ). eighteen and hours after the first measurement we found a strong correlation between pi and cerebral oxygen extraction ratio ( r = . , p = . and r = . , p = . ). we.also found hours after the first measurement a significant correlation between pi and cgmp levels ( r = . , p = . ). we found no correlation between pi and endothelin or nitrate levels. conclusion.~; our results show a high cerebral vascular resistance in the first few hours after cardiac arrest, gradually decreasing during the next hours. this is accompanied by an initially high cerebral oxygen extraction ratio and low cgmp levels, suggesting that the cerebral vascular resistance is induced by active vasoconstriction because of insufficient cgmp levels, leading to a decrease in cerebral blood flow and a compensatory ~ncrease in cerebral oxygen extraction. objectives: sudden cardiac arrest is a major cause of mortality in western countries accounting for over half of all cardiovascular deaths. in most cases the mechanism of death is prolonged cardio-circulatory arrest due to ver:tricular fibrillation (vf) preceding final asystole. recurrent syncopes due to idiopathic vf with good neurological prognosis have been reported in patients with and without cardiac etiology ( , ). in the past measurements of cerebral hemodynamics have been repeatedly done in humans during cpr, but until today no studies of cerebral blood flow velocity (cbfv) have been reported during controlled cardiac arrest in humans not under-going cpr. it was the purpose of our study to evaluate the acute hemodynamic effects of untreated vf on cbfv. methods: after approval by the local university ethics comittee, five male patients aged - years without evidence of cerebral disease were investigated during vf while undergoing implantation of a pacer cardioverter defibrillator system (model d; medtronic| a standard anaesthetic regimen was used (propofol, fentanyl). after implantation of the automated cardiac defibrillator vf was induced by electrical countershock to test effective sensing, pacing, and defibrillation. to measure cerebral blood flow velocities (cbfvmca) the doppler probe was placed above the zygomatic arch between the lateral margin of the orbit and the ear and directed towards the m segment of the middle cerebral artery (mca). results: a total of phases of vf were investigated. duration of vf ranged from to seconds, with cbfvmc a (mean_+sd, cm sec - ) flow pattern changing from pulsatile to laminar flow immediately after onset of vf. conclusions: the underlying mechanism of the laminar cerebral blood flow observed during vf in our patients is uncertain, but it may provide insight into the prognosis of patients with idiopathic vf. theoretically, the laminar cerebral blood flow observed in our pulseless patients may provide a substantial amount of cerebral perfusion even during clinical cardiocirculatory arrest objective: to investigate whether the intensive care nursing staff can inflate more accurately a specific air volume with the laerdal resuscitation bag when they receive feedback after each inflation about the delivered volume compared to no feedback. method: icu nurses were asked to inflate a testlung model times with a specific air volume ( ml, ,ml or ml) under three different conditions (normal, decreased compliance and increased resistance) without and with feedback. we measured the mean absolute difference from the specific airvolume after each ten inflations. results: the largest absolute difference was found when icu nurses inflated ml ( ml). the mean inflated volume for this group was ml. when the icu nurses had to inflate ml the mean absolute volume difference was ml with a mean inflated volume of ml. inflating ml produced an absolute volume difference of ml with an mean inflated volume of ml. the absolute volume difference decreased when the compliance of the testlung was decreased and even more when the resistance of the used endotracheal tube was increased. when the icu nursing staff received volume feedback after each inflation the mean absolute volume difference was reduced between the ml and ml for all specific air volumes. % of the last inflations with feedback were significantly smaller than ml from the specific air volume (p < . ). conclusion: the majority of nurses overinflated the specific air volumes. the largest over inflation occurred when ml and the smallest when inflating ml. when nurses were provided with volume feedback the performed significantly better. we concluded that icu nurses are not able to inflate a specific air volume with the laerdal resuscitation bag without receiving volume feedback. feedback is desirable in order to reduce the volume trauma. objectives: a pro_found impairment in systolic and diastolic myocardial function following successful cardiopulmonary resuscitation (cpr) has been demonstrated by using langerdorff method in rats. in the present study we have investigated post resuscitation myocardial dysfunction in a porcine model of cpr. methods: ventricular fibrillation (vf) was electrically induced by alternating current applied to the ep{cardium of the right ventricle in domestic pigs. following rain of untreated vf, precordial compression and mechanical ventilation was initiated and maintained for min. electrical defibrillation was then attempted and of animals were successfully resuscitated. results: following successful cardiac resuscitation, stroke volume index (svi) decreased from prearrest value of . ml/kg to . ml/kg (p< . ), and left ventricular stroke work index (lvswi) from . to . mmhg,ml/kg (p< . ). both svi and lvswi remained depressed for another hours. these decreases were associated with increases in heart rate from bpm to bpm (p< . ). no significant changes from baseline in mean arterial pressure, mean pulmonary pressure, right atrial pressure and pulmonary artery wedge pressure were observed. prehospital resuscitation efforts c. k ppel. g. fahron, h. lufft, a. kruger, c. th(jrk, f. bertschat, f. martens dept, of nephrology add medical intensive care, virchow-klinikum, humboldt-universit~t, d- bedin, germany obiective: the success rate of prehospital resuscitation in patients with cardiocirculatory arrest in an emergency medical system (ems) may reach - % depending on the time of calling the ems, the distance to cover by the emergency ambulance and the training of the emergency physician and his staff. in the berlin ems, which is associated with the berlin fire brigade, the time between alarm and arrival at the scene ranges from - min, mean min. resuscftation is based on the advanced cardiac life support (acls) according to the guidelines of the american heart association. if resuscitation efforts fail to restore circulation, they are terminated after - min, depending on duration of cardiocirculatory arrest, pre-existing disease, age, absence of an even transient response to cpr. however, there is a lack of practical criteria for termination of cpr in individual decision making. patients: we report cases of prehospital cpr with primary asystolia terminated after - rain of frustraneous cpr efforts including highdose epinephrine and dopamine. results: after termination of cpr, the ecg monitor remained connected and showed permanent asystolia in all patients while the emergency physician completed his records. spontaneous resumption of respiration and circulation was observed in these patients after - min and cpr efforts were immediately resumed, nevertheless, of the patients died at the scene, while could be hospitalized with stable circulation. one of them died hours after admission to the icu, the other survived for weeks in a vegetative state. spontaneous resumption of circulation and respiration is most likely due to the development of extreme hypercapnia and acidosis, which -at least in some patients -seems to be a stronger stimulant of the circulatory and respiratory brainstem centers than cpr with high-dose catecholamines, conclusion: because of the legal and ethical implications of this rare phenomenon, emergency physicians should continue ecg monitoring for at least rain. after termination of cpr efforts. pulmonary artery catheterezation is used for patient's monitoring [ ]. we reported our results on such monitoring in [f.coaobbeb,r.fe enb~-kap~monorm~, ,n ,p. - ] .however not all of the received criteria assessments meet demands that are necessary for early diagnosis of critical states. here we report the data on po ,pco (mm rg),so ,ph levels in femoral [af) and pulmonary (ap) arteries blood, as well as on summary gas pressure (sgp) calculated from pe=(po +pco ) in mm hg in ap blood. these data were derived from:i) subjects free of cardiovascular pathology according to catheterization data during their spontaneous air breathing (n group in ap blood appears to be a measure of adequacy ratio between pc and sgp in ap blood during air breathing; partly its characteristics and variations ranges are presented earlier [ j. in control group it is equal to , • mm hg. tests on sgp neither exclude nor substitute conventional (pc and pco ) tests, but rather include them as a part choosing only additive characteristic -pressure. they appear to be a part of general system of human metabolism regulation by pressure (arterial,venous,intracardiac, tissue,liquor,onco-osmotic,etc ietraabdeminal pressure produces perturbations of cardiac, pulmonary, and renal physiology. this most often occurs fonowing eeliotomy for peritonitis or intestinal obstruction; bowel edema and distention prevent wound closure without unacceptable compromise of blood pressure or pulmonary compliance. a variety of temporizing measures have been reported for managing wounds that cannot be closed: ) using towel clips to reapproximate skin only, )i sewing silastic, marlex or other prosthetic grafts to the fascia to "enlarge" the peritoneal cavity, ) using loosely tied retention sutures for partial closure, ) simply packing the wound without attempts at c~osure. these techniques either traumatize the abdominal wall (complicating definitive closure), expose the bowel to damage, or allow excessive loss of fluid and heat. since we have evolved a suturelees technique which permits the abdomen to be partially closed in a quick, safe, sterile, sealed, atraumatic fashion -while providin! decompression of unphysiologic intraabdominal pressure. methods: whenever possible omentum is interposed between bowel and the open incision. viscera are covered by a layer of sterile, non-reactive plastic, placed deep to the fascia and extending we~t beneath the edges. sump tubes are placed above the plastic and covered in turn by two layers of an adhesive plastic drape which sticks to the skin and seals the wound in all directions, the patients remain intubated and paralyzed. results: we have used this technique in a total of patients, four of whom suffered from compartment syndrome. all of the latter were males and ranged in age from to . all four showed immediate physiologic improvement. all four incisions were eventually closed without complication. one compartment syndrome patient died t days later of multiple organ failure. there were no complications related to the closure technique in any of the patients. conclusions; . selected patients with abdominal compartment syndrome will benefit from decompression using this temporary sutureless technique. the technique a) is quick, safe, sterile, sealed, and atraumatic, b) minimizes loss of fluid and heat, c) facilitates eventual definitive abdomina| closure. although m. brunner m. mitllncr objectives: to determine incidence and predisposing factors for cardiac arrest occurring during the first hours after open heart surgery. methods: the study included patients who, following open heart surgery, had adequate cardiac function and in whom cardiac arrest was not anticipated. all data were prospectively recorded and analyzed. results: from / through / , pts underwent open heart surgery at our hospital. of th~se, pts ( %) (age _+ yrs) had a cardiac arrest during the first hours after transfer to icu. they were operated on for coronary artery bypass grafting (cabg) ( pts), valve replacement (vr) ( pts), cabg and vr ( pts) and aortic aneurysm ( pt). the preoperative ejection fraction was _+ % whereas bypass and aortic cross-clamp time were + and + rain, respectively. prior to arrest, they had a cardiac index of . _+ . l/min/m and were receiving . + inotropes. arrythmias leading to cardiac arrest were ventricular tachycardia/fibrilation ( pts) and bradyarrythmia ( pts). closed-chest cpr was initially performed on all pts and was followed by open-chest cpr in pts. eighteen pts ( %) survived to icu discharge. causes of arrest included perioperative myocardial infarct (t pts, %), tamponade ( pts, %), rupture of the proximal vein gra& anastomosis ( pt, %), graft occlusion ( pts, %); no cause was found in pts ( %). conclusions: postoperative cardiac arrest in stable cardiac surgery pts is relatively infrequent (- % incidence) and is associated with a high survival rate following successful cpr. perioperative myocardial infarct is the most common predisposing factor. group ~deptof anaesthesia and intensive care, semmelweis univ. medical school, buda military hospital intensive care unit, budapest background: when a cardiac arrest occurs in-hospital, the outcome can be improved by a higher quality of basic life support provided by the witnessing health care workers until the code team arrives. this basic life ~pport (bls) should include the best available method for airway management as well. since not all medical staff are ready for carrying out endatracheal intnbation, we investigated the effieacy of the use of different airway management methods during bls. methods: we have investigated the efficacy of airway management of doctors and nurses from different hospital wards: internal medicine, department of surgery, trauma, urology and gynaecolagy. comparing the bag-valve-mask, laryngeal mask and the endotracheal intubafion, we have measured the following parameters: time needs for correct application (sec.), number of incorrect applications (out of ten trial), efficacy of artificial ventilation provided by the device. we used a computerised als trainer manikin for the evaluation of the performance. total performance score was created after the measurement between - . after the first screening we held a x hours training. doctors and nurses were trained for the endotracheal intubation (group it , t ) , doctors and nurses were trained to use the laryngeal mask (group lm , lm ) . all respondent were trained to use the bag-valve-mask device. day, month and month after the training we have carried out retention study using the same method. results: we have found that the efficacy of the artificial ventilation using the above mentioned devices were poor before the training. the average after-training performance scores of the groups are presented in the table below. (bls) should be initiated by the witnessing health care professional. the cpr study introduced a multi level code system, which means bls included sophisticated airway management, early defibrillation and early epinephrine administration provided before the code team arrives. our previous studies confirmed a poor level of cpr performance and a high demand for cpr training among health care professionals. method: we established a cpr training course centre, where doctors and nurses are being trained for in-huspital basic and advanced life support. x hours of training were held. after the theoretical introduction a step-by-step training method ws used for trainees to be familiar with all sequences of basic and advanced life support. then we synthetised all separated sequences. afterwards, a r e play of rescue groups was taken in simulated situations. we also trained the multi level alarm system fur the in-hospital resuscitations. after the training all respondents had to sit for examination. the quality of performance was scored and compared to our previous results. semi-structured interviews were carried out before and aider the training among all respondents to collect information about the course. results: we have found a remarkably high interest among doctors and nurses in our cpr training courses. it was very important to use proper equipment for the training: audio-visual training facilities, computerised als trainer manikin, manual and automatic defibrillator units. the evaluation of the examination held immediately a~er the training course showed a significant higher quality of performance than before the training. the self.-eonfidence of the trainees for initiating and carrying out resuscitation had increased. their overall feeling about the course was positive and % responded the course "very useful". . % of doctors and . % of nurses claimed fur regular training facilities with als trainers, conclusion: the cpr training for health care werkers is mandatory including the training of sophisticated airway management and use of elad~l~ills~tt~r wlaa ~en ~r a~ti~atir ~nel r rm~a'*h*nr m~thnd for training will improve the efficacy, the satisfaction of trainees, therefore their compliance for further co-operation will also increase. s objectives: the effect of reinfusion in emergency surgery and gynecology. methods: we had an experience of autologous blood transfusion in patients whom was produce t an emergency surgical or gynecological interventions in occasion with break tubal pregnancies ( . %), penetrating abdominal wounds with injuries of mesenterial vessels ( . %), injuries of the liver ( . %), blunt abdominal trauma with lien ruption ( . %). in . % patients had the previous somatic pathology. blood loss volume was - ml, & the reihfuside blood volume was - ml, consisting - % of blood loss. it was needn't to fransuse donor blood in . % in further but - ml of contanined erythrocytes were frasfused for supporting of hb concentration on the g/l ( g/dl) rate at the other patients with isovolemie hemodiluttion. results: the arterial blood pressure fast stabilisation on the perfusion level had noted after reinfusion, excluding the case, when the volume of reinfused blood had conisted just % of blood loss at the patient with massive blood loss. complications have noted in two cases. one patient with slash wound, injury of arteria gastrica dextra and total blood loss of ml, has an episode of asystoly, dic (disseminated intravascular coagulation) syndrome, acute renal failure, and acute pancreatitis that we haven't connected to reinfusion. all the complications were successfully corrected and at thirty first day patient with subcapsular wound of the lien that has happened days before complicated with external rupture of the capsull & massive intraabdominal bleeding, has the hemolytical shock, dic syndrome, acute renal failure developed after reinfusion. he was died. all another have no complications. posthemorrhagic anemia had corrected rapidly than in case when hemorrange corrected exclusively by donor blood. conclusions: we consider that simplicity, accessibility, high effectiveness, quite well further results of blood reinfusion, except the case of blood reinfusing that was for time-expired out of blood vessels (more than days in our case) will promote to the wide spreading of this method, especially in emergency surgery, in massive injuries, & in disarters, all the cases of insufficiently of time for selection of lot of donor blood. objectives: study of a reaction of the oardioreepiratory system of pregnant women to i/v microperfusion of clophelinum which is known to eliminate hemodynsmic and endocrine nociceptive reactions and can be used for treating hypertensive syndrome in pregnancy and labor. methods: the following non-invasive methods were used: capnography, spirometry, oxygenography, indirect fick principle based on the circle breathing, plethysmography and integral rheography~ functional indices of cardiorespiratory function were evaluated. results: pregnant women with ~h-gestosis were examined before and after i/v infusion of i ml of . % clophelin solution, . mg/kg/hour. before the treatment intensification of carbohydrate metabolism, hyperventilation with moderate hypooapnia and complete respiratory compensation of metabolic acidosis~ increased alveolar ventilation, decreased alveolar volume, predomination of perfusion over ventilation, hypokinetio type of circulation with dominated load by peripheral vascular resistance to the blood flow was observed in this group of patients. microperfusion of clophelin imp~-oved the ventilation/perfusion ratio, ventilatory and gaseous exchange efficiency, resulted in a decrease of congestion in the pulmonary circulation, possibly owing to a decrease of peripheral vascular resistance by %, of the heart rate by io. %, of the oardial output index by . %. conclusionm: the resulted type of circulation with a decreased load on the heart both by resistance and volume allowed to improve the cardioreepiratory system function in pregnant patients. objectives: the injury severity score is a measure of severity of anatomic injuries. iss is a sum of squares of the highest degrees of the abbreviated injury scale (ais) for each of three most severity injured regions. the purpose of the study is to establish correlation between the iss values and mortality rate in older, polytraumatized patients. methods and results: iss was determined for patients. the mean iss value was . + . while the median value was . minor injuries were present in ( %) patients with iss less than , while ( %) patients with iss more than had severe injuries. increased mortality of the older patients was noted in the range - . all patients older than died while % of patients below yrs of age survived, indicationg correlation between iss and mortality rate in polytraumatized patients above yrs of age. conclusions: this mode of evaluating severity of injuries may help in triage, determining appropriate level of care and as an indicator of future outcome of polytraumatized patients. objectives : tissue hypoxia is a non exclusive cause of hyperlactatemia. other serious medical situations induce hyperlactatemia. therefore, lactatemia could be a non specific indicator of severity in patients admitted in emergency unit. the aims of this study were to examine the correlations between lactatemia with the short term survival course prognosis and the unit of hospitalisation; intensive care unit (icu) or medicine unit, in patients admitted in our emergency department. methods -lactatemia was measured as soon as the admittance, in arterial blood sample of patients which needed arterial blond gas. sixty-one patients were included during months. to assess the statistical performances of lactatemia, sensitivity (se), specificity (sp) and accuracy (ac) were calculated for the threshold determined by the youden's test (se+sp- ). results : fifteen patients were admitted in icu and in a medical unit. fifteen patients died. a group of patients had a lactatemia up to mmol.l" . in this group of patients, had acidocetosis, had asthma, had cerebral vascular ischemia, had neoplasia, had cardiogenic shock, was epileptic, had congestive heart failure, had acute respiratory failure, had septicaemia, had hyperosmolar status finally had medicinal intoxication. lactatemia was significantly higher in non survivor than survivor ( . • vs. . + . , p<o.oool, respectively), the cut point of lactatemia was . mmoll" se was %, sp was % and the accuracy was %. on the other hand lactatemia was higher in patients admitted in icu than in medical unit ( . + . vs. . • p<o. , respectively). conclusions : this preliminary results suggest that lactatemia is a good indicator of the short term survival course in patients admitted in an emergency unit. furthermore, hyperlaotemia is present in several pathology seen in emergency. objective: to determine the pattern of injury, total peripheral white cell, neutrophil, and lymphocyte responses, and the outcome of trauma patients who are leucopaenic on admission to the icu. design: prospective, descriptive study of consecutive admissions over months. setting: a -bed surgical intensive care in a teaching hospital. patients: thirty consecutive adults admitted to the icu following trauma. leucopaenia was defined as a total peripheral white cell count of < x , neulropaenia < x , and lymphopaenia < . x ~ cells per litre. measurement and results: the total peripheral white cell count was documented daily and the neurtophil and lymphocyte counts and differential percentages on days , , and . the incidence of leucopaenia was significanfiy higher in patients with gunshot wounds (p < . ) and hollow visceral intra-abdominal injury (p < . ). eight ( %) patients died. no significant differences were found in the initial mean total white cell, neutrophil, or lymphocyte counts nor in the differential percentages between survivors and non-survivors. the total peripheral white cell count increased significantly in survivors compared to those who died (p < . ) and significant differences were found in absolute neutrophil counts (p < . ) and differential percentages (p < . ) on days and . no significant differences were found in lymphocyte counts or differential percentages. conclusions: there is a signficant association between leucopaenia, neutrepaenia, and intra-abdominal hollow visceral injury and peritoneal contamination. survival is related significantly to resolution of these white cell deficiencies. these findings suggest a possible role of granulocyte colony stimulating factor in the trauma patient with intra-abdominal infection and persistent neutropaenia. amelioration of organization emergency care team in order to improve caring for urgent cases. objectives: emergency care team (ect), as integral part of health, respectively as activity of primary health protection care all acute difficult conditions which vitaly danger patients and distressed. the aim of our investigations was to indicate on the possibilities of amelioration of organization ect in order to improve caring for urgent cases. methods: in our investigations we used epidemiologicai and statistical metods all informations and matherials from terrain ects. results: the number of traumatized in traffic accidents etc. have a epidemic character. it is well known that . % traumatized died in first two hours. ect isn't enough qualified to care a traumatized on the place of accident and during transport. because that medical personnel must have an education with solid qualities. conclusions: . besides a physician specialized (vii --+ vii -~ viii gradus) in urgent medicine, it's necessary to introduce two ( ) medical technicians instead of one as is existing now ( ~ ). .the medical technicians can drive cars and one of them always, drives the ambulance car ("b" category). .the technicians have been specially educated for urgent cases (iv ~ v ~ vi). . such a new team structure should be more capable in professional sense. .we can see an importance of team-work in ects. . such teams should also be more economic in comparison with existing one. . we think, that on the general medical studies need to include a new discipline-urgent medicine! objectives: to detoxicate an organism since we have used biological sorbents: isolated from liver and spleen of human or animal cells or tissue fragments. methods: cellular dialysis ( dialyses) in patients with an acute hepatic insufficiency poisoning by hepatotropic poisons: cc , dichloethane, mushrooms -were conducted using "artificial kidney" apparatus, by means of arteriovenous shunt, formed at forearm with disposable dialyzers. hepatocytes suspension was poured into dializing circuit of dialyzer at - mg of cells per i kg of patients weight. dialysis was performed during - hrs. patients with purulent-septic states were treated as for hemoperfusion through prepared sorptional column: . ml of hemosorbent and . ml of fragmented spleen or hepatocytes suspension with the help of roller pump with the rate of - ml/min, during - min. average volume of hemoperfusion made . . conclusions: in all cases we used both native and cryopreserved biomaterial. analysis of the dynamics of clinical, biochemical, scintigraphic and us-investigastions allows to conclude that application of cellular-sorptional method of detoxication enable to prolong life and reduce lethal outcome in some severe category of patients with endotoxicosis. after infusion of diazepam ( . mg/kg),thiopentone ( mg/ kg) and vecuronium (lmg/kg),patient was intubated and mechanical ventilation was adjusted to mantain normoca= pnia. ct scan showed left parieto-occipital hypodensity with brain swelling. after admission in neurological icu,dexamethasone ( mg/ kg/die),mannitol ( .smg/kg) and diphenylydantoin ( mg/ kg/die) were administred. two hours later neurological status of the patien~ was normal and she was extubated. the risks of stereotactie radiosnkgety are related to: hemorrhgge during the latency interval;transient radia= tion effects;permanent radiatio~einduced complications; radiation induced neoplasia. no epilepsy is reported in pts with avm and no seizure before radiosurgery. in c nclusion, epilepsy can be a posmib~e delayed eompli c~t~n, ~fe~r rgdi surgery for cerebral avm. serum potassium deficiency is a frequently reported finding in the time course of acute myocardial infarction (ami). if this is also correct for patients with ami undergoing primary percutaneous transluminal coronary angioplasty (ptca) is unknown.for that reason we analysed in patients ( m., f., + y.) serum potassium concentrations on ad ,mission and directly after ptca.the reference intervall for potassium in our clinical laboratory is , - , mmol/l. although more than % of the patients with ami undergoing ptca showed normal potassium serum concentrations on admission a measurable decrease of potassium could be found in % of patients ( ) after ptca.therefore for the majority of patients with ami potassium supplementation prior to ptca can be justified to avoid electrolyte disturbances as a possible trigger factor for cardiac arrhythmias in the setting of ami and acute reperfusion due to primary ptca. objectives: diagnostic procedures are very important in the management of abdominal injures in trauma. the aim of this paper is to present our experience with peritoneal lavage as diagnostic procedure in abdominal injury. methods: we analyzed patients to whom peritoneal lavage was applied in the surgical emergency from st of january till st of december . results; in this four years period there were abdominal injures. there were blunt injures. among them in patients peritoneal lavage was applied. results were positive in patients and negative in patients. false positive finding were in patients and false negative in two patients. in patients with positive lavage there were more than , /mm red blood cells, more than , /mm white blood cells and the level of amylase was up to u/i. the gall, urine and stool were positive as well. in patients with negative lavage there were less than , /mm red blood cells, less than /mm white blood ceils and amylase were negative. conclusion: peritoneal lavage is useful and important diagnostic procedure in the management of abdominal injures in trauma. our experience with urgent surgical management of the acute gastric and duodenal bleeding s.se en md, z.milo~evi md, *s.srdi md, k.sar ev md. clinic for abdominal and endocrine surgery, institute for surgery; *clinic for cardiology, institute for cardiovascular diseases; school for medicine novi sad, university of novi sad, yugoslavia objectives: acute gastric and duodenal bleeding are very common complication of gastric and duodenal ulcer. the aim of this paper is to present efficiency of our surgical management of these acute conditions. methods: in this paper results of surgical management of patients with acute gastric and duodenal bleeding, treated in our clinic from the st of january till st of december , are presented. results: among operated patients there were females ( . %) and males ( . %). there were patients ( . %) with gastric bleeding and patients ( . %) with duodenal bleeding. bleeding from gastric ulcer were treated with the following methods: excision of ulcer with suture in patients ( . %), ulcer suture in patients ( . %), billroth i in patients ( . %) and billroth ii in patients ( . %). heinecke-mikulicz-weinberger pyloroplastica was the most frequently used in the treatment of the duodenal ulcer bleeding. bilateral truncal vagotomy was done in patients ( %), duodenotomy with ulcer suture was done in three patients ( . %) and three patients underwent billroth ii operation. we had three complicationsduodenal dehiscence in pyloroplasty. there were no lethal complications. conclusions: based on our own experience we conclude that acute bleeding from gastric and duodenal ulcer can be safely managed with urgent and modern operative techniques. dept. of anaesthesiology. emergency center of serbia, belgrade, srj b ectives and methods: cardiac contusion was evaluated by serial determination of cpk-mb fraction and co using non-invasive doppler technique in patients with blunt trauma of the chest. results: miooardial contusion was diagnosed in ( %) patients, while in ( %) it appeared unaffected. cpk-mb of % and more in comparison to total cpkwas . + , % in patients, and , + , % in pts (p< . ).c of . + . l/min in patients with cardiac contusion, measured hrs after admission at the latest, was significantly lower than in group of patients with co of . + . l/min (p< . ). conclusions: co values were significantly lower in patients with cardiac contusion and correlated with pathological values of cpk-mb fraction. objectives: extracorporal plasmophoresis (pph) was implemented by non-stop method in patients with obstructive jaundice. methods: changes of serotonin (s) and histamine (n) in arterial (ab) and venous (vb) blood were investigated before and after one-time session of pph. s and h in blood serum were determined with fluoremetric method. results: before pph the average s contents in ab and vb did not differ. after one-time pph session s in the blood outflowing lungs was % lower than in the blood inflowing. hours after extracorporal detoxication implemented the indices kept the same level. similar dynamics after pph was observed in h. before the session h contens was equal both in the blood inflowing and in the blood outflowing lunge. after pph h contents in ab was % lower compared to the vb and did not change for hours. conclusions: dynamics of changes of biogene amines shows that under the influence of pph there takes place not only mechanical removal of their surpluses together with plasm, but there sharply grows inactivating role of lungs towards ba substances, which is confirmed by reduction of their concentration in the blood outflowing lungs. this effect is probably connected with the "deplasmation" of the lung cellular elements. simultaneously lungs' cells are freed not only from plasm but from toxic adsorbents on their surface. as a result the lung cells activate absorption of the surplus number of amines from the vessel channel. it is not excluded that s inactivation is due to growing activity of monoaminooxidase resulting in deminishing of intoxication. acute pulmonary embolism: thrombolytic therapy or pulmonary embolectomy? i.lodiena md, phd, s.shevchenko md, pphd., medical university, kharkov, ukraine objectives: pulmonary embolism (pe) remains a challenging problem for diagnosis and management for the emergency physician. the aim of this work is to identify the best treatment for massive pulmonary thromboembolism. methods: during recent years patients with symptomatic acute serious pe were reffered to our observations. selective pulmonary arteriography confirmed this diagnosis in all cases. ( . %) underwent urgent surgery, of them ( . %) with cardiogenic shock and ( . %) with massive pulmonary embolism. patients ( . %) underwent thrombolytic therapy. results: in the patients who received thrombolytic therapy successful results were achieved in cases ( . %), in ( . %) patients subsequent pulmonary embolectomy was performed. mortality rate was ( . %) in the patients who underwent pulmonary embolectomy after unsuccessful thrombolytic therapy and ( %) in the patients with cardiogenic shock and massive pe. lower extremity deep venous thrombosis caused pe in % patients. pe mortality rate is repoted to be %, but all patients with cardiogenic shock and massive pe died. this very high mortality rate related to the clinical status of the patients whose condition became worse despite intensive treatment. conclusions: the results of this study show that in most cases thrombolytic therapy is an effective rapid method of treating pe. however, surgical treatment is preferable when the patients reveal adverse effects to drug therapy, when medical therapy is unsuccessful or when the patients are seriously ill with reccurent cardiac arrest. high-quality pulmonary angiography remains the most accurate and reliable means of diagnosing pe. this prospective study was conducted to investigate the serum thyroid hormone levels in traumatized critical ill patients. serum thyroid stimulating hormene(tsh),total thyroxine(tr ),free thyroxine(ft ),total tri-iodothyronine(tr ),free tri-iodothyronine (ff ) levels were measured within hr.of intensive care unit admission(first day) in multiple tratmmtized male patients(injury severity score higher than ). in fifth day the same hormone levels were repeated. tsh,et ,ft ,tr and ft levels were determined by radioimmueoassay(ria). the levels of 'i~sh,xt ,fr ,et and ft in survivors and nonsurvivors were compared with first and fifth days (table) . in conclusion, we are convinced that there was a high correlation between low ser~n thyroid hormone levels and mortality, serum thyroid hormone levels are prognostic value in traumatized critical ill patients. objectives: glucagon improves myokardium contractility, intensifies kidney blood flow, stops bronchospasm ( ), these were the reasons of investigating its effect on hemodynamics and metabolism in hypovolemic shock expermentally and in clinic. methods : in experiments on white rats with traumatic shock glucagon (novo nordisk) was injected intraperitoneally in dose rocg/kg. patients with hypovolemic shock (trauma, hemorrage) were injected glucagon intravenously in dose mg on the background of infusion therapy. results : glucagon hightened recovery indexes of glucose in rats and patients with shock, whereas in groups without glucagon hyperglycemia developed. rats with glucagon injection had double times urea content than the norm ( , + , mmol& norm - , + , mmol/i ), whereas rats without glucagon had urea content , + , mmol/ ( p < , ). osmolarity of blood plasma in rats having glucagon injections was , + , mosm/kg h , without the drug - , + , mosm/kg h ( p < , ), ldh activity - , + . and , + , ( p < , ) mcmol cec- accordingly. lethality in the group of rats without glucagon was % /n= /, with glucagon - (n = ). in patients with hypovolemic shock in minutes after glucagon administration stroke volume increased to % (sv), miocardium contractility -to % (mc), peripheral resistance of vessels ( vr ) decreased to %. in - , hrs sv increased to %, mc-to %, pvr -decreased to %. conclusion : the study provides the evidence that glucagon has an anti-shock effect, improves hemodynamics and metabolism indexes in cases of hypovolemic shock. reference : picazo j. glucagon in acute medicine : pharmacological, clinical and therapeutic implications (norwell, mass:kluwer publishing, ), p. n, vasina (t) ,n.sebbota hph ( ). dept; of acute endotoxicosis, n.v. s~lifosovslay scientific research institute of ermergency ltealth care, boscow, lk'ussia (i}. institute for problems of cryobiology and cryouledicine of the national academy of sciences of the f/maine, kl'k r-key, [ maine ( ), objectives: the investigation of isolated hepatocytes using's efficacy in patients with acute hepatic fai lln-e. methods: native and crioconsrved allo-and xeno-!mmatocztes fixed on semi;ermeable ~mbr~s were used. results: the artificial supporting system with isolated hepatocttes as metabolic ~its was. ap-plied in patients. during tl~ treatmen~ with this cytotherapz an improvement of clinic state and biochemical rates were observed even inthe first we~s. for instance, the kncreasing of glutamin acid's level in blood up to normal value and decreasing of ammontes -concentration from i ~ mmol/l down to # mol/l were discovered. ~ae diminution of ence,%halo;athy was noted too. general lethality was' equal z, there of i z concerned acute hepatic failure (/k~). conclusions: the using of sum~rting hepatic system is able to cope the ~nenomenon of ~i~. objectives: fat embolism (ee) is an important and insufficiently studied problem of the intensive care medicine. fe is clinically diagnosed in % and morphologically in - % of the victims with severe multiple skeletal injury that is accompanied by the shock. methods: during the last years patients with the cerebropulmonary form of fe were treated in the icu. the prognosis of the probability of fe development was done using the computer system "cite-prognosis" in which the triss-method, dynamic and statistical prognosis of the injury outcome~ and the values of the most severe injury in points were realized. the treatment consisted of the surgical stabilization of the fractures with the authors' design of the rod apparatus in the acute period, long-term mechanical ventilation with peep via tracheostomy, complex fluid therapy using perfluorochemical emulsions (pe), and electrochemically active solution of na hypochlorite (snh) via the central vein. results: the treatment of patients with fe gave a good result that was manifested by the complete regression of psychoneurologic and respiratory disorders. conclusions~taking into account the prognostic data~ it is necessary to provide early complex of intensive care to the polytraumatized patients. it includes the surgical stabilization of fractures, fluid therapy using pe and snh~ early long-term mechanical ventilation. dr. alexandr e. poladko, station of medical aid. kiev ukraine. objectives: the reason of investigation is to prove the necessity of beginning of the intravenous infusion of nitroglycerin before the hospitalisation. methods: from january i to june protocols of treatment myocardial infarction patients in kiev medical aid station. results: the results of treatment are better if infusion began early or prolonged during hospitalisation. conclusions: there were patients with acute myocardial infarction treated before hospital by the cardiological groups. patients were treated with the early infusion of nitroglycerin and without. the results of treatment were: in the group with infusion: mortality in the first hours % the full disappear of pain % in the group without infusions mortality in the first hours % the full disappear of pain % that's why our opinion is that infusion of n. is necessary in the treatment of the patients with myocardial infarction from the first minutes of illness. dr. gennady d. kyrzhner, station of medical aid, kiev, ukraine. object: looking for safe medication which is good for the treatment of arterial hypertension and is simple for use. we inspected the effect of prazosin in the conditions of the cail during the year. method: we used mg prazosin tablets sub lingua and measured blood pressure ones during hours. the parameters were registrated in protocol. result." one hundred patients took part in investigation. the middle age of patients was . the reason of hypertension was not taken into consideration. in two hours after beginning of the treatment we caught the reliable lowering of blood pressure in % of patients. the general condition of patients became better in - min. it was only one accident of complication during the treatment -the orthostatic hypoter~sion, conclusion: prazosin hydrochloride in the dose mg sub lingua is safe and simple for use in the urgent situations. objectives: hypomagnesemia is frequently observed in severely burned patients during the early period after injury. increased urinary excretion is insufficient to explain the magnitude of the magnesium (mg) depletion. the possibility of exudative cutaneous mg losses has been proposed, but not yet demonstrated. the study aimed at measuring the mg content of the cutaneous exudates and urine during the first week after major burns. methods: patients, aged _+ years (mean _+ sd), and burnt _+ % of body surface, were studied from day (d ) to d . serum samples were collected at do, serum and urine from d to d , and on dio, d , d . cutaneous exudates were extracted from the textiles surrounding the patients, collected over h periods from d to d , using bidistilled acidified water. mg supplements ( . to mmol/ h) were prescribed from d to dio according to the severity of hypomg (serum mg < . mmol/i). results: mg serum levels decreased below reference ranges in patients between d and d , and normalised thereafter during supplementation. urinary mg excretion was increased in patients, mean excretion being . _+ . mmol/ h until d . mean daily mg cutaneous losses, were mmol/ h, i.e. mmo; in days. large inter-& intra-patient variability: the daily exudative losses ranged from to mmol/ h. conclusions: the mean daily mg cutaneous losses after burns were larger than the urinary losses, and equivalent to the recommended intakes for mg; the addition of the exudative and urinary losses largely explained the increased mg requirements after burns. complex immunologic alterations occur following thermal injury. the activation and consumption of the complement and dotting systems are suggested to play an important role in the development of the capillary leak syndrome, tn burned patients, a generalized inflammatory reaction as well as the impairment of the host defense are considered to be the major reasons for complications, such as sepsis and multiple organ failure. in a pig model we investigated a possible protective effect of cl-inhibitor (berinert, behring). before conducting the animal experiments the human cl-inhibitor concentrate was analyzed for its inhibitory capacity on purified pig cls and its pharmacoldnetic behaviour in pigs (t / ,id ). pigs received anesthesia and analgesia and arterial, venous and pulmonary (swan ganz) katheters were placed into the carotis and jugular veins. the pigs were scalded for seconds with ~ hot water to achieve a % tbs partial-thickness burn. blood samples were taken prior and after surgery as well as , minutes, , , and every further hours after thermal trauma. two control groups (each n= ) included animals which were either scalded or not scalded and treated only by resuscitation of ringers lactat solution. besides various parameters blood samples were analyzed for complement. the pigs (n= ) received c -inhibitor concentrate at an initial dose of u/kg body weight either immediately or hours after thermal trauma (n- ), followed by three further applications (of reduced amounts) every hours. the clinical outcome as indicated by vital parameters and as well as demonstrated by reduced edema and inflammatory tissue destruction suggested a protective effect of cl-inhibitor. complement analysis revealed a faster recovery of the alternative and classical pathway activities in cl-inhibitor treated pigs as compared to the control group but only if the regulator was given immediately after thermal trauma. from these results a protective function of c -inhibitor on thermal trauma can be assumed. objectives: the aim of study was to characterise the pattern of secretion of interleukin- (il- ) and tumor necrosis factor alpha (tnf alpha) in multiply injured or not injured critically ill patients and to relate these results to their outcome. methods: blood samples of multiply injured ( ( ) ( ) ( ) il- (nis) ( ) ( ) ( ) il- (nin) ( ) ( ) ( ) conclusions: this data suggest tnf alpha is a better prognostic marker in patients with multiple injury, than in critically ill patients without injury. il- is not significantly higher in nonsurvivors of both groups. sepsis is associated with an increased production of nitric oxide (no), as reflected by a rise in plasma levels of nitrites (no ) and nitrates (no ). severe bum injury is associated with similar symptoms of inflammation like hypotension, high cardiac output low vascular resistance and increased vascular permeability so that an increased no production may be involved. the present study included patients admitted to the intensive care unit of the burn center of brussels (age : - years; burned surfaee area - %), and control (non-septic) patients hospitalized in the neurological rehabilitation unit of the erasme hospital (age - years). the patients in both groups were fed enterally with to kcal/kg/day of a standard solution. in the burn group, daring the study period, patients were mechanically ventilated, required vasopressor (dopamine) therapy, and received antibiotics; patients were discharged alive from the intensive care unit, and no patient died during the study period. plasma was sampled for no /no determinations (griess reaction) daily from day to day (n=ll) or to discharge (day , n= ; day , n= ) in the burn group, and once the control group. in the burn group, no /no levels were elevated at day ( _+ #moles/i), reached a maximal value on day ( - p.moles/l) and progressively decreased to day (fig). these values were higher than in the control group ( . :t: . #moles/l, all differences p< . ). however, no correlation was found between the plasma no /no levels and the age of the patient or the total burned surface area; burned patients who became infected tended to have higher plasma no /no levels than those who did not ( + vs - #moles/i, ns). the present study indicates that burn noa/noa (llmol**/l) injury is associated with increasedloo] [__ ] ~ no /no plasma levels, which are ao so consistent with an enhanced no pro- o duction, ao obiectives:urapidil has been recommanded for therapy of hypotension in neurosurgical patients, because it was found not to increase intracranial pressure in patients with compromised intracranial dynamics ( ). in contrast several authors reported an increase of icp after urapidil administration in patients with head injury ( ). our study was designed to determin the influence of urapidil on mean lumbar cerebrospinal fluid pressure (csfp) in awake humans with uncompromised intracranial compliance. methods: after approval by the local university ethics comittee, six volunteers (asa , male, female) were studied in the lateral decubitusposition with the vertebral column positioned horizontally. a gauge needle was inserted into the lumbar subarachnoid space at level l /l and connected to a trancducer (mx | medex inc.) for csfp measurements. the volunteers were advised to keep respiratory rate and etco constant. after a resting period of minutes basline measurements were performed including csfp, cvp, map, hr, etco (cardiocap | datex). then the volunteers were given urapidil . mg/kg over a period of minute. minutes later measurements were repeated. results: statistics: wilcoxon signed rank test, p< . significant; values: mean_+sd, si = mmhg. - _ " _+ * _+ * - _+ " _+ csfp: cerebrospinal fluid pressure, cpp: mean cerebral perfusion pressure. conclusions: during normoventilation urapidil leads to a decrease in map parallel by an increase in csfp and therefore in icp, most likley mediated by an autoregulatory dilatation of cerebral vessels. if this cerebrovascular response is suppressed by hyperventilation, no increase in icp is found despite a uredipil induced drop in map ( ). after longterm hyperventilation cerebralbloodflow is normalized. this might be the reason why the drop in bloodpressure following urapidil administration again led to an increase in icp ( background and objectives: the intestine is one of the most sensitive tissues to ischemia-reperfusion injury. reperfusion of the intestine is often associated with increase in mucosal permeability and ulceration. d(-)-iactate is produced by indigenous bacteria found in the gastrointestinal tract and mammals do not possess the enzyme systems to rapidly metabolize it. the present study was designed to determine the kinetics of plasma d(-)-iactate alteration in rats paused by acute intestinal ischemia-reperfusion injury. methods: following the anesthesia, the superior mesentcric artery (sma) was exposed and it was occluded by a micro-bulldog clamp applied at its origin from the aorta. after min of occlusion, the arterial clamp was removed and the supply area of the sma was allowed to be reperfused ( h). plasma d(-)lactate levels were measured by an enzymatic spectrophotometric assay. the endotoxin content of plasma sample was assayed by the limulus amebocyte lysate test with a kinetic modification of the test kit procedure. results: intestinal ischemia for min resulted in a significant increase in d(-)-lactate levels within the portal vein as compared to sham-operated animals. plasma d(-)-lactate levels had a tendency to further increase after reperfusion up to h. it was showed that significant elevation of endotoxin concentrations in portal vein was alread~r detected at the end of -min ischemia, reaching peak at . h post-reperfusion and decreasing gradually throughout the study period. at the end of ischemia, marked mncosai damaged such as edema, hemorrhage and necrosis was observed. there was evidence of injury to ti, e muscuiaris propria together with diffuse mucosal damage and destruction following reperfusion, particular at h postreperfusion. in addition, penetration of bacteria was commonly found in the intestinal wall at various time points following ischemia/reperfusion injury. conclusions: these data suggest that acute intestinal ischemia is associated with permeability change of mucosal barrier resulting in increased plasma d(-)qactate, which is also remarkably influenced by subsequent reperfusion. plasma d(-)-lactate may be a useful marker of intestinal injury following both ischemia and reperfusion insult. objective: to assess the clinical usefulness of two methods of intracranial pressatre (icp) monitoring: intraparonquimatous recording (icpc) and epidural recording (icpe), versus intraventricular icp (icpv) as a gold standard. we prospectively studied patients with severe head injury (glasgow coma score < ) admitted to our icu between fobmaly and december . icpv was monitored in all pativrats by means of a multipzffolated catheter connected to a water coinnm. six of patients were additionally icpc monitored by a fiber optic transducer (comma r~), and seven of patients were icpe monitored by a couplvd fluid system (plastimedr). icpc was placed homolatetal to the focal, lesion m two cases and contralateral in three; icpe was placed homolateral to the focal lesiou in two cases and contralateral in three. all three systems were calibrated at the ear level. stali~cs: correlation coefficient and lineal regression were done between icpe and icpv, and between icpe and icpv with the hourly p~rs of values obtained dttting assistontial period. results: of the six icpc -icpv studied pa~onts, we observed a correlation coef~cieut r = . (p < . ) with a regres~on line y = . + . x. four of ~hx lcpc -icpv patients had r > . when correlaliou eoet~dent was obtained indixddually. of the seven icpe -]cpv studied patients, we observed a cortelafiau ooeffioiont r = . (p < . ) with a regression line y = . + . x. corralalmu eoetfieiont was inwer than . in all seven patients. corrdation eoelfieients for levals of icpv > man hg, > mm hg and > tuna hg with icpe showed r = . , r = . and r = . respectively; and with icpe r = . , r = . and r = . . the obtained values did not change during the study. conclusdns: in our study icpe was considered a good type of icp monitoring. /cpe signiticantly infravalorates icp values. we observed a good correlatinn between icpc and icpv values in patients with high inttacramal presanre. objective: midazolam is a benzodiazepine agonist widely used for sedation in emergency medicine. few studies in animals and humans point to a direct analgesic effect of midazolam probably mediated by spinal antinociceptive receptors and/or peripheral benzodiazepine receptors ( , ). in our experience in the berlin emergency medical system (unpublished results) with anecdotal cases of extreme chest pain due to binge drinking but no evidence of acute myocardial infarction or extreme abdominal pain due to peritonitis, acute intermittent porphyria, peutz-jeghers syndrome or testicular torsion, we found that small doses of midazolam ( - mg i.v.) were much more effective in relieving pain than repeated administration of high doses of buprenorphine or morphine, which may be associated with a considerable respiratory depressant effect. the dose of midazolam required for pain relief in these patients is non-narcotic and allowed further communication on the character and localization of' the residual pain, which might be very important for the further diagnostic procedure. patients: ten patients with abdominal pain due to acute gastrointestinal bleeding, suspected pancreatitis, suspected acute porphyria, and chest pain with no evidence of acute myocardial infarction received first-line midazolam i.v. at an initial dose of mg and were asked how it affected the intensity and character of pain. results: at the chosen dose of midazolam ( - mg), all patients were responsive to detailed questioning on basic orientation, the character, intensity and localization of the pain, and medical history. none of the patients required an additional opiate. all patients stated that the pain was tolerable after midazolam alone. conclusion: our preliminary clinical observations suggest that low-dose midazolam might be an alternative to opiates in extreme pain of presumably visceral odgin. objectives: it is known that severe head injury in elderly patients is associated with higher mortality than in younger patients. it remains however to be clarified whether the preinjury pathology which is frequent among these patients, affects the outcome. methods: in an attempt to investigate this hypothesis, patients aged over years suffering from head injury, with glasgow coma scale (gcs) of or less, were studied retrospectively. twenty-six patients ( . %) had preinjury pathology i.e. diabetes mellitus, arterial hypertension, heart failure, alcoholism, parkinson's disease etc. (group a) and fifty-three ( . %) did not (group b). the following data were recorded: mortality in the i.c.u., duration of hospitalisation, incidence of infective complications and neurologic status at discharge. results: groups were comparable in terms of mean gcs ( . vs. . ) and median age ( . vs. ). the incidence of brain pathology in the two groups was the following: epidural haematoma . % vs. . %, acute subdural! haematoma . % vs. . %, intracerebral haematoma . % vs. . %, subarachnoid haemorrhage . % vs. . %, diffuse haemorrhage . % vs. . %, contusion . % vs. . % and non-visible pathology (normal ct) . % vs. . %. unilateral pupilary dilatation was found to be . % in group a and , % in group b. the mortality during hospitalisation in the i.c.u. was almost the same: % iu group a and . % in group b patients. however, group a patients had significantly more infective complications, required longer hospitalisation and had lower gcs at discharge. conclusions: the results show that the existence of preinjury pathology does not seem to affect the short-term outcome of elderly patients with severe head injury. it has however an impact on morbidity and perhaps long-term survival of these patients. the assessment of clinical development in intensive care patients with severe head injury still remains a problem. to optimize the monitoring of intracraniel prassure (icp) we rautlr~dly implant an eplduml measuring device in our hospital. the aim of this study was to prove the correlation of the icp-values with ct findings and clinical development. during a month period ( - r the icp was monitored in p~,tients ( male, female) with severe head injury by an eplclural measuring device (epldyn~/$plegelberg| the mean age was . years ( - ). the glasgow coma scale at admission was . ( - ). in all cases the device was placed wfihln the first hours after admission. the tcp was compared with physical examination, radioidglcal or intraoperatlve findings and cunlca! outcome. the average time of measuring was . days ( - ) . the traatment depended on the !cp values recorded. rising icp-valuea ~ed to radlologlcal c ntra!s by ct-scan. in case an intracranlai hemorrhage was detected and drained. the overall survival rate was . %. showed a complete resolutl n, in other . % psychological residuals like decreased mentatlon, in . % sensomotorlc residuals like cerebral nerve dysfunction and aphasia, and . % of the injured remained in a comatous status. in % of our cases the measured values correlated with clinical course and management. in cases ( . %) we observed a displacement of the icp-pevice. there was no icp induced infecllon. istituto di anestesiologia e rianimazione, universit& ,,la sapienza", rome, italy * istituto superiore di sanit& -servizio di epidemiologia e biostatistica, rome, italy objectives: acute renal failure (arf) can be a severe complication of trauma. the current incidence of post-traumatic arf is associated with high mortality . identification of risk factors and prevention of this complication could improve the outcome of trauma patients. methods: one hundred fifty three consecutive trauma patients (age . _+ . , injury severity score . + . ) admitted to icu were studied. incidence of arf was . % ( / ). arf was defined as persisteat plasma creatinine > mg/dl with or without oligoanuria . arf was defined as early when occurring within the first hours (earf) and late when the onset was after the first four days (larf). results: earf occurred in patients while larf developed in patients. age, iss, and incidence of rhabdomyolysis and acute respiratory failure were not different in the two groups. an higher incidence of multiple organ failure (mof) and sepsis ( . % for both) were observed in larf group, when compared to earf ( % and % respectively). abdominal trauma was more frequent in earf group ( % vs %). the gs for earf and larf were respectively _+ . and _+ . while in the group who not developed arf (narf) the gs was . • conclusions: gs score difference seems suggestive and can be that an abnormal cerebral activity (hipofisary hormones?) may play a crucial role on onset of arf in these patients. moreover the frequency of acute respiratory failure in the group of arf was higher ( . versus . ) than narf group. the early ipoxia in the early phase of trauma, then, may be another crucial point for development organ failure. these are preliminary data. a more exact statistical analysis must be perform to have definitive conclusions. to compare the active compression-decompression cardiopulmonary resuscitation (acd-cpr) with the standard cardiopulmonary resuscitation (s-cpr) in out of hospital cardiac arrest patients. is a controlled, randomized study. two groups of patients with cardiac arrest out of the hospitalwere formed. group i, (acd-cpr) and group ii (s-cpr). for the acd-cpr groupweusedthecardiopumpdeviceofambulnternational. asfortherest, the erc ( ) algorithms for acls were followed. the utstein style (for out of hospitat cardiac errest) was used for listing and evaluating all cases of the study. the cpr was contucted by the crew and the doctors of our mobile intensive care units (micu). we studied consequitive patients ( in group i) and ( in .group ii). demographics pre-cpr characteristics (e.g. ecg form of cardiac arrest) and procedures (eg bystanders or second tiers crew cpr, defibrillation, drugs) were quite similar for both groups. the mean arrival time of micu was min. in group i we recorded r.o.s.c. (return of spontaneous circulation) , %, death %, continuation of cpr efforts , %. while in group ii, %, %, and , % respectively (recorded percentage until the admission to the hospital). no significant difference was found in anyofthe short term outcome parameters. no complications related to the acd-cpr technique, were noted. not any significant difference between the two methods was proven (from this small evaluated sample). the results of previous clinical studies are controversial (i) . more sophisticated studies proved the superiority, in a certain number of parameters (e.g pressures, flow, etc) of the new technique although there are many difficulties for establishing clinical results. in the pre-hospital setting that is related to many parameters (speed of the intervention, effectiveness of bystanders cpr, education ofparamedics, etc.)the evaluation is even harder. the superiority ofthe acd-cpr can be proven when it is performed in almost times increased number of studied patients as w~ll as improvement of the technique could lead us to more established results. objectives; infectious morbidity is the major cause of mortality after burn injury, and is due to multiple factors. trace elements (te), which are involved in both humeral and cellular immunity, exhibit severely altered status after burns. te supplementation has been shown to be associated with increased leukocyte counts and shortened hospital stay. the trial aimed at studying the immune responses in severely burnt patients receiving normal te supplies or early large supplements. methods: patients, aged _+ yrs (mean_+sd), with burns covering + % of body surface were studied from day (d ) to d post-injury, were randomised in groups (g): g -control receiving recommended te supplies + placebo; g -receiving in addition large supplements of cu, se and zn from d to d . enteral nutrition was started within hours of injury in all patients. immunological parameters: peripheral leukocyte counts, proliferation of mononuclear cells to mitogens, cell surface molecule expression, and neutrophil chemotaxis at d and d . infectious episodes and micro-organisms were monitored until d . results: the patients' characteristics were similar g & g . the total leukocyte counts were higher in g between d and d , due to increased neutrophils (significant from d to d ). total cd + and cdlg+ cells did not differ, whereas cd + (monocytes) were significantly increased at d . proliferation to mitogens was significantly depressed in all patients. chimiotactism was not altered. the number of infectious episodes was significantly decreased in g with a mean of . _+ . infections during the first days versus . _+ . in the control group (p < . ). conclusions: the large te supplements for days was associated with a significant decrease of the number of infectious episodes. supplementation was associated with increases in total leukocyte, monoeyte and neutrophit numbers. further studies are required to determine the precise mechanism underlying the improved immune defences. objectives: evaluate the efficiency of local adsorption (la) with the use of carbon adsorbents in case of severe burns in expertment and clinic. methods: experimental studies on la were performed on a model of % body surface area iiib-iv burn in rats. a burn eschar was excised on the rd day after burn, the wounds were dressed with the gauze bandages (control) or with adsorptive dressings (la), dressings were regularly changed. clinical investigations were carried out in the course treatment of patients with severe thermal and radiation ilia-iv burn. in the dynamics of bum disease some indices of proteometabolism and intoyacation criteria were evaluated. results: the experiments have demonstrated that the application of la after early excision of a burn eschar exerts a pronounced normalizing effect on a protein electrophoregram and the activity of proteases and their inhibitors in burned tissues preserving vitality. thus, by the th day after burn infliction the activity of cathepsin d in injm'ed muscles is times lower under an adsorptive dressing than under a gauze bandage (control) (p< , ), the activity of trypsin-like proteases is . - . times lower and the antitryptie activity does not differ significantly from the normal level. the cytotoxicity of extracts of burned tissues after the adsorptive dressing application fn vivo and adsorption in vitro is - % and - %, respectively, of the toxicity of control extracts. a similar normalizing effect of la is ok~rved for an intact muscular tissue and blood serum. the dectron-spin-resonance studies have demonstrated that la allows to normalize antitoxic activity of liver and functional activity of kidneys. the application of la in the treatment of patients with severe burns have been shown to localize a region of irreversible tissue changes, accelerate rejection of a burn eschar, attenuate an endogenous intoxication level and, as a result, shorten the time for grafting of a burn wound and accelerate wound heating. conclusions: proceeding from the obtained results, we can consider la as an effective method of localization of a region of irreversible tissue changes as well as of correction of local and general metabolism failures and overcoming burn autointoxication during burn disease. c de deyne, t vandekerckhove*, j. decruyenaere, b. vaganee, v vandewalle*, f colardyn depts of intensive care and neurosurgery*-university hospital gent-belgium. jugular bulb oximetry is the first bedside available cerebral monitoring technique providing an estimation of the adequacy of cerebral perfusion. its routine use in all patients suffering from severe head injury admitted to our ic unit enabled an extensive analysis of all very early cerebral perfusion data in order to evaluate the incidence of abnormal sjo~ data (and their possible causes) in this very eady period after traumatic insult and to search for possible implications as to the emergency management. these very early data were defined as the first hours icu data and icu admission had to occur within h of traumatic insult. over the last years, pts with severe head injury (gcs< ) were monitored by jugular bulb oximetry, starting immediately after their arrival at the icu (mean of . h after trauma, range between - h). in a total of pts (= . %), jugular bulb desaturatiens (< %) were noticed during this early h period. in pts (= %), jugular bulb saturations higher than % were observed, whereas pts (= . %) revealed no abnormal sjo data ( - %) during these first h. concerning the periods with too low jugular bulb saturations (n: ), we found the following correlation ; in pts (= . %) cerebral perfusion pressure (cpp) was below mmng, in pts (= . %) paco~ was below mmhg and finally in pts (= %) we found primary intracranial hypertension. for the high jugular saturations (n: ) we found a primary intracraniaf hypertension in f pts (= %), and a pace level above mmhg in pts (= %). in all patients we could restore jugular bulb saturation within normal range ( - %) with the correct!on of the presumed causative factor. we can conclude that ultra early jugular bulb saturation data revealed a high incidence of abnormal values, with a predominance of jugular bulb desaturations, confirming once again the high incidence of disturbed and too low cerebral perfusion within the first hours after severe head injury. these jugular bulb desaturations were especially correlated to systemic causes, as a too low cpp (caused in the vast majority by primary map insufficiency, and not by intracranial hypertension) and hyperventilation were the major causes of the desaturation periods. as jugular bulb desaturatione are known to be significantly correlated to a worse neurological outcome after severe head injury, one might improve outcome by an emergency management avoiding these possible causes of jugular desaturation. therefore, extreme attention should be paid to the maintenance of an adequate mean arterial blood pressure (above mmhg?) even duhng the few time spent at the emergency department. one should be as attentive to the maintenance of normoventilation during this very early period of admission and hyperventilation without any knowledge of icp or sjo should be abandonned. recently, indomethacine has been proposed for the treatment of therapy refractory intracranial hypertension in pts suffedng from severe head injury ( ). indomethacine, a cyclo-oxygenase inhibitor, gives rise to a significant fall in cerebral blood flow by inducing cerebral vasoconstriction. therefore, its use could result in a drastic lowering of the intraeranial pressure (;cp) in pts suffering from intracranial hypertension secondary to cerebral hyperaemia and in whom the use of other cerebral vasoconstrictive drugs (barbiturates or hyperventilation) appears insufficient to control icp. for the last months, we included the use of indomethacine in our therapeutic flow chart for severe head injury management. pts revealing intracranial hypertension (icp> mmhg) and cerebral hyperaemia (sjo~> %) and in whom icp was not efficiently controlled by the combined use of hyperventilation and barbiturates were given indomethacine in a trial to control icp. a total of head injured pts received treatment for intracranial hypertension over the last months. six of them met the criteria set for the administration of indomethacine. in pts, no decrease in icp or in sjo was observed and both pts died due to therapy refractory intracranial hypertension. in the other pts, a significant fall in icp and in sjo was observed shortly after indomethacine administration. in pts we observed a catastrophic fall of sjo= even below %, indicating an extreme cerebral vasoconstriction with the possible risk of inducing cerebral ischaemia. in one of the pts, icp remained under control without further administration of indomethadne, but he died days later in multiple organ failure. the other pts, needed multiple indomethacine administrations (for pt even during consecutive days) to finally control icp. in all pts, icp was finally controlled, but only pt survived. both other pts died from systemic causes (multiple organ failure in pt, massive gut infarction in the other tat, possibly due to the systemic vasoconsttictive effects of the indomethacine administration). in conclusion, indornethacine might have a role in the treatment of intraoranial hypertension, especially when caused by cerebral hyperaemia. we observed however a poor final outcome and a threatening high incidence of systemic events (multiple organ failure, gut infarction) in those pts receiving indomethacine for icp control. therefore, indomethacine in the treatment of intracranial hypertension should be reevaluated in controlled study settings, before its routine use can be considered. untill recently, intracranial hypertension (ich) in pts suffering from severe head injury was managed in a staircase approach, with csf drainage as first therapeutic step, mannitol as second step, hyperventilation as third step, and finally, barbiturates as the last rescue step for therapy refractory ich. this staircase approach for the treatment of tch was only guided by the intracraniat pressure, and not by other parameters such as e.g. the actual state of cerebral perfusion of the concerned pt. jugular bulb oximetry provides us with the first, bedside and continuous available, estimation of cerebral perfueion. its implementation in a rigourous flow chart, based on as well icp-as jugular bulb oximetry-data might result in an altered strategy for ich management. we adopted a '~ugular bulb saturation (sjo~)-guided approach" for ich management in consecutive pts, suffering from severe head injury (gcs< ). we maintained csf drainage as first therapeutic step, but the decision for the second step was guided by sjo information. pts revealing ich and sjo=values above %, were treated with hyperventilation, and did not receive mannitol. if ich persisted, barbiturates were added as a third step. on the other hand, pts with ich and sjo= vales less than %, received mannitol administration as second step. hyperventilation and/or barbiturates were only added if ich persisted and if no cerebral hypoperfusion was discerned (sjo=> %). our objectives were to prospectively analyze this new therapeuticstrategy, as compared to the formerly used staircase approach of ich. we managed pts with ich, with an overall mortality of . % due to therapy refractory ich. all pts received standard primary care with head elevation, full sedation and normovenfilation. fer pts, csf drainage alone was sufficient to control ice of the remaining pts, pts received mannitol and pts were hyperventilated as second approach. in the third line, pts were managed with barbiturates, with mannitol and pts with hyperventilation. finally, barbiturates were used as the final rescue in pts. these results reveal a less frequent use of mannitol as only pts received mannitol, compared to the pts that would have received mannitol using the former staircase approach. hyperventilalien was used much earlier in the treatment course, as lots were already hyperventilated in the second line approach, were this was formerly exclusively reserved for the third line approach. finally, also barbiturates were used much eadier ( pts received barbiturates as third approach). we may therefore conclude to a important change in the management of ich, induced by a sjo -guided flowchart. however, future studies will have to elucidate if this new strategy for the intensive care management of severe head injury will also result in an improved outcome. obsectives: in a first series of experimental brain injury we investigated the course of brain po , icp and cerebral blood flow after traumatic brain injury (tbi), whilst accordingly there are very few data available and the mechanisms leading to secondary brain damage are poorly understood. methods: in piglets ( days old, , - kg) of either sex we produced a moderate brain injury ( , arm., msec.) using a lateral fluid percussion {fp) device. complete measurements were made before and min. after brain trauma and after , and hours including blood gases, cardiac output (htermodilution), heart rate, eeg, laser doppler flow probe (ldf} and icp values (camino), brain temp., po by a clake type oxygen electrode (licox) and coloured microspheres for regional blood flow. results: immediately after the trauma a typical "cushing"response to the icp peak up to mm hg being highly significant (before mean i mm hg, range - mm hg) could be observed: mean arterial blood pressure rose from appr. mm hg to ii mm hg for - min. in two animals this was followed by an ischemic period lasting min. accordingly icp values gradually returned to starting measures within hours; in the ischemic animals they remained at a level of about mm hg.-no secondary increase of icp could be observed, once icp dropped to starting values within hours. cerebral blood flow (ldf) fell from mean values being i before trauma to appr. zero and recovered to around . brain po started at mean values of mm hg (range - mm hg) and fell to around zero depending upon the severity of the ischemic reaction. on average values of mm hg were reached over the time course. conclusions: with our fp trauma model we can reproduce the well known "cushing"-response after brain injury; secondary icp elevations cannot be achieved, although local edema is observed. direct brain po measurement seems to be a very sensitive variable for detection of cerebral ischemia and anticipates eventually following icp elevations by far. pulmonary aspiration s,traoaras. v. sgountzos, p. agouridakis, m eforakopoulou, e. ioannidou. intensive care unit (tcu) of "kat" hospital, athens, greece ob!e=ives: the reported mortality rate after pulmonary aspiration is variable in several series. the purpose of this study was to find out the influence of preexisting disease or situation on morbidity and mortality of intensive care unit (icu) patients with pulmonary aspiration. methods: patients who were treated in icu and had pulmonary aspiration, were studied, entrance's criteria in the study, all of them obliged, were: ) suction of gastric contents from trachea during intubation, ) presense of a predisposing factor, e.g. coma. ) recent hypoxaemia or new infiltrates in xray. preexisting disease was recorded and correlated with complications and outcome. patients with glasgow coma scale , because of cerebral injury, and patients who died within days from cause other than aspiration, were excluded from the study. method of statistical analysis: chi-square test, results: one hundred forty five patients were studied. the trauma patients were and the non trauma patients . from the trauma patients, had cerebral injury and were polytreumatized without cerebral damage. from the non trauma patients, had malignant neoplasms, neurological diseases in terminal stage, old age, drug overdose, and several diseases. eighty seven from trauma patients ( %) and from non trauma patients ( %) manifested several complications (pneumonia, ards, etc), so there was no statistical difference in complications' frequency between the groups (p> , ). the severity of complications was also proportional in the groups. eighteen deaths were recorded in the trauma patients (mortality %). only deaths correlated directly or indirectly with the aspiration ( %). in non trauma patients, deaths were recorded ( %). twelve deaths were recorded in patients with neoplasms, deaths in patients with neurological diseases, deaths in aged patients, death in drug overdose patients, and death in patients with several diseases, the mortality difference in trauma and non trauma patients was statistically significant (p< , ). in patients with drug overdose the mortality was significantly lower from the other non trauma patients and the difference was statistically significant (p< , ). conclusion: the preexisting disease or situation plays a major role in the outcome of the patients with pulmonary aspiration. the mortality of patients with aspiration seems to be caused by severe preexisting situations rather, that lead to death, than from the pulmonary aspiration per se, which may be a final happening in a predetermined course. obiectives; the purpose of this study was to compare fluconazole and amfotericin-b in the treatment of fungal infections in severe trauma patients. methods: thirty five severe trauma patients who were treated in intensive care unit (icu), were studied prospectively. they all developed fungal infections, prooved with blood positive cultures and at least one of the following: fever, positive urine or bronchial secretions cultures, infiltrates in xrays. the patients were separated randomly in groups. the patients of group a ( patients) received fluconazole rag/day for days. and the patients of group ( patients) amfotericin-b rag/day for also days. compaiison's criteria were the clinical responce to treatment (fever etc), the fungal elimination (blood and other cultures), the relapses of the disease, the side effects of drug, and the outcome of the patients. as method of statistical analysis was used the chi-square test. results: nine patients from of the group a ( %), and from of the group b ( %), presented remission of fever (patients of group b had better clinical responce than patients of group a, and the difference was statistically significant, p< , ). all the patients before treatment had positive for fungi blood cultures. after days of treatment, patients of group a and none of group b had positive cultures. eight patients (from who had positive cultures of bronchial secretions before treatment) of group a. and (from ) of group . had positive cuttures of bronchial secretions after days of treatment, so positive bronchial secretions were fewer in group b than in group a, but this difference wasn't statistically significant, (p< , and p> , ): ten patients (from ) of group a and patients (from ) of group b had positive urine cultures, after days of treatment (positive urine cultures were fewer in group b than in group a and this difference was statistically significant. (p< , ). two patients of group a and none of group b had a relapse of fungal disease. in group a, no side effects were obsepced, while in group b were observed only minor side effects (small increase of serum creatinine in patients, chills and fever during infusion in patients, and hypokalemia in patients). three patients of group a and patient of group b died, because of sepsis. conclusion: amfotericin-b (even i~ short regimen of days), is superior to fluconazole in the clinical and laboratory responce and also in the relapse of fungal disease, fluconazole is superior to amfotericin-b as it has no side effects. ob!ectives: flail chest after thoracic trauma is a serious injury. it is controversial if flail chest by itself orthe concomitant intrathoracic injuries e.g. pulmonary contusion, is the cause of the reported significant morbidity and mortality. in this study we searched the influence of concomitant thoracic injuries in the course and outcome of patients with flail chest. methods: eighty five patients with flail chest after isolated chest injuries were studied, for the purpose of analysis, we separated the patients into groups, patients with isolated flail chest were included in group a, patients with flail chest and hemo-pneumothorax in group b, patients with flail chest and pulmonary contusion in group c, and patients with flail chest and hemo-pneumothorax and pulmonary contusion in group d. complications from the chest, duration of mechanical ventilation and mortality were compared in the groups. statistical comparison of results belween groups was made using chi-square and t-studend tests. results: the patients were . all patients received mechanical ventilation, twenty eight patients were ihcluded in group a, in group b, in group c. and in group d. seventy three patients manifested complications from the chest, especially pulmonary infections. there was no statistical difference among the groups as to number of complications ( twenty four patients had chest complications in group a, in group b, in group c, and in group d. p> , }. the duration of mechanical ventilation was not statistically different among the groups (the mean duration was , days in group a, , in group b, , in group c, and , in group d, p> , ). there was also no statistical difference in mortality among the groups (six patients died in group a. in group b, in group c, and in group d, p> , ). conclusion: flail chest by itself is a serious thoracic damage with many complications, regardless of the presense of other thoracic injuries, which don't contribute to greater morbidity and mortality. the present study investigated the correlation between blood lactate mortality and organ failure in trauma patients admitting between december , and july , in the icu. road traffic accidents were the most common cause of trauma in this studded population. brain damage was the main cause of mortality .nevertheless, of patients died from sepsis and multiple organ failure without significant brain damage and these deaths were potentially preventable. respiratory failure was the most common complication and was developed in ( %) of survivors and in ( %) of non survivors .we noted low fncidence of renal failure may be do to the early and aggressive ittv'asive hemodynamic monitoring and cardiopulmonary support. as part of our routine case protocol serial blood lactate levels were measured in each patient at least times a day until the valses returned within the normal range or until death. we analysed the blood lactate levels on admission, the highest value and the number of days until the first normal value (<l.smeq/i). initial lactate and highest lactate levels were significantly higher in patients with than without organ failure.( . vs . , . vs . meq/l, p< . )the duration of hyperlactemia also was higher in the patients with organ complications. ( . vs . days, p< . ). both initial lactate and highest lactate levels were higher in the non survivors than in the survivors.( . vs . , . vs . meq/l, p< . ) the present study demonstrated that not only the degree but also the duration of hyperlactemia can be related to the development of posttraumatic complications. serial blood lactate measurements are reliable indicators of morbidity and mortality following trauma. s current evidence suggest that peep only affects intracrenisl pressure (zcp)when it interferes with systemic arterial pressure, although the effects of peep over cerebral oxygenation remains unknown. objective: determine the effects of peep over icp and cerebral metabolism measured by sj , kjdo and ceo in severe head injured patients. meterial ~ methgds: patients with glasgow coma scale l at arrival, with difusse brain injury in the first gt, according to marshall criteria,lop and jo monitored, under analgesia and sedation, normoventilated with zeep, without mannitol treatment in the previous hours, normal x ray chest and within the first hours from injury, were considered candidates. peep value where increased fro~ zero to cmh , in three different steps, each one with min of duration. all date were analized on line, pmax p'p ..... p.._, from the ventilator, systemlc haemodynem]c data, cerebra perfuslon pressure (cpp), icp and sjo , in the case of hemodynamic deterioration, during the study, ppc ommhg, extra-volume were administered. if persistence, dopamine were begun or increased dosage. if no good response were obtained, patients were retired from the study. results. patients were candidates, of them were exc;uded due to haemodynamic instability, k total of completed all steps and were e~amined, men and women, age ! . yrs. at hospite; arrival, glasgow were < in patients, and > in the rest . patients mmhg at the beginning. zeep ob/ectives. critically ill patients are transpoded to an intensive care unit(icu), under conditions, which have not been systematically evaluated. therefore, we set suite investigate transportation and admission condition of these patients to our department. methods. we studied patients( females), aged (mean-..+-sd) . _ . yrs, which were consecutively (from august to march ) admitted to the icu, through the greek national emergency transporta~on service. apache ii severity score upon admission was . -+ . (range - ). the following data were evaluated: ) number of medical departments, where health care was provided until final admission to the icu, ) ambulance transportation conditions, ) catheters and tubes inserted before admission, ) vital signs upon admission ) information provided by referring physician (scored on a to scale: history, electrocardiogram, chest x-ray, laboratory data, drug therapy already administered), ) comparison of the state of the patient described by referring physicians, to the actual state u pen admission. resu/ts. one to four medical departments had provided health care before the palient was admitted the icu ( : . %, : . %, : . %, : %). thirty/ ( . %) patients were escorted by a physician. twenty-six/ ( . %) were transported on oxyge n, fio (mean__.sd): -+ %, pao : . -+ . mmhg. five of the remaining , for whom no oxygen was provided, had pao : . -+ mmhg. twelve/ ( . %) were intubated and ventilated during transportation. thirtyfour/ had a peripheral venous line, / had an arterial line, / had a nasogastdc tube, / had a urinary catheter. eleven/ were sedated and / were paralysed. three/ were on inotropes. vital signs upon admission were: arterial blood pressure, systolic . -+ mmhg, diastolic -+ mmhg, heart rate -+ bpm, temperature . -+ cc. patient information score was --. . . the actual state upon admission was found substantially different, as compared to the description of the referring physician, in / ( . %) patients. conclusions. we conclude that several aspects of the greek national emergency transportation service to an icu should be reevaluated and further improved, i. e. ventilatory support, adequacy of information provided and accuracy of prior description of the patient's state. a new perspective must be applied for critically ill patients transportation since . % of the patients were evaluated and treated in more than one, medical departments, mostly primary care, before they were finally admitted to our icu. dclhb is a human derived hemoglobin molecule that has been cross-linked to stabilize and permit heat pasteurization to remove residual proteins and inactivate viruses. dclhb is mixed with a lactated electrolyte solution to yield a total hemoglobin concentration of log/dl objective: to present an overview of four recently completed clinical safety studies of dclhb in the u.s. and europe, and to discuss the properties, actions and potential indications for dclhb. method: patient populations in the four studies included males and females ranging in age from to years. dosing ranged from mglkg to mg/kg. the controlled randomized safety studies were conducted in chronic renal failure patients, surgical patients undergoing total hip replacement or abdominal aorta repair and in hemorrhagic hypovolemic shock patients. these very diverse patient populations allowed safety evaluation of the product in patients who were generally elderly, often hypertensive with some degree of cardiovascular disease, and receiving medications for treatment of other conditions. results: over patients received dclhb in the four:studies. no product related sarious adverse events occurred during the clinical trials. conclusion: results from phase itll safety studies of dclhb in patients undergoing chronic renal dialysis, abdominal aorta repair, or total hip replacement and in patients in hemorrhagic hypovolemic shock, indicate that the product was well tolerated in these distinct populations. although these studies were designed to evaluate safety, the data suggest clinical benefit. follow-up efficacy trials are indicated. prehospital emergency services represent the extension of emergency care into the community and constitutes the manpower, communications, transportations and facilities used to provide care for patients outside hospital. one of the main points of the system is how to decide the hospitalization of patients and what kind of facilities to provide : emergency medical service, fire brigade, locat general praclitionner or ambulance officers. objectives : to realize guidelines for using the prehospital emergency medical service in case of patient'calls outside hospital. methods : from st june to july , all the calls for emergency care were analysed using a questionnaire of items (origin of the call, responses to the questions of an emergency practitionner, kind of emergency service provided and the issue of the patient). after taking account of the appropriatness of the decision, statistical method used was a logistic regression. results : calls were analysed. the criteria, for prehospital emergency medical service using, given by the logistic regression were as following : existence of a call for emergency, thoracic pain, dyspnea, seizures, cyanosis, drug intoxication, fall of the patient, fracture, age, the state of consciousness and the neurologic reactivity. the minimal and maximal predictive values of the model given by the logistic regression are respectively % and %. the performance of the model is %. conclusion : it seems possible to help medical decision of emergency medicine by using only some easy criteria and a predictive model. (italy) objective: to evaluate the incidence of blunt carotideal injury (bci) in patients admitted to our icu after head injury. methods: we reviewed the medical records of all patients diagnosed to have a bci. at admission, the severity of trauma was assessed either with glasgow coma scale (gcs) and with ct scan. bci was demostrated by doppler ultrasography (us) and by angiography (ang). results:since may to april , patients were admitted to our icu with bci ( m, f, age + ). a history of direct trauma was present in patients. admission gcs was in all patients, and was associated with hemiparesis in of them; the last became paretic hours thereafter. two patients had concomitant injuries (a homoiateral clavicular and a controlateral zygomatic fracture, respectively). the initial ct scan was negative in every patient, and showed signs of ischemia after a variable timespan ( - days) after the onset of the symptoms. the bci was diagnosed with us and ang, which demonstrated a thrombosis of the internal carotid artery (ic). in two patients, an intimai dissection was also present. three patients were treated with heparin associated with antiaggregating agents and were discharged alive. the last patient was referred to our icu after the development of a massive hemispheric infarction, and died three days after the admission. at necropsy, the ic thrombosis was associated to an extensive homolateral extra and intracranial venous thrombosis. conclusions:the presence of focal neurological signs despite a negative ct scan should address the diagnosis toward a bci, thus implementing the diagnostic workup with us and/or ang. tab i: distribution of l~tients (%) in the groups the outcome were monitorett results were sabmitted to statistical analysis using a continence table x in z test. res.cl~s: of patients were submitted to thrombolysts and died. the higher incidence of bracb, ar~lhmias (ii degree gg p t e and av block. i degree av block. avsb . <ii. sinus arrest) that requited the insertion of avsc . <cl temporar~ pace-maker was recorded in group a b vs c . ns in % of the cas ~. the rapid recognition of life tab li:;~ test. threatening conditions suggests the monitoring of v r-lead r b' in the course of inferior ami. the authors report their own expirience in application of ringer lact.(rl)and , %nacl/ %dextran . methods:in polytraumatized patients with developed hae morrhagic shock,injures of the chest(qg)and abdomen(q ) prevalid.replacement of the volume loss egan in institutions of general medicine,frequently by rl and dextran or haemaccel.after receiving necessary medical aid,polytraumatized patients wer transported to mma by helicopter,continuing replacing of circulation volume by the same solution. results:average quantities of the solution dministered ~o the injured wer~ - ml.a group of the inoured which,after the admission to mma was resuscitated by adml nistration of the , %nacl/ %dextran @(groupii)( -sml/kg observed to the final surgical management,had statistically higher map(increase of % in relation to admission), cvp(average increase of , cmh~o),diuresis(averagely omi after min.),better gas ~nalyses and acid-base status in relation to the group which was administered only rl(groupi)(increase of the map of q %,average increase c~ of cvp , cmh and average diuresis oml after omin). total quantity of the administered solutions was significantly smaller in the groupii( ml: ml).the only ob served complication was hyperhatr~f~a::and~moderat~hyper osmolerity of plasma which disappeared within hours. the quantity of replaced blodd was considerably smaller in the groupii(qooofnl: ooml).in the group i interstitial pulmonary oedema was observed in two patients(qo%),while: in the group ii no complication was observed.coagulation i disorder and hypotension were not recorded because of the fast infusion of hypertonic/hyperoncotic solution in the groupil as the infusion of , %nacl/ %dextran lasted minutes. w.scherzer(l~,k.lechner( ),r.simon( ). ll)dept.anaesthesiology,trauma hospital,vienna-meidlin !( )neurotraum.rehabilitation center,vienna-meidling both austrian workers'compensation board,vienna,austria what we usually call"unconcious" means only that the patient is not able to interact in any kind of way.experiences in intensive care medicine (robinson, ) ,in general anaesthesia (bennet, ) and with evoked potentials show,that unconcious patients are not automatically unhble to process and recall information.this implicates a challenge to start the efforts to restore the traumatica-!ly desintegrated brain function as early as possible in the acute phase ia (zieger, ) .we present a method to ~repare the patient for the rehabilitation goals of the postacute phase ib,the phase of stabilisation ii and of rehabilitation iii within one concept. to achieve sensory stimulation in phase la we use: attempt at some kind of dialogue by speaking to and tou-ching the patient,to make him experience his body limits, ~acio-oral therapy by ice application,tast and smell pro vocations and trials of feeding,early adaption to circadian rhythm and guiding the patient in every-day-life-ac-tivities e.g.:in the brushing of teeth,washing etc. to achieve motor stimulation and orientation in terms of ~-ace,time and gravity in phase la we use: avoidance of perceptual impairment as produced by air-:sack-beds or habituation to supine position,using method~ according to affolter( ) ,basal stimulation (bienstein, ) , bobath-therapy( ) and facilitation of a physiological moving pattern(pnf)according to knott( ) . conclusions: by integrating all these measures in the ~herapy and nursing even in the acute phase la one prei ares the comatose patient for multisensory stimulation nd motor training and all other rehabilitation activities in the following phases of therapy. s objectives." measurement of cardiac output (co) and stroke volume (sv) requires insertion of a central venous catheter and is associated with a considerable risk for complications. non-invasive methods for determination of hemodynamic parameters have been introduced recently. one of these methods is the aortic modelflow program, which provides co and sv continously using a three-element windkessel model. the aim of the study was to evaluate the accuracy of the aortic modelflow program in critically ill patients. methods: patients (mean age: ) admitted to the emergency department after cardiopuimonary resuscitation (n=ll) and for myocardial infaction (n= ), acute congestive heart failure (n= ) and anaphylactic shock (n=l) were included to the study protocol. after stabilization all patients received a swan-ganz catheter (baxter~; edwards swan-g-anz) via a central vein. co and sv were measured by the use of a cardiac output catheter and injection of rrd ice-cold glucose % non-invasive cardiac output measurement was done by using the continuous cardiac output software package modelflow (tno; portapres| results: overall, paired measurements were used for the evaluation of the accuracy of non-invasive obstained sv and co. mean values, standard deviation and range of co and sv evaluated by invasive and non-invasive methods are summarized in the aortic modelflow provides reliable hemodynamic data in critically ill patients. it may be a useful alternative due to its non-invasive approach and continous measurement. objectives: to determine the feasability and accuracy of a rapid urine screening test (triage tm, merck-diagnostika) in an emergency department. methods: prospective analysis of the triage tm testkit (tt) in patients admitted because of suspected drug abuse during an observational period of months. the tt is a eompetitve immunoassay which gives qualitative results within i minutes for methadone, benzodiazepines, cocaine, amphetamine, opiates, barbiturates and cannabis. urine samples were analysed with the tt and compared to the results of a enzyme-lihked tmmuno-assay (el.a) in our labratory (gold standard). results: during the study patients were enrolled, in of these patients substance abuse was proven by tt and verified by eia. we recorded no false positive or false negative results for benzodiazepines, barbiturates, opiates, cocaine and cannabis. two results were false positive and one false negative for methadone; one result was false negative for amphetamines. the triage-testldt had an overall sensitivity of . and specificity of . . conclusions: the triage tm testkit seems to be a a useful rapid test device in addition to quantitative tests for drugs of abuse in an emergency department. objectives: the purpose of this study was to evaluate the influence of several factors of the renin-angiotensin-aldosterone system on blood pressure response in patients with hypertensive crises. methods: patients with systolic blood pressure > rorohg and diastolic blood pressure > nunllg were included into the study. prior to treatment blood samples for determination of plasma renin activity (pra), angiotensin converting enzyme (ace), angiotensin ii (ang ii) and aldosterone (aldo) were collected. all patients received rog enalaprilat intravenously. success of treatroent was defined as a reduction of systolic blood pressure below mmi-ig and diastolic blood pressure below mmi-ig within minutes after start of treatment. results: patients were included in our study, ( %) patients responded successfully to treatment. mean arterial pressure decreased in responders by . mmhg and in non-respenders by . mmhg (p< . ). responders and non-respenders differed signii'icantly concerning pra (p= . ), ace (p= . ) and ang ii (p= . ). . . the extent of blood pressure reduction correlated positively with the pretreatment pra and ang ii concentrations (correlation coefficient for pra: r= . ; ang ii: r= . ). conclusion: our data confirm that in patients with hypertensive crises blood pressure response to ace inhibition is mainly determined by circulatory pra, ace and ang ii. as the extent of blood pressure reduction correlates with pra, ace-inhibitors in patients with suspected high renin status cannot be recommended, as excessive blood pressure reduction, which carries a considerable risk for further organ damage, may occur. f. staikowsky, n. grillon, f.pevirieri, c.jedrecy, c. zanker, f. michard, a. haft medical emergency department. hospital bichat, paris epidemiology of acute intentional self medications-poisoning (smp) in france is especially known by data of poison control centei,s and intensive care units (icu). the purpose of this study is pro~,ided characteristics of this problem in a med for adults. method: july to june , files of patients consulting to the ed for smp have been retrospectively analyzed. results: patients, women and men, . + years old (range - ) have been admitted for episodes of smp ( % of all consultations) whose relapses during the period of study. psychiatric disorders, drug addiction or hiv patients was found for respectively . %, . % and , % of patients. the interval of time between the ingestion and emergency consultation was noted for % of smp ( + min, ranges - ). the involved products name was known in totality in % of cases with an average number by episode of . + drugs (ranges - ). the most often, ( %) or ( %) different products were interfered. the nonbarbiturate psychotropic drugs accounted for . % of the products (benzodiazepines %, antidepressants . %, neuroleptics %, carbamates . %, imidazopyridines . %, cyclqpyrrol nes . %). analgesics and nonsteroidal antiinflammatories represented . % of all drugs, anticonvulsants . %, cardiovascular drugs %, antiinfective agents . %, drugs against cough . %, muscle relaxants . % and antihistamines h . %. the benzodiaz pines were present in episodes, alone in episodes. in . % of cases, there was a simultaneous intoxication with alcohol. the processing consisted of gastric lavage in . % of cases, activated charcoal in . % of cases, flumazenil in . % of cases, naloxone and acetylcysteine in . % of cases; orotracheal intubation was performed in patients. admission in hospital was effective for patients, in medical ward (n = ), psychiatry (n = ) or icu (n = ); no fatal case was recorded. conelusion: smp to ed are often benign. the benzodiaz pines are the most often incriminated but the new anxiolytics and hypnotics (imidazopyridines and cyclopyrrolones) take a growing place. the latsion burn center of athens. its planning constructive and functional refinements j. ioannovich, a. petalas-vourekus, d~ serbetis, h. carsin a bed burns unit is under construction following a donation to the general hospital of athens. the plan of the unit, covering a surface of approximately . m is based on the principle of three identical bed satelites which may function totally independent from each other. in the center of the unit the common facilities are installed, like operation theatres, storage rooms etc. this new modification in the plan of a burn unit is presented in this paper. the advantages from the fucntional, administrative and medical point of view are discussed. tiffs anisotropic conduodon could favour the ocenrence of a circular movement of the impulse that leads to tachyeardias by reentry. purposes of this work were to study, with the help of epicardial mapping, the influence of a trieyclie antidepressant, clomipramine (c), on the conduction velocity longitudinal (vl) and transverse (vt) to myocardial fiber orientation and on anisotropy (a = ratio vl/vt), and their modificutions by the sodium bicarbonate ( ). method: a plaque of electrodes, positioned on the left anterior ventricular wall of anesthetized dogs, allowed to deliver, thanks to central electrodes, programmed electrical stimulations inducing vcuttienlar complexes, and to collect them. each entailed unipolar dectrogram was processed by a computer system that drew the isochrones and a map of activation allowing the calculation of v. the c was infused ( . mg/kg/min iv) during rain; at t , dogs received the b until the retuni of qrs to its initial value fro). a lengthening of qrs of at least % of its value at to was demanded before the administration of b. results: dog was excluded because of an.~nsufficient prolongation of qrs before the administration of b. all values (map : mean arterial pressure, i-ir : heart rate, qrs andqt intervals, v) differed significatively ( < . ) compared to values control fro)except qrs at t . the b ( + ml/kg; ranges . and . ml/kg) modified no studied dements outside of the ( }rs. to ti t t t t t a , + , , + , , + , , + , , + , , + , , +- ,~ conclusion : the c slowed v l and v t without modify the anisotropy. the b did not modify the v of~conduction while the qrs prolongation was corrected. the c acts as a class i antiarrythmie drug on the inward sodium current during the phase of action potential; the gap junctions have shown to be important in the conduction and an action on the gap junctions such as a modulation of the junctional resistivity, can not be rule out. is the doctor a heroe ? p. t.schies~.he, t. bauer, m. seyr dept. of anaesthesiology and intensive care, aokh krems, austria objectives: helicopter emergency services (hes) are getting popular more and more. the results concerning outcome are encouraging. however, some recent accidents with dead or badly wounded hescrew-members have shown the relatively high risk for the crews. therefore we were interested to eval ate the motivation of physicians to participate in a hes. this survey was designed to investigate current concerns about safety and motivation of doctors on emergency call. methods: a questionnaire was sent to doctors of the austrian emergency system. the survey consisted of multiple choice questions and subjective scoring tables from (--full agreement) to (=disagreement). overall, "/. of the active emergency physicians participated in the survey. results: . % of the doctors assume the system is basically safe, experienced doctors tended to have less trust in safety. only % would not hesitate to go into action by dark. . % stdctly refuse night flights to accidents outdoors. although defibrillations are assumed to be safe dudng flight, only % would do it. . % of the doctors would rather stop flying. the most common reasons for ,uitting were wish of family and fear of an accident. . % conclusioq: short transportation times help to avoid trauma related stress, pain and shock-induced organ complications. therefore the physiologic and economic advantages of hes are undebatable. however, the survey data indicate a considerable concern about safety of the medical personal in a hes. crash landings within less than years with deadcases and badly wounded crew members in a small country like austda make desire for safe flying conditions understandable. obiectives: to evaluate the clinical usefulness of trachlight. methods: trachlight is a new device facilitating endotracheal intubation. a stylet with a lightprobe is inserted into the endotracheal tube. intubation is guided by the light glowing through the neck tissues, thus rendering direct laryngoscopy unnecessary. intubation using trachlight was studied in patients (age - years). the indication for intubation was elective surgery in patients (asa i-ii) and emergency intubation in patients. in the elective patients, anaesthesia was induced with thiopentone supplemented with fentanyl, and intubation was facilitated with vecuronium. the cause for intubation in the emergency patients was dyspnea in , cardiac arrest in , trauma in, and unconsciousness due to drug overdose or seizures in patients. intubation was facilitated with medication in patients. results: of the elective patients, ( %) were successfully intubated. six patients ( %) needed two attempts before successful intubation. the duration of intubation exceeded seconds in patients ( %). of the emergency patients, ( %) were successfully intubated. six patients ( %) needed two attempts, and the duration of intubation was more than seconds in patients ( %). in % of all patients, intubation was assessed as easy. no or insufficient glow, prolonging intubation or necessitating two attempts, was noted in patients ( %). oesophageal intubation occurred in patients. conclusions: trachlight may be a valuable adjunct for intubation in varoius settings provided that adequate training is provided. a learning curve was found to exist. objectives: to compare enoxaparin and standard heparin in cavhd and calculate the value of laboratory controls in the treaanent. patients and methods: twenty patients needing dialysis for acute renal failure participated in the study. the main exclusion criteria were massive bleeding or a thrombocyte level < x e /i. in each treatment the same type (av- , fresenius ag, germany) of a polysulfone capillary haemofilter was used. the study scheme consisted of two consecutive four-day cavhd treatments, one course for each type of heparin. the order of heparin administration was counterbalanced between patients. the standard heparin was given as a continuous infusion aiming at an activated coagulation time between and s. the initial enoxaparin dose was rag every :th hour intravenously, but was modified by any signs of coagulation in the dialysis blood lines or bleeding complications. results: the dialysis treatment was adequate in both treatment modes, with mean blood urea levels . and . mmol/l respectively (ns). the bleeding complications were moderate and similar in both treatment modes. the mean life-span of haemofilter using enoxaparin as an anticoagulant was some longer than using heparin ( . + . h versus . + h, ns). the mean aptt-levcl during heparin treatment was s and during enoxaparin treatment s (ref. - s). the mean daily dose of heparin was nag, that of enoxaparin lg mg. the mean anti-xa activities were . u/mi and . u/mi, respectively, reflecting a better bioavallability of enoxaparin. conclusions: both anticoagniation modes were equally effective and well tolerated. the amount of enoxaparin needed for a proper anticoagulation was, however, less than half of that of standard heparin. the changes in aptt level were too slight to make its use possible in controliing the dose of enoxaparin. the use of enoxaparin seems to be rather safe in cavhd even without laboratory controls. the adv~ucea in the management of computerized data of an intensive care unit have been petalled to the clinical advauces and the increasing sophistication of methods of diagnosis fop the clinical application an therapy. this has led our unit to design and develop a computational system called timbu which is used to help physicians assist patients. among its various uses, this system has a software for the hemodynsmic control of a critic patient. this program was carried out to get as fast as possible the hemodynamic data of the patients in an intensive care unit. as an example, we can mention that when we load data obtained through direct measurement from the monitors and the lab, the program calculates parameters that guide, intelligently, to the diagnosis and therapeutic behaviour of the hemodynamic problem through screen messages. the validation of this program in the unit of intensive care has demonstrated that its use allows a more efficient handling of the patient with serious hemodynamics and respiratory disorders. ohieetlve: traema is a heterogeneotm 'disease' that ecatr~ a~"o~s all age ~oupe with v~ying degrees of severity. this imerogeneity has made the di~e, trmma, diflkaflt to r the ehn of this stady wa~ to assr the fitaen of saps in ibis popeleties. methode: in order to compute the ~ probability, a model derived from logistic regression w~ developed. meam'e of calibration (goodaess-of-fit stetislj.r and di~'riminafion (roc ou~e) were adopted in developmm~ and validetlon set randomly taken from a database of pts eeeseemivety admitted in icu (arohidia). ~ witho= salm, p~ yom~ am is yam, with los ~horter thma hotam wore exr fa'om thi~ mmly~ir thi~ model v~s then evahmed on the ~per ~mbgro~ (i.e., trmma pts). if'it did t~t fit the data well ~, new model wm developed rer the logit only on trm=~apm. reims: data were availabte for pts during aperiod of three .y~m , treama pts were . %), teats of calibration iadioaled probability model did mot provide m adequate refle~on of the mortality ezperieace in pm with ireutae, being the observed mortality lower flma the expected (figm'o). a aew model was then variable. this oastomized model fit~ the de~t of trmara pts very well (g =- a p> . ; roc = , ). the di:lferencea between the two modele were evident. conclusion: this ltudy shows that mortality in iramna pts is over wcfe~d when ~se~ed by menm of saps. however the r mode! meets high standmcd in terms of calibration mid dil~'iminat'~o~ ']"he advaatage of ~imd models meaas the colleotion of the ~ set of variables for all pm admitted in icu e~einat the ase of diasma specific ~oring syatex~. ("sl"): effects on cardiovascular and hemostasis systems (cvs, hss) a.oborin~ph, ~.~yndiuk~ph, b.kondratsky ~pt. of'""su~gery and transfusiology, research institute of hematology, lvov, ukraine objectives: great interest has been shown recently in the use of hoss for the initial resuscitation of hypovolemic shock. methods: the study was carried out in dogs -~h hs was induced by jet momentary hemorrhage (h) from a. femoralls (the bloodloss volume made . + . ml/kg). the treatment was begun after .u+o. hrs of h. "sl", created on the basis of-sorblt and natrium lactate ( mosm/l) was injected into v. femofalls at the dose of io. ml/kg. results: it is established that before treatmen-~rterial blood and central venous pressures (abp, cvp) diminished to . mm hg and - . + . cm h (p .o ), while heart rate (hr)-increased to . + . per min (p<.o ). by this the indices of ~latelet counts (pic) and plasma fibrinogen (pf) lowered by . % (p<.i) and . % (p~. ), while fibrin degradation products (fdp) enlarged by . % (p~ . ). after - min of treatment termination abp and cvp increased to . + . mmhg and . +o. cm h (p<.o ), and ~[r diminished to t . + . per min (p>. ). at the same time the indtces of pic and pf enlarged by . % and . % (p>.i), while fdp diminished by . % (p>.i). one of dogs survived. life duration of the other dogs was . + . hrs. conclusions: the obtained data are ~he evidence of normalizing influence of "sl" on cvs and hss, and allow to recommend it as a mean of initial resuscitation of hs in clinic. oblectives: we prospectively studied icu patients with severe head injury (hi), which cerebral lesions monitorized with sjo through opljcal fiber and the cerebral flux with tcd. methods: since january until june , we collected ht admitted to the icu, and of them monitorized with optical fiber in the right jugular bulb and tcd. all patients needed mechanical ventilation related to gcs <__ , with ct in admission (classifing lesions according to marshall and al.) . we related the final results to the evolution of sjo and tcd, with other monitorizing methods like gcs, ct and icp. ~sults: conclusions: in patients with gcs _< , sjo is useful to evaluate the evolution towards vegetative state, still more in cases with ct type ii in admission and higher apache ill. elevation of icp implies an evolutive nsk to brain death and data of tcd is a good indicator of brain death, the complete monitorization of these patients can improve the therapeutic control of this neurologic problem, , ( m, f) , (m. age: + years), divided in two groups (a and b) under specific criteria(tremor and/or fever during admission in i.c.u., or not). the injury severity score was > in all studied patients. tbe group a ( m, ") had no tremor and/or fever on admisskm, while em group b (tin, the above criteria were ix)sitive. bhx~d samplings were taken - hours after accident and - rain. after admisskm in i.c.u. micro-eli~ method was used for measuring cytokinc-levcls. statistic analysis was performed by studcnt-t test. as control group, healthy people were examined. _resu!_ts-il-lct, il-ii~, il- and tnf-tt levels were similar to control group levels in both groups a and b. i!,- and g-csf levels were found increased in both groups (p< jxjl), while il- levels were statistically significant comparing to group a. in con_tin_skin, during immediate post raumatic period,proinflamatory cylokines il-i~, il-i~ and tnf.-ct, produced in an earlier stage than ,. , cannot be detected,whereas .- was increased significantly, especially in group b. g-csf was fimnd in increawal levels in both gr(mps, without statistically significant difference between gnmps a and i|. objectives-l~valantc proteolitic activity, disorders in" eariy, period after combined trauma and p(~.ssibilit, i' of their correction by injection of proteo[ysis inhibitors contrycal and s-fto~:nracil in combination with driving an isotonic snlu~ion of sodlum chloride and polig[ucine. methods: biochemicai studies of proteolitic activity in dogs with limited deep burn and acute bloodloss, . result:s: in case of deep % burn, cornplicated by bloodshed the of blood grows at - times. it; is the restdt of the pancreas glandischemi demage, caused by the centralised circulation of blood and intensifies the deviations of haemodiaamics and albumin exchange. the degree of endogene intoxication by mean mofecular peptides which are the products of albumin decay reses to %, and % in hours. in hours after the trauma the-process is accompanied b ! , % lower inhibitory activity of blood, where as at the peak of the trauma it was , ~ higher. that proves the nnfavuurahle process of the shock in case a combined trauma. conclusion: the vein injection of 'proteolysis inhihitotz cnntrycal and -fforuraei[ in cumbination with driving an isotonic solution of sodium chloride and p.dligh]cine to refill lhe loss of blood helps to lower at times the profeolitic activity of blood. but it still remains above the initial level. the degree of endogene intoxication lowers at times; [ emodinamics aml albumin exchange stahilised. objectives: nimodipine, a known calcium antagonist, has been shown to dispose a beneficial effect on patients with subarachnoid hemorrhage, but its efficacy on traumatic or spontaneous intracerebral hematoma has not been justified. therefore, we studied the effect of nimodipine on the histopathological changes following an experimental intracerebral haematoma in rabbits. methods: twenty-three new zealand albin rabbits of both sexes, weighing - , kgr and at age of - months were anesthetized and a small burr hold in the left parietal aerea was carried out under aseptic conditions. the dura was opened and . ml (this volume assuring a normal incranial pressure after kaufman ) of autologous blood was injected into a depth of mm via a needle of . mm bore. the wound was closed and the animals were left to recover. nimodipine, of , mg/kgr of by weight per day was given via a nasogastric tube to fifteen animals for a period of time of fifteen days (group b). six rabbits were given water and served as control (group a). both groups of animals weie sacrified on the fifteenth day, their brains were removed and immersed into % formalin solution. tissue sections of ~ were embedded into paraphin and stained with haematoxyline and eosin, mason and gfap stain for gliac cells. results: two animals died after the surgical procedure, because they developed large intracerebral bematoma. no animal developed neurological deficit except one of group a which manifested a right side hemiparesis. the results of the bistopathological changes are the following: i) the mean -+ sd diameter of the lesions in the group a was --. ~t while that of group b was + ~t (p< , ) ii) secondary ischaemic neural tissue changes, characterized by the extravasatlon of red cells, the presence of haemosiderin-containing macrophages and signs of low grade inflammation zpredominated in the specimens of group a and were totaly absent from those of group b. iii) a ring of gliac hyperplasia and a low grade local fibrosis was found, encircling the lesions in the specimens of group a in contrast to those of group b. conclusions: nimodipine when administered in rabbits following the development of a non increasing the icp experimental intracerebral haematoma, prevents the extention and the severity of the lesion. objectives: to study the efficacy and side effects of adding intramuscular clonidine (clophelinum) to analgesic regimen in early management of patients with serious burn injury. methods: pts with - % bsa second to third degree flame burns (respiratory tact injury excluded) to yrs of age were randomised to study (n= ) and control (n= ) groups. burn shock was treated with hypertonic saline -bicarbonate solutions ( mmol/l na +) ml/kg/%bsa for the first hours and ml/kg/%bsa for second day. analgesia in control group for the first hours was provided by regular hourly intramuscular administration of mg of morphine sulphate and mg of analgesic -antipyretic analgin with mg of diphenhydramine (dimedrol). from the rd day regular administration of morphine was finished. in the study group ixg of clonidine was added -hourly for hours and dose of morphine halved. vas, verbal rating scale for sedation (vrs, - ), sleeping time, spo , hr, bp, diuresis, vomiting and other complications were comparatively evaluated during patients' stay in icu. results: addition of ~g of intramuscular clonidine daily allowed to achieve better analgesia and sedation with halved consumption of morphine. mean vrs in study group for the first days was . - . vs . - . in control group with twice longer sleeping time. there was significantly less tachycardia in study group; dynamics of bp for the first hours did not differ considerably; later, there, was tendency for hypotension in study group without adverse effects on diuresis or other indices of tissue perfusion. because of high incidence of chronic ethanol abuse among study population pts of control group suffered from psychomotor agitation or delirium, probably as a sign of alcohol withdrawal syndrome (aws). this made regular evaluation of vas impossible. in the study group only pt showed sign of aws. mean vas score was in . - . range for first postburn days. pts appeared excessively drowsy due to clonidine, but it had no adverse effect on their overall clinical course. mean spo values in study group were in - % range, among controls - %; vomiting was absent in. cionidine group vs cases among controls conclusions: clonidine could be a valuable addition to analgesic -sedative regimen in burns, especially for prevention of aws and deserves further study in this regard. hemodialysis -hemoflltration modifications and/or intratracheal gas insuflation have been recently used for blood gas exchange in several models of respiratory failure. objectives: evaluate the combination of cavh-m and igi for respiratory support in experimental acute lung injury. methods: five mongrel dogs ( -+ kgr) were mechanically ventilated inroom air, paralysed, heparinized, connected with a cavh-m system (diafilter- polysulphone membrane) and remained stable for one hour (pao~= . • peco = -+ mmhg, ph= . -+ . , bp= -+ mmhg and pap= -+ mmhg). all was induced two hours after oleic acid infusion ( . ml/kgr) into the pulmonary artery (poo~= . _+ -p< . , paco~- . _+ -p< . , ph= . -+ . -p< . , bp= -+ -p=ns, and pap= _+ -p< . ). fio % for the next minutes did not significantly altered the b ood gas abnormalities. afterwards, pure oxygen applied simultaneously a) through the inlet of the filtrate's compartment of the hemofilter ( l/min) while filtrate and gas were removed from the outlet port (bypass flow ml/min) b) through a thin intratracheal catheter positioned cm above the carina ( l/min). the fio given through the ventilator readjusted to %. results replacement fluids/filtrate during the next four hours were not exceed . l/hour, whilst the blood gases and pressures were improved as follow: cavh-inlet:pao.= . objective. to compare the changes in humoral immunity in trauma patients following massive transfusion of autologous and homologous blood. methods. we studied randomised clinical groups of patients each containing patients with trauma and operation of large arterial vessels. the amount of autologous or homologous blood transfused to the patients was exceeding ml, while the patients in the control group did not recieve blood or blood products. results. we recorded most pronounced and characteristic changes on the -st and on the -th day in the group of patients recieving homologous blood transfusion, i.e. decreased amount of igg,iga,igm,c and c fractions of the complement system, haptoglobin and significant and sustained rise of circulating immune complexes up to the end of the study period. in the control group of patients the decrease was weaker and lasted only during the -st post-operative day; the dynamics of the circulating immune complexes level were almost the same as in the first group of patients. in the group of patients recieving autologous blood transfusion, the parameter values did not change significantly from preexisting levels after the -st day, while on the -th and on the -th day showed a tendency towards aslight rise. conclusions. autologous blood has a favourable effect upon humoral immunity and should be the transfusion medium of choice in cases where autologous blood reinfusion is technically possible. ivan petkov, m.d., rumen farashev, m.d. and dimitar terziiski, m. d. medicine, military medical academy, g. sofiiski str., sofia, bulgaria objective. the amount of blood lost during trauma and operation could hardly be forseen and donor blood supplies are not always available in sufficient amounts. rare blood group types and/or unexpected haemorrhage pose a great challenge to the transfusion therapy and the methods of intraoperative autologous blood transfusion. methods. we report a case of a -year old male patient with extremely massive intraabdominal haemorrhage ( m( blood loss ) during an abdominal aorta reconstruction following a traumatic injury of the abdominal aorta. we achieved a successful reinfusion of ml of autologous blood using an original autotransfusion system developed by us ( pat. no / . . ) . results and conclusions. the autotogous blood in the case reported here was the only and the most suitable transfusion medium for the rapid intraoperative compensation of the acute haemorrhage and the favourable outcome of the patient. the post-operative period was smooth and no significant disorders in the clinical course as well as in the laboratory tests ( morphological,biochemical,coagulation and immunological) were recorded. there were no complications during the postoperative period despite the fact that the amount of blood reinfused to the patient was slightly exceeding his own volume of circulating blood. objective. the haemoglobin concentration and the perfusion pressure value could not be the only criteria for the early signs of tissue and organ dysfunction. because of this, we employed the extensive monitoring of oxygen transport during severe trauma in order to. achieve dynamic evaluation of physiologic compensatory mechanisms and to assess the efficacy of intensive care management. methods. we conducted a prospective controlled trial on the blood oxygenation, oxygen transport and tissue perfusion during the first days after the trauma in patients with polytrauma. we used a swan -ganz pulmonary artery catheter (beckton -dickinson, u.s.a.), deseret cardiac output computer (medical inc., u.s.a.) and hewlett -packard monitor (hewlett -packard, germany) to measure and calculate all the parameter values. the severity of the injury was assessed using the apache ii score system. all the patients had scores over . results. the results show a significant decrease in the arterial blood oxygen content and in the arterio-venous difference, as well as an increase in alveolo-arterial oxygen difference and in the transpulmonary right-to-left shunt. the tissue oxygen supply and the tissue oxygen consumption reveal a tendency towards a decrease below the physiologic minimum of adeqate values. the erythrocyte current velocity and the ratio between oxygen transport and erythrocyte current velocity also decrease inspite of the optimal blood rheology. conclusions. the dynamics in the parameters values are most pronounced between the -nd and the -th hr after trauma, which predisposes patients to the risk of developing stable hypoxemia and characterizes this period as the most critical for tissue metabolism and organ dysfunction. posttraumatic changes in immune mechanisms in lung compartment in trauma were analyzed in ao and da inbred strains of rats which differ in their immunological reactivity: the former being low responder and lat-~er hiperresponsive. methods: the levels of tnf-alpha activity in the supernatants of cultured lung lobes and dynamics of cells migration from tissue explants in h lung cultures were assessed in ao and da rats subject ted to severe burn trauma. results: increased levels of tnf activity ( + pg/ml compared to + . pg/ml in control) were found od day following trauma in lung sups of ao rats while no changes in the levels of activity of this cytokine were found in lung-sups od da rats more pronounced extent and dynamics of cell emigration were noted in da rats, while almost unchanged in ao rats sharp rise in pmn percentages h following trauma ( - % compared to rare pmns in control), followed by increase in lymphocyte numbers at later time points among lung cell emigrants was detected in ao rats. slower but persistent increase ( %, h following trauma and % and % on days and after trauma infliction, respectively) in pmn numbers among da lung cell emigrants was detected, which appeared to be activated, as judged by their nbt reduction capacity. increased percentages of peripheral blood pmns and increased state of leukocyte aggregation/adhesion were detected in both strains, but different levels of plasma tnf: increased levels in ao rats on days and following trauma, and initially but persistently high levels of plasma tnf alpha in da rats ( - fold higher compared to initial levels in ao rats). conclusions:different patterns of local (lung) and systemic changes in cell numbers and cytokine levels implicate differential posttraumatic migratory capacity of pmns vs. lymphocytes in lungs in ao and da rats. early diagnosis of acute intestinal ischemia by color doppler sonography e. danse, b.van beers, p.goffette, f.hammer,aav.dardenne, f.thys, p-f.laterre, m,s. reynaert, .lpringot dept of radiology (profb.maldague) and dept of intensive care ( prof m,s.reynaert), st.luc univ.hospital, brussels, belgium ob emergeny medical squad service is the most important segment in the process of saving the people, in the cases of mass accidents, like industrial accidents caused by the: explosion, fire, chemical poisoning, traffic accident, elemental catastrophes and the war. because of that, each emergency medical squad service needs to have in its motor-pool vehicle for the mass accidents/ for provoding at least people, wounded as well as the people became ill/. objectives: presentation of such special vehicle, produced by "zastava-kamioni" and it's medical-technical equipment. methods: descriptive and comparative analysis of the medical and technical characteristics, based on the actual norms/din, , iso , yus.../ results: on the base of doctrinaired requirements of the emergency medical squad in the case of mass accidents, our researches resulted in the following medical and technical characteristics -the vehicles for mass accidents are gvw/with a payload off cca - t, with the fixed, closed body, type: universal van, -technical equipment aggregates, stretches, anti-fire device, equipment for pitching the tent and for maintaing technical conditions of the work -medical equipment: linen bags with complete sets of bandage material, means for the reanimation and immobilization, for the infusion, medical instruments and remedies as well as the tent for lodging at least wounded and sik people. in federal republic yugoslavia, it was proposed such vehicles for the emergency medical squad needs. conclusion: we suggest to introduce this vehicle in the production range of the ambulance vehicles for saving, especially in the circles where can occur serious accidents. introduction : carbon monoxide (co) poisoning commonly generates central nervous system abnormalities though an important cardiac morbidity and mortality must be considered. long-term exposure to co with cohb levels < % may be more dangerous than short-term levels of - %. we report a case of an adolescent who after prolonged exposure to co developed a severe reversible cardiac dysfunction with low levels of bloed cohe c a.ase history : a year old boy was found comatose at home. his mother in the neighbouring bathroom died severn hours earlier of what was later proven to be a co intoxication. on arrival the gcs was / and the patient was breathing spontaneously. a postictal status with eventual postanoxic encephalopathy was suspected. a coh'b level of % was objectivated. the cardiorespiratory situation quickly deteriorated requiring mechanical ventilation. chest x-ray showed diffuse bilateral patchy infiltrates. ecg revealed signs of ischemia. severe left ventricular dysfunction was evidenced by pulmonary artery catheterisation and echecardiography and later by isotopic angiography (lvef %). treatment was intensified with inotropic support, intta-aortic balloon counterpulsation and oxygen therapy. the clinical course was further complicated by a crush syndrome and renal failure. the patient's condition gradually improved and he fully recovered without any residual lesions (lwf %) conclusion : even after prolonged exposure cohb levels can be misleadingly low. high tissue levels of accumulated co can be associated with coma and fulminant cardiorespiratory failure requiring advanced life support facilities. introduction : both neuroleptics (nlp) and tricyclic antidepressive agents (tca) can induce arrhythmias, prolongation of the qt segment and the pr interval and hypotension. we report a case illustrating that combined overdose of these agents increases the toxicity of each compound and the risk for adverse cardiac events. .c, gse history : a year old male ingested mg doxepin (sinequanr), a tca and mg prothipendyl (dominalr), a potent nlp in an attempted suicide. upon arrival in the emergency department the patient was unconscious (gcs / ), breathing superficially, and presenting signs of recent vomiting. physical examination revealed a taehycardia of b.p.m., an arterial blood pressure of / mmh g. ecg showed a brood qrs complex tachycardia. a chest x-ray revealed the presence of an aspiration pneumonia. laboratory investigation demonstrated increased levels of crcatine phosphokinase, lactate dehydrogenase and aspartate transaminase ; hyperglycemia and leucocytosis were present. the plasma concentrations of doxepin and prothipendyl were respectively gg/l (toxic level #g/l) and i.tg/l (no reference). treatment consisted of mechanical ventilation, gaslric lavage and administration of activated charcoal and iv fluids and antibiotics. a hemodynamically well tolerated veatricular tachycardia developed / h later. nahco ( meq/ h) was administrated inducing an ectopic atrial tachycardia with a normal qrs complex and prolonged qt. h after admission a normal sinus rhythm was present; the prolongation of the qt segment persisted for days. the patient fully recovered. conclusion : the treatment with nahco~, alkalizing the blood and thus increasing the protein binding of the tricyclic antidepressant molecule, can readily correct the potentially life-threatening cardiac arrhythmias and therefore should be part of the routine treatment of combined tca-nlp overdose. ob/ectives: the development of diabetes insipidus (di) in patients with brain injury is a known negative prognostic sign. the aim of this study was to investigate whether this is also a reliable early prognostic sign of brain death. methods: this is a retrospective study of patients treated" during a two year period ( - - to - - ) in our i.c.u who meeted the following criteria: ( ) coma score _< gcs within the first hours, ( ) positive brain ct scan on admission classified according to marshall's diagnostic classification (classes - ), ( ) normal renal function during the entire icu stay. for the definition of di were used the usual di criteria plus hypematriaemia (serum na" >_ meq/l). survival was defined up to the th postadmission day. conclusions: according to the findings of this study, the development of diabetes insipidus in brain injured patients seems to be a highly specific index for brain death (positive predictive value = . ). however, further prospective studies are needed for the definitive evaluation of these findings in such patients. emergency care in italy, despite all efforts, is still lacking a nationwide organized prehospital care system and, until today, there are only different regional solutions. the majority of these realities imply rather simple ambulance first-aid services without attending emergency physicians and without resuscitation equipment. the emergency medical service (ems) system in falconara m., italy, was implemented in august by a collaboration between the school of anesthesiology and intensive care of the university of ancona and the, already existing, volunteer rescuer organisation "yellow cross". according to the guidelines pubblished in [ ] the pre-existing equipment of the volunteers was completed with type a ambulances and special equiped motorcar (patient monitor, defibrillator) for ambulance indipendent physician transpur[. a special data collecting schedule was created to memorise every emergency intervention in a computerised data-base. the intraining members of the school of anesthesiology and intensive care provide hour ready intervention. in this report the authors describe their experience concerning primary firstaid medical interventions. for a preliminary evaluation we considered, retrospectively, consecutive emergency interventions in the time period from novembre , to april , . the emergency physicians treated male ( %) and female ( %) patients, patients died before hospital admission and patients ( %) were treated at home by the ambulance indipendent physician and did not need any further medical treatment. in the same time period year earlier (november to april ) without attending physician the volunteer rescuers transferred all first-aid interventions to near-by hospitals. we conclude that the presence of an attending, iudipendently motorised physician in emergency interventions is essential for the establishment of precise priorities and may be helpful to reduce hospital admissions by ambulance intervention, though reducing primary" health care costs. we have developed the method of liquor filtration which allows to purify the cerebrospinal liquor from blood and its decay products in the subarachnoid bloodstroke. the hemipermeable dialysis membrane was used as a filter, which lets only in water, electrolytes and substances with small molecular weight. the liquor filtration was used for the treatment of patients with the subarachnoid bloodstrokes of different etiology. the perfusion of liquor was performed at the rate ml/min in the recirculatory mode. its duration was - min depending on the bloodstroke intensity. the filtration makes possible the most completely purifying of the hemorragic liquor, the reducing of the content of blood ceils and its decay products - times as less. the monitoring of the patient's state during the perfusion didn't revealed the departure from the norm of the main vital part. the liquor filtration technique compares favo-~ rsbly with the routine method of cleaning by the absence of toxical effect of heterogenous solutions on the central nervous system. the filtrstion of the cerebrospinal liquor in the subarachnoid bloodstroke sllows to provide the the early cleaning of liqour, the regression of meningeal syndrome and to improve the patient's state of health. e tabli~mczr bd ~ of rei~idnal medical first-aid zhoulittoing, ed., tan zi, m.d. dept. of sargery, the first teaching t[ospitat, yejin-l)a-l)ao, wuhan fltlna objectives: the medical first-aid is the most important task of the public hc atth department. in general, single hospital model couldn't fatty, effective ly rescue mony severe patients who need mergant treatment in the scene. bub establishing the medical first-aid network, the severe patients can be given the most timely und the most scientific emergent treatment. so that, the suc cessfut rate of the saving wilt be greatly increased. methods..; our hospital is a general big hospital. through developing and cons tructlng for more than ten years, the medical first-aid network distributed art over the area under our jurisdiction has been set up. it consists of thr ee units: the medical first-aid unib center comartd and mnagment unit, co m~nlcation and tiaison unit. the principle of the network operation is with oat having to far to mergoncy, specialized emergency and the best merge acy. results: the results of the network operation were notable. cmpari~ the to tat successful rate of the saving ( . ~), the successful rate of saving tra ma ( .~), the suscessfut rate of saving shock ( .~) and the successful rate of cardioputmonary resuscitation ( . ~) daring the three years after t he network operated with these before ( . ~), ( ]. ~), ( . ~) and ( ft. ~), the successful rates after operating were remrk~iy higher ( p<i).o ). conctusions~ the above results showed estabiishmnt and mena emont of region at medical first-aid network had very si~nificont action during mergentty s avin the severe patients. moreover, the regi~at medical first-aid network atso take an important part in prevention and health protection of the mass. objectives: se related mortality is due to the occurrence of both rv and lv dysfunction evoking cardiogenic shock and pulmonary edema (f. abroug, intensive care med ; s. nouira. chest ) . prospective evaluation of scorpion antivenon (sav), the only available specific treatment, is lacking. the aim of this study is to assess the effects of sav on the basis of a case-control study. methods:among consecutive victims of se presenting to the emergency department, were managed using sav (group sav+). these patients were matched to envenomated patients who did not receive sav (group sav- chest injuries are the cause of death in % of trauma fatalities and a major contributing factor in an additional %. pneumothorax is a major complication of chest injuries and can be initially overlooked bringing to additional morbidity and mortality especially in patients who require mechanical ventilation. the real incidence of pneumothorax in severe blunt chest trauma hasn't yet been established, as many pneumothorax can be missed on the initial chest x-ray (cxr) and computed tomography (ct) has not been routinely used. to evaluate the incidence of pneumothorax in patients with severe blunt chest trauma. methods: a prospective study. from january to december , all trauma patients with one of the followings conditions: fractures of four or more ribs, signs of lung contusion on the initial cxr or presenting a severe hypoxemia on admission (pao /fio < ) in the absence of pre-existing pathologies, were evaluated by initial cxr and subsequently submitted routinely to a ct. results: severe trauma patients were considered. of them, presenting a severe hypoxemia on admission, had no evidence of major chest trauma (ais< ). hypoxemia was the consequence of severe trauma in other districts; these patients were therefore excluded. patients with severe thoracic trauma (ais>= ) were admitted into the study. the mean iss was . ( - ). thirty-six patients required artificial ventilation for at least hours during the icu slay. three of them, who had a tension pneumothorax, were submitted to an emergency thoracic decompression on the field by the emergency helicopter team. in cases pneumothorax was diagnosed an the initial cxr more patients had a pnx which was identified only on the ct. in cases a large pnx with lung collapse was missed on the cxr. in our group of severe blunt trauma patients, % ( / ) presented a pnx that required the insertion of a thoracic drainage. only one third ( / ) of the pneumothorax could be recognised on the initial cxr, while other were decompressed before performing the cxr. as many as % of the cases of clinically significant pnx were missed on the cxr, and a ct performed soon after admission allowed an early diagnosis bringing to changes in the treatment. (as the patients were mechanically ventilated a chest tube was inserted in all these cases). in cases, the initial cxr overlooked a huge tended pnx which was the cause of hemodynamie instability. conclusion: in patients with severe blunt chest trauma even large pnx can be missed on the initial cxr. moreover due to the non compliant compressible lung, a % pneumothorax which can be recegnised only on a ct, can bring to high intrapleural pressure altering eardiopulmonary function. n. andoeli , .~osid, m.zesevid, m.risovid, d.stepi , d.djokid b~rga~yc~qterclinicalcaqterafserbia, belgrade cb~ctives:~lis study ~ the use of ~rq]ofol earbired with k~t~ine (aq a~sjgh~ic s@~qt widn inirjrsic armlgesic pro~mities) or with fsqtmtyl,with psrtial azgmsis an hgenxlyn-a~ic ~ durirg ~ ~ re:~ver~ f~m ~ in hxh ~ of ~ti~. ~: yali~mial and ~bod: a~it p~tie~ts a~ i-ii were included in ibis shxly. patients were rsrd]nly dieided in two ~ns. all d~tie~ts ~me given - prcpofol bolus doses (o, ~gkg) for ird~iqn of ~. ~ia ~s m~sjn~ with an infusion ~ ~ropafol. as sdflitianal were given fan-i~l (o, n]g) ~tely before ~ anj trad~e~ irfojoation followad by feasted bolus of o,i mg in ~ro o l.patients in gr~ o received i~ (an initial bolus dose of rg slowly intcavax~ rd mg as infusion over ~ rain) .infusions of pro~fol or imcpofol with kg~mine ~ stopfsj - rain ]:~o~ extuhation.arterial blood ~ (sistolic arterial blood preassu-re~zap,mean ~rterial blood pr~,d~lic arterial preassure-[zp a~ h~art rate-~) ~ m~ before induction of a~ io, snd rain aftem ~ intutation. results: arterial blood preasstre ~s decreases duri~ irn~ction of sn~wd~sia in hy~ ~n~s,tnt mare in th~ ~ who r~eived fsqtanyl.~ere w~s statisticslly sifnific~ntly difemerme dmir~ m~ of an~ia. arterial blood r~easatre and heart rate were stable in the t-..e~min -~a ~. all th~,fl-e keta'nire grcqo hsd e~rly :~e~y time. ctrmlusi~s: ~e ombiretion of protxfol wilh keta/ne for irduorion a~d ~ of sn~sd~esis w~s yell accept~ by p~tierfcs anj coald he ~ as an alterrstive ~o ccnva~icrsl a~es -d~sia. objectives : assess the relation between cytokine or endotoxin release and indices of splanchnic malperfasion after hemorragic shock in multiple trauma patients. ]~r study was approved by the local ethical committee. trauma patients admitted to the emergency room who met the entrance criteria of more than hour map < mmhg or use of vasoactive agents or blood lactates > mmol/ were selected for study. a nasogastric tonometer (tonometrics, inc, plastimed, france) and a swan ganz catheter were placed on admission. phi, lactates, hemodynamics, plasma cytokine and endotoxin concentrations were measured on admission and at . , , , hrs. an immunoradiometric assay was used to determine plasma concentrations of il (n< . ng/ml) and tnfc~ (n< pg/ml). plasma endotoxin concentrations were measured using a chromogenic limulus assay (n< . eu/ml)( endotoxine unit= pg). results : severe multiple trauma patients (age = _+ yrs, iss = -!-_ , saps = +'~, mean-+sd) were studied. they received + packed red cells during the first h. mean duration of collapsus before inclusion was . _+ . hrs. death occm'red in ~tients. ~ pglml, *: ng/ml, etox : endotoxin(eu/ml), lact: lactate (retool/l) a significant correlation between initial il level and saps was observed. in the early post-injury period phi, sao , svo , vo were significantly associated with ;il release (p< . at ho, h , h ). later a significant correlation existed between lactates and ii (h , h ). a peak of tnf was detected at and hrs. it was associated with low phi and low arterial ph of the early post-injury period (p< . iat ho, h , h ,h , h ) and with high lactate levels of later period (_>h ). only the late release of endotoxins (i{ ) was correlated significantly with initial !oxygea-delivered parameters. iconclusion : there was a marked increase in il in the early phase of trauma . i and tnf release after major trauma iwith hemorragic shock is associated with splanchnic malperfusion, as assess by the ivery low values of phi. lactates seem to be a later indice. toxic effects are a well-known complication of an overdosage of prescription theophylline. what is less known is that over-the-counter (otc) asthma medications contain theophylline, and that in some cases this might cause toxic effects. a case seen by us involved toxic effects from theophylline in an otc medication and to date is the only published case in the english literaturet the rationale for this study was to delineate the otc products containing theophylline from whatever data sources available. hyperthermia frequently occurs in intensive care treated patients and intentional application of whole body hyperthermia together with chemotherapy is a therapeutical access to treatment of malignant disorders. anaesthetic support is required in either condition. due to the marked decrease in systemic vascular resistance seen in hyperthermia an additional vasodilatory effect of the anaesthetic is unwanted. the vascular effects of anaesthetics in hypertherm organisms is not known in detail. therefore, we performed an experimental study to detect the effects of inhalational anaesthetics in whole body hyperthermia. in sprague-dawley-rats katheters were inserted into trachea, jugular vein, and carotid artery. for continuous monitoring of cardiac output a flow probe was placed around the aortic arch. the rats were mechanically ventilated with different concentrations of inhalational agents in oxygen. we compared the effects of enflurane, isoflurane, and halothane in stepwise increased body temperature by submerging in a temperature controlled water bath. results: isoflurane lowers arterial pressure more than halothane or enflurane. the inhalational anaesthetics lower the cardiac output similarily and independently of temperature. isoflurane decreases systemic vascular resistance independently of core temperature and the decreasing effect of halothane on the resistance is completely abolished in hyperthermia. conclusions: the influence of hyperthermia on the systemic vascular resistance is dangerous. this allows no additional effect of the anaesthetic management. in spite of the vasodilating effect of inhalational agents in normotherm subjects, this effect is abolished in hypertherms using halothane. the condition of management of analgosedation in hyperthermia is different from normothermia. objectives: to evaluate a bedside computer processed cerebral function monitor for assessment of brain wave activity when clinical/visual clues are not present. methods: ten icu patients undergoing neuromuscular blockade monitored with the aspect brain wave monitor from january to june , . results: time to onset and depth of sedation were readily apparent to icu physicians not specifically trained in eeg reading. objectives: to determine whether non-depolarising neuromuscular blockade reduces oxygen consumption (vo ) in sedated, apnoeic patients. methods: haemedynamic. metabolic and oxygen transport variables were determined in sedated, apnoeic patients with severe acute lung injury. all patients were ventilated using a puritan-bennett ae ventilator with integrated metabolic monitor. inclusion criteria were; ) stable cardiorespirator s" status; ) systemic and pulmonary artery catheters already in situ; ) inspired oxygen < %. patients were sedated with midazolam or propofol to abolish response to verbal stimuli, and sufficient morphine or alfentanil to abolish all spontaneous respiratory efforts. following baseline measurements, neuromuscular blockade was induced with intravenous vecuronium, ug/kg, followed by an infusion of ug/kg/h to maintain the train-of-four ratio at . a further four sets of measured and calculated variables were obtained at min intervals. results: statistical analysis was by repeated measures anova. there were no significant changes in any variable over time. the changes in calculated oxygen consumption (vo fick) , and measured oxygen consumption (vo gas), and in energy expenditure (ee), are shown in the table. objetive: to study the effects on coronary hemodyrtamics and myocardiai metabolism of administering propofol during postoperation sedation of patients with normal coronary circulation and good ventricular function undergoing cardiac surgery. patients and methods: patients ( women and men) undergoing aortic and/or mi~-a/ valvular cardiac surgery were selected, with an ejection fraction greater than . and normal coronary circulation. for postoperation sedation propofol was administered in . mg/kg i.v. bolus, followed by a . mg/kgth perfusion. all data were registered before administering propofol and after minutes, the patients being hemodynamically stable and a rectal temperature of _+ . -~ systemic and pulmonary hemodynamics, and global, as well as regional myocardial blood flow, and metabofic variables were measured. results: the patients studied were about years old, and the average period of aortic cross-clamp was . min. the adminstering of propofol caused a decrease in the coronary blood flow (- %), great curonary vein flow (- %), myocardial oxygen consumption (- %), regional myocardial oxygen constanption (- %), myocardial oxygen extraction (- %), regional myocardial ooxygen extraction (- %), while coronary vascular resistances and global coronary vascular resistances did not change. oxygen saturation increased in the coronary sinus (+ %) as well as in the great cardiac vein (+ %). in no patient were significant changes suggestive of myocardial ischemia objectified. there was also found a decrease in systolic (- %), diastolic (- %) and mean (- %) arterial pressure, systemic vascular resistance (- %), and cardiac output (- %). conclusions: in accordance with the clinical conditions of this study, the administering of propofol is not likely to cause changes in coronary autoregulation, oxygenation and myocardial metabolism. obietive: analyse the effects of . % "end tidal" isoflurane (sedative dosage) on the metabolism and coronary hemodynamics during the postoperation period of patients undergoing cardiac surgery. patients and methods: patients ( women and men) undergoing aortic and/or mitral valvular cardiac surgery, with an ejection fraction greater than . and normal coronary anatomy, were selected. after the surgical operation, . "end tidal" isoflurane was administered for postoperadon sedation. the determination of variables to be studied was carried out before and minutes after administering isoflurane, die patients being hemodynamically stable and a rectal temperature of _+ . -+c. systemic and pulmonary hemodynamics, and global, as well as regional myocardial blood flow, and metabolic variables were measured. results: the average age of the patients studied was -+ . years. during surgical operation the period of aortic cross-clamp was . _+ . rain. the administering of isoflurane was followed by a statistically significant drop in coronary perfusion pressure (- %), coronary vascular resistance (- %), regional coronary vascular resistance (- %), regional myocardial oxygen consumption (- %), regional myocardial oxygen extraction (- %) and accompanied by a significant rise in oxygen saturation in the coronary sinus (+ %) and in the great cardiac vein (+ %). myocardial oxygen consumption, myocardial exu'action of lactate and regional myocardial lactate extraction did not change. in no patient were enzyme or electrocardiograph changes objectified. systolic (- %), diastolic (- %), mean (- % ) arterial pressure, and systemic vascular resistances (- %) decreased, while cardiac output did not. discussion: the administering of . % "end ddal" isoflurane, in the clinical conditions of this study, produced a decrease in systemic arterial pressure due to a reduction of systemic vascular resistance without deteriorate cardiac output. at coronary circulation level, has and effect on coronary autoregulation but had no effect on oxygenation and myocardial metabolism. the idea of tiva implies the realisation of major anesthesia components (los of consciousness, neurovegetative inhibition, analgesia, myorelaxatiou, providing the adequate gas-exchange) through i.v. introduction of drugs exclasively. aim: providing for the main tiva components with minimal side effects of the drugs used, taking into consideration the patients characteristics and the surgery specific character. methods: anaesthesias have been conducted in patients aged years ( females, males), undergoing planned and urgent operations with the pathology of lower, extremities, perinaeum, small pelvis, hypogastrium and with reserved spontaneus respiration against a background of % insnffladon through mask. operations lasted from . - . h. anaesthesia adequacy was assested by constant monitoring: "cardiocap" (nibr hr, rr, sao , t), through glykhaemia level and mimicry reactions. standart premedicatioo of m-cholinolytics ( . mg/kg) and h -blockers ( . mg/kg) on the operational table was sumplemented by administration of . - . mg/kg of lidocaine, . . mkg/kg of clonidine, . - . mg/kg of pentamidine by the tachifilaxia method. the premedication adequacy was assessed through haemodynamics characteristics. sedation: . - . mg/kg of droperidoi, .l- . mglkg of diazepam and analgesia: - mkg/kg of phentanyl, . -- . mg/kg of ketamine were introduced fractionally according to indications. infusion rate of ringer-lactat solution was - ml/kg/h and depended on the intraoperational blood loss volume and on the patients preoperational condition. the duration of postoperative analgesia was registered. results: clinical assessment of analgesia according to this techniques allowed to decrease the anaigetics dosage to the subauaesthetic levels. smooth stabilisation of haemodynamics (bp) at proper age norms in patients with the initial hypertension by the -th min. of anaesthesia as well as the absence of its increase in response to the additional introduction of anaesthetic have been achieved. (hr) had no abrupt changes and remained in the range of - per rain. adequate external breathing: decrease (rr) by - per rain., with sao increase from % to - %. hypoventilation was avoided by respirate ventilator. according to unauthentic data the glykhaemia level had been lowered by -t % to the end of the operation with the initial moderate hyperglykhaemia of up to mmol/l the cutaneous covering grew warm and got pink colouring. no mimicry reactions. in the postoperative period patients were in the superficial sleep state ( - ) and analgesia lasted - b. there were no complications due to anaesthesia. conclusion: combined using of bz, opiates, neuroleptics potentiate the i.v. anaesthetics effects allowing lowering of each tiva component dosage and, as a consequence avoiding their negative influence on respiratory and heart vascular systems. complex application of adrenergetics (therapeutic doses of cionidine and pentamini with using of taehfilaxy effects) permitted to provide for analgetic and neurovegetative components of general anaesthesia under subanacsthetic doses of tiva main components, and manifestation of hyperdynamic reactions of haemodynamics decreased while using of lidocaine -the economicai activity of heart-vascular system. good level of muscle relaxation was achieved allowing for widening of surgical intervention extent without respirator ventilators and inhalation anaesthetics application. anaesthesia is easily controlled due to fractional introduction of drugs with quick recovery of cns functions after anaesthesia. postanaesthetic analgesia is increased while concurrent opiates doses are decreased. absence of marced haemodynamic, endocrine and metabolic reactions during the operation and after it resulted in shortening the period of patients staying in hospital. a yo white man was admitted to hospital for dyspnea and a productive cough. he had cabg in past, but no recent cardiac ischemia. physical exam: decreased breath sounds over right lung. chest xray: consolidation of right lung. admission medications included diltiazem, furosemide (both were continued) and trazodone (which was discontinued). admission ecg: sinus rhythm, qt . /qtc . sec, with st and t wave abnormalities similar to prior tracings. he required intubation and mechanical ventilation for progressive hypoventilation and hypoxemia. between icu days and he received haloperidol, - mg/d (cumulative dose rag) for agitation and delirium. icu day : qt . /qtc . sec. icu day : for better control of delirium, trazodone " mg q hs was added. icu day : he developed frequent nonsustained ventdcular ectopy. icu day : qt . /qtc . sec, pha . , paco mm hg, pao mm hg, k . meq/l, mg . meq/l. later in icu day the patient had brief episodes of torsades de pointes, each responding to precordial thump, and finally rhythm stabilized with i.v. lidocaine and magnesium. haloperidor and trazodone were discontinued. ecg was unchanged and myocardial infarction was ruled out. next day, icu day : qt . /qtc . sec. torsades de pointes, a form of ventricular tachycardia characterized by a twisting qrs axis, is commonly associated with qt prolongation. haloperidol is used frequently in icu for control of agitation and delirium, with reported doses up to mg/day. over past decade, cases of torsades de pointes with prolonged qt related to haloperidol have been reported. trazodone may also prolong qt and cause ventricular arrhythmias, especially in patients with pre-existing cardiac disease. in this patient, trazodone likely exacerbated qt prolongation from halopeddol leading to torsades de pointes. critical care physicians must be aware of this interaction. it is imperative to follow the qt interval for patients receiving halopeddol, especially when another drug also known to prolong qt is added. one must consider discontinuing the drug when qt/qtc becomes prolonged. objectives: analgesics and intravenous anesthetic drugs are routinely used in critically fll patients, who often suffer from a secondary impairment of the immune system. previous in vitro studies have demonstrated inhibitory effects of these drugs on polymorpho nuclear cells (pmn). the potentially important role of endothelial cells (ec), however, was not investigated, since suitable test systems were not available until recently. therefore a physiologically more relevant in vitro migration assay through cultured human endothelial cell monolayers (ecm) we established. using this assay system, the comparative effects of fenlanyl, sufentanil, propofol and the known pmn inhibitor thiopontal were tested. methods: human umbilical vein endothelial cells (huvec) were isolated and cultured on microporous membranes (cyclopererm) until an ecm was grown. pmn from male and female volunteers were separated by standard procedures. ecm and pmn were preincubated with clinically relevant concentratious of thiopental ( m), propofol ( p_g/ml), the solvent of propoful (intralipid), fentanyl ( ng/ml) and sufentanil (sng/ml). after preincubatiun (ecm minutes, pmn minutes) with the reslx~tive drug, leukocyte migration towards the chemoatfractant fmlp ( o - m) was measured in a two chamber well system for hours. the migration rate of untreated (untr.) and treated (treat.) pmn through untreated and treated ecm were determined. as a control untreated pmn and untreated ecm were used. results are given as means from independent duplicate determinations and expressed as a percentage of control (table) . statistical analysis was done with student's t-test. results: clinical concentrations of fentanyl, sufentanil and prupofol showed similar inhibitor~ effects as the known pivin inhibitor thit e ). % conclusions: for the first time we could show that analgesics and anesthetics exert their inhibitory effects not only on pmn, but mainly on the interaction of pmn with endothelial cells. moreover, we could shmv a significant suppressive effect of the opinids fentanyl and sufentanil on both ec and pmn. the known inhibitory effect of thiopental obtained in ec-free test systems were also confirmed in our physiologically more relevant assay system. objectives: to investigate when and how sedation is used in a consecutive cohort of patients admitted in a large sample of italian intensive care units (icus), gathered in a network named giviti, representative of the italian icus system. methods; the study called for a recruitment period of one month, from january to february , , data collection included age and other demographic variables, acute diagnostic broad profiles, severity of illness scores, treatments, lenght of stay and vital status at icu discharge. as concerned sedation, each patient was observed until discharge or for a maximum period of seven days. information on all the drugs used for analgesia/sedation, the route and modalities of administration, the timing, dosages and purpose of the administration have been recorded. results: the study involved the cooperation of icus, of which enrolled at least one case. the total sample included patients. overall, . % of patients analyzed (t / ) received at least one prescription of sedative during their stay. globally, at least one sedative drug was prescribed to these patients in days in icu. although over drugs were reported to be used, pharmacological principles accounted alone for % of all prescriptions. opioids were actually used in % of prescriptions; propofol in % and benzodiazepine in . %. as regards the way of administration, intravenous administration was applied in % of cases and, followed by intramuscular in . %. moreover, non-steroidal anti-inflammatory drugs (nsald) were used in % of patients and neuromuscular blockade agents (nmba) in %. detailed analysis on certain subgroups (surgical, trauma, ventilated patients etc.) have been also carried out in order to describe the practice of sedation in these peculiar subgroups. findings will be widely discussed during the presentation. conclusions: these results should be interpreted keeping in mind how peculiar is the intensive care setting compared to many other less complex settings of hospital care. in conclusion we thought it was important to present the data currently available in the most neutral form, to start moving in a direction which will enable us -by means of more specific and detailed studies, and with the cooperation and involvement of all those participating in the project -to shed light on one of the many aspects of medical practice in the field of intensive care which deserve closer attention. introduction: the aged run perilously high risks in cardiac surgery: among others, of haemodynamic fluctuations, respiratory depresskm and organ failure. response to anaesthetics is a crucial determinant for post<)perative complications, none the less being reintubation due to mechanical ventilation difficulties which increase morbidity, mortality and intensive cdre unit (icu) stay. objective: we wanted to assess our a,aesthesia window (selection, and a view of the induction -extubation period) for predicting safe and swift awaking, thus: icu dismissal for the aged. methods: in , selected patients (pts) (> y, f) followed a regular elective cardiac surgery protocol (propofol given at precisely designated time intervals). upon cu arrival, they were subjected to an admission protocol. our predictive criteria for early extubation at h included: a) alertness and ready response to commands; b) adequate gag reflex and sufficient protection for respirak)ry tract; c) pao > mmhg with flu < . ; d) stable ph> . with spontaneous respiration; d) stable haemodynamics without dysrhythmias; e) adequate perfusion and diuresis (> .(i ml/kg/h); f) mediastinal bfeeding< ml/h for at least h; g) normothermia (core temp> ~ and no shivering). subsequent reintubation was for: ) rr> /min; ) spontancx)us ventilation for rain with paco > mmhg; ) pao < mmhg with fio > . ; ) ph> . ; ) heart rate>] bm; and/or ) non mental alertness; and ) other medical disorders, after which adequate weaning therapy was necessary. then, successful weaning after h was considered: ) spontaneous breathing without any forrn of mechanical assistance; ) stability in haemodynamics; and ) elimination of fever threat. results: pts ( %) were extubated at h without complication; other pts ( %) at h but had to be reintubated because they were hypoxic and began weaning therapy; finally, they were all re-extubated by h. only pts ( %) proved problematic. conclusion: a,aesthesia wimhlw options (selectkm, extubation, reintubation and weaning) predicted quick (times propofol administration) and safe (rigid criteria) extubation ( %= h and %= h), exempting pts with developed post-operative complications ( %=extubation< h) unrelated to al~aesthesia window or icu protocol. dismissal and recovery then became an abbreviated question of time. fifisetll p, domeneg~i ~, sforzini i., veronesi i~, maconi a.g. *, breg~ massone p.p h [] ic+pca request conclusions:using e~aprenorphine, a synthetic,long-acting, ago-antagemist opinid drug as analgesic, in the major surgery we obtained the best clinic results with association of conttheus infusion of haft dose drug with bohts of pca in the first - hours and just pca in the secmad day after surgery when the patient is less sleepy. in this way we dent have a great sav~g of suppled drug but the major well-belng of patient without ~erious side-effects and quick mobilization; the dosage used don't compromise a good awake of patient: all patients are sleepy but ready for answer, no allueinatian, bradipnea but not less than b/m without ipoxia. also the patient proffered this kind of truit meut than the traditional at demand. the ward staff feel it useful] and rehabl~ the negative feed-back technology of the electronic infuser system makes possible to use it safe in the ward with high drug's concentration too. the infusion rate of low dose of drug assure a continuative analgesic covering ~n the first postoperative periad; the pca mode involves the patient him-self in the managemenl of therapy and enables him to choose the best way to confront the dll~icuity of postoperative period without call medical stall using pca-device we have had no probicm~ no accident. analgesia during extracorporeal shook wave lithot ripsy a .levit, b.grinbezg regional hospital, ekaterinbu~g, russia b~ectives: our task was to compare ~he analgetic effect of norphin and tramel. methods: study was made of two groups of uro-li~patients aged - . group a ( patients) received baprenorphine hydrochloride (norphin) at dosages of #. • mg/kg. group b ( patients) received tramadel hydrochloride (t~aasl) st dosages of . z . mg/kg. before the procedure diazepam was administrated i.v. ( . ! . mg/kg). blood saturation (spoz), hemodynamics incides (bp, hr,sv,co,sap,svr) were examined and the patients' subjective assessments of snsesthesis quality were analyzed. the hospital ethics committee approved the investigation. results: when using norphin hr increased by . % on the onset of the procedure while sap and sv decreased by .%% and . %, respectively (p< . ). however, there were no reliable co chsnges. spoz ~educed by @. % (p< . ) and remained lower than the initial one after the procedure was oyez. when administrating tramsl min. after ste~ting the procedure sap and svr increased by ~ . % and . % respectively. sv and co decreased insignificantly. nine patients in group b saffeting some dlscomfo~t needed additional tm~msl in~ection. in the course of the whole p~oced~e spo, was constant and was highez than that in ~he case of nozphin (p<o. ). conclusion: respiratory suppression by no~phin can limit its use in case of lithotzip@y while the advantages of tremsl a~e: lack of dyspnoe and good contact with the patti-b_ the role of uncommon agents of antinociception, placed epidurally, in the control of pain transmission in the spinal cord is well documented. somatostatin as an inhibitory agent is found in the dorsal horn of the gray matter of spinal cord. the effects of somatostatin is similar to the opiates if injected into the epidural space (ref. i, , , ) . the aim of the present study is to present the clinical effect of above mentioned palliative therapy in the case of cancer and non cancer pain. informed consent had been obtained from every patient before treatment was initiated under the legalisation of the local ethics committee. using the permanent epidural catheter and continuous infusion pump, we administer somatostatin in the dose of up to microgram per hour for one up to three days. the patients paln feeling was evaluated using a vas (visual analogue scale). we found that the opiate resistant pain level decreased by %. the rest pain could be controlled by pereral opiate analgetics or by combination of somatostatin and an opiate plus a local anaesthetic agent epidurally. theoretically, it seems that epidural administration of somatostatin and local anaesthetic agent is useful in the control of acute pancreatic pain and systemic effect of somatostatin is beneficial in the treatment of acute pancreatitis. few studies have been performed in the critically ill (ci) and because of the complex pharmacodynamic and pharmacokinetic changes that occur, it is difficult to predict accurately drug responses and interactions in individual patients. midazolam (m) is a watersoluble benzodiazepine with a rapid onset and short duration of action in normal individuals; however its metabolism is decreased in the ci. critical care physicians every day experience suggest that among the ci there is a different pattern of response to m; here it is hypothized that such a response could be due to different metabolic behaviours of ci. m (i.v.infusion rate - rag/h) and antipyrine ( rag p.o.) were infused to ci with ( patients -group ) and without ( patientsgroup ) endotracheal intubation. blood samples were collected at fixed times during and after m infusion. total urine nitrogen and antipyrine elimination half-life demonstrated different metabolic characteristics in group chypermetabolizer") as compared to group chypometabolizer"). results follow. the results of our study are preliminary and more kinetic data in critically ill patients are needed to statistically confirm our approach of "hypometabolizer" and "hypermetabolizer". objectives: some clinieai and experimental studies suggest that propofol decreases myocardial contractility in coronary artery bypass grafting (cabg) patients. the intrinsic negative inotropic action of the drug may be independent from changes of preload and afterload, whereas the myocardial depression induced by propofol may depend on changes in ca ++ ious availability. aim of this study was to verify the hemodynamic effects of propofoi in a group of cabg patients with uneompromised contractile function and to minimize myocardial depression, during induction of anesthesia, choosing to associate calcium chloride (cac ) in an other group and to define its role in producing this effect. methods: fourty patients, randomly divided in two groups ( pts a and pts b), undergone elective cabg, were enrolled in this study. anesthesia was induced by senior anesthetist in both groups by means of fentanyl mg• kg < in ", pancuronium . mg x kg - and propofol mg • kg - in ". a blind investigator administered via another venous way at same speed ( ") saline in patients of group a and mg x kg - cac in patients of group b. hemodynamic data (heart rate hr, mean arterial pressure map, mean pulmonary artery pressure pap, pulmonary capillary wedge pressure pcwp, central venous pressure cvp, cardiac index ci, stroke volume index svi, systemic and pulmonary vascular resistances indexed svri and pvri) were obtained at baseline (to), ' after anesthesia induction (t ) and " after tracheal intubation (t ). results: hr decreased moderately in both groups (p = ns). map decreased as well, more markeatly in group a at ti and t . this trend was statistical significant (p < . ) in both groups. pap, pcwp and cvp unchanged following induction in any of two groups. ci decreased in group a (p < . ) dramatically dropping at t , while in group b it showed a negligible decrease at t (p = ns) and value similar to baseline at t . svri and pvri did not exhibit statistically significant changes. conclusions: the use of propofol as a starter of anesthesia in cabg patients allows to reduce total dose of fentanyi, dramatically reducing post-operative intubation time. propofol-fentanyl association prevented the hyperdynamic response to stress (i. e. laryngoscopy, intubation) but severely depressed ci and svi. cac simoultaneous administration effectively minimized the negative inotropic effect of propofol. moreover no unwanted side-effects due to cac were observed. diseoordinated labor activity (dla) is one of most serious in obstetric pathology.medication sleep effect to a woman in birth is of limitation of pathologic impulsation from the central nervous system, but it does not influence processes resulting in and supporting dla on the organ level. constant discoordinated uterine contractions during medication sleep (ms) imerease disturbances of uterine blood flow, organ hepoxemia connected with hyperergia of vascular wall and myometrium to catecholamines, that reduces efficiency of anesthesiologic protection. we applied hexoprenalin in complex with ms to primaparas. efficiency control was being accomlished through hysterograms, grade scale of analgetic effect where hemodynamics reaction to pain, significance of emotional reactions and their vegetative manifestations before and during ms were registered, and also through hydrocortisone level in plasma before and during ms. the examined women's average duration of ms was hours more than in control and made hours, though their average labor duration and in control was the same and made hours. % of the examined women experienced independant labor, as for the control group -only %. supplementary methods of anesthesia were required in % in control,that increased medicamentous depression of the fetus, but for the examined group -only in %. the examinees's newborns experienced favourable terminations, in control newborns were in state of light rate asphixia. analgetic effect was complete in control just in i %, and of examinees -in %. on the women's hysterogrnms before ms discoordinated contractions were registered on the background of increased tonus. during ms in control similar uterine contractions were constantly registered, but for the examinees they were not marked at all or had the proper character. the examinees' hydrocortisone level was reduced for % and in control only for %. the study has allowed to make a conclusion that hexoprenalin applications in complex with ms in case of dla make anesthesiologic care safer and more effective, promote simultaneous removal of patholgic processes in the central nervous system and uterus, which lead to dla development. objectives: the aim of report is to present a clinical study results for the evaluation of anesthesia for a patients in unconscious states by eeg examination: methods: the study was conducted on patients after a severe abdominal operations on stomach and intestine and on one patient after traumaticat exarticulation of upper extremity. all patients have different unconscious state levels from somnolence to coma ]. also thay hav~ had respiratory insufficiency and control mandatory ventilation have been used. we were used intrave,~ous injections of morphine hydrochloride from initial dose of mg. than we were increased the dose to mg i.v. by drops with an accompanying eeg monitoring and fourier spectral analysis. initially all patients have had -rhythm with slow and a-activity. an c~-activity index have been lower than %. results: after anesthesia the o-and a-activity have disappeared. the or-activity index have increased to %. also we have noted decreasing of the unconscious state levels to a possibility of a verbal contacts ( - points gcs). conclusion: the quality of anesthesia could be evaluated by eeg monitoring. a regaining consciousness afte~ the injections of high doses of morphine, probably, may be a result of an opiate deficiency (full or partial). anesthesia with the following drugs: clonidine, l-arginine, l-n-arginine-methyl-ester (l-name), and their combinations. tail-flick latency (tfl) was determined at time zero and min after each treatment. clonidine (i- ~g/mouse) prolonged tfl in a dose-dependent manner. at a clonidine concentration of gg/mouse, tfl increased . -fold compared to time zero. l-arginine increased tfl at a high concentration (i gg/mouse). l-name suppressed tfl . -fold compared to time zero at a concentration of gg/mouse. conclusion: we have found that no is involved in clonidine spinal analgesia. studies are currently being undertaken to assess the effect of combination treatment of the above drugs on clonidine supraspinal analgesia. objectives: hemodynamic changes ussualy accompany laryngoscopy and tracheal intubation.the aim of this prospective study vas tu present the effectivness sufentanil in preventing reflex circulatory respone of laryngoscopy and tracheal intubation and provides stable hemodynamio condition for induction of balanced anaesthesia. methods: adult asa i-ii patients sheduled for elective surgery.they were allocated randomly and divided into two groups:fifteen patients received single bolus of placebo prior to laryngoscopy.and tracheal intubation. anaesthesia induction was then performed with thiopental (smg/kg) and atracurium ( , mg/kg), followed by neurolept anaesthesia. mean arterial preassure (map) and heart rate (hr) were measured before, during and min after intubation. althought ecg was recorded at the same time intervals. results: the groups were compared with regard to the changes in arterial blood pressure,heart rate and electrocardiogram. mean arterial preassure and heart rate were incresed significantly during and after laryngoscopy and tracheal intubation in control group but remained unohange the baselin values in the group who received sufentanil. control group ecg suggested more changes than sufentanil group. conclusions: the results indicated that , mg/kg sufentanil for anaesthesia induction reducing the pressor response to laryngoscopy and tracheal intubation. obiective: the aim of this experimental study was to evaluate morphologically the influence of anesthesia in liver as well as in isolated hepatocytes (hc). methods: a total of female swine ( - kg) were used as liver donors and were randomly assigned to one of two groups regarding anesthesia protocol: group a (n= ): induction with intravenous sodium thiopental in a dose of mg/kg, group b (n= ): propophol in a dose of mg/kg for induction'and mg/kg/h for maintainance of general anesthesia. both groups were under the same preanesthetic regimen (diazepam, ketalar and atropin) and received standarised doses of fentanyl and pancuronium during anesthesia. in beth groups total hepatectomy was performed and the liver was perfused with - it of cold ( oc) university of wisconsin solution for a period of hours before hepatocyte isolation. liver tissue samples were fixed in formalin for the morphological study and stained with hematoxylin-eosin and pas. for hc isolation collagenase solution (type v, sigma, c- , . mg/ml) was infused via portal vein and the liver was incubated at oc for rain. cells were filtered and then washed in cold hanks' solution. isolated hc were fixed and prepared for staining or simply cryopreserved (- oc). results: histology was completed in / experiments ( in group a and in group b). mononuclear infiltration (halothane type injury) was found in all specimens ( / ). focal zonal necrosis and acidophilic bodies were found in specimens from group a ( / and / respectively) while portal inflammation with piece meal necrosis was found in one specimen from group b ( / ). smears of hepatocytes -beth formalin fixed and cryopreserved at - oc -were stained with hematoxylin-eosin and showed morphologically intact hepatocytes. conclusion: pre[imineq~' study of our material reveals mote frequent livet injury in the thiopental group, but this finding has yet to be established by increasing the number of observations. objectives: in this paper we present our experience and point out the importance of sedation of those patients who suffered severe head injuries/contusic cerebri with signs of decelebration/and who were put on ventilatory machine to obtain better mechanical ventilation in neurosurgical intensive care unit of emergency center in belgrade. methods: patients were treated from jan. till dec. results: in patients we successed to reduce agitation and decelebration. conclusions: the major demand of sedation in neurosurgical patients are that the patient should be calm, comfortable and painless. references we compared three analogous groups of patients in each, with orthopedic operations on lower extremities. in each group we applied different kind of analgesia: first group rece-ned local anesthetic ( ml . ~ bupivacaine) when analgesia was first demanded; second group received ml fentanyl via peridurai catheter when analgesia was first demanded, and third group received m] fentanyi intravenously on demand for analgesia. we used visual analog scale (vas) for estimation of pain intensity and success of applied therapy. statistical data analysis was performed using student's t-test. tha best vas had group in which local anesthetic was applied periduraly. second was the group with periduraly applied fentanyl, and third was the group with intravenously applied fentanyl the longest duration of the effect of analgesia ~/as in the second group. there were no adverse effects and complications, apart from mild sedation in the third group. for orthopedic operations on lower extremities, application of peridural catheter for anesthesia and successful postoperative analgesia with local anesthetic, or opioid analgesics is acceptable. background and obiective : tympanic temperature measurement (ttm) is a relatively new procedure which provides accurate estimates of core temperature in stable postoperative patients and in patients admitted to the emergency ward. however, experience with this technique in hemodynamically unstable adult icu patients is limited. design : prospective study with patients serving as their own control. se:ttijlg : adult medico-surgical icu in a tertiary care hospital. patients : consecutively enrolled patients with thermodilution catheters in place and without contraindieation for rectal temperature measurement and without hypothermia (core temperature < ~ interventions : tympanic temperature, measured by a commercialized tympanic thermometer (genius a first temp) was compared with pulmonary artery (pat) and rectal temperature (rt). within minutes, core temperature was assessed in each patient by the same trained individual using the three techniques in random order. measurements and main results : mean bias (ix~ and its variability (sdr of method comparison pairs were calculated using the methods comparison analysis as described by bland and alunan (lancet, ; i : - objective: to measure the prevalence of pressure sores on the intensive care unit and the effect of risk calculation on pressure score prevalence and pressure score severity. method:in during a period of months a series of prevalence studies was carried out on the sicu to investigate how many patient days with pressure sores were taken care for by the icu nursing staff, what kind of preventive interventions were done and what the patient risk was on developing a pressure score. results: on average there was a prevalence of pressure sores on the buttocks of . % on the short stay unit and . % on the long stay unit; preventive interventions increased when the pressure score was visible for the nurse and the majority of patients had a high risk or extra high risk for developing pressure sores according the pressure score risk calculator. as a result of these findings the nursing management decided in that nurses had to complete daily on every patient the pressure score risk assessment in order to be able to take adequate preventive interventions. when the results of the two studies were compared, the most important results were that: ) there is no indication of a reduction in patient days with pressure sores (short stay unit: %, long stay unit: %); ) there is a reduction in severity of pressure sores (grade iv decreased from . % to . %) because adequate preventive measurements are initiated by icu nurses in an earlier stage. possible explanations for the increase of patient days with pressure sores on the long stay unit are that the average pressure score risk score was increased from . to . and the mean frequency of nursing patients on alternate sides decreased from . to . times each day. conclusion: daily assessment of the individual patient risk on developing pressure sores does not decrease development but reduces the severity of the developed pressure sores. method: the conventional woundcare method of patients with an open abdomen is to change frequently the saline soaked ribbon gauze pads ( - times each day). this method is labour intensive for the itu nursing staff and rather uncomfortable for the patient. problems that often occur are: insufficient hygiene, frequent nursing interventions, a progressive risk for deterioration of the skin and underlying tissues, difficult to measure abdominal output and in case of bowel fistulas enteral feeding is hardly possible. in using the new method, stomahesive is applied on the skin surrounding the wound. a large size of surgical film dressing, opsite | is applied over the abdomen. two or more foley ~ catheters ch are inserted through an opening in the surgical filmdressing. the application of several lateral openings in the catheters is advised. the drains are held firmly in place between two layers of sterile opsite | "flexigrid ~'' x with the so called bookend method and are connected to a low vacuum suction system ( - kph) results: we studied the frequency of dressings changes on patients in the itu. in total they had days with an open abdomen. during this period there were dressing changes. this means one dressing change every days. further advantages of the new method are; more hygiene in patient care, no maceration and irritation of the skin, nursing on alternate sides is possible, output can be measured, in case of bowl fistula, enteral feeding is possible and an abdominal lavage is possible on the sicu by opening the opsite | conclusion: this new method of woundcare management is more patient friendly, prevents several nursing complications and decreases the work load for the nursing staff. objective: to investigate the interaction between the ventilator and the closed suction system related to possible induced negative pressure by this sytem. method: we studied in a testlung model what the effect was of the different ventilators (evita: dr~iger; servo c: siemens), ventilation modes ppv, simv) and ventilator settings (tv, trigger level, frequency, peep level) on the induced negative pressure by the closed suction system during suctioning. results: when using the evita the magnitude of the negative pressure increased when the ventilation frequency and tv decreased.. the largest negative pressure (- cm h ) was produced with a tv of ml and a frequency of /min in the ippv mode with trigger level on - cm h and a peep level of + cm h . the servo c showed a complete different pattern. the largest negative pressures were measured when no trigger level was set ( cm h ), the induced negative pressure was not depended on the tv or ventilation frequency but more depending on the ventilator mode. the simv mode produced the smallest negative pressures ( - cm h ) and the ippv mode the largest ( - cm h ). conclusion: the effectiveness of the closed suction system is very much depending on the kind of ventilator, ventilator mode and ventilator setting that is used. if the interaction with the used ventilator is not known by the icu nurse this piece of equipment can cause damage to the patient by inducing large negative pressure in the comprimised lung and there fore creating the possibility of alveolar collaps and atelectasis or oedema. introduction : ethical problems are daily and disturbing preoccupations for the icu staff. objectives : improving ethical management in icu by creation of an intelprofessional group of ethical reflexion ( iger ). methods : existing was evaluated by a preliminary formulated series of questions sended to the whole staff (q , n = , items) after two training sessions (laws, deontology, professional values, culture, norms of quality) followed by persons ( %) and directed by an external chairman, satisfaction and needs of the staff were evaluated by a second series of questions (q , n = , items). at the issue, iger was created. results : q : responders ( %). law's misinformation : to %, disagreement for limitation of intensive cares : %, hope to improve collective decisions and creation of iger : % q : responders ( %) : satisfied by the training sessions : %, non satisfied : %, want to continue the project : %, refuse : %. iger was constitute by physicians, nurses, secretary, dietetic (n = ). the first working theme was {< therapeutic's withholding and withdrawing decisions in icu ~>. four subgroups of iger's members (having access to an ethical library) worked independautly and submitted their reflexions in a tdmestrial plenary session of iger in the presence of an external chairman, allowing a synthesis. at the issue a report was writted to be used as a reference for bedside and individual decisions. conclusions : constitution of iger seems to improve ethical management in icu. the first result of iger is that it is now possible to began collectively a reflexion concerning therapeutic's withholding and withdrawing in icu. the work is going on and further subjects will be studied. objectives: ) to compare the value of heat-moisture exchangers with bacterial filters (hmef) and without bacterial filters (hme) in the prevention of colonization of ventilator tubing and ventilator-associated respiratory infections. ) to asses the temperature and relative humidity of inspired all using both types of heat-moisture exchangers. methods: mechanically ventilated patients were randomized, to either hmef or hme. endotraeheal aspirates, pharyngeal swabs and samples from tubing were collected for bacterial cultures on the st, nd day mechanically ventilation and weekly thereafter. temperature and relative humidity were measured in patients ( hmef and hme) h and h after placing the hme or the hmef. results: both groups were comparable as regards age, mechanical ventilation period, severity score (saps ii), leukocyte count, and number of patients with prior antibiotic treatment. from the hmef group, ( %) ventilator tubing yielded microorganisms in, at least, one sample as compared to ( %) of the hme group; p=ns. the incidence of respiratory infection was similar in both groups ( % vs %, p:ns, for hmef and hme respectively). among the bacterial species isolated from ventilator tubing in the hmef group, ( %) were not isolated from pharyngeal swabs. a similar ratio was shown in the hme group ( / , %). both heat-moisture exchangers were efficacious in keeping a good relative humidity of inspired air ( % • vs % • .%; p=ns, for hmef and hme respectively). relative humidity was significantly higher after h of mechanical ventilation in the hme group as compared to hme group ( . % • vs . % • %; p= . ). conclusions: both types of heat-moisture exchangers have the same effect on the prevention of colonization of ventilator tubing. similar relative humidities are achieved when using either type of heat-moisture exchanger. results: tumor and nontumer enhrgements of the thyroidea were present in ~ of the operated, surgicel adrenal disease in io!, hyperplssle or persthyroid gland tumor in ~ end endocrine pancreatic tumors in %. in the intensive oere unit, these patients wore screened by noninwsive monitoring in ~ of cases: and invasive monitoring was applied in % of ceses.the basic noninvesive methods included: electrocardiogram with standard end precerdial leeds, percutaneous eutomotlc measurement of systolic, diastolic and mean arterial pressure, measurement of hourly diuresis and body temperature, frequency, hearing capacity and rhythm of one s own breathbng bs well as pulse oxymetry. a special plece in monitoring and control of vital parameters in postoperative period belonged to the nurse, thoroughly trained for enelysis end interpretation of the observed parameters which would be discussed in the paper. it has been believed that the leader sits at the pinnacle of power. over the years, this has proven to produce frustruation and anguish instead of the expected results. leaders have not been able to produce the changes they know are essential to their organization's survival with this command-and-control paradigm. through literature reviews and evaluating leadership styles, one can clearly see the most effective form is that of empowering people to a new level of performance -not ordering it. changing the leadership paradigm to a manner/style that has been shown to be effective and one of people empowerment shifts the focus to personal responsibility for performance. removing obstae}es~ stimulating self-directed actions, and determining focus and direction are just a few elements used to create the successful environment of empowerment. with increasing pressure in the health care arena, it becomes critical that a leader's job is to get the people to be responsible for their own performance. developing ownership, creating an environment where people want to be responsible, being a mentor or coach, and learning faster while encouraging others to do so demonstrates the commitment to effective leadership. this presentation will illustrate the critical components that are achieved when every person in the institution is empowered to perform at a level that is directed toward positive, effective results. herrera m. (md) . icu. hospital regional. malaga. spain. the systems of veno-vanous continuous haemofiltration (wchf) have a high cost and a limited life span. in an attempt of lengthening their mean life it has been proposed to accomplish programmed washes of the ~-stems. this practice supposes an increase in nursing workload. in order to evaluate the real efficiency of this practice we have accomplished this study. material: prospective randomized study of all the filters of vvchf used during the last year in our icu. we have determined two groups of filters, in the first (group a) we accomplished washed in a programmed way, and in the other (group b) only when the alarms of the system suggested a clotting of the filter. for the statistical analysis we used the kaplan-meier test for survival analysis. results: we have studied a total of patient submitted to wchf during the last year. we used a total of filters with this results. objectives. sounding out the nurses about the need to inform patients" relatives and the rigth kind of such information, like a preliminary approach to an information cuality assessment, methods: we inquired all the nurses of the intensive care unit of an regional hospital by an semiestructurated questionary which included personal data: age, sex, contractual relation, professional experience.., and opinion data: do you think to inform relatives is a nurse task?. which of the next informafions do you think is more important?, please, write others topics about information you think are relevant. we process the data on epi-info estatistical program and use x test to compare the results. results" from nurses of staff refused to flu the quetionary, and were not available. of the remaining, %were v~men and % men. the mean age were . % had an svable contract and ( eventual, the mean professional experience were of years and % worked in the unit since more than years. the % answered that offer information to relatives is part of the nurse activities. we did not find differences with nurses who answered negatively comparing by sex, age, contractual relation or proffesional experience. the three information topics found out like more important were: ) to inform about patient mood. ) to inform about happenings from the last visit. ) to inform about dressing instrument required by the patient, nurses who answered negatively think that to inform is a doctors task or that nurses are not competent. conclusion~ intensive care unit teams (nurses, doctors and auxiliar personnel) should get accord on who and how to inform relatives, we consider the nurses' role on information as unquestionable. objective: investigate the respiratory and cardiovascular response after discontinuing oxygen therapy durir~ intr~/]o~pital transport. desiqn: fifty-one patients ( male and female, aged + , and , , years respectively, ~+sym) being on therapy were studied prospectively in two consecutive intrahospital transports. oxygen therapy was continued in the first transport while the second one was performed as usually, i,e, without . during transport each patient was monitored by pulse oxymeter and holter whereas arterlal blood gases were tested just before a~xl aft~-trar~portation. results: compared to daseline, pa and sa were signif~canthy decreased in the case of oxygen discontinuation (p< , i). paco was significantly inur~ds~i only in the subgroup of patients with obstructive lun[ disease (p< , ) . heart rate increased in all phases of the transport when administratlon was discontinued. blood pressure remained stable in either case. the percentage of supraventricu!ar extrasysto!es, ectopic v~r[hicui~r contractions and st-s ~ment depression was progressively increasing and became very high at the end of transport in the case of therapy discontinuation. other arrhythmias did not change significantly. conclusion: discontinuation of oxygen therapy during intrahospital transport causes severe drop of pao and sa , increases the heart rate and contributes to the appearance of arrhythmias which were not present before. methods:for evaluation of the functional state of brain the complex of methods was used,whieh included electro encephalngraphy ( brain mapping ), rheoencephalography, tetrapolar transtorax rheography. for the estimation of humoral status the level of histamine and serotonine, products of free-radical oxidation,enzimatic markers of ishemic damage of brain and of endogenous intoxication was investigated. results: patients with encephalopathies after resuscitation were observed.asystolia was as a result of:shock, trauma, asphyxia,poisonings,appiication of drugs, eclamp sia,injury of the heart,diseases of fhe cardiac vessels. all patients with postasystolic syndrome entranced in comafose condition.in the group (reconvalescents) the depth of coma by glasgo~ pittsburg"s scale was , +- , . the duration of coma was from rain. to hour,average , +- ,sh.ln the group (the deads) the depth of come was , +- , .the artificial lung ventilation was used in all patients:in the group , +- , days,in the ~ , +- , days.apallish syndrome developed in cases,in patients diagnozed <<brain death~. the th degree encephalopathy (coma) was found to be associated with disorganized eeg-pattern with predomi nant alpha-( group) and slow ( group) activity. the relative power of delta-and theta-ranges was about - per cent.the patients with apallich syndrome demonstrated greatly elevated theta-range power, that of beta -range was essentially decreased. the degree of disturbances of circulation in the both groups was different.cardiac index (ci) and stroke index (si) in the group decreased on , % and , z, in the -on , % and (; , %.general peripheral resistance (gpr) increased in the group on , %,in the -on (; , %.in the group brain blood flow was increased, in the -decreased on , n.in the group there was the normotonic type of reg-curve,in the -atonic or hypotonic type (without reaction on pharmacologic influ ence).disturbances of permeability of cellular membranes (enhanced free-radical oxidation with an increase in di enic conjugates on and n) and vascular ones (an increase of serotonin concentration on and %, hi stamine content on and %) resulted in hyperfermentia (an increase of concentration of creaune phosphoki nase in the group on %,in the - %.the level of middle molecules (mm) increased in the group on , %, in the -on , %,of polyamines (p) (spermidin,spermin,putrescin).coefficient of correlation between mm and p was , . immediate correction of neurocyte metabolism is impossible due to marked brain oedemaswelling,severe dis ordes of cerebral circulation, disturbances of membrane permeability.thus,the following treatment algorythm might be advisable: . protective inhibition of brain and reduction of its energy requirements. . recovery of cell and vascular membrane fuoctions. .recovery of blood circulatiom .oxygenation of nervous tissue and drainage of brain disintegration products.in patientshbo carried out. .active methods of detoxication (homo-and enterosorption). .correction of cerebral metabolism. . dehydrative therapy must be very cautious. conclusion: the activation of energetic metabolism in neurocytes must be carred out only under neurophysiolngical control and after definite preparation. ( ). the clinical estimation of acute cerebral failure carried out by olasgo-pittsburg"s classification of coma. we studied such groups of patients: poisoning co ( ), asystolia ( ), eclampsia ( ), acute renal failure ( ), control group ( ). methods: electroeneephalngraphy (brain mapping) was fulfilled by means of encephalograph <,medicor ~ in monopolar channels. the estimation of eeg patterns by zhirmunskaya method ( ) was carried out. there were analyzed and changes of eegb by results of rapid transformation furie after rhythmical photostimulation(phts) , , , hz. we studied also the figures of absolute and relative power in such diapason : delta ( - hz), theta ( - hz), alpha ( - hz), betal( - hz), beta ( hz and more). results: all eeo changes were divided into following types: -organized ( , groups); iii -asynehronic ( group); iv -disorganized with prevalence of alpha-waves ( , , groups); v -disorganized with prevalence of delta-and theta activity ( , , ; , groups) akkording to our model of hormonal-metabolic disbalance in pregnancy , one of the main reason of destosis is hypoergos , reesults in endotoxemia and neuro-endokrine disregulation. so, stady of central nervous system function give us the information about adaptation processes. the aim of our work is to study the degree of neurologikal deficit in destosis when olifen and lipin were used. there were studied pregnants with different severe forms of gestosis. the degree of neurologikal deficit was valued by datas of neurologikal status . eeg with ,~brain mappinng~, , electrikal resistance of the skin. the komplex inteensive therapy with applikation of olifen and lipin allowed to improve the patient,s condition , decrease the degree of neurolodikal deficit and mortality . kostenko v.phd,kabanko t.,phd,galalu s.md,beliavtseva n. ,shramenko k. phd intensive care department,donetsk medical university, donetsk, ukraine plasmapheresis (pph),as other extracorporal methods of detoxicatin,has a great importance in contemporary medicine. the role of pph is special,because of its simplicity, effectiveness, atraumatic.we incalcated pph in obstetrical clinic. there are rough changes in agregate condition of blood in more of pregnants.these changes lead to disturbances of central,organ and peripheral hemodynamic.the therapeutic effect of pph is due to influence on agregate condition of blood. we considered that application of pph is very effective in pregnants with:bronchial asthma, severe forms of diabet, psorias, gestosis, allergic diseases. we used the membrane pph in pregnants: apparatus-,,hemos-pf>,, plasmofllter pmf- ,with effective area- cm,the volume of extracorporal contour- ml.such pph has no the ~ agressive effect,,, as in cases of application another extracorporal methods. this method was incalcated in our practice recently, so results will be reported in further publications. ( ). post-operative cerebral neoplasm ( ), post-operative subdural hematoma ( ). icp was monitored via a catheter inserted in the lateral ventricle and values were continuously digitally recorded by means of a bedside computer data acquisition system (maclab). the fiberoptic tracheobroucosenpe, which guided the procedure, was passed between the nasotracheal tube and the trachea in order to avoid hypoventilalion. the patients had stable baseline hemodynaimcs. propofol infusion and fentanyl boli were administered to mantain stable mean arterial pressure values. peak (mean(sd)) icp duping the minutes pre-ciaglia procedure (baseline values) were compared with values during ciaglia procedure, and the minutes p st-ciaglia procedure. data were compared with repeated measures anova. results: ciaglia procedure duration was (mean(sd)) ( ) objectives: transient global amnesia (tga) is a syndrome caracterized by impairment of short-term memory, inability to form new memories, retrograde amnesia and repetitive queries, without other neurological signs and symptoms. the pathophysiology of tga is unknown; thromboembolic, epileptic, migrainous and metabolic mechanisms have been suggested. to address some of these issues, we undertook a study of cases of tga in whom we examined clinical, laboratory data, electroencephalogram, ct of the head, ultrasonography ecodoppler. methods: patients were included in this study: men and women. the mean age was years. all cases underwent a standard clinical examination, electrocardiogram, routinary humoral tests and x-ray, electroencephalogram (eeg), ct scan of the head, ultrasonography ecodoppler. results': the mean duration of amnesia was h. m. +/- h. m. hypertension was found in patients ( %), ischemic heart disease in patients ( %), hypercholesterolemia in patients ( %), hypertrigliceridemia in patients ( %), smoking in patients ( %), atrial fibrillation in patient ( %), history of epilepsy in patient ( %), migraine history was not recorded. ct scans of the head showed multiple small deep infarcts in patients ( %), a single hypodense lesion in patients ( %). in patients electroencephalogram was normal ( %), in patients there were widespread nonspecific electrical changes ( %), in patients there were focal nonspecific eeg abnormalities ( %). conclusion: in our study tga was more common in women ( %). we showed a prevalence of hypertension, hypercholesterolemia and cerebral infarcts compared to normal controls. we have demonstrated a higher incidence of nonspecific electrical changes in tga of lower length, while ischemic lesions in ct of the head were more frequent in tga of greater length. these data seem to be in agreement with the hypothesis that tga is a heterogeneous clinical syndrome, consisting of pure, epileptic, and ischemic types. however we did not find any correlation useful in discriminating pure from associated tga forms. from our study it is tempting to speculate that pure tga is a rare event, underlying still unknown mechanisms wich differ from ischemic, epileptic, migraineous causes. objectives: aneurysmal subarachnoid haemorrhage (sah) is special condition increasing intracranial pressure (icp) in various ways. at the other hand cerebral vasospasm and related delayed ischaemic deficit (did) could answer for the poor outcome. triple h therapy seems today a basic option to prevent did, but it may increase the icp worsening the altered intracranial pressure condition and thereby the cerebral perfusion pressure (cpp). is there any way to individualise the triple h therapy when it is necessary? methods: between sept. march thirty-seven patients with intracranial aneurysms were operated on within hours following sah. five patients were in hunt-hess iv at admission. all patients received triple h therapy in a preventive fashion following surgery and were monitored by daily transcranial doppler ultrasonography (tcd). icp and cpp was measured in twenty-four cases. twenty-two of them received lumbar liquor drainage (lld) and nineteen were administered induced hypertension. the other group was treated by basic triple h therapy. results: in group with monitored icp the outcome was twenty-one excellent, one poor, two died (one of them died from extracranial decease). in the other group four had excellent, six moderate, two poor outcome, and one died. conclusion: according to our recent observation the patients can be divided into two groups of therapy. in group i, the patients with elevated tcd values and either low or high icp reacted to lld. we are concerned that haemodilution and slight hypervolaemia should dominate in the triple h therapy. in group ii patients having high icp with tcd and/or symptomatic vasospasm should be managed by the induced hypertensionhypervolaemia dominated therapy focusing on cpp (icp) and focal neurological signs. air emboli were detected in lo% (n= ) of natients undergoing coronary srtery bypass craftin~ (cabg). central nervous system ~ysfunction occured in ~$ of the nstients with air embnli and in none of those ~ithhout air embo!i. hvtothermia is the classic form of oro-tect~on used dur~nc ~"~" " ~ ~ ca~.,~modu] :r, on~_,_. bj/oass. the surf~eon sho,;,ed thorough!~: evecnnte air from the heart, but the onesthesio!o[[ist can signifieamt!y influence the outcome by emt!oyin ~ methods to detect and treat air emboli. the changes in head rate are primarily due to alterations of autonomic tone. the heart rate variability (hrv), that express the degree of heart rate fluctuation around the mean heart rate, reflects somehow the condition of central nervous system. hrv may be measured by a number of techniques. short-term time-domain variables of hrv are reflect generally the vegal activity. in this study the changes in hrv variables of patients with brain damage, and in addition the changes in hrv measurements in comparison with the clinical evolution were evaluated. eight patient with brain damage and six normal individuals as control group were studied. a elecrocardiographer with availability of computation the sequence of beat-to-beat intervals for one minute was used. the following variables of hrv were measured: ) standard deviation (sd) of beat to beat r-r interval differences that reflects the respiratory control, )the maximum/minimum (max/rain) interval that reflect variability related to baroreflex and thermoregulation and ) the coel~cient of variation (cv), the results are shown in the in the patients with brain death and in vegetate state there were virtually no hrv. increased hrv pattern was found with clinical improvement, the changes of hrv precede of the changes of gcs, we conclude that time-domain hrv could reflects the degree of brain damage, it is good prognostic index of the brain damage and may change earlier than the gcs. objectives: cerebral co vasoreactivity is an important determinant of cerebral blood flow (cbf) and has been shown to be of prognostic value in head trauma (acta anaesthesiol. scand. ; : - ) . we wondered whether co vasoreactivity could be selectively altered in one hemisphere in comatose patients. methods: patients ( m/ f, age - yrs, glasgow - ) in coma due an acute brain lesion (trauma, hemorrhage, or infection) were studied. cbf was measured bilaterally using jugular thermodilution at paco , , , and mmhg by increasing pico with mechanical ventilation kept constant. normal co vasoreactivity was defined as an increase in cbf of at least i ml/min. g per mmhg paco . results: patients had normal co vasoreactivity bilaterally, patients had altered co vasoreactivity at both sides, and patients had a normal response at one side (left or right) with an altered response on the other side (dght or left). for the patients left cbf was in mean ! ml/min. g lower than right cbf (figure methods: following institutional approval piglets (body weight :tl . ) were anaesthetized by % fluothane. a catheter was placed in the right femoral artery for blood pressure monitoring and a fiberoptic catheter (oxymetncs- abbott) was advanced via the right internal jugular vein to the jugular bulb for sjo determinations. another catheter with a balloon on the tip was advanced in the right atrium via the right femoral vein. a mean arterial pressure (bp) at mmhg was achieved by appropriate balloon inflation for rain and two groups were cleated: i) the hypoxemic group by respirator disconnection (*) and it) the hyperoxemic group by fio =l on respirator (o). samples were obtained at time ( ), ' min at hypoperfusion ( ) arid at reperfijsion at ' ( ), ' ( ) and ' ( ). pao , pjo and oxidative brain stress evaluation was performed from jugular bulb blood. the latter included: i) no synthase (nos) and xanthine oxidase (xo) activities by a method based on the oxidation of scopoletin detected fluorometrically, it) no levels estimated as onoo-by luminol enhanced chemiluminescence in the presence of ~tm hydrogen peroxide (h ). resul'~s: the mean pao was mmt-ig for group i and methods: we retrospectively reviewed all upper gi-endoscopies, performed in the period january -july in patients ( men and women) admitted at the icu's of our hospital. results: it concerned surgical, medical, eardiological and neurological patients with a mean age of . yrs (range: - ). in %, the endoscopy was performed at the icu and in % at the endoscopy department. in % of the cases, the endoscopy was primarily diagnostic, of which % was performed for localization of upper gi blood loss. in % the endoscopy was primarily thempentic, of which % was performed for placement of a duodenal feeding canula. location of the upper gi bleeding was: variees ( %), duodenal ulcer ( %), oesophagitis ( %), gastric ulcer ( %), others ( %) and none ( %). as coincidental findings were noted: cesophagitis ( %), gastritis ( %), gastric deer ( %), duodenal ulcer ( %), duodenitis ( %), oesophageal ulcer ( %) and others ( %). conclusions: there were marked differences in indications and findings of endoscopy at the different icu's. these differences reflect an admission bias and differences in populations and treatment preferences. compared with cardiological and neurological icu's, substantially more endoscopies were performed at surgical and medical icu's. in a considerable number of cases, no source of upper gi blood loss could be found endoscopicaiiy. when upper gi blood loss was the icu admission diagnosis, the main cause was needing varices, which could be controlled endoscopically in the vast majority of cases. when upper gi blood loss was ndt the icu admission diagnosis, peigie ulcer and oesophagifis were the main causes of bleeding. because of the considerable number of coincidental almom~adities found at endoscopy, there is still room for debate whether antacid medication and/or motility stimulating agents should be given prophylactically at icu's. many studies have shown that blood lactate levels in survivors and nonsmvivors of traumatic and septic shock are significantly different. the degree of multiple organ failure is related to the duration of lactic acidosis ( ). the aim of this study was to evaluate blood lactate level as a prognostic marker of high risk postoperative patients who may benefit from invasive hemodynamic monitoring and aggressive fluids administration and early inotropic support based on oxygen transport parameters. methods: patients undergoing elective long term vascular and abdominal surgery (asa i-bi) were studied. blood lactate levels were measured after icu admission. in the case of blood lactate level above mmoltl, measurement was repeated every hours for hours or until normaiisation (blood lactate level less than mmol/ ). type of surgery, length of surgery, amount of fluids delivered intraoperatively and postoperatively, hemoglobin levels, hemodynamic variables, diuresis, postoperative complications, length of icu stay and clinical outcome were recorded. because no attempts were made to randomisr therapy or change our standard therapy protocol institutional approval was not required. rebuts: the frequency of postoperative complications was , % and mortafity was , % in a group of patients with blood lactate level less than , mmol/l (n = ). frequency of complications ( , %) was significantly increased in a group of patients with blood lactate levels , - mmol/l (n = ), mortality was , %. mortality ( %) and frequency of complications ( %) were significantly increased in a group of patients with blood lactate levels above mmol/l (n = ). conclusion: blood lactate levels can serve as early marker of high risk postoperalivr patients and may predict increased risk of postoperative complications mad ~e death. objective.~: investigated practicability and clinical value of the routine measurement of hepatic venous oxygen saturation (shvo ) after major liver surgery, as shvo is considered an indirect parameter for splanchthc and hepatic blood flow. methods: consecutive patients were included in this study after liver resections for primary or secondary liver tumors. patients suffered from liver cirrhosis (childs a). immediately after post-operative admission on the icu a pa-catheter ,was inserted under fluoroscopy via the right jugular internal vein into the hepatic vein contralateral to the resection area. hepatic venous and arterial blood samples were drawn every two hours. shvo was correlated to the clinical course, macro hemedynamics, abgs aug other established lab parameters. results: in out of attempts the catheter could be placed correctly. in four cases after right hemihepatectomy the left hepatic vein could not be intubated due to a dorso-lateral tilting of the left liver. this is also reflected in a significantly longer time of fluoroscopy for catheterization of the left hepatic vein ( . _+ % rain vs. . + . rain; p < . ). the procedure requires a total of between and minutes. relevant clinical complications were not observed except for short term supraventricular arrhythmias during passage of the catheter through the right atrium. hemodynamics and pulmonary function could be considered normal in all individuals at time of measurement. shvo showed a span from . % to . % with a mean of . % -+ . %. the following statistically significant findings could be obtained: (a) patients with liver cirrhosis showed a significantly lower shvq than patients without ( . % • . % vs. . % • . %; p < . ). (b) a negative correlation between shvo immediately after operation and the duration of intraoperative hepatic vascular occlusion could be observed (r = - . ; p < . ). this correlation could also be seen for the first post-operative hours (r = - . ; p < . ). (c) a negative correlation between shvo and the difference between arterial and hepatic venous lactate levels was found (r = - . ; p < . ). conclusions: the routine measurement of shvo appears to be a promising extension of post-operative monitoring after major liver surgery. it is a safe method easily feasible on any major surgical icu though relatively time consuming. a further validation of this method is necessary in larger studies. therapeutic recommendations on the basis of shvo findings cannot be given yet. methods: in cases after major liver resection, in which abnormally low readings of shvo suggested an impaired hepatic blood flow, pgi was applied at a dose rate of ng/kg/min. as shvo can be considered an indirect parameter for hepatic blood flow, the effect of pgi infusion on shvo was measured. moreover, the changes of macro hemodynamics and pulmonary function were monitored. results: before the application of pgi z mean shvo for all patients .was . % ( - - - ). in three cases without major structural alteration of the remaining liver tissue the continuous intravenous administration of pgi lead to a sustained increase of shvo z to an average of . % ( . - , ). the postoperative course in these three cases was uneventful. in two cases with compensated liver cirrhosis after hepatitis c no change in shvoz under pgi infusion could be observed. both patients died and days respectively after operation in protracted liver failure. side effects of pgi included a slight decrease of systemic and pulmonary vascular resistances. consequently map decreased by up to % as did intrapuimonary right-left shunt increase. in none of the observed patients did these side effects posed a limitation of continuous application of pgi z. conclusions: in patients without structural alteration of the liver the systemic application of prostacyclin at a dose rate of ng/kg/min could significantly increase an abnormally low hepatic venous oxygen saturation after major liver resections, tn two cases of severe liver cirrhosis a similar increase could not be observed. after first clinical investigations and with the results of recent studies in animal further controlled clinical studies of prostacyclin in the postoperative management after liver surgery appear justified. any delay in gastric emptying can promote micro-aspiration and give rise to ventilator associated nosoarnnial pneumonia. h -receptor antagonists have been suspected of promoting pneumonia by changing the gastric ph. in a few tri',ds on humans ranitidine was noted to delay gastric emptying. the aim of this prospective, randomised, blinded study was to evaluate in a ventilated icu population if there was a difference between cimetidine (c) and ranitidine (r) on the gastric filling index (gfi conclusion: in this population there was no difference in gfi between c and r; however the age and creatinine were significantly different and could have favoured the c group. also the very long t/ could have hidden smaller differences between c and r as has been described in volunteers. between april , and april , , patients with severe acute pancreatitis were admitted to participating hospitals. patients were entered into the study if severe acute pancreatitis was indicated, on admission, by multiple laboratory criteria (imrie score >_ ) and/or computed tomography criteria (balthazar grade d or e). patients were randomly assigned to receive standard treatment (control group) or standard treatment plus selective decontamination (norfloxacin, colistin, amphotericin; selective decontamination group). all patients received furl supportive treatment, and surveillance cultures were taken in both groups. results: fifty patients were assigned to the selective decontamination group and were assigned to the control group. there were deaths in the control group ( %), compared with deaths ( %) in the selective decontamination group. (adjusted for imrie score and balthazar grade: p = . ). this difference was mainly caused by a reduction of late mortality (> weeks) due to significant reduction of gram-negative panreatic infection (p = . ). the average number of laparotomies per patient was reduced in patients treated with selective decontamination (p < . ). failure of selective decontamination to prevent secondary gram-negative pancreatic infection with subsequent death was seen in only three patients ( %) and transient gramnegative pancreatic infection was seen in one ( %). in both groups of patients, all gram-negative aerobic pancreatic infection was preceded by colonization of the digestive tract by the same bacteria. reduction of gram-negative colonization of the digestive tract, preventing subsequent pancreatic infection by means of selective decontamination, significantly reduces morbidity and mortality in patients with severe acute necrotizing pancreatitis. ieco by sodium hypochlorite (nacio) infusion is considered to be a model of microsomal oxidation in liver on cytochrome p- . active c provides oxidation of toxic metabolic products in the blood and exfused during plasmapheresis plasma, and also hydrophobic to hydrofilic transformation of substanses. sterile nacio in necessery concentrations was obtained by electrolysis of saline ( , - , % naci solution) in electrochemical set e~io- (russin,moscow). methods: . the nacio in concentration ragfl ( - ml/ h ) was administred into central veins in patients with extensive peritonitis and endotoxicosis - /t. erytrocytes resistance to nacio, circulating blood volume glycemia and hemostasis were initially estimated. . after plasmapheresis exfused toxic plasma was mixed with nacio conccantration of i mg/t in : ratio in sterile "hemacons".the effectiveness of plasma detoxication and possibility of its reinfusion were evaluated by determination of albumin effective concentration (eca g/l), the concanlration of medium molecular oligopeptides (mm , ) and other biochemical tests (bilimbin, creatinine, carbomide and so on). results: . the intravenous administration of nac excels detoxicative effect of hemosortion by - % provides effictive presentation of protein components and blood cells and improves the transport function of albumin by %. . the return of exfused plasma after its purification ieco was - %. only the remaning - % of deficient plasma were compensated by fresh cryoplasma and albumin solutions. ischemic hepatitis (ih) is a severe complication in critically ill patients. acute circulatory failure of multiple etiology can lead to splachnic hypoperfusion and cause acute and reversible anoxic damage. over a period of mos pts, m and f, mean age + . yrs developed liver disease compatible with ih. eight pts had a documented hypotensive episode (six pts with septic shock and two hypovolemic shock), while cardiogenic pulmonary edema in the absence of hypotension was responsible for ih in the remaining four pts. all the pts had a rapid striking elevation of ast, &lt and ldh with equally rapid resolution of these parameters to near normal wimin days (mean . ). the mean peak level of ast, alt and ldh was iu/l (range to ), iu/l (range to ) and iu/l (range to ) respectively. serum total bilirubin levels rose transiently with a moan t:eak level of . mg/dl (range . to . ), while altered coagulation paran-,ete's (pt> . times normal) was observed in four pts and clinically significant coagulopathy with fibrin degradation products occurred in one pt ( . %). renal impairment (cr> . mg/dl) was manifest in all pts; six pts developed non-oliguric renal failure ( %) while two pts required hemodialysis. ten lots required vasoconstrictor inotropes [dobutamine (range - pg/kg/min) and dopamine (range - pg/kg/min), while replacement of circulatory blood volume was performed in two pts with hypovolemic shock. eight lots expired ( . %), but none died as a direct result of hepatic damage. the mortality rate was higher among pts with concurrent renal failure ( %). it is concluded that: ) ih is not uncommon complication in the icu with the prognosis depending on the underlying disease. ) clinically significant coagulopathy is uncommon complication of ih. ) titration of inotropes is required to obtain optimal cardiac output support and subsequently liver blood flow. it is difficult to ascertain the perfusion of free flaps such as jejunal loops after surgery. objectives: to assess ischaemia as evidenced by intramural ph of jejunal free flaps used for reconstructive surgery following total pharyngolaryngectomy. methods: the sigmoid ph tonometer ( tonometrics inc.,usa ) was used to monitor intramural ph of the jejunal free microvascular flaps ( phig ) in patients who underwent total pharyngolaryngectomy. a standard general anaesthetic was given and all patients were admitted to the icu for controlled ventilation and monitoring. all had similar postoperative care. phig was measured pre, post-revascularization of the flap and on icu admission, , and hours postrevascularization. objectives: to classificate the wide spectrum of itc of anp into distinct pathophysiological patterns according to presentation and course. patients (pts) and methods: pts, ~( , %), ( , %) were admitted in the icu because of anp and acute respiratory failure(arf), ilean age: , • years. hean stay in icu: , • days. pts were operated, of them twice. hean value of ranson's scale: , • ( - ). we analyzed hemodynamic measurements,arterial blood gases(abg), x-ray findings(xrf), ct-scans and operative records. results: patterns of pleuropulmonary complications were identified: a)early hypoxia without xrf - pts. b)early ards with typical xrf - pts( died), c)early arf with xrf(atelectasis,infiltrates)- pts( died). d)late ards with typical xrf- pts( died), e)pleural effusions in various combinations with the above patterns - pts. overall mortality rate: / = , %. conclusions: l)frequent x-rays and abg are important for the classification of itc of anp. )even though patterns of classification in anp are not clearly distinguishable,they facilitate an anticipatory management. )deterioration of abg and xrf indicates that preventive measures for arf must be intensified and agressive surgical therapy is required. )delay of surgical therapy is related to worse prognosis(p<o, ) and prolonged hospitalisation time(p<o,ol). in the contrary, the early timing of the operation before infection and extrapancreatic necrosis is essential for a better prognosis (p<o, ). objectives: the development of cholestasis during intensive care treatment is allied with an inferior prognosis. this study investigates the sensivity, specification and also the positive and negative forecast of patients survival -exemplary for bilirubine. methods: during a period of months all surgical patients on icu were registrated prospectively (n = ). for documentation of disease development a standard foldcrform based on a computer-data-system was used. the results of this kind of documentation showed aapprax. , m!ll. of single patient informatioas. results: of patients didn't suffer from liver disease or have any operation on liver or bile tract. of them have had a normal scale of bilimbine in the postoperative period, a higher scale of bilirabine was regisu'atcd by patients. at a ,,cut-off" of rag% (total-bilirubine) the sensitivity was , , specivity , , positive predicive level , , negative predictive level , for survival criteria of a patient. the max. reached level of bilirubine, also the daily increase turned out almost the same results as they were found for other parameters nf cholcstasis like ap or gamma-gt. objective: the aim of this experimental protocol was to evaluate the morphological and functional parameters of isolated pig liver grafts, perfused in an extracorporeal liver support system. methods: the system consists of the graft liver, a membrane oxygenator (oxygenation surface . cm z, flow= itlmin), a heater, a centrifuge pump and a fluid reservoir. twenty pig livers, mean weight gr (min , max gr) were obtained and after a mean cold ischemia time of min were perfused fo} a mean of . h (min . , max h). perfusion solution consisted of r/l and hemacell. inflow to the graft liver was performed through the portal vein at a mean pressure of ( - ) mmhg at ~ while outflow was secured through the suprahepatic inferior vena cava. during perfusion the following parameters were evaluated through pre-and posthepatic hourly (to-t ) sampling: po , " + + " pco , ph, hco -, na , k , ca , osmolality, glucose, lactate, ast, alt, alp, u bilirubin and coagulation factors i, v and viii. biopsies were obtained periodicallty. b_p_~: results were as follows: mean ph fell from . at t o to . at t while mean output po fell from at t o to at t . mean output ast values increased from at t o to > at t while mean output alp values increased from . at t o to at t . mean output k + values increased from . at t o to > at t . histology revealed lesions of ischemic necrosis, more prominent after t . conclusion: results show that the isolated liver graft presents satisfactory function and morphology at least for a five hour perfusion period in the described extracorporeal circuit. correction of ph contributed to an increase in bile flow. between and the practice of transplantation has changed drasticaily in switzerland -besides kidneys also hearts, heart and lung, lung, iiver and pancreas transplantation has started in several centers. major information efforts have been made, organ exchange rules were set up and a national coordination center was initiated. the aim of this retrospective single center study was to assess the influence of transplantation on organ donation. in the past eleven years organs were donated from potential donors i single, multi organ donations) analysis of refusal was evaluated categorized into medical and/or familiar reasons. the number of potential donors increased from ( ) ,to ( ) with a concomitant drastic reduction of donations from % in to % in ; amounting to a net unchanged number of donations over the last years ( = ; = ) . the import and export of donor organs was balanced since the introduction of the national coordination center. in contrast multi organ donation increased from % in to % in despite of the more stringeant selection criteria, in conc]usion the introduction of a full range of transplantation procedures at several new university programs and the increase of multi organ donation has not had the forecasted impact on organ donation despite a sustained informative and promotional campaign, objective: monitoring hepatic venous oxygen saturation (svho ) provides online information about hepatic-splanchnic oxygen supply-demand ratio [ ]. previously, x~ reported hepatic venous catheterization in patients undergoing orthotopic liver traru~lantation (olt) [ ] . in the present study, we assessed the effects of nitroglycerin (ng), a vasudilator that affects the venous capacitance vessels more than arterial vessels and prostaeyclin (pgi , flolan r~, wellcome, uk), an arterial and splanchnic vasodilator on hemodynamies and hepatic venous oxygen saturation (svho ) in human liver transplantation. methods: with institutional approval and informed consent, consecutive patients, mean age - -_ years, were studied following olt. postoperatively, fiberoptic pulmonary artery catheter was inserted into the right hepatic vein. timed infusions of ng at a rate of . gg/kg/min and pgi at ng/kg/min were initiated for a rain period. each sequence was followed by baseline therapy for rain. results are expressed as mean=tsd. statistical analysis was performed using friedman's-two-way-anova-test, significance was accepted at p< , . results: ng at . gg/kg/min induced a decrease of mean arterial pressure (map) ( _ [baseline] vs. + mmhg) and pulmonary artery wedge pressure (pcwp) ( j: [baseline] vs. : mmhg). cardiac index (ci) ( - vs. + l/rain/m ), oxygen delivery index (do i) ( -+ vs. + mgnfin) and svho ( _~ vs. -l-_ %) were decreased (p< . ). pgi at ng/kg/min induced a reduction in map ( • nm~. _g) and pcwp ( + mmhg). ci ( _+ l/rain/m ), do i ( : ml/min) and svhoz ( + %) were increased (!o< . ). vasedilatation induced by ng decreased systemic oxygen supply and impaired splanclmie oxygenation. pgi increased systemic oxygen delivery in parallel with svho , suggesting a corresponding improvement of hepatic-splanchnic okygenation. thus, if vasedilator therapy is indicated in th orient receiving liver grafting, pgi appears to be advantageous. however, due to its platelct aggregation inhibiting properties, the usefulness and safety of pgi in olt patients has still to be determined. objectives: to analyze the effect of steroid treatment given to donor on the early function of transplanted kidney. methods: from january, until now donors were involved into this prospective study. every other donor was treated with mg/kg solu-medrol one hour before organ retrieval. according to the steroid treatment of the donor the recipients were divided into two groups: group -steroid pretreatment goup (y~= ), and group -control group (n= ). the donors and the recipients were treated using the same kidney transplantation protocol onl~r the adults, and the first cadaver kidney transplanted patients were involved into the study. the daily routine parameters were analyzed pre-and intraoperafive, and on the - th, th and th postoperative days. results: we could not show any clinically important differences between the two groups in respect of donor parameters. preoperative, the patients in group had slightly lower ereatinin level ( -+ g.,non vs. -+ gmol/ ) which persisted into the early postoperative phase. the values of the other examined pre-and intmoperativc parameters were almost the same. during the first postoperative days the patients in group i needed less diuretics (furosemide and renal dose of dopamine) and their sodium excretion was closer to the physiological range than in group . the other parameters did not differ significantly. the less furosemide need in group ! pe~isted to the end of the first month. conclusions: according to our data the steroid treatment of the donors improves the early function of the transplanted kidney in some respects. to prove the real benefit of the donor steroid treatment needs more data and further analysis. objectives: severe infections may compromize the outcome of liver transplantation..determination of new parameters may increase the knowledge of pathophysiologic mechanisms and may lead to changes in postoperative therapeutic management of patients at risk. methods: between august and september , patients with transplants were monitored for cytokines and extracellular matrix pammeters on a daily basis. serious infections (n= ) included microbiologic evidence and more than secondary organ failures. patients with cholangitis (n=ll) or uneventful postoperative course (n= ) referred as control groups. results: -year patient survival was . % ( / ): patients died due to serious infections, while died for other reasons. mean bilimbin, stnf-rii-, ifn- -, il- -, il- -, il- -, laminin-and neopterin levels were significantly elevated in patients with serious infections compared with patients experiencing mild cholangitis or with an uneventful postoperative course. a further increase of all parameters was observed in patients who subsequently died; tnf-ri/: _+ pg/ml vs • pg/ml; ifn- : _+ pg/ml vs . -+ . pg/ml; il- : -+ pg/ml vs -+ pg/ml; il- : -+ pg/ml vs _+ pg/ml; il- : _+ pg/ml vs • pg/ml; laminin: -+ ng/ml vs -+ ng/ml; neopterin: _+ nmol/ vs _+ nmolb for non surviving vs-surviving patients. a significant decrease of sialic acid yeas observed in patients with serious infections; and a further decrease occurred in patients who subsequently died: -+ mg/l vs • mg/ . conclusions: the increase or decrease of various cytokines and extracellular matrix parameters may be indicative for severity of infectiolx routine monitoring of these parameters may improve current diagnostic tools and poss~ly lead to changes in therapeutic management of patients at ~k. objectives: evaluation of the cytokine network after liver transplantation may give some insight in pathophysiologic mechanisms of rejection and may lead to detection of patients at high risk. methods: patients with transplants were monitored for various cytokines on a daily basis between august and september . rejection was assessed by histology in combination with clinical signs of rejection and laboratory investigations. results: during the first postoperative month, patients ( . %) developed rejection; patients were successfully treated with methylprednisolone (steroid-sensible rejection), while further patients required additional treatment with fk or okt (steroid-resistant rejection). patients subsequently developed chronic rejection. mean levels of various cytokines and extracellular matrix parameters including tnf-rii, ifn- , il-ib, il- r, il- , il- , il- , hyaluronic acid and neopterin were significantly higher in patients with steroid-resistant than in patients with steroid-sensible rejection. a further increase of some parameters was observed in patients who subsequently developed chronic rejection; bilirubin: . -+ . mg/dl vs . -+ . rag/all; tnf-rii: -+ pg/ml vs _+ pg/ml; il- : +- pg/ml vs -+ pg/ml; neopterin _+ nmol/ vs -+ nmol/ ; hyaluronic acid: _+ ~tg/l vs _+ ~tg/l for patients with chronic versus patients with acute steroid-resistant ~ejection. sialic acid levels decreased in patients with acute steroidresistant rejection; and a further decrease was observed in patients who tieveloped chronic rejection: _+ mg/l vs _+ mg/ . ~onclusions: various cytokines and extraeeuular matrix parameters were indicative of severity of rejction. the extensive increase of bilirubin, tnf-ii, il- , hyaluronic acid and neopterin may indicate subsequent chronic ection. monitoring of these parameters may, therefore, lead to changes in immunologic management after liver transplantation. background : combined kidney and pancreatic transplantation is being performed with increasing frequency in patients with diabetes mellitus and renal failure, as it offers more chances of success and better results than kidney transplantation alone. mycotic arterial aneurysm constitutes a devastating complication following pancreatic transplantation. all cases of mycotic arterial aneurysms have been however reported with exocrine pancreatic drainage into the gastrointestinal tract. intervention : we describe a series of consecutive whole kidney-pancreas transplantation performed at the university of geneva hospitals ( beds) between december and may . exocrine pancreatic drainage into the bladder (epdb) was performed to improve early detection of rejection episodes. epdb was hypothesized to reduce the risk of contamination from the gastrointestinal tract and the subsequent possible occurrence of potentially fatal infectious complication. in all patients the dual transplantation was performed through a median incision according to the procedure described by nghiem. results : two out of the patients who received kidney-pancreatic transplant developed arterial mycotic aneurysms and days following surgery. aneurysms developed at the site of the arterial anastomosis used to rearterialize the homograft. both patients had peritonitis caused by candida albicans requiring surgical drainage and intravenous antifungal therapy. rupture with hemorragic shock occured in both patients leading to graft removal in one patient, and three episodes of lffetreateniug hemorragic shock followed by graft failure and removal days after transplantation in the other. conclusion : arterial mycotic aneurysm constitutes an early, lifetreatening complication of kidney-pancreatic transplantation; it mandates graft removal. although exocrine pancreatic drainage into the bladder consitutes a definitive advantage for caller diagnosis of graft rejection, it does not eliminate the risk for retrograde colonization and subsequent severe infection in our experience. s. bocharov, i. teterina, regional clinical hospital, irkutsk, russia acute profound loss of blood can result from the very different injuries and hepato-pancreato-duodenai operations enter such a rank. ill-timed and inadeguate correction of operation hemorrage is one of the reasons for postoperation complications, including polyorganic insufficiency. the pathogenesis seems to be very complex. in early stages of bleeding the liquid enters the vessel bed, followed by hypoproteinosis and hematocrit fall. however, as decompensation develops, the fluid leaves the vessel system in the result of increasing postcapillary resistance and lowering col-ioidnooncotic blood pressure (cop). the resulting hypovolemia causes primarily acute disturbance of central hemodynamics and then of microcirculations and transcapillary exchange. central hemodynamic failure after acute loss of blood manifests itself through cardiac output lowering and capillary blood flow deceleration. taking into consideration, that % is critical value for cpv loss and for cev it is %, we consider arising the level of cop to the immediate task. cop raising allows to normalize transcapillary exchange, which we assess through cop and mcp (mean capilary pressure) gradient. the next task is to make up for globular volume till homeostasis providing level. considerable attention is given to catabolism inhibition and maximum possible enegry provision. control over high proteolitic activity of blood and callicreinkinin system activity implies direct proteases inhibitors. reologic, membrane stabilizing, antihypoxanthine and anticoagulant therapies are obligatory. virehow clinic, dept. of surgery, humboldt university berlin, germany regarding a high mortality up to % of fulminant hepatic failure orthotopic liver transplantation seems to be the only promising therapeutic approach in many cases. this study shows experiences from a transplantation center. between june and april patients suffering fulminant hepatic failure were admitted to our surgical intensive care unit all patients showed severe liver dysfunction with grade ii to iv encephalopathy. after a period of diagnostics and conservative treatment ranging from few hours to days (mean . days) we reported of these patients as possible organ recipients to eurotransplant. all of these patients were transplanted within hours, ( %) of them even within hours. the principal aetiologies were hepatitis b ( ), hepatitis c ( ), nanb hepatitis ( ), mushroom poisoning (amanita phalloides ). after transplantation patients suffered from initial-non-function and underwent re-transplantation. the one-year-survival rate was %, patients died within months after transplantation due to various reasons. patients were not referred for liver transplantation. of them never met transplantation criteria, improved by conventional therapy and could finally be discharged from hospital. the known reasons for liver failure in this group were mushroom poisoning ( ), paracetamol intoxication ( ) and fulminant hepatitis a ( ). patients suffering from fulminant hepatitis ( ) or intoxication ( ) were excluded from emergency liver transplantation for various contraindications. of these patients ( %) died despite conventional intensive care. we don't know if some of the patients in the transplantation group would have survived without transplantation, because whenever we decided on transplantation we could perform the operation within hours. but the good survival rate in the transplantation group ( %) the % recovery rate in the group, where there was no transplant-indication in our opinion and the fatal outcome ( % mortality) in patients with contraindications are an encouraging proof of a successful therapeutic strategy in acute liver failure. these results are based on a close cooperation between experienced transplant surgeons, hepatologists and intensive care doctors, using sophisticated laboratory and imaging techniques in a specialized center. introduction: during brain death patients suffer from multiple endocrinologic disturbances. one of the most important are those related with thyroidal axis. it is well described the euthyroid sick syndrome whose more frequent pattern consist of decreased triiodothyronine (t ), increased reverse t (rt ) with normal levels of tetraiodothyronine ( " ) and tsh, this lacking in " " levels lead to a change from aerobic to anaerobic metabolism which results in tissular damage. objective: .to study thyroidal pattern in brain death patients potential organ donors. .to avoid organ impairment by administration of t . .to study the hemodynamic and hormonal changes after the administration of t in these patients. material and methods:population: brain death patients of any etiology potential organ donors admitted to the intensive care unit. patients were classified in hemodynamically stable (group ) and unstable (group ). group received a bolus of . p.gr/kg. and a perfusion at a dose of - . p.gr]h of t . hormonal assays: total t (tt ), total " (tt ), tsh. fxee t (ft ), free " (ft ) and rt were determine at the moment of clinical brain death ( hrs) and in group two these assays were repeted at hours , and . results: patients ( male) with a mean age of years (range to yrs.) were studied. the clinical brain death was confirm later with other explorations (eeg, doppler). there were patients in group ( , %) and patients in group ( , %). hormonal pattern: at the moment of brain death tt was normal in cases ( , %) and decreased in i ( , %); tt was normal in patients ( , %) and decreased in ( , %); ft was normal in cases (i , %), decreased in ( , %); fl' was normal in patients ( , %) , decreased in ( , %) .rt was normal in cases ( , %) and increased in cases ( , %). there were no statistically significant differences in hormonal pattern between the two groups. only t levels at hours , and were significant in group . in the cases with ft decreased, the tt was normal in ( %) and decreased in ( %), tt was decreased in ( , %) and normal in ( , %), tsh was decreased in i ( , %), normal in ( , %) and increased in i( , %) and ft decreased in ( , %) and normal in ( , %) and rt was normal in ( , %) and increased in ( , %). there were no statistically significant differences in cardiac index, vascular resistances and pulmonary shunt before and after the administration ef t . conclusions: . the hormonal pattern most often find in brain death patients was: normal tt , decreased tt , normal tsh, decreased ft , normal fr and normal rt . . there were discrepancies in the values of ft and tt . there were no statistically significant differences in hemodynamic and pulmonary parameters. objectives: magnetic resonance angiographie (mra), a non-invasive procedure, provides flow-related information additionly to the anatomy of the vascular system. measurement of signal intensity and edge detection of vessel structures permits to calculate blood flow velocity and vascular diameters. we examined whether cerebral hemodynamic changes by altering the arterial pressure of carbon dioxid (pace ) could be detected by mra. methods: following institutional approval and informed consent, mechanically ventilated patients without elevated intracraltial pressure underwent mra with defined periods of hyper-, hypo-and normoventilation (pace : , , mmhg; arterial blood gas probes; avl). mra was performed with a . tesla magnetom (vision, siemens). two different mra techniques were used: a conventional time-of-flight- d-angiography (tr: ms; te: ms; fl: deg; slab: mm) for vessel diameter detection and a flash- d-gradient-echo-sequence (tr: ms; te: ms; fl: dog) for measurements of blood flow velocity. an axial view parallel to the ac-pc-iine (anteriorposterior-commissur-line) was used for repeated imaging of identical regions of interest toi) of the proximal part of the internal carotid (ica) and middle cerebral artery (mca) as well as of peripheral branches of the mca and the posterior cerebral artery (pca). results: changes of pace correlated with changing signal intensities, whereby under hyperventilation a decrease of , % (p . ) and under hypoventilation an increase of . % (p . ) was observed compared with normoventilation. blood pressures were stable throughout the whole study period, pace dependent changes in vessel diameters were more pronounced in peripheral branches of mca and pca. a change from normo-to hyperventilation produced a decrease in proximal vessel diameter of - . % (p _< . ) and in peripheral diameter of - . % (p _< , ). a change from normo-to hypoventilation produced an increase in proximal diameter of + . % (p < . ) and of + . % (p -< . ) in peripheral diameter. conclusions: pace related changes of cerebral vessel diameter can be easily detected by mra without injecting a contrast agent. the results confirm that co -reactivity is more pronounced in peripheral cerebral vessels, which are subjected to greater changes in diameter than major basal arteries. hyperventilation leads to a decrease and hypoventilation to an increase in signal intensity thus reflecting the corresponding changes in blood flow velocity, intensive care unit (icu) of "kat" hospital, athens, greece, ob!ective$; the value of bronchoscopy in pulmonary atelectasis of icu patients is under question the presence of an air bronchogram sign in xrays, which is considered as evidence of central bronchus patency, is referred in several studies as a negative criterion for bronchoscopy, whereas its absence as a positive one. it is also referred that air bronchogram sign correlates with delayed resolution of atelectasis, probably because of obstruction of many periferal airways (not central). the purpose of this prospective study was the evaluation of the air bronchogram sign on frontal chest film as a negative criterion for bronchoscopy and as criterion of delayed resolution of atetectasis, methods: icu patients with atelectasis were studied prospectively. they underwent bronchoscopy, bronchoscopic findings, presense of air bronchogram sign, and outcome of atelectasis were recorded, correlations were made, between: ) bronchoscopic potency of airways and air bronchogram sign } resolution time of atelectasis and broncoscopic potency of airways. ) resolution time'of atelectasis and air bronchogram sign, methods of statistical analysis were the t-student test and the chi square test, results:the patients were , men women , seventeen patients had atelectasis of whole lung, of upper lobe, and of lower lobe. ten patients had atelectasis in right and in left lung. eight from patients had air bronchogram sign in x-ray, there was no statistical correlation between air bronchogram sign and bronchoscopic potency of airways [ from patients with air bronchogram sign ( %) and from without air bronchogram sign ( %), had bronchoscopic potency of airways, p> . ], resolution time of atelectasis didn't correlate statistically with bronchoscopic potency of airways (mean resolution time in patients with bronchoscopic potency , days and in bronchoscopically closed bronchi , days, p> , ). there was also not a statistical correlation between resolution time of atelectasis and air bronchogram sign (mean resolution time in patients with air bronchogram sign , days, and without air bronchogram sign , days. p> ). conclusion~i; the presense of an air bronchogram sign in x-ray of icu patients with atelectasis, does not coexist obligatorily with bronchoscopic patency of airways and cannot be used as a negative criterion for bronchoscopy, neither as a criterion of delayed resolution of atelectasis. th. wertgen chest sonography (cs) is routinely used in our department to examine icu patients with clinical symptoms of pulmonary embolism, pneumonia, pleural effusion or unclear chest pain. we perform cs with a sector transducer ( . mhz) and a linear transducer ( . mhz) using acuson xp/ c. the sonographic signs of pulmonary embolism and infarction are most well demarcated, mainly wedge shaped and triangular pleural based lesions, more roughly structured, observed with a hyperechoic reflex in the center corresponding to the bronchitic (fig. ) . pneumonia is characterized by homogenously hypoechoic, wedge shaped parenchymal lesions, containing air or fluid bronchograms; they move with respiration (fig. ) . pleural effusions are spaces of various echogenicities, from anechoic to homogeneously echogenic, which may contain floating strands or complex septa, located between visceral and parietal pleuras (fig. ) . from march to april we did examinations by cs in icu patients ( male, female; age from - ). patients examinations pulmonary embolism pneumonia pleural effusion us-guided thoracic punctions were performed in patients. in two patients we found pneumonia or pleural effusion caused by a lung carcinoma. another two patients showed a normal cs (diagnosis: inflammation of the gall bladder, inflammation of the myocardium). conclusion: cs is a very useful method for icu patients with chest diseases. it takes less time and is less expensive than ctand sometimes of a higher diagnostic value than x-ray. last but not least cs is invaluable for the icu patient, because the examination is done save and quickly at bed side and the results of cs are very helpful in diagnoses and treatment. results : inter-observer reliability was evaluated as an % concordance. results of the tee classification were : class : n = ( %) ; class : n = ( %) ; class : n = ( %) ; class : n = ( %) class : n = ( %). therapeutic implications of tee in class patients were : cardiac surgery in patients (two cases of acute mitral regurgitation, two valvular abscesses and one hematoma compressing the left atrium), discontinuation of peep in one ventilated patient with an atrial septal defect, weaning of mechanical ventilation in one patient with an atrial septal defect, prescription of antimicrobial therapy in patients with endocarditis and prescription of anticoagulant therapy in patients with left atrial thrombus. the only noteworthy complication was a case of spontaneously resolving supraventrieular tachycardia. conclusion : tee is safe and well tolerated, and is useful in the management of icu patients with shock, unexplained and severe hypoxemia or suspected endecarditis. the aim of this study was to determine whether ultrasound guidance can help interns to improve the results of jugular vein access in icu. methods : in a prospective and randomized study, we compared, in patients admitted to the icu, an ultrasound-guided method (ultrasound group : patients) with an external landmark guided technique (control group : patients). all jugular vein accesses were performed by young interns with an experience of < procedures. results : internal jugular cannulatian vein was aci~ieved in all patients in the ultrasound group and in patients ( p.cent) in the control group (p < . ). average access time was longer in the control group ( • sec. vs • see. ; p = . ) and puncture of the carotid artery occurred in patients in each group (p = . ). patients ( p.cent) in the ultrasound group and patients ( p.cent) ia the control group (p < . ) were cannulated in rain. or less. the cannula was therefore unabie to be inserted within minutes in patients in the control group, with failure of eannulation in of these patients ( p.cent). failure was due to thrombosis (n = ), small calibre of the internal jugular vein (< ram) (n = ), abnormal vascular relations (n = ) or cervical irridation (n = ). among the primary failures of cannulation, an internal jugular vein catheter was able to be inserted in cases by an experienced physician on the side initially selected and with ultrasound guidance in cases. the catheter was inserted into the contralateral internal jugular vein under ultrasound guidance in the remaining cases. jugular cannulation was obtained at the first attempt in p.cent in the control group and p.cent in the ultrasound group. conclusion : ultrasound guidance improved the success rate of jugular vein cannulation by inexperienced operators in icu patients. when the internal jugular vein has not been successfully eannulated within minutes by the external landmark guided technique, the authors recommend the use of the ultrasound guidance. in the majority of cases right atrial or ventricular thrombi represent pulmonary emboli in transit. these may be fatal in patients (pts) treated conservatively with anticoagulation only. in literature the incidence of right heart thrombi in pts with proven pulmonary embolism (pe) is said to be in the range of - %. extremely mobile, long, worm-shaped masses in the right heart cavities carry an especially high early thrombus-related mortality rate which ranges from - %. current therapeutic strategies favour fibrinolytic therapy with consecutive anticoagulation. we report five cases ( male, i female, - years) of right heart and pulmonary thromboembolism. in these pts diagnosis and regression of thromboemboli following systemic intravenous lysis therapy with recombinant tissue-type plasminogen activator (rt-pa) was documented by transesophageal echocardiography (tee). a submassive pe occured in pts, a massive pe in pts. one patient (pt) had a cardiac arrest. in all cases tee clearly identified the extensive thrombns formation in the right-sided cavities of the heart and in the central pulmonary artery in cases. all pts were treated with mg rt-pa, pts in a front-loaded regimen over minutes, pt over minutes, and, due to the life threatening situation, in one case a bolus injection as ultima ratio was performed with no intracerebral bleeding complication. regression of thromboembolic masses after fibrinolytic therapy was demonstrated by transthoracic and transesophageal echocardingraphy after to hours. all pts survived and were put on coumadine, pt developed an intracerebral bleeding with persistent hemiplegia. conclusions: the use of thrombolytic therapy is highly efficacious for the therapy of pts with pe and concomitant right or ventricular thrombus formation. transthoracic and especially transesophageal echocardiography are powerful bed-side diagnostic tools for the immediate diagnosis and follow-up of successful treatment in this life-threatening condition. although widely used, catheterisation of the femoral vein in the groin using "landmark" technique is frequently complicated by accidental arterial puncture. suboptimal hygiene and patient discomfort are also associated with this technique. with regard to these last two factors cannulation of the femoral vein - cm below the inguinal ligament would seem an attractive alternative. as "landmark" technique is not possible for the cannulation of the femoral vein in this part of the thigh, ultrasound was used to locate the vessel and the results of this technique were evaluated. methods: a portable compact ultrasound device (site rite,dymax corp.) featuring a . mhz transducer (ultrasound depth - cm) fitted with a needle guide and a cm screen was used by residents with no previous experience in ultrasound guided cannulation. patients consisted of a surgical icu population. results: in patients catheters were introduced.in cases more than one ( - ) attempt was made and in patients the procedure was unsuccesfull due to the fact that the vessel was situated out of reach of the ultrasound (vessel depth > - cm), during the procedures one accidental arterial punction was registered. the catheters remained in situ for a mean of days (range - ) and were used for volume suppletion, medication, parenteral nutrition and haemodialysis.co-ionisation rates compared to those of subclavian catheters in our icu. in the first patients cases of asymptomatic thrombosis of the femoral vein were seer on ct-scans performed for other indications, in the following patients duplex scanning performed after removal of the catheter yielded another cases of asymptomatic femoral vein thrombosis. conclusions: ultrasound guided femoral vein catheterisation - cm below the inguinal ligament is a safe and simple technique that can easily be performed by residents without prior experience. the incidence and impact of thrombo-embolic complications associated with this technique are still subject to further investigation. objectives: to estimate the cost of antibiotherapy (ab-cost) in a multidisciplinary -bed greek icu and to correlate ab-cost with total cost of drugs and consumables and with patient's outcome, severity of illness and type of admission. methods: prospective data from consecutive patients admitted to the icu from / / to / / were studied. a tick chart was designed to record all drugs, materials and consumables regularly used for icu patients, but did not include low price drugs and consumables, which are provided from hospital's pharmacy as stock and were included in a fixed icu cost calculated for a month period. the chart also contained demographic details and data necessary for the calculation of several illness severity scoring systems. obiectives: over years evaluate the necessary efforts and expenses to implement a cis in the routine of a -bed stcu. methods: in june a commercially available, unix-based cis was installed on a -bed surgical icu. the goal was a paperless documentation at the bedside. after more than years clinical experience two aspects were investigated: what effort is necessary to install and support a cis, and what is the benefit for patients and personnel on the icu? results: the installation and support of a full-fledged cis requires a considerable effort: (a) the conceptual framework for the cis has to be defined. this includes the definition of documentation standards, as well as nursing and therapeutic standards, which is the essential basis for the configuration of any cis. (b) configuring a cis, i.e. "fine-tuning" it to the user's specific needs, is always a laborious task. moreover, constant maintenance is necessary. these tasks require the following personnel: experienced health care professionals for defining the conceptual framework, - trained health care professionals for configuration, system administrator. on a single icu ( - beds) these are not considered full-time jobs. (c) training is best done employing the "train-the-trainers" approach. (d) beside the necessary amount of man power and money to install and purchase a cis, administrative and mis support is needed, especially when interfaces to the hospital and laboratory information systems have to be set up. in general, a cis needs the commitment of all people involved. without a really professional approach with a longterm goal any major cis can turn into an unnecessary but inevitable night mare. after years clinical use and a thorough implementation of a cis on a major sicu it can be said that full-fledged cis offers an opportunity to dramatically improve the working environment on an icu. moreover, it adds to patient safety, quality of care and cost efficiency in one of the most advanced and expensive areas of medicine. conclusion: a major investment in man power and money is necessary to install and maintain a full-fledged cis. a sincere professional commitment to the goals of a cis is necessary. in exchange, a well configured and well maintained cis dramatically improves the quality of therapy and care on the icu. even return of investment and financial profitability of a cis seem feasible todayl from the clinical perspective it appears that the users themselves are the central determinant whether a cis makes a dream come tree or turns into a night mare. objectives: to establish a relationship between the activities of the staff and the occurrence of auditory alarms on the i. c.u. ard to evaluate confusion between auditory alarms. methods: laboratory based studies which investigated aspects of confusion between alarms in current use on the i. c. u. the observational studies were conducted over an month period and examined the frequency and duration of alarms together with the concurrent activites being undertaken by staff on the unit. the laboratory based studies showed that there were enduring confusions between the alarms on various items of medical equipment, for example a ventilator alarm and an e. c. g. monitor alarm. the results of the observation studies demonstrated that alarms are activated when specific activities are being undertaken by staff. sounds could be used in future recommendations for alarms on medical equipment. suggestions are also discussed for improving and rationalising auditory warnings in the i. c. u. obiectives: we investigated inferior petrosal sinus (ips), the lowest affluent to jugular bulb (jb), as a possible source of contamination of samples in jb for monitoring oxyhemogiobin saturation (sjbo ). pulling back the catheter the oxyhemoglobin saturation usually rises indicating extracerebral contamination (jakobs en met al: j cereb blood flow metab ; : ). methods: the study was carried out on patients undergoing ips sampling to differentiate cushing disease from ectopic acth syndrome and to lateralize any resulting pituitary lesion. we studied the value of oxyhemogiobkn saturation high in jb (sjbo ), at ips (sipso ) and at mid jugular vein ( th cervical vertebra) (smj ) bilaterally. results: we found significant differences between right sjbo and both right sipso (p= . ) and right smjo ( p= , ) and between left sjbo and both left sipso (p= . ) and left smjo (p= . ) we did not fred any difference bilaterally. objectives: we studied various methods of receiving and editing of clinical datas in critically ill patients (different ethiology). patients were investigated in regional intensive care center. methods : the following datas were studied : anamnesis, status praesens objectivus ( organs and systems ) ,. clinical and biochemical markers of critical condition , datas of eeg ,rheography . the medical information complex contained : channel electroencephalograph, -channel roencephalograph, ad-converter ( analog inputs, bit resolution, k hz), ibm dx , software includes set of routines for spectral eeg analysis, eeg-mapping, correlative analysis, and brain bloodstream reg-monitoring (written in turbo pascal . ), expert programs for estimation objective and humoral patient status (written in clipper . ) and statistics. there were used following programme-language instruments : borland c++ . , nantucket clipper . , ca-clipper tools ii. as the methods of statistical processing of dates were used: t-students criterion , fisher criterion, methods of correlation analisis, calculation of the regression levels, dispersion analysis, results : there was created the optimal structure of hard and sofware complex of search steady objective regularity in dynamic of critically ill patients condition. conclusion : the created system allowed to value effectiveness of intensive care and give us new opportunities in study pathogenesis of systems disorders in critical condition . over a five year period a patient data management system has been installed which allows individualised patient data to be accurately collected. using this data a costing system has been developed which ascribes costs thus: . direct costs -drugs, fluids, consumables, interventions. these are ascribed to individual patients, according to data collected from the pdms. . indirect costs -energy, depreciation, admm costs, maintenance etc. these are summed for the year and ascribed as an overhead per patient day. n.b staffcusts contain art element of both cost types the aim is to make as many costs as possibie 'direct', hence 'activity costs' have been calculated winch comprise staff time, drugs and consumables -these are direct costs. these costs of patient care are then searnlessly integrated into the financial and budget management of the icu environment. it was found that by calculating costs in this manner % of the total cost of icu are captured within the 'direct' element, and so are able to be ascribed to individual patients. this is much more accurate than simply dividing the total costs of ~cu by the number of patient days. temporal costs (variations during patient stay) and cross sectional costs (cost differences between admitting specialities) were also noted with interest. results of the initial analysis of data captured by the system will be presented. little is known about the resource costs (not simply cash costs) of icu. even less is known about individual patient costs, with previous estimates of these costs varying widely. however, if cost effectiveness studies are to be undertaken accurate calculation of individual, group and total icu cost is an essential, prerequisite, which, via this system of costing, is now achievable. information about intensive care of cancer patients is limited in the literature, despite the increasing use of such facilities in oncology over the two last decades. in order to determine if and how critical care facilities can be used specifically for these patients, we performed a world-wide inquiry in anticancer centers selecting the hospitals by using the international directory of cancer institutes and organizations. we mailed a questionnaire to centers and we received responses ( . %). there was at least one uncological (i.e. with > % of cancer patients) icu in (% % an -year old woman with graves disease presents with sore throat, vomiting, diarrhea, sinus tachycardia at /minute and a temperature of ~ several weeks before, treatment with propylthiouraeil had been stopped (rash and fever) and replaced by methimazole and ledide prior to a minor surgery. however, both drugs were discontinued by the patient two weeks before admission. shortly after arrival in hospital, patient's condition progressed to respiratory failure (upper airway edema), delirium and shock requiring icu admission, intubation and resuscitation with fluids and vasopressors. white blood count was /mm ~ with neutrophils. patient's hemodynamic data showed initial hyperdynamic profile followed by low output state with decreased sv ( %) (n - %) and cardiac index ( , ) (n , - ). echocardiogram confirmed cardiac chambers dilation as previously described in thyroid storm. lithium carbonate, corticosteroids, antibiotics and beta-blocker perfusion were given. plasmapheresis was started. free t& (n= , - pmo/l) went from , to , after the first two pheresis. after a remarkable clinical recovery, sub-total thyroideetomy was done i days after admission. in life-threatening thyroid storm, plasmapheresis is a very effective therapy when anti-thyroid drugs are counterindicated. purpose: to compare the reliability of prognostic indexes in crhically iu patients admitted in an intesive care unit (icu) who had acute renal failure (arfi and were treated with different dialytic techniques. material and methods: patients were included in a prospective study from june to november . patients presented arf defined by creatinin serum leve(s greater than pmol/l and previous normal levels. patients were divided in three groups. group i (control) : patients with arf who did not receive substitutive techniques. group ih patients under intermittent hemodialysis (hd) or peritoneal dialysis (pd). group ii : patients under continuous hemodiafiltrstion (hf). the statistical analysis was chi-square test and analysis of variance. results: the table shows the results we obtained, we did not find any significant difference betwen the two groups of patients undergoing dialysis. d(fferences were observed only between group i and the other groups as shown below. we did not find any significant association between the theoretical mortality predicted and the observed mortality according to saps in the three groups. due to exposure to a wide variety of unpleasant stimuli, for example, tracheal suctioning, venipuneture and physiotherapy, most pataents admitted to the icu will require some form of sedation. this review will describe the suggested properties of an ideal sedative agent for use in the icu and review the current limitations of some of the available agents from this perspactive. methods used to quantify the level of sedation, such as the ramsay score, glasgow coma score, newcastle sedation score and visual analogue scores, and their deficiencies will be examined. consideration will be given to defining the optimal level of sedation and the circumstances under which sedation might be varied over the icu course will be discussed. preliminary results from an ongoing study examining the role of light versus heavy sedation and ischaemia in a cardiac surgical icu population will be presented. the pharmacceconomics of icu sedation will be briefly addressed. finally, the role that sedation may play in increasing morbidity, pastieuiarly nosocomial pneumonia, in the icu will be discussed. objectives : therapy cost(tc) in icu patients is a substantial component of total hospital care cost. estimation of tc during this year, partitioning to various groups of drugs used and attempt to minimise it, were considered practically useful. methods : in collaboration with the hospital pharmacy we were able to have a complete report of au drugs used for icu patients (including enteral and parenteral nutrition). mean apache ii severity score upon admission was . and mean length of tcu stay was . days. price per drug unit and cost per group of drugs were also available drugs were divided into two groups: antibiotics ( ) cardiovascular drugs ( ), gastrointestinal system drugs ( ), enteral and parenteral nutrition ( ), respiratory system drugs ( ), sedative, analgesics and paralysing agents ( ), parenteral solutions with electrolytes, vitamins and trace elements ( ), anti-inflammatory agents ( ), protein substitutes and immunomodulation agents ( ), anticoagulative agents ( ). antibiotics were further subdivided into those "freely" prescribed (a) and those whose prescription and administration requires filling of a relevant form (b). results : !) tc for icu patients/day was . drs ($ ). total tc/patient was . drs ($ . . ). ii) partitioning total tc per group of drugs reveals : ( ) %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %. t ) concerning antibiotics which consist the major cost component, group a and group b contributed by . % and . % to the total icu tc respectively. group b were administered to . % of all icu patients. conclusions : i) for the above studied patient population antibiotics consist almost half of total tc followed by protein substitutes and immunomodulation agents. ii) if tc control could be attempted in the icu, prescription of beth groups must be reviewed. appropriate treatment should be prescribed and readily provided to any patient. clinical significance of routine protein substitution, currently controversial, should be re-evaluated. new antibiotics (third & fourth generation cephalosporins, quinolones, carbaponems) should be prescribed on the basis of strict diagnostic procedures using modern technology available. rationalisetion of antibiotic therapy will lead to cost control, redistribution of icu expenses and substantial contribution to infection policy in our country. objectives: i -to investigate the clinic efficiency of the monitoring of the rso cerebral, in relationship to the stroke prevention, in patient undergoing carotid surgery. -to determinate the variations of the rso during the different surgical and anesthetic procedures in these patients methods: ten patients undergoing carotid endarterectomy. precise neurological exploration previously to the surgery and in the immediate postoperative period. angiography evaluation to the extend of carotid artery disease. invasive blood pressure, ecg, pulse-oximetry ( pso ) and rso were collected previousty to the induction of anesthesia. the premedication was administered intravenously -midazolam ( mcgr/kg) and fentanyl (i rncgr/kg) -. thiopental ( mg/kg),fentanyl ( mcgr/kg) and atracnrium ( , mg/kg) have been used for induction of anesthesia. co te is monitoring al~er the orotraqueal intubation ! the anesthetic maintenance is accomplished with lsofluorane ( , - , %) and bolus of atracurium and fentanyh the surgical procedure is standard (without arterial shunt during the carotid cross-clamping). we register each minutes: blood pressure, cardiac frequency, pso , co te and rso . the rso cerebral variate in relation with: the anesthetic induction, blood ~ressure, co te, cross-ulampping carotid and with the modifications of the head position. the maximum decrease of rso cerebral was in relation with the :ross-clampping carotid ( minimal value: ). no patient had neurologic complications and postoperative stroke after carotid endarterectomy were not observed. objectives: there are more than anesthesia in chelyabinsk emergency hospital every year. to % patients of it emergency anesthesia is applied. more than patients have ishemie heart disease (ihd), hypertansion (hp) and previos miocardial infarction (pmi). more than % of all patients are old patients (op). the resalts deep noninvasive bioimpedance monitoring (nbm) in surgical patients have been studied by us. methods: our nbm system "kentavr" includes parameters of cardiac and vessels function. it is realised by monitors in operation theatres and computer network. moreover we are able to examine surgery patients before anesthesia and perioperatively by using special computers system for cardiovascular reflex control by fast fourie transform (fft) of parameters simultaneously. results: pathients extremly needed peryoperative monitoring of hemodinamics. from these patients more % had stroke volume (sv) less than ml, n -co less than . /mim/m , % -ejection fraction (ef) less than n and % -puls bioimpedans microvessels (pbm) less than morn. patient had intensive care in special department. out of died. comparing with survived with these patients before operation hr was larger, sv, co,ef, pbm and puls bioimpedance aortha was smaller. much more of these patients were with ihd, pmi, hd, op. even with survived patients these parameters decreased the towards the end of operation. surgery patients had different variability of basic hemodinamical parameters with common tendency to increase power amplitude in low frequency by fft. conclusions: using of bioimpedanee noninvasive parameters allows to have criteria for corrections (infusies, vasodilatators, inotrops and others) and then us the final goal, to have more sucssesful surgery. with survived patients was perioperatively and postoperatively care more intensive. obiectives: the aim of the study was to compare the phi with the hemodynamically derived tissue oxygenation indexes as: oxygen delivery (do ), oxygen consumption (vo ), cardiac index (el), and arteriovenous difference in oxygen [(a-v)do ]. methods: patients ( males and females) with major trauma or major abdominal surgery were studied. on admission, a nasogastric tube allowing phi measurement was introduced and a pulmonary artery catheter was inserted for optimal hemodynamic management. each phi measurement was accompanied with a complete hemodynamic study comprising systemic and pulmonary artery pressures, blood gases, and cardiac output measurements with the thermodilution method. derived parameters vo , do , ci, (a-v)do were measured according to the standard formula. hemodynamic parameters were opt• as soon as possible with fluids, inotrepes, and vasopressors according to repetitive hemodynamic measurements. all patients were under mechanical ventilation. after hemodynamic stabilisation phi and hemodynamic measurements were repeated every eight hours, during a -hour study period. a total number of measurements were obtained and compared. statistics: results are presented as means + sd, correlations were performed between phi and the hemodynamically derived oxygenation parameters. a p< . value was considered as significant. results: mean values were phi= . + . , do = + , vo = + , c. = . + . , (a-v)do = . + . . no correlation was found between phi and do , phi and vo , phi and c.i, phi and (a-v)do . on the contrary in patients phi remained below . for more than hours despite adequate hemodynamically derived tissue oxygenation parameters. mortality in this group of patients was very high ( %). conclusion: no correlation was found between phi and the hemodynamically derived tissue oxygenation parameters our data suggest that phi is a better oxygenation indicator than the hemodynamically derived tissue oxygenation parameters, because it is closely related to the patient's outcome. objectives: the pathogenesis of septic shock and multiorgan failure is believed to be related to tissue hypoxia of the gastrointestinal tract. therefore new monitoring techniques, preferably organ specific, are required to establish the adequacy of tissue oxygenation. peep is used to reduce pulmonary shunt volume and improve blood oxygenation, but is accused to impair splanchnic perfusion. we studied mucosal oxygenation and perfusion on the capillary level in the stomach and the duodenum. methods: we used the erlangen microlightguide spectrophotometer (empho ll) together with a specifically designed fibre probe (bodenseewerk ger~tetechnik, berlingen) in combination with a standard gastroscope. measurements were performed on ventilated, traumatized patients (ages - years), with no evidence of shock or severe infection, after informed consent was obtained from the relatives. all patients were hemodynamically stable without inotropic support. an area of cm was analysed in the gastric corpus, the antrum and in the duodenum. in three patients we simultaneously measured the muc sal blood flow using a laser doppler flowmeter ( objectives: to investigate the influence of hb-o affinity in the monitoring of svo~ during improvement of cardiac index (ci) in cardiogenic shock. design: to state whether changes in svo: were associated in changes in actual pso (p~ ) and standard p~ (ps st) consecutive measurements of artero-venous bga, before an.d after therapy-induced changes in ci, were evaluated in patients (mean age -* y) suffering from cardiogenie shock, all under mechanical ventilation in psv modality. methods: together the hemodynamic measures, m~xed venous samples were analysed at ~ c using the abl radiometer for po , pco: and ph, and the osm radiometer for hbo %, hbco% and methb%. psost (i.e. the p~ at ph= . , pco:= mmhg and temperature at ~ c) was calculated automatically by the instruments on mixed venous blood as was the ps "in vivo" (i.e. the pso at the patient's value of ph, pco and temperature), using siggaard-andersen's computerizated algorithm. mean time between paired measurements was . -* . houm. the data were compared by anova test for linear regression and t-test for paired samples. results: a dose linear relationship was found between svo and oxygen extraction ratio (oer), r= . ,p= . . the improvement of ci ( . -* . to . + . l/min/m , p< . ) induced a significant increase in svo~ ( . -* . to . • . %, p<. ). a significant decrease in p ( . • . to . • . mmhg, p< . ) without any significant change in p~ st ( . • . to . • . mmhg, p=ns) was also found. these data show that either oer or the shift to the left of the oxygen dissociation curve account for increase in svo occurring with restoration of systemic blood flow. the program is intended to help the intensive care unit interne providing him with a practical tool when making decisions concerning patients in a critical condition. in his daily practice in intensive care unit, in this case the interne of the unit, uses this program for each patient as follows: on the first stage of data collection he should complete the following modules: ( )personal data ( )patient's pathology ( ) laboratory and~ monitor lug data ( )drugs prescribed or toxic elements ingested. in this way, the system allows optionally the consult with a computerized data base about the drugs prescribed, standardized parameters and techinques performed by the central laboratory. ( )reference to an antibiotics guide regarding becterian sensitivety in our unit, whitch ee checked every six month ( ) access to de questionnaired apache ii to load up new data. ( ) statistcs about patient's admission and discharge. results: once all data collection is finished the system performs the followin duties: ( )detailed drugs interactions, including toxic elements ( )diagnosis starting from the clinical, laboratory and monitoring data. in some cases, it also establishes therapeutic strategies, e.g. a coagulopathy ( ) give the l~narmacological incompatibilities between the drugs p~escribed and %he diagnosis established, and ( )perform dosage adjustments based upon the personal and pathological data. objeatve: to assess the power of diseri~,~ion ofa multiperpose severity score (sai~) when applied to subgroups ofpatieals (pta) according to their lemg~ of ~ay (los) in icu. design: in order to compute the saps probability, a model derived fi~m legible regression was developed. meaumree of calibration (goodmem..of.fit statistics) end discrimination (roc cm've and relative area under the cm've) were adopted in develotammtul asd validation set. the whole databue was ~ati~ed in five gronps reeked on los as follows: los = days, los = - days, los = - da~, los = - days, los > day~. area under the carve (auc) was ud~ninted for each ro~. s~ing: imlimlcus. patents: of ~ pts comec~ively admired ~ a period of three yeet~ ( ) ( ) ( ) , a total of was i~leded in this study. pts without saps, p~ yolmger them yearn, p~ with los shorter ~ hom'~ were excluded from this maly~is. iaterventinns: nose mema'onm~ end result: the logistic model developed gave good remits in terns of calibration md discrimin~on, both in developmental set (do.s g : . , p > . ; auc = . i- . ) and in validation ~t (g.o.g g : . , p > . ; auc = . ..+ . ). auc of each grottp showed a loss in di~zimination (i.e., prediaton) closely related with los, being . i- . in pts with los = days el . ~. ia tm with los > da~ (figure). following the present guidelines of integral management, in order to achieve optimization of sanitary resources and better use of facilities, we feel that the setting up of objetives is a key factor in the continuous process of improvement of quality care. postsurgical intensive care services maintain an interdepent relationship with other hospital services. within the general plan of the hospital it's of the utmost importance to delegate autonomy to the various depertments and service units in determining and achieving objetives. it's also necessary to establish mechanism for coordination of the activities in order to assure the succes of the program. the objetives cannot be improvised, they must be carried out in a specific manner in the following stages: .-analysis of the present situation (starting point). where are we?. defining objetives and making explicit the activities and methods to achieve them is to anticipate the future; it is of the utmost importance to comunicate said plans to all whom affect by encouraging them to attain the desired results. in the present paper we intend to show the guidelines to follow in carrying out a course of objetives. introduction:we presents results related to the quality of life (qol)of critical patients, from paeec project data. material and methods: the paeec project is a multicentre study define the type of patients cared for in spanish icus, and the therapeutic activity provided. ninety-five icus from spain are taking part. this study analyzes the qol of critical patients prior to their icu admission.for the evaluation of qol a questionnaire designed by our team for critical patients was used, with items grouped in sub-scales: physiological functions ( items); functional capacity ( items) and subjective aspects ( items). qol is classified in levels: normality ( points); slight deterioration ( - points);moderate deterioration ( - points); significant deterioration (>i points). the we present results related to therapeutic activity in critical patients and their age, from the paeec project. material and methods: the paeec project is a multicentre study to define the type of patients in spanish icus, and the therapeutic activity provided. ninetyfive icus from spain are participating. this study analyzes therapeutic activity in the first hours as evaluated by tiss, and related factors. results: the sample was , patients, sge . ~ . years. severity by apache ii system was . • points. the tiss score was . • points, distributed as follows: i (<i points): %; ii (i - points): %; iii ( - points): %; iv (> points): %.there is a positive correlation between the level of therapeutic activity and severity by apache ii (r = . , p < . ), and a very weak but negative correlation between tiss and age (r = - . , p < . ), so that an increase in age corresponds to a lower level of therapeutic activity.patients the multivariate analysis of the relationship between tiss and age took into account: severity, existence of previous history, need for mechanical ventilation, size of hospital, diagnosis and mortality. it indicated that there continued to be a relationship between therapeutic activity and age, so that as age increased, therapeutic activity diminished. conclusions: therapeutic activity performed on critical patients is less in the oldest patients, in whom excessively aggressive procedures are limited. a relational data base management system in the icu. c. kotsavassiloglou*, d.matamis, g. dadoudis, j. kioumis, d. riggos. icu dep., g. papanicolaou gen. hosp., exohl, thessaloniki, and * a' neurological clinic of aristotelian university, thessaloniki, greece. objectives: the introduction of the information technology in the i. c. u seems to be unavoidable because of the large amount of produced data and the need for their systematic analysis. such an information system should be a) easy to use, b) friendly to the user, c) powerful and d) modular. on that basis, we created a patient data management system (pdms) according to the expectations of the medical staff of an eighteen bed multidisciplinary icu. methods: we selected paradox for windows v . for the implementation of a relational data base because this program meets the above mentioned criteria. informations regarding the patients include a) demographic data, b) previous medical history, c)diseases upon admission, d)complications during hospitalization and e) outcome data. the diseases' registration consists of items classified in categories upon the principal system affected. specific informations about the need and duration of mechanical ventilation, nutrition, renal replacement, right heart catheterization and icp monitoring are also available. an extension was added concerning icu infections and related informations about antibiotic-resistant pathogens. all icu pathogens can be matched to their resistance or sensitivity and cost of antibiotics. the program can perform queries and various statistical analyses based on complex criteria. new modules can be added later according to the future needs and remarks of the users. results: the program was well accepted by the medical staff and patients were registered as a test. the first analysis of the data related a) observed mortality versus the apache ii predicted mortality, b) mortality according to the age, gender, pathology aud duration of icu stay and c) pathology upon admission and icu related complications. conclusions: the long term use of this pdms can be an efficacious research tool. it can be used in retrospective or prospective studies by addition of necessary modules. the first data analysis revealed the iack of an international diseases' classification system. the development of a worldwide common classification system is essential for the compatibility of the data analysis among various icus. this will allow the realization of multicenter trials on a large scale. s. nanas= n. sphiris, a. precates, a. lymberis, m. pirounaki, and ch. roussos dept. of critical care, university of athens, athens, greece the complexity of the cases submitted to an icu, the variety of underline disease, tbe severity, as well as the large number of substances administered to each patient constitute obvious the need of support with an easy available dss. this system will assure the safety of the administered treatment will help to adjust the dose according to the situation of each patient and it will screen for possible interaction and incompatibilities between the administered drugs. the goal of the present effort is the design and development of a software system acting as a decision support tool to physicians of icu. the application is organised around a relation database management system (rdbms) that consist of: a) all available substances ( . ), b) all generic names of medications available in our country for each substance, c) incompatibilities ( . cases) and d) interactions with other substances ( . cases). the following figure shows the structure of the rdbms. y ta~ortato~ [ c~rs using the stored parameters for each patient the dose and the rate of administration of selected substances will be possible to calculate. the continuous monitoring of the treatment for each patient supports the medical staff to make the necessary changes of the prescriptions. the application is currently developing in wireless pen based computer systems which place patients at the centre of "islands of information" located throughout icu. in conclusion this dss is a powerful and useful tool for icu staff because it provides without additionai work to the routine of daily practice, the currently available information for each order concerning drug interaction and incompatibilities as well as treatment monitoring is to obsea~ among critically ill pfdieats, stdjdivided following the diagn~s at the adn~ssio~ the diffmeax:es in the ~ and oxyplx~efic l~mmems bawe~ strvwors [s] and non sumvors ins] and to test the pc~'bih'ty to have soar survival criteria, as earliest as tx~able. method~ :we made a ~ study on consexa~e ~ilically ill paliffas, subdivided in series following the diastases at the admission: medical pafiea~ ( s and ns), surgical patients ( s and ns), a~d poliwauntas ( s and ns). follow up was done at d,.ays from the admission in ice. all the patienls were ramitored with a ~ c~eter and laeno:lymmi. "c and o .x.xyphorefic txuamaers va:~e couected at fin~es (t): at fiae ~draission (t ), at x~ars from t (t ), at (f ), (y ), (t ), % (t ) and horus from t cf ). in~,h ~ies, for ~y ~ a all the lin'~ n~an and sandaid d~viation was ~ tx~h for s and for ns. th~ betw~ s and ns tl~ roeaas of ~h porarneter ~e ccmpared tt~ng t-lest and p < . w~ considered ska~ significant in each series in the t wheae the mast significative diffemx:as ~goeamd bet~en s and ns, we made a txedictive criterion, asamting as predictive indices for stnvival the i:r values, higher or lower than flae treans of the ~rar~ers of au flae patients, axx)rdhlg to those ones t~iatistically diff~'e~ betw~m s and ns. fhmlly xse co:weatxt onaong the series the nrametees of the st~rs with the analysis of variance, to daserve the lxjsable differealt irea~ of sty hflices, following the diagn~s of admission: :nedkal, angical patient or poll~tam results: we c~ld not find ~ predictive criterion for politraonaas, perhaps ixx:ause of the few ntanber of l~fients. for high ri~ saw~cal patieras the following criterion at t has a sensitivi .ly of ~ ,and a ~ecificity of . %: sv > . nffmin/n~, map> mmhg, pmap< nmalqg cvp<i nunhg will nmah& lvswi> g m/m , sxo > ~ do > mlhnin/m , o er< %. for lx~dical l~tienls at t the following criteric~a has a ser~tivi.ty of % and a ~zificity of . ~ cvp< . mn~g, sao > %, s,g) > ~ vo i< ml/nfin/m , o er< %, shunt< % survlvops' data of the series ~ signitic~atly differenl~ both for the t~mody~nic a~ for fl~e ox rphomfic lxlmn~s; moreover we ~ that the vatt~ of hemodynamic mad ox.~ho~tic indices were higher in politrautms. conclus'ions: acx~ording to the fftffe~mt patho!o~es, the ~ rnelabo~c needs are diffeten~ so that it is juslified to mash ~ the~alceutic goals, following the type oflmthology. hen~ we foru~d for high ~k mrgical pmka~ and for medical patier~s assme, ff mllslied, a good prognosis while, if n [ ntljsfled~ the plinsliclioil ofdl~tth is no[ g(ioct finally, ab~ high iis~ supgical palieaats, according to what other atmhors say, txatws sh ~'n~ers ' therapeutic goalsvvould seem inadeqt~te, bec~jse they need a gear physiologic and themtx~ic elth~ in rdation to the rretabolic needs. figure ) . thus, the smaller european nations had a greater participation than ~e larger ones, with the exception of norway. a similar result was evidenced for contributions to intensive care medicine (figure ). these findings can be explained by different submission policies and language banners. however, there was no significant correlation with the gross national product of each country. conclusion: we conclude that the smaller european countries generally contribute more to international intensive care journals than the larger ones. objectives: to evaluate the agreement between a new and three old methods measuring ctp and to assess their reproducibility. methods: we studied patients ventilated with a siemens c respirator. we measured ctp by dividing the tidal volume with the increase in airway pressure (paw), either with the respirator setting used (ca) or with a fixed setting (cf). by modifing the inspiratory time (ti) without changing inspiratory flow, we were able to deliver two series of inflations ( , ,... ml) before and after curarisation of the patient. the same volumes were also inflated in paralysed patients with a super syringe. at the end of each inflation a plateau of sec was performed and paw was recorded. the above three sets of pressure-volume (pv) points were used to reconstruct the corresponding pv-curves (( , c , c the new method for ctp measurement without a super-syringe had the best reproducibility in paralysed patients and gave similar results without curarisation in the majority of them. however, agreement between the methods tested was unacceptable for clinical purposes. further investigation is required in order to improve the accuracy of ctp measurement in icu patients. m kunert, r.sorgenicht, l.scheuble, k.emmerich, h.g ker med.clinic b (dept.of cardiology) i heart center of wuppertal/university witten-herdecke,germany objective to determine the accuracy of activated partial thromboplastin time (apl-l) and activated clotting time (act) studies when samples are drawn through heparinized central venous catheters (cvc). methods a total sample of paired act/p't-/" values was analysed in patients ( m., f., + y.) for monitoring heparin therapy.all patients had a cvc (certofix trio,braun,frg) in the internal jugular vein receiving a continous infusion of . u heparin via the central catheter.act (hr-act, hemotec,usa) and ap'i-f (neothromtin, behring,frg) samples were drawn from the cvc using the double syringe technique (removing and discarding ml blood before drawing the sample). these blood samples were compared to act/ap'cf blood samples obtained by venipuncture (v.fem.) at the same time, act values were analysed directly in the intensive care unit (icu),api-i samples were measured in the hospital laboratory within minutes. results ac-i -~ pi-f~ cact/~pi r = , ) cvc samples + + . v.femoralis samples " + + p-value n.s. n.s. conclusion there is no difference in heparin anticoagulation studies drawn from heparinized central venous catheters compared to those obtained by femoral venipuncture,withdrawing ml blood prior to obtaining the blood specimen is a safe way for eliminating heparin contamination.not only the aptt test but also the act test is a useful method for heparin anticoagulation assessment in the icu. objectives: evaluation of the delicate balance between filter-coagulation and patient-hemorrhage using heparin as anticoagulant in continuous renal replacement procedures. methods: from january through august , we studied filter surviva[ and hemorrhagic complications during filter periods in critically d[ patients, treated with continuous arterio-venous hemo(dia)filtration, with special emphasis on the heparin dose, concurrent use of coumarins, systemic activated partial thromboplastin tirne(aptr), platelet count, mean arterial bloodpressure and the type of filter used. results: filters ( %) were disconnected because of coagulation. mean survival of multiflow an filters was twofold shorter compared to survival of fh gambm filters. a total of hemorrhagic complications occurred of which three patients died at aptt values of respectively , and seconds. after adjustment for mean arterial bloodpressure, platelet count and the type of the filter, the risk for filter-coagulation decreased % (relative risk . , %c . - . ) for each ten seconds increase in aptt. the risk for patient-hemorrhage increased % (relative risk . , %ci . - . ) at an aptt-increase of ten seconds. the occurrence of filter-coagulation and patienthemorrhage was not correlated with the administered dose of heparin. concurrent use of cournarines had a positive effect on filter-survival, without increasing the overall incidence rate of patient-hemorrhage. conclusions: the systemic apt]" is a good predictor of the risk for filtercoagulation and patient-hemorrhage. heparine therapy seems optimal at an aptt between and seconds, although one should realize that fatal hemorrhagic complications still can occur. objectives: the alterations in vascular tone which are primarily regulated by adreno-sympathetic tone(ast) are compensatory responses in hemorrhagic patients. this study was designed to evaluate the correlation between vascular tone and ast in patients with hemorrhage, methods: the vascular tone was expressed by volume elastic modulus (ev) that is defined as; ev = ap/(av/v) (ap; the arterial pulse pressure, av/v; the volume change ratio). ev was measured using a non-invasive transmittance infrared photoelectric plethysmography (tipp) and a volume oscillometric sphygmomanometer . we prospectively studied patients with hemorrhage. the initial ev measurement was performed on arrival and repeated for a hours duration. as a parameters of ast, serum concentrations of adrenalin (ad), noradrenalin (nor), plasma renin activity(pra) were measured simultaneously. we analyzed the correlation of ev and conventional parameters to ast by multivariate statistical analysis. results: ev values at transmural pressure mmhg on admission and hours later were respectively . + . mmhg, . +_ . mmhg (mean + sd). systolic pressure(pas) and serum hormones on arrival and hours later were respectively, pas; . _+ . , + . mmhg, ad; . _+ . , . _+ . ng/ml, nor; . _+ . , . + . ng/ml, pra; . _+ . , . _+ . ng/ml/hr. the ev values correlated significantly with ad (r= . , p= . , n= ), nor (r= . , p= . , n= ), pra (r= . , p= . , n= ). by multivariate statistical analysis, ev correlated more significantly with ad and nor and pra (p= . ) than the conventional parameters such as pas, heart rate and pulse pressure. conclusions: the alterations of ev correlates closely with ast. the compensatory mechanism in hemorrhagic patients can be detected noninvasively by ev monitoring. obiectives and method: autologous oxygenator blood was processed at the end of cardiopulmonary bypass (cpb) by either hemofiltration (hf , , m , fresenius) or by cell washing with a onntinous autologous transfusion system (cats, fresenius). prospectively the blood of patients for each group was processed and then retransfused intravenously to the patient. besides, volume and time requirements, standard hematologic chemistry, coagulation and complement activation were measured. results (mean values for oxygenator blood at the end of cpb, and results of concentrate after processing by filtration or washing): both processing techniques show excellent hemoconcentration of the diluted cpb blood with a good transfusion effect for the patient. filtration retains all plasma proteins and large molecular weight plasma bound waste products. in contrast, cell washing with cats significantly depletes plasma proteins and waste products. the newely developped cats machine gives eonsisinnt laboratory result in a fully automatic continuous processing mode. in conclusion, both filtration and washing are effective for processing cpb blood. filtra tion yields a highly concentrated whole blood, whereas cats washing produces a high quality autologous erythrocyte concentrate. soluble fibrin has during the last years gained interest as a marker for the activation of the coagulation in connection with various clinical conditions, e.g. disseminated intravascular coagulation, deep venous thrombosis and myocardial infarction. elevated levels of soluble fibrin in plasma can be detected by the chromogenic assay coaset fibrin monomer, relying on the ability of fibrin to enhance the tpa-catalyzed conversion of plasminogen to ,plasmin. using this test, it has been shown that the level of soluble fibrin can be correlated to severeness of illness in critically ill intensive care unit patients. a revision of the coaset fibrin monomer kit has now been made and the new product, coatest soluble fibrin, is considerably more convenient to handle and gives higher resolution at low fibrin levels. the test is performed by the addition of a buffer dilution of the plasma sample to a microstrip well containing the colyophilized mixture of tpa, plasminogen and the plasmin specific cbromogenic substrate s- . the reaction is allowed to proceed at,. room temperature for minutes before discontinuation. the absorbance at nm, measured in a microplate reader, is proportional to the content of soluble fibrin in the sample. the assay is carefully standardized and calibration curves are provided in the kit. the convenient and rapid assay procedure makes the coatest soluble fibrin test well suited for single test analysis in acute situations. objectives : blood coagulation abnormalities have been reported in the systemic blood of patients with cerebral lesions. the physiopathology of such events is not yet completely understood. we compare the coagulation profile of blood from the right jugular bulb with systemic blood of patients with head injury. methods: we studied patients, who were admitted to our neurosurgical intensive care unit between january and march with head injury and no other associated pathology (age - yrs), a glasgow coma score <= g, no abnormality in baseline coagulation profile and no history of coagulopaties. the patients did not undergo angiography. a one-way gauge certofix catheter was inserted through the right internal jugular vein up to the jugular bulb. an identical catheter was inserted through a subclavian vein. blood was sampled from either catheter (a=atrial; j=jugular) - hours after trauma (t ) and t hours later (t the inddence dpontolx'rative thmmhi~e and haumord~gic complieatiom were assessed in padents treated with indobefen, heparin calcine caeca), low mollecolar weight heparin (lmwh) (f.nosheparin) and undergoing hemodiludun, blood predeposhing, intra mad postoperative blood saving. ]'he indolmfon tempota~.norks platelet aggregation through ,,elective inhibition of the cyclatygenasis and thus atacbldonicadd( ).tbe n'mimum effect occurs after hours from the fast administration and is still present after hours. ~- patients, mean age --- yrs., weight --- kg were studied. ( . %) were male and ( . %) female. onderwent hip prosthesis ( previously plate and screw removal) hip revim'un ( stem, cop and stem + cop), tutal knee prosthesis, in the st anaesthesidogy depl from - to - - . as for antithromboembolic ptephylam, apart from hemodihitiun pts were with treated indobufen ndo), with heparin ealdum caeca) and with low mo!lecular weight hepam (lwr, ). as the slightest clinical and/or imtmmental suspidon of deep vein thrombosis (dv'i') or polmonary umbolism(pe), a phlebogram or sdndgram were respectively carried out. -the inddence of homologom transhisiom was significandy lower (p= . l) in the padeats treated with indobufen ( . ) compared .'ith heca ( . %). the con~gency table shows statistical signifleance for the use of heca in patients with vein deficiency in the lower limbs, past dvr and/or pe, coronary heart disease (cdh'), while there is no correlation for renal, cardiac or liver defidency, obesity, systemic hypertemion, atrhythmy, diabetes, chronic bronchitis and rheumatoid arthritis. by comparing the postoperative cumplications with the risk factors, there ks a highly significant correlation (p= . l) between cdh and thrombotic and humord~agic complieatiom (pe, death, he~atoma, die use of hum_ologous blood). thee data show that hep~in, preferred in patients with c'dh, roost likely for leagal-tuedical reasons, did not have the de~'ed effect. conclusions -the stastisfical aar~ais shows ~nifieanfly different efflea~ (pro . ) between the therapies (see table) : it can be seen that in patients undergoing autotramfusiun and hemedihidon, indobufen produo~ a lower incidence of haemotrhagic complieatiens compared to heca and lmwh and is more effective in the prevention d ~c complications at clinical e~idence. the duration of i~toperadve hospital stay is signi~cantlylonger for patients transfused with homologous red ceils and treated with hec, .a ( . -+ . days) and lmwh ( . +- a days) compared with indo(ll. _+ a days). one of the main causes for postoperative complications in major orthopaedic surgery is postopemtive bleeding with local effects in the operation site (hematomata, pain and delayed mobilization) and/or systemic and subsequent cardiodrculamry repercussions that are sometimes severe. the aim of this study is to assess the possibility to apply a new system of monitoring, control and saving postopemtive blood loss from the drainage. the bt recovery dideco (marandola, modena-italy) ~ used since it is the only apparatus capable of doing this. the apparatus consists of a pressure transducer, adjustable from - a + mmhg, which activates a peristaltic pump connected m drainage robes. the bt recovery display shows hourly bleeding in the first hours, total bleeding, time passed since the start of monito~g and subsequent salvage and the aspimtioo pressure on the drainage robes; the latter is inserted at - mmhg and then modified according to bleeding/minute, g bt recovery also has an alarm that sounds automatically if.' blood loss is more than ml/hour; air is in the circuit; the batteries are running low. materials and methods: pts were studied ( m and ~), aged . -+ .lyears, basal hemoglobin . -+ (range . - . )g/all, treated from st january, to mst december, in the st service of anesthesia and intensive care unit of our hospital. the patients underwent the following surgical treatment: total hip revision ( pts), cup revision (~ipts), stem revision ( pts), total knee revision ( pts). the average dumtion of the operations was -+ min. intranpemtive monitoring and blood salvage was applied to all patients. genera! anesthesia was used on pts. and integrated (epidural analgesia + light general) on the remaining t . anttthromboembolic prophylaxis consisted of external pressure bandage, isovolemic hemodilution with iodobufen in ( . %)pts., calalc heparin in ( . %)pts., low molecular weight heparin in ( . %)pts.; pt did not give a predepoalt of blood, gave unit, pts units, pts units, pts units. the data obtained was statistically analysed using contingency tables and anova. results: average intmop salvage was -+ ml, average postop salvage was -+ mi the average intra+postop +- ml. average postop loss was -+ ml. the global incidence of postop complications was: h~natomata . %, dvt . %, pulmonary thromboembolism , , myocardiac ischemia . %, acute myocardic infarction . %, respiratory deflciecy . %, arrhythmia %, cystitis . % there were nn complications in . % of pts. postop bleeding over ml in under minutes (with bleeding alarm activation) occurred in pts ( . %). this sta~tically correlates only with the type of operation performed (more frequently in total hip revision p= . ) and with a significant decrease (p~ . ) in the pruthrombic activity detected about hours after the operation. this bleeding, also made the alarm sound, calling the attention of staff who could act accordingly, by making the drainage pressure positive and incre~sthg the tension of the external pressure bandage. conclusions postop monitoring, control and blood loss salvage combined with predepoalting and intmop salvage has enabled allogenic transfusions in % of cases to be avoided in operations with high postop blood loss like hip or knee revision. the usefulness of the system can be seen by the fact that in the patients with so much bleeding to set off the alarm, there was no significant difference in the incidence of allotransfusions and complications. references )borghi b., bassi a., de simone n., laguardia am., fonnaro g. an injury of the brain may result in various disorders of hemostasis caused by the release of • into the circulation through a damaged blood-brain bar tier. disseminated intravascular coagulation(dic) is one of these disorders. it is a freguent but relatively rare ly diagnosed complication of subaraohnoidal haemorrhage. the aim of this study was to evaluate some parameters of both blood coagulation and fibrynolisis in patients with sah.in addition one wanted to find out wh~ther potential changes correlated with the pa• condition in the acute phase of sah and whether they influenced the course of this disease. patients with sah were studied. in of them sah was due to closed eraniocerebral injury and in the rema ining resulted from vascular malformation. the following parameters were evaluated:the prothrombine time,the activated partial thromboplastin time, the thrombine time,level of factor v,fibrinogen degrada tion products and fibrin monomers. the results let us show the presence of oic in patients with closed craniocerebral injury and in with vas. cular malformation despite the lack of clinical symptoms the tests in posttraumatic patients and in patients from second group showed incomplete dic.on admission patients with such changes in measured parameters were in poor condition.the course of the disease and the effe cts of treatment were also worse in these patients. the results showed ihal in patients with sah complex disorders of both coagulation and fibrynolisis occur, and they depend on clinical condition of the patient. they also influence the course of the disease. methods : charts of all patients admitted with d.i.c. over a ten year period ( - ) were reviewed. diagnosis of dic was based on the association of fibrinogen < g/ -platelets < / -fpd > ~tg/ml in the hours of the admission. results : patients -mean age + y -saps +_ -gestanional age _+ weeks -the two first conditions associated with d.i.c. were placental abruption ( %) and preeclampsia or eclampsia ( , %). bleeding episode was present in pts ( %) and surgical treatment has always been necessary. pts ( %) were given packed red ceils ( + u) and fresh frozen plasma ( + u). patients were given platelets packs. heparin was never administered. pts required mechanical ventilation and two patients hemodialysis. all the patients survived. correction of prothrombin time (p.t.) and fibrinogen (f) was quick (p.t. at t h ~ % -f at t h , + , g/i). but platelets count remained low (plat. at t h + / ) -no difference was observed in patients who received platelets. conclusion : prognosis of critically ill o.p. is good. blood loss is the main complication. correction of hypovolemia and anemia with concomitant surgical treatment are essential. the administration of coagulation factors or platelets is still under discussion. objectives: to evaluate the effects of antithrombin iii i at-iii) and a protease inhibitor, gabexate mesilate foy), on the coagulation and fibrinolysis in disseminated intravascular coagulation (dic). methods: after the approval of our institution and consent from patient's family, patients with a dic score ( , japan) more than points (dic or having a risk for dic) entered this study. they were randomly divided into two groups, foy (i- mg/kg/h for days or more) treated group and no foy group, each of patients. platelet count (plt), fibrinogen (fen), at-iii fibrin degradation product (fdp), d-dimer (do), fibrin monomer (fm), thrombin-antithrombin complex (tat), plasmin-plasmin inhibitor complex (pic), and prothrombin time ratio (ptr) were measured before the start of treatment (at admission) and i, , and days after the admission. at-iii at units for days was administered if the at-iii at admission was less than %. finally the patients were divided into four groups: group a, foy (+) and the at-iii ~ %; group b, foy (+) and the at-iii < %" group c, foy (-) and the at-iii %; group d, foy (~) anffthe at-iii < %, each of patients, to match the patients for backsrounds. all parameters, dic score and survival rate in a month following treatment were compared among the four groups. results: the at-iii and plt from day to were significantly higher in groups a and c than in groups b and d. the fdp, dd, tat, and pic after treatment decreased significantly from the baselines in groups a and c but not in groups b and d. the fgn and fm were not significantly different among the four groups. the ptr decreased in groups c and d but increased in group b. the dic score decreased significantly in groups a and c than in groups b and d. survival rates were %, %, % and % in groups a, b, c and d, respectively, although not significantly different. conclusions: in patients with dic or a risk for dic, foy had no expected effects but at-iii had suppressive effects on the coagulation and fibrinolysis mechanisms. a prognostic factor ? carbon monoxyde intoxication is a classical complication of inhalation injury. carbon monoxyda is also physiologically produced during the heme metabolism: heme is conversed to bi]irubin by the hemeoxygenase which is an intracellular stress protein. icu patients (pts) were studied prospectively for apache ii score and carboxyhemnglobin (hbco) arterial level to assess if hbco level could be correlated with the severity of the pts. objective: to evaluate a new technique of non-surgical tracheotomy. patients: adults, mean age years and children, mean age months ( me.- yrs). method: through a needle inserted in the trachea, a guide wire is retmgradely pushed out of the mouth and attached to a special device formed by a flexible plastic cone with pointed metal tip joined to an armoured tracheal cannula. this device is then pulled back through the oral cavity, larynx and trachea, and outwards across the neck wall by applying traction on the wire with one hand and counterpressure on the neck wall with the fingers of the operator's other hand. when the cone and / of the eannula have emerged, the cannula is cut off from the cone, straightened perpendicular to the skin, rotated and advanced caudally to its final position. results: endoscopic control facilitates and improves the safety of all manoeuvres. the pointed cone easily pierces the tissues, and the cannula is extracted without difficulty since it has the same outer diameter as the cone. tissue adherence around the cannula is absolute thus preventing local inflammation. the time in apnea required for dilation and cannula placement does not exceed see., and it is well tolerated because within safety limits in patients hyperventilated with oxygen. only one case of bleeding occured in a patient on dialysis with severe coagulopathy. autoptic findings in subjects who died due to progression of primary disease showed a very regular stoma with an almost complete lack of hematic and flogistie infiltration in recent tracheotomies. .conclusions: translaryngeal tracheotomy (tlt), by virtue of its greater inherent safety and lower tissue trauma than percutaneous techniques, can also be carded out in infants and children, a severe test bench for any tracbeotomy technique. further specific indications are recently stemotomized patients, since tlt is associated with a low rate of infection, and short term tracheotomies after laryngeal surgery, to prevent obstructive complications. references: fantoni a., translaryngeal tracheotomy, apice, ed. gullo, trieste, , . background: inhalation of no has been shown to reverse hypoxic pulmonary vasoconstriction , to reduce pulmonary pressure in pulmonary hypertension of different origin and to improve gas exchange. in putmoflary embolism, pulmonary hypertension is caused by mechanical vascutar obstruction and by reactive vasoconstriction. the effects of inhaled no in putmonary embofism has been partiatly studied' the purpose of this study was to investigate and determine the effects of no inhalation on pulmonary hemodinamica and gas exchange in a hypoxic canine model of pulmonary embolism. methods: two groups of adult mongrel dogs were studied: group (control} dogs and group (no inhaled) dogs. both groups were anestesized with tiopental, mechanically normoventilated with an hypoxjc mixture of and n~ (f[q , ) and instrumented (swang-ganz catheter, femoral artery catheter) pulmonary embolism (pe) was induced by fisher's method s. no inhalation ( ppm) in group was started rain. pdor to pe and kept constant throughout the experiment. no inhaled concentration was analyzecf by chemiluminiscence technique. pulmonary artery pressure (pap), central venous pressure and sistemic arterial pressure were continuosly recorded. cardiac output, artedat po~ (pan ) and mixed venous po~ were measured in both groups under hypo)dr conditions, before pe and , , and rain. after pe. pulmonary vascular resistance (pvr) and gas exchange (pao fio:~ ratio), were calculate using standard formulas. data were process and analyzed with non pararnetdc test, and reported as mean -so and statistical significance was considered if p < , . : no produced an increase in arterial oxigenation (pao /fio~ ratio) and reduced pap before pe induction in group . after pe we found no significant difference with .respect to the time eour.se of pap, pvr and gas exchange between beth groups throughout the experiment. probably, the severe mechanical obstruction produced in pulmonary embolism masked the small effects of no inhaled. obiectives: blood volume measurement would be useful in critically ill patient management if it were easy to perform. this is not the ease and current methods are based on radiolabelled red cell dilution. inhalation and uptake of a known mass of carbon monoxide (co) gas and measurement of earboxyhaemoglobin increase can give results accurate enough for clinical use. this requires a rebreathing system providing oxygenation and carbon dioxide removal, yet complete retention of all carbon monoxide administer&l, and so most authors hand ventilate with a bag and waters soda-lime canister, adding oxygen as necessary. we aim to popularise this method by; i)design of an automatic co administration system driven by the itu ventilator and ii)writing of software for a portable computer to perform all necessary calculations method: we show the computer is use estimating the co dose required and later estimating the blood volume. we also show the new gas administration system. this is a fully closed circle attached to a "bag in bottle", driven by the ventilator. the novel feature is the mechanism by winch driving gas (set to % ) spills automatically into the circle, balancing o uptake by the patient, yet allowing no co loss. conclusions: this equipment is easy to use, reduces human error and allows optimum ventilator settings to remain. the operator merely administers the volume of co determined by the computer and takes blood on two occasions. carboxyhaemoglobin measurement is easy to perform, thus there is a cost saving also. with our modifications use of this technique may potentially become more widespread, the video demonstrates the method in use in our itu. - ( %) underwent conventional surgical therapeutics. " ( %) with resection of tracheal stenosis with end-to-end anastomosis(rts). i ( %) with broncoscopic dilatation. one patient died and the others still have stable patency(sp) without continued treatment. - ( , %) have received endoscopic laser ablation with or without calibration tubes. of them ( , %) are receiving continued endotracheal treatment until now. ( , %) have sp wihout continued treatment. -i ( , %) endoscopic laser therapeutic case turned to rts and is having sp. conclusion: conventional surgical aproach has been progressively replaced in our hospital by endoscopic laser ablation and silicone calibration tubes. this study suggests that these technics are effective and could be the elective treatment for iatrogenic stenosis. obiectives: hemorrhagic disorders due to thrombocytopenia and thrombocyiopathia remain one of the most serious complications during long-term extracorporeal membrane oxygenation (ecmo) in patients with severe acute respiratory distress ~drome (ards). in the presented study, nitric oxide (no), kwown as a potent endogenous platelet antiadhesive, disaggregating and antiaggregating compound, was evaluated for its possible antagonistic effect on platelet trapping when added to the gas compartment of membrane oxygenators (mo). meti~ods: two parallel separated extracorporeal circuits, consisting of heparin bonded hollow fiber oxygenators (minimax, medtronic, carmeda eioactive surface), tubing systems, low pressure reservoirs, and roller pumps were prepared. for each measurement, a pair of circuits was simultaneously filled blood from the same volunteer. low-heparinized fresh warm blood was obtained from four healthy volunteers, who had no drugs for at least two weeks. the gas inlets of both oxygenators received dry gas ( % oxxygen, % carbon dioxide, % nitrogen); gaseous no ( ppm) was added to the gas of one of the oxygenators (no-mo), whereas the other one (mo) was used as control. after minutes no gas was switched off, so that the no-mo received no more no, and no was added to the gas inlet of the membrane, which had no no before_ to assure iutracircnit volume stability, drawn blood for measurements was replaced with saline, and platelet counts were corrected for dilution by hemoglobin values. the mean of four platelet counts (coulter counter) of each timepoint (start, , , , , , , , and minutes) was used for statistical analysis (paired sample t-test). results: in the no-mo platelets remained at + , % (percentage of baseline value, mean -+ sd) until min. in contrast, platelets of the mo continuously decreased after start and were significantly lower after minutes ( , + , % vs _+ , %(p< . ); min. , -+ , %vs , _+ , %(p< . ); min. , _+ , % ( p < . ). after switching of no gas to the mo, further decrease of plateleta was stopped and platelets remained at , +_ , % until termination of circulation. platelets of the former no-mo decreased slightly after cessation of no gas to , _+ , %. conclusions: these data indicate that gaseous no significantly attenuates platelet trapping in hollow fiber oxygenators, when added to the gas compartment. this might be a new therapeutical approach for membrane oxygenator induced thrombocytopenia during long-term ecmd. objectives: nitric oxide (no) plays a pivotal role in regulation of vascular hemostasis. several studies elucidated the antiadhesive, antiaggregating, and disaggregating properties of endothelially synthesized no to platelets. additionally, agonist-induced no production in platelets by the l-arginine-no pathway was found as a negative feedback mechanism after platelet activation. although noplatelet interactions were intensively studied by several investigators, no data exist, about changes in platelet surface molecule expression in no-modulated platelets measured by flow cytometry using monoclonal antibodies (moabs). methods: p-selectin (alpha-granule-membrane protein, gmp- , cd p) and glycoproteiu (gp , lysosomal protein, cd ) are expressed only after platelet activation and degranulation. activation was quantified in thrombin ( . u/ml) and adp ( . ram) stimulated platelet rich plasma samples (prp). blood was obtained from healthy volunteers (n= ), who had no drugs for at least days. for evahiation of no-modulated activation, the spontaneously noreleasing compound sin-i ( . mm) ( -morpholino-syndonimin-hydrochlorid) was added in parallel prepared samples prior to the addition of agonist. platelet surface molecule expression was evaluated with moabs directed against cd a (gpilbliia, fibrinogen-receptor, phycoerythrin(pe)-conjugated), cd p (fitcconjugated), and cd (fitc). only cd a-positive signals were gated in sideangled light scatter, and assayed for activation marker expression (defined as percent of gated population). results: basal p-selectin expression was . + . %, and increased to . _+ . % after thrembin-activation, and to . + . % in adp-stimulated samples. addition of sin- attenuated p-selectin expression to . - - % in thrombin (p<. , two-tailed paired t-test), and . + . % (p<. ) in adpactivated platelets. basal gp expression was . _+ . % and increased to . + . % in thrombin, and to . _+ . % in adp-stimulated samples. with sin-l, gp expression decreased to _+ . % (p<. ) in thrombin, and . : . (p . ) in adp-stimulated samples. conclusions: these data implicate, that no leads to a significantly reduced activation of surface molecule expression in thrombin and adp-stimulated platelets. in addition, flow cytometry might be a useful tool for studying modulation of platelet activation by no or no-releasing compounds. introduction: acute cadmium poisoning is very rare. on initial presentation may mimic metal-fume fever, but acute inhalation cadmium toxicity may produce fatal chemical pneumonitis. case report: we present a case of acute fatal respiratory failure secondary to cadmium-fume irthalation. a year old patient was trasferred from another hospital with acute respiratory failure presumably due to pneumonia. the last days before he had had commom cold symptoms. he had been cutting with a welder during one hour without any respiratory protective measure. three hours after exposure he developed progressive dispnea and was admitted to hospital. with presumtive diagnosis of respiratory infection, antibiotics were begun, however be failed to improve. all microbiological studies were negative. chest x-ray showed bilateral diffuse infiltrates. on seventh day he needed intubation and mechanical ventilation and on th he was admitted to our icu. antibiotics were stopped and new microbiological studies were performed including brochoalveolar lavage and virologic studies. all results were negative. he developed progressive hipoxemia and hipercapmia and finally, multiorganic disfunction syndrome. he died days after exposure. the metal he had been working with was a % cadmium alleation. blood cadmilam concentration days after exposure was . mcg cd/g cr, and urine cadmium concentration was . mcg/l. on postmortem examination, tissue cadmium concentrations were: blood ng/ml, liver ng/g, kidney ng/g and lung ng/g. these values confirm that cadmium was the cause of the fatal respiratory illness in this patient. conclusion: this case evidences the considerable hazard of acute poisoning after inhalation of eadmium-fume and stresses the need of appropiated safety measures against metal-fume poisoning. aim : lactic acidosis is considered the hallmark of cyanide poisonirig. however, the relationship between plasma lactate and blood cyanide levels has not been determined. the aim of this study was to determine the significance of plasma lactate concentration (plc) during the course of cyanide poisonings. methods : the patients were included according to the clinical suspicion of pure cyanide poisoning at the time of presentation. fire victims were excluded. serial blood samples were collected before and after intravenous hydroxocobalamin (hoco). blood cyanide concentration (bcc) was measured colorimetrically. plc was measured enzymatically. results : patients were studied. on admission, plc ranged from . to mmol/l, and bcc from . to gmol/l. mean systolic blood pressure was • mm hg, mean arterial ph . • . , mean anion gap was . + . mmol/l and mean pao . • . kpa. three patients died. before antidotal treatment, there was a significant correlation between plc and arterial ph (p = . ), anion gap (p = . ) and bcc (p = . ) but not with heart rate, pao , paco and blood glucose, or blood pressure. during the whole course of the poisoning, a plc _> retool/ was a sensitive and specific indicator of a blood cyanide concentration > ~tmol/ . sustained catecholamine administration reduces the correlation coefficient. conclusion : baseline measurement of plc allows assessment of severity of acute cyanide poisoning. thereafter, plc may be used to assess the adequacy of antidotal treatment, more especially in patients not requiring sustained infusion of catecholamines. aim: the aim of this case report was [o study the correlation between the plasma lactate levels and several clinical, biological, and toxicological parameters serially measured during the course of a cyanide poisoning treated with a high dose of hydroxocobalamin. a -year-old male ingested potassium cyanide leading to cardiac arrest. cpr was performed prior to hospital arrival where the patient received g hydroxocobalamin. sbp rapidly returned to normal allowing withdrawal of epinephrine. the patient remained comatose and died from brain injury days after the ingestion. methods plasma lactate and blood cyanide levels were measured serially. blood cyanide levels were measured using a colorimetric method.~ plasma lactate levels were measured using an enzymatic method. for correlation spearman rank correlation test was used. results. initial plasma lactate and blood cyanide levels were mmol/l and gmol/l, respectively. there was no overall correlation between sbp and either blood cyanide or plasma lactate levels. similarly, there was no overall correlation between arterialvenous oxygen saturation difference with either blood cyanide or plasma lactate levels. in contrast there was a strong correlation between blood cyanide and plasma lactate levels (r= . , p< . ). the time-course of the blood cyanide concentrations was described by a mono-exponentiai decay (r = . ) with a blood half-life of . h. similarly, the time-course of plasma lactate levels was described by a mono-exponential decay (r = . ) with a blood half-life of . h. discussion. in this case of acute human poisoning, sbp was a much poorer indicator of continuing cyanide effect both before and after antidotal treatment, than was lactate production. this suggests a potential clinical role for following serial plasma lactate levels as a marker of the evolution of cyanide toxicity. aim : cyanide (cn) poisoning in fire victims is frequent and rapidly fatal. in a prospective study we tried to assess the clinical tolerance of a high dose of hydroxocobalamin (hoco) administered at the scene of the fire in fire victims suspected of cn poisoning. methods : inclusion criteria : soot in mouth or sputum ~ any degree of neurological impairment. exclusion criteria : children, pregnant women, burns of total surface body area > %, multiple trauma. protocol desigrl following examination and the collection of a blood sample in dry heparin, a g dose of hoco ( g in case of cardiovascular collapse) was administered intravenously over min. the systolic blood pressure was monitored before and after the administration of hoco, and one hour later. results : there were females and males. the mean blood cn concentration was • pmol/ . the mean blood carbon monoxide was . • . mmol/ . nineteen fire victims eventually died. among the non-cn-intoxicated patients (blood cn < ~mol/ ), there was no significant change in arterial blood pressure. in the cn-intoxicated patients (blood cn > gmol/ ) a significant increase in blood pressure was observed both immediately (p < . ) and hour later (p < . ) after the admistration of hoco. no allergic reactions were observed. conclusions : in fire victims with cyanide poisoning, the administration of a high dose of hydroxocobalamin was associated with an improvement in systolic blood pressure. hydroxocobalamin is well tolerated in fire victims without cn poisoning. objectives: tricyclic antidepressant (tca) overdose can lead to serious complications including cardiac arrhythmias [ ] . because of the known risk of early deterioration and the implication for management, emergent evaluation is essential. we determined the diagnostic usefulness of the electrocardiogram (ecg) in tca poisoning. methods: retrospective study of all patients with tca intoxication (pos. ,toxicology screening in urine and/or pos. history) in a -beduniversity hospital from through . the severity was graded with mild= no symptoms or agitation; medium= disorientation, somnolence, tachycardia, or convulsions; and sever~ coma, significant arrhythmias or death. we analysed the first ecg after admission with a special emphasis on qrs-and qtc-intervals and the terminal ms frontal plane qrs-vector (tqrs), which, was reported to lie typically between + and * + + • the best correlation with severity grade was found with qrs-and qtc-duration (p= . ), the tca-dose (p= . ) and hf (p= . ); tqrs did not correlate. patients died ( . %). conclusion: qrs-and qtc-prolongation in the admission ecg, and the reported dose of ingested drugs are useful predictors for severity of poisoning due to tricyclic antidepressants. we did not find additional benefit in determining the terminal ms frontal plane qrs-vector. objectives: since treatment of amphetamine poisoning is usually symptomatic and often associated with a fatal outcome, a search for specific drugs to help the amphetamine-intoxicated victim is sorely needed. methods: we report a case of a suicidal ingestion of large amounts of the amphetamine-derivative , -methylenedioxy-ethamphetamine (mdea) and heroin (diacetylmorphine) and present the hypothesis that the two drugs produce opposing clinical effects. results: a year old caucasian male was admitted to the emergency ward because of acute-onset confusion. at presentation, he was agitated and showed increased muscular rigidity. he had taken tablets of "eve" (mdea, approx. g) and g of "smack" (heroin) by oral route approximately h before admission. because of rapidly progressive tachypnea and exhaustion, the patient was intubated and ventilated. the serum concentration of "eve" on admission was ng/ml (lethal range - ng/ml). trace amounts of cocaine and substantial amounts of heroin ( ngtml; mean value in heroin-related deaths: ng/ml) were also found in the serum. the patient was successfully weaned from the ventilator by day and recovered without persistent neurobehavioral disturbance. despite high serum levels of both drugs, the patient did not present with the classic signs and symptoms normally seen during intoxication with these drugs. amphetamines in general, and mdea in particular, have opposite clinical effects to heroin or diacetylmorphine. none of these were however present in the case presented despite the high ingested doses and the serum levels in the lethal range. conclusions: the fascinating fact that, apart from the respiratory depression, none of the clinical signs reported after massive overdose with these two drugs were present, might be attributed to the opposite pharmacological effects of mdea and heroin. we believe that the patient unwittingly saved his own life by the oral coingestion of both mdea and heroin. our clinical data raise an interesting point about the pharmacological treatment of acute poisoning with amphetaminederivatives. introduction: the acute attack of aip still carries a significant risk of mortality of around %. a succesful outcome depends on early diagnosis, removal of pricipitating factors and provision of intensive supportive therapy. objectives: twenty one patients ( females, male) with documented aip were seen over a -year period in the university hospital. patient was in clinical remission and were with the acute attack of aip, among them with respiratory paralysis were required artificial lung ventilation and -assistant ventilation with peee pathologic treatment during the attack was normosany, adenil, androgenes, glueosa, riboxin parenteral and enteral nutrition via nasogastric tube. symtomatic treatment -pethidine, propranoton, antibiotics, bronchoscopia. methods: intermittent phasmapheresis was performed on patients. the following measurements were peformed: level of porphobilinogen (pbg) in the wire and delta-aminolevulinic acid in the blood. hematological and routine chemical evaluations, hepatic, hemodynamic and respiratory function. results: after plasmapheresis the median pbg excretion (normal range - mkg per/ kgr creatinine) fill from mkg on admission . mkg, then on - day raise to mkg and then during treatment with normosong and prasmapheresis lowest level was . mgk. fatalities occured in two females during attacks with proforma cerebral involvement and patients attained clinical remission. conclusion: after therapy with plasmapheresis normosong we found that there was consistently reduce the urinary excretion of pbg and shortening the duration of the acute attack. objectives: pigs has been reported to present with a higher pulmonary arterial pressure (ppa) and stronger pulmonary vascular reactivity than many other species, including man. aim of the present study was to compare pulmonary vascular impedance (pvz) before and after embolisation in weight-matched adult dogs and minipigs. methods: we investigated pvz spectra in anaesthetized and ventilated (fio . ) minipigs and dogs. after baseline measurements the animals were embolised with autologous blood clots to reach a ppa above mmhg. results: flow ( and ppa matched pvz data (mean-+sem) are shown in the table. [zo = hz impedance (z; {dyn.sec_em- }); zl = first harmonic z; zc = characteristic z; z phase = first harmonic phase a@e {radians}; fmin = frequency of pvz the first m{n~mam; *, f p at least < . between dog and minipig, and before v~. after embolisation respectively]. before case report: a -yr-o]d woman affected by legs recurrent thmmbophlebitis, was admired in medmine department for tach.~pnea, chest pain, tachycardia and cyanosis. before starting two-dimensional transesophageal echocardiography (tee) to confirm the suspicion of pulmonary embolism, she suddenly had ventricular fibrillation. resuscitation and defibrillation were readily performed. when sinus rhythm was reinstituted she was in superficial coma with preserved corneal and light reflexes: right hemiplegia, poor perfusion and h~posphygrma of the left arm. tee showed dilation of rigth ventricle (rv), incomplete occlusion of pulmonary arter~ (pal at it~ hifurcation, severe tigth-to-left shunt through a patent foramen ovate, paradoxical embolism with incomplete occlusion of left subclavian artery mechanically ventilated with vt= ml, rr= /mm, fio =l, the patient had ph= . , pao = mmhg and paco = . systemic bp was / mmhg and hr= b/min with low dose epinephrine ( . g/kg/min) a thrombolytic infusion (rtpa: mg/ h) through a peripheral vein was started tee imaging and clinical status hours later were unmodified. a new rtpa infusion was performed through the pulmonary hole of a swan-ganz catheter with the tip close to the embolus. one hour later pa pressure decreased from / mmhg to / mmhg, etco increased from to mmhg and sao improved from % to % three days later the parietal, spontaneously breathing and with normalized tee scans of rv and pa, was transferred to rehabilitation service to perform physical therapy. conclusions: massive pulmonary embolism in a patient with patent foremen ovale, paradoxical embolism and refractory hypoxaemia was unaffected by systemic rtpa infusion, while intrapulmonary rtpa administration dramatically improved gas-exchange, hemodinamics and the general conditions of the patient. the presence of a large rigth-to-left _atrial shunt and the rapid rtpa metabolism could likely explain the effectiveness of its intrapulmonary administration in front of failure of systemic thrombolysis. introduction. cardiogenic shock during massive pulmonary embolism (blpe) is due to an acute increase of right ventricle (rv) afterload and possibly rv ischemia causing a failure of rv pump function. the rec~;mmended therapeutic strategies are: xoiume augmentation ~n ~rder m }ncrease rv pre-h~ad, adrenergic drugs to increase t'ontractillly and maybe coronary perfusion, fibrinolytic drugs to delermine clot lysis. there have been several reports of noradrenaline (na) as a useful drug in this setting for its sluing ~z, but also ~, properties. case report.an obese },ears old woman was transferred to our icu for tetanus. she was given the usual antibiotic and immunoglobuline therapy. l'wo thoracic epidural catheters were put in place at different levels and replenished with marcaine qid. a continous infusion of sedation (diazepam § was started together with mechanical ventilation. curarization ~,as given occasionally. fraxiparine . /die was used for prophylaxis of thrombotic disease, on day th at . a.m. she started to be hypoxic (sa %), tach ,tardic l l(i b/rain.), her blood pressure(rp) dropped frum norma~ values to r mm/hg, the central venous pressure (cvp) raised [rom lb to mm/hg and the end tidal co was mm/hg lower than one hour before. the physical examination of the chest revealed a clear bilateral ventilation and the chest x-ray was normal apart from an elevation of the :tiaphragm as compared to the previous. an e.c.g. showed sinus tachycardia, right bundle branch block and a possible inferior necrosis (which was already present on admission). a trans-thoracic echozardiography was performed which showed "an acute overload of the right centricle wilh remarkable dilatation. tricuspidal regurgitation ++. paradoxical movement of septum. small left ventricle with normal wall kinetics". the cardiac enzymes were later shown to be normal. an acute massive pulmonary embolization was assumed m be present.. a bolus of streptokinase x i(i u. was given fonowed by a continous infusion . two liters of colloids were also given in a sh~rt time, two hours later the patient was still deeply hypotensive, hypoxemic and anurir(bp / mm/hg, cvs mm/hg, spo %) despite a cominnus infusion of dobutamine fag/kg/min and adrenaline . ~tg/kg/min. at this stage a bolus of aoradrenaline ,g was given followed by a cnntinous infusion of . !*g/kg/min. an immediate improvement of the hemodynamics was noticed and one hour later the bp was / mmhg, the cvp mm/hg, the sao % and a brisk diuresis started. the hemodynamics kept stable and weaning from vasoactive drugs was achieved within two days. one month iater the patient was discharged home in good conditions.. con c i u sio n.ne administration may help to restore rv coronary flow and ;~ump function during mpe. aeute putmonary t~omboembo~sm [ffe) cou be mamfeslated with either respiratory or cardiovascular syndromes or both. the arm of the study was to establish leading respn'atory symptoms, frequency and form of the roendganographic (rig) changes as well as blood gas disturbance degree in acute pte with dommam respiratory disease appearance. the study includes retrospeotive analysis of i pte patients (pts), males (average age , yrs) and .q females (average age , yrs). they were admitted at university, olinie" with suspection ofpleuropnlmonary disease, including pte. final diagnosis of pte was based o~ evident risk factors in , % of the eases (deep venous thrombosis, surgery, trauma, imobilisation, malignancy ere), acceptable clinical, rtg, sdntigraphic and laboratory findings, as well as deep veins examination by dopple~-sonographie and radioisotopic -~enogmphy. respiratory symptoms appeared in all cases: sudden pleural pain ( %), dyspnea ( %), hemoptysis ( %), cough ( %) with association of two or more symptoms in %. chest xrays findings were abnormal in % with diaphragmal elevation ( , ~ lung opaeilies ( , %), atelectasis ( , %), plemal effusion ( , %), main pulmonary brancah asimetry ( , ~ oligemia ( %), heart shadow changes ( , %) and pulmonary arteries "cut off' ( , %). the association of two or more abnormalities was found in , % while normal chest x-rot was found in ~ of the cases. hypoxemia with pao < , kpa was found in , % followed with hypocapnia and respiratory alealosis in , % in , % of the gas exchage analysis were within normal limits. among cardiovascular symptoms short syn~cpa appeared in i , %, ecg changes-st q t type in "~ , %. results show high frequency of positive ~g findings in pte pts that is opposite to oppinion that chest x-ray in acute fie is the most ofran normal. leading symptoms are pleural pain and dyspnea, while hemoptysis were found in a half of the study group. blood gas changes were present in two thirds of the cases. kakkar, in his classic work ,clearly demonstrated the efficiency of low doses of heparin in prevention of deep vein thrombosis (lancet : , ) .after this first study the application of heparin prophylaxis became more and more diffused until to be considered a routine in many surgical departement.actually application of blood saving technique induces postoperative hemodilution effect. in that condition prophylaxis routinely applied seems a nonsense and can be at risk for postoperative hemorrhage. methods: to analize this problem we compared patients arrived in our intensive care unit (i.c.u.) in. : (group a) with arrived in : (group b) .every patient was operated for major abdominal surgery.in each one we considered the hemoglobin (hb) value,hematocrit(hct), and coagulation pattern (c.p.) at the arrive in i.c.u. and hours later. the patients was also divided in those receiving heparin prophylaxis (i) from not treated patients (ii) results:the application of blood saving technique clearly appears from the hb and hct level wich have a mean value of , +/- , (hb) and +/- (hct) in group a while in group b mean value are , -/- , (hb) and +/- (hct).patients of group a (ii) are the only one where a pathologycal c.p. with statistical significance has been demonstrated.in this goup we got four cases of evidence of venous thrombosis and one of pulmonary embolism.in patients of group b(i) we encontered the incidence of two cases of severe hemorrhage despite the absence of statistical significance in c.p.modifications. oxygen desaturation during broncho-alveolar lavage: role of oxygen saturation monitoring in prevention of acute respiratory insufficiency g. galluccio, b. valeri, s.batzella, m. di lazzaro*, servizio di endoscopia toracica, ospedale forlanini, rome, italy * servizio die anestesia a rianimazione, osp. forlanini the broncho-alveolar iavage is a diagnostic procedure employed in interstitial diseases of the lung. it requests the introduction through the working channel of a fiberoptic bronchoscope, after occlusion of a segmentary bronchus, of aliquots of saline solution at c, subsequently gently reaspired, in order to remove cells and proteins from elf (endoalveolar lining fluid), which is related to interstitial medium. bronchoalveolar lavage induces deep effects on pulmonary function: -lowering of the alveolar surface of exchange; -shunt effect, depending on the perfusion of non-ventilated districts; -increased pulmonary arterial pressure, due to hypoxic vasoconstriction; -decrease of lung compliance. in this report the authors present the result of oxygen saturation monitoring in a group of patients with interstitial lung disease, who underwent diagnostic broncho-alveolar lavage. in most patients with severe interstitial involvement, the lavage performed without supplement of oxygen induced a severe fall in the oxygen saturation during the late phase of the procedure. if supplementary oxygen was delivered during bronchoscopy, since its beginning, only slight modifications of the curve were detected. in patients without thickening of interstitium, in whom the lavage was performed in order to obtain material for bacterial or cytologic examination, no modification of oxygen saturation was observed in standard procedure. as conclusion the authors strongly reccomend monitoring oxygen saturation in patients with radiologic evidence of interstitial involvement also in patients with no evidence of dyspnoea. g. galluccio, b.valeri, s.batzella, m. di lazzaro*, servizio di endoscopia toracica, ospedale forlanini, rome, italy * servizio die anestesia a rianimazione, osp. forlanini the treatment of choice in patients with alveolar proteinosis consists of pulmonary lavage. this procedure requests the introduction, through the working channel of a fiberoptic bronchoscope, segment by segment, of aliquots of saline solution at c, subsequently gently reaspired, in order to remove the proteins deposited in the alveolar spaces. the method is very similar to that used in bronchoalveolar iavage, a diagnostic procedure used to obtain cells and substances from elf (endoalveolar lining fluid), which is related to interstitial medium. as known, bronchoalveolar lavage induces oxygen desaturation, because of shunt effect. understandably, one lung lavage has remarkably more deep effects on pulmonary function than bronchoalveolar lavage, for the amount of fluid introduced, the length of the procedure and the conditions of controlaterai lung. in this report the authors present the result of oxygen saturation monitoring in a patient who underwent pulmonary lavage for alveolar proteinosis. in the lavage performed without supplement of oxygen a severe fall in the oxygen saturation was observed during the late phase of the procedure. if supplementary oxygen was delivered during bronchoscopy, since its beginning, only slight modifications of the curve were detected. as conclusion the authors strongly reccomend the subministration of supplementary oxygen in pulmonary lavages, also in patients with excellent respiratory conditions. a. b. dublisky prof., m. r. isaakjan ass., v. a. zasukha, s. m. vinichuk prof., v. p. tserty ass. prof., chair of anaesthesiology, resuccitation and medicine of catastrophes, neurology of ukrainian state medical university, kiev, ukraine. objectives: detection of plasmophoresis's influence of results in treatment of ishemic insult. methods: we ve investigate patients with ishemic insult, treated with reverse plasmopheresis in complex treatment. after primary infusive therapy we took ml of patients' blood and separated it within min with rotation frequensy of /rain. after separation of erythrocytes from plasma, the latter has been returned to patients. we made - procedures during - days. hemoglobin, hematokrit, time of blood coagulation were determinated. the brain blood flow in internal carotid arteries, regional volum brain blood flow and total brain biood flow were evaluated with tetrapotar chest rheography and tetrapolar rheoencephalography. obtained date were comparised with control group after traditional treatment. results: it was found that after reverse plasmopheresis the hemoglobin and hematokrit levels decreased significantly in studied patients' plasma (from + . g/l to _+ . g/ and from + . % to _+ . % respectively). the time of blood coagulation by lee-white has increased by - . times (up to - rain). the level of brain blood flow has been increased significantly after reverse plasmopheresis in comparison with control group. the following tests of brain blood flow have been increased: a) the total volume brain blood flow from . + . ml/min to . _+ . ml/min (p < . ); b) the regional brain blood flow from . _+ . ml/min to . + . ml/min (p < . ); c) the brain blood flow in internal carotid arteries from . _+ . ml/min to . + . ml/min (p < . ). conclusions: the use of reverse plasmopheresis in complex treatment of patients with ishemic insult aiiows to improve rheological blood patterns, helps to increase volume brain blood flow. it results in quicer reparation of neurological functions. objectives: a prospective evaluation of the efficacy of continuous infusion of verapamil in reducing the incidence of postoperative atrial fibrillation after pulmonary surgery. methods: a total of consecutive patients, on verapamil, on placebo was included after lobectomy or pneumouectomy. a loading bolus of verapamil ( mg over minutes) was followed by a rapid loading infusion ( . mg/min) for minutes and finally a maintenance infusion ( . rag/rain) for hours. results: a mean plasma level of verapamil of ng/ml was obtained only after more than hours. atrial fibrillation occurred in five out of patients who tolerated the verapamil infusion, and in out of patients on placebo (p = . ). verapamil infusion was not tolerated in patients because of hypotension or a heart rate of less than /min, within hours of the start of the therapy. when atrial fibrillation occurred, the ventricular response, mean _+ sd, was not significantly slower during verapamil infusion ( + ) compared to placebo ( + ). conclusions: because of its frequent side effects and the only modest efficacy verapamil should not be considered for prophylactic therapy of atrial fibrillation after pulmonary surgery, and is probably not a good first choice for slowing the heart rate in case of rapid ventricular response once atrial fibrillation has occurred in these patients. results: study of haemostasis in these patients has showed deep disturbances of blood coagulation. fibrogen level has reduced to . + . g/l, fibrinogen and/or fibrine degradation products concentration have enhanced to . _+ . g/l, monofibrin soluble complex concentration to . -+ . g/l, blood plasmin level was enhanced to . + . mmol/ , plasminogen proactivator level was also enhanced to . + . ram, plateletes aggregation has decreased to %. after plasmopheresis aggregation was decreased in . times. it has been connected with decrease of fibrin and/or fibrinogen degradation products level and level plasmin in . times, and plasminogtnt activator level in . times. at the same time we have observed increase in total antifibrinalitic activity of blood in . times. activity of activators plasmine and plasminogene proactivators has decreased in . times and in the same time activity of activation inhibitors and antiplasmines has increased in times. conclusions: plasmapheresis leads to considerable improvement of a general condition and reduction of the haemorrhagic syndrom's sings (controlling of gastrointestinal haemorrage, reduction of intensity of subcutaneons haematoma). evaluation of continuous cardiac output (cc ) monitoring based on thermodilution technique in critically ill patients. methods: cardiac output (co) was monitored continuously using a modified pulmonary artery (pa) catheter, on which a heating filament is located and by which energy is transmitted to the circulating blood. a microprocessor calculated co by a new algorithm. standard bolus thermodilution technique ( ml of ice-cold saline solution) was used to compare cc with intermittent bolus cardiac output (ic ) measurements. the following subgroups were prospectively studied: i. heart rate (hr) > beats/min, . cardiac output > i/min . cardiac output < . i/min, . rectal temperature > . ~ and . pa catheter was inserted for more than days. results: a total of pairs of ic and cc measurements were obtained from the patients. bias (ico measurement minus cc measurement) of all measurements were . • i/min and the % confidence limits (mean difference• were - . / . i/min. also in the subgroups, cc measurement agreed closely with ico measurement (c > i/min: bias= . • i/min; co < . i/min: bias=- . • i/mln). elevated temperature and prolonged lay-days of the pa catheter did influence agreement of cc measurement with ic measurement neither (> ~ bias= . • i/min). conclusions: monitoring of cc using a modified pulmonary artery catheter with a heated filament has proven to be accurate and precise also in the critically ill when compared with "standard" intermittent bolus thermodilution technique. this method enhances our armamentarium for more intensive monitoring of these patients under various circumstances. background: the number of patients who need coronary artery surgery was) grows every year. most of these surgical operations are with extrar eircuiation (ecc). since january , this surgery is made without ecc in selected patients in our hospital. this technique is exceptional in spain. this type of surgery has proved useful in patients requiring revascularization of the left anterior descending, eireunflex or right coronary artery (not for grafting the pos~tefio~r descending branch}. blethods and results: since , patients aged to years (mean years) underwent cas without ecc. the mortality in programmed surgery was %. no patient was reexplored for hemorrhage. the mean values of some clinics parameters v~ere: a) blood requeriments: units per patient, b) need of mechanical ~entilation: i , hours, c) postoperative bleeding: cc, d) days at icui , . we used the student % t test or fisber~s exact test to compare these results with the mean values of surgery with ecc: a) blood requeriments per patient (p< , ), b) need of mechanical ventilation: hours (p< , ), c) postoperative bleeding: cc (p< , ), d) days at icu: (p< , ), e) programmed surgery mortality: % (p< , ). conclusion: our limited experience shows that this surgery is an alternative in the treatment of coronary disease, especially for aged patients with associated pathology and in jehova's witness. the need of mechanical ventilation, days at icu, blood requeriments and morbi-mortality were fewer than surgery with ecc. to study the hemodynamic and antiarrhythmic influence of ace-inhibitor enalapril in acute myocardial infarction (mi). methods: holter ecg monitoring, heart rate variability analysis, echocardiography ( and l days after beginning of the treatment), stress-echocardiography and stress ecg ( - -th day after the onset of mi). enalapril was included into the treatment of pts with mi (study group), with normal or increased blood pressure, from the -st day of the disease. the data were compared with pts treated without enalapril (control group). results: silent ischemia during stress-test was registered in pts of the study group and of control group, the arrhythmia episodes during stress test -in and pts and episodes of silent nocturnal isehemia -in and pts correspondingly. enalapril importantly attenuated the hypertensi~re re~aetioh % stress test. in pts of the study group the number of perifocal hypokinesis zones decreased; in the control group it didn't change. the quantity of ventricular extrasystoles in the patients of the study group decreased by %; the heart rate variability indices improved as well; in the control group the character of ventrieulir arrhythmias, heart rate and its va]~i~bili%y didn't change significantly. conclusions: the inclusion of enalapril into the treatment of mi is a useful t ol to improve hemodynamie parameters and decrease the incidence of ventricular arrhythmias. objectives: to study left ventricular (lv) systolic function in the patients with acute myocardial infarction (ami) before and after peroral captopril test. methods: the original echocardiographic parameter of lv contractility, "coefficient of effective systolic function" (cesf), was proposed in the study. cesf is calculated from lv stroke volume (sv), obtained from doppler aortic flow in lv outflow tract and lv end-diastolic diameter (edd): cesf =sv/edd. the study included patients with ami, who had local lv dyskinesia and global lv systolic dysfunction (ef< %). besides cesf, the ejection fraction was calculated before and after administration of mg eaptopril (on the fifth day of ami) by methods of bullet and simpson. results: the dynamics of these parameters, as well as heart rate (hr) and mean blood pressure (bp), is shown in the tabte. before cal~topril ef (bullet) . • . ef (simpson) . introduction: the cold system is a monitoring system for measurement of right (copa) and left (coart) ventricular cardiac output, cardiac function index (cfi), fight ventricular ejection fraction crvef), fight ventricular cnddiastolic volume (rvedv), intrathoracic blood volume (!tbv), global enddiastolic volume (gedv), lung water (etv) and excretory liver function (pdr). patients and methods: pts have been monitored by the cold system. above mentioned parameters are measured by thermal dye dilution and a fiheroptic femoral artery catheter. copa, rvef and rvedv measurements additionally were compared to measurements by the baxter explorer. :::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: ;;;k;;;;i cov (%) explorer ! ! [ gedv, itbv and pdr showed a significant decrease dufing the first - h after the operation, cfi and rvef si~canfly improved after k wheras etv showed a i~ in the early postoperative phase and fell to normal ranges at h. comparison of cold/explorer m~ements sb wed good correlations. discussion: concerning m ~toring of ri,ght ventric~ar function cold and explorer can he seen as equal. rvef gives an ar report about the performance of the right ventricle without use o f echocardiography. measuring itbv and gedv ~ improve ~gement and con~ol of th.e volume status, monitoring etv helps preventing lung edema. pdr shows good corre|ati n to liver blood chemistry and is bedside avai|ab|e. thus the cold system offers additional parameters for comprehensive m~nitofing of pts. ~e~ ~c surgery. obiectives: to evaluate the influence of an a!'~ered cardiac function on the cardiovascular response to the increase in oxygen demand induced by an increase in core temperature. methods: this preliminary study included adult critica!ly ill patients monitored by arterial and pulmonary artery catheters in whom thermodilution cardiac index {ci) and arteria! and mixed-vef)ous blood gases measurements could be obtained before and after an acute change in core temperature of at least . ~ (max rain apartl the patients were separated in two groups according to their cardiac function: patients had an impaired cardiac function as defined by a history of cardiac disease and an ejection fraction below % and patients had normal cardiac function. results: individual data are shown in the figure. in contrast to the control group (continuous line) in which c! increased without changes in oxygen extraction ( er), the q er in patients with impaired cardiac function (dottled line) increased without changes in ci. conclusions: the increase in oxygen demand associated with changes in temperature is met by an increase in c! in patients with unaltered cardiac function and in an increase in o er in patients with altered cardiac function. temperature should be taken into account in the assessment of the adequacy of cardiac output in patients with impaired cardiac function. objectives: to define the hemedynamic and metabolic response to physical therapy(pt) in relation to the type/level of sedation and the cardiac status in icu patients. methods: we studied mechanically ventilated icu patients ( • years) in stable hemodynamic status (no change in vasoactive treatment for at least hours), separated in groups: group = deep sedation, cardiac dysfunction required dobutamine (n= )r group = deep sedation (barbiturates), unaltered cardiac function (h=lo), group = moderate sedation, altered cardiac function (h= ) and group = moderate sedation, unaltered cardiac function (n= ). complete hemodynamic data, arterial and mixed venous blood gases, respiratory gas analysis (metabolic cart ccm, medgraphics) were obtained at baseline ( x) and twice (q. min) during leg mobilization. data were analyzed by anova. calcium channel blockers were used in complex preoperative preparation of hypertensive surgical patients. patients were allotted to groups based on their hemodynamic profile: hypokinetic: ejection fraction (ef)< . , patients; eukinetic (ef> . ),i patients and hyperkinetic (ef> . ),i patients. the most noticable change in hemodynamics was in the hypokinetic group: ef and cardiac output (co) were significantly decreased (p< . ) while systolic arterial pressure (sap) (p< . ) and peripheral resistance (pr) (p< . ) were elevated. the results showed that in hypokinetic patients on nifedipine ef (p< . t) stroke volume (sv) (p< . l) and co (p< . ) were increased while pr(p< . t), sap(p< . ) and diastolic arterial pressure(p< . ) were decreased. eukinetic type patients also showed an increase in ef,albiet to a lesser extent,than in the hypokinetic group. increased sv and co(p< . ) were observed in eukinetic patients though this was to a lesser extent than in the hyperkinetic group. in the hyperkinetic group of patients nifedipine had no effect on the aforementioned parameters except for a decrease in sap(p< . i). nifedipine increased ef in all hypokinetic patients. comparative results show that isoptin was less effective than nifedipine in decreasing peripl~eral vascular resistance and had a depressive effect on the myocardium. it can be concluded that the action of calcium channel blockers normalizing the circulation in the hypertensive surgical patient depends on: the condition of myocardium, the patients hemodynamic profile and their pharmacological properties. they were most effective in the hypokinetic group. zalo/nthinos e., daniil z. zakynthinos s., armaganidis a., kotanidou a., nikolaou ch..,roussos ch. critical care department, university of.athens, evangelismos hospital, athens, greece. introduction : surgical is the optimal treatrnent for ioculated effusions and the preferable procedure when multiple bands are seen in the pericardial sac by echo. patients : palients, post cardiac surgery, uremic ( men, women) with large pericardial effusion and clinical or echocardiographic findings of tamponade or both. these particular patients displayed numerous linear echo-dense bands and s~'ands crossing the pericardial space (in one of them a ioculated effusion compressed the left ventricule). one had aptt increased, four were mechanically ventilated. technklue : a fr polyurethane catheter with end and multiple side holes over ga needle was echo-guided to the ideal site (fluid abundant and closest to the transducer). the catheter was attached to a close system with a heimlich valve for continuous drainage (pneumothorax kit). subcostal entry was selected in one patient and chest wall in five. the patient's position was changed every hour at least. (we believe that the small changes in the position of the catheter and the mechanical breaking of the bands in relation with the movement of the heart assist the pericardial fluid to remove). results : in all cases only a small quantity of fluid was withdrawn in the first minutes( - ml) with some clinical and echo-findings improvement. the fluid was bloody or serosanuginous with high protein content (ht= % ,protein , gr/dl) in all cases. in first hours the mean volume of fluid removed was ml ( to ml). in that period echo showed no residual fluid. the catheter remained within the pericardium to days .. no complications are mentioned. conclusion : cardiac tamponade due to hemorrhagic high protein pericardial effusion in uremic and postcardiac surgery patients,, as it is revealed by echo dense bands, can be faced by -d echo guided perieardiocentesis. a -fr polyurethane catheter with multiple side holes, attached to a heimlich valve was effective to evacuate the pericardial fluid. no catheter was occluded though heparin infusions were not used. multiple changes of the patient's position may be fundamental. this -d echo guided pericardiocentesis performed in in~nsive care unit seems to be useful , safe and quick technique. determining the best inotropic drug represents a very serious problems. the use of more selective and potential inotropic and vasodilatative drugs does not always lead to improvement of hemodynamic parameters in patients with low cardiac output syndrome. this paper presents patients with acbp who need an inotropie support after extracorporeal circulation in first hours. the patients were divided into dobutamin et dopamine groups. the heart rate (hr). mean sistemic arterial pressure [map), central venous pressure (cvp). and termodilution cardiac index (ci) were measured. the measurements were without using inotropic drugs, and then using them after rain, min, and finally with one hour rate, within first hours. the statistical analysis shows that both drugs lead to an increase in hr in the first hour of the application. the final effect of dobutamine is no change in hr, whereas the effect of dopanime is very significant increase in hr. thus. an absence of taehyeardie response selects the dobutamine as a better choice. backeround: pulmonary vascular eadothelium possesses major metabolic functions, which when altered contribute to the development of serious pathologies such as ards. one such function is the conversion of angiotensin i to angiotensin ii, catalyzed by angiotensin converting enzyme (ace), located on the luminal surface of the endothelial cells. ace activity has been extensively studied in animals in vivo, by means of indicator-dilution techniques, providing: i) under toxic conditions, an early index of lung injury, and it) under normal conditions, estimations of dynamically perfused capillary surface area (pcsa). objectives: to validate the use of these techniques in matt: i) for pulmonary endothelial function assessment, and it) for pcsa estimation. methods: ace activity was estimated in ten adult haman volunteers, with no pulmonary medical history and normal pulmonary artery pressures, undergoing cardiac catheterization for coronary artery disease assessment. single-pass traspulmonary hydrolysis of the specific ace substrate hbenzoyl-phe-ala-pro (bpap; p.ci) was measured by means of indicatordilution techniques, and expressed as %metabolism (%m) and v=-hi( -m). bpap was injected as a bolus i) into a main pulmonary artery, and it) inside the right atrium, to assess ace activity in one and both lungs. we also calculated a,~,/i~, an index of pcsa. pulmonary plasma flow (fv) was determined by thermodilution. fp in one lung was estimated as . xf v. results: similar values of %m ( . + . vs . • and v ( . • vs . • were observed in both and one lung respectively. a~k~ decreased from • ml/min (both ltmgs) to :~ (one lung). conclusions: i) pulmonary endothelial ace activity and thus pulmonary endothelial function may be assessed in humans by means of indicator-dilution techniques, it) our data denote homogeneous pulmonary capillary ace coneentratious and capillary transit times in both haman lungs, iii) the % reduction of a=~/k~ in one lung suggests that this procedure can be used to quantify pcsa in man. (supported by the fonds de la recherche en saute du quebec and the national health system of greece). objective: verify whether antioxidant activity is higher in reperfused than in no-reflow myocardium after i.v. thrombolysis for acute myocardial infarction (ami). methods: patients with ami were included. blood for estimation of catalase (cat), glutathione peroxidase (gpx) and mn-superoxide dismutase (sod) was drawn before initiation of i. the mechanism of myocardial cell defence against free radicals is probably identical in both reperfusion and no-reflow phenomena. therefore, antioxidants cannot be used as reperfusion markers. objectives_ to evaluate the precipitating factors of hypothermic phrenic nerve injury following cabg with lima. methods: fifty two consecutive patients ( females), with a mean age of + (mean +sd) years were studied. during the ischemic arrest time topical hypothermia was obtained in al~ patients wffh ice slush and no cardiac insulation pad was used. all patients received a lima graft, with or whithout additional vein grafts. supramaximai, bilateral phrenic nerve stimulation was performed percutaneously preoperatively and whithin hours postoperatively. square wave stimuli of . msec duration were applied at the posterior border of the sternomastoid muscle. the compound muscle action potential of the diaphragm was recorded, using surface electrodes on the anterior chest wall. the time interval from the application of stimulus to the onset of diaphragmatic activity, phrenic nerve conduction time (pnct), was measured. values exceeding . msec were considered as abnormal. besults: preoperatively, all patients had normal (mean+sd) pnct, . • msec for the left nerve and . • mseo for the right nerve. on the first postoperative day, right pnct was normal in atl patients ( . • msec) , whereas left pnct was normal in patients ( . • msec) and abnormal in patients (incidence . %). in patients the left phrenic nerve was inexcitable and in patient left pnct was prolonged ( . msec). comparing patients with normal and abnormal pnct there was no difference in age, gender, number of grafts used, aortic cross-clamp and bypass time. however, patients with abnormal pnct had a lower preoperative ejection fraction ( • vs • p= . ). moreover, in all of them lima was dissected from its origin ligating all upper arterial branches, which provide the blood supply to the left phrenic nerve, whereas in those with normal pnct the small vessels originating from the upper to cm of lima were preserved (p= . ). conclusiojel~ a hypoperfused left phrenic nerve seems to be more susceptible to hypothermic injury during cabg with a lima conduit. objectives: to test if necessary interventions on systemic vascular resistance (svr) along with preset pump flew (q) during cpb could adversely affect autoregulatory response and cause vo shifts. methods: we studied males ( - yrs) who underwent cpb for cardiac surgery. at o oesophageal temperature - c we set pump flow at . i.m~ .min - . when map was higher than mmhg we calculated vo by using fick equation. then we infused sodium nitropruaside (sn) to control map at - mmhg for min and we calculated vq . without changing the sn infusion rate we set q at . i.m' .min " . ten min later we measured vo . we took vo changes into consideration if greater than %. statistical analysis using students-t-test for paired data and analysis of variance was used as appropriate. results: depending on the biphasic vo response to sn infusion during low and high q we classified pts in four groups (table). i. vo increases with sn and increases further during high q unmasking hypoperfusion and supply dependency. ii. vo increases with sn but the addition of high q results in systemic shunt. iii. vo increase during high q proves that vasodilatation can turn flow insufficient. iv. vo does not change with any intervention. the small number of pts and the wide standard deviation did not allow any statistical significance. conclusions: cpb is an interesting model for the behavior of microcirculation. intervention on svr and q can improve or impair effective regional oxygen delivery, resulting in either better perfusion or systemic shunt. vo monitoring seems necessary during cpb. preoperative cardiovascular optimization (opt) to ci > . l/min/m , _< paop < mm hg,and svri __< mmhg/ll/min/m decreases cardiac events (events) and mortality (mort) in peripheral vascular surgery patients (pvs). objectives: to determine if opt to the same endpeints decreases events in patients undergoing abdominal aortic aneurysm repair (aaar) and to study the r predictive value in pvs patients. methods: aaar patients and pvs patients were admitted to the s cu monitored with e pa and arterial catheters and treated to achieve opt. patients underwent surgery independent of success of opt data included demograph cs, incremental risk factors, laboratory and hemodynamic data pre, intra, a~nd postoperatively events, and mort. events included arrhythmias requiring treatment or prolonging the sicu stay > hours, a st depression > !mm or t wave inversion, an acute mr defined by a new q wave > . sec or cpk-mb > %. results are presented as means _ -. sd. opt was achieved in of ( %) and in of ( %) in the pvs and aaar group, respectively. events did nat differ between groups of ( , %) and of ( , %) in the pvs and aaar group, respectively (p>o. ). mort was of ( %) and of ( . %) in the pvs and aaar group, respectively (p > . ), while there was no difference in endpoints of opt between patients with and with.out events in the aaar group, there was a significant difference in ci between patients with and without events in the pvs group. of note, of ( %) patients who developed events in the pvs group had a ci < . in contrast to of ( %)in the aaar group. the positive and negative predictive value were % and % in the pvs and % and % in the aaar group. conciusione: f. the endpoints of opt used for pvs patients cannot be ~sed to reduce events in aaar patients; . pvs patients who have net achieved opt are at extraordinary risk of perioperative events; . preoperative card ovascu ar opt in aaar patients makes no difference in cardiac related events, background : comparison of the right and left filling pressures (cvp/pcwp ratio) is considered as a useful diagnostic clue : the normal ratio is _< . ; ratio >_ . may suggest right ventricul~ infarction while equalization of the cvp and pewp is a classic sign of tamponade ( ). however after cardiac surgery, many conditions (diastolic dysfunction, pulmonary hypertension, positive pressure ventilation) are susceptible to modify the '*normal" cvp/pcwp ratio. material and method : we determined cvp/pewp ratio in consecutive patients (pts) after uncomplicated cardiac surgery ( coronary artery bypass grafts; valvular replacements) measurements were made before and after tracheal axtubation. results :cardiac index : . _+ . /minlm~; laotate: + rag/i; cvp range : - rnmhg; pewp range : - mmhg. mean cvp/pcwp ratio before extubation is . ( % confidence imerval : . - . ) and after extubation, . ( % confidence interval : . -. . ), (ns, paired t-test). in % of the pts, cvp was higher than pewp. there are no correlation between the cvp/pcwp ratio and c! before (r = - . ) and after extubation (r = - . ) nor between the cvp/pcwp ratio and mean pulmonary arterial pressure (mpap), before (r = . ) and after extubation (r = - . ), discussion : cardiac performance is adequate according to ci and lactate. however the cvp/pcwp ratio is markedly higher than the "normal" (_< . ) ratio. this difference is not related to mechanical ventilation because the ratio is similar before and after extubation, nor to pulmonary hypetaension because of absence of any correlation with mpap, post-cpb diastolic dysfunction of the right ventricle could be an alternative explanation. in this group of pts, increased cvp/pewp is not associated with any impairment of cardiac performance (absence of correlation with ci), conclusions : cvp/pcwp ratio as high as within a large range of cvp ( - mmhg) and pcwp ( - mmhg) may still be considered as normal after cardiac surgery. this emphasizes the limitations of the hemodynamic monitoring after cardiac surgery (in comparison with echographic technics). careful analysis of the morphology of the cvp and right ventricular pressure curves (x descent, y descent, dip-plateau) is mandatory rather than relying on the quantitative assessment alone. reference : ( ) ntensive care.-university hospital -m~laga (spaink introduction. fibrinolitic treatment (ft) permits the treatment of acute myocardial infarction (ami) addressing the etiology, thereby eading to mproved ventncular function and a marked reduction m mortality. the main clinical oroblem is the reduced time of application. delay in hospitalization, which can be from to minutes, is potentially the most avoidable delay. method. to reduce delays in hospitalization, the following was carried out in two chases. audit: analysis of the time lapse from onset of symptoms to start of ft. showed that during "(he period june to december , patients with chest paros were treated within a eriod varying from minutes to hours from onset of symtoms. ages ranged from to (average , ), oelng males and females. they were glved initial ecgs to determine st mcreases suggesting ami. median t~me for this orocedure was l m.. potentia ami patients were then admitted to the coronary unit, [)atients, under age with no contraindications received ft the median time apse from admission to corona-y care and administration of ft was minutes ( . ), -he total median delay was minutes ~ -i h. min,~ delays n start of this procedure are grouped as follows: extra-hosdita delays (from onset of symtoms to arrival at hospital) diagnostic delays (from hospital arrival to ecg). treatment delays (from diagnosis to ft). objectives: protocol of procedure to implement a fast-track method. a protoco was drawn up with the object of reducing diagnostic delays to -i minutes and treatment delays to less than i minutes results. following rmplementatlon of this protocol in january , fts were glven, with an over all average delay of minutes. this fast-track method did not reveal any inappropnate ft or any increase m complications, conclusions: detailed study of the various times taken for diagnosis ane treatment of ami patients, showed up weaknesses in the system and improvements througn the protocol based on performence orocedures which led to a % reduction in the start of ft background: the importance of the early use of thrombo!ytic agents in acute myocardial infarction (ami) is based in the better remaining ventrictjlar function and smaller mortality rate because of the greater reperfusion and sma!ler infarction size, therefore, it is very impodant to apply this treatment to the maximum number of patients without thrombolytic contraindicati n, and within the minimun period of time. the "thrombolytic fast track" implementation allows to optimize the time to administrate thrombelytic agents avoiding multiple delays~ methodology: we anal!ze the application of thromboly c agents to patients with suspect of ami from the begin!ng of september until the end of february . in this time there are two different periods, during the first months thrombolytic agent were admin!strated at intensive care unit (icu), and during the second period we carried out a protocol of quick detection and thrombolysis therapy in susceptible patients at the emergency room in order to reduce the time to treatment. ma!n results are shown in the faffewins de ay h=hours m=minutes the implementation of the fast track does not need supplementary personal or equipment but a protocelized approach and training of the personal involved the main problem detected was the usual attendance overload of the emergency department that makes difficult to follow many structurated actions. conclusions: pratocqlized changes in the management of ami can significantly reduce the detay in the administration ef thrombolytic agents. it is not necessary to eomplet the procedure iq the emergency department, as the use of bolus schedules allows to begin the treatment in this area and to transfer the patient to icu afterwards. elective cardiac surgery. b calvet, f ryckwaert, p trinh duc, p colson. anesthesia -reanimation, hopital arnaud de villeneuve, montpellier, france. obhectives: the study was aimed at analysing the incidence of renal dysfunction following cardiac surgery and its prognosis (acute renal failure, post-operative morbidity and mortality). methods: two hundred and thirty seven patients (aged from to ) were consecutively operated on for elective cardiac surgery and retrospectively included in the study. patients with preoperative infections and operated on in emergency were excluded. each patient had preoperative invasive cardiac investigation with angiography and calculated ejection fraction (ef). anaesthesia, cardiopulmonary bypass (cpb) and cardiac arrest management were similar in all patients. general body temperature was reduced to - ~ c. renal dysfunction was defined as a % increase from baseline of serum creatinine. demographic data, asa, treatments, pre-operative creaunine level, cpb and clamping (axc) times, intra and postoperative use of inotrope, serum lactate level before surgery, at the end of cpb, at the time of admission in intensive care unit (icu) and on post operative day one and apache score were compared in patients with or without renal dysfunction using anova test for repeated mesures and x when appropriate. data are expressed as mean +__sd. p value less than . was considered statistically significant. results: thirtytwo patients ( , %) suffered from renal dysfunction. age, serum lactate level at the end of cpb, at admission in icu, at pod and apache level at admission in icu, intra-operative use of inotropes were statistically different in patients with or without renal dysfunction (p< , ). mortality rate was statistically different in patients with or without renal dysfunction(~, , % and %, respectively, p= , ). incidence of acute renal failure following renal dysfunction was , % ( patients required hemodialysis). conclusions: although our cdteria for defining renal dysfunction were very sensitive, the incidence of renal dysfunction following elective cardiac surgery was lower than communly accepted in the litterature ( ). however renal dysfunction appeared significantly associated with a poor prognosis. reference: -settergren g, ohqvist g current opinion in anaesthesiology , : - r ; , tzelepis, g. , , late complications were observed in % of cannulations: local infection in (i, %), catheter displacement by the patient in cases ( , %), catheter displacement during nursing care in ( , %) and malfunction in cases ( , %). conclusions: central venous catheterizations are followed by immediate and late complications in almost the same percentage acute poisoning with amphetamines (mdea) and heroin: antagonistic effects between the two drugs methods: after institutional approval and informed consent, selected patients ( _+ years) undergoing peripheral vascular surgery (n= ) or carotid endarterectomy (n= ) were investigated. patients included had either documented cad (n= ) or two or more (n= ) dsk factors (age > years, smoking, diabetes meltitus, hypertension, hypercholesterolaemia > mg/dl). -lead ecg recordings were carded out preoperatively, on ardval in the postanaesthetic care unit, and h, h, h, and h postoperatively. ecg recordings were analysed by an independent blinded cardiologist for signs of pmi (new st segment depression > . mv and/or new t inversion). in addition results: of the patients investigated developed ecg-documented pmi, % occurdng in the immediate postoperative phase. troponin i levels > . ng/ml were found in of these patients thus, comparing a cardiac troponin i cut-off level of ng/ml with intermittent -lead ecg recordings, we found a sensitivity of % and a specificity of % methods: demographic, clinical and ecg data were analyzed. . % of patients were male; . % female. cad was the most common underlying cardiac disease ( . %) and . % underwent open heart surgery. % received proeainamide for supraventricular and % for ven~cular arrhythmias. % received a loading dose. maintenance was provided by iv route in . % and by po in . % ( . %sr end . % ir). . % of patients were obese right ventricular function following cardiopulmonary bypass: is important the mode of myocardial protection we underwent this study in order to examine its safety and usefulness in pts with trustable coronary conditions (unstable angina ua the mean age for group a was • years, for group b • years, and for group c • years. a history of previous myocardial infarction was present in pts of group a, in of group b and in of group c. three pts in group a, in group b and in group c had previous coronary artery bypass grafting. the median time between the onset of symptoms and a was days ( - ) for group a we used a continuous fixed intravenous a infusion at a dose of the sn was % in groups a and b, % in c, and sp % for group a, (fixed defects included) and % for groups b and c. there was no difference of side effects among groups: chest pain (i pt -group a, pts -group b, and pts -group c), transient hypotension ( pt -group c), headache ( pts, group c), dyspnea ( pt -group a), while st depression was seen in pts of group b and in pts in group c. the rate of a infusion was decreased to /kgr/min in one group b pt due to development of chest pain s five year follow up of humoral immunity in paced patients athens polyclinic hospital, department of cardiology athens, greece author index a abiad ch bertschat, e betbes blanch, l del nogal saez e -meneza nolla, j. nolla-salas pilz~ u puig de la bellacasa e scarpa, n. van de wetering objectives: only % of patients suffering from acute guillain-barr@ syndrome (gbs) respond promptly to established therapies like plasma exchange or intravenous immunoglobulines. in contrast to serum, cerebrospinal fluid (csf) of gbs and ctdp patients contains enriched portions of antiexcitatory factors(i) and cytokines ( ) able to induce pronounced conduction block ( ). to reduce or remove such pathologic factors we introduced a technique with direct access to the subarachnoid space. methods: with informed consent we lumbally inserted g catheters in gbs-and cidp -patients under sterile conditions. some of them had not responded very well to established therapies. - ml of csf were withdrawn and retransfused by a bidirectional pump (flofors) after passing newly developed filters (pall). daily filtrations with several cycles were performed ( - ml) over one week. results: the gbs patients improved after days (median) for one grade (according to the gbs-scale from the gbs study group) . the ventilator dependent patients were weaned after days (median). patients not at all treated before ( / ) responded better than patients that had been pretreated ( / ) with plasmaexchange or intravenous immunoglobulines. / cidp patients drew benefit from treatment, stabilized iongterm. conclusions: csf-filtration is a relatively save and well tolerated additional procedure. the costs are considerably lower ( / ) than those for plasmaexchange or intravenous immunoglobulines. references:( )wsrz aet al: csf and serum from patients with inflammatory polyradiculopathy have opposite effects on sodium channels. muscle nerve ( ) . ( ) clinical observations were made in patients admitted to the clinic. they were in coma associated with acute alcohol intoxication.standard evaluations (ecg-monitoring, electrocardiography, neuromonitoring, studies of acid-alkali condition, biochemical and toxicologic investigation of blood and urine) prior to and following the treatment conducted were undertaken in all the patients.to correct irreversible impairement of functions twofold laser blood irradiation by means of alok- apparatus, the exposure within minutes, was carried out.the data obtained confirm more rapid coma withdrawal of the patients, reconstruction of the heart and central nervous system electrophysiologic indeces, reliable reduction in complications compared with the control group. objective: to know the actual incidence of the critical illness polyneuropathy(cip). setting: fourteen intensive/critical care unit beds, in bed university hospital, covering . inhabitants (majority rural area). the icu patients are medical, surgical and coronary, excluded the neurotrauma and neurosurgical. design: a conseculive and prospective study. all the patients admitted during three months, from january lth to march th , were eligible (patients with admittance diagnosis of polyneuropathy were excluded ). methods: patients with apache ii score > , at the admission and six days after admissions were included into the study protocol. diagnosis of sepsis, mof, and all the drugs administered days before were recorded. a complete neurological exam, by a neurologist, in absence of ssdatives and muscles reliant ( th, ~ and th days after icu admittance) was made. we evaluated the nerve and muscles function with and electromyography study in all patients, at same days. in some paeents with cip we performed a nerve biopsy. results: from patients ( apache ii score: . ) admitted in the icu, ( . %) enter the study protocol. seven ( , %) had an axonal polyneuropathy(cip), three very severe. only four of the patients with cip had pathologic clinical exam. apache ii score: cip vs non-cip was . vs . . the incidence of cip by diagnosis (cip/diagnosis) was: sepsis, / and mof, / . conclusions: . -we think that it is necessary to define the "critically ill" for some score, before designing a study to know the incidence of this syndrome. . -we think that the incidence of the cip is lower that the latest papers say. objectives:acute pancreatitis(ap)is becoming a more important problem among the elderly as the population ages. the increasing presence of gallstone disease,as well as the use of certain drugs,may also contribute to the occurrence of pancreatitis. methods:all patients(> years)admitted to our medical department over an eight year period were included.pancreatitis was confirmed by biochemical tests and imaging techniques.scores were developed using ranson's criteria and a multiple organ system failure(mosf)index . overall, patients were evaluated; ( %)had pancreatitis of unknown etiology . results:( )patients with pancreatitis of ~nlqnown etiology were sicker and had greater morbidity( % vs %),mortality( % vs %),and longer hospital stays than p~tierf~ with pancreatitis of known cause.( )the best predicto~of severity and outcome was the mosf index and not ranson's criteria;the higher the score,the greater the associated disease,the worse the outcome.( )curlously,no difference existed in associated medical conditions between patierts withknown and ur ~own causes of pancreatitis. conclusions:greater organ dysfunction exists in patients with pancreatitis of unknown etiology, even though age and associated medical conditions do not differ . the application of the total enteral nutrition in the burns disease has minimized the complication rate and consequently increased the survival rate of children and adults. time of initiation, composition, duration and way of administration are very important in obtaining the optimum beneficial effect from the treatment and diminishing the complication rate and side effects. the above features will be discussed in view of our experience in cases. ta buckle?,, ra freebalm, c gomersall g joynt, r young. tg short. department of anaesthesia and intensive cm+e, prince of wales hospital. the chinese university of hong kong, shatin, hong kong introduction: gastric mucosal ph (phi) monitoring has been proposed as a relatively noninvasive index of the adequacy of aerobic metabolism in the gut. to examine the accuracy of gastric intramucosal pit measurements as a function of time and as a function of the catheter itself to determine whether the measurement error between catheters is clinically acceptable. patients with a gastric tonometer (trip tm, tonometrics, worcester. ma) insitu for > days were studied. following informed consent two new tonometers were inserted equidistantly & correct position was confirmed radiographically. measurements of intramucosal gastric ph were then performed over a hr period. eight -ten measurements were made in each of ten critically ill patients.percent differences between the two new catheters were . % ie at ph . _+ . ( % limits) and between old & new catheters were . %, ie ph j _+ . ( % limits). conclusions: the results suggest that the function of the tonometer deteriorates over time and that the absolute values of phi m~ not ~ufficiently accurate. however as a trend monitor phi may be useful in the clinical setting. despite a continuous decline both in li'equency and severity of gastro-intestinal stress-lesion/-bleeding (gisb) due to both improvement in preclinical support and in intensive care medicine, patients with cerebral lesion are still considered at high risk for developing gis . therefore the question arises, whether m> specific (}lsb-prophylaxis besides general and neurological intensive care, specific pharlnaeothcrapy or even the combination of two specific drugs reveals any protective efli~ct on frequency and severity of gisb.this pntspcclive randomized study has been perfornted in patients snfrering t'rttna head-injury/cerebral lesion and with a glasgow-coma-scale on admission (gcs:,)of < . according to randomization the patients have been grouped as tbllows: h analgesia/sedation (n= ); ih analgesiajsedation plus pirenzepine mg/day (n= ); .[ih anatgcsia/sedalkm plus sncraltate x [ g/day (n= ); iv: analgesidsedatkm plus pirenzcpine mghlay plus sucralfate x e/day (n= ). slalislical analysis has been performed by chl:*tt~sl. rank correlatinn and unpaired t-test; statistical significance has been set with p < . . / patients ( . %) developed gisb. although the mean gcs~-value (x -+ sd) did not reach significance between patients with and without gisb ( . + . vs . -+ . ). a significant inverse correlation between gcs:, and the incidence of gtsb (rs~ = . ) has been shown. the frequency of gisb among the groups is as follows: h . %; lh . %; llh . %; iv: . % (ch -~ = . ; not signilicant). no gisb-induced blood translusion or mortality, respectively, could be demonstrated. survival rate between the groups did not differ significantly (chi-" = . ; p= . ) and reached an overall-value of . %.drug-specific glsb-prophylaxis -administered either as monotherapy (pirenzepine, sueralfate) or in combination of these two specific-drugs -reveals no additional significant influence on the incidence of gisb in patients with cerebral lesion compared to no specific prophylaxis besides the general trauma-/disease-specific intensive care measures. critical care dpt, evangelismos hospital, athens university scho~" of medicine objectives: the correlation of longterm presence of nasogastric tube (ngt) to gastroesophageal reflux (ger) is still in question. in case of positive correlation, peg should represent an alternative to tube feeding in patients unable to be fed orally. therefore, we investigated: i) the correlation between ng and ger and ii) the effect of peg on ger. methods: a -h esophageal ph-metry was performed in patients in recumbent position at ~ who had a ngt for more than days and were on sucralfate for gastric mucosal protection. the tip of the ph-probe was lied cm over the esophagogasttie junction, confirmed by x-rays. patients who presented a percentage of ger-total (i.e. with a ph less or more than ) (ger-t) more than %, underwent ~t peg. the presence of a creseent-notch on the esophagogastric junction persisting on inspiration and the grade os endoseopic and histologic esophagitis (scale= - ) was noted. two ph-metrles repeated on h and on days post-peg were compared to the pre-peg one, with the followin~ parameters taken in consideration: i) % ger-t, ii) number of ger-total per hour (no/h ger-t) and iii) the duration that ph was less than (tph< ). in case ot ger persistence at the ph-metry on ?th day post-peg (group ii) another endoscopy was performed, while patients with reduced ger (group i) were considered as esophagifis-free.results: out of patients presented a ger-t> %. eleven out of group i group (n= ) i ( objectives: the aim of the present study was to compare the performance of a specially modified version of a photo-and magnetoacoustic (pa/ma) gas analyzer (br~)el & kjaer, denmark) with a conventional quadrupole mass spectrometer (ms) (innovision, denmark) in inert gas rebreathing (rb) tests such as determination of functional residual capacity (frc), pulmonary capillary blood flow (pcbf) and lung tissue volume (vtc). methods : from simultaneous readings of inert gas concentrations with the ms and the pa/ma analyzer during rb experiments a comparison was made of the pcbf, vtc and frc values. the rb tests were performed during rest and exercise ( , and w) in ten healthy subjects. results: the differences (mean +/-sd) between simultaneous estimates of rebreathing parameters were the following (pa/ma -ms) for pooled data, pcbf: . +/- . i/min, vtc: - +/- ml and frc: . +/- . liters. conclusions: smell but significant differences were found between the estimates of pcbf, vtc and frc using the ms and pa/ma, respectively. reference: p. clemensen, p. christensen, p. norsk, and j. gr~nlund. a modified photo-and magnetoacoustic multigas analyzer aplied in gas exchange measurements. j appl physiol ; : - . objectives: because transcranial doppler (tcd) has been proposed to explore cerebral co vasoreactivity in brain injury (stroke ; : - ), we compared this technique with the kety-schmidt reference method to assess cerebral vasoreactivity in comatose patients. methods: mechanically ventilated patients (age - yrs, glasgow - ) in coma due to acute brain injury were investigated during stepwise changes in paco ( , , , and mmhg) by increasing inspired pco . middle cerebral artery velocity (vm) was measured by tcd. after insertion of a catheter in the ipsilateral jugular bulb, cerebral blood flow (cbf) was determined by the kety-schmidt method, using the inhalation of % n through the inspiratory line of the ventilator. for each patient a cerebral co~ vasoreactivity index was calculated as the slope of linear relationship between vm or cbf and paco . objectives: after cardiac surgery the fluid shill, between interstitial and intravasal space may be marked. this is due either to the intraoperative volume loading by the extracorporeal circulation or the increased postoperative diuresis. therefore, infusion of a large amount &fluids is necessary during the first postoperative hours. it still remains unclear which of the substances at disposal is the best for this purpose. aim of the present study was to compare the different fluids with special regard to postoperative bleeding and rheological behaviour. methods: patients undergoing cabg-surgery were investigated and randomizedly distributed to three different groups of postoperative volume replacement to stabilize the mean arterial pressure at mm hg. . ringer's solution, . . % gelatine solution, . % hydroxyaethylstarch (mean m.w. . ). we evaluated the following parameters within intervals of min: arterial and central venous pressure, heart rate, postoperative bleeding, urinary output, volume replacement. results: there was no statistically significant difference between the groups with regard to urinary output and bleeding. in spite of larger amounts of fluids necessary in the ringer treated group patients of this group showed symptoms of hypovolemia. hematocrit was increased in the ringer patients. this was statistically significant. introduction: pulmonary wedge pressure (pcwp) and central venous pressure (cvp) are frequently used as parameters for cardiac preload, although it is known that both are poorly correlated to the cardiac index (ci). it has been claimed that intrathoracic blood volume (itbv) measured with the thermal dye dilution method reflects cardiac preload better than pcwp and cvp. we studied the correlation between itbv and ci in a mixed population of critically ill patients. methods: in consecutive patients ( sepsis/sirs, acute heart failure, ards, transjugular intrahepatic portosystemic shunt) monitored with a pulmonary artery catheter, itbv was measured on regular intervals using the pulsion cold z- system (pulsion, munich, germany). ci, pcwp, and cvp were recorded simultaneously. results: a total of ol measurements was made. pcwp and cvp did not correlate to ci, nor did apcwp or acvp correlate to aci. itbv was correlated to ci in a non-linear fashion (f - , df = , p < . , (figure) ). aitbv was correlated to ac in a linear fashion (r = . , f = , df = , p < .o ). a rapid and efficient circulatory support system may save a patient in cardiogenic shock. left heart bypass with percutaneous and transseptal placement of the aspiration canuia simplifies the circuit and avoids the need for an oxygenator. we assessed this preclinical set-up in anaesthetized pigs using a centrifugal pump with a f arterial catheter and a f left atrial aspiration line. animals were supported for two hours at a mean flow of . liter ( ' rpm), a mean hematocrit of % and low heparinisetion (act double baseline). hemodynamic and laboratory samples were taken at baseline (a), minutes (b), one hour ( pulmonary hypertension (ph) usually involves obliteration and loss of functional pulmonary microvasculature. the microvaseular endothelium normally acts as a major metabolic organ, converting angiotensin i to angiotensin ii via the angiotensin-converting ectoenzyme (ace). it is unknown whether the loss of functional vasculature and altered pulmonary blood flow seen in ph will affect lung ace metabolic activity. we therefore estimated pulmonary vascular ace activity in patients with ph of various causes: primary; post atrial septal defect closure (asd); chronic thromboembolic (te); anorexigen; iv drugs; collagen disease. single-pass transpulmonary hydrolysis of the specific ace substrate h-benzoyl-pbe-ala-pro (bpap) was measured and expressed as % metabolism (%me . we also calculated an index of peffused functional capillary surface area (amax/km). all patients with ph had an abnormality of %met or amax/km, or both. as compared to control humans (mean %met = . % _+ . % s.d.), the mean %met in ph patients was . % _+ %. the %met in ph patients correlated inversely with cardiac output (r= . ), possibly reflecting more complete bpap hydrolysis with longer pulmonary transit times. amax/km was markedly decreased in ph ( + ml/min) as compared to controls ( _+ ml]min), consistent with a significant loss of functional capillary surface area. patients with collagen disease, asd and anorexigen-induced ph had the most marked abnormalities. in conclusion, patients with pulmonary hypertension have decreased pulmonary endothelial angiotensin converting enzyme activity, likely due to a loss of functional or perfused pulmonary microvaseulature. supported by the funds de la recherche en same du quebec and the national health system of greece. objective: to investigate adrenocortical function in patients with ruptured aneurysm of the abdominal aorta (raaa). studies investigating adrenocortical insufficiency in critically ill patients report an incidence ranging from % to less than %. this may in part be explained by difference in methods used (single cortisol measurement vs short acth stimulation test) and populations studied (heterogenous groups of patients with great individual variation in underlying disease as well as duration and severity of illness). methods: we investigated the adrenocortical function in patients with (raaa).a short acth stimulation test (synacthen test; ug - acth iv) was performed at hrs within hrs of admission. plasma cortisol was measured before (cort basal) and after stimulation (cort stim). a plasma cortisol level > . umol\l before or after stimulation was considered normal, severity of illness was assessed using apache ii. results: of the patients investigated died and survived. mean cort basal in nonsurvivors was significantly (p< .o ) higher than in survivors; . (range . - . ) vs . (range . - , ). this difference between nonsurvivors and survivors was also present for cort stim but lacked significance; . (range . - . ) vs . (range . - . ). while patients showed a cort basal < . , no cort stim < . was found. there was no significant difference in mean age or apache ii score between survivors and nonsurvivors; vs and vs . conclusions: single plasma cortisol levels were inadequate to assess the adrenocortical function in the patients studied, judged by a short acth stimulation test, our investigation in patients with raaa showed no adrenocortical insufficiency. mortality in raaa is associated with elevated plasma cortisol levels. obiectives: mortality in acute myocardial infarction (ami) prinicipally depends on hemedynamic impairment. thus, patients (pts) with elevated pulmonary wedge pressure (pwp) present high in-hospital mortality. however, the complete right heart catheterization is laborious, so the central venous pressure (cvp) alone is frequently used to assess the severity of ami. the accuracy of cvp in estimating pts with ami was tested in this retrospective study. methods: pts. aged + years, admitted to our ccu from to with their first ami, were inctuded in this study. all had undergone right heart catheterization because of overt or suspected heart failure. swan-ganz catheters ( f, cm, abbott, il, usa) had been used, every treatment had been temporarily interrupted l h before the calheferization. based on ecg findings the pts were retrospectively divided into groups. in group a we included pts with anterior ami, in group b, pts with inferior ami, and in group c, pts with inferior and right ventricular ami. the initial values of cvp and pwp were considered for the linear regression of the pwp variable on cvp and p< . was accepted as statistically significant.results: in g~oup a, the cvp and pwp vaiues were + mmhg and _+ mmhg respectively. despite the signifanf correlation (p< . ) between the two variables, it was not possible fo predict the exact value of pwp based on cvp value, pts ( %) presented cvp> mrnhg and of these ( %) had pwp_> mmhg. in group , the cvp was _+ mmhg and the pwp, _+ mmhg. significant correlation (p< . ) between the two variables also existed, however it was impossible to predict the pwp value. pts ( %) had cvp> mmhg but only of these ( %) had pwp> mmhg, similar was the relation between cvp and pwp in group c (p< . ). cvp averaged + mmhg, and pwp, _+ mmhg. pts ( %) had cvp> mmhg and from these ( %) presented pwp> mmhg,conclusions: a single measurement of cvp in ami does not ensure an accurate assessment of pwp. because every pt with ami needs optimal values of pwp in order to prevent pulmonary congestion or manifestations of low preload, the significance of complete right heart catheterization becomes apparent. in patients (pts) with advanced hf the need and the prognosis for heart transplantation (ht) can be predicted from vo= max. indirect measure of functional capacity with the six-minute walk test can also predict smvival in moderate hf. to predict vos max from indirect astinmtions of functional capadty such as - ~q~/, pulmonary and heart function tests, and to assess the prediddve value of the above parameters in hf pts survival. we evaluated pts (age + yeats nyha class: ii, hi, iv) with hf for pit. they underwent a pmgmmive exercise test on cycle ergometer for vo max determination, a -mw, a right heart catheterization and a spirometry and dlco estimation. introduction: brain death causes myocardial impairment by mechanisms that are not well understood yet. the aim of this work was to assess the echocardiographic features found in these patients from the clinical onset of brain death to somatic death, methods: seven brain dead patients were studied (patients" relatives refused to allow them to be used as donors). mean age was . ( - ) years old. four of the patients were female, none of the patients had any history of cardiac disease. transthoracic echocardiogram (echo) and electrocardiogram (ecg) were obtained at the onset of clinical brain death and were repeated every hours until somatic death. we we detected severe diffuse hypokinesia (ef< %) in patients and mild hypokinesia in others (ef - %). systolic function was strictly normal in only patients. corrected qt interval (qtc) in ecg was . _+ . msec (normal range - msec) just before somatic death (b). conclusion: in patients with brain death we observed a significant increase of left ventricular mass due mainly to ivs "hypertrophy" without any important change in the dimensions of the left ventricle. to our knowledge, this finding has never been reported before and its importantance in heart transplantations may be of particular interest. predict right ventricular outcome. l. jacquet, r. dion, p. noirhomme. m. van dijck. m. goenen cardiothoracic intensive care unit, st-luc univ. hospital(ucl) we have registred: heart rate (hr), blood pressure (bp), pulmonary artery pressures (pap), central venous pressure (cvp), pulmonary capillary wedge pressure (pcwp), pulmonary and systemic vascular resistances (pvr, svr), right ventricle end-diastolic end end-systolic volume (redv, resv), right ejection fraction (ref), right sistolyc ventricular work (rsvw) and cardiac output (co) using a thermodilution thechnique and a microprocessor (model ref- ; baxter-edwards laboratory); duration of cpb and aortic clamping, and the requirements of haemodynamic support after cpb.results: in the c group an increase post-cpb of the fc ( + . + . , p < . ) was produced without significantly changes in the redv, resv, ref, rsvw neither co. in the w group, hr increased from . + . to . + . (p < . ); redv was reduced from . -+ to . _+ . (p < . ); resv was reduced from • . to + . (p < . ). there were not changes in the other haemodynamyc parameters. there was a trend (no significantly) to an increase of ref in the w group ( . + . |• . ) compared with the c"group ( • . ($ . • . ) post-cpb. the need for haemodynamic support was similar in both groups.conclusions: the warm, continuous, anterograde-retrogade myocardial protection has obtained a decrease of preload, hr, and a trend to an increase in the ref, making an improvement in the right ventricular global performance when is compared with the classic form of cold myocardial protection. objective: to evaluate the effect of dobutamine on gastric mucosal ph (phi) after coronaly artery bypass surgery. design: prospective study in a university hospital intensive care unit (icu). subjects: elective cardiac surgery patients. interventions: dobutamine was infused at ug/kg/min for hours immediately after admission to the icu. hemodynamics were measured every minute periods until hours and again hours after stopping dobutamine. results: there were no significant differences in mean gastric phi between the groups but mean phi decreased in both groups during the study period. oxygen delivery and consumption both increased during dobutamine infusion but decreased to the control group level after stopping the dobutamine infusion. lactate levels did not change. baseline objectives: the aim of the study was to evaluate the usefulness of a low dobutamine dose in conjunction with intraaortic balloon pumping and mechanical ventilation in cardiogenic shock. we studied patients . -+ t . years of age suffered of post infarction cardiogenic shock characterized by a systolic arterial pressure< mmhg, urine output< ml/h and mental confusion or purpueral signs of low output, non responded to dobutamine infusion up to pg/kg/min. all patients underwent mechanical assistance by the intra-aortic balloon pump (iabp). five patients were additionally placed on mechanical ventilation due to blood gases disturbances. the end points in our study were: reversion of cardiogenic shock, improvement of patients survival or both on the th post infarction day and months later. results: three patients refused iabp treatment and / survived on the th day. on the th day / supported by the iabp and / that underwent mechanical ventilation plus iabp were alive (p < . ). on the th month / supported by the iabp and / that underwent mechanical ventilation plus iabp were alive (p< . ). conclusions: in conclusion, the combined use of mechanical ventilation and iabp assistance in severe cardiogenic shock might improve survival. obiectives: the study was aimed at analysing predictive factors of swan ganz pulmonary catheter (pc) requiremen t during elective cardiac surgery according to the need of sustained inotropic support after surgery. methods: three hundred patients (aged from to ; females and males)were consecutively operated on for elective coronary artery bypass surgery (cabg, n= ), valvular replacement (vr, n= ), combination of both (vr-cabg, n= ), or others (n= ) and retrospectively included in the study. each patient had preoperative invasive cardiac investigation with calculated ejection fraction (ee). anaesthesia, cardiopulmonary bypass (cpb) and cardiac arrest managements were similar in all patients. pc requirement was estimated from the need of either dobutamine, adrenaline, dopamine or enoximone use during the first hours after cardiac surgery. demographic data, asa and nyha classifications, preoperative ef and treatments, type of surgery, cpb and aortic cross clamping (axc) times, and postoperative incidence of complications were compared in patients with or without inotropic support using either student's t test or x with continuity correction when appropriate. results: seventy hree patients ( . %) required inotropic support after surgery. axc .and cpb times, mean stay in icu were significantly longer in patients with inotropie support (p< . ). type of surgery, preoperative ef, and nyha classification are the first significant factors related to inotropic support (p< . ). most patients operated on for double-vr or vr=cabg required inotropic support ( and %, respectively). postoperative mortality was higher in patients receiving inotropic support ( , % vs , % 'overall mortality, p= . ). conclusions: since pc insertion is most.often justified because inotropes are required, these results suggest that elective rather than routine systemic pc insertion could be helped by considering several but selected preoperative factors. background: cardiovascular depression due to anaesthesia, old age and major gastrointestinal surgery is becoming an increasingly frequent challenge .to the anaesthesia-surgory team. deliberate preoperative manipulation of haemodynamics and oxygen transport parametres towards prede~t~mined optimal values may prove to be effective "in reducing morbidity ~nd mortality in high risk surgical patients,. a new concept of using conlimaous perioperative measurement of cardiac'output to obtain and maintain supranormal oxygen delivery (do i) is presented. methods: continuous measurement of cardiac output is a relatively new form of on-line monitoring, in which trains of impulses are emitted from a thermal filament mounted on a pulmonary artery catheter. computer software recognizes patterns generated by minute changes in blood temperature and ealoalates cardiac output every - seconds. cardiac output and mixed venous blood oxygen saturation are displayed graphically on line. in tins tm study cardiac output was measured continuously by vigilance cardiac outpu t compl/ter (baxter). preoperative haemodynamic optimization was performed with the goal of increa- sing do i to at least ml/min/m accordfing to shoemaker's algorithm . this was.done by infusing colloids (albumin or hydroxy ethyl starch (haes-steril| until the desired do was reached. infusion was stopped if cardiac output ceased to increase with infusion, if there were signs of pulmonary oedema or if wedge pressure reached mmhg. vasoactive or inotropic drugs were infused if the desired do was not reached by infusion alone. anaesthetic technique included continuous thoracic epidural and isoflourane anaesthesia. expected mol:bidity and mortality rates were calculated by the "possum" score aasing preoperative clinical and paradinical estimates of organ function as well as surgery characteristics . materials: asa group ill-iv patients with a mean age of years (range - ) and a mean weight of kg (range - )) scheduled for major abdominal surgery were included. results: patients were excluded because do i could not be raised at all. mean do i was increased from ml/min/m (range - ) to ml/min/m (range - ). mean volume of preoperativdy infused colloid was ml (range - ). during surgery ml (range ) of colloid was infused. mean length of surgery was minutes (range - ). mean blood loss was ml (range ). expected mortality and morbidity rates ("possum") were % and %, respectively, whereas patient follow up upon discharge or at death revealed mortality and morbidity rates of % and %, respectively. conclusion: based on experience from the present study, continuous measurement of cardiac output has proved to be a valuable tool for perioperative optimization of do in asa group ili and iv patients during major surgery. however further studies including a greater number of patients are necessary to confirm the promising preliminary findings. we studied the hemodyn~c effects of three different combinations of positiv inotropic .agents, vasodilators, diuretics and av-filtration (av) in patients (pts) with severe left heart faille (left veutrieul x filling pressure (lvfp) > mmhg) due to acute myocardial infarction. hemodynamic measurements (intravascular pressures (lvfp), thermodilution (cardiac index (ci)) were made before (control) and after each therapy. in furosemide (f) + d butamin (d) + nitroglycerin (ni) reduced lvfp and a small increase of ci occurred. in of these pts :(group a) nitroprusside (hip) instead of ni increased ci significantly, in the other pts adding of amrinone (a) resulted in a pronounced increase of ci. group c (n= ): the combination of ni and av reduced lvfp but did not increase ci which was achieved by av+d+ni. in order to optimize the treatment of acute heart failure a combination of inotropic agents, vasodilators, diuretics and av-filtration should he used guided by hemodynamic monitoring. arias jr, miragaya d, sandard, san pedro dm ~, herndndez d, valenzuela . objectives: to evaluate the variation in nomdrenaline (na) plasma concentrations in patients with acute myocardial infarction (am ) after thrombolytic therapy with noniltvasive reperfusion criteria (clinical, electrocardiographic and enzymatic), in relation to infarct size and location.methods: consecutive patiens with ami, from october , to february , , admitted within hours alter onset of symptoms, undergone successfull systemic thrombolysis. of them were anterior (group a) and inferior (group b) . noradrenaline plasma levels at (na ), (na ) and (na ) minutes after admission were compared with ck-peak plasma levels by linear regression. differences were tested for significance by student-t-test for paired and unpaired values. na plasma concentration was measured by high-presssure liquid chromatography. p< ns . ns means -sem (normal limit for our laboratory: na < / pg/ml; ck < u/i ) conclusions: . the na plasma levels at admission (nai) are more increased in anterior than inferior amis, probably in relation to infarct size. . the decrease in na is more evidence in amis with anterior location. . this decrease is probably due to the major efficacy of thrombolytic therapy in amis with anterior location. arias jd, miragaya (group b) , probably due to certain degree of t~cg'rfueion. . there is not significant variation in na in conventional treated ami (group c). v.suchanov, a.levit, p.trofimov, icu, regional hospital, ekaterinburg, russiaobjectives: our task was to improve the technique of preservation of platelet rich plasma. methods: patients scheduled for multiple cardiac valve replacement in were divided into two groups: group i ( patients) -without pp; group ii ( patients) -pp was performed preoperatively. the first pp was made ten days and the second - days before the operation. prp was preserved by cryoconservation. our technique of cryoconservation is distinguished by the speed of freezing ( - ~ and absence of dmso. this made it possible to preserve % functionally active platelets during days. the prp was transfused back after heparin neutralization. the hospital ethics committee approved the investigation.results: the blood loss through the st p. o. d. was significantly greatest in the group i ( _+ ml) and all the patients required transfusion of the donor blood ( + ml) whereas the blood loss in group ii was +_ ml and olny patients required the donor blood. the number of platelets on the st p.o.d, was _+ . /l (group i) and + . /l (group ii), p < . .conclusions: our technique of prp cryoconservation makes it possible to avoid the crystallization phase during freezing of prr thus the infusion of prp may improve hemostasis after open heart surgery and limit the use of the donor blood. in-hospital outcome of women suffering an ami is generally considered worse than that of men, but it is still debated whether female sex is per sea negative prognostic factor or is merely associated with other negative determinants of prognosis. the purpose of the present study is to evaluate the independence of the association between female sex and mortality (in the patients of the swiss centers) and in the patients randomized in the isis- trail mortality rate in women was . % ( / ) compared to . % ( / ) in men; in switzerland: in-hospital mortality for women was . % ( / ), for men . % ( / ).the table shows the results of isis- in terms of odds ratios and their % confidence intervals either after unadjusted analysis or after adjustment for age, known to be the major confounding variable when prognosis of women after myocardial infarction is considered, and for all the available clinical and epidemiological characteristics collected at trial entry: these observations suggest that there is a small but independent effect of female sex on short-term mortality after acute myocardial infarction. ( ) and bubble ( ) oxygenators a, ere used. anaesthesia was balanced and pts were extubated to hrs after cpb. pts were monitored with swan-ganz catheters (sgc) for hrs after cpb. at that time qs/qt was calculate( according to )be standard shunt equation. after the sgc had been removed, an estimated shunt was calculated. measurements of qs/qt were performed: before induction of anaesthesia ( ), after induction of anaesthesia (i[), mins after cpb (iii) (iv) and (v) hrs afiter cpb, rains after extubation (vi), hrs after cpb (v[ ) and on the nd, rd, th, th and tb postoperative day (pd) (viii, x, x, xi, xi , respectively). analysis of data was performed by two-way analysis of variance, p < . being regard as significant.results: the figure shows the values for qs/qt expressed as means + sd. there was a significant increase in qs/qt above b~setine throughoul the whole investigated period except on the th pd. qs/qt reached maximum at rains after extubation (vi). objectives: many stndies have shown advantages of membrane oxygenalors over ubbie type oxygenators. the aim of this study was to evaluate the influence of x 'genator type on pulmonary shunt (as/at) after coronary surgery. methods: patients (pts) gave their informed consent to the study which was approved by the university ttuman research committee. pts were divided into two groups: a (n = ) with a membrane o~genator and a (n = ) with a bubble oxygenalor used during cardiopulmonary bypass (cpb). ths were monitored with swan-ganz catheters (sgc) for hrs after cpb. at that tfme os/ot was calculated according to the standard shunt equation. alter the sgc had been removed, an estimated shunt was calculated..measurements of os/qt were performed: betore induction of anaesthesia (i), mins after extubation ( ), hrs alter cpb ( ) and on the nd, rd, th, th and th postoperative day (iv, v, vi, vii> viii, respectively). analysis of data was performed by one-way analysis of variance, p < . being regarded as significant.results: the figure shows the values for qs/qt expressed as means _+ sd. os/qt was significantly greater at rains after extubation (ii) in a group. the difl'ereuce between the two groups was no more significant from hrs after cpb (iii) to the end of the investigated period. ! i * p < a. s betw~n ~o~ conclusions: membrane ox 'genation during cpb is accomplished by reduction in blood cellular destruction and less alteration in blood. the results of our study show the influence of oxygenator type on value of qs/ot only after extubation ( to hrs after cpb). the difference in qs/qt disappeared his after cpb and since that time the oxygenator type had no influence on qs/qt. it may be of particular importance in patients with severe forms of cardiopulmonary disease who are at risk of higher postoperative morbidity and mortality. objectives: hypomagnesemia has been reported with a variable prevalence ( to % ) in icu patients. magnesium deficiency can induce a number of climcal symptoms (primarily cardiovascular and neuropsychiatric) but can also be clinically silent ( - % are asymptomadc), methods: we measured whole blood ionized magnesium (lmg++) in patients on admission to the icu, using a nova electrolyte analyzer (nova biomedical), containing an img++ electrode. blood was collected in syringes with dry heparin (radiometer qs ). normal range of img++ was found between . - . mmot/l (healthy volunteers). results: for the entire population, we found a % prevalence ( / ) of hypomagnesemia (figure ) . among the surgical patients, the prevalence was highest after cardiac surgery ( %) and after thoracic surgery ( %) and was lowest after neurosurgery ( %). hypomagnesemia was also common in patients after liver transplantation (lvtx) or with hepatic failure ( % for both groups). conclusion: our findings confirm that hypomagnesemia is common in acutely ill patients, especially in those after cardiothoracic surgery or those with liver disease. nevertheless. it is difficult to define the associated factors with sufficient specificity, so that measurements of img++ are warranted to diagnose hypomagnesemia. hepariu influences platelet function and may lead to thrombocytopenia called heparin-associated thrombocytopenia (hat) regardless of the dose and route of administration. additinnal venous and/or arterial thrombosis may lead to life-threatening complications. the incidence of so-calied heparin-associated thrombocytopenia and thrombosis (hatt) ranges between i- %. hatt is confirmed by a heparin induced platelet activation assay (hipa). results: from / to / consecutive patients of our icu were reviewed retrospectively. all patients were treated with heparim the incidence of hatt was % ( ). in all cases diagnosis was proven by a positive hipa. / patients died. in / hatt could be confirmed before severe thromboembolic complications occured. / patients developed a deep vein thrombosis (dvt), / dvt and pulmonary embolism (pe), / dvt, pe and arterial thrombosis (at) and / a dvt, pe~ at and a sinus thrombosis. conclusion: the incidence of hatt in a r series of pts. is %. presence of thrombocytopenia and thrombosis of the great 'vessels is associated with a significant mortality ( / ). computed tom graphy (ct) and transthoracic/transesophageal echocardiography (tte/tee) are important tools in diagnosing and monitoring the extent of cenlrai venous and arterial thrombosis. a. cabral md, m. shahla md c. meneses-oliveira md and jl vincenl md.phd. department of intensive care. erasme university hospital, brussels, belgium objective: to determine extreme hemodynanuc patterns in cardiogenic shock. although ~.~xdiogenic shock is characterized by a low cardiac index (ci), high systemic w~,scular resistance index (svri), and high cardiac filling pressures, some patients may develop art atypical pattern. we reviewed the hemodyuamic pattern of patients with cardiogenic shock, as defined by an initial ct below . l/rain/m: in the presence of myocardial dysfimction attributed to ischemic heart disease (n= ), heart failure (n= ), valvulopathy (n= ) or recent cardiac surgery (n= ). after exclusion of patients with concurrently suspected/documented infection, this study included patients, of whom ( . %) survived. treatment of shock included dopamine (n= ), dobutamine (n= ), norepinephrine (n= ) and epinephrine (n= ). patients with arterial hypertension (ah) and initially law plasnla renin activity (pra) had been studied. in all patient changes of arterial pressure (ap) after single administration of enap was studied. nypotensive reaction wiht deereasin e of average ap about - mm hg ayter single drug administration observed only in patients. ezap monotherapy accomplished during one week with mg daily dose. hypotensive effect observed in patients including ones which were susceptible to single enap administration. after that first stage of therapy all patints began to combinate enap with hypothyazid in dose of mg per day~ after week of treatment such drugs combination lead to veritable ap lowering in addition patients. in the remaining resistant to such drug combination patients was add corinfar in daily dose of mg. this new drug combination permits to lower ap in patients. subsequent discontinuation of enap administration to such patients aid not connected with increasing of again.therefore the most of the patients with ah and law pra( , %)did not susceptible to enap therapy and enap and hypothyazid combination. on the contrary-combination of corinfar with hipothyazid was effective in % patients with ah and low pra. methods: in patients with cardiogenic shock due to ischemic heart disease (n= ), heart failure (n= ) and valvulopathy (n= ), hemod aamic data including measures of intravascular pressures, cardiac output and mixed venous gases were collected at regular times intervals, at least times a da?. all measurements were obtamed in a relative steady state and in the absence of severe anemia or hypoxemia. treatment of shock included dobutamine (n= ), dopamine (n= ), norepinephrine (n=i ) and epinephrine (n= objective: based on our previous studies of the function of isolated liver grafts, this experimental protocol aims at developing a novel extracorporeal liver support circuit, with an incorporated pig liver. methods:the graft liver was obtained from pigs weighing - kg. under general anesthesia the aqimals underwent total hepatectomy,following cannulation of the portal vein, the infrarenal aorta and the infrahapatic vena cava and peffusion wit h it of heparinised r/l solution at ~ the circuit consisted of the graft liver connected to a fluid reservoir and a centrifuge pump. ten healthy pigs weighing - kgr were connected to the circuit as follows: the rt carotid artery was connected to the portal vein of the graft and the rt jugular vein was connected to the fluid reservoir, through the centrifuge pump. the fluid reservoir collected the outflow from the graft's suprahepatic inferior vena cava. the cystic duct of the graft was ligated and the bile.duct cannulated for bile collection and measurement. bridges were adapted to the circuit to bypass the graft liver when necessary, in cases of by pass blood perfusing the graft was oxygenated through a bubble oxygenator. mean total priming volume of the circuit was ml. temperature was maintained at ~ and portal vein pressure at ( - ) mmhg. the flow was . - . ml/gr of graft liver mass per minute. observation period was hours (t ). results: results of the hemadynamic and metabolic monitoring of the recipients [map (t = mmhg , t = mmhg), hr (t = , t = ), rap (t = mmhg , t = mmhg), pap (t = mmhg, t = mmhg), pcwp (t = mmhg, t = ~mhg), svr (t = dyn'sec/cm ' , t = dyn'seclcm~ pvr (t = dyn.sec/cm o, t = dyn.sec/cm ,'~), co (t = . t/min, t = . t/min), do (t = ml/min, t = . ml/min), vo (t = ml/min, t = ml/min), o er (t = . %, t = . % ), ph (to= . , t = . ), po (t = mmhg, t = mmhg), pco (t = mmhg, t = mmhg), pvo (t = mmhg, t = mmhg), svo (t = %, t = %), be, na, k, ca ++, lactate, osmolality, ast, alt, pt, aptt, revealed hemodynamic and metabolic stability of the animal. consumption, co production and tissue oxygenation of the graft were also studied. conclusion; the described circuit proved to be safe and well tolerated by healthy animals but its value for temporary liver support is currently being estimated, in a surgically induced experimental fulminant hepatic failure modal. introduction: prosthetic materials like silikone, dacron, teflon e.tc. produce auto immune responses and may even trigger clinical syndromes like scleroderma, sjogren, sle el.c. in our study we followed the evolution of humorial immunity parametrs for up to five years in a cohort of paced pts with implanted metallic and silicone materials. method: paced pts (mean age +- yrs) without clinical or laboratory findings of malignancy or immune disorders were included. we measured the immunoglobulins, the complement, the auto antibodies and the proteins involved in inflammatory reactions every months. the initial and final mean values are shown in the obiectives: hsp, a systemic leucocytoclastic vasculitis and anaphylactoid purpura can be accompanied by abdominal pain and life-threatening intestinal bleeding. recently we could disclose, that these patients develop severe fxiii-deficiency and immense haemorrhagic oedema of the intestinal wall. by the following case report we will demonstrate and discuss the importance of fxiiideficiency for pathogenesis, therapy and outcome in hsp. case report: a year old man developed typical skin manifestations of hsp following an episode of severe (biliary ?) pancreatitis and percutaneous draining of a pancreatic pseudocyst. two days later he had a paralytic "ileus with immense hemorrhagic wall-oedema and massive dilatation of the small bowel. he got fever up to . ~ and developed severe gastrointestinal haemorrhage (blood transfusions necessary). the coagulation data disclosed a severe fxhi-deficiency (activity %), whereas quickvalues, platelet count and atiii-level were found to be within the normal range. elastase was markedly elevated. substitution of fxiii to normal levels leeds to the cessation of bleeding symptoms and abdominal pain, later resulting in a restitutio ad integrum. conclusions: hsp with intestinal involvement is a life-threatening vasculitis, in which careful and frequent examinations of the coagulation system, especially of fxiii are necessary. detailed analysis of the coagulation data suggest, that the severe fxiiideficiency is due to a specific degradation by proteolytic enzymes (like elastase) as well as consumption within the immense haemorrhagic oedema of the intestinal wall. knowing these facts, even most severe cases of hsp with intestinal involvement can be successfully treated by substitution of fxih. a -year-old woman presented a year history of occasional self-limited episodes of weakness, generalized edema and o!!~aria. the immunologic testing showed no~nnai levels of complements, clq inhibitor, and serum chemistry values, between or during a attack, she was not treated. she was a~mitted to the hospital with symptoms including nausea, vomiting, weakness and ol!guria. on examination, the patient presented facial and g~neralized edema. the systolic blood pressure was mm hg, pulse beats/mir~ute, hematocrit . , seln~n protein /i, and se~um albumin q/l. an leg-kappa pa[apfotein was demostrated ( . g/l) and urine was neaative for puotein. c~'stalloid and colloid don't increased the blaod pressure but resulted in anasarca, with a total of ii lit[as of in~ravenous fluids. therapy wink flozen plasma, . units of clq inhibitor, cortlcosteroids, annihistwnines and antifibrinolytic agents was uns~iccessfull. the a~minist~ation of dopamine, norepineph~ne and epinephrine was inefective. the patient died at the bores, only a few cases have been reported, all had igg paraprotein, the pathophysio!o~] is urd~no~n% but is possible that the paraprotein may be zesponsib!e for the increased capillary pe~leabilityo despite efforts to res~scinate the patients during an acute attack, the syndrome is often fatal. the variable course of systemic uapiliary leak syndrome and the unpredictability and self-limited nature of attacks cloud assessment of therapeutic inte~-vention. the purpose of the present work is to provide some information about the nursing care and results from our experience in continous arteriovenus hemofiltration (cavh).cavh is an extracorporeal technique, especially applicable in the critically ill patients, for disturbances, and for the control of azotemia.we used this method in critically ill patients men and women ages from - who had sepsis -arf congestive heart failure postoperative multiple organ failure and polytrauma .this method was applied to these patients from to hours. % of the patients recovered completely their kidney function, % improved their kidney function and % died.we concluded therefore that this method was very effective for the critically ill patients to whom it was applied, but it requires excellent and continuous nursing care; under the above mentioned circumstances the method works effectivelly. an animal model with rats undergoing a dialysis procedure was designed to test the hypothesis that recovery from ischemic acute renal failure (airf) may be affected by the type of membrane used in hemodialysis. male sprague dawley rats were allocated to groups: in group i, (n= ) airf was inducted by bilateral renal artery clamping for rain. group h (n= ) rats underwent a sham procedure. in each group, rats were dialyzed twice ( th and th day) with either a cuprophan (cupro), a hemophan (hemo) or a pan (an ) minidialyscr or stayed nondialyzed (no hi)). renal function was monitored daily by measuring urea and creatinine values and by two single shot inulin clearances on the days following dialysis. additionally hemolytical activity of complement was determined. inulin clearance on day was reduced significantly but there was no difference in the degree of decrement in glomular filtration rate (gfr) between dialyzed and undialyzed rats, nor between the dialyzed animals with different membranes (gfr: no hi): . _+ . ; cupro: . _+ . ; hemo: . _+ . ; an : . _+ . ). the evaluation of renal function by day nine revealed significant recovery for all airf-groups compared to day (p< . ), irrespective of wether they underwent dialysis or not, or the type of dialysis membrane. complement activation could be detected in all dialyzed groups but no statistical differences between the animal groups dialyzed with different membranes were noticed. our findings refute the hypothesis that in airf exposure to complement-activating cellulosic membranes impairs the recovery of renal function in rats. changes patients: patients who underwent first cadaver kidney transplantation in our unit between january and december in were involved. the recipients were divided into groups: group i." non functioning graft (n= ); group ii: delayed graft function (n= ), group ili: good graft function (n= ). the grouping criteria were: a/haemodialysis in the fii~t postoperative days, b/diuresis in the i st postoperative day, c,' scram crcatininc difference between the st postoperative day and the preoperative level. all of the parameters were involved into the exarainatio, which we measllre in our every, day practice. results: the preoperative haematocrit level differed significantly between group i. ( . ) and croup ii. and iii. ( . and . , p< . ). intmo! emtive significant differences were found between the different groups in systolic blood pressure (group i. hgrmn, group ii. hgnnn, group iii. hgmm, p< . ), mean arterial pressure (group i. hgmm, vs. group ii. hgnun p< . , vs. group iii. hgmm p< . ), and pulse-amplitude and rate-pressure product too. the second warm ishaemic time in group iii. was significantly shorter than in the other two groups (group iii. inin. vs. group ii. rain. p< . , vs. group i. rain. p< . !). the rejection rate was higher in the first days in the patients with non-functioning grafts (group i. % and group ii. % vs. group iii. %) . the other examined parameters have not differed significantly. conclusion: according to our results the success of the kidney transplantation is mnitifactorial. the most important factors of this relationship are: the perioperative fluid-balance, the maintenance of adequate perfusion blood pressure during the operation, good surgical technique and immunological problems. key: cord- - fqfbys authors: hardy, michaël; michaux, isabelle; lessire, sarah; douxfils, jonathan; dogné, jean-michel; bareille, marion; horlait, geoffrey; bulpa, pierre; chapelle, celine; laporte, silvy; testa, sophie; jacqmin, hugues; lecompte, thomas; dive, alain; mullier, françois title: prothrombotic disturbances of hemostasis of patients with severe covid- : a prospective longitudinal observational study date: - - journal: thromb res doi: . /j.thromres. . . sha: doc_id: cord_uid: fqfbys nan studies only describe the longitudinal follow-up of hemostasis parameters -a worrying gap in the close assessment of the course of the hemostasis disturbances during the acute phase of the disease. the aim of this prospective study was therefore to describe the longitudinal changes in hemostasis parameters assessed daily in covid- patients during their intensive care unit (icu) stay. our main findings were that (i) daily standard measurements consistent with a prothrombotic state persisted over the first days and improved thereafter, but did not normalize in all patients; (ii) increased thrombin potential (hypercoagulability) and decreased fibrinolysis were frequent and (iii) a high inter-patient variability was observed. the study was conducted at the chu ucl namur (godinne site, belgium) after approval from the local ethics committee (nub: b ). all adult patients managed at the icu for an rt-pcr-confirmed sars-cov- infection from march to april , were considered for inclusion. one patient was not included due to refusal of advanced respiratory support or resuscitation. - ). the patient who fulfilled isth criteria for overt dic died, as two other did after confirmed thrombotic complications, which were considered as main contributors of death. twelve patients presented at least one bleeding event during the study period (major according to the isth in six; no deaths). changes in hemostasis parameters and c-reactive protein (crp) monitored daily during icu stay are represented in figure ; in total there were patients-days. patients initially were in a high inflammatory state (median crp levels of mg/dl during the first ten days after icu admission); crp levels progressively decreased over time thereafter. daily platelet counts were often normal and never below x /l. prothrombin time was only moderately (+ to + seconds) and transiently increased in four patients, and markedly increased (+ seconds) in the patient who fulfilled overt dic criteria. fibrinogen levels were markedly and persistently high (median value over the icu stay: mg/dl). the same held true for factor viii levels (median value over the icu stay: %). the median value of d-dimers levels was ' ng/ml, reaching very high levels in seven patients, above the upper limit of measurement ( , ng/ml), and tended to decrease over time. these findings are in line with previous reports ( ) . in addition they show that the increase in d-dimers levels is a sustained process despite heparin administration (even with intensified prophylactic regimens), clinical improvement and decrease in crp levels. antithrombin deficiency (< %) was detected in patients, severe (< %) in three, contributing to hypercoagulability. there was very little evidence for a consumptive process though since platelet counts were preserved, clotting times were only slightly prolonged, and fibrinogen was increased, not decreased. one of the best approaches to evidence hypercoagulability in vitro is thrombin generation, which is now more accessible in the clinical environment thank to automated analyzers. neutralization of heparin permitted the use of reagents more sensitive to coagulation abnormalities (i.e. stg-thromboscreen) ( ) . at variance with previous reports we observed increased thrombin potential ( - ), median etp values being above the published reference range ( ) over the first week after icu admission. further work is required to understand the discrepant reports. pai- plasma levels were increased at some time-points at least since the start of the observation period of all patients, fitting with the reduced global fibrinolytic capacity we observed. published data so far are consistent with defective fibrinolysis in covid- patients (which is not unique to this infectious condition), using viscoelastometric assays modified with tpa addition ( , , ) . it is intriguing that d-dimers plasma levels can be so high with defective fibrinolysis. as already hypothesized, this could be due to extravascular (e.g. pulmonary alveoli) fibrin deposits and tissue, not intravascular, fibrinolysis ( ). importantly, laboratory markers showed complex temporal profiles during the icu stay, which were quite variable among patients (figure see also companion paper with individual data). for the two functional integrative tests (etp and gfc), median ranges between daily extreme values among patients were % and minutes respectively; median ranges for intraindividual extreme values over the whole icu observation period were % and minutes, respectively. this is a hint for a varying thrombotic risk, and anticoagulation intensity could be tailored in a timely manner with frequent reassessments to minimize the bleeding risk. in light of these results and of the current knowledge on hemostasis disturbances of covid- patients, we suggest that a close monitoring of a sensible set hemostatic parameters would be useful to assess individual thrombotic risk. we identified an increased thrombin potential and a decreased fibrinolytic capacity using newly available tests, which are suitable for clinical use and decision making in real time. further prospective and preferably multicenter studies using standard operating protocols for the management of covid- patients are required to validate the clinical usefulness of such a monitoring approach. ( )). the population with laboratory testing at each day is shown under the individual plots. d is the day of admission to an icu, but not necessarily in namur (there were transfers from a belgian icu to namur icu and one patient already admitted to namur icu before the start of the study). of note there were less tests during the first few days (transfers), and less results as well beyond d (censoring or discharge). results of gfc are represented with a logarithmic scale. covid- versus hit hypercoagulability features of severe covid- : a systematic review and meta-analysis prevention of thrombotic risk in hospitalized patients with covid and hemostasis monitoring: proposals from the french working group on perioperative haemostasis (gihp) the french sdy group on thrombosis and haemostasis (gfht), in collaboration with the french society for anaesthesia and intensive care (sfar) a new assay for global fibrinolysis capacity (gfc): investigating a critical system regulating hemostasis and thrombosis and other extravascular functions studies on hemostasis in covid- deserve careful reporting of the laboratory methods, their significance and their limitations hypofibrinolytic state and high thrombin generation may play a major role in sars-cov associated thrombosis evaluation of covid- coagulopathy; laboratory characterization using thrombin generation and nonconventional haemostasis assays thrombin generation measurement using the st genesia thrombin generation system in a cohort of healthy adults: normal values and variability fibrinolysis resistance: a potential mechanism underlying covid- coagulopathy management of the thrombotic risk associated with covid- : guidance for the hemostasis laboratory the authors would like to thank professor bernard chatelain (université catholique de louvain) for providing very sound and helpful advice on the content of the manuscript. the authors would like also to thank mrs justine baudar, mrs maité guldenpfennig and mr philippe devel for performing the experiments. finally, we would like to thank ms norma ceesay for carefully editing the manuscript. key: cord- -h tmi w authors: sanfilippo, filippo; bignami, elena; lorini, ferdinando luca; astuto, marinella title: the importance of a “socially responsible” approach during covid- : the invisible heroes of science in italy date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: h tmi w nan the importance of a "socially responsible" approach during covid- : the invisible heroes of science in italy filippo sanfilippo * , elena bignami , ferdinando luca lorini and marinella astuto we would like to emphasize the importance of "socially responsible" approaches from physicians and societies during the coronavirus disease- pandemic. in italy, a valuable example has been provided by the intensive care (icu) community. it is important that other disciplines follow such "socially responsible" behavior, as irresponsible communication has generated potentially dangerous consequences. we summarize the "socially responsible" approach of our icu community in three key points. cornerstone has been the avoidance of "public notoriety" at all costs, even when journalists are eager to obtain "shocking" news and notoriety is easily gained. "shocking" news increase audience, sales, and sharing, but diffusion of unsupported information irresponsibly generates public disorientation with loss of guidance. ironically, icu physicians commented we desperately need football games back, so that millions of people become again football managers rather than covid- experts! the second key point is the identification of few strategic scientists delivering information. only crisis-unit coordinator for lombardy icus and a couple of highly respected scientists who have (or held) apical positions at national and/or international level (siaarti and esicm) were in charge to talk. one of them was recognized as "healthcare hero" [ ] . few other experienced physicians (icu director in "red areas" of north italy) fighting covid- on the frontline rarely appeared on tv programs for short communications. the third key point is the scientific interaction between icu physicians. they preferred to interact scientifically via webinars with the idea of sharing knowledge gained on the battlefield, generating protocols and, hopefully, improving outcomes of covid- . such webinars were responsibly promoted by both siaarti and esicm. in summary, italian icu physicians avoided "compulsory public notoriety," behaving as "invisible heroes of science." unfortunately, the same has not happened in other disciplines with compulsory appearance on tv, social media, and newspapers by physicians with low h-index, predatory publication attitude, and no experience in coronavirus delivering highly misleading and scientifically unsupported information. among other "self-proclaimed experts," we had previous "nobel-prize candidates" stating the coronavirus will disappear in summer or others reporting % survival on a couple of patients treated with a drug, generating false beliefs in the population. such approach is "socially irresponsible" and should be stopped. more than ever, laypeople should be maturely informed. a "socially responsible" approach to public information should be implemented to all fields involved in covid- , and the one delivered by the italian icu "invisible heroes" should be a leading worldwide example for other disciplines and countries. health care heroes of the covid- pandemic +health+care+heroes+of+the+covid- +pandemic.+jama+ . publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to wholeheartedly thank all the healthcare personnel that worked extremely hard under the pressure of this pandemic, always putting patients at the top of their priorities, even before their own health and in some instances the safety of their own families. unfortunately, we lost a lot of these heroes and they will be sincerely missed. key: cord- -ellr l z authors: reif, sarah jordan; layon, a joseph title: a pilot volunteer reader programme decreases delirium days in critically ill, adult icu patients date: - - journal: bmj open qual doi: . /bmjoq- - sha: doc_id: cord_uid: ellr l z nan delirium, a form of acute brain dysfunction presenting as altered mental status, and impairment of memory, emotion, thinking, perception and behaviour develops over hours to days and is seen in %- % of adult intensive care unit (icu) patients, depending on the diagnostic method and severity of illness. delirium diagnosis is often missed, as only % of patients experiencing this disorder are hyperactive. more prevalent is hypoactive delirium: patients appearing sedated, responding slowly to instructions or questions and, rarer still, mixed delirium patients may be hyperactive and hypoactive. there is also subsyndromal delirium, representing an intermediate state-not normal and yet not fully developed delirium. delirium can lead to serious complications including increased length of icu stay and increased readmission, institutionalisation and mortality rates. if not diagnosed or treated, delirium may lead to irreparable and delayed - cognitive failure. the risk factors for, and pathophysiology of, delirium are unclear. social isolation is, however, a presumptive risk factor. we hypothesised that a programme of interaction-reading to critically ill icu patients on a daily basis-might decrease delirium days. the data presented herein comprises our preliminary report. the icu reader programme was born as a service project, using volunteers, in which we hoped to identify a decrease in delirium days-the 'signal'-that would prove our hypothesis. readers were enrolled through the volunteer services department, undergoing infection control and confidentiality training. the programme was composed of readers, mostly high school and college students, and ran from january to august ; patient data analysed for the study were collected between july and august . the programme was designed and implemented by the authors (sjr, ajl) and principally managed by one of us (sjr). hospital volunteer services had no available volunteers and advised us to recruit. students were recruited due to their willingness to volunteer. each day, the volunteer asked the icu charge nurse which patient they felt would be most suitable for reading and/or companionship. readers would then ask the patientor surrogate if the patient was unable to interact-if they desired to be read to. when the answer was positive, the reader would commonly spend - min reading and/or talking to two and three patients, individually, each day. we averaged - patients being read-to or talked-with weekly at the height of the programme. books used included the bible (old and new testaments), koran, the local newspaper or one of several novels (eg, to kill a mockingbird or sherlock holmes detective novels). some of the intubated and mechanically ventilated patients longed for more interaction, so notes were written on whiteboards or paper, and passed between the patient and reader. some patients desired only companionship. delirium was diagnosed using the updated version of the confusion assessment method-icu (cam-icu) scoring system, [ ] [ ] [ ] shown to tightly correlate with the diagnostic and statistical manual- delirium diagnosis. cam-icu is a bedside scoring system that looks at altered levels of consciousness, inattention and disorganised thinking, at either acute or fluctuating levels. a patient is cam-icu positive if, either acutely or episodically, they meet the criteria for inattention and either altered level of consciousness or disorganised thinking. cam-icu scores, performed every hours by bedside registered nurse, were compared hours before and hours after the reading episode; thus, patients served as their own controls. delirium days were used for the outcome of the entire population, before and after reader intervention. a patient was positive for a delirium day if, during any one of the three daily evaluations, they met the cam-icu criteria for delirium. data were analysed for normality and, thereafter, parametric or non-parametric statistical methods were used. a p value of < . was considered clinically and statistically significant. twelve of patients we report on were diagnosed with delirium. due to the small sample size, the data were not normally distributed. thus, a non-parametric test (the mann-whitney test) was performed. there were total delirium days hours before reader intervention and total delirium days hours after reader intervention. the number of delirium days per patient, respectively, were . ( / patients) versus . ( / patients) (p< . ) (figure ). as the programme began as a service project, we were not able, for this preliminary communication, to account for other factors such as age, gender, days in the icu, medications, comorbidities and so forth. delirium is known to increase not only costs of care but also duration of mechanical ventilation, length of stay, reintubation rate, long-term cognitive function, discharge to a long-term care facility and patient mortality. our icu reader programme was a controlled, non-randomised study. the presence of a signal showing reduction of total delirium days in the cohort, as well as delirium days per patient, suggests that reading and talking with patients in the icu may be an effective, simple and low-cost intervention. as a service project, the icu reader programme was well-designed and successfully implemented. as a research project, the programme was limited, having only collected data over a -month period. due to unforeseen circumstances beyond our control, the programme was terminated and our access to data was limited to what is presented here. nonetheless, there was a positive signal noted; clearly age, comorbidities and medications need to be taken into account in further studies. icu patients need to be maintained, as much as possible, with a normal sleep-wake cycle and with minimisation of social isolation to avoid the onset of delirium; this also could maintain their safety, comfort and overall physical and psychological function. the icu reader programme was a pilot project, and the signal we have noted must be taken as preliminary. a randomised, controlled and multicentre study is warranted, as the potential for bias is real. the number of patients studied is small, and individuals considered 'appropriate' for interaction with our readers were chosen by the icu charge nurse; both these issues may have inadvertently introduced bias. it will require further study and analysis to determine if the material read matters as much, or more, than the act of reading itself. this is of particular importance in the era of severe acute respiratory syndrome coronavirus when, for patients considered 'person under investigation' (patients with symptoms but no confirmed diagnosis), isolation is the norm and the risk of delirium is significant. an icu reader programme appears to decrease risk for, and duration of, delirium in adult icu patients. whether this effect is related to the reading itself or simple companionship, as well as the impact of comorbidities, age, gender and medications, is unclear. twitter a joseph layon @ajlayon acknowledgements we thank the icu reader programme volunteer readers and the nurses of the geisinger medical centre adult icu. contributors sjr and ajl designed and carried out the icu reader project. sjr organised the volunteers and managed the programme. ajl compiled and analysed the data, and drafted the initial version of the paper. sjr and ajl revised the paper and are responsible for the overall content. funding the authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. competing interests none declared. patient and public involvement patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research. patient consent for publication not required. provenance and peer review not commissioned; externally peer reviewed. data availability statement all data relevant to the study are included in the article. open access this is an open access article distributed in accordance with the creative commons attribution non commercial (cc by-nc . ) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. see: http:// creativecommons. org/ licenses/ by-nc/ . /. sarah jordan reif http:// orcid. org/ - - - delirium in hospitalized older adults concordance between dsm-iv and dsm- criteria for delirium diagnosis in a pooled database of prospectively evaluated patients using the delirium rating scale-revised- delirium in the intensive are unit -a review subsyndromal delirium in the icu: evidence for a disease spectrum delirium in older adults: diagnosis, prevention, and treatment the impact of delirium in the intensive care unit on hospital length of stay delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit the association between delirium and cognitive decline: a review of the empirical literature delirium in elderly adults: diagnosis, prevention and treatment delirium in critically ill patients (commentary) the updated version of the confusion assessment method for the intensive care unit compared to the th version of the diagnostic and statistical manual of mental disorders and other current methods used by intensivists confusion assessment method for the icu (cam-icu). the complete training manual delirium in older persons: advances in diagnosis and treatment key: cord- -hf sh vs authors: salazar, m. r.; gonzalez, s. e.; regairaz, l.; ferrando, n. s.; gonzalez, v.; carrera, p. m.; munoz, l.; pesci, s. a.; vidal, j. m.; kreplak, n.; estenssoro, e. title: effect of convalescent plasma on mortality in patients with covid- pneumonia date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: hf sh vs abstract background convalescent plasma, widely utilized in viral infections that induce neutralizing antibodies, has been proposed for covid- , and preliminary evidence shows that it might have beneficial effect. our objective was to compare epidemiological characteristics and outcomes between patients who received convalescent plasma for covid- and those who did not, admitted to hospitals in buenos aires province, argentina, throughout the pandemic. methods this is a multicenter, retrospective cohort study of -month duration beginning on june , , including unselected, consecutive adult patients with diagnosed covid- , admitted to hospitals with pneumonia. epidemiological and clinical variables were registered in the provincial hospital bed management system. convalescent plasma was supplied as part of a centralized, expanded access program. results we analyzed , patients with pneumonia, predominantly male, aged {+/-} , with arterial hypertension and diabetes as main comorbidities; . % were admitted to the ward, . % to the intensive care unit (icu), and . % to the icu with mechanical ventilation requirement (icu-mv). -day mortality was . %; and was . %, . % and . % for ward, icu and icu-mv patients. convalescent plasma was administered to patients ( . %); their -day mortality was significantly lower ( . % vs. . %, p< . ). no major adverse effects occurred. logistic regression analysis identified age, icu admission with and without mv requirement, diabetes and preexistent cardiovascular disease as independent predictors of -day mortality, whereas convalescent plasma administration acted as a protective factor. conclusions our study suggests that the administration of convalescent plasma in covid- pneumonia admitted to the hospital might be associated with decreased mortality. convalescent plasma, widely utilized in viral infections that induce neutralizing antibodies, has been proposed for covid- , and preliminary evidence shows that it might have beneficial effect. our objective was to compare epidemiological characteristics and outcomes between patients who received convalescent plasma for covid- and those who did not, admitted to hospitals in buenos aires province, argentina, throughout the pandemic. this is a multicenter, retrospective cohort study of -month duration beginning on june , , including unselected, consecutive adult patients with diagnosed covid- , admitted to hospitals with pneumonia. epidemiological and clinical variables were registered in the provincial hospital bed management system. convalescent plasma was supplied as part of a centralized, expanded access program. we analyzed , patients with pneumonia, predominantly male, aged ± , with arterial hypertension and diabetes as main comorbidities; . % were admitted to the ward, . % to the intensive care unit (icu), and . % to the icu with mechanical ventilation requirement (icu-mv). -day mortality was . %; and was . %, . % and . % for ward, icu and icu-mv patients. convalescent plasma was administered to patients ( . %); their -day mortality was significantly lower ( . % vs. . %, p< . ). no major adverse effects occurred. logistic regression analysis identified age, icu admission with and without mv requirement, diabetes and preexistent cardiovascular disease as independent predictors . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . . https://doi.org/ . / . antibodies, has also been proposed [ ] [ ] [ ] . it was used during outbreaks of severe acute respiratory disease caused by other coronaviruses, sars-cov- and mers-cov, with varying results and when administered early, it decreased length of hospital stay [ ] [ ] [ ] . convalescent plasma utilization has an acceptable safety profile and its administration constitutes a feasible approach to implement during a pandemic, even in low-resource settings. in covid- , it might reduce viral burden, improve clinical status, and decrease mortality [ ] [ ] [ ] . on march , , the food and drug administration of the united states launched an expanded access program to collect convalescent plasma donated by individuals who had recovered from covid- , and on august approved emergency use [ ] . a study conducted in , patients confirmed the safety of convalescent plasma and, thereafter, in a study of , patients, the same group of researchers demonstrated a decrease in mortality when convalescent plasma was . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint administered early in the course of covid- [ ] [ ] .convalescent plasma is currently being evaluated in clinical trials [ ] . early in the emergency caused by the covid- pandemic, the ministry of health of the province of buenos aires, argentina, created the centralized registry of convalescent plasma donors (crocpd-ba), with the aim of collecting, processing and distributing convalescent plasma, and issuing recommendations for its use in patients with covid- [ ] . accordingly, the objective of the present study is to compare the epidemiological characteristics, outcomes and independent predictors of mortality among patients who received convalescent plasma and those who did not receive it, who were admitted to hospitals in buenos aires province for covid- throughout the pandemic. this was a multicenter retrospective cohort study conducted over months, beginning on june , , which included consecutive patients ≥ years diagnosed with sars cov- with rt-pcr, admitted to hospitals with pneumonia. data were obtained from the national vigilance system (snvs . ), the provincial hospital bed management system, and the crocpd-ba. collected variables were age, gender, comorbidities [ ] [ ] (arterial hypertension, diabetes, preexistent cardiovascular disease, chronic obstructive pulmonary disease, immunodeficiency), requirement of mechanical ventilation, treatments, death or discharge, and convalescent plasma administration. severe adverse events related to plasma infusion, as transfusion-related acute lung injury (trali) and transfusionassociated circulatory overload (taco) were also recorded [ ] . information about plasma collection and characteristics is available in the supplement. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint the requirement of convalescent plasma was initiated by assistant physicians as part of a program of expanded access [ ] . the indications issued by the crocpd-ba were presence of pneumonia, defined as of lung infiltrates, plus one of the following: were confirmed on patient death certificates. statistical analysis: continuous variables were expressed as mean ± standard deviation (sd) or median, [ . - . ] percentiles. categorical variables were expressed as percentages. differences between survivors and nonsurvivors, and between patients who received plasma or not, were analyzed with chi-square, t, or mann-whitney u-tests, as appropriate. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint to identify independent predictors of -day mortality, variables differing between survivors and nonsurvivors with a p value < . were entered into a multivariable regression model, using a forward stepwise analysis. adjusted risks were expressed as odd ratios (or) and confidence intervals of % [ci %] data were analyzed with ssps- (amonk, ny, us). a two-tailed p value < . was considered significant. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint . during the study period, , patients with covid- pneumonia were admitted to hospitals. epidemiological data of the entire group and comparisons between survivors and nonsurvivors are shown in table . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . logistic regression analysis identified age, icu admission with and without mv, diabetes and preexistent cardiovascular disease as independent predictors of -day mortality, while convalescent plasma administration was associated with decreased mortality (table ). the main finding of our study was that the administration of convalescent plasma to patients with covid- pneumonia was associated with a decrease of . % in adjusted mortality. this effect was consistent over all grades of severity on admission, although it was greater in less critical patients-those admitted to the general ward. in this study, the global mortality of . % was higher than the - % shown in observational studies [ ] [ ] [ ] [ ] which can be ascribed to a different patient case-mix. the proportion of patients admitted to the icu was . %, of which . % required mechanical ventilation on admission. these figures are notably higher than those reported by two studies from spain (respectively for each: n= , and , , with icu admission of . % and %;and mortality of % and %); united states (n= , , icu admission of . %, and mortality of . %), and united kingdom (n= , , icu admission . %, and mortality of %) [ ] [ ] [ ] [ ] . the efficacy of convalescent plasma in covid- has been subject to much debate, due to the lack of a clinical trial with sufficient power to confirm it. for example, a study . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint carried out in wuhan was prematurely terminated due to the end of the pandemic, although significant clinical improvement was observed in patients with severe disease [ ] . likewise, a study from the netherlands was stopped because % of patients already had high titers of neutralizing antibodies before receiving convalescent plasma [ ] . a recent clinical trial from india which excluded critically ill patients did not find any clinical benefit. however, these results might be ascribed to the absence of neutralizing antibodies or to titers lower than : in % and % of convalescent plasma units, respectively [ ] . moreover, % of patients in the plasma subgroup had detectable neutralizing antibodies on enrollment; so it is uncertain if the intervention would have been efficacious. conversely, two small clinical trials demonstrated a significant decrease in mortality: in a study from spain (n= ) including severely ill patients, mortality in the convalescent plasma subgroup was % vs. . % in the control, and in an iraqi study (n = ), it was . % vs. . %, respectively [ - ]. many observational studies support a probable efficacy of convalescent plasma. for example, a case-control study from china (including cases and , controls) reported . % mortality for the convalescent plasma subgroup, versus . % for the control [ ] . furthermore, in a case-control study from the us including non-ventilated patients, -day mortality was . % in the subgroup that had received convalescent plasma, vs. . % in the control [ ] . similar results were reported in a matched casecontrol study, also from the us ( cases, controls), which showed lower mortality in patients receiving early administration of convalescent plasma with high titers of antibodies: . % vs . % [ ] . finally, the large case-series from the mayo clinic . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . [ ] . our study develops a different approach to this very relevant issue. we analyzed a cohort of , unselected, consecutive patients with covid- pneumonia, of whom received convalescent plasma; its administration was evaluated as any other prognostic variable for mortality. we observed an independent, favorable effect on survival, and this is a novel finding. although the nature of our study was observational, it was carried out using a robust database composed of observations prospectively collected, within the framework of a pre-established government program. other independent predictors of mortality were age, diabetes and cardiovascular disease, similar to current literature on the topic [ , [ ] [ ] [ ] . this effect of convalescent plasma was more pronounced in less severe patients -those admitted to the ward, suggesting the importance of timely administration. even though age > was one inclusion criterion for receiving convalescent plasma, surprisingly, those who received it were, in fact, younger. we cannot discard selection bias of physicians prescribing a seemingly promising therapy to patients with greater chances of responding to it. nevertheless, older age was an independent predictor of mortality, as expected [ , ] the main limitation of this study is the lack of randomized assignment of convales cent plasma administration. additionally, unmeasured confounders might have influenced the . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint results, such as other risk factors or treatments. since severity of illness on admission could not be evaluated with an established score, misclassification of patients might have occurred. however, the use of severity of illness on admission as a surrogate of acuity has already been utilized [ ] . a more detailed analysis of the clinical variables collected could not be done, because of the type of data recorded in the register. finally, the reason why assistant physicians chose not to administer convalescent plasma to patients with covid- pneumonia fulfilling the inclusion criteria are unknown, but we speculate that some physicians might have felt uncomfortable with prescribing an experimental treatment to their patients. in conclusion, our study suggests that the administration of convalescent plasma in covid- pneumonia might be associated with decreased mortality. large, welldesigned clinical trials are required to confirm these findings. is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted october , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint cronolog a de la respuesta de la om a la covid- recovery collaborative group, et al. dexamethasone in hospitalized patients with covid- -preliminary report convalescent plasma: new evidence for an old therapeutic tool? blood transfus treatment of covid- with convalescent plasma: lessons from past coronavirus outbreaks the emerging role of convalescent plasma in the treatment of covid- use of convalescent plasma therapy in sars patients in hong kong challenges of convalescent plasma infusion therapy in middle east respiratory coronavirus infection: a single centre experience experience of using convalescent plasma for severe acute respiratory syndrome among healthcare workers in a taiwan hospital effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening covid- : a randomized clinical trial evidence favouring the efficacy of convalescent plasma for covid- therapy. medrxiv epub ahead of print. . fda issues emergency use authorization for convalescent plasma as potential promising covid- treatment convalescent plasma in , hospitalized patients effect of convalescent plasma on mortality among hospitalized patients with covid- : initial three-month experience. medrxiv rudpcba) para la obtención, procesamiento, distribución y recomendaciones terapéuticas sobre su uso en el tratamiento de pacientes con covid- clinical characteristics of coronavirus disease in china baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region, italy jama transfusion-associated circulatory overload after plasma transfusion features of uk patients in hospital with covid- using the isaric who clinical characterisation protocol: prospective observational cohort study arribas jr; covid- @spain study group. characteristics and predictors of death among , consecutively hospitalized patients with covid- in spain convalescent plasma for covid- . a randomized clinical trial. medrxiv convalescent plasma in the management of moderate covid- in india: an open-label parallel-arm phase ii multicentre randomized controlled trial (placid trial). medrxiv improved clinical symptoms and mortality among patients with severe or critical covid- after convalescent plasma transfusion convalescent plasma treatment of severe covid- : a propensity score-matched control study association of hypertension, diabetes, stroke, cancer, kidney disease, and high-cholesterol with covid- disease severity and fatality: a systematic review comorbidities, clinical signs and symptoms, laboratory findings, imaging features, treatment strategies, and outcomes in adult and pediatric patients with covid- : a systematic review and meta-analysis presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area case characteristics, resource use, and outcomes of patients with covid- admitted to german hospitals: an observational study key: cord- - srk ohb authors: bagnato, sergio; boccagni, cristina; marino, giorgio; prestandrea, caterina; d’agostino, tiziana; rubino, francesca title: critical illness myopathy after covid- date: - - journal: int j infect dis doi: . /j.ijid. . . sha: doc_id: cord_uid: srk ohb we describe a patient who developed diffuse and symmetrical muscle weakness after a long stay in the intensive care unit (icu) due to coronavirus disease (covid- ). the patient underwent a neurophysiological protocol, including nerve conduction studies, concentric needle electromyography (emg) of the proximal and distal muscles, and direct muscle stimulation (dms). nerve conduction studies showed normal sensory conduction and low-amplitude compound muscle action potentials (cmaps). emg revealed signs of myopathy, which were more pronounced in the lower limbs. the post-dms cmap was absent in the quadriceps and of reduced amplitude in the tibialis anterior muscle. based on these clinical and neurophysiological findings, a diagnosis of critical illness myopathy was made according to the current diagnostic criteria. given the large number of patients with covid- who require long icu stays, many of these patients are very likely to develop icu-acquired weakness, as did the patient described here. health systems must plan to provide adequate access to rehabilitative facilities for both pulmonary and motor rehabilitative treatment after covid- . we describe a patient who developed diffuse and symmetrical muscle weakness after a long stay in the intensive care unit (icu) due to coronavirus disease . the patient underwent a neurophysiological protocol, including nerve conduction studies, concentric needle electromyography (emg) of the proximal and distal muscles, and direct muscle stimulation (dms). nerve conduction studies showed normal sensory conduction and low-amplitude compound muscle action potentials (cmaps). emg revealed signs of myopathy, which were more pronounced in the lower limbs. the post-dms cmap was absent in the quadriceps and of reduced amplitude in the tibialis anterior muscle. based on these clinical and neurophysiological findings, a diagnosis of critical illness myopathy was made according to the current diagnostic criteria. given the large number of patients with covid- who require long icu stays, many of these patients are very likely to develop icu-acquired weakness, as did the patient described here. health systems must plan to provide adequate access to rehabilitative facilities for both pulmonary and motor rehabilitative severe acute respiratory syndrome coronavirus (sars-cov- ) causes coronavirus disease (covid- ), which reached pandemic-level diffusion in march . patients with covid- frequently experience muscular symptoms, such as myalgia, but myopathic changes have not been evaluated fully in this population. a recent review of the neurological complications of included studies with data on skeletal muscle problems, but no study examining the use of electromyography or another diagnostic test to detect myopathic changes (pinzon et al., ) . notably, an unexpectedly large number of patients with covid- requires intensive care unit (icu) admission and long stays (lewnard et al., ) . critically ill patients are likely to develop muscular complications, such as critical illness myopathy (cim), which adversely affect short-and long-term outcomes (vanhorebeek et al., ) . in this report, we describe neurophysiological findings from a patient who developed severe muscular weakness, likely due to cim, after hospitalization for covid- . a -year-old woman with a history of hypertension developed fever, cough, myalgia, and diarrhea at the beginning of march . after a few days of treatment with levofloxacin, which resulted in no clinical improvement, she went to the emergency room of a covid hospital in palermo, italy, where sars-cov- infection was diagnosed by chest computed tomography (ct) and nasopharyngeal swab testing for sars-cov- rna. seven days after clinical onset, the patient was admitted to an infectious disease unit, where she was treated with lopinavir/ritonavir, hydroxychloroquine, and tocilizumab. nine days after onset, the patient's respiratory function worsened, necessitating transfer to an icu, where she underwent endotracheal intubation and mechanical ventilation. the icu stay was complicated by staphylococcus aureus and candida tropicalis bloodstream infections. during her icu stay, the patient received therapy with neuromuscular blocking agents, antibiotics, antifungal drugs, and corticosteroids. after days, she j o u r n a l p r e -p r o o f was moved to an infectious disease unit for days, but respiratory worsening necessitated another transfer to the icu, where she stayed for days. the patient was then moved to a covid pulmonology unit. in the first days of this stay, she presented psychomotor agitation and temporospatial disorientation; a brain ct examination was normal and, after neurological and psychiatric evaluations, the patient was treated with olanzapine for about weeks, which resulted in progressive improvement of her cognitive functions. sixty-eight days post-onset, and with sars-cov- negativity on three consecutive nasopharyngeal swab tests, the patient was moved to a rehabilitation unit. at the beginning of rehabilitative treatment, the patient required a % fraction of inspired oxygen and presented dyspnea after mild effort. she had muscle atrophy in the lower limbs. segmental muscle strength evaluation showed diffuse and symmetrical muscle weakness, ranging from / to / on the medical research council scale for muscle strength assessment, and greater in the lower limbs and proximal muscles. the patient was able to walk a few steps with assistance. deep tendon reflexes were reduced in the lower limbs. the patient's serum creatine kinase level was normal. eighty days post-onset, the patient underwent a thorough neurophysiological protocol, including conventional nerve conduction studies (of the ulnar, peroneal, tibial, and sural nerves), concentric needle electromyography (emg) of the proximal and distal muscles, and direct muscle stimulation (dms). the neurophysiological study was performed bedside using a micromed system plus evolution electromyograph (mogliano veneto, italy). dms was performed in the right quadriceps and tibialis anterior muscles using two monopolar needle electrodes (rich et al., ) , and the evoked compound muscle action potential (cmap) was recorded with two monopolar needle electrodes placed about . cm distal to the midpoint of a line connecting the two stimulating electrodes. the ratio of the amplitudes of the cmaps evoked by motor nerve stimulation and dms was calculated. this ratio aids discrimination between neuropathic and myopathic processes during overall neurophysiological evaluation; values < . are indicative of neuropathy and those near are indicative of myopathy (rich et al., ; trojaborg et al., ) . the normal limits were defined as j o u r n a l p r e -p r o o f means ± two standard deviations from normative data from our laboratory (standard age-matched data for the electroneurographic studies; obtained from subjects for the dms study) (bagnato et al., ) . the neurophysiological findings are summarized in table stay in the rehabilitation unit lasted days during which the patient received a rehabilitation program hours a day for days a week. at discharge, she did not require oxygen supplementation, had a mild weakness in lower limb proximal muscles and was able to walk without assistance. the patient described here had myopathy, with greater involvement of the proximal muscles in the lower limbs, probably reflecting icu-acquired weakness. indeed, the patient met the clinical and neurophysiological criteria for cim (stevens et al., ) . the pathophysiology of cim is complex and not fully understood, but it probably involves microcirculatory changes, metabolic alterations, electrical muscle alterations with abnormal excitation-contraction coupling, and energetic failure with mitochondrial dysfunction (zhou et al., ) . a recent metanalysis identified several risk factors associated significantly with icu-acquired weakness (including cim and/or critical illness polyneuropathy) (yang et al., ) ; among them, female sex, sepsis, hyperglycemia, use of neuromuscular blocking agents, and lengthy mechanical ventilation and icu stay were present in this case. preventive and supportive measures, such as glycemic control, nutritional intervention, early mobilization, and physical therapy, but no specific therapy, have been shown to be beneficial in cim management [zhou et al. ; vanhorebeek et al., ] . how covid- make patients susceptible j o u r n a l p r e -p r o o f to muscle damage is an open question. in the previous coronavirus outbreak, causing the severe acute respiratory syndrome in - , a postmortem study showed a spectrum of myopathic changes, suggesting a common occurrence of cim in non-survived patients (leung et al., ) . in conclusion, increasing evidence shows that patients with sars-cov- infection may develop various neurological complications as a direct or indirect viral action (pinzon et al., ) . in addition, icu-acquired weakness should be suspected and properly diagnosed in all patients who develop symmetrical weakness after hospitalization for covid- . in light of the large number of patients with covid- who require lengthy icu stays, many of these patients are very likely to develop icu-acquired weakness, as did the patient described here, in the next months. since rehabilitation programs can be effective to reverse muscle weakness caused by cim, health systems must plan to provide adequate access to rehabilitative facilities for patients requiring both pulmonary and motor rehabilitative treatment after covid- . this work received no specific grant from any funding agency in the public, commercial, or not-forprofit sectors. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. because this report just reviewed clinical data, there was no need of a specific ethical approval. informed consent was signed by the patient for the publication of this report. j o u r n a l p r e -p r o o f ☒ the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. neuromuscular involvement in vegetative and minimally conscious states following acute brain injury myopathic changes associated with severe acute respiratory syndrome: a postmortem case series incidence, clinical outcomes, and transmission dynamics of severe coronavirus disease in california and washington: prospective cohort study neurologic characteristics in coronavirus disease (covid- ): a systematic review and meta-analysis direct muscle stimulation in acute quadriplegic myopathy a framework for diagnosing and classifying intensive care unit-acquired weakness electrophysiologic studies in critical illness associated weakness: myopathy or neuropathy -a reappraisal van den berghe g. icu-acquired weakness risk factors for intensive care unit-acquired weakness: a systematic review and meta-analysis critical illness polyneuropathy and myopathy: a systematic review key: cord- -mmbzxz authors: lord, heidi; loveday, clare; moxham, lorna; fernandez, ritin title: effective communication is key to icu nurses willingness to provide nursing care amidst the covid- pandemic date: - - journal: intensive crit care nurs doi: . /j.iccn. . sha: doc_id: cord_uid: mmbzxz background: the covid- pandemic posed and continues to pose challenges for health care systems globally, particularly to intensive care units (icu). at the forefront of the icu are highly trained nurses with a professional obligation to care for patients with covid- despite the potential to become infected. the aim of this study was to explore icu nurses’ willingness to care during the covid- pandemic. methods: a prospective cross-sectional study to explore icu nurses’ willingness to provide care during the covid- pandemic was undertaken between march to april at a large principal and referral teaching hospital in sydney, nsw australia. results: a total of icu nurses completed the survey. approximately % reported receiving sufficient information from managers regarding covid- and about caring for a patient with covid- . ninety percent of nurses were concerned about spreading covid- to their family. sixty one percent of the nurses indicated that they were willing to care for patients with covid- . receiving timely communication from managers was the only predictor of willingness to care among icu nurses. conclusions: effective communication is a vital component during a public health emergency in order to promote nurses’ willingness to care for patients in the icu. causing a severe pneumonia like illness (gong et al., ; zhou et al., ) . rapidly spreading globally, by early march , the world health organization (who) declared covid- a pandemic. by april , covid- had infected . million people and caused , deaths (who, ) . the covid- pandemic posed and continues to pose c immense challenges for health care systems, particularly to intensive care services. the burden of covid- on health care resources of affected patients in countries other than australia indicates that approximately - % of confirmed covid- cases required admission to intensive care units (icu) grasseli et al., ) . this is predominately due to covid- related shortness of breath resulting in hypoxemic respiratory failure requiring mechanical ventilation (bhatraju et al., ) . following the first reported covid- case in australia on january (liebig et al., ) , transmission continued, with strict public health measures implemented in march . icu services however, outside of australia were struggling to deal with a surge in critically ill covid- cases (liew et al., ) . icu nurses in australia were acutely aware of international trends and thus had to be prepared to respond to this potential situation nationally. being at the forefront of the icu and having the most amount of close patient contact, nurses have a professional obligation to respond to the covid- pandemic through delivering health care to critically ill infected patients (liew et al., ; seale et al., ) . a nurse's willingness to provide nursing care during a pandemic can be influenced by their own perceptions of risk of exposure to covid- , but also fear for their family's health (corley et al., ) . this perception of risk cannot be underestimated as in some instances, nurses have experienced post-traumatic stress disorder (ptsd) as a direct consequence of working during a pandemic (corley et al., ; ives et al., ) . previous research fernandez et al., ; koh et al., ; liu & liehr, ) on the psychological distress and wellbeing of health care workers during a pandemic, have indicated that many health care workers exhibit high levels of psychological stress, have concerns about stigmatization and internalize fear associated with their own personal health and their family's wellbeing and health. nurses' anxiety, concerns and psychological distress in previous pandemic responses have been substantially associated with social isolation, physical and emotional exhaustion, increased job stress, media scrutiny and rapidly changing information and communication (liu & liehr, ; maunder, ) . psychological distress can likely cause both short and long term effects on the nursing workforce (liu & liehr, ) of which there is already a shortage. gaining an understanding of their motivations and willingness to engage in their professional duty of providing nursing care in the midst of extreme challenges can inform future pandemic planning and identify strategies to alleviate psychological distress. to date, there is limited literature on nurses' willingness to provide nursing care during a pandemic; what evidence there is, predominately relates to hypothetical situations. this study explores the willingness of icu nurses to provide nursing care during the covid- pandemic with the purpose of identifying the response of nursing staff to the pandemic and implementing support services to assist current and future pandemic response. this prospective cross-sectional study design to explore icu nurses' willingness to provide nursing care during the covid- pandemic was undertaken at a large principal and referral teaching hospital in sydney, nsw australia. all registered nurses, including nurse educators and nurse unit managers (nums) who worked in the icu during the study period ( march - april ) were invited to participate in the study. potential participants were asked to partake in the study via a link to the survey in their work email. completion and submission of the questionnaire were considered as implied consent. no identifiable information was obtained and participants were informed that their participation was voluntary. data collection occurred during the study period march to april , capturing the first few weeks under the newly implemented covid- restrictions in australia. data were collected using a self-administered questionnaire via a surveymonkey link. the questionnaire was investigator developed based on an extensive literature review. the questionnaire was then reviewed and tested for content validity by a panel of experts in icu and nursing academics. information collected in the questionnaire included: ( ) demographic data (age, gender, employment status, and length of time worked as a registered nurse and in the icu, ( ) willingness to work in icu during the pandemic ( item) ( ) knowledge about covid- ( items), ( ) communication from managers about covid- ( items), ( ) preparedness of the icu ( items) and ( ) personal concerns about covid- ( item). participants were asked to respond to the questions using a -point likert scale (strongly disagree= , disagree= , neither agree nor disagree= , agree= , strongly agree= ), with two questions requiring an open-ended response. ethical approval was obtained from the hospital's human research ethics committee (hrec) for this study /eth . quantitative data were analysed using spss version . categorical data was presented as percentages and continuous data as means and standard deviation (sd). t-tests and one-way annova were used to assess the relationship between willingness to provide nursing care and the demographic variables. pearson's correlational analysis was used to investigate the relationships between willingness to care and knowledge of the covid- pandemic, communication from managers, preparedness of the icu and personal concerns. only scores for knowledge of the covid- pandemic, communication from managers, preparedness of the icu and personal concerns scores were included in a standard multiple linear regression analysis to determine the predictors of willingness to provide nursing care. the beta (b) values and the % confidence intervals were calculated in the multiple regression analyses. statistical significance was set at p less than . . qualitative data consisted of responses to open-ended questions. data analysis was undertaken using a qualitative thematic analysis conducted by two authors independently. the qualitative data was used to gain a deeper insight on the quantitative data. a total of icu nurses ( females and males) completed the survey. the overall response rate to the questionnaire was % ( / ). sixty six percent of the respondents were aged below years and the majority ( %) worked full time. a quarter of the nurses (n= ) had worked as a registered nurse for three years or less and half had worked in the icu for three years or less (table ) . sixty percent of the respondents reported that they had sufficient knowledge of covid- and agreed that they understood how to protect their patients and themselves during the covid-willingness to care for patients has been defined as the nurses' intention or wanting to provide nursing care during the pandemic. the aim of this study was to assess icu nurses willingness to provide nursing care for a patient with covid- during the first few weeks of the covid- pandemic in australia. this study is novel as it was conducted immediately following the declaration of the pandemic by the who and thus at the height of community distress and fear. our study demonstrated that % of the nurses were willing to provide nursing care for a patient in the icu during the covid- pandemic. these results are higher than in previous studies (wong et al., ; etokidem et al., , damery et al., irvin et al., ) where willingness to care during a pandemic ranged from % (wong et al., ) to % (irvin et al., ) . conversely, a study (ma et al., ) conducted in an icu in china reported a high ( . %) willingness to care during the h n influenza pandemic. these results could be due to the fact that the majority ( %) of the staff had received training in caring for a patient with h n prior to the commencement of the study and knowledge training prior to patient care was an independent predictor of willingness to care for patients with h n . notably, there was a vaccine available for h n influenza, which may have increased the icu staffs' willingness to care as the vaccine could be viewed as a protective mechanism. results from our study concurs with the previous study (ma et al., ) where icu nurses with greater knowledge about covid- were more willing to provide nursing care for patients. what is new in our study is that it was conducted in the midst of the pandemic when there was limited knowledge globally about the pathobiology of covid- . it is also interesting to note that regardless of their knowledge of the covid- pandemic, their perceptions of the preparedness of the icu and their personal concerns, the multiple regression analysis identified organizational communication regarding covid- as the only predictor of icu nurses' willingness to provide nursing care. that is nurses who felt that they received higher level of communication from the organization were more willing to provide nursing care during the pandemic. our study was conducted in the first few weeks of the covid- pandemic in australia and the icu had instantaneously implemented additional communication strategies to update staff with the latest information about covid- in order to allay anxiety and engender confidence in working in the icu. such communication included information about the transmission of covid- , restrictions required due to the risks associated with covid- , use of ppe, availability of education and access to mental health services. the specific communication strategies implemented in the icu in our study were: the covid chronicle, which was a weekly newsletter of updates regarding covid- ; the covid- faq, which was a daily factsheet to answer the many questions staff had, that was emailed to staff and also displayed as a hard copy in the main staff areas; a daily covid- staff huddle to update key staff; and lastly, a face to face question and answer session during in-service time that occurred times a week to capture all icu staff. the most efficient and effective communication strategy implemented was the daily covid- staff huddle and the covid- faqs. our study found that the majority ( %) of icu nurses reported that they understood the risk of covid- for patients, however just over half of the icu nurses ( %) felt they had sufficient knowledge regarding covid- . in addition, many ( %) agreed that they understood how to protect their patients and themselves from infection during the covid- pandemic. of note is the high level of reported understanding of the risks of covid- to patients among icu nurses compared to the lower levels of participants reporting sufficient knowledge for self. perhaps understanding high level of risks to patients could be associated with icu nurses obtaining their information from mass media coverage of the effects of the pandemic on patients globally. furthermore, icu nurses are often experienced at caring for patients with respiratory complications, which may have contributed to their higher levels of knowledge regarding protecting patients. the lower levels of participants identifying insufficient knowledge for self, could be due to covid- being a novel virus, where global understanding of the pathophysiology of the disease was limited. nevertheless, our findings are consistent with the results of a study by ma et al., ( ) undertaken in a chinese icu during the h n influenza pandemic which found that less than half the icu staff reported sufficient knowledge, despite receiving education sessions. interestingly, the willingness of icu nurses in our study to provide nursing care during the covid- pandemic had no association with demographic factors. that is, irrespective of age, gender or years of experience, icu nurses are willing to work during the pandemic. these results are similar to another study (ma et al., ) that demonstrated no difference between willingness to care and demographic variables. these studies emphasis that icu nurses need to feel protected in order to perform their duties regardless of their age, gender or years of experience. a sense of confidence in their skills, knowledge, safety and risk perceptions have been identified in a systematic review (aoyagi et al., ) as enablers for health care workers willingness to care during the pandemic. our study identified that the majority ( %) of the nurses were concerned about spreading covid- to their family, which could have an effect on their willingness to care. providing nurses with adequate information and resources on how to protect themselves may assist with alleviating any fears associated with transmission of covid- to family members. concerns for personal and family safety was a synthesized finding from a systematic review undertaken by fernandez et al., ( ) who examined nurses' experiences of working in acute care hospital settings during a respiratory pandemic. therefore, it is vital that pandemic preparedness planning include comprehensive communication strategy for icu staff, which in turn can reduce factors that cause hesitation and increase factors that cause motivation for willingness to provide nursing care during a pandemic. the icu in our study was proactive and instituted early strategic communications activities based on scientifically derived risk communications principles. this provided adequate and essential communication which enabled the icu nurses to improve their knowledge about caring for a patient the covid- pandemic. it also facilitated being able to make the best possible decisions within short time frames in order to reduce the impact of covid- on mortality and morbidity. like all studies, our study has several limitations that require acknowledgement. firstly, there is the potential for selection bias due to only icu nurses who responded to the survey. additionally, our study was conducted in a single centre. conducting a multicentre study would have provided more robust evidence. while the findings of the single centre study may be relevant to and resonate with other centres, the results are not generalisable to all icus. a further limitation of this study was that it did not assess previous experience or training in pandemic or emergency preparedness response. further studies will need to assess these. this study highlights that icu nurses' willingness to care is associated with receiving adequate and timely communication from managers. once again, highlighting the importance of staff management relationships. it is imperative that nurses working in icus during a pandemic have all the information they need to rapidly and accurately provide high standards of nursing care. enabling a rapid response in a pandemic situation has the potential to significantly save lives. nil funding. nil conflict of interest. healthcare workers' willingness to work during an influenza pandemic: a systematic review and meta-analysis covid- in critically ill patients in the seattle region-case series the experiences of health care workers employed in an australian intensive care unit during the h n influenza pandemic of : a phenomenological study will the nhs continue to function in an influenza pandemic? a survey of healthcare workers in the west midlands influenza a h ni (pandemic ): how prepared are healthcare providers in calabar implications for covid- : a systematic review of nurses' experiences of working in acute care hospital settings during a respiratory pandemic china's local governments are combating covid- with unprecedented responses-from a wenzhou governance perspective critical care utilization for the covid- outbreak in lombardy, italy: early experience and forecast during an emergency response clinical characteristics of coronavirus disease in china survey of hospital healthcare personnel response during a potential avian influenza pandemic: will they come to work healthcare workers' attitudes to working during pandemic influenza: a qualitative study risk perception and impact of severe acute respiratory syndrome (sars) on work and personal lives of healthcare workers in singapore what can we learn the current state of covid- in australia: importation and spread preparing for covid- : early experience from an intensive care unit in singapore instructive messages from chinese nurses' stories of caring for sars patients knowledge and attitudes of healthcare workers in chinese intensive care units regarding h n influenza pandemic the experience of the sars outbreak as a traumatic stress among frontline healthcare workers in toronto: lessons learned the community's attitude towards swine flu and pandemic influenza world health organization, . coronavirus disease (covid- ) pandemic will the community nurse continue to function during h n influenza pandemic: a cross-sectional study of hong kong community nurses clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study. the lancet acknowledgements: we would like to thank sofia russo for her administrative assistance.funding: nil funding for this research.conflict of interest: nil conflict of interest to declare. key: cord- -lzqsh jf authors: gomersall, charles d.; joynt, gavin m.; ho, oi man; ip, margaret; yap, florence; derrick, james l.; leung, patricia title: transmission of sars to healthcare workers. the experience of a hong kong icu date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: lzqsh jf objective: to describe the extent and temporal pattern of transmission of severe acute respiratory syndrome (sars) to intensive care unit staff. design: retrospective observational cohort study. setting: university hospital intensive care unit, caring solely for patients with sars or suspected to have sars. participants: thirty-five doctors and nurses and healthcare assistants who worked in the icu during the sars epidemic. interventions: infection control measures designed to prevent transmission of disease to staff were implemented. measurements and results: sixty-seven patients with sars were admitted to the intensive care unit. four nurses and one healthcare assistant contracted sars, with three of these developing symptoms within days of admission of the first patient with sars. doctors were exposed to patients with sars for a median (iqr) of ( – ) h, while nurses and healthcare assistants were exposed for a median (iqr) of ( – ) h. the icu did not meet international standards for physical space or ventilation. conclusions: in an icu in which infection control procedures are rigorously applied, the risk to staff of contracting sars from patients is low, despite long staff exposure times and a sub-standard physical environment. electronic supplementary material: the electronic reference of this article is http://dx.doi.org/ . /s - - - the online full-text version of this article includes electronic supplementary material. this material is available to authorised users and can be accessed by means of the esm button beneath the abstract or in the structured full-text article. to cite or link to this article you can use the above reference. the intensive care unit. four nurses and one healthcare assistant contracted sars, with three of these developing symptoms within days of admission of the first patient with sars. doctors were exposed to patients with sars for a median (iqr) of ( - ) h, while nurses and healthcare assistants were exposed for a median (iqr) of ( - ) h. the icu did not meet international standards for physical space or ventilation. conclusions: in an icu in which infection control procedures are rigorously applied, the risk to staff of contracting sars from patients is low, despite long staff the global epidemic of severe acute respiratory syndrome (sars) illustrated the risk to healthcare workers from this disease [ ] . the risk may be particularly high amongst healthcare workers in intensive care units (icu) [ ] , but there are only limited data from which to estimate this risk. previous studies have reported selected cases or outbreaks and may therefore give an overestimate of the risk to icu staff [ , , ] . this is important, because the perceived risk of infection may affect the willingness of staff to work in the icu in any future epidemic. we describe our experience of infection of healthcare workers in our icu, which was entirely dedicated to the care of patients suspected to have sars for months. outcome data from the first patients admitted to our icu have previously been published [ ] . some of these data have previously been published in abstract form [ ] . the study was carried out with the approval of the clinical research ethics committee of the chinese university of hong kong. it was a retrospective audit of the outcome of measures to prevent sars infection amongst icu staff. the study period was from march (the day after admission of the first patient with sars) to may. by the end of the period, all patients remaining in the icu had been in the icu for at least weeks, and there were no further admissions with sars. during the study period, only patients with sars or suspected to have sars were admitted to our icu. the layout of the icu is shown in fig. . the icu is normally a -bed adult multidisciplinary facility, but for days during the first week of the epidemic, the capacity was increased to beds by converting one of the four-bed cubicles into a six-bed cubicle. the number of air changes per hour was . in open patient areas, . in isolation rooms and . in offices. seventy percent of exhaust air was recycled, except in isolation rooms, where % was recycled. recycled air was filtered prior to recirculation. the quoted efficiency of the filters was % of . µm saline particles. isolation rooms were either not used for isolation or were used for protective isolation of patients in whom the diagnosis of sars was unclear. the nurse-to-patient ratio was : . the following data were collected from patient notes and charts by a trained research nurse: patient demographic data and factors that might affect the rate of transmission of sarsduration of invasive mechanical ventilation, place of intubation, icu length of stay, number of days with diarrhoea and days from symptom onset to icu admission. diarrhoea was defined as two or more loose bowel motions in a calendar day. duration of exposure to sars patients was obtained from nursing and medical rosters. only staff on the roster solely to work in the icu were included in the study. time for rest periods was taken into account when calculating number of exposure hours. the exposure hours therefore reflect time spent in contaminated areas of the icu. all staff who became infected were questioned shortly after becoming infected, to obtain the data presented in table . all other staff who worked in the icu during the study period were asked, after the end of the study period, to give a sample of blood to test for sars seroconversion, to detect asymptomatic infection. written informed consent was obtained from all staff who agreed to testing. infection control procedures are given in detail in the electronic supplementary material. the procedures evolved during the first few weeks of the epidemic. the fig. . in brief, the final protocol consisted of the following: all staff entering the icu were required to clean their hands and don a waterproof gown, gloves, cap, full-face shield and fit-tested n or n mask. initial fit testing involved a qualitative fit test, with a subsequent quantitative test for those who failed the qualitative test. staff for whom an adequate fit could not be achieved with a n or n mask were issued powered air-purifying respirators. a nurse was stationed at the entrance of the icu to ensure compliance, and staff were encouraged to ensure each other's safety by pointing out protocol errors. entry and exit from the icu were segregated. hoods were the only additional personal protective equipment used for high-risk procedures, such as intubation. patients were given oxygen at flow rates of up to l/min via simple and reservoir face masks. venturi-type masks were not used. descriptive statistics were calculated using excel (microsoft, redmond, wa, usa) and hutchon's confi-dence interval calculator (http://www.hutchon.freeserve. co.uk/wilsons.htm). during the study period, patients who met the us centers for disease control and prevention (cdc) criteria for sars were admitted, with eight patients being admitted twice. all had subsequent laboratory confirmation by serological examination for sars coronavirus. the level of sars coronavirus igg antibody was measured by an immunofluorescence assay. paired serum samples were tested. the tests were regarded as positive if a seroconversion or fourfold rise in antibody titre was detected. one hundred fifty-two nurses and healthcare assistants worked for a median (iqr) of ( - ) h. the difference in working hours between doctors and nurses and healthcare assistants was statistically significant (p< . ). five icu healthcare workers developed sars ( . %, % confidence intervals . - . ). details are given in table . none were involved in intubation at the time of likely exposure (based on incubation period of - days). none of the icu staff who underwent testing for asymptomatic infection tested positive. this included one nurse who suffered a needle-stick injury with a hollow needle contaminated with blood. the incidence of sars amongst healthcare workers in our icu was low despite a prolonged period of exposure to patients with sars and a physical environment which was poor in terms of space and ventilation. the bed spaces in our icu are considerably smaller (fig. ) than current minimum standards [ ] , and, although the air changes in our icu exceed the recommendation for isolation rooms, a very high proportion of the air is re-circulated. cdc guidelines recommend not re-circulating exhaust air [ ] . furthermore, the re-circulated air should be filtered through a hepa filter, which filters . % of . µm saline particles, whereas our filtration system filters only %. in an intensive care unit that meets current international recommendations for space and ventilation, it might be expected that the risk to staff would be lower. it is likely that the patients were maximally infectious during their icu stay. the patients were admitted a median of . days after symptom onset, and maximal virus shedding occurs at around days [ ] . the majority of cases of healthcare worker infection occurred early in the outbreak (table ) , with three of five cases becoming symptomatic within days of admission of the first patient with sars. the average incubation period of sars is days, with a range of - days [ , ] . this strongly suggests that the three healthcare workers who became symptomatic within days of admission of the first patient with sars were infected in the first few days of exposure, when the protective strategies were being developed and vigilance in the correct use of protective equipment was probably lowest. thereafter, only two members of staff became infected. none of the staff who agreed to testing showed evidence of asymptomatic infection. our data suggest that, with adequate infection control measures, the risk to healthcare workers in icu may not be as high as earlier reports suggested [ , , ] . although significant asymptomatic infection amongst untested staff remains a possibility, this is unlikely, as other data suggest subclinical infection is rare [ , ] . we believe that the personal protective procedures adopted in our icu were effective when rigorously applied and that this was responsible for the relatively low infection rate amongst our staff. a zero infection rate has been reported by a singapore icu that admitted patients with sars following strict imposition of infection control procedures [ , ] . this unit used an even higher level of protection, using negative-pressure isolation rooms for each patient and powered air-purifying respirators. in contrast, data from a toronto hospital, in which personal protective equipment was only inconsistently used by a substantial proportion of staff, showed that eight out of critical care nurses exposed to three patients developed sars. this occurred despite relatively short exposure times ( - min) [ ] . one of the difficulties in determining the effectiveness of infection control measures in sars is the bimodal nature of spread with the existence of "super-spreading" incidents, whereby, one individual infects many others, while many individuals do not infect any others [ , ] . different rates of infection may simply reflect the presence or absence of "super-spreading" events and may be unrelated to infection control measures. data from a hospital in vietnam which treated patients over a -week period revealed that no staff became infected despite lax infection control measures during the first week of exposure [ ] . it is therefore possible that our low infection rate merely reflects an absence of exposure to super-spreading events. however, we believe this unlikely. firstly, excluding super-spreading events, sars is moderately transmissible, with an estimated . secondary infections per case at the start of the epidemic [ ] . secondly, as discussed above, our patients were likely to be maximally infectious during their icu admission. thirdly, many of the individual components of our infection control measures (e.g., use of gloves, gowns, caps and masks) are associated with a decreased sars infection risk [ , ] . fourthly, super-spreading events appear to be associated with older patient age, more severe illness, and larger number of close contacts [ ] . although our patients were relatively young, they were severely ill and, as hospitalised patients, had a large number of close staff contacts. if our protective measures were effective when fully developed and rigorously applied, then the logical con-clusion is that intensive care units should have strategies in place to prevent infection of healthcare workers; all staff should be fully aware of the procedures and be fully trained in the use of protective equipment. strategies to enforce infection control procedures should also be devised [ ] . this need for preparation is given greater urgency by the threat of an avian influenza pandemic. all the staff who were infected were nurses or healthcare assistants, although the exposure time was greater for doctors. we speculate that the difference relates to the type of exposure. it is likely that the nurses, in particular, spent a greater proportion of their exposure time in close proximity to the patients, and both nurses and healthcare assistants are likely to have had greater exposure to the patients' faeces. the study period did not correspond to the entire period during which there were patients with sars in our icu, as we felt that it was unlikely that the staff was significantly exposed to sars virus beyond the end of our study period. the last patient was discharged from the icu days after the end of the study period. no staff were infected during this time. in summary, our data indicate that, with infection control measures, the risk to icu healthcare workers of acquiring sars is low, despite prolonged exposure to patients with sars. the timing of staff infections suggests that it is important that infection control procedures are applied rigorously from the start of the epidemic. a major outbreak of severe acute respiratory syndrome in hong kong cluster of severe acute respiratory syndrome cases among protected health-care workers -toronto, canada possible sars coronavirus transmission during cardiopulmonary resuscitation short-term of outcome of critically ill patients with severe acute respiratory syndrome protecting healthcare workers from sars clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study minimum standards for intensive care units guidelines for environmental infection control in health-care facilities: recommendations of cdc and the healthcare infection control practices advisory committee (hicpac) clinical features and short-term outcomes of patients with sars in the greater toronto area healthcare worker seroconversion in sars outbreak seroprevalence of antibody to severe acute respiratory syndrome (sars)-associated coronavirus among health-care workers in sars and non-sars medical wards clinical features and predictors for mortality in a designated national sars icu in singapore a journey through the severe acute respiratory syndrome (sars) crisis in singapore-observations of an intensivist transmission dynamics of the etiological agent of sars in hong kong: impact of public health interventions super-spreading sars events lack of sars transmission among public health workers effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (sars) sars transmission among hospital workers in hong kong appropriate use of personal protective equipment among healthcare workers in public sector hospitals and primary healthcare polyclinics during the sars outbreak in singapore the authors would like to thank ms. sammei tam and ms. florence lau for providing details of nurse and healthcare assistant scheduling. key: cord- -onzzpkye authors: halaÇli, burçin; kaya, akın; topelİ, arzu title: critically ill covid- patient date: - - journal: turk j med sci doi: . /sag- - sha: doc_id: cord_uid: onzzpkye coronavirus disease (covid- ) stands out as the major pandemic that we have experienced in the last century. as it affects every social structure, it brought the importance of intensive care support once again to the agenda of healthcare system after causing severe acute respiratory syndrome. the precautions to be taken against this virus, where our knowledge is extremely small, intensive care units take an indispensable place in pandemic planning. in this review, we aimed to emphasize the crucial points regarding intensive care management of covid- patients, which we have written not only for intensivists but also for all healthcare professionals. the consequences of coronavirus disease (covid- ) caused by severe acute respiratory syndrome coronavirus (sars-cov ) which was originated in wuhan region of china and spread all over the world, have influenced all stages of health services. eventually, world health organization (who) has declared pandemic for this virus. this pandemic is accepted as a viral pneumonia pandemic not a simple flu, therefore, intensive care unit (icu) admission, follow-up, and management of the critically ill patients with covid- is extremely important. due to the paucity of studies on covid- , suggestions are generally within the framework of the experiences gained from china, italy, usa, and uk that have the biggest war against this disease. in this review, we summarized the essential points of icu management for covid- patients. the need for intensive care might differ according to institutions or even countries, depending on the demand and supply ranging from % to % [ ] [ ] [ ] . severe disease may present with severe acute respiratory infection (sari) i.e. severe pneumonia and acute respiratory distress syndrome (ards) which is reported in %- % of patients; sepsis and septic shock reported in %; myocarditis, arrhythmia, and cardiogenic shock in %- %; and acute kidney injury in %- % of patients [ ] . although respiratory failure is often hypoxemic, hypercapnic respiratory failure might also be seen mainly due to mucus plugs. there is a male dominance with male to female ratio being / in severe cases, whereas according to a recent data from italy, % of patients were male. although hypertension and diabetes mellitus are the most common reported comorbidities, advanced age is also a risk factor for the development of severe disease [ ] . the main icu admission indications according to turkish guidelines (turkish public health general directorate guidelines), which are prepared according to covid- advisory committee proposals are shown in table. patients who are hemodynamically stable and do not need advanced respiratory and organ support anymore might be transferred to wards [ ] . the median time between the initiation of clinical signs to the development of pneumonia is about days and the median icu admission time after development of hypoxemia is about - days ( ). icu mortality due to covid- varies from % to % according to different studies [ , , [ ] [ ] [ ] . the current reported mortality rate was % in a recent multicentre study from italy. however, % of patients were still in icu and only % of patients were able to be discharged which means mortality rate could be higher [ ] . older age, presence of comorbidities such as hypertension, diabetes, cardiovascular disease, chronic lung disease, cancer, higher d-dimer and c-reactive protein, and lower lymphocyte levels are associated with higher mortality [ ] . in part of a pandemic plan of the country and hospitals, icu beds should be organized as well as all devices, equipment, and personnel. it is appropriate to reserve some icus for covid- patients. if this is not possible, patient cohorts should be done within the icu. patients should be followed in isolated rooms, necessary personnel protective equipment (ppe) should be provided and a dedicated team for covid icu should be organised. for this purpose, patient to nurse ratio could be : , if possible. a stand-by clean medical team may also be considered. this team can work in other icus. it is recommended to change the team that takes care of covid- patients in every days. hereby, a wash-out period is provided. it is also suggested that health care workers should not work for longer than h a day in order to minimise risk of infection. they must be warned that the whole team should report their body temperature and symptoms twice a day and they will not leave the city during rest periods [ ] . it should be considered that the existing intensive care beds and organization may not be sufficient due to the pandemic. potential solutions are expanding intensive care outside icus, like high-dependency units, general wards, postanaesthesia care units, and even operating rooms. on the other hand, surging in the icu capacity brings an incremental demand for equipment such as ventilators, consumable materials, therapeutics and as well as human force as healthcare workers (hcw). for this purpose, elective in-patient admissions and surgeries should be delayed and available wards could be adapted for stepping down other icu patients in order to evacuate icus. another point is to increase hcw trained in intensive care. therefore, hcw who are currently working out of icu should be systematically trained in terms of covid- protocol for supporting icu staff [ ] . to ensure proper infection control measures in the icu are crucial. contact and droplet isolation precautions should be undertaken . faecal-oral transmission has also been reported . viral shedding is expected to be extremely high in critically ill patients. interventions such as bag-valvemask ventilation, noninvasive mechanical ventilation (nimv), high flow nasal cannula oxygen (hfno), nebulisation and oro-tracheal intubation automatically bring high risk in terms of aerosol production. expanded aerosol production might increase airborne transmission risk as well. that is why airborne isolation (with negative pressure) should ideally be implemented as soon as possible in a single room with negative pressure supply that should be provided at least > h/day .. fluid-resistant gown, two oxygen requirement ≥ l/min with nasal cannula lactate > mmol/l hypotension (systolic blood pressure (sbp) < mmhg, > mmhg drops from usual sbp, mean arterial pressure (map) < mmhg) organ dysfunction such as confusion, kidney and liver tests abnormalities, thrombocytopenia, elevated troponin level and arrhythmia https://hsgm.saglik.gov.tr/depo/covid /rehberler/covid- _rehberi.pdf longer sleeved gloves to prevent exposure of the wrists with glove subsiding, eye glasses, full face shield, hair covers or hood, n mask and shoe worn are recommended for exposure to confirmed or suspected covid- patients. disposable shoe covers might increase the risk of selfcontamination during removal of protection clothing and should be avoided. all icu team should wear hospital's scrubs which should not be worn outside the hospital . zones should be provided for wearing and taking off properly. powered air purifying respirators (paprs) are other protective equipment which has not been proven so far, but it seems reasonable to use in order to decline the viral transmission. it is more convenient for prolonged resuscitations [ ] . hypoxemic respiratory failure should be recognized early. despite conventional oxygen therapy, increased work of breathing and hypoxemia could become progressively worse. supplemental oxygen should be given via low-flow o delivery systems such as nasal cannula ( - l/min to provide fio of . - . ), simple face mask ( - l/min to provide fio up to . - . ), nonrebreather masks with reservoir providing fio up to > . with - l/min oxygen, titrated according to spo . venturi and diffuser masks are suggested to be avoided. it should be remembered that fio > . for > h might create o toxicity. hfno therapy and nimv support may be applied in selected hypoxemic respiratory failure cases with proper ppe because of high risk of aerosol generation. however, these patients should be followed closely in terms of clinical deterioration, if no positive response is obtained in the first few hours (refractory hypoxemia, tachypnoea, tidal volume (vt) > ml/kg meaning increased minute ventilation and work of breathing). when applying nimv, a helmet mask may be used, applied with intensive care ventilators or dualcircuit ventilators; a viral/bacterial filter should be added to the circuit. nimv should not be applied to patients whose secretions cannot be controlled; who have high aspiration risk, impaired mental status, cardiac complications and multiple organ failure; and who are hemodynamically unstable [ ] . prolonged spontaneous breathing may cause uncontrolled intrathoracic negative pressures and induce patient-self-inflicted lung injury similar to ventilator induced lung injury and therefore, must be prevented by utilization of intubation as soon as possible [ ] . almost % of patients may require invasive mechanical ventilation. endotracheal intubation should be applied by a trained and most experienced physician with a rapid sequential intubation protocol. intubation should be performed with video-laryngoscope, if possible. intubation with flexible bronchoscopy can be used in difficult intubation. however, bronchoscopy is a high-risk procedure for aerolisation. use of bag-mask ventilation should be avoided during preoxygenation. preoxygenation could be performed with nonrebreather mask with reservoir. if bag-mask would be used, a filter should be attached to the bag mask. neuromuscular blockers can be administered to suppress cough before intubation. positive pressure ventilation should not be initiated before the endotracheal cuff is inflated and patients must be connected to mechanical ventilator directly without bag ventilation [ ] . closed system aspiration should be provided and bacterial/viral filters should be placed in both inspiratory and expiratory ports of the ventilator. for airway humidification, heat and moisture exchanger (hme) filter could be used. unless absolutely necessary, bronchoscopic procedures should be avoided and metered dose inhaler (mdi) should be preferred instead of nebulization for bronchodilator therapy. however, due to mucus plugs, and increased resistance and deadspace ventilation, active heated humidifier (hh) can be preferred . in patients developing ards, low tidal volumes ( - ml/kg) and low inspiratory pressures (plateau pressure < cm h o, driving pressure which is plateau pressure minus positive end expiratory pressure < cm h o) should be applied. deep sedation may be required to achieve target tidal volumes. in terms of low ph like < . , tidal volume can be increased up to ml/kg. otherwise permissive hypercapnia may be allowed [ ] . if there is no evidence of tissue hypoperfusion, conservative fluid support should be provided. peep titration should be applied at pressures that will prevent atelectotraumas and over distention. in moderate (pao /fio < ) and severe (pao / fio < ) ards patients, high peep may be applied instead of low peep. there is not enough data regarding recruitment manoeuvres. even if the use of neuromuscular blocking agents is not routinely recommended, it can be applied in the presence of resistant hypoxemia or hypercapnia, despite sedation in moderate to severe ards with ventilator dyssnchrony and in the first - h of mechanical ventilation. in patients with pao /fio < , more than h of prone position could be applied daily in patients who are managed by conventional mv interventions. prone position has been demonstrated to be helpful even in spontaneously breathing nonintubated patients, even with nimv and hfno. inhaled nitric oxide (no) administration could be used as a rescue therapy and could also theoretically be helpful to improve ventilation/ perfusion match, since it has been speculated that perfusion is also impaired in ards due to covid- and these patients have preserved compliance. routine use of corticosteroids is not recommended [ ] . extracorporeal membrane oxygenation (ecmo) may be considered in patients with refractory hypoxemia despite lung-protective ventilation, and appropriate patients should be referred to experienced centres. due to paucity of evidence for this virus and disease pathophysiology, probable advantages of ecmo is ambiguous. ecmo is not a therapy that should be considered in case of a major pandemic regarding the appropriate allocation of resources [ ] . dr. gattinoni and his colleagues suggested that covid- patients with respiratory failure have phenotypes [ ] . phenotype characterized by low elastance (high compliance), so called type l, has low ventilator perfusion ratio, low lung weight, and low recruitability, whereas type h, characterized by high elastance (low compliance) has high right-to-left shunt, high lung weight, and high recruitability. severe hypoxemia for high compliant lungs may be elucidated by the loss of lung perfusion regulation and hypoxic vasoconstriction. they recommend to increase fio as a solution for hypoxemia for those who are not experiencing dyspnoea, in which type l patient responds well. early intubation may even cause transition to type h phenotype. however, for intubated hypercapnic type l patients, ventilation with more than ml/kg up to - ml/kg does not bring risk of ventilatorassociated lung injury. since type l phenotypes could have a tolerance in terms of mechanical power by the help of high compliance. furthermore, administration of high peep for nonrecruitable lungs may cause hemodynamic impairment and fluid retention as well. type h phenotype looks like usual severe ards. therefore, higher peep, prone positioning, and even extracorporeal support are classical therapeutic choices. this suggestion has not been proved in large scale studies and postponing intubation in severe hypoxemia and increased work of breathing might be detrimental and early intubation in patients unresponsive to conventional o treatment and perhaps short course of nimv and hfno is recommended. during weaning from mechanical ventilation, patients under very low or no sedation should be evaluated for readiness as such, decreased o requirement (fio < . , peep < cm h o), hemodynamic stability, acceptable consciousness with preserved gag, and cough reflex. rapid shallow breathing index could be checked so that patients with respiratory rate to tidal volume ratio < , have high likelihood of being successfully weaned from mechanical ventilation. instead of weaning trial through t-piece, weaning from pressure support ventilation could be chosen due to less aerosol generation. in covid- patients, high mucus plugs are being reported, therefore, to reduce the risk of reintubation timing of weaning and extubation should be individualized. whether the cuff leak test should be performed routinely prior to extubation is unclear. if postextubation stridor is highly expected (female sex, fluid overload, prolonged intubation > - days, age > years, large endotracheal tubes > - . f, difficult and traumatic intubation), cuff-leak test could be performed weighing against risks and/or corticosteroids could be given during extubation. if possible, extubation should be performed in airborne isolation rooms with maximum ppe use. for postextubation respiratory failure, nimv and/or hfno should be applied very carefully in selected patients and if there is stridor, immediate intubation should be performed. for patients who fail weaning, a tracheostomy may be indicated which is considered to be a high-risk procedure for aerosolization [ ] . patients should receive pulmonary and extremity rehabilitation especially when they have low risk of infection transmission and meticulous nutritional support should be provided to prevent icu-acquired weakness. sepsis is defined as organ failure due to dysregulated host response accompanying by suspected or documented infection. organ failure symptoms and signs are; changes in consciousness, difficulty breathing, low oxygen saturation, decreased urine output, increased creatinine and heart rate, weak pulse, cold extremities or low blood pressure, signs of coagulopathy, thrombocytopenia, acidosis, increased lactate level or hyperbilirubinemia. septic shock is thought in terms of fluid therapy resistant hypotension, vasopressor requirement and lactate level > mmol/l to maintain mean arterial pressure (map) ≥ mmhg. it should be remembered that myocarditis and associated arrhythmias, and cardiogenic shock may be seen in these patients [ ] . due to lack of evidence, most of the recommendations are weak or as best practice statements regarding management of covid- patients with shock. it is recommended not to use static parameters in order to assess fluid responsiveness. dynamic parameters like skin temperature, capillary refilling time, and/or serum lactate measurement are suggested. conservative fluid management is superior to liberal approach for acute resuscitation. buffered/balanced crystalloids are preferred over unbalanced in the initial treatment. hydroxyethyl starch is not suggested which is a strong recommendation. in addition, gelatines and dextrans should not be used as well. routine usage of albumin is not recommended. norepinephrine is the first-line vasoactive agent. vasopressin and then adrenalin should be added as a second-line agent, over titrating norepinephrine dose, if target map cannot be achieved by norepinephrine alone. dopamine has no place but could be utilized if norepinephrine is not available as a last choice. target map is - mmhg, rather than higher values. in spite of fluid resuscitation and norepinephrine, if patients have persistent cardiac dysfunction and hypoperfusion signs, dobutamine could be started . first hour sepsis bundle should be implemented as baseline lactate measurement and repeated if first measurement is > mmol/l; blood cultures before antibiotics and antimicrobial therapy should be started within h. if bacterial infection is suspected, appropriate empirical antimicrobial therapy should be initiated. the choice of antibiotic treatment is made according to the local epidemiological data and treatment guidelines of the patient's clinical condition (community-acquired pneumonia, healthcare-related pneumonia, comorbidities, immunosuppression, health care admission in the last months, prior antibiotic use). in intubated patients, diagnostic tests such as polymerase chain reaction (pcr) has higher sensitivity if it is done on tracheal aspirates rather than oro-nasal specimens . for both corona pcr and bacterial cultures, tracheal aspirates should be preferred over bronchoscopic techniques. although ml/kg crystalloid (normal saline or ringer lactate) is suggested in the original bundle, due to the presence of ards fluid treatment should be individualized. patients who are hemodynamically unstable, safety of airway should be provided by taking protective measures. patients should not be transferred until stabilization especially of the airway. if the central catheter cannot be inserted, vasopressor treatment can be given through the possible widest vascular access. however, extravasation should be kept in mind . in the critically ill patients, venous thromboembolism prophylaxis should be undertaken due to immobility. however, in covid- patients, presence of hypercoagulopathy is hypothesized and therefore, therapeutic anticoagulation and perhaps antiaggregant therapy should be considered in patients with no contraindications especially in patients with high d-dimer levels [ ] . in case of cardiac arrest, cpr should be managed with as few people as possible with ppe which must be worn by all members of the team before entering the room. no chest compressions or airway procedures should be done without full ppe use. cpr should be initiated by only chest compressions which could also be performed by automatic resuscitators and preoxygenation could be provided with nonrebreather face masks with reservoir to prevent aerosol contamination. recognising the shockable rhythms as soon as possible and appropriate interventions might maintain circulation and prevent the need of further respiratory support like intubation. if bag mask ventilation and tracheal intubation are needed, at least two physicians can apply this procedure by the help of oropharyngeal airway and video-laryngoscope. all procedures should be debriefed after cpr for personal safety check and patient clinical evaluation . in the differential diagnosis of covid- pneumonia, imaging tests should also be used in addition to the patient's history, clinical and laboratory findings and coronavirus specific diagnostic tests. thorax computerised tomography (ct) examination can be useful in diagnosis and can provide important clues in the initial evaluation of novel coronavirus pneumonia. multiple patched groundglass opacities in bilateral lobular style, with peripheral location, are reported as characteristic thorax ct findings of covid- pneumonia [ ] . if ct is not applicable during icu stay due to cardiorespiratory instability, lung ultrasound could be a surrogate imaging method to chest radiography or ct scanning being a highly sensitive and specific technique for the diagnosis and follow-up of these cases [ ] . ultrasound may also be used to make sure the proper placement of the endotracheal tube and diagnosis of complications such as pneumothorax [ ] . in the light of the data obtained from covid- pandemic and hospital follow-up of these critically ill patients, the needfulness of intensive care units with well-organized structure and trained hcw, has emerged once again. intensive care science plays a locomotive role in this kind of outbreak management. the contribution of intensivists who are dealing with complex organ failures is very important in the training of healthcare professionals for outbreak planning. providing the emotional support of hcw while organising these plans, increasing the motivation by using the available communication tools is crucial to prevent burnout by minimizing fear and anxiety [ ] . clinical characteristics of coronavirus disease in china clinical features of patients infected with novel coronavirus in wuhan, china baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region intensive care management of coronavirus disease (covid- ): challenges and recommendations clinical characteristics of hospitalized patients with novel coronavirusinfected pneumonia in wuhan a rapid advice guideline for the diagnosis and treatment of novel coronavirus ( -ncov) infected pneumonia (standard version) clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study characteristics and outcomes of critically ill patients with covid- in washington state clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study preparing for covid- : early experience from an intensive care unit in singapore intensive care during the coronavirus epidemic why, where, and how paprs are being used in health care. in: institute of medicine. the use and effectiveness of powered air purifying respirators in health care: workshop summary- aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review. semple mg (editor) mechanical ventilation to minimize progression of lung injury in acute respiratory failure practical recommendations for critical care and anesthesiology teams caring for novel coronavirus ( -ncov) patients acute respiratory distress syndrome: advances in diagnosis and treatment treatment for severe acute respiratory distress syndrome from covid- preparing for the most critically ill patients with covid- : the potential role of extracorporeal membrane oxygenation (published online ahead of print covid- does not lead to a "typical" acute respiratory distress syndrome american journal of respiratory and critical care medicine expert consensus on preventing nosocomial transmission during respiratory care for critically ill patients infected by novel coronavirus pneumonia the third international consensus definitions for sepsis and septic shock (sepsis- ) incidence of thrombotic complications in critically ill icu patients with covid- clinical characteristics and imaging manifestations of the novel coronavirus disease (covid- ): a multi-center study in wenzhou city can lung us help critical care clinicians in the early diagnosis of novel coronavirus (covid- ) pneumonia? ultrasound for airway management: an evidence-based review for the emergency clinician advisory committee of ministry of health of turkey. key: cord- - ywpcd authors: hu, xiaoyun; zhang, zhidan; li, na; liu, dexin; zhang, li; he, wei; zhang, wei; li, yuexia; zhu, cheng; zhu, guijun; zhang, lipeng; xu, fang; wang, shouhong; cao, xiangyuan; zhao, huiying; li, qian; zhang, xijing; lin, jiandong; zhao, shuangping; li, chen; du, bin title: self-reported use of personal protective equipment among chinese critical care clinicians during h n influenza pandemic date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: ywpcd background: critically ill patients with h n influenza are often treated in intensive care units (icus), representing significant risk of nosocomial transmission to critical care clinicians and other patients. despite a large body of literature and guidelines recommending infection control practices, numerous barriers have been identified in icus, leading to poor compliance to the use of personal protective equipment (ppe). the use of ppe among critical care clinicians has not been extensively evaluated, especially during the pandemic influenza. this study examined the knowledge, attitudes, and self-reported behaviors, and barriers to compliance with the use of ppe among icu healthcare workers (hcws) during the pandemic influenza. methodology/principal findings: a survey instrument consisting of questions was developed and mailed to all hcws in icus in provinces in china. a total of physicians, nurses, and other professionals were surveyed, and ( . %) were included in the analysis. fifty-six percent of respondents reported having received training program of pandemic influenza before they cared for h n patients, while % reported to have adequate knowledge of self and patient protection. only % of respondents were able to correctly identify all components of ppe, and % reported high compliance (> %) with ppe use during patient care. in multivariate analysis, vaccination for h n influenza, positive attitudes towards ppe use, organizational factors such as availability of ppe in icu, and patient information of influenza precautions, as well as reprimand for noncompliance by the supervisors were associated with high compliance, whereas negative attitudes towards ppe use and violation of ppe use were independent predictors of low compliance. conclusion/significance: knowledge and self-reported compliance to recommended ppe use among chinese critical care clinicians is suboptimal. the perceived barriers should be addressed in order to close the significant gap between perception and knowledge or behavior. on april , , the world health organization (who) announced the outbreak of a novel influenza a (h n ) virus to be a public health emergency of international concern [ ] , which ultimately led to the declaration of the first phase global influenza pandemic on june , [ ] . as of september , , the who had reported more than , laboratoryconfirmed cases, with at least , deaths [ ] . studies estimated that up to . million patients would be hospitalized, and about % of these patients might experience rapid deterioration, leading to intensive care unit (icu) admission within day after hospitalization, equivalent to an increase in the volume of mechanical ventilation of % to % over the current use [ , ] . all these data suggested an excessive workload during the initial period of the pandemic, as perceived by % of frontline healthcare workers (hcws) [ ] . a simulation study by swaminathan and the colleagues reported that, for a patient with suspected avian or pandemic influenza who was not clinically unwell or hypoxic, the mean number of close contacts was . (range - ; % hcws), and mean exposures were . (range [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] during the first hours in the emergency departments [ ] . in comparison, critical care clinicians are likely to encounter even more repeated close contacts, and are at significantly high risk of acquiring such an infectious disease during patient care. evidence does exist suggesting nosocomial transmission within hospital settings. apart from earlier findings that more than % of patients who acquired severe acute respiratory syndrome (sars) were hcws [ ] , possible healthcare-related h n influenza transmission was identified in out of exposed hcws [ ] . protection of hcws from acquisition of infectious diseases can be achieved by compliance to established infection control guidelines [ ] [ ] [ ] [ ] , including rigorous infection control practices, prescriptive instructions for the use of personal protective equipment (ppe), and postexposure antiviral prophylaxis [ ] . however, reported compliance to ppe use might be extremely low. in response to a survey conducted by the center for disease control and prevention following the pandemic influenza, among hcws with probable or possible patient-to-hcw transmission, only reported always using either a surgical mask or an n respirator [ ] . a variety of barriers have been identified to hinder compliance to infection prevention and control guidelines, including knowledge, attitude, belief and behavioral factors [ ] . daugherty and colleagues explored the behavior, knowledge, and attitudes of critical care clinicians about recommended precautions for prevention of healthcare-associated influenza infections in an anticipated influenza pandemic [ ] . with the same methodology using a modified questionnaire, we previously reported that . % of the icu hcws expressed willingness to work in a pandemic, with professions, knowledge training prior to patient care, and the confidence to know how to protect themselves and the patients independently associated with more likelihood to care for h n patients [ ] . however, little is known about their behavior and factors influencing compliance during a real influenza pandemic. as the second part of the above survey, we wish to evaluate the self-reported compliance to the use of ppe during the current influenza pandemic among critical care clinicians in chinese icus, as well as independent predictors of the compliance. this study was approved by the institutional review board (irb) of peking union medical college hospital. all participants were informed about the study. however, the irb waived the need for written informed consent from the participants because the identities of all respondents would be completely anonymous during data collection and analysis, and there would be minimal risk as perceived by the irb for being involved in this study. the design of this study was described in details elsewhere [ ] . in brief, this study was conducted in adult icus in provinces in china. all participating icus admitted patients with h n influenza during the pandemic. a -item survey questionnaire was designed based on the study of daugherty and coworkers [ ] , to assess the knowledge, attitudes, and behaviors of icu hcws related to the h n influenza pandemic, which was available as supporting information; see questionnaire s . on december , , the questionnaire with an instruction was sent by e-mail to the contact persons of individual participating icus, who encouraged as many hcws as possible to participate the study. all questionnaires were collected and sent back by e-mail before january , . any hcws not responding after the deadline were regarded as non-respondents. data on the demographic characteristics of respondents, including age, sex, marital status, living status, status of influenza vaccination, and profession, were recorded. the professional status of the respondents was categorized as physicians, and nurses, and others (including respiratory therapists, student nurses, and nurse assistants). for the purpose of this study, we only included physicians and nurses in the final analysis. the respondents were asked to report their experience of caring for h n patients, as well as relevant training. they were also required to report the level of knowledge and the level of confidence in their ability to protect themselves and their patients from exposure to influenza at work. a -point likert scale (complete agree, agree, neither agree nor disagree, disagree, and complete disagree) was used to elicit preferred answers. we defined recommended ppe as use of hand hygiene, gloves, gown, mask (including surgical mask and n respirator), and goggles [ ] . in the final analysis, answers with a higher level of protection than recommended (e.g. use of goggles when no aerosolgenerating procedures were anticipated) were deemed as correct because they represented adequate protection [ ] . as a response to the h n influenza pandemic, all hospitals were required by local healthcare authorities to provide training programs to all hospital staffs during seminars. these training programs were mainly to -hour lectures, developed based on the guidelines issued by ministry of health, often involving diagnosis, treatment, and infection control of h n influenza. there was no posttest to evaluate the extent of information attainment by the attendees. all likert-scale responses were dichotomized into complete agree/agree versus neither agree nor disagree/disagree/disagree/ complete disagree, and expression in proportions. continuous variables were compared with student's t-test or mann-whitney u test. categorical variables were compared with chi-square test or fisher's exact test when appropriate. self-reported compliance to ppe use of . % was considered as high compliance [ ] . correlations were measured using kendall rank correlation coefficient. for determination of independent predictors for high compliance to ppe use during patient care, odds ratio (or) was estimated on the basis of both univariate analysis and multivariate logistic regression analysis. variables including clinicians characteristics, knowledge, attitudes, and behaviors were added into the model using stepwise conditional forward entry, if p, . in univariate analysis. an or of less than was associated with low compliance to ppe use, while an or of greater than was associated with high compliance to ppe use during patient care. in the icus surveyed, eligible participants were identified, and returned completed surveys, for an overall response rate of . %. forty-five respondents were excluded (including other professionals, and with missing data), therefore respondents (including physicians and nurses) were included in the final analysis (table ) . compared with physicians, more nurses were single, and living with parents or living alone. more than half respondents received vaccination for h n influenza. five hundred and eighty-six respondents ( . %) reported that they had received the pandemic training program, although only ( . %) claimed to complete the pandemic training program before they cared for h n patients. in comparison, about three-fourths of respondents reported to wear goggles and gown during aerosol-generating procedures, and to wear n respirator in droplet precaution or close contact, respectively. however, respondents ( . %) reported to wear goggles and gown during entire treatment and/or nursing care, indicating overprotection. significant correlation was found between self-reported adequate knowledge of pandemic influenza and correct identification of ppe and knowledge of goggles (kendall tau-b . and . , p, . and p = . , respectively), but not knowledge of hand hygiene or mask (kendall tau-b . and . , p = . and . , respectively). about % of respondents believed that they knew self-and patient protection during the pandemic (table ). in particular, . % of respondents believed that use of appropriate ppe would confer adequate protection for hcws, while only . % stated that this protection was adequate for vulnerable patients. half of respondents reported that ppe use was inconvenient, while . % believed that ppe use would interfere with patient care, with no difference observed between physicians and nurses. no significant correlation was found between self-reported adequate knowledge of both self-protection and patient protection and correct knowledge of hand hygiene, goggles, or masks. however, selfreported adequate knowledge was significantly correlated with the perception of further improvement of ppe compliance (kendall tau-b . , p, . ). with regards to organization factors, . % of respondents reported that appropriate ppe was readily available in their icus (table ). more physicians than nurses knew when influenza precautions were initiated in their patients (p = . ). by contrast, significantly more nurses than physicians ( . % vs. . %, p = . ) reported being reprimanded by the supervisor for noncompliance. as to behaviors of ppe use, about % of respondents reported that their colleagues often forgot to use ppe during patient care, while a similar proportion reported themselves to forget to change ppe between patients. among all respondents, ( . %) reported high compliance (. %) to ppe use, with significant inter-institutional variation ranging from % ( / ) to . % ( / (table ). to our knowledge, this study represents the first effort to examine self-reported knowledge, attitude, behavior and influencing factors of ppe use during the pandemic influenza in chinese icus. among respondents, although up to % reported to have adequate knowledge of self-and patient protection, fewer than % could correctly identify all components of ppe or exhibited correct knowledge of ppe use during patient care. this suggested significant gaps in the perception and actual knowledge with regards to infection control practices, in particular ppe use, among our critical care clinicians [ ] . moreover, about % of respondents reported high compliance to the recommended ppe use. vaccination status, positive attitudes towards ppe use, cultural factor (perceived reprimand for noncompliance), and organizational factors (availability of ppe in icu, notice of influenza precautions) were identified as independent predictors of high compliance, while negative attitudes towards ppe use and violation of recommended ppe use were associated with low compliance. ppe referred to a variety of barriers and respirators used alone or in combination to protect mucous membranes, airways, skin, and clothing from contact with infectious agents [ ] . the critical importance of compliance to ppe use was not only recognized in a variety of practice guidelines of infection control [ ] [ ] [ ] [ ] [ ] , but also demonstrated during the outbreak of sars in [ , ] . unfortunately, compliance by professionals was often suboptimal [ , ] , due to knowledge, attitudes, and behavior among professionals, as well as to organizational and other factors [ , ] . in this survey of chinese critical care clinicians, only % of respondents reported high compliance (. %) to recommended ppe use, consistent with other relevant studies [ , ] . however, significant gaps between perception and practice were a common finding in icu [ ] , indicating overestimation of clinical practice judged by self-reported behavior, especially for infection control measures, such as hand hygiene [ ] and ppe use [ , ] . similar to the study of daugherty and coworkers [ ] , we found a similar proportion ( %) of respondents claiming their confidence to improve compliance to ppe use, again suggesting perception of inadequate ppe use among most respondents. our results indicated that a number of factors, including attitudes, behavior, and organization, might significantly influence clinical practice. although behavior could be changed without knowledge or attitude being affected, behavior change (i.e. selfreported high compliance to ppe use) based on improving knowledge and attitude (e.g. ppe use could confer adequate protection for hcws) was probably more sustainable than indirect manipulation of behavior alone [ ] . in the meanwhile, it was also self-intuitive that a negative attitude (e.g. perception that ppe use might interfere with patient care) often predicted low compliance. likewise, daugherty and coworkers found that the belief that ppe use was inconvenient was predictive of poorer adherence [ ] . the perception that ppe use interfered with patient care was supported by previous studies. despite the fact that critical care clinicians were probably highly compliant with ppe use, patients in contact isolation might suffer from adverse effect of inadequate patient care, including less time spent in patient rooms not explained by severity of illness [ , ] , less time examining patients [ ] , more incomplete records of vital signs and progress notes, and increasingly likelihood of preventable adverse events. moreover, almost half hcws reported difficulty in communicating with patients through enhanced infection precautions during the sars outbreak [ ] . organizational factors were commonly acknowledged as barriers that impede and hamper professionals' compliance to ppe. compliance to ppe use was closely related to the professionals' perception about the risks they were exposed to and their susceptibility to these risks. our study showed that, if critical care clinicians were aware of the patients on isolation precautions, they were twice likely to report high compliance to ppe use. similarly, in a survey of physicians working in canadian pediatric emergency departments, almost % considered identifying patients with complaints requiring ppe use prior to the physician entering the room as an important factor promoting ppe use [ ] . in a study performed during the first wave of h n influenza, banach and coworkers observed more unprotected exposures in patients who did not present with influenzalike illness [ ] . this finding was not unexpected because such patients would not have been identified by the screening protocol, which might result in delays in consideration of influenza as a potential diagnosis when these patients were subsequently evaluated by clinicians, as well as delays in implementation of recommended infection control measures. studies have consistently demonstrated significant association of the availability of ppe in icu and self-reported compliance, as in our study, indicating unavailability as the major reason for noncompliance [ , , ] . however, among the critical care clinicians surveyed by daugherty and coworkers, self-reported high compliance was only %, despite the fact that % reported that recommended ppe was readily available near patients' rooms [ ] . this evidenced the complexity of compliance to ppe, which might go beyond availability, confirming the interference of individual factors, perceptions, and relations in the work environment in decision making towards protection. professional's behavior was an important factor that determined the commitment to, and the style and proficiency of, an organization's health and safety management [ ] . a study in examined the role of organizational factors in hospitals in the united states, and found that severity-adjusted mortality were related more to the interaction and coordination of each hospital's icu staff than the icu administrative structure, amount of specialized treatment used, or the hospital's teaching status [ ] . similar to other studies [ ] , our study found close association between self-reported compliance and safety culture (i.e. hcw behavior, and perceived reprimand for noncompliance by the supervisors), underscoring the importance of icu safety culture in promoting behavior change, or even patient outcome [ ] . perceived barriers of compliance to ppe use as described above should be addressed during development of practice guidelines, in order to prevent transmission of infectious diseases within hospital setting. despite the lack of data validating such concept with regards to h n influenza in icu, studies did suggest that implementation of protocoled care and/or educational program, by addressing knowledge, attitude, and behavioral barriers, might significantly reduce catheter-related bloodstream infection [ ] , and improve mortality in patients with severe sepsis [ ] . the major limitation of our study was that it might be subject to social desirability bias (individuals may wish to present themselves or their organization in a favorable way) due to its reliance on self-reporting [ ] . in addition, cause-effect relationship could not be determined due to the inherent ''chicken or egg'' caveat of the observational study. nevertheless, these data provided clue of the barriers that existed with regard to the implementation of infection control guidelines in icus and provided useful suggestions for the implementation. only % of chinese critical care clinicians reported high compliance to ppe use during pandemic influenza, putting hcws and their patients at risk. both attitudes towards ppe use and perceived organizational norms have been recognized as predictors of compliance, which should be addressed while developing educational program and/or practice guidelines, in order to prevent nosocomial transmission of influenza. questionnaire s survey questionnaire. (doc) swine influenza. statement by who director-general, dr margaret chan world now at the start of influenza pandemic. statement to the press by who director-general dr margaret chan h n flu: international situation update swine origin influenza a (h n ) virus and icu capacity in the us. are we prepared? hospitalized patients with h n influenza in the united states impact of the influenza a(h n ) pandemic on public health workers in the netherlands personal protective equipment and antiviral drug use during hospitalization for suspected avian or pandemic influenza sars plague: duty to care or medical heroism transmission of pandemic influenza a (h n ) virus among healthcare personnel -southern california guideline for infection control in health care personnel healthcare infection control practices advisory committee guideline for hand hygiene in health-care settings. recommendations of the healthcare infection control practices advisory committee and the hicpac/shea/apic/idsa hand hygiene task force guideline for isolation precautions: preventing transmission of infectious agents in healthcare settings pandemic influenza: guidance for infection control in critical care. dh novel influenza a (h n ) virus infections among health-care personnel -united states why don't physicians follow clinical practice guidelines? a framework for improvement the use of personal protective equipment for control of influenza among critical care clinicians: a survey study knowledge and attitudes of healthcare workers in chinese intensive care units regarding h n influenza pandemic effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory distress syndrome (sars) use of personal protective equipment in pediatric emergency departments a method for evaluating health care worker's personal protective equipment technique barriers to implementing infection prevention and control guidelines during crises: experience of health care professionals practice and perception -a national survey of therapy habits in sepsis understanding adherence to hand hygiene recommendations: the theory of planned behavior adverse effects of contact isolation contact isolation in surgical patients: a barrier to care? do physicians examine patients in contact isolation less frequently? a brief report the immediate psychological and occupational impact of the sars outbreak in a teaching hospital factors associated with unprotected exposure to h n influenza a among healthcare workers during the first wave of the pandemic intensive care unit safety culture and outcomes: a us multicenter study an evaluation of outcome from intensive care in major medical centers an intervention to decrease catheter-related bloodstream infections in the icu improvement in process of care and outcome after a multicenter severe sepsis educational program in spain implementing quality indicators in intensive care units: exploring barriers to and facilitators of behavior change key: cord- - wnmdvg authors: nan title: p – p date: - - journal: clin microbiol infect doi: . /j. - . . _ _ .x sha: doc_id: cord_uid: wnmdvg nan resistance rates (rr) over a period of years were generally better than those reported for a total of icus. the mean mrsa rr was . %, for all the sari icus, whereas it was only . % in the study icu. by the end of duration of treatment for pneumonia had been reduced to - days and written guidelines on empiric antibiotic treatment and prophylaxis were revised with respect to the resistance situation of the study icu. the significant decrease between and in total antimicrobial ad from , to in the study icu resulted mainly from the reduced consumption of nd generation cephalosporins, carbapenems and imidazoles. ni did not change significantly over time. compared to the year , the costs for antibiotics were halved from € , to , , which corresponds to € . /pd and € . /pd, respectively. the percentage of antibiotics in the total icu budget for pharmaceuticals decreased from . % to . %. conclusion: surveillance and feedback of antibiotic use and resistance can serve as a valuable quality control instrument and can have an impact on antibiotic treatment. from to , antibiotic use was reduced by % and costs for antibiotics/pd were cut by two third in the icu study without any increase in device associated nosocomial infection rates. the resistance situation was generally better than in all sari icus, but showed heavy fluctuations. similar illness burden but different antibiotic prescription to children: a population-based study k. hedin, m. andre, a. håkansson, n. rodhe, s. mö lstad, c. petersson (växjö, falun, malmö, linköping, se) objectives: respiratory tract infections are the most common reason for antibiotic prescription in sweden as in other countries. the prescription rates vary markedly in different countries, counties and municipalities. the reasons for these variations in prescription rates are not obvious. the aim of the study was to find possible explanations for different antibiotic prescription rates in children. therefore a prospective population based log book study was conducted in four municipalities which, according to official statistics, had high and three municipalities which had low antibiotic prescription rates. methods: during one month, parents recorded all infectious symptoms, physician consultations and antibiotic treatments, from -month-old children in a log book. the children's parents also answered a questionnaire about socioeconomic factors and concern about infectious illness. results: antibiotics were prescribed to . % of the children in the high prescription area and . % in the low prescription area (crude or . ( % ). after multiple logistic regression analyses taking account of socioeconomic factors, concern about infectious illness, number of symptom days and physician consultations, differences in antibiotic prescription rates remained (adjusted or . ( %ci . - . )). the variable that impacted most on antibiotic prescription rates although it was not relevant to the geographical differences was a high level of concern about infectious illness in the family. conclusion: the differences in antibiotic prescription rates could not be explained by socioeconomic factors, concern about infectious illness, number of symptom days and physician consultations. the differences may be attributable to different prescription customs, in which case physicianś prescription patterns are not always rational. decreasing outpatient antibiotic prescribing in germany, germany, - , does not include newer macrolides, fluoroquinolones and extendedspectrum beta-lactams w.v. kern, k. de with, k. nink, h. schrö der (freiburg, bonn, de) objective: the esac (european surveillance of antibiotic consumption, www.ua.ac.be/esac) project has shown that outpatient antibiotic prescribing in germany has been comparatively low among european countries. we assessed trends over time and regional variation of outpatient antibiotic use in germany, and wondered if the observable decreasing trend included all drug classes to a similar extent. methods: prescription data (compulsory health insurance covering > % of the population, sample of . % until the year , all prescriptions thereafter) were analysed using the atc/who methodology and current ddd definitions. we specifically defined the following drug groups: ''basic'' penicillins (bpens, oral penicillin or aminopenicillins), extended-spectrum betalactams (esbls, oral cephalosporins, staphylococcal penicillins, aminopenicillin/betalactamse inhibitor combinations, parenteral cephalosporins and broadspectrum betalactams), newer macrolides (nmls, roxithromycin, clarithromycin, azithromycin) versus older macrolides (omls). quinolones (fqs), folate synthesis inhibitors (t/ss) and tetracyclines (tets) were also assessed. data were expressed in yearly ddd/ persons covered by the insurance (ddd/ ). findings: outpatient prescribing in was ddd/ (corresponding to . did = ddd/ and day) and decreased to ddd/ in the year and to ddd/ in . the decreasing trend over the last years was observed in all regions. the decrease was most significant for omls () %), t/ss () %), tets () %), and bpens () %) while there was no decreasing use of esbls (± %) and increases in the rate of prescribing nmls (+ %) and fqs (+ %). tets and bpens, however remained the most prescribed antibiotics in . regional variations in remained large for bpens (> -fold) with very low prescribing rates in the eastern region, but were small for t/ss, nmls and fqs (< -fold). conclusions: over a decade we observed a % decreasing outpatient antibiotic prescribing that included relevant antibiotic drug classes except esbls, nmls and fqs. the relative increase was most significant for fqs. severe community-acquired pneumonia admitted to the intensive care unit: impact of antibiotic therapy delay on hospital mortality antibiotic therapy were enrolled in the study. pts were divided in groups according to time to treatment (< h gi, [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . baseline severity scores (apache ii, sofa, psi, curb- ), microbiological documentation, and hospital outcome were compared for all groups. results: pts were included in the study. microbiological documentation was achieved in % of all pts, positive blood cultures in / ( . %), s. pneumoniae in / ( %). mean age was ± , apache ii . ± . , sofa . ± . , psi ± , curb- . ± , mechanical ventilation in . % and vasopressors use in . %. overall icu and hospital all-cause mortality were . % and . %, respectively. baseline severity scores were comparable in all groups and their respective hospital mortality is provided in table . conclusions: in severe cap, treated with a combination therapy, time to treatment seems to have an impact on hospital all-cause mortality. based on our results, antibiotic treatment should be initiated within the first hours after hospital admission. (period ii) -cefoperazone/ sulbactam ( g a day) as monotherapy were used as the empirical antibacterial therapy of vap. the rotation from cefepime to cefoperazone/sulbactam was performed due to our previous study demonstrated high frequency of esbl producers among enterobacteriaceae. the samples from the lower respiratory tract were obtained by mini-bal. the sensitivity of microorganisms to the antibiotics studied (ceftazidime, cefepime, cefoperazone/sulbactam and carbapenems) was determined by the disk diffusion method. results: the main pathogens of vap were s. aureus ( %), p. aeruginosa ( %), enterobacteriaceae ( %) and this structure did not changed during both periods. the antibiotic sensitivity of p. aeruginosa and enterobacteriaceae (k. pneumoniae and e. coli), was studied separately. a high level of resistance of enterobacteriaceae to cefepime can be explained by the strains prevailing in the given icu, which produced extended spectrum beta-lactamases (ctx-m). the resistance of enterobacteriaceae to cefepime was . % in i period and . % in ii period, to ceftazidime - . and %, meropenem - and %, imipenem - . and . %, cefoperazone/sulbactam - . and . %, respectively. a change of cefepime for cefoperazone/sulbactam was not followed by any decrease of enterobacteriaceae resistance level to cefepime during ii period. the resistance level of p. aeruginosa to cefepime was . % in i period and . % in ii period, to ceftazidime - . and . %, meropenem - . and . %, imipenem - . and . %, cefoperazone/ sulbactam - . and . %, respectively. conclusion: the exclusion of cefepime for months didn't improved the sensitivity of enterobacteriaceae to this medication. the level of resistance of p. aeruginosa and enterobacteriaceae to cefoperazone/sulbactam did not increased despite a wide use of this antibiotic during months. antibiotic consumption in german acute care hospitals m. steib-bauert, k. de with, e. meyer, p. straach, w.v. kern (freiburg, frankfurt, de) objective: outpatient antibiotic use in germany differs substantially between eastern and southern parts of the country (relatively low use) and western part (relatively high use). there is no nationwide estimate of hospital antibiotic use and its geographic variation if any. the aim of the present study was to provide an estimate of recent hospital antibiotic use density in germany and to identify basic unit/hospital characteristics associated with excess use. methods: data on hospital consumption of systemic antibiotics in anatomical therapeutic chemical (atc) class j were obtained from a convenience sample of acute care hospitals in germany that participated in an ims survey in the year and had complete data (dispensed drugs and patient-days per year) for at least one non-paediatric, non-psychiatric department or ward. a total of non-icu surgical departments/wards, non-icu non-surgical (general medicine, oncologyhaematology, neurology/stroke) departments/wards, and icus covering > million patient-days were analysed. data were expressed in ddd (who/atc definition version ) or ''prescribed/recommended daily doses'' (pdd, better reflecting [high] dosages given to hospitalized patients) per patient days (ddd/ and pdd/ ). findings: the weighted mean over all departments/wards incl. icus was . ddd/ ( . pdd/ ). as expected, icu antibiotic use density was much higher than use in non-icu areas, and use in haematology-oncology was higher than in other non-surgical departments/wards. in univariate analyses, bed-size category and university affiliation (icus, surgical wards), region (icu, surgical and non-surgical wards) and haematology-oncology as specialty (non-surgical wards) were associated with use density, but these associations were only partly confirmed in multivariate logistic regression analyses of factors associated with excess ( ‡ %) use density which showed university affiliation and haematology-oncology to be independently associated with high use. conclusions: based on this hospital sample, antibiotic use in german hospitals shows little, non-significant regional variation and appears to be similar to what has been described from other european countries. adjustment of the data at least for university affiliation and haematology-oncology is important in comparative analyses of hospital antibiotic consumption. impact of formulary change in medical intensive care unit on outcome of infection and antimicrobial resistance sought to evaluate a formulary change and impact it has on infection and resistant. methods: prospectively, all patients in a -bed icu were followed for a period of months in phase i ( patients per patient days) and to collect baseline data after a decrease in the use of piperacillin-tazobactam (pt) when substituted by cefepime for a period of months in phase ii ( patients per patient days). results: total infections in phase i vs. phase ii were lower respiratory tract (lrti) patients ( %) vs. patients ( %); urinary tract infection (uti) patients ( %) vs. patients ( %); and sepsis of undetermined aetiology patients ( %) vs. patients ( %), respectively. there were no significant differences in death ( % vs. %) , cure or improvement of infection ( % vs. %), readmission to the unit ( . % vs. . %), hospital risk of death ( . % vs. . %), mean length of icu stay ( . days vs. . days), or rates of nosocomial infection ( . % vs. . % for lrti; . % vs. . % for uti; . % vs. . % for soft tissue infection; . % vs. . % for bacteremia; . vs. . per patient days for intravenous catheter infection) in phase i and ii respectively. the cost of antimicrobial acquisition in phase i and ii were $ and $ per patient respectively (p < . ). the mean antimicrobial treatment costs per patient for pt were $ vs. $ and cefepime were $ vs. $ in phase i and ii respectively (p < . ). the in vitro susceptibility and rate of infection and colonization with escherichia coli were unchanged in both study periods. there were vs. staphylococcus aureus (p < . ); of these percnt vs. percnt were methicillinresistant s. aureus and vs. enterococcus faecium ( % vs. % vancomycin-resistant enterococci) in phase i and ii respectively. there were % vs. % pseudomonas aeruginosa and % vs. % klebsiella pneumoniae extended spectrum beta lactamases in phase i and ii respectively. conclusion: the implementation of formulary substitution of pt to cefepime in the medical icu had resulted in a decrease in the use of pt. in addition, there were decreased costs and less s. aureus infections without adversely affecting the outcome of infection or antimicrobial resistance. intravenous antibiotic use in scottish hospitals; evaluation of the glasgow antimicrobial audit tool r.a. seaton, d. nathwani, p. burton, e. douglas (glasgow, dundee, uk) introduction: there are few data on antibiotic prescribing within scottish hospitals and a coordinated multisite point prevalence survey had not been performed before. there is concern that antimicrobials are overused in hospitals. methods: antibiotic use in acute medical and surgical units in scottish hospitals across trusts, was investigated using a point prevalence survey. data were collected by pharmacists. appropriateness of the iv route of administration was determined by review of data by an infectious diseases physician (idp) and compared with a specifically designed computerised algorithm. the idp also judged the appropriateness of the chosen iv agent against local guidelines. patients from hospitals in regions were surveyed on a single day. ( . %) were receiving an antibiotic, ( . %) intravenously. receiving oral antibiotics had received an iv previously. median duration of iv therapy was days (iqr - days) and time from iv to oral switch was . ( ) ( ) ( ) ( ) ( ) . the idp judged appropriate iv route in % patients compared with . % by the algorithm. the sensitivity of the algorithm was . % and specificity . %. the positive predictive value was . % and the negative predictive value was . %. the idp judged iv agents to have been chosen and administered appropriately in %. most frequently prescribed iv agents were rd generation cephalosporins ( gc) ( . %), co-amoxiclav ( . %), metronidazole ( . %), glycopeptides ( . %). significant regional differences were seen for most antibiotic groups including gcs ( . % (site ) vs . % (sites , , , ) , p < . ) and glycopeptides [ . % (site ) vs . % (site , , , ) , p < . ]. it is possible to coordinate, collect and compare data from scottish hospitals. the gaat gives a good estimate of the appropriateness of iv therapy. significant differences in prescribing patterns between similar patient groups across different hospital sites were demonstrated. such data may usefully inform local and national audit and support prescribing initiatives. associations between continuous variables were tested in univariate analysis with the spearman correlation test (r). multiple linear regression analysis was performed in a backward stepwise approach. results: the median rate of total hospital glycopeptides use was . (range . to . ) ddds per , pd with higher consumption in large public hospitals. consumption was higher in intensive care areas (median . ; range . to ) than in surgery areas (median . ; range . to . ) and in medicine (median . ; range to ). glycopeptides use correlated with number of central line per , pd (r: . ; p: . ) and with size of the various areas in the hospital (for intensive care, r: . ; for medicine areas, r: . and for surgery areas, r: . ; p < . ). median incidence of mrsa was . per , pd. incidence of mrsa explained a small proportion of the variation in hospital glycopeptides consumption (r : . ). in a multivariate linear regression model, incidence of mrsa and number of beds in surgery areas were independent predictors of total glycopeptides use in the hospital (r adjusted: . ). after controlling for these factors, number of central-line per , pd was no more associated with glycopeptides use. conclusion: in our hospitals, total glycopeptides use was not heavily determined by incidence of mrsa. although glycopeptides use in surgery areas was not the highest, the total number of surgery beds in the hospital explained a large variation of the total hospital glycopeptides use. therefore we had to take it into account to interpret these consumption and to decide further evaluation. antibiotic management of acute lower respiratory tract infections among dutch elderly patients in primary care j. bont, c. birkhoff, t. verheij, e. hak on behalf of esprit objectives: acute lower respiratory tract infection (lrti) can cause various complications leading to morbidity as well as mortality notably among elderly patients. antibiotic treatment of lrti is common, despite dutch clinical guidelines recommending antibiotics only in case of pneumonia or high risk of serious complications. we assessed the course of illness and outcome of pneumonia, acute bronchitis and exacerbations of copd or asthma among dutch elderly patients in primary care and assessed whether gps were inclined to prescribe antibiotics more readily to patients with potential risk factors for complications in acute bronchitis or exacerbations of copd/ asthma. methods: we retrospectively analysed medical data from , episodes of lrti among patients ‡ years of age presenting in primary care to describe the course of illness and outcome. the relation between prescriptions of antibiotics and patients with risk factors for a complicated course was assessed by means of multivariate logistic regression. risk factors for a complicated course included heart failure, history of myocardial infarction, angina pectoris, diabetes, history of stroke, dementia, malignancy, and history of pneumonia or hospitalisation in preceding year. results: one or more complications arose in % of episodes of lrti. among these, % suffered from pulmonary complications, % had cardiovascular complications (heart failure, myocardial infarction etc.), % had a protracted course and . % had a diabetes event. in . % of the patients complications led to hospital admission and in . % lrti were fatal. antibiotics were more readily prescribed to patients aged ‡ years, when heart failure was present and in patients with diabetes. no significant association was observed in patients with other co-morbid conditions. patients diagnosed with an exacerbation of copd or acute bronchitis with a history of pneumonia or hospitalisation in the preceding year were not more likely to receive antibiotics. conclusions: a considerable part of elderly patients with a lrti suffers from a severely complicated course in primary care. although gps are inclined to prescribe more readily antibiotics in the very old and those with heart failure or diabetes, other potential risk factors are not taken into account. objectives: in this study it was aimed to analyse the infectious diseases (id) trainees' night/weekend shift consultation process in terms of patient and consultant characteristics, types of recommendations, and compliance with recommendations. methods: all consultations performed by id trainees in night shift and at the weekends between june th-august th were analysed in terms of consultation type [treatment continuation (tc), consultation for surgical antibiotic prophylaxis (pa), and consultation with or without a request of a specific antibiotic (others)]. appropriateness of recommendations was assessed the day after the consultation by infectious diseases specialists (ids). adherence to recommendations was assessed days after the consultation by idss. recommendations including antibiotics were considered appropriate, if they were appropriate according to national and international guidelines. recommendations were considered complied, if they were done in up to hours after the consultation (except the consultations in the emergency medicine and the consultations in which antibiotics were started by the counselling idss). results: of consultations was for tc, was for pa and was for others. the clinic where id consultations were requested mostly was general surgery clinic ( / , . %) . in % of all consultations trainees consulted the specialists. overall consultations ( for sp, for a clinical infectious disease diagnosed clinically, for an infectious disease diagnosed microbiologically) were for requesting spesific antibiotic(s). pa were approved in of consultations. antibiotic was not recommended in of other consultations. in six of consultations for pa antibiotic was changed for a clinically diagnosed infectious disease. in one of consultations for tc antibiotic was changed due to lack of response to the given antibiotic, in others tc was approved. inappropriate antibiotic recommendation rate was . % ( / , inappropriate choice, inappropriate dosage, one antibiotic unnecessary). overall compliance to id recommendations was . % ( / ). rate of compliance to antibiotic recommendations was evaluated in consultations and was found . % ( / ) and was higher than compliance to other (microbiology etc.) recommendations ( . %, / , chi square p < . ). conclusion: methodologies to improve the compliance to nontreatment based recommendations and optimizing antibiotic selection is necessary. study of the influence of online practice guidelines on the appropriateness of antibiotic prescribing in a university-affiliated psychiatric hospital j.f. westphal, c. nonnenmacher, d. gregoire, m. hittinger, c. oulerich, f. jehl (brumath, strasbourg, fr) background: problems with the dissemination of guidelines are frequently cited as a major reason for failure to impact practice. reviews of the effectiveness of various methods of guideline dissemination show that the most predictable impact is achieved when the guideline is made accessible through computer-based reminders that are integrated into the clinician's workflow. we report a time-series prospective investigation aimed at comparing the appropriateness of antibiotic (ab) orders for pneumonia at the treatment initiation level after vs. before having embedded our current ab guidelines for pneumonia in the computerized physician drug-order entry system of our teaching psychiatric hospital comprising adult beds. methods: in total, consecutive ab orders for pneumonia were evaluated by the pharmacy department, including orders just before and orders just after implementation of online ab guidelines. appropriateness of ab orders relative to the guidelines was assessed according to criteria: ( ) the choice of ab with respect to the mode of acquisition (community-or hospital-acquired) of pneumonia or the presence of clinical risk factors for involvement of gramnegative bacilli, ( ) the daily dosage, ( ) the planned duration of treatment. data were extracted from the computerized infection declaration system that recorded all ab-requiring infections in our hospital. results: the number of ab orders with at least criterion of inappropriateness tended to decrease, yet not significantly (p = . ), after vs. before implementation of online guidelines: / ( . %) and / ( . %), respectively. the number of criteria of inappropriateness relative to all ab orders for pneumonia was significantly lower in the post-implementation period: . % vs. . % before implementation (difference . %, % ci . - . , p < . ) , with a trend to a decreased number of orders containing more than criterion of inappropriateness. analyzed separately, the numbers of inappropriate orders for the choice of the ab, or the daily dosage, or the planned duration of treatment decreased, yet not significantly (p > . for each criterion), in the post-vs. preimplementation period : vs. , vs. , vs. , respectively. conclusion: in this study, the moderate impact on ab prescribing practices of online guidelines available at the time of drug order shows that additional types of intervention are needed to improve further the quality of ab prescribing. material: the pilot hospitals had a median capacity of (range, to ) beds; their regional distribution was representative of population size; were general hospitals, teaching hospitals and general hospitals with teaching beds. results: ams were internists ( ), microbiologists ( ) and pharmacists ( ). amts included a mean of members who met every weeks on average. all hospitals irrespective of size or affiliation had undertaken a wide range of antibiotic management interventions in , which increased in ; these included (in and , respectively) : major review of formulary (in and hospitals), development of clinical guidelines ( and topics), restricted access to selected antibiotics (carbapenems, glycopeptides, quinolones, new drugs; in and hospitals). in , antibiotic consumption databases were established in hospitals and antibacterial susceptibility databases in hospitals. in , cross-analysis of these databases was performed in hospitals. in , prescribing assistance, antibiotic stop orders, treatment streamlining and iv/po therapy switch were implemented in , , and hospitals, respectively. in , hospitals reported a better use of target antibiotics, hospitals a decrease in consumption of restricted antibiotics, hospitals a decrease of total antibiotic consumption, hospitals a decrease in high consumer departments. conclusion: all hospitals participating in the amt pilot scheme have developed multiple antibiotic policy interventions and established monitoring and guidance of antibiotic prescription. preliminary data from some hospitals indicated success in meeting self-defined targets of appropriate use and reducing the consumption of selected antimicrobial agents. more systematic evaluation using standard quantitative and qualitative indicators is planned. antibiotic prescribing practices at two linked london teaching hospitals p comparison of different antibiotic consumption measurement methods in large multidisciplinary hospital e. pujate, i. apine, u. dumpis (riga, lv) objectives: antibiotic selection pressure is determined by the total amount of antibiotics, number and density of patients treated with antibiotics in the particular geographical area. several antibiotic consumption detection methods should be combined in the hospital setting. our objective was to evaluate efficacy of different approaches in large multidisciplinary hospital. methods: point prevalence studies were repeated annually at [ ] [ ] [ ] in stradins university hospital ( beds) in latvia. all patients receiving antibiotics on the day of the survey were identified and their medical records were reviewed. data on antibiotics, dose and route of administration were collected. in addition, annual data on antibiotics dispensed to the departments were collected from pharmacy. total used grams for each antibiotic were expressed into defined daily doses (ddd-who). bed days (bd) and admission days (ad) were used as denominators. results: table total use of antibiotics in stradins university hospital hospital - the most commonly used antibiotic groups in the pharmacy study were st generation cephalosporins ( . ddd/ bd in , . in , . in ) and penicillin's with extended spectrum ( . , . , . ) followed by fluoroquinolones ( . , . , . ) and metronidazole ( . , . , . ). there was no significant difference between distribution of different antibiotics from prevalence and pharmacy studies if calculated in ddds. in contrast, distribution of antibiotics calculated per patient in the prevalence study was quite different; st generation cephalosporins ( . %, . %, . % in , , respectively) and fluoroquinolones ( . %, . %, . %) with smaller proportion of extended spectrum penicillins ( . %, . %, . %) and metronidazole ( . %, . %, . %). conclusions: there were no differences in the distribution of antibiotics calculated in ddds per bed days and admissions. distribution of antibiotics in annual pharmacy studies and point prevalence studies if calculated in ddds were also similar. in contrast, the prevalence data expressed as a proportion of patients with selected antibiotics showed quite different distribution. studies using only ddds may overestimate use of certain antibiotic groups in our setting where who ddds are significantly different from actual pdds used. a study of prescribing patterns and errors of antibiotics in a saudi hospital m. al-jamal, m. al-barrak (riyadh, sa) background: the term ''prescribing patterns'' has been used extensively in studies to describe different aspects of the prescribing process. antibiotics as well as other drugs are prescribed for the purpose of achieving definite therapeutic outcomes that improve a patient's quality of life while minimizing risk. in the clinical literature, the incidence of antibiotics prescribing errors ranges between . % and . %. objective: in this study we will address antibiotics prescribing patterns and the incidence of prescribing errors in a tertiary hospital and the potential relationship between them. methods: a prospective study of all prescriptions in a -month period (june to august ) in a tertiary hospital has been analysed. the hospital provides both primary and secondary levels of care. criteria used include frequency of selected prescribed drugs, average number of items per prescription, compliance to the hospital formulary, frequency of prescriptions for antibiotics, generic prescribing and diagnosis. the prescribing patterns and the incidence of prescribing errors were performed. results: total number of prescriptions for the -month study was , . emergency room (er) and primary care have the highest number of prescriptions ( . %). the average number of items per prescription is . . the most prescribed drugs by primary care ( . % errors), emergency are antibiotics ( . %), medicine ( . ), ophthalmology ( . ), gynaecology ( . ), and paediatrics ( . ). the prescription errors were . % in primary care and . % in emergency department. discussions and conclusions: over prescriptions were included in this study. the incidence of prescribing errors was . % the average number of items per prescription was . . total prescription errors are also related to frequency of prescribing antibiotics. there was a relation between prescribing of antibiotics and prescribing of trade names (p < . ), and compliance to the hospital formulary (p < . ). several factors influence prescribing patterns and variations in prescribing rates has been identified. these include general physician behavior, differences in morbidity and mortality patterns, social perception toward illness, and physician clinical skills, experience and qualification, as well as physician continuing education and training. special antibiotic prescribing guidelines and restrictions should target primary care and emergency department physicians. effect of a policy for restriction of selected classes of antibiotics on antimicrobial drug cost and resistance of the non-restricted antibiotics. the logistic regression model we performed showed that the new policy had an independent positive effect on the in vitro antimicrobial susceptibility of pseudomonas aeruginosa (p = . ) but not of acinetobacter baumannii and escherichia coli isolates. conclusion: our data suggest that there are considerable limitations of the programs aiming to reduce the consumption of restricted antibiotics through the approval of their use by specialists, at least in a proportion of settings. education programs that aim to involve the medical staff directly responsible for the care of patients in voluntary decisions regarding the appropriate use of antimicrobial agents may have more profound and sustainable success, and thus, deserve to be studied. estimating hospital versus ambulatory care consumption of antibiotics in southwestern germany k. de with, m. steib-bauert, h. schrö der, k. nink, w.v. kern (freiburg, bonn, de) objective: preliminary data from the esac (european surveillance of antibiotic consumption, www.ua.ac.be/esac) project indicated that the proportion of hospital care (hc) antibiotic use on total antibiotic use in several european countries ranges between and %. only few countries, however, have so far been able to report representative countrywide information on both hc and ambulatory care (hc) antibiotic consumption. we estimated ac versus hc consumption of antibiotics for one of the german federal states located in the southwestern part of the country with a . million population. methods: data on hc consumption (atc class j ) were obtained from a convenience sample of acute care general hospitals (n = ), extrapolated to state-wide consumption (using official statistics for the total state-wide general plus special non-psychiatric/non-paediatric/non-radiotherapy hospitals), expressed in defined daily doses per inhabitants and day (did), and finally compared to ambulatory care antibiotic use density in the same region and period of time (years and ) . findings: the estimated state-wide hc consumption of antibiotics was . did ( % confidence interval, . to . did) in both years. state-wide antibiotic consumption in the ac setting during the same time was did (~ % of total consumption). ac consumption of fluoroquinolones ( . - . did, %) and macrolides/clindamycin ( . did, %) made up a major proportion of total use of that drug classes. conclusions: hospital antibiotic use in the southwestern part of germany can be estimated to contribute~ % to overall antibiotic consumption in the general population. antibiotic use profile and temporal trends during a -year period at a greek university hospital: implications for antibiotic policy changes e.i. kritsotakis, p. assithianakis, p. kanellos, n. tzagarakis, m.c. ioannides, a. gikas (heraklion, gr) objectives: to investigate the profile and temporal trends of inpatient antimicrobial use over a -year period at the university hospital of heraklion crete, greece. further, to examine the way in which frequency of data collection and stratification by different patient-care areas provides guidance to antibiotic policy changes. methods: retrospective monitoring of antimicrobial consumption was carried out according to the who anatomic therapeutic chemical classification (atc) and defined daily dose (ddd) measurement methodology. pharmacy records were used to obtain aggregate data of drug deliveries to individual wards. results were expressed as usage density rates in ddds per bed-days (ddd/ bd). linear regression was used in order to assess the statistical significance of a temporal trend in usage densities. results: during - , hospital-wide antimicrobial use (atc group j ) significantly increased by %, from . to . ddd/ bd. the annual average increase rate was . ddd/ bd. stratification by clinical service demonstrated differences in the intensity and profile of class use, as well as varying temporal trends (figures , ) . pooled usage rates in ddd/ bd, overall percentage increases and annual average increase rates were respectively . , . %, . for medical wards; . , . %, . for icu's; and . , . %, . for haemato-oncology wards. surgical wards had a fairly constant usage rate ( . ). a shift towards the newer broad-spectrum antibiotics to the detriment of the older penicillins and cephalosporins was noted in all hospital areas. conclusion: surveillance of aggregate data on the consumption of antimicrobials using the atc/ddd system provided a clear picture of the profile of hospital usage. monthly data over a sufficient surveillance period allowed the assessment of temporal trends. stratification of usage rates by clinical service allowed areas of concern to be specified. thus, surveillance of monthly antimicrobial consumption rates stratified by patientcare area can provide a simple, rapid and efficient tool for triggering antibiotic policy changes in the hospital and targeting more detailed quality-of-use audits. appropriate use of aminoglycosides: the impact of an antibiotic control team c. rioux, p. lesprit, j.r. zahar, a. hulin, a. bernier-combes, c. brun-buisson, e. girou (créteil, paris, fr) objectives: many factors are involved in the appropriate use of aminoglycosides (ag), such as modalities of administration, serum monitoring and duration of treatment. we assessed prospectively the risk factors and the impact of an antibiotic control team on the appropriateness of ag prescriptions. methods: in a setting of a restricted delivery system of ag in our hospital, we first performed an observational audit (oa) to assess the appropriateness of prescriptions including justification of prescribing, adequacy of drug choice, adequacy of administration modalities, modalities of serum monitoring and duration of treatment. after implementation of specific guidelines hospital wide, we then performed an interventional audit (ia) where an antibiotic control team could interfere when ag prescriptions were considered inappropriate. appropriateness of ag prescriptions between the audits was then compared. results: prescriptions were analysed. during the ia, % of prescriptions were modified by the control team. as compared to the oa, prescriptions in the ia were significantly more appropriate with regard to treatment duration ( vs %, p = . ) and serum monitoring ( vs %, p = . ). median treatment duration was shorter in the ia ( d) than in the oa ( d) (p < . ). a logistic regression model showed that risk factors for appropriate treatment duration were (adjusted or, % ci, p value): hospitalization in intensive care unit ( . , . - . , . ) , polymicrobial infection ( . , . - . , . ) and antibiotic control team intervention ( . , . - . , . ) . table: conclusions: despite a restricted delivery system, ag use was frequently associated with excessive treatment duration and errors in monitoring modalities. reinforcing practice guidelines through direct counselling improved appropriateness of prescriptions. hospital antibiotic consumption in southern and eastern mediterranean countries: preliminary results from the armed project p. zarb, m.a. borg, h. goossens, m. ferech for the armed participants introduction: armed is an international research project investigating antimicrobial resistance and consumption in southern and eastern mediterranean countries through the collection of comparable and validated antimicrobial resistance data as well as information about antibiotic consumption patterns and infection control initiatives. objectives: the consumption part of the study aims to collect data on antimicrobial use within participating hospitals in the region, which information is currently unavailable. methods: data collection is planned over a -month period using anatomical therapeutic chemical (atc) classification, a validated methodology adopted by the european surveillance of antimicrobial consumption (esac -www.ua.ac.be/esac). hospitals are participating: cyprus ( hospitals); egypt ( ); jordan ( ); malta ( ); tunisia ( ); turkey ( ). results are expressed in ddd/ bed-days. results: data from , the first year of data collection, indicates that turkish hospitals seem to show the lowest overall consumption [ - ddd/ bed days], whilst the cypriot hospitals show highest values [ - ddd/ bed days]. the most common antibiotics used are the beta-lactams, especially the penicillins although in jordan and turkey cephalosporin consumption is very close to the penicillins. broad-spectrum penicillins [j ca] are the mostly utilised penicillins in cyprus, jordan and tunisia whereas in malta and turkey the combination penicillins [j cr] are the most widely used. there is more variability where cephalosporin consumption is concerned. cyprus utilises mainly first generation, jordan and malta the second generation. in egypt, tunisia and turkey there is significant variability between hospitals; nevertheless use of third generation cephalosporins appears to be significant. conclusion: a significant variability was evident between countries. this is likely to be multifactorial depending on the antibiotics licensed in a country, the national and/or hospital formulary, the type of hospital as well as any antibiotic donations that are relevant in some of the study hospitals. nevertheless, the preliminary results suggest that trends within hospitals of the same country tend to be similar. furthermore, the region as a whole seems to utilise a considerable quantity of broad-spectrum antimicrobials. this can be a factor in the high prevalence of resistance already documented in the study. russian pharmacoepidemiology study of the antibiotic prescription during pregnancy results: mean age of the patients was . ± . (min - , max - ) years, mean gestational ages at admission to hospital was . ± . ( to ) weeks. most often ( . %) infection was community acquired and . % -nosocomial, in % patients there was not to estimate origin of the infection. the most prevalent infections during pregnancy in russia was urinary tract infections - . %, std - . %, candidiasis - . %, rti - . % therefore the most interest was analysing the antibiotic prescription for uti in pregnancy (table) . in % cases were used topical (intravaginal) antimicrobial administration. most often of topically administrated antimicrobials ( . % of all prescriptions) were prescribed combined drugs included antibacterials and amtimycotics. in . % cases antimicrobials were prescribed systemically. mostly prescribed antimicrobials were beta-lactams ( . % for outpatients and . % for inpatients), ampicillin was prescribed more often ( . % for outpatients and . % for inpatients). amoxicillin + clavulanic acid was prescribed in . % of outpatients and . % inpatients pregnant women with uti. cephalosporins were prescribed in . % and . % for outpatient and inpatient uti (mainly iii-and ist generations). mitroimidazoles - . - . % (in general metronidasole), nitro-furanes - . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . %, aminolglycosides - . - . % were prescribed quite often but unjustified. other antimicrobials (fluoroquinolones, doxicicline, antiviral drugs, antifungals) were prescribed relatively rarely. despite the fact that most prescribed drugs were class b by fda, . % all antimicrobials prescribed to pregnancy were class c, . % class d and . % were unclassified. conclusions: most often prescribed antimicrobials for uti (the most prevalent infections during pregnancy in russia) are betalactams and combined topical antibacterials. in . % cases were prescribed antimicrobials of class c, d or unclassified by fda. in % outpatient and . % inpatient were used antibiotics with low in vitro activity for uropathogens. objectives: to study the dynamics of the antibiotic usage in children from orphanages located in different russian cities as the result of interventions with the increased use of the most active antimicrobials and restrictions on use of the least active. methods: the study was performed in orphanages ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) from cities of european russia (moscow, saint-petersburg, smolensk, karachev, bryansk) . use of antimicrobials during the previous months was analysed upon reviews of medical records of children < years in . appropriate recommendations on predominant use of selected beta-lactams (e.g. amoxicillin/clavulanate -amc) with restriction of antimicrobials of other classes (e.g. co-trimoxazole -sxt) were made where applicable on the basis of the expert analysis of antibiotic usage and pneumococcal nasopharyngeal resistance rates. repeated antibiotic usage analysis was performed months later in upon reviews of medical records of children < years. results: total usage of antimicrobials increased . increase of resistance to pen and aminopenicillins. enhanced use of cephalosporins led to increase of resistance to these drugs. in spite of recommendations to restrict usage of am/ox, aminoglycosides and sxt, the analysis showed that these antimicrobials still accounted for . %, . % and . % of all prescriptions, respectively, thus dictating the need for further enforcement measures. antibiotic consumption in ambulatory care in latvia, s. berzina, m. ferech, g. ozolins, h. goosens (riga, lv; antwerp, be) objectives: to collect data on antibiotic consumption in ambulatory care (ac) in latvia according to the esac data collection protocol. esac (european surveillance of antimicrobial consumption, granted by dg sanco of the ec) is an international network of national surveillance systems, aiming to collect reliable and comparable data on antibiotic consumption in europe. methods: the data on ac antibiotic consumption for have been collected using atc/ddd classification (who, version ) and expressed in defined daily doses per inhabitants per day (did). data were obtained from the state medicinal agencybased on the reports of the wholesalers for ac. results: the overall use of antibiotics in ac was . did in , which positions latvia to countries with comparatively low antibiotic consumption in europe. the mostly used class of antibiotics in ac were penicillins with extended spectrum (mainly amoxicillin) - . did ( . %). other frequently used antibiotics were tetracyclines (mainly doxycycline), representing . did ( . %), combinations of penicillins/with betalactamase inhibitors (essentially co-amoxiclav) - . did ( . %), macrolides (mainly clarithromycin) . did ( . %), fluoroquinolones (essentially ciprofloxacin) - . did ( . %) and combinations of sulphonamides and trimethroprim, incl.derivatives - . did ( . %). the most frequently used antibiotics in ac in latvia, in , were amoxicillin ( . did) , doxycycline ( . did) , and co-amoxiclav ( . did) . conclusions: valid data on outpatient antibiotic use in latvia has been for the first time collected and delivered to european surveillance of antimicrobial consumption. this allows international comparison of the pattern of antibiotic consumption in latvia with other european countries. trends in glycopeptide antibiotics consumption over a -year period in a general hospital, athens, greece introduction: glycopeptide use is under restriction in hellenic hospitals since late ' s. the aim of our study was to record trends in their consumption over the last years in our hospital (''a. fleming'' general hospital - beds) and to correlate these data with the numbers of important gram (+) strains isolated in our hospital during the same time period. methods: we measured glycopeptide use for the period - by using data from the pharmacy computer. consumption was expressed as ddds/ patient days (abc calc . ). furthermore we correlated these data with data from the microbiology department concerning numbers of mrsa, mrse and enterococci isolated during the same period. results: glycopeptide consumption was . , . , . , . , . and ddds/ patient days for the years , , , , , ( % increase) . at the same time the cumulative number of mrsa, mrse and enterococci isolated were , , , , , respectively ( % increase) . when both types of data were put on the same graph, glycopeptide consumption correlated well with the number of important gram(+) strains isolated (figure). furthermore vre percentage among enterococci was , , . , . , . , for the study years respectively. it is worth noting that % of our mrsa strains were sensitive to rifampin, % to clindamycin, % to cotrimoxazole, % to clindamycin + rifampin and % to cotrimoxazole + rifampin. linezolid has not been introduced in our hospital yet. conclusions: (a) despite the restriction policy, a tremendous increase in glycopeptide use was recorded in our hospital during the study period and this correlated to the number of the important gram(+) strains isolated; (b) nevertheless, vre is not a significant problem for our hospital yet; and c. the huge increase in glycopeptide use could be avoided at least in part, since other, older and simpler antibiotics could substitute for glycopeptides in many cases. an audit of linezolid use in a university teaching hospital, galway, ireland objective: to audit linezolid use over a six-month period among the in-patient population of a -bed teaching hospital that includes most medical and surgical specialties with the exception of nephrology, rheumatology and orthopaedics. methods: a prospective audit was carried out of the prescribing of linezolid to in-patients from october to april . the ward pharmacist recorded the details of all patients who were prescribed linezolid. a chart review was performed to assess the profile of patients prescribed linezolid, clinical and microbiological indications for treatment, adherence to treatment guidelines and documented adverse events. results: over the -month period courses of linezolid were prescribed. fifty two percent of the patients for whom linezolid was prescribed were from surgical specialties; half of these patients were under the care of one surgeon. pneumonia was the clinical indication for use in % of cases and soft tissue infection in % of cases. the microbiological indication was clear in % of cases where mrsa or vre had been isolated. in % of cases therapy was either ( ) empiric with no significant organisms isolated prior to prescription of linezolid or ( ) therapy was directed against an organism that could have been treated with an alternative agent. duration of treatment exceeded to days in % of courses. an adverse event was recorded in the case of only one course of linezolid. conclusion: in more than a third of cases linezolid use was prescribed without clear justification. avoidable use of linezolid is associated with increased costs and risks of acquired resistance. participants prior to on an oral interview during which the interviewer filled in the answers. results: a total of cm specialists completed the inquiry. this represents approximately % of the national quorum. mean age was years ( - ). of the interviewed cm specialists worked full-time with more full-time employment in hospital labs (hl). next to routine microbiology, other activities performed by cm specialists are mainly the other domains of clinical biology, hospital hygiene and to a lesser extent quality control and lab management. almost two thirds of the interviewed cm specialists believes that their training hasn't prepared them properly for the tasks they are performing now. most desired changes include more emphasis on the clinical aspect of infectious diseases and on antibiotic treatment counselling. cm does not exist as a separate speciality in belgium but is included in the 'clinical biology' speciality training. the majority of the respondents thinks that cm should become a sub-speciality (still part of clinical biology) but with a specific minimal training that needs to be defined. the majority of the cm specialists also believes that cm can share lab infrastructure with other disciplines and that the essential aspect of cm lies predominantly in the medical expertise. conclusion: cm training should put more emphasis on the clinical aspect of infectious diseases and on antibiotic treatment counselling. the majority of the respondents feels that cm should become a sub-specialty (still part of clinical biology), with a well defined training curriculum. objectives: since more than years, all infectious disease consultations have been recorded in a computerized database (epi info . d, cdc). here we report on consultations of a fellow, conducted during year, compared with consultations conducted by two veteran board-certified infectious disease consultants during the same period. methods: we analysed computerized consultation records, including demographic details of patients; referring department; initiative for, route and purpose of the consultation; and recommendations; and compared between the different consultants. results: a larger percentage of veterans' compared to the fellow's consultations, were requested by attending physicians ( % vs. %, p < . ), while follow-up ( % vs. %, p < . ), laboratory results ( % vs. %, p < . ) or prescription for a restricted antimicrobial agent ( . % vs. . %, p < . ) were more prevalent in fellow consultations. the fellow had a higher rate of additional consultations (in which the patient was seen more than once) ( % vs. %, p < . ), and performed more bedside consultations ( % vs. %, p < . ) or consultation by curb side discussion ( % vs. . %, p < . ), and less consultations by telephone ( . % vs. . %, p < . ). diagnosis and prophylaxis were more often the purposes of the veterans' consultations ( . % vs. . %, p < . , . % vs. . %, p < . , respectively), and they also offered new diagnoses more frequently (p < . ). the veteran consultants more often conducted consultation for communityacquired infections ( % vs. %, p < . ), and more often started antibiotic treatment ( % vs. . %, p < . ). conclusions: significant differences were detected between consultations conducted during the first year of a fellow compared to those of veteran infectious disease consultants. these differences reflect the changing demands and activities in the consultant's work as experience and knowledge accumulate. periodic analysis of computerized data of consultations facilitates supervision as well as direction of consultants' work, addressing issues such as antibiotic use and patterns of microbial resistance. bridging the gap between health care and public health; capacity building in infectious disease control objectives: in recent years, the european union (eu) has developed and supported many activities in the field of communicable diseases. these activities not only concern surveillance networks of specific infectious diseases (e.g. enter-net for salmonella and escherichia coli infections, ewgli for legionella infections, eiss for influenza infections), but also eu training programmes like epiet (european programme for intervention epidemiology training) and a eu communicable disease bulletin. even more recent are the eu's initiative bichat to improve preparedness and response to bioterrorism, and the development of a eu cdc. moreover, a major part of the new programme of community action in the field of public health (ph) ( ) ( ) ( ) ( ) ( ) ( ) concerns id, with not only a commitment to improve information and information exchange, but particularly to strengthen the international rapid response capacity.all this, to illustrate the importance of idc on the eu agenda. methods: the european public health association (eupha) is an umbrella organisation for ph associations in eu. in eupha has created an eupha section idc bringing together eupha members with expertise in this field and representatives of the various above mentioned eu initiatives in order to: promote and strengthen research in the field of idc; provide a platform for the exchange of information, experience and research in idc; bring together researchers, ph practitioners and policymakers active in idc; encourage joint activities in idc; and improve idc training. results: by now the section has members from different countries. as of the section is represented in the ecdc advisory forum. different section activities: organising workshops, a breakfast meeting and a pre-conference meeting on timely idc topics during eupha conference. objectives: to establish a cross-border dutch-german network (www.mrsa-net.org) providing a user-friendly knowledge centre for hospitals, public health authorities, gps, nursing homes and laboratories. primary purpose is to aid in the reduction of mrsa-rates and limit the cross-border transmission of mrsa. guidelines and their implementation play a significant role in reaching these aims. cross-border (ca-) mrsa guidelines will be redesigned according to international standards and socio-cultural differences between the nations. methods: based on quality standards for safety and healthcare documentation used in high risk chemical organizations, a framework for a systematic content analysis of national mrsaguidelines was developed. national guidelines were analysed on the basis of this framework. results: a content analysis of the current national mrsaguidelines showed five dominating mrsa-perspectives: rule-, expert-, risk-, demand-and community-driven. german guidelines are mainly dominated by the rule-and expertdriven perspectives (guidelines are literally derived from law and follow the infection transmission route), in contrast to the dutch which focus on the demand of the user and the community (addressed to public health and acceptability of guidelines by users). conclusion: the analysis showed that the fact that there are different guideline-perspectives results in an enormous, confusing set of guidelines. the management and use of guidelines becomes uncontrollable and leads to an illusory organisation where healthcare workers don't act in accordance with the guidelines and start applying their own insights. this might lead to cost-increasing and contrasting situations. to implement guidelines successfully in a cross-border situation, a cultural and technical synchronisation alongside an integrated approach of the different perspectives of guidelines is necessary, inline with the current disease management models. further research about the redesign and the evaluation of those guidelines in practice will help achieving this. r. tsiklauri (tbilisi, ge) background: animal bites are a common but under recognized public health problem. it has been estimated that there are - bites each year in georgia, and based on an average visit and post-exposure treatments cost at list $ per year. despite the frequency and expense of these injuries, there is little information about the incidence of animal bites because of a lack systematic reporting and a lack of measurement of the quality and completeness of reported data. objectives: to investigate animal bites and rabies reported cases, revealed unreported cases, analyse and based on study results find more effective epidemiological measures of animal bites and deaths (due to rabies) prevention in georgia. methods: the capture-recapture method was used, along with log-linear modelling. for sources were used to identify victims: policlinic/ambulatory reports, hospital reports, animal control reports and victim reports. results: in - years dog and other animal bites were reported. the capture-recapture method estimated that there were unreported bites. during these period deaths due to rabies was registered in georgia and ( %) cases among them have been registered during the last years. the reasons of fatal cases were untreated ( %), uncompleted treated ( %) and late began post-exposure treated ( %) cases of bites (mostly dog bites). about % of bitted persons did not know about rabies and it's prevention measures. about % had incorrect information about prevention and only % of them knew epidemiological and clinical aspects of disease. about % of physicians who were responsible on quality post-exposure treatment had not an adequate knowledge. conclusion: dog and other animal bites are common but preventable injuries. to improve surveillance and prevention of rabies in georgia, the focus should be on educating the general public about the serious consequences of animal bite injuries and developing the animal's vaccination strategy. pharmacoeconomics and electronic resources p the expected economic burden of methicillinresistant staphylococcus aureus in complicated skin and skin structure infections: a modelling approach a. kuznik, r. mallick, d. weber (collegeville, chapel hill, us) objective: to model the expected rate of clinical failure of initial empiric therapy and economic burden likely to be associated with the increasing prevalence of methicillinresistant staphylococcus aureus (mrsa) in patients hospitalised with complicated skin and skin structure infections (csssi) in the united states. methods: using published data on ( ) the prevalence of mrsa and other bacterial pathogens causing csssi in the us, ( ) the in-vitro susceptibility rates of commonly used regimens in csssi in the us in relation to the most pervasive pathogens identified above, and ( ) estimated costs of failure of initial, empiric treatment from a recent study of a large us multi-hospital database, we developed a model to predict the expected clinical and economic impact of increasing prevalence of mrsa. specifically, clinical failure of of the more commonly used initial regimens in csssi was modeled in terms of their in-vitro susceptibility rates with respect to mrsa, weighted by mrsa prevalence. varying the rate of mrsa further yielded projected clinical failure rates and costs attributable to increasing levels of methicillin resistance over time. results: given current % prevalence of s. aureus pathogens in csssi, half of them methicillin-resistant (base case mrsa = %), the model projected an overall clinical failure rate of . % for of the more commonly used initial regimens, with an expected overall treatment cost (in us dollars) of $ , per patient (range, $ , - , ) . if none of the s. aureus pathogens were resistant (mrsa = %), clinical failure rate was projected to be . % and treatment cost to be $ , per patient. the differences in the two scenarios translated to an expected clinical failure rate of . %, an incremental cost of $ per patient, and for the , patients hospitalised for csssi annually in the us, an expected health care system burden of $ million attributable to mrsa. under a "worst-case" scenario in which mrsa was the only causative pathogen (mrsa = %) in csssi, clinical failure rate was projected to be . %, and treatment cost per patient was expected to be $ , . conclusions: going beyond existing estimates, our model generated a substantial expected clinical failure rate and economic impact attributable to current mrsa levels, as well as simulations of the expected impact of increasing mrsa prevalence over time, varying levels of mrsa across regions and choice of initial empiric regimens. treatment of complicated skin and skin structure infections in the us: expected cost differences between tigecycline and vancomycin/aztreonam r. mallick, a. kuznik, d. weber (collegeville, chapel hill, us) objective: to compare tigecycline and vancomycin/aztreonam in terms of treatment-related costs for patients hospitalised in the united states with complicated skin and skin structure infections (csssi). methods: we conducted a retrospective analysis of pooled data from us centres in two randomized, double-blind clinical studies comparing tigecycline and vancomycin/aztreonam in the treatment of csssi. using regression analysis, we estimated the effect of tigecycline treatment on hospital length of stay (los), controlling for other significant predictors. using published estimates of daily hospitalisation cost of csssi in the us from a multi-hospital audit, we then translated the estimated impact on los into economic terms. this analysis was repeated for the subgroup of patients in which the primary pathogen was methicillin-resistant staphylococcus aureus (mrsa). clinical efficacy (tigecycline %, vancomycin/aztreonam . %; p = . ) was similar across treatments and was not included as a model parameter. results: our retrospective analysis of the pooled clinical data from us centres found that tigecycline was associated with a shorter los [) . days (p = . )] compared with the combination of vancomycin/aztreonam in the treatment of patients with csssi. at a mean daily hospitalisation cost (in us $) of $ , excluding antibiotic costs, this translated into expected medical cost savings of $ , per patient for tigecycline compared with vancomycin/aztreonam. in the mrsa subgroup, comprising % of the clinical study sample, tigecycline was associated with a greater reduction in los [) . days (p = . )] compared with vancomycin/ aztreonam, translating to expected medical cost savings of $ , per patient treated with tigecycline. these expected medical cost savings more than offset the higher average daily drug acquisition costs of tigecycline ($ /day) relative to the vancomycin/aztreonam combination ($ /day). conclusion: in a retrospective analysis of pooled clinical data of patients with csssi treated at us centres, tigecycline was associated with a significantly reduced length of hospital stay relative to vancomycin/aztreonam; this translated into substantial cost savings, especially in the subset of csssi patients with mrsa. the economic impact of linezolid in the treatment of skin and soft tissue mrsa infections in italy m. eandi, p. dale, s. sorensen, t. baker, m. procaccini, s. duttagupta (turin, it; london, uk; bethesda, us; rome, it; new york, us) objective: linezolid has been shown to be highly effective against infections caused by methicillin-resistant staphylococcus aureus (mrsa) in patients with complicated skin and soft tissue infections (cssti). the objective of this study was to evaluate the clinical and economic consequences of using linezolid for the empiric treatment of cssti from the italian hospital perspective. methods: a decision-analytic model was developed to calculate the clinical and cost outcomes of empiric treatment of hospitalized patients with cssti in italy prescribed linezolid, vancomycin or teicoplanin. efficacy data were derived from clinical trials. costs from published sources were applied to tests, adverse events, and days of intravenous and oral (linezolid only) treatment and hospitalization by ward type (general, intensive-care). resource use and utilization patterns were obtained from a combination of clinical trial data and expert opinion. outcomes included total costs per patient, cost per cure and cost per death avoided. uncertainty surrounding the ce ratio was tested using one-way sensitivity analysis. results: starting empiric treatment with linezolid resulted in . % of patients cured from mrsa compared to . % with vancomycin. the average cost per patient treated with linezolid was € , versus € , for patients treated with vancomycin. this resulted in a cost per cure of € , . in a separate analysis more patients were cured using linezolid ( . %) compared to teicoplanin ( . %). the average total cost per episode was € , for linezolid treated patients versus € , for teicoplanin treated patients, resulting in a cost per cure of € , . the most sensitive parameters included hospital los and mrsa resistance rate. conclusions: in the treatment of cssti due to suspected mrsa in italy, the empiric use of linezolid is cost-effective when compared to vancomycin and teicoplanin p outpatient and home parenteral antimicrobial therapy for the treatment of cellulitis: evaluation of efficacy and cost h. ziglam, r. tilley, c. wootton, j. morrison, d. nathwani (dundee, uk) objective: outpatient and home parenteral antibiotic therapy (ohpat) programmes are effective, well tolerated and economically advantageous in carefully selected patient populations. skin and soft tissue infections represent a high burden disease which in amenable to treatment by ophat programmes. we retrospectively analysed our outcomes registry to evaluate the clinical and health economic impact of treating cellulitis in this setting. methods: we have reviewed patients with cellulitis and erysipelas who were treated with ohpat. each patient treatment has a full integrated care pathway (icp). the icp documents the microbiological outcome, drug and vascular access complication rates, impact on drug costs and in-patient bed days on the number of patients treated from april to march are presented here. we also reviewed using the smr o inpatient discharge diagnosis data from the information statistics division scotland (isd) and the dundee infectious diseases units (didu) outcomes registry database. the key diagnosis (icd codes) groups considered were cellulitis (lo , , , , , ) and erysipelas (a x) over eight consecutive years ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . results: the patients received intravenous antibiotic therapy for a mean duration of . days. the two primary agents administered were once-daily ceftriaxone in %of patients and teicoplanin in . % of patients. of the patients, ( . %) were cured or improved; worsened and required surgery. tinea pedis was found in % of patients treated for cellulitis. economic benefits were realized despite use of more expensive agents. data from the dundee outcomes registry revealed a mean reduction in length of hospitalization from . days ( / ) to . in - -a reduction of % compared to scottish data from isd which did not show any changes in length of hospitalization between year / ( . days) and year - ( . days) . conclusions: we have found that ohpat is clinically effective and can be administered safely and successfully in an outpatient setting. the majority of complications were minor, and % of patients were cured. tinea pedis and were found to be significant risk factors for acute cellulitis and indicate that improved awareness and management of toe web intertrigo might reduce the incidence of cellulitis. this analysis also supports the premise that an adult ohpat programme can substantially reduce healthcare resource use in the european healthcare setting. cost-effectiveness analysis of intravenous moxifloxacin compared to levofloxacin in hospitalised elderly patients with communityacquired pneumonia objective: to evaluate the cost-effectiveness of moxifloxacin compared to levofloxacin in hospitalised patients aged ‡ with community acquired pneumonia (cap). methods: a randomised double-blind parallel group study was conducted in us hospitals. patients had radiological evidence of bacterial pneumonia confirmed by at least other signs, were aged ‡ years and were managed as inpatients on initiation of treatment. patients initially received moxifloxacin mg iv o.d. or levofloxacin mg iv o.d., and once stabilised were switched to oral therapy with the same agent. the effectiveness endpoint for the economic analysis was the percentage of patients successfully treated, defined as patients with marked improvement, resolution or clinical cure at test of cure visit after - days of therapy who did not experience a serious cardiac adverse event. total costs were estimated from the perspective of the treating hospital and included antibiotic drugs, hospital stay, hospital re-admission within days and cost of managing treatment failures. results: patients were included in this analysis, randomised to moxifloxacin and to levofloxacin. % ( % ci: - %) of moxifloxacin and % ( - %) of levofloxacin treated patients were successfully treated (resolution, clinical cure at toc and no serious drug related aes). in the moxifloxacin group patients reported a mean of . days of iv antibiotic treatment and . days inpatient stay with . days iv antibiotic treatment and . days inpatient stay in the levofloxacin group. mean per patient drug cost was $ in the moxifloxacin group, $ in the levofloxacin group. mean total cost was $ , in the moxifloxacin group and $ , in the levofloxacin group. findings were consistent across a range of patient subgroups. costs were sensitive to length of hospital stay. conclusions: patients in the moxifloxacin group had higher rates of successful treatment at slightly lower average costs than the levofloxacin group. this confirms the results of the target study where moxifloxacin showed superior clinical efficacy in comparison to co-amoxiclav with or without clarithromycin in hospitalised cap patients. antibiotic costs were slightly higher in the moxifloxacin group than the levofloxacin group but total costs were slightly lower, due to reduced hospital stay. economic impact of invasive fungal infections in icu patients in a tertiary care hospital in switzerland a. imhof, w. zingg, r. laffer, c. ruef (zurich, ch) objectives: invasive fungal infections (ifi) cause significant morbidity and mortality. the management of invasive fungal infections is currently undergoing important changes due to the availability of new therapeutic agents with improved safety profiles but the acquisition costs of these new agents are high. we evaluated the average overall cost of management (microbiological diagnosis and treatment) of invasive fungal infection in critically ill patients at a large university hospital. methods: a retrospective ( ) ( ) , pairwise-matched cohort study was performed on surgical icus and one medical icu at our university hospital. icu patients with documented ifi (n = ) were matched with control subjects (n = ) on the basis of disease severity, sex and age (± years). clinical outcome was principally evaluated by in-hospital mortality. the economic impact of microbiological studies and antibiotic treatment was assessed. calculations were based on the period between admission and diagnosis of ifi in cases and the duration of hospital stay in controls, respectively. results: the median length of hospital and icu stay differed significantly between cases and controls ( vs days, vs days, p < . , respectively). ifi occurred after a median hospital stay of (range - ) days. the mortality rate for patients with ifi and matched control subjects were . % and . %, respectively (p = . ). there was no significant difference between cases and controls for charlson index, mccabe and saps ii score. median number of antibiotic treatment courses was for cases and for controls (p = . ), with a median duration of therapy of days vs day (p < . ), respectively. microbiological studies (mis) were conducted times/ patient-days (pd) in cases and times/ pd in the control group (p = . ). the most frequent samples were bloodcultures in both groups. swabs were ordered significantly more frequently in cases (median (range: - ) vs. ( - ); p = . ). the cost for mis was ' euro/ pd in cases vs. euro/ pd in controls, and the costs for antifungal therapy ' euro/ pd vs. euro/ pd, respectively. conclusions: ifi is associated with excess length of icu and hospital stay, increased use of antibiotics and microbiological diagnostics. the microbiological studies have a significant economic impact on the treatment of ifi. cost-effectiveness of voriconazole to amphotericin b deoxycholate in early and late treatment of invasive aspergillosis r. greene, j. mauskopf, c. roberts, t. zyczynski, h. schlamm (boston, research triangle park, new york, us) objective: we estimate the cost-effectiveness of alternative initial drug treatments of invasive pulmonary aspergillosis (ipa) in suspected earlier and later lung involvement, based on the presence or absence of the halo sign on thoracic computed tomography (ct). methods: we constructed a decision analysis model comparing -week treatment outcomes for a subset of patients enrolled in a clinical trial of initial treatment of ipa with amphotericin b dexoycholate (ambd) vs voriconazole (vor). patients included those with suspected lung involvement who underwent a baseline thoracic ct. the subset was subdivided into two groups based on the presence or absence of a characteristic ct halo sign, a perimeter of ground glass ct opacity surrounding a solid lung nodule ‡ cm diameter, known as an early indicator of ipa. healthcare resource use and survival data were obtained directly from the clinical trial. us unit costs for drugs and health care services were applied from standard data sources. cost and survival at -weeks were estimated for those with and without a halo sign at baseline. incremental cost-effectiveness ratios comparing vor to ambd were calculated for both patient subgroups. sensitivity of results to uncertainty in health care use and cost estimates was tested. results: patients in the halo subgroup had better survival than those in the no-halo subgroup ( . % vs . %), with lower total treatment cost ($ , vs $ , ) . survival was higher for vor than for ambd in both patient subgroups (halo: . % vs . %; no-halo: . % vs . %). in the halo subgroup, total costs were lower for those treated with vor than for those treated with ambd ($ , vs $ , ) . in the no-halo subgroup, total cost per patient was slightly higher for those treated with vor ($ , vs $ , ) . accounting for the difference in survival, the incremental cost-effectiveness ratio for vor compared to ambd was $ , per additional -week survivor in this subgroup. conclusions: earlier identification and treatment of ipa appears to result in better survival and potentially lower costs than later treatment. initial treatment of ipa with vor improves survival in patients with early or late disease compared with ambd, is cost saving in the halo sub-group, and is cost-effective in the no-halo subgroup, within the constraints of our analysis. objective: to describe and compare the nursing labor time required for preparation and administration of liposomal amphotericin b (l-amb), amphotericin b deoxycholate (ambd), and voriconazole (vor). methods: activities associated with nurse preparation and administration of the three study drugs were timed by trained observers at five hospitals (one in italy, three in france, and one in the united kingdom). target tasks were classified as those likely to be affected by the difference between the drugs and excluded those tasks likely to differ because of site-specific factors (e.g., travel time to a patient room in different hospitals). target tasks included: obtain supplies and medications; prepare medications; educate patient; administer medications; monitor for adverse events; and prepare follow-up medications. the mean times for administration of a single day of study drug were summarised and compared, accounting for a single daily dose of l-amb and ambd and daily doses of vor iv or oral. results: sixty-nine patients were observed receiving doses of study medications at the five hospitals. time of administration in minutes per day was , , , and for l-amb, ambd, vor iv, and vor oral, respectively. administration time was significantly lower for vor iv compared with l-amb (p < . ) and for vor oral compared to all iv regimens (p < . ). the task of preparation of medications required the most time for iv formulations, and was longer in the l-amb group than the others (l-amb: mins vs ambd: mins; vor iv: mins). ambd required more time for patient monitoring and administration of followup drugs than other formulations (ambd: mins vs l-amb: mins; vor iv: mins). conclusion: vor iv required significantly less time to prepare and administer on a daily basis compared to l-amb. measurements of iv antifungal versus oral vor administration suggest the opportunity to save - minutes per day by switching to oral therapy when possible. need of cost-effectiveness investigation focused on diagnosis, management and prevention of osteopenia and osteoporosis in the setting of hiv disease treated with haart: when to act, how to act, which patients are the first target of intervention r. manfredi, l. calza, f. chiodo (bologna, it) background: osteopenia/osteoporosis are emerging untoward effects of hiv infection/haart. the pathogenesis is multifactorial, involving all classes of anti-hiv drugs, although protease inhibitor use, overall haart duration, and the male sex, seem related to a greater risk.epidemiologicalclinical data. in an ongoing study at our centre where > hiv-infected patients (p) are followed, bone mineral density was assessed in lumbar spine/femural head by a dual energy xray absorptiometry (dexa) exam to estimate the prevalence of osteopenia/osteoporosis. in a screening of~ p, the frequency of osteopenia and osteoporosis (based on lumbar t-score) was % and~ %, respectively. an increased risk was found in p treated with protease inhibitors versus those receiving nonnucleoside reverse transcriptase inhibitors or triple nucleoside/ nucleotide combinations. discussion and future insights: prospective studies of extensive p samples are needed, to elucidate the epidemiology, pathogenesis, clinical issues and evolution of hiv-associated bone metabolism anomalies. when planning strategies for their early diagnosis, prevention and management also cost-effectiveness issues should be considered, since no pharmacoeconomic data still exist in this setting. although severe consequences (e.g. pathological fractures, prosthetic implants) are expected to be infrequent their consequences in terms of length and intensity of hospitalization, related costs, and especially severe consequences on the p's quality of life, play a notable role. anyway, the most reliable diagnostic procedure (dexa) has affordable costs (around eur . for a total-body scan which also offers a body composition assessment), as well as the first-line drugs for osteopenia, e.g. supplementation with calcium (eur - . /month), and vitamin d (eur /month). these costs cannot be compared with the costs of a standard care of an asymptomatic haart-treated p (eur to /month) and the immunological, virologic, laboratory and clinical controls made at least quarterly. like postmenopausal osteopenia/osteoporosis (burdened by a greater risk of bone mass anomalies) also hiv disease should be investigated from multiple cost-effectiveness points of view to establish which p are the preferred candidates for a dexa screening when this examination is more useful during hiv disease course and therapy, when the exam should be repeated and when and how to intervene pharmacologically to prevent serious and potentially invalidating complications. a comparative study on the cost of new drugs in different therapeutic categories m. falagas, k. fragoulis, g. zouglakis, i. karydis (athens, gr) objectives: drug treatment is becoming more expensive due to the increased cost for the introduction of new drugs and there seems to be an uneven distribution of medication cost for different therapeutic categories. we hypothesized that the cost of new antimicrobial agents may differ from that of other therapeutic categories and this may play a role in the stagnation of development of new antibiotics. methods: we performed a pharmaco-economical comparative analysis of the drug cost of treatment for new agents introduced in the united states drug market in various therapeutic categories. we calculated the drug cost [in us dollars (usd)] of a -day treatment of all new drugs approved by the fda during the period between january and july , according to the red book pharmacy's fundamental reference. results: new anti-neoplastic agents were found to be the most expensive drugs in comparison to all other therapeutic categories with a median -day drug-treatment cost of usd compared to the median -day drug-treatment costs of all other categories ranging from to usd (table) . on the other hand, new antimicrobial drugs were found to be much less expensive with a median -day drug-treatment cost of and usd for all anti-microbial agents and for anti-microbial agents excluding anti-hiv medications, respectively. conclusion: the drug-treatment cost of new medications varies considerably by different therapeutic categories. this fact may influence industry decisions regarding the development of new drugs and may play a role in the shortage of new anti-microbial agents in the fight against the serious problem of anti-microbial resistance. usage and expenditure of f-quinolones in a tertiary hospital in t.a. peppas, k. malengou, n. zachos, d. voutsinas, o. kosmopoulou, n. galanakis (piraeus, athens, gr) objective: our aim was to assess -f-quinolone ( fq) usage, distribution and expenditure over years. objective: to analyse antiobiotic utilization in croatia using anatomical-therapeutic-chemical (atc) drug classification system and number of defined daily doses (ddd). methods: data on the number of packages and purchase price were collected for each individual drug. these data were used to calculate the number of defined daily doses (ddd) and ddd per inhabitants per day (ddd/tid). data obtained from % of pharmacies and % of hospitals were extrapolated to the total number of pharmacies and hospitals in croatia. drug utilization % (du %) segment was used as a prescribing quality indicator. results: in , the overall utilization of antibiotics in croatia amounted to . ddd/tid. according to drug groups, penicillins (j c) showed highest utilization ( . ddd/tid), predominated by the subgroup of penicillin combinations (including beta-lactamase inhibitors, j cr) with . ddd/ tid, within which the combination of amoxicillin + clavulanic acid accounted for . % with . ddd/tid. broad-spectrum penicillins (j ca) accounted for . %( . ddd/tid) of total penicillin utilization, with a . % predominance of amoxicillin ( . ddd/tid). cephalosporins (j d) ranked second with . ddd/tid, followed by macrolides and lincosamides (j f) with . ddd/tid, with an . %predominance of macrolides (j fa) with . ddd/tid. among the latter, azithromycin showed highest utilization with . ddd/tid, accounting for . % of total macrolide utilization. tetracyclines (j a) ranked fourth with . ddd/tid, accounting for . % of overall antibiotic utilization, followed by quinolones with . ddd/tid, other antimicrobials with . ddd/tid, and aminoglycosides with . ddd/tid. sulfonamides (j e) accounted for a negligible proportion of overall utilization. du % segment included of antibiotics registered in croatia, with amoxicillin + clavulanic acid as the leading one, followed by cephalexin with . , cefuroxime with . , azithromycin and norfloxacin with . each, nitrofurantoin with . and clarithromycin with . ddd/tid. hospital utilization accounted for . % of overall antibiotic utilization expressed in ddd/tid and . % of the respective financial cost, predominated by aminoglycosides (j g) with % and . %, and lowest proportion of tetracyclines (j a) with . %, and . %, respectively. conclusion: the utilization of antibiotics in croatia is among the highest in europe, mostly due to overuse of amoxicillin + clavulanic acid, which has no rational ground in professional guidelines. objective: the objective of the research was to analyse antibiotics prescripsion behavior by family doctors and specialists treatments prior to and after the introduction of the health care reform in poland. materials and methods: prescriptions from the first six months of and were compared. the data was collected from two randomly chosen pharmacies in the city of zabrze that supply the citizens of the silesian agglomeration from various social backgrounds. taking into account the value of a single antibiotics package and the price a patient has to pay for it an average price of medications prescribed by family and specialist doctors was calculated. results: a total of prescriptions were analysed out of which dated from and from .in the first half-year of the percentage of prescriptions for antibiotics reached . % on average, and in the year -the average was . %. in the first half-year of family doctors mostly prescribed: penicyllins ( %), makrolids ( %), cephalosporins ( %), tetracyclins ( %), chinolons ( %). in the same period spcialist doctors prescribed: penicyllins ( %), cephalosporins ( %), makrolids ( %), tetracyclins ( %), lincozamids ( %), chinolons ( %). in the first half-year of family doctors most often prescribed penicyllins -( . %), makrolids -( . %), cephalosporins -( . %), tetracyclins -( . %) and lincozamidsbased ( . %) treatments specialist doctors, on the other hand, prescribed penicllins ( . %), makrolids ( . %), cephalosporins ( . %), tetracyclins ( . %), lincozamids ( . %) and chinolons ( %). the average prices of the prescribed medications in the years and were, respectively: for family doctors-eu . and . , for specialist doctors eu . and . . conclusions: there has been a considerable increase in the percentage of prescriptions for antibiotics from . % (in ) to . % (in ). the tendency towards prescribing antibiotics in the specific groups of doctors has not changed significantly. in both years prescriptions for antibiotics were in line with the recommendations. also, prices of medications prescribed by family doctors have risen. internet guide on antimicrobial resistance a. sosa, f. traub, s. valovic, p. chea (boston, us) objectives: ( ) to organize the plethora of information available, providing clinicians the tools to easily access available online resources that include academic institutions, professional societies as well as sites maintained by private individuals; ( ) to inform clinicians of new advances in the epidemiology, diagnosis, treatment, and prevention of most common infections; ( ) to inform on subjects such as clinical trials in antimicrobial resistance, information about specific pathogens and their infections, genomic resources, culture collections, electronic images of pathogens and antimicrobial agents, antimicrobial resistance lecture and teaching materials, environmental health and safety information, and a listing of websites of infectious disease and clinical microbiology professional societies. methods: we defined four inclusion criteria after extensive consulting with apua staff and scientific advisory members: ( ) recognized/reputable source; ( ) high quality of information presented; ( ) potential usefulness to medical professionals and the general public; and ( ) ease of navigation. ideal parameters were determined for the guide's scope and the appropriate sources identified online were subsequently reviewed. a set of broad categories was established to organize the topics and the online resources. sites reviewed included those maintained by the federal government, academic institutions, nonprofit organizations, and commercial entities. some personal websites were included because of their quality and their association with academic institutions. this review is intended as an introduction to amr websites. results: with use of popular search engines, such as google, yahoo!, and altavista, we initially identified a great number of websites. using broad search terms, such as "antibiotic resistance," we identified , , web addresses. the term "antimicrobial resistance" generated , hits, and the term "drug resistance" generated , , hits. conclusions: websites found were classified following a systematic topic structure. each website listed describes: ( ) full citation of the resource: author/editor and title of website; ( ) date of publication or last revision; ( ) methods and results: the portal is free to use but requires registration and has more than registered users as of november . of these, % are in-training positions, % hold a faculty position in infectious diseases (id), microbiology or hemato-oncology, % are specialists in a non-university, but a teaching setting. the remaining are a mixed group of primary physicians, other speciality doctors and pharmaceutical company workers. running costs of the portal are partially covered by educational grants from pharmaceutical sponsors who have no role in organization of the site, but their names are acknowledged. articles chosen by the two faculty members, one id physician and one haematologist, are sent to registered users by daily e-mail postings. these are selected from toc alerts of various core clinical journals and well known educational web sites (e.g. cdc, who, medscape). a short turkish summary is provided and the reader is referred to the abstract and if available, to the free full text of original article with a link. other materials included guidelines, free slide sets, study protocols and updates from the group, cme activities and meeting announcements. registrants may also use the site for expert opinion. during the trial period, the site has been visited times with hits. approximately . gb material was downloaded. the frequency of readings are related with the time (highest between . - . am during weekdays and lowest during weekends), the type of documents (i.e. educational materials and guidelines), popularity of the news (e.g. peaked during an epidemic of avian influenza when related news and articles announced). the pages are most frequently visited by id specialists followed by clinical microbiology, haematology and pharmaceutical company workers ( %, %, % and % respectively). conclusion: timely published medical data have high attraction rates among physicians. our results also indicated that, a web page gets ''old'' after about a month of publishing, emphasizing the importance of well-timed announcements of the portal material. neli and nric survey: information needs of infectious disease professionals p. kostkova, s. d'souza, g. madle, j. mani-saada, s. wiseman, a. roy, j. weinberg (london, uk) healthcare professionals are increasingly facing the problem of information overflow. it is getting impossible to keep up-to-date with the latest research findings, care guidelines and pathways, government strategies and national and local policies. internet enables an instant information dissemination enabling access to the latest results at any time as well as informal knowledge exchange by using chat rooms and discussion forums. however, it is getting increasingly difficult for busy professionals to find reliable quality-assured information on the internet when they need it. national internet libraries in the uk are addressing this problem: the umbrella portal national electronic library of infection neli (http://www.neli.org.uk) providing a single access portal to quality-assured information on treatment, diagnosis, prevention and management of infection diseases, and the national resource for infection control nric (http:// www.nric.org.uk) -a single-stop shop for policies, guidelines and research around infection control, hosted by neli. to better meet the information needs of these internet portals, accessed by unique users per month, we are conducting an information needs study to explore clinical questions, user needs and disease priorities of users seeking answers on neli and nric. a pilot qualitative online questionnaire-based study revealed that our users come from the variety of professionals: clinical scientist, consultant, registrar, psychotherapist, lecturer, gp, medical librarian, information scientist, health protection. these have questions mainly around hiv, tinea, molluscum contagio, meningitis, cold, mrsa, lyme, toxoplasma, chicken pox, influenza, diarrhoea and vomiting, rash, staph. aureus, traveller infections antibiotics resistance, malaria, mmr, meningitis, viral myocarditis, anthrax, smallpox, and tb. this is in line with our quantitative weblog-based evaluation of the most commonly access topics on neli by nhs-based users: antimicrobial resistance and hae ( . %), tb ( . %), meningitis ( . %), hiv ( . %), chlamydia ( . %), e. coli ( . %), staph. aureus ( . %), adenovirus ( . %), blood borne infections ( . %). the results of the ongoing analysis of google search keywords that brought users to neli and nric will be discussed. further results identifying the needs specific to the infection disease professions will be discussed in relation to differences in the national variations in information needs and priorities. training in infection s. d'souza, p. kostkova, f. cooke, a. holmes (london, uk) specialists today require prompt access to quality information in order to work effectively. the diversity of specialist interests in the field of infection has led to the formation of a large number of professional and scientific societies. these play an increasingly important role in ensuring that the trainee is effectively supported, not only during the period of training, but also in longer-term personal development. details of relevant societies, conferences, grants etc are, on most society websites, confined to those for either that society or others in that specialty only, and knowledge of the numerous places in which to look for this information is necessary to find out the latest information. training in infection (tii -www.trainingininfection.org.uk) is an online resource, primarily aimed at infection specialist trainees but useful throughout the career path, which brings together this information into one central access point, so that users from all infection specialties can find the appropriate information for their specialty quickly and easily. it identifies and links to the key relevant resources covering a broad range of infection related disciplines in a dynamic database structure. information on societies, conferences, grants, journals, textbooks and more are available on the site, and have been put together to create a one-stop infection training portal. online discussion forums to be implemented will allow trainees' to share ideas and make the most of their combined expertise, and users will be able to receive alerts on new information in their specialty as well as be reminded of conference deadlines, journal submission deadlines etc. the ability to discuss regional issues online within specialties also aims to promote greater local and international collaboration. training in infection is endorsed by the national electronic library of infection (neli -www.neli.org.uk), an established digital library bringing together the best available online evidence-based resources on the investigation, treatment, prevention and control of infectious diseases. research designs and statistical methods in medical abstracts m. kompoti, m. matsagoura, a. koutsovasilis, a. koutsovasili, s. drimis (athens, gr) statistical methods used in biomedical research articles are being increasingly scrutinized in medical journals. however, no such strict policy is generally applied in abstracts presented in medical congresses. objective: this study aimed at assessing the frequency of research designs and statistical methods reported in abstracts presented in two successive years of the european congress of clinical microbiology and infectious diseases (eccmid). material and methods: we reviewed all abstracts included in the abstract book of the th eccmid (prague ) (pg) and the th eccmid (copenhagen ) (cp). all abstracts of original research studies but no abstracts of lectures were included in our study. two independent investigators read all abstracts and extracted information concerning origin, type (clinical, laboratory, animal model), research design, sample size and statistical methods used in the study. data analysis was performed with logistic regression and pearson's chi-square test for categorical variables and student's t-test for continuous variables. statistical significance level was set at p < . . results: a total of abstracts were included in the analysis according to eligibility criteria ( from pg and from cp). laboratory studies prevailed ( %) followed by clinical studies ( %) and experimental studies with animal models ( %). the majority ( . %) of the studies were observational (retrospective, prospective, cross-sectional) of which . % concerned diagnostic accuracy testing of laboratory methods and . % were pharmacological studies, . % were randomized controlled trials. statistical evaluation was clearly described in . % of abstracts ( . % in pg and . % in cp, p < . ), while the rest of abstracts included only descriptive statistics or no statistics at all. the proportion of statistical methods reporting varied according to the type of the study (animal model studies . %, clinical studies . % and laboratory studies . %, p < . ). multicentre research studies reported statistics more frequently than single-center studies ( . % vs. . %, respectively, p = . ). conclusions: statistical analysis is an inseparable part of original research. research design as well as the implemented statistical methods should always be reported in an adequate manner, thus improving the scientific quality of abstracts. antimicrobial pk/pd p nxl -oral streptogramin: a phase i, doubleblind, single escalating oral dose study to evaluate safety, tolerability and pharmacokinetics in healthy adult male volunteers m. rangaraju, j. rey, j. hodgson (romainville, vitry sur seine, fr) background: nxl (formerly xrp ) is a novel semisynthetic oral streptogramin that consists of a / (w/w ratio) association of a pristinamycin ia (pi) derivative and a pristinamycin iib (pii) derivative. nxl is being developed for the treatment of respiratory tract and skin and skin structure infections. methods: healthy male subjects were enrolled in this study. subjects in each of cohorts ( mg, mg, mg, mg, mg and mg) received either nxl ( ) or placebo ( ) . an additional cohort of subjects received a single dose of mg nxl in fasting and fed conditions. blood and urine samples for pk analysis were collected at multiple time points. safety was assessed via adverse events, physical examination, clinical laboratory data, ecg and cardiac monitoring. results: nxl administered as mg capsules at single doses from mg to mg was well tolerated and safe. there was no serious or severe adverse event, no dosedependency in the number of aes or their severity, no significant variation in blood pressure or heart rate, no abnormality on ecg recording, and no clinically significant changes compared to baseline for laboratory parameters. both components were rapidly absorbed; pi being slightly more rapidly absorbed than pii. the cmax and auc ( -t) increased approximately in proportion with dose. the proportion of pi and pii components estimated on mean exposure values was approximately comparable to that administered ( / ), indicating that the relative bioavailabilities of pi and pii are simila. elimination half-life ranged from between to hours for pi to to hours for pii. food increased the bioavailability of pi and pii by approximately %. conclusions: nxl is safe, well tolerated and exhibits predictable pk properties in healthy volunteers in doses up to mg administered as a single dose. correlation of vancomycin and daptomycin susceptibility in staphylococcus aureus in reference to accessory gene regulator polymorphism and function w. rose, m. rybak, b. tsuji, g. kaatz, g. sakoulas (detroit, new york, us) objective: polymorphism at the accessory gene regulator (agr) locus in s. aureus (sa) defines groups (i-iv). agr group ii sa have been associated with glycopeptide treatment failure in patients. sa with loss of agr function appear to have a higher tendency to become vancomycin (v) resistant. it is unknown whether this association only pertains to glycopeptides. we examined the effect of varying v and daptomycin (d) against agr+ and agr null pairs in an in vitro pharmacodynamic model (ivpm). methods: agr group i and ii wild-type prototype and knockout (tetm::agr) pairs were evaluated. mic values were determined according to clinical laboratory standards institute. ivpm glass and hollow fibre models were used to simulate dosages and auc/mic exposures for v ranging from . mg- g q h fauc/mic range - mg/l*h, and d . mg/kg- mg/ kg/day fauc/mic range . - . the dosage regimen and auc/mic breakpoints that produced resistance was then evaluated in the hollow fibre ivpm. all ivpm simulations were performed in duplicate over h. resistance was evaluated using and x mic screening plates at , , , , and h. results: pre-exposure mic values for agr i± and agr ii± were . / and for v and . lg/ml for d respectively. vintermediate resistance (mic = mg/l) was detected in both agr i and ii null strains at a simulated v dosage of . mg q h (auc/mic ), representing an mic increase of - fold. this breakpoint for resistance was verified in the hollow fibre model. although significant regrowth was noted with suboptimal dosing of d, no resistance was detected on d screening plates for any daptomycin regimen evaluated. conclusions: exposure of sa to v approximating / of optimal serum concentrations resulted in the development of heteroresistance in the agr null group i and ii. loss of agr function did not correlate with the development of d resistance despite suboptimal simulations of d exposures. these results implicate loss of agr function important to the development of glycopeptide resistance but not to loss of susceptibility to d. teicoplanin efficiently penetrates into the rabbit infected vitreous but may enhance expression of virulence factors at sub-inhibitory concentrations e. forestier, f. jehl, c. gallion, r. andres, s. bronner, l. leininger, g. prévost (strasbourg, fr) objectives: fluoroquinolones are the antibiotics that most efficiently penetrate inside vitreous. however, alternative treatments for endophtalmitis may be required in some cases for example resistant bacteria. we used a rabbit experimental model of endophtalmitis to evaluate the penetration of teicoplanin in different conditions. the influence of subinhibitory concentrations of teicoplanin was also evaluated on the expression of s. aureus virulence factors. methods: new zealand rabbits (> kgs) received one or repeated doses of intra-venous (iv) teicoplanin ( mg/kg) every hours for days plus one dose a day for more days. another group of rabbits was infected by cfu of a methicillin resistant s. aureus ibs (cmi = . mg/l) producing enterotoxin a, panton-valentine leucocidin and luke-lukd. they were administrated - hours later with mg/kg teicoplanin, as a single dose or as to reach the steady state. vitreous ( ll) was sampled before new injections of teicoplanin or at indicated time as well as blood before or min after teicoplanin injection. teicoplanin concentrations were measured by hplc. bacterial counts were recorded and expression of virulence factors was semi-quantified by dedicated competitive rt-pcr tests. results: in safe eyes, teicoplanin penetration remains moderate reaching about mg/l within about - h after one iv injection. the half-life of teicoplanin in the rabbit vitreous is about hours. after days of repeated injections, intra-ocular concentration stabilises around mg/l while residual blood concentrations were comprised between - mg/l. in infected eyes, teicoplanin, when repeatedly administrated after the beginning of clinical signs, i.e. h postinfection = cfu/ml, reaches intra-vitreal concentrations of . ± . mg/l h post-infection, and increases to . ± . mg/l h post-infection and h after a fourth injection. however, at sub-inhibitory concentrations (~ mg/l), it may be responsible for a significant increase of agr, gammahemolysin hlga, luked and panton-valentine leucocidin luk-pv expressions with ratio ranging from to folds. conclusion: these preliminary results strongly suggest that teicoplanin iv administration constitutes an interesting alternative therapy for endophtalmitis provided high intraocular concentrations are rapidly obtained. investigations now concern optimisation of teicoplanin dosage regimen. pharmacokinetics of temocillin in intensive care patients and monte carlo simulations to evaluate susceptible breakpoints j.w. mouton, r. dejongh, v. basma, p. tulkens, s. carryn (nijmegen, nl; genk, brussels, be) background: temocillin (tmo) is a narrow spectrum penicillin with good activity against gram negative micro-organisms including esbl and ampc producers. little pharmacokinetic data are available however. we performed a pharmacokinetic study in icu patients receiving tmo g q h. parameter estimates were used to predict concentrations during continuous infusion (coinf) and compared with data obtained from other icu patients receiving coinf to validate the model. the model was then used to perform monte carlo simulations (mcs) to determine probabilities of target attainment (ptas) for pharmacodynamic indices (pdi) in order to evaluate and suggest clinical breakpoints. methods: blood samples were taken from icu patients prior to (t = ) and after (t = , , , , h) a m infusion of g tmo (n = ) or after h during coinf with g/ h (n = ), and then cooled, centrifuged and stored at ) °c until analysis by hplc. protein binding was determined using an ultrafiltration method. results were used to estimate population pharmacokinetic parameters by winnonmix including the covariance matrix. miclab was used to perform simulations for coinf as well as to perform mcs ( cycles) and obtain ptas for the unbound fraction including % confidence intervals (ci) for the target concentrations. ft>mic was chosen as the pdi because of the pharmacodynamic properties of tmo. results: protein binding was %. a one-compartment model best fitted to the data, with estimates (se) of vc = . ( . ) l and k = . ( . ) /h corresponding to a mean half-life of . h. using these estimates, the predicted unbound concentration during coinf was . mg/l, while the mean concentration in the other patients was . mg/l, a bias of less then %. the breakpoint mic for a mean ft>mic of % was mg/l. however, mcs -taking the variation in the population into account -indicated that % ptas of a g q h dose were obtained at , , and mg/l for , and % ft>mic, respectively. the % ci at % ft>mic indicated a clinical breakpoint of mg/l. the % ci was relatively large, as expected from data obtained in patients rather than volunteers. conclusion: the population pharmacokinetic estimates from icu patients were very well in agreement with the validation study, with a bias of < %. the mcs indicate a susceptible breakpoint for temocillin of £ mg/l provided an administration of g q h is used. tissue penetration and pharmacokinetics of moxifloxacin in diabetic foot infections:an interim analysis j. majcher-peszynska, k. karrasch, m. saß, r. mundkowski, a. gussmann, p. kujath, b. ruf, w. schareck, h. koch, b. drewelow (rostock, bad saarow, lubeck, leipzig, beeskow, de) objectives: with its broad spectrum of activity against grampositive, gramnegative and anaerobic organisms moxifloxacin covers the pathogens of the mainly polymicrobial infections associated with the diabetic foot. inflammatory and fibrotic processes in diabetic foot infections (dfi) contribute to impaired tissue penetration of antibiotics. in addition, diabetic patients represent a pharmacological risk population, physiological changes in diabetic patients may alter the pharmacokinetics of antibiotics. the study was designed to investigate the penetration of moxifloxacin into perinecrotic tissue in patients with dfi and the pharmacokinetic properties of moxifloxacin in diabetic patients. methods: the interim analysis of this open, multicentre study included adult, hospitalized male and female patients (mean age: . years) with type diabetes mellitus and dfi. the pharmacokinetic parameters of moxifloxacin and penetration into dfi tissue at steady state (day to ) following once daily administration of mg iv or po were evaluated. correlations between penetration of moxifloxacin and clinical and laboratory parameters were examinated. results: in all patients the moxifloxacin concentrations measured in infected diabetic foot wounds hours after administration exceeded the in vitro mic values of susceptible staphylococci ( . mg/l). the moxifloxacin concentrations achieved in dfi tissue correlated more strongly with the auc - (r = . ; p < . ) than with the corresponding plasma concentrations (r = . , p < . ), but not with the extent of the systemic inflammation and the blood glucose level. taking into account the predictive pk/pd parameters for moxifloxacin (based on an in vitro mic value of . mg/l for staphylococcus aureus) a therapeutic success can be expected (auc /mic: . ; cmax/mic: . ). significant differences between the routes of administration (iv vs po) were only observed for tmax (p < . ) and t / (p < . ), but not for other clinically relevant parameters (auc - , cmax, moxifloxacin tissue concentration). this allows sequential therapy i.v./p.o. in this indication. conclusion: based on adequate plasma concentrations in diabetic patients, the sufficient penetration into dfi tissue and the possibility of a sequential therapy, moxifloxacin representsfrom a pharmacological point of view -a valuable therapeutic option in the treatment of diabetic foot infections caused by susceptible organisms. fluoquinolones effects on patient lymphocytes during prolonged treatments e. bertazzoni minelli, a. benini, d. doria, p. franceschetti, m.e. fracass (verona, it) fluoroquinolones (fq), widely used in clinical practice, are well tolerated. the most common adverse reactions are those affecting gastrointestinal tract, phototoxicity and allergy. the aim of the study is to evaluate the possible cellular damage in lymphocytes of patients treated with different fqs according to pharmacokinetic data. blood samples obtained from thirty-six patients treated with ciprofloxacin (cpx, pts), levofloxacin (lvx, pts.) and moxifloxacin (mfx, pts) at different doses were analysed. patients treated with cpx and lvx were in therapy with other drugs (diuretics, cardiovascular drugs, omeprazole, antiinflammatory drugs, etc.). mxf treated patients were not in therapy with other drugs. samples were collected at time (before fqs administration) and after and days of treatment. serum levels of fqs were determined with microbiological method and hplc. comet test was performed on lymphocytes, to evaluate dna damage. gsh levels were determined as efficiency marker in metabolic process of detoxification. cpx showed good serum concentrations; its levels increases proportionally with administered doses (from to mg). lvx concentrations resulted in good inhibitory levels after treatments ( mg) both per os and i.v. patients orally treated with mg showed similar serum levels (from . to . mg/l). mfx levels were between . and . mg/l after and days. repeated cpx administration induced a dose-dependent increase in all dna damage parameters, with statistical differences after treatments. mfx ( mg) and lvx administration didn't induce dna damage after and days. intracellular levels of gsh were similar in all treated groups, even if cpx treated patients showed the lowest concentrations. no statistical correlations were found between all parameters studied. these data indicate that cpx induce dna damage in lymphocytes in combination with a reduced efficiency in detoxification system. this effect does not seems to depend on high intersubject variability for fqs administered doses, co-administration of other drugs, different ages of patients and low samples numbers. effects of single fqs molecules seems to be structurespecific and selective. objectives: ertapenem is a carbapenem commonly used to treat intra-abdominal infections. the antibacterial spectrum includes the major causative pathogens. clinical trials proved excellent clinical and microbiological efficacy in peritonitis. on the other hand in inflammatory pancreatic diseases sufficient antibiotic concentration in the inflammatory tissue is vital for the outcome of the disease. we therefore investigated ertapenem concentrations in pancreatic tissue and juice in comparison to the plasma levels measured at the same time. methods: in a prospective clinical trial ertapenem was given in a dosage of g i.v. minutes prior to operation in patients ( - years) suffering from chronic pancreatitis or pancreas carcinoma undergoing pancreas resection. blood samples were collected every minutes during the operation. moreover we collected pancreatic tissue and pancreatic juice shortly before resection and shortly before finalisation of the anastomosis. the samples of ertapenem (blood, juice, tissue) were determined by hplc. results: in patients ( female, male, mean age . ± . years) ertapenem blood concentrations were determined and demonstrated intraoperatively high concentration ( ± mg/l) above mic values for major expected pathogens. concomitantly in of these patients ertapenem concentration was determined also in pancreas tissue and pancreas secretion (in further patients in pancreas secretion only). in / patients sufficiently high ertapenem levels were detected in pancreatic tissue. in patients with chronic pancreatitis no accumulation was seen. mean pancreas tissue concentration was . ± . lg/g tissue. of patients with pancreas carcinoma had increased ertapenem levels in pancreas secretion but only of patients with chronic pancreatitis. conclusion: in patients with pancreas carcinoma, ertapenem levels were measured in pancreatic tissue as well as in pancreatic secretion and penetration seems to be similar to imipenem. due to chronic inflammation and possibly altered microcirculation only in one half to one third of chronic pancreatitis patients ertapenem levels were detected. bacterial strain-independent pharmacodynamics of linezolid/doxycycline combinations with staphylococcus aureus: -day simulations using an in vitro dynamic model m. smirnova, i. alferova, i. lubenko, y. portnoy, s. zinner, a. firsov (moscow, ru; cambridge, us) objective: to delineate the possible advantages of linezolid (l)/doxycycline (d) combinations over monotherapy, the pharmacodynamics of l, d and l+d were studied with s. aureus. methods: s. aureus atcc and a clinical isolate s. aureus were exposed to twice-daily l (half-life h) and once-daily d (half-life h), alone and in combination ( : ratio based on -h auc/mics), for five consecutive days. to provide simultaneous mono-exponential elimination of l and d with different half-lives, a previously described dynamic model was modified according to blaser and zinner. the mics of l were . and . mg/l and mics of d were . and . mg/l for s. aureus atcc and s. aureus , respectively. nine dosing regimens were simulated with each organism exposed to different auc/mics (in hours): l , l and l ; d , d and d ; l + d , l + d and l + d . the cumulative antimicrobial effect was expressed by its intensity (ie) measured from the start of treatment to the time after the last antibiotic dose when numbers of antibiotic-exposed bacteria reached at least cfu/ml. emergence of resistance was monitored daily by quantitating surviving organisms on agar plates containing x and xmic of l or d. results: with both s. aureus atcc and s. aureus exposed to l or d, ie increased with increasing simulated auc/ mic ratios, although significantly higher ies were produced with l , l and l treatments relative to d , d and d treatments. each of the combined treatments, i.e., l + d , l + d and l + d , produced much greater ies than the sum of l and d ies observed in the respective mono-treatments with both s. aureus strains. based on population data, a pronounced selection of s. aureus resistant to d occurred in all mono-treatments with d. it was also observed with l + d and, to a lesser extent, with l + d but not with l + d . no resistance to l was observed with l mono-or combination treatments. conclusions: these data predict a synergistic interaction of l with d against s. aureus. anti-staphylococcal effects of telavancin in an in vitro dynamic model: impact of different half-lives and initial concentrations that simulates normal (nek) and impaired elimination kinetics (iek). materials and methods: a glycopeptide intermediately susceptible strain of s. aureus (gisa) mu- with a telavancin mic of . mg/l was selected for the study. with both nek and iek simulations at a starting inoculum of log cfu/ml, gisa mu- was exposed to different ratios of the peak concentration (cmax) to the mic of telavancin (as a single dose), i.e., . , . and . based on time-kill data, the intensity of the antimicrobial effect (ie -the area between control growth and time-kill curves) was determined from time zero to the time when the effect no longer could be detected, i.e. the time after the last dosing at which the number of antibiotic-exposed bacteria reached log cfu/ml. results: in each treatment, bacterial regrowth followed gradual reduction in the starting inoculum during the first h (similar in nek and iek simulations) that led to significantly lower minimal numbers of surviving organisms in iek simulations compared to nek simulations. despite similar rates of initial killing, times to regrowth were much longer in iek than nek simulations. at a given cmax/mic ratio, the ies observed in iek were greater than in nek simulations (figure). conclusions: these findings demonstrate pharmacokineticdependent pharmacodynamics of telavancin with staphylococci. pharmacokinetics of amoxicillin in pregnant women with pre-term premature rupture of the membranes objectives: amoxicillin is widely used during pregnancy, in particular to treat group b streptococcus. insufficient knowledge on the pharmacokinetics just before and during delivery, could pose patients with preterm premature rupture of the membranes (pprom) at serious risk for under dosing. we investigated the pharmacokinetics in patients with pprom in this critical situation. methods: seven healthy women at - weeks of gestation were included. they received g (first dose g) amoxicillin for pprom according to local guidelines. from each patient - blood samples were taken. antibiotic serum concentrations were determined by a validated hplc method. pharmacokinetic parameters were estimated by population pk modeling using nonmem. to discriminate between various models the minimum value of the objective function (mvof) was used. a reduction of > in mvof was considered significant. results: a three-compartment pharmacokinetic model best described the time course of amoxicillin. the clearance and volume of distribution of the central compartment (vc) were estimated at respectively ± . l/h and ± . l (mean ± se). estimates of the parameters and model discrimination improved when we assumed the size of the third compartment to be equal to the first compartment. the residual error was found to be proportional to the serum concentrations. most of the inter-individual variability could be explained by variation of clearance. the mean volume of distribution at steady state (vss) and terminal half-life were . l and . h respectively. estimated values of elimination and distribution rate constants were: k = . h- , k = . h- , k = . h- , k = . h- and k = . h- . as was to be expected due to the small population size, no significant relationship was observed between the individual posthoc estimates for clearance and patient characteristics. conclusion: here we describe the pharmacokinetics of amoxicillin in pregnant women with pprom. it was found that the pharmacokinetics clearly differs from that in nonpregnant individuals. clearance and vss were significantly higher and the terminal half-life was shorter. furthermore, a -compartment model was found to describe the data better than a -compartment model. it is an intriguing question whether this rd compartment is a unique feature associated with pregnancy. these data offer a theoretical basis to make proper dose-adjustments in a particular patient group in a critical condition. penetration of piperacillin and tazobactam in severe acute pancreatitis objectives: acute necrotizing pancreatitis is still related to an extremely high mortality rate, based on local infectious complications, particularly in necrotizing areas. limited penetration of antimicrobial drugs in these areas is considered to be a major cause for failure of therapy of severe infections. combinations of beta-lactamase inhibitors (bli) and beta-lactam antibiotics like broad-spectrum penicillines (bsp) have antibacterial activity against most of the common pathogens in severe necrotizing pancreatitis. co-administration leads to an increase of antibacterial activity due to an inhibition of betalactamases. on that score, the penetration of co-administrated pip and bli into inflamed or necrotic pancreatic tissue has not been investigated yet. methods: adressing the penetration capability of bsp and bli a clinical trial was designed to investigate the penetration of piperacillin (pip) and tazobactam (taz) in patients with severe necrotizing pancreatitis undergoing pancreas surgery. samples (n = ) were taken from plasma (pl), necrotic areas of pancreatic tissue (pn), peripancreatic fatty tissue (pft) and bursa secretion (bs) following intravenous administration of . g pip and . g taz. concentrations of pip/ taz were determined by hplc/ uv. results: mean plasma concentrations at . h after application were . ± . mg/l (pip) and . ± . mg/l (taz). exceeded in pl and bs, nearly reached in pn but not in pft. the concentration of pip in combination with taz exceeded or reached the mic in pl, pn and bs against e. coli, klebs. spp., enterobacter, proteus spp. and clostr. spp., in pl and bs even against pseudomonas and bacteroides. conclusion: given in combination both -pip and taz -have been demonstrated to reach rapidly effective inhibitory concentrations in inflamed and necrotic compartments of pancreatic and peripancreatic tissue. co-administration of piperacillin and tazobactam may have a potential clinical benefit in prevention and treatment of local infectious complications of severe necrotizing pancreatitis. pk/pd challenges of in vitro time-kill curves -a new modelling approach s. schmidt, o. burkhardt, w. treyaprasert, h. derendorf (gainesville, us; bangkok, th) objective: in vitro pk/pd models, based on time-kill curve data, have become a powerful tool to predict the in vivo situation. up to date, several modelling approaches have been undertaken to develop suitable pk/pd models that fit in vitro data sufficiently well. widely used simple sigmoid emax models meet these criteria only partly. a further approach was undertaken to address the weak points of currently used models and applied to model the effects of ceftriaxone against escherichia coli. methods: constant concentration time-kill curves were performed in mueller-hinton broth (mhb, difco) with and without bovine serum albumin (bsa) g/l. using concentrations of ceftriaxone, ranging from . mic to mic, the change in number of bacteria (cfu/ml) versus time was linked to its effect. escherichia coli atcc was employed as the test organism. samples were taken at , . , , . , , , , and hours. the data were modelled simultaneously, using a modified sigmoid emax model and the software scientist Ò for windows tm . results: a differential equation, characterized by growth rate constant (k ) times the starting number (n) of bacteria represent the simplest case. barging from log-growth phase to stationary phase can be described by an additional nmax term. however, bacteria do not necessarily start growing in the loggrowth phase. this delay in onset of growth can be modeled by an exponential term, characterized by a factor beta (b) and time (t). to describe the overall change in number of bacteria not only growth but also concentration (c) dependent kill has to be taken into account. from certain drug specific concentrations on, a maximum effect is reached, described by the maximum kill rate constant kmax. however, it may be necessary to model a delay in the onset of kill with an additional exponential term, characterized by a factor alpha (a) and time (t). finally, a hill factor/shape factor (h) is necessary to smooth the predicting curves out. as shown in figure this new model meets the in vitro time-kill curve data sufficiently well. the final equation including all parameters described above is: conclusion: the proposed model was able to describe the observed data much better than a simple emax-model. incorporating two additional terms into the model, the in vitro situation could be described much better, taking the delay in onset of growth and kill into account. objectives of this study were ( ) to describe the pharmacodynamic (pd) profiles of bpr mg iv q h as a hr infusion & mg iv q h as a -hr infusion; ( ) to determine the overall probability of target attainment (pta) by weighting for the expected distributions (dis) of renal function (rfx) in the populations (pop) of interests; ( ) to determine the organism-specific pta against the pathogens encountered in phase ii trials. methods: subjects (total samples) were studied (phase i/ii subjects). samples were analysed using bignpod. to assess the impact of differing degrees of rfx impairment on pta, crcl (crcl-cockcroft & gault method) was employed as a covariate in the pop pk analysis. monte carlo simulation (mcs) ( subjects) was performed with adapt ii. overall pta was calculated for - % ft>mic. weighting for the expected dis of rfx in the pop of interests was accomplished by using the dis of crcl observed in previous registration studies of the same indications (cssti and np). dis of mics for pathogens was supplied by sponsor. results: in the pop pk analysis, the pop mean (sd) values for volume, clslope, clintercept, kcp and kpc were: . ( . ) l, . ( . ) l/hr, . ( . ), . ( . ) hr- and . ( . ) hr- , respectively. the obs-pred plot was obs = . x pred + . ; r = . after the bayesian step. in the mcs analysis of bpr mg iv q h, the pta of achieving % ft>mic & % ft>mic exceeded % for mics values £ mg/l & £ . mg/l, respectively. for bpr mg iv q h, the pta of achieving % ft>mic exceeded % for mics values £ mg/l. in the organism-specific analysis, the pta of a static effect ( % ft>mic) exceeded % for both mssa & mrsa for bpr mg iv q h. bpr mg iv q h provided a > % pta of a cidal effect ( % ft>mic) for both mssa & mrsa. for gnb, the pta of bpr mg iv q h in achieving a cidal effect ( % ft>mic) exceeded % for non-ampc-bearing gnb. for ampc-bearing gnb, the pta of achieving a cidal effect was . %. conclusions: an extensive evaluation of the pd of bpr was performed to estimate the overall activity of bpr against target pathogens. these findings need to be validated in the clinical trial arena. investigation of different levofloxacin regimens in patients with acute complicated urinary tract infections p. tenke, r. benko (budapest, szeged, hu) objective: in the present study we aimed to find out if a continuous or an intermittent levofloxacin ( · mg) treatment is more advantageous for patients with acute complicated urinary tract infection (uti) caused by urinary obstruction. we investigated if levofloxacin adsorbs to the surface of the foreign body, which was inserted with the aim of temporary resolution of ureteral obstruction. preventive effect of levofloxacin on bacterial biofilm formation and incrustation was also evaluated. methods: we enrolled and randomised patients who had acute uti caused by urinary obstruction. obstruction was resolved with double j stent (djs) insertion or percutaneous nephrostomy (pcn) and meanwhile, antibiotic treatment was started in all patients. patients (group ) were on antibiotics till the day of definitive curative operation when all foreign bodies were removed. in the other % of the patients (group ) the antibiotic therapy was stopped days after the djs or pcn insertion. short term antibiotic course -which is advisable for prevention of uti before invasive endoscopic treatmentwas administered in both groups from the day of the operation (after djs or pcn removal) and it was continued until the removal of all possible urinary foreign bodies used during the operation. in both groups of patients we recorded and evaluated early and late clinical and microbiological recovery. retrieved stents were sectioned for further laboratory examinations. adsorbed levofloxacin in the conditioning film layer and on the stent surface was detected by hplc. rasterelectron microscopy (rem) was used to examine biofilm formation and encrustation. results: we did not find any significant differences between the two groups of patients, neither in clinical (presence of fever, back pain, flank pain, leukocyte count) nor in microbiological recovery. statistical analysis showed that significantly greater amount of levofloxacin adsorbed to the conditioning film than to the stent surface in both groups of patients ( . ± . vs. . ± . in group and . ± . vs. . ± . in group ). no viable, adherent bacteria were recovered by sonication and culture in any of the patients, and no biofilms or encrustation were seen under rem either. conclusion: our data prove the hypotheses that continuous antibiotic treatment does not have any clinical or microbiological advantages in patients with indwelling ureteral stents compared to intermittent therapy. objective: the prophylaxis of bacterial infections during cardiac surgery is widely used in clinical practice. staphylococcus aureus, staphylococcus epidermidis and enterococcus spp are the pathogens most frequently involved in infective complications of cardio-pulmonary bypass (cpb) surgery. it is generally agreed that the success of prophylaxis is dependent on the ability to reach and maintain free antibiotic concentration in tissues higher than the mics for the most common pathogens. so we estimated the tissue concentrations of linezolid into sternal bone of patients undergoing cpb surgery. methods: six patients undergoing routine cpb surgery were given mg linezolid as a min iv infusion along with conventional prophylaxis of . g of cefuroxime immediately before surgery. two hours after the end of infusion blood samples and sternal bone tissues were collected. the local medical research ethics committee approved this study and all patients gave written informed consent. samples were assayed for the presence of linezolid by a high-performance liquid chromatography (hplc) method. results: following a mg infusion of linezolid, mean serum concentration for the six patients were . mg/l (range . - . mg/l) hours after the end of infusion. the concentration of linezolid into sternal bone was . mg/l (range . - . mg/ l) hours after the end of infusion. the penetration of linezolid into sternal bone was . %. conclusion: the penetration of linezolid into bone was . % of the simultaneous blood levels. in all bone samples the concentration of linezolid exceeded the mic for susceptible pathogens (< mg/l). although these data have been obtained from healthy, well-perfused bone the values suggest that linezolid may be a useful agent in the management of multidrug-resistant gram-positive bone infections. the antibacterial effect of daptomycin, teicoplanin and vancomycin against s. aureus studied in an in vitro pharmacokinetic model of infection a. noel, k. bowker, a. macgowan (bristol, uk) objectives: daptomycin (dap) is the first cyclic lipopeptide antibiotic approved for parenteral use in gram-positive infection. as yet, no comparative pharmacodynamic studies have been performed using dap and the two most common iv therapies teicoplanin (tei) and vancomycin (van). we used a pharmacokinetic (pk) model to study the antibacterial effect (abe) of these agents against two typical mrsa strains (ukemrsa & ) and a hetero vancomycin intermediate mrsa (hvisa). methods: an in vitro dilutional model was used to simulate the free drug concentration over h associated with doses of -dap mg/kg hrly (cmax . mg/l, t / h); tei mg hrly (cmax . mg/l, t / h); van g hrly (cmax . mg/l, t / h). an inoculum of cfu/ml was used and the experiments performed in triplicate. abe was assessed by area-under-the-bacterial-kill-curve - h (aubkc ) and logcfu/ml.h objectives: linezolid, the first oxazolidinone, is active against methicillin resistant staphylococcus aureus and has been effective in a variety of acute infections. however long-term administration, although desirable in bone infections caused by resistant gram-positive organisms, is hampered by the occurrence of anaemia and thrombocytopenia. administration of vitamin b has been reported to prevent myelosuppression. methods: patients attending the infectious disease clinic with bone infections caused by resistant gram-positive bacteria and treated with linezolid ( mg b.d. orally), received vitamin b ( mg o.d. orally) for the period of administration of linezolid. full blood counts were followed-up weekly. linezolid treatment was discontinued if haemoglobin declined below mg/dl or platelets below /ll. data from sixteen patients with osteomyelitis and with prosthetic joint infections were evaluated. comparisons were performed with matched historical controls receiving linezolid without b by kaplan-meyer curves with the log-rank test. results: the median follow-up of patients receiving b was . weeks and of controls weeks. in the b group % of the patients discontinued while in the control group % of the patients discontinued treatment because of side effects (p ns). % of patients receiving b discontinued due to thrombocytopenia and % due to anaemia. respective percentages in the control group were % and % (p ns for all comparisons). mean time to the occurrence of thrombocytopenia was weeks in the patients who received b and . weeks in the control patients. respective times to occurrence of anaemia were . and . weeks. all cases of myelosuppression were reversible. conclusions: administration of b failed to prevent or delay both thrombocytopenia and anaemia in patients receiving linezolid. other methods should be investigated to facilitate longer administration of linezolid in this group of patients. therapeutic drug monitoring of colistin -a -year review from a uk clinical antibiotic assay service k. bowker, a. noel, s. tomaselli, a. macgowan (bristol, uk) objectives: over the last years there has been increased use of colistin (col). however, little clinical data is available on the therapeutic levels of colistin. monitoring of col is useful in terms of therapeutic levels and avoidance of toxicity for patients with cystic fibrosis and complicated gram-negative infections. previous in vitro data has shown that col is bactericidal at col concentration is ‡ mg/l. here we assessed col data collected from our antibiotic assay service from the last seven years in order to establish if such levels were obtained. methods: col levels were determined by bioassay. data was retrospectively collected from the hospital information management system. data was assessed collectively and stratified by known cystic fibrosis patients, sex and age. objectives: ßlactams like ceftriaxone (cfx) and quinolones such as moxifloxacin (mox) are widely used to treat pneumococcal infection. we studied the antibacterial effect of (abe) after the first dose exposure to free drug serum concentrations of iv cfx g and po mox mg against s. pneumoniae strains with typical mics at low and high inocula. methods: a hollow fibre in vitro model was used to simulate free drug concentrations over h of cfx ( g h iv, cmax mg/l, auc mg/laeh, t / h) and mox ( mg, po, cmax . mg/l, auc mg/laeh, t / . h). the cfx mic was . mg/l (t>mic cfx %) and mox mic . mg/l (auc/ mic ). initial abe was measured by the slope of the log viable count - h and total abe over the dose interval ( h) by log reduction in viable count at h (d ) and the area-underthe-bacterial-kill-curve (aubkc ). inocula of cfu/ml and cfu/ml were used. results: the initial and total abe at low and high inocula were: given the pk/pd indices modelled both drugs showed a maximal effect. clearance from the model occurred at h ( inoculum) and h ( inoculum). there were no significant differences in speed or extent of abes comparing cfx and mox. conclusion: the abes of iv cfx and po mox against s. pneumoniae is similar in the first hrs of drug exposure. emergence of resistance in e. coli and ent. cloacae after exposure to ceftriaxone or ertapenem in an in vitro model of infection k. bowker, a. noel, a. macgowan (bristol, uk) objectives: emergence of resistance (eor) is an emergent factor in therapeutic choice. we studied eor to ceftriaxone (cfx) and ertapenem (ert) in e. coli (ec) and ent. cloacae (entclo), a more challenging species within inducible blactamases. methods: an in vitro dilutional model was used to simulate free drug concentrations associated with g hrly cfx (cmax mg/l, t½ h) and ert (cmax mg/l, t½ h) over h. two inocula and cfu/ml were used and eor assessed by population-analysis-profiles (pap). the area under the pap (auc-pap) was used to measure eor. ert mics were . mg/l ec and . mg/l entclo, cfx mic . mg/l ec and . mg/l entclo. experiments were performed in triplicate and mean values presented. results: observations at h were similar to those at h, hence data to h is given. at and cfu/ml, ec viable counts were reduced by fi logs, there was no eor. against entclo inoculum and , cfx resulted in an initial - log drop, then regrowth, ert produced a > log reduction. eor as measured by the mean auc-pap (n = ) with entclo is shown below: dosing with cfx resulted in eor to cfx and ert at high and low inoculum. dosing with ert resulted in no eor at inoculum, at resistance emerged to both cfx and ert. conclusions: eor depends on species (entclo > ec); duration of exposure (long > short) and agent (cfx > ert). ert appears to induce less eor both to itself and cfx than cfx does to itself and ert. however, initial use of cfx may reduce the effectiveness of ert. comparative serum activity of telithromycin, azithromycin, and amoxicillin/clavulanate against aerobic and anaerobic respiratory pathogens objectives: the purpose of this investigation was to study the clinical potential of telithromycin, a new ketolide antibiotic, for the treatment of mixed aerobic/anaerobic respiratory infections. in this study, we compared the pharmacodynamics (duration of inhibition/killing) of telithromycin (tel) to azithromycin (azi) and amoxicillin/clavulanate (a/c) against aerobic and anaerobic pathogens associated with mixed respiratory infections. methods: following written informed consent, ten healthy adult subjects (ages, - yrs) received single doses of tel ( mg), azi ( mg), and a/c ( mg) one week apart following a -h fast. venous blood samples were obtained at , , , and h after the dose and stored at ) °c. inhibitory and bactericidal titre s were determined by microdilution (s. pneumoniae & h. influenzae) and agar dilution (peptostrep. magnus, peptostrep. micros, prev. bivia, & prev. melaninogenica) procedures following clinical & laboratory standards institute methodology. bactericidal titres in serum endpoint was determined as the highest dilution of serum yielding . % killing. the median titres at each time point were calculated and the duration of activity was used for comparison of these agents. conclusions: in this ex-vivo study, we found that tel can provide prolonged ( % of the dosing interval) inhibitory activity in serum against macrolide-resistant strains of s. pneumoniae, bl pos. and neg. strains of h. influenzae, and common respiratory anaerobic pathogens. these findings suggest that tel could have clinical utility in the treatment of community-acquired mixed aerobic-anaerobic respiratory tract infections, including sinusitis, bronchitis, and pneumonia. objectives: increasing resistance in isolates of e. coli ( %) and p. aeruginosa ( %) to fluoroquinolones (fq) is a concern since these antibiotics are commonly used in the treatment of complicated urinary tract infections (utis). currently, no interpretive standards exist for ''susceptible'' isolates in urine for the newer fq. the purpose of this investigation was to evaluate the activity of high-dose levofloxacin against fqresistant urinary pathogens. methods: in this study, we determined the serum and urine levels of high dose ( mg) levofloxacin (l) as well as its bactericidal activity in urine (uba) against l-resistant isolates of e. coli (mics = to lg/ml) and p. aeruginosa (mics = to lg/ml). following written informed consent, blood and urine samples were collected from healthy adult (ages, - y/o) fasting subjects ( m and f) prior to and at . , , , , and hours after a single mg dose of l. serum and urine concentrations were measured by a validated hplc assay ( . - . % cv). the testing methodology for uba was similar to the microdilution assay used for serum bactericidal testing (clsi) with the exception that antibiotic-free urine was used to dilute these samples. the median titre ( : - : ) at each time point for the subjects was used to determine uba. results: the mean serum pharmacokinetic parameters were similar to previously published values: cmax = . lg/ml, auc = mgaeh/l, and t / = . h. mean urine concentrations ranged from lg/ml ( h) to lg/ml ( h). uba (titres > : ) was maintained for at least hours in all subjects for e. coli isolates with mics = , , and lg/ ml. for the e. coli strain with a mic = lg/ml, subjects exhibited uba at h but only subjects exhibited uba at h. similar results were observed against the p. aeruginosa isolates. conclusions: the results from this ex-vivo pharmacodynamic study in healthy volunteers found that mg of l provides prolonged (at least half the dosing interval) uba against l-resistant strains of e. coli and p. aeruginosa up to lg/ml. this suggests that a separate urinary susceptibility breakpoint is indicated for urine isolates treated with mg doses of l. objectives: exposure of methicillin-resistant s. aureus (mrsa) to acid ph restores its susceptibility to beta-lactams (sabath and al., aac, ) . in macrophages, s. aureus is mainly confined within phagolysosomes where the ph is acidic. we showed that meropenem (mem) displays similar intracellular activity against mrsa atcc and mssa atcc in macrophages. in the present study, we have investigated the intraphagocytic activity of mem and cloxacillin (clx) against mrsa clinical isolates (including one visa strain), in comparison with the reference mrsa atcc and mssa atcc strains. methods: mic's were determined in mhb (plus nacl %) by micro-dilution method. meca expression was examined at neutral and acidic ph by a semi-quantitative rt-pcr ( s rrna as housekeeping gene). intracellular activity was assessed in human thp- macrophages exposed to extracellular concentrations equivalent to human cmax (total drug; mem: mg/l; clx: mg/l) by examining the decrease in cellassociated cfu after h from the original, post-phagocytosis inoculum (controls [no antibiotic]; approx. log cfu increase). results: the table shows the mics (in broth) at neutral and acid ph and the intracellular activity for the strains studied. in atcc , meca expression was similar for bacteria maintained in broth at ph . conclusions: the intracellular environment markedly enhances the activity of beta-lactams against mrsa, probably through exposure to acid ph, although the latter does not affect meca expression. comparative activity of dalbavancin against european gram-positive isolates i. morrissey, c. dencer, j.w.t. dallow, j. childers, a. brook, j. cowan (london, uk) objectives: dalbavancin (dal) is a new semisynthetic lipoglycopeptide with a half-life of . days, enabling onceweekly dosing. this study compared the activity of dal with other agents against gram-positive isolates from europe. methods: isolates from belgium, the czech republic, denmark, finland, france, germany, hungary, italy, the netherlands, poland, spain, sweden and the uk were included. the clsi broth microdilution method was used to determine mic using dried microtitre plates. the following antimicrobial agents were evaluated: dal, vancomycin (van), teicoplanin (tei), daptomycin (dap), linezolid (lzd), dalfopristin/quinupristin (syn), erythromycin (ery), levofloxacin (lev) and tetracycline (tet). results: selected data are shown in the objectives: dalbavancin (dal) is a next generation lipoglycopeptide antibiotic in development for the treatment of complicated skin and skin structure infections (csssi). a population pharmacokinetic (pk) analysis was performed to estimate patient parameters and to determine significant covariates. incorporating the pk model, pharmacodynamic (pd) parameters were simulated to support the effectiveness of a weekly dosage. methods: the pk analysis included dal concentrations from patients across clinical trials. most patients received mg on day and mg on day . possible covariates examined included demography and concomitant medications, including medications that are considered inhibitors, inducers, and substrates of cytochrome p enzymes. the pk-pd analysis employed monte carlo simulations of time-dependent and concentration-dependent parameters. distributions of mics were obtained directly from clinical studies, and were also simulated to explore the effect of higher mics. results: dal pk fit a -compartment model with interpatient variability (ipv) on all parameters. the typical value and ipv (cv%) of clearance (cl) was . l/h ( . %), influenced by body surface area (bsa) and creatinine clearance (clcr). volume of distribution (v ) was . l ( . %) and influenced by bsa. the inter-compartmental clearance and peripheral volume were . l/h and . l, respectively. free drug concentrations were simulated using a dal protein binding of %. for a weekly -dose regimen, free dal remained above mg/l for the majority (> %) of patients for more than days. using previously described area under the curve (auc)/mic targets for staphylococcus aureus, a proposed mic of at least . mg/l was associated with a greater than % probability of target attainment. conclusions: dal pk were predictable, demonstrating low ipv. bsa and clcr were the only sources of variability, but described less than % of the ipv. pd simulations support the use of dalbavancin in a weekly regimen. objectives: methicillin-resistant staphylococcus joint infection due to peri-operative contamination is a complication after arthroplasty. the objective of this study was to assess the distribution of radioactivity in bone and related structures using quantitative autoradiography after administration of [ c]dalbavancin in rabbits. methods: new zealand white male rabbits were given a single intravenous (iv) bolus dose of mg/kg [ c]-dalbavancin (n = ) or control vehicle (n = ). plasma, cerebrospinal fluid (csf), bone, bone marrow, and nucleus pulposus were collected at , , , , and h post-dose by necropsy, homogenized, combusted, and analysed for total drug-derived radioactivity using liquid scintillation counting (lsc). in addition, the left hindlimb from rabbit/time point was flash-frozen and cryosectioned for quantitative autoradioluminography. results: [ c]-dalbavancin-derived radioactivity was rapidly and widely distributed into bone, bone marrow and, to a lesser extent, in csf and nucleus pulposus. autoradioluminography data indicated that concentration of radioactivity was highest in bone marrow, whole blood, articulate cartilage, ligament, epiphyseal plate, periostium, and meniscus. at h postdose, [ c]-dalbavancin-derived radioactivity was measurable in all tissues, and remained at relatively high concentrations in bone marrow ( . lg equiv/g), epiphyseal plate ( . lg equiv/g), periostium ( . lg equiv/g), and articular cartilage ( . lg equiv/g). in homogenized bone using lsc, mean concentration after hours was . lg equiv/g. conclusion: [ c]-dalbavancin-derived radioactivity rapidly penetrated knee joint tissues and persisted at relatively high concentrations for at least h after a single iv dose in rabbits. objectives: telavancin (tlv), a bactericidal lipoglycopeptide with multiple mechanisms of action, is in phase trials for the treatment of hospital-acquired pneumonia (hap) with a focus on infections due to methicillin-resistant s. aureus. tlv is primarily eliminated by the kidneys and requires dosage adjustment for renal dysfunction. tlv is highly protein bound ( %) in healthy subjects which would suggest that it would not be removed by dialysis, but its small volume of distribution ( . l/kg) means that it may be removed by cvvh. cvvh is widely used in the management of critically ill patients. the objective of this study was to determine cvvh telavancin transmembrane clearance (cl) with commonly used hemofilters (an , polysulfone) at conventional ultrafiltrate flow rates. methods: tlv cl was assessed in our in vitro cvvh model using citrate anticoagulated bovine blood and b. braun diapact machine. experiments were run using an (m , gambro) and polysulfone (f nr, fresenius) hemofilters. ultrafiltrate (uf) flows were , , and l/hr with sufficient blood flows [(qb) - ml/min] to maintain uf rates. blood samples were collected from the pre-filter line and uf samples from the post-filter uf port. concentrations of tlv in plasma and uf samples were assayed using validated lc-ms/ms methods. tlv cl was determined using the following formula:cl = (uf flow rate) [tlv]uf/[tlv]arterial. cl differences between the filter types were compared using a two-tailed, unpaired t-test. conclusion: tlv is substantially cleared by cvvh and cl increases significantly with increasing uf rate. cl did not differ by hemofilter type. cvvh cl at higher uf flows exceeds the total cl reported in patients with normal renal function. tlv likely will require dose adjustments in patients receiving cvvh. objectives: telavancin (tlv), a bactericidal lipoglycopeptide with multiple mechanisms of action, is in phase trials for the treatment of hospital-acquired pneumonia (hap) with a focus on infections due to methicillin-resistant s. aureus. tlv is primarily eliminated by the kidneys and requires dosage adjustment for renal dysfunction. tlv is highly protein bound ( %) in healthy subjects which would suggest that it would not be removed by dialysis, but its small volume of distribution ( . l/kg) means that it may be removed by cvvhd. cvvhd is used in the management of critically ill patients. the objective of this study was to determine cvvhd tlv transmembrane clearance (cl) with commonly used hemodialyzers at conventional cvvhd dialysate flow rates. methods: tlv cl was assessed in our in vitro cvvhd model using citrate anticoagulated bovine blood and b. braun diapact machine. experiments were run times using an (m , gambro) and polysulfone (f nr, fresenius) hemodialyzers. dialysate flows were , , and l/hr with sufficient blood flows [(qb) - ml/min] to maintain appropriate transmembrane pressures. blood samples were collected from the pre-filter port (a) and post-filter port (v), and spent dialysate samples (d) from the post-filter d port. plasma tlv concentrations (arterial and venous) and dialysate samples were assayed using validated lc-ms/ms methods and tlv cl was determined using the following formula: cl = (d flow rate) [tlv]d/(([tlv]arterial+[tlv]venous)/ ). dialytic cl between filter types was compared using a two-tailed, unpaired t-test. conclusion: tlv is effectively cleared by cvvhd. the higher permeability polysulfone dialyzer was associated with significantly increased cl vs. the an dialyzer as dialysate flow increased. the degree of tlv cl seen with cvvhd suggests that dose adjustments will be necessary in patients receiving cvvhd. objective: it is still a subject of controversy that only free, unbound drug is responsible for antibacterial activity of antibiotics. to provide further proof, that only free drug contributes to antimicrobial efficacy a comparative, doseranging time-kill curve study was performed. to exclude influence factors resulting from different mechanisms of action this was done within the antibiotic class of carbapenems, using compounds with different serum protein binding. methods: constant concentration time-kill curves were performed in % serum for the slightly serum protein bound mer-openem (~ %) and imipenem ( %) as well as for the highly serum protein bound ertapenem ( %) and faro-penem ( - %), ranging from · mic to · mic. the change in number of bacteria (cfu/ml) versus time was linked to their effect. escherichia coli atcc , klebsiella pneumoniae bay , staphylococcus aureus bay and streptococcus pneumoniae atcc were used as the test organisms. samples were taken at , . , , , and hours. the data were modelled simultaneously using the software scientist Ò for windows tm and a modified sigmoid emax model characterized by growth rate constant (k ), maximum kill rate (kmax), and concentration at half maximum effect (ec ). results: for all four bacterial strains investigated, there were dramatic increases ( - %) in ec for the highly se-rum protein bound carbapenems (ertapenem, faropenem) in the presence of serum proteins (fig. ) . for both substances no significant differences in k and kmax were determined. in contrast, imipenem and meropenem showed only minor differences in ec in the presence and the absence of % serum. conclusion: only free, unbound drug is responsible for the antimicrobial activity. analysis of these time-kill curves clearly showed that the antibacterial efficacy was significantly decreased in the presence of % serum for the highly bound ertapenem and faropenem while being unaltered for the slightly bound meropenem and imipenem. objective: numerous in vitro experiments have shown that protein binding (pb) is an important factor for antimicrobial activity, especially for highly bound antibiotics. however, the experimental conditions that simulate the in vivo situation best are still subject of controversy. therefore, an in vitro microdialysis experiment was performed that evaluates various influence factors on the pb of the highly bound betalactams ceftriaxone (pb - %). methods: a comparative, dose-ranging in vitro microdialysis study was conducted to determine free, unbound ceftriaxone concentrations in lactated ringer's solution and todd hewitt broth (thb) both with and without bovine serum albumin (bsa; sigma, st. louis) g/l and human plasma at °c. furthermore, in vitro constant concentration time-kill curves were performed, using escherichia coli atcc , streptococcus pneumoniae atcc and streptococcus pneumoniae atcc as the test organisms. the data was analysed using an appropriate pk/pd model, characterized by growth rate constant (k ), maximum kill rate (kmax), and concentration at half maximum effect (ec ) and correlated to free ceftriaxone thb concentrations determined by hplc-uv. results: there were only minor differences in both unbound drug concentrations and anti-infective activity when bsa g/ l was added to either lactated ringer's (pb % and . ± . %, with and without bsa respectively) or thb (pb % and . ± . %, with and without bsa respectively). no significant changes in k , kmax and ec were observed. however, using human plasma, unbound concentrations (pb %) %) were altered dramati-cally. conclusion: only free, unbound drug is responsible for the antimicrobial activity. however, one cannot rely on that binding to commercially purchased bsa is consistent with reported protein binding values. unbound concentrations should be measured under the respective experimental conditions to be able to correctly interpret the experimental results. in vitro postantibiotic effect of faropenem on penicillin-resistant streptococcus pneumoniae and beta-lactamase-producing haemophilus influenzae c.l. young, i.a. critchley, u.a. ochsner, n. janjic (louisville, us) objectives: faropenem (far) is an oral penem with potent activity against respiratory pathogens such as penicillin (pn)resistant streptococcus pneumoniae (sp) and beta-lactamase (bla)-producing haemophilus infleunzae (hi). the postantibiotic effect (pae) is a pharmacodynamic (pd) parameter that monitors suppression of bacterial growth following short exposure and removal of the drug. paes are clinically important for agents such as far with short half-lives ( h) . the aim of the study was to determine the pae of far on resistant phenotypes of sp and hi. methods: nine clinical isolates of sp, pn-s, pn-i, and pn-r and six clinical isolates of hi, bla-negative and blapositive were tested in pae studies. paes were determined in cation-adjusted mueller-hinton broth with - % lysed horse blood for sp and haemophilus test medium for hi. exponential cultures ( cfu/ml) were exposed to far at , and x mic. far was removed by serial washing ( , -fold dilution) prior to transfer to fresh media. control cultures were treated in the same way. bacteria were incubated with shaking and viable cfus determined at , , , , and h. counts of log cfu were plotted against time and pae defined as the difference is the time required for count in test culture and control (untreated culture) to increase log above the count observed immediately after removal. results: significant paes of > . h were observed for all strains of sp at and x mic. however, the pae was more prolonged on the pn-r strains with mean paes of . h at and x mic. among hi, little or no pae was observed on bla-negative strains but a significant pae was observed on the bla-positive isolates (mean paes of . h and . h at and x mic respectively). conclusions: far demonstrates a prolonged pae on key resistant phenotypes of sp (pn-r) and hi (bla-positive) compared with susceptible strains. the observation of pae in bla-positive hi is unique in the class of beta-lactams. far exhibits in vitro pd properties that may contribute to its clinical efficacy against pn-r sp and bla-positive hi. telavancin is more efficacious than vancomycin in a murine model of bacteraemic peritonitis induced by methicillin-resistant staphylococcus aureus s. hegde, n. reyes, b. benton, r. skinner (south san francisco, us) objective: telavancin (tlv) is a novel lipoglycopeptide that operates through multiple mechanisms to produce potent and rapid bactericidal activity against clinically relevant grampositive bacteria including methicillin-resistant staphylococcus aureus (mrsa). the present studies evaluated the in vivo efficacy of tlv vs vancomycin (van) in a model of mrsa induced peritonitis in neutropenic mice. methods: female nsa immunocompromised mice were inoculated intraperitoneally with atcc mrsa and treated, beginning at h post-infection, with subcutaneous doses (q h) of vehicle (veh) or test compound. mouse pharmacokinetic data were generated and used to choose doses of tlv ( mg/kg) and van ( mg/kg) in order to equate clinical exposures (auc's (free drug) of and lg.hr/ml, respectively). in survival studies, deaths were recorded for days post-infection and survival curves were compared using log-rank test. in bacterial titer determination studies, designated groups of control and drug-treated surviving animals were humanely euthanized at various times post-treatment and their blood and spleen were harvested to determine bacterial titers. results: mics of tlv and van were . and . lg/ml, respectively. mortality was % in animals treated with veh or van. mortality was % in tlv-treated animals (p < . vs veh and van). the pre-treatment bacterial titres were . log cfu/ml and . log cfu/g in the blood and spleen, respectively. analysis of the time kill curves for both blood and spleen revealed that tlv exhibited significantly greater killing activity than van (p < . , two-way anova). at hrs after the first dose, the titers in the blood were reduced to a greater extent by tlv () . log cfu/ml) compared to van () . log cfu/ml). at hrs after the second dose, the splenic titers were reduced to a greater extent by tlv () . log cfu/g) when compared to van () . log cfu/g). conclusions: the data described here demonstrate that tlv's in vivo bactericidal activity is superior to that of van against mrsa and results in successful infection resolution and, consequently, improved survival in the murine peritonitis model. proper use of carbapenems for blood-derived clinical isolates of pseudomonas aeruginosa y. kobayashi (tokyo, jp) methods: regimens of carbapenems were given to healthy adult subjects. changes in their blood concentrations of carbapenems were compared by using pharmacokinetic parameters (two-compartment model analysis) of meropenem (mepm), imipenem (ipm), and panipenem (papm) and by applying the lognormal distribution to the probability distribution of distribution volume and plasma half-life with monte carlo simulation (mcs). based on the data on distributions of the minimal inhibitory concentrations (mic) of various carbapenems for blood-derived clinical isolates of pseudomonas aeruginosa isolated/identified at keio university hospital between october and october (mic : mepm mcg/ml, ipm mcg/ml, papm mcg/ml), the mics in the subjects were obtained with mcs. from the changes in blood concentrations and mics in the subjects, the probability of achieving t>mic was calculated for each carbapenem regimen, using the formula reported by kuti et al.: %t>mic = ln (dose/vd*mic)*(t / / . )*( /di) <<ln: natural logarithm, dose: dose (mg), vd: distribution volume (l), t / : plasma half-life (h), di: dosing interval (h)>>. based on craig's data, the maximum bactericidal effect on gram negative bacilli is attained when %t>mic is approximately %. we focused on this information and analysed our data. results: the probability of achieving t>mic % was . % for mepm mg bid, followed by . % for ipm mg bid and . % for papm mg bid. when the dose was increased from mg to mg, it was . % for mepm mg bid, followed by . % for ipm mg bid and . % for papm mg bid. when the dose remained at mg and the dosing frequency was increased to three times daily, it was . % for mepm mg tid, followed by . % for ipm mg tid and . % for papm mg tid. regarding mepm, it was . % for mg gid? and . % for mg tid showing higher probabilities. discussion: in severe sepsis caused by pseudomonas aeruginosa, remarkably higher t>mic % was achieved with carbapenems at mg tid, although the daily dose ( mg) was lower, compared to mg bid. carbapenems with a low mic distribution, i.e. a superior antibacterial activity, showed higher probability of achieving t>mic. therefore, the optimal treatment for such sepsis is mepm mg tid. mepm mg qid appeared to provide comparable therapeutic effects with those at mg tid, the usual dose in foreign countries. penetration of moxifloxacin into normal and infected subcutaneous tissue in patients with spinal cord injury measured by microdialysis background: skin breakdowns, also termed decubitus ulcers or pressure sores, are a major complication associated with spinal cord injury, resulting in infection and tissue death. moxifloxacin (mfx) is approved for the treatment of sssi. our objective was to construct a population pk model for mfx disposition in plasma, normal and infected subcutaneous tissue in spinal cord injured patients with infected decubitus ulcer. methods: patients receiving mg mfx orally daily were enrolled in this study. blood, saliva and interstitial tissue fluid samples (microdialysis in normal and infected tissue) were collected over a time period of hrs. mfx concentrations were measured by a validated hplc. concentration-time data obtained in the present study were pooled with previously published mfx data (n = ). population pk modelling was performed with nonmem. results: the concentrations of mfx achieved in plasma, saliva, normal subcutaneous tissues and infected decubitus ulcers showed parallel profiles versus time. the pk was best described by a -compartment model with a link to interstitial tissue fluid. the population pk parameters were as follows (given as estimate with percent interindividual variability in parentheses): cl . l/h ( %); central vd . l ( %); intercompartmental cl . l/h ( %); peripheral vd . l ( %); and elimination rate constant for interstitial tissue fluid . h) ( %). with a conservative mic of . mg/l, the peak/mic ratios were higher than and the auc /mic ratios were higher than for plasma, saliva and interstitial tissue fluids. conclusions: this study showed the good diffusion of mfx into subcutaneous tissue in spinal cord injured patients with decubitus ulcers. the interstitial tissue fluids reached bactericidal levels for common bacteria found in infected skin lesions. objective: investigations of pharmacodynamic parameters such as postantibiotic effect and postantibiotic subminimum inhibitory concentration effect have been employed for design of dosing schedules of antimicrobial agents. in this study we compared postantibiotic effect and postantibiotic subminimum inhibitory concentration effect of ciprofloxacin, levofloxacin, and moxifloxacin for clinical isolates of methicillin susceptible staphylococcus aureus, methicillin resistant staphylococcus aureus and pseudomonas aureginosa. methods: the following strains were tested in this study: methicilline-susceptible staphylococcus aureus (n: ), methicilline resistant -staphylococcus aureus (n: ) and pseudomonas aeruginosa (n: ). the pae was determined by viable plate count method using mueller hinton broth. tubes containing ml of broth and the antibiotic to be tested at , , and x the mic were inoculated with approximately · cfu/ml. growth controls with an inoculum but not antibiotic were included with each experiment. result: postantibiotic effects of ciprofloxacin, levofloxacin and moxifloxacin increased with increasing concentration of the drug. the longest postantibiotic effect was observed for moxifloxacin. moxifloxacin showed no postantibiotic effect one p. aureginosa at all concentration and had no post antibiotic effect to another p. aureginosa at x mic and mic. in our study the longest postantibiotic subminimum inhibitory concentration effect against mssa was determined with moxifloxacin. similarly the moxifloxacin induced the longest effect against mrsa. however, this time frame was shorter than that of mssa. conclusions: all three antibiotics, showed for longer postantibiotic subminimum inhibitory concentration effect in all submic concentrations, immeasurable within the study period i.e. hours. lack of horizontal transmission of fluoroquinolone resistance between s. mitis and s. pneumoniae objectives: fluoroquinolone (fq) resistance can arise in s. pneumoniae through acquisition of dna from s. mitis and subsequent homologous recombination. the frequency at which this occurs is unknown, and while likely a rare event, increases in fq resistance among s. mitis may increase the rate at which horizontal transmission occurs. we sought to determine the frequency at which fq resistance could be transferred from s. mitis to s. pneumoniae or from s. pneumoniae to s. mitis. methods: s. mitis (either fq^r,tetracycline[tet^s], fq^r,penicillin[pen^s], or fq^s,pen^r) and s. pneumoniae (either fq^s,tet^r, fq^s,pen^r or fq^r,pen^s) were grown in co-culture using a pharmacodynamic model in the presence of either moxifloxacin (mxf) or levofloxacin (lfx) at salivary drug concentrations. after incubation, aliquots were plated onto either tet or pen containing sba plates to select for the recipient strains. fq susceptibility was performed using microbroth dilution. the entire parc and gyra genes were amplified and sequenced to determine if horizontal transmission occurred. results: in initial experiments tet was used as the selective agent. however tet resistance was transferred and therefore pen^r was used as a selective marker. an increase in the lfx mic in was observed in s. pneumoniae and s. mitis strain. sequencing of the parc gene revealed the selection of ser phe and ser tyr mutations in s. pneumoniae and ser phe in s. mitis consistent with fq resistance. sequencing of the entire gene failed to uncover evidence of horizontal transmission. no mutations were detected in gyra. selection of st step parc clinical microbiology and infection, volume , supplement , mutations occurred only after exposure to lfx. mxf eradicated both s. mitis and s. pneumoniae and failed to either select for resistance or support horizontal transmission. conclusions: although st step parc mutations were selected in strains ( s. pneumoniae, s. mitis), we failed to find evidence of horizontal transmission between s. pneumoniae and s. mitis under our laboratory conditions. the phenomenon of horizontal transfer resulting in fq resistance has been described, however, based on our results, we must speculate that it is an extremely rare event and not likely to be a major driver of fq resistance. of interest, the parc mutations were selected only under the selective pressure of lfx. mxf completely eradicated both s. pneumoniae and s. mitis and did not select for the development of fq^r mutations. objectives: the aim of the present study was to assess the killing activity of ertapenem (ert) and metronidazole (mtr) against four selected bacteroides fragilis strains with different mic values in an in vitro pharmacokinetic/pharmacodynamic (pk/pd) model. since anaerobes are often present in mixed infections, kill kinetics were also established for mixed inocula employing the b. fragilis strains together with four selected escherichia coli strains. the killing activity was analysed for kinetic concentrations of the antimicrobial agents simulating human serum kinetics. methods: a pk/pd in vitro model was established by adding appropriate amounts of broth every half hour. at the same time intervals samples were obtained and plated. after incubation colony forming units were counted. human serum concentrations were simulated with cmax = mg/l and t / of hours for ert and cmax = . mg/l and t / of hours for mtr. mann trend test was used for statistical analysis. results: as to be expected the e. coli strains were not killed by mtr both in pure as well as in mixed cultures whereas the susceptible e. coli strains were effectively killed by ert. in pure cultures the b. fragilis strains were effectively killed by mtr and the growth of the susceptible b. fragilis strains was reduced by ert by about two to four logs. however, in some mixed cultures the killing activity of mtr against the b. fragilis strains was significantly reduced. conclusion: the in part moderate in vitro activity of ert against the b. fragilis strains and the reduced activity of metronidazole in mixed cultures against the b. fragilis strains may explain some of the difficulties in treating mixed aerobic/ anaerobic infections. penetration of ciprofloxacin into human cerebrospinal fluid and brain tissue a. tsona, s. metallidis, e. koumentaki, j. nikolaidis, p. kollaras, g. lazaraki, p. nikolaidis (thessaloniki, gr) objectives: the aim of the present study was to determine the penetration of ciprofloxacin into cerebrospinal fluid (csf) and brain tissue of humans. methods: a total of patients undergoing brain tumor excision were evaluated. the patients received a single intravenous dose of mg ciprofloxacin. samples of blood, cerebrospinal fluid and brain (brain-adjacent tumour tissue) were collected during surgery h after drug administration. ciprofloxacin concentrations in serum, cerebrospinal fluid and brain homogenate were analysed by means of a validated hplc method. results: ciprofloxacin concentrations in plasma (mcg/ml), cerebrospinal fluid (mcg/ml) and tissue homogenate (mcg/g), respectively, after h ranged . - . mcg/ml, . - . mcg/ ml and . - . mcg/g. csf-to-serum ratio ranged between . and . . tissue-to-serum ratio ranged between . and . . mean (±s.d.) csf/serum concentration ratios and brain tissue/serum concentration ratios were respectively . ± . and . ± . . conclusion: these findings suggest that valuable informations on brain tissue penetration can be obtained only from brain material. data from csf penetration cannot be extrapolated to the brain since the blood: sf barrier differs from the blood:brain barrier. concentrations of ciprofloxacin in cerebrospinal fluid were lower than those in serum, in contrast to the brain tissue concentrations that exceeded serum concentrations. the achieved concentrations in brain tissue were generally above the mic of common pathogens in central nervous system infections (h. influenze, n. meningitidis, s. pneumoniae, l. monocytogenes, escherichia coli, aerobic gram-negative bacilli, group b streptococci, mssa). cerebrospinal fluid concentrations exceed the mics of neisseria meningitidis and most gram-negative aerobic bacilli. our findings suggests that ciprofloxacin may be an acceptable alternative for the treatment of meningitis due to susceptible gram-negative aerobic organisms and for the treatment of brain abscesses. objective: to model the performance of imipenem (imi), meropenem (mem), and ertapenem (etm) against esbl producing e. coli and klebsiella spp in order to identify possible pd differences among compounds. methods: minimal inhibitory concentrations (mics) were generated for randomly selected esbl producing isolates of ec (n = ) and kl (n = ) collected during from brazilian hospitals as part of the mystic program. mic testing for imi, mem, etm, ceftazidime (ctz), and cefotaxime (ctx) were done by e-test methodology. esbls were confirmed via ctz/clavulanate and ctx/clavulanate e-test. pd exposure, measured as percent time above the mic for free drug (ft>mic), was modelled via a subject monte carlo simulation for the following -minute infusions:imi gram every hours, mem gram every hours, and etm gram every hours, using pharmacokinetics from healthy volunteers. the bactericidal cumulative fraction of response (cfr) was calculated for each regimen against the populations of ec, kl, and against all esbl isolates together. bactericidal cfr was defined as % ft>mic for all agents. results are reported as cfr ( % confidence interval). results: isolates were % susceptible (s) to imi and mem (mic range . - . and . - mg/l, respectively), and % s to etm (mic range . - mg/l conclusions: these findings support other data that although etm is likely to be an effective empiric agent against most esbl producing ec and kl, its ability to achieve high bactericidal pd exposure will be dependent on the presence of less susceptible organisms in the population. imi and mem should remain first line for esbl infections. objectives: this study analyses eradication and resistance selection in streptococcus pneumoniae with moxifloxacin, levofloxacin and azithromycin, using a parental serotype infecting strain (a) and subsequent resistant step-mutants (isolates b, c and d) selected in vivo in a patient with pneumonia. methods: moxifloxacin, levofloxacin and azithromycin mics were , and . lg/ml for the parental strain, , , and lg/ ml for isolate b, and , and > lg/ml for isolates c and d, respectively. a pharmacokinetic computerized device was used to simulate serum and epithelial lining fluid (elf) concentrations. initial inocula was approx. cfu/ml. population analysis profiles were performed using plates with increasing antimicrobial concentrations on a mic basis. results: in serum, moxifloxacin eradicated the parental isolate (isolate a), with an auc - h/mic value of . . serum auc - h/mic values of . and . for levofloxacin and azithromycin, respectively, were not able to eradicate isolate a. in elf, moxifloxacin showed a bactericidal pattern against all isolates with a minority (approx. cfu/ml) of the survival population (isolates b, c and d) growing in plates with moxifloxacin concentrations higher than those obtained in elf. levofloxacin and azithromycin showed a bactericidal pattern only against isolate a, with the whole population of isolates b, c and d growing in plates with levofloxacin concentrations higher ( - lg/ml) than those obtained in elf, and in plates with azithromycin concentrations as high as lg/ml (for isolates c and d). in elf, moxifloxacin auc - h/mic values were . for isolate a, and . for isolates b, c and d. levofloxacin auc - h/mic values were . for isolate a, and . for isolates b, c and d. azithromycin auc - h/mic values were . for isolate a; . for isolate b; and for isolates c and d. conclusion: if prevention of resistance depends more on the eradication of possible emerging mutants in pulmonary tissues than of the parental susceptible strain, moxifloxacin concentrations in elf may provide advantages over previous quinolones and macrolides in preventing clinical failures. objectives: to explore how antimicrobial pressure influences the evolution of streptococcus pneumoniae populations sharing the same ecological niche. methods: an in vitro computerized pharmacodynamic model simulating physiological concentrations obtained over h after mg o.d levofloxacin, mg b.i.d ciprofloxacin, and mg o.d azithromycin was used to investigate its effect on a mixed culture of five s. pneumoniae serotypes (s) as an approach to ecology of population dynamics. resistance patterns were: s was susceptible to study drugs, s was low-level macrolideresistant (efflux phenotype), s was high-level macrolideresistant (erm genotype), s v was low-level quinoloneresistant, and s was high-level quinolone-resistant. initial mixed inocula (time ) included similar percentages of each serotype. results: mean colony counts in antibiotic-free plates (whole pneumococcal population) increased (from to h) from log . to . in drug-free simulations (control), from log . to . in levofloxacin simulations, from log . to . in ciprofloxacin simulations, and from log . to . in azithromycin simulations. at h of control drug-free experiments, dominant strains were s v ( . %) and s ( . %) with marginal populations of s , s and s . azithromycin selected in a much higher extent the strain with low-level resistance to macrolides (s ) than the strain with high-level resistance (s ) (accounting for . % vs. . % of total population at h). ciprofloxacin selected in a higher extent low-level (s v) than high-level (s ) quinolone resistance ( . % vs. . %). levofloxacin decreased the proportion of the predominant s v in controls to . % (an intermediateresistant strain with mic = lg/ml), and unmasked the highlevel resistant strain (mic = lg/ml) up to . %. conclusion: strain distribution in antibiotic-free environment depends on bacterial fitness in mono-and multi-strain niches. the selective pressure of antimicrobial regimens eradicate some populations and unmask minor populations, thus redistributing the whole population. selective potential only for resistance phenotypes with very low prevalence (as high-level quinolone resistance) in the community should be preferred to that selecting more prevalent resistance phenotypes. re-evaluation of the role of broad-spectrum cephalosporins against staphylococci applying contemporary in vitro results and pharmacokinetic-pharmacodynamic principals h. sader, s.m. bhavnani, p.g. ambrose, r. jones (north liberty, us) objectives: to re-evaluate the current in vitro activity and to assess the pk-pd target attainment of cefepime (cpm), ceftriaxone (cro) and ceftazidime (caz) against staphylococcus spp. methods: the potency of cpm, cro and caz against staphylococci was accessed through the sentry antimicrobial surveillance program database, worldwide. during the - period , s. aureus (sa; % oxacillin [oxa]-susceptible [s]) and , coagulase-negative staphylococci (cons; % oxa-s) were s tested against cpm, cro, caz and numerous comparators by clsi broth microdilution methods. using volunteer pk data and a linear intermittent intravenous infusion model, and an animal-derived pk-pd target of % time above mic, expected probabilities of target attainment (pta) for cephems were evaluated using monte carlo simulation. pta were determined for the following dosing regimens: cpm gm q and q hours, caz gm q hours and cro gm q hours, each representing the most common dosing patterns applied clinically. cephem susceptibility (%s) was calculated based on the current clsi ( ) breakpoints (bkps) and also on bkps derived from a pta > %. results: against oxa-s sa, mic / values were (in mg/l): / for cpm, / for cro and / for caz, respectively; and against oxa-s cons mic / values were (in mg/l) . / for cpm, / for cro, and / for caz, respectively. the calculated %s of these cephems are summarized in the table: twenty year-old clsi bkps would rank the tested agents cpm ‡ cro > caz and by pk-pd pta cpm ‡ caz > cro. cpm has a potency advantage over caz ( -to -fold) and superiority at the usual dosing over cro ( . - . %) for oxa-s staphylococci. caz pk overcomes by-weight activity disadvantages, while a low proportion (< %) of active freedrug penalizes cro in the pta calculations. pta remained at > % to a bkp of mg/l for cpm ( gm q ) and caz and to a bkp of mg/l for cro. conclusions: regardless of applied bkp (clsi or pk-pd), cpm has the widest and more potent anti-staphylococcal activity among commonly used ''third-or fourth-generation'' cephems. when used at doses ‡ gm/day, cpm assures maximal coverage of oxa-s staphylococci whether using existing (clsi) or modified (pk/pd) bkps. cro should be used with caution. methods: the mic for all strains were determined by serial two-fold macrodilutions. an in vitro kinetic model was used to investigate the antibacterial efficacy of constant drug concentrations during hours. the selection of the doses of azithromycin tested in each bacterial strains was based on their mic values. bacterial counts were determined on appropriate agar plates using an adapted drop-plate method. twelve different pk/pd models were fitted and compared to the time-kill data by using non-linear regression. results: a simple pk-pd model was not sufficient to describe the pharmacodynamic effects for the four bacterial strains. appropriate models that gave good curve fits included a saturation term for the number of bacteria (nmax), delay terms ( -e-zt) for the initial bacterial growth phase and/or the onset of anti-infective activity as well as a hill factor (h) to capture the steepness of the concentration-response relationship. azithromycin had high potency against s. pneumoniae strains and m. catarrhalis while the potency of azithromycin against h. influenzae was poor. conclusions: the developed pk/pd models are suitable for describing the pharmacodynamics of azithromycin. applications of these pk-pd models will eventually provide a tool for rational antibiotic dosing decisions. objectives: optimal antimicrobial dosage regimens aim to achieve successful clinical outcomes without drug toxicity or emergence of bacterial resistance. for concentration dependent antibiotics, such as the fluoroquinolones, in humans a cmax:mic ratio of > is considered more important for efficacy and reduced selection of resistance than prolonged antibiotic concentrations just above the mic. fluoroquinolone resistance in zoonotic bacteria is a matter of public health concern, and fluoroquinolone treatment of poultry can rapidly select for bacteria with reduced fluoroquinolone susceptibility. in this study we compared basic pharmacokinetic parameters for the recommended dose of baytril (enrofloxacin) % oral solution in poultry to . x this dose for birds dosed by continuous water (standard) compared to pulsed water treatments and dosing by gavage.methods. for the pulsed versus continuous water treatments, groups of chickens received baytril % oral solution at (recommended) or ppm continuously in the water or at (recommended) or mg/kg pulsed in the water. for each group, three birds were killed at , , , , , and hours after start of antibiotic treatment and caecal contents, liver, lung and sera were taken and the concentration of fluoroquinolone determined by fluorescence hplc. for gavage treatment, dosing was at and mg/kg by crop intubation and four birds were killed in each group at , and hours after gavage; caecal contents, liver and sera were taken and analysed as above. basic pharmacokinetic parameters were determined using pk solutions software. results: the mean fluoroquinolone cmax in caecal contents (and sera) for gavage, pulsed water and continuous water treatments respectively was . ( . ), . ( . ) and . ( . ) mg/ml after the recommended dose and . ( . ), . ( . ) and . ( . ) mg/ml after . x the recommended dose. cmax of antibiotic in liver and lung was increased by the modified regimens in similar proportions to above. both pulsed water and gavage treatment not only resulted in higher cmax values, but also a faster rate of fluoroquinolone clearance than continuous water treatment ( figure ). dosing by gavage is not practical for thousands of chickens. however, pulsed dosing at . x the recommended dose can increase cmax values about fourfold and so could improve efficacy and reduce selection of resistance, compared to the current recommended treatment regime. objectives: nephrotoxicity is the major concern arising with the use of intravenous colistimethate sodium. methods: a prospective cohort study was performed at ''henry dunant'' hospital, a -bed tertiary care center in athens, greece. patients who received intravenous colistin for at least days for the treatment of multidrug resistant gram-negative bacterial infections were included in the study. the development of nephrotoxicity through evaluations of serum creatinine, blood urea, serum electrolytes, urinalysis, and creatinine and sodium in -hour urine collection during intravenous colistin therapy was the primary end point of the study. results: twenty-six patients were included in the study, of whom received colistimethate sodium (cms) for at least days and were evaluated further. the mean (± sd)/median daily dose, cumulative dose, and duration of treatment of intravenous cms was . (± . )/ million iu, . (± . )/ million iu, and . (± . )/ days (range - days), respectively. three of the evaluable patients ( . %) developed nephrotoxicity during the intravenous treatment with cms. the cumulative dose of the administered cms was statistically correlated with the difference between the end and start of cms treatment values of serum creatinine (r = . , p = . by spearman's test). a statistically but not clinically significant decrease of the mean baseline serum sodium concentration was observed between start and end of treatment [mean . (± . ) to . (± . ) mmol/l, p = . ]. no other toxic events were noted during the intravenous administration of colistimethate sodium. conclusion: although this is an evaluation of a small number of patients, our prospective study shows that nephrotoxicity was not commonly observed in this group of patients who received intravenous colistimethate sodium. however, caution should be taken to avoid the prolonged administration of the antibiotic. objectives: the objective of the present work is quantitative structure-activity relationship (qsar) analysis of antimicrobial activity of the -thiazolidone derivatives and consequent computational design of new antimicrobials. methods: for the achievement of the formulated objectives the qsar investigation has been carried out using computational chemistry approach based on simplex representation of molecular structure (sirms). on the framework of sirms it is possible to develop the molecular design of the new effective antimicrobials. results: systematic researches of relationship between antimicrobial activity (staphylococcus aureus -methicillin-sensitive (mssa) strain, pseudomonas aeruginosa -r and s strain, klebsiella pneumoniae, candida albicans s and Ñ itrobacter freundii) and a structure of about one hundred fifty compounds ( -thiazolidone derivatives and analogs). the elucidation of structure-activity relations allows predicting biological properties of such compounds, to execute their direct synthesis and to receive the indispensable information for research of mechanisms of their biological effect. completely adequate statistical partial least squares models (r = . - . , q = . - . ) have been obtained for all of the studied cultures. on the base of the first ones the molecular fragments both promoting and interfering the given antimicrobial activity have been determined. they give a possibility to realize the computer high throughput screening and molecular design of active compounds. the results of prognosis are verifying by the experimental investigations. also the influence of heterocycle system evolution on antimicrobial activity has been revealed. conclusion: qsar analysis of antimicrobial activity of -thiazolidone derivatives allows us to discover that the presence of naphthalene-substituted fragment (independently on its location in molecule) has distinctly negative influence on antimicrobial action. the requirements to molecular design have been formulated. for example, high active compounds must include -indolyl fragment. computational design of the new antimicrobials based on the substituted crown ethers activity of the row of substituted crown ethers and consequent molecular design of new antimicrobials. methods: the well-known hierarchic system of qsar models based on simplex representation of molecular structure has been used for the solution of the formulated problem, within the framework of which one it is possible to develop the molecular design of the new effective antimicrobial agents. results: we tried to conduct systematic researches of relationship between antimicrobial activity (planococcus citreus, streptococcus lactis, micrococcus lysodeiktious, staphylococcus aureus, streptococcus faecalis, bacillus subtillum) about two hundred fifty crowns ethers including aromatic, cyclic and heterocyclic etc. fragments and a structure of these molecules, in particular -macro cycle size, it dentacy, lipophily, nature of the substituents, and other factors. the elucidation of similar relations allows predicting biological properties of crown compounds, to execute their direct synthesis and to receive the indispensable information for research of mechanisms of biological effect of such kind of compounds. completely adequate qsar models (r = . - . , q = . - . ) have been obtained using partial least squares method for all of the studied cultures. on the base of the first ones the molecular fragments with positive or negative influence on the explored properties have been determined. they give a possibility to realize the virtual screening and molecular design of compounds with the high level of target activity. the results of prognosis are verifying by the experimental investigations. conclusion: qsar analysis of antimicrobial activity of crown ethers allows us to suppose the presence of two different mechanisms of their antimicrobial action. it is discovered that the presence of diphenyloxide and tert-butyl fragments promotes; diphenyl-sulphide and diamino-biphenyl -prevents the antimicrobial action. it is shown that the hexadenthal crown ethers containing aromatic fragments with a tert-butyl group are the most perspective antimicrobials. objectives: methionyl trna synthetase (mrs) catalyses the covalent attachment of methionine to its cognate trna. rep is a synthetic inhibitor of mrs with potent antibacterial activity against staphylococcus aureus including clinically-relevant resistant strains (mic equals . to . lg/ml). we determined the biochemical potency and mechanism of action of rep and related compounds with respect to s. aureus mrs enzymatic activity. we also evaluated the enzyme kinetic properties of mutated forms of s. aureus mrs. methods: the mets gene from s. aureus was expressed in e. coli and mrs was purified to near homogeneity by ammonium sulfate fractionation and anion exchange chromatography. aminoacylation of trnamet was measured using scintillation proximity assays (spa). the kinetics of the atp:ppi exchange were determined using thin layer chromatography (tlc). mutants of s. aureus mrs were selected by serial passage and spontaneous resistance in the presence of rep . results: rep exhibited strong inhibition of s. aureus mrs in the aminoacylation reaction, having an ic limited by the enzyme concentration. in order to estimate the true inhibition constant (ki), we utilized an atp:ppi exchange assay. rep showed potent inhibition of s. aureus mrs, with a ki of pm. related inhibitors were analysed, and a correlation was observed between the ki for mrs and the mic for s. aureus. rep was found to be competitive with methionine binding, but uncompetitive with atp binding (i.e., increasing the atp concentration resulted in tighter binding of rep ). the majority of analogs exhibited comparable mechanism of action; altered mechanism of action was observed with a subset of analogs. mutated s. aureus mrs variants (derived from strains with elevated mics) showed substantially weaker binding by rep . all of the mutated enzymes exhibited impaired trna aminoacylation activity, with defects ranging from reduced turnover rates to weaker affinities for one or more substrates. conclusions: rep is a potent inhibitor of s. aureus mrs. enzymatic potency of this class of inhibitors correlates with microbiological potency. mutations that confer resistance to rep result in functionally impaired mrs, encompassing a wide variety of enzymatic phenotypes. we report here the antibacterial and antifungal activity of newly synthesized and physico-chemically characterised thioureides of -( -chlorophenoxy)-benzoic acid. the new compounds were prepared in three stage. firstly, the -( -chlorophenoxymethyl)-benzoic acid was prepared by treating the phtalide with p-chlorophenol potassium salt in xylene. the second stage was the synthesis of -( -chlorophenoxymethyl)benzoyl chloride by treating the corresponding acid with thionyl chloride using anhydrous , -dichloroethane as solvent, followed in the third stage, by the treatment of the above-mentioned chloride with ammonium thiocyanate. the -( -chlorophenoxymethyl)-benzoyl isothiocyanate resulted after refluxing the reaction mixture in dry acetone. the new compounds were prepared by refluxing the isothiocyanate with primary aromatic amines in dry acetone. the obtained compounds have been characterized by their physical properties and their chemical structures were confirmed using the spectral analysis. the aim of this study was also to evaluate the in vitro antimicrobial activity of the new compounds. the in vitro antimicrobial testing was performed by binary microdilution method, in multi-well plates, in order to establish the minimal inhibitory concentration (mic), against gram-positive (listeria (l.) monocytogenes, staphylococcus (s.) aureus, bacillus (b.) subtilis), gram-negative (psedomonas (p.) aeruginosa, escherichia (e.) coli, salmonella (s.) enteritidis), as well as candida sp., using both reference and clinical, multidrug resistant strains. our results showed that the tested compounds exhibited a specific antimicrobial activity, depending on the nature of the substituents and their position on the benzene ring, both concerning the microbial spectrum and the mic value. the mics values widely ranged between mcg/ml and mcg/ml. the most active proved to be n-[ -( -chlorophenoxymethyl)-benzoyl]-n'-( , -dichloro-phenyl)-thiourea and n-[ -( -chlorophenoxymethyl)-benzoyl]-n'-( -bromo-phenyl)-thiourea, showing a large spectrum of antimicrobial activity against enterobacterial strains (e. coli and s. enteritidis), l. monocytogenes, s. aureus and candida sp. all the tested compounds were highly active against s. aureus (mic = mcg/ml). four of the tested compounds exhibited antifungal activity (mic = - mcg/ml), and p. aeruginosa as well as b. subtilis were resistant to all tested compounds. in vitro antimicrobial activities of novel dianthraquinones produced by a marine streptomyces sp. against clinical staphylococcus aureus and enterococcus faecium isolates k.l. laplante, k. lor, a. socha, d.c. rowley (providence, north kingston, us) objectives: the escalation of antibiotic resistance among grampositive pathogens presents increasing treatment challenges and requires the development of new therapeutic agents. recently we discovered a new class of dianthraquinone antibiotics produced by a marine streptomycete. the inhibitory and bactericidal activity of four dianthraquinone secondary metabolites and four semi-synthetic derivatives were measured against clinical strains of vancomycin resistant e. faecium (vre), methicillin susceptible and methicillin resistant s. aureus (mssa and mrsa, respectively). two compounds, daq a and daq , were tested against an expanded panel of pathogens. methods: thirty-two clinical strains of vre (n = ), mssa (n = ) and mrsa (n = ) were obtained from patients at the veterans affairs medical center in providence, ri. mic's were performed using methodologies described by clsi. control isolates were atcc and atcc . the bactericidal activity of each antimicrobial agent was evaluated with time-kill experiments using randomly selected mssa (n = ), mrsa (n = ), and vre (n = ) isolates tested at times the respective mic. conclusions: the potent activities and unusual structures of the dianthraquinones tested here suggest that these may provide a new molecular scaffold for the development of novel antimicrobial agents. more biological testing is warranted to more fully explore the clinical potential of these antibiotics. efficacy of the novel antimicrobial peptide plectasin to staphylococci objective: the purpose of the investigation was to investigate the in vitro efficacy and kill kinetics of plectasin against staphylococcus aureus. plectasin is a newly discovered defensintype antimicrobial peptide found in the fungus pseudoplectania nigrella which showed activity against several gram-positive bacteria including drug resistant strains (mygind ph. et al. plectasin is a peptide antibiotic with therapeutic potential from a saprophytic fungus. nature ; : - ). methods: all experiments were determined according to clsi/ nccls guidelines. bactericidal activity was characterized by time kill experiments at and times the mic. staphylococcus aureus (s. aureus) atcc were used as the test organism and vancomycin was used for comparison. the kill kinetics and post antibiotic effect (pae) were evaluated by cfu determination. inoculum sizes ranging from e to e cells were used to test the inoculum effect. e cells were employed for determination of mutant prevention concentration (mpc) and the frequency of spontaneous resistance. results: plectasin is bactericidal as evidenced by kill kinetics showing a . log reduction in cfu/ml after hour of incubation and a reduction of . log cfu/ml after hours. this is superior compared to the activity of vancomycin. no inoculum effect was observed in the employed range of cells. the observed pae had a duration of hours and minutes. no spontaneously resistance mutation was observed among e cells of staphylococci and the mpc were determined to be times mic. conclusions: plectasin is a novel antimicrobial peptide that shows potent antimicrobial activity against gram-positive bacteria including drug-resistant organisms. the potent, excellent bactericidal activity in vitro, lack of cross-resistance to clinical used antibiotics, low spontaneously resistance mutation frequency and good pae properties, suggest that plectasin may have potential as a therapeutic agent against staphylococci. in vitro antimicrobial activity of the novel polymeric guanidine akacid plus Ò c. kratzer, s. tobudic, w. graninger, a. buxbaum, a. georgopoulos (vienna, at) objectives: cationic antimicrobials are widely used for disinfection within clinical settings. in the present study the bactericidal and fungicidal activity of akacid plus Ò , a novel polymeric compound of the cationic family of disinfectants, was evaluated against quality control strains of staphylococcus aureus, enterococcus hirae, escherichia coli, pseudomonas aeruginosa, candida albicans and aspergillus niger in comparison to chlorhexidine digluconate. methods: the in vitro activity of akacid plus Ò and chlorhexidine was determined by quantitative suspensions tests according to the european committee for standardization at concentrations of . - . % against bacterial strains and c. albicans and at concentrations of . - % against a. niger after exposure for , and min in the presence and absence of . % bovine albumin and dilution in distilled and hard water. results: in the basic quantitative suspension test akacid plus Ò destroyed all bacterial pathogens at a concentration of ‡ . % in £ min contact time. chlorhexidine was also highly active against s. aureus, e. coli and p. aeruginosa, but failed to eliminate e. hirae within min. under high organic burden, the bactericidal activity of both disinfectants was slightly reduced. akacid plus Ò showed fungicidal activity against c. albicans within - min and eliminated a. niger at a concentration of ‡ % in min contact time. chlorhexidine was fungicidal against c. albicans, but did not achieve biocidal activity against a. niger. conclusion: the novel polymeric guanidine akacid plus Ò when compared to chlorhexidine digluconate showed similar bactericidal activity against s. aureus, e. coli and p. aeruginosa and superior biocidal activity against e. hirae and a. niger. investigation of emergence of bacterial resistance to the novel antibacterial photodynamic agent xf- are novel, light activated antibacterial agents ( ) active against gram-positive bacteria, which have greater potency than antibiotics. the emergence of resistance to xf- has been investigated. methods: . mg/l of xf- was added to cells/ml of mrsa. after minutes incubation in the dark the unbound xf- was removed and the culture illuminated with . j/cm of light at nm and cfu analysis undertaken to determine the number of viable cells remaining. surviving clones of the treatment were cultured and subjected to further treatment. cycles were undertaken to determine whether the number of surviving cells increased, suggesting resistance build up to xf- . results: the survival of methicillin-resistant staphylococcus aureus (mrsa) (atcc baa- ) is expressed as log n /n, where n and n are the cfu of untreated and treated suspensions, respectively. the results demonstrate that no detectable resistance build up to the activity of xf- was seen after successive treatments. a low propensity for emergence of resistance is a valuable attribute for new anti-bacterial agents. xf- might be effectively employed in the clinical setting for prophylactic use to decolonise skin and nares and therapeutic use to treat infected wounds/ulcers. objectives: the xf drugs are novel, light activated antibacterial agents ( ) active against gram-positive bacteria which have superior potency to antibiotics but possess a low propensity to induce resistant bacterial strain emergence. a novel ex-vivo porcine skin model has been developed to test the antibacterial activity of xf- on the surface of skin. methods: x cells of methicillin-resistant staphylococcus aureus (mrsa) were inoculated onto a . cm area of ex-vivo porcine skin samples, immobilised in agar. after drying, solutions of xf- were applied and after minutes, the samples were illuminated for minutes with blue light ( nm) with various total light doses using a lumacare tm lc- m lamp. cfu analysis were undertaken to determine the number of viable cells remaining after treatment. controls of drug alone and light alone were included. results: using . mg/l of xf- , cfu analysis demonstrated that at a total light dose of j/cm , there was~ % kill of bacteria. at j/cm , there was . % kill of bacteria, and . % at j/cm and j/cm . at a total light dose of j/ cm , it was found that there was a < % kill by xf- at concentrations of . , . and . mg/l. at a concentration of . mg/l, there was a > . % kill. this kill did not significantly increase at . and . mg/l. conclusions: the results demonstrate that xf- has exceptional activity at low concentrations against mrsa on the surface of porcine skin. xf- and light are non-toxic to skin at therapeutic concentrations. work is in progress to clinically evaluate the effectiveness of this compound in eradicating staphylococcal nasal carriage. objectives: the rise of epidemic methicillin-resistant staphylococcus aureus (emrsa) and the emergence of mupirocin resistance means that it is essential to develop new therapies that cannot be readily overcome by microorganisms. the xf series of novel light activated antibacterial agents ( ) active against gram-positive bacteria addresses this issue and have superior levels of activity to antibiotics but with less likelihood of resistance emergence. the antibacterial activity of the xf drugs against emrsa has been investigated. methods: mic and mbc assays were used to investigate the antibacterial activity of xf- , a novel antimicrobial photodynamic agent against a range of staphylococcus aureus strains. a concentration range of - . mg/l was investigated. minutes of nm light activation ( j/cm ) was applied. light alone had no effect. results: conclusions: the results demonstrate that xf- has exceptionally low mic and mbc values against all of the s. aureus strains tested. the results also demonstrate that xf- is equally effective against mrsa and methicillin-sensitive staphylococcus aureus (mssa) indicating its mode of action is independent of antibiotic resistance. xf- may therefore be useful in prevention and treatment of emrsa. xf- is non-toxic to skin at prophylactic/therapeutic concentrations and has potential for the treatment of skin sepsis and the eradication of nasal and skin mrsa carriage. work is in progress to evaluate the effectiveness of this compound in eradicating staphylococcal nasal carriage. objective: nxl is a novel antibacterial currently in preclinical development. the mechanism of action is directed against topoisomerase, and the spectrum of activity is exclusively against gram positive organisms. the goal of the study was to characterise the activity and time/kill kinetics against common aerobic cocci in comparison to currently marketed molecules: linezolid (lin), vancomycin (van), quinupristin/dalfopristin (q/d) and moxifloxacin (mox). methods: (i) in vitro susceptibility tests: the strains used were from the culture collection of novexel and were of clinical origin. mics were determined by an agar dilution technique. mueller hinton agar medium was used, supplemented with % horse blood for group a streptococci (gas), group b streptococci and s. pneumoniae. overnight cultures were diluted to obtain the final inoculum of cfu/spot. the mic was the lowest concentration which inhibited all visual growth ( or less colonies were ignored). (ii) time/kill kinetics: experiments were performed against strains of s. aureus (n = ) and s. pneumoniae (n = ) in ml volumes of appropriate growth medium with initial inoculum of around cfu/ml of logarithmically growing culture. timed samples over a hour period were enumerated using a spiral plating method. nxl was compared to linezolid and vancomycin and the concentrations tested were , and -fold the mic for both species. results: (i) the mic s of nxl versus comparators are shown in the table. (ii) time kill experiments showed that nxl was bactericidal against s. aureus, including methicillin resistant strains (> log reduction within - hours) compared to a slowly bactericidal effect for vancomycin ( hours). nxl and vancomycin were both bactericidal against s. pneumoniae within - hours. linezolid was bacteriostatic against all strains tested. conclusion: nxl exhibits bactericidal activity against common gram positive cocci, including strains which exhibit resistance to methicillin, vancomycin and fluoroquinolones. nxl warrants further investigation. objectives: the aim of this study was to identify bacterial proteins as targets of the endogenous antiseptic n-chlorotaurine (nct), which is a promising microbicidal agent for topical treatment of infections. in addition, a combination of nct with ammonium chloride which enhances the microbicidal activity significantly was investigated. methods: escherichia coli and staphylococcus aureus were treated with nct and nct plus ammonium chloride for different incubation times between and min -a period where killing takes place. to find out protein changes, d-page of bacterial proteins followed by mass spectrometry was performed. results: incubation in % nct revealed a change of the charge and a separation of numerous proteins into a series of spots with a different isoelectric point. moreover, in e. coli heat shock protein appeared, while ribosome releasing factor, d-ribose periplasmic binding protein, and malonyl-coa transacylase spots decreased. in s. aureus, enolase and a translation elongation factor decreased. these changes appeared more rapidly in the presence of ammonium chloride, which can be explained by formation of the more lipophilic and microbicidal monochloramine. molecular mechanisms of attack comprised mainly oxidation of thio and amino groups as confirmed with model peptides. conclusion: these results fit very well to previous preclinical and clinical findings. they indicate both surface attack and penetration of oxidation capacity into the bacteria and destruction of essential proteins by nct and nct plus ammonium chloride, respectively. objectives: ceftobiprole is a new extended-spectrum cephalosporin with activity against methicillin-susceptible and methicillin-resistant staphylococci, as well as against most enterobacteriaceae. in this study the anti-staphylococcal activity of ceftobiprole is reported from a set of isolates from a recent clinical trial. methods: consecutive clinical isolates of staphylococci from patients enrolled in a multicentre clinical trial involving complicated skin infections were examined for their susceptibility to ceftobiprole and selected anti-gram-positive agents. mics were determined using clsi methodology. results: among these isolates, staphylococcus aureus and coagulase-negative staphylococci (cons) were identified. the percentages of methicillin-resistant strains were % for s. aureus and % for cons. all strains (except one cons with a linezolid mic of mg/l) were susceptible to vancomycin and linezolid, with mics < mg/l.against methicillin-susceptible s. aureus, ceftobiprole mic and mic values were . and . mg/l, respectively, and against methicillin-resistant s. aureus, ceftobiprole mic and mic values were . and mg/l, respectively. ceftobiprole mics ranged from £ . to mg/l against methicillin-susceptible-cons (ms-cons) and methods: consecutive, non-duplicate bacterial isolates ( , strains) acquired from patients with bloodstream, respiratory, and skin and skin structure infections both nosocomial and community acquired were submitted from > medical centres in europe, the americas and the asia-pacific region. all isolates were tested using clsi/nccls broth microdilution methods against grn, the currently marketed fluoroquinolones (fq) including cipro, levofloxacin (levo), gatifloxacin (gati) and representative comparator agents. oxa-and cipro-s and -r subsets were included. a grn-s breakpoint of £ . mg/l was applied for comparative purposes only and was based upon the mic population distributions of strains that included quinoloneresistance determining region (qrdr) mutations. results: potency for grn and comparator fqs tested against sa: (see table) . key resistance patterns (%) among this sa collection included oxa ( . ), cipro ( . ), erythromycin ( . ), clindamycin ( . ), tetracycline ( . ), and trimethoprim/ sulfamethoxazole ( . %); gram-positive-targeted comparator including vancomycin, linezolid, daptomycin and quinupristin/dalfopristin all remained > % s. compared with currently marketed fqs when tested against all sa, grn was -to -fold more active (mic , £ . vs. . or . mg/ l). against both oxa-s and -r sa, grn displayed markedly enhanced potency compared with cipro and levo ( ‡ -fold), and gati ( -to -fold). among cipro-r isolates, grn also maintained ‡ -fold greater potency (mic , vs. ‡ mg/l) although overall s for all fqs was - %. compared to the fq agents tested against sa, grn was the most potent agent and maintained the broadest coverage against oxa-and cipro-r strains even when applying a very conservative epidemiologic breakpoint. when a fq is indicated for staphylococcal coverage, this des-f( ) quinolone may represent a superior alternative among fq class agents, while minimizing selection of resistance. objective: to assess the garenoxacin (grn) potency against a vast number of international respiratory tract infection (rti) pathogens, especially versus phenotypic (high mic) or genotypic (sequence change) qrdr mutants. a total of , isolates from continents were analysed ( ) ( ) ( ) ( ) ( ) ( ) ( ) table) conclusions: grn maintains clinically usable activity (mic, £ mg/l) against important community-acquired rti pathogens having r to presently marketed fluoroquinolones and against those isolates with documented qrdr mutations. continued development of this novel des-f( ) quinolone agent appears desirable. in vitro activity of garenoxacin tested against ciprofloxacin-susceptible and -resistant enterobacteriaceae and acinetobacter spp. strains collected worldwide by the sentry antimicrobial surveillance program ( ) ( ) h. sader, t. fritsche, p. strabala, r. jones (north liberty, us) objective: to evaluate the contemporary activity of garenoxacin (grn) against ciprofloxacin (cipro)-susceptible (s) and cipro-resistant (r) enterobacteriaceae (ent) and acinetobacter spp. (asp). unlike recently marketed fluoroquinolones (fq), grn, a des-f( ) quinolone lacks the c- fluorine. methods: a total of , isolates ( , ent and asp) were consecutively collected from > medical centres from bloodstream, respiratory, urinary and skin and soft tissue infections and tested by reference broth microdilution methods according to clsi/nccls methods and interpretative criteria. a grn s breakpoint of £ mg/l was applied for comparison purposes only. results: the results of the major organism groups tested: (see table) . grn showed excellent activity against this large collection of ent (mic , . mg/l) and . % of isolates were inhibited at £ mg/l. objectives: garenoxacin (grn) is a novel, broad-spectrum des-f( )-quinolone with activity against gram-negative and grampositive aerobes and anaerobes including quinolone-resistant staphylococcus aureus. the objective of this analysis was to compare the microbiologic efficacy of grn to that of comparators against common pathogens involved in complicated skin and skin structure infections (csssi). methods: two multinational, double-blind, randomized studies were conducted. in the first study, subjects received grn ( mg iv to po qd) or piperacillin/tazobactam ( . g iv q h) with transition to po amoxicillin/clavulanate ( mg po q h). in the second study, subjects received grn ( mg po qd) or ciprofloxacin/metronidazole ( mg q h/ mg q h). all antimicrobials were administered for to days. subjects were adults ( ‡ y) newly hospitalized or ambulatory outpatients with evidence of csssi who did not have underlying osteomyelitis. microbiologic efficacy was determined to days post-therapy. results: a total of subjects were microbiologically evaluable (grn, n = ; comparators, n = ). the disease diagnosis was similar between grn and comparators and included infected pressure sore ( % vs %), infected diabetic foot ulcer ( % vs %), major abscess ( % vs %), or postsurgical wound infection ( % vs %). the majority of common skin pathogens were eradicated by grn background: acute bacterial sinusitis (abs) is a common infection world-wide, with many patients having an associated an allergic component/history. however the role of antibacterials in these patients (pts) has not been examined. as some fluoroquinolones (fq) have an in-vitro immunomodulatory effect (ie) the clinical efficacy of gem was compared other agents in abs pts with or without allergic rhinitis (ar). methods: phase clinical trials were pooled and pts where allergic rhinitis was identified ( pts) were compared with pts not reporting ar ( pts). clinical response (success or failure) at end of therapy (eot) & at follow-up (fu, approx. - weeks after treatment) was studied. comparators (cmp) were cefuroxime (cef) and trovafloxacin (tro). results: % success based on clinical outcome at eot and fu for ar and non ar pts are shown in the table. for all treatments eot success was high for the non ar pts, but at fu this was reduced, especially with both fqs. in contrast, gem retained a high clinical success rate in pts with ar unlike cef or tro. conclusion: gem has been shown to be very efficacious in a sub group of problematic abs pts. this advantage may be due to the high antibacterial activity of gem vs key abs pathogens and/or a stimulatory ie. both being important with pts having decreased local immune defences. these data also show that not all fluoroquinolones have immuno-stimulatory properties. garenoxacin efficacy against multidrug-resistant streptococcus pneumoniae: retrospective analysis of community-acquired pneumoniae isolates obtained from nine phase ii and iii clinical studies ( ) ( ) ( ) ( ) ( ) t. black, h. waskin, r. hare (kenilworth, us) objective: garenoxacin (grn) is a novel, des-f( )-quinolone with excellent activity against s. pneumoniae, one of the most common pathogens causing community-acquired pneumoniae (cap). the incidence of infections caused by antibiotic-resistant isolates of streptococcus pneumoniae is on the increase, therefore information regarding the activity of new anti-infective drugs against populations of s. pneumoniae that are multi-drug resistant (mdr) is critical. mdr s. pneumoniae (mdrsp) includes isolates previously known as prsp (penicillinresistant s. pneumoniae), as well as strains resistant to two or more of the following antibiotics: second-generation cephalosporins, macrolides, tetracyclines, and trimethoprim/ sulfamethoxazole. methods: pretreatment sputum and blood isolates collected worldwide during grn phase / clinical cap trials ( ) ( ) ( ) ( ) ( ) were retrospectively analysed for the mdrsp phenotype. of the s. pneumoniae isolates originally identified, from subjects were subjected to secondary mdr susceptibility testing by central laboratories. confirmed mdrsp isolates were matched to individual subjects to assess clinical and microbiological outcomes for mdrsp-infections treated with grn. results: expanded susceptibility testing identified / mdrsp isolates from unique subjects. the lowest mic and mic values for mdrsp isolates tested against a panel of representative drugs were observed for grn (table ; . lg/ ml and . lg/ml, respectively). the incidence of resistance to the five classes of drugs was %, %, %, % and % for penicillin, nd generation cep., macrolides, tetracycline and tri/sulf, respectively. no isolates were resistant to grn using a proposed susceptibility breakpoint value of £ lg/ml. thirtyfive percent, %, %, % and % of isolates were resistant to , , , and drug classes, respectively. the worldwide incidence of mdrsp was % with an equivalent geographic distribution of %, % and % among north america, europe and the rest of world. overall, grn provided clinical and bacteriological success for / ( %) cap evaluable subjects with mdr infection, which was similar to clinical success for evaluable subjects with non-mdrsp cap infections / ( %). conclusions: these data demonstrate the ability of grn to successfully eradicate mdrsp associated with cap. . per cent success is shown in the table (ab, antibiotics, copd, chronic bronchitis and obstructive lung disease, hd, heart disease). results: although gemifloxacin showed lower % success than comparator against cap patients with no defined risk factor, gemifloxacin was considerably more successful than comparator against patients associated with risk factors, especially diabetic patients where comparator success was low. this advantage was often more prominent at fu than at eot. patients with other comorbidities such as renal failure or malignancy were not recruited in sufficient number for analysis. conclusions: these data support the use of gemifloxacin in the treatment of cap, especially where the patient has recognised idsa risk factors. microbiologic efficacy of garenoxacin vs. comparators against common pathogens associated with community-acquired pneumonia objectives: garenoxacin (grn) a novel, broad-spectrum des-f( )-quinolone is active against many clinically important respiratory pathogens including penicillin-resistant strains of streptococcus pneumoniae. grn has dual sites of inhibition (dna gyrase and topoisomerase iv) and may be less likely to promote resistance. the objective of this analysis was to compare the microbiologic efficacy of grn to that of comparators against common pathogens involved in community-acquired pneumonia (cap). methods: two multinational, double-blind, randomized studies were conducted. in the first study, subjects received grn ( mg po qd for d) or amoxicillin/clavulanate (a/c; mg po q h for - d). in the second study, subjects received grn ( mg po qd for - d) or levofloxacin (lev; mg po qd for - d). adults ( years of age or older) were enrolled with clinical and radiologic evidence of cap [new infiltrate(s) on chest radiograph and fever, leukocytosis, cough, chest pain, auscultatory findings, or sputum production]. the majority of subjects were fine class i/ii in both studies. bacteriologic eradication was assessed to days post therapy. results: a total of treated subjects had pretreatment pathogens (grn, n = ; comparators, n = ) . the overall eradication rate in all treated subjects was % ( / ) for grn and % ( / ) for the comparators. eradication rates for s pneumoniae were % ( / ) for garenoxacin and % ( / ) for the comparators. eradication of s pneumoniae was % and % for a/c and lev, respectively. in strains with reduced susceptibility to penicillin eradication rates were % ( / ) vs % ( / ) in favour of grn. eradication rates for h. influenzae were % ( / ) and % ( / ) for grn and comparators, respectively. lev eradicated % of h. influenzae isolates and a/c eradicated % of the strains isolated. there were very few isolates ( ) of moraxella catarrhalis in the studies. in study grn was % effective against strains of m. catarrhalis and in the other a/c was % effective against the strain isolated. grn eradicated % ( / ) of the staphylococcus aureus isolates vs % ( / ) for the comparators. conclusions: grn was highly active against pathogens commonly associated with cap including drug-resistant strains of s pneumoniae and represents an effective therapeutic option for this patient population. objectives: garenoxacin (grn) a novel, broad-spectrum des-f( )-quinolone is active against many clinically important respiratory pathogens including penicillin-resistant strains of streptococcus pneumoniae. there is a growing problem of resistance in strains of s pneumoniae, with multi-drug-resistant s pneumoniae (mdrsp) becoming increasingly more common. the objective of this study was to evaluate the clinical and microbiologic efficacy of grn in the treatment of communityacquired pneumonia (cap) caused by mdrsp. methods: this was a multinational, open-label, noncomparative study. subjects were adults ( ‡ and < y) with clinical (clinical signs, sputum production), radiologic (new infiltrates on chest radiograph), or microbiologic (predominance of gram-positive cocci in pairs on sputum gram-stain or a positive blood culture for s. pneumoniae) evidence of cap caused by s. pneumoniae. subjects received grn mg po qd or grn mg iv with transition to mg po qd for to days. clinical and microbiologic responses were determined at a test-of-cure visit to days posttherapy. results: a total of subjects were enrolled. of these, ( po only, iv to po) were clinically and microbiologically evaluable. clinical and microbiologic success rates were % ( / ) and % ( / ), respectively. clinical success rates were % ( / ) and % ( / ) for po and iv to po, respectively. documented s. pneumoniae bacteremia was present in % (n = ) of subjects with a clinical success rate of %. among evaluable subjects, resistance rates for s. pneumoniae were penicillin %, second-generation cephalosporin %, macrolides %, tetracyclines %, and trimethoprim/ sulfamethoxazole %. twelve evaluable subjects had pneumonia caused by mdrsp. clinical success rate was % ( / ) in subjects with mdrsp and % ( / ) in non-mdrsp subjects. clinical success of grn for strains resistant to , , , or antimicrobial drug classes, were % ( / ), % ( / ), % ( / ), and % ( / ), respectively. microbiologic success was % ( / ) and % ( / ) for mdrsp and non-mdrsp (susceptible or resistant to class) strains, respectively. grn was generally well tolerated with drug-related adverse events (ae) reported in % ( / ; po) and % ( / ; iv to po) of subjects. conclusions: grn (po or iv to po) is an effective treatment for cap caused by mdrsp and non-mdrsp. grn is well tolerated. in vitro bactericidal activity of daptomycin against staphylococcus aureus and enterococcus spp.: comparison with vancomycin, teicoplanin and linezolid h. drugeon, m. juvin (nantes, fr) objectives: the aim of this study was to evaluate the bactericidal activity (by killing kinetics) of daptomycin (dap) against staphylococcus aureus (sa) clinical isolates with different teicoplanin mics and against enterococcus faecalis (efl) and e. faecium (efm) with different mechanisms of glycopeptide resistance. dap has been compared with teicoplanin (tei), vancomycin (van) and linezolid (lin). methods: sa strains ( mssa and mrsa) with tei mic distributed from . to mg/l, enterococcus ( efl and efm) with glycopeptide phenotypes [s, r-vana, r-vanb] were studied using a killing curve method. antibiotic concentrations were used from mg/l to mg/l in two fold dilutions. surviving bacteria were counted at t , t ', t , t , t , t and t hours using agar plates with inhibitors to prevent antibiotic carry-over. antibiotics tested were daptomycin (dap), teicoplanin (tei), vancomycin (van) and linezolid (lin). results: all the sa isolates were susceptible to dap (mic = . - mg/l), to lin (mic = - mg/l), to van (mic = - mg/l) regardless of susceptibility to methicillin. dap showed the same strong concentration dependent bactericidal activity with mssa and mrsa: at t ' bactericidal activity (ba) (decrease of log cfu/ml) was observed with - mg/l of dap; at t hours, - mg/l of dap was sufficient and at t hours, ba was obtained with mg/l of dap. the other antibiotics showed a time dependent bactericidal activity but ba was observed only with long exposure ( ‡ hours) and with high concentrations. all the enterococcus isolates were susceptible to dap (mic = - mg/ l) and to lin (mic = - mg/l) regardless of the resistance to glycopeptides. ba of dap was also concentration dependent. ba was obtained with - mg/l after hours of contact and with mg/l after hours of contact for efl. ba was observed with - mg/l after hours of contact and with - mg/l after hours of contact for efm. the other antibiotics had a time dependant activity but didn't show bactericidal activity with concentrations mg/l. conclusion: the bactericidal activity of daptomycin was very strong, concentration dependent, and not influenced by the level or mechanism of glycopeptide resistance the bactericidal activity of linezolid was time dependent and observed only with the highest concentration and the bactericidal activity of vancomycin and teicoplanin was time dependent but was influenced by the mechanism of glycopeptide resistance. objectives: telavancin (tlv) is a bactericidal lipoglycopeptide with multiple mechanisms of action that is in phase clinical trials for the treatment of complicated skin and skin structure infections and hospital-acquired pneumonia with a focus on infections due to methicillin-resistant staphylococcus aureus (mrsa). this study evaluated and compared the antibacterial activity of tlv with that of other antibacterial agents against recent gram-positive clinical isolates from germany. methods: a total of aerobic gram-positive bacterial strains recently collected were included. antibiotics tested were tlv, vancomycin (van), teicoplanin, penicillin, oxacillin, ampicillin, cefuroxime, ceftriaxone, daptomycin (dap), linezolid (lzd), quinupristin-dalfopristin, clindamycin, ciprofloxacin, levofloxacin, gentamicin, streptomycin, erythromycin, telithromycin, co-trimoxazole and tetracycline. mics were determined by the broth microdilution procedure according to the guidelines of the clsi. results: tlv exhibited potent activity against all grampositive bacteria including resistant isolates such as mrsa, van-resistant enterococci, pneumococci (including multiple resistant strains with various antibiotic resistance phenotypes) and other streptococcal species. tlv showed excellent in vitro activity against the species irrespective of the antibiotic phenotype tested. for methicillin-susceptible s. aureus (mssa, n = ) and mrsa (n = ) mic of tlv for both phenotypes were . mg/l. for coagulase-negative staphylococci (n = , incl. msse, mrse, mssh, mrsh and others) mic s were . or mg/l. mic s of tlv for enterococcus faecalis (n = ) and e. faecium (n = ) were and mg/l, respectively. for van-resistant strains of e. faecalis (n = ) or e. faecium (n = ) mics for tlv ranged from . to mg/l. against streptococcus pneumoniae (n = ) tlv mics ranged from £ . to . mg/l. all streptococcus pyogenes, streptococcus agalactiae and all viridans group streptococci (n = ) had mics of £ . mg/l. conclusion: based on mic , tlv was more potent than van, dap or lzd against staphylococci, streptococci and e. faecalis. it was superior to dap and lzd against e. faecium and at least as active as dap or lzd against most van-resistant enterococci. tlv appears to be a promising new antimicrobial agent for the treatment of infections caused by gram-positive organisms including multiply resistant isolates. the extent of protein binding (pb) of dap is still under investigation and data available so far indicate pb of either % or %. therefore we tested two fscs: . (corresponding to % pb) and . (corresponding to % pb). the activity of dap was determined in mueller-hinton broth supplemented with mg/l calcium. viability counts were performed at . , . , , , , and h. one methicillin-susceptible staphylococcus aureus (mssa), two methicillin-resistant s. aureus (mrsa), one vancomycin-susceptible (van-s) and one van-resistant (van-r) enterococcus faecalis, one van-s and one van-r enterococcus faecium were tested. bactericidal activity was defined as > . % killing during incubation. results: dap was bactericidal at concentrations of . mg/l and . mg/l in all seven strains. the concentration of . mg/l was bactericidal against the two mrsa and against the van-s e. faecium. in the other four strains the maximum reduction of initial inoculum ranged from . to . log cfu/ml. in six strains a bactericidal effect at . mg/l and . mg/l of dap, respectively, occurred between minutes and h and after h in the van-s e. faecalis. van at . mg/l or . mg/l was bactericidal in only two strains after h ( mssa, mrsa). against the other five strains, van was bacteriostatic with maximum reduction of initial inoculum between . and . log cfu/ml at mg/l after h, respectively. both tpl and lzd were consistently bacteriostatic against the test strains. conclusion: dap at psc of . mg/l as well as at fsc of . mg/l showed a pronounced bactericidal effect within h in / strains. van was bactericidal in only / strains after h. compared to van bacterial killing by dap was very rapid. tpl and lzd were bacteriostatic only. the effect of human serum on the bactericidal activity of daptomycin and comparators against staphylococcus aureus and enterococcus spp. background: daptomycin is a new cyclic lipopeptide antibiotic that shows rapid bactericidal activity and has high protein binding when assessed by standard methodology. this study investigated the bactericidal activity of daptomycin and the effect of protein binding by the addition of % human serum (hs). methods: exponentially-growing methicillin-susceptible andresistant s. aureus (mssa, mrsa) and vancomycin-susceptible enterococcus faecium (vse) and -resistant enterococcus faecium (vre) (ca. cfu/ml) were exposed to daptomycin (dap), vancomycin (van), teicoplanin (tei), piperacillin-tazobactam (ptz) or linezolid (lzd) at peak (p) and trough (t) serum concentrations in mueller hinton broth supplemented with ca + to mg/l with or without hs. viable count was determined at . , . , , & h. plots were made of log reduction in viable count over time and the area-under-thecurve measured to calculate bactericidal indices (bis) from these plots (j antimicrob chemother , : - ). results: daptomycin reduced viable count of mssa & mrsa by approx. logs or more within . h and vse or vre within h at p. other agents either did not achieve this or required h to do so (not shown). bi data are shown below (>represents kill beyond the limit of detection). hs had little effect on dap kill, except against the vre at t. nevertheless, dap at t against vre was more bactericidal than any other antibacterial except dap at p. conclusions: dap was the most bactericidal agent tested as measured either by bi or rate of kill. dap at p reduced mssa and mrsa to below detection within min. the effect of hs was minimal which suggests that protein binding is either weak or highly reversible. these data support the use of dap in the treatment of infections caused by these organisms. daptomycin activity against multi-resistant staphylococcus haemolyticus bloodstream isolates from severe infections objectives: daptomycin, a new cyclic lipopeptide with activity against multidrug-resistant gram-positive pathogens including mrsa, is approved for use in cssst infections (us-fda) and is being reviewed by emea for approval in eu member countries. the rapid bactericidal activity of daptomycin, due to its unique mechanism of action, makes it an attractive antibiotic for serious gram-positive infections. the study was performed: (i) to evaluate the activity of daptomycin and other drugs against multi-resistant clinically relevant staphylococcus haemolyticus (mrsh), isolated from bloodstream infections in various hospitals in italy (ii) to determine epidemiologic and genetic correlation among strains, and (iii) to characterize the sccmec dna of these strains. methods: the mrsh strains were tested against a panel of antimicrobial agents, by broth microdilution method performed according to clsi (clinical laboratory standards institute) guidelines, including supplementation of mg/l calcium for daptomycin. moreover, phenotypic tests and antibiotic susceptibility profiling were carried out and the results compared with molecular typing analysis by using smai-pfge fingerprints and pcr to characterize the mec-complex. results: all isolates were resistant to erythromycin, gentamicin, ciprofloxacin, strains showed reduced susceptibility to vancomycin (mics mg/l), strains were resistant to cotrimoxazole, strains to clindamycin, strains to chloramphenicol and strains to tetracycline. almost all isolates were inhibited by £ mg/l of daptomycin, and only four strains exhibited a mic value of mg/l. pfge analyses showed the existence of at least two multi-resistant s. haemolyticus clones widespread in different hospitals. methicillin-resistance was correlated to the presence of the meca and preliminary results regarding the genetic element carrying the gene, showed an organization of the mec-complex of class a and class c. conclusions: our results suggest that daptomycin has excellent activity against multiresistant mr s. haemolyticus isolates, which represent a serious threat in catheter-related bloodstream infections. furthermore, the emergence of s. haemolyticus exhibiting reduced susceptibility to vancomycin is of particular concern, probably due to the common use of vancomycin as initial therapy for such infections. moreover, the use of additional molecular techniques to fingerprint isolates makes this study of clinically important cons more accurate. objectives: ceftobiprole is a new cephalosporin with a broad spectrum of action including methicillin-resistant staphylococci (mrs) as well as many other gram-positive and gram-negative pathogenic bacteria. this study investigates the structural basis for the good activity against mrs. methods: the primary beta-lactam resistance determinant of mrs, penicillin-binding protein pbp ' (or a) has been cloned and expressed as a soluble form in which the amino-terminal residues forming a membrane-anchor have been deleted. the soluble form has been crystallized and the structure of the complex formed after soaking crystals in a solution containing ceftobiprole has been determined at . angstrom resolution. additional data on the structure of the ceftobiprole-pbp ' complex formed in solution has been obtained using spectroscopic methods such as uv-circular dichroism. results: ceftobiprole reacts rapidly with pbp ' to form a stable acyl-enzyme complex. the ceftobiprole moiety is positioned deep within the active site of the acyl-enzyme complex formed with pbp ', where it forms several hydrogen bonds and hydrophobic interactions. in particular, the -aminothiadiazolylhyroxyiminoacetyl side chain of ceftobiprole sits more deeply within the side-chain binding pocket of pbp ' than does the -acylamino side chain of nitrocefin in the previously determined complex structure. the additional interactions probably add to the enhanced stability of the acyl-enzyme complex formed with ceftobiprole, compared to complexes formed with other betalactams that are inactive against mrs. significant structural rearrangements between apo-enzyme and acyl-enzyme are evident in the crystal structure and in solution. conclusion: ceftobiprole readily forms a stable inhibitory acylenzyme complex with the pbp ', the beta-lactam resistance determinant of mrs. this, together with potent inhibition of the normal complement of beta-lactam sensitive penicillin-binding proteins, accounts for its excellent activity against staphylococci and probably accounts for the low rates of resistance development observed in experimental conditions. incidence of staphylococcus aureus with reduced susceptibility to glycopeptides in a french hospital (november -april c. morate, a. charron, c. bebear, j. maugein (bordeaux, fr) staphylococcus aureus are a major cause of nosocomial infections around the world. glycopeptides remain the drug of choice for severe infections caused by mrsa. however, after the emergence of vancomycin resistance in enterococcus and in the coagulase negative staphylococcus, strains of staphylococcus aureus with reduced susceptibility to glycopeptides (gisa) have been reported in different countries like japan, france, spain, the uk and the united states. the aim of our study was to determine the proportion of vancomycin resistance in clinical s. aureus isolates in a french university hospital, between november and april , then we wanted to define if there was an epidemic clone and study the clinical impact of these gisa strains. the protocol of detection was, first, a screening test on bhi agar containing mg/l of teicoplanin, then, the vancomycin and teicoplanin mics were determined by the method of etest with an inoculum of . mcf on the selected strains. finally, the isolates with mic of the teicoplanin ‡ mg/ l and mic of the vancomycin ‡ mg/l or mic of the teicoplanin ‡ mg/l and mic of the vancomycin £ mg/l were studied on population analysis. after that, pulsed-field gel electrophoresis (pfge) was performed on the different isolates and the pulsotypes were compared. from november to april , s. aureus isolates were collected from patients and screened for glycopeptide resistance on an initial agar screening test containing mg/l of teicoplanin. the teicoplanin mic was > mg/l for isolates ( . %) from patients and these strains were selected for the determination of the mics by ''macromethod'' etest. by this technique, strains were selected and studied by population analysis. all the profiles were compared to the reference strain mu profile. this procedure detected isolates (from patients) with heterogeneous reduced susceptibility to glycopeptides (hgisa). so the incidence of staphylococcus aureus with reduced susceptibility to glycopeptides in our hospital was found to be . %. four strains were resistant to methicillin and were also resistant to gentamicin. the diversity of the strains was confirmed by pfge: there was not an epidemic clone in the hospital. the clinical history showed that patients had received a prior treatment with vancomycin, and that patients had a failure in treatment: of them had cystic fibrosis. objectives: enterococcus faecalis was the most prevalent organism ( . %) involved in enterococcal infections at tehran hospitals followed by e. faecium ( . %). due to widespread expansion of aminoglycoside modifiying enzymes (agmes) genes, the rate of resistance to high level concentration of aminoglycosides has increased in these years. the rate of high level gentamicin resistant isolates of enterococci (hlgr) is high in iran ( %). the aim of this study was to determine the genes encoding resistance to aminoglycosides among enterococci in iran. methods: disks containing lg gentamicin were used to detect hlgr isolates. primers specific for aac ( ') aph ( ") and aph ( ') iiia genes were used in pcr to possibly detect acetyltransferases and phosphotransferas, the common agmes among isolates of enetrococci. theses isolates were resistance to different concentration of gentamicin. results: a bp region of the aac ( ')-aph ( ") gene was amplified by pcr in % hlgr isolates as well as in % of low level getamicin resistant isolates (llgr). moreover the gene aph ( ') iiia was detected in . % and % of isolates of hlgr and llgr respectively. differences between isolates of e. faecalis and e. faecium were found in term of prevalence of aph ( ') iiia gene. conclusion: the bifunctional enzyme aac ( ')-aph ( ") is the main cause of resistance to high concentration of aminoglycosides in our collection of enterococci. this enzyme confers resistance to all clinically useful aminoglycosides with the exception of streptomycin. in the absence of aac ( ')-aph ( "), gentamicin could be used in combination therapy. prevalence and genetic analysis of methicillinresistant staphylococcus aureus expressing highlevel and low-level mupirocin resistance m. kural, t. us, y. akgun (eskisehir, tr) objectives: to investigate the genetic location of mupa gene which encoded mupirocin resistance and characterize mupirocin-resistant methicillin resistant staphylococcus aureus (mrsa) isolated from patients in a turkish university hospital by polymerase chain reaction (pcr) and plasmid analysis. methods: methicillin and mupirocin resistance were detected by disk diffusion (oxoid, uk). the etest (ab biodisk, sweden) was performed to determine mupirocin minimum inhibitory concentrations (mics). the presence of mupa and meca were detected by pcr using specific primers. plasmid analysis were used to study the genetic location of mupa gene. results: a total of ( . %) mrsa strains were identified by disk diffusion in s. aureus. of the clinical isolates ( . %) were from wound, ( . %) from blood, ( . %) from catheter, ( . %) from lower respirator tract (bronchoalveolar lavage, pleural fluid and transtracheal aspirates), ( . %) from sputum, ( . %) from urine and ( . %) from other (serebrospinal fluid, parasynthesis fluid, peritoneal fluid, and bone marrow) clinical samples. among the mrsa isolates, mupirocin resistance was detected in ( . %) strains with disk diffusion and etest. of the mupirosin-resistant isolates ( . %) expressed high-level (muh) and ( %) expressed lowlevel (mul) mupirocin resistance. all isolates were vancomycin, teicoplannin susceptible and chloramphenicol resistant with disk diffusion. isolates with high-level and low level mupirocin resistance due to the mupa gene were also detected with pcr. plasmids were detected in all of the isolates. however only the muh isolates contained a kb plasmid that encoded highlevel resistance. all of the isolates contained a . kb plasmid and resistant to chloramphenicol. conclusion: our results indicated that the mrsa clones detected in the hospital had acquired a high-level mupirocin resistant plasmid. the past observations and recent studies suggested that the numbers of such strians have increased following extensive topical use of mupirocin. the usage of mupirocin in our hospital has not yet been systematically implemented. it is frequently prescribed for the treatment of staphylococcal skin infections and less to eliminate nasal carriage of mrsa. in our hospital we should be aware of the possible emergence and increase of mupirocin highly resistant mrsa strains in the future so that we should be considered when using mupirocin to control the spread of mrsa in hospital. emergence and spread of acquired fusidic acid resistance in staphylococcus aureus objectives: a major route to fusidic acid resistance (fusr) in s. aureus involves acquisition of fusb, a resistance determinant first clinical microbiology and infection, volume , supplement , identified on plasmid pub . here we show that (i) the two currently-circulating major clones of fusr s. aureus identified to date have acquired fusb from pub (or from the same ancestral source as pub ), and (ii) that the pub -encoded fusb is only one of at least three lineages of this protein that appear to have evolved since recruitment of the original, ancestral fusb to the staphylococci. methods: plasmid purification, dna sequencing, pcr amplification, and cloning in s. aureus rn using shuttlevector pcu , were all performed using established methods. antibiotic susceptibility testing was performed by agar dilution. results: the epidemic european fusidic acid-resistant impetigo clone (eefic) and community-acquired mrsa strain st have been shown to carry chromosomal and plasmid-encoded fusb, respectively. dna sequencing of fusb and its surrounding regions in these backgrounds revealed that they are identical to sequences on pub . however, acquired fusr does not always result from acquisition of the prototypical fusb gene. a gene encoding a fusb homologue was recently identified during sequencing of s. aureus strain mssa , and we identified an additional homologue encoded in the genome of s. saprophyticus strain atcc . the products of these genes exhibit~ % homology to fusb and to each other. cloning of pcr amplicons corresponding to these genes and their upstream expression signals into s. aureus established that they both confer resistance to fus. since these functional homologues are more closely related to each other than to those from other gram-positive organisms, it is highly likely that they evolved from an ancestral fusb after its recruitment to the staphylococci. conclusions: the three members of the staphylococcal family of fusb proteins appear to have evolved from the same ancestral protein, which, based on the low level of sequence homology between fusb genes at the nucleotide level, clearly occurred well before the introduction of fus into the clinic. of the three, the fusb protein encoded by pub is by far the most successful, and this gene/plasmid represents the source of (or shares a source with) the major fusr strain lineages. telithromycin activity is reduced by efflux in streptococcus pneumoniae c. benvenuti, r. koncan, g. bahar, a. mazzariol, g. cornaglia (verona, it; ankara, tr) objectives: telithromycin shows an excellent activity against m-type erythromycin-resistant streptococcus pneumoniae, thus is commonly regarded as being capable of overcoming the efflux resistance mechanism. nevertheless, telithromycin mic values in those strains appear to be distinctly higher than in the erythromycin-susceptible ones. the possibility of telithromycin acting as an actual efflux substrate, as it was already demonstrated in streptococcus pyogenes, seemed worth investigating. methods: telithromycin mic distribution was analysed in a collection of italian s. pneumoniae strains originating from multi-centre studies ( ) ( ) ( ) ( ) . the effect of an efflux mechanism was investigated using [ h]-telithromycin. results: telithromycin mic ranges were £ . - . mg/l (mic . mg/l and mic . mg/l) in erythromycinsusceptible strains (lacking both mef and erm genes) and . - mg/l (mic . mg/l and mic . mg/l) in strains endowed with the m phenotype. a distinct telithromycin efflux was detected in the strains expressing the mef gene, but not in those expressing the erm(b) gene, nor in the susceptible strains lacking mef or erm genes. efflux reversibility by addition of an inhibiting compound (sodium arsenate) was demonstrated. an msr-like sequence was also found in all strains effluxing telithromycin, but not in the others. conclusions: this is the first time that telithromycin has been shown to be effluxed by s. pyogenes isolates. that the efflux is related to the presence of both the mef and the msr-like genes is clearly demonstrated, but -owing to the increasingly evident complexity of s. pneumoniae efflux systems -other genes might also contribute to the efflux. an unusual phenotype of enterococcus faecalis in greece expressing low-level resistance to clindamycin and dalfopristin but susceptibility to quinupristin-dalfopristin m. maniati, f. kontos, p. liakos, e. petinaki, i. spiliopoulou, a. maniatis (larissa, patras, gr) objectives: to investigate the resistance mechanism of a new described phenotype among enterococcus faecalis expressing lowlevel resistance to clindamycin and dalfopristin but susceptibility to quinupristin-dalfopristin (q-d). methods: in greece, during , three enterococcus faecalis isolates, expressing this unusual phenotype, were recovered from urine samples. the isolates were studied by pcr for the lsa-gene and by pfge. nucleotide sequencing analysis of lsa and bp of the upstream region was performed. the isolates were also tested by rt-pcr for the expression of the lsa-gene. results: the isolates belonged to three distinct clones and carried the lsa-gene. no stop codons were found in any strain, while some point mutations in the lsa-gene were detected. comparing the lsa mrna production of these unusual strains with that obtained from fully q-d resistant ones no quantitative differences were found. conclusions: the findings of the present study clearly show that the resistance mechanism of quinupristin-dalfopristin is not only correlated with the presence and the expression of the lsagene. some mutations detected in the lsa gene probably are responsible for the production of an lsa protein with decreased activity, resulting to the q-d susceptibility. the presence of erm tr gene is responsible for the macrolide-resistance of streptococcus agalactiae objectives: to investigate the mechanism of resistance to macrolides in strains of streptococcus agalactiae in the area of thessalia, greece during the period - . methods: the subject of this study were strains of s. agalactiae which were collected from clinical specimens ( % vaginal swabs) from pregnant and non pregnant women. the strains were identified by gram stain, the lancefield b antigen, and by api strep system (biomerieux, france). susceptibility to macrolides, lincosamides and streptogrammines b was studied by the disk diffusion method. the mics were also measured by the use of e-test. the differentiation between m and mlsb inducible type was tested by the double disk synergy test (ddst). the detection of the genes mef a, erm tr, and erm b was performed by polymerase chain reaction (pcr). the clonality of the resistant strains was studied by pulse-field gel electrophoresis. results: of the strains, were resistant to erythromycin, lincosamid and streptogrammines b. none was found to be resistant to erythromycin only (m-phenopype). % of the strains were mlsb constitutive phenotype, while % were mlsb inducible. all strains were found to carry the erm tr gene. only one strain was found to carry both erm tr and erm b genes. pfge analysis revealed the emergence of multiple resistant clones. conclusions: the resistance of s. agalactiae to mlsb antibiotics is related with the presence of erm tr gene in central greece. emergence of novel clindamycin resistance phenotype among invasive streptococcus pyogenes isolates in sweden a. jasir, b. luca, c. schalen (lund, se) objectives: in some recent throat group a streptococci (gas) isolates from our diagnostic laboratory total resistance to clindamycin but susceptibility to erythromycin and other -as well as -membered macrolides was found. the isolates were susceptible to -membered macrolides and streptogramin b. these atypical strains thus did not agree with previously known mls resistance phenotypes. the main objective was to characterize theses resistance phenotype and genotypes. method and results: the isolates were examined for resistance genes by pcr. out of strains one harboured an erma gene. the gene was sequenced and showed a mutation in regulatory part and was localized on a transposons. all other strains were negative for any erm genes and were also tested for s rrna mutations with negative outcome. strains were t-and emm typed and showed to belong to different types. conclusions: gas account for common human infections such as acute pharyngotonsillitis and impetigo, which untreated may be followed by the nonsuppurative complications rheumatic fever and acute poststreptococcal glomerulonephritis gas may also give rise to invasive, often life-threatening acute disease, such as scarlatina, erysipelas, endometritis, necrotising fasciitis and sepsis, often accompanied by toxic shock. without known exceptions, gas are fully susceptible to betalactams, which are first-choice drugs for treatment. in cases of allergy or intolerance to penicillins, macrolides are most used, and possibly as a consequence, a significant resistance development to these agents has evolved in many parts of the world. though the role of clindamycin for treatment of streptococcal disease is more limited this drug was shown to be particularly effective in eradicating streptococci after penicillin treatment failure of pharyngotonsillitis. clindamycin, often as a supplement to betalactams, also may have a life-saving effect in the treatment of fulminant streptococcal infections. due to its important role in the treatment of invasive streptococcal disease, resistance development to clindamycin in gas is considered highly undesirable. the alarming finding of a possibly new phenotype of selective clindamycin resistance in gas will motivate a thorough analysis of the phenotype as well as identification of its resistance determinants. a. al-lahham, m. van der linden, r.r. reinert (aachen, de) objectives: telithromycin is a novel ketolide antibiotic with significant in-vitro activity against streptococcus pneumoniae. the aim of this study is to characterize the resistance mechanisms of clinical isolates of s. pneumoniae with reduced susceptibility to telithromycin (> mg/l) and to perform the time-kill kinetics with telithromycin. methods: determination of mics was performed by the microbroth dilution method according to the clsi and the serotyping by the neufeld quellung reaction. multilocus sequence typing, sequencing of the s rrna, sequencing of genes encoding ribosomal proteins (l and l ), and ermb were performed according to standard methods. four isolates were selected for time-kill, two of which with a telithromycin mic mg/l and two strains with a telithromycin mic of mg/l. results: in two nation-wide studies and one european surveillance study (n = ) performed at the national reference center for streptococci (nrcs) in germany, reduced susceptibility to telithromycin (> mg/l) was detected in isolates ( . %). mic /mic (mg/l) of the strains to other antibiotics were as follows: telithromycin / , penicillin g / , cefuroxime / , erythromycin a > /> , clindamycin > /> , tetracycline / , and gatifloxacin . / . . two major serotypes were observed, serotype ( . %) and serotype a ( . %). all isolates possess the cmlsb phenotype (ermb positive). the isolates showed a wide range of combinations of resistance determinants including multiple alterations in the s rrna (a g, c t, a g, a t, and c t), a s n alteration in the ribosomal protein l (n = ), and a n s alteration in the erm(b) gene (n = ). the predominant clone was serotype sequence type ( of isolates), which was seen in france (n = ) and germany (n = ). telithromycin-resistance has also spread to the spain f- clone (st ; n = ) and its serotype a variant. in vitro time-kill showed a minimal kill from - hours and then regrowth. bactericidal activity was achieved only with times the mic in all strains. conclusions: although the incidence of telithromycin resistance remains rare world-wide, the spread of telithromycin resistance to multi-drug resistance clones with world-wide distribution is worrisome. gbs obtained from non-pregnant women. the erythromycin resistant-gbs were identified, phenotypically analysed, screened by pcr for mre(a) gene and for erythromycin resistance genes: erm(b), erm(tr), mef(a) and mef(e), and serotyped with type specific antisera for serotypes ia, ib, ii, iii, iv, and v. results: among the total of gbs, ( . %) were erythromycin-resistant: ( . %) erythromycin-resistant gbs were isolated from vaginal swabs of pregnant women and ( . %) from non-pregnant women. the frequency of serotypes in erythromycin-resistant gbs tested, the distribu-tion of their resistance genes and the distribution of serotypes among the different genotypes are illustrated in the table. nt, nontypeable, the mre(a) gene was found in all the gbs strains tested. mics of erythromycin in erythromycin-resistant gbs were: mic and mic , > mg/l; range, to > mg/l for gbs harbouring erm(b) and erm(b)+erm(tr) and mic and mic , mg/l and > mg/l, respectively; range, . to > mg/l for gbs harbouring erm(tr). conclusion: erm(b) was the erythromycin-resistant gene most prevalent among the gbs isolates and these isolates showed the highest mics of erythromycin. the commonest serotypes among erythromycin-resistant gbs isolated were iii, ii and i, and showed genotypic variability harbouring either of the two most prevalent genes, erm(b) or/and erm(tr). methods: we studied the rates of resistance to tetracycline and minocycline among erythromycin-resistant gbs strains isolated at the university hospital lozano blesa of zaragoza, spain. isolates were subsequently phenotypically analysed by means of the disk diffusion method and screened by pcr for erythromycin and tetracycline resistance genes [erm(b), erm(tr), mef(a/e), tet(m) and tet(o)]. the susceptibility to erythromycin, josamycin, tetracycline and minocycline was tested by the agar dilution method according to the nccls. the strains were serotyped with type specific antisera for serotypes ia, ib, ii, iii, iv, and v. results: among the total of isolates of macrolide-resistant gbs collected from may to april in our hospital ( . % of the total sgb isolated), ( . %) were tetracyclineresistant. the distribution of tet(m) and tet(o) among the erythromycin-resistant gbs harbouring erm(b) was ( . % and . %, repectively) and harbouring erm(tr) was ( . % and . %). the distribution of tetracycline resistance genes and serotypes among the different genotypes in gbs are illustrated in the table.*nt: non typable isolates carrying tet(m) or tet(m)+tet(o) presented the following mics: tetracycline (mic , mic , range - mg/l); minocycline (mic , mic , range - mg/l). isolates carrying tet(o) presented the following mics: tetracycline (mic , mic , range - mg/l); minocycline (mic , mic , range - mg/l). conclusion: the majority ( . %) of tetracycline-resistant gbs harboured tet(m) alone or in combination with tet(o). the most prevalent serotypes among the total of tetracycline-resistant gbs was the serotype iii ( %) and the serotype ii ( %). serotype iii was more prevalent among the gbs harbouring the tet(m) gene and serotype ii was more prevalent among the gbs harbouring the tet(o) gene. objectives: to know the prevalence of resistance to macrolides in viridans streptococci, its mechanism and the genetic elements which are involved. methods: we studied viridans streptococcus pharyngeal isolates from different patients. mics for macrolides were determined by the agar dilution method. the presence of mef and erma, ermb and ermtr genes, and the presence of mega (macrolide efflux genetic assembly) or tn in resistant, mef + isolates was determined by pcr with specific primers. the similarity to mef genes first described in pneumococci (mefe) and streptococcus pyogenes (mefa) was determined by sequencing. results: viridans streptococci isolates were resistant to macrolides ( . %). out of the resistant isolates harboured mef genes ( . %), one harboured ermb ( . %), and isolates harboured both mef and ermb genes ( . %). no isolates harboured erma or ermtr genes. we studied genetics elements which harbour mef genes in other streptococci, in mef (+) isolates. we found mega insertion element in of isolates ( . %), all of them harbouring mefe. the only isolate in which we found mefa, did not harbour mega, but tn . conclusions: m phenotype is frequent in viridans streptococci, and all of them harbour mef genes. most mlsb phenotype viridans streptococci do not harbour erm genes alone; most of them combine erm and mef genes. most isolates contained the mef sequence corresponding to mefe, and the genetic element (mega) usually described in pneumococci as harbouring this gene. one isolate contained the sequence corresponding to mefa, and the genetic element usually described in s. pyogenes (tn ). the increasing presence of macrolide-resistant pneumococci harbouring mega element might be related with its wide presence in viridans streptococci. the acquisition of mega by pneumococci from viridans streptococci through transformation is being studied. objectives: the principal mechanism of macrolide resistance in streptococcus pneumoniae in italy is target site modification mediated by erm(b). the erm(a) gene is common in streptococcus pyogenes but rare in s. pneumoniae, even if recent studies have demonstrated an increased detection of this resistance determinant. recently, a clinical s. pneumoniae isolate carrying erm(a) has been obtained from a patient with meningitis in italy. the aim of this study is the molecular characterization of this isolate. methods: antimicrobial susceptibility tests were determined by etest. the presence of erythromycin resistance determinants was detected by pcr assays. genotyping was performed by pfge and mlst. the flanking regions of erm(a) were analysed by sequencing a fragment amplified by inverse pcr. transformation and conjugation experiments were carried out. transformants were analysed by pfge and hybridization with an erm(a) probe. results: the isolate belonging to serotype (st) a, was resistant to erythromycin, inducibly resistant to clindamycin and susceptible to penicillin and tetracycline. by pcr, the only macrolide resistance determinant detected was erm(a). pfge analysis revealed the genetic correlation of this strain with other st a s. pneumoniae italian isolates. mlst confirmed this data since the isolate belonged to st , which is a single-allele variant of st , the most common st among italian st a isolates. a bp dna fragment, obtained by inverse pcr and containing the erm(a) gene, was sequenced. this fragment contains an orf upstream erm(a), the gene erm(a) identical to that described in s. pyogenes and orfs, downstream erm(a), one homologous to a hypothetical kinase and the other two to transposases of other gram-positive species. in transformation experiments the gene erm(a) was transferred to an erythromycin susceptible recipient. hybridization analysis of one transformant revealed that the size of the transferred dna fragment was approximately kb. no transconjugant was obtained in mating experiments. conclusions: this is the first italian report of an s. pneumoniae isolate carrying erm(a). erm(a) appears to be contained in a genetic element that includes two transposases, although the gene is not transferable by conjugation. objective: treatment with the first oxazolidinone antibiotic, linezolid, of infections caused by staphylococci has proved effective in most cases. in the present study we present the first three cases of linezolid resistant staphylococci in our hospital. methods: we examined three coagulase negative staphylococcus strains isolated from blood cultures (bactec, becton dickinson). identification and susceptibility testing were performed by the vitek ii automated system (biomerieux) and the results were confirmed by the api system (biomerieux) and e-test (ab biodisk, solna, sweden), according to nccls guidelines. results: three linezolid resistant staphylococci were isolated from blood cultures. identification showed that all three isolates were staphylococcus cohnii subsp. urealitycum and the mic values were lg/ml (n = ) and lg/ml (n = ) which are much higher than the value of lg/ml that characterizes sensitive strains. the isolates derived from three patients in different wards of our hospital. the first two isolates were recovered from two icu patients in april and august and the last staphylococcus cohnii was isolated from a patient in the neurosurgery ward, who is still hospitalized. all patients received prolonged treatment with linezolid. conclusions: although six linezolid resistant clinical isolates of s. aureus were previously reported in the literature, these three isolates are the first coagulase negative staphylococcus isolates resistant to linezolid. it is imperative to screen for resistance to linezolid all staphylococci and take the necessary precausions in order to prevent the spread of a linezolid resistant strain in other wards of our hospital. correlation between mic and number of mutated s rrna genes in oxazolidinone-resistant staphylococcus aureus objectives: to determine the number of mutated s rdna alleles present in clinical and laboratory-generated linezolidresistant staphylococcus aureus isolates. methods: linezolid-resistant isolates were tested, of them clinical isolates (mics - mg/l) and mutants selected in-vitro (mics - mg/l). the mutants were raised by repeated passage on increasing linezolid concentrations and their parentage was verified by pfge. mics were determined by agar dilution. genomic dna was digested with ecori and hybridized with a bp probe corresponding to domain v of the genes encoding s rrna, to determine gene copy number. pyrosequencing was used to quantify the proportions of wildtype and mutated alleles present; assays were designed to detect the presence of mutations conferring oxazolidinone resistance. pyrosequencing and hybridization data were combined to determine the number of mutated alleles present. results: resistance selected in-vitro proved less stable than that in the clinical isolates. pyrosequencing showed that all clinical isolates had the g t mutation, of the in-vitro selected mutants had g t, had t c, had t a, had a g and had g a. the s rdna copy number in the oxazolidinone-resistant clinical isolates varied from - , and from - in the laboratory-generated mutants; / laboratoryselected mutants had changes in copy number, compared with their parent strains, and had changes in fragment size, but not number. the number of mutated copies in lin-resistant isolates ranged from - in laboratory-selected mutants and from - in clinical isolates. an increasing number of mutated genes correlated with increasing linezolid mic. conclusions: in combination, pyrosequencing and hybridization successfully determined the number of mutated s rdna alleles. exposure to linezolid selected changes in s rrna gene copy number as well as sequence in % of in-vitro selected mutants. there was a positive correlation between both the number and proportion of mutated s rdna copies and mic, previously unproven for staphylococci. objectives: linezolid (lzd) is an important antibiotic for the treatment of enterococcal infections, especially when the corresponding strain possesses multiresistance including resistance to vancomycin (van). we report the emergence lzd resistance in clonally related van-susceptible and vanresistant enterococcus faecium isolates originated from an icu patient only days after initiation of linezolid therapy. patient and methods: van-resistant e. faecium was repeatedly isolated from intraabdominal cultures of a -year-old female icu-patient with infected necrotizing pancreatitis after pancreaticoduodenectomy (whipplés procedure). antibiotic susceptibility testing of the bacteria was performed by e-tests; vana gene were detected by pcr. the possible lzd resistance mechanism (mutation in the s rdna of one or more of the six s rrna alleles of e. faecium) was examined by a pcr-based method. molecular typing of the strains was performed by smai macrorestiction analysis. results: van-resistant but lzd-sensitive e. faecium (vrlse) were initially detected in intraabdominal cultures, however, already twelve days after initation of lzd therapy, van-and lzd-resistant e. faecium (vrlre) strains were detected. resistance to lzd was confirmed: mics ranged from to mg/l. all e. faecium isolates showed identical or closely related pfge patterns. throughout the icu period, van-and lzd-susceptible e. faecium (vslse) strains were repeatedly detected in the same specimens from which the vrlse and vrlre were isolated. additionally, van-susceptible e. faecium isolates with resistance to lzd (vslre) were detected. mutations in the s rdna of three out of six alleles led to lzd resistance in the e. faecium isolates examined. two weeks after termination of the lzd therapy, no lzd-resistant strain could be detected in follow-up swabs. conclusions: resistance to lzd in e. faecium can occur already shortly after the initiation of lzd therapy. assessment of antibiotic susceptibilities of all isolates at the start of therapy and regularly during the therapy is advisable, especially during therapy of severe infections. the epidemiological and clinical repercussions of resistance to lzd among enterococci cannot be predicted at this time. attention to proper dosing and prompt removal of infected devices, when feasible, could limit occurrence and spread of lzd-resistant e. faecium. objectives: to investigate the mechanisms of resistance to tetracycline in shigella spp. methods: one hundred and eleven tetracycline-resistant shigella spp strains ( s. sonnei, s. flexneri), were isolated as a cause of enteritis in our geographical area and the remaining recovered from patients with traveller's diarrhoea. antimicrobial susceptibility to tetracycline was determined by the kirby-bauer method. presence of teta, tetb and tetg genes was established by pcr. sequencing of amplified products were used to corroborate the reliability of the pcr results. maentel haenszel test was used to establish the statistical significance. results: the statistical analysis showed that the teta gene was more frequent in s. sonnei (p < . ), while tetb was more usual in s. flexneri (p < . ). although without statistical significance (p: . ), presence of non-determined mechanisms of tetracycline-resistance seems to be more frequent among s. sonnei. conclusions: species-specific differences in the distribuition of the teta and tetb genes has been shown. moreover . % of the analysed strains did not show any of the analysed determinants of tetracycline-resistance. the concomitant presence of more than one of the analysed genes is a rare event. distribution and genetic determinants of tetracycline resistance in laribacter hongkongensis isolates from humans and fish objectives: to study the distribution of tetracycline resistance and to clone and characterize a tetracycline resistance determinant in laribacter hongkongensis, a recently discovered bacterial genus and species associated with communityacquired gastroenteritis. methods: twenty-four l. hongkongensis strains isolated from patients with community-acquired gastroenteritis and l. hongkongensis strains isolated from freshwater fish in hong kong were used in this study. genetic determinants for tetracycline resistance were looked for by screening a genomic dna library of l. hongkongensis. the prevalence of teta gene in other strains of l. hongkongensis was studied by pcr using laboratory-designed primers. the presence of the tetracycline resistance determinants in plasmid was examined by southern blot analysis. results: among human and fish isolates tested, human and fish isolates were tetracycline-resistant. a -bp gene cluster, which consists of putative transposases, a tetr and a teta gene, was cloned by inserting restriction fragments of genomic dna from a resistant strain, hlhk , into pbk-cmv. the -bp teta and -bp tetr genes shared significant nucleotide sequence homology with known teta and tetr genes. while the flanking regions and ' end of the teta were identical to the corresponding regions of a tetc island in chlamydia suis, the teta was almost identical to that of transposon tn and plasmids found in many gram-negative bacteria, suggesting that illegitimate recombination may have occurred to produce the present tetracycline resistant determinant. southern hybridization suggested that the teta gene of hlhk was plasmid-encoded. the tetracycline resistance in l. hongkongensis was associated with teta. pcr amplification of the teta gene in the isolates of l. hongkongensis, including hlhk , showed the presence of teta in all the four tetracycline resistant isolates but none of the tetracycline susceptible ones. in contrast to strain hlhk , the teta of two strains were identical to that of tn , while that of the other strain was more closely related to other gram-negative bacteria plasmids. conclusion: our results indicate that horizontal transfer of genes, especially through tn and related plasmids, between l. hongkongensis and other gram-negative bacteria is probably a frequent event and is an important mechanism for acquisition and dissemination of tetracycline resistance in l. hongkongensis. succesful treatment of infective endocarditis with linezolid t. hryniewiecki, u. lopaciuk, j. stepinska (warsaw, pl) objectives: there is an increasing proportion of resistant strains causing infective endocarditis in recent years. it has changed the approach to choice of antibiotic therapy. linezolid (zyvoxid Ò ) is a new bacteriostatic antibiotic with a wide spectrum of activity against gram-positive organisms and with good efficacy in experimental animal models of endocarditis. unfortunately clinical experience with linezolid in the treatment of endocarditis is limited. the aim of the study was to observe efficacy of linezolid in the treatment of infective endocarditis. methods: the study group consisted of patients hospitalised in institute of cardiology in warsaw ( warsaw ( - due to clinically resistant infective endocarditis. the diagnosis of endocarditis was established according to the duke criteria by clinical examination, echocardiography, laboratory investigations and positive blood cultures with vancomycin mic estimation (in pts). all patients were treated surgically (valve replacement, artificial material removal) in conjunction with different conventional antibiotics and afterwards with mg of linezolid every hours intravenously. results: infective endocarditis was diagnosed as caused by mrcns in pts, mssa in pt, enterococcus faecalis in pt and staphylococcus epidermidis mr in pt. vancomycin mic vary from to mg/l. in pts culture-negative endocarditis was diagnosed. all patients were treated with linezolid intravenously to weeks (average , ). clinical response and eradication of bacteremia were achieved in all patients. leukopenia nad thrombocytopenia as an adverse reaction occurred in patient. conclusions . linezolid is effective in patients with grampositive endocarditis. . linezolid could be also effective in some patients with culture-negative endocarditis. . linezolid may provide an alternative in the treatment of infective endocarditis due to multi-resistant bacteria, in patients with resistant course or with adverse reaction to conventional antibiotics. objectives: to evaluate the safety and efficacy of lzd in a chinese population. methods: this randomized, double-blind, multi-centre study was conducted in china. after obtaining written informed consent, patients from to years of age with pneumonia (pneu) or skin and soft tissue infection (ssti) known or suspected to be caused by a gram-positive pathogen were randomized : to receive either lzd, mg, or vancomycin (van), g, each given iv q h. patients were to be treated for to days, and outcomes were assessed at end-of-treatment (eot) and follow-up (f-u) visits. results: one hundred forty-two patients were enrolled and received study medication, with pneu and with ssti. clinical assessments (effective = ''cured'' plus ''marked improvement'') for patients in the fully evaluable population are summarized in the table. the most frequently isolated pathogen was staphylococcus aureus: all isolates were susceptible to both study drugs. the eradication rates for all pathogens in evaluable patients at the f-u evaluation were / ( . %) in lzd-treated patients and / ( . %) in van-treated patients (p = . ). all patients receiving study drug were evaluated for safety. drug-related adverse events (aes) were reported in ( . %) lzd-treated and ( . %) van-treated patients. the most commonly reported drug-related aes in lzd-treated patients were mild abnormalities in liver function tests and leucopenia ( . % each); rash ( . %) was the most commonly reported ae in van-treated patients. seven ( . %) lzd-treated and ( . %) van-treated patients discontinued study drug because of an ae. conclusions: linezolid is an effective drug for the treatment of infections caused by gram-positive pathogens and is welltolerated. eradication in one patient, by rifamycinlinezolid, of a methicillin-resistant staphylococcus aureus producing panton-valentine leukocidin, responsible for relapses over months, and decolonisation of her family by mupirocin objective: we report the case of the mother who experienced relapses over the period. methods: pvl-mrsa were isolated on routine and mrsa agars (biorad). antibiotypes were studied by disk diffusion method. genetics and pulsotypes were studied by the french centre national de référence des staphylocoques in lyon (cnr). results: mrs kym had her th child on october , in the hospital of orléans. she was healthy and presented no risk factor for delivery. three weeks later she was addressed for surgical treatment of an abscess on buttocks. cultures yielded the special antibiotype: methicillin-r, kanamycin-r and tobramycin-s, of the pvl-mrsa currently spreading across europe and maghreb. the cnr found the luks-pv and lukf-pv-genes.through march , she relapsed times and was treated by pyostacin for a total of weeks. two of her children were addressed for abscesses ( buttocks, thumb) yielding the same bacteria. in march , mrs kym was addressed to the infectious diseases ward because of nasal furonculosis. samples yielded a pvl-mrsa with mls-b phenotype. treatment by rifamycin-linezolid d was initiated. the whole family was screened. the father and the boy, , who had the infected thumb months earlier, were carriers. the girl, , who had an abscess on buttocks months earlier was not. in april the whole family accepted an attempt for decolonisation by % nasal mupirocin or /d for d. cure and decolonisation were confirmed by nares and cutaneous folds samples in may and june. they missed an additional appointment in the beginning of term, but a phone call to the social worker confirmed none of them relapsed. the cnr studied strains ( from mrs kym , , from children abscesses in and , from boy's and father's nares ), and confirmed that they were all identical along the period and across the family. conclusion: short treatment with linezolid-rifamycin in the relapsing case associated with familial decolonisation by nasal mupirocin was an effective strategy to stop a time-prolonged familial outbreak of pvl-mrsa infection. multiple brain abscesses and purulent meningitis by listeria monocytogenes in an otherwise healthy man. favourable linezolid response, hampered by a suspected early drug myelotoxicity introduction: l. monocytogenes cns infection in immunocompetent adults remains rare. meningitis is the most common cns manifestation, with brain abscesses being < % of overall episodes. anecdotal episodes of cns l. monocytogenes infection were reported from immunocompetent patients where both diagnosis and treatment may be hampered by low clinical suspicion and a frequent non-specific presentation. in a -yearlong survey conducted in dallas (us), only cases of nonneonatal l. monocytogenes meningitis were found (estimated incidence rate: . %). case report: a -year-old male with a negligible history and no obvious exposure to l. monocytogenes was hospitalized owing to dizziness. a brain ct scan showed a small, late ischemic lesion. a few days later hyperpyrexia, headache, vomiting and altered mentation occurred. the csf study detected an elevated albumin content ( mg/dl), low glucose ( mg/dl) and a wbc count of cells/ll ( % neutrophils) so that ceftriaxone-chloramphenicol were immediately started. clinical-neurological conditions deteriorated while l. monocytogenes was cultured from the csf so that treatment was changed towards high-dose ampicillin-gentamicin. the persistence of severe clinical-neurological conditions and altered csf assay prompted the introduction of rifampicin-cotrimoxazole after days, but days later other focal neurological deficits appeared and a mri showed small, hyperintense focal lesions involving the medulla oblongata, interpreted as multiple abscesses. the introduction of linezolidmeropenem, despite anemia (requiring rbc transfusions after - days) led to a progressive clinical-csf improvement. our patient recovered completely and a control mri carried out month after discharge confimed the complete disappearance of the multiple brain listeria abscesses. discussion: the l. monocytogenes meningitis and multiple subtentorial abscesses (including rare localizations at cerebellum, bulb, and pons varolii), had an evolving cumbersome presentation. despite the in vitro activity of a broad spectrum of agents, multiple therapeutic changes became necessary, until the last linezolid-meropenem combination, which was proved very effective, although it was affected by relapsing anemia probably attributable to linezolid. linezolid, due to its elevated csf-brain penetration, and its activity against a broad spectrum of cns pathogens (including the intracellular l. monocytogenes), is expected to become a key antimicrobial compound, waiting for rct. discrepancy between favourable in vitro microbiological data and a severe clinical course of a staphylococcal knee and soft tissue infection responsive to oxazolidinone linezolid only after failure of all other therapeutic attempts introduction: to offer therapeutic alternatives for the emerging, multiresistant, serious gram-positive infections, novel molecules (quinupristin/dalfopristin, linezolid, daptomycin) were introduced and are made available when multiresistant gram-positive cocci are documented as no more susceptible to all available drugs including glycopeptides. however, inezolid encompasses unique tissue penetration and diffusion features (regarding soft tissues, lungs, joints and central nervous system) which make this last drug extremely promising in all circumstances where the penetration rate into infectious foci becomes critical. clinical experience: a very intriguing case report of a severe, staphylococcal knee arthtiris associated to an extensive local cellulitis/fasciitis and haematogenous dissemination occurring after a surgical curettage was characterized by a complete lack of response to a prolonged vancomycin/teicoplanin plus rifampicin therapy based on the apparently favourable in vitro sensitivity assays of methicllin-resistant staphylococci, but rapidly responded to i.v. (followed by oral) linezolid administration. the complete lack of clinical activity of a -week glycopeptiderifampicin administration cannot be explained by the in vitro measured mic values of isolated pathogens which showed complete sensitivity of staphylococcus aureus against vancomycina/teicoplanin and rifampicin and susceptibility of a concurrent hematogenous s. epidermidis strain to glycopeptidesrifampicin. since an abscess formation and an underlying osteomyelitis were carefully excluded by adequate instrumental examinations, from a theoretical point of view the active glycopeptide-rifampicin molecules should have been provided appropriate cure. on the other hand, from a strictly clinical issue, only a -week administration of i.v. linezolid followed by one more week of oral linezolid allowed to obtain a complete clinical-bacteriological cure and a complete function recovery without any sequelae after a . -year follow-up. conclusions: when the management of severe, multiresistant gram-positive infections is of concern, the in vitro activity of single drugs and therapeutic classes should be carefully evaluated in relation with the expected penetration and diffusion rates of these drugs into the relevant organs and tissues involved by the ongoing infectious localizations. otherwise, apparently unexplained failures may occur also when in vitro studies point out a complete activity of the tested compounds. epidemiology of resistance to antibiotics -ii p contemporary prevalence of bro betalactamases in m. catarrhalis: report from the sentry antimicrobial surveillance program (usa; l. deshpande, h. sader, r. jones (north liberty, us) objectives: to evaluate the prevalence of bro- and bro- among b-lactamase (bl)-producing m. catarrhalis (mcat) in the usa. although the bl-mediated penicillin (pen) resistance (r) in mcat has been stable at %, the bro- and - occurrence has not been determined in usa isolates since . bro- rates have been reported at < ( s), . ( - ), . ( - ) and . % ( - ) . methods: community-acquired mcat isolates (sentry program were tested by clsi broth microdilution methods including: , worldwide and , in north america (na). bro- and - was detected by pcr methods (levy and walker; ), compared to epidemiologic tests, and mic values. b-lactamase-positive (bl+) mcat samples per year from usa ( sites) and canada (ca; sites) were tested for the odd-numbered years. results: the bro- rate was , , , and % for , , and , respectively; rates in ca ( isolates) > usa ( ). several agents remained active: amoxicillin/clavulanate (mic , £ . mg/l), ceftriaxone (ctri; . ), cefuroxime ( ), erythromycin (£ . - . ), levofloxacin (£ . - . ), tetracyclines ( ) and trimethoprim/sulfamethoxazole (tmp/ smx; £ . / . ). pen mic distribution was tri-modal (£ . , - , > mg/l) and ctri bi-modal ( . , . ), yet bro- and - mic/zone distributions overlap (best discriminated by methicillin (mean zone, . vs. . mm) and pen ( . vs. . ) disks). possible bro- epidemic clusters could not be excluded due to a very common ribotype in centres (ca, sites; usa, ). conclusions: this bro- and - enzymes na prevalence update in mcat isolates ( ) ( ) ( ) ( ) ( ) ( ) ( ) shows stability at - % and - %, respectively. phenotypic tests (zones or mics) cannot easily distinguish between these b-lactamase types, necessitating the use of molecular applications. objective: although resistance to penicillin in beta haemolytic streptococci has not been reported yet, increasing resistance rates for alternative drugs, such as erythromycin, clindamycin or tetracycline is an emerging concern which brings the necessity to carefully monitor penicillin susceptibility. materials and methods: in order to detect any changes in penicillin mics, we performed antimicrobial susceptibility testing for all isolated beta haemolytic streptococci in our hospital between january and november . identification to serogroup level was done using a commercial latex agglutination kit (avipath strep, omega diagnostics ltd., scotland, united kingdom). results: a total of isolates were identified, distribution of groups for serogroup a, b, c and g were . %, . %, . % and . %, correspondingly. penicillin susceptibility was determined using etest (ab biodisk solna, sweden) strips according to manufacturers' instructions. when results are evaluated in year periods, mic increased from . to . mg/ml for group a, from . to . mg/ml for group b, from . to . mg/ml for group c and from . to . mg/ml for group g (table) . conclusions: even though highest mic values were to be found in group b ( . mg/ml), our results indicate the steady increase in penicillin mic for all serogroups. three group a and six group b isolates with penicillin mic of . mg/ml, reaching susceptibility breakpoint concentration according to clsi, and also highly elevated mic concentrations for group b streptococci may be messengers of possible forthcoming resistant strains. objective: to study trends in macrolide resistance rates among s. pneumoniae isolated from children aged to months attending day-care centres in france following implementation of prudent antibiotic use campaigns (alpes maritimes , france and pneumococcal conjugate vaccine (pcv) ( ) . method: nasopharyngeal aspirates were obtained from a random -stage cluster sample of children attending day-care centres in the nord (n) and alpes maritimes (am) areas during consecutive surveys between january and march march , march and . susceptibility to erythromycin and clindamycin and resistance phenotype were analysed by disk diffusion method. serotypes were determined using the quelling reaction. pneumococcal immunization status and antibiotic prescriptions over the previous months were recorded. results: sp was isolated from / , / and / children in , and , respectively (p < ) ). resistance to macrolides declined overall from . % to . % of strains between and (p < ) ). among erythromycin-resistant (e-r) isolates, percentage of erm-b phenotype increased from . % to . % (p = . ). while the proportion of penicillin non-susceptible strains declined from . % to . % of sp isolates (p < ) ), erythromycin resistance remained stable among these strains at . %. overall proportion of treated children fell from . % to . % (p < ) ) between and ; in am this reduction was observed in ( . %; p < ) ), while in n it occurred in ( %; p < ) ) and the percentage of macrolides among prescriptions fell from . % to . % (v for trend: p = . ). serotype distribution showed most e-r isolates were b, , f and f. a % reduction in serotype f was observed in am in and in n in . immunisation with pcv concerned at least . % of children in . conclusion: macrolide resistance has followed a parallel decline with penicillin resistance as a result of antibioticprescription reducing campaigns and pneumococcal immunization against the most prevalent macrolide-resistant serotypes. objective: to evaluate the prevalence of resistance of invasive strains of s. pneumoniae to erythromycin after decline in macrolide consumption. methods: the number of packages of antibiotics was obtained from the institute of public health of slovenia. for the period - the data on outpatient antibiotic consumption were collected using the atc/ddd classification (who version ) and the results were expressed in ddd/ inhabitants per day (did). all invasive strains of s. pneumoniae isolated from sterile body fluids in all slovenian hospitals were included in the study. susceptibility testing was performed using nccls approved disk diffusion test. results: during - the total use of antibacterials in slovenia decreased for . % from . did to . did. the consumption of macrolides which constituted . - . % of total use of antibacterials decreased for . % ( . to . did). short-acting (erythromycin, miocamycin), intermediate-acting (midecamycin, roxithromycin, clarithromycin), and long-acting (azithromycin) decreased for . %, . % and % respectively. in all years the use of intermediate-acting macrolides was the most prescribed subclass of macrolides corresponding for . - . did, followed by long-acting ( . - . did) and short-acting ( . - . did). the resistance of s. pneumoniae strains to erythromycin increased from . % ( / ) to . % ( / ); in children from . % ( / ) to . % ( / ) and in adults from . % ( / ) to . % ( / ) respectively. rates of the isolates resistant to erythromycin and at least of the following agents: penicillin, tetracycline, tmp/smx, chloramphenicol increased from . % ( / ) to . % ( / ); in children from % ( / ) to . % ( / ) and in adults from . % ( / ) to . % ( / ) respectively. conclusion: despite a reduction of macrolide consumption in outpatients the resistance of invasive strains of s. pneumoniae was increasing during the observation period especially in children. multiple drug resistance explains best the changes in s. pneumoniae resistance in a ten-year surveillance study in belgium objective: belgium is located between countries with very high and very low antibiotic resistance rates. modeling how resistance changes over time and place in belgium provides insights into correlates of s. pneumoniae resistance at the population level. methods: surveillance data consists of , s. pneumoniae invasive isolates from - , identified by postal code as well as clinical and demographic information. antimicrobial consumption (ims health services) is expressed in defined daily doses (ddd) per inhabitants per day. changes in resistance by month and postal code were evaluated using mixed effects models for repeated measures, using mathematical models of transmission for the curve shape, and taking into account seasonality. resistance to penicillin, erythromycin, tetracycline, and ofloxacin was considered in the analysis. results: resistance to penicillins, macrolides and tetracyclines peaked in the year , and their levels in were . %, . % and . % respectively. the shape of the curves is similar for most of the antibiotics studied, with a steep rise from to and a plateau thereafter. resistance to two or more antibiotic classes corresponded to % of all resistant isolates and in a multivariate model explains most of the variability through time and place of the antibiotics studied. resistance to only one antibiotic (any) decreased from . % in to . % in , while resistance to two or more increased . times ( % ci . - . , p < . ) from . % in to . % of all isolates years later. more than nine out of ten isolates that were macrolide or tetracycline resistant were also multiply resistant (mr). mr increases . % for each ddd of overall cumulative antimicrobial consumption, and out of all antibiotic classes, macrolides and broad-spectrum penicillins are most associated with resistance. conclusion: resistance to two or more antibiotics is the most important factor in understanding the changes over time for all studied antibiotic classes in belgium. the cumulative impact of antimicrobial exposure of separate antibiotic classes at the population level facilitates the survival and transmission of any isolate that is resistant to two or more antibiotic classes. methods: the isolates were identified by biochemical tests and specific serotyping. antimicrobial susceptibility to ampicilllin (amp), amoxicillin plus clavulanic acid (auc), cloramphenicol (cm), gentamicin (gm), cotrimoxazole (sxt), nalidíxic acid (nal) and tetracycline (tc) were established by the method of kirby bauer. the presence of beta-lactamases encoding genes (tem, carb, oxa -like) as well as the teta, tetb, tetc, tetg, cmla and flor genes, and integrons type was established by pcr, while the presence of plasmid-mediated dhfr was determined by pcr-rflp and the cat activity by a colorimetric assay. results: seven different resistance patterns were identified: i. susceptible ( strains); ii. amp, sxt, gm, a/c ( ); iii. amp, tc, cm ( ); iv. amp, tc, sxt, cm ( ); v. amp, a/c ( ); vi. amp, sxt, a/c ( ); vii ( ). -sxt. no isolate resistant to nalidixic acid was detected. resistance to beta-lactam agents was due to the presence of beta-lactamases type tem-like (pattern v), carb- (iii) and tem-like plus oxa- (ii, v, vi). meanwhile resistance to cloranphenicol and tetracycline was associated to cat activity (iii, iv) and flor (iii), and tetb (iv) and tetg (iii) respectively. no mechanism of cotrimoxazole resistance was detected in the isolates of the patterns ii, vi and vii, while dfra was detected in the isolates of the group iv. resistance to gm was associated to the presence of the gene aadb, detected in the analysis of integrons type . type integrons were detected in isolates belonging toi the pattern ii ( bp -aadb; bp -oxa , aada ), iii ( bp -carb , -aada ), iv ( bp -dfra , aada ), v and vi ( bp -oxa , aada ). conclusions: a great diversity of resistance mechanisms has been detected. those mechanisms might spread among microorganisms resulting in a serious health problem due to the limited number of antibiotic treatments available in the area. small outbreaks of veb- esbl producing acinetobacter baumannii in belgian nursing homes and hospitals through cross-border transfer of patients from northern france methods: from / to / , all belgian acute hospitals were invited to report cases of nosocomial infections/colonisations due to mdr ab isolates presenting a resistance profile similar to the french epidemic strain (resistance to all agents except carbapenems and colistin) and to send such isolates to the reference laboratory for phenotypic confirmation and for genotypic characterization (pcr of veb- and class integron, pfge typing). guidelines for detection of the epidemic strain, screening for carriage in patients transferred from hospitals or nursing homes (nh) close to the french border as well as infection control measures were sent to all hospitals. results: overall ab strains from hospitals were sent to the reference laboratory. only, of these fulfilled the phenotypic resistance patterns and were definitely confirmed as veb- ab and had a pfge pattern identical to the french epidemic clone. two mini-outbreak clusters (each involving cases) were documented in hospitals from two cities (tournai and chimay) closed to the french border. two patients died from their infection. in the first outbreak, all patients were residents who lived in the same nh. two of them were french citizens who had been hospitalised in different acute care hospitals in the north of france within the last year. in the second outbreak, the index case had also been previously hospitalised in a french hospital. secondary transmission to two other hospitalised patients occurred in this outbreak. conclusion: despite the large extension of the veb- ab outbreak in france no similar problem occurred in belgium. however, this national alert allowed to detect two small outbreaks in belgian institutions located close to the french border. in both outbreaks the epidemic strain was imported from france through patient circuits. this study illustrates that transfers between acute care hospitals and nh may explain cross-border spread of multi-resistant epidemic strains. types of extended-spectrum beta-lactamases in salmonella spp. and decreased susceptibility to fluoroquinolones objectives: the aim of this study was to determine the rate of esbl production in clinical isolates of salmonella spp. and to detect decreased susceptibility to fluoroquinolones in esbl positive isolates in turkey. methods: a total of salmonella spp. isolated from clinical samples from thirteen centres between and were included in the study. in vitro susceptibility to ampicillin, amoxicillin/clavulanic acid, cefotaxime, gentamicin, chloramphenicol, tetracycline, trimethoprim/sulfamethoxazole and ciprofloxacin were determined using the agar dilution method on mueller-hinton agar following the clinical and laboratory standards institute (clsi) guidelines. decreased susceptibility to ciprofloxacin was defined as an mic of . - mg/l. salmonella isolates were screened for esbl production by double disk synergy method using amoxicillin/clavulanic acid, cefotaxime and ceftazidime disks. types of esbl enzymes were analysed by pcr for tem, ctx-m, shv and per- genes. results: in salmonella spp. the highest level of resistance was observed against ampicillin ( . %) followed by chloramphenicol ( . %), tetracycline ( . %) amoxicillin/ clavulanic acid ( . %), trimethoprim/sulfamethoxazole ( . %), gentamicin ( . %), and cefotaxime ( . %). ciprofloxacin resistance was observed in one isolate ( . %). among salmonella isolates, ( . %) were shown to produce esbl by double disk synergy testing. these isolates were salmonella typhimurium (n = ), serogroup c (n = ) and salmonella enteritidis (n = ). three isolates were from fecal samples two were from urine and one was from blood. one of the esbl producing isolates were susceptible to cefotaxime in vitro. two isolates showed decreased susceptibility to ciprofloxacin. all the esbl producers were resistant to ampicillin, amoxicillin/ clavulanic acid, chloramphenicol and harbored ctx-m type enzymes. in three isolates a tem-type enzyme was also present. conclusion: albeit being rare, esbl production is an important resistance factor among salmonella spp. in order to prevent treatment failures, decreased susceptibility to fluoroquinolones should be investigated routinely in invasive isolates as well as esbl production. incidence of faecal carriage of esbl-producing enterobacteriaceae in hospital and community patients during two non-outbreak periods of time the identities of the esbl-producing isolates recovered during were: e. coli (n = ), k. pneumoniae (n = ), p. vulgaris (n = ) and e. cloacae (n = ), and isolates recovered during were: e. coli (n = ), k. pneumoniae (n = ), k. oxytoca (n = ), p. vulgaris (n = ), p. mirabilis (n = ), e. cloacae (n = ) and e. aerogenes (n = ). conclusions: a dramatic, significant increase in the frequency of faecal carriage of esbl-producing isolates was demonstrated in among hospitalized ( . %) and ambulatory patients ( . %).the results revealed that the prevalence of faecal carriage among ambulatory patients and hospitalized patients was not significantly different in both periods of time. outpatients came from the community carrying enterobacteria harbouring esbl in the intestinal tract, suggesting that the community could be a reservoir for these microorganisms and enzymes. methods: a total of k. pneumoniae, k. oxytoca, e. coli, c. freundii, s. marcescens, and e. cloacae from university hospitals, isolated from blood, wound, urine, sputum and other clinically significant specimens were proven to produce esbls. antimicrobial susceptibility was determined according to clsi, ; conjugation on a solid medium was performed; isoelectric focusing was followed by bioassay; pcr with beta-lactamase group-specific oligonucleotides was applied, followed by nucleotide sequencing; rapd with eric- a and eric primers was performed. results: mic of ceftazidime varied from to > mg/l, mic of cefotaxime - - mg/l; the addition of sulbactam : reduced mic > -fold. transconjugants exhibited resistance both to extended-spectrum cephalosporins and aminoglycosides in of strains. according to their pi, two clusters of betalactamase producers could be described: first one -esbls focussed at pi . , and the second -pi at . . results from pcr confirmed the presence of two groups esbls: tem and shv. sequencing of representative strains showed the presence of shv- in two participating hospitals and of shv- in only one strain e. cloacae, while tem- like enzyme was found in centres and had a clonal dissemination. objectives: during treatment with selective decontamination of the digestive tract (sdd), four strains of multidrug-resistant (mdr) gram-negative bacteria (three escherichia coli strains and one klebsiella pneumoniae) were isolated at the intensive care unit (icu) in the academic medical center (amc) in amsterdam. these isolates were extended spectrum betalactamase (esbl) positive. we investigated whether this was due to interspecies transfer of resistance genes. methods: the strains were typed by amplified fragment length polymorphism analysis. the plasmids from these strains were characterized by restriction fragment length polymorphism. resistance genes of the mdr-strains were characterized by pcr and sequence analysis. results: aflp analysis confirmed that the three mdr e. coli isolates represented three different strains. the mdr-strains were shown to harbour the same plasmid with identical extended-spectrum â-lactamase (esbl) genes; ctx-m- and shv- . conclusions: identification of the emergence of such mdr gram-negative bacteria and recognition of resistance plasmid transfer during sdd treatment is crucial for optimal application of this regimen in icus. the use of the third generation cephalosporins in sdd may associate with emergence and increase in the prevalence of esbls. therefore, for optimal screening of resistance to cephalosporins in icus, the screening for esbls should be included. objective: carbapenems are the drugs of choice for the treatment of serious infections caused by esbl-producing enterobacteriaceae and the emergence of carbapenem resistance is rarely documented. we investigated pairs of carbapenem-susceptible and resistant k. pneumoniae isolates from three patients, collected before and after therapy with carbapenems. methods: pre-and post-therapy pairs of esbl-producing k. pneumoniae isolates were from three patients with urinary catheter-associated infections who were treated with ertapenem (erp, cases) or meropenem (mem, one case) in a district general hospital with a low incidence of esbl-producing organisms ( . / bed days), and meropenem use of ddd/year. isolates were compared by pfge of xbai-digested genomic dna. mics were determined and interpreted by british society for antimicrobial chemotherapy methodology. blactx-m alleles were sought by multiplex pcr. outer membrane proteins (omps) were extracted, and analysed by sds-page. results: the three patients relapsed following erp or mem therapy, and the post-therapy isolates from repeat urine samples were resistant (table), with mics erp>mem>ipm. all six isolates from the three patients belonged to the same pfge strain, but transmission of the resistant variants is unlikely as the patients were geographically and temporally unrelated and separate selection of resistance in individual patients seems more likely. all isolates had a group ctx-m esbl; the resistant isolate in each pair had lost a major omp, consistent with a porin, compared with its susceptible 'parent'. all three patients were successfully treated with amikacin. the emergence of carbapenem resistance in ctx-m-producing k. pneumoniae following therapy severely limits treatment options. whilst unusual in general, such selection has occurred repeatedly with this strain. wide geographic spread of diverse acquired ampc beta-lactamases in escherichia coli and klebsiella spp. in the uk and ireland objective: to determine the distribution of genes encoding acquired ampc beta-lactamases in cephalosporin-resistant isolates of e. coli and klebsiella spp. submitted to the uk national reference laboratory. methods: mics were determined by agar dilution and interpreted according to breakpoints of the british society for antimicrobial chemotherapy. isolates of e. coli or klebsiella spp. resistant to cefotaxime and ceftazidime, irrespective of addition of clavulanic acid, were inferred to have possible ampcmediated resistance. genes encoding six phylogenetic groups of acquired ampc enzymes were sought with a multiplex pcr assay (perez-perez & hanson. j clin microbiol ; : - ) . selected isolates were compared by pfge, and selected blaampc amplicons were sequenced. results: e. coli isolates and klebsiella spp. from separate patients yielded pcr amplicons indicating the presence of genes encoding acquired ampc enzymes. forty of these e. coli isolates (from hospitals) produced cit-type enzymes, (from irish hospitals) produced acc types, and a dha type. the klebsiella spp. produced acc ( isolates from irish hospitals), fox ( isolates from welsh hospitals) or dha ( irish isolate) enzymes. genes encoding ebc-/ent-and moxtype enzymes were not detected. twelve e. coli isolates from one hospital all produced a cit-type enzyme; these isolates belonged to an epidemic uk strain, designated strain a; isolates also contained blactx-m- linked to an upstream copy of is , as is characteristic of strain a; isolates lacked blactx-m- . sequencing of a representative blaampc amplicon indicated production of a novel cmy- variant in these isolates. conclusions: diverse acquired ampc enzymes are present in e. coli and klebsiella spp. in the uk and ireland, with cit-types the most common, and acc types linked to ireland. the broad resistance profiles of ampc enzymes compromises patient management. hence, the acquisition of a cmy- -like enzyme by epidemic e. coli strain a suggests that acquired ampc enzymes are poised to become an important public health issue in the uk. objective: to characterize the spectrum of activity and potency of dor (formerly s- ) and comparator agents against contemporary wild-type bacterial isolates from medical centres in europe and the middle east in . dor is a novel parenteral -b-methyl carbapenem in late stage clinical development whose molecular structure confers stability to b-lactamases and resistance (r) to renal dehydropeptidases. methods: the collection included non-duplicate, consecutive clinical isolates from patients in medical centres in europe ( ), turkey ( ) and israel ( ) that were submitted to the dor surveillance program ( ) for identification confirmation and susceptibility (s) testing. mic values for > antimicrobials were determined using nccls broth microdilution methods ( ) . a tentative dor susceptible (s) breakpoint of £ mg/l (£ . mg/l for s. pneumoniae) was used for comparative purposes; clsi ( ) criteria were used for other tested agents. results: antimicrobial activities of dor and other carbapenems vs. selected isolates. dor consistently displayed activity against staphylococci and streptococci (mic , . and . mg/l) most similar to that of imipenem, and against e. coli and klebsiella spp. (mic , . and . mg/l, respectively, including . and . % of strains that met esbl screening criteria), most similar to that of meropenem. enterobacter spp. isolates, including . % that were ceftazidime-r (indicative of ampc production), were also highly s to dor and other carbapenems ( . to . % r). dor also provided slightly enhanced coverage against p. aeruginosa ( . % s) and acinetobacter spp. ( . % s) compared to other carbapenems. carbapenem r among these latter strains is, however, a particularly worrisome development. conclusions: dor is a new carbapenem with a competitive profile that incorporates both potent gram-negative and grampositive activity, with enhanced activity against the commonly occurring non-fermentative gram-negative bacilli. carbapenems are assuming a greater therapeutic role in many nations as multi-drug resistance (including emergence of ambler class a, c and d b-lactamases) spreads, necessitating their accelerated development. phenotypic and genetic characterisations of enterococcal isolates in tehran sewage, with emphasis on detection of vana and vanb genes objectives: enterococci are members of the normal gut flora of animals and humans and are thus released into the environment directly or via sewage outlets, where they can survive for long time periods. during the last decade the concern has been focused on enterococci that are resistant to the glycopeptide antibiotic vancomycin [vancomycin-resistant enterococci (vre)]. the aim of the study was to detect and to analyse the biochemical diversity of the entrococci strains in tehran sewage and to determine the genetic characterization of vre. methods: a total of isolates of enterococci were selected on me agar medium. all of the isolates were identified at the species level by the common biochemical tests. drug susceptibility test of isolates was done by disk diffusion method with antibiotics vancomycin, erythromycin, gentamicin, tetracycline, chloramphenicol and ciprofloxacin. the mic was also done by macrobroth dilution assay. analysis of the plasmid profiles and the pcr tests for vana and vanb genes were done. methods: we studied vre isolates collected in the north and center of portugal ( portugal ( - from: (i) clinical isolates from hospitals in different cities, (ii) faecal samples from healthy volunteers, (iii) river water samples, (iv) samples collected downstream of hospital sewage water, (v) samples from urban sewage water, (vi) swine faeces (vii) poultry food samples for human consumption. identification and characterization of vancomycin resistant genes vana, vanb, vanc and vanc were determined by a multiplex pcr. the backbone structure of tn was characterized by a pcr overlapping assay ( overlapping fragments), and further sequencing. conclusion: beta-lactamase production among hi strains has declined significantly since among children attending daycare centres as antibiotic prescriptions fell among this population. results: the mic distribution of am showed % of strains (n = ) with a mic > mg/l and % with a mic of > mg/l, indicating that resistance to am is still relatively rare and does increase as compared to nethmap . the lognormal distribution of both am and amc ( strain r) extended to mg/l but showed tailing to mg/l. this may indicate hidden less susceptible strains but could equally well be explained by testing circumstances, since the left part of the mic distribution showed comparable tailing. all strains were susceptible to moxifloxacin, levofloxacin and cefotaxim. the lognormal distribution of sxt extended to . mg/l with % of strains showing higher values. doxycyclin resistance was less than %. most of the strains were resistant to clarithromycin and azithromycin with a mic > . mg/l for both. conclusions: resistance of hi to common antimicrobials in the netherlands is still low and does not increase. objectives: s. pneumoniae (sp) and h. influenzae (hi) are the two most common pathogens associated with community-acquired pneumonia. changes in the prevalence of resistance or multidrug resistance (mdr) among these pathogens have important therapeutic ramifications. the global surveillance initiative is a longitudinal study that benchmarks antibacterial resistance among respiratory pathogens. methods: during , sp and hi were isolated from patient specimens collected at hospital laboratories in france (fr), germany (ger), italy (it), spain (spa), and the united kingdom (uk). isolates were centrally tested by broth microdilution against lev, penicillin (pen; sp only), azithromycin (azi), erythromycin (ery), clindamycin (cli), ceftriaxone (ctx), cefuroxime (cfx), and trimethoprimsulfamethoxazole (tmp-smx) (nccls, ) . data were analysed according to pen resistance, mdr, and b-lactamase status. mdr was defined concurrent resistance to ‡ of the following agents: ctx, cfx, ery, lev, pen, and tmp-smx. results: for sp, pen r was . % in ger, . % in the uk, . % in it, . % in spa, and . % in fr. azi r was . % in the uk, . % in ger, . % in spa, . % in it, and . % in fr. overall, lev r was rare (£ %) and mic s = mg/l in all countries. . % of isolates were susceptible to all of the drugs tested, the most common phenotype encountered. the prevalence (%) of mdr among sp ranged from . in uk to . in fr. resistance to pen, ery, cfx, and tmp-smx was the most prevalent mdr phenotype found in europe. overall . % of mdr sp were susceptible to lev. for hi, b-lactamase rates varied by country from . % in it to . % in fr. based on mic lev and ctx were the most active agents tested against hi, regardless of b-lactamase status. conclusions: lev showed potent activity against sp and hi. for sp, lev activity was independent of resistance to pen or mdr phenotype. lev maintained consistent activity against sp based on mic , regardless of country studied. antimicrobial surveillance data from studies such as the global offer guidance to physicians for empiric prescribing. sxt was obtained ( sxt was obtained ( - . conclusions: our results suggest that beta-lactamase production does not constitute a threat in hi therapy since values were almost constant. although with an unregulated fluctuation on arnblp percentages, it seems that this mechanism is gaining importance in relation to beta-lactamase production. thus, we conclude the need to be aware of arnblp, as these strains are difficult to detect using the nccls ( ) breakpoints. further molecular studies of the resistance genes responsible of this resistance mechanism are needed. resistance of beta-lactamase producer strains, to other antibiotics decreased during the period of study, due to the diminished use of these antibiotics. this study shows the importance of monitoring antibiotic resistance in hi in order to detect emerging mechanisms. antimicrobial susceptibility of respiratory haemophilus influenzae strains in northern greece k. koraki, p. karapavlidou, d. sofianou (thessaloniki, gr) objectives: to investigate the antimicrobial susceptibility of haemophilus influenzae, one of the most frequent bacterial pathogens of respiratory tract infections. treatment of these infections is most often empirical and considerable geographical resistance variation has been reported. methods: eighty h. influenzae strains were collected from respiratory tract specimens (sputum, bronchoalveolar lavages, endotracheal secretions) in a -year period ( ) ( ) ( ) ( ) ( ) . identification was made by colonial morphology, gram staining characteristics, x-and v-factor requirements and api nh (biomerieux, france). antibiotics were selected to reflect representative current treatment options and susceptibility was determined by kirby-bauer disc diffusion method on haemophilus test medium according to nccls guidelines. results: out of the h. influenzae strains were isolated from children and from adults. % of isolates came from children admitted to the intensive care units and . % from cystic fibrosis patients. a seasonal trend was reported for infections since . % of isolates were collected during springtime and % during autumn months. overall ampicillin resistance was . % and resistant strains were isolated exclusively from children. ampicillin resistance was doubled among cystic fibrosis patients ( . %). all isolates were susceptible to amoxicillin/clavulanate, chloramphenicol, ciprofloxacin and imipenem. the rank order of cephalosporin activity was cefotaxime and ceftriaxone ( %) followed by cefuroxime and cefaclor ( . % and . % respectively). trimethoprim/ sulfomethoxazole was active against . % of isolates while erythromycin was the least potent antimicrobial agent with % of isolates being susceptible to it. no multiresistant phenotypes were detected. conclusion: our results demonstrated that ampicillin resistance among h. influenzae in our area is still relatively low and overall antibacterial susceptibility rates are high. knowledge of antimicrobial resistance among these pathogens is imperative for physicians to choose the most appropriate therapeutic agent. results: nosocomial gram-negative uropathogens were studied. most common uropathogens were p. aeruginosa ( . %), e. coli ( . %), k. pneumoniae ( . %), followed by a. baumannii ( . %), enterobacter spp. ( . %), s. marcescens ( . %), proteus spp. ( . %) and other gram-negative rods ( . %). resistance rates (i+r, %) among p. aeruginosa were: gentamicin - %, levofloxacin - %, ciprofloxacin - %, cefoperazone - %, cefoperazone/sulbactam - %, cefepime - %, piperacillin - %, amikacin - %, ceftazidime - %, imipenem - %, meropenem - %, piperacillin/tazobactam - %, polymyxin b - %. resistance rates (i+r, %) among e. coli were: piperacillin - %, ticarcillin/clavulanic acid - %, amoxicillin/clavulanic acid - %, ciprofloxacin - %, gentamicin - %, moxifloxacin - %, levofloxacin - %, cefoperazone - %, ceftriaxone - %, cefepime - %, ceftazidime - %, cefoperazone/sulbactam - %, piperacillin/tazobactam - %, amikacin - %, all strains were susceptible to ertapenem, imipenem, meropenem. resistance rates (i+r, %) among k. pneumoniae were following: piperacillin - %, cefoperazone - %, ceftriaxone - %, gentamicin - %, amoxicillin/clavulanic acid - %, cefepime - %, ceftazidime - %, ciprofloxacin - %, piperacillin/ tazobactam - %, moxifloxacin - %, cefoperazone/sulbactam - %, levofloxacin - %, amikacin - %, ertapenem - %, imipenem and meropenem were active against all isolates. conclusion: p. aeruginosa, e. coli and k. pneumoniae are the main gram-negative uropathogens in russian icus patients. imipenem, meropenem, ertapenem showed prominent activity against e. coli and k. pneumoniae. cefoperazone/sulbactam, piperacillin/tazobactam, amikacin exhibited considerable activity versus e. coli, while k. pneumoniae were more resistant to them. p. aeruginosa were highly resistant to all tested antimicrobials except polymyxin b, thus leaving virtually no choices for therapy in terms of acceptable patient safety. results: overall gram-negative anaerobic bacteria from patients were studied. isolation sites were represented by intraabdominal - ( . %), soft tissue - ( . %), prostate fluid - ( . %), bone - ( . %), and dental - ( . %) infections. susceptibility of ( . %) prevotella spp., ( . %) bacteroides spp. (predominantly b. fragilis group - strains), ( . %) fusobacterium spp., ( . %) porphyromonas spp., and ( . %) veillonella spp. to ampicillin, clindamycin, metronidazole, imipenem, ertapenem, amoxicillin/clavulanic acid and cefoperazone/sulbactam was determined. all species were susceptible to carbapenems. in prevotella spp. there were % and % strains resistant to ampicillin and clindamycin and % of strains with intermediate resistance to metronidazole. among bacteroides spp. % of strains were resistant to ampicillin and % to clindamycin. no resistance to metronidazole was detected in bacteroides spp. objectives: the objectives of this study were to: analyse our current blood culture practice; describe the frequency of occurrence and antimicrobial susceptibility of bloodstream infections (bsi) isolates; determine the contamination rate. methods: we performed a prospective survey of all positive blood cultures received in the department of microbiology of tartu university hospital ( beds) in . blood culture system used was bactec . duplicates within one week were excluded. isolates were identified using conventional microbiology methods and susceptibility tests were those recommended by nccls. to determine extended spectrum beta-lactamase (esbl) producers an e-test with cefepime and cefepime combined with clavulanic acid was used. nosocomial infections were defined according to cdc criteria. results: during study period blood culture bottles were received, comprising blood culture sets ( . sets per patient-days). these resulted in ( . %) positive blood cultures, ( . %) were considered contaminants and contamination rate was . %. a total of bsi episodes involving patients were identified and ( %) of these were nosocomial. the incidence of nosocomial bsi (n-bsi) and community-acquired bsi (ca-bsi) was . and . per patient-days, respectively. polymicrobial bsi was detected in patients. among n-bsi dominated coagulase-negative staphylococci ( / . %), staphylococcus aureus ( / . %), klebsiella spp. ( / %), and escherichia coli ( / . %). the most frequent pathogens of ca-bsi were e. coli ( / . %), s. aureus ( / . %), haemophilus influenzae ( / . %), and streptococcus pneumoniae ( / . %). susceptibility to oxacillin of s. aureus and cons was % and . %, respectively. all s. pneumoniae isolates were susceptible to penicillin. . % of e. coli strains were susceptible to ciprofloxacin, . % to ampicillin, and % to gentamicin. susceptibility of klebsiella spp. to both ciprofloxacin and gentamicin was . %, and to ampicillin . %. . % of klebsiella spp. and none of e. coli isolates were esbl-producers. the susceptibility patterns of n-bsi and ca-bsi pathogens were similar to each other. conclusion: compared to west and north european countries our number of blood culture sets per patient-days is low. this may explain the relatively low incidence of bsi. the interventions to reduce contamination rate need to be implemented. the susceptibility among bsi isolates was high. recent outbreaks of c. difficile associated diarrhoea (cdad) reported in north america, united kingdom and the netherlands have emphasized the importance for an ongoing surveillance of cdad. the aims of the present study was to determine the epidemiology of cdad over the past years and the rate of nosocomial transmission in our acute care hospital ( -beds). materials and methods: all the cases of cdad diagnosed between january st and december st were retrospectively reviewed. a cdad case was defined as diarrhoea in hospitalised patients with a positive result for c. difficile cytotoxin or with a positive toxigenic culture. cdad was considered as severe if patient fulfilled at least of the following criteria: fever > . c abdominal pain or leukocyte count > , /mm or if the patient had an endoscopically proven pseudomembranous colitis or complications (toxic megacolon, perforation…). cdad was considered as community acquired if the diarrhoea occurred in patients within h after admission and if the patient had no history of hospitalisation in the previous months, otherwise cdad was considered as nosocomial. all the strains were serogrouped and characterized by toxinotyping and pcr-ribotyping. detection of toxin a, toxin b and binary toxin was performed by pcr. results: cases of cdad were diagnosed: clinical charts could be reviewed and strains were studied. global incidence of cdad was . per thousand discharges with higher rates in and . diarrhoea was community acquired in % of patients. for patients with nosocomial cdad, transmission of the strain from patient to patient (i.e. strain with the same serogroup and pcr-ribotype than the strain from another patient hospitalised in the same ward in the previous months) was demonstrated in . % of cases. binary toxin was positive in % of strains. binary toxin was associated to a more severe diarrhoea (p < . ) and to a higher case fatality (p < . ). a specific clone accounted for % of all the strains (serogroup h, pcr-ribotype '' '') but this clone was found both in nosocomial or community cases. three strains belonged to toxinotype iii but further investigations are needed to know whether these strains correspond to the hypervirulent strains involved in recent outbreaks. conclusion: incidence of cdad is low in our hospital and cross infection is limited. these results also suggest that strains with binary toxin might be more virulent. the development and application of a new exact typing method for clostridium difficile: multilocus variable number of tandem repeat analysis objectives: to study the epidemiology of clostridium difficile, a typing method with a higher discriminatory power, typeability and reproducibility than currently available methods is required. multi-locus variable number of tandem repeat analysis (mlva) is a new candidate technique, that has already been tested successfully on a number of bacterial and fungal species. using the whole genomic sequence, we developed mlva for c. difficile and compared the method to standardized pcr-ribotyping. additionally, mlva was tested on a collection of the new emerging hypervirulent pcr-ribotype strains. methods: short tandem repeat loci ( to bp) were identified using tandem repeat finder v . on the genome of c. difficile strain . amplification of the repeats was performed using a single pcr-protocol. pcr-fragments were analysed using multicoloured capillary electrophoresis on an abi , with a rox -marker as internal marker for each sample. the number of repeats per fragment was subsequently determined.the discriminatory power of the mlva was tested on reference strains representing serogroups and toxinotypes. the ability to subtype specific pcr-ribotypes was investigated with subtypes of pcr-ribotype (rep-pcr types - ), tcda-/tcdb+ strains of pcr-ribotype , and strains belonging to pcr-ribotype . of these type strains, were isolated from outbreaks and from endemic cases. results: a total of regions with short tandem repeats were identified. mlva discriminated all reference strains and the known reference strains of pcr-ribotype (rep-pcr - ). two mlva-types were recognized among tcda-/tcdb+ strains; the differences were present in only one of the repeat-regions. of pcr-ribotype strains, outbreak-related strains were identical to each other. interestingly, two endemic type strains differed from the other strains in of the regions. conclusion: mlva is a highly discriminatory genotyping method for c. difficile and is capable to subtype various crribotypes. mlva is also an important new tool to study the epidemiology of the emerging pcr-ribotype strains. comparative study of clostridium difficile diarrhoea in elderly patients treated with moxifloxacin versus amoxycillin for lower respiratory tract infections l. mooney, m. wilcox (leeds, uk) fourth generation fluoroquinolones such as moxifloxacin have improved anti-anaerobic activity. consequently, these new agents could induce c. difficile infection (cdi) by inhibition of 'protective' anaerobic flora. recent reports have suggested such an association. however, further studies are warranted to determine the risk of cdi in elderly in-patients treated with these agents, and notably where exposure to cd is measured/ controlled. methods: we prospectively investigated the propensity of moxifloxacin (mox) or amoxycillin/macrolide (aml/mac) to induce cdi when used to treat lower respiratory tract infections (lrtis) in elderly in-patients, using a -ward, crossover design ( months total). patients prescribed mox or aml/mac were monitored for gastrointestinal symptoms. diarrhoea was assessed as due to cd, viral or other cause. relevant clinical data were collected. concurrent epidemiological surveillance was also performed to determine environmental exposure to cd. results: patients were studied, receiving mox and had aml/mac. univariate analysis indicated that there was no significant difference between mox and aml/mac patients in gender, age ( . vs . mean years, respectively), or duration of hospitalisation (total, prior to and post diarrhoea). duration of antibiotic therapy did not differ significantly between mox and comparator patients (either total days or days before diarrhoea onset). there was a significant association between mox and overall risk of diarrhoea. however, there was no significance between mox treatment and cd, viral or other cause of diarrhoea. risk factor analysis to inform on possible confounders was performed. initial epidemiological survey results indicate that there was no change in environmental exposure levels to cd on each hospital ward. molecular typing of all clinical and environmental isolates of cd is ongoing. conclusions: although recent reports have highlighted a risk of cdi associated with fluoroquinolones (and increased age), none have specifically studied hospitalised elderly populations prospectively and controlled for exposure to cd. diarrhoea occurs relatively frequently after antibiotic therapy in the elderly. mox was associated with an increased rate of diarrhoeal symptoms, but causes other than cdi explained this association. mox treatment was not significantly associated with cdi when compared with amox/mac treatment for lrti in elderly in-patients. prevalence and association of macrolidelincosamide-streptogramin b resistance with resistance to moxifloxacin in clostridium difficile strains isolated from symptomatic adults and children hospitalised in two university hospitals in warsaw h. pituch, d. wultanska, g. nurzynska, p. obuch-woszczatynski, f. meisel-mikolajczyk, m. luczak (warsaw, pl) objectives: clostridium difficile is the main aetiological agent of nosocomial diarhoea. clindamycin, penicillins, and cephalosporins have been associated with cdad. however, several case reports of fluoroquinolone-associated c. difficile diarrhea have been published. c. difficile strains usually exhibits susceptibility to metronidazole, and vancomycin. we describe prevalence and association of macrolide-lincosamide-streptogramin b (mlsb) type resistance with resistance to moxifloxacin of c. difficile strains isolated from adults and children. methods: eighty-three c. difficile strains recovered from adults and children hospitalised in two university hospitals were investigated (hospital : adults n = , and children n = ; hospital : adults n = ). toxin types were determined by commercial test for toxin a and cytotoxicity test for toxin b. tcda, tcdb were detected by pcr. mics of erythromycin, clindamycin, moxifloxacin, vancomycin and metronidazole were determined by e-test (ab biodisk, sweden). the ermb gene was detected by pcr. results: sixty-seven ( %) c. difficile strains were toxigenic. among these, were a+b+, and were a-b+. all strains were susceptible to vancomycin and metronidazole. high level resistance to erythromycin, clindamycin and moxifloxacin was found in %, %, % of the tested strains, respectively. twenty-one c. difficile strains harboured high level resistance to erythromycin, clindamycin and moxifloxacin, simultaneously. among these, all were a-b+ and were isolated from adults, only. twenty-one of the macrolide-lincosamide-streptogramin b (mlsb)-resistant a-b+ strains carried the erythromycin resistance methylase gene (ermb). conclusion: resistance against clindamycin, erythromycin and moxifloxacin among polish a-b+ c. difficile strains was very frequent. fluoroquinolone resistance is associated with resistance to mlsb antimicrobials. we suggest that increasing use of fluoroquinolones is selective pressure for clonal dissemination of a-b+ c. difficile strains. fluoroquinolones use is a strong risk factor for cdad in our hospitals. acknowledgement: this work was supported by the ministry of scientific research and information technology, grant no. p d . national surveillance to the incidence of clostridium difficile-associated diarrhoea in the netherlands s. paltansing, r. guseinova, r. van den berg, c. visser, e. van der vorm, e.j. kuijper (leiden, amsterdam, nl) objectives: the recent outbreaks of clostridium difficileassociated diarrhoea (cdad) due to the new emerging pcrribotype , toxinotype iii strains has renewed the interest of cdad as an important nosocomial infection. to determine the incidence of cdad in the netherlands, we conducted a prospective surveillance study in hospitals in the netherlands. clinical microbiology and infection, volume , supplement , methods: from may st to july st of , participating hospitals registered all patients diagnosed with cdad. a standardized questionnaire was devised to obtain patient information. faeces samples or isolated strains were sent to the reference laboratory at the lumc for culture and the presence of genes for toxins a and b (tcda and tcdb). pcrribotyping was performed according to the method of bidet and toxinotyping as described by rupnik et al. results: routine methods to diagnose cdad in laboratories included combinations of cytotoxicity tests ( %), enzymeimmunoassays ( %) and culture of toxinogenic strains ( %). in total, patients with cdad were reported. the overall incidence (median) of cdad was for , patient admissions and varied from to . of patients with cdad, % was community acquired. the median age of patients with nosocomial acquired cdad was years. of patients with cdad, ( . %) died during the study period. at least different pcr-ribotypes could be recognized among strains. type was identified in patients from hospital. toxinotyping revealed the presence of at least different types. of strains, % were tcda+/tcdb+, % tcda-/tcdb-and % tcda-/tcdb+. conclusions: the incidence of cdad in the netherlands is lower than reported in usa and canada, but varied considerably per hospital. the new emerging type was found in patients from hospital with a high incidence of cdad ( per , admissions). outbreak of clostridium difficile pcr-ribotype toxinotype iii in harderwijk, the netherlands objectives: since , several epidemics of clostridium difficileassociated diarrhoea (cdad) caused by c. difficile pcr-ribotype toxinotype iii have occurred in usa, canada, and the uk. in april , the first outbreak encompassing patients was observed in a medium large hospital of beds in the netherlands. the isolated strain was completely resistant to erythromycin and ciprofloxacin. the patient characteristics, predisposing factors and outcome of cdad were studied. methods: a case-control study was performed in patients and at random selected controls without diarrhoea who stayed at the same department as the patients when the diagnosis of cdad was made. standardized questionnaires were designed to collect data from the patient records and all surviving patients were interviewed months after the diagnosis. faeces samples were cultured for the presence of c. difficile and isolates were typed. results: the incidence of cdad increased from per , patient admissions in to . per , admissions in . between april and september , patients with cdad due to type were identified. of patients, ( %) died of which ( %) as a direct result of cdad. eleven ( %) patients experienced one or more relapses. the average age of the cases was yrs, . % of the patients was male. in a multivariate analysis, antibiotic use (or . , p < . ), duration of hospital stay (cases days, controls days; p < . ) and tube feeding (or . , p = . ) were found to be significantly associated with cdad. in particular, the use of ciprofloxacin (or . , p < . ) and cephalosporins (or . , p < . ) were associated. no association was found between the use of protonpump inhibitors and the risk of cdad. the use of erytromycin was significantly higher in cases ( . %) than in controls ( . %) in a univariate analysis (p < . ), but this relation was not significant in a multivariate analysis. conclusion: antibiotic use (especially ciprofloxacin and cephalosporins), duration of hospital stay and tube feeding were significantly associated with cdad caused by c. difficile type , toxinotype iii in the netherlands. we could not confirm the previously described relation between use of protonpump inhibitors and risk of cdad. clostridium difficile pcr ribotype , toxinotype iii in the netherlands objectives & methods: shortly after the reports in june of clostridium difficile pcr ribotype , toxinotype iii in england, this more virulent type was also detected in the netherlands. in response, the dutch centre for infectious disease control has undertaken measures to monitor and control the outbreak. c. difficile guidelines for infection control and treatment were formulated, separately for hospitals and nursing homes. the leiden university medical centre serves as a reference centre for diagnostics and typing of c. difficile. laboratories are encouraged to send in samples for typing in case of a clear rise in the incidence in c. difficile, rapid spread, or several clinically suspect cases.organisation-based surveillance was set up: questionnaires are sent monthly to institutions with c. difficile associated diarrhoea (cdad) outbreaks to obtain information on incidence, c. difficile testing strategies, antibiotics use and control measures taken.measures taken in hospitals dealing with an outbreak of type include: treatment of cdad with vancomycin in stead of metronidazole, emphasis on frequent and thorough cleaning and disinfection, isolation of all patients with diarrhoea until tested negative for c. difficile toxin, cohort isolation of cdadcases if individual isolation capacity is exceeded and strong restriction of certain antibiotics, including fluorochinolones. results: until november st, , samples from institutions have been sent in for typing, resulting in type positives. epidemic spread of type has been detected in hospitals and one nursing home. furthermore, in retrospective studies in four hospitals isolated cases of type were detected. it became clear that in one region with three hospitals, the cdad incidence had already risen in , and , respectively . unfortunately, no samples from that period were available for typing. in the hospitals with epidemic spread of type , a wide range in the monthly incidence of cdad was observed, from to per , admissions during the outbreaks. the incidence in the pre-epidemic period varied from to (see figure) . conclusions: the outbreaks in hospitals are difficult to control: most hospitals continue to have new cases for a long period, although the incidence is decreasing in several hospitals. fortunately, once a c. difficile outbreak in a hospital is recognised, spread to other hospitals has not been observed. objectives: c. difficile is a major cause of antibiotic associated diarrhoea (aad) and colitis (c). the aim of this study was to determine the incidence of these infections in our hospital ( beds), during a period of months (march-october ) . methods: a number of liquid stools from equal adult patients (mean age y, m: , f: ) receiving broad spectrum antibiotics (especially cephalosporins) were plated in ccfa (oxoid) and anaerobic brucella agar (ba), after alcohol shock procedure. if the culture was positive, an immunochromatographic test was performed for toxin a (colorpactm toxin a, bd, usa). if the last test was negative, a rapid enzyme immunoassay was performed for toxins a+b (immunocard, meridian bioscience inc. cincinatti, ohio). results: c. difficile was isolated in / ( . %) samples. seventeen men (pathological -p, pneumological -pn, surgical -s, urologic -u, outpatients -o, , , , , respectivly) and women (p: , pn: , o: ) harbored c. difficile in their intestin. twelve out of strains ( %) produced toxin a, while the remaining ( %) produced toxin b. eleven patients had severe diarrhoea ( - days). one patient got endoscopic examination, which confirmed colitis findings. the two outpatients received oral cefuroxime in the preceding week of the positive culture. conlusions: ( ) the incidence of c. difficile infections in this study is among these reported in international bibliography ( . %). ( ) since toxigenic b c. difficile strains were demonstrated in half cases, the use of the tests detecting both toxins a and b by clinical laboratories is recommended.( ) molecular technics application (e.g. pfge and ribotyping) will offer a better knowledge of c. difficile spread in our hospital. assay of the cytotoxicity of stool samples to cells in tissue culture is commonly considered the 'gold standard' for detection of c. difficile toxin. however the method is slow and therefore its use can result in delayed patient treatment and implementation of infection control measures. we undertook a comparison of two microtitre plate-based elisa kits (techlab c. difficile tox a/b ii and meridian premier toxins a & b) and three rapid immunoassay card kits (remel xpect clostridium difficile toxin a/b, meridian immunocard toxins a & b and techlab tox a/b quik chek) with an in-house cytotoxin assay. all samples tested had been referred for routine microbiological examination. toxin tests were done on unformed samples from adult hospital in-patients and bone marrow transplant recipients and on samples where c. difficile toxin testing was requested by the referring clinician. all kits were used according to manufacturers' instructions. three hundred and thirty three specimens were tested using all five kits and cytotoxin assay. sensitivities and specificities were calculated both (a) assuming the cytotoxin assay to be the 'gold standard' (universally correct) test and (b) taking a concensus view that any sample with at least two tests positive is truly positive. data are shown in the table below. overall, the microtitre plate-based elisa kits were more sensitive than the rapid immunoassay card kits. the cytotoxin assay was negative for seven samples that were positive by at least two other tests. thus the plate-based elisa kits were also more sensitive (but less specific) than the cytotoxin assay if consensus data was used to judge true positivity. we conclude that some immunoassay kits offer an acceptable alternative to cytotoxin assays for the detection of c. difficile toxin, allowing more rapid diagnosis. location of the enterotoxin gene in strains of clostridium perfringens associated with gastroenteritis objectives: clostridium perfringens type a is a common cause of food poisoning and is also associated with non-food borne gastroenteritis including antibiotic associated, infectious and sporadic diarrhoea. the disease symptoms are due to an enterotoxin produced when the organism sporulates in the human small intestine. the c. perfringens entertoxin gene (cpe) has been shown to be located either on the chromosome or on one of two large plasmids and it is generally accepted that c. perfringens strains associated with food poisoning have a chromosomal cpe gene whilst strains isolated from non-food borne diarrhoea have a plasmid encoded cpe gene. spores from strains possessing a chromosomal cpe gene have been found to be far more heat resistant than spores from strains with a plasmid encoded cpe gene. heat resistant spores are more able to survive the cooking process and go on to cause food poisoning, thus explaining why most food poisoning strains have been found to have chromosomally located cpe genes. the purpose of this study was to determine the location of the cpe gene in a range of c. perfringens strains from the uk, including those from both food borne and non-food borne illness. method: a multiplex pcr assay described by miyamoto et al., ( ) was used to determine the location of the cpe gene in strains of c. perfringens isolates associated with food borne illness and strains associated with non-food borne illness. results: by multiplex pcr assay % of c. perfringens strains associated with food borne outbreaks in the uk were found to have a plasmid encoded cpe gene. these findings have not been described before. all strains associated with non-food borne illness had the cpe gene located on one of two plasmids, as anticipated. conclusions: a significant number of food borne outbreaks of c. perfringens food poisoning were found to be caused by strains of c. perfringens carrying a plasmid encoded cpe gene. since strains of c. perfringens with a chromosomal cpe and plasmid cpe genes have different physiological characteristics this may have a profound impact on their mode of transmission. references miyamoto, k., wen, q. and mcclane, b. a. ( ) multiplex pcr genotyping assay that distinguishes between isolates of clostridium perfringens type a carrying a chromosomal enterotoxin gene (cpe) locus, a plasmid cpe locus with an is -like sequence, or a plasmid cpe locus with an is sequence. journal of clinical microbiology , - . novel multiplex-pcr method for simultaneous detection of clostridium difficile toxin a and toxin b and the binary toxin (cdta/cdtb) genes applied on a danish cohort k.e.p. olsen, s. persson (copenhagen, dk) objectives: a new multiplex pcr method was developed for the detection of the clostridium difficile toxin genes: tcda, tcdb, cdta and cdtb. this method was applied on clostridium difficile strains isolated from danish hospitalised patients with diarrhoea in the period from april to october , in order to investigate the present toxin profiles and their correlation to sex and age. method: a -gene multiplex pcr method was developed for the simultaneous amplification of the four clostridium difficile toxin genes tcda, tcdb, cdta, cdtb and s rdna as an internal positive control. template dna was prepared from plate grown bacterial colonies by a simple boiling procedure, and amplicons were visualized by standard gel electrophoresis. results: three different toxin profiles were detected in the danish cohort: tcda+, tcdb+, cdta+/cdtb+; tcda+, tcdb+, cdta-/cdtb-and non-toxigenic tcda-, tcdb-, cdta-/ cdtb-. the prevalence of the binary toxin genes in this study was % of the clinical isolates.more than half of the strains ( %) were isolated from the elderly part of the population (> years), and % of these strains displayed the tcda+, tcdb+, cdta+/cdtb+ profile. of the non-toxigenic strains, % of the patients were females. one fourth of the strains isolated from children under years of age were non-toxigenic. in four patients, two different toxin profiles were obtained from independent faecal samples. conclusion: this method offers a one-step, rapid and specific identification of clostridium difficile toxin genes. this specific toxin profiling allows an evaluation of the pathogenic potential of the isolated clostridium difficile and surveillance of emerging toxin profiles. further studies of the isolated toxigenic clostridium difficile strains will include gene deletion analyses of the tcda and the tcdc (toxin regulating gene) which independently have been observed to cause enhanced pathogenicity. prevalence of clostridium difficile-associated diarrhoea in hospitalised patients with nosocomial diarrhoea in university of medical sciences hospitals, tehran, iran objectives: this study was aimed at determining the prevalence of clostridium difficile associated diarrhoea in hospitalized patients with nosocomial diarrhoea at three university hospitals in tehran from december to august . methods: during the study period, the stool samples of hospitalized patients with nosocomial diarrhoea were cultured and tested by stool cytotoxin assay, toxigenic culture and also of the samples were examined by enzyme immunoassay. results: in ( . %) of samples c. difficile grew and stool samples (prevalence: . %) were toxin positive by stool cytotoxin assay, enzyme immunoassay or toxigenic culture. there were no significant relationships between c. difficileassociated diarrhoea and sex and age of patients. the results of the present study showed that among requested samples the highest percentage of c. difficileassociated diarrhoea was observed from the transplantation department ( . %), followed by icu and paediatric section. objectives: the prevalence of toxigenic clostridium difficile (c. difficile) has been reported about - % in korea. toxin a(-)/ toxin b(+) variant c. difficile strain is also important in nosocomial c. difficile infection. however, characterization of clostridial toxin (toxin a, toxin b) had not been studied. methods: we used pcr for toxin a and toxin b genes in c. difficile isolates from patients admitted in three tertiary hospitals during january to december, . primers for toxin a genes were nk -nk , nk -nk and nk -nk and toxin b gene was nk -nk . results: toxin a and toxin b positive rates using nk -nk , nk -nk and nk -nk were concordant and ranged from . % to . % in hospitals. the proportions of non-toxigenic strains were - %. however, we could differentiate toxin a(-)/toxin b(+) variants using nk -nk primers. the proportion of toxin a(-)/toxin b(+) c. difficile variants were . %, . % and . % in hospitals respectively. objective: administration of antibiotic drugs has long been known to cause alterations in the gut ecosystem. in some patients, these alterations may create a niche that allows the overgrowth of some pathogens such as clostridium difficile, the main causative agent in nosocomial infectious diarrhoea. a predictive tool to assess the risk of development of clostridium difficile, would be of utmost clinical relevance. it remains to be determined whether specific patterns in pre-existing gut microbiota can predict the risk of onset of clostridium difficile, upon initiation of antibiotic treatment. using samples from subjects enrolled in a previously published clinical study on antibiotic-associated diarrhoea (aad), we investigated the potential relationship between their dominant faecal microbiota and the subsequent development of clostridium difficile when subjects received antibiotics. methods: temporal temperature gradient gel electrophoresis (ttge) was used to assess dominant species distribution in gut microbiota. each electrophoregram was digitised from the migration distances and a regression model [partial least square-discriminant analysis (pls)] was built to investigate the correlation between pre-treatment dominant faecal microbiota and the acquisition of clostridium difficile during antimicrobial chemotherapy. results: this pls model could explain % of the subsequent onset of clostridium difficile. this result supports the concept of ''permissive'' flora with preliminary data focusing on clostridium coccoides-phylogenetic group. conclusion: to our knowledge it is the first time that dominant faecal microbiota is found to heighten susceptibility to the subsequent onset of clostridium difficile upon initiation of antibiotic treatment. these findings insinuate that strategies reinforcing the control of dominant faecal microbiota at homeostasis would be of clinical relevance. this study has been partially financed by biocodex laboratories. objectives: selective therapy of c. difficile diarrhea (cdd) requires the reduction of pathogen counts in the colon, but spare the normal flora. to determine if par is selective for cdd, serial stool samples were collected at study entry, at day , and weekly x during the conduct of a phase a study of cdd treatment. methods: patients (n = ) were randomized to receive , or mg twice daily of par for days. no prior therapy was given to patients; receive or doses of standard therapy. as treatment controls, additional patients were treated with vancomycin mg qid for days. five well persons donated stools as normal flora controls. fresh stool samples were cultured - , , , for c. difficile vegetative and spore forms; faecal filtrates were tested for cytotoxin b by cell assay. strains were characterized by tcda/b, ermb, cdta/b pcr and by ribotyping. at study entry and day , aerobic and anaerobic faecal flora cultures, diluted - , , , , were examined for major floral shifts. since bacteroides group organisms are ubiquitously present and cultivable, this genera was selected as a indicator of the integrity of the microbial flora. results: at study entry, mean log cfu + sd vegetative counts of c. difficile (all par patients) were . + . , range - . ; at day , with the exception of one patient receiving mg, all other patients had c. difficile quantitative counts reduced < log /gm faeces. vancomycin was similarly effective. at study entry, bacteroides group counts were < , - , & . - log cfu/gm in~ / each of patients. all normal stools showed complex, multi-genera in high counts, with - bacteroides group species > log cfu/g. mean + sd of log cfu of bacteroides group counts/g feces wet weight at study entry and day for mg/day (n = ) were . + . / . + . (p = . , wilcoxon matched pairs signed-ranks test, tailed); for mg/day (n = ) were . + . / . + . (p = . ); for mg/day (n = ) were . + . / . + . (p = . ); and for vancomycin (n = ) . + . / . + . (p = . ). conclusion: patients with cdd have variably impaired normal flora. par was effective in all dosages in eradicating c. difficile. a dose-dependent reduction in bacteroides counts was not observed. vancomycin significantly reduces bacteroides counts during cdd treatment. par is effective against c. difficile in-vivo, and is relatively sparing of the normal flora. results: the three rt pcr assays were able to detect all enterovirus strains in cell culture supernatants. however the detection limit of the mgb rt pcr was to log more sensitive in out of dilutions assays of vc supernatants compared to the rab and ver rt pcr. all ver and mgb negative csf were vc negative. thirty-two csf specimens from patients suspected of viral meningitis were positive by all rt pcr ( . %), whereas only were found positive by vc ( . %). the rab rt pcr failed to detect csf confirmed positive by vc ( echo and non typable ev). among samples positive by rt pcr, sensitivity of ver, mgb and rab was respectively %, % and . %. conclusion: in our laboratory, mgb rt pcr has a good correlation with ver rt pcr whereas rab rt pcr is less sensitive especially for the detection of echovirus . the mgb rt pcr seems to be the most sensitive of the rt pcr. further studies, including more ev strains should help to precise the sensitivity of this assay. a. dalwai, s. ahmad, e. hussein, a. pacsa, w. al-nakib (kuwait, kw) objectives: enteroviruses generally share tissue tropism and present with overlapping disease spectrum, however certain enteroviruses may be over represented in certain diseases than others. coxsackievirus a though has been reported to cause several diseases such as febrile illness, herpangina, aseptic meningitis and acute flaccid paralysis, the frequency was very low. the study aimed to determine the prevalent enteroviruses causing non-specific febrile illness, aseptic meningitis, encephalitis, neonatal disease and myositis, in kuwait. it also aimed to study the association between a certain enterovirus and a particular disease and its severity. methods: diagnosis of enteroviral infection was based on detection of enteroviral rna by semi-nested rt-pcr of a portion of the 'utr of the enteroviral genome followed by southern hybridization with an enterovirus specific probe to confirm the results. the enterovirus was genotyped by sequencing of the 'utr, the vp and a portion of the vp encoding regions, and the sequence was analysed by blast analysis, clustalw alignment and phylip phylogenetic analysis package. results: enteroviruses were the only etiological agents detected in % ( ) of disease cases investigated. coxsackievirus a was identified to be the second most predominant enterovirus ( %; of cases genotyped) associated with disease, after only echovirus ( %; / ). although identified in all the diseases investigated, coxsackievirus a occurred less frequently in cns disease cases ( %; / ) than in febrile illness cases ( %; / ). in a preliminary study, it was also predominantly detected in % ( / ) of myositis cases. the 'utr of this virus showed % homology with that of coxsackievirus a prototype strain (parker strain) whereas the vp and the adjoining region showed greater homology to human enterovirus b genotype sequence. conclusions: coxsackievirus a was determined to be an emerging enterovirus associated with different diseases in kuwait. it was frequently represented in mild febrile illness and myositis cases than in cns disease suggesting that the isolate might be less neurovirulent. molecular analysis suggests that the isolate might have emerged due to recombination between coding and non-coding segments of coxsackievirus a and human enterovirus b group genomes. acknowledgement: supported by research administration project grants mi / , ym / and college of graduate studies, kuwait university. the new proposed enterovirus type is causing meningitis in spain introduction: several new proposed enteroviruses (ev) have been recently described, including the named ev [ ] . a total of isolates of this serotype were identified from to in america, africa or asia associated mainly with acute flaccid paralysis or unspecified disease. objective: to determine if this new serotype circulates in spain and what type of disease produces. methods: a total of ev isolates coming in to the spanish enterovirus reference laboratory were studied both by micro neutralization assays and by typing pcr [ ] . in the isolates in which ev was suspected by the mentioned methods complete vp gene was amplified and sequenced with specific designed primers. results: four isolates from two different regions of spain were identified as ev (more than % of homology with the published sequences). three of them corresponded to aseptic meningitis in children and were isolated from csf. discussion: the present work demonstrates that this new proposed virus circulates also by europe and is associated to aseptic meningitis. till the moment it seems that is represented in a minor proportion ( / studied), however the possibility of spreading of this viral infection should be considered, as evs may behave in that way, as previously have been demonstrated [ ] . objectives: rotavirus is the most important cause of severe gastroenteritis in infants and young children through the world and is responsible of , deaths annually, mostly in developing countries. therefore, development of rotavirus vaccine is a high priority. rotavirus strains with g types account for the majority of the diarrhoea episodes. recently, a monovalent g attenuated rotavirus vaccine was licensed in mexico. in view of a hypothetical introduction of such vaccine in europe, we investigated the variability over time of vp antigenic genes of g rotavirus strains in our area. methods: fifty strains were selected from a total of g strains obtained from children of less than years of age hospitalised with acute gastroenteritis at the ''g. di cristina'' children's hospital of palermo in the period - . the selected strains were genotyped by rt-pcr and of them were submitted to vp gene sequence analysis. results: all but one of the strains were genotyped as g p( ). the vp sequences of of them were distributed into lineages i and ii. lineage i included strains from different years in the range - . lineage ii included strains from different years in the range - . the degree of similarity among the nucleotide sequences of italian strains in each lineage were comprised between % and %. an alignment of the deduced amino acid sequences showed major lineage specific amino acid changes in the variable antigenic regions with respect to the reference wa strain. conclusions: sequence analysis indicated that in palermo there was co-circulation of g strains belonging to two different lineages. overall, the g strains showed a high degree of similarity inside each lineage and shared specific amino acid modifications. the antigenic differences between circulating strains might permit them to escape neutralization and persist in the infantile population. our results suggest that rotavirus strains belonging to the two g lineages should be both included in a rotavirus vaccine preparation. epidemic spread of recombinant noroviruses with four capsid types in hungary objectives: noroviruses (''winter vomiting diseases'') are the predominant etiological agent in hungary and common pathogen worldwide in outbreaks of gastro-enteritis in humans. noroviruses are genetically diverse group of viruses with multiple genogroups (gg) and genotypes. more recently, naturally occurring recombinant noroviruses were identified. these viruses had a distinct polymerase gene sequence (orf , designated ggiib/hilversum) and were disseminated through waterborne and food-borne transmission in europe. our aim was to characterize these emerging recombinant noroviruses causing outbreaks of gastro-enteritis in hungary. methods: stool and rna samples -from norovirus outbreaks between january and may -containing ''ggiib/ hilversum polymerase'' (ggiib-pol) were selected for analysis of the viral capsid region (orf ) by reverse transcriptionpolymerase chain reaction (rt-pcr) followed by sequence-and phylogenetic analysis. results: forty ( . %) of confirmed norovirus outbreaks were caused by the new-variant lineage with the ggiib-pol. viral capsid region was successfully characterized in ggiibpol outbreaks. four different recombinants were detected with capsids of hu/nlv/ggii- /mexico/ (n = , . %), hu/ nlv/ggii- /snow mountain/ (n = , . %), hu/nlv- /ggii/hawaii/ (n = , . %) and hu/nlv/ggii- / lordsdale/ (n = , . %). interestingly, outbreaks caused by recombinant ggiib-pol strains mostly associated with outbreaks among children ( . %) and had non-winter seasonality. conclusions: epidemic spread of emerging multiple recombinant norovirus strain ggiib-pol were detected in hungary that became the second most common norovirus variants -next to the endemic ggii- /lordsdale virus -causing epidemics of gastroenteritis in the last . years. the respiratory infections are the most common diseases in the world being the origin of a great morbidity and mortality especially in infants and elderly. ( ) human metapneumovirus (hmpv) was first described in dutch children with acute respiratory tract infections (artis) in june . ( ) very limited studies data are available from tropical and developing countries. we sought to determine the role of hmpv in upper and lower respiratory tract infections in cuban patients and correlated the presence of virus with clinical characteristics of the disease. between october to september clinical samples received from the national surveillance program of artis at the national reference laboratory of respiratory viruses, for virological study, were used to detect hmpv by rt-nested pcr, amplifying a conserved fragment of nucleotides in the polymerase gene. we found rna hmpv in . % of samples from the patients with artis. . % of individuals who tested positive for hmpv were under months of age. patients with evidence of hmpv had symptoms consistent with either upper or lower respiratory tract disease or both. . % of hmpv positive individuals were detected during august-october (table ). the results of this preliminary study shows that hmpv is present among cuban patients with arti. constitute the first report of the frequency of hmpv infection in a non-preselected group of cuban patients with ages ranged from months to years old. it should be noted that this is the first report of hmpv infection in central america and in the caribbean region, further confirming the worldwide distribution of the virus ( ) ( ) ( ) . detection of human metapneumovirus in paediatric nasopharyngeal aspirates by a taqman minor groove binder probe assay: a one-year prospective study in belgium w. verstrepen, p. bruynseels, a. de smet, a. mertens (antwerp, be) objective: human metapneumovirus (hmpv) has a relative high incidence in acute respiratory infections in children but is difficult to isolate in culture. the aim of the study was to decrease the number of undiagnosed viral respiratory infections in our hospital by means of a taqman minor groove binder (mgb) probe assay. methods: from october to september a total of nasopharyngeal aspirates from children presenting at our paediatric facility were analysed. rna extracts from specimens negative for rsv, parainfluenzavirus and influenzavirus with an (in) direct immunofluorescence assay (ifa) were subjected to a taqman mgb probe assay in parallel with a previously published taqman assay. results: of the specimens, ( %) were positive by ifa for either rsv ( ), parainfluenzavirus ( ), influenzavirus a ( ) or influenzavirus b ( ). hmpv was detected in ( . %) of the remaining specimens subjected to the newly developed pcr. of the patients with a positive hmpv assay, / ( . %) presented with respiratory symptoms. % of the positive specimens were from children less than year as compared to only % from children older than years. viral load was highest in children less than year. a prominent seasonal variation was noted since more than half of the positive specimens occurred during the months march and april. there was no significant difference in the proportion nor viral load of positive specimens from ambulatory patients, patients admitted to a general ward or patients requiring intensive care. as compared to the published taqman assay, diagnostic sensitivity and specificity were . % and . % respectively, whereas ppv and npv were . % and . %. method comparison (nccls guideline ep- a) failed to demonstrate a significant difference between both assays when the threshold cycle (ct) was between and . strongly positive specimens (ct < ) were associated with a lower ct using the published taqman assay. however, the new taqman mgb probe assay appeared to be more sensitive for weakly positive specimens (ct > ). conclusion: the number of viral respiratory infections confirmed in our hospital was substantially increased by means of the hmpv taqman mgb probe assay. the new assay is a reliable alternative to the previously published taqman assay for detection of hmpv in nasopharyngeal aspirates. nucleic acid sequence based amplification and molecular beacon detection for the real-time identification of respiratory syncytial virus in paediatric respiratory specimens r. manji, f. zhang, c. ginocchio (lake success, us) background: respiratory syncytial virus (rsv) is the leading cause of lower respiratory tract infection in infants and young children, with bronchiolitis and pneumonia being the major clinical manifestations. the rapid diagnosis of rsv infections is of central importance for individual patient management (rational use of antibiotics and antiviral agents), hospital infection control and monitoring epidemiological disease patterns. this study included a technical validation and a retrospective clinical evaluation of a real time nasba assay for the detection of rsv a and rsv b in paediatric respiratory samples. methods: samples tested included: dilution panels of in vitro transcribed rna, local rsv isolates, isolates of common respiratory pathogens, and frozen respiratory specimens (nasopharyngeal aspirates, washes or swabs) from children (age range: d to yr) who were evaluated in the paediatric emergency department for respiratory disease. nucleic acid (na) isolation, amplification and detection were performed using the nuclisens easyq basic kit and nuclisens easyq rsv a+b reagents (biomérieux). specimen nas and a rsv specific internal rna control (ic) were co-extracted using nuclisens magnetic extraction reagents and the nuclisens minimag instrument (biomérieux) and co-amplified using a single rsv specific primer pair. included in the reaction were a rsv specific molecular beacon ( '-fam) and an ic specific molecular beacon ( '-rox). target amplification and continuous monitoring of emitted fluorescence were performed using a nuclisens easyq analyzer (biomérieux). results were compared to direct immunofluorescence (dfa) and/or viral culture using r-mix cells (diagnostic hybrids, oh). results: the limit of detection for rsv was rna copies/rxn and the % detection rate was copies/rxn. the assay was % specific for rsv with no cross reactivity to other respiratory pathogens. the nasba assay detected % more positive specimens than dfa and % more positive samples than vc. the npvs of the assays were: nasba . %, dfa . % and vc . %. the nuclisens easyq rsv assay demonstrated superior sensitivity to both dfa and viral culture for the detection of rsv a and b from respiratory specimens. the assay was easy to use, required minimal hands on time ( hr) and a faster time to results as compared to rapid culture ( hr vs. - hr). respiratory syncytial virus (rsv) is a major cause of acute lower respiratory tract infection in infants and young children. it has previously been shown that hrsv isolates can be divided into two antigens groups a and b. the g protein is the most divergent both between and within the two subgroups and appears to accumulate amino acid changes with time, suggesting evolution under selective pressure. our knowledge of the molecular epidemiology of rsv has so far been based mainly on studies done in the developed world with e temperate climate. very limited epidemiological data are available from tropical and developing countries, where rsv infections may follow a different pattern. in this report we examine the molecular epidemiology and evolutionary pattern of the g protein of both subgroups a and b rsv through consecutive epidemics in cuba. sixthly four nasopharyngeal swabs were collected from children under years of age with respiratory disease to different hospitals in cuba between and , to examine the molecular epidemiology and evolutionary pattern of the g protein of rsv. all samples collected from to were rsv subgroup a; however both subgroups co-circulate during . the cuban isolated from to showed a great homogeneity between them and were resemble to an ancient strain (long) with only five nucleotide differences, this also occur in and with two strain. furthermore was detected different size of g protein ( or for rsv a and for rsv b) due to change in stop codon used he genetic homogeneity of the cuban isolates ( ) ( ) ( ) and their resemble to an ancient strain such as long was an unusual finding in our country. in both subgroups was observed the predominance of strains with almost similar sequences. phylogenetic analysis for subgroup a strains showed that strains were cluster in different genotypes with virus isolated in different geographic regions. both subgroups co-circulated during and clustered whit south african strains that circulate during at the same time. point mutations in respiratory syncytial virus detected by lightcycler pcr and melting curve analysis u. germer, l. nielsen, k. boye, h. westh (copenhagen, dk) objective: the objective was to analyse rsv real-time pcrpositive isolates from clinical samples, which appeared to belong to three different groups according to melting temperature (tm) of the amplicons. the analysis was done according to genotypic and phenotypic difference and related to geographical distribution. materials and methods: nasopharyngeal aspirates were collected from children with respiratory distress in the city of copenhagen. viral rna extracted using the magnapure lc automated extraction system was amplified in a real-time rt-pcr previously described ( ) . five samples from each of the three groups with different tm's were selected for bidirectional dna sequencing using the rsv primers. sequences were analysed using chromas lite version . . results: a total of clinical samples were analysed. ( %) of the samples were positive and ( %) were negative for rsv. three distinctive groups with different tm's could be identified from the melting curve analysis. group (n = ) had a tm with a median of . °c, group (n = ) and (n = ) had lower tm's with a median tm of . °c and . °c respectively. sequence analysis of amplicons showed that the difference in tm was due to differences in genotype between the three groups. genotype and were closely related, differing only in two nucleic acids in position (c to t) and (a to t). both were silent mutations. only position is targeted by the probe. genotype and were both blasted to a complete genome sequence of respiratory syncytial virus subgroup a (genbank rsu ) with the highest identity score for genotype . genotype sequences were blasted to human respiratory syncytial virus mutant cp subgroup b (genbank af ). geographical analysis showed a higher prevalence of the mutant strain (genotype ) in the northern areas of the greater copenhagen area compared to central, southern and western areas (p = . ). conclusion: we found three genotypes of rsv according to the tm of the pcr product. two of the genotypes were closely related with only two point mutations and the same phenotype. genotype was mainly found in clinical isolates from the northern part of copenhagen, suggesting a local epidemic spread. objectives: biomerieux is developing a real-time nasba assay to detect influenza a and b rna in different kind of respiratory clinical samples, by using the nuclisens Ò easyq basic kit in combination with specific primers and molecular beacons. methods: nasal/throat swabs in transport medium from hospitalised children ( - yrs from edouard herriot hospital, lyon, france) were used for this evaluation. influenza rna is isolated using the nuclisens Ò minimag extraction. an internal control is added to the sample prior to nucleic acid extraction. the assay is designed to detect in a single tube, using a three-label approach, the internal control and both influenza a and influenza b rna. amplification reactions were performed in a nuclisens Ò easyq analyser allowing real-time detection. the results of the clinical samples were compared to cell culture results. results: among swabs tested, real-time nasba detected ( . %) samples for influenza a and ( . %) samples for influenza b. comparatively, by cell culture only ( . %) samples were identified as influenza a and non as influenza b. interestingly, influenza a positive sample identified by cell culture was found negative in real-time nasba. conclusions: the data showed that nuclisens Ò easyq influenza a/b assay detected % more influenza a virus than cell culture method. moreover, real-time nasba detected influenza positive samples, which were not detected by cell culture. with this assay a qualitative detection of influenza a and influenza b viruses in a single reaction can be done within hours. it provides a valuable alternative to cell culture method for the clinical management of patients with influenza infections. results: patients have developed mumps meningitis and patients were diagnosed with mumps meningoencephalitis. age limits were from to years and sex ratio m/f was / .clinical manifestations involved fever ( %), stiff neck ( %), nausea and vomiting ( %), headaches ( %), photophobia ( %) and neurological manifestations such as: equilibrium disorders and drowsiness ( %), convulsions ( . %), cerebellum syndrome ( . %). meningeal symptoms have occurred shortly after parotiditis in % of cases and before parotiditis in % of cases; the other cases have evolved without parotid swelling. other localizations of the mumps infection were: parotiditis ( %), pancreatitis ( %), submaxillitis ( %) and orchitis ( %). lumbar puncture yields csf containing between and wbc/mm . the predominating cells were usually lymphocytes, but % of the patients have polymorphonuclear leukocyte predominance at the first puncture. protein levels are normal to mildly elevated in all cases and hypoglycorrachia was founded in % of the patients. therapy for mumps meningitis was symptom-based (analgesics and antipyretics) in % of cases and glucocorticoid therapy in % of cases. conclusions: ( ) neurological involvement in mumps occurred in . % of cases; ( ) men are afflicted two times more often as women, but the age distribution is the same as for uncomplicated mumps; ( ) mumps meningitis was the only localization of the mumps infection in % of cases. mumps is acute generalized infection occurs primarily in schoolaged children and adolescents. most prominent manifestation of mumps is swelling and tenderness of salivary glands especially parotid gland. uveitis is a rare manifestation of mumps. here we present a mumps case complicating with uveitis. years old paediatric nurse was admitted to our emergency department because of headache and malaise. on physical examination bilateral parotid enlargement was noticed. opthalmology consulatation revealed anterior uveitis. local prednisolon and cyclopentholate treatment were prescribed. lumbar puncture revealed lymphocytic pleocytosis without hypoglychorachea and elevated protein levels. mumps igm was found positive. differential diagnosis made with other viral infections and sarcoidosis. her headache diminished day after the hospitalisation. uveitis responded very well to local therapy and patient got well in weeks. clinical and epidemiological aspects of a measles epidemic, bucharest, romania results: there were cases; sex ratio m/f: / . the mainly affected age group is under months ( . %) followed by months- years ( . %), - years ( . %), > years ( . %) and - years ( . %). . % cases were hospitalacquired (mostly in paediatric clinics), . % were communityacquired; in . % cases the source was unknown. the most common clinical features were fever ( %), rash ( %), conjunctival hiperemia ( . %), cough ( . %), micropoliadenopatia ( . %), diarrhoea ( . %). pulmonary complications were described in . % of cases; . % of them were bacterial pneumonia, . % were viral pneumonia. in . % of cases we diagnosed acute stomatitis, in . % bacterial conjunctivitis; in . % of cases -otitis; in . % of cases -pharingitis, and in one case ( . %) -urinary tract infection. . % of the patients were previously diagnosed and treated for pulmonary tb. all cases were confirmed serologically through detection of specific igm antibodies. patients ( . %) had severe clinical forms of measels. the evolution was good in all cases. conclusion: . this year in the south-east part of the country, evolves a measels epidemic with different features comparing to the previous one ( ) ( ) we investigated the recombinant proteins np and hn to develop new antigen with useful properties for applied in elisa test systems. methods: significant antigenic epitopes of nucleoprotein (np) and haemagglutinin (hn) measles virus strain edmonston were generated by computer analysis. using standard geneengineering techniques was evaluated two fusion peptides np and hn consist from only linear t-cell antigenic determinants. the virus-neutralization activity of hyperimmune serum on recombinant proteins was determined by plaque reduction neutralization test (prn). the level of specific igg in serum to genotypes a, d , and d of measles virus was determined by enzyme-linked immunosorbent assay (elisa). we used recombinant proteins np and hn as antigens for elisa. results: hyperimmune serum was collected from mice after immunization by np and hn recombinant proteins. the level of neutralize activity was measured in the prn assay with strain edmonston. the titre reached up to : . and : . for np and hn recombinant proteins, respectively. interestingly that, hyperimmune serum on recombinant protein np in elisa reacted both with np (titre : ) and with hn (titre : ), and in turn serum on recombinant protein hn reacted only with hn (titre : ). the estimation immunological properties of proteins with use of the panel of serum ( samples) collected from patients. the diagnosis of measles infection was confirmed in laboratory (by rt-pcr). the nucleotide sequences of rt-pcr products used for genotyping of mv. selective interaction of antibodies in elisa with recombinant proteins in relation to various genotypes is revealed. the interaction with genotypes a and d was expressed with high level of correlation whereas with genotype d any serum did not react authentically (as the control was used recombinant protein n of sars virus). conclusion: we have shown that neutralize antibodies formed hot only on superficial proteins such as hn, f and sh but also on core proteins such as np. our data demonstrate that the recombinant proteins np and hn could be a cost-effective alternative to current whole virus based elisas for surveillance for immunity to measles and could more efficient in detecting susceptibility to measles in relation to genotypes a and d . episode : a pregnant woman with thirty-eight week of gestation was hospitalized in obstetrics clinic with the complaints of fever, malaise, and severe vaginal bleeding. on admission, white blood cell count was /mm , haemoglobin was . g/l, platelet count was /mm . the level of ast was iu, alt iu, lactate dehydrogenase iu, and creatinin phosphokinase iu. the baby was delivered by cesarean section. in serum cchf igm was positive by elisa, and per oral ribavirin was administered after delivery. at the first day of delivery, the clinical and laboratory of findings of the baby were found to be normal. however, on his th day, he died because of massive bleeding. his cchf igm was found to be negative. episode : a pregnant woman with week of gestation was admitted to the hospital. her complaints were fever, malaise, headache, myalgia, nausea, vomiting, diarrhoea, and subconjuntival bleeding. in her laboratory investigation, white blood cell count was /mm , haemoglobin level was . g/l and platelet count was /mm . the level of ast was iu, alt iu, and ldh iu. in her serological analysis cchf igm and cchf virus -pcr was found to be positive. at the twenty six week of gestation in obstetric ultrasound, fetal intraabdominal fluid was visualized and amniocentesis was performed. in serological analysis of amniotic fluid cchfv-pcr was found to be negative. intraabdominal fluid had increased and scrotal edema was visualized at thirty eighth weeks of the gestation. after her vaginal delivery, baby was severely ill and was operated with the diagnosis of necrotizing enterocolitis. his laboratory findings were normal except high white blood cell count. on his fifth day, thrombocytopenia occurred and he died because of massive bleeding. his cchf igm and pcr were negative. conclusion: to our knowledge, these are the first episodes of intrauterine cchf infection. these episodes show that cchfv can transmit through placenta. obstetricians in endemic countries should consider cchf infection among the patients with massive bleeding and thrombocytopenia. objective: to detect the asymptomatic crimean congo hemorrhagic fever virus (cchfv) infections in an endemic area, and calculate the attack and the infection rate. methods: the study was performed in a cchf endemic region. the household members of the index cases were screened for cchfv igg and igm by elisa. the data related to risk exposure were obtained by a structured form. results: eleven index cases were admitted to the clinic, household members of these cases were screened. all the index patients had positive igm or pcr for cchfv. among the household members, three individuals had igg positivity (%), and only one patient had igm positivity. none of the screened individuals had symptoms. the mean age was (sd ), and % of the subjects were female. tick bite was detected a risk factor (p = . ) for cchv infection, whereas patient care and contact with body fluids of the patients were not (p > . ). eighteen patients had the history of tick bite, and became infected ( %), and five ( %) became ill. among the infected eight individuals, five became ill ( %). conclusion: although we consider that some of the patients do not notice tick bite, we can still suggest that the infection rate of the virus is rather high compared to similar diseases. tick bite is the major risk factor, in comparison to exposure to blood and body fluids of the infected cases. results: children were included in our study. distribution according sex was: . % female and . % male. median of age was years (iqr = ). during the follow-up study we recorded years when the number of cases increased. the distribution of cases among the study was: . % in , . % in , . % in , . % in , . % in and . % in . the proportion of paediatric patients also varied from; . % in , . % in , . % in , . % in , . % in and . % in . in panama city we recorded . % of the infants. we detected an increase in the number of patients in the rain season, from may till november. the mean of days between the onset of symptoms and the first blood sample was . days (ds: . ) a second sample was obtained in . % of our infants with an average time of . days (ds: . ). the frequency of classical symptoms related to dengue virus infection was: fever ( . %), severe headache ( . %), chill ( . %) rash ( . %), myalgia ( . %), retro-orbital pain ( . %), arthralgia ( . %), gastrointestinal symptoms ( . %), inflamed pharynx ( . %), cough ( . %), mild respiratory symptoms ( . %) and diarrhoea ( . %). in our infants the symptoms which were detected first were; fever, severe headache, chill, myalgia, retroorbital pain, arthralgia, mild respiratory symptoms, cough and inflamed pharynx. we did not observed differences on clinical features between girls and boys. however, we detected detected significative differences among symptoms when we compared infants who were £ years old with those who were older (p < . ). four of our patients died because of dengue hemorrhagic fever. conclusion: dengue is endemic in panama as in most tropical countries and is one of the world s major emerging infectious disease. more data about this illness are needed to elaborate sanitary programmes which contribute to control this infection. diagnosis of dengue infection by enzyme-linked immunosorbent assay and reverse transcriptionpolymerase chain reaction from oral specimens dengue. salivary elisa has been shown by various investigators to be useful for dengue diagnosis. we sought to perform a pilot evaluation of diagnostic value of elisa and pcr of oral brushes and saliva for dengue diagnosis in adults. methods: adults with acute fever and suspected of dengue infection admitted to our university hospital were enrolled. dengue diagnosis was made by standard elisa using serum or plasma. patients with negative elisa served as controls. buccal mucosal cells were collected for rt-pcr and saliva for both rt-pcr and elisa at least twice, - days apart. our elisa criteria for saliva were single igm > units or single igg > units or -fold increase in igg titre with the second titre > units for secondary dengue infection. criteria for primary dengue infection were the same as secondary infection plus igm:igg ratio of over . . results: cases and controls were enrolled. our country is endemic for dengue and thus there was no primary dengue adult case in this study. as the study was performed in hospitalized patients, most of the first samples were collected one day before or on the day of defervescence. the specificities of either methods and the sensitivity of elisa method for saliva were %. sensitivities were approximately - % for rt-pcr using buccal cells or saliva specimens. however, a combination of rt-pcr results for both types of oral specimens gave a sensitivity of %. the results are summarised in the table. conclusions: collection of oral specimens is less invasive and may be more acceptable in certain situations. a single, acute specimen is adequate for diagnosis by rt-pcr. our specimens, however, were collected late in the course of illness which affected the sensitivity of rt-pcr's. earlier specimens may give a better yield. a study in paediatric patients is needed to assess the value of these methods for primary dengue infection. objective: the aim of this study was to assess the proportion of seropositives against hantaviruses among healthy blood donors. methods: volunteer donors were recruited by the institute of transfusion medicine, representing the demographic situation in the tyrol regarding gender and residence. sera were tested for igg with a commercially available elisa. positive samples were confirmed by a commercially available dot blot which was also used for identification of the serovar. setting: the study area comprises north tyrol (austria, north of the main ridge of the alps), south tyrol (italy) and east tyrol (austria, both south of the main ridge of the alps). south tyrol belongs to the catchment area of the etsch river, which drains into the adriatic, while north-and east tyrol are part of the catchment area of the danube, which drains to the black sea. results: none of samples from the italian part of the study area yielded a positive result, wherein of donors of the austrian part turned out to be seropositive. two patients were positive for hantaan, patients were positive for puumala, one patient was positive for dobrava and one patient had antibodies against hantaan and dobrava. only one of those patients reported extensive travelling abroad. conclusions: evidence was found for the occurrence of hantaviruses in the austrian part of the region covering the catchment area of the danube, but not in the italian part of the study area covering the catchment area of the etsch river. seropositivity to hantaviruses differs by hydrogeographic areas. objectives: canine coronavirus (ccov) is an enveloped, singlestranded rna virus, belonging to group i coronaviruses within the family coronaviridae. two different ccov genotypes have been recognised, that are designated ccovs type i and type ii on the basis of their genetic relatedness to feline coronaviruses (fcovs) type i and type ii, respectively. ccov is usually responsible for mild, self-limiting infections restricted to the enteric tract. we report the molecular characterisation of a pantropic variant of ccov that caused fatal disease in pups. methods: ccov type ii strain cb/ was isolated from an outbreak of fatal disease affecting seven dogs housed in a pet shop in apulia region, italy and characterised by fever, lethargy, inappetance, vomiting, haemorrhagic diarrhoea, neurological signs, and severe lesions in the parenchymatous organs. in all tissues, ccov antigen was detected by immunoistochemistry and ccov type ii rna was identified by genotype-specific realtime rt-pcr. the ' end of the genome of strain cb/ was determined by amplification of seven partially overlapping fragments. the pcr-amplified products were subjected to direct sequencing and the obtained nucleotide (nt) sequences were assembled and analysed using the bioedit software package and the ncbi's and embl's analysis tools. genbank accession number dq was assigned to the sequenced . -kb fragment. the inferred amino acid sequences (aa) were compared to the analogous proteins available in the online databases. results: the structural proteins s, e, m, n of strain cb/ displayed a high degree of aa identity to the cognate orfs of ccov type ii, although the s protein showed the highest identity to type ii fcovs. while the nonstructural protein (nsp) a had the same length of known ccovs, the nsp b was -aa shorter than expected due to the presence of a -nt deletion at position and to a frame shift in the sequence downstream the deletion that introduced an early stop codon. conclusions: association of strain cb/ to a severe, fatal disease of dogs, together with virus isolation from organs with remarkable lesions, strongly suggests that this virus has changed the tropism, acquiring the ability to spread from the enteric tract to the internal organs. by sequence analysis of the viral genome, the only striking change was the truncated form of nsp b, but the role of the deletion in the orf b in determining the patho-biological change deserves more in-depth investigation. objectives: to perform a surveillance study for sars coronavirus (sars-cov)-like virus in non-caged wild animals from the wild of hong kong special administrative region (hksar). methods: from summer to spring , bats, rodents and monkeys from locations in hksar were captured. nasopharyngeal and anal swabs and blood samples were collected and tested for sars-cov-like virus rna by rt-pcr using conserved primers targeted to a -bp fragment of the rna-dependent rna polymerase (pol) gene. the complete genome of the sars-cov-like virus from bats (bat-sars-cov) was sequenced using rna extracted from three anal swabs of three bats as template. phylogenetic tree construction was performed using neighbor-joining method with growtree using jukes-cantor correction. prediction of signal peptides and cleavage sites was performed using signalp, transmembrane domains using tmpred and tmhmm, potential n-glycosylation sites using scanprosite and protein family analysis using pfam and interproscan. antibodies were detected using a recombinant bat-sars-cov nucleocapsid protein enzyme immunoassay and neutralization assay for human sars-cov. results: we identified a coronavirus closely related to sars-cov (bat-sars-cov) from ( %) of anal swabs of wild chinese horseshoe bats by rt-pcr. sequencing and analysis of three bat-sars-cov genomes from samples collected at different dates showed that bat-sars-cov is closely related to sars-cov from humans and civets. phylogenetic analysis showed that bat-sars-cov formed a distinct cluster with sars-cov as group b coronaviruses, distantly related to known group coronaviruses. most differences between the bat-sars-cov and sars-cov genomes were observed in the spike gene, orf and orf , which are the regions where most variations were also observed between human and civet sars-cov genomes. in addition, the presence of a -bp insertion in orf of bat-sars-cov genome, not in most human sars-cov genomes, suggests that it has a common ancestor with civet sars-cov. antibody against recombinant bat-sars-cov nucleocapsid protein was detected in % of chinese horseshoe bats using an enzyme immunoassay. neutralizing antibody to human sars-cov was also detected in those with lower viral loads. conclusion: our data support the existence of sars-cov-like virus in chinese horseshoe bats in hksar. noroviruses are genetically heterogeneous and form at least genotypes within genogroups, gi, gii, giii, giv, and gv, based on the capsid genes. human novs cause an estimated million cases of illness annually in the united states alone and > % of nonbacterial epidemic gastroenteritis worldwide. porcine calicivirus have been found to be genetically similar to human gii novs or to sapoviruses but calicivirus rna has been detected at low frequency by rt-pcr in adults or fattening pigs. the close genetic relationships between human and porcine novs raise public health concerns regarding their potential for zoonotic transmission and as a potential source of new epidemic human strains. methods: a total of faecal samples of nursing and weaning piglets with enteritis were collected during - in porcine herds in italy. an additional samples were include in the analysis, that had been collected during a rotavirus (rv) surveillance study in - , all which tested positive to rv by electron microscopy and by rt-pcr. viral rna was extracted by the guanidine thiocyanate/glass milk method to eliminate enzyme inhibitors. primer pair con -con , targeted to the vp outer capsid protein, was used for rv detection. a degenerated version of primer pair / was used for nv detection, that targets a conserved region in the rnapolymerase. results: nov rna was detected in / of the screened samples, while rvs were detected in / samples. mixed infections nov+rv were found in samples. screening of the rv positive samples allowed detection of mixed infections with novs. conclusions: in previous investigations novs were detected in of , normal slaughtered pigs in japan, in of pooled pig faecal samples of -to -month-old fattening pigs in the netherlands and in out of healthy adult and finisher pigs in the united states. interestingly, in this study a high rate of positivity to novs ( / ) was found in nursing and weaning piglets with diarrhoea, a finding that may suggest a higher frequency of infection by nov in young pigs or an association between nov infection and occurrence of enteric disease. altogether, these findings demonstrate that novs are common in porcine herds in italy and provide new insights into the ecology of novs. detection of calicivirus genome in calves using ni/e primers m. mahzounieh, t. zahraeisalehi, e. moghtadaei khorasgani (shahrekord, tehran, ir) caliciviruses may cause a wide spectrum of disease in animals and are important etiological agent of viral gastroenteritis in humans. members of the family caliciviridae are small nonenveloped viruses to nm in diameter. they possess a single stranded poly adenylated rna genome. caliciviruses have been isolated from mink, dog, cattle and non-human primates. "norwalk-like viruses" (nlvs) are the most common cause of acute non-bacterial gastroenteritis in humans. cattle may be a reservoir of nlvs although never bovine nlvs have been found in humans. in this study, we try to detect enteric caliciviruses genome from faecal samples of dairy cattle herds in shahrekord area using reverse transcriptase polymerase chain reaction (rt-pcr) assays specific for nlvs found in humans. the primers used for pcr amplification were ni and e , which amplify a -bp product for the detection of both genogroups i and ii srsv rna in fecal material. our results showed that nine specimens ( %) were positive. these findings suggest that calicivirus infection is endemic in dairy herds in shahrekord, iran and may be have an important role in calf diarrhea. objectives: reoviruses are non-enveloped, -segmented dsrna viruses. in humans and mammalians three distinct serotypes exist, whose prototypes are strains lang (t ), jones (t ) and dearing (t ). although reoviruses have been isolated both from the enteric and respiratory tract, no diseases has been clearly associated to reovirus infection in humans. the potential association with extra-hepatic biliary atresia, myocarditis, and, above all, neurological and cutaneous diseases require further investigations. reoviruses are ubiquitous and scarcely speciesspecific. reovirus identification is usually based on electronic microscopy or gel electrophoresis and reovirus incidence seems to be very low in humans and most mammalians. in this study, we investigated the presence of reoviruses in dogs by means of molecular methods. methods: one hundred ninety-two rectal samples from dogs with diarrhoea, ocular swabs, nasal swabs and oropharyngeal swabs from dogs with ocular/nasal discharge were subjected to an rt-pcr assay targeting a conserved region of viral genome segment l (primers l -rv /l -rv ). positive samples were characterised by polyacrylamide gel electrophoresis (page), serotype-specific rt-pcr assays targeting segment s and sequence analysis. to increase the sensitivity, a nested pcr using primers l -rv /l -rv was performed on samples tested rt-pcr negative. results: only faecal swabs ( . %) were found positive (rt-pcr product of bp). by using a serotype-specific rt-pcr assay and/or sequence analysis, two strains was characterised as type and the other ones as type . page of viral dsrna confirmed the genetic characterisation. unexpectedly, in secondround pcr faecal samples ( %), ocular swabs and nasal swabs yielded a bp product, while no oropharyngeal swab was positive. conclusions: these data suggest a wider distribution of reoviruses in dogs than previously thought, even if most reovirus infections were detected only by nested pcr. the ability of reoviruses to induce disease in dogs, alone or in synergism with other pathogens, is still unclear, since attempts to reproduce a specific disease in germ-free dogs have given contradictory results. due to their poor species-specificity, reoviruses may be easily transmitted from animals to humans (and vice-versa). further studies are required to understand reovirus ecology and their potential zoonotic impact. objectives: parvovirus b is a member of a family parvoviridae. on the basis of genetic distances and evolutionary relationships, human parvoviruses are divided into three genotypes: genotype i corresponding to b -related isolates, genotype ii to lali-related isolates, and genotype iii to v -related isolates. parvovirus b causes a common exanthematous disease in childhood or adult age, arthropathy, hydrops fetalis, various haematological disorders and myocarditis. up to now, we have had no data of the prevalence of b virus in slovenian population. consequently, we also lack information on the genotypes of parvovirus b that are involved in the patients who suffer from the infection. methods: to gather information of the genetic variants of b virus present in slovenia, we extracted dna from serum samples that were sent for serologic diagnostic of parvovirus b infection and were positive for specific igm in the period from january to june . nearly half of all patients were children and young adults up to years. the ns region of parvovirus b was amplified by the nested pcr (primers pb f , r and pb f , r ). all pcr products were directly sequenced. the results of our study show that dna of parvovirus b was present in all samples that tested positive for specific igm antibodies. after the first round of pcr reaction, samples were positive, and after the second reaction, all samples were positive. altogether unique genotype variants of parvovirus b were identified and all were clustered in the genotype i group of b -related isolates. most of the distinct genetic variants differed in % to % from the sequences deposited in gene bank. the majority of sequences obtained from the b virus epidemic in represents a single variant of genotype i with the gene bank acc. no. aj . we also found that different genetic variants of parvovirus b were circulating in and were % or % identical to the genotype i variant with the gene bank acc. no. z . in our study, we were not able to identify any variants of other rare genotypes (lali or v ). conclusion: parvovirus b dna was successfully amplified from all igm positive serum samples of the patients. the genotype i of parvovirus b is dominating in infections with parvovirus b in slovenia. objectives: great britain has been free of animal brucellosis since (european commission decision / ). the main source of infection for uk residents is through contact with infected material in foreign countries. the objective of this study is to type human samples received in the uk since using variable number tandem repeats (vntr) molecular typing to confirm results obtained by classical typing and relate these results to the suspected source of infection. methods: classical typing is traditionally used and is based on the phenotypic attributes of each strain and biovar. vntr typing is a recently developed molecular method, which is based on short repeats contained in the dna that can be amplified to give a banding pattern specific to each strain. results: results found using both methods are consistent. the results show geographical differences, consistent with observations of strain genotype distribution found in animal brucellosis. conclusion: patient history has been gathered where possible giving information on recent travels. along with results found by classical typing and confirmed by vntr typing we can draw a picture of the sources of infection. these results illustrate the potential of vntr typing as a tool to aid conventional approaches to epidemiological traceback that, in the presence of a suitably comprehensive database of strain genotypes, could help identify the source of an infection. is -fingerprinting of brucella isolates from humans e.stubberfield (surrey, uk) objective: brucellosis is a zoonotic disease usually associated with cattle, sheep, goats and pigs. human infection has been attributed to b. melitensis, b. abortus, b. suis, b. canis and b. maris. although the uk is officially bucellosis free there are a number of human cases due to travel and occupation that are submitted to our laboratory for diagnosis. definitive diagnosis of brucella is by bacteriological culture and microbial tests (classical typing), however these require skilled personnel and the results can be subjective. there are a number of molecular tests that have been developed to assist with diagnosis more rapidly and in some cases to strain level less subjectively. is -fingerpinting is a molecular technique that has proved useful for the identification of brucella isolates to species and in some cases stain level. is -fingerprinting relies on the variable number and location of the is mobile genetic element found in all brucella isolates. method: brucella isolates from humans have been tested. genomic dna was extracted, digested using restriction endonuclease ecor , and electrophoresed. southern blotting was performed, hybridising with a dig-labelled is probe. results: the number of brucella is copies range from to more than . brucella melitensis remains the most commonly acquired brucella species of travellers, while occupational infections have included b. abortus isolated from cattle farmers and b. suis associated with pig butchers. two marine brucella strains have been isolated originating from an occupational perspective (a laboratory worker) and a natural setting from an unknown source. unusual patterns have been observed, of which are unique. one of the new patterns has been observed only in isolates originating in east african countries. conclusion: although the diagnosis of brucella to species and strain level is not essential for the treatment of human brucellosis, it is useful for epidemiological studies. is fingerprinting is able to identify the three biovars of b. melitensis, many other techniques do not offer this capability, because of this it may be a useful test in epidemiological studies. this method remains an important diagnostic tool for brucella identification. rapid diagnosis of brucellar epididymo-orchitis by real-time pcr assay in urine samples objectives: to study the diagnostic yield of a real-time pcr assay in urine samples for the rapid diagnosis of brucellar epididymo-orchitis, in comparison with conventional microbiological techniques. methods: ten consecutive patients with brucellar epididymoorchitis were included in the study. the diagnosis of brucellosis was established according to one of the following criteria: first, isolation of brucella spp in blood or any other body fluid or tissue sample or, second, the presence of a compatible clinical picture together with the demonstration of specific antibodies at significant titers or seroconversion. epididymo-orchitis was diagnosed in patients with scrotal enlargement, swelling and pain not due to other causes.for dna amplification we used a sybr green i lightcycler-based real-time pcr assay. the assay amplifies a bp sequence of a gene that codes for the synthesis of an immunogenetic membrane protein (bcsp ). the pair of nucleotide primers b ( ' tgg ctc ggt tgc caa tat caa ') and b ( ' cgc gct tgc ctt tca ggt ctg ) were used in the amplification process. after dna amplication, we performed melting curve analysis to verify the specificity of the pcr products. in order to study the specificity of the technique, all the samples from the patients with brucellosis were paired with an equal number of samples from controls with urinary tract infection. (e. coli four cases, k. pneumoniae two cases, p mirabilis two cases, and c. freundii and p. aeruginosa one of each). results: the mean age was . years (range - ). the duration of the symptoms prior to diagnosis was . ± . days (range: - ). b. melitensis was isolated from blood cultures in nine cases ( %). wright's seroagglutination was negative or inconclusive in % of cases. brucella was isolated from urine in only one case whereas real-time pcr assay in urine was positive in nine ( %) cases and the results were available in four hours, whereas the mean time to availability of the final blood culture results was . days (range . - days). real-time pcr was negative for all the control samples from patients with urinary tract infections. conclusion: sybr green i lightcycler-based real-time pcr assay in urine samples is highly sensitive and specific, easy to perform and could provide the clinician with the results in under five hours. the technique could be a practical and useful tool for the rapid diagnosis of genitourinary complications of human brucellosis. objectives: although the united kingdom remains brucellosisfree, there are more than , new cases of human brucellosis reported each year according to the world health organisation. uk residents returning from worldwide travel may have encountered exposure through contact with infected animals and animal products such as dairy produce and meat. phenotypic characterisation or classical methods remain the definitive diagnosis though require skilled personnel and have their limitations. the increasing range of molecular techniques can aid the rapid detection and characterisation of brucella species and their biovars and may have significance in epidemiological studies. methods: a study of brucella reference and field strains of mainly human isolates from different geographic locations were analysed for diversity of their genes encoding the outer membrane proteins (omps) , a and b. pcr products of the three genes digested with seven restriction enzymes were analysed for polymorphisms. results: a re-occurring unique pattern profile seen only in human isolates was observed originating in some european countries and beyond. a growing database of strain types giving a recent overview of brucella infection of humans of many countries. conclusions: molecular typing methods may have an advantage over classical typing concerning brucella melitensis, the most common brucella infection of humans. the characterisation of human brucella isolates may be useful in epidemiological studies for a variety of purposes. objectives: a study to demonstrate the rapid detection and speciation of campylobacter jejuni and of campylobacter coli isolates directly from enrichment broth using a taqman Ò assay. single nucleotide polymorphism analysis of mapa positive strains was used for rapid identification of c. jejuni clonal complexes. methods: thermotolerant campylobacter species were initially confirmed by culture according to the modified draft iso method, where water samples were filtered through . mm pore size nylon membrane. the filters were transferred to selective enrichment in preston broth to improve their recovery and therefore detection of any campylobacter cells present. dna was extracted directly from the enrichment broth culture for real-time detection of c. jejuni and c. coli using the taqman Ò . samples, which were map a positive were, further characterise by single nucleotide polymorphism profiling for rapid recognition of c. jejuni clonal complexes. results: environmental samples, which were confirmed by culture were also map a positive by taqman Ò . snp profiling of mapa positive isolates identified clonal complexes, which are predominantly contained in isolates of human disease and chicken. conclusions: this study has demonstrated the feasibility of rapid detection and identification of c. jejuni and c. coli following short enrichment incubation using a taqman Ò assay. a rapid turnaround time of between - h per batch of samples was achieved. snp profiling offers important epidemiological grouping at strain level, enabling accurate and phylogenetically valid strain identification for c. jejuni, which may have important host associations for tracing sources of infection and consequently improve public health responses. objectives: campylobacter jejuni and c. coli are recognized as the most common causes of acute bacterial gastroenteritis in humans, c. jejuni being the predominant species in most developed countries. the hippurate hydrolysis test is widely used to differentiate c. jejuni from other campylobacter species. about % of c. jejuni isolates fail to hydrolyze hippurate under laboratory conditions. molecular methods represent an alternative to the phenotype-based methods. we tested two multiplex pcr assays for species identification of human campylobacter strains and compared the results with the hippurate hydrolysis test. methods: campylobacter strains isolated from patients were tested for hippurate hydrolysis with rosco diagnostic tablets. hippurate-negative and hippurate-positive strains were selected for two multiplex pcr assays. one pcr-method was based on distinctive ceue-genes of c. jejuni and c. coli, the other pcr-method detected genes from five major clinically relevant campylobacter species: hipo from c. jejuni, glya from c. coli, c. lari and c. upsaliensis, sapb from c. fetus subsp. fetus, and s rrna gene from campylobacter spp. as an internal validation control. results: the c. jejuni hipo gene was detected in all of the hippurate-positive strains and of the hippurate-negative strains. the c. coli glya was detected in of the hippuratenegative strains. in one hippurate-negative strain, sapb from c. fetus subsp. fetus was detected. species-specific genes were detected in of the strains with the ceue-based pcr assay. c. jejuni ceue was detected in hippurate-positive and hippurate-negative strains. c. coli ceue was detected in hippurate-negative strains. conclusion: all hippurate-positive strains were identified as c. jejuni. of the hippurate-negative strains, % were identified as c. coli, whereas % were identified as c. jejuni and one strain as c. fetus subsp. fetus. the results of the two pcr assays were concordant, although some strains could not be identified with the ceue-based pcr assay. the results suggest that molecular species identification should be performed on hippuratenegative strains after the hippurate hydrolysis test for accurate species identification. multiplex-pcr is quick and easy to perform. using the pcr assay that simultaneously detects five campylobacter species also diminishes the need for further phenotypic testing. phenotypic typing of cryptosporidium species isolated from children in kuwait: a role in unique transmission j. iqbal, p. hira (safat, kw) background: cryptosporidiosis is recognized worldwide as a significant cause of diarrhoeal diseases in both adults and children especially in children less than years of age. objective: cryptosporidium spp. isolated from young children in kuwait were characterized at the molecular level to understand the transmission of infection. the study was approved by the ethical committee, faculty of medicine, kuwait. methodology: over a period of years, faecal specimens from kuwaiti children with persistent diarrhoea found to be positive for cryptosporidium spp. by microscopy were genotyped and sub-typed with a small subunit rrna-based pcr-restriction fragment length polymorphism analysis. informed consent was taken from all individuals included in the study. results: the median age of infected children was . years, and the majority of the infections (> %) occurred during the cooler months january-april, indicating a marked seasonal variation. more than % of the children with cryptosporidiosis had only cryptosporidium infection. socio-demographic information did not reveal any particular mode of transmission of infection. genotyping of the organisms isolated showed that ninety-two ( %) of the children had c. parvum, ( %) had c. hominis, and ( %) had both c. parvum and c. hominis. altogether, subtypes of c. parvum and c. hominis were observed. objectives: the intracellular respiratory pathogen chlamydophila pneumoniae (cp) might be involved in the pathogenesis of atherosclerosis. several studies have demonstrated a serological association between cp and cardiovascular disease and dna from the bacteria has been found in various atheromatous vessels. after infection in the respiratory tract, cp is believed to be disseminated systemically within alveolar macrophages. the prevalence of cp within peripheral blood mononuclear cells (pbmc) has in some studies been shown to be higher in patients suffering from cardiovascular disease than in control patients. we investigated the presence of cp dna in aortic heart valves and pmbc in patients ( men; women; mean age years) undergoing aortic valve replacement because of aortic stenosis. also, the presence of cp mrna was investigated in the sclerotic aortic heart valves as a marker of viable bacteria. methods: dna was extracted from aortic valve biopsies and pbmc using the qiaamp dna mini kit (qiagen). mrna and dna were extracted from another piece of the same biopsy using trizol (invitrogen). real-time pcr directed against the chlamydia momp gene was used to detect cp-specific dna and mrna. patient sera were tested for cp-specific igm, igg and iga antibodies by the microimmunofluorescence technique. results: cp dna was found in aortic heart valves from % ( / ) of the patients and in pbmc from % ( / ) of the patients. in one patient cp dna was found in both pbmc and heart valve. no patient had cp-specific igm antibodies. in patients that were pcr-positive for cp dna in the aortic heart valves, % had igg ‡ : and % had iga ‡ : . in patients that were pcr-negative in the aortic heart valves, % had igg ‡ : and % had iga ‡ : . cp-specific mrna in aortic heart valves will be presented on the poster. conclusion: cp-specific dna was found in sclerotic aortic heart valves from % of patients undergoing aortic valve replacement. this confirms previous investigations supporting a role for cp in the pathogenesis of aortic valve sclerosis. the prevalence of cp in pbmc was % which is comparable to that reported in healthy blood donors and lower than that recorded in patients suffering from other cardiovascular diseases. if the bacteria are involved in the pathogenesis of aortic sclerosis they have likely been spread to the aortic valve long before the patient is in need of surgery because of the stenotic valve. introduction: diarrhoea is one of the most common causes of morbidity and mortality among young children in developing countries. diarrheagenic e. coli strains include several emerging pathogens of worldwide public health. six important categories are entero-aggrigative e. coli (eaec), entropathogenic e. coli (epec), enterotoxigenic e. coli (etec), enterohemorrahgic e. coli (ehec), entroinvasive (eiec) and shigatoxin-producing e. coli (stec). this study investigated the role of different diarrheagenic e. coli in iranian children with acute diarrhoea by molecular methods and the antibiotic susceptibility of isolated strains. methods: from april to january , one thousand eighty five children with acute diarrhoea in tehran hospitals in were enrolled in the study. the fecal samples were cultured on macconkey for conventional bacterial pathogen and sorbitol macconkey agar for non sorbitol fermenting phenotype, than they were incubated in ordm;c. the primary stool cultures were subjected to six different pcr reactions targeting stx and stx gene, heat-labile enterotoxin (lt) producing gene, heatstable enterotoxin (st) producing gene, eae gene and pcvd plasmid. the kirby -bauer disc diffusion method was used for antibiogram of isolated strains from different diarrheagenic e. coli by different antibiotics. results: two hundred seventy one diarrheagenic e. coli strains were detected. stec was the most prevalence with ( . %). the frequency of other strains was . %, . %and . % for etec, eaec and epec, respectively. out of stec isolated strains (% . ) had stx or stx gene, and strains had stx and stx gene. the eae gene was found in ( . ) stec strain. out of tested strains, ( . %) were resistance to ampicllin and cefalotin, and ( %) to streptomycin. conclusion: in this study stec was the most frequent associated with diarrhoea. the strong association between use of antibiotics and colonization with antibiotic resistant e. coli, suggest a major role for selection of resistant strains while using antibiotics. the existence of other unknown intestinal adherence factors has been suggested by the isolation of stec strains that lack the eae gene but are still associated with bloody diarrhoea or hemolytic ureamic syndrome (hus). since there is no specific treatment, there is an urgent need for effective preventive measures based on detailed understanding of the epidemiology of stec infections. identification of shiga toxin-producing escherichia coli in raw beef using dna hybridization with digoxigenin-labelled probes and multiplex pcrs m. weiner, j. osek (pulawy, pl) shiga toxin-producing escherichia coli (stec) is an important cause of bloody diarrhoea, haemorrhagic colitis, haemolytic uremic syndrome and thrombotic thrombocytopenic purpura. transmission of stec occurs through consumption of contaminated food, especially meat, dairy products and water. objectives: to develop a three-steps procedure based on two multiplex pcrs and dna hybridization with digoxigeninlabelled probes for identification of stec in raw beef. methods: beef samples inoculated with different number of e. coli o :h cells were incubated in tsb medium at °c for h. the cultures were then transferred to tsb with mitomycin c and incubated for another h. the resulted cultures were used as a source of dna template. the mpcr- was established to identify shiga toxins genes (conserved sequence). the positive culture samples were subjected to dna hybridization with dig-labelled probes as follows: the culture was diluted and inoculated onto agar plates supplemented with tergitol Ò and incubated at °c for h. then, the nylon membranes were put on agar plates, carefully removed and incubated in denaturation, neutralisation and equilibration solutions following incubation with the stx-specific dig-labelled probes, anti-dig conjugates and finally developed with enzyme substrates (bcip and nbt). dark spots visible on the membranes were compared with the respective bacterial colonies on the original agar plates. the corresponding bacterial colonies were isolated and characterized using the mpcr- test which allows amplification of stx (shiga toxin type ), stx (shiga toxin type ), rfbo (e. coli o ) and flich gene (h antigen). an internal control of amplification (e. coli s rrna gene) was also included in both mpcr tests. results: the first mpcr resulted in two amplification products: bp for stx and bp for s rrna genes. the positive meat samples were further tested with dna probes and positive colonies were then characterized with the second test (mpcr- ), generating the amplicons either of bp (stx ), bp (stx ), bp (rfbo ), bp (flich ) or bp ( s rrna). the specificity of this procedure was confirmed by testing e. coli o :h , o :h-and non-stec bacteria. the sensitivity of the method was estimated as cfu/g of meat. conclusion: the obtained results demonstrated the high specificity of the procedure developed and the possibility of using it for identification of shiga toxin-producing e. coli in raw beef. correlation between virulence pattern, phylogenetic group and extended spectrum betalactamases genes in escherichia coli strains isolated from blood cultures m. damian, c. usein, d. tatu-chitoiu, s. ciontea, d. jardan, a. palade (bucharest, ro) e. coli, heterogeneous species consisting of commensal and pathogenic strains, is causing a broad spectrum of human diseases, including extra intestinal and enteric infections.the strains isolated from invasive infections were documented to be carriers of a large number of genetic structures coding for virulence, as well as for resistance to antimicrobial agents. the aim of this study was to evaluate the virulence of strains in comparison with the presence of esbl genes and their distribution among the different phylogenetic groups. a total of e. coli strains, isolated from blood cultures, in hospitalised patients, adults and children, were screened for virulence factors-encoding genes (pap, sfa/foc, afa, hly, cnf, aer and fimh), for genes encoding resistance to extended spectrum betalactam antibiotics (bla shv and bla tem genes) and the appurtenance to one of the main four phylogenetic group based on presence or absence of markers chua, yjaa and tspe .c three strains, negative for all virulence genes, were included in the phylogenetic group a. ten strains, which were positive for five or six virulence genes, were identified as b group. no matter the phylogenetic grouping, the remaining strains possessed at least one virulence gene. no strain was pcr positive for all seven virulence genes targeted. among the strains which were positive in the double disk test, strains exhibited both bla shv and bla tem genes and strains only bla tem gene. restriction with pst i and dde i and sequencing of the amplicons were performed in order to identify the type of esbl gene expression product. taking into account the link between phylogenetic group and virulence, we obtained a good correlation for the bacteremic e. coli strains analysed, but there was no relationship with the production of esbls. isolation of shiga-toxin producing escherichia coli from meat samples, phenotypic and genotypic characterisation of isolated strains f. baghbani-arani, f. jafari, m.r. zali, s. salmanzadeh-ahrabi (tehran, ir) objective: shiga-toxin producing escherichia coli (stec) is an emerging foodborne pathogen of worldwide public health importance. this bacterium has been reported as an etiological agent of many outbreaks and sporadic cases. definition of the diversity and antimicrobial susceptibility of (stec) may be helpful in the management of sporadic cases and outbreaks. studies in different countries show that food items maybe contaminated by this pathogen. the present study was carried out to determine the frequency of contamination of meat samples by stec collected in tehran as well as defining genotypes, serotypes, antibiogram susceptibility patterns and molecular diversity of isolated bacteria. methods: from july to june , beef samples were collected from different part of tehran. a grams of each samples was enriched in ec broth and subculture on mac-conkey agar. dna was extracted from a loop full of bacteria taken from primary first streaking area of mac-conkey agar and was subjected to three different pcr reactions targeting stx , stx and eae genes. as much as colonies required were tested for finding the colony responsible for positive results in the first pcr. antibiogram susceptibility patterns of isolated strains were determined by standard disk diffusing method. the antimicrobial agents were used at this study. all isolates were serotyped by slide agglutination test using standard antisera (mast groups) subtyping of strains was done with rapd-pcr by primer. results: among samples, ( %) samples were positive and their genotypes were as follow: ( . %) stx +, stx -, eae-, ( %) stx -, stx +, eae-, ( . %) stx -, stx + and eae+. ( . %) stx +, stx +, eae-, ( . %) stx +, stx +, eae+. among these positive samples strains were isolated. according to the antibiotic susceptibility tests, all isolates were resistance to erythromycin (e) and oleandomycin (ol), and were sensitive to imipenem (i); gentamicin (g) norofloxazin (nx) enterofloxazin (ex) ciprofloxazin (cf) and ceftazidim (ca). in otyping and htyping the most frequency were o ac and h serotypes. analysis of isolates by rapd-pcr yielded different patterns. conclusion: our results show that contamination of meat samples by stec is a life-threatening health problem. combinational analysis of antibiogram susceptibility patterns and serotypes with rapd-pcr patterns can aid to survey the characteristics of stec strains. factors affecting the conjugative transfer of plasmid pip in enterococcus faecalis a.m. al-qurashi (dammam, sa) objectives: factors which are known to influence plasmid transfer were studies using the conjugative plasmid pi , which encodes erythromycin resistance, in enterococcus faecalis. methods: the donors strains streptococcus a agalactiae v (group b) is resistant to in rifampicin and fusidic acid, non hemolytic and b-lactamase-negative. it contains the broad host range plasmid pi , which confers resistance to erythromycin and chloramphenicol. the recipient is enterococcus faecalis strain jh - group d. results: transfer of pip occured on a agar, on filters and in broth cultures at relatively high densities ( - bacteria/ml). transfer frequency was largely unaffected over a wide range of temperatures ( - °c). the ph of the medium, in the range ph - had little effect on the transfer frequency. log phase cultures and donor: recipient ratios of : - : were required for optimal for plasmid transfer. conclusion: factors which modified the transfer efficiency of the conjugative plasmid pip were mating media, solid or liquid environment, mating time, mating temperature, selection temperature, growth temperature of donor and recipient of prior to mating, ph culture age, and donor/recipient cells ratio, to obtain a better understanding of this plasmid and its transfer process will help understand what role they may have in the dissemination resistance among streptococcal and enterococcal populations. enterococcus faecium blood-culture isolates collected during a five-year period h. billströ m, Å . sullivan, b. lund (stockholm, se) background: enterococcus faecalis and enterococcus faecium have during the last years become a significant nosocomial problem. this could be due to the enterococcus hardy nature combined with intrinsic and acquired antibiotic resistance. since most individuals harbour enterococci in their normal intestinal microflora there has been a discussion regarding the origin of these isolates. during the last ten years the isolation ratio between e. faecalis and e. faecium have shifted from : to : . this could be because of increasing antibiotic resistance among infectious e. faecium isolates compared to infectious e. faecalis ones. it is possible that this increase also depends upon different virulence genes such as enterococcal surface protein (esp), hyaluronidase variant gene (hylefm) and e. faecalis antigen a variant (efafm). objectives: the objectives in this study were to determine the presence and frequencies of seven different enterococcal virulence genes in infectious isolates. further objectives were to see if the number of virulence genes in these isolates vary or increase over time. methods: a total of strains isolated from bacteraemia patients during year - at the karolinska university hospital, huddinge were used. all isolates were screened for seven different virulence genes using a multiplex pcr. these seven virulence genes were aggregation substance (asa), cytolysin (cyt), collagen binding protein (ace), e. faecalis antigen a variant (efafm), enterococcal surface protein (esp), gelatinase (gel) and hyaluronidase (hyl). results: according to the results about half of all isolates were esp-positive. the prevalence of the other virulence genes asa, efafm, gel and hyl were detected, but in low frequencies (< %). conclusion: it seems like the esp gene is the most dominant virulence gene in e. faecium isolates. the occurrence of virulence traits in these isolates further indicates that the potential to cause infection is potentiated among this enterococcal population the data from this investigation supports the hypotheses that enterococci causing infection in hospitalized patients are probably of nosocomial origin rather than endogenous. objectives: the ability of l. monocytogenes to tolerate alkaline stress is of particular importance, as this pathogen is often exposed to such stress in food processing environments cleaned with alkaline detergents or in the mildly alkaline ph values which prevail within engulfing phagolysosomes. this study aims to investigate the alkaline tolerance response (altr) in listeria monocytogenes s using dna microarray technology. knowledge of the alkaline-induced stress response will be useful in understanding how this pathogen tolerates alkaline stress. methods: transcription profiling of l. monocytogenes s was carried out at , and min at high ph in order to capture an early, an intermediate and a prolonged expression response to alkaline stress using oligo arrays from the pathogen functional genomic resource centre. to verify the microarray results the regulation of some ph stress response genes were confirmed by real time quantitative polymerase chain reaction (rt-pcr). results: about genes were upregulated and genes (of open reading frames represented on the arrays) were down regulated at least . fold upon alkaline shock. many of the repressed genes encode enzymes that are involved in the biosynthesis of amino acids, nucleotides and coenzymes, indicating a metabolic adjustment of the cells to the high ph. notably, the strongest alkaline-inducible genes were involved in the membrane transport systems. conclusion: the analysis of the data revealed that cells sense and respond to alkaline stress with an extensive program of changes in gene expression. interestingly, there is a strong correlation between the altr and virulence gene expression. comparison to various microarray data already in the literature revealed similarity between the response to alkaline stress and the transcriptional response to stresses such as osmotic shock. engineering improved listerial stress tolerance "with a twist"! r. sleator, c. hill (cork, ie) objectives: to engineer listeria monocytogenes strains with a significantly improved ability to tolerate stresses encountered in the external environment and during gastrointestinal transit, thus, improving listeria's efficacy as a potential vaccine and drug delivery platform. methods and results: using a directed evolution approach, based on a random mutagenesis strategy involving the e. coli xl -red mutator strain, we generated a mutant variant of the listerial betl gene (designated betl*), encoding a secondary betaine uptake system. the mutant betl* promotes a dramatic increase in resistance to a number of biologically relevant stresses when expressed in a variety of different surrogate hosts. using a luciferase (lux) reporter system in combination with the ivis imager system (xenogen corporation, alameda, ca), we tracked betl* expression, in real time, both in vitro under various environmental stresses and in vivo in animal models of infection. in each case strains expressing betl* demonstrated a marked improvement over those expressing wild type betl, both in terms of gene expression and bacterial growth. sequence analysis of the mutated gene revealed a single nucleotide deletion in the spacer region between the - and ) promoter elements upstream of the betl coding region. this deletion presumably introduces a conformational 'twist' in the putative promoter, thereby increasing its transcriptional output. furthermore, the betl* mutation appears to counter the heretofore unreported 'twisted' cell morphology observed using scanning electron microscopy of l. monocytogenes grown at elevated osmolarities. conclusions: it is possible to selectively improve genes required for bacterial stress survival both inside and outside the host. such mutated genes systems may ultimately be used for the construction of more physiologically robust bacterial based vaccine and drug delivery platforms. a.r. samarbaf-zadeh, s. tajbakhsh, s.m. moosavian (ahwaz, ir) introduction: peptic ulceration following infection of stomach with h. pylori is a common disease. accurate and rapid detection of the bacteria can lead to implementation of appropriate treatment and recovery. this research was undertaken to evaluate the sensivity and specificity of fluorescent in-situ hybridization (fish) in the detection of h. pylori in patients who were suffering from dyspepsia. methods: for this purpose, one hundred gastric biopsy samples taken from antrum and corpus of stomach by endoscopy were tested by fish and compared with conventional culture method complemented with biochemical tests. results: fish detected h. pylori in clinical samples while conventional method detected samples. the sensivity and specificity of fish for detection of h. pylori were calculated as % and % respectively. conclusion: the findings of this study suggest that fish is a highly suitable and rapid method for diagnosis of h. pylori, especially when the samples are taken from the antrum and the corpus of the stomach this technique potentially can be applied routinely for detection of this bacterium in clinical samples. objective: numerous studies have demonstrated that h. pylori is ubiquitous; approximately % of the world's population is infected with the organism. gastroduodenal diseases associated with h. pylori infection are manifested principally in adults. however, it's usually during chilhood that the infection is acquired, and it is possibile that mucosal and humoral responses at this time may determine, at least in part, the course of the natural infection. our study will describe the prevalence of the h. pylori oral carriage in children resident in bari, south of italy, using the pcr method. methods: the evaluation was performed in children, with ages ranging from to years, from primary school district of local health unit of bari, italy (ausl ba/ ). the school and the class have been selected using the cluster sampling method. a standardized questionnaire was used to verify socio-economic standard, hygiene and history of previous gastrointestinal disorder. a standard full-mouth examination was made to detect periodontal diseases, then dental plaque and saliva collected from children were placed in pbs and transported in laboratory. h. pylori infection status was checked by pcr method. dna was extracted from oral samples by the boiling method and evaluated for the presence of h. pylori caga and urea genes using commercial kit (ab analitica, padova). results: a total of children ( females and males) partecipated to the study. the presence of gene coding for caga was found in children ( %), but gene urea was detected only in ( %). the bacteria was detected in saliva, supragingival and subgingival plaque, suggested that these sites may be considered reservoirs for h. pylori in ureasi-positive patients. there was statistically significant relationship between who didn't wash their hands frequently and the presence of urea gene (o.r. . ). conclusions: current knowledge implies that acquisition of h. pylori seems to occur predominantly in childhood and that once acquired the infection persists life-long in most infected subjects. it has been reported at a worldwide level that h. pylori infection prevalence in children varies between % and % and increases with low socio-economic and educational levels and age. the results of this study suggest that oral carriage of h. pylori may play a role in the transmission of infection and that the hand may be instrumental in transmission. the role of helicobacter pylori in otitis media with effusion t. yilmaz, m. ceylan, y. akyon, o. ozcakir, b. gursel (ankara, tr) objectives: otitis media with effusion (ome) is such a common disease of childhood and its pathogenesis still remains unsettled. pepsinogen and pepsin has been shown in the middle ear fluid of patients with ome, indicating that gastric juice could reach as far as middle ear. if gastric juice could enter the middle ear, helicobacter pylori, a common inhabitant of gastric juice and mucosa, would also be expected to be found in the middle ear of patients with ome. the objective of this study was to evaluate possible role of helicobacter pylori in pathogenesis of otitis media with effusion. methods: the study group consisted of children who are to undergo bilateral ventilation tube insertion, adenoidectomy, tonsillectomy with a diagnosis of ome, adenoid hypertrophy and chronic tonsillitis. the control group consisted of children who are to undergo adenoidectomy, tonsillectomy with a diagnosis of adenoid hypertrophy and chronic tonsillitis. for the study group, middle ear fluid was aspirated and a small biopsy was taken from the promontorium mucosa. for the control group, myringotomy was done and a small biopsy was taken from the promontorium mucosa. for both groups, mm deep tissue specimens were obtained from tonsil and adenoid. for all the specimens taken from the patients, culture and a nested-pcr were performed to show helicobacter pylori. results: middle ear fluid culture was positive for h. pylori in patients and mucosa culture was positive in patient only. in the control group middle ear mucosa cultures were always negative. when culture and pcr results were combined together; the middle ear was positive for h. pylori in patients in the study group and in patients in the control group. this difference was statistically significant. h. pylori presence in the tonsillar and adenoid tissues by culture and pcr was also significantly more frequent in the study group compared to the control group. conclusion: this study is the first to grow h. pylori in the middle ear in ome. significantly increased colonization by h. pylori of the middle ear, tonsillar and adenoid tissue in patients with ome indicates that the bacteria reaching the middle ear through gastroesophageal reflux might be involved in the pathogenesis of ome. for ome cases resistant to medical treatment it may meaningful to evaluate the patient for gastroesophageal reflux and h. pylori. distribution of the serine-aspartate repeat protein-encoding sdr genes among nasal carriage and invasive staphylococcus aureus strains objectives: this study was designed to examine the distribution of the sdr genes among nasal carriage and invasive staphylococcus aureus strains as well as methicillinsensitive s. aureus (mssa) and methicillin-resistant s aureus (mrsa). methods: the presence or absence of the sdr genes using dna from s. aureus strains was determined by a novel triplex pcr procedure. the two-tailed fisher's exact test was used to analyse the distribution of the sdr genes among s. aureus strains originating from different hosts. p values less than . were considered a statistically significant difference. results: the sdr locus was found in all investigated s. aureus strains although in strains it contained only the sdrc gene (sdrd -sdre-). the sdrc + sdrd -sdre-gene profile was exclusive to mssa strains (fisher's exact test; p = . ) and was not found in the strains collected from bone infections (p = . ). we also found a strong association between the presence of the sdrd gene and mrsa strains (p < . ). conclusion: our findings suggest that mssa strains with the newly uncovered sdrc + sdrd -sdre-gene profile have a substantially decreased potential to establish bone infection. sequencing of luks-pv and lukf-pv in methicillin-sensitive and methicillin-resistant staphylococcus aureus of diverse genetic backgrounds in a swedish county c. berglund, b. sö derquist (Ö rebro, se) objectives: community-aquired methicillin-resistant staphylococcus aureus (ca-mrsa) have been reported to carry the loci for panton-valentine leukocidin (pvl) in high frequency. the aim of this study was to describe variations within the pvl genes (luks-pv and lukf-pv) in methicillinsensitive and methicillin-resistant s. aureus of diverse genetic backgrounds. methods: twelve pvl-positive s. aureus were characterised by multilocus sequence typing (mlst) and mrsa also by staphylococcal cassette chromosome mec (sccmec) typing. ten of these were isolated between - in Ö rebro county, sweden. oligonucleotide primers were designed to yield a product size of~ bp including luks-pv and lukf-pv and flanking regions by pcr amplification. cyclic sequencing was performed with several sets of primers to overlap the sequences on both strands and was separated on abi prism Ò genetic analyzer (applied biosystems). the nucleotide sequences were analysed using abi prism Ò autoassembler tm dna sequence assembly . . software and compared using bioedit . . . results: analysis with mlst differentiated the pvl-positive ca-mrsa into six different sequence types (st , , , , and ) with either sccmec type iv, iv c, v or unknown types. six additional sts (st , , , , and new) were detected among the pvl-positive methicillin-sensitive s. aureus. sequencing luks-pv and lukf-pv revealed eight point mutations among these isolates with twelve different origins. five substitutions had occurred in luks-pv and three in lukf-pv. only one substitution was nonsynonymous (histidine fi arginine). conclusion: the pvl-genes were well conserved despite the different genetic origins of the isolates analysed. the pvl is an extracellular product and the genes are not subject to any selective forces and thereby diversify very slowly. additional nonsynonymous mutations might result in a non-functional toxin. the first case of staphylococcus pseudintermedius in humans isolated from an icd lead l. van hoovels, a. vankeerberghen, k. van vaerenbergh, a. boel, h. de beenhouwer (aalst, be) introduction: staphylococcus pseudintermedius is recently described as a new coagulase-positive species from animals (devriese et al., ) . the pathogenic significance of this novel species remains unclear and to our knowledge no human infection due to s. pseudintermedius has been reported to date. here, we present the first isolation of s. pseudintermedius in humans with important clinical significance. patient and methods: a -year old male patient was referred to our centre for an ischemic cardiomyopathy and ventricle tachycardia for which he recieved an implantable cardioverterdefibrillator (icd) in january . in august he presented with complaints of migration of the icd device. clinical examination revealed perforation of the icd pocket. infection was suspected and confirmed by the presence of pus in the pocket. the infected icd was completely removed and several samples (ventricular lead, pus and a tissue sample from the pocket) were sent for culture.bacteria obtained by routine culture were further characterised by phenotypical identification, pastorex Ò staph-plus (biorad), api staph Ò (biomérieux) and phoenix Ò (bd). for molecular analysis, pcrs were performed targeting the nuclease (nuc) and coagulase (coag) genes of s. aureus. additionally, sequencing of the s rrna gene was performed and further analysed using blast. results: staphylococci with identical phenotypical appearance were isolated from of the icd samples (lead and pus). colonies were beta-hemolytic on sheep blood agar, dnase and coagulase positive but clumping factor, mannitol and pastorex Ò negative. biochemical identification by api staph Ò and phoenix Ò gave a presumptive identification of s. aureus with a confidence value of respectively , % and %.the pcrs for the nuc and coag genes were both negative. s rrna gene sequencing resulted in the identification of s. pseudintermedius based on a % sequence similarity with a previous reported sequence by devriese et al. conclusion: this case report describes the first identification of s. pseudintermedius as a significant pathogen in human. growth characteristics and commercial identification systems misidentify the organism as s. aureus. when confronted with an inconsistent phenotypical identification pattern, clinical labs should consider the use of s rrna gene sequencing for final confirmation. characterisation of staphylococcus aureus isolates recovered from dairy sheep farms (agr group, adherence, slime, resistance to antibiotics) e. vautor, m. sabah, g. mancini, m. pepin, h. carsenti-dellamonica (sophia-antipolis, nice, fr) objectives: the purpose of this study was to investigate staphylococcus aureus natural isolates associated with dairy sheep mastitis for epidemiological key features (agr group, adherence, slime production and antibiotics resistance). methods: the s. aureus isolates (n = ) were recovered from a field study in the southeast of france in - ( from subclinical mastitis, from clinical mastitis, from the environment of the dairy sheep farm). a total of thirteen dairy sheep farms, producing cheeses manufactured with raw ewe's milk, were involved. the agr group were determined by multiplex and real-time pcr. the evaluation of adherence and slime production were assessed with methods previously described by christensen et al. ( ) . the susceptibility patterns to antibiotics were determined using the discdiffusion method on mueller-hinton agar plates. oxacillin susceptibility testing was performed on all the isolates. the others antibiotics susceptibility was only studied on the isolates recovered from subclinical mastitis as they represent the major source of cheese contamination. results: % ( / ) of the isolates belonged to agr group , regardless of clinical findings. % ( / ) were adherent, strongly adherent or with maximal adherence (biofilm producers). % ( / ) were slime producers (moderate or strong producers). all the isolates (n = ), but seven, were susceptible to all the antibiotics tested. two isolates recovered from subclinical mastitis were resistant to oxacillin and partly resistant to ampicillin and penicillin-g. the five other isolates were found: partly resistant to erythromycin (n = ), cefoperazone and penicillin-g (n = ), erythromycin (n = ), neomycin (n = ) or resistant to enrofloxaxin and partly resistant to ampicillin and penicillin (n = ). conclusions: s. aureus isolates recovered from sheep mastitis in the southeast of france are mainly related to agr group suggesting a role for agr-regulated proteins in the persistence of this bacteria in the sheep udders. biofilm and slime production may also be an important aspect for intracellular survival of s. aureus which could promote the development of persistent intramammary infections. finally, ewe's milk does not appear to represent a source of resistant s. aureus and specially methicillin (oxacillin)-resistant s. aureus (mrsa) for human health. detection of virulence genes in staphylococus aureus isolates from dairy sheep, goats and cows mastitis, using single-dye dna microarray e. vautor, v. magnone, g. rios, m. pepin, p. barbry (sophia-antipolis, fr) objectives: staphylococcus aureus is a common cause of mastitis in dairy farms animals. although many putative virulence factors have been identified in s. aureus genomes (kuroda et al., ) , the differences in pathogenic potential between naturally occurring isolates remain largely unaddressed. the relative importance of host (tissue) factors versus bacterial virulence determinants in disease pathogenesis is not well known, but it is widely accepted that bacterial factors including toxins, cell wall-associated adhesions, and secreted exoproteins are involved in the process. in this study, we use a single-dye dna microarray assay to investigate the presence or absence of putatives virulence genes in s. aureus isolates recovered from cases of ovine, caprine and bovine mastitis. methods: mastitis s. aureus isolates: sheep (n = ), goats (n= ), cows (n = ).dna microarray: the arrays were spotted with long oligonucleotides ( -mer) representing known virulence genes and new candidates identified in mu genome (a human strain) and other s. aureus genomes. each gene were spotted four time. dna extracted from the strains were labelled with fluorescent cy using the bioprime Ò array cgh (invitrogen). control strains with known genetic and phenotypic characteristics were used to normalize the data. results: (i) the majority of the virulence gene was detected in all the isolates (e.g. coa, ica adbc operon, htra, hysa, nuc, sbi, sdre, ssp, feob, fnb, sib, spa). (ii) genes were not detected in the majority of the isolates (e.g. cna, edin, lukf-pv, sav ,…). (iii) genes were not found in isolates, depending on the herd (e.g. aur or sav absent in isolates from some dairy sheep farm), on the isolates whatever the species (i.g. bsap, caph, entk, eta, fnbb, hsds, lpl , lukd, …) . but we found gene mainly related to species (e.g. agriii, sav ,…) comprehensive results will be given in the poster. conclusions: the present study indicated that the prevalence of virulence genes among s. aureus isolates recovered from dairy farm species depends on the gene. these observations suggest a common occurrence of host-adapted (or tissueadapted) s. aureus strains in which particular virulence genes may play a significant role. when taken with complementary methods such as pcr or/and southern hybridisation, singledye dna microarrays may provide a powerful tool to type s. aureus strains for epidemiological and possibly pathogenesis studies. detection of dna sequences distinguishing two closely related genomes of staphylococcus aureus from subclinical versus gangrenous ewe mastitis strains n. chevalier, c. huard, r. thiery, e. vautor (sophia-antipolis, fr) objectives: staphylococcus aureus is a common cause of mastitis in dairy sheep. the severity of mastitis ranges from subclinical to gangrenous forms. subclinical mastitis is an inflammation that is not readily detected clinically whereas gangrenous form is an acute necrotizing mastitis. with the ain to find genetic markers or virulence factors that are only present in gangrenous strains a suppression substractive hybridisation (ssh) method was used in the present study to compare two strains of s. aureus respectively recovered from subclinical or gangrenous mastitis in the same dairy sheep herd. methods: ewes were held in the investigated farm. the subclinical strain was recovered in january from the milk of ewes. the gangrenous strain was recovered in december from an primipare dairy sheep that subsequently died from this acute mastitis. dna extracted from the strains were first compared by pulsed field gel electrophoresis (pfge). then, ssh was performed by using dna from the subclinical strain (driver), as described in a commercial kit (clontech pcr-select bacterial genome substraction kit). results: using pfge, four band differences were found between the two strains. two dna fragments, presumably specific from the gangrenous strain were detected by ssh and sequenced: (i) a bp ( % of homology with the sulfide quinone reductase contained in orf pathogenicity island of the mrsa strain) (ii) bp ( % homology with a gene coding a bacteriophage holine contained in the s. aureus n genome). control pcr tests using primers designed from these specific gene candidates confirmed that they were only present in the s. aureus gangrenous strain. conclusions: according to tenover et al. ( ) , a band difference using pfge indicates that the strains may possibly be related genetically. although genes classically involved in the virulence of s. aureus were not detected in the present study, two putative virulence factors were detected. the sulfide quinone reductase allows s. aureus to growth on sulfide (found in animal manure). the holine protein breaks the internal membrane of s. aureus to release daughter phages suggesting that a mechanism of horizontal gene transfer could have been mediated by bacteriophages and could explain the acquisition of virulence factors. antimicrobial clinical trials p outpatient treatment of acute pyelonephritis in pregnancy after weeks. a randomised controlled trial z. ahmadinejad, s. hantooshzadeh (tehran, ir) objectives: the purpose of this study was to compare the safety and efficacy of outpatient and inpatient treatment of acute pyelonephritis in pregnancy. methods: this was a randomized controlled, clinical trial. one hundred twenty eight gravidas past weeks' gestation admitted in imam khomeini hospital, tehran & sahid dr bahonar hospital, kerman, divided by random blocks to outpatient or inpatient therapy, received two -g doses of intramuscular ceftriaxone at -hour intervals while hospitalized, then were discharged and reevaluated within - hours or remained hospitalized until afebrile for hours. all patients completed a -day course of oral cephalexin. we performed urine cultures on admission and - days after therapy. results: the two groups were similar with respect to age, parity, temperature, estimated gestational age, initial white blood cell count, and incidence of bacteremia. there were not any significant differences between two groups about the clinical improvement after - hours, bacteriuria - days after treatment, relapse of pyelonephritis, requirement to change in antibiotic, date of pregnancy at delivery and preterm labor. the relapse of bacteriuria and preterm labor in inpatients were significantly more than outpatients (pv = . and . respectively). the birth weight of neonate in outpatients were significantly more than inpatients (pv = . ). conclusion: outpatient antibiotic therapy is effective and safe in selected pregnant women with pyelonephritis. however in this study, the neonatal outcomes were better in outpatients and the maternal outcomes in inpatients. experience with daptomycin in patients with renal insufficiency investigators collected demographic, disease state, clinical and microbiological data; outcomes were defined using standard definitions. patients nonevaluable for outcome were excluded. core data were divided and data on cohorts of pts with a creatinine clearance (crcl) ‡ or < ml/min were examined. results: of the pts enrolled, ( %) had evaluable pt outcomes and either crcl ‡ ml/min (nml, n = ) or crcl < ml/min not yet requiring renal replacement therapy (ri, n = ). the distribution of males and females was equal in both groups. ri pts were older ( % ‡ yrs vs %, p < . ). the groups did not differ in the percent coming from the community setting prior to starting dap (nml %, ri %). nml had more frequent history of fractures/orthopaedic procedures ( vs %, p < . ) and haematological cancers ( vs %, p < . ) while ri had higher rates of any renal disease ( vs %, p < . ), chf ( vs %, p < . ) and other immunologic/ inflammatory disease ( vs %, p < . ). ri had higher rates of skin infections ( vs %, p < . ) and endocarditis ( vs %, p < . ). infections that were frequently reported for nml and ri were bacteremia, non-catheter-related ( vs %), bacteremia, catheter-related ( vs %), osteomyelitis ( vs %), and foreign body-orthopaedic ( vs %), all p > . . methicillin-resistant staphylococcus aureus was the most common pathogen; nml %, ri %. ri had higher rates of coagulase-negative staphylococci ( vs %, p < . ) and viridans streptococci ( . vs . %, p < . ). there was no difference in the percentage receiving antibiotics prior to dap; nml %, ri %. the mean dap dose and duration were similar; nml . mg/kg for d, ri . mg/kg for d. the most frequent dose was mg/kg; nml %, ri %. ri initial dap dosing was more frequent than recommended (q h) in %. the mean time to clinical response was similar; nml . d, ri . d. more pts in nml received concomitant antibiotics with dap; vs %, p < . ). the clinical success (cure and improved) rates were; nml %, ri %. conclusion: dap shows favourable clinical success rates in pts regardless of the presence of renal insufficiency. in vitro activity of second line antibiotics against helicobacter pylori infection objective: the aim of our study was to determine the in vitro activity of levofloxacin, ciprofloxacin and rifampicin in clinical strains of h. pylori. material and methods: isolates of h. pylori from biopsies of dyspeptic patients were obtained following standard methodology. in vitro activity of metronidazole, clarithromycin, levofloxacin, ciprofloxacin and rifampicin was determined by e-test using % sheep blood agar and incubated at ordm;c during - days in a co atmosphere. mic was determined as the point of complete inhibition of growth. breakpoint of the nccls for other microorganisms were considered for fluorquinolones: resistant if mic > mg/ l. for rifampicin we considered the strain susceptible if mic < mg/ l, as same studies reported. results: . % of the strains were resistant to metronidazole and % to clarithromycin. mic , mic and range (mg/l) was: . , . and . fi for levofloxacin, . , . and . fi for ciprofloxacin and . , . , and < . - for rifampicin. all the strains were susceptible to rifampicin and only % of them were resistant to fluorquinolones. conclusions: the fluorquinolones tested and rifampicin showed an excellent in vitro activity against h. pylori, despite the high resistance rate to metronidazole and clarithromycin. however, in vitro susceptibility test should be done before the use in clinical practice. vibrio antibodies in serum and breast milk samples of parturient women in calabar, nigeria objectives: serum and breast milk samples from parturient women and serum from non-parturient controls were analysed for prevalence and titres of vibrio antibodies. methods: v. cholerae agglutinins and vibriocidal antibodies in serum samples were analysed by direct agglutination and immune bacteriolysis techniques respectively, using well microtitre plates. the protective value of breast milk was evaluated by haemagglutination inhibition and rabbit intestinal mucosal attachment of v. cholerae cells. results: vibrio agglutinins were detected in serum samples of ( . %) parturient and ( . %) non-parturient subjects (p < . ). high prevalence rates of . % and . % occurred among parturient and control subjects of - years of age respectively. at : cut off titre to evaluate vibrio cholerae specific bacteriocidal antibodies, activity was detected in samples of ( . %) and ( . %) parturients and controls respectively aged - years. breast milk from ( . %) parturients contained vibrio agglutinins with titres ranging between : and : , while milk samples from subjects showed haemagglutination inhibition (hi) activity titres of p : . of the hi positive milk samples ( . %) showed inhibition of v. cholerae adherence to rabbit intestinal mucosa at titres p : , and - % reductions in cell attachment. conclusion: our study confirms that parturient women in calabar may benefit from significant serum titres of v. cholerae antibodies and provide immune protection for their babies through breast milk secretions. moxifloxacin vs clarithromycin for treatment of community-acquired pneumonia associated with common respiratory pathogens: a pooled analysis objectives: streptococcus pneumoniae and haemophilus influenzae are pathogens commonly associated with community-acquired pneumonia (cap). this study compared the clinical and bacteriologic efficacy of moxifloxacin (mxf) to clarithromycin (clar) in cap patients with these pathogens. patients and methods: data were pooled from three doubleblind, multicenter, phase iii trials comparing oral mxf mg qd to clar mg bid for days. all patients included had mild-to-moderate cap. clinical and bacteriologic success rates were identified for s. pneumoniae and h. influenzae isolated from these studies. data for the efficacy-valid population was recorded at the test-of-cure (toc) visit ( - days post-therapy). results: patients were entered, of which were microbiologically evaluable. infection with s. pneumoniae and/or h. influenzae was documented in ( %) of patients ( mxf and clar patients had mixed infection). within this cohort, the two treatment groups were well balanced based on demographic/baseline medical characteristics ( % male, mean age yrs, % smokers, % recent antimicrobial therapy). clinical success and bacteriologic eradication rates (one response per patient) at toc are presented in the table. conclusions: in cap associated with s. pneumoniae and h. influenzae there was a trend towards greater bacterial eradication for mxf vs clar. clinical success rates were significantly higher for mxf monotherapy vs clar. variability of creatinine clearance measurements in inpatients with community-acquired pneumonia r. grossman, s. choudhri, d. haverstock (mississauga, ca; west haven, us) objectives: moxifloxacin, levofloxacin and gatifloxacin have been recommended as empiric therapies for patients with community-acquired pneumonia (cap). levofloxacin and gatifloxacin require dose-adjustment for renal insufficiency while no dose adjustment is required for moxifloxacin. this study was designed to determine the frequency and underlying variability of renal insufficiency in patients with cap. methods: a pooled analysis of data from patients with mild to moderate or severe cap entered into one of six randomized, controlled clinical trials was undertaken. renal function (calculated creatinine clearance; crcl) was assessed in each patient prior to treatment with mxf and then again during and post-treatment. results: baseline crcl levels in this pooled population of patients with cap were: < ml/min in ( . %) of patients, - . ml/min in ( . %) and ‡ ml/min in ( . %) patients. after the pre-treatment crcl measurement patients ( %) were lost to follow-up, so there was no during or post treatment value. in patients with cap the crcl improved from baseline in many patients during or post-treatment, while some patients experienced a worsening of renal function (see table) . conclusions: renal function (crcl) is highly variable in cap patients with baseline evidence of renal insufficiency. renal function should be monitored closely to permit appropriate dose adjustments if levofloxacin or gatifloxacin is used in this patient population. moxifloxacin may be a better empiric choice in this setting as it does not require dose adjustment in patients with renal insufficiency or renal failure. a prospective, controlled, randomised, nonblind, comparative study of the efficacy and safety of high-dose single daily ceftriaxone plus ciprofloxacin versus thrice-daily ceftazidime plus amikacin in the empirical therapy of febrile neutropenic patients objective: empirical antibiotic treatment for febrile neutropenia is well established. the best regimen is still controversial. the purpose of this study was to evaluate the efficacy, safety and cost of high-dose single daily ceftriaxone plus ciprofloxacin versus thrice daily ceftazidime plus amikacin in neutropenic febrile patients. patients and methods: ninety-five patients with febrile neutropenia were included in a prospective, controlled, randomized, non-blind, comparative study. patients were randomly assigned to either treatment group ( in the ceftriaxone/ciprofloxacin group and in the ceftazidime/ amikacin group) and evaluated as successes or failures according to defined criteria. daily assessments were made on all patients all adverse events were record. results: the overall incidence of documented infections was . %: / ( . %) in the ceftriaxone/ciprofloxacin group and / ( %) in the ceftazidime/amikacin group. there was significant difference in clinical efficacy between groups (p = . ) at the end of therapy. ceftriaxone/ciprofloxacin group had an overall incidence of resolution and improvement of , % in comparison to the % of the ceftazidime/amikacin group. thirty-nine organisms were isolated, ( . %) gramnegative and ( , %) gram-positive. there was low incidence of adverse events in both groups. conclusion: the combination of high dose single daily ceftriaxone plus ciprofloxacin was more effective than the standard combination of thrice daily ceftazidime plus amikacn with no significant adverse events in either group. objective: in past studies of azithromycin in children, a posttreatment (pt) benefit was observed at day . in recent phase trials in adults, single-dose zmax was at least as effective as standard comparators for treatment of respiratory tract infections (rtis), including cap. our objective is to demonstrate a pt benefit in this adult population. methods: post-hoc analyses, including respiratory adverse event burden (raeb), were conducted on the all treated population (n = ; az-m, comparators) in the phase studies. the raeb is the sum of duration, in days, of all respiratory adverse events, divided by total number of observation days of all patients, normalized to year. the overall and per study day raeb were calculated for zmax and the pooled comparators for the studies combined. results: raeb, in days/patient year, was . for az-m patients vs . for comparator patients (p = . ). the difference in raeb consistently and progressively favoured zmax, beginning at day and achieving statistical significance between days and , when the upper limits of the % cis around the differences were below zero (figure). faropenem medoxomil (fm) is an oral penem with potent activity against streptococcus pneumoniae and haemophilus influenzae. this integrated analysis was conducted to summarize the efficacy of days of mg bid of fm compared with other beta lactams in the management of community acquired pneumonia (cap). methods: efficacy was determined in three multicenter randomized double-blind controlled trials (rct) and a single uncontrolled study of faropenem medoxomil. comparators were days of cefpodoxime (c), days of amoxicillinclavulanate (ac), or days of amoxicillin (a). the analysis allowed examination of treatment effects by age, race, gender and study site subgroups. results: a total of subjects were studied. studies and were conducted in n. america, studies and in europe, latin america, israel, and s. africa. n. american vs. other studies included subjects at least (vs. at least ) years of age and only out patient (vs. outpatient and hospitalized) subjects. the clinical responses for fm in both per protocol and intention-to-treat populations were non-inferior to comparator for each study and for the three trials combined. no differences were found in treatment effect by age, race, gender, or country. recovery of an etiologic agent from initial respiratory or blood culture varied between . and . % of cases in the studies for a total of microbiologically evaluable subjects. s. pneumoniae was eradicated or presumed eradicated in / ( . %) and / ( . %), h. influenzae in / ( . %) and / ( . %), s. aureus in / ( %) and / ( %), h. parainfluenzae in / ( %) and / ( %), and m. catarrhalis in / ( . %) and / ( %) fm and comparator recipients, respectively. clinical response for s. pneumoniae bacteremic patients was / ( . %) for fm. conclusions: fm efficacy was consistent across studies, within subgroups, and non-inferior to comparators. it is efficacious against the most common bacterial pathogens and in the most severe form (bacteremic) disease. fm is a good option for the treatment of cap. propionibacterium acnes strains isolated from acne vulgaris and severe infections c. oprica, c.e. nord (stockholm, se) propionibacterium acnes is a member of the resident flora of the skin and is an important factor involved in inflammatory reactions in acne patients. during the last years the prevalence of different severe infections due to p. acnes has increased. objectives: ) to detect the prevalence of resistant p. acnes strains isolated from acne patients in stockholm and different severe infections in europe; ) to identify the mechanisms of resistance and the genetic diversity among resistant strains. methods: p. acnes strains isolated from acne vulgaris and severe infections were tested against clindamycin, erythromycin, linezolid and tetracycline and pulsed-field gel electrophoresis was used for further characterization. pcr and sequencing of the genes encoding domain v of s rrna for clindamycin and erythromycin resistant strains and s rrna for tetracycline resistant strains were performed. results: i) antibiotic-resistant strains were more often isolated from antibiotic treated patients with moderate to severe acne area than from non-antibiotic treated acne patients. an individual might harbor different pulsotypes of p. acnes with various degrees of resistance. ii) among the clinical isolates from european countries were found resistant strains to tetracycline, clindamycin, and erythromycin. overall, in the southern europe a higher prevalence of erythromycin-resistant strains was noticed and in southern and eastern europe a higher prevalence of resistance to clindamycin. it was noticed a high genomic diversity and the geographical spread of some clones in related areas but also in geographically distant countries. most clindamycin or erythromycin resistant p. acnes isolates, were found to be members of a single clone that has spread in different geographically countries. iii) p. acnes clindamycin and erythromycin resistant strains carrying one of the described mutations within the s rrna were predominantly isolated from swedish acne patients compared to strains from other infections. forty-four per cent of tetracycline resistant strains were found to carry a mutation in the s rrna. these strains were isolated from swedish acne patients, were highly resistant and were clustered in one pulsotype. conclusion: surveillance of both the prevalence of resistant p. acnes strains and associated resistance mechanisms is important due to the rapid variation in resistance patterns, both in acne patients and other severe infections. antimicrobial activity of unisepta quick and deconex solarsept on the surface contamination and dental instrument in dental clinics in iran f. shahcheraghi (tehran, ir) objectives: quaternary ammonium compounds (qacs) are amphoteric surfactants that are widely used for the control of bacterial growth in clinical and industrial invironment.unisepta quick and deconex solarsept are new generation of qacs is widely used as adjuncts in iran to hygine in dental clinics.the aim of present study was to investigate clinical efficiency of these substances on the surface and instruments in dental clinics. material and methods: the following bacteria and fungi on the base of aoac standard were used.pseudomonas aeruginosa (atcc ), staphylococcus aureus (atcc ) bacillus. subtilis atcc ( ), mycobacterium bovis atcc ( ) and wild types of trichophyton mentagraphit, p. aeruginosa and salmonella typhimorium (a common fungi in iran). a stock solution of deconex solarsept (borer chemie) and unisepta quick (micro unident) was prepared as recommended by the manufacturer. the concentration of bacterial suspention was . macfarland and the results were reported on the base of decreasing in (cfu) colony forming unit from to . results: the results shows that both of these disinfectants have bactericidal and fungicidal activity on the standard p. aeruginosa, s. aureus, s. typhimurium and trichophyton mentagraphit, the number of bacteria decreased significantly (p < . ), but no significant difference was seen with b. subtilis, wild type of p. aeruginosa and m. bovis. conclusion: the results confirm that these qacs are not able to sterilize or disinfect medical and dental instruments, and they can not be used lonely, and it must be used with the other methods for sterilization of surface and dental instruments. macrolide as long-term treatment in patients with bronchiectasis colonised by p. aeruginosa background: a certain efficacy of macrolide against p. aeruginosa has been described in vitro, mainly through mechanisms such disruption of quorum sensing and suppression of inflammation. aim: to evaluate the efficacy of macrolide in patients with bronchiectasis colonised by p. aeruginosa. methods: the study prospectively included patients with bronchiectasis and p. aeruginosa isolated in sputum in stable state. all subjects received either azithromycin mg · days/week or clarithromycin mg daily on long term and completed daily diary cards for symptoms and pef values until the end of therapy. follow-up period was year. results: patients with bronchiectasis and p. aeruginosa evidence in sputum were included ( men, mean age . ± . yrs.). patients received azithromycin and patients clarithromycin, with a mean duration of . ± . months. five ( . %) patients discontinued treatment after less than weeks because of adverse events. at the end of therapy, ( . %) patients showed no evidence of p. aeruginosa in sputum while ( . %) patients still had ps. aeruginosa in sputum. an improvement in the following parameters could be observed in all patients: sputum volume ( . ml/day before therapy versus . ml/day after therapy, p = . ); pef ( . ± . l/min before therapy versus . ± . l/min after therapy, p = . ); number of exacerbations/year ( . in the previous year versus . in the follow-up year, p = . ). conclusion: the study shows that macrolide may be an effective therapy in patients with bronchiectasis colonised by p. aeruginosa. independently of the microbial eradication, an improvement of the clinical symptoms and a reduction of exacerbations were observed in all patients. fungal pathogens from haematoncology patients and their susceptibility to new and old antifungal drugs the expanding population of immunocompromised hosts has been infected with many established and emerging opportunistic fungi. most pathogens can be treated empirically whereas for an increasing number of species proper treatment starts once the mic becomes available. though invasive aspergillosis remains the principle life threatening complication in the haematoncology patients (hop) other pathogens cannot be ignored as selection and resistance during prophylaxis increases the risk of treatment failure.in order to understand the frequency of rare fungal pathogens, selection and emergence of resistance in our trust all fungi from hop were identified using standard mycological techniques and the mics to amphotericin b (amb), flucytosine ( fc), fluconazole (fcz), itraconazole (itz), voriconazole (vcz) and caspofungin (cfg) were determined using the nccls method. specimens were processed, % respiratory, . % blood, . % oral, . % other sterile (bile, csf, drains, lines and tissue biopsies) and . % nonsterile sites. yeasts accounted for % and filamentous fungi (ff) for %, representing candida sp, other types of yeast, aspergillus sp and other types of ff. c. albicans represented . %, c. glabrata . %, c. krusei . %, a. fumigatus % and other aspergillus sp % of all isolates. the mic s for all isolates were amb . , fc , fcz > , itz , vcz and cfg . mg/ l. with the exception of acremonium sp, a. versicolor, a. terreus and scedosporium apiospermum all isolates including the isolates of c. lusitaniae were sensitive to amb. most but not all ff and only one isolate of c. albicans from the yeasts were resistant to fc. all ff, rhodotorula sp, c. albicans %, c. glabrata % and c. krusei % were resistant to fcz. only absidia corymbifera, acremonium sp %, c. albicans %, c glabrata % and saccharomyces cerevisiae % were resistant to itz. for vcz a. corymbifera, acremonium sp %, c. albicans %, c. glabrata %, c. krusei %, c. tropicalis %, rhodotorula sp . % and p. aecilomyces variotii % had an mic ‡ mg/l. with cfg the effective concentration was ‡ . mg/l for a. corymbifera, fusarium solani, geotrichum capitatum, sporobolomyces salmonicolor, acremonium sp % and c. parapsilosis %.the data show that hop are exposed to many different fungal pathogens some of which are resistant to the old and the new antifungals and that amb is still the drug with the broader spectrum and less developed resistance for both yeasts and ff. faropenem medoxomil in the treatment of acute bacterial sinusitis: an integrated analysis s. kowalsky, r. tosiello, r. echols (milford, us) background: faropenem medoxomil (fm) is an orally absorbed, synthetic, penem antibacterial agent with in vitro activity against community-acquired respiratory pathogens. methods: the efficacy of fm in subjects with acute bacterial sinusitis (abs) was evaluated in phase iii trials; , , and . study was conducted in n. america, study was conducted in europe and israel and study was conducted in the us and argentina. and were prospective, randomized, double-blind, active comparator trials and was an open-label ''sinus tap'' trial. the dose of fm was mg bid in all studies. the comparator in and was cefuroxime axetil (cfx) mg bid. the duration of fm treatment in was days and days vs cfx for days. in , fm or cfx were given for days. in , fm was administered for days. the primary efficacy variable in all studies was clinical response at the test-of-cure (toc). microbiologic response at the toc was a secondary efficacy variable in (sinus puncture and endoscopic collection) and (sinus puncture and aspiration). non-inferiority was defined as the difference in cure rates (fm minus comparator) where the lower boundary of the % ci was greater than - %. results: the cure rates at the toc are shown in the table for the valid per protocol (vpp) and the intent-to-treat (itt) populations. the frequency of isolation of key pathogens and the rate of eradication in samples obtained by endoscopicallyguided swab and in samples obtained by tap were consistent across studies. the eradication rates for s. pneumoniae, h. influenzae, and m. catarrhalis were . % vs. . % (fm / d vs. cfx / d), . % vs. . % (fm vs. cfx) and . % vs. . % (fm vs. cfx), respectively. conclusions: fm mg bid x days was shown to be noninferior to cfx in clinical efficacy in two prospective, doubleblind, comparative trials. a third, open-label trial, demonstrated similar efficacy in microbiologically documented abs caused by key pathogens. longer ( d treatment) with fm provided no additional efficacy. faropenem medoxomil in the treatment of acute exacerbation of chronic bronchitis: an integrated analysis s. kowalsky, r. tosiello, r. echols (milford, us) background: faropenem medoxomil (fm) is an orally absorbed, synthetic, penem antibacterial with in vitro activity against community-acquired respiratory pathogens. methods: the efficacy of fm in subjects with acute exacerbation of chronic bronchitis (aecb) was evaluated in phase iii trials. study was conducted in europe, israel, mexico, and south africa. study was conducted in the us and argentina. both were prospective, randomized, double-blind, active comparator trials. the dose of fm was mg bid for days in both studies. the comparators were clarithromycin (clr) mg bid for days and azithromycin (azi) qd for days ( mg on day and mg on . the primary efficacy variable was clinical response at the test-of-cure (toc). microbiologic response at the toc, in subjects with a baseline pathogen was a secondary variable. non-inferiority was defined as the difference in cure rate (fm minus comparator) where the lower boundary of the % ci was greater than ) %. results: the cure rates are shown below for the valid per protocol (vpp), intent-to-treat (itt) and modified itt populations (all itt subjects who met inclusion/exclusion criteria). in both the individual studies and the pooled analyses, for all populations, treatment with fm was not less effective than either comparator. % of treated subjects in and % of subjects in were evaluable for microbiological response. in , the eradication rates for the microbiologically evaluable population was higher in the clr group ( . %) compared with the fm group ( . %) ( % ci ) . , . ) . in contrast, the eradication rate in was similar in the fm ( . %) and azi ( . %) groups ( % ci - . , . ). when the data were pooled across studies, the response rates were similar with fm ( . %) and combined comparator ( . %) groups ( % ci - . , . ). the combined eradication/presumed eradication rates in the pooled fm and comparator groups were . % vs. . %, respectively for s. pneumoniae and . % vs. . %, respectively, for h. influenzae. conclusions: fm was shown to be non-inferior to either azi or clr in clinical efficacy in two adequate and well-controlled trials. pooled analysis further strengthened the clinical noninferiority conclusion. the difference in eradication rates observed in study (clr) was not supported by study (azi). an integrated safety analysis of faropenem medoxomil: results of , subjects from phase ii/iii clinical trials r. echols, r. tosiello (milford, us) objective: to evaluate the safety profile of faropenem medoxomil (fm), a novel oral penem antibiotic. methods: , subjects from phase ii and phase iii clinical trials received fm, mg bid for - days for treatment of acute bacterial infections. randomized controlled trials (rcts) included , fm and comparator treated subjects. analyses were conducted to identify possible disparate adverse event (ae) reporting based on type of infection, subject age ( - , - , , - , > ) and gender, duration of treatment ( / d v. / d), geography (na, eu, row), study design (open label v rct), relationship to treatment. comparisons were made to control treatment based on antibiotic class (b-lactam v. other), and individual antibiotic treatments. results: fm compared favourably to penicillins, cephalosporins and macrolides. fm was better tolerated than tmp/smx and co-amoxiclav. open labeled trials had higher aes reported v. rcts. aes reporting na = row > eu except serious aes and deaths where row = eu>na. aes for fm / d = fm / d. underlying infection did influence ae reporting. female gender had higher ae reporting than male gender. fm was tolerated equally well across age ranges, although deaths and saes were more common in > age group. common aes (> %/related from rcts) were diarrhoea, nausea, fungal vaginosis and headache and were generally less frequent with fm than control rx. no evidence of neuro or cardio toxicity was identified. laboratory tests identified no hepatic, renal or hematopoietic signals. conclusion: faropenem medoxomil, a novel oral penem antibiotic, has the safety profile expected of a b-lactam but is better tolerated than co-amoxiclav with approximately one-third the gi side effects. the efficacy of non-surgical and systemic antibiotic treatment regimens in smoking and non-smoking patients e. pähkla, k. lõ ivukene, p. naaber, m. saag (tartu, ee) periodontitis is a chronic infectious disease, which leads to the destruction of periodontal ligament fibres and alveolar bone until tooth loss. the objective of this study was to compare the longitudinal effect of combination of non-surgical periodontal therapy with systemic antibiotics in smoking (s) and nonsmoking (ns) patients. methods: there were total of patients with severe generalized chronic periodontitis involved in this study ( s, ns), who did not respond well to previous mechanical periodontal treatment. the clinical examination included recordings of visible plaque index (vpi), modified gingival index (mgi), bleeding on probing (bop) and suppuration after probing (sup), probing pocket depths (pd) and clinical attachment levels (cal). the non-surgical periodontal therapy was performed within weeks. clinical parameters were recorded at baseline, - weeks after the first mechanical treatment and months after combined treatment, during a regular check-up visit. as the patients did not respond to the conventional periodontal therapy, the microbiological analyses were taken and a combination of systemic amoxicillin mg · and metronidazole mg · for days, was prescribed. results: the results suggested that the combined systemic antibiotic therapy is effective in case of severe generalized chronic periodontitis, as vpi, bop, sup, cal, and mgi improved significantly after the treatment. in the ns group all parameters, except cal, improved significantly after the treatment. the s showed markedly smaller reduction in sup, mgi, and cal.after instrumentation, no periodontal pathogens were isolated in ( %) patients, while patients ( %) were infected with one to three different pathogens. among the pathogens, prevotella intermedia/nigrescens ( patients) and actinobacillus actinomycetemcomitans ( patients) were dominating. the total level of microbial load (log cfu/ml) as well as the spectrum of pathogens in s and ns patients remained similar. conclusions: despite of positive treatment effect in general, there were insignificant improvements in any clinical parameters in the smoking group. smoking has adverse effect on periodontal therapy; therefore the dentist should cooperate with patients in counselling of smoking cessation to achieve better results in the treatment of periodontitis. objectives: laminin (ln), which is a large multidomain glycoprotein of the extra cellular matrix, has attracted much attention because of its importance in many cellular functions, including induction of cell adhesion, growth promotion and mediation of cell communication. the target of this study was to find out whether there is any relation between the levels of serum ln and the inflammatory activity of a microbial infection. patients/methods: from june to october , immunocompetent adults, with confirmed bacterial infection were admitted to our hospital ( with pneumonia, with pyelonephritis and with cholecystitis) (group ). at the same time hospitalised patients for non-infectious causes (stroke, gastrointestinal bleeding, anaemia) were also studied (group ). the levels of serum ln and crp were measured on the day of admission in both groups. the levels of ln were measured using an enzyme immunoassay kit (takara laminin eia kit) and healthy volunteers were used to determine its normal limits ( - ng/ml). plasma crp concentration was assessed by immunoturbidometric method (using randox, uk kits). normal values were considered those below . results: the mean serum ln levels of patients of group were . ± . (much higher that the normal limits), while the mean crp value was . ± . . the mean corresponding values in group were . ± . for ln (within normal limits) and . ± . for crp. there is a statistically significant difference between the mean ln levels of the two groups (p < . ). additionally, there is a statistically significant correlation between the levels of ln and crp (a well studied serum inflammatory marker) in patients with bacterial infection (group ) (pearson correlation coefficient r = . , p = . ). conclusions: the definition of the ln levels could constitute a new reliable, simple, direct serum marker for the confirmation of an active bacterial infection. additionally, as the crp levels are above normal in group too (patients without infection) while ln lies within normal limits, maybe ln is even more specific than crp. more studies are required in the future, with more patients included, in order to confirm the outcome of this study. performance and clinical significance of a direct tube coagulase test using serum separator tubes for rapid identification of staphylococcus aureus from blood culture broth d. kwa, t. schü lin-casonato, p. sturm (nijmegen, nl) objective: blood cultures are important in the diagnosis of serious infections. early administration of effective antibiotics is associated with improved patient outcome. the performance of the direct tube coagulase (dtc) using serum separator tubes (ssts) for rapid identification of s. aureus from blood culture broth (bcb) was investigated. the clinical significance of rapid identification was assessed. methods: consecutive blood cultures with gram-positive cocci in clusters were tested. bcb was collected in ssts using a subculture-venting unit. after centrifugation, the supernatant was discarded and ml rabbit plasma was added to the remaining pellet of bacteria. coagulation was evaluated after and hours incubation at °c, and after overnight incubation at room temperature. in parallel, a direct tube coagulase test was performed using a : saline dilution of bcb as described previously. isolates were identified by standard microbiology procedures. clinical significance was measured by comparison of antimicrobial prescription based on gram stain results, direct coagulase results, and culture results. results: over a -week period, bcbs from patients were tested. s. aureus was present in bcbs. using the serum separator tube method and the saline dilution method, the sensitivity of the dtc after hours incubation was % and %, and after hours % and %, respectively. the specificity of both methods was %. rapid identification of s. aureus resulted in initiation (n = ) or streamlining (n = ) of antimicrobial therapy in of patients with s. aureus bacteremia. rapid identification of coagulase-negative staphylococci resulted in changes in antimicrobial therapy in of patients. conclusion: the dtc using ssts for bacterial enrichment is a very reliable, rapid, cheap and easy to perform method for identification of s. aureus from bcb. implementation of this test can improve antimicrobial therapy. evaluation of the results of the spanish seimc external quality control program for the diagnosis of enterococcus faecalis and klebsiella pneumoniae infections r. guna, j.l. pérez, n. orta, c. gimeno on behalf of seimc objectives: to evaluate the results obtained from four shipments of two different strains by the participants in the seimc external quality control program (eqcp). these controls were intended to analyse the percentages of correct species identification and the ability of the participants in detecting some special features of the control strains: vanb phenotype in the case of e. faecalis, and the production of extended spectrum betalactamase (esbl) in k. pneumoniae. methods: the same strain of each microorganism was sent in two different shipments. the vanb e. faecalis strain was sent both in a control of year as well as in other of , while the esbl-producing k. pneumoniae was sent in and in to an average of laboratories. the results obtained were compared with those of a reference laboratory that certified both the species identification and the resistance features. results: in the control, . % of participants identified correctly e. faecalis, while . % did it in . as for the glycopeptide resistance pattern of the enterococcal strain, . % and . % of participants detected the vanb phenotype in and , respectively. overall, the k. pneumoniae strain was correctly identified in both separate controls by most of the participants ( . % and . %, respectively). interestingly, the percentage of laboratories that detected the presence of the esbl in the k. pneumoniae strain sharply increased from . % in to . % in . the overall percentages of correct species identification were high for the two microorganisms and for both control points. most important, the ability of the spanish clinical laboratories in detecting the special resistance features of these strains clearly improved along the study period. these data confirm the importance of implement a continuous surveillance of the diagnostic training in the clinical laboratory, as well as the possible positive intervention of the seimc external quality control program in such improvement, since the analysis of results is accompanied of updated reviews on the subject of each control. a. bonnet-pierroz, a. resenterra, o. péter (sion, ch) objective: to evaluate new elisa ridascreen Ò borrelia igg and igm for antibody response in patients with confirmed lyme borreliosis and to compare to the results of vidas lyme (igg-igm) and in-house immunoblots (b. garinii igg and igm for early cases or b. burgdorferi sensu stricto, b. afzelii, b. garinii, b. valaisiana igg for late cases). methods: elisa ridascreen Ò borrelia igg and igm was used to screen sera from patients with clinically confirmed erythema migrans em (n = ). patients with confirmed neuroborreliosis by intrathecal antibody synthesis (n = ) were evaluated for igg antibodies to borrelia. sera from patients with acrodermatitis chronica atrophicans aca (n = ) and sera and synovial fluids from patients with lyme arthritis (n = ) were also evaluated for igg antibodies. patients with syphilis (n = ) and infectious mononucleosis (n = ) were screened for igg and igm antibodies to borrelia in order to estimate the specificity. conclusion: the elisa ridascreen Ò borrelia igg and igm have shown a good sensitivity for the serological diagnosis of lyme borreliosis. the short evaluation for the specificity of the igg test revealed a good assay with few false positive reactions, whereas the igm assay was, as expected more prompt to give false positive results with sera from patients with infectious mononucleosis. so far any equivocal or positive tests should be confirmed by immunoblots. is it necessary to incubate the bact/alert blood culture bottles more than days? objective: to assess the incubation time reduction of the aerobic and anaerobic bact/alert system bottles from to days. methods: from to we processed . blood culture sets and detected . ( %) positive blood cultures with clinical significance. we retrospectively examined the detection time of positive bottles and assessed the clinical significance of the bottles that were positive between the fourth and fifth day. results: out of positive blood cultures with clinical significance, ( . %) were detected within the first days of incubation. out of the positive blood cultures detected between the fourth and fifth incubation days, were recovered in concurrent cultures within the first days. chart reviews were conducted from patients with the remaining isolates. only in patients ( . % positive blood cultures) changes in antimicrobial therapy based upon the positive blood culture results on day to were made, in the other patients the empirical treatment was adequate. the isolated microorganisms in those patients were: gram-positive cocci ( staphylococcus spp. not s. aureus, staphylococcus aureus, streptococcus viridans and streptococcus pyogenes), anaerobes, enterobacteriaceae, pseudomonas aeruginosa, campylobacter spp., candida spp. cryptococcus neoformans, brucella spp. and haemophilus influenzae. conclusions: incubation of bact/alert blood cultures bottles only for days would have represented a detection loss of . % of the clinically significant isolates, which led to antimicrobial therapy changes. although we keep employing a -day incubation for routine blood cultures, we could reduce the incubation time to days depending on current instrument capacity. an enzyme immunoassay for anti-diphtheria antibodies: a practical alternative to the vero cell assay r. budd, e. harley, r. george, a. efstratiou, k. broughton, a. bradwell (birmingham, london, uk) introduction: in this extended study, results from an anti-diphtheria toxoid enzyme immunoassay (eia), specifically designed to detect higher affinity antibodies, were compared with those from a vero cell assay (vca). methods and results: serum samples with antibody concentrations ranging from . - . iu/ml on the vca from the respiratory and systemic infectious laboratory (rsil) were assayed by eia (the binding site ltd, uk). a further samples from rsil selected on the basis of being close to the protective level, were assayed to confirm the performance of the eia. the eia was calibrated, against the nibsc reference material / and the assay measuring range was . - . iu/ml results were compared using the who guidelines of . - . iu/ml as minimum protective level, and > . iu/ml as protective. relative agreement, sensitivity and specificity for the first samples were: . %, . % and . % respectively, for the second set of samples performance was: . %, . % and . %, and for the combined samples results were: . %, . % and . % respectively. roc analysis of the total samples confirmed the highest sensitivity . % and specificity . % occurred at a cut-off of precisely . iu/ml for the elisa assay. conclusion: of the total discrepant samples, had vca and eia values < . iu/ml, therefore we suggest the possibility of establishing an equivocal zone for the interpretation of the eia results. if the test is part of a general immune status assessment a grey zone is not required. if undertaken to determine the requirement for immunization, the use of the equivocal zone is recommended. by applying these criteria in the eia, only one sample would have suggested inappropriate immunization, as indicated by a vca result > . iu/ml. because of the > % agreement between the two assays, significant advantages of cost and speed, ease of use and the potential for automation, the eia could therefore be considered as an alternative to the vca. evaluation of accuracy limits of countable colony-forming units on agar plates j. arbique, a. rendell, k. forward (halifax, ca) objectives: accurate colony counts are an essential component of many microbiology research projects and clinical laboratory processes. the suggested range of accuracy of colony-forming units (cfu) extends from to (standard methods for the examination of water and wastewater). this recommendation dates to , and fails to adequately address the numerous sources of inter-and intra-variability. without more detailed analysis it is difficult to estimate the sample size and number of replicates necessary to ensure accurate results. the purpose of this study was to determine the validity of accuracy limits for quantifying cfus on agar plates. methods: escherichia coli (atcc ) and staphylococcus epidermidis (atcc ) were used to prepare series of four organism densities ranging from approximately - cfu, on three different days. on each day, each of the densities for both organisms was plated on sba and viable organisms were counted following incubation. an average of the margins of error obtained over the days of testing was used to determine the reproducibility of agar plate counts, and to estimate the optimum number of replicate plates (sample size) required for each organism at each concentration. results: margins of error for both organisms were greatest with suspensions yielding approximately cfu, and lowest for suspensions yielding and cfu. nine replicate plates were required for a suspension of s. epidermidis yielding cfu to achieve the same margin of error as obtained with replicate plates at concentrations yielding - cfu. seven replicates plates were required for a suspension of e. coli yielding and cfu to achieve similar margins of error to those obtained with replicate plates at concentrations yielding cfu, and replicate plates at concentrations yielding cfu. conclusion: we found that the greater the concentration ( and cfu), the fewer replicate plates necessary to reliably estimate organism concentrations. the lower the organism density ( cfu), the more plates necessary to reliably estimate cfus. contrary to the recommendations described in standard methods for the examination of water and wastewater, cfu of were reliably reproducible. for greatest accuracy, experiments should be conducted so as to assure that colony counts are in the range of - . direct microscopy: a valuable instrument for diagnosis and prognosis of periodontal disease objective: to appreciate the composition of micro flora from periodontal pockets, using light microscopy and to compare it with clinical status. introduction: it is generally accepted that periodontal disease occurs when anaerobic gram-negative flora increase in number with the subsequent decrease of facultative anaerobe grampositive bacteria. in other words, the switch from gram-positive to gram-negative of sub-gingival flora has a pathologic significance and could be observed using direct microscopy. materials and methods: specimens sampled with sterile paper points from periodontal pockets and samples from clinical healthy persons were included in this study. each sample was diluted in . ml saline solution and, with a calibrated loop, was taken ll aliquots in order to prepare a smear for microscopic examination and for inoculation on solid media (columbia with % sheep blood). the smears were gram stained and the culture plates were incubated in anaerobic conditions ( h, °c) and in air ( h, °c). results: in % of samples from patients with periodontal disease, easily notable, high number of gram-negative bacteria at direct microscopy, associated with abundant growth in anaerobic condition and poor growth in air. in from healthy patients, the gram-negative flora was almost absent and gram-positive bacteria were in high number, correlated with the absence of bacterial growth in anaerobiosis and some growth in air.the presence of treponema spp. at direct microscopy was associated with deep and bleeding periodontal pockets. after few days of proper therapy, the good clinical status was well correlated with an increasing number of gram-positive bacteria. conclusions: ) using a diluted sample for microscopic examination, the value of the method increase, offering important information about the composition of sub-gingival flora. ) the good correlation between the clinical status and microscopic finding recommend it as an easy to use diagnostic method in dentistry. identification of species and glycopeptide resistance among enterococcal isolates by bd phoenix objectives: vancomycin resistant enterococci are emerging in europe necessitating their fast and accurate identification by the laboratory. there was an attempt to evaluate the performance of the bd phoenix automated microbiology system (bd diagnostic systems, sparks, md.) for the correct identification of species and glycopeptide resistance in comparison to the gold standard of diagnosis, pcr, using a large collection of clinical strains. methods: a total of enterococcal isolates were tested by the bd phoenix sytem. these strains were isolated from faecal, urine, pus, blood and samples from other body sites cultures. a multiplex pcr was applied using different pairs of primers, specific for the identification of e. faecium, e. faecalis and the vana, vanb, vanc, vand, vang, vane glycopeptide resistance genotypes. susceptibility to the glycopeptides was also confirmed by the etest (ab biodisk, solna, sweden). results: according to the pcr, there were e. faecium (including vana-positive strains), e. faecalis (including vana-positive and vanb-positive strains) and e. cass/gall isolates. two strains were not identified and were excluded from the analysis. discrepant results between the multiplex pcr and the phoenix system were obtained for / isolates ( %) with similar rates amongst faecal ( / , . %) and the rest of the isolates ( / , . %). the most common discrepancies were the misidentification of e. faecium vana strains and e. faecalis strains as e. cass/gall by phoenix. two e. faecalis strains were incorrectly characterized as vancomycin resistant, two e. faecium strains were misidentified as e. hirae and e.cass/gall, respectively, and one e.cass/gall strain was reported as e. faecium resistant to both glycopeptides. thus, the sensitivity and specificity for the identification of e.cass/gall by phoenix were . % ( / strains) and . % ( / strains), respectively, while . % of vana strains ( / strains) were not recognized by this system. conclusion: this study demonstrates that the new identification system, phoenix, similarly to other automated or manual systems, presents with problems regarding correct identifica-tion of enterococcal species and glycopeptide resistance. specifically, laboratories should be aware that clinically significant isolates identified as e.cass/gall should be confirmed by another method. an audit of sputum requisition practices p. lal, i. balakrishnan (london, uk) objectives: to analyse the indications and rationale for the processing of sputum specimens in a london teaching hospital. methods: sputum samples received from / / - / / were included in this study. data were obtained from the patient requisition forms and the winpath systems and were analysed further as per the objectives. results: a total of specimens were received during this period. ( %) from hospital in-patients and ( %) from general practitioners. out of the total of samples received from hospital-in patients ( . %) had > epithelial cells/ lpf. no clinical details were mentioned in ( . %) and ( . %) were from patients already on antibiotics. repeat specimens within one week were sent in ( . %) cases and ( %) had atypical serology also sent. out of the hospital-in patient samples ( . %) had a significant isolate and ( . %) had normal respiratory tract flora isolated. others were reported as: ''gross oral contamination'' [ ( . %)], ''no growth'' [ ( . %)] and ''no significant growth'' [ ( . %)]. there were a few specimens reported as ''inappropriate specimen -two days old'' [ ( . %)] and ''leaking'' or ''saliva only' ' [ ( . %) ]. out of a total of samples received from gp patients ( . %) of samples had > epithelial cells/lpf, ( . %) had no clinical details provided, ( . %) samples were sent while patients were on antibiotics and ( . %) samples were repeated within one week. only ( . %) had atypical serology also sent. conclusions: -less than one-third of specimens yielded a significant pathogen.-adequate clinical details were lacking in about one-fifth of specimens.-nearly one-third of specimens were repeated within one week, without a clear indication.-about % of specimens were of poor quality.-atypical serology was only performed in . % of outpatients, as compared with % of in-patients.this audit brings forth the fact that the clinical indications for which sputa are being sent for culture need to be clearly defined and an educational campaign instituted amongst relevant healthcare professionals. sputum collection techniques need to be rigorously applied if good-quality specimens are to be obtained. indications for performing atypical serology need to be defined and reinforced, particularly in primary care. a new approach to laboratory diagnostic of infectious gastroenteritis -a follow-up objectives: in order to optimize use of laboratory facilities and ensure flexibility in relation to current epidemiology, a new approach to laboratory diagnosis of infectious gastroenteritis was applied: from an algorithm the decision of which organisms to test for was defined by the demographic, clinical and epidemiological information submitted to the laboratory on paper/electronic request forms. methods: from april , -june , , hospitals and general practitioners submitted a request form with the following information together with the stool sample (s): ( ) acute or persistent diarrhoea (duration > weeks); ( ) bloody stools; ( ) recent history of foreign travel; ( ) > patients within same epidemiological setting; and ( ) nosocomial infection. provision of data is mandatory when submitting electronically. based on these data, analyses were performed according to an algorithm. examination for salmonella, shigella, yersinia, campylobacter, and clostridium difficile was done by culturing. verotoxin producing e. coli (vtec), enteropathogenic e. coli (epec), enterotoxigenic e. coli (etec) and enteroinvasive e. coli (eiec) were identified by pcr for virulence genes and serotyping. rota and adenovirus were detected by antigen tests and parasites by microscopy. results: in total we examined , samples from , patients. a pathogen was isolated in % of patients. in cases ( %) clinical/epidemiological data were missing. • , patients had diarrhoea < weeks: % with campylobacter, % with salmonella, % with etec, % with giardia, and % each with eiec and vtec • , patients had diarrhoea > weeks: % with campylobacter, % with giardia, % each with epec and vtec • patients had a history of foreign travel: % with campylobacter, % with etec, % with salmonella, and % with giardia • patients had bloody stools: % with campylobacter, % with salmonella, and % with vtec • patients were < years: % with campylobacter, % with epec, % each with giardia, vtec and salmonella, and % with etec conclusions: campylobacter was the most common bacterial pathogens in all groups and rotavirus was the most common pathogen in children < years. the new approach had a number of advantages: more relevant microbiological analysis, collection of data on defined patient groups, and flexibility regarding adaptation to current epidemiological knowledge. increasing use of electronic submission of request forms will optimize the approach used. objectives: small colony variants (scvs) are an emerging infectious disease problem, presenting as a naturally occurring, slow-growing subpopulation of staphylococcus aureus that are characterized by tiny colonies on solid media. studies on scvs recovered from patients with persistent infections are hampered due to their frequent unstable phenotype. in particular, scvs are not easily distinguishable from the normal phenotype in broth media and a reversion of scvs into the normal phenotype is not traceable. methods: a set of isogenic s. aureus isolates comprising the (i) normal and the (ii) scv phenotype (isogenic to the isolate with normal phenotype) recovered from clinical specimens, as well as (iii) corresponding mutants mimicking the scv phenotype (knock-out of hemb), and (iv) their complemented mutants were used to investigate the feasibility of fourier-transform infrared (ftir) spectroscopy to trace the expressed phenotype in broth media. the respective isolates cultured on solid media served as controls. in addition, all isolates were genotyped by pulsed-field gel electrophoresis and spa typing. results: using first-derivative infrared spectra to calculate spectral distances, hierarchical clustering based on spectral information in three different spectral ranges resulted in a dendrogram that showed a clear discrimination between both staphylococcal phenotypes. distinct clusters comprising the clinical and mutant scv phenotype on one hand and the normal phenotype (isolate with normal phenotype and complemented mutant) on the other hand were found. thus, scvs from different clonal lineages gave spectra that were more similar to one another than to their normal growth parent. ftir was also shown to be able to trace the switch of the phenotypes in broth when the medium was supplemented. conclusion: ftir spectroscopy allows a rapid, reproducible and clear discrimination of different phenotypes of s. aureus in fluid media for diagnostic and research purposes. in contrast to genotyping approaches, ftir staphylococcal fingerprinting is only reliable for typing purposes if the isolates exhibit the same phenotype. in future studies, this technique may also provide an approach for tracing the scv phenotype in infected tissues. objectives: triggering receptor expressed on myeloid cells- (trem- ) is a recently discovered cell surface molecule whose expression on phagocytes is up regulated by exposure to bacteria or fungi. a soluble form of trem- (strem- ) can be measured in various body fluids. we studied whether strem- in cerebrospinal fluid (csf) could serve as a biomarker for the presence and outcome in patients with bacterial meningitis. methods: in this retrospective study on diagnostic accuracy we used an elisa to determine levels of strem- in csf from adults with bacterial meningitis, confirmed by csf culture, who participated in the prospective dutch meningitis cohort study; patients with viral meningitis, confirmed by polymerase chain reaction of csf; and healthy control subjects, who underwent lumbar puncture to exclude the diagnosis of subarachnoid haemorrhage. the mann-whitney u test and the chi-square test were used to identify differences between groups. a receiveroperating-characteristic curve (roc) was constructed to illustrate various cut-off csf levels of strem- in differentiating between the presence and absence of bacterial meningitis and diagnostic accuracy was quantified by % confidence intervals ( % ci). results: levels of strem- in csf were higher in patients with bacterial meningitis as compared to those with viral meningitis [median, pg/ml (range, to pg/ml) versus . pg/ml (range, to pg/ml); p = . ] and controls [ pg/ml (range, to pg/ml); p < . ; fig]. patients with viral meningitis and controls had similar csf strem- levels. the area under the roc curve for discriminating between patients with and without bacterial meningitis was . ( % ci, . to . ; p < . ). at a cut-off level of pg/ml, strem- yielded a sensitivity of . ( % ci, . to . ) and a specificity of . ( % ci, . to . ). in patients with bacterial meningitis, csf strem- levels were associated with mortality [survivors versus nonsurvivors: median pg/ml (range, to pg/ml) versus pg/ml (range, to pg/ml); p = . ]. conclusions: measuring strem- in csf may be a valuable new approach to accurately diagnose bacterial meningitis and identify patients at high risk for adverse outcome. therefore, a prospective study on strem- as biomarker in bacterial meningitis is needed. systematic review of rapid diagnostic tests for enterohaemorrhagic e. coli i. abubakar, l. irvine, l. shepstone, s. schelenz, c. aldus, p. hunter (norwich, uk) objective: a variety of rapid tests for the detection of enterohaemorrhagic escherichia coli (ehec) have recently emerged. culture on sorbitol macconkey (smac) agar and biochemical identification, while easy to use and inexpensive, is slow and lacks sensitivity in the detection of non o :h serotypes. this study sought to determine the accuracy of rapid serological or polymerase chain reaction (pcr) assays which have been evaluated for the detection of all ehec serotypes compared to culture. methods: a systematic review and meta-analysis of articles, identified via searches of electronic databases, hand searching of selected journals, and through contact with experts and commercial test manufacturers. the majority of these needed to be excluded due to low quality or lack of accuracy data. sensitivity and specificity of each method was calculated using full biochemical identification as the reference standard. twenty-one studies met the inclusion criteria, of which used pcr methods and used serological assays and were based on culture. a summary receiver operator curve (sroc) was constructed from these data and the area under the curve (auc) calculated (using the trapezium rule). results: serological tests had individual sensitivities ranging from . to . and specificities ranging from . to . . pcr tests had individual sensitivities ranging from . to . and specificities ranging from . to . . additional analysis comparing smac agar culture with toxin detection methods showed poor sensitivity compared to pcr and serological tests (ranging from . to . ) yet the specificity was very good ( . for all studies considered). our results suggest that both molecular and serological tests may have a potential role in detecting ehec infection. whilst there is very little difference in the effectiveness of these techniques, both are faster and have improved sensitivity when compared to traditional culture methods. fast, reliable diagnosis could lead to more informed treatment choices and improved outbreak control measures. however, given the substantial extra cost of these assays, an assessment of economic feasibility is necessary prior to use in everyday practice. antibodies against bordetella pertussis detected by slow agglutination test and elisa in two agerelated groups of vaccinated people suspected of acute pertussis: a comparative study objective: the aim of presented study was to describe differences between results of two tests used for detection of antibodies against bordetella pertussis (slow agglutination and elisa) in two age-related groups of patients suffering from respiratory infection. each of the people has undergone vaccination against b. pertussis. methods: paired sera obtained from two age-related groups of patients [( ). age - years, n = ; ( ). age above years, n = ] suffering from acute respiratory infection were tested. the first group comprised the children who were vaccinated earlier than one year before testing; the second group was determined by longer interval between the vaccination and the testing. the criterion of positivity of the slow agglutination was based on quadruple increase/decrease of the titer of specific antibodies; the criterion of serodiagnosis of the illness was the same. each of the patients was tested by elisa iga,igg,igm (virotech) during the same period, positive results of each of class of immunoglobulins were evaluated as positive elisa. the differences of results obtained by the two tests were assessed inside and between the groups. results: there were found . % (respective . %) concordant positive and . % (respective . %) concordant negative results between the tests in the first (respective second) group. there were found the following discrepancies in the frame of non equal results: agglutination positive/elisa negative sera were present in . % (respective . %) persons and agglutination negative/elisa positive samples were present in . % (respective . %) persons. conclusion: ( ) . the frequency of serologically confirmed infection based on results of slow agglutination is higher in the group of people older six; the interpretation of the results in the younger group is limited by the influence of actual vaccination. ( ) . the elisa evaluated as described above shows extremely high frequency of positivity in both groups, thus, the usefulness for diagnostics of acute infection seems to be low. ( ) . the study will be continued to asses relationships between the positive results detected by slow agglutination and the positive ones detected by elisa in separate classes of specific immunglobulins. accuracy of the microscan walkaway system to identify coagulase-negative staphylococci a. sáez, b. ruiz, l. martínez-martínez (santander, es) objective: to determine the reliability of the identification of coagulase-negative staphylococci (cons) with the microscan walkaway (wa, dade behring) system at species level when a > = % probability is obtained, considering as a reference the results of molecular identification. methods: one hundred and sixty-eight isolates of cons from clinical samples (october -may for which the identification with the wa system was ‡ %, and atcc type strains were evaluated. bacteria were identified with the wa system using pos combo s panels. absence of coagulase was determined with a latex assay (pastorex Ò staph-plus, bio-rad). reference identification was established by sequencing of the s rrna; when identification with wa and s rrna disagree, definitive identification was defined after sequencing of the soda and tuf genes, as previously described (drancourt et al. jcm ; : - and heikens el al. jcm ; : - ) . for identification, the sequences of s rrna, soda and tuf were compared with those in genebank. homologies values above % were considered reliable. results: all type strains were correctly identified by s rrna sequencing as named by the atcc. among the clinical isolates, the molecular method identified the following species (number): s. hominis ( ), s. haemolyticus ( ), s. saprophyticus ( ), s. epidermidis ( ), s. lugdunensis ( ), s. schleiferi ( ), s. capitis ( ), s. simulans ( ), s. pasteuri ( ), s. warneri ( ), s. intermedius ( ) and s. equorum ( ). the wa system correctly identified out of the atcc strains. s. pasteuri is not included in the wa database, and the corresponding atcc strain was misidentified as s. warneri. one hundred and fiftyseven out of the ( . %) clinical isolates were correctly identified by the wa. five s. haemolyticus were identified by wa as s. auricularis ( ), s. simulans ( ) and s. warneri ( ) . other errors corresponded to: two s. pasteuri misidentified as s. warneri, one s. epidermidis as s. hominis, one s. lugdunensis as s. schleiferi, one s. hominis as s. haemolyticus and one s. equorum as s. cohnii. all isolates of s. saprophyticus, s. schleiferi, s. capitis, s. simulans, s. warneri and s. intermedius were correctly identified by the wa system. conclusions: the microscan walkaway is reliable to identify cons at species level when a probability of > = % is obtained. s. pasteuri should be incorporated to the wa database in order to improve its performance. objectives: the aim of this study was to analyse the results of proficiency testing obtained by polish microbiology laboratories participating in polmicro. haemophilus influenzae is an important pathogen causing a variety of community-acquired respiratory tract infections, acute otitis media and purulent meningitis. two mechanisms of ampicillin (amp) resistance in this organism are described. one is mediated by the production of beta-lactamases tem- and rob- ; these amp-resistant strains are termed beta-lactamase-producing, amp-resistant (blpar). the second mechanism involves development of altered penicillin-binding proteins (pbp) with decreased affinity to amp and other beta-lectam agents. strains with resistance mechanisms mediated by pbp alterations are termed beta-lactamase-nonproducing, amp-resistant (blnar) h. influenzae. methods: four hundred seventy eight laboratories participated in this part of the scheme. each participating laboratory received haemophilus influenzae (pm- )-beta-lactamase negative, ampicillin-resistant strain (blnar). the laboratories were asked to provide identification to the species level and of the susceptibility results and interpretation. results: correct identification to the species level of this strain was reported by laboratories ( . %) of the labs involved. thirteen laboratories reported the analysed strain as haemophilus parainfluenzae. three hundred ninety eight laboratories ( . %) of correctly detected the mechanism of resistance to beta-lactams. only three laboratories incorrectly reported the organism as beta-lactamase producer. the greatest dispersion of inhibition zone was observed in the susceptibility of h. influenzae to ampicillin, amoxicillin-clavulanic acid and clarithromycin. conclusions: over % of the laboratories correctly identified and interpreted beta-lactamase-nonproducing, amp-resistant (blnar) h. influenzae strain. purpose and methods.the architect syphilis tp assay is a chemiluminescent eia that employs three recombinant antigens of treponema pallidum on the solid phase and an anti-human igm and igg conjugate. we evaluated this assay in comparison with a conventional eia (diesse enzywell syphilis screen recombinant) on unselected routine serum samples and on repository specimens for whom the results for specific igg and igm and of the rapid plasma reagin (rpr) assay were already known. in both instances an immunoblot (ib: inno-liatm syphilis score, innogenetics) has been employed on discordant specimens as a confirmatory assay. the precision and robustness of the architect assay were also evaluated.results.on . routine samples ( from volunteer blood donors and from in and outpatients) the concordance between architect and eia was high ( . samples, or . %; positives, , negatives). one of the discordant, positive by architect and negative by eia, was confirmed by ib. the specificity of the architect assay was . % ( % confidence limits: . - . ). the repository samples assayed belonged to three groups: ) biological false positives from subjects: all negative by architect; ) true positives, all positive by architect, with a significantly stronger signal (average s/co: . vs. . ) on the igm positive samples, all of whom were also positive by rpr; ) samples positive by rpr and negative by eia igg: of them were negative by architect as well and for igm, while two specimens were strongly positive by architect and positive also for specific igm and with three specific bands by inno-lia, suggesting a pattern of recent infection. the reproducibility of the architect assay was good, with cvs of . %, . % and . % on replicates over weeks of the assay's negative and positive control and of an internal control; finally, the s/co distribution of negative specimens confirmed the robustness of the assay, with a mean of . , a median of . , standard deviations between the mean and the cut-off value and the th percentile at a s/co value of . .conclusion.the automated assay for anti-treponema pallidum antibodies on the architect system has an excellent sensitivity and a good specificity. the analytical performances, coupled with the elevated throughput and minimal samples handling, make this method a first-choice option for syphilis screening and diagnosis in medium and large volume laboratories. objective: quantitative urine culture is the gold standard for defining the diagnosis of urinary tract infection (uti), because it allows identification of the uropathogenic species. however, this method is time consuming and expensive. approximately, up to % of urine cultures are negative with high cost for unnecessary testing. thus, we have evaluated the usefulness of two automated analysers for uti screening to quickly identify the negative samples that can be prompt reported to the clinicians, improving in the quality of patient care and allowing the laboratory to direct more effort into positive samples. methods: . of midstream urine samples submitted for microbiological examination were analysed by conventional urine culture plates (mcconkey agar + trypticase soy agar + bile esculine azide), sysmex uf- (sysmex, japan) and coral uti screen (coral biotechnology, ca, usa) automated analysers. uti was defined positive as follows: one or two strains of bacteria with at least ufc/ml for the culture plates, more than . bacteria/ll and more than wbc/ll for the uf- and/or an rlu value grater than % of the calibrator value for the coral. when more than two strains of bacteria were found, the culture was classified as contamined. results: the diagnostic performance of sysmex uf- and coral uti screen are shown in table . the sensitivity ( . %) and negative predictive value ( . %) confirm that sysmex uf- and coral uti screen are an excellent screening for uti. after this evaluation, we decide the use of the sysmex uf- and coral uti screen on our routine workflow for uti screening. the results of both the analysers are sent to a software system (labfinity dasit, italy) connected to the lis. if the results are lower than the cut-off values, uti can be excluded and directly reported to the physician. positive results are submitted to microbiological culture and reported within or hours depending on negative or positive bacterial growth. in our experience, evaluated on further . samples, this means that % of samples are immediately reported within very few hours. of the % of positive samples, ( %) were confirmed by culture and reported within hours, ( %) were not confirmed and reported within hours. comparison of the blood and bone marrow culture positivity rates for the diagnosis of brucellosis objectives: brucellosis is a common disease, seen worldwide as well as in our country. the diagnosis of brucellosis is made with certainly when brucellae are recovered from blood, bone marrow. in our study, we aimed to compare the blood and bone marrow culture positivity rates in patient with brucellosis. methods: this study was performed in the infectious diseases and clinical microbiology department of ankara research and training hospital between and . the diagnosis of brucellosis was made on the history, physical findings, serologic findings and the isolation of the organism. the number of patients with brucellosis included to the study was . blood and bone marrow samples were taken from all of the patients on admission and cultured by using the bactec system. results: blood culture positivity for brucellosis was % ( / ), while bone marrow culture positivity was % ( / ). the difference between those positivity rates was found to be statistically significant (p < . ). the isolation ratio from blood cultures among acute cases was % ( / ) while it was % ( / ) among subacute cases. brucella isolation from blood was not detected in chronic cases. the isolation rates of the microorganism from bone marrow of acute, subacute and chronic cases were . %, . %, . % respectively. among our patients, had history of medical therapy for brucellosis before admission and of them was treated inadequately. of those cases, the organism was isolated in ( %) from blood and in ( %) from bone marrow.in the cases with high standard tube agglutination titers, the rate of positivity was also high both in blood and bone marrow cultures. however when compared with low standard tube agglutination titers, that difference was not statistically significant.the mean growing time for the positivity of cultures was . days for bone marrow and was . days for blood cultures. the difference between the mean growing times of two culture types was found statistically significant (t-test. p < . ). conclusion: premedication, subacute and especially chronic phases decrease the possibility of isolation of the microorganism from blood culture. therefore we suggest taking bone marrow culture only for these kinds of patients as it. is a traumatic process. serological findings in blood sera of patients with yersinia-triggered arthritis e. golkocheva, r. stoilov, h. najdenski (sofia, bg) objectives: immunoblot analysis of iga and igg antibody response of blood sera from patient with yersinia triggered reactive arthritis and with undifferentiated arthritis were made. patients and methods: serum samples were obtained from patients admitted to clinic of rheumatology at medical university, sofia, bulgaria with suspicion of yersinia triggered reactive arthritis, based on diagnostic criteria. a total of blood serum samples were analysed by immunoblot analysis with specific antigens-yops (yersinia outermembrane proteins). when y. enterocolitica is cultivated at o c under calcium restriction ( . mm ca + ), large amounts of yops are secreted into medium. these proteins were separated by d-sdselectrophoresis. results: immunoblot analysis of iga and igg antibody response against yops in blood sera from patients with arthralgias and polyarthropathies was carried out. yersinia enterocolitica, serotype o: , was used as source for yop. seven strong bands of the molecular weights kda-yope, kda-yopn, kda-yopd, kda -v-ag, kda-yopb, kda-yopm and kda-yoph were visualized. for immunoblot assay the optimal concentration of antigen was established by analytical electrophoresis. of the blood sera from the patients with yersinia triggered reactive arthritis igg antibodies were detected against yoph, yopm, yopb, yopd, yopn and yope. iga antibodies were established against yopm, yopb, yopd, yopn and yope. all sera from the patients with other rheumatic diseases were negative for the presence of anti-yersinia iga antibodies and two of them were positive for igg against yopd. antibodies from two classes were not detected in sera samples from healthy people. conclusions: yops are borne by the virulence plasmid, which mean that they are clearly associated with virulence properties of pathogenic strains. moreover, yops is not restricted to single serotype and this made them a specific antigen in diagnosis of different yersinia infections. conventional techniques such as culture and demonstration of serum agglutinins prove to be insufficient to demonstrate invasive or chronic yersiniosis in contrast with the determination of specific serum iga and igg antibodies by immunoblot analysis and antigen detection. the detection of anti-yops igg and iga antibodies by immunoblot can be used for diagnosis of yersinia triggered arthritis. acknowledgements: this work was sponsored by natoreintegration grant . objectives: to evaluate the identification and susceptibility results by using suspensions obtained directly from positive blood cultures. methods: during the period between st august and st october we selected all positive cultures grown in bact/ alert Ò sa and sn bottles (biomérieux) from gram-negative bacilli. only the first culture positive from each patient was included. we inoculated ml fluid from a positive bottle into a serum separator tube (bd vacutainer systems, plymouth, united kingdom) and centrifuged at x g for minutes and the supernatant was carefully aspirated. using a cotton swab the bacteria were removed from the top of the separator layer to be suspended in . % saline solution to get . mcfarland. the suspension was processed according to standard inoculation procedure for gn and ast-n vitek Ò cards. positive bact/alert d bottles were also sub cultured and after an overnight incubation several colonies were used to make a . mcfarland suspension in . % saline. the suspension was processed according to standard vitek Ò inoculation procedure for gn and ast-n cards. results: identification: a total gram-negative bacillus from positive blood cultures were investigated. fifty ( . %) strains were correctly identified to the species level, four ( . %) strains were not identified and two ( . %) strains were misidentified. antimicrobial susceptibility testing: in all, mics were determined for isolated by both methods. the unidentified strains ( ) were excluded. the overall mic agreement between direct and standard inoculation was . %. all individual antimicrobial agents scored > %. the overall minor error rate was . % ( of ). the overall major error rate was . % ( of ). the overall very major error rate was . % ( of ). the highest rate of mic agreement was for amikacin, norfloxacin ( %), meropenem ( %), gentamicin and ofloxacin ( . %). conclusion: the direct method from positive bact/ alert&# ; cultures cannot totally replace the approved methods of identification and susceptibility but in some cases provides earlier information which allows a better patient management and also reduce cost in patient care. investigation of listeria monocytogenes "o" antibodies in maternal and cord sera with the agglutination test e. us, a.t. cengiz, o. gelisen (ankara, tr) objectives: listeria monocytogenes is a gram-positive food borne pathogen that is responsible for listeriosis, a human infection with a mortality rate of %, which could cause severe motherto-child infections. this serious pathogen in pregnancy could be treated if diagnosed, but there is no routine screening test for susceptibility to listeriosis during pregnancy. therefore, we investigate different l monocytogenes serotype o antibodies for diagnosis of listeriosis in maternal sera with agglutination test. of them had spontaneous abortion, premature labour or stillbirth (group i), while had no obstetric patology (group ii) in their previous pregnancies. cord bloods were also obtained at the delivery and tested. methods: all sera were being tested against antigens with the o formulation of serotype / c, b, ab, c and d. the antigens were prepared by the method of osebold, and larsen et all. the bacterial suspensions were trypsinized for min at °c to prevent cross-reactions and contaminations. sera were diluted by doubling serially in saline followed by addition of an equal volume of antigen. a positive titre of greater than or equal to : was chosen as positive test result to maximize the sensitivity and specificity. results: . % of cases have ingested raw milk and diary products, . % ready-to-eat foods, and . % developed nonspecific febrile illness (nfi) during their pregnancies. % of group i were found positive ( . % developed nfi) while at group ii % had positive ( . % developed nfi) agglutination titres to one ore more serotypes. all the cord blood sera of group i were found negative, whereas two in group ii (all ab) were positive, with the positive maternal sera of the same serotype. it's evaluated as transmission of the antibody from mother to foetus. at group i the frequent serotypes were / c = ab, at group ii ab, / c, respectively. the newborns showed no symptoms or signs of listerial foeto-maternal infection. conclusion: the women encountered the antigens of l monocytogenes in any period of their life time (most - years of age) and produce antibodies against this pathogen. there is a relationship between nfi and positive titres. if the disease is recognized, it is possible to treat the mother and allow the birth of a healthy infant. we propose the less time consuming and easy to perform agglutination test as a routine screening test for susceptibility to listeriosis during pregnancy to prevent bad pregnancy outcomes. objectives: to evaluate the performance of a real time pcr assay (with a fluorogenic target-specific probe), mrsa-idi (geneohm sciences) for mrsa detection directly from mucocutaneous swabs in hospitalized patients. methods: clinical swabs ( to samples with a median of . samples per patient) from nares (n = ) and skin (n = ) were prospectively collected for mrsa screening from patients admitted to a -bed teaching hospital. swabs were inoculated onto selective mrsa agar (mrsa-id, biomérieux), into the buffer extraction solution for idi-mrsa pcr assay and into enrichment broth (bhi with . % nacl). after h, bhi broths were subcultured onto mrsa-id agar. selective agars were incubated for h at ordm;c and examinated daily. suspected colonies were identified by coagulase testing; oxacillin resistance was tested by cefoxitin disk diffusion according to clsi recommendations. the pcr assay was performed according to the manufacturer's instructions. pcr results were compared with phenotypic identification test results. in case of discordant results, the assay was repeated, but only results from first testing were considered for calculating test performance. results: mrsa was detected by culture in specimen ( . %) from patients. the sensitivity and specificity of the pcr compared with culture was . % and . %, respectively. positive predictive value and negative predictive value were . % and . %, respectively. the sensitivity of pcr ( %) was higher on nasal swabs than on swabs from other sites ( . %, p < . ). the pcr assay detected mrsa in patients ( . %). the pcr assay provided results in to versus to hours for conventional method. conclusion: in our hospital, the id-mrsa pcr assay detected . % mrsa carriers in less than hours when performed on multiple specimen. the assay appeared more sensitive in testing nasal swabs than other clinical specimens. prospective studies are needed to evaluate the impact of this assay for rapid implementation of infection control procedures and its global costs and benefits. the purpose of this study was to establish a rapid and sensitive real-time polymerase chain reaction (pcr) method for detection of methicillin-resistant staphylococcus aureus (mrsa) from blood culture bottle. as a result of over use of broad-spectrum antibiotics after the s in whole the world, an outbreak of mrsa infection has been seen. severe nosocomial infections with mrsa such as bacteraemia and sepsis may lead to multiple organ failure and high mortality in the hospital. although standard method took at least hours to identify mrsa by the blood culture method, the presence of meca and nuc genes which is specific for methicillin resistance and s. aureus was determined by real-time pcr method within only hours after blood culture signal positivity. nineteen s. aureus and coagulase negative staphylococci positive blood culture bottles were studied retrospectively for detection of s. aureus and methicillin resistance. staphylococci were identified with classical methods and mics of oxacillin were determined by etest (ab biodisk) on mueller-hinton agar supplemented with % nacl. real-time pcr was performed to all positive blood culture samples for s. aureus and methicillin resistance determination. nineteen ( %) s. aureus were determined correctly by real-time pcr method. forty-four methicillin resistant and methicillin sensitive staphylococci were detected by etest. using the real-time pcr method, the meca gene was detected in staphylococci except . when compared with etest and realtime pcr method gave sensitivity, specificity, and positive and negative predictive values of %, %, %, % for both positive and negative tests, respectively. agreements between two methods were high ( %); there were discrepant results among the strains were tested. detection of mrsa bacteraemia and methicillin resistance with real-time pcr definitely is useful for reducing mortality and morbidity of this type infection. in conclusion, this method, as many as sensitive and specific for detection of mrsa bacteraemia and clinically should be beneficial for prevention of unnecessary antibiotic use and determination of appropriate antibiotic treatments of mrsa infection. pcr detection of class b, c and d betalactamases in environmental and clinical aeromonas strains t. fosse, c. giraud-morin, f. la louze (nice, fr) objectives: aeromonas spp. strains are waterborne opportunistic pathogens. they are able to produce different types of beta-lactamases (class b, c and d). the determination of beta-lactamase content is not easy by phenotypic methods. we have developed a pcr tool to study diversity and distribution of class b, c and d beta-lactamases in a set of representative clinical and environmental aeromonas species. method: a total of references, environmental and clinical strains were tested. identification was realized by conventional tests and gyrb sequence analysis. beta-lactam antibiotic susceptibility was determined by diffusion agar and micro broth dilution methods. three sets of specific primers were defined for the pcr amplification of the internal region of class b beta-lactamase (mei and mei , bp size), class c beta-lactamase (aercp and aercp , bp) and class d betalactamase (aerd and aerd , bp). all pcr products were sequenced. results: class d pcr was positive with most strains except a. trota, a ticarcillin susceptible species ( strains) . class c pcr was positive with most cephalothin resistant strains (mic > mg/l; / strains, %) including a. hydrophila and a. caviae phenospecies. class b pcr was positive with most strains of a. hydrophila and a. veronii phenospecies ( / ; %) including three imipenem susceptible strains (mic < mg/l). beta-lactamase type distribution was species related and was particularly useful to better characterize environmental species such as a. bestiarum, a. popoffii and a. allosaccharophila. partial beta-lactamase gene sequence analysis allowed phylogenic studies. some cephalosporinase gene from environmental species was probable progenitor of ampc plasmidic beta-lactamase. conclusion: pcr with specific primers was a good method to detect class b, c and d beta-lactamase in aeromonas species. beta-lactamase type distribution and sequence analysis phylogeny were largely species related and could be helpful for molecular diagnostic and taxonomic purpose. objectives: the aim of this study was to develop a convenient dna extraction method and to optimise a pcr reaction in order to detect enterotoxin b producing s. aureus strains directly from milk. methods: we applied a chemical extraction method of bacterial dna from milk samples artificially inoculated with s. aureus. a pcr based method was used for the detection of seb gene (coding for enterotoxin b) and nuc gene (coding for termonuclease). a protocol for the multiplex pcr was developed and optimized. the sensitivity of the reaction was checked by determining the minimum number of organismsaeml - , which can be detected in the multiplex pcr and in each single pcr reaction. amplification specificity of the seb gene was verified by amplicon digestion with restriction endonucleases. results: the specific bands for both genes in the multiplex pcr were detected in samples containing a dna quantity corresponding to organismsaeml ) . in the same reaction, the amplicon for nuc gene was visible for as little as the dna concentration corresponding to organismsaeml ) . the sensitivity of each single pcr reaction was similar with those of multiplex pcr reaction. conclusion: the applied dna extraction method allowed us to obtain a good quality dna and can be used for a direct milk extraction. multiplex pcr reaction is a simple, rapid and reliable method for detecting enterotoxin b producing s. aureus strains from milk. objective: to detect the resistance to fluoroquinolones in acinetobacter baumannii strains by a pcr-rflp assay. methods: thirty a. baumannii clinical isolates were obtained from different specimens (bronchial aspirates, blood-cultures, catheters, etc.) . the mics (minimal inhibitory concentrations) for ofloxacin were determined by agar dilution following standard methodology.a pcr-rflp method using one primer pair for amplification of a bp fragment related to gyra gene (which codifies subunity a of dna-gyrase) and using one restriction enzyme hinf i was developed to study the resistance to ofloxacin in the different a. baumannii strains. when an a. baumannii strain is resistant to fluoroquinolones, a mutation in the position ser of the dna-gyrase has been detected, decreasing the affinity for the antimicrobial. agarosa gel was used to determine the dna pattern: fragments of bp and bp when there is not mutation and fragment of bp when the ser to leu mutation is present. results: the relationship between the pcr-rflp pattern and the mic to ofloxacin is shown in the table . the results of pcr-rflp analysis of most strains were in agreement with the results of mic. one isolate was susceptible to ofloxacin by agar dilution (mic = . mg/l) whereas by pcr-rflp this isolate seems to be resistant because it presents the mutation in gyra gene. two isolates with intermediate mic ( mg/l) showed mutation in gyra. the genotypic study by pcr-rflp proved that ofloxacin resistant a. baumannii strains showed a punctual mutation in gyra gene, in the same position inside the sequence of gene. evaluation of a rapid amplification-detection assay for the identification of vancomycinresistant enterococci j. fuller, l. turnbull, s. shokoples, b. lui, l. rosmus, r. rennie (edmonton, ca) objective: the routine identification of vancomycin-resistant enterococci (vre) in clinical laboratories often yields a lengthy turn-around-time that may impede infection control efforts, particularly in an outbreak situation. in search of an improved vre test, we evaluated the genotype Ò enterococcus assay (hain lifescience, germany), which provides both species and van gene identification for vre, and compared the results to conventional methods. methods: forty clinical enterococcal strains isolated on vrescreen agar media were selected for study. lactococcus and pediococcus were used as negative controls. conventional testing involved basic culture and identification tests, e-test susceptibility testing for vancomycin and teichoplanin, and pcr for vana, b, and c genes. the genotype Ò enterococcus assay involved multiplex dna amplification and reverse hybridization of amplified product on an immobilized dna strip-blot containing probes for e. faecium, e. faecalis, e. casseliflavus, e. gallinarum, vana, vanb, vanc , and vanc / . the genotype Ò enterococcus assay produced correct species and van gene identification for all ( %) vre isolates, including e. faecalis vanb, e. faecium vana, e. faecium vanb, e. gallinarum vanc , e. gallinarum vana-vanc , and e. casseliflavus vanc / . the only minor discrepancy was an e. casseliflavus that hybridized very weakly with the vanc probe in addition to the expected vanc /c probe. the costs per specimen were comparable for each test method. however, the genotype Ò enterococcus assay could be completed within a normal working day in contrast to conventional testing, which required a minimum of two days from the point of isolation on the vancomycin-screen media. conclusion: from this preliminary evaluation, the genotype Ò enterococcus amplification-detection assay provides vre species and van genotype identification in a rapid and costeffective manner, superior to conventional culture methods. although further study is required, this kit may have clinical utility during a vre outbreak. application of minimal sequence quality values prevents misidentification of blashv type in single bacterial isolates carrying different shv extended-spectrum beta-lactamase genes background: detection of extended spectrum beta-lactamase (esbl) genes by pcr and sequence analysis is the gold standard for detection of shv-type beta lactamases. usually, quality values of sequence analyses are not reported. during a study on esbl epidemiology, three strains for which the default sequence assembly showed an shv) or shv- gene, showed low quality values at certain positions in individual sequence traces. we investigated the reason for these lower values. methods: shv genes were amplified by pcr from three isolates (escherichia coli, enterobacter cloacae and pseudomonas aeruginosa). individual sequence traces were analysed with the computer programs phred and codon code. pcr products were ligated in vector pcr . and transformed to e. coli. sequence analysis was performed on eight individual clones from each transformation. results: visual inspection of the low quality positions in the sequence traces showed signals for two different nucleotides at three positions in the shv sequence: a or t at position , a or g at position and a or g at position . the polymorphisms at positions and lead to aminoacid substitutions, the four different combinations would give shv types , a, or . the double signals suggested that two or more blashv alleles were amplified. pcr amplicons were cloned in e. coli, in the sequences of individual clones only two combinations of the three polymorphisms were present: a g a and t a g . these two combinations correspond to shv- and shv- , respectively. conclusions: (i) in isolates of three different species, two different shv genes were present: shv- and shv- . (ii) genotypic detection with default sequence assembly parameters may lead to misidentification of the number and type of shv genes carried by a single strain. (iii) careful interpretation of sequence data of shv genes, including analysis of low quality positions, may further improve our understanding of the epidemiology and evolution of these esbl genes. antimicrobial susceptibilities and epidemiological analysis of salmonella typhimurium human isolates in slovakia by phage typing and pulsed-field gel electrophoresis v. majtán, l. majtánova, m. szabó ová (bratislava, sk) objectives: salmonella typhimurium is a common cause of salmonellosis among humans and animals in many countries. in the last few decades the incidence of multidrug-resistant s. typhimurium infections appears to pose a particular health risk. the objectives of this study were analysis by antibiotic susceptibility, phage typing and pulsed-field gel electrophoresis (pfge) of s. typhimurium human isolates. methods: a total of strains isolated during -september were analysed. the susceptibility of isolates to ten antibiotics was evaluated by a disk diffusion method. the phage types were identified according to anderson et al. ( ) in the national reference center for phage typing of salmonellae. pfge was used to resolve xbai macro restriction fragments from all strains. results: of human isolates ( . %) were resistant to more than two antibiotics. sixty-three of isolates ( . %) showed a classic dt resistance profile to ampicillin, chloramphenicol, streptomycin, sulfonamides, tetracycline (acssut). among this resistance type . % were dt , . % were dt and one strain was dt a. isolates encompassed phage types. the majority of isolates was found to be definitive phage type dt , representing . % of all isolates. other phage types were mainly dt , dt and dt a. nine pulsotypes and subpulsotypes were obtained using xbai restriction enzyme, but pattern x with its subtypes predominated ( . %). a major pulsotype x was represented by . % of dt isolates and was also found among dt isolates. conclusion: results indicated the spread of different clones of the multidrug-resistant s. typhimurium in the slovakia, but with predominance of one clone represented mainly by dt isolates. the phage typing as well as pfge may offer an improved level of discrimination for the epidemiological investigation of s. typhimurium human strains. novel reverse hybridisation assay to identify ctx-m genotype in cephalosporin-resistant isolates from uk and india to validate the assay results by dna sequencing. methods: isolate collection : enterobacteriaceae resistant to extended-spectrum cephalosporins, isolated in london and south-east england. these isolates were known to carry phylogenetic group blactx-m, but precise genotypes had not been determined. isolate collection : enterobacteriaceae resistant to extended-spectrum cephalosporins, isolated in aligarh, north india. resistance determinants had not been investigated previously. a novel multiplex pcr was used to amplify blactx-m. reverse hybridisation was carried out using biotinylated pcr amplicon and sequence-specific oligonucleotides designed to identify members of ctx-m phylogenetic group . hybridisation results were validated by dna sequencing for representative isolates from each collection. results: / london and se england isolates known to carry group blactx-m gave a consistent profile, corresponding to that for ctx-m- and ctx-m- ; / gave a profile corresponding to ctx-m- and ctx-m- . / indian isolates had blactx-m genes, all of which belonged to group , and all these gave a hybridisation profile corresponding to ctx-m- or ctx-m- . ctx-m- and ctx-m- are rare variants, suggesting that the enzymes present were more likely to be ctx-m- and ctx-m- , and this was confirmed by dna sequencing. conclusions: this is the first reported application of this novel reverse hybridisation assay to the analysis of large numbers of cephalosporin-resistant enterobacteriaceae. results were validated by dna sequencing. the assay is cheap and convenient, enables reasonable throughput, provides results within one day and can be used in place of dna sequencing. we believe it will be valuable for monitoring the prevalence and genotypes of blactx-m genes in enterobacteriaceae. detection of mexa and mexx efflux genes in p. aeruginosa: correlation between qc-rt-pcr and real-time pcr objectives: efflux systems are rarely identified as such in clinical microbiology laboratories. yet, over expression of transporters such as mexab-oprm and mexxy-oprm are likely to cause antibiotic multi-and cross-resistance in pseudomonas aeruginosa, leading to potential clinical treatment failures because of their inducible character. we have previously developed and validated with reference strains a qc-rt-pcr method to quantify mexa and mexx expression levels (eccmid . in the present study, we have developed a real-time-pcr assay and present here the correlation between both methods using control strains and clinical isolates. methods: expression levels of mexa and mexx were measured by both techniques in (i) reference strains expressing only one of these efflux mechanisms [mexa ( ) or mexx ( ) ]; and (ii) clinical isolates, in comparison with the wild-type strain pao (basal mexa and mexx expression levels). results: real-time pcr showed an inter-day reproducibility of ± . % (triplicates of strains). among the clinical strains, over expressed mexa and mexx. the table shows (i) the mean level of overexpression of mexa and mexx in comparison with the wild type strain pao (set at ), as detected by real-time pcr for all strains; (ii) the ratio of these values to those observed by qc-rt-pcr for the corresponding transporters. conclusions: both qc-rt-pcr and real-time-pcr are potentially useful in clinical laboratories as sensitive and rapid diagnostic tools to quantify the expression level of mexa and mexx in p. aeruginosa. combined with phenotypic characterization, this approach may help in a better understanding of the resistance mechanisms and epidemiology of resistance in this difficult-to-treat nosocomial pathogen. molecular detection of penicillin resistance in streptococcus pneumomiae n.g. rizk, n.a. abo khadr, s.m. abdel salam, n.m. gamil, m. hassan (alexandria, eg) objectives: the aim of the study was to detect penicillin resistant streptococcus pneumoniae by using seminested polymerase chain reaction (pcr) and to compare it with minimum inhibitory concentration (mic) of penicillin g. methods: fifty clinical isolates of streptococcus pneumoniae where isolated from patients admitted to alexandria main university hospital in egypt and were recovered from sputum ( strains), throat swabs ( strains), and pleural effusion ( strains) . two species-specific primers a- and a- , which amplified bp region of the pbp a penicillin-binding gene, were used for pneumococcal detection. two resistance primers, a-r and a-r , were used to bind to altered areas of pbp a gene which, together with the down stream primer a- , amplify dna sequences of bp and bp from isolates with penicillin mic > . objective: lipopolysaccharide-binding protein (lbp) is an acute phase protein produced in the liver. the objective of our study was to evaluate lbp as a marker of severity and prognosis in patients with bacteraemia. methods: adult patients with community-acquired bacteraemia were included in a prospective manner. daily blood sampling for lbp and interleukin- (il- ) was performed. the patients were classified according to the systemic inflammatory response syndrome (sirs) criteria. demographic data, co-morbidity, microbiological aaetiology, routine biochemical parameters, focus of infection, severity score and mortality on day were recorded. lbp and il- levels were analysed on plasma samples with a chemiluminescent immunometric assay (immulite- Ò ). results: the median age was yrs. the mortality rate on day was . %. patients had bacteraemia without sirs, patients had sepsis and patients had severe sepsis. lbp concentrations are presented as medians and range: . lg/ml ( . - . ) in patients without sirs, ) in patients with sepsis and . lg/ml ( . - . ) in patients with severe sepsis (p < . ). lbp levels correlated to levels of il- (rs . ), c-reactive protein (rs . ), leukocytes (rs . ) and neutrophils (rs . ) (p < . ). lbp did not predict the outcome of the patients with bacteraemia. conclusion: lbp levels increased with the severity of sepsis in patients with bacteraemia. lbp correlated to il- , c-reactive protein, leukocytes and neutrophils. lbp did not predict the outcome of the patients in this small cohort. pyrosequencing of the gra gene to discriminate type i, ii and iii toxoplasma gondii in clinical samples b. edvinsson, b. evengård on behalf of the esgt objectives: infection with toxoplasma gondii in immunocompromised transplant recipients is rare but often fatal. to increase our knowledge about the significance of the genotype of the parasite during infection, methods suitable for routine use need to be developed. pyrosequencing is a rapid sequencing-bysynthesis method performed in real-time. it is developed for detection of short nucleotide polymorphisms (snps), and is suitable for molecular genotyping of microorganisms. we here present a pyrosequencing assay for rapid and reliable discrimination of toxoplasma gondii type i, ii and iii in clinical samples. methods: twenty-two isolates of t. gondii were used for pyrosequencing analysis of the gra gene. real-time pcr was performed using a lightcycler . instrument to amplify a bp fragment of the gra gene. pyrosequencing analysis of two different snps contained within a bp fragment of the amplified product was preformed to identify t. gondii type i, by detection of nucleotides g and a at these respective positions. type ii was g and g, and type iii was a and a. to test the assay in a clinical context, blood samples and lung tissue from an immunocompromised patient was analysed. results: the detection limit of the assay is parasitic genomes in a sample. reproducibility (r) was calculated as r = nr/n (nr = the number of isolates assigned the same type on repeat testing and n = the number of isolates tested). r was determined using three independent runs, and was , suggesting clearly interpretable results with little variation. typeablility (t) of the assay was calculated as t = nt/n (nt = the number of typeable strains and n = the number of isolates tested). t was determined using three independent runs, each including four atypical isolates. t was . , suggesting that the assay discriminates correctly between the three main genotypes of t. gondii, but does not detect atypical strains. analysis of the clinical samples revealed type ii t. gondii in blood samples and lung tissue. conclusion: when preceded by real-time pcr, pyrosequencing is a rapid process with a high reproducibility and throughput. this makes it a good candidate for routine use. the method does, however, not detect atypical or recombinant strains. more than one gene may have to be analysed for that purpose. acknowledgement: in particular, we want to thank marie-laure dardé and hervé pelloux for provision of the t. gondii isolates. virulence genes in escherichia coli isolates from calves in shahrekord area, iran shiga toxin-producing escherichia coli (stec) strains, also called verotoxin-producing e. coli (vtec) strains, represent the most important recently emerged group of food-borne pathogens around the world. members of this group are a major cause of gastroenteritis that may be complicated by hemorrhagic colitis (hc) or the hemolytic uremic syndrome (hus), which is the main cause of acute renal failure in children. domestic ruminants, mainly cattle, sheep, and goats, have been implicated as the principal reservoir. transmission occurs through consumption of undercooked meat, unpasteurized dairy products and vegetables, or water contaminated by feces of carriers because stec strains are found as part of the normal intestinal floras of the animals.we studied the prevalence of shiga toxinproducing escherichia coli (stec) in stool specimens of calves with diarrhoea or other gastrointestinal alterations from dairy cattle farms of shahrekord city (central of iran). the virulence genes, stx , stx , eae, intimin hly, enterohemolysin, st, lt, were detected by multiplex pcr method. stec strains were detected in ( . %) of e. coli from cases investigated. stec o was isolated in cases ( . %), whereas non-o stec strains were isolated from animals ( %). stec strains were the most frequently recovered enteropathogenic bacteria. pcr showed that ( . %) isolates carried st gene. none of isolates carried an ehxa, eae, and lt (labile toxin) genes. our results suggest that stec strains are a significant cause of calf infections in this area and confirm that, infections caused by stec non-o strains are more common than those caused by o :h isolates. the high prevalence of stec strains (both o and non-o strains) also found in human patients by other investigators, and their association with serious complications, strongly supports the utilization of protocols for detection of all serotypes of stec in spanish clinical microbiology laboratories. objectives: shiga toxins are a-b holotoxin including one enzymatically active a subunit associated non-covalently to five identical receptor binding b subunits. each subunit can cause different signalling pathways in different cells. to assess the effect of each single subunit the specific clones for expressing the single subunit was designed. periplasmic expression yielded native ab holotoxin or b pentamer. methods: o was used as bacterial strain for pcr amplification of shiga toxin gene. each subunit was amplified by specific primers and the amplified genes were cloned in pbad expression vector. the expression of the cloned genes was induced and optimized by different concentration of arabinose. the expressed proteins was assessed on sds-page and detected by elisa and western blotting. the expressed recombinant ab holotoxin and b subunit were purified and assessed for its biological activity on cells. cell cytotoxicity was shown by the expressed (ab ) holotoxin. moreover inhibition was observed by b subunit and antibody against it. results: e. coli clones expressing recombinant shiga toxin a and recombinant shiga toxin b subunits were established to release the toxin to periplasmic space. expressed toxin was examined by sds-page to visualize two subunits. the whole structure of these expressed subunits was checked in native gel. active ab structure expressed in periplasmic space was extracted by polymyxine b. the biological activity of the constructed recombinant shiga toxin showed both vero cell cytotoxicity and inhibition of in vitro protein synthesis. conclusion: in this study it was shown that for b subunit assembly and secretion to periplasmic space as b pentamer homologous leader sequence is not needed. although for biological active holotoxin (ab ) secretion to periplasmic space the presence of homologous leader sequence of gene is essential. these subunits can be used for studying on cell cytotoxicity and also as a vector for antigen presentation in immunotherapeutic approaches. characterisation of gram-positive anaerobic cocci by biochemical tests and partial s rrna sequencing a. bryk, a. kanervo-nordstrom, m. hyvonen, e. kononen (helsinki, fi) objective: gram-positive anaerobic cocci, which are common findings in various infections, are difficult to identify in clinical microbiology laboratories, where identification is based only on few phenotypic tests. in recent years, this group of organisms (traditionally known as peptostreptococci) has encountered several taxonomic changes. the aim of the present study was to compare the characterization made by a selection of key phenotypic tests to that by partial sequencing of the s rrna gene. methods: fifty-nine clinical isolates sent to our laboratory as gram-positive anaerobic cocci were examined for their colony and cell morphologies and biochemically characterized using spot catalase and indole reaction, enzyme reactions by individual diagnostic tablets (rosco), sodium polyanethol sulphate susceptibility, glucose fermentation, and determination of metabolic end products. in addition, commercial identification test kit (rapid id a) patterns were performed. the sequencing of the s rrna gene of the clinical isolates and reference strains comprised of about bp, and the sequences obtained were compared to those in genbank database by using the multisequence advanced blast comparison software from the national center of biotechnology information. results: the biochemical characteristics of the isolates were consistent with those of peptostreptococcus anaerobius (n = ), peptostreptococcus (micromonas) micros (n = ), finegoldia magna (n = ), peptoniphilus asaccharolyticus (n = ), peptoniphilus sp. (n = ) and anaerococcus sp. (n = ), whereas isolates remained as unidentified gram-positive anaerobic cocci. biochemical identification correlated with that obtained by partial s rrna sequencing in / ( %) isolates at genus level and in / ( %) isolates at species level. the agreement of the biochemical and sequence-based identification was % for p. micros and f. magna. of isolates biochemically identified as p. asaccharolyticus, isolates were identified as peptoniphilus harei and remained as peptoniphilus sp. by sequencing. according to the sequence data, the unidentified isolates were peptoniphilus ivorii. conclusion: most isolates from human infections proved to be f. magna. a relatively good agreement of identification was obtained using biochemical testing and partial s rrna sequencing. objectives: molecular methods for identification of infectious agents in patients with clinical infectious disease are increasingly being used. especially in cases where antibiotics have been given prior to sampling or when fastidious bacteria difficult to grow are the aaetiology of the infection. infectious arthritis is a serious disease where identification of the etiological agent is mandatory for optimal antibiotic treatment as well as indication of the primary focus if not the joint it self. methods: in the present prospective study, synovial fluids taken from patients in elucidation of affected joints and sent to a clinical microbiological laboratory in the copenhagen area, denmark, were examined by conventional (culture, phenotypic tests) and molecular methods (pcr/sequencing of s ribosomal genes). conventional methods included gramstaining and microscopy, aerobic and anaerobic culture and identification. pcr/sequencing included dna extraction, pcr assay which produced a bp fragment of s rdna, and sequencing of both dna strands of the amplicons. sequencing data were edited and a blast search in the ncbi database was done. results: overall a microorganism was identified in of the synovial fluids ( . %). in synovial fluids from nine patients bacteria were identified by either methods [staphylococcus aureus (n = ), streptococcus pneumoniae (n = ), streptococcus dysgalactiae (n = ), citrobacter freundii (n = )]. six synovial fluids were only culture positive; in four of those six specimens coagulase negative staphylococci were isolated. in three of the synovial fluids a microorganism was identified by s pcr only. in two synovial fluids s pcr identified only one microorganism, whereas culturing resulted in two isolates. conclusion: the present study indicates a significant contribution by molecular methods (pcr/sequencing of s ribosomal genes) in recognizing and identification of microorganisms from foci normally considered sterile like synovial fluids. continued suspicion of infected arthritis despite of negative cultures should result in use of molecular diagnostics. direct detection of cardiobacterium hominis by broad-range s rrna pcr and sequencing in the serum of a patient with infective endocarditis e. malli, d. klapsa, a. vasdeki, m. morava, m. pitsitaki, e. petinaki, a. maniatis (larissa, gr) objectives: to describe the detection of cardiobacterium hominis directly in the serum of a patient with infective endocarditis, by employment of broad-range s rrna pcr followed by sequencing. methods: a series of blood cultures were taken from the patient before starting empirical treatment. in addition, ml whole blood was collected in rubber sealed pyrogen-free tubes for direct detection of bacterial dna. bacterial dna was detected by a broad range pcr reaction and sequencing process allowed identification of bacteria species. results: cardiobacterium hominis was identified as the causative agent of infective endocarditis, on two days after the serum collection. blood cultures, simultaneously obtained with the serum sample, remained negative after days of routine incubation; however, after a prolonged incubation of twelve days a gram negative bacterium was isolated from the aerobic bottles, that was identified as c. hominis species, by the usual phenotypic studies (catalase, oxidase reaction, indole, nitrate, etc) which are time-consuming. conclusions: to our knowledge this is the first report of direct detection of c. hominis in the serum using molecular methods, emphasizing the need for the establishment of such methods especially for infections caused by fastidious organisms. identification of dangerous bacterial pathogens by s ribosomal rna gene sequence analysis w. ruppitsch, a. stoeger, a. indra, d. schmid, k. grif, c. schabereiter-gurtner, a. hirschl, f. allerberger (vienna, at) to assess the usefulness of partial s rrna sequence analysis for identification of dangerous bacterial pathogens, a total of isolates comprising bacillus anthracis, brucella melitensis, biovars melitensis, suis, abortus and bovis, burkholderia mallei, burkholderia pseudomallei, francisella tularensis, yersinia pestis, and genus-related and unrelated control strains were sequenced and analysed using the genbank database (blast . . , national institute of health, u.s.a), the microseq database (version . . and v . , applied biosystems, foster city, u.s.a.) , the ribosomal database project-ii database (rdp-ii, release , update , michigan state university, u.s.a), and the ribosomal differentiation of medical microorganisms database (ridom, university of wuerzburg, germany). on genus level all isolates were identified using genbank, rdp-ii, and microseq v . . the older microseq . . database identified % of the tested samples correctly on genus level. the ridom database did not include sequence data of the tested species even on genus level, the ridom database none (''there seems to be, at least currently, no close relative available''). genbank and rdp-ii identified all dangerous pathogens correctly. the microseq v . database identified four of the six species of dangerous pathogens. on species level none of the dangerous pathogens was correctly identified using microseq . . or ridom. as previously noted by various other authors, the most important reason for failure of databases in identifying a bacterium is a lack of the s rrna gene sequence of the particular bacterium in the database rather than misidentification because of poor sequence quality. one must also be aware that the following bacterial species or subspecies have the same s rrna gene sequence, which makes differentiation by sequence analysis impossible: b. anthracis and b. cereus, y. pestis and y. pseudotuberculosis, all brucella subspecies, and francisella tularensis ssp. holarctica and mediasiatica. in addition to s rrna gene analysis complementary methods are essential to discriminate between these bacteria on species or subspecies level. identification of nontuberculous mycobacteria by sequence analysis of the s ribosomal rna, the heat-shock protein and the rna polymerase beta-subunit genes s. shin, j.h. yoon, e.c. kim (seoul, kr) objectives: the diagnosis of diseases caused by nontuberculous mycobacteria (ntm) is difficult because ntm are prevalent in the environment such as soil and water and because they have fastidious properties. in this study, we investigated the distribution pattern of ntm clinical isolates and the identification to the species level. methods: among the presumptive ntm clinical isolates, cultured in a third referral hospital from -jan- to -jan- in seoul, south korea, which were negative by probe hybridization method for mycobacterium tuberculosis complex, we selected those of more than colonies or those cultured more than twice in a same patient. a total of isolates were studied for the distribution of ntm including isolates recruited for species identification by direct sequencing of s rrna, hsp and rpob gene segments. ( . %) were also identified in the presumptive ntm isolates. the identification rate by sequencing of s rrna, rpob, and hsp were %, % and %, respectively. hsp or rpob gene was more efficient than s rrna in identification of ntm by sequencing. conclusions: some ntm are considered to be the causative organisms of clinical diseases even in the countries with intermediate burden of tuberculosis, so accurate identification method by direct sequencing can be adapted to clinical laboratories. evaluation of the genotype mtbdr assay for the simultaneous detection of resistance to rifampicin and isoniazid of mycobacterium tuberculosis clinical strains f. brossier, c. truffot-pernot, n. veziris, v. jarlier, w. sougakoff (paris, fr) objectives: the rapid determination of drug resistance in mycobacterium tuberculosis is an important challenge to ensure a rapid effective chemotherapy. the genotype mtbdr test is a commercially available dna strip assay enabling the molecular genetic identification of the m. tuberculosis complex and its resistance to rifampicin (rif-r) and isoniazid (inh-r) by detecting the most commonly found mutations in the genes rpob (asp val, his tyr, his asp, ser leu) and katg (ser thr). here, we report the evaluation of the genotype mtbdr assay from a set of clinical isolates of m. tuberculosis. methods: clinical isolates were collected in france over a years period ( ) ( ) and were included in the study: were rif-r, were inh-r (of which were also rif-r) and were susceptible to both drugs. the susceptibility tests were carried out by the standard proportion method. the mutations involved in rif-r and inh-r in rpob, katg, inha and his promoter region, were characterized by dna sequencing. results: the genotype mtbdr assay identified % of the rif-r strains harbouring mutations in the rpob gene, of which ( %) showed a ser leu mutation and ( %) a his asp or tyr mutation. of the inh-r strains ( %) harboured a ser thr mutation in katg, all identified by the genotype mtbdr assay. of this strains displayed a high level of inh-r. among the other inh-r strains, showed a katg mutation at the level of the regions, which was different from ser thr ( of which showing a low level of inh-r), and one harboured a deletion in katg (with a high level of inh-r). these mutations were also detected by the strip. finally, among the remaining inh-r strains not detected by the mtbdr assay, were characterized by a mutation in position - of the promoter region for the maba-inha regulon ( with a low level of inh-r), by a ser ala mutation in inha (all with a low level of resistance) and by other mutations. conclusions: the mtbdr assay, which can readily be included in a routine laboratory workflow, identified % and % of the strains resistant to rif and inh, respectively. interestingly, of the inh-r strains showing a high level of resistance ( %), but only of the inh-r strains with a low level of resistance ( %), were detected by the mtbdr assay, indicating that complementary tests are necessary for detection of the m. tuberculosis strains having a low level of resistance to inh. variation in the streptococcal s rdna detected by pyrosequencing m. haanperä, p. huovinen, j. jalava (turku, fi) originally the aim of this study was to identify alpha-haemolytic streptococcal isolates to the species level by pyrosequencing the v and v regions of the s rdna and comparing the results to the sequences of type strains that have been determined earlier. however, the isolates could not be unambiguously identified due to sequence variations detected in the alpha-haemolytic isolates. materials and methods: invasive s. pneumoniae isolates (n = ), alpha-haemolytic streptococcal blood culture isolates (n = ) and alpha-haemolytic streptococcal isolates from the normal pharyngeal microbiota (n = ) of six elderly persons were analysed by pyrosequencing the v and v regions. results: varying degree of genetic variation was found in different types of streptococcal isolates. in the pneumococcal isolates, no sequence variation was detected as all the isolates contained the sequence specific for s. pneumoniae in both regions. also the sequences of the alpha-haemolytic blood culture isolates were well in agreement with the sequences of the streptococcal type strains. however, most of these isolates could not be unambiguously identified, as they contained sequences belonging to different species in the v and v region. consequently, only five of the isolates could be unequivocally identified as s. gallolyticus (n = ), s. anginosus (n = ), s. mitis (n = ) and s. sanguinis (n = ). the commensal streptococci contained numerous sequences to which an identical type sequence could not be found. also sequences identical to type strains were found; but similarly to the blood culture isolates, the results enabled the identification of only four isolates: s. mitis (n = ), s. parasanguinis (n = ), and s. salivarius or s. vestibularis (n = ). moreover, the pyrograms of three blood culture isolates and ten pharyngeal isolates indicated heterogeneous s rdna alleles. one such pyrogram of the v region is presented in the figure. interestingly, four of the eight different nonheterogeneous v and v sequence combinations of the blood culture isolates were also present among the pharyngeal isolates. the results of this study indicate that the variation in commensal streptococci is greater than that of the streptococcal type strains and pathogenic isolates. the presence of identical sequence combinations among the blood culture and pharyngeal isolates supports the assumption that potentially pathogenic isolates are present in the normal microbiota. evaluation of partial s rrna gene sequencing for identification of clinical isolates of nocardia species m. marín, m. sánchez, m. del rosal, e. cercenado, p. martín-rabadán, e. bouza (madrid, es) new species of nocardia are being described. conventional identification based on biochemical characteristics and pcrrestriction enzyme analysis is frequently unable to distinguish them. partial sequencing of s rrna gene has proven useful in the identification of bacteria. objective: to evaluate the utility of 'end s rrna gene pcr and sequencing in the identification of clinical isolates of nocardia sp. compared with conventional methods and pcr-rflp of hsp . methods: clinical isolates of nocardia sp. were characterized by biochemical reactions and disk diffusion susceptibility testing. molecular identification was performed by hsp pcr-rflp and pcr of 'end of s rrna gene followed by sequencing. the sequences obtained were compared with those included in genebank. only alignments with similarities higher than % were considered. a comparison of sequences of our nocardia isolates with those deposited in genebank and well characterized phenotypically was performed using clustal x . software. results: distribution of species after pcr-rflp of hsp was n. asteroides vi ( ), n. farcinica ( ), n. nova ( ), n. asteroides i ( ), n. otitidiscaviarum ( ) and n. asteroides iv ( ) . partial sequence analysis of s rrna revealed a great heterogeneity between the isolates of n. asteroides vi, as follows: n. cyriacigeorgica ( isolates), n. abscessus ( isolates) and n. carnea ( isolate). for isolates, no genebank sequence was found with more than % similarity. all n. farcinica isolates had the same sequence and showed % similarity with those deposited in genebank. n. nova, n. asteroides i and n. otitidiscaviarum also showed sequence heterogeneity. three n. nova isolates matched with the recently described n. veterana and with n. nova. n. asteroides i isolates were identified as n. abscessus ( ) and n. beijingensis ( ) . all n. otitidiscaviarum were identified properly. the isolate of n. asteroides iv was identified as n. transvalensis. conclusions: sequencing of 'end s rrna gene is a useful and rapid molecular tool for the identification of nocardia clinical isolates. this method could provide more accurate results than the conventional ones used routinely in our laboratory. sequence analysis of the 'end s rrna has enabled us to recognize great diversity and new species among our nocardia isolates. several species would have gone unnoticed using non-sequencing-based methods. antibacterial susceptibility studies-iii p anaerobic bacteraemia due to fusobacterium necrophorum and clostiridium cadaveris: a case report m. panopoulou, e. alepopoulou, e. chrisafidou, a. tsaroucha, c. simopoulos, s. kartali (alexandroupolis, gr) introduction: anaerobic bacteremia is uncommon accounting . - % of bacteremias and it is associated with a high mortality rate, which is strongly and independently associated with underlying liver disease. case report: a year-old man presented to our hospital with a -day fever and rigor. he had a history of cancer of the extrahepatic biliary tree, which was found incidentally during an operation for the treatment of echinococcal cyst of the liver. physical examination reveals high fever ( c) and tachycardia. blood tests showed the following results: hb: . gr/dl, wbc: . /ul, plt: . /ul, tprot: . each colony type subcultured to blood agar plates and incubated aerobically and anaerobically (aerotolerance test). after hours of incubation the two organisms grew only in anaerobic conditions. they identified by the api a system (bio-merieux-france) as fusobacterium necrophorum and clostiridium cadaveris. the patient's treatment started with metronidazole, amikacin and ceftriaxone and followed by metronidazole and imipenem. he was discharged after weeks in a good condition. conclusions: although anaerobic bacteremia is rare, there is value in performing separate anaerobic blood cultures. the early recognition of anaerobic bacteremia and administration of the appropriate antimicrobial therapy play a major role in preventing mortality especially in patients with underlying disease. fluoroquinolone resistance among enterobacteriaceae strains isolated from urinary tract infections v. skandami-epitropaki, p. fostira, a. tsiringa, a. xanthaki, k. zampitha, m. toutouza (athens, gr) objectives: to study the frequency and antibiotic susceptibility of quinolone resistant bacterial stains isolated from patients with community-aquired bacteriuria and compare it with urinary pathogens from hospitalized patients. methods: during a -month period (october -october a total of bacterial strains were isolated out of urine samples submitted for culture in our hospital laboratory from the community and from hospitalized patients with urinary tract infection symptoms. cultures and bacterial identification were obtained by conventional methods. antibiotic susceptibility testing was done by kirby-bauer disk diffusion method according nccls criteria. results: of the bactrial strains studied (escherichia coli , klebsiella pneumoniae , proteus mirabilis ), . % of them were found to be quinolone resistant. the percentage of quinolone resistance was . % for hospitalized patients (hp) and . % for community patients (cp). the quinolone resistance for e. coli was . % ( . % for hp and . % for cp), for k. pneumoniae . % ( . % for hp and . % for cp) and for p. mirabilis . % ( . % for hp, . % for cp). susceptibility pattern of the quinolone resistant isolates to other antimicrobial agents was for hospitalized patients and community patients respectively as following: for e. coli ampicillin (am) %- . %, amoxicillinclavulanate (amc) . %- . %, piperacillin-tazobactam (tzp) . %- . %, cefuroxime (cxm) . %- . %, trimethoprimsulfamethoxazole (sxt) . %- . %, ceftazidime (caz) . %- . %, cefepime (fep) . %- . %, gentamicin (gm) . %- . %. for k. pneumoniae am %- %, amc %- %, tzp . %- %, cxm . %- %, sxt . %- %, caz . %- %, fep . %- %, gm . %- %. for p. mirabilis am . %- %, amc . %- %, tzp . %- %, cxm %- %, sxt . %- %, caz . %- %, fep %- %, gm . %- %. seven strains of k. pneumoniae ( . %) were carbapenem resistant and metallo-beta lactamase producing. conclusions: high resistance rates to fluoroquinolones were observed in uropathogen bacteria isolated not only from hospitalized patients but also from patients with communityacquired urinary tract infections in greece. increasing resistance rates to the rest antibiotic agents make the treatment of urinary tract infections a very difficult problem. susceptibility of pseudomonas aeruginosa isolated from the mystic programme to the carbapenems: meropenem and imipenem p.j. turner (macclesfield, uk) objectives: the meropenem yearly susceptibility test information collection programme (mystic) was initiated in in order to track the susceptibility of organisms in centres that were prescribing meropenem. this poster seeks to examine the susceptibility of pseudomonas aeruginosa isolates over this period to the carbapenems; meropenem and imipenem and, in particular, records the susceptibility of imipenem-resistant isolates to meropenem and vice versa. methods: pseudomonas aeruginosa isolates were speciated by the methods in current use at the participating centres. minimum inhibitory concentrations of meropenem and imipenem were determined using reference methods described by clsi. results: a total of isolates of pseudomonas aeruginosa have been tested globally, of these . % were susceptible to meropenem at the breakpoint of < mg/l and . % to imipenem. globally, susceptibility to the two carbapenems has remained stable over the period - , however when imipenem-resistant isolates were examined (n = ) . % proved to be susceptible to meropenem, conversely of the meropenem-resistant isolates only . % proved to be susceptible to imipenem. a similar pattern was seen when isolates were separated into global regions:usa imipenem-resistant isolates, . % susceptible to meropenemusa meropenem- results: bacteroides fragilis group (bafg) accounted for % of the isolates, fusobacterium spp. for %, other gram negative bacilli (ognb) for %, clostridia (clos) for %, nonsporeforming gram-positive bacilli (nsfgpb) for % and cocci for %. beta-lactamases (bl) were detected in % of isolates. most bl + strains belonged to bafg ( %) and ognb ( %). at nccls-recommended breakpoints, more than % of isolates were susceptible to tzp, mtz, chl and mem, % to amc but only %, %, % and % to fox, ctt, cli and pen respectively. no nccls-breakpoints for anaerobes are available for mxf, lzd and tig. mic and mic for mxf were and mg/l, for lzd and mg/l and for tig . - mg/l. in comparison with similar surveys conducted in and - susceptibility of bafg to clindamycin decreased from % in , to % in - and % in in bafg % of b. fragilis and % of non-b. fragilis were susceptible to amc in this study; in - susceptibility in these groups was % and % and in - % and % respectively. all isolates, except bafg and clos, were susceptible to mem. % of the isolates were susceptible to chl. susceptibility to mtz remains stable and is high in all groups except nsfgpb where mtz is active on merely % of the isolates. conclusions: tzp, mem and mtz remain very potent antimicrobial agents in the treatment of anaerobic infections. although still rare, resistant organisms were detected to each of them. therefore susceptibility testing of anaerobic isolates is indicated in severe infections to confirm appropriateness of antimicrobial therapy. further monitoring of background susceptibility is necessary to guide empiric treatment. comparative in vitro activity of levofloxacin against escherichia coli isolated from acute pyelonephritis in france in c.j. soussy, c. lascols, c. dib-smahi and the multicenter group study. objectives: the objective of this study was to evaluate the in vitro activity of levofloxacin (lvx) comparatively to other antibiotics against escherichia coli strains isolated from acute pyelonephritis in women consulting emerging rooms by french hospitals in . methods: mics of lvx, ofloxacin (ofx), ciprofloxacin (cip), nalidixic acid (nal), amoxicillin-clavulanic acid (amc), ceftriaxone (cro), cefixime (cfm), amikacin (an), gentamicin (gm) and cotrimoxazole (sxt) were determined by agar dilution according to the eucast breakpoints approved by recommendations of the comité de l'antibiogramme de la société française de microbiologie. quality control was performed with e. coli strain atcc . results: a total of strains were collected. . % of strains were isolated from urinary samples, . % from blood culture and . % from the two specimens. mics / (mg/l), the range of mics and the percentage of susceptibility (%) are presented in the following table: concerning the fluoroquinolones, mics / of lvx were one/two dilution lower than those of ofx and two/one dilution higher than those of cip. for the other antibiotics, a higher percentage of susceptibility was observed with cro and an, when a lower percentage of susceptibility was observed with amc and sxt. conclusions: levofloxacin exhibited good in vitro activity against e. coli strains isolated from acute pyelonephritis with . % of susceptible strains. in vitro activity of double and triple combinations of colistin, imipenem, rifampicin and linezolid against epidemic strains of multidrug-resistant acinetobacter baumannii producing oxa carbapenamases d.w. wareham, d.c. bean (london, uk) objectives: a. baumannii has emerged as an important cause of nosocomial infection in critically ill patients worldwide. in the uk three strains in particular exhibiting multi-drug resistance and producing oxa carbapenamases have been responsible for ongoing outbreaks. treatment options for infection with these organisms are limited as only colistin and tigecycline retaining significant activity in vitro. animal models and in vitro studies using other multi-resistant strains suggest that drugs in combination with colistin may be effective. we assessed the activity of colistin in combinations including imipenem, rifampicin and linezolid against epidemic strains from a recent uk outbreak. methods: isolates of a. baumannii exhibiting resistance to carbapenems were recovered from patients at barts and the london nhs. isolates were referred to the health protection agency and confirmed as belonging to clones producing oxa carbapenemases. activities of polymyxin, imipenem, rifampicin and linezolid alone and in double and triple combinations were determined using standard chequerboard assays with increasing concentrations of drug on the x axis, drug on the y axis and drug three in multiple replicate plates. after incubation at hours wells were examined for growth and mic's determined for each combination. synergy between agents was defined as a fixed inhibitory concentration index (fici) of < . . results: the isolates tested belonged to the oxa- clone , oxa- clone and the south east clone, as confired by the hpa. colistin was the most active agent alone with mics from - mg/l. imipenem mic's varied from - mg/l. the most active combinations were colistin plus rifampicin (fici = . ) and colistin, rifampicin and imipenem (fici = . ). synergy was not seen with colistin in combination with imipenem alone. linezolid in combination with colistin (fici = . ), or imipenem (fici = . ) was synergistic but at therapeutically unobtainable linezolid concentrations ( mg/l). conclusion: multidrug resistant strains of a. baumannii from the uk producing oxa carbapenemases remain susceptible to polymyxin in vitro. polymyxin exerts its effect on the bacterial cell wall; theoretically assisting other antibiotics to reach their respective targets, and seems a logical choice for inclusion in combination therapy. we have shown that rifampicin is synergistic with polymyxin against these isolates in vitro and may be effective in treating severe a. baumannii infections in man. a comparative in vitro evaluation of resistance development after exposure to teicoplanin, vancomycin, linezolid and quinupristin/ dalfopristin in staphylococcus spp. and enterococcus spp. mssa, mrse, msse, e. faecium and e. faecalis strains was determined on agar plates containing each antibiotic at clsi resistance breakpoints and at peak blood concentrations. after incubation at °c for h colonies were counted and compared to the inoculum to calculate frequency of mutation. colonies grown in plates containing antibiotics were sampled for determination of mic values. results: frequency of mutation was less than - for all the tested antibiotics at peak blood concentrations. same results were obtained when breakpoint concentrations for each drug were used. conclusion: this one-step in vitro study demonstrated the ability of teicoplanin, vancomycin, linezolid and quinupristin/ dalfopristin to prevent growth of resistant mutants of staphylococci and enterococci, thus suggesting no occurrence of mutational events leading to resistance when bacteria are exposed to blood concentrations of these drugs. in order to establish the development of resistance after in vitro serial exposure to the same antibiotics simulating different in vivo concentrations, further studies are needed and are now in progress (multi step induction of resistance). in vitro activity of antimicrobial agents against legionella obtained from hotel water systems in turkey objectives: the aim of this study was to evaluate the in vitro activity of colistin against endemic pan-resistant acinetobacter baumannii (including resistance to imipenem) isolated during a year period in a university hospital. methods: imipenem-resistant acinetobacter spp. isolates were collected between january and october , from a variety of clinical specimens of different patients attending distinct wards in a university teaching hospital. isolates were identified by api gn and by sequencing the s rrna gene. mics of colistin were determined by agar dilution method, according to nccls susceptible breakpoint (£ mg/l). pfge (apai restriction enzyme) was performed. results: of a. baumannii isolates ( %) were susceptible to colistin. colistin resistance (mic ‡ mg/l) was observed in isolates ( isolates with a mic of ‡ mg/l and isolates with a mic of mg/l) recovered from different patients in distinct wards. among these imipenem-and colistin-resistant isolates, distinct pfge patterns were identified (clones a, b, and c). resistance to almost all beta-lactams (including carbapenems) and variable susceptibility to aztreonam, amikacin and tobramycin was a common feature of clone a. isolates belonging to clone b showed resistance to imipenem, amoxicillin and its association with clavulanic acid (amc), ureidopenicillins and their associations; susceptibility to ceftazidime; and variable behaviour to meropenem, cefepime, cefpirome and aztreonam. the susceptibility profile to aminoglycosides was variable, differing from clone a in its susceptibility to netilmicin and minocycline. clone c was resistant to imipenem, amoxicillin, amc, piperacillin, piperacillin + tazobactam, ticarcillin and ticarcillin + clavulanic acid, but remained susceptible to meropenem, aztreonam, cefpirome, ceftazidime and cefepime. conclusion: only colistin, one of the few effective drugs available against multi-drug-resistant acinetobacter infections, showed in vitro activity against the majority of acinetobacter spp. strains isolated within the sampled hospital. the observed % a. baumannii resistance to the recently re-introduced colistin seems like the first chapter of a novel repeatedly told for several antibiotics. emergence of high-level gentamicin resistance in clinical enterococcal isolates of companion animals in portugal objectives: to characterize in vitro gentamicin susceptibility among enterococci causing infections in cats and dogs, in order to evaluate the impact of high-level gentamicin resistance in small animal therapeutics. methods: the samples were collected at the veterinary teaching hospital of the faculty of veterinary medicine and at veterinary private practices in the lisbon area. from january until november , a total of enterococci were isolated from dogs and cats with urinary tract infection (uti), otitis externa (oe) and pioderma. bbl crystal gram positive id system was used for identification at the species level. minimal inhibitory concentrations (mic) were determined by the microdilution method according to nccls ( ) . the bifuntional enzyme gene that confers high-level gentamicin resistance (hlgr) was detected using pcr ( ) . results: enterococcus faecalis was the predominant isolate (n = ), followed in frequency by enterococcus faecium (n = ). mic cumulative data analysis showed that mic values were lg/ ml and mic lg/ml. six ( %) hlgr clinical enterococcal isolates were detected, with mic ranges between - lg/ml. four of these enterococci were isolated from uti and from oe. four of the phenotypically high-level gentamicin resistant isolates carried the aac( ')-ie-aph( '')-ia gene. conclusions: the importance of enterococcal infection in small animal clinical samples has increased over the last years. mic cumulative data points out low-level gentamicin resistance among clinical enterococci isolates of veterinary origin and the emergence of high-level isolates, as previously detected ( ). this fact compromises cell-wall active agents (such as ampicillin or vancomicin) and aminoglicoside in vivo synergy. the aac ( ')-ieaph( '')-ia gene carriage is of concern because its expression confers resistance also to tobramicin, netilmicin, amikacin and kanamicin. our findings are of critical importance, as they may have a direct impact in therapeutic decision in the management of companion animal's infections by enterococci. furthermore, transfer of resistance genes and resistance strains between animals and owners/caretakers by direct contact is a concerning probability. references: ( ) results: interpretative criteria were used according to nccls .during the study period penicillin resistant strains of s. pneumoniae was noted as follows: % in sputum or ta, % in blood, %in csf,and % in others,against cefuroxim resistant strains: % in sputum or ta, % in blood, % in csf.regarding the susceptibility to ofx,penicillin resistant s. pneumoniae strains from sputum or ta revealed . %.the penicillin resistant strains coming from sputum or ta showed resistance as follows; % to em and % to sxt,against strains isolated from others: % to em and % to sxt.no resistant strain to va was found. conclusion: the percentage of the penicillin resistant s. pneumoniae isolates from the lower respiratory tract, middle ear fluid, eye fluid and sinus was markedly higher than that of the isolates from blood and csf. the most efficient drugs against penicillin resistant pneumococci were cefuroxim and ofloxacin. these results from romania also underline the previous observations regarding the higher emerging rates of resistance in s. pneumoniae worldwide. penicillin resistance in streptococcus agalactiae objectives: streptococcus agalactiae has become recognized as a cause of serious illness in newborns, pregnant women, and adults with chronic medical conditions. heavy colonization of the genital tract with streptococcus agalactiae also increases the risk that a woman will deliver a preterm low-birthweight infant. early-onset infections (occurring at < days of age) are associated with much lower fatality than when they were first described, and their incidence is finally decreasing as the use of preventive antibiotics during childbirth increases among women at risk. penicillin or ampicillin remains the drug of choice for intrapartum antibiotic prophylaxis for streptococcus agalactiae colonization in pregnant women. erythromycin and clindamycin are the drugs of choice for women with serious penicillin allergy who are colonized with streptococcus agalactiae. the objective of this study is to estimate the insorgence of penicillin resistance among streptococcus agalactiae. methods: all streptococcus agalactiae were tested against penicillin by agar dilution method according to clinical and laboratory standards institute (clsi); breakpoints for resistance were those recommended by the clsi. antimicrobial agents were obtained from their manufacture as laboratory grade powder. results and discussion: four hundred seven ( ) clinical isolated were analysed during . streptococcus agalactiae resulted resistant to penicillin in case; and about % resulted borderlines.the present findings indicate a probable evolution in s. agalactiae toward penicillin resistance this finding suggest the need a continuous national and international surveillance programs to provide timely data on the evolution of incidence of penicillin resistance in this pathogen. ciprofloxacin susceptibility of the most common isolates at bacterial conuctivitis conclusion: according to the average numerals we concluded that all the isolated strains are highly susceptible at ciprofloxacin. its application in the conuctivial saccus is especially important in curing the conuctivial infections with resistent strains like pseudomonas aeruginosa. we successfully cure the bacteria chronic conuctivitis with the adequately used therapy according to antibiogram. antimicrobial resistance patterns of acinetobacter baumannii in clinical isolates g.t. tsilika, v.p. pliatsika, m.t. tsivitanidou, d.s. sofianou (thessaloniki, gr) objectives: a. baumannii is a nosocomial pathogen, commonly isolated from critically ill and immunocompromised patients. the aim of the present study was to evaluate the antimicrobial resistance of a. baumannii strains isolated in a tertiary care hospital througout a three-year period. methods: a total of a. baumannii strains were selected from january to december .the specimens were obtained from inpatients hospitalized in intensive care unit (icu) and pediatric intensive care unit (picu) and other departments of our hospital.the identification and the antimicrobial susceptibility testing were performed using the vitek automated system(biomerieux,france conclusions: the emergance and rapid spread of multidrug resistant a. baumannii isolates are of a great concern worldwide.imipenem was one of the most potent agents for treatment of those infections caused by multiresistant strains.the increasing prevalence of imipenem resistance limits therapeutic options and leads to outbreaks of carbapenems resistant strains. tigecycline in vivo studies objectives: antibacterial agents disrupt the ecological balance of the normal human microflora. disturbances may lead to the emergence of antibiotic resistance and/or to infections by potentially pathogenic bacteria. tigecycline, a member of a new class of antibiotics (glycylcyclines), has been shown to have a potent expanded broad-spectrum activity against most grampositive and gram-negative aerobic and anaerobic bacteria. the aim of the study was to investigate the ecological effects of tigecycline on the normal oropharyngeal and intestinal microflora in healthy subjects. methods: thirteen ( ) white subjects ( women, men) aged to years, received mg of tigecycline in the morning on day as a -minute intravenous (iv) infusion, followed by mg doses of tigecycline given every hours as a -minute infusion for days. one ( ) subject was withdrawn on day because of an adverse event. serum, saliva, and faecal samples were collected before, during, and after administration for microbiologic cultivation and for assays of tigecycline. all new colonizing bacteria were tested for susceptibility (resistance > mg/l) during the investigation period. results: the serum concentrations on day , hours after dosing, were . to . mg/l (mean value . mg/l, median value . mg/l, and sd . mg/l). the faecal concentrations on day were . to . mg/kg (mean value . mg/kg, median value . mg/kg, and sd . mg/l). saliva concentrations were generally low, with highest mean value . mg/l, median value . mg/l, on day , hours after dosing. a minor effect on the oropharyngeal microflora was observed. the numbers of enterococci and escherichia coli in the intestinal microflora were reduced at day , while other enterobacteria and yeasts increased. there was a marked reduction of lactobacilli and bifidobacteria but no impact on bacteroides. no clostridium difficile strains were isolated. two ( ) klebsiella strains and enterobacter strains resistant to tigecycline were found. conclusion: tigecycline had a minor effect on the oropharyngeal microflora. tigecycline's effect on the intestinal microflora was due to its spectrum of antibacterial activity and intestinal concentrations. objectives: to examine and report the use of tigecycline (wyeth) in the treatment of multidrug resistant acinetobacter (mdra) culture positive sepsis in patients requiring mutiorgan support. methods: all patients were managed within the liver intensive care unit. physiological data was collected prospectively and entered onto a specialist database. patients received standard intensive care management; antibiotic and antifungal therapy administered as indicated by microbiological cultures. systemic inflammatory response (sirs) features initiated blood cultures (vascular lines and peripheral), drain fluid culture and broncoalveolar lavage (bal). screening swabs were undertaken weekly and samples sent for culture at laparotomy. mdra positive cultures from blood, bal, drain fluid or samples taken at laparotomy in the context of sirs resulted in the initiation of tigecycline treatment. results: patients received tigecycline treatment for mdra infections. the underlying disease states were necrotizing pancreatitis ( ), post hepatectomy ( ), polytrauma ( ), all with postive intra-abdominal cultures. acute and acute on chronic liver failure ( ), mdra +ive broncho-alveolar lavage ± blood cultures and post liver transplant patients (necrotising pancreatitis in one, with recurrent small bowel perforation and with retroperitoneal haemorrhage) all with positive blood cultures and in positive intra-abdominal tissue/clot. mean time from admission to treatment for mdra was days. mean duration of treatment was days (range - ). mean apache ii score at initiation of therapy was (range - ); / patients survived to intensive care discharge and / to hospital discharge. microbiological clearance of mdra was observed in / cases. in those who did not achieve microbiological clearance cause of death was intra-abdominal haemorrhage, recalcitrant organ failure with recurrent small bowel perforation and vasopressor resistant shock. in these patients one remained culture positive for intraabdominal sepsis despite full treatment (small bowel perforation x ). the drug was well tolerated with the only side effect being that of hypercalcaemia observed in / patients, mean corrected calcium . mmol/l, range . - . . in all cases this resolved on drug discontinuation. conclusion: tigecycline appears to be an efficacious agent in the treatment of deep seated mdra infections. objectives: nausea (n) and vomiting (v) have been reported with tigecycline, a new glycylcycline with expanded broad spectrum activity. exposure-response relationships and patient covariates predictive of the first n and v occurrence were evaluated in patients with complicated intra-abdominal infections (ciai). methods: data from patients from ciai trials (one phase and two phase ), receiving mg loading dose and mg every hours, were pooled for analysis. n and v (definitely, possibly, or probably related to tigecycline) reported from the start of infusion until hours after the last dose were included. individual exposure measures [auc - and cmax] were calculated using a previously developed population pk model. logistic regression was used to evaluate predictors of first n and v occurrence. covariates included age, weight, sex, region of treatment, and baseline n and v. results: the dataset included patients ( with pk). mean (sd) age and weight were ( ) years and ( ) kg. % of patients were men and %, %, and % were enrolled in north america, europe, and latin america, respectively. baseline nausea or vomiting was reported in % and %. overall, n and v occurred in % and % of patients receiving tigecycline, however most ( %; %) of first n and v events were mild in nature. women had more n and v ( %; %) than men ( %; %). n and v were lower in europe ( %; %) than in other regions. auc - and cmax were not predictive. the final nausea model included weight, sex, region, baseline nausea, and the interaction of weight/region as predictors of the first nausea occurrence (p = . , . , . , . , & . , respectively objective: because hospitalisation for community-acquired pneumonia (cap) is associated with substantial morbidity and health resource utilisation, we evaluated the predictors of prolonged hospital length of stay (los) and treatment duration. methods: we conducted a retrospective analysis of data from a double-blind, randomised, multicentre clinical study that compared the efficacy and safety of tigecycline with that of levofloxacin in the treatment of patients with cap requiring hospitalisation. patients were stratified by the fine pneumonia severity index and randomly assigned to receive tigecycline or levofloxacin via iv administration for at least days. treatment duration and hospital discharge were based on physician assessment of signs and symptoms of infection and patient condition. we used cox proportional hazards modelling with stepwise selection to identify statistically significant predictors (p < . ) of treatment duration and hospital los. results: among patients with cap in the clinical intent-totreat population with complete hospitalisation data, mean age was . years (range - ) and . % of patients were aged ‡ years. diabetes ( . %), chronic obstructive pulmonary disease ( . %), and congestive heart failure ( . %) were leading co-morbidities. about . % of patients were smokers and . % were characterised by alcohol abuse. median fine pneumonia severity index score was ; . % of patients had a score > . . there were no significant differences between the groups in treatment duration or los. conclusions: tigecycline, a first-in-class glycylcycline, was associated with treatment duration and los similar to that of levofloxacin, adjusting for several identified risk factors. tigecycline effective in treating patients with intra-abdominal or skin/skin structure infections who have bacteraemia e.j. ellis-grosse, r. maroko (collegeville, us) objectives: the treatment of bacteraemia, which is a potentially fatal complication of infections originating at other body sites, is complicated by increasing resistance. tigecycline, a first-in-class glycylcycline, has an expanded spectrum of activity against gram-positive, gram-negative, anaerobic, and atypical bacteria including resistant strains. tigecycline is safe and effective in treating complicated skin and skin structure (csssi) and intraabdominal infections (ciai). this analysis examines tigecycline clinical trial experience in patients with ciai or csssi who had bacteraemia (presence of bacteria in blood) at baseline. objectives: treatment of complicated intra-abdominal infections (ciai) is challenging due to diverse bacteriology and bacterial resistance. the efficacy and safety of tigecycline (tgc), a first-in-class glycylcycline approved in mexico, brazil, peru, colombia and usa for treating ciai and complicated skin and skin structure infections, was compared with imipenem/cilastatin (imi/cis) in adult hospitalised patients with ciai in two double-blind, phase multinational trials. this analysis evaluated tgc efficacy and safety in the european region of the integrated results of these two trials. methods: one study was conducted in centres ( countries) and the other study was conducted in centres ( countries). patients were stratified by disease severity (apache ii score £ vs > but £ ), and randomly assigned to iv tgc ( mg loading, then mg q h) or iv imi/cis ( / mg q h) for - days. clinical response at test-of-cure (toc, - days after therapy) for microbiological evaluable (me) and microbiological modified intent-to-treat (m-mitt) were co-primary efficacy endpoints where cure/failure responses were determined. safety was assessed by physical examination, laboratory results, and adverse event (ae) reporting. results: in the european analysis, patients were mitt (received ‡ dose), m-mitt ( tgc, imi/cis) and me ( tgc, imi/cis). treatment groups were balanced with respect to demographics. patients were mostly white ( . %) men ( %) with a mean age of years. for me, clinical cure rates at toc were . % ( / ) for tgc vs . % ( / ) for imi/cis ( % ci = ) . , . ; test for non-inferiority p < . ). clinical cure rates for m-mitt were . % ( / ) for tgc vs . % ( / ) for imi/cis ( % ci = ) . , . ; test for non-inferiority p < . ). most commonly reported treatment emergent aes (teaes, mitt) for tgc and imi/cis were nausea ( . % and . %, p = . ) and vomiting ( . % and . %, p = . ). the imi/cis group had significantly higher teaes of fever ( . % imi/cis vs . % tgc, p = . ), hyperglycaemia ( . % imi/cis vs tgc, p = . ) and dyspnoea ( . % imi/cis vs . % tgc, p = . ) where tgc had significantly higher amylase increase ( . % tgc vs . % imi/cis, p = . ) and bun increase ( . % tgc vs imi/cis, p = . ). conclusions: similar to the overall integrated analysis of the two phase trails, in the european analysis, tgc was safe and effective in the treatment of hospitalised patients with ciai in comparison with imi/cis. tigecycline is safe and effective in the treatment of complicated skin and skin structure infections: european experience of two double-blind phase comparison studies with vancomycin/aztreonam r. maroko, n. dartois, d. sarkozy, j. goodrich, e.j. ellis-grosse on behalf of the tigecycline and study groups objectives: tigecycline (tgc) a first-in-class expanded spectrum glycylcycline, has been approved in mexico, brazil, peru, colombia and usa for treating complicated skin and skin structure infections (csssi) and complicated intraabdominal infections. two phase , randomised, double-blind studies were conducted in hospitalised men and women with csssi to determine tgc safety and efficacy compared with vancomycin/aztreonam (v/a). the objective of this analysis was to evaluate the efficacy and safety seen in the european population of the integrated analysis of these phase trials. methods: one study was conducted in centres in countries while the other study was conducted in centres in countries. patients were randomly assigned ( : ) to receive either tgc ( mg, followed by mg iv twice daily) or vancomycin ( g iv twice daily) plus aztreonam ( g iv twice daily) for up to days. clinical response at test-of-cure (toc, - days after therapy) for clinically evaluable (ce) and clinical modified intent-to-treat (c-mitt) populations were coprimary efficacy endpoints in which cure/failure responses were determined. secondary objectives included determination of in vitro susceptibility to tgc of a range of bacteria that cause csssi and microbiological efficacy. safety was assessed by physical examination, laboratory results, and adverse event (ae) reporting. results: in the european analysis, patients comprise mitt (received ‡ dose of study drug), comprised ce ( tgc, v/a/cis) and comprised c-mitt ( tgc, v/a/ cis). treatment groups were balanced with respect to demographics. patients were mostly white ( . %) men ( . %) with a mean age of years. in the european region, clinical responses to tgc and v/a at test-of-cure were similar: c-mitt, . % ( / ) versus . % ( / ), difference tgc-v/a was - . % ( % ci - . , . ). similar results were noted in the ce population with tgc curing . % ( / ) and v/a curing . % ( / ), difference tgc-v/a was - . % ( % ci - . , . ).most commonly reported treatment emergent aes (teaes, mitt) for tgc and v/a were nausea ( . % and . %, p < . ) and vomiting ( . % and . %, p = . ). the v/a group had significantly higher teaes of sgpt increase ( . % v/a vs . % tgc, p = . ) and rash ( . % v/a vs tgc, p = . ). conclusion: in the european analysis of the integrated phase worldwide clinical studies, tgc monotherapy is as safe and efficacious as the combination of v/a in the treatment of patients with csssi. safety and tolerability of tigecycline r. maroko, n. dartois, g. rose, e.j. ellis-grosse (collegeville, us; paris, fr) objectives: tigecycline (tgc), a glycylcycline, is a first-in-class, extended, broad-spectrum iv antibiotic that has demonstrated clinical activity in patients with complicated intra-abdominal infections (ciai) and complicated skin and skin-structure infections (csssi). the safety of tigecycline was evaluated in four phase iii trials. methods: a total of hospitalized patients from these trials were pooled and evaluable for safety analysis. in the ciai trial, patients received tgc mg q hrs (following a -mg loading dose) or imipenem mg and cilastin mg q hrs. those in the csssi study were treated with either tgc (same dose/schedule) or vancomycin gm with or without aztreonam gm q hrs. results: the most frequently reported adverse events (aes) in both tgc-treated groups were nausea (n) and vomiting (v). the incidence of n was . % while v was approximately . %; these were generally mild to moderate in severity. infection-related serious aes were slightly more frequent with tgc versus comparators ( . % vs . %). discontinuations due to treatment-emergent aes (including n/v) occurred at similar rates with tgc and comparators ( . % vs . %). six patients ( . %) treated with tgc presented with intestinal perforations and developed sepsis/septic shock compared with ( . %) for imipenem/cilastatin, with higher baseline apache ii scores in the tgc group; the relationship to treatment could not be determined. in the overall efficacy analysis, subjects with ''perforation of the intestines'' were balanced between the two groups, and overall efficacy was not statistically different. no clinically significant renal, hepatic, cardiac (qtc), bone marrow, or cns toxicities were noted with tgc. conclusion: tgc appears to be safe and tolerable for patients with ciai and csssi. n/v were generally mild to moderate in severity, self-limiting, and did not result in increased overall drug discontinuation. there did not appear to be clinically significant renal, hepatic, cardiac, bone marrow, or neurological toxicities related to tgc treatment. all-cause mortality rates did not statistically differ between those treated with tgc and the comparators. its demonstrated efficacy and favourable toxicity profile make tgc a good monotherapy option for selected serious infections. tigecycline as effective as imipenem/cilastatin in the treatment of complicated intra-abdominal infections: experience in india objective: due to diverse bacteriology and bacterial resistance, treatment of complicated intra-abdominal infections (ciai) is a challenge. in a double-blind, phase , multinational trial, the efficacy of tigecycline, a first-in-class glycylcycline, was compared with imipenem/cilastatin (imi/cis) in hospitalised patients with ciai. this subanalysis evaluated tigecycline safety and efficacy from investigational sites in india. methods: patients were stratified by disease severity (apache ii score £ vs > but < ), and randomly assigned to iv tigecycline ( mg loading, mg q h) or iv imi/cis adjusted for body weight ( / mg q h for ‡ kg) for - days. clinical response at test-of-cure (toc, - days after therapy) for microbiological evaluable (me) and microbiological modified intent-to-treat (m-mitt) populations were co-primary efficacy endpoints where cure/failure responses were determined. safety evaluations included vital signs, laboratory tests and record of adverse events (aes). results: in india, patients received at least dose (mitt, tigecycline, imi/cis), patients were clinically evaluable (ce), were me, were m-mitt. treatment groups were balanced with respect to demographic/baseline medical characteristics. primary diagnoses (mitt) were complicated appendicitis ( %), gastric/duodenal perforation ( %), perforation of intestine ( %), cholecystitis ( %), peritonitis ( %), and intraabdominal abscess ( %). cure rates at toc in me in india were / ( . %) tigecycline and / ( . %) imi/ cis, which are consistent with overall me results [ . % ( / ) tigecycline vs . % ( / ) imi/cis ( % ci = ) . , . ; non-inferiority p < . )]. in india m-mitt, cure rates at toc were / ( . %) tigecycline and / ( . %) imi/cis, similar to the overall m-mitt results [ . % ( / ) tigecycline vs . % ( / ) imi/cis ( % ci = ) . , . ; non-inferiority p < . )]. noninferiority of tigecycline among india patients could not be statistically demonstrated because of insufficient sample sizes, however, magnitude of response to study drugs in patients treated in india was comparable to that in overall patients. in india, treatment aes were similar with significantly higher incidence of dyspnoea in tigecycline ( . %) vs imi/cis ( . %), p = . . conclusions: efficacy results in india are consistent with findings from the overall study and results at other centres, suggesting tigecycline is noninferior to comparator in treating ciai. nosocomial infection: control of environment, viral infections p bacterial flora contamination of blood pressure cuffs in use on hospital wards n. walker, r. gupta, j. cheesbrough (preston, uk) blood pressure cuffs are a plausbile vehicle for the transmission of nosocomial infection between patients. despite this, few studies have examined the level of bacterial contamination and tested for the presence of common nosocomial pathogens on their surface. we swabbed cuffs currently in use on hospital wards. using sterile gloves, a disposable template measuring · cms was placed onto the cuff and a moistened sterile swab was rubbed onto the defined area for minute and then transported in mls of buffer medium. from each sample, . mls of the buffer was plated onto different media which included a non-selective agar medium for total viable count (tvc) and selective media for s. aureus, mrsa, c. difficile, coliforms and vancomycin resistant enterococci (vre.) bacterial growth was recovered from all cuffs. pathogenic organisms were isolated from cuffs ( %). mssa from , mrsa from and c. difficile from . the remaining three cuffs grew more than one pathogenic organism; mssa + mrsa + c. difficile from one and mssa + c. difficile from cuffs. colifroms and vre were not isolated from any of the cuffs. the range of total viable counts recovered per cm area of the cuff varied from > cfu and the cuffs with the highest counts tended to have more pathogens present. mssa and c. difficile were isolated from % of the cuffs sampled and mrsa from %. while the actual importance of this potential route of transmission for nosocomial pathogens remains unclear, it can not be dismissed. the impracticality of decontaminating blood pressure cuffs between patients suggests that single patient use cuffs or a barrier between cuff and skin would be a more viable option on a busy general ward. needlestick and sharp injuries of health care personnel in a newly founded tertiary hospital: a prospective study m. falagas, i. karydis, g. georgoulias, p. hatzopoulou, d. nikita, i. kostogiannou (athens, gr) objectives: needlestick and sharp injuries of health care workers are a major cause of anxiety and may expose susceptible employees to the risk of infectious diseases. however, the incidence of such injuries has not been examined in a newly founded hospital while preventive programmes are taking place. methods: we prospectively studied the needlestick and sharp injuries of employees in a newly founded tertiary hospital in athens, greece while a vaccination program against hepatitis b virus as well as educational activities for avoidance of injuries were taking place. serologic studies for hepatitis b and c virus as well as human immunodeficiency virus (hiv) were performed in all injured employees and the source patients (when known). results: sixty-eight needlestick, sharp injuries, and splashes were reported during the study period ( / / to / / ) in nurses, housekeepers, technicians, and ambulance workers. the overall incidence (percutaneous injuries and splashes) per full-time employment-years ( fteys) was . % whereas the incidence of percutaneous injuries alone per fteys was . %. a higher incidence of injuries was noted during the first than the second half of the study period ( . % versus . %, p = . ). no source patient was found positive for hepatitis c or hiv. the use of high-titre immunoglobulin after adjustment for the incidence of injuries was higher in the first than the second half of the study period ( . % vs . %, p = . ). conclusion: although we did not adjust for possible confounders, our data show that educational and vaccination preventive programs for needlestick and sharp injuries led to a statistically significant decrease in the incidence of such injuries and use of high-titre immunoglobulin. epidemiology of occupational needlestick and sharps injury among healthcare-workers in turkey s. hosoglu on behalf of the occupational infections study group, turkey background: health care workers (hcws) are frequently exposed to the danger of infectious agents through needle stick and sharps injury (nssi) in their occupational efforts. in turkey, the hepatitis b and c viruses cause an essential threat to the hcws because of their prevalence rate ( %- % and . %- %, respectively). a cross-sectional countrywide survey study was performed on the epidemiology of nssi among hcws at hospitals in cities throughout the country. data relating to the epidemiology of nssis were collected using a standard questionnaire in . results: totally hcws completed the questionnaire forms. nurses are the leading group ( persons) that joined into the study were followed by doctors ( persons) andlaboratory technicians ( ). totally of them ( . %) declared an occupational exposure or nssi in the last months related their job. needle stick injury was reported in of them ( . %), splash into the eye in ( . %), sharp injury in ( . %), and the other injuries in ( . %). the hepatitis positivity was reported in cases ( . %) objectives: to assess the microbiological status of reprocessed single-use devices for interventional cardiology by testing bioburden, sterility and pyrogenic load. methods: a total amount of electrophysiology non-lumen catheters (ep) were collected after the first clinical use on patient. devices were contaminated with bacteria spiked human blood and underwent four different pre-sterilization protocols including chlorine, polyphenol, and enzymatic agents. treated samples were assayed by cultural quantitative methods (cqm) for bactericidal properties and electron microscopy (em) for biologic residuals. ep were tested for sterility. by the repetition of simulated-use (bacteria spiked blood) and regeneration (enzymatic and chlorine treatment, gas plasma sterilization) we obtained , , , , , samples respectively reprocessed , , , , , times. devices were cultured for days in trypticase soy broth. the pyrogenic status of ep was monitored after clinical use, after decontamination-cleaning treatments and after complete reprocessing by lal test. results: high-resolution em and cqm confirmed the superior properties of chlorine releasing agent added to enzymatic detergent for devices treatment before sterilization. hypochlorous acid based protocols were more biocide (> . log cfu reduction) than polyphenolic ( . - . log cfu reduction). sterility tests showed no positive sample to inoculated strain until the fourth cycle of reprocessing. catheters showed the growth of the inoculated strain, bacillus subtilis in / and / samples after five cycles and six cycles respectively. every reprocessed device was non-pyrogenic (< eu/catheter). in addition, tests conducted on in-vitro spiked catheters showed that pyrogenic loads of eu/device were reduced to less than eu/device. conclusions: reprocessing procedures following the adopted regeneration protocol were able to satisfy the fundamental microbiological requirements until five in-vitro reuses. sterility tests showed that devices' sterility was not guaranteed after five reuses. pre-sterilization treatments including enzymatic solutions and chlorine revealed high cleaning properties with effective bioburden reduction. storage intervals among reprocessing steps longer than hours should be avoided in order to limit contamination and pyrogenic load. technical considerations suggest to consider the introduction of reprocessing procedure only in hospitals with a considerable workload. room disinfection in the hospital setting using akacid plus Ò c. kratzer, s. tobudic, w. graninger, a. buxbaum, a. georgopoulos (vienna, at) objectives: akacid plus Ò , a novel polymeric guanidine with broad antimicrobial activity also against multi-resistant bacterial strains, was used in the present study as room disinfectant. methods: disinfection of closed rooms experimentally contaminated with antibiotic-susceptible and multi-resistant staphylococcus aureus (mrsa), pseudomonas aeruginosa and escherichia coli was performed using akacid plus Ò at concentrations of . %, . % and . % for minutes. bacterial suspensions were distributed on stainless steel plates and placed in a test and control room. recovery of the test bacteria was determinedbefore nebulizing, and minutes after the beginning and hours after the end of room disinfection by a modified simple swab-rinse technique. for the detection of mrsa in isolation units, surface samples were collected by direct swab and enrichment culture. results: the swab-rinse method demonstrated a dose-and time-dependent effectiveness of akacid plus Ò in eradicating s. aureus, e. coli and p. aeruginosa on stainless steel plates. nebulizing of . % akacid plus was successful in eliminating all hospital pathogens in min contact time, while mrsa was still detectable after use of . % akacid plus Ò . . % akacid plus Ò achieved a reduction > cfu of s. aureus and p. aeruginosa, but was only able to eradicate e. coli during the observation time. the results suggest that nebulized akacid plus Ò at a concentration of . % is a potent substance for eradication of pathogenic organisms in the hospital setting. study on the antiviral efficacy of citrofresh Ò , a flavonoid based organic acid complex sanitizer z. nack (north-geelong, au) objective: determine the antiviral efficacy of this organic sanitizer against enveloped and non-enveloped viruses using a carrier based method. seeking registration for citrofresh Ò in australia and in the eu as a hospital grade antiviral sanitizer. methods: the study was performed according to the american society of testing and materials (astm) designation (e - ) recommended by the australian therapeutic goods administration (tga) to determine the efficacy of a disinfectant intended to use on inanimate, environmental surfaces. we tested citrofresh Ò (diluted in standard hard water) in three different concentrations: %, % and % on adherent cell lines (pk- , mrc- , mdck, a , l ) in four replicates against five different viruses including: porcine parvovirus (non-enveloped, high resistant against sanitizer); human rhinovirus- (non-enveloped, high resistant against sanitizer); human adenovirus- (non-enveloped, moderate resistant against sanitizer); human influenza type a (h n ) virus (enveloped, moderate resistant against sanitizer); human herpes simplex virus type (enveloped, low resistant against sanitizers). prior to the viral testings, acute toxicity assay was carried out to determine the adherent cells viability against citrofresh Ò . results: cell lines exhibited > % viability after exposure to all three concentration. herpes simplex type , human influenza type a and human adenovirus- exhibited the most significant viral log reduction of log to at % concentration of citrofresh Ò followed by the human rhinovirus- and porcine parvovirus log reduction at % concentration. the reduction of viable virus load was exhibited after minute exposure time to citrofresh Ò , which means no time-dependant activity. citrofresh Ò clearly exhibited concentration and ph dependent viral load reduction activity against influenza type a and the human adenovirus - and human herpes simplex type virus. the reduction in viral titre for porcine parvovirus and human rhinovirus- is probably ph dependent (the ph of % citrofresh Ò is . , % is . and % is . ). conclusion: our investigation shows that citrofresh Ò is an effective disinfectant on environmental surfaces, eliminating enveloped and non-enveloped viruses and sufficient to achieve the minimum -log reduction with complete viral inactivation which is prerequisite for registration. rapid environmental recontamination of an intensive care unit after decontamination with hydrogen peroxide vapour objectives: to evaluate the effectiveness of hydrogen peroxide vapour (hpv) to reduce the levels of total bacterial and methicillin resistant staphylococcus aureus (mrsa) environmental contamination on an intensive care unit (icu), and to establish the rate of environmental recontamination. methods: the study took place on a bed open plan icu. on each environmental screen sites in each bed space (under the bed, the workstation and the monitor) were examined using broth enrichment for the detection of mrsa. in addition total bacterial counts were determined for under the bed and workstation using rodac plates. environmental screening was carried out monthly for the months preceding the usage of hpv, increasing to weekly for the weeks prior to usage. additional sampling was carried out immediately before patients were discharged from icu, following the subsequent terminal clean and then immediately after hpv use. after readmission of patients sampling was carried out at h, h and then weekly for a period of weeks. patients were screened for mrsa on admission and then weekly. results: sampling of the environment prior to the usage of hpv revealed contamination of the environment with mrsa on / occasions, with mrsa colonised patients being present on only / occasions. after discharge of the patients and terminal cleaning of the environment, mrsa was isolated from ( %) environmental sites. after the use of hpv, mrsa was not isolated from any environmental sites upon immediate sampling, but h after patients were readmitted, including patients known to be colonised with mrsa, mrsa was isolated from sites. these sites were not clustered around the colonised patients but were widespread across the icu. in the weeks post hpv usage mrsa has been isolated every week. the mean total bacterial counts prior to the use of hpv were . / cm underneath the beds and . / cm on the workstations, this was reduced after hpv to . / cm and . / cm respectively. after patients readmission the counts were . / cm underneath the beds and . / cm on the workstations after h and returned to pre-hpv levels of . / cm and . / cm at each site respectively after week. conclusion: hydrogen peroxide vapour is effective in eliminating bacteria from the environment. the rapid rate of recontamination of the environment suggests that the use of hpv is not an effective means of maintaining low levels of environmental contamination on an open plan icu. objectives: the nosocomial infections are more serious and dangerous than community acquired infections since they have high rate of morbidity and mortality as well as they increase the cost of therapy. recently many precautions have been taken to prevent these infections. one of these applications is that covering of the floor of the wards, clinics, intensive care units and operating rooms of the hospitals with vinyl flooring material, which is believed to be cleaned easily and effectively. in this study it was aimed to determine the duration of survive of the staphylococcus aureus, enterococcus feacalis, escherichia coli and pseudomonas aeruginosa, which were most common encountered as nosocomial infection agents, on the surface of flooring materials such as vinyl flooring, ceramic laminated wood and galvanized sheet at room temperature. methods: four kinds of flooring materials were prepared approximately in - cm coupons and sterilized. separate bacterial suspensions equal to mc farland turbidity were swapped to the surface of each flooring materials by sterile cotton swabs. all contaminated test materials were put in sterile petri dishes with cover and kept at room temperature without subjecting to the direct sunlight. on the third day, culture samples were taken from the surface of each material by sterile cotton swaps soaked with sterile saline and streaked on the blood agar surface. culturing procedure was repeated every other day until no growth detected. in case of three consequently, negative culture results obtained culturing was ended. results: overall results of the study were presented on table . conclusions: among the four flooring materials, galvanised sheet seemed to be the most unsuitable one for the bacteria to survive long period. in other words this material should be preferred as to laminated wood for covering benches and laboratory tables. as for the flooring of the floors the vinyl flooring material is better than ceramic. covering the complete cmv ie- and pp proteins.results: cmv seropositive transplant recipients had significantly hightened ie- and pp specific t cell frequencies compared to seronegative individuals. patients withevidence of cmv antigenemia or dnaemia could not be discriminated based on cmv-and donor-reactive t cells or serum creatinine. however, recipients of seropositive grafts with low ie response showed a tendency towards more frequent cmv infection. cmv disease was observed in only / individuals. had no detectable ie or pp -t cell response, the third presented with a dominant pp response. interestingly, ie -specific t cells correlated inversely with early post-tx donor-reactive t cell frequencies during weeks - post-tx. most importantly, ie -specific t cell frequencies correlated inversely with serum creatinine at and months at several times post-tx. in patients without acute rejection, even pre-transplant ie- specific t cells correlated inversely with and months creatinine. conclusion: these data suggest subclinical control of cmv infection by ie- specific t cells and subsequently less graft injury by (cmv-induced) alloimmunity. universal precautions: knowledge, attitude and practice of healthcare workers regarding hiv, hepatitis b and c v. gupta, s. bhoi, a. goel, p. aggarwal (new delhi, in) objectives: increasing incidence of hiv, hepatitis b (hbv) and hepatitis c (hcv) in the patients expose the healthcare professionals of acquiring these infections during occupational exposure. we studied the knowledge, attitudes and practices of healthcare workers regarding hiv, hbv, hcv and the risk of occupational transmission of these diseases. methods: an interview survey was conducted among all the health care workers (hcw) using a standardised questionnaire comprising of items in english and local language, as suitable, by an expert in the emergency ward of a tertiary care teaching hospital of a developing nation. data analysis (bivariate and multivariate analysis) was done using spss version . results: (response rate: %) hcw participated in the study. the mean age was ± years, were females. the study population comprised of % doctors, % nurses, % lab technicians and % support staff. respondents had adequate knowledge about causative ( %) usual transmission ( %), symptoms ( %) of aids but poor knowledge about hbv and hcv ( %, % and % respectively). inadequate knowledge was also revealed about the infectious bodyfluids ( %), disinfection of equipments ( %), pregnancy in hcw as a susceptibility factor ( %), post exposure prophylaxis ( %) and comparative infectivity of hiv and hepatitis ( %). % of hcw became anxious while treating these patients. poor compliance with universal precautions was noticed. high compliance was reported for wearing masks ( %) and wearing gloves ( %). doctors were more likely to suffer needlestick injury (p = . ) occupational exposures was found to be high ( %) with poor declaration rate ( %). guidelines adherence was influenced by profession (p < . ), availability or adequacy of protective equipments but not by work experience as hcw (p = . ). all of the respondents urged for an interactive information session. conclusions: results from this study reveal that there is a fair level of knowledge about hiv/aids but hepatitis b and c have not generated adequate concern among the hcw. incongruity between perceived knowledge and reported practice suggests that there is a need for an interactive awareness course about the universal precautions. the educational programmes need to consider attitudes in conjunction with empirical knowledge. objectives: the sero-prevalence of hepatitis a (hav) antibodies are known to be low in young adults in korea. recently, seventeen cases of hepatitis a have been reported in health-care workers (hcw) of icu in a university hospital from may to july . we performed surveillance, and determined molecular identification of outbreaks. methods: . we checked the hav igm from all the patients of sicu with elevated ast/alt retrospectively and screened ast/alt level from all the nurses and the doctors in contact with suspicious index case. . when we determined the existence of outbreak, the molecular subtypes of hav from a blood of hcw were determined to provide the data for epidemiologic study. we determined the index case, a transmission route and the intervention for control an outbreak were planned. results: . seventeen hcw including nurses and doctors who are to years old, suffered from acute hav over weeks period. . the possible transmission of hav was fecaloral route from the bed-ridden patients with diarrhea to the exposed hcw. . seventeen hcw were identified with a positive anti-hav igm. the eight hcw had a positive hav rna. analysis of the vp -p a region of each isolate showed genotype a in five strains and co-circulation of a and b in others. conclusions: the occurrence of hav outbreak highlights the importance of standard precaution in a hospital. the hav vaccination is considered in young aged-hcw. the genotype identification of blood would be useful for the epidemiologic study of suspicious hav outbreak in a hospital. management of a norovirus-associated gastroenteritis outbreak on two psychiatric wards a. buehling, u. arnold (magdeburg, de) objectives: we report a norovirus-associated outbreak of gastroenteritis on a closed psychiatric and a gerontopsychiatric wards from december to february . during this time patients and healthcare workers (hcws) were affected. introduction and results of hygiene measures based on published guidelines on psychiatric wards are described. methods: effective and adapted measures had to be implemented to stop the outbreak and to prevent the spread of disease to other areas of our hospital. isolation or cohorting of the psychiatric patients was excluded for therapeutic reasons. regular hand disinfection in patient rooms was impossible because of the high risk of abuse. the following measures have been introduced: use of gowns, masks and gloves by hcws during care of infected patients-frequent hand disinfections with alcohol-based disinfectants by hcws using ''pocket bottles''; recommendation for all persons entering the station to use gowns, gloves and masks and to disinfect their hands frequently, distribution of handouts describing the measures; hand disinfection by all patients after using toilet, before and after taking meals (distribution of disinfectants by hcw); increased frequency of routine surface disinfection ( times daily) instead of routine cleaning once daily; routine disinfection of door handles, handrails, wash-basins and -fittings and light switches - times a shift; avoidance of patient transfer via hospital; visitor restriction during outbreak time; daily evaluation of recommended measures and adaptation to the current situation; exclusion of affected staff from the ward until h symptom free. results: the hygienic measures have been explained to the local hcws in daily meetings. they have been fully accepted only after a severe staff shortage in the fifth week of outbreak because of new cases of gastroenteritis during hcws and newly infected patients. because of the restrictive application of the adapted guidelines for these special wards the outbreak has been stopped within further weeks. conclusion: in case of norovirus-based gastroenteritis outbreaks on closed psychiatric wards hygienic measures which are adapted to the concrete situation are necessary. especially in these cases the compliance with guidelines can be increased by daily meetings and daily evaluation of recommendations. staff shortage during the outbreak forced the strict compliance with the recommended measures. regional spread of antibiotic resistance methods: we performed surveillance of patients, healthcare stuff and icu environment and we registered the infections of ab during periods of days each one. the interval between st- nd period was months and nd- rd period was year. rectal, oropharyngeal swabs tracheal aspirates from patients, handswabs from stuff and samples from environment were taken weekly. the identification of ab was performed using vitek ii system the susceptibility was tested by kirby-bauer and mic methods and the <<dna fingerprints>>obtained by pulsed field gel electrophoresis (pfge). results: during the st nd and rd period, patients ( men, women), patients ( men, women) and patients ( men, women) were hospitalized in icu respectively. ab was isolated in from samples ( . %) at the st period, from ( . %) at the nd and from ( %) at the rd period. totally ab was isolated in from specimens ( %) at the st nd and rd period among the patients carrying ab, / ( %), / ( %) and / ( %) were infected respectively. the infections observed during the study period were: sepsis ( ), urinary tract infection ( ), pneumonia ( ), meningitis ( ), thrombophlebitis ( ) . all the isolated ab strains were multiresistant to antimicrobial agents. molecular analysis of isolated strains by pfge distinguished the following types: a ( , subtypes a -a ), b ( ) at the st period a( ), c( ), d( ), e( ), f( ), g( ), h( ), i( ). j( ) at the nd period a( ), b ( ), d( ), h( ), k( ). l( ) at the rd period. infections were caused mainly by a and d types while the same types were isolated from the environment and the hands of the icu stuff. conclusion: there was a high rate of colonization and infection of icu patients by multiresistant clones of ab. the persistence of clone a of a. baumannii and the appearance of b type at the rd period after its disappearance at the nd period despite the application hygiene measures, indicates the need for more strict reinforced infection control in icu. the transmission via the hands of stuff to patients has become the most important contributor factor in patient colonization and/or infection. objectives: the antibiotic resistance and its mechanism of group a streptococci (gas) varies according to nations or study period. we have investigated antibiotic resistance and mechanism of macrolide resistance for the strains isolated from korean children and compared to the previous ( ) results. methods: throat cultures were taken from elementary school children in jinju, korea from october to december, to isolate gas. antibiotic susceptibility test to erythromycin (em), clindamycin (cc), and tetracycline (tc) was performed by disk diffusion method. macrolide resistance phenotype and genotype as well as emm genotype were studied. results: isolation rate of gas was . % ( / ). resistance rates of em, cc, and tc were . %, . %, and . % respectively, which were dramatically decreased from %, %, and % in at the same area. emm / was prevalent ( %), while emm was the most common type ( %) in . cmlsb, m, and imlsb were observed in . %, . %, and . % respectively, compared to %, %, and % in . the strains with cmlsb and imlsb had ermb gene and the ones with m phenotype were positive with mefa gene. conclusion: the resistance rates to em and cc were dramatically decreased compared to the past ( ). education to the public and physicians, decreased consumption of antibiotics, acquisition of immunity to the resistant strains, or change of prevalent emm types could be considered to explain the reason of decrease of antibiotic resistance. although antibiotic resistance rate was decreased, cmlsb type which has high mic was prevalent suggesting treatment failure for those children carrying these resistant strains in jinju, korea. analysis of skin and soft tissue infections in european medical centres: report from the sentry antimicrobial surveillance program ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) g. moet, p. strabala, h. sader, t. fritsche, r. jones (north liberty, us) objective: to analyse the skin and soft tissue infections (ssti) or wound infections in hospitalized patients in the sentry program for pathogen prevalence and resistance (r) variations in european (eu) medical centres for the years to ( years). this program also included north america (na) and latin america (la) for the same years, except . methods: consecutively isolated pathogens/site were collected from each centre per year and varied in number of sites each year in eu: eu: ( ), eu: ( ), eu: ( ), eu: ( ), eu: ( ), eu: ( ), and . susceptibility testing was determined by clsi (formerly the nccls) broth microdilution methods and interpreted by current ( ) breakpoints. results: table of all years total of ssti pathogens. (see table) sa was the predominant pathogen in eu ranging from . % of ssti isolates in to . % in . the top most prevalent organisms accounted for . % of isolates in all years with psa and ec ranking second and third, respectively with . % combined, and enc and ent ranked fourth and fifth with . % of the total isolates. compared to the americas, mrsa and vre isolation was at a lower occurrence rate in the eu; but between the rates of other monitored continents for ctz-r psa, cipro-r ec and ctz-r ent (ampc). vre increased in eu over the year. conclusions: pathogen prevalence in ssti for eu has been consistent over the monitored years although sa (with mrsa) appears to be increasing. eu is not a world leader in any key r marker compared to the americas. however, the r rates are evolving which suggests continued need for surveillance programs at regular intervals to detect mobile genetic r elements. objectives: carbapenems play an important role in the therapy of pseudomonas aeruginosa infections. the aim of our study was to characterize the molecular alteration responsible for changed susceptibility towards carbapenems in multiresistant p. aeruginosa strains from germany. methods: multiresistant p. aeruginosa strains from cystic fibrosis and non cystic fibrosis patients were collected in german hospitals in . the strains showed reduced susceptibility (intermediate or resistant; din guidelines) to imipenem, piperacillin, ciprofloxacin and gentamicin. clonality was tested using pfge. a pcr screening for vim and imp was carried out. effluxpump overexpression was detected using an effluxpump inhibitor (epi) test. oprd and for strains with positive results in the epi test the effluxpump repressorgenes mexr and nfxb were sequenced. results: pfge patterns revealed no clonal relationship among the multiresistant strains. neither vim nor imp was detected. the geno-and phenotypes found are depicted in table . defective oprd genes caused by premature stopcodons or frameshifts were found in strains. among those had no mutations in mexr or nfxb and showed the highest mics found ranging from to > and to mg/l of imipenem and meropenem, respectively. additionally had defective mexr genes, but intact nfxb genes, also had modifications in mexr and nfxb, and showed only in nfxb additional alterations. for strains no alterations in oprd but in mexr were proven. conclusions: the predominating mechanism of carbapenem resistance in multiresistant p. aeruginosa strains from germany was the loss of oprd. accessory overexpression of mexaboprm due to modifications in mexr did not result in significantly elevated mics of meropenem. moreover, the additional overexpression of mexcdoprj did not lower the mic of imipenem. in strains with modifications only in mexr only elevated mics of imipenem indicate a reduced expression of oprd accompanied by overexpression of mexefoprn as conferred by nfxc-type mutants. objective: mart (study for monitoring antimicrobial resistance trends) is an ongoing global antimicrobial surveillance program focused on clinical isolates from intraabdominal infections (iai). the aim of this sub-analysis was to assess antimicrobial susceptibility patterns among gramnegative bacilli from different regions of the world during . methods: pa total of major medical centres in north america, latin america, europe, middle east/africa, & asia/ pacific tested the in vitro activity of antimicrobial agents commonly used to treat iai against consecutive unique aerobic and facultative gram-negative bacilli from iai using microdilution techniques according to clsi guidelines & breakpoints. results: enterobacteriaceae were recovered from ( %) & non-enterobacteriaceae were recovered from ( %) of the patients in the study worldwide, constituting ( %) & ( %) of the total isolates, respectively. e. coli (n = ; %) and klebsiella spp. (n = ; %) were the most commonly isolated enterobacteriaceae. pseudomonas spp. (n = ; %) and acinetobacter spp. (n = ; %) were the most commonly isolated non-enterobacteriaceae. isolates from asia/pacific and latin america were generally more resistant. ( %) of the enterobacteriaceae & ( %) of the non-enterobacteriaceae were recovered < hours after hospitalization. the % susceptible isolates are reported below: conclusion: in this study, enterobacteriaceae were the predominant intraabdominal isolates recovered both < h and > h after hospitalization. carbapenems were overall the most active agents against enterobacteriaceae worldwide. resistance rates varied among geographic regions, with the asia/pacific and latin america regions generally having the most resistance. characterisation of streptogramin resistance genes among enterococcus faecium isolates from austrian animal husbandry a. eisner, g. gorkiewicz, g. feierl, f. dieber, e. marth, j. kö fer (graz, at) objectives: the streptogramin virginiamycin has been widely used as a growth promoter in animal husbandry in the european union but was banned in because of concerns about evolving cross-resistance to the streptogramin quinupristin-dalfopristin used in human medicine. the aim of the present study was to investigate the prevalence of streptogramin resistance genes of enterococcus faecium recovered from animal faecal specimens collected in southeast austria. methods: we analysed e. faecium isolates of cattle (n = ), pig (n = ), and poultry (n = ) for the presence of streptogramin resistance genes. we used selective enterococcal broth for isolation. species identification was done on basis of gram stain, catalase and pyrrolidonyl arylamidase activity, motility, lancefield group d antigen typing, and by the strep apitest (biomérieux). detection of the resistance genes vat(e), vat(d), and erm(b) was done by pcr. results: the erm(b) gene encoding macrolide, lincosamine, and streptogramin b (mlsb) resistance was found in each e. faecium isolates recovered from pig and cattle, none of the isolates from these animals carried genes coding for streptogramin a resistance. on the contrary, e. faecium isolates from broiler specimens contained the vat(e) gene and one isolate contained the vat(d) gene. all of these isolates also contained the erm(b) gene. conclusion: our data indicate that the use of the meanwhile banned antimicrobial feed additive virginiamycin has created a reservoir of streptogramin-resistant e. faecium in southeast austrian poultry. characterisation of macrolide-resistant streptococcus pneumoniae isolates from russia objectives: streptococcus pneumoniae (spn) resistance to macrolide antibiotics continues to be of major concern. the aim of present study was to analyse phenotypic and genotypic characteristics of macrolide resistant spn isolates. methods: eighty one macrolide resistant spn isolates were collected in moscow, moscow, - . the susceptibility testing was performed according to the clsi guidelines. macrolide resistance phenotypes were characterized by triple-disk diffusion test, using erythromycin, clindamycin and rokitamycin disks. detection of genes, coding resistance to macrolides, was done by rt-pcr. sequencing for qrdr mutations was performed on levofloxacin resistant spn isolates. selected isolates were analysed by mlst. results: by the triple-disk test, isolates were assigned to the m phenotype, of them were carrying mefa gene, and one was negative. twenty eight isolates were cmlsb-phenotype, of them were carrying both ermb and mefa genes, in two isolates only ermb was detected, and one isolate was negative for both genes. imclsb phenotype was demonstrated by isolates, both ermb and mefa genes were detected in of them, and only ermb in . three isolates didn't demonstrated blunting of zone of inhibition around rokitamycin disk. associated resistance to penicillin g, tetracycline, chloramphenicol and co-trimoxazole was observed in . %, . %, . % and . % of spn isolates respectively. nine multidrug resistant isolates, harbouring both mefa and ermb genes, were subjected to mlst. among them one isolate was found to share the allelic profile st (spain f- clone), and four isolates were single-allele variants of st . in four isolates new allelic profiles were detected. three isolates were resistant to levofloxacin (mic ‡ mg/l), in two of them with levofloxacin mic > mg/l (st single-allele variants) e k, s f and i v substitutions were detected in gyra, parc and pare, respectively. d n and i v substitutions were detected in parc and pare of one isolate with new allelic profile. conclusion: high prevalence of macrolide resistant spn, harboring both ermb and mefa genes is observed in moscow, macrolide resistance is associated with resistance to other groups of antibacterials. some multidrug resistant isolates are highly related to internationally disseminated multiresistant clone spain f- . strains with fluoroquinolone resistance in moscow were all single locus variants of the spain f- clone. occurrence of tet(w) gene in a clostridium difficile clinical isolate p. mastrantonio, f. barbanti, p. spigaglia (rome, it) objectives: to investigate the presence of tet(w), a tetracycline resistance gene recently identified in anaerobic commensal bacteria from animals and humans, in c. difficile clinical isolates. methods: several c. difficile clinical isolates from different italian hospitals were analysed for the presence of a tet(w) gene by pcr assays. the primers used were designed on the tet(w) sequences available in genbank. pcr fragments obtained by these amplifications were sequenced. tet(w) dna flanking regions were also examined with a set of pcrs constructed on the sequence of the conjugative transposon tnb of butyrivibrio fibrisolvens . , that is the only element carrying a tet(w) partially characterized so far. tet(w) positive isolates were also examined for the tet(m) gene and for the presence of int and tndx, markers for the tn and the tn like elements, respectively. the tn -like elements were further characterized by pcrs designed on enteroccus faecalis tn sequence. tetracycline mic values were determined by the e-test method. tetracycline resistance gene transfer was evaluated by filter mating experiments, using c. difficile p r strain as recipient. results: a tet(w) gene was found in only one isolate, c. difficile cd , also positive for the tet(m) gene. this isolate was resistant to tetracycline with a mic of mg/l. sequence analysis of the tet(w) pcr fragment (about bp) showed that this gene had an identity of % with the genes found in clostridium spp strain k , mitsuokella multacida and butyrivibrio fibrisolvens. no amplifications were obtained with the primers designed on tnb , indicating the presence of a different genetic support for tet(w) in c. difficile. tet(m) gene of c. difficile cd was carried by a tn -like element that showed nucleotide sequence mutations in the region containing orf - compared to the element of e. faecalis. conjugative transfer of tet(w) was not observed, whereas the tet(m) gene was transferred to the recipient strain. c. difficile transconjugants were resistant to tetracycline with a mic of mg/l. conclusion: the results obtained in this study demonstrate for the first time the presence of a tet(w) gene in a clinical isolate of c. difficile, providing further evidence of the spread of this resistance determinant among gastrointestinal bacteria. macrolide resistance determinants are prevalent and readily selected for in viridans group streptococci among healthy norwegian adults background: norway has a low prevalence of antimicrobialresistant bacteria including macrolide resistant (mr) respiratory tract pathogens. we have observed an increase in macrolide consumption in norway and there is a lack of knowledge on the reservoir of macrolide resistance determinants among viridans group of streptococci (vgs) in the pharyngeal flora. objectives: examine the occurrence, selection and persistence of macrolide resistance determinants in vgs pharyngeal flora in healthy norwegian adults before and after treatment with azithromycin. methods: throat samples were collected before (day ), after treatment (day ) and after months (day ) from healthy volunteers. the samples were plated directly as a lawn on pdmii agar plates with % defibrinated blood with an erythromycin etest strip. photos were used as quantitative comparisons. up to morphological different colonies with erythromycin etest mic ‡ lg/ml from each specimen were collected; day (n = ), day (n = ) and day (n = ). in total representatives mr, vgs-isolates were selected for further studies: (i) mics of erythromycin, tetracycline and penicillin were determined by etest. (ii) pcr's for erm(b), erm(tr), and mef(a/e), and subsequent sequence-typing of mef. species identification was performed by soda sequencing. results: a total of / persons carried a low number (< ) of mr vgs in day specimens, while / had a significant higher number (> ) of mr strains in day specimens. in day specimens, / carried a low number of mr, resembling day . reduced susceptibility to penicillin was observed in / ( %) isolates. tetracycline resistance was found in / ( %), and mainly in erm(b)-positive strains. mef(a/e)-positive dominated day ( %) and erm(b) day specimens %. sequence typing revealed mef(e) (n = ) and mef(a) (n = ). soda sequence; s. mitis (n = ), s. oralis (n = ), s. parasanguinis (n = ), s. salivarius (n = ), and s. sanguinis (n = ). conclusion: there is a pool of vgs carrying macrolide resistance determinants in the normal pharyngeal flora of healthy adults that are readily selected for during azithromycin exposure. the mef(e) and erm(b) were the most prevalent resistance genes and co-resistance to tetracycline was frequently observed, resembling the findings in norwegian clinical isolates of s. pneumoniae. these vgs may provide a pool of resistant bacteria that may transfer resistance determinants to more pathogenic organisms. relationships in genotype, phenotype, t type and pfge type among macrolide-resistant streptococcus pyogenes strains isolated in the czech republic v. jakubù , p. urbášková, l. straková (prague, cz) objectives: to determine relationships between phenotypic and genotypic methods among erythromycin-resistant s. pyogenes strains. methods: a total of clinical isolates of s. pyogenes resistant to erythromycin were collected in microbiology laboratories during - . erythromycin susceptibility was tested by the disk diffusion method. strains with an inhibition zone < mm around the erythromycin disk ( lg) were sent to the national reference laboratory for antibiotics (nrl). presences of mlsb resistance genes (ermtr, ermb and mefa) were tested by pcr. t serotypes were determined in randomly selected representatives of each phenotype (n = ). pfge type were determined in strains from year only (n = ). results: the rate of the most prevalent phenotype (constitutive mlsb resistance) was %, % in the year and , respectively. the major prevalent t types among the analysed strains were serotype t ( %), t ( %), t ( %) and t b ( %). gene ermb was the most frequent ( %). the results of pcr method was highly congruent with observed phenotype of resistance. pfge patterns of strains with constitutive mlsb resistance were highly identical. conclusion: m phenotypes, constitutive and inducible resistance to mlsb antibiotics were found and ermtr, ermb and mefa genes were detected among the analysed strains. the t serotype was identified the mainly prevalent in our collection. the majority of strains harbouring t serotype were constitutively resistant to macrolides. the study showed close relationships among genotypes, t types, specific resistotypes (phenotype) and pfge types. objectives: since recognition of transferable clindamycin and tetracycline resistance in bacteroides, we have undertaken a us national survey on the susceptibility of b. fragilis group to analyse emergence of resistance and trends, since these species are not routinely tested for susceptibility in hospital clinical laboratories. methods: agar dilution mics were determined for isolates from - for b. fragilis and related species from geographically diverse centers in the us. antibiotics included carbapenems, b-lactam/b-lactamase inhibitors, quinolones, a tetracycline, clindamycin, metronidazole, chloramphenicol, a glycylcycline and linezolid. isolate identity was confirmed by api a. results: analysis of resistance trends from - showed a decrease in geometric mean mic's (geomic) for imipenem ( . mcg/ml to . mcg/ml, p < . ) and meropenem ( . mcg/ml- . mcg/ml, p = . ) for the bacteroides species. ertapenem geomic remained unchanged ( . mcg/ ml). for the b-lactamase inhibitors, piperacillin-tazobactam geomic declined from . mcg/ml to . mcg/ml (p < . ). ampicillin-sulbactam geomic did not change. few isolates were resistant to any carbapenem or b-lactamase inhibitor combination. clindamycin resistance increased, especially for b. fragilis, b. ovatus and b. thetaiotaomicron (all p < . ). among quinolones, resistance of bacteroides to moxifloxacin increased (geomic went from mcg/ml to . mcg/ml, p < . ). b. fragilis remains the most sensitive bacteroides species to moxifloxacin, although approximately % of stains have mic's ‡to mcg/ml in . tigecycline susceptibility, tested over years, did not change. the first confirmed metronidazole-resistant isolate (mic = mcg/ml) obtained in the us was noted in but none were noted in or . conclusion: improved susceptibility of bacteroides species to some carbapenems and the b-lactamase inhibitor combinations is unexplained but significant. clindamycin resistance continues to increase, especially for b. fragilis. moxifloxacin susceptibility for the non fragilis species shows that the majority of strains are resistant. the first metronidazole resistant isolate has been reported from the us. since resistance trends are associated with species, the differentiation within the species is of extreme importance, since it may impact the choice of antimicrobial agent for the treatment of infections caused by this group of anaerobes. observed duration of nasopharyngeal carriage of penicillin-resistant pneumococci: relations to age and serogroup p. geli, l. hö gberg, h. ringberg, e. melander, m. lipsitch, k. ekdahl (solna, malmö, lund, stockholm, se; boston, us) background and objectives: knowledge of how the duration of pneumococcal carriage varies with age and serogroup is essential to understanding how immunity to carriage arises throughout the course of life, and designing appropriate models for the effects of vaccination or other public health initiatives aiming to reduce the pneumococcal transmission in the community. using data from an ongoing swedish intervention project, the duration of nasopharyngeal carriage of penicillinresistant pneumococci (mic pcg > . mg/l) stratified by both serogroup and age of the carrier were estimated. methods: the mean duration and corresponding % confidence interval was estimated by fitting a gamma distribution to the observed duration of carriage for each serogroup and age stratum. results: the mean duration of carriage for all cases was days ( % ci - ). children below the age of years carried prp for significantly longer periods ( days, % ci - ) compared with older individuals ( days, % ci - ). there were also differences within the group of cases below the age of years, as the duration of carriage became significantly shorter for each year older the cases were. serogroup and were carried for significantly shorter periods compared with serogroup . serogroup also had significantly shorter carriage duration compared with serogroups and for cases - years. for cases years or older, no significant difference in carriage duration for different ages or serogroups could be noted. conclusions: even though the estimate does not cover any correction for the censored carriage duration and therefore not yield an estimate of the total length of carriage, the results highlight the importance to take both serogroup and age of the p exploring the molecular basis for differences in phenotype of salmonella enteritidis typing phage n. delappe, d. morris, m. cormican (galway, ie) objectives: the salmonella enteritidis phage tying scheme of the laboratory of enteric pathogens, health protection agency, uk, is a widely used method for subtyping this important pathogen. the method is rapid and highly discriminatory. interpretation of results can be subjective and the typing phage which are central to the method have not been well characterised. complete sequence data is available for the salmonella typhimurium podovirus phage p . methods: the typing phage were propagated on s. enteritidis pt b (pb ). phage were visualised by electron microscopy. phage dna was extracted and digested with hindiii. consensus pcr primers were designed based on sequences of p and other s. typhimurium phage. additional primers were designed based on the sequence of the s. enterititidis typing phage (a siphovirus). amplification, sequencing and dna probe hybridisation of various phage genes were performed using standard techniques. results: on em the typing phage comprise podoviridae (phage , , , , and ) , siphoviridae (phage , , , , and ) and myoviridae (phage , , and ). digestion with hindiii subdivided each morphotype into groups. the podoviridae contained genes homologous to p while the siphoviridae contained genes homologous to the sequenced s. enteritidis typing phage . some sequence variation was detected in podovirus and siphovirus genes however in some cases phage, which differ in their phenotype had no difference detected in hindiii digestion pattern or partial sequence. conclusions: the s. enteritidis typing phage set comprise distinct phage morphotypes. in some instances distinct phage that contribute to differentiation between s. enteritidis phage types had no dna sequence variation detected. variations in phage typing reactions may in part be due to epigenetic difference in typing phage, e.g. due to methylation of phage dna. salmonella enteritidis typing phage biology could provide a model for developing approaches to phage therapy. tularemia is a zoonotic bacterial disease. the causative agent, francisella tularensis, is spread to humans by direct contact with infected rodents, inhalation, ingestion of contaminated water or by arthropod bites. in some endemic regions, outbreaks occur frequently, whereas nearby rural parts may be completely free. we presented two cases of tularemia in non endemic region of the turkey. case : a year old female patient referred to tertiary hospital due to swollen on the neck for months. before admission beta lactam antibiotics had been prescribed to her for tonsilopharyngitidis. but her complaints had been continued. so she admitted to our hospital. she had been suffered fever sore throat and neck pain. she had a palpable and painfull cervical lymphadenopathy which was not suppurated. leukocytosis and elevated c reactive protein were predominant. at screening there were not any lymphadenopathy detected elsewhere. she had been examined about cytomegalovirus epstein barr virus and brucellosis. they were negative. fine needle aspiration from neck was negative considered as malignancy. cultures were negative for routine bacteriologic examination. microagglutination test for tularemia was / positive. then we decided to treat her with gentamycin for days. after treatment cervical lymphadenopathy became small. leukocyte count and c reactive protein levels were reach normal range. case : a year old female patient referred to university hospital due to cervical lymphadenopathy and fever and sore throat. before admission beta lactam antibiotics were prescribed to her for weeks. but no apparent benefits had been detected. there was a palpable and fistulated cervical lymphdenopathy. drainage was examined microscopically and cultured for bacteria, mycobacteria and fungi. on routine cultures no microorganisms were grown. fine needle aspiration was done. it was reported that suppurative granulamatous lympadenitis. so we were examined for tularemia, cat scratch disease. microaggltunation test for tularemia was / positive. then streptomycin had been given for days and excision of lymphadenopathy had been done. no complications or recurrence occur. results: both patients were applied to us from non endemic and different regions of the turkey. they had no known insect bite history. both of them were diagnosed by serological tests. conclusions: in the differential diagnosis of tonsillopharyngitidis, tularemia also must be considered in the non endemic regions. tularaemia presenting with tonsillopharyngitis and cervical lymphadenitis: two case reports b. kandemir, i. erayman, m. bitirgen, e. turk aribas, a.c. inkaya, s. guler (konya, tr) tularemia is a zoonotic disease caused by francisella tularensis. francisella tularensis is transmitted to humans by direct contact or ingestion of infected animal tissues, through the bite of infected arthropods, by consumption of contaminated food or water, or from inhalation of aerosolized bacteria. in this report we describe two cases of oropharyngeal tularemia who presented with tonsillopharyngitis and cervical lymphadenitis. case i: a years old woman with multiple cervical lymphadenitis has been admitted to our clinic. her complaints started months ago with signs and symptoms of tonsillopharyngitis. she had received non specific treatment (ampicillin+sulbactam) and ten days later cervical lymph nodes appeared. the diagnosis was made serologically. the antimicrobial therapy (streptomycin · g im) was given for fourteen days. the patient recovered completely. case ii: a years old girl with multiple cervical lymphadenitis was admitted to hospital. her complaints started months ago with throat ache after which multiple cervical lymphadenitis appeared. she was admitted to our out patient clinics and diagnosed to have tularemia. anti-microbial therapy (streptomycin · g im+doxycyciline · mg) was given for four weeks but no clinical response was achieved. patient was admitted to the hospital and surgical drainage was performed. treatment against tularemia was prolonged. patient was finally recovered at the end of nine weeks of therapy. it can be concluded that early diagnosis and treatment of tularemia are important. some patients may benefit from surgical drainage and prolonged therapy. a case of nonclostridial crepitant cellulitis which is due to escherichia coli c. ayaz, m. ulug, m.k. celen, m.f. geyik, s. hosoglu (diyarbakir, tr) objectives: this condition is caused by gas forming bacteria that involve the skin, either or as an extension from deeper structures. the origin of infection is an abdominal wound, perianal disease, or operative incisions that have become secondarily infected. tracking of gas-forming organisms from deeper sites of infection may also present as crepitant cellulitis without a break in the skin. diabetics are more likely to acquire such infections, especially in the lower extremites. among the bacteria isolated are anaerobic organisms such as bacteriodes or anaerobic streptococci, or coliform bacteria, especially escherichia coli and klebsiella. because of this reason we reported a case of a nonclostridial crepitant cellulitis which is due to escherichia coli. case: a year old man who was previously healthy, has come with fever, pain, oedema, erythema, crepitant and limitation of movement at the right lower extremity. in his history he had no complaint until weeks ago. perianal abscess has developed at this time and it has drainged spontaneously days later. than his complaints has comprised day duration. on physical examination, the temperature was . °c, pulse rate / minute, respiratory rate /minute and blood pressure was / mmhg. laboratory evaluation showed a haemoglobin . g/dl, leucocyte count of /mm (neutrophils %). serum electrolytes, renal and liver function tests were within normal limits. c reactive protein was elevated up to mg/dl, esr was mm/h. escherichia coli was isolated from wound and blood cultures. he was treated initially with ampicilinsulbactam ( g/day) and required attempt. even with optimal surgical and medical therapy, he dies at the third day of the treatment from septic shock. conclusion: the onset is generally gradual, and there is usually mild local pain and systemic toxicity, allowing clinical differentiation from the more fulminant clostridial myonecrosis. the surgical approach should be aggressive, but tailored specifically to the underlying cause of infection. antibiotic therapy is directed at a mixed aerobic-anaerobic flora, until culture reports are available. a case of iliopsoas abscess which is due to pseudomonas aeruginosa objectives: pyogenic psoas abscess, a rare but life-threatening infection, results from primary suppuration or is secondary to the spread of infection from an adjacent structure. primary iliopsoas abscess occurs probably as a result of hematogenous spread of an infectious process from an occult source in the body. primary iliopsoas abscess can occur in diabetus mellitus, intravenous drug abuse, aids, renal failure and immunosupression. ultrasound is diagnostic in only % of the cases. computed tomography should be done for definitive diagnosis and is considered the gold standard. stapylococcus aureus is the causative organism in patients with primary iliopsoas abscess, but pyogenic psoas abscess caused by pseudomonas aeruginosa is uncommon. because of this reason we reported this case. case: a previously well year old woman presented with a month history of right loin to groin pain, limping or limitation of hip movement, fever and nausea. she was a diabetus mellitus patient for years. on her physical examination, the temperature was . °c, pulse rate /minute, respiratory rate /minute and blood pressure was / mmhg. examination of the respiratory system, cardiovascular system and abdomen were found to be normal. laboratory investigations revealed total leucocyte count of /mm (polymorphs %), c reactive protein was elevated up to mg/dl, esr was mm/h. serum electrolytes, renal and liver function tests were within normal limits, but serum glucose level was elevated to mg/dl. her blood cultures were sterile, but abscess culture yielded pseudomonas aeruginosa which was taken during the surgery. she was treated imipenem ( g/ day) + amicasin ( . g/day) and required surgical drainage. she was treated and followed up days, and discharged at the end of the treatment. conclusion: in these patients treatment involves the use of appropriate antibiotics along with drainage of the abscess. an adequate knowledge of the causative organisms should guide the initial choice of antibiotics. depending on the results of the abscess fluid culture and sensitivity, adjustments should be made. percutaneous drainage or surgical drainage may be done in them. in conclusion early recognition, empiric antimicrobial coverage and aggressive drainage or debriment are indicated in these patients. cervical lymphadenitis in a diabetic woman f. Ç okça, a. azap, s. gö çmen, h. erdi sanli, s. gü l (ankara, kirikkale, tr) objective: rhodococcus equi infections are commonly seen in immunocompromised patients. exposure to domestic animals, such as horses and pigs may play a role in some cases. two thirds of the r. equi infections in immunocompromised were reported in hiv infected patients, and the rest divided between transplant recipients, immunosupressive medications and other kinds of immunosupression. the clinical picture presents with pulmonary infection in % of patients. here, we report a rare case of cervical lymphadenitis in a diabetic women due to r. equi. case: a sixty-year-old diabetic woman was admitted with the complaints of fever, right cervical erythematous swelling with tenderness and warmth. on physical examination; inflammation beginning from the right submandibular region and descending to the upper chest was detected. a tender mass of · · cm. was palpated on the right cervical region. ampicillin/sulbactam g/day was given emprically for a week with no improvement. the ct scan of the neck showed conglomerated lymphadenopathy extending from the submandibular area to the supraclaviculary region with . · cm in size. the mass began to fluctuate and cc abscess material was drained surgically. gram's stain of the purulent material showed polymorphonuclear leukocytes with pleomorphic gram positive coccobacilli. the cultures of the material grew r. equi. therapy was changed to teicoplanin and ciprofloxacin combination and surgical care of the wound with antiseptics was performed. after a month, intrevenous medical therapy was changed to oral route with roxythromycin and ciprofloxacin and was continued to months with complete resolution. conclusion: increased awareness and improved laboratory techniques help for the early diagnosis of rhodococcal infections. timely diagnosis is important because the microorganism is usually resistant to penicillin g, oxacillin, ampicillin, carbenicillin and cefazolin. the use of at least one antibiotic with intracellular activity is necessary in the treatment of r. equi infections. empirical two drug regimens with erythromycin, rifampin and/or ciprofloxacin are recommended. objectives: to analysed the features of spondylodiscitis (sd), their clinical presentation, the commonest diagnostic methods and the kind of treatment applied according to the different groups of the study. methods: a retrospective and descriptive study taking place amongst the patients diagnosed as having sd from till . in each case we studied the presence of underlying disease, primary infectious sources in the prior months, the way symptoms started, location, diagnostic methods, treatment and evolution, comparing between different aetiologies. results: patients with sd were studied. of them had pyogenic sd,( had spontaneous sd and had an sd after spinal surgery) and patients had tuberculous sd. were men ( to years; mean . ). patients with postoperative sd were the youngest (mean . y, p = . ). underlying diseases were found in % of patients, mainly in postoperative sd ( % of cases) (p = . ). an episode of previous bacteremia or infectious source was found in % and % respectively of patients with spontaneous pyogenic sd, significantly higher than in surgical sd ( % had bacteremia and % other infectious source, p < . ). the most common presenting symptoms were back pain ( . %) and neurological deficits ( %). frank fever occurred in % of cases, being more frequent in spontaneous sd ( %) than in postoperative sd ( %) or tuberculous sd ( %), p £ . . leukocytosis was found only in % of patients. postoperative sd presented the lowest levels of esr (p = . ). s. aureus was the most frequent bacteria isolated ( %) in pyogenic spontaneous sd, as coagulase negative staphylococci was in surgical sd. lumbosacral localization was detected in % of spontaneous pyogenic sd and in % of postoperative sd. tuberculous sd predominate in dorsolumbar region. paravertebral abscess formation was observed in % of pyogenic sd and in % of tuberculous sd (p = . ). surgical treatment was required in . % of tuberculous sd and in % of pyogenic sd (p = . ). outcome of patients with spontaneous sd was worse (sequelae in %), than in patients with surgical sd ( . %) or tuberculous sd ( %) (p = . ). conclusions: ) spontaneous sd was the most frequent and it occurred mainly in patients suffering from underlying diseases; ) nearly all patients had pain but only in / of them was accompanied by fever; ) the lumbar zone was the most frequent location; ) the majority of patients had a complete resolution of their symptoms only with medical treatment. background: the ethiopathogenesis of cns abscess includes a broad spectrum of pathogens and predisposing conditions, so that a polymicrobial flora is a quite frequent event. capnocytophaga spp. includes fastidious gram-negative organisms, usually underestimated in the common clinical practice, and poorly tested in vitro for antimicrobial susceptibility. surprisingly, also agents usually active on gram-positive pathogens demonstrated some efficacy against capnocytophaga spp. (i.e. erythromycin, rifampin, tetracyclines, cotrimoxazole, chloramphenicol, and glycopeptides), which is usually responsible of anecdotal episodes of cns infection (meningitis, brain abscess, and subdural empyema). methods and results: the fourth case report of capnocytophaga spp. brain abscess is herewith reported. a probable origin from a recent cat bite and a mandibular granuloma is suspected. due to the lack of clinical and neuroradiological response to neurosurgical debridement and an association therapy including imipenem, amikacin, clindamycin and fluconazole, empiric administration of linezolid ( mg/day) was attempted, and a rapidly favorable clinical, microbiological, and neuroradiological response was achieved. notwithstanding the identification of capnocytophaga spp. as the sole microorganism yielded by purulent drainage of a cns abscess, patients with multiple risk factors and recent surgery are expected to suffer from a polymicrobial cns infection. due to its favourable cns penetration and its dual mode of administration (both i.v. and oral), linezolid may represent an alternative option in the event of cns diseases borne by numerous risk factors and a suspected polymicrobial origin, especially when a lack of response to first therapeutic attempts is of concern. in the management of a cns abscess where the role of microorganisms with an unpredictable sensitivity profile remains of concern, chemotherapy should be directed also against potentially multiresistant organisms. considering also the relevant limitations given by the often poor cns penetration, the activity of glycopeptide agents is limited, compared with that of linezolid. aetiologies and antimicrobial resistance profiles of purulent meningitis study carried out in a hospital of infectious diseases, algiers objectives: bacterial meningitis is a serious clinical and medicolegal consequences if management is incorrect. meningitis protocols have recently been published by the british infection society/meningitis research foundation and are widely disseminated in our institution. local guidelines are also available on the hospital intranet and in the emergency department and acute medical admissions wards. this study investigated the level of understanding about meningitis and knowledge of the guidelines in medical staff of different grades working in the emergency department and the acute medical admissions unit in a large teaching and emergency hospital. methods: medical staff were interviewed faced to face and asked a series of questions on the management of meningitis. results were stored on a database and responses were analysed. results: general knowledge about meningitis was variable. although % knew that bacterial meningitis was a notifiable disease only % knew the procedure for informing the health protection agency and only % would notify viral meningitis. only % of responders were aware that guidelines could be viewed on the hospital intranet. only % correctly identified the indications and cautions for lumbar puncture. although the majority recognised the need for urgent administration of antibiotics % would omit antibiotics until further assessment and lumbar puncture results. only % were aware of the need to consider adding ampicillin to cover listeria in patients over years of age and there was uncertainty about the management of patients with penicillin resistance. conclusions: although protocols and guidelines for meningitis have been produced and are easily accessible the majority of medical staff were uncertain how to access and utilise this information. the level of knowledge and expertise in managing meningitis amongst medical staff working in a and e and the acute medical unit was poor and there is a need for further education to improve patient management. guidelines are of no value if they are not disseminated to front-line medical staff. objectives: the aim of this study was to evaluate the prevalence of penicillin resistant and multi-drug resistant pneumococci isolates in streptococcus pneumoniae meningitis. methods: a retrospective study was carried out on clinical records between january and october . among the csf samples the pneumococcal ethiology was confirmed by % positive cultures and % latex agglutination. antibiotic susceptibility testing was performed by disk diffusion method according to nccls standards. isolates of pneumococci with oxacillin zone sides of > mm are susceptible (mic < . microg/ml) to penicillin, while at those of < mm the mic has to be determined (by e -test). results: isolates from patients ( %) were found with penicillin-resistance (prp) -of which % were multi-drug resistant-and ( %) with penicillin susceptibility -of which % were resistant to other drugs. an abrupt onset of disease was found in % prp patients and % from non-prp ones. chest x ray pulmonary determinations were found in % prp patients and % non-prp ones. sixty-six per cent of prp patients and % of non-prp ones had a prior hospitalization. only % of non prp patients had a positive blood culture. antibiotic switch was made in % cases with prp isolates and % cases with non prp ones. the overall rate of mortality was %, with % for prp patients and % for non-prp ones. conclusions: non-prp isolates were the prevalent ethiology of s. pneumoniae meningitis. % of non -prp strains developed other drug resistance, and % prp strains were multi -drug resistant. prp meningites evolved more as a hospital-related pathology, with an abrupt onset, frequently associated with pulmonary determinations and higher mortality rate. background: although vaccination strategies have shifted the age distribution of meningitis to older age groups, few studies have specifically examined bacterial meningitis in the older adult. methods: from october to april , we prospectively included episodes of community-acquired bacterial meningitis, confirmed by culture of cerebrospinal fluid, which occurred in patients aged > years. we dichotomized the cohort with respect to age: patients aged ‡ years were defined as older adults and patients aged - years as younger adults. predictors for an unfavourable outcome (defined as score - on the glasgow outcome scale) were determined by logistic regression. we tested for statistical interaction between age group and potential prognostic factors by adding multiplicative interaction terms to the model. the mann-whitney u test and the chi-square test were used to identify differences between groups. results: of episodes ( %) occurred in older adults and episodes in younger adults ( %). streptococcus pneumoniae was the most common pathogen in older adults ( %). meningitis in younger adults was caused by neisseria meningitidis and s. pneumoniae in % and % of the episodes, respectively. older adults were more likely to present with the classic triad of bacterial meningitis (fever, neck stiffness and altered mental status) than younger adults ( % versus %; p < . ). the prognostic value of independent risk factors for unfavourable outcome was similar in both age groups. older adults had more complications during clinical course, resulting in a higher mortality rate than in younger adults ( % versus %; p < . ). sepsis was the most common cause of death in both age groups ( % in older adults versus % in younger adults; fig) . whereas older adults tended to die more often due to cardiorespiratory failure ( % versus %; p = . ), younger adults more often died due to brain herniation ( % versus %; p = . ). conclusions: bacterial meningitis in older adults is associated with high morbidity and mortality rates. elderly patients often present with classic symptoms and s. pneumoniae is the most common pathogen within this age group. whereas older adults often die due to cardiorespiratory failure, younger adults more often die due to brain herniation. incidence of serogroups and penicillin susceptibility in neisseria meningitidis isolates ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) objective: the aim of this study was to analyse the serogroup incidence and penicillin susceptibility in n. meningitidis before and after spanish epidemic outbreak in . in this year the public health service decided a massive vaccination in our sanitary area (galicia, north-west of spain, . inhabitants) and in autum of the inclusion of vaccine against n. meningitidis serogroup c in vaccination programme. methods: retrospective study of all cases of meningococcal disease confirmed by culture and/or pcr in the health care area of santiago de compostela (galicia) from to . results: in the period - we identified meningococcal disease episodes by microbiologic diagnosis ( . %, . % and . % to b, c and w respectively). in , serogroup c were the % of the isolates. in and the serogroup incidence was almost the same (b = . %, c = . %). from an increase in b serogroup cases were detected, in ( . %), in ( . %) and in ( . %). the most frecuent phenotype has been b p : . in c serogroup. during this period an increase in penicillin susceptibility was observed (in b serogroup % in and % in of the isolates were susceptible and in c serogroup % in and % in ). conclusions: the b serogroup is the most frecuent isolate during this period except in the years and . the strain that cause the epidemic outbreak in (c: b p : . ) was not isolated since . in our health care area, c: a serotype, was isolated for first time in , and since then, is the unique serotype isolated in c serogroup. incidence rate in c serogroup has changed from . / . in to . / . in . this decrease was caused by the drop of incidence rate on the youngest groups (< years and - years). the incidence rate in b serogroup during these years was modified from . / . in to . / . in . a four-year retrospective analysis of infective endocarditis in a belgian university hospital n. de visscher, b. delaere, b. krug, y. glupczynski (yvoir, be) objectives: to establish the epidemiology of infective endocarditis (ie) and determine the prognostic factors for adverse outcome in patients admitted to a university hospital with a cardiovascular surgery department. methods: between / and / , the clinical and laboratory features of all consecutive adult patients with a definite diagnosis of ie (duke criteria) were evaluated retrospectively by two infectious diseases physicians on the basis of clinical data charts and microbiological laboratory. results: patients ( men, women) presented with a definite diagnosis of ie. mean age was , yrs; cases ( %) were native valve endocarditis (nve) and ( %) were prosthetic valve endocarditis (pve); % of patients with nve had underlying valvular abnormalities ( bicuspidies, mitral prolapsus or regurgitation, others). ten out of cases of pve were late-onset episodes (> year after surgery). global mortality was % ( / pts), including patients ( %) still under antibiotic therapy. a higher mortality rate was observed in pve [ / ; ( %)] than in nve [ / ; ( %)]. overall, pts ( %) underwent surgery (mean: days following admission). valvular replacement was contra-indicated in pts because of critical status and/or major co-morbidities. the distribution of isolated pathogens was: streptococci: cases ( %) including cases of s. bovis, s. aureus: cases ( %, including mrsa), enterococci: cases ( %), miscellaneous: cases. the affected valves were: only aortic: ( %), only mitral: ( %), only tricuspidal: , aortic and mitral: , mitral and tricuspidal: , aortic, mitral and tricuspidal: . a high mortality rate was observed in s. aureus ie ( / [ %]), especially in the subgroup of patients with a pve ( / pts [ %] ). the mortality rate in patients with ie episodes caused by streptococci amounted % ( / pts). clinical microbiology and infection, volume , supplement , related, % (n = ) had previous surgery and % (n = ) were related to urinary or digestive tract procedures. only patients had illegal substance abuse. the most frequent predisposing acquired cardiac condition for native valve endocarditis was degenerative valvular disease in % ( / ). twelve percentage (n = ) had prior ie. the most frequent predisposing congenital cardiac condition was a bicuspid aortic valve in % (n = ). in % (n = ), no predisposing heart disease was discernible. causative microorganisms included: staphylococci in % (n = ) with s. aureus in % (n = ), cons in % (n = ), streptococci in % (n = ) with s. viridans in % (n = ), s. bovis in % (n = ), enterococci in % (n = ) and other pathogens in % (n = ). culture negative ie was reported in % (n = ). both in community-acquired and nosocomial ie, s. aureus was the most frequent causative agent. twenty-three percentage ( / ) were methicillin-resistant s. aureus. s. viridans ie was mainly community-acquired while enterococcal ie was nearly equally distributed between community and nosocomial origin. conclusion: compared to older series, we observed a high proportion of nosocomial ie and of prosthetic valve ie. s. aureus and e. faecalis were the most prevalent causative microorganisms. enterococci were nearly equally distributed between community and nosocomial origin, suggesting that nosocomial enterococcemia should be added as a major criterion, as proposed before for s. aureus. the role of aminoglycosides in combination with a beta-lactam for the treatment of bacterial endocarditis: a meta-analysis of comparative trials m. falagas, d. matthaiou, p. papastamataki, i. bliziotis (athens, gr) objectives: the addition of an aminoglycoside to a beta-lactam for the treatment of patients with infective endocarditis has been supported mainly from data from laboratory and animal studies. we sought to review the evidence from the available comparative clinical trials regarding the role of aminoglycosides in combination with a beta-lactam for the treatment of bacterial endocarditis due to gram-positive cocci. methods: the studies for our meta-analysis were retrieved from searches of the pubmed database and from references of relevant articles. included studies were trials that provided comparative data regarding the effectiveness of the treatment and/or mortality in patients receiving monotherapy with a betalactam or beta-lactam/aminoglycoside combination therapy. two independent reviewers performed the literature search, study selection, and extraction of data from relevant studies published in english during the period / - / . results: no clinical trial comparing beta-lactam monotherapy to beta-lactam/aminoglycoside combination therapy for the treatment of enterococcal endocarditis was found. we performed a meta-analysis of available comparative trials ( randomized controlled trials and comparative prospective trial) that included patients with bacterial endocarditis in native valves due to staphylococcus. aureus ( studies) or streptococcus viridans ( study). there was no statistically significant difference between the compared arms regarding mortality (or . , ci % . - . ), treatment success (or = . , ci % . - . ), treatment success without surgery (or = . , , and relapse of endocarditis (or = . , . nephrotoxicity was less common in the beta-lactam monotherapy arm compared to the beta-lactam/aminoglycoside combination therapy (or = . , ci % . - . , p = . ). conclusion: the limited evidence from the available prospective comparative studies does not offer support for the addition of an aminoglycoside to beta-lactam treatment of patients with endocarditis due to gram-positive cocci. a large multicenter randomized controlled trial may be necessary to reach a definitive conclusion on this issue. outpatient antimicrobial therapy for infective endocarditis. single-centre experience objectives: to evaluate the characteristics and outcome of infective endocarditis (ie) patients included in a outpatient antimicrobial therapy (opat) program. methods: from january to may all patients who received opat therapy for an ie were prospectively evaluated. inclusion in opat program require clinical stability and agreement of patients. active drug addiction was contraindicated for inclusion. antibiotic treatment was administered in bolus for once-daily antibiotics regimens. we used cadd-legacy tm plus (deltec, inc. st paul. usa) portable infusion system for either continuous or intermittentprogrammed bolus infusion. results: we included patients, male ( %), mean age years old (sd: . years). the diagnostic of ie was definite in cases ( with pathologic diagnosis), probable and possible. mostly of the cases were community-acquired ie ( %). mitral valve ie was the most frequent anatomical site involved ( %), followed by aortic ( %). native-valve ie represent the majority of cases ( %), but % were prostheticvalve and % were pacemaker lead ie. viridans group streptococci was the most frequent isolate ( patients, %) with cases of s. bovis ie. eleven patients had s. aureus ie ( %). at the time of the diagnosis, patients had valve rupture and patients had periannular abscess. a total of patients required some surgical intervention for the ie [ valvular replacement ( of them associated with aortic graft), pacemaker extraction and aortic graft]. the majority of the patients received outpatient monotherapy ( %). the most frequent antibiotic used was ceftriaxone ( % of the cases), followed by cloxacillin %, gentamycin %, vancomycin %, teicoplanin %, ampicillin % and other antibiotics in %. in % of the patients the vascular access was a perifericallyinserted venous central catheter and in % we used a portable infusion system. twelve patients ( %) had some complication during opat that require hospital readmission, of which could return to opat program. three patients had a fatal outcome (deaths) during admission, not related to ie complications. the mean duration of opat was . days per patient, and globally supposed . days of hospital admission savings. conclusion: opat for ie can be a good therapeutic option for ie stable patients. this procedure can represent a considerable amount of hospital admissions savings, improving also patients' well-being, and must be take into account for the treatment of this disease. objectives: botulism, a neuroparalytic illness, is caused by toxin produced by clostridium botulinum. food born botulism, a potentially lethal neuroparalytic disease, is caused by ingestion of preformed toxin. clinical illness is characterised by cranial nerve paralysis, followed by descending flaccid muscle paralysis. in this article we report a case series including a family group of type e botulism after ingestion of an iranian traditional soup. methods: in january , patients of a family group developed clinical manifestations of botulism - hours following ingestion of a traditional soup. their main clinical presentations were severe weakness ( . %- case) and lethargy ( . %- case). other signs and symptoms were blurred vision, fixed and dilated pupils, diplopia, dry mouth and decreased gag reflex. based on clinical finding, all patients received monovalent antitoxins (a, b, c). stool, gastric fluid and serum samples were sent for toxicological evaluation using the standard mouse bioassay. results: type e toxin was detected in the stool and serum sample of only one patient. all patients recovered and discharged one week after admission. conclusion: this study confirmed that prompt administration of antitoxin can prevent progression of disease based on clinical judgment and also may be life saving. in this case series study, we observed a short incubation period of - hours only in type e botulism. an outbreak of group g streptococcal pharyngitis among hospital personnel considered to be foodborne n. karabiber, a. gurbuz ertas, m. karahan, e. aykut arca, z.c. karahan, a. tekeli (ankara, tr) introduction: food-born outbreaks of streptococcal pharyngitis are relatively rarely reported,and while group a streptococci are the main causative agents, only a few epidemics caused by group g streptococci have been published. we describe here an outbreak of group g streptococcal pharyngitis occurred among the staff of a teaching hospital in ankara.the outbreak: an explosive outbreak of pharyngitis occured mainly among the staff working in certain departments (i.e. intensive care units, operation rooms) of tü rkiye yü ksek ihtisas teaching hospital, in january . methods: a total of ( and ; and from catering firm personel) throat cultures were evaluated in days,and bhs strains were isolated, and on the first and the second days, respectively. presumptive identification by nbacitracin and trimethoprim/sulfametoxazole disk diffusion test showed that strains were non-group a, strains were group a streptococci. in definite grouping by streptococcus grouping kit (avipath-strep,omega), strains were found to be lancefield group g, strains were found to be group a streptococci (gas). one of the gas strains was isolated from a catering staff on the first day, the other two were isolated from two health care personnels on the second day. during the outbreak, of catering firm personel ( %) were found to positive for group g streptococci. all the bhs tested were found sensitive to penicillin g and erythromycin by agar disc diffusion method. conclusions: the configuration of the epidemic curve suggested a common source of exposure. since respiratory spread of streptococci in such a rapid fashion would be highly unlikely and that of positive throat culture were from the staff of the catering firm that provide all the food services for the hospital, and that most of them were working at the departments in which the outbreak occurred, we considered that the outbreak might be food-borne. prompt treatment with penicillin all the ill personnel and -day holiday coming consequently january, terminated the outbreak. all the strains were cryopreserved for further typing studies.we are now typing these strains by pulsed field gel electophoresis (pfge) after digestion with smai restriction endonuclease. our initial results show that these strains are of the same origin. outbreak of acute gastroenteritis in an air force base in western greece e. jelastopulu, t. constantinidis, t. kolokotronis, d. venieri, g. komninou, c. bantias (patras, andravida, gr) objectives: on september , an operative training day at the air force base in western greece, soldiers and staff experienced an outbreak of acute gastroenteritis. the purpose of this study was to determine the causes of the outbreak and develop control measures. methods: following the assessment of descriptive epidemiology, a case-control analytic approach was utilized with randomly selected cases and controls. patients completed a questionnaire pertaining to the presence and severity of gastrointestinal disturbances, date and time of symptoms onset and consumption of food items served in the base on the implied training day. adequate questionnaire was administered to the controls. odds ratios were calculated and statistical significance was determined using x test. samples of food items were collected for bacteriological examination. results: the overall attack rate was at least % among the approximately attendees. the outbreak started abruptly in the late afternoon on september, peaked at midnight and ended about hours later. from the interviews and the analysis it was established that the lunch (beef, macaroni, tomato sauce and grated cheese) consumed several hours prior to onset of symptoms by affected military personnel was the likely source of the outbreak with a strong statistical association. there was only one subject who did not eat lunch. among the symptoms the most prominent were watery diarrhoea ( %) and abdominal pain ( %). relatively few indicated vomiting ( %) and nausea ( %). the mean incubation period was h. in the bacteriological examination, staphylococcus aureus was detected in a sample of raw beef and in two samples of grated cheese (rest-cheese from lunch and an unopened package). conclusion: the short incubation period with abrupt onset, the symptomatology and the short, self-limiting nature of the illness, are suggestive of gastroenteritis caused by an enterotoxin-producing bacterium. s. aureus is considered to be the most likely cause. although mortality and longer-term morbidity are uncommon with food poisoning caused by enterotoxin-producing bacteria, this outbreak highlights its capacity to cause short term, moderately-severe illness in a young and healthy population. it underscores the need for proper food handling practices and reinforces the importance of appropriate microbiological specimen collection from cases, as well as the public health importance of timely notification of such outbreaks. occurrence, characterisation and antimicrobial resistance pattern of staphylococcus aureus strains isolated from dairy products in southern italy g. la salandra, e. goffredo, c. pedarra, m.c. nardella, a. parisi, a. dambrosio, n.c. quaglia, g.v. celano, g. normanno (foggia, valenzano, it) objectives: the ingestion of food contaminated by enterotoxins (ses) synthesized by staphylococcus aureus is responsible of one of the most common foodborne diseases (staphylococcal food poisoning-sfp). since s. aureus is often involved in cases of subclinical mastitis of ruminants, milk may results contaminated. infact, the dairy products are frequently related to cases of sfp, expecially in areas characterized by a high level of consumption of these products. consequently an active microbiological surveillance is needed in order to control the risk of sfp and to allow the improvement of the public health standards. s. aureus also show a large antimicrobial resistance pattern. in this work are reported the results of a survey conducted on the occurrence of s. aureus in dairy products from apulia region (southern italy). furthermore, the isolated strains were characterized in order to determine their ability in synthesizing ses and to evaluate their antimicrobial resistance pattern. methods: samples of dairy products (milk, cheese, mozzarella cheese, ricotta cheeses) were analysed for the detection of s. aureus. the isolated strains were tested for the detection of ses, using the reverse passive latex agglutination test (sea to sed) and submitted to pcr to detect enta, entb, entc, entd and ente genes. furthermore, the strains were tested for susceptibility to ampicillin, tetracycline, gentamicin, eritromycin, enrofloxacin, co-trimoxazole, teicoplanin and vancomycin, by the agar diffusion method. results: out of samples analysed, ( . %) resulted contaminated with s. aureus and, among these, ( . %) have been recognized as enterotoxigenic strains ( samples of milk, samples of mozzarella cheese, samples of cheese from ovine milk and sample of cheese). all the strains tested (one per each positive sample) showed antimicrobial resistance properties but none of these was resistant to teicoplanin and vancomicin. conclusions: the results obtained from this survey show that milk and dairy products from southern italy are frequently contaminated by enterotoxigenic strains of s. aureus and highlighted the need to implement strict hygienic control measures along the food chain in order to decrease the risk of spf. furthermore, the presence of antimicrobial-resistant strains of s. aureus in food may be considered a source of communityacquired infections, with the direct risk of transfer of the antimicrobial-resistance to intestinal human microflora. objectives: infection accounts for about one-third of cases of fever of unknown origin (fuo), which remains a major diagnostic challenge. recently, f- -fluorodeoxyglucose (fdg) positron emission tomography (pet) has entered the field of clinical infectious diseases. fdg accumulates in tissues with a high rate of glycolysis, which is present in malignant cells and in all activated leukocytes. the aim of this prospective multi-centre study was to validate the use of fdg-pet as part of a structured diagnostic protocol in the general patient population with fuo. methods: from december to july , patients with fuo, defined according to the revised petersdorf criteria, were recruited from one university hospital and five community hospitals. a structured diagnostic protocol was used. fdg-pet was performed after certain obligatory laboratory tests, chest xray and abdominal ultrasound. the final clinical diagnosis was used for comparison with the fdg-pet results. results: a final diagnosis was established in patients ( %): infections, malignancies, non-infectious inflammatory disorders and miscellaneous causes. of the total number of fdg-pet-scans, % were helpful. positive predictive value of fdg-pet was % and negative predictive value was %. fdg-pet was helpful in all patients diagnosed with an infection except for one case of pyelonephritis. contribution of fdg-pet to the final diagnosis did not differ significantly between the university hospital and the community hospitals. fdg-pet was not helpful in any of the patients with normal erythrocyte sedimentation rate (esr) and c-reactive protein (crp). conclusion: in addition to the apparent value of fdg-pet in diagnosing different infectious diseases as described in several case series, fdg-pet is a valuable imaging technique as part of a diagnostic protocol in the general patient population with fuo and a raised esr or crp. based on previous studies comparing gallium- -citrate or labelled leukocyte scintigraphy and fdg-pet in patients with fuo and resulting from favourable characteristics of fdg-pet, conventional scintigraphic techniques may be replaced by fdg-pet in institutions where pet is available. emergence of clindamycin-resistant streptococcus pyogenes causing cellulitis epidemiology of viral respiratory infections a newly discovered human pneumovirus isolated from young children with respiratory tract disease human metapneumovirus as a cause of community-acquired respiratory illness seroprevalence of human metapneumovirus in japan - . carriers into account when studying the dynamics of pneumococcal transmission and modelling the effect of pneumococcal vaccination in young children erythromycin-resistant streptococcus pneumoniae isolated in spain: serotypes, clones and mechanisms of resistance ( %) and f ( %) that accounted for % of eryr strains. among eryr strains ( %) had mlsb phenotype ( % constitutive and % inducible) and ( %) had m phenotype. the genes detected in mlsb isolates were: ermb in isolates, and ermb and mefe genes in isolates. all ( %) mlsb isolates with resistance to tet had tetm gene and of them had int gene (related to tn -like). seven positive ermb strains susceptible to tet had int gene spain f- , spain b- , sweden a- and st - f) accounted for % of these strains. capsular switching was observed in two clones, spain f- (serotypes f and a) and sweden a- (serotypes a, f suggesting the spread of tn -like elements. the ermb positive strains, related to spain f- , spain b- , sweden a- and st - f clones, were more frequently isolated in adults us) objective: to characterize changes in the frequency of occurrence of bacterial pathogens responsible for pneumonia in hospitalized patients in europe for the years - and examine select antimicrobial susceptibilities (s) for predominant pathogens. the emergence of resistance (r) among pathogens responsible for pneumonia has resulted in changes to empiric therapy, with increasing reliance upon third-and fourthgeneration cephalosporins, beta-lactam/beta-lactamase inhibitor combinations, carbapenems and fluoroquinolones. methods: participating european medical centres ( - /year) referred consecutive, non-duplicate pathogens ( isolates) from lower respiratory tract sites determined to be significant by local criteria as the probable cause of pneumonia. all identified isolates were tested for s by the broth microdilution method and . %, respectively), increased significantly in ( . % s), and returned to near- levels in . esblphenotypes (cro or caz or aztreonam mic ‡ mg/l) remained essentially unchanged among ec between and ( . % and . %, respectively), whereas among ksp increases were more substantial ( . % and . %). metallobeta-lactamase-producing pa were identified during the study from italy vim- ) methods: four-hundred consecutive mrsa isolates were collected at centres (max. isolates per centre) as part of a multicentre study conducted throughout germany in . isolates were collected from various sources, including colonization sites as well as infectious foci. only one isolate per patient was included and all isolates were spa-genotyped. cps were determined by slide agglutination with cp-specific antibodies (anti-t -dt, anti-t -conjugate, anti- -repa). the serotypes were confirmed by immunodiffusion using lysostaphin-digested cell lysates. results: in the present study, we serotyped mrsa isolates collected most recently in a german multicentre study. all mrsa isolates evaluated were one of the serotypes tested invasive pneumococcal disease in adults in north-rhine westphalia methods: surveillance for our current study focused on north-rhine westphalia, the largest federal state in germany ( million inhabitants). ( . %) acute care hospitals microbiological laboratories serving these hospitals agreed to participate. we studied hospitalized patients older than years of age. a case of ipd was identified by the isolation of s. pneumoniae from an otherwise normally sterile site. isolates were verified for species diagnosis by optochin testing and bile solubility, and for serotyping by the neufeld quellung reaction. mics of penicillin g, amoxicillin, cefotaxime, cefpodoxime, cefuroxime, clarithromycin us) objectives: carbapenems are the most reliably active betalactam antibiotics against enterobacteriaceae and are often the treatment of choice for infections caused by multi-drug resistant isolates. while carbapenem resistance has occasionally been reported in enterobacteriaceae, there are limited data on its frequency and distribution. methods: two large ongoing surveillance databases were searched for imipenem (imp) and ertapenem (etp) resistance in enterobacteriaceae: smart (study for monitoring antimicrobial resistance trends), a worldwide program focusing on community-and hospital-acquired intra-abdominal pathogens, and iss (icu surveillance survey), a us program focusing on icu isolates from any sterile body site. results: the overall frequencies of carbapenem-resistant enterobacteriaceae remained < % in smart and < % in iss throughout the periods of observation (see table). for % of esbl producing k. pneumoniae and e. coli were resistant to etp or imp and rates varied by geographic region. all isolates studied to date have exhibited multiple resistance mechanisms. conclusion: carbapenem resistance was uncommon among clinical isolates of enterobacteriaceae in these surveillance studies. its observed frequency varied by species and geographic region no significant seasonal variability in the prevalence of emergence of streptococcus b-haemolyticus strains in swabs was observed. conclusions: . seasonal fluctuations of pharyngeal discussion: with regard to high prevalences of giardiasis and enterobiasis it increase the prevalence that intestinal parasitic infections. it is suggested to decrease the rate of these parasitic infections in the region by strict programes that help to increase the knowledge of students, their parents and teachers about hygen. results: the study included patients, with a mean age of . ± . . ( . %) were women. the predisposing factors were: renal lithiasis patients ( . %), prostatic adenoma ( . %), vesical structure disease ( . %), vesical functional disorder ( . %), chronic kidney failure ( . %). the underlying diseases included: diabetes mellitus ( . %), immunosuppression ( . %), previous urinary tract instrumentation ( . %), permanent catheter ( . %). the mean hospital stay was . ± . days. the mean duration of symptoms was . ± . days the absence of leukocyturia or mictional syndrome does not exclude the presence of complicated upper uti. ) the high percentage of bacteriemia necessitates blood cultures, with e. coli being the most common pathogen. ) the associated morbidity and mortality are important in association with sepsis or septic shock gr) objectives: to estimate the incidence of streptococci in community acquired urinary tract infections (uti) and also to carry out the in vitro antibiotic resistance of streptococci in urinary tract infections %) were enterococcus avium, ( . %) were enterococcus gallinarum and ( . %) were streptococci group b. the in vitro antibiotic resistance of enterococcus faecalis was: penicillin g . %, ampicillin . %, gentamicin %, streptomycin . %, nitrofurantoin %, ciprofloxacin . %, tetracyclines . %, vancomycin . %, linezolid %. the in vitro antibiotic resistance of enterococcus faecium was: penicillin g %, ampicillin . % tremolieres for the french aup study group background: short-course therapy for acute uncomplicated pyelonephritis (aup) is the newly suggested standard. talan et al. have demonstrated that oral ciprofloxacin (cip) for days, was associated with greater cure rates than a -day trimethoprim-sulfamethxazole regimen. we assessed efficacy and tolerance of a -d. regimen of cip (study i), then of levofloxacin (lvx) in study ii results: of (i) and (ii) enrolled pts. aged . ± . y., and , aged . ± . y. were retained for itt analysis; . % and . % had positive blood cultures. escherichia coli was the uropathogen in . % and % of cases. finally (i) and (ii) were retained for per protocol (pp) analysis. at v bacterial eradication rates were . % and . %. global cure rates were . and . % at v and . % and . % at v with only less than % of lost to follow-up between v and v in both cases. side effects were observed in . % and . % of pts. who received or more fq doses. conclusions: aup treatment with lvx mg hiv-infected patients and drug addicts were excluded. antimicrobial susceptibilities of all s. pyogenes isolates were studied by microdilution method, and macrolide resistance phenotype by double disc test. macrolide resistance genes were detected by pcr. results: over the -year study period, there were episodes of cellulitis. the infection was microbiologically ). of note, all cases of cellulitis due to clindamycin-resistant strains occurred during the last years of the study. five ( %) patients presented with stss and died ( due to an erythromycin-resistant strain). overall mortality (< days) was % this resistance might become a problem when treating s. pyogenes infections, especially stss cases. p risk factors for community-acquired bacteraemic gram-negative cellulitis an administrative database was used. then we selected the patients with blood cultures obtained at the time of the cellulitis episode using the microbiology laboratory database. nosocomial cellulitis were excluded. a standardized data collection form was used to review the hospital records. in statistical analyses, student's t test was used for the comparison of mean values and chi square test and fisher's exact test for the comparison of categorical data (two tailed). results: of the patients with limb cellulitis identified in the study period, patients had blood cultures and were selected for the analysis. bacteremia was detected in of the patients ( . %), of them due to gram-negative microorganisms hemorrhagic rash was present in . % cases. koplick spot was found in . % cases. measles was associated with streptococcal tonsillitis in . % cases, with oral candidiasis in . % cases and with pulmonary tuberculosis in . % cases. severe forms of evolution were observed in complicated cases with: encephalitis ( . %) or bronchopneumonia ( . %), which required intensive care unit survey. we registered only one deceased, in a case of measles encephalitis in gipsy collectivities even it's very difficult, it's necessary to was performed. respiratory samples were tested routinely for twelve common respiratory pathogens. results: over the study period, of samples processed, -six cases were community-acquired and ( %) patients had significant co-morbidities. cough was the predominant reported symptom. chest x-ray was performed in cases, of which showed abnormalities. bronchiolitis ( / ) was the commonest initial clinical diagnosis. the majority ( %) of patients received antibiotic therapy, but a convincing bacterial pathogen was isolated in less than half of these cases. thirty patients were admitted for management. more than one virus was identified from patients, with rhinovirus being the predominant co-infection. overall, the average length of stay was . days. however, where hmpv was the sole pathogen identified, average length of stay was . days. conclusion: our data suggests that hmpv infections are more common in children with underlying co-morbidities. the rate of radiological imaging was higher than expected and perhaps is a reflection of the patient population or the degree of severity of illness. nosocomial acquisition occurred in cases, which has implications for patient cohorting acknowledgements: the financial support for this study was provided by kuwait university research grant / . evaluation of infection control practices in haematopoietic stem-cell transplant facilities in german-speaking countries: variation of measures reflects lacking evidence s. wenzler-rö ttele, a. conrad, w.v. kern, h. bertz, f.d. daschner, m. dettenkofer (freiburg, de) objective: haematopoietic stem cell transplant (hsct) recipients are highly immunocompromised during pre-and postengraftment. thus, they are cared for in specialised facilities and versatile precautions are practised in order to prevent nosocomial infections. however, there is a lack of evidence whether these interventions are effective. furthermore, most of the measures are cost-intensive and restrict the patients' comfort. for evaluation of precautions, a survey was performed to assess the spectrum of measures commonly practised. methods: a questionnaire was compiled asking in detail for infection control measures differing according to allogeneic and autologous hsct recipients. the questionnaire was sent to hsct facilities in germany, austria and switzerland. results: questionnaires ( %) were filled in and sent back. among the centres, were university hospitals, and teaching hospitals. the overall number of transplantations that were performed by the facilities varied considerably and ranged from to /y for auto hscts and from to /y for allo hscts. % of the institutions performing allo and auto hsct have implemented different precaution standards for each group. some measures regarding allo hsct were routinely adhered to in practically all institutions: accommodation in single rooms ( %), interdiction of plants and opening of windows ( % each) and protection from waterborne bacteria by use of terminal tap water filters ( %). % of hsct facilities perform their allo transplantations in hepa-filtered rooms and % are providing laminar air-flow for this population. there was a broad spectrum of different measures regarding barrier precautions: gowns when entering the room (required in % of centres for allo and % for auto hsct) and face masks ( % allo and % auto hsct). precautions to be followed by the patient varied among centres, e.g. specification of the face mask/respirator to be worn outside the isolation room (for allo hsct: % surgical mask, % ffp , % ffp and % ffp ). conclusion: the broad variety of different preventive measures performed by the different facilities reflects lacking evidence for many infection control precautions that are commonly practised in the care of hsct recipients. this survey provides the basis for further studies within the onko-kiss project (hospital infection surveillance system for patients with haematologic/ oncologic malignancies). objectives: in this study it was our aim to evaluate the microbiological contamination of physiological serum flasks in use in medical day center for wound cleaning and to identify the isolated microorganisms. methods: we have collected saline solutions from health care centres localized in the health sub-region of coimbra. from each centre we have recovered aleatory flasks in current use.the samples were transported at ordm;c and maintained at this temperature until its processing. saline solutions were seeded by the pour-plate technique in plate count agar and plates incubated at and ordm;c for h. the saline solutions were evenly spread over the surface of blood agar and sabouraud chloramphenicol agar (sab chl-d). the transfers of saline solutions flasks were also tested for microbiological contamination with a sterile cotton swab that was rubbed vigorously, over the transfer surface and directly applied on blood agar media. blood agar plates were incubated at °c for h and sab chl-d plates were incubated at °c and °c and examined daily for a period of days before declared as culture negative. microbial identification was firstly accomplished by employing conventional morphological and biochemical tests. when identification was not possible by these methods, s rrna gene sequence determination and phylogenetic analysis were used for bacterial strains and in the case of moulds we performed the amplification and sequencing of internal transcriber spacers region of . s gene. results: from the saline solutions analysed, . % were contaminated. a total of strains were isolated, % could be identified to species level using morphological and biochemical tests, the remaining % were identified by gene amplification and sequencing. about . % of the identified strains were gram-positive cocci, the second dominant type of strain were gram-positive bacilli ( %), and the third dominant type of strains were gram-negative bacilli and moulds, both with . %. the most frequent contaminants belong to human normal flora ( %), supporting the idea that the source of contamination of saline solutions analysed was human, in contrast with % of contamination due to the environment. conclusions: the contamination of the saline solutions is due to inadequate clinical practices. these results claim for more strict hygienic measures and for the replacement of big flasks by single use flasks with an incorporated overture used for wound irrigation. frequencies of cmv-ie specific memory t cells are inversely correlated with alloimmune memory and serum creatinine in kidney transplant patients p. nickel, g. bold, f. presber, c. schö nemann, j. pratschke, d. bitti, f. kern, h.-d. volk, p. reinke (berlin, de) background/aims: cytomegalovirus infection is a significant cause of morbidity in transplant patients and has been associated with allograft rejection. in this study frequencies of ifng-producing t cells following ex-vivo stimulation with protein-spanning peptide pools for cmv proteins pp and ie as well as donor-reactive t cell frequencies were serially determined during the first months after renal transplantation (tx) to analyse the relation of cmv specific t cells, virus control and alloimmunity. patients: kidney transplant recipients were included. immunosuppression generally consisted of anti-il- r mab, calcineurin inhibitor, mmf and steroids. presensitized patients received an induction by x low dose okt- , anti-tnf mab, anti-cd mab and x plasmapheresis. patients received fty- , cyclosporine and steroids. methods: pbmcs from renal transplant recipients were analysed in a computer-assisted elispot assay before and at multiple times (mean ) post-transplantationfor ifn-yproducing t cells following in-vitro stimulation for hrs by irradiated donor cells and pools of overlapping peptides conclusions: although temporary r declines were seen among some european pneumonia pathogens, all showed increasing r to most class agents during the study period. the increase in esbl among enterobacteriaceae, and r among pa to most agents except polymyxin b, are especially worrisome. continued longitudinal comparisons of emerging pathogens and changing susceptibility profiles are critical elements in guiding empiric therapies and epidemiologic interventions. week, all participating hospital inpatients were swabbed on three anatomical sites: throat, nose and groin. we investigated the molecular epidemiology of the mrsa isolates collected from patients in hospitals using the pfge method with the smai restriction enzyme. cluster analysis was carried out using bionumerics software. band-based similarity dice coefficients were used for dendrogram construction, which provides a quantitative assessment of strain similarity. samples were defined to belong to a cluster using a similarity coefficient of % or higher. pfge profiles were compared with the most similar strains from the harmony iums global mrsa database.results: different restriction profiles were observed among the mrsa isolates and patients. isolates from the same patient but from different anatomical sites had similar pfge profiles. clusters of mrsa strains could be identified with the two largest clusters containing ( %) and ( %) patients, respectively. strains from these major clonal clusters occurred in and out of the hospitals, respectively. isolates from the cluster with patients were most similar to the well-known iberian clone: france a ( strains), belgium e ( strains), france b, france c and northern germany i ( strain each). isolates from the next largest cluster of patients correlated with a group of strains previously found in finland and belgium: belgium e ( strains), finland e ( strains) and finland e ( strain). the remaining strains were most closely related to belgium ec ( strains), berlin iv ( strain), southern germany ii ( strains) and uk e ( strains). conclusion: two major clonal clusters of mrsa strains were found to be dominant among hospitals inpatients in luxembourg. the molecular diversity of circulating strains was fairly diverse and profiles were very similar to previously described patterns in neighbouring countries and europe. further sequence-based genotyping is warranted to gain a better understanding of the clonal structure and elucidate transmission patterns. enterococci were identified by basic tests and by pcr amplification of ddl genes. susceptibility testing was performed using the icls broth microdilution method. resistance genes were detected by pcr, selected vana, vanb and vanc amplicons were sequenced. macrorestriction analysis (smai) resolved by pulsed-field gel electrophoresis (pfge) was performed. results: during the study vre isolates with different phenotypes of resistance to glycopeptides were obtained from specimens. the prevalence of vre in the gastrointestinal tract was . %. one e. faecalis (isolated from patient arrived from us) and e. faecium isolates, harbouring vana genes, demonstrated mic's of vancomycin (van) and teicoplanin (tec) - and - mg/l respectively. three e. faecium and four e. gallinarum isolates were vanb-positive, with van and tec mic's > and . - mg/l respectively. all stains were susceptible to linezolide. among e. faecium isolates with vana genes one predominant pegf type was observed, differentiated in nine pegf sub-types. each of three other pegf types detected seemed to be unique. among six vana genes sequenced, four demonstrated similarity to vana gene from e. faecium (genebank af ) and two to -vana gene from e. faecalis (genebank ay ). in two sequenced vanb genes from in e. gallinarum nucleotide substitutions, resulting in seven new amino acid substitutions, were detected. conclusions: heterogeneity of glycopeptide-resistance genes, circulating in haematological centre, leads to the conclusion that their spread is not a local phenomenon. spread of vre is an emerging and, possibly, underestimated problem for russia. study of resistance and clonal relatedness of clinical isolates of stenotrophomonas maltophilia from a hospital in northern spain c. valderrey, e. sevillano, f. calvo, l. gallego (bilbao, es) objectives: the aim of this work was to study the antibiotic resistance and genetic relatedness among clinical isolates of s. maltophilia isolated from patients with tract respiratory infections. methods: the study included s. maltophilia isolates obtained in a hospital from bilbao (northern spain) during (from january to october). susceptibility to antimicrobial agents was determined by the disk diffusion method following the nccls recommendations. the antibiotics tested were imipenem, meropenem, cefotaxime, ceftazidime, cefepime, aztreonam, amikacin, tobramicin, ciprofloxacin, ofloxacin and trimethroprim/ sulfamethoxazole. total dna was used as target for pcrfingerprinting experiments with primers rd , eric , ap , m and rnar and . to detect class integrons, primers cs and cs were used in amplification experiments.results: resistance to antibiotics tested was the following: imipenem ( %), meropenem ( %), cefotaxime ( %), ceftazidime ( %), cefepime ( %), aztreonam ( %), amikacin ( %), tobramicin ( %), ciprofloxacin ( %), ofloxacin ( %) and trimethroprim/sulfamethoxazole ( %). pcr-fingerprinting technique was only useful when eric primer was used identifying distinct genotypes. the other primers were not able to produce reliable band patterns. patients with several isolates maintained the same clone along time, although there are two patients from which two different genotypes have been isolated, and two clones that have been isolated from more than one patient. class integrons were detected in % of isolates ranging in size from of to bp ( isolates bored combinations of two structures). conclusions: trimethroprim/sulfamethoxazole and amikacin showed the best activity against the isolates tested. for pcrfingerprinting experiments the best primer was eric which produced reliable and reproducible band patterns. there was a high clonal diversity since different genotypes were identified among the patients included in the study. many isolates bored class integrons with sizes similar to those detected in other nonfermenters bacilli from the same environment.methods: -identification: the strains were identified by colonial morphology, haemolysis on blood agar plates, biochemistral and antigenic identification; antibiotic susceptibility testing: all the strains were tested by disk diffusion according to the national committee for clinical laboratory standard methods. mics were determinated by screening test or mic evaluation in solid media. results: our study concerns bacterial strains isolated from january to june . among the strains isolated, neisseria meningitidis represented the most number of cases with . %.these were distributed among all different age groups. serogroup a was the most predominant and represented . % of total strains while groups b and c represented . % and . % respectively. streptococcus. pneumoniae represents the second causes of purulent meningitis with . % while haemophilus. influenzae b is the third causative bacterial agent with . %.this last agent is most predominant among infants less than years of age in % of cases. neisseria. meningitis is susceptible to all types of antibiotics tested. however, haemophilus. influenzae b produced an inactivating enzyme (penicillinase) in . % of cases. the resistance was associated to cotrimoxazole in . % of cases. the results of mic done on streptococcus. pneumoniae show that . % of strains has an intermediate resistance to penicillin and high level of resistance in . %. the amoxycillin is active in . % of the strains,in the opposite cefotaxim has an intermediate resistance in . % and a high level of resistance in . % of the strains. the resistance to penicillin was associated with resistance to erythromycin, cotrimoxazole or to both in some cases. conclusion: streptococcus. pneumoniae represents the second causative bacterial agent responsible of purulent meningitis and showed an increasing prevalence of resistance profiles to penicillin and cefotaxim in our hospital. this implicates an effective microbiological and epidemiological control.conclusion: as expected in a referral hospital with a cardiac surgery department, the prevalence of s. aureus ie was elevated as well as the attributable mortality rate. the high global mortality rate may be explained by the high frequency of severe co-morbidities and by the late referral of patients to hospital. our data suggest that there is room for improvement in the diagnosis and management of ie in a multidisciplinary collaborative approach. objective: to determine the clinical, epidemiological, diagnostic, and therapeutic characteristics of a series of cases of prosthetic valve endocarditis. methods: we undertook a retrospective, descriptive study of cases of prosthetic valve endocarditis obtained from a series of definite or probable left sided infectious endocarditis from six second-or third-level andalusian hospitals from to . results: of the cases of prosthetic valve endocarditis, ( . %) were definite and ( . %) possible. the mean age was ± years, and they were more common in men ( %). late infection was more common than early involvement ( vs. cases). the aortic valve was involved in cases ( %) and the mitral valve in cases ( %. most ( %) of the valves were made of metal and prior handling had taken place in cases ( %). clinical characteristics were fever %, constitutional syndrome %, murmur %, vascular events %, and immune phenomena %. complications included left ventricular failure %, kidney failure %, peripheral embolism %, cns embolisms % and heart block %. the etiology was as follows: in early prosthetic valve endocarditis the three most common pathogens were s. coagulase-negative ( %), s. aureus ( %) and enterococcus ( %). late prosthetic valve endocarditis involved s. viridans ( %), s. coagulase-negative ( %) and s. aureus ( %). transesophageal echocardiography alone in cases ( %), and transthoracic followed by transesophageal echocardiography in cases ( %). medical therapy was applied in cases ( . %) and surgery in ( . %). a cure was achieved in cases ( %), the other ( %) dying. of those who underwent surgery, . % died and . % of those who were treated medically died. the death rate from early prosthetic valve endocarditis was greater than that for late prosthetic valve endocarditis ( % vs. %). conclusions: ) prosthetic valve endocarditis is a very serious infection which is still associated with an excessively high mortality, despite advances in diagnosis and treatment. ) early prosthetic valve endocarditis has a worse prognosis than late prosthetic valve endocarditis, due to its distinguishing pathophysiological features. ) the greater mortality seen in patients who underwent surgery is probably associated with the fact that they had more complications, such as perivalvular abscesses or persistent infection. outcome of infective endocarditis e.e. hill, s. vanderschueren, p. herijgers, m-c. herregods, p. claus, w.e. peetermans (leuven, be)objectives: despite progress in diagnosis and therapy, almost half of patients with infective endocarditis (ie) has at least one complication and overall mortality remains high. the aim of the present -year prospective observational study was to define predictors of outcome in patients with ie. methods: from june through december , all first episodes of definite ie by the modified duke criteria, encountered in a single tertiary-care medical center, were registered and followed-up for months. results: overall, patients suffered ie episodes. sixtyone percentage were males. the median age was years (range - ). fifty-five percentage of episodes were referred from another hospital. at least one complication occurred in %. surgical intervention was performed in % and was mainly indicated because of congestive heart failure. the median time from diagnosis to surgery was days (range - ). six-months mortality was % (n = ). in bivariable analyses, factors associated with -months mortality were: age, female gender, causative microorganism, nidus of infection and therapeutic policy. six-months mortality was % for native valve ie and % for prosthetic valve ie; twenty-five% for nosocomial ie and % for community-acquired ie. six-months mortality rates for microorganisms were: staphylococci % (n = ) [s. aureus % (n = ) and cons % (n = )], enterococci % (n = ), streptococci % (n = ) and other microorganisms % (n = ). the -months mortality for patients with a contraindication to surgery was % (n = ), for patients conservatively treated without a contraindication % (n = ) and for combined surgical-medical treatment % (n = ). in multivariable logistic regression predictors of -months mortality were age (or, . ; % ci, . - . ; p = . ), causative microorganism (or, . ; % ci, . - ; p = . ) and a contraindication to surgery (or, . ; % ci, . - ; p < . ). conclusion: in the present prospective single centre study of patients with definite ie, -months mortality rate was . , and was especially high in patients with preestablished contraindications to surgery, in the elderly and in patients with staphylococcal ie. six-months mortality in patients with combined surgical-medical treatment versus exclusively medical therapy in patients without a contraindication to surgery was not statistically significant. staphylococcal and enterococcal ie had a worse prognosis compared to streptococcal ie. epidemiology and aetiology of infective endocarditis e.e. hill, p. claus, m-c. herregods, p. herijgers, s. vanderschueren, w.e. peetermans (leuven, be)objectives: the epidemiological features of infective endocarditis (ie) have changed. we report the results of a -year prospective observational study investigating trends in the epidemiology and etiology of ie. methods: from june through december , we registered definite ie episodes according to the modified duke criteria in patients older than years, hospitalized in a single tertiary-care center. results: sixty-one% of episodes involved males. the median age was years (range - ).fifty-five percentage (n = ) were referred from another hospital. forty-four percentage (n = ) were nosocomial. thirty-four percentage (n = ) involved prosthetic valves and % (n = ) thereof were of early postoperative onset. the mitral valve was most frequently involved. exposure to ie risk factors during the previous months was recorded in % (n = ) of the episodes. twenty-four percentage (n = ) were intravascular catheter- objective: to determine the eco-epidemiology of cryptosporidiosis in the health services executive -western area (formerly the western health board).concerns about the incidence of cryptosporidiosis in the western area prompted the department of public health to undertake further investigation of potential links between cryptosporidiosis and environment by focusing on farming activity and water supplies in the first instance. background: cryptosporidiosis was not notifiable in the republic of ireland prior to , unless cited as a cause of gastroenteritis in a child less than two years old. as a result the incidence of cryptosporidiosis in the republic of ireland at the time was unknown. nationally it was estimated that up to % of cases of gastroenteritis in children less than two years old could be attributed to cryptosporidium. in the western area from to the proportion of cases of gastroenteritis in children less than two years old attributable to cryptosporidium ranged from . % to . %. this was cause for concern.many rural locations in the western area are served by voluntarily-operated water schemes. water quality from these schemes is often microbiologically unsatisfactory. the department of public health methods: initial research involved analysis of notification records for cases of cryptosporidiosis received from to inclusive. crude incidence rates for cryptosporidiosis in the western area were compared with crude incidence rates in england & wales, northern ireland, and scotland for the same time period. cases of cryptosporidiosis from the western area were geo-coded and mapped to visualize the geographic spread of cases, and are being contrasted with geographic data for farming activity, and also with available data on water supplies. the results of the initial phase of this research indicated the incidence of cryptosporidiosis in the western area may be cause for concern. the geographic spread of cases and potential links to farming practices and water supplies will be presented. objective: the evaluation of epidemiology and seasonal fluctactions of bacterial flora in pharyngeal swabs taken from family doctors' patients. material and methods: a total of of positive pharyngeal swabs ordered by primary care physicians from silesia were examined during the - period. the microbiological analysis was performed in silesian analytic laboratories. the intake of material, its transport and final identification complied with laboratory standards. results: the most common pathogens were, in order of prevalence: streptococcus viridans ( . %), moraxella catarrhalis ( . %), staphylococcus aureus along with mrsa ( . %) and mrsa alone ( . %), e. coli ( . %), klebsiella pneumoniae ( . %), streptococcus b. haemoliticus ( . %). candida albicans was identified in . % of positive specimens. considering seasonal fluctuation, the number of positive swabs in each month tended to gradually increase in spring with its culmination in may ( . %). as for the most common pathogens streptococcus viridans and moraxella catarrhalis mirrored the general tendency and dominating in spring season (up to . and . %, respectively) and having less stronger impact in automn (up to . and . %). the frequency of isolation of the other pathogens revealed seasonal fluctuations confined to either spring, as in the case of klebsiella pneumoniae, escherichia coli and staphylococcus aureus strains (up to . , . clinical microbiology and infection, volume , supplement , aim: the aim of this study was to identify the microorganisms isolated from corneal and conjuntival samples, isolated from patients attending the ophtalmology department of a spanish hospital. material and methods: a total of corneal scrapes and conjunctival swabs were obtained since october of to october of in an university hospital of madrid. samples were cultured into blood and chocolate agar plates and incubated at ordm;c in o and co atmospheres, respectively, for two days (conjunctival swabs) and fifteen days (corneal scrapes). identification and susceptibility tests were performed following standard methodology. results: thirty four ( . %) out of corneal samples and ( . %) out of conjunctival swabs yielded positive cultures, respectively. results are summarized in the following table:conclusions : corneal scrapes yielded a higher number of positive cultures than conjunctival swabs. gram-positive microorganisms were more prevalent both from corneal scrapes and conjuntival swabs although the difference was more evident in corneal scrapes. s. aureus was the specie most prevalent in conjunctival samples meanwhile cns were the most prevalent in corneal scrapes. methods: vitreous fluid samples (n = ) were obtained from patients ( male, female) undergoing vitrectomy for endophthalmitis between january and october . specimens of undiluted aqueous and vitreous fluid were cultured for aerobic, anaerobic bacteria and fungi by conventional methods. identification and antibiotic susceptibility were performed by the api system, vitek ii system (biomerieux) and the agar disk diffusion methods according to clsi recommendations. results: ninety one isolates were recovered from the samples. gram stain was positive in / ( . %), while cultures were positive in / ( . %) samples. gram-positive bacteria were the most common isolates ( / , %), followed by gramnegative bacteria ( / , %) and fungi ( / , %). staphylococci coagulase-negative were isolated in / ( %). the next most common species isolated among gram-positive bacteria were s. aureus ( . %), streptococcus spp ( . %), propionibacterium acnes ( . %), bacillus spp ( . %), streptococcus. pneumoniae ( %) and enterococcus faecalis ( %). among gramnegative bacteria eight isolates were enterobacteriaceae, two were non fermenters and one was haemophilus inlfuenzae. two of the fungal isolates were candida albicans, one acremonium spp and six aspergillus fumigatus. polymicrobial growth was observed in six patients with two at least isolates. of staphylococci coagulase-negative / ( %) were resistant to methicillin. only one strain of staphylococcus aureus was methicillin resistant. all gram positive isolates were susceptible to vancomycin. all isolates were sensitive to amikacine and ceftazidime while resistance was observed in / ( %) isolates to fluoroquinolones. conclusion: a variety of microorganisms was isolated from the vitreous fluid of patients. the predominant isolates were grampositive bacteria, especially staphylococci coagulase-negative with low resistance rate to methicillin. so, therapy should be based on the isolation and identification of the infecting agent and the in vitro antibiotic susceptibility to the appropriate antibiotics. the prevalence of intestinal parasitic infection in the students of primary schools in nazloo region in urmia during [ ] [ ] k. hazrati tappeh (urmia, ir)background: intestinal parasitic infections are of the most important hygienic and economical problems of millions of people in all over the world, mostly from developing countries. understanding their epidemiological situation and relation to environmental and social factors is necessary for struggling with them in every society. this investigation was designed to study the prevalence of parasitic intestinal infections among primary school attending students in nazloo region of urmia district in . materials and methods: students were chosen randomly from schools upon their population. having their questionnaires filled, two faecal samples were taken from each student and examined with direct wet mount and formalinether sedimentation technique. scotch tape was also applied in order to detect the enterobiasis and taeniasis. students completed the test. all infected persons by e. vemicularis, h. nana were treated by mebandazole and giardia lamblia were treated by metronidazole. results: overall prevalence of parasitic protozoan infections was . %. giardia lamblia was found in cases ( . %), entamoeba coli in cases ( %) and blastocystis hominis in cases legionella pneumophila as an occupational risk factor for inter-city bus drivers y. polat, Ç . ergin, i. kaleli, a. pinar (denizli, ankara, tr)objectives: legionellaceae are ubiquitous aquatic microorganisms that usually isolated from evaporative condensers. various man-made sources such as cooling towers, whirlpools and spas are sources for legionella pneumophila. in hot climate, bus air-conditioning and aircirculating systems are possible sources for the organism. in this study, serologic status of bus drivers and their assistants for legionella infections as well as bus air-conditoner moisture exit samples for legionella species were investigated.methods: serum samples were collected from bus drivers (n = ) and their assistants (n = ). samples were tested for anti-legionella antibodies by indirect immunofluorescence technique. / dilution was accepted as a positive result for anti-legionella pneumophila antibodies. results were analysed according to risk factors based on hot/cold climate route (aegean and mediterranean parts of the turkey were accepted as hot climate region), immundeficiency, chronic diseases and work hours. according to serologic test results, air-conditioners of buses which has been driven by / dilution seropositive persons, were investigated. air-conditioner moisture exit samples were cultured on bcye-alpha agar supplied with bmpa. same samples were tested by pcr targeting a -bp fragment of the s rrna gene of legionella. results: anti-legionella pneumophila antibodies were positive in ( . %) bus-persons. bus drivers' seropositivity was higher than assistants (p < . ). in hot climate route, seropositivity was higher than cold climate route (p < . ). no positive pcr result was detected. coclusion: in conclusion, higher seropositivity rates in bus drivers were pointed out a newer occupational risk factor for legionellosis. although pcr positivity was not detected for bus air-conditioners, high seropositivity rates show that bus drivers have been somehow exposed to legionella. further legionellosis surveillance studies for bus drivers may help to understand legionella exposure during travel. objective: asymptomatic bacteriuria is an important risk factor contributing to pyelonephritis and renal disfunction in diabetic patients. in this study, the relationship between microalbuminuria and age, body mass index, duration of the disease, the level of glycohemoglobin, glycosuria and glomerular filtration rate is studied prospectively in diabetic patients who have asymptomatic bacteriuria. methods: a hundred and twenty-three type diabetic outpatients who were admitted to baskent university konya medical and research center between january-october were included in the study. ages of the patients were within the range of - years. the diagnosis of asymptomatic bacteriuria was established according to the cdc criteria. concurrent samples for urinary culture, glomerular filtration rate, microalbuminuria and glycohemoglobin were obtained. results: twenty-two of ( . %) patients had significant bacteriuria. of these patients % were female. although age, body mass index, creatinine clearence and presence of microalbuminuria were similar, there was a significant difference in glycohemoglobin levels, duration of diabetes and glycosuria between the two groups (p < . ). e. coli was the most common microorganism obtained from urinary samples. risk factors for asymptomatic bacteriuria were shown in the table. conclusion: the frequency of asymtomatic bacteriuria was found to be similar with the previous studies. high glycohemoglobin levels and long duration of diabetes were found to be the risk factors contributing to asymptomatic bacteriuria in type diabetic patients. descriptive study of complicated pyelonephritis objective: the evaluation of prevalence and contributory factors associated with the development of urinary tract diseases among women with urinary incontinence. material and methods: women aged from to years had their urine culture examination performed. the material was taken from the central stream of first catch urine and transported on uromedium. antibiogram was carried out with the use of becton-dicinson's discs. results: in cases the urine culture tested positively which accounted for . % of subject women. the most common pathogens of urinary tract were, in order of prevalence:e. coli- . %, staphylococcus aureus - . %,citrobacter diversus- . % and klebsiella pneumoniae- . %. candida albicans strains were isolated in one patient. e. coli had the highest sensitivity to norfloxacin - % and cefuroxim - %, amoxicillin with clavulonian acid - . %, ampicillin nitrofurantoin and trimethiprim -sulfamethoxazole - . % in each case, cefalothin - . %, tetracycline - . %, and amikacin - . % but only in . % to amoxacillin. staphylococcus aureus proved sensitivity only to gentamicin ( %) and nitrofurantoin ( %). in the case of citrobacter diversus % sensivity to norfloxacin, nitrofurantoin, tetracycline, trimethoprim / sulfamethoxazole, ceftazidim and cefotaksym was confirmed.klebsiella pneumoniae also proved sensitivity to amoxicillin with clavulonian acid, cefuroksime, nitrofurantoin, norfloxacine, tetracyclin and trimethoprim / sulfamethoxazole. when considering the sensitivity of pathogens to antibiotics in the family practise setting of higher reliabilty are nitrofurantoina, norfloksacyna.after the administration of guided therapy complete release from symptoms was observed in women ( %).conclusions: women with urinary incontinence relatively seldom suffer from urinary tract infections. the most common pathogen among women with urinary incontinence was e. coli sensitive to floxacins and cephalosporins but with impaired reaction to amoxycillin. incidence and in vitro antibiotic resistance of streptococci in community-acquired urinary tract infections uncomplicated community-acquired urinary tract infections (ca-utis) and non-pregnant women in london hospital in kuwait over a period of two years. methods: eighty-six pregnant and non-pregnant women with signs of ca-utis were enrolled in the study. the strains isolated from the patients who had significant bacteriuria were included in the microbiological analyses. the identification of the strains was performed using the api e system (biomerieux), while their susceptibility was determined by disk diffusion method. the interpretation of the results was realized according to nccls guidelines. quality control was performed using reference strain e. coli atcc . oserotyping was carried out with polyvalent and monovalent antisera. hemolysin production was tested on human blood agar plates. possession of k antigen by e. coli was tested with agglutination by murine monoclonal antibodies to the group b meningococcal capsule. results: we found o serogroups o , o , o , o , o , o and o among strains isolated from pregnant and non-pregnant women. hemolysin was presented in % and % respective. k antigen was presented in % of strains in studied groups.there are some statistically significant differences in antimicrobial resistance between both groups. amoxicillinclavulanate (amx-clv) resistance was higher among uti haemolytic isolates of e. coli in pregnant women ( %) then in non-pregnant women ( %). similar distinction in cefuroxime resistance was found - % and . amikacin resistance was higher among uti isolates of e. coli in non-pregnant women ( %) then in pregnant women ( %).conclusions: there are no significant differences in expression of virulence factors of e. coli from pregnant and non-pregnant women with ca-utis in london hospital, kuwait. the resistance rates of e. coli from pregnant women to amx-clv and cefuroxime are significantly higher than in non-pregnant women. the penetration of telithromycin in gynaecological tissues and activity in cervicitis patients h. mikamo (gifu, jp)objectives: chlamydia trachomatis and neisseria gonorrhoeae are major causative organisms for sexual transmitted infections in japan. although several oral antimicrobial agents are active against c. trachomatis, few effective oral antimicrobial agents against n. gonorrhoeae exist in japan. two studies were conducted: a clinical pharmacology study examining penetration of telithromycin (tel), an oral ketolide antibiotic, in female genital organ tissues and a clinical study examining tel mg once daily (qd) in cervicitis patients (pts chronic prostatitis (cp) is believed to be an infectious disease in most cases. both aerobic and anaerobic bacteria are involved in the polymicrobial microbiocenosis found in prostate specific specimens. coryneform bacteria form a remarkable part of this community, yet scarce knowledge exists about their clinical significance, species composition and antibiotic susceptibility.our aim was to compare the corynebacteria of the seminal fluid of cp patients and controls and to evaluate their antibiotic susceptibility.material and methods: semen samples from controls and cp patients (nih iiia or iv category) were analysed. corynebacterium seminale was identified by beta-glucuronidase activity, the rest of coryneforms using api coryne (biomerieux). e-test method was used for susceptibility testing.results: coryneforms were found from % cp patients and % controls (p > . ). twelve species and genera were found among strains identified, the most frequent being c. seminale (in % cp patients and % controls). cp patients harboured significantly more arthrobacter sp. ( % vs %, p = . ) andcorynebacterium group g ( % vs %, p = . ), the latter association was especially eminent in case of patients with serious inflammation (> wbc/ml): % vs %, p = . . all tested strains were susceptible to ampicillin-sulbactam, single strains were resistant to doxycycline ( %) and tmp/smx ( %), however, moderate resistance was common to doxycycline ( %). resistance to clindamycin ( %), benzylpenicillin ( %), nitrofurantoin ( %), erythromycin ( %) and norfloxacin ( %) was observed as well. half of cp-related corynebacterium group g strains showed resistance to nitrofurantoin and benzylpenicillin. in addition, they were often moderately resistant to clindamycin, erythromycin and, finally, norfloxacin frequently used to treat cp. conclusions: most of men have coryneforms in their semen, more than half harbour c. seminale. corynebacterium group g and arthrobacter sp are more frequently found in cp patients than the controls. in the treatment of cp of unknown etiology it is useful to take into consideration the susceptibility profile of corynebacterium group g. objective: to evaluate the role of cmv and listeria monocytogenes in abortion.methods: this descriptive prospective study was done on women, women with spontaneous abortion before th weeks of pregnancy as a case group and healthy woman with full term delivery as a control group. serum samples were taken from all patients. elisa test was done for evaluation of cmv (igg and igm) and listeria antibodies in both groups. prevalence of seropositivity was determined. data were analysed by x and chi-square test.results: seologic tests were done on samples. average age in case group was . ± . and in control group was . ± . years. in cases with abortion ( . %) and in control group ( . %) were seropositive for listeria monocytogenes. difference in seropositivity between groups is statistically significant (p = . ). cmv igg antibodies were positive in ( %) of case group and in ( %) of control group; the difference is significant statistically (p = . ). cmv igm antibody was positive in ( . %) of case group and none in control group. difference is significant (p < . ) there was no correlation number of previous abortion and seropositivity for listeria and cmv. conclusion: the present study showed an important role of listeria monocytogenes and cmv infection in abortion. serum and prostatic tissue concentrations of moxifloxacin ( mg) after a single intravenous infusion in patients with benign prostatic hyperplasia undergoing transurethral resection of the prostate background: the spectrum of bacterial prostatitis comprises gram-negative, gram-positive and atypical pathogens. because of its broad spectrum of activity, moxifloxacin might be a suitable antibiotic for the treatment of bacterial prostatitis. aim: in this study the penetration of moxifloxacin into prostatic tissue after intravenous application of mg as single dose was investigated.methods: in a prospective, multicentric study patients with benign prostatic hyperplasia received a single dose of moxifloxacin mg in an hour lasting infusion ( ml) for perioperative prophylaxis before undergoing transurethral resection of the prostate (tur-p). serum concentrations were determined in all patients before infusion, at the end of infusion (time point ), . , and h after the end of infusion. patients were randomized for tissue sampling either , . , or h after the end of infusion. at the beginning of tur-p approximately g of tissue was sampled for analysis. concentrations of moxifloxacin in serum and tissue were determined by hplc. results: patients were evaluated in the study. the concentrations (mean, sd, median, / % quantile) are shown in the table. the prostatic tissue concentrations of moxifloxacin were approximately twice as high as in serum. at the end of infusion the tissue and serum concentrations were already equilibrated, because the tissue-serum ratios did not differ significantly from the end of infusion until h after the end of infusion. after an intravenous infusion of mg the serum and prostatic tissue concentrations of moxifloxacin were well above the mic values of the most important prostatic pathogens until h after the end of infusion. therefore, moxifloxacin might be a good alternative for the treatment of bacterial prostatitis and/ or perioperative prophylaxis for tur-p. statistical significant differences were detected between patients with and without bgnc in the proportion of patients older than years ( . % vs . %), the antecedent of recent animal bite ( . % vs . %), the presence of immunosuppression ( . % vs . %), the presence of haematological illness ( . % vs . %), and the degree of leukocytosis at admission ( ± vs ± cel/ll). conclusions: bgnc is frequently detected in our patients. age older than years, the existence of immunosuppression, the existence of haematological illness, and the antecedent of animal bite are more frequent among patients with bgnc. patients with bgnc had a lower degree of leukocytosis at admission. these factors should be borne in mind to select empiric therapy for patients with cellulitis. is erysipelas-associated tinea pedis a site of streptococcal colonisation? objectives: tinea pedis is considered the most frequent portal of entry of erysipelas of legs (sel) but whether it is the site of streptococcal colonisation is unknown. methods: from june to october we prospectively searched for clinical tinea pedis in patients hospitalised in our infectious diseases ward for sel (acute and unilateral feature with fever were only retained). all patients had bacteriological samples on inter-digital spaces of both feet (sel side and contra lateral side).results: fifteen patients were included. all but one were treated by intra-venous penicillin-g followed by oral amoxicillin. on sel side: tinea pedis was found in / ( %) and, when present, streptococcal colonisation (c or g streptococcal groups) was found in / ( %), although streptococcal colonisation was never found ( / ) in its absence. on contra lateral sides : no streptococcal colonisation was found without tinea pedis, which was observed in / , with streptococcal colonisation in / . then there is a strength statistical association between streptococcal colonisation and tinea pedis, on sel side (p = . ) as well as on contra lateral side (p = . ). in one patient blood-cultures yielded with the same streptococcus than found in foot samples. discussion: streptococcal colonisation of tinea pedis is a common finding on both feet of patients hospitalised for sel. whether inter-digital colonisation is a primary stage of invasive disease remains unproved. in our experience, a strain of streptococcus that colonised inter-digital space was isolated in patient's blood, suggesting this hypothesis may be true in some cases. if confirmed, this concept could lead to a new strategy for secondary prophylaxis of recurrent sel by decontaminating streptococcal colonisation of tinea pedis. among ggs, different emm types were found; stg , stg and stg predominated. among gas, types were found, emm predominated. one patient had the same ggs isolate in throat and skin. six patients had recurrent infections during the study; two of them with disease episodes. of the culture positive skin samples, were taken from the erysipelas infection focus ( % positive for ggs) and from another site ( % positive for ggs), e.g. wound, intertrigo, between toes or an unknown site.conclusion: a predominance of ggs was seen in the throat of erysipelas patients and their families whereas ggs was not present in control subjects. ggs, instead of gas, also seems to predominate in erysipelas skin lesions. several emm types were present in both groups and there was no clear predominance of a distinct type. the recurrent nature of erysipelas became evident also during this study. the evaluation of fournier's gangrene severity index score in patients m. ulug, m.k. celen, m.f. geyik, c. ayaz, s. girgin (diyarbakir, tr)objectives: fournier's gangrene is synergistic necrotizing fasciitis of the perineum and abdominal wall along with the scrotum and penis in men and the vulva in women. it is rare but life-threatening process. in this study we identify effective factors in the survival of patients with fournier's gangrene and to determine the accuracy of the fournier's gangrene severity index score (fgsis). methods: we evaluate patients with fournier's gangrene who were threated and follewed up from us between january and september in the department of general surgery prospectively.results: the results were evaluated in two groups: those who died (n: ) and those who survived (n: ). no statiscally significant difference was found between the age of the survivors and those who died. the admission and final laboratory parameters that correlated statiscally signinificant with outcome includes leucocyte count, hematocrit, urea, creatinine, lactate dehydrogenase, bicarbonate and albumin. sites of culture were skin/soft tissue ( , and %), respiratory tract ( , , and %) , blood ( , and %), urine ( , and %) , and other ( , and %) . -day mortality was % in this population. % of patients received antibiotic therapy alone, % surgery alone, % antibiotics + surgery, % other therapy, and % no treatment. the most common antimicrobial classes received were vancomycin ( %), beta-lactams ( ), fluoroquinolones ( ), and cotrimoxazole ( ) with % of patients receiving multiple agents. median duration of antibiotic therapy was , , and days, in the ca-mrsa, ha-mrsa and ca-mssa groups respectively. , , and % received adequate antimicrobial therapy (p < . ). hospital admission was required in , , and % of patients (p < . ). clinical success rates of initial therapy were , , and % (p < ), and recurrences were more common in the ca-mrsa group, ( , , and %, p < ). characteristics associated with outcome are listed in table . in multivariate analysis, presence of mrsa and diabetes were predictive of clinical failure.conclusion: in the community setting, mrsa infections are associated with an adverse impact on outcome compared to mssa infections and patients with ca-mrsa are significantly less likely to receive adequate antibiotic therapy. microbiological analysis of root canals associated with periapical abscesses and the antimicrobial susceptibility of isolated bacteria s. ozbek, a. ozbek, m. koseoglu, s. evcil, a. erdogan, a. ayyildiz (erzurum, tr)objective: the periapical abscess is a collection of pus in the pulp or around the root of teeth. many odontogenic infections can be managed without antimicrobial therapy or bacteriologic investigation. however, when an acute bacterial infection has progressed or antimicrobial therapy might be of benefit to patients, antibiotics are prescribed. we aimed to identify microorganisms in root canals with periapical abscess and the antimicrobial susceptibility profile of them and to revise antimicrobial treatment protocols when antimicrobials is used empirically. methods: patients with odontogenic infections included in this study. the microbiologic investigation was performed under strict aseptic conditions. a standardize routine of root canal therapy was instituted, and in each case a single root canal was sampled. in multirooted teeth only the largest canal was sampled to preserve the identity of a single endodontic/ microbiologic ecosystem. for microbial sampling, two sequential paper points were introduced into the full length of the canal, and kept in place for min. one of the paper points was used for aerobic culture and the other one for anaerobic culture. to identify isolated bacteria, whole bacterial fatty acid profiles were evaluated by using microbial identification system. antimicrobial susceptibility results were obtained by disc diffusion test for aerobics, and e-test for anaerobics. results: totally bacterial strains were isolated. of them were aerobic and of them were anaerobic. or % of cultured specimens yielded mixed (aerobic and anaerobic) species. the most prevalent bacteria were staphylococcus spp. as aerobic, peptostreptococcus prevotii and streptococcus morbillorum as anaerobic. conclusion: beta-lactam antibiotics combined with beta-lactam inhibitor (amoxicillin-clavulanic acid) had a quite effect on gram (+) and (-) aerobics. when we take into consideration that beta-lactam antibiotics stimulate production of beta-lactamase, amoxicillin-clavulanic acid combination appears a good first step antimicrobial. clindamycin may be second alternative for that purpose. for anaerobics, cefoxitin and metronidazol had well effect. although imipenem and piperasilin-tazobactam are perfect, they should not be first step of therapy. due to the frequency of mixed infections, a combination of amoxicillinclavulanic acid and metronidazol or a combination of clindamycin and metronidazol considered to have well effect for mixed infections. clinical microbiology and infection, volume , supplement , study is to review the spectrum of p. multocida infections in our centre. methods: we studied the medical records of all patients who had positive cultures for p. multocida between and . demographic, epidemiological, clinical and microbiological data including age, sex, animal exposure, site of infection, underlying diseases, type of therapy and outcome were evaluated. all isolates were identified by standard conventional microbiological methods. antibiotic susceptibility testing was performed by the disk diffusion method onto muller-hinton agar supplemented with % sheep blood and the mics of the antibiotics tested were determined by the e-test method. results: thirteen cases of p. multocida infections were diagnosed during this period. the male to female ratio was : and most patients ( %) were > years of age. respiratory tract infections were most commonly encountered ( . %), followed by soft-tissue infections ( . %) and septicemia ( . %). underlying disease was present in ( . %) patients. among them, presented a kind of malignancy. bullous pemphigoid, mitral valve stenosis, coronary disease, chronic obstructive pulmonary disease, and intracranial haemorrhage served also as predisponding factors. a traumatic animal exposure was reported in only patients and non-traumatic in cases. all isolates were susceptible to beta-lactams (penicillin, amoxicillin, amoxicillin/clavulanic acid, cefepime, cefuroxime, ceftriaxone, imipenem, and meropenem), quinolones (ciprofloxacin, norfloxacin, levofloxacin, and sparfloxacin), chloramphenicol, tetracycline, trimethoprim/sulfamethoxazole and % were intermediately resistant to aminoglycosides (gentamicin). appropriate antibiotic therapy was administered to all patients and a clinical response was observed in ( %) of them. mortality rate was %. conclusions: pasteurella multocida must be considered as a possible etiology for a variety of infections, even without an obvious animal exposure. although this organism is susceptible to a large spectrum of antibiotics, a failure to treatment may be recorded especially in severe infections and in compromised patients. infections caused by nocardia cyriacigeorgici in zaragoza, spain: identification and antibiotic susceptibility c. villuendas, b. moles, v. rodriguez-nava, a. couble, f. laurent, m. revillo, p. boiron (zaragoza, es; lyon, fr)objectives: nocardia species known to date differ in their clinical presentation, antibiotic resistance patterns and geographic distribution. nocardia cyriacigeorgici is a recently described species.the aim of this study is to analyse the identification results, antimicrobial susceptibility together with the clinical data, of n. cyriacigeorgici clinical isolates, recovered from to in our laboratory. methods: identification of nocardia spp. isolates was achieved in our laboratory on the basis of the following: visualization of the colony, gram stain and parcial acid-fast positivity by modified acid-fast staining, casein, xanthine and tyrosine hydrolysis, opacification of middlebrook h agar, production of arylsulphatase after days incubation and antimicrobial susceptibility pattern.identification at species level was achieved by s rdna gene sequencing (laboratoire de mycologie. faculté de pharmacie. lyon. france)antimicrobial susceptibility tests included commercial broth microdilution (emiza ef sensititre Ò ) and gradient strip agar dilution (e-test ab biodisk Ò ). interpretation of results was done according to nccls standard guidelines. in the six years of study, isolates of nocardia spp. were recovered, of them belonging to n. cyriacigeorgici species ( %). n. cyriacigeorgici represents the third species in frecuency in our serie, after n. abscessus and n. farcinica. the strains were recovered from patients, from respiratory specimens and one from blood-culture.pneumonia was the most frequent clinical manifestation, being copd and previous corticosteroid therapy the most common predisposing conditions. all n. cyriacigeorgici isolates showed susceptibility to: amikacin, tobramycin, cefotaxime, imipenem, trimethoprimsulfamethoxazole and linezolid, and resistance to: amoxicillinclavulanic acid and ciprofloxacine. conclusion: n. cyriacigeorgici is not an infrequent cause of nocardiosis in our geographical area. the uniformity showed in the antimicrobial profile can be useful for its identification. in our hospital, patients with copd and receiving corticoid therapy is the most important group of risk for adquiring n. cyriacigeorgici infection. whit the technics available in our laboratory the isolates were identified as nocardia spp. and identification at species level was only possible by phylogenetic analysis using rdna sequencing. high frequency of single-step resistance mutations in nocardia farcinica exposed to quinolones u.s. jensen, j.d. knudsen, k. schønning (hvidovre, dk)objectives: nocardia farcinica infections often require prolonged antibiotic therapy and perorally administered agents are desirable. isolates commonly display in vitro susceptibility to quinolones when tested by disc diffusion methodology. in the present study, we investigated the activity of three different quinolones (ciprofloxacin, levofloxacin and moxifloxacin) against n. farcinica and assessed the robustness of their activity by determining the frequency of single step resistant mutants when exposed to inhibitory concentrations of quinolones. methods: isolates of n. farcinica were used in the study; correct identification to the species level was verified by s rdna sequencing. mics of ciprofloxacin, levofloxacin and moxifloxacin against n. farcinica as well as s. aureus atcc and e. coli ccug were determined by the agar dilution method using inocula of approximately . cfu and h of incubation. single step mutation frequencies were determined by heavily inoculating selective agar plates containing quinolone at a concentration of x mic and counting resistant colonies after days incubation. inoculum was quantified by seeding a dilution series of the inoculum employed on unselective plates and counting colonies after h of incubation and frequencies were calculated by dividing the number of resistant colonies by the number of cfu present in inoculum. results: when mics were determined by agar dilution method all quinolones displayed roughly the same potency against n. farcinica isolates (mics between . and ). as expected moxifloxacin were the most potent quinolone against s. aureus. however, all three quinolones selected for single step resistant mutants, the frequency of which was higher for ciprofloxacin (~ ) ) than for levofloxacin ( ) - ) ), which again was higher than for moxifloxacin ( ) - ) ). however, even for moxifloxacin the frequency against n. farcinica was comparable to the single step mutation frequency of ciprofloxacin against s. aureus ( - ).conclusions: although quinolones may exhibit activity against n. farcinica, n. farcinica is capable of rapid development of resistance. therefore, quinolones should probably be avoided, at least as single agents, in the treatment of nocardia infections. correlation between clinico-laboratory findings and a positive igm elisa test for leptospira: a retrospective study e. mendrinou, p. goudas, a. regli (patra, gr) objective: to correlate a positive elisa test for igm antibodies against leptospira with the clinical and laboratory findings in patients with suspected leptospirosis. method: we retrospectively analysed the history, clinical course and laboratory findings in a total of patients, with suspected leptospirosis. all patients fulfilled the criteria for clinical diagnosis of leptospirosis. from the patients, had to be transferred to the dialysis unit for haemodialysis and patients had to be admitted to the intensive care unit (icu) due to severe pulmonary haemorrhage. serum samples from all patients were tested for igm antibodies against leptospira. results: from the total of patients death occurred to only four, due to respiratory failure from severe pulmonary haemorrhage. the rest of the patients recovered completely. from the total of patients had a positive elisa igm test for leptospirosis ( . %). however, from the patients that were transferred to the dialysis unit, had a positive leptospirosis test ( %) and from the six patients admitted to the icu, three had a positive test ( %). among other laboratory findings there was a stronger correlation between very low platelet levels (< . mm ) and very high blood bilirubin levels (> mg/dl) with a positive test for leptospirosis. all patients with a positive test had less than . platelets per mm and had blood bilirubin over mg/dl. the differential diagnosis of icterohemorrhagic fevers includes a vast number of pathogens, some of which are untraceable with the common laboratory methods. in our study, from the total of patients, only . % had a positive test for leptospirosis. in of the rest patients, many different pathogens were traced, most of them being several kinds of viruses (cmv, ebv), brucella and coxiella. in of the patients no pathogen was traced. conclusions: taking into consideration the high sensitivity of the elisa test we conclude that: . icterohemorrhagic leptospirosis comprises only a small subtotal of icterohemorrhagic fevers; . there is a correlation between higher levels of bilirubin and/or very low platelet levels with leptospira infection; . there seems to be a correlation between leptospira infection and severity of icterohemorrhagic fevers. evaluation of continuous ambulatory peritoneal dialysis-related peritonitis attacks in ankara s. tekin koruk, m.a. yetkin, i. koruk, f.s. erdinc, s. sahan, n. tulek, m. duranay, a.p. demirö z (ankara, konya, samsun, tr) objectives: peritonitis is a common clinical problem that occurs in patients with end stage renal disease treated by peritoneal dialysis. the aims of this study were to assess demographic aspects, rates of peritonitis, causative organisms, clinical outcomes and treatment approach for continuous ambulatory peritoneal dialysis (capd) -related peritonitis cases. methods: seventy cases of peritonitis occurred in patients treated in infectious diseases and clinical microbiology department between may and april were enrolled into this study. the mean age of the patients was . years (range - years). cloudiness of the peritoneal dialysis fluid and/or abdominal pain were considered suggestive of peritonitis and were confirmed by cell count and culture. baseline cell count, gram stain, and cultures were obtained, and repeated with periodic follow-up. results: the overall incidence of peritonitis was . ± . episodes/patient-year. in . % of patients there were only one peritonitis attack, where as in . % of them had two or more attacks. age, gender, education and profession of the patients have not been found as a risk factor in peritonitis attacks.the most common presenting symptoms of the patients were abdominal pain, cloudiness of the peritoneal dialysis fluid, nausea and vomiting. peritoneal dialysate fluid white blood cell count was ± /mm in episodes. cultures were positive in ( . %) peritonitis episodes; coagulase-negative staphylococci was the most common organism (% . ), followed by staphylococcus aureus (% . ), episodes (% . ) had negative culture results. there was a statistically significant decrease in serum crp and esr levels and at the end of the treatment when compared with the levels on admission.at the end of the study, episodes of peritonitis cases were treated with ip cefazolin and gentamicin protocol. seven of the patients did not respond initiate therapy and the therapy was converted to iv protocol. seven episodes were treated with iv antibiotics on admission for medical reasons (systemic infection and/or concurrent exit-side or tunnel infection). there were two deaths. two catheters were removed and the patients were transferred to haemodialysis programme. conclusion: despite all technical improvements during recent decades peritonitis is still the major complication of capd. for the accurate treatment of complications, causative organisms and their antimicrobial susceptibilities must be known. objective: viruses are a frequent cause of upper respiratory tract infections in children. among the respiratory viruses, influenza viruses are known to cause outbreaks globally. the present study was carried out to identify the influenza virus serotypes causing acute respiratory infection in children attending univesity hospital in konya in turkey. methods: thorat swabs were collected from acute viral upper respiratory infection suspected children attending the out patient clinic of meram medical faculty hospital. two swabs were taken fron each chidren and one of the swabs was used for bacteriological cultures and if these were negative the other one was used for viral diagnosis. totally bacteriological cultures negative swabs were investigated by real-time pcr for the presence of parainfluenza , and , influenza a and b. results: one or more viral pathogens were detected in children, with parainfluenza % being the most commonly identified virus. parainfluenza in % and parainfluenza in %, influenza a were identified in % and influenza b in %. from the specimens of children more than one virus detected. conclusion: the influenza viruses cause morbidity and mortality among children and elderly. this study analysed the occurrence of influenza and paranfluenza respiratory ifections due to influenza and paranfluenza viruses. molecular methods used directly on clinical material have an important role in the rapid diagnosis and surveillance of influenza viruses and can be applied in clinical practice for correct diagnosis and administration of effective treatment. , , , , , and . the demographics, clinical presentations and laboratory findings of the patients with serotype were presented. results: the mean age was y m, ranging from months to y m. seventy percents of children with serotype infection clustered between october and january . the mean duration of a positive culture result was . days. the mean duration of fever was . days, with days before admission. forty ( %) children were treated as outpatients. the mean length of hospital stay was . days. the most common diagnoses were exudative tonsillitis ( %), pneumonia or bronchopneumonia ( %) and pharyngoconjunctival fever ( %). the most common symptoms and signs were fever ( %), cough ( %) and coryza ( %). neurologic complications were noted in children. eighteen children had documented coinfection (including virus, bacteria and mycoplasma pneumoniae). leukopenia (wbc < /microliter) was noted in two of cases while leukocytosis (wbc > /microliter) in ( %). six ( . %) of cases had a normal serum c-reactive protein (crp) level (< mg/l), while % of children had a serum crp greater than mg/l. seventy ( . %) of children ever received antibiotics therapy. the outcomes were excellent in these cases. conclusion: recognizing that children with adenoviral serotype infection may present with prolonged high fever, leukocytosis and elevated crp, which mimics bacterial infection, the clinician may not prescribe unnecessary antibiotics for these children. the infectious mononucleosis like syndrome (im) is an acute febrile disease of older children and young adults, and is characterized by lymphadenopathy, tonsillitis, splenomegaly, liver dysfunction and by the presence of peripheral lymphocytosis with > % atypical lymphocytes. epstein -barr virus (ebv) is responsible for over % of the cases, cytomegalovirus (cmv) for %- % and toxoplasma gondii < %.herpes simplex, rubella and adenovirus are rare. the infection is usually characterized by mild symptoms. however in some cases the clinical manifestations may be rather atypical and severe. objective: to determine the prevalence of im like syndrome among patients in a children's hospital and its possible association with etiologic factors, age, major symptoms and atypical manifestations. material and methods: during a one-year period (january to december ) a total of samples were examined in our laboratory. the study population was children between - years old, which either examined in the outpatient's clinic or hospitalized. all serum specimens were examined by . indirect immunofluorescence for the presence of igg and igm antibodies against the viral capsid antigen (vca) ebv, .immuno chemistry luminescence for the detection of igg and igm antibodies to cmv and .eia for the detection of igg,igm abs of herpes simplex i and ii and toxoplasma gondii. results: of the children examined ( . %) were found positive for igg and igm vca antibodies and ( %) showed positive specific igg and igm antibodies for cmv. these patients had one or more of the primary following symptoms: fever ( %), lymphadenopathy ( %), pharyngalgia ( %), cough ( %), skin eruption ( %). atypical manifestations as meningoencephalitis were found in two children one aged months (caused by ebv) and the other of years old (caused by hsv i) confirmed by pcr. the laboratory data showed positive serology for ebv and cmv infection, the existence of atypical lymphocyte ( %), ldh, asat and alat were moderately elevated ( %) and crp increased ( %). conclusion: the frequency of im like syndrome in greece, though it's relatively low, it's not rare. the above results suggested that ebv, cmv, hsv should be considered in any young patient with im and acute neurological illness of uncertain etiology. objectives: enterovirus, parvovirus b and human herpes virus type (hhv- ) are a common cause of infection in young infants. the objective of this study was to determine what portion of the infants who received a clinical diagnosis of febrile syndrome have a viral etiology by these three genera of viruses. methods: ninety-six patients were included in the study, all of them were admitted to the pediatric casualty of a tertiary care hospital, and all of them presented a febrile syndrome without a clear focus of infection (urinary tract, lung and meningeal infections were discarded). the assay was carried out in blood samples by real-time pcr. dna was isolated from ll of blood by semi-automated system magna pure lc total nucleic acid isolation kit (roche diagnostics, nederland bv). pcr was performed in a lightcycler instrument (roche molecular biochemicals) by a uniform cycling parameters: min at °c for polymerase activation, and cycles of s at °c and s at °c for amplification of the specific target sequence ( utr gene for enterovirus, vp gene for parvovirus b and dna polymerase gene for hhv- ). pcr product formation was detected continuously by the use of taqman probes. results: a viral amplification was detected in ( %) of the patients included in this study. enterovirus was detected in ( . %) of the patients, parvovirus b in ( . %) and hhv- in ( . %). in five cases two viral amplifications were detected at the same time: parvovirus b /hhv- and enterovirus/hhv- . the mean age of the patients was years old (range from days to years). in group of infants < months old (n = ) there were enterovirus and hhv- . in the infants from months to years old (n = ) there were enterovirus, parvovirus and hhv- . in the last group of infants > years old (n = ) there were enterovirus and parvovirus b . conclusions: viral infections are an important cause of sepsis in infants admitted to hospital. enterovirus was the most frequent virus detected in infants < months, parvovirus b the most frequent in children > years old, and the hhv- was detected in all age groups. qualitative real-time pcr in blood is a rapid and sensitive method for diagnosis of enterovirus and parvovirus. however, is not the better method for diagnosis of hhv- , a latent virus, in which this technique is not capable of distinguish between recent and acute infection. objectives: group a rotaviruses are a major cause of acute gastroenteritis in infant and young children worldwide. in this study, the molecular epidemiology and clinical features of rotavirus infection in iranian children was investigated. methods: between february to january , thirty hundred and seventy two diarrhoea stools from children under -years-old with acute diarrhoea that attended the biggest paediatric hospital in tehran (iran), were analysed using elisa, electropherotyping and reverse transcriptionpolymerase chain reaction (rt-pcr). results: ninety-four samples ( . %) were positive for the presence of rotavirus either by page, elisa, or both. according to page, the predominant electrophoretic pattern detected was the long profile of ( . %) followed by the short electropherotype five of ( . %). out of the positive samples, were further characterized by rt-pcr typing assay for identification of g types, resulting in strains of g genotype while samples could not be assigned a g type. all of g genotypes had a long rna electropherotype. among the patients with rotavirus infection, ( . %) required hospitalization. watery diarrhoea ( . %), vomiting ( . %) and fever ( . %) were significantly more frequent in children suffering from rotavirus gastroenteritis. seven out of rotavirus-positive patients had severe dehydration (p < . ). rotavirus infection mostly affected children under years of age with a peak incidence of % in children - years of age and it occurs year round with a seasonal pattern: more frequently during winter ( . %). conclusion: this study revealed that rotavirus is an important etiological agent of acute gastroenteritis in tehran. we found that a major proportion of the specimens were untypeable. improved detection and characterization of incompletely typed strains will help to develop comprehensive strain information that may be required for tailoring effective rotavirus vaccines. serological study of prevalent rotaviruses in tehran e. habibi, s. ghorbani, a. jarollahei, z. habibi (tehran, zanjan, ir)objectives: rotaviruses are icosohedral and non-enveloped viruses that belong to reoviridae family which consist of three layers of protein surrounding segments of dsrna. rotavirus is one of the most important agents of acute gastroenteritis in children. in this survey, the most prevalent serotypes in tehran and seasonal distribution in a year were detected. methods: in this study, a total number of specimens of faecal samples of children and infants with acute gastroenteritis were collected from two children hospitals in tehran. the samples were tested by elisa procedure. serotyping investigation of iranian rotavirus isolates, using serotypes monoclonal antibodies (g -g -g -g -g -g -g ) in elisa tests and immunosorbent electron microscopical studies using trapping and decoration techniques were performed. results: rotavirus type a infection was identified in samples ( %). serotyping investigation in elisa tests proved that serotypes g and g were the most common serotypes circulating among infected children and infants in tehran. by electron microscopic studies the characteristic of rotavirus particles were observed in the faecal samples of infected children. the maximum incidence of infection was determined to occur among the cold months of the year. conclusion: it was approved that g and g serotypes are the main rotavirus serotypes present among children in tehran. it was detected that rotavirus diarrhoea was most prevalent among children of under years of age. results: from patients with varicella presented neurological manifestations (sex ratio m/f: / ). had acut cerebellar ataxia and one had encephalitis. we estabilished the diagnosis on the basis of clinical aspects (including neurological examination), cerebrospinal fluid examination and electroencephalogram. the age interval was between months and years. most cases were diagnosed in children and teenager ( ); one case toddlers, and cases in adults. neurological manifestations appeared in most cases among and days after the onset of rash ( cases). in the order of frequency: gait disorders ( ), cerebellar ataxia ( ), fever ( ), vomiting ( ), nistagmus ( ), seizures and coma ( ) . csf showed limphocytic pleiocytosis and elevated levels of protein ( cases); in cases csf had normal aspects. electroencephalogram had dominant theta wave with totally or partially suppression of alpha activity in all patients. all cases showed clinical and eeg improvement at the end of the treatment. conclusions: the most frequent neurological manifestation was cerebellar. the evolution was good under treatment, with no sequelae at month of follow up. key: cord- -r bqqovo authors: qian, hao; gao, peng; tian, ran; yang, xufei; guo, fan; li, taisheng; liu, zhengyin; wang, jinglan; zhou, xiang; qin, yan; chang, long; song, yanjun; yan, xiaowei; wu, wei; zhang, shuyang title: myocardial injury on admission as a risk in critically ill covid- patients: a retrospective in-icu study date: - - journal: j cardiothorac vasc anesth doi: . /j.jvca. . . sha: doc_id: cord_uid: r bqqovo objective: the aim of this study was to investigate the incidence, clinical presentation, cardiovascular (cv) complications and mortality risk of myocardial injury on admission in critically ill icu inpatients with covid- . design: a single-center, retrospective, observational study. setting: a new-built icu in tongji hospital (sino-french new city campus), huazhong university of science and technology, wuhan, china. participants: seventy-seven critical covid- patients. interventions: patients were divided into myocardial injury group and non-myocardial injury group according to the on-admission levels of high-sensitivity cardiac troponin i. measurements and main results: demographic data, clinical characteristics, laboratory tests, treatment and clinical outcome were evaluated stratified by the presence of myocardial injury on admission. compared with non-myocardial injury patients, patients with myocardial injury were older ( . ± . vs. . ± . years; p= . ), had higher prevalence of underlying cv disease ( . % vs. . %; p= . ) and in-icu cv complications ( . % vs . %; p= . ), higher acute physiology and chronic health evaluation ii scores ( . ± . vs . ± . ; p= . ) and sequential organ failure assessment scores [ , interquartile range (iqr) - vs. ,iqr - ; p< . ]. myocardial injury on admission increased the risk of -day mortality [hazard ratio (hr), . ; % confidence interval (ci) . to . ; p= . ]. age ≥ years was another risk factor for mortality (hr, . ; % ci . to . ; p= . ). conclusion: critically ill patients with covid- held high risk of cv complications. myocardial injury on admission may be a common comorbidity and is associated with severity and a high risk of mortality in this population. the outbreak of novel coronavirus disease (covid- ) caused by sars-cov- has now become a global health emergency. , covid- -related pneumonia and acute respiratory distress syndrome (ards) are the major causes of hospital admission in most patients. however, cardiovascular (cv) complications including myocardial injury and arrhythmia have been reported in recent literature. [ ] [ ] [ ] [ ] [ ] the specific incidence of myocardial injury and its association with the mortality in patients with covid- have been widely demonstrated. [ ] [ ] [ ] however, investigations focusing on the incidence and mortality risk of myocardial injury in critically ill in-intensive care unit (icu) patients with covid- are still limited. therefore, a need exists to characterize cv complications and myocardial injury because an increasing number of countries are facing the difficult situation of a vast number of critically ill patients and increasing cases of cv complications that china encountered from jan. to apr. . we conducted a retrospective study of data from patients admitted to a newly constructed icu in wuhan, compared patients with and without myocardial injury, detailed the relationship of myocardial injury with the survival rate and cv outcomes, and presented the following conclusions: ) myocardial injury is a common complication in critically ill covid- patients; ) patients with myocardial injury are more likely to develop adverse events and fatal outcomes during hospitalization; ) myocardial injury and advanced age (≥ years old) are independent risk factors for -day in-icu mortality. this single-center, retrospective, observational study enrolled patients admitted to a newly constructed icu in tongji hospital (sino-french new city campus), huazhong university of science and technology, wuhan, china. "newly constructed" indicates that the quarantine icu was equipped and modified from a previous general ward within days and designated to treat critically ill covid- patients. the icu was staffed with a multidisciplinary team including health care providers from peking union medical college (pumc) hospital, beijing, china. because of the emergency nature of the situation, this icu lacked sufficient equipment, such as invasive hemodynamic monitors, at the beginning of operation. we retrospectively analyzed patients who were admitted to the icu from feb. to mar. , . the confirmation of novel coronavirus infection was defined as a positive result of a throat-swab specimen on a real-time reverse transcription-polymerase chain reaction (rt-pcr) assay. the cutoff of data for investigation of survival status was mar. , . patients were followed up at least days or died before the cut-off date. the study was approved by ethical committee of pumc hospital. the data analyzed in this study were extracted from electronic medical records and included demographics and baseline characteristics (i.e., pre-existing cv diseases [cvd] and cv risk factors), clinical information (i.e., vital signs and therapeutic management), laboratory results and outcomes. acute physiology and chronic health evaluation ii (apache ii) and sequential organ failure assessment (sofa) scores were determined on the date of icu admission. the time from symptom onset to icu admission, intubation and death were also recorded. patients were categorized into two groups, including those with or without myocardial injury (myocardial injury and non-myocardial injury group) on admission according to troponin test results on the first day in the icu. covariates of interests were compared between these two groups. myocardial injury was defined as an elevated cardiac troponin value above the th percentile upper reference limit (url) according to the fourth universal definition of myocardial infarction. a high-sensitivity cardiac troponin i (hs-ctni)assay was implemented in this study, and the th url was ng/l. prior cvd included a prior medical history of coronary artery disease (cad), myocardial infarction, heart failure and stroke. cv death was defined as a death caused directly by cv complications, such as cardiogenic shock, and occurrence of sudden cardiac arrest and/or fatal ventricular arrhythmia in relatively stable patients. cv complications included in-icu cardiac arrest, cardiac shock, acute myocardial infarction, atrial fibrillation and malignant ventricular arrhythmia. ards and acute kidney injury were diagnosed according to the berlin definition and kidney disease: improving global outcomes (kdigo) clinical practice guidelines, respectively. , we defined liver abnormalities as any parameter greater than the upper limit of the normal values of alanine aminotransferase (alt) and total bilirubin (tbil). vasoconstrictive support was mostly applied in patients with shock status (combined with blood pressure lower than / mmhg or evidence of insufficient perfusion). the v-v mode of extracorporeal membrane oxygenation (ecmo) was used in these patients and was mainly performed to improve oxygen supply and attenuate severe hypercarbia under mechanical ventilation. in the further analysis of risk factors for mortality, we conducted a survival study based on age (≥ and < years old), prior cvd history and myocardial injury on admission. the primary endpoint was -day mortality after icu admission, and the secondary outcome was cv death. continuous variables are presented as the mean ± standard deviation (sd) for those with a normal distribution or the median and inter-quartile range (iqr) for those with a non-normal distribution. categorical variables are described by the number (%). two-sample t test and mann-whitney u test were applied to assess the differences in continuous variables between patients with and without myocardial injury. the differences in categorical variables were assessed using χ² test and fisher's exact test (for small sample sizes). survival analyses were based on the time from icu admission to the event. kaplan-meier plots and cox proportional hazards regression models were used to assess survival data. statistical significance was determined by a two-sided α value less than . . all statistical analyses were performed using the spss . software (ibm, armonk, ny). table . compared to the non-myocardial injury group, patients with myocardial injury were significantly older ( . ± . years vs. . ± . years; p= . ), had more concurrent cvd ( . % vs. . %; p= . ), including cad ( . % vs. . %; p= . ), and were more likely to be smokers ( . % vs. . %; p< . ). however, the prevalence rates of other cvds, such as myocardial infarction, heart failure and stroke, or other cv risk factors, such as hypertension and diabetes, were not significantly different. as summarized in table , there was no significant difference in vital signs (heart rate, respiratory rate and blood pressure) between the two groups on icu admission. when two important indices for assessing and predicting icu performance and icu mortality, the apache ii and sofa scoring systems, were compared, the myocardial injury group had significantly higher scores than the non-myocardial injury group (apache ii: . ± . vs. . ± . , p< . ; sofa: iqr - vs. iqr - , p< . , respectively). when complications were considered, a significant difference in cv complications ( . % vs. . %; p< . ) was observed between the two groups ( table ). most patients ( of , . %) had ards on admission, and there was no significant difference in acute kidney injury or liver dysfunction between the two groups. the admission laboratory findings revealed that patients with myocardial injury had a significantly lower platelet count, longer prothrombin time (pt), higher n-terminal pro-b-type natriuretic peptide (nt-probnp) and d-dimer levels, and reduced renal function according to higher serum creatinine and blood urea nitrogen (bun) levels compared to the non-myocardial injury patients (table ). there was no significant difference in life support therapy, including in-icu oxygen therapy, intubation rate, vasoconstrictive agents and blood purification therapy, between the groups. similar in-icu usage of antiviral and/or antibacterial agents, immunoglobulin and glucocorticoids was observed. the only significant difference in therapy was that more non-myocardial injury patients received anticoagulation therapy than myocardial injury patients ( . % vs. . %, p< . ) ( table ) . when survival outcomes were summarized, ( . %) patients had died within days of icu admission, including ( . %) patients who died from cv causes. as indicated in table , the patients with myocardial injury had significantly higher rates of all-cause death and cv death than non-myocardial injury patients ( . % vs. . %, p= . and . % vs. %, p= . , respectively). although the durations from symptom onset to icu admission and intubation were similar in these two groups, the duration from symptom onset to death in patients with myocardial injury was significantly shorter than that of non-myocardial injury patients ( . ± . vs. . ± . days, p= . ). we conducted cox regression analyses to compare survival between patients ≥ years and those < years, with or without admission myocardial injury and pre-existing cvd. adjusted variates included smoking history, creatinine levels greater than μmol/l (normal limitation), d-dimer levels greater than . mg/l (median level) and nt-probnp levels greater than ng/l (median level). the older patients had a higher risk of all-cause death (hr, . ; % ci . to . ; p= . ) than patients < years (figure a) . consistently, the in-icu cumulative survival curve of myocardial injury patients was significantly lower than that of non-myocardial injury patients (hr, . ; % ci . to . ; p= . ) ( figure b ). however, no significant difference was observed in survival between patients with or without pre-existing cvd (hr, . ; % ci . to . ; p= . ) ( figure c ). in this study, we report critically ill patients with confirmed novel coronavirus elevated hs-ctni or myocardial injury is well-recognized as a primary complication contributing to increased respiratory syndrome severity and total mortality in patients infected with covid- , - especially in critically ill patients. several studies have indicated that myocardial injury occurrence was a predictor for disease progression, as more than % of myocardial injury patients infected with novel coronavirus developed critical illness. , this speculation was documented by our study, as the apche ii and sofa scores of the myocardial injury patients were significantly higher than those of patients without myocardial injury. additionally, we further compared the mortality and time from icu admission to death between the myocardial injury and non-myocardial injury patients, which suggested the predictive value of co-existing myocardial injury on admission as a high-risk factor in critically ill patients with covid- in this study. however, serum troponin level elevation should be carefully interpreted by specialized physicians because of its high sensitivity. various non-cardiovascular factors, such as fever with rapid heart rate, electrolyte disorder and kidney dysfunction, may contribute to troponin level elevation. , in critical patients, myocardial injury results from various clinical mechanisms that may include severe hypoxia, insufficient perfusion, systemic inflammation and coagulation dysfunctions. [ ] [ ] [ ] there was no evidence of acute coronary syndrome or coronary artery-related cv events as the major cause of elevated troponin based on electrocardiography and echocardiography findings. in our patients, severe hypoxia was suggested as the major cause of myocardial injury, as most had rapid progression of dyspnea with an oxygenation index (pao /fio ) < , and more than % (including all myocardial injury patients) developed ards. moreover, although patients were intubated and sedated before being sent to the icu, the mean baseline respiratory rate still exceeded times per minute, suggesting the wide occurrence of dyspnea in our patients. additionally, patients received vasoconstrictive agents on the first day of admission, indicating a prevalence of shock or insufficient peripheral perfusion. the imbalance of increased cardiac metabolic demand and decreased blood perfusion/oxygen supply may contribute to myocardial injury and dysfunction. a high prevalence of coagulation disequilibrium was also closely observed in our patients, especially in those with myocardial injury (higher d-dimer levels and longer pt). anti-coagulation therapies such as low molecular weight heparin or unfractionated heparin were empirically prescribed. these therapies seemed to be effective for restoring coagulation abnormalities and coagulopathy, which might potentially benefit the prognosis. additionally, a high systemic inflammatory burden was demonstrated to be positively associated with myocardial injury in critically ill patients with covid- . in this study, anti-inflammation therapies such as glucocorticoids or tocilizumab were used in some patients, and we found that inflammatory cytokine levels were decreased. however, related clinical investigations were not performed in this study. concrete clinical values for anti-coagulation and anti-inflammation therapies in critical patients with covid- should be explored in further studies. age and pre-existing cvd have been associated with higher mortality in critically ill patients with viral infection. older patients may have more comorbidities (i.e., cad, hypertension, chronic kidney disease and diabetes) and a higher rate of cv complications. in fact, no patients over years had survived at the end of this study. however, this does not mean that young adults will not develop critical illness. the youngest patient in our icu with invasive mechanical ventilation was years, and two more patients in their thirties were admitted. the youngest death was years old in our study. our study verified that covid- patients with myocardial injury had a higher prevalence of prior cvd. no significant difference in survival rate was noted between patients with or without pre-existing cvd. we suspect that the extremely high mortality might partially conceal the contribution of previous cvd to death. thus, our study cannot exclude the risk of pre-existing cvd in mildly or moderately ill patients with covid- (patients with respiratory symptoms [fever, cough, etc.] and/or manifestations of pneumonia in imaging examinations). in our study, the prevalence of pre-existing cvd in patients with myocardial injury was higher than that in patients without myocardial injury, but the prevalence of myocardial injury in patients with prior cvd was not explored. whether pre-existing cvd increases the incidence of myocardial injury in covid- patients requires further investigation. there is no direct evidence indicating that covid- -related viral myocarditis is a major cause of myocardial injury and death in this study. in our previous echocardiography study, although several presentations of cardiac dysfunction (e.g., pericardial effusion, increased left ventricular [lv]) mass index, decreased lv stroke volume index and impaired right ventricle systolic function) were general features of critical patients, lv systolic dysfunction (such as decreased lv ejection fraction [lvef] or newly diagnosed abnormal ventricular wall movement) was not common. there were only four cases of reduced lvef, including two related to prior myocardial infarction/ischemia, one patient with hypothermia and one patient with unconfirmed dilated cardiomyopathy. as for the electrocardiography presentations, sinus tachycardia, atrial fibrillation, ventricular tachyarrhythmias and non-specific st-t changes were commonly found in these patients, but no indications for fulminant covid- -related myocarditis were found. we do not have cardiac magnetic resonance images because this procedure was not applicable for these quarantined critically ill patients. therefore, viral myocarditis was also not presented in pathology studies. in a report of three autopsies of covid- patients, no pathological findings indicated viral myocarditis, and the nucleic acid tests for the novel coronavirus were negative in heart tissue, although mild infiltration of lymphocytes, monocytes and neutrophils and necrosis of cardiomyocytes were observed. similar results were also reported by xu et al., who found that novel coronavirus infection might not directly impair the heart tissue in another autopsy report, as they found a few interstitial mononuclear inflammatory infiltrates without other substantial damage in the myocardial tissue. we have close communication with the pathologists and are expecting further results of autopsies including several of our patients. the prevalence of admission myocardial injury was considered as an increased risk of -day mortality in our study, but it was not likely to be the cause of death. we considered hs-ctni elevation on admission as a biomarker of risk. we carefully investigated the six patients with cardiovascular death, and they all had myocardial injury. two patients with prior myocardial infarction (without revascularization) had sudden cardiac death, which were considered as coronary thrombosis events. two cases of fatal ventricular fibrillation were reexamined and found to have underlying hypokalemia during urgent intubation or deep vein catheterization. one cardiac arrest was related to hyperkalemia ( . mmol/l). only one patient had troponin elevation, cardiac shock without evidence of sepsis or respiratory failure, significantly reduced lvef and four chamber enlargements; however, we did not exclude the prior history of dilated cardiomyopathy. this study focused on critically ill patients with covid- and found that myocardial injury was a common complication and indicative of a poor prognosis in these patients. furthermore, advanced age was also positively associated with high mortality. regarding the pathogenesis, the critical status of multi-organ failure or high systemic inflammatory burden may partially explain the onset of myocardial injury. evidence for viral myocarditis is currently lacking. it is necessary to pay increased attention to myocardial injury during treatment of critically ill patients with covid- . clinical characteristics of coronavirus disease in china characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention clinical features of patients infected with novel coronavirus in wuhan a novel coronavirus from patients with pneumonia in china epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study with myocardial injury and mortality association of cardiac injury with mortality in hospitalized patients with covid- in wuhan, china cardiovascular implications of fatal outcomes of patients with coronavirus disease (covid- ) acute respiratory distress syndrome: the berlin definition kdigo clinical practice guidelines for acute kidney injury clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study left ventricular performance in patients with severe acute respiratory syndrome: a -day echocardiographic follow-up study cardiovascular complications of severe acute respiratory syndrome middle east respiratory syndrome coronavirus infection dynamics and antibody responses among clinically diverse patients, saudi arabia elevated troponin and myocardial infarction in the intensive care unit: a prospective study troponin i and myocardial injury in the icu cardiac intensive care unit management of patients after cardiac arrest: now the real work begins coronaviruses and the cardiovascular system: acute and long-term implications high inflammatory burden: a potential cause of myocardial injury in critically ill patients with covid- cardiac complications associated with the influenza viruses a subtype h n or pandemic h n in critically ill patients under intensive care. the brazilian journal of infectious diseases : an official publication of the brazilian society of the effects of age on clinical characteristics, hospitalization and mortality of patients with influenza-related illness at a tertiary care centre in malaysia epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study swollen heart in covid- patients who progress to critical illness: a perspective from echo-cardiologists. esc heart failure pathological findings of covid- associated with acute respiratory distress syndrome cardiac involvement in a patient with coronavirus disease (covid- ) * non-normal distribution. alt, alanine aminotransferase; bun, blood urea nitrogen; hscrp, high-sensitivity c-reactive protein inr, international normalized ratio; hs-ctni: high-sensitivity cardiac troponin i; nt-probnp: n-terminal pro-b-type natriuretic peptide. p values present the differences between myocardial injury and non-myocardial injury patients key: cord- -donflx w authors: khan, raymond m.; al-juaid, maha; al-mutairi, hanan; bibin, george; alchin, john; matroud, amal; burrows, victoria; tan, ismael; zayer, salha; naidv, brintha; kalantan, basim; arabi, yaseen m. title: implementing the comprehensive unit-based safety program model to improve the management of mechanically ventilated patients in saudi arabia date: - - journal: am j infect control doi: . /j.ajic. . . sha: doc_id: cord_uid: donflx w background: ventilator-associated events are common in mechanically ventilated patients. they are associated with more days on mechanical ventilation, longer intensive care unit (icu) stay, and increased risk of mortality. theoretically, interventions that prevent ventilator-associated events should also reduce associated morbidity. we evaluated the comprehensive unit-based safety program approach to improve the care of mechanically ventilated patients. methods: all mechanically ventilated patients admitted to the icu between october , , and october , , were prospectively monitored for the development of ventilator-associated events according to the national healthcare safety network criteria. a process care bundle (endotracheal intubation with subglottic suctioning, head-of-bed elevation ≥ °, target sedation scores, daily spontaneous awakening trials, spontaneous breathing trials), daily delirium assessment, and an early mobility protocol were instituted. the bundle compliance, ventilator-associated events rates, icu length of stay, and mortality rate were noted. the database allowed viewing of current rates, trends, and averages of all participating sites. results: in the study period, , patients were admitted to the icu, and , required mechanical ventilation ( , ventilator days). there were ventilator-associated events: ventilator-associated conditions, infection-related ventilator-associated conditions, and possible cases of ventilator-associated pneumonia. the icu mortality rate was . %, compared with . % for those mechanically ventilated patients with ventilator-associated events (p = . ). there was increased compliance for spontaneous awakening trials ( . %- . %, p = . ) and spontaneous breathing trials ( . %- . %, p = . ) and a decrease in infection-related ventilator-associated conditions ( . - . per , days), possible cases of ventilator-associated pneumonia ( . - . per , days), icu mortality ( . %- . %, p = . ), and ventilator-associated events associated mortality rates ( . %- . %, p < . ). physical therapy participation and mobility were . % and . %, respectively. conclusion: the implementation of a multipronged program like the comprehensive unit-based safety program could improve the care processes and outcomes of mechanically ventilated patients. in , the institute for healthcare improvement (ihi) , lives campaign introduced the concept of a "care bundle" for the prevention of ventilator-associated pneumonia (vap). a care bundle identifies a set of key interventions that, when implemented together as a best practice approach, are expected to improve patient outcomes. in recent years, approaches to the care of mechanically ventilated patients have evolved from fixating only on vap prevention to focusing on a more comprehensive strategy based on the recent finding of benefit from the combined approach of the abcde bundle (awakening and breathing trial coordination, delirium management and early mobilization) and the wake up and breathe collaborative trial. although previous improvement initiatives used vap rates as the primary outcome measure, it has been increasingly recognized that mechanical ventilation (mv) causes harm beyond just vap. hence, wider outcome measures were needed to determine the value and success of safety programs. the centers for disease control and prevention, together with several critical care societies, convened a group to address the limitations of the national healthcare safety network definition of injury caused by mv, and they proposed a new approach in . besides vap, the new algorithm uses objective criteria for the diagnosis of ventilator-associated events and conditions and infection-related ventilator-associated complications. this approach thereby broadens the definition of harm suffered by ventilated patients beyond pneumonia to include pulmonary edema, atelectasis, and acute respiratory distress syndrome. the comprehensive unit-based safety program (cusp) approach was developed by patient safety researchers at the johns hopkins hospital, baltimore, maryland. cusp is designed to improve teamwork and safety culture and to guide organizations to learn from mistakes by using a validated and structured framework. cusp involves a repetitious process that trains a multidisciplinary team about the science of safety, asking them to identify defects, learn from them, implement improvement tools, and establish a partnership with senior leaders. key components include identifying evidence-based interventions that improve the outcomes of interest, converting these interventions into behaviors, placing value on the wisdom of frontline staff, and empowering frontline staff to be actively involved in safety improvements. the cusp intervention has achieved great success in reducing vap, central lineÀassociated bloodstream infections, catheter-associated urinary tract infections, surgical care complications, mortality, and associated costs. , our hospital's infection control and intensive care departments implemented a vap prevention program in , which led to the reduction of vap rates from . to per , ventilator days in . despite our success in reducing the vap rates, our data indicated that intensive care unit (icu) length of stay (los) ( . vs . days) and mortality rates ( % vs . %) were both higher in the post-vap prevention bundles compared with the pre-vap prevention intervention group, implying that merely decreasing the rate of vap was not enough. we needed to implement other strategies to optimize patient care to improve outcomes. we joined the johns hopkins armstrong institute comprehensive unit-based safety program for mechanically ventilated patients and ventilator-associated pneumonia (cusp mvp-vap) project in october with the objective of improving the care delivery process and reducing the mortality of our mechanically ventilated patients. this article describes the impact of implementing the cusp mvp-vap project on patient care in our icus at the ministry of national guard health affairs in riyadh. this was a prospective quality improvement and patient safety study to describe the impact of implementing the cusp mvp-vap in a cohort of patients in our icus. this improvement project was performed at king abdul aziz medical city in riyadh, saudi arabia, for all adult patients who received invasive mv in the icu between october , , and october , . the icu had beds and was covered by onsite board-certified intensivists hours per day, days per week, with a nurse-to-patient ratio of approximately : and a respiratory therapist-to-patient ratio of approximately : . the hospital was a , -bed tertiary-care center accredited by the joint commission international, with an active infection prevention and control program that collaborated with the icu medical and nursing staff to ensure the implementation and monitoring of infection control practices. the institutional review board and king abdullah international medical research center ethics committee of national guard health affairs, riyadh, saudi arabia, approved this study and waived the requirement for informed consent. a multidisciplinary cusp mvp-vap team was created in september to implement evidence-based practices for all mechanically ventilated patients. the group was led by an intensivist but included other physicians, nurses, respiratory therapists, physical therapists, infection control practitioners, and quality management personnel. the team monitors (nurses and research coordinators) were trained on data collection and monitored compliance on a daily basis. they reviewed the electronic charts of all patients on mv in the icu daily. the implementation of each care process bundle element, along with the confusion assessment method for the icu (cam-icu) score and the maximum level of mobility for that day were recorded on a standard data collection form and entered into the johns hopkins armstrong institute database, which generated a compliance rate for our hospital. this compliance rate was compared with those of other institutions in the project, so that we could benchmark our performance. if a component of the bundle was not performed, the inspectors used this moment to elucidate any barriers to the implementation of the particular element. the first month (october ) was considered the baseline data point. we defined a ventilator-associated condition (vac) as an increase in fio . or positive end expiratory pressure (peep) cm h o sustained for calendar days in a patient on mv for > days with a baseline period of stability or improvement, defined by calendar days of stable or decreasing daily fio or peep values. an infection-related ventilator-associated complication (ivac) occurred on or after days of mv when a patient met the criteria for a vac plus both of the following: temperature > °c or < °c and white blood cell count , or , cells/mm , as well as a new antimicrobial agent(s) started and continued for calendar days. a possible vap (pvap) occurs in a patient with the criteria for an ivac and of the following: positive culture meeting quantitative or semiquantitative thresholds from endotracheal aspirate ( colony-forming units [cfu]/ml), bronchoalveolar lavage ( cfu/ml), lung tissue ( cfu/g), or protected specimen brush ( cfu/ml); purulent respiratory secretions (> neutrophils and < squamous epithelial cells per low-power field plus organism identified from sputum, endotracheal aspirate, bronchoalveolar lavage, lung tissue, protected specimen brush); or organism identified from pleural fluid, lung histopathology, legionella tests, or diagnostic test on respiratory secretions for influenza virus, respiratory syncytial virus, adenovirus, parainfluenza virus, rhinovirus, human metapneumovirus, or coronavirus. ventilator-associated events (vaes) are the sum of vac, ivac, and pvap. all patients on mv were reviewed prospectively and independently by physicians who confirmed the diagnosis. the incidence of vae, vac, ivac, and pvap was expressed as cases per , ventilator-days. the project had arms: daily care process, early mobility, and low tidal volume ventilation. participation could be in , , or all of the arms (fig ) . our hospital selected daily care process and early mobility, because low tidal volume ventilation was already a standard practice in our icus for all patients on mv. i. daily care process a. endotracheal tube with subglottic suctioning (sub-g eet) all patients anticipated to need mv for > hours were intubated with a taperguard evacuation oral tracheal tube (covidien, mansfield, ma). the data collectors inspected patients for the presence of sub-g eet when indicated and documented whether the subglottic drainage lumen was connected to the wall suction at the appropriate intermittent negative pressure. b. head of bed (hob) °t he hospital was equipped with hill-rom hospital beds (hill-rom, chicago, il). the angle of the hob was measured with an electronic device or built-in protractor present on the bed. elevation of the hob was the default order for all patients on mv. exceptions were hypotension; unstable physiological status; low cardiac index; recent cervical, thoracic, or lumbar surgery or instability; ventricular assist device; intra-aortic balloon pump; open abdomen; and patient refusal. this element required that the data collector directly observe the angle of the hob. a nurse-led sedation vacation protocol was implemented that allowed the nurse to stop all sedation at : a.m. if the patient fulfilled certain criteria. the sat was continued until either the patient was agitated or fully awake and could be assessed for delirium. for this element, the data collectors asked the bedside nurse whether sedation was interrupted. they then reviewed the patient's daily flow sheet to confirm the nurse's statement. if the chart did not reflect sedation interruption, then this bundle was considered noncompliant. d. sedation-minimized (sedation score target) sedation orders were entered via a standardized computer order set, with dosage adjusted based on the patient's weight and renal and hepatic functions. in addition, a target sedation score (richmond agitation-sedation scale [rass]) had to be assigned to the patient by the physician before the order could be completed. the targeted rass was addressed daily in rounds, and the nurse's documentation was examined to determine whether the patient's actual sedation score matched the planned target. a ventilator weaning protocol was drafted that allowed respiratory therapists to wean all patients on mv starting at : a.m., hour after the sedation was held. patients who met the following criteria were weaned to pressure support ventilation: awake or off sedation with rass or for > hour spontaneous inspiratory efforts oxygen saturation > % the spontaneous breathing trial was conducted by placing the patient on pressure support ( - cm h o) with or without cm h o peep. both the patient's icu flow sheet and respiratory therapist's notes were monitored to assess this element. the cam-icu advocated by the society of critical care medicine was used to evaluate for delirium. in our hospital the assessment tool was translated into arabic, and, after a validation process of several plan-do-study-act cycles, staff were trained to perform this appraisal. the cam-icu score was recorded at a.m. daily and documented : p if the patient is positive for delirium based on cam-icu assessment n if the patient is negative for delirium based on cam-icu assessment uta if unable to assess (ie, rass = ¡ or ¡ ) x if cam-icu assessment was not completed nk if cam-icu was completed, but results are not known nk was also used if it was not known whether the cam-icu was performed ii. early mobility a. mobility-tailor goals to maximize mobility all patients admitted to the icu had standing orders for physical therapy (pt) and occupational therapy as part of the admission order sets. the level of mobility ( to ) was recorded: : passively rolled or exercised; : transfer from bed to chair without standing; : sitting in bed/exercising in bed; : sitting at edge of bed; : standing with or without assistance; : transfer from bed to chair with standing; : marching in place; : walking at least steps; and : unknown what level of activity occurred. additionally, any perceived barrier to achieving a higher level of mobility was documented. there were bimonthly meetings among the cusp team and monthly webinars with the armstrong institute. frequencies and percentages were used for categorical variables, whereas means with standard deviations were presented for continuous variables. the fisher exact test was used to evaluate differences between categorical variables, and the t test was used to evaluate differences between continuous variables. comparisons for mortality, los, and mv days were made, with the first month (october ) used as the base line. the unadjusted risk of death from developing a vae was compared using the fisher exact test; for those patients receiving mv who did not develop a vae. p < . was considered statistically significant. during the study period , patients were admitted to the icu; , ( %) required mv, with , episodes of mv and , ventilator days. there were vaes, of which were vacs, ivacs, and pvaps (table , fig ) . the overall icu mortality rate was . % compared with . % for those with development of a vae (p = . ). the icu mortality rate for mechanically ventilated patients decreased from . % to . % (p = . ), whereas the mortality rate associated with vaes decreased from . % to . % (p = . ) over the study period (fig ) . there were significant increases in mv days and icu los for patients with vaes ( table ) . the mean care bundle compliance for all the elements was . %. the compliance rates for endotracheal intubation with subglottic suctioning, hob elevation °, daily sats, and sbts were . %, . %, . %, and . %, respectively. the greatest improvement was seen in sats, which increased from . % in november to . % in october ( . % absolute increase, p = . ). this was followed by sbts, which increased from . % to . % ( % absolute increase, p = . ). the compliance of endotracheal intubation with subglottic suctioning decreased by . % (p = . ), whereas for hob it remained around % throughout the project (fig ) . the target rass was achieved in . % of mechanically ventilated patients, whereas . % had a rass of ¡ to + . however, . % of patients had their sbt done off sedation, and the percentage of mechanically ventilated patients without sedation increased from . % to . % (p = . ). the delirium assessment compliance rate was . %, with . % reporting a negative cam-icu. the percentage of incorrectly reported cam-icu scores was . %, which significantly decreased from . % (november ) to . % (october ) (p = . ). the pt and occupational therapy participation rates were . % and . %, respectively. only . % of mechanically ventilated patients were moved from bed to chair. the most frequent level of mobility achieved was (passively rolled or exercised [ . %]). the other levels were (transfer from bed to chair without standing . the most common perceived barriers to mobilization were the following: patient weakness ( %), hemodynamic instability ( . %), low rass on sedation ( . %), low rass off sedation ( %), and the patient labeled comfort care ( . %). however, the most documented adverse event was circulatory or respiratory instability ( . %). in our study the implementation of the multifaceted cusp -mvp vap approach resulted in an increase in sat ( . %- . %, p = . ) and sbt ( . %- . %, p = . ) compliance; an increase in the number of mechanically ventilated patients without sedation ( . %- . %, p = . ); and a decrease in ivacs ( . - . per , mv days), pvap ( . - . per , mv days), icu mortality rates ( . %- . %, p = . ), and vae mortality rates ( . %- . %, p < . ). finally, we found that our compliance with pt participation and mobility were suboptimal. in , the centers for disease control and prevention replaced their vap surveillance definitions with vae objective criteria, in response to a series of concerns about the traditional vap definitions, including their complexity, subjectivity, burden on surveyors, lack of comparability between institutions, narrow focus, and limited association with adverse outcomes. furthermore, vap did not consistently identify patients at increased risk for poor outcomes, and interventions that reduced vap rates often had no effect on patient-centered outcomes, such as duration of mv or hospital mortality. this is demonstrated in our previous vap prevention project, in which, in spite of the rate of vap decreasing from . to per , ventilator days, the days on mv remained unchanged, whereas the icu los and icu and hospital mortality rates all significantly increased in the postbundle implementation group. the failure of most vap prevention strategies to yield better outcomes for ventilated patients raises the question of whether vap is the best target to drive surveillance and safety prevention programs, because quality improvement initiatives must focus on identifying and preventing objective complications that are unambiguously associated with poor outcomes. thus the explicit intent of the a vae criteria was to broaden the focus of quality surveillance beyond just pneumonia. klompas et al, in a retrospective study of , episodes of mv found that vaes were associated with more days to extubation (relative risk, our data also demonstrated that vaes are associated with increased mechanical ventilator days, icu los, and icu mortality, highlighting the point that a vae appears to be a clinically important event. the synthesis of the vae criteria has created a new opportunity for health care facilities to reexamine their approach to preventing complications and improving outcomes of mechanically ventilated patients. vae surveillance has a quality metric character and appears to identify potential safety opportunities to improve care and outcomes for patients. theoretically, interventions most likely to prevent vaes are those that help patients avoid intubation, minimize the duration of mv, or prevent the conditions that most commonly trigger a vae (pneumonia, volume overload, acute respiratory distress syndrome, and atelectasis). use of high-flow nasal oxygen for hypoxemic and noninvasive ventilation for hypercapnic respiratory failure may avoid intubation. minimizing sedation, performing daily coordinated sats and sbts, and perhaps early mobility are strategies to decrease the duration of mv. strategies to prevent pneumonia, volume overload, acute respiratory distress syndrome, and atelectasis include hob elevation, conservative fluid management, conservative blood transfusion thresholds, low tidal volume ventilation, and early mobility. these interventions are consistent with the best care practices advocated by the abcdef bundle, the surviving sepsis campaign, and the society for healthcare epidemiology of america's recommendations to prevent vap. [ ] [ ] [ ] growing data support that implementing and optimizing these practices can lower vae rates and improve patient outcomes. the cusp mvp-vap project was engendered to continue this wider focus of implementing an evidence-based practice bundle while caring for mv patients. our study showed that sat and sbt rates were . % and %, respectively. this is similar to data published from icus in maryland and pennsylvania with , ventilated patient-days in which compliance with sat and sbt was . % and %, respectively. our icus have a nurse-led sedation vacation protocol and target sedation scores for all sedated patients. furthermore, we have an sbt protocol that is respiratory therapist driven. our low compliance rates could highlight the difficulty of translating evidence-based practice to bedside, or they may represent a defect in our protocol design preventing meaningful change in the practice behavior and culture of our front-line staff. our data demonstrated that . % of mechanically ventilated patients were mobilized into a chair, and only . % were evaluated by a physical therapist while receiving mv. early and progressive mobilization has been demonstrated to be both safe and feasible for patients admitted to critical care. implementing early mobility programs has led to improvements in physical function and mobility levels, significant reductions in both icu and hospital los, and ventilation days and a reduction in both the incidence and duration of delirium. in fact, the abcde bundle is centered on approaches to implement the integrated pain, agitation, and delirium clinical practice guidelines to reduce delirium and weakness related to oversedation, prolonged mechanical ventilation, and immobility in mechanically ventilated critically ill patients. despite this, point prevalence surveys have shown that rehabilitation levels remain low. goddard and colleagues, using a theoretical domains framework of behavior change, found that the social influences domain (local champions, icu leadership, discord between team members and family members) and behavioral regulation domain (feedback and having a unit protocol) may act as barriers or facilitators to early rehabilitation. based on these findings, we formulated a multidisciplinary team and a mobility protocol to provide tools to standardize the care of our patients (appendix ). the strengths of our study include the use of prospective collected data, a large sample size with all patients observed daily until icu discharge, and a common surveillance system using standardized definitions with a web-based portal for real-time reports. despite its strengths, our study has several potential limitations. first, a reduction in vae rates might be beyond the effect of just implementing the bundle, because the vae rates might have decreased secondary to other simultaneous infection control projects in our icus. second, this was not a preintervention and postintervention study, so analyzing the full effect of the bundle is difficult. third, despite having standardized data collection techniques and sources, team members might be motivated to demonstrate improvement and potentially could bias results. fourth, we report vae rates per , ventilator days, and any intervention that decreases ventilator days may paradoxically increase vae rates and underestimate the impact of the intervention on vae outcomes. fifth, icu los may depend on multiple complex factors and not only vaes. finally, the data represent a cohort study from a single center, and our inventions might not be generalized to other institutions. sustaining a safety culture should be a public health priority of all health care facilities. a strategic framework for preventing vaes is to pair clinical bundle with practice behavior and culture change interventions. the implementation of a multipronged program like the cusp mvp-vap that places ownership on front-line staff, reduces appendix a early mobility protocol complexity, provides standardized tools, engages executives, and uses communication tools to strengthen teamwork could improve the care processes and outcomes of mechanically ventilated patients. the impact of a ventilator bundle on preventing ventilator-associated pneumonia: a multicenter study guidelines for severe infections: are they useful? liberation and animation for ventilated icu patients: the abcde bundle for the back-end of critical care the preventability of ventilator-associated events. the cdc prevention epicenters wake up and breathe collaborative search for direct top squark pair production in final states with one isolated lepton, jets, and missing transverse momentum complications of mechanical ventilation-the cdc's new surveillance paradigm observation of a new chi(b) state in radiative transitions to upsilon( s) and upsilon( s) at atlas creating high reliability in health care organizations targeted implementation of the comprehensive unit-based safety program through an assessment of safety culture to minimize central line-associated bloodstream infections introducing the comprehensive unit-based safety program for mechanically ventilated patients in saudi arabian intensive care units comprehensive unit-based safety program (cusp) to improve patient experience: how a hospital enhanced care transitions and discharge processes the impact of implementing multifaceted interventions on the prevention of ventilator-associated pneumonia ventilator-associated events years later ventilator-associated events and their prevention descriptive epidemiology and attributable morbidity of ventilator-associated events the clinical impact of ventilatorassociated events: a prospective multi-center surveillance study the impact of ventilator-associated events in critically ill subjects with prolonged mechanical ventilation should ventilator-associated events become a quality indicator for icus? potential strategies to prevent ventilator-associated events improving hospital survival and reducing brain dysfunction at seven california community hospitals: implementing pad guidelines via the abcdef bundle in , patients surviving sepsis campaign: international guidelines for management of sepsis and septic shock strategies to prevent ventilator-associated pneumonia in acute care hospitals: update two-state collaborative study of a multifaceted intervention to decrease ventilator-associated events safety of patient mobilization and rehabilitation in the intensive care unit. systematic review with meta-analysis earlier and enhanced rehabilitation of mechanically ventilated patients in critical care: a feasibility randomised controlled trial a feasibility study of a randomised controlled trial to examine the impact of the abcde bundle on quality of life in icu survivors barriers and facilitators to early rehabilitation in mechanically ventilated patients-a theory-driven interview study we thank dr. sean m. berenholtz (professor, johns hopkins armstrong institute for patient safety and quality) and the johns hopkins armstrong institute for patient safety and qualityÀcusp mvp vap team. key: cord- -mrm paiq authors: meijer, eelco f. j.; dofferhoff, anton s. m.; hoiting, oscar; buil, jochem b.; meis, jacques f. title: azole-resistant covid- -associated pulmonary aspergillosis in an immunocompetent host: a case report date: - - journal: j fungi (basel) doi: . /jof sha: doc_id: cord_uid: mrm paiq covid- -associated pulmonary aspergillosis (capa) is a recently described disease entity affecting patients with severe pulmonary abnormalities treated in intensive care units. delays in diagnosis contribute to a delayed start of antifungal therapy. in addition, the emergence of resistance to triazole antifungal agents puts emphasis on early surveillance for azole-resistant aspergillus species. we present a patient with putative capa due to aspergillus fumigatus with identification of a triazole-resistant isolate during therapy. we underline the challenges faced in the management of these cases, the importance of early diagnosis and need for surveillance given the emergence of triazole resistance. there have been suggestions that coronavirus disease (covid- ) might increase the risk of superinfections [ ] and, particularly, invasive pulmonary aspergillosis (ipa) co-infection [ ] . covid- -associated pulmonary aspergillosis (capa) is a recently described disease entity affecting patients in intensive care unit (icus) with severe pulmonary abnormalities. small cohorts of patients in the netherlands [ ] , patients in france [ ] and patients in germany [ ] have been published, showing capa rates of . %, % and %, respectively. an additional two fatal cases of capa were recently reported [ , ] . the numbers resemble what has been observed in influenza, where influenza in icu patients has been identified as an independent risk factor for invasive pulmonary aspergillosis and which is associated with an even higher mortality rate than ipa alone [ ] . in addition, in the netherlands, an estimated . % of cases with invasive aspergillosis are infected with an azole-resistant isolate [ ] , potentially increasing mortality to - % [ ] . we present the first case of azole-resistant aspergillus fumigatus in a sars-cov- -positive immunocompetent patient admitted to the icu. a -year-old patient was admitted because of respiratory insufficiency amid the covid- crisis. eleven days prior to admission, she had been suffering from fever ( . • c) and a dry cough. three days after symptom onset, she developed diarrhea. her medical history included complaints of reflux and pain due to arthrosis of the hip and knees, for which she uses a proton-pump inhibitor and a nonsteroidal anti-inflammatory drug pantoprazol and etoricoxib, respectively. she stopped smoking years ago and was healthy and fit otherwise. patient characteristics can be found in table . this study, "clinical course and prognostic factors for covid- " with project identification code cwz-nr - , was approved in march by the canisius wilhelmina hospital medical ethics committee and patient informed consent was acquired antemortem with opt out possibility. at presentation to the emergency department, she had been feeling progressively dyspneic for two days. on physical examination, her oxygenation was %, with breaths per minute in room air, pulmonary wheezing and an extended expiration. oxygenation improved to % with l o via a nasal cannula, but she desaturated during speech. her bmi was . ( kg) and her temperature . • c. no other aberrant observations on physical examination were made. her glasgow coma scale was and her ecg was normal. her c-reactive protein (crp) was mg/l, and other laboratory findings included slightly elevated leucocytes ( . × /l) and neutrophils ( . × /l), elevated liver enzymes (alkaline phosphatase u/l; ggt u/l; ast u/l; ld u/l), slightly elevated pro-calcitonin ( . µg/l; < . µg/l not suggestive of bacterial infection), increased ferritin ( µg/l), and normal electrolyte, glucose and renal function. sars-cov- nasopharyngeal and throat swabs were taken. a low-dose chest ct demonstrated extensive centralized and peripheral bilateral ground glass opacities with left-sided consolidations and bilateral fibrotic bands without pleural effusions and vascular enlargement ( figure ). the co-rads score was and ct-severity score was out of [ ] . because of the high probability of sars-cov- infection, chloroquine treatment was started ( mg and mg on day , mg q h days - ), which was national policy at the time. the sars-cov- pcr of a nasopharyngeal swab was positive (ct . ; e gene [ ] ). blood cultures remained negative, as were nasopharynx bacterial cultures taken at admission. the patient was subsequently admitted to our general inpatient respiratory ward. an overview of her hospital course is depicted in figure . the crp remained highly stable over the following days at around mg/l with a range of - . however, the patient needed increasing oxygenation with a non-rebreathing mask. empirical treatment of a suspected bacterial superinfection was started with ceftriaxone i.v. mg q h. five days after admission, the maximum ( l o ) oxygenation with the non-rebreathing mask became insufficient and the patient was admitted to the icu for respiratory support and intensive monitoring. because of the high probability of sars-cov- infection, chloroquine treatment was started ( mg and mg on day , mg q h days - ), which was national policy at the time. the sars-cov- pcr of a nasopharyngeal swab was positive (ct . ; e gene [ ] ). blood cultures remained negative, as were nasopharynx bacterial cultures taken at admission. the patient was subsequently admitted to our general inpatient respiratory ward. an overview of her hospital course is depicted in figure . because of the high probability of sars-cov- infection, chloroquine treatment was started ( mg and mg on day , mg q h days - ), which was national policy at the time. the sars-cov- pcr of a nasopharyngeal swab was positive (ct . ; e gene [ ] ). blood cultures remained negative, as were nasopharynx bacterial cultures taken at admission. the patient was subsequently admitted to our general inpatient respiratory ward. an overview of her hospital course is depicted in figure . in the icu, hfno (high-flow nasal oxygen therapy) and selective digestive decontamination (sdd) were initiated, which includes ceftriaxone i.v. mg q h for days and a combined oral non-absorbable suspension of amphotericin b, colistin and tobramycin q h. in this patient, ceftriaxone was continued de facto for another days. routine bacterial and fungal (peri-anal, throat and tracheal aspirate) surveillance cultures were done twice weekly in adherence with our local sdd policy [ ] . within a few hours after admission to the icu, her blood oxygenation became insufficient with hfno at fio % and l/min flow. therefore, she was sedated, intubated and put on a mechanical ventilator. a ct angiography of the chest was performed which demonstrated significant bilateral pulmonary emboli. anticoagulants (enoxaparine anti-factor xa) were initiated in therapeutic dosages. pressure control ventilation was required with the patient in prone position. because of the need for increasing noradrenaline dosages during circulatory shock, hydrocortisone mg q h was initiated and continued for five days. cardiac ultrasound showed a minor tricuspid insufficiency but no major pathology. aspergillus fumigatus was recovered from high-volume tracheal aspirate cultures [ ] obtained at icu admission. aspergillus galactomannan (platelia aspergillus; bio-rad, marnes-la-coquette, france) ratio at this time was > . (positive) in a tracheal aspirate and β-d-glucan (fungitell assay; associates of cape cod inc., east falmouth, ma, usa) in serum was pg/ml (positive), after which a putative diagnosis of capa was made. serum galactomannan remained negative (< . ) in three subsequent samples. voriconazole i.v. mg/kg q h was started in addition to caspofungin i.v. mg q h until the vipcheck (mediaproducts bv, groningen, the netherlands), used to detect azole resistance, was negative. mics determined with broth microdilution using clsi methodology of the a. fumigatus isolate were as follows: amphotericin b . mg/l, micafungin and anidulafungin < . mg/l, itraconazole mg/l, voriconazole . mg/l, and posaconazole . mg/l. voriconazole was switched to oral administration of mg q h with discontinuation of caspofungin. during sdd, bacterial cultures remained negative throughout her stay in the icu. on day after admission (day at the icu), continuous venovenous hemofiltration was initiated because of rapidly progressive acute renal failure. a. fumigatus was persistently cultured from tracheal aspirate samples during voriconazole treatment and β-d-glucan levels remained positive with and pg/µl, at and days (day and after hospital admission) of voriconazole therapy, respectively. voriconazole serum therapeutic drug monitoring was performed as recommended [ ] , with therapeutic concentrations of . mg/l, . mg/l and . mg/l at day , and , respectively. the respiratory situation improved marginally in the subsequent days but declined steadily thereafter. pressure support and pressure control ventilation were alternated between days and and attempts to return the patient to a supine position failed several times. after days, a. fumigatus grew on the itraconazole and voriconazole wells of the second vipcheck on day (tracheal aspirate culture). mics of this a. fumigatus isolate were as follows: amphotericin b . mg/l, anidulafungin and micafungin < . mg/l, itraconazole mg/l, voriconazole mg/l and posaconazole . mg/l. voriconazole treatment was changed to liposomal amphotericin b mg q h. subsequent cyp a gene sequencing identified a tr /l h mutation, probably responsible for the observed azole resistance. on day , ventilation and oxygenation of the patient deteriorated further without further treatment options and therapy was discontinued on day . an autopsy was not performed. we report the first case of azole-resistant capa, which occurred in an immunocompetent host during icu support without a previous history of azole therapy. the a. fumigatus cyp a gene tr /l h mutation found in this patient has been well described as an environmentally acquired mutation [ ] , which is in line with data from clinical studies where two-thirds of patients with azole-resistant infections had no history of azole pretreatment [ ] . this case underscores the importance of early diagnosis and the need for resistance surveillance, comparable to what has been described in influenza patients [ , ] , given the emergence of triazole resistance [ , ] . the sensitivity for detection of resistance in primary cultures with the vipcheck plate depends on the number of a. fumigatus colonies that are tested, as clinical cultures may contain both mixed azole-susceptible and azole-resistant isolates during an infection [ ] . we suspect that a. fumigatus isolated in the first tracheal aspirate was already a mixed culture but was missed in initial fungal cultures due to abundance of azole-susceptible a. fumigatus spores. molecular detection could have given a suggestion to the presence of a mixed culture [ ] but pcr could not be performed due to absence of material. the tr /l h had a phenotype with high itraconazole mic (> mg/l) and low voriconazole mic ( mg/l), similar to strains which have been described only recently in the netherlands [ ] . ipa is known to be problematic to diagnose in the non-neutropenic icu host [ ] . regardless of the compelling evidence for capa in this patient, the eortc/msgerc [ ] host criteria for invasive fungal disease were not met, nor did the patient meet the aspicu algorithm because we tested tracheal aspirates instead of bronchoalveolar lavage (bal) fluid [ ] . this is in line with findings from other groups, where capa patients did not meet the eortc/msgerc host criteria either [ ] [ ] [ ] [ ] . in addition, the american association for bronchology and interventional pulmonology (aabip) has issued a statement advising against routine bronchoscopy in covid- patients, as it poses substantial risk to patients and staff [ ] . bal should only be considered in intubated patients if upper respiratory samples are negative and bal would significantly change clinical management. tracheal aspirate cultures, as performed twice weekly in our patient, repeatedly identified a. fumigatus as the only micro-organism present. in the first positive culture, five colonies were tested for resistance with the vipcheck plate as is recommended to exclude azole resistance [ ] . when surveillance cultures of tracheal aspirates were persistently cultured positive with a. fumigatus during voriconazole therapy, we suspected the selection of resistant isolates which were probably already present in the first samples, albeit in undetectable numbers. an autopsy to confirm ipa was not done. serum galactomannan testing has been shown to be a fairly sensitive diagnostic tool ( %) in neutropenic patients with pathology-proven invasive aspergillosis [ , ] . however, in patients who are non-neutropenic, serum galactomannan sensitivity of around % has been reported [ ] , which may explain the low number of serum galactomannan positive findings in recently published case reports [ , ] and case series [ ] [ ] [ ] . the role of β-d-glucan and the aspergillus-specific lateral flow device (lfd) as an adjunct to the diagnosis of ipa in covid- is not yet clear [ , ] . serum β-d-glucan was persistently strongly positive in this patient over the course of a week. the specificity for invasive fungal disease of β-d-glucan testing in a mixed icu population has been shown to be high ( %), with two consecutive positive results [ ] compared to those with only fungal colonization and no invasive fungal disease. in addition, multiple other studies report a good sensitivity for the diagnosis of invasive aspergillosis in critically ill patients [ ] [ ] [ ] [ ] [ ] . bal β-d-glucan in the icu setting is, however, not recommended, due to its poor specificity and confounders causing false positive results [ ] . the lfd is particularly interesting in the icu due to its short turnaround time. it has demonstrated a higher sensitivity but lower specificity in bal fluids compared to galactomannan [ ] and β-d-glucan [ ] in ipa-probable and proven immunocompromised patients. in the icu setting, however, lfd is suggested to have a lower sensitivity but comparable specificity to galactomannan testing in bal fluids [ , ] . noteworthily, a negative predictive value of > % has been reported in the icu setting [ ] . we used the olm lateral flow device (asplfd) on sequential patient tracheal aspirates, yielding positive results on all samples confirming the positive galactomannan result. although suitable for its negative predictive value or as an additional diagnostic measure, further evaluation of lateral flow technology in critically ill patients is warranted. altogether, we describe the clinical course of the first reported patient with azole-resistant capa. the contribution of a. fumigatus to this fatal covid- course is highly likely, although autopsy was not performed, as in all previously reported capa cases [ ] [ ] [ ] [ ] [ ] . covid- , superinfections and antimicrobial development: what can we expect? diagnosing covid- -associated pulmonary aspergillosis covid- associated pulmonary aspergillosis high prevalence of putative invasive pulmonary aspergillosis in critically ill covid- patients fatal invasive aspergillosis and coronavirus disease in an immunocompetent patient invasive pulmonary aspergillosis complicating covid- in the icu -a case report invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study burden of serious fungal infections in the netherlands clinical implications of globally emerging azole resistance in aspergillus fumigatus co-rads -a categorical ct assessment scheme for patients with suspected covid- : definition and evaluation detection of novel coronavirus ( -ncov) by real-time rt-pcr swab-richtlijn: selectieve decontaminatie bij patiënten op de intensive care high-volume culture and quantitative real-time pcr for the detection of aspergillus in sputum diagnosis and management of aspergillus diseases: executive summary of the escmid-ecmm-ers guideline emergence of azole-resistant aspergillus fumigatus strains due to agricultural azole use creates an increasing threat to human health post-influenzal triazole-resistant aspergillosis following allogeneic stem cell transplantation azole-resistant aspergillosis: epidemiology, molecular mechanisms, and treatment triazole resistance in aspergillus fumigatus: recent insights and challenges for patient management concomitant occurrence of itraconazole-resistant and -susceptible strains of aspergillus fumigatus in routine cultures high-frequency direct detection of triazole resistance in aspergillus fumigatus from patients with chronic pulmonary fungal diseases in india paradoxal trends in azole-resistant aspergillus fumigatus in a national multicenter surveillance program diagnosing invasive pulmonary aspergillosis in icu patients: putting the puzzle together revision and update of the consensus definitions of invasive fungal disease from the european organization for research and treatment of cancer and the mycoses study group education and research consortium a clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients american association for bronchology and interventional pulmonology (aabip) statement on the use of bronchoscopy and respiratory specimen collection in patients with suspected or confirmed covid- infection galactomannan in bronchoalveolar lavage fluid: a tool for diagnosing aspergillosis in intensive care unit patients failure to detect circulating aspergillus markers in a patient with chronic granulomatous disease and invasive aspergillosis a prospective study of fungal biomarkers to improve management of invasive fungal diseases in a mixed specialty critical care unit a prospective comparison of galactomannan in bronchoalveolar lavage fluid for the diagnosis of pulmonary invasive aspergillosis in medical patients under intensive care: comparison with the diagnostic performance of galactomannan and of ( → )-β-d-glucan chromogenic assay in serum samples prospective study in critically ill non-neutropenic patients: diagnostic potential of ( , )-β-d-glucan assay and circulating galactomannan for the diagnosis of invasive fungal disease detection of invasive pulmonary aspergillosis in critically ill patients by combined use of conventional culture, galactomannan, , -β-d-glucan and aspergillus specific nested polymerase chain reaction in a prospective pilot study beta-d-glucan detection as a diagnostic test for invasive aspergillosis in immunocompromised critically ill patients with symptoms of respiratory infection: an autopsy-based study comparison of , -β-d-glucan with galactomannan in serum and bronchoalveolar fluid for the detection of aspergillus species in immunosuppressed mechanical ventilated critically ill patients diagnosis of invasive aspergillosis in intensive care unit patients aspergillus-specific lateral-flow device and real-time pcr testing of bronchoalveolar lavage fluid: a combination biomarker approach for clinical diagnosis of invasive pulmonary aspergillosis performance of galactomannan, , -β-d-glucan, aspergillus lateral-flow device, conventional culture, and pcr tests with bronchoalveolar lavage fluid for diagnosis of invasive pulmonary aspergillosis point-of-care diagnosis of invasive aspergillosis in non-neutropenic patients: aspergillus galactomannan lateral flow assay versus aspergillus-specific lateral flow device test in bronchoalveolar lavage multicenter evaluation of a lateral-flow device test for diagnosing invasive pulmonary aspergillosis in icu patients this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license we thank paul e verweij m.d. for helpful discussions. the authors declare no conflict of interest. j. fungi , , key: cord- -mlju f u authors: haas, lenneke e. m.; de lange, dylan w.; van dijk, diederik; van delden, johannes j. m. title: should we deny icu admission to the elderly? ethical considerations in times of covid- date: - - journal: crit care doi: . /s - - -x sha: doc_id: cord_uid: mlju f u nan the sars-cov- (covid- ) pandemic leads to severe shortages of intensive care unit (icu) facilities in many countries. although most people appear to be asymptomatic, some reports suggest that to % of infected people require hospitalization and - % require mechanical ventilation [ ] . this strains many icus beyond their maximum capacity. national critical care societies have adopted protocols to increase their beds up to % or more. however, although a lot of effort can be done to increase the icu capacity, demand may still outpace the supply. as a consequence, a scenario can arise in which not every patient who needs icu treatment can be admitted, and difficult decisions about allocation of icu beds need to be made [ ] [ ] [ ] . in this article, we discuss the use of age as a criterion for icu treatment in times of scarce icu capacity by contrasting it with deciding under normal conditions. medical treatment has to be justified by serving the wellbeing of the patient, and it should be aligned with the wishes of the patient. the burden of an icu treatment has to be carefully balanced against the estimated chance of recovery. this chance of recovery is affected by age and many other factors like the admission diagnosis, severity of organ failure, comorbidities, frailty, and preadmission performance status [ ] . sometimes, icu admission might be more appropriate for a fit -year-old patient than for a vulnerable -year-old patient. elderly patients (defined as years and older) have a higher risk of death and of functional decline than younger patients. however, the majority of them survives, and in addition, several studies have demonstrated that elderly icu survivors might accept their disabilities and accommodate to a degree of physical disability quite well, consider their quality of life to be good or satisfactory, and report good emotional and social well-being after hospital discharge [ ] . the carefully balancing of pros and cons of icu treatment should be done before icu admission (as advance care planning) but also during a (prolonged) icu admission. what is common to all decisions on starting, continuing, or foregoing life support is that they should be justified by the autonomous wish of the patient and the benefit of treatment for that unique patient. age may play a role in these decisions in several ways. it is proxy for the medical condition of the patient, and advanced age is clearly a factor that should be weighed together with other risk factors for a poor outcome of icu treatment. elderly patients themselves may also have the feeling that they have lived life to its full and that therefore life-sustaining treatments should not be applied in their own case. there is, however, no valid reason to limit icu admissions to those under a specific age. elderly patients admitted to the icu with covid- are at increased risk of death [ , ] . although we need more robust data about short-and long-term outcomes of elderly patients admitted to the icu because of covid- , the mortality rates reported up to now are to % [ , ] . these numbers will even become higher, since at the time of reporting a substantial portion of the patients was still in the icu and the follow-up was short. in circumstances of a pandemic, not only the autonomy of the patient and proportionality of treatment, but also shortage of resources may play a role in decisions about icu treatment. emanuel and colleagues proposed to use a utilitarian framework [ ] . this strategy aims to maximize the benefits for the largest number of people and prioritize care based on the (estimated) greatest advantage of icu treatment, the so called incremental probability of survival. according to this approach, for instance, parents of young children should be prioritized, then parents of teenagers, middle-aged people, then elderly. chances of survival rates after icu admission decrease with increasing age, making age an important factor in this utilitarian approach. the use of age as a selection criterion in case of scarcity can also be justified by pointing at the "fair innings" that a patient has had, meaning that older patients have already had their opportunity to reach a certain "mature" age, which has given them a fair equality of opportunity. the idea is that everyone should have an equal opportunity to lead a life of a certain duration. while there is no hard and fast rule for what is an unfulfilled life age for a person, most policies distributing lifesaving resources look to those under as gaining priority while those in their s and beyond, who have had a chance to experience life and flourish as human being, receive lower priority. we submit that this strategy does not amount to age discrimination as all people are treated alike: when they become older, their claim on lifesustaining treatment decreases. in this article, we discussed two ways of using age in the triage of icu admission. under normal circumstances, age should be weighed as a risk factor for poor outcome. together with other risk factors, it may lead to the shared decision to forego icu treatment. it cannot be justified to withhold icu admission for all patients above a certain age. in times of scarcity, however, we believe it is justified to prioritize the younger patients, in order to maximize the benefits for the largest number of people, and because of the fair innings that an elderly patient has already had. abbreviation icu: intensive care unit clinical characteristics of coronavirus disease in china intensive care management of coronavirus disease (covid- ): challenges and recommendations facing covid- in italy -ethics, logistics, and therapeutics on the epidemic's front line triage: care of the critically ill and injured during pandemics and disasters: chest consensus statement the contribution of frailty, cognition, activity of daily life and comorbidities on outcome in acutely admitted patients over years in european icus: the vip study long-term survival, quality of life, and quality-adjusted life-years among critically ill elderly patients baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a singlecentered, retrospective, observational study icnarc case mix programme database publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. authors' contributions lh, ddl, dvd, and jvd contributed to the ideas of this paper. all authors contributed to the writing of the paper and read and approved the submitted final version. not applicable.availability of data and materials not applicable.ethics approval and consent to participate not applicable. the authors have approved the manuscript for submission and consent for publication. the content has not been published elsewhere. the article does not contain individual person's data. the authors declare that they have no competing interests. key: cord- -b f a o authors: neuwirth, c.; gruber, c.; murphy, t. title: investigating duration and intensity of covid- social-distancing strategies date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: b f a o the exponential character of the recent covid- outbreak requires a change in strategy from containment to mitigation. meanwhile, most countries apply social distancing with the objective to keep the number of critical cases below the capabilities of the health care system. due to the novelty and rapid spread of the virus, an a priori assessment of this strategy was not possible. in this study, we present a model-based systems analysis to assess the effectiveness of social distancing measures in terms of intensity and duration of application. results show a super-linear scaling between intensity (percent contact reduction) and required duration of application to have an added value (lower fatality rate). this holds true for an effective reproduction of r > and is reverted for r < . if r is not reduced below , secondary effects of required long-term isolation are likely to unravel the added value of disease mitigation. we recommend an extinction strategy implemented by intense countermeasures. this article is written in mid-april where globally the number of confirmed in the long-term, school closure and home confinement will negatively affect children's health [ ] and the global economy, to name only two big drawbacks of these measures. in this light, it is of particular interest, for what duration these exceptional interventions must remain in place. according to recent estimates, we are probably at least year to month away from large-scale vaccine production [ ] . independent of the time it takes to develop a vaccine, the epidemic spread will also come to an end, if sufficient people have been infected to establish herd immunity. studies on the effectiveness of the concept of disease mitigation with the objective to establish herd immunity shows some potential in the case of pandemic influenza [ ] . in this study, we present an exploratory and model-based systems analysis that is aimed at investigating the application of social distancing strategies to covid- . specific objectives of this research are: ) to investigate the effectiveness of contact reduction policies with respect to intensity and duration and ) to estimate the amount of time to establish herd immunity by considering the national health care systems of austria and sweden, which are very different in terms of critical care capabilities. a detailed description of model equations, assumptions as well as uncertainty of currently available data are presented in the following section. data uncertainty is addressed by the analysis of alternative scenario runs to enhance robustness of model results. in a concluding section, we compare our results to similar studies, discuss current limitations of data availability and give recommendations based on exploratory results. method adapted sir model the current scenario of novel pathogen emergence includes considerable uncertainty [ ] . this means that a reliable scientific evidence base on covid- is yet to be established. under these preconditions, the use of models for exploratory rather than predictive purposes is more appropriate [ ] . accordingly, the simulation model presented in this study was designed to identify and systematically explore important qualitative behavior of this dynamic system that remains unchanged irrespective of parameter variations. an adaptation of the popular susceptible-infected-recovered (sir) model turned out to be most suitable for this purpose (see fig. ). in order to meet the specific requirements of a simulation model on covid- mitigation, the structure of the original model was adapted accordingly. for instance, pathological findings of covid- indicate that there is a considerable number of cases that develop mild or no symptoms [ ] . to account for this characteristic, we separated the infected population into those that are asymptomatic and those that are not, which in the latter case leads to isolation or hospitalization. the asymptomatic infected get resistant without prior isolation. exponential growth in numbers of infected poses a challenge to health care facilities. in italy, specialists are already considering denying life-saving care to the sickest and giving priority to those patients most likely to survive [ ] . this will inevitably cause potentially avoidable deaths. in the model, deaths caused by a lack of intensive care is considered independently. the calculation of population quantities in respective compartments (s, iu, ra, ii, d, dl and r) is in line with the logic of the standard sir model. initially everyone in the total population t p is susceptible. the number of susceptible is reduced over time by infections i where i r is the infection rate (rate of contacts between uninfected and infected that result in infections) and c ui is the number of contacts between infected and uninfected, which is calculated as april , / . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . . where c d is the personal contacts per day, s t is the susceptible at time t and iu is the number of unknown infections. to take account for a lower infection rate of asymptomatic infected, the unknown infections iu in equation is substituted by with iu c being the unknown infected corrected for asymptomatic infected, a f the fraction of asymptomatic among infected and a p the asymptomatic population's potential to infect. the flows from compartment iu to r a and ii -i.e. asymptomatic cases getting resistant r a and isolation of infected iso -are calculated by parameter i t is the time between infection and isolation and d a is the duration of asymptomatic infection. the flows from compartment ii are given by where parameter d s is the duration of distinct symptomatic sickness, c f r is the case fatality rate and icu d and icu s is the intensive care demand and supply respectively. the intensive care demand icu d is calculated by taking the critical fraction c f (see table of infected in isolation ii. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . reproduction, case fatality rates and proportion of asymptomatic cases is quite substantial and growing. the wide range of suggested parameter values, however, poses a considerable challenge to model parametrization. for instance, estimates of the basic reproduction number r vary within a range from . [ ] to . [ ] . part of this variation is explained by geographic variation of population densities and social habits. moreover, there is uncertainty in the percentage of asymptomatic cases. the outbreak in a smaller isolated population is an opportunity to derive representative numbers by applying comprehensive and repeated laboratory testing. one such example is the outbreak of covid- on board of the diamond princess cruise ship. however, given that most of the passengers were years and older, the nature of the age distribution may lead to underestimation of asymptomatic cases if older individuals tend to experience more symptoms [ ] . in a normal population higher ratios of up to % asymptomatic carriers of covid- are expected ( [ ] . the question whether or not asymptomatic carriers are able to infect others is still controversial (e.g. [ ] ). the severity of the disease does also play an important role in estimating the ratio of critically ill patients who need intensive care. according to chinese statistics, % of positively tested patients are admitted to intensive care [ ] . this number was adopted by the world health organization [ ] and other studies (e.g. [ ] , whereas national statistics show significant deviations; e.g. to % in italy [ ] and . % in austria [ ] . a potential explanation for these considerable differences is that in italy a lot of the older population were infected [ ] . the specific age distributions of affected communities may also show some biasing effect on estimated case fatality rates. another factor that contributes to regional differences in case fatality is the occupation or over-occupation of available intensive care beds (icu beds). in a few instances, national critical care capabilities are exceeded by the number of critically ill patients (e.g. italy and france), which drastically elevates fatality rates. by contrast, the true case fatality rates are lower if theoretically all cases were found by testing the entire population. accordingly, a lower case fatality rate (cfr) was reported by countries who were effective in extensive testing and maintaining the prevalence of critical cases below critical care capabilities like south korea [ ] . a higher cfr was reported by countries who refrain from extensive testing and/or are overwhelmed by the pace of new infections like iran, italy and others [ ] . in the model, we use the more reliable south korean figures and simulate the additional fatalities due to the critical care limit based on capability limits of national critical care units (see eq. and eq. ). among the parameters in table , the basic reproduction number r is the only parameter without explicit representation in the model equations. this parameter is the number of secondary cases, which an infected person produces in a completely susceptible population [ ] . in the model, r is defined as the arithmetic product of it the time between infection and isolation, c d the personal contacts per day and i r the infection rate. in response to the outbreak of an epidemic disease, changes in contact behavior diminish the reproduction. we refer to this modified reproduction as effective reproduction number r. in model scenarios where contact behavior is not constant, effective reproduction is denoted as r t . the choice of appropriate scenarios is based on parameter uncertainty and model sensitivity. sensitivity analysis indicate a linear response in model output to variations in c f r and c f , and interestingly non-linear effects in response to variations in r, a f and a p . accordingly, the latter variables were selected as scenario parameters (see table ). dependent on the research objectives and (see introduction); prolonged and april , / . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . [ ] was applied in respective scenarios (see table ). whereas prolonged social distancing is defined by constants c r and d m , intermittent social distancing is implemented by dynamic adaptation of contact reduction c r during simulation runtime dependent on the amount of icu beds available. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . fig. ). consequently, social distancing flattens the curve of daily infections, while higher proportions of asymptomatic cases elevate the peak. this flattening effect can be expressed analytically. the daily infections resemble a normal distribution, which is defined by a mean µ (days between outbreak and peak of april , / . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . daily infections) and a standard deviation σ. a lower r will lead to a higher µ (see fig. ) and a broader distribution σ (see fig. ). additionally, the number of initial infected people reduces µ (see fig. ), whereas σ is independent of it. is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . measures in terms of contact reduction, the longer the duration needs to be to have an added value; i.e. a relatively lower fatality rate. in other words, the harder you break, the longer it takes. for instance, % contact reduction needs to be applied for additional days to outperform a % contact reduction in scenario (see fig. ). the lower the basic reproduction in the scenarios, the larger the time lag associated with an intensification of social distancing (see fig. , scenarios , , , and ). this is in line with above-mentioned relationships that show increased effects of r on µ and σ with lower r. given the trade-offs associated with required long-term lockdown, the effectiveness of additional social distancing decreases with r close to . the secondary effects of lock down have not been modelled, but it is speculated that reductions in social contacts will increase mortality (e.g. social isolation and homicide; obesity and cardiovascular diseases etc.) making moderate contact reduction more adequate. interestingly, if social distancing is intense enough to drop r below one, a further increase in intensity removes the pandemic earlier (see fig. , scenario ) . this is contrary to the case of r > where the effectiveness of more intense measures is in danger to be unraveled by the super-linear increase in duration. the curve flattening effect of social contact reduction also explains why drastic contact reduction may cause more deaths than mild contact reduction, if measures are applied for too short time. in the worst case, intense social distancing will hardly have any effect (see fig. ). duration to establish herd immunity intensity and duration are also closely related in the intermittent social distancing and herd immunity scenario (see fig. ). the strategic objective in this scenario is to keep the demand for icu beds within the bounds of icu supply until herd immunity is established. independent of what values the policy thresholds have (see section model inputs and parameters), the demand for the icu beds behaves like a damped oscillation (see fig. ). this is explained by the delay in the system, diminishing number of susceptible people and the negative feedback between number of available icu beds and social contacts. in the early phase of the outbreak, the number of patients exceeds the number of available icu beds due to high reproduction potentials. higher basic reproduction r results in additional over-occupation of icu capabilities (fig. , scenario and ). moreover, the variation of the constant of availability of intensive care brings about a shift in the time needed to achieve the strategic objective of herd immunity (compare sweden and austria in fig. ). this relationship exhibits an almost linear scaling. independent of national health care capabilities, results show that social distancing and herd immunity strategies require extraordinary endurance. this is also the case under more favorable conditions. in austria, for instance, it is estimated that only . % of confirmed cases are admitted to icu [ ] . combined with austria's high performance health care system and low effective reproduction, the time to establish herd immunity is still estimated to be about years (see fig. ). given that the icu beds are also needed for patients other than covid- , an even longer period has to be expected. is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . infections. as a consequence of this delay, measure intensity scales super-linearly with the required duration of application to show added value; i.e. a relatively lower fatality rate. given the large scale of temporal delay (up to multiple years for a % increment of additional contact reduction), secondary effects of long-term social isolation such as psychological distress, depression [ ] , and increased mortality [ ] are likely to unravel the added value of disease mitigation. this holds true for effective reproduction numbers above one. below this threshold, more intense measure applications are associated with earlier termination of viral spread. in the absence of a vaccination, mitigation strategies are crucial to keep the number of severe and critical cases below the capabilities of the health care system. if the use of mitigation interventions is well balanced against capability limits, the time required to establish herd immunity linearly scales with available capabilities of the health care system (defined by the number of icu beds in the simulation). other important factors are the reproduction number and the severity of the disease (expressed by the fraction of cases that need icu admission). depending on the calibration of those factors, it is estimated that herd immunity on a national level will be established in more than years from now. this is in line with an agent-based simulation study by [ ] , who indicate a duration of years and months for the netherlands. according to a deterministic simulation by [ ] in the united states the epidemic could last into under current critical care capabilities. it is important to mention that assumptions and policies implemented in models are not exactly reproducible in reality. for instance, bock et al. [ ] argue that mitigation measures imposed by state authorities can hardly be fine-tuned enough to hit the narrow feasible interval of epidemiologically relevant parameters with which a successful mitigation is possible. given those constraints, as well as trade-offs associated with required long-term lockdown, we conclude that the success of a strategy based on social distancing, delay and herd immunity is unrealistic under known preconditions. according to [ ] , an extinction strategy implemented by intense countermeasures seems promising. this is supported by our low effective reproduction scenario (r < ). to . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint date, a more differentiated assessment of alternative countermeasures such as the selective isolation of vulnerable individuals or approaches of contact tracing and isolation are limited by data scarcity and in part data inconsistency. for instance, there is little reliable information about age-stratified asymptomatic ratios. there is also few studies on secondary effects of social distancing and isolation in the case of a global pandemic. up until now, the impact of country-based measures has hardly been empirically assessed by methods of inferential statistics. while such studies will shed light on important system dependencies, large-scale investment into health care and medical research is essential to spawn game-changing innovation such as the development of vaccines, drugs and affordable test kits. coronavirus covid- global cases by the center for systems science and engineering (csse) at jhu [www document evaluation of the effectiveness of surveillance and containment measures for the first patients with covid- in singapore-january from containment to mitigation of covid- in the us covid- and community mitigation strategies in a pandemic how will country-based mitigation measures influence the course of the covid- epidemic? the lancet covid- : getting ahead of the epidemic curve by early implementation of social distancing mathematical modeling of covid- transmission and mitigation strategies in the population of ontario the variability of critical care bed numbers in europe estimating the number of infections and the impact of non-pharmaceutical interventions on covid- in european countries the psychological impact of quarantine and how to reduce it: rapid review of the evidence. the lancet mitigation of pandemic influenza: review of cost-effectiveness studies novelty and uncertainty: social science contributions to a response to covid- the exploratory modeling workbench: an open source toolkit for exploratory modeling, scenario discovery, and (multi-objective) robust decision making pathological findings of covid- associated with acute respiratory distress syndrome covid- and italy: what next? the lancet social distancing strategies for curbing the covid- epidemic. medrxiv modelling the epidemic trend of the novel coronavirus outbreak in china. biorxiv estimating the asymptomatic proportion of coronavirus disease (covid- ) cases on board the diamond princess cruise ship covid- health care demand and mortality in sweden in response to non-pharmaceutical (npis) mitigation and suppression scenarios. medrxiv presumed asymptomatic carrier transmission of covid- clinical characteristics of novel coronavirus infection in china health systems respond to covid- -creating surge capacity for acute and intensive care recommendations for the who european region critical care utilization for the covid- outbreak in lombardy, italy: early experience and forecast during an emergency response schutzschirm für das gesundheitswesen in zeiten von covid- . health systems intelligence case-fatality rate and characteristics of patients dying in relation to covid- in italy transmission potential and severity of covid- in south korea cross-country comparison of case fatality rates of covid- /sars-cov- . osong public health res perspect real-time estimation of the risk of death from novel coronavirus (covid- ) infection: inference using exported cases the reproductive number of covid- is higher compared to sars coronavirus interventions to mitigate early spread of sars-cov- in singapore: a modelling study the estimation of the basic reproduction number for infectious diseases sars control and psychological effects of quarantine social relationships and health: the toxic effects of perceived social isolation a phased lift of control: a practical strategy to achieve herd immunity against covid- at the country level. medrxiv mitigation and herd immunity strategy for covid- is likely to fail. medrxiv key: cord- -dmgd d authors: berardi, giammauro; colasanti, marco; levi sandri, giovanni battista; del basso, celeste; ferretti, stefano; laurenzi, andrea; guglielmo, nicola; meniconi, roberto luca; antonini, mario; d’offizi, gianpiero; ettorre, giuseppe maria title: continuing our work: transplant surgery and surgical oncology in a tertiary referral covid- center date: - - journal: updates surg doi: . /s - - - sha: doc_id: cord_uid: dmgd d covid- is rapidly spreading worldwide. healthcare systems are struggling to properly allocate resources while ensuring cure for diseases outside of the infection. the aim of this study was to demonstrate how surgical activity was affected by the virus outbreak and show the changes in practice in a tertiary referral covid- center. the official bulletins of the italian national institute for the infectious diseases “l. spallanzani” were reviewed to retrieve the number of daily covid- patients. records of consecutive oncological and transplant procedures performed during the outbreak were reviewed. patients with a high probability of postoperative intensive care unit (icu) admission were considered as high risk and defined by an asa score ≥ iii and/or a charlson comorbidity index (cci) ≥ and/or a revised cardiac risk index for preoperative risk (rcri) ≥ . patients were operated, including ( . %) liver and kidney transplantations. patients had few comorbidities ( . %), low asa score ( . ± . ), cci ( . ± . ), and rcri ( . ± . ) and had overall a low risk of postoperative icu admission. few patients had liver cirrhosis ( . %) or received preoperative systemic therapy ( . %). ( %) high-risk surgical procedures were performed, including major hepatectomies, pancreaticoduodenectomies, total gastrectomies, multivisceral resections, and transplantations. despite this, only patients ( . %) were admitted to the icu. only oncologic cases and transplantations were performed during the covid- outbreak. careful selection of patients allowed to perform major cancer surgeries and transplantations without further stressing hospital resources, meanwhile minimizing collateral damage to patients. since december , the world is struggling against coronavirus disease and in the past months, the life of more than one-third of the planet's population has radically changed [ ] . severe acute respiratory syndrome coronavirus (sars-cov- ) has shown to be a very contagious virus potentially causing complicated atypical pneumonia and associated with significant mortality [ ] . despite initially confined to hubei province, china and asia, covid- promptly spread to western countries, and in march , , the world health organization (who) declared a public health emergency of international concern [ ] . by early april, we are counting over , , cases and , deaths worldwide, with countries involved over continents [ ] . italy was one of the first western countries diagnosing covid- patients in late january and was certainly the one suffering the most by the sudden outbreak of the disease. indeed, sars-cov- rapidly spread throughout the country by the end of february, challenging the healthcare system toward its collapse, increasing the mortality rate and raising the question concerning the need for special measures to contain the crisis. as a matter of fact, by mid-march the italian cases of covid- were already , with almost patients requiring mechanical ventilation in the intensive care unit (icu) [ ] . consequently, the italian government announced extraordinary measures to contain the spread of the pandemic, by means of small confinements in northern italy, reaching a nationwide lockdown that is still limiting the population [ ] . covid- outbreak seriously stressed the healthcare system worldwide, with the urgent need of extra icu beds, dedicated hospital paths, personnel training, and infection control measures [ , ] . care of diseases outside the covid- has rapidly changed, and healthcare providers are currently adapting to maximize and properly allocate resources [ ] . surgical activity has shifted to pursue only emergency and elective cancer cases as described in different specialties [ ] [ ] [ ] [ ] . furthermore, the big picture and the full impact is still unknown as its effects on economy, hospital infrastructure, healthcare strategy, and prognosis of oncologic patients [ ] . indeed, people with cancer might suffer the most by this worldwide outbreak as the access to surgery is limited by the significant reduction in available resources, eventually influencing the decision making and the therapeutic allocation of patients [ ] . the italian experience anticipated what the world is currently facing, and the measures for containment, the healthcare adaptations, and the changes in hospital practice have been already tested and are somehow established in our country where the peak of the infection seems to be reached and overcome [ ] . as the italian national institute for the infectious diseases, we have hospitalized the first italian covid- patients and since then, our general surgery department had to face this reality [ ] . the aim of this study was to demonstrate how our surgical activity was affected by the covid- outbreak, what adaptations were made and how our practice changed, eventually sharing the lessons learned as anticipators in a health issue of international concern. on january , two covid- -positive individuals were hospitalized at the italian national institute for the infectious diseases "l. spallanzani" of rome. in this hospital, four departments and five daily outpatient clinics are dedicated to the diagnosis and treatment of various infectious diseases. health emergencies, such as sars in and ebola in , have been nationally referred and managed at our hospital previously [ , ] . in the same institution, our general surgery department operates in two daily operative rooms (or) more than cases per year, including liver, kidney, and pancreas transplantations. the icu of the hospital admits both medical and surgical patients in a -bed department. the records and official bulletins of our hospital were reviewed to retrieve the number of daily covid- patients hospitalized, those requiring icu admission and those discharged home. furthermore, all the records of consecutive surgical procedures performed during the covid- outbreak were reviewed, and the following data were extracted: age, gender, disease, comorbidities, neoadjuvant therapy, cirrhosis, previous surgery, type of surgical procedure, type of approach (open vs. laparoscopic), conversion, operative time, blood loss, and admission to the icu. the search was limited between the nationwide lockdown (march , ) and april , . informed consent was obtained from each patient, and every oncologic case was discussed in a multidisciplinary meeting involving surgeons, medical oncologists, gastroenterologists, radiologists, and pathologists. comorbidities were graded using the american society of anesthesiology (asa) score, the charlson comorbidity index (cci), and the revised cardiac risk index for preoperative risk (rcri). patients with a high probability of postoperative icu admission were considered as high risk and defined by an asa score ≥ iii and/or a cci ≥ and/or a rcri ≥ as previously validated [ ] [ ] [ ] . major hepatectomies were defined as the resections of three liver segments or more [ ] . pancreatic resections, total gastrectomies, major hepatectomies, and multivisceral resections as well as liver and kidney transplantations were considered as the high-risk surgical procedures because of the increased likelihood of postoperative icu admission. distribution of variables was assessed using kolmogorov-smirnov and shapiro-wilk tests. data are expressed as the mean ± standard deviation for parametric continuous data and as median and interquartile ranges for non-parametric distribution. categorical data were expressed as number and percentages. categorical data are expressed as number and percentages. chi-squared or fisher exact test with yates correction when appropriate was used to compare differences in categorical variables. unpaired student's t-test was used to compare differences in continuous parametric variables and the mann-whitney test for continuous non-parametric variables. statistical analysis was performed with spss software (version . . armonk, ny, ibm corp) for macosx. a p value of < . was considered statistically significant. on january , (day ), the first two covid- -positive patients in italy were admitted to the department of infectious diseases of our hospital with mild fever and atypical pneumonia requiring no invasive treatment. on february (day ), due to the worsening clinical conditions, mechanical ventilation was needed, and the two patients were admitted to the icu. three days later (day ), a third patient with positive nasopharyngeal swab was admitted and monitored at the department of infectious diseases. from day to day (march , ), diagnostic nasopharyngeal swabs for symptomatic patients were implemented at our institution as part of a regional referral policy; however, no further patients tested positive to sars-cov- , picturing a stable phase of the epidemic. on march (day ), two individuals had a positive swab and were hospitalized; since then, an exponential growth of covid- cases admitted to our hospital was registered as part of a national trend. sixty-five hospitalized cases were reached on day , nine of which required mechanical ventilation, therefore saturating the capacity of the icu. on the evening of march , the italian government announced the national lockdown, and the following day (day ), the first institutional guidelines on extraordinary covid- measures were released by our hospital (fig. ) : ( ) all healthcare workers were required to enhance hygienic measures and wear surgical masks and gloves within the hospital building. ( ) construction works in the icu started with the aim of increasing the number of beds from to . ( ) one of our daily general surgery operating rooms was closed to reallocate anesthesiologists and nurses to the management of covid- cases. ( ) the or personnel was trained on how to wear and un-wear special equipment and how to deal with contagious patients. ( ) our surgical department was asked to re-consider and re-work the or planning to perform only oncological cases and transplantations; outpatient clinics were significantly reduced. ( ) questionnaires on possible infection or contacts with covid- cases were administered to all patients admitted and scheduled for surgery; nasopharyngeal swabs were performed in suspicious cases. ( ) all gatherings, including our multidisciplinary meetings, were forbidden and reworked on a webinar platform. on march (day ), further institutional guidelines were released: ( ) relatives were forbidden to visit patients before and after surgery. ( ) nasopharyngeal swabs were administered to all patients admitted and scheduled for surgery and isolation was maintained until test's response. as a result, the first covid- patient of our surgical ward was identified on day : the man had a klatskin tumor and was scheduled to receive a right hepatectomy with hepaticojejunostomy. unfortunately, he was shifted to percutaneous transhepatic biliary drainage and transferred to the infectious disease department. seventy-two patients ( males and females) with a median age of ( - ) were operated at our surgical department in the study period (table ) . most patients had colorectal cancer ( . %) and colorectal liver metastases ( . %), followed by cholangiocarcinoma ( . %) and pancreatic ductal adenocarcinoma ( . %). twelve patients ( . %) had liver or kidney disease requiring transplantation and no patients died while on the waiting list. compared to the same period of time in , fewer procedures were performed in ( in vs. in ); furthermore, a statistical significant difference in terms of type of operations was found between years ( . % benign, . % malignant, and . % transplantations in vs. % benign, . % malignant, and . % transplantations in ; p < . ). overall, patients operated during the covid- outbreak had few comorbidities ( . %), low asa score ( . ± . ), cci ( . ± . ), and rcri ( . ± . ), being overall at lower risk of postoperative icu admission (table ) . furthermore, few patients had liver cirrhosis ( . %) or received preoperative systemic therapy ( . %). type of surgical procedures and operative details are depicted in table . we have performed ( . %) high-risk operations in the study period of which ( . %) were liver and ( . %) were kidney transplantations. despite this, few patients were admitted to the icu ( . %). one patient ( . %) died during the study period (one hyperacute allograft dysfunction following liver transplantation for autoimmune hepatitis). morbidity rate was . % and five patients ( . %) developed a major grade complication according to clavien-dindo. as mentioned above, during the first period (january -march , ), covid- hospitalizations were stable at our hospital, with two cases admitted to the icu and one monitored at the department of infectious diseases. in the second period (march -april , ), an exponential growth in number of admissions was registered, with a median of ( - ) positive cases per day (fig. ) . at the same time, a median of ( - ) cases per day were operated by our surgical team in the first period, while fewer cases were operated in the second (median of ( - ) per day; p = . ). thirty-nine ( . %) benign conditions, ( . %) oncological patients, and ( . %) transplantations were performed in the first period, while only malignant cases and transplantations (n = , %) were performed in the second. considering only the transplantations and the operations performed for cancer, patients in the second period had fewer comorbidities, lower asa score, cci, and rcri, being overall at lower risk of postoperative icu admission (table ) . furthermore, fewer patients had previous surgery ( . % vs. . %; p < . ) and/or received preoperative systemic therapy ( . % vs. . %; p < . ). the number of high-risk operations was higher in the second phase of the pandemic ( . % vs. . %; p = . ). despite this, fewer patients were admitted to the icu in period and this was statistically significant ( . % in period vs. . % in period ; p = . ). in this study, we have shown how the recent covid- outbreak affected our department of surgery and transplantation. fewer surgeries were performed and these were only for cancer and for urgent liver or kidney transplantations. notwithstanding, we have maintained our standard practice by enhancing selection of patients, meanwhile allowing for the re-allocation of the hospital resources. sars-cov- virus infection has dramatically changed the world recently. more than two hundred countries all over the world had to undertake extraordinary measures to contain the epidemic and reduce possible side effects on healthcare and economy [ ] . indeed, many eastern and western governments followed the example of china and are currently in lockdown, with few exceptions. a deep impact was expected on the healthcare systems all over the world: re-allocation of resources was urgently required in an effort to contain the devastating consequences of the pandemic. as a domino effect, patients with other medical conditions, such as cardiovascular diseases, cancer, and chronic conditions, suffered and are still suffering as a collateral damage [ ] . in response to the rapid increase of covid- cases, institutional guidelines called for the re-arrangement of the anesthesiologists and nurses were re-allocated, and dedicated teams for both covid- patients and surgical practice were created. our department suffered the sudden closure of one daily or and the significant reduction in the possibility to use icu beds after surgery, as these were day by day used for the management of covid- patients. as surgeons, we had to completely re-consider our roles and our surgical activity, reckoning with the limited resources. we had to face a healthcare emergency with uncertain future course and adapt accordingly. surgeries for benign conditions were stopped and the waiting list for cancer was handled and reworked entirely. the most important limitation was the hampered access to the icu as many patients require intensive monitoring after surgery for cancer, especially when major procedures are needed. furthermore, we had to deal with the fact that transplantations normally require intensive care management in the postoperative. we were advised to limit the number of surgeries requiring icu admission as much as possible, to avoid the saturation of resources and failure of the system. as an institutional policy, our transplant center remained opened and we decided to continue with our standard surgical oncology activity, improving selection of patients to limit the need for postoperative intensive care management. waiting list for liver and kidney transplantations was maintained respecting the same inclusion and exclusion criteria and using the same prioritization. transplantations were still admitted to the icu for monitoring through a dedicated pathway with dedicated personnel, despite limiting their length of stay and discharging them to the surgical ward as soon as possible. notably, we have performed standard numbers of the high-risk surgical procedures, selecting more surgically fit individuals. furthermore, patients were less commonly having preoperative neoadjuvant chemotherapy and/or previous surgery, significantly lowering intraoperative risks. all the transplantations performed were admitted to the icu, while only three oncologic patients required intensive care management after surgery: these latter were patients with significant comorbidities that were scheduled for the high-risk surgeries (two pancreaticoduodenectomies for adenocarcinoma and one right hepatectomy for hepatocellular carcinoma). our policy was pursued in an effort to prioritize patients by cancer prognosis. indeed, malignancies requiring high-risk surgical interventions (i.e., cholangiocarcinoma, liver metastasis, pancreatic adenocarcinoma, and sarcoma) are generally those with the worst prognosis and more likely to suffer by a delay in treatment [ ] . a different approach would have been to rework the waiting list for cancer prioritizing less-invasive procedures (i.e., colorectal resections) with no strict selection of candidates in order to cope with the limited resources [ ] . the main issue here is that both strategies will generate a gap in cure that has to be considered in the near future when the covid- crisis will be over. surgical delay should not affect oncological prognosis, in order to minimize future repercussions of this international health crisis [ ] . the alternatives to surgery and their efficacy should be reviewed and discussed for each type of cancer and case by case, in an effort to minimize the waiting list and the loss of patients due to cancer progression [ , ] . in some cases, systemic treatment could be prolonged or adapted, while in others the window of cure might be missed; sometimes surgery can be postponed, while some other patients need surgical treatment to stay on their pathway [ , ] . in this setting, multidisciplinary meetings should be reworked to consider patients with cancer in the covid- era, in which resources and future are uncertain. balancing the prognosis of cancer with the potential alternatives and the characteristics of patients might eventually lead to improve the treatment allocation exploiting resources and maintaining oncologic principles [ ] . finally, an "hub and spoke" system based on a regional policy should be encouraged in the near future to allow for immediate referral and faster access to treatments, eventually improving quality of care. patients with cancer are paying the price at different levels, not only because of the limited access to cure but also because of the delay in diagnosis [ ] . indeed, the significant reduction of outpatient clinics and the limitation in imaging modalities and/or endoscopies might hamper a rapid diagnosis and a prompt referral. as a further issue, it has already been shown that cancer patients are more susceptible to covid- infections: % of covid- patients in china had a history of cancer as compared to . % among normal chinese population [ ] . these patients were also having more severe infections and most commonly required intubation and invasive ventilation. one lesson that we have learned in our hospital is that the diagnostic modalities for covid- are important not only to contain the infection and avoid the spread of the disease but also to ensure safe treatment of patients. questionnaires are useless in our opinion, as we are at the point that this pandemic cannot be detected by recalling contacts or possible exposure to the infection [ ] . indeed, once we have shifted to nasopharyngeal swabs for all patients admitted to our department, we had our first sars-cov- -positive surgical candidate, this patient earlier tested negative to the questionnaire. on one hand, this highlights the importance of swabs for all surgical candidates to contain the infection among patients and healthcare workers; on the other hand, it sheds the light on the need for further evidence concerning the management of positive covid- patients with cancer. indeed, our patient with cholangiocarcinoma was shifted to non-surgical treatment: our team was unprepared at that time as no recommendations were available and issues regarding potential complications and transmission were raised. recently, lei et al. have demonstrated that positive asymptomatic covid- patients undergoing surgery had a % mortality rate, and all developed atypical pneumonias. furthermore, it is very important to stress that our decision unfortunately altered the patient's prognosis, and this highlights the impact of this pandemic on our healthcare system. finally, special considerations should also be made concerning covid- transplanted patients [ ] [ ] [ ] : indeed, immunosuppressive therapy might lead to an atypical clinical manifestation, such as unspecific viral disease or gastrointestinal symptoms [ ] . this should be taken into account in order to minimize unexpected clinical complications and unpredictable outcomes. in our institution, we have recently standardized the use of ppe to limit the possible transmission of disease during surgery. it has been speculated that laparoscopy might increase transmission due to the aerosolized biological fluids [ , ] . in line with this, we are now using extra protection (double gloves, shield, and filter mask) and filtered gas evacuation systems to avoid any possible transmission during minimally invasive procedures. however, as possible aerosolized fluids happen also as a result of cauterization during open surgery, the surgical community needs more evidence and guidelines concerning the proper use of equipment and resources to be used during surgery [ ] . this study has some limitations mainly being the retrospective analysis that might have introduced selection bias. in this setting, anesthesiologists could have decided subjectively whether the patient required icu admission or not. furthermore, as mentioned above, our hospital is a national referral for the infectious diseases and we have already faced previous emergencies [ , ] ; therefore, the rapid adaptation that we have shown in this manuscript could be the result of experience and competences gained over years. since the recent worldwide spread of the disease, many editorials, letters, and expert opinions have been published on covid- crisis and many have speculated that surgical activity has suffered the spread of this pandemic [ , , , [ ] [ ] [ ] [ ] [ ] . to the best of our knowledge, this is the first manuscript presenting numbers and statistical analysis highlighting the changes in surgical practice during covid- outbreak. as we write, italy is already in its fourth week of lockdown, and the emergency seems to have reached the peak. we will be probably moving toward more relaxed containment measures despite a total opening is unlikely. meanwhile, countries worldwide are facing the ascending phase of this outbreak with a delay of days or even weeks. we believe it is important to share our anticipatory experience on how we have changed and adapted our surgical practice to face this crisis and optimized resources. future evolution of this infection is uncertain: evidence, policies, and recommendations may change on daily bases hopefully improving the quality of care and minimizing the side effects on more patients. we must be prepared to face the consequent need for care in the coming months. by then, a progressive inverse trend should be encouraged, reallocating resources to assist those who suffered the most by the outbreak, both re-enforcing diagnostic steps, and treatment possibilities to counteract the delay we have so far accumulated. besides the emergency of patients infected by sars-cov- infection, our healthcare system is facing the side effects of covid- pandemic. adjustments were necessary in many environments as well as in the surgical field. a shift toward the exclusive management of oncologic diseases and urgent cases has been recently recommended worldwide. rearrangements of resources require adaptations in clinical practice. multidisciplinary meetings should be reworked in the context of covid- reality and selection of patients should be enhanced to ensure cure and minimize loss of patients. we foresee a difficult phase for the time being in which all the non-covid health issues will re-emerge. international cooperation is required, and resources should be allocated accordingly to better tackle this future emergency. conflict of interest all the authors declare no conflict of interest or financial support. research involving human participants and/or animals all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the helsinki declaration and its later amendments or comparable ethical standards. informed consent informed consent was obtained from all individual participants involved in the study. smeden m ( ) prediction models for diagnosis and prognosis of covid- infection: systematic review and critical appraisal cancer patients in sars-cov- infection: a nationwide analysis in china characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention an interactive web-based dashboard to track covid- in real time elaborazione e gestione dati a cura del dipartimento della protezione civile. ministero della salute covid- and italy: what next? recommendations for general surgery activities in a pandemic scenario (sars-cov- ) covid- : how can a department of general surgery survive in a pandemic what happened to surgical emergencies in the era of covid- outbreak? considerations of surgeons working in an italian covid- red zone management of ibd during the covid- outbreak: resetting clinical priorities inflammatory bowel disease care in the covid- pandemic era: the humanitas, milan experience the possible impact of covid- on colorectal surgery in italy covid- global pandemic: options for management of gynecologic cancers covid- : all non-urgent elective surgery is suspended for at least three months in england cancer care during the spread of coronavirus disease (covid- ) in italy: young oncologists' perspective national institute for the infectious diseases "l. spallanzani", irccs. recommendations for covid- clinical management enabling rapid response to the - ebola epidemic: the experience and the results of the national institute for infectious diseases lazzaro spallanzani severe acute respiratory syndrome: the first transmissible disease of the st century a new method of classifying prognostic comorbidity in longitudinal studies: development and validation multifactorial index of cardiac risk in noncardiac surgical procedures a review of asa physical status -historical perspectives and modern developments nomenclature of hepatic anatomy and resections: a review of the brisbane system are we harming cancer patients by delaying their cancer surgery during the covid- pandemic society of surgical o ( ) management of cancer surgery cases during the covid- pandemic: considerations covid- and cancer: lessons from a pooled meta-analysis readaptation of surgical practice during covid- outbreak: what has been done, what is missing and what to expect a combined approach to priorities of surgical oncology during the covid- epidemic how technology can help in oncologic patient management during covid- outbreak managing cancer care during the covid- pandemic: agility and collaboration toward a common goal how covid- outbreak is impacting colorectal cancer patients in italy: a long shadow beyond infection minimally invasive surgery and the novel coronavirus outbreak: lessons learned in china and italy preliminary analysis of the impact of covid- outbreak on italian liver transplant programs the covid- outbreak in italy: initial implications for organ transplantation programs how to guarantee liver transplantation in the north of italy during the covid- pandemic. a sound transplant protection strategy case report of covid- in a kidney transplant recipient: does immunosuppression alter the clinical presentation? characterization of smoke generated during the use of surgical knife in laparotomy surgeries covid- pandemic: perspectives on an unfolding crisis supply of personal protective equipment (ppe) during the covid- pandemic covid- outbreak and surgical practice: unexpected fatality in perioperative period covid- outbreak in northern italy: viewpoint of the milan area surgical community impact of the covid- pandemic on surgical services: early experiences at a nominated covid- centre response of a european surgical department to the covid- crisis neurosurgery during the covid- pandemic: update from lombardy, northern italy key: cord- - hjzzxtm authors: viasus, diego; oteo revuelta, josé a.; martínez-montauti, joaquín; carratalà, jordi title: influenza a(h n )pdm -related pneumonia and other complications date: - - journal: enfermedades infecciosas y microbiología clínica doi: . /s - x( ) - sha: doc_id: cord_uid: hjzzxtm abstract influenza a(h n )pdm virus infection was associated with significant morbidity, mainly among children and young adults. the majority of patients had self-limited mild-to-moderate uncomplicated disease. however, some patients developed severe illness and some died. in addition to respiratory complications, several complications due to direct and indirect effects on other body systems were associated with influenza a(h n )pdm virus infection. the main complications reported in hospitalized adults with influenza a(h n )pdm were pneumonia (primary influenza pneumonia and concomitant/secondary bacterial pneumonia), exacerbations of chronic pulmonary diseases (mainly chronic obstructive pulmonary disease and asthma), the need for intensive unit care admission (including mechanical ventilation, acute respiratory distress syndrome and septic shock), nosocomial infections and acute cardiac events. in experimentally infected animals, the level of pulmonary replication of the influenza a(h n )pdm virus was higher than that of seasonal influenza viruses. pathological studies in autopsy specimens indicated that the influenza a(h n )pdm virus mainly targeted the lower respiratory tract, resulting in diffuse alveolar damage (edema, hyaline membranes, inflammation, and fibrosis), manifested clinically by severe acute respiratory distress syndrome with refractory hypoxemia. influenza a(h n )pdm -related pneumonia and other complications were associated with increased morbidity and mortality among hospitalized patients. influenza a(h n )pdm virus infection was associated with significant morbidity, mainly among children and young adults. the majority of patients had self-limited mild-to-moderate uncomplicated disease. however, some patients developed severe illness and some died. in addition to respiratory complications, several complications due to direct and indirect effects on other body systems were associated with influenza a(h n )pdm virus infection. the main complications reported in hospitalized adults with influenza a(h n )pdm were pneumonia (primary influenza pneumonia and concomitant/secondary bacterial pneumonia), exacerbations of chronic pulmonary diseases (mainly chronic obstructive pulmonary disease and asthma), the need for intensive unit care admission (including mechanical ventilation, acute respiratory distress syndrome and septic shock), nosocomial infections and acute cardiac events. in experimentally infected animals, the level of pulmonary replication of the influenza a(h n )pdm virus was higher than that of seasonal influenza viruses. pathological studies in autopsy specimens indicated that the influenza a(h n )pdm virus mainly targeted the lower respiratory tract, resulting in diffuse alveolar damage (edema, hyaline membranes, inflammation, and fibrosis), manifested clinically by severe acute respiratory distress syndrome with refractory hypoxemia. influenza a(h n )pdm -related pneumonia and other complications were associated with increased morbidity and mortality among hospitalized patients. © elsevier españa, s.l. all rights reserved. r e s u m e n si bien la mayoría de los pacientes infectados por el virus de la gripe a(h n )pdm tuvieron enfermedad no complicada, autolimitada, leve a moderada, la infección se caracterizó por una morbilidad significativa, especialmente entre niños y adultos jóvenes, de forma que algunos pacientes desarrollaron una enfermedad grave y algunos murieron. la infección por virus de la gripe a(h n )pdm se asoció no sólo con complicaciones respiratorias, sino también con complicaciones debidas a los efectos directos e indirectos sobre otros sistemas del organismo. en los pacientes adultos hospitalizados las complicaciones principales fueron neumonía (neumonía primaria por gripe y neumonía bacteriana concomitante/secundaria), exacerbaciones de enfermedades pulmonares crónicas (principalmente enfermedad pulmonar obstructiva crónica y asma), necesidad para la admisión en unidad de cuidados intensivos (incluso ventilación mecánica, síndrome de dolor respiratorio agudo y shock séptico), infecciones nosocomiales y acontecimientos cardíacos agudos. en los animales de experimentación infectados con virus de la gripe a(h n )pdm el nivel de replicación del virus a nivel pulmonar era más alto que el de los virus de la gripe estacional. los estudios anatomopatológicos de muestras de autopsia mostraron que el virus de la gripe a(h n )pdm actúa principalmente sobre el tracto respiratorio inferior, provocando lesión difusa del alveolo (edema, membranas hialinas, inflamación y fibrosis), lo que se traduce clínicamente en un síndrome de distrés respiratorio agudo grave con hipoxemia refractaria. la neumonía y otras complicaciones relacionadas con la gripe por virus a(h n )pdm se asociaron a una mayor morbilidad y mortalidad en los pacientes hospitalizados. © elsevier españa, s.l. todos los derechos reservados. since the th century, influenza pandemics have been described all over the world, at intervals ranging from to years and with varying degrees of severity. in april , a novel influenza virus now known as influenza a(h n )pdm virus caused an outbreak of respiratory disease in mexico and spread rapidly worldwide, resulting in the first influenza pandemic of this century. spain was the first country in europe to report a laboratory-confirmed case of influenza a(h n )pdm virus infection. the number of hospitalizations and deaths due to influenza a(h n )pdm increased continuously until december . it was recently reported that influenza a(h n )pdm virus infection during the - influenza season was associated with higher morbidity than that observed during the pandemic period. , children and young adults accounted for most cases of influenza a(h n )pdm virus infection. the majority of patients had selflimited, mild-to-moderate uncomplicated disease. however, some patients developed severe illness and some died. common symptoms included cough, fever, sore throat, myalgia and headache. some cases experienced gastrointestinal symptoms (nausea, vomiting and/or diarrhea). the major complications of influenza were those involving the lower respiratory tract, mainly pneumonia. in addition, secondary bacterial infections, rhabdomyolysis with renal failure, seizures, and worsening of underlying conditions such as cardiovascular disease were also reported. , influenza a(h n ) pdm -related pneumonia and other complications were associated with increased morbidity and mortality. the purpose of this article is to summarize the experience of the spanish network for the research in infectious diseases (reipi) with regard to influenza a(h n )pdm -related pneumonia and other complications. we also performed a literature review regarding complications associated with influenza a(h n )pdm . the most frequent serious complications of influenza are pulmonary, and fall into four categories: primary influenza pneumonia, secondary bacterial pneumonia, pneumonia due to unusual pathogens or in immunocompromised hosts, and exacerbations of chronic pulmonary diseases. interestingly, in experimentally infected animals, the level of pulmonary replication of the influenza a(h n )pdm virus was higher than that of seasonal influenza viruses. the frequency of complications in the reipi cohort of hospitalized patients with influenza a(h n )pdm virus infection is detailed in table . in the reipi cohort, patients (median age years) required hospitalization. chest radiography was obtained on . a total of patients ( . %) had pneumonia, of whom underwent one or more bacterial microbiologic studies. pneumonia was primary viral in of these patients and concomitant/secondary bacterial in . similarly, in a study performed in united states, of hospitalized patients on whom chest radiographs were performed, ( %) had pneumonia (bacterial infections were reported in patients with pneumonia). in other studies, the reported frequency of pneumonia in hospitalized patients ranged between % and %. [ ] [ ] [ ] pneumonia was associated with high morbidity, as assessed by the length of hospital stay and the rates of intensive care unit (icu) admission and in-hospital complications, including mortality. , pathological studies on autopsy samples from patients with fatal influenza a(h n )pdm virus infection revealed that the virus targeted the lower respiratory tract, resulting in diffuse alveolar damage (edema, hyaline membranes, inflammation, and fibrosis), as manifested clinically by severe acute respiratory distress syndrome (ards) with refractory hypoxemia. however, a significant proportion of influenza a(h n )pdm case-patients in that report also showed viral localization along with inflammation or other histopathological changes in trachea, bronchi, or bronchioles. these pathological data have been found in other studies. the first conclusive evidence that the influenza virus could cause pneumonia came during the to pandemic. pathologic findings in pure influenza pneumonia include necrotizing bronchitis, hyaline membranes, intra-alveolar hemorrhage and edema, and interstitial inflammation. in the reipi cohort of hospitalized patients with primary viral pneumonia, ( . %) were below the age of and ( . %) were males. nearly % of patients had underlying medical comorbidities, mainly chronic pulmonary disease ( . %), immunosuppression ( . %), diabetes mellitus ( . %) and chronic cardiac disease ( . %). obesity (bmi > ) was documented in . % and pregnancy in seven women. the most frequent clinical features reported were fever, cough, arthromyalgia and dyspnea. pleuritic chest pain was present in % of patients and gastrointestinal symptoms in %. findings on physical examination included diffuse rales and wheezing. radiographs revealed multilobar infiltrates in . %. forty-one ( . %) required icu admission and in-hospital mortality was . %. it is significant that most patients requiring icu admission during the pandemic had respiratory failure due mainly to primary influenza pneumonia. [ ] [ ] [ ] in a spanish study of patients requiring icu admission, more than half ( . %) of subjects with primary viral pneumonia were male and the mean age was years. mechanical ventilation was used in . % of the patients, . % with invasive modes and . % with noninvasive. obesity was the most frequent comorbidity ( . %), followed by chronic obstructive pulmonary disease (copd) ( . %), diabetes ( %) and asthma ( . %). overall mortality was . %. it has long been recognized that influenza infection is closely associated with an increased incidence of bacterial pneumonia. in previous pandemics, secondary bacterial pneumonia was considered when a typical viral influenza infection was followed by near resolution, subsequently complicated to days later by a recurrence of fever, dyspnea, productive cough, and pulmonary consolidation. in contrast, concomitant bacterial pneumonia was considered when a bacterium was isolated during the first days of influenza virus infection onset. , this classification had important implications for the etiologic agents identified in these patients. during pandemic (h n ) , bacterial pneumonia was infrequent in mexico and california. , however, in studies of autopsy specimens, shieh et al reported bacterial co-infection in of patients with fatal influenza a(h n )pdm . other studies found the frequency of bacterial pneumonia in patients requiring icu admission to range between . % and . %. , in the reipi cohort, the prevalence of concomitant/secondary bacterial pneumonia was . %. streptococcus pneumoniae was the most frequent causative pathogen of bacterial coinfection in this cohort and in other studies. , several reports identified methicillin-resistant staphylococcus aureus as the etiologic agent for secondary/concomitant bacterial pneumonia during the pandemic. other pathogens isolated were haemophilus influenzae, streptococcus spp., legionella pneumophila, pseudomonas aeruginosa, acinetobacter baumannii, and aspergillus sp. studies have reported an association between bacterial coinfection and disease severity. , one study found that % of patients with influenza a(h n )pdm virus infection and invasive group a streptococcus died, compared with an overall mortality rate of - % for hospitalized influenza a(h n )pdm patients in other studies. investigators have sought to determine the clinical features and factors associated with concomitant/secondary bacterial pneumonia. compared with patients with primary viral pneumonia, patients with bacterial pneumonia in the reipi cohort were more likely to have chronic liver disease, purulent sputum, tachycardia, pleural effusion, leukocytosis, and c-reactive protein (crp) levels above mg/l at hospital admission. conversely, interstitial bilateral infiltrates in chest x-rays were more frequent in patients with primary viral pneumonia ( table ). moreover, dhanoa et al. reported that age > years, presence of comorbidity, liver impairment, development of complications, supplemental oxygen requirement, leukocytosis and neutrophilia were clinical factors associated with bacterial co-infection. interestingly, studies have found that procalcitonin and crp both alone and in combination can detect pneumonia of mixed bacterial infection in this context. , furthermore, patients with co-infection at icu admission were older and presented a higher apache (acute physiology and chronic health evaluation) ii score and sofa (sequential organ failure assessment) score compared with patients with primary viral pneumonia. bacterial pneumonia presents distinctive radiographic features because it is often associated with pleural effusion, lymphadenopathy and lobar consolidations. conversely, the characteristic imaging findings in primary viral pneumonia are ground-glass opacities with areas of consolidation. , infectious agents are recognized as a major pathogenic factor in exacerbations of chronic pulmonary diseases. the relevance of viral infections has been studied in exacerbations of copd and asthma. patients were stratified into the following risk groups according to the curb- score: low risk (≤ points, groups and ) and high risk (≥ points, groups and ). rhinovirus, coronavirus, respiratory syncytial virus, and influenza are the main viral pathogens that cause exacerbations. , , chronic pulmonary diseases, mainly copd and asthma, are frequent comorbidities reported in hospitalized patients with influenza a(h n )pdm virus infection. , , information about clinical features and prognosis from these groups of patients during pandemic is scarce; most of the information available comes from hospitalized asthmatic children. in the reipi cohort, ( . %) patients had copd and ( . %) had asthma. pneumonia was documented in copd patients. of the copd patients without pneumonia, ( . %) had exacerbation of pulmonary disease (evidence of wheezing at hospital admission). among patients with copd exacerbation, five required icu admission (three needed mechanical ventilation); there were no deaths. bacterial co-infection was documented in only one copd patient. moreover, pneumonia was documented in asthma patients (chest x-rays were performed in asthma patients). of the asthma patients without pneumonia, ( . %) had exacerbations of pulmonary disease. among patients with asthma exacerbation, seven required icu admission (two needed mechanical ventilation) and none died. bacterial co-infection was not documented in these patients. characteristics of icu patients and clinical outcomes of the reipi cohort were similar to those described elsewhere. [ ] [ ] [ ] although our mortality rate was lower than that reported in the earliest studies of hospitalized patients, it was similar to that of other studies. , severe disease occurred in patients ( . %), of whom required icu admission and died. among the patients requiring icu admission, had pneumonia, underwent mechanical ventilation, and developed ards. fifty-two ( . %) of the icu patients had chronic comorbid conditions, mainly chronic pulmonary disease ( patients), chronic heart disease ( ), diabetes mellitus ( ) and immunosuppression ( ) . only of pregnant women required icu admission. in-hospital mortality was . % ( of patients). the median time from hospital admission to death was nine days (range - ). among the patients who died, nine were under years of age, eight were women, had comorbid conditions, two had morbid obesity, had multilobar pneumonia, and five had bacterial coinfection. causes of death were respiratory failure/acute respiratory distress syndrome ( out of patients), shock/multiorgan failure ( patients), decompensated comorbid conditions ( ) and nosocomial infection ( ) . in the reipi cohort, independent factors associated with severe disease were younger age, chronic comorbid conditions, morbid obesity and bacterial co-infection. conversely, early oseltamivir therapy was a protective factor. in another study, investigators identified all patients with confirmed influenza a(h n )pdm virus infection who were admitted to australian or new zealand icus during winter . interestingly, the number of icu admissions due to influenza a(h n )pdm was times higher than that due to viral pneumonitis in previous years. infants and younger adults were found to be at particular risk of icu admission. pregnant women, obesity, and indigenous australian and new zealand populations also appeared to have an increased risk. in-hospital mortality exceeded %. furthermore, in icu patients in canada, influenza a(h n )pdm affected primarily young, female, and aboriginal patients without major comorbidities; -day mortality was . %. chronic lung disease, obesity, hypertension, and diabetes were the most common comorbidities. critical illness occurred rapidly after hospital admission and was associated with severe oxygenation failure, a need for prolonged mechanical ventilation, and the frequent use of rescue therapies such as extracorporeal membrane oxygenation. factors associated with icu admission or mortality during pandemic (h n ) are detailed in table . it is important to note that we documented that influenza a(h n ) pdm was not associated with poorer outcomes in hospitalized pregnant women compared with non-pregnant women of reproductive age in a context of early diagnosis and antiviral therapy. similarly, in the reipi cohort, well controlled on haart hiv patients had a similar clinical outcomes and prognosis to that of non-hiv patients. interestingly, cap-specific scores demonstrated moderate usefulness for predicting icu admission and/or mortality in hospitalized patients with influenza a(h n )pdm complicated by pneumonia in the reipi cohort and other studies. , consistent with these data, severity assessment tools (general severity of illness and cap-specific scores) undervalued prognosis and should not be used as instruments to guide decisions on patients requiring icu admission. a limitation of these scores is that age is the variable with the most weight, and most patients affected by pneumonia during pandemic were younger adults. in addition, other risk factors for severe influenza a(h n )pdm such as obesity were not included in these scores. in addition to respiratory complications of viral influenza, several other complications due to direct and indirect effects on other body systems have been reported to be associated with influenza a(h n ) pdm virus infection. influenza virus frequently exacerbates underlying heart problems and has been associated with triggering myocardial infarction. in the reipi cohort, patients had concurrent acute cardiac events during hospitalization (nine had acute heart failure, five had arrhythmias and one had acute coronary syndrome). among these patients, seven were over years old, ten had comorbid conditions (mainly chronic heart disease and copd) and five were current smokers. regarding outcomes, two had pneumonia, ten required icu admission, and one died. interestingly, other studies documented myocarditis, pericarditis, electrocardiographic abnormalities and left ventricular systolic dysfunction concurrent with influenza a(h n ) pdm virus infection. [ ] [ ] [ ] it is well known that influenza has neurological manifestations and complications. neurological complications of influenza include encephalopathy, encephalomyelitis, transverse myelitis, aseptic meningitis, focal neurological disorders, and guillain-barre syndrome. most cases occur in children. in a recent study on hospitalized pediatric patients with influenza a(h n )pdm infection, the most common manifestation was seizure with underlying neurological disease followed by encephalopathy with or without neuroimaging changes. in another study, the primary influenza-associated neurologic complications were encephalopathy/ encephalitis, seizures, meningitis, and guillain-barre syndrome. in table factors associated with intensive care unit admission or mortality in patients with influenza a(h n )pdm virus infection the reipi cohort of adult patients, two developed neurological complications: one had meningoencephalitis and the other acute visual disturbances related to oseltamivir treatment. nosocomial infections were reported in patients in the reipi cohort, mainly catheter-associated bacteremia and nosocomial pneumonia. in this regard, influenza viruses have been reported to cause immune defects. in addition, our data and those of other studies suggest that patients with influenza infection receiving corticosteroids present higher rates of nosocomial infections and sepsis. other complications reported during influenza were myositis and rhabdomyolysis, reye's syndrome, and preterm delivery. psychiatric complications after influenza infection are considered controversial. acute kidney failure was also reported, with some patients requiring renal replacement therapy. risk factors for acute kidney injury included age, obesity, chronic kidney disease, and elevated creatine kinase. complications of influenza a(h n )pdm virus were frequent and involved numerous organ systems. the main complications were pneumonia, icu admission (ards, septic shock, mechanical ventilation), exacerbations of chronic pulmonary diseases, nosocomial infections, and acute cardiac events. most hospitalized patients with pneumonia had primary viral pneumonia; mortality, though low, occurred mainly in patients with this complication. younger age, comorbidities, morbid obesity and bacterial co-infection were risk factors for severe disease. influenza a(h n )pdm related complications were associated with increased morbidity and mortality. this study was supported by the ministerio de ciencia e innovación, instituto de salud carlos iii, (ministry of science and innovation, carlos iii health institute), programa de investigación sobre gripe a/h n (influenza a/h n research program) (grant: gr / ), and co-financed by european regional development fund "a way to achieve europe", spanish network for the research in infectious diseases (reipi rd / ). dr. viasus is the recipient of a research grant from the institut d´investigació biomèdica de bellvitge (biomedical research institute of bellvitge, idibell). iner working group on influenza. pneumonia and respiratory failure from swine-origin influenza a (h n ) in mexico surveillance group for new influenza a(h n ) virus investigation and control in spain. new influenza a(h n ) virus infections in spain changes in epidemiology, clinical features and severity of influenza a (h n ) pneumonia in the first post-pandemic influenza season influenza surveillance during the post-pandemic influenza / season in greece clinical aspects of pandemic influenza a (h n ) virus infection complications of viral influenza in vitro and in vivo characterization of new swine-origin h n influenza viruses novel influenza a(h n ) study group of the spanish network for research in infectious diseases (reipi). pneumonia complicating pandemic (h n ) : risk factors, clinical features, and outcomes finelli l;for the pandemic influenza a (h n ) virus hospitalizations investigation team. influenza-associated pneumonia among hospitalized patients with pandemic influenza a (h n ) virus-united states surveillance of the first confirmed hospitalised cases of pandemic h n influenza in ireland pandemic influenza a (h n ) virus hospitalizations investigation team. hospitalized patients with h n influenza in the united states california pandemic (h n ) working group. factors associated with death or hospitalization due to pandemic influenza a(h n ) infection in california pandemic influenza a (h n ): pathology and pathogenesis of fatal cases in the united states lung histopathological findings in fatal pandemic influenza a (h n ) critical care services and. h n influenza in australia and new zealand canadian critical care trials group h n collaborative. critically ill patients with influenza a(h n ) infection in canada h n semicyuc working group. intensive care adult patients with severe respiratory failure caused by influenza a (h n )v in spain corticosteroid therapy in patients with primary viral pneumonia due to pandemic (h n ) influenza pneumococcal pneumonia and influenza: a deadly combination studies on influenza in the pandemic of - . ii. pulmonary complications of influenza pneumonia complicating asian influenza infection and death from influenza a h n virus in mexico: a retrospective analysis pandemic influenza a in argentina: a study of patients on mechanical ventilation streptococcus pneumoniae coinfection is correlated with the severity of h n pandemic influenza community-acquired pneumonia due to pandemic a(h n ) influenzavirus and methicillin resistant staphylococcus aureus co-infection invasive aspergillosis complicating pandemic influenza a (h n ) infection in severely immunocompromised patients invasive group a streptococcal infection concurrent with h n influenza epidemiology and clinical characteristics of hospitalized patients with pandemic influenza a (h n ) infections: the effects of bacterial coinfection significance of high levels of procalcitonin in patients with influenza a (h n ) pneumonia role of procalcitonin and c-reactive protein in differentiation of mixed bacterial infection from h n viral pneumonia h n semicyuc working group. community-acquired respiratory coinfection in critically ill patients with pandemic influenza a(h n ) virus pulmonary imaging of pandemic influenza h n infection: relationship between clinical presentation and disease burden on chest radiography and ct during the "herald wave" of the pandemic bacterial pneumonia relatively rare with fatal swine influenza (h n ) pneumonia: if chest films have no focal segmental/lobar infiltrates, antibiotic therapy is unnecessary a -year prospective study of the infectious etiology in patients hospitalized with acute exacerbations of copd respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation: a case-control study children with asthma hospitalized with seasonal or pandemic influenza clinical findings and demographic factors associated with intensive care unit admission in utah due to novel influenza a (h n ) infection hospitalizations for pandemic (h n ) among maori and pacific islanders surveillance of the first confirmed hospitalised cases of pandemic h n influenza in ireland factors associated with severe disease in hospitalized adults with pandemic (h n ) in spain prognosis of a(h n ) influenza in hospitalized pregnant women in a context of early diagnosis and antiviral therapy clinical presentation and prognosis of the h n influenza a infection in hiv- -infected patients: a spanish multicenter study early use of glucocorticoids was a risk factor for critical disease and death from ph n infection risk factors for severe outcomes following influenza a (h n ) infection: a global pooled analysis risk factors for hospitalization and severe outcomes of pandemic h n influenza in quebec timing of oseltamivir administration and outcomes in hospitalized adults with pandemic influenza a(h n ) virus infection the role of pneumonia scores in the emergency room in patients infected by h n infection severity assessment tools in icu patients with influenza a (h n ) pneumonia influenza as a trigger for acute myocardial infarction or death from cardiovascular disease: a systematic review acute myocarditis mimicking acute myocardial infarction associated with pandemic (h n ) influenza a virus cardiac manifestations in patients with pandemic (h n ) virus infection needing intensive care electrocardiographic abnormalities in patients with novel h n influenza virus infection pediatric neurological complications of pandemic influenza a (h n ) a population-based study of neurologic manifestations of severe influenza a(h n )pdm in california influenza virus infection induces functional alterations in peripheral blood lymphocytes effect of immunomodulatory therapies in patients with pandemic influenza a (h n ) complicated by pneumonia current concepts in sars treatment influenza a infection and acute kidney injury: incidence, risk factors, and complications all authors declare that they have no conflicts of interest in this article. key: cord- -umv q d authors: stachowska, ewa; folwarski, marcin; jamioł-milc, dominika; maciejewska, dominika; skonieczna-Żydecka, karolina title: nutritional support in coronavirus disease date: - - journal: medicina (kaunas) doi: . /medicina sha: doc_id: cord_uid: umv q d the epidemic that broke out in chinese wuhan at the beginning of presented how important the rapid diagnosis of malnutrition (elevating during intensive care unit stay) and the immediate implementation of caloric and protein-balanced nutrition care are. according to specialists from the chinese medical association for parenteral and enteral nutrition (cspen), these activities are crucial for both the therapy success and reduction of mortality rates. the chinese have published their recommendations including principles for the diagnosis of nutritional status along with the optimal method for nutrition supply including guidelines when to introduce education approach, oral nutritional supplement, tube feeding, and parenteral nutrition. they also calculated energy demand and gave their opinion on proper monitoring and supplementation of immuno-nutrients, fluids and macronutrients intake. the present review summarizes chinese observations and compares these with the latest european society for clinical nutrition and metabolism guidelines. nutritional approach should be an inseparable element of therapy in patients with covid- . coronavirus (cov) infections have been a major public health concern for almost two decades. the very first corona-viral epidemic outbreak took place in in china and was linked to severe acute respiratory syndrome-the entity that gave the name for this viral agent, sars-coronavirus (sars cov). a second coronavirus outbreak with similar symptoms spread throughout middle east in . consequently the virus name was mers-cov. during these two epidemics, as many as , cases were confirmed with the mortality rate of about % [ ] . on february , the world health organization (who) announced the epidemic outbreak of the novel coronavirus family members, sars cov- . a month later, the status was pandemic. the virus was reported to be very contagious and has spread globally in a short period of time, as the infections seem to have originated in china, in december [ ] . as for the end of march , who reported about , confirmed cases of infection and , deaths in almost countries around the world [ ] . the clinical features of sars-cov- infection, namely a coronavirus disease (covid- ) , range from asymptomatic to severe conditions including respiratory and multiorgan failure. major symptoms are fever, dry cough, fatigue, myalgia, and dyspnea. headache, hemoptysis and diarrhea occur less commonly [ ] [ ] [ ] [ ] . medical protocol consists mainly of symptomatic treatment and the prevention of secondary infection [ ] . effective antiviral treatment for sars-cov- has not been identified yet. the antiviral drugs, including ganciclovir, oseltamivir, ritonavir, ribavirin, and lopinavir have been used to prevent the likelihood of respiratory complications in several studies, but the efficacy awaits to be verified within coming months [ ] . the data on nutritional support in covid- patients is still elusive. this refers to the nutritional status of the patients, including as well mild to severe cases, and most importantly the malnutrition that enhances the probability of poor outcome [ , ] . this work summarizes what has already been done in the field and drawn some general recommendations for the dietary management in coronaviruses treatment. viral etiology of community-acquired pneumonia (cap) may by underdiagnosed. as it was shown, about % of cases are due to influenza virus infection, whilst the lowest proportion might be caused by rhinovirus, coronavirus and respiratory syncytial virus. the odds of death during a hospital stay were shown to be significantly higher in case of both bacterial and viral infections [ ] . consequently, due to lack of specific covid- data, the recommendations in our review are based on viral and bacterial pneumonia studies, as well as recommendations made for critically ill patients. literature review was conducted by all authors. studies published until / / were included. search words were: ("coronavirus" or "severe acute respiratory syndrome coronavirus " or "severe acute respiratory syndrome coronavirus " or "sars cov " or"sars-cov- " or "covid- " or "severe acute respiratory syndrome coronavirus ") and ("nutrition" or "diet" or "home nutrition" or "enteral nutrition" or "energy expenditure" or "parenteral nutrition" or "probiotics" or"pneumoniae" or "sepsis" or "intensive care" or "critical illness" or "nutrition" or "diet" or "home nutrition" or "enteral nutrition" or "energy expenditure" or "parenteral nutrition"). the articles included were, however, not selected on a systematic basis, thus the evidence reviewed might not be exhaustive. summarized data were analyzed together with existing recommendations for nutritional interventions published by espen and aspen and reviewed in perspective of covid- pandemic. data concerning patients with cap show that % of persons admitted to hospitals are malnourished and their nutritional status may serve as both short and long-term prognostic factord of mortality especially among the elderly [ ] . to add, low albumin level was associated with higher -day and . -year mortality rates [ ] . age and preexisting comorbidities like cardiovascular disease, diabetes, chronic respiratory disease, hypertension, and cancer were found to be linked to higher case-fatality rate in covid- pneumonia [ , ] . moreover, the clinical status of patients with mild symptoms at the time of diagnosis may deteriorate during the observation time. consequently, we advise nutritional screening including mild cases of covid- infections. medical staff should monitor effective oral nutrition and are encouraged to prescribe oral nutritional supplements (ons) for patients who are not able to cover the energy and protein requirements with fortified meals. elderly patients should be repeatedly screened and advised to fill in a dietary recall diaries. this should also apply for nursing and long term facilities, as significant prevalence of malnutrition in home-care services have been described [ ] . moreover, screening for dysphagia in prehospital setting and after hospital admission is advised. oropharyngeal dysphagia in patients with pneumonia has been correlated with higher mortality and worse long-term outcome [ ] . easy and validated questionnaires could be useful for swallowing disorders screening. for instance, "eat- " survey, which does not require direct contact with a patient and can be done using telemedical devices [ ] (figure ). patients receiving home parenteral nutrition (hpn) and home enteral nutrition (hen) are at risk of the severe course of the covid- infection, predominantly due to coexisting diseases. to our knowledge, there are no publications concerning modification of nutritional treatment in hpn or hen during the covid- pandemic. however, sanitary and epidemiological issues during a pandemic should be addressed at the same time as nutrition-related procedures. home care units should limit personal visits and contacts with patients to life-threatening circumstances. patients should be under continuous monitoring using telemedical solutions. hospital treatment should be considered if any signs of infection are noted. family and care holders are to follow strict epidemiological guidelines, which is a potential source of infection for the patients. no clinical trials showed the benefits of probiotic usage in covid- infection. however, several studies underlined a possible relation between lung microbiome and pulmonary diseases. the hypothesis of the gut-lung axis refers to a link between diet and bacterial metabolites like short chain fatty acids (scfa) and lung microecological niche [ ] . experimental studies in animals have demonstrated the protective role of trans nasal administration of lactobacillus species against patients receiving home parenteral nutrition (hpn) and home enteral nutrition (hen) are at risk of the severe course of the covid- infection, predominantly due to coexisting diseases. to our knowledge, there are no publications concerning modification of nutritional treatment in hpn or hen during the covid- pandemic. however, sanitary and epidemiological issues during a pandemic should be addressed at the same time as nutrition-related procedures. home care units should limit personal visits and contacts with patients to life-threatening circumstances. patients should be under continuous monitoring using telemedical solutions. hospital treatment should be considered if any signs of infection are noted. family and care holders are to follow strict epidemiological guidelines, which is a potential source of infection for the patients. no clinical trials showed the benefits of probiotic usage in covid- infection. however, several studies underlined a possible relation between lung microbiome and pulmonary diseases. the hypothesis of the gut-lung axis refers to a link between diet and bacterial metabolites like short chain fatty acids (scfa) and lung microecological niche [ ] . experimental studies in animals have demonstrated the protective role of trans nasal administration of lactobacillus species against influenza infection [ ] [ ] [ ] . there are no precise guidelines for microbial agents to use in the critically ill, however, a number of studies have shown potential benefits of such administration in the intensive care unit (icu) setting [ , ] . covid- patients on antibiotic therapy with gastrointestinal symptoms may be the target group for probiotic supportive therapy. above-mentioned data, however, provide insufficient data to recommend probiotic use in covid- infection. experimental studies are to show future directions for human trials. nutritional treatment for critically ill patients diagnosed with covid- (especially in case of respiratory and multiorgan failure) [ ] is a key element of comprehensive treatment aimed to reduce the mortality. the observations made by chinese nutritionists might help to improve the efficacy of nutrition-based approaches in covid- patients [ ] . the development of malnutrition among critically ill covid- patients is caused by imbalances in energy intake and expenditure secondary to: ( ) increased energy consumption due to fever, mechanical ventilation, exacerbated activity of breathing muscles, and hyper catabolism. ( ) insufficient intake of nutrients due to decline in appetite, dyspnea, mechanical ventilation, and disturbance of consciousness. in case of direct attack of coronavirus on the gastrointestinal tract, nausea, diarrhea, or vomiting caused either by enteral nutrition intolerance or antiviral drug treatment might occur [ ] . ( ) metabolic disorders involving (a) impaired glucose metabolism (increased blood sugar and insulin resistance, reduced glucose oxidation, increased glycolysis and gluconeogenesis); (b) impaired protein metabolism (increased protein breakdown, and enhanced synthesis of acute phase proteins, decreased muscle protein synthesis and negative nitrogen balance in the body); (c) increased fat mobilization and decomposition. for critically ill patients, dynamic nutritional risk screening is recommended. the assessment and the setting of nutritional support objectives should be conducted during admission to the icu and during the implementation of enteral nutrition, during the first - h [ ] . a meta-analysis conducted in icu patients demonstrated that early enteral nutrition within h of icu admission reduced mortality compared with delayed enteral intake (odds ratio, . ; % ci, . - . , p = . ) [ ] . the evaluation of malnutrition should be repeated regularly and frequently due to the dynamics of the disease and increased risk of dysphagia in the elderly after pneumonia, and after prolonged respiratory therapy (post-extubation dysphagia) [ ] [ ] [ ] . nutrition risk screening form (nrs ) [ ] is a recommended tool. a modified nutric score is recommended for screening [ ] whenever history of body weight and dietary habits in critically ill patients are available [ ] . the basic recommendations following these surveys are as follows: nrs: score ≥ points, nutritional risk intervention is needed; score ≥ high nutritional risks, intervention as early as possible. nutric: ≥ points (not considering il- ), suggesting that patients have higher nutritional risk and need nutritional support as early as possible. it is of high importance to remember that the nutritional status of critically ill patients may change rapidly, thus, this strategy should be ongoing. it is recommended to screen patients with low nutritional risk again after days [ , ] . the ideal method for measuring the actual energy consumption in human body is an indirect calorimetry (ic). however, reduced medical staff and high patient/nurse ratio in covid- pandemic conditions limit the usage of ic. therefore, in practice, the calculation the resting energy expenditure (ree) can be applied: where the v co value should be measure by the ventilator. whenever it is impossible to measure v co directly, energy requirement needs should be estimated according to body weight: ideal body mass should be calculated with brock formula [ ] , but only for persons between cm and cm tall. otherwise, the hamwi formula is more sufficient [ ] . brock formula: in patients in whom, due to fever/discomfort, reduced calorie intake was demonstrated, it is recommended to reach the target energy supply as soon as possible. typically, in critically ill patients, - kcal/kg/d is advised. according to european society for clinical nutrition and metabolism (espen) guidelines and chinese professionals, the initiation of nutritional support should be as soon as possible: h/ h after hospital admission starting with low dose energy for the first days [ ] . chinese doctors recommended the intake of - kcal/kg/day in the first few days [ ] . hypocaloric nutrition not exceeding % of estimated needs is advised, and - % after days. nutritional treatment might be implemented on the principles of five-step regimen for malnutrition [ ] , as demonstrated in table . all-in-one preparation is recommended. contraindications for en include: uncontrolled shock, uncontrolled hypoxemia and acidosis, upper gastrointestinal bleeding, intestinal ischemia, intestinal obstruction, abdominal compartment syndrome, and high-output fistula without distal feeding pathways. observational studies have shown that increasing the protein content in the diet of patients in critical condition can reduce their mortality, but it is still difficult to determine what is the optimal demand of a patient for protein [ ] . for this reason, it is necessary to carefully observe side effects, evaluate the effects of treatment, and dynamically adjust the treatment plan toward covid- clinical course. protein supply should be about . - . g/(kg/day). when the protein supply does not cover the demand, a standard protein preparation is recommended [ ] . to reduce oxidative stress and the incidence of acute respiratory distress syndrome (ards) and sepsis, a mixture of fish fats-docosahexaenoic acid (dha) + eicosapentaenoic acid (epa) might be used. for enteral feeding, mg of epa + dha might be added daily for parenteral feeding from . to . g/(kg/d) [ ] . fluid therapy: it has been highlighted that most patients admitted to the ward are dehydrated due to high fever and loss of appetite at the beginning of the disease [ ] . gastric access is recommended by espen [ ] as the standard approach for en (table ) . patients with high risk of aspiration require post-pyloric feeding. american society for parenteral and enteral nutrition (aspen) criteria for increased risk for aspiration are: inability to protect the airway, mechanical ventilation, age > years, reduced level of consciousness, poor oral care, inadequate nurse: patient ratio, supine positioning, neurologic deficits, gastroesophageal reflux, transport out of the icu, and use of bolus intermittent en. most of those characteristics are typical for covid- patients with severe disease course [ ] . non-endoscopic methods of naso-jejunal or naso-duodenal tube placement are to be considered due to increased risk of covid- transmission. table . nutrition therapy of critical ill patients, espen recommendations [ ] . patients staying in the icu, mainly for more than h (considered at risk for malnutrition); careful and progressive re-introduction of nutrition; severely malnourished and starved patients are at risk of refeeding syndrome; en should be ceased in patients with uncontrolled shock, uncontrolled hypoxemia and acidosis, uncontrolled upper gi bleeding, gastric aspirate > ml/ h, bowel ischemia, bowel obstruction, abdominal compartment syndrome, and high-output fistula without distal feeding access ) ; key points should be aimed for: ( ) oral nutrition as early as possible while considering the risks of complications (e.g., aspiration); ( ) early en at a low rate and progressive increase within h if oral nutrition is not possible while considering the risk of complications; this progressive increase should be ruled by local protocols; ( ) determination of the optimal starting point and dose of (supplemental) pn based on the risk of complications from oral or en, state of acute illness and presence of previous under/malnutrition; ) anamnesis, report of unintentional weight loss or decrease in physical performance before icu admission; physical examination; general assessment of body composition (if possible) to detect the loss of lean body mass and sarcopenia; assessment of muscle mass and strength (if possible); considering the abovementioned parameters (the critically ill patient is compared to a geriatric patient); main tools: grading of malnutrition according to the espen glim recommendations (see table to avoid overfeeding, early full en shall not be used but shall be prescribed within to days; in the early phase of critical illness the provision of excessive amounts of nutrients by any route should be avoided; energy supply should be restricted for h and then progressively increased; measurements of electrolytes (potassium, magnesium, phosphate) during initiation of feeding is necessary to detect development of refeeding syndrome; refeeding hypophosphatemia is a warning signal (< . mmol/l or a drop of > . mmol/l); electrolytes monitoring two to three times a day and supplemented if needed; table . cont. oral diet preferred (patients who are able to eat) over en or pn; if the patient is able to cover % of his needs from day three to seven, without risks of vomiting or aspiration; en if oral intake is not possible; early en (within h) should be preferred over delaying en and early pn; enteral feeding should be delayed when grv is > ml/ h and application of prokinetics should be considered; pn should be implemented within to days if contraindications to oral and en exist; low-dose pn (if en is not feasible) should be implemented in patients with high nutrition risk (e.g., nrs ≥ ) or severely malnourished because of the risks of overfeeding and refeeding; gastric access-use as the standard approach to initiate en; postpyloric feeding-in patients with gastric feeding intolerance despite the use of prokinetic agents; postpyloric (mainly jejunal feeding) can be performed in patients at high risk for aspiration: inability to protect the airway, mechanical ventilation, age > years, reduced level of consciousness, poor oral care, inadequate nurse:patient ratio, supine positioning, neurologic deficits, gastroesophageal reflux, transport out of the icu, use of bolus intermittent en; the small bowel feeding is associated with a reduced risk of pneumonia compared to gastric feeding; continuous rather than bolus en is recommended; decreased risk of diarrhea comparing continuous versus bolus administration; erythromycin should be intravenously administered (usually at dosages of - mg three times a day) as a first line prokinetic therapy; recommended to patients with gastric feeding intolerance; should be used for - h or maximum days; if a large (> ml) grv still persists, the use of post-pyloric feeding should be considered over withholding en; metoclopramide can be used alternatively, or in combination with erythromycin; effectiveness of prokinetics is decreased after days and should be discontinued; several parameters must be considered in order to estimate caloric needs: the nutritional status prior to icu admission (body weight and its alterations); the number of days of hospitalization before icu admission and/or in the icu; the endogenous nutrient production and autophagy; the energy balance during icu stay; the time elapsed and energy balance during hospital stay; the occurrence of refeeding syndrome (or at least hypophosphatemia) at the time of feeding; indirect calorimetry (ic) is recommended in critically ill mechanically ventilated patients; if ic is not available use v o (oxygen consumption) from pulmonary arterial catheter or v co (carbon dioxide production) derived from the ventilator (ree = v co × . ); if ic and v o or v co measurements are not available, use of simple weight-based equations (such as - kcal/kg/day); isocaloric nutrition if indirect calorimetry is used; after the early phase of acute illness can be progressively implemented; ) after day , caloric delivery can be increased up to - % of measured ee; hypocaloric nutrition (not exceeding % of ee), if predictive equations are used to estimate the energy need, should be administered in the early phase of acute illness especially for the first week of icu stay; should be achieved progressively and not before the first h to avoid over-nutrition ) ; full targeted medical nutrition therapy is considered to achieve more than % of the resting energy expenditure (ree), but not more than % ) ; . g/kg protein equivalents per day (delivered progressively); . - . g protein/kg/day in older people who are malnourished or at risk of malnutrition table . cont. patients staying in the icu, mainly for more than h (considered at risk for malnutrition); should not exceed mg/kg/min; citrate (used in continuous veno-venous hemo-dia-filtration (cvvh)) increases carbohydrate load and should be included as a non-nutritional calorie intake; high-fat administration can lead to lipid overload and especially unsaturated fat to impaired lung function and immune suppression ) ; the best ratio of fat can be established by monitoring of triglycerides and liver function tests; propofol (lipid solution- . kcal/ml) is associated with calorie overload; additional enteral gln should not be administered (exception: burn and trauma patients); en enriched with omega- fa within nutritional doses can be used; high doses omega- enriched enteral formulas should not be given on a routine basis and by bolus administration; should be provided daily with pn; the repletion of micronutrients (i.e., trace elements and vitamins) in conditions of chronic and acute deficiency is recommended; as high dose monotherapy should not be implemented without proven deficiency; intense inflammation reduces the circulating levels (below reference ranges) of the antioxidant micronutrients (in particular copper, selenium, zinc, vitamins e and c); a high dose of vitamin d ( , iu) as a single dose within a week after admission can be supplemented if there are low plasma levels ( -hydroxy-vitamin d < . ng/ml, or nmol/l); in patients who do not tolerate full dose en during the first week in the icu, the safety and benefits of initiating pn should be weighed on a case-by-case basis ) ; pn should not be started until all strategies to maximize en tolerance have been attempted ) ; when the level of energy needs provided by en is below % days after icu admission, supplementary pn should be initiated to reach a maximum of % of the energy needs (measured by indirect calorimetry whenever possible) ) ; an iso-caloric high-protein diet is recommended; energy requirements are guided by indirect calorimetry (if not available use "adjusted body weight"*); protein requirements are guided by urinary nitrogen losses or lean body mass determination (if not available, . g of protein/kg "adjusted body weight"*/day); *"adjusted body weight" = (actual body weight-ideal body weight) × . + ideal body weight ideal body weight for obese patients = . × bmi + . × bmi × (height − . m) or use pragmatic approach: energy requirements = ÷ % × (actual body weight-ideal body weight) + ideal body weight early en, gastrointestinal tolerance and progressive increase in nutrition recommended similarly as in all other icu patients; may improve the beneficial effects of nutritional therapy; ) early en should be performed in patients: receiving ecmo (extracorporeal membrane oxygenation); with traumatic brain injury; with stroke (ischemic or hemorrhagic); with spinal cord injury; with severe acute pancreatitis; after gi surgery; after abdominal aortic surgery; with abdominal trauma when the continuity of the gi tract is confirmed/restored; receiving neuromuscular blocking agents; managed in prone position; with open abdomen; and regardless of the presence of bowel sounds unless bowel ischemia or obstruction is suspected in patients with diarrhea; ) in non-intubated patients not reaching the energy target with an oral diet, oral nutritional supplements should be considered first and then en; ) in non-intubated patients with dysphagia, texture-adapted food can be considered; if swallowing is proven unsafe, en should be administered; ) in non-intubated patients with dysphagia and a very high aspiration risk, postpyloric en or, if not possible, temporary pn during swallowing training with removed nasoenteral tube can be performed; blood glucose after icu admission or after nutrition therapy initiation and at least every h, for the first days in general; insulin: when glucose levels exceed mmol/l; insulin therapy initiation when blood glucose exceeds or mg/dl ( mmol/l); blood glucose should target a concentration of - ·mmol/l; electrolytes (potassium, magnesium, phosphate): at least once daily for the first week; refeeding hypophosphatemia: two to three times a day and supplemented if needed ) exact recommendations indicated in "espen guideline on clinical nutrition in the intensive care unit" ( ). vitamin d and zinc are nutrients that support optimal immune function [ ] . vitamin d receptors are present in many immune cells and modulate response to viral lung diseases reducing also the risk of respiratory infections [ ] . vitamin d deficiency is common in critically ill patients probably as a result of a reduction of vitamin d binding protein (vdbp), and this has been associated with the increased icu length of stay, mechanical ventilation and mortality [ ] [ ] [ ] . zinc is involved in the regulation of inflammatory responses through its influence on leukocytes and lymphocytes function, including their proliferation, differentiation and maturation and also has direct antiviral effect [ ] . although the data on direct antiviral effect of zinc on covid- are limited, it has a significant impact on number of viruses involved in respiratory system pathology i.e. altering their replication [ ] . the inflammatory process may influence intestinal mucosal integrity, causing malabsorption of essential nutrients and their blood concentration to decrease [ ] . many studies have indicated that zinc deficiency concerns - % of patients at the time of icu admission [ ] [ ] [ ] [ ] [ ] [ ] . consequently, we advise to estimate vitamin d and zink concentration in covid- patients within the icu and if necessary begin the supplementation. espen recommendations concerning vitamin d and micronutrients administration in critically ill patients are presented in table . covid- pandemic is a challenging health care problem. no specific antiviral interventions are effective to eliminate the covid- infection, therefore, the multidisciplinary supportive medical approach is required to improve the outcome. data concerning nutritional interventions for covid- patients are still needed, nevertheless, conclusions from studies in severe viral and bacterial pneumonia could be integrated. poor nutritional status is a prognostic factor for mortality in severe pneumonia and critical illness, especially for elderly patients. espen and aspen guidelines for nutritional support in critical illness are applicable for covid- patients requiring icu support. chinese experiences have shown that the medical approach is be adjusted for a low patient:medical staff ratio and war-like conditions in hospitals. patients with a mild course of the disease should also be in the target of nutritional support, especially in advanced age or polymorbidity. moreover, nutritional and dysphagia screening is advised for recovered individuals, and thus, long term outcomes of the infection have still not been analyzed. the authors declare no conflict of interest. evaluation and treatment coronavirus (covid- ) early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia|nejm preliminary estimation of the basic reproduction number of novel coronavirus ( -ncov) in china, from to : a data-driven analysis in the early phase of the outbreak characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study covid- ): what we know? characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention covid- pathophysiology: a review viral infection in community-acquired pneumonia: a systematic review and meta-analysis prognostic significance of malnutrition for long-term mortality in community-acquired pneumonia: a propensity score matched analysis risk factors for long-term mortality after hospitalization for community-acquired pneumonia: a -year prospective follow-up study nutritional status in older persons according to healthcare setting: a systematic review and meta-analysis of prevalence data using mna ® prevalence and prognostic implications of dysphagia in elderly patients with pneumonia validity and reliability of the eating assessment tool (eat- ) espen guideline on clinical nutrition in the intensive care unit the impact of lung microbiota dysbiosis on inflammation lactobacillus plantarum dk as a probiotic confers protection against influenza virus by modulating innate immunity intranasal administration of live lactobacillus species facilitates protection against influenza virus infection in mice probiotic and synbiotic therapy in critical illness: a systematic review and meta-analysis probiotic and synbiotic therapy in the critically ill: state of the art impact of early nutrition and feeding route on outcomes of mechanically ventilated patients with shock: a post hoc marginal structural model study expert recommendations on nutrition therapy for critically ill patients with new type of coronavirus pneumonia the keypoints in treatment of the critical coronavirus disease patient early enteral nutrition provided within hours of icu admission dysphagia in mechanically ventilated icu patients (dynamics) dysphagia in the intensive care unit: epidemiology, mechanisms, and clinical management clinical approaches to assess post-extubation dysphagia (ped) in the critically ill eurooops: an international, multicentre study to implement nutritional risk screening and evaluate clinical outcome guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient metabolic support of the obese intensive care unit patient: a current perspective determination of ideal body weight for drug dosage calculations predicted vs measured energy expenditure in critically ill, underweight patients analysis of estimation methods for resting metabolic rate in critically ill adults efficacy of hypocaloric parenteral nutrition for surgical patients: a systematic review and meta-analysis protein requirements in the critically ill: a randomized controlled trial using parenteral nutrition guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of critical care medicine (sccm) and american society for parenteral and enteral nutrition optimal nutritional status for a well-functioning immune system is an important factor to protect against viral infections vitamin d and critical illness outcomes high dose vitamin d administration in ventilated intensive care unit patients: a pilot double blind randomized controlled trial vitamin d supplementation in the critically ill: a systematic review and meta-analysis zinc and respiratory tract infections: perspectives for covid- (review) heavy metal in the intensive care unit serum concentrations of trace elements zinc, copper, selenium, and manganese in critically ill patients prognostic value of serum zinc levels in critically ill patients a comparison of zinc metabolism, inflammation, and disease severity in critically ill infected and noninfected adults early after intensive care unit admission assessment of plasma and red cell trace element concentrations, disease severity, and outcome in patients with critical illness serum zinc in critically ill adult patients with acute respiratory failure key: cord- -k wvvnmd authors: yifan, tang; ying, liu; chunhong, gao; jing, song; rong, wang; zhenyu, li; zejuan, gu; peihung, liao title: symptom cluster of icu nurses treating covid- pneumonia patients in wuhan, china date: - - journal: j pain symptom manage doi: . /j.jpainsymman. . . sha: doc_id: cord_uid: k wvvnmd abstract objective in treating highly infectious covid- pneumonia, icu nurses face a high risk of developing somatic symptom disorder (ssd). the present study aims to investigate the symptoms and causes of ssd of icu nurses treating covid- pneumonia. the research results are expected to provide evidence for the establishment of a better management strategy. methods this study enrolled a total of icu nurses who were selected by jiangsu province hospital to work in wuhan (the epicenter of the covid- epidemic in china) on rd february . a questionnaire “somatic symptom disorders for icu nurses in wuhan no. hospital” was designed based on the “international classification of functioning, disability and health” (icf). exploratory factor analysis was performed to cluster the symptoms, and logistic regression analysis to find the risk factors of the symptoms. results five major symptoms were chest-discomfort-and-palpitation ( . %), dyspnea ( . %), nausea ( . %), headache ( . %), and dizziness ( . %). in exploratory factor analysis, the symptoms were classified into three clusters: cluster a of breathing and sleep disturbances (dizziness, sleepiness, dyspnea); cluster b of gastrointestinal complaints and pain (nausea, headache), and cluster c of general symptoms (xerostomia, fatigue, chest-discomfort-and-palpitation). in cluster a, urine/feces splash, sex, and sputum splash were independent predictive factors. in cluster b, fall of protective glasses and urine/feces splash were independent predictive factors. in cluster c, urine/feces splash and urine/feces clearance were independent predictive factors. conclusion the icu nurses in wuhan showed varying and overlapping ssds. these ssds could be classified into three symptom clusters. based on the characteristics of their ssds, specific interventions could be implemented to safeguard the health of icu nurses. covid- pneumonia has been listed category b infectious disease and is being treated in a category similar to that of category a by the national health commission of china. a large proportion of covid- patients will progress to a critical condition which needs intensive care. however, given the challenges in treating this disease, icu nurses are highly prone to somatic symptom disorder (ssd) which is associated with the interaction of biology, cognition, emotion, behavior and environment . the icu nurses must manage a heavy workload requiring frequent invasive procedures and high attention levels. therefore, safeguarding the physical and psychological health of icu nurses can provide a major contribution to the success of epidemic control , . a symptom cluster is a stable group of two or more co-existing symptoms. the symptom clusters in one population may show overlaps and interactions, a phenomenon that should be resolved to improve the efficiency of managing the disorder , . currently, no study has investigated ssds in icu nurses fighting at the frontline against the covid- epidemic. previous studies have confirmed that an individual's response to ssd is dependent on physical, emotional and social factors the questionnaires were handed out through wechat, an online app. participants who met the study criteria logged onto a website (http://www.wjx.cn) to complete the survey. the other general data are shown in table . cluster was the total of each symptom score (table ) . were independent predictive factors of cluster b; and urine/feces splash and urine/feces clearance were independent predictive factors for cluster c (table ) . "public health emergency of international concern". the infection, with a route of reducing the stress on clinicians working in the icu clinical features of patients infected with novel coronavirus in wuhan the covid- epidemic symptom clusters : concept analysis and clinical implications for cancer nursing the effectiveness of non-pharmacological interventions in the management of symptom clusters in adult cancer patients:a systematic review protocol cognitive and affective factors predicting daily somatic complaints in college students world health organization. international classification of functioning, disability and health (icf) refinements of the icf linking rules to strengthen their potential for establishing comparability of health information a revised classification by the german society for social medicine and prevention (dgsmp) public responses to the novel coronavirus ( -ncov) in japan: mental health consequences and target populations effects of two -min naps on the subjective sleepiness, fatigue and heart rate variability of night shift nurses. ind health symptom clusters and quality of life in subjects wax rs, christian md. practical recommendations for critical care and anesthesiology teams caring for novel coronavirus qigong exercise for chronic fatigue syndrome physical activity and sleep in chronic fatigue syndrome and fibromyalgia syndrome: associations with symptom severity in the general population cohort lifelines randomized controlled trial of a brief cognitive-behavioral strategies intervention for the pain, fatigue, and sleep disturbance symptom cluster in advanced cancer clinical features of patients infected with novel coronavirus in wuhan a rapid advice guideline for the diagnosis and treatment of novel coronavirus ( -ncov) infected pneumonia (standard version) the digestive system is a potential route of -ncov infection: a bioinformatics analysis based on single-cell transcriptomes anxiety symptomatology, sex and chronotype: the mediational effect of diurnal sleepiness needle stick injuries and their related safety measures among nurses in a university hospital personal protective equipment in an influenza pandemic: a uk simulation exercise health surveillance for employees who work in "areas suspected of pollution" or confined key: cord- -ov gkgpc authors: bonizzoli, manuela; arvia, rosaria; di valvasone, simona; liotta, francesco; zakrzewska, krystyna; azzi, alberta; peris, adriano title: human herpesviruses respiratory infections in patients with acute respiratory distress (ards) date: - - journal: med microbiol immunol doi: . /s - - -z sha: doc_id: cord_uid: ov gkgpc acute respiratory distress syndrome (ards) is today a leading cause of hospitalization in intensive care unit (icu). ards and pneumonia are closely related to critically ill patients; however, the etiologic agent is not always identified. the presence of human herpes simplex virus , human cytomegalovirus and epstein–barr virus in respiratory samples of critically ill patients is increasingly reported even without canonical immunosuppression. the main aim of this study was to better understand the significance of herpesviruses finding in lower respiratory tract of ards patients hospitalized in icu. the presence of this group of herpesviruses, in addition to the research of influenza viruses and other common respiratory viruses, was investigated in respiratory samples from patients hospitalized in icu, without a known microbiological causative agent. moreover, the immunophenotype of each patient was analyzed. herpesviruses dna presence in the lower respiratory tract seemed not attributable to an impaired immunophenotype, whereas a significant correlation was observed between herpesviruses positivity and influenza virus infection. a higher icu mortality was significantly related to the presence of herpesvirus infection in the lower respiratory tract as well as to impaired immunophenotype, as patients with poor outcome showed severe lymphopenia, affecting in particular t (cd +) cells, since the first days of icu hospitalization. in conclusion, these results indicate that herpesviruses lower respiratory tract infection, which occurs more frequently following influenza virus infection, can be a negative prognostic marker. an independent risk factor for icu patients with ards is an impaired immunophenotype. human herpes simplex virus (hsv ), human cytomegalovirus (hcmv) and epstein-barr virus (ebv) are wellknown members of the herpesviridae family, which are highly prevalent and ubiquitous. primary infection takes place in the majority of cases early in the life and is followed by a lifelong latent infection, from which reactivation may occur with viral shedding at least in the saliva. the outcome of reactivation strongly depends from the host immunological status. in immunodepressed patients, all these three viruses may cause severe diseases, which may be different depending on the virus and on other factors, including host defences. mostly, hcmv and also hsv may cause severe respiratory diseases, whereas the role of ebv in pneumonia is debated [ ] . in addition to a direct involvement of these viruses in respiratory diseases, their detection has been associated with other clinical aspects, which may promote viral reactivation or which outcome may be influenced by viral reactivation. an increasing number of papers report the presence of hsv , hcmv and ebv in respiratory samples of critically ill patients even without canonical immunosuppression [ ] [ ] [ ] [ ] [ ] . in patients requiring mechanical ventilation, herpesviruses, mainly hsv and hcmv, may be frequently detected from either upper or lower respiratory tract abstract acute respiratory distress syndrome (ards) is today a leading cause of hospitalization in intensive care unit (icu). ards and pneumonia are closely related to critically ill patients; however, the etiologic agent is not always identified. the presence of human herpes simplex virus , human cytomegalovirus and epstein-barr virus in respiratory samples of critically ill patients is increasingly reported even without canonical immunosuppression. the main aim of this study was to better understand the significance of herpesviruses finding in lower respiratory tract of ards patients hospitalized in icu. the presence of this group of herpesviruses, in addition to the research of influenza viruses and other common respiratory viruses, was investigated in respiratory samples from patients hospitalized in icu, without a known microbiological causative agent. moreover, the immunophenotype of each patient was analyzed. herpesviruses dna presence in the lower respiratory tract seemed not attributable to an impaired immunophenotype, whereas a significant correlation was observed between herpesviruses positivity and influenza virus infection. a higher icu mortality was significantly related to the presence of herpesvirus infection in the lower respiratory tract as well as to impaired immunophenotype, as patients with poor outcome showed severe lymphopenia, affecting in particular t (cd +) cells, since the first days of icu hospitalization. in conclusion, these results indicate that herpesviruses lower respiratory tract infection, which occurs samples [ , ] . it has been suggested that the presence of hsv in the respiratory samples of icu patients correlates with the duration of tracheal intubation [ ] . the detection of hsv in the lower respiratory tract of icu patients is reported with a variable frequency, from to % depending on the population and the diagnostic method used [ , , ] . moreover, it is not always clear whether the demonstration of hsv dna in lower respiratory tract samples of non-immunocompromised ventilated patients is the consequence of a contamination from mouth or throat or is the result of local viral reactivation [ , , , ] . some studies showed that there was a significant association between an hsv viral load > . copies/ml of bal and admission to the icu (p < . ), mechanical ventilation (p < . ) and death (p < . ) [ , , ] . active hcmv infection, either restricted to the lower respiratory tract or involving both the lower respiratory airways and the systemic compartment, has been shown to occur frequently during critical illness in adult hcmv-seropositive patients [ ] , and has been associated with prolonged icu hospitalization, extended periods of mechanical ventilation, higher rates of nosocomial infection and overall mortality [ , [ ] [ ] [ ] [ ] . the role of ebv presence in respiratory tract of icu patients is not clear. high degree of variability concerning the prevalence of ebv in bal samples from patients admitted in icu is reported in the literature [ , [ ] [ ] [ ] [ ] . ards is today a leading cause of hospitalization in icu. ards and pneumonia are closely related to critically ill patients [ ] ; however, it is not always identified the etiologic agent. in most cases, bacterial infections are the main causative agent of pulmonary infections that evolve into framework of ards; more recently, viral infections, mainly related to influenza viruses, represent a new category of emerging cause of ards, and also viruses belonging to other families, in association or not to bacterial infections, may be involved. in still other cases, the causative agent remains unrecognized [ ] . furthermore, the critically ill patients develop a state of immunosuppression, which can promote the onset and exacerbation of viral infections [ ] . the aim of this study was to better understand the significance of herpesviruses finding in lower respiratory tract of patients hospitalized in icu and to assess the diagnostic and prognostic value of these findings. patients' characteristics, with attention to their immunological setting, were analyzed together with the virological data. institutional internal committee approval was waived for this study as it involved retrospective analysis of anonymous, routinely collected, group data. during the period september -may , patients with diagnosis of ards were admitted to icu (intensive care unit of emergency department-careggi teaching hospital, florence-italy), from different clinical setting. for out of these patients, the causative agent of ards was unknown. the following samples were collected for microbiological analysis: • throat swab (ts) and bronchoalveolar lavage (bal) sent to general laboratory for research of common germs; • ts and bal sent to virology laboratory for the detection of influenza virus and other respiratory viruses like adenovirus (adv), parainfluenza viruses - (piv - ), enterovirus/rhinovirus (ev/rhv), respiratory syncytial virus (rsv), human coronaviruses (hcov) group i and group ii, human metapneumovirus (hmpv) and herpetic viruses. for each patient, the following data were collected: • anamnestic data: age, sex, body mass index (bmi), charlson comorbidity index (cci) adjusted for age; • data and severity scores at icu admission: saps ii at admission, sofa at admission, gcs at admission, provenience, length of stay before icu admission; • data related to respiratory samples: sampling timing, positivity for influenza viruses rna as well as for other respiratory viruses genome sequences, hsv /hcmv/ ebv dna; hsv /hcmv/ebv viral load in bal; • immunophenotyping analysis at icu admission; • data related to icu stay: treatment with antiviral, steroid; need for extracorporeal membrane oxygenation (ecmo) support and duration of treatment with ecmo; • outcome data: saps ii at discharge, gcs at discharge, ventilation length of stay (los), icu los, icu mortality, post-icu los, post-icu mortality. in the study period, samples were analyzed with the aim to look for the presence of herpesviruses in patients. all clinical samples were collected using standard techniques [ ] . the throat swab was obtained with a nylon fiber tip (copan eswab™ system) inserted and rotated into the throat of patient. the bal samples were taken with sterile flexible bronchoscope through the oro-tracheal tube or the tracheal cannula; after the assessment of the tracheal-bronchial tree, ml of sterile saline solution was instilled and picked up in a specimen trap (covidien argyle™). the detection and typing of influenza viruses were achieved as already described, using primers and probe sequence as indicated by the us centers for disease control (cdc) [ ] . for the detection of other respiratory viruses, duplex real-time pcr, already described, was used [ ] . the detection of hsv dna, hcmv dna and ebv dna was performed by in-house assays. the in-house assays here described were already used in the laboratory of virology and had shown a performance comparable with commercial assays, at a lower cost. any way the results here reported were confirmed by comparison with commercial, validated assays (realtime q-pcr kit, elitech molecular diagnostics). extraction of viral dnas from clinical samples was carried out using a commercially available kit (hp pcr template preparation kit, roche diagnostics, milan, italy). to detect hcmv, hsv and ebv dna in ts and bal samples, three real-time pcrs were developed, using primers listed in table . the real-time pcrs were performed using x hrm pcr master mix (qiagen, valencia, ca, usa). the reaction volume for each amplification was μl ( . μl of master mix, . μl of each primer [ μm], μl of dna and h o to reach the final volume). after initial activation step, cycles of amplification [ °c for s, °c for s, °c for s (acquiring green)] were performed. for melting analysis, ramp from to °c was used, rising by . °c each step. the reaction was performed on rotor gene (qiagen, valencia, ca, usa). all herpesvirus-positive bal samples were quantified by quantitative real-time pcrs. to perform the calibration curves, serial dilutions of dna calibrator for each virus were used. these calibrators consisted of dna sequences obtained by the cloning the product of the pcr of viral dna of each virus in the pgem-t easy vector system (promega, madison, wisconsin, usa). the plasmid dna was purified by qiaprep spin miniprep kit (qiagen, valencia, ca, usa). the analytical sensitivity of all pcrs was determined using serial dilutions of cloned calibrators, quantified by nanodrop spectrophotometer (thermoscientific, wilmington, de, usa). the real-time pcr for ebv was able to detect copies number/ml. the sensitivity of real-time pcr for hcmv and hsv was copies number/ml. as the volumes and other characteristics of bal samples can vary, each bal sample was quantitatively analyzed also for the β-globin gene, as described below. then, the results obtained for each sample were normalized according to the ratio [sample target ct value × sample β-globin ct value/mean β-globin ct value] [ ] . the detection of β-globin gene was performed using the primers described in the literature [ ] . the sequence of primers was pf gh ′-caadttcatccacgttcacc- ′ and pr pc ′-gaagagccaaggacaggtac- ′. the real-time pcr was performed using x hrm pcr master mix (qiagen, valencia, ca, usa). the reaction volume was μl ( . μl of master mix, . μl of each primer [ μm], μl of dna and h o to reach the final volume). after initial activation step, cycles of amplification [ °c for s, °c for s, °c for s (acquiring green)] were performed. for melting analysis, ramp from to °c was used, rising by . °c each step. the reaction was performed on rotor gene (qiagen, valencia, ca, usa). peripheral blood samples ( µl) were incubated with the appropriate fluorochrome-conjugated mabs (anti-cd , cd , cd , cd , cd , cd and hla-dr) at room temperature for min; red blood cells were then lysed by an appropriate lysing solution ( µl, bd biosciences) and acquired with a bdlsr ii flow cytometer according to manufacturer's instructions (bd biosciences). at least . cells were acquired and analyzed by using the facs diva software (bd biosciences) [ ] [ ] [ ] . the descriptive analysis is presented as mean and percentage frequencies. the mean values of the groups were compared using the student's t test for numeric values and chi-square test for ordinary variables. the analysis of variance (anova) was used for comparison of the four groups divided according to positivity for viral infections. we created a logistic model to search for variables predictors of death and a receiver operating characteristic (roc) curve to identify the cutoff of saps ii and cd + that discriminate for mortality. a p value < . is considered statistically significant. for statistical analysis and graphic representation of data were used software microsoft excel © , graph pad prism . © and pasw . © for windows (ibm corporation, armonk, ny, usa). this study includes patients who, since september to may , were admitted to icu, from different clinical settings (other icus in . %, ward in . % and emergency department in . %; mean hospital stay pre-icu admission was . ± . days). this group represents . % of all patients admitted in icu with diagnosis of ards, without a known microbiological causative agent; within h after icu admission, clinical samples from these patients were sent to the laboratory for the detection both bacterial and viral infections and for immunophenotyping analysis to assess the immunological status of patients. the descriptive analysis of the entire sample of patients is illustrated in table . in . % of cases, patients required extracorporeal membrane oxygenation (ecmo) for severe ards, with hypoxia and/or hypercapnia unresponsive to conventional treatment. the ecmo los was on average . ± . days. one hundred and eight clinical samples from upper and lower respiratory tract from the icu patients were analyzed to detect influenza and other respiratory viruses and a group of herpesviruses (ebv, hcmv and hsv ). a total of patients ( %) were positive for one or more herpesviruses in at least one respiratory sample ( tf only, bal only, both samples). thus, altogether, herpesviruses were present in bal from patients ( %) and in ts from patients ( %). ebv was detected in out of patients ( %), either as a single infection or as mixed infection. in only patients ( %), ebv dna was demonstrated in bal samples. in cases, it was present as a single infection and in the two other as a mixed infection. hcmv was detected in patients ( %), either as single (in patients) or mixed infection (in patients). in seven patients ( %), hcmv dna was demonstrated in bal samples. as regards hsv , viral dna was detected in patients ( %). in of these ( %), it was present in bal. in addition, as bal represents a sample more suggestive of lower respiratory tract infection and/or of more invasive infection/reactivation, to understand better the significance of herpesviruses presence in this site, herpesviruses dna load in bal samples was assessed by quantitative realtime pcrs. ebv dna viral load in bal samples varied between traces (not quantifiable) in one sample to × copies number/ml in another sample with a median value of copies/ml. altogether, ebv dna load (mean ± sd) was , ± , . the range of hcmv dna load varied between traces (not quantifiable) in one sample to × copies number/ml with a median value of copies/ml also in this case. altogether, hcmv dna load (mean ± sd) was ± . the load of hsv in bal samples varied between copies number/ml in one sample only and copies number/ml with a median value of . altogether, hsv dna load (mean ± sd) was , , ± , , . according to herpetic viral infection positivity, patients were divided into groups: group of hcmv-positive patients (n = ); group of ebv-positive patients (n = ); group of hsv -positive patients (n = ); and group of herpesvirus-negative patients (n = ). patients positive for more than herpesvirus have been included in more than one group. the analysis of the groups is shown in table . there were no statistically significant differences in the medical history data, the severity score values at icu admission and the provenience data. no statistically significant difference in corticosteroid treatment and in the need for extracorporeal treatment was observed. outcome data showed no statistically significant differences, except for a higher mortality in icu in patients with herpetic viral infection (hcmv group: . %, hsv group: . %, ebv group: . %, herpesvirus-negative group: . %; p < . ). a significant correlation emerged between influenza virus infection and herpetic viruses coinfection (p < . ). all patients with influenza positivity were treated with oseltamivir. in patients with persistent influenza infection, zanamivir was added. dividing patients into two groups, based on the positivity for influenza virus, no correlation emerged between influenza infection and icu mortality. the statistically significant data observed are reported in table : patients with influenza infection showed higher incidence of herpesviruses coinfection in comparison with patients without influenza ( . vs . %; p = . ); saps ii demission score was ± . for influenza-positive patients, whereas it was ± . for patients without influenza. in addition, the cd + percentage was . ± . for influenzapositive patients and . ± . for influenza-negative patients. this observation is in agreement with the presence of lymphocytosis as a risk factor for icu admission in laboratory confirmed influenza patients [ ] . an additional analysis was performed by dividing patients into two groups on the basis of icu mortality: the group of survivors included patients discharged from the icu; the group of non-survivors included patients died in icu. the statistically significant data are shown in table . icu mortality was significantly associated with herpesviruses infection in the lower respiratory tract. in fact, % of herpesviruses infected patients died in icu only few patients with laboratory confirmed herpesviruses infection were treated with acyclovir/ganciclovir and despite the treatment they died; however, the small number of observations and the lack of virological monitoring does not allow us to tray any conclusion. several immunological parameters were significantly impaired in the group of patients icu died. in particular, a clear reduction in circulating lymphocytes was evident in this group when compared to the group of patients discharged from icu. the cell reduction involves all lymphocytes populations: t (cd +), b (cd +) and nk cells (cd cd / +). these data can account for both extravasation of cells that are recruited in inflamed organs and for cell apoptosis that typically affects hyper-activated lymphocytes. to evaluate the influence on icu mortality of viral coinfections, patients were divided into groups depending on the presence of influenza and/or herpetic infection. anova analysis showed no statistically significant difference in icu mortality. in the group (n = ) with presence of both infections (herpes and influenza), icu mortality was %; in patients with only influenza positivity (n = ), icu mortality was . %, while in patients with only herpetic positivity (n = ), it was . %; icu mortality was . % in patients with no one viral positivity (n = ) (p = . ). even if these differences are not significant, these data add further evidence to the association of icu mortality with herpesviruses infection, whereas icu mortality in patients with only influenza infection is similar to that of patients negative for both viruses. to better investigate the variables most associated with mortality, we built a logistic model with saps ii, herpesviruses positivity and total cd value. candidate variables were chosen as those statistically significant and/or clinically relevant to the outcome. table shows that the only variable significantly associated with mortality is herpetic infection; this indicates that herpesviruses positivity is an independent predictor of death. moreover, we researched a cutoff value for saps ii and cd + (table ; figs. , ). the logistic regression is slightly over-fitted, but the hosmer-lemenshow test is not significant (p = . ), suggesting a good calibration of the model. ards is a relevant disease today, affecting patients of all ages that may require admission to intensive care unit. the mortality for this pathology is still high, despite the implementation of specific therapies in recent years. in patients with ards, bacterial infections are prevalent; however, there are no enough studies that highlight the presence of viral etiology. among respiratory viruses, influenza a viruses, above all of the subtype (h n )pdm , may be associated with ards, as it became evident during and after the last influenza pandemic. some studies report the frequent presence of herpesviruses in respiratory samples of patients with ards [ ] [ ] [ ] [ ] [ ] [ ] [ ] ] . however, the significance of this positivity is still debated. this report concerns a group of patients admitted to icu because of ards with unknown causative agent; of them were infected by influenza virus, as demonstrated by the detection of viral rna in both upper and lower respiratory tract samples. instead, two other patients, influenza negative, were positive in the bal for rhv and adv, respectively. this study confirms that influenza viruses, mainly the h n pandemic subtype, are frequently related to ards requiring icu hospitalization, whereas other common respiratory viruses showed to be involved only sporadically. in of influenza-positive patients, also the dna of one or more herpesvirus was present in the bal, whereas no coinfection with herpesviruses was found in the patients with rhv or adv infection. thus, in bal of patients, dna of herpesviruses alone was found. these data indicate that in / patients viral infections seem to be involved in ards. however, the number of respiratory virus-positive patients could be underestimated because of the time elapsed between the onset of symptoms and the icu hospitalization. in addition, this study concerned the common respiratory viruses, whereas others like bocavirus and mimivirus were not included. moreover, it is possible that other already unknown viruses exist. data on other causative agents as bacteria or fungi have not been considered in this study. in addition to the detection of a direct viral cause of ards, this study highlights the existence of some interaction among different viruses and also among viruses, immune status and outcome of ards. in fact, a significant correlation was observed between influenza infection and herpesviruses reactivation, demonstrated by the detection of the viral dna in the bal. this observation could suggest that the respiratory mucosa damage caused by influenza virus replication can trigger herpesviruses reactivation. as regards each herpesvirus searched in the respiratory tract of the patients included in this study, ebv was the more frequently detected ( %), whereas both hcmv and hsv were present in the respiratory tract of % of patients. however, in bal ebv dna was found in patients only ( %), and hcmv dna and hsv dna were found in ( %) and ( %) patients, respectively. the frequency and dna load of hsv in bal samples were higher than that of hcmv and ebv, and in patients, it was higher than , copies/ml, a value that is reported in the literature [ ] as related to higher mortality. these results are in agreement with those of tachikawa [ ] who reported that reactivation of hsv was predominantly observed in intubated patients regardless of their immune status, whereas reactivation of hcmv and ebv was rare in immunocompetent patients. herpesviruses reactivation, as could be inferred by the detection of viral dna in bal, was not significantly associated with impaired immunophenotype, whereas it showed to be related to icu mortality. in particular, the highest icu mortality was observed among patients with hcmv reactivation, followed by those with hsv reactivation and then by those with ebv reaction. as regards the role of each herpesvirus here considered, the small number of data for each virus does not allow to draw a definitive conclusion. altogether, it seems that ebv may be involved in ards like the two other herpesviruses, with a slightly lower frequency. furthermore, the data analyzed in this study indicate that icu mortality was significantly related to an impaired immunophenotype as patients with poor outcome showed severe lymphopenia, affecting in particular t (cd +) cells, since the first days of icu hospitalization. in the present study, for the first time, as far as we know, several factors, like respiratory viral infections, respiratory infection/reactivation by some herpesviruses and immune status of the patients, have been considered and analyzed together. the results obtained, even if on a small number of patients, suggest that in a situation such complex as ards and in its outcome these factors may act at same time and synergistically: among these, viral respiratory infection, mainly by influenza a(h n )pdm , herpesviruses reactivation (more frequently hsv , hcmv and also ebv), which may be triggered by the influenza infection, and immune factors (as impaired immunophenotype). this study has several limitations which are in part related to its observational nature and the scanty samples number. it emphasizes the importance of bal analysis, whereas the analysis of viremia was performed only in few patients so that we were not able to afford a systematic analysis of these data, which must be implemented in future studies. in addition, it lacks dynamic data on herpesviruses infection, like resolution or persistence of viral infections. in addition, the usefulness of acyclovir/ganciclovir administration needs to be better studied. the data obtained imply that in ards icu patientsinfluenza virus laboratory diagnosis should be performed more frequently and as soon as possible; herpesviruses lower respiratory tract infection should monitored, together with the immunological evaluation. this could allow for a timely anti-influenza treatment which could decrease the influenza virus damage on the respiratory mucosa and eventually decrease the probability of herpesviruses reactivation. data deriving from the study of the immunological setting suggest that the evaluation of the immunophenotype is essential in order to improve the risk stratification in patients affected by systemic virus infection. detection of herpesvirus ebv dna in the lower respiratory tract of icu patients: a marker of infection of the lower respiratory tract? herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation detection of herpes viruses in respiratory secretions of patients undergoing artificial ventilation monitoring of herpes simplex virus in the lower respiratory tract of critically ill patients using real-time pcr: a prospective study clinical impact of hsv- detection in the lower respiratory tract from hospitalized adult patients herpes simplex virus the most frequently isolated pathogen in the lungs of patients with severe respiratory distress herpes simplex virus from the lower respiratory tract in adult respiratory distress syndrome herpes simplex virus in the respiratory tract of critical care patients: a prospective study comment on: 'nosocomial viral ventilatorassociated pneumonia in the intensive care unit' by daubin et al herpes simplex virus pneumonia: clinical, virologic, and pathologic features in patients active cytomegalovirus infection is common in mechanically ventilated medical intensive care unit patients the clinical interest of hsv semi-quantification in bronchoalveolar lavage immunological insights into the pathogenesis of active cmv infection in non-immunosuppressed critically ill patients prevalence and mortality associated with cytomegalovirus infection in non-immunosuppressed patients in the intensive care unit cmv in critically ill patients: pathogen or bystander increased mortality in long-term intensive care patients with active cytomegalovirus infection active cytomegalovirus infection in patients with septic shock epstein-barr virus: years on quantitative detection of herpes simplex virus dna in the lower respiratory tract quantitative detection of epstein-barr virus in bronchoalveolar lavage from transplant and nontransplant patients herpesviruses detection by quantitative real-time polymerase chain reaction in bronchoalveolar lavage and transbronchial biopsy in lung transplant: viral infections and histopathological correlation acute respiratory distress syndrome and pneumonia: a comprehensive review of clinical data respiratory microbiology patterns within the first h of ards diagnosis: influence on outcome assessment of immunological status in the critically ill a fiberoptic bronchoscopy technique to obtain uncontaminated lower airway secretions for bacterial culture the who collaborating centre for influenza at cdc atlanta, united states of america. cdc protocol of real time rt pcr for swine influenza a(h n ) detection of respiratory viruses by duplex real time pcr assays in respiratory samples pandemic a(h n ) influenza virus detection by real time rt-pcr:is viral quantification useful? genital human papillomavirus infection in female university students as determined by a pcr-based method mortality prediction to hospitalized patients with influenza pneumonia:po /fio combined lymphocyte count is the answer persistent lymphopenia after diagnosis of sepsis predicts mortality lymphopenia associated with highly virulent h n virus infection due to plasmacytoid dendritic cell-mediated apoptosis of t cells subjects hospitalized with the pandemic influenza a (h n ) virus in a respiratory infection unit: clinical factors correlating with icu admission clinical relevance of herpes simplex virus viremia in intensive care unit patients detection of herpes viruses by multiplex and real-time polymerase chain reaction in bronchoalveolar lavage fluid of patients with acute lung injury or acute respiratory distress syndrome key: cord- -d e y r authors: knighton, andrew j.; kean, jacob; wolfe, doug; allen, lauren; jacobs, jason; carpenter, lori; winberg, carrie; berry, jay g.; peltan, ithan d.; grissom, colin k.; srivastava, raj title: multi-factorial barriers and facilitators to high adherence to lung-protective ventilation using a computerized protocol: a mixed methods study date: - - journal: implement sci commun doi: . /s - - -x sha: doc_id: cord_uid: d e y r background: lung-protective ventilation (lpv) improves outcomes for patients with acute respiratory distress syndrome (ards) through the administration of low tidal volumes (≤ . ml/kg predicted body weight [pbw]) with co-titration of positive end-expiratory pressure and fraction of inspired oxygen. many patients with ards, however, are not managed with lpv. the purpose of this study was to understand the implementation barriers and facilitators to the use of lpv and a computerized lpv clinical decision support (cds) tool in intensive care units (icus) in preparation for a pilot hybrid implementation-effectiveness clinical trial. methods: we performed an explanatory sequential mixed methods study from june to march to evaluate the variation in lpv adherence across icus in an integrated healthcare system with > mechanically ventilated patients annually. we analyzed key informant interviews of icu physicians, respiratory therapists (rts), and nurses in of the icus using a qualitative content analysis paradigm to investigate site variation as defined by adherence level (low, medium, high) and to identify barriers and facilitators to lpv and lpv cds tool use. results: forty-two percent of patients had an initial set tidal volume of ≤ . ml/kg pbw during the measurement period (site range – %). lpv cds tool use was % (site range – %). this study’s main findings revealed multi-factorial facilitators and barriers to use that varied by icu site adherence level. the primary facilitator was that lpv and the lpv cds tool could be used on all mechanically ventilated patients. barriers included a persistent gap between clinician attitudes regarding the use of lpv and actual use, the perceived loss of autonomy associated with using a computerized protocol, the nature of physician-rt interaction in ventilation management, and the lack of clear organization measures of success. conclusions: variation in adherence to lpv persists in icus within a healthcare delivery system that was an early adopter of lpv. potentially promising strategies to increase adherence to lpv and the lpv cds tool for ards patients include initiating low tidal ventilation on all mechanically ventilated patients, establishing and measuring adherence measures, and focused education addressing the physician-rt interaction. these strategies represent a blueprint for a future hybrid implementation-effectiveness trial. acute respiratory distress syndrome (ards) occurs when an acute lung injury (e.g., pneumonia, sepsis, trauma) causes bilateral non-cardiogenic pulmonary edema and hypoxemic respiratory failure requiring mechanical ventilation [ ] . an international study in countries found that % of patients admitted to the intensive care unit (icu) and % of mechanically ventilated patients had ards [ ] . during the novel coronavirus (covid- ) pandemic, - % of hospitalized patients and - % of patients admitted to the icu will develop ards [ ] . ards is associated with high morbidity, mortality, and healthcare cost [ , , ] . lung-protective ventilation (lpv), which combines low tidal volume ventilation (ltvv) with step-wise cotitration of positive end-expiratory pressure (peep) and the fraction of inspired oxygen (fio ), improves outcomes for patients with ards in clinical studies [ , ] and is recommended by the american thoracic society (ats) clinical practice guidelines [ , ] as well as in other recent reviews [ , ] . barriers to consistent use of lpv persist and have hindered progress toward improved ards outcomes [ ] . general agreement exists among physicians, respiratory therapists (rts), and nurses that lpv is warranted for patients with ards, although studies demonstrate a substantial divide between belief and actual practice [ ] . identified barriers to the use of lpv include physician's ability to recognize ards in a timely fashion [ , ] , lack of written protocols [ , ] , lack of concordance with clinician perceptions of patient needs [ , , ] , and perceptions by nurses and rts that ltvv is more labor-intensive and that present staffing is inadequate to achieve full adherence [ , ] . intermountain healthcare (intermountain) was involved in early ards network studies [ ] and demonstrated high adherence at one hospital site, but high system-wide adherence was not attained across all sites. we recently deployed an electronic medical record (emr)-integrated lpv clinical decision support (cds) tool to the icus in our system designed to standardize lpv practice across all sites and increase overall lpv adherence. we conducted a mixed methods study to identify barriers to utilization of lpv and the lpv cds tool in patients with ards in preparation for a pilot hybrid implementation-effectiveness trial (nct ) designed to increase adherence to lpv and the lpv cds tool in ards patients. we performed an explanatory, sequential mixed methods study (quant -> qual) from june to march to ( ) measure the variation in adherence to lpv and to the use of the lpv cds tool across icu sites and ( ) understand, through qualitative interviews, the reasons for variation and to identify implementation barriers and facilitators to lpv and lpv cds tool in routine practice for patients with ards at three of those icu sites [ , ] . the research protocol was approved by the intermountain healthcare institutional review board (irb# ). we adhered to published best practices for reporting of mixed methods studies [ , ] and qualitative research [ ] . intermountain healthcare's icus are part of an integrated, -hospital system that includes frontier hospitals, tertiary care centers, and a children's hospital. across the system, roughly adult patients are ventilated annually. approximately % of these ventilated research has shown that lung-protective ventilation (lpv) improves outcomes for patients with acute respiratory distress syndrome and is not consistently applied in intensive care settings. clinical decision support (cds) tools are being evaluated as one mechanism to standardize lpv use. while cds tools may assist in normalizing the use of lpv, we found multi-factorial barriers and facilitators to lpv and to lpv cds tool use in an organization involved in early lpv studies. these findings contribute to recognized gaps in the literature, including detailing barriers to lpv and cds tool use and describing theory-informed, tailored implementation strategies. to initiate the use of the open-loop protocols, physicians must place an electronic order for each protocol component. once ordered, the rt measures patient height and sets parameters for tidal volume, respiratory rate, fio , and peep. the protocol order does not specify the starting settings. however, if the rt does not use an ltvv setting, the protocol will give instructions to the rt to move to an ltvv setting. an arterial blood gas (abg) is obtained within h. oxygenation and ventilation protocols are then run, generating instructions for the rt to adjust or maintain fio , peep, tidal volume, and respiratory rate. the rt must accept or reject each instruction and, if instructions are rejected, provide a reason. the ventilation protocol is intended to run each time an abg result is received. the oxygenation protocol is intended to be run after abg results and also every h based on oxygen saturation measured from pulse oximetry (spo ) during each rt ventilator assessment. during initial deployment, lpv cds tool implementation strategies included didactic education, communications, audit and feedback to physicians and rts, and executive leadership emphasis on compliance. however, some icus were not achieving consistent adherence to the initial set tidal volumes ≤ . ml/kg pbw or consistent utilization of lpv cds tools in mechanically ventilated patients. we used two provisional measures to explore the variation in adherence by site. using an encounter cohort of icu-admitted adult patients (age ≥ years) receiving invasive mechanical ventilation, we calculated the percentage of patient icu encounters that were treated with an initial set tidal volume ≤ . ml/kg pbw. for the second measure, we calculated the percentage of patient icu encounters that were treated using at least one of the four protocols in the lpv cds tool during the stay. the cohort excludes patients who died on the day of admission. the cohort represents data from a restricted study time period from the improvent clinical trial (nct ). the measurement period for cohort identification began on the date the lpv cds tool was deployed at each site (ranging from april to july ) and ended on october , . the calculations were made from data queried from the intermountain emr systems. spearman's rank test was used to observe any initial correlation between the two measures. a twosample test of proportions was used to explore the differences in both measures at the aggregate level by hospital type. we developed an interview guide using a deductive, multi-method approach: a scoping review [ ] [ ] [ ] [ ] to examine the barriers and facilitators to the use of lpv and the lpv cds tool and interventions to improve adherence; a technical expert panel that included critical care physicians, hospitalists/health services researchers, icu nurse managers, emergency department (ed) physician, respiratory therapist (rt), and implementation scientist, to identify already known or suspected barriers to implementation (simultaneous triangulation) [ ] ; and categorization and summary of findings according to the consolidated framework for implementation research (cfir) [ , ] by two experienced implementation scientists (ak, rs). this approach is consistent with the efforts to develop contextual implementation frameworks for complex system interventions [ ] . cfir constructs identified as relevant through both the scoping review and by the multi-disciplinary expert panel formed the theoretical basis for the interview guide questions. common, relevant cfir domains (and related constructs) identified for both lpv and the lpv cds tool included the individual (knowledge and beliefs), intervention (relative advantage, adaptability, design quality, and packaging), and the inner setting (learning climate, compatibility, and available resources). lpv also included intervention (evidence strength and quality) and inner setting domains (tension for change, relative priority, and leadership engagement). the lpv cds tool also included individual (individual stage of change), intervention (complexity), and inner setting domains (goals and feedback). no constructs were initially identified as relevant from the external setting and implementation domains. validated interview questions related to the selected cfir constructs were then drawn from the "barriers to physician adherence to practice guidelines" model and adapted for interdisciplinary interviews to guide the assessment of knowledge, attitudes, and behaviors of sites and individual caregivers regarding lpv use [ ] . to assess the barriers and facilitators of lpv cds tool use, validated questions were adapted from the "unified theory of acceptance and use of technology" (utaut) to explain user intentions to use an information system and subsequent usage behavior [ ] . upon completion, the interview guide and questions were reviewed by the intermountain lead critical care physician (cg) and respiratory therapist (cw) for clarity and relevance. to understand the primary reasons for the variation in adherence at each site using a grounded theory approach [ , ] , key informant semi-structured interviews were conducted using the interview guide with clinicians at intermountain icus. to ensure an information-rich sample [ ] , three pilot icu sites were selected by the research team from the quantitative analysis. the team used a stratified purposeful sampling approach [ ] based upon site adherence ranking (high-medium-low), icu type (medical/surgical, respiratory, cardiac, neurologic, and thoracic), and local leadership support. local leadership support was determined through conversations between the system icu leader and local site icu leaders. given the study focus on patients with ards, site selection was limited to medical/surgical, trauma, and respiratory icu sites. a two-person team of trained, experienced qualitative researchers (ajk, dw) conducted the key informant interviews with a purposive sample of - key informants using a role-based criterion. interview participant roles included the icu physician director, critical care physicians, icu rt manager, icu rts, and icu nurses with the goal to achieve uniform participation at each site across roles, with an option to sample additional roles as needed. for roles that were not limited to a single individual at a site (intensivists, rts, and nurses), interviews continued until thematic saturation was reached (no new ideas emerged during three consecutive interviews for a particular role at a site) [ ] . each interview was min. while adherence data was available to individual sites, the investigators did not present site adherence data in the discussion. research funds were made available on the day of each site visit at all three sites to schedule additional clinical resources to ensure patient coverage. participants at each site were invited to participate on the day of the site visit by the local icu director and rt manager via email or direct conversation, subject to availability. efforts were made to identify individuals within each role that varied in terms of years of their experience and attitudes and beliefs regarding lpv and the lpv cds tool. preliminary assessments of attitudes and beliefs were based upon the local icu director or site rt manager's experience working with each clinician. the qualitative research team met frequently during each site visit to review interview data and to assess thematic saturation more generally and to identify additional interview needs by role. at the end of each site visit, emerging themes and ideas were summarized and shared with system and site clinical leaders and were used to identify follow-up interviews to address the gaps in understanding. a hybrid qualitative content analysis paradigm was applied to interview data, incorporating both directed and open-iterative methods to provide a reflexive approach to identify barriers and facilitators to high adherence to the use of lpv and the lpv cds tool [ ] . a study investigator and experienced qualitative researcher (ak) organized a preliminary codebook by interview guide question number as the unit of analysis. (the interview guide was originally organized deductively by relevant cfir construct.) two research assistants were trained by the study co-investigator on both the clinical and non-clinical aspects of the study, including specific training on the use of the preliminary codebook. the study investigator (ak) then read and conducted line-by-line coding of a preliminary sample of five interviews using the preliminary codebook, allowing for the open coding of new or emerging themes not already captured. the five transcripts were divided between the two research assistants who separately read and independently conducted line-by-line coding using a similar approach. for each coded transcript, the study co-investigator and the independent reviewers compared the results, agreeing on the name and definition of each code. this codebook was then used to assist the researchers in the analysis of the remaining interview data. the study team followed a similar process for the remaining interviews. during the coding process, the coding team met frequently to identify and agree on new or emerging concepts not captured in the current codebook and recoded prior transcripts accordingly. for each coded transcript, the arbitration for discordant coding was done through a discussion between the study coinvestigator and the assigned independent reviewer until consensus was reached. reported implementation barriers and facilitators were then summarized according to the levels of the cfir framework overall, by site and by clinical role [ ] . all coding was done in atlas.ti version . (scientific software development gmbh, berlin, germany). the provisional estimate of the initial set tidal volume ≤ . ml/kg pbw was % system-wide. icu-level adherence estimates ranged from to % (table ) . the estimated lpv cds tool utilization was %, with icu-level utilization ranging from to %. the five tertiary care hospitals accounted for % of the total icu beds and % of all mechanically ventilated patients. non-tertiary hospitals, which represent smaller urban, rural, and frontier coverage areas, had significantly higher rates on both adherence measures (p < . ) and represented % of patient encounters. higher icu-level use of the cds tool in the provisional estimates was positively correlated with the percentage of patients receiving an initial low tidal volume strategy (ρ = . , p = . ). forty-seven key informant interviews were conducted and analyzed at three icu sites with varying levels of adherence. demographic characteristics by role and by site are shown in table . saturation was reached with each role at each site. initial adherence estimates were inconsistent with comments from key informant interviews that an initial set tidal volume of ≤ . ml/kg pbw was the standard practice for patient care at all three sites and that physicians consistently ordered the lpv cds protocols for all mechanically ventilated patients. rts reported that of the four protocols, the oxygenation and ventilation protocols were the most commonly used in actual practice. based upon qualitative analysis of the nurse interviews, the principal finding was that nurse exposure to lpv management and use of the lpv cds tool was limited to coordinating with the rt on nurserelated aspects of care, such as sedation management, at all three sites. nurses consistently stated they had no visibility to barriers and facilitators to lpv and lpv cds use with limited understanding or influence regarding ventilation management activities. nurses consistently reported that ventilation management was the purview of the physician and rt. given this, the results below focus on physician and rt implementation barriers only. implementation barriers and facilitators-individual/ clinician (table ) physicians at all three sites were able to recall the key criteria for the diagnosis of ards. identification of lowto-moderate severity ards cases, shown to be a challenge in prior studies, remained so for physicians and rts in this study. since non-ards mechanically ventilated patients were similarly started with an initial tidal volume setting of ≤ . ml/kg pbw, physicians felt that the detection of ards was less important to initiate a low tidal volume strategy. once mechanical ventilation was initiated, clinicians at the low adherence site more frequently described returning to alternative ventilation and oxygenation strategies that they have used in the past versus applying lpv and lpv cds tool instructions to non-responsive patients. we're happy to try it. but if it doesn't work, we're not going sit and watch our patient languish when we have something in our back pocket that in our experience has worked fine. physician, low-adhering site what we've found is… sometimes we're playing catch-up…for us it's hard to keep at a high fio , at a high peep, for x number of days, when in the past we've had huge changes and differences as soon as we've swapped to an open lung strategy. rt, lowadhering site at the low and moderate adherence sites, uncertainty regarding the purpose and use of each of the four lpv cds tool protocols, including when it was acceptable to depart from the protocol recommendations, was experienced as impinging on clinician self-efficacy. despite the underlying variation in adherence, clinicians at all sites expressed confidence in their ability to use lpv and lpv cds tool technology and expressed the intention to use them to deliver patient care. while clinicians at the low-and moderate-adhering sites resented being told to adopt an intervention that they did not assist in selecting and developing, physicians at all sites felt that the use of the lpv cds tool provided certain advantages relative to no computerized protocol. rts at the high-adhering site felt that the use of the tool actually increased their self-efficacy when implementing an lpv strategy for ards patients. critical care physicians and rts agreed that an ltv setting was beneficial for patients with ards, but there was some i'm always trying to adapt the ventilator as much as possible to the work and breathing of the patient… and trying to stay within their protocols of six mils per kilo. but sometimes it's extremely difficult and near impossible. i worry because i see that patient retracting and fighting against the ventilator and i see more lung injury occurring. rt, low-adhering site this misperception regarding lpv appears associated at least in part with a misunderstanding regarding the role and use of peep strategies in lpv. as intervention facilitators, rts, and critical care physicians felt that the lpv cds tool was easy to use after training and that major changes in the technology were unnecessary. critical care physicians noted the benefit of being able to place a single order to facilitate patient ventilation management with change orders only required on an exception basis for significant departures from the lpv cds protocols. i really love the protocols. i worked at the univer-sity…and i can see the difference between not having protocols and having protocols. [at the university], all the vent changes had to be actively managed by the physicians…and it takes up a huge amount of time…it allows the rts to really just run the protocol. physician, high-adhering site rts at the high-adhering site felt that the lpv cds tool actually made them more responsive to their patient's needs when considering long-term patient health. the way that we do vent checks every two hours… makes a big difference. we're in the patients room more often, having eyes on the patient and seeing what's going on…and then with our experience in the protocols, i think it does help us make those decisions in a faster way to wean patients and get them off the vent. rt, high-adhering site in contrast, rts at the low and moderate adherence sites felt that the use of the lpv cds protocols slowed their response to patient needs and increased their workload. more experienced rts noted that the use of the lpv cds tool was not necessary to adhere to an initial tidal volume setting ≤ . ml/kg, which was inconsistent with the correlation observed in the quantitative data between lpv cds tool use and initial tidal volume setting. more experienced clinicians felt that following implementation barriers and facilitators-organization/ inner setting (table ) clinicians at the low-adhering site resented the perception that the use of lpv and the lpv cds tool was a system-level mandate that limited their autonomy to select ventilation and oxygenation strategies. we've never been asked. we've never been surveyed. we've never been talked to. we've been told. physician, low-adhering site the lack of agreement both within and across sites regarding lpv adherence standards was itself a barrier to adherence. clinicians felt a limited degree of accountability to achieve high adherence without a clear understanding of what constitutes high adherence. the lack of a clear definition of success impacted perceptions of the lpv cds tool, particularly for more influential, experienced rts who were familiar with earlier iterations of the tool or with the use of paper-based protocols. at low-adhering sites, some more experienced rts who had this view actively opposed both routine and consistent applications of lpv as well as utilization of the lpv cds tool. these "anti-champions" often described being historically given substantial autonomy for ventilator management and tended to feel the lpv cds tool reduced their autonomy. informant interviews suggested these clinicians' views were influential, impacting general attitudes among both rts and physicians and low and moderate adhering regarding the benefits of lpv and the lpv cds tool. limited formal training to assist protocol users, including having convenient, accessible resources to obtain answers to questions, exacerbated frustrations. while physicians did not indicate discussing the lpv cds tool frequently with their peers, physician discussions with rts and between rts were commonly reported. primary reasons for discussions centered on understanding and responding to instructions generated by the tool. under the process, the rt needs to log into the emr to conduct the ventilation assessment. once the required ventilation assessment is conducted, the data is automatically loaded into the ventilator protocol. the rt is then required to open another page and click for instructions and then read and accept or reject generated instructions. reasons for declining instructions are documented by the rt using a drop-down list. perceptions of rts from low-performing sites were that the additional steps and documentation in the workflow took too much time. this was particularly true when they had to repeatedly reject an instruction with each ventilation assessment. impact of the initial approach to lpv cds tool implementation (table ) strategies implemented during the initial rollout led to a meaningful increase in adherence rates for both lpv and the lpv cds tool but were not sufficient alone to achieve high adherence. sustainment efforts following the initial rollout at each site included ongoing executive leadership emphasis in team and organization meetings and site-level audit and feedback reporting. the initial lpv cds tool implementation involved the rollout of all four components in a phased manner by individual site following the implementation of the new emr. at the point of this study initiation, the phased rollout was complete and all cds tool protocols had been in place from to months, depending on the site. users struggled to disentangle their sentiments about the lpv cds tool itself from the impact on lpv cds tool users' experience of system downtime and network delays during the broader emr rollout. there was a system rt champion available on site during the lpv cds tool implementation and a system physician champion available by phone. the lack of an organized effort to discern from front-line clinicians what the barriers were, however, impaired the implementation team's ability to understand and address concerns. adherence data was available by site but was only available with a - -month lag, limiting transparency to site and physician-level performance. this study provides a rich understanding of implementation barriers and facilitators to the use of lpv and an lpv cds tool in icus in an integrated system that was an early innovator in the use of lpv strategies, but has yet to achieve consistent high system adherence. this study's main findings revealed multi-factorial facilitators and barriers to use that varied by icu site adherence level. the primary facilitator was that lpv and the lpv cds tool could be used on all mechanically ventilated patients. barriers included a persistent gap between clinician attitudes regarding the use of lpv and actual use, the perceived loss of autonomy associated with using a computerized protocol, the nature of physician-rt interaction in ventilation management, and the lack of clear organization measures of success. while clinicians consistently agreed that a set tidal volume ≤ . ml/kg pbw was optimal for patient care, we found more variation than expected when clinicians were asked to define ltvv and the appropriateness of ventilator modes other than volume control-our system standard-for the delivery of low tidal volumes. consistent with prior studies [ , ] , clinician's failure to recognize less-severe ards cases likely impedes lpv implementation. however, clinicians did not differentiate ards and non-ards patients when ordering the protocols or initiating an initial set tidal volume ≤ . ml/kg pbw but applied the standard to all mechanically ventilated patients. the fact that clinical teams are not required to differentiate ards patients when making decisions to utilize the lpv cds tool or to initiate an initial low tidal volume setting is an important finding that simplifies implementation. this becomes important in situations, such as the covid- pandemic, where icus are experiencing high rates of ards and are likely to benefit from consistent use of lpv [ ] . consistent with earlier studies [ ] , physician and rt statements that lpv strategies were most appropriate for patients with ards and indicated that they were consistently ordered and that an initial ltvv was used were not consistent with the provisional adherence data. this attitude-behavior gap [ ] between intent and actual practice is consistent with earlier studies demonstrating that clinician beliefs and perceived barriers to using lpv were not correlated with lpv initiation [ , ] . several factors may begin to explain this gap. efforts to promote adherence continued between the time when we generated provisional measurement data and when field interviews were conducted. these findings also suggest that non-attitudinal barriers such as perceptions of control; structural elements, such as workflows; and normative influences, including perceptions by the care team regarding patient impact [ ] , may continue to limit the use of lpv. these findings should be addressed in the development of implementation strategies [ ] . the perceived loss of autonomy associated with following the lpv cds protocol tools was difficult for more experienced rts at low-performing sites. under earlier paper-based systems, more experienced rts may have felt empowered to function without physician orders in certain circumstances. under relationship models theory, the traditional interaction between the physician and rt is based upon an authority ranking dyad relationship, asymmetrically ranked in a linear hierarchy with the critical care physician as the authority [ , ] . at the low-performing sites, the traditional interaction was supplanted over time by an informal, negotiated market pricing relationship between the physician and rt. the critical care physician sought to optimize time in exchange for empowering more seasoned rts to act in the patient's interest as the rt saw fit, without always obtaining a physician's order. the development of this informal, mutually protective dyad made it difficult to isolate and address the actual root causes of low adherence. given that positive ventilation management outcomes are associated with the successful interaction of the physician and the rt, implementation strategies that target joint determinants should be considered. for example, using encounter-level data to identify on an exception basis those dyads that have higher nonadherence rates and conducting simulation training with each dyad to ensure that the required interaction is reasonably scripted and understood. the lack of a definition for successful adherence to lpv and use of the lpv cds tool was perceived as a key barrier at low-adhering sites. relevant and timely information about performance on intermediate outcomes provides transparency at both the team level and with accountable system leadership and improves performance [ ] . given the low-volume, high-complexity nature of patient care in the icu [ ] , detailed encounterlevel data enables local teams to review performance on individual cases and diagnose implementation barriers and facilitators in real-life settings [ ] . the lack of a definition of success also impacted perceptions of the lpv cds tool. teams focused on achieving a high adherence to a low initial tidal volume did not see the lpv cds tool as useful in achieving this goal. however, higher-adhering sites described a broader view of the lpv cds tool use benefits that was embedded in the way they do things, introducing a shared language for treating ards and driving their teams toward standardization in practice. this study had certain limitations by design. the study does not establish a clear causal relationship between specific implementation barriers and facilitators and adherence. adherence data available to inform site selection was initially limited to two provisional measures of performance and included all mechanically ventilated patients undifferentiated on ards status. inclusion of all mechanically ventilated patients was likely not a significant weakness, however, as clinicians at all three sites indicated that ordering the protocols and use of an initial low tidal volume setting was the routine goal for all mechanically ventilated patients. given that lpv and the lpv cds tool protocols are used on all mechanically ventilated patients, some comments regarding barriers and facilitators to use may have been referencing all mechanically ventilated patients and not ards patients alone. we were not able to interview all individuals in each role at the three selected sites given practical considerations but relied upon local site leadership to identify people for the team to meet with on the day of the site visit. efforts were made to identify individuals within each role that varied in terms of years of experience and attitudes and beliefs regarding lpv and the lpv cds tool. evidence of saturation at each site mitigated the risk that important perspectives were not captured. further, the field interview team reviewed the site interview list at the beginning of each site visit and debriefed throughout the day to determine if additional individuals should be added. the use of researchers employed by the delivery system may have impacted the results, highlighting potential strengths and challenges of conducting embedded research linked to healthcare improvement [ ] [ ] [ ] . while clear communication regarding the purpose of the interviews was included in the consent process and clinicians appeared forthright, we cannot rule out the possibility that interview participants' comments were influenced by the investigator's institutional alignment. the investigators' individual biases, including the employment relationship, may also impact results. variation in adherence to lpv persists in icus that were early adopters of lpv. multi-factorial strategies usa. population health sciences ut , usa. complex care, division of general pediatrics, boston children's hospital intermountain healthcare, south state street rd floor acute respiratory distress syndrome: the berlin definition epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries interim clinical guidelines for management of patients with confirmed coronovirus disease (covid- recovery and outcomes after the acute respiratory distress syndrome (ards) in patients and their family caregivers ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. the acute respiratory distress syndrome network timing of low tidal volume ventilation and intensive care unit mortality in acute respiratory distress syndrome. a prospective cohort study liberation from mechanical ventilation in critically ill adults. an official ats/ accp clinical practice guideline summary for clinicians: mechanical ventilation in adult patients with acute respiratory distress syndrome clinical practice guideline acute respiratory distress syndrome ventilator-induced lung injury a critical care clinician survey comparing attitudes and perceived barriers to low tidal volume ventilation with actual practice barriers to providing lung-protective ventilation to patients with acute lung injury underuse of lung protective ventilation: analysis of potential factors to explain physician behavior barriers to low tidal volume ventilation in acute respiratory distress syndrome: survey development, validation, and results patient and intensive care unit organizational factors associated with low tidal volume ventilation in acute lung injury mixed method designs in implementation research research design: qualitative, quantitative and mixed methods approaches the quality of mixed methods studies in health services research standards for reporting qualitative research: a synthesis of recommendations driving pressure is not associated with mortality in mechanically ventilated patients without ards scoping studies: towards a methodological framework scoping studies: advancing the methodology guidance for conducting systematic scoping reviews systematic review or scoping review? guidance for authors when choosing between a systematic or scoping review approach approaches to qualitative-quantitative methodological triangulation fostering implementation of health services research findings into practice: a consolidated framework for advancing implementation science a systematic review of the use of the consolidated framework for implementation research contextual frameworks for research on the implementation of complex system interventions. rockville: agency for healthcare and research quality why don't physicians follow clinical practice guidelines? a framework for improvement technology acceptance models in health informatics: tam and utaut. stud health technol inform constructing grounded theory qualitative research and evaluation methods purposeful sampling for qualitative data collection and analysis in mixed method implementation research what is an adequate sample size? operationalising data saturation for theory-based interview studies three approaches to qualitative content analysis surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ). read online: critical care medicine | society of critical care medicine diffusion of innovations the theory of planned behavior the four elementary forms of sociality: framework for a unified theory of social relations a generic model of dyadic social relationships use of process measures to monitor the quality of clinical practice implementing evidence-based clinical practice in the critical care setting the case study approach applied research and development in health care -time for a frameshift the future of health services research: advancing health systems research and practice in the united states the time has come: embedded implementation research for health care improvement the authors would like to acknowledge the physicians, respiratory therapists, and nurses of intermountain healthcare who contributed time and effort to this research, as well as to their tireless efforts to "help our patients live the healthiest lives possible." we also want to acknowledge other participants including dr. kimberly a. brunisholz, phd, mst, who participated in the initial site interviews, as well as brian garate reyes, a research assistant, who supported the coding of qualitative data. that address the distinctive implementation barriers and facilitators of the icu environment at the individual, team, and unit level appear necessary to achieve high adherence. as part of an implementation plan, organizations should consider initiating low tidal volume ventilation on all mechanically ventilated patients, identifying and agreeing upon standard adherence measures and designing education strategies that address physician-rt interaction during the care process. these strategies represent a blueprint for a future hybrid implementation-effectiveness trial. supplementary information accompanies this paper at https://doi.org/ . /s - - -x.additional file . authors' contributions ak, jb, ip, cg, and rs made substantial contributions to the development of the mixed methods study design. ak, dw, la, jj, lc, cw, ip, cg, and rs made substantial contributions to the acquisition, analysis, and/or interpretation of the study data. ak, jk, ip, cg, and rs were the major contributors in writing the manuscript. all authors read and approved the final manuscript. editorial services were not used in the development of this manuscript. not applicable. this study was funded under a u- grant from the national heart, lung, and blood institute (nhlbi) of the national institutes of health (nih) [u hl ]. dr. peltan received additional support from the national institute of general medical sciences (k gm ). dr. knighton received additional support from the national center for advancing translational sciences of the national institutes of health (kl tr ). the funding bodies were not involved in the study and collection, analysis or interpretation of the data, in writing the manuscript. all provisional quantitative data generated or analyzed during this study is included as aggregated in the published article in table . the majority of qualitative data for this study is made available in the publication tables. however, the detailed interview dataset generated and analyzed during the current study is not publicly available due to individual privacy concerns. the study was approved by the intermountain healthcare institutes review board, reference number irb# . all human subjects provided consent to participate in this study and to have their de-identified interview results disseminated for research purposes. all interview participants consented to have their de-identified interview results disseminated for research purposes, including publication. key: cord- -cq t authors: ismaeil, taha; almutairi, jawaher; alshaikh, rema; althobaiti, zahrah; ismaiel, yassin; othman, fatmah title: survival of mechanically ventilated patients admitted to intensive care units: results from a tertiary care center between - date: - - journal: saudi med j doi: . /smj. . . sha: doc_id: cord_uid: cq t objectives: to estimate the survival of adult and pediatric patients receiving mechanical ventilation and determine the associated risk factors methods: a retrospective cohort study was carried out in the intensive care unit (icu) at king abdulaziz medical city (kamc) and king abdullah children’s specialist hospital (kacsh), riyadh, saudi arabia. the analysis includes data from medical records of all patients admitted to icus who received mechanical ventilation between - . for each patient, potential risk factors were collected. the main outcome of this study was the mortality during the stay in icu after receiving mechanical ventilation results: a total of adults and pediatric patients were admitted to icus and received mechanical ventilation during the study period. for adult patients, the overall mortality was %, with a median survival time of days (interquartile range [iqr] - days). the main risk factors independently associated with the increased mortality rate were being aged - (odds ratio [or] . , % confidence interval [ci] . - . ) and factors related to icu admission. for the pediatric population, the mortality rate was %, with a median survival time of days (iqr - days). prematurity with respiratory problems was the main recorded cause of initiation of mechanical ventilation ( % of patients). neonates who had mechanical ventilation within one month of their birth and were born extremely preterm had a high mortality rate after the initiation of mechanical ventilation. conclusion: both patient age and the causes of the initiation of mechanical ventilation were influencing the survival of patients who required mechanical ventilation. m echanical ventilation is considered an important aspect of the supportive management of patients in intensive care units (icus). many studies have reported an increased rate of using mechanical ventilation over the last years. this increase is attributable to increases in demand for acute and critical care delivery in many health care systems. this demand is being caused by an increasingly aging population, an increase in the survival of patients with comorbidity and cancer, an increase in the number of icu beds, and the advancements in therapy management. [ ] [ ] [ ] thus, many observational studies have examined the use of mechanical ventilation and its associated outcomes, some of which have focused on estimating the mortality rate and identifying the factors related to the survival of patients who received mechanical ventilation. [ ] [ ] [ ] [ ] data on the survival of patients admitted to icus and requiring mechanical ventilation, therefore, are varied. the variability in survival data reflects differences in icu patients' selection criteria, patient care standards, and the characteristics of the population. in , esteban et al evaluated the outcomes of adult patients admitted to icus and showed that the overall mortality rate was % among patients receiving mechanical ventilation. another study by the same research group showed that crude mortality rate in icus had been decreased in compared to that in ( % versus %). this improvement was related to the improvement in clinical practices over the period. additionally, studies have reported that many factors related to the initiation of mechanical ventilation as well as other factors related to the management plan and complication during the course of mechanical ventilation affect the survival of patients receiving mechanical ventilation. , in saudi arabia, many studies have examined the mortality outcome of patients admitted to icus; however, some of those studies have evaluated the outcome of patients receiving mechanical ventilation for specific indications, such as with severe respiratory conditions, , or have focused on a specific population such as that with a hematological malignancy. [ ] [ ] [ ] [ ] however, the survival of patients admitted to an icu and received mechanical ventilation with various indications and among heterogenous population has not been reported in saudi arabia. the aim of this study; therefore, was to estimate the survival of adult and pediatric patients admitted to icu and received mechanical ventilation, and to determine the associated factors influencing the survival. the results of this study will help in identifying patients at risk and planning appropriate preventive measures. methods. a retrospective cohort study was conducted between february and february in the medical-surgical intensive care department at king abdulaziz medical city (kamc) and king abdullah children's specialist hospital (kacsh), riyadh. the intensive care department has a -bed capacity kacsh. , data were collected consecutively from all intubated patients (pediatric and adult) who had been admitted to the icu and required mechanical ventilation for more than consecutive hours during the study period; therefore, we included all eligible patients in this study who met the study inclusion criteria. we excluded patients who received non-invasive ventilation, and those who died within hours of receiving the mechanical ventilation. the main outcome of this study was all the causes of mortality during the stay in icus after receiving mechanical ventilation. the mortality rate was calculated as all mechanically ventilated patients who died in icus during the study period over the total number of mechanically ventilated patients in icus during the same year. also, we estimated the length of stay in icus for those patients as we collected information on time and date of receiving mechanical ventilation, time and date of death, and time and date of icu discharge. moreover, for the adult population, the following information was collected from each patient's medical file on the day of icu admission: ) demographic variables, body mass index (bmi) (categorized into underweight, normal, overweight, and obese); ) source of icu admission (from emergency department, other that includes hospital ward, transfer from other hospital, or outpatient department); ) glasgow coma scale that (classified into severe brain injury, score - ; moderate brain injury, score - , and mild brain injury, score - ); ) mechanical ventilator setting; ) cause of the initiation of mechanical ventilation (classified into coma, respiratory failure type i, respiratory failure type ii, and other causes such as involved in motor vehicle accidents, burns, or post-operative complications); and ) diagnosis at icu admission (mapped on the icd- classification of disease). for pediatric patients, we also extracted information on the demographics (in which we classified the age into first month, - months, and more than months), source of icu admission (from er, labor suite, or other hospital), gestational disclosure. authors have no conflict of interests, and the work was not supported or funded by any drug company. week (classified according to the who classification of prematurity), cause of the initiation of mechanical ventilation (classified into prematurity with respiratory problems, respiratory distress syndrome, post-operation, and congenital), and diagnosis at icu admission (mapped on the icd- classification of disease). baseline characteristics of patients at the time of icu admission were reported as number and percentage for categorical variables and as mean and standard deviation (sd) for normally distributed continuous variables, or as the median and interquartile range (iqr) if not. the primary outcome measure was the mortality during the icu stay after the initiation of mechanical ventilation. a kaplan-meier curve was used to describe the probability of survival after the initiation of mechanical ventilation; thus the exit time was set as the earliest of either the death date or the icu discharge date. to examine the association effect of the factors on the survival among those who survived and those who died, a univariate analysis was performed using logistic regression to estimate the odds ratio (or) and % confidence interval ( % ci), whereby p< . was considered as significant. the statistical analyses were performed using stata® software, version (statacorp, college station, tx, usa). the study was approved by the research ethics committee of king abdullah international medical research center, riyadh, saudi arabia protocol number (sp / /r). results. overall, among the patients (all populations), patients died after receiving mechanical ventilation. thus, the overall mortality for patients admitted to the icu and receiving mechanical ventilation during the study period was %, with a median survival time of days (iqr - days). kaplan-meier curve (figure ) compared the survival rates between the adult and pediatric populations in which the p value from the log rank test was (p< . ) which indicates a significant difference between the population survival curves. we reported the results for the adult and pediatric populations separately as the cause of the initiation of mechanical ventilation and the type of mechanical ventilation mode are different between the adult and pediatric populations. in the analysis of adult population, a total of patients were admitted to icus and received mechanical ventilation during the study period. the mean age of those patients was (sd ) years, and the majority were male ( %). of patients, patients died after receiving mechanical ventilation. thus, the overall mortality for patients admitted to icus and receiving mechanical ventilation during the study period was %, with a median survival time in the icu of days (iqr - days). because the average duration of mechanical ventilation was days, the analysis was restricted to within days of receiving mechanical ventilation. the mortality rate was . per -person years ( % ci . to . ). the kaplan-meier survival curves for -day icu mortality is shown in figure . at the end of days after receiving the mechanical ventilation, the overall survival rate was % after the fifth day and % after the tenth day of receiving the mechanical ventilation. the main indication of mechanical ventilation among those patients was respiratory failure type i ( patients, . %) followed by a coma ( . %) as summarized in table . although most of the patients had multiple diagnoses for their icu admission, circulatory disease was the second most common primary diagnosis for this ( %), followed by respiratory disease ( . %). a total of ( . %) of the patients were intubated in the icu while . % had already been intubated before . ( . ) values are presented as numbers and percentage (%). * % ci: % confidence interval. sd -standard deviation, icu -intensive care unit, iqr -interquartile range, acpc -assist-control/pressure control, acvc -assist-control/volume control, prvc -pressure-regulated volume control, psv -pressure support ventilation, vc -volume control icu admission. among those who were intubated in the icu, the majority were intubated within the first hours of icu admission. the table indicates that the patients whose mechanical ventilation was initiated due to other causes had a significantly lower risk of death compared to those in a coma or with respiratory failure the ventilator settings and parameters and monitored variables on day one of mechanical ventilation are presented in (table ). in relation to the clinical and morbidity variables, the results of the univariate analysis of factors associated with the mortality of ventilated patients in icus ( table ). among the factors we collected in this study and included in the univariate analysis, the following were found to be associated with the mortality among mechanically ventilated adult patients: being aged - (or . , % ci . - . ); admission to icus with diseases of the circulatory system (or . , % ci . - . ); and admission to icus with certain infectious or parasitic diseases (or . , % ci . - . ). in this analysis, a total of patients were admitted to icus and received mechanical ventilation during the study period. most of the patients were below month ( % of the whole population) and % were boys. a total of ( %) of this study population died after the date of mechanical ventilation with a median survival time of days (iqr - days). the mortality rate was . per -person years ( %, ci . to . ). the kaplan-meier survival curves for -day icu mortality as shown in figure . the curve shows that by the end of one month, % of patients on mechanical ventilation are still alive. the characteristic of the population as demonstrated in table . the main source of the admission of those neonates was labor and delivery by c-section, with the mean gestational week being (sd ) weeks. prematurity with respiratory problems ( %) was the main recorded cause of the initiation of mechanical ventilation, followed by respiratory distress syndrome ( %). the majority of admissions to icus were premature. neonates who received mechanical ventilation within the first month of their life and who were born extremely preterm had a high mortality rate after the initiation of mechanical ventilation. a total of ( %) of the neonates were intubated in icu while only % had already been intubated before their icu admission. variables related to mechanical ventilation parameters on day one of mechanical ventilation are presented in table . for the results of the univariate analysis of factors associated with mortality among this population, table shows that neonates who received mechanical ventilation within the first month of life and who were born extremely preterm had a high mortality rate after the initiation of mechanical ventilation. in addition, those neonates who had respiratory distress syndrome as the cause of initiating the mechanical ventilation had a high rate of mortality; however, the univariate analysis showed no significant association. neonates who had congenital anomalies as the cause of receiving mechanical ventilation were more likely to have a lower survival rate (or , % ci . - . ). discussion. the results of this study showed that the mortality rate of adult patients who required mechanical ventilation was % and that of the pediatric population was %. elderly patients and those with circulatory system disease and infection as admission cause to icu have higher mortality rate after , [ ] [ ] [ ] [ ] these studies provide valuable information on the epidemiology of mechanical ventilation and address the outcome of patients receiving mechanical ventilation. , the finding of this study pertaining to the mortality rate among the adult population is consistent with the findings from earlier studies. previous studies carried out in developed countries have shown an overall mortality rate of - % among their population, while this reaches % in countries with a low-resource setting. , a prospective cohort study including , patients estimated that the all-cause mortality was % in patients who received mechanical ventilation because of ards, while this was % in patients with copd. the authors of that study estimated % as the mortality of patients receiving mechanical ventilation, while in our study we report % as the overall mortality. on the other hand, multicenter international studies have reported that short-term mortality has decreased among mechanically ventilated patients over time. however, the finding in this study concerning mortality in adult patients was higher than in another study that examined the trend of using mechanical ventilation over years, from to , during which the mortality rate declined by %. thus, in the published research, many studies have reported that age is an independent factor associated with mortality. those studies have shown an effect of age on the mortality of patients who received mechanical ventilation, whereby they reported that age has an independent effect on the outcomes of those patients. our data showed a higher percentage of patients who died after the initiation of mechanical ventilation in the age categories - , - , and more than years old. also, the results of this study showed that the percentage of patients who were overweight was higher compared to the percentage of patients who died after the initiation of mechanical ventilation in the same category. this finding supports the concept of the obesity paradox, whereby many studies have indicated that obesity and morbid obesity are associated with a lower mortality rate in patients with ards. however, this was not significant in the univariate analysis in addition, we were able to examine mortality among the pediatric population. therefore, extreme prematurity was associated with a low survival rate, which is consistent with previous studies that examined the outcome of prematurity. , as reported in many studies, , we found that a higher percentage of patients who received mechanical ventilation were male; however, they were similar to females in terms of additionally, in the current study the majority of the pediatric population was within one month of age, thus this population is different from classic pediatric patients and this finding limits our generalizability of the results to the wider pediatric population. the published prospective studies examining the mortality of mechanically ventilated patients described the mortality and evaluated the effect of many comorbidity variables that potentially related to mortality. they found that the survival of icu patients depends on factors that develop during the course of the ventilation in addition to those factors that cause the initiation of mechanical ventilation. although this point is considered a limitation in the current study, as we did not collect such information, the main aim of this study was to estimate the survival of a heterogeneous group of patients who were admitted to the icu and required mechanical ventilation at one center in saudi arabia. thus at a national level, many studies have been carried out that estimated mortality as one of many outcomes of patients admitted to icus. thus, a limited number of studies has addressed this issue among patients with certain conditions such as malignancy or acute renal failure. , an important consideration in our study was the outbreak of the middle east respiratory syndrome coronavirus (mers-cov) infection that occurred during the study period. thus, mers-cov infection requiring admission to icus was associated with high the strengths of this study were, first, that the data were extracted from electronic records rather than handwritten to minimize errors in measurement; and second, that it addresses the mortality rate among both adult and pediatric ventilated patients without specifying conditions. both kamc and kacsh assign icd- diagnosis codes for icu admission diagnosis, whereby we adopt the same categories in the classification of the reason for icu admission. although this may be complex, re-grouping the principal diagnoses of icu admission into mutually exclusive categories would impose further challenges as we may under-or overestimate the association of specific categories with others. on the other hand, one of the limitations of the study is related to the information concerning the severity of the patients: the apache ii score, chronic use of corticosteroids, failure previous to mechanical ventilation, and other conditions occurring during mechanical ventilation were not studied. this study was observational in nature and the effect of many factors as well as unmeasured confounders cannot be fully controlled. however, we acknowledge that the presence of such information would be useful to give the full picture of our study population. thus, based on previous studies, the severity of the disease and co-existing comorbidity are predictor factors associated with higher mortality among icu patients. the small sample size in this study is considered one of the limitations of our analysis. nevertheless, our purpose was to assess the overall mortality among mechanically ventilated patients who were admitted to the icu in one center. a further retrospective multicenter study with appropriate statistical power and study design to include further confounders is essential to provide more realistic survival data on icu patients in saudi arabia. in conclusion, both patient age and the causes of the initiation of mechanical ventilation were influencing the survival of patients who required mechanical ventilation. future studies should be planned to address the associated risk factor through integrating appropriate statistical approaches that encounter severity of the disease and co-existing comorbidity are predictor factors with mortality among icu patients. for the meanwhile, efforts should be carefully planned when mechanical ventilation is needed among icu patients. increasing critical care admissions from u.s. emergency departments icu occupancy and mechanical ventilator use in the united states critical care service in saudi arabia long-term outcome in medical patients aged or over following admission to an intensive care unit outcome of older patients requiring ventilatory support in intensive care: impact of nutritional status long-term treated intensive care patients outcomes: the one-year mortality rate, quality of life, health care use and long-term complications as reported by general practitioners survival analysis of elderly patients in intensive care units characteristics and outcomes in adult patients receiving mechanical ventilation: a -day international study evolution of mortality over time in patients receiving mechanical ventilation characteristics and outcomes of ventilated patients according to time to liberation from mechanical ventilation outcome of patients with severe asthma in the intensive care unit mortality rate of icu patients with the middle east respiratory syndrome -coronavirus infection at king fahad hospital, jeddah, saudi arabia characteristics and predictors of mortality of patients with hematologic malignancies requiring invasive mechanical ventilation profile, outcome and predictors of mortality of abdomino-pelvic trauma patients in a tertiary intensive care unit in saudi arabia ministry of national guard health affairs. king abdullah specialist children's hospital survival in patients receiving prolonged ventilation: factors that influence outcome survival following mechanical ventilation for acute respiratory failure in adult men hospital survival rates of patients with acute respiratory failure in modern respiratory intensive care units. an international, multicenter, prospective survey prevalence, etiologies and outcome of the acute respiratory distress syndrome among hypoxemic ventilated patients. srlf collaborative group on mechanical ventilation. société de réanimation de langue française characteristics, outcome of patients on invasive mechanical ventilation: a single center experience from central india obesity and survival in critically ill patients with acute respiratory distress syndrome: a paradox within the paradox outcomes for extremely premature infants respiratory severity score on day of life is predictive of mortality and the length of mechanical ventilation in premature infants with protracted ventilation outcome of acute kidney injury in pediatric patients admitted to the intensive care unit key: cord- -xu pb ul authors: guillamet, c. v.; guillamet, r. v.; kramer, a. a.; maurer, p. m.; menke, g. a.; hill, c. l.; knaus, w. a. title: toward a covid- score-risk assessments and registry date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: xu pb ul abstract importance critical care resources like ventilators, used to manage the current covid- pandemic, are potentially inadequate. established triage standards and guidelines may not contain the most appropriate severity assessment and outcome prediction models. objectives develop a draft pandemic specific triage assessment score for the current covid- pandemic. design a website where initial toward a covid- scores (tacs) can be quickly calculated and used to compare various treatment strategies. create a tacs registry where data and outcomes for suspected and confirmed covid- patients can be recorded. use the tacs registry to develop an influenza epidemic specific database and score for use in future respiratory based epidemics. design, setting, participants retrospective analysis of , icu admissions with respiratory failure admitted to u.s. intensive care units from - . independent external validation on , similar icu admissions using identical entry criteria from barnes jewish hospital (bjh), washington university from - . main outcomes tacs was created with readily available predictive variables for risk assessment of hospital mortality hours after icu admission and the need for prolonged assisted mechanical ventilation (pamv) ( >> hours) at - and -hours post icu admission. results tacs achieved an area under the curve (auc) for hospital mortality after hours of . in the development dataset; . in the internal validation dataset. at a probability of % hospital mortality, positive predictive value (ppv) was . , negative predictive value (npv) . ; sensitivity %, specificity %. for pamv after hours, the auc was . in the development dataset, . in the validation dataset. for pamv after hours, the auc was . in the development dataset, . in the validation dataset. in the external validation the auc for tacs was . +/- . . we launched a website that is scaled for mobile device use ( https://covid score.azurewebsites.net/) that provides open access to a user-friendly tacs calculator for all predictions. we also designed a voluntary tacs registry for collection of data and outcomes on icu admissions with covid- . conclusions and relevance toward a covid- score is a starting point for an epidemic specific triage assessment that could be used to evaluate various approaches to treatment. the tacs registry provides the ability to establish a respiratory specific outcomes database that can be used to create a triage approach for future such pandemics. critical care resources like ventilators, used to manage the covid- pandemic, are reported inadequate worldwide . in the us established triage standards, such as ventilator allocation guidelines developed by new york state , by johns hopkins , and pennsylvania , have been recently endorsed .these represent substantial efforts to design an ethical allocation system for a range of disaster scenarios. one component of these may not be optimal in the current pandemic: sole reliance on the sequential organ failure assessment (sofa) score for severity measurement . sofa was developed primarily for use in hospitalized sepsis. it has one respiratory measurement: the pao /fio ratio. the other five measures document deterioration in other organ systems. published data consistently report many covid- patients did not develop multi organ failure during the intensive care unit stay [ ] [ ] [ ] . us and european colleagues treating covid- patients confirm that many deaths are from primary respiratory, not multiple system, failure . sofa scores for triage in a covid- pandemic may then not discriminate who would benefit from intubation and only be useful late in a patient's course, after they have received multiple days or weeks of mechanical ventilation. more so, since covid- patients will presumably have lower sofa score at the time of intubation compared to septic patients they will be allocated a ventilator even though current articles report a significantly higher mortality , . our objective was to begin a process whereby a primarily respiratory based severity assessment measure that also incorporated other known patient characteristics associated with . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint this covid- epidemic and patient outcomes could be established. more importantly, we sought to establish a covid- registry so a database that could be used to develop a new score for future pandemics. we designed and validated an initial tacs based on , adult patients with a clinical diagnosis of respiratory distress admitted to icus in the us from - . we performed an additional external validation of the tacs in , icu admissions to barnes jewish hospital (bjh), washington university from - . the statistical models were initially developed and internally validated on admissions from / / through / / in medical decision network's , charlottesville, va. (mdn) phoenix icu database. phoenix provides data critical to research efforts such as the development of tacs as well as providing insight and understanding to clinicians and administrators making front line decisions that impact patient care. the dataset provided by mdn for the development of tacs consists of , de-identified admissions admitted to adult icus. to qualify, an icu had to send electronically captured vital signs to mdn. these icus were situated in the southeast, northeast, mid-atlantic and pacific west regions. patients had to be years and above and have one of the following admitting diagnoses: asthma, copd, pneumonia (bacterial, viral, or parasitic), pulmonary edema, respiratory arrest, restrictive lung disease (fibrosis, sarcoidosis), sleep apnea, or hemorrhage/hemoptysis. variables considered as predictors were organized as demographics, comorbidities and , pulmonary physiology parameters. vital signs and labs were formatted dependent on methodology taken from the acute physiology, age, and chronic health evaluation (apache) system [ ] [ ] [ ] . the vital signs data were aggregated into minimum and maximum value within the first hours after admission (e.g. max_hr ) and within and hours (e.g. max_temp ). the same was carried out for albumin and ph. based on clinical knowledge the following vitals and labs were entered into the multivariable models: maximum heart rate maximum respiratory rate minimum mean arterial pressure maximum temperature minimum albumin minimum ph missing values for albumin were imputed as the median value of . , while missing ph values were imputed with the median value of . . none of the min/max vital signs had missing values. along with vital signs and the two lab values, a patient's age, gender = female, square root of the length of time between hospital admission and icu admission, (this was done to reduce the . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint effect of extreme ( long stay) patients), .minimum pao :fio ratio during the first hours after admission, maximum glasgow coma score during the first hours after admission, the presence or absence of the following comorbidities: copd, congestive heart failure, chronic alcoholism, body mass index > , and chronic tobacco use. when arterial blood gases where not available, pao /fio ratio was imputed by the apache methodology, = /. . . another variable combined seven comorbidities indicative of immunosuppression was derived by a patient having one or more of the following comorbidities based on the apache methodology: aids, cirrhosis, leukemia, lymphoma, metastatic cancer, hepatic failure, and diabetes. finally, interaction terms were created for age with copd, congestive heart failure, body mass index, and male gender. all of these variables were chosen based on clinical expertise, the emerging literature describing covid- cases, and descriptions provided by front-line practitioners and no addition or removal of variables was performed based on statistical significance. to account for the effects of when a patient was placed on mechanical ventilation, a variable called "initmv" was computed as the duration between icu admission and hospital admission. if greater than . days, this value was set equal to zero for the -hour model (see below); for the -hour models (see below) initmv was truncated at . days. the mdn data set was divided randomly : into development and validation data sets. a logistic regression procedure was carried on the development data set. variables remained in the model regardless of statistical significance, as they were deemed clinically important. model accuracy was determined by the area under the receiver operating characteristic curve and the ratio of observed to predicted outcomes. the coefficients from the development data set model were then fed into the validation data set, and the same statistics on this group of patients were obtained. finally, a cut-point probability of . was used to calculate the positive predictive value, negative predictive value, sensitivity and specificity of the model. there were three outcomes for which the above procedures were carried out: hospital mortality given labs and vital signs at hours, pamv given labs and vital signs at hours, and pamv given labs and vital signs at hours. for the outcome mortality at hours, only a patient's first icu admission was included (to avoid counting one patient twice). when developing the models with pamv as the outcome, all icu admissions were included, except patients not in the icu after and hours respectively were excluded. for external validation, the h tacs mortality model was replicated in the barnes jewish hospital dataset. the patients were selected with the same entry criteria as our developmental and validation datasets (see statistical appendix). university -bjh datasets, respectively. all values given are the mean or percentage, depending on the variable's distribution. the mdn data set had patients who were older, had less immunocompromised comorbidities, longer previous length of stay, icu length of stay, and a higher percentage of patients with prolonged acute mechanical ventilation ("pamv"; duration on ventilation > hours) ( ) . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . table displays the performance for predicting hospital mortality within the first hours of icu admission and prolonged ventilation within the first and hours. tacs achieved an area under the curve (auc) for predicting hospital mortality after hours of icu treatment of . in the development dataset; . in the internal validation dataset. at a probability of % for hospital mortality, the positive predictive value (ppv) is . , negative predictive value (npv) . ; sensitivity %, specificity %. we also performed an external validation of the tacs -hour mortality model on , icu patients to washington university/bjh treated between - . mortality prediction at hours the tacs auc was . +/- . . we have developed an initial model of a respiratory oriented toward a covid score designed to be useful in possible triage decisions and to compare outcomes from various treatment approaches in the current pandemic. it was designed specifically with this pandemic in mind. we used the early reports from china and discussions with front line practitioners treating covid- patients as the basis for selecting predictor variables. while it focuses on respiratory physiology parameters, it also has seven possible choices for immunosuppression among other pre-existing conditions, as these are well-documented and very important risk factors. the final model is broad enough to include all possible current and future covid trajectories but also narrow enough to focus on death from respiratory causes such as adult respiratory distress syndrome (ards). while previous attempts at developing an ards mortality prediction models were inferior to more general multi organ failure scores such as apache, those models combined a very heterogenous ards population the model relied on age, bilirubin, hematocrit and net volume balance over hrs. pneumonia severity prediction tools including respiratory parameters have maintained their predictive performance (curb- , psi). since current reports describe covid- pneumonia as predominantly a single organ failure we decide to focus on respiratory parameters. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint a precursory study by luo et al described that direct ards had fewer organ failures and different mortality predictors than indirect ards (e.g. non-pneumonia sepsis) despite similar mortality rates. the lung injury scores correlated with mortality in direct ards but not in indirect ards . in our study we also focused on lung physiology parameters along with variables that have been described in covid reports. in rationing situations, the main use for a risk stratification score would be to discriminate survivors and non-survivors among the critically ill so patients more likely to survive will be allocated a ventilator. a secondary use would be serial measurements to assess the trajectory of intubated patients and predict patients who will require prolonged mechanical ventilation. a third use would be to compare outcomes from various treatment strategies. we initially focused on these objectives. while earlier reports from china showed that higher sofa scores were associated with higher mortality, all hospitalized patients were included . more than half of the patients were admitted to the general wards therefore comparing non-critically ill and critically ill patients. this comparison will not be relevant in crisis situations when the selection criteria will be applied solely to critically ill patients. this is why in our model, we included patients who had an icu stay. other studies have used sofa in critically ill patients but with very small samples sizes, only outcomes thus questioning the validity of the analysis . when analyzing critically ill patients, yang et al found the initial hr sofa score was in survivors compared to in non-survivors . the traditional cutoff for sofa is < which correlates with a mortality of % . the findings by yang et al reinforce the concept that early sofa will not discriminate between survivors and non-survivors as most patients present to the icu in single organ failure. in the study by yang et al, the in-hospital mortality was . % although the sofa score in non-survivors predicted a mortality below %. the final tacs hour mortality model displayed good discrimination within the independent external washington university dataset. we anticipate, however, that when the model is applied to a covid- icu cohort, the observed hospital death rates will be much higher than the % - % found in our derivation, validation, and external datasets . under these circumstances, the model's ppv at higher probabilities will be strengthened. in a pandemic, patients with the highest likelihood of survival should have priority access to therapy. it is our expectation that tacs should be able to identify early the patients more likely to benefit from life support when resources are limited. the major limitation of tacs is that it has not been applied to patients with a confirmed covid diagnosis. this is a major question. but, waiting for a substantial database of covid- cases with confirmed outcomes in this country, meant there will have been many deaths and many decisions made with only a potentially adequate severity/outcome estimate, sofa, as part of the decision making. we have therefore chosen to release it now with the intent of being able to acquire new covid cases as quickly as possible and improving upon this base. we will commit to providing new data on tacs's performance with covid- patients as soon as possible. we also acknowledge that we will need to create outcome predictions for later in . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint the icu stay. these will be a major focus of the tacs registry along with development of a database in order to create a new revised score for use in the next such pandemic. we have launched a website with mobile access ( https://covid score.azurewebsites.net/) that give open access to a user-friendly tacs calculator for all predictions. because tacs was developed on non-covid cases, we believe it can be applied to other causes of respiratory failure as appropriate. a voluntary registry option reporting subsequent patient outcomes will enable us to further validate and make improvements in the score and our understanding of covid- . the tacs registry requests registration and the recording of patient outcomes ( hospital mortality, hospital los, and duration of mechanical ventilation). it also enables data to be recorded over the course of the hospital stay. collection of a pandemic specific database will allow use to create a new respiratory based resource for use in future such pandemics. the toward a covid- score is designed to be used within an overall rationing approach when critical care resources are scarce ( ) ( ) ( ) ( ) . it provides an earlier and conceptually superior prediction of outcomes compared to sofa. it also can be used to compare outcomes from various approaches to treatment of covid- icu admissions. finally, we have established a covid- registry to collect and store data and outcomes on patients treated during this pandemic. tacs registry data will hopefully be available to develop a new score for use in the next such pandemic ( ). . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . an smr > . indicates more outcomes ( mortalities or prolonged ventilations ) than expected based on patient characteristics. an smr < . indicates fewer observed outcomes then estimated. p-value is the probability under the chi-square distribution that the test statistic Σ(observed ( , ) -predicted)^ / Σ(observed ( , ) * predicted ) exceeds . . au-roc = area under the receiver operating characteristics curve. auc ranges in value from to . a model whose predictions are % wrong has an auc of . ; one whose predictions are % correct has an auc of . . a value of . means a prediction equal to a coin flip or chance. positive predictive value is probability that subjects with a positive prediction truly have the outcome ( hospital mortality and/or prolonged ventilation). negative predictive value is the probability that subjects with a negative prediction truly don't have the outcome (hospital mortality and/or prolonged ventilation). . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . observed vs. predicted prolonged ventilation at hr. observed predicted . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . facing covid- in italy -ethics, logistics, and therapeutics on the epidemic's front line new york state department health. ventilator allocation guidelines too many patients…a framework to guide statewide allocation of scarce mechanical ventilation during disasters a framework for rationing ventilators and critical care beds during the covid- pandemic the toughest triage -allocating ventilators in a pandemic prognostic accuracy of the sofa score, sirs criteria, and qsofa score for in-hospital mortality among adults with suspected infection admitted to the intensive care unit risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease association of cardiac injury with mortality in hospitalized patients with covid- in wuhan, china. jama cardiol covid- in critically ill patients in the seattle region -case series john e. arbo, md, associate director of the albert einstein contacted / / . douglas b. white md, vice chair and professor of critical care medicine characteristics and outcomes of critically ill patients with covid- in washington state apache ii: a severity of disease classification system the apache iii prognostic system. risk prediction of hospital mortality for critically ill hospitalized adults acute physiology and chronic health evaluation (apache) iv: hospital mortality assessment for today's critically ill patients the meaning and use of the area under a receiver operating characteristic (roc) curve short-term mortality prediction for acute lung injury patients: external validation of the ardsnet prediction model clinical predictors of hospital mortality differ between direct and indirect ards clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study. the lancet clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study. the lancet respiratory medicine use of the sofa score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. working group on "sepsis-related problems" of the european society of intensive care medicine key: cord- - dfgfz authors: drożdżal, sylwester; rosik, jakub; lechowicz, kacper; machaj, filip; szostak, bartosz; majewski, paweł; rotter, iwona; kotfis, katarzyna title: covid- : pain management in patients with sars-cov- infection—molecular mechanisms, challenges, and perspectives date: - - journal: brain sci doi: . /brainsci sha: doc_id: cord_uid: dfgfz since the end of , the whole world has been struggling with the pandemic of the new severe acute respiratory syndrome coronavirus (sars-cov- ). available evidence suggests that pain is a common symptom during coronavirus disease (covid- ). according to the world health organization, many patients suffer from muscle pain (myalgia) and/or joint pain (arthralgia), sore throat and headache. the exact mechanisms of headache and myalgia during viral infection are still unknown. moreover, many patients with respiratory failure get admitted to the intensive care unit (icu) for ventilatory support. pain in icu patients can be associated with viral disease itself (myalgia, arthralgia, peripheral neuropathies), may be caused by continuous pain and discomfort associated with icu treatment, intermittent procedural pain and chronic pain present before admission to the icu. undertreatment of pain, especially when sedation and neuromuscular blocking agents are used, prone positioning during mechanical ventilation or extracorporeal membrane oxygenation (ecmo) may trigger delirium and cause peripheral neuropathies. this narrative review summarizes current knowledge regarding challenges associated with pain assessment and management in covid- patients. a structured prospective evaluation should be undertaken to analyze the probability, severity, sources and adequate treatment of pain in patients with covid- infection. since the end of , the whole world has been struggling with the epidemic of the new severe acute respiratory syndrome coronavirus (sars-cov- ), which was first detected in the chinese province of hubei. not long after its outbreak, the coronavirus disease (covid- ) was declared an epidemic by the world health organization (who) and has become a global health threat [ ] . the novel virus is classified as a member of the coronaviridae family, single-stranded rna viruses [ , ] . in recent history, there have been recorded human infections with other viruses from this family: severe in covid- , more than one-third of patients experience different neurological symptoms, which may involve the central nervous system (dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, and epilepsy), the peripheral nervous system (taste impairment, smell impairment, vision impairment, and neuralgia) and skeletal muscular damage [ , ] . mao et al. reported peripheral nervous system (pns) effects in their study presenting in the form of dysgeusia ( . %), dysosmia ( . %), visual disturbances ( . %), and neuralgia ( . %) [ ] . abdelnour et al. reported a case of peripheral neuropathy manifesting before the onset of the typical flu-like symptoms of the novel covid- infection [ ] . in this case, the patient had no flu-like symptoms until day seven of symptom onset had distal lower limb weakness and hyporeflexia without back pain or sensory level, suggestive of peripheral neuropathy [ ] . sheraton et al. hypothesized that cns symptoms may occur due to the inflammatory mechanisms and pns due to immune-mediated processes [ ] , but more research is needed to explain sars-cov- related neuropathy [ ] . meanwhile, the number of reports on patients suffering from covid- with neurological symptoms is growing and the role of the sars-cov- role in the neuropathogenic invasion remains unclear and needs further studies [ , ] . helms et al. showed that patients with covid- had neurological symptoms such as perfusion abnormalities, confusion, agitation and ischemic stroke. there is no data to determine whether the occurrence of these disorders is a characteristic or coincidence [ ] . su et al. suggest that central pain could be induced through the ace -positive cells in the human spinal dorsal horn via the decrease of functional ace (angiotensin-converting enzyme ), which then results in the accumulation of ang. ii (angiotensin ii) and the decrease of ang. ( - ) (angiotensin - ) [ ] . the pain induced by covid- infection could result from the effect of spinal ace on pain sensation and the direct or indirect tissue damage, but the ace role in the transmission and management of pain in infected patients needs further investigation [ ] . one of the most common causes of pain in covid- infection is the associated muscle pain. multiple studies have shown that myalgia is one of the most common symptoms at onset, seen in nearly % of patients [ ] . myalgia during viral infection is most commonly mediated by interleukin- (il- ), whose upregulation causes muscle and joint pain [ ] . it is believed that myalgia in covid- patients might reflect the generalized inflammation and cytokine response [ ] . as sars-cov- induces a strong inflammatory response, elevated cytokine levels (il- , il- , and tnf α) are present, especially in patients with a moderate or severe disease course [ , ] . inflammasomes are a crucial part of the inflammatory cascade [ , ] . they are engaged in the production of proinflammatory cytokines [ ] . microglia, astroglia and neurons are numbered amongst cells expressing inflammasomes [ ] [ ] [ ] . specific inflammatory ligands (pathogen-associated molecular patterns and damage-associated molecular patterns) participate in the activation of inflammasomes [ , ] . the former ones are particles of pathogens like nucleic acid or lipopolysaccharides, the latter ones are released from distressed cells in the central nervous system. however, the sars-cov- presence in brain inducing inflammasomes is unlikely because the brain sections of patients who died due to covid- did not show any cytoplasmic viral staining or encephalitis [ ] . therefore, pain pathogenesis must involve the inflammatory reaction [ ] . microglial cells participating in this process might promote either regeneration or toxic neuroinflammation [ ] , depending on many factors, such as gonadal steroid hormones [ , ] . it might lead to differences between genders in the clinical presentation [ ] . microglia are implicated in the spinal cord [ , ] . unfortunately, the link between analgesics and inflammasomes' role in pain transmission is not well elucidated [ ] . the exact mechanisms of headache and myalgia during viral infection are still uncertain [ , ] . figure presents the most likely pathomechanism of those common viral infection symptoms. during the covid- pandemic, patients with neurologic manifestations and suffering from different types of pain cannot be ignored. the neurologic manifestation of the sars-cov- infection seems to be underestimated and they should be taken into account with significant care to set appropriate diagnosis and prevention of the transmission of the infection. especially for patients with covid- neurological symptoms, these manifestations may contribute to the severity of the infection and lead to rapid deterioration and death [ ] . significant neurological system involvement is an additional reason to undertake further research and studies regarding the diagnostics, mechanisms, and therapeutic options in covid- [ ] . putative mechanisms of myalgia and headache during viral infection. the specific mechanism of headache during infection remains unclear. the assumed pathomechanisms involve the overexpression of proinflammatory cytokines, such as tnf-α and pge , in the cerebrospinal fluid (csf), which sensitize and stimulate trigeminal ganglia (tg) neurons to produce calcitonin generelated peptide (cgrp). cgrp has a crucial role in the pathogenesis of migraine, influencing arteries' dilatation and possibly to direct a nociceptive transmission. the myalgia during viral infection is believed to be the effect of proinflammatory cytokines influence on muscle tissue. tnf-α is responsible for the intensified breakdown of muscle proteins and pge could increase the nociceptive signaling. many patients with sars-cov- infection will suffer from severe pain and require reliable pain assessment to provide adequate analgesia, often with multiple drugs, including opioids, non- putative mechanisms of myalgia and headache during viral infection. the specific mechanism of headache during infection remains unclear. the assumed pathomechanisms involve the overexpression of proinflammatory cytokines, such as tnf-α and pge , in the cerebrospinal fluid (csf), which sensitize and stimulate trigeminal ganglia (tg) neurons to produce calcitonin gene-related peptide (cgrp). cgrp has a crucial role in the pathogenesis of migraine, influencing arteries' dilatation and possibly to direct a nociceptive transmission. the myalgia during viral infection is believed to be the effect of proinflammatory cytokines influence on muscle tissue. tnf-α is responsible for the intensified breakdown of muscle proteins and pge could increase the nociceptive signaling. many patients with sars-cov- infection will suffer from severe pain and require reliable pain assessment to provide adequate analgesia, often with multiple drugs, including opioids, non-steroidal inflammatory drugs or analgosedation [ ] . the golden standard for the assessment of pain are tools based on patient self-assessment, e.g., visual analogue scale (vas) or numerical assessment scale (nrs), which assume patient-physician cooperation [ ] . assessing the intensity of pain in intubated, non-verbal patients with respiratory failure who are admitted to the intensive care unit (icu), mechanically ventilated and sedated, remains a constant challenge for icu clinicians [ ] [ ] [ ] [ ] . pain in icu patients can be divided into four categories: acute pain associated with the disease, continuous pain/discomfort associated with icu treatment, intermittent procedural pain and chronic pain present before admission to the icu [ ] . daily care and medical interventions in the icu can also be a potential source of pain, so it is very important to use simple tools to monitor it. undertreatment of pain, especially when using neuromuscular blocking agents, prone positioning or extracorporeal membrane oxygenation (ecmo) may trigger delirium [ , ] and cause persistent neuropathies [ ] . therefore, it is recommended that, in patients who are unable to self-report pain, behavioral pain assessment scales should be used, namely the behavioral pain scale (bps) and the critical care pain observation tool (cpot) [ , ] . the cpot scale was designed for the critical detection of pain in sick patients and includes four behavioral categories-facial expressions, body movements, muscle tone, susceptibility with a fan (for intubated patients) or verbalization (for extubated patients). each category is scored on a - scale ( - points in total) [ , ] . bps was developed by payen et al. to assess pain in mechanically ventilated unconscious patients. the scale is based on three types (ranges) of behavior: facial expressions, upper limb movements and ventilation compatibility [ , ] . all these elements of pain assessment in a patient admitted to the icu, including patients infected with covid- , can be helpful in selecting appropriate treatment. there are currently no clinical trials or specific guidelines regarding the topic of pain management in covid- patients [ , ] ; therefore, the aim of this narrative review is to discuss the problems associated with pain treatment during the covid- pandemic. optimal pain management may be extremely challenging in mechanically ventilated covid- patients who are often deeply sedated and receive neuromuscular blocking medications. both the nursing and physiotherapy teams may be spending less time at the patients' side making pain management suboptimal and extended periods of high-dose intravenous opioid infusions may be inevitable [ ] . nonsteroidal anti-inflammatory drugs (nsaids) are one of the most widely used drugs worldwide. the popularity of nsaids is the result of their easy accessibility and efficacy as anti-inflammatory and analgesic agents. they can be divided based on their chemical structure or ability to selectively inhibit cyclooxygenase isoenzymes [ ] . the chemical classification of nsaids is presented in figure . nsaids influence the arachidonic acid cascade and prostaglandins biosynthesis through the inhibition of cyclooxygenase (cox) [ ]- figure . the cox enzyme was firstly described in , and later the existence of at least two isoforms of the enzyme (cox- and cox- ) was established [ ] . the constitutive expression in various tissues is characteristic for the cox- isoenzyme. its activity is responsible for maintaining homeostasis, but particularly for gastrointestinal mucosal cytoprotection, the regulation of renal blood flow, platelet aggregation, and endothelial functioning. cox- expression is highly restricted in a physiological state; however, it is constitutively active in the brain, spinal cord, kidneys, testes, and bronchial epithelium. not only inflammatory mediators, but also hormones secreted by the ovaries, uterus, and fetal membranes can greatly induce cox- expression. . initial stage of the cascade is mediated by phospholipase a , whose activity leads to the release of arachidonic acid from membrane phospholipids. arachidonic acid can be further transformed by cyclooxygenase (cox) into prostanoids (prostaglandins, prostacyclins and thromboxane) or by lipoxygenase (lox) into leukotrienes. the cox enzyme was firstly described in , and later the existence of at least two isoforms of the enzyme (cox- and cox- ) was established [ ] . the constitutive expression in various tissues is characteristic for the cox- isoenzyme. its activity is responsible for maintaining homeostasis, but particularly for gastrointestinal mucosal cytoprotection, the regulation of renal blood flow, platelet aggregation, and endothelial functioning. cox- expression is highly restricted in a physiological state; however, it is constitutively active in the brain, spinal cord, kidneys, testes, and bronchial the cox enzyme was firstly described in , and later the existence of at least two isoforms of the enzyme (cox- and cox- ) was established [ ] . the constitutive expression in various tissues is characteristic for the cox- isoenzyme. its activity is responsible for maintaining homeostasis, but particularly for gastrointestinal mucosal cytoprotection, the regulation of renal blood flow, platelet aggregation, and endothelial functioning. cox- expression is highly restricted in a physiological state; however, it is constitutively active in the brain, spinal cord, kidneys, testes, and bronchial furthermore, this isoenzyme influences the menstrual cycle and embryo implantation. the discovery of the cox- isoenzyme further led to the development of its selective inhibitors, as the main activity of this enzyme is linked with inflammation. this approach was established to reduce the renal and gastrointestinal adverse effects associated with the blockade of cox- [ ] . recently, concerns about the possible higher frequency of adverse effects and exacerbation of symptoms of viral respiratory tract infections, such as covid- , in patients treated with nsaids have been raised [ ] . however, according to the who (as of th of april ), there is no evidence for the aforementioned hypothesis [ ] . the who has evaluated studies, conducted on adults and children treated with nsaids for respiratory tract infection. however, in none of the studies was the infection caused by covid- , sars or mers [ ] . the number of infected by sars-cov- is constantly increasing worldwide. the supportive therapy is the main treatment regimen for patients with mild and moderate clinical symptoms of covid- , and the widely available nsaids, such as ibuprofen are commonly used. the controversies regarding the safety of ibuprofen in covid- have emerged after a report to public media was made by a french infectious disease specialist, who observed the decompensation and development of severe symptoms in an early stage of infection in four children after administration of ibuprofen [ ] . the report was firstly confirmed by the french minister of health and the who. however, having reviewed the available data, the who published their recommendations, underlining no evidence of covid- patient decompensation after the usage of nsaids [ ] . nonetheless, the previous study by kotsiou et al. reported that pre-hospital usage of nsaids in the treatment of symptoms of community-acquired pneumonia is connected with the exacerbation of pneumonia, prolonged hospitalization, and more severe pleural effusions [ ] . several studies suggest that this effect should be considered in covid- treatment [ , ] . in conclusion, no study to date has reported higher mortality of covid- patients treated with ibuprofen [ ] . despite this, in doubtful cases, paracetamol or metamizole should be used instead of ibuprofen, especially in over the counter (otc) usage [ ] . there are, however, some cases where the use of paracetamol might not be beneficial, due to its pharmacokinetic properties. as paracetamol is metabolized mainly by two cytochrome p isoenzymes-cyp a and cyp e -cytokine storm associated with viral infection can potentially disrupt the metabolic functioning of cytochrome p [ ] . this disturbance could paradoxically escalate the risk of adverse effects in patients treated with paracetamol. as far as metamizole is concerned, it does not interact with therapeutic agents, commonly used in sars-cov- therapy [ ] . moreover, it affects sars-cov- main protease (mpro), curbing its transcription and replication [ ] . however, the role of metamizole in infection symptoms control is questionable because of its association with agranulocytosis [ ] -the adverse effect that could lead to a sudden worsening of covid- patient condition. overall, both the ema (european medicines agency) and the who do not recommend altering or discontinuing nsaid therapy in patients using them in chronic treatment, with suspected or diagnosed sars-cov- infection. at this stage, there is a lack of evidence suggesting that therapeutic regimens should be changed to other non-opioid analgesics [ ] . it is also worth remembering that nsaids could interfere with the inhibition of platelet cox- by aspirin. the number of patients using acetylsalicylic acidin the anti-platelet dosing range is still increasing and any influence on their therapy could result in an increased risk of cardiovascular events. cardiovascular or cerebrovascular comorbidities of covid- patients preclude the use of nsaids. moreover, heart failure and substantial cardiac damage, which also preclude nsaids administration, lead to around % of deaths amongst covid- patients [ ] [ ] [ ] . although the use of opioids for pain management inside and outside of an icu is inevitable, problems associated with their use must be acknowledged. the lack of clinical trials conducted on patients infected with covs (sars, mers or covid- ) makes it impossible to unambiguously estimate their usefulness during the covid- pandemic. opioids have been proven to reduce dyspnea amongst patients with lung diseases, such as chronic obstructive pulmonary disease (copd), or lung cancer [ ] [ ] [ ] . ekstrom et al. in their meta-analysis found that small doses of opioids are safe and efficacious in reducing shortness of breath [ ] . however, they do not improve exertion capacity in advanced copd. woodcock et al. and light et al. found that oral administration of single-dose morphine significantly decreased tidal volume and respiratory frequency during exercises in isotime and reduced nervous inspiratory drive to the larynx and diaphragm [ , ] . these results are coherent with opioids influence on the chemoreflex that influences the respiratory drive [ ] . opioids have been found to increase both mortality and the risk of adverse clinical events amongst patients with severe pulmonary disease [ , , ] . moreover, morphine and diamorphine are used to reduce respiratory disturbances [ ] . yamamoto et al. verified the effects of oxycodone intravenous administration. it was found to reduce dyspnea in almost % of patients, without causing any significant adverse effects [ ] . fentanyl, in comparison with oxycodone and morphine, significantly reduced brain oxygen supply [ ] . similar to other opioids, its use was associated with not only decreases in respiratory rate, mediated by µ receptor agonism, but also reduced tidal volume [ ] . respiratory depression induced by fentanyl is similar to that induced by oxycodone and subsides much sooner than with morphine or buprenorphine use [ ] . differences in the pharmacodynamic properties of fentanyl lead to a significantly higher risk of overdose than other opioids used in medicine or heroine [ ] . moreover, fentanyl overdose might lead to difficulties in intubation [ , ] . another property of opioids is the induction of immunosuppression. in an animal model, flores et al. found that morphine induces adrenal-dependent lymphopenia and reduces the response to mitogenic stimulation (dose = mg/kg) by nearly % [ , ] . the suppression of immunity after fentanyl administration is dose dependent [ ] . with regards to a decrease in nk cells' activity [ ] [ ] [ ] [ ] and the concentration of proinflammatory cytokines, a change in il- [ ] and il- [ ] are the most notable characteristics [ ] . the immunosuppressing properties of fentanyl over the course of therapy decrease sooner than during morphine treatment [ ] . meanwhile, oxycodone immunosuppressing properties are not totally understood. the results of preclinical studies do not offer a coherent argument regarding its effect on lymphocyte proliferation [ , ] . however, multiple dissertations suggest that oxycodone has a higher safety profile than morphine or fentanyl [ ] [ ] [ ] , ] . the quality of clinical data concerning this topic is poor. hernandez et al. suggest that oxycodone immunosuppressing effect subsides sooner (after around h) than after morphine administration [ ] . wiese et al. have found that the immunosuppressing attributes of opioids influence the frequency of infections [ ] . the relative risk (rr) of oxycodone treatment comparing to morphine was . [ ] . other opioids, tramadol and buprenorphine seem to be a clinically superior choice. neither of them has immunosuppressive properties, so, in theory, they do not prolong viral shedding [ , ] . in addition, buprenorphine is safe in multiorgan failure and has a ceiling effect for respiratory depression [ , ] . corticosteroids were widely used in clinics during the sars-cov outbreak and several positive effects of their use were noted, which is attributed mainly to their ability to modulate the inflammatory response. multiple studies were established in that time and reached conclusions that steroids are efficacious in decreasing the extent of immunopathological damage. however, the side effects indivertibly associated with their long-term use dissuaded physicians from prolonged therapy, fearing the rebound effect of the infection, and consequentially the development of adverse effects, such as acute respiratory distress syndrome. in one of the randomized clinical trials, where viral load was measured in regular time periods in intubated patients with sars-cov, a higher concentration of viral rna was noted during weeks and of infection in those treated with steroids in comparison with placebo [ ] . one of the studies using a mice model identified the n-protein of sars-cov as a factor responsible for triggering the pulmonary inflammatory response and acute lung injury, which was associated with an increase and imbalance of proinflammatory cytokines. dexamethasone was successful in alleviating this response in mice [ ] . similarly, animal studies involving swine infected with cov provided further evidence that one or two doses of corticosteroid during the acute phase of the infection can successfully ameliorate the early inflammatory response; however, their prolonged use might promote replication of the virus [ ] . further observational studies aiming to evaluate the efficacy of agents used in sars reported no survival benefit and possible harms (mainly delayed viral clearance) in patients treated with corticosteroids [ ] . a study involving patients receiving corticosteroids in mers infection, when adjusted for time-varying confounders, found no effect of corticosteroids on mortality. moreover, the treatment delayed lower respiratory tract viral clearance [ ] . based on these findings, the current who guidelines for the management of severe acute respiratory infection with sars-cov- do not recommend routine corticosteroid use [ ] . it is advised to weigh risk against benefit in individual patients, with the use of steroids being justified for the treatment of other concurrent conditions, such as asthma or copd exacerbation, or septic shock. as far as the treatment of sepsis in covid- is concerned, recent guidelines recommend conditional use of steroids for all patients with sepsis and septic shock, on the condition that the potential reduction in mortality outweighs prolonged coronavirus shedding. in those patients, glycemia, natremia, and kalemia must be monitored [ ] . peripheral nervous system involvement, including painful neuropathies, was reported in many patients with sars-cov- and now with sars-cov- infection [ , , , ] . this may be a consequence of either viral invasion of the peripheral nerves (neurotropism) [ ] or prolonged immobility during severe illness [ ] , or both. peripheral neuropathies are prevalent in covid- patients and may require an addition of gabapentinoids to the pain treatment regime [ ] . the gabapentinoids (gabapentin and pregabalin) are commonly used in pain management in adults, but there is a scarcity of research on their effectiveness in children [ ] . gabapentin and pregabalin are calcium channel α -δ ligands commonly used in the treatment neuropathic pain. while the numbers needed to treat (nnt) for % pain relief for these therapeutic agents are similar ( . -gabapentin; . -pregabalin) [ , ] pregabalin acts quicker than gabapentin [ ] . they are usually well tolerated [ ] and characterized by similar adverse effects [ ] [ ] [ ] ] . their potency in the therapy of neuropathy acquired due to sars-cov- is hard to predict due to a lack of dissertations on gabapentinoids in cov infections. currently, there are no clinical trials exploring this topic. however, calcium channel ligands reduce respiratory drive; therefore, combined therapy with opioids might be potentially hazardous and the use of duloxetine in such cases ought to be thoroughly considered [ ] . apart from pandemic control and the prevention of the spread of covid- , medical staff worldwide try to improve patient care, including the quality of pain treatment. there are reports of a significantly higher use of opioids because of sedation requirements during respiratory failure caused by sars-cov- , which highlights the importance of undertaking a study aiming to determine efficacious and safe procedures of pain management in patients with covid- . apart from pain symptoms caused by the virus, including myalgia, arthralgia, sore throat, headache and peripheral neuropathies, problems associated with during icu treatment (procedural pain, prolonged mechanical ventilation, muscle wasting, immobility during prone positioning) may arise. covid- , despite its prevalence, is virtually unknown. for the treatment of pain, each patient requires an individual approach based on available knowledge and, more importantly, the patient's condition and comorbidities. the information provided is a cross-section of the available knowledge aimed at improving the patient's clinical condition. a structured prospective evaluation should be undertaken to analyze the probability, severity, sources and adequate treatment of pain in patients with covid- infection and those suffering due to an unavailability of pain services during the covid- pandemic. the authors declare no conflict of interest. general's opening remarks at the media briefing on {covid}- origin and evolution of pathogenic coronaviruses animal coronaviruses: a brief introduction severe acute respiratory syndrome: historical, epidemiologic, and clinical features middle east respiratory syndrome coronavirus (mers-cov) infection: epidemiology, pathogenesis and clinical characteristics a familial cluster of infection associated with the novel coronavirus indicating potential person-to-person transmission during the incubation period covid- : gastrointestinal symptoms and potential sources of -ncov transmission covid- : gastrointestinal manifestations and potential fecal-oral transmission familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia clinical features of patients infected with novel coronavirus in clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspected; world health organization cardiovigilance in covid the patient with heart failure in the face of the coronavirus disease pandemic: an expert opinion of the heart failure working group of the polish cardiac society covid- in patients with cardiovascular diseases palliative care in the time of covid- who. report of the who-china joint mission on coronavirus disease covid- : icu delirium management during sars-cov- pandemic chronic pain management in covid- era pain and depression: an integrative review of neurobiological and psychological factors managing patients with chronic pain during the covid- outbreak: considerations for the rapid introduction of remotely supported (ehealth) pain management services risk of covid- for patients with cancer. the lancet. oncol. , , e creating a palliative care inpatient response plan for covid- -the uw medicine experience pain management during covid- viral infection covid- immunopathology and the central nervous system: implication for multiple sclerosis and other autoimmune diseases with associated demyelination neurologic manifestations of hospitalized patients with coronavirus disease covid infection presenting as motor peripheral neuropathy a review of neurological complications of covid- . cureus , , e neurological manifestations of covid- and other coronavirus infections: a systematic review neurologic features in severe sars-cov- infection pain: a potential new label of covid- covid- patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis mechanisms involved in il- -induced muscular mechanical hyperalgesia in mice towards an artificial intelligence framework for data-driven prediction of coronavirus clinical severity clinical and immunological features of severe and moderate coronavirus disease sars-cov- : a storm is raging a fatal alliance between microglia, inflammasomes, and central pain the two-hit hypothesis for neuroinflammation: role of exogenous atp in modulating inflammation in the brain the inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proil-beta acute neurodegeneration and the inflammasome: central processor for danger signals and the inflammatory response? nlrp inflammasome in neurological diseases, from functions to therapies complexity of danger: the diverse nature of damage-associated molecular patterns how inflammasomes inform adaptive immunity neuropathological features of covid- identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord sexual differentiation of microglia regulation of brain microglia by female gonadal steroids toll-like receptor mediates peripheral nerve injury-induced nadph oxidase expression in spinal cord microglia elevation of csf tumor necrosis factor α levels in new daily persistent headache and treatment refractory chronic migraine understanding the symptoms of the common cold and influenza sars-cov- infection leads to neurological dysfunction availability of internationally controlled essential medicines in the covid- pandemic methods of pain assessment in adult intensive care unit patients-polish version of the cpot (critical care pain observation tool) and bps (behavioral pain scale) behavioral and physiologic indicators during a nociceptive procedure in conscious and unconscious mechanically ventilated adults: similar or different? validation of the critical-care pain observation tool in adult patients assessing pain in critically ill sedated patients by using a behavioral pain scale covid- : what do we need to know about icu delirium during sars-cov- pandemic? anaesthesiol validation of the polish version of the critical care pain observation tool (cpot) to assess pain intensity in adult, intubated intensive care unit patients: the pol-cpot study validation of the behavioral pain scale to assess pain intensity in adult, intubated postcardiac surgery patients: a cohort observational study-pol-bps rethinking sedation during prolonged mechanical ventilation for covid- respiratory failure sedation of mechanically ventilated covid- patients: challenges and special considerations strategies to optimize icu liberation (a to f) bundle performance in critically ill adults with coronavirus disease ajc editor's consensus: selective and nonselective nonsteroidal anti-inflammatory drugs and cardiovascular risk use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the american heart association the x-ray crystal structure of the membrane protein prostaglandin h synthase- cyclo-oxygenase (cox) inhibitors and cardiovascular risk: are non-steroidal anti-inflammatory drugs really anti-inflammatory? covid- and treatment with nsaids and corticosteroids: should we be limiting their use in the clinical setting? ecancermedicalscience , , world health organization. the use of non-steroidal anti-inflammatory drugs (nsaids) in patients with covid- covid- : european drugs agency to review safety of ibuprofen prehospital nsaids use prolong hospitalization in patients with pleuro-pulmonary infection french society of pharmacology and therapeutics. non-steroidal anti-inflammatory drugs, pharmacology, and covid- infection non-steroidal anti-inflammatory drugs in management of covid- : a systematic review on current evidence bar-haim, a.; youngster, i. ibuprofen use and clinical outcomes in covid- patients sars-cov- /covid- : evidence-based recommendations on diagnosis and therapy regulation of cytochromes p during inflammation and infection metamizole (dipyrone): mode of action, drug-drug interactions, and risk of agranulocytosis molecular docking reveals the potential of aliskiren, dipyridamole, mopidamol, rosuvastatin, rolitetracycline and metamizole to inhibit covid- virus main protease dipyrone and agranulocytosis: what is the risk? lancet caring for patients with pain during the covid- pandemic: consensus recommendations from an international expert panel effects of opioids on breathlessness and exercise capacity in chronic obstructive pulmonary disease: a systematic review the current practice of opioid for cancer dyspnea: the result from the nationwide survey of japanese palliative care physicians opioid utility for dyspnea in chronic obstructive pulmonary disease: a complicated and controversial story effects of dihydrocodeine, alcohol, and caffeine on breathlessness and exercise tolerance in patients with chronic obstructive lung disease and normal blood gases effects of oral morphine on breathlessness and exercise tolerance in patients with chronic obstructive pulmonary disease using laboratory models to test treatment: morphine reduces dyspnea and hypercapnic ventilatory response predictors of opioid-related adverse pulmonary events among older adults with copd incident opioid drug use and adverse respiratory outcomes among older adults with copd effect of continuous intravenous oxycodone infusion in opioid-naïve cancer patients with dyspnea in vivo profiling of seven common opioids for antinociception, constipation and respiratory depression: no two opioids have the same profile mechanisms of morphine-induced immunosuppression: effect of acute morphine administration on lymphocyte trafficking immunosuppression by morphine is mediated by central pathways effects of fentanyl on natural killer cell activity and on resistance to tumor metastasis in rats. dose and timing study effects of anesthesia based on large versus small doses of fentanyl on natural killer cell cytotoxicity in the perioperative period does analgesia and condition influence immunity after surgery? effects of fentanyl, ketamine and clonidine on natural killer activity at different ages comparative effects of flurbiprofen and fentanyl on natural killer cell cytotoxicity, lymphocyte subsets and cytokine concentrations in post-surgical intensive care unit patients: prospective, randomized study relationship between fentanyl dosage and immune function in the postoperative period reasons to avoid fentanyl long-acting opioid use and the risk of serious infections: a retrospective cohort study twelve reasons for considering buprenorphine as a frontline analgesic in the management of pain treating chronic pain: an overview of clinical studies centered on the buprenorphine option the management of coronavirus infections with particular reference to sars a study of pulmonary inflammatory reaction induced by n-protein of sars-cov in rat models and effects of glucocorticoids on it cytokine responses in porcine respiratory coronavirus-infected pigs treated with corticosteroids as a model for severe acute respiratory syndrome systematic review of treatment effects corticosteroid therapy for critically ill patients with middle east respiratory syndrome the spectrum of neurologic disease in the severe acute respiratory syndrome coronavirus pandemic infection: neurologists move to the frontlines the neuroinvasive potential of sars-cov may play a role in the respiratory failure of covid- patients systematic review of the efficacy and safety of gabapentin and pregabalin for pain in children and adolescents pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis treatments for neuropathic pain diabetic neuropathy: a position statement by the american diabetes association neuropathic pain. continuum (minneap. minn) gabapentin, opioids, and the risk of opioid-related death: a population-based nested case-control study this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license key: cord- -phl kh f authors: anthi, anastasia; konstantonis, dimitrios; theodorakopoulou, maria; apostolopoulou, olympia; karampela, irene; konstantopoulou, georgia; patsilinakou, stavroula; armaganidis, apostolos; dimopoulos, george title: a severe covid- case complicated by right atrium thrombus date: - - journal: am j case rep doi: . /ajcr. sha: doc_id: cord_uid: phl kh f patient: male, -year-old final diagnosis: severe covid- pneumonia complicated by right atrium thrombus symptoms: fever • dyspnea • cough medication:— clinical procedure: — specialty: critical care medicine objective: educational purpose background: recent studies demonstrated evidence of coagulation dysfunction in hospitalized patients with severe coronavirus disease (covid- ) due to excessive inflammation, hypoxia, platelet activation, endothelial dysfunction, and stasis. effective anticoagulation therapy may play a dominant role in the management of severe covid- cases. case report: a -year-old man with a -day history of fever up to . °c, dyspnea, cough, and fatigue was diagnosed with covid- . he had a past medical history significant for hypertension and coronary artery bypass grafting. two days after hospital admission, the patient developed acute respiratory failure, requiring intubation, mechanical ventilation, and transfer to the intensive care unit (icu). he received treatment including antibiotics, hydroxychloroquine, tocilizumab, vasopressors, prone positioning, and anticoagulation with enoxaparin at a prophylactic dose. after a -day icu stay, the patient was hemodynamically stable but still hypoxemic; a transthoracic echocardiogram at that time, followed by a transesophageal echocardiogram for better evaluation, revealed the presence of a right atrium thrombus without signs of acute right ventricular dilatation and impaired systolic function. since the patient was hemodynamically stable, we decided to treat him with conventional anticoagulation under close monitoring for signs of hemodynamic deterioration; thus, the prophylactic dose of enoxaparin was replaced by therapeutic dosing, which was a key component of the patient’s successful outcome. over the next few days he showed significant clinical improvement. the follow-up transesophageal echo-cardiogram weeks after effective therapeutic anticoagulation revealed no signs of right heart thrombus. conclusions: the presented covid- case, one of the first reported cases with evidence of right heart thrombus by transesophageal echocardiography, highlights the central role of diagnostic imaging strategies and the importance of adequate anticoagulation therapy in the management of severe covid- cases in the icu. the coronavirus disease of (covid- ) is a viral illness caused by the severe acute respiratory syndrome coronavirus (sars-cov ). the world health organization has recently declared covid- a public health emergency of international concern. patients with older age and comorbidities such as cardiovascular disease are at higher risk for severe disease. common laboratory abnormalities found in patients with covid- include lymphopenia and elevation in lactate dehydrogenase (ldh) and inflammatory markers such as c-reactive protein (crp), d-dimers, ferritin, and interleukin- (il- ). older age, higher sequential organ failure assessment (sofa) score, and elevated d-dimers at hospital admission are risk factors for death [ ] [ ] [ ] [ ] . data analysis of the clinical characteristics of chinese patients with confirmed covid- showed that % of patients required intensive care unit (icu) admission, . % underwent invasive mechanical ventilation and . % died [ ] . covid- may predispose patients to thrombotic disease in both venous and arterial circulations because of excessive inflammation, hypoxia, platelet activation, endothelial dysfunction, and stasis [ , [ ] [ ] [ ] . recent studies underline the importance of venous thromboembolic events in severe covid- patients. the reported incidence of thrombotic complications in patients with covid- requiring icu admission is high, ranging from . % to %. [ ] [ ] [ ] [ ] [ ] . it is notable that at least half of thromboembolic events were diagnosed within the first h of admission, and thus were not preventable by the initial in-hospital thromboprophylactic anticoagulation [ , ] . in addition, the low number of associated deep venous thromboses in covid- patients may suggest the presence of pulmonary thrombosis rather than embolism [ , ] . we report our experience to highlight the crucial role of efficient anticoagulation therapy in the management of severe covid- cases requiring icu admission; the importance of diagnostic imaging strategies, including transesophageal echocardiography, is also emphasized. a -year-old man presented to the emergency room after days of fever up to . °c, dyspnea, cough with some yellowish sputum, and fatigue. the physical examination showed respiratory rate /min, arterial oxygen saturation % on l of supplemental oxygen, blood pressure / mmhg, heart rate /min, and chest auscultation revealed bilateral coarse crackles in the lungs. no leg swelling or signs of deep venous thrombosis were present. his past medical history included hypertension and coronary artery bypass grafting years earlier; he was receiving combination therapy for hypertension, and acetylsalicylic acid mg/day. he had no known personal or family history of hypercoagulability. the computed tomography of the lungs showed bilateral multifocal ground-glass opacities. no lower-extremity venous ultrasound was performed. the white blood cell count was /μl (lymphocyte count /μl, %), whereas all markers of infection were increased (ferritin ng/ml, crp mg/l, procalcitonin . μg/l, d-dimers ng/ml, ldh u/l). the differential diagnosis included community-acquired pneumonia, atypical pneumonia, and covid- . the patient was initially treated with azithromycin mg intravenously (iv) once daily and ampicillin/sulbactam gr iv, times daily. prophylactic dose for thromboembolism with enoxaparin was also initiated, and therapy with acetylsalicylic acid was maintained. after the testing for sars-cov- infection by real-time polymerase chain reaction by nasopharyngeal swab, which came out positive the next day, hydroxychloroquine was added to his therapy according to our hospital protocol, with mg twice daily on the first day and mg times daily for the next days. nevertheless, the patient's condition rapidly deteriorated, and he required intubation and mechanical ventilation days after hospital admission; at that time, a central line into the right internal jugular vein was also inserted. thereafter, he was admitted to the icu for further management; his sofa score at icu admission was . during the next few days, the patient was febrile, hypoxemic, and hemodynamically unstable, requiring vasopressors; he received tocilizumab (il- inhibitor) and antibiotics including ceftaroline, meropenem, colistin, and linezolid. he was treated for severe acute respiratory distress syndrome, including prone positioning for days, with beneficial effects. he continued to receive enoxaparin at prophylactic dose for thromboembolism and acetylsalicylic acid; no other treatment modalities for immobilization were applied. two weeks after the icu admission, the patient was afebrile and hemodynamically stable, but still hypoxemic with a pao / fio ratio of mmhg, requiring continuation of mechanical ventilation. at that time a transthoracic echocardiogram, followed by a transesophageal echocardiogram for better evaluation, revealed the presence of a right atrium thrombus ( figure ) without signs of acute right ventricular dilatation and impaired systolic function; a pulmonary embolism (pe) might also have occurred. since the patient was hemodynamically stable and the levels of cardiac troponin t were not elevated ( pg/ml), we decided to treat him with conventional anticoagulation, consisting of an increased dose of enoxaparin, mg subcutaneously (sc) twice daily, to attain therapeutic anti-xa levels ( . - . u/ml). in addition, the patient was under close monitoring for signs of hemodynamic deterioration or massive pe; initiation of systemic thrombolysis would immediately follow in this scenario. on the basis of the abovementioned anticoagulation treatment and related monitoring, we chose not to transfer the patient to radiology for pe assessment. no other tests for genetic or acquired hypercoagulable states were done at that time. during the next few days the patient had significant clinical improvement; the followup transesophageal echocardiogram weeks after effective therapeutic anticoagulation revealed no signs of right heart thrombus ( figure ). the patient remained hemodynamically stable, maintaining a pao /fio ratio of mmhg, without need of mechanical ventilation. he was in a process of tracheostomy closure and icu discharge to a rehabilitation facility. recent data have shown that sars-cov- infection and the associated systemic inflammatory storm in severe cases results in endothelial dysfunction and activation of the coagulation cascade. there is an ongoing discussion regarding the effectiveness of routine prophylactic anticoagulation therapy in preventing thrombotic complications in severe covid- cases [ ] [ ] [ ] . the presence of the right atrium thrombus in our patient, who was already in prophylactic anticoagulation therapy, generates some questions. how long was the thrombus in the right atrium? could it be related to the coagulation dysfunction observed in covid- , as part of the initial presentation? could it be associated with the stasis, hemodynamic instability, mechanical ventilation, or central line placement during the icu stay? is the therapeutic coagulation after the thrombus diagnosis a crucial therapeutic intervention for the final outcome of the patient? finally, what is the appropriate initial anticoagulation therapy for severe covid- cases admitted in the icu? as the computed tomography of the lungs at the time of covid- diagnosis was without contrast, we do not have information regarding the presence of the right heart thrombus or even pulmonary embolism at icu admission. however, we do know that after the change of prophylactic anticoagulation to therapeutic dosing, the transesophageal echocardiogram revealed no signs of residual right atrium thrombus and the patient had continuous significant improvement in both hemodynamics and oxygenation. we should emphasize the critical role of transesophageal echocardiography in the management of the patient by providing reliable and safe information. the detection of intracardiac thrombus or clot in transit by transthoracic and transesophageal echocardiography, and the subsequent therapeutic interventions, have been recently reported in a few cases with severe covid- [ ] [ ] [ ] [ ] [ ] . currently, transesophageal echocardiography is strongly endorsed by experts as an invaluable tool for managing critically ill patients with covid- [ ] . since we are at the beginning of studying covid- complications, we cannot have sufficient answers to questions arising from the challenges and management issues of severe covid- cases. however, it seems that thromboembolic complications are common in patients with severe covid- requiring icu care, and low-molecular-weight heparins may be preferred in patients unlikely to need procedures. the optimal initial dose remains unknown; some physicians consider that prophylactic anticoagulation is needed, whereas others think that therapeutic anticoagulation is reasonably necessary [ , , , ]. the presented covid- case, one of first to provide evidence of right heart thrombus by transesophageal echocardiography, highlights the central role of diagnostic imaging strategies and the importance of adequate anticoagulation therapy in the management of severe covid- cases. clinical characteristics of coronavirus disease in china clinical course and risk factors for mortality of adult in patients with covid- in wuhan, china: a retrospective cohort study coronavirus disease (covid- ) situation report - covid- and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up will complement inhibition be the new target in treating covid- related systemic thrombosis? circulation incidence of thrombotic complications in critically ill icu patients with covid- pulmonary embolism in covid- patients: awareness of an increased prevalence venous and arterial thromboembolic complications in covid- patients admitted to an academic hospi prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia routine venous thromboembolism prophylaxis may be inadequate in the hypercoagulable state of severe coronavirus disease covid- and thrombotic complications: pulmonary thrombosis rather than embolism? thrombosis and covid- pneumonia: the clot thickens! clot in transit on transesophageal echocardiography in a prone patient with covid- acute respiratory distress syndrome. case (phila) acute pulmonary embolism in conjunction with intramural right ventricular thrombus in a sars-cov- -positive patient right ventricular clot in transit in covid- : implications for the pulmonary embolism response team thrombus in transit and impending pulmonary embolism detected on pocus in a patient with covid- pneumonia acute cor pulmonale in critically ill patients with covid- critical care transesophageal echocardiography in patients during the covid- pandemic the authors thank dr. stylianos orfanos for his valuable contribution to this work and the icu nursing staff for their devotion and assistance. none. key: cord- -oktu ieq authors: krishna, lalit kumar radha; neo, han yee; chia, elisha wan ying; tay, kuang teck; chan, noreen; neo, patricia soek hui; goh, cynthia; peh, tan ying; chiam, min; low, james alvin yiew hock title: the role of palliative medicine in icu bed allocation in covid- : a joint position statement of the singapore hospice council and the chapter of palliative medicine physicians date: - - journal: asian bioeth rev doi: . /s - - - sha: doc_id: cord_uid: oktu ieq facing the possibility of a surge of covid- -infected patients requiring ventilatory support in intensive care units (icu), the singapore hospice council and the chapter of palliative medicine physicians forward its position on the guiding principles that ought to drive the allocation of icu beds and its role in care of these patients and their families. involvement of pm physicians in triaging patients for ventilated icu beds (british medical association ) should be led by clear ethical and practical considerations. we believe that this ought to take the form of the following considerations. everyone matters and everyone matters equally. individuals with an equal chance of benefiting from a resource should have an equal chance of receiving it. individuals with a greater and more urgent need should be given greater and more urgent consideration. it is not unfair for individuals to wait if they could attain the same benefit later. individuals should be given the chance to express their views on matters that affect them and their personal choices about care and treatment should be respected as much as possible. they should be kept informed and educated on available care and treatment options. decisions made should equitably consider and balance the needs of the society, rights of the individual and availability of resources. decisions should be as transparent, inclusive and reasonable as possible. they should be rational, evidence-based, practical in the circumstances and the result of a careful deliberation process. harm should be minimized through constant review and adoption of best practices. to the fullest ability, standard of care should be maintained for all individuals and disruptions should be curtailed. all stakeholders should stand united in supporting each other, taking responsibility for their own behavior, and sharing information readily and appropriately. information communicated to relevant stakeholders must be proportionate to risks involved; restrictions on rights must be proportionate to intended positive outcomes. an open-minded approach should be adopted and strategies should constantly strive to reflect and address the unique needs of the situation. pre-emptive guidelines should be formulated by experts in infectious diseases, critical care, emergency medicine, clinical ethics and palliative care before the spike in demand for icu beds (hick et al. ; biddison et al. ; white and lo ) . this will facilitate clear communication with the public regarding the practical and ethical issues surrounding allocation of scarce icu resources and attenuate concerns about discrimination against minority groups, boost trust in the public healthcare system, facilitate transparent, accountable and evidence-based decision making, and build solidarity within the community. this will ensure respect of autonomy, patient preferences and respect for antecedent preferences contained within acps and amds. wherever possible, triage teams or an independent interdisciplinary team of experts dedicated to deliberating complex triage decisions if the primary care team faces difficult ethical dilemmas should be established. the triage team should be available for consultation throughout the day and include at least one ethicist, two senior healthcare professionals (hcps) and a pm physician who will offer support and experience in identifying, assessing and treating the physical and psychosocial issues of the critically ill and dying. the triage team will help ensure accountability in care determinations and ensure these decisions are rational, transparent, inclusive, reasonable, evidence-based and practical. in singapore, stable patients are decanted to private hospitals, community hospitals and community isolation facilities to optimize resources in public acute hospitals (ministry of health ; channel news asia ). resources including availability of icu beds, key medications such as sedatives and opioids, supportive treatments such as dialysis machines, and personal protective equipment within all hospitals should be closely monitored. a clear grasp of the situation and available resources would allow for greater efficacy and quality of care across the continuum. this ensures balanced decisionmaking and distribution of resources, and boosts collaborations. concurrently there should be flexibility in the deployment of manpower to internal medicine and icu care to ensure resources are easily redistributed and portable across care settings. the guiding ethical principles should be adhered to by the triage team and should be informed by evidence-based prognostic tools such as the sequential failure assessment (sofa) score, simplified acute physiology score (saps ), or the acute physiology and chronic health evaluation (apache) score. a multi-dimensional scale that includes measures of frailty and physical function such as age and clinical frailty scale (cfs) may also be used in tandem (poole et al. ; zhou et al. ; zhang et al. ; mdcalc ; chen et al. ) . understanding the potential benefits that the patient is likely to accrue from ventilatory support, their prognosis and their previously stated wishes will determine the proportionality and beneficence of an icu admission. strategies adopted should be rigorously reassessed and adapted as the pandemic situation evolves. the pm team must also be involved in the care of patients and their families who are allocated icu beds, and those patients and their families who are not. in addition the pm team must be involved in supporting healthcare professionals in the icu and those caring for patients not been allocated icu beds. prevailing models in singapore have seen pm physicians integrated into the icu care team and working together with dedicated medical social work (msw) teams to meet the following roles. pm physicians together with msws should be involved in the creation of early pm consultation protocols, be part of daily ward rounds with the icu teams, participate in education sessions for the icu multidisciplinary team and provide regular debriefs for the icu teams. for patients not allocated icu beds, pm physicians and msws should be involved immediately to support the patient's and their family's needs. to ensure effective care of these patients and families, the pm team should formulate guidelines and decisionmaking algorithms for pragmatic pharmacological and non-pharmacological methods of alleviating symptoms commonly associated with covid- pneumonia, such as dyspnoea, excessive respiratory secretions, delirium and pain. this will empower primary care teams to act swiftly and safely in delivering generalist palliative care in a manner that is consistent with the patient's values, beliefs and wishes. specialist pm support should be available for the treatment of distressing symptoms such as dyspnoea, which may require rapid bedside titration of medications and the use of palliative sedation therapy if symptoms remain recalcitrant. similar care and consideration should be provided to patients whose ventilatory support is to be withdrawn as a result of progressive deterioration despite maximal icu support. early identification and pm involvement will help support these families and patients as well as the hcps involved. hcps should act as patient advocates and address their fears when deprived of traditional social networks and family support as a result of isolation protocols. active screening for spiritual and existential distress should be carried out and provided in a timely, appropriate and personalized manner. families suffer too and are often wrought with worry, guilt and helplessness. concurrently as funeral rituals are shortened or disallowed in line with social distancing measures, some families may feel disenfranchised and have additional difficulty processing their grief. flexibility in addressing these needs without compromising safety is required to support families. here the combined pm, msw and icu teams should be proactive in addressing grief and bereavement needs. this may take the form of regular virtual 'visits', timely follow-ups and reassurances. bereavement support should be provided in a timely, appropriate and personalized manner. hcps frequently experience moral distress and the decision to withhold or withdraw ventilatory support may be traumatizing especially if it results in death. it is imperative to holistically assess and support the team either individually or as a group and provide them with resources to support themselves. here, having the triage team discuss these issues with them will certainly provide an added source of support. scarce resource allocation during disasters covid- : ethical issues covid- patients who are 'well and stable' to be transferred to selected private hospitals: moh. channel news asia epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical review: allocating ventilators during large-scale disasters -problems, planning, and process simone piva, discussing the brescia-covid respiratory severity score (bcrss). mdcalc, updates on covid- (coronavirus disease ) local situation comparison between saps ii and saps in predicting hospital mortality in a cohort of italian icus. is new always better? a framework for rationing ventilators and critical care beds during the covid- pandemic epidemiologic features and clinical course of patients infected with sars-cov- in singapore zhiyong peng, and huaqin pan. . clinical features and short-term outcomes of patients with covid- in wuhan clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study key: cord- -j gm vpz authors: michard, frédéric; malbrain, manu lng; martin, greg s; fumeaux, thierry; lobo, suzana; gonzalez, filipe; pinho-oliveira, vitor; constantin, jean-michel title: haemodynamic monitoring and management in covid- intensive care patients: an international survey date: - - journal: anaesth crit care pain med doi: . /j.accpm. . . sha: doc_id: cord_uid: j gm vpz purpose: to survey haemodynamic monitoring and management practices in icu patients with the coronavirus disease (covid- ). methods: a questionnaire was shared on social networks or via email by the authors and by anaesthesia and/or critical care societies from france, switzerland, belgium, brazil, and portugal. intensivists and anaesthetists involved in covid- icu care were invited to answer questions about haemodynamic monitoring and management. results: globally, questionnaires were available for analysis. responses came mainly from europe (n = ) and america (n = ). according to respondents, a majority of covid- icu patients frequently or very frequently received continuous vasopressor support ( %) and had an echocardiography performed ( %). echocardiography revealed a normal cardiac function, a hyperdynamic state ( %), hypovolaemia ( %), a left ventricular dysfunction ( %) and a right ventricular dilation ( %). fluid responsiveness was frequently assessed ( %), mainly using echo ( %), and cardiac output was measured in %, mostly with echo as well ( %). venous oxygen saturation was frequently measured ( %), mostly from a cvc blood sample ( %). tissue perfusion was assessed biologically ( %) and clinically ( %). pulmonary oedema was detected and quantified mainly using echo ( %) and chest x-ray ( %). conclusion: our survey confirms that vasopressor support is not uncommon in covid- icu patients and suggests that different cardiac function phenotypes may be observed. ultrasounds were used by many respondents, to assess cardiac function but also to predict fluid responsiveness and quantify pulmonary oedema. although we observed regional differences, current international guidelines were apparently followed by most respondents. little is known about the haemodynamic consequences of the coronavirus disease and the haemodynamic management of patients requiring intensive care unit (icu) admission. these patients have several reasons to become haemodynamically unstable. first, they may be hypovolaemic because of fever and fluid restriction, which has been recommended from hospital admission to limit the development of pulmonary oedema [ , ] . like any patients with systemic inflammation, they may also have some degree of vasodilation, which may be amplified by sedative drugs during mechanical ventilation. circulating cytokines may induce ventricular dysfunction [ ] , and, although postmortem studies suggest it is uncommon, coronavirus-induced myocarditis may be a cause as well of systolic and diastolic dysfunction [ ] [ ] [ ] . mechanical ventilation with positive endexpiratory pressure (peep) may impede right ventricular ejection and induce ventricular dilation, which may in turn decrease left ventricular filling (acute cor pulmonale) [ , ] . finally, coagulation disorders are common in covid- patients and pulmonary embolism seems to be more frequent than on the general icu population [ , ] . despite these pathophysiological considerations, large observational studies published so far focused on lung injury [ ] , mentioned myocardial injury and arrhythmia as possible complications [ ] , but did not report much information about the haemodynamic status and management of critically ill covid- patients. according to a few studies, the proportion of icu patients requiring vasopressor support may range between and % [ ] [ ] [ ] . the who (https://www.who.int/publications-detail/clinical-management-of-severe-acuterespiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected) and the nih (https://covid treatmentguidelines.nih.gov/critical-care/hemodynamics/) released recommendations for the haemodynamic management of covid- patients. the surviving j o u r n a l p r e -p r o o f sepsis campaign guidelines were quickly updated [ ] . the asian critical care clinical trials group also published guidelines based on their experience with the covid- pandemic from the very beginning [ ] . they all emphasised the importance of ultrasounds to assess cardiac function and the need to predict fluid responsiveness to rationalise fluid management. an electronic survey was designed to investigate current haemodynamic monitoring and management practices in covid- icu patients, as well as alignment with recent guidelines. questionnaires not filled by an intensivist or anaesthetist (certified or trainee), or that did not contain the geographical information, or with more than three unanswered questions were considered invalid. responses were monitored on a daily basis and the database was j o u r n a l p r e -p r o o f locked for analysis after receiving valid questionnaires. data are presented as numbers and percentages. multiple answers were allowed for several questions (see appendix a) so that cumulative percentages presented in the text or the figures may exceed %. comparisons between regions were done with a chi-square test. a p value < . was considered statistically significant. the survey database was closed on may after receiving responses. thirty-four questionnaires were filled by non-intensivists or non-anaesthetists, questionnaires contained more than three unanswered questions and two questionnaires did not contain the geographical information. the remaining valid questionnaires were used for analysis. responses came mainly from europe (n = ) and america (n = ) (figure ). most responders were intensivists (n = ), were intensivists and anaesthetists, were anaesthetists, and were trainees. two hundred thirty-seven respondents had more than years of experience working in the icu. a comparison between the three main geographical areas (europe, south america and north america) is presented in figure . to monitor blood pressure, the first choice was the radial catheter in the three main regions. the femoral catheter was less often used in north america ( %) than in europe ( %, p < . ) or in south america ( %, p < . ). to measure cardiac output, ultrasounds were the first choice in the three main regions. transpulmonary thermodilution was less often used in north america ( %) than in europe ( %, p < . ) or in south america ( %, p < . ). to predict fluid responsiveness, ultrasounds were also the first choice in the three main regions, followed by the pulse pressure variation (ppv) and the passive leg-raising (plr) manoeuvre in comparable proportions. to assess pulmonary j o u r n a l p r e -p r o o f oedema, ultrasounds were the first choice in europe and in south america, and the second choice after chest x-ray in north america. extravascular lung water measurements were more often used in europe ( %) and in south america ( %) than in north america ( %, p < . ). our survey confirms that haemodynamic instability is not uncommon in covid- icu patients and that different cardio-vascular profiles or phenotypes may be observed with echocardiography. from a monitoring standpoint, svo was reported to be frequently measured from central venous catheters, and ultrasounds were reported to be widely used, not only to assess cardiac function but also to predict fluid responsiveness and to assess pulmonary oedema. therefore, current guidelines regarding the use of echocardiography and the need to predict fluid responsiveness were apparently followed by most respondents. echocardiographic patterns reported by survey respondents were consistent with cardiovascular clusters recently described in septic shock [ ] and underscore the value of ultrasound evaluations to identify the underlying mechanisms of shock and select the most appropriate therapy. only a minority of echocardiographic evaluations were done using a transesophageal approach. obesity (frequently reported in covid- patients), mechanical ventilation and prone positioning may render the transthoracic approach challenging. however, the proximity of airways, the risk of aerosol generation and contamination, uncertainties regarding the optimal modalities for probe cleaning, as well as time constraints may have restricted the use of transesophageal echocardiography (tee). our survey also j o u r n a l p r e -p r o o f suggests that hand-held or pocket echo devices were not widely adopted. this may be explained by the fact that these tools are relatively new and that many icus have high-end trolley ultrasound machines readily available (e.g. to guide cvc insertion). one factor that may have influenced the importance of ultrasounds in the haemodynamic management of covid- patients is the lack of availability of haemodynamic monitors. echo evaluations usually take less than minutes so that, pending proper cleaning, the same device can be used for the haemodynamic assessment of several patients. in contrast, hemodynamic monitors are dedicated to the monitoring of a single patient and are often used several consecutive days. therefore, the shortage of haemodynamic monitors may have magnified the role of ultrasound techniques in this pandemic context. another contributing factor is the ability to gather a lot of information from a single echo evaluation. many respondents used echo not only to assess biventricular function but also to measure cardiac output, to predict fluid responsiveness and to detect lung b lines. cardiac output was frequently measured ( %). for many respondents (figure ), and across the three main regions (figure ), measurements were performed during echocardiographic evaluations. otherwise, transpulmonary thermodilution was used by a significant number of respondents, with the exception of north america where uncalibrated pulse contour methods were used more often ( figure ). this is somewhat surprising given the fact that uncalibrated pulse contour methods are known to have limited accuracy and precision to measure cardiac output in septic shock [ ] , and their use is not recommended beyond the surgical population [ ] . the swan ganz catheter was rarely used. although pulmonary thermodilution remains a monitoring option in patients with septic shock [ , ] , this finding is aligned with the global decline of this invasive tool [ ] for which the new j o u r n a l p r e -p r o o f generation of intensivists did not receive much training. in addition, some clinicians may be reluctant to use a pulmonary artery catheter in the context of hypercoagulability and thromboembolic complications associated with covid- [ , ] . the prediction of fluid responsiveness was adopted by a vast majority of respondents ( %). this finding contrasts with the results of a worldwide observational study suggesting that the prediction of fluid responsiveness is not routinely done in icus [ ] . however, this study done seven years ago may not reflect current practice anymore. the behaviour of our respondents is supported by recent studies showing outcome benefits when predicting fluid responsiveness in septic patients [ , ] . echo was ranked # for the prediction of fluid responsiveness, globally and in the three main regions. it was mainly performed with a transthoracic probe (tte). the prediction of fluid responsiveness with tte requires the evaluation of the inferior vena cava (ivc) respiratory variations [ ] or of the velocity-time integral (vti) respiratory variations recorded at the level of the left ventricular outflow tract [ ] . it is worth noticing that the fully automatic calculation of these variables is not available and that they have a limited sensitivity in patients ventilated with a low tidal volume for protective mechanical ventilation. indeed, in this context, large ivc or vti respiratory variations are highly suggestive of fluid responsiveness, but small variations cannot exclude it (false negative). the same limitation applies to ppv and stroke volume variation (svv) that were also popular methods among our respondents (figure ) [ ] . the passive leg-raising manoeuvre is an alternative to tte-derived variables, ppv and svv to predict fluid responsiveness during protective mechanical ventilation [ ] . it was used by of the respondents ( %) who predicted fluid responsiveness. the use of the plr manoeuvre requires the simultaneous use of a fast response cardiac output monitoring j o u r n a l p r e -p r o o f system (typically a pulse contour technique) in order to capture transient changes in stroke volume or cardiac output during the manoeuvre [ ] . venous oxygen saturation was very frequently measured from a central venous catheter. the three main determinants of venous oxygen saturation are haemoglobin, cardiac output and arterial oxygen saturation. assuming haemoglobin stability, measuring venous oxygen saturation is a simple way to ensure that fluid restriction and positive end-expiratory pressure (peep) application do not decrease oxygen delivery. both are used in an attempt to increase arterial oxygenation, but at the same time they are susceptible to decrease cardiac output. therefore, at least from an oxygen delivery standpoint, the right volume status and the right peep level are those associated with the highest venous oxygen saturation [ ] . this might be the reason why venous oxygen saturation was so popular among our respondents, but this remains a hypothesis. indeed, our survey was a snapshot of current behaviours and was not designed to explain these behaviours. the assessment of tissue oxygenation was almost exclusively based on clinical (e.g. capillary refill time) and biological (e.g. kidney function, lactates) evaluations. new techniques such as nirs and video-microscopy were rarely used. they are probably considered as research tools [ , ] and one may imagine they were not available in many icus from many countries. our study has limitations. in addition to emails that are clearly targeted, we used social networks (linkedin, twitter, whatsapp) to invite clinicians answer the survey and share the link. therefore, we were not able to control the number of clinicians who received the survey and hence to determine the percentage of respondents. because the survey was built on a google platform, it was not accessible from china and we were not able to include the j o u r n a l p r e -p r o o f feedback from chinese doctors who have been involved in the pandemic from the very beginning. however, this is one of the largest surveys ever published in critical care [ ] and we have been able to collect almost responses from europe and america, which are critical areas of the pandemic as well. finally, this is a survey and not an audit nor an observational study. therefore, the feedback gathered from clinicians reflects the perception they have of what is done or should be done in their unit, which may sometimes differ from reality [ ] . in any case, our survey results remain of interest to understand where clinicians see value in haemodynamic monitoring tools and practice. according to the intensivists and anaesthetists who sent back a valid questionnaire, vasopressor support was not uncommon in covid- icu patients. several cardiac function phenotypes were reported, highlighting the importance of echocardiography. ultrasounds were used by many respondents, not only to assess cardiac function but also to predict fluid responsiveness and quantify pulmonary oedema. venous oxygen saturation measurements from a central venous catheter were also reported to be common practice. although we observed regional differences, current international guidelines were apparently followed by most respondents. the authors declare the following financial interests/personal relationships which may be considered as potential competing interests: surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) intensive care management of coronavirus disease (covid- ): challenges and recommendations sepsis-induced myocardial dysfunction (simd): the pathophysiological mechanisms and therapeutic strategies targeting mitochondria potential effects of the coronaviruses on the cardiovascular system. a review recognizing covid- related myocarditis: the possible pathophysiology and proposed guideline for diagnosis and management right heart function during acute respiratory distress syndrome acute cor pulmonale in critically ill patients with covid- autopsy findings and venous thromboembolism in patients with covid- confirmation of the high cumulative incidence of thrombotic complications in critically ill icu patients with covid- : an updated analysis baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region association of cardiac injury with mortality in hospitalized patients with covid- in clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study icu and ventilator mortality among critically ill adults with coronavirus disease clinical characteristics of covid- in new york city cardiovascular clusters in septic shock combining clinical and echocardiographic parameters: a post-hoc analysis disagreement in cardiac output measurements between fourth generation flotrac and critical care ultrasonography in patients with circulatory shock: a prospective observational study pressure waveform analysis is there still a place for the swan-ganz catheter? we are not sure less invasive hemodynamic monitoring in critically ill patients is there still a place for the swan-ganz catheter? no fluid challenges in intensive care: the fenice study. a global inception cohort study characteristics of resuscitation, and association between use of dynamic tests of fluid responsiveness and outcomes in septic patients: results of a multicenter prospective cohort study in argentina fluid response evaluation in sepsis hypotension and shock: a randomized clinical trial the respiratory variation in inferior vena cava diameter as a guide to fluid therapy respiratory changes in aortic blood velocity as an indicator of fluid responsiveness in ventilated patients with septic shock applicability of pulse pressure variation: how many shades of grey? principles of fluid management and stewardship in septic shock: it is time to consider the four d's and the four phases of fluid therapy passive leg raising: five rules use of centreal venous oxygen saturation to guide therapy peripheral muscle near-infrared spectroscopy variables are altered early in septic shock second consensus on the assessment of sublingual microcirculation in critically ill patients: results from a task force of the european society of intensive care medicine quality of reporting of surveys in critical care journals practice and perception -a nationwide survey of therapy habits in sepsis key: cord- -dmiplvt authors: almekhlafi, ghaleb a.; albarrak, mohammed m.; mandourah, yasser; hassan, sahar; alwan, abid; abudayah, abdullah; altayyar, sultan; mustafa, mohamed; aldaghestani, tareef; alghamedi, adnan; talag, ali; malik, muhammad k.; omrani, ali s.; sakr, yasser title: presentation and outcome of middle east respiratory syndrome in saudi intensive care unit patients date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: dmiplvt background: middle east respiratory syndrome coronavirus infection is associated with high mortality rates but limited clinical data have been reported. we describe the clinical features and outcomes of patients admitted to an intensive care unit (icu) with middle east respiratory syndrome coronavirus (mers-cov) infection. methods: retrospective analysis of data from all adult (> years old) patients admitted to our -bed mixed icu with middle east respiratory syndrome coronavirus infection between october , and may , . diagnosis was confirmed in all patients using real-time reverse transcription polymerase chain reaction on respiratory samples. results: during the observation period, patients were admitted with mers-cov infection (mean age ± years, [ %] males). cough and tachypnea were reported in all patients; ( . %) patients had bilateral pulmonary infiltrates. invasive mechanical ventilation was applied in ( . %) and vasopressor therapy in ( . %) patients during the intensive care unit stay. twenty-three ( . %) patients died in the icu. nonsurvivors were older, had greater apache ii and sofa scores on admission, and were more likely to have received invasive mechanical ventilation and vasopressor therapy. after adjustment for the severity of illness and the degree of organ dysfunction, the need for vasopressors was an independent risk factor for death in the icu (odds ratio = . , % confidence interval: . – . , p = . ). conclusions: mers-cov infection requiring admission to the icu is associated with high morbidity and mortality. the need for vasopressor therapy is the main risk factor for death in these patients. electronic supplementary material: the online version of this article (doi: . /s - - - ) contains supplementary material, which is available to authorized users. middle east respiratory syndrome coronavirus (mers-cov) is a novel betacoronavirus that was first reported in september [ ] . by january , , a total of laboratory-confirmed cases of infection with mers-cov, including at least related deaths, had been reported to the world health organization [ ] . although mers-cov infections have been reported from countries around the world, the majority of cases have originated in saudi arabia, south korea, the united arab emirates, jordan and qatar [ ] . interhuman mers-cov transmission occurs in community and healthcare settings [ ] [ ] [ ] [ ] [ ] . the exact source and mode of transmission of mers-cov to humans remains uncertain. however, mers-cov circulates among dromedary camels in africa and the middle east with occasions of documented camel-human inter-transmission [ ] . there have been several reports outlining the clinical features and outcomes of patients with mers-cov infection [ , [ ] [ ] [ ] [ ] [ ] [ ] . however, very few have focused on critically ill patients in intensive care units (icu) [ ] [ ] [ ] . there is therefore a need for more data to understand the various clinical and prognostic aspects of this potentially lethal disease, particularly for the most severe cases that require admission to the icu. we performed a retrospective study to describe the clinical features and outcomes of patients admitted to our icu with laboratory-confirmed mers-cov infection. the study was approved by the institutional review board of prince sultan military medical city ( riyadh, saudi arabia), a large tertiary-care referral center in riyadh, saudi arabia. informed consent was waived due to the retrospective, anonymous nature of data collection. we included all patients aged years or more with confirmed mers-cov infection who were admitted to our -bed mixed medico-surgical icu between october , and may , . all icu patients with a confirmed diagnosis of mers-cov were registered in a special logbook. for the purpose of the current study, all patients' records were reviewed by a senior intensivist (s. hussain, a. alwan, a. abudayah, s. altayyar, m. mustafa, t. aldaghestani, a. alghamedi, a. talag or m. malik). clinical data and laboratory parameters from confirmed cases of mers-cov were transcribed onto specially developed case record forms. these included the initial manifestations of respiratory infection, the clinical picture on admission to the icu, laboratory indices of organ failure, radiographic findings, interventions during the icu stay, treatment modalities, and final outcome. the acute physiology and chronic health evaluation ii (apache ii) score was calculated from the data obtained within hours of admission to the icu [ ] . the sequential organ failure assessment (sofa), score, calculated daily by the physician in charge of the patient, was also noted [ ] . since the first reported cases of mers-cov in saudi arabia in september , all suspected cases in our institution are strictly isolated and nasopharyngeal swabs are obtained for initial screening. deep respiratory samples (tracheal aspirates or bronchoalveolar lavage fluid) are obtained from all patients admitted to the icu with suspected respiratory infections, in addition to blood samples to perform cultures and polymerase chain reaction for common respiratory viruses and atypical microorganisms. urinary samples were obtained to detect legionella antigens in only two patients (legionella infections are not common in saudi patients). cultures of tracheal aspirates are analyzed quantitatively and bacterial counts of at least colony-forming units are considered positive. these investigations are repeated in the icu whenever secondary infections are suspected. clinical specimens aimed at detecting possible mers-cov infection are processed and analyzed at the national reference laboratory of the saudi ministry of health. mers-cov infections are identified using real-time, reverse transcription polymerase chain reaction (rt-pcr). the standard assays target amplifications of the upstream e protein (upe gene) and open reading frame (orf) a; both need to be positive to confirm infection, otherwise another sample is required to confirm the diagnosis [ ] . the sample requires days of processing for the final results to be available. routine laboratory testing in our icu includes complete blood counts, coagulation profile, electrolytes, renal function, liver profile and arterial blood gases. these parameters are measured on admission to the icu and at least once daily thereafter (at : am) throughout the icu stay. all patients with suspected or confirmed mers-cov infection were isolated in single rooms, either on the hospital floor or in the icu. patients were admitted to the icu according to the guidelines of the society of critical care medicine for icu admission, discharge, and triage [ ] . patients were classified into four categories according to their icu admission priority: priority one comprised critically ill patients who were unstable and need intensive treatment and monitoring, with significant likelihood of recovery; priority two were stable patients who required intensive monitoring because of the possibility of decompensation; priority three were unstable patients who had a low likelihood of recovery because of the severity of acute disease or because of comorbidities; priority four were those who had little or no anticipated benefit from icu admission. patients classified as priority one and two and most of those classified as priority three were admitted to our icu or full critical care services were mobilized and provided for in the isolation ward until a bed was available in the icu. priority four patients were not admitted to the icu and remained in the isolation ward. general ward patients with mers-cov infection were transferred to the icu if their condition deteriorated or organ failure developed. the infection control precautions recommended by the saudi ministry of health guidelines were strictly implemented to prevent possible transmission of mers-cov to other patients or to the healthcare staff [ ] . supportive treatment was provided according to our standard operating procedures and in accordance with the surviving sepsis campaign guidelines [ , ] . antiviral therapies, such as oseltamivir, and ribavirin/interferon alfa- a, were prescribed at the discretion of the attending physician. protective lung ventilation was applied in mechanically ventilated patients. prone positioning was considered in some patients with severe refractory hypoxemia. extracorporeal membrane oxygenation (ecmo) and high-frequency oscillation were also available as a last resort, when considered necessary by the attending physician. statistical analyses were performed using spss statistics for windows (ibm corp., armonk, ny, usa). the kolmogorov-smirnov test was used to verify whether there were significant deviations from the normality assumption of continuous variables. nonparametric tests of comparison were used for variables evaluated as not normally distributed. difference testing between groups was performed using student's t test, mann-whitney test, chi-square test and fisher's exact test, as appropriate. friedman's test was used to assess the time course of organ function. to identify the risk factors for death in the icu, we performed multivariable logistic regression analyses. due to the relatively small number of deaths in our study, we adjusted only for the severity of illness on admission to the icu (apache ii score) and the degree of organ dysfunction as assessed by admission sofa score. potential risk factors for icu mortality were selected among the demographic characteristics, comorbidities, mode of acquisition of mers-cov, initial manifestations, procedures and therapies, and superimposing infections. variables yielding p < . in the univariate analysis, apa-che ii score and sofa score were included in a multivariable logistic regression analysis. these variables were introduced separately into multivariable models including apache ii and sofa scores on admission to the icu. adjusted odds ratios (or) and % confidence of interval (ci) were computed. none of the covariates simultaneously introduced in a multivariable model were collinear. data are presented as mean ± standard deviation (sd), median value ( th- th interquartile range [iqr]) or number (%), as appropriate. all statistics were two-tailed and a p < . was considered statistically significant. during the observation period, cases with confirmed mers-cov infections were diagnosed in our institution [ ] (fig. ) ; patients were managed in the hospital ward, patients were admitted to other icus or received critical care service in the ward, and patients were admitted to our icu ( between october , and december , and between january and may , ). patients were admitted to our icu because of respiratory failure (pao /fio < mmhg). the mean age of the patients admitted to our icu (n = ) was (sd ) years and ( %) were males. the characteristics of these patients on admission to the icu are shown in table . eighteen ( . %) patients had community-acquired mers-cov infection, while for ( . %), including two healthcare staff, infection was acquired in the hospital. twenty-seven patients ( . %) had at least one comorbidity. the median number of concomitant comorbid conditions was three (iqr: - ). initial clinical manifestations had occurred at a median of days (iqr: - ) prior to hospital admission. patients had been treated for a median of days (iqr: - ) in general hospital wards before their admission to the icu. only four patients ( . %) were admitted to the icu on arrival at the hospital. cough and tachypnea were reported in all patients. other common initial symptoms were fever ( . %), abdominal pain ( %), sore throat ( . %), and fatigue ( . %) (additional file ). crackles ( . %), tachycardia ( . %), and rhonchi ( . %) were the most commonly identified initial physical signs. bilateral pulmonary infiltrates were present in the chest x-rays of ( . %) patients and lobar infiltrates in six ( . %). only one patient had a normal chest x-ray at the time of admission to the icu. on admission to the icu, no patients had microbiologically proven co-existing bacterial pneumonia. secondary infections, as evident from positive quantitative cultures of deep tracheal aspirates, occurred in ( . ) patients within a median of days (iqr: - ) after admission to the icu. the most commonly isolated microorganisms were acinetobacter baumannii ( . %), only four ( . %) patients had positive blood cultures; acinetobacter baumannii (n = ), escherichia coli (n = ), methicillin-resistant staphylococcus aureus (n = ), and vancomycin-resistant enterococcus species (n = ). invasive mechanical ventilation was applied in ( . %) patients during the icu stay; ( . %) within hours of admission to the icu, and ( . %) patients received noninvasive ventilation (table ) . eleven ( . %) patients were treated with high-frequency oscillation and five ( . %) with prone positioning. only one patient received ecmo. the ventilatory parameters are presented in additional file . vasopressor therapy using norepinephrine was initiated in ( . %) patients (table ) . oseltamivir was administered to ( . %) patients for a median of days (iqr: - ). combined ribavirin plus interferon alfa- a therapy was used in ( . %) patients ( table ). all patients received at least one antimicrobial agent during the icu stay (additional file ). antifungal therapy was only used in four of the five patients with positive cultures for candida but the necessity of this therapy is uncertain. the overall icu mortality rate was . % (n = ). the median icu and hospital lengths of stay were (iqr: - ) and (iqr: - ) days, respectively. the major causes of death were hypoxemic respiratory failure ( . %) and refractory septic shock ( . %). one patient died from sudden cardiac arrest after icu discharge but while still in the hospital. furthermore, one patient died within year after discharge from the icu because of septic shock related to an infected wound. only one patient was lost to follow-up after hospital discharge. the sofa score and glasgow coma scale (gcs) increased markedly over the first weeks in the icu in the whole cohort, while other parameters of organ function remained largely unchanged (additional file ). compared with those who were discharged alive from the icu, nonsurvivors were older, had higher apache ii and sofa scores on admission to the icu, and were more likely to require invasive mechanical ventilation and vasopressor therapy and to have been ventilated using highfrequency oscillation (tables and , and additional files and ). nonsurvivors had a persistently low pao /fio throughout the first weeks in the icu, whereas survivors showed a slight increase over time (fig. ) . after adjustment for the severity of illness and the degree of organ dysfunction, the need for vasopressors was the only independent risk factor for death in the icu (or . , % confidence interval . - . , p . ) (additional file ). the critically ill patients with confirmed mers-cov infection in our cohort frequently had organ failure with an overall mortality rate greater than %. comorbidities were common in this cohort of patients. not surprisingly, mortality in the icu was associated with older age, severe disease and organ failure. the need for vasopressor therapy was an independent risk factor of death in the icu. since the first reported case of mers-cov infection in , several authors have described various cohorts of patients with this serious infection [ , - , , , ] . [ , ] . our facility is a large tertiarycare medical center in riyadh, central saudi arabia. we herein provide a detailed account of the largest single cohort of critically ill mers-cov infected patients reported thus far. in agreement with previous reports from saudi arabia, comorbid conditions were common in our patients with mers-cov infections with a median of three comorbidities per patient [ , , , ] . in contrast, only . % of the individuals involved in the recent mers-cov outbreak in south korea had any preexisting chronic medical conditions [ ] . however, only . % of patients in the korean outbreak were aged years or older and nearly half ( . %) were caregivers or healthcare personnel [ ] . the differences in the demographic characteristics of our cohorts and the mode of acquisition of mers-cov infection may explain, at least in part, the discrepancy in the patterns of associated comorbidities between the saudi and korean cohorts. the respiratory manifestations of mers-cov infection in our cohort were similar to those observed in previous reports from saudi patients [ , , , , ] . cough and tachypnea occurred in all patients and % of cases had bilateral pulmonary infiltrates, denoting severe respiratory illness, which required a median of days to reach the peak of clinical deterioration such that icu admission and organ support therapy were required. gastrointestinal manifestations, such as abdominal pain, diarrhea, vomiting, and abdominal tenderness, were relatively common in our cohort. this was also a common finding in the previous literature in patients with mers-cov infection as well as those with severe acute respiratory syndrome (sars) [ , , , , , ] . our data confirm previous studies that reported a high prevalence of nonrespiratory organ failure in critically ill patients with mers-cov [ , ] . the mechanisms of organ dysfunction and failure in these patients are yet to be determined. cytokine dysregulation has been suggested to be involved in the pathophysiology of mers-cov-related organ failure. direct viral invasion may also occur as the virus was recovered from urine and stool in one patient [ ] . in agreement with the results of the previous reports on critically ill patients with mers-cov infection [ ] [ ] [ ] , more than % of our patients received vasopressor support, underscoring the high prevalence of cardiovascular dysfunction in these patients, and suggesting that disturbances in tissue perfusion may also have been involved in the pathophysiology of the organ failure. lower rates of vasopressor support have been reported in patients with sars [ , , , , , ] with, as a result, lower mortality rates than those reported in patients with mers-cov infections. even though overall mortality rate was high in our cohort, it is still comparable with rates reported in previous studies ( . - . %) [ ] [ ] [ ] . in all studies, almost all patients had significant comorbidities and median apache ii scores of or higher. we observed significantly higher apache ii and sofa scores in icu nonsurvivors compared to those who survived severe mers-cov infection, underscoring the strong association between mortality and the severity of disease. epidemiological analyses have suggested that mers-cov is unlikely to trigger sustained human epidemics at present [ , ] . nevertheless, nosocomial outbreaks have resulted in considerable morbidity and mortality, in addition to disruption of medical services and substantial economic losses [ , , ] . the most severe infections usually require icu admission, necessitate major resource utilization and result in high fatality rates. identifying possible risk factors for poor prognosis in patients with mers-cov infection is therefore crucial to enable appropriate allocation of healthcare resources and early transfer of high-risk patients to the appropriate medical facilities. our data show that the need for vasopressor therapy was an independent risk factor for death in the icu. indeed, the major causes of death in our study were hypoxemic respiratory failure and refractory septic shock, which confirm the role of respiratory and cardiovascular system failures as determinants of outcome in this population. this was also evident from the persistent hypoxemia observed in the nonsurvivors. to date, published data on the risk factors for poor prognosis specific to critically ill patients with mers-cov infection are lacking. in cohort studies of patients with any degree of severity of mers-cov infection, older age, diabetes, chronic renal failure, chronic respiratory disease, high viral load in lower respiratory tract samples, shorter incubation period and mers-cov viremia have all identified as independent predictors of mortality [ , , [ ] [ ] [ ] . secondary respiratory infections occurred commonly in this cohort, predominantly with gram-negative bacteria. although candida species were frequently isolated, these are probably not relevant as respiratory pathogens and the necessity of antifungal therapy is uncertain. interestingly, acinetobacter baumannii, which is an emerging fatal infection in icu patients worldwide, was isolated from deep tracheal aspirates in one in four patients. this may explain, at least in part, the relatively high mortality rates in this cohort. specific therapeutic options for mer-cov infections are limited and their efficacy is not well established [ ] . all patients in this report received antiviral treatment with either oseltamivir or combined ribavirin/interferon alfa- a therapy; two patients received both. although a previous study from the same institution showed that combined ribavirin/interferon alfa- a therapy was associated with significant improvement in survival at days, this benefit was not maintained at days after the onset of the disease [ ] . the retrospective and observational nature of this study does not allow precise assessment of the efficacy of these therapies. in the absence of a vaccine or a specific treatment, prevention of viral transmission through adequate infection control methods is the mainstay in the management of mers-cov outbreaks. appropriate isolation of patients with suspected or proven infections is crucial. in view of the high fatality rates of these patients in the icu, it may be reasonable to closely monitor patients with suspected infections in the general wards for early signs of organ dysfunction to prevent unnecessary delay in the provision of intensive care services and reduce mortality rates in these patients. our study has some limitations. we included patients with confirmed mers-cov infection from one icu of a large medical center. possible variations in the geographic distribution of the disease and in local practice may hinder extrapolation of these data to other cohorts in saudi arabia and other countries. the relatively low number of patients may have biased the statistical comparisons presented in this report and overestimated mortality rates. multivariable adjustment was also limited to the variables included in the models. collaborative efforts are needed to provide an insight into the risk factors for poor prognosis in these patients. isolation of a novel coronavirus from a man with pneumonia in saudi arabia middle east respiratory syndrome coronavirus (mers-cov european centre for disease prevention and control. epidemiological update: middle east respiratory syndrome coronavirus ?id= &list= db c-fe d- c- - ff cb b &source=http% a% f% fecdc% eeuropa% eeu% fen% fpress% fepidemiological% fupdates% fpages% fepidemiological% f updates% easpx. accessed a family cluster of middle east respiratory syndrome coronavirus infections related to a likely unrecognized asymptomatic or mild case community case clusters of middle east respiratory syndrome coronavirus in hafr al-batin, kingdom of saudi arabia: a descriptive genomic study hospital outbreak of middle east respiratory syndrome coronavirus mers-cov outbreak in jeddah-a link to health care facilities middle east respiratory syndrome coronavirus outbreak in the republic of korea middle east respiratory syndrome coronavirus (mers-cov): what lessons can we learn? epidemiological, demographic, and clinical characteristics of cases of middle east respiratory syndrome coronavirus disease from saudi arabia: a descriptive study clinical aspects and outcomes of patients with middle east respiratory syndrome coronavirus infection: a single-center experience in saudi arabia hospital-associated outbreak of middle east respiratory syndrome coronavirus: a serologic, epidemiologic, and clinical description middle eastern respiratory syndrome corona virus (mers cov): case reports from a tertiary care hospital in saudi arabia ifn-alpha a or ifn-beta a in combination with ribavirin to treat middle east respiratory syndrome coronavirus pneumonia: a retrospective study middle east respiratory syndrome coronavirus: a case-control study of hospitalized patients characteristics and outcomes of middle east respiratory syndrome coronavirus patients admitted to an intensive care unit in jeddah, saudi arabia clinical course and outcomes of critically ill patients with middle east respiratory syndrome coronavirus infection acute management and long-term survival among subjects with severe middle east respiratory syndrome coronavirus pneumonia and ards apache ii: a severity of disease classification system the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine assays for laboratory confirmation of novel human coronavirus (hcov-emc) infections guidelines for intensive care unit admission, discharge, and triage. task force of the american college of critical care medicine, society of critical care medicine infection prevention and control guidelines for patients with middle east respiratory syndrome coronavirus (mers-cov) infection surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: multifacility outbreak of middle east respiratory syndrome in taif, saudi arabia middle east respiratory syndrome: an emerging coronavirus infection tracked by the crowd middle east respiratory syndrome in the shadow of ebola middle east respiratory syndrome coronavirus: another zoonotic betacoronavirus causing sars-like disease clinical features and virological analysis of a case of middle east respiratory syndrome coronavirus infection interhuman transmissibility of middle east respiratory syndrome coronavirus: estimation of pandemic risk transmission scenarios for middle east respiratory syndrome coronavirus (mers-cov) and how to tell them apart spread of mers to south korea and china mers coronavirus: diagnostics, epidemiology and transmission mortality risk factors for middle east respiratory syndrome outbreak, south korea association of higher mers-cov virus load with severe disease and death, saudi arabia association between severity of mers-cov infection and incubation period therapeutic options for middle east respiratory syndrome coronavirus (mers-cov) infection: how close are we? curr treat options infect dis ribavirin and interferon alfa- a for severe middle east respiratory syndrome coronavirus infection: a retrospective cohort study we would like to thank dr. hassane nijimi (free university of brussels) for the statistical revision of this study and dr. karen pickett for editorial assistance with the manuscript. the study was supported only by institutional funds. mers-cov infections requiring admission to the icu are associated with high morbidity and mortality rates. the need for vasopressor therapy is the main risk factor for death in these patients. this report describes the clinical features and outcomes of critically ill patients with confirmed middle east respiratory syndrome coronavirus (mers-cov) infection. patients with mers-cov infections frequently had organ failure, and mortality rates were greater than %. the need for vasopressor therapy was an independent risk factor for death in the icu. the authors declare that they have no competing interests.authors' contributions gaa, ym, aso, mma, and ys conceived the study. sh, aal, aab, sa, mm, ta, aalg, at, and mkm participated in data collection. ys processed the data and performed the statistical analyses. ys and gaa drafted the manuscript. all authors read, revised, and approved the final manuscript.• we accept pre-submission inquiries • our selector tool helps you to find the most relevant journal submit your next manuscript to biomed central and we will help you at every step: key: cord- - mczuxsy authors: biran, noa; ip, andrew; ahn, jaeil; go, ronaldo c; wang, shuqi; mathura, shivam; sinclaire, brittany a; bednarz, urszula; marafelias, michael; hansen, eric; siegel, david s; goy, andre h; pecora, andrew l; sawczuk, ihor s; koniaris, lauren s; simwenyi, micky; varga, daniel w; tank, lisa k; stein, aaron a; allusson, valerie; lin, george s; oser, william f; tuma, roman a; reichman, joseph; brusco, louis; carpenter, kim l; costanzo, eric j; vivona, vincent; goldberg, stuart l title: tocilizumab among patients with covid- in the intensive care unit: a multicentre observational study date: - - journal: the lancet rheumatology doi: . /s - ( ) - sha: doc_id: cord_uid: mczuxsy summary background tocilizumab, a monoclonal antibody directed against the interleukin- receptor, has been proposed to mitigate the cytokine storm syndrome associated with severe covid- . we aimed to investigate the association between tocilizumab exposure and hospital-related mortality among patients requiring intensive care unit (icu) support for covid- . methods we did a retrospective observational cohort study at hospitals within the hackensack meridian health network (nj, usa). we included patients (aged ≥ years) with laboratory-confirmed covid- who needed support in the icu. we obtained data from a prospective observational database and compared outcomes in patients who received tocilizumab with those who did not. we applied a multivariable cox model with propensity score matching to reduce confounding effects. the primary endpoint was hospital-related mortality. the prospective observational database is registered on clinicaltrials.gov, nct . findings between march and april , , patients with covid- required support in the icu, of whom ( %) received tocilizumab. factors associated with receiving tocilizumab were patients' age, gender, renal function, and treatment location. patients were included in the propensity score-matched population, of whom received tocilizumab and did not receive tocilizumab. ( %) of patients died, ( %) who received tocilizumab and ( %) who did not receive tocilizumab. overall median survival from time of admission was not reached ( % ci days–not reached) among patients receiving tocilizumab and was days ( – ) for those who did not receive tocilizumab (hazard ratio [hr] · , % ci · – · ; p= · ). in the primary multivariable cox regression analysis with propensity matching, an association was noted between receiving tocilizumab and decreased hospital-related mortality (hr · , % ci · – · ; p= · ). similar associations with tocilizumab were noted among subgroups requiring mechanical ventilatory support and with baseline c-reactive protein of mg/dl or higher. interpretation in this observational study, patients with covid- requiring icu support who received tocilizumab had reduced mortality. results of ongoing randomised controlled trials are awaited. funding none. worldwide more than million individuals have been infected with severe acute respiratory syndrome corona virus (sarscov ), the coronavirus causing covid . as of aug , , almost deaths have been reported globally. infection causes destruction of alveolar epithelial cells, activation of the innate immune sys tem, and dysregu lation of adaptive immune responses, includ ing release of proinflammatory cytokines and chemo kines. this socalled cytokine storm might have an important role in the progression to respiratory and multi organ failure. , tocilizumab, a recombinant monoclonal antibody against the interleukin (il) receptor, has been used to miti gate the cytokine release syndrome associated with chi meric antigen receptor (car) tcell therapy and has been proposed as a potential therapy for the cytokine storm syndrome associated with severe covid pneumonia based on small phase studies. [ ] [ ] [ ] [ ] [ ] [ ] [ ] preliminary unpublished results of the phase french corimunotoci trial, involving patients, noted a reduction in mortality and requirement for mechanical ventilation in patients who received tocilizumab. a large multinational randomised placebocontrolled phase trial evaluating tocilizumab in the treatment of severe covid pneu monia is under way (nct ). additional trials of tocilizumab are also ongoing. without data from randomised trials, observational studies can provide useful early insights into effective treatment strategies. , however, treatment allocations are often based on the clinician's judgment in an observational study, rather than random assignment, which increases the risk of bias and does not account for known and unknown risk factors. thus, causal inferences on effec tiveness of treat ments are challenging, but confounding effects can be partly mitigated via statistical methods. understanding the limitations of observational studies, but with the urgency to assess potential therapeutic approaches, the hospitals within the hackensack meridian health network (nj, usa) considered offlabel use of tocilizumab in patients with severe sarscov infection who required intensive care unit (icu) support. to evaluate treatments for covid , we established an observational database using an integrated electronic health record system (epic; verona, wi, usa). we aimed to compare outcomes between patients with covid in the icu who received tocilizumab and those who did not receive tocilizumab. we did a retrospective, observational, multicentre cohort study at the hospitals within the hackensack meridian health network. we derived data from electronic health records of patients with covid who received icu support. our selection criteria were adult patients (aged ≥ years) with a positive sarscov diagnosis by rtpcr who were hospitalised at one of hackensack meridian health's hospitals during the study period and required icu support. we excluded patients who were pregnant and those who were partici pating in a clinical therapeutic trial. patients receiving tocilizumab for chronic rheumatological conditions were not excluded. we obtained institutional review board (irb) approval for access to the prospective observational database. the requirement for patient's informed consent was waived by the irb because this project represented a noninterventional study using routinely gathered data for secondary research reasons. we obtained data from hackensack meridian health's electronic health record, which is used throughout the hospital network. hospitalised patients were flagged by the electronic health record if sarscov pcr tests were positive. these reports generated by the electronic health record served as our eligible cohort sample. demographics, clinical characteristics, treatments, and outcomes were manually abstracted by research nurses and clinicians from the john theurer cancer center at hackensack meridian health. assignment of patients to our data team occurred in real time but was not random ised. data abstracted by the team were entered, using research electronic data capture. quality control was done by two of us (ai and slg). demographic information was gathered on an elec tronic face sheet. gender and race or ethnicity were selfreported. academic centres were defined as quaternary referral centres with accredited residency, fellowship, and medical student programmes. comorbidities were defined as diagnosed before hos pitalisa tion for covid . history of cardiovascular disease, chronic lung disease, cancer, renal failure, and rheumatological disease was abstracted from provider notes or medical history sec tions within the electronic health record. if not listed, the patient's comor bidities were recorded as absent. icu support included all patients receiving mechanical ventilator support, patients hospital ised within a dedicated icu, and patients with assignment to icu staff regardless of geographical place ment (over flow during pan demic conditions). patients who received remdesivir were treated in the context of a clinical study and were excluded. lopinavir was not on evidence before this study we searched pubmed, embase, cochrane reviews, and scopus from jan to april , , with the terms "tocilizumab" and "covid" or "coronavirus". this search identified an increasing interest in the rationale to use tocilizumab in patients with severe covid- and several case reports or small observational studies reporting a benefit with its use. preliminary results from france of the phase corimuno-toci trial showed a reduction in mortality and requirement for mechanical ventilation in patients who received tocilizumab. a large, multinational, randomised, placebo-controlled phase trial evaluating tocilizumab for treatment of patients with severe covid- -related pneumonia is underway (nct ). we did a retrospective, observational cohort study to investigate mortality in patients with severe covid- needing support in the intensive care unit and receiving tocilizumab. use of tocilizumab was associated with improvement in median overall survival from time of admission compared with patients who did not receive tocilizumab. in a post-hoc analysis, patients with baseline c-reactive protein levels of mg/dl or higher were most likely to show an associated improved survival with tocilizumab, whereas no association was seen in patients with lower levels of c-reactive protein. our findings support the preliminary findings of the corimuno-toci trial and show an association between c-reactive protein levels, tocilizumab, and survival, potentially suggesting that tocilizumab might exert its best effects among patients with covid- progressing to an inflammatory state. current evidence supports continued evaluation of tocilizumab in a randomised trial for patients with severe covid- . data capture see https://www. project-redcap.org/ institutional formulary or used for covid treat ment and, if used in another context, data were not gathered. presenting clinical information was abstracted from thorough review of unstructured notes and structured data. hospital readmissions were counted as the same admission, with baseline data used from the initial hos pitalisa tion. if multiple positive or indeter minate results were found in a patient's record for sarscov , the first initial positive test was used as the date of diagnosis. exposure to tocilizumab was defined as receipt of the drug as found in the electronic health record. if no evidence of tocilizumab administration was found, we recorded that the patient had not received tocilizumab. offlabel use of tocilizumab within the hackensack meridian health network was guided by the pharmacy and therapeutics committee, with recommendations to consider treatment in patients with evidence of acute respiratory distress syndrome on mechanical ven tila tion, or worsening oxygenation with high oxygen requirements ( - %) on highflow nasal cannula or l non rebreather mask. symptoms had to be present for days and documentation of informed consent was needed. however, the final decision to use tocilizumab was at the discretion of the treating clinician. the pharmacy and therapeutics committee suggested one intravenous dose of mg tocilizumab. a randomised placebocontrolled trial of tocilizumab was available at one academic centre within the hackensack meridian health network (hackensack university medical center, hackensack, nj, usa). the rationale for selection of the mg intravenous dose of tocilizumab was based on published work from china, albeit preclinical and not peer reviewed at that time, which showed improved oxygenation using a dose of tociliz umab around mg/kg. a second dose of tocilizumab was permitted at the point of worsen ing oxygenation (eg, increased oxygen [o ] require ment, high flow o ) and before mechan ical ven tilation, with adminis tration at the treating clinician's discretion. the primary outcome measure was hospitalrelated mortality, which was identified on chart review as a note from the treating clinician announcing time of death during hospitalisation or if the electronic health record labelled the patient as deceased after hospital discharge. cause of death was identified using the electronic health record by identifying the most immediate cause or causes recorded. respiratory cause of death included any hypoxic condition related to covid . cardiac cause of death included cardiac arrest, myocardial infarction, or arrhyth mia. infectious cause of death inclu ded bacterial sepsis or secondary infections not includ ing covid . other cause of death included multiorgan failure in addition to alternative causes. preplanned secondary outcome measures were changes in inflammatory markers (creactive protein, il , ferritin, and ddimer), change in oxygena tion require ments, infections (defined as bacteraemia or pneumonia with positive sputum culture), and use of vasopressors. demographic and clinical variables of tocilizumab treat ment were summarised using median (iqr) for con tinuous variables and by frequency (%) for categorical variables. differences in the median and distribution of demographic and clinical variables between patients who received tocilizumab and those who did not were com pared using mood's median test for continuous variables and fisher's exact test or pearson's χ² test for categorical variables. to analyse overall survival we plotted kaplanmeier curves and did the logrank test to compare outcomes of patients who received tocilizumab and did not receive this drug. the index date used for overall survival was the date of hospital admission. adjusted cox proportional hazards regression models were fitted to estimate the associ ation between tocilizumab use and overall survival, using clini cally likely confounders including age, gender, diabetes, chronic obstructive pulmonary disease (copd) or asthma, hypertension, cancer, renal failure, obesity, oxygena tion less than %, quick sequential organ failure assessment (qsofa) score, use of steroids, creactive protein mg/dl or higher, and intubation or mech anical ven tilator support. to account for immortal time bias in the group receiving tocilizumab, time to tocilizumab treatment after admis sion was also adjusted. when the goodnessoffit model was not satisfied, we further reduced all these con founders using stepwise variable selection. hazard ratios (hrs) and % cis were summarised. to reduce confounding effects secondary to imbalan ces in receiving tocilizumab treatment inherent to a retro spective cohort study, we did propensity score matching. propensity score-matched patients (n= )* first, we calculated a propensity score of receiv ing tocilizumab treatment for each patient using multi variable logistic regression with the confounders age, gender, diabetes, copd or asthma, hypertension, cancer, renal failure, obesity, oxygenation less than %, qsofa score, use of steroids, creactive protein mg/dl or higher, and intubation or mechanical ventilator support. goodness of fit of the multivariable logistic model was examined using the hosmerlemeshow test. we then used nonparametric nearestneighbour matching of propensity scores to generate a matched cohort in a : ratio to pair a patient with tocilizumab treatment to two patients who did not receive tocilizumab, using the matchit package in r. , in the propensity scorematched population, we repeated the adjusted cox modelling done in the unmatched population. moreover, we compared the medi ans of each biomarker between patients who received tocilizumab and those who did not receive tocilizumab at days , , , and using mood's median test. subgroup analyses were done of patients who received mechanical ventilator support and who were older than years and aged years or younger, using the same datasets. missing data for categorical con founders with more than % missing data were coded as a missing data category and were included in all analyses. completely observed dataonly analyses were followed. we assessed the sensitivity of hr estimates to varying sets of confounders, including the propensity score as a covariate in the unmatched model and includ ing confounders chosen by stepwise selection. we judged statistical significance when the p value was less than · . for subgroup analyses, bonferroni correction (type i error of · ) was applied and % cis were also reported (appendix pp - ). for secondary outcome analyses, no multiplicity correction was applied. all statistical analyses were done using r version . . propensity score-matched patients (n= )* data are n (%) or median (iqr). copd=chronic obstructive pulmonary disorder. qsofa=quick sequential organ failure assessment. fio =fractional concentration of oxygen in inspired air. peep=positive end-expiratory pressure. pao =partial pressure of arterial oxygen. * variables were used for propensity score matching: age, gender, diabetes, copd or asthma, hypertension, cancer, renal failure, obesity, oxygenation < %, qsofa score, use of steroids, c-reactive protein > mg/dl, and intubation or mechanical ventilator support. hosmer and lemeshow goodness-of-fit test, p= · . †number of comorbidities from diabetes, copd or asthma, hypertension, coronary disease, cerebrovascular disease, heart failure, arrhythmia, cancer renal failure, rheumatological disorder, and body-mass index ≥ kg/m². the prospective observational database is registered on clinicaltrials.gov, nct . this study received no external funding. ai, slg, nb, ja, mm, bas, and sw had access to raw data. the corres ponding author had full access to all data in the study and had final responsibility for the decision to submit for publication. between march and april , , patients were flagged in the electronic health record with a diagnosis of covid . to reduce sampling bias, data were abstracted for ( %) patients. the remaining ( %) patients were not abstracted because of limited human resources during the peak of the covid pandemic in new jersey. ( %) patients needed support in the icu (figure ). no patients were known to have been receiving tocili zumab for chronic rheumatological conditions. the distribution of baseline characteristics according to tocilizumab exposure is shown in table . in the unmatched population, patients who received at least one infusion of tocilizumab were significantly younger than patients who did not receive tocilizumab (median age years [iqr - ] vs years [ - ]; p= · ). ( %) of patients who did not receive tocilizumab had three or more comorbidities, compared with ( %) of patients who received tocilizumab. a propensity scorematched population was constructed of patients, who received at least one infusion of tocilizumab and who did not receive tocilizumab. the propensity scorematched population was well balanced except with respect to nursing home residents ( of patients in the propensity scorematched population who received tocilizumab, ( %) received mg flat dosing, two ( %) received mg/kg, and two ( %) received other doses; ( %) received one infu sion and ( %) received a second infusion. tocilizumab was administered a median of days (iqr - ) after the start of patientreported symptoms, a median of days ( - ) from the date of hospitalisation, and a median of days ( - ) from the date of icu support. patients were followed up until may , . median followup of patients in the propensity scorematched population was days (iqr - ). ( %) of patients died, ( %) of who received tocilizumab and ( %) of who did not receive tocilizumab. causes of death among the patients who received tocilizumab were respiratory (n= ), cardiac (n= ), infectious (n= ), and other causes (n= ); for patients the cause of death was not apparent. causes of death among the patients who did not receive tocilizumab were respiratory (n= ), cardiac (n= ), infectious (n= ), and other causes (n= ); for patients the cause of death was not apparent. median overall survival from time of admission for patients receiving tocilizumab was not reached ( % ci days-not reached) and for those who did not receive tocilizumab it was days ( - ; hr · , % ci · - · ; p= · ; figure ). in the unmatched cohort, there was a similar finding in median overall survival in patients receiving tocilizumab (not reached, % ci days-not reached) versus those not receiving tocilizumab ( days, - ; p= · ; overall survival data were not available for patients in the unmatched population; appendix p ). after adjusting for time from initial tocilizumab treat ment, the findings were also similar (appendix p ). in the primary multivariable cox regres sion analysis with propensity score matching, exposure to tocilizumab was associated with lower hospitalrelated mortality (hr · , % ci · - · ; p= · ; table ). sensitivity analyses showed similar associations (appen dix pp - ). in the subgroup of patients in the propensity score matched population who required mechanical ventilation, patients who received tocilizumab had reduced hospital related mortality (hr · , % ci · - · ; p= · ; table ; appendix p ). hospitalrelated mortality was slightly reduced in patients younger than years (hr · , % ci · - · ; p= · ), but not in those aged years or older ( · , · - · ; p= · ; table ; appendix pp [ ] [ ] . dose intensity of steroid treatment was not obtained in the study. however, use of steroids was not associated with decreased hospitalrelated mortality in the overall propensity scorematched population (hr · , % ci · - · ; p= · ; table ), or among any of the patient subpopulations (table ; appendix p ). sensi tivity inspired by findings of a nonpeerreviewed tocilizumab study, a posthoc analysis was done of creactive protein (≥ mg/dl or < mg/dl). creactive protein data were available for ( %) of patients in the propensity scorematched population. a reduction of creactive protein with tocilizumab exposure was noted at , , and days after initiation of treatment in the propen sity scorematched population (appendix p ). among patients with creactive protein levels of mg/dl or higher, tocilizumab exposure was associated with decreased hospitalrelated mortality (hr · , % ci · - · ; p= · ; table ; appendix p ). however, among patients with baseline creactive protein levels less than mg/dl, little protective association was seen between tocilizumab and hospitalrelated mor tality (hr · , % ci · - · ; p= · ; table ; appendix p ). a transient increase in il concentration was noted at days and among patients who received toci lizumab. no associations were identified for amounts of ddimer, ferritin, or lactate dehydrogenase (appendix p ). in the propensity scorematched population, ( %) of patients who received tocilizumab and ( %) of who did not receive tocilizumab developed bac ter aemia during icu support. positive sputum cultures were identified in ( %) and ( %) patients, respectively. overall secondary bacterial infections were recorded in ( %) of patients who received tocilizumab and ( %) of patients who did not receive tocilizumab. cardiac vasopressor support was used equally, regardless of receipt of tocilizumab ( [ %] of and [ %] of , respectively). no association was reported in reduction of fractional concentration of o in inspired air requirements and receipt of tocilizumab at day after treatment, and little association was seen in changes of positive endexpiratory pressure or partial pressure of o in arterial blood values (appendix p ). in this multicentre observational study of patients with covid requiring icu support, receipt of tocilizumab was associated with a reduction in hospitalrelated mortality. moreover, patients who required mech anical ventilator support and those younger than years showed a favourable reduction in hospitalrelated mortality with tocilizumab. furthermore, in a posthoc analysis, a reduction in mortality was seen in patients who received tocilizumab who had concentrations of creactive protein of mg/dl or higher. therefore, tocilizumab seems to be among the first potentially successful treatments for patients with severe covid requiring icu support, pending confirmation by an ongoing randomised trial (nct ). the cytokine storm noted in patients with latestage sarscov infection is typically the primary cause of death. the aberrant host immune response includes increased concentrations in plasma of pro inflammatory cytokines, including il , which trigger further organ tissue damage. , in view of similarities between the cytokine storm syndrome of covid and the cytokine release syndrome associated with car tcell therapy, a rationale for il directed blockade is easily drawn. , we identified an association between concentrations of creactive protein, tocilizumab, and overall survival, poten tially suggesting that tocilizumab could exert its effects among patients whose covid illness is progressing to an inflammatory state. patients who received tocilizumab showed a reduction in creactive protein levels at , , and days after administration of tocilizumab compared with patients who did not receive tocilizumab. the potential beneficial association of tocilizumab was seen only in patients with creactive protein of mg/dl or higher at baseline. creactive protein and il have been reported to be the most sensitive and reliable factors in dis tinguishing disease severity and prognosis. missing vs no · ( · - · ) · · ( · - · ) · qsofa score missing regulate creactive gene expression in transgenic animals and serves as one of the necessary drivers of increased creactive protein. , several reports have described a correlation between concentrations of ferritin, ddimer, and lactate dehydro g en ase with severity of covid . , il blockade has also been reported to reduce covid mortality, and a study from the groupe hospitalier paris saintjoseph showed a significant decrease in risk for icu admission, mechanical ventila tion, or death with use of the il receptor antagonist anakinra. recognition of inflam ma tory markers or other cytokinedirected treatment could have important implications for treatment selection. tocilizumab was administered early in the icu course, typically on the day of admission for icu support, and a median of days since the start of selfreported symptoms. whether earlier administration of tocilizumab at the time of hos pital admission might improve outcomes and decrease overall resource use requires study. in the recovery trial, steroid use was associated with improvement in survival among patients with severe sarscov infection. among all patients in our propen sity scorematched population, steroid use was not associ ated with a reduction in hospitalrelated mortality. baseline mortality for intubated patients in the icu in our study was significantly higher than in the recovery study ( [ %] of who did not receive tocilizumab in our study vs [ %] of without dexamethasone in recovery), suggesting possible differences in patient populations. we did not note an associated increase in secondary bacteraemia with tocilizumab treatment. the frequency of secondary bacterial infec tions was % in patients who received tocilizumab and % in those who did not. our infec tion rates seem low for a cohort of critically ill patients. however, we administered a lower dose of tocilizumab (a mg flat dose as a onetime infusion in most patients) by contrast with mg/kg dosing used in the ongoing, international, randomised placebocontrolled trial. an increase in use of hydroxychloroquine was noted in patients who received tocilizumab compared with those who did not receive tocilizumab, which we do not believe had a relevant effect on our findings because most observational studies have not reported a benefit for hydroxychloroquine among hospitalised patients, despite potentially some activity in early sarscov infection. our observational study has limitations. first, obser vational studies cannot draw causal inferences because of inherent known and unknown confounders. we attempted to adjust for known confounders using our propensity scorematched approach. we also did several sensitivity analyses, including models with the propensity score as a covariate, models with stepwise selection of covariates based on the akaike information criterion, and models selected by lasso. second, misclassifications of data are possible because we manually abstracted struc tured and unstructured data from electronic health records. missing data were addressed by creating a category for missing in the multivariable cox regression analysis for the key (categorical) confounders with more than % missing data. we also did a sensitivity analysis when we excluded patients with missing information (appendix pp - ). our study focused on patients in the us state of new jersey, limiting applicability to other geographical regions, although this us state's population is diverse and the hackensack meridian health network included hospitals with differing treatment protocols. further, we acknowledge the possibility of indication bias, because it was not always clear why some patients were given tocilizumab or not. patients considered to have severe sarscov infection by institutional guidelines were permitted to receive tocilizumab at the discretion of their treating clinician. our cohort had a high prevalence of comorbidities and were older, in the setting of an over burdened healthcare system, and represented the peak incidence of sarscov infec tion, which probably skewed our mortality rates higher than those reported in other cohorts. finally, we acknow ledge the possibility of sampling bias since we obtained data from a convenience sample in attempts to do a rapid investigation during a pandemic. tocilizumab exposure among patients with severe sarscov infection requiring icu support was associ ated with a reduction in hospitalrelated mortality. these data could help to inform current clinical practice while randomised controlled trials are underway. cytokine release syndrome in severe covid : interleukin receptor antagonist tocilizumab may be the key to reduce mortality pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology fda approval summary: tocilizumab for treatment of chimeric antigen receptor t cellinduced severe or lifethreatening cytokine release syndrome pathological findings of covid associated with acute respiratory distress syndrome effective treatment of severe covid patients with tocilizumab tocilizumab treatment in covid : a single center experience efficacy and safety of tocilizumab in severe covid patients: a singlecentre retrospective cohort study offlabel use of tocilizumab for the treatment of sarscov pneumonia in tocilizumab for the treatment of severe covid pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of patients in tocilizumab improves significantly clinical outcomes of patients with moderate or severe covid pneumonia realworld evidence: what is it and what can it tell us? use of electronic health record data in clinical investigations: guidance for industry framework for fda's realworld evidence program a simplified method of calculating an overall goodnessoffit test for the cox proportional hazards model matching as nonparametric preprocessing for reducing model dependence in parametric causal inference matching methods for causal inference: a review and a look forward effects of tocilizumab on mortality in hospitalized patients with covid : a multicenter cohort study why tocilizumab could be an effective treatment for severe covid ? cytokine storms in infectious diseases the role of cytokines including interleukin in covid induced pneumonia and macrophage activation syndromelike disease validation of predictors of disease severity and outcomes in covid patients: a descriptive and retrospective study interleukin is necessary, but not sufficient, for induction of the human creactive protein gene in vivo creactive protein: eighty years from discovery to emergence as a major risk marker for cardiovascular disease the role of biomarkers in diagnosis of covid : a systematic review ddimer levels on admission to predict inhospital mortality in patients with covid interleukin blockade with highdose anakinra in patients with covid , acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study hydroxychloroquine or chloroquine for treatment or prophylaxis of covid : a living systematic review slg, ai, and nb had the idea for and designed the study. ja, sw, ahg, iss, and lsk contributed to study design. nb, ai, rcg, and slg did the literature search. nb, ai, ja, and sw prepared the figures. all authors contributed to data collection and data analysis. nb, ai, ja, sw, and slg contributed to data interpretation. nb, ai, ja, rcg, sw, dss, and slg contributed to writing of the report. rcg is the primary investigator for the roche genentechcovacta study at hackensack university medical center. sm reports consultancy for regional cancer care associates and hackensack meridian health, outside of the submitted work. eh reports consultancy from regional cancer care associates and hackensack meridian health, outside of the submitted work. dss reports equity in cota. ahg is a primary investigator for genentechhoffman la roche, during the conduct of the study; reports personal fees and research funding as study investigator from acerta, astrazeneca, celgene, kite pharma, elsevier's practiceupdate oncology, gilead, medscape, mjh associates, onclive peer exchange, physicians education resource, and xcenda, outside of the submitted work; and reports research funding as study investigator from constellation, infinity, infinity verastem, janssen, karyopharm, and pharmacyclics, outside of the submitted work. alp reports equity in cota. lsk is a coinvestigator for the roche genentechcovacta study at hackensack university medical center. slg reports equity in cota. all other authors declare no competing interests. this study received no external funding. we thank the nurses, data managers, and clinicians who-after caring for their patients-assisted in abstraction of clinical data. key: cord- -knd avhu authors: mulpuru, sunita; aaron, shawn d.; ronksley, paul e.; lawrence, nadine; forster, alan j. title: hospital resource utilization and patient outcomes associated with respiratory viral testing in hospitalized patients date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: knd avhu testing patients for respiratory viruses should guide isolation precautions and provide a rationale for antimicrobial drug therapies, but few studies have evaluated these assumptions. to determine the association between viral testing, patient outcomes, and care processes, we identified adults hospitalized with respiratory symptoms from through at a large, academic, tertiary hospital in canada. viral testing was performed in % ( , / , ) of hospital admissions and was not associated with reduced odds for death (odds ratio . , % ci . – . ) or longer length of stay (+ day for those tested). viral testing resulted in more resource utilization, including intensive care unit admission, but positive test results were not associated with less antibiotic use or shorter duration of isolation. results suggest that health care providers do not use viral test results in making management decisions at this hospital. further research is needed to evaluate the effectiveness of respiratory infection control policies. i n , the coronavirus responsible for the severe acute respiratory syndrome (sars) outbreak infected and killed , persons worldwide ( ) . it was quickly recognized that this virus spread between close contacts, because % of infected case-patients were health care workers caring for patients infected with the sars coronavirus ( , ) . during the outbreak, respiratory infection control policies were developed by clinical infectious disease and public health experts, and their use was mandated in all canadian hospitals. these measures were attributed to the eventual control of the outbreak ( ) ( ) ( ) ( ) . as a result, infection control practices, including strict hand hygiene, viral testing of patient samples, and use of isolation precautions, quarantine rooms, and personal protective equipment, were mandated for routine use with all patients who sought treatment at emergency departments (eds) with respiratory symptoms and fever ( , ) . national guidelines suggest that patients admitted to acute care hospitals with infectious respiratory symptoms should receive screening for viral infections by answering symptom-based questionnaires, and they should be placed under droplet isolation precautions until definitive evidence rules out a transmissible respiratory illness ( , ) . viral testing in this setting is carried out with a nasopharyngeal (np) swab sample, which is processed by direct fluorescent antibody (dfa), pcr, or both to identify a viral pathogen. viral testing in these patients should improve diagnostic clarity, reduce the number of subsequent diagnostic tests and procedures required, and prevent infection transmission to other patients and health care workers by guiding the use of isolation precautions. however, these outcomes can only occur if physicians and infection control practitioners assess the results of the viral test and feel confident ruling out viral disease on the basis of the results. to date, whether respiratory viral testing in patients improves outcomes or care processes has not been proven in large studies. two small studies demonstrated that knowledge of the viral test results did not affect length of stay and subsequent antibiotic use ( , ) . however, previous study demonstrated reduced length of stay, mortality, and cost when using viral testing ( ) . these studies were limited by the following: relatively small sample sizes; only single winter seasons being evaluated; and utilization of hospital resources, including isolation precautions, not being assessed ( ) ( ) ( ) . to address this gap in evidence, we set main objectives for this study. first, we aimed to determine the association between the use of viral testing and subsequent hospital resource utilization (antibiotic/antiviral drugs prescribed; radiology studies conducted; cultures and bronchoscopies performed), including the duration of isolation precautions. second, we aimed to determine whether viral testing was associated with in-hospital deaths, admission to intensive care, and length of stay in the hospital. we conducted a large retrospective observational cohort analysis based at the ottawa hospital (toh), an adult academic hospital located in ottawa, ontario, canada, with ≈ , inpatient beds. toh is a tertiary care referral center that provides care for . million patients in the eastern ontario region. we created the study cohort using hospital administrative and clinical data from the ottawa hospital data warehouse, a relational database containing information from toh's patient registration system, the clinical data repository (containing laboratory, pharmacy, radiology, and clinical notes), and the discharge abstract database. data from these operational systems are loaded into the database on a daily basis and linked by patient unique identifiers. extensive assessments of data quality were performed during the development of the database. we identified hospitalizations of adult patients from january , , through december , . hospitalizations were included if the patient was admitted through the ed with any combination of cough, fever, or shortness of breath. we excluded hospitalizations resulting from a transfer from another health institution (such as a long-term care facility or another regional hospital). if a patient had been seen in the ed with respiratory symptoms but was not subsequently admitted, the patient was also excluded from the study. the np swab sample, processed by dfa or pcr, was the exposure of interest for each hospitalization. the standard of practice at our center during the study period was to process np swab samples with dfa. however, during the influenza a(h n ) pandemic season, multiplex pcr was used to detect viruses. the multiplex pcr can detect influenza a or b, respiratory syncytial virus, parainfluenza virus, enterovirus, adenovirus, human metapneumovirus, rhinovius, and coronavirus. we developed and validated an algorithm within our dataset to determine whether np swab samples were analyzed, and categorized them as positive or negative on the basis of the dfa or pcr result (positive test refers to identification of a respiratory virus). the primary outcomes considered in this study were number of inpatient deaths, and length of hospital stay. secondary outcomes included admission to the intensive care unit (icu) and measures of resource utilization, including antibiotic and antiviral prescriptions, chest radiograph and computed tomography imaging, blood and sputum cultures, bronchoscopy, and use and duration of isolation precautions in the hospital. the unit of analysis in this study was the patient's hospitalization. patient characteristics were compared across groups (with and without viral testing performed) and were described by using proportions, means with sds, and medians with interquartile range when appropriate. using similar methods, we then compared groups with positive and negative np swab sample results among the hospitalizations in which an np swab sample was analyzed. we assessed the difference of means and sd for continuous variables using a -way analysis of variance test (anova) and for differences between proportions using a χ test. for all statistical tests, p< . was considered statistically significant. we measured patient coexisting conditions using the elixhauser score ( , ) , a validated scoring system which summarizes comorbid illness and can predict the patient's risk of death in the hospital ( ) . it was derived and validated by using hospitalization data from toh, and the score was based on the original comorbidity diagnosis groups in the elixhauser comorbidity classification system ( , ) . the elixhauser summary score ranges from a minimum of - to + , which are associated, respectively, with a . % and . % risk of in-hospital death ( ) . baseline risk of death at the time of hospitalization was calculated for each hospitalization by using a regression model previously validated by data from toh's patient population ( , ) . we defined influenza seasons on the basis of dates recorded in the public health agency of canada's national surveillance system for influenza, flu-watch ( ). we used this information to categorize hospital admissions according to whether or not they occurred during an influenza season. we created multivariate logistic regression models to investigate whether having an np swab sample obtained and tested was associated with probability of death and icu admission. for each outcome in which the patient died or was admitted to the icu, univariate odds ratios (ors) were calculated for patient sociodemographic factors, clinical factors related to the hospitalization, patient comorbidity, and whether the patient was admitted to the hospital during influenza season. a multivariate model was created on the basis of significant predictors of death and icu admission and was reduced by using stepwise variable selection. we used unadjusted and adjusted linear regression models to determine the change in length of stay in hospital when an np swab sample was tested during the admission process. we used a natural logarithm transformation of the length of stay variable to adjust for the left skewed distribution of this variable. in a secondary analysis, the same methods were used to develop multivariate logistic regression models to investigate the association between the np swab sample testing (positive or negative test result) and odds of death and icu admission. multivariate linear regression was used to evaluate length of stay. we conducted a sensitivity analysis of a subgroup of hospitalizations in which the most responsible discharge diagnosis was a pulmonary infection or exacerbation. this was done to account for the fact that patients seeking treatment for respiratory symptoms could have received a diagnosis of a noninfectious condition (such as heart failure or pulmonary embolism). we limited the discharge diagnosis to diagnoses of respiratory infections or exacerbations to determine whether there was any effect on the study outcomes. in this group, we assessed the potential association between having an np swab sample tested and clinical outcomes (online technical appendix table , http://wwwnc. cdc.gov/eid/article/ / / - .pdf). all analyses were conducted by using sas . statistical software (sas institute inc., cary, nc, usa). this study was approved by the ottawa health sciences network research ethics board, and a waiver of patient consent was granted. during the -year study period, we identified , hospital admissions in which the patient sought treatment at the ed reporting chief symptoms of fever and/or cough and/or shortness of breath. these admissions represented , unique patients. baseline characteristics of the study cohort are described in table . an np swab sample was tested in % ( , / , ) of admissions. overall, patients who had an np swab sample tested were younger, more likely to be admitted during influenza season, and more likely to be female. table describes likelihood of deaths, icu admission, length of stay, and use of isolation precautions in the study cohort and among hospitalizations in which the patient had a positive or negative np swab sample. during hospitalizations in which an np swab sample was tested, length of stay in hospital was longer ( . days vs. . days, p< . ) and mean duration of isolation precautions was longer ( . days vs. . days, p< . ) than in hospitalizations in which an np swab sample was not tested. there was no significant difference in the mean number of days spent in isolation between hospitalizations in which the patient had positive or negative np swab samples ( . ± . vs. . ± . days, p = . ). table describes the use of hospital resources (antibiotic drugs, antiviral drugs, chest imaging studies, cultures, and bronchoscopy) among hospitalized patients with positive and negative np swab samples. among hospitalizations in which the sample was positive ( / , ) and hospitalizations in which it was negative ( , / , ), no significant differences were found in process of care variables, with exception of more antiviral drug use and less use of computed tomography chest scans in the group with positive swab samples. hospitalizations in which an np swab sample was analyzed used statistically more resources than those in which no swab sample was tested (p< . , for all hospital resources measured). after adjustment for confounding variables, there was no association between having an np swab sample tested in the hospital and odds of death (or . , % ci . - . ). we identified a significant increase in icu admission when a patient's np swab sample had been tested (or . , % ci . - . ). finally, linear regression analysis demonstrated a nonsignificant -day increase in length of stay among hospitalized patients for whom a sample was tested (p = . ; ors with % cis are shown in online technical appendix table ). among the hospitalizations in which an np swab sample was tested (n = , ), no significant associations were found between a positive swab sample and odds of death, icu admission, or length of stay (online technical appendix table ). in a restricted cohort of hospitalized patients in which an infectious respiratory diagnosis was made (n = , ), the fact that an np swab specimen was tested was not associated with reduction in chance of death but was significantly associated with increased icu admission. length of stay was also significantly increased by day ( % ci . - . days, p = . ), which was not the case in the primary analysis (online technical appendix table ). in this study, viral testing of respiratory samples during hospitalization was not associated with a significant reduction in odds of patient deaths or length of hospital stay after adjustment for critical clinical confounding factors. viral testing, however, was associated with increased likelihood of admission to the icu. our study also did not find that respiratory viral testing was associated with significant reductions in antibiotic use, chest imaging studies, bronchoscopy, or microbiologic cultures among patients with infectious respiratory symptoms. most notably, a positive viral test result did not lead to significant reductions in antibiotic use, number of chest radiographs obtained, and number of blood cultures requested. it is plausible that lack of any observable beneficial effect on these outcomes is a result of health care providers neglecting to adjust care processes on the basis of the testing results. although more isolation precautions were used with patients with positive viral test results than with those with negative test results ( % vs. %, p< . ), the test result did not influence the duration of isolation precautions. no statistical difference was found in the mean number of isolation-days between hospitalizations in which positive and negative viral test results were obtained ( . days vs. . days, p = . ). this finding could have several potential causes, however. first, health care providers may not be translating negative test results into the action of removing isolation precautions because of lack of infection control directives for front-line staff (nurses and physicians) to guide the safe removal of isolation precautions. as a result, patients may remain under isolation precautions for a standard fixed duration, regardless of the viral test result. second, perhaps front-line staff fear the possibility of infection transmission (even when the np swab sample is negative) and continue the precautions as a conservative measure. we found that hospitalized patients for whom np swab samples were tested had a greater chance of icu admission, after adjustment for confounders, including admission during influenza season, isolation status, and baseline risk for death. this observation remains unexplained. it may be due to residual confounding, but it is also conceivable that obtaining the np swab sample and subsequent isolation precautions may put some patients at risk for adverse events that require icu admission. abad et al. conducted a systematic review and found that isolation precautions are associated with greater adverse drug events, less physician and nurse care, and increased patient scores for anxiety and depression ( ) . in a prospective study, stelfox et al. found that patients in isolation experienced more preventable adverse events in the hospital, made more formal complaints to the hospital about their care, were more likely to have had no vital signs done when ordered, and had more days with no physician progress notes, when compared with nonisolated controls ( ) . relatively few studies have evaluated the effects of respiratory viral testing on processes of care and clinical ( ) . their overall conclusion was that early knowledge of the viral test result did not significantly reduce the duration of antibiotics, or costs, when compared with those of a group in which the viral test results were not made available ( ) . the results of these small prospective studies are generally congruent with our results. however, we also found that a positive viral test result did not affect other processes of care, including whether blood and sputum cultures, bronchoscopy, and chest radiographs were obtained and, most notably, duration of isolation precautions. our study also examined the outcomes of patient death and icu admission, which were not addressed in the previous studies. our study has several strengths. it is the largest study conducted to evaluate the effects of respiratory viral testing on clinical outcomes in adult hospitalized patients. also, our data spanned years, including seasons of viral infections. given our sample size, all adjusted regression models had adequate power to evaluate the chance of death and icu admission outcomes ( ) . our study also has several limitations. the retrospective nature of this study makes the results vulnerable to unmeasured confounding. we accounted for temporal confounding due to influenza seasonality and for confounding by indication using validated measures of baseline mortality risk and comorbidity in the adjusted regression models. however, we did not capture acute vital signs and other nonlaboratory clinical data at the time patients sought treatment, which may have influenced the outcomes we studied. finally, the study was conducted by using data from a single academic center, which has implications for the generalization of these results to other medical institutions. however, the tertiary care hospital in this study follows national and international recommendations for infection control practices, which reduces the likelihood that practices would be significantly different from other major medical centers. our results suggest that in this academic center during the study period, respiratory viral testing did not achieve the goals of reducing antibiotic prescriptions and other diagnostic tests, nor did it result in timely discontinuation of isolation precautions. because the duration of isolation is not guided by the viral test result, one questions whether the process of viral testing is helping reduce viral infection transmission in the hospital. we could not assess infection transmission in this study, but future work is required in this area. our findings should encourage hospital administrators and infection control practitioners to reevaluate current practices, so that viral test results are used appropriately to modify subsequent treatments and guide provision of isolation precautions. this study sets the foundation for further research to ensure that current policies and practices result in efficient resource utilization and prevent infection transmission in hospitals. world health organization global alert and response. summary of probable sars cases with onset of illness from epidemic viral pneumonia preventing respiratory illnesses: protecting patients and staff. recommended infection control and surveillance standards for febrile respiratory illness (fri) in non-outbreak conditions identification and containment of an outbreak of sars in a community hospital the sars outbreak and its impact on infection control practices transmission of influenza: implications for control in health care settings routine practices and additional precautions for preventing the transmission of infection in healthcare settings best practices for infection prevention and control programs in ontario in all health care settings no impact of early real-time pcr screening for respiratory viruses on length of stay and use of antibiotics in elderly patients hospitalized with symptoms of a respiratory tract infection in a single center in norway impact of rapid detection of viral and atypical bacterial pathogens by real-time polymerase chain reaction for patients with lower respiratory tract infection clinical and financial benefits of rapid detection of respiratory viruses: an outcomes study comorbidity measures for use with administrative data a modification of the elixhauser comorbidity measures into a point system for hospital death using administrative data the kaiser permanente inpatient risk adjustment methodology was valid in an external patient population risk-adjusting hospital inpatient mortality using automated inpatient, outpatient, and laboratory databases adverse effects of isolation in hospitalised patients: a systematic review safety of patients isolated for infection control impact of the rapid diagnosis of influenza on physician decisionmaking and patient management in the pediatric emergency department: results of a randomized, prospective, controlled trial effect of point-of-care influenza testing on management of febrile children clinical impact of rt-pcr for pediatric acute respiratory infections: a controlled clinical trial the effect of rapid diagnostic testing for influenza on the reduction of antibiotic use in paediatric emergency department a simulation study of the number of events per variable in logistic regression analysis key: cord- -p jdpt authors: levy, yael; bonnet, marie‐pierre; chemam, sarah; sabourdin, nada; louvet, nicolas; constant, isabelle title: unexpected benefits of the covid challenge: when critically ill adult patients are managed in a pediatric pacu date: - - journal: paediatr anaesth doi: . /pan. sha: doc_id: cord_uid: p jdpt nan and gynecology department: we have no "on-site" adult icu, cardiology, pneumology, and infectiology. despite the local pediatric medical culture, the entire staff showed great motivation and enthusiasm to take up the challenge. as surgical procedures were restricted to emergency cases, we decided to locate the temporary covid-icu in the pediatric postanesthesia care unit (pacu). partition walls were quickly built in this m open-space, allowing the creation of icu rooms, while ensuring a safe working space for healthcare providers. glass doors delimited a special airlock containing ffp- masks, protective gowns, glasses, face shields, gloves, hoods, and hydro-alcoholic gel. this area was dedicated to staff preparation before entering or after leaving the icu. to limit cross-transmission, covid and non-covid-specific care pathways had been defined previously in our hospital. as our standard equipment was mainly intended for small children, supplemental external supplies were necessary: that is, large tracheal tubes, central venous and arterial catheters, and adult-sized beds. local drug supplies had to be increased; formulations and concentrations had to be adjusted to adult requirements. ventilators, standard monitors, and syringe pumps were supplied by the anesthesiology department, and hemodynamic monitors were lent by manufacturers. radiology, biochemistry, and pharmacy departments provided specific resources on site. a new dedicated medical and paramedical team had to be created. doctors and nurses came mainly from the anesthesiology department. three of the physicians were recruited from the picu and the pediatric emergency department. the paramedical team included professionals: physiotherapists, nurse anesthetists, nurses from the operating rooms, pacu, and picu. three doctors ( during the night shift), one medical student, nurses, and assistant nurses worked simultaneously in the icu. every professional was rapidly trained for the use of personal protection equipment. one of our physicians had worked for five years in adult critical care before joining the pediatric anesthesia team: she gathered resources from several adult icus, and coordinated the redaction of medical and paramedical protocols for our team. in addition, doctors were encouraged to use the online resources dedicated to covid management: webinars, moocs…, etc a daily teleconference was held to exchange information, provide medical advice, and discuss cases between the different icus of paris. two simulation sessions for a caesarean section in emergency in the pediatric operating room as one of our patients were a pregnant woman. our icu was designed as a step-down unit, dedicated to the management of ventilated patients transferred from standard adult icus. seven patients ( - years old) were admitted in this temporary unit. the most frequent comorbidities were hypertension ( / ), diabetes ( / ), and obesity ( / ). on admission in our icu, all patients had been ventilated for at least days in a different hospital, and still required mechanical ventilation. after the peak of the epidemic, the regional icu bed capacity increased, allowing us to relocate our patients in adult hospitals. at this time, one patient had been successfully extubated, two patients had died, and were still ventilated. one medical student was tested positive for covid- . this experience had several unexpected benefits. managing critically ill covid- -infected adults was medically and scientifically challenging for our pediatric team. the multidisciplinary collaboration also allowed building solid relationships among caregivers from different departments of our institution, and from other regional icus. as pediatric hospitals were, at this moment, spared from the work overload observed in adult structures, all the professionals from our pediatric hospital were enthusiastic and proud to participate in this local adventure and national effort. sincere thanks to all the staff of trousseau covid- critical care unit. thank you for your dedication and courage. none financial or material support. the challenge of congenital heart disease worldwide: epidemiologic and demographic facts heart care international website children's heartlink website haiti cardiac alliance website heartgift foundation website unexpected benefits of the covid challenge: when critically ill adult patients are managed in a pediatric pacu | union/european economic area and the united kingdom french pandemic resistance the authors report no conflict of interest. key: cord- -abzpfdcu authors: martindale, robert; patel, jayshil j.; taylor, beth; arabi, yaseen m.; warren, malissa; mcclave, stephen a. title: nutrition therapy in critically ill patients with coronavirus disease (covid‐ ) date: - - journal: jpen j parenter enteral nutr doi: . /jpen. sha: doc_id: cord_uid: abzpfdcu in the midst of a worldwide pandemic of the coronavirus disease (covid‐ ), a paucity of data precludes derivation of covid‐ ‐specific recommendations for nutritional therapy. until more data are available, the focus needs to center on principles of critical care nutrition modified for the constraints of this disease process, i.e., covid‐ ‐relevant recommendations. delivery of nutritional therapy must include strategies to reduce exposure and spread of the disease by providing clustered care, adequate protection of healthcare providers, and preservation of personal protective equipment. enteral nutrition (en) should be initiated early after admission to the intensive care unit (icu) using a standard isosmolar polymeric formula, starting at trophic doses and advancing as tolerated while monitoring for gastrointestinal intolerance, hemodynamic instability, and metabolic derangements. intragastric en may be provided safely, even with use of prone positioning and extracorporeal membrane oxygenation. clinicians, though, should have a lower threshold for switching to parenteral nutrition in cases of intolerance, high risk of aspiration, or escalating vasopressor support. while data extrapolated from experience in acute respiratory distress syndrome (ards) warrants use of fiber additives and probiotic organisms. the lack of demonstrated benefit precludes a recommendation for micronutrient supplementation. practices which increase exposure or contamination of equipment, such as use of gastric residual volumes as a monitor, indirect calorimetry to calculate requirements, endoscopy or fluoroscopy to achieve enteral access, or transport out of the icu for additional imaging should be avoided. at all times, strategies for nutritional therapy need to be assessed on a risk/benefit basis, paying attention to risk for both the patient and the healthcare provider. this article is protected by copyright. all rights reserved as with any other critically ill patient, managing nutrition is an integral component of good supportive care. worldwide reports have revealed patterns that may be important to consider when planning nutrition support in critically ill patients with covid- . clinical predictors of infection severity and mortality include advanced age, obesity, diabetes mellitus, and clinical evidence of systemic inflammation (e.g., elevated crp, ferritin, and il- ). while most patients complain of fever, cough, and shortness of air, some covid- patients present with gastrointestinal (gi) symptoms (diarrhea, nausea, vomiting, abdominal discomfort and, in some cases, bleeding) and evidence of acute kidney injury. these variables have implications for nutritional interventions: [ ] older patients are at-risk for pre-existing disease and sarcopenia which increases their risk for pre-existing malnutrition and increased risk of refeeding syndrome, [ ] severe acute respiratory distress syndrome (ards) with refractory hypoxemia may require prone-positioning and/or extracorporeal membrane oxygenation (ecmo), [ ] circulatory failure and concomitant feeding may increase the risk of gut ischemia and feeding intolerance, [ ] multiple organ failure (mof) and the need for early enteral nutrition (en) to attenuate or mitigate gut derived inflammation, and [ ] cytokine release syndrome which alters nutrient utilization (especially lipids). these aforementioned factors may lead to prolonged illness, which often requires artificial nutritional therapy through the enteral and/or parenteral route. the nutritional management of the icu patient with covid- is in principle very similar to any other icu patient admitted with pulmonary compromise. however, due to limited evidence specifically regarding nutritional therapy in patients with covid- , the recommendations put forth in this document are based on indirect evidence from critically ill patients in general and those with sepsis and ards. december , thus updated modifications to this information are necessary for this report. , in this manuscript, we will address timing, route, and monitoring of nutritional therapy based on this article is protected by copyright. all rights reserved. best available evidence, but also provide guidance on management relevant to covid- by taking into consideration key guiding principles related to this disease process. nutritional therapy is an integral component of critical illness supportive care measures. critical illness exists in phases and includes an early acute phase, the immediate post-acute phase, and the recovery period. the acute phase is dominated by a hypercatabolic state in which amino acids are mobilized as substrate for acute phase protein and immune system products. furthermore, the rapid breach in gut barrier function, the immune dysregulation, and the ensuing dysbiosis propagate and accentuate the inflammatory response. like all interventions related to the care of the patient with covid- , the delivery of nutritional therapy in critically ill patients should take into consideration the following principles: . "cluster care," meaning all attempts are made to bundle care to limit exposure. adherence to the center for disease control (cdc) and world health organization (who) recommendations to minimize aerosol/droplet exposure with an emphasis on hand hygiene and utilization of personal protective equipment (ppe) to protect healthcare providers and limit spread of the virus. this article is protected by copyright. all rights reserved. . preserve use of ppe, which in many health care settings is becoming a depleted commodity, by limiting the number of staff providing direct patient care, decreasing the number of entries into the covid- patient rooms, and optimizing other strategies which reduce consumption of these resources. recommendation : we recommend all healthcare providers, including dietitians, nurses, and physicians follow ppe standards set forth by the cdc and/or the who and adhere to their institutional guidelines when conducting bedside nutritional assessments for all patients with confirmed or suspected covid- disease. ppe includes protective eyewear, isolation gown, a face shield, and an n respirator (https://www.coronavirus.gov). rationale: pragmatically, with limited ppe supply, many dietitians are not entering icus or the rooms of patients in isolation and are not performing a nutrition-focused physical examination, but rather relying on other providers to collect physical examination data on the covid- patients. dietitians are using other means to collect assessment data, such as icu remote monitoring capabilities, calling the patient or family, and using telehealth visits involving various platforms (audio and visual). it is more important than ever that the dietitian document assessment findings, where/how the information was received, and collaborate and coordinate with the medical teams to develop a safe and effective nutrition care plan. this article is protected by copyright. all rights reserved. show that provision of early en to interventional patients improved mortality and reduced infections compared to controls for whom such therapy was delayed or withheld. , assuming patients were nutritionally replete prior to contracting covid- and the acute phase of illness is limited, the major societal guidelines for initiating and maintaining icu nutrition will suffice. most patients with sepsis or circulatory shock have been shown to tolerate early en at a trophic rate. unless vasopressor dose is escalating and/or enteral feeding intolerance ensues (e.g. ileus, abdominal distention, vomiting), circulatory shock associated with sars-cov- should not be seen as a contraindication to trophic en. early en may not be preferred in a subset of covid- patients with gi symptoms. before the onset of respiratory symptoms, some covid- patients first present with diarrhea, nausea, vomiting, abdominal discomfort and, in some cases, gi bleeding. in a meta-analysis of studies including patients; although not all these patients were critically ill the prevalence of anorexia was . %, nausea/vomiting . %, diarrhea . %, abdominal pain/discomfort . % and "any" gi symptom . %. some evidence suggests that the development of gi symptoms indicates greater disease severity. the presence of viral rna components has been documented in the feces of such patients (one trial showing % testing positive by stool studies alone). further, gi this article is protected by copyright. all rights reserved. involvement has been confirmed by the presence of an ace protein (a cell receptor for sars-cov- ) found in glandular cells on biopsy of esophageal, gastric, duodenal and rectal mucosa. , these findings suggest a fecal-oral route of transmission in addition to the aerosolized droplet respiratory mode of transmission for the sars-cov- virus, and another possible route of entry into the host cells. , patients with severe gi symptoms and/or enteral feeding intolerance should be considered for early parenteral nutrition (pn). the transition back to en should be attempted when symptoms subside. recommendation b: we recommend starting early pn as soon as possible in patients for whom early gastric en is contraindicated or not feasible and who are at high nutrition risk, malnourished or have an expected prolonged icu stay. , contraindications for en may include patients with gi symptoms, shock requiring escalating vasopressor support, or use of non-invasive positive pressure ventilation (nippv) such as bilevel or cpap. pn may be delayed in patients at low nutrition risk for - days, unless this level of risk changes. rationale: nippv has been utilized for management of respiratory failure related to covid- , although there are controversies about its effectiveness in preventing the need for intubation. practically, enterally feeding a patient on nippv may increase the risk for complications such as aspiration due to the gastric insufflation associated with this mode of ventilator support. in addition, placement of a feeding tube into a patient on nippv increases the risk for aerosolization and exposes healthcare personnel to virus transmission. thus, instituting early pn in this population is advised, particularly when nippv is utilized without interruptions for oral intake and there is increased concern for aspiration and who are at high nutrition risk or malnourished, pn may be considered. continuous postive pressure ventilation through helmet has been used exensively in italy for covid- patients, and nutition maybe provided more effectively and safely than mask nippv, but data are needed. non-occlusive bowel ischemia is rare with use of en in shock, with observational and contemporary rcts reporting an overall incidence of . %. however, in the this article is protected by copyright. all rights reserved. unusual circumstance of covid- disease where concern for ischemic bowel may be greater and a prolonged icu stay is expected, the threshold to initiate pn in lieu of en should be lower. early pn, as compared to no artificial nutritional therapy, has been shown to improve mortality in patients with pre-existing malnutrition. pn may subvert concerns for ischemic bowel and may reduce droplet aerosol transmission to healthcare providers by avoiding procedures involved in the initial placement and maintenance of an enteral access device. recommendation a: we recommend en be infused into the stomach via a - fr orogastric (og) or nasogastric (ng) feeding tube. if a larger bore og/ng tube was placed at time of intubation, it may be used for feeding. rationale: infusion of formula into the stomach via an og/ng tube requires minimal expertise and facilitates earlier initiation of feeding. if gastric feeding is unsuccessful due to enteral feeding intolerance, use of a prokinetic agent to enhance motility is recommended as the second step. these agents have been associated with qt prolongation, predisposing to cardiac arrhythmias which should be monitored. postpyloric en delivery is recommended only after these strategies fail. to minimize breach of airborne isolation and limiting exposure to healthcare providers, patients requiring a post pyloric feeding tube should undergo bedside placement with techniques that do not require use of endoscopy or fluoroscopic guidance. placement strategies using real time fda approved electromagnetic or integrated imaging guidance may eliminate the need for placement confirmation by abdominal x-ray if this adheres to the institution's policy and procedures. confirmatory abdominal x-rays should be clustered with chest x-rays as feasible. placement of any enteral access device may provoke coughing and should be considered an aerosol-generating procedure. if possible, keep the patient's mouth covered during placement in this article is protected by copyright. all rights reserved. the nares and follow cdc and who guidelines regarding the use of n- masks or powered, airpurifying respirator (papr). post-pyloric feeding tubes tend to be smaller caliber and therefore are more likely to become clogged with decreased flushing than a larger bore ng/og tube, which may occur with clustering of care and the goal to limit patient contact. in addition, use of en in these high-risk patients often necessitates monitoring by more frequent abdominal exams which may not be ideal given potential shortages of ppe. lastly, placement of post-pyloric feeding tubes may take longer to place than gastric tubes, increasing the absolute exposure time of the healthcare practitioner. recommendation b: we recommend continuous rather than bolus en in critically ill patients with covid- . the recommendation for continuous en delivery is supported by both the espen and sccm/aspen guidelines. - multiple meta-analyses have shown a significant reduction in diarrhea with no differences in other outcome parameters with continuous en. in addition, since bolus en delivery would require more frequent patient interaction, continuous en delivery decreases exposure of the healthcare team to sars-cov- . if the patient room allows, pumps should to be placed "outside" the room to minimize patient exposure and avoid contamination and particularly during shortages where pumps needs to be shared, this should also include the feeding pump and bag set if possible. as much extension tubing as needed may be utilized, as long as it allows for proper flow and is compatible with en connectors and delivery system. rationale: resuscitation of the critically ill patient takes priority. introducing en into a severely hypoperfused gut increases the risk for enteral feeding intolerance and non-occlusive bowel ischemia. en may be initiated/restarted after the patient is adequately resuscitated and/or has been on a stable vasopressor dose with sustained mean arterial pressure of > mmhg. , recommendation c: we recommend switching from en to pn in patients with persistent or significant enteral feeding intolerance as manifested by unexplained abdominal pain, unremitting vomiting, unexplained diarrhea (e.g., antibiotic-induced or clostridial colitis), abdominal distention, dilated loops of bowel with air/fluid levels, or pneumatosis intestinalis. , this article is protected by copyright. all rights reserved. rationale: covid- patients have been reported to have prolonged mechanical ventilation, lasting weeks. insufficient nutritional therapy due to enteral feeding intolerance predisposes the patient to a greater calorie deficit, negative nitrogen balance, and deteriorization of nutritional status. furthermore, enteral feeding intolerance may predispose bedside personnel to more frequent patient exposures, increasing the risk of virus transmission and ppe utilization. early pn in this population may reduce calorie deficits and provide amino acids to improve nitrogen balance. recent pragmatic studies comparing early en to pn in critically ill patients have shown no increased infectious risk with early pn and no difference in mortality, suggesting early pn is safe and feasible when early en cannot or will not be provided. , recommendation d: we recommend obtaining a history and performing a bedside assessment, when possible, to identify pre-existing malnutrition and risk factors for refeeding syndrome. rationale: we recognize some healthcare institutions have limited bedside patient access to avoid exposure to sars-cov- . when bedside examination is restricted, obtaining history and performing a nutrition assessment can be conducted in conjunction with a non-nutrition expert under the principle of clustering care. critically ill patients with covid- tend to be older with multiple co-morbidities. such patients are often at-risk of refeeding syndrome. , thus, identifying pre-existing malnutrition or other risk factors for refeeding syndrome in critically ill patients is vital. if risk for refeeding syndrome is present, we recommend starting at approximately % of caloric requirements while advancing slowly to goal ( - % of requirements) over to days, in either en or pn fed patients, combined with frequent monitoring of serum phosphate, magnesium and potassium levels. the first hours of feeding is the period of highest risk. this article is protected by copyright. all rights reserved. recommendation a: we recommend using a standard high protein (> % protein) polymeric isoosmotic enteral formula in the early acute phase of critical illness. as the patient's status improves and vasopressor requirements and gi dysfunction abate, addition of fiber should be considered. a fiber containing formula or supplement provides non-nutritional benefits to the gut microbiota. recommendation c: we recommend monitoring serum triglycerides in patients receiving propofol and/or intravenous lipid emulsions early in their course, taking into consideration and context that elevated serum triglyceride levels may be due to secondary hemophagolymphocytic histiocytosis this article is protected by copyright. all rights reserved. (hlh), which is a hyperinflammatory response secondary to cytokine storm that occurs in a subset of covid- patients. rationale: there have been numerous anecdotal reports from several centers from around the world that covid- patients who receive propofol or pure soy-based lipids rapidly develop severe hypertriglyceridemia. elevated serum triglyceride in patients receiving propofol may in fact be due to secondary hlh, which occurs in a subset of covid- . serum triglyceride is a component of criteria for identifying secondary hlh and it is vital to distinguish secondary hlh from propofolrelated hypertriglyceridemia. the pathogenesis for elevated serum triglyceride in secondary hlh is unclear. recommendation a: we recommend not checking gastric residual volumes (grv) in patients receiving en. rationale: enteral feeding intolerance is common during the early and late acute phases of critical illness. early experience with critically ill covid- patients suggests that gi symptoms (which might manifest as enteral feeding intolerance) are associated with greater severity of illness. grv monitoring is not reliable for detection of delayed gastric emptying and risk of aspiration, has been shown to be a deterrent to the delivery of en, and should not be utilized as a monitor of feeding tolerance. furthermore, per the guiding principles in caring for the critically ill patient with covid- disease, this recommendation is relevant to decrease the risk of covid- transmission to the healthcare provider. recommendation b: we recommend patients be monitored by daily physical examination and confirmation of passage of stool and gas and that these observations should be "clustered" with other provider activities to minimize healthcare team virus exposure. as with any icu patient, the percent of calories and protein delivered should be recorded for both en and pn. this article is protected by copyright. all rights reserved. rationale: enteral feeding intolerance is common during the acute phase of critical illness. abrupt worsening of clinical status has been observed in covid- patients, hallmarked by heightened inflammation, worsening oxygen requirements, and multiple organ failure. these conditions increase the risk for enteral feeding intolerance. thus, where available, bedside assessment through physical examination remains imperative to guide further delivery of en or the need for transitioning to pn. , several retrospective and small prospective trials have shown en during prone positioning is not associated with increased risk of gi or pulmonary complications. [ ] [ ] [ ] [ ] many patients tolerate en delivered into the stomach while in the prone position, but on occasion, post-pyloric placement of the feeding tube may be indicated. however, placement of post-pyloric tubes increases exposure to sars-cov- and thus their use should be evaluated on a case-by-case basis in covid- patients. when en is introduced during prone positioning, elevating the head of the bed (reverse trendelenburg) to degrees may decrease the risk of aspiration, facial edema, and intra-abdominal hypertension. , this article is protected by copyright. all rights reserved. other observational data shows safety and tolerability of gastric en delivery during ecmo. extrapolating from observational data from the h n pandemic, most patients tolerated early en within hours of initiating ecmo. in the largest observational study of en during veno-arterial (va) ecmo, ohbe found early en, compared to delayed en, was associated with a reduction in -day mortality, with no cases of bowel ischemia reported. park et al noted similar experience, finding that increased en calories and protein delivery was associated with a decreased day mortality. recommendation a: we recommend providing protein at a dose of . to . gm/kg abw/day (or . gm/kg ideal body weight/day in those patients with bmi > ) in critically ill patients with acute kidney injury (aki) undergoing renal replacement therapy (rrt). , this article is protected by copyright. all rights reserved. rationale: critically ill patients with aki undergoing rrt lose up to grams of amino acids per day in the dialysate. observational data have demonstrated that up to . gm/kg/day is well tolerated and is associated with a positive nitrogen balance. , recommendation b: we recommend monitoring and repletion of micronutrients in critically ill patients undergoing rrt as recommended in the aspen/sccm and espen guidelines. [ ] [ ] [ ] rationale: micronutrients in the critically ill with severe aki has been recently evaluated by ostermann et al. they reported below normal range plasma levels of zinc, iron, selenium, vitamin d , vitamin c, and several amino acids in patients undergoing continuous renal replacement therapy (crrt). they concluded micronutrient levels were low in patients with aki regardless of the rrt modality. disclaimer: supplementation with several specific vitamins, minerals, probiotics and pharmaconutrients have been proposed in several icu populations over the past years with some studies demonstrating benefit. as we navigate untested therapeutic strategies in the covid- population, we acknowledge no covid- specific data for their use is available. providing false hope with untested or unstudied nutritional agents will only be a detriment to our patients and their families. we acknowledge any intervention (not just nutritional ones) for our patients cannot be driven by fear and misinformation, which often supersedes the scientific evidence. thus, the this article is protected by copyright. all rights reserved. information for the following nutrition interventions are, at best, hypothesis-generating, in the covid- population. probiotics: coronavirus along with several other viruses can cause upper respiratory infections (uris) in humans. these include viruses such as respiratory syncytial virus, adenovirus, human coronavirus and human parainfluenza virus. these viruses are responsible for up to % of uris in adults globally. the use of probiotics for uris (not specifically covid- ) has shown benefit in patients with viral uris. in studies comparing placebo vs probiotics, the probiotic supplemented groups showed fewer uris and were noted to be better than placebo in reducing the mean duration of uri symptoms. vitamins: no consistency is noted in supplementation of the b vitamins in viral illnesses or icu care. the literature is so widely variable that at this point no recommendation is made other than that supported by the societal guidelines. vitamin d has been shown to be beneficial in some animal viral infection models as well as some human studies. several articles widely speculating on the effects of vitamin d in covid- virus either prevention or treatment are being published as we navigate this new pandemic. caution must be exercised before wide acceptance of unsubstantiated or unstudied recommendation are made in patients with covid- infections. two recent icu trials evaluated vitamin d supplementation in patients admitted to the icu with documented deficiency of vitamin d. both well done studies showed no benefit of diets supplemented with vitamin d. , vitamin a has been studied in an animal model (chickens) given a low vitamin a diet. the deficient animals did show an increased susceptibility to coronavirus. this was not covid- . no human trials have been done. like vitamin a, vitamin e has been shown to benefit viral infections in animal studies (murine and this article is protected by copyright. all rights reserved. bovine) but no data is available in human icu trials. vitamin c has also been studied in chickens and it was reported that the animals showed increased resistance to coronavirus. a meta-analysis published in reported inadequate supportive data to make a specific recommendation for supplemental vitamin c in icu patients. in a more recent large human rct in septic patients with ards, vitamin c was given over a hour infusion at a relatively high dose. when compared to placebo the supplemental vitamin c reported no benefit. trace minerals: the trace minerals selenium and zinc have received a lot of attention in viral infections. selenium has been shown in-vitro and in some animal studies to alter viral replication and reduce the viral-induced oxidative stress. selenium has well described benefits as a cofactor for several antioxidant enzymes such as superoxide dismutase, thioredoxin reductase and glutathione peroxidase. the data are inconsistent across these studies regarding dosing, timing of delivery, and documentation of any pre-existing deficiency state. no recommendation can be made other than the standard icu recommendations found in the societal guidelines. , zinc is important in the development and function of the immune system, both innate and humoral. it has also been reported that zinc is required for the antioxidant complex metallothionein production in response to lung stretch. this has lead to the suggestion by some to be protective in mechanical ventilation. in-vitro experiments have shown that zinc impairs viral replication and has beneficial effects on rna viruses like coronavirus. zinc supplementation in children documented to be deficient has been shown to decrease mortality, although data is inconsistent. , no consistent data showing zinc supplementation in intensive care patients to be of benefit. as with selenium, the dosing, timing, and target population of those patients most likely to benefit from zinc supplementation is yet unknown. as a result, no recommendations for supplemental zinc, above the levels recommended for any icu patient, can be supported until more data is available. this article is protected by copyright. all rights reserved. anecdotal real-time lessons learned from the field are coming to light rapidly. while not necessarily evidence-based, these observations may be helpful to frontline clinicians in addressing barriers imposed by the current pandemic and important implications to consider. in efforts to preserve ppe and reduce exposure, many nutrition professionals are finding ways to evaluate their patients away from the bedside including chart review and caregiver interviews. bedside nurses provide invaluable information regarding gi function and physical assessment. however, some nursing staff and providers, especially those coming from a variety of (non-icu) work areas, may not place as high a level of importance or face timeconstraints resulting in inconsistent documentation of en, pn and oral intake, as well as urine, stool and drain outputs. the nutrition provider must be diligent in their communication with bedside staff and providers on the importance of these parameters and how best to obtain the information. coordinating phone calls with providers or less ill patients may be beneficial. fortunately, cms has lifted many restrictions and expanded coverage for telehealth visits (virtual and telephone) including using various platforms such as facetime, blue jeans, zoom, skype, and google duo (audio and visual). this applies to all providers (physicians, nps, pas and dietitians). clinicians should check with their facility for specific support and application of state licensure rules. this article is protected by copyright. all rights reserved. frequent reassessment of the patient's metabolic status and employed medical interventions is necessary to determine if an alteration in the nutrition prescription is required. covid- patients on large doses of propofol, may require a decrease in calories to avoid overfeeding and an order for triglyceride monitoring. patients with aki may or may not be able to start dialysis in a timely fashion as some institutions are reporting a lack of machines. in these patients, en/pn regimens should become fluid and electrolyte restricted; with the potential for short-term underfeeding or reduced protein until dialysis treatment can be initiated. patients receiving non-invasive ventilation may require scheduled oral supplements and fortifying snacks that can be readily available at bedside, to optimize energy and protein intake while off treatment, especially in those who no longer have an enteral access device. close monitoring of oral intake is necessary as patients recovering from covid- disease are typically deconditioned and weak and often unable to meet nutrition needs with oral intake alone. if supplemental en is needed during non-invasive ventilation, smaller bore nasoenteric feeding tubes (less than french) may improve mask seal. dietitians should remain engaged in covid- icu rounds via distancing (fewer team members during rounds, wearing appropriate ppe, separated by feet) and/or virtual communication. it is imperative to be "present" (in person or virtually) when the plan and goals for the day are discussed. throughout the day, scheduling calls with bedside caregivers when they are out of the patient room can be challenging. feeding pumps, en feeding bags and tubes may be in short supply during a surge of admitted covid- patients. priority in the distribution of en pumps should be given to patients with this article is protected by copyright. all rights reserved. mild symptoms of gi intolerance at admission, or those with a small bowel feeding tube in place. continuous gravity feeding should be attempted if pumps and/or pump feeding sets are not available. in general, there are drops per ml of formula. however, actual "drop rates" can be difficult to set "by hand" by the bedside nurse. some latitude should be accepted for the time required to deliver the daily goal volume, for example, if the patient tolerates ml (trophic feeding goal) delivered over hours as opposed to hours, this should be considered a success. some formulas are too viscous to flow freely via gravity drip (generally concentrated or fiber containing), this should be verified based on the manufacturer recommendations. for these formulas or when shortages of gravity bags exist, bolus feeding via the syringe method may be attempted. administering formula in amounts equivalent to unit (can, carton, or pouch) will decrease formula waste. parenteral nutrition provided in multi-chamber bags may become necessary if institution shortages of individual components exist or there is a need to decrease pharmacist compounding time. if feasible, extension tubing should be used to locate the pn pump outside the room to decrease practitioner viral exposure and allow for easy access. the delivery of nutritional therapy to the patient with covid- disease should follow the basic principles of critical care nutrition as recommended by european and north american societal guidelines. specific to these patients, is the need to promote strategies which help cluster care, reduce the frequency with which healthcare providers interact with patients, minimize contamination of additional equipment, and avoid transport out of the icu. this may be accomplished by simple measures such as utilizing continuous rather than intermittent or bolus infusion, calculating energy requirements by weight-based equations instead of indirect this article is protected by copyright. all rights reserved. calorimetry, avoiding use of gastric residual volumes as an indicator of en intolerance, and reducing the need for endoscopic or fluoroscopic techniques for feeding tube placement. like most icu patients, those with covid- are expected to tolerate en and benefit from the favorable physiologic response to bathing the intestinal mucosa with luminal nutrients. intragastric delivery of a standard polymeric formula should be initiated at trophic doses and advanced as tolerated to protein and energy goals over the first week. once daily supplementation with fiber additive and probiotic organisms is warranted, but lack of benefit precludes a recommendation for routine infusion of micronutrient vitamins or trace elements. in contrast to other populations of critically ill patients, the threshold for switching to pn for the patient with covid- disease may need to be lower. use of pn in these patients, especially those with severe septic shock or when high pressure respiratory support is required (niv, cpap, or peep), may help minimize risk of ischemic bowel and reduce droplet aerosol transmission to healthcare providers by avoiding procedures involved in the initial placement and the nursing care required to maintain an enteral access device. . guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of critical care medicine (sccm) and american society for parenteral and enteral nutrition guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of critical care medicine this article is protected by copyright. all rights reserved. (sccm) and american society for parenteral and enteral nutrition espen guideline on clinical nutrition in the intensive care unit early enteral nutrition provided within hours of icu admission: a meta-analysis of randomized controlled trials safety and outcomes of early enteral nutrition in circulatory shock clinical characteristics of covid- patients with digestive symptoms in hubei, china: a descriptive, cross-sectional, multicenter study gastrointestinal manifestations of sars-cov- infection and virus load in fecal samples from the hong kong cohort and systematic review and metaanalysis evidence for gastrointestinal infection of sars-cov- covid- : gastrointestinal manifestations and potential fecal-oral transmission enteral nutrition is a risk factor for airway complications in subjects undergoing noninvasive ventilation for acute respiratory failure. respiratory care safety and outcomes of early enteral nutrition in circulatory shock drug-induced qt-interval prolon-gation: considerations for clinicians national heart, lung, and blood institute acute respiratory distress syndrome (ards) clinical trials network permissive underfeeding or standard enteral feeding in critically ill adults energy-dense versus routine enteral nutrition in the critically ill enteral nutrition should not be given to patients on vasopressor agents nutrirea- trial investigators; clinical research in intensive care and sepsis (crics) group. enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (nutrirea- ) trial of the route of early nutritional support in critically ill adults enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (nutrirea- ) restricted versus continued standard caloric intake during the management of refeeding syndrome in critically ill adults: a randomised, parallel-group, multicentre, single-blind controlled trial aspen consensus recommendations for refeeding syndrome. nutrition in clinical practice this article is protected by copyright. all rights reserved influenza--time to target the host? summary of proceedings and expert consensus statements from the international summit hlh across speciality collaboration, uk. covid- : consider cytokine storm syndromes and immunosuppression clinical research in intensive care and sepsis (crics) group. effect of not monitoring residual gastric volume on risk of ventilator-associated pneumonia in adults receiving mechanical ventilation and early enteral feeding: a randomized controlled trial before-after study of a standardized icu protocol for early enteral feeding in patients turned in the prone position proseva study group. prone positioning in severe acute respiratory distress syndrome enteral nutrition in patients receiving mechanical ventilation in a prone position enteral nutrition during prone positioning in mechanically ventilated patients enteral feeding in the critically ill: comparison between the supine and prone positions: a prospective crossover study in mechanically ventilated patients this article is protected by copyright. all rights reserved effect of rotational therapy on aspiration risk of enteral feeds the vexing problem of ventilator-associated pneumonia: observations on pathophysiology, public policy, and clinical science. respiratory care ecmo for severe acute respiratory distress syndrome nutrition therapy in adult patients receiving extracorporeal membrane oxygenation: a prospective, multicentre, observational study. critical care and resuscitation nutrition support in adult patients receiving extracorporeal membrane oxygenation early enteral nutrition for cardiogenic or obstructive shock requiring venoarterial extracorporeal membrane oxygenation: a nationwide inpatient database study nutritional support and clinical outcomes in critically ill patients supported with veno-arterial extracorporeal membrane oxygenation protein requirements for critically ill patients with renal and liver failure micronutrients in critically ill patients with severe acute kidney injury -a prospective study critical care management of adults with community-acquired severe respiratory viral infection this article is protected by copyright. all rights reserved probiotics for preventing acute upper respiratory tract infections evidence that vitamin d supplementation could reduce risk of influenza and covid- infections and deaths early neuromuscular blockade in the acute respiratory distress syndrome effect of high-dose vitamin d on hospital length of stay in critically ill patients with vitamin d deficiency: the vitdal-icu randomized clinical trial potential interventions for novel coronavirus in china: a systematic review effect of vitamin c infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the citris-ali randomized clinical trial selenoproteins and viral infection zinc deficiency primes the lung for ventilator-induced injury. jci insight zinc sulfate in narrow range as an in vitro anti-hsv- assay this article is protected by copyright. all rights reserved zinc supplementation for the treatment of measles in children. cochrane database syst rev zinc supplementation in intensive care: results of a uk survey the aspen adult nutrition support core curriculum enteral nutrition care pathway for critically-ill adult patients surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease these recommendations do not constitute medical or other professional advice and should not be taken as such. to the extent that the information published herein may be used to assist in the care of patients, this is the result of the sole professional judgment of the attending healthcare professional whose judgment is the primary component of quality medical care. the information presented is not a substitute for the exercise of such judgment by the healthcare professional. circumstances in clinical settings and patient indications may require actions different from those recommended in this document and in those cases, the judgment of the treating professional should prevail. key: cord- - i mhz authors: fox, gregory j; trauer, james m; mcbryde, emma title: modelling the impact of covid‐ on intensive care services in new south wales date: - - journal: med j aust doi: . /mja . sha: doc_id: cord_uid: i mhz nan a modelling group at imperial college london, a who collaborating centre for infectious disease modelling, has modelled the effect of different mitigation policies upon peak healthcare demand. the imperial college model adopted a number of assumptions regarding the natural history and clinical management of the covid- epidemic. we applied the outcomes of the imperial college model to the population of nsw, accounting for local demographic distribution. the age distribution between the two settings is similar, shown in figure we developed a simple seir-type compartmental model (susceptible (s), exposed/incubation period (e), infectious (i) and removed(r)) ( figure ). the standard model is modified to allow for pre-symptomatic transmission during the incubation period (e ), a delay between the onset of symptoms and presentation to healthcare (i ), diagnosed disease (i ), hospitalization (h), and icu admission (icu). in this model, compartments e , i and i are infectious. the force of infection is therefore given by: where: infectious period = + + we also performed a simple seir (susceptible-exposed/incubating -infected-removed) model in order to explore the effect of varying the basic reproduction number (r ) which may be reduced by effective social distancing measures and subsequently is called the effective reproduction number (r eff ). the modelled outcome was hospitalised cases, and icu cases, per , population. we modelled two scenarios: (a) no intervention, with a r of . , and (b) social isolation policies, leading to a r eff of . , both with a start prevalence on march of persons per million. detailed model parameters are included in table . we conducted a partial rank correlation coefficient study of nine key model parameters; reproduction number, probability of hospitalisation, duration of hospitalisation, probability of being admitted to icu given hospitalisation, duration of icu admission, time in e , time in e , time in i , time in i against four key outcomes; peak hospitalisation numbers, peak icu numbers, time to peak hospitalisation and time to peak icu as shown in figure . our approach has several limitations. modelling studies depend upon the assumptions upon which t hey are based, and parameters including the current reproduction number remain uncertain as the epidemic is still unfolding. the trajectory of the epidemic, and the magnitude of peak icu demand will be highly dependent upon the effectiveness of mitigation strategies. the present report does not estimate the effect of more intensive suppression strategies, which would be likely to reduce the peak icu requirement. despite the usual limitations inherent in modelling studies, such studies have an important role in informing contingency planning, where applicable parameters are available. further modelling is needed to inform resource planning for the covid- epidemic in australia, including for critical care services. such models will help to inform the public debate regarding the timing, intensity and duration of mitigation strategies. this modelling study did not enrol participants, and so ethics review was not warranted. it is evident that the size of both peaks (c, d) are highly sensitive to the reproduction number (as expected) and also highly sensitive to the time spent in the hospital/icu states of the model. the time to peak is negatively correlated with the reproduction number (as reflected in figure ) and also to the length of the stages of infection, particularly e . as of march , the case notification rate is lower in nsw ( . cases per , ) compared with the uk ( . cases per , cases). , figure table shows the estimated cumulative hospitalisations, icu admissions and deaths in one local health district (sydney lhd) under an optimal mitigation scenario comprising case isolation, household quarantine and social distancing of over year-olds. the timing and magnitude of the peak demand will be strongly dependent upon the effectiveness of mitigation strategies. ongoing surveillance of transmission in the community will be essential to allow healthcare services to anticipate the effects of national covid- mitigation policies upon healthcare resource requirements. imperial college covid- response team. impact of non-pharmaceutical interventions (npis) to reduce covid- mortality and healthcare demand population by local health district principal projection: uk population in age groups a picture of health: sydney local health district health profile temporal variation in transmission during the covid- outbreak australia estimates of the severity of covid- disease total uk cases: covid- covid- (coronavirus) key: cord- -vmsdhccp authors: mandell, lionel a.; wunderink, richard g.; anzueto, antonio; bartlett, john g.; campbell, g. douglas; dean, nathan c.; dowell, scott f.; file, thomas m.; musher, daniel m.; niederman, michael s.; torres, antonio; whitney, cynthia g. title: infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults date: - - journal: clin infect dis doi: . / sha: doc_id: cord_uid: vmsdhccp nan improving the care of adult patients with communityacquired pneumonia (cap) has been the focus of many different organizations, and several have developed guidelines for management of cap. two of the most widely referenced are those of the infectious diseases society of america (idsa) and the american thoracic society (ats). in response to confusion regarding differences between their respective guidelines, the idsa and the ats convened a joint committee to develop a unified cap guideline document. the guidelines are intended primarily for use by emergency medicine physicians, hospitalists, and primary care practitioners; however, the extensive literature evaluation suggests that they are also an appro-reprints or correspondence: dr. lionel a. mandell priate starting point for consultation by specialists. substantial overlap exists among the patients whom these guidelines address and those discussed in the recently published guidelines for health care-associated pneumonia (hcap). pneumonia in nonambulatory residents of nursing homes and other long-term care facilities epidemiologically mirrors hospital-acquired pneumonia and should be treated according to the hcap guidelines. however, certain other patients whose conditions are included in the designation of hcap are better served by management in accordance with cap guidelines with concern for specific pathogens. . locally adapted guidelines should be implemented to improve process of care variables and relevant clinical outcomes. (strong recommendation; level i evidence.) it is important to realize that guidelines cannot always account for individual variation among patients. they are not intended to supplant physician judgment with respect to particular patients or special clinical situations. the idsa considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances. enthusiasm for developing these guidelines derives, in large part, from evidence that previous cap guidelines have led to improvement in clinically relevant outcomes. consistently beneficial effects in clinically relevant parameters (listed in table ) followed the introduction of a comprehensive protocol (including a combination of components from table ) that increased compliance with published guidelines. the first recommendation, therefore, is that cap management guidelines be locally adapted and implemented. documented benefits. . cap guidelines should address a comprehensive set of elements in the process of care rather than a single element in isolation. (strong recommendation; level iii evidence.) . development of local cap guidelines should be directed toward improvement in specific and clinically relevant outcomes. (moderate recommendation; level iii evidence.) almost all of the major decisions regarding management of cap, including diagnostic and treatment issues, revolve around the initial assessment of severity. site-of-care decisions (e.g., hospital vs. outpatient, intensive care unit [icu] vs. general ward) are important areas for improvement in cap management. hospital admission decision. . severity-of-illness scores, such as the curb- criteria (confusion, uremia, respiratory rate, low blood pressure, age years or greater), or prognostic models, such as the pneumonia severity index (psi), can be used to identify patients with cap who may be candidates for outpatient treatment. (strong recommendation; level i evidence.) . objective criteria or scores should always be supplemented with physician determination of subjective factors, including the ability to safely and reliably take oral medication and the availability of outpatient support resources. (strong recommendation; level ii evidence.) . for patients with curb- scores у , more-intensive treatment-that is, hospitalization or, where appropriate and available, intensive in-home health care services-is usually warranted. (moderate recommendation; level iii evidence.) physicians often admit patients to the hospital who could be well managed as outpatients and who would generally prefer to be treated as outpatients. objective scores, such as the curb- score or the psi, can assist in identifying patients who may be appropriate for outpatient care, but the use of such scores must be tempered by the physician's determination of additional critical factors, including the ability to safely and reliably take oral medication and the availability of outpatient support resources. icu admission decision. . direct admission to an icu is required for patients with septic shock requiring vasopressors or with acute respiratory failure requiring intubation and mechanical ventilation. (strong recommendation; level ii evidence.) . direct admission to an icu or high-level monitoring unit is recommended for patients with of the minor criteria for severe cap listed in table . (moderate recommendation; level ii evidence.) in some studies, a significant percentage of patients with cap are transferred to the icu in the first - h after hospitalization. mortality and morbidity among these patients appears to be greater than those among patients admitted directly to the icu. conversely, icu resources are often overstretched in many institutions, and the admission of patients with cap who would not directly benefit from icu care is also problematic. unfortunately, none of the published criteria for severe cap adequately distinguishes these patients from those for whom icu admission is necessary. in the present set of guidelines, a new set of criteria has been developed on the basis of data on individual risks, although the previous ats criteria format is retained. in addition to the major criteria (need for mechanical ventilation and septic shock), an expanded set of minor criteria (respiratory rate, breaths/min; arterial oxygen pressure/fraction of inspired oxygen (pao /fio ) ratio, ! ; multilobar infiltrates; confusion; blood urea nitrogen level, mg/dl; leukopenia resulting from infection; thrombocytopenia; hypothermia; or hypotension requiring aggressive fluid resuscitation) is proposed (table ). the presence of at least of these criteria suggests the need for icu care but will require prospective validation. . in addition to a constellation of suggestive clinical features, a demonstrable infiltrate by chest radiograph or other imaging technique, with or without supporting microbiological data, is required for the diagnosis of pneumonia. (moderate recommendation; level iii evidence.) recommended diagnostic tests for etiology. . patients with cap should be investigated for specific pathogens that would significantly alter standard (empirical) management decisions, when the presence of such pathogens is suspected on the basis of clinical and epidemiologic clues. (strong recommendation; level ii evidence.) recommendations for diagnostic testing remain controversial. the overall low yield and infrequent positive impact on clinical care argue against the routine use of common tests, such as blood and sputum cultures. conversely, these cultures may have a major impact on the care of an individual patient and are important for epidemiologic reasons, including the antibiotic susceptibility patterns used to develop treatment guidelines. a list of clinical indications for more extensive diagnostic testing (table ) was, therefore, developed, primarily on the basis of criteria: ( ) when the result is likely to change individual antibiotic management and ( ) when the test is likely to have the highest yield. . routine diagnostic tests to identify an etiologic diagnosis are optional for outpatients with cap. (moderate recommendation; level iii evidence.) . pretreatment blood samples for culture and an expectorated sputum sample for stain and culture (in patients with a productive cough) should be obtained from hospitalized patients with the clinical indications listed in table but are optional for patients without these conditions. (moderate recommendation; level i evidence.) . pretreatment gram stain and culture of expectorated sputum should be performed only if a good-quality specimen can be obtained and quality performance measures for collection, transport, and processing of samples can be met. (moderate recommendation; level ii evidence.) . patients with severe cap, as defined above, should at least have blood samples drawn for culture, urinary antigen tests for legionella pneumophila and streptococcus pneumoniae performed, and expectorated sputum samples collected for culture. for intubated patients, an endotracheal aspirate sample should be obtained. (moderate recommendation; level ii evidence.) the most clear-cut indication for extensive diagnostic testing is in the critically ill cap patient. such patients should at least have blood drawn for culture and an endotracheal aspirate obtained if they are intubated; consideration should be given to more extensive testing, including urinary antigen tests for l. pneumophila and s. pneumoniae and gram stain and culture of expectorated sputum in nonintubated patients. for inpatients without the clinical indications listed in table , diagnostic testing is optional (but should not be considered wrong). empirical antimicrobial therapy. empirical antibiotic recommendations (table ) have not changed significantly from those in previous guidelines. increasing evidence has strengthened the recommendation for combination empirical therapy for severe cap. only recently released antibiotic has been added to the recommendations: ertapenem, as an acceptable b-lactam alternative for hospitalized patients with risk factors for infection with gram-negative pathogens other than pseudomonas aeruginosa. at present, the committee is awaiting further evaluation of the safety of telithromycin by the us food and drug administration before making its final recommendation regarding this drug. recommendations are generally for a class of antibiotics rather than for a specific drug, unless outcome data clearly favor one drug. because overall efficacy remains good for many classes of agents, the more potent drugs are given preference because of their benefit in decreasing the risk of selection for antibiotic resistance. . a b-lactam plus a macrolide (strong recommendation; level i evidence) (preferred b-lactam agents include cefotaxime, ceftriaxone, and ampicillin; ertapenem for selected patients; with doxycycline [level iii evidence] as an alternative to the macrolide. a respiratory fluoroquinolone should be used for penicillin-allergic patients.) increasing resistance rates have suggested that empirical therapy with a macrolide alone can be used only for the treat-ment of carefully selected hospitalized patients with nonsevere disease and without risk factors for infection with drug-resistant pathogens. however, such monotherapy cannot be routinely recommended. inpatient, icu treatment . a b-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) plus either azithromycin (level ii evidence) or a fluoroquinolone (level i evidence) (strong recommendation) (for penicillin-allergic patients, a respiratory fluoroquinolone and aztreonam are recommended.) . for pseudomonas infection, use an antipneumococcal, antipseudomonal b-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) plus either ciprofloxacin or levofloxacin ( -mg dose) or the above b-lactam plus an aminoglycoside and azithromycin or the above b-lactam plus an aminoglycoside and an antipneumococcal fluoroquinolone (for penicillin-allergic patients, substitute aztreonam for the above b-lactam). (moderate recommendation; level iii evidence.) . for community-acquired methicillin-resistant staphylococcus aureus infection, add vancomycin or linezolid. (moderate recommendation; level iii evidence.) infections with the overwhelming majority of cap pathogens will be adequately treated by use of the recommended empirical regimens. the emergence of methicillin-resistant s. aureus as a cap pathogen and the small but significant incidence of cap due to p. aeruginosa are the exceptions. these pathogens occur in specific epidemiologic patterns and/or with certain clinical presentations, for which empirical antibiotic coverage may be warranted. however, diagnostic tests are likely to be of high yield for these pathogens, allowing early discontinuation of empirical treatment if results are negative. the risk factors are included in the table recommendations for indications for increased diagnostic testing. risk factors for other uncommon etiologies of cap are listed in table , and recommendations for treatment are included in table . pathogen-directed therapy. definitions and classification. . the use of a systematic classification of possible causes of failure to respond, based on time of onset and type of failure (table ) , is recommended. (moderate recommendation; level ii evidence.) as many as % of patients with cap may not respond appropriately to initial antibiotic therapy. a systematic approach to these patients (table ) will help to determine the cause. because determination of the cause of failure is more accurate if the original microbiological etiology is known, risk factors for nonresponse or deterioration (table ) figure prominently in the list of situations in which more aggressive and/ or extensive initial diagnostic testing is warranted ( [ ] . despite advances in antimicrobial therapy, rates of mortality due to pneumonia have not decreased significantly since penicillin became routinely available [ ] . groups interested in approaches to the management of cap include professional societies, such as the american thoracic society (ats) and the infectious diseases society of america (idsa); government agencies or their contract agents, such as the center for medicare and medicaid services and the department of veterans affairs; and voluntary accrediting agencies, such as the joint commission on accreditation of healthcare organizations. in addition, external review groups and consumer groups have chosen cap outcomes as major quality indicators. such interest has resulted in numerous guidelines for the management of cap [ ] . some of these guidelines represent truly different perspectives, including differences in health care systems, in the availability of diagnostic tools or therapeutic agents, or in either the etiology or the antibiotic susceptibility of common causative microorganisms. the most widely referenced guidelines in the united states have been those published by the ats [ , ] and the idsa [ ] [ ] [ ] . differences, both real and imagined, between the ats and idsa guidelines have led to confusion for individual physicians, as well as for other groups who use these published guidelines rather than promulgating their own. in response to this concern, the idsa and the ats convened a joint committee to develop a unified cap guideline document. this document represents a consensus of members of both societies, and both governing councils have approved the statement. purpose and scope. the purpose of this document is to update clinicians with regard to important advances and controversies in the management of patients with cap. the committee chose not to address cap occurring in immunocompromised patients, including solid organ, bone marrow, or stem cell transplant recipients; patients receiving cancer chemotherapy or long-term ( days) high-dose corticosteroid treatment; and patients with congenital or acquired immunodeficiency or those infected with hiv who have cd cell counts ! cells/mm , although many of these patients may be infected with the same microorganisms. pneumonia in children (р years of age) is also not addressed. substantial overlap exists among the patients these guidelines address and those discussed in the recently published guidelines for health care-associated pneumonia (hcap) [ ] . two issues are pertinent: ( ) an increased risk of infection with drugresistant isolates of usual cap pathogens, such as streptococcus pneumoniae, and ( ) an increased risk of infection with less common, usually hospital-associated pathogens, such as pseudomonas and acinetobacter species and methicillin-resistant staphylococcus aureus (mrsa). pneumonia in nonambulatory residents of nursing homes and other long-term care facilities epidemiologically mirrors hospital-acquired pneumonia and should be treated according to the hcap guidelines. however, certain other patients whose conditions are included under the designation of hcap are better served by management in ac-cordance with cap guidelines with concern for specific pathogens. for example, long-term dialysis alone is a risk for mrsa infection but does not necessarily predispose patients to infection with other hcap pathogens, such as pseudomonas aeruginosa or acinetobacter species. on the other hand, certain patients with chronic obstructive pulmonary disease (copd) are at greater risk for infection with pseudomonas species but not mrsa. these issues will be discussed in specific sections below. the committee started with the premise that mortality due to cap can be decreased. we, therefore, have placed the greatest emphasis on aspects of the guidelines that have been associated with decreases in mortality. for this reason, the document focuses mainly on management and minimizes discussions of such factors as pathophysiology, pathogenesis, mechanisms of antibiotic resistance, and virulence factors. the committee recognizes that the majority of patients with cap are cared for by primary care, hospitalist, and emergency medicine physicians [ ] , and these guidelines are, therefore, directed primarily at them. the committee consisted of infectious diseases, pulmonary, and critical care physicians with interest and expertise in pulmonary infections. the expertise of the committee and the extensive literature evaluation suggest that these guidelines are also an appropriate starting point for consultation by these types of physicians. although much of the literature cited originates in europe, these guidelines are oriented toward the united states and canada. although the guidelines are generally applicable to other parts of the world, local antibiotic resistance patterns, drug availability, and variations in health care systems suggest that modification of these guidelines is prudent for local use. methodology. the process of guideline development started with the selection of committee cochairs by the presidents of the idsa [ ] and ats [ ] , in consultation with other leaders in the respective societies. the committee cochairs were charged with selection of the rest of the committee. the idsa members were those involved in the development of previous idsa cap guidelines [ ] , whereas ats members were chosen in consultation with the leadership of the mycobacteria tuberculosis and pulmonary infection assembly, with input from the chairs of the clinical pulmonary and critical care assemblies. committee members were chosen to represent differing expertise and viewpoints on the various topics. one acknowledged weakness of this document is the lack of representation by primary care, hospitalist, and emergency medicine physicians. the cochairs generated a general outline of the topics to be covered that was then circulated to committee members for input. a conference phone call was used to review topics and to discuss evidence grading and the general aims and expectations of the document. the topics were divided, and committee members were assigned by the cochairs and charged with presentation of their topic at an initial face-to-face meeting, as well as with development of a preliminary document dealing with their topic. controversial topics were assigned to committee members, from each society. an initial face-to-face meeting of a majority of committee members involved presentations of the most controversial topics, including admission decisions, diagnostic strategies, and antibiotic therapy. prolonged discussions followed each presentation, with consensus regarding the major issues achieved before moving to the next topic. with input from the rest of the committee, each presenter and committee member assigned to the less controversial topics prepared an initial draft of their section, including grading of the evidence. iterative drafts of the statement were developed and distributed by e-mail for critique, followed by multiple revisions by the primary authors. a second face-to-face meeting was also held for discussion of the less controversial areas and further critique of the initial drafts. once general agreement on the separate topics was obtained, the cochairs incorporated the separate documents into a single statement, with substantial editing for style and consistency. the document was then redistributed to committee members to review and update with new information from the literature up to june . recommended changes were reviewed by all committee members by e-mail and/or conference phone call and were incorporated into the final document by the cochairs. this document was then submitted to the societies for approval. each society independently selected reviewers, and changes recommended by the reviewers were discussed by the committee and incorporated into the final document. the guideline was then submitted to the idsa governing council and the ats board of directors for final approval. grading of guideline recommendations. initially, the committee decided to grade only the strength of the evidence, using a -tier scale (table ) used in a recent guideline from both societies [ ] . in response to reviewers' comments and the maturation of the field of guideline development [ ] , a separate grading of the strength of the recommendations was added to the final draft. more extensive and validated criteria, such as grade [ ] , were impractical for use at this stage. the -tier scale similar to that used in other idsa guideline documents [ ] and familiar to many of the committee members was therefore chosen. the strength of each recommendation was graded as "strong," "moderate," or "weak." each committee member independently graded each recommendation on the basis of not only the evidence but also expert interpretation and clinical applicability. the final grading of each recommendation was a composite of the individual committee members' grades. for the final document, a strong recommendation required у (of ) of the members to consider it to be strong and the majority of the others to grade it as moderate. the implication of a strong recommendation is that most patients should receive that intervention. significant variability in the management of patients with cap is well documented. some who use guidelines suggest that this variability itself is undesirable. industrial models suggesting that variability per se is undesirable may not always be relevant to medicine [ ] . such models do not account for substantial variability among patients, nor do they account for variable end points, such as limitation of care in patients with end-stage underlying diseases who present with cap. for this reason, the committee members feel strongly that % compliance with guidelines is not the desired goal. however, the rationale for variation from a strongly recommended guideline should be apparent from the medical record. conversely, moderate or weak recommendations suggest that, even if a majority would follow the recommended management, many practitioners may not. deviation from guidelines may occur for a variety of reasons [ , ] . one document cannot cover all of the variable settings, unique hosts, or epidemiologic patterns that may dictate alternative management strategies, and physician judgment should always supersede guidelines. this is borne out by the finding that deviation from guidelines is greatest in the treatment of patients with cap admitted to the icu [ ] . in addition, few of the recommendations have level i evidence to support them, and most are, therefore, legitimate topics for future research. subsequent publication of studies documenting that care that deviates from guidelines results in better outcomes will stimulate revision of the guidelines. the committee anticipates that this will occur, and, for this reason, both the ats and idsa leaderships have committed to the revision of these guidelines on a regular basis. we recognize that these guidelines may be used as a measure of quality of care for hospitals and individual practitioners. although these guidelines are evidence based, the committee strongly urges that deviations from them not necessarily be considered substandard care, unless they are accompanied by evidence for worse outcomes in a studied population. . locally adapted guidelines should be implemented to improve process of care variables and relevant clinical outcomes. (strong recommendation; level i evidence.) enthusiasm for developing this set of cap guidelines derives, in large part, from evidence that previous cap guidelines have led to improvement in clinically relevant outcomes [ , [ ] [ ] [ ] . protocol design varies among studies, and the preferable randomized, parallel group design has been used in only a small minority. confirmatory studies that use randomized, parallel groups with precisely defined treatments are still needed, but a consistent pattern of benefit is found in the other types of level i studies. documented benefits. published protocols have varied in primary focus and comprehensiveness, and the corresponding benefits vary from one study to another. however, the most impressive aspect of this literature is the consistently beneficial effect seen in some clinically relevant parameter after the introduction of a protocol that increases compliance with published guidelines. a decrease in mortality with the introduction of guidelinebased protocols was found in several studies [ , ] . a -year study of , patients with pneumonia who were admitted during implementation of a pneumonia guideline demonstrated that the crude -day mortality rate was . % lower with the guideline (adjusted or, . ; % ci, . - . ) [ ] , compared with that among patients treated concurrently by nonaffiliated physicians. after implemention of a practice guideline at one spanish hospital [ ] , the survival rate at days was higher (or, . ; % ci, . - . ) than at baseline and in comparison with other hospitals without overt protocols. lower mortality was seen in other studies, although the differences were not statistically significant [ , ] . studies that documented lower mortality emphasized increasing the number of patients receiving guideline-recommended antibiotics, confirming results of the multivariate analysis of a retrospective review [ ] . when the focus of a guideline was hospitalization, the number of less ill patients admitted to the hospital was consistently found to be lower. using admission decision support, a prospective study of emergency department (ed) visits in hospitals randomized between pathway and "conventional" management found that admission rates among low-risk patients at pathway hospitals decreased (from % to % of patients in pneumonia severity index [psi] classes i-iii; p ! ) without differences in patient satisfaction scores or rate of . readmission [ ] . calculating the psi score and assigning the risk class, providing oral clarithromycin, and home nursing follow-up significantly ( ) decreased the number of low-p p . mortality-risk admissions [ ] . however, patient satisfaction among outpatients was lower after implementation of this guideline, despite survey data that suggested most patients would prefer outpatient treatment [ ] . of patients discharged from the ed, % required hospitalization within days, although another study showed lower readmission rates with the use of a protocol [ ] . admission decision support derived from the ats guideline [ ] recommendations, combined with outpatient antibiotic recommendations, reduced the cap hospitalization rate from . % to . % [ ] , and admission rates for other diagnoses were unchanged. not surprisingly, the resultant overall cost of care decreased by half ( ). p p . protocols using guidelines to decrease the duration of hospitalization have also been successful. guideline implementation in connecticut hospitals decreased the mean length of hospital stay (los) from to days ( ) [ ] . an ed-p ! . based protocol decreased the mean los from . to . days ( ), with the benefits of guideline implementation p ! . maintained years after the initial study [ ] . a -site trial, randomized by physician group, of guideline alone versus the same guideline with a multifaceted implementation strategy found that addition of an implementation strategy was associated with decreased duration of intravenous antibiotic therapy and los, although neither decrease was statistically significant [ ] . several other studies used guidelines to significantly shorten the los, by an average of . days [ , ] . markers of process of care can also change with the use of a protocol. the time to first antibiotic dose has been effectively decreased with cap protocols [ , , ] . a randomized, parallel group study introduced a pneumonia guideline in of small oklahoma hospitals [ ] , with the identical protocol implemented in the remaining hospitals in a second phase. serial measurement of key process measures showed significant improvement in time to first antibiotic dose and other variables, first in the initial hospitals and later in the remaining hospitals. implementing a guideline in the ed halved the time to initial antibiotic dose [ ] . . cap guidelines should address a comprehensive set of elements in the process of care rather than a single element in isolation. (strong recommendation; level iii evidence.) common to all of the studies documented above, a com- prehensive protocol was developed and implemented, rather than one addressing a single aspect of cap care. no study has documented that simply changing metric, such as time to first antibiotic dose, is associated with a decrease in mortality. elements important in cap guidelines are listed in table . of these, rapid and appropriate empirical antibiotic therapy is consistently associated with improved outcome. we have also included elements of good care for general medical inpatients, such as early mobilization [ ] and prophylaxis against thromboembolic disease [ ] . although local guidelines need not include all elements, a logical constellation of elements should be addressed. in instituting cap protocol guidelines, the outcomes most relevant to the individual center or medical system should be addressed first. unless a desire to change clinically relevant outcomes exists, adherence to guidelines will be low, and institutional resources committed to implement the guideline are likely to be insufficient. guidelines for the treatment of pneumonia must use approaches that differ from current practice and must be successfully implemented before process of care and outcomes can change. for example, rhew et al. [ ] designed a guideline to decrease los that was unlikely to change care, because the recommended median los was longer than the existing los for cap at the study hospitals. the difficulty in implementing guidelines and changing physician behavior has also been documented [ , ] . clinically relevant outcome parameters should be evaluated to measure the effect of the local guideline. outcome parameters that can be used to measure the effect of implementation of a cap guideline within an organization are listed in table . just as it is important not to focus on one aspect of care, studying more than one outcome is also important. improvements in one area may be offset by worsening in a related area; for example, decreasing admission of low-acuity patients might increase the number of return visits to the ed or hospital readmissions [ ] . almost all of the major decisions regarding management of cap, including diagnostic and treatment issues, revolve around the initial assessment of severity. we have, therefore, organized the guidelines to address this issue first. hospital admission decision. the initial management decision after diagnosis is to determine the site of care-outpatient, hospitalization in a medical ward, or admission to an icu. the decision to admit the patient is the most costly issue in the management of cap, because the cost of inpatient care for pneumonia is up to times greater than that of outpatient care [ ] and consumes the majority of the estimated $ . -$ billion spent yearly on treatment. other reasons for avoiding unnecessary admissions are that patients at low risk for death who are treated in the outpatient setting are able to resume normal activity sooner than those who are hospitalized, and % are reported to prefer outpatient therapy [ , ] . hospitalization also increases the risk of thromboembolic events and superinfection by more-virulent or resistant hospital bacteria [ ] . . severity-of-illness scores, such as the curb- criteria (confusion, uremia, respiratory rate, low blood pressure, age years or greater), or prognostic models, such as the psi, can be used to identify patients with cap who may be candidates for outpatient treatment. (strong recommendation; level i evidence.) significant variation in admission rates among hospitals and among individual physicians is well documented. physicians often overestimate severity and hospitalize a significant number of patients at low risk for death [ , , ] . because of these issues, interest in objective site-of-care criteria has led to attempts by a number of groups to develop such criteria [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the relative merits and limitations of various proposed criteria have been carefully evaluated [ ] . the most interesting are the psi [ ] and the british thoracic society (bts) criteria [ , ] . the psi is based on derivation and validation cohorts of , and , hospitalized patients with cap, respectively, plus an additional combined inpatients and outpatients [ ] . the psi stratifies patients into mortality risk classes, and its ability to predict mortality has been confirmed in multiple subsequent studies. on the basis of associated mortality rates, it has been suggested that risk class i and ii patients should be treated as outpatients, risk class iii patients should be treated in an observation unit or with a short hospitalization, and risk class iv and v patients should be treated as inpatients [ ] . yealy et al. [ ] conducted a cluster-randomized trial of low-, moderate-, and high-intensity processes of guideline implementation in eds in the united states. their guideline used the psi for admission decision support and included recommendations for antibiotic therapy, timing of first antibiotic dose, measurement of oxygen saturation, and blood cultures for admitted patients. eds with moderate-to high-intensity guideline implementation demonstrated more outpatient treatment of low-risk patients and higher compliance with antibiotic recommendations. no differences were found in mortality rate, rate of hospitalization, median time to return to work or usual activities, or patient satisfaction. this study differs from those reporting a mortality rate difference [ , ] in that many hospitalized patients with pneumonia were not included. in addition, eds with low-intensity guideline implementation formed the comparison group, rather than eds practicing nonguideline, usual pneumonia care. the bts original criteria of have subsequently been modified [ , ] . in the initial study, risk of death was increased -fold if a patient, at the time of admission, had at least of the following conditions: tachypnea, diastolic hypotension, and an elevated blood urea nitrogen (bun) level. these criteria appear to function well except among patients with underlying renal insufficiency and among elderly patients [ , ] . the most recent modification of the bts criteria includes easily measurable factors [ ] . multivariate analysis of patients identified the following factors as indicators of increased mortality: confusion (based on a specific mental test or disorientation to person, place, or time), bun level mmol/l ( mg/dl), respiratory rate у breaths/min, low blood pressure (systolic, ! mm hg; or diastolic, р mm hg), and age у years; this gave rise to the acronym curb- . in the derivation and validation cohorts, the -day mortality among patients with , , or factors was . %, . %, and . %, respectively. mortality was higher when , , or factors were present and was reported as . %, %, and %, respectively. the authors suggested that patients with a curb- score of - be treated as outpatients, that those with a score of be admitted to the wards, and that patients with a score of у often required icu care. a simplified version (crb- ), which does not require testing for bun level, may be appropriate for decision making in a primary care practitioner's office [ ] . the use of objective admission criteria clearly can decrease the number of patients hospitalized with cap [ , , , ] . whether the psi or the curb- score is superior is unclear, because no randomized trials of alternative admission criteria exist. when compared in the same population, the psi classified a slightly larger percentage of patients with cap in the lowrisk categories, compared with the curb or curb- criteria, while remaining associated with a similar low mortality rate among patients categorized as low risk [ ] . several factors are important in this comparison. the psi includes different variables and, therefore, relies on the availability of scoring sheets, limiting its practicality in a busy ed [ ] . in contrast, the curb- criteria are easily remembered. however, curb- has not been as extensively studied as the psi, especially with prospective validation in other patient populations (e.g., the indigent inner-city population), and has not been specifically studied as a means of reducing hospital admission rates. in eds with sufficient decision support resources (either human or computerized), the benefit of greater experience with the psi score may favor its use for screening patients who may be candidates for outpatient management [ , [ ] [ ] [ ] . . objective criteria or scores should always be supplemented with physician determination of subjective factors, including the ability to safely and reliably take oral medication and the availability of outpatient support resources. (strong recommendation; level ii evidence.) studies show that certain patients with low psi or curb- scores [ , , ] require hospital admission, even to the icu [ , , ] . both scores depend on certain assumptions. one is that the main rationale for admission of a patient with cap is risk of death. this assumption is clearly not valid in all cases. another is that the laboratory and vital signs used for scoring are stable over time rather than indicative of transient abnormalities. this is also not true in all cases. therefore, dynamic assessment over several hours of observation may be more accurate than a score derived at a single point in time. although advantageous to making decisions regarding hospital admission, sole reliance on a score for the hospital admission decision is unsafe. reasons for the admission of low-mortality-risk patients fall into categories: ( ) complications of the pneumonia itself, ( ) exacerbation of underlying diseases(s), ( ) inability to reliably take oral medications or receive outpatient care, and/or ( ) multiple risk factors falling just above or below thresholds for the score [ ] . use of the psi score in clinical trials has demonstrated some of its limitations, which may be equally applicable to other scoring techniques. a modification of the original psi score was needed when it was applied to the admission decision. an arterial saturation of ! % or an arterial oxygen pressure (pao ) of ! mm hg as a complication of the pneumonia, was added as a sole indicator for admission for patients in risk classes i-iii as an added "margin of safety" in one trial [ ] . in addition to patients who required hospital admission because of hypoxemia, a subsequent study identified patients in low psi risk classes (i-iii) who needed hospital admission because of shock, decompensated coexisting illnesses, pleural effusion, inability to maintain oral intake, social problems (the patient was dependent or no caregiver was available), and lack of response to previous adequate empirical antibiotic therapy [ ] . of patients in low psi risk classes who were treated as inpatients, ( %) presented with at least of these factors. other medical or psychosocial needs requiring hospital care include intractable vomiting, injection drug abuse, severe psychiatric illness, homelessness, poor overall functional status [ ] , and cognitive dysfunction [ , ] . the psi score is based on a history of diseases that increase risk of death, whereas the curb- score does not directly address underlying disease. however, pneumonia may exacerbate an underlying disease, such as obstructive lung disease, congestive heart failure, or diabetes mellitus, which, by themselves, may require hospital admission [ , ] . atlas et al. [ ] were able to reduce hospital admissions among patients in psi risk classes i-iii from % in a retrospective control group to % in a psi-based intervention group. ten of patients in the latter group (compared with patients in the control population) were subsequently admitted, several for reasons unrelated to their pneumonia. also, the presence of rare illnesses, such as neuromuscular or sickle cell disease, may require hospitalization but not affect the psi score. the necessary reliance on dichotomous predictor variables (abnormal vs. normal) in most criteria and the heavy reliance on age as a surrogate in the psi score may oversimplify their use for admission decisions. for example, a previously healthy -year-old patient with severe hypotension and tachycardia and no additional pertinent prognostic factors would be placed in risk class ii, whereas a -year-old man with a history of localized prostate cancer diagnosed months earlier and no other problems would be placed in risk class iv [ ] . finally, patient satisfaction was lower among patients treated outside the hospital in one study with a psi-based intervention group [ ] , suggesting that the savings resulting from use of the psi may be overestimated and that physicians should consider additional factors not measured by the psi. . for patients with curb- scores у , more-intensive treatment-that is, hospitalization or, where appropriate and available, intensive in-home health care services-is usually warranted. (moderate recommendation; level iii evidence.) although the psi and curb- criteria are valuable aids in avoiding inappropriate admissions of low-mortality-risk patients, another important role of these criteria may be to help identify patients at high risk who would benefit from hospitalization. the committee preferred the curb- criteria because of ease of use and because they were designed to measure illness severity more than the likelihood of mortality. patients with a curb- score у are not only at increased risk of death but also are likely to have clinically important physiologic derangements requiring active intervention. these patients should usually be considered for hospitalization or for aggressive in-home care, where available. in a cohort of ∼ patients, the mortality with a curb- score of was only . %, whereas - points were associated with % mortality [ ] . because the psi score is not based as directly on severity of illness as are the curb- criteria, a threshold for patients who would require hospital admission or intensive outpatient treatment is harder to define. the higher the score, the greater the need for hospitalization. however, even a patient who meets criteria for risk class v on the basis of very old age and multiple stable chronic illnesses may be successfully managed as an outpatient [ ] . . direct admission to an icu is required for patients with septic shock requiring vasopressors or with acute respiratory failure requiring intubation and mechanical ventilation. (strong recommendation; level ii evidence.) the second-level admission decision is whether to place the patient in the icu or a high-level monitoring unit rather than on a general medical floor. approximately % of hospitalized patients with cap require icu admission [ ] [ ] [ ] , but the indications vary strikingly among patients, physicians, hospitals, and different health care systems. some of the variability among institutions results from the availability of high-level monitoring or intermediate care units appropriate for patients at increased risk of complications. because respiratory failure is the major reason for delayed transfer to the icu, simple cardiac monitoring units would not meet the criteria for a highlevel monitoring unit for patients with severe cap. one of the most important determinants of the need for icu care is the presence of chronic comorbid conditions [ ] [ ] [ ] [ ] [ ] . however, approximately one-third of patients with severe cap were previously healthy [ ] . the rationale for specifically defining severe cap is -fold: • appropriate placement of patients optimizes use of limited icu resources. • transfer to the icu for delayed respiratory failure or delayed onset of septic shock is associated with increased mortality [ ] . although low-acuity icu admissions do occur, the major concern is initial admission to the general medical unit, with subsequent transfer to the icu. as many as % of patients with cap who ultimately require icu admission were initially admitted to a non-icu setting [ ] . many delayed transfers to the icu represent rapidly progressive pneumonia that is not obvious on admission. however, some have subtle findings, including those included in the minor criteria in table , which might warrant direct admission to the icu. • the distribution of microbial etiologies differs from that of cap in general [ ] [ ] [ ] [ ] , with significant implications for diagnostic testing and empirical antibiotic choices. avoidance of inappropriate antibiotic therapy has also been associated with lower mortality [ , ] . • patients with cap appropriate for immunomodulatory treatment must be identified. the systemic inflammatory response/severe sepsis criteria typically used for generic sepsis trials may not be adequate when applied specifically to severe cap [ ] . for example, patients with unilateral lobar pneumonia may have hypoxemia severe enough to meet criteria for acute lung injury but not have a systemic response. several criteria have been proposed to define severe cap. most case series have defined it simply as cap that necessitates icu admission. objective criteria to identify patients for icu admission include the initial ats definition of severe cap [ ] and its subsequent modification [ , ] , the curb criteria [ , ] , and psi severity class v (or iv and v) [ ] . however, none of these criteria has been prospectively validated for the icu admission decision. recently, these criteria were retrospectively evaluated in a cohort of patients with cap admitted to the icu [ ] . all were found to be both overly sensitive and nonspecific in comparison with the original clinical decision to admit to the icu. revisions of the criteria or alternative criteria were, therefore, recommended. for the revised criteria, the structure of the modified ats criteria for severe cap was retained [ ] . the major criteriamechanical ventilation with endotracheal intubation and septic shock requiring vasopressors-are absolute indications for admission to an icu. in contrast, the need for icu admission is less straightforward for patients who do not meet the major criteria. on the basis of the published operating characteristics of the criteria, no single set of minor criteria is adequate to define severe cap. both the ats minor criteria [ ] and the curb criteria [ ] have validity when predicting which patients will be at increased risk of death. therefore, the ats minor criteria and the curb variables were included in the new proposed minor criteria (table ) . age, by itself, was not felt to be an appropriate factor for the icu admission decision, but the remainder of the curb- criteria [ ] were retained as minor criteria (with the exception of hypotension requiring vasopressors as a major criterion). rather than the complex criteria for confusion in the original curb studies, the definition of confusion should be new-onset disorientation to person, place, or time. three additional minor criteria were added. leukopenia (white blood cell count, ! cells/mm ) resulting from cap has consistently been associated with excess mortality, as well as with an increased risk of complications such as acute respiratory distress syndrome (ards) [ , , [ ] [ ] [ ] [ ] [ ] . in addition, leukopenia is seen not only in bacteremic pneumococcal disease but also in gram-negative cap [ , ] . when leukopenia occurs in patients with a history of alcohol abuse, the adverse manifestations of septic shock and ards may be delayed or masked. therefore, these patients were thought to benefit from icu monitoring. the coagulation system is often activated in cap, and development of thrombocytopenia (platelet count, ! , cells/mm ) is also associated with a worse prognosis [ , [ ] [ ] [ ] . nonexposure hypothermia (core temperature, ! Њc) also carries an ominous prognosis in cap [ , ] . the committee felt that there was sufficient justification for including these additional factors as minor criteria. other factors associated with increased mortality due to cap were also considered, including acute alcohol ingestion and delirium tremens [ , , ] , hypoglycemia and hyperglycemia, occult metabolic acidosis or elevated lactate levels [ ] , and hyponatremia [ ] . however, many of these criteria overlap with those selected. future studies validating the proposed criteria should record these factors as well, to determine whether addition or substitution improves the predictive value of our proposed criteria. with the addition of more minor criteria, the threshold for icu admission was felt to be the presence of at least minor criteria, based on the mortality association with the curb criteria. selecting criteria appears to be too nonspecific, as is demonstrated by the initial ats criteria [ ] . whether each of the criteria is of equal weight is also not clear. therefore, prospective validation of this set of criteria is clearly needed. . in addition to a constellation of suggestive clinical features, a demonstrable infiltrate by chest radiograph or other imaging technique, with or without supporting microbiological data, is required for the diagnosis of pneumonia. (moderate recommendation; level iii evidence.) the diagnosis of cap is based on the presence of select clinical features (e.g., cough, fever, sputum production, and pleuritic chest pain) and is supported by imaging of the lung, usually by chest radiography. physical examination to detect rales or bronchial breath sounds is an important component of the evaluation but is less sensitive and specific than chest radiographs [ ] . both clinical features and physical exam findings may be lacking or altered in elderly patients. all patients should be screened by pulse oximetry, which may suggest both the presence of pneumonia in patients without obvious signs of pneumonia and unsuspected hypoxemia in patients with diagnosed pneumonia [ , , ] . a chest radiograph is required for the routine evaluation of patients who are likely to have pneumonia, to establish the diagnosis and to aid in differentiating cap from other common causes of cough and fever, such as acute bronchitis. chest radiographs are sometimes useful for suggesting the etiologic agent, prognosis, alternative diagnoses, and associated conditions. rarely, the admission chest radiograph is clear, but the patient's toxic appearance suggests more than bronchitis. ct scans may be more sensitive, but the clinical significance of these findings when findings of radiography are negative is unclear [ ] . for patients who are hospitalized for suspected pneumonia but who have negative chest radiography findings, it may be reasonable to treat their condition presumptively with antibiotics and repeat the imaging in - h. microbiological studies may support the diagnosis of pneumonia due to an infectious agent, but routine tests are frequently falsely negative and are often nonspecific. a history of recent travel or endemic exposure, if routinely sought, may identify specific potential etiologies that would otherwise be unexpected as a cause of cap (see table ) [ ] . . patients with cap should be investigated for specific pathogens that would significantly alter standard (empirical) management decisions, when the presence of such pathogens is suspected on the basis of clinical and epidemiologic clues. (strong recommendation; level ii evidence.) the need for diagnostic testing to determine the etiology of cap can be justified from several perspectives. the primary reason for such testing is if results will change the antibiotic management for an individual patient. the spectrum of antibiotic therapy can be broadened, narrowed, or completely altered on the basis of diagnostic testing. the alteration in therapy that is potentially most beneficial to the individual is an escalation or switch of the usual empirical regimen because of unusual pathogens (e.g., endemic fungi or mycobacterium tuberculosis) or antibiotic resistance issues. broad empirical coverage, such as that recommended in these guidelines, would not provide the optimal treatment for certain infections, such as psittacosis or tularemia. increased mortality [ ] and increased risk of clinical failure [ , ] are more common with inappropriate antibiotic therapy. management of initial antibiotic failure is greatly facilitated by an etiologic diagnosis at admission. de-escalation or narrowing of antibiotic therapy on the basis of diagnostic testing is less likely to decrease an in- dividual's risk of death but may decrease cost, drug adverse effects, and antibiotic resistance pressure. some etiologic diagnoses have important epidemiologic implications, such as documentation of severe acute respiratory syndrome (sars), influenza, legionnaires disease, or agents of bioterrorism. diagnostic testing for these infections may affect not only the individual but also many other people. although pneumonia etiologies that should be reported to public health officials vary by state, in general, most states' health regulations require reporting of legionnaires disease, sars, psittacosis, avian influenza (h n ), and possible agents of bioterrorism (plague, tularemia, and anthrax). in addition, specific diagnostic testing and reporting are important for pneumonia cases of any etiology thought to be part of a cluster or caused by pathogens not endemic to the area. there are also societal reasons for encouraging diagnostic testing. the antibiotic recommendations in the present guidelines are based on culture results and sensitivity patterns from patients with positive etiologic diagnoses [ ] . without the accumulated information available from these culture results, trends in antibiotic resistance are more difficult to track, and empirical antibiotic recommendations are less likely to be accurate. the main downside of extensive diagnostic testing of all patients with cap is cost, which is driven by the poor quality of most sputum microbiological samples and the low yield of positive culture results in many groups of patients with cap. a clear need for improved diagnostic testing in cap, most likely using molecular methodology rather than culture, has been recognized by the national institutes of health [ ] . the cost-benefit ratio is even worse when antibiotic therapy is not streamlined when possible [ , ] or when inappropriate escalation occurs [ ] . in clinical practice, narrowing of antibiotic therapy is, unfortunately, unusual, but the committee strongly recommends this as best medical practice. the possibility of polymicrobial cap and the potential benefit of combination therapy for bacteremic pneumococcal pneumonia have complicated the decision to narrow antibiotic therapy. delays in starting antibiotic therapy that result from the need to obtain specimens, complications of invasive diagnostic procedures, and unneeded antibiotic changes and additional testing for false-positive tests are also important considerations. the general recommendation of the committee is to strongly encourage diagnostic testing whenever the result is likely to change individual antibiotic management. for other patients with cap, the recommendations for diagnostic testing focus on patients in whom the diagnostic yield is thought to be greatest. these priorities often overlap. recommendations for patients in whom routine diagnostic testing is indicated for the above reasons are listed in retrospective studies of outpatient cap management usually show that diagnostic tests to define an etiologic pathogen are infrequently performed, yet most patients do well with empir-ical antibiotic treatment [ , ] . exceptions to this general rule may apply to some pathogens important for epidemiologic reasons or management decisions. the availability of rapid point-of-care diagnostic tests, specific treatment and chemoprevention, and epidemiologic importance make influenza testing the most logical. influenza is often suspected on the basis of typical symptoms during the proper season in the presence of an epidemic. however, respiratory syncytial virus (rsv) can cause a similar syndrome and often occurs in the same clinical scenario [ ] . rapid diagnostic tests may be indicated when the diagnosis is uncertain and when distinguishing influenza a from influenza b is important for therapeutic decisions. other infections that are important to verify with diagnostic studies because of epidemiologic implications or because they require unique therapeutic intervention are sars and avian (h n ) influenza, disease caused by agents of bioterrorism, legionella infection, community-acquired mrsa (ca-mrsa) infection, m. tuberculosis infection, or endemic fungal infection. attempts to establish an etiologic diagnosis are also appropriate in selected cases associated with outbreaks, specific risk factors, or atypical presentations. . pretreatment blood samples for culture and an expectorated sputum sample for stain and culture (in patients with a productive cough) should be obtained from hospitalized patients with the clinical indications listed in the only randomized controlled trial of diagnostic strategy in cap has demonstrated no statistically significant differences in mortality rate or los between patients receiving pathogendirected therapy and patients receiving empirical therapy [ ] . however, pathogen-directed therapy was associated with lower mortality among the small number of patients admitted to the icu. the study was performed in a country with a low incidence of antibiotic resistance, which may limit its applicability to areas with higher levels of resistance. adverse effects were significantly more common in the empirical therapy group but may have been unique to the specific antibiotic choice (erythromycin). the lack of benefit overall in this trial should not be interpreted as a lack of benefit for an individual patient. therefore, performing diagnostic tests is never incorrect or a breach of the standard of care. however, information from cohort and observational studies may be used to define patient groups in which the diagnostic yield is increased. patient groups in which routine diagnostic testing is indicated and the recommended tests are listed in table . blood cultures. pretreatment blood cultures yielded positive results for a probable pathogen in %- % in large series of nonselected patients hospitalized with cap [ , , [ ] [ ] [ ] . the yield of blood cultures is, therefore, relatively low (although it is similar to yields in other serious infections), and, when management decisions are analyzed, the impact of positive blood cultures is minor [ , ] . the most common blood culture isolate in all cap studies is s. pneumoniae. because this bacterial organism is always considered to be the most likely pathogen, positive blood culture results have not clearly led to better outcomes or improvements in antibiotic selection [ , ] . false-positive blood culture results are associated with prolonged hospital stay, possibly related to changes in management based on preliminary results showing gram-positive cocci, which eventually prove to be coagulasenegative staphylococci [ , ] . in addition, false-positive blood culture results have led to significantly more vancomycin use [ ] . for these reasons, blood cultures are optional for all hospitalized patients with cap but should be performed selectively (table ). the yield for positive blood culture results is halved by prior antibiotic therapy [ ] . therefore, when performed, samples for blood culture should be obtained before antibiotic administration. however, when multiple risk factors for bacteremia are present, blood culture results after initiation of antibiotic therapy are still positive in up to % of cases [ ] and are, therefore, still warranted in these cases, despite the lower yield. the strongest indication for blood cultures is severe cap. patients with severe cap are more likely to be infected with pathogens other than s. pneumoniae, including s. aureus, p. aeruginosa, and other gram-negative bacilli [ - , , , ] . many of the factors predictive of positive blood culture results [ ] overlap with risk factors for severe cap (table ) . therefore, blood cultures are recommended for all patients with severe cap because of the higher yield, the greater possibility of the presence of pathogens not covered by the usual empirical antibiotic therapy, and the increased potential to affect antibiotic management. blood cultures are also indicated when patients have a host defect in the ability to clear bacteremia-for example, as a result of asplenia or complement deficiencies. patients with chronic liver disease also are more likely to have bacteremia with cap [ ] . leukopenia is also associated with a high incidence of bacteremia [ , ] . respiratory tract specimen gram stain and culture. the yield of sputum bacterial cultures is variable and strongly influenced by the quality of the entire process, including specimen collection, transport, rapid processing, satisfactory use of cytologic criteria, absence of prior antibiotic therapy, and skill in interpretation. the yield of s. pneumoniae, for example, is only %- % from sputum cultures from patients with bacteremic pneumococcal pneumonia in studies performed a few decades ago [ , ] . a more recent study of cases of bacteremic pneumococcal pneumonia found that sputum specimens were not submitted in % of cases and were judged as inadequate in another % of cases [ ] . when patients receiving antibiotics for h were excluded, gram stain showed pneumococci in % of sputum specimens, and culture results were positive in %. for patients who had received no antibiotics, the gram stain was read as being consistent with pneumococci in % of cases, and sputum culture results were positive in %. although there are favorable reports of the utility of gram stain [ ] , a meta-analysis showed a low yield, considering the number of patients with adequate specimens and definitive results [ ] . recent data show that an adequate specimen with a predominant morphotype on gram stain was found in only % of hospitalized patients with cap [ ] . higher psi scores did not predict higher yield. however, a positive gram stain was highly predictive of a subsequent positive culture result. the benefit of a sputum gram stain is, therefore, -fold. first, it broadens initial empirical coverage for less common etiologies, such as infection with s. aureus or gram-negative organisms. this indication is probably the most important, because it will lead to less inappropriate antibiotic therapy. second, it can validate the subsequent sputum culture results. forty percent or more of patients are unable to produce any sputum or to produce sputum in a timely manner [ , ] . the yield of cultures is substantially higher with endotracheal aspirates, bronchoscopic sampling, or transthoracic needle aspirates [ ] [ ] [ ] [ ] [ ] [ ] [ ] , although specimens obtained after initiation of antibiotic therapy are unreliable and must be interpreted carefully [ , , ] . interpretation is improved with quantitative cultures of respiratory secretions from any source (sputum, tracheal aspirations, and bronchoscopic aspirations) or by interpretation based on semiquantitative culture results [ , , ] . because of the significant influence on diagnostic yield and cost effectiveness, careful attention to the details of specimen handling and processing are critical if sputum cultures are obtained. because the best specimens are collected and processed before antibiotics are given, the time to consider obtaining expectorated sputum specimens from patients with factors listed in table is before initiation of antibiotic therapy. once again, the best indication for more extensive respiratory tract cultures is severe cap. gram stain and culture of endotracheal aspirates from intubated patients with cap produce different results than expectorated sputum from non-icu patients [ , ] . many of the pathogens in the broader microbiological spectrum of severe cap are unaffected by a single dose of antibiotics, unlike s. pneumoniae. in addition, an endotracheal aspirate does not require patient cooperation, is clearly a lower respiratory tract sample, and is less likely to be contaminated by oropharyngeal colonizers. nosocomial tracheal colonization is not an issue if the sample is obtained soon after intubation. therefore, culture and gram stain of endotracheal aspirates are recommended for patients intubated for severe cap. in addition to routine cultures, a specific request for culture of respiratory secretions on buffered charcoal yeast extract agar to isolate legionella species may be useful in this subset of patients with severe cap in areas where legionella is endemic, as well as in patients with a recent travel history [ ] . the fact that a respiratory tract culture result is negative does not mean that it has no value. failure to detect s. aureus or gram-negative bacilli in good-quality specimens is strong evidence against the presence of these pathogens. growth inhibition by antibiotics is lower with these pathogens than with s. pneumoniae, but specimens obtained after initiation of antibiotic therapy are harder to interpret, with the possibility of colonization. necrotizing or cavitary pneumonia is a risk for ca-mrsa infection, and sputum samples should be obtained in all cases. negative gram stain and culture results should be adequate to withhold or stop treatment for mrsa infection. severe copd and alcoholism are major risk factors for infection with p. aeruginosa and other gram-negative pathogens [ ] . once again, gram stain and culture of an adequate sputum specimen are usually adequate to exclude the need for empirical coverage of these pathogens. a sputum culture in patients with suspected legionnaires disease is important, because the identification of legionella species implies the possibility of an environmental source to which other susceptible individuals may be exposed. localized community outbreaks of legionnaires disease might be recognized by clinicians or local health departments because у patients might be admitted to the same hospital. however, outbreaks of legionnaires disease associated with hotels or cruise ships [ ] [ ] [ ] are rarely detected by individual clinicians, because travelers typically disperse from the source of infection before developing symptoms. therefore, a travel history should be actively sought from patients with cap, and legionella testing should be performed for those who have traveled in the weeks before the onset of symptoms. urinary antigen tests may be adequate to diagnose and treat an individual, but efforts to obtain a sputum specimen for culture are still indicated to facilitate epidemiologic tracking. the availability of a culture isolate of legionella dramatically improves the likelihood that an environmental source of legionella can be identified and remediated [ ] [ ] [ ] . the yield of sputum culture is increased to %- % when associated with a positive urinary antigen test result [ , ] . attempts to obtain a sample for sputum culture from a patient with a positive pneumococcal urinary antigen test result may be indicated for similar reasons. patients with a productive cough and positive urinary antigen test results have positive sputum culture results in as many as %- % of cases [ ] [ ] [ ] [ ] . in these cases, not only can sensitivity testing confirm the appropriate choice for the individual patient, but important data regarding local community antibiotic resistance rates can also be acquired. other cultures. patients with pleural effusions cm in height on a lateral upright chest radiograph [ ] should undergo thoracentesis to yield material for gram stain and culture for aerobic and anaerobic bacteria. the yield with pleural fluid cultures is low, but the impact on management decisions is substantial, in terms of both antibiotic choice and the need for drainage. nonbronchoscopic bronchoalveolar lavage (bal) in the ed has been studied in a small, randomized trial of intubated patients with cap [ ] . a high percentage ( %) of nonbronchoscopic bal culture results were positive, even in some patients who had already received their first dose of antibiotics. unfortunately, tracheal aspirates were obtained from only a third of patients in the control group, but they all were culture positive. therefore, it is unclear that endotracheal aspirates are inferior to nonbronchoscopic bal. the use of bronchoscopic bal, protected specimen brushing, or transthoracic lung aspiration has not been prospectively studied for initial management of patients with cap [ ] . the best indications are for immunocompromised patients with cap or for patients with cap in whom therapy failed [ , ] . antigen tests. urinary antigen tests are commercially available and have been cleared by the us food and drug administration (fda) for detection of s. pneumoniae and l. pneumophila serogroup [ , , [ ] [ ] [ ] [ ] . urinary antigen testing appears to have a higher diagnostic yield in patients with more severe illness [ , ] . for pneumococcal pneumonia, the principal advantages of antigen tests are rapidity (∼ min), simplicity, reasonable specificity in adults, and the ability to detect pneumococcal pneumonia after antibiotic therapy has been started. studies in adults show a sensitivity of %- % and a specificity of % [ , , ] . this is an attractive test for detecting pneumococcal pneumonia when samples for culture cannot be obtained in a timely fashion or when antibiotic therapy has already been initiated. serial specimens from patients with known bacteremia were still positive for pneumococcal urinary antigen in % of cases after days of therapy [ ] . comparisons with gram stain show that these rapidly available tests often do not overlap, with only % concordance ( of ) among patients when results of either test were positive [ ] . only ∼ % of binax pneumococcal urinary antigen-positive patients can be diagnosed by conventional methods [ , ] . disadvantages include cost (approximately $ per specimen), although this is offset by increased diagnosis-related group-based reimbursement for coding for pneumococcal pneumonia, and the lack of an organism for in vitro susceptibility tests. falsepositive results have been seen in children with chronic respiratory diseases who are colonized with s. pneumoniae [ ] and in patients with an episode of cap within the previous months [ ] , but they do not appear to be a significant problem in colonized patients with copd [ , ] . for legionella, several urinary antigen assays are available, but all detect only l. pneumophila serogroup . although this particular serogroup accounts for %- % of communityacquired cases of legionnaires disease [ , ] in many areas of north america, other species and serogroups predominate in specific locales [ , ] . prior studies of culture-proven legionnaires disease indicate a sensitivity of %- % and a specificity of nearly % for detection of l. pneumophila serogroup . the urine is positive for antigen on day of illness and continues to be positive for weeks [ , ] . the major issue with urinary bacterial antigen detection is whether the tests allow narrowing of empirical antibiotic therapy to a single specific agent. the recommended empirical antibiotic regimens will cover both of these microorganisms. results of a small observational study suggest that therapy with a macrolide alone is adequate for hospitalized patients with cap who test positive for l. pneumophila urinary antigen [ ] . further research is needed in this area. in contrast, rapid antigen detection tests for influenza, which can also provide an etiologic diagnosis within - min, can lead to consideration of antiviral therapy. test performance varies according to the test used, sample type, duration of illness, and patient age. most show a sensitivity of %- % in adults and a specificity approaching % [ ] [ ] [ ] . advantages include the high specificity, the ability of some assays to distinguish between influenza a and b, the rapidity with which the results can be obtained, the possibly reduced use of antibacterial agents, and the utility of establishing this diagnosis for epidemiologic purposes, especially in hospitalized patients who may require infection control precautions. disadvantages include cost (approximately $ per specimen), high rates of false-negative test results, false-positive assays with adenovirus infections, and the fact that the sensitivity is not superior to physician judgment among patients with typical symptoms during an influenza epidemic [ , , ] . direct fluorescent antibody tests are available for influenza and rsv and require ∼ h. for influenza virus, the sensitivity is better than with the point-of-care tests ( %- %). they will detect animal subtypes such as h n and, thus, may be preferred for hospitalized patients [ , ] . for rsv, direct fluorescent antibody tests are so insensitive (sensitivity, %- %) in adults that they are rarely of value [ ] . acute-phase serologic testing. the standard for diagnosis of infection with most atypical pathogens, including chlamydophila pneumoniae, mycoplasma pneumoniae, and legionella species other than l. pneumophila, relies on acute-and convalescent-phase serologic testing. most studies use a microimmunofluorescence serologic test, but this test shows poor reproducibility [ ] . management of patients on the basis of a single acute-phase titer is unreliable [ ] , and initial antibiotic therapy will be completed before the earliest time point to check a convalescent-phase specimen. a new pcr test (bd probetec et legionella pneumophila; becton dickinson) that will detect all serotypes of l. pneumophila in sputum is now cleared by the fda, but extensive published clinical experience is lacking. most pcr reagents for other respiratory pathogens (except mycobacterium species) are "home grown," with requirements for use based on compliance with nccls criteria for analytical validity [ ] . despite the increasing use of these tests for atypical pathogens [ , ] , a review by the centers for disease control and prevention (cdc) of diagnostic assays for detection of c. pneumoniae indicated that, of the pcr reagents, only satisfied the criteria for a validated test [ ] . the diagnostic criteria defined in this review are particularly important for use in prospective studies of cap, because most prior reports used liberal criteria, which resulted in exaggerated rates. for sars, several pcr assays have been developed, but these tests are inadequate because of high rates of false-negative assays in early stages of infection [ , ] . a major goal of therapy is eradication of the infecting organism, with resultant resolution of clinical disease. as such, antimicrobials are a mainstay of treatment. appropriate drug selection is dependent on the causative pathogen and its antibiotic susceptibility. acute pneumonia may be caused by a wide variety of pathogens (table ) . however, until more accurate and rapid diagnostic methods are available, the initial treatment for most patients will remain empirical. recommendations for therapy (table ) apply to most cases; however, physicians should consider specific risk factors for each patient (table ) . a syndromic approach to therapy (under the assumption that an etiology correlates with the presenting clinical manifestations) is not specific enough to reliably predict the etiology of cap [ ] [ ] [ ] . even if a microbial etiology is identified, debate continues with regard to pathogen-specific treatment, because recent studies suggest coinfection by atypical pathogens (such as c. pneumoniae, legionella species, and viruses) and more traditional bacteria [ , ] . however, the importance of treating multiple infecting organisms has not been firmly established. the majority of antibiotics released in the past several decades have an fda indication for cap, making the choice of antibiotics potentially overwhelming. selection of antimicrobial regimens for empirical therapy is based on prediction of the most likely pathogen(s) and knowledge of local susceptibility patterns. recommendations are generally for a class of antibiotics rather than a specific drug, unless outcome data clearly favor one drug. because overall efficacy remains good for many classes of agents, the more potent drugs are given preference because of their benefit in decreasing the risk of selection for antibiotic resistance. other factors for consideration of specific antimicrobials include pharmacokinetics/pharmacodynamics, compliance, safety, and cost. although cap may be caused by a myriad of pathogens, a limited number of agents are responsible for most cases. the emergence of newly recognized pathogens, such as the novel sars-associated coronavirus [ ] , continually increases the challenge for appropriate management. table lists the most common causes of cap, in decreasing order of frequency of occurrence and stratified for severity of illness as judged by site of care (ambulatory vs. hospitalized). s. pneumoniae is the most frequently isolated pathogen. other bacterial causes include nontypeable haemophilus influenzae and moraxella catarrhalis, generally in patients who have underlying bronchopulmonary disease, and s. aureus, especially during an influenza outbreak. risks for infection with enterobacteriaceae species and p. aeruginosa as etiologies for cap are chronic oral steroid administration or severe underlying bronchopulmonary disease, alcoholism, and frequent antibiotic therapy [ , ] , whereas recent hospitalization would define cases as hcap. less common causes of pneumonia include, but are by no means limited to, streptococcus pyogenes, neisseria meningitidis, pasteurella multocida, and h. influenzae type b. the "atypical" organisms, so called because they are not detectable on gram stain or cultivatable on standard bacteriologic media, include m. pneumoniae, c. pneumoniae, legionella species, and respiratory viruses. with the exception of legionella species, these microorganisms are common causes of pneumonia, especially among outpatients. however, these pathogens are not often identified in clinical practice because, with a few exceptions, such as l. pneumophila and influenza virus, no specific, rapid, or standardized tests for their detection exist. although influenza remains the predominant viral cause of cap in adults, other commonly recognized viruses include rsv [ ] , adenovirus, and parainfluenza virus, as well as less common viruses, including human metapneumovirus, herpes simplex virus, varicella-zoster virus, sars-associated coronavirus, and measles virus. in a recent study of immunocompetent adult patients admitted to the hospital with cap, % had evidence of a viral etiology, and, in %, a respiratory virus was the only pathogen identified [ ] . studies that include outpatients find viral pneumonia rates as high as % [ ] . the frequency of other etiologic agents-for example, m. tuberculosis, chlamydophila psittaci (psittacosis), coxiella burnetii (q fever), francisella tularensis (tularemia), bordetella pertussis (whooping cough), and endemic fungi (histoplasma capsulatum, coccidioides immitis, cryptococcus neoformans, and blastomyces hominis)-is largely determined by the epidemiologic setting (table ) but rarely exceeds %- % total [ , ] . the exception may be endemic fungi in the appropriate geographic distribution [ ] . the need for specific anaerobic coverage for cap is generally overestimated. anaerobic bacteria cannot be detected by diagnostic techniques in current use. anaerobic coverage is clearly indicated only in the classic aspiration pleuropulmonary syndrome in patients with a history of loss of consciousness as a result of alcohol/drug overdose or after seizures in patients with concomitant gingival disease or esophogeal motility disorders. antibiotic trials have not demonstrated a need to specifically treat these organisms in the majority of cap cases. smallvolume aspiration at the time of intubation should be adequately handled by standard empirical severe cap treatment [ ] and by the high oxygen tension provided by mechanical ventilation. resistance to commonly used antibiotics for cap presents another major consideration in choosing empirical therapy. resistance patterns clearly vary by geography. local antibiotic prescribing patterns are a likely explanation [ ] [ ] [ ] . however, clonal spread of resistant strains is well documented. therefore, antibiotic recommendations must be modified on the basis of local susceptibility patterns. the most reliable source is state/provincial or municipal health department regional data, if available. local hospital antibiograms are generally the most accessible source of data but may suffer from small numbers of isolates. drug-resistant s. pneumoniae (drsp). the emergence of drug-resistant pneumococcal isolates is well documented. the incidence of resistance appears to have stabilized somewhat in the past few years. resistance to penicillin and cephalosporins may even be decreasing, whereas macrolide resistance continues to increase [ , ] . however, the clinical relevance of drsp for pneumonia is uncertain, and few well-controlled studies have examined the impact of in vitro resistance on clinical outcomes of cap. published studies are limited by small sample sizes, biases inherent in observational design, and the relative infrequency of isolates exhibiting high-level resistance [ ] [ ] [ ] . current levels of b-lactam resistance do not generally result in cap treatment failures when appropriate agents (i.e., amoxicillin, ceftriaxone, or cefotaxime) and doses are used, even in the presence of bacteremia [ , ] . the available data suggest that the clinically relevant level of penicillin resistance is a mic of at least mg/l [ ] . one report suggested that, if cefuroxime is used to treat pneumococcal bacteremia when the organism is resistant in vitro, the outcome is worse than with other therapies [ ] . other discordant therapies, including penicillin, did not have an impact on mortality. data exist suggesting that resistance to macrolides [ ] [ ] [ ] and older fluoroquinolones (ciprofloxacin and levofloxacin) [ , , ] results in clinical failure. to date, no failures have been reported for the newer fluoroquinolones (moxifloxacin and gemifloxacin). risk factors for infection with b-lactam-resistant s. pneumoniae include age ! years or years, b-lactam therapy within the previous months, alcoholism, medical comorbidities, immunosuppressive illness or therapy, and exposure to a child in a day care center [ , [ ] [ ] [ ] . although the relative predictive value of these risk factors is unclear, recent treatment with antimicrobials is likely the most significant. recent therapy or repeated courses of therapy with b-lactams, macrolides, or fluoroquinolones are risk factors for pneumococcal resistance to the same class of antibiotic [ , , , ] . one study found that use of either a b-lactam or macrolide within the previous months predicted an increased likelihood that, if pneumococcal bacteremia is present, the organism would be penicillin resistant [ ] . other studies have shown that repeated use of fluoroquinolones predicts an increased risk of infection with fluoroquinolone-resistant pneumococci [ , ] . whether this risk applies equally to all fluoroquinolones or is more of a concern for less active antipneumococcal agents (levofloxacin and ciprofloxacin) than for more active agents (moxifloxacin and gemifloxacin) is uncertain [ , , ] . recommendations for the use of highly active agents in patients at risk for infection with drsp is, therefore, based only in part on efficacy considerations; it is also based on a desire to prevent more resistance from emerging by employing the most potent regimen possible. although increasing the doses of certain agents (penicillins, cephalosporins, levofloxacin) may lead to adequate outcomes in the majority of cases, switching to more potent agents may lead to stabilization or even an overall decrease in resistance rates [ , ] . ca-mrsa. recently, an increasing incidence of pneumonia due to ca-mrsa has been observed [ , ] . ca-mrsa appears in patterns: the typical hospital-acquired strain [ ] and, recently, strains that are epidemiologically, genotypically, and phenotypically distinct from hospital-acquired strains [ , ] . many of the former may represent hcap, because these earlier studies did not differentiate this group from typical cap. the latter are resistant to fewer antimicrobials than are hospitalacquired mrsa strains and often contain a novel type iv sccmec gene. in addition, most contain the gene for panton-valentine leukocidin [ , ] , a toxin associated with clinical features of necrotizing pneumonia, shock, and respiratory failure, as well as formation of abscesses and empyemas. the large majority of cases published to date have been skin infections in children. in a large study of ca-mrsa in communities, % of ca-mrsa infections were pneumonia [ ] . however, pneumonia in both adults [ ] and children has been reported, often associated with preceding influenza. this strain should also be suspected in patients who present with cavitary infiltrates without risk factors for anaerobic aspiration pneu-monia (gingivitis and a risk for loss of consciousness, such as seizures or alcohol abuse, or esophogeal motility disorders). diagnosis is usually straightforward, with high yields from sputum and blood cultures in this characteristic clinical scenario. ca-mrsa cap remains rare in most communities but is expected to be an emerging problem in cap treatment. outpatient treatment. the following regimens are recommended for outpatient treatment on the basis of the listed clinical risks. the most common pathogens identified from recent studies of mild (ambulatory) cap were s. pneumoniae, m. pneumoniae, c. pneumoniae, and h. influenzae [ , ] . mycoplasma infection was most common among patients ! years of age without significant comorbid conditions or abnormal vital signs, whereas s. pneumoniae was the most common pathogen among older patients and among those with significant underlying disease. hemophilus infection was found in %mostly in patients with comorbidities. the importance of ther-apy for mycoplasma infection and chlamydophila infection in mild cap has been the subject of debate, because many infections are self-limiting [ , ] . nevertheless, studies from the s of children indicate that treatment of mild m. pneumoniae cap reduces the morbidity of pneumonia and shortens the duration of symptoms [ ] . the evidence to support specific treatment of these microorganisms in adults is lacking. macrolides have long been commonly prescribed for treatment of outpatients with cap in the united states, because of their activity against s. pneumoniae and the atypical pathogens. this class includes the erythromycin-type agents (including dirithromycin), clarithromycin, and the azalide azithromycin. although the least expensive, erythromycin is not often used now, because of gastrointestinal intolerance and lack of activity against h. influenzae. because of h. influenzae, azithromycin is preferred for outpatients with comorbidities such as copd. numerous randomized clinical trials have documented the efficacy of clarithromycin and azithromycin as monotherapy for outpatient cap, although several studies have demonstrated that clinical failure can occur with a resistant isolate. when such patients were hospitalized and treated with a b-lactam and a macrolide, however, all survived and generally recovered without significant complications [ , ] . most of these patients had risk factors for which therapy with a macrolide alone is not recommended in the present guidelines. thus, for patients with a significant risk of drsp infection, monotherapy with a macrolide is not recommended. doxycycline is included as a cost-effective alternative on the basis of in vitro data indicating effectiveness equivalent to that of erythromycin for pneumococcal isolates. the use of fluoroquinolones to treat ambulatory patients with cap without comorbid conditions, risk factors for drsp, or recent antimicrobial use is discouraged because of concern that widespread use may lead to the development of fluoroquinolone resistance [ ] . however, the fraction of total fluoroquinolone use specifically for cap is extremely small and unlikely to lead to increased resistance by itself. more concerning is a recent study suggesting that many outpatients given a fluoroquinolone may not have even required an antibiotic, that the dose and duration of treatment were often incorrect, and that another agent often should have been used as firstline therapy. this usage pattern may promote the rapid development of resistance to fluoroquinolones [ ] . comorbidities or recent antimicrobial therapy increase the likelihood of infection with drsp and enteric gram-negative bacteria. for such patients, recommended empirical therapeutic options include ( ) a respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [ mg daily]) or ( ) combination therapy with a b-lactam effective against s. pneumoniae plus a macrolide (doxycycline as an alternative). on the basis of present pharmacodynamic principles, high-dose amox-icillin (amoxicillin [ g times daily] or amoxicillin-clavulanate [ g times daily]) should target % of s. pneumoniae and is the preferred b-lactam. ceftriaxone is an alternative to highdose amoxicillin when parenteral therapy is feasible. selected oral cephalosporins (cefpodoxime and cefuroxime) can be used as alternatives [ ] , but these are less active in vitro than highdose amoxicillin or ceftriaxone. agents in the same class as the patient had been receiving previously should not be used to treat patients with recent antibiotic exposure. telithromycin is the first of the ketolide antibiotics, derived from the macrolide family, and is active against s. pneumoniae that is resistant to other antimicrobials commonly used for cap (including penicillin, macrolides, and fluoroquinolones). several cap trials suggest that telithromycin is equivalent to comparators (including amoxicillin, clarithromycin, and trovafloxacin) [ ] [ ] [ ] [ ] . there have also been recent postmarketing reports of life-threatening hepatotoxicity [ ] . at present, the committee is awaiting further evaluation of the safety of this drug by the fda before making its final recommendation. inpatient, non-icu treatment. the following regimens are recommended for hospital ward treatment. level i evidence) . a b-lactam plus a macrolide (strong recommendation; level i evidence) (preferred b-lactam agents include cefotaxime, ceftriaxone, and ampicillin; ertapenem for selected patients; with doxycycline [level iii evidence] as an alternative to the macrolide. a respiratory fluoroquinolone should be used for penicillin-allergic patients.) the recommendations of combination treatment with a blactam plus a macrolide or monotherapy with a fluoroquinolone were based on retrospective studies demonstrating a significant reduction in mortality compared with that associated with administration of a cephalosporin alone [ ] [ ] [ ] [ ] . multiple prospective randomized trials have demonstrated that either regimen results in high cure rates. the major discriminating factor between the regimens is the patient's prior antibiotic exposure (within the past months). preferred b-lactams are those effective against s. pneumoniae and other common, nonatypical pathogens without being overly broad spectrum. in january , the clinical laboratory standards institute (formerly the nccls) increased the mic breakpoints for cefotaxime and ceftriaxone for nonmeningeal s. pneumoniae infections. these new breakpoints acknowledge that nonmeningeal infections caused by strains formerly considered to be intermediately susceptible, or even resistant, can be treated successfully with usual doses of these b-lactams [ , , ] . two randomized, double-blind studies showed ertapenem to be equivalent to ceftriaxone [ , ] . it also has excellent activity against anaerobic organisms, drsp, and most enterobacteriaceae species (including extended-spectrum b-lactamase producers, but not p. aeruginosa). ertapenem may be useful in treating patients with risks for infection with these pathogens and for patients who have recently received antibiotic therapy. however, clinical experience with this agent is limited. other "antipneumococcal, antipseudomonal" b-lactam agents are appropriate when resistant pathogens, such as pseudomonas, are likely to be present. doxycycline can be used as an alternative to a macrolide on the basis of scant data for treatment of legionella infections [ , , ] . two randomized, double-blind studies of adults hospitalized for cap have demonstrated that parenteral azithromycin alone was as effective, with improved tolerability, as intravenous cefuroxime, with or without intravenous erythromycin [ , ] . in another study, mortality and readmission rates were similar, but the mean los was shorter among patients receiving azithromycin alone than among those receiving other guideline-recommended therapy [ ] . none of the patients with erythromycin-resistant s. pneumoniae infections died or was transferred to the icu, including who received azithromycin alone. another study showed that those receiving a macrolide alone had the lowest -day mortality but were the least ill [ ] . such patients were younger and were more likely to be in lower-risk groups. these studies suggest that therapy with azithromycin alone can be considered for carefully selected patients with cap with nonsevere disease (patients admitted primarily for reasons other than cap) and no risk factors for infection with drsp or gramnegative pathogens. however, the emergence of high rates of macrolide resistance in many areas of the country suggests that this therapy cannot be routinely recommended. initial therapy should be given intravenously for most admitted patients, but some without risk factors for severe pneumonia could receive oral therapy, especially with highly bioavailable agents such as fluoroquinolones. when an intravenous b-lactam is combined with coverage for atypical pathogens, oral therapy with a macrolide or doxycycline is appropriate for selected patients without severe pneumonia risk factors [ ] . inpatient, icu treatment. the following regimen is the minimal recommended treatment for patients admitted to the icu. . a b-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) plus either azithromycin (level ii evidence) or a fluoroquinolone (level i evidence) (strong recommendation) (for penicillin-allergic patients, a respiratory fluoroquinolone and aztreonam are recommended.) a single randomized controlled trial of treatment for severe cap is available. patients with shock were excluded; however, among the patients with mechanical ventilation, treatment with a fluoroquinolone alone resulted in a trend toward inferior outcome [ ] . because septic shock and mechanical ventilation are the clearest reasons for icu admission, the majority of icu patients would still require combination therapy. icu patients are routinely excluded from other trials; therefore, recommendations are extrapolated from nonsevere cases, in conjunction with case series and retrospective analyses of cohorts with severe cap. for all patients admitted to the icu, coverage for s. pneumoniae and legionella species should be ensured [ , ] by using a potent antipneumococcal b-lactam and either a macrolide or a fluoroquinolone. therapy with a respiratory fluoroquinolone alone is not established for severe cap [ ] , and, if the patient has concomitant pneumococcal meningitis, the efficacy of fluoroquinolone monotherapy is uncertain. in addition, prospective observational studies [ , ] and retrospective analyses [ ] [ ] [ ] have found that combination therapy for bacteremic pneumococcal pneumonia is associated with lower mortality than monotherapy. the mechanism of this benefit is unclear but was principally found in the patients with the most severe illness and has not been demonstrated in nonbacteremic pneumococcal cap studies. therefore, combination empirical therapy is recommended for at least h or until results of diagnostic tests are known. in critically ill patients with cap, a large number of microorganisms other than s. pneumoniae and legionella species must be considered. a review of studies that included patients with cap who were admitted to the icu demonstrates that the most common pathogens in the icu population were (in descending order of frequency) s. pneumoniae, legionella species, h. influenzae, enterobacteriaceae species, s. aureus, and pseudomonas species [ ] . the atypical pathogens responsible for severe cap may vary over time but can account collectively for у % of severe pneumonia episodes. the dominant atypical pathogen in severe cap is legionella [ ] , but some diagnostic bias probably accounts for this finding [ ] . the recommended standard empirical regimen should routinely cover the most common pathogens that cause severe cap, all of the atypical pathogens, and most of the relevant enterobacteriaceae species. treatment of mrsa or p. aeruginosa infection is the main reason to modify the standard empirical regimen. the following are additions or modifications to the basic empirical regimen recommended above if these pathogens are suspected. pseudomonal cap requires combination treatment to prevent inappropriate initial therapy, just as pseudomonas nosocomial pneumonia does [ ] . once susceptibilities are known, treatment can be adjusted accordingly. alternative regimens are provided for patients who may have recently received an oral fluoroquinolone, in whom the aminoglycoside-containing regimen would be preferred. a consistent gram stain of tracheal aspirate, sputum, or blood is the best indication for pseudomonas coverage. other, easier-to-treat gram-negative microorganisms may ultimately be proven to be the causative pathogen, but empirical coverage of pseudomonas species until culture results are known is least likely to be associated with inappropriate therapy. other clinical risk factors for infection with pseudomonas species include structural lung diseases, such as bronchiectasis, or repeated exacerbations of severe copd leading to frequent steroid and/or antibiotic use, as well as prior antibiotic therapy [ ] . these patients do not necessarily require icu admission for cap [ ] , so pseudomonas infection remains a concern for them even if they are only hospitalized on a general ward. the major risk factor for infection with other serious gram-negative pathogens, such as klebsiella pneumoniae or acinetobacter species, is chronic alcoholism. (moderate recommendation; level iii evidence.) the best indicator of s. aureus infection is the presence of gram-positive cocci in clusters in a tracheal aspirate or in an adequate sputum sample. the same findings on preliminary results of blood cultures are not as reliable, because of the significant risk of contamination [ ] . clinical risk factors for s. aureus cap include end-stage renal disease, injection drug abuse, prior influenza, and prior antibiotic therapy (especially with fluoroquinolones [ ] ). for methicillin-sensitive s. aureus, the empirical combination therapy recommended above, which includes a b-lactam and sometimes a respiratory fluoroquinolone, should be adequate until susceptibility results are available and specific therapy with a penicillinase-resistant semisynthetic penicillin or first-generation cephalosporin can be initiated. both also offer additional coverage for drsp. neither linezolid [ ] nor vancomycin [ ] is an optimal drug for methicillin-sensitive s. aureus. although methicillin-resistant strains of s. aureus are still the minority, the excess mortality associated with inappropriate an-tibiotic therapy [ ] would suggest that empirical coverage should be considered when ca-mrsa is a concern. the most effective therapy has yet to be defined. the majority of ca-mrsa strains are more susceptible in vitro to non-b-lactam antimicrobials, including trimethoprim-sulfamethoxazole (tmp-smx) and fluoroquinolones, than are hospital-acquired strains. previous experience with tmp-smx in other types of severe infections (endocarditis and septic thrombophlebitis) suggests that tmp-smx is inferior to vancomycin [ ] . further experience and study of the adequacy of tmp-smx for ca-mrsa cap is clearly needed. vancomycin has never been specifically studied for cap, and linezolid has been found to be better than ceftriaxone for bacteremic s. pneumoniae in a nonblinded study [ ] and superior to vancomycin in retrospective analysis of studies involving nosocomial mrsa pneumonia [ ] . newer agents for mrsa have recently become available, and others are anticipated. of the presently available agents, daptomycin should not be used for cap, and no data on pneumonia are available for tigecycline. a concern with ca-mrsa is necrotizing pneumonia associated with production of panton-valentine leukocidin and other toxins. vancomycin clearly does not decrease toxin production, and the effect of tmp-smx and fluoroquinolones on toxin production is unclear. addition of clindamycin or use of linezolid, both of which have been shown to affect toxin production in a laboratory setting [ ] , may warrant their consideration for treatment of these necrotizing pneumonias [ ] . unfortunately, the emergence of resistance during therapy with clindamycin has been reported (especially in erythromycinresistant strains), and vancomycin would still be needed for bacterial killing. clinicians should be aware of epidemiologic conditions and/ or risk factors that may suggest that alternative or specific additional antibiotics should be considered. these conditions and specific pathogens, with preferred treatment, are listed in tables and . pathogen-directed therapy . once the etiology of cap has been identified on the basis of reliable microbiological methods, antimicrobial therapy should be directed at that pathogen. (moderate recommendation; level iii evidence.) treatment options may be simplified (table ) if the etiologic agent is established or strongly suspected. diagnostic procedures that identify a specific etiology within - h can still be useful for guiding continued therapy. this information is often available at the time of consideration for a switch from parenteral to oral therapy and may be used to direct specific oral antimicrobial choices. if, for example, an appropriate culture reveals penicillin-susceptible s. pneumoniae, a narrowspectrum agent (such as penicillin or amoxicillin) may be used. this will, hopefully, reduce the selective pressure for resistance. the major issue with pathogen-specific therapy is management of bacteremic s. pneumoniae cap. the implications of the observational finding that dual therapy was associated with reduced mortality in bacteremic pneumococcal pneumonia [ ] [ ] [ ] [ ] [ ] are uncertain. one explanation for the reduced mortality may be the presence of undiagnosed coinfection with an atypical pathogen; although reported to occur in %- % of cap cases in some studies [ , ] , much lower rates of undiagnosed coinfection are found in general [ ] and specifically in severe cases [ ] . an alternative explanation is the immunomodulatory effects of macrolides [ , ] . it is important to note that these studies evaluated the effects of initial empirical therapy before the results of blood cultures were known and did not examine effects of pathogen-specific therapy after the results of blood cultures were available. the benefit of combination therapy was also most pronounced in the more severely ill patients [ , ] . therefore, discontinuation of combination therapy after results of cultures are known is most likely safe in non-icu patients. oseltamivir or zanamivir is recommended for influenza a. (strong recommendation; level i evidence.) . use of oseltamivir and zanamivir is not recommended for patients with uncomplicated influenza with symptoms for h (level i evidence), but these drugs may be used to reduce viral shedding in hospitalized patients or for influenza pneumonia. (moderate recommendation; level iii evidence.) studies that demonstrate that treatment of influenza is effective only if instituted within h of the onset of symptoms have been performed only in uncomplicated cases [ ] [ ] [ ] [ ] . the impact of such treatment on patients who are hospitalized with influenza pneumonia or a bacterial pneumonia complicating influenza is unclear. in hospitalized adults with influenza, a minority of whom had radiographically documented pneumonia, no obvious benefit was found in one retrospective study of amantadine treatment [ ] . treatment of antigen-or culture-positive patients with influenza with antivirals in addition to antibiotics is warranted, even if the radiographic infiltrate is caused by a subsequent bacterial superinfection. because of the longer period of persistent positivity after infection, the appropriate treatment for patients diagnosed with only of the rapid diagnostic tests is unclear. because such patients often have recoverable virus (median duration of days) after hos-pitalization, antiviral treatment seems reasonable from an infection-control standpoint alone. because of its broad influenza spectrum, low risk of resistance emergence, and lack of bronchospasm risk, oseltamivir is an appropriate choice for hospitalized patients. the neuraminidase inhibitors are effective against both influenza a and b viruses, whereas the m inhibitors, amantadine, and rimantadine are active only against influenza a [ ] . in addition, viruses recently circulating in the united states and canada are often resistant to the m inhibitors on the basis of antiviral testing [ , ] . therefore, neither amantadine nor rimantadine should be used for treatment or chemoprophylaxis of influenza a in the united states until susceptibility to these antiviral medications has been reestablished among circulating influenza a viruses [ ] . early treatment of influenza in ambulatory adults with inhaled zanamivir or oral oseltamivir appears to reduce the likelihood of lower respiratory tract complications [ ] [ ] [ ] . the use of influenza antiviral medications appears to reduce the likelihood of respiratory tract complications, as reflected by reduced usage rates of antibacterial agents in ambulatory patients with influenza. although clearly important in outpatient pneumonia, this experience may also apply to patients hospitalized primarily for influenza. parenteral acyclovir is indicated for treatment of varicellazoster virus infection [ ] recent human infections caused by avian influenza a (h n ) in vietnam, thailand, cambodia, china, indonesia, egypt, and turkey raise the possibility of a pandemic in the near future. the severity of h n infection in humans distinguishes it from that caused by routine seasonal influenza. respiratory failure requiring hospitalization and intensive care has been seen in the majority of the recognized cases, and mortality is ∼ % [ , ] . if a pandemic occurs, deaths will result from primary influenza pneumonia with or without secondary bacterial pneumonia. this section highlights issues for consideration, recognizing that treatment recommendations will likely change as the pandemic progresses. more specific guidance can be found on the idsa, ats, cdc, and who web sites as the key features of the pandemic become clearer. additional guidance is available at http://www.pandemicflu.gov. the who has delineated phases of an influenza pandemic, defined by increasing levels of risk and public health response [ ] . during the current pandemic alert phase (phase : cases of novel influenza infection without sustained person-to-person transmission), testing should be focused on confirming all suspected cases in areas where h n infection has been documented in poultry and on detecting the arrival of the pandemic strain in unaffected countries. early clinical features of h n infection include persistent fever, cough, and respiratory difficulty progressing over - days, as well as lymphopenia on admission to the hospital [ , , ] . exposure to sick and dying poultry in an area with known or suspected h n activity has been reported by most patients, although the recognition of poultry outbreaks has sometimes followed the recognition of human cases [ ] . rapid bedside tests to detect influenza a have been used as screening tools for avian influenza in some settings. throat swabs tested by rt-pcr have been the most sensitive for confirming h n infection to date, but nasopharyngeal swabs, washes, and aspirates; bal fluid; lung and other tissues; and stool have yielded positive results by rt-pcr and viral culture with varying sensitivity. convalescent-phase serum can be tested by microneutralization for antibodies to h antigen in a small number of international reference laboratories. specimens from suspected cases of h n infection should be sent to public health laboratories with appropriate biocontainment facilities; the case should be discussed with health department officials to arrange the transfer of specimens and to initiate an epidemiologic evaluation. during later phases of an ongoing pandemic, testing may be necessary for many more patients, so that appropriate treatment and infection control decisions can be made, and to assist in defining the extent of the pandemic. recommendations for such testing will evolve on the basis of the features of the pandemic, and guidance should be sought from the cdc and who web sites (http://www.cdc.gov and http://www.who.int). patients with confirmed or suspected h n influenza should be treated with oseltamivir. most h n isolates since have been susceptible to the neuraminidase inhibitors oseltamivir and zanamivir and resistant to the adamantanes (amantidine and rimantidine) [ , ] . the current recommendation is for a -day course of treatment at the standard dosage of mg times daily. in addition, droplet precautions should be used for patients with suspected h n influenza, and they should be placed in respiratory isolation until that etiology is ruled out. health care personnel should wear n- (or higher) respirators during medical procedures that have a high likelihood of generating infectious respiratory aerosols. bacterial superinfections, particularly pneumonia, are important complications of influenza pneumonia. the bacterial etiologies of cap after influenza infection have included s. pneumoniae, s. aureus, h. influenzae, and group a streptococci. legionella, chlamydophila, and mycoplasma species are not important causes of secondary bacterial pneumonia after influenza. appropriate agents would therefore include cefotaxime, ceftriaxone, and respiratory fluoroquinolones. treatment with vancomycin, linezolid, or other agents directed against ca-mrsa should be limited to patients with confirmed infection or a compatible clinical presentation (shock and necrotizing pneumonia). because shortages of antibacterials and antivirals are anticipated during a pandemic, the appropriate use of diagnostic tests will be even more important to help target antibacterial therapy whenever possible, especially for patients admitted to the hospital. time to first antibiotic dose for cap has recently received significant attention from a quality-of-care perspective. this emphasis is based on retrospective studies of medicare beneficiaries that demonstrated statistically significantly lower mortality among patients who received early antibiotic therapy [ , ] . the initial study suggested a breakpoint of h [ ] , whereas the subsequent analysis found that h was associated with lower mortality [ ] . studies that document the time to first antibiotic dose do not consistently demonstrate this difference, although none had as large a patient population. most importantly, prospective trials of care by protocol have not demonstrated a survival benefit to increasing the percentage of patients with cap who receive antibiotics within the first - h [ , ] . early antibiotic administration does not appear to shorten the time to clinical stability, either [ ] , although time of first dose does appear to correlate with los [ , ] . a problem of internal consistency is also present, because, in both studies [ , ] , patients who received antibiotics in the first h after presentation actually did worse than those who re- temperature р . ؇c heart rate р beats/min respiratory rate р breaths/min systolic blood pressure у mm hg arterial oxygen saturation у % or po у mm hg on room air ability to maintain oral intake a normal mental status a note. criteria are from [ , , ] . po , oxygen partial pressure. a important for discharge or oral switch decision but not necessarily for determination of nonresponse. ceived antibiotics - h after presentation. for these and other reasons, the committee did not feel that a specific time window for delivery of the first antibiotic dose should be recommended. however, the committee does feel that therapy should be administered as soon as possible after the diagnosis is considered likely. conversely, a delay in antibiotic therapy has adverse consequences in many infections. for critically ill, hemodynamically unstable patients, early antibiotic therapy should be encouraged, although no prospective data support this recommendation. delay in beginning antibiotic treatment during the transition from the ed is not uncommon. especially with the frequent use of once-daily antibiotics for cap, timing and communication issues may result in patients not receiving antibiotics for h after hospital admission. the committee felt that the best and most practical resolution to this issue was that the initial dose be given in the ed [ ] . data from the medicare database indicated that antibiotic treatment before hospital admission was also associated with lower mortality [ ] . given that there are even more concerns regarding timing of the first dose of antibiotic when the patient is directly admitted to a busy inpatient unit, provision of the first dose in the physician's office may be best if the recommended oral or intramuscular antibiotics are available in the office. with the use of a potent, highly bioavailable antibiotic, the ability to eat and drink is the major consideration for switching from intravenous to oral antibiotic therapy for non-icu patients. initially, ramirez et al. [ ] defined a set of criteria for an early switch from intravenous to oral therapy (table ). in general, as many as two-thirds of all patients have clinical improvement and meet criteria for a therapy switch in the first days, and most non-icu patients meet these criteria by day . subsequent studies have suggested that even more liberal criteria are adequate for the switch to oral therapy. an alternative approach is to change from intravenous to oral therapy at a predetermined time, regardless of the clinical response [ ] . one study population with nonsevere illness was randomized to receive either oral therapy alone or intravenous therapy, with the switch occurring after h without fever. the study population with severe illness was randomized to receive either intravenous therapy with a switch to oral therapy after days or a full -day course of intravenous antibiotics. time to resolution of symptoms for the patients with nonsevere illness was similar with either regimen. among patients with more severe illness, the rapid switch to oral therapy had the same rate of treatment failure and the same time to resolution of symptoms as prolonged intravenous therapy. the rapid-switch group required fewer inpatient days ( vs. ) , although this was likely partially a result of the protocol, but the patients also had fewer adverse events. the need to keep patients in the hospital once clinical stability is achieved has been questioned, even though physicians commonly choose to observe patients receiving oral therapy for у day. even in the presence of pneumococcal bacteremia, a switch to oral therapy can be safely done once clinical stability is achieved and prolonged intravenous therapy is not needed [ ] . such patients generally take longer (approximately half a day) to become clinically stable than do nonbacteremic patients. the benefits of in-hospital observation after a switch to oral therapy are limited and add to the cost of care [ ] . discharge should be considered when the patient is a candidate for oral therapy and when there is no need to treat any comorbid illness, no need for further diagnostic testing, and no unmet social needs [ , , ] . although it is clear that clinically stable patients can be safely switched to oral therapy and discharged, the need to wait for all of the features of clinical stability to be present before a patient is discharged is uncertain. for example, not all investigators have found it necessary to have the white blood cell count improve. using the definition for clinical stability in table , halm et al. [ ] found that . % of patients were discharged from the hospital with у instability. death or readmission occurred in . % of patients with no instability on discharge, in . % of patients with instability, and in . % with у instabilities. in general, patients in higher psi classes take longer to reach clinical stability than do patients in lower risk classes [ ] . this finding may reflect the fact that elderly patients with multiple comorbidities often recover more slowly. arrangements for appropriate follow-up care, including rehabilitation, should therefore be initiated early for these patients. in general, when switching to oral antibiotics, either the same agent as the intravenous antibiotic or the same drug class should be used. switching to a different class of agents simply because of its high bioavailability (such as a fluoroquinolone) is probably not necessary for a responding patient. for patients who received intravenous b-lactam-macrolide combination therapy, a switch to a macrolide alone appears to be safe for those who do not have drsp or gram-negative enteric pathogens isolated [ ] . most patients with cap have been treated for - days or longer, but few well-controlled studies have evaluated the optimal duration of therapy for patients with cap, managed in or out of the hospital. available data on short-course treatment do not suggest any difference in outcome with appropriate therapy in either inpatients or outpatients [ ] . duration is also difficult to define in a uniform fashion, because some antibiotics (such as azithromycin) are administered for a short time yet have a long half-life at respiratory sites of infection. in trials of antibiotic therapy for cap, azithromycin has been used for - days as oral therapy for outpatients, with some reports of single-dose therapy for patients with atypical pathogen infections [ ] [ ] [ ] . results with azithromycin should not be extrapolated to other drugs with significantly shorter half-lives. the ketolide telithromycin has been used for - days to treat outpatients, including some with pneumococcal bacteremia or psi classes уiii [ ] . in a recent study, highdose ( mg) levofloxacin therapy for days was equally successful and resulted in more afebrile patients by day than did the -mg dose for - days ( . % vs. . %; p p ) [ ] . on the basis of these studies, days appears to be . the minimal overall duration of therapy documented to be effective in usual forms of cap. as is discussed above, most patients become clinically stable within - days, so longer durations of therapy are rarely necessary. patients with persistent clinical instability are often readmitted to the hospital and may not be candidates for shortduration therapy. short-duration therapy may be suboptimal for patients with bacteremic s. aureus pneumonia (because of the risk of associated endocarditis and deep-seated infection), for those with meningitis or endocarditis complicating pneumonia, and for those infected with other, less common pathogens (e.g., burkholderia pseudomallei or endemic fungi). an -day course of therapy for nosocomial p. aeruginosa pneumonia led to relapse more commonly than did a -day course of therapy [ ] . whether the same results would be applicable to cap cases is unclear, but the presence of cavities or other signs of tissue necrosis may warrant prolonged treatment. studies of duration of therapy have focused on patients receiving empirical treatment, and reliable data defining treatment duration after an initially ineffective regimen are lacking. drotrecogin alfa activated is the first immunomodulatory therapy approved for severe sepsis. in the united states, the fda recommended the use of drotrecogin alfa activated for patients at high risk of death. the high-risk criterion suggested by the fda was an acute physiologic and chronic health assessment (apache) ii score у , based on a subgroup analysis of the overall study. however, the survival advantage (absolute risk reduction, . %) of drotrecogin alfa activated treatment of patients in the cap subgroup was equivalent to that in the subgroup with apache ii scores у [ , , ] . the greatest reduction in the mortality rate was for s. pneumoniae infection (relative risk, . ; % ci, . - . ) [ ] . subsequent data have suggested that the benefit appears to be greatest when the treatment is given as early in the hospital admission as possible. in the subgroup with severe cap caused by a pathogen other than s. pneumoniae and treated with appropriate antibiotics, there was no evidence that drotrecogin alfa activated affected mortality. although the benefit of drotrecogin alfa activated is clearly greatest for patients with cap who have high apache ii scores, this criterion alone may not be adequate to select appropriate patients. an apache ii score у was selected by a subgroup analysis of the entire study cohort and may not be similarly calibrated in a cap-only cohort. two-organ failure, the criterion suggested for drotrecogin alfa activated use by the european regulatory agency, did not influence the mortality benefit for patients with cap [ ] . therefore, in addition to patients with septic shock, other patients with severe cap could be considered for treatment with drotrecogin alfa activated. those with sepsis-induced leukopenia are at extremely high risk of death and ards and are, therefore, potential candidates. conversely, the benefit of drotrecogin alfa activated is not as clear when respiratory failure is caused more by exacerbation of underlying lung disease rather than by the pneumonia itself. other minor criteria for severe cap proposed above are similar to organ failure criteria used in many sepsis trials. consideration of treatment with drotrecogin alfa activated is appropriate, but the strength of the recommendation is only level ii. . hypotensive, fluid-resuscitated patients with severe cap should be screened for occult adrenal insufficiency. (moderate recommendation; level ii evidence.) a large, multicenter trial has suggested that stress-dose ( - mg of hydrocortisone per day or equivalent) steroid treatment improves outcomes of vasopressor-dependent patients with septic shock who do not have an appropriate cortisol response to stimulation [ ] . once again, patients with cap made up a significant fraction of patients entered into the trial. in addition, small pilot studies have suggested that there is a benefit to corticosteroid therapy even for patients with severe cap who are not in shock [ ] [ ] [ ] . the small sample size and baseline differences between groups compromise the conclusions. although the criteria for steroid replacement therapy remain controversial, the frequency of intermittent steroid treatment in patients at risk for severe cap, such as those with severe copd, suggests that screening of patients with severe cap is appropriate with replacement if inadequate cortisol levels are documented. if corticosteroids are used, close attention to tight glucose control is required [ ] . patients who do not require immediate intubation but who have either hypoxemia or respiratory distress should receive a trial of niv [ , , ] . patients with underlying copd are most likely to benefit. patients with cap who were ran-domized to receive niv had a % absolute risk reduction for the need for intubation [ ] . the use of niv may also improve intermediate-term mortality. inability to expectorate may limit the use of niv [ ] , but intermittent application of niv may allow for its use in patients with productive cough unless sputum production is excessive. prompt recognition of a failed niv trial is critically important, because most studies demonstrate worse outcomes for patients who require intubation after a prolonged niv trial [ , ] . within the first - h of niv, failure to improve respiratory rate and oxygenation [ , , ] or failure to decrease carbon dioxide partial pressure (pco ) in patients with initial hypercarbia [ ] predicts niv failure and warrants prompt intubation. niv provides no benefit for patients with ards [ ] , which may be nearly indistinguishable from cap among patients with bilateral alveolar infiltrates. patients with cap who have severe hypoxemia (pao /fio ratio, ! ) are also poor candidates for niv [ ] . . low-tidal-volume ventilation ( cm /kg of ideal body weight) should be used for patients undergoing ventilation who have diffuse bilateral pneumonia or ards. (strong recommendation; level i evidence.) distinguishing between diffuse bilateral pneumonia and ards is difficult, but it may not be an important distinction. results of the ardsnet trial suggest that the use of low-tidalvolume ventilation provides a survival advantage [ ] . pneumonia, principally cap, was the most common cause of ards in that trial, and the benefit of the low-tidal-volume ventilatory strategy appeared to be equivalent in the population with pneumonia compared with the entire cohort. the absolute risk reduction for mortality in the pneumonia cohort was %, indicating that, in order to avoid death, patients must be treated [ ] . other aspects of the management of severe sepsis and septic shock in patients with cap do not appear to be significantly different from those for patients with other sources of infection. recommendations for these aspects of care are reviewed elsewhere [ ] . because of the limitations of diagnostic testing, the majority of cap is still treated empirically. critical to empirical therapy is an understanding of the management of patients who do not follow the normal response pattern. although difficult to define, nonresponse is not uncommon. overall, %- % of hospitalized patients with cap do not respond to the initial antibiotic treatment [ , , , ] . the incidence of treatment failure among patients with cap who are not hospitalized is not well known, because population-based studies are required. almirall et al. [ ] described an overall hospitalization rate of % in a population-based study, but the rate of failure among the % of patients who initially presented to their primary care physician was not provided. the frequency of prior antibiotic therapy among medicare patients admitted to the hospital with cap is %- % [ , ] , but the percentage who received prior antibiotic therapy for the acute episode of pneumonia itself versus other indications is unclear. for patients initially admitted to the icu, the risk of failure to respond is already high; as many as % will experience deterioration even after initial stabilization in the icu [ ] . mortality among nonresponding patients is increased several-fold in comparison with that among responding patients [ ] . overall mortality rates as high as % have been reported for an entire population of nonresponding hospitalized patients with cap [ , , ] , and the mortality rate reported in one study of early failure was % [ ] . apache ii score was not the only factor independently associated with mortality in the nonresponding group, suggesting that the excess mortality may be due to factors other than severity of illness at presentation [ ] . . the use of a systematic classification of possible causes of failure to respond, based on time of onset and type of failure (table ) , is recommended. (moderate recommendation; level ii evidence.) the term "nonresponding pneumonia" is used to define a situation in which an inadequate clinical response is present despite antibiotic treatment. lack of a clear-cut and validated definition in the literature makes nonresponse difficult to study. lack of response also varies according to the site of treatment. lack of response in outpatients is very different from that in patients admitted to the icu. the time of evaluation is also important. persistent fever after the first day of treatment differs significantly from fever persisting (or recurring) at day of treatment. table provides a construct for evaluating nonresponse to antibiotic treatment of cap, based on several studies addressing this issue [ , , , ] . two patterns of unacceptable response are seen in hospitalized patients [ ] . the first is progressive pneumonia or actual clinical deterioration, with acute respiratory failure requiring ventilatory support and/or septic shock, usually occurring within the first h of hospital admission. as is noted above, as many as % of patients with cap who ultimately require icu admission are initially admitted to a non-icu setting and are transferred because of deterioration [ ] . deterioration and development of respira-tory failure or hypotension h after initial treatment is often related to intercurrent complications, deterioration in underlying disease, or development of nosocomial superinfection. the second pattern is that of persistent or nonresponding pneumonia. nonresponse can be defined as absence of or delay in achieving clinical stability, using the criteria in table [ , ] . when these criteria were used, the median time to achieve clinical stability was days for all patients, but a quarter of patients took у days to meet all of these criteria for stability [ ] . stricter definitions for each of the criteria and higher psi scores were associated with longer times to achieve clinical stability. conversely, subsequent transfer to the icu after achieving this degree of clinical stability occurred in ! % of [ ] . given these results, concern regarding nonresponse should be tempered before h of therapy. antibiotic changes during this period should be considered only for patients with deterioration or in whom new culture data or epidemiologic clues suggest alternative etiologies. finally, nonresolving or slow-resolving pneumonia has been used to refer to the conditions of patients who present with persistence of pulmonary infiltrates days after initial pneumonia-like syndrome [ ] . as many as % of these patients will be found to have diseases other than cap when carefully evaluated [ ] . two studies have evaluated the risk factors for a lack of response in multivariate analyses [ , ] , including those amenable to medical intervention. use of fluoroquinolones was independently associated with a better response in one study [ ] , whereas discordant antimicrobial therapy was associated with early failure [ ] . in table , the different risk and protective factors and their respective odds ratios are summarized. specific causes that may be responsible for a lack of response in cap have been classified by arancibia et al. [ ] (table ) . this classification may be useful for clinicians as a systematic approach to diagnose the potential causes of nonresponse in cap. although in the original study only ( %) of cases could not be classified [ ] , a subsequent prospective multicenter trial found that the cause of failure could not be determined in % [ ] . management of nonresponding cap. nonresponse to antibiotics in cap will generally result in у of clinical responses: ( ) transfer of the patient to a higher level of care, ( ) further diagnostic testing, and ( ) escalation or change in treatment. issues regarding hospital admission and icu transfer are discussed above. an inadequate host response, rather than inappropriate antibiotic therapy or unexpected microorganisms, is the most common cause of apparent antibiotic failure when guidelinerecommended therapy is used. decisions regarding further diagnostic testing and antibiotic change/escalation are intimately intertwined and need to be discussed in tandem. information regarding the utility of extensive microbiological testing in cases of nonresponding cap is mainly retrospective and therefore affected by selection bias. a systematic diagnostic approach, which included invasive, noninvasive, and imaging procedures, in a series of nonresponding patients with cap obtained a specific diagnosis in % [ ] . in a different study, mortality among patients with microbiologically guided versus empirical antibiotic changes was not improved (mortality rate, % vs. %, respectively) [ ] . however, no antibiotic changes were based solely on sputum smears, suggesting that invasive cultures or nonculture methods may be needed. mismatch between the susceptibility of a common causative organism, infection with a pathogen not covered by the usual empirical regimen, and nosocomial superinfection pneumonia are major causes of apparent antibiotic failure. therefore, the first response to nonresponse or deterioration is to reevaluate the initial microbiological results. culture or sensitivity data not available at admission may now make the cause of clinical failure obvious. in addition, a further history of any risk factors for infection with unusual microorganisms (table ) should be taken if not done previously. viruses are relatively neglected as a cause of infection in adults but may account for %- % of cases [ ] . other family members or coworkers may have developed viral symptoms in the interval since the patient was admitted, increasing suspicion of this cause. the evaluation of nonresponse is severely hampered if a microbiological diagnosis was not made on initial presentation. if cultures were not obtained, clinical decisions are much more difficult than if the adequate cultures were obtained but negative. risk factors for nonresponse or deterioration (table ) , therefore, figure prominently in the list of situations in which more aggressive initial diagnostic testing is warranted (table ) . blood cultures should be repeated for deterioration or progressive pneumonia. deteriorating patients have many of the risk factors for bacteremia, and blood cultures are still high yield even in the face of prior antibiotic therapy [ ] . positive blood culture results in the face of what should be adequate antibiotic therapy should increase the suspicion of either antibiotic-resistant isolates or metastatic sites, such as endocarditis or arthritis. despite the high frequency of infectious pulmonary causes of nonresponse, the diagnostic utility of respiratory tract cultures is less clear. caution in the interpretation of sputum or tracheal aspirate cultures, especially of gram-negative bacilli, is warranted because early colonization, rather than superinfection with resistant bacteria, is not uncommon in specimens obtained after initiation of antibiotic treatment. once again, the absence of multidrug-resistant pathogens, such as mrsa or pseudomonas, is strong evidence that they are not the cause of nonresponse. an etiology was determined by bronchoscopy in % of patients with cap, mainly in those not responding to therapy [ ] . despite the potential benefit suggested by these results, and in contrast to ventilator-associated pneumonia [ , ] , no randomized study has compared the utility of invasive versus noninvasive strategies in the cap population with nonresponse. rapid urinary antigen tests for s. pneumoniae and l. pneumophila remain positive for days after initiation of antibiotic therapy [ , ] and, therefore, may be high-yield tests in this group. a urinary antigen test result that is positive for l. pneumophila has several clinical implications, including that coverage for legionella should be added if not started empirically [ ] . this finding may be a partial explanation for the finding that fluoroquinolones are associated with a lower incidence of nonresponse [ ] . if a patient has persistent fever, the faster response to fluoroquinolones in legionella cap warrants consideration of switching coverage from a macrolide [ ] . stopping the b-lactam component of combination therapy to exclude drug fever is probably also safe [ ] . because one of the major explanations for nonresponse is poor host immunity rather than incorrect antibiotics, a positive pneumococcal antigen test result would at least clarify the probable original pathogen and turn attention to other causes of failure. in addition, a positive pneumococcal antigen test result would also help with interpretation of subsequent sputum/tracheal aspirate cultures, which may indicate early superinfection. nonresponse may also be mimicked by concomitant or subsequent extrapulmonary infection, such as intravascular catheter, urinary, abdominal, and skin infections, particularly in icu patients. appropriate cultures of these sites should be considered for patients with nonresponse to cap therapy. in addition to microbiological diagnostic procedures, several other tests appear to be valuable for selected patients with nonresponse: • chest ct. in addition to ruling out pulmonary emboli, a ct scan can disclose other reasons for antibiotic failure, including pleural effusions, lung abscess, or central airway obstruction. the pattern of opacities may also suggest alternative noninfectious disease, such as bronchiolitis obliterans organizing pneumonia. • thoracentesis. empyema and parapneumonic effusions are important causes of nonresponse [ , ] , and thoracentesis should be performed whenever significant pleural fluid is present. • bronchoscopy with bal and transbronchial biopsies. if the differential of nonresponse includes noninfectious pneumonia mimics, bronchoscopy will provide more diagnostic information than routine microbiological cultures. bal may reveal noninfectious entities, such as pulmonary hemorrhage or acute eosinophilic pneumonia, or hints of infectious diseases, such as lymphocytic rather than neutrophilic alveolitis pointing toward virus or chlamydophila infection. transbronchial biopsies can also yield a specific diagnosis. antibiotic management of nonresponse in cap has not been studied. the overwhelming majority of cases of apparent nonresponse are due to the severity of illness at presentation or a delay in treatment response related to host factors. other than the use of combination therapy for severe bacteremic pneumococcal pneumonia [ , , , ] , there is no documentation that additional antibiotics for early deterioration lead to a better outcome. the presence of risk factors for potentially untreated microorganisms may warrant temporary empirical broadening of the antibiotic regimen until results of diagnostic tests are available. vaccines targeting pneumococcal disease and influenza remain the mainstay for preventing cap. pneumococcal polysaccharide vaccine and inactivated influenza vaccine are recommended for all older adults and for younger persons with medical conditions that place them at high risk for pneumonia morbidity and mortality (table ) [ , ] . the new live attenuated influenza vaccine is recommended for healthy persons - years of age, including health care workers [ ] . postlicensure epidemiologic studies have documented the effectiveness of pneumococcal polysaccharide vaccines for prevention of invasive infection (bacteremia and meningitis) among elderly individuals and younger adults with certain chronic medical conditions [ ] [ ] [ ] [ ] . the overall effectiveness against invasive pneumococcal disease among persons у years of age is %- % [ , , ] , although efficacy may decrease with advancing age [ ] . the effectiveness of the vaccine against pneumococcal disease in immunocompromised persons is less clear, and results of studies evaluating its effectiveness against pneumonia without bacteremia have been mixed. the vaccine has been shown to be cost effective for general populations of adults - years of age and у years of age [ , ] . a second dose of pneumococcal polysaccharide vaccine after a у -year interval has been shown to be safe, with only slightly more local reactions than are seen after the first dose [ ] . because the safety of a third dose has not been demonstrated, current guidelines do not suggest repeated revaccination. the pneumococcal conjugate vaccine is under investigation for use in adults but is currently only licensed for use in young children [ , ] . however, its use in children ! years of age has dramatically reduced invasive pneumococcal bacteremia among adults as well [ , ] . the effectiveness of influenza vaccines depends on host factors and on how closely the antigens in the vaccine are matched with the circulating strain of influenza. a systematic review demonstrates that influenza vaccine effectively prevents pneumonia, hospitalization, and death [ , ] . a recent large observational study of adults у years of age found that vaccination against influenza was associated with a reduction in the risk of hospitalization for cardiac disease ( % reduction), cerebrovascular disease ( %- % reduction), and pneumonia or influenza ( %- % reduction) and a reduction in the risk of death from all causes ( %- % reduction) [ ] . in longterm-care facilities, vaccination of health care workers with influenza vaccine is an important preventive health measure [ , , ] . because the main virulence factors of influenza virus, a neuraminidase and hemagglutinin, adapt quickly to selective pressures, new vaccine formulations are created each year on the basis of the strains expected to be circulating, and annual revaccination is needed for optimal protection. many people who should receive either influenza or pneumococcal polysaccharide vaccine have not received them. according to a survey, only % of adults у years of age had received influenza vaccine in the past year, and only % had ever received pneumococcal polysaccharide vaccine [ ] . coverage levels are lower for younger persons with vaccine indications. among adults - years of age with diabetes, % had received influenza vaccine, and % had ever received pneumococcal vaccine [ ] . studies of vaccine delivery methods indicate that the use of standing orders is the best way to improve vaccination coverage in office, hospital, or long-term care settings [ ] . hospitalization of at-risk patients represents an underutilized opportunity to assess vaccination status and to either provide or recommend immunization. ideally, patients should be vaccinated before developing pneumonia; therefore, admissions for illnesses other than respiratory tract infections would be an appropriate focus. however, admission for pneumonia is an important trigger for assessing the need for immunization. the actual immunization may be better provided at the time of outpatient follow-up, especially with the emphasis on early discharge of patients with cap. patients with an acute fever should not be vaccinated until their fever has resolved. confusion of a febrile reaction to immunization with recurrent/superinfection pneumonia is a risk. however, immunization at discharge for pneumonia is warranted for patients for whom outpatient follow-up is unreliable, and such vaccinations have been safely given to many patients. the best time for influenza vaccination in north america is october and november, although vaccination in december and later is recommended for those who were not vaccinated earlier. influenza and pneumococcal vaccines can be given at the same time in different arms. chemoprophylaxis can be used as an adjunct to vaccination for prevention and control of influenza. oseltamivir and zanamivir are both approved for prophylaxis; amantadine and rimantadine have fda indications for chemoprophylaxis against influenza a infection, but these agents are currently not recommended because of the frequency of resistance among strains circulating in the united states and canada [ , ] . developing an adequate immune response to the inactivated influenza vaccine takes ∼ weeks in adults; chemoprophylaxis may be useful during this period for those with household exposure to influenza, those who live or work in institutions with an influenza outbreak, or those who are at high risk for influenza complications in the setting of a community outbreak [ , ] . chemoprophylaxis also may be useful for persons with contraindications to influenza vaccine or as an adjunct to vaccination for those who may not respond well to influenza vaccine (e.g., persons with hiv infection) [ , ] . the use of influenza antiviral medications for treatment or chemoprophylaxis should not affect the response to the inactivated vaccine. because it is unknown whether administering influenza antiviral medications affects the performance of the new live attenuated intranasal vaccine, this vaccine should not be used in conjunction with antiviral agents. other types of vaccination can be considered. pertussis is a rare cause of pneumonia itself. however, pneumonia is one of the major complications of pertussis. concern over waning immunity has led the acip to emphasize adult immunization for pertussis [ ] . one-time vaccination with the new tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine-adsorbed (tdap) product, adacel (sanofi pasteur)is recommended for adults - years of age. for most adults, the vaccine should be given in place of their next routine tetanus-diphtheria booster; adults with close contact with infants ! months of age and health care workers should receive the vaccine as soon as possible, with an interval as short as years after their most recent tetanus/diphtheria booster. smoking is associated with a substantial risk of pneumococcal bacteremia; one report showed that smoking was the strongest of multiple risks for invasive pneumococcal disease in immunocompetent nonelderly adults [ ] . smoking has also been identified as a risk for legionella infection [ ] . smoking cessation should be attempted when smokers are hospitalized; this is particularly important and relevant when these patients are hospitalized for pneumonia. materials for clinicians and patients to assist with smoking cessation are available online from the us surgeon general (http://www.surgeongeneral.gov/tobacco), the centers for disease control and prevention (http://www.cdc.gov/ tobacco), and the american cancer society (http://www .cancer.org). the most successful approaches to quitting include some combination of nicotine replacement and/or bupropion, a method to change habits, and emotional support. given the increased risk of pneumonia, the committee felt that persons unwilling to stop smoking should be given the pneumococcal polysaccharide vaccine, although this is not currently an aciprecommended indication. . cases of pneumonia that are of public health concern should be reported immediately to the state or local health department. (strong recommendation; level iii evidence.) public health interventions are important for preventing some forms of pneumonia. notifying the state or local health department about a condition of interest is the first step to getting public health professionals involved. rules and regulations regarding which diseases are reportable differ between states. for pneumonia, most states require reporting for legionnaires disease, sars, and psittacosis, so that an investigation can determine whether others may be at risk and whether control measures are necessary. for legionnaires disease, reporting of cases has helped to identify common-source outbreaks caused by environmental contamination [ ] . for sars, close observation and, in some cases, quarantine of close contacts have been critical for controlling transmission [ ] . in addition, any time avian influenza (h n ) or a possible terrorism agent (e.g., plague, tularemia, or anthrax) is being considered as the etiology of pneumonia, the case should be reported immediately, even before a definitive diagnosis is obtained. in addition, pneumonia cases that are caused by pathogens not thought to be endemic to the area should be reported, even if those conditions are not typically on the list of reportable conditions, because control strategies might be possible. for other respiratory diseases, episodes that are suspected of being part of an outbreak or cluster should be reported. for pneumococcal disease and influenza, outbreaks can occur in crowded settings of susceptible hosts, such as homeless shelters, nursing homes, and jails. in these settings, prophylaxis, vaccination, and infection control methods are used to control further transmission [ ] . for mycoplasma, antibiotic prophylaxis has been used in schools and institutions to control outbreaks [ ] . . respiratory hygiene measures, including the use of hand hygiene and masks or tissues for patients with cough, should be used in outpatient settings and eds as a means to reduce the spread of respiratory infections. (strong recommendation; level iii evidence.) in part because of the emergence of sars, improved respiratory hygiene measures ("respiratory hygiene" or "cough etiquette") have been promoted as a means for reducing transmission of respiratory infections in outpatient clinics and eds [ ] . key components of respiratory hygiene include encouraging patients to alert providers when they present for a visit and have symptoms of a respiratory infection; the use of hand hygiene measures, such as alcohol-based hand gels; and the use of masks or tissues to cover the mouth for patients with respiratory illnesses. in a survey of the us population, the use of masks in outpatient settings was viewed as an acceptable means for reducing the spread of respiratory infections [ ] . for hospitalized patients, infection control recommendations typically are pathogen specific. for more details on the use of personal protective equipment and other measures to prevent transmission within health care settings, refer to the healthcare infection control practices advisory committee [ ] . performance indicators are tools to help guideline users measure both the extent and the effects of implementation of guidelines. such tools or measures can be indicators of the process itself, outcomes, or both. deviations from the recommendations are expected in a proportion of cases, and compliance in %- % of cases is generally appropriate, depending on the indicator. four specific performance indicators have been selected for the cap guidelines, of which focus on treatment issues and of which deals with prevention: • initial empirical treatment of cap should be consistent with guideline recommendations. data exist that support the role of cap guidelines and that have demonstrated reductions in cost, los, and mortality when the guidelines are followed. reasons for deviation from the guidelines should be clearly documented in the medical record. • the first treatment dose for patients who are to be admitted to the hospital should be given in the ed. unlike in prior guidelines, a specific time frame is not being recommended. initiation of treatment would be expected within - h of presentation whenever the admission diagnosis is likely cap. a rush to treatment without a diagnosis of cap can, however, result in the inappropriate use of antibiotics with a concomitant increase in costs, adverse drug events, increased antibiotic selection pressure, and, possibly, increased antibiotic resistance. consideration should be given to monitoring the number of patients who receive empirical antibiotics in the ed but are admitted to the hospital without an infectious diagnosis. • mortality data for all patients with cap admitted to wards, icus, or high-level monitoring units should be collected. although tools to predict mortality and severity of illness exist-such as the psi and curb- criteria, respectivelynone is foolproof. overall mortality rates for all patients with cap admitted to the hospital, including general medical wards, should be monitored and compared with severity-adjusted norms. in addition, careful attention should be paid to the percentage of patients with severe cap, as defined in this document, who are admitted initially to a non-icu or a high-level monitoring unit and to their mortality rate. • it is important to determine what percentage of at-risk patients in one's practice actually receive immunization for influenza or pneumococcal infection. prevention of infection is clearly more desirable than having to treat established infection, but it is clear that target groups are undervaccin-ated. trying to increase the number of protected individuals is a desirable end point and, therefore, a goal worth pursuing. this is particularly true for influenza, because the vaccine data are more compelling, but it is important to try to protect against pneumococcal infection as well. coverage of % of adults у years of age should be the target. the burden of community-acquired pneumonia in seniors: results of a population-based study mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, - guidelines for community-acquired pneumonia: are they reflected in practice? guidelines for the initial management of adults with community-acquired pneumonia: diagnosis, assessment of severity, and initial antimicrobial therapy medical section of the american lung association guidelines for the management of adults with community-acquired pneumonia: diagnosis, assessment of severity, antimicrobial therapy, and prevention community-acquired pneumonia in adults: guidelines for management. the infectious diseases society of america practice guidelines for the management of community-acquired pneumonia in adults. infectious diseases society of america update of practice guidelines for the management of communityacquired pneumonia in immunocompetent adults guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia frequency of subspecialty physician care for elderly patients with community-acquired pneumonia guide to development of practice guidelines attributes of ats documents that guide clinical practice. recommendations of the ats clinical practice committee systems for grading the quality of evidence and the strength of recommendations i: critical appraisal of existing approaches the grade working group clinical practice guidelines for the management of pneumonia-do they work why don't physicians follow clinical practice guidelines? a framework for improvement do guidelines for community-acquired pneumonia improve the cost-effectiveness of hospital care? influence of deviation from guidelines on the outcome of community-acquired pneumonia decreased mortality after implementation of a treatment guideline for community-acquired pneumonia a controlled trial of a critical pathway for treatment of community-acquired pneumonia. capital study investigators. community-acquired pneumonia intervention trial assessing levofloxacin improvement of process-of-care and outcomes after implementing a guideline for the management of community-acquired pneumonia: a controlled before-and-after design study effects of a pneumonia clinical pathway on time to antibiotic treatment, length of stay, and mortality effects of a practice guideline for community-acquired pneumonia in an outpatient setting effects of guidelineconcordant antimicrobial therapy on mortality among patients with community-acquired pneumonia safely increasing the proportion of patients with community-acquired pneumonia treated as outpatients: an interventional trial preferences for home vs hospital care among low-risk patients with community-acquired pneumonia a statewide initiative to improve the care of hospitalized pneumonia patients: the connecticut pneumonia pathway project implementation of an evidencebased guideline to reduce duration of intravenous antibiotic therapy and length of stay for patients hospitalized with community-acquired pneumonia: a randomized controlled trial improving the quality of care for patients with pneumonia in very small hospitals early mobilization of patients hospitalized with community-acquired pneumonia a comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. prophylaxis in medical patients with enoxaparin study group weingarten sr. a prospective, multicenter study of a pneumonia practice guideline limited impact of a multicenter intervention to improve the quality and efficiency of pneumonia care the cost of treating community-acquired pneumonia outpatient care compared with hospitalization for community-acquired pneumonia: a randomized trial in low-risk patients risk factors for venous thromboembolism in hospitalized patients with acute medical illness: analysis of the medenox study variation in hospital admissions among small areas: a comparison of maine and michigan the hospital admission decision for patients with community-acquired pneumonia: results from the pneumonia patient outcomes research team cohort study community-acquired pneumonia in adults in british hospitals in - : a survey of aetiology, mortality, prognostic factors, and outcome predicting the need for hospitalization of ambulatory patients with pneumonia predicting hospital-associated mortality for medicare patients: a method for patients with stroke, pneumonia, acute myocardial infarction, and congestive heart failure a prediction rule to identify low-risk patients with community-acquired pneumonia hospitalization decision in patients with community-acquired pneumonia: a prospective cohort study validation of a pneumonia prognostic index using the medisgroups comparative hospital database defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study community-acquired pneumonia requiring hospitalization: -year prospective study outcome and prognostic factors in community-acquired pneumonia requiring hospitalization appropriateness of hospitalization of patients with community-acquired pneumonia assessing prognosis and selecting an initial site of care for adults with community-acquired pneumonia effect of increasing the intensity of implementing pneumonia guidelines: a randomized, controlled trial community acquired pneumonia: aetiology and usefulness of severity criteria on admission use of prognostic scoring and outcome assessment tools in the admission decision for community-acquired pneumonia assessment of illness severity in community acquired pneumonia: a useful new prediction tool? validation of a predictive rule for the management of community-acquired pneumonia a prediction rule to identify allocation of inpatient care in community-acquired pneumonia prospective comparison of three validated prediction rules for prognosis in community-acquired pneumonia implementation of admission decision support for community-acquired pneumonia how should we make the admission decision in community-acquired pneumonia? improving the implementation of community-acquired pneumonia guidelines hospitalization for community-acquired pneumonia: the pneumonia severity index vs clinical judgment cost and incidence of social comorbidities in low-risk patients with community-acquired pneumonia admitted to a public hospital criteria for severe community-acquired pneumonia severe community-acquired pneumonia: use of intensive care services and evaluation of american and british thoracic society diagnostic criteria understanding physician adherence with a pneumonia practice guideline: effects of patient, system, and physician factors factors influencing in-hospital mortality in community-acquired pneumonia: a prospective study of patients not initially admitted to the icu testing strategies in the initial management of patients with community-acquired pneumonia applying a prediction rule to identify low-risk patients with community-acquired pneumonia etiology, reasons for hospitalization, risk classes, and outcomes of community-acquired pneumonia in patients hospitalized on the basis of conventional admission criteria etiology of severe pneumonia in the very elderly community-acquired pneumonia: etiology, epidemiology, and outcome at a teaching hospital in argentina clinical aspects and prognostic factors in elderly patients hospitalised for communityacquired pneumonia process of care performance, patient characteristics, and outcomes in elderly patients hospitalized with community-acquired or nursing home-acquired pneumonia study of community acquired pneumonia aetiology (scapa) in adults admitted to hospital: implications for management guidelines a five-year study of severe community-acquired pneumonia with emphasis on prognosis in patients admitted to an intensive care unit validation of predictive rules and indices of severity for community acquired pneumonia initial microbiologic studies did not affect outcome in adults hospitalized with community-acquired pneumonia the clinical features of severe community-acquired pneumonia presenting as septic shock. norasept ii study investigators severe community-acquired pneumonia severe community-acquired pneumonia: assessment of microbial aetiology as mortality factor inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients causes and factors associated with early failure in hospitalized patients with community-acquired pneumonia severe community-acquired pneumonia: assessment of severity criteria causes of death for patients with community-acquired pneumonia: results from the pneumonia patient outcomes research team cohort study risk factors of treatment failure in community acquired pneumonia: implications for disease outcome alcoholism, leukopenia, and pneumococcal sepsis adult bacteremic pneumococcal pneumonia in a community teaching hospital, - : a detailed analysis of cases severe community-acquired pneumonia in icus: prospective validation of a prognostic score ) • mandell et al. moniae bacteremia at an urban general hospital severe community-acquired pneumonia due to acinetobacter baumannii plasma d-dimer levels correlate with outcomes in patients with community-acquired pneumonia pneumococcal bacteraemia during a recent decade severe community-acquired pneumonia as a cause of severe sepsis: data from the prowess study hypothermia and cytokines in septic shock. norasept ii study investigators: north american study of the safety and efficacy of murine monoclonal antibody to tumor necrosis factor for the treatment of septic shock high alcohol intake as a risk and prognostic factor for communityacquired pneumonia predicting bacteremia in patients with community-acquired pneumonia diagnosing pneumonia by physical examination: relevant or relic? effect of routine emergency department triage pulse oximetry screening on medical management arterial blood gas and pulse oximetry in initial management of patients with community-acquired pneumonia high-resolution computed tomography for the diagnosis of community-acquired pneumonia coccidioidomycosis as a common cause of community-acquired pneumonia antimicrobial treatment failures in patients with community-acquired pneumonia recurrent invasive pneumococcal disease: a population-based assessment sepsis and cap: partnerships for diagnostics development ackroyd-stolarz s. the contribution of blood cultures to the clinical management of adult patients admitted to the hospital with community-acquired pneumonia: a prospective observational study the influence of the severity of community-acquired pneumonia on the usefulness of blood cultures antibiotic therapy for ambulatory patients with community-acquired pneumonia in an emergency department setting respiratory syncytial virus infection in elderly and high-risk adults comparison between pathogen directed antibiotic treatment and empirical broad spectrum antibiotic treatment in patients with community acquired pneumonia: a prospective randomised study timing of antibiotic administration and outcomes for medicare patients hospitalized with community-acquired pneumonia prognosis and outcomes of patients with community-acquired pneumonia: a meta-analysis is the lateral decubitus radiograph necessary for the management of a parapneumonic pleural effusion? an international prospective study of pneumococcal bacteremia: correlation with in vitro resistance, antibiotics administered, and clinical outcome etiology of community-acquired pneumonia: impact of age, comorbidity, and severity acute respiratory failure in patients with severe communityacquired pneumonia: a prospective randomized evaluation of noninvasive ventilation the nonvalue of sputum culture in the diagnosis of pneumococcal pneumonia nonvalue of sputum culture in the management of lower respiratory tract infections diagnostic value of microscopic examination of gram-stained sputum and sputum cultures in patients with bacteremic pneumococcal pneumonia sputum gram stain assessment in community-acquired bacteremic pneumonia sputum gram's stain in community-acquired pneumococcal pneumonia: a meta-analysis assessment of the usefulness of sputum culture for diagnosis of community-acquired pneumonia using the port predictive scoring system diagnostic accuracy of transtracheal aspiration bacteriologic studies bacteriology of expectorated sputum with quantitative culture and wash technique compared to transtracheal aspirates diagnostic fiberoptic bronchoscopy in patients with community-acquired pneumonia: comparison between bronchoalveolar lavage and telescoping plugged catheter cultures influence of three factors on the diagnostic effectiveness of transthoracic needle aspiration in pneumonia the value and complications of percutaneous transthoracic lung aspiration for the etiologic diagnosis of communityacquired pneumonia efficacy of transthoracic needle aspiration in community-acquired pneumonia diagnosis of bacterial infections of the lung misinformation from sputum cultures without microscopic examination a fiberoptic bronchoscopy technique to obtain uncontaminated lower airway secretions for bacterial culture legionella and legionnaires' disease: years of investigation community-acquired pneumonia due to gram-negative bacteria and pseudomonas aeruginosa: incidence, risk, and prognosis legionnaires' disease: description of an epidemic of pneumonia recurrence of legionnaires disease at a hotel in the united states virgin islands over a -year period outbreak of legionnaires' disease among cruise ship passengers exposed to a contaminated whirlpool spa a large outbreak of legionnaires' disease at a flower show, the netherlands legionnaires' disease outbreak in murcia outbreak of legionnaires' disease associated with a display whirlpool spa detection of legionella pneumophila antigen in urine samples by the binaxnow immunochromatographic assay and comparison with both binax legionella urinary enzyme immunoassay (eia) and biotest legionella urin antigen eia sensitivity of three urinary antigen tests associated with clinical severity in a large outbreak of legionnaires' disease in the netherlands contribution of a urinary antigen assay (binax now) to the early diagnosis of pneumococcal pneumonia a -year prospective study of a urinary antigen-detection test for streptococcus pneumoniae in community-acquired pneumonia: utility and clinical impact on the reported etiology comparison of two urinary antigen tests for establishment of pneumococcal etiology of adult community-acquired pneumonia rapid urinary antigen test for diagnosis of pneumococcal community-acquired pneumonia in adults an emergency departmentbased randomized trial of nonbronchoscopic bronchoalveolar lavage for early pathogen identification in severe community-acquired pneumonia value of intensive diagnostic microbiological investigation in low-and high-risk patients with community-acquired pneumonia detection of streptococcus pneumoniae antigen by a rapid immunochromatographic assay in urine samples rapid diagnosis of bacteremic pneumococcal infections in adults by using the binax now streptococcus pneumoniae urinary antigen test: a prospective, controlled clinical evaluation evaluation of the binax and biotest urinary antigen kits for detection of legionnaires' disease due to multiple serogroups and species of legionella evaluation of the immunochromatographic binax now assay for detection of streptococcus pneumoniae urinary antigen in a prospective study of community-acquired pneumonia in spain evaluation of a rapid immunochromatographic test for detection of streptococcus pneumoniae antigen in urine samples from adults with community-acquired pneumonia performance of the binax now streptococcus pneumoniae urinary antigen assay for diagnosis of pneumonia in children with underlying pulmonary diseases in the absence of acute pneumococcal infection the now s. pneumoniae urinary antigen test positivity rate weeks after pneumonia onset and among patients with copd diagnosis of legionella infection legionella and communityacquired pneumonia: a review of current diagnostic tests from a clinician's viewpoint microbial etiology of acute pneumonia in hospitalized patients azithromycin in the treatment of legionella pneumonia requiring hospitalization performance of virus isolation and directigen flu a to detect influenza a virus in experimental human infection evaluation of a rapid test (quickvue) compared with the shell vial assay for detection of influenza virus clearance after antiviral treatment comparison of binax now and directigen for rapid detection of influenza a and b clinical signs and symptoms predicting influenza infection comparison of conventional viral cultures with direct fluorescent antibody stains for diagnosis of community-acquired respiratory virus infections in hospitalized children evaluation of the directigen flua+b test for rapid diagnosis of influenza virus type a and b infections lack of sensitivity of rapid antigen tests for the diagnosis of respiratory syncytial virus infection in adults interlaboratory reliability of microimmunofluorescence test for measurement of chlamydia pneumoniae-specific immunoglobulin a and g antibody titers diagnostic test for etiologic agents of community-acquired pneumonia standardizing chlamydia pneumoniae assays: recommendations from the centers for disease control and prevention (usa) and the laboratory centre for disease control (canada) improved diagnosis of the etiology of community-acquired pneumonia with real-time polymerase chain reaction community-acquired pneumonia: impact of immune status clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study surveillance case definition for severe acute respiratory syndrome (sars) and update on sars cases-united states and worldwide community-acquired pneumonia new and emerging etiologies for community-acquired pneumonia with implications for therapy: a prospective multi-center study of cases prediction of microbial aetiology at admission to hospital for pneumonia from the presenting clinical features. british thoracic society pneumonia research subcommittee ambulatory patients with community-acquired pneumonia: the frequency of atypical agents and clinical course multiple pathogens in adult patients admitted with community-acquired pneumonia: a one year prospective study of consecutive patients viral community-acquired pneumonia in nonimmunocompromised adults nonsevere communityacquired pneumonia: correlation between cause and severity or comorbidity protective effect of intravenously administered cefuroxime against nosocomial pneumonia in patients with structural coma decreasing b-lactam resistance in pneumococci from the memphis region: analysis of , isolates from decreased susceptibility of streptococcus pneumoniae to fluoroquinolones in canada. canadian bacterial surveillance network macrolide resistance among invasive streptococcus pneumoniae isolates geographical and ecological analysis of resistance, coresistance, and coupled resistance to antimicrobials in respiratory pathogenic bacteria in spain antibacterial drug resistance: implications for the treatment of patients with community-acquired pneumonia streptococcus pneumoniae in community-acquired pneumonia: how important is drug resistance? management of community-acquired pneumonia in the era of pneumococcal resistance: a report from the drug-resistant streptococcus pneumoniae therapeutic working group the effect of cephalosporin resistance on mortality in adult patients with nonmeningeal systemic pneumococcal infections emergence of macrolide resistance during treatment of pneumococcal pneumonia breakthrough pneumococcal bacteremia in patients being treated with azithromycin and clarithromycin failure of macrolide antibiotic treatment in patients with bacteremia due to erythromycin-resistant streptococcus pneumoniae resistance to levofloxacin and failure of treatment of pneumococcal pneumonia increasing resistance of streptococcus pneumoniae to fluoroquinolones: results of a hong kong multicentre study in drug-resistant streptococcus pneumoniae multivariate analysis of risk factors for infection due to penicillin-resistant and multidrug-resistant streptococcus pneumoniae: a multicenter study predicting antimicrobial resistance in invasive pneumococcal infections risk factors for acquisition of levofloxacin-resistant streptococcus pneumoniae: a case-control study streptococcus pneumoniae bacteremia: duration of previous antibiotic use and association with penicillin resistance emergence of levofloxacin-resistant pneumococci in immunocompromised adults after therapy for community-acquired pneumonia fluoroquinolone-resistant streptococcus pneumoniae associated with levofloxacin therapy community-acquired methicillinresistant staphylococcus aureus in hospitalized adults and children without known risk factors community-acquired methicillinresistant staphylococcus aureus infections in france: emergence of a single clone that produces panton-valentine leukocidin severe staphylococcus aureus infections caused by clonally related communityacquired methicillin-susceptible and methicillin-resistant isolates methicillin-resistant staphylococcus aureus: an evolutionary, epidemiologic, and therapeutic odyssey methicillin-resistant staphylococcus aureus disease in three communities pleuropulmonary complications of panton-valentine leukocidin-positive community-acquired methicillin-resistant staphylococcus aureus: importance of treatment with antimicrobials inhibiting exotoxin production community-acquired pneumonia: a prospective outpatient study empirical atypical coverage for inpatients with community-acquired pneumonia: systematic review of randomized controlled trials effectiveness of b-lactam antibiotics compared with antibiotics active against atypical pathogens in nonsevere community acquired pneumonia: meta-analysis current status of antibiotic treatment for mycoplasma pneumoniae infections fluoroquinolone utilization in the emergency departments of academic medical centers: prevalence of, and risk factors for, inappropriate use a review of evidence supporting the american academy of pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients clinical and bacteriological efficacy and safety of and day regimens of telithromycin once daily compared with a day regimen of clarithromycin twice daily in patients with mild to moderate community-acquired pneumonia efficacy and tolerability of oncedaily oral telithromycin compared with clarithromycin for the treatment of community-acquired pneumonia in adults efficacy and tolerability of once-daily oral therapy with telithromycin compared with trovafloxacin for the treatment of community-acquired pneumonia in adults telithromycin in the treatment of community-acquired pneumonia: a pooled analysis brief communication: severe hepatotoxicity of telithromycin: three case reports and literature review associations between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia empiric antibiotic therapy and mortality among medicare pneumonia inpatients in western states antimicrobial selection for hospitalized patients with presumed community-acquired pneumonia: a survey of nonteaching us community hospitals impact of initial antibiotic choice on clinical outcomes in community-acquired pneumonia: analysis of a hospital claims-made database a fresh look at the definition of susceptibility of streptococcus pneumoniae to beta-lactam antibiotics a prospective, randomized, double-blind multicenter comparison of parenteral ertapenem and ceftriaxone for the treatment of hospitalized adults with community-acquired pneumonia ertapenem versus ceftriaxone for the treatment of community-acquired pneumonia in adults: combined analysis of two multicentre randomized, double-blind studies doxycycline is a cost-effective therapy for hospitalized patients with communityacquired pneumonia atypical pneumonia in the nordic countries: aetiology and clinical results of a trial comparing fleroxacin and doxycycline. nordic atypical pneumonia study group azithromycin vs cefuroxime plus erythromycin for empirical treatment of community-acquired pneumonia in hospitalized patients: a prospective, randomized, multicenter trial clinical efficacy of intravenous followed by oral azithromycin monotherapy in hospitalized patients with community-acquired pneumonia. the azithromycin intravenous azithromycin monotherapy for patients hospitalized with community-acquired pneumonia: a / -year experience from a veterans affairs hospital efficacy of exclusively oral antibiotic therapy in patients hospitalized with nonsevere community-acquired pneumonia: a retrospective study and meta-analysis comparison of levofloxacin and cefotaxime combined with ofloxacin for icu patients with community-acquired pneumonia who do not require vasopressors severe community-acquired pneumonia: epidemiology and prognostic factors bacteremic pneumococcal pneumonia in one american city: a -year longitudinal study, - combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia addition of a macrolide to a b-lactam-based empirical antibiotic regimen is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia clinical characteristics at initial presentation and impact of dual therapy on the outcome of bacteremic streptococcus pneumoniae pneumonia in adults multicenter study of hospital-acquired pneumonia in non-icu patients selection of high-level oxacillin resistance in heteroresistant staphylococcus aureus by fluoroquinolone exposure bacteremic pneumonia due to staphylococcus aureus: a comparison of disease caused by methicillin-resistant and methicillin-susceptible organisms trimethoprim-sulfamethoxazole compared with vancomycin for the treatment of staphylococcus aureus infection linezolid versus ceftriaxone/cefpodoxime in patients hospitalized for the treatment of streptococcus pneumoniae pneumonia linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant staphylococcus aureus nosocomial pneumonia subinhibitory concentrations of linezolid reduce staphylococcus aureus virulence factor expression american thoracic society/centers for disease control and prevention/infectious diseases society of america: controlling tuberculosis in the united states anti-inflammatory effects of macrolides-an underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions? clinical implications of the immunomodulatory effects of macrolides ) • mandell et al. oseltamivir in treatment of acute influenza: a randomised controlled trial efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza a and b virus infections impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations antivirals for influenza in healthy adults: systematic review hospitalizing influenza in adults influenza virus neuraminidase inhibitors high levels of adamantane resistance among influenza a (h n ) viruses and interim guidelines for use of antiviral agents-united states, - influenza season adamantane resistance among influenza a viruses isolated early during the - influenza season in the united states impact of zanamivir on antibiotic use for respiratory events following acute influenza in adolescents and adults efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. us oral neuraminidase study group use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment early treatment with acyclovir for varicella pneumonia in otherwise healthy adults: retrospective controlled study and review avian influenza-a challenge to global health care structures human disease from influenza a (h n ) world health organization. production of pilot lots of inactivated influenza vaccines from reassortants derived from avian influenza viruses: interim biosafety assessment avian influenza a (h n ) infection in humans avian flu: isolation of drug-resistant h n virus oseltamivir resistance during treatment of influenza a (h n ) infection quality of care, process, and outcomes in elderly patients with pneumonia early administration of antibiotics does not shorten time to clinical stability in patients with moderate-tosevere community-acquired pneumonia rapid antibiotic delivery and appropriate antibiotic selection reduce length of hospital stay of patients with community-acquired pneumonia: link between quality of care and resource utilization community-acquired pneumonia: compliance with centers for medicare and medicaid services, national guidelines, and factors associated with outcome early switch from intravenous to oral cephalosporins in the treatment of hospitalized patients with community-acquired pneumonia efficacy and safety of oral and early-switch therapy for community-acquired pneumonia: a randomized controlled trial early switch from intravenous to oral antibiotics in hospitalized patients with bacteremic community-acquired streptococcus pneumoniae pneumonia early switch from intravenous to oral antibiotics and early hospital discharge: a prospective observational study of consecutive patients with community-acquired pneumonia what factors influence physicians' decisions to switch from intravenous to oral antibiotics for community-acquired pneumonia? instability on hospital discharge and the risk of adverse outcomes in patients with pneumonia time to clinical stability in patients hospitalized with community-acquired pneumonia: implications for practice guidelines comparative efficacies and tolerabilities of intravenous azithromycin plus ceftriaxone and intravenous levofloxacin with step-down oral therapy for hospitalized patients with moderate to severe community-acquired pneumonia high-dose, short-course levofloxacin for community-acquired pneumonia: a new treatment paradigm efficacy of a three day course of azithromycin in moderately severe community-acquired pneumonia comparison of three-day and five-day courses of azithromycin in the treatment of atypical pneumonia comparison of vs days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial efficacy and safety of recombinant human activated protein c for severe sepsis drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis systemic host responses in severe sepsis analyzed by causative microorganism and treatment effects of drotrecogin alfa (activated) effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock role of glucocorticoids on inflammatory response in nonimmunosuppressed patients with pneumonia: a pilot study hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study hydrocortisone and tumour necrosis factor in severe community acquired pneumonia intensive insulin therapy in the critically ill patients noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease noninvasive ventilation in severe hypoxemic respiratory failure: a randomized clinical trial predictors of failure of noninvasive positive pressure ventilation in patients with acute hypoxemic respiratory failure: a multi-center study ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. the acute respiratory distress syndrome network efficacy of low tidal volume ventilation in patients with different clinical risk factors for acute lung injury and the acute respiratory distress syndrome surviving sepsis campaign guidelines for management of severe sepsis and septic shock reaching stability in community-acquired pneumonia: the effects of the severity of disease, treatment, and the characteristics of patients epidemiology of communityacquired pneumonia in adults: a population-based study nosocomial pneumonia: a multivariate analysis of risk and prognosis time to resolution of morbidity: an endpoint for assessing the clinical cure of community-acquired pneumonia radiographic resolution of community-acquired pneumonia microbiology of severe aspiration pneumonia in institutionalized elderly diagnostic fiberoptic bronchoscopy and protected brush culture in patients with community-acquired pneumonia invasive and noninvasive strategies for management of suspected ventilator-associated pneumonia: a randomized trial noninvasive versus invasive microbial investigation in ventilator-associated pneumonia: evaluation of outcome fluoroquinolones vs macrolides in the treatment of legionnaires disease prevention and control of influenza: recommendations of the advisory committee on immunization practices (acip) prevention and control of influenza: recommendations of the advisory committee on immunization practices (acip) pneumococcal polysaccharide vaccine efficacy: an evaluation of current recommendations the clinical effectiveness of pneumococcal vaccine in the elderly the protective efficacy of polyvalent pneumococcal polysaccharide vaccine preventing pneumococcal bacteremia in patients at risk: results of a matched case-control study effectiveness of pneumococcal polysaccharide vaccine in older adults cost-effectiveness of vaccination against pneumococcal bacteremia among elderly people cost-effectiveness of vaccination against invasive pneumococcal disease among people through years of age: role of comorbid conditions and race safety of revaccination with pneumococcal polysaccharide vaccine decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine impact of childhood vaccination on racial disparities in invasive streptococcus pneumoniae infections changing epidemiology of invasive pneumococcal disease among older adults in the era of pediatric pneumococcal conjugate vaccine the efficacy of influenza vaccine in elderly persons: a meta-analysis and review of the literature efficacy and effectiveness of influenza vaccines in elderly people: a systematic review influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly effects of influenza vaccination of health-care workers on mortality of elderly people in longterm care: a randomised controlled trial influenza vaccination of health care workers in long-term-care hospitals reduces the mortality of elderly patients public health and aging: influenza vaccination coverage among adults aged у years and pneumococcal vaccination coverage among adults aged у years-united states influenza and pneumococcal vaccination coverage among persons aged у years and persons aged - years with diabetes or asthma-united states from the centers for disease control and prevention. facilitating influenza and pneumococcal vaccination through standing orders programs zanamivir prophylaxis: an effective strategy for the prevention of influenza types a and b within households management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis efficacy of an acellular pertussis vaccine among adolescents and adults cigarette smoking and invasive pneumococcal disease. active bacterial core surveillance team surveillance for legionnaires' disease: risk factors for morbidity and mortality sars in healthcare facilities an outbreak of multidrugresistant pneumococcal pneumonia and bacteremia among unvaccinated nursing home residents azithromycin prophylaxis during a hospital outbreak of mycoplasma pneumoniae pneumonia respiratory hygiene/cough etiquette in health-care settings experiences with influenza-like illness and attitudes regarding influenza prevention-united states, - influenza season guideline for isolation precautions in hospitals. the hospital infection control practices advisory committee the committee wishes to express its gratitude to robert balk, christian brun-buisson, ali el-sohl, alan fein, donald e. low, constantine manthous, thomas j. marrie, joseph f. plouffe, and david a. talan, for their thoughtful review of an earlier version of the guidelines. supplement sponsorship. this article was published as part of a supplement entitled "infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults," sponsored by the infectious diseases society of america. key: cord- -kb gsig authors: riou, marianne; marcot, christophe; canuet, matthieu; renaud-picard, benjamin; chatron, eva; porzio, michele; dégot, tristan; hirschi, sandrine; metz-favre, carine; kassegne, loïc; ederle, carole; khayath, naji; labani, aissam; leyendecker, pierre; blay, frédéric de; kessler, romain title: clinical characteristics of and outcomes for patients with covid- and comorbid lung diseases primarily hospitalized in a conventional pulmonology unit: a retrospective study date: - - journal: respir med res doi: . /j.resmer. . sha: doc_id: cord_uid: kb gsig background: scant data are currently available about a potential link between comorbid chronic lung diseases and the risk and severity of the coronavirus disease (covid- ) infection. methods: to describe the clinical characteristics of and outcomes for patients with covid- infection, including patients with comorbid respiratory diseases, who have been primarily hospitalized in the pulmonology department of strasbourg university hospital, france. in this retrospective, single-center study, we included all confirmed cases of covid- from march to april , . we then compared the symptoms, biological and radiological findings, and outcomes for patients with and without chronic lung disease. results: of the patients that were enrolled, the median age was years, and patients ( %) were male. overall, % of patients (n = ) had preexisting comorbid lung disease, including chronic obstructive pulmonary disease (copd) (n = , %) and asthma (n = , %). twenty-eight patients were transferred to the intensive care unit (icu), and six patients died in our unit. comorbid lung diseases were not predictive of icu hospitalization, but a significantly higher total mortality was observed ( . % vs. . %, p < . ) in these patients. conclusions: our results suggest the lack of an over-representation of cld in covid- , representing % of patients in this cohort and even within a pulmonology department. cld were not a risk factor for icu management. however, a tendency to higher global mortality was observed in covid- patients with cld. further studies are warranted to determine the risk of covid- for patients with comorbid chronic lung diseases. the coronavirus disease pandemic, caused by severe acute respiratory syndrome coronavirus (sars-cov- ) has spread worldwide rapidly, with several million individuals infected and more than , deaths [ ] . despite a relative poor characterization of the mechanisms of covid- , known complications including pneumonia and acute respiratory failure led pulmonologists to prepare for the worst for their patients with comorbid chronic lung diseases (cld) [ , ] . indeed, many respiratory viruses cause more serious illness in patients with chronic airway diseases, such copd or asthma [ ] [ ] [ ] . moreover, it has been demonstrated that sars-cov- gains entry into type ii pneumocytes through the membrane-bound angiotensin-converting enzyme (ace ) receptor. in view of these data, we can easily understand why rapidly progressive severe diffuse alveolar damage is frequently observed in covid- . strasbourg is in a part of france that has had an extremely high number of cases of covid- since the epidemic started in february .we report our experiences of patients with covid- , including patients with cld, who were primarily hospitalized in the pulmonology department at strasbourg university hospital, france. the aims of the present study were: - to assess the frequency of comorbid cld in these patients. -to compare clinical, biological, and radiological findings and outcomes of patients with and without cld. this study retrospectively included all consecutive covid- - detecting the presence of sars-cov- rna from a nasopharyngeal swab was performed for all patients on admission, in accordance with the protocol of our institution. a low-dose chest ct (aquilon prime sp, canon medical systems) without injection of iodine contrast was carried out for patients on admission. the global percentage of abnormal lung parenchyma was visually estimated by a radiologist and classified into four categories: absent/minimal (< %), moderate ( %- %), extensive ( %- %), and severe/critical (> %) [ ] . descriptive analyses of quantitative data comprised the mean or median and dispersion parameters. qualitative data were described according to population sizes and percentages. the charlson comorbidity index score was calculated for each patient. we compared covid- patients with and without cld. on a second time, patients that had died or been transferred into the icu were compared to the others. comparisons between groups were conducted using the chi-squared test for percentages and the wilcoxon rank-sum test for continuous variables. to determine the association between potential predictors of either transfer to the icu or death, we used multivariate logistic regression analysis. p < . was considered statistically significant. all patients had either positive real-time reverse transcriptase-polymerase chain reaction (rt-pcr) results for sars-cov- detection and/or typical covid- images on chest ct scan. typical chest ct lesions consisted of diffuse bilateral ground-glass opacities in subpleural regions and pulmonary alveolar infiltrates as described in the literature [ ] . global percentages of abnormal lung parenchyma were > % in patients, %- % in patients, %- % in patients, and < % of the total lung parenchyma in patients. the median age of the patients was years old (interquartile range [iqr]: - ), and % were male. the median interval between the onset of covid- symptoms and hospitalization was days (iqr - ). the most common symptoms were fever ( %), cough ( %), dyspnea ( %), fatigue ( %), myalgia ( %), and diarrhea ( %). two and patients reported have taken non-steroidal anti-inflammatory drugs and oral corticosteroids before hospitalization, respectively. the most common extra-respiratory comorbidities were hypertension ( %), diabetes mellitus ( %), sleep apnea syndrome ( %), and chronic heart failure ( %). obesity was present in patients ( %). fortyfive patients ( %) were either active (n= ) or former (n= ) smokers. these baseline characteristics are summarized in table . presented with well-controlled asthma, according to the global initiative for asthma's guidelines. eighty percent had atopic asthma. only one patient received biotherapy and oral corticosteroids. among the patients with copd, median forced expiratory volume in one second was % (iqr - ), according to the last spirometry that was performed before hospitalization. one and patients were treated with noninvasive ventilation (niv) and oxygen at home, respectively. one patient received long-term azithromycin three times a week. nine patients were previously followed-up for lung cancer, including six for adenocarcinoma. five patients had undergone lung lobectomy a few years before the infection. three patients received osimertinib, lorlatinib and alectinib, respectively, and patients were treated with chemotherapy. the lung transplanted patients were treated with immunosuppressants (tacrolimus, mycophenolate mofetil and corticosteroids). a total of patients ( %) required icu management and mechanical ventilation (table ) . six cases died in our unit, and patients underwent therapeutic limitation, including eight with cld (the decision not to transfer the patient to the icu was made in the event of clinical aggravation). up to date, a total of cases ( %) had been discharged alive. all patients received antibiotics for pneumonia: ( %) received cephalosporin, and ( %) received a combination of cephalosporin and macrolide. patients were also given antiviral treatment (lopinavir/ritonavir; n= ), hydroxychloroquine (n= , %), and tocilizumab (n= , %). patients who were treated with tocilizumab have participated to the clinical trial corimmuno-toci (nct ). ten patients were treated with curative anticoagulation before hospitalization: with vitamin k antagonists and with direct oral anticoagulants. curative anticoagulation with low-molecular-weight heparin treatment was started in patients; all required icu and had a proved pulmonary embolism by chest ct angiography. during hospitalization, patients received intravenous or oral corticosteroids. in terms of ventilatory support, patients ( %) underwent nasal oxygen on admission, including patients with cld. the median maximal oxygen requirement during hospitalization was l.min - . an arterial blood gas test was performed for each patient on admission, including patients under oxygen. the median partial pressure of oxygen (po ) and partial pressure of arterial carbon dioxide (pco ) were mmhg (iqr - ) and mmhg (iqr - ), respectively. patients with cld had higher pco than other patients (p < . ; table ), but only five patients had hypercapnia over mmhg at admission, including three patients with copd. during hospitalization, patients, including eight patients with cld, underwent niv to treat either acute respiratory failure with acidosis or continuous airway pressure (cpap). during this procedure, limitation of virus aerosolization was primordial, using niv systems with a minimum air leak and functional expiratory filters. one patient used high flow nasal oxygenotherapy (hfno) during hospitalization with a favorable issue. no patient with sleep apnea syndrome underwent their usual cpap treatment during hospitalization, so as to limit virus aerosolization. characteristics of patients transferred to the icu or died are summarized in table . median time between admission in hospital and transfer in icu was days (iqr - ). the icu criteria were severe hypoxemic respiratory failure defined by desaturation requiring supplemental oxygen at a high rate (a mean of ± l.min - ) or worsening tachypnea with a high respiration rate (mean ± /min). all patients were hypoxemic, despite oxygen administration (mean po ± mmhg) at the time of transfer to the icu, and no patient was hypercapnic (mean pco ± . mmhg). these patients had more severe pneumonia on the chest ct scans that were performed on admission (p = . ). ten patients developed ventilator-associated pneumonia. having an underlying cld was not a risk factor for admission into the icu in the multivariate logistic regression analysis. a tendency of higher mortality in the pulmonology unit for these patients was observed ( % vs. . %, p= . ). however, cld were not considered a risk factor for death in the multivariate logistic regression analysis. hypoxemia and the severity of the chest ct pulmonary damage on admission were independently associated with icu admission or death (nagelkerke r square = . , p < . ). moreover, the charlson comorbidity index score was not predictor of mortality or icu admission. in response to the covid- pandemic, pulmonologists have been rapidly confronted with a massive influx of patients that were infected by sars-cov- . our data confirm that severe covid- cases are due to pneumonia that is associated with hypoxemic respiratory failure [ ] . the most common symptoms in our cohort were fever, tachypnea, cough and crackles. this agrees with prior literature data [ ] [ ] [ ] [ ] . hypoxemia on admission was a predictor of either admission into the icu or of death. furthermore, monitoring oxygen saturation with pulse oximetry and respiration rate helped identify patients at risk of severe respiratory failure, which subsequently prompted earlier transfer to the icu. moreover, our study confirmed that the severity of chest ct pulmonary damage on admission was a predictive factor for admission into the icu, suggesting that these patients should be closely monitored during hospitalization [ ] . only one patient used hfno during hospitalization. in march , during the first outbreak of the pandemic, there was an important concern that hfno may increase bio-aerosol dispersion in the environment, leading to a trend to avoid hfno among covid- patients and to prefer early intubation. to date, the scientific evidence of generation and dispersion of bio-aerosols via hfno shows a similar risk to standard oxygen masks, and clinicians should consider hfno in hypoxemic selected covid- patients [ ] . ace receptors being abundant on the surface of type i and ii pneumocytes, pulmonologists expected a more severe clinical presentation and massive hospitalization for covid- in patients with cld [ ] . it was confirmed by meta-analyses in patients with copd [ , ] . in a large cohort of patients with covid- , concomitant cld were associated with worse outcomes [ ] . however, contrary to these expectations, patients in our cohort with cld were not hospitalized more often than other patients. in our study, % of patients had preexisting cld. asthma was the main cause ( patients, . %) and copd was the second-most common cause ( patients, %), including four patients with acos. as the risk of covid- infection in patients with underlying cld in the general population remains unknown, and general data on covid- in asthma or copd patients appear discordant, it is difficult to conclude about the frequency of hospitalization of the patients with cld [ , , [ ] [ ] [ ] [ ] . a recent article has highlighted a low incidence of covid- in copd patients ( cases in , ) [ ] . this aligns with a recent meta-analysis that included studies involving , patients hospitalized for covid- , which revealed a copd rate of . % [ ] . as a pulmonology care unit, we expected even more patients with comorbid cld, especially since these patients were primarily referred to us for hospitalization at strasbourg university hospital. the percentages of patients with cld in our cohort are relatively similar to those reported in the general french population, which emphasizes the absence of over-representation of comorbid cld in covid- , especially since these results are based on pulmonology hospitalizations [ , ] . our results align with recent data from the american centers for disease control (cdc) [ ] . moreover, these data must be interpreted with caution owing to asthma and copd being heterogeneous diseases with a large number of subtypes and phenotypes. several hypotheses have been proposed to explain the absence of over-representation of comorbid respiratory diseases in covid- : / an underdiagnosis of comorbid cld, which is also observed in the general population [ ] : in a range of reported studies, as well as in our cohort, copd was identified through known diagnosis, which may itself be underestimated. in addition, no spirometry was performed during hospitalization, due to a high-risk of virus aerosolization. / the french covid- containment strategy: early on, patients' associations and the media warned patients with cld to self-isolate through preventive actions. indeed, these patients may have begun respecting these containment rules prior to the general population. preventive measures (i.e., social distancing, respiratory hygiene, handwashing, and wearing face coverings in public settings) are beneficial to protect the general public and persons with underlying medical conditions. moreover, increased adherence to daily inhaler medication therapy has been reported for patients with asthma or copd, during the first weeks of the covid- pandemic [ ] . / a protective role of cld against covid- : reduced ace gene expression in airway cells from asthmatic allergic patients has been previously described [ ] , which could contribute to decreased susceptibility to covid- in these patients. importantly, non-atopic asthma was not associated with reduced ace expression. conversely, it has recently been demonstrated that smokers and those with copd have increased airway expression of ace [ ] . the relevance of these findings still must be confirmed in larger cohort studies. moreover, specific autoimmune responses that are elicited by the chronic disease itself could also play a protective role [ , ] . pneumonia that were successfully treated with ciclesonide inhalation [ ] . inhaled corticosteroids (ics), either alone or in combination with bronchodilators (long-acting muscarinic antagonists and ß- agonists), which are employed in both asthma and copd, have been shown to inhibit in-vitro coronavirus replication and cytokine production [ ] . in view of these data, ics might (at least partially) mitigate local inflammation in the lungs and inhibit proliferation of the virus by antiviral activity [ ] . peters et al. reported lower expression of ace and transmembrane protease serine (tmprss ) in the sputum cells of asthmatic patients taking ics [ ] . conversely, ics use in asthma and copd has been associated with an increased risk of upper respiratory tract infections and change in the lung microbiome [ , ] . macrolides, which are at times prescribed as long-term therapy in copd, could represent another beneficial treatment in covid- , although the mechanisms of azithromycin against sars-cov- are still unclear [ ] . further controlled studies are warranted to confirm the ics' potential benefits in covid- . in our cohort, two lung transplant recipients were hospitalized for covid- . one of these patients did not exhibit severe infection, while the other displayed severe infection and required immediate transfer to the icu for mechanical ventilation. currently, data on covid- in solid organ transplant recipients are limited [ ] . no patients with pulmonary arterial hypertension (pah) were hospitalized for covid- in our pulmonology unit during the observation period. pah-specific medication, such as phosphodiesterase- inhibitors and endothelin receptor antagonists, may exert protective effects in these patients, in terms of the paucity of hospitalized pah-covid- patients [ ] . in our study, cld were not a risk factor for icu management. however, a tendency to higher global mortality was observed in patients cld, though this was not considered a risk factor for death in the multivariate logistic regression analysis. similar results have been described in a recent metanalysis [ ] , and data from two studies have revealed a higher mortality rate of % [ , ] . in our cohort, these results could be partially explained by more medical decisions about therapeutic limitations for patients with advanced lung disease. in our center, therapeutic limitation was a collegial decision that involved icu staff, pulmonary department staff, and patient and family discussion. there are several limitations to this study. first, it was a single-center retrospective study, and we only considered patients that were primarily hospitalized in the conventional pulmonology unit. data on patients with cld that were directly managed in the icu were not taken into account. furthermore, cld include a lot of different diseases with various prognosis (copd with long term oxygen therapy versus asthma for example). quantitative variables are presented as median and interquartile range. n (%), where n is the total number patients with available data. two groups of patients (with or without comorbid lung disease) were compared. respectively, and patients were active smokers in the group of patients with chronic respiratory disease and the other group. the charlson comorbidity index score was calculated for each patient to compare all comorbid diseases. abbreviations: bmi = body mass index (calculated as weight in kilograms divided by height in meters squared); copd = chronic obstructive respiratory disease; covid- : coronavirus disease a pneumonia outbreak associated with a new coronavirus of probable bat origin risk factors for disease severity among hospitalised patients with pandemic influenza a (h n ) in spain chronic obstructive pulmonary disease and the covid- pandemic: reciprocal challenges respiratory viruses and exacerbations of asthma in adults viruses and bacteria in acute asthma exacerbations--a ga len-dare systematic review the respiratory virome and exacerbations in patients with chronic obstructive pulmonary disease covid- patients and the radiology department -advice from the european society of radiology (esr) and the european society of thoracic imaging (esti) prevalence of comorbidities and its effects in patients infected with sars-cov- : a systematic review and meta-analysis pathological findings of covid- associated with acute respiratory distress syndrome clinical characteristics of patients infected with sars-cov- in wuhan clinical characteristics of coronavirus disease in china relation between chest ct findings and clinical conditions of coronavirus disease (covid- ) pneumonia: a multicenter study high-flow nasal cannula for covid- patients: low risk of bio-aerosol dispersion do chronic respiratory diseases or their treatment affect the risk of sars-cov- infection? the impact of copd and smoking history on the severity of covid- : a systemic review and meta-analysis chronic obstructive pulmonary disease is associated with severe coronavirus disease (covid- ) clinical features of patients infected with novel coronavirus in wuhan, china distinct characteristics of covid- patients with initial rrt-pcr-positive and rrt-pcr-negative results for sars-cov- risk factors for severity and mortality in adult covid- inpatients in wuhan pneumonia in hospitalized asthmatic patients did not induce severe exacerbation comorbidity and its impact on patients with covid- in china: a nationwide analysis prevalence of underlying diseases in hospitalized patients with covid- : a systematic review and meta-analysis hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease -covid-net, states detection of asthma and chronic obstructive pulmonary disease in primary care changes in medication adherence among patients with asthma and copd during the association of respiratory allergy, asthma, and expression of the sars-cov- receptor ace ace- expression in the small airway epithelia of smokers and copd patients: implications for covid- autoimmune responses in severe asthma therapeutic potential of ciclesonide inahalation for covid- pneumonia: report of three cases inhibitory effects of glycopyrronium, formoterol, and budesonide on coronavirus hcov- e replication and cytokine production by primary cultures of human nasal and tracheal epithelial cells inhaled corticosteroids and covid- : a systematic review and clinical perspective covid- related genes in sputum cells in asthma: relationship to demographic features and corticosteroids long-term use of inhaled corticosteroids and risk of upper respiratory tract infection in chronic obstructive pulmonary disease: a meta-analysis inhaled corticosteroids and risk of upper respiratory tract infection in patients with asthma: a meta-analysis macrolide treatment for covid- : will this be the way forward? covid- in solid organ transplant recipients: initial report from the us epicenter could pulmonary arterial hypertension patients be at a lower risk from severe severity and mortality associated with copd and smoking in patients with clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study icu hospitalization (n/%) abbreviations: crp = c-reactive protein; icu = intensive care unit; po = partial pressure of oxygen; pco = partial pressure of arterial carbon dioxide abbreviations: bmi = body mass index (calculated as weight in kilograms divided by height in meters squared); copd = chronic obstructive respiratory disease; covid- : coronavirus disease ; po = partial pressure of oxygen; pco = partial pressure of arterial carbon dioxide.for patient not transferred in icu or died (other), the respiratory rate on transfer corresponds to the value at the time of hospital discharge. key: cord- -y rx ky authors: mattioli, francesco; fermi, matteo; ghirelli, michael; molteni, gabriele; sgarbi, nicola; bertellini, elisabetta; girardis, massimo; presutti, livio; marudi, andrea title: tracheostomy in the covid- pandemic date: - - journal: eur arch otorhinolaryngol doi: . /s - - - sha: doc_id: cord_uid: y rx ky purpose: the role of tracheostomy in covid- -related ards is unknown. nowadays, there is no clear indication regarding the timing of tracheostomy in these patients. methods: we describe our synergic experience between ent and icu departments at university hospital of modena underlining some controversial aspects that would be worth discussing tracheostomies in these patients. during the last weeks, we performed tracheostomies on patients with ards due to covid- infection who were treated with imv. results: no differences between percutaneous and surgical tracheostomy in terms of timing and no case of team virus infection. conclusion: in our experience, tracheostomy should be performed only in selected patients within - and -day orotracheal intubation. to date, over , "coronavirus disease " (covid- ) cases have been confirmed, with over , deaths. at the writing time, the covid- epidemic is striking hard in italy, being the second country in terms of infected and dead people. the mortality appears to be around %; early published data indicate . % with covid- pneumonia required intensive care unit (icu) admission and . % developed acute respiratory distress syndrome (ards) [ , ] . non-invasive support methods (i.e., cpap, bipap, niv, hfno) might correct hypoxemia and avoid endotracheal intubation but may either delay intubation with potential complications. invasive mechanical ventilation (imv) via an endotracheal tube (ett) is being commonly employed during this outbreak. tracheostomy is a widely used intervention in patients with acute respiratory failure, especially when clinicians predict a patient's need for prolonged imv, but at the moment, no recommendation on covid- -affected patients exists [ ] . herein, we describe our synergic experience between ent and icu departments at university hospital of modena underlining some controversial aspects that would worth discussing tracheostomies in these patients. during the last weeks, we performed tracheostomies on patients with ards due to covid- infection who were treated with imv. there are no studies addressing mechanical ventilation strategies in covid- outbreaks. covid- -related ards often requires prolonged intubation as observed in our experience. in addition, early extubating attempts frequently require a re-intubation procedure. according to meng et al. these should be considered difficult and complicated intubations for different reasons (i.e., no respiratory reserve, strict infection control and urgency, personal protective equipment, psychological pressure) [ ] . tracheostomy offers several advantages in terms of improved comfort management, reduced sedative, and paralytic medical support, reducing death space. moreover, tracheostomy reduces airways resistance, lessening the work of breathing optimizing the tracheal secretion control [ ] . this procedure results in better patient comfort and facilitates restoring patient autonomy, even if it carries its own risks. aerosol-generating procedures, such as endotracheal intubation, extubation, and tracheostomy, have been implicated with the transmission of infectious agents to healthcare personnel in previous papers regarding the sars outbreak. an increasing need for icu admission due to covid- -related ards can be expected within the next months. the magnitude of this demand may cause an imbalance between the real clinical needs of the population and the effective availability of intensive resources. this scenario can be substantially assimilated to the field of "disaster medicine" where tracheostomy is a tool for early icu discharge [ ] . indeed, tracheostomy could allow discharge from icu to intermediate care ward in patients with ongoing imv. in the lung safe study, involving ards patients from icus across countries, tracheostomy was performed in % of patients, whose % after the first week of icu stay [ ] . the median timing of tracheostomy was days after the onset of ards. the difficulty for clinicians in predicting which patients will require prolonged ventilation support in the early phases of critical illness is a caveat. there is no identified time point when afflicted patients either improve, remain stable, or progress toward death due to pulmonary complications. no recommendation can be given about tracheostomy within days in covid- patients. in this early phase, aggressive treatments and intensive care are needed for critically ill patients and tracheostomy could not result in improvement in hypoxia, multiple organ dysfunction, virus clearance, and in shorter duration of imv. if the patient meets weaning targets like fio less than %, peep < , pao /fio > , pressure support < cmh o, extubation could be reached between and days, tracheostomy should be postponed. after days in patients far from reaching weaning targets, tracheostomy could be performed, but there is a lack of data regarding this topic. additional critical outcome scores, such as high respiratory sofa score, might be beneficial to identify those covid- patients who are too sick to benefit from further interventional procedure [ ] . moreover, performing a tracheostomy appears to be influenced by other factors as local medical practices and expertise and costs relating to the procedure and equipment. in our experience, several delayed (> oti days) tracheostomies were performed especially in the first-affected intubated cases who required re-intubation without clinical improvement, and in case of lack of icu places. we report a case where important tracheomalacia and posterior tracheal wall damage were observed after the opening of the trachea, probably caused by prolonged over-cuffed intubation and/or prone position ventilation or previously repeated extubation and re-intubation procedures. we did not delay tracheostomy timing until the covid- deactivation time was reached and no one has been infected. however, unless emergent, surgical procedures should only be undertaken after ascertaining the covid- status to decrease potential virus exposure to the team. it is recommended during aerosol-generating procedures on patients with covid- to wear a fit-tested n mask in addition to gloves, gown, face/eye protection and to perform these procedures in an airborne isolation room. both percutaneous and surgical tracheostomies can be performed. surgical tracheostomy should be indicated for bmi > patients with short neck and documented thyroid gland hypertrophy. we have been always performing trans-isthmus tracheostomy with tracheal-toskin stitches on inferior margin without ett removal to avoid accidental displacement of tracheal cannula. cuffed non-fenestrated cannula should be used to limit diffusion of the virus. every effort should be made not to pierce the cuff of the ett when performing tracheostomy. initial advancement of the ett should be performed prior to tracheostomy window being made. ventilation has to cease prior to tracheostomy tube insertion, which has to be swift and accurate with prompt inflation of the cuff. most skilled ent surgeon should perform the procedure due to the uncomfortable setting of the icu covid- room and personal protective equipment. the role of tracheostomy in covid- -related ards is unknown. nowadays, there is no clear indication regarding the timing of tracheostomy in these patients. there is no evidence that tracheostomy improves patient's clinical course. it is established that tracheostomy reduces the icu stay. in the context of prolonged imv required in covid- experience, tracheostomy should be suggested to avoid potential tracheal damages within and days. surgical tracheostomy should be proposed only in selected patients. the ent and icu specialists should pay meticulous attention to the details of infection control, to minimize cross-contamination and their own risk of contracting the illness. we suggest other colleagues to share their experience with this topic. funding none. conflict of interest the authors declare that they have no conflict of interest. ethical approval not applicable. informed consent not applicable. severe acute respiratory syndrome coronavirus (sars-cov- ) and coronavirus disease- (covid- ): the epidemic and the challenges surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) intubation and ventilation amid the covid- outbreak: wuhan's experience. anesthesiology clinical ethics recommendations for the allocation of intensive care treatments, in exceptional, resource-limited circumstances. italian society of anesthesia, analgesia, resuscitation, and intensive care (siaarti) epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine key: cord- -lhphdjeu authors: whittle, john; molinger, jeroen; macleod, david; haines, krista; wischmeyer, paul e. title: persistent hypermetabolism and longitudinal energy expenditure in critically ill patients with covid- date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: lhphdjeu nan covid- infection results in respiratory failure requiring icu care in a small, yet significant, number of patients [ ] . the longitudinal metabolic phenotype and energy expenditure of this novel pandemic disease has yet to be described. as a marked and often prolonged, systemic inflammatory response (sirs) has been suggested to be a hallmark of severe covid- infection [ ] , we hypothesized a prolonged hypermetabolic state would evolve over icu stay that would persist beyond the - day hypermetabolic phase described previously in other icu conditions [ ] . further, understanding the energy expenditure of covid- icu patients is essential to help determine safe, optimal nutrition needs for the icu provider [ ] , as both over-/underfeeding is associated with increased icu mortality [ , ] . prediction of resting energy expenditure (pree) using standardized formulas or bodyweight calculations often correlates poorly with measured ree (mree) [ ] . thus, our aim was to assess longitudinal mree via indirect calorimetry (ic) in intubated covid- patients. here, we report the first results from the leep-covid study (clinicaltrials.gov nct ) from march to may, . following irb approval, ic was conducted every h (q-nrg, cosmed/baxter, usa) [ ] . prior to testing, patients were confirmed to be in stable condition with only steady-state measures for ≥ min considered valid. mree was compared to pree, which was calculated at same timepoints via commonly utilized harris-benedict equation (hbe). for calculations, actual body weight (abw) was used for non-obese (bmi < ) and both actual and adjusted body weight (adjbw) was utilized for obese subjects (bmi > ) [ ] . data from covid- icu patients are summarized in table and fig. . during the st icu week, mree was observed to fall between and kcal/kg (for abw in bmi < and adjbw in obese subjects [ ] .). increasing hypermetabolism and wider variability in mree were observed post- st icu week. unlike data from smaller studies in other icu populations [ ] , observed hypermetabolism persisted, and in fact increased during rd icu week (mean mree = % pree in rd icu week). certain individuals exhibited metabolic rates greater than two-times predicted via hbe, which significantly underpredicted ree post- st icu week. changes in mree may not be significantly related to severity of organ failure and only minorly affected by paralysis/ prone positioning, as these were not significantly different over the study period (table ) . longitudinal ic data presented here demonstrate a progressive hypermetabolic phenotype beginning week post-intubation in covid- icu patients, with significantly greater mree versus predictive equations or aspen-recommended - kcal/kg abw for obese subjects used currently to determine energy requirements. our data support use of standard predictive equations or~ kcal/kg as a reasonable approximation of mree in st icu week in covid- patients. current espen/aspen icu guidelines suggest hypocaloric (~ % pree) feeding during acute phase to prevent overfeeding risk as it is believed icu patients have initial early endogenous nutrient production that we currently are unable to measure [ , ] . to our knowledge, this is the first description of longitudinal mree in a covid- icu population. the covid- metabolic phenotype may be unique from previously described icu models of metabolic response [ ] , with a more prolonged hypermetabolic phase that may be independent of severity of organ failure and, as previously published, may only be minorly affected by interventions such as paralysis [ ] . further, it is one of the largest single-icu diagnosis cohorts with longitudinal ic measures for days. in conclusion, we demonstrate progressive hypermetabolism and considerable variation in ree throughout icu stay. we hope this data assists icu clinicians in further understanding the effects of covid- on metabolism and in assessing nutrition care needs. these data suggest personalization of nutrition delivery, including ic use [ , ] , should be considered to provide more accurate assessments of energy expenditure and help guide nutrition delivery in covid- icu patients. this study was funded in part by an investigator-initiated grant from baxter inc. (deerfield, il) to paul e. wischmeyer via duke university. the sponsor (baxter) did not participate in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. only the authors and investigators at duke university participated in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. all raw data available upon request ethics approval and consent to participate leep-covid study was approved by duke institutional review board. a waiver of consent was granted by duke irb due to minimal risk to patient from fda-approved qnrg indirect calorimeter assessment. all patients were provided an information sheet when able to be awake and oriented (if possible) and given option to withdraw from the study with no data retained. not applicable; all authors have seen and approved the final version of the manuscript. severe covid- components of energy expenditure in patients with severe sepsis and major trauma: a basis for clinical care espen guideline on clinical nutrition in the intensive care unit guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of critical care medicine (sccm) and american society for parenteral and enteral nutrition the clinical evaluation of the new indirect calorimeter developed by the icalic project the effect of cisatracurium infusion on the energy expenditure of critically ill patients: an observational cohort study springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the primary authors acknowledge the commitment and many hundreds of hours spent conducting this trial by the study research coordinators, respiratory therapists, dietitians, critical care attendings, nurses, and other icu staff at duke university hospital that made the many daily measurements in critically ill coivd- patients possible. we also acknowledge the leep-covid study group co-authors who made this research possible: anthony sung md, marat fudim md, lindsie boerger rd, kathryn lessig rd, jessica lumbard bs, leslie c. murray rd, sue steves rd, jhana parikh bs, jacob ribet bs, rrt ldn, and melanie hollidge md. dr. wischmeyer reports receiving investigator-initiated grant funding related to this work from national institutes of health, canadian institutes of health research, baxter, and fresenius. dr. wischmeyer has served as a consultant to abbott, fresenius, baxter, cardinal health, and nutricia, for research related to this work. dr. wischmeyer has received unrestricted gift donation for nutrition research from musclesound. dr. wischmeyer has received honoraria or travel expenses for cme lectures on improving nutrition care from abbott, baxter, and danone-nutricia. key: cord- -y vhh oq authors: zhang, yimin; liu, jimin; yu, liang; zhou, ning; ding, wei; zheng, shufa; shi, ding; li, lanjuan title: prevalence and characteristics of hypoxic hepatitis in the largest single-centre cohort of avian influenza a(h n ) virus-infected patients with severe liver impairment in the intensive care unit date: - - journal: emerg microbes infect doi: . /emi. . sha: doc_id: cord_uid: y vhh oq avian influenza a(h n ) virus (a(h n )) emerged in february . liver impairment of unknown cause is present in % of patients with a(h n ) infection, some of whom experience severe liver injury. hypoxic hepatitis (hh) is a type of acute severe liver injury characterized by an abrupt, massive increase in serum aminotransferases resulting from anoxic centrilobular necrosis of liver cells. in the intensive care unit (icu), the prevalence of hh is ∼ %– %. here, we report a . % ( / ) incidence of hh in the largest single-centre cohort of icu patients with a(h n ) infection. both hh patients presented with multiple organ failure (mof) involving respiratory, cardiac, circulatory and renal failure and had a history of chronic heart disease. on admission, severe liver impairment was found. peak alanine aminotransferase (alt) and aspartate aminotransferase (ast) values were and u/l, and and u/l, respectively, in the two patients. unfortunately, both patients died due to deterioration of mof. a post-mortem biopsy in case confirmed the presence of centrilobular necrosis of the liver, and real-time reverse transcription polymerase chain reaction of a(h n )-specific genes was negative, which excluded a(h n )-related hepatitis. the incidence of hh in a(h n ) patients is similar to that in icu patients with other aetiologies. it seems that patients with a(h n ) infection and a history of chronic heart disease with a low left ventricular ejection fraction on admission are susceptible to hh, which presents as a marked elevation in alt at the time of admission. avian influenza a(h n ) virus (a(h n )) emerged in february and infected patients according to the latest world health organization (who) report, updated on february . - the mortality rate of a(h n ) infection is . % ( / ). liver derangement commonly occurs in a(h n )-infected patients. [ ] [ ] [ ] indeed, these patients can suffer from severe liver injury; however, the underlying reason remains unclear. the causes of severe acute liver impairment include hepatotropic virus infection, drug-induced liver injury (dili), ischaemic liver injury and liver trauma. thus, whether the novel a(h n ) virus is hepatotropic and plays an important role in the dramatic liver injury sometimes seen in patients with severe liver impairment warrants investigation. furthermore, it is also necessary to identify other causes of severe liver impairment if a(h n )-related hepatitis is excluded in these patients. hypoxic hepatitis (hh) is characterized as a massive but transient increase in serum alanine aminotransferase (alt) activity secondary to anoxic necrosis of centrilobular liver cells. the prevalence of hh in intensive care unit (icu) patients is %- %. hh is one cause of acute liver injury in patients with respiratory failure. , severe a(h n ) infection always leads to respiratory failure, which reduces oxygen supply to the liver. hence, hh is likely one possible cause of severe liver impairment in a(h n )-infected patients with respiratory failure. hh patients are not always on hepatology wards, which may complicate its recognition. to the best of our knowledge, there has been no report of hh in patients infected with a(h n ) or any other type of avian influenza virus. however, the overall in-hospital mortality rate of hh can be as high as %- % due to accompanying multiple organ failure (mof). [ ] [ ] [ ] [ ] because of this high mortality rate, early diagnosis and treatment of hh are necessary to ensure a good outcome. from march to february , patients with a(h n ) infection were admitted to the icu of the first affiliated hospital, zhejiang university school of medicine which represents the largest single-centre cohort of patients with a(h n ) infection worldwide. we report here the prevalence of hh in this single-centre cohort. the clinical characteristics of a(h n )-infected patients with hh are described. post-mortem biopsies were obtained from one fatal case of hh with a(h n ) infection. the pathological features were reported, and a(h n )-related hepatitis was excluded based on a negative viral real-time reverse transcription polymerase chain reaction (rt-pcr) assay of liver tissue. a total of patients with avian flu h n infection admitted to the icu at the first affiliated hospital, zhejiang university school of medicine from march to february were screened. this study was approved by the ethics committee of the first affiliated hospital. liver function was tested daily for the first week and at least twice during the remainder of the hospital stay. the presence of respiratory, cardiac, renal or circulatory failure was recorded. serologic testing for viral hepatitis a, b, c, d, e, epstein-barr virus and cytomegalovirus was performed. serum autoantibodies were also assayed. liver ultrasound, echocardiogram and chest radiography were performed. all relevant medical information, such as past history, recent contact with live poultry, coagulation function and medications taken during the hospital stay, was recorded. patients who met all of the following criteria were diagnosed as having hh according to previous reports , , : (i) a massive but transient elevated alt level (more than -fold the upper limit of normal (uln)), (ii) the presence of respiratory, cardiac or circulatory failure and (iii) exclusion of other causes of liver injury. post-mortem biopsy, histological examination and rt-pcr a limited post-mortem biopsy that included the liver, lung and kidney was performed in one confirmed fatal case of hh with a(h n ) infection (case ). written consent was obtained from the relatives of the patient prior to the biopsy. two post-mortem biopsy cores from the liver and one biopsy from each lung and kidney were taken according to institutional protocols. one biopsy core from each organ was fixed in % formalin for histopathological examination by haematoxylin and eosin staining. the second liver biopsy core was directly homogenized and subjected to real-time rt-pcr for a(h n )-specific genes as reported previously. the primers and probes used are listed in table . statistical analysis was performed using the spss software package (version . , chicago, il, usa). non-parametric variables are presented as n (%). parametric variables are presented as means sd and were compared by t-test. a p-value , . (two-tailed) was considered to indicate significance. the patients in the icu with a(h n ) infection were predominantly male (n , . %), aged - years (n , . %) ( table ) . their underlying medical conditions, described in table , included hypertension (n , . %), coronary heart disease (n , . %), chronic obstructive pulmonary disease (n , . %), cerebrovascular disease (n , . %), chronic liver disease (n , . %), chronic renal disease (n , . %), diabetes mellitus (n , . %), rheumatoid arthritis (n , . %) and cancer (n , . %). the proportion of patients with liver impairment was lower on admission than during the hospital stay (n ( . %) vs. n ( . %), p , . ). antiviral therapy was performed in all patients, while antibiotic therapy was performed in ( . %) and glucocorticoid therapy in ( . %) ( table ). an alt level of . -fold the uln was found in only two patients, not only on admission but also during the hospital stay. the extent of hypoxic hepatitis in a(h n )-infected patients y zhang et al alt elevation was considerably higher in hh patients than in non-hh patients with liver injury (on admission, . . u/l vs. . . u/l, p , . ; hospital stay, . . u/l vs. . . u/l, p , . ) ( table ). these two cases were diagnosed as hh. the incidence of hh in our single-centre cohort of icu patients with a(h n ) infection was . % ( / ). both cases exhibited respiratory, renal, circulatory and cardiac failure. in addition, viral hepatitis and autoimmune diseases were excluded based on the negative results of serum marker tests. dili was excluded based on no history of drug intake (such as acetaminophen, chinese herbs, etc.) suspected to induce dili prior to admission. liver ultrasound excluded surgical biliary tract diseases and space-occupying lesions. details of the two patients are reported below. an -year-old male was admitted to the icu with a -day history of shortness of breath and sudden deterioration with a fever of . c prior to admission. on admission, the patient exhibited ventricular tachycardia and was in atrial fibrillation ( bpm), and had tachypnoea ( /min), oliguria and a low oxygen index (pao /fio ) (, mmhg). his mean arterial pressure was maintained at mmhg by norepinephrine administration at a dose of . mg/kg?min. the patient had a history of contact with live poultry seven days before admission. chest radiography showed bilateral pulmonary infiltrates with consolidation at admission ( figure a ). respiratory secretions were positive for a(h n ) h , n and m genes by realtime rt-pcr. on admission, severe liver injury was identified. serum alt, aspartate aminotransferase (ast) and lactate dehydrogenase (ldh) activities were elevated to , and u/l, respectively. total bilirubin level was mmol/l. the international normalized ratio (inr) was prolonged to . with a d-dimer value of mg/l. the dynamic changes in liver function are shown in figure . peak alt, ast and ldh activities ( , and u/l, respectively) occurred on the second day of admission, while the inr peaked at . on the sixth day. renal failure was identified as the creatinine level reached mmol/l with anuria. serologic test results were negative figure d) . the patient had a -year history of hypertension and coronary artery disease status and had twice undergone placement of intracoronary stents at six and two years previously. concomitant acute myocardial infarction was excluded according to the echocardiogram, electrocardiogram (ecg), myocardial enzyme spectrum and troponin (tni) results. the patient was identified as having a severe a(h n ) infection with mof and hh, placed on a mechanical ventilator and given fluid resuscitation. antiviral therapy with oral osetalmavir ( mg) twice daily was administered through a feeding tube. plasma exchange and haemofiltration were performed in the patient as liver and renal replacement therapies. unfortunately, the patient died on day of hospitalization. the liver biopsy showed well-demarcated multifocal centrilobular coagulative necrosis without accompanying inflammation. the necrotic hepatocytes were partially replaced by red blood cells, outlined by sinusoidal endothelial cells. sinusoid congestion and mild hepatocellular atrophy were identified in adjacent tissue ( figure a and b). the lung showed interstitial pneumonitis with hyaline membranes, congestion, intrapulmonary haemorrhage and anthracosis ( figure c ). acute tubular necrosis and generalized renal tubule atrophy were found in the kidney ( figure d ). a -year-old male was admitted to the icu with a two-week history of cough with sputum and sudden deterioration with a fever of . c prior to admission. on admission, the patient had paroxysmal ventricular tachycardia, and his mean arterial pressure was maintained at mmhg by administration of norepinephrine at a dose of . mg/kg?min. oxygen inhalation through a nasal tube was administered to maintain oxygen saturation at . %. the patient had a recent history of contact with live poultry days prior to admission. respiratory secretions were positive for a(h n ) h , n and m genes. chest radiography on admission showed bilateral pulmonary infiltrates ( figure a ). on admission, an echocardiogram showed a dilated left ventricle with a low lvef of . % ( figure d ), together with weakened cardiac wall motion. the serum creatine phosphokinase (ck) level was u/l, and tni was negative. ecg did not show the evidence of acute myocardial infarction on admission. a second echocardiogram showed recovery of lvef to % without accompanying weakened cardiac wall motion at day . the patient had a -year history of bronchiectasia that had been progressing to pulmonary heart disease for years. on admission, severe liver injury was identified. alt, ast and ldh activities were elevated to , , and u/l, respectively, the highest levels seen during the patient's hospital stay ( figure ). total bilirubin level was mmol/l. inr was prolonged to . with a d-dimer value of mg/l. the dynamic changes in liver function and inr are described in figure . the patient was identified as having a severe a(h n ) infection with mof and hh. antiviral therapy of oral oseltamavir ( mg) twice daily was administered. due to the progression of the infiltrates and consolidation ( figure b and c), the patient was placed on a kidney, heart, etc. , , , according to early reports, the occurrence of liver injury in a(h n ) patients was relatively frequent. , our study is not only in agreement with these reports, but it also indicated a higher frequency of liver impairment during the hospital day (n , . %) than on admission (n , . %) (p , . ). however, severe liver impairment (alt . -fold the uln) was rare (n , . %). the distinct difference between the extent of elevated alt between hh patients and non-hh patients with liver impairment indicated that hh could be differentiated from other types of liver injury by means of a sharp elevation in the alt level. the majority of a(h n )-infected patients are treated with antiviral medications, antibiotics and steroids, which are potentially hepatotoxic. [ ] [ ] [ ] [ ] there are also reports of liver impairment induced by respiratory viruses, such as severe adult respiratory syndrome coronary virus (sars-cov). hence, it is meaningful to identify the cause of liver injury, especially in cases of severe liver impairment. hh is a common cause of acute liver injury in the icu setting and is characterized by an abrupt and massive increase in aminotransferase activity secondary to anoxic centrilobular liver necrosis. , in other words, it is the clinical syndrome underlying hepatic necrosis homogeneously distributed around the central veins. centrilobular liver necrosis without inflammation was found in this study, which is consistent with the typical histological changes of hh ( figure a and b) . , the pathologic features differed from those of sars-cov-associated viral hepatitis, in which hepatocyte ballooning and lobular lymphocytic infiltration are commonly found. the negative results of rt-pcr testing of post-mortem liver tissue excluded a(h n )-related viral hepatitis. in addition, the peak ldh activities of and u/l in these patients were notable (figures a and a ). these may be useful for differentiation of hh from viral hepatitis. according to previous reports, the occurrence of hh requires a pre-existing condition that chronically compromises oxygen supply to the liver, together with an acute event that further decreases hepatic oxygen supply. , severe a(h n ) infection will lead to respiratory failure, and respiratory failure will in turn induce a sudden decrease in oxygen supply to the liver. the presence of a chronic disease that reduces baseline oxygen supply to the liver is an indicator of hh risk in a(h n ) patients. in case , coronary artery disease that chronically reduced blood flow, and hence oxygen supply, to the liver was found in both hh cases. in case , chronic pulmonary dysfunction decreased blood oxygen saturation, which led to an insufficient baseline oxygen supply to the liver. in addition, temporary left ventricular failure and respiratory failure decreased the oxygen supply to the liver. temporary left ventricular failure was suspected due to myocarditis. the ck, tni and ecg results supported this speculation. in another temporary left ventricular failure patient with a(h n ) infection, typical myocarditis histological changes, such as cluster lymphocyte infiltration, were found in post-mortem heart tissue. cardiac dysfunction was confirmed on cardiogram by the decrease in lvef to % and . % in the two patients on admission. in case , the detection of dilated intrahepatic veins by abdominal ultrasound ( figure b) and a prolonged history of coronary disease with two intracoronary stent implantation procedures suggested chronic right ventricular failure. during hospitalization, these two patients required persistent intravenous norepinephrine transfusion to maintain diastolic blood pressure. this clearly indicated circulatory failure, which would also reduce oxygen supply to the liver. the reduction in oxygen supply caused by respiratory failure was ameliorated in the icu. the peak alt and ast levels occurred on the day of admission or the following day in this study, which is in accordance with the report of raurich et al. ours is the largest centre for the treatment of a(h n ) patients in the world. a(h n ) patients in our icu represent , % ( / ) of the total number of patients confirmed infected with a(h n ) according to the latest report by the who. the prevalence of hh in icu patients with a(h n ) infection in our centre is . %. the incidence of hh in icu patients varies from . % to . %. most studies have reported a prevalence of %- %. this is in agreement with our findings, which suggest that patients with a(h n ) infection in the icu setting have a similar prevalence of hh to that of those with other aetiologies. the in-hospital mortality rate of hh is o %. according to raurich et al., risk factors for mortality include prolonged inr and need for renal replacement. , both of these risk factors were present in the two patients reported herein, which was indicative of a poor prognosis. both patients died despite treatment of the accompanying mof (such as by fluid resuscitation and blood purification). according to previous reports, a cytokine storm can occur in severe a(h n ) or a(h n ) patients. , , moreover, inflammatory cytokines were found to contribute to hypoxic hepatopathy in animal models. a cytokine storm was also detected in two hh patients with a(h n ) infection. however, the relatively low prevalence of hh ( hh cases vs. non-hh cases) makes it difficult to reach a conclusion regarding the contribution of a cytokine storm to the pathogenesis of a(h n ) infection in hh. a large-scale study of a(h n )infected patients should be performed to determine the contribution of a cytokine storm to hh and the correlation between them. in conclusion, we report here a . % prevalence of hh in icu patients with a(h n ) infection. the typical pathological change of hh, centrilobular necrosis of the liver, was confirmed. a(h n )related viral hepatitis was excluded based on negative real-time rt-pcr for viral genes in liver tissue. a lower lvef accompanying underlying chronic heart disease and abrupt elevation of serum alt levels at the time of admission in patients with a(h n ) infection suggest the need for identification and treatment of hh. h n influenza-infected patients with chronic heart disease accompanying acute heart failure are at elevated risk of severe liver damage. lan-juan li and colleagues at zhejiang university in hangzhou studied patients admitted to intensive care with h n influenza over years, two of whom had hypoxic hepatitis, a type of acute severe liver injury caused by reduced oxygen supply to the liver. the results indicated a combination of pre-existing heart conditions and sudden decreasing of left ventricular ejection fraction in the two patients, combined with the respiratory failure caused by h n , reduced oxygen supply to the liver, which caused hereditary hemochromatosis. the researchers suggest that h n patients with a history of heart disease and acute left heart failure on admission should be carefully checked for liver damage. this research summary is based on your manuscript that was recently accepted for publication in emerging microbes & infections (emi). it provides a non-specialist audience with a synopsis of your key research outcomes and conclusions. this value-added service provided by npg is designed to raise interest in your research across the broader community. npg will publish the summary on the journal's website, and it will be freely available under a creative commons ''by-nd-nc . unported'' license (see the journal website for details). we encourage you to re-use the summary to bring attention to your research; for example, you can host it on your own website and share it via social-networking platforms. please attribute the summary to emi and your article (e.g. by providing a link to your article) and do not make derivatives. please note that to maximize the usefulness of these summaries they must follow several stringent guidelines: -spelling, punctuation and style are set according to nature editorial guidelines. as this summary is aimed at non-expert readers, some concepts and technical terms will be simplified. -total length must be no more than words. it is likely that not all points in the paper will be covered. -the first sentence must be no more than characters, including spaces, to allow use on microblogging sites. -the headline must consist of a brief generic subject identifier followed by a short description. no more than words in total. please contact the editorial office (editorial@emi .org) immediately with corrections should you find any factual errors in this research summary. human infection with a novel avian-origin influenza a (h n ) virus who risk assessment of human infection with avian influenza a(h n ) virus as of epidemiology of human infections with avian influenza a(h n ) virus in china h n influenza-the laboratory presentations: a letter to editor laboratory findings in patients with avian-origin influenza a (h n ) virus infections unique reassortant of influenza a(h n ) virus associated with severe disease emerging in hong kong hypoxic hepatitis hypoxic hepatitis: a challenging diagnosis clinical findings in cases of influenza a (h n ) virus infection hypoxic hepatitis: clinical and hemodynamic study in consecutive cases hypoxic hepatitis: underlying conditions and risk factors for mortality in critically ill patients hypoxic hepatitis in critically ill patients: incidence, etiology and risk factors for mortality hypoxic hepatopathy: pathophysiology and prognosis human infections with the emerging avian influenza a h n virus from wet market poultry: clinical analysis and characterisation of viral genome clinical findings for early human cases of influenza a(h n ) virus infection a recombinant viruslike particle influenza a (h n ) vaccine sars-associated viral hepatitis caused by a novel coronavirus: report of three cases hepatic histological findings in suspected drug-induced liver injury: systematic evaluation and clinical associations evaluation of prognostic markers in severe drug-induced liver disease hypoxic hepatitis -epidemiology, pathophysiology and clinical management extreme serum elevations of aspartate aminotransferase surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock fatal outcome of human influenza a (h n ) is associated with high viral load and hypercytokinemia cytokine and chemokine levels in patients infected with the novel avian influenza a (h n ) virus in china comparison of the cytotoxic actions of hypoxia and endotoxin in the perfused cat liver this work was supported by the grants zx and zx from the china national science and technology major project and zb from the zhejiang ctm science and technology project. we thank prof. rajiv jalan from university college london for his constructive suggestions in the revision of the manuscript. key: cord- -zzl c nj authors: sukhonthamarn, kamolsak; grosso, matthew j.; parvizi, javad title: response to letter to the editor titled ‘risk modeling for unplanned intensive care unit (icu) admission’ date: - - journal: j arthroplasty doi: . /j.arth. . . sha: doc_id: cord_uid: zzl c nj nan to the editor in reply, we are grateful to the letter authors for their interest in our study regarding risk factors for unplanned intensive care unit (icu) admission after elective total joint arthroplasty, which was recently published in the journal of arthroplasty [ ] . we agreed with the authors that in this arduous situation of the covid- pandemic nationwide and around the world, issues related to medical resource utilization have become paramount for healthcare providers. therefore, the american college of surgeons (acs) and the centers for medicare and medicaid services (cms) have recommended postponing or canceling elective procedures, including total joint arthroplasty (tja) [ , ] . the questions from the letter writers are timely and appropriate regarding triage of urgent-procedures related to total joint arthroplasty, including periprosthetic joint infection, periprosthetic fracture, and prosthetic dislocation. our ultimate goal is to have an arthroplasty procedure based calculator that can cover these urgent procedures, similar to the current acs nsqip risk calculator [ ] . as we hopefully return to normalization during this critical period and re-start elective cases, we hope our findings in the published study can help surgeons reduce the risk of icu admission. we report significantly increased risks with bilateral versus unilateral hip there is previously published work on predictors and risk-stratified model development, which was created from stratified preoperative and intraoperative factors to predict unplanned icu admission after total hip arthroplasty (tha) [ ] [ ] [ ] . we think this model is interesting and important for clinical use. therefore, as suggested by the letter writers, we are developing a risk calculator tool from our database and extending it to evaluate multiple preoperative factors that influence and weight the risk for icu admission. we want to thank the authors for their invaluable comments and suggestions. we hope that our future work can further help plan appropriately for healthcare resource management, especially in this time of crisis for both surgeons and patients. risk factors for unplanned admission to the intensive care unit after elective total joint arthroplasty covid- : recommendations for management of elective surgical procedures american college of surgeons unplanned admission to the intensive care unit after total hip arthroplasty prospective study of unplanned admission to the intensive care unit after total hip arthroplasty which patients need critical care intervention after total joint arthroplasty?: a prospective study of factors associated with the need for intensive care following surgery key: cord- -a jk w authors: ding, ji-guang; sun, qing-feng; li, ke-cheng; zheng, ming-hua; miao, xiao-hui; ni, wu; hong, liang; yang, jin-xian; ruan, zhan-wei; zhou, rui-wei; zhou, hai-jiao; he, wen-fei title: retrospective analysis of nosocomial infections in the intensive care unit of a tertiary hospital in china during and date: - - journal: bmc infect dis doi: . / - - - sha: doc_id: cord_uid: a jk w background: nosocomial infections are a major threat to patients in the intensive care unit (icu). limited data exist on the epidemiology of icu-acquired infections in china. this retrospective study was carried out to determine the current status of nosocomial infection in china. methods: a retrospective review of nococomial infections in the icu of a tertiary hospital in east china between and was performed. nosocomial infections were defined according to the definitions of centers for disease control and prevention. the overall patient nosocomial infection rate, the incidence density rate of nosocomial infections, the excess length of stay, and distribution of nosocomial infection sites were determined. then, pathogen and antimicrobial susceptibility profiles were further investigated. results: among patients admitted over the period of time, the overall patient nosocomial infection rate was . % or . per patient days., lower respiratory tract infections (lrti) accounted for most of the infections ( . %), followed by urinary tract infections (uti, . %), bloodstream (bsi, . %), and gastrointestinal tract (gi, . %) infections. there was no significant change in lrti, uti and bsi infection rates during the years. however, gi rate was significantly decreased from . % in to . % in . in addition, a. baumannii, c. albicans and s. epidermidis were the most frequent pathogens isolated in patients with lrtis, utis and bsis, respectively. the rates of isolates resistant to commonly used antibiotics ranged from . % to . %. conclusion: there was a high and relatively stable rate of nosocomial infections in the icu of a tertiary hospital in china through year – , with some differences in the distribution of the infection sites, and pathogen and antibiotic susceptibility profiles from those reported from the western countries. guidelines for surveillance and prevention of nosocomial infections must be implemented in order to reduce the rate. nosocomial infections, also called healthcare acquired infections or health care-associated infections, is defined by the cdc as a localized or systemic condition resulting from an adverse reaction to the presence of an infectious agent(s) or its toxin(s), without any evidence that the infection was present or incubating at the time of admission to the acute care setting [ ] . nosocomial infections have become an important public health issue worldwide. nosocomial infections may result in an excess length of stay in hospital for up to days and an increase in the costs of hospitalization. [ , ] nosocomial infections pose a critical threat to patients, especially in the high-risk departments, such as the intensive care unit (icu). [ , ] in industrialized countries, nosocomial infections occurs in - % of hospitalized patients, with the rates being up to % in icu, while the rates are - % in hospitalized patients with the rates being up to % in icu. [ ] [ ] [ ] [ ] [ ] [ ] [ ] in china, there are more than , hospitals with significant differences among each other in the size, facilities, administration, teaching, research and academic levels. a few studies reported nosocomial infections in china, but these studies were limited in small sample sizes and short period of time, publication in chinese journals, with or without english abstracts. [ ] [ ] [ ] recently, we carried out a retrospective study to determine the current status of nosocomial infections in a tertiary hospital in east china. all data on nosocomial infections between year and were retrieved and reviewed. the overall patient nosocomial infection rate, the incidence density rate of nosocomial infections, the excess length of stay, and distribution of nosocomial infection sites were determined. then, pathogen and antimicrobial susceptibility profiles were further investigated. the study was performed in the affiliated hospital of wenzhou medical university, which situates in zhejiang province, east china, with over beds and one mixed icu of beds. since , the hospital started an infection control program, including collection of data on infections acquired in the hospital. in the present study, data from january to december for patients in the icu were retrieved by the infection control team since completed raw data of the patients in icu were available only after . this retrospective study was approved by the medical ethics committee of the third affiliated hospital, wenzhou medical college. all patients admitted to the icu for more than hours were monitored for nosocomial infections, which were defined according to the american cdc. [ ] infections developed within hours of discharge from the icu were also considered to be icu-acquired unless there was an identified cause after discharge. the major nosocomial infections, including lower respiratory tract infections (lrtis), urine tract infections (utis), bloodstream infections (bsis) and gastrointestinal tract infections (gis) were defined as followings. lrtis refer to lower respiratory tract infection, other than pneumonia, i.e. bronchitis, tracheobronchitis, bronchiolitis, tracheitis, without evidence of pneumonia. bsis refers to laboratoryconfirmed bloodstream infections, utis refers to symptomatic urinary tract infections and gis refers to gastrointestinal tract (esophagus, stomach, small and large bowel, and rectum) infections excluding gastroenteritis and appendicitis. the detailed criteria to diagnose these nosocomial infections were described in the cdc documents [ ] . data on the date and site of infection, patient demographic information and device use were collected for each infection. moreover, data on the isolated pathogens and their susceptibility testing to antimicrobial agents, if available, were also collected. the overall patient nosocomial infection rate was calculated by dividing the total number of patients with nosocomial infections by the total number of patients in the icu (× ) during the defined period of time (i.e. each year). the incidence density rate of nosocomial infections was calculated by dividing the total number of nosocomial infections by the total patient days (× ) during the defined period of time. the total patients days were calculated by summating the days of each patient in the icu. in the meantime, the length of stay, which was defined as the overall days of a patient spent in the hospital including the icu and another department to which the patient was transferred from icu after stabilization of the conditions. the excess length of stay was then calculated by subtracting the average length of stay for patients without nosocomial infection from that of patients with nosocomial infections. statistical analyses were performed using spss software version . (spss inc., chicago, ill., usa). chi-square test and spearman's rank-correlation coefficients were applied where appropriate. for all analyses, a p value of less than . was considered statistically significant. from to december , medical data of patients discharged from the hospital icu were colleted. the average length of stay was . days, giving patient-days. among these patients, patients acquired a total of nosocomial infections, including patients with two infections, patients with three infections, patients with four infections and one patient with five infections ( table ) . the overall patient nosocomial infection rate was . %, ranging from . % to . % among the years. there was a significant difference in the infection rates among the years (χ = . , p = . ). the incidence density rate of nosocomial infections was . per patient days, ranging from . to . among the years. the excess length of stay was . days, ranging from . lower respiratory tract infections (lrtis) including bronchitis, tracheobronchitis and pneumonia, were the most common infections, occurring in . % of the patients, followed by urine tract infections (utis) ( . %), and bloodstream infections (bsis) ( . %). among the nosocomial infections, lrtis accounted for . %, followed by utis ( . %), bsis ( . %) and gastrointestinal tract infections ( . %). most ( . %) patients with nosocomial lrtis had received mechanical ventilation or tracheotomy before the infections, whereas . % of nosocomial utis and . % of nosocomial bsi were catheter associated (table ) . there is no significant change in lrti, uti and bsi rates during the years. the gi infection rate was significantly decreased from . % in to . % in (χ = . , p = . ), whereas nosocomial infections in other sites was increased significantly (χ = . , p = . ). the nosocomial infection rates at the surgical sites and skin and soft tissues remained under % (table ) . pathogens were isolated and identified from ( . %) of nosocomial infections, or, in ( . %) of the patients. the isolated pathogens responsible for nosocomial infections differed among the infection sites ( table ). in patients with lrtis, acinetobacter baumannii and klebsiella pneumoniae were the most frequently isolated pathogens, followed by pseudomonas aeruginosa and staphylococcus aureus, accounting for more than half of the lrti related pathogen population. in patients with utis, the fungi, especially candida albicans, were the most com-mon pathogens, followed by escherichia coli. staphylococcus epidermidis, e. coli, and s. aureus were the first three most common pathogens for bsis. in addition, a. baumannii was commonly isolated in utis and bsis (table ) . data on susceptibility testing were available for isolates, including isolates of e. coli, isolates of s. aureus, and isolates of p. aeruginosa. overall, . %, . %, . % and . % of e. coli isolates were resistant to trimethoprim/sulfamethoxazole (tmp/smx) and ciprofloxacin, cefotaxime, and amoxicillin/clavulanic acid, respectively. all s. aureus isolates were sensitive to vancomycin, but . %, . %, . % and . % of isolates were resistant to nitrofurantoin, tmp/smx, rifampin and ciprofloxacin, respectively. in addition, . %, . % and . % of p. aeruginosa were resistant to tmp/smx, ciprofloxacin and levofloxacin, respectively [see additional file ]. all patients with nosocomial infections were treated with empirical antimicrobial therapies or according to the antimicrobial susceptibility test results, when available. the in the present study, the overall patient nosocomial infection rate in the icu was . % during and , which was higher than in the icus in many industrialized countries where the rates ranging from . % to . %, [ ] [ ] [ ] and even higher than the rate ( . %) observed in icus of developing countries. [ ] however, the rate is comparable with those reported in some latin american countries such as argentina and brazil [ ] , and slightly lower than that reported in india. [ ] over the years, the lowest rate was reported in ( . %), and the highest was reported in ( . %). one plausible explanation is that in the early of the country was suffering from the outbreak of highly infectious pneumonia, namely severe acute respiratory syndrome (sars). due to the massive campaign to prevent the spread of sars, nosocomial infections were indirectly reduced. being fatigued from the campaign over the previous year, disinfection and sterilization procedures might be loosen in , explaining the moderate rebound in . however, the incidence density rate of nosocomial infections was the lowest in , due to considerably longer stay of some patients in the icu ( table ). the average length of stay in the hospital varied from . to . between and , with the overall average being . days, which is generally in agreement with those ( . - . days) reported in european and the united states [ ] [ ] [ ] , but much less than that reported in taiwan [ ] . however, the it must be also mentioned that sars outbreak had some impact on the overall length of stay. although the average stay in the icu was only . days, the shortest among the years, the average stay in the hospital was the longest for both patients with and those without nosocomial infections due to the isolation policy imposed in the special period of time. the distribution of nosocomial infections in the present study differed from that reported in the united states. we found that the lrtis were the most common infections in the icu, accounting for . % of overall infections, whereas utis was the most frequently reported infections in the icus in the united states, with the rate of %, followed by pneumonia of %. [ ] the proportions of utis and bsis in the present study were relatively lower than the data reported in the united states ( . % vs. % and . % vs. %, respectively). [ ] although data from europe revealed same three most common infection sites as the present study did, the absolute proportion of lrtis was %, [ ] which was lower than the rate in the present study. the common reasons proposed by studies in many western countries have suggested that nosocomial lrtis are mainly due to mechanical ventilation. [ , ] in china, air pollution, high density of population, and improper health habits such as smoking may also account for the high rate of lrtis. the rate of lrtis slightly, but insignificantly, decreased from to . there was no change in utis and bsis rates during the years. notably, the gi rate significantly and stably decreased every year, suggesting an improvement in the environment and food sanitary in the region. since the lower respiratory tract and the urinary tract were the first two sites that nosocomial infections frequently occurred in the icu, constituting more than % of all nosocomial infections in and , more efforts were later made to control these two kinds of infections, leading to decreased rates of lower respiratory tract and the urinary tract infections, and correspondingly increased rates of nosocomial infections at other sites. the present study showed three quarters of lrti patients received mechanical ventilation or tracheotomy, more than half of nosocomial uti and bsi cases were catheter associated. these findings are consistent with previous studies, [ , , , , ] and indicate that the nosocomial infections are often associated with the use of invasive device. therefore, to effectively reduce nosocomial infections, the use of invasive device should be minimized and specific disinfection precautions taken during the device application. in the present study, pathogens were isolated from . % of overall nosocomial infections or . % of all patients with nosocomial infections. similar to the us report, gram-negative bacteria accounted for . % of the lrtis in the present study, but the most frequently pathogens were a. baumannii and k. pneurnoniae in the present study whereas p. aeruginosa and s. aureus were the most common pathogens in the us report. [ ] consistent with the us report, fungi was the most frequently pathogen for nosocomial utis; candida accounted for . % of utis in the present study, suggesting a relatively narrow profile of pathogens in nosocomial utis. s. epidermidis was the most common pathogen for bsis in both the present study and the us report; however, e. coli, instead of enterococci, was the second common pathogen in the present study. [ ] e. coli was the most common bacterial cause of nosocomial utis, and also frequently found in bsis and lrtis. it has been shown that the activity of beta-lactam antibiotics against e. coli is greatly reduced as a result of beta-lactamase production, but is restored by the addition of clavulanic acid. [ ] in the present study, only . % of e. coli isolates were sensitive to the formula amoxicillin combined with clavulanic acid, while . % of e. coli isolates exhibited susceptibility to the combination in an uk study. [ ] a high rate of resistance to tmp/smx ( . %) was observed in these e. coli isolates, in contrast to the rate of % reported in uk [ ] . in addition, there was a high proportion ( . %) of e. coli isolates resistant to ciprofloxacin, whereas the rate was less than % in uk and the united states. [ , ] these findings indicate that treatment with these antimicrobial agents for nosocomial infections caused by e. coli in china is likely to result in clinical failure in a substantial proportion of patients. we also found that a considerable number of p. aeruginosa isolates were resistant to fluoroquinolones, from . % to ciprofloxacin to . % to levofloxacin, which is comparable with the fluoroquinolone-resistant rates ( % to %) reported for patients in icus of eight developing countries, [ ] but much higher than that ( %) reported in the united states. [ ] all s. aureus isolates in the present study were sensitive to vancomycin, which was similar to the observation by tsuji et al in japan. [ ] in addition, we observed relatively low resistant rates to nitrofurantoin ( . %) and tmp/smx ( . %), which renders these antimicrobial agents suitable for empirical treatment for s. aureus infections. in china, the guidelines for surveillance and prevention of nosocomial infections was established in , and modified in . [ , ] however, surveillance systems and control measures for nosocomial infections described in the guidelines were not completely implemented and executed in all hospitals, due to the imbalanced development and health care resources within the countries, and less attention to nosocomial infections in some hospitals. therefore, it is believed that the nosocomial infection rates must be higher in some rural hospitals or even nontertiary hospitals. in addition, due to empirical use or abuse of antibiotics, the proportion of antibiotic resistant pathogens for nosocomial infections in many lower level hospitals would also be higher than that reported in the present study. it is noticed that although the mortality rates in patients nosocomial infections were between %- %, there was no mortality directly caused by nosocomial infections. the major reasons for this observation would be the fact that refractory nosocomial infections are relatively less encountered based on our susceptibility testing, which showed that most pathogens were sensitive to many most commonly used antibiotics, indicating that they can be effectively controlled. moreover, zhejiang is one of richest provinces in china where medical and healthcare systems are relatively well established and antiinfectious therapies are not a big problems. finally, it should be emphasized that our hospital is an tertiary infectious hospital with experience, methodologies and facilities to combat against various infections including nosocomial infections. the present study has some limitations, due to the retrospective nature. first, data on risk factors, except for the use of the medical device, that are potentially associated with nosocomial infections were not available. these factors may include the primary diseases for admission to the icu, patient resting posture (e.g. semirecumbent or supine body position), continuous prophylactic use of anti-peptic ulcer drugs, utilization of the alcohol-based handrubs and oral care, which need to be taken into consideration in the prospective studies. second, the data on the identification and isolation of the pathogens and their susceptibility were available only for half of the nosocomial infections. it would produce more accurate data if these numbers were increased. finally, the data on the clinical consequences were not available for most cases, making it impossible to compare the clinical outcomes between patients with and those without nosocomial infections. however, the present study was able to show that the length of stay in the hospital was significantly increased in patients with nosocomial infections, compared with those without the infections. in conclusion, there was a high and relatively stable rate of nosocomial infections in the icu of a tertiary hospital in china through year - , with some differences in the distribution of the infection sites, and pathogen and antibiotic susceptibility profiles from those reported in the western countries. the guidelines for surveillance and prevention of nosocomial infections must be implemented national wide in order to reduce the rate. cdc definitions for nosocomial infections effect of intensive care unit nosocomial pneumonia on duration of stay and mortality prolongation of hospital stay and extra costs due to ventilator-associated pneumonia in an intensive care unit nosocomial infection rates in adult and pediatric intensive care units in the united states prevalence and risk factors for nosocomial lower respiratory tract infections in german hospitals selected aspects of the socioeconomic impact of nosocomial infections: morbidity, mortality, cost, and prevention the prevalence of nosocomial infection in intensive care units in europe. results of the european prevalence of infection in intensive care (epic) study. epic international advisory committee mortality attributable to nosocomial infections in the icu national nosocomial infections surveillance (nnis) system report, data summary from nosocomial infections in medical-surgical intensive care units in argentina: attributable mortality and length of stay prevalence rate of nosocomial infection in a general hospital surveillance of risk factors for nosocomial infection in patients in intensive care units study on the changing trends in national nosocomial infection transaction investigation results nosocomial infections in medical intensive care units in the united states nosocomial infections: prospective survey of incidence in five french intensive care units nosocomial infections in a neurosurgery intensive care unit device-associated nosocomial infections in intensive care units of developing countries epidemiology, risk factors and outcome of nosocomial infections in a respiratory intensive care unit in north india the estimation of the cost of nosocomial infection in an intensive care unit the impact of adverse patient occurrences on hospital costs in the pediatric intensive care unit excess length of stay, charges, and mortality attributable to medical injuries during hospitalization impact of nosocomial infection on cost of illness and length of stay in intensive care units national healthcare safety network (nhsn) report, data summary for amoxycillin/clavulanic acid: a review of its antibacterial activity, pharmacokinetics and therapeutic use a uk multicentre study of the antimicrobial susceptibility of bacterial pathogens causing urinary tract infection antimicrobial resistance in community and nosocomial escherichia coli urinary tract isolates identification and pretherapy susceptibility of pathogens in patients with complicated urinary tract infection or acute pyelonephritis enrolled in a clinical study in the united states from november gram-negative antibiotic resistance: there is a price to pay communityand health care-associated methicillin-resistant staphylococcus aureus: a comparison of molecular epidemiology and antimicrobial activities of various agents anonymous: guidelines for nosocomial infections control and prevention (draft) anonymous: guidelines for nosocomial infections control and prevention (draft) the authors acknowledge that the manuscript was edited by a professional company, medjaden biomedical services. the authors declare that they have no competing interests. j-gd, q-fs and k-cl were the principal investigators who designed and conducted the study, analyzed the data, performed literature research and prepared the manuscript. m-hz, x-hm and wn participated in the design of the study, contributed to the data analysis and made constructive comments on the manuscript. lh, j-xy, z-wr, r-wz, h-jz and w-fh participated in the design of the study, collected the all required original data, and generated results and tables that were the basis of the manuscript. all authors have read and approved the final manuscript. the pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/ - / / /pre pub key: cord- -wlnss bg authors: al shareef, khaled; bakouri, mohsen title: cytokine blood filtration responses in covid- date: - - journal: blood purif doi: . / sha: doc_id: cord_uid: wlnss bg the real issue with the covid- pandemic is that a rapidly increasing number of patients with life-threatening complications are admitted in hospitals and are not well-administered. although a limited number of patients use the intensive care unit (icu), they consume medical resources, safety equipment, and enormous equipment with little possibility of rapid recovery and icu discharge. this work reviews effective methods of using filtration devices in treatment to reduce the level of various inflammatory mediators and discharge patients from the icu faster. extracorporeal technologies have been reviewed as a medical approach to absorb cytokines. although these devices do not kill or remove the virus, they are a promising solution for treating patients and their faster removal from the icu, thus relieving the bottleneck. the new coronavirus disease (covid ) caused by sars-cov- virus has been identified by the world health organization (who) as an international public health emergency [ ] . the disease is rapidly spreading to other countries from wuhan city in china [ ] . in contrast to the other coronavirus targets of the who, sars-cov and mers-cov, sars-cov- is lethal. the chinese national health commission survey of february , , recorded a total of , deaths in china due to sars-cov- [ , ] . patients with covid- can develop mild to severe symptoms following infection. symptoms such as fever, cough, dyspnea, myalgia, fatigue, and dehydration develop in patients with mild infection. this can lead to severe pneumonia, acute respiratory distress syndrome (ards), or multi-organ failure in some patients [ ] . sars-cov- infection is also associated with inflammatory cytokine storms, primarily characterized by elevated interleukin (il)- levels in most dying patients. interestingly enough, several recent clinical trials of covid- have shown a higher level of il- in the extreme community than in a moderate group. nevertheless, the relationship between il- and mortality remains unclear in dying patients [ , ] . many covid- patients were also affected by anxiety, especially in the intensive care unit (icu). nonetheless, currently, minimally invasive treatment options are urgently needed as no vaccine has yet been developed for covid- . in recent clinical trials, several antivirals have been tested to study the effect of inhibitors such as remdesivir, favipiravir, and ritonavir on this new coronavirus [ ] . in general, thalidomide has anti-inflammatory activity, suppresses cell proliferation, reduces pulmonary fibrosis, and has a protective effect on lung lesions due to its ability to speed up the degradation of messenger rna in blood cells and thus reduce tumor necrosis factor-(tnf) [ ] . the protective effect of thalidomide, combined with the use of antiviral medications and low-dose glucocorticoids, on lung lesions and immunological stress due to covid- pneumonia [ ] is still under investigation. clearly the efficacy of therapies used in covid- management needs to be better identified. the evidence of any further research must be validated by broad randomized controlled clinical trials and submitted to rigorous peer review prior to publication. the main concern during the covid- pandemic is that severely diseased patients in italy and china are flooding hospitals, overwhelming the capacity of the healthcare systems. although icu rooms are well equipped, in some cases, infection breaks out between the limited number of patients with covid- , such as ards, trauma, kidney failure, acute heart damage, and secondary bacterial infection. the leading cause of these complications is usually cytokine storms, which contribute to a significant systemic inflammatory reaction, leading to damage in many instances to the vital organs, including the lung, heart, and kidney [ , ] . currently, cytokine filtration is a proposed way to mitigate the overwhelming admission of patients in the icu. in contrast, cytosorb is a potentially useful way to handle these patients more effectively and discharge them from the icu to alleviate the bottleneck. while cy-tosorb does not destroy or remove the virus, it has been used in more than , eu procedures as an approved treatment for cytokine storms. it has been distributed worldwide to countries, helping doctors control severe inflammation, help reverse shocks, and improve breathing and other functions of the heart, which are some of the primary reasons patients suffer from co-vid- infection [ , ] . using the extracorporeal circuit was suggested as a solution to remove inflammatory mediators from plasma, thus reducing their effects [ ] . there are many extracorporeal techniques, but this article focuses on cytosorb and high cutoff membranes. cytosorb cytosorb is a hemoadsorption column able to remove inflammatory mediators from the blood. it contains highly absorbent coated beads, as shown in figure . the beads are coated with polyvinylpyrrolidone to enhance biocompatibility [ ] . since cytosorb is a column, it can be configured as standalone, or added to the extracorporeal circuit, pre-dialyzer, or post-dialyzer, as shown in figure [ ] . there were medical reports that cytosorb was used for the removal of inflammatory mediators. the first case was a patient with septic shock who developed mof that was connected to continuous veno-venous hemodiafiltration due to aki. the il- level was above , pg/ml, and a cytosorb column was added to the hemodiafiltration circuit. the duration of filtration lasted for h, and il- was reduced significantly. hemodiafiltration was discontinued because the kidney was functioned normally, and the patient fully recovered [ ] . the second case was a patient who developed severe and progressive respiratory failure during laparotomy even though the patient was mechanically ventilated. as a result, the patient was connected to veno-venous ecmo. unfortunately, the patient's condition deteriorated as he developed right ventricular failure, so the patient was switched to veno-arterial ecmo. despite that, the patient t t t t t t t t t t figure . in the end, the patient's kidney function returned to normal, and the patient was weaned off the mechanical ventilator [ ] . high cutoff membrane high cutoff (hco) membrane is a type of membrane that is able to remove substances with molecular weight in the range of - kda [ ] . hco membrane was able to remove inflammatory cytokines in several studies. a patient was admitted to the icu with inflammation, severe rhabdomyolysis, and aki, and was placed on renal replacement therapy with the hco membrane. after sessions, with each session lasting h, except the second session which lasted h, il- decreased significantly [ ] . another study involved patients with septic shock associated with aki who were treated with cvvhd with hco membrane for h. the inflammatory mediator levels were collected at different time points: before the start of the treatment, h and h after the initiation of the treatment procedure, and h after the termination of cvvhd. in the end, patients survived, while patients died during the cvvhd. however, the level of cytokines in both groups was reduced significantly, especially in the survival group (fig. ) [ ] . oxiris membrane oxiris membrane is an an membrane with the surface treated with polyethylenimine and grafted with heparin [ ] . the oxiris membrane has been investigated in septic shock patients for cytokine reduction. sixty patients were examined in an observational study, where the patients were received cvvhd with the oxiris membrane for a mean duration of h. at the end of the treatment, there was a significant reduction in cytokines: il- decreased from pg/ml to pg/ml, and il- decreased from pg/ml to pg/ml [ ] . a crossover randomized double-blinded study was conducted to investigate the effect of the oxiris membrane on septic shock patients with aki. the patients were divided into groups: the first group received crrt with the oxiris membrane for h and crrt with standard filter for an-other h; the other group was treated with the reverse order of treatment. in the first h, there was a significant reduction in inflammatory mediators (fig. ) [ ] . polymethyl methacrylate (pmma) membrane's ability to remove inflammatory cytokines has been studied. a -year-old patient was admitted to the icu due to septic shock caused by an infected giant venous malformation. despite conventional treatment that includes infusion of fluids and blood transfusion, the patient's hemodynamics did not improve. the patient received hemodiafiltration using the pmma membrane due to aki. after days, the il- concentration significantly decreased (from , pg/ml to pg/ml) [ ] . cardiopulmonary bypass surgery causes inflammation due to different factors, such as the blood being exposed to the extracorporeal circuit and ischemia. in another study, patients were on maintenance hemodialysis before surgery and patients were not on maintenance hemodialysis. the patients were randomized into groups: patients received crrt with polysulfone (ps) membrane, while patients were treated with crrt with pmma membrane. the maintenance hemodialysis group was the control group. the pmma and ps groups were treated with crrt before, during, and after the surgery. the cytokine level post-surgery was lower in the pmma membrane group (il- : pg/ml, il- : . mg/ml) than in the ps membrane group (il- : pg/ml, il- : . pg/ml) [ ] . ha is a synthetic resin hemofilter used for cytokine removal [ ] . the effect of ha on cytokine removal was investigated in hyperlipidemic severe acute pancre- atitis patients. twenty patients were divided into groups: the control group and the study group. the study group received cycles of high-volume hemofiltration (hvhf) and hemoperfusion (hp) using ha . each cycle consists of h of hvhf and h of hp. the combination of the treatments resulted in a significant reduction in inflammatory cytokines, as illustrated in figure [ ] . hp using ha combined with pulse hvhf was used to investigate their effect on septic shock patients. fifteen patients were treated with the combined treatment, while the other group received cvvh. in addition, both groups were treated based on the international sepsis guidelines. the cytokine level decreased in both groups; however, it was significant in the combined treatment group, as illustrated in figure [ ] . an st membrane is an acrylonitrile/methallyl sulfonate copolymer membrane that has the ability to remove cytokines. this membrane with continuous hemo- diafiltration (chdf) was used to treat septic shock patients in addition to the conventional treatment according to the surviving sepsis campaign guidelines. the duration of chdf with an st membrane was more than h. the il- level before the initiation of treatment procedure was , pg/ml, and that of lactate was mg/dl. after the treatment, the inflammatory mediators decreased significantly: il- was , mg/ml and lactate was . mg/ml, as demonstrated in figure [ ] . a patient with hemophagocytic lymphohistiocytosis was admitted to the hospital and treated, yet the patient's conditions did not improve and the patient developed ards, aki, and multiple organ dysfunction syndrome that led the patient to be admitted to the icu. the inflammatory mediators were elevated: tnf-α was . pg/ml and interferon-γ was , mg/ml. the patient received at st-chdf that resulted in a reduction in the cytokine level: tnf-α was . pg/ml and interferon-γ was . mg/ml. moreover, the patient's multiple organ dysfunction syndrome condition improved [ ] . coupled plasma filtration adsorption coupled plasma filtration adsorption (cpfa) is a method of extracorporeal filtration that removes plasma from blood, passes the removed plasma into a sorbent, and returns the plasma to blood. the sorbent is nonspecific, where it removes inflammatory mediators from the plasma [ ] . severe sepsis patients with aki were categorized into groups: the cpfa group ( patients) and the control group ( patients). both groups received standard treatment that includes antimicrobials, fluid resuscitation, and vasopressors. the duration of cpfa was h for days. after the treatment procedure, the cytokine levels, such as il- , tnf-α, il- , and il- , decreased significantly in the cpfa group compared to the control group [ ] . severe acute pancreatitis patients (the study group) were treated with a combination of cpfa and cvvh, while the control group received cvvh. there was a significant reduction in inflammatory cytokines with combined treatment compared with the cvvh, as illustrated in figure [ ] . the number of deaths from covid- has increased rapidly, and il- is one of the significant inflammatory factors in cytokine storms, which mainly increases vascular permeability and affects heart function. the authors recommend using blood filtration devices in addition to current treatment to reduce the number of patients admitted to icus. correction to: clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china. intensive care med clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study coronavirus epidemic and extracorporeal therapies in intensive care: si vis pacem para bellum. blood purif correlation analysis between disease severity and inflammation-related parameters in patients with covid- pneumonia. medrxiv immune responses in covid- and potential vaccines: lessons learned from sars and mers epidemic detectable serum sars-cov- viral load (rnaaemia) is closely correlated with drastically elevated interleukin (il- ) level in critically ill covid- patients reduction and functional exhaustion of t cells in patients with coronavirus disease (covid- ) regulation of interferon production as a potential strategy for co-vid- treatment clinical trials on drug repositioning for co-vid- treatment the epidemiology and pathogenesis of coronavirus disease (co-vid- ) outbreak multiscale biofluidic and nanobiotechnology approaches for treating sepsis in extracorporeal circuits cytokine removal with high cut-off membrane: review of literature early report: the use of cytosorb™ haemabsorption column as an adjunct in managing severe sepsis: initial experiences, review and recommendations what have we learned about the use of cytosorb adsorption columns? cytokine reduction in the setting of an ards-associated inflammatory response with multiple organ failure severe myoglobinuric acute kidney injury in a kidney recipient: rapid recovery after hemodialysis with the super high-flux membrane theralite® organ dysfunction during continuous veno-venous high cut-off hemodialysis in patients with septic acute kidney injury: a prospective observational study application of endotoxin and cytokine adsorption haemofilter in septic acute kidney injury due to gram-negative bacterial infection continuous renal replacement therapy with the adsorbing filter oxiris in septic patients: a case series bodelsson m. endotoxin and cytokine reducing properties of the oxiris membrane in patients with septic shock: a randomized crossover double-blind study septic shock due to infected giant venous malformation complicated by massive bleeding continuous renal replacement therapy with a polymethyl methacrylate membrane hemofilter suppresses inflammation in patients after open-heart surgery with cardiopulmonary bypass effect of ha resin-directed hemoadsorption on a porcine acute respiratory distress syndrome model. ann intensive care high-volume hemofiltration plus hemoperfusion for hyperlipidemic severe acute pancreatitis: a controlled pilot study clinical effects of hemoperfusion combined with pulse high-volume hemofiltration on septic shock continuous hemodiafiltration with a cytokine-adsorbing hemofilter in patients with septic shock: a preliminary report successful treatment of fatal macrophage activation syndrome and haemophagocytic lymphohistiocytosis by combination therapy including continuous haemodiafiltration with a cytokine-adsorbing haemofilter (an st) in a patient with systemic lupus erythematosus coupled plasma filtration adsorption: rationale, technical development and early clinical experience lps removal reduces cd -mediated albuminuria in critically ill patients with gram-negative sepsis coupled plasma filtration adsorption combined with continuous veno-venous hemofiltration treatment in patients with severe acute pancreatitis the authors would like to thank the deanship of scientific research, majmaah university for providing support. the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article. the authors extend their appreciation to the deanship of scientific research, majmaah university for supporting this work under project number r- - . conceptualization, m.b.; methodology, k.a.; review and analysis, k.a.; writing -original draft preparation, all authors equally contributed to this; writing -review and editing, m.b. all authors contributed equally to the manuscript and approved submission. key: cord- -djp onk authors: verma, v. r.; saini, a.; gandhi, s.; dash, u.; koya, d. m. s. f. title: projecting demand-supply gap of hospital capacity in india in the face of covid- pandemic using age-structured deterministic seir model date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: djp onk background: due to uncertainties encompassing the transmission dynamics of covid- , mathematical models informing the trajectory of disease are being proposed throughout the world. current pandemic is also characterized by surge in hospitalizations which has overwhelmed even the most resilient health systems. therefore, it is imperative to assess supply side preparedness in tandem with demand projections for comprehensive outlook. objective: hence, we attempted this study to forecast the demand for hospital resources for one year period and correspondingly assessed capacity and tipping points of indian health system to absorb surges in demand due to covid- . methods: we employed age- structured deterministic seir model and modified it to allow for testing and isolation capacity to forecast the demand under varying scenarios. projections for documented cases were made for varying degree of mitigation strategies of a) no-lockdown b) moderate-lockdown c) full-lockdown. correspondingly, data on a) general beds b) icu beds and c) ventilators was collated from various government records. further, we computed the daily turnover of each of these resources which was then adjusted for proportion of cases requiring mild, severe and critical care to arrive at maximum number of covid- cases manageable by health care system of india. findings: our results revealed pervasive deficits in the capacity of public health system to absorb surge in demand during peak of epidemic. also, continuing strict lockdown measures was found to be ineffective in suppressing total infections significantly, rather would only push the peak by a month. however, augmented testing of , tests per day during peak (mid-july) under moderate lockdown scenario would lead to more reported cases ( , , - , , ), leading to surge in demand for hospital resources. a minimum allocation of % public resources and % private resources would be required to commensurate with demand under that scenario. however, if the testing capacity is limited by , tests per day under same scenario, documented cases would plummet by half. coronavirus disease (covid- ) is a contagious disease caused by a novel strain of coronavirus (sars-cov- ) which was first informed as the cluster of viral pneumonia cases of unknown etiology detected in wuhan city, hubei province, china. coronaviruses are enveloped, positive single-stranded large rna virus that infect humans, but also a wide range of animals ( ) . amongst humans, they have known to cause myriad of illness with varying degree of severity ranging from relatively benign common cold to more severe forms like sars (severe acute respiratory syndrome) and mers (middle east respiratory syndrome). however, illness onset among rapidly increasing number of people and mounting evidence human-to-human transmission suggests that sars-cov- is more contagious than its predecessors ( ) . following the outbreak of covid- , the who emergency committee declared it a global health emergency on january , and a pandemic on march , . within a short span of time, a localized outbreak evolved into pandemic with three defining characteristics: a) speed and scale-the disease has spread quickly to all corners of the world, and its capacity for explosive spread has overwhelmed even the most resilient health systems b) severity-overall, % cases are severe or critical, with a crude clinical case fatality rate currently of over %, increasing in older age groups and in those with certain underlying conditions c) societal and economic disruption-shocks to health and social care systems and measures taken to control transmission having deep socio-economic consequences ( ) . currently, approximately , , confirmed cases of covid- has been reported including an estimated , deaths in countries and territories as on may , . around three months have elapsed since the first case of covid- was reported in india on january , . since then, the number of cases have surged to , with , deaths as on may , . as part of the pandemic preparedness, in the absence of vaccines or antivirals, india adapted gamut of nonpharmaceutical interventions such as lockdown, quarantining and tracing and testing concomitantly to alter the trajectory of pandemic. these interventions encompassed two types of strategies a) suppression, which aims to reverse epidemic growth, by minimizing the effective reproduction number (average number of secondary cases each case generates), r, to below and thus, reduce case numbers to low levels and maintaining that indefinitely b) mitigation, which aims to slow the spread of epidemic with the rationale of preventing significant overload on health system and gradually allowing the population to develop herd immunity ( ) . who enforced a binding instrument of international health regulation (ihr) in to prevent, detect and respond to public health emergencies. the ihr monitoring and evaluation framework includes state party annual reporting tool (spar) which underscores capacity indicators to gauge the preparedness of nations to mitigate the effect of public health emergencies, including the emergence of novel pathogen (who, ) . in , although india's spar composite score ( . ) was above the international average ( . ), albeit, the scores for indicators pertaining to health service provisioning and laboratory capacity were incongruous as india had only half the average readiness in these indicators as compared to international scores. therefore, it is imperative to unravel the supply side readiness especially, with regards to infrastructural capacity of india to handle the surge of hospitalization cases. demand for hospitalization services for covid- can be estimated by analyzing the interface between transmission curve, age-structure, contact patterns and morbidity status of population. disease progression is characterized by myriad of uncertainties and the trajectory of an epidemic is defined by some key factors and parameters. specifically, for a novel infection whose disease dynamics are still unclear, mathematical models are thus, pertinent to understand the mechanics of transmission. deterministic compartmental models such as susceptible-exposed-infectious and recovered (seir) are widely used to provide insight into disease progression and can be chosen over complex models due to minimum number of assumptions. yet, there is a caveat in using the baseline seir model as it doesn't incorporate the testing capacity in the model which punctuates the dynamics in two ways. firstly, in basic model, the undetected yet infectious individuals are not accounted in determining probability of infection and potential transmissibility and secondly, there's reduced transmissibility from confirmed positive cases which no longer transmit the disease once they are tested and isolated. modelling exercises allowing for testing and isolation capacity and undetected cases are rather scarce. further, covid- has differential impact on different age groups and additionally, heterogeneities in contact networks have a major effect in determining whether pathogen can become epidemic or persist at endemic levels. consequently, mathematical models of disease transmission incorporating age and social contact structures are more congruous to the reality. therefore, in this study we have attempted the short and long term prediction of transmission of covid- using age-structured compartment based model allowing heterogeneities in contact networks and simulating for varying assumptions and scenarios around containment and mitigation strategies. drawing from international experience and literature on covid- , we determined the proportion of high-risk population with underlying conditions in india who are more vulnerable to progress into severe condition upon infection that can guide triage and targeted intervention decisions. further, we assessed the capacity and tipping points of indian health system to absorb surges in the number of people that will need hospitalization and critical care because of covid- based on varying scenarios. the objectives of the study can be elucidated as follows: -a) estimate the projected demand for hospital resources under various mitigation strategies of reduced social mixing and varying levels of testing capacity in india. b) analyze the hospital surge capacity of the indian health system to absorb the surge in demand under different scenarios. the spread of any virus is incumbent upon the infectivity of pathogen and the pool of susceptible population. we formulated the transmission dynamics model for the outbreak of covid- in a heterogeneously mixing population. compartmental disease models divide population into groups (or compartments) based on each individual's infection status and track the corresponding population sizes through time. seir model in which the population was divided according to infection status into susceptible(s), exposed (e), infected (i) and removed(r) was employed in the study. susceptible individuals become infected at a given rate when they interact/contact with an infectious person and enter the exposed state. these exposed pool transition to infectious state after a latency period and later either recover or die. however, it is crucial to consider host age structure to enable realistic modelling for disease prevention policy. also, the spread of an infectious disease is sensitive to the contact patterns in the population as person-to-person transmission is largely driven by who interacts with whom. the agespecific mixing patterns of individuals in age group i alter their likelihood of being exposed to the virus given the extent of infections in the group. the assumption of homogenously mixing population can lead to an overestimation of the final epidemic size and magnitude of interventions needed to stop an epidemic ( ) . contrarily, including contact patterns that vary across age and locations (e.g. home, work, and schools) as predictors in transmission dynamic model improves the model's realism. thus, we investigated the impact that different mixing assumptions have on the spread of covid- in an age structured seir model with infectivity in both latent and infectious period described by a system of ordinary differential equations. our model incorporates two sections as illustrated in figure where left part represents the classic seir model with additional post latency node accounting for infections in the terminal stage of incubation period. the transmission dynamics is further branched out into asymptomatic, symptomatic, severe and critical on the right-hand side constrained by the testing coverage. following equations represents the dynamics of the model. where β' is the probability of infection upon contact with infectious people, n is the total number of considered age groups, cij is the number of age wise interaction between infectious and susceptible population. where si, ei, li, ii and rui are the susceptible, exposed, post latency, infectious and undocumented recovered group of people of age group i. rate constant k = t_latency is defined by time from exposure to onset of infectiousness (latent period), k ' and k ' are rate for testing, k is defined by part of incubation time after latent period and k is rate at which undocumented infectious people recover or die. documented cases in the model are determined and constrained by the testing. positive cases can be presymptomatic, symptomatic and asymptomatic. pre-symptomatic and symptomatic may progress to severe and critical state before either recovery or death. whereas true asymptomatic positives recover without exhibiting any symptoms over the course of illness. where tpi is tested positive, asi is asymptomatic, ssi is symptomatic, svi is severe, cri is critical, di is dead and rdi is documented recovered for age group i. rates of progression are given as follows . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . to account for the mitigation factor such as social distancing, the contact matrix is divided into household contacts, workplace contacts, school contacts and other contacts using the following form where tw, ts and to can range from to allowing various degree of interactions of contacts delineating the impact of same on progression of the epidemic. main parameters of the model are surmised in table which were extracted/estimated from various sources. population age distribution for india was obtained from website of population pyramid ( ) and social contact matrices were adapted from state-of-the-art compilation by prem et. al in which matrices were projected by bayesian hierarchical model for countries using contact surveys and demographic data ( ) .time parameters were extracted from a recently published systematic review which synthesized parameters using meta-analysis of studies on covid- ( ) . further, age-distributed data from u.s. was used to estimate the epidemiological parameters in the study. as reported in table , age wise fractions of transition from one state to another and case fatality ratio (cfr) was calculated from the report published by u.s. center for disease control ( ), as currently in india (as of nd may), cfr is analogous to that of usa when cdc carried out the study. also, we collated the data on confirmed positive cases, hospitalizations, recovery and deaths from publicly available time series data of usa published by u.s. cdc ( ) to estimate the probability of infection β'. remaining model parameters such as latency rate, testing rate and rate of recovery/death were estimated using crowdsourced indian data ( ) from th march till nd may, while incorporating mitigation strategies of lockdown starting from th march to rd may and current social distancing guidelines based on the zones which is issued by indian government starting from rd may to th may. three scenarios of mitigation measures were modeled -(a) full lockdown (assuming closure of schools, workplace and community spaces and doubling of contacts in households) (b) social distancing measures and moderate lockdown (assuming closure of schools, staggered opening of workplace and community spaces with half strength and social distancing of vulnerable population including aged above years and people with at-least one underlying high risk chronic condition with % compliance) post th may, and (c) no lockdown (assuming % contacts in schools, workplace, community spaces and households). the model is augmented to incorporate the testing coverage and test to positive (ttp) ratio of % till may nd in india. the underlying set of assumptions characterizing the transmission dynamics are elucidated as followsi) india was assumed to be a closed system with constant population size of . billion (s+e+l+i+r= . billion) throughout the course of epidemic. ii) different inflows and outflows and imbalance by demographics, migration etc. is not considered. iii) seasonal effects, weather conditions like temperature and humidity and mutations not included in the model. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint iv) heterogeneous mixing in the contact networks is assumed and interactions at four spheres are considered: home, work, school and other locations. v) infectivity from latency period is considered, a latent individual can transmit the disease to the susceptible, i.e., individual has force of infection in both latent and infectious period. vi) asymptomatic transmission from truly asymptomatic cases is accounted in the model. vii) positively diagnosed cases are documented and isolated from rest of the susceptible pool, thus, less likely to spread the infection. viii) the recovered individuals develop the immunity and do not revert back to the susceptible pool. multi country evidence suggest that there are certain underlying conditions most associated with severe and critical cases of covid- . in conjunction with elderly, younger and working population group with chronic health conditions are also vulnerable and can be classified as high risk for developing complications. u.s. center for disease control and prevention in its morbidity and mortality weekly report ( )divulged that as of march , , % hospitalized non-icu cases and % icu cases had one or more precondition. similarly, evidence from italy ( ) affirmed that in a sample of deaths in italy, . % patients had some pre-condition(s). overall, among dead, . % had single disease, . % had diseases and . % had or more underlying diseases in italy. therefore, analyzing the prevalence of highrisk underlying condition associated with covid- is germane to understand the progression of cases from mild to severe/critical stage and identify the vulnerable population to design more effective interventions. hence, we used the information on burden of chronic diseases from a study conducted by london school of hygiene and tropical medicine ( ) therefore, we used the information on prevalence of these underlying conditions in india (table ) by culling out information from above-mentioned study to estimate proportion of population with at-least one underlying condition. data on indian health infrastructure was coalesced from different sources. information on beds in public hospitals (phc+chc+dh) and medical college hospitals was extracted from national health profile, ( ) . however, there was missing information in this data source for some states and colleges, which was then scrapped individually from websites of the colleges. beds under ayush, defense, railways and esi corporation are also incorporated in the analysis as india is likely to rope in beds from these institutions during surge in demand. the data for bed availability in these institutions was taken from national health profile, ( ) . further, due to absence of veritable data available on private sector, approximations using utilization rates for hospitalizations in private hospitals from recently released national sample survey organization th round ( ) was used and crude estimations were made based on proportion of . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint inpatients treated in private hospitals. further, there is major lacunae in credible data availability for icu beds and ventilators required for critical care. henceforth, another assumption was made that only % of total beds are icu beds and % icu beds are equipped with ventilators in india. health system's capacity to accomodate the increasing number of covid- patients was computed using an open access tool developed by giannakeas et al ( ) ( ) . this tool enables the modelling of steady state patient flow dynamics that can guide the tipping point of health care system in terms of the availability of hospital beds, icu beds and mechanical ventilators. entire dynamics of supply side readiness is explained in figure . the left-hand panel in the figure is representative of the current health capacity with total number of hospital beds, icu beds and ventilators. average length of stay determining the daily turnover rates for mild, severe and critical cases were set as . days, . days and . days respectively (parameter values from model). using population-weighted age-stratified probabilities, number of cases requiring hospital beds, icu beds and ventilators was estimated. further, the daily turnover of each of these resources was measured by dividing the number of available resources with average length of stay for that resource. thereafter, the daily turnover rates were divided by the proportion of cases requiring mild, severe and critical care to arrive at the maximum number of covid cases manageable by health care system of india. three distinct cases based on the allocation of resources were made to discern the surge capacity for each of these cases. in all three cases, we assumed that public health facilities dedicate fixed % of their hospital beds, icu beds and ventilators for covid- patients since existing bed occupancy rate of public hospitals in india is around % ( ) . however, for private sector hospitals, varied assumptions pertaining to allocation was made. under case , the provision of private infrastructure was assumed to be . whereas, the allocation of hospital beds, icu beds and ventilators in private hospitals was % under case and further expanded to % under case- main findings of the study are presented in this section. figure encapsulates various transmission curves under the scenario of ramping up of testing coverage (number of individuals tested daily) and increased ttp from % to % when the pandemic reaches final stage of community transmission. the impact of other non -pharmaceutical interventions like social distancing and lockdown is also explicated in the figure. while the lockdown was effective in slowing down the infection rate and shifting the peak to later months of the year , it perpetuated heavy socio-economic costs in india. therefore, it is pertinent to compare how continuing with moderate lockdown or lifting the restrictions completely would impact the number and spread of total covid- cases in india. the detailed representation of our modelling results is exhibited in figure . our modelling exercise revealed that with the current testing rate of , individuals tested daily on an average in india from th march, till nd may and % ttp ratio, the estimated total documented covid- infections in india would not exhibit any significant difference ( , to , in an year) across the scenarios of no lockdown, full lockdown and moderate lockdown guidelines. lifting the lockdown completely after th may would hasten the surge in demand to th july as compared to rd august if the full lockdown . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . continues for one year. although, moderate lockdown would push the peak to early august, total number of infections will not plummet by this intervention. current ttp ratio in india is around % which is exiguous as compared to ttp in usa of %. there could be plethora of reasons for low ttp in india such as absence of widespread-community spread, untargeted testing or less sensitivity of diagnostic kits. however, we estimated the number of total infections and peak time for surge in demand for expanded testing coverage of , and , tests per day at current % ttp as well as for % ttp modelling for worst case scenario. assuming no/limited community spread with ttp of % and augmenting the testing to , , in the absence of lockdown, our model estimated the peak to be around mid-july with total documented cases ranging from , to , during peak time. however, continuing moderate lockdown (with % contacts in schools, workplaces and others), estimated number of documented cases would be around , at the peak time of th july. with this increased testing of , individuals per day, surge in demand would be highest (~ , , ) if stringent lockdown measures are imposed after th may. this is because complete lockdown will delay the overall community spread and more people will be diagnosed and tested positive during peak time. under the worst case scenario of widespread community spread in india with ttp of %, peak will be witnessed around early july to mid-august . total documented infections under moderate lockdown scenario will range from , , to , , around rd july if , individuals are tested daily. however the total documented infections will increase with higher testing rate of , individual per day ranging from , , to , , cases around peak time on th july. in a no lockdown situation during worst case scenario with ttp %, number of cases will peak a week ahead around th july with similar number of infected cases in moderate lockdown. our analysis indicated paucity of resources in india to handle surge in demand during the peak time for both mild infections and severe cases. the capacity of indian healthcare system to absorb increases in caseload is constrained by availability of beds and ventilators. india has a total (public +private) bed capacity of , , which can be allocated for covid- infections according to existing bed occupancy rate and government guidelines. the availability of health care infrastructure which is collected from multiple sources is presented in table . according to case- where no allocation is made by private sector and only % resources are dedicated in public infrastructure, actual availability of hospital beds, icu beds and ventilators is , , , and , respectively. the estimated inflow/outflow of mild, severe and critical cases per day are , and . under this scenario, india has the capacity to accommodate only , mild cases, , severe and critical new covid cases every day. however, leveraging upon expansive private health care system in india can bolster the capacity. the tipping point for beds and ventilators increases significantly when % (case ) and % (case ) private health care resources were assumed to earmarked to accommodate covid- patients. for example, under case- , we found that the surge capacity of health system for mild, severe and critical care is distinctly higher than case as can be seen in figure and figure . moreover, when the allocation of private infrastructure increases by %, the capacity to manage new covid cases doubles. we computed the surge capacity, which is determined by trajectory of cases and infrastructure dedicated to covid- patients by accessing the time period around which indian hospitals will face serious crisis in terms of availability of beds and ventilators. the demand-supply gap during peak time if the moderate lockdown is continued after th may for mild, severe and critical cases is presented in the form of heat map ( figure ). green coloured boxes are indicative of the availability of infrastructure during peak time in respective scenarios, whereas non-green coloured boxes suggest the extent of health infrastructure that has to be upgraded to meet the real demand during peak time. as mentioned earlier, surge capacity is likely to vary across different testing scenarios. for example, when the partial lockdown is considered with increased testing coverage of , and , per day and ttp of %, our demand and supply side projections indicate that the indian health care system is likely to face a huge deficit in terms of the availability of health care infrastructure, especially for severe and critical case. assuming the community spread and scaling up of testing to , tests per day with ttp of %, under case- , india will have to increase the availability of icu beds by more than five times ( %) and availability of ventilators by . times( %) before th july . however, under current scenario where ttp is %, if we increase testing to , cases per day, we will have to ramp up the availability of icu beds by . % and ventilators by . % before th july . under case- , where % of capacity in public facilities and % in private facilities is apportioned for covid- , and testing coverage is , per day with ttp of %, the estimated demand for severe and critical cases can only be met if supply of icu beds and ventilators is increased by . % and . % before th july . however, increasing the testing even further to , , number of icu beds must double, and supply of ventilators must be increased by . % before th july. therefore, necessary steps must be made to include private-sector hospitals in the treatment of covid- patients in order to be prepared for the widespread community transmission and increase in detected cases due to aggressive testing. time to surge in capacity or tipping point will occur much earlier than the peak. hence, this analysis delineates an urgent need of procuring the ventilators and upgrading the capacity in this months window. our study calibrated the model to preliminary data arising from outbreak in india in order to project the demand for hospital resources under three transmission curve scenarios: no lockdown, moderate lockdown and full lockdown across varying testing coverage. we also evaluated the extent to which the full lockdown and moderate lockdown delays the peak of outbreak, thereby, prolonging the window of time to augment the health-system capacity in order to accommodate the surge in demand during peak period. our analysis of indian healthcare system's preparedness to absorb surges for infected cases exhibited pervasive deficits. there was a substantial variation in tipping points of supply side capacity across the assumptions on resource allocation in private sector to accommodate covid- patients. one of the important finding of our analysis is relative ineffectiveness of further extending the strict lockdown measures, as full lockdown is likely to push the surge in demand for hospital resources by a month without suppressing the total number of cases significantly. india was amongst the countries to implement lockdown early with highest stringency in the world which is also indicated by the stringency index of lockdown ( % for india) prepared by university of oxford ( ) . due to the high costs of lockdowns, there's a policy conundrum if the countries should quarantine everyone at a large social cost or test everyone and apply quarantine in a more directed fashion. the increase in documented cases with augmented testing in our study suggests that lockdown should be replaced gradually with more thrust on public health intervention of testing, tracing and isolating in conjunction with surveillance and real time data. more targeted sequestering of infected case(both symptomatic and asymptomatic) aided with increased random testing, along-with the social distancing measures for containment zones with higher incidence of cases and isolating vulnerable with underlying conditions and aged population is recommended rather than stringent lockdown in order to prevent the negative shock from deepening further. our analysis underscored the absence of surge capacity for severe and critical cases under all of the transmission and testing scenario. there is some capacity available for mild cases, provided documented cases are constrained by testing capacity, albeit, in an event of expanded testing and community transmission, mild cases will also be subjected to deficit of beds. the shortage of beds for even mild and asymptomatic cases can be corroborated with the recent reports from indian cities of chennai ( ) and mumbai ( ) where government hospitals are running out of beds due to explosion of cases. many countries are resorting to home isolation of mild and asymptomatic cases, a measure which union health ministry of indian government has also announced recently. however, we recommend to ramp up institutional capacity to isolate infected cases under institutional care as india's congested housing conditions are not conducive to quarantining at home. the national sample survey office data ( ) reveals that for % indians, per capita space available is less than a single room leading to unprecedented challenges for effective home isolation. our model didn't consider the potential staff shortages in transmission dynamics and capacity readiness due to uncertainty around their predictions and unavailability of quality data. age-distributed data on severe, critical and recovered cases is rather sparse in india, therefore, we adapted/estimated some parameters from detailed data released by other countries. modelling is rather a necessary input to guide policy decisions, however, a more comprehensive approach incorporating stakeholder's analysis, case studies and triangulating information across multitude of sources should be adapted for nuanced decision making. the study can be further extended to map the geographical accessibility of facilities providing covid- care, specifically spatial accessibility for critical care needs to be explored. also, rapid health facility assessments for covid- preparedness unravelling mean availability of tracer items for emergency response should be conducted for targeted interventions at hospital level. finally, study can be extended at more granular level to inform demand-supply gap so that resources can be mobilized in commensuration with demand at more local level, thereby enabling local government systems to combat covid- in india. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . the covid- epidemic method study design [internet]. cdn.onb.it mise à jour de la stratégie covid- impact of non-pharmaceutical interventions (npis) to reduce covid mortality and healthcare demand mathematical models of mixing patterns between age groups for predicting the spread of infectious diseases. pdfs.semanticscholar.org [internet projecting social contact matrices in countries using contact surveys and demographic data epidemiological characteristics of covid- ; a systemic review and meta-analysis . medrxiv.org [internet preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease -united states covid- india tracker case-fatality rate and characteristics of patients dying in relation to covid- in italy. jamanetwork how many are at increased risk of severe covid- disease? rapid global, regional and national estimates for . medrxiv.org [internet directorate general of health services m of h and fw. national health profile directorate general of health services m of h and fw estimating the maximum capacity of covid- cases manageable per day given a health care system's constrained resources utilization pattern and financing of public hospitals: a report ^ variation in government responses to covid- bed-medical-personnel-shortage-as-cases-rise/story/ .html . ministry of statstics and programme implementation. drinking water, sanitation, hygiene and housing condition in india updated rapid risk assessment from ecdc on the novel coronavirus disease (covid- ) pandemic: increased transmission in the eu/eea and the uk. ncbi.nlm.nih.gov key: cord- -h dsnex authors: kulkarni, sagar title: the bone prone team date: - - journal: j clin orthop trauma doi: . /j.jcot. . . sha: doc_id: cord_uid: h dsnex when the covid- pandemic arrived in the united kingdom, elective orthopaedics was halted. this article tells the tale of the orthopaedic surgeons who rose to the challenge of helping to treat coronavirus patients on the intensive care unit. authors: sagar kulkarni i recall the first time we called the orthopaedic surgeons for assistance. a lone, lumbering orthopaedic consultant arrived, his eyebrows slightly furrowed, unsure of what was about to happen. he looked around the icu, at the ventilators, the invasive blood pressure monitoring equipment and the infusion pumps. like a boy on his first day at school, he was thrust into an unfamiliar environment. initially, proning was haphazard. the icu would bleep a surgeon to request help with proning, only to find out that the surgeon was occupied. once, an orthopaedic surgeon attended the icu after a challenging trauma case, asking, "i got bleeped two hours ago; is everything okay? do you need my help?" some would say he was late, but his enthusiasm to help us was undeniable. quickly, however, they learned, morphing into a highly efficient proning team. with typical orthopaedic precision, proning would happen on a schedule -every day, the bone prone team, composed of several consultants, registrars and senior house officers, would attend the icu at am and pm, ready to prone. additionally, if proning was needed at any other time, we would bleep the orthopaedic registrar, who would immediately send their consultant (sometimes multiple consultants) to prone. one morning, the bone prone team attended the icu, like a sports team descending from a tour bus. amidst chatter of tendons and joints, one of them called out, "we're ready when you are!" as i was donning my personal protective equipment (ppe), i saw mr jones (not his real name), one of the senior surgeons, approach me. i wondered whether he was about to scold me for doing something wrong. to my surprise, he said, "shall i do up your gown?" "oh, that'd be great, thanks." i replied, surprised at this out-of-character offer. once we (the icu and orthopaedic teams) had all donned our ppe, we entered the unit together. mr jones grabbed the pre-proning checklist and assumed his position. "you take the left, i'll take the right. ready, steady, slide!" in a fluid motion, we proned the patient, like synchronised skaters. that day, we had a good round of proning, successfully flipping four patients. six weeks later, all patients who were proned on that day survived icu. we thanked the orthopaedic team for their help, to which one of their number responded, "we aren't the heavy-lifters here -you are." as time went on, proning became a communal activity in the hospital. at our scheduled proning times, doctors from emergency medicine, haematology and surgery rubbed shoulders to prone, for the benefit of the patient. at times, we had too many hands on deck, and had to turn people away. when asked why they wanted to join in, they all had the same response, "it's the least i can do to help." by late april, our caseload began to decline, and proning was needed less frequently. eventually, the bone prone team was disbanded, its cause now defunct. however, the camaraderie behind it still persists. to me, proning came to symbolise our struggle against coronavirus -the doctors of my hospital, and indeed the nation, came together to defeat a common enemy. the covid- pandemic brought about a new sense of unity in the national health service (nhs). hospital hostilities became collegial; expanded wellbeing services were offered to staff; and clinicians, like the orthopaedic surgeons, stepped into unfamiliar territory for the greater good. as the number of coronavirus patients wanes and we begin our return to normality, one can only hope that this spirit of kindness, generosity and teamwork will persist in the nhs. orthopaedic surgeons: as strong as an ox and almost twice as clever? multicentre prospective comparative study key: cord- -do i ymq authors: banu, buyukaydin title: pneumonia date: - - journal: encyclopedia of biomedical gerontology doi: . /b - - - - . - sha: doc_id: cord_uid: do i ymq pneumonia remains the main cause of morbidity and mortality from infectious diseases in the world. the important reason for the increased global mortality is the impact of pneumonia on chronic diseases especially in the elderly population and the virulence factors of the causative microorganisms. because elderly individuals present with comorbidities, particular attention should be paid for multidrug-resistant pathogens. streptococcus pneumoniae remains the most frequently encountered pathogen. enteric gram-negative rods, as well as anaerobes, should be considered in patients with aspiration pneumonia. interventions for modifiable risk factors will reduce the risk of this infection. the adequacy of the initial antimicrobial therapy and determination of patients’ follow-up place is a key factor for prognosis. also, vaccination is one of the most important preventive measures. in this section it was focused on several aspects, including the atypical presentation of pneumonia in the elderly, the methods to evaluate the severity of illness, the appropriate take care place and the management with prevention strategies. pneumonia is defined as an acute respiratory infection that affects lung parenchyma. despite the availability of antibiotic therapy and severity of illness assessments, pneumonia continues to be a leading cause of death worldwide. in the elderly population, the impact of pneumonia is greater than in other age groups. the mechanisms that increase the incidence and mortality rates in elderly pneumonia patients are not fully understood. the immunological changes that called immunosenescence are known to be responsible for the increased sensitivity of elderly people to infection diseases. the world population reached . billion and the people years and over amounted % of the total, million according to data united nations world population prospects (kaplan et al., ) . the annual incidence of pneumonia in the elderly is fourtimes that of the younger population. older adults have also higher rates of hospitalization and mortality (chong and street, ) . therefore, a better understanding of the pathophysiology, microbiology, treatment, and prevention of this common affliction is required. for proper diagnosis and treatment advice, pneumonia is classified as community-acquired pneumonia (cap), hospital-acquired pneumonia (hap), and ventilator-associated pneumonia (vap) along with the recent guidelines. in this section, the most recent data regarding the epidemiology, microbiology, diagnosis, classification, treatment, and prevention strategies are presented. the incidence of pneumonia varies according to geographical location, healthcare setting, and population. including pneumonia, lower respiratory tract infections are the fourth most common cause of death all over the world. in a study carried out in the us, the annual incidence of pneumonia was observed as . cases/ , adults, with the highest rates among adults between and years of age; . cases/ , adults and in patients up to years old; . cases/ adults (konomura et al., ) . in terms of economic impact, two studies carried out in the netherlands and japan, sustained remarkable results. the majority of cap episodes ( %) occurred among patients years and older and these episodes incurred % of the costs. the second study included , patients with cap aged years and over and reported median treatment costs of us$ per outpatient cap and us$ per hospitalized cap (klausen et al., ; kothe et al., ) . mortality in elderly patients may be % higher than in the general population ( %). in this population group, hospitalization rates are five times more likely than other patients' groups also (chong and street, ) . because of these negative impacts, several studies have attempted to identify risk factors. a population-based cohort study with , elderly patients found that immunosuppression, copd, smoking, congestive heart failure, diabetes, malignancy, and previous hospitalizations for pneumonia are independent risk factors for developing the disease in this age group (barlow et al., ) . for mortality risk, available data is useful. comorbid illness (including cerebrovascular disease, congestive heart failure, and chronic liver disease), higher infection activity index and ineffective therapy were presented along with higher mortality risk in elderly. other factors linked to increased mortality are accepted as bedridden status, delirium, the absence of fever, tachypnea, c-reactive protein levels greater than mg/l, hypoalbuminemia, acute organ failure, suspicion of aspiration and swallowing disorders (centers for disease control and prevention (cdc), ). identifying the causative agent can be useful for guiding antimicrobial therapy. although the microbiological diagnosis is fundamental to ensure appropriate therapy, it is achieved in less than % of the cases. in order to avoid the delaying that associated with increased mortality, antimicrobial therapy should be administered empirically. pathogens associated with communityacquired pneumonia in elderly patients are presented in table . in this age group, the possibility of obtaining a diagnostic sputum sample has been very low. causative organisms are only identified in %- % of the cases. globally s. pneumoniae is accepted as being the most common pathogen. also in elderly, this microorganism remains the single most common organism identified in hospitalized patients. the diagnosis of pneumococcal pneumonia has increased in recent years, due to the introduction of the pneumococcal urine antigen test. but the incidence has probably decreased because of pneumococcal vaccines along with the decreased rate of smoking (garcia vidal et al., ) . the differences in the chemical and antigenic composition of the pneumococcal capsule result in different serotypes. serotype is the most common serotype associated with adult pneumococcal infection and with septic shock (cilloniz et al., ) . haemophilus influenzae was also frequently isolated accounting for %- % in elderly. in patients with chronic obstructive lung disease, infection with this organism may be more common. moraxella catarrhalis and staphylococcus aureus (methicillin sensitive) have also been described as pathogens, with frequencies % and %, respectively (cdc, ) . intracellular pathogens are one of the other frequent microorganisms (donowitz and cox, ) . the incidence is variable depending on the difficulties with microbiological cultures. they grow poorly in standard culture media and performing additional serologic tests on all patients is not common practice. legionella pneumophila, mycoplasma pneumoniae, chlamydophila pneumoniae, chlamydophila psittaci, and coxiella burnetii are the well-established intracellular pathogens. no clinical features exist that make it possible to distinguish intracellular pathogens from classical ones. but extra-pulmonary manifestations are often associated with intracellular pathogens. severe pneumonia caused by these pathogens accounts for %- % of the cases. the major problem with these pathogens is that most antibiotics are unable to access intracellular spaces and to reach the optimal therapeutic concentrations is difficult. in those aged over years, the atypical organisms are less frequently encountered but play a significant role in the clinical spectrum (macfarlane et al., ) . chlamydophila pneumoniae is the most common, with rates of %- %, mycoplasma pneumoniae is less frequently encountered ( %- %) and coxiella burnetii is a rare causative agent in elderly (cdc, ) . although legionella pneumophila is relatively uncommon in the elderly, it should be considered presenting with atypical symptoms for example, headache, altered mental status, gastrointestinal signs or bradycardia (ruuskanen et al., ) . it appears to be reasonable to exclude this bacteria with urinary antigen testing in all elderly patients with pneumonia before atypical coverage is discontinued. infections with gram-negative bacteria are often related to comorbid illnesses. excluding nursing-home residents and hospitalized patients, these infections are infrequent in the elderly. but in severely debilitated or chronically ill elderly patients from the community, especially in those who fail to improve on standard therapy, a high index of suspicion may be warranted for this bacteria (cdc, ) . among other pathogens, respiratory viruses are considered responsible in one-third of the cases. influenza viruses (a and b), respiratory syncytial virus (rsv), parainfluenza viruses , , , coronaviruses and rhinoviruses, are the most commonly encountered ones. it is estimated that million cases of viral pneumonia occur annually (ruuskanen et al., ) . influenza virus (a and b) is usually selflimiting, but severe complications like pneumonia can occur especially in high-risk patients like elderly with comorbidities along with increased mortality risk. routine influenza screening appears reasonable in an elderly presenting with pneumonia-like complaints, but the sensitivity of available screening tests is poor and treatment decisions should not be based only the results of rapid flu testing. aspiration pneumonia is another common cause of cap. the most frequent microorganisms are anaerobic bacteria and microaerophilic streptococci from the oral flora. aspiration pneumonia may be the second most common etiology of cap in patients years and older (teramoto et al., ) . approximately % of the cap cases, a multidrug-resistant (mdr)-resistant to more than three classes of antibiotics-pathogen is an agent that most frequently being s. aureus and p. aeruginosa. in a recent european study, mdr pathogens were presented as . % of the . % cap cases with most commonly presented with methicillin-resistant s. aureus (mrsa) . community-associated methicillin-resistant s. aureus (ca-mrsa) raises concern for infection in elderly adults. the production of the toxin panton-valentine leukocidin (pvl) is the main characteristic of ca-mrsa. this toxin causes leukocyte destruction and tissue necrosis. in elderly, ca-mrsa should be considered in presentation with influenza, such as prodromes, skin lesions, cavitary infiltrates, hemoptysis or rapidly progressing pneumonia. table pathogens associated with community-acquired pneumonia in elderly patients pseudomonas aeruginosa endemic and opportunistic infections p. aeruginosa is not a frequent pathogen in the cap but severe cap requiring intensive care unit (icu) admission it was the causative agent in . %- . % of the cases with the mortality rate of between % and % (yoshimoto et al., ) . prior antibiotic treatment is the only risk factor associated with cap caused by mdr p. aeruginosa. also, s. pneumoniae has increased its resistance to several antibiotics (cephalosporins, macrolides, and fluoroquinolones) in the last two decades. between % and % of pneumococcus disease cases worldwide have mdr pattern. nevertheless, the therapeutic failure involving b-lactams has not been reported because of pharmacodynamic properties (draghi et al., ) . hap is defined as pneumonia occurring h or more after hospital admission. vap is defined as pneumonia occurring > h after endotracheal intubation. hap is the second most frequent nosocomial infection and is considered the main cause of mortality for nosocomial infections. vap is considered the main nosocomial infection in the icu. hap is divided into two groups according to the time of onset from admission. early onset is defined when pneumonia development within the first days of hospitalization. this presentation is associated with better clinical prognosis. late onset is defined when pneumonia occurs after days of hospitalization. the recently published guidelines propose that the presence of risk factors for mdr should take precedence rather than early or late onset pneumonia distinction (kalil et al., ) . the top six pathogens causing % of the hap cases are s. aureus, p. aeruginosa, klebsiella spp., escherichia coli, acinetobacter spp., and enterobacter spp. ( table ) . gram-negative bacteria are the major agent with %- % for hap cases in icu. the most frequent pathogens include p. aeruginosa, a. baumannii, h. influenzae, and enterobacteriaceae spp. (k. pneumoniae, e. coli, enterobacter species, serratia species, proteus species, etc.). the mortality increase to % with advanced age, increased disease score and inadequate initial antimicrobial treatment. an independent factor for predicting the mortality is the using of vasopressors in the case of vap where p. aeruginosa is isolated (micek et al., ) . gram-positive pathogens account for %- % of hap cases. the most frequent microorganisms; methicillin-resistant and methicillin-sensitive s. aureus, s. pneumonia, and streptococcus spp. pneumonia caused by more than two pathogenic microorganisms is defined as a polymicrobial infection. approximately %- % of vap cases are considered to have polymicrobial etiology. polymicrobial etiology generally did not influence the outcome when empiric antibiotic treatment was appropriate. mdr pathogens are a major problem for this group of patients. the clinical practice guidelines summarize the following risk factors for mdr (weiskopf et al., elderly persons suffer from a variety of comorbidities. associated factors predisposing patients to develop pneumonia are presented in table . also, multimorbidity was associated with death, hospitalization or return to the emergency department within days of discharge. in a recent study % of the cases presented with at least one comorbidity according to the aging group: - years old, . %; - years old, . % and > years old, . %.the most frequent comorbidity was presented as chronic pulmonary disease. because of immunosenescence in elderly, the risk of misdiagnosis or delayed diagnosis is more frequent. specific symptoms of pulmonary infection such as a cough, sputum, fever, chills, and chest pains may not be available. the complaints must be taken care of are altered mental status (i.e., delirium), falls, fatigue, lethargy, delirium, anorexia, tachypnea, tachycardia, and, less commonly, pleuritic pain, cough, and fever (rockwood et al., ) . in elderly, pneumonia sometimes presents as an exacerbation or decompensation of previous comorbidities and also % of the cases the radiographic findings are inconclusive or difficult to interpret. many biomarkers of infection such as leukocyte count, c-reactive protein (crp), procalcitonin have been found to play a role in the early diagnosis, but in elderly with cap, the reliability on these biomarkers is limited (liu et al., ) . all patients should be screened by pulse oximetry, for unsuspected hypoxemia in patients with diagnosed pneumonia or to determine the presence of pneumonia without obvious signs. since the microbiological diagnosis of pneumonia is important for a better clinical outcome, to follow national and international guidelines is recommended. these recommendations regarding samples and diagnostic tests are presented in table . clinical indications for more extensive diagnostic testing should be decided on a clinical basis ( table ) . some etiologic diagnoses have important epidemiologic implications and agents that should be reported to public health officials vary according to countries. in general, legionnaires disease, sars (severe acute respiratory syndrome) psittacosis, avian influenza (h n ), and possible agents of bioterrorism (plague, tularemia, and anthrax) are accepted as microorganisms to be notified. in low to mild cases of cap, recommendations for the microbiological diagnostic test is optional. in the case of the severe cap, to take blood cultures, sputum staining, sputum culture, urinary antigen test for legionella and pneumococcus are recommended. the main problems from these methods are the low yield, long turnaround time ( - h) and the effects of previous antibiotic use on microbiological results (chastre and fagon, ) . for all cases of hap, microbiological tests should be performed on respiratory samples. samples can obtain spontaneous expectoration, sputum induction, nasotracheal suctioning, and endotracheal aspiration in a patient with requires mechanical ventilation. for vap cases noninvasive sampling with endotracheal aspiration cultures and blood culture is recommended (kalil et al., ) . blood and pleural cultures: before antimicrobial treatment, performing blood culture have a high specificity but a low positivity (less than % of the cases). blood cultures are optional but especially in patients with host defect, for example, asplenia, complement deficiencies, chronic liver disease or leukopenia is indicated along with in patients with hap, the positivity of blood cultures varies from % to %. because the spreading of the infection to the blood occurs in < % of vap cases, blood cultures availability is limited. approximately % of cap cases have a pleural effusion. patients with pleural effusions cm in height on a lateral upright chest radiograph should undergo thoracentesis because of empyema is considered a risk factor for poor outcome. in pleural fluid samples, pneumococcal antigen or molecular detection are recommended also (falguera et al., ) . sputum gram stain and culture: before antimicrobial therapy, sputum sample collection is performed. for diagnostic accuracy, an adequate collection and transport of the sample are recommended. the good quality sample is considered when the sputum sample contains less than epithelial cells and more than lymphocyte cells. the benefits of a sputum gram stain; it broadens initial empirical therapy for a less common etiologies such as s. aureus and gram-negative organisms and it validates the subsequent sputum culture results. for pneumonia caused by s. pneumoniae, the sensitivity of the gram stain is $ % and for s. aureus, it is % (anevlavis et al., ) . the endotracheal aspirate is the equivalent of sputum in vap cases. gram stain and culture of the endotracheal aspirates are recommended for intubated patients. both samples share the same criteria for quality. in vap cases, for distinguishing colonization from infection, a threshold ! colony forming units/ml is recommended (cook and mandell, ) . antigen tests: legionella serotype and pneumococcus antigens are renally excreted and can be detected. sensitivity for pneumococcus ranges from % to % with specificity from % to %. for pneumococcal pneumonia, disadvantages of this test are costing amount ($$ per specimen) and false positive results with children and with chronic respiratory diseases who are colonized with s. pneumoniae (navarro et al., ) . along with legionella serogroup , %- % sensitivity and % specificity was reported. the problem is that the recommended empirical antibiotic regimens will cover both of these microorganisms and further researches are necessary to investigate the clinical usefulness of this method. the rapid antigen detection test for influenza can help for consideration of antiviral therapy. although test performance varies according to patient age, the test used, sample type and duration of illness, %- % sensitivity and $ % specificity was observed in adults. the disadvantages include cost ($$ per specimen), high rates of false-negative results and false-positive results with adenovirus and not superiority according to physician judgment. in the last years, for microbiological diagnosis of respiratory pathogens, molecular diagnostic tests are investigated. these tests provide identification of specific pathogens and differentiate bacterial and viral infection. antibiotic susceptibility, response to antibiotic therapy, assessment for prognosis and disease surveillance is evaluated with these techniques. the methods are approved by the food drug administration (fda) (gadsby et al., ) . approximately % of the cases remain without microbiological identification. conventional methods together with molecular testing will improve the microbiological diagnosis and clinical management of cases with pneumonia. a chest radiograph is required for the routine evaluation the patients who are likely to have pneumonia. chest radiographs are sometimes useful for suggesting the etiologic agent, alternative diagnoses and associated conditions. computerized tomography scans may be more sensitive when findings of radiography are negative or unclear. for patients who are hospitalized for suspected pneumonia but who have negative chest radiographic findings, it is advanced to treat presumptively with antibiotics and repeat the imaging in - h. when managing elderly patients who present with pneumonia, evaluation of severity and site-of-care decisions are critical. in elderly patients with cap, several mortality predictors have been reported. chronic comorbidities were the main predictors of mortality and readmission. the prognostic value of glucose levels was investigated and markedly elevated blood glucose levels on admission were associated with increased short-term and long-term mortality. in another study, the neutrophil-to-lymphocyte ratio was evaluated and presented better for prediction -day mortality according to the pneumonia severity index (psi) and curb- (fine et al., ; lim et al., ) . when a comparison is made in terms of mortality, between crp, white blood cell (wbc) count and these indexes, psi and curb- are observed significantly associated with mortality and icu admission. the psi is based on parameters that are evaluated at the time of clinical presentation as three demographics, five comorbid conditions five physical examination findings, and seven laboratory/imaging variables ( table ) (fine et al., ) . the primary purpose of this score is to distinguish patients that could be safely treated in an outpatient setting versus inpatient observation and treatment. the major limitations of the psi score are its focusing by age and comorbidity and not consider psychosocial variables, infrequent comorbidities, or patient preferences regarding treatment. the curb- is a less complex scoring system only requires six variables to be evaluated at presentation (table ) . (lim et al., ) . for severity assessment and hospitalization decision, the usefulness of these scores are presented in table . in curb- , age is an extremely significant variable. these scores highlight that elderly patients with pneumonia are at risk for higher severe disease and poorer clinical outcome, but the limitations of the curb- score that not contain data such as hypoxemia, electrolyte disturbance or the inability to take oral medications. for prediction icu admission and the risk of death in patients with severe cap, several other tools have also been designed. the examples include the ps-curxo , smart-cop, and cap-piro scores. all of these guidelinesdexcept onedinclude age as one of the variables associated with poor outcomes. ps-curxo uses age above years old as one of the minor criterion for determining the severity of illness. the smart-cop scoring system evaluates the need for respiratory and vasopressor support. in this score, age is not one of the severity markers but tachypnea and poor oxygenation are used as an adjustment tool. rello and colleagues developed the cap-piro score. this score evaluates predisposition, infection, response, and organ dysfunction variables (espana et al., ; charles et al., ; rello et al., ) . detailed information for all of these scores is presented in table . icu admission is another important medical decision for these patients. direct admission to an icu is required for patients with septic shock requiring vasopressors or with acute respiratory failure requiring intubation and mechanical ventilation. also, for patients with three of the minor criteria for severe cap listed in table , direct admission to an icu or high-level monitoring unit is recommended . but it must bear in mind that early recognition of sepsis in elderly compromised patients can be challenging. the classical criteria to define the systemic inflammatory response syndrome can be absent in anergic patients. in conclusion, in addition to objective criteria such as age, the clinician experience, and clinical judgment is always recommended for proper evaluation. curb- is practical and functional in order to decide when to admit a patient to the hospital and idsa/ ats guidelines major and minor criteria are proper parameters to admit a patient to the icu . antimicrobials are the mainstay of treatment for elderly patients with cap. selection of antimicrobials for empirical therapy is based on the prediction of the most likely pathogen and knowledge of local susceptibility patterns. unless outcome data clearly do not favor one drug, recommendations generally take place for a class of antibiotics. overall efficacy remain the major factor for many classes of agents, other factors like pharmacokinetics/pharmacodynamics, compliance, safety, and cost must be into consideration. the most common pathogens of cap are presented in table according to the severity of illness as judged by the site of care. in terms of analyzing the microbial etiology in elderly, a cohort study with cap patients was shown that when patients divided by age, the microbiological diagnosis possibility decreases steadily with age; - years old, %; - years old, %; and years and older, % (cillóniz et al., ) . in this age group, to consider the substantial risk factors can help for prediction the responsible microorganisms and finally select the proper antimicrobial therapy (table ) . current international guidelines for the treatment of cap do not have specific recommendations for elderly patients. in this guidelines, evaluation, following, and treatment of the patients is taking place into three categories; outpatient treatment, inpatient-non icu treatment and inpatient icu treatment . the recommendations for outpatient treatment with the listed clinical risks: . previously healthy and no use of antimicrobials within the previous months a macrolide (azithromycin, clarithromycin, or erythromycin) (strong recommendation) doxycycline (weak recommendation) . presence of comorbidities such as chronic heart, lung, liver or renal disease; diabetes mellitus; alcoholism; malignancies; asplenia; immunosuppressing conditions or use of immunosuppressing drugs; or use of antimicrobials within the previous months a respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [ mg]) (strong recommendation) ( point) ats, american thoracic society; cap, community-acquired pneumonia; icu, ıntensive care unit; idst, infectious diseases society of america; piro, predisposition, infection, response and organ dysfunction score; ps curxo , ph, systolic blood pressure, confusion, urea nitrogen, respiratory rate, x-ray finding, oxygen arterial pressure and age of years or more; smart-cop, systolic blood pressure, multilobar chest radiography, albumin level, respiratory rate, tachycardia, confusion, oxygenation and ph; bun, blood urea nitrogen; wbc, white blood cell. a b-lactam plus a macrolide (high-dose amoxicillin [e.g., g three times daily] or amoxicillin-clavulanate [ g two times daily] is preferred; alternatives include ceftriaxone, cefpodoxime, and cefuroxime [ mg two times daily]; doxycycline is an alternative to the macrolide) (strong recommendation) . in regions with a high rate (> %) of infection with high-level (mic > mg/ml) macrolide-resistant s. pneumoniae, consider the use of alternative agents listed above in ( ) for patients without comorbidities (moderate recommendation). the recommendations for hospital ward treatment with the listed clinical risks: . a respiratory fluoroquinolone (strong recommendation) . a b-lactam plus a macrolide (strong recommendation) preferred b-lactam agents include cefotaxime, ceftriaxone, and ampicillin; ertapenem for selected patients (patients with risks for infection with these pathogens and for patients who have recently received antibiotic therapy) with doxycyclinedas an alternative to the macrolide a respiratory fluoroquinolone should be used for penicillin-allergic patients. for most hospitals admitted patients, initial treatment should be given intravenously, but some without risk factors for severe pneumonia could receive oral therapy, especially with highly bioavailable agents such as fluoroquinolones. when an intravenous b-lactam is combined with coverage for atypical pathogens, a macrolide or doxycycline with oral therapy is appropriate for selected patients without severe pneumonia risk factors. the recommendations for icu treatment with the listed clinical risks: minimal recommended treatment is; . a b-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) plus either azithromycin or a fluoroquinolone (strong recommendation) for penicillin-allergic patients, a respiratory fluoroquinolone and aztreonam. the most common pathogens in the icu population were (in descending order of frequency) s. pneumoniae, legionella species, h. influenzae, enterobacteriacea species, s. aureus and pseudomonas species. the recommended standard empirical regimen should routinely cover the three most common pathogens, all of the atypical pathogens, and most of the relevant enterobacteriaceae species. but for treatment of mrsa or p. aeruginosa infection, modification the standard empirical regimen is necessary. along with suspicion of these pathogens, modification to the basic empirical treatment is; . for pseudomonas infection, use an antipneumococcal, antipseudomonal b-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) plus either ciprofloxacin or levofloxacin ( -mg dose) or the above b-lactam plus an aminoglycoside and azithromycin or the above b-lactam plus an aminoglycoside and an antipneumococcal fluoroquinolone. for penicillin-allergic patients, substitute aztreonam for the b-lactam. structural lung diseases, such as bronchiectasis, or repeated chronic lung disease exacerbations as well as prior antibiotic therapy are other clinical risk factors for infection with pseudomonas species. requiring for icu admission is not routine with these pathogens. in patients with chronic alcoholism other serious gram-negative pathogens, such as k. pneumoniae or acinetobacter species are important. clinical risk factors for cap with s. aureus include end-stage renal disease, injection drug abuse, rapid presentation and progression, associated skin lesions, prior influenza, and prior antibiotic therapy. for mssa empirical combination therapy recommended above is adequate. actually, vancomycin has never been specifically studied for cap. linezolid is detected superior to vancomycin in the retrospective analysis for nosocomial mrsa pneumonia. as newer presently available agents, daptomycin should not be used for cap, and for tigecycline, there is no available data. pathogen-directed therapy . the etiology of cap has been identified with reliable microbiological methods, antimicrobial therapy should be oriented at that pathogen (moderate recommendation) because of the benefit of combination therapy was also most pronounced in more severely ill patients, after results of cultures, discontinuation of combination therapy is most likely safe in only non-icu patients (cillóniz et al., ). . early treatment (within h of onset of symptoms) with oseltamivir or zanamivir is recommended for influenza a (strong recommendation). . oseltamivir and zanamivir is not recommended for patients with uncomplicated influenza with symptoms for > h, but these drugs may be used to reduce viral shedding in hospitalized patients or for influenza pneumonia (moderate recommendation). . parenteral acyclovir is indicated for varicella zoster or herpes simplex virus pneumonia. no antiviral treatment of proven value is available for other viral types of pneumonia. . an increasing greater than % is observed for enterobacteriaceae with esbl especially in patients with recent hospitalization or elderly. ertapenem is a good therapeutic option with good sensitivity. . patients should be switched from intravenous to oral therapy when they hemodynamically stable, are able to ingest medications, and have a normally functioning gastrointestinal tract (strong recommendation). . patients should be discharged as soon as they are clinically stable, inpatient observation while receiving oral therapy is not necessary (moderate recommendation). patients with higher psi risk score take longer to reach clinical stability than do patients at lower risk, so elderly patients with multiple comorbidities generally recover more slowly. appropriate follow-up and rehabilitation planning should be initiated early for these patients. in elderly presented with delirium, its resolution may represent a clinical marker of improvement. . patients with cap should be treated for a minimum of days, should be afebrile for - h, and should have not clinical instability sign no more than one before discontinuation of therapy (moderate recommendation) (waterer et al., ; ramirez et al., ) . . if initial therapy was not active against the identified pathogen or if it was complicated by extrapulmonary infection, a longer duration of therapy may be needed (weak recommendation). criteria for clinical stability is presented in table (arnold et al., ). . most patients with cap have been treated for - days or longer, but few well-controlled studies evaluated the optimal duration of therapy. short-duration may be suboptimal for patients with bacteremic s. aureus or pseudomonas infection. the presence of cavities or other signs of tissue necrosis may require prolonged treatment. other important treatment considerations . patients with cap along with persistent septic shock despite adequate fluid resuscitation should be evaluated for therapy with drotrecogin alfa activated within h of admission (weak recommendation)dadvice patients' groups; patients with septic shock, sepsis-induced leukopenia and organ failure criteria. . hypotensive, fluid-resuscitated patients with severe cap should be screened for adrenal insufficiency (moderate recommendation). stress-dose ( - mg of hydrocortisone per day or equivalent) steroid treatment improves outcomes of vasopressordependent patients with septic shock who have documented inadequate cortisol levels. . patients with hypoxemia or respiratory distress should receive a cautious trial of noninvasive ventilation (niv) unless they require immediate intubation (moderate recommendation). . low-tidal-volume ventilation ( cm /kg of ideal body weight) should be used for patients undergoing ventilation who have diffuse bilateral pneumonia or ards (strong recommendation). . other management protocols of severe sepsis and septic shock in patients with cap do not appear to be different from those patients with other infections. advice for management of nonresponding pneumonia . %- % of hospitalized patients with cap do not respond to the initial antibiotic therapy. mortality among nonresponding patients is increased several-fold according to responding patients. the using a systematic classification for possible causes is recommended (table ) (moderate recommendation). . two patterns of undesirable response are seen in hospitalized patients: the first is progressive pneumonia or clinical deterioration, with acute respiratory failure requiring ventilatory support and/or septic shock, within the first h of hospital admission. the second pattern is that of persistent or nonresponding pneumonia. . nonresponding to antibiotics generally result in three patterns of clinical approachment ( ) transferring of the patient to a higher level of care ( ) further diagnostic testing, and ( ) changing the treatment. firstly, patients with nonresponding or deterioration are reevaluated for initial microbiological results and further history for risk factors for infection with unusual pathogens. blood cultures should be repeated. in % of the patients with cap, the etiology determined by bronchoscopy. rapid urinary antigen test can remain positive for days after initiation of antibiotics and is considered in nonresponding patients an also concomitant or subsequent extrapulmonary infections, such as an intravascular catheter, urinary, abdominal, and skin infections must be kept in mind. . other tests for selected patients with nonresponse: chest ct, bronchoscopy with lavage and transbronchial biopsies and thoracentesis. current international guidelines for cap do not provide specific recommendations for elderly patients but convenience to guidelines was associated with shorter time for clinical stability, shorter length of hospital stay, and lower in-hospital mortality (egger et al., ). an international, multicenter observational study for elderly patients is reported that adherence to the idsa/ats guidelines for hospitalized non-icu elderly patients was cost-effective but was not the most cost-effective strategy in icu patients (faverio et al., ) . in elderly patients, another important issue is age-related changes for antibiotic therapy that modify tolerability, metabolism, excretion of drugs and the risk of drug-drug interactions. in case of qt prolongation or concomitant medication that prolongs qt, using macrolides or fluoroquinolones is not suggested. in elderly, achilles tendon rupture has been reported with fluoroquinolones. with aminoglycosides, nephro and ototoxicity must be kept in mind and presence and degree of renal and/or hepatic failure is always evaluated when choosing the antibiotic treatment (faverio et al., ) . another important risk in the elderly is the frequency of aspiration. risk factors for aspiration pneumonia are age, male gender, neurologic impairment, parkinson's disease, lung disease, diabetes mellitus, malnutrition, periodontal diseases, poor oral hygiene, vomiting, proven dysphagia, proton pump inhibitor, antipsychotic or sedative drug use. diagnosing can be challenging, as a diagnostic tool, fiberoptic endoscopic evaluation of swallowing (fees) can be performed at the bedside. the most common pathogens are oropharyngeal flora including anaerobes, gram-positive cocci, and gram-negative bacilli. antibiotics against indigenous oral flora including anaerobes should be administered and both swallowing rehabilitation and oral healthcare management should be initiated. percutaneous endoscopic gastrostomy (peg) is often performed for preventing aspiration, but there is little evidence to indicate that it prevents pneumonia. a head-up position, by $ degree and mosapride, a gastroprokinetic agent may be preventing gastroesophageal regurgitation and associated aspiration. angiotensinconverting enzyme (ace) inhibitors and cilostazol have been reported effective for prevention of pneumonia, because these medications increase substance p levels in the airways and plasma, improving both swallowing and cough reflexes. for prevention, also anticholinergic agents, tricyclic antidepressants, diuretics, and selective serotonin reuptake inhibitors that which cause dry mouth should be administered cautiously. in elderly patients with pneumonia, the development of cardiac complications was associated with a % increased mortality risk. even only advanced age is associated with higher risk of long term-mortality. other causes of death after following an episode were mainly related to comorbidities, malignancy, copd and vascular diseases. as are cardiovascular and cerebrovascular events, to increase the rehabilitation and nutritional status after a cap could ameliorate physical dysfunction in elderly. the effectiveness of pneumococcal polysaccharide vaccines for prevention of invasive infections among elderly individuals and younger adults have documented with epidemiologic studies. currently, two types of vaccine are available: polyvalent pneumococcal polysaccharide vaccine (ppv )d pneumococcal serotypes includeddand the pneumococcal conjugate vaccines (pcv ). the only difference of pcv is the capsular polysaccharides that conjugated to a carrier protein for enhancement the immunogenicity. pneumococcal vaccine naïve > years old persons should receive a single dose of pcv first, followed by a dose of ppv year later. prior vaccination with ppv at age > years should also receive a dose of pcv if they have not yet received one. a dose of pcv should be given > year after of the most recent ppv dose. in patients who need to repeat ppv , the period between administration of pcv and the new dose of ppv should be at least and years since the most recent dose of ppv . for influenza, chemoprophylaxis can be used as an adjunct treatment to vaccination. oseltamivir and zanamivir are both approved for prophylaxis and may be useful for household exposure to influenza and those who work in institutions with an influenza outbreak (hayden et al., ) . as other preventive measures, modifiable risk factors as reducing or cessation of alcohol consumption, smoking cessation, improving oral hygiene, ensuring good nutritional status, avoiding contact with lower respiratory infections were accepted. cap is the fifth leading cause of death and the most common cause of death from infectious diseases in people aged years and over. s. pneumoniae is still the most common pathogen. elderly patients have a significant number of risk factors associated with higher risk for mdr pathogens. to establish supportive measures, systematic evaluation of cognitive, nutritional (hydration included) and functional status must be an important part of the clinical examination. antimicrobial selection for elderly patients with cap does not differ from that of younger adults. in clinical practice guidelines, early antibiotic administration and strict adherence to the regimes is recommended. it is not appropriate to restrict intensive care and ventilatory support only on the basis of chronologic age. there is no difference for management the patients with hap and vap in this age group. the long-term mortality rate after cap hospitalization is really high in the elderly population. as prevention, immunization measures must be improved. vaccination for pneumococcus and influenza and smoking cessation programs may help for decrease the incidence and severity of cap, especially in this age group. choose the target specific antibiotics associated with hap/vap as narrowly as possible. without risk factors for mdr organisms, empiric therapy should include one antibiotic (against p. aeruginosa, other gram-negative organisms, and methicillin-sensitive s. aureus) suggested agents include piperacillin-tazobactam, cefepime, levofloxacin, imipenem in patients with risk factors for mrsa infection, empiric coverage should include vancomycin or linezolid hap/vap treatment should always include antipseudomonal coverage. dual antipseudomonal agents from different classes are recommended for empiric therapy in patients with a risk factor for mdr gram-negative pathogens. decisions about dual coverage should be individualized there is no difference in regard to mortality, treatment failure, recurrent pneumonia, or duration of mechanical ventilation. a longer duration may be appropriate where the patient may have a delayed clinical response the guidelines recommend that discontinuation of antibiotics be based on clinical criteria and procalcitonin testing preventive measures international guidelines recommend specific measures for preventing pneumonia pneumococcal polysaccharide vaccine is recommended for persons > years of age and for those with selected high-risk concurrent diseases (chronic cardiovascular, pulmonary, renal, or liver disease, diabetes mellitus, alcoholism, asplenia, immunocompromising conditions/medications, long-term care facility residents all persons > years of age, others at risk for influenza complications; high-risk persons with household contacts and health care workers should receive inactivated influenza vaccine (strong recommendation). influenza and pneumococcal vaccines can be given at the same time in different arms vaccination status should be evaluated at hospital admission for all patients, especially those with medical illnesses (moderate recommendation) vaccination may be performed either at hospital discharge or during outpatient status (moderate recommendation) influenza vaccine should be offered to persons at hospital discharge or during outpatient therapy during the fall and winter (strong recommendation) respiratory hygiene measures, including hand hygiene and respiratory masks, should be used in outpatient settings and in emergency departments (strong recommendation) multidrug-resistant pathogens in hospitalized patients coming from the community with pneumonia a european perspective a prospective study of the diagnostic utility of sputum gram stain in pneumonia improving outcomes in elderly patients with community-acquired pneumonia by adhering to national guidelines: community-acquired pneumonia organization international cohort. study results reducing door-to-antibiotic time in community-acquired pneumonia: controlled before-and-after evaluation and cost-effectiveness analysis current cigarette smoking among adultsdunited states smart-cop: a tool for predicting the need for intensive respiratory or vasopressor support in communityacquired pneumonia ventilator-associated pneumonia pneumonia n the elderly: a review of the epidemiology, pathogenesis, microbiology, and clinical features impact of age and comorbidity on cause and outcome in community-acquired pneumonia community-acquired pneumonia related to intracellular pathogens frailty in elderly people endotracheal aspiration in the diagnosis of ventilator-associated pneumonia bacterial community-acquired pneumonia in older patients geographically-based evaluation of multidrug resistance trends among streptococcus pneumoniae in the usa: findings of the fast surveillance initiative cost-effectiveness of adherence to idsa/ats guidelines in elderly patients hospitalized for community-acquired pneumonia development and validation of a clinical prediction rule for severe community-acquired pneumonia evaluation of the polymerase chain reaction method for detection of streptococcus pneumoniae dna in pleural fluid samples the management of community-acquired pneumonia in the elderly a prediction rule to identify low-risk patients with community-acquired pneumonia the impact of frailty on icu and -day mortality and the level of care in very elderly patients ( years) comprehensive molecular testing for respiratory pathogens in community-acquired pneumonia pneumococcal pneumonia presenting with septic shock: host-and pathogen-related factors and outcomes immunology of the aging management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis community-acquired pneumonia requiring hospitalization among u.s. adults management of adults with hospital-acquired and ventilator-associated pneumonia: clinical practice guidelines by the infectious diseases society of america and the hospitalized community-acquired pneumonia in the elderly: age-and sex-related patterns of care and outcome in the united states advisory committee on immunization practices (acip), acip adult immunization work group. advisory committee on immunization practices recommended immunization schedule for adults aged years or older united states outcomes in elderly danish citizens admitted with community-acquired pneumonia. regional differences, in a public healthcare system economic burden of community-acquired pneumonia among elderly patients: a japanese perspective outcome of community-acquired pneumonia: influence of age, residence status and antimicrobial treatment defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study etiologic analysis and predictive diagnostic model building of community-acquired pneumonia in adult outpatients in beijing, china comparative radiographic features of community-acquired legionnaires' disease, pneumococcal pneumonia, mycoplasma pneumonia, and psittacosis infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults pseudomonas aeruginosa nosocomial pneumonia: impact of pneumonia classification performance of the binaxnow streptococcus pneumoniae urinary antigen assay for diagnosis of pneumonia in children with underlying pulmonary diseases in the absence of acute pneumococcal infection early switch from intravenous to oral cephalosporins in the treatment of hospitalized patients with communityacquired pneumonia piro score for community-acquired pneumonia: a new prediction rule for assessment of severity in intensive care unit patients with community-acquired pneumonia a global clinical measure of fitness and frailty in elderly people viral pneumonia procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections update on the pathogenesis and management of pneumonia in the elderly-roles of aspiration pneumonia effect of aging on respiratory skeletal muscles monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia the aging of the immune system severe community-acquired pneumonia in an intensive care unit, risk factors for mortality guideline for isolation precautions in hospitals. the hospital infection control practices advisory committee empirical antimicrobial therapy of septic shock patients: adequacy and impact on the outcome society for healthcare epidemiology of america and infectious diseases society of america joint committee on the prevention of antimicrobial resistance: guidelines for the prevention of antimicrobial resistance in hospitals antibiotic use, hospital admissions, and mortality before and after implementing guidelines for nursing home-acquired pneumonia infectious diseases society of america and the society for healthcare epidemiology of america guidelines for developing an institutional program to enhance antimicrobial stewardship incidence, direct costs and duration of hospitalization of patients hospitalized with community-acquired pneumonia: a nationwide retrospective claims database analysis key: cord- -lih f cj authors: du, bin; xi, xiuming; chen, dechang; peng, jinmin title: clinical review: critical care medicine in mainland china date: - - journal: crit care doi: . /cc sha: doc_id: cord_uid: lih f cj critical care medicine began in mainland china in the early s. after almost years of effort, it has been recognized as a specialty very recently. however, limited data suggest that critical care resources, especially icu beds, are inadequate compared with those of developed countries. national critical care societies work together to set up good practice standards, and to improve academic levels with scientific meetings, education programs, and training courses. critical care research in mainland china is beginning to evolve, with great potential for improvement. although advanced life support techniques, especially positive pressure ventilation, inspired the development of critical care medicine in europe and north america in the s, critical care medicine is still one of the newest disciplines of clinical medicine in mainland china. as in many other countries, critical care was initially practiced in a variety of postoperative recovery rooms and/or an isolation area within the general ward. it is well recognized that the fi rst icu in mainland china was set up in the peking union medical college hospital in , in the form of a surgical icu with only one bed [ , ] . two years later, it became the fi rst department of critical care medicine in mainland china, with a seven-bed general icu in the peking union medical college hospital, chaired by dr dechang chen, the well-recognized founding father of critical care medicine in mainland china. in november , the ministry of health issued the regulation of hospital accreditation and management, which required the establishment of an icu as a prerequisite for accreditation as a tertiary hospital [ , ] . many icus were set up in hospitals all over china following the release of this document. many physicians (including general surgeons, internists, emergency physicians, and anesthesiologists) were sent to other hospitals for critical care training, either abroad or domestically, before returning to practice as intensivists [ , ] . in mainland china, physicians of other relevant specialties were the fi rst to be assigned to work in icus because of their familiarity with the necessary techniques (anesthesiologists), disease entities (surgeons and internists), and required urgency of treatment (emergency physicians). however, after years of hard work, the important role of intensivists, as a coordinator during patient evaluation and treatment, has gradually been recognized and respected by other specialties. junior physicians interested in critical care training can choose to be intensivists after they fi nish or years of fellowship training in surgery or internal medicine. however, the traditional specialties often still assume responsibility for or 'ownership' of patients, as well as have a desire to treat critically ill patients, as refl ected by the fact that the proposal for setting up a critical care society under the chinese medical association (cma) was rejected in . public healthcare crises in china since have provided intensivists with an opportunity to demonstrate their knowledge and skills. epidemics of severe acute respiratory syndrome (sars) in , of streptococcus suis in , and of avian infl uenza, as well as the wenchuan earthquake in , caused extreme anxiety in the public due to the vulnerability of the general population, the high communicability of the diseases, and the high case fatality rate. th erefore, intensivists were often convened by the government to be involved in crisis management very early [ ] . th eir ability to coordinate, cooperate, and communicate with regard to both patient management and policy-making was well demonstrated during daily work, and recognised by the general public and healthcare authorities. as a result, critical care medicine was offi cially recognized as a specialty of clinical medicine in [ ] . th ere is no census on critical care resources in china, including the number of icus, intensivists, icu nurses, and relevant facilities (for example, bedside monitors, artifi cial ventilators), because no national survey has ever been performed. we performed computerized literature searches of the china academic journals full-text database of the china national knowledge infrastructure. we used the search terms 'intensive care unit' or 'intensive care' or 'critical care unit' and 'survey' , and found only eight relevant papers concerning critical care resources in mainland china [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] that were published within the past decade (table ) . unfortunately, none of these eight papers selected a representative sample of icus in china. table summarizes data from these eight papers [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , in addition to those of the china critical care clinical trial group (cccctg) [ ] . based on the above data, we made a rough estimation that, in mainland china, icu beds might account for . % (interquartile range . % to . %) of total hospital beds [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in , the ministry of health reported that there were a total of , , beds in , hospitals in china [ ] . th erefore, we estimate that there were , ( , to , ) icu beds in china in , corresponding to . ( . to . ) icu beds per , population, with hospital beds per , population. th is fi gure is comparable to that of the united kingdom ( . icu beds per , population), which was the lowest of eight countries in north america and western europe [ ] . among all icus, about half were closed (mean . %, range % to . %), more than one-third were semiclosed (mean . %, range . % to . %), and the others were open icus (mean . %, range % to %) [ ] [ ] [ ] [ ] [ ] [ ] [ ] . th e relative distribution of specialty icus versus general icus was not uniform across the country, with specialty icus making up from % (shandong) to % (jiangsu) of units, or % (shandong) to % (beijing) of icu beds [ , , ] . in addition, the icu nurse-to-bed ratio ranged from . to . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , corresponding to , to , icu nurses in mainland china. according to limited data, there is no signifi cant diff erence in icu beds and nurse-to-bed ratios between coastal areas and inland areas. although there are usually more icu beds in tertiary hospitals than local hospitals, there is no diff erence in nurse-to-bed ratio. even few data are available for bedside monitors, mechanical ventilators, and dialysis machines, which preclude the possibility of making any estimation. th ere has been no large-scale observational study about case mix in chinese icus, although some data are available. among patients receiving mechanical ventilation for more than hours in icus, mean age was . ± . years, and ( . %) were male [ ] . medical reasons accounted for . % of all icu admissions, followed by emergency surgery ( . %), and elective surgery ( . %) [ ] . data from the cccctg showed that, among , patients admitted to icus in and , about two-thirds ( . ± . %) were treated with invasive mechanical ventilation, pulmonary artery catheters or arterial pulse contour analysis was used in . ± . % of patients, and continuous renal replacement therapy was used in . ± . % of patients [ ] . th e hospital mor tality rate was . ± . % [ ] . a -month prospective observational study in surgical icus identifi ed . % ( / , ) of patients had severe sepsis, with a hospital mortality rate of . % [ ] . prospective and retrospective observational studies suggested that . % to . % of icu patients developed acute respiratory distress syndrome [ , [ ] [ ] [ ] ; the hospital mortality rate ranged from . % to . % [ ] [ ] [ ] . th e mean hospital cost for severe sepsis was usd , ± , , and the mean daily cost was usd ± [ ] , corresponding to % and % of annual income per capita in (table ). as mentioned above, anesthesiologists, general surgeons, emergency physicians and pulmonologists are all involved in icu management in mainland china. th eir infl uence is well described by the presence of critical care sections although the cma refused to set up a critical care society in , the fi rst national critical care society in mainland china was established in , called the chinese society of critical care medicine (csccm), and currently has about members. th e major objective of the csccm is to provide a multidisciplinary platform for promoting critical care medicine all over china, provide expert opinion to the government and other bodies, and encourage both national and international academic exchange. th e csccm organizes a -day biennial national conference, with attendees increasing from in to more than , people in , including physicians, nurses, and company representatives. in , the csccm hosted the th international congress of the asia pacifi c association of critical care medicine (apaccm) in beijing. th e scientifi c program included plenary lectures, lectures and workshops by speakers from countries. th is was the fi rst time that an international conference on critical care medicine had ever been held in mainland china, a milestone demonstrating more involvement in the international community. since its establishment, the csccm has developed close relationships with multiple international profes sional societies, such as the society of critical care medicine (sccm), the european society of intensive care medicine, the société de réanimation de langue française, the apaccm, and the world federation of societies of intensive and critical care medicine (wfsiccm). right now, the csccm is the only member society representing mainland china in both the wfsiccm and apaccm. th e second national critical care society, the chinese society of intensive care medicine, was established in under the cma (csicm-cma). csicm-cma has been working actively to enact clinical practice guidelines, including nutritional support, mechanical ventilation, and sepsis management. th e third national critical care society, the chinese association of critical care physicians (caccp), was founded in july . as an affi liation to the china medical doctors association, the aim of the caccp will include professional certifi cation of intensivists. th ese three societies have the common philosophy to cooperate with each other in the future because they share almost the same leadership. at present, there is no formal accredited critical care training program in china. residents can choose critical care medicine as their specialty after graduation from medical school. rotation in other departments, such as anesthesia or internal medicine, is not obligatory, and is organized according to institution and department requirements. on the other hand, residents may consider critical care medicine as a subspecialty after fi nishing a fellowship training program in internal medicine, anesthesia, general surgery, or emergency medicine. icu physicians can register as intensivists (for those working in general icus), or, alternatively, remain registered under their primary specialty of anesthesiology, internal medicine, general surgery or emergency medicine (for those working in specialized icus) [ ] . in mainland china, most nursing education programs employ only a -year curriculum after senior high school. although colleague education programs have become more and more popular, there is still a signifi cant demand for professional education for nurses. in , the beijing nursing association started to implement a critical care nurse certifi cation program, with around trainees every year. th e program is composed of month of lectures and month of clinical practice, followed by examination of knowledge and skills. trainees are also required to fi nish a review before certifi cates are issued. in , the china nursing association followed the same model in order to meet the need in other cities in mainland china. respiratory therapists are present in only a few icus. sichuan university set up the fi rst program of respiratory therapy in a medical school in mainland china in [ ] . th e lack of a national accredited critical care training program is believed to be a major obstacle for improving professional education in china. although access to state-of-the-art advances might be available during national and international conferences, basic knowledge and skills are inadequately, and sometimes incorrectly, taught in many hospitals. for the past years, the csccm has dedicated itself to promoting professional education with regard to basic knowledge and skills in critical care medicine. th e csccm successfully organizes a fundamental critical care support course, a funda mental disaster management course, and a multiprofessional critical care review course, with support from the sccm. in , the csccm endorsed the basic assessment and support intensive care course, and promoted the course in mainland china. nine provider courses have been organized until november , with more than participants. however, an advanced training program is still under development, and the number of trainees is very limited compared with the large number of intensivists in mainland china. more over, a national board exam for critical care medicine is not yet available, which suggests that we do not have a minimum national standard for intensivists. critical care research in mainland china is in its infancy. most study results are published in national medical journals in the chinese language, while very few investigators succeed in publishing their studies in peerreviewed international medical journals. possible reasons might include: inadequate training and experience in clinical research; inadequate staffi ng dedicated to research; inadequate funding for critical care research; and inadequate language profi ciency. however, chinese intensivists have become more actively involved in international multicenter studies during recent years. for example, a total of , patients in icus in mainland china were enrolled in an observational study, accounting for % of patients and % of icus (s finfer, unpublished data). th is suggests a great potential for future improvement in clinical research in mainland china. considering the above limitations and potential improve ment, we do believe that chinese intensivists may benefi t from academic exchange with the international medical community with regard to the following: development of a series of training programs fulfi lling international standards; development of a national board exam for critical care medicine; and conduction of multicenter trials compatible with good clinical practice. overall, critical care medicine in mainland china is still in a phase of development. after years of dedicated hard work, critical care medicine has been recognized as a specialty by the government and other specialties. however, due to scarce resources and limited experience, critical care training and clinical research are still underdeveloped, which also represents a great potential for future improvement. health systems: improving performance. geneva: world health organization statistical communique of the people's republic of china on the ministry of health: statistical communiqué of people's republic of china on the national healthcare development on exploration into critical care medicine and disciplinary construction the emergence and development of icu on behalf of the china critical care clinical trial group: natural disaster. in intensive and critical care medicine: wfsiccm world federation of societies of intensive and critical care medicine ministry of health of the people's republic of china the fi rst questionnaire survey of present situation of intensive care unit in whole country the survey of icu for neonates and children in china a questionnaire survey of present situation of icu in jiangsu province investigation on establishment and management of intensive care units in hospitals in beijing a survey of general intensive care units in guangxi survey of present situation of intensive care unit in hospitals and construction of intensive care network in guangdong province a survey of present situation of general intensive care unit in second grade hospitals and construction of intensive care network in guangdong province the questionnaire survey of present status of intensive care units in shandong province china critical care clinical trials group; cccctg participating centers: summary of clinical information variation in critical care services across north america and western europe an investigation on current practice of nutrition support for critically ill in chinese icu china critical care clinical trials group; cccctg participating centers: summary of icu admissions epidemiology of severe sepsis in critically ill surgical patients in ten university hospitals in china a -month clinical survey of incidence and outcome of acute respiratory distress syndrome in shanghai intensive care units retrospective analysis on acute respiratory distress syndrome in icu epidemiological investigation on acute respiratory distress syndrome occurring in anonymous: introduction of program on respiratory therapy critical care medicine in mainland china the authors declare that they have no competing interests.published: february key: cord- - dergkha authors: wang, tiehua; liu, zhuang; wang, zhaoxi; duan, meili; li, gang; wang, shupeng; li, wenxiong; zhu, zhaozhong; wei, yongyue; christiani, david c.; li, ang; zhu, xi title: thrombocytopenia is associated with acute respiratory distress syndrome mortality: an international study date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: dergkha background: early detection of the acute respiratory distress syndrome (ards) has the potential to improvethe prognosis of critically ill patients admitted to the intensive care unit (icu). however, no reliable biomarkers are currently available for accurate early detection of ards in patients with predisposing conditions. objectives: this study examined risk factors and biomarkers for ards development and mortality in two prospective cohort studies. methods: we examined clinical risk factors for ards in a cohort of patients in beijing, china who were admitted to the icu and were at high risk for ards. identified biomarkers were then replicated in a second cohort of , patients in boston, usa. results: of patients recruited from participating hospitals in beijing, developed ards. after multivariate adjustment, sepsis (odds ratio [or]: . , % ci: . – . ), pulmonary injury (or: . ; % ci: . – . ), and thrombocytopenia, defined as platelet count < × ( )/µl, (or: . ; % ci: . – . )were significantly associated with increased risk of developing ards. thrombocytopenia was also associated with increased mortality in patients who developed ards (adjusted hazard ratio [ahr]: . , % ci: . – . ) but not in those who did not develop ards(ahr: . , % ci: . – . ). the presence of both thrombocytopenia and ards substantially increased -daymortality. sensitivity analyses showed that a platelet count of < × ( )/µlin combination with ards provide the highest prognostic value for mortality. these associations were replicated in the cohort of us patients. conclusions: this study of icu patients in both china and us showed that thrombocytopenia is associated with an increased risk of ards and platelet count in combination with ards had a high predictive value for patient mortality. acute respiratory distress syndrome (ards), the most severe form of acute lung injury (ali), is caused by several direct and indirect insults to the lung,life threatening and often lethal. ards usually requires mechanical ventilation and admission to an intensive care unit (icu); ards is a major cause of icu morbidity and mortality worldwide [ ] . emerging viral diseases such as severe acute respiratory syndrome (sars) coronavirus, h n avian-origin influenza virus, and h n swine-origin influenza virus not only possess the potential for pandemic spread, but also cause ards [ ] [ ] [ ] .these factors highlight the need for additional research to improve understanding of the pathogenesis of ards, with the ultimate goal of developing specific treatment [ ] . ards is associated with several clinical disorders, including direct pulmonary injury from pneumonia and aspiration and extra-pulmonary injury from sepsis, trauma, and multiple transfusions [ ] . although low tidal volume ventilation, neuromuscular blockers and prone positioning ventilation have advanced treatments [ ] [ ] [ ] , there are currently no reliable predictive markers for early detection of ards in predisposed individuals. nonetheless, many efforts have been mounted to identify biologic markers, or biomarkers, for ards in critically ill patients, including studies of pulmonary edema fluid, blood, and urine [ ] [ ] [ ] . recent advances on the pathophysiological mechanisms underlying ards have identified several clinical biomarkers to assess disease severity and outcome, including specific cytokines and their receptors (il- , il- , soluble tumor factor receptors i and ii), products of epithelial and endothelial injury [receptor for advanced glycation end-products (rage), surfactant protein d, icam- , and von willebrand factor antigen], and markers of altered coagulation (protein c and plasminogen activator inhibitor- ) [ ] . however, no individual biomarker is strongly associated with outcomes and thus cannot provide sufficient discriminating power for either diagnosis or prognosis. biomarker discovery and validation requires patient samples and must be combined with comprehensive clinical data collected from properly designed trials in different populations. given the acute onset and rapid clinical progress of ards, a prospectively enrolled cohort study in multicenter icus is suitable for more complete and unbiased ards/ali research [ ] . using a protocol modified from a molecular epidemiology ards study established in boston, ma (boston cohort) [ ] , we established a multicenter ards cohort in beijing, china (beijing cohort) in . the overarching objectives of establishing this prospective cohort are to validate relevant biomarkers to ards, as well as genetic polymorphisms, discovered in previous usa studies in chinese population, and discover new biomarkers of ards with a comprehensive sampling protocol. in this report, we present initial results on the clinical factors associated with ards development and mortality in individuals with or at risk for ards. associated clinical factors were replicatedin the boston cohort. this study was approved by the institutional review boards(irbs) of the peking university third hospital, beijing friendship hospital, china-japan friendship hospital, beijing chao-yang hospital, and harvard school of public health and a written informed consent was obtained from each subject or an appropriateproxy of the patient. four medical and surgical icus within four tertiary hospitals participated in the study; hospitals covered the metropolitan area of beijing, china and included peking university third hospital in the northwest ( beds), beijing friendship hospital in the south ( beds), beijing chao-yang hospital in the east ( beds), and china-japan friendship hospital in the northeast ( beds). as an international collaboration, we used a modified study protocol for recruitment as previously described [ ] . briefly, we screened each icu admission for eligible subjects, which were defined as critically ill patients with at least one predisposing condition for ards: ) sepsis; ) septic shock; ) trauma; ) pneumonia; ) aspiration; ) massive transfusion of packed red blood cells (prbc; defined as . prbc units during the hours prior to admission); or ) severe pancreatitis. to avoid interference in biomarker research from certain clinical conditions, exclusion criteria included: ) age , years; ) history of chronic lung diseases, such as interstitial pulmonary fibrosis or bronchiolitis; ) history of pneumonectomy; ) treatment with immunomodulating therapy other than corticosteroids, such as granulocyte colony stimulating factor, cyclophosphamide, cyclosporine, interferon, or tnf-a antagonists; ) presence of other immunodeficient conditions, such as hiv infection, leukemia, or neutropenia (absolute neutrophil count , /ml); ) history of solid or bone marrow transplant other than autologous bone marrow transplant; and ) directive to withhold intubation. sepsis and septic shock were defined by the american college of chest physicians/society of critical care medicine (accp/sccm) consensus conference [ ] . after enrollment, subjects were followed daily for the development of ards, as defined by the american-european consensus committee (aecc) as follows [ ] : a) evidence of hypoxemia with pao /fio # mm hg; b) evidence of bilateral infiltrates on chest radiographs; and c) absence of left atrial hypertension with pulmonary arterial occlusion pressure # mm hg or no congestive heart failure. controls were identified as at-risk patients who did not meet criteria for ards during the icu stay and had no prior history of ards. infiltrates on chest radiographs were defined as opacities that could not be explained completely by pleural effusions, mass, body habitus, or collapse. upper zone redistribution and pulmonary vascular congestion were not considered infiltrates. two pulmonary and critical care physicians interpreted daily chest radiographs; any disagreement went to a third intensivist for arbitration. all physicians underwent a consensus training session on the radiologic criteria for ards. all were blinded to the clinical status of the patients. we collected clinical data by chart review, including demographic information of age, gender, race, height, weight and medical history of ards, diabetes, tobacco and alcohol abuse, and liver disease. baseline clinical information, worst vital signs, and laboratory testing results in the first hours of icu admission were collected for calculation of the acute physiological and chronic health evaluation (apache ii) score for severity of illness [ ] . we also collected ventilatory parameters including the requirement and mode of mechanical ventilation, pao /fio ratio, positive end-expiratory pressure, tidal volume, and peak and plateau pressures. all enrolled patients were followed until one of the following situations occurred: hospital discharge, death, or days after study entry. starting in late , based on finding from ards network trials, chinese icus universally adopted lower tidal volume for mechanical ventilation [ ] . baseline characteristics were compared between groups with fisher's exact test or chi-square test for dichotomous or categorical variables and with student's t test or mann-whitney test for continuous variables. for risk analysis of ards development, we initially used a logistic regression model with a backward stepwise elimination algorithm to select clinical risks or predictors from the univariate analyses with p, . ; the final logistic regression models also included predictors from backward elimination. for mortality analysis, we used the log-rank test as a univariate measure of association and employed cox proportional hazards models to investigate each clinical variable's effect on clinical outcome. we used the time-dependent receiver operating characteristic (roc) method to determine the best cut-off value of thrombocytopenia in the prediction of prognosis of critically ill patients by exploring the area-under-the-curve (auc) values at -day mortality, and selected the maximal sumof sensitivity and specificity [ ] . all analyses were performed with the sas statistical software package (version . , sas inc., cary, nc), and p, . was considered statistically significant. between july and april , we recruited patients with at least one predisposing condition for ards from the participating hospitals in beijing, china. the majority of patients were male (n = , %) and the mean age was years (median: ; interquartile range: - years) ( table ). median apache ii score was (interquartile range: [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and median length of time in the icu was . days (interquartile range: - days). mechanical ventilation was used on patients ( %) for a median length of six days (interquartile range: - days). thirtynine patients had diabetes, and one patient had chronic kidney disease. during hospitalization, ( %) patients developed ards;among identified cases, ( %) and ( %) of the ards patients were diagnosed within the first and hours of icu admission, respectively. there were no significant differences in age, gender, smoking status, and initial apache ii score between ards patients and at-risk non-ards patients (table ). in addition, the major physiological variables during the first hours of icu admission were comparable, except that patients who developed ards had higher respiratory rates (p = . ). although not significant, ards patients were in the icu longer (ards median = days; non-ards median = days; p = . ) and on mechanical ventilation longer (ards median = days; non-ards median = days;p = . ) than non-ards patients. low tidal volume (, ml/kg) was used in treating patients with mechanical ventilation. although patient specific data was not available, protocolled low tidal volume ventilation was standardized in study icus. among predisposing conditions for ards in all enrolled patients, sepsis and/or septic shock (n = , %) were the most [ ] were associated with development of ards.respiratory rate (. breaths/min), aspiration, and . risks for ards were also evaluated in model selection but were eliminated during model selection (not significant). apache ii score (removing age and gender components), age, and gender were forced in as covariatesbut not significant in logistic regression analyses. known factors related to ards, including septic shock, diabetes, and alcohol use, were also tested either by forcing as covariates, individually or combined into the model, and did not change the significant associations of sepsis, direct pulmonary injury, and thrombocytopenia with the development of ards (data not shown).because drinking habits in china differ from those in the u.s.,and it was difficult to develop a comparable criterion for alcohol abuse, we did not including alcohol abuse as risk factor in the analysis. we further conducted a stratified analysis and found that thrombocytopenia was significantly associated with ards in both the beijing cohort (univariate analysis, p = . ) and the boston cohort (univariate analysis, p, . ) (table s ), which has ards and , non-ards patients recruited at massachusetts general hospital in boston, usa [ ] , in the subgroup patients with septic shock, but not in non-septic shock subgroup (p = . and p = . , respectively). some patients had already developed ards before icu admission, and this subgroup caseswas usually mixed with those patients who were diagnosed ards during the first hours of icu admission, together accounting for a total of % ards in the beijing cohort and % in the boston cohort ( of identified cases). since the thrombocytopenia was defined by the lowest platelet counts during the first hours of icu admission in these cohorts, some patients developed thrombocytopenia before the onset of ards, who were difficult to be distinguished within this subgroup ards, and could interfere with the finding that thrombocytopenia was associated with development of ards. we then performed a nested analysis on a clean subgroup patients, by removing ards patients who were diagnosed during the first hours of icu admission, and found that thrombocytopenia was still significantly associated with ards risk (or = . ; % ci = . - . ; p = . ). because of the small sample size of the beijing cohort, we further conducted the sensitivity test in the boston cohort in ards cases and , non-ards patients after removing ards patients who were the -day mortality rate for all patients was %, and the development of ards did not increase mortality risk (table ) . among predisposing conditions for ards, septic shock was associated with increased mortality (p = . ), but pancreatitis was associated with decreased mortality (p = . ) in ards patients ( table ). in contrast, pneumonia (p = . ) and external pulmonary injury (p = . ) had higher mortality rates in non-ards patients. univariate examination of demographic characteristics and physiologic variables in the first hours of icu admission revealed that higher apache ii scores and older age were associated with increased mortality for both ards and non-ards patients ( table ) . thrombocytopenia was significantly associated with mortalityof ards (p = . ) but not non-ards (p = . ) patients. in contrast, high serum creatinine levels (. . mg/l) were associated with higher mortality in non-ards (p = . ) but not ards (p = . ) patients. there were no statistically significant differences between survivors and nonsurvivors for gender, history of diabetes, and tobacco or alcohol use. in multivariate analysis, apache ii score was consistently associated with increased mortality in ards, non-ards, and all patients (table ) . thrombocytopenia was a mortality covariate for ards and all patients, but not for non-ards patients (table ) . when replaced with coagulation points of the sequential organ failure assessment score (sofa), thrombocytopenia remained associated with higher mortality in ards [adjusted hazard ratio (ahr) = . ; % ci = . - . ; p = . ]and all patients (ahr = . ; % ci = . - . ; p = . ), but not in non-ards patients (ahr = . ; % ci = . - . ; p = . ). to replicate our findings, we analyzed data from the boston cohort. although univariate analyses identified more physiologic variables in the first hours of icu admission and ards-predisposing conditions significantly associated with mortality (table s and s ), multivariate analyses identified apache ii score and thrombocytopenia as major risk factors for mortality in ards, non-ards, and all patients ( table ) . we also found similar results when thrombocytopenia was replaced with coagulation points of the sofa score (data not shown). we further investigated the interaction between thrombocytopenia and ards on mortality of all patients by creating a combined covariate of the boston and beijing cohorts. in both univariate ( figure ) and multivariate (figure ) analyses, the combination of thrombocytopenia and ards had consistently higher patient mortality. taking advantage of the size of the boston cohort, we conducted a sensitivity analysis to determine the optimal platelet count for prognosis.with adjustmentsfor age, gender, apache ii score, and sepsis, a platelet count of /mlhad the maximal roc value (auc = . ; sensitivity = . ; specificity = . ; p = . ). a sensitivity analysis confirmed a platelet count of /ml by considering a series of stepped ( /ml)cut- this prospective multicenter cohort was established using a modified protocol originally implemented in the boston cohort [ ] . among at-risk icu patients, % developed ards during icu admission, and a majority of those patients ( %) developed ards within the first hours of admission. these observations are consistent with previous reports in the mostly-caucasian boston cohort [ ] . moreover, the profiles of baseline physiologic variables and the major clinical risk factors between ards and atrisk non-ards patients are similar to previous reports from chinese [ , ] andamerican [ ] icus.furthermore, the observation of high baseline respiratory rate (. breaths/min) associated with ards cases was consistent withthe findings from several previous studies [ ] [ ] [ ] . in this cohort, in addition to sepsis and direct pulmonary injury, thrombocytopenia was associated with the development of ards.enhanced platelet activation resulting in platelet deposition within the damaged pulmonary microvasculature has been supported by several clinical and preclinical studies of ali [ , ] , and thrombocytopenia has been reported as a key feature of sars [ ] . in the boston cohort, thrombocytopenia (named hematologic failure) was also identified as a risk factor for ards in multivariate analysis [ ] . in another cohort of ali in rochester, minnesota (mayo clinic), however, researchers did not observe significant difference of platelet count between ali and non-ali patients with septic shock [ ] . since the rochester cohort only focuses on a subgroup icu patients with septic shock, our stratified analysis revealed that thrombocytopenia was significantly associated with ards in both the beijing cohort and the boston cohort in the subgroup patients with septic shock, but not in non-septic shock subgroup. the different results might be explained by that the beijing cohort and the boston cohort focused on ards, which is the most severe form of ali. a major finding of this study is the association ofthrombocytopenia with increased ards mortality. extensive evidence demonstrates that platelet count and function are independently associated with increased icu morbidity and mortality [ ] . although thrombocytopenia is a well-established prognostic marker for mortality in patients with sepsis and septic shock [ ] , which are risk factors for developing ards, thrombocytopenia has been inconsistently associated with ards mortality in two previous studies with small patient series representing noncontemporary treatment eras [ , ] . besides apache ii score, thrombocytopenia was the only risk factor for ards mortality identified in the beijing cohort. further, this association was replicatedwitha larger population and different ethnicities in the boston cohort. these results provide strong evidence that thrombocytopenia is a prognostic marker for ards mortality. in both beijing and boston cohorts, the combination of thrombocytopenia and ards further increased risk of -day mortality among critically ill patients. thrombocytopenia in icu patients is caused by multiple factors [ ] and is considered a marker of illness severity with multiple organ dysfunction scores (mods), simplifiedacute physiology scores (saps), and apache scores.sepsis alone can cause moderate thrombocytopenia, as maladaptive platelet-neutrophil interactionssignificantly increase platelet activation and aggregation, as well as tissue injury [ ] . the lung epithelium is central to both the pathogenesis and resolution of ards, and intra-alveolar coagulation changes (e.g., platelet-fibrin deposition and pulmonary vascular thrombi) are hallmarks of pathologic changes in ards [ ] . thus, thrombocytopenia likely contributes to the development of ards; in return, the coexistence of ards may aggravate thrombocytopenia to increase mortality of critically ill patients. we used the same platelet count criterion from the boston cohort (, /ml)to define thrombocytopenia [ ] . although platelet counts are routinely measured daily in the icu, the epidemiology of thrombocytopenia in critically ill patients has not been well studied. further, illness severity scoring systems inconsistently consider platelet count;for example, the sofa score incorporates platelet count, whereas the apache score does not. different platelet count thresholds have been used in epidemiological studies for the prevalence, incidence, risk factors, and consequences of thrombocytopenia among critically ill patients [ ] . currently, the rand/ucla appropriateness methodrecommends a platelet count threshold of , / ml, or a . % decrease in platelet counts, for epidemiological research of thrombocytopenia [ ] . taking advantage of a large patient population in the boston cohort, we conducted a sensitivity analysis and determined that platelet count (, /ml) was a significant prognostic marker for ards. we further replicated this cut-point value in the beijing cohort. there were some differences between the beijing and boston cohorts. when evaluated individually, there were different association profiles for thrombocytopenia and ards with mortality of all patients with at least one risk factor for ards. thrombocytopenia was significantly associated with higher mortality in the beijing cohort, but not the boston cohort. conversely, ardswas associated with higher mortality in the boston cohort, but not the beijing cohort. it is unexpected that ards did not increase mortality in the beijing cohort, and. it is counter-intuitive that in the univariate analysis thrombocytopenia would be associated with increased mortality in the ards group but not in the non-ards group given that thrombocytopenia is a marker of severity of illness in critical care populations generally. however, the raw numbers were in the direction of higher mortality with lower platelets in the non-ards group, these findings could be explained by the limitation of multiple subgroup analysis in a relatively small dataset. moreover, for several known risk factors or comorbidities of ards [ , [ ] [ ] [ ] , such as septic shock, pneumonia, pancreatitis, trauma, multiple transfusions, and diabetes, we did not observe significant different between ards and non-ards patients in the beijing cohort. due to the relative scarcityand high cost of medical resources to the general chinese population, the participating hospital icus in the beijing cohortmay have admitted more severely ill patients, resulting in less difference in illness severity between ards and non-ards patients. accordingly, although most physiologic variables of the first hours of icu admission, including apache score, were comparable between ards and non-ards beijing cohort patients, thrombocytopenia (platelet counts , /ml) was more common in the beijing cohort than the boston cohort ( . % vs. . %, respectively; p, . ). it is also possible that different ethnicities account for the observed differencesbetween cohorts. based on the boston cohort, our study protocol was modified by the inclusion of severe pancreatitis as a predisposing condition for ards. severe pancreatitis is a well-established risk factor for the development of ards [ ] and is frequently observed in critically ill patients in china. in the beijing cohort, we identified ( . %) cases of severe pancreatitis, similar to a previous report of . % in a large chinese icu survey [ ] . about % of severe pancreatitis cases eventually developed ards during icu admission. severe pancreatitis was not associated with ards risk, but was associated with lower mortality. however, the beijing study is limited by a small sample size. with the patients' enrollment keeps, we will further evaluate severe pancreatitis as a clinically important factor in the development and outcome of ards. this study describes the successful establishment of a prospective, multicenter cohort study of critically ill patients at-risk for ards in beijing, china. initial characterization of the clinical factors associated with ards risk and mortality revealed an association between thrombocytopenia and ards mortality. we replicated these findings in the larger and more diverse boston cohort, suggesting that the beijing cohort can provide comprehensive data and samples to identify biomarkers for the early diagnosis, prognosis, and treatment of ards. epidemiology of acute lung injury and acute respiratory distress syndrome interactions between influenza and bacterial respiratory pathogens: implications for pandemic preparedness clinical features and outcomes of severe acute respiratory syndrome and predictive factors for acute respiratory distress syndrome newly recognized causes of acute lung injury: transfusion of blood products, severe acute respiratory syndrome, and avian influenza future research directions in acute lung injury: summary of a national heart, lung, and blood institute working group the acute respiratory distress syndrome higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome prone positioning in severe acute respiratory distress syndrome neuromuscular blockers in early acute respiratory distress syndrome plasma protein c levels in patients with acute lung injury: prognostic significance elevated plasma levels of soluble tnf receptors are associated with morbidity and mortality in patients with acute lung injury higher urine nitric oxide is associated with improved outcomes in patients with acute lung injury the pathogenetic and prognostic value of biologic markers in acute lung injury clinical predictors of and mortality in acute respiratory distress syndrome: potential role of red cell transfusion sepsis change bundles: converting guidelines into meaningful change in behavior and clinical outcome the american-european consensus conference on ards. definitions, mechanisms, relevant outcomes, and clinical trial coordination apache ii-a severity of disease classification system ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury time-dependent roc curves for censored survival data and a diagnostic marker management of thrombocytopenia in the icu (pregnancy excluded) prognostic significance of elevated cardiac troponin-t levels in acute respiratory distress syndrome patients epidemiological investigation on acute respiratory distress syndrome occurring in intensive care units in beijing from retrospective analysis on acute respiratory distress syndrome in icu risk factors for the development of acute lung injury in patients with septic shock: an observational cohort study early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study early acute lung injury: criteria for identifying lung injury prior to the need for positive pressure ventilation* intravascular coagulation associated with the adult respiratory distress syndrome the risk factors, incidence, and prognosis of ards following septicemia the severe acute respiratory syndrome thrombocytopenia and prognosis in intensive care multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome adult respiratory distress syndrome. prognosis after onset adult respiratory distress syndrome. sequence and importance of development of multiple organ failure. the prostaglandin e study group coagulopathy in critically ill patients: part : platelet disorders beyond thrombosis: the versatile platelet in critical illness the epithelium in acute lung injury/ acute respiratory distress syndrome the frequency and clinical significance of thrombocytopenia complicating critical illness: a systematic review acute lung injury and ards in acute pancreatitis: mechanisms and potential intervention risk factors for the prognosis of acute kidney injury under the acute kidney injury network definition: a retrospective, multicenter study in critically ill patients the authors would like to thank michelle gong, ednan k. bajwa, and taylor thompson from the molecular epidemiology of ards project for help in study design and preparation of study protocols. key: cord- -xbuqd j authors: felten-barentsz, karin m; van oorsouw, roel; klooster, emily; koenders, niek; driehuis, femke; hulzebos, erik h j; van der schaaf, marike; hoogeboom, thomas j; van der wees, philip j title: recommendations for hospital-based physical therapists managing patients with covid- date: - - journal: phys ther doi: . /ptj/pzaa sha: doc_id: cord_uid: xbuqd j objective: the covid- pandemic is rapidly evolving and has led to increased numbers of hospitalizations worldwide. hospitalized patients with covid- experience a variety of symptoms, including fever, muscle pain, tiredness, cough, and difficulty breathing. elderly people and those with underlying health conditions are considered to be more at risk of developing severe symptoms and have a higher risk of physical deconditioning during their hospital stay. physical therapists have an important role in supporting hospitalized patients with covid- but also need to be aware of challenges when treating these patients. in line with international initiatives, this article aims to provide guidance and detailed recommendations for hospital-based physical therapists managing patients hospitalized with covid- through a national approach in the netherlands. methods: a pragmatic approach was used. a working group conducted a purposive scan of the literature and drafted initial recommendations based on the knowledge of symptoms in patients with covid- , and current practice for physical therapist management for patients hospitalized with lung disease and patients admitted to the intensive care unit (icu). an expert group of hospital-based physical therapists in the netherlands provided feedback on the recommendations, which were finalized when consensus was reached among the members of the working group. results: the recommendations include safety recommendations, treatment recommendations, discharge recommendations, and staffing recommendations. treatment recommendations address phases of hospitalization: when patients are critically ill and admitted to the icu, and when patients are severely ill and admitted to the covid ward. physical therapist management for patients hospitalized with covid- comprises elements of respiratory support and active mobilization. respiratory support includes breathing control, thoracic expansion exercises, airway clearance techniques, and respiratory muscle strength training. recommendations toward active mobilization include bed mobility activities, active range-of-motion exercises, active (−assisted) limb exercises, activities-of-daily-living training, transfer training, cycle ergometer, pre-gait exercises, and ambulation. as of publication date, the number of patients with respiratory syndrome caused by coronavirus (sars-cov- ), the virus that causes coronavirus disease (covid- ) , is still increasing rapidly worldwide. spreading of covid- occurs mainly through respiratory droplets and aerosols produced when an infected person coughs or sneezes. to our knowledge, there is currently no consensus on the period the virus is transmissible to other humans, however the duration and transmissibility seem to differ between patients with differing severity of illness. even after resolution of symptoms, individuals might keep shedding the virus. diagnosis of covid- requires detection of sars-cov- rna using a combination of nasopharynx-and throat sample. , sars-cov- rna can also be detected in stool and blood. chest computed tomography (ct) images from patients with covid- typically demonstrate bilateral, peripheral ground glass opacities. unfortunately, this pattern is nonspecific and overlaps with other infections; therefore, the diagnostic value of chest ct imaging for covid- may be low. , recent data from china and italy indicate that in percent of cases covid- infection causes 'mild and moderate illness', approximately percent of cases develop 'severe illness' leading to hospitalization, and percent develop 'critical illness' requiring icu treatment. , [ ] [ ] [ ] hospitalized patients with covid- experience a variety of symptoms, including fever, muscle pain, tiredness, cough, and difficulty breathing. elderly people and those with underlying health conditions are considered to be more at risk of developing severe symptoms, and have a higher risk of physical deconditioning during their hospital stay. , physical therapists have an important role in supporting hospitalized patients through respiratory support and active mobilization. physical therapist management should be tailored to the individual patient's needs concerning frequency, intensity, type and timing of the interventions, in particular for those with severe/critical illness, > years of age, obesity, comorbidity and other complications. , yet, physical therapists need to be aware of potential challenges when treating patients with covid- . in a recent study, an international group of authors described the physical therapist management for covid- in the acute hospital setting, including workforce planning, screening, delivery of physical therapist interventions and personal protective equipment (ppe). in line with this international study and the consensus statement of italian respiratory therapists we aim to provide guidance and detailed recommendations for hospital-based physical therapists managing patients hospitalized with covid- through a national approach in the netherlands. [h ] scope this study focuses on adult patients admitted to the (acute) hospital setting due to covid- . in general, patients with covid- experience the following signs and symptoms: fever ( %- %), cough ( %- %), fatigue ( %- %), weight loss ( %- %), shortness of breath ( %- %), secretion production ( %- %) and myalgias ( %- %). , recent studies showed that illness severity can range from mild to critical: , [ ] [ ] [ ]  mild to moderate (mild symptoms up to mild pneumonia): %  severe (dyspnea, hypoxia, or > % lung involvement on imaging): %  critical (respiratory failure, shock, or multiorgan system dysfunction): % critical cases, needing icu treatment, may show symptoms of acute respiratory distress syndrome (ards) like lung disease, with widespread inflammation in the lungs. consolidation lesions also remain at long-term and can leave fibrotic changes in the lungs. furthermore, patients who are critically ill, needing icu treatment, are at risk of developing post-intensive care syndrome (pics) including icu-acquired weakness (icu-aw). [ ] [ ] [ ] mortality among patients admitted to the icu ranges from % to %. health care professionals should be aware that the clinical progression of symptoms might occur one week after illness onset. , , important subgroups are elderly people (≥ years of age) and those with underlying health conditions (eg, hypertension, diabetes, cardiovascular disease, chronic respiratory disease and cancer), who are considered to be more at risk of developing severe symptoms, but also at risk of physical deconditioning during hospital stay. , figure is based on recent literature and shows the flow of patients with covid- with their signs and symptoms before , , and during hospital admission; , , - , , , the severity classification , - and the physical therapy goals during hospital stay. [ ] [ ] [ ] [ ] these recommendations focus on the physical therapist management for adult patients with covid- admitted to the (acute) hospital setting. recommendations contain specific physical therapy goals concerning respiratory problems and deconditioning including icu-aw and pics. the recommendations are outlined in sections:  section : patients who are critically ill with covid- admitted to the icu.  section : patients who are severely ill with covid- admitted to the covid ward. we used existing international recommendations , as basis for further specification and contextualization. when our recommendations diverge from the international recommendations, we clarified this in the main text and through a separate paragraph with reflections. the recommendations are structured in the following order: safety recommendations, treatment recommendations (specified for different phases of hospitalization), discharge recommendations, and staffing recommendations. due to the acute and sudden spreading of covid- , the evidence base for optimal treatment for this group of patients is evolving rapidly and new insights are emerging at a similar pace. nevertheless, clear recommendations for hospital-based physical therapist management, either based on evidence or bestpractices, are crucial to support the recovery of patients and safety of health care professionals. these recommendations will be updated periodically based on new evidence and experience, and will be made available through the website of the royal dutch society for physical therapy and the world confederation for physical therapy. to cope with this rapidly evolving evidence base, we utilized a pragmatic approach, rather than a formal approach (such as grade), respiratory droplets and aerosols may be released from patients during physical therapist interventions and may cause further spread of the virus. direct contact between physical therapists and patients with covid- , therefore, should be minimized to avoid risk of virus transmission and reduce usage of scarce ppe. therefore, we recommend physical therapists make optimal use of telecommunication and written information material. if direct (face-to-face) contact with patients with covid- is required, physical therapists should use ppe. recommended ppe include a gown, gloves, eye protection and a facemask.  active mobilization, which may lead to coughing and secretion mobilization or disconnection of the mechanical ventilation. if one of the above procedures is performed, physical therapists are recommended to wear a facemask that filters at least % of airborne particles (ie, ffp mask, n facemasks). physical therapists should ensure that they are fully competent in the use of ppe. safety recommendations need to be taken into account during all  recommendation: make optimal use of digital and/or written information for the instruction of patients. physical therapist management for patients hospitalized with covid- comprises elements of respiratory support and active mobilization. , recommendations toward respiratory support, defined as the "proactive approach to minimize respiratory symptoms during the acute phase of a pulmonary disease," are presented in detail. in the treatment of patients with covid- , respiratory support can consist of breathing control, thoracic expansion exercises, airway clearance techniques and respiratory muscle strength training. recommendations toward active mobilization concern the "proactive approach to support any physical activity where patients assist with the activity using their own strength and control: patients may need assistance from staff or equipment, but they are actively participating in the exercise." examples of active mobilization are bed mobility activities (eg, bridging, rolling, lying to sitting), active range-of-motion exercises, active (-assisted) limb exercises, adl training, transfer training, cycle ergometer, pre-gait exercises, and ambulation. [h ] phase a: patient is unconscious-respiratory support. patients with critical illness due to covid- may develop acute respiratory distress syndrome (ards)-like symptoms, requiring admission to the icu. initially, the majority of patients are deeply sedated (rass ≤ - ) and mechanically ventilated in prone position. these patients often receive neuromuscular blocking agents in order to support mechanical ventilation, as this drug application can improve chest wall compliance, eliminate ventilator dyssynchrony, and reduce intraabdominal pressures. given the lack of therapeutic goals in this phase, physical therapist management concerning respiratory support is not recommended. this might be different for physical therapists outside the netherlands with other scope of practice concerning respiratory support. [h ] phase a: patient is unconscious-active mobilization. [h ] phase b: patient is conscious and able to cooperate-respiratory support. the moment sedation is reduced (rass ≥ - ) and the patient is conscious and able to cooperate (s q ≥ ), a new phase starts. normally, this is the phase to start active mobilization and respiratory support; however, in patients with covid- , detachment of the closed mechanical ventilation system circuit should always be avoided due to the risk of virus transmission. even in the case of weaning from mechanical ventilation, where physical therapists typically aim to ensure sufficient inspiratory muscle strength, , the risk of virus transmission via droplets or aerosols in using medical assistive testing devices is too high. therefore, we recommend to not detach the ventilation system for the purpose of respiratory function testing, respiratory muscle training, or breathing exercises. to our knowledge, it remains unclear if both droplets and aerosols are filtered by disposable bacterial filters. in case of prolonged weaning, patients who fail more than weaning attempts or require more than seven days of weaning after the first spontaneous breathing trail, respiratory muscle training should be discussed in the multidisciplinary team. the team may decide that benefits of respiratory muscle training outweigh the safety risks. in the phase after prolonged (assisted) mechanical ventilation, inspiratory (imt) and expiratory muscle training (emt) can be used to counterbalance the weakness of the respiratory muscles. however, the use of these devices is not recommended in patients with covid- due to the increased risk of virus transmission. in this situation, training can be started pragmatically (ie, without respiratory testing results) using a threshold training device, with low resistance (< cmh o) and can be increased based on clinical presence, experienced dyspnea and borg score for perceived exhaustion. for respiratory muscle strengthening, a combination of both imt and emt is recommended, as this combination is superior to imt alone in improving respiratory muscle strength. as respiratory muscle training devices could carry the virus (prolonged), the use of these devices should be discussed with hospital officers for hygiene and infection prevention. recommendation: discuss with the multidisciplinary team whether to pragmatically initiate respiratory muscle strengthening in patients with prolonged weaning. [h ] phase b: patient is conscious and able to cooperate-active mobilization. when patients become conscious and cooperative, active mobilization can be considered. active mobilization should aim to prevent icu-aw and deconditioning from immobilization and illness. the medical research council sum-score (mrc-ss) is widely used to diagnose icu-aw, which is defined as an mrc-ss < . it is assumed that patients diagnosed with icu-aw may benefit from active mobilization also following their icu admission. physical activities for patients who are critically ill should be planned and targeted following the evidence based statement for physical therapist management in the icu as much as possible. patient safety criteria according to sommers et al. for active mobilization that always need to be considered at the icu, are presented in figure . close monitoring of respiratory and hemodynamic functions of patients is crucial to ensure patients' safety. , as a first step, bed mobility activities can be performed by assisting bridging, rolling, and transferring from supine to sitting. medical assistive devices (eg, a bed cycle) might be used to support active mobilization. however, use of these devices should be discussed with hospital officers for hygiene and infection prevention. to evaluate and increase training intensity, frequency and/or activities, criteria of american college of sports medicine (acsm) guidelines for exercise testing and prescription, ideally, the physical therapist is the leading health care professional to guide active mobilization. however, safety recommendations can also be decisive in initiating physical therapist management. if safety recommendations for health care providers do not warrant direct physical therapy contact, we recommend to instruct nurses to combine active mobilization with daily care activities. in this case the physical therapist has a coaching role. patients who are severely ill with covid- who require hospitalization can present with complications such as pneumonia, hypoxemic respiratory failure/ards, sepsis and septic shock, cardiomyopathy and arrhythmia, acute kidney injury, and complications from prolonged hospitalization, including secondary bacterial infections. because the consequences of the infection impact the respiratory system, one of the goals of physical therapist management is to optimize respiratory function. therefore, respiratory support aims to improve breathing control, thoracic expansion, and mobilization/evacuation of secretion. active mobilization aims to increase (or maintain) physical functioning and independence in activities of daily living (adl). these recommendations also apply for patients recovering from critical illness due to covid- . additionally, in patients recovering from critical illness respiratory muscle strength/endurance training can be continued. [h ] respiratory support. respiratory support serves several purposes: to improve vital capacity, to evacuate secretion, and to strengthen respiratory muscle. techniques and goals are briefly introduced as follows: breathing control and thoracic expansion exercises, and combines these with huffing and coughing. , , huffing and coughing contribute to the formation of respiratory droplets and aerosols and should be avoided in direct contact with health care professionals. therefore, these maneuvers are only recommended in case of airway obstruction due to excess secretions. the multidisciplinary team should carefully evaluate whether airway obstruction is present through medical history taking (eg, the presence of productive cough), physical examination (eg, the presence of pulmonary rhonchus), and observations. telecommunication and/or written instruction material can be used to support the use of acbt. if patients fail to effectively use acbt, teaching these techniques under direct supervision of a physical therapist can be considered.  strengthening of respiratory muscle: patients with covid- might have suspected respiratory muscle weakness caused by prolonged mechanical ventilation during icu stay. after transfer to the covid ward, respiratory muscle strengthening can be continued for patients recovering from critical illness according to the recommendations in section , phase b. training protocols typically use resistive loads ranging between % and % of mip. however, the use of noninvasive handheld manometers is not recommended in patients hospitalized with covid- due to the increased risk of virus transmission. according to section , phase b, training can be started pragmatically (ie, without respiratory testing results) using a threshold training device with low resistance (< cmh o), and can be increased based on clinical presence, experienced dyspnea and borg score for perceived exhaustion. one of the unique advantages of respiratory muscle training is that it can be implemented in shorter intervals ( breaths, times/day). training effects from respiratory muscle training have been observed for multiple protocols lasting only weeks. a telehealth or mobile app- [h ] active mobilization. if patients are bedridden and suffering from covid- , pulmonary ventilation can be stimulated by bed mobility activities through bridging, rolling, and sitting. if possible, patients might assist with their own strength and control. if needed, staff and equipment can be used to support the activity. a vertical position can be obtained with less support of patients by tilting the bed or using a tilt table. in order to prevent further deconditioning, patients should be stimulated to be physically active through active mobilization as much as possible through the hospitalization period. physical therapists can provide specific exercises and training that meet the needs and preferences of patients with covid- . maintaining or improving physical functioning should be executed following common safety recommendations, monitoring, and guidance. , based on our expert opinion, at least patient's saturation and heart rate should be monitored before and during active mobilization, due to the low and fluctuating vital capacity of patients with covid- . active mobilization interventions that need to be considered are bed mobility activities, active range of motion exercises, active(-assisted) limb exercises, adl training, transfer training, cycle ergometer, pre-gait exercises, and ambulation. the hospital-based physical therapist should screen patients with severe illness due to covid- on whether physical therapist management should be continued after hospital discharge. hospital-based physical therapists with these skills and knowledge should be tasked with training of less experienced colleagues to provide them with the necessary skills, knowledge and self-confidence for physical therapist management of patients with covid- .  recommendation: deploy physical therapists with sufficient skills, knowledge and self-confidence in care for patients who are severely ill at a covid- ward or in the icu. the covid- outbreak presents new challenges for health care professionals. physical therapists will work intensively with patients who are severely ill, which can lead to mental health distress. it is recommended for managers to plan sufficient recovery time between work shifts of physical therapists and to let less experienced colleagues carefully be supervised by experienced peers. in these turbulent times, provision of psychosocial support should be considered.  recommendation: provide psychosocial support for hospital-based physical therapists. in this manuscript we provide detailed recommendations and intervention descriptions for hospital-based the royal dutch society for physical therapy (kngf) supported the development of the recommendations. the early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia covid- and italy: what next? lancet time kinetics of viral clearance and resolution of symptoms in novel coronavirus infection. american journal of respiratory and critical care medicine interim clinical guidance for management of patients with confirmed coronavirus disease (covid- ) handbook of covid- prevention and treatment characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention corona -: situation report, . geneva: world health organization preventable iatrogenic disability in elderly patients during hospitalization she was probably able to ambulate, but i'm not sure response to pulmonary rehabilitation: toward personalised programmes? the european respiratory journal personalised pulmonary rehabilitation in copd physiotherapy management for covid- in the acute hospital setting: clinical practice recommendations joint statement on the role of respiratory rehabilitation in the covid- crisis: the italian position paper improving long-term outcomes after discharge from intensive care unit: report from a stakeholders' conference the incidence of intensive care unit-acquired weakness syndromes: a systematic review exercise rehabilitation following intensive care unit discharge for recovery from critical illness: executive summary of a cochrane collaboration systematic review physiotherapy in the intensive care unit: an evidence-based, expert driven, practical statement and rehabilitation recommendations grade guidelines: a new series of articles in the journal of clinical epidemiology covid- : respiratory physiotherapy on call information and guidance physiotherapy for adult patients with critical illness: recommendations of the european respiratory society and european society of intensive care medicine task force on physiotherapy for critically ill patients expert consensus and recommendations on safety criteria for active mobilization of mechanically ventilated critically ill adults european respiratory society statement on pulmonary rehabilitation. american journal of respiratory and critical care medicine early intervention (mobilization or active exercise) for critically ill adults in the intensive care unit. the cochrane database of systematic reviews severe acute respiratory syndrome coronavirus (sars-cov- ) and coronavirus disease- (covid- ): the epidemic and the challenges critical care crisis and some recommendations during the covid- epidemic in china the use of neuromuscular blocking agents in the icu: where are we now? bewegingsbeperkingen bij patiënten die in buikligging worden verpleegd stretch for the treatment and prevention of contractures. the cochrane database of systematic reviews inspiratory muscle rehabilitation in critically ill adults. a systematic review and meta-analysis weaning failure and respiratory muscle function: what has been done and what can be improved the bacterial and viral filtration performance of breathing system filters weaning from mechanical ventilation. the european respiratory journal combination of inspiratory and expiratory muscle training in same respiratory cycle versus different cycles in copd patients: a randomized trial american journal of respiratory and critical care medicine ers statement on respiratory muscle testing at rest and during exercise. the european respiratory journal respiratory muscle rehabilitation in patients with prolonged mechanical ventilation: a targeted approach psychophysical bases of perceived exertion interobserver agreement of medical research council sum-score and handgrip strength in the intensive care unit relationship of medical research council sum-score with physical function in patients post critical illness. american journal of respiratory and critical care medicine acsm's guidelines for exercise testing and prescription bronchiectasis toolbox: the active cycle of breathing technique incentive spirometry: . respir care time course of lung changes on chest ct during recovery from novel coronavirus (covid- ) pneumonia the active cycle of breathing technique: a systematic review and meta-analysis efficacy of a novel method for inspiratory muscle training in people with chronic obstructive pulmonary disease evaluation of the effectiveness of a home-based inspiratory muscle training programme in patients with chronic obstructive pulmonary disease using multiple inspiratory muscle tests role of physical therapists in reducing hospital readmissions: optimizing outcomes for older adults during care transitions from hospital to community surviving critical illness: what is next? an expert consensus statement on physical rehabilitation after hospital discharge survivors of critical illness and their relatives. a qualitative study on hospital discharge experience physiotherapy treatment approaches for survivors of critical illness: a proposal from a delphi study sars: sequelae and implications for rehabilitation key: cord- -kqpnwkg authors: sun, yingcheng; guo, fei; kaffashi, farhad; jacono, frank j.; degeorgia, michael; loparo, kenneth a. title: insma: an integrated system for multimodal data acquisition and analysis in the intensive care unit date: - - journal: j biomed inform doi: . /j.jbi. . sha: doc_id: cord_uid: kqpnwkg modern intensive care units (icu) are equipped with a variety of different medical devices to monitor the physiological status of patients. these devices can generate large amounts of multimodal data daily that include physiological waveform signals (arterial blood pressure, electrocardiogram, respiration), patient alarm messages, numeric vitals data, etc. in order to provide opportunities for increasingly improved patient care, it is necessary to develop an effective data acquisition and analysis system that can assist clinicians and provide decision support at the patient bedside. previous research has discussed various data collection methods, but a comprehensive solution for bedside data acquisition to analysis has not been achieved. in this paper, we proposed a multimodal data acquisition and analysis system called insma, with the ability to acquire, store, process, and visualize multiple types of data from the philips intellivue patient monitor. we also discuss how the acquired data can be used for patient state tracking. insma is being tested in the icu at university hospitals cleveland medical center. each year, more than four million acutely ill patients are admitted to intensive care units (icus) in the u.s. alone; approximately , of them do not survive [ ] [ ] [ ] . in extreme situations, like the current covid- pandemic, icus are essential for treating critically ill coronavirus patients. given the high stakes involved, timely and effective care is paramount, and this requires continuous patient surveillance using sophisticated monitoring equipment. as a result, icus are complex, data-intensive environments and dozens of systemic parameters are monitored, including heart rate, respiration, arterial blood pressure, oxygen saturation, temperature, end tidal co concentration, etc. enormous volumes of multimodal physiological data are generated including physiological waveform signals, patient monitoring alarm messages, and numerics and if acquired, synchronized and analyzed, this data can been effectively used to support clinical decision-making at the bedside [ , ] . clinical personnel rely on information from these signals provided on the patient monitor display for visual assessment or as numerics in the emr to understand the current state of the patient, and how it is changing over time. continuous digital monitoring is intended to allow clinicians to dynamically track changes in patient state more closely than would be possible with more sporadic measurements [ ] . the hope has been that this would allow for more accurate diagnosis, earlier anticipation of deterioration, and a clearer understanding of the impact of administered treatments, improving quality of care and lowering costs [ ] . even when data can be viewed in real-time, standard approaches provide little insight into a patient's actual pathophysiologic state. understanding the dynamics of critical illness requires precisely time-stamped physiologic data (sampled frequently enough to accurately recreate the detail of physiologic waveforms) integrated with clinical context, but this will produce an overwhelming amount of data-far too much to be routinely reviewed manually. it is thus necessary to develop a data acquisition system that facilitates the access and review of historical data for medical personnel. the acquired data needs to be synchronized across disparate devices, archived, analyzed and presented to clinical personnel in a manner that supports clinical decision-making at the patient bedside. previous work includes, for example: matam and duncan adopt the real-time data recording system used for f race cars to acquire and analyze data from bedside monitors in the pediatric intensive care unit [ ] . this system supports the storage and review of electrocardiogram (ecg) data retrospectively. raimond et al. developed a platform called "waveformecg" that provides interactive analysis, visualization and annotation of ecg signals [ ] . alexander et al. developed an alarm data collection framework to acquire all alarms generated from philips intellivue mp patient monitors installed in each icu room with the objective of reducing false alarms by leveraging annotations provided by clinicians [ ] . hyung and chul introduced a physiological data acquisition and visualization program "vital recorder" with a user-friendly interface similar to that of a video-editing program for anesthesia information management, where physiological data can be manipulated like editing video clips [ ] . much of the previous work has focused on the acquisition or visualization of certain physiological data, a complete general purpose solution for data collection, analysis and visualization of multimodal icu data is currently unavailable. icu clinical personnel need the ability to effectively deal with different data sources on a patient or departmental level, and need advanced analytic methods that transform this data to actionable and clinically meaningful outcomes for each patent. we have been working on building the integrated medical environment (time) [ ] to address this critical opportunity and in this paper, we discuss an integrated system (insma) that supports multimodal data acquisition, parsing, real-time data analysis and visualization in the icu. in the current implementation, insma acquires data from the philips intellivue patient monitor, and has the ability to store and review the multimodal data acquired either in real-time or on request. the system has been tested in the icu at university hospitals cleveland medical center, for multimodal data analysis and patient state tracking. the remainder of the paper is organized as follows. in section , we discuss some related work. in section , we present the insma framework, and introduce the details of the data acquisition, parsing and visualization modules. in section , we discuss the applications of our proposed system. we conclude our work and suggest possible future work in section . icus provide treatment to patients with the most severe and life-threatening illnesses and injuries. it requires uninterrupted attentiveness and medical care from various clinical specialists and medical equipment to sustain life and help nurture the patients back to health. effective and reliable patient monitoring and data analysis are of ultimate importance in the icu to ensure early diagnosis, timely and informed therapeutic decisions, effective institution of treatment and follow-up [ , ] . several clinical information systems have been developed from both industry and academia to meet the demanding needs of the icu. general electric (ge) co.'s centricity critical care system introduced in creates actionable insight across the healthcare system and the care pathway in intensive care units, enabling enhanced clinical quality and operational efficiency. the system collects data from monitors and ventilators and displays it in spreadsheets reminiscent of the typical icu chart. data are collected from medical devices through device interfaces that connect with ge's unity interface device network [ ] . the datex-ohmeda s/ ™ collect program proposed by ge healthcare can obtain high-resolution data from the datex-ohmeda s/ ™ series monitors [ ] . the program was developed for windows xp and is not compatible with current windows operating systems, and the manufacturer does not intend to update it. philips offers data management solutions that link the philips als monitor/defibrillator and aed and allow quality assurance officers using a direct connection that downloads and forwards every event automatically. quality assurance officers can then retrieve and review an event summary with confidence [ ] . often, the commercial off-the-shelf products do not support the acquisition, archiving, or annotations of high-resolution physiologic data with bedside observations for clinical applications. systems have also been developed in academic settings primarily to support clinical research. tsui et al. developed a system to acquire, model, and predict icp in the icu using wavelet analysis for feature extraction [ ] . goldstein et al. proposed and developed a physiologic data acquisition system that could capture and archive parametric data, but the annotation of important clinical events such as changes in a patient's condition or timing of drug administration, was limited [ ] . kool et al. reported that they collected numerical data at five-second intervals from the datex ohmeda s/ tm monitoring system using their own information management system [ ] . liu et al. [ ] also reported the collection of vital signal data from surgical patients, from philips intellivue mp series monitors, using a self-developed program that was not disclosed. lee and jung developed an anaesthesia information management system (aims) for the acquisition of high-quality vital signal data (vital recorder) to support research [ ] . physiological data of surgical patients were collected from operating rooms by vital recorder through the patient monitor, anaesthesia machine and bispectral index monitor. winslow et al. proposed a platform called waveformecg for visualizing, annotating, and analyzing ecg data [ ] . as discussed in the first section, these systems only focus on acquiring and analyzing one or two types of physiological data, and that is not sufficient for icu applications. matam and duncan used real-time data recording software, atlas from mclaren electronics systems that continuously monitor and analyze data from f racing cars to implement a similar real-time data recording platform system adapted with real time analytics to suit the requirements of the intensive care environment [ ] . the parameter data recorded by philips mp bedside monitors can be transferred to the server in real-time. however, such a third-party data acquisition tool is not flexible enough to customize the functions according to the clinician's requirements, and the compatibility of the data format is another issue. to address the issues described above, our research proposed the insma with the aim of obtaining clinical physiological data including electroencephalography (eeg), electrocardiography (ecg), photoplethysmogram (ppg), peripheral capillary oxygen saturation (spo ), blood pressure (bp) and other signals to be acquired and stored for data sharing, mining, analysis and visualization. the primary data source in our first implantation comes from the intellivue mp (philips, germany) series of monitors. insma contains three independent but data related modules: data acquisition module, parsing module and visualization module. figure shows the insma architecture and its data flow. the data acquisition module establishes the connection with the patient monitor and requests the physiological measurements that are acquired. the raw multimodal data obtained from the monitor includes physiological waveforms, alarm messages and numeric (vitals) data. the specific types of data to be acquired can be chosen by the users according to their needs through the "data type selector" and "physiological signal selector". the data transport rate can also be set by the "serial port selector". once the raw data has been acquired from the monitor, the data parsing module will process, parse and transform the data into a time-series using the physiological identifiers or codes provided by the monitor. the data visualization module will display the graphs for the parsed time-series results. it can plot both real-time signals and historical data given a time range. all three modules are developed using mfc and c/c++, so that they all run in the same operating environment and use compatible data formats, and therefore provide a complete solution for data acquisition, parsing and visualization. the details of these modules are discussed in next sections. the bedside patient monitor is the most common long-term monitoring medical device used in an icu. it is used to continuously monitor the physiological parameters of an patient through specially designed sensors, signal acquisition modules, and invasive or noninvasive interfaces: cardiac activity including ecg and heart rate, circulation including blood pressure & cardiac output indices, spo , respiratory function including respiration rate, oxygenation, capnography, and brain through eeg waveforms and derived indicators, temperature and metabolic rate, etc. the philips intellivue mp is a bedside patient monitoring device that displays various physiological waves (e.g. ecg and blood pressure) and provides important functions such as displaying numeric vitals data (e.g. heartrate, oxygen saturation) and performing alarm functions based on minimum and maximum limits set by the clinical staff in the monitor. a variety of sensors and associated clinical measurement modules can be connected to the monitor, and these modules are generally interchangeable with other monitors provided by philips [ ] . one of these modules is the philips vuelink module that provides an interface to more than third-party specialty measurement devices like baudrate protocol is a connection-oriented, message-based request/respond protocol, based on an object-oriented model concept. all information is stored as attributes within a set of defined object types. the following objects are defined in the protocol: medical device system (mds), alert monitor, numeric, and patient demographics. in order for a client application to access the attributes of instantiated objects, it first has to poll the mds object. then, the client gets the information of the instantiated object via queries that return the attribute values of these objects. after building the association, the following data can be accessed from the intellivue monitor: all measurement numerics and alarm data (real-time update rates up to ms), wave data, and patient demographic data entered by the user in the intellivue monitor. the data acquisition module collects and stores real-time data from patient monitors in intensive care units for further data analytics that supports clinical decision-making. we developed an interface using mfc, to make the data acquisition process easy to be controlled by users. figure shows the interface with function areas - . the data acquisition and preprocessing tools can perform high-resolution recording and processing tasks, such as simultaneously recording of - ecg (at samples/s) channels, and additionally up to non-ecg (at or . samples/s) waves, along with other signal types such as all available numeric values and alert messages. after the program is started, a text file including the monitoring results of the selected data type and signals will be generated for further analysis. the file is named by the date time and patient's demographic information. the data parsing module runs synchronously with the data acquisition module to continuously parse real-time data being streamed from the monitor to increase the efficiency of the data collection and archiving process and to also when parsing the data, we first identify each frame by locating its bof ( xc ) and eof ( xc ), and get the type and length of the message from hdr. next, we interpret the time stamp from the user data. in the data export protocol defined by philips intellivue monitor, the time stamps contain two types of data: absolute time and relative time. for the waveform signals, the intellivue patient monitor supports the wave types ( table i) that are defined by sample period, sample size, array size, update period and bandwidth requirement. the data visualization module can display the multimodal data including the wave signals and numeric data of patients. figure illustrates the main interface. the timestamp is displayed above the chart. the selector ( ) lists all the numeric data types obtained from the parsed results. when a numeric data type is chosen, its value will be displayed in the panel ( ) in real-time. the list in ( ) will update automatically when the program finds "new" data type in the parsed results of that numeric data. the numeric data is displayed as markers (dots) instead of a continuous curve, and each dot represents one data value at that time point. different types of waveforms or numeric values are displayed in different colors, so it is easier for users to distinguish them. all the control commands are displayed in panel ( ) in a log style. the patient's id, wave and numeric data type list can be set in the "option" menu. in addition to providing the patient's physiological status in a real-time mode, the data visualization module can also display waveforms from archived data. users first need to choose the patient and types of waves that are to be visualized, and then set the time range in the "plot setting" window, as shown in figure . in order to evaluate the performance of insma, the system was deployed in the neurological surgery icu at university hospitals cleveland medical center using a dell minicomputer with an intel(r) dual core celeron processor, gb of ram, and gb hard disk storage. results to date indicate that it is reliable for collecting data from the patient monitor. the waveform signals (e.g. ecg, respiration, pleth/co ), numeric signals and alarm event signals when streamed continuously from the monitor over a -hour period generate an approximately mb data file for each patient. the parsed results will be larger in size because the absolute time stamp information is added to each sample point in the file. how the patient is progressing by observing the art and icp waveforms, and how they are temporally correlated. we also collected alarm messages and numeric measurements in the parsed results. the analysis of icu data from patients in the clinical setting is generally limited to visualizing waveform and numeric data and computing simple values such as average heartrate, average respiratory rate, average blood oxygen saturation, etc. in insma, each waveform can be analyzed independently or in conjunction with other waveforms to extract more information, as shown in fig. . it is possible to zoom in to provide additional waveform details for visual inspection or apply different analytical analysis techniques to single or multiple waveform signals to better understand the status of the patient and support clinical decision-making. it has been well established that feature extraction for quantifying the complexity and/or variability in physiological time-series data can provide important information related to health and disease [ ] . specifically, even though temporal patterns of variability can be leveraged as powerful diagnostic and/or prognostic indicators, the current use of beat-tobeat and cycle-to-cycle variability dynamics at the bedside is hampered by: ( ) lack of high-resolution real-time multimodal clinical data, ( ) non-trivial interpretation and integration of these variability metrics into clinical workflows, and ( ) lack of a unified framework for classifying variability dynamics into meaningful clinical categories. algorithms that quantify variability dynamics over multiple temporal scales, such as multiscale entropy (mse) and multifractal detrended fluctuation analysis (mfdfa) have shown a lot of promise as diagnostic tools in clinical research settings, but the difficulty in interpreting these measures by non-specialists prevents their routine implementation and use in the icu. the acquired data from patient monitors can be used to develop novel and generalizable methods for quantifying and tracking patient state in real-time [ ] . we are developing a patient state tracking system based on the analysis of physiologic time-series dynamics as shown in fig. . in stage ii, the data is analyzed using the beat-to-beat or cycle-to-cycle time-series data that is of interest. a new dataset is analyzed (step ) with the same algorithm used in step , the ann classifies the output of the algorithm in step , and the result of the ann classification is then mapped into the physiological phase space in step . this methodology reduces the dimensionality of multiscale variability dynamics in a clinically relevant manner, thereby facilitating the development of clinician-centric visualization tools that can be implemented in a bedside display, and easily integrated in the icu workflow as a generalized early warning system for clinical decompensation in icu patients [ ] . any algorithm that quantifies multiscale variability dynamics [ ] [ ] can be used to process the waveform data in order to classify the information extracted from the raw data in an intuitive and physiologically relevant manner [ ] [ ] , and thus to facilitate the incorporation of subtle and dynamic fluctuations in physiological waveform data. by assessing the current status of a patient in the icu, the system will provide a wealth of information on future trajectories for extracting related clinical information [ ] [ ] [ ] . the amount of data that is available for clinicians to use in support of real-time patient care at the bedside is growing rapidly as a result of advances in medical monitoring and imaging technology. advances in informatics, whether through data acquisition, physiologic alarm detection, or signal analysis and visualization for decision support have the potential to markedly improve patient treatment in icus. clinical monitors have the ability to collect and visualize important numerics or waveforms, but more work is needed to interface to the monitors and acquire and synchronize multimodal physiological data across a diverse set of clinical devices. patient monitors offer the opportunity to acquire a number of different physiological signals in a single device, but in certain cases there are other monitors and devices whose data is critical to patient care, but do not interface to the patient monitor. the time framework that we are developing is directly addressing this unmet clinical need. an integrated solution for multimodal data acquisition, parsing and visualization in the icu (insma) presented in this paper is an important first step in achieving this overall vision [ ] . particularly in the neuro-intensive care unit, there are a variety of different devices that provide valuable information for patient care that do not interface directly to a patient monitor including eeg signal data, real-time tissue blood flow (perfusion) data, and advanced hemodynamic data monitoring (e.g. continuous cardiac output) that are cornerstones in the management of critically ill patients. there are options, for example, with nihon-kohden eeg acquisition systems to collect patient vitals (similar to a bedside patient monitor) as well as interface to specialized devices such as for hemodynamic monitoring. simultaneous acquisition of data from philips patient monitors and nihon-kohden eeg systems in the icu was done to augment data provided in the mimic study [ ] . the objective of data acquisition was to stream real-time data from both monitors for archiving in a single biorepository. this provides valuable data for research, but the intent of time is to stream data for real-time patient care at the bedside. insma is an important first step, and we have also developed data techniques for synchronizing data acquisition from a variety of different icu devices as a core technology for future implementations of time in the icu. we have also demonstrated that patient data acquired from the patient monitor can be used for patient state tracking. the prototype system we developed was optimized to identify the type of dynamics observed in cardiac (ecg or blood pressure) beat-to-beat time-series data collected from icu patients. the prototype system has been tested using icu patient data from ecg to understand how variability in the heartbeat time-series can be used to dynamically track patient state [ ] . in the current development of insma and time, we have implemented the insma software on lenovo thinkcentre m computers, and currently have one system connected to the philips patient monitor in the neurosurgery icu at university hospitals cleveland medical center under the direction of dr. degeorgia to continuously collect patient data. we are completing the development of additional insma units that will be connected to each of the neurosurgery icu beds. the insma system operates in background and once setup for data collection at the bedside and does not require attention from any clinical icu personnel. insma allows the client to send messages to request for patient demographic information, and we implemented a patient demographic request function that monitors any modification of patient information. new patient demographic information will be entered when patients admitted into the icu are connected to the monitor, and this information will be requested and stored in the raw data file. when the patient is discharged and a new patient is admitted and connected to the monitor, the parsing algorithm will capture the change of patient demographic information (e.g. first name, last name, age, weight) and a new patient archive corresponding to the new patient identifier will be created, as shown in fig. . each unit is equipped with a wireless communication link that supports remotely monitoring the insma units only from within the hospital firewall to protect the privacy and security of the data, and then also moves the data to a permanent secure data storage unit. example data from patient monitoring is shown in fig. . the future of critical care will require "information management", that includes the real-time collection, integration, and interpretation of various types of physiological data from multiple sources. the possible research work will focus on ( ) the integration and analysis of massive heterogenous medical data to provide scientific decision-making with machine learning methods [ ] [ ], and ( ) the acquisition and processing of vast amount of multi-channel high-density and real-time streaming data using multivariate and nonlinear time series analysis methods to facilitate rapid diagnosis and treatment [ ] . patient care in the icu can be significantly improved through the application of complex system analysis and information management methods. daily cost of an intensive care unit day: the contribution of mechanical ventilation evaluation of acute physiology and chronic health evaluation iii predictions of hospital mortality in an independent database estimating lives and dollars saved from universal adoption of the leapfrog safety and quality standards clinician-in-the-loop annotation of icu bedside alarm data big data analytics in healthcare: promise and potential technical challenges related to implementation of a formula one real time data acquisition and analysis system in a paediatric intensive care unit waveformecg: a platform for visualizing, annotating, and analyzing ecg data vital recorder-a free research tool for automatic recording of high-resolution time-synchronised physiological data from multiple anaesthesia devices intensive care window: a multi-modal monitoring tool for intensive care research and practice information technology in critical care: review of monitoring and data acquisition systems for patient care and research streamlining data management workflow acquiring, modeling, and predicting intracranial pressure in the intensive care unit entropy module and the bispectral index® monitor during propofol-remifentanil anesthesia artifacts in research data obtained from an anesthesia information and management system university of queensland vital signs dataset: development of an accessible repository of anesthesia patient monitoring data for research context aware image annotation in active learning intensive care window: a multi-modal monitoring tool for intensive care research and practice data acquisition and complex systems analysis in critical care: developing the intensive care unit of the future a framework for patient state tracking by classifying multiscalar wavform features neurocritical care inforamtics: translating raw data into bedside action system for collecting biosignal data from multiple patient monitoring systems physiologic data acquisition system and database for the study of disease dynamics in the intensive care unit learning-based adaptation framework for elastic software systems context aware image annotation in active learning with batch mode eliminating search intent bias in learning to rank information extraction from free text in clinical trials with knowledge-based distant supervision knowledge-guided text structuring in clinical trials complex query recognition based on dynamic learning mechanism a common gene expression signature analysis method for multiple types of cancer deep learning for heterogeneous medical data analysis. world wide web opinion spam detection based on heterogeneous information network raim: recurrent attentive and intensive model of multimodal patient monitoring data  integrated system for icu multimodal data acquisition, analysis and visualization yingcheng sun: conceptualization, methodology, software, visualization, writing -original draft. fei guo: conceptualization, software, methodology, visualization. farhad kaffashi: conceptualization, methodology, formal analysis. frank j. jacono: resources, data curation, validation. michael degeorgia: resources, data curation, validation. kenneth a. loparo: conceptualization, funding acquisition, investigation, methodology this work was supported in part by ahrq grant r hs - a (pi: dr. leo kobayashi). ☒ the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☐the authors declare the following financial interests/personal relationships which may be considered as potential competing interests: key: cord- - o tt authors: ceruti, s.; roncador, m.; gie, o.; bona, g.; iattoni, m.; biggiogero, m.; maida, p. a.; covid- clinical management team,; garzoni, c.; mauri, r. title: reduced mortality and shorten icu stay in sars-cov- pneumonia: a low peep strategy date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: o tt background intensive care unit (icu) management of covid- patients with severe hypoxemia is associated with high mortality. we implemented a "care map", as a standardized multidisciplinary approach to improve patients monitoring using: uniform patient selection for icu admission, a low-peep strategy and a pharmacologic strategic thromboembolism management. methods a standardized protocol for managing covid- patients and icu admissions was implemented through accurate early warning score (ews) monitoring and thromboembolism prophylaxis at hospital admission. dyspnea, mental confusion or spo less than % were criteria for icu admission. ventilation approach employed low peep values (about cmh o in presence of lung compliance > ml/cmh o) and fio as needed. in presence of lower lung compliance (< ml/cmh o) peep value was increased to about cmh o. results from march th to april nd , covid- patients were admitted to our icu from a total of patients. % ( ) of them needed mechanical ventilation. the ventilation approach chosen employed low peep value based on bmi (peep +/- . ( - ) cmh o if bmi < kg/m ; peep +/- . ( - ) cmh o if bmi > kg/m ). to date, ten patients ( %) died, four ( . %) received mechanical ventilation, two were transferred to another hospital and ( . %) were discharged from icu after a median of nine days. discussion a multimodal approach for covid- patients is mandatory. the knowledge of this multi-organ disease is growing rapidly, requiring improvements in the standard of care. our approach implements an accurate pre-icu monitoring and strict selection for icu admission, and allows to reduce mechanical ventilation, icu stay and mortality. funding no funding has been required. echocardiography (to establish the global cardiac function before any pronation). a thoracic ct-scan was considered available if it has been performed during the stay in the internal medicine department during the last hours before the admission in the icu. indication for icu admission and oro-tracheal intubation (oti) was routinely established by the intensive care specialist or senior anesthesiologist on duty, according to the 'care map' based on standardized criteria selection, low peep strategy and pharmacologic antithrombotic management. requests of counseling for icu admission came from the department of internal medicine and from the emergency department (ed). with the aim of quickly identifying the worsening of clinical conditions , , all consultations were recorded by reporting patient's symptoms, spo , blood gas analysis values (if available) and clinical decision for admission or not to the icu. patients presenting partial respiratory failure combining peripheral saturation (spo ) lower than % and dyspnea (or mental confusion), or patients with dyspnea (or mental confusion) alone, were eligible to be admitted in icu. exclusion criteria were the will of the patient not to be intubated, cardiocirculatory arrest following hypoxia, metastatic oncological disease, end-stage neurodegenerative disease, severe and irreversible chronic disease (heart failure nyha iv, copd gold d, liver cirrhosis child-pugh > , severe dementia) . with the aim to avoid a misleading interpretation in icu mortality, we decided to perform an extra evaluation on patients excluded from icu, to ensure about their survival status. after endotracheal intubation, we initially provided low peep-value strategy based on bmi (peep cmh intensive supportive care was managed according to the evolution of the inflammatory parameters (crp, ck, ldh and ferritin) and the stability of the p/f-ratio after each supination during the following days. in case of a favorable evolution, sedation was reduced to rass - /- switching on propofol. by improvement of blood oxygen levels, we proceeded to reduce fio up to - % fio values without reducing peep. once all the clinical and biological inflammatory parameters were constantly reduced for almost three consecutive days, patients were gently weaned from peep by keeping a pao > mmhg ( kpa) . the choice of removing the endotracheal tube was made by the doctor in charge according to usual standard of care. deep vein thrombosis, pe, ventilator-associated-pneumonia (vap) and acute kidney injury (aki) have been the main complications arose in patients admitted to icu: dvts and pes were defined as suspected with an increase in serum d-dimer values over , ng/ml, while they were considered as confirmed by ultrasound or ct-scan positive finding, defined according to current clinical standards. vaps were identified according to usual standard care with an increase in secretions, in their quality and quantity, requiring an increase in the fio administration . each case of aki rifle f requesting cvvhdf has also been reported. all complications, administered drugs and adverse events occurring during the stay in intensive care, were registered and reported in the electronic medical record. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . descriptive statistics were used to summarize the clinical data collected. no statistical sample size calculation was performed. we present continuous measurements as mean (min-max, sd) otherwise as median (iqr) if they are normally distributed. categorical variables were reported as counts and percentages. test statistics and survival analysis were performed with r v. . . and the kaplan-meier estimator from cran "surv" package. data was subsequently compared with a similar in number and follow-up cohort published by bhatraju et al - complete patient data was retrieved from the supplementary appendix. this study has been notified to the ethics committees of canton ticino. according to the local federal rules, it has been approved as a clinical data collection case series. no funding has been required. the corresponding author confirms that he had full access to all the data in the study and he had final responsibility for the decision to submit for publication. patients with covid- symptoms presented to our clinic. according to exclusion criteria, of them were not admitted to the icu as they had a "do not resuscitate" order (dnr) in place before hospital admission table . patients had a mean age of ± · years; most of them were men, often burdened by one or more chronic medical conditions (table ) . at icu admission, most patients showed hemodynamic stability. a chest ct-scan was obtained in ( %) patients; all of them showed bilateral ground glass opacities and four of them showed consolidations in addition (table ) . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint at admission pao :fio ratios had a median of ( - ); with a median fio of % ( % - %) at the icu admission. thirty-two ( %) patients received invasive mv, the others were treated with high-flow nasal cannula (table ) . globally, mean peep for patients with bmi < kg/m was cmh o ( - , sd · ), while mean peep for patients with bmi > kg/m was cmh o ( - , sd · ). after the onset of mv, the median fio improved around % ( % - %), with first pao :fio ratio with a median of ( - ) ( table ) . thirty-one ( · %) patients were placed in a prone position (with an average number of pronations of four). in these patients, pao :fio ratio progressively improved during next days, with a median value of ( · - ) during the first day, · ( · - · ) during the second day and ( - ) during the third day (table ). no patient presented any contraindication to be treated with parenteral anticoagulation; ( %) patients were simply treated through prophylaxis, while ( %) patients were managed by full therapeutic anticoagulation ( - % -with unfractioned heparin, - % -with lmwh). no patient presented any bleeding complication, nor clinical sign requiring anticoagulation reduction or removal. the median length of icu stay was nine days ( - · ); the median duration of mv was seven days ( - ) (table ) . on th april, of the patients, ten ( · %) has died, four ( · %) are still in the icu receiving mv (two endotracheal tube, two tracheostomy), two patients were transferred to another hospital and ( . %) have been discharged from the icu ( figure ) in good medical condition with no additional death in the following days. at day from icu discharge, patients ( %) presented a karnofsky performance status of more than . no patients have been reintubated within or after hours. the intensivist consultant performed clinical counseling of patients admitted to the internal medicine department, ed or from other hospital. the mean age was ± years ( - ), presenting spo median of % ( - ), pao median of · mmhg ( · - · ), a pco median of · mmhg ( · - · ) and a median value of hb of · g/l ( · - · ). twenty-six of these patients moved to our icu and five of them . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint had already been intubated in other hospitals. intriguingly, the remaining patients consulted but not admitted improved their conditions from an initial median value of spo of % ( - %) without being highly symptomatic nor requesting admission in icu, even for extremely low spo values, but with no symptoms of fatigue such as dyspnea (figure ). we compared our patients with a cohort of patients published by bhatraju et al. . mean age of admission was comparable between the two studies (median ± vs ± yrs), with patients admitted in lugano having a slightly lower bmi value ( · ± · vs · ± · , p-val . ). no significant difference was found in the hematological status of the two cohorts (wbc, lymphocytes and platelets) and comparable level of lactate, maximal crp level during recovery and liver transaminases (table ) pandemic , . it requires adequate preparation in terms of hospital structure, triage systems and clinical training in order to be correctly addressed and minimize the burden for the patients and the icu capacity. as covid- is a multisystemic disease, a multidisciplinary approach is mandatory . to optimize management of tachypnea without dyspnea, also with spo lower than normal, surveillance tools such as routine and regular early warning score (ews) measurement (every hours if stable, reduced hourly if spo < %) , were implemented for intermediate care patients. patients with covid- interstitial pneumonia present tachypnea correlating with the desaturation degree, without dyspnea or severe neurological . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint symptoms or any organ damage. high pulmonary compliance is probably the responsible for the absence of dyspnea ; we waited until the onset of dyspnea or to a value of % of spo before admitting any of the patients to the icu; in such a way, an overload of the icu was avoided. none of the patients who after a specialist consultation were not admitted to icu but only placed under clinical surveillance, died in a follow-up from seven up to days. most of these patients improved their clinical status without being dyspnoeic and some of them have already been discharged from the hospital. patients showing a worsening degree of dyspnea transferred to the icu received "low peep ventilatory strategy", on the contrary to what has been reported in the literature . after intubation we found lungs easy to ventilate, with a higher compliance (on average above ml/cmh o) compared to the "classic ards" . even if the "classic" criteria for defining the ards were confirmed , there were aspects as the absence of a reduced lung compliance, a "baby-lung" and a consequent tendency to hypercapnia, which induced us to evaluate a more specific treatment, at least in the initial phase. in according to ardsnet peep table , , we preferred to ventilate patients with peep tailored to patients' own bmi, carefully following lungs physiology , . this approach would agree with gattinoni et al and bendjelid et al , which suggested two different icu patient populations in covid- pneumonia. the first one presents a high lung compliance and a probable alveolitis, with a shunt effect due to loss of local hypoxic vasoconstriction; this population represents the great majority of our patients. the second one presents a low lung compliance and a picture of baby-lung compatible with "classic ards" (only two patients in our set). the "low peep ventilatory strategy" we applied allowed us to decrease quickly sedation depth once the inflammation level was reduced. this strategy led to less complications (like icu paralysis, delayed awakening, agitation, etc..) and an easier and faster extubation without resorting to large-scale tracheotomy. during daily screening of the lower limb ultrasound, covid- icu patients showed a high prevalence rate of dvts and pes, even under preventive anticoagulation. in addition, many patients had a marked increase in ddimers level, partly linked to the finding of dvt and pe in other sites of the body, partly secondary to pe phenomena also on the pulmonary venous side. in this context, it appears reasonable to protect the patient through a pro-active anticoagulant approach than the normal routine. furthermore, the fact that patients did not encounter any major bleeding phenomenon, supports the idea that in these patients a more aggressive . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . anticoagulation may counterbalance a phenomenon of prothrombotic diathesis, even if the complete mechanism is still unclear. we observed an increased survival compared to other groups (figure and ) , , , . a possible explanation could be that the relative low-pressure ventilation avoids transforming an initial alveolitis into an ardsiatrogenic framework, in which the local ongoing inflammation is rather damaged than helped by high peep (generating a ventilation-induced-lung injury -vili) in a context that is the "not-classic" ards. we observed a very few cases of "classic" ards and, in particular, the absence of ards cases at the time of admission to the icu. mortality in icu is reported to be as high as - % , , while in our dataset is . %. median days of mv reported by bhatraju et al. ( ( - ) ) is longer ( · ( - ) ) than what experienced in our clinical setting. in all, this suggests that a less traumatic approach to ventilation by low peep and avoiding unnecessary mv by delaying icu admission can be of help in managing covid- patients and in improving survival. our study was burdened by several limitations. first, it was a monocentric observational retrospective study, with a relatively small series of patients. second, our comparison with current literature is performed on different patient populations, even if cohorts could be considered similar in terms of disease severity and biochemical investigations. this notwithstanding, early data are very encouraging and needs a validation in bigger prospective studies. in conclusion, the implementation of a multimodal "holistic" approach for covid- patients is highly recommended. we implemented ews monitoring for intermediate care patients, in order to perform a strict selection of icu admission and employ mv as little as necessary. mv ventilation was adapted to the real patient needs -i.e. peep tailored to patient's bmi -in order to reduce alveolar traumatism. anticoagulation screening and therapy has been regulated in order to prevent any sign of thrombosis or thromboembolism. this multimodal program allowed us to reduce the number of icu admissions, the number of ventilation days and mortality, and could be the base for a further specific patients' management in this specific contest. all authors disclose any financial and personal relationships with other people or organizations. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . management of the covid- patients evaluated at the clm. patients status admitted to the icu. at april th , , patients ( . %) died, ( . %) are still receiving mechanical ventilation, were transferred to another hospital and ( . %) were discharged from icu after a mean of days. all data up to days from extubation have been reported. overall survival rate during and after icu admission comparison between the study cohort (class lug; light blue, continuous line) and the data published by bhatraju et al (class sea; light green, dashed line) (p-value = · ). . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . icu mechanical ventilation and laboratory data. continuous measurements were presented as mean (min-max, ±sd) otherwise as median (iqr) if they are normally distributed. categorical variables were reported as counts and percentages. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint coronavirus covid- global cases clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study critical care utilization for the covid- outbreak in lombardy, italy: early experience and forecast during an emergency response critical care crisis and some recommendations during the covid- epidemic in china severe sars-cov- infections: practical considerations and management strategy for intensivists mechanical ventilation redistributes blood to poorly ventilated areas in experimental lung injury prevention and treatment of acute lung injury with time-controlled adaptive ventilation: physiologically informed modification of airway pressure release ventilation covid- does not lead to a "typical" acute respiratory distress syndrome treating hypoxiemic patients with sars-cov- pneumonia. back to applied physiology covid- pandemic: triage for intensive-care treatment under resource scarcity management of adults with hospital-acquired and ventilatorassociated pneumonia: clinical practice guidelines by the infectious diseases society of america and the international ers/esicm/escmid/alat guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia covid- in critically ill patients in the seattle region -case series novel coronavirus infection during the - epidemic: preparing intensive care units-the experience in sichuan province, china a comparison of the quick sequential (sepsis-related) organ failure assessment score and the national early warning score in non-icu patients with/without infection characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention management of critically ill adults with covid- critical care crisis and some recommendations during the covid- epidemic in china less is more" in mechanical ventilation acute respiratory distress syndrome: the berlin definition clinical characteristics of coronavirus disease in china characteristics and outcomes of critically ill patients with covid- in washington state jama demographic characteristics and blood tests at admission. continuous measurements were presented as mean (min-max, ±sd) otherwise as median (iqr) if they are normally distributed. categorical variables were reported as counts and percentages. key: cord- -oorac he authors: nair, girish b.; niederman, michael s. title: community-acquired pneumonia: an unfinished battle date: - - journal: med clin north am doi: . /j.mcna. . . sha: doc_id: cord_uid: oorac he community-acquired pneumonia remains a common illness with substantial morbidity and mortality. current management challenges focus on identifying the likely etiologic pathogens based on an assessment of host risk factors, while attempting to make a specific etiologic diagnosis, which is often not possible. therapy is necessarily empiric and focuses on pneumococcus and atypical pathogens for all patients, with consideration of other pathogens based on specific patient risk factors. it is important to understand the expected response to effective therapy, and to identify and manage clinical failure at the earliest possible time point. prevention is focused on smoking cessation and vaccination against pneumococcus and influenza. have shown that patients with cap in a medicare population have a -year mortality of more than %, suggesting that pneumonia may be a surrogate marker of severe underlying comorbidity, or that it initiates a series of adverse consequences for some patients that leads to their eventual death. despite the availability of different guidelines and treatment options, the economic burden associated with cap remains high at more than $ billion annually in united states alone. although most patients with cap are outpatients, the greatest portion of the cost for this illness is borne by those admitted to hospital, making the decision about admission an important one for several reasons. a recent study noted that decreasing the length of stay by day in a patient with cap had a potential economic benefit of $ . with new health care reforms imminent and the emphasis on better health care delivery, cost-effective treatment of pneumonia will assume greater significance. there are several challenges with the management of cap, from the accurate diagnosis of lung infiltrates, decisions about the site of care, and the choice of appropriate antibiotics. the infectious disease society of america (idsa)/american thoracic society (ats) guideline from provides a summary of the approach to the treatment of cap directed mainly towards primary care physicians, hospitalists, and emergency medicine physicians. multiple validated severity assessment scores have been developed that stratify patients according to the risk of death and can be used as decision support tools to guide site-of-care decisions. , the emergence of drugresistant organisms, particularly drug-resistant streptococcus pneumoniae (drsp), is another challenge in disease management. biomarkers are increasingly being used to distinguish bacterial pneumonia from other causes and to help reduce the duration of antibiotic therapy. this article reviews the recent advances in the diagnosis, management, and potential complications associated with cap. in cap, the major route of infection is microaspiration from a previously colonized oropharynx, but inhalation of suspended aerosolized microorganisms is the mechanism of infection for viruses, legionella, and tuberculosis. interactions between the host immune response, the virulence of the infecting organism, and the size of the inoculums determine whether a patient develops pneumonia. defective cough, mucociliary clearance, and impaired local and humoral immunity predispose to severe pneumonia. alcohol consumption and smoking are independent risk factors for the development of pneumonia. medical comorbidities such as chronic obstructive pulmonary disease (copd), congestive heart failure, chronic kidney disease, liver disease, and immune deficiency states have an increased predisposition for the development of cap. recent use of proton pump inhibitor therapy started within days has been identified as a risk factor for cap. elderly patients are at increased risk for development of pneumonia and, when it occurs, they are more likely to die than younger individuals. although many patients develop severe pneumonia because of immune impairment, others develop acute lung injury (acute respiratory distress syndrome [ards]) as a consequence of unilateral pneumonia because of an inability to localize the immune response to the initial site of infection, possibly because of the presence of a genetic variation in their immune responsiveness. , the most common organism causing cap, in all patient populations, is s pneumoniae, or pneumococcus. other pathogens include hemophilus influenzae (particularly in cigarette smokers), moraxella catarrhalis, staphylococcus aureus (after influenza and recently in the form of methicillin-resistant s aureus [mrsa]), viruses (including influenza, respiratory syncytial virus, parainfluenza, and epidemic viruses), and atypical pathogens such as mycoplasma pneumoniae, chlamydophila pneumoniae, and legionella pneumophila. in most series, atypical pathogens are common, including in those admitted to the icu, where they can account for up to % of the identified pathogens. in addition, many investigators have documented that atypical pathogens may coexist with bacterial pathogens, accounting for their presence in up to % of patients with cap, when serologic testing is used. gram-negative bacteria (pseudomonas aeruginosa, klebsiella pneumoniae, escherichia coli, enterobacter spp, serratia spp, proteus spp) are the causal agents in up to % of patients with cap, but may be more common in patients who develop pneumonia out of the hospital and have hcap risk factors. gram-negative bacteria have been associated with severe cap, and k pneumoniae was noted to be an independent risk factor for mortality in severe cap. in one study from korea, in a multivariate analysis, the risk factors associated with gram-negative cap were septic shock (with an odds ratio of . ), cardiac disease, smoking, hyponatremia, and dyspnea, emphasizing the association of these organisms with severe illness. enterobacter cap behaves more like hospital-acquired pneumonia and is associated with prolonged mechanical ventilation, delay in initiation of antibiotics, and longer icu stay. risk factors for community-acquired p aeruginosa pneumonia include bronchiectasis, immunocompromised state, use of multiple courses of antibiotics, prolonged glucocorticoids in patients with copd, and recent hospitalization. anaerobic organisms should be considered when aspiration is suspected. influenza is a common viral cause of cap, with a seasonal variation in frequency. primary influenza pneumonia tends to cause severe pneumonia, which can be either caused by the virus itself or a result of secondary bacterial infection with pneumococcus, s aureus, or h influenzae. high-risk patients include those with chronic heart or lung disease, diabetes, immunosuppression, hemoglobinopathy, renal disease, and otherwise healthy individuals more than years of age. other viruses that cause cap include parainfluenza virus, respiratory syncytial virus (rsv), human metapneumovirus, severe acute respiratory syndrome virus, varicella, hantavirus, and adenovirus. many of these patients have viral infection as part of a mixed infection, often with bacterial pathogens. emergence of drsp and community-acquired mrsa is a matter of concern that has complicated the empiric therapy choices for patients with cap. drsp is seen most often in patients older than years of age, and in those with a history of alcoholism, antibiotic therapy within months, multiple medical comorbid conditions, exposure to children in day care, or those with immune-compromised states. community-associated mrsa (ca-mrsa) pneumonia occurs in patients with no prior health care exposure, usually after influenza, and may lead to a severe necrotizing pneumonia, although milder forms of illness have also been reported. in patients with severe illness, the organism may produce a variety of exotoxins, including the panton-valentine leukocidin (pvl), which may contribute to lung necrosis. multidrug resistance has been reported with ca-mrsa strains but, in general, these organisms are more drug sensitive than their hospital-acquired counterparts. other less common causes of cap include mycobacterium tuberculosis, coxiella burnetii (q fever), burkholderia pseudomallei (melioidosis), chlamydophila psittaci (psittacosis), endemic fungi (histoplasmosis, coccidioidomycosis, blastomycosis), pasteurella multocida, bacillus anthracis, actinomyces israeli, francisella tularensis (tularemia), and nocardia spp. these organisms should be included in the differential diagnosis when evaluating a patient with cap, depending on the presence of specific risk factors that are noted in the clinical history. patients with cap usually present with an acute illness of to days duration. in those with intact immune response, systemic and respiratory symptoms such as cough, dyspnea, fever, and pleuritic chest pain predominate. fever and chills have a sensitivity of % to %, and dyspnea a sensitivity of % for the diagnosis of cap, whereas purulent sputum has a sensitivity of only %. hemoptysis suggests necrotizing infection, such as lung abscess, tuberculosis, or gram-negative pneumonia, but is also a common finding, even in patients with bronchitis. in patients with disease and age-associated impairments in the immune response, the clinical presentation may be subtle, and involve primarily nonrespiratory findings. in the elderly, chest pain and cough may be absent in the early course of the disease, and fever and confusion may be the only symptoms. other complaints such as lethargy, falling, poor oral intake, and decompensation of a chronic illness could also occur in patients with comorbid conditions and among the elderly. a good history and physical examination are essential for determining the possible causal agent and assessing the severity of illness, which in turn helps with management. risk factors for hcap, such as hospitalization or antibiotic therapy in the past days, residence in a long-term care facility, chronic dialysis, outpatient wound care, or home infusion therapy, needs to be identified, because these patients are at risk for drug-resistant gram-negative organisms and s aureus. the history should identify risk factors for drsp and gram-negative organisms, as discussed earlier. it is also important to elicit recent travel history and exposure to birds, bats, farm animals, and rabbits ( table ) . on physical examination, patients may have tachypnea, tachycardia, crackles, bronchial breath sounds, and findings of pleural effusion. clinicians should pay attention to other clues, such as relative bradycardia in relation to fever, which can be seen in infections caused by agents like legionella, chlamydophila, and mycoplasma. mycoplasma can also cause cervical lymphadenopathy, arthralgia, and bullous myringitis. poor outcomes are noted in patients with a respiratory rate greater than breaths/min, diastolic blood pressure less than mm hg, systolic blood pressure less than mm hg, heart rate greater than beats/min, and temperature less than c or greater than c. these clinical findings can be used to determine the risk of death, by incorporating them into prognostic scoring, using the pneumonia severity index (psi), the curb- criteria (a modification of the british thoracic society scoring system), or other tools (discussed later). other than raising clinical suspicion, no combination of symptoms and signs can accurately diagnose pneumonia in the clinical setting, and the definitive diagnosis requires a chest radiograph. the clinical diagnosis has an overall sensitivity ranging from % to % and specificity between % and %. therefore, whenever there is suspicion of cap, a chest radiograph should be obtained for corroboration of the physical findings. certain chest radiographic findings can also suggest more severe illness, including the presence of multilobar infiltrates, rapid progression of infiltrates, pleural effusion, and findings of necrotizing pneumonia. in the outpatient setting, extensive diagnostic testing is not routinely performed, because results are nonspecific, and antibiotic treatment should be initiated nair & niederman empirically. even for inpatients, the value of diagnostic testing is limited and, when outcomes were compared using pathogen-directed therapy, compared with empiric therapy, there was limited benefit of testing. in one prospective study of patients from the netherlands, a pathogen was identified in % of cases. adequate sputum samples were obtained from only patients, gram stain was diagnostic and confirmed by a positive sputum in %, urine pneumococcal antigen was positive in % of cases, blood cultures were positive in %, and bronchoscopic samples added benefit to diagnostic yield when sputum could not be expectorated. in most studies, a specific causal diagnosis is obtained in less than % of patients with cap, even with extensive diagnostic testing, and the major focus of laboratory testing should be to assess severity of illness and allow early identification of the presence of pneumonic complications. white blood cell count may be normal on admission, and leukopenia is seen in patients with overwhelming pneumococcal pneumonia with sepsis and pneumonia caused by gram-negative organisms. thrombocytosis and thrombocytopenia are associated with worse -day mortality in patients admitted with cap. hyponatremia (< meq/l) is also associated with a poor outcome, if present on admission, in patients with cap. the idsa/ats guidelines recommended testing for patients with pneumonia ( table ) . radiographic evidence of lung infiltration provides a sensitive, but not specific, confirmation of community-acquired pneumonia. chest radiograph may show areas of consolidation, pleural effusion, lung abscess, necrotizing pneumonia, or multilobar illness. it may help in pattern recognition of the disease process: h influenzae has a peribronchial distribution of bronchopneumonia; s pneumoniae infection can have either lobar consolidation or bronchopneumonia; atypical pathogens may have an alveolar and interstitial pattern; aspiration most commonly involves the superior segment of the right lower lobe or the posterior segment of the right upper lobe; hematogenous dissemination follows the distribution of blood flow and may lead to bilateral nodular infiltrates. cavitation or necrotizing pneumonia suggests infection with anaerobes, gram-negative bacteria, or s aureus, including mrsa. loculated effusion can be ruled out by decubitus film or computed tomography (ct). chest ultrasound is increasingly being used to assess the size, and to identify a safe site for sampling of pleural fluid. the usefulness of chest radiography is suboptimal in patients with very early infection, dehydration, severe granulocytopenia, structural changes such as with bullous emphysema, and in obese patients. it is reasonable to repeat a follow-up radiograph in to hours in patients who have had a negative initial finding, but have clinical signs of pneumonia. there may be interobserver variability in chest radiographic interpretation of pneumonia. in a study that compared the readings of at least radiologists, positive agreement ( %) was less frequent than negative agreement ( %). ct has better sensitivity in diagnosing an infiltrate than chest radiography, but it is not routinely used, because there is a lack of evidence that use of ct scan improves outcomes. sputum should be sent for gram stain and culture before starting therapy, but primarily in patients suspected of infection with drug-resistant or unusual pathogens. a good specimen contains no more than squamous epithelial cells and more than polymorphonuclear cells per low per field. the gram stain pattern on sputum can help with tailoring of antibiotics, particularly if it shows a pathogen that would not be treated routinely (such as clumps of gram-positive cocci, suggesting s aureus). the sensitivity of identifying s pneumonia is only % to % and specificity is greater than %. it is less likely to have s aureus or gram-negative pneumonia in the absence of these organisms on gram stain of a good sputum sample, but this test is more valuable if positive than if negative. routine culture of expectorated sputum is not useful in the absence of an informative gram stain. the usefulness of realtime polymerase chain reaction testing of sputum samples has not been shown. culture can be obtained from intubated patients by collecting an endotracheal aspirate. a positive blood or pleural culture is seen in less than % of patients with pneumonia but, if present, helps with establishing the diagnosis. most positive cultures are of s pneumoniae. the idsa/ats guidelines recommend blood culture testing in patients admitted to icu, and in those with multiple other risk factors, including active alcohol abuse, liver disease, cavitatory lung disease, asplenia, leukopenia, and pleural effusion. these recommendations are based, in part, on the data from , medicare patients who showed that a true-positive blood culture was associated with no previous antibiotics, underlying liver disease, systolic blood pressure less than mm hg, fever less than c or greater than c, pulse greater than beats/ min, blood urea nitrogen greater than . mmol/l ( mg/dl), serum sodium less than mmol, and leukocyte count less than or greater than , cells/ ml. the diagnostic yield of blood cultures increased in patients with or more risk factor and in those who had not received antibiotics before blood was collected. urinary antigen testing (uat) is commercially available for detection of capsular polysaccharide of s pneumoniae and l pneumophilia serogroup . pneumococcal urinary antigen tests have a sensitivity of % to % and specificity of more than %. the degree of positivity is correlated with the psi for s pneumoniae. false-positive tests occur in patients who have had cap from pneumococcus within the previous months. uat for legionella has a sensitivity of % to % and a specificity of up to % for detection of infection with serogroup , by far the commonest species to infect humans. however, it does not detect other types of legionella, so a negative finding cannot rule out this infection. in one study, the use of uat for legionella had increased with time, leading to more diagnoses of serogroup infection, but a decreased mortality from legionella, suggesting that urinary antigen testing was finding milder illness than had been recognized previously. although one prospective study of episodes of cap from spain found that s pneumoniae was diagnosed by urinary antigen test in . % and helped physicians optimize antibiotic choice, in general, it remains uncertain whether a positive result of any urinary antigen test changes cap management, or whether it is primarily of epidemiologic interest. serologic tests are of questionable importance in the initial setting, but are useful for the epidemiologic diagnosis of agents that are not readily cultured, although results are generally not available for weeks, and require the collection of both acute and convalescent serum samples. the diagnosis of most pathogens is based on acute and convalescent blood serologies showing a fourfold increase in immunoglobulin (ig) g obtained to weeks apart, which applies to c pneumoniae, c psittaci, q fever, and m pneumoniae. ig m antibodies start to increase in the acute phase and are useful in the early course of the disease. cold agglutinins are sometimes present in patients with m pneumoniae. nucleic acid amplification tests provide rapid test results in cap for atypical agents such as viruses, mycoplasma, chlamydophila, and legionella. polymerase chain reaction (pcr) assays were widely used for detecting influenza virus in the recent h n epidemic. direct immunofluorescence or enzyme immunoassay are available for detection of viral antigens like influenza, rsv, adenovirus and parainfluenza viruses. the usefulness of pcr assays in managing cap has not been proven, and the concern with this method is that it is so sensitive that, if a respiratory sample is positive, it cannot distinguish colonization from infection unless the presence of a specific pathogen is itself diagnostic of infection (such as m tuberculosis). however, the test may be valuable if negative, because the absence of a suspected pathogen by pcr may permit a more focused antibiotic therapy approach. several newer biomarkers have been developed (midregional proadrenomedullin, midregional proatrial natriuretic peptide, proarginin-vasopressin, proendothelin- , procalcitonin [pct], c-reactive protein [crp]) to identify patients with bacterial infection and to define the prognosis of cap. in one recent study, cardiac biomarkers, such as midregional proadrenomedullin, were better predictors of -day and -day mortality than inflammatory biomarkers such as pct. in that study, biomarkers correlated with disease severity and mortality, but did not help with causal diagnosis. in another prospective study evaluating the relationship between biomarkers and icu admission, inflammatory biomarkers helped identify patients needing intensive care monitoring, including those requiring delayed icu admission. the inflammatory biomarkers that have been studied most extensively are crp and pct, both of which are acute-phase reactants primarily produced by the liver in the presence of bacterial infection, but not viral illness. crp may identify which patients with acute respiratory symptoms have infectious pneumonia; levels are higher in patients who require hospitalization and in those with pneumococcal and legionella infection. pct is a hormokine, produced in response to microbial toxins and certain host responses associated with bacterial infection, but inhibited by viral-related cytokines. serum levels tend to be high in patients with cap, who benefit from antibiotic therapy, and in those with an increased risk of death from cap. serial measurements of serum levels have also been used to define when antibiotics can be safely stopped in the presence of cap. , , in one study of patients with radiographic infiltrates and suspected cap, initiation of antibiotics and duration of therapy were determined by randomizing patients to management by an algorithm dictated by serial pct measurements versus management by clinical assessment. the pct-guided group had significantly fewer antibiotic prescriptions on admission and less antibiotic usage, and the duration of therapy was reduced from to days with similar clinical success. one of the most important decisions in the management of pneumonia is to assess the severity of the disease, which can be used to predict mortality risk and may be nair & niederman a surrogate measure to define the site of care (outpatient, hospital ward, or icu). proper site-of-care decisions can have an impact on mortality, with several studies showing that delayed admission to the icu leads to a poor outcome. , the most widely used prognostic scoring systems are the psi and the curb- score. in clinical practice, the psi is not widely used because it is complex and difficult to calculate a score. in addition to these general scoring tools, some evaluations are designed to identify the need for icu admission, including the idsa/ats criteria for severe cap, and an australian method called the smart-cop, which is designed to predict the need for intensive respiratory or vasopressor support. other prediction rules are available and their clinical application varies widely. the psi was developed to identify patients with a low risk of dying who could be safely discharged home and receive outpatient treatment. the psi stratifies patients into categories based on -day mortality, by using a scoring system based on factors. it includes demographic characteristics, coexisting illnesses, physical examination findings, laboratory measurements, and radiographic finding. patients in classes iv ( -day mortality risk of %- %) and v ( % risk of death at days) are usually admitted to the hospital and often to the icu. those in low-risk classes i and ii are often treated as outpatients, whereas it is a clinical judgment whether those in class iii should be hospitalized. the psi score includes age as an important determinant of point scoring and hence can overestimate the severity of illness in the elderly and in those with comorbidity. in one study of patients in psi class v, only approximately % needed icu admission, and these tended to be individuals who scored points based on acute illness features, and not on age and comorbid illness factors. in contrast, the psi may underestimate severity of illness in young patients without comorbid illness, especially if their vital sign abnormalities are slightly less than the cutoffs used in the scoring system. this was a particular problem during recent influenza epidemics that have involved primarily younger populations, in which psi scoring was not valuable for defining the need for icu admission. the curb- score from the british thoracic society is an easy scoring system to use, with the score ( - ) being defined ( point each) by the presence of confusion, blood urea nitrogen greater than . mol/l ( . mg/dl), respiratory rate of breaths/min or greater, systolic blood pressure less than mm hg or diastolic blood pressure no greater than mm hg, and age years or older. patients with of these criteria have a high enough risk of death that they should probably be admitted to the hospital, while those with or more points should be considered for icu admission. modifications of this tool, without the laboratory measurement of blood urea nitrogen (crb- ) have also been found to be similarly accurate. the limitation of this approach is its focus on assessment of only clinical parameters, such as vital signs, but without measurement of oxygenation or serial measurement of severity of illness after the initial hospital admission, and that it does not evaluate the presence of comorbid illness and its decompensation from baseline. serum biomarkers can be used to supplement data obtained by prognostic scoring. data from the german competence network for the study of community acquired pneumonia (capnetz) study group, showed that all new biomarkers were good predictors of short-term and long-term all-cause mortality and correlated with crb- score. in other studies, low levels of pct were able to define patients at low risk of death regardless of findings using severity scoring. huang and colleagues as well as kruger and colleagues found, that even in patients identified as high risk using curb- or psi, a low pct value predicted a low chance of dying. , severe cap scoring systems can also be used to help define which patients need icu care, identifying those with severe illness. the idsa/ats guidelines and the piro (predisposition, insult, response, and organ dysfunction) scoring system were developed to help define mortality risk in patients with severe pneumonia. according to the idsa/ats guidelines, severe cap is present if a patient needs invasive mechanical ventilation or requires vasopressors or has any of from the minor criteria listed later. liapakou and colleagues found that patients meeting the major criteria needed icu admission, but those patients who had only minor criteria present had no increased mortality risk, regardless of how many criteria were met. more recently, brown and colleagues found that both the positive and negative predictive value of minor criteria exceeded % if criteria were used to define the need for icu admission rather than just criteria. the piro score is calculated within hours of icu admission, with point given for each variable: comorbidities (copd, immunocompromise), age greater than years, multilobar opacities on chest radiograph, shock, severe hypoxemia, acute renal failure, bacteremia, and acute respiratory distress syndrome. the maximum score that can be achieved is . patients are stratified into levels of risk: (a) low, to points; (b) mild, points; (c) high, points; and (d) very high, to points. the piro score performed well as a -day mortality prediction tool in patients with cap requiring icu admission, with a better performance than apache ii and idsa/ ats criteria. the smart-cop tool was developed to identify the need for intensive respiratory or vasopressor support (irvs), rather than a specific site-of-care decision. this tool uses a complex scoring system with the following values: low systolic blood pressure (< mm hg) ( points), multilobar pneumonia ( point), low albumin level (< . g/dl) ( point), high respiratory rate ( - breaths/min) ( point), tachycardia (> beats/min) ( point), confusion ( point), poor oxygenation ( points), and low arterial ph (< . ) ( points). when this method was used, the finding of a patient with a score of more than points identified % of those needing irvs, with a specificity of . %, whereas the psi and curb- did not perform as well for this an algorithm for decision on site of care based on scoring system and treatment strategy is provided later (fig. ) . early diagnosis and timely administration of antibiotics are associated with improved outcomes in patients with cap. , although administration of therapy within to hours of arrival at the hospital can reduce mortality, it is important to only use antibiotics when the diagnosis is certain, because indiscriminate use of antibiotics in the absence of radiographic pneumonia has limited benefit and a real risk of community-acquired pneumonia antibiotic-associated adverse events, including drug-induced infectious diarrhea. according to idsa/ats guidelines, the first dose of antibiotic should be given in the emergency department, preferably within to hours of arrival, but no time period is specified. because no diagnostic testing can rapidly identify the causal pathogens in a patient with cap, initial therapy is empiric, based on an epidemiologic assessment of patient risk factors for specific pathogens. this assessment requires a careful history of patient comorbidity, recent antibiotic therapy history (within the past months), and identification of pathogen-specific risk factors (see table ; box ). the idsa/ats guidelines recommend outpatient treatment with a macrolide or doxycycline for previously healthy adult patients with no risk factors for drsp. in patients with risk factors for drsp, a respiratory fluoroquinolone or a b-lactam antibiotic plus a macrolide or doxycycline is recommended. in choosing between these options, it is important to take a history about antibiotic usage in the past months and to use an agent that is different from what has recently been used, because recent therapy may predispose to pneumococcal resistance to the agent used, rendering that therapy less effective. for patients admitted to the hospital, but not to the icu, an intravenous respiratory fluoroquinolone or a b-lactam plus a macrolide should be used. as mentioned earlier, the choice should be influenced by a history of which antibiotics have been used in the past months, using agents from a different class, if possible. doxycycline is an in patients allergic to penicillin -respiratory fluoroquinolone plus aztreonam. if community-acquired mrsa is suspected vancomycin (and possibly clindamycin) or linezolid alone added to above regimen. if pseudomonas is suspected a b-lactam with activity against p aeruginosa (piperacillin-tazobactam, cefepime, imipenem, or meropenem) plus either ciprofloxacin or levofloxacin, or a b-lactam with activity against pseudomonas plus an aminoglycoside and azithromycin or a nonpseudomonal respiratory fluoroquinolone (moxifloxacin) alternative to a macrolide. ertapenem is an alternative to b-lactam agents such as cefotaxime, ceftriaxone, or ampicillin-sulbactam, and should be considered for patients with risk factors for infection with gram-negative pathogens other than p aeruginosa. all patients with cap should have routine therapy directed at pneumococcus and atypical pathogens, plus other organisms, as dictated by specific risk factors. the routine coverage for atypical pathogens is based on outcome studies that show that the addition of a macrolide to a b-lactam, or the use of a quinolone alone, leads to better outcome than b-lactam monotherapy. in addition, some studies have shown a high frequency of atypical pathogen coinfection in patients with bacterial cap. current cap guidelines do not recommend monotherapy with any agent, including a quinolone, for patients with severe cap who are admitted to the icu. in patients with bacteremia (pneumococcal and other), atypical pathogen coverage with a macrolide (monotherapy or combination) improves mortality compared with treatment regimens with a quinolone, particularly quinolone monotherapy. , combination therapy with a b-lactam and a macrolide has a survival advantage compared with quinolones alone in patients in the icu, and in the prospective study that compared quinolone monotherapy with a b-lactam/quinolone combination therapy the monotherapy arm was not as effective. in addition, in patients with pneumococcal bacteremia, especially in those with severe illness, the use of dual therapy (usually by adding a macrolide to a b-lactam) is associated with better outcome than with monotherapy, implying benefit from atypical pathogen coverage or from the antiinflammatory effect of the macrolide. in a prospective study by rodriguez and colleagues on patients with cap and shock requiring vasopressors, combination therapy with either a b-lactam and a macrolide or a b-lactam and a quinolone had a -day survival advantage compared with monotherapy with a b-lactam or a quinolone alone. based on these data, in patients in the icu, an intravenous b-lactam plus either a macrolide or respiratory fluoroquinolone is recommended for patients without pseudomonal risk factors. in patients with risk factors for pseudomonal infection, an antipseudomonal b-lactam should be combined with either levofloxacin or ciprofloxacin, or the antipseudomonal b-lactam can be combined with both an aminoglycoside and either azithromycin or a respiratory quinolone. in patients allergic to penicillin, a respiratory fluoroquinolone should be used with aztreonam as an alternative regimen. when ca-mrsa is suspected, vancomycin or linezolid should be added to the other recommended agents. however, it may be necessary to add an anti-toxin producing agent, because part of the illness caused by ca-mrsa is mediated by bacterial exotoxin production. to stop toxin production, it may be necessary to add clindamycin to vancomycin, or to use linezolid alone. outpatients with mild-to-moderate cap are treated for days or fewer with oral antibiotics, and therapy is stopped if they are afebrile and clinical features of pneumonia are resolving (cough, dyspnea, and sputum production). for inpatients, antibiotics are switched from intravenous to oral once the patient is afebrile for at least occasions hours apart, is able to take food by mouth, and there are clinical signs of improvement (in parameters such as cough, dyspnea, sputum production, oxygenation, and vital sign abnormalities), and this usually happens by the second or third hospital day. the switch to oral antibiotics can also be done for bacteremic patients, although it may take longer for these patients to reach clinical stability compared with nonbacteremic patients. use of pct as a guide to decide on the duration of antibiotic use is supported by clinical trial data. the duration of therapy should be a minimum of days, providing that the patient is afebrile for to hours, there is no sign of community-acquired pneumonia extrapulmonary infection, the correct therapy was used initially, and the organism identified is not s aureus or p aeruginosa. with appropriate antibiotic treatment, most cases of cap resolve without complications. however, the treating physician should be alert to potential complications that, if not detected early, can lead to adverse outcomes. if the patient is responding well to therapy, no immediate follow-up radiograph is needed, and imaging is only done to weeks after discharge to define a new radiographic baseline. in most patients, the chest radiograph usually clears within weeks, especially in patients younger than years without underlying pulmonary disease or bacteremia. however, resolution may be delayed for weeks or longer in older individuals and those with underlying lung disease and bacteremia. in about % of patients, there is a lack of response or clinical deterioration despite antibiotic therapy. the idsa/ats guidelines define early failure as progressive pneumonia or clinical deterioration, occurring in the first hours of therapy, usually with respiratory failure or septic shock, and is a consequence of inappropriate antibiotic therapy or an incorrect initial diagnosis. later failure or nonresponse is often caused by a nosocomial infection, a disease-related or therapy complication, or a noninfectious process (eg, pulmonary embolism, inflammatory lung disease). if the patient has persistent fever, worsening dyspnea, unresolving pneumonia symptoms, and continued debility, a repeat radiograph should be done focusing on a broad differential diagnosis, including therapy for an unusual or drug-resistant pathogen (tuberculosis, endemic fungus, or a zoonosis), a pneumonic complication (empyema), an antibiotic complication (drug-induced colitis) or a nonpneumonic diagnosis (inflammatory lung disease, malignancy). diagnostic testing can include a chest ct scan, bronchoscopy, and, in some cases, open lung biopsy. organizing pneumonia is a complication of viral lung infection and other processes, and is characterized by fibroblast proliferation and diagnosed by a combination of radiographic findings, bronchoscopic lung biopsy, and the absence of ongoing infection. it is often managed with a therapeutic trial of steroids. the definitive investigation is an open lung biopsy. parapneumonic effusion and empyema are complications that can lead to apparent treatment failure. the chest radiograph shows an effusion, which should be sampled, and, if a low pleural fluid ph is present (< . if previously healthy, but < . if chronically ill) or if organisms are present, chest tube drainage and prolonged antibiotic therapy is required. a connection between the pleural space and the lung can develop and result in a bronchopleural fistula, which can be caused by erosion of the lung infection to the pleural surface. bronchopleural fistula is initially treated conservatively with antibiotics and a chest tube, but sometimes requires surgical repair. localized bronchiectasis can be a long-term sequela of cap, as a result of injury and dilation of the bronchus, and can be seen on ct scan of the chest. patients present with chronic productive sputum and recurrent infection on the same area. treatment is with postural drainage, antibiotics for exacerbation, and bronchodilators for coexisting airflow obstruction. recurrent pneumonia can occur after clinical and radiographic resolution of pneumonia. if it is present, whether it is in the same or a different area as the original infection should be determined. if it is in the same area, an anatomic problem (obstruction by tumor or foreign body) needs to be considered, whereas, if it is at another site, it may be the consequence of general immune impairment. the risk of this problem is higher in the elderly, those with a history of alcoholism, and in smokers. an underlying systemic immune deficiency should be ruled out by measuring quantitative ig levels. a detailed discussion of prevention is beyond the scope of this article. in the idsa/ats guidelines, the mainstay of prevention is pneumococcal and influenza vaccination for at-risk individuals, and provision of smoking cessation information to those smoking cigarettes at the time of pneumonia onset. influenza vaccine is recommended during the appropriate season, for all persons aged years or older, and for those with specific risk factors, including pregnant women and those with chronic heart, lung, metabolic, hematologic, or immune-compromising illnesses. pneumococcal polysaccharide vaccine should be given to all patients aged years or older, and to younger patients with chronic heart or lung disease, asplenia, diabetes mellitus, and to residents of long-term care facilities. one revaccination after years should be given to those with either a poor immune response or after age years for those first immunized before the age of years. in guidelines, and also in performance measures for hospitalized patients, vaccination should be given before discharge for all patients admitted with cap. infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults management of community-acquired pneumonia: a review and update deaths: preliminary data for deaths: final data for . national vital statistics reports . national center for health statistics prognosis and outcomes of patients with community-acquired pneumonia. a meta-analysis global and local epidemiology of community-acquired pneumonia: the experience of the capnetz network pneumonia: still the old man's friend? burden of community-acquired pneumonia in north american adults economic benefit of a -day reduction in hospital stay for community-acquired pneumonia (cap) validation of a predictive rule for the management of community-acquired pneumonia prospective comparison of three validated prediction rules for prognosis in community-acquired pneumonia biological markers to determine eligibility in trials for communityacquired pneumonia: a focus on procalcitonin community-acquired pneumonia: pathophysiology and host factors with focus on possible new approaches to management of lower respiratory tract infections proton-pump inhibitor use and the risk for community-acquired pneumonia genetic risk of acute pulmonary infections and sepsis inflammation in severe pneumonia: act locally, not globally atypical pathogens in community-acquired pneumonia severe community-acquired pneumonia: assessment of microbial aetiology as mortality factor asian network for surveillance of resistant pathogens (ansorp) study group. clinical outcomes and risk factors of communityacquired pneumonia caused by gram-negative bacilli severe community-acquired enterobacter pneumonia: a plea for greater awareness of the concept of health-careassociated pneumonia community-acquired pneumonia due to gram-negative bacteria and pseudomonas aeruginosa: incidence, risk, and prognosis viral community-acquired pneumonia in non immunocompromised adults in the clinic -community-acquired pneumonia expanded clinical presentation of communityacquired methicillin-resistant staphylococcus aureus pneumonia severe community-onset pneumonia in healthy adults caused by methicillin-resistant staphylococcus aureus carrying the panton-valentine leukocidin genes emergence of multidrug-resistant, community associated, methicillin-resistant staphylococcus aureus clone usa in men who have sex with men murray and nadel's textbook of respiratory medicine does this patient have community-acquired pneumonia? diagnosing pneumonia by history and physical examination canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the canadian infectious diseases society and the canadian thoracic society comparison between pathogen directed antibiotic treatment and empirical broad spectrum antibiotic treatment in patients with community acquired pneumonia: a prospective randomised study value of intensive diagnostic microbiological investigation in low-and high-risk patients with community-acquired pneumonia thrombocytopenia and thrombocytosis at time of hospitalization predict mortality in patients with community-acquired pneumonia hyponatremia in community-acquired pneumonia inter-observer variation in the interpretation of chest radiographs for pneumonia in community-acquired lower respiratory tract infections high-resolution computed tomography for the diagnosis of community-acquired pneumonia predicting bacteremia in patients with community-acquired pneumonia rapid diagnosis of bacteremic pneumococcal infections in adults by using the binax now streptococcus pneumoniae urinary antigen test: a prospective, controlled clinical evaluation utility of a pneumonia severity index in the optimization of the diagnostic and therapeutic effort for community-acquired pneumonia trends in legionnaire's disease, - : declining mortality and new patterns of diagnosis current and potential usefulness of pneumococcal urinary antigen detection in hospitalized patients with community-acquired pneumonia to guide antimicrobial therapy cardiovascular and inflammatory biomarkers to predict short-and long-term survival in community-acquired pneumonia: results from the german competence network, capnetz inflammatory biomarkers and prediction for intensive care unit admission in severe community-acquired pneumonia contribution of c-reactive protein to the diagnosis and assessment of severity of community-acquired pneumonia procalcitonin-guided antibiotic therapy and hospitalisation in patients with lower respiratory tract infections (prohosp) study group. prognostic value of procalcitonin in communityacquired pneumonia procalcitonin levels predict bacteremia in patients with community-acquired pneumonia: a prospective cohort trial procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial association between timing of intensive care unit admission and outcomes for emergency department patients with community acquired pneumonia late admission to the icu in patients with community-acquired pneumonia is associated with higher mortality reasons why emergency department providers do not rely on the pneumonia severity index to determine the initial site of treatment for patients with pneumonia a prediction rule to identify low-risk patients with community-acquired pneumonia pneumonia severity index class v patients with community-acquired pneumonia: characteristics, outcomes, and value of severity predicting mortality in the elderly with communityacquired pneumonia: should we design a new car or set a new 'speed limit crb- predicts death from communityacquired pneumonia effects of delayed oxygenation assessment on time to antibiotic delivery and mortality in patients with severe community-acquired pneumonia risk prediction with procalcitonin and clinical rules in community-acquired pneumonia procalcitonin predicts patients at low risk of death from community acquired pneumonia across all crb- classes. eur respir severe community-acquired pneumonia: validation of the infectious diseases society of america/american thoracic society guidelines to predict an intensive care unit admission validation of the infectious disease society of america/american thoracic society guidelines for severe community-acquired pneumonia piro score for community-acquired pneumonia: a new prediction rule for assessment of severity in intensive care unit patients with community-acquired pneumonia smart-cop: a tool for predicting the need for intensive respiratory or vasopressor support in community-acquired pneumonia timing of antibiotic administration and outcomes for medicare patients hospitalized with community-acquired pneumonia quality of care, process, and outcomes in elderly patients with pneumonia antibiotics for bacteremic pneumonia: improved outcomes with macrolides but not fluoroquinolones combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia comparison of levofloxacin and cefotaxime combined with ofloxacin for icu patients with community-acquired pneumonia who do not require vasopressors combination antibiotic therapy improves survival in patients with community-acquired pneumonia and shock early switch from intravenous to oral antibiotics in hospitalized patients with bacteremic community-acquired streptococcus pneumoniae pneumonia key: cord- -hrz bypr authors: omrani, ali s.; almaslamani, muna a.; daghfal, joanne; alattar, rand a.; elgara, mohamed; shaar, shahd h.; ibrahim, tawheeda b. h.; zaqout, ahmed; bakdach, dana; akkari, abdelrauof m.; baiou, anas; alhariri, bassem; elajez, reem; husain, ahmed a. m.; badawi, mohamed n.; abid, fatma ben; abu jarir, sulieman h.; abdalla, shiema; kaleeckal, anvar; choda, kris; chinta, venkateswara r.; sherbash, mohamed a.; al-ismail, khalil; abukhattab, mohammed; ait hssain, ali; coyle, peter v.; bertollini, roberto; frenneaux, michael p.; alkhal, abdullatif; al-kuwari, hanan m. title: the first consecutive patients with coronavirus disease from qatar; a nation-wide cohort study date: - - journal: bmc infect dis doi: . /s - - - sha: doc_id: cord_uid: hrz bypr background: there are limited data on coronavirus disease (covid- ) outcomes at a national level, and none after days of follow up. the aim of this study was to describe national, -day all-cause mortality associated with covid- , and to identify risk factors associated with admission to an intensive care unit (icu). methods: this was a retrospective cohort study including the first consecutive patients with covid- in qatar who completed days of follow up by june , . the primary outcome was all-cause mortality at days after covid- diagnosis. in addition, we explored risk factors for admission to icu. results: included patients were diagnosed with covid- between february and april , . the majority ( , . %) were males and the median age was years [interquartile range (iqr) – ]. by days after covid- diagnosis, patients ( . %) had died, ( . %) were still in hospital, and two ( . %) were still in icu. fatal covid- cases had a median age of . years (iqr . – ), and were mostly males ( , . %). all included pregnant women ( , . %), children ( , . %), and healthcare workers ( , . %) were alive and not hospitalized at the end of follow up. a total of patients ( . %) required hospitalization, out of which ( . %) were admitted to icu. most frequent co-morbidities in hospitalized adults were diabetes ( . %), and hypertension ( . %). multivariable logistic regression showed that older age [adjusted odds ratio (aor) . , % confidence interval (ci) . – . per year increase; p < . ], male sex (aor . , % ci . – . ; p < . ), diabetes (aor . , % ci . – . ; p . ), chronic kidney disease (aor . , % ci . – . , p . ), and higher bmi (aor . , % ci . – . per unit increase; p . ), were all independently associated with increased risk of icu admission. conclusions: in a relatively younger national cohort with a low co-morbidity burden, covid- was associated with low all-cause mortality. independent risk factors for icu admission included older age, male sex, higher bmi, and co-existing diabetes or chronic kidney disease. supplementary information: supplementary information accompanies this paper at . /s - - - . conclusions: in a relatively younger national cohort with a low co-morbidity burden, covid- was associated with low all-cause mortality. independent risk factors for icu admission included older age, male sex, higher bmi, and co-existing diabetes or chronic kidney disease. keywords: coronavirus, covid- , sars-cov- , mortality, qatar background severe acute respiratory syndrome coronavirus (sars-cov- ), the cause of coronavirus disease , emerged in china in late . by july , , more than million confirmed sars-cov- infections were confirmed worldwide, with over thousand associated deaths [ ] . based on the number of deaths as a proportion of reported covid- cases, the overall estimated covid- -associated mortality rate is around . % [ ] . however, the accuracy of such a figure is uncertain given the variation in case finding policies from one healthcare setting to another [ , ] . furthermore, reported mortality has been mostly based on in-hospital outcomes or relatively short follow up [ ] [ ] [ ] [ ] [ ] . in their recently published recommendations for a minimal common outcome measure set for covid- research, the world health organization (who) favored that mortality outcomes are assessed at days [ ] . single and multi-center cohort studies suggested that risk factors for severe covid- include male sex, older age, and the presence of multiple comorbidities [ , , ] . the extent to which such risk factors are important at a population level in settings with ample healthcare resources, a covid- control program based on active case finding and isolation, and a low burden of comorbidities, is unknown. in this study, we describe -day outcomes of a nationwide covid- cohort from qatar, and explore patient characteristics associated with the need for admission to an intensive care unit (icu). hamad medical corporation (hmc) encompasses multiple hospital facilities and provides all covid- medical care for the . million population of qatar. in response to the covid- pandemic, existing clinical services were re-organized and two brand new hospital facilities were opened ahead of their originally planned dates. in total, non-icu bed capacity was increased from to ( . % increase), and icu beds from to ( . % increase). from a healthcare delivery perspective, hmc defines adults as those aged above years. sars-cov- infection was diagnosed by real-time polymerase chain reaction (rt-pcr) assays taqpath covid- combo kit (thermo fisher scientific, waltham, massachusetts) or cobas sars-cov- test (roche diagnostics, rotkreuz, switzerland) on respiratory tract specimens. severity of covid- was classified according to the who guidelines [ ] . sars-cov- testing was offered to all individuals presenting with symptoms suggestive of covid- , known close contacts of confirmed cases including healthcare workers, and all returning travelers. patients with asymptomatic sars-cov- infection or mild covid- without significant co-morbidities were isolated in dedicated community facilities until they had two consecutive negative sars-cov- rt-pcr results from upper airway samples taken more than h apart. covid- patients with significant co-morbidities or moderate to severe disease were hospitalized for inpatient management. standard care for hospitalized patients involved supportive care and investigational antiviral therapy. individual regimens were selected by the treating physicians based on severity of disease, the presence of contra-indications or potential drug-drug interactions, and the patients' preferences. twenty five individuals included in this study had been elsewhere reported [ ] . we used the hmc covid- database to identify the first consecutive patients with rt-pcr-confirmed covid- who would complete days of follow up from date of diagnosis by june , . during the period between may and june , , clinical and laboratory data were retrieved from hmc's electronic healthcare system. final status days after covid- diagnosis was ascertained against the electronic healthcare system and qatar's national deaths records. the report was prepared according the strengthening the reporting of observational studies in epidemiology (strobe) recommendations [ ] . the primary endpoint was all-cause mortality within days after rt-pcr confirmation of sars-cov- infection. for hospitalized patients, we also assessed risk factors for admission to icu. we summarized categorical data as numbers and percentages and compared them using pearson's chisquared or fisher's exact test, as appropriate. continuous data are presented as medians and interquartile ranges (iqr) and compared among groups using wilcoxon rank-sum test. the majority ( patients, . %) of admissions to icu occurred within of the first h from hospitalization. we therefore used logistic regression to explore predictors of admission to icu. baseline variables were included in the univariable logistic regression analysis if their between groups differences were associated with p values of < . . independent variables in the multivariable regression model were chosen based on their association with p values of < . in the univariable logistic regression, and on their ready availability before any covid- -related clinical evaluation. due to the number of events in the study, we limited the number of independent variables in the multivariable regression analysis to eight to avoid overfitting the model. the final multivariable logistic regression model included age, male sex, body mass index (bmi), defined as body weight in kilograms divided by squared height in meters, and co-existing diabetes mellitus, systemic hypertension, coronary artery disease, chronic liver disease, and chronic kidney disease. multiple imputations approach was applied for variables with > % missingness. all p values were two-sided with a threshold of < . for statistical significance. statistical analyses were performed using stata statistical software release . (statacorp llc, college station, texas). individuals included in this study were diagnosed with sars-cov- infection between february and april , . initial sars-cov- cases were diagnosed in travelers returning from iran and europe. sustained local transmission became established thereafter (fig. ) . of the rt-pcr-confirmed covid- cases included in this report, ( . %) were in males and the majority belonged to age groups - years ( , . %) and - years ( , . %) (fig. ) . the cohort included ( . %) individuals aged years or less, ( . %) pregnant women and ( . %) healthcare workers (table s , appendix). most individuals in this study did not require hospitalization ( , . %). those who were not hospitalized were significantly younger and had fewer co-existing chronic medical conditions (table s , appendix). of patients who required hospitalization, ( . %) were admitted to icu. overall, days after covid- diagnosis, patients ( . %) had died, patients ( . %) were still in hospital and two ( . %) were still in icu (fig. ) . out of individuals aged > included in this report, ( . %) were hospitalized. the majority ( , . %) were males and the median age was years (iqr - ). nationalities from who's south-east asia region ( , . %) and eastern mediterranean region ( , . %) were most frequent. diabetes ( , . %) and hypertension ( , . %) were the most common co-existing medical conditions. fever ( . %) and cough ( . %) were the most common presenting symptoms. median bmi was . kg/m (iqr . - . ). most patients ( , . %) did not require oxygen therapy within the first h of hospitalization. hydroxychloroquine ( , . %), azithromycin ( , . %), and lopinavir-ritonavir ( , %) were the most commonly used investigational antiviral agents. compared with those who did not require icu admission, icu patients were significantly more likely to be males (p . ), have higher median age (p < . ) and to have multiple co-morbidities (p < . ) ( table ) . they also had significantly higher median bmi ( . versus . , p < . ) and were more likely to present with fever, cough and dyspnea (p < . for each). within the first h of hospitalization, icu patients had significantly higher median heart rate ( versus per minute, p < . ), and respiratory rate ( . versus per minute, p < . ), significantly lower oxygen saturation ( % versus %, p < . ) ( table ). in addition, baseline blood investigations from icu patient were significantly more likely to show lower median peripheral lymphocyte count ( . versus . × /l, p < . ), and higher median serum creatinine ( versus μmol/ l, p < . ), and c-reactive protein (crp) ( . versus , p < . ). complications such as acute kidney injury ( . % versus . %), and myocardial injury ( . % versus . %, p < . ) were more common in icu compared with non-icu patients. other baseline characteristics, management, and complications variables in hospitalized covid- adults included in this study are shown in table . in univariable analysis, the odds of admission to icu were significantly higher in older patients, males compared with females, and in those with diabetes, hypertension, coronary artery disease, or chronic lung, liver, or kidney disease, and in those with higher bmi ( table ). the presence of cough, dyspnea, or fever, elevated baseline heart rate or respiratory rate, decreased oxygen saturation, lower lymphocyte count, and increased serum creatinine, crp, and alanine transaminase (alt) were also associated with admission to icu ( table ). in the multivariable logistic regression, we found that older age, male sex, co-existing diabetes or chronic kidney disease, and higher bmi were all independently associated with increased risk of need for icu admission ( table ) . a total of patients ( . %) died within days of follow up. the median age of fatal covid- cases was . years (iqr . - ). most deceased patients were males ( , . %) and most ( , . %) had two or more comorbidities (see table s in supplementary material). two patients died without hospitalization. the first was a -year-old man with a history of hypertension and heavy smoking. he had asymptomatic sars-cov- infection and was isolated in a community facility pending viral clearance. he developed severe chest pain and cardiopulmonary arrest days after covid- diagnosis. the second patient was a -year-old man with end-stage kidney disease, hypertension, diabetes and coronary artery disease. he developed cardiopulmonary arrest shortly after presenting to the emergency department in severe respiratory distress. a post-mortem examination to confirm the cause of death was not performed in either case. the remaining deaths all occurred in patients who were in icu with severe acute respiratory distress syndrome requiring prolonged invasive mechanical ventilation. deaths occurred after a median of days (iqr - ) from covid- diagnosis. ten ( . %) deaths occurred in patients aged or older. the remaining two were in patients aged years and years. the former had diabetes, hypertension, and obesity (bmi . ). the latter patient presented with fulminant hepatitis and his hepatitis b serology was positive for surface igm antibodies. he died within days with encephalopathy and multi-organ failure. the study included pregnant women with sars-cov- infection with median age of years (iqr . - ). nineteen ( . %) were hospitalized, including one ( . %) in icu, and all were discharged within the follow up period. ten ( . %) pregnant women with covid- gave birth during the follow up period; all resulting in healthy babies with negative sars-cov- tests (see table s in supplementary material). a total of patients in this cohort were healthcare workers. their median age was years ( - ) and the majority were males ( , . %). the most frequent professional background of affected healthcare workers was nursing ( , . %), and allied healthcare ( , %) (see table s in supplementary material). out of ( . %) who required hospitalization, three ( . %) required admission to icu. all healthcare workers in this table s in supplementary material). there were individuals aged years or less in the study, of which ( . %) were males. median age was years (iqr - ). children were mostly diagnosed in the context of contact screening ( / , %), and were not hospitalized ( , . %). the majority ( , . %) of children, including all seven infants, had family members with confirmed covid- (see table s in supplementary material). in this national covid- cohort, only ( . %) out of patients died within days of diagnosis, and ( . %) required ongoing hospitalization at the end of the -day follow up period. sars-cov- infection are generally slightly more common in males than females [ ] . however our report shows that . % of sars-cov- infections in qatar were in males. our findings reflect the country's demographic characteristics. male to female ratio in qatar's general population is . and the corresponding male to female sars-cov- incidence per , population in our report is . . notably, the population's male to female ratios are . - . in age groups between to ( . - . ), where . % of sars-cov- infections where reported (table s , supplement). our mortality rates are considerably lower than previously reported form large covid- cohorts from china, europe and united states [ ] [ ] [ ] [ ] [ ] . there are the other hand, nearly one third of patients reported in our study were identified through screening efforts. our lower mortality rates could therefore be in part due to higher detection of milder covid- cases. secondly, our cohort's demographic profile is consistent with the country's population being largely constituted of male migrants working in the country's numerous infrastructure projects (table s , supplement). older age and the presence of multiple co-morbidities have consistently been associated with increased risk of severe covid- , need for critical care support, and mortality [ , , ] . the majority ( %) of patients in our study did not have any pre-existing chronic medical conditions. moreover, with a median patient age of years (iqr - ), our patients were considerably younger than those reported in large cohorts from lombardy region in italy (median year, iqr - ), the united kingdom (median years, iqr - years) and new york city (median years, iqr - ) [ ] [ ] [ ] . note should also be taken of qatar's population being relatively younger than most countries reporting high covid- -associated mortality. for example, the median age in qatar is only . years, whereas the median population age is . years in italy, and . years in the united kingdom [ ] . in addition, the proportion of population aged over years is only . % in qatar, while it is % in italy and . % in the united kingdom [ ] . a third factor in explaining our low covid- associated mortality is the rapid escalation of the healthcare system's capacity to accommodate the expected hike in demand for hospital beds in general, and for icu support in particular. it has been suggested that some of the worst covid- -associated mortality rates have in part been the result of overwhelmed critical care resources that could not support a large influx of severely ill covid- patients [ , ] . this has stimulated discussions around rationing of critical care support for covid- patients, including potentially difficult decisions to withdraw resources from one patient to provide them to another [ ] . on the other hand, critical care support is rarely withheld in our setting, even in cases where the prognosis appears to be unfavorable. while diabetes mellitus, coronary artery disease, chronic liver disease, hypertension and chronic kidney diseases all appeared to be associated with risk of admission to icu in our univariate analysis, the association was statistically significant only for the latter wo in the adjusted logistic regression analysis ( table ). this is probably the result of interactions between our cohort's co-morbidities and their age. deaths observed in our study have largely occurred in older patients with multiple co-morbidities. though . % of deaths occurred in those aged years or above, this group constituted only . % of our entire cohort. our age group-specific mortality was . % in those aged - years, and . % in those aged years or more. these figures are comparable with mortality rates in similar age groups in china, italy, and the united states, but are considerably lower than those reported from the united kingdom [ , , , ] . one patient in our cohort died while in a community isolation facility with asymptomatic sars-cov- infection. his rapid demise after complaining of chest pain suggests that his death was caused by myocardial infarction or pulmonary embolism. both complications are increasingly recognized associations with covid- [ , ] . an increase in out-of-hospital cardiac arrests has been observed in association with sars-cov- pandemic, including in patients with symptoms compatible with covid- [ ] . moreover, . % of our icu patients and . % of our non-icu patients had evidence of myocardial injury during their hospitalization. the diagnosis of covid- in patients with known or increased risk of coronary artery disease should be an opportunity to review and optimize medical therapy to reduce the risk of acute coronary events. most hospitalized patients in our study received investigational antiviral therapies. however, recent reports from large cohort and randomized clinical trials do not support the use of hydroxychloroquine, alone or in combination with azithromycin, or lopinavir-ritonavir for patients with covid- [ , ] . it is likely that covid- management will continue to evolve as more results from ongoing clinical trials become available [ ] . our analysis showed that increasing age, male sex, higher bmi, and the presence of diabetes or chronic kidney disease are risk factors for admission to icu. remarkably, hypertension, chronic lung disease, and coronary artery disease, all of which are frequently reported as important predictors for severe covid- in previous studies, were not independently associated with icu admission in our setting [ ] . furthermore, our univariable analysis showed that presenting with dyspnea and cough as well as baseline blood abnormalities such as lower lymphocyte count, higher crp and serum creatinine are associated with increased risk of admission to icu [ , ] . higher bmi as a risk factor for severe covid- is particularly noteworthy [ ] . median bmi in our hospitalized patients was . kg/m (iqr . - . ), a reflection of the growing concern over the increasing prevalence of overweight and obesity in developing countries, along with its consequent health problems such as diabetes and cardiovascular disease [ ] . in the context of covid- , it is important to recognize the role of overweight and obesity as a driver of severe covid- . our findings help guide deployment of medical resources to better select patients for hospitalization, closer clinical monitoring, and early clinical support. healthcare workers represented . % of cases in our report. three ( . %) of our healthcare workers required admission to icu. unlike some unfortunate reports from elsewhere, all healthcare workers in our study fully recovered within the study follow up period [ ] . risk to healthcare personnel is highest in those with prolonged direct contact with symptomatic patients, especially where personal protective equipment are either in short supply or not used appropriately [ ] . also noteworthy is that . % of healthcare workers in this study were asymptomatic. single center healthcare worker screening studies reported asymptomatic rates ranging from . to % [ , ] . the most efficient healthcare worker screening strategy that combines practicality with patient protection is still unclear. like previous reports, children in our study had a largely uneventful sars-cov- infection [ ] . while only . % of the entire cohort were hospitalized, the majority ( . %) of pregnant women with covid- in our report were hospitalized. however, only one ( . %) out of pregnant women in this report required admission to icu, and none died within days of follow up. our findings are consistent with recent reports indicating that pregnancy may be independently associated with increased risk of hospitalization and severe covid- [ , ] . the limitations of this study include its observational nature and missing data for some variables. to address those limitations, we used multivariate analyses with multiple imputations to assess independent associations with the outcome. despite this, our study benefits from being, to the best of our knowledge, the first to report -day outcomes of sars-cov- , and to do so at a nationwide level. in a setting of proactive sars-cov- case finding, a younger population, and low co-morbidity burden, sars-cov- was associated with low all-cause mortality. independent risk factors for icu admission included older age, male sex, higher bmi, and co-existing diabetes or chronic kidney disease. supplementary information accompanies this paper at https://doi.org/ . /s - - - . additional file table s . baseline characteristics and outcomes of individuals with coronavirus disease in qatar. table s . qatar population and corresponding sars-cov- infection incidence per , population by sex and age group. qatarpo box . division of critical care, department of medicine, hamad medical corporation, doha, qatarpo box . hazm mebaireek general hospital, hamad medical corporation, doha, qatar. hamad general hospital rumailah hospital qatarpo box . references . world health organization. coronavirus disease (covid- ) situation report - real estimates of mortality following covid- infection what other countries can learn from italy during the covid- pandemic covid- : investigation and initial clinical management of possible cases baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region features of uk patients in hospital with covid- using the isaric who clinical characterisation protocol: prospective observational cohort study factors associated with hospital admission and critical illness among people with coronavirus disease in new york city: prospective cohort study vital surveillances: the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- ) -china severe outcomes among patients with coronavirus disease (covid- ) -united states a minimal common outcome measure set for covid- clinical research clinical management of covid- -interim guidance tocilizumab for the treatment of severe coronavirus disease the strengthening the reporting of observational studies in epidemiology (strobe) statement: guidelines for reporting observational studies novel coronavirus infection (covid- ) in humans: a scoping review and meta-analysis data. coronavirus (covid- ) testing estimating clinical severity of covid- from the transmission dynamics in wuhan, china list of countries by median age list of countries by age structure potential association between covid- mortality and health-care resource availability a framework for rationing ventilators and critical care beds during the covid- pandemic case-fatality rate and characteristics of patients dying in relation to covid- in italy pulmonary embolism in patients with covid- pneumonia association of cardiac injury with mortality in hospitalized patients with covid- in wuhan, china out-ofhospital cardiac arrest during the covid- outbreak in italy association of treatment with hydroxychloroquine or azithromycin with inhospital mortality in patients with covid- in new york state a trial of lopinavirritonavir in adults hospitalized with severe covid- ongoing clinical trials for the management of the covid- pandemic risk factors of critical & mortal covid- cases: a systematic literature review and meta-analysis predictive symptoms and comorbidities for severe covid- and intensive care unit admission: a systematic review and meta-analysis high prevalence of obesity in severe acute respiratory syndrome coronavirus- (sars-cov- ) requiring invasive mechanical ventilation epidemic obesity and type diabetes in asia deaths from covid- in healthcare workers in italy-what can we learn? reasons for healthcare workers becoming infected with novel coronavirus disease (covid- ) in china covid- screening of health-care workers in a london maternity hospital characteristics of healthcare workers who underwent nasopharyngeal swab testing for sars-cov- in milan covid- in children, pregnancy and neonates: a review of epidemiologic and clinical features public health agency of sweden's brief report: pregnant and postpartum women with severe acute respiratory syndrome coronavirus infection in intensive care in sweden characteristics of women of reproductive age with laboratory-confirmed sars-cov- infection by pregnancy status -united states publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to thank all colleagues in hamad medical corporation and the ministry of public health for their outstanding service and dedication. the publication of this article was supported by the medical research center, hamad medical corporation. no other funding was required. the datasets used and analyzed during the current study are available from the corresponding author on reasonable request. the study was approved by hamad medical corporation's institutional review board (mrc ), with a waiver of informed consent. no additional administrative permissions were required to access the raw data. all data used in this study were anonymized before their use. not applicable. the authors declare that they have no competing interests. key: cord- -nfpzcago authors: crispi, f.; crovetto, f.; larroya, m.; camacho, m.; sibila, o.; badia, j. r.; lopez, m.; vellve, k.; garcia, f.; trilla, a.; faner, r.; blanco, i.; borras, r.; agusti, a.; gratacos, e. title: low birth weight as a risk factor for severe covid- in adults date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: nfpzcago the identification of factors predisposing to severe covid- in young adults remains partially characterized. low birth weight (lbw) alters cardiovascular and lung development and predisposes to adult disease. we hypothesized that lbw is a risk factor for severe covid- in non-elderly subjects. we analyzed a prospective cohort of patients ( - y) with laboratory-confirmed sars-cov- infection attended in a tertiary hospital, where % required admission to intensive care unit (icu). perinatal and current potentially predictive variables were obtained from all patients and lbw was defined as birth weight [≤] , g. age (adjusted or (aor) . [ - . ], p= . ), male sex (aor . [ . - . ], p< . ), hypertension (aor . [ . - . ], p= . ), and lbw (aor . [ . - . ], p= . ) independently predicted admission to icu. the area under the receiver-operating characteristics curve (auc) of this model was . [ % ci, . - . ], with positive and negative predictive values of . % and . % respectively. results were reproduced in an independent cohort, from a web-based survey in , subjects who self-reported laboratory-positive sars-cov- infection, where patients ( . %) needed icu admission (auc . [ % ci . - . ]). lbw seems to be an independent risk factor for severe covid- in non-elderly adults and might improve the performance of risk stratification algorithms. covid- is a mild or asymptomatic condition in the majority of patients, but in up to - % it may result in severe disease and death. , older age, male sex and coexisting conditions are the main risk factors described so far for severe covid- disease. [ ] [ ] [ ] [ ] [ ] [ ] however, a small proportion of young and apparently healthy adults may eventually require critical care. there is a need for comprehensive models that identify factors associated to the risk of severe forms of covid- . the association between low birth weight (lbw) and adult health has long been recognized. [ ] [ ] [ ] lbw, defined as ≤ , g, [ ] [ ] can result from fetal growth restriction, prematurity or both. fetal growth restriction has been associated with increased cardiovascular mortality, , lower lung functional capacity - and increased respiratory morbidity [ ] [ ] in adulthood. likewise, prematurity has been described as a risk factor for suboptimal cardiovascular and lung development and a greater predisposition to heart failure and lung disease later in life. for studies in adults, birth weight is an accessible and robust surrogate for fetal growth restriction and preterm births, and a strong predictor of short and long-term morbidity. from the above observations, we hypothesized that lbw could increase the risk of developing severe illness in non-elderly adults with covid- . to test this hypothesis, we designed a prospective study in confirmed covid- patients ( - years) admitted to our institution, a public, tertiary, referral, university hospital in spain (development dataset) and validated the model in an independent cohort of self-reported laboratory-confirmed covid- subjects recruited through a web-based survey (validation dataset). . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint table displays the characteristics of the non-critically ill patients (home hospitalization (n= ) or in hospital (n= )) with those treated in the icu (n= ). the latter were older, more frequently males, had a higher body mass index (bmi) and a higher prevalence of hypertension. of note, they were also born with lbw ( . vs. . %, p= . ) and suffered fetal growth restriction ( vs. . %, p= . ) more often. individuals born with lbw had a higher probability for icu admission as compared with those with normal birth weight ( figure ). p= . ) remained independent predictors of icu. as shown in figure (left), the area under the receiver-operating characteristics curve (auc) for predicting icu admission was . ( % ci, . - . ). the model had a sensitivity of . %, specificity of . %, . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint positive predictive value (ppv) of . % and negative predictive value (npv) of . % (table ) . figure (right panel) presents the consort diagram of the validation dataset. we received , responses of subjects aged to years who referred symptoms suggestive of covid- . among them, , self-reported covid- confirmed by rt-pcr. a total of , of them ( %) reported mild symptoms and did not require hospital admission whereas ( %) were hospitalized of whom ( %) patients required icu admission ( of them ( % of icu patients) were mechanically ventilated, and one male patient ( % of icu patients) died at the age years as reported later by her daughter. table shows the characteristics of the , non-critically ill patients (treated at home (n= , ) or in hospital (n= )) with those treated in the icu (n= ). like we observed in the developing cohort, icu patients in the validation dataset were older, more frequently males, had a higher bmi and a higher prevalence of hypertension. importantly, again, they were born with lbw ( . vs. . %, p= . ) and suffered fetal growth restriction ( . vs. . %, p= . ) more often. in this validation dataset, the prevalence of prematurity was also higher in icu patients ( . vs. . %, p= . ). the model obtained in development dataset was applied to the validation dataset, obtaining an auc of . ( % ci . - . ) (figure , right panel), with a sensitivity of . %, specificity of . %, ppv of . % and npv of % (table ) . . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint this study provides evidence that recording birth weight might improve the prognostic stratification of covid- in non-elder patients. most young patients present mild forms of covid- , but a small proportion might require admission to icu for severe complications, [ ] [ ] [ ] [ ] [ ] [ ] which is clearly associated to non-obvious predisposing factors. early interventions in covid- have demonstrated to reduce mortality. , consequently, the identification of predisposing factors -particularly in a priori non high-risk subjects-might allow early therapeutic measures eventually preventing serious evolution to serious illness. in this study we evaluated an innovative approach by studying early life risk factors not usually taken into account in current clinical practices. birth weight is one of the most universally recorded information for any given individual and self-recalled birth weight has demonstrated to be a reliable information, particularly in subjects born after the s. if confirmed that lbw identifies high risk for complicated covid- , this should be included in initial assessment of non-elder infected subjects and would offer opportunities for early interventions to prevent complications. despite the large number of studies on prognostic factors for severe covid- , - , - to our knowledge no previous study has investigated the predictive role of early life events as a risk factor for severe covid- in adulthood. results confirmed our working hypothesis, which was aligned with a long-standing research line in this field. [ ] [ ] [ ] [ ] besides, results confirmed previous studies showing a strong predictive value for severe covid- of older age, male sex and coexisting conditions such as hypertension. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the fact that we studied non-elderly adults (≤ years) may have limited the identification of significant . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint associations with other reported coexisting conditions such as chronic lung disease, , - , diabetes, [ ] [ ] [ ] [ ] , , [ ] [ ] , obesity , , or cancer. , current or previous smoking status and chronic treatment with ace inhibitors were not associated with covid- severity in our dataset. our results show that lbw is an independent risk factor for severe covid- in adulthood. this finding is consistent with previous epidemiological and experimental studies supporting the developmental origin of adult diseases. adverse in utero environment induces permanent changes in the structure, function and metabolism of the developing fetal organs. most developmental changes of early life persist in the long term which leads to a greater risk of disease in adulthood. , it is suggested that fetal adaptation to perinatal events represents a 'first hit' leading to latent susceptibility, which combined with a 'second hit' later in life could increase the risk for adult diseases. , this notion has been consistently demonstrated in experimental research, but evidence in humans is limited. the covid- pandemic represents a unique opportunity to study the response of a significant number of individuals born lbw to a specific and well-defined stressor. lbw has been consistently associated with increased adult cardiovascular mortality, hypertension, metabolic syndrome, diabetes and lung morbidity. , , , - lbw can be a result of being born too small -fetal growth restriction-and/or too early -prematurity-. fetal growth restriction is caused by placental insufficiency leading to a sustained reduction in fetal oxygen and nutrient supply. this triggers an adaptive fetal response including cardiovascular remodeling, , increased blood pressure, altered lipoprotein profile, lost of nephrons, and disturbed pulmonary alveolarization and vascular growth. in . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint prematurity, key developmental stages have to take place ex utero in non-physiological conditions leading to cardiovascular hypertrophy and impaired lung development, insulin sensitivity and bone density. [ ] [ ] [ ] this study has some strengths and limitations that merit comment. among the strengths, we prospectively collected information spanning the full covid- clinical spectrum, from mild to hospitalized and icu patients. likewise, we validated our observations in an independent dataset. finally, we included only non-elderly subjects (< years) to avoid the potential confounding effect of age-related comorbidities. the study sample size was too small to assess the predictive value of lbw across age ranges. we acknowledge that the evidence here presented should be validated in another prospective hospital cohort. we opted for an online survey to shorten validation time. we acknowledge also a potential selection bias since there were virtually no deaths in our study population. firstly, mortality rate for covid- was very low in our hospital ( %, / , ) with most cases occurring in subjects > years-old. secondly, we tried to contact all covid- patients identified in the emrs, but a few very severe cases were directly intubated and died preventing the interview for the study. finally, we acknowledge the potential inaccuracy of the perinatal data obtained by interview or online survey. however, self-reported birth weight has demonstrated to be a good surrogate of adverse in utero environment, particularly in nonelderly subjects. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . low birth weight increases the risk of severe covid- in non-elderly adults. this new information further supports the importance of early life events in adult diseases and should be considered in future risk stratification algorithms. prospective observational cohort that included non-elderly adults (aged to years) pneumonia) and therapeutic management while in hospital followed the in-house protocols. the primary outcome of the study was admission to the icu, which was determined by the attending physician on a patient by patient basis following standard clinical assessment criteria. follow-up time was censored on may , so that each patient had at least days of observation. the study was approved by the ethical committee of our institution (hcb/ / ) and informed consent was obtained from all patients. cases were identified by daily review of hospital attendance logs in electronic medical records. likewise, demographics, smoking exposure, coexisting conditions, treatment received during the last two weeks before hospitalization, need for icu admission, complications or death during the clinical course, and therapeutic management . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . interventions were obtained by reviewing electronic medical records. on the other hand, perinatal (birth weight and gestational age at delivery) and childhood ("asthma" or other respiratory disease in childhood) data were obtained by a face-to-face or telephone interview. birth weight centiles were calculated adjusted by gender and gestational age at birth according to local standards. lbw was defined as birth weight equal or below , g. fetal growth restriction was defined as a birth weight below the th centile for gestational age and preterm delivery as born before weeks of gestation. to validate externally the performance of the prognostic algorithm created by the development cohort, we collected independent data from self-selected volunteers who results are presented as counts (percentage) or mean (sd) as appropriate. variables with p< . on univariate analyses were entered in the multivariate logistic regression analysis . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint to determine independent risk factors for icu admission. a forward stepwise selection algorithm was applied to select the final model in the development dataset. odds ratio and % confidence interval [ %ci] were calculated. hosmer and lemeshow test were used to assess the goodness of fit of the final model. analysis of the receiver operating curve (roc) was used to evaluate the predictive performance of the model in the development datasets and the optimal cut-off was computed using youden criteria. the model determined in the development dataset was used to predict icu admission in the validation dataset and we report the statistical parameters for development and validation. all pvalues are -sided and considered statistically significant if < . . data were analysed with spss v and r software version . . (r project for statistical computing, vienna, austria). . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september , . . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint authors thank all participants in the study for their willingness to contribute to medical research as well as all the health workers who fought the covid- pandemia. this research was partially supported by "la caixa" foundation. the funding source had no involvement in study design, in the collection, analysis, and interpretation of data; in the writing of the report; nor in the decision to submit the paper for publication. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint §according to the logistic regression model, criteria positive is defined as a probability greater than . % . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study comorbidity and its impact on patients with covid- in china: a nationwide analysis [internet]. the european respiratory journal clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china host susceptibility to severe covid- and establishment of a host risk score: findings of cases outside wuhan identifying patients with increased risk of severe covid- complications: building an actionable rules-based model for care teams the fetal and infant origins of adult disease long-term cardiovascular consequences of fetal growth restriction: biology, clinical implications, and opportunities for prevention of adult disease fetal growth restriction results in remodeled and less efficient hearts in children determinants of low birth weight: methodological assessment and meta-analysis low and very low birth weight in infants conceived with use of assisted reproductive technology reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of swedish men and women born - long term respiratory consequences of intrauterine preterm birth: risk factor for early-onset chronic diseases long-term effects of intrauterine growth restriction on cardiac metabolism and susceptibility to ischaemia/reperfusion validity of self-reported birthweight: results from a norwegian twin sample icu admission, discharge, and triage guidelines: a framework to enhance clinical operations, development of institutional policies, and further research customized birthweight standards for a spanish population american college of obstetricians and gynecologists. fetal growth restriction american college of obstetricians and gynecologists. definition of term pregnancy applied logistic regression index for rating diagnostic tests key: cord- -lurzcliy authors: van mol, margo m. c.; wagener, sebastian; latour, jos m.; boelen, paul a.; spronk, peter e.; den uil, corstiaan a.; rietjens, judith a. c. title: developing and testing a nurse-led intervention to support bereavement in relatives in the intensive care (bric study): a protocol of a pre-post intervention study date: - - journal: bmc palliat care doi: . /s - - - sha: doc_id: cord_uid: lurzcliy background: when a patient is approaching death in the intensive care unit (icu), patients’ relatives must make a rapid transition from focusing on their beloved one’s recovery to preparation for their unavoidable death. bereaved relatives may develop complicated grief as a consequence of this burdensome situation; however, little is known about appropriate options in quality care supporting bereaved relatives and the prevalence and predictors of complicated grief in bereaved relatives of deceased icu patients in the netherlands. the aim of this study is to develop and implement a multicomponent bereavement support intervention for relatives of deceased icu patients and to evaluate the effectiveness of this intervention on complicated grief, anxiety, depression and posttraumatic stress in bereaved relatives. methods: the study will use a cross-sectional pre-post design in a -bed icu in a university hospital in the netherlands. cohort includes all reported first and second contact persons of patients who died in the icu in , which will serve as a pre-intervention baseline measurement. based on existing policies, facilities and evidence-based practices, a nurse-led intervention will be developed and implemented during the study period. this intervention is expected to use ) communication strategies, ) materials to make a keepsake, and ) a nurse-led follow-up service. cohort , including all bereaved relatives in the icu from october until march , will serve as a post-intervention follow-up measurement. both cohorts will be performed in study samples of relatives per group, all participants will be invited to complete questionnaires measuring complicated grief, anxiety, depression and posttraumatic stress. differences between the baseline and follow-up measurements will be calculated and adjusted using regression analyses. exploratory subgroup analyses (e.g., gender, ethnicity, risk profiles, relationship with patient, length of stay) and exploratory dose response analyses will be conducted. discussion: the newly developed intervention has the potential to improve the bereavement process of the relatives of deceased icu patients. therefore, symptoms of grief and mental health problems such as depression, anxiety and posttraumatic stress, might decrease. trial registration: netherlands trial register registered on / / as nl , www.trialregister.nl (continued from previous page) discussion: the newly developed intervention has the potential to improve the bereavement process of the relatives of deceased icu patients. therefore, symptoms of grief and mental health problems such as depression, anxiety and posttraumatic stress, might decrease. the integration of bereavement care into the support services offered to relatives of intensive care unit (icu) patients has been described and endorsed by national and international icu societies [ ] [ ] [ ] [ ] . when a patient is approaching death in the icu, relatives need to make a rapid transition from focusing on the recovery of their beloved one to preparing for their unavoidable death. the actual risk of death depends on the underlying disease and may surpass % in high-risk icu patients [ ] . withholding and/or withdrawing life-sustaining measures in those patients has become common practice preceding death among patients in icus worldwide, with frequencies varying within and between countries from . to % [ ] . death might occur within minutes to days after the initiation of withdrawing life-sustaining therapy [ ] . furthermore, the time of death is sometimes postponed, for example, in the situation of an organ donation procedure or to provide the relatives some extra time to say goodbye to their loved one. therefore, a patient's death in an icu can have a strikingly guided character and is difficult to compare with the dying situations in other healthcare settings or at home [ ] . palliative care in this phase aims to improve the quality of dying and death with personalized attention to physical, social, psychological and spiritual dimensions of care and well-being [ , ] , using variable methods and care plans [ ] . supporting the bereavement process of relatives during the icu admission of their dying loved one has been incorporated into the daily care offerings of professionals worldwide [ , ] . however, a gap exists in adequate icu-based studies evaluating family-centered experiences and long-term health outcomes of bereavement care other than 'satisfaction' after the death of an icu patient [ ] . grieving, with intense feelings and behavior of mourning, is a normal emotional reaction to the loss of a meaningful loved one and refers to the transition from the experience of loss to the adaptation to it [ ] . grieving is not restricted to specific thoughts, feelings, and behaviors, nor is it restricted to a limited time period. grief after a sudden and unexpected death of a beloved person in the icu is going to be hard and will probably last longer than months. a wide variety of phenomena impede the establishment of complicated grief, which is described as serious and persistent grief with adjustment problems in the long term [ ] . the diagnostic and statistical manual of mental disorders (dsm) th edition defines 'persistent complex bereavement disorder' while the international classification of diseases (icd) - includes 'prolonged grief disorder' as practically the same diagnostic entity, differing merely semantically [ ] . this disorder is, among other signs, characterized by intense symptoms of grief lasting for more than months post-loss, separation distress, intrusive thoughts, and feelings of emptiness or meaninglessness [ ] . a recent meta-analysis revealed a prevalence of approximately % for grieving disorders among bereaved adults in a general population [ ] which could lead to negative health outcomes, increased medical service utilization, and economic cost due to absenteeism from work [ ] . relatives of deceased icu patients may develop complicated grief as a consequence of the unpredictable and burdensome situation of losing their loved one. therefore, complicated grief has been included in the post intensive care syndrome-family (pics-f) framework [ , ] . demographic variables such as gender, relationship status, and cultural background, might be associated with complicated grief [ , ] . in addition, factors related to quality of dying and death, communication of staff, and bereavement care might impact the process of grieving for icu relatives [ , ] . however, little is known about the determinants and actual prevalence of complicated grief in bereaved relatives of deceased icu patients. in two small single-center studies, the prevalence of complicated grief measured by the inventory of complicated grief (icg) ranged from % (two out of ) [ ] to % (six out of ) [ ] . a french multicenter study among the relatives of deceased icu patients reported an incidence of complicated grief assessed by the icg in half of the respondents at months ( %), which remained unchanged at months [ ] . the same study presented a decline in posttraumatic stress symptoms from to months, and % respectively, as measured by the impact of event scale-revised (ies-r). despite the robust study design, the generalizability of these results to other countries remains unclear due to cultural differences in end-of-life perspectives and subsequent bereavement care. to our knowledge only one study has measured the experiences of bereaved relatives in a dutch icu [ ] . among respondents the most reported complaints were sleeping problems, while % returned to work and normal activities within - months. although this study did not measure complicated grief nor symptoms of stress, it reflects the normal grieving reactions being hard and lasting for a longer period for bereaved relatives in the icu [ ] . patients could die rapidly, resulting in a dignified death with a low burden of suffering and few signs of discomfort [ ] . a dutch study found that the quality of the dying and death process was perceived as being high by both care-givers and relatives [ ] . therefore, it is important to explore grief and the experiences with the quality of bereavement care in relatives of deceased icu patients in the netherlands compared to the existing international findings. to support relatives during icu admission, multidisciplinary icu teams have previously developed supporting interventions in the bereavement process [ , , ] . effective communication between relatives and icu professionals, professionals' empathic attitudes, and personalized interactions are highly valued aspects of care in the relatives' perspective, particularly during the dying and death process of the patient [ , ] . these aspects may improve preparedness for the expected death and should be tailored to the relatives' specific needs [ ] . in addition, bereaved relatives may need follow-up services to discuss the patient's suffering or distress, to find answers to any remaining questions regarding the death of their beloved one, to discuss their own feelings of loneliness and to explore their expectations for the future [ ] . relatives also reported a preference for more formal support for their emotional situation and psychological symptoms in the early bereavement period (< months) [ ] . according to a european study among icu nurses from countries, bereavement follow-up services vary between countries and icus, such as 'viewing the dead patient in the unit' ( %) and 'a phone call at a certain timepoint' ( . %) [ ] . this international group of experts suggested in their study to further explore the needs of the relatives, to test the efficacy of interventions in bereavement care and to develop guidelines for icus aiming to adequately deliver support to relatives during this difficult situation. the aims of the bric (bereavement in relatives in the intensive care) study for bereaved relatives of deceased icu patients are: ) to develop and implement a multicomponent nurse-led intervention, ) to explore the experiences with bereavement care such as aspects of communication, quality of ding and death, and quality of support to relatives, ) to determine the effectiveness of this intervention on complicated grief, anxiety, depression and posttraumatic stress and ) to identify determinants and risk factors of complicated grief. we hypothesize the following: intervention, including communication strategies, materials to make a keepsake, and a nurse-led follow-up service, improves the quality of experiences with bereavement care in the icu from the perspectives of the bereaved relatives. . symptoms of complicated grief depression, anxiety and posttraumatic stress, decrease after implementation of the multicomponent nurse-led intervention. the bric study is a cross-sectional pre-post intervention study. two different consecutive groups of bereaved relatives, cohort and , will be approached to participate in a single-site study to compare complicated grief, anxiety, depression, posttraumatic stress and experiences with bereavement care. cohort will receive the standard of care, including icu nurses' presence and support for relatives, explanation of the process of dying and death, and empathic communication skills. cohort will receive additional bereavement support through a newly developed multicomponent nurse-led intervention. the study setting is a university hospital in the netherlands with a -bed mixed icu divided into four units. the study population consists of bereaved relatives after the death of an adult (age ≥ ) icu patient who fulfil all inclusion criteria and none of the exclusion criteria. hospital records are used to identify the patients' relatives, i.e., the first and second contact persons. respondents will be selected using four criteria: ) their loved one had died in the predefined period; ) they were present during the icu stay preceding death; ) they have sufficient knowledge of the dutch language (to read and understand information on the study and the questionnaires); and ) they are considered legally responsible. relatives with unknown contact details will be excluded. this study protocol follows the standard protocol items: recommendations for interventional trials (spirit) checklist [ ] . the recommended schematic diagram detailing the schedule of enrolment, interventions and assessments is provided in table . the study is nonblinded and non-randomized due to practical issues in the multicomponent intervention elements, which were applied intuitively and in a tailored fit to the relatives by icu nurses. consecutive icu patients dying in the icu between january and march will be identified from the icu database. descriptive data such as age, gender, length of stay, cause of illness and date of death will be extracted. eligible relatives will be approached by telephone, where they are informed about the study and invited to participate in a survey exploring their current health situation and experiences with the quality of bereavement care. if interested, contact details such as email or postal address will be gathered to send additional written information and an informed consent form. after receiving the bereaved relative's signed consent form, questionnaires will be send according to the participants' preference of a digital version of the questionnaires or paper version with a stamp-free envelope. based on existing (inter) national policies, facilities and evidence-based practices [ ] , we aim to develop a nurse-led support intervention with subsequent implementation in practice during the study period. this intervention is expected to include ) communication strategies, such as an information leaflet on loss and grief [ ] , a condolence greeting card [ ] , and a checklist with relevant topics to discuss in the process of dying and death [ ] ; ) materials to make a keepsake [ ] , such as a lock of hair and a fingerprint; and ) a nurseled follow-up service, such as a memorial meeting and telephone follow-up calls months post-loss [ ] . the intervention will be developed in a multidisciplinary collaboration, including intensivists, spiritual service and social workers. the nurses will be invited to extend the standard of care with elements of the intervention applied to the needs and values of the relatives, thus providing personalized bereavement support. this multicomponent nurse-led intervention will be developed in co-creation with bereaved relatives to maximize care according to their ideals and perspectives, and not solely built on professional beliefs. therefore, the dutch foundation 'family and patient centered intensive care' (fcic) will be involved in the development process. to strengthen the development and implementation of the intervention fidelity measures will be used which will help to understand whether planned intervention was effective [ ] . several methods can be used assessing the quality and include both acceptability of measures in relation to the needs of the stakeholders (bereaved relatives) and practicality of the measures in relation to applicability for the users (icu professionals). the implementation evaluation of this complex intervention will be performed by applying the re-aim model; reach, efficacy, adoption, implementation and maintenance. the re-aim model is an instrument that measures the total impact of an intervention and provides insight into causes for (in)efficacy. re-aim is widely used in public health research, and will support the applicability and dissemination of the study results [ ] . table provides an overview of the re-aim model applied in the current study. both cohorts will be performed in study samples of relatives per group, all participants will be invited to complete questionnaires measuring complicated grief, anxiety, depression and posttraumatic stress. cohort includes all reported first and second contact persons of patients who died in the icu in , which will serve as a pre-intervention baseline measurement. eligible relatives were approached from march to may (−t ) and participants received the questionnaires directly after they signed the consent form (t ). the intervention was conducted from june onwards. cohort , including all bereaved relatives in the icu from october until march , will serve as a post-intervention follow-up measurement. eligible relatives will be approached weeks after the death of their loved one (−t ) and participants will receive the questionnaires directly (t ) and at months (t ) after they signed the consent form. the study design and timeline is presented in fig. . for each deceased patient, up to relatives can be included in the study. this recruitment process has been shown feasible in a previous study [ ] . complicated grief will be measured with the dutch version of the 'traumatic grief inventory-self report version' (tgi-sr), items [ ] . respondents are asked to rate the extent to which they experienced the symptoms listed during the preceding month on a -point scale: = 'never,' = 'rarely,' = 'sometimes,' = 'frequently,' and = 'always'. the tgi-sr demonstrated strong internal consistency, cronbach's alpha = . . a total tgi-sr score, providing an index of the severity of potentially problematic grief, can be obtained by summing the items. a total symptom severity score (range - ) can be obtained by summing the scores for items - and - . elevated scores (tentatively, a cut-off score of ≥ meets the criteria for a provisional diagnosed grief disorder) correlate significantly with elevated scores on indices of psychopathology and lower quality of life, attesting to the concurrent validity [ ] . therefore, in our study, the risk of complicated grief will be categorized as 'low risk' ( to ) or 'high risk' (≥ ). dutch version of the 'impact of events scale-revised' (ies-r) [ ] . this measuring instrument is used worldwide to self-report the frequency of intrusive and avoidant phenomena after a variety of traumatic experiences. the reliability of the dutch version of the ies is adequate across the various stressors [ ] . scores range from to , categorized [ ] and 'the quality of dying and death questionnaire' (qodd) [ , ] , includes items in total. both instruments have been developed and validated in dutch, and report high internal consistency reliability and construct validity. the subscales measure aspects of communication, quality of dying and death, and quality of support to relatives. -questions to evaluate which intervention elements were actually received and how they were appreciated will be added to the questionnaires for cohort . -the applicability and opinions of icu professionals will be measured with a self-composed questionnaire including items to evaluate the fit of the intervention to daily practice and to assess the implementation process. also, a semi-structured interview with one icu manager will be performed for deepening the evaluation and describe learned lessons before further dissemination. these measures administered to icu staff will be performed between october and march , when the development and implementation of the nurse-led multicomponent intervention to support bereavement in relatives in the ic has been finished. data will be collected using limesurvey (version . lts build , ) and exported to a secure spss database (© ibm spss statistics for windows, version . . armonk, ny: ibm corp) for management and analysis. all principal investigators will have access to the final study dataset, of which one delegate has control over study codes with links from personal data of the patients and their relatives. to avoid potential bias, the researchers will be blinded from any results that can relate data back to the individual respondents. personal data will be anonymised. power and feasibility: baseline (retrospective; t ) and follow-up measurements ( weeks; t and months; t ) will be performed in study samples of relatives per group. these numbers are feasible, starting from a mean of icu deaths each year in the study setting, given a ( x) -month inclusion period, an expected . loved one per death, and an expected inclusion rate of % at weeks and a retention rate of % at months. these numbers ensure an effect size of . with a gpower t-test for the´difference between two independent means( -β = %, p < . , two-tailed, d = . ) [ ] . analyses: descriptive statistics (e.g., means, medians, or proportions as appropriate) and student's t-test between pre-post groups on demographic variables (e.g., gender, age, educational level) and outcome measures (e.g., complicated grief, anxiety, depression, posttraumatic stress, experiences with care) will be used to present noticeable differences between the baseline and intervention groups. missing data will be handled using the multiple imputation. the scores will be analysed based on original data, and when available, according to established cut-offs. all test will be bilateral and significance will be defined as p < . . to test the hypotheses repeated measure analyses of variance (anova) will be conducted with time as the within-subject factor (pre-versus post-intervention) and group (cohort and ) as the between-subject factor. cohen's d will be calculated to present effect sizes if applicable. hierarchical regression analyses will be performed to explore determinants and identify subgroups (such as gender, ethnicity, risk profiles, relationship with patient) of bereaved relatives in the icu who are at particular risk of developing mental health problems (i.e., those with scores above established cut-offs). covariates, such as reason of admission, severity of illness, cause of death, bereavement care, time to say goodbye and social support, will be included in the regression model. this model will be adapted for cluster effects to correct for multiple relatives per deceased patient. the study is currently ongoing with recruiting relatives, which started with cohort on march st . subsequently, the intervention has been developed as scheduled ( fig. ) and implemented in daily practice accordingly. recruiting of respondents for cohort has been postponed because of the covid- pandemic and will start immediately after management consent. providing bereavement care to relatives in the icu is an important part of palliative care. alongside a temporary disruption in their personal life, grief might have negative social and economic consequences as well, such as reduced time at work and decreased income. in today's society and culture, talking about death is not always taken for granted. the added value of this research project is to improve psychosocial care for relatives during and after the death of their loved one. the newly developed multicomponent intervention may improve the bereavement process of the relatives; therefore, symptoms of complicated grief and related mental health problems of pics-f such as depression, anxiety and posttraumatic stress, might decrease. while most bereaved relatives do not require bereavement support from a specialist (such as psychologist, psychiatrist), a considerable minority will benefit from non-specialized support (e.g., mutual help-groups) [ ] . identifying relatives at risk for mental health problems, will help to recognize the need for specialized support in an early stage. another strength of the current study is the retrospective baseline measurement combined with a longitudinal prospective approach, thus collecting data in several timepoints to assess changes in mental health over time. these findings can inform icu professionals on strategies to build an evidence-based guideline in bereavement services [ ] . this single-site study, based on the self-reported questionnaire answers of the respondents, may provoke bias in the results and limit generalizability. however, comparing the results with previous findings and international literature will minimize inappropriate conclusions. a stepped wedge or cluster randomized study could provide more general results, which is not the case in this study due to grant requirement of the institution. another limitation may be difficulties with the implementation of multicomponent intervention. the adherence of the professionals may be influenced by workload pressure in clinical practice, insufficient knowledge, focus on high-tech and medical priorities, and their own vulnerability in delicate situations [ ] . moreover, icu nurses may experience barriers in knowledge and competences in communication during the end-oflife situation [ ] . oncology nurses have built a broad expertise in the signs of complicated grief [ ] , which can provide a starting point to support the educational needs of icu nurses [ ] . six strategies have been developed to stimulate the usage of the multicomponent intervention and limit the risk of non-adherence [ , [ ] [ ] [ ] : -educational sessions for all icu nurses presenting the new tools and discussing communication strategies; -information strategies such as an informational pamphlet and reminders in a weekly newsletter; -champions in each icu team, empowered by a twoday training in loss and bereavement care; -regular interactions between the investigators, the local champions and the team members to discuss difficulties; -including the nurse managers in advocating the bereavement tools if doomed necessary during daily start-up; -close collaboration with the department of public health and erasmus mc university medical center, with extended expertise in this domain of palliative care and used practices among nurses and other allied healthcare providers. this particular area of research, and some items in the questionnaires specifically, may be a confronting issue for participants. bereaved relatives are vulnerable, and even voluntary participation in the study might evoke negative flashbacks of the icu admission and death of their loved one. this possibility is taken into account by allowing the participants to share their own experience when completing the questionnaires. they choose what to reveal, and they are not required to answer. previous studies have shown that comparable respondents usually characterize their participation as helpful and not harmful [ , ] . furthermore, information about supporting services such as contact with the research team, social work, and an independent medical specialist, is included in the participant information form and at the beginning of the survey. those who express a need for support will be brought into contact with a social worker, a psychologist or their general practitioner (gp). the gp will be informed in advance on participation of their patient in the current study by an information letter. the study protocol is approved by the medical ethics committee of erasmus mc (mec- - ). protocol modifications will be communicated to the study sponsor by email and to the medical ethics committee by protocol amendment. public access to the study protocol, study details, participant-level dataset, and statistical code can be obtained from the correspondence author. the results will be disseminated to healthcare professionals, health services authorities and the public via presentations at national and international meetings and published in peer-reviewed journals. a lay summary of the results will be written and shared with the dutch foundation fcic and made available to participants on request. an accurate assessment of the implementation process through the re-aim model, combined with a high degree of fidelity to the intervention, is critical to the reliability, validity, replicability, and scale-up of the results of an intervention research study. the findings and evaluation of this study will be used to design and conduct a future multicentre trial. nurses from other icus and nurses of other subspecialties, such as cancer nursing, will be encouraged to implement the developed intervention and to study the effects gaining comparative data. finally, guidelines will be developed for icus aiming to adequately deliver support to relatives during the process of dying and death. anova: analysis of variance; dsm- : diagnostic and statistical manual of mental disorders; fcic: family and patient centered intensive care hads: hospital anxiety and depression scale; icd- : international classification of diseases; icg: inventory of complicated grief; icu: intensive care unit; ies-r: impact of event scale-revisited; tgi-sr: traumatic grief inventory-self report version; pics-f: post intensive care syndrome family; pif: participant information form; re-aim: reach, efficacy, adoptation, implementation and maintenance end-of-life care in the intensive care unit: report from the task force of world federation of societies of intensive and critical care medicine guidelines for family-centered care in the neonatal, pediatric, and adult icu national consensus project for quality palliative care. clinical practice guidelines for quality palliative care effectiveness of supporting intensive care units on implementing the guideline 'end-of-life care in the intensive care unit, nursing care': a cluster randomized controlled trial basic data icus in the netherlands an observational study on a protocol for withdrawal of lifesustaining measures on two non-academic intensive care units in the netherlands: few signs of distress, no suffering? exploration of withdrawal of life-sustaining therapy in canadian intensive care units survey into bereavement of family members of patients who died in the intensive care unit. intensive critical care nurs tasking the tailor to cut the coat: how to optimize individualized icu-based palliative care? palliative care interventions in intensive care unit patientsa systematic review protocol caesar: a new tool to assess relatives' experience of dying and death in the icu bereavement as a psychosocial transition: processes of adaptation to change correction: prolonged grief disorder: psychometric validation of criteria proposed for dsm-v and icd- internet-based grief therapy for bereaved individuals after loss due to haematological cancer: study protocol of a randomized controlled trial prevalence of prolonged grief disorder in adult bereavement: a systematic review and meta-analysis prolonged grief symptoms related to loss of physical functioning: examining unique associations with medical service utilization postintensive care syndrome: right care, right now … and later improving long-term outcomes after discharge from intensive care unit: report from a stakeholders' conference complicated grief after death of a relative in the intensive care unit culturally sensitive communication in end-of-life care: the care for muslim patients as an example a communication strategy and brochure for relatives of patients dying in the icu effect of a condolence letter on grief symptoms among relatives of patients who died in the icu: a randomized clinical trial psychiatric illness in the next of kin of patients who die in the intensive care unit posttraumatic stress and complicated grief in family members of patients in the intensive care unit perception by family members and icu staff of the quality of dying and death in the icu: a prospective multicenter study in the netherlands guiding intensive care physicians' communication and behavior towards bereaved relatives: study protocol for a cluster randomized controlled trial (cosmic-eol) quality of dying in the icu: understanding ways to make it better family-centered care: meeting the needs of patients' families and helping families adapt to critical illness preparing caregivers for the death of a loved one: a theoretical framework and suggestions for future research family members' perceived needs for bereavement followup the desirability of an intensive care unit (icu) clinician-led bereavement screening and support program for family members of icu decedents (icu bereave) elements of intensive care bereavement follow-up services: a european survey spirit explanation and elaboration: guidance for protocols of clinical trials identifying improvement opportunities for patient-and family-centered care in the icu: using qualitative methods to understand family perspectives the doctor's letter of condolence research participation for bereaved family members: experience and insights from a qualitative study developing quality fidelity and engagement measures for complex health interventions evaluating the public health impact of health promotion interventions: the re-aim framework no negative impact of palliative sedation on relatives' experience of the dying phase and their wellbeing after the patient's death: an observational study the traumatic grief inventory self-report version (tgi-sr): introduction and preliminary psychometric evaluation the validity of the hospital anxiety and depression scale: an updated literature review a validation study of the hospital anxiety and depression scale (hads) in different groups of dutch subjects the impact of event scale: revised, in cross-cultural assessment of psychological trauma and ptsd construct validation of the dutch version of the impact of event scale quality of care in the intensive care unit from the perspective of patient's relatives: development and psychometric evaluation of the consumer quality index 'r-icu'. bmc evaluating the quality of dying and death comparing quality of dying and death perceived by family members and nurses for patients dying in us and dutch icus * power : a flexible statistical power analysis program for the social, behavioral, and biomedical sciences the effect of caregiving on bereavement outcome: study protocol for a longitudinal, prospective study patient-and family-centred care in the intensive care unit: a challenge in the daily practice of healthcare professionals critical care nurses' perceptions of obstacles, supports, and knowledge needed in providing quality end-of-life care effect of palliative care nurse champions on the quality of dying in the hospital according to bereaved relatives: a controlled beforeand-after study palliative care communication in the icu: implications for an oncology-critical care nursing partnership improving patient care: the implementation of change in health care the state of bereavement support in adult intensive care: a systematic review and narrative synthesis closing the gap between research and practice: an overview of systematic reviews of interventions to promote the implementation of research findings identifying and responding to ethical and methodological issues in after-death interviews with next-of-kin conducting research interviews with bereaved family carers: when do we ask? publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors would like to thank all participating bereaved relatives and the department of intensive care unit adults of erasmus mc, the netherlands for their involvement in the study. mvm, cdu and jr jointly designed the study, raised funding and established the development of the study protocol. mvm and sb prepared the study materials and produced the first draft of the article outline. all authors (mvm, jml, sw, pb, ps, cdu, jr) contributed substantially to analyses of literature, critically revised the content of the manuscript, have read and approved the final version. this work has been supported by a grant from erasmus mc "evidence based care by nurses", project - , which had no role in the design of this study and has no role in its execution, analysis and interpretation of data, or publication of results. anonymized data gathered and analysed during the current study are not publicly available due to legal and ethical restriction. these can be requested from the corresponding author as well as text and photo material of the developed intervention. participants will be informed about the study both orally and by letter. consent for participation will be given by written informed consent. not applicable. the authors declare no conflicts of interest. key: cord- -a y vdv authors: alshukry, a.; ali, h.; ali, y.; al taweel, t.; abu-farha, m.; abubaker, j.; devarajan, s.; dashti, a. a.; bandar, a.; taleb, h.; al bader, a.; aly, n. y.; al-ozairi, e.; al-mulla, f.; bu abbas, m. title: clinical characteristics of coronavirus disease (covid- ) patients in kuwait date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: a y vdv abstract background: in early december , the first clusters of coronavirus disease (covid- ) were identified in wuhan, china and attributed to a novel coronavirus, now known as severe acute respiratory syndrome corona virus (sars-cov ). kuwait reported its first cases of covid- on february th and since then the number of cases has been increasing rapidly. methods and findings: this is a retrospective single-center study of consecutive covid- patients admitted to jaber al-ahmad hospital between / / and / / . the mean age of cohort was . years (s.d. . ) and . % of cases were males. patients were divided into four groups; asymptomatic group, symptomatic group with mild form of the disease, icu survivors and icu death. in total, . % of patients were asymptomatic, % were symptomatic with mild symptoms, . % were admitted to icu and recovered and . % died. mean age of icu patients was . years (s.d. . ). comorbidities were more prevalent in icu death group when compared to other groups (p< . ) including diabetes ( %), hypertension ( . %), asthma ( . %) and cardiovascular disease ( . %). blood biochemistry analysis showed that icu death group had a characteristic abnormal pattern of certain markers upon admission in the icu. including significantly high wbc and neutrophil counts (p< . ) and prolonged prothrombin time (pt) and activated partial thromboplastin time (aptt) (p< . ). d-dimer, c-reactive protein and procalcitonin (pct) showed significantly high levels in icu admissions and in icu death group in particular (p< . ). kidney injury complications were reported in % of icu death group (p< . ) which also showed significantly elevated urea levels (p< . ). we also reported rapid deteriorating kidney function (egfr) in icu death cases during icu stay until the outcome was reached. conclusions: in this single-center study of covid patients in kuwait. the disease showed varying degree of severity ranging from asymptomatic status to death. our comprehensive laboratory analysis revealed distinct abnormal patterns of markers that are associated with poor prognosis. our dynamic profiling of egfr in covid- icu patients highlight potential role of renal markers in forecasting disease outcome and perhaps identify patients at risk of poor outcome. in early december , the first clusters of coronavirus disease were identified in wuhan, china . initially, these cases were reported as pneumonia of unknown cause. still, they later were attributed to a novel coronavirus, now known as severe acute respiratory syndrome corona virus (sars-cov ), an enveloped single-strand rna β-coronavirus with a thousand bases genome . on march th , the world health organization (who) confirmed covid- as a pandemic. since then, the disease has been spreading hastily affecting more than million people and resulting in more than thousand deaths, which emphasize the threat it poses on global health . clinical manifestations of covid- showed a high degree of variability including asymptomatic carriers, acute respiratory distress syndrome (ard), and pneumonia with variable severity , . most of the identified patients experience mild symptoms, including fever, cough, dyspnea, myalgia, and fatigue. in contrast, patients in severe cases develop ards and severe cardiac and renal complications, which can potentially lead to death , . additionally, a worse prognosis has been associated with older age, being male, and having pre-existing chronic conditions such as hypertension, cardiovascular disease, and diabetes. at the same time, pediatric cases showed a milder clinical course . countries worldwide have been affected differently by the covid- pandemic ranging from high infection and high mortality rates in countries like the usa, france, and spain to low infection and mortality rates in countries like new zeeland for example , . multiple theories have been suggested to explain the current infection and death rate, including tight measures, better health . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint care system as well as genetic factors amongst others. one particular hypothesis focused on genetic variants within the angiotensin converting enzyme (ace ) gene , . multiple studies have suggested that variants within the ace gene can influence the viral entry into the host cell , . in a recent study, we have shown that one variant within the ace gene (n d) was responsible for reduced infection rates in middle eastern countries compared to europeans . such findings highlight the importance of investigating various populations worldwide to gain more insight into this disease. this study is focused on presenting a cohort from kuwait, a small country located on the northern tip of the persian gulf, with a population of nearly . million. kuwait reported its first cases of covid- on february th in passengers coming from iran. since then, the reported cases were increasing exponentially, reaching over , cases at the time of writing this report and more than registered deaths , . while the search for effective treatment and vaccine for covid- continues, health care systems, including kuwait, are trying to strengthen their frontline clinical services to cope with the pandemic. here, we describe the demographics, baseline comorbidities, clinical characteristics, and outcomes of covid- patients' cohort in kuwait. we further investigate the dynamics of certain laboratory parameters in intensive care unit (icu) admissions in relation to clinical outcomes. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint this is a retrospective study reviewed and approved by the standing committee for coordination of health and medical research in the ministry of health in kuwait (irb / ). the medical records of the confirmed covid- cases admitted to jaber al-ahmad hospital in kuwait between / / and / / were included in the study. covid- diagnosis was established based on a positive result of real-time reverse transcriptase-polymerase chain reaction (rt-pcr) assay of nasal and/or nasal and pharyngeal swabs, in accordance with (who) interim guidance . cases were divided into three groups; asymptomatic, mild/moderate and intensive care unit (icu) group. all cases admitted to jaber al-ahmad hospital between / / and / / were included in the study. a total of covid- confirmed cases were included in the study. cases medical records were accessed and analyzed by the research team at dasman diabetes institute, kuwait university and jaber al ahmad hospital. epidemiological, clinical, laboratory, radiological characteristics, in addition to treatment plans and outcomes, were accessed and obtained from the medical records. recorded information included demographic data, medical history including underlying comorbidities, travel history, contact tracing data, clinical chemistry and hematology laboratory findings, chest radiological images, treatments, complications, intensive care unit (icu) admission, durations and dynamics of hospital stay and outcomes. signs, symptoms and . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint laboratory findings were recorded on the day of hospital admission (ward and icu). ards was determined in accordance with berlin definition . acute kidney injury was determined in accordance with kidney disease: improved global outcomes definition . cardiac injury was concluded based on blood cardiac markers, electrocardiography and/or echocardiography . the period in which cases were enrolled in this study, a % hospitalization policy was implemented in jaber al ahmad hospital, by the ministry of health. any patient with a positive rt-pcr test was admitted, isolated, and put under clinical surveillance, including asymptomatic cases. patients with mild to moderate covid- symptoms who were hemodynamically stable and without any signs of respiratory distress were admitted to the ward after rt-pcr confirmation for isolation and clinical surveillance and re-evaluation. patients in this sub-group were transferred to the (icu) only if they developed signs of respiratory distress and desaturation of oxygen levels -confirmed by pulse oximetry and arterial blood gases -and/or signs of hemodynamic instability requiring close monitoring and intensive re-establishment of homeostasis. patients with severe to critical covid- symptoms were directly admitted to the icu should they meet any of the following criteria of severity: hypoxemic respiratory failure that required respiratory support such as cases that developed ards, hemodynamic instability due to cardiogenic or septic shock and clinical/radiological/laboratory evidence of heart failure, acute cardiac injury and acute kidney injury secondary to covid- manifestations. for icu dynamic analysis, we divided subjects into two groups; icu survivors and icu death. clinical analysis of blood samples was done for all subjects on daily bases. the daily values of selected laboratory parameters were averaged and plotted until an outcome was achieved. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint the variables analyzed in the study were divided into categorical and continuous variables. the categorical variables were described as frequencies and percentages, while continuous variables were presented as medians and interquartile range (iqr) values and means and standard deviations. means between groups were compared using one-way analysis of variance (anova). categorical variables were analyzed by using the chi-square test, and wherever the data were limited, fisher exact test was used. differences between groups means and medians are considered significant when a p value is < . . all statistical analyses were performed using . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint in our study, hospitalized covid- cases with a positive viral pcr test were enrolled. the cohort had a median age of years (iqr - years), and % of the cohort were males. the age structure of the cohort showed that the majority of patients belonged to the - years age group, and notably, only . % belonged to the - years age group ( figure and table ). the cohort consisted of . % asymptomatic patients, % symptomatic (mild to moderate), . % admitted to the icu, and recovered, while . % admitted to icu and died (table. ). the majority of admissions to icu belonged to the age group ( - years, . %), while . % belonged to the - years and % to the - years age group ( figure. and table. ). no icu admissions were recorded for the youngest age group ( - years). out of cases, we recorded death cases, the majority of such cases belonged to the age group ( - years), which represented . % of all death cases reported with a case fatality rate of . % ( figure. and table. ). however, case-fatality rate was highest in the - years age group as it was . % (table. ). covid- patients were divided into four groups. the first group was composed of asymptomatic patients. these patients have positive viral pcr but did not show any symptoms and were kept in hospital isolation until a negative viral pcr was achieved with an average hospital admission length of . ± . days (table. ). the asymptomatic group made up . % of the cohort, with an average age of . ± . years. symptomatic cases made up % of the cohort. this group consisted of cases that exhibited mild/moderate symptoms but did not require icu . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint admission. % of these patients experienced fever, % of them presented with a dry cough, . % of them reported sore throat, and . % described symptoms of myalgia (table. ). cases admitted to icu were divided into two groups based on outcome; the icu survivors groupcomposed of cases ( . % of the cohort) and the icu death group -composed of cases counting for . % of the cohort (table. ). the pattern of symptoms in the icu survivors' group was similar to the symptomatic group except for the shortness of breath, which was present in . % of cases (table. ). shortness of breath was more prevalent in the icu death group ( . %). furthermore, this group had more comorbidities than other groups -including diabetes, hypertension, asthma, cardiovascular disease, chronic renal disease, and malignancies (table. ). clinical data analysis indicated significant differences between covid- patients' groups. the asymptomatic group generally showed normal laboratory findings with minimal borderline abnormalities (table. ). numerous markers showed significant differences between the symptomatic/mild group and patients admitted to icu, including complete blood count (cbc) ( table. ). inflammatory markers, including procalcitonin (pct) and c-reactive protein (crp) showed progressive increasing patterns from symptomatic group to icu death group. markers of blood clotting, including prothrombin time (pt) and activated partial thromboplastin time (aptt) showed prolonged timings in the icu death group. markers related to renal function showed significant abnormalities in the icu death group, including declined egfr and increased urea (table. ), which coincide with reported kidney injury complications in % of cases in this particular group (table. ). markers associated with heart . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint injury including troponin and lactate dehydrogenase (ldh) showed significant increase in subjects admitted to icu and in particular the icu death group (table. ), which coincided with reported heart failure in % of cases in this specific group and cardiac injury in . % of them (table. ). d-dimer was within normal range in the asymptomatic and symptomatic groups but was significantly elevated in icu groups and the icu death group (table. ). . % of cases in the icu survivor group developed ards compared to % of cases in the icu death group (table. ). chest radiographs of patients in the icu survivor and death groups showed diffuse bilateral airspace opacification with patches of consolidation ( figure. ). high-resolution ct chest in icu death case showed multifocal large patchy areas of ground glass opacification mixed with dense consolidations (figure. ). intubation was required for % of the cases in icu survivor group and in . % in the icu death group (table. ). treatment-wise, antibiotics, like amoxicillin, augmentin, rocephine and piperacllin/tazobactam, were the most commonly administered medication as . % of symptomatic, % of icu survivors and . % of icu death group received them. antiviral drugs, such as oseltamivir and lopinavir, were given to % of cases in icu survivor group and . % of icu death cases. antimalarial drug hydroxychloroquine were given to % of icu survivor group and . % of icu death group (table. ). we tracked the levels of blood markers associated with infection, inflammation, and kidney function in icu patients to study disease progression and outcome. the icu death group showed elevated levels of white blood cells (wbc) after the second day of disease onset onward. in contrast, icu survivor group had an average below x cells/l ( figure. a) . a similar pattern . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint was observed in the neutrophil count ( figure. b) . icu death cases also showed lymphocytopenia when compared to icu survivors ( figure c ). inflammatory markers, namely crp and pct, showed a significant increase during icu stay until outcome in the icu death group ( figure. d and e). renal function declined progressively in the icu death group during stay until outcome ( figure f ). . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint to our knowledge, this report is one of the first detailed reports of covid- clinical characteristics in kuwait and the region. kuwait reported its first cases from travelers arriving from iran on the th of february followed by further cases arriving from europe before cases from community transmission started to accumulate . we have recruited our cohort between / / and / / during which the hospitalization rate was % for all sars-cov- positive cases. capturing all the cases during a specific period and from one place allows more comprehensive clinical insights, especially in relation to the inclusion of asymptomatic cases, which were isolated in the hospital with full medical surveillance. the most prevalent symptoms in our cohort were fever which was present in . % of the cohort, dry cough ( . %) and shortness of breath ( . %), with the latter being more prevalent in icu admissions (table. ). prevalence's of symptoms varied between studies, for instance fever was reported in . % of patients on admission in a multi-centers study in china . while in another study conducted in the city of wuhan a fever prevalence of . % was reported . these variable findings are influenced by the diagnostic criteria utilized and effectiveness of surveillance strategies. it is more of a question of which lead to admission; a symptom or random surveillance testings based in viral pcr which shall result in capturing asymptomatic individuals. the age structure of the cohort provided a good representation of the population in kuwait ( figure. , . capturing asymptomatic individuals is challenging as these cases do not raise any . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint flags for medical attention; therefore, they can intensify infection . in kuwait, extensive viral pcr testing was conducted for every passenger entering the country during the period of recruitment in addition to active contact tracing being put in action. the case fatality rate (cfr) calculated for the cohort was . %, which could represent an overestimation due to the proportion of ongoing cases, especially at the early stage of the outbreak, as is the case in our study . the highest case fatality rate was recorded in the - years age group ( . %), which is close to what has been reported in new york city . ards was one of the main causes for icu admissions as it was reported in all death cases and . % of icu survivors. patients admitted to the icu were older in comparison to other groups. our results also indicated that the icu death group had higher prevalence of comorbidities and were pronominally males (table. ). several studies have shown significant association between poorer outcome with being a male. that was the case in during the sars-cove outbreak and now with covid- . while the reasons underlining this observation are not fully understood, the levels of ace in males were suggested as a possible explanation . death outcome also correlated with higher prevalence of comorbidities, as seen in the icu death group with hypertension being the most prevalent comorbidity followed by diabetes. similar findings were also reported in new york and wuhan . direct comparison between groups revealed than icu admissions and particularly the icu group indicated significantly lower levels of hemoglobin (hb) ( table. ). this observation has been reported previously in patients with other kinds of pneumonia and was associated with higher mortality rates . icu death group also showed prolonged prothrombin time (pt) and activated . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint partial thromboplastin time (appt) when compared to other groups (table. ), which indicate abnormalities in coagulation. such abnormal coagulation parameters were reported by previous studies and showed an association with poor prognosis . recent recommendations advise that such prolonged appt should not halt the use of anticoagulation therapies to prevent or treat venous thrombosis in covid- patients . d-dimer levels were also significantly elevated in the icu death group (table. ). previous studies indicated that patients who required intubation and have higher levels of d-dimer would have a higher risk of developing pulmonary embolism , which highlights the need for a protocol to identify and treat such cases with anticoagulants. for icu admissions, a dynamic analysis of a set of markers was performed throughout the stay in icu until an outcome was reached (recovery or death). in the icu death group, the wbc and neutrophil counts continued to increase until day , where the averages dropped but remained above the upper normal limit, which with the decreasing lymphocytes indicate active ongoing infection. pct levels continued to increase in the icu death group until an outcome was concluded which could be caused by bacterial coinfection and has been associated with severe disease outcome . crp also followed a similar increasing pattern, which could indicate a severe inflammatory cascade possibly associated with ards (table. ) and eventually leading to death . kidney injury was more prevalent in the icu death group when compared to icu survivor and symptomatic groups ( % vs. . % and . % respectively). this matched the reported progressive impairment of kidney function in icu death group as suggested by the declining egfr low total protein and albumin and increased urea ( figure. , table , ) . ace may play an important role in the involvement of kidney in covid- and notably in severe cases as it is highly expressed in the tubular epithelial cells in the kidneys . when sars-cov infect the renal . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . moreover, . % of death cases had a history of hypertension which could negatively impact the deteriorating kidney function . the burden of kidney injury on covid- prognosis should not be underestimated as our results indicated that kidney injury is a negative prognostic factor for survival. therefore, therapeutic and preventive protocols need to be developed and adapted to control the burden of kidney injury and reduce morbidity and mortality. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint in here, we provide a detailed clinical analysis of a cohort of consecutively recruited covid- patients from a single hospital in kuwait. in total, . % of patients were asymptomatic, % were symptomatic with mild symptoms, . % were admitted to icu and recovered and . % died. notably kidney damage was the most prevalent complication reported in death cases which is supported by renal markers laboratory findings. our dynamic profiling of egfr in covid- icu patients highlight potential role of renal markers in forecasting disease outcome and perhaps identify patients at risk of poor outcome. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint figure . categorical age structures. each age group percentage is calculated by dividing the count by the total in each category. majority of cohort belonged to the age group ( - years) while highest numbers of death cases were recorded in the age groups ( - years). is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint clinical features of patients infected with novel coronavirus in wuhan a new coronavirus associated with human respiratory disease in china an interactive web-based dashboard to track covid- in real time presumed asymptomatic carrier transmission of covid- asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus (sars-cov- ): facts and myths clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan sars-cov- infection in children estimating the burden of sars-cov- in france a comprehensive germline variant and expression analyses of <em>ace </em>, <em>tmprss </em> and sars-cov- activator <em>furin</em> genes from the middle east: combating sars-cov- with precision medicine ace gene variants may underlie interindividual variability and susceptibility to covid- in the italian population structural variations in human ace may influence its binding with sars-cov- spike protein ace receptor polymorphism: susceptibility to sars-cov- , hypertension, multi-organ failure, and covid- disease outcome real-time tracking and forecasting of the covid- outbreak in kuwait: a mathematical modeling study. medrxiv clinical management of covid- . interim guidance. (world health organization acute respiratory distress syndrome: the berlin definition definition and classification of chronic kidney disease: a position statement from kidney disease: improving global outcomes (kdigo) clinical characteristics of coronavirus disease in china population estimates in kuwait by age, nationality and sex at l l estimating the extent of asymptomatic covid- and its potential for community transmission: systematic review and meta-analysis. medrxiv comparison of clinical characteristics of patients with asymptomatic vs symptomatic coronavirus disease asymptomatic transmission, the achilles' heel of current strategies to control covid- estimating case fatality rates of covid- presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the gender differences in patients with covid- : focus on severity and mortality. front public health lower hemoglobin transfusion trigger is associated with higher mortality in patients hospitalized with pneumonia abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia lupus anticoagulant and abnormal coagulation tests in patients with covid- d-dimer in patients infected with covid- and suspected pulmonary embolism procalcitonin in patients with severe coronavirus disease (covid- ): a meta-analysis clinical characteristics of death cases with covid- : a retrospective review of medical records in a single medical center ace alterations in kidney disease management of acute kidney injury in patients with covid- public knowledge of cardiovascular disease and its risk factors in kuwait: a cross-sectional survey hypertension and kidneys: unraveling complex molecular mechanisms underlying hypertensive renal damage key: cord- - w ojgd authors: cavayas, yiorgos alexandros; noël, alexandre; brunette, veronique; williamson, david; frenette, anne julie; arsenault, christine; bellemare, patrick; lagrenade-verdant, colin; leguillan, soazig; levesque, emilie; lamarche, yoan; giasson, marc; rico, philippe; beaulieu, yanick; marsolais, pierre; serri, karim; bernard, francis; albert, martin title: early experience with critically ill patients with covid- in montreal date: - - journal: can j anaesth doi: . /s - - -z sha: doc_id: cord_uid: w ojgd purpose: montreal has been the epicentre of the coronavirus disease (covid- ) pandemic in canada. given the regional disparities in incidence and mortality in the general population, we aimed to describe local characteristics, treatments, and outcomes of critically ill covid- patients in montreal. methods: a single-centre retrospective cohort of consecutive adult patients admitted to the intensive care unit (icu) of hôpital du sacré-coeur de montréal with confirmed covid- were included. results: between march and may , patients were admitted, with a median [interquartile range (iqr)] age of [ – ] yr and high rates of obesity ( %), hypertension ( %), and diabetes ( %). healthcare-related infections were responsible for % of cases. the median [iqr] day sequential organ failure assessment score was [ – ]. invasive mechanical ventilation (imv) was used in % of patients for a median [iqr] of [ – ] days. patients receiving imv were characterized by a moderately decreased median [iqr] partial pressure of oxygen:fraction of inspired oxygen (day pao( ):f(i)o( ) = [ – ]; day = [ – ]) and compliance (day = [ – ] ml/cmh( )o; day = [ – ] ml/cmh( )o) and very elevated estimated dead space fraction (day = . [ . – . ]; day = . [ . – . ]). overall hospital mortality was %, and % in the imv patients. mortality was % in patients ≥ yr old. conclusions: characteristics and outcomes of critically ill patients with covid- in montreal were similar to those reported in the existing literature. we found an increased physiologic dead space, supporting the hypothesis that pulmonary vascular injury may be central to covid- -induced lung damage. related infections were responsible for % of cases. the median [iqr] day sequential organ failure assessment score was [ ] [ ] [ ] [ ] [ ] . invasive mechanical ventilation (imv) was used in % of patients for a median [iqr] of [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days. patients receiving imv were characterized by a moderately decreased median [iqr] overall hospital mortality was %, and % in the imv patients. mortality was % in patients c yr old. conclusions characteristics and outcomes of critically ill patients with covid- in montreal were similar to those reported in the existing literature. we found an increased physiologic dead space, supporting the hypothesis that pulmonary vascular injury may be central to covid- induced lung damage. objectif montre´al a e´te´l'e´picentre de la pande´mie du coronavirus (covid- ) au canada. e´tant donne´les disparite´s re´gionales dans l'incidence et la mortalite´dans la population ge´ne´rale, nous avons tente´de de´crire les caracte´ristiques locales, les traitements et le devenir des patients atteints de la covid- en e´tat critique am ontre´al. méthode notre e´tude de cohorte re´trospective monocentrique a inclus tous les patients adultes admis conse´cutivement a`l'unite´de soins intensifs de l'hôpital du sacre´-coeur de montre´al avec un diagnostic confirme´de covid- . résultats soixante-quinze patients ont e´te´admis entre le mars et le mai . ceux-ci avaient un aˆge me´dian [e´cart interquartile (e´iq)] de [ - ] ans et pre´sentaient une incidence e´leve´e d'obe´site´( %), d'hypertension ( %) et de diabe`te ( %). les transmissions associe´es aux soins de sante´e´taient responsables de % des cas. au jour , le score sofa (sequential organ failure assessment -e´valuation se´quentielle de de´faillance des organes) me´dian [e´iq] e´tait de [ ] [ ] [ ] [ ] [ ] . la ventilation me´canique invasive (vmi) a e´te´utilise´e chez % des patients, pour une dure´e me´diane [e´iq] de [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the catchment area of our hospital has been particularly affected with more than , confirmed cases of covid- . a rate of , confirmed cases/ , population was reached in one of the covered boroughs, the highest reported rate in the country and similar to that reported in new york city. severe acute respiratory syndrome coronavirus infection can result in a wide range of clinical manifestations, ranging from asymptomatic to critically ill. exaggerated inflammatory mediator release triggered by the cytopathic viral infection and coagulation dysregulation are thought to be central to the development of severe lung damage. different distribution of determinants of this host response may significantly impact the expression of the disease in different populations. older populations with higher rates of hypertension, diabetes, and obesity have a higher risk of more severe disease. extrinsic factors, including healthcare system characteristics (i.e., number of hospital or icu beds), may also impact patient management and disease progression towards severe forms. finally, cultural differences in terms of goals of care and end-of-life decision-making may also affect icu admission and choice of supportive therapy. given regional differences in the above-mentioned factors, detailed characterization of critically ill patients is needed to understand how covid- affects our population. our aim was to describe the demographics, presentation, treatments, and outcomes of a cohort of critically ill adult patients with covid- hospitalized in a large academic icu in montreal, canada. we conducted a single-centre retrospective observational study of consecutive adult patients with confirmed covid- admitted to the icu of hôpital du sacré-coeur de montréal between march and may . diagnosis was established in all cases by reverse transcriptasepolymerase chain reaction in nasopharyngeal, tracheal aspirate, or bronchoalveolar lavage specimens. the institutional review board approved the study and waived the requirement for informed consent. hôpital du sacré-coeur de montréal is a large academic hospital with a pre-pandemic -bed capacity mixed medical-surgical icu and a : . nurse to patient ratio. it is a level- trauma centre and severe acute respiratory failure centre, with extracorporeal membrane oxygenation (ecmo) capacity. hôpital du sacré-coeur de montréal was among the first designated covid- centres in the province. an organizational plan was in place to progressively increase the number of icu beds to [ in a stepwise approach if needed. all covid- cases were managed by boardcertified intensivists supported by a multidisciplinary team according to international treatment guidelines, including lung-protective ventilation, prone position, neuromuscular blockade, and conservative fluid management. , intensive care unit admission criteria for covid- patients included an oxygen requirement of [ lÁmin - accompanied with signs of respiratory distress. patients with pre-established limitations of care excluding invasive mechanical ventilation (imv) and cardiopulmonary resuscitation (cpr) were only admitted if considered for a trial of highflow oxygen therapy or non-invasive positive-pressure ventilation (nippv). these therapies were permitted only in negative-pressure icu rooms and their use was initially strongly discouraged because of aerosol generation. some patients admitted from the emergency department (ed) did not have pre-established goals of care (goc). such patients were admitted quickly in an effort to liberate ed beds and goc were discussed in the icu. in patients with respiratory distress, nippv was sometimes started to provide time to discuss goc. although goc were continuously reviewed as per patient evolution and families' wishes, only initial goc at icu admission were used for analysis. an early intubation strategy was initially advocated, with a slightly longer period of observation before intubation as experience was gained. with a few exceptions, no antimalarial, antiviral, or immunomodulating agents were administered outside of clinical trials. corticosteroids were used at the discretion of we recorded baseline characteristics, laboratory parameters, icu day sequential organ failure assessment (sofa) score, treatments, and outcomes. day of imv arterial blood gas values and imv parameters were collected (those closest to : am). data were extracted from our icu database (semi criticareÒ, montreal, qc, canada), complemented by retrospective chart review. the ventilatory ratio, estimated dead space fraction (v d :v t ; weir rearrangement using the harris-benedict equation for the resting energy expenditure), and mechanical power (simplified) were calculated according to published formulas. [ ] [ ] [ ] descriptive statistics were used to summarize clinical data. categorical variables were presented as counts and percentages and continuous variables as median [interquartile range (iqr)]. in patients missing pao measurements, we used the spo :f i o ratio to calculate the respiratory component of the sofa score. missing data imputation was not performed. data were analyzed acei = angiotensive coverting enzyme inhibitor; ast = aspartate aminotransferase; alt = alanine aminotransferase; arb = angiotensive receptor blockers; ast = aspartate aminotransferase; bmi = body mass index; ckd = chronic kidney disease; copd = chronic obstructive lung disease; crp = c-reactive protein; hs = high sensitivity; icu = intensive care unit; ldh = lactate dehydrogenase; nsaid = non-steroidal antiinflammatory drugs; pulm. dis. = pulmonary disease; sofa = sequential organ failure assessment; wbc = white blood cell count using ibm spss statistics, version . (ibm corp, armonk, ny, usa). between non-invasive respiratory support a high-flow nasal cannula was used in only two patients ( %) because of concerns over aerosolization. noninvasive positive-pressure ventilation was also initially avoided, but as the pandemic evolved, it was used more frequently ( / ; %), mainly in patients with respiratory distress who declined imv ( / ; %). failure of nippv was high in that context (seven deaths/ ; %). in the remaining six patients that consented to imv, nippv was used as the initial support modality in two patients likely to have poor outcomes with imv (advanced chronic pulmonary diseases); intubation was successfully avoided in both. in the other four patients, nippv was used post-extubation; it failed in three of those four instances (one patient who declined re-intubation died and two patients were re-intubated). a total of patients underwent imv ( % figure. only two patients below yr of age died ( / ; %). fifteen of the patients who died ( %) gave do-notresuscitate orders upon icu admission. the mortality was % ( / ) for patients with initial goc excluding both resuscitation and imv, % ( / ) for patients with initial goc excluding resuscitation but allowing imv, and % ( / ) for those with initial full-code status. there were no missing data on icu therapies and outcomes. patients were categorized into three groups (table ). group a consisted of patients agreeing to imv but did not receive it (n = ). this group was younger and had fewer comorbidities. they presented with the lowest rate of lymphopenia, the lowest ferritin, and lowest d-dimers, while having the highest median c-reactive protein levels. all but one patient survived and the icu los was short - , ] ). the majority were treated with nippv ( / ; %). mortality in this group was %. in this first account of critically ill covid- patients treated in the canadian epicentre of the pandemic, we have found encouraging outcomes despite facing one of the largest numbers of cases per capita. we observed a high proportion of overweight and obese patients with hypertension and diabetes, as previously described. patients typically presented to the icu more than a week after symptom onset with lymphopenia, a hyperinflammatory profile, and evidence of coagulation activation. of concern, nosocomial transmission was responsible for more than a third of cases. invasive mechanical ventilation was used in % of patients. these were characterized by moderately low pao :f i o and compliance and very elevated estimated dead space fraction and ventilatory ratio. hospital mortality was % overall and % in imv patients. critically ill patients with limitations of care excluding imv had a high non-invasive ventilation failure rate ( %) and a high mortality rate ( %). finally, patients c yr old had an % mortality rate. as of july, , hcw had been infected in montreal, representing % of covid- cases in the city. no official figures on nosocomial transmission have been published by provincial authorities, with scarce data worldwide. early records from china reported that only . % of covid- patients were hcw, while in italy they represented % of total cases and - % of hospitalized covid- patients in the uk. inpatients who acquire covid- during hospitalization are already ill and may be more likely to require icu. our observations, in conjunction with the strong representation of hcw among covid- cases reported by public health authorities, may suggest that nosocomial transmission acted as a major amplifier in our region despite strict adherence to national guidelines for infection prevention. documented in-hospital clusters of infection did initially occur in our institution, originating from nonisolated asymptomatic patients in whom covid- was not suspected. in response, we modified our infection control policies to consider all inpatients as suspected covid- cases, and these new measures sharply reduced nosocomial transmission. with deaths per , inhabitants, the covid- -related mortality in the montreal metropolitan area is among the highest reported. nevertheless, nursing ratios were preserved throughout the crisis and no triage was needed. a centralized dispatch centre helped distribute cases more evenly between designated hospitals. importantly, the vast majority of individuals who died were never transferred to hospital wards or icus, as % of deaths in the province occurred in nursing homes. nursing-home physicians made substantial efforts to discuss goc at the crisis onset. this spared hospital resources as no nursing-home patient was admitted to our icu. avoidance of imv in group c patients may have prevented lengthy icu stays. a shared decision-making model with prompt recognition of patients with poor prognosis by clinicians and realistic patient and family expectations may have considerably preserved resources. resources could then be allocated fully to those who would benefit the most, perhaps contributing to the relatively low mortality seen in patients with a full-code status. nevertheless, caution is warranted in the interpretation of the association between goc and outcomes as there is a potential self-fulfilling prophecy. the hospital mortality rate observed in our cohort was similar to that reported in a recent meta-analysis of international cohorts of critically ill patients ( %), but higher than in a recent cohort from vancouver ( %). one of the main limitations of these comparisons is that baseline patient characteristics and extrinsic factors may strongly influence the observed mortality rates. while group b patients are cared for in the icu in most settings, some group a and c patients could be treated in highdependency units outside of the icu in some hospitals. in our institution, resources from our high-dependency units were merged with those of our icu to adapt more easily to sudden increases in demand for negative-pressure rooms. respiratory rate (breathsÁmin - ) [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] plateau pressure (cmh o)* [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] peep (cmh o) [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] driving pressure (cmh o)* [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] pressure support (cmh o) [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] hospital characteristics and intensity of icu-bed demand greatly influence the relative composition of patients in a given icu, with significant impact on overall mortality. restricting comparisons between cohorts to patients that underwent imv (group b) may circumvent this limitation. interestingly, the mortality observed in imv patients ( %) was similar to that described in cohorts from boston ( %), new york ( %), and vancouver ( %), and lower than that in lombardy ( %), germany ( %), and china ( %). , - differential follow-up may explain some of the differences. the mortality may be underestimated in cohorts with a significant number of patients still in the icu at the time of reporting, which was not the case in our study. as the indications and timing of initiation of imv may vary significantly, we could also compare different patients. nevertheless, baseline physiologic indices of severity seem to suggest otherwise. pao :f i o ratios were similar across cohorts: in boston, in lombardy, in vancouver, and in our cohort. [ ] [ ] [ ] our cohort had a higher c rs ( ml/cmh o) than reported in boston ( ml/cmh o) and vancouver ( ml/ cmh o). , nevertheless, c rs was not associated with survival in a recent unadjusted retrospective analysis of a cohort of covid- patients. moreover, we found a higher v d :v t ( % vs %) and ventilatory ratio ( . vs . ) than in boston, indicators that have previously been shown to predict worst outcomes in patients with acute respiratory distress syndrome. , we suspect that the high v d :v t and ventilatory ratio may be caused by alveolar capillary microthrombi, as seen in autopsy specimens. the high rate of vte we report ( %), despite a high rate of therapeutic anticoagulation ( % to %), supports a prothrombotic state. moreover, signs of widespread capillary angiopathy were recently shown on computed tomography (ct) pulmonary angiography and dual-energy ct in patients with severe covid- . the increased dead space, in conjunction with the hyperinflammatory profile with repeated febrile episodes, resulted in the persistent need for high minute ventilation in a significant proportion of imv patients. this manifested as relentless air hunger whenever neuromuscular blockers and sedation were weaned, as illustrated by the relatively high p . despite high opiate doses in patients on imv for more than a week. when patients were re-sedated, potentially injurious highintensity imv (mechanical power [ jÁmin - ) had to be applied to maintain acid-base balance, even with bicarbonate infusions. the high ventilatory requirement potentially resulted in a vicious cycle of ventilator or selfinflicted lung injury promoting further lung damage, which in turn increased ventilatory intensity. this is nicely illustrated by the slowly increasing plateau and driving pressures and steep increases in mechanical power with decreasing c rs over time. our group was conservative with ecmo use because of the relatively good response of hypoxemia to prone positioning and inhaled nitric oxide. one wonders, however, if ecmo could have broken this vicious cycle if instituted early in selected patients with high ventilatory intensity, even with easily managed hypoxemia. our study has limitations. the single-centre design limited the sample size and prohibited inferential statistics. all cases of morbidity and mortality may not have been captured as only in-hospital outcomes were assessed. strengths of our study include it being the first subgroup analysis of patients according to their goc, shedding light on the excellent prognosis of patients with full-code status. moreover, no patients were still in the icu upon data extraction, compared with % overall in previous cohorts presenting outcomes of critically ill patients. this draws a much more accurate picture of clinical outcomes. we found that characteristics and outcomes of critically ill patients with covid- in montreal were similar to those reported in the existing literature. some findings did stand out. a significant proportion of icu patients likely acquired the virus in healthcare facilities, highlighting the importance of appropriate infection control policies. noninvasive positive-pressure ventilation had a high failure rate ( %) when used in critically ill patients with limitations of care excluding imv. finally, we found a significantly increased physiologic dead space in patients on imv, supporting the hypothesis that pulmonary vascular injury may be at the heart of covid- -induced lung damage. hco = bicarbonate pbw = predicted body weight; peep = positive end expiratory pressure; paco = arterial partial pressure of carbon dioxide; pao :f i o = partial pressure of oxygen:fraction of inspired oxygen v t = tidal volume; v d :v t = dead space fraction. *only reported for a novel coronavirus from patients with pneumonia in china données covid- au québec données détaillées covid- -ensembble des régions du québec test results table view. covid- tracker characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention the trinity of covid- : immunity, inflammation and intervention development and validation of a clinical risk score to predict the occurrence of critical illness in hospitalized patients with covid- mechanical ventilation in covid- : interpreting the current epidemiology augmentation of hospital critical care capacity after bioterrorist attacks or epidemics: recommendations of the working group on emergency mass critical care surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) an official american thoracic society/european society of intensive care medicine/ society of critical care medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome use of the sofa score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. working group on ''sepsis-related problems'' of the european society of intensive care medicine estimating deadspace fraction for secondary analyses of acute respiratory distress syndrome clinical trials ventilator-related causes of lung injury: the mechanical power physiologic analysis and clinical performance of the ventilatory ratio in acute respiratory distress syndrome derivation and validation of spo /fio ratio to impute for pao /fio ratio in the respiratory component of the sequential organ failure assessment score presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area covid- integrated surveillance: key national data covid- : doctors sound alarm over hospital transmissions challenges in end-of-life care in the icu mortality rates of patients with covid- in the intensive care unit: a systematic review of the emerging literature baseline characteristics and outcomes of patients with covid- admitted to intensive care units in vancouver, canada: a case series respiratory pathophysiology of mechanically ventilated patients with covid- : a cohort study baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region. italy case characteristics, resource use, and outcomes of patients with covid- admitted to german hospitals: an observational study clinical course and outcomes of intensive care patients with covid- icu and ventilator mortality among critically ill adults with coronavirus disease pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid pulmonary angiopathy in severe covid- : physiologic, imaging and hematologic observations time-varying intensity of mechanical ventilation and mortality in patients with acute respiratory failure: a registry-based, prospective cohort study publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations author contributions yiorgos alexandros cavayas, alexandre noe¨l, ve´ronique brunette, david williamson, karim serri, francis bernard, and martin albert contributed to all aspects of this manuscript, including study conception and design; acquisition, analysis, and interpretation of data; and drafting the article. anne julie frenette, christine arsenault, patrick bellemare, colin lagrenade-verdant, soazig le guillan, e´milie levesque, yoan lamarche, marc giasson, philippe rico, yanick beaulieu, and pierre marsolais contributed to interpretation of data and drafting the article.acknowledgements we would like to thank icu nurses, respiratory therapists, orderlies, and all the other support staff who are the real heroes behind every life saved. moreover, we would like to recognize all the difficult work accomplished by our research coordinator, virginie williams, without whom no research would have been accomplished during these difficult times.disclosures none. editorial responsibility this submission was handled by dr. sangeeta mehta, associate editor, canadian journal of anesthesia. key: cord- -rycbeax authors: cao, jianlei; hu, xiaoyong; cheng, wenlin; yu, lei; tu, wen-jun; liu, qiang title: clinical features and short-term outcomes of patients with corona virus disease in intensive care unit date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: rycbeax nan isolated. seventeen patients died (discharge mortality, . %; % confidence interval [ci], . - . %), and eighteen patients were admitted to the icu with a rate of . % ( % ci, . - . %). the reasons for admission included need for mechanical ventilation (n = ), breathing rate increases/oxygen saturation < %/no-compliance with noninvasive ventilator (n = ), and combined shock and/or organ failure (n = ). the timeline of sars-cov- onset in icu patients is shown in fig. as shown in the supplementary table , the treatment in icu included the administration of a antiviral therapy ( . %), the use of antibiotics ( . %), glucocorticoid therapy ( . %), oxygen inhalation ( . %), noninvasive ventilation ( . %), invasive mechanical ventilation ( . %), extracorporeal membrane oxygenation ( . %) and crrt ( . %). furthermore, there were no significant difference in drugs treatment, oxygen inhalation and noninvasive ventilation between icu group and non-icu group (p > . all). icu patients received more intensive treatment with invasive mechanical ventilation ( . % vs. . %), extracorporeal membrane oxygenation ( . % vs. %) and crrt ( . % vs. . %). they also more likely (see figure on previous page.) fig. the timeline of sars-cov- onset in icu patients. a timeline of sars-cov- onset in icu survivors (n = ) . b timeline of sars-cov- onset in icu non-survivors (n = ). the results were presented as number (%). the onset of symptom was defined as day . the points represent the median value. icu, intensive care unit; sars-cov- , severe acute respiratory syndrome coronavirus ; mv, mechanical ventilation; nv, noninvasive ventilation; imv, invasive mechanical ventilation; emco, extracorporeal membrane oxygenation; oi, oxygen inhalation; aci, acute cardiac injury; aki, acute kidney injury; ali, acute liver injury . icu patients had a higher mortality rate than non-icu patients ( . % vs. . %), but this difference was not significant (p = . ). our results suggest that icu patients suffer at admission from more comorbidities and develop many complications due to hospitalization. during hospitalization they receive more aggressive treatment, and can result in a similar mortality when compared to non-icu patients. we found that . % of patients required admission to the icu and . % died. a previous study including patients with covid- showed that % of patients required admission to the icu and . % died [ ] . another study reported that % of patients with covid- required admission to the icu and . % died [ ] . it should be noted that most patients in those two studies were still hospitalized at the time of manuscript submission [ , ] . our hospital is one of the major tertiary teaching hospitals and is responsible for the treatment of critically ill patients with covid- . thus, our cohort might represent the more severe covid- patients and the rates of death and icu admission may be overestimated. a recent large-sample and multicenter study showed that only % of the included covid- patients were admitted to icu and . % succumbed [ ] . clinical features of patients infected with novel coronavirus in wuhan a novel coronavirus from patients with pneumonia in china clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical characteristics of novel coronavirus infection in china we thank all patients included in this study. we are really grateful to all the health workers around the world. their expertise & humanity are fundamental to stop sars-cov- from spreading further. . jc and xh contributed equally as the co-author. wjt and ql contributed equally as senior authors. jc and wjt had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. jc, xh, wc, ly, wjt, and ql were involved in concept and design. jc, xh, wc, ly, wjt, and ql contributed to acquisition, analysis, or interpretation of data. jc, xh, wjt, and ql were involved in drafting of the manuscript. jc and ly were involved in critical revision of the manuscript for important intellectual content. jc and wjt contributed to statistical analysis. jc, xh, wc, wjt, and ql were involved in administrative, technical, or material support. jc, xh, and wc contributed to supervision. wjt and ql obtained funding. data available can be obtained from the corresponding author. none reported. the study funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. not applicable. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.accepted: february key: cord- - yzybukk authors: li, xinye; pan, xiandu; li, yanda; an, na; xing, yanfen; yang, fan; tian, li; sun, jiahao; gao, yonghong; shang, hongcai; xing, yanwei title: cardiac injury associated with severe disease or icu admission and death in hospitalized patients with covid- : a meta-analysis and systematic review date: - - journal: crit care doi: . /s - - -z sha: doc_id: cord_uid: yzybukk background: cardiac injury is now a common complication of coronavirus disease (covid- ), but it remains unclear whether cardiac injury-related biomarkers can be independent predictors of mortality and severe disease development or intensive care unit (icu) admission. methods: two investigators searched the pubmed, embase, cochrane library, medline, chinese national knowledge infrastructure (cnki), wanfang, medrxiv, and chinaxiv databases for articles published through march , . retrospective studies assessing the relationship between the prognosis of covid- patients and levels of troponin i (tni) and other cardiac injury biomarkers (creatine kinase [ck], ck myocardial band [ck-mb], lactate dehydrogenase [ldh], and interleukin- [il- ]) were included. the data were extracted independently by two investigators. results: the analysis included studies with total individuals. the proportions of severe disease, icu admission, or death among patients with non-elevated tni (or troponin t [tnt]), and those with elevated tni (or tnt) were . % and . %, . % and . %, and . % and. . %, respectively. patients with elevated tni levels had significantly higher risks of severe disease, icu admission, and death (rr . , % ci . to . , p < . ; rr . , % ci . to . , p < . ; rr . , % ci . to . , p < . ). patients with an elevated ck level were at significantly increased risk of severe disease or icu admission (rr . , % ci . to . , p < . ). patients with elevated ck-mb levels were at a higher risk of developing severe disease or requiring icu admission (rr . , % ci . to . , p = . ). patients with newly occurring arrhythmias were at higher risk of developing severe disease or requiring icu admission (rr . , % ci . to . , p < . ). an elevated il- level was associated with a higher risk of developing severe disease, requiring icu admission, or death. conclusions: covid- patients with elevated tni levels are at significantly higher risk of severe disease, icu admission, and death. elevated ck, ck-mb, ldh, and il- levels and emerging arrhythmia are associated with the development of severe disease and need for icu admission, and the mortality is significantly higher in patients with elevated ldh and il- levels. graphical abstract: [image: see text] conclusions: covid- patients with elevated tni levels are at significantly higher risk of severe disease, icu admission, and death. elevated ck, ck-mb, ldh, and il- levels and emerging arrhythmia are associated with the development of severe disease and need for icu admission, and the mortality is significantly higher in patients with elevated ldh and il- levels. keywords: cardiac injury, biomarkers, covid- , meta-analysis, mortality coronavirus disease (covid- ) has spread worldwide, becoming a public health and medical care challenge in many countries. as of april , , covid- had spread to countries, areas or territories, with , , confirmed cases and , confirmed deaths worldwide [ ] . covid- , the clinical manifestation of severe acute respiratory syndrome coronavirus- (sars-cov- ) infection, is characterized by respiratory tract symptoms. severe cases can involve acute respiratory distress syndrome (ards) and shock [ ] . covid- is considered mainly a respiratory tract disease, but cardiovascular complications can also occur, eventually leading to sudden deterioration [ , ] . a large-scale study including , patients reported that cardiovascular disease was the risk factors for fatality of covid- patients [ ] . intensive care unit (icu) occupancy is very fluid, and covid- patients still require better evidence-based cardiovascular treatment [ ] . inciardi et al. reported the case of a patient who recovered from the influenza-like syndrome but then developed symptoms of heart failure [ ] . a recent study recommended that cardiac biomarkers should be evaluated in all hospitalized patients with confirmed covid- [ ] . however, there has been less concern about cardiac complications in other published studies. data such as those from transthoracic echocardiography, cardiac magnetic resonance imaging (mri), coronary angiography, and other examinations of cardiovascular diseases, as well as the biomarkers of cardiac injury have been less often described or are even missing. recent case reports have suggested that acute cardiac injury can cause cardiac dysfunction, leading to cardiogenic shock and the proclivity for malignant arrhythmia [ ] . another study reported that covid- was associated with myocarditis and arrhythmia [ ] . studies have shown that cardiac injury is related to higher in-hospital mortality rate [ ] and is commonly observed in severe covid- cases [ ] . therefore, paying attention to the occurrence of cardiac complications in patients with covid- and performing risk stratification may greatly reduce patient mortality rates, especially of those with severe disease or requiring icu admission. to our knowledge, this is the first study to comprehensively evaluate the impact of cardiac injury and its related biomarkers on mortality and other prognosis in patients infected with sars-cov- . this meta-analysis was performed according to the preferred reporting items for systematic reviews and meta-analysis statement [ ] . two investigators (x.l. and y.x.) independently conducted a comprehensive search of the relevant literature published until march , , in the pubmed, embase, cochrane library, medline, chinese national knowledge infrastructure (cnki), wanfang, medrxiv, and chinaxiv databases. combinations of the relevant medical subject heading (mesh) terms, key words, and word variants of "novel coronavirus," "coronavirus disease ," "covid- ," " -ncov," "sars- -cov," "clinical or characteristic," and "relative risk or rr" were utilized to identify all potentially relevant studies. after the elimination of duplicates, the titles and abstracts of all retrieved studies were assessed by two independent reviewers (y.l. and n.a.) to eliminate irrelevant articles. any disagreements were settled by consensus or by a third reviewer. language restrictions were not applied during filtering, to maximize search sensitivity. the inclusion criteria were as follows: ( ) diagnosis of covid- according to the world health organization interim guidance [ ] and ( ) ( ) studies with overlapping or unusable data. the primary outcome was the incidence of death, severe disease, or icu admission in covid- patients with elevated tni levels versus nonelevated tni levels. the secondary outcomes were as follows: ( ) incidences of elevated tni, ck, ck-mb, ldh, or interleukin- (il- ) of the non-severe disease/non-icu versus severe disease/icu groups; ( ) incidences of elevated tni, ck, ck-mb, ldh, or il- of the survivors versus non-survivors groups; ( ) tni, ck, ck-mb, ldh, or il- levels of the non-severe disease/non-icu versus severe disease/icu groups; ( ) tni, ck, ck-mb, ldh, or il- levels of the survivors versus non-survivors groups; ( ) incidence of arrhythmia (defined as newly occurring of any type) of the non-severe disease/non-icu versus severe disease/icu groups. two investigators (x.l. and x.p.) independently extracted the relevant data from the eligible studies using predesigned forms. disagreements were resolved by consensus. if the mean and standard deviation (sd) of the laboratory findings were not directly given, we used the estimation formula based on the median, range, and sample size [ ] . definitions used for severity assessment, icu admission, and cardiac injury were also extracted. two researchers (x.p. and n.a.) independently assessed the quality of the included studies, using the newcastle-ottawa quality assessment scale [ ] . studies were defined as high quality if a score of or higher was attained [ ] . potential publication bias was evaluated using the visual inspection of funnel plots and formal testing with the egger's testing [ ] . effect estimates are presented as relative risk (rr) or standard mean differences (smd) with % confidence interval (ci). the i statistic was used to quantify the heterogeneity across studies. i > % suggested significant statistical heterogeneity [ ] . in this case, a random-effects model was used considering the intraand interstudy variation. otherwise, the pooled effect was calculated using a fixed-effects model. all analyses were performed using stata . (statacorp, college station, tx, usa). values of p < . were considered statistically significant. we identified studies using the predefined search terms. after the removal of duplicates and filtering of titles and abstracts to exclude irrelevant articles, records remained. the full text of the records was reviewed; of them, records were excluded for the following reasons: data not available (n = ), literature review or letter or case report (n = ), unrelated to relevant predictive factors (n = ), and meta-analysis (n = ). finally, studies were included in this metaanalysis, of which one was not written in english. the flow diagram of this study selection is shown in fig. . the primary characteristics of the included studies are listed in table , with individuals incorporated. the sample size of studies was greater than . the definition of cardiac injury was extracted ( table ). the clinical characteristics of all included patients with covid- are shown in additional file : table s . overall, studies reported cardiac injury biomarkers, and reported arrhythmias. all the results calculated using stata are shown in table . fig. c ). twelve studies including individuals reported the ck levels or the number of patients with above-normal ck levels. the incidence of elevated ck in the severe disease/icu group was significantly higher than that in the nonsevere disease/non-icu group ( . % and . %, respectively; rr . , % ci . to . , p < . ; i = . %, fig. a) . the mean ck level was significantly higher in severe disease/icu group than in the nonsevere disease/non-icu group (smd . , % ci . to . , p = . ; i = . %, fig. b ). the proportion of patients with an elevated ck-mb level in the non-severe disease/non-icu and severe disease/icu groups was . % and . %, respectively. patients in the severe disease/icu admission group were at higher risk of developing an elevated ck-mb level than those in the nonsevere disease/non-icu group (rr . , % ci . to . , p = . ; i = . %, fig. c ). of the patients from studies, . % of those in the non-severe disease/non-icu group versus . % of the severe disease/ icu group had elevated ldh levels. covid- patients with elevated ldh levels were at significantly increased risk of developing severe disease or requiring icu admission (rr . , % ci . to . , p < . ; i = . %, fig. a ). ldh levels were significantly higher in the severe disease/icu admission group than in the non-severe disease/non-icu group (smd . , % ci . to . , p < . ; i = . %, fig. b ) and in nonsurvivors than in survivors (smd . , % ci . to . , p = . ; i = . %, fig. c ). arrhythmia and il- the incidence of arrhythmia was . % in the non-severe disease/non-icu group versus . % in the severe disease/icu group. patients with newly occurring arrhythmias were at a higher risk of developing severe disease or requiring icu admission (rr . , % ci . to . , p < . ; i = . %, fig. a ). il- levels were significantly higher in the severe disease/icu group than in the non-severe disease/non-icu group, as well as in non-survivors than in survivors (smd . , % ci . to . , p < . ; i = . %, fig. b ; smd . , % ci . to . , p < . ; i = . %, fig. c , respectively). this systematic review and meta-analysis of highquality retrospective studies systematically evaluated the risk of severe disease, icu admission, or death associated with covid- -related cardiac injury performance. our findings are as follows: ( ) covid- patients with elevated tni levels are at significantly higher risk of developing severe disease, requiring icu admission, or death; ( ) elevated ck, ck-mb, ldh, and il- levels and emerging arrhythmia are associated with the development of severe disease or requirement for icu admission; and ( ) mortality rates are significantly higher among patients with elevated ldh and il- levels. cardiac injury was defined as a serum cardiac biomarker level (e.g., troponin i) above the th percentile upper reference limit or new abnormalities seen on electrocardiography (ecg) and echocardiography [ ] . ck, ck-mb, and ldh are also indicators associated with cardiac injury [ , ]. an elevated cardiac tni level has high specificity for cardiac injury and is a preferred biomarker of cardiac injury. overall, in studies including patients, the rates of elevated tni or tnt in the nonsevere disease/non-icu admission group and severe disease/icu admission group were . % and . %, respectively; in the total population, elevated tni or tnt bnp b-type natriuretic peptide, ck creatinine kinase, ck-mb creatinine kinase-myocardial band, icu intensive care unit, ldh lactate dehydrogenase, il- interleukin- , n number, na not available, nt-probnp n-terminal pro-b-type natriuretic peptide, rr risk ratios, smd standard mean occurred at a rate of . %. our analysis suggests that covid- patients with elevated tni levels are at higher risk of developing severe disease, requiring icu admission, and death. two studies from wuhan (one with cases, another with cases) reported higher mortality among patients with cardiac injury than among those without ( . % vs. . %; p < . ; . % vs. . %, p < . , respectively) [ , ] . patients with cardiac injury had higher serum concentrations of nt-probnp than those without cardiac injury [ , ] . patients with cardiac injury more commonly developed ards, were more likely to have ventricular tachycardia (vt) or ventricular fibrillation (vf), and had higher mortality rates than those without vt or vf [ , ] . tni has great prognostic significance for patients with covid- as well as those with other influenza virus infections. in a study of inpatients with sars, acute myocardial infarction was the cause of of deaths [ ] . elevated tni levels are also common in infections caused by other influenza virus subtypes [ ] [ ] [ ] [ ] [ ] . tni may play an important role in predicting the acute or long-term risk of influenza virus infection. other biomarkers closely related to cardiac injury, such as ck, ck-mb, and ldh, were also selected in the meta-analysis. our analysis showed that those with elevated ck, ck-mb, and ldh were at a higher risk of developing severe disease or requiring icu admission. the ldh level had a predictive value for death. previous studies suggested that ck at icu admission serves can be used as a biomarker of the severity of pandemic influenza a (ph n ) infection [ ] . elevated tni and ck-mb levels indicate cardiac injury such as viral myocarditis or myocardial infarction as well as multiple organ injury [ ] . initial reports showed that the possible pattern of myocardial injury is the early presentation of primary cardiovascular symptoms, as well as changes on echocardiography and ecg [ , , [ ] [ ] [ ] . stress cardiomyopathy, supply demand mismatch (type ii myocardial infarction), and myocarditis, sometimes similar to st-segment elevation myocardial infarction, are all possible mechanisms [ , , ] . in a study describing a single case without a history of cardiovascular disease, the patient had myocardial injury, and diffuse edema was seen on cardiac mri [ ] . twelve lead ecg showed minimal diffuse st-segment elevation and an st-segment depression with t-wave inversion of lead v and avr. even in the absence of respiratory tract or infection symptoms, sars-cov- infection may cause cardiac involvement. however, it is a pity that an endomyocardial biopsy was not performed; thus, there was no histological evidence [ ] . cardiac injury is an important prognostic factor for covid- . it is rational to presume that the virus affects the myocardium, and once patients develop severe pneumonia, cardiac injury or dysfunction is more likely to occur, leading to deterioration. in a study of critically ill patients, including who had sars-cov- infection in the usa, the incidence of cardiomyopathy was high (n = [ %]) [ ] . in a patient without fever and respiratory symptoms, the initial ecg showed diffuse st elevations and an admission tni level of . ng/ml, but angiography demonstrated non-obstructive coronary artery disease. after fig. forest plots comparing of the proportion of patients with elevated troponin i or troponin t levels in the severe disease/icu group and in the non-severe disease/non-icu group (a), the troponin i levels in the severe disease/icu group and in the non-severe disease/non-icu group (b), and the proportion of patients with elevated troponin i or troponin t levels in the survivors and non-survivors groups (c). icu, intensive care unit; rr, risk ratios; smd, standard mean treatment, this patient improved in the short term, but the long-term effects of myocardial injury remain to be determined [ ] . the etiology of cardiac dysfunction may be multifactorial and related to infective myocarditis and/or ischemia. pathological findings suggested a few interstitial fig. forest plots comparing of the proportion of patients with elevated creatinine kinase levels in the severe disease/icu group and in the non-severe disease/non-icu group (a), the creatinine kinase levels in the severe disease/icu group and in the non-severe disease/non-icu group (b), and the proportion of patients with elevated creatinine kinase-myocardial band levels in the severe disease/icu group and in the non-severe disease/non-icu group (c). icu, intensive care unit; rr, risk ratios; smd, standard mean mononuclear inflammatory infiltrates in the myocardial interstitial [ ] . viral invasion may cause direct cardiac injury, and covid- -induced cytokine storm may also have toxic effects on the myocardium [ ] . cytokine storm may play a role in the development of ards and fulminant myocarditis. in our analysis, studies reported the laboratory findings of il- levels in patients. il- levels were significantly higher in the severe disease/ fig. forest plots comparing of the proportion of patients with elevated lactate dehydrogenase levels in the severe disease/icu group and in the non-severe disease/non-icu group (a), the lactate dehydrogenase levels in the severe disease/icu group and in the non-severe disease/non-icu group (b), and the lactate dehydrogenase levels in the survivors and non-survivor groups (c). icu, intensive care unit; rr, risk ratios; smd, standard mean fig. forest plots comparing of the risk of developing to severe disease or requiring icu admission among patients with or without newly occurring arrhythmias (a), the interleukin- levels in the severe disease/icu group (b), and in the non-severe disease/non-icu group and the interleukin- levels in the survivors and non-survivors groups (c). icu, intensive care unit; rr, risk ratios; smd, standard mean icu groups than non-severe disease/non-icu groups, as well as in non-survivors than in survivors. cardiac involvement reportedly occurred a few days after the influenza syndrome, suggesting the mechanisms of a potential myocyte dissemination of the virus activating the immune system, eventually leading to the onset of heart failure [ ] . a study reported that, compared to survivors, non-survivors had increased concentrations of creactive protein, decreased lymphocyte counts, and significantly reduced numbers of cd + cd + t cells, resulting in an immune response [ ] . anti-il- , as a drug targeting cytokine pathway and based on its mechanism of action, has potential benefits in covid- related ards and pneumonia [ ] . our analysis also found that the patients with emerging arrhythmia are at a higher risk of developing severe disease or requiring icu admission. in a study of patients with covid- , atrial fibrillation occurred in of severe and critical patients with tachycardia, with a peak heart rate of bpm [ ] . newly occurring arrhythmias are often closely related to cardiac injury. the incidence of ventricular arrhythmias (vt/vf) among patients with covid- was . %, primarily affecting those with elevated cardiac troponin levels [ ] . one study reported that of acute myocardial injury patients had more than two kinds of ecg abnormalities, including st-t/q curve abnormality, atrioventricular block, and arrhythmia [ ] . severe pneumonia increases the resistance of the pulmonary circulation, increasing the pressure of the right atrium, and leading to atrial tachyarrhythmia. antiviral drugs such as hydroxychloroquine may also prolong the qt interval. alternatively, the virus directly damages the myocardium and the cardiac conduction system, causing multiple ventricular premature and atrioventricular block. more attention is needed on arrhythmia among severe disease/icu admission covid- patients. however, in the studies reviewed here, ecg or echocardiography was rarely performed and the occurrence of arrhythmia was rarely reported. this meta-analysis included the largest sample size and is the first to analyze the correlation of cardiac injury biomarkers and arrhythmia with mortality and other prognosis. our systematic review and meta-analysis indicate that patients with elevated tni (tnt) levels are at significantly higher risk of developing severe disease, requiring icu admission, or death. our analysis also reveals that patients with elevated ck, ck-mb, and ldh levels and emerging arrhythmia were at a higher risk of developing severe disease, requiring icu admission. ldh levels also have predictive value for death. therefore, we strongly recommend the close monitoring of cardiac injury-related biomarkers in covid- patients, especially during the acute disease phase. the current clinical attention given to cardiac injury may be insufficient, and the strong infection of the virus makes cardiovascular examinations such as mri, echocardiography, and coronary angiography difficult to perform [ ] . the evaluation of cardiac injury biomarkers combined with cardiac examinations may help better assessments of the condition. there are few reports on cardiac injury in covid- patients, and a large amount of evidence is still needed to make the necessary risk predictions and stratifications. the present results provide some evidence for covid- treatment guidelines. in the future, it well be necessary to strengthen the monitoring of cardiac injury biomarkers, combined with echocardiography [ ] , ecg, mri, and other cardiac examinations, in patients with severe sars-cov- infection. when circulation support is needed in severe covid- cases, the use of an intra-aortic balloon pump or extracorporeal membrane oxygenation may be considered [ ] . covid- ) pandemic. accessed clinical features of patients infected with novel coronavirus in wuhan cardiac involvement in a patient with coronavirus disease (covid- ) association of cardiac injury with mortality in hospitalized patients with covid- in wuhan clinical determinants for fatality of , patients with covid- covid- pandemic-some cardiovascular considerations from the trench a care pathway for the cardiovascular complications of covid- : insights from an institutional response the variety of cardiovascular presentations of covid- potential effects of coronaviruses on the cardiovascular system: a review the prisma extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspected: interim guidance estimating the mean and variance from the median, range, and the size of a sample critical evaluation of the newcastle-ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses publication and related bias in metaanalysis: power of statistical tests and prevalence in the literature prior gastroscopy and mortality in patients with gastric cancer: a matched retrospective cohort study clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study hypokalemia and clinical implications in patients with coronavirus disease (covid- ) influence factors of death risk among covid- patients in wuhan, china: a hospital-based case-cohort study clinical characteristics of coronavirus disease in china clinical and radiographic features of cardiac injury in patients with novel coronavirus pneumonia clinical features and progression of acute respiratory distress syndrome in coronavirus disease clinical characteristics of patients discharged from hospital with covid- in chongqing epidemiological and clinical features of -ncov acute respiratory disease cases in chongqing municipality, china: a retrospective, descriptive, multiple-center study clinical characteristics of patients with severe pneumonia caused by the novel coronavirus in wuhan, china heart injury signs are associated with higher and earlier mortality in coronavirus disease (covid- ) acute myocardial injury of patients with coronavirus disease clinical findings in critical ill patients infected with sars-cov- in guangdong province, china: a multi-center, retrospective, observational study clinical features and outcomes of novel coronavirus-infected patients with cardiac injury clinical characteristics and outcomes of cardiovascular disease patients infected by -ncov clinical features and outcomes of patients with covid- in wuhan, china the potential role of il- in monitoring severe case of coronavirus disease early antiviral treatment contributes to alleviate the severity and improve the prognosis of patients with novel coronavirus disease (covid- ) clinical characteristics of deceased patients with coronavirus disease : retrospective study cardiovascular implications of fatal outcomes of patients with coronavirus disease (covid- ) creatine kinase myocardial band -a biomarker to assess prognostically relevant periprocedural myocardial infarction lactic dehydrogenase isoenzyme determination in the diagnosis of acute myocardial infarction sanchis-gomar f. cardiac troponin i in patients with coronavirus disease (covid- ): evidence from a meta-analysis clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study echocardiographic manifestations of pandemic (h n ) influenza a virus infection pandemic h n -associated myocarditis in a previously healthy adult cardiac manifestations in patients with pandemic (h n ) virus infection needing intensive care influenza myocarditis and myositis: case presentation and review of the literature the prevalence and findings of subclinical influenza-associated cardiac abnormalities among japanese patients elevation of creatine kinase is associated with worse outcomes in ph n influenza a infection cardiac troponin is the most effective translational safety biomarker for myocardial injury in cardiotoxicity coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin acute myocarditis presenting as a reverse tako-tsubo syndrome in a patient with sars-cov- respiratory infection first case of covid- complicated with fulminant myocarditis: a case report and insights characteristics and outcomes of critically ill patients with covid- in washington state pathological findings of covid- associated with acute respiratory distress syndrome coronavirus disease (covid- ) and cardiovascular disease predictors of mortality for patients with covid- pneumonia caused by sars-cov- : a prospective cohort study exploring pharmacological approaches for managing cytokine storm associated with pneumonia and acute respiratory distress syndrome in covid- patients catheterization laboratory considerations during the coronavirus (covid- ) pandemic: from acc's interventional council and scai using echocardiography to guide the treatment of novel coronavirus pneumonia publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. received: april accepted: july supplementary information accompanies this paper at https://doi.org/ . /s - - -z.additional file : table s . clinical characteristics of patients with covid- . all the data supporting the conclusions of this article are included within the article. this article is meta-analysis and does not require ethics committee approval or a consent statement. all authors have agreed to the publication of this manuscript. the authors declare that they have no competing interests. key: cord- -bt qsbyf authors: zhou, jian; sun, jingjing; cao, ziqin; wang, wanchun; huang, kang; zheng, fang; xie, yuanlin; jiang, dixuan; zhou, zhiguo title: epidemiological and clinical features of covid- patients in changsha city, hunan, china date: - - journal: medicine (baltimore) doi: . /md. sha: doc_id: cord_uid: bt qsbyf in december , a cluster of coronavirus disease (covid- ) occurred in wuhan, hubei province, china. the present study was conducted to report the clinical characteristics of covid- patients in changsha, china, a city outside of wuhan. all of the patients with confirmed covid- were admitted to the first hospital of changsha city, the designated hospital for covid- assigned by the changsha city government. the clinical and epidemiological characteristics, data of laboratory, radiological picture, treatment, and outcomes records of covid- patients were collected using electronic medical records. this study population consisted of hospitalized patients with laboratory-confirmed covid- in changsha by april , . the median age of the patients was years (iqr – ). about half ( . %) of the patients were male, and most of the infected patients were staff ( [ . %]). concerning the epidemiologic history, the number of patients linked to wuhan was ( . %). the most common symptoms were fever ( [ . %]), dry cough ( [ . %]), fatigue ( [ . %]), and pharyngalgia ( [ . %]). one hundred and forty-four ( . %) enrolled patients showed bilateral pneumonia. fifty-four ( . %) patients showed unilateral involvement, and three ( . %) patients showed no abnormal signs or symptoms. the laboratory findings differed significantly between the intensive care unit (icu) and non-icu groups. compared with non-icu patients, icu patients had depressed white blood cell (wbc), neutrocytes, lymphocytes, and prolonged prothrombin time (pt). moreover, higher plasma levels of erythrocyte sedimentation rate (esr), c-reactive protein (crp), procalcitonin (pct), alanine aminotransferase (ala), aspartate aminotransferase (ast), creatine kinase (ck), creatine kinase-mb (ck-mb), creatinine (crea), and lactate dehydrogenase (ldh) were detected in the icu group. in this single-center study of covid- patients in changsha, china, . % of patients were admitted to icu. based on our findings, we propose that the risk of cellular immune deficiency, hepatic injury, and kidney injury should be monitored. previous reports focused on the clinical features of patients from wuhan, china. with the global epidemic of covid- , we should pay more attention to the clinical and epidemiological characteristics of patients outside of wuhan. in december , a series of covid- occurred in wuhan, hubei province, china, [ ] [ ] [ ] [ ] which was caused by sars-cov- infection. most of the covid- patients were concentrated in wuhan, and their exposure history related them to the huanan seafood wholesale market at the beginning. [ ] however, the infection rapidly spread from wuhan to all over the country because of the population movement during the spring festival. [ , ] acute respiratory infection symptoms, including high temperature, dry cough, fatigue, and breathing difficulty, are the main early symptoms of the disease. [ ] along with disease progression, some patients rapidly develop acute respiratory distress syndrome (ards), acute respiratory failure, and other several complications, especially for older patients or those with immunodeficiency. in the past month, several studies [ ] [ ] [ ] [ ] [ ] reported the epidemiological, demographic, clinical, laboratory, and radiological characteristics of covid- patients in wuhan city. in the present study, we performed a comprehensive analysis to describe the clinical features, epidemiologic characteristics, treatment, and outcomes of covid- patients in changsha, china, a city outside of wuhan, and the differences of clinical features between icu and non-icu patients were analyzed. our study findings provide information about covid- patients outside of wuhan. related data were collected from the first hospital of changsha city, the designated hospital for covid- assigned by the changsha city government. all of the patients enrolled in this report were admitted from january , to april , . during the entire outbreak, a total of patients received treatment in the first hospital of changsha city. forty-one patients were excluded because of plenty of data missing and covid- patients were involved in the present study. criteria for patients admitted into icu: according to previous study, [ ] the basic reproductive number (r ) was . ( % ci = . - . ) and that . % ( % ci = . - . %) of total cases were not reported, so many patients might not be reported in changsha, china. the first hospital of changsha city is located in changsha, hunan province, a neighboring province of hubei province. the ethics commissions approved this study of the first hospital of changsha city, and written consents were obtained from the enrolled patients. all of the patients involved in the present study were diagnosed according to world health organization interim guidance. [ ] the clinical outcomes, including discharge and death, were recorded up to april , . the research team from the second xiangya hospital of central south university and the first hospital of changsha city conducted a comprehensive analysis of the medical information of covid- patients. in this report, we obtained the clinical and epidemiological characteristics, data of laboratory, radiological picture, treatment, and outcomes records using electronic medical records. the medical information, including demographic data (age, gender, and occupation), exposure history, medical history, comorbidities, signs, symptoms, chest computed tomographic (ct) scans, laboratory results, and treatment, such as antibacterial therapy, glucocorticoid therapy, and antiviral therapy, was collected. the durations from exposure to wuhan to the onset of disease and the course of disease were recorded. the laboratory test assays of -ncov were conducted according to the who recommendation. [ ] laboratory identification of -ncov was performed in three different institutions: the first hospital of changsha city, hunan center for disease control, and prevention (hunan cdc) and chinese cdc (ccdc). upper and lower respiratory tract specimens were collected for extracting sars-cov- rna. rna was obtained and further tested by rt-pcr through the same method previously described. [ ] other respiratory viruses (influenza a virus, influenza b virus, respiratory syncytial virus) and parainfluenza virus were also tested in this study. continuous variables were described as median and iqr. categorical variables were expressed using the number and percentages. mann-whitney u test was performed for continuous variables, and the x test or fisher's exact test was conducted for categorical variables. a two-sided a < . was considered to be statistically significant. additionally, normality test was also conducted to test whether the data conforms to the normal distribution. all of the statistical analyses were performed using statistical package for the social sciences (spss) version . software. the study funders/sponsors had no role in the design and conduction of the study, including the collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication. the datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request. this study population consisted of hospitalized patients aged (fig. ) . fifty-four ( . %) patients showed bilateral pneumonia, and three ( . %) patients showed no abnormal signs or symptoms. resting heart rate and mean arterial blood pressure did not differ between the two groups (p > . ). compared with patients who did not receive icu care, patients who received icu care had a higher respiratory rate (p = . ). forty-five ( %) patients, ( . %) patients, and ( . %) patients in the icu group received treatments of antibiotic, glucocorticoid, and immunoglobulin, respectively; the frequency of patients who received no icu care receiving these treatments was lower ( table ) . the laboratory findings differed significantly between the icu and non-icu groups. concerning the blood counts of patients on admission, the white blood cell count of patients ( . %) was < Â /l, and the lymphocyte count of patients ( . %) was < . Â ) and a higher level of d-dimer (median . [iqr . - . ]) on admission were found in the icu patients. levels of ala, ast, ck, and ldh were significantly increased in the icu group. these laboratory results were recorded on the first day after admission for all of the patients, and then on those who later received icu care or not (table ) . the number of covid- patients is increasing, and so is the death toll. [ , ] several studies [ ] [ ] [ ] [ ] [ ] reported the epidemiological and clinical characteristics of covid- patients, providing information for sars-cov- evolution, infectivity, transmissibility, and pathogenicity. in this study, we reported a total of patients with sars-cov- infection outside of wuhan, china. among them, ( . %) patients required icu care, and ( . %) were admitted to the isolation ward of the first hospital of changsha city. patients in the icu group were older, while no significant difference in sex ratio was found between the two groups, which suggests that age may be a risk factor for a poor outcome. the occupational composition of the icu group differed from the non-icu group, and the number of patients exposed to wuhan city in the icu group was significantly higher than that of the non-icu group, which indicates that the exposure history to wuhan city may affect the outcome of covid- patients. no significant differences in the duration and incubation were found between the icu group and the non-icu group. as of april , , ( %) of patients had been discharged. two ( %) patient of the icu group in this study died. more patients had a poor prognosis in icu group compared to non-icu group (p < . ) and this overall mortality was lower than that reported for wuhan ( . %). [ ] in terms of clinical features, patients with cardiovascular or respiratory diseases were more likely to require icu care. in addition, the maximum temperature of patients in the icu group was significantly higher than that in the non-icu group, and more patients in the icu group presented fatigue and anhelation. moreover, the respiratory rate of cases in the icu group was higher than those of the non-icu group, which may be attributed to inflammation of the lungs. patients in the icu group must breathe more frequently to provide the oxygen required compared to patients in the non-icu group. the most common laboratory abnormalities observed in the present report included depressed wbc, neutrocytes, lymphocytes, prolonged prothrombin time, and elevated esr, crp, pct, and ldh. previous studies indicated the role of neutrophil biology and related signaling in covid- . yu et al reported that elevated levels of neutrophil activation in covid- patients were related to higher risk of morbid thrombotic complications. [ ] liu et al indicated that neutrophil-to-lymphocyte ratio was an independent risk factor of the in-hospital patients. [ ] the rising trend in neutrophil-to-lymphocyte ratio may indicate a risk of death for participants with covid- . [ ] the interplay between stat and stat signaling pathways from normal and diseasespecific g-csfr may lead to abnormal neutrophil productions. [ ] compared with the non-icu group, numerous laboratory abnormalities were detected in the icu group. a previous study [ ] indicated that sars-cov- might mainly act on lymphocytes, including t lymphocytes. sars-cov- could induce a cytokine storm in the body, thereby generating a series of immune responses and causing changes in peripheral white blood cells and lymphocytes. additionally, several reports confirmed that the decrease of lymphocytes indicates that coronavirus consumed many immune cells and inhibited cellular immune function, which might lead to exacerbations of covid- patients. [ ] in this report, lower levels of neutrocytes and lymphocytes were detected in the icu group, which may be caused by the cellular immune deficiency of the icu group. in addition, higher levels of esr, crp, and pct were detected in the icu group, which indicated higher levels of inflammation in the icu group. a longer prothrombin time was found in the icu group, which might represent coagulation activation in the icu group. compared with non-icu patients, higher levels of ala, ast, ck, ck-mb crea, and ldh were detected in patients of the icu group, which was similar to previous reports. [ ] these abnormalities suggest that the sars-cov- infection may be associated with myocardial injury, hepatic injury, and kidney injury. it may also be that people with these organ dysfunctions are more likely to be infected by sars-cov- . according to the suggestion of the diagnosis and treatment of pneumonitis with -ncov infection (dtpi) published by the national health commission of the prc, all of the patients in this study were given lopinavir, and ritonavir tablets ( pills bid peros), which were used for hiv infection in the past, combined with interferon alfa- b injection ( million iu add into ml of sterile water, inhalation bid), and . % received antibacterial agents. during the severe acute respiratory syndrome (sars) period in , usage of high doses of glucocorticoids caused a series of sequelae in survivors such as osteonecrosis of the femoral head and glucose metabolism disorders. because of this lesson, we gave a small dose ( - mg/day) of glucocorticoid therapy in a short period ( days) and adjusted the dose and time of medication according to the dynamic changes of the patient's chest ct imaging to control the immune response in the lungs. the patients avoided the occurrence of cytokine storms, thereby reducing the risk of complications, such as acute ards, in patients. glucocorticoid therapy was given to . % of patients. there are several limitations to this study. first, covid- was diagnosed by rt-pcr using throat swab samples, while no in this single-center study of covid- patients in changsha, china, . % of patients were admitted to icu. we found that the risk of cellular immune deficiency, hepatic injury, and kidney injury was higher in icu group, which should be monitored. because sars-ncov- has pandemic potential, the continuing -ncov epidemic threat of novel coronaviruses to global health -the latest novel coronavirus outbreak in wuhan, china outbreak of pneumonia of unknown etiology in wuhan, china: the mystery and the miracle early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia report of novel coronavirusinfected pneumonia in china clinical features of patients infected with novel coronavirus in wuhan, china novel coronavirus ( -ncov) situation reports. situation report - wuhan coronavirus ( -ncov) global cases a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster clinical characteristics and intrauterine vertical transmission potential of covid- infection in nine pregnant women: a retrospective review of medical records epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china clinical and high-resolution ct features of the covid- infection: comparison of the initial and follow-up changes clinical and ct features in pediatric patients with covid- infection: different points from adults estimation of unreported novel coronavirus (sars-cov- ) infections from reported deaths: a susceptibleexposed-infectious-recovered-dead model available at: https:// www.who.int/publications-detail/clinical-managementof-severe-acute-re spiratory-infection-when-novelcoronavirus-(ncov)-infection-is-sus pected laboratory diagnostics for novel coronavirus a novel coronavirus from patients with pneumonia in china epidemiologic and clinical characteristics of novel coronavirus infections involving patients outside wuhan, china neutrophil extracellular traps and thrombosis in covid- neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with covid- dynamic changes of d-dimer and neutrophillymphocyte count ratio as prognostic biomarkers in covid granulocyte colony-stimulating factor receptor signaling in severe congenital neutropenia, chronic neutrophilic leukemia, and related malignancies t-cell immunity of sars-cov: implications for vaccine development against mers-cov medicine ( ) : www.md-journal the authors would like to thank all of the co-investigators and colleagues who made this study possible. the authors would like to thank changsha cdc, hunan cdc, and ccdc for their assistance with laboratory testing. we thank letpub (www. letpub.com) for its linguistic assistance during the preparation of this revised manuscript. conceptualization: jian zhou and zhiguo zhou. key: cord- - qh vgtc authors: pinto pereira, joão; hantson, philippe; gerard, ludovic; wittebole, xavier; laterre, pierre-françois; lambert, catherine; hermans, cédric title: management of covid- coagulopathy in a patient with severe haemophilia a date: - - journal: acta haematol doi: . / sha: doc_id: cord_uid: qh vgtc a -year-old man with a long history of severe haemophilia a treated prophylactically with efmoroctocog alpha ( , iu twice weekly) was diagnosed with covid- infection. he had multiple risk factors for covid- severity including obesity, diabetes mellitus and hypertension. he required prolonged intensive care unit (icu) stay due to the severity of respiratory failure until his death on day . during his icu stay, he received a continuous infusion of efmoroctocog alpha in order to maintain factor viii activity between and %, together with therapeutic doses of low-molecular-weight heparin targeting anti-xa activity above . iu/mol. he tolerated numerous invasive procedures without bleeding. at post-mortem examination, there was no evidence for thrombosis or haemorrhage in the different organs. during the recent covid- pandemic, the difficulties to maintain an accurate balance between thrombotic and haemorrhagic risks have been outlined. as illustrated by the following observation, this would be more particularly the case for patients with severe haemophilia requiring intensive care and invasive procedures. a -year-old man with severe haemophilia a regularly followed at our comprehensive haemophilia treatment centre was admitted to the emergency department in march with flu-like symptoms, cough, dyspnoea and fever. the patient had severe haemophilia with diffuse arthropathy that required bilateral knee replacements and ankle arthrodesis. he had a past history of hcv infection that was successfully eradicated and never developed an inhibitor. his haemophilia was treated prophylactically with an extended half-life factor viii concentrate (efmoroctocog alpha, , iu twice a week). genetic investigations had revealed an in frame deletion of codons in exon (. - _ del -p. gly gludel .). he was obese ( kg body weight, bmi kg/ m ) and had type diabetes mellitus and hypertension. he had no past history of venous or arterial thrombosis. the diagnosis of covid- infection was rapidly obtained by reverse transcription-polymerase chain reaction (rt-pcr) on the nasopharyngeal swab, and lung computed tomography revealed bilateral ground glass opacities. he first received oxygen therapy and hydroxychloroquine on the general ward but was transferred to the intensive care unit (icu) days later after the progression of respiratory distress. the apache-ii score on admission was . after failure of non-invasive ventilation, orotracheal intubation was required for mechanical ventilation. ventilation was performed using the volume control ventilation mode under deep se-pinto pereira/hantson/gerard/wittebole/ laterre/lambert/hermans acta haematol doi: . / dation (propofol, sufentanil, clonidine, ketamine) and neuromuscular blockade. inhaled nitric oxide therapy was also applied. the patient had received a last bolus of efmoroctocog alpha h before icu admission. coagulation tests on icu admission revealed: aptt s ( - ) and pt . s ( . - . ). in the icu, a continuous infusion of efmoroctocog alpha was started by a bolus infusion and maintained at a rate of iu/h in order to obtain a factor viii activity between and % [ ] . the patient received subcutaneous low-molecular-weight heparin (lmwh) (nadroparine) targeting anti-xa activity above . (initially , anti-xa iu once a day, then twice a day, and , anti-xa iu twice a day from day after the recurrence of numerous episodes of atrial fibrillation). during the icu stay, he did not experience any clinically patent haemorrhagic or thrombotic event and tolerated invasive procedures (insertion of central venous line, arterial lines, orotracheal intubation, insertion of nasogastric feeding tube and bladder catheter) and postural changes for ventilation in prone position. the level of d-dimers never exceeded , ng/ml (normal < ), with normal platelet count. anti-xa activity ranged from . to . u/ml, aptt from . to . s, and pt from . to . s. among inflammatory parameters, the peak level of crp was mg/l, and , µg/l for ferritin. the patient had also an augmented renal clearance (peak value ml/min). unfortunately, acute respiratory distress syndrome progressively worsened with refractory hypercapnia. intravenous methylprednisolone ( mg/ kg/day for days) was initiated without any result. the patient died on day from refractory septic shock caused by pseudomonas aeruginosa septicaemia as the primary cause of death. a post-mortem examination was obtained. the macroscopic examination of the lungs failed to reveal significant thrombi in the different arterial segments. there was no evidence of thrombosis or recent bleeding in the other organs. the ultrastructural examination of the lung was well consistent with diffuse alveolar damage, consisting of the presence of hyaline membranes and "acute fibrinous and organizing pneumonia-like" intra-alveolar fibrin deposition [ ] . there was no sign of fibrinoid vessel wall necrosis, vasculitis/capillaritis or haemorrhage. with a medical history of obesity, diabetes mellitus and hypertension, our patient was particularly illustrative of the population at risk for covid- infection, independently from his history of bleeding disorder [ ] . not surprisingly, haemophilic patients were also affected at variable degree of severity by the recent covid- pandemic. in most of them, the severity was comparable to that of the general population. few data are currently available regarding haemophilic patients requiring invasive procedures following icu admission for covid- severe infection, with a difficult balance between thromboprophylaxis and prevention of bleeding complications. among other complications, covid- infection has been strongly associated with coagulopathy with a high prothrombotic risk secondary to the intense inflammatory response to the viral infection. although its mechanism remains rather obscure, its occurrence seems to be associated with higher mortality rates [ ] . anticoagulation has been suggested to reduce the thrombotic events related to the covid- infection and higher anticoagulation targets have been proposed in critically ill patients [ , ] . the beneficial effect of heparin has been linked with its potential effects on inflammation, endothelial protection, thrombus formation, etc. [ ] . in some reports, the incidence of venous thromboembolic events in patients with a severe coronavirus disease can be as high as % and seems to be correlated with the d-dimer increase [ ] . of particular interest is the more specific finding in the lungs of some patients of widespread vascular thrombosis with micro-angiopathy and occlusion of alveolar capillaries [ , ] . on the other hand, haemorrhagic symptoms seem far less commonly associated with the covid- infection [ , ] . exceptionally, acquired haemophilia a has been reported to be triggered by covid- infection [ ] . additionally, there is a theoretical risk of bleeding tendency with some drugs used in specific protocols for covid- [ ] . as illustrated by the present case, permanent correction of factor viii deficiency by continuous infusion of a factor viii concentrate combined with intensified thromboprophylaxis with lmwh proved to be effective in preventing bleeding and thrombotic complications. such treatment required a close collaboration between the haemophilia-treating physicians and the icu team as well as regular monitoring of several haemostatic parameters (d-dimers, factor viii level and anti-xa) [ ] . more experience on the complex management of co-vid- coagulopathy in patients with haemophilia treated with non-replacement therapies such as emicizumab should be collected [ ] . our case illustrates that factor viii concentrates present several desirable features to correct the haemostatic defect in haemophilia a patients with severe covid- infection. these are the rapid onset of action, rapid reversibility, titration of effect by measuring the factor viii level, the safety of use and wellknown effects on blood coagulation. ongoing registries should provide more information on the optimal combined haemostatic and antithrombotic managements of the complex covid- coagulopathy in patients with severe haemophilia. finally, there are no definitive recommendations for the adaptation of lmwh in patients with augmented renal clearance [ ] . in-hospital management of persons with haemophilia and co-vid- : practical guidance diffuse alveolar damage (dad) from coronavirus disease infection is morphologically indistinguishable from other causes of dad. histopathology risk factors for sars-cov- among patients in the oxford royal college of general practitioners research and surveillance centre primary care network: a cross-sectional study abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy crics triggersep group (clinical research in intensive care and sepsis trial group for global evaluation and research in sepsis) the versatile heparin in cov-id- incidence of thrombotic complications in critically ill icu patients with covid- pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- autopsy findings and venous thromboembolism in patients with covid- letter to editor: severe brain haemorrhage and concomitant covid- infection: a neurovascular complication of covid- hemorrhagic problem among the patients with covid- : clinical summary of thai infected patients the first case of acquired hemophilia a associated with sars-cov- infection confronting cov-id- : issues in hemophilia and congenital bleeding disorders online ahead of print emicizumab: a review in haemophilia a. drugs impact of augmented renal clearance on enoxaparin therapy in critically ill patients the authors have no conflict of interest. no financial support. joão pinto pereira, ludovic gerard, xavier wittebole: conception of the manuscript; catherine lambert, cédric hermans: literature review; philippe hantson, pierre-françois laterre: supervision and approval of the final version. key: cord- -ym mf wz authors: li, jia; he, xue; yuanyuan; zhang, wei; li, xue; zhang, yuhua; li, shaoxiang; guan, chunyan; gao, zifen; dong, gehong title: meta-analysis investigating the relationship between clinical features, outcomes, and severity of severe acute respiratory syndrome coronavirus (sars-cov- ) pneumonia date: - - journal: am j infect control doi: . /j.ajic. . . sha: doc_id: cord_uid: ym mf wz objective: we aimed to investigate the relationship between clinical characteristics, outcomes and the severity of severe acute respiratory syndrome coronavirus (sars-cov- ) pneumonia. methods: we performed a systematic review and meta-analysis using pubmed, embase, and cochrane library databases to assess the clinical characteristics and outcomes of confirmed covid- cases and compared severe (icu) and non-severe (non-icu) groups. results: we included cohort studies including patients with covid- . compared with non-severe (non-icu) patients, severe (icu) disease was associated with a smoking history (p= . ) and comorbidities including chronic obstructive pulmonary disease (or= . , p< . ), diabetes (or= . , p< . ), hypertension (or= . , p< . ), coronary heart disease (or= . , p< . ), cerebrovascular diseases (or= . , p= . ), and malignancy (or= . , p= . ). we found significant differences between the two groups for fever, dyspnea, decreased lymphocyte and platelet counts, and increased leukocyte count, c-creative protein, procalcitonin, lactose dehydrogenase, aspartate aminotransferase, alanine aminotransferase, creatinine kinase, and creatinine levels (p< . ). significant differences were also observed for multiple treatments (p< . ). patients in the severe (icu) group were more likely to have complications and had a much higher mortality rate and lower discharge rate than those with non-severe (non-icu) disease (p< . ). conclusions: investigation of clinical characteristics and outcomes of severe cases of covid- will contribute to early prediction, accurate diagnosis, and treatment to improve the prognosis of patients with severe illness. a series of pneumonia cases of unknown cause appeared in wuhan, china in december, . scientists isolated the pathogen that caused the pneumonia, which was named -ncov, a novel type of beta-coronavirus . the world health organization later renamed the new virus severe acute respiratory syndrome coronavirus (sars-cov- ) and named the illness caused by the virus coronavirus disease . as of april , the total number of patients with covid- had risen sharply to , , patients globally, with , deaths and a mortality rate close to . % (data from the website of the who). people infected by sars-cov- have a very broad spectrum of illness, from being asymptomatic to critically ill (bai et al. ) . thus, it is crucial to detect patients who are more likely to develop severe illness at diagnosis, to decrease mortality in these patients. in this study, we aimed to determine the predictors of severe disease or admission to an intensive care unit (icu) in a meta-analysis by comparing patients with covid- in severe (icu) and non-severe (non-icu) groups. we searched the pubmed, embase, and cochrane library databases for studies on covid- published between december and april , . the search terms and key words used included "novel coronavirus" or " -ncov" or " novel coronavirus" or "ncip" or "novel coronavirus infected pneumonia" or "covid- " or "severe acute respiratory syndrome coronavirus " or "sars-cov " and "clinical". we also searched the medrxiv website, a free online archive and distribution service of unpublished preprints in the medical field (https://www.medrxiv.org), to identify the latest studies on the novel coronavirus. there was no language restriction. this meta-analysis followed the recommendations established by the preferred reporting items for systematic reviews and meta-analyses (prisma) statement (moher et al. ) . studies included in this meta-analysis were selected based on the following inclusion and exclusion criteria. the inclusion criteria were: ( ) cohort studies or case-control studies reporting the clinical characteristics of patients with sars-cov infection; ( ) one or more clinical features were analyzed, including epidemiology, clinical symptoms, laboratory findings, comorbidities, treatment, complications, and outcomes; ( ) patients were grouped according to the severity of disease, e.g., severe and non-severe groups or icu and non-icu groups. the exclusion criteria were: ( ) review articles, opinions, and letters, which did not present original data; ( ) studies without grouping according to the severity of illness; and ( ) studies grouping patients by age or survival status. all articles were managed using endnote x . software. we first screened article titles and abstracts to exclude those that clearly did not meet the inclusion criteria. we then read the full text to select the articles to finally include in this meta-analysis. two researchers (j. l and x. h) extracted the data from eligible studies independently, to minimize bias. if any disagreements arose, discussions were held with a third investigator (g. d) to reach consensus. we extracted and analyzed items from eligible studies including the country, year, date of publication, the number of reported cases, sex, age, clinical symptoms and signs, comorbidities, laboratory findings, complications, and outcomes of patients with sars-cov infection who had severe (icu) and non-severe (non-icu) disease. to evaluate quality, we used the newcastle-ottawa scale to assess cohort studies and case-control studies (stang ) . the highest quality rating was stars and the lowest was stars. assessment scores ≥ indicated high-quality studies. we used the number of events per group to calculate odds ratios (ors) and their % confidence intervals (cis) with stata version . (statacorp llc, college station, tx, usa). the pooled results were presented as forest plots. the pooled prevalence and % ci in severe (icu) cases was calculated using a single-arm meta-analysis. measures of heterogeneity, including the cochran's q, i , and chi-squared tests were estimated and reported (higgins et al. ) . ors were combined using the mantel-haenszel fixed-effects model to estimate and compare risk factors and their confidence intervals. when substantial heterogeneity was detected (i > %), the dersimonian-laird random-effects model was used (dersimonian and laird ). to further explore sources of heterogeneity and to examine whether the results differed by study characteristics, subgroup analyses were performed by geographic region (wuhan area and outside wuhan area) and by study size (≤ cases and > cases). p< . was considered to indicate a statistically significant test result for the pooled ors. a total of papers were retrieved using the search strategy, and articles were excluded because of duplication. after screening the article titles and abstracts, papers were selected for full-text assessment. of these articles, were excluded because of a lack of information on severe cases and five were excluded because study participants were grouped by age or survival status. study selection and flow are shown in figure . finally, we included a total of twelve studies, conducted between january st and april , and representing patients with confirmed sars-cov- infection; among these, had severe illness or were admitted to the icu (cao et al. , chu et al. , feng et al. , gao et al. , guan et al. , wan et al. . all studies were conducted in china and all articles were written in english. the characteristics of the included articles are shown in table . the pooled prevalence of severe or icu cases was . ( % ci: . - . ) ( figure ). the data on demographic characteristics (sex, smoking history, wuhan exposure history) and comorbidities (hypertension, diabetes, and so on) among patients with severe (icu) and non-severe (non-icu) covid- were extracted and pooled for meta-analysis. the results showed that there was no significant association between sex (or= . , % ci: . - . , i = . %, p= . ) or wuhan exposure history (or= . , % ci: . - . , i = . %, p= . ) and increased risk of severe disease ( figure a , b). however, our results showed that a smoking history was significantly associated with severe covid- (or= . , % ci: . - . , i = . %, p= . ) ( figure c ). compared with non-severe patients, those with severe illness or admission to the icu were more likely to have one or more comorbidities (or= . , % ci: . - . , p< . , i = . %), including chronic obstructive pulmonary disease (or= . , % ci: . - . , p< . , figure a - g) . no significant differences were observed between the two groups for chronic liver disease (p= . ) and chronic renal disease (p= . ) (supplementary figure h, i) . among all clinical symptoms, fever and dyspnea were found to be significantly associated with more severe covid- . the combined ors ci: . - . , p< . , i = . %), and creatinine (or= . , % ci: . - . , p= . , i = . %) were observed to be significantly associated with severe (icu) cases as compared with non-severe (figure a- c ). no significant difference was detected for the complication of acute cardiac injury in the two groups (p= . ) ( figure d ). by the end of the follow-up period, the outcomes of patients with covid- included hospitalization, discharge, and death. a small number of patients were lost to follow-up. there was a significant difference between the severe (icu) group and non-severe (non-icu) group in the number of discharges (or= . , % ci: . - . , p= . , i = . %) and deaths (or= . , % ci: . - . , p= . , i = . %) ( figure a, b) . patients with more severe illness have a much higher mortality rate and lower discharge rate than those with mild or moderate illness.there was no significant difference in the number of hospitalized patients (p= . ) ( figure c ). we conducted subgroup analyses of geographic region and study size to explore potential sources of heterogeneity (i > %). no clear sources of heterogeneity were identified from these subgroup analyses (table ) . to date, this is the first systematic review and meta-analysis to investigate the relationship between clinical characteristics, outcomes, and severity of sars-cov- pneumonia. we collected data from published articles including patients with confirmed sars-cov- infection and patients with severe disease or icu admission. the pooled prevalence of severe or icu cases was %. there was no association between sex or wuhan exposure history and severity of covid- . however, our results showed that smoking history might be a high-risk factor for severe illness, which was consistent with the conclusion of recently reported research . among clinical symptoms, fever and dyspnea were found to be significantly associated with severe illness or icu admission for covid- . however, in patients with fever, high fever (> ℃) was not a risk factor of severe illness. based on this study, fever that is not particularly high might be associated with severe covid- . thus, greater attention is needed for patients with fever or dyspnea. patients with any comorbidities had a higher rate of severe illness; these included chronic obstructive pulmonary disease (copd), diabetes, hypertension, coronary heart disease, cerebrovascular diseases, and malignancy. assessment of all potential comorbidities is challenging in any study, so the most common and well-studied comorbidities assessed in the original articles were chosen for evaluation. as for laboratory findings, increased leukocyte count, decreased lymphocyte and platelet counts, increased levels of c-creative protein, procalcitonin, ldh, ast, alt, ck, and creatinine were related to severe illness or icu admission with covid- . different from the results of previous studies , guan et al. , our study indicated that severe illness or icu admission for sars-cov- pneumonia had more to do with leukocytosis than leukopenia. we speculate that leukocytosis is a reflection of excessive inflammation, which is also reflected in the much higher c-reactive protein levels among patients with severe (icu) covid- .lymphopenia was more common in severe (icu) than in non-severe (non-icu) patients, probably owing to translocation of lymphocytes from peripheral blood to the lungs . our results regarding elevated levels of alt, ast, creatinine, ck, and ldh indicated that patients with severe disease or those in the icu had more obvious liver function, kidney function, and myocardial injury. continuous tracking of laboratory findings is crucial to identify those patients who may progress to severe status. currently, there are no specific treatments for covid- . at present, effective measures to control the disease are early diagnosis, isolation, and supportive treatment for infected patients. as we found in our study, patients with severe illness or those in the icu most commonly received antibiotics, antivirals, corticosteroid therapy and especially advanced life support treatments including ecmo, mechanical ventilation, and continuous renal replacement therapy. significant differences were also observed in the complications of ards, shock, and acute kidney injury between the groups with different degrees of disease severity. severely ill patients or those cared for in the icu had a higher mortality rate and lower discharge rate than non-severe patients or patients without icu admission. this study has several limitations that must be mentioned. first, the studies included in our research divided patients into severe and non-severe groups ( studies) or by admission to the icu or no icu admission ( studies). the grouping criteria were not strictly consistent; mild and moderate cases were included in non-severe groups. second, there were differences in the range of normal values for laboratory indicators between different clinical laboratories. third, all patients in the included studies were from china, and the number of cases was limited. at the time of writing, few studies have yet been published from other countries experiencing covid- outbreaks such as italy, spain and the usa. in fact, no articles from countries other than china met the inclusion criteria for our analysis. further investigation including a greater number of studies with a broad geographic scope and larger sample size is needed, to obtain a more comprehensive understanding of covid- . finally, significant heterogeneity was detected in the statistical results for several items. to address this heterogeneity, we used random effects modeling and performed subgroup analyses to identify potential sources of heterogeneity. unfortunately, no clear source of heterogeneity was identifiable. clinical characteristics are related to many factors including basic physical condition, disease progression, and examination and treatment conditions. multiple factors may have contributed to high heterogeneity; these require further research and exploration. this is the first meta-analysis to investigate the differences in clinical characteristics and outcomes between patients with covid- who have different degrees of disease severity. our study results will be helpful in identifying high-risk factors in patients with severe illness, which will contribute to early prediction, accurate diagnosis, and treatment of patients with covid- . jia li, xue he and gehong dong participated in study design; jia li and xue he performed data extraction and data analysis; jia li and yuan yuan drafted the manuscript; all authors provided critical review of the manuscript and approved the final draft for publication. approval was not required. a novel coronavirus from patients with pneumonia in china presumed asymptomatic carrier transmission of covid- preferred reporting items for systematic reviews and meta-analyses: the prisma statement critical evaluation of the newcastle-ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses measuring inconsistency in meta-analyses meta-analysis in clinical trials clinical features and laboratory inspection of novel coronavirus pneumonia (covid- clinical characteristics of medical staff with covid- : a retrospective study in a single center in wuhan covid- with different severity: a multi-center study of clinical features diagnostic utility of clinical laboratory data determinations for patients with the severe covid- clinical characteristics of coronavirus disease in china clinical features of patients infected with novel coronavirus in wuhan clinical and transmission characteristics of covid- -a retrospective study of cases from a single thoracic surgery department clinical features and treatment of covid- patients in northeast chongqing clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan clinical and computed tomographic imaging features of novel coronavirus pneumonia caused by sars-cov- analysis of clinical characteristics and laboratory findings of cases of novel coronavirus pneumonia in wuhan, china: a retrospective analysis clinical characteristics of cases of corona virus disease (covid- ) in changsha genetic recombination, and pathogenesis of coronaviruses isolation of a novel coronavirus from a man with pneumonia in saudi arabia the impact of copd and smoking history on the severity of covid- : a systemic review and meta-analysis epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study pathological findings of covid- associated with acute respiratory distress syndrome we thank liwen bianji, edanz group china (www.liwenbianji.cn/ac), for editing the english text of a draft of this manuscript. key: cord- -vb ks mq authors: damiani, giovanni; pacifico, alessia; bragazzi, nicola l.; malagoli, piergiorgio title: biologics increase the risk of sars‐cov‐ infection and hospitalization, but not icu admission and death: real‐life data from a large cohort during red‐zone declaration date: - - journal: dermatol ther doi: . /dth. sha: doc_id: cord_uid: vb ks mq during covid‐ outbreak there are discordant opinions toward the impact on biologics in psoriatic (pso) patients. thus we performed a single‐center case‐control study in lombardia, the italian region with the higher number of covid‐ confirmed cases. we enrolled pso patients treated with biologics and small molecules and we used the entire lombardia population as controls. notably, pso patients covid‐ confirmed were quarantined at home and five hospitalized, no pso patients were admitted to intensive care unit (icu) or died. with respect to the general population of lombardy, patients on biologics were at higher risk to test positive for covid‐ (odds ratio [or] . [ % confidence interval (ci) . ‐ . ], p < . ), to be self‐quarantined at home (or . [ % ci . ‐ . ], p < . ) and hospitalized (or . [ % ci . ‐ . ], p = . ), however, not increased risk of icu admission or death were found. pso patients on biologics should be carefully monitored with telemedicine during covid‐ outbreak and early treated at home to limit hospital overwhelm. since march , , lombardia region experienced covid- lockdown and only after days the entire italy became red-zone. nowadays, lombardia is the italian region with more confirmed, hospitalized, and dead covid- patients. despite the higher risk for covid- displayed by obese, active smokers, and copd patients, almost no data are present toward psoriatic (pso) patients and biologics. moderate to severe psoriasis benefit from systemic treatment as biologics and small molecules; at the same time these drugs, capable to clear psoriasis, are related also to an increased risk of airway infections. pso patients also display a baseline airway inflammation that triggers the constellation of chronic respiratory comorbidities, such as asthma and chronic obstructive pulmonary disease (copd). furthermore, pso patients are frequently smokers and cigarettes increased flares as well as psoriasis severity, predisposing to copd and exacerbating asthma crisis. thus, we performed this study aiming to understand the effect of biologics in pso patients during covid- outbreak focusing on symptomatic patients quarantined at home, hospitalized, and their prognosis. pso patients on biologics displayed higher risk to be infected and to be hospitalized/self-quarantined at home, but icu hospitalization and death did not differ from the general population. notably, pso patients display baseline airway inflammation that clears with anti-pso therapies, preliminary data suggest that airways inflammation is downregulated by treating skin inflammation. the lung-skin inflammatory reciprocal interactions was modelized by nadeem et al claiming that skin inflammation via il- /stat signaling modulates airway inflammation and vice versa. these findings offer also a rationale to continue biologics in pso patients to prevent the lung-skin inflammatory axis and to inhibit the progression to the hyperinflammatory phase. despite this study is the first to assess the impact of biologics among pso patients during covid- , it did not assess the family members, so future studies should also evaluate this aspect. biologics may not increase the risk of icu hospitalization and death; however, they increase the risk of mild to moderate disease. thus, pso patients on biologics should be carefully monitored with teledermatology and early treated at covid- symptoms early onset. clinical features and short-term outcomes of patients with covid- in wuhan safety of systemic agents for the treatment of pediatric psoriasis psoriasis and respiratory comorbidities: the added value of fraction of exhaled nitric oxide as a new method to detect, evaluate, and monitor psoriatic systemic involvement and therapeutic efficacy lifestyle changes for treating psoriasis covid- illness in native and immunosuppressed states: a clinical-therapeutic staging proposal a subset analysis of efficacy and safety outcomes from phase clinical studies of ixekizumab for the treatment of patients with severe plaque psoriasis why tocilizumab could be an effective treatment for severe covid- ? increased airway inflammation in patients with psoriasis psoriatic inflammation enhances allergic airway inflammation through il- /stat signaling in a murine model biologics increase the risk of sars-cov- infection and hospitalization, but not icu admission and death: real-life data from a large cohort during red-zone declaration the authors declare no potential conflict of interest. https://orcid.org/ - - - alessia pacifico https://orcid.org/ - - - key: cord- -iheq ub authors: de jong, audrey; wrigge, hermann; hedenstierna, goran; gattinoni, luciano; chiumello, davide; frat, jean-pierre; ball, lorenzo; schetz, miet; pickkers, peter; jaber, samir title: how to ventilate obese patients in the icu date: - - journal: intensive care med doi: . /s - - -x sha: doc_id: cord_uid: iheq ub obesity is an important risk factor for major complications, morbidity and mortality related to intubation procedures and ventilation in the intensive care unit (icu). the fall in functional residual capacity promotes airway closure and atelectasis formation. this narrative review presents the impact of obesity on the respiratory system and the key points to optimize airway management, noninvasive and invasive mechanical ventilation in icu patients with obesity. non-invasive strategies should first optimize body position with reverse trendelenburg position or sitting position. noninvasive ventilation (niv) is considered as the first-line therapy in patients with obesity having a postoperative acute respiratory failure. positive pressure pre-oxygenation before the intubation procedure is the method of reference. the use of videolaryngoscopy has to be considered by adequately trained intensivists, especially in patients with several risk factors. regarding mechanical ventilation in patients with and without acute respiratory distress syndrome (ards), low tidal volume ( ml/kg of predicted body weight) and moderate to high positive end-expiratory pressure (peep), with careful recruitment maneuver in selected patients, are advised. prone positioning is a therapeutic choice in severe ards patients with obesity. prophylactic niv should be considered after extubation to prevent re-intubation. if obesity increases mortality and risk of icu admission in the overall population, the impact of obesity on icu mortality is less clear and several confounding factors have to be taken into account regarding the “obesity icu paradox”. electronic supplementary material: the online version of this article ( . /s - - -x) contains supplementary material, which is available to authorized users. obesity (defined by a body mass index (bmi) ≥ kg/ m ) is a disease caused by excess or abnormal distribution of fat tissue and resulting in chronic diseases related to chronic inflammation and metabolic dysfunction [ ] . obesity has become a global epidemic with prevalences rising both in developed and developing countries. front runners in are the united states of america (usa, %) and australasia ( %), with a prevalence expected to increase in the usa until % by [ ] , whereas european countries have prevalences between and %. the percentage of patients with obesity in the intensive care unit (icu) can be expected to increase concomitantly or even more since obesity increases the risk for a more severe disease course with more need for icu admission and mechanical ventilation [ ] as has been shown in trauma [ ] , traumatic brain injury [ ] patients, out-of-hospital cardiac arrest [ ] , during the h n pandemic [ ] and recently also in patients affected by coronavirus disease (covid- ) [ ] [ ] [ ] [ ] . obesity, especially abdominal obesity (android fat distribution) and severe obesity [ ] , results in altered respiratory anatomy and physiology and, therefore, complicated airway management and adapted ventilator settings during mechanical ventilation. obesity appears to be associated with an increased risk of acute respiratory distress syndrome (ards) [ ] and infection, mainly pneumonia [ ] , probably related to an imbalanced production of adipokines [ ] . in ventilated patients, obesity increases icu length of stay and the duration of mechanical ventilation [ ] . the phenomenon whereby obesity increases morbidity but seems to protect against mortality in selected critically ill patients, known as "obesity paradox", has been evocated in patients with ards [ ] and in those on mechanical ventilation [ ] , even if it remains highly debated. this narrative review will summarize current insights into the impact of obesity on the respiratory system and the measures to be taken to optimize airway management and mechanical ventilation in icu patients with obesity. the patient with obesity suffers from increased respiratory workload and impaired gas exchange. both disturbances reduce physical capacity and health margin if exposed to respiratory stress. a basic triggering factor is reduced lung volume, caused by cranial displacement of the diaphragm by increased tissue mass in the abdomen, and by increased chest wall tissue. the decrease in resting lung volume after normal expiration, functional residual capacity (frc), is - % per kg/m increase in bmi [ ] . the consequence of the increased tissue mass will be greater in the supine than upright position, due to a stronger cranial displacement of the diaphragm. in addition, a further decrease in the frc can be seen during anesthesia with loss of respiratory muscle tone and, most likely, in icu by the use of sedatives and muscle relaxants. the fall in frc promotes airway closure and atelectasis formation, as will be discussed later, and an illustration of one representative case with no ventilation in the dorsal part of the lung, likely because of dependent atelectasis formation [ ] , is shown in fig. . there are several causes of increased work of breathing in the patient with obesity. one is the increased displacement of tissue during the breathing, both in the abdomen and in the lung and chest wall. another is increased airway resistance because of smaller airway dimensions, and increased asthma incidence. finally, increased tissue resistance adds to the work of breathing [ ] . the patient with obesity may easily develop respiratory fatigue on physical exercise and, in the most severe cases, already at rest. it is often assumed that chest wall elastance or its inverse, chest wall compliance, is affected by obesity. however, the increased weight of the abdomen and of the chest wall requires work when moving the tissue, but when the move is over, no additional pressure is required [ ] . end-inspiratory and end-expiratory pauses should be long enough when measuring chest wall compliance. lung compliance, on the other hand, is reduced [ ] . the decreased lung volume may require pressure during inspiration to open closed units, and that may be recorded as a decrease in compliance. airways may close in dependent lung regions during an expiration, a normal age-dependent phenomenon. in patients with obesity, using non-invasive ventilation (niv) is advised both to prevent and treat acute respiratory failure. when invasive mechanical ventilation is needed, pre-oxygenation with niv and appropriated choice of intubation devices will decrease complications. during invasive mechanical ventilation, patients with obesity are more prone to lung collapse and require higher peep to avoid it; low v t is calculated on predicted body weight. when acute respiratory distress syndrome occurs, careful recruitment maneuver might be used associated with prone positioning. fig. impedance changes due to regional ventilation in a patient with obesity. thoracic transversal electric impedance tomography images show impedance changes due to regional ventilation summarized for tidal ventilation cycles in a patient with a body mass index of kg/m . images were recorded during spontaneous breathing before intubation (a) and about h after extubation (c) in a patient without lung pathology. note the ventral shift of ventilation during mechanical ventilation with a positive end-expiratory pressure (peep) of cmh o (b), which is likely due to atelectasis formation in dependent lung areas. obviously, the peep level was insufficient to keep the lung open while this has been known for many years, a more extensive, indeed complete airway closure has been shown during the last few years in anesthetised patients with obesity [ ] or icu patients with obesity on mechanical ventilation. this means that a certain airway pressure is needed to start inflation of the lungs and it is not caused by a time-dependent intrinsic positive end-expiratory pressure (peep). where the complete closure occurs is not clear but may be in the most central airways and not in the periphery. the latter would require simultaneous closure of thousands of airways, as recently discussed [ ] . hopefully, the morphology behind complete closure can be demonstrated in the near future. a consequence of the classic airway closure is impeded ventilation where the closure occurs and the decrease in ventilation will be larger the longer the closure lasts during the respiratory cycle. if airways are continuously closed, as can be seen during anesthesia and most likely in icu, the alveoli distal to the closure will collapse because of gas absorption [ ] . the higher the oxygen concentration is in the inspired gas, the faster is the collapse. with pure oxygen, it can take a few minutes and with air, a couple of hours. the complete closure, on the other hand, will delay onset of inspiration without affecting the distribution per se. uneven ventilation distribution caused by airway closure will occur primarily in dependent lung regions. perfusion of the lung, on the other hand, increases down the lung independent of anatomy. regions that are poorly but still ventilated will cause ventilation-perfusion mismatch and regions that collapse because of continuous airway closure will cause shunt [ ] . both impede oxygenation [ ] and a large shunt may even impair carbon dioxide (co ) elimination. with an extreme shunt, oxygenation is poorly or not at all improved by increasing oxygen in the inspired gas. finally, in patient with obesity, there is significant heterogeneity in both resistance and compliance, therefore, inhomogeneous inflation or deflation of the lungs can cause dynamic pressure differences between regions and lead to interregional airflows known as pendelluft effect. however, the patients with obesity are not a homogeneous group regarding the physiological modifications, the level of obesity and the fat distribution (gynoid versus android) being confounding factors that should be taken into account. although hypoxemic acute respiratory failure (arf) is not the first cause of arf in the patient with obesity [ , ] , hypoxemia is frequent as it is favored by increased oxygen consumption or work of breathing and atelectasis formation, especially in cases of patients with morbid obesity and during arf [ ] . non-invasive strategies should first optimize body position with reverse trendelenburg position, "beach chair position" or sitting position, which improve respiratory compliance and gas exchange in patients with morbid obesity [ , ] . in patients having postoperative hypoxemia or arf, non-invasive ventilation (niv) is recommended with moderate certainty of evidence, justified by a decreased need of intubation, mortality and morbidity as compared to standard oxygen [ , ] . an observational study including patients with arf after abdominal surgery reported that niv avoided intubation in % of cases [ ] . in a post hoc analysis of a large trial of postoperative thoracic patients [ ] , it was shown that among the patients with obesity (mean bmi of kg/m ), niv was not superior to high-flow nasal cannula oxygen therapy (hfnc), with treatment failure occurring in % and % in niv and hfnc groups, respectively. therefore, niv could be considered as the first-line therapy in patients with obesity having a postoperative arf [ ] , but further studies are needed to confirm the role of continuous positive airway pressure (cpap) and/or hfnc in this setting [ , ] (table ) . data addressing the management of hypoxemic arf with non-invasive ventilatory/oxygen strategies are scarce, especially in patients with obesity. the recent international guidelines failed to offer a recommendation on the use of niv in hypoxemic arf [ ] . one large trial has compared niv with standard oxygen and hfnc in non-selected patients with hypoxemic arf [ ] . results showed lower mortality rates with hfnc than niv, thereby suggesting deleterious effects of niv. similarly, an observational study including patients with bmi > kg/m showed that, after adjustment on high severity scores, hypoxemic arf caused by pneumonia was associated with niv failure [ ] . however, according to physiological abnormalities in patients with obesity, niv could play a role, especially in patients with morbid obesity, through peep that may improve oxygenation and lung volume or alveolar recruitment [ ] . finally, possible use of niv or hfnc as alternative to standard oxygen in patients with obesity and hypoxemic arf is not determined, and future trials are needed (table ) . hypercapnic arf in patients with obesity can not only be part of the clinical course of cardiogenic pulmonary edema, pneumonia, asthma, and exacerbation of chronic lung diseases, but also may be due to exacerbation of obesity hypoventilation syndrome (ohs) [ ] . positive airway pressure, i.e. cpap (refer to one level of airway pressure) or niv (refer to two levels of airway pressures), is the recommended ambulatory treatment for ohs patients [ ] . similarly, niv is the usual treatment applied in ohs exacerbation, but no trial has evaluated its benefit as compared to other oxygen strategies. niv brings together potentially beneficial physiological effects, including peep preserving upper airway patency and pressure support to control central hypoventilation. however, an observational study including severely patients with obesity reports a lower bmi ( kg/m ) in patients with niv success versus kg/m in those who failed niv [ ] . in this setting, niv may be an appropriate treatment, but hfnc interspaced between niv sessions should be evaluated. in addition to the pathophysiological modification of the respiratory system discussed above, patients with obesity have peculiar morphological alterations potentially associated with difficulties during mask ventilation and airway management: reduced neck mobility, limited mouth opening, increased size of pharyngeal and glossal soft tissues, unfavorable conformation and positioning of the larynx, increased neck circumference and decreased thyromental distance [ ] . moreover, patients with obesity have a high incidence of obstructive sleep apnea [ ] , which is directly related to many of the complications occurring during airway management of this sub-population of critically ill patients [ ] . obesity contributes to airway compression through increased airway fat deposits [ ] , and placing the patient with obesity recumbent may lead to sudden death [ ] . it is very important to encourage upright positioning and avoid supine positioning. overall, obesity, especially super obesity (bmi ≥ kg/m ) with android fat distribution, is an important risk factor for major complications, morbidity and mortality related to intubation procedures in the icu [ ] . most of the literature existing on the airway management of patients with obesity is related to the operating room setting [ ] . in this context, several strategies are often recommended, including the adoption of ramped position using specific devices or pillows/blankets under the patient's head and shoulder, pre-oxygenation with positive pressure ventilation [ ] and the use of videolaryngoscopes [ ] . however, compared to the elective surgical patient with obesity, the intubation of the critically ill patient has profound differences in indications, timing and co-existing conditions; therefore, caution should be applied when translating in the icu the recommendations based on evidence in the operating room. in the icu, the incidence of difficult intubation is double compared to the or and the occurrence of severe complications is dramatically higher [ ] . pre-procedural patient preparation is key to successful intubation. an ideal preparation aims at prolonging timeto-desaturation, which in patients with obesity is mainly related to the rapid loss of frc after sedation. concerning positioning, a randomized controlled trial questioned the usefulness of the ramped position applied in critically ill patients [ ] ; however, the study included a large proportion of patients without obesity. therefore, patient positioning should be individualized on the patient anatomy, based also on the intensivist's expertise. a semi-sitting position during pre-oxygenation could help to decrease positional flow limitation and air trapping [ ] . conventional bag-mask ventilation can result in rapid desaturation in patients with morbid obesity. several studies confirmed that pre-oxygenation with cpap or niv improves oxygenation allowing a longer time window for intubation [ , ] . for these reasons, positive pressure pre-oxygenation should be considered the reference in critically ill patients with obesity, considering that obesity carries an intrinsic increased risk for difficult mask ventilation. hfnc might also have a role [ ] , especially in rapid sequence intubation in non-severely hypoxemic patients, where avoidance of bag ventilation might be desirable but is associated with higher incidence of severe desaturation [ ] . however, the value of hfnc value in patients with obesity must be clarified, and cannot replace a preoxygenation using positive pressure [ ] . the intubation maneuver should be always considered as potentially difficult in patients with obesity [ ] , with older age, higher bmi, high mallampati and macocha scores and reduced neck mobility being independent risk factors for both difficult mask ventilation and intubation. a meta-analysis in surgical patients with obesity suggested an advantage of videolaryngoscopes over direct laryngoscopy [ ] . in icu patients with obesity, it seems reasonable to consider the use of videolaryngoscopes by adequately trained intensivists, especially in patients with several risk factors. obesity is associated with abdominal and thoracic tissue mass, which transmit additional hydrostatic pressure via the chest wall and diaphragm to the pleural space and, thus, the alveoli. if pleural pressure is higher than intraalveolar pressure, the alveoli will collapse, and compression atelectasis will occur predominantly in dependent lung areas, where hydrostatic pressure is highest. for example, functional residual capacity is impaired by up to % in non-ventilated subjects with obesity in the supine position [ ] and total lung and vital capacity are reduced as well. induction of anesthesia with muscle relaxation following pre-oxygenation with % o further reduces end-expiratory lung volume (eelv) by about %, if a positive end-expiratory pressure (peep) of cmh o is used after initiation of mechanical ventilation (fig. ) [ ] . the main mechanism of gas exchange impairment is, therefore, shunt (atelectasis) in patients with obesity [ ] . because the opening pressure of alveoli is higher than the pressure needed to keep them open, application of an initial recruitment maneuver (rm) followed by adequate peep after intubation or disconnection of the patient from the ventilatory circuit seems intuitive. due to the high pleural pressure in patients with obesity, opening pressures up to cmh o applied during a rm in patients with obesity without lung injury may not result in full lung recruitment [ ] . potential side effects of applying such high airway pressures include a decrease in venous return and, thus, cardiac preload with a drop in cardiac output and systemic blood pressure. in addition, barotrauma such as pneumothorax or pneumomediastinum especially in patients with pre-existing structural lung damage such as emphysema, and a mechanically triggered boost of pre-existing lung inflammation may occur. thus, rm is not generally recommended, and their use remains a decision based on individual risk/benefit considerations. in mechanically ventilated patients, peep is used to keep alveolar pressure above the closing pressure of alveoli thereby maintaining end-expiratory lung volume (eelv) and arterial oxygenation. in another words, peep does not strictly induce alveolar recruitment but peep avoids alveolar derecruitment by maintaining open alveoli. thus, protective ventilation strategies may improve clinical outcomes even in patients without ards [ ] . due to the superimposed pressure transmitted by adipose tissue on the pleural space, closing pressures in patients with obesity are higher and lungs of these patients are more prone to such complications (fig. ) . despite these considerations, routinely used peep levels applied for ventilation of patients with obesity are often not higher than in normal weight patients [ ] . in previous studies, different methods to find the individualized "best" peep in patients with obesity have been used. these approaches targeted improvements in oxygenation, lung mechanics, and regional ventilation distribution. in patients undergoing bariatric surgery, individualized peep resulted in a range of peep levels between and cmh o with a median of cmh o [ ] and restored eelv to the same level before intubation and initiation of mechanical ventilation. other studies regularly found peep levels > cmh o [ , ] . however, a large trial of ventilation in patients with obesity during anesthesia did not demonstrate a difference in postoperative pulmonary complications for constant peep levels of versus cmh o [ ] . the peep levels in this pragmatic study, however, were not aiming at and resulting in full lung recruitment. as mentioned above, use of higher airway pressures is often associated with hemodynamic depression and higher requirements for fluids and vasopressors [ ] . at least in the perioperative setting, evidence from meta-analyses and clinical trials are somewhat conflicting regarding improved clinical outcomes [ , ] . limiting tidal volume (v t ) has been shown to reduce ventilation-associated lung injury and inflammation in non-selected patients with and without ards. the idea of normalizing v t for predicted body weight (pbw) is based on the expected lung volume (dependent on patient's height and sex) and aims to limit the v t /eelv ratio, i.e., mechanical lung strain. as mentioned above, eelv is regularly below the values in a normal weight population. thus, referencing v t to pbw per se can result in higher strain than in normal weight patients. if pbw is not formally calculated but just estimated, there is a tendency to overestimate pbw and, thus, v t in patients with obesity [ ] . positioning patients with obesity in ramped or sitting positions and even early mobilization may facilitate unloading the diaphragm from increased abdominal pressure and may thereby improve aeration of dependent lung areas. early implementation of spontaneous breathing activity can preserve diaphragmatic tension, redistribute ventilation to dependent lung areas [ ] , may avoid diaphragmatic muscle atrophy caused by muscle relaxation [ ] and reduce duration of mechanical ventilation [ ] . anzueto et al. [ ] and karla et al. [ ] showed that ards patients with obesity were ventilated with higher v t (per kg of pbw) compared to ards patients without obesity. it is tempting to speculate that the amount of atelectasis was different between patients with and without obesity and that the higher v t was chosen by the clinicians to maintain an adequate alveolar ventilation. a study by grasso et al. [ ] tempted to confirm this hypothesis by reporting a decrease in the use of extracorporeal membrane oxygenation (ecmo) in patients with abdominal hypertension by increasing the airway pressure-often above cmh o-based on a transpulmonary pressure target. interestingly, in the study by karla et al. [ ] , the airway plateau pressure and driving pressure were similar between patients with and without obesity. of note, in both studies, the outcome was similar between the two groups. similarly, de jong et al. [ ] , in ards patients with obesity did not find any difference in driving pressure between survivors and non survivors [ ] . when ards patients with obesity were compared to patients with ards but with a normal bmi, it was found that the two groups had similar recruitability and changes in oxygenation when peep was increased from to cmh o [ ] . in these two groups, abdominal pressure and chest wall elastance were also similar. in contrast, fumagalli et al. [ ] found an impressive improvement in oxygenation and lung elastance using higher peep ( cmh o) compared to lower peep ( cmh o). the higher peep was selected according to transpulmonary pressure, while the lower peep was selected according to a peep/fio table. once again, the abdominal pressure was not measured (or reported). the same authors in a retrospective study of patients with severe ards found better gas exchange, respiratory mechanics, and survival in patients treated according to a personalized approach (based on transpulmonary pressure) compared to patients treated with a standard protocol [ ] . the personalized approach resulted in much higher peep levels of cmh o compared to cmh o used in the standard approach. a retrospective analysis of the alveoli trial showed improved outcome using peep cmh o compared to cmh o [ ] . in this trial, however, patients with a weight > kg/cm of height and bmi usually > kg/m were not included. we may wonder why the reported effect of different levels of peep differs among studies. we have to note that the bmi of the population of the different studies was kg/ m , as in the study of chiumello et al. [ ] and likely in the alveoli study [ ] , versus a bmi higher than kg/m in the study by fumagalli et al. [ ] . given such a different bmi, it is likely that the abdominal pressure and mechanical impairment were different in the different populations. the normalized mechanical power, that has been shown being strongly associated with mortality [ ] , was not monitored. moreover, rm was not consistently used, and their use and timing remain a matter of debate in ards patients with and without obesity [ ] . a peep decremental trial preceded by a rm may decrease lung overdistension and collapse in ards obese patients [ ] . in ards patients with severe obesity (bmi = ± kg/ m ) [ ] , rm was performed during pressure controlled fig. effect of obesity in main pressures of the respiratory system. the respiratory system includes the lung and the chest wall, and the airway pressure is related to both transpulmonary and transthoracic pressures, which differ in the patient with obesity compared to the patient without obesity. the relative part of pressure due to transthoracic pressure is often higher in the patient with obesity than in the patient without obesity (elevated pleural pressure, which can be estimated by esophageal pressure). the plateau pressure represents the pressure used to distend the chest wall plus lungs. in patients with obesity, elevated plateau pressure may be related to an elevated transthoracic pressure, and not an increase in transpulmonary pressure with lung overdistension. frc functional residual capacity ventilation with delta pressure of cmh o, peep was increased until a plateau pressure of cmh o for min. after, the ventilator mode was switched to volume controlled ventilation ( ml/kg of pbw), and the peep dropped by cmh o every s. the optimal peep was determined by the peep value with the best compliance of the respiratory system plus cmh o. finally, a second lung rm was performed and the selected optimal peep was set. required peep was increased to [ , ] cmh o above traditional ardsnet settings with improvement of lung function, oxygenation and ventilation/perfusion matching, without impairment of hemodynamics or right heart function. moreover, in a retrospective study [ ] , the same authors also reported that patients treated with rm and with higher peep were weaned from vasopressors agents faster (and improved survival) than patients who were treated with low ardsnet peep table. future investigations would be beneficial to clarify the lungheart interaction when high airway pressure is used in the settings of high pleural pressure. given that the setting of mechanical ventilation (v t , peep) and the indicators of ventilator-induced lung injury (mechanical power, driving pressure) are crucially dependent on chest wall elastance, it is our opinion that it is difficult to propose any treatment if key variables such as transpulmonary pressure and intra-abdominal pressure are not measured or ignored (fig. ) . prone position [ ] also deserves attention in patients with ards and obesity. the safety and efficiency of this therapeutic were similar between patients with and without obesity, and the ratio of alveolar pressure in oxygen over fraction of inspired oxygen (pao /fio ) was significantly more increased after prone position in patients with obesity compared to patients without obesity [ ] . prone position is a therapeutic of choice in patients with severe ards and obesity, and the mechanisms of action, caution and clinical effects are detailed in fig. . in case of severe ards after failure or inability to use prone positioning and neuromuscular blockers, veno-venous extracorporeal membrane oxygenation (ecmo) can also be safely used in ards obese patients [ , ] . the spontaneous breathing trial should be clearly separated from the level of pressure support and peep set before extubation and the respiratory support following extubation. a physiological study specifically assessed the inspiratory effort during weaning of mechanical ventilation in critically ill patients with morbid obesity [ ] . the main result of this study was that for patients with obesity, t-piece and pressure support ventilation + peep cmh o were the weaning tests predicting post-extubation inspiratory effort and work of breathing the most accurately [ ] . if the work of breathing is closely the same between t-tube and after extubation [ ] , the patient with obesity remains prone to atelectasis, and therefore, atelectases should be avoided as much as possible. that is s why after a t-tube, the obese patient should be reconnected to mechanical ventilation, as already demonstrated in patients without obesity [ ] , and put again under pressure support with sufficient peep and pressure support. similarly, following extubation, as detailed below, preventing atelectasis has to start as soon as possible, using cpap or niv. moreover, to perform extubation as soon as possible, sedation should be stopped as early as possible and benzodiazepines avoided, even more than in patients without obesity due to prolonged release of drugs in patients with obesity [ ] . prophylactic niv after extubation decreases the risk of arf by % and length of icu stay [ ] . in hypercapnic icu patients with obesity, using niv after extubation is associated with decreased mortality [ ] . a randomized controlled trial performed in patients with morbid obesity undergoing bariatric surgery found an improvement of ventilatory function when cpap was implemented immediately after extubation as compared to cpap started min after extubation [ ] (table ). in case of positive pressure therapy already used at home, it should be reintroduced as early as possible in the icu as soon as higher levels of assistance requiring the use of an icu ventilator are no longer needed. home positive pressure therapy could also be introduced in icu for selected patients with obesity. cpap is indicated for use in patients with severe obstructive sleep apnea syndrome, as first-line therapy in these indications. in the case of combined obstructive apnea syndrome and moderate hypercapnia between and mmhg, a cpap device will be offered as first-line therapy, and a niv device, allowing ventilation at pressure levels, will be offered in case of failure. if there is a history of respiratory decompensation with acute hypercapnic respiratory failure, hypercapnia greater than mmhg and/or no associated obstructive sleep apnea syndrome, a niv device will be offered [ ] . hfnc was not found to be superior to standard oxygen to prevent extubation failure in post-cardiac surgery patients with obesity [ ] . among cardiothoracic surgery subjects with obesity with or without respiratory failure, the use of continuous hfnc compared to niv did not result in a worse rate of treatment failure [ ] (table ) . similarly, in the study by hernandez et al. [ ] including % of patients with obesity, among high-risk adults who have undergone extubation, preventive hfnc was not inferior to preventive niv for reducing reintubation rate and postextubation respiratory failure. in a randomized controlled trial of the same team comparing hfnc to standard oxygen [ ] in high-risk non-hypercapnic patients including % of patients with obesity, the study was stopped due to low recruitment after patients, without any difference in extubation failure rate found between the two groups. the specificities of weaning and extubation in icu patients with obesity are summarized in supplemental table . a summary of the main respiratory physiological modifications and some suggestions for mechanical ventilation in critically ill patients with obesity are proposed in fig. . in the general population, obesity is one of the top risk factors of chronic diseases and a risk factor for death. consistent with this trend in the general population, the number of obese patients admitted to the icu is rapidly increasing [ ] . obesity decreases life expectancy in the population, and obesity in childhood is now a healthcare crisis for our next generation with unknown consequences. there are overwhelming scientific data on overall mortality/morbidity, the healthcare system shortcomings to deliver adequate care, and the social discrimination and injustice that individuals with obesity are subject on daily basis. however, in icu, patients with obesity may be more likely to develop ards, but their survival sometimes appeared to be better, a phenomenon called the 'obesity paradox' [ ] . patients with obesity have immunological and pulmonary mechanics differences compared to patients without obesity detailed in the supplemental content (see supplemental content ). these differences are increased for patients with higher level of obesity. furthermore, clinicians may overestimate the lung size of patients with obesity, by considering real instead of pbw, and use higher v t during mechanical ventilation, risking ventilator-induced lung injury. the mentioned patient factors may also cause respiratory muscle fatigue and difficult weaning. indeed, meta-analyses show that in close to , ards patients, obesity is linked to a higher risk of developing ards and patients with obesity need mechanical ventilation for a longer period of time, compared to critically ill patients without obesity [ , ] . as a consequence, icu-length of stay is also prolonged in patients with obesity, while hospital length of stay is not [ , ] . while patients with obesity are on mechanical ventilation for a longer period of time, these meta-analyses also demonstrate a survival advantage for patients with obesity. this observation is coined the 'obesity paradox' as a survival benefit may appear counterintuitive in view of the detrimental alterations in respiratory function as described above. several reasons to explain the obesity paradox in ards patients with obesity have been put forward. apart from the described immunological differences, patients with obesity have more metabolic reserve and may, therefore, tolerate the catabolic stress of critical illness during ards better, because of energy stores in the form of adipose tissue. it is important to also address the possibility that patients with obesity may have a lower threshold for icu admission, e.g., because of the need of more nursing staff not available on the ward or monitoring purposes. this would mean that patients with obesity admitted to the icu are less sick and therefore may show a better survival because of selection bias, not representing a real phenomenon. as in the meta-analyses, adjustments for covariates like disease severity were not possible; this may appear plausible. in a large study in over , icu patients, however, the obesity paradox remained present even when adjusted for several covariates including disease severity [ ] . also, patients with obesity may have been misclassified as ards if atelectasis is interpreted as bilateral infiltrates. using a causal inference approach to reduce residual confounding bias due to missing data, it was found that the survival of patients without obesity would not have been improved if they had obesity [ ] , findings which question the obesity paradox. in summary, patients with obesity are more likely to develop respiratory complications, including arf and ards. considering some physiological studies, for non-invasive management, using niv has to be considered both for preventing and treating arf, even if the level of proof is low, especially in comparison with hfnc. airway management in critically ill patients with obesity poses specific challenges, and adequate patient evaluation, pre-oxygenation and choice of intubation devices might improve outcomes. after intubation procedure for invasive mechanical ventilation, patients with obesity being more prone to lung collapse require higher peep to avoid it. low v t according to pbw should be used both in non-ards and ards fig. main respiratory physiological modifications and suggestions for mechanical ventilation in critically ill patients with obesity. the main respiratory physiological modifications (functional residual capacity decreased, abdominal pressure often increased, pulmonary and chest wall compliance often decreased, cephalic ascension of diaphragm, oxygen consumption and work of breathing increased) lead to shunt via atelectasis and gas exchange impairment. comorbidities are often associated with obesity: obstructive apnea syndrome and obesity hypoventilation syndrome. consequences on airway management, potentially difficult, include the preparation of adequate material for difficult intubation as videolaryngoscopes, preoxygenation with noninvasive ventilation in a semi-sitting position, considering adding apneic oxygenation (optiniv method), rapid sequence induction and recruitment maneuver following intubation after hemodynamic stabilization. ventilatory settings include low or limited tidal volume ( - ml/kg/pbw or less), moderate to high peep ( - cmh o) if hemodynamically well tolerated, recruitment maneuver (if hemodynamically well tolerated, in selected patients), monitoring of esophageal pressure if possible, use of prone positioning in a trained team in case of severe ards, without contra-indicating ecmo. after extubation, cpap or niv should be considered early, as implementation of positive pressure therapies at home after evaluation. pbw predicted body weight, peep positive end-expiratory pressure, ards acute respiratory distress syndrome, ecmo extracorporeal membrane oxygenation, cpap continuous positive airway pressure, niv noninvasive ventilation, hfnc high-flow nasal cannula oxygen patients. rm is not systematically recommended, and their use remains a decision based on individual risk/ benefit considerations. prone positioning should be used in severe ards patients with obesity. body-mass index and all-cause mortality: individual-participant projected us state-level prevalence of adult obesity and severe obesity obesity in the critically ill: a narrative review prevalence of cardiovascular and respiratory complications following trauma in patients with obesity isolated severe blunt traumatic brain injury: effect of obesity on outcomes obesity was associated with worse neurological outcome among japanese patients with out-ofhospital cardiac arrest obesity is associated with higher risk of intensive care unit admission and death in influenza a (h n ) patients: a systematic review and meta-analysis comorbidities and the risk of severe or fatal outcomes associated with coronavirus disease : a systematic review and meta-analysis increased mortality in patients with severe sars-cov- infection admitted within seven days of disease onset how important is obesity as a risk factor for respiratory failure, intensive care admission and death in hospitalised covid- patients? results from a single italian centre implications of obesity for the management of severe coronavirus disease pneumonia the role of visceral adiposity in the severity of covid- : highlights from a unicenter cross-sectional pilot study in germany obesity paradox" in acute respiratory distress syndrome: asystematic review and meta-analysis body mass index and the risk of infection -from underweight to obesity obesity altered t cell metabolism and the response to infection is body mass index associated with outcomes of mechanically ventilated adult patients in intensive critical units? a systematic review and meta-analysis the effects of body mass index on lung volumes individualized positive end-expiratory pressure in obese patients during general anaesthesia: a randomized controlled clinical trial using electrical impedance tomography physiology of obesity and effects on lung function the effects of body mass on lung volumes, respiratory mechanics, and gas exchange during general anesthesia airway closure during surgical pneumoperitoneum in obese patients airway closure, more harmful than atelectasis in intensive care? respiratory function during anesthesia: effects on gas exchange oxygenation impairment during anesthesia: influence of age and body weight impact of obesity in mechanically ventilated patients: a prospective study outcomes of morbidly obese patients requiring mechanical ventilation for acute respiratory failure the impact of morbid obesity on oxygen cost of breathing (vo( resp)) at rest effects of sitting position and applied positive end-expiratory pressure on respiratory mechanics of critically ill obese patients receiving mechanical ventilation the effects of the reverse trendelenburg position on respiratory mechanics and blood gases in morbidly obese patients during bariatric surgery official ers/ats clinical practice guidelines: noninvasive ventilation for acute respiratory failure effect of noninvasive ventilation on tracheal reintubation among patients with hypoxemic respiratory failure following abdominal surgery: a randomized clinical trial outcomes of patients with acute respiratory failure after abdominal surgery treated with noninvasive positive pressure ventilation high-flow nasal cannula therapy versus intermittent noninvasive ventilation in obese subjects after cardiothoracic surgery noninvasive respiratory support in the hypoxaemic peri-operative/periprocedural patient: a joint esa/esicm guideline use of nasal high flow oxygen during acute respiratory failure prevention and care of respiratory failure in obese patients high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure determinants of noninvasive ventilation success or failure in morbidly obese patients in acute respiratory failure noninvasive ventilation and alveolar recruitment maneuver improve respiratory function during and after intubation of morbidly obese patients: a randomized controlled study evaluation and management of obesity hypoventilation syndrome. an official american thoracic society clinical practice guideline perioperative care of the obese patient respiratory management of the obese patient undergoing surgery mechanical ventilation in obese icu patients: from intubation to extubation pathophysiology of sleep apnea cardiac arrest and mortality related to intubation procedure in critically ill adult patients: a multicenter cohort study difficult intubation in obese patients: incidence, risk factors, and complications in the operating theatre and in intensive care units videolaryngoscope versus macintosh laryngoscope for tracheal intubation in adults with obesity: a systematic review and meta-analysis a multicenter, randomized trial of ramped position vs sniffing position during endotracheal intubation of critically ill adults positive end-expiratory pressure during induction of general anesthesia increases duration of nonhypoxic apnea in morbidly obese patients nasal high-flow preoxygenation for endotracheal intubation in the critically ill patient: a randomized clinical trial bag-mask ventilation during tracheal intubation of critically ill adults focus on noninvasive respiratory support before and after mechanical ventilation in patients with acute respiratory failure prevention of atelectasis in morbidly obese patients during general anesthesia and paralysis: a computerized tomography study protective versus conventional ventilation for surgery: a systematic review and individual patient data meta-analysis intraoperative ventilation settings and their associations with postoperative pulmonary complications in obese patients noninvasive monitoring of lung recruitment maneuvers in morbidly obese patients: the role of pulse oximetry and volumetric capnography positive endexpiratory pressure optimization using electric impedance tomography in morbidly obese patients during laparoscopic gastric bypass surgery effect of intraoperative high positive end-expiratory pressure (peep) with recruitment maneuvers vs low peep on postoperative pulmonary complications in obese patients: a randomized clinical trial a trial of intraoperative lowtidal-volume ventilation in abdominal surgery spontaneous breathing with airway pressure release ventilation favors ventilation in dependent lung regions and counters cyclic alveolar collapse in oleic-acid-induced lung injury: a randomized controlled computed tomography trial nava in acute respira-tory failure (naviator) network ( ) neurally adjusted ventilatory assist in acute respiratory failure: a randomized controlled trial influence of body mass index on outcome of the mechanically ventilated patients higher class of obesity is associated with delivery of higher tidal volumes in subjects with ards ecmo criteria for influenza a (h n )-associated ards: role of transpulmonary pressure impact of the driving pressure on mortality in obese and non-obese ards patients: a retrospective study of cases driving pressure in obese ventilated patients: another brick in the (chest) wall effect of body mass index in acute respiratory distress syndrome transpulmonary pressure describes lung morphology during decremental positive end-expiratory pressure trials in obesity a lung rescue team improves survival in obesity with acute respiratory distress syndrome high positive end-expiratory pressure is associated with improved survival in obese patients with acute respiratory distress syndrome mechanical power normalized to predicted body weight as a predictor of mortality in patients with acute respiratory distress syndrome effect of lung recruitment maneuver on oxygenation, physiological parameters and mortality in acute respiratory distress syndrome patients: a systematic review and meta-analysis lung recruitment in obese patients with acute respiratory distress syndrome lung rescue team investigators ( ) high pleural pressure prevents alveolar overdistension and hemodynamic collapse in ards with class iii obesity a prospective international observational prevalence study on prone positioning of ards patients: the apronet (ards prone position network) study feasibility and effectiveness of prone position in morbidly obese patients with ards: a case-control clinical study class iii obesity is not a contraindication to venovenous extracorporeal membrane oxygenation support lack of association between body weight and mortality in patients on venovenous extracorporeal membrane oxygenation spontaneous breathing trial and post-extubation work of breathing in morbidly obese critically ill patients reconnection to mechanical ventilation for h after a successful spontaneous breathing trial reduces reintubation in critically ill patients: a multicenter randomized controlled trial immediate interruption of sedation compared with usual sedation care in critically ill postoperative patients (sos-ventilation): a randomised, parallel-group clinical trial noninvasive ventilation for prevention of post-extubation respiratory failure in obese patients continuous positive airway pressure via the boussignac system immediately after extubation improves lung function in morbidly obese patients with obstructive sleep apnea undergoing laparoscopic bariatric surgery how can i manage anaesthesia in obese patients? direct extubation onto high-flow nasal cannulae post-cardiac surgery versus standard treatment in patients with a bmi >/= : a randomised controlled trial effect of postextubation high-flow nasal cannula vs noninvasive ventilation on reintubation and postextubation respiratory failure in high-risk patients: a randomized clinical trial high-flow nasal cannula to prevent postextubation respiratory failure in high-risk non-hypercapnic patients: a randomized multicenter trial intensive care in the obese the obesity paradox in surgical intensive care unit patients body mass index is associated with hospital mortality in critically ill patients: an observational cohort study the obesity paradox in critically ill patients: a causal learning approach to a casual finding key: cord- -u eri authors: qian, z.; alaa, a. m.; van der schaar, m.; ercole, a. title: between-centre differences for covid- icu mortality from early data in england date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: u eri the high numbers of covid- patients developing severe respiratory failure has placed exceptional demands on icu capacity around the world. understanding the determinants of icu mortality is important for surge planning and shared decision making. we used early data from the covid- hospitalisation in england surveillance system (from the start of data collection th february - th april ) to look for factors associated with icu outcome in the hope that information from such timely analysis may be actionable before the outbreak peak. immunosuppression, chronic renal disease and age were key determinants of icu mortality in a proportional hazards mixed effects model. however variation in site-stratified random effects were even more appreciable, suggesting substantial between-centre variability in mortality. notwithstanding possible ascertainment and lead-time effects, these early results motivate comparative effectiveness research to understand the origin of such differences and optimise surge icu provision. since the first cases emerged in november [ ] , the spread of sars-cov- infections has placed an unprecedented strain on healthcare resources globally. the intensive care unit (icu) is a setting of particular concern as high numbers of patients developing severe respiratory complications from covid- means that advanced outcome-critical resources may be rapidly exhausted. indeed, in some areas, icus have been completely overwhelmed [ ] . understanding the determinants of icu outcome is crucial both for surge planning and shared decision making with patients and relatives. whilst a number of risk scores have been published [ ] they do not specifically look at this population. furthermore, icu availability, admission policy and structure varies substantially across europe [ ] as do population demographics and government policy for surveillance and containment. as a result, it is likely that icu outcomes could vary significantly from region to region which motivates an individualised approach to modelling. the uk, where cases are still rising, is of particular concern as recent reports suggest mortality may prove be particularly high. to this end, we sought to identify predictors of mortality in patients admitted to the icu with covid- . we obtained de-identified covid- hospitalisation in england surveillance system (chess) data from public health england (phe) for the period from th february (data collection start) to th april ( , cases icu cases- deaths, discharges from nhs trusts across england). we used a cox proportional hazards mixed-e↵ects model for mortality, with the nhs trust as the random e↵ect. predictors were normalised. the estimated coecients associated with each predictor are shown in figure . immunosuppression, chronic renal disease and age were key predictors of mortality. in comparison with these fixed e↵ects, the magnitude of the between-centre variation (log hazard ratio varying between - to + ) is greater even the strongest fixed e↵ects predictors. the cause of such between-centre variation is unclear and may have a variety of case-mix, severity or structural explanations. in particular, icu demand varies both regionally and locally and we may hypothesize that high levels of strain or constraints on surge capacity could be actionable determinants, although we do not have data to examine this. such considerations are important to understand as they may influence optimal configuration or transfer considerations locally. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . in an attempt to create an analysis on a timescale which is actionable, we have built this model on early data which inevitably su↵ers from incomplete ascertainment, particularly before approx th march . furthermore the earlier deaths in the elderly group may result in some lead time bias due to censoring and we cannot track outcomes on patients who are transferred. nevertheless, the magnitude of the random e↵ects is striking. this motivates urgent comparative e↵ectiveness research to better characterise between-centre di↵erences in outcome which may inform best practice in surge situations both in england and elsewhere. clinical characteristics of imported cases of covid- in jiangsu province: a multicenter descriptive study baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region prediction models for diagnosis and prognosis of covid- infection: systematic review and critical appraisal the variability of critical care bed numbers in europe we would like to acknowledge public health england for providing us access to the chess dataset. in particular, we would like to acknowledge anees pari and geraldine linehan for their support. none to declare. not externally funded. ae and mvds conceived of and supervised the study. zq and ama coded the statistical models. all authors contributed to the manuscript. key: cord- -zpq byml authors: poulsen, nadia nicholine; von brunn, albrecht; hornum, mads; blomberg jensen, martin title: cyclosporine and covid‐ : risk or favorable? date: - - journal: am j transplant doi: . /ajt. sha: doc_id: cord_uid: zpq byml the coronavirus disease (covid‐ ) pandemic is declared a global health emergency. covid‐ is triggered by a novel coronavirus: severe acute respiratory syndrome coronavirus (sars‐cov ). baseline characteristics of admitted patients with covid‐ show that adiposity, diabetes and hypertension are risk factors for developing severe disease, but so far immunosuppressed patients that are listed as high‐risk patients have not been more susceptible to severe covid‐ than the rest of the population. multiple clinical trials are currently being conducted, which hopefully can identify more drugs that can lower mortality, morbidity and burden on the society. several independent studies have convincingly shown that cyclosporine inhibit replication of several different coronaviruses in vitro. the cyclosporine‐analog alisporivir has recently been shown to inhibit sars‐cov in vitro. these findings are intriguing, although there is no clinical evidence for a protective effect to reduce the likelihood of severe covid‐ or to treat the immune storm or adult respiratory distress syndrome (ards) that often causes severe morbidity. here, we review the putative link between covid‐ and cyclosporine, while we await more robust clinical data. in recent months the corona virus disease (covid- ) pandemic has stressed health care systems worldwide and the world health organization has declared it a global health emergency. patients treated with immunosuppressive treatment e.g. due to organ transplantation or autoimmune disease are instructed to isolate at home because of a presumed higher risk of more serious disease and possible death. covid- is triggered by a novel coronavirus identified in december in wuhan china and has been named severe acute respiratory syndrome coronavirus (sars-cov ). two drugs have shown promising effect on covid- patients, remdesivir proved in a recent trial to reduce time to recovery, but had no effect on mortality . dexamethasone has in a preprint shown to reduce -day mortality in a subgroup of patients . dexamethasone and remdesivir obviously targets covid- differently, which highlights that the pathogenesis of the disease is complex. sars-cov induces a variety of symptoms such as fever, myalgia, dry cough, loss of smell and in some patients progress to a more severe disease requiring admittance to intensive care units (icu). the first clinical characteristics from china showed that a more severe disease outcome defined as need for icu admittance or death was associated with presence of comorbidities particularly diabetes, obesity, hypertension, cardiovascular disease and chronic kidney disease [ ] [ ] [ ] [ ] [ ] . there exist only very limited data on disease severity in transplanted patients treated with calcineurin inhibitors in combination with other drugs such as prednisolone or mycophenolate mofetil. however, the first sparse available data indicates that transplanted patients have no increased risk of severe disease despite of multiple and diverse comorbidities. li et al report of two cases of covid- in heart transplant recipients. one had severe disease and both patients recovered. in two heart transplant recipients with covid- in the us, one patient died from multiorgan failure and the other patient had mild disease and were discharged on day eight . in four kidney transplant recipients from wuhan, china it was stated that all patients benefitted from reduction of immunosuppressants, since all four patients had mild disease . a years old covid- patient in spain, treated with tacrolimus due to previous kidney transplantation needed treatment in the icu on day . these early case reports have now been supported by three cohort studies from transplanted patients in europe - . in a study from spain, kidney transplant recipients with covid- were evaluated. one group of patients (n= ) were reduced in calcineurin inhibitor dose and the second group (n= ) either continued their usual cyclosporine dose or were switched from tacrolimus to cyclosporine. the first group had a mortality of % and the second group only . % thus supporting the idea that continuous use of cyclosporine might be beneficial in covid- patients. however, the study is observational and not a blinded randomized clinical trial (rct) and both groups were also treated with multiple non-protocolized drugs: two thirds of this article is protected by copyright. all rights reserved the patients were given high dose steroid, one third were given intravenous immunoglobulin, one third an il- inhibitor and all patients were given hydroxychloroquine, thus making it difficult to draw definite clinically conclusions from these interesting observations from rodriguez-cubillo and colleagues . the transplantation society currently recommend close attention to patients with medication-induced lymphopenia, but no specific instructions on anti-rejection regimen exist due to current lack of evidence . romanelli et al. have suggested that clinicians must consider to pause immunosuppressants in transplanted patients with covid- , which is a common strategy in transplanted patients with infections. this suggestion may in part be based on data from the epidemic of middle east respiratory syndrome (mers) as some case reports of kidney transplant recipients infected with mers died , . the above-listed covid- clinical observations may be premature, but they all indicate that immunosuppression and use of calcineurin inhibitors impose no increased risk for severe disease, and we speculate that calcineurin inhibitors may protect from severe disease and ultimately death because transplanted patients often have a high prevalence of other risk factors such as hypertension, diabetes and obesity. however, there may exist other explanations to why covid- seems to be mitigated in transplant recipients e.g that this patient group is particular compliant to hygiene recommendations and preventive measures. another explanation could be the easier access to hospitals and thus increasing numbers of detected covid- infected with mild symptoms, which would otherwise not be found in the general population thus diluting the case fatality rate. computational methods looking into host-virus interactions and possible antiviral drug targets with repurposed drugs suggests tacrolimus among others as a potential drug against covid- , . a letter by russel et al suggests that there is tantalizing in vitro evidence for cyclosporine as an anti-coronavirus agent as well as a potential disease-modifying role through inhibition of severe acute respiratory syndrome (sars) coronavirus-mediated il- induction and authors advocate that a trial of cyclosporine should be considered in the event of a future sars epidemic . these promising pilot data require appropriate power in larger studies before immunosuppression can be considered a low risk or maybe even protective for severe covid- but here we review how cyclosporine may influence covid- . six coronaviruses have previously been shown to cause human disease but four of these are considered low pathogenic coronaviruses ( e, hku , oc and nl ) that causes mild upper respiratory tract infections , in contrast to the highly pathogenic β-coronaviruses: severe acute respiratory syndrome- this article is protected by copyright. all rights reserved sars-cov is also a β-coronavirus, it shares % homology with sars , and has % sequence identity with bat coronavirus (batcov ratg ) [ ] [ ] [ ] . to understand the pathogenesis of covid- it is important to discriminate between the tissue damage induced by the pathogen and the indirect and later effects caused by the immune response, which on one hand is required in order to eradicate the virus but also may induce significant organ damage. the main target for sars-cov is the lungs like sars. severe pneumonia develops and is often associated with massive inflammatory cell infiltration (lymphocytes, macrophages, neutrophils) and elevated proinflammatory cytokine/chemokine responses resulting in acute lung injury and ards . the incubation period of sars-cov is typically - days before the patients present with fever, cough, dyspnea, fatigue and myalgia , - , which may be accompanied by rhinorrhoea, pharyngalgia, anosmia, ageusia and diarrhea . the high frequency of ards may be the cause for admittance to icu but other studies investigating hospitalized patients with no icu admittance report ards in - % of all hospitalized patients , and a case fatality rate of . - . % , . early data from china showed a mortality rate of - % among hospitalized patients , , . the late but typically abrupt onset of severe covid- with hypoxemia and dyspnea requires hospital admission and some rapidly progressed to ards that eventually would lead to septic shock, metabolic acidosis, coagulation dysfunction, and multiple organ dysfunction syndrome , , . it remains to be shown if these symptoms are similar or reduced in immunocompromised patients due to inhibition of the cytokine response as previously shown for parainfluenza virus . data from solid organ transplant recipients from switzerland showed almost similar clinical presentation, however, remarkably the severity and complication rates were not higher than in the general population with % developing ards, . % died and % needed icu admission . another spanish study including kidney transplant recipients showed that % were admitted to icu, % needed mechanical ventilation and % died . the study this article is protected by copyright. all rights reserved concluded that the severity of covid- was not different in immune compromised patients. although these findings are in opposition to a small american cohort study reporting more severe outcome in transplant recipients with % icu admission and % death of hospitalized cases . severity of covid- is related to the onset of lower respiratory tract disease and pneumonia that typically occur - days after onset. this seems slightly delayed compared with influenza virus pneumonia , , . lymphocytopenia has been suggested to be a negative predictor of disease progression and prognosis, while newer data suggest that elevated d-dimer, crp, viral load and low albumin are poor prognostic signs. none of these markers have been reproduced consistently and they all need to be validated in larger ongoing clinical trials. the most common finding on ct scan was bilateral pneumonia and ground-glass opacities that were associated with more severe disease manifestations. other radiological findings such as interlobular septal thickening, pulmonary consolidations and the so called white lung due to atelectasis and pleural effusion were also associated with severe covid- , . a comprehensive chinese study showed that older age and lower cd -t-cell count were associated with icu-admission and ards, and highly elevated interleukin- (il- ) levels in icu patients was suggestive of a cytokine storm and an inappropriate host-inflammatory response in patients with severe disease . indeed, patients admitted to the icu had higher levels of numerous cytokines when compared to patients not in the icu . it has been speculated that the reason why children has less severe disease during this pandemic is because of the role of the thymus gland and thus the difference in cytokine expression . on the other hand, the overactive immune reaction may be due to impaired viral clearance again highlighting that appropriate immune system activity is required at all times. postmortem studies of covid- patients showed diffuse alveolar damage, cellular fibromyxoid exudates, desquamation of pneumocytes and hyaline membranes in the lung equivalent to ards , . they also report of a hyperactive state with overactivated t-cells and suggest that most of the lung injury seems to be caused by severe immune injury. the outbreak of sars, mers and now covid- has demonstrated human vulnerability to coronavirus epidemics. neither vaccines nor therapeutics are available against human or animal coronaviruses and most of the drugs used in ongoing clinical trials to treat covid- have been selected because they repress coronavirus replication in vitro. one of the consequences of the sars epidemic was an increase in this article is protected by copyright. all rights reserved efforts to understand coronavirus replication and identify additional possible targets for anti-viral therapy including calcineurin . pfefferle et al investigated coronavirus-host interactions using a genome-wide yeast-two hybrid screening and identified the coronavirus non-structural protein (nsp- ) and several immunophilins as important in virus-host response and luo et al report that the nucleocapsid protein of sars-cov bind to cyclophilin a. cyclosporine and tacrolimus are the most used calcineurin inhibitors in daily clinical practice for prevention of alloimmune response in transplantation , . both compounds suppress the immune system and the main action is prevention of interleukin- (il- ) production in t cells . cyclosporine and tacrolimus are chemically distinct molecules that bind to the intracellular immunophilins cyclophilin [ ] [ ] [ ] [ ] and fk binding protein (fkbp)- ng/ml [ ] [ ] [ ] . this implies that the dosage used to treat most patients with cyclosporine is too low to effectively eradicate the virus. one of the challenges is to obtain sufficient tissue concentration, as the main virus load is in the airways and lungs and not in serum and the concentration of cyclosporine in the lungs is lower than in serum. moreover, the required dosage for actively treating patients with severe covid- would be - fold higher, which in turn would cause severe adverse and possible toxic effects especially nephrotoxicity , . moreover, the free available fraction and particularly the local tissue concentration of cyclosporine in the lungs would be too low to induce a substantial inhibition of virus replication. peak concentration in serum cyclosporine could in theory reach levels that approximate antiviral concentrations but the only way to reach high local tissue concentrations would be through cyclosporine inhalation. inhaled cyclosporine has been tested in animals , healthy volunteers and lung transplant recipients , and the lung concentration of inhaled cyclosporine is three times higher than when systemically administered . it is generally well tolerated although a few cases of transient reduced forced expiratory volume in the first second (fev ) following inhalation, has been reported. inhaled cyclosporine is not available as routine treatment and cannot be advised at this moment for covid- patients as there is no human in vivo proof of an antiviral effect. the immunonephrology working group of the european renal association-european dialysis and transplant association has published recommendations for the management of patients with immune-mediated kidney disease during this current pandemic, and authors point out that patients with mild covid- might continue low dose of cyclosporine due to the in vitro evidence of inhibition of coronavirus replication . moreover, a recent comment supports the idea that cyclosporine might be the drug-of-choice during the covid- pandemic for kidney transplant recipient due to the in vitro evidence and thus providing an "old" alternative to the routine rejection regimens . however, rejection rates are higher in patients on cyclosporine compared to tacrolimus in kidney , heart and liver transplant recipients . the defining evidence would be to investigate cyclosporine treatment in hospitalized patients with covid- . there is reason to believe that it would be safe to treat this patient group with low dose cyclosporine (< mg/kg). previous studies have shown, that cyclosporine is safe to use in critically ill patients with severe infections, inflammatory diseases and even circulatory vulnerable patients, and high-accepted article dose cyclosporine ( . - . mg/kg) is well tolerated in steroid-refractory ulcerative colitis . moreover, a meta-analysis showed that cyclosporine had a beneficial effect on mortality for stevens-johnson syndrome and toxic epidermal necrolysis where rapid onset of treatment response as in covid- is warranted. in a randomized, double-blinded, placebo-controlled trial cyclosporine improved lung function when given to severe asthma patients for months and significantly lowered exacerbation rate compared to the placebo group and was well tolerated in patients with severe asthma . in a multicenter, doubleblind, randomized trial of bolus injection of cyclosporine was tested in patients with an acute anterior stsegment elevation myocardial infarction (stemi) who were undergoing primary percutaneous coronary intervention. cyclosporine did not result in improved clinical outcomes compared to placebo, however interestingly the authors did not find any significant difference in the safety profile between the two treatment groups thus indicating that cyclosporine treatment in these circulatory unstable patients was well tolerated . in a randomized controlled trial of cyclosporine plus intravenous immunoglobulin (ivig) treatment or ivig alone to children with kawasaki disease found that combined treatment with cyclosporine and ivig reduced the incidence of coronary artery abnormalities. authors report no difference of adverse effects in the two groups and concludes that cyclosporine treatment is safe and well tolerated . this is of particular interest due to the observed increased incidence of kawasaki disease during the covid- pandemic . one case report from japan of a year old boy with a mycoplasma pneumoniae lung abscess with laboratory indication of cytokine storm was treated with cyclosporine which suppressed the hypercytokinemia . based on the presented findings, all of these studies show that cyclosporine is safe to give to a broad range of critical ill patients and we believe that it is safe to investigate cyclosporine in a placebo or dexamethasone controlled trial of covid- patients requiring admittance to hospital. we cannot recommend switching anti-rejection regimen during covid- , as the available data reviewed here is not sufficient to recommend replacing tacrolimus with cyclosporine during severe covid- . however, we do suggest that revised guidelines should recommend continuing cyclosporine to patients during covid- except in cases of renal failure, severe leucopenia or high serum cyclosporine levels. a switch from tacrolimus to cyclosporine would at this point be based purely on positive observational data with a putative benefit for covid- morbidity but with a possible higher risk of rejection and we warrant controlled studies to test whether this switch is advisable or not. this article is protected by copyright. all rights reserved remdesivir and dexamethasone are the only drugs available with proven effect on covid- , although more efficient therapy is warranted and most patients are still only receiving supportive care including oxygen and empirical antibiotic therapy to prevent secondary infections. currently, more than new clinical trials are registered at clinicaltrials.org testing various treatments e.g. ace-inhibitors, serine protease inhibitors, il- inhibitors, jak-inhibitors, interferons, antivirals or azithromycin. to the best of our knowledge no clinical controlled trial is being conducted to test the effect of any calcineurin inhibitor. several groups have found in vitro evidence of cyclosporine mediated inhibition of replication of several coronaviruses including severe acute respiratory syndrome-cov (sars) and middle east respiratory syndrome cov (mers) and the cyclosporine-analog alisporivir inhibits sars-cov in vitro. due to the limited number of patients and quickly contained sars and mers epidemics, these compounds have never been tested in a clinical setting before. we are still awaiting robust data from covid- patients actively treated with calcineurin inhibitors due to transplantation or autoimmune diseases but so far there is no evidence that use of cyclosporine possess an additional risk for severe covid- in addition to the co-morbidities such as diabetes, smoking, hypertension and obesity that often co-exist in these patients. more controversial but not less intriguing is the putative impact of cyclosporine on severe covid- , which ultimately should be tested in a rct in hospitalized patients during this current pandemic to determine whether cyclosporine could reduce the need for icu admittance and high oxygen demand. the authors of this manuscript have no conflicts of interest to disclose as described by the american journal of transplantation. remdesivir for the treatment of covid- -preliminary report effect of dexamethasone in hospitalized patients with covid- : preliminary report. medrxiv are patients with hypertension and diabetes mellitus at increased risk for covid- infection? clinical features of patients infected with novel coronavirus in wuhan asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus (sars-cov- ): facts and myths coronavirus -ncov: a brief perspective from the front line kidney disease is associated with in-hospital death of patients with covid- first cases of covid- in heart transplantation from china. j hear lung transplant early experience of covid- in two heart transplant recipients: case reports and review of treatment options identification of kidney transplant recipients with coronavirus disease case report of covid- in a kidney transplant recipient: does immunosuppression alter the clinical presentation? accepted article this article is protected by copyright. all rights reserved preliminary data on outcomes of sars-cov- infection in a spanish single centre cohort of kidney recipients first experience of sars-cov- infections in solid organ transplant recipients in the swiss transplant cohort study clinical outcome in solid organ transplant recipients with covid- : a single-center experience should cyclosporine be useful in renal transplant recipients affected by sars-cov- ? covid- ) for transplant clinicians crucial aspects of the management of solid organ transplant patient with covid- : a narrative review mers cov infection in two renal transplant recipients: case report clinical features and viral diagnosis of two cases of infection with middle east respiratory syndrome coronavirus: a report of nosocomial transmission a sars-cov- protein interaction map reveals targets for drug repurposing drug repurposing for new, efficient, broad spectrum antivirals cyclosporine has a potential role in the treatment of sars all rights reserved . channappanavar r, perlman s. pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology a novel coronavirus associated with severe acute respiratory syndrome identification of a novel coronavirus in patients with severe acute respiratory syndrome coronavirus infections and immune responses update related to the current outbreak of covid- genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding a pneumonia outbreak associated with a new coronavirus of probable bat origin fullgenome evolutionary analysis of the novel corona virus ( -ncov) rejects the hypothesis of emergence as a result of a recent recombination event genomic characterization of the novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting wuhan clinical characteristics of coronavirus disease in china imaging and clinical features of patients with epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china clinical progression of patients with covid- in shanghai respiratory virus infection among hematopoietic cell transplant recipients: evidence for asymptomatic parainfluenza virus infection covid- in solid organ transplant recipients: initial report from the us epicenter community respiratory virus infections in immunocompromised patients: hematopoietic stem cell and solid organ transplant recipients, and individuals with human immunodeficiency virus infection. semin respir crit care med respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center ct manifestations of coronavirus disease- : a retrospective analysis of cases by disease severity current scenario of covid- in pediatric age group and physiology of immune and thymus response accepted article this article is protected by copyright pathological findings of covid- associated with acute respiratory distress syndrome postmortem examination of patients with covid- coronaviruses post-sars: update on replication and pathogenesis the sars-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors nucleocapsid protein of sars coronavirus tightly binds to human cyclophilin a cyclosporin a in patients receiving renal allografts from cadaver donors fk for liver, kidney, and pancreas transplantation mechanisms of action of cyclosporine cyclophilins and cyclophilin inhibitors in nidovirus replication host factors in coronavirus replication suppression of coronavirus replication by cyclophilin inhibitors the mechanism of action of cyclosporin a and fk emerging picture of host chaperone and cyclophilin roles in rna virus replication drugs to cure avian influenza infection multiple ways to prevent cell death calcineurin-nfat signalling in myeloid leucocytes: new prospects and pitfalls in immunosuppressive therapy replication of human coronaviruses sars-cov, hcov-nl and hcov- e is inhibited by the drug fk human coronavirus nl replication is cyclophilin a-dependent and inhibited by non-immunosuppressive cyclosporine a-derivatives including alisporivir influences of cyclosporin a and non-immunosuppressive derivatives on cellular cyclophilins and viral nucleocapsid protein during human coronavirus e replication genetic deficiency and polymorphisms of cyclophilin a reveal its essential role for human coronavirus e replication cyclosporin a inhibits the replication of diverse coronaviruses cyclophilin inhibitors block arterivirus replication by interfering with viral rna synthesis mers-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin a or interferon-α treatment accepted article this article is protected by copyright. all rights reserved effect of interferon alpha and cyclosporine treatment separately and in combination on middle east respiratory syndrome coronavirus (mers-cov) replication in a human in-vitro and ex-vivo culture model alisporivir inhibits mers-and sarscoronavirus replication in cell culture, but not sars-coronavirus infection in a mouse model sars-coronavirus- replication in vero e cells: replication kinetics, rapid adaptation and cytopathology inhibition of sars-cov- infection by the cyclophilin inhibitor alisporivir (debio ) in vivo effects of cyclosporine on influenza a virus-infected mice the cyclophilin inhibitor debio- shows potent anti-hepatitis c effect in patients coinfected with hepatitis c and human immunodeficiency virus the cyclophilin inhibitor scy- suppresses viral replication and induces endogenous interferons in patients with chronic hcv genotype infection safety, pharmacokinetics, and antiviral activity of the cyclophilin inhibitor nim alone or in combination with pegylated interferon in hcv-infected patients receiving days of therapy the role of immunophilins in viral infection an overview of immunosuppression in solid organ transplantation therapeutic monitoring of calcineurin inhibitors for the nephrologist decline in cr-labelled edta measured glomerular filtration rate following lung transplantation calcineurin inhibitor nephrotoxicity in the lung aerosol cyclosporine provides a regional concentration advantage over intramuscular cyclosporine a randomized trial of inhaled cyclosporine in lungtransplant recipients a randomised single-centre trial of inhaled liposomal cyclosporine for bronchiolitis obliterans syndrome post-lung transplantation recommendations for the management of patients with immune-mediated kidney disease during the severe acute respiratory syndrome coronavirus pandemic covid- : implications for immunosuppression in kidney disease and transplantation reduced exposure to calcineurin inhibitors in renal transplantation tacrolimus versus cyclosporine microemulsion for heart transplant recipients: a meta-analysis cyclosporin versus tacrolimus as primary immunosuppressant after liver transplantation: a meta-analysis the use of cyclosporin a in acute steroid-refractory ulcerative colitis: long term outcomes systemic immunomodulating therapies for stevens-johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis trial of cyclosporin in corticosteroid-dependent chronic severe asthma cyclosporine before pci in patients with acute myocardial infarction efficacy of primary treatment with immunoglobulin plus ciclosporin for prevention of coronary artery abnormalities in patients with kawasaki disease predicted to be at increased risk of non-response to intravenous immunoglobulin (kaica): a randomised cont an outbreak of severe kawasaki-like disease at the italian epicentre of the sars-cov- epidemic: an observational cohort study lung abscess caused by mycoplasma pneumoniae nucleocapsid/nsp -cyclophillin coronavirus replication this article is protected by copyright. all rights reserved this article is protected by copyright. all rights reserved key: cord- -wz u e authors: fernandez, javier; gratacos-ginès, jordi; olivas, pol; costa, montserrat; nieto, susana; mateo, dolors; sánchez, maría belén; aguilar, ferran; bassegoda, octavi; ruiz, pablo; caballol, berta; pocurull, anna; llach, joan; mustieles, maría jesús; cid, joan; reverter, enric; toapanta, nestor david; hernández-tejero, maría; martínez, josé antonio; claria, joan; fernández, carlos; mensa, josé; arroyo, vicente; castro, pedro; lozano, miquel title: plasma exchange: an effective rescue therapy in critically ill patients with coronavirus disease infection date: - - journal: crit care med doi: . /ccm. sha: doc_id: cord_uid: wz u e infection by severe acute respiratory syndrome coronavirus- can induce uncontrolled systemic inflammation and multiple organ failure. the aim of this study was to evaluate if plasma exchange, through the removal of circulating mediators, can be used as rescue therapy in these patients. design: single center case series. setting: local study. subjects: four critically ill adults with coronavirus disease pneumonia that failed conventional interventions. interventions: plasma exchange. two to six sessions ( . plasma volumes). human albumin ( %) was used as the main replacement fluid. fresh frozen plasma and immunoglobulins were administered after each session to avoid coagulopathy and hypogammaglobulinemia. measurements and main results: serum markers of inflammation and macrophage activation. all patients showed a dramatic reduction in inflammatory markers, including the main cytokines, and improved severity scores after plasma exchange. all survived to icu admission. conclusions: plasma exchange mitigates cytokine storm, reverses organ failure, and could improve survival in critically ill patients with coronavirus disease infection. s ome patients affected by coronavirus disease (covid- ) develop severe inflammation and progressive organ failure that threaten survival. laboratory tests in these patients usually show elevation of inflammatory and coagulation markers (c-reactive protein [crp] , d-dimer) and data of macrophage activation (elevation of triglycerides, lactate dehydrogenase [ldh] , and ferritin) ( ) ( ) ( ) ( ) . corticosteroids and other immunosuppressive agents have been proposed in this setting ( ) ( ) ( ) ( ) ( ) ( ) . however, some patients do not respond to this therapy and develop multiple organ failure. therapeutic plasma exchange removes endogenous and exogenous inducers of the systemic inflammatory response (pathogen-associated molecular pattern and damage-associated molecular pattern) and proinflammatory mediators (cytokines and reactive oxygen species) that are involved in the pathogenesis of organ failure ( ) . sporadic case reports suggest that therapeutic plasma exchange can be an effective rescue therapy in patients with hemophagocytic lymphohistiocytosis ( ) or severe influenza a (h n ) infection ( ) . we report a case series of four critically ill patients infected by severe acute respiratory syndrome coronavirus www.ccmjournal.org xxx • volume xx • number xxx (sars-cov- ) successfully treated with plasma exchange. therapeutic plasma exchange, two to six sessions, was performed with % albumin as the main replacement fluid ( / ). fresh frozen plasma (ffp) was used ( / ) at the end of the plasma exchange to avoid coagulopathy. iv immunoglobulin (ivig) was administered after each session ( mg/kg) to prevent the hypogammaglobulinemia induced by the procedure. a -year-old man with obesity, hypertension, and type diabetes was admitted to the hospital with fever and cough for week and progressive shortness of breath within the previous hours. oxygen saturation was % (fio %). laboratory tests indicated the following: serum crp . mg/dl, creatinine . mg/dl, ldh u/l, triglycerides mg/dl, ferritin , ng/ml, and d-dimer of , ng/ml. apart from lymphopenia ( . × ^ /l), blood cell counts were normal, as well as procalcitonin levels and coagulation variables (supplementary table , supplemental digital content , http://links.lww.com/ ccm/f ). arterial blood gases showed a pao of . mm hg, and chest radiograph revealed bilateral lung infiltrates. polymerase chain reaction (pcr) for sars-cov- in nasopharyngeal smear was positive. lopinavir/ritonavir, hydroxychloroquine, interferon beta- a, ceftriaxone, and linezolid were started. on day of hospitalization, the patient was admitted to the icu due to progressive respiratory failure and required orotracheal intubation and mechanical ventilation. after intubation, norepinephrine was started. echocardiography disclosed mild ventricular dysfunction. troponin levels were normal. deep sedation and muscle relaxation were required in the first hours after intubation due to severe hypoxemia (pafio : ) and poor adaptation to the ventilator. tocilizumab ( mg) was administered on days and of icu admission. tracheotomy was performed week after intubation. on day , he presented with high fever ( °c), sinus tachycardia with frequency-dependent left bundle branch block, and stage acute kidney injury (aki; creatinine: . mg/dl). mild cardiac hypomotility persisted at echocardiography. inflammatory and macrophage activation parameters increased markedly ( fig. table , supplemental digital content , http://links.lww.com/ ccm/f ). cultures and body ct-scan ruled out bacterial or fungal infection or pulmonary thromboembolism. upon suspicion of hyperinflammatory state due to cytokine storm and macrophage activation like syndrome, therapeutic plasma exchange was started on day . four sessions were performed following an every other day schedule (days , , , and ). the plasma volume exchanged by session was , ml. the patient condition improved in the following days: fever resolved days following the fourth session of plasma exchange (day ), renal, cardiac, and respiratory function normalized, and laboratory findings showed sustained improvement ( fig. table , supplemental digital content , http://links.lww.com/ccm/f ). plasma levels of most of the main cytokines decreased markedly after therapeutic plasma exchange (fig. ) . severe myopathy and catheter-related infection by klebsiella pneumoniae days after finishing plasma exchange were the most relevant problems during the rest of icu stay. on day , he was decannulated. the patient was discharged from the icu and from the hospital on days and , respectively. a -year-old man was admitted to the hospital for a -day course of cough, fever, asthenia, and diarrhea. his medical history revealed a liver transplantation in treated with mycophenolate until current hospitalization, hypertension, insulin-dependent diabetes, and chronic kidney disease (creatinine . mg/dl). physical examination at admission was unremarkable except for lung basal crackles. oxygen saturation at that time was % at fio %. arterial blood gases demonstrated a pao of . mm hg, and chest radiograph showed bilateral lung infiltrates. laboratory findings were as follows: crp . mg/dl, creatinine . mg/dl, ldh u/l, triglycerides mg/dl, ferritin , ng/ml, d-dimer , ng/ml. lymphopenia ( . × ^ /l) was also present (supplementary table , supplemental digital content , http://links.lww.com/ccm/f ). pcr for sars-cov- in nasopharyngeal smear was positive. he was started on lopinavir/ritonavir, hydroxychloroquine, azithromycin, ceftriaxone, and teicoplanin. twenty-four hours after admission, the patient developed progressive respiratory failure. in this setting, he was admitted to the icu and required invasive mechanical ventilation. after intubation, norepinephrine was started. an echocardiography disclosed moderate ventricular dysfunction suggestive of myocarditis. troponin levels were , ng/l. anakinra and stress dose hydrocortisone were started. although respiratory requirements improved over the next days, his overall condition worsened. he had persistent high fever without microbiological isolations and developed stage aki in the setting of persistent cardiac dysfunction. serum markers of inflammation and macrophage activation remained high or worsened ( fig. table , supplemental digital content , http://links.lww.com/ccm/f ). tracheotomy was performed days after icu admission. in this setting, therapeutic plasma exchange was started on day of icu stay. only two sessions were performed due to moderate ffp transfusion reaction at the end of the second session (tachycardia, hypotension requiring an increase in norepinephrine doses, maculopapular rash, and increased leukocyte count). these two sessions were performed in consecutive days. the plasma volume exchanged by session was , ml. patient clinical condition improved hours after the last session. fever resolved, cardiac and renal function normalized in few days, and regular laboratory tests ( fig. table , supplemental digital content , http://links.lww.com/ccm/f ) and plasma cytokines also improved (fig. ) . the patient was decannulated days after icu admission and was discharged from the icu and from the hospital on days and , respectively. a -year-old man with obesity and hypertension was admitted to the hospital with bilateral lumbar pain for days and diarrhea and loss of sensitivity and strength in the legs within the last hours. at admission, he had fever ( °c) and was diaphoretic, tachycardic, tachypneic, and hypotensive. oxygen saturation at that time was % at fio %. laboratory test showed crp . mg/ dl, procalcitonin . ng/ml, creatinine . mg/dl, ldh u/l, ferritin , ng/ml, troponin . ng/l, lactate . mg/dl, and d-dimer greater than . ng/ml (supplementary table , supplemental digital content , http://links.lww. com/ccm/f ). blood cell counts disclosed leukocytosis and thrombocytopenia ( . and . × /l, respectively). echocardiogram was normal. an angio-ct-scan showed bilateral infiltrates suggestive of covid- pneumonia, lobar and segmental acute right pulmonary thromboembolism, and multiple nonocclusive arterial thrombosis in distal aortic arch, splenic artery, aortoiliac bifurcation, iliac arteries, and right femoral artery. pcr for sars-cov- in nasopharyngeal swab was positive. the patient was admitted to the icu for respiratory (high flow nasal cannula) and vasopressor support (norepinephrine: . ug/ kg/min). he was started on lopinavir/ritonavir, hydroxychloroquine, azithromycin, and piperacillin-tazobactam. iv dexamethasone and heparin sodium infusion were also initiated. after initial improvement, the patient presented symptoms of acute limb ischemia on day and required urgent bilateral transpopliteal embolectomy. screen for thrombophilia factors identified positive immunoglobulin g (igg) anticardiolipin serum antibodies. on day , catastrophic antiphospholipid syndrome was diagnosed and table , supplemental digital content , http://links.lww. com/ccm/f ) and plasma cytokines levels (fig. ) decreased markedly. the patient was discharged from hospital days after admission on steroid and low molecular weight heparin therapy. no more thrombotic events were observed. a -year-old man with alcoholic liver cirrhosis, hypertension, and type diabetes was admitted to the hospital with fever ( . °c) for days. pcr for sars-cov- in nasopharyngeal swab was positive. treatment with lopinavir/ritonavir, hydroxychloroquine, azithromycin, interferon beta- a, ceftriaxone, and teicoplanin was started. four days after hospital admission, he presented progressive respiratory failure (oxygen saturation of % at fio %) and was admitted to the icu for invasive mechanical ventilation. chest radiograph showed bilateral lung infiltrates. at that time, laboratory test disclosed crp . mg/ dl, creatinine . mg/dl, ldh u/l, ferritin ng/ml, and d-dimer ng/ml (supplementary table , supplemental digital content , http://links.lww.com/ccm/f ). in this setting, methylprednisolone was started ( mg/d for d). nine days after icu admission, a tracheostomy was performed. however, days later, the patient developed grade hepatic encephalopathy and stage aki. laboratory tests also showed an increase in inflammatory and coagulation markers (wbc, crp, ferritin, and d-dimer) and deterioration of liver function (serum bilirubin . mg/dl, international normalized ratio . ). abdominal doppler ultrasonography ruled out vascular complications. test for hepatotropic virus were negative except for herpes (pcr in blood was weakly positive). with the orientation of an acute on chronic liver failure triggered by sars-cov- , therapeutic plasma exchange was started days after icu admission. the plasma volume exchanged by session was , ml. after completing three sessions performed on days , , and , liver (bilirubin . mg/dl, inr . ) and renal function improved, hepatic encephalopathy resolved, and inflammatory variables normalized (fig. ) innate and adaptative responses that may lead to tissue damage and multiple organ failure ( , ( ) ( ) ( ) ) . high serum levels of proinflammatory cytokines (tumor necrosis factor [tnf]-alpha, interleukin [il]- , il- , il- , il- , granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor) and chemokines (monocyte chemoattractant protein- , macrophage inflammatory protein -alpha, il- , interferon gamma-induced protein ) have been reported in patients with severe acute respiratory syndrome ( ) , middle east respiratory syndrome (mers) ( ) , and also in severe covid- ( , ) . macrophage activation syndrome may also occur ( ). therapeutic plasma exchange removes inflammatory mediators from the systemic circulation and could ameliorate this covid- -related cytokine storm and immunopathology, a hypothesis that has not been evaluated so far. our small case series supports this contention and suggests that plasma exchange combined to iv igg is an effective salvage therapy in patients with covid- pneumonia requiring critical care. three of our patients presented multiple organ failure despite having received conventional therapies that included antiviral and anti-inflammatory drugs. furthermore, two of them had analytical and clinical data of macrophage activation like syndrome. the initiation of therapeutic plasma exchange was temporarily associated with a marked clinical improvement with resolution of fever, improvement of renal and vascular function, decrease in sequential organ failure assessment and acute physiology and chronic health evaluation scores, and amelioration of inflammatory markers including variables of macrophage activation such as serum ferritin and triglyceride. a fourth patient was treated with therapeutic plasma exchange due to a catastrophic antiphospholipid syndrome induced by sars-cov- that was refractory to anticoagulation. importantly, systemic inflammatory markers decreased, and thrombotic events definitively resolved. our study also suggests that critically ill covid- patients show an hyperinflammatory state that can be mitigated by therapeutic plasma exchange. plasma levels of tnf-alpha and of other proinflammatory cytokines and chemokines were extremely high in samples taken before plasma exchange. this treatment effectively decreased levels of the great majority of cytokines and chemokines, therefore attenuating cytokine storm. it is important to remark that therapeutic plasma exchange was performed in our four patients using % albumin as the main replacement fluid. albumin is the main transporter and the main antioxidant and free-radical scavenger of human plasma ( ) . ffp was administered at the end of each session to prevent coagulopathy. ivigs were also administered after each session to prevent the development of hypogammaglobulinemia. this apheresis approach was safe with just one patient developing a moderate transfusion reaction related with ffp infusion. in summary, our small case series suggests that therapeutic plasma exchange is an effective recue therapy in critically ill patients with covid- infection who do not respond to conventional therapies. this treatment was safe, ameliorated cytokine storm, reversed organ failure, and improved survival in very severe covid- patients. a randomized controlled trial, the recambio plasmatico (rep)-covid (clinicaltrials. gov identifier: nct ), is currently ongoing to confirm or reject our hypothesis. dr. sanchez disclosed work for hire. dr. reverter disclosed off-label product use of plasma exchange. dr. arroyo received funding from grifols. dr. lozano's institution received funding from terumo bct and received funding from grifols and cerus. the remaining authors have disclosed that they do not have any potential conflicts of interest. for information regarding this article, e-mail: jfdez@clinic.cat. clinical features of patients infected with novel coronavirus in wuhan, china risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus diwww.ccmjournal.org xxx • volume xx • number xxx sease pneumonia in wuhan, china the role of cytokines including interleukin- in covid- induced pneumonia and macrophage activation syndrome-like disease covid- : immunopathology and its implications for therapy uk: covid- : consider cytokine storm syndromes and immunosuppression chinese clinical trial registry: a multicenter, randomized controlled trial for the efficacy and safety of tocilizumab in the treatment of new coronavirus pneumonia (covid- ) interleukin- receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase iii trial the mechanisms of action of plasma exchange role of plasma exchange, leukocytapheresis, and plasma diafiltration in management of refractory macrophage activation syndrome use of therapeutic plasma exchange as a rescue therapy in ph n influenza a-an associated respiratory failure and hemodynamic shock dysregulation of immune response in patients with covid- in wuhan, china plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome comparative and kinetic analysis of viral shedding and immunological responses in mers patients representing a broad spectrum of disease severity human serum albumin, systemic inflammation, and cirrhosis key: cord- -lkjsh fu authors: taccone, fabio silvio; gevenois, pierre alain; peluso, lorenzo; pletchette, zoe; lheureux, olivier; brasseur, alexandre; garufi, alessandra; talamonti, marta; motte, serge; nobile, leda; grimaldi, david; creteur, jacques; vincent, jean-louis title: higher intensity thromboprophylaxis regimens and pulmonary embolism in critically ill coronavirus disease patients date: - - journal: crit care med doi: . /ccm. sha: doc_id: cord_uid: lkjsh fu to assess the role of thromboprophylaxis regimens on the occurrence of pulmonary embolism in coronavirus disease patients. design: retrospective analysis of prospectively collected data on coronavirus disease patients, included between march , and april , . setting: icu of an university hospital in belgium. patients and interventions: critically ill adult mechanically ventilated coronavirus disease patients were eligible if they underwent a ct pulmonary angiography, as part of the routine management in case of persistent hypoxemia or respiratory deterioration. the primary endpoint of this study was the occurrence of pulmonary embolism according to the use of standard thromboprophylaxis (i.e. subcutaneous enoxaparin , international units once daily) or high regimen thromboprophylaxis (i.e. subcutaneous enoxaparin , international units bid or therapeutic unfractioned heparin). measurements and main results: of mechanically ventilated coronavirus disease , underwent ct pulmonary angiography after a median of days ( – d) since icu admission and days ( – d) days since the onset of symptoms. thirteen patients ( %) were diagnosed of pulmonary embolism, which was bilateral in six patients and localized in the right lung in seven patients. d-dimers on the day of ct pulmonary angiography had a predictive accuracy of . ( % cis: . – . ) for pulmonary embolism. the use of high-regimen thromboprophylaxis was associated with a lower occurrence of pulmonary embolism ( / ; %) than standard regimen ( / , %—odds ratio . [ . – . ]; p = . ); this difference remained significant even after adjustment for confounders. six patients with pulmonary embolism ( %) and patients without pulmonary embolism ( %) died at icu discharge (odds ratio . [ . – . ]; p = . ). conclusions: in this study, one third of coronavirus disease mechanically ventilated patients have a pulmonary embolism visible on ct pulmonary angiography. high regimen thromboprophylaxis may decrease the occurrence of such complication. objectives: to assess the role of thromboprophylaxis regimens on the occurrence of pulmonary embolism in coronavirus disease patients. design: retrospective analysis of prospectively collected data on coronavirus disease patients, included between march , and april , . setting: icu of an university hospital in belgium. patients and interventions: critically ill adult mechanically ventilated coronavirus disease patients were eligible if they underwent a ct pulmonary angiography, as part of the routine management in case of persistent hypoxemia or respiratory deterioration. the primary endpoint of this study was the occurrence of pulmonary embolism according to the use of standard thromboprophylaxis (i.e. subcutaneous enoxaparin , international units once daily) or high regimen thromboprophylaxis (i.e. subcutaneous enoxaparin , international units bid or therapeutic unfractioned heparin). measurements and main results: of mechanically ventilated coronavirus disease , underwent ct pulmonary angiography after a median of days ( - d) since icu admission and days ( - d) days since the onset of symptoms. thirteen patients ( %) were diagnosed of pulmonary embolism, which was bilateral in six patients and localized in the right lung in seven patients. d-dimers on the day of ct pulmonary angiography had a predictive accuracy of . ( % cis: . - . ) for pulmonary embolism. the use of high-regimen thromboprophylaxis was associated with a lower occurrence of pulmonary embolism ( / ; %) than standard regimen ( / ( ) . the presence of relatively well-preserved lung mechanics and the increased dead space suggested other mechanisms involved in this disease, which could be related to altered lung perfusion and hypoxic vasoconstriction ( ) . furthermore, the high mortality reported for covid- patients undergoing mechanical ventilation, when compared with contemporary ards cohorts, raised serious concerns on potential additional complications occurring during this disease that may further compromise lung function and recovery. a hallmark of severe covid- is a severe hypercoagulable state. in one study, more than % of covid- patients had criteria for disseminated intravascular coagulation; also, higher d-dimer levels and prolonged prothrombin (pt) and activated partial thromboplastin (aptt) times were observed in nonsurvivors when compared with survivors on hospital admission ( ) . the risk of venous thromboembolism is poorly defined in hospitalized covid- patients, but it is probably high. in one study from china, % of patients with severe covid- pneumonia had lower limb venous thrombosis ( ). more recently, acute pulmonary embolism (pe) was reported in of icu patients and associated with spontaneous prolongation of the pt and aptt ( ) . nevertheless, ct pulmonary angiography (ctpa) was not routinely performed in all patients, and no data on the role of different thromboprophylaxis regimens on the occurrence of pe were reported. we therefore studied the prevalence of pe in mechanically ventilated covid- patients as well as the impact of highdose thromboprophylaxis on its occurrence. we performed a retrospective analysis of prospectively collected data after approval by the local ethics committee (p / ), which waived the need for an informed written consent, as data were anonymized, patients were unable to consent, and relatives were not allowed to visit. patients were eligible for the study if they met all the following criteria: ) an age of years old or older; ) diagnosed of covid- using positive results on real-time polymerase chain reaction (rt-pcr) assay on the nasopharyngeal swab and/or bronchoalveaolar lavage (bal) specimens; ) being mechanically ventilated; ) a ctpa was performed, as part of the routine management. data collection and patient management are reported in the supplemental material (supplemental digital content , http://links.lww. com/ccm/f ). the primary endpoint of this study was the occurrence of pe according to the different thromboprophylaxis regimens. clinical and biological differences between patients with and without pe were also analyzed. all patients were followed up to april and were evaluated for mortality during the icu stay, icu discharge, and the occurrence of any bleeding events. statistical analyses are reported in the supplemental material (supplemental digital content , http://links.lww.com/ccm/ f ). of the patients admitted to the icu over the study period, ( %) were treated with mechanical ventilation; of those underwent ctpa (excluded patients: n = early deaths, n = rapid improvement). the characteristics of the study population are shown in supplemental table (supplemental digital content , http://links.lww.com/ccm/f ); most of patients were male, suffered from chronic hypertension and obesity. thirty-eight patients were diagnosed with positive rt-pcr assay on the nasopharyngeal swab, whereas two other patients tested positive only on bal. twenty of the patients ( %) died during the icu stay. ctpa was performed days ( - d) after icu admission and days ( - d) after the onset of symptoms; only one patient had acute hemodynamic instability before imaging. a total of patients ( %) were found to have pe, which was bilateral in six patients and unilateral, in the right lung, in seven patients. two patients had proximal bilateral pe (fig. a) , one patient had a subsegmental pe located in the right lower lobe (fig. b) , and all other patients had segmental pe. cardiac echography was performed in of the pe patients and revealed right ventricular dilation (n = ) or acute right heart failure (n = ). lower limb echo-doppler was performed in of these patients on the same day than ctpa and revealed no deep venous thrombosis. four of the patients without pe underwent a second ctpa during their icu stay, which yielded no pe. standard thromboprophylaxis was used in patients; of them ( %) developed pe; anti-xa activity at the moment of ctpa was . ( . - . ) (n = ). in the high-dose thromboprophylaxis group (i.e. six patients receiving continuous therapeutic infusion; dose ranges: , - , iu/hr- receiving subcutaneous enoxaparin , iu bid), only two of the patients ( %) developed pe, and days after the implementation of such regimen (odds ratio [or], . ( . - . ); p = . ). anti-xa activity at the moment of ctpa was . ( . - . ) (n = ; p = . vs standard thromboprophylaxis). in the multivariate analysis, the probability of developing pe in patients receiving high-dose thromboprophylaxis remained significantly lower than others (or . [ . - . ]; p = . ). patients with pe had lower wbcs count and higher pao /fio at admission than the other patients (supplemental table , supplemental digital content , http://links.lww. com/ccm/f ); also, on the day of ctpa, they had higher c-reactive protein and d-dimers levels and were ventilated with higher tidal volume and minute volume ventilation than those without pe. d-dimers on the day of ctpa had a high predictive accuracy (area under the receiver operating characteristics, . ; % cis, . - . ) for pe; a d-dimers concentration greater than , ng/ml had % ( % cis, - %) sensitivity and % ( % cis, - %) specificity to predict pe. all pe patients were eventually treated with continuous therapeutic infusion of unfractioned heparin; in one pe patient treated with ecmo, massive hemothorax developed, requiring interruption of anticoagulation and percutaneous thoracic drainage, whereas in another bleeding from gastric ulcer was detected on endoscopy. among patients receiving enoxaparin, two patients on standard doses (one with hemoptysis and one with gastric bleeding) and three on high dose (two with gastric bleedings and one with bowel bleeding) had hemorrhagic complications. six patients with pe ( %) and patients without pe ( %) died at icu discharge (or . [ . - . ]; p = . ); four of the patients without pe underwent autopsy, which confirmed the absence of pe. in this study, one third of patients ( %) who are mechanically ventilated for covid- have pe diagnosed on ctpa. high-dose thromboprophylaxis was associated with a higher prevalence of pe when compared with standard regimen. no association of pe with mortality was observed. covid- can be associated with a massive release of inflammatory cytokines, which can promote the development of endothelial cell damage and the occurrence of thromboembolic events. we found that elevated d-dimers could be a marker of pe occurrence and may therefore help to identify the patients requiring full anticoagulation therapy; lack of pe diagnosis and specific therapies could explain the association of high d-dimers with poor outcome in covid- patients ( ) . as such, daily monitoring of increasing d-dimers levels could be used to select patients at risk of pe, who could undergo chest cta. these data are consistent with those from cui et al ( ) showing that the sensitivity and specificity of d-dimers greater than , ng/ml to predict lower limb venous thrombosis were . % and . %, respectively. in another study including hospitalized covid- patients, d-dimers greater than , ng/ml had a sensitivity of % and a specificity of % to detect pe on ctpa ( ) . acute pe has been reported in of critically ill patients in one study, but with limited information and without systematic ctpa ( ) . in another series, patients of ( %) were diagnosed of pe after a median of days after icu admission ( ) ; in this study, ctpa was performed only in case of suspected pe upon admission and/or acute degradation of hemodynamic/respiratory status. a large cohort including hospitalized covid- patients showed that routine ctpa could identify pe in % of them; pe was more frequently observed in critically ill patients, in particular if treated with mechanical ventilation ( ) . as such, the occurrence of ep is significantly higher than in other critically ill patients population (i.e. around %) ( ) and might be underestimated because hemodynamic instability, right ventricular dysfunction, or concomitant venous thrombosis are rarely observed. the prevalence of pe appeared to depend on the thromboprophylaxis regimen. higher thromboprophylaxis doses or continuous therapeutic infusion of unfractioned heparin was more common among patients without than with pe. our findings suggest the need for increasing thromboprophylaxis doses in covid- patients. in previous studies, the failure rate for standard thromboprophylaxis in an icu setting is around % ( ) ; in the study from cui et al ( ) , % prevalence of deep venous thrombosis in the absence of any thromboprophylaxis. in another study, covid- patients treated with ufh and with a high coagulopathy score had a lower -day mortality than untreated patients ( ) . no prospective studies have been published so far adequately evaluating the effects on anticoagulation on covid- patients' outcome. this study has several limitations. first, this is a singlecenter, small cohort study; the results need to be confirmed in larger cohorts. second, final outcome could not be fully assessed, since some patients are still in the hospital. third, small subsegmental pe could have been undiagnosed in some patients, as this remains a diagnostic challenge in these patients in particular. also, systematic research of associated deep venous thrombosis was not performed in all patients, as this would not have changed the indication for therapeutic anticoagulation. finally, there is a risk of bias because the high frequency of pe observed in the standard thromboprophylaxis group might suffer from random fluctuation, which could explain a lower ep rate in the high dose thromboprophylaxis group, even without change in thromboprophylaxis regimen. in this study, acute pe may occur in one third of mechanically ventilated covid- patients. higher thromboprophylaxis regimens should be considered in these patients. baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region covid- does not lead to a "typical" acute respiratory distress syndrome abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia incidence of thrombotic complications in critically ill icu patients with covid- risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china acute pulmonary embolism in covid- patients on ct angiography and relationship to d-dimer levels lille icu haemostasis covid- group: pulmonary embolism in patients with covid- : awareness of an increased prevalence acute pulmonary embolism associated with covid- pneumonia detected by pulmonary ct angiography vte incidence and risk factors in patients with severe sepsis and septic shock prophylaxis for thromboembolism in critical care trial investigators: failure of anticoagulant thromboprophylaxis: risk factors in medical-surgical critically ill patients* anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy we thank all the icu team for the wonderful job in the management of severe coronavirus disease patients.drs. taccone, peluso, grimaldi, and creteur prepared this article; drs. gevenois, brasseur, motte, nobile, and vincent collaborated in the design of the trial and organized the initial ethics applications; drs. pletchette, garufi, and talamonti are responsible for study governance and roll out of the trial. dr. taccone is responsible for logistical support of the study. drs. peluso, pletchette, garufi, and talamonti collected the data; drs. taccone, creteur, and vincent supervised data collection. all authors contributed substantially to the design and methodology of this study and to the writing of this article. all authors have read and approved the final article.supplemental digital content is available for this article. direct url citations appear in the printed text and are provided in the html and pdf versions of this article on the journal's website (http://journals.lww.com/ ccmjournal).the authors have disclosed that they do not have any potential conflicts of interest.the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.for information regarding this article, e-mail: ftaccone@ulb.ac.be key: cord- -vt e crh authors: elabbadi, alexandre; pichon, jérémie; visseaux, benoit; schnuriger, aurélie; bouadma, lila; philippot, quentin; patrier, juliette; labbé, vincent; ruckly, stéphane; fartoukh, muriel; timsit, jean-françois; voiriot, guillaume title: respiratory virus-associated infections in hiv-infected adults admitted to the intensive care unit for acute respiratory failure: a -year bicenter retrospective study (hiv-vir study) date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: vt e crh introduction: acute respiratory failure is the main reason for admission to the intensive care unit (icu) in hiv-infected adults. there is little data about the epidemiology of respiratory viruses in this population. methods: hiv-infected adults admitted to two intensive care units over a -year period for an acute respiratory failure and explored for respiratory viruses with multiplex polymerase chain reaction (mpcr) were retrospectively selected. objectives were to describe the prevalence of respiratory viruses, coinfections with non-viral pathogens, and hospital outcome. results: a total of episodes were included. an hiv infection was newly diagnosed in % of cases and % of the population were on antiretroviral therapy. real-time mpcr tests identified at least one respiratory virus in the respiratory tract of ( %) patients, but with a non-viral copathogen in two-thirds of cases. rhinovirus was predominant, documented in patients, followed by influenza and respiratory syncytial viruses (both n = ). the prevalence of respiratory virus-associated infection did not vary along with the level of the cd t-cell deficiency, except for rhinovirus which was more prevalent in patients with a cd lymphocyte count below cells/µl (n = ( %) vs. n = ( %), p < . ). in multivariate analysis, respiratory virus-associated infection was not associated with a worse prognosis. conclusions: viruses are frequently identified in the respiratory tract of hiv-infected patients with acute respiratory failure that requires icu admission, but with a non-viral copathogen in two-thirds of cases. rhinovirus is the predominant viral specie; its prevalence is highest in patients with a cd lymphocyte count below cells/µl. acute respiratory failure (arf) is the leading cause of admission to the intensive care unit (icu) in hivinfected patients [ ] [ ] [ ] . infectious causes are predominant, although the proportion of opportunistic infections has decreased significantly in the era of combination antiretroviral therapy (art) [ , , ] . in contrast, the open access *correspondence: guillaume.voiriot@aphp.fr assistance publique -hôpitaux de paris, service de médecine intensive réanimation, hôpital tenon, sorbonne université, paris, france full list of author information is available at the end of the article burden of non-hiv-related pulmonary events, such as bacterial pneumonia, acute bronchitis and acute exacerbation of chronic obstructive pulmonary disease (copd) has been shown increasing [ , , ] . these important changes in the etiologic panel of arf in hiv-infected patients question the role of respiratory viruses. indeed, using nucleic acid amplification test such as multiplex polymerase chain reaction (mpcr), these pathogens have been shown highly prevalent ( - %) in large cohorts of adult patients admitted to the icu for all-cause arf [ , ] , community-acquired pneumonia [ , ] , hospitalacquired pneumonia [ ] , acute exacerbation of copd [ , ] , and asthma [ ] , compared to asymptomatic adults [ , ] . high prevalence has also been described in specific immunocompromised populations, such as cancer and hematology patients [ , ] . in contrast, little is known about the epidemiology of respiratory viruses in hiv-infected patients [ , ] , especially those admitted to the icu, and the prevalence of respiratory viruses according to the cd t-cell deficiency. moreover, coinfections with virus and opportunistic pathogens may occur. overall, respiratory virus-associated infections may affect prognosis. therefore, we conducted a comprehensive observational study among adult hiv-infected icu patients with arf explored with respiratory mpcr. our goals were to describe the prevalence of respiratory viruses, coinfections with non-viral pathogens, and hospital outcome. we conducted a retrospective bicenter observational study in two icu of the paris area (the -bed icu of the bichat university hospital and the -bed icu of the tenon university hospital). from april to april , all consecutive hiv-infected patients admitted to icu having undergone an mpcr in the respiratory tract within h following their icu admission were screened. medical records were independently reviewed by two physicians (ae and gv). all patients with arf at icu admission were included. arf was defined by the presence of at least two of the following criteria: cough, expectoration, dyspnea, rales, signs of respiratory distress (tachypnea exceeding /min, paradoxical abdominal breathing), chest pain, hypoxemia requiring oxygen therapy, noninvasive ventilation or intubation. in case of multiple admissions over the -year study period, only the first admission was analyzed. at icu admission and during icu stay, data regarding demographics, comorbidity, hiv-related characteristics, clinical examinations, laboratory and radiological findings, microbiologic investigations, and therapeutic management were collected (for details, see additional file ). mortality was defined as death from any cause within days following the icu admission. respiratory mpcrs were performed either in nasopharyngeal (np) swabs or in lower respiratory tract (lrt) specimen, usually bronchoalveolar lavage (bal) fluid otherwise endotracheal aspirate. during the study period, different respiratory mpcr kits (additional file : table s ) were used (for more details about microbiological evaluation, see additional file ). medical charts were independently reviewed by two clinicians (ae and gv). they determined the causative diagnosis of arf for each patient, using a -class classification. in case of an inter-reviewer discordance, a shared review of the medical charts was performed, and an agreement was found. the five mutually exclusive classes of causative diagnosis for arf were: (i) pneumocystis jirovecii pneumonia (pcp); (ii) other opportunistic lung infections; (iii) non-opportunistic acute lung infection; (iv) non-infectious lung disease, and (v) extra-pulmonary cause (for details, see additional file ). the primary endpoint was to determine the prevalence of respiratory viruses according to the cd lymphocyte count. a respiratory virus documented with mpcr was always considered as a pathogen of the respiratory tract, regardless of the type of specimen (np or lrt). the cd lymphocyte count measured during the icu stay was used to group patients, with a cut-off of cells/µl (≤ cells/µl for the low-cd group; > cells/µl for the high-cd group) [ , ] . secondary endpoints were to describe the epidemiology of respiratory viruses and coinfections with non-viral pathogens, to identify risk factors for respiratory virusassociated infection, and to study outcome. a composite criterion named "complicated course" included death from any cause within days following the icu admission or mechanical ventilation for more than days. continuous data were expressed as median [first through third quartiles] and were compared using the pairwise mann and whitney test. categorical data were expressed as number (percentage) and were evaluated using the chi-square test or fisher exact test. p values less than . were considered significant. a univariate logistic regression with clinically relevant variables was used to identify variables associated with a respiratory virusassociated infection. a multivariate conditional logistic regression, including variables with p value less than . in the previous step, was used to identify variables independently associated with a respiratory virus-associated infection. similar statistical analyses were performed to identify variables independently associated with death from any cause within days following the icu admission and mechanical ventilation for more than days in survivors at day- . quantitative variables that did not validate the log-linearity assumption were transformed into categorical variables according to their median value. missing data were imputed to the median or the more frequent value. the accuracy of the final model was tested using area under the receiver operating characteristic curve analysis and the hosmer-lemeshow chi-square test. analyses were performed using the sas software package (sas institute, cary, nc, usa). during the -year study period, hiv-infected adult patients were admitted at least once to icu and underwent a respiratory mpcr in the first h of the icu stay. among them, did not fulfill criteria of arf. the final study group consisted of patients. their main characteristics, stratified by the cd lymphocyte count at icu admission, are presented in table . of these patients, were admitted twice during the study period and one was admitted thrice. eleven patients ( %) were newly diagnosed as having hiv infection on icu admission; the remaining had been previously diagnosed, and were on art but with poor adherence to the treatment in patients, as mentioned by the infectiologist in the medical charts. latest available median cd lymphocyte count and hiv viral load were cells/µl [ - ] and log copies/ml [ - . ], respectively. at least one additional factor of immunosuppression was identified in ( %) patients. at icu admission, median cd lymphocyte count was cells/µl , with patients ( %) equal or below cells/µl (low-cd group) and ( %) above cells/µl (high-cd group). both these groups did not differ regarding demographics, performance status, factors of immunosuppression other than hiv and comorbidity, except for copd which was more prevalent in the high-cd group (n = ( %) vs. n = ( %), p = . ). the microbiological investigations are displayed in additional file : table s . mpcr was performed in np swabs exclusively (n = , %) or in lrt specimen exclusively (n = , %), or both (n = , %). respiratory tract specimens for bacterial culture have been obtained in ( %) patients. bal fluid has been obtained in ( %) patients. causative diagnoses of arf are displayed in table . an opportunistic lung infection was diagnosed in ( %) patients. seven of the patients with newly diagnosed hiv infection and patients receiving art, but with a poor adherence to the treatment had pcp. non-opportunistic acute lung infections were identified as causative diagnosis of arf in ( %) patients. all the bacteria-infected patients received an appropriate antimicrobial regimen within the first h of icu stay. eight patients had a clinical presentation suggestive of lung infection, but without microbiological documentation. the arf was attributed to a non-infectious lung disease in ( %) patients, mainly related to a decompensated chronic condition, i.e., acute exacerbation of copd and pulmonary edema. overall, respiratory viruses were identified in ( %) patients (table ) . rhinovirus was predominant (n = ), followed by influenza (n = ), respiratory syncytial virus (n = ) and parainfluenza virus (n = ). only one pure virus-virus coinfection was found. the prevalence of respiratory virus-associated infection did not differ among low-and high-cd groups (table ) ; therefore, the median cd lymphocyte count in respiratory virus-infected patients was cells/µl, in comparison with cells/µl in non-infected patients (fig. ) . however, the prevalence of rhinovirus-associated infection was higher in the low-cd group, and three-quarters of rhinovirus-infected patients exhibited a cd lymphocyte count below cells/µl (fig. ) . in patients, the viral documentation was accompanied by a non-viral documentation (additional file : figure s ), with bacteria-virus coinfection in patients, bacteria-virus-virus in patients, p. jirovecii-virus in patients and p. jirovecii-virus-virus in one patient. the rate of viral documentation among patients explored with np swab exclusively, lrt specimen exclusively, or both, did not differ significantly ( %, % and %, respectively; p = . ). documentation of respiratory viruses was more frequent during the winter period (october to march) (additional file : figure s ). conversely, rhinovirus documentation did not follow a seasonal distribution, since only / were observed during the period from october to march. characteristics of the population, stratified by respiratory virus-associated infection are presented in additional file : table s . at icu admission, respiratory virus-infected patients displayed higher respiratory rate and fever. in multivariate analysis, female gender, smoking and steroid therapy were shown as independently associated with respiratory virus-associated infection ( table ) . mortality at day- was %, and % of patients displayed a complicated course, without difference between high-cd and low-cd groups (table ) . we investigated whether a respiratory virus-associated infection table causative diagnosis of acute respiratory failure in hiv-infected patients admitted to the icu data are presented as number (%). cd refers to cd lymphocyte count (cells/µl) a other opportunistic lung infections included cmv-associated pneumonia (n = ) and pulmonary tuberculosis (n = ) b non-infectious lung diseases included acute exacerbation of copd of non-infectious etiology (n = ), cardiogenic lung edema without underlying lung agent (n = ), cryptogenic hemoptysis (n = ), intra-alveolar hemorrhage (n = ); acute interstitial pneumonia (n = ), mendelson syndrome (n = ), sickle cell disease (acute chest syndrome) (n = ); neoplastic pleural effusion (n = ) and castleman disease (n = ) c extra-pulmonary causes included histoplasmosis (n = ), cryptococcus neoformans meningitis (n = ), bacterial meningitis (n = ), pyelonephritis (n = ) and bacteremia of unknown origin (n = ) all extra-pulmonary cause c ( . ) ( . ) ( . ) affected prognosis. in the analysis stratified by respiratory virus-associated infection, outcome was similar between infected and non-infected patients (additional file : table s ). in multivariate analysis, a respiratory virus-associated infection was not identified as an independent factor of either a complicated course (table ) or death at day- (additional file : table s ). this retrospective study investigated the epidemiology of respiratory viruses in hiv-infected adults admitted to the icu for arf. real-time mpcr tests identified at least one virus in the respiratory tract of % of patients, but with a non-viral copathogen in two-thirds of cases. the prevalence of respiratory virus-associated infection did not vary along with the level of the cd t-cell deficiency, except for rhinovirus which was more prevalent in patients with a cd lymphocyte count below cells/ µl. in multivariate analysis, respiratory virus-associated infection was not associated with a worse prognosis. in this study, more than one patient out of four ( %) were infected with at least one respiratory virus. this finding illustrated the high yield of an aggressive diagnostic strategy with a broad panel mpcr on respiratory tract specimens. our results are original since prior works having described the etiological panel of arf in hivinfected icu patients were conducted before the era of real-time mpcr [ , , ] . interestingly, the rate of viral documentation that we observed was similar to what had been described ( to %) previously in non-hiv adults admitted to the icu for an acute respiratory disorder requiring intubation [ , ] . we identified at least one non-viral copathogen in more than two-thirds of the patients with a viral documentation, in line with a recent report in a population with a high prevalence of tuberculosis [ , ] . nonopportunistic acute lung infections, including pneumonia, acute bronchitis and exacerbation of copd, were the first cause of arf, consistent with previous reports in western countries [ , ] . this finding highlights the burden of chronic respiratory conditions in aging hivinfected populations [ ] . here, more than % of patients were smokers. synergistic effects of tobacco and hiv [ ] in promoting chronic bronchitis and pro-copd changes in the lung [ ] have been demonstrated. moreover, high rates of viral documentation within airways of copd patients both at stable state and during exacerbation have been reported [ ] . these data may explain the high rate of viral documentation that we observed. in multivariate analysis, smoking was independently associated with respiratory virus-associated infection. this finding is in line with previous works demonstrating that tobacco exposure alters immune responses to rhinovirus [ ] , influenza virus [ ] and respiratory syncytial virus [ ] . interestingly, female gender was associated with an increased risk of respiratory virus-associated infection on multivariate analysis. prior cohort studies in primary care described an increased risk for development of influenza-like illnesses in women compared to men [ , ] . however, to our knowledge, no prior study has specifically explored this point in hiv-infected populations admitted for arf. in this study, we also aimed to investigate a putative role of the hiv-related cd t-cell deficiency in promoting respiratory virus-associated infection. previous studies explored this point in children, but with conflicting results. annamalay et al. described similar rates of viral documentation in hiv-infected and non-infected children admitted for lower respiratory tract infections [ ] , whereas o'callaghan-gordo et al. observed that respiratory virus-associated infections were to times more prevalent among hiv-infected children admitted for pneumonia [ ] . as we did not include a comparative non-hiv population, we rather examined whether or not the rate of viral documentation varied along with the level of cd t-cell deficiency. finally, we found no association between the cd lymphocyte count and the risk of respiratory virus-associated infection, in line with a previous report focusing on influenza viruses [ ] . rhinovirus was the predominant virus, accounting for more than % of viral documentations. this high prevalence was consistent with that of previous reports in icu patients with arf [ ] , community-acquired pneumonia [ ] or acute exacerbation of copd [ ] . surprisingly, rhinovirus was much more prevalent in low-cd patients. this finding is original, since no prior work has specifically explored this point in adults. in hiv-infected children, rhinovirus has been shown highly prevalent, during both pneumonia and bronchiolitis, but without data regarding a putative association with the level of cd t-cell deficiency [ , ] . other data in hematology and cancer adults demonstrated high rates of rhinovirus documentation within airways during respiratory tract infections [ , ] . to explain this high prevalence in immunocompromised patients, a mechanism of prolonged viral shedding has been proposed, rather than iterative reinfections as observed in copd patients [ ] . the prolonged rhinovirus shedding may be attributable to an inefficient immunological control of a single infectious episode [ , ] . therefore, in pediatric hematopoietic stem cell transplant recipients with a persistent rhinovirus shedding (≥ days), piralla et al. demonstrated significant lower cd , cd and nk lymphocyte counts at the onset of infection, as compared to children with a brief rhinovirus shedding. moreover, a decrease in rhinovirus load was associated with significant increases of the same lymphocyte counts [ ] . these data would suggest an important role for the t-cell immunity in the control of rhinovirus infection, and subsequently, may explain a delayed rhinovirus clearance in low-cd hivinfected patients, resulting in persistent shedding and increased prevalence. we observed a high rate of dual infection, either virusbacteria or virus-opportunistic pathogen. these findings made us consider the prognostic impact of such coinfections. studies in icu adult patients with pneumonia suggested that virus-bacteria coinfection was associated with a worse prognosis [ ] . in mice, the coinfection of influenza with streptococcus pneumoniae [ ] , legionella pneumophila [ ] or staphylococcus aureus [ ] impaired the anti-influenza immune response and increased mortality. whether similar synergistic effects exist in virusopportunistic pathogen coinfection remain unknown. only one animal study has explored the couple pneumocystis jirovecii-influenza, but in a successive rather than concomitant model [ ] . unfortunately, in our study, the low number of observations prevented us from analyzing the prognosis according to the presence of coinfections. our study has several limitations. first, this study included adult patients with arf that required icu admission, preventing any conclusion on other populations such as hiv-infected children or hiv-infected adults with arf that did not require icu admission. second, the study was retrospective, so we did not control the microbiological investigations. the preferred sample for mpcr test in non-intubated patients was not the sputum, but the nasopharyngeal swab [ ] . several factors may have discouraged clinicians to use sputum, including the high number of patients unable to produce sputum [ ] and the highly viscous nature of this sample that can make nucleic acid extraction difficult [ ] . by definition, an mpcr was performed in the respiratory tract of every included patient because it was a criterion for patient screening. but some other microbiological tests were only occasionally performed, i.e., cytomegalovirus pcr. furthermore, the retrospective design prevented us from obtaining a number of data, which were rarely reported in medical records by physicians, including vaccine history, pneumocystis jirovecii prophylaxis, symptoms before hospital referral, and duration of symptoms before icu admission. third, only patients having undergone an mpcr in the respiratory tract within the h following their icu admission were screened; this might suggest a confounding of indication. fourth, the choice to classify patients according to their cd lymphocyte count on the icu admission, instead of the latest known value, might be criticized. however, this choice was guided by the high number of missing values in the latest cd lymphocyte count as well as the number of newly diagnosed patients without any prior cd lymphocyte count. fifth, we assumed that a virus identified with pcr in nasopharyngeal or lower respiratory tract samples was always a pathogen of the respiratory tract, whatever the clinical picture and radiological features. this might be criticized since respiratory viruses might be present in asymptomatic adult subjects [ ] , even if it seems rare, about % of asymptomatic adults seen at the emergency department [ ] . sixth, to avoid overinterpreting the data, we decided to consider respiratory viruses as a homogeneous group of pathogens in the analysis stratified by respiratory virus-associated infection. this might be criticized since the pathogenicity differs from one viral species to another. viruses are frequently identified in the respiratory tract of hiv-infected patients with arf that required icu admission, but with a non-viral copathogen in two-thirds of cases. rhinovirus is the predominant viral specie; its prevalence is highest in patients with a cd lymphocyte count below cells/µl. supplementary information accompanies this paper at https ://doi. org/ . /s - - - . additional file . additional information on material and methods, table s (panels of mpcr kits used in the two participating icus over the -year study period), table s (microbiological investigations performed in hiv-infected patients admitted to the icu for acute respiratory failure, according to the diagnosis of respiratory virus-associated infection), table s (baseline characteristics, behavior during icu stay, and outcome of hiv-infected patients admitted to the icu for acute respiratory failure, according to the diagnosis of respiratory virus-associated infection), table s (multivariate analysis of the risk factors for death at day- in hiv-infected patients admitted to the icu for acute respiratory failure), figure s (distribution of the microbiological documentations in hivinfected patients admitted to the icu for acute respiratory failure), figure s admissions to intensive care unit of hiv-infected patients in the era of highly active antiretroviral therapy: etiology and prognostic factors etiologies and outcome of acute respiratory failure in hivinfected patients temporal trends in critical events complicating hiv infection: - multicentre cohort study in france survival for patients with hiv admitted to the icu continues to improve in the current era of combination antiretroviral therapy pulmonary infections in hiv-infected patients: an update in the st century hiv infection and risk for incident pulmonary diseases in the combination antiretroviral therapy era epidemiology and clinical outcome of virus-positive respiratory samples in ventilated patients: a prospective cohort study respiratory viruses in invasively ventilated critically ill patients-a prospective multicenter observational study viral-bacterial coinfection affects the presentation and alters the prognosis of severe community-acquired pneumonia lower respiratory tract virus findings in mechanically ventilated patients with severe community-acquired pneumonia impact of respiratory viruses in hospital-acquired pneumonia in the intensive care unit: a single-center retrospective study virus infection in exacerbations of chronic obstructive pulmonary disease requiring ventilation procalcitonin algorithm to guide initial antibiotic therapy in acute exacerbations of copd admitted to the icu: a randomized multicenter study epidemiology of respiratory viruses in patients hospitalized with near-fatal asthma, acute exacerbations of asthma, or chronic obstructive pulmonary disease community surveillance of respiratory viruses among families in the utah better identification of germs-longitudinal viral epidemiology (big-love) study community-acquired pneumonia requiring hospitalization among u.s. adults clinical significance of upper airway virus detection in critically ill hematology patients management of respiratory viral infections in hematopoietic cell transplant recipients and patients with hematologic malignancies prospective etiological investigation of community-acquired pulmonary infections in hospitalized people living with hiv. medicine (baltimore) respiratory viruses in hiv-infected patients with suspected respiratory opportunistic infection outcome of critically ill human immunodeficiency virus-infected patients in the era of highly active antiretroviral therapy survival of hiv-infected patients in the intensive care unit in the era of highly active antiretroviral therapy etiology of pulmonary infections in human immunodeficiency virus-infected inpatients using sputum multiplex real-time polymerase chain reaction impact of hiv infection and smoking on lung immunity and related disorders cigarette smoke and hiv synergistically affect lung pathology in cynomolgus macaques a prospective, observational cohort study of the seasonal dynamics of airway pathogens in the aetiology of exacerbations in copd cigarette smoke decreases innate responses of epithelial cells to rhinovirus infection cigarette smoke attenuates the rig-i-initiated innate antiviral response to influenza infection in two murine models cigarette smoke suppresses tlr- stimulation in response to virus infection in plasmacytoid dendritic cells recording of influenza-like illness in uk primary care - : cohort study incidence and risk factors for influenza-like-illness in the uk: online surveillance using flusurvey respiratory viruses in young south african children with acute lower respiratory infections and interactions with hiv etiology and epidemiology of viral pneumonia among hospitalized children in rural mozambique: a malaria endemic area with high prevalence of human immunodeficiency virus pandemic (h n ) influenza virus seroconversion rates in hiv-infected individuals incidence of respiratory viruses in patients with community-acquired pneumonia admitted to the intensive care unit: results from the severe influenza pneumonia surveillance (sips) project clinical epidemiology of bocavirus, rhinovirus, two polyomaviruses and four coronaviruses in hiv-infected and hiv-uninfected south african children respiratory virus detection in immunocompromised patients with filmarray respiratory panel compared to conventional methods virological diagnosis in community-acquired pneumonia in immunocompromised patients prolonged shedding of rhinovirus and re-infection in adults with respiratory tract illness chronic rhinoviral infection in lung transplant recipients persistent human rhinovirus type c infection of the lower respiratory tract in a pediatric cord blood transplant recipient persistent rhinovirus infection in pediatric hematopoietic stem cell transplant recipients with impaired cellular immunity viral infection in community-acquired pneumonia: a systematic review and meta-analysis coinfection with streptococcus pneumoniae negatively modulates the size and composition of the ongoing influenza-specific cd + t cell response role of tissue protection in lethal respiratory viral-bacterial coinfection influenza virus primes mice for pneumonia from staphylococcus aureus pneumocystis infection enhances antibodymediated resistance to a subsequent influenza infection diagnosis and management of respiratory viruses in critically ill adult patients: an international survey of knowledge and practice among intensivists diagnostic value of microscopic examination of gram-stained sputum and sputum cultures in patients with bacteremic pneumococcal pneumonia comparison of sputum and nasopharyngeal swabs for detection of respiratory viruses publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. gv had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects. ae participated in the design of the study, participated in the data acquisition, analysis and interpretation, and the statistical analysis, and drafted the manuscript. jp, bv, as, lb, qp, jp and vl participated in the data acquisition, analysis and interpretation, and helped to revise the manuscript. rs participated in the data analysis and interpretation, and the statistical analysis. mf and jft participated in the design of the study, participated in the data analysis and interpretation, and helped to revise the manuscript. gv designed the study, participated in the data analysis and interpretation, and the statistical analysis, and revised the manuscript. all authors read and approved the final manuscript. none. data and materials supporting the findings of this study can be entirely shared if asked. not applicable. the authors have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. key: cord- - msd mqo authors: roselli, lucia reis peixoto; frej, eduarda asfora; ferreira, rodrigo josé pires; alberti, alexandre ramalho; de almeida, adiel teixeira title: utility-based multicriteria model for screening patients under the covid- pandemic date: - - journal: comput math methods med doi: . / / sha: doc_id: cord_uid: msd mqo in this paper, a utility-based multicriteria model is proposed to support the physicians to deal with an important medical decision—the screening decision problem—given the squeeze put on resources due to the covid- pandemic. since the covid- emerged, the number of patients with an acute respiratory failure has increased in the health units. this chaotic situation has led to a deficiency in health resources. thus, this study, using the concepts of the multiattribute utility theory (maut), puts forward a mathematical model to aid physicians in the screening decision problem. the model is used to generate which of the three alternatives is the best one for where patients with suspected covid- should be treated, namely, an intensive care unit (icu), a hospital ward, or at home in isolation. also, a decision information system, called sidtriagem, is constructed and illustrated to operate the mathematical model proposed. at the start of the current year ( ), the covid- disease, caused by the new coronavirus (the sars-cov- ), was deemed to be an epidemic. however, a few weeks later, it was reclassified as a pandemic. since the covid- has emerged, it has been present in different degrees of illness in the human organism, causing, in severe cases, acute respiratory failure [ ] [ ] [ ] . in this context, this disease has resulted in an increasing number of patients requiring hospital treatments, especially in intensive care units (icus) with the support of mechanical ventilation equipment. consequently, in many cities around the world, this increase in the demand for places in hospitals has placed a great strain on medical resources and revealed deficiencies in all forms of provision for a pandemic and therefore adequate treatment has not been available for all the severe cases. thus, to deal with this chaotic situation, it is fundamental to have decision-making strategies in place as these are important to ensure that the expectation of the survival of covid- patients can be maximized. in other words, in such situations, which involves a risk context, it is important to conduct a rational decision-making process in order to be able to save the majority of patients [ ] . therefore, in order to allow the rational conduct of an important medical decision-making problem-the screening decision problem-a utility-based multicriteria model is proposed in this study. this additive multicriteria decision-making model is based on the multiattribute utility theory (maut) approach [ ] , which considers the concepts of the utility theory [ ] , to deal with the uncertainty presented in medical diagnostics [ ] . thus, in this study, issues from operational research are considered to support a healthcare decision-making problem. also, a decision information system (dis), called sidtriagem, is constructed to implement this multicriteria decision-making model. the outcome of this dis is a recommendation about where a patient with suspected covid- should be directed to, considering the alternatives presented in the screening problem. it is worth mentioning that this model is a supplement to support physicians to deal with the screening problem. it is left to the physicians to decide whether or not to follow the recommendation made. this paper as organized as follows. section details the screening decision problem. section describes the utilitybased model proposed in this study. section presents the applicability of the proposed approach and discusses these results. finally, section draws some conclusions and indicates possible topics for future lines of research. the covid- pandemic has provoked several decision situations that physicians are facing in their routines in hospitals and other health units all over the world. one of the main decision problems that they encounter every day is how best to screen patients with suspected covid- . a patient arrives at a health unit with symptoms and other complaints. then, the physician has to decide, depending on the patient's clinical state, whether this patient should be sent for treatment in an intensive care unit (icu), in a hospital ward (but not in an icu) or whether he/she should be sent home to isolate instead of being hospitalized. this is the classical screening problem that is addressed in this paper, in which the context of the covid- pandemic has been made more acute. given that uncertainty is an inevitable factor that is inherently present in medical diagnostics and treatment decisions [ ] , a decision analysis (da) model based on the multiattribute utility theory (maut) is developed in order to aid physicians when they make such decisions. da support for screening patients within the context of other diseases has been widely explored in the literature. xu et al. [ ] used a da approach based on decision trees to investigate strategies for the triage of patients with symptoms of acute stroke. outcomes were measured based on workflow times. probabilities and input parameters were estimated based on guidelines and previously published studies. a practical analysis was conducted using treeage pro software. jiang et al. [ ] designed a da tree in order to evaluate the best strategy for treating patients after an esophagectomy. the treeage pro software was used to construct the decision tree. two strategies were compared based on several factors, such as length of stay in the hospital, costs, and possible complications. a sensitivity analysis was performed by using a monte-carlo simulation. felder and mayrhofer [ ] analyze the impact of risk preferences in decisions about medical screening, testing, and treatment. they conclude that a risk averse decision-maker tests and treats patients at lower probabilities of illness, compared to risk neutral and risk vulnerable decision-makers. cleary et al. ( ) [ ] applied da techniques for comparing three different strategies of screening for herpes, a simple virus, in pregnant women; probability estimations were derived from da on the literature. kiberd and forward [ ] developed a da-based study to investigate the impact of medical screening decisions for west nile virus in organ transplantation, by considering lives lost and saved. a cost-effective analysis approach was also widely used by authors when dealing with da models for screening patients, and these studies covered a wide range of diseases. wilson and howe [ ] developed a da model for screening methods of dysphagia after stroke. different strategies were compared based on a cost-effective analysis. medical costs were measured from a societal perspective, and effectiveness was measured in years of quality-adjusted life. sensitivity analysis using a monte-carlo simulation was performed. donnan et al. [ ] conducted a cost-effectiveness analysis for da of children with acute lymphoblastic leukemia. probabilities were obtained based on published evidence in the literature, and survival was measured in months of life. cooper et al. [ ] constructed a decision analysis model to handle health outcome states and costs of screening strategies for children in preoperative coagulation tests prior to a tonsillectomy and/or adenoidectomy. probabilities, costs, and utility data were estimated based on a review of databases. sensitivity analysis was performed so that parameters were widely varied. baeten et al. [ ] conducted a study to show the potential and impact of three approaches in the use of cost-effective analysis in the scope of breast cancer control: targeting specific groups, by comparing disparities; equity weighting, by valuing high and low health gains differently; and multicriteria decision analysis, giving weights for multiple equity and efficient criteria. oh et al. [ ] used da based on a cost-effective approach to compare different strategies for screening rheumatoid arthritis and systemic lupus erythematosus patients. data were obtained from previous studies and from real practical cases. rulyak et al. [ ] applied da for screening strategies in familial pancreatic cancer kindreds. life expectancy and lifetime medical care costs were modeled in order to conduct a cost-effective analysis. mcgrath et al. ( ) [ ] used da software (treeagre pro) for comparing four strategies for screening patients with colorectal cancer, taking into account the cost to find an advanced adenoma. probabilities, test characteristics, and costs were estimated based on a literature review and local costs. in this context, this paper is aimed at presenting a multicriteria model for screening patients with suspected covid- , based on a da approach within the multiattribute utility theory. two main factors are taken into account: the life of the patient being screened and the cost of the alternative indicated for that patient. these criteria are further detailed in this paper. subjective probabilities are considered for the construction of a decision tree for the screening problem. the next section details the whole structure of the mathematical model proposed for the screening problem. in this context, in the decision tree constructed, the alternatives indicated to conduct the health treatment for the patients with suspected covid- are identified. in the screening problem investigated in this study, three alternatives are considered; these alternatives are icu stay (icu), hospital stay (hs), and isolation at home (ih). also, for each one of these alternatives, the uncertainty is presented, since according to [ ] , uncertainty is an inevitable factor that is inherently present in treatment decisions. thus, in an uncertainty context, the consequences to be obtained depend on the alternatives and the state of nature [ , ] . in other words, for each alternative and each state of nature, which is represented by the chances to survive and chances to death, a consequence is obtained. for the alternative icu stay, the patient can survive the icu stay or die during the icu stay. for the alternative hospital stay, the patient can survive the hospital stay or die during the hospital stay. finally, for the alternative isolation at home, the patient can survive isolation at home or die during isolation at home. it is worth mentioning that in the decision tree technique the squares are the decision nodes, the circles are the chance nodes, and the arrows are used to connect these decision elements [ ] . in this context, in the decision tree constructed, four squares and three circles are presented. the decision tree constructed is illustrated in figure . based on the decision tree illustrated in figure , the mathematical model used to construct the utility-based multicriteria model is described in the next section. this mathematical model connected the decision elements presented in figure to obtain the recommendations (outputs) for the screening problem investigated. in this section, the mathematical model, presented in the utility-based multicriteria model, is described. this mathematical model is based on the multiattribute utility theory (maut) [ ] and takes into account the concepts of the utility theory [ ] and multicriteria approach [ , , ] . the utility theory [ ] is a very appropriate way to deal with decision-making under uncertainty. in this context, states of the world (or states of nature) are used to represent the uncertainty presented in the decision scenario. also, for each state of nature, probabilities are assigned to represent their chance of occurring, and these are obtained by an expert or by the decision-maker (from the subjective expected utility model) [ ] . in this context, regarding the screening decisionmaking process considered in this study, the states of nature are survival or death, and the alternatives are the options to conduct the healthcare treatment with the patients with suspected covid- , with three alternatives being considered: icu stay (icu), hospital stay (hs) and isolation at home (ih). also, two criteria are considered in this complex decision situation, the life of the patient being screened and the cost of the alternative indicated for that patient. the cost of an alternative is subjectively related to the impact on the health system, considering resource constraints. therefore, alternative "home isolation," for example, presents no cost for the health system, since the patient will stay at home and no health resources will be occupied by this patient. for alternative "icu stay," however, the cost for the health system might be high, especially when icu occupation is high and resources are scarce. the alternatives are evaluated in each one of these criteria, considering the multicriteria decision scenario [ , , ] . thus, for this decision-making problem, the decisionmaker's preferences are assumed to be represented by maut [ ] . in this context, from the corroboration of the additive independence condition, the additive aggregation analytic form is used to construct the mathematical model. the multiattribute utility function is presented in equation ( ), where a is the alternative, k j is the scaling constant for criterion j, and u j ðaÞ is the marginal utility function in criterion j: it is worth mentioning that the scaling constants are obtained by applying an elicitation procedure with a decision-maker. the values of the scaling constants, for both criteria, are equal to . and their sum is equal to , in accordance with maut concepts [ ] . the values of the scaling constants are presented in equation ( ): also, the utility functions represent the consequences in each state of nature. for this study, the marginal utility functions are also obtained in the elicitation procedure. in this context, for the criterion patient's life, the utility functions are equal for the three alternatives, namely, if the state of nature is survival and if the state of nature is death. equations ( ) and ( ) illustrate this condition: on the other hand, regarding the criterion cost, the utility function is the same, since it does not depend on the state of nature. in this situation, the resources were consumed in the hope of saving the patient, regardless of whether the patient survives or dies. in addition, for the criterion cost, the utility function for the alternative icu stay presented the worst value, since the health treatment in icu is more expensive. analogously, for the alternative isolation at home, the utility function presented the highest value, it being the most desirable alternative [ ] [ ] [ ] . an important consideration for the icu stay utility function is the dependence regarding another variable, which is associated to the probability of a "future patient" arriving in the healthcare system, in a severe condition, and requiring to be sent to the icu, combined with the occupation rate of the icu. this variable is called fp, this being an acronym of the probability of a future patient arriving in the healthcare computational and mathematical methods in medicine system. if fp is equal to , this indicates that no beds are available in the icu. in this context, the utility function for this situation presents the worst value, this being a chaotic situation. in this scenario, it is difficult to accommodate patients in the icu, with a tendency to recommend the alternatives hospital stay or isolation at home. as to these considerations, the utility function for an icu stay, for the evaluation in the criterion cost, is defined according to equation ( ): for the worst case, when the icu is completely occupied, fp is equal to (which means that sending the patient to the icu would lead to a very high cost, thus leading to an utility equal to ). in the opposite extreme case, fp would be equal to . however, a parameterization for three possible cases between these two extreme situations is considered for the decision information system: high occupation (fp = : ), intermediate occupation (fp = : ), and low occupation (fp = : ). in order to define these values of . , . , and . , three doctors were consulted and simulations were performed in order to verify which values fit best according to doctors' actual attitude. it is worth mentioning, however, that these values depend on the decision-maker judgments, and in the sidtriagem, these ranges can be adjusted if the user so desires. the utility function for isolation at home, in the criterion cost, i.e., ðuðchiÞÞ, is equal to . also, the utility function for hospital stay ðuðchsÞÞ is between and . in this study, the utility function equal to . is considered. however, a variation can be applied using the monte-carlo simulation, as presented in the next section. finally, another important variable to be considered in this mathematical model is the subjective probability assigned for each state of nature in order represent its chance of occurring. thus, these probabilities are given by the physicians, considering their subjective evaluation about the patient's state of health. in other words, the physician has to define a probability of surviving (chance of surviving) for the patient considering each one of the alternatives. these probabilities are represented by πðshiÞ,πðshsÞ, and πðsicuÞ; their sum being equal to . also, the chance to dying is the complementary probability of the chance to survive. therefore, based on these considerations, the utilitybased multicriteria model constructed for the screening decision problem is described by equations ( )- ( ) . computational and mathematical methods in medicine as to equations ( )- ( ) , the physicians receive a recommendation about which alternative is the best one for accommodating the covid- patient. this is the one that presents the highest multiattribute utility function. in the next section, a practical application of this utilitybased multicriteria model is presented in order to illustrate how this mathematical model is used to support the decision-making problem about screening. also, the decision information system, called sidtriagem, is presented. to apply the proposed model for aiding the screening of patients with suspected covid- , the physician should first input information about the patient's chances of survival in three scenarios: isolation at home, a hospital stay, or in an intensive care unit (icu). this information should be given based on the patient's symptoms and clinical state. these chances of survival, however, are not precisely established and involve subjective factors that may not be quantified. therefore, during the development of the system, three physicians were consulted by an analyst in order to find out what would make them feel more comfortable about providing such information. as a result of this consultation process, it was verified that the physicians preferred to give information about chances of survival on a verbal scale, instead of providing numbers. thus, a -point likert scale was developed for establishing such probabilities: very low, low, medium, high, and very high. each of these levels is associated to a probability range of % width, which was also calibrated with the physicians. the reason of using probability ranges instead of exact values of probabilities is related to the inherent imprecision and subjectivity of this information. table illustrates the association of each level of the scale with the probability ranges. according to those probability ranges, a monte-carlo simulation is performed in order to obtain a recommendation of conduct for the physician. at each simulation instance, a random number between the lower and upper limits of table is generated for each probability of survival, according to a uniform distribution and taking into account the levels of the verbal scale provided by the user. the recommendation given by the model is based on a robustness index that is computed for each alternative. the robustness index of an alternative is related to the percentage of simulation instances in which the expected overall utility of that alternative is greater than the expected utility of the other alternatives, in accordance with equations ( )- ( ) . the model therefore recommends that the user follow the alternative with the largest robustness index. the proposed approach for aiding the screening of patients with suspected covid- is operated by means of a dis, called sidtriagem, which is available for users at http://insid.org.br/sidtriagem/app/. physicians log on to the system and then he/she enters the patient's name, age, and gender (optional data). figure shows the interface of the system, with a practical hypothetical example. in figure , a year-old woman is considered to have been evaluated by the user of the system (a physician) at a healthcare unit. by examining this patient and analyzing all her symptoms and her clinical state, the physician enters information about the chances of survival of this woman in three scenarios: in an icu, in a hospital ward, and during isolation at home. let us assume that the physician evaluates her as either very high or medium or very low, respectively. then, the physician should estimate the icu occupancy rate at that time, also on a verbal scale: low, intermediate, and high. as previously explained in section . , this icu occupancy rate is for calibration of the fp parameter, which influences the utility of the cost of sending the patient to the icu. let us consider that there is intermediate occupancy rate at that moment. finally, the physician may optimally state how confident he/she is about the information provided: very unconfident, unconfident, neutral, confident, very confident, or even n/a. this information is not used by the mathematical model, but it may be further used in future studies to evaluate the behavior of physicians in such situations. after entering all the input data, the user clicks on the "calculate" button and the recommendations obtained based on the simulations are shown to the user. in this case, the recommendation of the system is to send the patient to the icu, with % of robustness. this means that, in % of the simulations instances performed, this alternative had the highest expected utility, compared to hospital stay and isolation at home. hospital stay had a robustness index of %, which means that in % of the simulation instances this alternative had the greatest expected utility value. the robustness index for isolation at home was , indicating that this alternative never wins against the others in terms of expected utility. the system also provides user with an alternative way of visualizing the results. by clicking on the "switch to graphical visualization" button at the bottom of figure , a bar graphic appears as an alternative possible visualization, as figure shows. these two ways of visualization were included in the system due to the feedback of the physicians; some of whom prefer to visualize them in a table with numbers, and others prefer graphics. therefore, the system provides both numbers and graphics. finally, the user may choose to state whether or not he/she intends to follow the recommendation. also, there is a space for recording the feedback of the users of the system, by clicking on the "conclude" button. this feedback helps to make further improvements to the model and to the system itself. it should be highlighted here that this system should be used as a support tool for aiding screening decisions, based on a structured mathematical model. there are no normative computational and mathematical methods in medicine purposes, however, with the use of this system. a recommendation is given, but the final decision always rests with the physician, who should take into account all subjective factors involved in each specific situation. in this paper, a utility-based multicriteria model for aiding screening decision situations of patients with suspected covid- was proposed. the screening problem is critical due to the scarcity of treatment resources in hospitals, such as icu beds, for instance. therefore, a structured mathematical modeling of this problem is important for aiding physicians to decide if a suspected covid- patient should go to an icu, a hospital ward, or stay at home in isolation. the mathematical model was built based on the decision analysis concepts and multiattribute utility theory (maut), considering the inherent stochastic nature of this decision-making problem. considering the inherent imprecision associated to estimating the patient's chances of survival, the proposed model works with probability ranges that serve as an input for a monte-carlo simulation model. moreover, considering the difficulty that physicians have in providing this information due to the subjectivity of the factors involved, a verbal scale is used for estimating patients' chances of survival. the proposed approach is operated by means of a decision information system, which has a user-friendly interface and can be easily used by physicians in healthcare units worldwide. the information obtained from the occurrences registered in the system is stored in a database. finally, as suggestions for future research, the occurrences registered in the system would be extremely useful for conducting several kinds of analyses, including a comparative analysis of what the model proposes and what doctors actually do, in practice. also, behavioral studies based on the data computational and mathematical methods in medicine obtained from the physicians' records may be useful for improving the design of decision information systems and their functionalities. the database generated from the occurrences registered in the sidtriagem used to support the findings of this study are restricted by the ethical committee in research of the federal university of pernambuco with caae ("certificado de apresentação e aprecição Ética" -certificate of presentation and ethical appreciation) number . . . in order to protect patient privacy. data are available from the corresponding author upon request according with the criteria for access to confidential data. modeling the spread of covid- infection using a multilayer perceptron clinical characteristics of coronavirus disease in china clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study mathematical modeling and models for optimal decision-making in health care decision analysis with multiple conflicting objectives theory of games and economic behavior information provided by diagnostic and screening tests: improving probabilities decision analysis model for prehospital triage of patients with acute stroke decision analysis supports the use of drain amylase-based enhanced recovery method after esophagectomy risk preferences: consequences for test and treatment thresholds and optimal cutoffs typespecific screening for asymptomatic herpes infection in pregnancy: a decision analysis screening for west nile virus in organ transplantation: a medical decision analysis a cost-effectiveness analysis of screening methods for dysphagia after stroke a cost effectiveness analysis of thiopurine methyltransferase testing for guiding -mercaptopurine dosing in children with acute lymphoblastic leukemia a costeffectiveness analysis of coagulation testing prior to tonsillectomy and adenoidectomy in children incorporating equity-efficiency interactions in cost-effectiveness analysis-three approaches applied to breast cancer control pharmacoeconomic analysis of thiopurine methyltransferase polymorphism screening by polymerase chain reaction for treatment with azathioprine in korea cost-effectiveness of pancreatic cancer screening in familial pancreatic cancer kindreds screening for colorectal cancer: the cost to find an advanced adenoma probability of roadside accidents for curved sections on highways advances in decision analysis: from foundations to applications multiple criteria decision analysis: an integrated approach multicriteria and multi-objective models for risk, reliability and maintenance decision analysis physicians' perceptions and attitudes regarding inappropriate admissions and resource allocation in the intensive care setting economics of end-of-life care in the intensive care unit a review of cost studies of intensive care units the authors would like to acknowledge the academic qualifications of higher education personnel-brazil (capes), the brazilian research council (cnpq) ( / - ), and the foundation of support in science and technology of the state of pernambuco (facepe) (apq- - . / ), for the partial financial support for this research. the authors declare that there is no conflict of interest regarding the publication of this article. key: cord- -ny vvu h authors: clarfield, a. mark; jotkowitz, alan title: age, ageing, ageism and “age-itation” in the age of covid- : rights and obligations relating to older persons in israel as observed through the lens of medical ethics date: - - journal: isr j health policy res doi: . /s - - -y sha: doc_id: cord_uid: ny vvu h covid- , the illness caused by the sars-cov- virus, has reached pandemic proportions. although the virus can cause disease in anyone, it is particularly dangerous for those with various “co-morbidities” such as heart disease, hypertension, diabetes, obesity and others. furthermore, advancing age (from about on), even in those older persons without any accompanying illnesses, is a strong and independent risk factor for pneumonia, need for an icu bed and death from the virus. it is therefore essential to find ways to protect all at-risk persons (old or young) from the virus but at the same time not harming, more than absolutely necessary their essential freedoms as well as taking into account their social/psychological needs. compared with other oecd countries, israel’s population is still relatively young, with only . % being over + with a smaller proportion of older persons in long-term institutions than that found in most other comparable jurisdictions. these factors might explain a part of the country’s (so far) relatively low rates of serious disease and mortality compared to those seen in other developed countries. however there are still over a million older citizens at risk and the numbers of infected, hospitalized and seriously ill persons are rising once again. this is no time for complacency. an analysis of the effect of age on the disease as seen through the principles of medical ethics is followed by a proposal as to how best to balance these sometimes conflicting goals. this paper relates mainly to older persons in the community since the ministry of health early on in the pandemic initiated an effective program (magen avot) meant to protect those older persons in long-term care institutions. recommendations include the ministry of health publishing clear guidelines as to risk factors and offering sensible advice on how to practice physical (not “social”) distancing without exacerbating an older person’s sense of social isolation. in order to reduce the incidence of influenza (which can clinically be confused with covid- ) and the potentially disastrous consequences of a “double pandemic” this coming winter, a robust flu vaccination program needs immediate implementation. persons at all ages (but especially those +) should be encouraged and assisted to sign advance directives, especially those who do not wish to undergo invasive therapy. an individual older person’s wish to “make way” for younger people should be respected as an expression of his/her autonomy. as we enter the second wave, triage mechanisms and protocols need to be circulated in readiness for and well before a situation in which an acute imbalance develops between the availability for acute resources and the population’s need for them. the ministry of health, in cooperation with other relevant ministries and ngos, should take the lead in developing plans, ensuring that they are carried out in an orderly, timely and transparent manner. the blanket is indeed not large enough but we must place it as judiciously as possible in order as much as possible to protect, cover and keep warm the body politic. supplementary information: supplementary information accompanies this paper at . /s - - -y. the sars-cov- virus can effect anyone at any age. as it continues to spread throughout the world it will clearly be with us for the foreseeable future. fortunately, at any age, almost all infected people (even older persons) will overcome this infection without serious sequelae. that being said, the waning immunological vigour of older persons and presence of risk factors ("co-morbidity") often accompanying older age (hypertension, increased bmi, diabetes, chronic lung disease, immunomodulation-immunosuppression, smoking, ischemic heart disease and cerebrovascular disease, etc.) make the disease a much more serious event for many older people. furthermore, it presents special challenges to their doctors and to the health care system (ref [ ] ). for those infected, the incidence of severe disease rises inexorably and logarithmically with chronological age (beginning around age ). comorbidity adds to the risk but does not replace age as an independent factor. some older patients will develop viral pneumonia and a relatively small subgroup will require icu and ventilator support. however, should these numbers grow too quickly, they can easily overwhelm the number of medical staff, hospital beds and ventilators available -a dire situation already observed in several places around the world. many of these acutely ill patients will die and the majority, even if they do survive, remain in the icu for many weeks. in this paper we address the issue of old age and how this particular coronavirus specifically effects older people with israel's experience being the framework for this exploration. in order to do so we first describe the country's demography briefly followed by a few words about formal jewish law (halacha) and its role (or surprising lack thereof) in framing health policy. next, the issue of aging itself is dissected: its role as a risk factor for and the influence of lockdown policies on older persons. as well we define "ageism", explaining the concept's relevance: what it is and what it is not as well as how ageism can adversely affect older persons during this crisis. we then analyze some of the trenchant dilemmas relating to covid- through the lens of medical ethics, examining the issues of triage and distributive justice, maximizing non-maleficence and how to ensure that older people's autonomy is facilitated while ensuring that they also remain safe (beneficence). given all of the aforementioned, we offer a specific program for how to move forward and help older persons and the health system to stay afloat as we try to ride the second wave of the pandemic without drowning. compared with most other industrialized countries, israel's population is still relatively young. this demographic pattern effects the expression of the pandemic in the country. see sidebar for details. across the globe the reported case-fatality rate (ratio between confirmed deaths and confirmed cases) for covid- is around . % (more than times that for influenza), but this number can vary widely by locationas high as . % (italy) to less than . % (iceland) (https://ourworldindata.org/grapher/coronavirus-cfr; accessed oct., ). in israel, at least so far (as of late october, ), this rate is still relatively low at . % and despite the very sharp recent rise in confirmed cases it has held reasonably steady over the past few months. examining another ratio (again, as of late october, ), per million population have died here compared with in the uk or in the us, although the rate in israel may rise given the recent increase in new cases observed. (see https://www.worldometers.info/coronavirus/ accessed october , ) . for various reasons, early on, in the spring of , the country coped quite well -with a very low infection rate, few severe cases and a very low death rate. however, coinciding with (or because of) a too rapid release from the lockdown, the figures have deteriorated over the past few months, especially recently (late october). for example, according to the ministry of health's (hebrew language) dashboard (see https://datadashboard.health.gov.il/covid- /?utm_source=go.gov.il& utm_medium=referral; accessed oct., ) the number of new confirmed cases almost doubled in the last week of august and the number of severe and ventilated cases has gone up by % in the last week of august. as of late september the government had reclosed the country more or less hermetically after a failed policy of quarantining "hot" cities or neighbourhoods with particularly high rates of infection -most of these being haredi (ultra-orthodox) or arab municipalities. as such, beginning just before judaism's most holy day of atonement (yom kippur) the country has once again been hermetically closed down for a planned two week (at least) period. this after the failure of localized urban quarantines which failed to dampen the epidemic -most of these being in haredi (ultra-orthodox) or arab municipalities. this picture can hardly be considered successful policy management even if there remains legitimate argument about the variance caused by each of the many steps taken (or not) to date. clearly, these numbers express a moving target and it is not easy nor often possible to tease out the exact cause and effect for rising or falling rates which may be affected by many variables such as change in or extent of testing policy and others. furthermore, improved treatment protocols have brought the pressure for icu/ventilator resources down somewhat. equally important, with respect to a possible exhaustion of the health system through care seeking, the number of hospital beds, trained personnel etc. may be much more important than the number of ventilators. overall, given the larger number of asymptomatic people than those identified as infected, the overall death rate for those actually infected may be even lower than that reported. however, we do not yet know if all those who do survive serious illness will return to their premorbid state of health and function. there is some doubt that this will be the case, with a prediction that a significant minority may suffer serious long-term sequelae subsequently requiring rehabilitation (ref [ ] ). in israel, in response to this pandemic, as has been the case in many countries, initially broad and very strict social distancing measures were enacted for the whole population. however, after the number of cases fell precipitously in may these strictures were loosened. unfortunately, despite warnings by relevant professionals, this release was allowed to take place much too quickly and in a rather haphazard manner, with a resultant recrudescence of cases. not surprisingly, many older people found these lockdown steps very difficult to tolerate as a result of being almost totally cut off from family and friends, not to speak of having to look after themselves with minimal help from outside. there is concern that the dangers of social isolation for older people may equal or even outweigh its benefits (ref [ ] ). as such, some have called for a useful change in terminology from "social" to "physical" distancing. furthermore, some older people in israel were skeptical of the government's motives and felt that they were being "sacrificed" to keep the medical system functioning in order to favour younger citizens. for their part, many younger people continue to express skepticism relating to the dangers of sars-cov- as a result of their low chance of suffering a complication should they become infected and in part because of their understandable lack of faith in the present government and its actions. although we are dealing with a fast and erratically moving target, with the present situation in mind this paper will elucidate relevant issues and offer policy recommendations germane to when and how older persons can minimize risk and at some point in the future return to their pre-covid- routine in israel. the general approach taken is that of a "soft utilitarianism" (i.e. what promises the greatest good to the greatest number) while at the same time we make every effort to minimize damage to individual human rights and to ensure that the scourge of ageism does not manifest itself. against the odds, if the epidemic once again quickly subsides, the issues addressed herein will be much less relevant. however, this paper is meant to deal with the much more probable scenario in which sars-cov- will be with us for months, perhaps years to come, and especially as we now suffer a second wave more severe than the first. and as was the case in the / influenza epidemic, we may even have to endure a third wave. around the world, as a first and necessary step, blanket physical distancing has proven itself, as it did in previous influenza pandemics (both and ). along with heightened personal hygiene, hand washing, and especially the use of face masks, this blunt instrument had until very recently (mid-june) largely reduced and delayed peak attack rates in many countries as well as reducing mortality and the number of very sick persons requiring hospital care (ref [ ] ). in israel and elsewhere, but unfortunately not everywhere (see northern italy ref [ ] and spain), this tool helped save many lives as well as reducing pressure on acute and icu hospital beds, of which israel is lacking. as well, this step has helped at least so far to preserve precious icu/ventilator beds for the use of young and old alike. along with the whole population so far, at least physically, older persons have benefitted from these drastic measures, although the national economy is taking a severe blow adding not surprisingly to social and political instability. as the country locks down again, the question arises once more as to what approach should be taken. an excellent overview of how to manage such a challenge can be found in tomas pueyo's much cited article "the hammer and the dance" in which the "hammer" refers to the lockdown resulting in abrupt social distancing meant to flatten the curve and the "dance" to how we can get out of lockdown with the least possible loss of life whilst making every effort to maintain the economy (https://medium. com/@tomaspueyo/coronavirus-the-hammer-and-thedance-be b ). explaining the hammer in an interview pueyo stated, "i wanted to create a very strong metaphor ….that could represent the idea of something aggressive early on and then something less aggressive afterwards." he termed the next phase a dance …because it is a much more fluid phase. you need to know the steps of the dance and really apply them as if it were choreography. (see: https://abc news.com/society/viral-hammer-and-thedance-influences-reopening-amid-pandemic/ / accessed sept., ). with respect to older persons, however much it reduces risk, there is justifiable concern over the real health costs involved in physical distancing by keeping older persons confined too strictly and for too long to their homes. these include ill effects, both medical and psychological, especially on those of low socio-economic status (https://www.nytimes. com/ / / /opinion/coronavirus-elderly-suicide.html). furthermore, there is some early anecdotal evidence from both here and abroad that many people have delayed clinic or er visits for non-coronavirus conditions, putting their overall health at risk. it is also not clear under lockdown how many isolated older persons have been able to manage their day to day affairsgroceries, medications, household cleaning and repairs. all this is especially problematic when these people cannot avail themselves of the help of their children and/or neighbours. without this aid it is difficult for such older persons to cope with social isolation and resulting loneliness. in order to analyze this complex issue, whilst taking a morally defensible ethical stance, the approach herein attempts to balance the sometimes conflicting principles of medical ethics, namely: autonomy, beneficence (doing good), non -maleficence (not doing evil) and distributive justice. with % of its population being jewish and given the country's unique history, it will come as no surprise that jewish law and traditions will sometimes influence both israel's norms and laws. (see sidebar .) biological ageing: what is it? the phenomenon of ageing does not necessarily lead to disease but it does gradually reduce the human organism's ability to withstand stress and is thus relevant to considerations re the effects of the sars-cov- virus on older persons. (see sidebar ). just as for many other diseases, there are "risk factors" for developing covid- , this term refers not to the disease per se but as something that increases a person's chances of developing one. for example, cigarette smoking is a risk factor for lung cancer, as is the metabolic syndrome for heart disease. however, having a risk factor does not guarantee that one will inevitably develop the illness in question. it just makes the disease more likely. for its part, chronological age (even when controlling for other characteristics) is clearly one of the most significant risk factors for covid- pneumonia, the need for ventilator support and above all for death (ref [ ] ). why this is and what implications this fact might have for relevant policies will now be addressed. fortunately, for reasons not yet clear, young people (especially children - years old) seem hardly to be affected by this coronavirus. although they are indeed very efficient spreaders to adults for influenza, it appears that with the coronavirus this may fortunately not be the case. furthermore, although further work needs to be done to reach a firm conclusion, it is possible that young children may actually not constitute a significant danger to their teachers, parents or grandparents. however, at the other end of the spectrum, as alluded to above, increasing age is most definitely an independent risk factor for complications and death once a person is infected (ref [ ] ). for example, an intensive care audit from the uk showed a very poor covid- pneumonia icu survival rate for those over of less than a quarter (only . %) versus more than three quarters survival ( . %) for those - years of age (ref [ ] ). a more recent study from northern italy indicated an equally dire prognosis for older men admitted to icu with a death rate of % for those - years old and % for those - (ref [ ] ). the numbers were even higher if the patient had hypertension. there are similar figures from israeli icus and elsewhere across the world. tragically, although treatment protocols have indeed increased the chance of survival at all ages, the bottom line is that older persons who become ill enough to require ventilator support are very unlikely to survive. an understandable point has been made that not all older persons are the same. for example, it has been argued that one can find an year old who by a combination of good fortune, favourable genetics and careful lifestyle choices, is in better health than an individual year old with none of these three characteristics. in other words, the "biological" age of a particular year old may well be less than the chronological age of an individual younger by a decade or even two. while this may occasionally be the case, it would be very difficult to assess this phenomenon in any accurate or scientific way within an age cohort (e.g. - or +). and unfortunately, despite the wishful thinking of many older persons and some mistaken authorities, the facts show that the older one is, the higher the risk even when controlling for various relevant co-morbidities. one study indicated that an + year old with no known diseases still has fewer years left to live than does an - year old with (!) co-morbidities (ref [ ] ). sadly, these facts put to rest the attractive myth that a heathy older person can be at lower risk from covid- than younger people with co-morbidities. to this end, the renowned american centers for disease control (cdc) provide a simple guidance, listing two rubrics for risk: ) older adults -even without comorbidity and ) those with underlying conditions -at any age. (see: https://www.cdc.gov/coronavirus/ ncov/need-extra-precautions/people-at-increased-risk. html; accessed sept., ). so too did the canadian geriatrics society make similar recommendations using age + (unrelated to the presence or absence of risk factors) as the number at which risk begins to rise (see: https://cgjonline.ca/index.php/cgj/article/view/ / ; accessed sept., ). patients in nursing homes have been and likely will continue to be a particularly hard hit group, as has been observed in europe (https://www.theguardian.com/world/ /apr/ /half-of-coronavirus-deaths-happen-in-carehomes-data-from-eu-suggests), canada and in the us (https://www.nytimes.com/ / / /us/coronavirusnursing-homes.html). in israel, although the absolute numbers remain low relative to many other countries, institutionalized residents still make up about one-third of the covid- victims. this is of course bad news but fortunately we have not witnessed the terrible scenes of neglect observed abroad. fortunately, early on in the pandemic, the moh published and at least partially enforced comprehensive guidelines as to how to deal with this sector (https://govextra.gov.il/media/ /elderlycare-covid .pdf; accessed sept., ) with a special team dedicated to dealing with this situation. "lockdown" policies: ageism or age-protective? in israel, despite some protest, chronological age has been considered as one of the first criteria for social isolation or "stay at home directives", and ultimately considered the last to be released from lockdown. there are several reasons to support such a consideration as well as counter arguments. these are addressed now, followed by a possible solution which attempts to balance the main conflicting considerations. such guidelines need to be scientifically valid, transparent, workable, and insofar as possible, fair so that most in society will be able and agree to buy into it. however before moving on, one must address the complex issue of "ageism". it was the late, great gerontologist dr. robert butler who first defined the term, which according to the who constitutes " … the stereotyping, prejudice, and discrimination against people on the basis of their age [alone]. ageism is widespread and an insidious practice which has harmful effects on the health of older adults. for older people, ageism is an everyday challenge. overlooked for employment, restricted from social services and stereotyped in the media, ageism marginalizes and excludes older people in their communities." (see: https://www.who.int/ageing/ageism/en/ accessed sept., ). clearly, the use of someone's chronological age to stereotype and discriminate (in the social sense of the word) is completely unacceptable. for example, age cannot be a criterion for a job for which it is not relevant (e.g. accounting, childcare or academic promotions, etc.). but some well-accepted regulations do use chronological (not even "biological") age as an inclusion and exclusion criterion for certain types of work. common sense is called upon here. for example, it is unlikely that most passengers, even the most gerontophilic, would feel completely comfortable watching two otherwise healthy year old pilots enter the cockpit to preside over a h trans-atlantic flight. in recognition of this logic, even though one could claim it is an expression of ageism, most authorities restrict commercial airline pilots' license to those younger than . even then they must also prove that they are healthy (https://www.easa.europa.eu/sites/default/files/ dfu/easa_rep_resea_ _ .pdf). in contrast, a situation in israel where sadly ageism is still definitely at work can be found in the agemandatory retirement laws governing academia and the civil service. in our view these policies are wrongheaded but this issue is beyond the purview of this paper. on a more positive note, chronological age is used to entitle a universal pension or rights for certain services (e.g. in israel, homemaker hours according the nursing care act, etc.). age also confers discounts on public transport to wealthy older persons rather than poorer younger onesa case of "reverse ageism?" more trivial perhaps, but still relevant to this discussion, there seems to be no serious societal objection to older person receiving discounts to films, concerts and even municipal taxes, simply on the basis of age alone. one could even argue that we use age to discriminate to a significant degree against younger people, e.g. forcing (almost) all israeli youth to register for the military draft at age and obligating most of them to serve their country and possibly endangering themselves to protect their elders for at least - and sometimes many more years during their own early and formative years, returning to serve in the reserves for many subsequent years. might this not be considered another example of "reverse ageism"? writing recently in the bmj, one british authority pointed to a disturbing phenomenon. "what is undoubtedly ageist is a collective fear of ageing and death in our societal and media values, meaning that appearing old is seen as being diminished, invisible, and unvalued by society. this in turn leads to older people themselves 'othering' any older people they see as being vulnerable, different from their more youthful and active selves. this can lead to 'grey on grey' ageism." (ref [ ] ). true, but even worse in our view has been society's lack of preparedness for how this virus could affect older persons that constitutes the true expression of discrimination against older personsboth in israel and abroad. for those older persons who, despite knowing the facts, might chose to take risks and expose themselves to this virus, some will argue against an ageist "paternalism" that would prevent them from exercising their human rights. this means that a person at risk at any age must be free to make an individual decision as to whether he/ she is willing to go back out into society, take the risk of falling ill with covid- and accept the consequences, however dire they may be. this claim, in contrast to the one re the older airplane pilot falling ill and endangering all passengers, assumes that older persons are only endangering themselves were they end up needing hospitalization or an icu bed. indeed, should this second wave respond to steps being taken and wane quickly and israel be assured that we have enough icu beds to manage any surge, this claim will be valid and the older person or anyone with other risk factors must be free to take their chances. however, as we are now riding a second wave, this argument (supporting autonomy) seems much less valid in that it will be also be crucial to protect the stock of hospital and icu beds so that they would be available for as many as possibleyoung and old. in such a case it may well become necessary to be stricter in regulations taking distributive justice into account by enforcing isolation of all high risk groups, older persons among them. for its part, the israel gerontology association (long the lead in many important age advocacy initiatives) joining a coalition with four other organizations, have mobilized in the direction of protecting the autonomy of older persons against what they view as an ageist paternalism. they argue that using chronological age as a sole criterion discriminates against some older healthy persons who they claim may even be at less risk than younger sicker people. recently this coalition responded to the joint questionnaire of special procedures mandate of older persons sent out by the un (see: https://www. ohchr.org/en/hrbodies/sp/pages/joint-questionnaire-covid- .aspx; accessed sept., ). the coalition did make some important points, warning for example of the dangers posed by ageism to israel's older population brought on by the covid- crisis (personal communication prof yitzhak brick). unfortunately, the coalition members also made the incorrect claim that chronological age is not an independent risk factor for covid- complications, despite the clear evidence that it is. for example, in error they offer that, "[f] irst, it was clear that there is no difference between old and young people with regard to infection. secondly, most of the older persons who died from the disease suffered from co-morbidities and severe health risk factors. % of the people who died from the covid- , came from long term facilities." their statement goes on, claiming, " … .that the chronological age cannot be the sole criterion [as to who needs to stay at home], as some people at high age are fit and healthy and others who are younger can be sick and frail, old persons are not all the same. policy makers should not depend on the chronological age when they decide about who has the right to go out of his home or not, and the decision should be made by the person himself [italics ours]." this error of fact, the claim that chronological age is not an independent risk factor, does no service to the elderly and will in fact mislead those who need to make difficult decisions in the weeks and months ahead. others, such as the british society of gerontology have made similar claims (ref [ ] ). there is also a growing protest movement among some older people in israel (ref [ , ] ) as well as in europe (https://www.wsj.com/ articles/older-europeans-reject-calls-to-remain-in-isolation-as-lockdowns-ease- ; accessed sept., ) arguing against the justification of such strictures. beyond the issue of ageism, this argument rejects any offer of beneficence, adducing autonomy as the highest ethical value. however, most liberal democracies do put a limit on such considerations in other relevant domains and most citizens will accept these restrictions as reasonable. for example, at any age, one must wear a seat belt when driving. societies demand such steps not only to protect the individual and his/her family (principle of beneficence, aka "paternalism") but also in order to preserve the commons (principle of distributive justice). in the absence of such strictures, society would be more likely to lose the productive years left to an individual who is killed or badly injured in a car accident. in the spirit of both beneficence and distributive justice, lowering the costs to society of premature death or the subsequent rehabilitation of those who survive a car accident seems a reasonable consideration which justifies the (partial) curtailment of a citizen's autonomy. closer to the elder pilot argument is the dire effect that too many people (at any age) simultaneously falling ill with covid- would have on hospital servicesparticularly but not exclusively icu/ventilator beds (principle of distributive justice). although we are still not (yet) in that dire situation in israel, this is not just a theoretical argument as we have seen examples from around the developed world of health services becoming overwhelmed or coming very close to doing so as a result of too sudden and heavy a surge on bed and personnel availability (ref [ , ] ). according to this argument, it is not only in the personal interest of high risk people (older persons as well as younger people with co-morbidity) to make every effort to avoid infection. as well, the argument goes, they should do so in order to help maintain the viability of a health system given that this organization needs to be capable of looking after them should they (or their children or other younger persons) fall ill. of interest is the sense that despite the recent relaxation of formal strictures, preliminary data from israel's largest health fund (clalit) suggest that older persons seem to be voting with their feet to protect themselves. they seem to be voluntarily observing stricter behaviours than those demanded by the israeli government. as pointed out in the times of israel on july, , though israel's infection rate has soared to some - new cases a day in recent days, the percentage of serious cases has been far lower. for example, at the height of the first wave in mid-april, some of a total active cases were considered serious, or about . %. on saturday [ july, ], of , cases were considered serious, or about . %. (see: https:// www.timesofisrael.com/at-risk-groups-less-hard-hit-in- nd-wave-causing-fewer-serious-cases-analysis/; accessed sept., ). against the claim of "ageism" and in the spirit of supporting both "distributive justice" and intergenerational solidarity, others feel that especially in a situation of a critical imbalance between demand and icu resources, it is indeed justified to use chronological age as a criterion (among others of course) for the allocation of scarce resources. for example, a noted american medical ethicist franklin miller (himself years old) offered, "if demand for ventilators keeps growing and further outstrips supply, i believe it could be justifiable as a matter of policy to forgo mechanical ventilation for all patients years of age and older who have a medical condition that puts them at elevated risk of death, such as chronic renal disease, cardiovascular disease, diabetes, and chronic lung disease" (ref [ ] ). another authority, larry churchill went even further offering ("as i approach my year") his own personal ethical approach which would give priority to a younger person (ref [ ] ). closer to home, a.b. yehoshua one of israel's foremost writers and thinkers, expressed himself in a similar vein (ref [ ] ). not all will accept nor support this stance but it does seem to be a position taken by at least some older persons. of interest, colleagues from the field of social gerontology have objected that even such self-sacrifice is in their view still ageist. obviously, none of the three abovementioned distinguished older persons would agree. undoubtedly they would hold that not allowing one to take this approach constitutes an unjustified attack on their autonomy. should the present second wave tower high enough to threaten to overwhelm israel's limited supply of icu and ventilator stock (as was observed in italy, spain and ny state several months ago), the need for difficult choices will inevitably arise. much has been written about the vexed subject of ventilator triage (ref [ ] [ ] [ ] ). relevant statements have also been published by the israel geriatrics society in hebrew on the website of the israel medical association (ref [ ] ) and in a modified english version in a geriatrics journal (ref [ ] ) as well as by a public commission set up by the moh (ref [ ] ). should they wish, and we believe many might elect to do so, a significant number of older persons could voluntarily avoid ending up a triage case or at least ensure clarity relating to their wishes should they reach such a fork in the road. in a thoughtful piece in the nejm, aronson recently offered, "i know many happy engaged elders in their s, s, s, and s … who would not want to be put on a respirator … patients and [the us] health care system would be better served if all adults and elders use some of the spare time created by our new, home-confined lives to discuss and document their care preferences, whether the goal is aggressive, supportive or palliative care." (ref [ ] ). unfortunately, israel is still quite far behind other industrialized countries in this domain, only recently beginning any discussions on the possibility of "a good death" (ref [ ] ). even worse, it is still very difficult and expensive to legally appoint someone an enduring power of attorney which is another way to reduce conflict and misunderstandings over this fraught issue. furthermore, problems of cognitive decline, impaired vision and hearing, not to speak of linguistic mismatch between health care personnel and their older patients (not uncommon in israel), could interfere with an older persons' understanding their situation and expressing their relevant wishes. aronson bemoans the dire effects of the absence of such planning (for any reason) which " … increases the suffering at the end of life …" with the presence of such documents helping " … people with serious or lifelimiting illness to live and die according to their personal preferences" (ref [ ] ). relevant efforts must swiftly be made to avoid the maleficence that might follow from ignoring this urgent need. for various reasons related to history and culture, israeli elders, even those with a very short life span (including people with advanced cancer or severe dementia) are often subjected to far more aggressive treatment than would be the case in other western countries. sadly, this phenomenon is observed even when such interventions are clearly futile and painful (ref [ , ] ). as such, in many cases, when an older person falls acutely ill in israel, he/she may be subjected to invasive procedures and an admission to icu etc. this despite the fact that had the older person really understood what was actually involved, they may well not have agreed to such an intervention. it is thus society's solemn duty to ensure that older persons clearly understand what the automatic fallback options are should they not have made their prior wishes known. furthermore, as addressed above, it is essential that older persons understand the fact that age is an independent risk factor for covid- complications and death. suggesting otherwise, despite the clear evidence that it is, does them a terrible disservice in that they may act to endanger themselves by thinking that as a "healthy" older person they are at lower risk than they actually are. how to manage this second wave? as israel enters its second lock-down (in late september coinciding with the day of atonement [yom kippur]) it is worth studying the approach by pueyo alluded to above (ref https://medium.com/@tomaspueyo/coronavirus-the-hammer-and-the-dance-be b ). but the truth is that at this stage, no-one has yet choreographed either a perfect "hammer" or "dance". all agree that it is economically and socially unsustainable to keep most of the population locked down and laid off indefinitely, even at the cost of more covid- deaths. without health, there is no wealth; but the opposite is also true. as such we must open up our societies as quickly but as we safely can. all of the suggestions offered below, in order to be humane (encouraging beneficence and maximizing nonmaleficence) and fair (distributive justice) and in part to compensate older citizens for having to wait until the younger ones are first "released", will require that society take some important steps in parallel. these would include ensuring that during the hammer and even for some time afterwards, older housebound persons would have their daily needs metmaterial, medical and psychological. space does not allow us to go into detail but an example would be special "older hours" for food stores, facilitated home delivery, availability of handymen, plumbers and electricians who would be on call via a central number, etc. and other relevant supports. all of these suggestions require that the moh, along with other relevant government agencies, keeps its finger on the pulse of the epidemicopening the faucet, testing and opening or closing it further depending on the results of extensive and focused testing. a step-by-step proposal ) with respect to the at-risk populations (those with relevant medical illnesses and older age), so far, even though the number of infected person is rising once again, at the date of writing (late october, ) the program recommended herein is still voluntary. this however could change should the situation worsen significantly. one hopes that relevant professional organizations (such as the ministry of health and the israel geriatrics society) ngos such as joint-eshel and lay bodies will use their influence to convince older people and others at high risk to voluntarily follow these guidelines, as they are both in their own individual interest and that of society'swith or in the absence of a lockdown. many of these steps have been taken previously but we are aiming at a rapidly moving target. however, should we reach a catastrophic situation of overwhelmed emergency rooms, insufficient ventilators (and/or the team members needed to manage them), mandatory lockdown of all high risk persons of any age might be required. ) save lives and protect the system (in that order). although it should be obvious by now, the three essential steps are physical distancing, wearing a face mask and frequent hand washing. and it is indeed distressing to observe how few young people in israel (and others around the world) seem to have internalized the need for such simple but efficacious behaviours. there are even a few world leaders who demonstrably refuse to cover their offending upper airways although fortunately this is largely not the case in israel. to this end, the state needs to more aggressively ensure the promulgation, explication and enforcement of relevant regulations and the supply of appropriate kit in public spaces. here we would expect the moh to lead the way with public health announcements supported by the media, neither of which have as yet excelled in this domain. ) it is critically important that public personalities, cultural figures, athletes and above all politicians follow and are seen to follow the rules. it is particularly difficult to ask the populace to act in a compliant manner especially when at least three of israel's leaders (all over age ), prime minister benjamin netanyahu, president ruby rivlin, and most egregious of all, the then minister of health (!) rabbi yacov litzman all shamelessly broke the moh rules over the recent passover holiday. and in early july the newly appointed minister of health yuli edelstein also flouted his own ministry's regulations. we are not alone, as many leaders from around the world have acted in a similar irresponsible way, but in this domain all politics are local. of interest is the welcome public apology recently offered by pres rivlin for his un-leader-like behaviour during the last major jewish/national holiday of passover (see: https://www.timesofisrael. com/as-lockdown-set-to-begin-rivlin-apologizes-forleaders-virus-failures/#gs.gk fz accessed sept, ). however, to the best of our knowledge, he is the only miscreant who has offered any such contrition. ) all of the steps outlined herein are mutually supportive. sensible physical distancing must be explained and defined so that older persons aren't unnecessary "imprisoned" in their apartmentsin other words, needlessly distanced socially. for example there is very little risk involved in meeting children and grandchildren outside in a park or garden strictly separated by m and wearing masks, etc. overly stringent, contradictory and irrational guidelines offered by the moh characterized the first wave and caused significant and entirely unnecessary suffering among older persons, especially but not only in sheltered housing (diur mugan). ) in the fall and early winter it will also be especially important to ensure a robust influenza vaccination program with wide availability of anti-flu medications (e.g. oseltamivir [tamiflu] ) given that the rise in flu cases which usually begins in november will be superimposed on the ongoing covid- pandemic. in this vein health personnel must be encouraged and perhaps even legislated to take a mandatory flu vaccine, given the disappointingly low rates of uptake by this crucial sector in israel in past years. further clinical guidance must be offered to older persons and physicians in the field as to how to handle a patient presenting with nonspecific "flu-like" symptoms from nov-marchswabbing, an algorithmic strategy if positive or negative for flu or sars-cov- , etc. ) all persons over age , even without co-morbidity, must clearly understand that they are at increased risk for complications and death should they become infected; the older, the greater the danger. this is the case even for an otherwise robust older person. comorbidity adds risk to chronological age; patients and their doctors must understand this clearly. despite pushback by some ill-informed pollyanna's, this message must be forceful and clear. here ngos such as the israel association of gerontology and joint-eshel could help spread the evidence-based word. ) many who fall seriously ill may elect to be hospitalized and if necessary ventilated (see above). however, there will be those who do not wish to undergo this procedure, instead opting for a more palliative approach. in order to exercise their autonomy, all adult citizens (especially those with any relevant co-morbidity and all those > years) should sign an advance directive. these are available on line from the moh (see https://www.health. gov.il/services/citizen_services/dyingpatientlaw/ pages/dyingpatientrequest.aspx). as well, it is advisable to prepare an enduring power of attorney ( ‫י‬ ‫י‬ ‫פ‬ ‫ו‬ ‫י‬ ‫כ‬ ‫ו‬ ‫ח‬ ). it is most unfortunate that in israel this process is so complex and expensive and the ministry of law shares responsibility for this dire situation. hopefully in the near future, it will be simplified and further encouraged. in the true interest of their older clients, relevant groups such as the israel association of gerontology, joint-eshel and other members of the abovementioned "coalition" should lobby to simplify these procedures and to convince more citizens to take this essential step in order to protect the exercise of their autonomy. in the absence of such guidelines, faced with a patient ill with covid- , clinicians will find it difficult to know what the individual patients' wishes are re ventilation. from the legal point of view in israel, family members have no formal say in such decisions unless they are the legal guardian ( ‫א‬ ‫פ‬ ‫ו‬ ‫ט‬ ‫ר‬ ‫ו‬ ‫פ‬ ‫ו‬ ‫ס‬ ) of an older person or have the enduring power of attorney mentioned above. strain, israel's hospitals are still just able to cope with the influx of covid- patients. however, this balance could change rapidly and should a severe mismatch between needs and resources develop, one would seriously have to consider the need for triage (see above). in this domain much has been written about chronological age alone not being a relevant consideration but most understand that this factor cannot be ignored. furthermore, adding a moral twist to the debate, doing so may be considered by some as practicing ageism. however, in our view, while age alone should not be used as a factor in triage decision making, common sense and the fact that mortality goes up logarithmically with age as well as the chance of coming off a ventilator becomes vanishingly small, it cannot be ignored. the moh would do well to introduce these guidelines into the legal regulations where relevant. ) those persons with significant comorbidity (at any age) are considered as belonging to the older person ( +) category. under present conditions they should be advised, insofar as is possible, to stay "shielded". however, using similar logic to that pertaining to ventilator triage, should the situation worsen significantly, in the spirit of maximizing distributive justice, consideration would be given to enforcing such behaviour. ) returning to all older persons ( +), depending on the results of the steps described above, if the situation once again allows, they should be encouraged to return to normal function -but only gradually and carefully. this would pertain to all "vulnerable" persons at any age with serious underlying health conditions (as previously outlined) and those whose immune system is compromised such as by chemotherapy for cancer and other conditions requiring such therapy. ) unfortunately much poor (and confusing) advice was disseminated to older persons during the initial lockdown with the moh failing to provide timely and accurate advice re prevention and health promotion. as we have now entered a new lockdown, the following recommendations would pertain. even now these guidelines are relevant to all older persons and any younger people at high risk. i. although not always easy to do so accurately, each person can try to determine his/her own risk from the coronavirus and make decisions accordingly. the moh should help by providing simple evidence-based guidance to people, taking into account one's risk profile, medical history and, if necessary, consultation with the individual's family doctor. the moh has published a schema on their website, but it is difficult to find, confusing and not known to most older persons. ii. even in the event of a strict "lockdown", persons of any age should still get out of their apartment and enjoy as much physical exercise as possible. there is no good medical rationale to prevent people at any risk not to walk, jog, outdoor yoga /tai chi, etc. -as long as masking and physical distancing are maintained. iii. re essentials (health, shopping, essential services), people at risk should get as much help as possible from delivery services, friends, family and the local authorities in order to minimize going out for these needs. some people will need assistance from the state/municipality to manage. examples of sensible social engineering taken in other countries include having supermarkets maintain certain hours for high risk persons and directing shoppers through aisles in a "one way" direction while also enforcing the two meter rule. to the best of our knowledge, none of this exists today the health funds (kupot haholim) will need to be ready to provide adequate medical services at home and/or at specially configured clinics at specific hours in the day. iv. all persons at risk need to maintain strict physical (not social) distancing including from family members (especially those aged +). with any outside contact, masks must be worn by all and no physical contact is allowed, including for example, passing plates of food back and forth. family visits outside in a private garden or public park should be allowed as long as everyone stays more than m apart. v. some older people may choose, in the spirit of maximalising distributive justice and out of a sense social solidarity towards the younger generation (as for example expressed by a. b yehoshua among others alluded to above ref [ ] [ ] [ ] ) and out of concern regarding their individual risk, to maintain even stricter social isolation as well as to give priority to younger persons. this decision should be neither minimized nor mocked. whatever one's thoughts about ageism, this choice is to be honoured and respected as a legitimate expression of the at-risk person's autonomy. we live in a society where certain younger age and occupational groups sacrifice for the health, safety and security of those older than them and this must be a bidirectional phenomenonespecially between consenting adults. vi. as addressed above, all older persons should be encouraged and if necessary helped to make and document decisions about advanced directives so that their wishes can be respected should their health suddenly deteriorate. this expression of autonomy is of paramount importance, especially in times of crisis and uncertainty and given the default option of aggressive icu and ventilation measures too often taken in this country. should a triage situation develop,clarification of this domain will also help reduce family uncertainty as well as decreasing unnecessary pressures on the health care system. ) as alluded to in sidebar , israel enjoys a population of approximately . million citizens over years, . % of whom live in the community. all of these recommendations refer primarily to older persons dwelling in the community however, they would not be as applicable to the % of older persons receiving homemaker care according to the nursing law ( ‫ח‬ ‫ו‬ ‫ק‬ ‫ס‬ ‫י‬ ‫ע‬ ‫ו‬ ‫ד‬ ) or who had an authorization for a personal attendant (usually a foreign worker). such people will be much frailer than the usual older person, exhibiting even a higher prevalence of co-morbidity and cognitive decline. another vulnerable sector would also not be included in this schema, that is persons in institutions for older persons (approximately , , that is . % of the elderly) with the possible exception of those more independent elders living in sheltered housing ( ‫ד‬ ‫י‬ ‫ו‬ ‫ר‬ ‫מ‬ ‫ו‬ ‫ג‬ ‫ן‬ ). as mentioned above, the moh has designed an ongoing mechanism (magen avot) meant to protect this extremely vulnerable population. among other things, this program ensures an adequate supply of ppe as well frequent as pcr testing of both residents and staff. after a rocky start this program now seems to be working quite well and offers area example of what israel got right during the pandemic (ref [ ] ). ) planning needs to consider a sensible exit strategy from the ongoing second wave. these recommendations should be instituted gradually: releasing first those - years old; then - and finally all +. although such age categories are admittedly arbitrary, they clearly represent the increasing risk of the average person in each group from covid- (less clinical reserve, higher likelihood of co-morbidity and shorter life expectancy, etc.) as one climbs the age scale. ) outreach is needed to populations which traditionally have less access and/or trust in the healthcare system such as citizens from arab and ultra-orthodox communities where infection rates are increasing more than in the general population. this can be done by having citizens from those communities actively involved in the decision making process and encouraging local leadership to take an active role in disease prevention and management. in this paper we have tried to address the vexed issue of age; how a society such as israel's should make every attempt to meet the needs of older persons during the pandemic while taking into account those of the wider society as well as the sometimes conflicting principles of medical ethics. space does not allow us to deal with all relevant issues and for some we can only outline the topic. please see sidebar . a final (personal) word from the older author (amc) even today and especially as we ride and try to balance on the second wave without plunging into the roiling seas, this proposal puts much onus on israel's senior citizens, many of whom have not had an easy life. this will be the case whether or not these guidelines are statutory or voluntary. just as they may have begun to enjoy retirement, hobbies, their grandchildren etc., older persons are once again to be restricted (at least partially) by this terrible pandemic. it must however be kept in mind that it is the virus, not society which is responsible. this proposal asks a heavy price of older persons, i.e. to wait inside and struggle relatively alone for longer than younger people. but it is logical and meets the criterion of soft utilitarianism alluded to above (the greatest good to the greatest number.) i am almost and, according to this proposal, will have to wait my turn until i am allowed and/or allow myself more freedom -perhaps for quite a while. as are the two older medical ethicists and a.b. yehoshua quoted above (ref [ ] [ ] [ ] ), i am willing to do so because i believe in the science, logic and moral approach of this "dance". in addition, in social solidarity with younger people, i am willing to take these steps for the sake of my children and their generation which is the one which will drive the economic, defense and social engines of our society out of this crisis. and in the end, as an older israeli, i (and i know of others) am willing to do this for the sake of our society. while many infected persons are asymptomatic and most survive the sars-cov- virus, covid- can be a serious disease, especially for those with co-morbidity and for many older persons, even without. the sars-cov- virus has caused illness and death and wrought severe socio-economic disruption for people at all ages across the globe (see https://www.economist.com/international/ / / /the-pandemic-is-plunging-millionsback-into-extreme-poverty). given the iron laws of biology, on average healthy older persons are at higher risk than younger, even unhealthy people. as such, society pathophysiology, transmission, diagnosis, and treatment of coronavirus disease (covid- ): a review the stanford hall consensus statement for post-covid- rehabilitation the silent danger of social distancing from mitigation to containment of the covid- pandemic; putting the sars-cov- genie back in the bottle facing covid- in italy -ethics, logistics and therapeutics on the epidemic's front line estimating excess -year mortality associated with the covid- pandemic according to underlying conditions and age baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region covid- -exploring the implications of long-term condition type and extent of multimorbidity on years of life lost: a modelling study what the pandemic measures reveal about ageism the price of continued isolation for older persons -a social disaster. maariv (online-hebrew) sheltered housing in the days of corona -worse than a prison why i support age-related rationing of ventilators for covid- patients. the hastings center on being an elder in a pandemic ready to die if that will be instead of a younger person ventilator triage policies during the covid- pandemic at u.s. hospitals associated with members of the association of bioethics program directors the toughest triage -allocating ventilators in a pandemic fair allocation of scarce medical resources in the time of covid- israel ad hoc covid- committee: guidelines for care of older persons during a pandemic joint commission of the israel national bioethics council, the ethics bureau of the israel medical association and representatives from the ministry of health age, complexity, and crisis -a prescription for progress in pandemic death is inevitable -a bad death is not; report from an international workshop ethical issues in end-of-life geriatric care. the approach of three monotheistic religions: judaism, catholicism and islam enteral feeding in end-stage dementia: a comparison of religious, ethnic and national differences in canada and israel publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgements none. received: july accepted: october needs to protect all of those particularly susceptible to this virusboth from the disease as well as from the ill effects of the necessary constraints on their freedoms necessitated by this worldwide emergency. but equally important, governments must act transparently and solely in the interests of citizens. finally, they need to ensure a fair distribution of resources -especially if society is faced with an acute shortage. the trick will be in getting the balance right. supplementary information accompanies this paper at https://doi.org/ . /s - - -y. we alone are responsible for the whole text. the authors read and approved the final manuscript.funding none.availability of data and materials not relevant.ethics approval and consent to participate not applicable.consent for publication not relevant. author details key: cord- - tmtvw r authors: singh saraj, k.; mishra vishal, a.; jha vikas, c. title: modification of neurosurgical practice during corona pandemic: our experience at aiims patna and long term guidelines date: - - journal: interdiscip neurosurg doi: . /j.inat. . sha: doc_id: cord_uid: tmtvw r background: first case of covid- was confirmed on (th) january, in india. our state, bihar reported its first confirmed case of covid on (nd) march at aiims patna. for safety, electives surgeries and outpatient department was suspended temporary since (th) march. standard operating procedure (sop) was framed for covid suspected, covid positive and negative patients. neurosurgery department formulated their own strategy for successful and covid free management of neurosurgical patients along with zero transmission rate among doctors and staff. methods: all neurosurgical patients who got attended, admitted and operated from (th) march to (th) june (period of lockdown) were taken in this study. categorizations of the patients were done according to the urgency and elective nature of pathology after corona screening and rt-pcr testing of covid- . a proper training to all neurosurgical staff and residents were given for management of patients (admission to operation to discharge). results: total patients were attended and were admitted. we operated cases (major - , minor – ) during the lockdown period. out of this were corona positive (both eventually succumbed) and rest was corona negative. one patient who was operated with corona negative report became positive after days of surgery inward. all the residents, faculty and nursing staff remain asymptomatic throughout the lockdown period with zero infection rate and zero transmission rate. conclusion: following a properly made standard operating procedure and strictly implementing it can avoid any type of misadventure in neurosurgery during corona pandemic. key message: adequate planning and sufficient training is necessary to avoid any untoward incident of infection. proper utilization of limited human resources and infectious kit is needed at this time. the first case of covid- was reported in india on january . as of th may , the ministry of health and family welfare have confirmed a total of , cases, , recoveries (including migration) and , deaths in the country. [ ] india currently has the largest number of confirmed cases in asia with number of cases breaching the , mark on th may and million in august. [ ] after successful trial of brief curfew on nd march, indian prime minister narendra modi followed it with complete nationwide lockdown from th march for days. the period of lockdown was subsequently increased three times in two months. [ , ] first proven case of covid in bihar was reported on nd march at our institute, all india institute of medical sciences, patna. he was -yearold male with a travel history to qatar. [ ] the virus has spread in districts of the state, of which patna has the highest number of cases. [ ] the state with a population of more than million people was under complete lockdown from th march to st may. it remained in partial lockdown status till st july . approximately , people got infected with covid till th june . after th june our hospital got converted into covid dedicated hospital. the state government has responded to the outbreak by following a contact-tracing, testing and home to home surveillance model. all outpatient services were shut down in our hospital since th march . however emergency services were continued and standard operating procedure (sop) was made both for the institute and our department. as our department is the only neurosurgical unit dealing vascular neurosurgery in the whole region of million, our responsibility was more as compared to other hospitals. to avert crisis during such pandemic, hospital and department both need a strategy to meticulously manage their staff, emergency, operation theatre complex (otc), intensive care unit (icu) and wards. here we are discussing our department response, guidelines, drawbacks and analysis of one of the most important emergency services at aiims patna with safe execution and management of neurosurgical patients. we also finalized a roadmap for future management of neurosurgical patients for next few months till this pandemic gets over. consecutive patients of neurosurgery (both traumatic and non-traumatic) at our institution were considered for the study. all patients who attended, admitted and operated from th march to th june (period of lockdown) were taken in this study. all all admitted patients were categorized on the basis of emergency for intervention data collection methods: data was collected prospectively when the patient was in emergency and trauma in the form of demographic profile at the time of admission and operation, comorbidity, gcs at the time of surgery. all patients were assessed on the basis of severity and admission was done. all admitted patients were categorized on the basis of protocol we made for department. (table no ) management was done on the basis of this protocol. along with urgency of the cases. in category i, patients were operated in emergency within hours with only corona screening. in these patients, nasopharyngeal swab were sent before taking up for surgery. external ventricular drain insertion, vp shunting (ventricularperitoneal shunting), edh (extradural hematoma) evacuation and decompressive craniotomy were included in this category. in category ii, patients were operated on urgent basis within - days after admission. results of rt-pcr were assessed before taking up for surgery. category ii was formalized by keeping incubation period of covid - in minds ( - days the surgeries needing more than - hours of exposures were categorized in major group and less than hour were categorized in minor group. in emergency, total patients were attended during lockdown period. out of this, were admitted in which were female and were male. mean age was . years. total patients underwent procedures/operations. (table no (table no )out of patients that got admitted, two came out as positive and rest were negative. one was having hypertensive bleed with intraventricular extension. in this patient evd was inserted after wearing full ppe kit. other was chronic sdh with severe mass effect which came with poor gcs (gcs- ). here twist drill was done and hematoma evacuated. but both the patients eventually succumbed. one covid negative patient became covid positive at th postoperative day on routine testing. however she was asymptomatic. she was transferred to covid positive ward and discharged from there after testing negative on rt-pcr. after lockdown from th march, the whole outpatient department (opd) was closed. all patients with minor ailments were advised to stay at home and only emergency patients were getting attended at trauma and emergency. from the beginning, contact details of the department were getting circulated in local newspapers for benefit of the patients. for initial to days, patients having traumatic head injury and spinal injury were getting admitted. than later on stroke, aneurysm rupture and large intracranial space occupying lesions also started arriving in emergency. after triage from institute, our department was also categorizing the patient on the basis of severity. it was observed that just by differentiating the cases into emergency and elective procedure, we are just avoiding the bay and not the storms. most of patients with benign intracranial or spinal pathologies will land up in emergency within days or months. so by doing triage we are just segregating emergency and urgent cases at that particular point of time. even after development of vaccine, covid- is going to stay for a longer period of our life. so we needed a triage system where we can deal with all types of cases with avoidance of covid exposure. the study from italy has provided a framework for creating an emergency task force, streamlining a stringent protocol and adequate training to achieve zero infection and transmission rate. [ , ] they have created treatment hubs with interchanging of neurosurgeons along with transport of patients from one hospital to other hospitals. they also created a task force which helped in reducing non-urgent cases. most of the urgent neurosurgical procedures were performed by a strict number of operators. [ ] it was not possible for us, because our institution is the only institution where active and specialized neurosurgical procedures is happening presently in the whole state of bihar having a population of more than million. . our team was composing of seven junior residents, four senior residents and two actively working faculties. we made a team of seven residents who were attending and admitting the patients from emergency. all emergencies were first attended by our junior residents. one resident was given an emergency duty of hours followed by days off. they were exempted from duties of ward and icu. each resident was covered by senior resident and one faculty on alternate days. . all senior residents were rotated weekly. one resident was fixed for taking rounds of covid negative patients in the ward and icu for week. in second week he got shifted to total junior residents everyone attending emergency one day/week duty off for next days operation theatre. his assistance was utilized for week. during third week he got shifted to covid ward and he was taking rounds of covid positive/ covid suspected patients followed by week of quarantine. above mentioned cycle was followed by each resident and it got repeated every month. . two faculties were actively working in the department. both of them took alternate turns for operation theatre/ ward rounds. faculty a was posted on st and rd week, faculty b on nd and th week. both the faculties were getting week of quarantine. following this protocol we maintained minimal interaction between faculties, senior residents and junior residents. it was followed till th june, . after that our hospital got converted from covid care center into covid dedicated hospital and all emergency services were closed. week - week - week - week - mask, head and shoe cover, goggles). (figure ) lifesaving procedures were done in corona suspected ward, bed side only like evd (external ventricular drain) insertion, twist drills. if rt-pcr comes positive, then patient is shifted in corona ward/ corona icu for further management. category i patients were planned for urgent surgeries and category ii patients were planned for surgery within - days. these patients were operated under strict covid protocol and again shifted back to covid icu. a dedicated transportation route is recommended during this covid pandemic. [ , ] and our department complied with it and neurosurgical patients were carried to operation theatre complex (otc) from different route. the whole route was sanitized once the transportation was completed. it is advised to do ct chest for all the patients. [ , , , ] nasopharyngeal swab for all the patients were sent. in trauma ward / icu total admissions took place. on rt-pcr all came out as negative. negative patients were shifted to neurosurgical ward/ neurosurgical icu. sensitivity of rt-pcr of different body fluids had been analyzed and published in jama. in this bronchoalveolar lavage fluid is the most sensitive specimen ( %), followed by sputum ( %), nasal swab ( %), fibrobronchoscope brush biopsy ( %), pharyngeal swabs ( %), feces ( %), and blood ( %). [ ] but we don't recommend multiple testing from different sites even if it can improve sensitivity and reduces false-negative results. however we recommend multiple modalities of investigations like chest x ray, rt-pcr from swab along with thermal screening and most important clinical assessment. at our institution only corona screening, chest x ray and rt-pcr for nasopharyngeal swab was done for all the patients. recent guidelines at present recommend a single upper respiratory nasopharyngeal swab for suspect cases. [ ] also a recent survey has indicated that, nasopharyngeal swab was the preferred method for screening ( %), followed by ct scan ( %), and chest radiograph ( %). some respondents indicated more than one screening method, especially those from italy ( %) and india ( %), where the most common combination was the nasopharyngeal swab with chest radiograph. [ ] the most important thing during preoperative period is mobilization of patients. it is the most important factor as patient can acquire these infections from hospital surroundings. we suggest that mobilization should be grossly restricted. radiological investigations like chest x ray, ct, mri and dsa should be done after keeping in mind the usefulness of these in planning surgery. if possible, all should be done in single transportation and sittings. [ , ] all patients were operated under strict covid operating room protocol. training -it has been shown by hoz et al that without sufficient quantity of ppe kit and also without adequate training, the whole system will collapse and staff will suffer along with the patients. [ ] so a proper training is mandatory for the whole surgical team before going for any surgery. a rigid training was given to all dedicated neurosurgical staff, technicians, residents and faculties to prepare for emergency cases. all steps (in sequence) were revised for many days in a dummy class by neurosurgical residents and faculties. multiple classes were taken for proper donning and doffing sequence of ppe kit for all the staff. already neurosurgical procedure needs a very smooth coordination of staff and operating surgeon which was stressed during this pandemic. movement of technicians and staff were kept very minimal. and neurosurgical nursing staff was allowed to assist only on the allotted specific days for surgery for a week followed by quarantine on next week. for initial month preferably accidental cases were taken for surgery, as this surgery needs less expertise from neurosurgical point of view. it will also give neurosurgical team and staff to acclimatize to work in pandemic atmosphere. avoiding surgeries is neither beneficial for the surgeons and nor for the patient. so battling the fear and rigorous training can only help us achieving zero infection rates with good post-operative results. needed during such pandemic to avoid transmission of infection. [ , , ] it was advised to have dedicated operation theatre for neurosurgery during this pandemic. [ , ] but survey has indicated that majority of institutions and centers had not done it. [ ] however as it was getting not possible in our institute, we opted for high air flow otc to reduce viral load. after each operation the otc was fumigated twice with sodium hypochlorite ( %) before taking up another case. in otc, all major neurosurgical equipment was covered with sterile covers. operating microscope was covered with drape and vision guard. c-arm was draped with sterile covers. equipment (ppe). patient face was covered with square transparent box during intubation. as anesthetist are in direct contact, risk of aerosol dispersion is maximum during intubation, hence it has been suggested that the whole face area may be covered by a transparent sheet and the hands may be inserted under the sheet to intubate the patients, while the edges should be stuck to the surface. a preferred protocol is the use of a separate room for intubation and then bringing the patient to the or, so the risk is minimized to the surrounding health personnel. [ , ] however as it was not possible at our center, our anesthetist opted for intubation after wearing ppe kit and head shield. during anesthetic procedure (intubation, arterial line insertion, central line insertion), all neurosurgical team was advised to stay outside. operative procedure -patient positioning was done after wearing n mask and head shield. during initial phase while we were not having any ppe kit for otc, we utilized "universal precaution kit" for performing surgeries. later on we switched over to ppe kit. it has been advised that surgical procedure should be performed after wearing level - protections kit. [ , , , ] only disposable items were utilized in surgeries like coverings, draping and gowns at our center. it is mandatory to wear two layers of surgical gloves to avoid infection from breakage of gloves. all surgeries should be performed after proper distribution of various stages to different surgeons. aerosol dispersal and blood spillage should be minimal. [ , ] at our center, only one surgeon at a time was involved in operative procedure. opening and closure was done by senior residents. middle portion of surgery was performed by the faculty. for complicated and long procedure, other faculty was kept on standby. during macroscopic phase (craniotomy, laminectomy) of surgery, head shield and eye goggles were utilized. (figure ) throughout the drilling process, copious irrigation was continued to allow minimal dispersal of aerosols. drilling was kept at minimal level to avoid dispersal of aerosol. operative procedure was done slowly and meticulously, especially the opening phase to avoid blood loss and spillage. (figure a and b) craniotomy utilizing hudson burr and gigli wire/saw should be avoided. it causes inappropriate dispersal of bone dust and blood. also it is very cumbersome to use and injury prone. transnasal vs transcranial approach -throughout the pandemic and even after opening of lockdown, we are continuously giving transnasal approach (both microscopic and endoscopic) a back seat. transcranial and spinal procedures are considered as safe. csf dissemination of virus has been rarely reported. only one case from china and one from japan has been reported with covid meningitis. [ ] however during pandemic, we should treat all cases of neurosurgery as covid positive case. by avoiding transnasal route we are also nullifying the chances of invasive covid meningitis. operative time -many of the neurosurgical procedures needing longer stay in otc can be deferred. however some of them needing urgent intervention like giant craniopharyngiomas, skull base tumors (giant vestibular schwannonas, glomus jugulare), bypass for giant aneurysms, multiple intracranial tumors (neurofibromatosis) and multiple aneurysms can be staged. longer contact period with the patient on ot table is one of the factors for surgeons getting infected with covid. [ , ] young neurosurgeons with good experience, precision and adequate speed should perform major surgeries, as they can sustain longer time and contact period in otc. neurosurgeons with comorbidities (like copd, hypertension, and diabetes mellitus) and age more than years should not opt for performing major surgeries at this time of pandemic. however trainees should be given a back seat at this moment of epidemic. postoperative period -ideally all post-operative patients should be categorized as covid suspected. they should be quarantined in ward. it has been recommended to take throat swab and do a ct chest at least thrice weekly. [ , , ] majority of the patient in neurosurgery get shifted in icu. so ventilators and monitors are necessary equipment. also nutritional support is very important to regain natural immunity in post-operative period. [ , , ] at our center, all patients were shifted to neurosurgical icu in post-operative period. air duct of ventilators were getting replaced daily. nasopharyngeal swab was sent and chest x ray also done but only once in two weeks. we avoided unnecessary mobilization of patient postoperatively for multiple investigations. all the patients were started with early feeding, either orally or ryle's tube feeding. immunosuppressive drugs like steroids were avoided in majority of the patients in post-operative period. mobile ct machine and mobile x ray machines should be used aggressively during this pandemic and cover should be destroyed after each round of utilization. [ , , ] we kept a separate x ray machine and technician for neurosurgical icu. as mobile ct was not available, timing slots were given to respective departments. our patients were mobilized for postoperative or preoperative ncct head or mri / dsa at allotted time slots. none of the patients came positive on immediate postoperative swab. however one patient of ica cavernous segment aneurysm (ica trapping was done) came positive in the ward after days. on repeating pcr of rest of the patients in adjacent bed, it came negative. we fumigated that section of ward covered with glass shield. multiple articles have suggested that patients with stable condition should be postponed. [ , , , , , , , , ] the covid- outbreak had a relevant impact on surgical planning. in survey by fontanella et al most have responded with a significant change in surgical activity in their institutions ( %). [ ] the majority ( %) performed only urgent and emergency procedures; with few had ( %) completely closed the entire neurosurgical department. there is % reduction of surgical interventions. delaying elective procedures will contain the spread of sars-cov- by reducing no of visits and it will also reduce possibility of treating asymptomatic carriers. [ , , ] by following this zero infection and transmission rate can be achieved. however, as ours is an apex center catering around million population, we developed our own triage system. we categorized the patients according to the condition of the patient. stable patients were postponed but not cancelled indefinitely. they were taken up at later date after doing an rt-pcr of nasopharyngeal swab just before the operative procedure. at our department, the number of cases dipped minimally. however, number of elective cases went down but emergency cases went up significantly. as most of the private hospitals in our state got closed, our load remained fairly constant. academic activities -intra-hospital and intradepartmental movements were restricted and minimum residents were kept for functioning of the department. it is suggested that all the academic activities like mortality meetings, journal club, and case discussions should be done through video conferencing and webinars. it is also recommended that physical distancing should be maintained during rounds and departmental meetings also. [ ] we strictly adhered to it. however from st july, all rounds, operative teachings and classes were suspended. all the residents came into common pool and got involved in covid patient care only. but we are still continuing with webinars and online classes. future plan-it has been outlined that telemedicine and telephonic communication is the future. [ , ] our department is planning to initiate telemedicine for patients both telephonically and on video calls. it will help us to follow our post-operative cases. through this assessment of preoperative cases can be also be done and they can be given appointment for surgeries especially elective cases. semi urgent cases can be followed weekly and in case of deterioration they can be called up to emergency directly. our department is already having policy of giving contact details of our common duty mobile number to all our preoperative and post-operative patients and their relatives. during this pandemic we encouraged these types of communications significantly. this cell phone is carried by neurosurgical resident and covered by one of the faculty daily. it was planned to give dates to all elective cases, so that they can plan their transportation and safety before arriving in opd. they will come one day before opd and get themselves tested for covid- . maximum new cases and old cases will be entertained per day. we have planned to erect glass shield along with microphones so that clinical history can be taken maintaining physical distancing. clinical examination will be done after wearing protection kit. mri, ct scan, dsa will be done at our center. it will minimize our contact with fomites. if already done outside, every patient will be advised to carry dvd / cd of their imaging. majority of these things we had already started and practicing in our institute and department. however due to conversion of hospital into covid dedicated center, it took back seat. as patients are piling up, sooner we will restart our department and center with same protocol. however as more cases of covid related encephalitis are getting reported, it may get delayed. [ ] during corona pandemic, it is advised to do meticulous triage of neurosurgical patients. home | ministry of health and family welfare | goi hindustan times india to go into nationwide lockdown india's coronavirus lockdown: what it looks like when india's . billion people stay home india reports seven coronavirus deaths as die in mumbai what are red, orange, green zones". the times of india neurosurgery during the covid- pandemic: update from lombardy, northern italy neurosurgical practice at the time of covid- neurosurgical practice during the severe acute respiratory syndrome coronavirus (sars-cov- ) pandemic: a worldwide survey preliminary recommendations for surgical practice of neurosurgery department in the central epidemic area of coronavirus infection preparing for a covid- pandemic: a review of operating room outbreak response measures in a large tertiary hospital in singapore neurosurgery and neurology practices during the novel covid- pandemic: a consensus statement from india detection of sarscov- in different types of clinical specimens covid- ) neurosurgery in iraq at the time of corona roadmap for restarting elective surgery during / after covid- pandemic letter: safety instructions for neurosurgeons during covid- pandemic based on recent knowledge and experience letter: the coronavirus disease global pandemic: a neurosurgical treatment algorithm covid- in neurosurgery news, guidelines and discussion forum american college of surgeons. covid- : recommendations for management of elective sources of support (if applicable): none conflict(s) of interest: none key: cord- -mdy fcnn authors: zampieri, fernando godinho; soares, marcio; salluh, jorge ibrain figueira title: how to evaluate intensive care unit performance during the covid- pandemic date: journal: rev bras ter intensiva doi: . / - x. sha: doc_id: cord_uid: mdy fcnn nan reduce healthcare-associated infections. ( ) adherence to evidence-based medicine (ebm) practices is the first obvious marker of a good performing icu, and is a candidate for early performance assessment. therefore, measuring and tracking adherence to ebm for measures and processes of care can provide insightful and actionable information. ( , ) of course, many pressing issues may hamper the attempts to measure and improve performance during the covid- pandemic, including the abrupt shift in the icu case-mix (e.g. increased severity and number of ventilated patients), need for changes in the whole icu operation due to droplet precautions measures, costs increases due to additional personal protection equipment, and even a reduction of the available staff either due to illness or burnout. finally, although data is starting to be published, we have no current tool to accurately predict either covid- mortality or los. this represents a major limitation, not only for smr/sru but also this reduces the potential use of other metrics based on cumulative outcomes, such as variable-adjusted life displays. much caution is needed if one aims at using smr at this moment. illness severity scores usually performed poorly when single conditions (including sepsis or acute respiratory distress syndrome) are considered. ( , , ) additionally, larger periods (usually or months) are required to allow a relevant number of patients with hospital outcomes. therefore, if smr and sru are to be used and benchmarked, they should not be considered alone, neither be solely based on their absolute values, as larger temporal trends will be required. we, therefore, advoke that other variables should be measured to better understand the outcomes and help icu directors to identify where to invest and/or change practices, aiming to achieve better outcomes. a comprehensive, but pragmatic, understanding of the case-mix and resource use, and its benchmarking, can be both feasible and insightful, ( table ) and focus on adherence to the process of care may add substantial value to an approach strictly focused on outcomes. covid- pandemic represents an abrupt change in the icu outcomes ("producing survivors" process), with a sudden shift in the input, changes in process care, lack of effective and specific treatment protocols, an exceptional speed in changes of icu routines, among other factors. this situation can be aggravated by a lack of proper equipment to provide life support, especially in strained icus or resource-constrained scenarios. for some icus, the limiting factor can be lack of equipment, lack of staff, late patient referral, or all the above. an individual assessment of cases with unfavorable outcomes using simple ishikawa ("fishbone") diagrams may be useful, particularly early in the pandemic. however, as the cases accumulate, the evidence must come from larger series with proper analysis. additional ways to measure performance can be borrowed from economics, especially using the production-possibility frontier and data envelopment analysis. ( ) data envelopment analysis is an interesting econometric process where inputs and outputs are considered, and a benchmark performed. this analysis is flexible in the sense it accommodates with different metrics; for example, inputs may include staff levels, available equipment for organ support, number of beds and number of requested admissions (and their respective average illness severity) and outputs can include the number of survivors, mechanical ventilation free-days, icu-free days, etc. it can also aid the identification of potential restraining issues between units (figure ). this may be useful, even for icu comparison of performance over time, and benchmarking with other units. measuring the icu performance was never so important neither so difficult as during the covid- pandemic. while few data on prognostic scores is available, therefore limiting the use of more traditional metrics, icus should focus on measuring indirect performance parameters, especially analyzing case-mix, outcomes, and the rate of adherence to best practices. (oxygenation impairment of admitted patients, average severity, staff level) and "outputs" (mechanical ventilation free days and survival). the same unit at different points is shown. there are changes in illness severity, staff level, oxygenation over time, which results in differences in outputs. these trends together with relative efficiency are shown in panel (b) . note that at moments and the efficiency is maximized when compared with times and (marked with "*"), despite a reduction in staff level from - and fluctuations in severity. at point , performance seems to worsen (lower survival, less mechanical ventilation free days which are disproportional to increase in admission severity). data envelopment could point that staff reduction is probably the limiting step in this toy example. min -minimum; max -maximum; mv -mechanical ventilation; pf -partial pressure arterial oxygen/fraction inspired oxygen. postgraduate program in translational medicine and department of critical care hcor-hospital do coração -são paulo (sp) why try to predict icu outcomes? icu severity of illness scores: apache, saps and mpm prospectively defined indicators to improve the safety and quality of care for critically ill patients: a report from the task force on safety and quality of the european society of intensive care medicine (esicm) understanding intensive care unit benchmarking new perspectives to improve critical care benchmarking what every intensivist should know about prognostic scoring systems and risk-adjusted mortality. rev bras ter intensiva surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) organizational characteristics, outcomes, and resource use in brazilian intensive care units: the orchestra study development of actionable quality indicators and an action implementation toolbox for appropriate antibiotic use at intensive care units: a modified-rand delphi study efficiency analysis of federally funded hospitals: comparison of dod and va hospitals using data envelopment analysis key: cord- -tgpqnoq authors: liu, x.; zhang, x.; xiao, y.; gao, t.; wang, g.; wang, z.; zhang, z.; hu, y.; dong, q.; zhao, s.; yu, l.; zhang, s.; li, h.; li, k.; chen, w.; bian, x.; mao, q.; cao, c. title: heparin-induced thrombocytopenia is associated with a high risk of mortality in critical covid- patients receiving heparin-involved treatment date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: tgpqnoq background coronavirus infectious disease (covid- ) has developed into a global pandemic. it is essential to investigate the clinical characteristics of covid- and uncover potential risk factors for severe disease to reduce the overall mortality rate of covid- . methods sixty-one critical covid- patients admitted to the intensive care unit (icu) and severe non-icu patients at huoshenshan hospital (wuhan, china) were included in this study. medical records, including demographic, platelet counts, heparin-involved treatments, heparin-induced thrombocytopenia-(hit) related laboratory tests, and fatal outcomes of covid- patients were analyzed and compared between survivors and nonsurvivors. findings sixty-one critical covid- patients treated in icu included survivors and nonsurvivors. forty-one percent of them ( / ) had severe thrombocytopenia, with a platelet count (plt) less than x /l, of whom % ( / ) had a platelet decrease of > % compared to baseline; % of these patients ( / ) had a fatal outcome. among the nonsurvivors, . % ( / ) had severe thrombocytopenia, compared to . % ( / ) among survivors. moreover, continuous renal replacement therapy (crrt) could induce a significant decrease in plt in . % of critical crrt patients ( / ), resulting in a fatal outcome. in addition, a high level of anti-heparin-pf antibodies, a marker of hit, was observed in most icu patients. surprisingly, hit occurred not only in patients with heparin exposure, such as crrt, but also in heparin-naive patients, suggesting that spontaneous hit may occur in covid- . interpretation anti-heparin-pf antibodies are induced in critical covid- patients, resulting in a progressive platelet decrease. exposure to a high dose of heparin may trigger further severe thrombocytopenia with a fatal outcome. an alternative anticoagulant other than heparin should be used to treat covid- patients in critical condition. coronavirus infectious disease , caused by a novel coronavirus (sars-cov- ) that is structurally related to the virus that causes severe acute respiratory syndrome (sars), has developed into a global pandemic, with two million infections and deaths. [ ] [ ] [ ] currently, the mortality of covid- has reached as high as %, such as in france and italy. in china, approximately % of covid- patients have been mild cases, whereas % have been severe cases with acute respiratory distress syndrome (ards) that require ventilator support, and % have been critical patients who need intensive care unit (icu) admission. the survival rate of critical patients is no more than %. elderly people and people who have underlying medical conditions are at higher risk for developing more serious complications, such as septic shock, ards, acute kidney injury (aki), and fulminant myocarditis. , approximately % of deaths occurred among people aged > years in china. as a new infectious disease, covid- is characterized by severe acute respiratory injury and hyperinflammation-related syndromes. the poor prognosis predictors uncovered by retrospective studies include hypercytokinemia , significantly elevated hallmarks of an inflammatory response (e.g. il- , creactive protein (crp), and serum ferrin) and organ failure (e.g., aspartate or alanine transaminase (ast or alt), cardiac troponin, and blood urea nitrogen (bun)), , and sars-cov- -related rnaemia. additionally, severe thrombocytopenia, elevated neutrophils, and reduced lymphocyte have also been reported extensively in critical patients. , combined with progressive pulmonary lesions on ct imaging, these findings may be helpful to establish more appropriate clinical guidance for critically ill cases. a low platelet count or thrombocytopenia is associated with an increased risk of severe disease and mortality in patients with sars and covid- for reasons that are not fully understood. heparininduced thrombocytopenia (hit) is a well-recognized complication of heparin therapy, and can occur spontaneously, independent of heparin. [ ] [ ] [ ] hit is caused by the binding of heparin to platelet factor (pf ) released from activated platelets, as antibodies against the heparin-pf complex are induced in some patients. subsequently, the antibody-pf -heparin complex binds to the platelet fcγiia receptor, inducing platelet activation and aggregation, activation of the coagulation pathways and an eventual loss of circulating platelets, with a prothrombotic state. , nevertheless, hit can be induced in the absence of proximate heparin exposure, so-called spontaneous hit, by negatively charged bacterial, nucleic acids, and hypersulfated chondroitin. [ ] [ ] [ ] most patients who develop spontaneous hit have proximate episodes of infection or major surgery. in this study, critical icu patients and severe non-icu patients hospitalized from february to april at huoshenshan hospital (wuhan, china), an emergency hospital established in for covid- patients, were included. we found that a substantial percentage of the critical icu patients ( · %, / ) who showed severe, progressive decreases in platelet counts, often with fatal outcomes. further analysis showed an elevated level of anti-heparin-pf antibodies (hit antibodies) in critical patients, which suggested that hit contribute greatly to the fatal outcome in covid- patients in critical condition. sixty-one patients with confirmed covid- in critical condition were admitted to wuhan huoshengshan hospital, a hospital established for severe and critical covid- patients, from february to march . every patient had stayed in the intensive care unit for more than three days (herein and after referred to as icu patients) and had at least three consecutively detected platelet counts data. another patients with severe covid- who had never stayed in the icu were randomly selected from the hospital (herein and after referred to as non-icu patients). the diagnosis of covid- was made according to chinese clinical guidance for covid- . viral rna was confirmed in all patients by reverse transcription real-time pcr in the clinical laboratory of the hospital, except for patient p who was rna-positive before admission to the hospital but turned to be negative during the hospitalization. the clinical outcomes were recorded up to april , . routine blood tests and coagulation tests were performed in the hospital laboratory on admission and during the hospitalization. demographic data for the patients, including information on age and gender, are shown in supplementary table s . this study was approved by the ethics committee of huoshenshan hospital (wuhan, china). all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. human anti-heparin-pf complex antibodies (igg) were detected using an antigen-sandwiched enzyme-linked immunosorbent assay (elisa) kit produced by jonln biological company (cat jl ). briefly, µl of serum was added to a microwell coated with heparin-pf complex, incubated at °c and washed with washing buffer. then, horseradish peroxidase (hrp)-conjugated hepairn-pf was added, incubated, and carefully washed, hrp activity was determined by the ability to convert the substrate , ′, , ′-tetramethylbenzidine (tmb) to a blue products. the amount of hit antibodies was quantified using a set of calibration standards provided by the manufacturer. serum c a levels were determined by a two-antibody sandwich elisa similar to the hit assay. in the assay, the microplate well was coated with anti-c a antibody (capturing antibody), and the presence of c a in patient's serum was quantified with an hrp-conjugated c a antibody. for the survival rate and qualitative data comparisons among different groups, the p-value was calculated using the chi-square test (χ ) or fisher's exact test in r (version . . ). a t-test was used to determine the significant difference. p< . was considered statistically significant. data were presented as mean ± sd or mean ± sem. to address the fact that many patients in the icu received transfusions, the complete blood count data during hospitalization were analyzed. as expected, decreased red blood cell count (rbc) and hemoglobin (rgb) were observed in most icu patients ( figure a ). to our surprise, a progressive, severe decrease in platelet count (plt) occurred in critical icu patients with fatal outcomes (figure a and s a, and table ), but rarely occurred in icu survivors (figure and table ) and non-icu patients with severe covid- (figure s b). as shown in table , severe thrombocytopenia (plt≤ × /l) was observed in · % of non-icu patients ( / ), whereas it occurred in % of icu patients ( / ), of whom % were icu nonsurvivors ( / ). moreover, approximately · % of the icu nonsurvivors ( / ) had a plt count less than × /l, compared to · % among icu survivors ( / ) (table ) . notably, · % of icu nonsurvivors ( / ) had critical thrombocytopenia, with plt less than × /l in the very late phase ( - days before death) of the disease (figure b and table ). significant plt decreases (a decrease of > % at the last sampling date compared to that at the admission date) were also observed in · % of icu nonsurvivors ( / ) but in neither icu survivors nor non-icu patients ( figure c ). analysis the variations in plt in nine icu nonsurvivors (patient p -p and p -p ) during hospitalization in detail found that plt began to decrease - days after the onset of the illness and progressively decreased to a critical condition in the next - days (figure a and s a). countermeasures such as transfusion with blood cells, platelets or fresh frozen plasma (ffp) showed little if any effect on the plt decreases (figure a and s a), suggesting that progressive plt exhaustion occurred in dying covid- patients for unknown reason other than blood coagulation factor exhaustion. administration of tocilizumab (tcz), an inhibitor of inflammation that has been suggested for used in covid- by chinese guidelines for covid- , seemed to be able to reverse the changes in plt transiently in patient p -p , except p , but severe thrombocytopenia recurred a few days after the administration (figure a). as a control, only one out of fifteen icu survivors (patient p ) showed extremely low plt, but without a progressive plt decrease (figure a and b). these results suggested that severe thrombocytopenia with progressively platelet count decrease occurred in most critical covid- patients before a fatal outcome. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint continuous renal replacement therapy (crrt) is commonly used in the icu for correction of metabolic acidosis, removal of cytokines and other indications in critical covid- patients. however, among crrt patients (p -p ), crrt triggered a sharp decrease in plt in most patients (figure a, a, s a, and s c). notably, among the crrt-treated covdi- patients, patient p , the only survivor of crrt with moderate pneumonia but critical kidney failure, and patient p , who was viral rna-negative from the time of admission to the hospital, showed no decline in plt after crrt treatment compared with other crrt treated covid- patients (figure a), suggesting that crrt could induce a significant decrease in plt in critical patients with severe covid- characteristic pneumonia. accordingly, a seriously reduced plt to less than × /l was observed in · % of crrt patients ( / ) after crrt therapy, of whom · % ( / ) further decreased to a level less than × /l in a few days after crrt treatment (figure b and s c). comparing with that, only · % in non-crrt icu patients ( / ), and · % in non-icu patients ( / ) had a decreased plt less than × /l (table ) . moreover, a significant plt fall of more than % was also observed in crrt patients ( · %, / ) compared to non-crrt icu patients ( %, / ) (p= · ) (figure c), particularly for non-crrt icu survivors ( · %, / ) (figure d). for non-crrt patients, the average decrease in plt in nonsurviving patients was · %, compared to - · % (i.e., increased by · %) in survivors (figure d), indicating that a significant decrease in plt may be a risk factor for high mortality in covid- . in concert with severe thrombocytopenia, out of icu patients treated with crrt died within three days post crrt, and the other four died within - days post crrt treatment (figure a and a). the only surviving patient (p ) was admitted to the icu because of critical kidney failure but not severe sars-cov- -induced pneumonia, as mentioned above. the survival rate of patients who received crrt treatment was only · % ( / ), far lower than the icu patients who did not receive crrt treatment ( · %, / ) (figure e, left panel). these data collectively suggested that crrt might contribute to the high mortality of critical covid- patients by inducing severe thrombocytopenia. the progressive decrease in plt in icu patients suggested the possibility of hit, since lowmolecular-weight heparin (enoxaparine, lmwh) is routinely used as an anticoagulant in crrt therapy in the hospital. lmwh is also widely used in elderly, bedridden icu patients for the prevention of thrombosis and the management of coagulopathy and disseminated intravascular coagulation (dic). in all icu patients without crrt, patients received lmwh. a higher but not statistically significant (p= · ) percentage of these patients had severe thrombocytopenia (plt≤ × /l) than did patients without lmwh ( · %, / vs · %, / ) (table ) . a lower survival rate was also observed in the non-crrt patients exposed to heparin compared with non-crrt patients without heparin exposure ( · %, / vs · %, / ) (figure e, right panel). consistent with the fact that a smaller dose of lmwh was applied in non-icu patients just for flushing of the central venous catheter, a mild plt decrease was found only in four out of non-icu patients who received heparin, while the lowest number was - × /l (figure s b). a progressive plt decrease to a level around × /l was observed in only one of these four patients. these findings indicate that heparin exposure may be a risk factor for severe covid- . heparin exposure is correlated with the severe thrombocytopenia, suggesting that hit might be responsible for severe thrombocytopenia in covid- . to substantiate this hypothesis, hit antibodies against heparin-pf complexes, a marker of hit, were analyzed using an elisa kit. higher levels of hit antibodies were detected in the available sera from covid- icu patients (sera from all icu patients were always unavailable due to death or discharge), but not in mild covid- patients, convalescent covid- patients, or healthy people (figure a). to our surprise, an elevated hit antibodies level was also observed in some of these icu patients before crrt implementation, or before heparin exposure in non-crrt patients, suggesting that heparin pre-exposure was not absolutely required to induce hit in critical covid- patients ( figure b ). accordingly, among heparin-naïve nonsurvivors, seven patients experienced a progressive decrease in plt, and four of them had a plt decrease of more than % (figure c). consistent with the elevated hit antibodies, complement activation shown by c a accumulation was also observed in these patients ( figure d ). the concentration of serum hit antibodies was largely all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint correlated with c a levels ( figure e ). it has been reported that the release of heparin from master cells could be induced by complement activation, which may indicate the potential role of endogenous heparin in spontaneous hit after viral infection. , moreover, as reported by other studies, a higher percentage of neutrophils was observed in nonsurviving critical covid- patients, which may further contribute to the severity of hit, but not in surviving critical covid- patients (figure f and s d). , in addition to laboratory tests, venous and arterial complications, including deep venous thromboembolic complications, were observed in patients who died of covid- by autopsy. among three nonsurviving icu patients who received an autopsy, hyaline thrombus and other thrombi were found in patient p , who showed a progressive decrease in plt. bleeding in lung tissues but no thrombi were observed in patient p with constantly low plt counts (figure s a). furthermore, no obvious bleeding or thrombi occurred in patient p , who had a significant decrease in plt counts, but the lowest point was well above × /l. confirmed vein thromboembolism (vte) in icu covid- patients by ct pulmonary angiography (ctpa) or ultrasonography was also reported recently. although the platelet activation assay was not performed because of the limited capacity of huoshenshan hospital, current results still strongly suggested that hit or spontaneous hit, induced by the virus or a secondary bacterial infection, may occur in covid- , which would be significantly boosted and aggravated by further heparin exposure with a high dose, thereby resulting in a fatal outcome. severe thrombocytopenia and thrombosis-induced systemic clotting in severe and critically ill covid- patients resulted from complicated factors that greatly enhanced the risk of covid- . sars-cov- entry and infection may directly lead to endothelial damage, thereby triggering platelet activation and aggregation, a coagulopathy mechanism similar to that reported for sars-cov. moreover, the serious complications of covid- also result in elevated levels of d-dimer, a fibrin degradation product that indicates dic, and antiphospholipid antibodies, an autoantibody that induces thrombi in large veins and arteries. all these factors contribute to increased platelet consumption and eventually thrombocytopenia. here, we show that hit occurred frequently in severe covid- patients who received heparininvolved therapy, or were heparin-naïve (as spontaneous hit). the widely used diagnostic criteria of hit include: ) hit antibodies to complexes of heparinoid (heparin or similar glycosaminoglycans) and pf ; ) hit antibodies-mediated platelet activation; ) a progressive plt decrease of at least - % or more from baseline; ) onset of thrombocytopenia occuring within five to ten days after initiation of heparin or to hours after heparin re-exposure; and ) thrombosis in patients treated with heparin. , , in this study, severe thrombocytopenia (plt< × /l), a > % of plt decrease, rapid decrease upon crrt treatment (high level of heparin exposure), high levels of hit antibodies, and venous, arterial and even deep venous thrombi in patients who died of covid- basically fits the clinical definition of hit. notably, hit antibodies and a progressive decrease in plt were also detected in heparin-naïve patients (i.e., before crrt or other heparin exposure), even in non-icu patients (figure b), indicating the occurrence of spontaneous hit in covid- patients, which probably results from virus itself or a secondary bacterial infection, such as pf -conjugated staphylococcus aureus or escherichia coli, or severe tissue damage. immune thrombocytopenic purpura (itp), an autoimmune disorder similar to hit, has been reported in hku coronavirus infected patient. in non-icu patients, a progressive plt decrease is rarely occurred, either because of the less severe viral and secondary bacterial infection or the far lower level of heparin exposure, since heparin was primarily administered for flushing the central venous catheter but not for prevention blood clots and treatment of venous thrombosis in icu patients. the moderate plt decrease in non-icu patients with hit is transient and can be recovered during convalescence. although a protective effect of heparin-involved anticoagulation in severe covid- has been reported by tang et al., the potential risk of hit should be cautioned when it's used to treat critical icu patients with a high dosage. our findings strongly indicated the occurrence of hit in severe covid- , although current evidence did not fully meet the rigorous definition of spontaneous hit proposed by warkentin et al. because of the limited medical and laboratory capacity in de novo established huoshenshan hospital for covid- patients. the platelet serotonin-release assay (sra) for highly pathogenic hit in sera containing both heparin-dependent and heparin-independent platelet activation antibodies, should be performed later, which will provide more solid evidence of hit in covid- . in patients with hit, anti-heparin-pf igg could be generated as early as the first day of heparin treatment, indicating a preimmunization by antigens highly similar to heparin-pf complexes. this all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint preimmunization may be resulted from spontaneous hit. for preimmunized patients, subsequent exposure to a high dosage of heparin in anticoagulation therapy, such as crrt and coagulation control, will significantly boost the preformed b cells via a lot of heparin-pf complexes, thereby prompting the activation and consumption of platelet, resulting in progressive thrombocytopenia and extensive coagulation in deteriorating covid- patients. this may explain the high mortality in critically ill patients receiving crrt ( · %, / ). as an important supportive treatment for critically ill patients with sepsis or aki, crrt is used to efficiently remove proinflammatory mediators accumulated in the blood and maintain fluid balance in hemodynamically unstable patients, which has been recommended for renal failure and renal replacement therapy in the chinese clinical guidance for covid- . however, accumulating clinical data showed that there were nearly no survivors among critical covid- patients who received crrt treatment, indicating that patients did not benefit from crrt. , , here, we show that serious hit may be responsible for the high fatality of crrt in critical covid- patients. therefore, we suggeste that the clinical occurrence of hit in covid- patients, especially critical patients, should be detected and monitored carefully. for those covid- patients strongly suspected of having hit, the physician should stop all heparin-involved therapy and initiate an alternative anticoagulant other than heparin, such as platelet aggregation inhibitor prostacyclin, direct thrombin inhibitors (e.g., lepirudin), nonheparin glycosaminoglycan with anti-factor xa activity (e.g., fondaparinux), or regional citrate anticoagulation, to avoid the risk of hit-induced thrombosis in covid- patients. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint the informed consent and the approval from ethic committee of huoshensan hospital were obtained before the collection of the blood samples from covid- patients. the data is shown as mean ± sem and analyzed using a two-tailed student's t-test. differences were considered significant at **p< · , as indicated. the data are presented as the mean ± sem and were analyzed using a two-tailed student's t-test. differences were considered significant at **p< · , ***p< · , as indicated. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. a severe thrombocytopenia with platelets ≤ × /l. b moderate thrombocytopenia with platelets ≤ × /l, but > × /l. c containing · % of non-survivors ( / ), with critical thrombocytopenia (platelets less than × /l). all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint a novel coronavirus from patients with pneumonia in china genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding a pneumonia outbreak associated with a new coronavirus of probable bat origin the world health organization chinese center for disease control and prevention. the novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- )-china clinical features of patients infected with novel coronavirus in wuhan, china correction to: clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china clinical characteristics of coronavirus disease in china detectable serum sars-cov- viral load (rnaaemia) is closely associated with drastically elevated interleukin (il- ) level in critically ill covid- patients risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study thrombocytopenia is associated with severe coronavirus disease (covid- ) infections: a meta-analysis heparin-induced thrombocytopenia platelet-endothelial interactions: sepsis, hit, and antiphospholipid syndrome thrombocytopenic conditions-autoimmunity and hypercoagulability: commonalities and differences in itp, ttp, hit, and aps role of platelet surface pf antigenic complexes in heparin-induced thrombocytopenia pathogenesis: diagnostic and therapeutic implications heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin platelet factor binds to bacteria, [corrected] inducing antibodies cross-reacting with the major antigen in heparin-induced thrombocytopenia complex formation with nucleic acids and aptamers alters the antigenic properties of platelet factor spontaneous heparin-induced thrombocytopenia syndrome: new cases and a proposal for defining this disorder the antigenic complex in hit binds to b cells via complement and complement receptor (cd ) heparin-induced thrombocytopenia neutrophil activation and netosis are the major drivers of thrombosis in heparin-induced thrombocytopenia a pathological report of three covid- cases by minimally invasive autopsies incidence of thrombotic complications in critically ill icu patients with covid- thrombocytopenia in patients with severe acute respiratory syndrome (review) abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia coagulopathy and antiphospholipid antibodies in patients with covid- me or not me? the danger of spontaneity severe immune thrombocytopenia complicated by intracerebral haemorrhage associated with coronavirus infection: a case report and literature review anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy laboratory diagnosis of heparin-induced thrombocytopenia the incidence of thrombocytopenia associated with continuous renal replacement therapy in critically ill patients chinese center for disease control and prevention. chinese clinical guidance for covid- the authors wish to thank the staff of huoshenshan hospital (wuhan, china) for their unimaginable effort and devotion in covid- pandemic and generous help in medical cases sharing and consultation. qm, yx and zw collected covid- patients clinical data. zz, hl and kl performed the elisa detection. xz, gw, and yh analyzed the laboratory test results. wc, qd and sz provided laboratory detection materials, methods and equipment. cc, qm, sz, and ly interpreted clinical therapeutic outcome. xb was consulted on covid- autopsy. cc and tg made the figures. xl and cc wrote the manuscript. key: cord- -c jzty u authors: roberts, matthew b.; izzy, saef; tahir, zabreen; al jarrah, ali; fishman, jay a.; el khoury, joseph title: covid‐ in solid organ transplant recipients: dynamics of disease progression and inflammatory markers in icu and non‐icu admitted patients date: - - journal: transpl infect dis doi: . /tid. sha: doc_id: cord_uid: c jzty u background: covid‐ infection varies in severity from minimal symptoms to critical illness associated with a hyperinflammatory response. data on disease progression in immunosuppressed solid organ transplant (sot) recipients are limited. methods: we examined the electronic medical records of all sot recipients with covid‐ from massachusetts hospitals between february , and may , . we analyzed the demographics, clinical parameters, course, and outcomes of illness in these patients. results: of covid‐ ‐positive sot patients, % were hospitalized and % required icu admission. sixty‐nine percent of hospitalized patients had immunosuppression reduced, % developed suspected rejection. co‐infections occurred in % in icu vs % in non‐icu patients (p = . ). a biphasic pattern of evolution of laboratory tests was observed. in the first days of illness, inflammatory markers were moderately increased. subsequently, wbc, crp, ferritin, and d dimer increased with increasing stay in the icu, and lymphocyte counts were similar. five patients ( %) died. conclusions: our data indicate that sot is associated with high rate of hospitalization, icu admission, and death from covid‐ compared to data in the general population of patients with covid‐ . despite reduction in immunosuppression, suspected rejection was rare. the clinical course and trend of laboratory biomarkers is biphasic with a later, pronounced peak in inflammatory markers seen in those admitted to an icu. crp is a useful marker to monitor disease progression in sot. we extracted baseline demographic data (age, gender, race, ethnicity, zip code), smoking status, comorbidities, medications at time of covid- diagnosis, sot type and date, history of rejection within months prior to covid- diagnosis. for patients admitted within the mass general brigham system, details of admission including presenting symptoms and vital signs, therapeutic drugs and strategies, clinical outcomes, serial clinical and laboratory parameters (complete blood count, cbc, creatinine, liver function tests, lft, c-reactive protein, procalcitonin, ferritin, d dimer, il- level, hypersensitive troponin t, creatinine kinase, lactate dehydrogenase, ldh, and tacrolimus levels) through covid- illness. comparison is made between patients admitted and those managed as outpatients. in addition, among those admitted to the hospital, comparison is made between those admitted to icu at any point in their admission (icu patients) and those managed exclusively in a non-icu, general medical/surgical setting (non-icu patients). a total of solid organ transplant recipients were identified as covid- positive with demographic data ( most recipients were immunosuppressed with tacrolimus, mycophenolate, and low-dose corticosteroids. only recipient had experienced an episode of rejection within months prior to covid- diagnosis. hypertension ( subjects, %), diabetes ( %), and chronic renal insufficiency were common comorbid conditions. comparison between those admitted to any hospital (n = ) vs those managed at home (n = ) is shown in table . those admitted had a higher median age ( years vs years, p = . ) and were more likely to have a diagnosis of ischemic heart disease ( vs , p = . ). pre-admission medications included a statin in ( %) ta b l e demographic characteristics of sot recipients diagnosed with covid- , with comparison between those admitted and not admitted inpatient management is shown in table . all of those admitted to icu were intubated and required vasopressors ( , %); ( %) required prone positioning and ( %) required dialysis. median time to icu admission was days from symptom onset. only ( %) of the non-icu patients required supplemental oxygen at some point in their hospitalization with ( %) of these requiring supplemental oxygen on admission. antibiotics were more frequently given to icu patients than non-icu patients ( vs , p = . ). hydroxychloroquine was given to patients ( %) including ( %) admitted to icu. statins were given or continued in ( %), off-label tocilizumab was used in one patient, and nine patients ( %) were enrolled in therapeutic drug trials. immunosuppression was changed in ( %) of those admitted including ( %) of the icu patients and ( %) of the non-icu patients. of those on an antimetabolite (mmf or azathioprine), ( %) had these drugs held ( %) or reduced by half ( %). only one patient admitted to icu on mycophenolate had no adjustment. calcineurin inhibitors were held in one patient ( %), and mtor inhibitors were held in ( %) patients. belatacept tm was deferred in two of three patients on this agent. steroids were not withdrawn in any patients; ( %) patients in the icu group had stress dose steroids, usually in conjunction with reduction in other agents. median tacrolimus levels pre-covid diagnosis and during inpatient admission were not different between icu and non-icu patients ( figure s ). co-infections were more frequent in those admitted to icu compared to non-icu patients ( vs , p = . ) ( table in addition to the strengths discussed above and the large de- our data show that a significant proportion of admitted sot patients require icu care with high mortality. close follow-up and a infection in organ transplantation clinical characteristics of coronavirus disease in china covid- infection in kidney transplant recipients covid- in solid organ transplant recipients: a single-center case series from spain covid- in solid organ transplant recipients: initial report from the us epicenter covid- and kidney transplantation first experience of sars-cov- infections in solid organ transplant recipients in the swiss transplant cohort study presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area hospitalization and mortality among black patients and white patients with covid- additional supporting information may be found online in the supporting information section covid- in solid organ transplant recipients: dynamics of disease progression and inflammatory markers in icu and non-icu admitted patients key: cord- -sfr x ob authors: röst, gergely; bartha, ferenc a.; bogya, norbert; boldog, péter; dénes, attila; ferenci, tamás; horváth, krisztina j.; juhász, attila; nagy, csilla; tekeli, tamás; vizi, zsolt; oroszi, beatrix title: early phase of the covid- outbreak in hungary and post-lockdown scenarios date: - - journal: viruses doi: . /v sha: doc_id: cord_uid: sfr x ob covid- epidemic has been suppressed in hungary due to timely non-pharmaceutical interventions, prompting a considerable reduction in the number of contacts and transmission of the virus. this strategy was effective in preventing epidemic growth and reducing the incidence of covid- to low levels. in this report, we present the first epidemiological and statistical analysis of the early phase of the covid- outbreak in hungary. then, we establish an age-structured compartmental model to explore alternative post-lockdown scenarios. we incorporate various factors, such as age-specific measures, seasonal effects, and spatial heterogeneity to project the possible peak size and disease burden of a covid- epidemic wave after the current measures are relaxed. a cluster of pneumonia cases of unknown origin was detected in wuhan city, the capital of hubei province, china, with a population of million in december . on december china alerted the world health organization (who) china country office [ ] . on january the causative pathogen of the pneumonia outbreak was identified as a novel coronavirus, and, on february, the who officially named the novel coronavirus as sars-cov- and the disease it causes as covid- . sars-cov- infection quickly spread from china, where it emerged in december , to europe, where the first cases were confirmed on january in france (where, later in april, covid- was retrospectively confirmed for a patient hospitalized in late december ) [ , ] . around the same time, on january, the first infection in germany was confirmed in bavaria that led to a local outbreak. by february , subsequent cases have been confirmed and high-risk contacts have been identified via agile contact-tracing [ ] . the first epidemic in europe started in the lombardy region of italy with the first detection on february [ ] . the who director-general declared the covid- outbreak a public health emergency of international concern under international health regulations ( ) on january [ ] and then a pandemic on march [ ] . by that time, the number of daily new cases of covid- was over in several countries, including italy, france, and germany. manipulation and shiny version . . . [ ] for creating an interactive dashboard to carry out epidemiological analyses online (available in hungarian [ ] ). the full source code of this dashboard and related analysis is available at [ ] . effective reproduction number (r t ), the average number of secondary cases per primary case for those primary cases who turn infectious on day t, was tracked in real time based on the daily number of reported new cases using the methods of cori et al. [ ] and that of wallinga and teunis [ ] , among the several methods aimed to estimate r t [ , ] . in brief, the method of cori et al., is based on calculating the ratio of the actual number of infections on a day to the total infectiousness of all past cases on that day. thus, it measures r t by assuming that infected individuals will infect in the future as if conditions remain unchanged. in contrast, the method of wallinga and teunis makes no such assumption; it uses a likelihood-based inference on the possible infection networks underlying the epidemic curve. the fundamental difference is that the method of cori et al., solely uses past information ("backward looking approach"), due to which the result is sometimes called instantaneous reproduction number, while the wallinga-teunis method more closely corresponds to the concept of the usual definition of effective reproduction number; however, it requires future information in exchange ("forward looking approach"). for a discussion on the relative merits of these two approaches, see [ , ] . the wallinga-teunis method was used with the addition of cauchemez et al., who aimed to provide real-time estimation capability [ ] . both methods require-in addition to incidence data-information on the serial interval. depending on the used dataset, different estimations of the serial interval have been published: a mean of . days was found in [ ] , and . days in [ ] . here, we assume an intermediate value following [ ] , where the mean and standard deviation (sd) of the serial interval were estimated at . days ( % cri: . , . ) and . days ( % cri: . , . ), respectively. (the serial interval is assumed to follow gamma distribution.) they also concluded that the serial interval of covid- is close to or shorter than its median incubation period, which is coherent with our choice of parameters in the transmission dynamics model. the estimation was carried out using r packages r version . - [ , ] and epiestim version . - [ , ] . case fatality rate (cfr) is defined as the (conditional) probability of death from a disease for those contracting the disease (for diseases where asymptomatic state also exists, infection fatality rate (ifr) is defined analogously) and is estimated as the ratio of cumulative deaths and cumulative cases. this definition, i.e., where c t and d t are the daily, c t and d t are cumulative number of cases and deaths, respectively, on day t is however biased when used during the epidemic (thus the name crude/naive cfr or ncfr). the reason for this is that a proportion of cases counted in the denominator will die (in the future), thus they should have been counted in the numerator as well, but, as they're not, the ratio underestimates the true value [ , ] . fortunately, it is relatively easy to correct for this bias using information on the distribution of the diagnosis-to-death time [ , ] . the likelihood that the cumulative number of deaths on day t is d t is given by where f i denotes the (conditional) probability that death happens on day i after onset (for those who die) and π stands for the true value of the cfr. this observation allows both maximum likelihood and bayesian estimation for π using the observed series of c i and d i , the latter of which was employed in the present study, using a beta( , ) (i.e., uniform) prior. it was assumed that diagnosis-to-death time follows lognormal distribution with a mean of days and a standard deviation of . days, as found by linton et al. [ ] . the bayesian estimation was manually coded using the r package rstan version . . [ ] . a markov chain monte carlo approach was used to carry out the estimation with no-u-turn sampler, using chains, warmup iterations and iterations for each chain. the cfr mentioned in the previous subsection is still not the true value of the fraction of fatal outcomes of all infections, as there is another source of bias, but this time leading to overestimation: the underascertainment of cases. this is a substantial issue now as a-precisely not yet known, but epidemiologically significant-fraction of the covid- cases are asymptomatic or mildly symptomatic. since in many countries testing was extended to contacts (and in a few instances, even random sampling was carried out), the confirmed cases include some asymptomatic cases as well. however, the value of the estimated (corrected) ifr can also be used to estimate the ascertainment rate: by assuming that the ifr in reality takes a benchmark value (one derived from large-sample, well-designed studies accounting for underascertainment or sero-epidemiological surveys) and-crucially-assuming that the difference of the actual estimated ifr from that value is purely due to underascertainment. then, the ascertainment rate can be obtained by simply dividing the assumed true value of the ifr with the actual estimated cfr [ ] . note that this might be a strong assumption, as it rules out that there is a real difference in the country's ifr from the benchmark value; in particular, it rules out different virulence of the pathogen, different age-and comorbidity-composition in the country and different effect of the healthcare system on survival. mathematical models have been developed to better understand the global spread [ ] and the transmission dynamics of covid- for many countries, including australia [ ] , france [ ] , germany [ ] , uk [ ] , and the usa [ , ] . such models have been used to project the progress of the outbreak and to estimate the impact of control measures on reducing disease burden. the two most common approaches are compartmental models formulated as systems of ordinary differential equations, and agent based models used to generate an ensemble of stochastic simulations for possible outcomes. here, we establish a compartmental population model, adjusted to the specific characteristics of covid- , considering the following compartments. we denote by s the susceptibles, i.e., those who can be infected by the disease. latents (l) are those who have already contracted the disease but do not show symptoms and are not infectious yet. in accordance with studies indicating that viral shedding peaks before the onset of symptoms [ ] , in our model, we have introduced the presymptomatic infected compartment i p for those who do not have symptoms, but who already are capable of transmitting the disease to susceptibles. we divided the latent period into two compartments l and l , thus, together with i p , the incubation period follows a hypoexponential distribution, having a shape matching empirical observations [ , ] . since a large fraction of infected shows only mild or no symptoms, after the incubation period, we differentiate these individuals from those with symptoms. we assume a gamma-distributed infectious period with erlang parameter m = , similar to the sars study [ ] , hence, we have three classes for both asymptomatic and symptomatic infectious individuals (i a, , i a, , i a, and i s, , i s, , i s, , respectively). individuals from the i a, compartment will all recover and hence proceed to the recovered class r. immunity is assumed for those who have recovered from the disease, at least for the time scale of this modeling. individuals from i s, may either recover without requiring hospital treatment (and thus move to r) or become hospitalized. it is of crucial importance to project the number of hospital beds and intensive care unit (icu) beds needed; thus, in the model, we further differentiate symptomatically infected individuals who need hospital care and critical care, denoted by i h and i c , respectively. we operate with the assumption that the healthcare system will not be overwhelmed, and thus disease-induced death is only considered from critical care that fits with the data obtained from nphc. hence, individuals from i h will proceed to r after recovery. those from i c with fatal outcome transit to the d compartment. those who are out of icu and on the path to recovery are collected into the i cr , from where they eventually recover and move to the r class. to take into account the different characteristics of the disease in various age groups, we stratified the hungarian population into seven groups, corresponding to the available choices in the hungarian online questionnaire for the assessment of changes in the number of contacts following the lockdown [ ] . the compartments listed above corresponding to the different age groups are denoted by an upper index i ∈ , . . . , . accordingly, all of our parameters can be calibrated age-specifically. the transmission rates from age group k to age group i are denoted by β (k,i) j , with j ∈ {p, a, s}, where the three subscripts p, a, s stand for presymptomatic, asymptomatic, and symptomatic infected, respectively. the parameters described in the following all have an upper index i which stands for the corresponding age group. a fraction p i of exposed people will not show symptoms during his/her infection, while ( − p i ) will develop symptoms. the average length of the incubation period is (α i l, ) − + (α i l, ) − + (α i p ) − days, with the transition rates α i l, , α i l, , α i p , respectively. similarly, the average infectious period of asymptomatic and symptomatic infected individuals are with the corresponding transition rates, respectively. a fraction h i of the infectious compartment i i s, will be hospitalized, the remaining fraction − h i will recover without hospital care. out of those who need hospitalization, a fraction ξ i needs intensive care. for the hospitalized classes i i h , i i c , i i cr , the average time spent in these compartments is given as (γ i h ) − , (γ i c ) − and (γ i cr ) − , respectively. a fraction µ i of those leaving the i i c compartment will die due to the disease, while the remaining fraction will proceed to the i i cr class. the transmission dynamics of our model for one age group is illustrated in figure . . reproduction numbers are calculated using the next generation matrix method in section . . . we discuss the application and, then, some limitations of this model in sections . . and . . , respectively. the codes were implemented in wolfram mathematica and are available at [ ] . the governing equations of the transmission model described in section . take the form where the index i ∈ { , . . . , } represents the corresponding age group. next, we add the spatial locations of the population to the previous model. the population is divided into patches, where each patch represents a separate geographic region. within each region, we use the same compartmental model (but possibly with different parameters), and we also include spatial movement of individuals between the patches. the governing equations of such a metapopulation model, where p ∈ { , , . . . , #patches} are we have chosen our model parameters based on comprehensive literature review and present them here, except the transmission rates β (k,i) s,_ which are left for section . . . for the incubation period, we assume hypoexponential (generalized erlang) distribution with parameters ( . , . , ). this way, the average incubation period is . days: the same length and very similar shape of the probability distribution function was estimated in [ ] , and this distribution has the observed concavity properties as well (see [ ] ). in addition, this estimation is consistent with [ ] , and such values have been used in [ , , , ] . the first . days are the latent period [ ] and the past two days are the presymptomatic period [ ] , when transmission is already possible with similar rate as at symptom onset [ ] . therefore, we use the same transmission rates for the presymptomatic and symptomatic infectious periods. for the transmission rate of asymptomatic infected individuals, we use a reduction factor . [ , , ] . for the length of infectious periods (both symptomatic and asymptomatic), we assume a gamma distribution with erlang parameter (coherent with the sars study [ ] ), and an average length days of infectivity. although full recovery and viral shedding may take much longer, the infectiousness throughout the course of infection is mostly concentrated to this period [ , ] . the choice of days is also justified by [ , ] , who estimated that around % of transmissions occur during the presymptomatic period, and it is also within the range of infectious periods used by [ , ] . the average stay in hospital is assumed to be days, in accordance with the seven days median reported in [ ] using over , patients' data in the uk. similarly, the average duration of critical care is assumed to be days, in accordance with the intensive care national audit & research center (icnarc) report [ ] . very similar numbers were reported in the us [ ] , and were used in other modeling studies [ , , ] . for those who recover from intensive care, we assumed a -day hospitalized rehabilitation period. the periods above associated with the average time an individual spends in each compartment over the course of the infection are age-independent and summarized in table . table . age-independent epidemiological parameters of covid- . assumed to be valid for all age groups. references and explanations are in section . . . incubation period (α i l, ) − + (α i l, ) − + (α i p ) − . days latent period (α i l, ) − + (α i l, ) − . days presymptomatic (infectious) period (α i p ) − . days infectious period of i i a (γ i a, ) − + (γ i a, ) − + (γ i a, ) − . days infectious period of i i s (γ i p, ) − + (γ i p, ) − + (γ i p, ) − . days hospitalization (γ i h ) − presymptomatic vs symptomatic β next, we discuss the age-specific parameters, which are mostly related to the outcome of infections. we stratified the population into the following seven age groups: - , - , - , - , - , - , + years old. using the data from the hungarian central statistical office (ksh), we obtain the division shown in table . according to [ ] , a fraction . of infected children (under years old) are asymptomatic or mild cases. this value was used in [ ] as well. we set the probabilities of the infection following mild or asymptomatic course in an individual according to weitz et al. [ ] . the probabilities of hospitalization given infection h i and of requiring intensive care in addition ξ i are based on the work of moss et al. [ ] . the ratios of fatal outcomes µ i are derived from the icnarc report [ ] comprising icu case reports from uk. all these age-dependent parameters are listed in table . for creating our contact matrix m cont , we have utilized the work by prem, cook, and jit [ ] , where the estimated matrices are written for age groups, namely - , - ,. . . , - , +. as we have divided the hungarian population into seven age groups, see table , we aggregated the higher resolution data. first, we derived a symmetric matrix m total with elements where m = [m i,j ] is the original contact matrix and [p i ] is the age distribution of hungary for the same age groups as in [ ] . thus, m total contains the total number of contacts among age groups in its upper triangular part (with values relative to the contact pattern in m). the total number of contacts, w.r.t. the age distribution used in our work, is then obtained by summing up the corresponding elements of this matrix of size × resulting in m total cont of size × . finally, dividing element-wise each column of m total cont by the aforementioned population vector given in yields the following × contact matrix: for more insight, we include its heatmap in figure . additional technical details are to be found in our source code available at [ ] . recall that we have assumed presymptomatic patients, which are members of classes i i p , to be as infectious as symptomatic patients. in addition, patients with no or mild symptoms (those in i i a ) possess a transmission coefficient half of the baseline. thus, our task is to give reasonable estimates for the rates β (k,i) s,_ corresponding to the transmission rate of the symptomatic individuals from age group k to group i. to that end, we follow the terminology and techniques of [ ] to compute the next generation matrix (ngm) and the baseline transmission rate β . finally, the desired coefficients are obtained by taking into account the relative contact rates between age groups via the contact matrix presented in section . . . we note that the probabilities p i have a special role during ngm computations as their effect is what ultimately specializes the resulting transmission rate matrix for covid- . first, let us consider the infectious subsystem of ( ), namely, equations describing l i . . , }. linearizing this w.r.t. the disease free equilibrium yields the linearized infectious subsystem: where the matrices t and Σ are referred to as the transmission part and transitional part, respectively; the state is described by recall that the transmission matrix t has the form on the other hand, the transitional matrix Σ is block diagonal with blocks then, the ngm with large domain is given by follows with the, again, block diagonal e with e i = [ ]. the baseline transmission rate β may be factored out from k as β hence, k = β ·k, wherek may be readily constructed and we can compute its spectral radius ρ(k). then, we obtain the baseline transmission rate using the assumed basic reproduction number r as for other scenarios, the final steps are altered to align with the desired reproduction number r, resulting in an appropriate β and then the scaled transmission rates β (k,i) s . we omit presenting all transmission matrices but give the computed baseline transmission rates in table . we use the compartmental model described above to explore possible future scenarios, assuming widespread transmission in the population. in particular, we investigate the disease dynamics when different levels of general reductions of transmission, compared to the baseline, are in place. by manipulating the contact matrix, we investigate the effect of age-specific interventions, such as school closures and special measures aimed to protect the elderly. seasonality of respiratory viruses can be attributed to a combination of factors, including the survival of the virus in different environmental conditions, changes in contact patterns (such as school holidays), less time spent in closed spaces where the highest number of transmissive contacts are made, and potentially seasonal changes in the health conditions of the population as well. to express this behavior, we define a time-dependent parameter by which we scale the transmission rate β. parameter c denotes the magnitude of the effect of seasonality on the number of contacts. using such a time-dependent transmission rate, we compare possible disease dynamics generated by the interplay of control measures with different degrees of seasonal behavior. spatial heterogeneity is also considered using our patch model, where the country is divided into distinct geographic regions (patches). the transmission dynamics is described within each patch by our compartmental model (but potentially with different parameters and age group composition), and individuals may move between those patches. for obvious reasons, individuals in compartments i i h , i i c , i i cr and d i do not travel. let travel p,q denote the number of travels from patch p to patch q. to derive travel rates t p,q for each age group i, we divide the number of travels with the population of the appropriate patch numerical simulations for such situations show the differences in the transmission dynamics, healthcare demand, mortality, and overall disease burden. these scenarios are summarized in table . our work has several limitations. due to limited testing and the large number of asymptomatic and mild cases, there was a huge uncertainty in the number of true cases, especially in the early weeks. now, with the help of [ ] , we have a good estimation of the overall ascertainment rate over this period, but it is still unclear how this rate evolved in time. the transmission model has the same weaknesses that all compartmental models have: we assume a homogeneous population with random mixing, apart from the age structure. we added some further heterogeneity in space (patch model) and time (seasonality). in our scenarios, we assumed a constant reduction in transmission, while in reality the control measures and the behavior of the people were continuously changing. hence, such scenarios cannot be considered as predictions, as we cannot expect such unchanging circumstances for months. the role of children in this pandemic is still not clear, in our modeling, we assumed that they are equally susceptible, and equally infectious once they develop symptoms, but we used an age-specific probability for developing symptoms. since our transmission model is deterministic, it is suitable only when there is significant spread in the population. for very low case numbers, the development of the epidemics is largely influenced by random events. stochastic effects are important when considering extinction or resurgence of the disease, and possible case importations after travel restrictions are lifted. however, these issues are not in the scope of the present work. the model has a large number of parameters, many of those have uncertainty. the most important ones in regard to the burden on the healthcare system are hospitalization rates, probability of intensive care need, mortality, all of those depending on age. we do not have too much data for this from hungary, hence we used parameters taken from the literature. a full sensitivity analysis is beyond the scope of this study, but we present a sensitivity chart for a crucial output of an outbreak, see section . , which is of concern in many countries: the peak icu demand, including the need for mechanical ventilators, to assure that all patients receive the necessary care, and no additional excess mortality is caused by an overwhelmed healthcare system. this was one of the key questions in other modeling studies. the sensitivity analysis was conducted by running many simulations, sweeping through a two-parameter plane, and retrieving the icu peak from each individual run. the code can be found in [ ] . the first hungarian covid- cases were reported during the first week of march through the hungarian notifiable disease surveillance system operated by nphc which is the source of data described in this section (for the most recent information, see [ ] ). the first case, an iranian -year old man (studying and residing in hungary) who recently returned from tehran, was reported on march . by may , the cumulative number of reported confirmed covid- cases were ( . cases per , population), including deaths (crude cfr . %), see figure for the daily reported numbers. out of the cases, . % ( , cases) occurred in the + age group, . % ( cases) in the - age group, . % ( cases) in the - age group and . % ( cases) among people under -years old. age specific morbidity was highest in the + age group ( . cases per , population) and more than twice of the overall in the - age group ( . out of deaths, . % ( deaths) belonged to the + age group. as seen in figure , the highest crude cfr was observed in the + age group ( . %), followed by the - age group ( . %) and the - age group ( . %). no deaths were reported under years of age, see figure . additional details are provided in table . out of the cases, . % ( cases) were female and . % ( cases) male (gender is unknown for two cases). the morbidity among women was higher ( . vs. . cases per , population), so men were . ( % ci . - . ) less likely to become ill. however, men aged years and older had a . ( % ci . - . ) higher risk to die than women aged years and older ( . cases vs. . cases per , population). out of cases, at the stage of data consolidation as of may , , we have information about the symptoms of . % ( cases). out of cases, . % ( cases) had no symptoms, . % ( cases) had mild symptoms, and . % ( cases) had severe disease (including cases required intensive care and/or ventilation). most of the cases were reported from the central part of hungary, from the capital ( cases) and the surrounding pest county ( cases). see figure for a comparison of the capital region with the rest of hungary. the morbidity (per , population) was also the highest in budapest ( . ). the epidemic curve ( figure ) reflects a propagated source epidemic especially when we consider only those cases that cannot be connected to outbreaks in closed communities (like long-term care facilities or hospitals) or to health care associated infections. out of cases, . % ( cases) were associated with health care and/or outbreaks in hospitals, contributing to the daily reported new cases since mid-march. health care workers had . times ( % ci . - . ) higher risk to become a confirmed covid- case in comparison to the general population ( . cases vs. . cases per , population). out of cases, . % ( cases) were reported from long-term care facilities (nursing homes and other closed communities like homeless shelters) contributing to the daily reported new cases since early april. at the peak of the epidemic curve, . % ( cases) of cases on april were reported from the same retirement and assisted living facility. figure shows the results for the real-time estimation of the reproduction number. it showed a steady decline-apart from an outlying effect in early april-and became close to, or even below by mid-april, and remained at that level since then. this conclusion is robust to the chosen methodology. results for the real-time estimation of cfr are shown in figure . note that-as the outbreak is coming to its end-the naive method converges to the final value that was readily well estimated almost a month earlier by the corrected technique. (the naive estimator is increasing as deaths still occur, but case count is already low at the end of the epidemic.) the final cfr to characterize this phase in hungary is about %. various ifr estimations have been published, for example . % for china [ ] , . % for uk [ ] . recent serological studies found ifr values spanning from . % in a german town [ ] , to . % in milan [ ] . note that the testing intensity-and therefore the ascertainment rate-may very well change over time, e.g., with the increase of testing intensity. this analysis is based on the data from the early phase as a whole and, therefore, it is considered as an estimation of the average. the results for the estimation of the ascertainment rate are shown in table , where we explore a reasonable range of ifrs from . % to . %. note that earlier estimates based on [ , ] are consistent with the preliminary results of a large-scale hungarian sero-epidemiological study [ ] . most studies concerning the early growth-rate of the epidemic in wuhan estimated the value of the basic reproduction number to be around . - . (see e.g., [ , ] ), also later studies regarding the spread in other countries [ , ] used similar values. our estimations given in section . shows that in hungary the highest value of the effective reproduction number was . , by the wallinga-teunis method. hence, we choose r = . for the basic reproduction number (comparable with a similar reproduction number for germany in the early phase [ ] , . for italy [ ] ). modeling studies [ , , , ] highlighted that the worst case, i.e., "do nothing" scenarios lead to an outbreak when the healthcare demand substantially exceeds the capacities at the peak and the overall mortality reaches severe levels. given the current level of preparedness, we do not consider a "do nothing" scenario, and our most pessimistic case assumes that, even in the absence of any control measures, a % reduction in transmission is realized due to population awareness and behavior. on the other hand, the best case is the continuation of the current suppression scenario with r ≈ , resulting in very small case numbers. however, it is questionable whether it can be sustained until a vaccine is developed and deployed. below, we consider three scenarios illustrating the loss of control for suppressing the outbreak, and assuming a wide community spread of the disease. the efficacy of the mitigation efforts is expressed by a percentage in the reduction of transmission. the primary tool for this is the decrease of contact numbers, but other preventive measures such as hand hygiene or mask wearing may also have an effect in the reduction of transmission. first, let us consider a weak control of the epidemic assuming there is no centralized control measure introduced, but the number of transmissions is reduced by % following a level of behavioral response due to social awareness. such a reduction decreases the reproduction number to r = . . the first column of figure shows the hospitalization and icu demand on the top row and the daily incidences on the bottom row as a function of time with the application of this weak control. according to the simulations, in this case, there would be approximately . million infections with about , deaths by the end of the outbreak. this suggests that we can expect % of the population to gain immunity against the virus and this number is slightly larger than the threshold of herd immunity (that is ( − /r ) ∼ . % with r = . for the "do nothing" scenario). at the peak, there would be a need for more than icu beds and for , hospital beds with such a weak measure. we remark that there is a -days window when the daily incidences exceed , , and during this period more than . million people ( % of the population) get infected. in other words, % of all the infections occur during these three weeks. for further details, see table . we perform similar simulations for the case of a moderate control, assuming that the reproduction number is decreased to r = . as a result of the control measures. the simulations (second column of figure ) show that the number of hospital beds and icu beds needed is significantly reduced to and at the peak, respectively. meanwhile, the daily incidence at the peak is around , . we expect almost . % percent of the population to be infected throughout the epidemic and gain immunity upon recovery. this is less than required to reach herd immunity. for further information, we refer to table . finally, we consider a stronger control achieving a % reduction of transmission. this results a decrease of the reproduction number to r = . . the outcome of this strong control is shown in the third column of figure . a control of such strength significantly reduces the number of all infected and hospitalized cases and of those needing intensive care treatment. the number of required intensive care beds (around ) is far below the available capacity even at the peak of the epidemic and also the number of hospital beds needed is reduced to a rather low level-around at the peak. the total number of fatalities in this scenario is about . meanwhile, the epidemic would last for more than a year and the cumulative number of all infected remain far below the level of herd immunity threshold, so we can expect further outbreaks when the measures are relaxed. several key parameters of the model are highly dependent on age. intervention strategies and the relaxation of various measures have to take into account the fact that different age groups have different risks and different roles in the transmission. although the number of children infected with covid- has been reported worldwide relatively small in comparison with other age groups [ ], some evidence shows that children and adolescents may become infected and spread the disease as other age groups [ , ] . moreover, children and adolescents usually have a high number of contacts. thus, school closures can be expected to be an efficient tool to reduce the contacts and transmissions. besides school closures, it is important for younger individuals to avoid meeting older and other high risk people. elderly people have a higher chance of developing symptoms, and a higher percentage of them needs hospitalization and intensive care, hence these groups need more protection. age-specific interventions include avoiding contacts with elderly by providing special time slots for shopping, in post offices, etc., or closing/reopening schools. the introduction of various age groups in our model enables us to study such age-specific interventions and analyze their direct and indirect effects on all groups. on the stacked diagrams of figure , we present the contributions of the age groups to the mortality and the number of recovered individuals. columns of this figure show the effect of the weak, moderate, and strong control that we previously discussed in details in section . and table . here, we would like to emphasize that, in the case of each control measure, the most vulnerable age groups are the groups of elderly ( - , - , +) people as they suffer most of the fatalities; meanwhile, they are predicted to produce only a small fraction of the cases in the population. figure . age-specific mortality and recovery. the figure shows the effect of the weak, moderate, and strong control ( %, % and % general contact reduction, respectively). every age group covers at most one decade except the group of "middle aged" that represents three decades. according to our model, elderly people ( +) are predicted to produce most of the fatality cases in each scenario. the legend on the bottom applies for all figures. we consider two school closure scenarios: an optimistic and a pessimistic one (with respect to the outcome of the outbreak); both use the weak control scenario ( % general decrease in transmission, cf. section . ) as a starting point. the optimistic case is comprised of omitting the school component of the contact matrix and halving the other contacts [ ] of children and young adults (between age - ), which provides a new global contact matrix for this intervention. in the pessimistic scenario, we omit the school component of the contact matrix as well, but, instead of halving, it considers a % increase in the other contacts of children and young adults. arguably, the students might replace some school contacts by new other contacts, due to other activities. however, many of such contacts are lost as well: for example, they do not use public transportation to/from the school, and extracurricular activities also drop. since the exact balance is difficult to estimate, our two closure scenarios serve as a boundary to explore this regime of possibilities. note that, by school closure, we mean the closure of educational institutions from preschools to universities. as a reference, we also incorporate the weak control scenario to this analysis. figure shows that this measure decreases the peak hospital bed and icu needs to approximately % compared to the case when we only apply weak control in the optimistic scenario and by % in the pessimistic one. moreover, closing schools postpones the peak of the epidemic (by about one month in case of the above setting), suggesting that children may play a significant role in transmission due to their large number of contacts, even though they give negligible contribution to the overall mortality, cf. top row of figure ). note that this conclusion is based on the assumption that all age groups are equally susceptible, and symptomatic children are equally infectious to adults, and age specific difference appears only in the probability of developing symptoms, which is much smaller for children in our model (see parameters p i in table ). school closure in addition to the % contact reduction (pessimistic approach) school closure in addition to the % contact reduction (optimistic approach) figure . effect of school closure. simulations suggest that school closures-if maintained for a long period-effectively decrease peak hospital bed and icu needs and significantly postpone the peak of the epidemic. the effect of school closure combined with the % general reduction in transmission is comparable, in the optimistic case, with the effect of moderate control ( % reduction in transmission, cf. section . ) regarding the peak hospital bed and icu need, but not as significant in decreasing the mortality (figure middle column). however, to achieve this, schools need to be closed for an extended period of time, which may not be feasible. we also point out that a standalone closure of preschools and primary schools is not sustainable without a certain amount of home office of the parents, but this opens up sociological and economical questions that we do not address here. the elderly being the most vulnerable group of the population, when it comes to relaxation of measures introduced against the spread of covid- . most countries handle these age groups separately from the rest of the population, e.g., separate time slots for shopping continue to exist and elderly are encouraged to keep the same level of social distancing [ , ] . to include these effects in our model, we manipulate the entries of the contact matrix involving older age groups separately from the remaining parts. figure illustrates that, in addition to the weak control, if % and % reduction of the outside household connections of elderly people is applied, then we can expect about % and % reduction in the hospital, icu bed needs, and mortality. the epidemic curves only slightly shift to the right suggesting that elderly people do not play an important role in the transmission of the disease due to their low number of contacts. in addition, % reduction of contacts outside the household is again not feasible, as this would mean the complete isolation of a large sub-population. we plotted this scenario only to show the theoretical limits of this approach. general % contact reduction (weak control) % contact reduction for elders outside of households + weak control % contact reduction for elders outside of household + weak control figure . protection of the elderly. the figures show the effect of an additional contact reduction of elderly people in case of a weak control. the figures suggest that the selective protection of elderly people can successfully reduce the peak icu need and the overall mortality, yet it has a theoretical limit. in this section, we investigate the epidemic curves in case of the weak, moderate, and strong control with seasonality of various strengths expressed by parameter c ∈ { , . , . , . }, see ( ) . during the summer, these values of c eventuate a %, %, and % further decrease in transmission as that is when the seasonality curve attains its minimum. the case c = means that there are no seasonal effects at all, while c = . is a strong seasonality, which is similar to h n [ ] . see the top left image of figure for the seasonality functions ω(c, t) corresponding to the different c values. as we have seen in section . , decreasing the reproduction number decreases and postpones the peak of the epidemic curves. seasonality causes a similar delay in the peak of the epidemic due to decreased transmission rates in the summer months. counter-intuitively, it cannot be said in general that stronger seasonality leads to a smaller peak (cf. bottom left image of figure ). the reason for this is that the impact of seasonality is not only determined by the decrease in the transmission rate, but the temporal relation between the peak of the epidemic and the minimum of the seasonality function is also an important factor. this phenomenon is well illustrated in figure where three scenarios (weak, moderate, and strong control) are presented along with the assumed seasonality functions for the aforementioned values of c. in the upper right image of figure , corresponding to a weak control, one can observe that increasing the effect of seasonality first decreases the peak, but, after a certain value (c = . in our example), the epidemic is so much suppressed in the summer months that the peak shifts to the right and even slightly increases in winter months compared to the c = . scenario. for the case of moderate control, shown in the lower left figure, this effect is much more significant. note that the peak of the epidemic (without seasonality) is so far from summer (the minimum of the seasonality curves) that increasing the effect of seasonality results in a significantly higher peak. it can be seen that strong seasonality eventuates a long "plateau" phase when the epidemic curve does not increase in a period of six months. during this time, only a small fraction of the population goes through the infection and a massive number of susceptibles remain in the system, only to get infected a few months later. this phenomenon is responsible for the increased peak of c = . compared to the c = . case. the lower right figure shows that the reduction of transmission during the warm months together with a strong control can decrease the number of infected in such an extent that the peak, even if arriving in the winter months, is significantly smaller. a general observation is that seasonality has the largest impact on the epidemic curve if the peak time is close to the summer months. of course, this is highly dependent on the starting time of the outbreak. hungary is a relatively small country; however, significant differences were observed between regions in the reported case numbers. the capital, budapest, has . million inhabitants and a further . million people live in its surrounding pest county. budapest and pest county are highly connected by commuters with connections to other regions as well [ ] . the high connectivity of the capital with other countries contributed to the earlier appearance of the disease in budapest, and most of the cases were reported from this central region of the country. to address the role of spatial heterogeneity in the evolution of the epidemic curve, we considered a metapopulation model as in ( ) . hence, the population is distributed among patches, representing geographic regions of the country. for the sake of simplicity, here we only present results from a two-patch model, separating budapest and pest county (patch , population of approx. , , ) from the remaining parts of the country (patch , population , , ). we assumed different transmission parameter β for each patch. based on hungarian mobility data on commuters [ ] , we assumed , daily travels between the two patches in the case of normal circumstances and investigated the effect of the lockdown of budapest and the surrounding pest county by decreasing the number of daily travels to , . we considered the contact matrix for both patches to be the same as in the uniform model described in section . . . the biological and medical parameters are assumed to be the same in each patch, but the local reproduction number may differ, as well as the age structure of the population. the left-hand side of figure illustrates that the two-patch model reproduces the uniform model in case we use the same r = . for both patches as well as for the uniform model and we assume , daily travels between the patches. the middle figure shows that the uniform model slightly overestimates the size of the epidemic as the peak of the aggregated two-patch model is smaller than that of the uniform model in case r = . remains the same, and we reduce the daily travels to , corresponding to the separation of budapest and pest county from other regions. although the epidemic curves of the patches are shifted, the aggregated result shows that this setup does not provide significantly different dynamics. lastly, on the right-hand side of figure , we further investigate the scenario of , daily travels, and choose the local reproduction numbers of the patches to vary around r = . , namely, we take r budapest = . and r other regions = . . these values were selected to reflect the higher population density of the capital, proportionally to the population in the two patches. due to the difference in the local reproduction numbers, we may observe an increased number of cases in budapest with an earlier peak and fewer infections in other regions. figure . epidemic curves of the regions: sum of the infective compartments (i p , i a, , i a, , i a, , i s, , i s, , i s, ). first, we consider identical reproduction numbers r = . for both patches (budapest with pest county and other regions). without any travel reductions, the two-patch model gives identical results to the one-patch version, as seen in the left figure. next, if travel reductions are put in place, the one-patch model overestimates slightly the size of the epidemic for equal r values. finally, assuming different reproduction numbers and large reduction in travel, the peak occurs earlier in the patch with larger r (budapest and pest county); furthermore, the one-patch model and the aggregated two-patch model differ in both time and size of the peak. for an uncontrolled epidemic in the uk, ref. [ ] estimated a peak in icu bed demand more than times greater than the maximum capacity in these countries. in a study for the united states, ref. [ ] projected that, at the outbreak peak, three times more icu beds would be needed than the total number of icu beds in the us, and % isolation of cases reduces the demand for icu beds to the normal capacity. in the Île-de-france region, ref. [ ] estimated that the peak number of icu beds needed would exceed more than times the regional capacity if no strategy is implemented after lockdown, and only efficient case-finding and isolation applied parallel with social distancing could decrease icu demand below the maximum capacity throughout the epidemic. for australia, ref. [ ] studied three capacity expansion scenarios ( , and times expansion, respectively), and, even in mitigated scenarios, demand is estimated to be higher than the number of available beds. additional social distancing measures were shown to reduce the epidemic to a level where a reasonable expansion of icu capacity can be sufficient. the peak icu demand crucially depends on two factors: the probabilities of developing severe disease, and the shape (in particular the peak size) of the epidemic curve. we plotted a heatmap of the peak icu demand in figure , compiled from hundreds of numerical simulations. transmissibility (vertical axis) is expressed by the reproduction number r. disease severity, for simplicity, is expressed by the ifr. in fact, here we used a scaling factor for the probability of hospitalization, with the baseline corresponding to the parameters in table . in our weak control scenario (section . ), the ifr is . %, which is a bit lower than the finding of [ ] . however, during the first wave in hungary, the schools were closed and covid- disproportionately affected the vulnerable population. in our scenarios, we assume a widespread community spreading, hence younger generations appear in higher numbers, thus the ifr is expected to be smaller. in any case, by the scaling of the hospitalization rate (while leaving the probability of intensive care and fatal outcome given hospitalization intact), we explored a wider range of ifrs. we found that indeed the peak icu demand can vary across a large interval. from the shape of the level curves in the heatmap, we can conclude that the peak icu demand is more sensitive to r than to the ifr, hence flattening the curve is indeed of utmost importance to avoid exceeding healthcare capacities. [ ] . the white dot is our most pessimistic scenario (weak control). the most important implemented measures are summarized in table . to assess their impact, we compared the reported case numbers adjusted by the ascertainment rate : to the simulated outbreak curve with r = . ( figure on the left, logarithmic scale). here, we assumed that the ascertainment rate did not change in time, which may not be the case. one can see that the epidemic was on the r = . trajectory, which could have resulted in substantially more infections. the data shows a clear deviation from this scenario early april, two weeks after strict social distancing started. the slope of the epidemic curve further decreased mid-april, following the stay at home measures by two weeks. overall, due to the compliance of hungarian society with the social distancing measures, around half million infections were averted by the end of april, compared to the "do nothing" scenario, which could have reached - million in may if further doublings would have been allowed. the first covid- case was detected, the laboratory confirmed, and then reported through the hungarian notifiable disease surveillance system on march . well tailored, effective, combined non-pharmaceutical control measures have been introduced promptly in hungary in the very early phase of the outbreak (see table ), accompanied with a high level of compliance for social distancing. online surveys [ ] , polling, and indirect data (such as traffic data, passenger volumes on public transportation, etc.) all showed a drastic reduction in the number of contacts and mobility. in particular, the online questionnaire maszk [ ] showed a - % decrease (depending on the locality) in the daily number of physical contacts as well as in the number of closed contacts per capita, based on the replies of , respondents by may , constituting a non-representative, but rather large sample. accordingly, the hungarian epidemic curve was strongly suppressed. as of may , the cumulative number of reported confirmed covid- cases were ( . cases per , population), including deaths. the epidemic peaked on april with newly reported cases. sars-cov- was not able to sustain long transmission chains in the community; however, it was able to cause outbreaks mostly in healthcare institutions and long-term care facilities: nearly two thirds of the reported cases are connected to such institutions. the proportion of cases in health care workers gradually increased during the epidemic. they had tenfold risk to become confirmed covid- cases compared to the general population. due to effective measures, the virus could not spread significantly from closed communities and health care workers to the wider population. the age specific cfr showed a similar pattern to other countries: of the deaths reported by may, ( . %) belonged to the + age group. we tracked the temporal variation of the effective reproduction number in real time, which showed a steadily decreasing trend, interrupted by an outlying outbreak in a long-term care facility. we identified the time intervals when the effective reproduction number was below or around the critical threshold . the adjusted cfr was also estimated real-time, and predicted the eventual cfr one month in advance well. benchmarking the cfr to other countries, we estimated underascertainment rate to be - times, and the true cumulative number of covid- cases to be between , and , . these results are consistent with data from the preliminary results of a large scale seroepidemiological survey, carried out in hungary in may , where the seroprevalence of sars-cov- infection was estimated to be between , and , [ ] . based on these data and the number of reported cases, underascertainment is likely to be between . - . , and the true cfr may be lower than . %, and the ifr is roughly half of that. as control measures are being successively relaxed since may , we established an age-structured compartmental model to investigate several post-lockdown scenarios, and projected the epidemic curves and the demand for critical care beds assuming various levels of sustained reduction in transmission. special measures designed to reduce the contact number of the elderly population as well as school closures can reduce the peak hospital bed demand and the overall mortality; however, these measures also have their limitations. a metapopulation version of the transmission dynamics model has also been studied, and we reported some results for a two-patch case, where the budapest region is considered separately from the rest of the country. due to the high connectedness, the epidemic curves of the two-patch system are not much different from the spatially uniform case. to achieve a noticeable reduction in the overall peak size due to spatial heterogeneity (where the local peak times are shifted in the regions), a large reduction in the mobility rates is necessary. since the majority of the population is still susceptible (over %, according to [ ] ), a weak or even a moderate reduction in the transmission, compared to the baseline, could result in a large second outbreak with significant mortality and high peak icu demand. therefore, a high level of alertness needs to be maintained to avoid such scenarios. the seasonal behavior of sars-cov- is not completely understood yet [ , ] , thus we considered a range of possibilities from the absence of seasonality to a strong seasonality, which is similar to h n . the interplay of seasonal effects with the post-lockdown contact numbers can generate a variety of disease dynamics; thus, a confident forecast of the timing and the size of a potential second wave is not possible at the moment. the effectiveness of strict social distancing measures, such as school closures and stay at home measures with good compliance is likely to be very high; however, such interventions have negative consequences on the society and on the economy and are thus not sustainable in the long term. modeling results [ , ] suggest that combined multiple interventions, including moderate contact decrease, high covid- detection rate, effective contact tracing, and good compliance with personal protective instructions, may have substantial impact on transmission, and are able to keep the reproduction number around one. situation reports; world health organization france: surveillance, investigations and control measures cov- was already spreading in france in late investigation of a covid- outbreak in germany resulting from a single travel-associated primary case: a case series covid- epidemic in italy: evolution, projections and impact of government measures who. statement on the second meeting of the international health regulations ( ) emergency committee regarding the outbreak of novel coronavirus director-general's opening remarks at the media briefing on covid- ; world health organization covid- ) in the eu/eea and the uk-ninth update multiple sars-cov- introductions shaped the early outbreak in central eastern europe: comparing hungarian data to a worldwide sequence data-matrix covid- announcements of hungary r: a language and environment for statistical computing; r foundation for statistical computing elegant graphics for data analysis table: extension of 'data.frame'. r package version . . shiny: web application framework for r real-time epidemiology of covid- in hungary (a magyarországi koronavírus járvány valós idejű epidemiológiája-in hungarian) real-time epidemiology of covid- in hungary (a magyarországi koronavírus járvány valós idejű a new framework and software to estimate time-varying reproduction numbers during epidemics different epidemic curves for severe acute respiratory syndrome reveal similar impacts of control measures how generation intervals shape the relationship between growth rates and reproductive numbers the effective reproduction number of pandemic influenza: prospective estimation association of public health interventions with the epidemiology of the covid- outbreak in wuhan effective reproduction number estimation estimating in real time the efficacy of measures to control emerging communicable diseases serial interval of covid- among publicly reported confirmed cases epidemiological characteristics of covid- cases in italy and estimates of the reproductive numbers one month into the epidemic serial interval of novel coronavirus (covid- ) infections the r package: a toolbox to estimate reproduction numbers for epidemic outbreaks r : estimation of r and real-time reproduction number from epidemics. r package version . - estimate time varying reproduction numbers from epidemic curves. r package version . - . methods for estimating the case fatality ratio for a novel, emerging infectious disease assessing the severity of the novel influenza a/h n pandemic early epidemiological assessment of the virulence of emerging infectious diseases: a case study of an influenza pandemic real-time estimation of the risk of death from novel coronavirus (covid- ) infection: inference using exported cases incubation period and other epidemiological characteristics of novel coronavirus infections with right truncation: a statistical analysis of publicly available case data rstan: the r interface to stan using a delay-adjusted case fatality ratio to estimate under-reporting ( ). cmmid risk assessment of novel coronavirus covid- outbreaks outside china modelling the impact of covid- in australia to inform transmission reducing measures and health system preparedness expected impact of lockdown in Île-de-france and possible exit strategies a first study on the impact of current and future control measures on the spread of covid- in germany report -impact of non-pharmaceutical interventions (npis) to reduce covid- mortality and healthcare demand projecting hospital utilization during the covid- outbreaks in the united states covid- epidemic risk assessment for georgia temporal dynamics in viral shedding and transmissibility of covid- early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia effects of latency and age structure on the dynamics and containment of covid- appropriate models for the management of infectious diseases hungarian data supply questionnaire (maszk-magyar adatszolgáltató kérdőív-in hungarian) code basis for covid modelling in hungary contact tracing assessment of covid- transmission dynamics in taiwan and risk at different exposure periods before and after symptom onset quantifying sars-cov- transmission suggests epidemic control with digital contact tracing features of , hospitalised uk patients with covid- using the isaric who clinical characterisation protocol report on covid- in critical care incidence, clinical outcomes, and transmission dynamics of severe coronavirus disease in california and washington: prospective cohort study children with covid- in pediatric emergency departments in italy projecting social contact matrices in countries using contact surveys and demographic data the construction of next-generation matrices for compartmental epidemic models preliminary results of the h-uncover study estimates of the severity of coronavirus disease : a model-based analysis infection fatality rate of sars-cov- infection in a german community with a super-spreading event sars-cov- seroprevalence trends in healthy blood donors during the covid- milan outbreak pattern of early human-to-human transmission of wuhan covid- outbreak in italy: estimation of reproduction numbers over two months toward the phase . medrxiv ministry of health, welfare and sport, netherlands. children and covid- an analysis of sars-cov- viral load by patient age covid- and the consequences of isolating the elderly seasonal transmission potential and activity peaks of the new influenza a (h n ): a monte carlo likelihood analysis based on human mobility the salient targets of commuters social distancing strategies for curbing the covid- epidemic temperature, humidity, and latitude analysis to estimate potential spread and seasonality of coronavirus disease (covid- ) cmmid covid- working group. effects of non-pharmaceutical interventions on covid- cases, deaths, and demand for hospital services in the uk: a modelling study cmmid covid- working group. effectiveness of isolation, testing, contact tracing, and physical distancing on reducing transmission of sars-cov- in different settings: a mathematical modelling study the authors declare no conflict of interest. key: cord- -qatiqnac authors: kupczyk, maciej; antczak, adam; kuna, piotr; górski, paweł title: life threatening pneumonia in a lupus patient: a case report date: - - journal: cases j doi: . / - - - sha: doc_id: cord_uid: qatiqnac we report a case of systemic lupus erythematosus (sle) in a -year old caucasian woman complicated with pneumonia and severe respiratory failure requiring icu treatment and mechanical ventilation. symptoms developed in a generally well controlled sle course after sudden stop in immunosupresant therapy (methotrexate, cyclosporin and methylprednisolone). a fulminant course of the disease, an interstitial pattern in a high resolution computed tomography (hrct) and negative repeated sputum, blood and bronchoaspirate cultures enabled diagnosis of fulminant lupus pneumonitis. the response to pulses of cyclophosphamide and methylprednisolone was good but complicated with a significant leukopenia. hrct confirmed significant remission of pulmonary changes. fulminant lupus pneumonitis is a rare but potentially life threatening complication of sle. differential diagnosis requires exclusion of pneumonia induced by pathogens such as pneumocystis jirovevecii (carinii) and mycobacterium sp. intensive immunosuppressive therapy and close cooperation between icu, pulmonology and rheumatology departments is necessary in such a case to minimalize the risk of fatal outcome. systemic lupus erythematosus (sle) is an autoimmune chronic systemic disease which can involve several organs such as skin, lungs, brain and heart. pulmonary manifestations of sle can include a wide spectrum of diseases such as pleuritis, pneumonia, pulmonary embolism, pneumothorax and pulmonary haemorrhage [ , ] . as the basic treatment of sle include several drugs inducing immunosuppression pneumonia and acute respiratory distress syndrome (ards) followed by sepsis are the most common causes of admission to the icu and fatal outcome in these patients. only few cases of non-infectious fulminant lupus pneumonitis mimicking, by its interstitial pattern, atypical pneumonia has been presented in literature to date. differential diagnosis and treatment of this condition represent a real challenge but only early introduction of intensive immunosuppressive treatment and close cooperation between icu, pulmonology and rheumatology departments reduce the risk of fatal outcome. a -year old white woman was admitted to our hospital complaining of dyspnoea, non-productive cough and °c fever for the past days. she had been diagnosed with sle at the age of years. the course of her sle was well controlled in an outpatient clinic. she had never smoked. on examination on admission she was febrile, with tachycardia (hr /min) and tachypnoe /min. on auscultation loud crackles were audible over the both lungs. chest x-ray revealed an interstitial pattern with bilateral ground-glass shadow. her wbc was . × / μl, c-reactive protein mg/l, sedimentation rate mm after hour. blood gases measurement in the arterialized blood from the capillary vessels revealed severe respiratory failure with hypoxaemia (po . mmhg, pco . mmhg, sat . %). an atypical pneumonia was suspected. intravenous antibiotics (ciprofloxacin and spiramicin), oxygen ( l/min) and steroids (methylprednisolone in the dose mg/ kg of the body mass orally) were started. repeated blood gases evaluations showed no improvement thus the rate of oxygen flow was increased to l/min and methylprednisolone to . g daily intravenously. after days of such treatment a significant improvement was observed. she was afebrile, with hr / min, respiratory rate /min, po . mmhg, pco . mmhg, sat . %. on the rd day after admittion patient's condition suddenly deteriorated with severe dyspnoe, fever ( °c), shivers, hr - /min and respiratory rate /min. she has been transferred to the icu, required endotracheal intubation and mechanical ventilation. high resolution computed tomography (hrct) showed ground glass opacity ( figure. a.). there were negative repeated sputum and blood cultures. bronchoalveolar lavage (bal) cultures were also negative. the past medical history included symptoms of respiratory tract infection, arthralgia, oral ulcers, fever and skin rush noted in november . anti-nuclear antibodies (ana) level was : (range: till : ). patient was diagnosed in an immunology outpatient clinic as a recurrence of sle and effective treatment with methotrexate, cyclosporin and methylprednisolone was introduced. for an unknown reason the treatment has been suddenly stopped and changed to monotherapy with chloroquine just days before the development of symptoms and admission to our hospital. the level of pana was : . taking this and negative sputum and blood cultures into consideration we diagnosed fulminant lupus pneumoni-tis. intensive immunosuppressive treatment has been introduced with pulses of cyclophosphamide (cp) ( . g iv/daily on the first day in the icu, . g on the nd and rd days, . g for the next days and with following . g iv and later orally), methylprednisolone ( g iv/daily) (figure. . ) and mesna to prevent the urotoxicity of cp. the patient's condition gradually improved and she was extubated on the th day and transferred to the pneumonology department. a significant leukopenia as a side effect of the immunosuppressive agents was observed (drop in the wbc from . × /μl down to . × /μl during days) (figure. ). despite preventive antibiotic treatment (ceftriaxone g iv/daily) °c fever developed. antibiotics has been changed to levofloxacine ( g iv daily) and amikacin ( . g iv daily) and patient felt better. doses of cyclophosphamide previously reduced to mg po daily had been withdrawn. methylprednisolone was given orally mg/kg of the body mass daily. the bone marrow biopsy has been performed showing intensive hematopoietic cells differentiation and maturation which has been mirrored in the peripheral blood count (increase in the wbc to . × /μl after days without granulocyte colony-stimulating factor treatment). she was discharged week later with hrct confirmed significant remission of pulmonary changes ( figure. b.) and referred to follow up in an outpatient clinic. the above described case presents fulminant lupus pneumonitis a rare but life threatening complication of sle. pulmonary manifestations of sle can include a wide spectrum of diseases such as pleuritis, pneumonia, pulmonary embolism, pneumothorax and pulmonary haemorrhage with pneumonia and acute respiratory distress syndrome (ards) followed by sepsis as the most common cause of admission [ ] . the pathogens cultured in studied cases included pseudomonas aeruginosa, salmonella sp, staphylococcus aureus and epidermidis, streptococcus pneumoniae, e. coli and acinetobacter baumannii. in two patients disseminated tuberculosis was diagnosed. these findings are not surprising if we remember that glucocorticosteroids and other drugs used in the treatment of sle induce significant immunosupression thus increasing the risk of all kinds of infections. in line with the paper of hsu et al septic shock is associated with higher risk of fatal outcome in sle patient treated in icu, that is why identification of pathogen and immediate antimicrobial therapy is of great importance [ ] . only one patient ( , %) from the study group [ ] has been diagnosed with noninfectious pneumonitis. comer et al reported another case of a patient with sle, whose pregnancy was complicated by fulminant pneumonitis and pericarditis [ ] . single cases has been also presented by other authors [ , ] . isbister et al described a year old girl with sle, complicated with lupus pneumonitis, acute renal failure and aplasia [ ] . plasmapheresis, dialysis and immunosuppressive therapy were useful in the treatment. mok cc et al described two clinically very similar cases [ ] . one patient was confirmed to have coronavirus pneumonia while the other had fulminant lupus pneumonitis. diagnosis of fulminant lupus pneumonitis is a real challenge. as presented above several patogens should be taken into consideration in a case of interstitial pneumonitis including but not limited to viruses [ ] , pneumocystis carinii [ ] and mycobacterium sp [ ] . in the case we present diagnosis has been made basing on a data from several negative cultures and striking history of sudden reduction, not increase in the dosis of the immunosuppressive agents. intensive immunosuppressive treatment including glucocorticosteroids, cyclophosphamide, methotrexate, cyclosporin and in selected cases plasmapheresis should be introduced. a close cooperation between icu, pulmonology and rheumatology departments is required in such a case to minimalize the risk of fatal outcome. ana: anti-nuclear antibodies; ards: acute respiratory distress syndrome; bal: bronchoalveolar lavage; bmb: bone marrow biopsy; cp: cyclophosphamide; hr: heart rate; hrct: high resolution computed tomography; icu: intensive care unit; min: minutes; μl: micro liter; pco : partial presurre of carbon dioxide; po : partial pressure of oxygen; sat: saturation; sle: systemic lupus erythematosus cardiopulmonary involvement in juvenile systemic lupus erythematosus pulmonary involvement in childhoodonset systemic lupus erythematosus: a report of five cases outcome and prognostic factors in critically ill patients with systemic lupus erythematosus: a retrospective study fulminant lupus pneumonitis with acute renal failure and rbc aplasia. successful management with plasmapheresis and immunosuppression lupus pneumonitis or severe acute respiratory syndrome? lupus cytomegalovirusinduced interstitial pneumonitis in a patient with systemic lupus erythematosus risk factors for pneumocystis carinii pneumonia in patients with polymyositis/dermatomyositis or systemic lupus erythematosus acute lupus pneumonitis mimicking pulmonary tuberculosis: a case report written informed consent was obtained from the patient for publication of this case report and accompanying images. a copy of the written consent is available for review by the editor-in-chief of this journal. the authors declare that they have no competing interests. mk analyzed and interpreted the patient data regarding the pulmonary disease and was a major contributor in writing the manuscript, aa analyzed and interpreted the patient data regarding the pulmonary disease, performed bronchoscopies and bal, pk analyzed and interpreted the patient data regarding the rheumatological disease and was a contributor in writing the manuscript, pg analyzed and interpreted the patient data regarding the rheumatological disease and results of hrct. all authors read and aprooved the final manuscript. key: cord- - jzyyin authors: effenberger, maria; grander, christoph; grabherr, felix; griesmacher, andrea; ploner, thomas; hartig, frank; bellmann-weiler, rosa; joannidis, michael; zoller, heinz; weiss, günter; adolph, timon erik; tilg, herbert title: systemic inflammation as fuel for acute liver injury in covid- date: - - journal: dig liver dis doi: . /j.dld. . . sha: doc_id: cord_uid: jzyyin background: a cytokine storm conceivably contributes to manifestations of corona virus disease (covid- ). inflammatory cytokines such as interleukin- (il- ) cause acute liver injury while serum detectability indicates systemic inflammation. aims: we explored a link between systemic il- , related acute phase proteins and liver injury in hospitalized covid- patients. methods: patients with suspected covid- were screened in the emergency department at the university hospital of innsbruck, austria, between february and april . patients (∼ %) were hospitalized with covid- . patients required intensive-care treatment (ict). plasma aminotransferases, alkaline phosphatase, bilirubin, and gamma glutamyl transferase, as well as il- , c-reactive protein (crp), ferritin and lactate dehydrogenase (ldh) were determined by standard clinical assays. results: of all hospitalized covid- patients, ( %) showed elevated aspartate aminotransferase (ast) concentration. covid- patients with elevated ast exhibited significantly higher il- (p< . ), ferritin (p< . ), ldh (p< . ) and crp (p < . ) serum concentrations compared to patients with normal ast. liver injury correlated with systemic il- (p < . ), crp (p < . ), ferritin (p < . ) and ldh (p < . ) concentration. in covid- patients requiring ict, correlations were more pronounced. conclusion: systemic inflammation could be a fuel for hepatic injury in covid- . in december , a series of patients with pneumonia caused by a novel severe acute respiratory syndrome coronavirus (sars-cov- ) was reported from wuhan, hubei province in china [ ] . since then, coronavirus disease (covid- ) has spread globally with more than . . infections and, by date, more than . deaths worldwide. the typical symptoms of sars-cov- infection, such as fever, cough, sore throat, or dyspnea, are well recognized and have been widely described [ ] [ ] [ ] [ ] [ ] while also organs beyond the respiratory tract may be affected [ , ] . sars-cov- is a beta-coronavirus that is closely related to severe acute respiratory syndrome corona virus (sars-cov) [ ] . both viruses use the angiotensin-converting enzyme-related carboxypeptidase (ace ) as receptor to gain entry into mammalian cells [ ] . previous studies found that ace expression is related to the severity of acute respiratory distress syndrome (ards) caused by sars-cov infection, and mediates the production of cytokines in ards [ , ] . massive release of proinflammatory cytokines results in a cytokine storm (also termed cytokine release syndrome (crs)) which is characterized by elevated c-reactive protein (crp), interleukin (il- ), lactate dehydrogenase (ldh) and ferritin concentration that is accompanied by organ dysfunction (such as ards, progressive liver damage and liver failure). as such, the systemic release of pro-inflammatory cytokines seems to be a driver of disease progression in covid- [ ] [ ] [ ] . the impact of sars-cov- on liver disease is poorly understood [ , ] . several studies reported clinical features of liver injury in covid- patients [ ] [ ] [ ] [ ] [ ] [ ] [ ] with elevated aspartate aminotransferase (ast) or alanine aminotransferase (alt) in % to % of covid- patients [ , , ] which could be an indicator for severe pneumonia [ ] . similarly, delayed hospital admission after illness onset was associated with increased risk of liver injury in patients with covid- [ ] . notably, hepatic infiltration of lymphocytes, centrilobular sinusoidal dilation and patchy necrosis could be observed in covid- patients [ , ] , and sars-cov- might directly bind to ace -expressing cholangiocytes [ ] . however, the origin of liver injury remains unresolved and could be related to systemic inflammation, sars-cov- infection or drug administration [ ] . il- is a potent cytokine with diverse functions during hepatic inflammation and regeneration [ ] . il- serves inflammatory (danger) signaling and (because of its half life) better indicates systemic inflammation when compared to other cytokines, such as interleukin- beta (il- ) or tnf-alpha (tnf-) [ ] . the aim of this study was to explore a link between systemic inflammation and liver injury in covid- . the study was performed at the university hospital of innsbruck, austria, the only referral hospital in tyrol, austria. from february th , to april st , , patients with suspected covid- were evaluated. patients were diagnosed with covid- based on the world health organization interim guidance [ ] . patients were hospitalized without the need for intensive care, while patients required intensive care treatment on admission day. none of the included individuals was admitted to an intensive care unit (icu) months prior to study inclusion. of patients showed evidence of hepatic steatosis by ultrasonography ( / diagnosed with metabolic associated liver disease [ ] ) to month prior to hospitalization. no other chronic liver disease (such as chronic viral hepatitis, alcoholic liver disease, immune-mediated liver disorders or hemochromatosis) were documented in any patient and all patients had normal liver enzymes documented in previous biochemical studies ( . months ± . months prior to hospitalization) . none of the patients received any antibiotic or antiviral therapy in the past months. fever was defined as body temperature ≥ . °c and dyspnea was defined by a respiratory rate ≥ breaths/minute and resting finger oxygen saturation ≤ % [ ] . gastrointestinal symptoms were recorded based on medical history taken at hospital admission. diarrhea was defined by loose stools > times per day, vomiting was defined by ≥ per day. all reported parameters were collected on admission day. laboratory confirmation of sars-cov- infection was performed using previously described real-time polymerase chain reaction [ ] as recommended by the centers for disease control and prevention (dekalb, ga). elevated liver tests were defined by the ast ≥ units/liter (u/l), alt ≥ u/l, gamma-glutamyl transferase (ggt) ≥ u/l, alkaline phosphatase (ap) ≥ u/l and total bilirubin ≥ . u/l assessed on admission day. in covid- consensus on liver injury classification by biochemical means is lacking. therefore, patients displaying ast concentrations (≥ u/l) was considered to be increased (as in other clinical situations). il- , crp, ldh and ferritin were determined by cobas , (roche, basel, switzerland) according to the manufacturer´s specification. the lower detection limit of the assay for il- is < nanograms/mililter (ng/ml), for crp , miligrams/deciliter (mg/dl) and micrograms/liter (µg/l) for ferritin. the established cut-off value for crp is , mg/dl, for ldh u/l and for ferritin µg/l. ck, troponin t and crea were determined by cobas , (roche, basel, switzerland) according to the manufacturer´s specification. the lower detection limit of the assay for ck is < u/l, for troponin t i nanograms/deciliter (ng/dl) and , micrograms/deciliter (mgd/l) for crea. the established cut-off value for ck is u/l, for troponin t is ng/dl and , mg/dl for crea. data were expressed as mean ± standard error of mean or as median with first and third quartiles. for comparing quantitative variables, the student's t-test or the nonparametric mann-whitney u or wilcoxon signed-rank test were used as appropriate. normality of distribution was determined by kolmogorov-smirnov test. the correlation analysis was estimated using the spearman's p coefficient a p-value < . was considered as statistically significant. all statistical analyses were performed using spss statistics v. (ibm, chicago, il) and graphpad prism (la jolla, ca). the study protocol was approved by the institutional ethics commission with an amendment to an - / . and informed consent was obtained, if applicable, from each patient included in the study. the study protocol conforms to the ethical guidelines of the declaration of helsinki ( th revision, ) as reflected in a priori approval by institutional ethics commission. the mean age of patients included into our study was . years with . % (n= ) females. patients characteristics are listed in table (table ) . skeletal muscle, myocardium, and kidney might all be sources of ast, therefore ast levels were correlated with ck (non significant (ns), data not shown), troponin t (ns, data not shown) and crea (ns, data not shown). alt was elevated in only patients on admission day. these findings are going in line with other studies, suggesting alt elevation appears at a later timepoint during covid- [ , , ] . none of the patients showed elevated bili, ggt and ap at a such early stage of disease. icu patients displayed higher frequencies of fever (p= . ), dyspnea (p= . ) and imaging findings (p= . ) at admission, compared to non icu patients (table ) . during hospitalization none of the non icu-patients was transferred to the icu. the length of hospital stay was significantly longer in icu patients (p< . ) and mortality rate was significantly higher in icu patients (p< . ) ( table ) . patients admitted to the icu showed significantly higher levels of ast (p= . ), crp (p< . ), ldh (p< . ), procalcitonin (ptc, p< . ), ferritin (p< . ) and il- (p= . ) ( table ) . furthermore maximum ast (p< . ) and alt (p< . ) during hospital stay were significantly higher and peaked significantly later during disease course (p< . ) in icu patients (table ) . likewise, crp correlated with ast in all hospitalized patients (r = . , p< . , fig. a ). both icu (r = . , p= . , fig. b ) and non icu (r = . , p= . , fig. b) patients displayed a correlation with crp and ast at admission. in individuals with liver damage, crp levels were higher in non-icu patients (p< . , fig. c ), whereas we could not observe any significant difference in patients at the icu (p= . , fig. d) . similarly, ferritin concentration correlated with ast (r = . , p< . , fig. a) , although in icu patients this effect was more distinct (r = . , p< . , fig. b ) compared to non-icu patients (r = . , p< . , fig. b ). in both non-icu and icu patients, individuals with elevated ast seem to have higher concentrations of ferritin (fig. c-d) . furthermore, ldh concentration correlated with ast (r = . , p< . , fig. a) , although in icu patients this effect was more distinct (r = . , p< . , fig. b ) compared to non-icu patients (r = . , p< . , fig. b ). in non-icu patients ldh levels were higher in individuals with increased ast (p< . , fig. c ), whereas icu patients with altered ast only tended to be higher (p= . , fig. d ). furthermore, maximum ast and alt levels correlated directly with il- , ferritin and crp in non-icu patients (fig. e ). furthermore, we performed a longitudinal comparison of ast, alt and bilirubin. liver parameters were more pronounced in patients with higher il- levels. data are now presented in supplementary figure . we compared outcome data with il- and acute phase protein levels. il- was positively correlated with duration of hospital stay (r = . , p< . supp. fig. a) , icu stay (r = . , p< . supp. fig. a) , days of mechanical ventilation (r = . , p< . supp. fig. a) , and negatively correlated with mean arterial pressure (r = . , p< . supp. fig. a) . crp also showed a significant correlation whereas ldh, showed no significant correlation with mean arterial pressure. supp. fig. b and c) . ferritin was not significantly correlated to patient´s outcome (data not shown). previous studies reported signs of liver injury by biochemical and histologic means in covid- patients [ , , [ ] [ ] [ ] . however, the origin of hepatic damage in covid- is poorly understood and potentially involves systemic inflammation, viral replication or drug-induced liver injury. today, we lack evidence for sars-cov- replication in the liver and our study renders drug-induced liver injury as cause of elevated liver enzymes very unlikely. we rather found a direct correlation between systemic inflammation (indicated by il- , crp and ferritin) and liver damage. il- production may stem from immune cells [ ] fibroblasts, endothelial cells [ ] and hepatocytes [ , ] which orchestrates an hepatic acute phase response [ , , ] . while il- signaling impinges on hepatic regeneration [ ] , clinical studies (that for example tested the effect of il- administration in cancer patients) demonstrated a critical role of this pathway in hepatic injury and hepatotoxicity [ ] [ ] [ ] . in line with a critical impact of systemic inflammation and specifically il- on liver injury, we noted a direct correlation between acute phase proteins and il- in the serum of covid- patients with elevated ast. based on previous reports and our study, with the limitation of the cross-sectional design, we propose that the systemic inflammatory response to sars-cov- infection to covid- patients serves as a fuel of hepatic injury. in line with this, our findings appeared more pronounced in covid- patients with a more severe crs (i.e. that required intensive care measures). vice versa, tocilizumab, a recombinant humanized monoclonal antibody targeting the human il- receptor, reversed liver injury during crs that was induced by non-infectious means (i.e. car-t cell therapy) [ , ] . while experimental evidence suggests that blockade of an inflammatory response in sars-cov- -related crs improves the course of infection [ , ] , clinical trials are pending. in the previous mers-cov epidemic, il- and other inflammatory cytokines, such as il- have been identified as key players during infection and trigger hepatic injury [ , ] . in covid- patients, elevated il- concentrations (amongst others) have been described [ ] and a cytokine signature was indeed associated with loss of lung function, lung injury and outcome [ ] . as such, it appears that sars-cov- potently triggers a systemic cytokine response that is detrimental for some patients (as in crs) while factors that control this response remain undetermined. this cytokine response, but probably not viral burden, seems to play the key role in disease severity and patient outcome [ ] . novel coronavirus-infected pneumonia a novel coronavirus from patients with pneumonia in china clinical characteristics of coronavirus disease in china clinical features of patients infected with novel coronavirus in wuhan, china epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china faecal calprotectin indicates intestinal inflammation in covid- aga institute rapid review of the gi and liver manifestations of covid- , meta-analysis of international data, and recommendations for the consultative management of patients with covid- sars and mers: recent insights into emerging coronaviruses sars-cov- cell entry depends on ace and tmprss and is blocked by a clinically proven protease inhibitor early upregulation of acute respiratory distress syndrome-associated cytokines promotes lethal disease in an aged-mouse model of severe acute respiratory syndrome coronavirus infection expression of elevated levels of proinflammatory cytokines in sars-cov-infected ace + cells in sars patients: relation to the acute lung injury and pathogenesis of sars covid- : consider cytokine storm syndromes and immunosuppression cytokine release syndrome in severe covid- complex immune dysregulation in covid- patients with severe respiratory failure covid- and the liver: little cause for concern clinical characteristics of non-icu hospitalized patients with coronavirus disease and liver injury: a retrospective study characteristics of and important lessons from the covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention clinical and virological data of the first cases of covid- in europe: a case series liver impairment in covid- patients: a retrospective analysis of cases from a single centre in wuhan city characteristics of liver tests in covid- multicenter analysis of clinical characteristics and outcome of covid- patients with liver injury autopsy in suspected covid- cases pathological study of the novel coronavirus disease (covid- ) through postmortem core biopsies metabolic functions of gut microbes associate with efficacy of tumor necrosis factor antagonists in patients with inflammatory bowel diseases liver injury in covid- : management and challenges il- pathway in the liver: from physiopathology to therapy a guiding map for inflammation gut microbiome function predicts response to anti-integrin biologic therapy in inflammatory bowel diseases a new definition for metabolic associated fatty liver disease: an international expert consensus statement therapeutic and triage strategies for novel coronavirus disease in fever clinics interferon beta /b-cell stimulatory factor type shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells hepatic acute phase proteins--regulation by il- -and il- -type cytokines involving stat and its crosstalk with nf-κb-dependent signaling interleukin- signaling drives fibrosis in unresolved inflammation il- as a keystone cytokine in health and disease acute-phase proteins and other systemic responses to inflammation subcutaneous administration of recombinant glycosylated interleukin in patients with cancer: pharmacokinetics, pharmacodynamics and immunomodulatory effects a phase i trial of intravenous interleukin- in patients with advanced cancer up-regulation of hepatic heme oxygenase- expression by locally induced interleukin- in rats administered carbon tetrachloride intraperitoneally the cytokine release syndrome (crs) of severe covid- and interleukin- receptor (il- r) antagonist tocilizumab may be the key to reduce the mortality mechanisms, manifestations and management can we use interleukin- (il- ) blockade for coronavirus disease (covid- )-induced cytokine release syndrome (crs)? inhibition of nf-κbmediated inflammation in severe acute respiratory syndrome coronavirus-infected mice increases survival middle east respiratory syndrome: emergence of a pathogenic human coronavirus liver injury during highly pathogenic human coronavirus infections sars-cov- : a storm is raging in the eye of the covid- cytokine storm viral and host factors related to the clinical outcome of covid- no funders were involved in the study concept, design, conduct, data analyses, writing of this manuscript, or in the decision to submit this work for publication. all authors declare no conflict of interest. key: cord- -l d dc authors: robinson, a. j.; london, w.; kotan, l.; downing, w. title: a modification to the maquet flow-i anaesthesia machinefor icu ventilation date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: l d dc the authors present an easily manufactured modification of the getinge group maquet flow-i anaesthesia machine that gives it potential to be used long-term as an intensive care ventilator for emergency circumstances. there are some such machines in use worldwide, which could assist in increasing icu ventilated bed capacity in a number of nations. the authors believe this modification has potential as a solution to increasing ventilator numbers for the covid- pandemic, in hospitals where the flow-i is underutilised for its designed purpose during this emergency. the technical drawing files are downloadable on the grabcad website and are creative commons (cc-by . ) licensed to allow local manufacture of the modification. the covid- pandemic has already overwhelmed critical care capacity in italy and looks set to do the same in many other countries. if spread is not adequately contained, the critically ill cohort from this infection produces such a number of patients with sudden acute respiratory syndrome (sars) in whom positive pressure ventilation is indicated, that ventilated bed capacity is rapidly overwhelmed, and patients are left untreated. ventilated beds are in short supply worldwide, so access to additional ventilators of adequate quality to ventilate coronavirus sars patients is urgently required. this pre-paper introduces a 'proof of concept' modification to the maquet flow-i anaesthesia machine (getinge, a ) that makes it more suitable for use as an intensive care ventilator. the sars-cov- infection covid- has expanded worldwide since its lowly beginnings as a zoonotic infection in or near wuhan, prc (andersen et al., ) sometime in late . it is currently a who declared pandemic and wreaking havoc with the health and economic stability of the planet (who, ). unchecked, it has the capability to cause millions of deaths worldwide. who and most local public health responses throughout the world hves concentrated on 'flattening the epidemiological curve'. an exponential increase of sarscov- virus spread leads to unprecedented demand for critical care services. flattening the curve is an attempt to reduce the mortality rate and avoid completely overwhelming healthcare systems. an anticipated side effect of 'flattening the curve' is, however, sustained demand for intensive care services extending over a long period of time for those nations unable to reduce spread early on. while the risk of an individual patient needing respiratory care can appear low on first examination, across a population covid- produces a large . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not peer-reviewed) the copyright holder for this preprint . https: //doi.org/ . //doi.org/ . / number of such patients. these may require critical care for days or more (zhou et al., ) . demand for ventilators in the worst affected of these is thus predicted to be very high. ventilated bed capacity worldwide is low. new zealand has only some ~ ventilated beds nationwide under normal circumstances, and this number is barely adequate for normal demand. other nations are in a similar state. however, italy -the world epicenter of the disease as design commenced-had above average icu beds/ by european standards prior to the pandemic (rhodes et al., ) and was still overwhelmed. a variety of stop-gap solutions to expand ventilator capacity are therefore required while manufacture of these devices is ramped up to meet demand. this paper proposes one such solution for hospitals which have maquet flow-i anaesthesia machines available. the flow-i (getinge, a) is a modern anaesthesia machine designed for use in an operating room environment to provide short-term ventilation and delivery of volatile anaesthetic gases to patients undergoing general anaesthesia. there are some such units installed worldwide. the machine is based in part on ventilator technology that getinge group purchased from siemens and is substantially similar in function to the maquet servo-i intensive care ventilator (getinge, b) . modern intensive care ventilators are 'total loss' systems, in that the gases supplied to the breathing system are filtered through a high efficiency particulate air (hepa) filter then passively expelled to atmosphere after use. the flow-i anaesthesia machine, however (and in common with other such machines), is designed to allow the expiratory gases to be recirculated with co scavenging in 'low flow' mode with minimal losses to atmosphere. this 'partial loss' system allows preservation of expensive and environmentally damaging volatile anaesthetic gases and lowers consumption of piped oxygen and air. it does this by directing all expired air internally through a volume reflector, a convoluted reservoir that sits under the anaesthetist's writing surface that collects the . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint modified flow-i for covid- ventilation patient's expired air for recirculation. the volume reflector is connected to the patient cassette by the socket, a pair of linking tubes and silicone seals to prevent leaks. the patient cassette is the insert which contains the circle non-return valves and interfaces with the ventilator mechanisms, volatile delivery system, adjustable pressure limiting valve (apl), and internal gas bench. all three of these inserts are removable and sterilizable. anaesthetic machines are designed to be used for each patient for only hours rather than the days or weeks required of an icu ventilator, and clinical experience suggests that they tend to experience more condensation and rainout than machines purpose built for icu. experience of using such machines for longer term in a pandemic situation is absent from the literature but will no doubt become more available as the pandemic progresses. while anaesthesia machines are able to run for short periods of time without scavenging, they are designed to be used with a constant low-level vacuum applied via the anaesthesia gas scavenging (ags) port and in a positive pressure operating room environment. low flow not feasible for icu. when ventilating patients for longer procedures or in an emergency and in place of an icu ventilator, it is generally advised to run on low flows to maximise humidification. however, the first author's department has four years of experience of using the flow-i under low flow conditions for long procedures. there is generally considerable rainout in the breathing system which requires decanting from the circuit every few hours if water buildup is not to interfere with ventilation. when wet heat and moisture exchangers (hme) are less efficient at heating inspired gases, due to the energy lost to vaporizing excess water with each breath. this makes flow-i low flow undesirable for longer term use in covid- , as decanting will require loss of positive end expiratory pressure (peep) and increase potential for aerosol contamination with viral particles. low flow also . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https://doi.org/ . / requires the use of soda-lime to scrub co from the breathing gas, which adds another expense and a resource that might be depleted. total loss undesirable long-term with hme alone. in order to avoid the circuit rainout issue, the machine could be used in high flow modeand used as a total loss system like an icu ventilator by setting the fresh gas flow (fgf) above minute volume and thus allowing all unused air, oxygen, and carbon dioxide from cellular respiration to be vented to atmosphere or ags. this renders the hme more efficient in heating, but less so for humidification. reduced humidification risks drying patient mucosa, ciliary damage, thickened secretions, atelectasis (branson, ) , risks of poorer outcomes (misset et al., ) , and a higher incidence of artificial airway blockage. while a cochrane review of the available literature suggests there is not a major difference in icu outcomes between hme and active humidification, it did so with the caveat "hmes may not be suitable for patients with limited respiratory reserve or prone to airway blockage" (kelly et al., ) , something which certainly pertains in the covid- ards cohort of patients. our icu uses fisher & paykel (f&p) active humidification for patients ventilated for longer than hours, so the hme alone option was considered undesirable. total loss with active humidification too wet. when our normal icu ventilators are used with f&p active gas heating and humidification, we do not suffer significant rainout in the patient circuit. the flow-i was therefore set up with an appropriate circuit and allowed to operate as a total loss system over night. this was done once without scavenging (ags), and on the second night with ags. in the ags condition, the breathing system remained clear of liquid water, but condensation formed throughout the volume reflector. without ags, it was possible to decant liquid water from the volume reflector after a mere hours. it was concluded that use of a flow-i with active humidification would move the rainout problem from the breathing system, but result in water pooling in the volume . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https://doi.org/ . / reflector during the prolonged ventilation required for a covid- sars patient. this would be particularly so if used in an icu environment without ags. accumulated water would progressively interfere with ventilation dynamics and, at some point, require the patient cassette, socket, and volume reflector be re-processed and dried out. the interruption to ventilation and potential for aerosol contamination during this procedure would increase danger for patient and staff alike. on the other hand, ventilating covid- patients in an operating room (or) with ags is undesirable as it reduces hospital operating capacity, makes nursing more difficult, and the or is a positive pressure environment. any aerosol viral particles spilled in an unmodified or is spread throughout the theatre complex by positive pressure in the room. a solution that allows use of a humidified circuit, but without ags was thus sought to allow the use of icu bed spaces. such a solution would need to be a reversible change to the machine, pass the normal system check, and allow ventilation on a humidified circuit for an extended period without ags, but with no condensation within the anaesthetic machine. hours was chosen as a reasonable test period for any 'proof of concept' prototype. a kludge to the rescue? it was considered that bridging ports on the patient cassette with a section of breathing system tubing might provide a solution by replacing the volume reflector, shortening the gas pathway, and reducing the opportunity for condensation to form. however, although the tubing selected appeared to fit the cassette ports, and tubing could easily be hidden in the gap where the un-needed volume reflector normally sits, the machine failed to pass self-test. the failure was due to one of the connectors abruptly disconnecting during the pressure test. it was concluded that even if we could induce the machine to pass test, the risk of disconnection during ventilation would be too high. a manufactured solution? given the failure of the previous attempts to provide a workable solution, local manufacturing companies kilwell fibretube and subsequently . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https: //doi.org/ . //doi.org/ . / modified flow-i for covid- ventilation ram d were approached and asked to reverse engineer the socket. the intention being to make a u-tube which connects the patient cassette internal input and output tubing together, in order to bypass the volume reflector entirely. this device will be referred to as the bridge. the key design aspects of the bridge were that it must be simple to install; limit risk of failure during extended periods of operation; seal tightly on the cassette silicone seals intended for the socket; not interfere with normal functioning of the cassette; and be of a material which is suitable for autoclave or other sterilisation methods. in this instance d printing provides a simple, quick to innovate, and cost-effective method of manufacture. it is important to note that fdm style printers (the most common around the world) are not well suited for this device. the nature of the fdm system means that they will be prone to leakage either during pressure testing (which uses approximately cm h o ( . psi; . kpa) pulses of pressure to check the internal gas pathways); or as a result of fatigue during the extended cyclic loading during operation. there are a number of aspects of the cassette installation which creates risk of damage to an fdm manufactured part during installation. furthermore, the poor surface finish of fdm will create issues with the seals and cleaning. the successful prototype was designed and printed by ram d ( ). it was printed on a laser powder bed fusion machine from grade ti (medical grade titanium alloy). the key attributes of using a system such as this are the good surface finish, high relative strength, and a body safe material that is already approved for medical use. using this system also enabled a much simpler single piece design requiring no further assembly and very minor post printing processing to smooth the area of the seal. a critical factor of the design are the fine tolerances. alternative manufacturing methods must also reflect this, as even very small variations cause the seals to leak due to poor fit, or due to misalignment of the cassette with other gas seals. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https: //doi.org/ . //doi.org/ . / prototype test results. leak tests. the successful prototype passed system check when installed on six different flow-i machines in lakes dhb's theatre complex. the average leak was ml/min, well within the < ml/min allowed. each machine was then restored to stock and immediately passed system check normally before being returned to use. extended use. a test lung was ventilated for hours under the conditions the machine would experience in icu. pooled water appeared in the inspiratory limb of the humidified breathing system after hours, but this was easily decanted back into the water bath. that is an intended behaviour of the fisher & paykel humidification system. at hours the test was stopped, the anaesthetic machine stripped down and the anaesthetic machine gas pathways examined. there was no water in the patient cassette. the bridge and its seals were dry and there was no water in the scavenging exhaust system. there are problems which remain to be addressed in order to optimise patient use. the authors hope that by releasing this document and the device with a cc-by . license at an early stage, we can access the 'wisdom of the crowd' and collaboratively solve these issues. . scale manufacture is available in new zealand and near markets from ram d. however freight logistics have become a problem due to pandemic shutdowns, so design and production may need to be adapted to suit local manufacturing capabilities. production devices may be printed from a sterilizable patient safe material and reused, as we have done; or printed from a medical grade plastic for . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint single patient use. other manufacturers will need to confer with hospital central surgical sterilizing departments and test materials for suitability. . the end-tidal co line water trap is likely to fill relatively quickly and will need decanting. this water may be virally contaminated. internal contamination is not an issue as the sampled air is hepa filtered and dried prior to entering the gas bench. work will need to be done to mitigate the risk this poses to icu nurses, or the flow-i will need to be used without its gas bench. reflector. this may have unforeseen undesired effects during use. . choice of patient circuit will need to be tested by end users depending on local availability. the presented 'proof of concept' bridge device holds the potential to allow conversion of many maquet flow-i machines currently under-utilised for their primary purpose into intensive care ventilators. it may thus help bridge that period of time while more purpose-built intensive care ventilators are manufactured. local manufacture is available to new zealand and near markets from ram d, but the cad file is made available and allows the reader to replicate the bridge locally and investigate manufacture by local engineering firms. choice of material will depend on local manufacturing capability and available materials. this innovation is cc-by . licensed and the authors welcome collaboration and clinical exploration of the modification by the wider anaesthetics, intensive care, and engineering communities. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / the proximal origin of sars-cov- conditioning inspired gases: the search for relevant physiologic end points the maquet flow-i anaesthesia machine servo-i ventilator heated humidification versus heat and moisture exchangers for ventilated adults and children heat and moisture exchanger vs heated humidifier during long-term mechanical ventilation: a prospective randomized study flow-i bridge ventilator adapter the variability of critical care bed numbers in europe covid- stuation reports clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https: //doi.org/ . //doi.org/ . / key: cord- -wnd uss authors: singh, shalendra; cherian ambooken, george; setlur, rangraj; paul, shamik kr; kanitkar, madhuri; singh bhatia, surinder; singh kanwar, ratnesh title: challenges faced in establishing a dedicated bed covid- intensive care unit in a temporary structure date: - - journal: nan doi: . /j.tacc. . . sha: doc_id: cord_uid: wnd uss an intensive care unit (icu) is an organized system for the provision of care to critically ill patients that provides intensive and specialized medical and nursing care, an enhanced capacity for monitoring, and multiple modalities of physiologic organ support to sustain life during a period of life-threatening organ system insufficiency. while this availability of trained manpower and specialized equipment makes it possible to care for critically ill patients, it also presents singular challenges in the form of man and material management, design concerns, budgetary concerns, and protocolization of treatment. consequently, the establishment of an icu requires rigorous design and planning, a process that can take months to years. however, the coronavirus disease- (covid- ) epidemic has required the significant capacity building to accommodate the increased number of critically ill patients. at the peak of the pandemic, many countries were forced to resort to the building of temporary structures to house critically ill patients, to help tide over the crisis. this narrative review describes the challenges and lessons learned while establishing a bedded icu in a temporary structure and achieving functionality within a period of a fortnight. post planning and designing of the hospital, work on building the hospital commenced on june . the treatment area of the hospital consisted of four main hangars (each consisting of beds, with one hangar being designated the icu/unit/ high dependency unit), and a triage area for reception of patients (fig. , ) . all treatment areas of the hospital were connected by a concrete platform. apart from the treatment area, the hospital also contained a doctors' block, an administrative area, separate donning and doffing areas and a mortuary with the capacity to store the bodies. additional facilities available also included a liquid oxygen tank, a laboratory, radiology services including x-ray and ultrasonography, and an in-house pharmacy. all regions of the hospital were demarcated as 'red' zones (requiring donning of full complement personal protective equipment prior to entering), and 'green' zones, where freedom of movement was allowed. being a temporary set up, the frames of the hospital were made of aluminium alloy, and the sheet was made from fire-resistant poly-elastic material. the cubicles and partitions were made from octanorm® partitions. the description of the whole hospital including the technical specifications is beyond the scope of this article, which will deal primarily with the challenges faced during the operationalization of the icu. in its guidelines on icu planning and designing in india, the indian society of critical care medicine(isccm) has laid down recommendations for the setting up of an icu, including the initial planning, decisions about icu level, number of beds, icu design, equipment provision, support system recommendations, manning plans, human resource development, and environmental planning among others( ). these guidelines were developed by the isccm as a consensus document for the standards to be aspired for the provision of safe and high-quality intensive care in india and were taken as a baseline while planning the design and functionality of the icu. however, while the isccm guidelines do address resource limitations in the form of resources, size of the institution and variability across specialties and subspecialties, the j o u r n a l p r e -p r o o f designing of this icu differed at places with these guidelines due to the restrictions in place due to the disease process per se, as well as the time constraints due to the urgency of the project. in accordance with the isccm guidelines, the planning committee for the icu design and equipment provision included all the stakeholders -the architects, and engineers, the consultant intensivist, physicians, and was coordinated by an administrator to ensure smooth functioning and to ensure that everyone was on the same page. however, some difficulties were faced since a consultant intensivist was not involved during the initial (first days) of planning of the architectural design of the hospital, leading to a few points being overlooked during the initial planning, such as the integration of a shower area in the doffing zone, establishment of fire safety protocols and evacuation plan, maintenance of optimal temperature of the icu, and provision of uninterruptible power supply (ups) system and generator backup for the icu, especially the ventilators. these points were addressed subsequently, with separate shower areas being built in the doffing zones, fire safety protocols and evacuation plans being formalized, climate control of the icu is optimized, and ups and generator system is enabled. specific challenges faced concerning these points have been discussed in subsequent paragraphs. the first challenge in the designing of the icu was in deciding the level of the icu. the isccm defines three distinct levels of icu, with a level ii icu being recommended for large general hospitals, and a level iii icu (the highest tier) being recommended for tertiary care hospitals [ ] . it was also suggested that an icu comprises not more than beds in any setup. however, the fact that the structure was meant to be temporary, in addition to the urgency due to the rapid spread of the pandemic precluded such a design. the icu was consequently divided ventilators assembled in the icu (fig. ) . another challenge that we faced was that, even with robust manufacturer support, the haste at which the whole project had to be completed resulted in a few equipment glitches and faulty equipment (approximately %) being delivered. the faulty equipment was repaired post-inauguration but did not affect the functionality of the hospital since the initial days were covered by the functional equipment already available. perhaps the most specialized and maintenance reliant equipment in the hospital was to be established in the laboratory. it was realized that for organizations with a dearth of experience in laboratory design, the task of setting up a laboratory in a fortnight could prove complicated. however, an in-house laboratory with the facilities to run all basic investigations was considered essential for patient management. consequently, a private diagnostics firm was given the contract to establish a laboratory with all the basic investigations within the hospital premises. additionally, the liaison was maintained with a local diagnostics facility to conduct specialized tests. the quality control for the laboratory was done by specialists who were part of the duty contingent. the indenting procedures for drugs and other consumables in the icu also required fine-tuning and proved surprisingly difficult. the hospital had given the contract for the provision of all required consumables to a private pharmacy which, apart from maintaining an on-site pharmacy, would also liaise locally for any extra requirements should the need arise. however, the private pharmacy company did not have the requisite licenses to provide 'schedule x' drugs (strongly habit forming drugs, which have the potential to be abused -predominantly opioids); these had to be locally sourced from a sister hospital. additionally, the lack of universal nomenclature for many commonly used icu consumables resulted in erroneous materials being initially provided, which had to then be returned. however, most issues could be ironed out within the building period and did not significantly hamper icu functionality. with the project having to be completed in under a fortnight, difficulty was encountered in ensuring adequate electric supply and climate control for the hospital. electric supply was provided with a generator capable of providing . mw power. due to an oversight, the initial electrical design of the icu had only catered for three plug points per patient bed, which was inadequate and had to consequently be augmented to eight per bed. also, with the indented equipment arriving and being calibrated only three days prior to the inauguration of the hospital, load testing could not be conducted until two days prior to commencement of operation. load however, the same could not be catered due to the design and space constraints within the icu, and only two washbasins could be provided per icu partition of beds. it is well recognized that nutritional support is a cornerstone of good critical care [ ] . however, the catering services for the hospital had been outsourced to catering with limited experience in hospital diets. specific diet charts were provided to the firm, along with instructions, to ensure adequate nutrition of the admitted patients. apart from the monitoring of the nutritional value of the diets, regular patient feedback was also sought to assess the palatability of the hospital food, as this was deemed to be a significant determinant in overall patient satisfaction. the disinfection and disposal of biomedical waste (bmw) also proved to be a challenge, with extra caution needed to be exercised since improper handling of the waste could also lead to the icu was designed in such a way that it was connected to all the wards of the hospital by a common alleyway, and was easily accessible from any of these wards. this was considered essential to expedite the transfer of any patient who would deteriorate in the ward. specific logistical support remained a significant challenge, with considerable effort being needed to fine-tune the system to attain maximal efficiency. issues such as apparel size for the duty personnel, catering demands of the patient population, wi-fi connectivity issues and user unfamiliarity with the online database, all surfaced after the commencement of the functioning of the hospital. it was also found that despite extensive training and mock drills being carried out prior to accepting patients, there arose considerable confusion in certain facets relating to logistical support, and had to be proactively corrected by the administrative teams. requirements of the other collaborators. one valuable lesson learnt from the establishment of this icu was the importance of including the intensivist at the very beginning of the planning and designing process as the intensivist provides a unique viewpoint, which is often overlooked by administrators. the involvement of ground-level workers during the designing process could also help reap rewards, as they are often best placed to provide an insight into the patient perspective. the initial trends from the icu also showed that while concerns over the effectiveness of makeshift hospitals do still exist, when executed well, they have the potential to significantly augment the healthcare facilities in the event of an epidemic. however, there is a need for a more defined protocol for the establishment of a large-scale icu, which would aid significantly in the disaster response to future medical emergencies. covid- ) dashboard the indian perspective of covid- outbreak critical events in intensive care unit problems with systems of medical equipment provision: an evaluation in honduras, rwanda and cambodia identifies opportunities to nutritional and metabolic support in the adult intensive care unit: key controversies medical waste management practice during the - novel coronavirus pandemic: experience in a general hospital treatment algorithms and protocolized care critical care "normality": individualized versus protocolized care protocolized versus non-protocolized weaning for reducing the duration of invasive mechanical ventilation in critically ill paediatric patients sars-cov- causing pneumonia-associated respiratory disorder (covid- ): diagnostic and proposed therapeutic options molecular mechanism of remdesivir for the treatment of covid- : need to know the novel coronavirus disease (covid- ) pandemic: a zoonotic prospective a sars-cov- vaccine candidate key: cord- -kfxtctn authors: gomez, sofia; anderson, brian j.; yu, hyunmin; gutsche, jacob; jablonski, juliane; martin, niels; kerlin, meeta prasad; mikkelsen, mark e. title: benchmarking critical care well-being: before and after the coronavirus disease pandemic date: - - journal: crit care explor doi: . /cce. sha: doc_id: cord_uid: kfxtctn objectives: examine well-being, measured as burnout and professional fulfillment, across critical care healthcare professionals, icus, and hospitals within a health system; examine the impact of the coronavirus disease pandemic. design: to complement a longitudinal survey administered to medical critical care physicians at the end of an icu rotation, which began in may , we conducted a cross-sectional survey among critical care professionals across four hospitals in december to january . we report the results of the cross-sectional survey and, to examine the impact of the coronavirus disease pandemic, the longitudinal survey results from july to may . setting: academic medical center. subjects: four-hundred eighty-one critical care professionals, including critical care nurses, advanced practice providers, physicians, and pharmacists, participated in the cross-sectional survey; medical critical care physicians participated in the longitudinal survey through the coronavirus disease pandemic. interventions: none. measurements and main results: burnout was present in % of icu clinicians, ranging from % for critical care physicians to % for advanced practice providers. professional fulfillment was less common at %, with significant variability across provider (p = . ), with a low of % among critical care pharmacists and a high of % among physicians. well-being varied significantly at the hospital and icu level. workload and job demand were identified as drivers of burnout and meaning in work, culture and values of work community, control and flexibility, and social support and community at work were each identified as drivers of well-being. between july and march , burnout and professional fulfillment were present in % ( / ) and % ( / ) of medical critical care physician responses, respectively. in comparison, during the coronavirus disease pandemic, burnout and professional fulfillment were present in % ( / ) and % ( / ), respectively. conclusions: burnout was common across roles, yet differed across icus and hospitals. professional fulfillment varied by provider role. we identified potentially modifiable factors related to clinician well-being that can inform organizational strategies at the icu and hospital level. longitudinal studies, designed to assess the long-term impact of the coronavirus disease pandemic on the well-being of the critical care workforce, are urgently needed. measurements and main results: burnout was present in % of icu clinicians, ranging from % for critical care physicians to % for advanced practice providers. professional fulfillment was less common at %, with significant variability across provider (p = . ), with a low of % among critical care pharmacists and a high of % among physicians. well-being varied significantly at the hospital and icu level. workload and job demand were identified as drivers of burnout and meaning in work, culture and values of work community, control and flexibility, and social support and community at work were each identified as drivers of well-being. between july and march , burnout and professional fulfillment were present in % ( / ) and % ( / ) of medical critical care physician responses, respectively. in comparison, during the coronavirus disease pandemic, burnout and professional fulfillment were present in % ( / ) and % ( / ), respectively. conclusions: burnout was common across roles, yet differed across icus and hospitals. professional fulfillment varied by provider role. we identified potentially modifiable factors related to clinician wellbeing that can inform organizational strategies at the icu and hospital level. longitudinal studies, designed to assess the long-term impact of the coronavirus disease pandemic on the well-being of the critical care workforce, are urgently needed. key words: advanced practice providers; burnout, professional fulfillment, well-being, critical care; nurses; pharmacists; physicians b urnout, defined as a psychological syndrome related to job stressors, has reached epidemic levels among healthcare professionals ( ) . burnout syndrome, characterized by emotional exhaustion, depersonalization, and reduced sense of effectiveness and personal accomplishment, is common among critical care nurses and physicians ( , ) . specifically, % of intensive care nurses ( ) and % of icu physicians experience severe burnout syndrome ( ) . burnout has been linked to provider anxiety and depression ( ) , patient safety events, reduced quality of care for patients, and diminished patient satisfaction ( ) ( ) ( ) . burnout extends to non-physician, non-nurse healthcare roles outside of the critical care environment ( ) ( ) ( ) ( ) ; yet, information regarding burnout rates in critical care clinicians other than physicians or nurses is lacking ( ) . to mitigate the development of burnout and to promote wellness among critical care healthcare professionals, the critical care societies collaborative developed a "call to action" in ( ) . the "call to action" recommends that measures of well-being "should be benchmarked and compared across icus and medical centers" ( ) . likewise, the national of academy of medicine's (nam) action collaborative on clinician well-being and resilience recommends that to improve clinician well-being, institutions need to "measure it, develop and implement interventions, and then re-measure it" ( ) . to date, it remains largely unknown whether well-being differs by professional role or across icus or hospitals. in fact, few studies have benchmarked well-being and those conducted have focused on burnout. we therefore designed a mixed-methods study to measure well-being, defined as burnout and professional fulfillment ( ) , across the multidisciplinary team, icus, and hospitals of one health system. by including professional fulfillment, as originally designed ( ), we sought to capture the positive and negative aspects of the role and work of critical care professionals to provide a balanced assessment. as secondary objectives, we sought to better understand what drives critical care healthcare professional well-being and to examine the impact of the coronavirus disease (covid- ) pandemic on well-being. in may , we began a longitudinal, well-being assessment within the section of medical critical care ( ) . consistent with the nam recommendations ( ), we designed a research electronic data capture (redcap) survey to measure well-being among medical critical care attending physicians at the end of an icu rotation ( , ) . as detailed in mikkelsen et al ( ) , we identified a problem, implemented a solution (i.e., shorten icu rotations from -to -d rotations), and remeasured well-being and found that well-being improved as a result. we have continued these longitudinal well-being assessments to ensure improvements were sustained. in the fall of , we scaled our program up to the health system level. we redesigned our previously used redcap survey ( , ) to measure critical care healthcare professional well-being among clinicians practicing in one of icus across four hospitals at penn medicine. we included physicians, nurses, advanced practice providers (apps), and pharmacists who practice in the icu setting. the institutional review board approved the project as a quality improvement initiative (project number ). the automated redcap survey was sent to each practicing critical care clinician via email, beginning in december , with up to three reminders over months. as such, the cross-sectional health system survey was completed prior to the covid- pandemic. the survey contained a request for demographic information including clinical role, number of years in practice, primary department and annual icu service time for physicians, and icu type and hospital affiliations. for clinicians who provide care in multiple icus and/or hospitals, their information could be assigned to multiple areas. to examine well-being, we included two recommended ( ) , validated instruments in the survey: the stanford professional fulfillment index (spfi) ( ) and the well-being index (wbi) ( , ) . consistent with prior work ( ), we used the expanded, -item wbi, which includes two additional questions, as this approach has been shown to more fully capture well-being by including assessments of work-life integration and meaning in work ( ) . the spfi uses and items to measure professional fulfillment and burnout, respectively, within the last weeks ( ) . professional fulfillment-related items assess the "degree of intrinsic positive reward the individual derives from his or her work, including happiness, meaningfulness, contribution, self-worth, satisfaction, and feeling in control when dealing with difficult problems at work" ( ) . in the spfi, professional fulfillment is defined as an average fulfillment score of greater than or equal to ; burnout is defined as an average burnout score of greater than or equal to . . the wbi uses items to measure burnout within the last weeks, with burnout defined as a wbi score of greater than or equal to ( ) . if a participant met either spfi or wbi criteria for burnout, they were considered to have burnout. within the survey, we also examined candidate risk factors for wellness. derived from work by shanafelt and noseworthy ( ) , we asked critical care professionals to rate seven possible drivers of burnout on a range of ("this is driving my sense of burnout") to ("this is a source of my well-being"). the seven possible drivers included: workload and job demands, efficiency and resources, meaning in work, culture and values of work community, control and flexibility, social support and community at work, and worklife integration ( ) . respondents were invited to provide comments after each question. as noted previously, the cross-sectional survey was designed to parallel our longitudinal survey conducted within the section of medical critical care ( ) . therein, intensivist well-being is measured at the end of a clinical rotation (e.g., day of a -d rotation) among three icus at two hospitals. we continued these longitudinal surveys through the pandemic. we hypothesized that burnout would increase during this time period. to enhance our ability to benchmark critical care well-being, we report the rates of burnout and professional fulfillment in the academic year, beginning july to february (pre-pandemic), and then from march to may (during the pandemic), to coincide with the onset, peak, and plateau of the pandemic in philadelphia. to obtain a more accurate assessment of the impact of the pandemic, we limited these analyses to the medical critical care physicians who provided well-being assessments in both time periods. we present the rates of burnout and professional fulfillment as counts and proportions. we compared rates of burnout and professional fulfillment across providers, hospitals, and icus using the fisher exact test or chi-square test, as indicated. we used the kruskal-wallis test to examine differences in work experience across clinical roles. we tested for associations between candidate risk factors and burnout using the wilcoxon rank-sum test. we used stata . ic for analyses (stata datacorp, college station, tx), and considered p values of less than or equal to . as statistically significant. to provide context to the identified factors associated with burnout and well-being, we compiled and summarized the freetext response entries for assigned scores of less than or equal to (i.e., drivers of burnout) or greater than or equal to (i.e., source of well-being), respectively. we selected these thresholds to identify salient, representative comments. two independent investigators (s.g., m.e.m.) reviewed the qualitative data to identify themes and examples within each driver of well-being and to select illustrative quotes by consensus. of , critical care healthcare professionals contacted, ( %) completed the survey in december and january . the healthcare professionals included: critical care nurses, apps, physicians, and pharmacists. survey participation varied by clinical role, ranging from % for critical care pharmacists ( / ); % for physicians ( / ); % for apps ( / ), to % critical care nurses ( / ). the median years in practice, among respondents, was years, with an interquartile range (iqr) of - years. as presented in table , clinical experience varied by clinical role (p = . ), as critical care physicians and nurses had been in practice for more years than pharmacist and app respondents. of the critical care healthcare professionals surveyed, burnout and professional fulfillment were present in ( %) and ( %), respectively (table ). in general, survey respondents perceived their work to be meaningful, with a median score of out of (iqr, - ), with being "very strongly agree. " further, respondents agreed that their work schedules leave enough time for personal and family life, with a median score of out of (iqr, - ), with being "strongly agree. " as reported in table , we found that burnout was common in all healthcare professionals. burnout was most common among apps, at %, and least common among physicians, at %. burnout rates did not differ across clinical types (p = . ), nor among physicians by department (p = . ). the rate of burnout was similar by app type, being present in seven of ( %) physician assistants and of ( %) nurse practitioners (p = . ). burnout was associated with clinical experience (median of yr in practice among those with burnout, iqr: - , compared with yr, iqr: - among those not experiencing burnout; p = . ). in contrast to burnout, which was similar across clinical role, professional fulfillment differed by clinical role (p = . ). professional fulfillment was highest among physicians ( %) and lowest among critical care pharmacists ( %). there was no relationship between years of clinical experience and professional fulfillment, as those who were fulfilled were in practice a median of years, the same as those who were not fulfilled (p = . ). as reported in tables and , burnout and professional fulfillment differed across hospitals and icus, respectively. as reported in supplemental table (http://links.lww.com/ccx/a ), burnout rates within hospitals varied by provider type. for example, at hospital a, with an aggregate burnout rate of %, burnout rates ranged from % for physicians to % for apps; years in practice varied by provider type, suggesting clinical experience may explain, in part, the observed differences, within hospital a. as shown in table , compared with those not experiencing burnout, those experiencing burnout scored each potential risk factor lower (p < . ). among those with burnout, the strongest driver of burnout was related to workload and job demands. conversely, meaning in work, social support and community at work, and culture and values of my work community appeared to be protective of developing burnout as sources of well-being. in table , as context for the identified drivers of burnout and sources of well-being, we provide illustrative quotes from free-text responses. the free-text responses provide specific examples for how workload and job demands, inefficiency and lack of resources, lack of meaning in work, cultures and values, lack of control and sum of participants exceeds as some healthcare professionals surveyed (e.g., attending physicians) practice at more than one hospital within the health system. flexibility, loss of social support and community at work, and lack of work-life integration drive burnout. likewise, responses provide specific examples for how meaning in work, control and flexibility, social support and community at work, and work-life integration promote well-being. between july and march , , burnout and professional fulfillment were present in % ( / ) and % ( / ) of medical critical care physician responses, respectively. in comparison, during the covid- pandemic, burnout and professional fulfillment were present in % ( / ) and % ( / ), respectively. in the cross-sectional portion of this study, we benchmarked wellbeing across the multidisciplinary critical care team, icus, and four hospitals within a healthcare system. consistent with prior studies ( , ), we confirmed that burnout was common among critical care physicians and nurses. to our knowledge, for the first time, we found that burnout is also common among critical care apps and critical care pharmacists and our longitudinal well-being surveys suggested that burnout increased during the covid- pandemic. collectively, these results reveal that burnout is a threat to the entire multidisciplinary critical care team and serial assessments are urgently needed to assess the long-term impact of the covid- pandemic on the well-being of the critical care workforce. consistent with prior work ( , ) , we found that clinicians with less years of work experience were more likely to suffer from burnout. this finding appeared to partly explain the higher rates of burnout at one hospital. serial well-being assessments, targeted to provider types experiencing high rates of burnout and earlyto-practice providers, specifically, appear warranted. additional characteristics associated with burnout, drawn from existing literature, include: age, female gender, perfectionism, conflicts in interprofessional relationships, high frequency of end-of-life care, and sleep disruption ( ) ( ) ( ) . through a mixed-methods approach, we confirmed and elucidated how workload and job demands, inefficiency and lack of resources, lack of meaning in work, cultures and values, lack of control and flexibility, loss of social support and community at work, and lack of work-life integration drive clinician burnout in the critical care environment. while each is important, we found the strongest driver of burnout related to workload and job demands. this finding substantiates the relationship between burnout and increased workload among physicians ( , , , ) and lack of control over shift scheduling among nurses ( ). physicians experience increased rates of burnout when working more night shifts per week or consecutive working days ( , ) . related, our prior work suggests an ebb and flow to burnout exists among critical care physicians, with burnout subsiding to more modest levels when not attending in the icu and when icu rotations were shortened from to consecutive days ( ) . these observations can be used to inform organizational strategies to reduce burnout, ranging from flexible scheduling to encouraging paid time off from work to re-charge. future work is also required to understand how wellbeing changes over time among critical care physicians employed in private practice and among non-physician critical care professionals (e.g., apps, pharmacists), given that job responsibilities for these individuals are often largely or completely clinical. to help critical care providers cope with the demands of the job, especially those early-to-practice, organizations should consider offering nurse i came from a high acuity, busy icu at another hospital with a quarter of the resources and efficiency. i can say without a doubt i'm so much happier at this job because all i need to do is take good care of my patients. i'm not also expected to be the secretary, cna, and unit support person. nurse bedside nurses are often treated with disrespect by physicians from other services. they…leave trash, gauze packs and dirty dressings on the floor for nurses to clean up. they often do not communicate treatment plans…this makes nurses feel meaningless. caring for patients with advanced illness and only a small chance of getting better drives burnout. the main reason i choose to work here is meaningfulness of the work. clinical care is one aspect, but research and teaching are also what contribute to that feeling. nurse i enjoy what i do, and i feel like i make a difference, and appreciate when families thank me for my 'job well done. ' culture and values of my work community the culture at work is always to do more, more, more at work. the pressure in this area is tremendous. leadership seems distracted and not in tune with colleagues…although leadership may ask my opinion or the opinion of the group, they will proceed as they see fit…also, i don't feel recognized as a provider and i know that i'm just another warm body and completely replaceable. resilience training. these programs, which may include professional coaching and mindfulness training, have proven effective in improving mental health and quality of life among icu nurses and physicians ( , ) . conversely, meaning in work, social support and community at work, and culture and values of the work community were identified as sources of well-being that can be used to inform organizational strategies to enhance wellness. our findings, thereby, substantiate the theory that enhancing meaning in work is a recommended strategy to prevent burnout ( ) . while burnout was common across providers; unfortunately, professional fulfillment differed significantly across providers. in fact, professional fulfillment was less common than burnout among nurses, apps, and critical care pharmacists. given the untoward effects of burnout on clinician health, including compassion fatigue, job turnover, and patient satisfaction and quality of care ( ), these findings warrant confirmation and further study. beyond the clinician, at the organizational level, we found that burnout and professional fulfillment varied at the icu and hospital level. the variations observed suggest that unit and hospital factors likely contribute to burnout. in the next phase of our wellbeing initiative, we will conduct multidisciplinary focus groups to elucidate drivers of burnout and professional fulfillment in specific units with high rates of burnout and/or professional fulfillment. in parallel, we acquired a greater understanding of drivers of burnout and sources of wellness to inform the design of interventions to optimize well-being and promote resilience at the clinician, unit, and hospital level. specifically, areas to focus on at the icu and hospital level include managing workload (e.g., schedule), optimizing efficiency (e.g., electronic health record) and aligning resources (e.g., staffing) with the workload, and promoting culture and values at work that foster recognition, collegiality, teamwork, and a sense of community. given the known relationship between organizational leadership and clinician burnout ( ) and our findings that wellbeing differed across icus and hospitals, attention is also required in regards to the selection and training of unit-and hospitalbased leadership who interface with critical care professionals. additional organizational strategies to combat burnout include: team building, communication training, and structured communication during interprofessional rounds to enhance working relationships and reduce conflict; control and flexibility in scheduling; engagement in nonclinical professional activities (e.g., quality improvement, research) ( , ); and creating a culture where clinicians are encouraged to take time off in the spirit of work-life integration ( ). as our study was conducted in a single, academic health system, confirmatory studies are warranted. based on our longitudinal study of medical critical care physicians, we recognize the need to re-measure well-being across the complete spectrum of healthcare professionals, especially in light of the pandemic, and have prepared to do so. in this initial quality improvement focused assessment, we did not capture sociodemographics (e.g., age, gender) known to associate with burnout. while we did not include respiratory therapists in this initial survey, we will in subsequent surveys. we acknowledge a small sample size to assess the impact of covid- and acknowledge a low response rate among nurses; however, the response rate ( ) and observed rate of burnout were similar ( ) to prior studies. regardless, to augment our response rate, we intend to include personal as well as professional emails when contacting eligible participants in subsequent surveys. last, although we included free-text responses to inform our wellbeing assessment, we acknowledge the importance of alternative methods (e.g., focus groups) to elucidate critical care well-being. further, future studies incorporating more robust qualitative analysis techniques (e.g., inductive reasoning) and/or methods (e.g., qualitative software analysis) are warranted. in conclusion, we benchmarked well-being across critical care healthcare professionals, icus, and hospitals. we confirmed that burnout is common among critical care physicians and nurses and expanded our knowledge by finding that burnout is also common among critical care apps and pharmacists. of equal relevance, professional fulfillment, common among critical care physicians, was less common among nurses, apps, and pharmacists. at the organizational level, we found that burnout and professional fulfillment rates differed across icus and hospitals. we identified app = advanced practice provider. participants scored each factor on a scale ranging from ("this is driving my sense of burnout") to ("this is a source of my well-being"). potentially modifiable factors related to critical care healthcare professional well-being that can inform organizational strategies at the individual, icu, and hospital level. our findings support the recommendation that to improve clinician well-being, we need to "measure it, develop and implement interventions, and then remeasure it" ( ) . finally, we measured the short-term impact of the covid- pandemic on critical care physician well-being. longitudinal studies, designed to assess the long-term impact of the covid- pandemic on the well-being of the critical care workforce, are urgently needed. job burnout an official critical care societies collaborative statement: burnout syndrome in critical care healthcare professionals: a call for action burnout and joy in the profession of critical care medicine burnout syndrome in critical care nursing staff high level of burnout in intensivists: prevalence and associated factors the relationship between burnout, depression, and anxiety: a systematic review and meta-analysis association between physician burnout and patient safety, professionalism, and patient satisfaction: a systematic review and meta-analysis still an epidemic: the burnout syndrome in hospital registered nurses physician burnout: contributors, consequences and solutions measuring burnout in emergency medicine physician assistants factors associated with burnout among us hospital clinical pharmacy practitioners: results of a nationwide pilot survey academic leaders in critical care medicine (alccm) task force of the society of the critical care medicine: workforce, workload, and burnout among intensivists and advanced practice providers: a narrative review assessing and addressing practitioner burnout: results from an advanced practice registered nurse health and well-being study being and resilience: validated instruments to assess work-related dimensions of well-being a brief instrument to assess both burnout and professional fulfillment in physicians: reliability and validity, including correlation with self-reported medical errors, in a sample of resident and practicing physicians burnout, and fulfillment, in the profession of critical care medicine research electronic data capture (redcap)-a metadata-driven methodology and workflow process for providing translational research informatics support utility of a brief screening tool to identify physicians in distress ability of a -item well-being index to identify distress and stratify quality of life in us workers executive leadership and physician wellbeing: nine organizational strategies to promote engagement and reduce burnout job satisfaction and burnout among intensive care unit nurses and physicians feasibility and acceptability of a resilience training program for intensive care unit nurses effect of a professional coaching intervention on the well-being and distress of physicians: a pilot randomized clinical trial enhancing meaning in work: a prescription for preventing physician burnout and promoting patient-centered care impact of organizational leadership on physician burnout and satisfaction prevalence, risk factors and consequences of severe burnout syndrome in icu the prevalence and impact of post traumatic stress disorder and burnout syndrome in nurses we are grateful to our colleagues for participating in this inaugural well-being survey to understand burnout and fulfillment among critical care healthcare professionals at the university of pennsylvania health system. supplemental digital content is available for this article. direct url citations appear in the printed text and are provided in the html and pdf versions of this article on the journal's website (http://journals.lww.com/ccejournal).supported, in part, by the louis nayovitz foundation, in memory of julian "jay" brockway, to honor delivery of compassionate critical care.the authors have disclosed that they do not have any potential conflicts of interest.for information regarding this article, e-mail: mark.mikkelsen@uphs.upenn.edu key: cord- -ab mg j authors: pavoni, vittorio; gianesello, lara; pazzi, maddalena; stera, caterina; meconi, tommaso; frigieri, francesca covani title: evaluation of coagulation function by rotation thromboelastometry in critically ill patients with severe covid- pneumonia date: - - journal: j thromb thrombolysis doi: . /s - - - sha: doc_id: cord_uid: ab mg j critically ill patients with covid- pneumonia suffered both high thrombotic and bleeding risk. the effect of sars-cov- on coagulation and fibrinolysis is not well known. we conducted a retrospective study of critically ill patients admitted to an intensive care unit (icu) a cause of severe covid- pneumonia and we evaluated coagulation function using rotational thromboelastometry (rotem) on day of admission (t ) and (t ) and (t ) days after admission to icu. coagulation standard parameters were also evaluated. forty patients were enrolled into the study. the icu and the hospital mortality were % and . %, respectively. on icu admission, prothrombin time was slightly reduced and it increased significantly at t (t = . ± . vs t = . ± . , p = . ), while activated partial thromboplastin time and fibrinogen values were higher at t than t ( . ± . vs . ± . , p = . and . ± vs . ± , p = . , respectively); moreover, whole blood thromboelastometry profiles were consistent with hypercoagulability characterized by an acceleration of the propagation phase of blood clot formation [i.e., cft below the lower limit in intem / patients ( %) and extem / patients ( %)] and significant higher clot strength [mcf above the upper limit in intem / patients ( %), in extem / patients ( %) and in fibtem / patients ( . %)]; however, this hypercoagulable state persists in the first five days, but it decreases ten day after, without returning to normal values. no sign of secondary hyperfibrinolysis or sepsis induced coagulopathy (sic) were found during the study period. in six patients ( %) a deep vein thrombosis and in patients ( %) a thromboembolic event, were found; patients ( %) had a catheter-related thrombosis. rotem analysis confirms that patients with severe covid- pneumonia had a hypercoagulation state that persisted over time. the novel coronavirus disease is an evolving pandemic. approximately one-fifth of the infected individuals develops severe to critical disease requiring intensive care support a cause of pneumonia [ ] . as recent literature data described, severe covid- is commonly complicated with coagulopathy with elevated d-dimer [ ] [ ] [ ] [ ] ; moreover, a pooled analysis showed that d-dimer values are considerably higher in covid- patients with severe disease than those without [ ] . viral acute infections are associated with a procoagulant state, and the resultant hypercoagulability may in severe cases accelerate leading to disseminated intravascular coagulation (dic) [ ] . the excessive activation of coagulation involves consumption of platelets and coagulation factors, which may shift the hypercoagulant state into a hypocoagulant state [ ] . conventional coagulation and fibrinolytic tests, as prothrombin time (pt), activated partial thromboplastin time (aptt), and d-dimer value, only reflect limited parts of the coagulation system [ ] . rotational thromboelastometry (rotem) is point-of-care device that evaluate viscoelastic changes during coagulation [ ] , and it provides detailed information on clotting kinetics from clot formation through degradation [ ] . recently, there has been a growing interest in its use either to study hypo [ ] as well as hypercoagulable conditions [ ] . until now, the effect of covid- infection on haemostatic functions remains unknown. the aim of this study was to investigate consequences of severe covid- infection on global haemostasis using standard coagulation parameters and whole blood rotem over time. this single-centre, retrospective, observational study was done at anesthesia and intensive care unit (icu), santa maria annunziata hospital (bagno a ripoli, tuscany, italy), which is one of the designated hospitals to the tuscany region to treat patients with covid- pneumonia. forty consecutive adult patients (≥ years old) with severe covid- admitted to icu between february , (i.e., when the first patient was admitted), and april , were retrospectively enrolled. the diagnosis of severe covid- pneumonia was according to world health organization (who) [ ] interim guidance and it was confirmed by rna detection of the sars-cov- in clinical laboratory of santa maria annunziata hospital (bagno a ripoli, italy). the ethics commission of area vasta centro (tuscany, italy) approved this retrospective study. written informed consent was waived due to the emergence of this infectious disease in italy. demographic and clinical information were collected, including age, gender, body mass index (bmi), preexisting illness (diabetes, hypertension, cardiovascular disease, chronic obstructive pulmonary disease), onset of symptom to hospital admission and to icu admission, sequential organ failure assessment (sofa) on icu admission, pao / fio on icu admission, need to non-invasive ventilation or mechanical ventilation, total length of icu and hospital stay, and icu and hospital mortality. the sepsis induced coagulopathy (sic) score system including prothrombin time (pt), platelet count and sofa was calculated and a sic criteria total score ≥ was considered, as suggested by international society of thrombosis and haemostasis (isth) [ ] . at the time of admission (t ) and (t ) and (t ) days later, peripheral venous blood sample was taken and routine blood examinations with hemoglobin level, platelet count, coagulation parameters including pt, activated partial thromboplastin time (aptt), fibrinogen levels, d-dimer values, antithrombin iii, interleukin- (il- ), procalcitonin, were collected. an additional venous blood sample was placed into citrate-containing tubes (bd vacutainer®; bd plymouth, uk) and analyzed by rotational thromboelastometry (rotem® gamma; tem innovations gmbh, munich, germany) according to the manufacturer's recommendations. extrinsic and intrinsic coagulation cascades were evaluated by using the extem and intem tests, respectively. the influence of fibrinogen on clot firmness was estimated by using the platelet inactivating fibtem test. the following rotem® parameters were analyzed: ) clotting time (ct, s), time from the beginning of the coagulation analysis until an increase in amplitude of thromboelastogram of mm; ) clot formation time (cft, s), time between an increase in amplitude of thromboelastogram from to mm; ) a and a , clot strength at and min, ) maximum clot firmness (mcf, mm) or the maximum amplitude (mm) reached in the thromboelastogram and ) maximum lysis (ml, %), measure of fibrinolysis. all patients received antiviral and appropriate supportive therapies on the day of the admission and throughout the hospital stay. thromboprophylaxis with low molecular weight heparin (lmwh, - mg enoxaparin/day) was used in according to guidelines of surviving sepsis campaign [ ] . bilateral extended compression ultrasound (ecus) from common femoral vein through the popliteal vein up to the calf veins confluence was performed in each of the included patients on day of admission and five days after, using ge logiq-e vision scanner (ge, healthcare, italy). moreover, at the same time, ultrasound screening was helpful for detecting catheter-related thrombosis. the results were expressed as mean ± standard deviation or number (percentage), wherever appropriate. normally distributed data were compared by student's t-tests. categorical variables were compared using the chi-squared test. a p value of < . was considered statistically significant. spss software version . for windows (spss inc., chicago, il, usa) was used for statistical analysis. forty patients were enrolled into the study. the mean age was ± years; most of them were male ( %). sixteen patients ( %) had two chronic underlying diseases, including hypertension and diabetes. on admission, the mean of sofa was ± and the pao /fio ratio was ± . four patients died in the icu ( %) and one patient died during hospitalization, after icu discharge. table shows the demographic and clinical characteristics of studied patients. among standard coagulation parameters, on admission, pt value was slightly reduced and it increased significantly at t (t = . ± . vs t = . ± . , p = . ); moreover, aptt value was normal and it decreased at t ( . ± . vs . ± . , p = . ). platelet count was normal and increased over time. fibrinogen value was greatly increased in all patients and, subsequently, it decreased (t = . ± vs t = . ± , p = . ). on icu admission, patients ( %) had a d-dimer value above the upper limit of normal range (table ) . d-dimer value at t was lower than t , even if not statistically significant (p = . ). at levels remained in the normal value and none of the patients receiving at concentrate supplementation. bio humoral parameters at t showed high level of il- that resulted significantly reduced at t ( . ± . vs . ± . , p = . ). procalcitonin was not increased ( . ± . vs . ± . ) in the follow-up period ( table ) . rotem analysis showed normal ct and cft mean values both intem and in extem, but mcf in fibtem higher than normal ( . ± . ) ( table ). sixteen patients ( %) and ( %) had cft values lower than the lower limit of the normal range in intem and extem, respectively; moreover, ( . %) showed a value of mcf in fibtem above the upper limit of normal range (table ). figure showed typical rotem tracings in a patient with a covid- pneumonia, on icu admission and on icu discharge. in six patients ( %), a deep vein thrombosis (dvt) and in two patients ( %) a thromboembolic event, were found; patients ( %) had a catheter-related thrombosis. none of patients meet the sic criteria. in our study the whole blood thromboelastometry profiles of critically ill patients with covid- pneumonia were consistent with hypercoagulability characterized by an acceleration of the propagation phase of blood clot formation rotem technology provides a rapid and dynamic assessment of haemostasis in vitro. it is emerging as a quick, portable, and well-validated device for clinicians in making an early diagnosis of a specific coagulopathy and a decision of the most appropriate treatment [ ] . rotem also measures hypercoagulability in various clinical scenarios including major surgery, malignancy, which is not detected by routine coagulation tests [ ] . sepsis-induced coagulopathy is characterized by a predominant activation of the tissue factor pathway with a remarkable consumption of coagulation factors, platelet activation and fibrinolysis [ , ] . however, traditional coagulation tests (i.e. prothrombin time, activated partial thromboplastin time, platelet count) have shown several limitations in their ability to reliably and consistently detect coagulation disorders in sepsis [ ] . severe covid- may be complicated with dic or sic; development of sic would lead to secondary hyperfibrinolysis associated to lengthening to pt, reduction of platelet count and fibrinogen level [ ] . tang et al. [ ] reported . % mortality in patients with covid- pneumonia and noted that . % of non-survivor patients had abnormal coagulation profile consistent with dic. a metaanalysis [ ] found that a low platelet count was associated with over fivefold increased risk of severe disease (or, . ; % ci . - . ) and an even lower platelet count was associated with mortality in those patients. in our study, laboratory tests did not show a significant alteration of hemostatic parameters such as pt and aptt; platelet count and fibrinogen values were high over time. however, % of patients presented dvt confirmed by ultrasonography and two patients presented an incidental thromboembolic event documented with pulmonary computer tomography at hospitalization; moreover, % of patients suffered from related catheter thrombosis. klok et al. [ ] have found in a population of icu patients with covid- pneumonia, a dvt incidence of % and % of pulmonary embolism (pe). probably, our lower incidence of dvt than klok was correlated to the lower number of patients included in the study. moreover, in our study two cases of pe were incidental; therefore, we cannot really establish the incidence of venous thromboembolism (vte) in these patients. in our patient population we found a significative increase in pro-inflammatory cytokine il- as well as sepsis induced organ disfunction. recent evidence showed that "cytokine storms" triggered by covid- infection can cause clotting disorders which may increase the risk of thromboembolism [ ] . sepsis is considered a risk factor for vte, including upper and lower extremity dvt and pe [ ] . the underlying pathogenesis of vte in sepsis remains incompletely understood but is believed to be the result of multiple factors. in addition to risk factors for hypercoagulability, as originally described by virchow, incorporating the three original triad (stasis, endothelial injury, and hypercoagulability), severe inflammation observed in patient with sepsis and/ or septic shock represents the fourth factor for thromboembolic complications [ ] . inflammation increases pro-coagulant factors, and inhibits natural anticoagulant pathways and fibrinolytic activity, leading to dvt and pe [ ] . in fact, the inflammatory process initiated by septic shock may be strained by coexisting tissue hypoxia and systemic inflammation leading to endothelial damages and dvt complications. in our study the rotem analysis showed that an inflammatory state was associated with a state of severe hypercoagulability rather than a consumption coagulopathy; indeed, six patients presented dvt. probably, standard coagulation parameters fail to highlight the severity of prothrombotic phenotype. rotem analysis in addition hypercoagulability can detect impairment in fibrinolysis, expressed as increased lysis indices; coagulation profiles observed in our study population allowed us to conclude that we have not found secondary hyperfibrinolysis condition. further randomized studies, based on evaluation in vivo fibrinolysis, are needed to establish whether patients with severe covid- pneumonia, could benefit of an early anticoagulant therapy, in terms of improving clinical outcomes, in the balance between prothrombotic and hemorrhagic risks. author contributions vp and lg conceived the study, interpreted the data, and wrote the manuscript. mp, cs, tm performed thromboelastometry. fcf collected the data. all authors reviewed data and manuscript. conflict of interest the authors declare that they have no conflicts of interest. clinical features of patients infected with novel coronavirus in wuhun epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhun, china: a descriptive study abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia difference of coagulation features between severe pneumonia induced by sars-cov and non-sars-cov d-dimer is associated with severity of coronavirus disease : a pooled analysis the coagulant response in sepsis thrombin functions during tissue factors-induced blood coagulation coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices thromboelastometry as a supplementary tool for evaluation of haemostasis in severe sepsis and septic shock tests of global haemostasis and their applications in bleeding disorders whole blood coagulation assessment using rotation thromboelastogram thromboelastometry in patients with acute deep vein thrombosis clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspected: interim guidance diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation surviving sepsis campaign: international guidelines for management of sepsis and septic shock thromboelastography (teg) and rotational thromboelastometry (rotem) for trauma induced coagulopathy in adult trauma patients with bleeding the double hazard of bleeding and thrombosis in hemostasis from a clinical point of view: a global assessment by rotational thromboelastometry (rotem) dynamic evolution of coagulopathy in the first day of severe sepsis: relationship with mortality and organ failure utility of thromboelastography and/or thromboelastometry in adults with sepsis: a systemic review a rapid assay for the detection of circulating d-dimer is associated with clinical outcomes among critically ill patients thrombocytopenia is associated with severe coronavirus disease (covid- ) infections: a meta-analysis incidence of thrombotic complications in critically ill patients with covid- vte incidence and risk factors in patients with severe sepsis and septic shock the 'procoagulopathy' of trauma: too much, too late? acknowledgements we express our closeness to the patients and their families, and we thank all the nursing staff of intensive care unit of santa maria annunziata hospital who made it possible to treat patients in this pandemic. key: cord- -oid n qf authors: cuquemelle, e.; soulis, f.; villers, d.; roche-campo, f.; ara somohano, c.; fartoukh, m.; kouatchet, a.; mourvillier, b.; dellamonica, j.; picard, w.; schmidt, m.; boulain, t.; brun-buisson, c. title: can procalcitonin help identify associated bacterial infection in patients with severe influenza pneumonia? a multicentre study date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: oid n qf purpose: to determine whether procalcitonin (pct) levels could help discriminate isolated viral from mixed (bacterial and viral) pneumonia in patients admitted to the intensive care unit (icu) during the a/h n v influenza pandemic. methods: a retrospective observational study was performed in french icus during the h n pandemic. levels of pct at admission were compared between patients with confirmed influenzae a pneumonia associated or not associated with a bacterial co-infection. results: of patients with confirmed a/h n infection and not having received prior antibiotics, ( . %; % ci – %) had a documented bacterial co-infection, mostly caused by streptococcus pneumoniae ( %) or staphylococcus aureus ( %). fifty-two patients had pct measured on admission, including ( %) having bacterial co-infection. median (range – %) values of pct were significantly higher in patients with bacterial co-infection: . ( . – . ) versus . ( . – ) μg/l (p < . ). for a cut-off of . μg/l or more, the sensitivity and specificity of pct for distinguishing isolated viral from mixed pneumonia were and %, respectively. alveolar condensation combined with a pct level of . μg/l or more was strongly associated with bacterial co-infection (or . , % ci . – . ; p < . ). conclusions: pct may help discriminate viral from mixed pneumonia during the influenza season. levels of pct less than . μg/l combined with clinical judgment suggest that bacterial infection is unlikely. abstract purpose: to determine whether procalcitonin (pct) levels could help discriminate isolated viral from mixed (bacterial and viral) pneumonia in patients admitted to the intensive care unit (icu) during the a/h n v influenza pandemic. methods: a retrospective observational study was performed in french icus during the h n pandemic. levels of pct at admission were compared between patients with confirmed influenzae a pneumonia associated or not associated with a bacterial co-infection. results: of patients with confirmed a/h n infection and not having received prior antibiotics, ( . %; % ci - %) had a documented bacterial co-infection, mostly caused by streptococcus pneumoniae ( %) or staphylococcus aureus ( %). fifty-two patients had pct measured on admission, including ( %) having bacterial co-infection. median (range - %) values of pct were significantly higher in patients with bacterial co-infection: . ( . - . ) versus . ( . - ) lg/l (p \ . ). for a cut-off of . lg/l or more, the sensitivity and specificity of pct for distinguishing isolated viral from mixed pneumonia were and %, respectively. alveolar condensation combined with a pct level of . lg/l or more was strongly associated with bacterial co-infection (or the new pandemic a/h n influenza virus emerged and spread globally in , with a high rate of intensive care unit (icu) admissions among hospitalised patients [ ] . causes of death included an overwhelming viral infection and primary or secondary bacterial infection. because of the presumed high frequency of bacterial infection, most hospitalised patients with influenza pneumonia are administered antibiotics, even though bacterial co-infection is considered unlikely [ ] . indeed, bacterial pneumonia cannot be differentiated from viral pneumonia on the basis of the patients' characteristics, chest radiographic findings or routine laboratory results. procalcitonin (pct) is a recognised marker of bacterial infection and might be a prognostic marker in lower respiratory tract infections [ ] . few studies have assessed pct levels in viral infections, except for paediatrics studies in which pct was found to help distinguishing viral from bacterial meningitis [ ] or pneumonia [ ] . a small study in singapore during the coronavirus outbreak suggested that pct remained at low levels in viral infections [ ] . this study aimed to examine whether pct levels may help discriminate between viral from mixed (bacterial and viral) pneumonia among patients presenting to the icu with severe community-acquired pneumonia during the h n v influenza pandemic. this was an observational multicentre study conducted in conjunction with the 'reva-grippe-srlf' registry set up in france from november to april to record patients with severe a/h n v influenza infection admitted to icus. among the participating centres, volunteered to participate in this substudy and completed a specific case report form, whether or not a diagnosis of bacterial co-infection had been established. some of these centres routinely performed measurements of pct and/or c-reactive protein (crp) levels, and the biomarker levels were recorded and analysed for the present study. microbiological investigations and biomarker levels were obtained as part of the routine clinical management of patients, at the discretion of the treating physician. the study was approved by the ethics review board of the société de réanimation de langue française and informed consent was waived. patients with a confirmed diagnosis of h n influenza infection (by pcr on nasopharyngeal secretions or bronchoalveolar lavage fluid), associated with a clinical pattern of community-acquired pneumonia as defined by the association of the acute onset of clinical symptoms (cough, fever, dyspnoea), and compatible infiltrates on the chest radiograph, in the absence of an alternative diagnosis, were eligible for this study. to better distinguish patients with and without bacterial co-infection on admission, for this analysis we selected patients not having received antibiotics prior to icu admission. we excluded patients with suspected hospital-acquired influenza infection, a documented non-pulmonary bacterial infection, and severely immunocompromised patients. demographics, clinical and microbiological data obtained within the first h of icu admission were collected retrospectively. confirmation of bacterial pulmonary infection was obtained through blood cultures, urinary antigen (pneumococcal and legionella) tests and/ or culture of a respiratory tract secretions sample. patients were thus categorised as having or not having associated bacterial co-infection and levels of biomarkers were compared between these two subgroups. procalcitonin was assayed using time-resolved amplified cryptate emission technology on a kryptor analyser (brahms diagnostica, berlin, germany) and functional assay (detection concentration . lg/l). total pct assay imprecision was reported by the manufacturer to be % at . lg/l and less than % at more than . lg/l. fisher's exact test was used to compare proportions for categorical variables. for continuous variables, student's t test and mann-whitney u test were used for comparing parametric and non-parametric data, respectively. the diagnostic accuracy of biomarkers was examined by their receiver-operating curve (roc). statistical analyses were performed with pasw statistic . (spss inc, chicago, usa). this substudy from the french reva-srlf influenza registry was conducted in centres, where data on patients with or without a diagnosis of bacterial coinfection were recorded; of these patients were excluded from analysis based on our predefined exclusion criteria, and a further were excluded because of administration of antibiotics prior to icu admission. thus, patients formed the main cohort, of whom ( . %) had a documented bacterial co-infection associated with influenza a/h n v infection (table ) . microorganisms identified included streptococcus pneumoniae (n = , %), staphylococcus aureus (n = , %), group a streptococcus (n = , %) and other microorganisms (n = , %). they were recovered from blood cultures (n = , %) and/or a respiratory tract secretion specimen (n = , %), including bronchoalveolar lavage (n = , %) or protected distal sampling (n = , %) and/or urinary antigen tests (n = , %). table compares the admission characteristics of the two subgroups of patients, with and without bacterial coinfection. the former subgroup less often had comorbidities ( . vs. . %; p = . ), had a higher saps score ( vs. ; p = . ), and more often had alveolar condensation on chest x-ray ( . vs. . %, p = . ). the overall mortality in the icu was . % ( / patients), and did not differ between those with and without bacterial co-infection ( . vs. . %, respectively). patients with bacterial co-infection more often required invasive mechanical ventilation ( vs. , or . , % ci . - . ; p = . ), and had a longer length of stay in the icu (median . vs. days; p = . ). pct and crp levels were obtained respectively in and of the patients, and had both biomarkers measured simultaneously. of the patients having pct levels measured on admission, ( . %) had a documented bacterial co-infection associated with influenza a/h n v infection, mostly caused by streptococcus pneumoniae ( %) or staphylococcus aureus ( %). median (iqr) pct levels on icu admission were significantly higher in patients with bacterial co-infection: . (iqr . - . ) lg/l versus . (iqr . - . ) lg/l (p \ . ) (fig. ) . a cut-off of . lg/l or more identified bacterial co-infection with a sensitivity of %, a specificity of % and a negative predictive value of %. the area under the roc curve (auroc) for diagnosing bacterial co-infection using pct was . ( % ci . - ). a pct level less than . lg/l combined with the lack of alveolar condensation was strongly associated with the absence of bacterial co-infection (or . , % ci . - . ; p \ . ). mortality in the icu was . % ( / ) among this subgroup; pct levels of . lg/l or more were associated with a more severe outcome (invasive ventilation and/or death in icu) (or , % ci . - . ; p = . ). in the patients in whom crp levels were measured ( with and without bacterial co-infection), median (interquartile range - ) values were respectively of ( - ) and ( - ) (p = . , rank-sum test). for the patients in whom both biomarkers levels were (fig. ). we report on patients with severe a/h h influenzae pneumonia, almost one-half of whom had bacterial coinfection documented in the absence of prior antibiotic administration; most co-infections were caused by streptococcus pneumoniae. in the patients in whom pct was measured, we found that a pct level of . lg/l or more discriminated well between isolated viral and mixed (bacterial and viral) pneumonia. experience using biomarkers as an diagnostic adjunct during influenza pneumonia is very limited. studies describing the ability of pct or of crp to discriminate between viral and bacterial infection have included few patients with influenza or severe disease [ ] . a metaanalysis concluded that pct was more accurate than crp for the distinction between viral and bacterial infection [ ] . ingram et al. suggested that pct levels assisted in the discrimination between severe lower respiratory tract infections of bacterial or a/h n virus origin [ ] . our results suggest that the combination of low levels of pct and the lack of alveolar infiltrate on chest radiograph makes bacterial co-infection unlikely in patients presenting with severe viral pneumonia. pct has emerged as a diagnostic biomarker for estimating the likelihood for a bacterial infection and tailoring antimicrobial therapy [ ] ; however, its prognostic value is less clear. in critically ill patients, a high maximum pct level and a pct increase over day were independent predictors of -day all-cause mortality [ ] . in patients with legionella pneumonia, haeuptle et al. [ ] found a high accuracy of initial and serial pct levels for prediction of mortality and need for icu admission. high pct levels were associated in our series with bacterial co-infection and more severe outcomes such as mechanical ventilation and/or death. previous studies on patients with influenza pneumonia reported a rate of bacterial co-infection ranging from to % of patients [ ] ; similar rates were reported during the a/h n v pandemic season [ ] . this proportion may actually be underestimated because of the common administration of antibiotics prior to hospital or icu admission. overall, almost one-half of our patients had a documented bacterial co-infection, after excluding those having received prior antibiotics. this is clearly a much higher rate than that recorded during seasonal influenza [ ] . similarly to experience from argentina [ ] , the presence of bacterial co-infection was associated in our series with more severe disease. limitations of our study include its relatively small sample size, and the lack of repeated pct measurements. the 'true' proportion of patients with bacterial co-infection during influenza pneumonia is also difficult to ascertain. however, by excluding patients having received prior antibiotics, thus allowing a more accurate diagnosis of bacterial infection, we believe we have come closer to estimating the frequency and influence of bacterial co-infection in patients with severe influenza a/h n pneumonia. pct levels appear to discriminate well between patients having or not having bacterial coinfection during influenza pneumonia. despite the small sample of patients in our series in whom both measurements of pct and crp were obtained, pct levels appeared to more accurately discriminate viral from mixed viral and bacterial infection among patients presenting with community-acquired pneumonia of suspected viral origin during the influenza epidemic. in summary, bacterial co-infection likely affected almost one-half of patients with severe influenza a/h n pneumonia, and was associated with more severe outcomes. measurements of pct levels at admission can help discriminate patients having bacterial co-infection from those with isolated viral pneumonia. clinical trials from different settings have established that pct can be safely used to help decide upon initiation and duration of antibiotic therapy, and thus potentially help to reduce antibiotic overuse [ , ] . when combined with clinical judgment during influenza epidemics, a low pct level may identify a subgroup of patients in whom empiric antibiotic therapy may be withheld or withdrawn early. rouen. investigators: chu d'angers h n influenza in the united states the use of antimicrobial agents after diagnosis of viral respiratory tract infections in hospitalized adults: antibiotics or anxiolytics? biomarkers in respiratory tract infections: diagnostic guides to antibiotic prescription, prognostic markers and mediators measurement of procalcitonin levels in children with bacterial or viral meningitis serum procalcitonin, c-reactive protein and interleukin- for distinguishing bacterial and viral pneumonia in children procalcitonin in severe acute respiratory syndrome (sars) serum procalcitonin and c-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis procalcitonin and c-reactive protein in severe h n influenza infection use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (prorata trial): a multicentre randomised controlled trial procalcitonin increase in early identification of critically ill patients at high risk of mortality prognostic value of procalcitonin in legionella pneumonia insights into the interaction between influenza virus and pneumococcus influenza circulation and the burden of invasive pneumococcal pneumonia during a nonpandemic period in the united states streptococcus pneumoniae coinfection is correlated with the severity of h n pandemic influenza effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the prohosp randomized controlled trial acknowledgments the reva-srlf registry was supported by grants from the société de réanimation de langue française (srlf), the french research agency (anrs) and the french ministry of health. the authors gratefully acknowledge the contribution of the following physicians participating to the pct study within the reva-srlf h n registry: steering com- key: cord- -km zhn authors: potalivo, a.; montomoli, j.; facondini, f.; sanson, g.; lazzari agli, l. a.; perin, t.; cristini, f.; cavagna, e.; de giovanni, r.; biagetti, c.; panzini, i.; ravaiolo, c.; bitondo, m.; guerra, d.; giuliani, g.; mosconi, e.; guarino, s.; marchionni, e.; gangitano, g.; valentini, i.; giampaolo, l.; muratori, f.; nardi, g. title: sixty-day mortality among italian hospitalized covid- patients according to the adopted ventilatory strategy in the context of an integrated multidisciplinary clinical organization: a population-based cohort study date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: km zhn background: among covid- patients, the decision of which ventilation strategy to adopt is crucial and not guided by existing outcome evidence. we described the clinical characteristics and outcomes of hospitalized covid- patients according to the adopted respiratory strategy. methods: population-based cohort study including all covid- patients ( / / - / / ) within rimini italian province. hospitalized patients were classified according to the maximum level of respiratory support: oxygen supplementation (group oxygen), niv (group niv-only), imv (group imv-only), and imv after a niv trial (group imv-after-niv). sixty-day mortality risk was estimated with a cox proportional hazard analysis adjusted by age, sex, and administration of steroids, canakinumab, and tocilizumab. findings: we identified , symptomatic patients: ( . %) were hospitalized, the remaining ( . %) were treated at home with no -days death. according to the respiratory support, ( . %) were assigned to oxygen, ( . %) to niv-only, ( . %) to imv-after-niv, and ( . %) to imv-only groups. there was no significant difference in the p/f at imv inception among imv-after-niv and imv-only groups (p= . ). overall -day mortality was . % (oxygen: . %; niv-only: . %; imv-after-niv: . %; imv-only: . %; p = . ). compared with oxygen group, the -day mortality risk significantly increased for imv-after-niv (hr . ; p= . ) and imv-only group (hr . ; p= . ). conclusions: this study provides a population-based figure of the impact of the covid- epidemic. a similar -days mortality risk was found for patients undergoing immediate imv and those intubated after a niv trial. many patients had a favorable outcome after prolonged imv. more than , people died worldwide from the coronavirus-disease caused by the severe acute respiratory syndrome coronavirus (sars-cov- ). the percentage of covid- patients requiring non-invasive (niv) or invasive mechanical ventilation (imv) is unclear and strongly affected by the hospital organization and the availability of resources. three studies from china, us, and gemany reported the use of imv among hospitalized covid- patients to be . %, %, and %, respectively. - icu-mortality among mechanically ventilated covid- patients varies from % to %. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] such wide variations may have different explanations. first, few studies included all patients hospitalized for covid- able to provide a complete overview of characteristics and outcomes of covid- patients that required hospitalization. second, information regarding the respiratory management of covid- patients has been mainly described in the setting of the intensive care units (icus). , , , thus, the number of hospitalized covid- patients treated with oxygen supplementation and niv has been markedly underreported leading to inaccurate information regarding the overall use of the different respiratory supports and outcomes. third, most previous reports included a percentage of patients still admitted at the icu at the end of the follow-up ranging from . % to % and this may have led to different degrees of inaccuracy in estimating icu-mortality. finally, icu beds and human resources availability is likely to vary across different areas and it has not been generally described in clinical studies, affecting generalizability of the results. the province of rimini in northern italy was one of the areas more severely affected by the covid- outbreak. on march th , rimini province was declared "red zone" due to the high number of infected people and, therefore, it was isolated with no possibility of entry or exit. using clinical and demographics information routinely collected in a unique database including all residents in the entire province, we performed the present population-based cohort study with the following aims: ) to describe the characteristics of hospitalized covid- patients, ) to examine patient outcomes overall and stratified by the adopted respiratory support, ) to describe the organization of local healthcare system. setting covid- patients admitted to the rimini hospital were retrieved in the present observational population-based cohort study, following the strengthening the reporting of observational studies in epidemiology (strobe) reporting guideline. the italian national public healthcare system provides homogeneous and free access to any level of appropriate treatment to all the people including irregular immigrants through the hospital network, family doctors, and district health systems. the province of rimini consists of approximately , inhabitants and is served by a network of five public hospitals, with rimini hospital being the largest and providing up to beds. since the beginning of the outbreak and for the entire duration of this study, rimini hospital was identified as reference hospital for all covid- positive or suspected patients. with the increase of admitted patients, hospital bedsincluding in two newly opened wards-were progressively dedicated to infected subjects and negative pressure rooms -eight set up at emergency department (ed) and already available in the infectious diseases ward-were dedicated to patients requiring niv. during the first decade of march, the number of icu beds was progressively increased from to , of which dedicated to covid- patients and five to non-covid- patients. non-covid- patients exceeding local availability were transferred to another nearby hospital equipped with icu beds. all patients evaluated at one of the five eds of the province from february, to april, presenting symptoms suspicious for covid- infection (i.e. fever and/or respiratory symptoms) and tested for the sars-cov- (real-time rt-pcr) were considered for inclusion. patients with positive swab, as well those with chest x-ray or ct scan evidence of covid- -related pneumonia despite a negative swab were included. the more stable patients were discharged home and entrusted to the primary care, while patients identified to be at high risk for complications based on symptoms severity and associated comorbidities were admitted at the hospital and represented the study population. all included patients with a first negative swab had at least a positive subsequent swab during the same hospitalization except those patients that died at the ed before a second swab. a daily meeting -always attended by the heads of the emergency, infectious disease, pneumology, radiology, and intensive care departments-was planned regardless of the holidays or sundays respecting airborne and contact transmission precautions, with the aim to ensure a homogeneous and standardized treatment to all covid- patients. every day the relevant clinical information (e.g., comorbidities, respiratory status, medical treatments, and active clinical conditions) of the critically ill cases were updated and the overall therapeutic stewardship to be adopted (e.g., off-label medications, change in the respiratory support) was collegially discussed and agreed. moreover, for each patient the appropriate treatment to adopt in the event of worsening conditions was planned, taking into account the limitation of the available resources. all decisions were recorded and promptly communicated to physicians and nurses working at all covid- wards, comprising the icu. oxygen administration via ventimask or mask with reservoir was considered the standard of care for moderate/severe patients, while niv (comprising continuous positive airway pressure, cpap) and imv following tracheal intubation were chosen for the most critical cases. to avoid airborne viral transmission, high flow nasal cannulae were used only for respiratory weaning in patients become negative and helmet was identified as the only interface to be used for niv. conditions leading to the decision to start imv were: respiratory fatigue, new hemodynamic instability, or worsening of gas exchange notwithstanding oxygen/niv, also considering prognostic criteria and resources availability (e.g., icu beds and mechanical ventilators). according to the level of the respiratory support, the study population was divided in the following subgroups: oxygen (patients receiving no more than oxygen supplementation); niv-only (patients receiving no more than niv); imv-after-niv (patients undergoing imv after a failed niv trial); imv-only (patients starting imv at hospital admission or after a trial with oxygen). for the whole population, demographic data were retrieved by an administrative and clinical database (maria db, log , forlì-italy) and information about administered off-label medications related to the covid- treatment (i.e. hydroxichloroquine, antivirals, steroids, canakinumab, and tocilizumab) were collected by clinical documentation. for patients treated with niv and/or imv the charlson comorbidity index was computed, and the spo at the hospital admission, the pao /fio (p/f) ratio at the inception of niv and imv, and the duration of ventilatory supports were collected. for those patients the extent of lung damage was estimated from the chest radiogram using the brixia score: each lung was transversally divided into three sectors and to each obtained sector a score ranging from zero (no alteration) to three (interstitial-alveolar infiltrates) was assigned (total score range: - ). , for patients admitted to the icu (i.e., imv-after-niv and imv-only), the simplified acute physiology score ii (saps ) and the sequential organ failure assessment (sofa) score at icu admission were computed and the possible implementation of tracheostomy and renal replacement therapy were documented. all patients were followed up to days from hospital admission. the condition of being dead or alive at this time constituted the main study endpoint. accordingly, data collection was concluded on june , to ensure at least days of observation to the patients included last. the investigation conforms with the principles outlined in the declaration of helsinki. the ausl della romagna institutional review board approved the project (registration number nct ) with a waiver of informed consent. no additional procedure or investigation potentially related to the study was requested or provided. continuous variables were described as mean ± standard deviation. the differences between the means were analysed by a paired or unpaired student's t-test, as appropriate, after considering whether the subgroups had equal variance using levene's test. one-way analysis of variance (anova) was applied for all comparisons between the subgroups. the nominal variables were presented as numbers and percentages and compared either through  test or fisher's exact test, as appropriate. the ability of the p/f measured before a niv trial to predict niv failure (i.e., death or need of imv) was tested by calculating the area under the receiver operating characteristics curve (auc). the maximum youden index (j) was considered as the optimal p/f cut-off value. sixty-day mortality was computed using kaplan-meier technique overall and among groups. the mantel-cox log-rank test was adopted to assess differences among the survival rates. a multivariate cox proportional hazard analysis was used to estimate -day mortality risk among the study groups in comparison to the oxygen group (reference group), adjusted by age, sex, and administration of steroids, canakinumab, and tocilizumab. the results were presented as a proportional hazard ratio (hr) with % ci and adjusted cumulative survival curves. finally, in order to examine the potential impact of survival bias among patients treated with imv, especially among patients intubated after niv (a patient had to survive until endotracheal intubation), we computed the adjusted hrs for -day and to -day mortality, separately, as sensitivity analysis. moreover, minimally to fully adjusted hrs were reported in the supplemenatry material. for all tests, statistical significance was set at an alpha level of p = . . all statistical analyses were performed using the software ibm spss statistics, version . (armonk, ny, us: ibm corp.). during the study period, , symptomatic patients were evaluated at the eds in the province and had a positive swab and/or chest imaging suspicious for the covid- . nine-hundred and four ( . %) were treated at home without further ed accesses, while the remaining ( . %) were hospitalized and constituted the study population (males , . %; mean age . ± . , range - ). among hospitalized patients, ( . %) were treated with oxygen supplementation at the time of hospital admission, while the remaining received either niv or imv. during the subsequent days, patients ( . %) required an upgrade of the ventilatory support. almost all patients were treated with hydroxichloroquine and antiviral drugs. table describes the demographic characteristics and the administered medications of the study population overall and by groups. figure shows a complete synthesis of the respiratory support adopted and the -days mortality for each group. the main clinical characteristics of the ( . %) patients who received any ventilatory support (niv and/or imv, mean age . ± . years) are reported in table . among those, ( . %) patients received at least one trial of niv (mean age . ± . ) with a mean duration of . ± . days (range - , figure a ) and a mean p/f ratio of . ± . at the beginning of niv. thirty-eight ( . %) of the patients treated with niv improved and were transferred to a covid- ward, while ( . %) were intubated and admitted to the icu to undergo imv. the p/f ratio before starting niv differed significantly between patients with a successful trial and those that failed (successful: . ± . ; failing: . ± . ; p = . ). for patients who needed imv a statistically significant but clinically irrelevant improvement in p/f ratio was documented (before niv: . ± . ; before imv: . ± . ; p = . ). the remaining eight patients ( . %) died without being intubated (p/f ratio before niv . ± . ). the length of niv did not differ among patients with successful or failing trial ( table ). the ability of the p/f ratio obtained before niv to predict the failure of a niv trial showed an auc of . ( % ci . - . ; p-value . ) and provided a best cut-off of . (sensitivity . %, specificity . %; j . ). overall, patients (groups imv-after-niv and imv-only, mean age . ± . years) were admitted to the icu and treated with imv ( figure ). the mean interval between hospital admission and the onset of imv was . ± . days (range - ) ( figure b ). eleven ( . %) patients were intubated after or more days from hospital admission (p/f before intubation: . ± . ). no difference in p/f ratio at the time of the definitive ventilation support was found among the three study groups (p = . ). patients who failed the niv trial (n = ) had a brixia score of . ± . before niv which worsened to . ± . (p = . ) before imv. similar brixia score was obtain at the time of endotracheal intubation among patients that failed a niv trial and among patients that were treated with imv without a niv trial ( table ) . among the patients admitted to the icu, mean duration of imv was . ± . days (range - ). forty-six icu patients ( . %) received percutaneous tracheostomy (time from intubation: . ± . days). renal replacement therapy was performed in ( . %) patients, with a mean duration of . ± . days. none of the patients treated at home died during the follow-up. the overall -days mortality for hospitalized patients was . % (n = ), and was . % (n = ), . % (n = ), . % (n = ) and . % (n = ) for group oxygen, nivonly, imv-after-niv, and imv-only, respectively (p = . ). mortality among the patients receiving any ventilatory support (niv and/or imv) was . %. no between-groups difference in mortality was found by comparing the crude kaplan-meier curves (log-rank test: p = . , figure a ). age was a risk factor for death in groups oxygen and niv-only . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted august , . . but not for patients undergoing imv. the relationships between some characteristics of the study groups and mortality are described in table . the mean duration of imv was . ± . days for the patients alive at the end of the follow-up (range: - ) and . ± . days for the non-survivors (range: - ). among the survived, patients ( . %) underwent imv for more than four weeks (figure c) . two patients (one belonging to the imv-after-niv group and one to the imv-only group) were still on imv at the end of follow-up, with an imv duration of and days, respectively. compared with oxygen group, the multivariate cox regression analysis showed a -day mortality risk progressively increasing among the other groups being statistically significant for the imv-after-niv group (hr . ; % ci . - . ; p = . ) and the imv-only group (hr . ; % ci . - . ; p= . ) but not for group niv-only (hr . ; % ci . - . ; p = . ) (figure b ). among the explored covariates, older age (hr . ; % ci . - . ; p < . ) and male sex (hr . ; % ci . - . ; p = . ) showed a statistically significant association with the mortality. as expected, the sensitivity analysis showed a higher risk for -day mortality in the only-niv group but not in patients receiving imv compared to patients treated with oxygen, while similar results to the main analysis were provided for the to -day mortality (table and figure ). the present study showed how an integrated multidisciplinary clinical organization allowed to optimize the allocation of the available resources among hospitalized covid- patients. the overall -day mortality was . %. approximately % of patients were mechanically ventilated, with a mortality ranging from . % in patients treated with niv-only to . % in patients undergoing imv without a niv trial. to our knowledge, this is the first study reporting -day mortality in a cohort of hospitalized patients diagnosed with covid- overall and according to all adopted ventilatory strategies. a recent chinese multicentric study enrolling icu patients reported an overall -day mortality of . %, with patients deceased within h after icu admission. among mechanically ventilated patients, the -day mortality was %, %, and % for those treated with imv, with niv, and receiving both treatments, respectively. median p/f ratio in the chinese population was (iqr - ) and sofa score (iqr - ). it should be noted that in our study we documented for patients treated with niv and/or imv -despite a similar p/f ratio (median . ; iqr . - . ) and a higher sofa score (median ; iqr - )-a considerably lower -day mortality rate, overall and in individual groups. a study from six covid icus from us enrolled patients, of which ( . %) received imv, with a median imv length of days (iqr - ). among imv subjects, icu mortality was . % without any difference in imv days between deceased and survived. at the end of follow-up (median observation time [iqr: - ] days), hospital mortality was . % ( / ), being patients still in icu on imv. however, no information was provided neither about the adopted respiratory support, nor the outcome, for patients not undergoing imv. despite mortality reported by auld et al. is similar to the mortality reported in our study in the imv-only group, they reported a much shorter follow-up (maximum follow-up days) and . % of patients were still admitted to the icu. therefore, -day mortality among those patients is likely to be higher that the reported hospital mortality. recently, a nationwide study from germany including more than , hospitalized covid- patients was published. interestingly, despite the germany health-care system has not been overwhelmed by the pandemic the reported inhospital mortality was markedly higher among patients treated with niv ( % in patients with successfully niv, % in patients that failed niv) and imv ( % in patients treated with imv), while it was lower in patients without mechanical ventilation ( %). two further studies considering icu patients reported information about all adopted breathing support strategies. an italian multicentric study enrolling a cohort of , critically ill patients (median follow-up: days; ventilatory support: imv %, niv %, cpap/oxygen . %) reported a mortality rate at the censoring (median observation time [range, - ] days) of %, %, and % among patients treated with oxygen, niv and imv, respectively. accordingly, niv and imv were associated with an increased risk of death compared with patients treated only with oxygen (hr . , % ci . - . and hr . , % ci . - . , respectively). again, mortality reported in the present study is likely to underestimate -day mortality and mortality in the niv and imv groups is higher than the reported in our study population. it should be noted that in all above cited studies the reported mortality for patients treated with standard oxygen and niv was clearly conditioned by the reduced size of these subgroups, related to the study settings limited to icu. compared with the previously reported literature, mortality reported in our study is generally lower. the centralized multidisciplinary approach adopted at rimini hospital may partially explain the difference with the existing literature. the . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted august , . . sensitivity analysis and the differences between the crude and the adjusted hrs reported in the figure and table may help with the interpretation of the study findings. interestingly, in the present investigation, mortality was higher in the oxygen and niv-only groups in the first days compared to the other two groups. this is partially explained by the survival bias among the mechanically ventilated patients, especially among patients that were intubated after failing a niv trial. indeed, although hrs for the -day mortality risk did not reach the statistical significance, mortality risk was lower for patients intubated after a failed niv trial only in the first days of follow-up and not in the to -day mortality. on the other side, the fact that the oldest patients and those with severe coexisting disease were treated only with oxygen carrying a higher early mortality was clearly described by the difference between the crude hrs and the hrs adjusted only be age. this finding together with the information of a mean imv length of almost days may support the idea that those patients would have not survived anyway to the imv and, therefore, endorse the decisions taken by the multidisciplinary team. moreover, our results suggest that initial management of severe hypoxemia by oxygen or niv might be a valuable alternative to immediate imv in the occurrence of limited available resources. the decision about the best breathing support to be provided to covid- patients is anything but simple. although often severely hypoxic, they tend to present less severe dyspnea than expected, probably because many patients, at least in the early stages of the disease, have normal pulmonary compliance and therefore exert limited inspiratory efforts. in patients whose lung compliance tends to progressively decrease, the inspiratory effort increases and vigorous inspiratory effort can contribute to lung injury (patient self-inflicted lung injury-p-sili). this feature has been supposed to rise morbidity and mortality. therefore, early mechanical ventilatory support has been advocated for covid- associated respiratory distress. unfortunately, criteria to intubate covid- patients are controversial and the decision may locally reflect the available resources. older age and comorbidities burden have been largely reported as the two main conditions associated with increased mortality risk, , , so that prioritization of younger patients has been advised in case of shortage of resources. notably, in the present investigation -although age was higher among non-survivors than survivors in each of the four groups and each calendar year was associated with a % increased risk for mortality-the age difference was smaller and not statistically significant among survivors and non-survivors undergoing imv. moreover, the median age of patients submitted to imv in our study ( years) was slightly higher than reported by other authors ( to years), , , suggesting that the adopted criteria at our institution were less restrictive in term of age. furthermore, once a patient was considered as potentially salvageable by icu admission and imv, the length of imv was not a criterion to withdrawing treatment. we strongly think that this ethically crucial decision could be widely considered. another interesting finding of our study was that similar p/f ratio was found among patients treated with niv-only or with imv, either preceded by a niv trial or not. therefore, we speculated that a low p/f ratio should not be the only criterion to decide which patient would benefit from imv. it should be noted that among patients intubated after a niv trial or receiving immediate imv, the latter group had a higher sofa score and saps (table ). these findings highlight the fundamental role played by our organizational strategy, allowing to ensure a tailored treatment to each patient by taking into account the level of care that would have more benefited for her/him, and to daily re-discuss each decision at the light of new clinical reasons or changes in the resources availability. for example, during the very early phase of the outbreak not all patients with appropriate indications were treated with niv due to the scarce availability of helmets, while their subsequent increase in availability allowed more targeted choices in the following days. moreover, this strategy contributed to create a more collaborative way to approach difficult decisions, supporting healthcare professionals, especially the younger ones, during such ethically and emotionally demanding decisions. the main strength of the study consisted in having described the impact of the sars-cov- epidemic in an entire province. since all patients with moderate to severe covid- were managed at the same hospital, a shared and homogeneous standard of care was guaranteed. moreover, follow-up was established at days, taking into account all respiratory supports and without patients' loss. as many covid- patients require prolonged imv, a short follow-up time is an important limitation for the majority of the reports published so far. the number of patients requiring ventilatory support was smaller compared to other studies. , , consequently, the generalizability of our findings should be considered with caution. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted august , . . the covid- outbreak has strongly challenged the healthcare systems of many countries. a multidisciplinary panel in charge of the decision of the individualized breathing approach to adopt with hospitalized covid- patients maybe be a valuable option to maximize -day survival, dealing with the imbalance between the available resources and the clinical needs. our findings highlight the need of high quality follow-up data that could support the decision-making for the appropriate ventilatory support strategy for covid- patients. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted august , . . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted august , . . figure . adjusted kaplan-meier curves for the risk of -and to -day mortality in patients belonging to the study groups according to provided respiratory support. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted august , . . measurements are reported as mean and standard deviation or absolute number and percentages. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted august , . . https://doi.org/ . / . . . doi: medrxiv preprint table . characteristics of patients receiving either invasive or non-invasive mechanical ventilation. group imv-after-niv group imv-only p-value n; mean ± sd n; mean ± sd n; mean ± sd . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted august , . . clinical characteristics of coronavirus disease in china presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area case characteristics, resource use, and outcomes of patients with covid- admitted to german hospitals: an observational study icu and ventilator mortality among critically ill adults with coronavirus disease clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study. the lancet risk factors associated with mortality among patients with covid- in intensive care units in lombardy, italy prognostic factors associated with mortality risk and disease progression in critically ill patients with covid- in europe: initial report of the international risc- -icu prospective observational cohort. eclinicalmedicine epidemiology, clinical course, and outcomes of critically ill adults with covid- in new york city: a prospective cohort study. the lancet between-centre differences for covid- icu mortality from early data in england detection of novel coronavirus ( -ncov) by real-time rt-pcr a new method of classifying prognostic comorbidity in longitudinal studies: development and validation radiographic severity index in covid- pneumonia: relationship to age and sex in italian patients a new simplified acute physiology score (saps ii) based on a european/north american multicenter study use of the sofa score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. working group on "sepsis-related problems" of the european society of intensive care medicine clinical course and predictors of -day mortality in critically ill patients with covid- : a multicenter retrospective study from wuhan covid- pneumonia: ards or not? covid- pneumonia: different respiratory treatments for different phenotypes? intensive care med clinical ethics recommendations for the allocation of intensive care treatments in exceptional, resource-limited circumstances: the italian perspective during the covid- epidemic characteristics and predictors of hospitalization and death in the first , cases with a positive rt-pcr test for sars-cov- in denmark: a nationwide cohort should we deny icu admission to the elderly? ethical considerations in times of covid- breathing support -days mortality hr ( % ci); p-value -days mortality hr ( % ci) model # : unadjusted; model # : adjusted by age; model # : adjusted by age and sex; model # : adjusted by age, sex, and administration of steroids; model # : adjusted by age, sex, and administration of steroids, and canakinumab; model # : adjusted by age, sex, and administration of steroids, canakinumab the authors thank all nurses and physicians who cared for covid- patients during the study period the authors declare that they have no conflict of interest. this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. key: cord- -b ycocg authors: rutsaert, lynn; steinfort, nicky; van hunsel, tine; bomans, peter; naesens, reinout; mertes, helena; dits, hilde; van regenmortel, niels title: covid- -associated invasive pulmonary aspergillosis date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: b ycocg nan to the editor: since march , following in the footsteps of china, europe has been facing the covid- pandemic, caused by the sars-cov- virus [ ] . increasing numbers of patients are being admitted to intensive care units (icu) throughout the world, imposing multiple diagnostic and therapeutic challenges on stressed healthcare systems. in our -bedded mixed icu, we have encountered an unexpectedly high number of covid- patients developing invasive pulmonary aspergillosis. through our case series, we aim to raise awareness of this severe complication in the critical care community, point out different diagnostic obstacles and share our approach to the management of this complex problem. invasive pulmonary aspergillosis (ipa) is a well-known complication in immunocompromised patients and is encountered frequently in haematopoietic stem cell or solid organ transplant recipients [ ] . continued improvement in diagnostics has revealed that half of the cases of ipa occur in the icu, in patients who are often nonneutropenic [ , ] . severe influenza infection is a wellknown risk factor for developing ipa in non-neutropenic patients; a syndrome termed influenza-associated aspergillosis (iaa) [ ] [ ] [ ] . a damaged respiratory epithelium, dysfunctional mucociliary clearance and a local immune paralysis were demonstrated to be key pathophysiological factors [ ] . supported by the hypothesis that alveolar damage facilitates fungal invasion, acute respiratory distress syndrome (ards) has frequently been associated with ipa in the icu [ ] . with this in mind, the existence of covid- -associated pulmonary aspergillosis is deemed likely. between march th and april th , covid- patients were admitted to our icu, of whom ( %) required invasive mechanical ventilation. seven of these ventilated patients ( %) were suspected of ipa (table ) . median age in our patient cohort was (interquartile range - ) years. underlying comorbidities were primarily cardiovascular. only three patients were immunocompromised. one patient received chronic corticosteroid treatment for pemphigus foliaceous, one patient was hiv-positive (cd count > ; viral load < copies, treated with antiretrovirals [lamivudine/tenofovir/nevirapine]) and one patient had been treated for acute myeloid leukaemia years ago and had developed ipa during chemotherapy. all patients were intubated and mechanically ventilated due to severe covid- pneumonia. our suspicion was raised initially through an unusually rapid growth (< h) of aspergillus species in bronchial aspirates of three different patients. all samples were obtained during routine bronchoscopies, performed for atelectasis, respiratory deterioration or increasing inflammatory parameters. from that moment, routine galactomannan assays on serum and bronchoalveolar lavage (bal) fluid were assessed regularly and bronchoscopy-guided biopsies of suspicious tracheobronchial lesions were obtained whenever present. unfortunately, computed tomography (ct) scanning was deemed unfeasible in some patients due to extreme hypoxia or difficult mechanical ventilation and whenever performed, table shows the timing and results of the microbiological testing in our case series. differentiating between aspergillus colonization and ipa is notoriously difficult, especially in the icu. in the absence of host factors, as defined by the european organisation for research and treatment of cancer (eortc) diagnostic criteria, invasive or high-risk diagnostics (biopsy, ct scan) are required to support the diagnosis of ipa [ ] . the aspicu algorithm was designed to partially deal with the absence of host factors [ ] . based on this algorithm, four patients (no , , , ) were diagnosed with proven ipa, based on histopathological evidence. all of these patients showed positive galactomannan indices on bal fluid. in two patients, cultures and/or galactomannan bal only became positive post mortem (no , ), before ct scan or histopathological samples could be obtained. in one patient (no ), histopathological sampling was negative and galactomannan bal only mildly raised, but a raised serum galactomannan was later detected. in the remaining patients, the serum galactomannan index remained negative (< . ). the mean time between intubation date and the first microbiological signs of ipa was a striking (sd ) days. icu physicians often have to weigh the risks of further diagnostic tests against a delayed initiation of antifungal treatment, which is associated with mortality rates over % [ ] . because all patients with clinical features of possible ipa were suffering from severe respiratory failure and hemodynamic instability, we initiated antifungal therapy as soon as cultures or galactomannan assays were positive. five patients were started on voriconazole. in two of these patients, the treatment was escalated to isavuconazole due to pancytopenia or undetectable voriconazole levels under continuous renal replacement therapy. two patients died on treatment. to confirm and control this alarming incidence of covid- -associated ipa, a number of measures were taken. firstly, we ruled out an environmental source, by sampling room air and the oxygen and pressurized air supplies (mas , merck). prior to covid- , the incidence of ipa in our icu was not elevated. nonetheless, high-efficiency particulate air filters (hepa) (halton vita, helsinki, finland) were installed in the icu. secondly, all mechanically ventilated covid- patients were screened systematically by performing serum galactomannan assays twice weekly. whenever a bronchoscopy was needed, bal galactomannan indices and mould cultures were requested, regardless of the indication for bronchoscopy. finally, we initiated prophylactic nebulization of . mg of liposomal amphotericin b (ambisome ® , gilead, foster city, usa) in every mechanically ventilated patient without an established diagnosis of ipa [ ] . since the implementation of these measures, we have not encountered any new cases of ipa at the time of writing. using this case series, we would like to raise awareness about covid- -associated pulmonary aspergillosis, in view of its potential detrimental outcome. we believe that a low threshold for screening, prophylaxis and early antifungal treatment is of paramount importance, especially since different immunosuppressive therapies have been suggested to treat patients suffering from this alarming condition. sars-cov- infection among travelers returning from wuhan, china invasive pulmonary aspergillosis the clinical spectrum of pulmonary aspergillosis invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study invasive pulmonary aspergillosis complicating severe influenza: epidemiology, diagnosis and treatment diagnosing invasive pulmonary aspergillosis in icu patients: putting the puzzle together revised definitions of invasive fungal disease from the european organization for research and treatment of cancer/invasive fungal infections cooperative group and the national institute of allergy and infectious diseases mycoses study group (eortc/msg) consensus group inhaled amphotericin b as aspergillosis prophylaxis in hematologic disease: an update. microbiol insights publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we want to thank our entire icu team for their unwavering commitment during these challenging times. lr wrote the first draft of manuscript with input and revisions from nvr and ns. ns collected the data from the source documents. tvh and lr performed the literature search. pb and hd advised on the reporting of the clinical data; rn and hm on the reporting of the microbiological and infection prevention data. all authors had full access to all of the data. all authors read and approved the final manuscript. none. the datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. publication approval granted by the ethics committee. not applicable. the authors declare that they have no competing interests. key: cord- -j fw dfc authors: alviset, sophie; riller, quentin; aboab, jérôme; dilworth, kelly; billy, pierre-antoine; lombardi, yannis; azzi, mathilde; ferreira vargas, luis; laine, laurent; lermuzeaux, mathilde; mémain, nathalie; silva, daniel; tchoubou, tona; ushmorova, daria; dabbagh, hanane; escoda, simon; lefrançois, rémi; nardi, annelyse; ngima, armand; ioos, vincent title: continuous positive airway pressure (cpap) face-mask ventilation is an easy and cheap option to manage a massive influx of patients presenting acute respiratory failure during the sars-cov- outbreak: a retrospective cohort study date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: j fw dfc introduction: because of the covid- pandemic, intensive care units (icu) can be overwhelmed by the number of hypoxemic patients. material and methods: this single centre retrospective observational cohort study took place in a french hospital where the number of patients exceeded the icu capacity despite an increase from to beds. because of this, ( %) of the patients requiring icu care were referred to other hospitals. from th march to rd april, consecutive patients who had respiratory failure or were unable to maintain an spo > %, despite receiving – l/min of oxygen with a non-rebreather mask, were treated by continuous positive airway pressure (cpap) unless the icu physician judged that immediate intubation was indicated. we describe the characteristics, clinical course, and outcomes of these patients. the main outcome under study was cpap discontinuation. results: cpap was initiated in patients and performed out of icu in ( %). median age was years (iqr = – ) and ( %) were men. median respiratory rate before cpap was ( – ) and median spo was % ( – ) under to l/min oxygen flow. median duration of cpap was days (iqr = – ). reasons for discontinuation of cpap were: intubation in ( %), improvement in ( %), poor tolerance in ( %) and death in ( %) patients. a decision not to intubate had been taken for patients, including the who died while on cpap. two patients underwent less than one hour cpap for poor tolerance. in the end, ( %) out of evaluable patients recovered with only cpap whereas ( %) were intubated. conclusions: cpap is feasible in a non-icu environment in the context of massive influx of patients. in our cohort up to / of the patients presenting with acute respiratory failure recovered without intubation. a a a a a the pandemic of novel coronavirus disease (covid- ) began in wuhan, china in december . as of august th , the who reported a total of covid- cases globally, including deaths. in a large uk cohort, death from covid- was strongly associated with being male, older age, deprivation, uncontrolled diabetes and severe asthma [ ] . the nature of the pulmonary lesions triggered by sars-cov- is still a matter of debate. some histopathological studies suggest that diffuse alveolar damage is not the single pattern [ , ] . disorders of the pulmonary circulation (thrombosis, endothelial injury) and organizing pneumonia may also be present. the classical clinical features of ards after intubation such as low pulmonary compliance are not found in all patients [ , ] . in terms of clinical management, initial recommendations suggested early intubation and ards-type ventilator settings [ ] . although some studies suggest a role for non-invasive ventilation (niv) in mild ards [ ] [ ] [ ] [ ] , including a recent meta-analysis [ ] , invasive mechanical ventilation remains the standard of care, especially for severe cases. while cpap in cardiogenic pulmonary oedema has been shown to reduce intubation rate [ ] , a randomized trial in acute hypoxemic respiratory failure, showed no effect of cpap in reducing intubation rate and mortality, despite improved oxygenation [ ] . however, during the chinese and european covid- outbreaks, a number of critical care teams proposed using high flow oxygen through nasal cannula (hfonc) or niv at least for initial management [ ] [ ] [ ] [ ] [ ] . optimal respiratory support for covid- patients presenting with acute hypoxemic respiratory failure, however, remains unknown. the district of seine saint denis has been the worst affected area during the sars-cov- outbreak in parisian region, with a mortality in excess of . % as compared to the same period in [ ] . it is densely populated and has a high-deprivation index. from mid-march until end of april , the delafontaine hospital, a large public hospital in saint denis, experienced a massive influx of patients requiring invasive ventilation. both intensive care unit (icu) and emergency department (ed) were quickly overwhelmed. the number of patients admitted in the wards ( non-icu beds, for covid- admissions) exceeded our icu capacity ( beds, increased to during the crisis, for admissions). fifty-nine ( %) out of the patients requiring icu care during this period had to be referred to other hospitals (fig ) . therefore, we had an urgent need to delay the course of respiratory failure in the less severe patients in order to manage the flow of patients in the icu and the ed resuscitation room. to achieve this, we considered face-mask cpap because it does not require a ventilator. from th march onwards, patients with signs of respiratory failure despite to l/min of oxygen delivered by non-rebreather mask (nrm) were systematically assessed for face-mask cpap or immediate intubation. in this single centre retrospective observational cohort study, we describe the characteristics and outcomes of patients supported with cpap in our hospital during the sars-cov- outbreak. we reviewed the characteristics, clinical course and outcomes of all consecutive adults with proven covid- treated with face-mask cpap in icu or in wards between th march and april. during this weeks-period, patients receiving - l/min oxygen through nrm who had clinical signs of respiratory failure or were unable to maintain an spo > % were treated with face-mask cpap unless the icu physician judged that immediate intubation was indicated. every patient included had a thoracic ct scan suggestive of covid- pneumonia and/or a positive sars-cov- pcr on naso-pharyngeal swab or broncho-alveolar lavage. the primary outcome under study was reason for cpap discontinuation (poor tolerance, intubation, death or improvement). poor tolerance was defined as a refusal by the patient to do more cpap sessions, because of breathing discomfort. the following baseline patient characteristics were retrieved from patient electronic medical record: sex, age, comorbidities, body mass index (bmi), withholding / withdrawal of life- sustaining therapies, associated covid- therapies administered before the primary outcome under study occurred (antivirals, corticosteroids, immuno-modulating therapies, prone positioning), oxygen flow rate and spo before and after starting cpap treatment, duration of cpap treatment, medical unit where cpap treatment was performed, duration of invasive mechanical ventilation, saps score for patients admitted in icu, driving pressure and p/f ratio on first day of mechanical ventilation. the clinical outcomes (i.e. discharges from hospital, mortality) were recorded until the final day of follow-up on june th . cpap of to cm h o was delivered via a face-mask dedicated to niv (performa track ) with one of types of cpap valve (boussignac™ or cpap-o-two™) or alternatively, an icu ventilator (servo i or evita infinity v ). treatment was undertaken in a medical ward, the ed short-stay unit or the icu. an electrostatic heat and moisture exchanger filter (dar™) was placed between the mask and the cpap valve to prevent aerosolization of virus through expired gases. all patients were admitted to a single room with implementation of contact and airborne precautions. medical and nursing staff in wards, unfamiliar with niv, were trained by the intensivist who was initiating the cpap treatment. patients received an initial prolonged session lasting at least hours before being reassessed of their need of invasive mechanical ventilation. if the patient could be temporarily taken off cpap without an immediate fall of spo below % (on o l/min via nrm) or recurrence of clinical signs of acute respiratory failure, cpap treatment was resumed for hours every hours. progressive weaning of cpap was performed according to clinical signs, pulse oximetry and arterial blood gases. when possible, patients were managed in the icu (nurse/patient ratio : ). if no icu bed was available (as in over % cases), patients with cpap were shifted to the ed short-stay unit ( beds) adjacent to the icu (nurse/patient ratio : ) which allowed frequent re-evaluation of the patient's state by the intensivist on duty. in the eventuality of no available bed in the ed short stay unit, cpap treatment was instituted and managed in the medical ward were the patient had been admitted (nurse/patient ratio : during the outbreak). ward patients on cpap were systematically reviewed overnight by the resident on duty responsible for the covid- medical wards. no a priori statistical sample size calculation was performed. sample size was equal to the number of patients treated during the study period. quantitative values are expressed as the median (interquartile range, iqr), and qualitative values are presented as numbers (percentages). univariate analysis was performed using fisher exact test or wilcoxon test, as appropriate. all tests were two-sided and a p value < . was considered statistically significant. because of alpha inflation due to multiple comparisons, findings should be interpreted as exploratory. a cox hazard proportional model was fit for time to intubation, controlling for potential confounders in the cohort of patients analysed. all variables available at baseline and associated with intubation in univariate analysis with a p-value < . were selected. variables selected are: ct-scan severity (< % vs � % of lung involved), spo at the time of cpap initiation, dose of anticoagulant (simple, double or curative) and time between hospital admission and cpap initiation. because of the important differences in the proportion of patients on corticosteroids in the groups (though statistically non-significant in univariate analysis) and the impact on mortality of corticosteroid treatment found in the recovery trial [ ] , we included it as an additional variable in the model. variables with more than % missing values were not implemented in the multivariate analysis. the analyses were carried out using r version . . (the r project for statistical computing, vienna, austria; http://www. r-project.org). the study was approved by the national ethics review board (cnriph-commission nationale des recherches impliquant la personne humaine) under the number -a - . the ethic committee waived the requirement for informed consent: patients or their next-ofkin were informed by mail about the data collection process and their right to oppose. the database was declared to the commission nationale informatique et libertés (cnil) under the number . electronic medical records of the delafontaine hospital (saint-denis, france), concerning patients who sought care between march and april , were accessed between may and june . statistical analyses were conducted on anonymised data. forty-nine consecutive patients were treated with cpap between th march and rd april (fig ) . initiation of cpap occurred throughout the entire study period and followed the epidemic curve (fig ) . sars-cov- pneumonia was confirmed by pcr in ( %) patients and by thoracic ct scan in all patients. twenty-six ( %) patients were eventually intubated and a total of ( %) died. patients' characteristics are presented in table . the median age was years (iqr = - ) and ( %) were men. forty-one ( %) patients had at least one comorbidity. the most frequent were hypertension ( patients, %), obesity ( patients, %) and diabetes ( patients, %). the median duration of symptoms before hospital admission was days (iqr = - ). thoracic ct-scan at admission showed mild ( to %), moderate ( to %) or severe (> %) lung involvement in ( %), ( %) and ( %) patients respectively. modalities of cpap therapy and associated interventions are described in table . cpap was performed out of icu in ( %) cases. median duration of cpap therapy was days (iqr = - ). reasons for discontinuation of cpap were intubation for invasive mechanical ventilation in ( %) patients, improvement in ( %), poor tolerance in ( %) and death in ( %). a decision not to intubate had been taken with the patient and their family for the patients who died while on cpap. all patients received at least once daily prophylactic anticoagulation. twice daily (thus double dose) prophylactic anticoagulation, typically enoxaparin mg every hours, was administered in ( %) patients while ( %) received therapeutic anticoagulation. hydroxychloroquine was administered in ( %) patients, lopinavir/ritonavir in ( %), corticosteroids in ( %) and anakinra in ( %). awake prone positioning was used in ( %) patients. two of those were eventually intubated. eight patients had a withdrawal or limitation of life-sustaining therapies ("do-not intubate" decision). of the other patients, had poor tolerance of cpap, resulting in its discontinuation within less than one hour. we did not consider these patients as being significantly treated, which left patients suitable for analysis of outcome. fifteen patients ( %) out of showed sustained clinical improvement with cpap therapy and never required intubation, including patient ( %) in the - years age category, patients ( %) in the - years, patients ( %) in the - years and patients ( %) in the - years. the other patients ( %) eventually required invasive ventilation (fig ) . in this group, median time from cpap initiation to intubation was day (iqr = - ), median p/f immediately after intubation was (iqr = - ), and median duration of mechanical ventilation was days (iqr = [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . patients who improved with cpap were compared to patients who required invasive mechanical ventilation. characteristics regarding age, sex, comorbidities and disease presentation were similar in both groups. patient who improved with cpap were treated later in their hospital stay, had higher oxygen saturation before cpap initiation, longer duration of cpap and received more often concomitant double dose prophylactic anticoagulation. in multivariate analysis, only low oxygen saturation before initiation of cpap was independently associated with a higher risk of intubation (fig ) . twelve ( %) of the intubated patients had a fatal outcome. median saps score of ventilated patients was (iqr = - ), resulting in a standardized mortality ratio of . . at the time of final follow up, / ( %) patients were dead, ( %) were discharged ( from the group of patients who improved with cpap), ( %) was still hospitalized in intensive care unit but weaned from mechanical ventilation. our hospital experienced a massive influx of hypoxemic patients during the covid- outbreak, ( %) of the patients requiring icu care had to be referred to other hospitals for lack of icu beds. in this context we tried cpap as a temporizing treatment in the management of acute respiratory failure. we choose not to use bi-level pressure niv for several reasons. first, the number of ventilators available could not ensure surge capacity in the context of massive patients influx, and the cpap devices were cheap enough to be bought in a large amount ( € for a boussignac™, € for a cpap-o-two™). second, bi-level pressure modes could have exposed patients who already have increased respiratory drive to the risk of ventilation induced lung injury through excessive tidal volume [ ] . third, the increase in positive pressure during inspiration was suspected to carry a greater risk of aerosolization of virus particles, hence increasing the risk of contamination of health care workers [ , ] . the final reason was to keep pressure support ventilation as an option for pre-oxygenation before intubation when indicated [ ] . using bi-level pressure modes would have also required more intensive training of ward staff unfamiliar with niv techniques. hfonc was also not considered because of the lack of high flow oxygen delivery devices during the outbreak period. in addition, there was also a concern about a greater risk of aerosolization, especially in non icu settings were strict compliance with airborne precautions was more difficult to achieve. in this single center retrospective observational study, overall mortality of this cohort was % ( / ). sixteen ( %) patients improved with face-mask cpap, and eventually did not require invasive ventilation though they were very hypoxemic ( ( %) of them required l/min oxygen). apart from patients with a do-not-intubate orders, no death occurred during cpap therapy. mortality rate was % in the patient group requiring invasive mechanical ventilation, which was consistent with a large cohort of patients from hospitals in uk (international severe acute respiratory and emerging infections consortium-isaric). among admitted to critical care (high dependency unit or intensive care unit), mortality was % while % continued to receive care at the date of reporting. in the patients receiving invasive ventilation mortality was % while % were still in hospital [ ] . this mortality rate was related to the severity of illness (median saps score of ) but may also be due to delayed intubation. reports are emerging on the use of cpap in situations similar to ours during the sars-cov- pandemic. in a single center in uk, cpap was initiated in patients requiring more than % fio or l/mn oxygen in combination with awake proning [ ] . when compared to the isaric cohort [ ] , there were reduced icu admissions ( . versus . %) and invasive ventilation rates ( . versus . %), with comparable hospital mortality ( . versus . %). another single center retrospective study in uk suggest a positive effect of cpap therapy, with a favourable outcome (i.e. survival without mechanical ventilation) in ( %) patients, and an intubation rate of %, which was similar to our results [ ] . a french two period retrospective study favours cpap over oxygen: intubation-free survival was % ( / ) with cpap compared to % ( / ) with oxygen (p = , ). however it was performed in the absence of shortage of icu beds, and cpap was initiated in patients less hypoxemic than our population (oxygen flow > l/min for sp > %), those two points may be the reasons of a lower intubation rate compared to ours [ ] . in an italian prospective cohort, patients underwent helmet cpap with a % survival without mechanical ventilation. in this study, patients were less hypoxemic than in our cohort at cpap initiation (pao /fio < mmhg). the helmet interface was well tolerated with discontinuation in only patients [ ] . on the whole, despite the fact that non-invasive ventilation techniques (hfonc, bi-level pressure ventilation or cpap) have already been used in several respiratory virus outbreaks (sars, mers, h n ), we lack strong evidence on their efficiency because studies were mainly retrospective, with inappropriate control for selecting or confounding bias, or without any control group [ , ] . as a consequence, recommendations from scientific societies concerning non-invasive oxygen therapy in covid- are heterogenous, some favouring hfonc, cpap, or bi-level pressure, depending on the country [ ] . it is not possible to infer from our study any definite conclusion on the role of cpap to avoid invasive ventilation because of the small sample size and because we were unable to identify a population of patients that could have been a comparator. our study has several other limitations. first, due to its retrospective design, we were unable to collect additional data that could have contributed to a better understanding of the role of cpap in managing hypoxemic respiratory failure in covid- . data on actual pressure levels delivered to each patient and the number of hours per day of cpap could not be collected. it was also not possible to ascertain in all patients whether vital signs (spo , respiratory rate) and arterial blood gases were taken while on cpap or while on nrm, hence a high rate of missing values. patients with profound hypoxemia and high respiratory rate on cpap may be exposed to self-induced lung injury. we attempted to collect the values for driving pressures immediately after intubation and positive expiratory pressure levels during cpap therapy but these data were unfortunately only available in a few cases. this should be investigated in further studies. secondly, due to small sample size, the observed effect of cpap in avoiding invasive mechanical ventilation within a sub-group of patients could be biased by concomitant treatments (drugs and/or prone positioning during spontaneous breathing) administered to spontaneously breathing-patients. however, in the multivariate analysis, corticosteroid treatment, the main therapy that has been shown to impact mortality [ ] , was not associated with the success of cpap treatment. the absence of a control group does not allow us to make any firm conclusion on the role of cpap in avoiding intubation. in addition, some patients treated with cpap may simply have received higher fio because the seal of the mask is better and the o flow higher as compared to patients on nrm: for example with a boussignac™ cpap, o flow was usually set between to l/mn to reach the target pressure of to cm h o. this could have contributed to their clinical improvement. third, there might be several selections bias. we chose to include all patients with findings highly suggestive of covid- on thoracic ct scan among which only % had a positive pcr on respiratory samples. however, sars cov rt pcr on naso pharyngeal swabs is known to have an imperfect sensibility, and we considered that at the peak of the outbreak, alternative diagnosis were improbable [ ] . the group of patients who did not need mechanical ventilation may have been less severe. this may be an important bias for their favourable outcome, which may not be due to the effect of cpap only. this is suggested by the higher levels of spo at initiation of cpap in the group of patients who improved compared with the group of patients who progressed to intubation. response to cpap could be used to identify patients who do not require intubation despite being profoundly hypoxemic [ ] . however, cpap could also have worsened the condition of patients whose intubation was delayed. the high saps scores of the intubated patients in the study provide some evidence to this effect. fourth and finally, contamination of health care workers was not evaluated. expired gases dispersion during cpap seems to be limited if there is good mask interface fitting [ ] , but leaks do occur incidentally and niv is considered an aerosol-generating procedure [ ] . potential benefit from face-mask cpap should be weighed against the risk of contamination of health care workers, especially in settings were infection prevention and control precautions are difficult to maintain. choosing the appropriate interface is critical to decrease leaks and minimize aerosolization and there may be some advantages to select full face masks [ , ] . helmet is another option but is more difficult to handle in a non-icu setting [ ] . the role of face-mask cpap in managing acute hypoxemic respiratory failure in covid- patients warrants further investigation in larger prospective studies and comparison with other ways to manage hypoxemic respiratory failure, such as high flow nasal oxygen cannula [ , , ] . the simplicity and practicality of cpap in a number of contexts, including massive patient influx and resource limited settings, is appealing [ ] . however, the likely increased risk of contamination of health care workers, notably if personal protective equipment is inadequate, must be taken in account. cpap could also be considered as a first-line respiratory support strategy in less hypoxemic patients without significant respiratory failure in association with other strategies to improve oxygenation, such as awake prone positioning [ , , [ ] [ ] [ ] [ ] [ ] [ ] . we found that treatment with face-mask cpap was feasible in a non-icu environment and in the context of a massive influx of patients. in our situation, it was useful to post-pone intubation and to manage the flow of patient requiring invasive ventilation. we also found, that among patients who have low spo and /or signs of respiratory failure while on l/min o via nrm more than one third eventually did not need invasive mechanical ventilation. given the limitations of our study, the role of face-mask cpap in managing patients with hypoxemic respiratory failure should be investigated in further research. supporting information s dataset. (xlsx) opensafely: factors associated with covid- -related hospital death in the linked electronic health records of million adult nhs patients facing covid- in the icu: vascular dysfunction, thrombosis, and dysregulated inflammation time to consider histologic pattern of lung injury to treat critically ill patients with covid- infection covid- pneumonia: different respiratory treatments for different phenotypes? management of covid- respiratory distress surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) predictors of failure of noninvasive positive pressure ventilation in patients with acute hypoxemic respiratory failure: a multicenter study a multiple-center survey on the use in clinical practice of noninvasive ventilation as a first-line intervention for acute respiratory distress syndrome* is there a role for noninvasive ventilation in acute respiratory distress syndrome? a meta-analysis can non-invasive positive pressure ventilation prevent endotracheal intubation in acute lung injury/acute respiratory distress syndrome? a meta-analysis association of noninvasive oxygenation strategies with all-cause mortality in adults with acute hypoxemic respiratory failure treatment of severe cardiogenic pulmonary edema with continuous positive airway pressure delivered by face mask treatment of acute hypoxemic nonhypercapnic respiratory insufficiency with continuous positive airway pressure delivered by a face mask high flow nasal cannula is a good treatment option for covid- efficacy and safety of early prone positioning combined with hfnc or niv in moderate to severe ards: a multi-center prospective cohort study the experience of high-flow nasal cannula in hospitalized patients with novel coronavirus-infected pneumonia in two hospitals of chongqing early awake prone position combined with high-flow nasal oxygen therapy in severe covid- : a case series severity of respiratory failure and outcome of patients needing a ventilatory support in the emergency department during italian novel coronavirus sars-cov outbreak: preliminary data on the role of helmet cpap and non-invasive positive pressure ventilati la surmortalité durant l'é pidé mie de covid- dans les départements franciliens n dexamethasone in hospitalized patients with covid- -preliminary report mechanical ventilation to minimize progression of lung injury in acute respiratory failure exhaled air dispersion during high-flow nasal cannula therapy versus cpap via different masks evaluation of droplet dispersion during non-invasive ventilation, oxygen therapy, nebuliser treatment and chest physiotherapy in clinical practice: implications for management of pandemi non-invasive ventilation versus high-flow nasal cannula oxygen therapy with apnoeic oxygenation for preoxygenation before intubation of patients with acute hypoxaemic respiratory failure: a randomised, multicentre, open-label trial features of uk patients in hospital with covid- using the isaric who clinical characterisation protocol: prospective observational cohort study reduced icu demand with early cpap and proning in covid- at bradford: a single centre cohort is continuous positive airway pressure (cpap) a new standard of care for type respiratory failure in covid- patients? a retrospective observational study of a dedicated covid- cpap service continuous positive airway pressure to avoid intubation in sars-cov- pneumonia: a two-period retrospective case-control study helmet cpap treatment in patients with covid- pneumonia: a multicenter, cohort study noninvasive respiratory support in acute hypoxemic respiratory failure associated with covid- and other viral infections ventilation techniques and risk for transmission of coronavirus disease, including covid- : a living systematic review of multiple streams of evidence covid- pandemic and non invasive respiratory management: every goliath needs a david. an evidence based evaluation of problems diagnostic performance between ct and initial real-time rt-pcr for clinically suspected coronavirus disease (covid- ) patients outside wuhan, china a plea for avoiding systematic intubation in severely hypoxemic patients with covid- -associated respiratory failure exhaled air dispersion distances during noninvasive ventilation via different respironics face masks noninvasive mechanical ventilation in high-risk pulmonary infections: a clinical review helmet cpap to treat acute hypoxemic respiratory failure in patients with covid- : a management strategy proposal frugal innovation for critical care respiratory parameters in patients with covid- after using noninvasive ventilation in the prone position outside the intensive care unit use of prone positioning in nonintubated patients with covid- and hypoxemic acute respiratory failure prone positioning in awake, nonintubated patients with covid- prone positioning in awake, nonintubated patients with covid- hypoxemic respiratory failure is the prone position helpful during spontaneous breathing in patients with covid- ? early self-proning in awake, non-intubated patients in the emergency department: a single ed's experience during the covid- pandemic we thank the doctors, residents and nursing staff of the delafontaine hospital who managed patients under cpap therapy during the sars-cov- outbreak. key: cord- -ax sr zr authors: garrigues, eve; janvier, paul; kherabi, yousra; bot, audrey le; hamon, antoine; gouze, hélène; doucet, lucile; berkani, sabryne; oliosi, emma; mallard, elise; corre, félix; zarrouk, virginie; moyer, jean-denis; galy, adrien; honsel, vasco; fantin, bruno; nguyen, yann title: post-discharge persistent symptoms and health-related quality of life after hospitalization for covid- date: - - journal: j infect doi: . /j.jinf. . . sha: doc_id: cord_uid: ax sr zr nan in this journal, we recently reported a series of hospitalized patients with novel coronavirus disease and their short-term outcome. however, only a few studies have assessed post-discharge persistent symptoms and health-related quality of life (hrqol) after hospitalization for covid- . , here, we describe a single-centre study assessing post-discharge persistent symptoms and hrqol of patients hospitalized in our covid- ward unit more than days after their admission. covid- diagnosis was based on positive sars-cov- real-time reverse transcriptase-polymerase chain reaction on nasal swabs, and/or typical abnormalities on chest computed tomography. patients who were directly admitted to the icu without being hospitalized in our covid- unit were excluded. demographic and clinical data at admission were extracted from electronic medical records. we designed a short phone questionnaire to collect post-discharge clinical symptoms, modified medical research council (mmrc) dyspnoea scale scores, professional and physical activities, and attention, memory and/or sleep disorders. hrqol was assessed using the eq- d- l questionnaire, a widely used, validated european questionnaire . patients are asked to rate their health state from to in five domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and on a scale ranging from ("the worst possible health") to ("the best possible health") on a visual analogue scale (eq-vas). based on the answers, an eq- d-index can be calculated, ranging from states worse than dead (< ) to (full health). all eligible patients were contacted by phone by trained physicians and were asked to answer to the questionnaire. deceased, unreachable, demented, bedridden and non-french speaking patients were excluded. we compared patients managed in hospital ward without needing intensive care ("ward group") with those who were transferred in intensive care units (icu) for artificial ventilation, including non-invasive ventilation, high flow nasal cannula and/or mechanical ventilation (icu group), with t-tests for quantitative variables and chisquare tests for qualitative variables. all tests were two-sided, and a p-value < . was considered statistically significant. all analyses were performed with r version . after a mean of . days, the most frequently reported persistent symptoms were fatigue ( %), dyspnoea ( %), loss of memory ( %), concentration and sleep disorders ( % and . %, respectively) ( table ) . loss of hair was reported by ( %) patients, including women and men. comparisons between ward-and icu patients led to no statistically significant differences regarding those symptoms. thirty-five ( %) patients had a mmrc grade ≥ ("walks slower than people of the same age because of dyspnoea or has to stop for breath when walking at own pace"). before covid- infection, ( . %) were active workers. among them, ( . %) had gone back to work at the time of the phone interview. among the patients who had regular sports activity before their hospitalizations for covid- , ( . %) have been able to resume physical activity, but at a lower level for ( %). there was no statistically significant difference between ward and icu groups, but there was a nonsignificant trend towards a reduced proportion of patients returning to work among icu patients ( . % versus . %, p= . ). in both group, dimensions of the eq- d (mobility, self-care, pain, anxiety or depression, usual activity) were altered with a slight difference in pain in the icu group, but no statistically significant difference in the other groups (figure ). mean eq-vas was . % and mean eq- d index . , with no difference between icu and ward patients ( table ). the present study shows that most patients requiring hospitalization for covid- still have persistent symptoms, even days after being discharged, especially fatigue and dyspnoea. these results highlight the need for a long-term follow-up of those patients and rehabilitation programs. surprisingly, many patients (mainly women) spontaneously reported significant hair loss, which may correspond to a telogen effluvium, secondary to viral infection and/or a stress generated by the hospitalization and the disease. nevertheless, hrqol was quite satisfactory, as most patients who had a professional activity before the infection went back to work. except pain or discomfort, we found no significant difference regarding persistent symptoms and hrqol between ward patients versus icu patients. this clearly supports the interest of a full resuscitation for covid patients despite heaviness of cares. however, patients from our "icu group" were relatively non-severe, as those who were directly admitted to icu (thus corresponding to the most severe forms) were not included in our study. other limitations of our study include the limited number of patients, the single-centre nature of our series, and the high rate of unreachable patients, which could lead to differential bias. in conclusion, many symptoms persist several months after hospitalization for covid- . while there were few differences between hrqol between ward and icu patients, our findings must be confirmed in larger cohorts, including more severe icu patients. applicability of the curb- pneumonia severity score for outpatient treatment of covid- gemelli against covid- post-acute care study group. persistent symptoms in patients after acute post-discharge symptoms and rehabilitation needs in survivors of covid- infection: a cross-sectional evaluation development and preliminary testing of the new five-level version of eq- d (eq- d- l) a french value set for the eq- d- l sener serpil, colak cemil. evaluation of the effects of covid- pandemic on hair diseases through a web-based questionnaire the authors are indebted to all persons (physicians, surgeons, radiologists, biologists, medical students, and paramedical staff) who were involved in the beaujon covid- unit. the writing review and editing: all authors. none of the authors declared any competing interest in link with the present study. key: cord- -jj anf g authors: shang, you; pan, chun; yang, xianghong; zhong, ming; shang, xiuling; wu, zhixiong; yu, zhui; zhang, wei; zhong, qiang; zheng, xia; sang, ling; jiang, li; zhang, jiancheng; xiong, wei; liu, jiao; chen, dechang title: management of critically ill patients with covid- in icu: statement from front-line intensive care experts in wuhan, china date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: jj anf g background: the ongoing coronavirus disease (covid- ) pandemic has swept all over the world, posing a great pressure on critical care resources due to large number of patients needing critical care. statements from front-line experts in the field of intensive care are urgently needed. methods: sixteen front-line experts in china fighting against the covid- epidemic in wuhan were organized to develop an expert statement after rounds of expert seminars and discussions to provide trustworthy recommendation on the management of critically ill covid- patients. each expert was assigned tasks within their field of expertise to provide draft statements and rationale. parts of the expert statement are based on epidemiological and clinical evidence, without available scientific evidences. results: a comprehensive document with statements are presented, including protection of medical personnel, etiological treatment, diagnosis and treatment of tissue and organ functional impairment, psychological interventions, immunity therapy, nutritional support, and transportation of critically ill covid- patients. among them, recommendations were strong (grade ), were weak (grade ), and were experts’ opinions. a strong agreement from voting participants was obtained for all recommendations. conclusion: there are still no targeted therapies for covid- patients. dynamic monitoring and supportive treatment for the restoration of tissue vascularization and organ function are particularly important. the outbreak of novel coronavirus pneumonia that was first detected in wuhan in december resulted in a worldwide pandemic. on february , , the world health organization (who) formally named it coronavirus disease . a person with laboratory confirmation of virus causing covid- infection, irrespective of clinical signs and symptoms, is considered as a confirmed case [ ] . globally, more than , , confirmed individuals and over , deaths, across more than countries, territories or areas have been reported [ ] . approximately % of confirmed cases developed severe disease [ ] , while the grand fatality rate was . % [ ] . as the virus continues to spread at an alarming rate, healthcare workers are seeking effective and actionable management for affected patients. in china, physicians have been coping with covid- for over months. most of the people who contracted covid- presented with mild symptoms ( . %), then severe ( . %), and finally critical ( . %) ( table ) [ ] . most of the confirmed cases were between the ages of and ( . %), diagnosed in hubei ( . %), with the overall fatality rate of . %, and . % in health workers [ ] . the case fatality rate for critical cases was . % [ ] . patients with underlying diseases had much higher fatality rates than patients with no underlying diseases ( . % for cardiovascular disease, . % for diabetes, . % for chronic respiratory disease, . % for hypertension, . % for cancer, and . % for none) [ ] . the epidemic outbreak curve peaked around january - , , after which the decline ensued. a recent single-center study found that most critical patients developed organ dysfunction, where % were found to have acute respiratory distress syndrome (ards), % with acute kidney injury (aki), % with cardiac injury, % with liver dysfunction, and % with pneumothorax [ ] . besides these epidemiological findings, chinese experts have gained valuable experience in the management and pathology of this disease. we consider it our responsibility to share these experiences through the expert consensus. chinese specialists in critical care medicine were organized and worked together to develop an expert statement after five rounds of expert seminars and discussions. this statement represents a synthesis of evidence and experts' consensus on critical care, despite the lack of clinical trials. critical cases are characterized by exhibited respiratory failure, septic shock, and/ or multiple organ dysfunction/failure [ ] . in experts' opinion, the patients should also be considered as critical cases if they are suffering from high respiratory frequency (rr ≥ bpm) and low oxygen index (arterial partial pressure of oxygen (pao )/fraction of inspired oxygen (fio ) ≤ mmhg) under high-flow nasal cannula oxygen therapy (hfnc). the experts drew up sections on the management of covid- disease, mostly based on the experience in wuhan. the statements were drawn up by a group of front-line intensive care experts in china who fought against the covid- epidemic in wuhan. the group's agenda was predefined. the expert group first defined clinical questions to be addressed and then designated the experts in charge of each question after a first meeting. all the questions were formulated according to the population, intervention, control, and outcome (pico) format, which helps defining inclusion and exclusion criteria for the literature searches and identifying relevant studies. the quality of evidence was assessed using the methodology described in grades of recommendation, assessment, development, and evaluation (grade). the quality of evidence can be high, moderate, low, or very low. because of the sudden outbreak of a covid- , the proposed question could be the subject of a recommendation as an expert opinion due to inexistent or insufficient literature. in addition, the published data on severe acute respiratory syndrome (sars), middle east respiratory syndrome (mers) and other coronaviruses infections, as well as data on supportive care in the icu from studies on influenza and other respiratory viral infections, ards and sepsis was used as indirect evidence. a total of rounds of expert seminars and discussions were organized to provide trustworthy recommendation on the management of critically ill covid- patients (table ) . we use the wording "we recommend", "recommended", "should" or "should not" for strong recommendations, "should probably", "should probably not" or "should probably be considered" for weak recommendations, and "the experts suggest", "the experts suggest against", "suggested" or "not suggested" for expert opinion. the implications of the recommendation strength are presented in table . the proposed recommendations were discussed one by one. at least % of experts agree to approve a proposal for criteria, and at least % of experts must agree to reach a strong agreement. in the absence of strong agreement, choose to reformulate the proposal and re-rating, in order to reach consensus. only the expert opinions that give strong agreement are retained. the prevention and control of infections, diagnostic strategy, therapeutic management, and transportation of patients were defined. literatures were searched via pubmed and the cochrane library databases. only articles published in english or with an english abstract were included in the analysis focused on recent data according to an order of appraisal ranging from meta-analyses to randomized trials to observational research studies. the study population size and research relevance were considered for each study. according to the grade method and summary of the results, experts drew up statements. of these guidelines, had a high level of evidence (grade ±), had a low level of evidence (grade ±), and were expert opinions. a strong agreement was reached for all statements after two rounds of scoring. as the front-line of the covid- outbreak response, health care workers are exposed to a huge risk of infection. therefore, health care workers must follow the standard precautionary principles and try their best to ensure the personal protection, hand hygiene, ward management, environmental ventilation, and sanitization of the object surface, so as to avoid nosocomial cross-infection. statement implementation of standard precautions, strengthening ward management, and self-management are suggested safety measures for health care workers (expert opinion). rationale averted by the current epidemic situation of covid- , taking proper precautions is essential for avoiding the spread of infection among health care workers. thus, the following points need to be considered. as a high-risk environment, tertiary class protection is suggested for health care workers in intensive care unit (icu). personal protective equipment (ppe) includes disposable surgical cap, n mask, work uniform, disposable medical uniforms, disposable latex gloves, goggles, and full-face shields. full-face respiratory protective devices or powered air-purifying respirators are required when performing aerosol-generating procedures. destroying and disposing of masks properly, putting on and removing ppe, and practicing hand hygiene are necessary to avoid self-contamination. special attention should be paid to details such as the side exposure of the eyes and wrists with glove slippage, as well as the risks of infection while removing some disposable shoe covers [ ] . the hand hygiene system should be strictly implemented table statement timeline march , designating the experts in charge of each addressed question each expert made a detailed outline of their respective question march , discussing and resolving the problems encountered by the experts in the process of making the statements april , ( ) discussing the experts' respective statement and rational after revision; ( ) first round of scoring april , guideline finalization meeting for the second round of scoring table recommendations according to the grade methodology grade + strong recommendation "…we recommend…", "…recommended…" or "…should…" high level of evidence grade + weak recommendation "…should probably…" or "…should probably be considered…" low level of evidence expert opinion recommendation in the form of an expert opinion "…the experts suggest…", "…suggested…", "…the experts suggest against…", or "…not suggested…" [ ] . clinical triage system needs to be established to assess all patients at admission, allow for early recognition of possible covid- cases and immediate isolation of patients with suspected disease in an area separate from other patients (source control). the number of family members and visitors who are in contact with suspected or confirmed covid- patients should be limited or visiting should be prohibited altogether. the proper disposal of clinical waste should be ensured [ ] . health care workers need to self-monitor for signs of illness and self-isolate. if illness occurs, they should report it to managers and stay at home. a sensible diet, proper rest, and adequate exercise are advised to maintain physical and psychological health. health care workers should familiarize themselves with related working procedures so as to avoid mistakes [ ] . proper icu ward setting, necessary equipment and facilities, and strict icu environmental disinfection, are suggested (expert opinion). rationale it is suggested to adjust measures according to the differing conditions so as to set the icu ward rationally. contaminated areas, potentially contaminated area and clean areas need to be strictly divided. the buffer zone should be set between every two areas. posting eye-catching logos on each area is required to prevent straying into the wrong place. different points of access should be set for medical staff and patients, making sure they do not get crossed. for icu, tertiary class protection should be correctly performed in each area, which is of great importance for precaution of covid- [ ] . the use of negative pressure rooms with natural ventilation is recommended by the who guidance to prevent the spread of airborne pathogens among rooms [ , ] . first-aid materials and medicine such as oxygen tank, electrocardiogram (ecg) monitor, defibrillator, injection pump, infusion pump, endotracheal intubation supplies, portable vacuum extractor, noninvasive ventilator, invasive ventilator, hemofiltration equipment, extracorporeal membrane oxygenation (ecmo) equipment and so on should be prepared. other equipment, including air disinfecting machine and air cleaner, as well as medical gas systems including oxygen, compressed air, special gas, and vacuum suction systems, need to be assured too. it is of particular importance to implement effective measures to prevent the spread of covid- in icu. disinfection includes concomitant disinfection and terminal disinfection. concomitant disinfection must be conducted immediately for the materials and environment contaminated by the excretion of the suspected and confirmed patients. following the end of day's work in icu, or the patients' recovery or death in the isolation ward, terminal disinfection needs to be done carefully. key disinfection objects include patients' living supplies such as clothes and quilt, medical supplies, ground and wall space of icu wards, the surface of desks and bed tables, as well as air [ , ] . current evidence indicates that covid- is mainly transmitted from person to person through droplets, contact, and even high concentrations of aerosols [ ] . large amounts of droplets and aerosol are generated by sputum suction in the airway, specimen collection, tracheal intubation, fiber bronchoscopy, tracheotomy, etc. accordingly, surgeons are at a great risk of contamination. in order to avoid occupational exposure, recommendations during the aerosol-generating procedures in covid- patients are the following: statement if possible, covid- patients should probably be admitted to negative pressure rooms (grade +, weak recommendation). rationale negative pressure rooms are aimed to decrease the concentration of severe acute respiratory syndrome coronavirus (sars-cov- ) pathogens. in view of that, the risk of contamination would be decreased during the aerosol-generating procedures in such a setting. during the severe acute respiratory syndrome (sars) epidemic, it was reported that negative pressure settings were effective in preventing cross-contamination and protecting the staff and patients inside the room [ ] . according to who recommendations for covid- patients, such locations should be with a minimum of air changes per hour or at least l/ second/patient with natural ventilation [ ] . the experts suggest that operators wear a portable air-purifying respirator with level iii biosafety protection (expert opinion). rationale an observational study reported that among hospitalized patients diagnosed with confirmed covid- in zhongnan hospital in wuhan in january, , were healthcare workers [ ] . till march , , it has been reported that over health workers were confirmed with covid- , among whom died. the memory of what has happened during the sars outbreak is still fresh. a systematic review showed that the healthcare workers who performed aerosol-generating procedures, including endotracheal intubation (odds ratio, . ), noninvasive ventilation (odds ratio, . ), tracheotomy (odds ratio, . ), and manual ventilation before intubation (odds ratio, . ) were at higher risk of suffering from sars infection compared with the non-performers [ ] . most of the infections among healthcare workers occurred at the early stage of this outbreak when the self-protective directive has not yet been established and reinforced. after confirmation of human to human transmission of sars-cov- , the self-protection for healthcare workers was subsequently established and reinforced from the end of january . level iii biosafety protection is mandatory for intubation according to the guidance of the general office of the national health committee [ ] . ppe donning process should be strictly followed during high-risk operation: disposable hair cover, fit-tested n respirator or equivalent, fluid-resistant gown, two layers of gloves, goggle and face shield, and fluid-resistant shoe covers. the main operator should use portable airpurifying respirator. all the donning processes should be supervised by a professional nurse or assistant. doffing process of ppe after high-risk exposure should also be followed: hand hygiene, face shield and goggle removal, fluid-resistant gown removal, outer glove removal, shoe cover removal, inner glove removal, hand hygiene, n respirator or equivalent removal, and hair cover removal. the doffing process seems to be of greater importance. all the processes should also be supervised so as to reduce the risk of contamination [ ] . the aerosol-generating operations such as tracheal intubation and tracheotomy are suggested to be performed by senior physicians or specialists in the field. an electronic laryngoscope with light emitting diode is suggested during endotracheal intubation. if possible, disposable equipment is suggested to be used. b) fiber bronchoscopy is not suggested for patients without an artificial airway. the operation is suggested to be performed by senior physicians or professionally trained respiratory therapists. a bronchoscope with an external display is suggested for facilitating operations. if possible, the use of a disposable bronchoscope is suggested (expert opinion). rationale large amounts of aerosols generated by incubation can increase the risk of transmission and nosocomial infection [ ] . thus, visual devices are recommended to facilitate the procedure, limit operation time [ ] and ensure the distance between operator and patient. routine fiber bronchoscopy operations are not suggested for covid- patients. meanwhile, most covid- patients have few airway secretions [ ] so that the indication of bronchoscopy should be strictly minimized. according to the recommendations by the centers for disease control and prevention (cdc) [ ] and who [ ] , disposable medical equipment should be used for patient care if possible. statement (a) deep sedation (richmond agitation-sedation scale (rass): - ) is suggested for patients during the procedure of fiber bronchoscopy. (b) the artificial airway is suggested to be connected with a threeway connector allowing access to get into the airway to perform a bronchoscopy. (c) the use of a closed airway suction device is suggested (expert opinion). rationale severe covid- patients with artificial airway tend to suffer from severe hypoxemia [ ] . the patient's secretions, droplets, and aerosols can be widely spread during the operation. patients should be intubated within s [ ] . the procedure of fiber bronchoscopy should be performed gently with great caution in severe covid- patients. during bronchoscopy, following procedures should be followed to avoid aerosols spreading: artificial airway should be connected with a disposable three-way connector to a ventilator, then (a) ventilator needs to be set to standby mode, (b) the artificial airway needs to be briefly clamped, (c) the bronchoscopy should be quickly inserted into the connector, (d) the clamp should be opened, (e) ventilation should be restored [ ] . for the patients requiring mechanical ventilation, it is not advisable to disconnect patients from the ventilator. even though some clinical experts insisted that antiviral therapy is unnecessary for seriously ill patients with covid- since the course of disease in severe types is longer than weeks, multiple virus particles have been found at the lung lesions following histopathological examination. up to date, there is no specific antiviral drug that has been testified and globally recognized effective for treating covid- . in china, several antiviral drugs such as ribavirin, ganciclovir, oseltamivir, arbidol, alpha-interferon, chloroquine, lopinavir-ritonavir, and remdesivir have been used in clinical settings for the treatment of covid- . among them, oseltamivir and arbidol hydrochloride are the most commonly utilized; however, these antiviral drugs were originally designed for influenza, and their efficacy and safety for covid- need to be further investigated. no antiviral drugs are proven effective and should probably be considered for sars-cov- treatment (grade +, weak recommendation). rationale ribavirin is a broad-spectrum antiviral drug. clinical observations have suggested that early use of this drug is efficacious in containing covid- . to avoid possible aerosol transmission, we do not recommend alpha-interferon nebulization for covid- infected patients. according to a very recently published clinical study from france, hydroxychloroquine can significantly reduce viral load in covid- patients, and azithromycin can further enhance this effect [ ] . in this study, combination use of hydroxychloroquine (hcq) and azithromycin for at least days at an early stage could rapidly reduce the nasopharyngeal viral load and decrease the length of hospital stay for infected patients. it should be noted that treatment with higher chloroquine diphosphate (cq) dosage ( mg cq twice daily) is not recommended for severe covid- due to its potential safety hazards, especially when taken concurrently with azithromycin and oseltamivir [ ] . nonetheless, a randomized controlled trial (rct) trial conducted by cao et al. suggested monotherapy of lopinavir-ritonavir did not bring about any clinical benefits for severe covid- patients compared with standard supportive care, which may be partly caused by the higher throat viral loads in lopinavir-ritonavir group, delayed treatment initiation [ ] . of note, these clinical studies were limited by relatively small sample sizes. more large-scale and well-designed clinical trials are needed to confirm their potential therapeutic effects. arbidol monotherapy might be better than lopinavir-ritonavir in reducing viral load in covid- patients [ ] . a clinical study from gilead sciences showed that remdesivir could improve clinical conditions in critically ill patients with covid- , and stop patient from receiving invasive mechanical ventilation or ecmo [ ] . however, a recent multicentre study published in the lancet found no benefit of remdesivir in improvement of clinical outcomes for severe covid- [ ] . one recent study published in n engl j med showed that compassionate use of remdesivir improved clinical outcomes in a subset of severe covid- patients [ ] . however, the absence of control groups precludes a final conclusion. the definite therapeutic effectiveness of remdesivir in the treatment of severe covid- needs to be further verified. remdesivir has been approved as a potential treatment for severe covid- patients by the japanese ministry of health, labour and welfare (mhlw) on may , due to the covid- pandemic [ ] . the main side-effects of these antivirals include qt interval elongation, bradycardia, hepatic injury, and obvious gastrointestinal reactions such as serious diarrhea and vomiting which may contributed to disease deterioration. clinical trials testing remdisivir for the treatment of severe covid- patients are underway (nct , nct ). convalescent plasma therapy belongs to passive immunization, which is used for the treatment of virus infections when specific drugs and vaccines are unavailable. convalescent plasma, which has been used for more than one hundred years, can provide specific antibodies to neutralize and eradicate the viruses from the blood circulation. up to date, there is no particular treatment for covid- . in , the who recommended the use of convalescent plasma collected from patients who recovered from the ebola virus infection as an empirical treatment during the outbreak [ ] . during the covid- epidemic period, this method was also recommended by the national health commission of china for the treatment of severe and critical patients [ ] . statement convalescent plasma therapy should probably be used for severe and critically ill patients with covid- (grade +, weak recommendation). rationale convalescent plasma has been testified to suppress viremia, shorten the hospital stay, and reduce mortality during several virus epidemics. in during a spanish influenza pandemic, convalescent plasma reduced the mortality rate by > % in severe patients [ ] . since then, it was also used for prophylaxis or as a treatment for several virus infections such as measles, argentine hemorrhagic fever, influenza, chickenpox, and infection by cytomegalovirus. over the past two decades, its efficacy and safety were confirmed during pandemics of sars, mers, h n and h n avian flu. during the sars pandemic in , eighty patients received convalescent plasma at prince of wales hospital, hong kong. by the nd day, a higher discharge rate was observed in patients (n = ) given convalescent plasma before day than that given plasma after day ( . % vs. . %; p < . ) [ ] . a prospective cohort study conducted by hung et al. showed that convalescent plasma therapy (n = ) significantly reduced mortality compared to the control group (n = ) ( . % vs. . %; p < . ). meanwhile, plasma treatment lowered the upper respiratory tract virus load and decreased serum cytokines levels in patients with severe pandemic (h n ) virus infection [ ] . these studies verified the efficacy of convalescent plasma in patients with virus infections. it has been reported that among three severe mers patients who received convalescent plasma infusion, just two showed neutralizing activity [ ] . among five critically ill patients with covid- receiving mechanical ventilation convalescent plasma infusion, patients were discharged, while clinically ill patients improved and maintained the stable condition till the day after transfusion [ ] . a study performed in severe covid- patients found that convalescent plasma treatment could improve clinical outcomes, improve immune function, and promote absorption of lung lesions [ ] . nonetheless, just like any other treatment, convalescent plasma has its limitations. the main limitation refers to the reported studies, which are not randomized trials, but just prospective cohort studies or case series studies. therefore, it was not possible to eliminate the influence of baseline severity and other treatments when evaluating the effects of convalescent plasma therapy. other limitations include the risk of transmitting infections to transfusion service personnel, the need for adequate selection of donors with high neutralizing antibody titers, and the risk of other transfusion-transmitted infections [ ] . however, regardless of these limitations, since there are still no specific etiological treatments for covid- , and convalescent plasma is available, it is reasonable to use it in the treatment of covid- patients. respiratory failure is the primary organ dysfunction, which worsens the prognosis of covid- patients. oxygen therapy and respiratory support are the key treatments for covid- -induced ards. due to inflammatory and necrosis-induced small airway occlusion, which was confirmed by autopsy of covid- -induced ards, positive pressure ventilation is vital to restore the collapsed airway and improve gas exchanges. however, high end-inspiratory pressure increases stress and strain to normal alveoli and increases the risk of lung injury. oxygen therapy and respiratory support for covid- -induced ards should balance airway recruitment and risk of lung injury (fig. ). indication for hfnc and niv. statement niv and hfnc should probably be used for covid- -induced ards with pao / fio > mmhg (grade +, weak recommendation). rationale noninvasive ventilation support (niv) and hfnc are important treatments for covid- -induced mild and moderate ards. the mechanisms of the two treatments are positive end-expiratory pressure, decreased respiratory workload, decreased incidence of intubation, ease of use, and higher comfort. in a randomized trial of adult patients admitted to the icu for acute hypoxemic, nonhypercapnic respiratory insufficiency, continuous positive airway pressure (cpap) delivered by face mask was associated with an early improvement in oxygenation; however, it was not associated with a reduced need for intubation or with improved outcomes [ ] . a trial that compared hfnc oxygen, standard oxygen via face mask and face mask niv in patients with acute hypoxemic respiratory failure, reported that the intubation rate was significantly lower with hfnc oxygen than with standard oxygen or niv among patients with pao /fio ≤ mmhg at enrollment and, for the whole group (patients with pao / fio ≤ mmhg), patients managed with hfnc had improved survival. there were no differences in outcomes between niv and standard oxygen [ ] . a substudy examined the practice of niv use in ards of lungsafe study reporting that niv was associated with higher icu mortality in patients with a pao / fio < mmhg [ ] . for covid- , there is no sufficient evidence to prove that hfnc is superior to niv. statement when using niv and hfnc, oxygenation and breathing patterns are suggested to be closely monitored, and intubation delays is suggested to be avoided (expert opinion). rationale for all cases with noninvasive support, patients should be closely monitored, as deterioration can abruptly occur [ ] . in china, some patients presented with hypoxemia, later named "silence hypoxemia", since these patients were without corresponding clinical manifestations, e.g., no high respiratory rates, high heart rate, respiratory distress, and other hypoxia symptoms. these patients have a high risk of sudden death and should be closely monitored and timely provided with oxygen therapy. positive responses are usually evident soon after the initiation of niv and hfnc. if there is no substantial improvement in gas exchange and respiratory rate within a few hours, invasive mechanical ventilation should be started without delay. failure to recognize a lack of improvement during noninvasive support may result in further respiratory deterioration and/or cardiac arrest, often with devastating consequences. delayed intubation increases ards mortality; therefore, early recognition of ards severity could avoid delayed intubation. if the use of hfnc fails, endotracheal intubation is unavoidable even with the use of rescue niv [ ] . the indications for hfnc and niv intubation are a higher level of severity (saps ii score > ), hypoxemia (pao /fio ≤ mmhg), hypoxemia that is not improved following niv treatment for h, and strong spontaneous breathing (tidal volume with niv > ml/ kg pbw) [ ] . rox index can be used to predict hfnc failure and intubation for patients with respiratory failure; > . , suggests a high chance of success, < . suggests a high risk of failure, and intubating the patient should be discussed; index between . and . , suggests the patient should be monitored very closely and intubation delays should be avoided [ ] . [ , ] . another trial that employed a multilevel mediation analysis to analyze individual data from patients with ards, who were also included in nine previously reported randomized trials, identified driving pressure as the ventilation variable that best-stratified risk. decreases in driving pressure owing to changes in ventilator settings were strongly associated with increased survival [ ] . low tidal volume ( - ml/kg pbw), limited plateau pressure (< cmh o), and driving pressure (< cm h o) could decrease ards mortality. bedside measurements should probably be used for the evaluation of lung recruitability (grade +, weak recommendation). rationale alveolar collapse is mainly generated by inflammatory lung edema, impairment of chest wall movement, and surfactant deficiency. some reports have shown different effects of recruitment maneuvers in ards patients due to lung recruitability [ ] . from our experience in wuhan, most of the covid- patients had low lung recruitability [ ] . due to the infectiousness of covid- , ct, and the other necessary equipment cannot always be used to evaluate lung recruitability. however, some bedside measurements, such as the pressure-volume curve, recruitment to inflation ratio, and clinical parameters, can be measured by a ventilator and used to evaluate lung recruitability [ ] . based on low lung recruitability in covid- -induced ards, high peep should probably not be used, and peep setting should probably be based on various factors, including gas exchange, hemodynamics, lung recruitability, and driving pressure (grade +, weak recommendation). rationale use of positive end-expiratory pressure (peep) usually improves gas exchange and helps reduce the need for high fio . in addition, appropriate levels may limit vili by maintaining lung recruitment and improving lung homogeneity [ ] . when applied with a constant pplat, peep reduces the driving pressure and keeps the lung recruited. because of the lack of resources, peep selection criteria may include lung recruitability, peep/fio table, respiratory system compliance, optimal oxygenation, and driving pressure [ , , ] . based on the available data, all peep values represent a compromise between the extent of recruitment and overdistension, and hemodynamics. the experts suggest optimizing ventilator settings to improve hypercapnia (expert opinion). rationale in china, hypercapnia has been commonly found in covid- -induced ards. the mechanisms are related to lung injury inhomogeneity and an increase in dead space. firstly, optimization of ventilator setting is important; secondly, the prone position could decrease dead space and improve hypercapnia [ ] ; thirdly, tracheal gas inflation (tgi), which influences sputum drainage, could increase alveolar ventilation and co removal [ ] ; fourthly, extracorporeal life support or co removal equipment could improve hypercapnia. statement we recommend using prone positioning in severe covid- patients to prevent the deterioration of patients' condition (grade +, strong recommendation). rationale prone positioning has a beneficial effect on oxygenation, lung recruitment, and stress distribution. the physiological effects of prone positioning include redistribution of lung densities, often with the recruitment of well-perfused dorsal regions. although prone positioning increases chest wall elastance, this change is usually accompanied by improved lung recruitment, a reduction in alveolar shunt and improved ventilation/ perfusion ratio, subsequent improvement in oxygenation and co clearance, a more homogeneous distribution of ventilation and a reduced vili risk [ , ] . indications for prone positioning include moderateto-severe ards (pao /fio < mmhg), and/or hypercapnia. duration of prone positioning should be more than h, and the termination of prone positioning should be based on the response of oxygenation, lung mechanics, and hemodynamics. because prone positioning could improve lung inhomogeneity, early prone positioning should be provided for covid- infected patients with/without respiratory failure [ , ] since it could prevent respiratory failure. since covid- is highly infectious, implementation of the prone positioning might require more manpower, thus further increasing the workload of medical personnel. pressure injury of the skin and mucous, facial edema, corneal edema, displacement of the catheter, and airway obstruction must be avoided when placing patients in the prone position. most of the covid- patients presented with mild symptoms; however, about % of patients developed into severe cases, % of them were critically ill with mortality estimates of . − . % [ ] [ ] [ ] . mechanical ventilation alone may not be enough to resolve refractory hypoxemia and hypercapnia in these patients. ecmo could be initiated to maintain oxygenation and avoid ventilator-induced lung injury. a cross-sectional study found that ( . %) patients treated with ecmo [ ] . we recommend an early use of ecmo in covid- patients with refractory hypoxemia or hypercapnia who have received invasive mechanical ventilation and prone positioning (grade +, strong recommendation). rationale the appropriate timing of ecmo in covid- patients might be challenging due to enormous demand and uncertainty related to the reversibility of impaired lungs. to guarantee the reversibility of compromised lungs, ecmo should be launched before injurious mechanical ventilation, which is common in critically ill patients with covid- [ , ] . the primary purpose of ecmo is the maintenance of sufficient oxygenation, removal of co , avoidance of high respiratory drive, and sequencing of ventilator-induced lung injury. the following traditional indications for ecmo may be suitable for covid- patients: pao /fio < for over h; pao / fio < for over h; irreversible ph < . for over h. the experts suggest using the traditional indications for ecmo in hospitals with sufficient medical resources. however, for areas with poor medical resources, the indications for ecmo are suggested to be balanced between the available resources and expected outcomes (expert opinion). the who guidance released a statement, in which they suggest referring patients with refractory hypoxemia despite lung-protective ventilation to those settings with expertise in ecmo [ ] . the latest guidance document issued by elso also suggested that ecmo should be considered according to the standard management algorithm for ards in patients with viral lower respiratory tract infections [ ] . however, in reality, numerous patients who met the criteria for ecmo were admitted over a short period, which was beyond the capacity of the medical resource, including workforce and equipment. in this context, the priority of the ecmo supply should be balanced between the available medical resources and disease reversibility. younger patients with minor or no comorbidities should be given the highest priority when resources are limited. despite standard contradictions, patients who fit the criteria below may be excluded: ( ) patients with significant comorbidities; ( ) elderly patients with worsening prognosis; ( ) patients on mechanical ventilation for more than days. prone position, as well as other adjunct therapies should probably be used for critically ill patients even during ecmo (grade +, weak recommendation). rationale ventilation with the prone position, which is currently recommended by the guidelines, can improve lung heterogeneity as well as oxygenation [ ] . it should be considered in the early stages of the disease rather than as a delayed attempt [ ] . prone position ventilation is currently widely applied for severe covid- patients in china [ ] . even if an ultraprotective ventilation strategy is implemented with the aid of ecmo, prone ventilation is considered to benefit the recovery of the lung. elevated myocardial enzymes, such as cardiac troponin t (ctnt), creatine kinase (ck), creatine kinase-mb isoenzyme (ck-mb), have been widely observed in critically ill patients with the covid- , indicating potential myocardial injury. a significant elevation of myocardial enzymes often indicates a poor prognosis. most patients with elevated myocardial enzymes do not present compromised left ventricular systolic function (reduced ejection fraction) or abnormal electrocardiogram. left ventricular diastolic dysfunction or mild-to-moderate pulmonary arterial hypertension is common in some covid- patients. intensive hemodynamic monitoring should probably be considered for patients with hemodynamic instability. ecmo should probably be used for salvage therapy for patients with severe cardiac dysfunction (grade +, weak recommendation). rationale while sars-cov- and mers-cov share similar pathogenicity, it has been shown that mers-cov can induce acute myocarditis and heart failure [ ] . elevation of biomarkers of cardiac injury is common among critically ill patients with covid- and associated with a higher risk of in-hospital mortality [ , ] . reversible subclinical diastolic dysfunction without systolic impairment was observed in sars [ ] . comparable to sars, most covid- patients with elevated myocardial enzymes do not present compromised left ventricular systolic function. left ventricular diastolic dysfunction or mild-to-moderate pulmonary arterial hypertension have been commonly found in covid- patients. from our experience, tachycardia such as sinus tachycardia and atrial fibrillation were also common, while compensatory tachycardia was absent, even in patients with severe hypoxia or hemodynamic collapse. the exact mechanism of myocardial injury in covid- remains unknown. it has been suggested that direct myocardial injury is mediated via angiotensin converting enzyme (ace ). ace -dependent myocardial infection was observed in the murine model infected with sars-cov [ ] . one study published in n engl j med provides evidence that angiotensin-converting enzyme inhibitors (acei)/angiotensin receptor blockers (arb) medications in covid- patients did not show any association with increasing susceptibility to sars-cov- [ ] . in patients with hemodynamic instability, non-invasive or invasive monitoring, such as echocardiography or thermodilution methods, should probably be used to guide fluid therapy or administration of vasoactive agents. in patients with life-threatening cardiac dysfunction, extracorporeal life support might be salvage therapy. statement hypovolemia is common in critical covid- patients, easy-to-implement parameters should probably be considered for the assessment of the patient's volumetric status (grade +, weak recommendation). rationale the use of vasoactive drugs revealed that the incidence of shock in critically covid- patients was %, and % in non-survivor population [ ] . the shock could be the result of hypovolemia, cardiac injury, and sepsis. fever and mouth breathing could cause large amounts of fluid loss in critical covid- patients, while decreased water intake, acute gastrointestinal injury, depression, intubation, and sedation could exacerbate hypovolemia. previous studies reported on the relationship between dehydration and mortality in severe h n patients [ ] . moreover, older age, comorbidities (especially diabetes and cardiovascular disease), lower lymphocyte count, and higher d-dimer levels were identified as risk factors associated with shock [ , ] . cardiac injury was found in % critical covid- patients [ ] , which meant poor fluid responsiveness and the risk of pulmonary edema. for these reasons, the patients' volumetric status, as well as the fluid responsiveness, should be dynamically assessed. one meta-analysis of rcts showed that dynamic assessment of fluid responsiveness could improve the clinically relevant outcomes in icu, such as mortality reduction, reduced duration of icu length of stay, and mechanical ventilation [ ] . considering the limited clinical resources in the covid- pandemic, we recommend using simple bedside assessments, such as passive leg raising (plr), lactate clearance, pulse pressure variation (ppv), and inferior vena cava (ivc) collapsibility or distensibility. a recent meta-analysis determined that the plr induced changes in cardiac output, with a pooled sensitivity of . and a pooled specificity of . [ ] . ppv also accurately predicted fluid responsiveness in critical patients. in a meta-analysis including studies and patients, ppv predicted fluid responsiveness with the pooled sensitivity of . and a pooled specificity of . [ ] . ivc collapsibility resulted as a simple, non-invasive bedside predictor of fluid responsiveness with a sensitivity of . and a specificity of . [ ] . early lactate clearance-directed therapy was associated with reduced in-hospital mortality, shorter duration of mechanical ventilation, and shorter icu-stay [ ] . a recent observational study showed higher serum lactate levels in covid- non-survivors ( . vs. . mm/l) [ ] . besides, additional attention should also be paid to mental states, degree of thirst, oliguria, skin temperature, and prolonged capillary refilling time as well. conservative fluid strategy should probably be considered for covid- patients with ards while ensuring tissue perfusion (grade +, weak recommendation). rationale even though fluid management in covid- remains unknown, it could be assumed that these patients would respond to fluid therapy in the same way as other ards patients. previous studies have shown that higher cumulative fluid balance is related to the higher mortality of critically ill patients, especially in cases of ards [ ] and/or septic shock [ ] . due to pulmonary edema in critical covid- patients [ ] , excessive fluid therapy could increase extravascular lung water and affect gas exchange, resulting in a poor prognosis. one clinical trial found that the conservative fluid strategy improved lung function, shortened the icu-stay length and duration of mechanical ventilation compared with a liberal strategy in patients with acute lung injury [ ] . another study reported that more than half of critically covid- patients were older than years [ ] . when older patients develop cardiac injury and pulmonary edema, they tend to be less responsive to fluid intake [ ] . conservative fluid strategies could reduce the occurrence of positive fluid balance while ensuring tissue perfusion [ ] . although it has been reported that conservative fluid strategy and liberal strategy have a similar incidence of aki and the requirement for renal replacement therapy (rrt) [ ] , it is still necessary to closely monitor the renal function of patients. at the same time, attention should be paid to maintaining electrolyte balance and acid-base balance. rationale to date, there are still no studies on fluid types in covid- patients; thus, our observations are based on relevant studies of critically ill patients in general. a systematic review of studies that included , participants revealed that using colloids (such as starches, dextrans, albumin or fresh frozen plasma, or gelatins) had no difference in mortality in critically ill patients compared to crystalloids [ ] . considering the price and accessibility, fluid resuscitation with crystalloids should probably be used for critically ill patients. one single-center research reported that low serum albumin ( . ± . g/l) was associated with the progression of covid- pneumonia [ ] , while another study found no significant differences between the nonaggravation and aggravation patients in the early stage of the disease [ ] . serum albumin level < g/l was identified as an independent risk factor for the -day mortality in patients with community-onset pneumonia [ ] . based on the previous evidence and our clinical observations, hypoproteinemia is present in most covid- patients; thus, albumin supplement should probably be used for patients with serum albumin levels below g/l. statement psychological and humanistic care should probably be considered for conscious patients with covid- (grade +, weak recommendation). rationale besides experiencing physical impairment and stressful treatments, covid- patients are being subjected to closing monitoring, and are also witnessing various events in the ward such as sudden deterioration of illness, emergency resuscitation procedures and death, all of which could lead to posttraumatic stress disorder, anxiety, and depression according to previous studies [ , ] . it was reported that % to % of sars survivors had symptoms related to posttraumatic stress disorder, anxiety, and depression and that emotional support, such as communication with others and sharing worries could reduce symptom severity [ ] . accordingly, psychological implications should not be ignored in coronavirus patients. psychological health services and humanistic care could have an important role in rehabilitation. the previous study confirmed that citalopram could improve reappraisal ability and anxiety symptoms in children and adolescents [ ] and that olanzapine could improve psychotic symptoms [ ] . therefore, citalopram or olanzapine should probably be used to improve the psychological symptoms in patients or intervention of the psychologists in the isolation ward who would perform psychological assessment and psychotherapy for patients with new coronary pneumonia. the experts suggest assessing patients' sleep quality, implementing comprehensive measures to improve sleep and reduce the incidence of delirium, thus promoting recovery (expert opinion). nonpharmacological strategies and pharmacotherapy, including dexmedetomidine and melatonin, should probably be considered to decrease the incidence of delirium (grade +, weak recommendation). rationale sleep abnormalities, including abnormal sleep architecture, sleep deprivation, and disruption, frequently occur in the icu. numerous factors can affect sleep in covid- patients, such as stress, anxiety, pain, respiratory distress, tachypnea from the underlying hypoxemia, noise levels, stage lighting in the isolation ward, implementation of healthcare, procedures of healthcare workers, and the pathophysiology of the acute illness. sleep abnormalities may not only lead to mental disorders, but could also damage tissue repair, immune regulation mechanisms and cause delirium, all of which are associated with patient's poor prognosis [ , ] . nonpharmacological strategies for preventing sleep disturbances and treating delirium, such as keeping noise levels within and db range (a) during the day, and less than db (a) at night [ , ] , and providing critical patients admitted to the icu with earplugs can significantly improve patient's sleep and reduce the risk of delirium [ ] . however, in patients with sleep disturbances and delirium, pharmacotherapy care may be necessary. medications such as dexmedetomidine [ ] and melatonin [ , ] may promote sleep and decrease the incidence of delirium, although only limited data are available in support of their use [ ] . assessing pain and preferential use of analgesia over sedation should probably be considered for covid- patients (grade +, weak recommendation). rationale pain is defined as an uncomfortable physical and mental experience caused by physical injury, inflammation, or emotional stimuli. covid- patients tend to experience pain due to hypoxia, long-term immobility, inflammatory storm, impairment of heart, liver, kidney, and other organ functions, procedures, and mental stress. opioids, such as remifentanil and sufentanil, are the firstline options for analgesia in icu according to the pain, agitation/sedation, delirium, immobility, and sleep disruption (padis) guidelines [ ] . sufentanil can be used for covid- patients receiving invasive mechanical ventilation during the early stage of severe ards because of its stronger and faster onset of analgesia, and small accumulation [ ] . remifentanil is suitable for covid- patients receiving invasive mechanical ventilation, especially during person-ventilator confrontation [ ] due to stronger respiratory depression. previous research has confirmed that music or relaxation may diminish anxiety and discomfort in some patients [ , ] . therefore, nonpharmacological pain management strategy can be used for conscious patients with covid- or for patients who do not tolerate opioid therapy, such as covid- patients receiving hfnc oxygen therapy or non-invasive mechanical ventilation. assessment of the patient's pain is the foundation of pain management. accordingly, a numeric rating scale (nrs) should probably be used for evaluation of pain in all covid- patients able to self-report their pain. behavioral pain scale (bps) and critical-care pain observation tool (cpot) should be used to evaluate pain in critically ill patients unable to express the pain for themselves. the ideal target values are: nrs < points, bps < points and cpot < points. deep sedation should be performed for patients with severe ards, especially those receiving invasive mechanical ventilation, prone position, neuromuscular blockade, or ecmo treatment (grade +, strong recommendation). rationale it is well known that analgesia and sedation can eliminate pain and discomfort, reduce sympathetic nerve excitement, patient's metabolic rate, oxygen consumption, the metabolic burden of various organs, stress, and inflammation. however, plenty of evidence suggests that deep sedation is associated with adverse outcomes, including prolonged mechanical ventilation and icu-stay, higher mortality, lower rates of in-hospital, and -year follow-up survival [ ] [ ] [ ] [ ] [ ] . under 'real-life' conditions in wuhan, deep sedation was extremely important for reducing oxygen consumption and developing tolerance to mechanical ventilation by new coronavirus patients with severe ards who suffered from respiratory distress, tachypnea and respiratory overdrive even after receiving invasive mechanical ventilation. accordingly, deep sedation should be an important part of lung-protective ventilation strategy, especially during the early stage of severe ards. previous studies have confirmed that daily spontaneous awakening trials (interruption of sedatives) lead to better outcomes in patients receiving mechanical ventilation [ ] . however, critically ill patients with covid- have a longer mechanical ventilation time, and daily sedatives interruption is not suggested for patients receiving deep sedation in order to reduce lung damage during early stage of severe ards. midazolam and propofol are the primary medications used for icu deep sedation. the sedation-agitation scale (sas) and rass are the reliable and valid sedation assessment tools used for assessing the depth and quality of sedation in covid- patients. the sas and rass should be used to measure the depth after administering sedatives. the target value is rass - - points, sas points for deep sedation, and sas point. the target value of very deep sedation is rass - point for patients receiving neuromuscular blocking agents [ ] , prone position, or ecmo treatment. we suggest a bispectral index monitoring for patients undergoing very deep sedation, if available. light sedation is suggested for severe covid- patients receiving hfnc oxygen therapy and non-invasive mechanical ventilation, and also for critically ill patients in the recovering stage (expert opinion). rationale agitation and anxiety, which frequently occur in covid- patients, may be associated with adverse outcomes. appropriate sedation can reduce anxiety and agitation while preserving patients' comfort. light sedation can maintain frequent redirection, and increase the physiologic stress response, but not increase the incidence of myocardial ischemia. we suggest the use of light sedation for covid- patients receiving hfnc oxygen therapy or non-invasive mechanical ventilation. in addition, light sedation should be given to recovering patients in order to reduce the time of mechanical ventilation and the time of stay in icu [ ] when pao / fio ≥ - mmhg. dexmedetomidine can be used for patients receiving light sedation due to the small respiratory depression. the target value of light sedation is sas - points and rass − to + points. there is some evidence that immunotherapy may be effective against novel coronavirus infection. an article [ ] published on the medrixv website stated that the mortality of covid- patients might be negatively related to the number of lymphocytes in patients. patients tend to be below normal levels and lower level of helper t cells in the severe group. the percentage of naïve helper t cells increased, and memory helper t cells decreased in severe cases. this suggested that novel coronavirus might fight the immune system; thus, early lymphocytes and t lymphoid subgroups testing are required for early intervention, which may help to avoid lymphocyte depletion. currently, there are several available immunomodulatory drugs, including glucocorticoid, thymosin, and immunoglobulin. statement systemic corticosteroids should probably not be used for the treatment of covid- . for critically ill patients with ards at an early stage, corticosteroids should probably be prudently used at a low or moderate dose over the short course if there are no contraindications (grade -, weak recommendation). rationale glucocorticoid use in ards remains a controversial topic. it is well known that corticoids are beneficial in the treatment of ards since they can alleviate inflammatory response and delay fibrosis [ ] . a retrospective study conducted in guangzhou revealed that proper use of corticosteroids in confirmed critical sars patients led to lower mortality and shorter hospitalization stay and was not associated with significant secondary lower respiratory infections or any other complications [ ] . however, there are some inconsistencies in the existing studies. a study involving patients with ards, showed improved oxygenation and lung injury score in less than h but no change in -day mortality [ ] . another study found no differences in overall mortality, while mortality was increased when steroids were started after day [ ] . as for viral pneumonia, a few studies have found that the administration of corticosteroids in patients with influenza pneumonia is associated with increased icu mortality [ , ] . who does not recommend routine use of corticoids in the treatment of covid- , while treatment with methylprednisolone may be beneficial for patients who develop ards, as was shown by a retrospective cohort study of patients with confirmed covid- pneumonia admitted to wuhan jinyintan hospital in china [ ] . given the inconclusive evidence and urgent clinical demand, the guidance published by china national health commission on march , , suggested the use of glucocorticoids over the short time period ( to days) for patients with progressive deterioration of oxygenation indicators, rapid imaging progress, and excessive activation of inflammatory response. the dosage of methylprednisolone should not exceed - mg/kg/day. it should be noted that large doses of glucocorticoid might delay the removal of coronavirus due to immunosuppressive effects. thymosin is a peptide originally isolated from thymic tissue, which was initially selected for its ability to restore immune function to thymectomized mice. thymosin may act on precursor t cells to increase the number of activated t helper cells and expression of th -type cytokines such as interleukin- and interferon-alpha. the activated dcs and th cells then kill bacterial, fungal, or viral infections and lead to the stimulation of differentiation of specific b cells to antibody-producing plasma cells and an improvement in response to vaccines by stimulation of antibody production [ ] . the use of thymosin alpha therapy in combination with conventional medical therapies may be effective in improving clinical outcomes in a targeted population of severe sepsis [ ] . also, it has been observed that lower lymphocytes in covid- patients indicate worse prognosis [ ] . thus, thymosin may theoretically have an effect on covid- , which needs to be further investigated. immunoglobulin may regulate the host's immune response in a variety of ways, but it had no effect on mortality in previous sepsis studies. at present, it is not recommended in the treatment of covid- . a study performed in severe or critical covid- patients showed that tocilizumab treatment could improve clinical outcomes, promote absorption of lung lesions, improve immune function, and reduce inflammatory response [ ] . however, il- inhibitor sarilumab was shown to be ineffective in the treatment of severe covid- , leading to early termination of this clinical trial [ ] . large sample size studies using prospective cohort designs are required to verify the therapeutic effect of il- inhibitors for severe covid- . great attention should be paid to secondary infection since it may worsen the patient's prognosis. however, since the data on the epidemiology of secondary infection in covid- patients are lacking, we can only make some suggestions according to our own experience and some previous studies focused on h n . the experts suggest against using prophylactic antibiotics for covid- patients (expert opinion). rationale due to the nature of virus infection, it is not logical to use prophylactic antibiotics, and there is no evidence that this strategy could reduce the incidence of the secondary infection. on the other hand, according to the management guidelines of covid- from who and china [ , ] , empiric antibiotic treatment should only be used based on the clinical diagnosis (communityacquired pneumonia, healthcare-associated pneumonia or sepsis), local epidemiology and susceptibility data, and treatment guidelines. based on our observations from wuhan, many severe and critical covid- patients did not show any signs of bacterial infection (such as elevated wbc, pct and similar); thus, we do not suggest the routine use of prophylactic antibiotics in covid- patients, especially at the early stage or for non-intubated patients. the experts suggest closely monitoring the signs of secondary infection, especially in critically ill patients with covid- who have been admitted to icu > h (expert opinion). rationale both long course of the disease and immunosuppressive state place the severe and critical covid- patients at a high risk of secondary infection (including bacteria and fungus). unfortunately, the data on the epidemiology of secondary infection in covid- patients are lacking. however, based on the evidence from h n , secondary infection is very common in patients admitted to icu > h [ , ] . although a complete nosocomial infection prevention and control system was set up in wuhan according to the guidelines [ , ] , ventilator-associated pneumonia and hospital acquired pneumonia were very common occurrences in the icu. we suspect this is mainly because the medical staff is wearing heavy personal protective equipment, and heavy workload adhered to the incomplete implementation of these measures. consequently, the strategies for nosocomial infection prevention should be effectively implemented, and multiple site samples (blood, sputum, etc.) should be routinely collected to monitor the signs of secondary infection. in clinical practice, coagulation dysfunction is commonly found in covid- patients, and the symptoms range from mild disorders of coagulation indicators to disseminated intravascular coagulation (dic). the exact etiology of covid- -associated coagulopathy is unclear, diverse and multifactorial, and may include direct attack by the sars-cov- on vascular endothelial cells, cytokine storm-mediated inflammation-coagulation cascades, hypoxia, and complication with sepsis. coagulation dysfunction or thrombocytopenia is closely associated with the severity and poor prognosis in covid- patients [ ] . clinicians should increase awareness of covid- -associated coagulopathy, which in covid- patients is accompanied with the following abnormal coagulation indexes: platelet-lymphocyte ratio < × , the reduction of prothrombin time (pt) and activated partial thromboplastin time (aptt) by more than the lower limit of th percentile or the increase of pt by more than s or aptt by more than s, or the increase of fibrinogen, fibrin degradation product (fdp) and d-dimer by more than the lower limit of th percentile without clinical evidence of primary blood system diseases or chronic liver diseases. routinely assessing the coagulation dysfunction on admission and dynamically monitored thereafter should probably be performed to identify covid- -associated coagulopathy as early as possible (grade +, weak recommendation). rationale according to the available literature, the condition of covid- patients is commonly complicated with coagulopathy, where the symptoms range from mild disorders of coagulation indicators to dic. the increase of d-dimer in covid- patients is very common, accounting for % to . % of all cases [ , , , , ] . the degree of elevation and persistent elevation are indicators of poor prognosis. the nanshan zhong team has reported that among covid- patients in hospitals from provinces ( mild cases and severe cases), the proportion of severely ill patients with d- dimer higher than . mg/l was up to . %, and the proportion for the mild patients was . % [ ] . zhou et al. have demonstrated that among confirmed covid- patients ( deaths, survival), d-dimer > . g/l was an independent risk factor for clinicians to identify patients with poor prognosis at the early stage [ ] . the coagulation parameters (pt and aptt) in covid- patients vary with different severity and the different courses of the disease. covid- patients in the early stage show the activation of the exogenous coagulation system, manifested as decreased pt and hypercoagulable state. along with the progression of the disease, especially when patients develop dic, pt and aptt significantly increase, which is associated with the poor prognosis of patients. tang has reported increased fibrinogen ( . g/l vs. . g/l, p = . ) and fdp values ( . µg/ml vs. µg/ml, p < . ) in covid- patients [ ] , which indicated that instead of hyperfibrinolysis observed in the late stage of dic, fibrinolysis inhibition is the main feature accompanying the progression of covid- . the autopsies of covid- patients have revealed abundant transparent thrombus in the pulmonary alveoli, myocardium, portal area, and renal tubular epithelial cells, thus indicating that fibrinolysis inhibition may have a decisive role in covid- -associated coagulation dysfunction. the incidence of dic is low in covid- patients. it has been reported that among the covid- patients, only patient ( . %) was diagnosed as dic [ ] . however, tang's report has shown that the overall incidence of dic is . %. the existence of dic was more common in fatal cases, where . % met the isth diagnostic criteria for dic; the median time for dic diagnosis after admission was days, whereas among the patients who survived, only patient ( . %) met this criterion [ ] . medical institutes should dynamically detect the pt, international normalized ratio (inr), aptt, d-dimer, fibrinogen, and fdp to identify covid- -associated coagulation disorders, which might be helpful for making timely treatment decisions. it is also suggested to use the isth score system to diagnose covid- -associated dic [ ] ; if possible, sf and pai- should be used to detect the pre-dic status in the shortest possible time. routinely evaluating the risk of venous thromboembolism (vte) and hemorrhage should probably be performed in covid- patients. for critically ill covid- patients with low hemorrhage risk, subcutaneous injection of low molecular weight heparin (lmwh) should probably be used for preventing vte (grade +, weak recommendation). rationale the most common clinical features of coagulopathy in covid- patients are thrombosis in the deep vein or intermuscular vein of the lower extremity, which can be identified by the coagulation parameters and ultrasonic monitoring. it has been reported that the incidence of vte or thrombotic complications in patients with severe covid- admitted in the icu was - % [ , ] . it is necessary to pay attention to the clinical observation of patients with bed rest lasting for more than days and observe whether these patients are experiencing asymmetric pain, swelling or discomfort in unilateral lower limbs or bilateral lower limbs, or local swelling or superficial vein filling in the lateral limbs. especially when patients show chest pain, hemoptysis, dyspnea, or hypoxemia, which cannot be explained by ncp or other basal diseases, we should be alert to the occurrence of pulmonary thromboembolism. for critically ill covid- patients with low hemorrhage risk, a subcutaneous injection of lmwh should probably be used for the prevention of vte. for patients with severe renal dysfunction (creatinine clearance rate < ml/min), unfractionated heparin is recommended. for critically ill patients whose condition is complicated with high hemorrhage risk, intermittent pneumatic compression is recommended for mechanical prevention. mild or moderate covid- patients should probably avoid sedentary lifestyle or dehydration and are encouraged to engage in active activities and to drink more water appropriately. for mild or moderate covid- patients with a high or moderately high risk of vte according to the padua or caprini evaluation model, it should probably be considered to use lmwh for to days until the elimination of risk factors. anticoagulation therapy should probably be used for patients with hypercoagulant state without bleeding risk. lmwh or unfractionated heparin should probably be considered to be the first choice (grade +, weak recommendation). rationale hypercoagulant state is common in covid- patients. meantime, cytokine storm-mediated inflammation-coagulation cascades may have an essential role in covid- -associated coagulopathy. studies have found that in addition to the anticoagulant effect, heparin also has a certain anti-inflammatory effect [ ] . therefore, lmwh or unfractionated heparin is the first choice for anticoagulation: tang et al. have reported that lmwh or unfractionated heparin anticoagulation was associated with improved survival in the patients with a sepsis-induced coagulopathy (sic) score ≥ and in those with d-dimer levels more than times of the upper limit of normal(≥ mg/l) [ ] . it is suggested that lmwh u/kg or unfractionated heparin units subcutaneously twice daily could be given to patients without contraindication once d-dimer ≥ mg/l or sic ≥ . heparin-induced thrombocytopenia (hit) should be prevented during heparin treatment, and platelet counting should be monitored daily. for patients with hit, other anticoagulants, such as agatraban, bevaludine, fondaparinux, and rivaroxaban, could be used. for patients at high risk of bleeding, anticoagulants are not recommend, and chinese traditional medicine could be used to improve blood circulation and dispersing stasis. although diffuse alveolar damage and ards are the main features of covid- , the involvement of the kidney and other organs needs to be considered. aki was associated with a higher risk of in-hospital mortality. clinicians should increase awareness of aki in hospitalized covid- patients. kidney disease: improving global outcomes (kdigo) criteria should probably be used for the diagnosis of aki in covid- patients. measuring serum creatinine every days should probably be performed to avoid a missed diagnosis of aki (grade +, weak recommendation). rationale the incidence of aki in covid- patients varies with different severity of illness: mild cases have an aki incidence of . - %, severe cases have an aki incidence of - . %, and the aki incidence for those critical cases that require to be admitted in icu is up to . - % [ , , , , ] . according to kdigo aki diagnostic criteria, certifying aki is mainly based on changes in scr, and the frequency of scr tests has a substantial impact on the detection rate of aki. in a nationwide cross-sectional survey of hospitalized adult patients in china, the detection rate of aki was only . % by kdigo criteria [ ] . after adjusting for the frequency of scr, the incidence of aki in chinese hospitalized adults rose to . % [ ] . thus, in order to improve early recognition of aki, scr measurements should be performed more frequently throughout the course of the disease. it is necessary to measure scr every days throughout the course of the disease to avoid a missed diagnosis of aki. the experts suggest using standard aki care bundle ( r principle) for covid- -associated aki (expert opinion). rationale the exact pathogenesis of covid- associated aki is unclear. the etiology of kidney impairment in covid- patients, which is likely to be diverse and multifactorial, may include direct attack by the sars-cov- on target cells in the kidney, immune systemmediated damage, disease-related prerenal factors, a complication with sepsis and nephrotoxic drug-related factors [ , ] . covid- associated aki is an independent risk factor for poor prognosis in patients. clinicians should address standard aki following r principle (risk screen, recognition in the early phase, response in time, renal replacement therapy, and rehabilitation of the kidney). aki is significantly more likely to develop in severe covid- patients than in nonsevere patients [ , , , , ] . meanwhile, studies have shown that patients with elevated baseline scr are more likely to develop aki and develop more severe aki [ ] . therefore, we should routinely screen the risk of aki in covid - patients, particularly for severe cases, patients with elevated baseline scr or those having proteinuria and hematuria at admission. optimizing the volume status and oxygenation, maintaining hemodynamic stability, making sure the mean blood pressure above mmhg are the important measures for prevention and treatment of aki. the experts suggest using crrt for the critical cases accompanied by kidgo aki - stages, or cytokine storm syndrome (expert opinion). rationale according to the available literature [ , , , , ] , the percentage of covid- patients who require continuous renal replacement therapy (crrt) is . - %, and particularly the percentage of critical patients admitted in icu that requires crrt is . - . %. indications of the crrt in covid- patients include renal indications and non-renal indications. renal indications include severe aki (kidgo aki - stages) with hemodynamic instability. non-renal indications include complications with severe ards and persistent inflammatory fever, which cannot be controlled not even with glucocorticoid corticosteroid therapy, hypernatremia refractory to conservative medical treatment, volume overload or urine output, which cannot meet the needs of drug infusion and energy supply and diuretic resistance. multiple rct research has indicated that the application of crrt in critical patients in an early phase cannot effectively decrease the mortality rates [ , ] . however, considering the suggestion that restrictive fluid volume management strategy should be adopted for covid- patients complicated by ards based on the premise of sufficient tissue perfusion, we suggest crrt initiation in severe patients within h when they show rank aki under kdigo criteria or accompanied with cytokine storm syndrome. in clinical practice, the doctors in charge should comprehensively evaluate conditions including the covid- patient's level of systemic inflammation, severity and progress of illness, severity, and progress of aki, local medical resources, and the qualification of blood purification operators to give a reasonable choice of crrt application. statement crrt prescription is suggested to be target-oriented based on the patient's condition (expert opinion). rational crrt prescription should be prescribed before the application of crrt on patients, and the prescription must be target-oriented. continuous venovenous hemofiltration (cvvh) global surveillance for human infection with coronavirus disease (covid- ) world health organization. coronavirus disease (covid- ) situation reports clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspected the novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- )-china clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study national health commission & state administration of traditional chinese medicine. diagnosis and treatment protocol for novel coronavirus pneumonia practical recommendations for critical care and anesthesiology teams caring for novel coronavirus ( -ncov) patients world health organization, five moments for hand hygiene world health organization, infection prevention and control during health care when covid- is suspected covid- ) outbreak: rights, roles and responsibilities of health workers, including key considerations for occupational safety and health handbook of covid- prevention and treatment surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ). intensive care med world health organization, rational use of personal protective equipment (ppe) for coronavirus disease (covid- ) control measures for severe acute respiratory syndrome (sars) in taiwan clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review guideline of prevention and control of novel coronavirus infection within medical facilities chinese society of anesthesiology task force on airway management: expert recommendations for tracheal intubation in critically ill patients with novel coronavirus disease videolaryngoscopy versus direct laryngoscopy for adult patients requiring tracheal intubation: a cochrane systematic review interim infection prevention and control recommendations for patients with suspected or confirmed coronavirus disease (covid- ) in healthcare settings recommendations for bronchoscopy procedures in severe covid- patients clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in covid- patients with at least a six-day follow up: a pilot observational study effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus (sars-cov- ) infection: a randomized clinical trial a trial of lopinavirritonavir in adults hospitalized with severe covid- arbidol monotherapy is superior to lopinavir/ritonavir in treating covid- compassionate use of remdesivir for patients with severe covid- remdesivir in adults with severe covid- : a randomised, double-blind, placebocontrolled, multicentre trial compassionate use of remdesivir for patients with severe covid- announces approval of veklury ® (remdesivir) in japan for patients with severe covid- the convalescent sera option for containing covid- meta-analysis: convalescent blood products for spanish influenza pneumonia: a future h n treatment? use of convalescent plasma therapy in sars patients in hong kong convalescent plasma treatment reduced mortality in patients with severe pandemic influenza a (h n ) virus infection challenges of convalescent plasma infusion therapy in middle east respiratory coronavirus infection: a single centre experience treatment of critically ill patients with covid- with convalescent plasma effectiveness of convalescent plasma therapy in severe covid- patients convalescent plasma: new evidence for an old therapeutic tool? treatment of acute hypoxemic nonhypercapnic respiratory insufficiency with continuous positive airway pressure delivered by a face mask: a randomized controlled trial high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure noninvasive ventilation of patients with ards: insights from the lung safe study role of noninvasive ventilation in acute lung injury/acute respiratory distress syndrome: a proportion meta-analysis timing of intubation and clinical outcomes in adults with acute respiratory distress syndrome failure of noninvasive ventilation for de novo acute hypoxemic respiratory failure: role of tidal volume an index combining respiratory rate and oxygenation to predict outcome of nasal high-flow therapy a high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome driving pressure and survival in the acute respiratory distress syndrome recruitment manoeuvres for adults with acute respiratory distress syndrome receiving mechanical ventilation lung recruitability in sars-cov- associated acute respiratory distress syndrome: a singlecenter, observational study potential for lung recruitment estimated by the recruitment-to-inflation ratio in acute respiratory distress syndrome effects of positive end-expiratory pressure on regional distribution of tidal volume and recruitment in adult respiratory distress syndrome open lung approach for the acute respiratory distress syndrome: a pilot. randomized controlled trial prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis clinical studies of tracheal gas insufflation prone position ameliorates lung elastance and increases functional residual capacity independently from lung recruitment prone positioning and neuromuscular blocking agents are part of standard care in severe ards patients: yes protecting the right ventricle in ards: the role of prone ventilation prone positioning in severe acute respiratory distress syndrome coronavirus disease (covid- ) situation reports clinical characteristics of coronavirus disease in china characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china summary of a report of cases from the chinese center for disease control and prevention patients with covid- in icus in wuhan, china: a cross-sectional study clinical features of patients infected with novel coronavirus in wuhan epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study elso guidance document: use of ecmo in covid- patients during the pandemic an official american thoracic society/european society of intensive care medicine/society of critical care medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome intubation and ventilation amid the covid- outbreak acute myocarditis associated with novel middle east respiratory syndrome coronavirus association of cardiac injury with mortality in hospitalized patients with covid- in wuhan, china left ventricular performance in patients with severe acute respiratory syndrome: a -day echocardiographic follow-up study sars-coronavirus modulation of myocardial ace expression and inflammation in patients with sars renin-angiotensin-aldosterone system blockers and the risk of covid- mortality and severity evaluation by routine pneumonia prediction models among japanese patients with pandemic influenza a (h n ) pneumonia clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china. intensive care med incorporating dynamic assessment of fluid responsiveness into goal-directed therapy: a systematic review and meta-analysis passive leg raising for predicting fluid responsiveness: a systematic review and meta-analysis does pulse pressure variation predict fluid responsiveness in critically ill patients? a systematic review and meta-analysis diagnostic accuracy of the inferior vena cava collapsibility to predict fluid responsiveness in spontaneously breathing patients with sepsis and acute circulatory failure relative efficacy and safety of early lactate clearance-guided therapy resuscitation in patients with sepsis: a meta-analysis extravascular lung water is an independent prognostic factor in patients with acute respiratory distress syndrome sepsis in european intensive care units: results of the soap study pathological findings of covid- associated with acute respiratory distress syndrome comparison of two fluid-management strategies in acute lung injury colloids versus crystalloids for fluid resuscitation in critically ill people analysis of factors associated with disease outcomes in hospitalized patients with novel coronavirus disease risk factors associated with disease progression in a cohort of patients infected with the novel coronavirus mortality in patients with community-onset pneumonia at low risk of drug-resistant pathogens: impact of β-lactam plus macrolide combination therapy posttraumatic stress, anxiety, and depression in survivors of severe acute respiratory syndrome (sars) stress and psychological distress among sars survivors year after the outbreak emotional reactivity and regulation following citalopram therapy in children and adolescents with anxiety disorders effect of continuing olanzapine vs placebo on relapse among patients with psychotic depression in remission: the stop-pd ii randomized clinical trial sleep in the intensive care unit sleep in intensive care unit: the role of environment effects of intensive care unit noise on patients: a study on coronary artery bypass graft surgery patients monitoring sound and light continuously in an intensive care unit patient room: a pilot study the efficacy of earplugs as a sleep hygiene strategy for reducing delirium in the icu: a systematic review and meta-analysis effect of dexmedetomidine added to standard care on ventilatorfree time in patients with agitated delirium: a randomized clinical trial melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial preventive effects of ramelteon on delirium: a randomized placebo-controlled trial melatonin, ramelteon, suvorexant, and dexmedetomidine to promote sleep and prevent delirium in critically ill patients: a narrative review with practical applications interpreting and implementing the pain, agitation/sedation, delirium, immobility, and sleep disruption clinical practice guideline sedation with sufentanil in patients receiving pressure support ventilation has no effects on respiration: a pilot study could remifentanil reduce duration of mechanical ventilation in comparison with other opioids for mechanically ventilated patients? a systematic review and meta-analysis the effect of music on discomfort experienced by intensive care unit patients during turning: a randomized cross-over study comparison of ice packs application and relaxation therapy in pain reduction during chest tube removal following cardiac surgery early deep sedation is associated with decreased in-hospital and two-year follow-up survival early goal-directed sedation versus standard sedation in mechanically ventilated critically ill patients: a pilot study sedation and delirium in the intensive care unit: an australian and new zealand perspective sedation depth and long-term mortality in mechanically ventilated critically ill adults: a prospective longitudinal multicentre cohort study early sedation and clinical outcomes of mechanically ventilated patients: a prospective multicenter cohort study efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (awakening and breathing controlled trial): a randomised controlled trial clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit a randomized trial of protocoldirected sedation management for mechanical ventilation in an australian intensive care unit mortality of covid- is associated with cellular immune function compared to immune function in chinese han population paralytics, sedation, and steroids in acute respiratory distress syndrome treatment of severe acute respiratory syndrome with glucosteroids: the guangzhou experience hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome corticosteroid treatment in critically ill patients with severe influenza pneumonia: a propensity score matching study corticosteroid treatment in critically ill patients with pandemic influenza a/h n infection: analytic strategy using propensity scores risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china immune modulation with thymosin alpha treatment the efficacy of thymosin alpha for severe sepsis (etass): a multicenter, single-blind, randomized and controlled trial effective treatment of severe covid- patients with tocilizumab phase / adaptive-designed trial in hospitalized covid- patients invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study management of adults with hospital-acquired and ventilatorassociated pneumonia: clinical practice guidelines by the infectious diseases society of america and the clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: update by the infectious diseases society of america thrombocytopenia and its association with mortality in patients with covid- clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia guidance for diagnosis and treatment of dic from harmonization of the recommendations from three guidelines prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia incidence of thrombotic complications in critically ill icu patients with covid- the role of heparin in sepsis: much more than just an anticoagulant anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy kidney impairment is associated with in-hospital death of covid- patients clinical characteristics of novel coronavirus infection in china acute kidney injury in china: a cross-sectional survey epidemiology and clinical correlates of aki in chinese hospitalized adults diagnosis and treatment of covid- : acute kidney injury cannot be ignored initiation strategies for renal-replacement therapy in the intensive care unit timing of renal-replacement therapy in patients with acute kidney injury and sepsis expert recommendation for novel coronavirus pneumonia patients with blood purification treatment chinese society for parenteral and enteral nutrition. recommendations for parenteral and enteral nutrition therapy in critically ill covid- patients espen guideline on clinical nutrition in the intensive care unit calorie intake of enteral nutrition and clinical outcomes in acutely critically ill patients: a meta-analysis of randomized controlled trial gudielines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of critical care medicine (sccm) and american society for parenteral and enteral nutrition clinical nutrition in critical care medicine-guideline of the german society for nutrition medicine(dgem) recommendations for nutrition therapy in critically ill covid- patients safe patient transport for covid- publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. all the authors have participated in literature retrieval, viewpoint discussion, and writing the manuscript. all authors read and approved the final manuscript. none. not applicable. not applicable. not applicable. the authors declare that they have no competing interests. key: cord- -rhm ii d authors: kraft, miquel; pellino, gianluca; jofra, mariona; sorribas, maria; solís-peña, alejandro; biondo, sebastiano; espín-basany, eloy title: incidence, features, outcome and impact on health system of de-novo abdominal surgical diseases in patients admitted with covid- date: - - journal: surgeon doi: . /j.surge. . . sha: doc_id: cord_uid: rhm ii d objective to assess the epidemiology and features of de novo surgical diseases in patients admitted with covid- , and their impact on patients and healthcare system. summary background data gastrointestinal involvement has been described in covid- ; however, no clear figures of incidence, epidemiology and economic impact exist for de-novo surgical diseases in hospitalized patients methods this is a prospective study including all patients admitted with confirmed sars-cov- rt-pcr, between march and may at two tertiary hospitals. patients with known surgical disease at admission were excluded. sub-analyses were performed with a consecutive group of covid- patients admitted during the study period, who did not require surgical consultation. results ten out of covid- positive patients ( . %) required surgical consultation. among those admitted in intensive care unit (icu) incidence was . %. mortality was % in patients requiring immediate surgery and % in those suitable for conservative management. the overall median length of stay(los) of patients admitted to icu was longer in those requiring surgical consultation compared with those who did not ( . vs days,p= . ). patients requiring surgical consultation and treatment for de-novo surgical disease had longer median icu-los ( . vs days, p= . ). a median of two post-surgical complications were registered for each patient undergoing surgery. complication-associated costs were as high as , usd per patient. conclusions incidence of de-novo surgical diseases is low in covid- , but it is associated with significant morbidity and mortality. future studies should elucidate the mechanism underlying the condition and identify strategies to prevent the need for surgery. the outbreak of severe acute respiratory syndrome coronavirus (sars-cov- ) was initially detected in wuhan, capital of hubei, province of china in december - as pneumonia of unknown origin. on january th the novel coronavirus was officially announced as the causative pathogen by the chinese centre for disease control and prevention and it was named coronavirus disease (covid- ) by the world health organization (who) in february of . on march th the who declared covid- a pandemic . currently, more than million people have been infected, with over . deaths . hospitalized patients requiring icu admission are calculated around a % . in relation to surgery, poorer outcomes are associated after surgery in covid- -positive patients. up to % of patients undergoing elective surgery during the covid- incubation period might need postoperative intensive care unit (icu) care, with a mortality rate of . % . hence, most surgical societies recommend conservative management of covid- positive patients presenting with some urgent surgical diseases , . covid- patients might develop de-novo surgical diseases during hospitalization, requiring surgical consultation and treatment. spain is currently the second most affected country in europe, following uk, with , confirmed cases and , death by the th july , . recent reports suggest that, in catalonia region, the toll of deaths related to covid- exceeded , cases, when fatalities based on data from funeral services are taken into account . reporting on the spanish experience could be useful at a time when some countries have not yet "flattened the curve" and new infection waves are predicted. this study aims to assess the epidemiology, features, economic burden and outcome of lateonset surgical diseases in patients treated for covid- in two catalan hospitals, one of the most affected regions in spain. univerity hospital and bellvitge university hospital. ethical committee approval was obtained. all hospital admitted patients, -years-old or older, with confirmed covid- were prospectively assessed for inclusion (march -may ). patients who required surgical consultation/review during admission were identified. patients who were admitted with a known surgical disease were not included, as well as patients without confirmed diagnosis of covid- . the primary endpoint was the incidence of late-onset surgical diseases in covid- positive patients, the associated morbidity and outcome. all complications occurring after consultation and any therapies by the surgical team were used as outcome measures. the secondary endpoints included mortality and the estimated costs associated with the complications. collected data included demographics, underlying comorbidities and medications, date of hospitalization and discharge, testing pathway and date, length of stay, length of icu stay, medical treatment received for covid- , date of surgical consultation, treatment received for the surgical condition, treatment results, surgical complications, mortality cause and date. in all patients included in the analysis, icu admission was needed for covid- . covid- diagnosis was confirmed by sars-cov- reverse transcriptase-polymerase chain reaction (rt-pcr) testing with throat and nasal swab samples. in some patients, a chest ct was initially performed , with posterior rt-pcr confirmation. consultation and treatment for the following surgical diseases during hospitalization were included: bowel ischemia and/or perforation, bowel obstruction, appendicitis, cholecystitis, pancreatitis, peritonitis, and additional disease of surgical interest. all surgical treatments were assessed, including watchful monitoring, medical therapy (e.g. the complication costs were determined by cci class for each procedure performed and patient age using the assesssurgery tool (assesssurgery.com). categorical data are presented as absolute numbers and percentages, whereas continuous variables are presented as median with ranges. a descriptive analysis was performed to report on the incidence and outcomes of de novo surgical diseases. the overall incidence was computed by determining the rate of patients requiring surgical consultation among the entire number of patients who were admitted for covid- at both centers in the study period. sub-analyses were performed to assess the los and outcomes in patients who needed icu stay in the group who developed de-novo surgical disease during admission vs. a consecutive group of covid- patients who did not require surgical consultation. for the control group, only patients with completely available data were considered. the fisher's exact test was used to compare categorical data, whereas the mann-whitney u test was used for continuous data. a p value < . was considered statistically significant. between march the st and may the th , patients were admitted with proven covid- with no signs or symptoms of abdominal surgical diseases at both hospitals; of which ( . %) required surgical consultation. one patient was excluded from the final analysis because a ct scan ruled out appendicitis and another because surgical consultation was required because of an iatrogenic injury. therefore, patients required surgical consultation and treatment, accounting for . % of admitted patients with covid- . when only patients already admitted to the icu were considered, the incidence was . % ( / ). out of patients who required consultation, four ( %, / ) were diagnosed with bowel ischemia and perforation, two ( %, / ) with acute cholecystitis, two ( %, / ) with acute pancreatitis, one ( %, / ) with perforated colon carcinoma, and one ( %, / ) with perforated diverticulitis. flowchart of patient selection is represented in figure . table . a median of ( - ) days passed between admission and surgical consultation. the reason for consultation is reported in table , along with therapeutic decisions and outcomes. out of four patients with bowel ischemia, this occurred in the right colon/terminal ileum in two ( %, / ), and at the transverse colon in one ( %, / ), whereas one patient had massive small bowel ischemia due to mesenteric arterial thrombosis that could not be treated by interventional radiology. the latter patient was offered palliative treatment, whereas the other three were operated on. overall, five patients had a bowel perforation, and all underwent open surgery with no anastomosis, because of clinical instability. one of them ( %, / ) died within hours from surgery because of multi-organic sepsis. one patient ( %, / ) with perforated colon cancer died after myocardial infarction, five weeks after surgery. two patients were diagnosed with acute cholecystitis and underwent cholecystostomy. two patients were diagnosed with acute pancreatitis, one of them with a -cm collection. watchful monitoring was decided, which proved successful, with clinical and radiological improvement in subsequent ct scans. the pathology report of the patient with the perforated colon cancer was consistent with a g , pt n adenocarcinoma with a % mucinous component. perforation and invasion of small vessels was found. in two of the three ischemic perforations, involvement of small and medium vessels was observed, and micro-thrombosis in one. thirteen complications occurred in the five patients who underwent surgery, with a median of two (range - ) complications per patient. these ranged from wound infection to multi-organ failure and death ( table ) . each patient developed at least one complication. the overall median los was . (range - ), the median los in icu was . ( - ) days. los and mortality of patients admitted to icu who required surgical consultation were compared with a consecutive group of patients who were admitted to icu for covid- and did not require surgical consultation. the overall median los of those admitted to icu was longer in those who required surgical consultation, being . overall, mortality was % ( / ). among those who needed immediate surgery, mortality was % ( / ) and % ( / ) in those suitable for conservative management. mortality in patients who required surgical consultation during their icu stay was . % ( / ), which was higher but not statistically different from mortality in the control group of patients who did not require surgical consultation ( . %, / , p= . ). overall, the costs associated with the surgical complications were as high as , usd, with median costs of , (range , - , ) usd for each operated patient. in this study, the overall incidence of de-novo surgical disease in hospitalized patients for covid- was . % in two tertiary hospitals during the peak phase of the pandemic, which increased to . % when only considering patients already admitted in icu for covid- . mortality in those who required surgery was twice as high as that previously reported in covid- patients presenting with abdominal diseases. the onset of de-novo surgical diseases negatively impacts on hospital resources, increasing the overall los and stay in icu, and postoperative complications, which are frequent in this group of patients. this significantly increases the care associated costs. previous studies on non-covid- patients reported that approximately - , % of patients in icu develop an icu-acquired abdominal sepsis . it has been suggested that late-onset abdominal sepsis accounts for % of all cases of abdominal sepsis in icu . we found that the incidence of abdominal complications not present at the time of admission is overall negligible in confirmed covid- -patients; however, in the subgroup of patients admitted to icu, the rate is higher. a study on critically-ill covid- patients, found that five needed surgery for abdominal conditions ( . %), mainly represented by bowel ischemia ; when only cases with no signs/symptoms of abdominal disease at admission are evaluated, the rate might be lower. gastrointestinal involvement is common in covid- patients in icu, and may be managed with conservative approach depending on the involved pathology and the diseases progression . involvement of small vessels and viral entero-neuropathy has been suggested to occur in covid- patients, and might be responsible for the relatively high number of patients with bowel ischemia and ileus . in our series, all patients with bowel perforation had involvement of small vessels at pathology, suggesting that the virus itself might be responsible for the condition rather than the treatments delivered. discussing care-associated cost might be useful, given the resource shortage that has been reported during the mitigation phase, and the backlog of procedures that need to be performed in the upcoming months . it has been estimated that covid- will cause . usd billion in direct costs in the us over the course of the pandemic should % of the population be infected . early predictions in spain suggested that , billion euros would be required to face the pandemic . mechanical ventilation is associated with incremented costs, which are already high in covid- patients. the first two days are usually the most expensive as mechanical ventilation is often needed, whereas costs become more stable from day of icu stay (mechanical ventilation, , usd; no mechanical ventilation, , usd) . in our series, the los in icu was in median almost weeks longer in patients with de novo surgical disease compared with patients who did not need surgical consultation (p= . ). this generate much higher costs than can be predicted, since -after surgery -patients may need prolonged use of ventilators. postoperative complications add to the aforementioned costs. a median of two complications per patient occurred in the patients who underwent surgery, meaning that the costs for each patient increased by approximately , usd. the relatively small sample size requires that findings are interpreted with caution. the cost estimates were approximated and might have been higher in the context of the pandemic. however, this study was conducted prospectively on patients from two of the larger tertiary centres in spain, with high volume of covid- patients treated. incidence could be reliably estimated, and the morbidity and complication-associated costs might be useful in managing patients with such presentation. the incidence of de-novo surgical disease is low in covid- , similar to non-covid- critically ill patients. however, clinical symptoms should be detected and surgical review obtained, due to unacceptably high associated morbidity and mortality. surgical treatment prolongs admission in icu and increases costs of care. conservative treatment is a safe option, when possible. future studies should elucidate the mechanism underlying the condition, e.g. hypercoagulability and thrombo-inflammation in covid- patients [ ] [ ] [ ] , and identify strategies to prevent the need for surgery. j o u r n a l p r e -p r o o f outbreak of pneumonia of unknown etiology inwuhan china: the mystery and the miracle the continuing -ncov epidemic threat of novel coronaviruses to global health: the latest novel coronavirus outbreak inwuhan, china clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china a cluster of the corona virus disease caused by incubation period transmission in wuxi clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study world health organisation. who director general's opening remarks at the media briefing on covid- - the covid- dashboard the royal college of surgeons of edinburgh. clinical guide for the management of surgical patients during the coronavirus pandemic situación de covid- en españa". (date accessed coronavirus en catalunya: última hora del número de casos correlation of chest ct and rt-pcr testing in coronavirus disease (covid- ) in china: a report of cases classification of surgical complications: a new proposal with evaluation in a cohort of patients and results of a survey the comprehensive complication index: a novel continuous scale to measure surgical morbidity sepsis in intensive care unit patients: worldwide data from the intensive care over nations audit abses", a multinational observational cohort study and esicm trials group project gastrointestinal complications in critically ill patients with covid- mortality and pulmonary complications in patients undergoing surgery with perioperative sars-cov- infection: an international cohort study elective surgery cancellations due to the covid- pandemic: global predictive modelling to inform surgical recovery plans the potential health care costs and resource use associated with covid- in the united states la generalitat cifra en . millones el coste sanitario del coronavirus daily cost of an intensive care unit day: the contribution of mechanical ventilation coagulopathy and antiphospholipid antibodies in patients with covid- thromboinflammation and the hypercoagulability of covid- incidence of thrombotic complications in critically ill icu patients with covid- j o u r n a l p r e -p r o o f -incidence of de-novo surgical diseases is low in covid- patients -mortality of late-onset surgical diseases in these patients is near to % -length of stay and overall costs are increased in those patients -clinical symptoms should promptly be detected and surgical review timely obtained j o u r n a l p r e -p r o o f key: cord- -kbhljong authors: boilève, alice; stoclin, annabelle; barlesi, fabrice; varin, florent; suria, stéphanie; rieutord, andré; blot, françois; netzer, florence; scotté, florian title: covid- management in a cancer center: the icu storm date: - - journal: support care cancer doi: . /s - - - sha: doc_id: cord_uid: kbhljong a novel coronavirus, sars-cov- , was first reported as a respiratory illness in december in wuhan, china. since then, the world health organization (who) emergency committee declared a global health. covid- has now spread worldwide and is responsible of more than , persons, out of , , officially diagnosed worldwide since of june. in the context of cancer patients, covid- has a severe impact, regarding pulmonary infection but also cancer treatments in this fragile and immunocompromised population, and icu admission for cancer patients in the context of covid- requires ethical and clinical consideration. in our cancer center, intensivists, oncologists, pharmacists, and hospital administrators had to prepare for a substantial increase in critical care bed capacity (from icu beds, medical intensive care beds, and surgical intensive care beds, bed capacity was increased to medical intensive care beds with ventilating capacity) and to adapt infrastructure (i.e., icu beds), supplies (i.e., drugs, ventilators, protective materials), and staff (i.e., nurses and medical staff). overall, thirty-three covid- patients were admitted in our icu, cancer-free and with cancer, and required mechanical ventilation, resulting in deaths (of them two patients with cancer). we report here management of a dedicated intensive care unit of a cancer center during the covid- infection pandemic, considering resource allocation and redistribution of healthcare workers. a worldwide public health emergency of international concern has emerged since december , named coronavirus disease (covid- ) and caused by a novel coronavirus sars-cov- . first detected in china as a respiratory illness, this disease spread all around the world and achieved pandemic spread [ ] . it is now responsible for the death of , persons, out of , , officially diagnosed worldwide since of june [ ] . this new respiratory illness is characterized by a rapid human-to-human transmission, with a broad range of symptoms and severity, from asymptomatic cases to acute respiratory distress syndrome [ ] . importantly, the most severe cases require intensive care for high-flow oxygen therapy up to mechanical ventilation and management of potential other organ failure [ ] . in a chinese review, . % of patients were classified as critical (i.e., with respiratory failure, shock, or multiple organ dysfunction or failure) and . % were classified as severe (i.e., with a respiratory rate ≥ breaths per min, dyspnea, oxygen saturation ≤ %, partial pressure of arterial oxygen to fraction of inspired oxygen (pao /fio ) ratio < mmhg, or increase in lung infiltrates > % within - h) [ ] . in italy, until march , , around % of all positive patients required icu admission [ , ] . in france, the first patient was diagnosed on january , . covid- then rapidly spread, and an urgent need for more intensive care unit (icu) beds was noted. indeed, with large numbers of infected patients and rapidly increasing numbers of diagnosed and severe patients, covid- is a challenge for healthcare systems [ ] . in france, an inter-and intrahospital reorganization led to a creation of more than icu beds, more specifically in the east of france and in paris area, where the pandemic was the most virulent. the limited number of icu beds raised ethical consideration, with a reality of rationing care in a context of limited resources. in this context, cancer patients are a particular population with their own specificity, and one must realize that cancer mortality remains substantial [ ] . in a situation of predictable shortage of beds and resources due to patients with covid- requiring intensive care, the usual perception of cancer with a poor life expectancy population may lead to a limitation of aggressive management of this cohort. oncologists may face an unacceptable reality of rationing care for their patients. moreover, oncologists should also reason in terms of potential cancer progression due to treatment interruption for covid- infection. in this regard, some cancer centers have their own icu (dedicated to cancer patients only) that would receive covid- patients in the context of pandemic. moreover, these specific icu might be reassigned to host non-cancer patients to cope with the global influx of covid- patients. nevertheless, these cancer-dedicated centers must keep on cancer treatments and oncologic emergency. consequently, these specific icus have adapted to meet national requirements while continuing taking care of cancer patients. here, we report management of such a specific icu during the covid- infection pandemic, considering resource allocation and redistribution of healthcare workers, and anticipation of the influx of patients. even before the first covid- patient admitted at our hospital, a general reorganization of the hospital was planned, regarding oncology wards, surgery wards as well as icu wards. case definition for covid- infection in our center was a positive reverse transcriptase-polymerase chain reaction test (rt-pcr) for covid- or evocative symptoms with typical radiological images ion ct scan. in icu, all patients had a positive rt-pcr for covid- . all patients with evocative symptoms were tested (such as fever, upper or lower tract respiratory symptoms) or at physician discretion. all patients with planned surgery or interventional gesture were also tested. patients requiring hospital admission who met case definition for covid- were admitted in a specific ward awaiting test results since the microbiology lab is located in the hospital. results were available within h in march and then within to h since april. test was repeated if the patient met clinical case definition, and the first test was negative. a close flexibility was given on the needed number of beds in icu, to reassigned human (medical, paramedical, administrative, and technic staff) and material resources (beds, respirator, drugs such as narcotics and curare), depending on the anticipated needs. to increase icu capacity, and to reduce the number of patients admitted in the post-surgical care ward, a large number of non-urgent surgery were postponed, as well as cancer treatments that were adapted to preserve available beds in icu. therefore, some respirator form surgical rooms were reassigned to icu in order to increase ventilating capacity. we increased our capacity for extra renal purification in new icu beds. work has been done to open windows (needs to reach negative pressure inside the room to limit public area exposure to the virus) and separate covid-positive and covid-negative zone [ ] . the icu ward usually consists of three wards with icu beds, medical intensive care beds, and surgical intensive care beds. the intensive care beds are not supplied with ventilators. almost all beds were converted to icu beds raising the capacity to potential ventilated patients. at first, specific parts of the ward were dedicated to covid- patients with dedicated medical and paramedical staff in order to avoid nosocomial contamination of non-covid- patients. the of march, beds were dedicated to covid- patients, then one week later and the st of april, beds were available (i.e., then an increase by > % in just days). due to their icu hospitalization at the start of the crisis, only four beds were devoted to non-covid- cancer-patients. the influx of patients in our cancer-dedicated center was weeks behind other paris area hospitals, giving time to anticipation. our icu is usually dedicated to cancer patients which specific concerns such as critical adverse events, disease complication, and any other medical condition requiring icu. notably, these patients are not prioritized in most noncancer icu. in this context, our icu had to reorganize to face covid- patients influx in our frail population of cancer patients. from march to april , on a total of patients tested by pcr in the cancer center, % was covid- positive. the median age was (range - ), and % was female. a total of patients ( %) were admitted in icu; among them, were cancer-free, and patients were treated in gustave roussy cancer center for a cancer. figure shows the number of covid- patients in icu from march , (beginning of lockdown in france), to april , . regional health agency ordered on march to welcome cancer patients with covid- even if not managed in our hospital. four cancer patients with covid- were then admitted from other hospital. on march , considering the large influx of patients in paris area, order was given to admit covid- patients even without cancer. then, ventilated cancer-free patients and cancer patients (included ventilated) were admitted in days ( fig. ). to date (update april ), covid- patients were admitted in our icu, cancer-free and with cancer. twenty-three patients required mechanical ventilation, resulting in deaths (of them two patients with cancer). two patients required extracorporeal membrane oxygenation (ecmo) and were referred to specialized icu. ten patients did not require mechanical ventilation (all with cancer), resulting in two deaths (in a context of limited additional invasive intervention). eight patients were still in icu under mechanical ventilation, died ( %), and are home discharged ( %) (fig. ) . those results are confident with the icu outcomes in milan, italy (death . %, . % discharged) [ ] . to adapt to covid- pandemic, new organization was decided, regarding human and material resources. new nurses and caregivers were assigned in icu. first, specialized nurses from surgical rooms were trained for icu by colleagues, and new nurses and new caregivers were then available for icu. four nurses that previously worked in our icu came back from nurse school (n = ) or oncology/hematology wards (n = ). they received a time-limited training resulting in a -day observation course with their icu colleagues before caring icu patients. each nurse was in responsibility of patients, each caregiver for patients, with one extra nurse from surgical room occasionally. considering spatial organization of icu, each nurse from icu and extra nurses alternated for a better integration of the new icu actors. a special team for prone positioning was developed with the help of surgeons whose surgical activity had been restricted. four of them were assigned each day to help to turn on or turn back ventilated patients every morning and every afternoon. they were trained during two sessions and then were fully efficient and appreciated, while - people per patient were required. considering medical resources, a team of anesthetists and residents were requested to manage icu beds with their own night shift list. other beds were managed by senior intensivists and residents. moreover, residents from medical oncology wards that previously worked for one trainee ship in icu during their residency were reassigned for at least month in icu for day and night shifts. importantly, the oldest workers or workers with chronic illness were relocated in non-covid- wards of the hospital. all workers of covid- units were volunteers. notably, some people were allocated to work with covid- patients only and others with non-covid- patients only, as far as possible, to prevent nosocomial covid- infection. once the covid icu ward is fully opened, management of the patient influx was a challenging and determinant part of the organization. the incoming patients could therefore came from (i) inside medical patients (non-covid), (ii) inside surgical patients, (iii) inside covid patients (cancer patients and staff), and (iv) outside covid patients requiring icu care. in order to optimize organization, each day one doctor was in charge of admission decisions. more than managing the resource allocations, the purpose of this function was to distribute mental load due to complex ethical decisions. this global approach and close collaboration between oncologists, surgeons, and icu staff demonstrated the solidarity and multidisciplinarity of cancer centers. it is worth to note the huge adaptability and flexibility of all healthcare actors, to work with other colleagues, in different wards, with different kinds of patients, different software, and different rhythms. in order to preserve health status of these professionals, a training for protective measures and proper dressing was organized as well as meals with social distancing. to date, no healthcare worker was diagnosed positive for covid- while working in the icu ward ( nurses from surgical room were screened positive before being reassigned in icu). of note, a pcr testing was performed for all symptomatic workers and was not systematic at first. as our cancer-dedicated hospital includes psychologists and psychiatrists, a dedicated consultation was set up to prevent burnout. estheticians and sophrologists that used to work with cancer patient dedicated part of their time every day to icu workers. all these allowed the best possible conditions for all workers. material resource allocation can be challenging in a context of medical supply shortage and infectious disease. icu procedures were adjusted to enable caregivers and patients safety, with dressing protocol for nursing covidpositive patients, the use of close-loop system for endotracheal access in intubated patients, or bedside diagnostic procedures that were promoted (fibroscopy, ultrasound, radiography). the efficiency of those protocols was dependent of supply chain, and several innovative solutions have been found to secure it. a specific intubation protocol was followed: (i) appropriate respiratory protective equipment for all providers present during airway management. icu was always provided with surgical and ffp masks, since early order was performed by the hospital. new ways of supply were found for dressing material such as blouses or gloves. particulars helped to provide apron and protective visors. the pharmacy department has produced its own hydroalcoholic solution. there were no exceptions to security rules. therefore, no shortage in personal protective equipment (ppe) supplies was observed in our center. when taking care of patients, ppe standard was pajamas and blouses, as well as visors and ffp masks, shoe protections, and hair protections. when not taking care of patients, ppe standard was pajamas and ffp masks. a more worrying problem was medication shortage, especially narcotics and curares. the pharmacy department faced a real challenge to provide enough essential icu drugs since a national (and international) penury was observed. the first step consisted in needs analysis and anticipation. pharmacists and medical staff revised all sedative protocols and proposed therapeutic alternatives to restrict product use and to avoid a shortage. we establish the daily need per bed to guarantee the supply during this period for the beds (table ) . we set up a dedicated logistic loop twice a day monitoring any deviation with the calculated needs in order to correct it the fastest way possible. the second step consisted in elaborate a next strategy of supply. instead of ordering massive amount to usual supplier, we asked reasonable quantities to all our supplier panel. during the most epidemic period, the drug consumption drastically increases to % for curare and % for sedatives (midazolam and propofol) versus the same period last year. in the most critical situation, the number of patients really treated, the number of cumulated treatment days, and the number of vials used were extracted from the electronic prescribing system (grimoire®) the entire capacity of treatment is about days ( table ). the third step was to optimize drug administration. a close monitoring of curare effects through the train of four and sedative drugs with the bispectral index allowed more effective administration. the adjunction of other pharmacologic class to the sedative arsenal, such as ketamine, dexmedetomidine, and sevoflurane gas, allowed us to reduce the supply chain tension. in icu, specific covid- treatment consisted in hydroxychloroquine depending on oncovid protocol (nct ) for cancer patients and tocilizumab (corimuno-toci, nct ). most patients received only symptomatic treatment. since the icu staff was strengthened with adjunction of several various physicians, the daily activity was reconsidered. the main objective was to maintain a constant quality of care without spreading the virus among caregivers. the icu was divided into independent functional units, each one with different medical transmissions schedules and night shifts. meetings requiring outside stakeholders (ethical or infectious disease staff) were partially phone conducted. a consistency of patient care was ensured through the presence of one intensivist in every medical staff but also through the creation of dedicated medical protocols for covid patients that were implemented in the prescription software. finally, every medical information was available for any icu physician through secured local database. in accordance with hospital recommendation, there was a restrictive access to icu, which was a new paradigm. this was decided to decrease population movement and to protect non-covid- patients as well as families. no visit was allowed, except in case of life ending. all families could phone every day to be informed of every clinical change of their relative. additionally, a digital tablet has been acquired to allow visual contact between patients and their relatives. an absolute compliance to these new and difficult rules was observed, with a great agreement of every family. of note, the strict limitation of family access was applied the same way in all the hospital, to reduce the number of people within the hospital. as the pandemic spread, it was inevitable that patient with covid- would present at our hospital, for specific symptoms or as an accidental diagnosis. to maximized protection of non-covid- patients, a specific ward was early dedicated for covid- cancer patients. a daily ethical cross-disciplinary meeting allowed to discuss eventual clinical limitations for icu admission for every patient in respiratory degradation (with oncologist, intensivist, infectious disease specialist, and supportive care specialist). an ethical committee and psycho-oncological team was also set up that could meet at every moment, days and nights, for difficult decisions that could require a multidisciplinary discussion. in particular, a member from icu team attended each ethical meeting. in the context of cancer, and regardless covid- pandemic, icu admission is discussed depending ( ) patient wish; ( ) general state and comorbidities; ( ) reversibility of the supposed acute failure (number and type of organ failure, short-term prognosis); and ( ) cancer prognosis. covid- respiratory illness is considered as reversible, but ( ) covid- ards is worse than usual ards with an estimated mortality of - % when mechanical ventilation is required [ ] ; ( ) ards lasts often several weeks; ( ) rehabilitation time post-ards (respiratory, neuromuscular) is very long and proportional to duration of icu stay [ ] [ ] [ ] [ ] ; ( ) treatment limitation can be necessary during icu stay; and ( ) the prognosis is worse in cancer patients, especially when treatment is ongoing [ ] . most patients that survived this severe ards are young, without comorbidity and in good general state, without use of mechanical ventilation [ ] . therefore, a formalized list of criteria for icu admission was edited by the ethical committee and discussed for every patient. importantly, it was decided to discuss this potential icu admission before any clinical criteria for intensive care and irrespective of icu available beds. importantly, no patient was recused from icu for a lack of icu bed. moreover, a covid- protocol was applied at the entry of the hospital. all patients had body temperature measured before any hospitalization and tested if febrile. a questionnaire was also filled with the help of nurses at the entry. all patients with planned surgery or any interventional gesture were also tested to h before hospitalization. lastly, all patients with selfreported specific symptoms were also tested. if positive, patients were addressed at the specific covid- icu ward. to define the level of therapeutic commitment, the patient general state is preponderant. characteristics related to cancer were assessed in perspective of the initial seriousness of covid- , as well as the predictable duration of intensive care and rehabilitation. in this regard, an oncologic prognosis of less than months, considering an interruption of cancer treatments (for a three-month to six-month period), seems incompatible with mechanical ventilation. therefore, the only indication of intubation for covid- ards is a good general state, without heavy comorbidities, and an oncologic prognosis of more than months. age itself is not a limiting factor per se. as a referral center for cancer, our hospital was due to continue providing care for all cancer patients. nevertheless, it should address the security of patient and workers. in a series of patients from taiwan enrolled in clinical trials published in during sars epidemic, a questionnaire showed that almost two-third of patients were afraid coming to hospital for fear of being acquiring sras and three patients ceased further chemotherapy for this reason [ ] . in our hospital, a surgical mask and hydro-alcoholic friction was mandatory to enter the hospital, to prevent nosocomial and healthcare workers infections. a dedicated circuit was set up for suspicion of covid- to avoid too many covid- patients in the emergency room. some patients undergoing major surgery for cancer or systemic treatment (chemotherapy, immunotherapy) might require intensive care support. having icu with covid- patients reduced the capacity and available beds for non-covid- patients, and therefore diminished ability to perform major planned surgery. surgical room reopened as soon as the influx of covid- patients decreased, with more available icu beds, in order not to induce a lot of opportunity in case of postponed surgery for a resectable cancer. in this regard, some guidelines from various cancer core europe have been edited and were unanimous that priority should be given to neoadjuvant therapies and curative surgery if limited access to icu [ ] . all urgent medical and surgical treatments were maintained and realized. moreover, radiotherapy treatments were continued the same way for most patients. despite covid- crisis, our institute was able to keep on his core mission, which relies on care and research. more than patients were included into different interventional trials (one sponsored by our institute), translational studies, and observational studies (four sponsored by our institute), with an active participation to national databases. a biobanking was also realized to further explore covid- in the context of cancer. covid- pandemic highlighted the crucial role of intensive care, and our cancer-dedicated hospital icu was involved for national requirement and general solidarity (and non-cancer patients admitted for the first time of the hospital institute) but also for continuity of care for cancer patients. in this regard, ethical discussion provided a learning and insightful experience. this pandemic impacts directly our organization, with very serious patients requiring heavy care, with the reassignment of new health workers in icu that had to integrate and to be fully competent in a short delay, and with a change of practice especially regarding therapeutic commitment. uncertainty remains regarding successive waves, and anticipation of the recovery of standard activity is difficult, but facing this pandemic requires adaptability and solidarity. early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia asian critical care clinical trials group ( ) intensive care management of coronavirus disease (covid- ): challenges and recommendations who-china joint mission report of the who-china joint mission on coronavirus disease covid- and italy: what next? critical care utilization for the covid- outbreak in lombardy, italy: early experience and forecast during an emergency response fair allocation of scarce medical resources in the time of covid- risk of covid- for patients with cancer characteristics, treatment, outcomes and cause of death of invasively ventilated patients with covid- ards in clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study qualityadjusted survival in the first year after the acute respiratory distress syndrome the effect of acute respiratory distress syndrome on long-term survival pulmonary function and healthrelated quality of life in a sample of long-term survivors of the acute respiratory distress syndrome health-related quality of life after acute lung injury cancer patients in sars-cov- infection: a nationwide analysis in china predictors of survival in critically ill patients with acute respiratory distress syndrome (ards): an observational study impact of severe acute respiratory syndrome on the status of lung cancer chemotherapy patients and a correlation of the signs and symptoms caring for patients with cancer in the covid- era publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors' contribution alice boilève, florence netzer, annabelle stoclin, and florian scotté contributed to the study conception and design. material preparation, data collection, and analysis were performed by alice boilève, florence netzer, fabrice barlesi, florent varin, florian scotté, and annabelle stoclin. the first draft of the manuscript was written by alice boilève, and all authors commented on previous versions of the manuscript. all authors read and approved the final manuscript. key: cord- - jxtg y authors: blasi, annabel; von meijenfeldt, fien a.; adelmeijer, jelle; calvo, andrea; ibañez, cristina; perdomo, juan; carlos reverter, juan; lisman, ton title: in vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in covid‐ patients on anticoagulation date: - - journal: j thromb haemost doi: . /jth. sha: doc_id: cord_uid: jxtg y background: covid‐ is associated with a substantial risk of venous thrombotic events, even in the presence of adequate thromboprophylactic therapy. objectives: we aimed to better characterize the hypercoagulable state of covid‐ patients in patients receiving anticoagulant therapy. methods: we took plasma samples of patients with covid‐ who were on prophylactic or intensified anticoagulant therapy. twenty healthy volunteers were included to establish reference ranges. results: covid‐ patients had a mildly prolonged prothrombin time, high vwf levels and low adamts activity. most rotational thromboelastometry parameters were normal, with a hypercoagulable maximum clot firmness in part of the patients. despite detectable anti‐xa activity in the majority of patients, ex vivo thrombin generation was normal, and in vivo thrombin generation elevated as evidenced by elevated levels of thrombin‐antithrombin complexes and d‐dimers. plasma levels of activated factor vii were lower in patients, and levels of the platelet activation marker soluble cd ligand were similar in patients and controls. plasmin‐antiplasmin complex levels were also increased in patients despite an in vitro hypofibrinolytic profile. conclusions: covid‐ patients are characterized by normal in vitro thrombin generation and enhanced clot formation and decreased fibrinolytic potential despite the presence of heparin in the sample. anticoagulated covid‐ patients have persistent in vivo activation of coagulation and fibrinolysis, but no evidence of excessive platelet activation. ongoing activation of coagulation despite normal to intensified anticoagulant therapy indicates studies on alternative antithrombotic strategies are urgently required. patients with covid- have a profound risk for venous thrombotic events. particularly in patients admitted to an intensive care unit (icu), rates of deep vein thrombosis and pulmonary embolism are exceedingly high, even in the presence of pharmacological thromboprophylaxis [ , ] . in addition to macrovascular thrombotic events, microvascular thrombosis has been proposed to contribute to disease progression, with pulmonary clots contributing to respiratory failure [ ] [ ] [ ] , and clots in other vascular beds to multiple organ failure [ , ] . anticoagulant treatment has been shown to reduce mortality, perhaps due to reduction of microvascular thromboses [ ] . the high thrombosis risk in covid- patients has been linked to a hypercoagulable state that has not been well-defined. the in vivo hyperactivation of coagulation appears to be linked to a massive inflammatory response coupled with increases in acute phase proteins including fibrinogen [ ] , and involvement of neutrophil extracellular traps (nets) [ ] , which are newly recognized actors in thrombosis. routine hemostasis tests show mild prolongations in prothrombin time (pt) and activated partial thromboplastin time (aptt), and mild thrombocytopenia in some patients, but massively elevated levels of d-dimer in many patients [ ] , that appear to have prognostic value [ ] . whole blood thromboelastography has demonstrated a hypercoagulable profile [ , ] , and one of these studies concluded that the covid- coagulopathy does not have elements of typical disseminated intravascular coagulation (dic) as has been suggested by others [ ] . notably, increased (major) bleeding complications have been described in patients, especially in the critically ill, suggesting a fragile balance in hemostatic status of these patients [ ] , although others have demonstrated bleeding risks comparable to patients with non-covid- acute respiratory syndromes [ ] . in a large academic medical center in barcelona, spain, to which approximately patients were admitted at the peak of the covid- pandemic, the initial reports on thrombosis and hypercoagulability and their own observations led to an intensified thromboprophylactic regimen for part of the admitted covid- patients, particularly those with more advanced disease. although an anticoagulant protocol was instituted, during the period of our study this protocol was poorly adhered to and individualized decisions on anticoagulant dosing were taken. we aimed to study the effects of this individualized anticoagulant therapy on the hemostatic status of these patients. this article is protected by copyright. all rights reserved we included patients that were admitted with covid- (which was confirmed by polymerase chain reaction) to hospital clínic barcelona, spain, in april . almost all patients received the low-molecular-weight heparin (lmwh) enoxaparin. ethical approval from the medical ethical committee hospital clínic barcelona ( / ) was obtained. all patients, or in the case of incapacity their consultee, gave informed consent or assent, respectively, for participation in this study. twenty healthy controls were included to establish reference values for the various assays performed. exclusion criteria for healthy controls were age below years, pregnancy, hereditary thrombophilia or hemophilia, use of anticoagulant medications, history of venous thromboembolic events, and blood (product) transfusion up to seven days prior to inclusion. citrated blood samples were taken [ - ] days after admission to the hospital ( [ - ] days after onset of symptoms) on either a general ward or icu by venipuncture or from dedicated arterial lines. in all patients, anticoagulation was started on admission. blood samples were either used immediately for rotational thromboelastometry (rotem) measurements or processed to platelet-poor plasma within minutes of the blood draw by double centrifugation at g for minutes, and subsequently stored at - degrees celsius until used for analyses. complete blood cell counts, and creatinine, total bilirubin, c-reactive protein (crp) were measured as part of routine clinical care by the centre de diagnòstic biomèdic at the hospital clínic barcelona. we measured pt, aptt, international normalised ratio (inr), prothrombin, antithrombin, fibrinogen, and d-dimer on an automated coagulation analyzer (stacompact , stago, breda, the netherlands) using reagents and protocols from the manufacturer. von willebrand factor (vwf) plasma levels were determined with an in-house enzyme-linked immunosorbent assay (elisa) using commercially available polyclonal antibodies against vwf (dako, glostrup, denmark). plasma activity of a disintegrin and metalloproteinase with a thrombospondin type motif, member (adamts ) was measured using the frets-vwf assay (peptanova, sandhausen, germany). levels of vwf and adamts in pooled normal plasma were set at %, and values obtained in test plasmas were expressed as a percentage of pooled normal plasma. plasminogen activator inhibitor type (pai- ) levels were quantified by commercially available elisa from r & d systems (minneapolis, mn, usa). cell-free dna was quantified this article is protected by copyright. all rights reserved using the quant-it picogreen dsdna assay kit (fisher scientific, landsmeer, the netherlands) as described previously [ ] . the concentration of myeloperoxidase(mpo)-dna complexes in plasma was determined by enzyme-linked immunosorbent assay (elisa), as previously described [ ] . rotem analyses were performed on a rotem sigma according to the manufacturers' instructions. thrombin generation (tga) was performed using commercially available reagents containing recombinant tissue factor (final concentration: pm), phospholipids (final concentration: µm), and soluble thrombomodulin (the concentration of which is not revealed by the manufacturer) (thrombinoscope b.v., maastricht, the netherlands). anti-activated factor x (anti-xa) levels were measured on an automated analyzer (acl top) using heparin lrt (hyphen biomed, amsterdam, the netherlands). plasma fibrinolytic potential was estimated by studying lysis of a tissue factor-induced clot by exogenous tissue plasminogen activator (tpa) by monitoring changes in turbidity during clot formation and subsequent lysis as described previously [ ] . samples that were still clotted at hours after the start of the experiment were arbitrarily assigned a clot lysis time (clt) of minutes. plasma levels of thrombin-antithrombin (tat) complexes, prothrombin fragment + (f + ), plasmin-antiplasmin (pap) complexes, and soluble cd ligand were quantified by commercially available elisas (siemens, erlangen, germany for tat and f + , technoclone, vienna, austria for pap, and r&d systems, bio-techne, united kingdom for scd l). plasma levels of activated factor vii were quantified using the hemoclot factor viia kit (hyphen biomed, neuville-sur-oise, france). statistical analyses were performed using graphpad prism version . . (san diego, ca, usa). the results were presented as numbers (percentages) for categorical variables and medians [interquartile ranges] for continuous variables. test results were compared between covid- patients and healthy controls, and between patients admitted to the icu and the ward, using the mann-whitney u test. relations between laboratory parameters were made by simple linear regression. p-values < . were considered statistically significant. we studied patients of whom were admitted to the icu, and were on general wards. none of the ward patients later had to be admitted to the icu. three icu patients developed thrombotic complications; pulmonary embolism, myocardial infarction, distal ischemia of the fingers. general patient characteristics are shown in table . most icu patients received higher anticoagulant doses compared to ward patients; table ). routine diagnostic hemostasis tests and plasma levels of markers for nets are shown in table . compared to healthy controls, patients had a prolonged prothrombin time and inr, which are largely explained by decreased fvii levels that strongly correlated with the prothrombin time (r = . , p< . ). in addition, patients had a decreased platelet count, elevated fibrinogen levels, slightly decreased levels of prothrombin and antithrombin, high levels of vwf and fviii, and low levels of adamts . of note, patients had prothrombin and antithrombin levels < %, and two other patients had adamts levels < %. these results are consistent with a mild consumption coagulopathy with a thrombogenic vwf profile. plasma levels of pai- were approximately . times higher in covid- patients compared to controls. markers of nets were modestly elevated in patients compared to controls, and did not differ between patients that were or were not admitted to icu, which may argue against a key role of nets in the pathogenesis of covid- associated sequelae as was suggested previously. indeed, unlike previously described [ ] , net markers in our cohort did not correlate with c-reactive protein, d-dimer, platelet count, or use of mechanical ventilation. we next studied hemostatic potential of covid- patients by global tests (table ) . rotem parameters were largely within the normal range, except for elevated maximum clot firmness (mcf) in extem, intem, and fibtem in , , and patients, respectively. a limitation of these analyses was that normal ranges were not locally established, but taken from the rotem user manual. of note, rotem extem and fibtem reagents contain polybrene, which neutralizes heparin present in many of these samples. thrombomodulin-modified thrombin generation was preserved on a group level, but individual patients were clearly hyper-or hypocoagulable. the patient samples that generated little thrombin contained high levels of lmwh as evidenced by anti-xa activity assays, whereas hypercoagulable samples generally had low to undetectable anti-xa this article is protected by copyright. all rights reserved activity although one patient had marked thrombin generation even in the presence of high anti-xa levels. etp and peak thrombin levels were inversely correlated with anti-xa levels (r = . , p= . and r = . , p= . , without clear outlier these correlations became much stronger r = . , p< . and r = . , p= . ). samples taken from patients admitted to the icu generated substantially less thrombin, but this was directly related to much higher anti-xa levels in samples taken from patients on the icu compared to ward patients ( table ) . as samples were not taken at specific time points relative to the last lmwh injection, and since there was a substantial difference in dosing and timing of lmwh administration between icu and ward, this likely explains the difference in anti-xa and thrombin generating capacity between intensive care and ward patients. plasma clt was higher in covid- patients compared to healthy controls, but similar between patients on icu and ward. five patients had substantially elevated clt (> min). two of these had underlying liver disease and may have been hypofibrinolytic related to decompensating liver disease as we have described previously [ ] , the other were all admitted to the icu, and hypofibrinolysis is a common feature of patients that are critically ill. viscoelastic tests have shown evidence of fibrinolytic shutdown in a quarter of covid- patients and fibrinolytic shutdown was associated with thrombosis [ ] . however, the definition of hypofibrinolysis using viscoelastic tests is not straightforward as 'no lysis' is in fact part of the reference range [ ] . we found 'no lysis' (defined as clt > min) in only patients ( %), whilst our plasma-based test detects 'no lysis' in a much larger proportion of other patient populations (notably post-surgery [ ] , and patients with acute liver failure ( . %) [ ] ). this suggests that a true fibrinolytic shutdown is rare in covid- , which is also evidenced by highly elevated d-dimer and plasmin-antiplasmin complexes (see below). importantly, lmwh decreases clt across physiologically relevant concentrations [ ] , which may be why plasma clot lysis was only mildly impaired in our patients. thus, covid- patients have somewhat elevated clot formation, likely related to hyperfibrinogenemia, normal thrombin generating capacity despite the presence of lmwh, and hypofibrinolysis despite the presence of lmwh. this article is protected by copyright. all rights reserved in vivo markers of activation of coagulation are shown in table . tat and pap complex levels are strongly elevated in patients with covid- , indicating ongoing thrombin and plasmin generation in covid- patients despite anticoagulation with lmwh. interestingly, tat and pap levels were not different between patients admitted to the icu or to the general ward, while d-dimer levels were substantially higher in icu compared to ward patients. this may indicate that icu patients have a higher clot burden, which may be primarily intrapulmonary clots [ , ] , despite similar procoagulant activity. this might be explained by decreased (local) anticoagulant capacity in icu patients, perhaps related to increased endothelial injury that decreases availability of thrombomodulin and endogenous heparinoids. surprisingly, f + levels were not increased in covid- patients compared to controls, and we have no explanation for the discrepancy between tat and f + levels. d-dimer and tat levels were not correlated to anti-xa levels, but f + levels were inversely correlated with anti-xa levels (r = . , p= . ). viia levels were lower in patients, which may point to consumption of viia similar to what we have previously observed in patients during the acute phase of deep vein thrombosis [ ] . indeed, viia levels strongly positively correlated with zymogen vii levels (r = . , p=< . ). soluble cd ligand levels were similar between patients and controls, suggesting covid- patients are not characterized by excessive platelet activation. taken together, our data confirm a hypercoagulable status of enhanced thrombin generating capacity, enhanced ex vivo clot formation likely related to hyperfibrinogenemia, and a decreased ex vivo fibrinolytic capacity in patients with covid- . interestingly, despite normal to intensified anticoagulant treatment, in vivo activation of coagulation and fibrinolysis was evident and independent of anti-xa levels, whereas in vitro activation of coagulation proportionally decreased as a function of anti xa-levels. our observations that the hypercoagulable profile is more pronounced in the sicker patients are in line with the hypothesis that activation of coagulation, particularly in the pulmonary circulation, is a key feature of covid- and may contribute to progression of disease [ ] . these data suggest that low-therapeutic anticoagulant regimens are often insufficient to downregulate coagulation activation in covid- patients, and call for assessment of alternative or intensified antithrombotic strategies. however, careful individual patient assessment (especially in the critically-ill) is warranted, given the increased bleeding risk that is associated with covid- . this article is protected by copyright. all rights reserved this article is protected by copyright. all rights reserved this article is protected by copyright. all rights reserved anti-xa, anti-activated factor x; clt, clot lysis time. this article is protected by copyright. all rights reserved incidence of thrombotic complications in critically ill icu patients with covid- incidence of venous thromboembolism in hospitalized patients with covid- complement associated microvascular injury and thrombosis in the pathogenesis of severe covid- infection: a report of five cases microvascular covid- lung vessels obstructive thromboinflammatory syndrome (microclots): an atypical acute respiratory distress syndrome working hypothesis pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- the emerging spectrum of cardiopulmonary pathology of the coronavirus disease (covid- ): report of autopsies from houston, texas, and review of autopsy findings from other united states cities autopsy findings and venous thromboembolism in patients with covid- anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy covid coagulopathy in caucasian patients neutrophil extracellular traps in covid- accepted article this article is protected by copyright. all rights reserved abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia the procoagulant pattern of patients with covid- acute respiratory distress syndrome hypercoagulability of covid- patients in intensive care unit. a report of thromboelastography findings and other parameters of hemostasis covid and coagulation: bleeding and thrombotic manifestations of sars-cov infection high risk of thrombosis in patients with severe sars-cov- infection: a multicenter prospective cohort study elevated plasma levels of cell-free dna during liver transplantation are associated with activation of coagulation netting neutrophils in autoimmune small-vessel vasculitis haemostatic profiles are similar across all aetiologies of cirrhosis synergistic effects of hypofibrinolysis and genetic and acquired risk factors on the risk of a first venous thrombosis mixed fibrinolytic phenotypes in decompensated cirrhosis and acute-on-chronic liver failure with hypofibrinolysis in those with complications and poor survival accepted article this article is protected by copyright. all rights reserved decreased fibrinolytic capacity in cirrhosis and liver transplantation outcomes a sustained decrease in plasma fibrinolytic potential following partial liver resection or pancreas resection intact thrombin generation and decreased fibrinolytic capacity in patients with acute liver injury or acute liver failure enhancement of fibrinolytic potential in vitro by anticoagulant drugs targeting activated factor x, but not by those inhibiting thrombin or tissue factor sars- coronavirus-associated hemostatic lung abnormality in covid- : is it pulmonary thrombosis or pulmonary embolism? re the source of elevated plasma d-dimer levels in covid- infection decreased plasma levels of activated factor vii in patients with deep vein thrombosis comparisons between the two groups were made using the mann-whitney u test for non-parametric data * missing data of one (non-icu) patient for d-dimer and viia this article is protected by copyright. all rights reserved abbreviations: icu, intensive care unit; tat, thrombin-antithrombin; f + , prothrombin fragment f + ; vii(a), (activated) blood coagulation factor vii;pap, plasmin-antiplasmin; scd l, soluble cd ligand. key: cord- -x crng j authors: dhesi, z.; enne, v. i.; brealey, d.; livermore, d. m.; high, j.; russell, c.; colles, a.; kandil, h.; mack, d.; martin, d.; page, v.; parker, r.; roulston, k.; singh, s.; wey, e.; swart, a. m.; stirling, s.; barber, j. a.; o'grady, j.; gant, v. a. title: organisms causing secondary pneumonias in covid- patients at uk icus as detected with the filmarray test date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: x crng j abstract introduction. several viral respiratory infections - notably influenza - are associated with secondary bacterial infection and additional pathology. the extent to which this applies for covid- is unknown. accordingly, we aimed to define the bacteria causing secondary pneumonias in covid- icu patients using the filmarray pneumonia panel, and to determine this tests potential in covid- management. methods. covid- icu patients with clinically-suspected secondary infection at uk hospitals were tested with the filmarray at point of care. we collected patient demographic data and compared filmarray results with routine culture. results. we report results of filmarray tests on patients ( had tests): patients ( %) were male, the median age was yrs; were ventilated. median hospital stay before testing was days (range - ). fifty-nine ( %) tests were positive, with bacteria detected. most were enterobacterales (n= , including klebsiella spp. [n= ]) or staphylococcus aureus (n= ), as is typical of hospital and ventilator pneumonia. community pathogens, including haemophilus influenzae (n= ) and streptococcus pneumoniae (n= ), were rarer. filmarray detected one additional virus (rhinovirus/enterovirus) and no atypical bacteria. fewer samples ( % vs. %) were positive by routine culture, and fewer species were reported per sample; klebsiella species remained the most prevalent pathogens. conclusion. filmarray had a higher diagnostic yield than culture for icu covid- patients with suspected secondary pneumonias. the bacteria found mostly were enterobacterales, s. aureus and p. aeruginosa, as in typical hap/vap, but with klebsiella spp. more prominent. we found almost no viral co-infection. turnaround from sample to results is around h min compared with the usual h for culture, giving prescribers earlier data to inform antimicrobial decisions. the emergence of sars-cov as a pandemic virus of global importance drives a need for clinical and pathological evidence upon which to base optimal therapeutic decisions. whilst purely viral infections should not be treated with antibiotics, several respiratory viruses, notably influenza, are associated with secondary bacterial infection and additional pathology. these secondary infections reflect a combination of damage to the protective mucosa, facilitating bacterial colonisation and invasion, as well as virally-induced immunosuppression ( , ) . viral and bacterial respiratory coinfections exacerbate disease severity, and can prompt icu admission ( ) . the extent to which covid- , as the disease caused by sars-cov , is associated with secondary bacterial infection of the respiratory tract is unknown ( ) . anecdotal evidence suggests that hospitalised covid- patients are frequently prescribed empirical antimicrobials. whether this is microbiologically necessary, even in severe cases, is unknown ( ) . in a brief review of existing literature rawson et al conclude that there currently are insufficient data to inform empiric or reactive antibiotic decisions in a reasonable timeframe for critically-ill covid- patients ( ) . irrespective of covd- , investigation of clinically-suspected bacterial pneumonia is complicated by the poor sensitivity of sputum culture and by the considerable interval (typically circa h) from sample to susceptibility test results. recently-developed rapid tests have the potential to improve both the speed and sensitivity of investigation ( ) . inhale (isrctn ) is a uk nihr-funded research programme investigating the utility of rapid molecular diagnostics for the microbiological investigation of hap/vap in critical care ( ) . the programme incorporates an rct, run across uk hospitals, in which icu patients with suspected hospital-acquired or ventilator-associated pneumonia (hap/vap) are randomised to have either (a) standard empirical therapy or (b) to have the biofire filmarray pneumonia panel test (biomérieux) to support early treatment decisions ( ) . all patients have conventional microbiological investigation performed. the filmarray is a pcrbased test with a turnaround time of h min and can be performed inside the icu. an antibiotic-prescribing algorithm is provided to support decision-making based on the results, thus going beyond a "point of care test (poct)" to provide 'point of decision' clinical support. the covid- pandemic resulted in recruitment to the inhale trial being paused and, under the exigencies of the circumstances, we developed an observational sub-study to investigate the utility of the filmarray pneumonia panel for the diagnosis and characterisation of secondary bacterial infection in covid- icu patients. here, we report the results of this sub-study for patients from uk icus. the aims were to describe secondary bacterial, viral and "atypical" pathogens in covid- icu patients and to evaluate the potential of this panel for management of these patients. is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . guidelines. test results were immediately delivered to the clinical icu team along with the inhale rct prescribing algorithm (which allows some local variation), providing recommended treatment guidance ( ) . the foundation of this prescribing algorithm is to promote antimicrobial stewardship by indicating the narrowest spectrum antibiotic likely to cover the pathogen(s) detected and compatible with the patient's penicillin allergy status. a second filmarray test ≥ days from the first pneumonia panel test was permitted if a new or continuing bacterial pneumonia was suspected. in parallel, a respiratory sample was sent to the hospital laboratory for routine microbiological investigation, performed according to the standard uk laboratories operating procedures ( ) . baseline data including age, sex, comorbidities, date of covid- diagnosis, admission to hospital, and icu admission were collected. filmarray test results and clinical microbiology results were recorded, along with a brief statement of the reason for filmarray testing. antibiotic prescribing data were also collected, but remain under analysis and will be reported separately. a bespoke redcap database was used for data collection and storage ( ) ; this provides a number of features to maintain data quality, including an audit trail, ability to query spurious data, search facilities, and validation of predefined parameters/missing data. chi square tests were used to compare proportions. both the main trial and the sub-study have ethical approval from the london, brighton and sussex research ethics committee ( /lo/ ) and the health research authority. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . up to cut-off date of this analysis ( may, ), patients had been recruited at the icus (range - patients per site), with filmarray results available for , all recruited after april . sixteen patients had the test performed twice, giving a total of reports. demographic and background health data are summarised in table . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . clinicians were asked to record the clinical indication for performing the filmarray test. among responses provided, across the participating sites, the most widely cited reason was an increase in inflammatory markers/fever ( %), followed by 'considering a change of antibiotics' ( %), suspected bacterial pneumonia ( %), increased respiratory secretions/ hypoxia ( %), or to stop antibiotics ( %). the most prevalent pathogen found was klebsiella pneumoniae, followed by s. aureus, enterobacter cloacae and k. aerogenes. resistance genes were detected in samples: meca/c, which confers methicillin resistance in staphylococci, was found in samples from patients at icus (one patient had two tests, with meca/c found both times). all these source patients were positive for s. aureus, indicating an mrsa incidence of %. bla ctx-m genes, encoding extended-spectrum β−lactamases, were detected in samples, from different patients in the same icu; both samples were positive for k. pneumoniae, a frequent host of these enzymes. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . (including negative results but excluding multiple instances of the same species from a single patient) . out of the specimens run on the filmarray, ( . %) were not sent to the clinical microbiology laboratory and ( . %) were not reported; leaving ( %) with a routine microbiology result three analyses were performed to compare the agreement of the filmarray and routine results. first, we performed a concordance analysis, as shown in table , for tests where both results were available. most filmarray results ( . %) were fully concordant with routine culture. among those that were not fully concordant the common pattern was for filmarray to indicate pathogens in samples where routine microbiology reported no organisms ( . % of tests) or to flag additional organisms over and above those reported by routine microbiology ( . %). only % of cases were classified as major discordances with routine microbiology culturing an organism that was sought by the filmarray but not found by it. one patient had an opportunist pathogen (citrobacter koseri) not represented on the filmarray panel. *includes one case where routine microbiology did not report s. aureus and klebsiella spp., which were found by filmarray, but did report citrobacter koseri, which is not sought by filmarray secondly, we reviewed agreement by species group in relation to the organism load reported by filmarray (table ). only of organisms reported by the filmarray at a load of or cfu/ml were reported by routine microbiology, but this proportion rose to / for organisms found at a load of or cfu/ml (p= . , chi square test). thirdly, we considered agreements between phenotypic resistance and detection of corresponding resistance genes by filmarray. mrsa was reported by routine microbiology from of the samples where filmarray flagged meca/c and s. aureus; the remaining samples were reported by microbiology as yielding 'no growth'. culture did not detect esbl-producing organisms in either of the two samples where filmarray found bla ctx-m. genes and k. pneumoniae but, curiously, did find . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint an esbl-producing k. pneumoniae in another sample (where filmarray was negative) from the same icu on the same day, raising a possible confusion of samples, though this could not be confirmed. routine microbiology identified one k. oxytoca isolate with a phenotype suggesting hyper-production of k chromosomal β-lactamase; filmarray detected the k. oxytoca, but does not seek the mutations that cause hyper-production of this enzyme. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . the age, sex and co-morbidity profiles of these patients are in keeping with those reported by others in severe covid- disease ( ) . although the inclusion criteria permitted testing of patients at any point during their hospital and icu admission, the majority ( %) of tests were performed at least days after hospital admission. in context it should be noted that hospitalised covid- patients in the uk are typically admitted to a general ward then, after several days, if necessary, are transferred to icu, where our testing was conducted ( ) . although sites had the option of using the test earlier during the hospitalisation, they reported anecdotally that most recently-hospitalised covid- patients were unproductive for sputum and thus not eligible (data not shown). this observation may, of itself, suggest that early-onset bacterial secondary infections are uncommon in covid- illness, as they would be expected to provoke sputum production. nonetheless, it would be pertinent to examine the microbiology earlier in the patient's hospital journey, e.g. on the day of admission, to see whether there were more negative results or if different organisms are isolated. however, the lack of sputum production may constrain such studies, especially where deliberate sampling, such as collecting bal or induced sputum, is viewed as unnecessarily hazardous to staff and invasive for patients. among filmarray tests, representing patients, % recorded bacteria or, in one case, a second virus. the microbiology found resembled that typical of hap/vap, in being dominated by enterobacterales, p. aeruginosa and s, aureus ( ) . organisms typically associated with communityacquired pneumonia were much less prominent: nevertheless h. influenzae was detected in patients . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . and s. pneumoniae in one, with all these detections relating to patients who had been hospitalised for at least days, and for days in the case of the s. pneumoniae patient. similar observations in other studies of (covid- -unrelated) hap suggest that these 'community' organisms can, on occasion, be hospital-acquired ( ) . despite the dominance of pathogens typically associated with hap/vap the species distribution differed from that seen in inhale's earlier evaluation study of the filmarray test in hap/vap patients, conducted prior to the covid- pandemic ( , ) . in particular, klebsiella spp. (both k. pneumoniae and k. aerogenes) were significantly more prevalent ( / isolates versus / , p < . ; chi square test) in the covid- patients, whereas p. aeruginosa and e. coli were underrepresented, with the overall species distributions also significantly different (p < . ; chi square test). an altered species distribution in hap/vap may reflect the particular thrombotic lung pathology associated with covid- ( ) . the distribution of bacteria differed even more markedly from that typically seen following influenza, which is dominated by community-acquired pathogens such as s. pneumoniae and h. influenzae, with s. aureus also prominent ( ). in china, zhu et al. found s. pneumoniae to be the most prevalent bacterial pathogen in covd- patients, followed by k. pneumoniae and h. influenzae ( ) . in contrast to our study they mostly sampled early in the course of covid- disease and, using throat swabs, examined patients who varied greatly in disease severity, meaning that comparability is tenuous. also of note, only one of our patients had an additional respiratory virus whereas . % ( / ) of adult patients were positive for viruses in earlier inhale work ( ) . this contrasts with data from china and california, where . - . % of covid- patients had co-infection with other viruses ( , ) . the key difference may be that we specifically examined icu patients, many of whom had been hospitalised for prolonged periods, whereas these authors examined broader groups of covid- patients with more recent community residency. alternatively, the difference may be that these studies were done up to march , and so overlapped the winter respiratory season, whereas we recruited later, in april and may. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . in general, filmarray identified a larger proportion of samples as positive for bacteria than routine culture ( % vs. %); moreover, filmarray more often indicated multiple bacteria in a sample. these findings accord with our previous observations, where we demonstrated that various pcr systems including filmarray, curetis unyvero and also s rdna analysis, all tended to find more organisms than are reported by routine culture from respiratory samples and that they tended also to find the same additional organisms as one another, implying that the vast majority of these additional detections represent organisms genuinely present in the sample ( ) . a curious discrepancy was that routine serology, only obtained from one hospital, reported cases positive for mycoplasma among the cohort (table ) . m. pneumoniae was not detected by filmarray pcr in the corresponding specimens, suggesting either that the serology represented a false positive result, perhaps owing to an anamnestic response, as seen with dengue serology ( ) , or that mycoplasma species other than m. pneumoniae were present. icu clinicians have welcomed this new diagnostic platform to aid the rapid detection (or not) of bacteria in their patients' lower respiratory tracts, and as a guide to treatment. the hazard is, however, that the greater diagnostic yield compared with culture may lead to treatment of patients who merely had a few colonising bacteria. the significance of organisms detected at low population densities ( to cfu/ml) remains open to debate; those found at higher densities were more often reported also by routine microbiology, with this differentiation stronger than in the main inhale trial. more generally, we would underscore that the clinical context must be taken into account and that, as with many microbiological results, detection of an organism does not prove that it is causing infection. balancing these factors will need careful liaison between icus, microbiology and other antimicrobial stewards; furthermore, clinical antibiotic prescribing decisions are subject to factors beyond a valid test result, as demonstrated in the vaprapid study ( ) . that said, preliminary observational data from inhale's earlier work suggested that treatment of additional organisms detected by pcr may have the potential to improve patient outcomes ( ) . to examine the impact of filmarray results in the context of covid- , we are collecting and analysing additional data at the . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint largest of the present sites, assessing consequences for antimicrobial prescribing and patient outcomes. a behavioural sub-study is also underway to investigate how antibiotic decision making has been affected during the covid- pandemic, and how this is influenced by the filmarray. in summary we have shown, first, that the bacteria causing secondary pneumonias in severely-ill covid- patients mostly are enterobacterales, s. aureus and p. aeruginosa, as is typical of hap/vap. the organism distribution is different from 'typical' hap/vap, with k. pneumoniae and k. aerogenes more prominent and e. coli and p. aeruginosa less prominent. secondly, severe covid- patients do not appear to progress to secondary bacterial infection in the same way as do severe influenza patients and do not have the same pathogens; rather, invasive ventilation seems likely to be the main driver for secondary infections in covid- . thirdly, we have shown that filmarray had a higher diagnostic yield than culture-as reported also in inhale's pre-covid- work ( , ) . turnaround from sample to results was around h min compared with the usual h for culture, giving prescribers earlier data to inform antimicrobial decisions. further work is required to establish the contribution of secondary infections to the overall clinical outcome in severely ill covid- patients. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . viral-bacterial co-infections in the respiratory tract influenza and bacterial superinfection: illuminating the immunologic mechanisms of disease pneumonia with bacterial and viral coinfection co-infections: potentially lethal and unexplored in covid- . the lancet microbe bacterial and fungal co-infection in individuals with coronavirus: a rapid review to support covid- antimicrobial prescribing rapid syndromic molecular testing in pneumonia: the current landscape and future potential the impact of using filmarray pneumonia panel molecluar diagnostics for hospital-acquired and ventilator-associated pneumonia on antimicrobial stewardship and patient outcomes in uk critical care: a multicentre randomised controlled trial biomerieux. filmarray pneumonia panel instructions for use en designing an antibiotic prescribing algorithm to complement rapid microbiological investigation of hospital-aquired and ventilator-assoicated pneumonia with the filmarray pneumonia panel plus: the inhale trial uk standards for microbiology investigations. investigation of bronchoalveolar lavage, sputum and associated specimens guidelines for the management of hospital-acquired pneumonia in the uk: report of the working party on hospital-acquired pneumonia of the british society for antimicrobial chemotherapy performance of two multiplex pcr platforms against routine microbiology for the detection of pathogens causing nosocomial pneumonia across intensive care units in the uk appropriateness of antimicrobial prescribing for hospital-acquired and ventilator-associated pneumonia in uk icus assessed aganist pcr-based molecluar diagnostic tests severe covid- infection and thrombotic microangiopathy: success does not come easily co-infection with respiratory pathogens among covid- cases higher co-infection rates in covid a method to prevent sars-cov- igm false positives in gold immunochromatography and enzyme-linked immunosorbent assays biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia (vaprapid ): a randomised controlled trial and process evaluation key: cord- - beuvt u authors: hardy, michaël; michaux, isabelle; lessire, sarah; douxfils, jonathan; dogné, jean-michel; bareille, marion; horlait, geoffrey; bulpa, pierre; chapelle, celine; laporte, silvy; testa, sophie; jacqmin, hugues; lecompte, thomas; dive, alain; mullier, françois title: prothrombotic hemostasis disturbances in patients with severe covid- : individual daily data date: - - journal: data brief doi: . /j.dib. . sha: doc_id: cord_uid: beuvt u this data article accompanies the manuscript entitled: “prothrombotic disturbances of hemostasis of patients with severe covid- : a prospective longitudinal observational cohort study” submitted to thrombosis research by the same authors. we report temporal changes of plasma levels of an extended set of laboratory parameters during the icu stay of the covid- patients included in the monocentre cohort: crp, platelet count, prothrombin time; clauss fibrinogen and clotting factors ii, v and viii levels, d-dimers, antithrombin activity, protein c, free protein s, total and free tissue factor pathway inhibitor, pai- levels, von willebrand factor antigen and activity, adamts- (plasma levels); and of two integrative tests of coagulation (thrombin generation st genesia) and fibrinolysis (global fibrinolytic capacity - gfc). regarding hemostasis, we used double-centrifuged frozen citrated plasma prospectively collected after daily performance of usual coagulation tests. demographic and clinical characteristics of patients and thrombotic and hemorrhagic complications were also collected from patient's electronic medical reports. corresponding instruments and reagents of laboratory hematology for: platelet count, prothrombin time, clauss fibrinogen and clotting factors ii, v and viii levels, d-dimers levels, pai- levels, antithrombin activity, protein c activity, free protein s antigen, total and free tissue factor pathway inhibitor antigens, von willebrand factor antigen and activity, adamts- levels), thrombin generation, and global fibrinolytic capacity (gfc); and c-reactive protein. raw: public repository laboratory data: clinical laboratory tests that describe disturbances of haemostasis of icu patients, severely affected with covid- : primary haemostasis (platelet count, von willebrand factor antigen and activity; adamts- activity); coagulation (prothrombin time, clauss fibrinogen, clotting factors ii, v and viii levels, in vitro thrombin potential), natural anticoagulants (antithrombin activity, protein c activity, free protein s antigen, total and free tissue factor pathway inhibitor antigens); and fibrinolysis (d-dimers levels, pai- activity, global fibrinolytic capacity). clinical data: complications of hemostasis disturbances (thrombosis and hemorrhages) and relevant data for characterization of the cohort (age; sex, bmi, ethnicity, comorbidities, apache ii, sofa scores and pao /fio ratios at icu admission, icu stay duration, anticoagulation regimen, icu length of stay, need for respiratory, cardiocirculatory or renal support; death). the following laboratory tests were performed with a sta-r max (diagnostica stago, asnières-sur-seine) and reagents from stago: prothrombin time (sta-neoptimal), clauss fibrinogen (sta-liquid fib), clotting factor ii (sta-neoptimal and sta -deficient ii), v (sta-neoptimal and sta -deficient v) and viii (sta-ck prest and sta - • the data reported with individual time-courses during the icu stay show the variability of hemostasis parameters over time and between individuals, suggesting varying thrombotic risks and the need for individualization with frequent reassessment of thrombotic prophylaxis. they can benefit to all physicians and scientists dealing with covid- . • these data will be helpful to design further prospective studies focusing on covid- hemostasis disorders: which parameters to measure and at which frequency. demographic and clinical characteristics of observed icu patients are shown in table . values correspond to median (with interquartile and min-max ranges) for quantitative data and to number (percent) for qualitative data. baseline (d ) was defined as icu admission (in namur or elsewhere; patients were transferred from the icu of another belgian hospital), but the laboratory-monitoring period was restricted to the namur icu stay. tests on d were often missing due to delays in patients' inclusion. table represents the changes over time of hemostasis parameters along icu stay of severe covid- patients. observation period has been arbitrarily subdivided into three time-intervals of days starting from d . for each patient and time-interval, parameters medians were calculated. medians and interquartile ranges of patient's medians are presented for the three time-intervals. minimum and maximum values observed are also represented. d-dimers plasma levels are expressed in fibrinogen equivalent units (feu) and 'reference ranges' depicted correspond to dic thresholds according to the isth definition with the reagents we used [ ] . the figures represent the changes over time of measured hemostasis parameters during the icu stay of each of the patients. blue lines represent the reference range locally determined, or previously published under similar analytical conditions, or according to the manufacturer's (see figure legends). stars represent the follow-up period of the patients; orange stars represent the day of diagnosis of a thrombotic complication (which might be delayed form the actual onset). setting chu ucl namur (godinne site, yvoir, belgium), a tertiary academic hospital. all patients admitted to the intensive care unit (icu) of the chu ucl namur for an rt-pcr confirmed severe acute respiratory syndrome coronavirus (sars-cov ) infection from march to april , were considered for inclusion. twenty-one patients were finally included, one patient being excluded because of major therapeutic limitation (i.e.. refusal of tracheal intubation). patients' characteristics were collected at first icu admission. patients were managed according to local standard of care. anticoagulation guidelines from the groupe d'intérêt en hémostase périopératoire (gihp) were implemented in namur from april , [ ] . patients were screened for deep vein thrombosis (dvt) within a week after namur icu admission, and then once a week unless a thrombotic event occurred. pulmonary embolism (as a matter of fact could be in situ arterial thrombosis) was diagnosed directly by contract ct scan or indirectly by transesophageal ultrasonography (for unstable patients that cannot be transferred safely to the radiology department). bleeding events were defined as minor or major according to isth definitions [ ] . blood samples were collected from the arterial line as part of clinical patients' care and at least once a day around a.m. serum was prepared from plastic tubes containing alumina silicate as coagulation activator (vacuette, greiner bio one, kremsmünster, austria), whole blood was collected in k ethylenediaminetetraceatic acid (edta) tubes (vacuette, greiner bio one) and plasma was prepared from mm citrate tubes (vacuette, greiner bio one) using double centrifugation ( g, min, room temperature). plasma samples were frozen at - °c and thawed at °c for min immediately before analysis. laboratory tests were performed on a.m. samples whenever possible or on the temporally closest samples. crp levels were measured on a vitros integrated system (ortho clinical diagnostics, belgium) with crp gold latex reagents (diagam, ghislenghien, belgium) and platelet count on a sysmex xn- analyzer with cellpack reagent (sysmex corporation, kobe, japan). von willebrand factor antigen lt, lag time; ttp, time to peak, ph, peak height; etp, endogenous thrombin potential; tfpi, tissue factor pathway inhibitor. the observation was performed in accordance with the declaration of helsinki and after approval of the ethics committee of the chu ucl namur (nub: b ). sta-neoptimal; expressed as percentage [ ]), clauss fibrinogen (sta-liquid fib), clotting factor ii (sta-neoptimal and sta -deficient ii) thrombin generation was measured with st genesia and stg-thromboscreen reagent (stago) after neutralizing heparin with hexadimethrine bromide ( μg/ml; polybrene global fibrinolytic capacity was measured using the lysis timer instrument (hyphen biomed adamts- activity was measured using the technozym® adamts- von willebrand activity was measured with an acustar analyser (instrumentation laboratory, bedford, usa) and hemosil acustar vwf:rco reagent (instrumentation laboratory) some analyses were purposely performed only every days (i.e. vwf antigen and activity, adamts- , total and free tfpi, tissue-type plasminogen activator) or every other day prothrombotic hemostasis disturbances in patients with severe covid- : a prospective longitudinal observational cohort study a re-evaluation of the d-dimer cut-off value for making a diagnosis according to the isth overt-dic diagnostic criteria: communication from the ssc of the isth thrombin generation measurement using the st genesia thrombin generation system in a cohort of healthy adults: normal values and variability prevention of thrombotic risk in hospitalized patients with covid and hemostasis monitoring: proposals from the french working group on perioperative haemostasis (gihp) the french sdy group on thrombosis and haemostasis (gfht), in collaboration with the french society for anaesthesia and intensive care (sfar) subcommittee on control of a. definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the ssc of the isth evaluation of a new thromboplastin reagent sta-neoptimal on a sta r max analyzer for the measurement of prothrombin time, international normalized ratio and extrinsic factor levels assessment of the analytical performances and sample stability on st genesia system using the stg-drugscreen application a new assay for global fibrinolysis capacity (gfc): investigating a critical system regulating hemostasis and thrombosis and other extravascular functions r: a language and environment for statistical computing the authors would like to thank professor bernard chatelain (université catholique de louvain) for providing very sound and helpful advice on the content of the manuscript. the authors would like also to thank mrs justine baudar, mrs maité guldenpfennig and mr philippe devel for performing the experiments and hyphen biomed for providing the instrument and reagents for global fibrinolytic activity assay (lysis timer). this work was supported by the belgian fonds national de la recherche scientifique: 'anticoagulation fibrinolysis covid ' (reference: ). the authors declare that they have no known competing financial interests or personal relationships that have or could be perceived to have influenced the work reported in this article. key: cord- -jutof v authors: van de veerdonk, f. l.; janssen, n. a. f.; grondman, i.; de nooijer, a. h.; koeken, v. a. c. m.; matzaraki, v.; boahen, c. k.; kumar, v.; kox, m.; koenen, h. j. p. m.; smeets, r. l.; joosten, i.; brampuumlggemann, r. j. m.; kouijzer, i. j. e.; van der hoeven, h. g.; schouten, j. a.; frenzel, t.; reijers, m.; hoefsloot, w.; dofferhoff, a. s. m.; kerckhoffs, a. p. m.; blaauw, m. j. t.; veerman, k.; maas, c.; schoneveld, a. h.; hoefer, i. e.; derde, l. p. g.; willems, l.; toonen, e.; van deuren, m.; van der meer, j. w. m.; van crevel, r.; giamarellos-bourboulis, e. j.; joosten, l. a. b.; he, van den title: a systems approach to inflammation identifies therapeutic targets in sars-cov- infection date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: jutof v background infection with sars-cov- manifests itself as a mild respiratory tract infection in the majority of individuals, which progresses to a severe pneumonia and acute respiratory distress syndrome (ards) in - % of patients. inflammation plays a crucial role in the pathogenesis of ards, with immune dysregulation in severe covid- leading to a hyperinflammatory response. a comprehensive understanding of the inflammatory process in covid- is lacking. methods in this prospective, multicenter observational study, patients with pcr-proven or clinically presumed covid- admitted to the intensive care unit (icu) or clinical wards were included. demographic and clinical data were obtained and plasma was serially collected. concentrations of il- , tnf-, complement components c a, c c and the terminal complement complex (tcc) were determined in plasma by elisa. additionally, circulating biomarkers were assessed using targeted proteomics. results were compared between icu and non icu patients. findings a total of ( icu and non icu) patients were included. il- plasma concentrations were elevated in covid- (icu vs. non icu, median . pg/ml [iqr . - . vs. . pg/ml [ . - . ]), whereas tnf- concentrations were relatively low and not different between icu and non icu patients (median . pg/ml [iqr . - . ] and . pg/ml [iqr . - . ], respectively). c a and terminal complement complex (tcc) concentrations were significantly higher in icu vs. non icu patients (median . ng/ml [iqr . - . ]) vs. . ng/ml [iqr . - . for c a and mau/ml [iqr - vs. mau/ml [iqr - ] for tcc) on the first day of blood sampling. targeted proteomics demonstrated that il- (logfc . ), several chemokines and hepatocyte growth factor (logfc . ) were significantly upregulated in icu vs. non icu patients. in contrast, stem cell factor was significantly downregulated (logfc - . ) in icu vs. non icu patients, as were dpp (logfc - . ) and protein c inhibitor (log fc - . ), the latter two factors also being involved in the regulation of the kinin-kallikrein pathway. unsupervised clustering pointed towards a homogeneous pathogenetic mechanism in the majority of patients infected with sars-cov- , with patient clustering mainly based on disease severity. interpretation we identified important pathways involved in dysregulation of inflammation in patients with severe covid- , including the il- , complement system and kinin-kallikrein pathways. our findings may aid the development of new approaches to host-directed therapy. infection with sars-cov- manifests itself as a mild respiratory tract infection in the majority of individuals, which progresses to a severe pneumonia and acute respiratory distress syndrome (ards) in - % of patients. inflammation plays a crucial role in the pathogenesis of ards, with immune dysregulation in severe covid- leading to a hyperinflammatory response. a comprehensive understanding of the inflammatory process in covid- is lacking. in this prospective, multicenter observational study, patients with pcr-proven or clinically presumed covid- admitted to the intensive care unit (icu) or clinical wards were included. demographic and clinical data were obtained and plasma was serially collected. concentrations of il- , tnf-α, complement components c a, c c and the terminal complement complex (tcc) were determined in plasma by elisa. additionally, circulating biomarkers were assessed using targeted proteomics. results were compared between icu and non icu patients. severe acute respiratory syndrome coronavirus- (sars-cov- ) is a highly contagious virus that spread rapidly from china to the rest of a highly-interconnected world to become a pandemic in march . the clinical spectrum of sars-cov- infection (also termed varies from asymptomatic disease and symptoms of mild upper respiratory tract infection, to severe pneumonia with acute respiratory distress syndrome (ards), respiratory failure and death. the spread of sars-cov- around the world infected millions of people in several months and killed tens of thousands. effective treatments are therefore urgently needed for the high numbers of severely ill patients. although much has been learned in a very short time, a comprehensive understanding of the pathophysiology of covid- is still lacking. the most important complication in covid- is respiratory failure, which is mediated by local inflammation and edema, the development of ards, and subsequently hypoxia. inflammation plays a central role in the pathogenesis of ards and circulating concentrations of proinflammatory cytokines such as interleukin (il)- , tumour necrosis factor (tnf)-α, monocyte chemoattractant protein (mcp)- , macrophage inflammatory protein (mip)- α and interferon- inducible protein (ip)- are higher in covid- patients on the intensive care unit (icu) than in those who do not require icu admission. this systemic inflammatory response is also associated with elevated d-dimer concentrations in the circulation and hyperactive ccr +th + t-cells locally in the lung. , a recent study showed that hyperinflammation in covid- patients is characterised by a high cytokine production capacity of circulating monocytes despite the severity of the disease, a feature different from other types of sepsis. the systemic inflammatory response in covid- patients is accompanied by lymphopenia, which is one of the most striking features encountered in severely ill patients, with both cd and cd lymphocytes being deficient. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint whereas from these data an exuberant innate immune response appears to represent the main immune dysregulation in patients with severe covid- infection, so far only a limited number of inflammatory mediators known to be involved in other diseases have been assessed. a comprehensive, unbiased understanding of the inflammatory processes in covid- is lacking, while this is crucial for the development of effective host-directed therapies to restore the immune balance in covid- patients. in addition, it is not known whether the pathophysiology of covid- is homogeneous between patients, or whether immune endotypes are present which may lead to complications through different pathophysiological mechanisms, as have been identified in bacterial sepsis patients. in the present study, we used targeted proteomics and systems biology analyses in a systemsbased approach to analyze the inflammatory response in patients with mild versus severe covid- . we utilised a combination of multiple elisa measurements and olink panels to measure more than different circulating inflammatory parameters in the plasma of covid- patients. we subsequently identified several major inflammatory pathways that discriminate between severely ill patients and patients with mild disease, which therefore represent potential starting points for therapeutic targeting. subsequently, the unbiased analysis of the proteomics data also suggests a homogeneous inflammatory pathogenesis of the disease, with the main stratification of patients based on disease severity, rather than different inflammatory endotypes. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint this study was performed according the latest version of the declaration of helskini and guidelines for good clinical practice. the local independent ethical committee approved the study protocol (cmo - and cmo - ). all patients (or their representatives) admitted to the radboud university medical center (radboudumc), a tertiary care university medical care facility, with a pcr-proven sars-cov- infection or presumed infection (based on signs and symptoms and findings on computed tomography (ct) scans) were asked for informed consent for participation in this study. after obtaining verbal informed consent, ethylenediaminetetraacetic acid (edta) blood was collected three times per week (icu) or every hours (non icu wards) during times of routine venapuncture for laboratory testing and stored at c until further processing in the laboratory. after centrifugation for minutes at rpm ( g) at room temperature, plasma was collected and stored at either - c for later enzyme-linked immunosorbent assay (elisa) for cytokines and chemokines or stored at - c for later analysis. demographic data, medical history and clinical laboratory measurements were collected from the medical file, wehere available, and processed in encoded form in electronic case report forms using castor electronic data capture (castor edc, amsterdam, the netherlands). for complement data analysis, data from healthy controls (from the fg cohort; www.humanfunctionalgenomics.org) and bacterial septic shock patients early in their course of disease (classified according to the sepsis criteria) (from the provide study cohort; clinicaltrials.gov nct ) were used as comparisons for covid- patients. commercially available elisa kits (quantikine elisa kits, r&d systems, inc., minneapolis, mn, usa) were used for assessing concentrations of il- and tnf-α in patient plasma . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . according to the manufacturer's instructions. inter-assay variation was assessed by calculating the coefficient of variation (%cv) for the quality control samples between assay runs. a %cv of ≤ was considered low variation. circulating proteins were measured in plasma using the commercially available multiplex proximity extension assay (pea) from olink proteomics ab (uppsala sweden). in this assay, proteins are recognised by pairs of oligonucleotide-labeled antibodies ("probes"),. when the two probes are in close proximity, a new pcr target sequence is formed by a proximitydependent dna polymeration reaction. the resulting sequence is subsequently detected and quantified using a standard real-time pcr. in total, proteins from three different panels were for the proteomic analyses, biomarkers were excluded from the analysis when the target protein was detected in less than % of the samples. protein concentrations under the detection threshold were replaced with the proteins lower limit of detection (lod). in addition, olink proteomics performed quality control per sample during which samples that deviate less than . npx from the median pass the quality control. for demographic, laboratory, cytokine/chemokine and complement data, icu and non icu groups were compared using the mann-whitney test or kruskal-wallis test with dunn's . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint multiple comparison test (when comparing more than two groups), assuming non-gaussian distribution of variables. percentages were compared using fisher's exact test. a p-value < . was considered statistically significant. statistical analyses were performed using either graphpad prism for windows (version . , graphpad software, inc., san diego, ca, usa) or r/bioconductor (https://www.r-project.org/). differential expression (de) analysis of olink® proteins between icu and non-icu groups was performed using the r package limma, where a linear model was applied with age and sex as covariates. limma uses an empirical bayes method to moderate the standard errors of the estimated log-fold changes. unsupervised hierarchical clustering was performed to identify patient endotypes. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint plasma was collected from patients with confirmed or presumed (based on signs and symptoms, imaging results and epidemiological exposure) covid- admitted to icu departments (n = ) or designated clinical wards (n = ). age, sex, body mass index (bmi), day of admission at the time of first blood collection and percentages of polymerase chain reaction (pcr)-proven versus presumed covid- diagnosis are shown in table . more men than women were admitted, and the mean bmi was . kg/m (standard deviation (sd): table ). although circulating ferritin concentrations were also increased in icu patients as compared to non icu covid- patients, no statistically significant differences were observed ( µg/l [iqr . vs. µg/l [iqr . - ], p = . ; table ). plasma cytokine measurements showed that il- concentrations were elevated, especially in is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint p = . for day - ; figure a ). sequential sampling showed that tnf-α remained low during admission with few differences between patients in the icu or on the ward, with the exception of later during infection when icu patients had higher concentrations. il- concentrations declined over time but remained high after days in patients primarily admitted to the icu ( figure a ). complement activation was investigated in patients by measuring c a and terminal complement complex (tcc) (see supplementary table figure b ). to perform a comprehensive assessment of inflammatory biomarkers and pathways relevant to covid- , we used the proximity extension assay (pea) based immunoassay (olink platform) to measure approximately plasma biomarkers in covid- patients ( icu versus non icu patients), sequentially included in our study (see supplementary table for patient characteristics). figure shows that il- (adjusted p value . , log fold change (logfc) . ) and several chemokines are the most significantly elevated markers in patients with severe covid- in the icu as compared to non icu patients. strikingly, the most downregulated biomarker (with the lowest fold change difference) in . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . they both have a function in regulating the kinin-kallikrein system, in which dpp degradates bradykinin and serpina inhibits plasma kallikrein, , the enzyme that processes kininogen into bradykinin. patients with severe infectious diseases such as sepsis can be categorised into immune endotypes that differ in characteristics, trajectories and outcome. this is important because these endotypes indicate involvement of different pathophysiological mechanisms, which may require different immunomodulatory treatment strategies. unsupervised clustering analysis of the pea proteins that significantly differ between icu and non icu, c-reactive protein (crp), d-dimer, ferritin, c a, c c and tcc, revealed that icu patients cluster separately from non icu patients, but that within these clusters no significantly different profiles could be identified ( figure a ). all covid- patients have the same profile of markers, which is more pronounced in icu patients. this indicates that covid- is characterised by a homogeneous inflammatory response and that specific endotypes cannot be discerned. patients cluster according to disease severity but they all seem to share the same underlying pathophysiological mechanism: activated complement system, an imbalanced kinin-kallikrein system, increased inflammation, lymphopenia, and decreased apoptosis. although we did not demonstrate any endotypes related to disease severity, there are clear risk factors for severity of covid- . we compared men and women admitted to . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint non icu wards ( figure b ). among the differentially expressed inflammatory biomarkers, serpina , which is also called vaspin and is able to inhibit tissue kallikreins was lower in men compared to women. serum amyloid a , an acute phase protein with known roles in autoinflammatory syndromes, was also strongly decreased in men compared to women. interestingly, circulating angiotensin converting enzyme (ace) , which is also the sars-cov- receptor, was higher in men. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . il- is also an inducer of hepatocyte growth factor (hgf), , another cytokine strongly upregulated in critically ill covid- patients. hgf is secreted by mesenchymal cells and acts . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint as a multi-functional cytokine on cells of mainly epithelial origin, in which it regulates cell growth, morphogenesis and tissue regeneration. interestingly, recent studies have shown that hgf induces cmet through its receptor, a pathway that is important for plasma cell generation in multiple myeloma. this observation is paralleled by findings of large numbers of plasma cells in the circulation of covid- patients, as well as in the lungs, where they induce plasma cell endothelitis (kathrien grunberg, personal communcation). hgf's antiapoptotic and proliferative effects may also play a role in the long-term fibrotic complications in some patients. other pro-survival metabolic mediators such as fgf may also play a role in these processes. one of the most exciting findings of our analyses is that of the factors involved in the kininkallikrein system, which plays an important role in the local inflammation in the lung. ace/ace and dpp are important enzymes in the degradation pathway of bradykinin, a nonapeptide that regulates vascular permeability. we have recently hypothesised that the loss of bradykinin degradation capacity is a crucial mechanism leading to pulmonary angioedema in covid- . moreover, we now demonstrate that serpina , an inhibitor of plasma kallikrein and dpp , which degradates bradykinin, are significantly lower in severe covid- disease. plasma kallikrein processes high molecular weight kininogen (hmwk) into bradykinin, which in turn will activate bradykinin receptor (b r) that is constitutively expressed on endothelial cells in the lung. in addition, tissue kallikrein can also contribute to local bradykinin formation, and we observed that serpina , which is a specific tissue kallikrein inhibitor, was lower in men. the vicious cycle of an activated kinin-kallikrein system resulting in bradykinin receptor activation due to loss of inhibitory enzymes is key for the vascular leakage. the kinin-kallikrein system may thus represent an important therapeutic target in severe covid- with ards, and proof-of-principle clinical trials are currently under way to test this hypothesis in our institution. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint in addition to the inflammatory factors that are upregulated in covid- patients in the icu, a number of cytokines were shown to be lower in the severely ill patients. among them, most notable is the strong decrease in scf. scf (also known as kit-ligand) is a cytokine that binds to the c-kit receptor (cd ), and plays an important role in the regulation of haematopoietic stem cells (hscs) in the stem cell niche in the bone marrow. scf stimulates the survival of hscs in vitro and induces self-renewal and maintenance of hscs in vivo. it is thus tempting to speculate that the strong downregulation of scf in patients with severe forms of covid- contributes to the deep and sustained lymphopenia that accompanies a poor outcome. adjuvant host-directed therapies in severe infections such as sepsis have been proposed to have the potential to improve the outcome of patients. however, all immunotherapies investigated in sepsis in the last three decades failed to show clinical efficacy, and it has been hypothesised that the lack of adjustment of the immunotherapy approach to the (specific) immune status of the patient is one of the most important reasons for this. sepsis endotypes based on transcriptional patterns in circulating immune cells have been described to influence patient outcomes, and clinical trials have been designed to treat patients in a personalised approach. we also investigated whether we could identify inflammatory endotypes among covid- patients based on the comprehensive assessment of inflammatory markers measured: one could envisage that the pathophysiology of the disease in some patients would be characterised by excessive activation of the il- /il- pathway, while in other patients disease would be mainly caused by the kinin-kallikrein system or complement activation. however, unbiased clustering of covid- patients differentiated patients based on disease severity (icu versus non icu), rather than identifying different inflammatory clusters ( figure ). this suggest a relative homogeneity of the inflammatory pathophysiology of the patients. we cannot exclude late differentiation of patients more prone to specific complications (e.g., late progression to fibrosis), but these current insights suggest that the inflammation in the majority of patients follow a relatively homogeneous pattern which can be used as a guide for therapy. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint all these data allow to build a pathogenetic model of inflammation in covid- patients, which might guide immunotherapeutic approaches with the highest potential to translate into clinical benefit. in the beginning of the sars-cov- infection, a broad activation of innate immunity mechanisms is induced by the virus, which is necessary for the induction of host defense and virus elimination. while this is successful in the majority of patients, in a significant minority of them the disease progresses to a more severe form necessitating icu admission. in conclusion, the present study is the first comprehensive assessment of inflammatory pathways in covid- patients (figure ) . the main pathways of dysregulation of inflammation are described that correlate with increased severity, including an unknown role for the kinin-kallikrein system and depression of stem cell factor as a likely contributor to lymphopenia. future studies are needed to engage these pathways therapeutically, and to attempt to improve the outcome of severely ill patients with covid- . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . the other authors declare no competing interests. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . age and sex are used as covariates. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . b. volcano plot of circulatory proteins (n = ) of covid- patients on the non icu ward compared between males (n = ) and females (n = ). differential expression was . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint performed using a linear model with age as covariate, p values < . were considered statistically significant (depicted in red). . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint tables table . demographic and covid- . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint virtual press conference on covid- - clinical features of patients infected with novel coronavirus in wuhan, china pathological findings of covid- associated with acute respiratory distress syndrome clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study complex immune dysregulation in covid- patients with severe respiratory failure dysregulation of immune response in patients with covid- in wuhan, china classification of patients with sepsis according to blood genomic endotype: a prospective cohort study homogenous -plex pea immunoassay exhibiting high sensitivity, specificity, and excellent scalability limma powers differential expression analyses for rna-sequencing and microarray studies stem cell factor and hematopoiesis dipeptidyl peptidase iv in angiotensin-converting inactivation of human plasma kallikrein and factor xia by protein c inhibitor kallikrein-related peptidase is the second klk protease targeted by the serpin vaspin the role of interleukin- in septic shock global changes in interleukin- -dependent gene expression patterns in mouse livers after partial hepatectomy structural and functional characterization of the mouse hepatocyte growth factor gene promoter hepatocyte growth factor induces proliferation and morphogenesis in nonparenchymal epithelial liver cells identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product attenuation of pulmonary ace activity impairs inactivation of des-arg( ) bradykinin/bkb r axis and facilitates lps-induced neutrophil infiltration kinins and cytokines in covid- : a comprehensive pathophysiological approach regulation of hematopoietic stem cells by the steel factor/kit signaling pathway clinical characteristics of deceased patients with coronavirus disease : retrospective study the immunopathology of sepsis and potential therapeutic targets the authors would like to thank the entire rci-covid- study group: martin jaeger, helga dijkstra, heidi lemmers, liesbeth van emst, kiki schraa, cor jacobs, anneke hijmans, trees jansen, fieke weren, liz fransman, jelle gerretsen, hetty van der eng, noortje rovers, margreet klop-riehl, josephine van de maat, gerine nijman, simone moorlag, esther taks, key: cord- - nhgxoim authors: huang, chaolin; wang, yeming; li, xingwang; ren, lili; zhao, jianping; hu, yi; zhang, li; fan, guohui; xu, jiuyang; gu, xiaoying; cheng, zhenshun; yu, ting; xia, jiaan; wei, yuan; wu, wenjuan; xie, xuelei; yin, wen; li, hui; liu, min; xiao, yan; gao, hong; guo, li; xie, jungang; wang, guangfa; jiang, rongmeng; gao, zhancheng; jin, qi; wang, jianwei; cao, bin title: clinical features of patients infected with novel coronavirus in wuhan, china date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: nhgxoim background: a recent cluster of pneumonia cases in wuhan, china, was caused by a novel betacoronavirus, the novel coronavirus ( -ncov). we report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. methods: all patients with suspected -ncov were admitted to a designated hospital in wuhan. we prospectively collected and analysed data on patients with laboratory-confirmed -ncov infection by real-time rt-pcr and next-generation sequencing. data were obtained with standardised data collection forms shared by who and the international severe acute respiratory and emerging infection consortium from electronic medical records. researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. outcomes were also compared between patients who had been admitted to the intensive care unit (icu) and those who had not. findings: by jan , , admitted hospital patients had been identified as having laboratory-confirmed -ncov infection. most of the infected patients were men ( [ %] of ); less than half had underlying diseases ( [ %]), including diabetes (eight [ %]), hypertension (six [ %]), and cardiovascular disease (six [ %]). median age was · years (iqr · – · ). ( %) of patients had been exposed to huanan seafood market. one family cluster was found. common symptoms at onset of illness were fever ( [ %] of patients), cough ( [ %]), and myalgia or fatigue ( [ %]); less common symptoms were sputum production ( [ %] of ), headache (three [ %] of ), haemoptysis (two [ %] of ), and diarrhoea (one [ %] of ). dyspnoea developed in ( %) of patients (median time from illness onset to dyspnoea · days [iqr · – · ]). ( %) of patients had lymphopenia. all patients had pneumonia with abnormal findings on chest ct. complications included acute respiratory distress syndrome ( [ %]), rnaaemia (six [ %]), acute cardiac injury (five [ %]) and secondary infection (four [ %]). ( %) patients were admitted to an icu and six ( %) died. compared with non-icu patients, icu patients had higher plasma levels of il , il , il , gscf, ip , mcp , mip a, and tnfα. interpretation: the -ncov infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with icu admission and high mortality. major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. funding: ministry of science and technology, chinese academy of medical sciences, national natural science foundation of china, and beijing municipal science and technology commission. coronaviruses are enveloped non-segmented positivesense rna viruses belonging to the family coronaviridae and the order nidovirales and broadly distributed in humans and other mammals. although most human coronavirus infections are mild, the epidemics of the two betacoronaviruses, severe acute respiratory syndrome coronavirus (sars-cov) [ ] [ ] [ ] and middle east respiratory syndrome coronavirus (mers-cov), , have caused more than cumulative cases in the past two decades, with mortality rates of % for sars-cov and % for mers-cov. , the coronaviruses already identified might only be the tip of the iceberg, with potentially more novel and severe zoonotic events to be revealed. in december, , a series of pneumonia cases of unknown cause emerged in wuhan, hubei, china, with clinical presentations greatly resembling viral pneumonia. deep sequencing analysis from lower respiratory tract samples indicated a novel coronavirus, which was named novel coronavirus ( -ncov). thus far, more than confirmed cases, including in health-care workers, have been identified in wuhan, and several exported cases have been confirmed in other provinces in china, and in thailand, japan, south korea, and the usa. - we aim to describe epidemiological, clinical, laboratory, and radiological characteristics, treatment, and outcomes of patients confirmed to have -ncov infection, and to compare the clinical features between intensive care unit (icu) and non-icu patients. we hope our study findings will inform the global community of the emergence of this novel coronavirus and its clinical features. following the pneumonia cases of unknown cause reported in wuhan and considering the shared history of exposure to huanan seafood market across the patients, an epidemiological alert was released by the local health authority on dec , , and the market was shut down on jan , . meanwhile, suspected cases with fever and dry cough were transferred to a designated hospital starting from dec , . an expert team of physicians, epidemiologists, virologists, and government officials was soon formed after the alert. since the cause was unknown at the onset of these emerging infections, the diagnosis of pneumonia of unknown cause in wuhan was based on clinical characteristics, chest imaging, and the ruling out of common bacterial and viral pathogens that cause pneumonia. suspected patients were isolated using airborne precautions in the designated hospital, jin yintan hospital (wuhan, china), and fit-tested n masks and airborne precautions for aerosol-generating procedures were taken. this study was approved by the national health commission of china and ethics commission of jin yin-tan hospital (ky- - . ). written informed consent was waived by the ethics commission of the designated hospital for emerging infectious diseases. local centres for disease control and prevention collected respiratory, blood, and faeces specimens, then shipped them to designated authoritative laboratories to detect the pathogen (nhc key laboratory of systems biology of pathogens and christophe mérieux laboratory, beijing, china). a novel coronavirus, which was named -ncov, was isolated then from lower respiratory tract specimen and a diagnostic test for this virus was developed soon after that. of suspected cases, patients were confirmed to be infected with -ncov. the presence of -ncov in respi ratory specimens was detected by nextgeneration se quencing or real-time rt-pcr methods. the primers and probe target to envelope gene of cov were used and the sequences were as follows: forward primer ′-acttctttttcttgctttcgtggt- ′; reverse primer ′-gcagcagtacgcacacaatc- ′; and the probe ′cy -ctagttacactagccatccttactgc- ′bhq . conditions for the amplifications were °c for min, °c for min, followed by cycles of °c for s and °c for s. initial investigations included a complete blood count, coagulation profile, and serum biochemical test (including renal and liver function, creatine kinase, lactate dehydrogenase, and electrolytes). respiratory specimens, including nasal and pharyngeal swabs, bronchoalveolar lavage fluid, sputum, or bronchial aspirates were tested for common viruses, including influenza, avian influenza, respiratory syncytial virus, adenovirus, parainfluenza virus, sars-cov and mers-cov using real-time rt-pcr assays approved by the china food and drug administration. routine bacterial and fungal examinations were also performed. given the emergence of the -ncov pneumonia cases during the influenza season, antibiotics (orally and intravenously) and osel tamivir (orally mg twice daily) were empirically administered. corticosteroid therapy evidence before this study human coronaviruses, including hcov- e, oc , nl , and hku , cause mild respiratory diseases. fatal coronavirus infections that have emerged in the past two decades are severe acute respiratory syndrome coronavirus (sars-cov) and the middle east respiratory syndrome coronavirus. we searched pubmed and the china national knowledge infrastructure database for articles published up to jan , , using the keywords "novel coronovirus", " novel coronavirus", or " -ncov". no published work about the human infection caused by the novel coronavirus ( -ncov) could be identified. we report the epidemiological, clinical, laboratory, and radiological characteristics, treatment, and clinical outcomes of laboratory-confirmed cases infected with -ncov. ( %) of patients had a history of direct exposure to the huanan seafood market. the median age of patients was · years (iqr · - · ), and ( %) patients had underlying disease. all patients had pneumonia. a third of patients were admitted to intensive care units, and six died. high concentrations of cytokines were recorded in plasma of critically ill patients infected with -ncov. implications of all the available evidence -ncov caused clusters of fatal pneumonia with clinical presentation greatly resembling sars-cov. patients infected with -ncov might develop acute respiratory distress syndrome, have a high likelihood of admission to intensive care, and might die. the cytokine storm could be associated with disease severity. more efforts should be made to know the whole spectrum and pathophysiology of the new disease. (methylprednisolone - mg per day) was given as a combined regimen if severe community-acquired pneumonia was diagnosed by physicians at the designated hospital. oxygen support (eg, nasal cannula and invasive mechanical ventilation) was administered to patients according to the severity of hypoxaemia. repeated tests for -ncov were done in patients confirmed to have -ncov infection to show viral clearance before hospital discharge or discontinuation of isolation. we reviewed clinical charts, nursing records, laboratory findings, and chest x-rays for all patients with laboratoryconfirmed -ncov infection who were reported by the local health authority. the admission data of these patients was from dec , , to jan , . epidemiological, clinical, laboratory, and radiological characteristics and treatment and outcomes data were obtained with standardised data collection forms (modified case record form for severe acute respiratory infection clinical characterisation shared by who and the international severe acute respiratory and emerging infection consortium) from electronic medical records. two researchers also independently reviewed the data collection forms to double check the data collected. to ascertain the epidemiological and symptom data, which were not available from electronic medical records, the researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. to characterise the effect of coronavirus on the production of cytokines or chemokines in the acute phase of the illness, plasma cytokines and chemokines (il b, il ra, il , il , il , il , il , il (also known as cxcl ), il , il , il p , il , il , il a, eotaxin (also known as ccl ), basic fgf , gcsf (csf ), gmcsf (csf ), ifnγ, ip (cxcl ), mcp (ccl ), mip a (ccl ), mip b (ccl ), pdgfb, rantes (ccl ), tnfα, and vegfa were measured using human cytokine standard -plex assays panel and the bio-plex system (bio-rad, hercules, ca, usa) for all patients according to the manufacturer's instructions. the plasma samples from four healthy adults were used as controls for crosscomparison. the median time from being transferred to a designated hospital to the blood sample collection was days (iqr - ). each µl plasma sample from the patients and contacts was added into µl of trizol ls ( ; thermo fisher scientific, carlsbad, ca, usa) in the biosafety level laboratory. total rna was extracted by direct-zol rna miniprep kit (r ; zymo research, irvine, ca, usa) according to the manufacturer's instructions and µl elution was obtained for each sample. µl rna was used for real-time rt-pcr, which targeted the np gene using agpath-id one-step rt-pcr reagent (am ; thermo fisher scientific). the final reaction mix concentration of the primers was nm and probe was nm. real-time rt-pcr was per formed using the following conditions: °c for min and °c for min, cycles of amplification at °c for s and °c for s. since we did not perform tests for detecting infectious virus in blood, we avoided the term viraemia and used rnaaemia instead. rnaaemia was defined as a positive result for real-time rt-pcr in the plasma sample. acute respiratory distress syndrome (ards) and shock were defined according to the interim guidance of who for novel coronavirus. hypoxaemia was defined as arterial oxygen tension (pao₂) over inspiratory oxygen fraction (fio₂) of less than mm hg. acute kidney injury was identified and classified on the basis of the highest serum creatinine level or urine output criteria according to the kidney disease improving global outcomes classification. secondary infection was diagnosed if the patients had clinical symptoms or signs of nosocomial pneumonia or bacteraemia, and was combined with a positive culture of a new pathogen from a lower respiratory tract specimen (including the sputum, transtracheal aspirates, or bronchoalveolar lavage fluid, or from blood samples taken ≥ h after admission). cardiac injury followed the definition used in our previous study in h n patients. in brief, cardiac injury was diagnosed if serum levels of cardiac biomarkers (eg, troponin i) were above the th percentile upper reference limit, or new abnormalities were shown in electrocardiography and echocardiography. continuous variables were expressed as median (iqr) and compared with the mann-whitney u test; categorical variables were expressed as number (%) and compared by χ² test or fisher's exact test between icu care and no icu care groups. boxplots were drawn to describe plasma cytokine and chemokine concentrations. a two-sided α of less than · was considered statistically significant. statistical analyses were done using the sas software, version . , unless otherwise indicated. the funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. the corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. by jan , , admitted hospital patients were identified as laboratory-confirmed -ncov infection in wuhan. [ %]) of the -ncov-infected patients were aged - years, and ( %) were aged - years (figure a). the median age of the patients was · years (iqr · - · ; table ). in our cohort of the first patients as of jan , no children or adolescents were infected. of the patients, ( %) were admitted to the icu because they required high-flow nasal cannula or higher-level oxygen support measures to cor rect hypoxaemia. most of the infected patients were men ( ). the symptom onset date of the first patient identified was dec , . none of his family members developed fever or any respiratory symptoms. no epidemiological link was found between the first patient and later cases. the first fatal case, who had continuous exposure to the market, was admitted to hospital because of a -day history of fever, cough, and dyspnoea. days after illness onset, his wife, a -year-old woman who had no known history of exposure to the market, also presented with pneumonia and was hospitalised in the isolation ward. the most common symptoms at onset of illness were fever ( most patients had normal serum levels of procalcitonin on admission (procalcitonin < · ng/ml; [ %] patients; table ). four icu patients developed secondary infections. three of the four patients with secondary infection had procalcitonin greater than · ng/ml ( · ng/ml, · ng/ml, and · ng/ml). on admission, abnormalities in chest ct images were detected among all patients. of the patients, ( %) had bilateral involvement (table ). the typical findings of chest ct images of icu patients on admission were bilateral multiple lobular and subsegmental areas of consolidation ( figure a) . the representative chest ct findings of non-icu patients showed bilateral groundglass opacity and subseg mental areas of consolidation (figure b). later chest ct images showed bilateral ground-glass opacity, whereas the consolidation had been resolved (figure c). initial plasma il b, il ra, il , il , il , il , basic fgf, gcsf, gmcsf, ifnγ, ip , mcp , mip a, mip b, pdgf, tnfα, and vegf concentrations were higher in both icu patients and non-icu patients than in healthy adults (appendix pp - ). plasma levels of il , il p , il , eotaxin, and rantes were similar between healthy adults and patients infected with -ncov. further comparison between icu and non-icu patients showed that plasma concentrations of il , il , il , gcsf, ip , mcp , mip a, and tnfα were higher in icu patients than non-icu patients. all patients had pneumonia. ; table ). invasive mechanical ventilation was required in four ( %) patients, with two of them ( %) had refractory hypoxaemia and received extracorporeal membrane oxygenation as salvage therapy. all patients were administered with empirical antibiotic treatment, and ( %) patients received antiviral therapy (osel tamivir). additionally, nine ( %) patients were given systematic corticosteroids. a comparison of clinical features between patients who received and did not receive systematic corticosteroids is in the appendix (pp - ). as of jan , , ( %) of patients have been dis charged and six ( %) patients have died. fitness for discharge was based on abatement of fever for at least days, with improvement of chest radiographic evidence and viral clearance in respiratory samples from upper respiratory tract. we report here a cohort of patients with laboratoryconfirmed -ncov infection. patients had serious, sometimes fatal, pneumonia and were admitted to the designated hospital in wuhan, china, by jan , . clinical presentations greatly resemble sars-cov. patients with severe illness developed ards and required icu admission and oxygen therapy. the time between hospital admission and ards was as short as days. at this stage, the mortality rate is high for -ncov, because six ( %) of patients in this cohort died. the number of deaths is rising quickly. as of jan , , laboratory-confirmed -ncov infec tions were reported in china, with fatal cases. reports have been released of exported cases in many provinces in china, and in other countries; see online for appendix some health-care workers have also been infected in wuhan. taken together, evidence so far indicates human transmission for -ncov. we are concerned that -ncov could have acquired the ability for efficient human trans mission. airborne precautions, such as a fit-tested n respirator, and other personal protective equipment are strongly recommended. to prevent further spread of the disease in health-care settings that are caring for patients infected with -ncov, onset of fever and respiratory symptoms should be closely moni tored among health-care workers. testing of respiratory specimens should be done immediately once a diagnosis is suspected. serum antibodies should be tested among health-care workers before and after their exposure to -ncov for identification of asymp tomatic infections. similarities of clinical features between -ncov and previous betacoronavirus infections have been noted. in this cohort, most patients presented with fever, dry cough, dyspnoea, and bilateral ground-glass opacities on chest ct scans. these features of -ncov infection bear some resemblance to sars-cov and mers-cov infections. , however, few patients with -ncov infection had prominent upper respiratory tract signs and symptoms (eg, rhinorrhoea, sneezing, or sore throat), indicating that the target cells might be located in the lower airway. furthermore, -ncov patients rarely developed intestinal signs and symptoms (eg, diarrhoea), whereas about - % of patients with mers-cov or sars-cov infection had diarrhoea. faecal and urine samples should be tested to exclude a potential alternative route of transmission that is unknown at this stage. the pathophysiology of unusually high pathogenicity for sars-cov or mers-cov has not been completely understood. early studies have shown that increased amounts of proinflammatory cytokines in serum (eg, il b, il , il , ifnγ, ip , and mcp ) were associated with pulmonary inflammation and extensive lung damage in sars patients. mers-cov infection was also reported to induce increased concentrations of proinflammatory cytokines (ifnγ, tnfα, il , and il ). we noted that patients infected with -ncov also had high amounts of il b, ifnγ, ip , and mcp , probably leading to activated t-helper- (th ) cell responses. moreover, patients requiring icu admission had higher concentrations of gcsf, ip , mcp , mip a, and tnfα than did those not requiring icu admission, suggesting that the cytokine storm was associated with disease severity. however, -ncov infection also initiated increased secretion of t-helper- (th ) cytokines (eg, il and il ) that suppress inflammation, which differs from sars-cov infection. further studies are necessary to characterise the th and th responses in -ncov infection and to elucidate the pathogenesis. autopsy or biopsy studies would be the key to understand the disease. in view of the high amount of cytokines induced by sars-cov, , mers-cov, , and -ncov infections, corticosteroids were used frequently for treatment of patients with severe illness, for possible benefit by reducing inflammatory-induced lung injury. however, current evidence in patients with sars and mers suggests that receiving corticosteroids did not have an effect on mortality, but rather delayed viral clearance. [ ] [ ] [ ] therefore, corticosteroids should not be routinely given systemically, according to who interim guidance. among our cohort of laboratory-confirmed patients with -ncov infection, corticosteroids were given to very few non-icu cases, and low-to-moderate dose of corticosteroids were given to less than half of severely ill patients with ards. further evidence is urgently needed to assess whether systematic corticosteroid treatment is beneficial or harmful for patients infected with -ncov. no antiviral treatment for coronavirus infection has been proven to be effective. in a historical control study, the combination of lopinavir and ritonavir among sars-cov patients was associated with substantial clinical benefit (fewer adverse clinical outcomes). arabi and colleagues initiated a placebo-controlled trial of interferon beta- b, lopinavir, and ritonavir among patients with mers infection in saudi arabia. preclinical evidence showed the potent efficacy of remdesivir (a broad-spectrum antiviral nucleotide prodrug) to treat mers-cov and sars-cov infections. , as -ncov is an emerging virus, an effective treatment has not been developed for disease resulting from this virus. since the combination of lopinavir and ritonavir was already available in the designated hospital, a randomised controlled trial has been initiated quickly to assess the efficacy and safety of combined use of lopinavir and ritonavir in patients hospitalised with -ncov infection. our study has some limitations. first, for most of the patients, the diagnosis was confirmed with lower respiratory tract specimens and no paired nasopharyngeal swabs were obtained to investigate the difference in the viral rna detection rate between upper and lower respiratory tract specimens. serological detection was not done to look for -ncov antibody rises in patients with undetectable viral rna. second, with the limited number of cases, it is difficult to assess host risk factors for disease severity and mortality with multivariableadjusted methods. this is a modest-sized case series of patients admitted to hospital; collection of standardised data for a larger cohort would help to further define the clinical presentation, natural history, and risk factors. further studies in outpatient, primary care, or community settings are needed to get a full picture of the spectrum of clinical severity. at the same time, finding of statistical tests and p values should be interpreted with caution, and non-significant p values do not necessarily rule out difference between icu and non-icu patients. third, since the causative pathogen has just been identified, kinetics of viral load and antibody titres were not available. finally, the potential exposure bias in our study might account for why no paediatric or adolescent patients were reported in this cohort. more effort should be made to answer these questions in future studies. both sars-cov and mers-cov were believed to originate in bats, and these infections were transmitted directly to humans from market civets and dromedary camels, respectively. extensive research on sars-cov and mers-cov has driven the discovery of many sars-like and mers-like coronaviruses in bats. in , ge and colleagues reported the whole genome sequence of a sars-like coronavirus in bats with that ability to use human ace as a receptor, thus having replication potentials in human cells. -ncov still needs to be studied deeply in case it becomes a global health threat. reliable quick pathogen tests and feasible differential diagnosis based on clinical description are crucial for clinicians in their first contact with suspected patients. because of the pandemic potential of -ncov, careful surveillance is essential to monitor its future host adaption, viral evolution, infectivity, transmissibility, and pathogenicity. bc and jw had the idea for and designed the study and had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. ywa, gf, xg, jixu, hl, and bc contributed to writing of the report. bc contributed to critical revision of the report. ywa, gf, xg, jixu, and hl contributed to the statistical analysis. all authors contributed to data acquisition, data analysis, or data interpretation, and reviewed and approved the final version. all authors declare no competing interests. the data that support the findings of this study are available from the corresponding author on reasonable request. participant data without names and identifiers will be made available after approval from the corresponding author and national health commission. after publication of study findings, the data will be available for others to request. the research team will provide an email address for communication once the data are approved to be shared with others. the proposal with detailed description of study objectives and statistical analysis plan will be needed for evaluation of the reasonability to request for our data. the corresponding author and national health commission will make a decision based on these materials. additional materials may also be required during the process. clinical virology a novel coronavirus associated with severe acute respiratory syndrome newly discovered coronavirus as the primary cause of severe acute respiratory syndrome identification of a novel coronavirus in patients with severe acute respiratory syndrome middle east respiratory syndrome coronavirus (mers-cov): announcement of the coronavirus study group isolation of a novel coronavirus from a man with pneumonia in saudi arabia summary of probable sars cases with onset of illness from who. middle east respiratory syndrome coronavirus who. novel coronavirus -japan (ex-china) novel coronavirus -republic of korea (ex-china) first travel-related case of novel coronavirus detected in united states a novel coronavirus genome identified in a cluster of pneumonia cases -wuhan relationship between the presence of hypoxemia and the inflammatory response measured by c-reactive protein in bacteremic pneumococcal pneumonia kidney disease: improving global outcomes (kdigo) acute kidney injury work group. kdigo clinical practice guideline for acute kidney injury cdc definitions for nosocomial infections association between cardiac injury and mortality in hospitalized patients infected with avian influenza a (h n ) virus coronaviruses post-sars: update on replication and pathogenesis a major outbreak of severe acute respiratory syndrome in hong kong epidemiological, demographic, and clinical characteristics of cases of middle east respiratory syndrome coronavirus disease from saudi arabia: a descriptive study plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome mers-cov infection in humans is associated with a pro-inflammatory th and th cytokine profile expression of elevated levels of pro-inflammatory cytokines in sars-cov-infected ace + cells in sars patients: relation to the acute lung injury and pathogenesis of sars distinct immune response in two mers-cov-infected patients: can we go from bench to bedside? treatment with interferon-α b and ribavirin improves outcome in mers-covinfected rhesus macaques sars: systematic review of treatment effects corticosteroids as adjunctive therapy in the treatment of influenza corticosteroid therapy for critically ill patients with middle east respiratory syndrome clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspected role of lopinavir/ritonavir in the treatment of sars: initial virological and clinical findings treatment of middle east respiratory syndrome with a combination of lopinavir-ritonavir and interferon-β b (miracle trial): study protocol for a randomized controlled trial broad-spectrum antiviral gs- inhibits both epidemic and zoonotic coronaviruses comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against mers-cov origin and evolution of pathogenic coronaviruses isolation and characterization of a bat sars-like coronavirus that uses the ace receptor bats as animal reservoirs for the sars coronavirus: hypothesis proved after years of virus hunting we acknowledge all health-care workers involved in the diagnosis and treatment of patients in wuhan; we thank the chinese national health commission for coordinating data collection for patients with -ncov infection; we thank who and the international severe acute respiratory and emerging infections consortium (isaric) for sharing data collection templates publicly on the website; and we thank prof chen wang and prof george f gao for guidance in study design and interpretation of results. key: cord- -dr a ug authors: hall, william j. title: benefits of intensive care unit hospitalization for patients older than years date: - - journal: j am geriatr soc doi: . /jgs. sha: doc_id: cord_uid: dr a ug this editorial comments on the article by haas et al. g eriatricians realize that the decision to admit our oldest patients to an intensive care unit (icu) is never easy. the potential medical benefits are less clear, especially in the case of individuals aged years and older. those potential benefits have to be weighed against well-known downsides, including isolation from family. complications are almost inevitable, including delirium, infection, and adverse reaction to medications. often, these decisions have to be made by surrogates and may infringe on patient autonomy. somewhat surprisingly, there is scant literature regarding the outcomes of icu care for patients older than years in the pre-coronavirus disease (covid- ) era. recently, during the early days of the covid- pandemic, icus were full of patients and in some instances critically short of ventilators. a new ethical debate quickly emerged, namely, how should the oldest patients be regarded when it might become necessary or preferable to develop a triage system to decide which patients receive ventilators? what value set would be most fair and rational? who decides to remove an older patient from a ventilator, so that someone judged to have a better prognosis could benefit? could these decisions be made when even such basic data, such as icu mortality in the pre-covid- era, are not readily available? some of these icu admitting recommendations would have had the decision made by third parties, independent of family considerations. fortunately, stocks of ventilators became available and the benefits of ventilator therapy in all cases have become called into question. but the reality is, fundamental data on what benefit icu care might have for older adults were not a paramount decision tool. where are the data in in the pre-covid- universe to address even crude end points, such as mortality in the patients older than years? therefore, it is timely that in this current issue of the journal of the american geriatrics society, hass and colleagues report on a large-scale clinical review comparing short-term mortality after icu admission (i.e., icu and hospital mortality) in the population aged to years versus a cohort in the older than years group. the study found that mortality statistics were similar in both cohorts. icu mortality of the patients aged years and older was actually lower ( . % vs . %; p < . ) and hospital mortality was similar ( . % vs . %; p < . ) compared with octogenarians. after months, mortality was higher for the patients aged years and older ( . % vs . %; p < . ), and after year, mortality was . % versus . % (p < . ). thus, long-term mortality was higher in the nonagenarians, yet % of nonagenarians were living year following hospital stay. nonagenarians and octogenarians had relatively similar prognoses. this study has several outstanding aspects. first, the investigators were able to identify every icu admission in the netherlands ( icus) from january through december . in aggregate, , patients, including , nonagenarians, were included. this study may have included the largest cohort of icu patients reported in the medical literature. second, access to advance health care is universally available in the netherlands. the data reported were unlikely to be confounded by access issues due to class differences, such as potential differences in mortality due to socioeconomic variables. third, some attempt was made to factor in key postadmission clinical characteristics of illness severity, such as acute physiologic assessment and chronic health evaluation (apache) scores. there have been previous studies with perhaps lower statistical power that have documented mortality rates among older adults hospitalized in icus similar to those reported here, but hass and colleagues have added a decade of hospital experience for the entire country. hass and colleagues acknowledge they were not able to characterize key differentiating risk factors. chief among these would have been prehospitalization measures of frailty, which at present are recognized as being central predictive factors for morbidity and mortality. apache scores, which the authors factored into their analysis, are recognized as a valuable tool to measure acute illness severity, but do not provide data on prehospitalization functional status. as acknowledged by the authors, the study did not have sufficient granularity to assess how frailty measures might have predictive value in both the and years cohorts. some studies not focused on nonagenarians have reported that the use of relatively simple screening tools, such as the clinical frailty scale, may be highly predictive of the impact of frailty on acute hospital stays and icu mortality. future prospective studies incorporating frailty scores in nonagenarians admitted to the icu will be of great interest, especially when one considers the well-known demographic projections of the oldest populations worldwide. for example, by the year , the u.s. population aged years is projected to be . million, almost double the estimated . million in . of these, . million will be older than years. in addition to the challenge of caring for these oldest, there may be an additional unanticipated change in the physician workforce. in my community, as is true throughout the nation, the bulk of hands-on care for older adults with covid- respiratory involvement requiring icu care is being shouldered by selfless young physicians, nurses, and other care providers. they are witnessing the extraordinary respiratory-related mortality in covid- patients in this subset of old adults. might these impressionable experiences influence the attitudes of this next generation of caregivers even to the point that it adversely contravenes the somewhat optimistic data presented by hass and colleagues about prognosis of older adults in the icu environment? the evolutionary biologist richard dawkins in his book, the selfish gene, introduced the concept of a "meme" that he characterized as units of cultural transfer that catch on and pass between people and cultures. his analogy was that a meme was the cultural equivalent of a gene. a wellrecognized example of a medical meme from prior generations might be the description of pneumonia in older adults as "the old man's friend," first attributed to the influential william osler in the first edition of his textbook on medicine. , "(pneumonia) in the debilitated, in drunkards, and in the aged, the chances are against recovery. so fatal is it in the latter class that it has been termed the natural end of the old man." the meme may have resurfaced in the late s. few physicians trained or years ago will not recognize a variation in the use of the meme, "gomers go to ground" in the book, house of god. fast forwarding to the present time, the meme may reappear when the popular press describes the phenomenon of fatal respiratory complications of covid- infection as "only in the elderly." is it possible that the stark experiences of this new generation of frontline healthcare providers will be imbedded with a skewed pessimistic view of the oldest? historically, it has been the responsibility and mission of each successive generation of geriatricians to counter the many memes that still creep into the cultural response of healthcare providers when they encounter older adults. that is perhaps why evidence-based studies, such as that presented by hass and colleagues, are so important to our work. evidence can still trump prejudice. william j. hall, md highland hospital, division of geriatrics, department of internal medicine, university of rochester school of medicine and dentistry, south avenue, rochester, new york, fair allocation of scarce medical resources in the time of covid- outcomes of intensive care patients over years old, a -year national observational study vip study group. the impact of frailty on icu and -day mortality and the level of care in very elderly patients≥ years clinical frailty scale in acute medicine unit: a simple tool that predicts length of stay an aging nation: the older population in the united states: current population reports the old man's friend. pneumonia the principles and practice of medicine covid- kills only old people: only? sponsor's role: there is no sponsor. key: cord- -od zex f authors: savary, d.; lesimple, a.; beloncle, f.; morin, f.; templier, f.; broc, a.; brochard, l.; richard, j.-c.; mercat, a. title: reliability and limits of transport-ventilators to safely ventilate severe patients in special surge situations. date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: od zex f background: several intensive care units (icu) have been overwhelmed by the surge of covid- patients thus necessitating to extend ventilation capacity outside the icu where air and oxygen pressure are not always available. transport ventilators requiring only o source may be used to deliver volume-controlled ventilation. objective: to evaluate the performances of four transport ventilators compared to an icu ventilator simulating severe respiratory conditions. materials and methods: two pneumatic transport ventilators, (oxylog , draeger; osiris , air liquide medical systems) and two turbine transport ventilators (elisee , resmed; monnal t , air liquide medical systems) were compared to an icu ventilator (engstrom carestation - ge healthcare) using a michigan training test lung. we tested each ventilator with different set volumes vtset ( , , ml) and different compliances ( or ml/cmh o) and a resistance of cmh /l/sec based on values recently described in covid- acute respiratory distress syndrome. volume error was measured, as well as the trigger time delay during assist-control ventilation simulating spontaneous breathing activity with a p . of cmh . results: grouping all conditions, the volume error was . +/- . % for engstrom carestation; . +/- . % for osiris ; . +/- . % for oxylog ; . +/- . % for monnal t and . +/- . % for elisee . grouping all conditions, trigger delay was +/- ms, +/- ms, +/- ms, +/- and +/- ms for engstrom carestation, osiris , oxylog , monnal t and elisee , respectively. conclusions: in special surge situations such as covid- pandemic, most transport ventilators may be used to safely deliver volume-controlled ventilation in locations where only oxygen pressure supply is available with acceptable volume accuracy. performances regarding triggering function are generally acceptable but vary across ventilators. during the covid pandemic, some hospitals experienced the greatest shortage of ventilators ever seen since the heroic times of the polio epidemic in the s. in this context, different alternative solutions including ventilator sharing and use of anesthesia ventilators have been considered to manage intubated patients with severe lung failure outside the walls of the icu [ , ] . for this purpose, ventilators must be relatively easy for the users, able to deliver reliable volume-controlled ventilation in difficult mechanical conditions adapted to the principles of protective lung ventilation. importantly, they must allow to vary fio without requiring two pressurized sources of gas, (i.e. wall air and oxygen at psi). several transport ventilators are based on pneumatic systems and venturi systems for gas mixing; others use an internal turbine for pressurization; in this case, a low pressure source of oxygen is needed for increasing oxygen concentration, but not as a pressure source. they all represent interesting solutions in this context and could fulfill the requirements mentioned. pneumatic transport ventilators have been used for decades both for in-and out-of-hospital transport. their robustness and their relative technological simplicity could potentially facilitate massive industrial production. the general view on these ventilators is, however, that their limitations make them acceptable for a short period like transport but make them incompatible with the safe delivery of difficult ventilation for very sick patients over prolonged periods. undoubtedly, they have limited capacities regarding ventilation modes and monitoring, but we questioned whether their performance for delivering lung protective ventilation in patients with ards merited to be tested again with these objectives in mind. indeed, discarding their use in a context of surge could limit the extension of offering icu beds possibilities for mechanically ventilated patients. the performance and limits of these ventilators have not been specifically tested with the appropriate settings and realistic conditions simulating the respiratory mechanics of patients with covid- induced ards [ ] [ ] [ ] [ ] . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint the aim of the present study was to evaluate the safety, reliability and limitations of ventilation provided by these different technologies in simulated bench conditions of severe respiratory mechanics mimicking patients with covid- induced ards. . cc-by-nc-nd . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint four portable ventilators necessitating only one o pressurized gas source were included in the study. two pneumatic transport ventilators using venturi systems to mix air to oxygen were tested: the oxylog (draeger, lubeck, germany) and the osiris (air liquide medical systems, antony, france). two turbine transport ventilators necessitating additional oxygen only to increase fio were also tested: the elisee (resmed, san-diego, usa) and the monnal t (air liquide medical systems, antony france). the objective was to assess their capability to deliver acceptable ventilation by comparing their performances to a standard icu ventilator: engström carestation (ge healthcare, madison, usa). the characteristics of the five ventilators are given in table . in the two pneumatic transport ventilators tested (oxylog and osiris ), the working pressure that generates ventilation comes from the high-pressure oxygen supply. these ventilators based on "venturi-distributor" technology work as flow generator. with the oxylog , the air-o mixing is regulated from % to % via a venturi system coupled with a proportional inspiratory valve that also permits to directly set the volume (vt set ). the inspiratory flow depends on both the respiratory rate (rr) and the inspiratory:expiratory (i:e) ratio. in other words, for a given set volume, changing rr and/or i:e ratio keep the set vt but affects inspiratory flow. the monitoring of the expired vt is available via a specific flow sensor inserted between the endotracheal tube and the patient circuit. with the osiris , the pneumatic system is based on the venturi effect to entrain ambient air into the ventilator for fio management coupled with a distributor for inspiratory flow setting. only two . cc-by-nc-nd . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint positions are available for fio : % or an fio around %. for a given combination of i:e ratio and respiratory rate, the vt is set by directly adjusting a vt knob that regulates the inspiratory flow. the monitoring of the expired vt is available via a specific flow sensor inserted between the endotracheal tube and the patient circuit. the elisee and t are two turbine-based ventilators which need oxygen only to adjust fio . on those ventilators, the vt and the inspiratory flow are directly set. changing the respiratory rate does not affect neither vt nor inspiratory flow. the engström carestation is a classical high-quality icu ventilator requiring two sources of pressurized gas for oxygen and air (usually wall pressure at - psi). we assessed the volume effectively delivered (vtemeasured) by the ventilators in different conditions of respiratory mechanics simulated on a michigan test lung (michigan instruments, kentwood, mi, usa). is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint conditions tested were: compliance of ml/cmh o and ml/cmh o, both combined with a resistance of cmh o/l/s. the combinations of compliance and resistance tested were based on recently described covid- respiratory mechanics [ ] [ ] [ ] [ ] . assist control ventilation (acv) mode was selected and similar ventilator settings were applied for each ventilator (respiratory rate cycles/min). the pneumatic transport ventilators were set with an inspiratory:expiratory ratio of : (i:e) whereas a flow of l/min was adjusted on the engström carestation, elisee and monnal t . the three set volumes were tested with fio % and % (air-o mix for osiris ) as follows: fio was selected, vt set was adjusted on the ventilator and vtemeasured was recorded and averaged over cycles after stabilization. fio was measured on osiris when air-o mix was selected with a pf gas analyzer (imt medical, buchs, switzerland) in different conditions (vt = - - ml and compliance = - ml/cmh o). the performances of venturi-based ventilation in terms of volume delivery could be altered by set inspiratory flow values [ ] . to assess the impact of the inspiratory flow, vte error was calculated on the osiris ventilator. we set a volume of ml using a wide range of inspiratory flows achieved by changing respiratory rate (rr). acv mode with air-o mix was selected, a resistance of cmh o/l/s and a compliance of ml/cmh o were applied and we set a i:e ratio of : . the lowest rr ( cycles/min) was chosen and was progressively increased by cycles/min until reaching the maximum rr of cycles/min. vte set had to be adjusted in consequence at each rr increment to keep its value at ml. vte error was estimated at each step. two levels of peep were applied ( cmh o and cmh o) and the accuracy of the effective peep (peep measured ) was assessed. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint the relative volume error (vte error ), which is the difference between the effective expired volume (vte measured ) and the set volume (vte set ) was calculated and averaged as previously described over the four different conditions [ , ] : ventilation was considered safe and acceptable when vte measured was within ± . ml/kg pbw, which covers a volume between . and . ml/kg pbw. this corresponds to an % difference between set and measured vt. end-point for peep: a difference between measured peep and set peep was acceptable when less than cmh o. assist control ventilation (acv) with the inspiratory trigger function "on" was tested by connecting is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint connection between the two chambers, so that a positive pressure created in the driving lung induced a negative pressure in the experimental lung, leading to trigger the ventilator tested. the driving lung was connected to an evita xl ventilator (draeger, lubeck, germany) and set in volumecontrolled mode with constant flow. the respiratory rate was set at breaths/ min. the ventilatory settings were chosen to achieve a decrease in airway pressure ms after occlusion (p ; ) of cmh (consistent with p ; values recently described in covid patients [ ] ), measured at the airway opening of the lung model [ ] . a level of peep was applied to the driving lung to obtain a perfect contact of the lung-coupling clip between the two chambers at the end of expiration. for each configuration, trigger performance was assessed by measuring airway pressure changes using the flow trace to determine the start of inspiration [ , ] . negative pressure drop (∆p, cmh ), triggering delay (td, ms) and pressurization delay (pd, ms) as defined on figure were computed. the overall inspiratory delay (id) corresponds to the addition of td and pd. end-point: triggering function was considered as "safe and acceptable" when td was less than ms. continuous variables were expressed as mean ± sd values averaged from consecutive breaths. these variables were compared using an anova test. the type i significance level was set at . . when the . cc-by-nc-nd . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint global f was significant, post hoc tests were computed using a student t-test with bonferroni correction, which sets the level of significance for pairwise differences between the five ventilators at . . . cc-by-nc-nd . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint results are displayed in figure and mean volume errors (vte error ) for each ventilator are shown in table . when all conditions and set volumes were included, the engström carestation was the most precise ventilator, and the oxylog was comparable. each ventilator performance was considered as acceptable (delta vt ± . ml/kg pbw) except for one turbine ventilator (elisee ). the impact of fio selection (fio % or %) on volume error was significant considering all ventilators (p < . ), reaching a maximum of . % for elisee with fio % (changes for each ventilator are available on when all conditions were put together, differences between measured peep and set peep were less than cmh o as shown on table . the effect of inspiratory flow rates on vte error for osiris is shown on figure . the lowest values of inspiratory flow are associated with a vte error above % (delta vt ± . ml/kg pbw). performances are acceptable when inspiratory flow (resulting from the combination of vt, i:e ratio and respiratory rate) was strictly above l/min, which corresponds to a respiratory rate higher than cycles/min. inspiratory trigger was evaluated for each ventilator and results are displayed on figure . all simulated efforts triggered a ventilatory cycle. the triggering delay was ± ms, ± ms, ± ms, ± ms and ± ms for engström carestation, osiris , oxylog , monnal t and elisee , is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint respectively (all conditions grouped). each ventilator performance was considered as acceptable (td < ms) except for one pneumatic ventilator (oxylog ). the inspiratory delay (id) was measured at ± ms for engström carestation, ± ms for osiris , ± ms for oxylog , ± ms for monnal t and ± ms for elisee and (p < . ; pairwise differences between ventilators were all significant with a p-value < . ). a similar trend was observed for triggering delay. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint the results of the present bench test study comparing turbine and pneumatic transport ventilators to an icu ventilator, can be summarized as follows: . turbine ventilators show performance in vc and acv very close to the icu ventilator tested for most of the settings. . in severe respiratory mechanics conditions, the volume error exceeds . ml/kg pbw only for one turbine ventilator. . inspiratory trigger reactivity is less than ms except for one pneumatic transport ventilator. . volume error delivered by the simplest pneumatic ventilator significantly increases when inspiratory flow is less than l/min indicating a technological limit of the venturi system. worldwide crisis, and the ventilators shortage reported in some severely affected countries, has led to discuss the possibilities to manage intubated patients outside the walls of the icu [ ] . according to this dire scenario, simple and easy to set ventilators that only require one oxygen pressure source to function and able to deliver lung protective ventilation could be considered. in addition, an assisted volume mode that ensures the set vt with peep up to cmh o and fio up to % is required to manage high elastic load and severe shunt that characterize potentially severe covid - ards [ , ] . recent turbine transport and emergency ventilators have performances which are very close to conventional icu ventilators [ , ] . in the context of "mass casualty", as experienced with the covid- crisis, pneumatic transport ventilators could be used to extend the possibility to manage intubated patients in case of icu beds shortage. the working principle of these pneumatic ventilators is based on a "venturi system" which is a simple technological solution that permits to manage ventilation generated by the oxygen pressurized source when a position called air-o mix is selected. interestingly, the simplicity of such pneumatic systems permits to consider massive industrialization faster and at a lower cost. on the opposite, the venturi system explains the limits observed with low inspiratory flow previously described with this technology [ ] . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint in case of high impedance, a low inspiratory flow may increase significantly volume error when the o air mix position is selected "on". in turn, manipulating i:e ratio, respiratory rate and increasing inspiratory flow above l/min permits to reverse the vt error that is directly explained by the working principle of this ventilator (see figure ) . the technological adaptations available on oxylog (venturi coupled with proportional inspiratory valve) solve this problem while expired vt monitoring available on osiris simplifies settings adaptation if required. previous bench test studies have reported a vt error with pneumatic basic transport ventilators that reached % of set vt with resistive load [ , ] . these experiments were performed with very low set inspiratory flow thus explaining the vt reduction observed. for this purpose, an essential recommendation is to set the i:e ratio at : (minimal available value), and set the rr above /min before adjusting the knob (that controls the inspiratory flow) to reach the set vt as indicated on the ventilator. with these recommendations, volume error measured on pneumatic transport ventilators at low compliance are closed from turbine performances and acceptable since it did not exceed . ml/kg pbw. of note, only the icu and turbine ventilators tested compensate for the loss in vt due to the compression of gas inside the circuit. nevertheless, this effect previously quantified in icu ventilators with inspiratory-expiratory circuits is significantly less in basic transport ventilators since they are equipped with a single limb circuit [ ] . of note, an hepa filter can be easily adjusted on the expiratory limb and they should not expose to higher risks of viral contamination. recent experience with covid- induced ards reports that these patients often exhibit high respiratory drive and asynchrony that may require deep sedation and sometimes paralysis [ ] . we therefore evaluated the behavior of these two pneumatic transport ventilators during triggered breaths since performances of their trigger have been questioned [ , ] . the synchronization was overall respected except for the oxylog exhibiting the poorest triggering performances. the is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint triggering time delay was consistently longer in pneumatic ventilators but acceptable except on the oxylog , compared to the icu ventilator [ ] . the results obtained in vitro necessitate some caution to be translated to the clinical practice, but previous studies showed that this type of simulation predicts the results observed in clinical situations with a high fidelity [ , , ] . the lung model gives the unique opportunity to compare ventilator performances according to several simulated but standardized clinical conditions. bench experiment also permits to accurately depict and understand advantages and limits of the different ventilator's technologies as previously done [ ] . our experiment reported performances of only two pneumatic and two turbine ventilators while several other ventilators with similar technology are available worldwide. we did not evaluate pressure support ventilation while this approach can be useful to manage weaning of covid- patients. previous studies already showed that turbine-based ventilator significantly outperform pneumatic transport ventilators during pressure mode ventilation [ , ] . the present bench study suggests that turbine technologies may replace icu ventilators to extend icu beds where only oxygen pressure supply is available, in special surge situations such as covid - crisis. pneumatic transport ventilators provide acceptable volume accuracy even in severe simulated conditions. for this purpose, attention is required to maintain sufficient inspiratory flow in the osiris (or any other pneumatic ventilator using a venturi system). a monitoring of expired vt available on the two pneumatic transport ventilators tested greatly facilitates settings. performances regarding triggering function are non-acceptable in one of the pneumatic transport ventilator thus rendering hazardous its use in assist control ventilation. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint compliance, resistance and peep were set at ml/cmh o, cmh o/l/sec and cmh o respectively. black circles were obtained with % fio while the white circles were obtained with % fio . respiratory rate associated with each point is also displayed. this figure illustrates that for an inspiratory flow below l/min, the vt error is substantial with % fio . the vt error is within ± . ml/kg pbw (which corresponds to an % difference between set and measured vt) whatever the inspiratory flow when % fio is selected. ventilator sharing during an acute shortage caused by the covid- pandemic fair allocation of scarce medical resources in the time of covid- lung recruitability in covid- -associated acute respiratory distress syndrome: a single-center observational study covid- does not lead to a "typical" acute respiratory distress syndrome. am j respir crit care med. mars ;rccm covid - pneumonia: different respiratory treatments for different phenotypes? baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region fractional inspired oxygen on transport ventilators: an important determinant of volume delivery during assist control ventilation with high resistive load bench test evaluation of volume delivered by modern icu ventilators during volume-controlled ventilation evaluation of ventilators used during transport of critically ill patients: a bench study. respiratory care the respiratory drive: an overlooked tile of covid - sept ;rccm airway occlusion pressure as an estimate of respiratory drive and inspiratory effort during assisted ventilation bench testing of pressure support ventilation with three different generations of ventilators a bench study of intensive-care-unit ventilators: new versus old and turbine-based versus compressed gas-based ventilators bench-test comparison of emergency and transport ventilators. crit care evaluation of ventilators used during transport of icu patients -a bench study patient-ventilator asynchrony during noninvasive ventilation performance of noninvasive ventilation modes on icu ventilators during pressure support: a bench model study • vteerror global = mean volume error including all conditions of resistance ( cmh o/l/sec), compliance ( - ml/cmh o) and peep ( - cmh o) for both % fio and % fio • vteerror % fio = mean volume error including all conditions of resistance ( cmh o/l/sec), compliance ( - ml/cmh o) and peep ( - cmh o) for % fio • vteerror % fio = mean volume error including all conditions of resistance ( cmh o/l/sec), compliance ( - ml/cmh o) and peep ( - cmh o) for % fio • vteerror c = mean volume error including all conditions of resistance ( cmh o/l/sec), fio ( - %) and peep ( - cmh o) for a compliance of ml/cmh o • vteerror c = mean volume error including all conditions of resistance ( cmh o/l/sec), fio ( - %) and peep ( - cmh o) for a compliance of ml/cmh o • mean peep = mean peep measured when peep was set at cmh o including all conditions of resistance ( cmh o/l/sec) and compliance ( - ml/cmh o) for both % fio and % fio • mean peep = mean peep measured when peep was set at cmh o including all conditions of resistance ( cmh o/l/sec) and compliance ( - ml/cmh o) for both % fio and % fio key: cord- -usfvulc authors: sharifipour, ehsan; shams, saeed; esmkhani, mohammad; khodadadi, javad; fotouhi-ardakani, reza; koohpaei, alireza; doosti, zahra; ej golzari, samad title: evaluation of bacterial co-infections of the respiratory tract in covid- patients admitted to icu date: - - journal: bmc infect dis doi: . /s - - -z sha: doc_id: cord_uid: usfvulc background: covid- is known as a new viral infection. viral-bacterial co-infections are one of the biggest medical concerns, resulting in increased mortality rates. to date, few studies have investigated bacterial superinfections in covid- patients. hence, we designed the current study on covid- patients admitted to icus. methods: nineteen patients admitted to our icus were enrolled in this study. to detect covid- , reverse transcription real-time polymerase chain reaction was performed. endotracheal aspirate samples were also collected and cultured on different media to support the growth of the bacteria. after incubation, formed colonies on the media were identified using gram staining and other biochemical tests. antimicrobial susceptibility testing was carried out based on the clsi recommendations. results: of nineteen covid- patients, ( %) patients were male and ( %) were female, with a mean age of ~ years old. the average icu length of stay was ~ days and at the end of the study, cases ( %) expired and only was case ( %) discharged. in total, all patients were found positive for bacterial infections, including seventeen acinetobacter baumannii ( %) and two staphylococcus aureus ( %) strains. there was no difference in the bacteria species detected in any of the sampling points. seventeen of strains of acinetobacter baumannii were resistant to the evaluated antibiotics. no metallo-beta-lactamases -producing acinetobacter baumannii strain was found. one of the staphylococcus aureus isolates was detected as methicillin-resistant staphylococcus aureus and isolated from the patient who died, while another staphylococcus aureus strain was susceptible to tested drugs and identified as methicillin-sensitive staphylococcus aureus. conclusions: our findings emphasize the concern of superinfection in covid- patients due to acinetobacter baumannii and staphylococcus aureus. consequently, it is important to pay attention to bacterial co-infections in critical patients positive for covid- . a novel coronavirus known as severe acute respiratory syndrome coronavirus (sars-cov- , also called covid- and -ncov) was first reported in wuhan, hubei province, china in december . ever since the virus has been spreading worldwide claiming thousands of lives. due to serious respiratory disease in humans, some patients need to be hospitalized and in severe cases intensive care with mechanical ventilation support is essential (~ - %) [ , ] . although covid- associated deaths have mainly occurred in the elderly with serious underlying diseases [ ] , nosocomial pneumonia (np) in intensive care units remains a major risk factor for the patients and the health of patients, especially when intubated, may deteriorate in the presence of lower respiratory tract infections. nosocomial infections (nis) are usually described as infections acquired during hospitalization within - h after admission and they mainly spread through person-to-person contact, devices, and instruments [ ] . among microorganisms, the bacteria including staphylococcus spp., enterococcus spp., klebsiella pneumoniae, enterobacter spp., escherichia coli, acinetobacter spp., and pseudomonas spp. are the most frequently detected causative agents of nis [ ] . these opportunistic pathogens can also cause superinfections, especially in combination with viral respiratory tract infections in hospitalized patients. however, even patients without underlying diseases and in all age groups may be at the risk of co-infections as well [ , ] . some studies have shown that viral agents such as influenza viruses can be associated with secondary bacterial pneumonia that might occur throughout hospitalization and lead to the death of individuals with or without preexisting respiratory diseases [ ] . the damage of ciliated cells can also be observed in association with respiratory syncytial virus infection; it can result in deterioration of mucociliary clearance, increased adhesion of bacteria to mucins and, enhanced colonization of the bacteria in the airway. moreover, new receptors for bacterial adherence can emerge following the virus-induced death of the airway epithelial cells [ ] . in addition, after an acute inflammatory reaction and pulmonary tissue damage induced by viral infections, a resolving/repair phase of the lung tissue takes place. due to varied immune responses in different individuals, this phase may cause an enhanced susceptibility to respiratory bacterial infections. thus, bacterial superinfection can occur after a viral infection, which in turn might lead to increased morbidity and mortality [ ] . nevertheless, any probable contribution of the bacteria to the development of the infectious diseases caused by the newly discovered coronavirus is still completely unknown. in a study by póvoa et al., the risk of ventilatorassociated bacterial pneumonia in covid- patients was studied [ ] . in addition, although there are a few recently published retrospective reports of co-infections in patients with covid- [ , ] , our study is adding to a growing evidence base of the role bacterial coinfections may have in covid- patients. therefore, our aim was to evaluate secondary bacterial infections and their antibiotic resistance in covid- positive patients admitted to icus in qom, the first city in iran to report covid- disease [ ] . nineteen critically ill patients admitted to the icu wards in two referral hospitals for coronavirus in qom, iran, were enrolled in the present study. patients were given antibiotics such as ceftriaxone and azithromycin before admission to the icus. inclusion criteria were being infected by covid- , hospitalized, intubated, and mechanically ventilated > h in icus. ventilator-associated pneumonia (vap) was identified based on the following criteria: a new and persistent (> h) or progressive infiltrate on the chest radiograph plus of the following minor criteria: fever > °c or hypothermia < °c, blood leukocyte count of > , cells/ml or < cells/ml, purulent tracheal secretions, or decrease in the pao /fio . in cases with clinically suspected pneumonia, vap diagnosis was established with a positive quantitative culture (cut-off point ≥ [colony-forming units (cfu)/ml]) [ , ] . all patients in our study were also neutropenic with elevated erythrocyte sedimentation rate and c-reactive protein (crp); and had a history of sore throat, cough, and shortness of breath. to determine the status of the patients, i.e. death or discharge, we waited until the end of the admission of the last patient in our icus. reverse transcription real-time polymerase chain reaction (rt-pcr) for the detection of covid- this step was carried out once for each patient. briefly, naso-pharyngeal samples were obtained using a specific swab (medical wire, uk) and then placed in a separate collection tube containing two ml of viral transport medium and immediately sent to the coronavirusreference laboratory of the university. first, the extraction of the viral rna was performed using a commercial kit according to the manufacturer's protocol (geneall, seoul, south korea). next, rt-pcr was performed using lightmix® modular sars and wuhan cov e-gene kit and using one-step rt-pcr polymerase mix (tib-molbiol, berlin, germany) [ ] . the collection of the samples for bacterial infections was repeated at four stages with an interval of~ days for each patient who still stayed in icus. endotracheal aspirate (eta) specimens were collected in sterile tubes based on a standard clinical protocol [ ] . the specimens were immediately transferred to the bacteriological laboratory and were evaluated by conventional methods. first, the samples were cultured on blood agar, chocolate agar, eosin methylene blue (emb), and macconkey agar and then incubated at °c for - h under standard conditions. the colonial growth of the bacteria was confirmed by gram staining and other media and standard biochemical testing including (e.g. . minimum inhibitor concentration (mic) was also performed for colistin and vancomycin according to clsi protocol [ ] . s. aureus atcc and e. coli atcc were used as standard strains. phenotypic detection of mbl-producing clinical isolates was evaluated by the combination disk diffusion test (cddt) and modified hodge test (mht) as previously described by lee et al. [ ] . all patients were positive for bacterial infections. out of patients, ( %) patients were male and ( %) were female, with a mean ± standard deviation (sd) age of . ± . years (range of age - years). of all patients, cases ( %) had underlying diseases such as kidney disease, diabetes, hypertension, or heart diseases. at the end of the study, cases ( %) were dead ( . ± . years old), % ( cases) of whom had underlying diseases, and case ( %) was discharged ( years old). at first collection, a total of clinical specimens, all patients ( %) were found positive for bacterial infections, cases ( %) for acinetobacter (a.) baumannii and cases ( %) for staphylococcus (s.) aureus. in the stage of the , , and of sampling, , , and patients were included, respectively. in all samplings, the bacterium isolated from each patient remained the same. more information is presented in table . overall, the mean ± sd length of pre-icus stay for all included patients was . ± . days, while the average in our icus was . ± . days ( . ± . and days for expired and discharged patients, respectively). the median icu length of stay for a. baumannii -positive and s. aureus -positive patients was . ± . and ± . days, respectively. results of the antimicrobial susceptibility testing showed a high-level resistance of a. baumannii isolates to all tested antibiotics, except colistin with a resistance rate of %. no isolated a. baumannii strain produced mbls and the resistance pattern of a. baumannii isolates was not different between expired and discharged patients. one of the s. aureus isolates was detected as methicillin-resistant staphylococcus aureus (mrsa) and resistant to all other evaluated agents i.e. penicillin, cefoxitin, azithromycin, erythromycin, gentamycin, cotrimoxazole, linezolid, and ciprofloxacin. no resistance was observed to vancomycin or tetracycline. the mrsa strain was isolated from a patient who expired on the th day of icu admission. another s. aureus strain, isolated from a discharged patient, was identified as methicillin-sensitive staphylococcus aureus (mssa) and susceptible to all the above-mentioned drugs. three of our patients ( %) had no underlying diseases. one of them was infected with the mssa and the other two cases were infected with the a. baumannii strains. among, only mssa-infected patient was discharged and other two a. baumannii-infected patients were expired. covid- , a viral pneumonia with an unusual outbreak, is considered as a new public health concern threatening us worldwide. recent studies show that -ncov or sars-cov- originated from an animal source and later adapted to other variants as it crossed the species barrier to ultimately infect humans [ , ] . in recent months, less attention has been paid to hospital-acquired infections and opportunistic microorganisms, which could be due to the outbreak of covid- and its consequent long-term hospitalization of patients, and high workload on the healthcare personnel. in this study, with a focus on secondary infection of the lower respiratory tract of patients, a. baumannii was the most common organism followed by s. aureus. in recent years, emerging strains of both species that have acquired additional genetic features have shown to be commonly associated with hypervirulence and resistant to many types of antibiotics [ , ] . according to our infection control committee and laboratory reports, these were associated with other bacteria including pseudomonas aeruginosa, escherichia coli, klebsiella pneumoniae, enterobacter spp., serratia marcescens, and citrobacter freundii, etc. that were previously isolated from the icu wards and non covid- patients admitted to our icus. in addition, both a. baumannii and s. aureus were among the most isolated bacteria from non covid- icu patients in iran and other countries [ ] . in a study conducted in tehran, iran, klebsiella pneumoniae and acinetobacter had the highest rates of incidence in icus [ ] . in a study, a. baumannii and klebsiella spp. were the most common organism isolated in mysuru, india [ ] . in , the most common icu-acquired strains were acinetobacter baumannii, pseudomonas aeruginosa, stenotrophomonas maltophilia, staphylococcus aureus, enterococcus spp., and klebsiella pneumonia in shanghai, china [ ] . in the present study, our first samplings were performed in the patients who were admitted to icus for ≥ days, except for case with days of admission. certainly, this duration was an excellent opportunity for bacteria to infect the patients, and thus all of our first cultures were positive with secondary infection ( / , %) . this incidence rate is higher than similar recently published articles. in fu et al. study, . % ( of ) of the patients in the icu were diagnosed with severe acute respiratory syndrome coronavirus and secondary bacterial infection. in another report that was published from a uk secondary care setting, amongst patients identified as sars-cov- , cases ( . %) had early confirmed bacterial isolates identified ( - days post admission) rising to cases ( . %) during the admission [ , ] . in addition, our result indicates a higher incidence than other published studies on non covid- patients. in a study conducted in shiraz, iran, in , hassanzadeh et al. suggested that icu-acquired infections were documented in . % of icu patients, with a mortality rate of . % ( patients) [ ] . one of the reasons for the increase in infection rate in our study can be due to the simultaneous infection of the virus and bacterium. as previously mentioned, viruses can facilitate the attachment and colonization of the bacteria in the respiratory tract, which is certainly no exception for covid- ; however, understanding the accurate mechanisms of interactions between novel coronavirus and other bacteria requires further research. nevertheless, other factors such as icu type, used equipment rate, admission/ discharge criteria, high workload/nurse ratio, etc. can also affect the quality of care and the rate of icu acquired nosocomial infection [ , ] , especially in pandemics. except for colistin, a. baumannii strains showed widespread resistance to all different classes of antibiotics and no inhibition zone was observed in the disk diffusion method. resistant isolates of the bacteria, especially a. baumannii, are not uncommon among admitted patients in the hospitals and hospital-acquired infections have become a major concern to health systems. wang et al. showed that the resistance rate of a. baumannii isolates was approximately > % to piperacillin, imipenem, ceftriaxone, ciprofloxacin, and ceftazidime [ ] . castilho et al. also reported that a. baumannii isolates from icus in goiânia, brazil, were classified as multidrug resistant (mdr) with a high incidence of resistance to carbapenems. the development of resistance to carbapenems and other β-lactams may be due to the production of the mbls. these are one of the most common participating in resistance mechanisms that can inactivate a wide range of β-lactam antibiotics [ ] . nevertheless, no mbl-producing a. baumannii strain was isolated. however, the bacteria may use other strategies to resist the effects of antibiotics [ , ] . in our study, one of the strains of s. aureus was identified as mrsa. this organism plays an important role in the severe complication of infections in icu environments. the probability of acquiring mrsa may increase (> . - times) in patients with longer stays in the ward, i.e. more than one week [ ] . different studies have also shown that lower respiratory tract infections caused by mrsa can be associated with a significant level of mortality in the patients admitted to icus [ , ] . due to the covid- crisis conditions, we were not able to carry out mic and other phenotypic confirmatory tests for evaluating extended-spectrum betalactamases or esbls, etc., as well as molecular assays for detecting resistance genes. nevertheless, these pathogens showed extremely high rates of resistance to the majority of the antibacterial agents tested. this could not only delay the process of treatment and recovery of covid- patients but also increase the mortality rate. based on our local strategies, all patients in the current study routinely received ceftriaxone and azithromycin (except for some contraindications or interactions) before admission to the icus. in the cases of the infection in icu, these were changed to extended-spectrum antibiotics such as meropenem and vancomycin, but no changes in the isolation of our resistant bacteria were observed at different stages of sampling. however, the treatment protocols have been changed by the icu medical team based on the obtained results of the cultures and the pattern of antibiotic resistance, e.g. in this study, combination therapy with meropenem, colistin, and ampicillin-sulbactam was used for the treatment of infections caused by the resistant strains of acinetobacter. among our patients, three cases had no underlying diseases. one patient, infected by a susceptible strain of staphylococci, was discharged, while two other patients, infected with multidrug-resistant a. baumannii, expired. due to some limitations, the sample size of the current study was not sufficient for comparing and accurate statistical evaluation. however, further work is required to investigate whether there are increased mortality rates associated with patients co-infected with covid- and antibiotic-resistant bacteria. the median length of icu stay among patients in our study was higher, days (interquartile range, to ), compared with zhou et al. study, which reported a length of stay of . days ( . - . ) of all patients with covid- admitted to their icu. moreover, no bacterial pathogens were detected in their patients on admission [ ] . it seems that the length of icu stay can be prolonged, if patients become co-infected. a study on respiratory co-infection in patients with pandemic influenza a (h n ) virus infection showed that icu length of stay was days longer among patients who had co-infection [ ] . in addition, infections and antibiotic resistance in icu patients can also result in higher cost of treatment, and increased mortality [ ] . in a study conducted by toufen and colleagues on icu patients in brazil, the rate of mortality was . %, while the patients with infection had a mortality rate of . % and the most frequently reported infections were related to respiratory infections ( . %) [ ] . chastre et al. study also suggested that the mortality rate of vap in icu patients varies from to %, and even higher when caused by high-risk pathogens [ ] . according to previous studies, viral-bacterial synergistic interactions are reviewed and the mortality rate can be further increased when there is simultaneous an acute respiratory viral infection and a bacterial infection. a multicenter retrospective cohort study conducted by arabi et al. on mers sari (middle east respiratory syndrome severe acute respiratory infection) patients who were admitted to the participating icus showed that % ( cases) and % ( cases) of them had bacterial and viral co-infections, respectively [ ] . it has also been estimated that one-third of the world's population (~ million people) may have been clinically infected during the - influenza pandemic, which resulted in the death of at least million people worldwide (https://www.cdc.gov/flu/pandemic-resources/ -pandemic-h n .html). the findings suggest that the vast majority of individuals who died during the pandemic were infected by a bacterial infection [ ] . the co-infection of the influenza virus with staphylococcus aureus, especially mrsa, has been previously documented. in a study performed by bhat et al. during the - influenza season, bacterial co-infections were identified in of cases. accordingly, s. aureus was the most common etiology ( cases); six of these cases were detected as methicillin-resistant strains [ ] . randolph et al. also reported that among children with influenza a (h n ) virus admitted to a pediatric intensive care unit during the influenza a (h n ) pandemic, ( . %) had a presumed diagnosis of early s. aureus co-infection of the lung with % positive for mrsa [ ] . moreover, jia et al. project on mouse model findings also showed that secondary infection with methicillin-resistant staphylococcus aureus after infection with influenza virus was associated with high mortality rates [ ] . another study by liu et al. also confirmed that the co-infection of avian influenza a (h n ) virus and extensively antibiotic-resistant a. baumannii in the patients with invasive mechanical ventilation is a key factor for the severity of the disease and high mortality [ ] . our report is one of the first to demonstrate the presence of superinfections in the lower respiratory tract of patients with covid- . our findings emphasize the concern of bacterial infections in the patients due to a. baumannii and s. aureus that are resistant to the extended-spectrum antibiotics commonly used for the treatment of life-threatening bacterial diseases, especially in icu patients. secondary bacterial infections may develop during or following covid- and thus they are an undeniable fact. due to severe pandemic conditions, it was not possible to have a negative control group without covid- in our icus simultaneously. therefore, we could not certainly state what percentages of deaths in our patients were caused by bacterial coinfections. however, when mortality rates compared to other non covid- studies, e.g. . % in shiraz [ ] and . % in mysuru [ ] , it seems that mortality is increased in covid- patients and may be attributed to bacterial co-infections. thus, further studies are recommended to confirm this finding. mortality in covid- positive patients with no underlying diseases may be due to bacterial infections that this concern also requires more investigations. overall, it is important to limit the risk of infection and the spread of these resistant strains through controlling nosocomial infections accurately and bringing secondary infections caused by resistant bacteria that can increase the mortality rate in covid- critical patients into attention. coronavirus disease (covid- ): a perspective from china ventilation of covid- patients in intensive care units the covid- epidemic nosocomial bacterial infections and their antimicrobial susceptibility patterns among patients in ugandan intensive care units: a cross sectional study nosocomial pneumonia in critically ill patients characterization and sensitivity to antibiotics of bacteria isolated from the lower respiratory tract of ventilated patients hospitalized in intensive care units virus-induced secondary bacterial infection: a concise review influenza and bacterial superinfection: illuminating the immunologic mechanisms of disease the biology of bacterial colonization and invasion of the respiratory mucosa mechanisms of bacterial superinfection post-influenza: a role for unconventional t cells covid- : an alert to ventilatorassociated bacterial pneumonia secondary bacterial infections in critical ill patients of covid- bacterial and fungal coinfection among hospitalised patients with covid- : a retrospective cohort study in a uk secondary care setting the covid- outbreak in iran; the first patient with a definite diagnosis ventilator-associated pneumonia: diagnosis, treatment, and prevention ventilator-associated pneumonia: incidence, risk factors and outcome in paediatric intensive care units at cairo university hospital detection of novel coronavirus ( -ncov) by real-time rt-pcr clinical microbiology procedures handbook clsi supplement m . wayne: clinical and laboratory standards institute modified hodge and edta-disk synergy tests to screen metallo-beta-lactamase-producing strains of pseudomonas and acinetobacter species a review of coronavirus disease- (covid- ) molecular immune pathogenesis and diagnosis of covid- klebsiella pneumoniae: going on the offense with a strong defense staphylococcus aureus in the intensive care unit: are these golden grapes ripe for a new approach? ventilator-associated pneumonia in adults: a narrative review prevalence of streptococcus pneumoniae in ventilator-associated pneumonia by real-time pcr antibiotic prescription, organisms and its resistance pattern in patients admitted to respiratory icu with respiratory infection in mysuru epidemiology and antimicrobial resistance among commonly encountered bacteria associated with infections and colonization in intensive care units in a university-affiliated hospital in shanghai prevalent bacterial infections in intensive care units of shiraz university of medical sciences teaching hospitals, shiraz, iran nosocomial infections in the intensive care unit: incidence, risk factors, outcome and associated pathogens in a public tertiary teaching hospital of eastern india are high nurse workload/staffing ratios associated with decreased survival in critically ill patients? a cohort study analysis of multidrugresistant bacteria in patients with hospital-acquired infections (hai) from a tertiary general hospital in china acinetobacter baumannii strains isolated from patients in intensive care units in goiania, brazil: molecular and drug susceptibility profiles mechanisms of antibiotic resistance multidrug resistant acinetobacter methicillin resistant staphylococcus aureus in the critically ill methicillin-resistant staphylococcus aureus in a general intensive care unit ventilator-associated pneumonia by staphylococcus aureus. comparison of methicillin-resistant and methicillin-sensitive episodes clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study community-acquired respiratory coinfection in critically ill patients with pandemic influenza a (h n ) virus prevalence rates of infection in intensive care units of a tertiary teaching hospital ventilator-associated pneumonia critically ill patients with the middle east respiratory syndrome: a multicenter retrospective cohort study deaths from bacterial pneumonia during - influenza pandemic influenza-associated deaths among children in the united states critically ill children during the - influenza pandemic in the united states severe pneumonia caused by coinfection with influenza virus followed by methicillin-resistant staphylococcus aureus induces higher mortality in mice clinical, immunological and bacteriological characteristics of h n patients nosocomially co-infected by acinetobacter baumannii: a case control study publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we wish to thank the research council of qom university of medical sciences and the personnel of our hospitals for supporting the study. the authors declare that they have no competing interests. authors' contributions ss, es, and jk developed and supervised the work. me and rfa performed the experiments. ss, ak, and sejg drafted the manuscript. zd contributed to data interpretation. all authors reviewed the manuscript. all authors read and approved the final manuscript. the study was supported by research council of qom university of medical sciences. the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. the study was reviewed and approved by medical ethics committee of qom university of medical sciences (code: ir.muq.rec. . ). participants provided written informed consent to participate in this study. in unconscious patients or those under mechanical ventilation, consent was obtained from the relatives of them. not applicable. key: cord- -s nfejq authors: kumar, abhyuday title: covid- pandemic and the need for objective criteria for icu admissions date: - - journal: j clin anesth doi: . /j.jclinane. . sha: doc_id: cord_uid: s nfejq nan j o u r n a l p r e -p r o o f abhyuday kumar drabhyu@gmail.com room no. , ot complex, all india patna, bihar , india. as we are in the middle of the covid- pandemic, many european and north american countries are hard hit by increasing death tolls. condition is expected to be worst in developed countries with its widespread. with the increase in the influx of patients, hospitals all over the world are facing a crisis of essential equipment and manpower and thus a rational decision is required considering the resources available in the hospital. early recognition of the patients who will require icu admission and will benefit most from it is of utmost importance. for that triage of the patients admitted to the emergency department is needed. this warrants the formulation of a uniform criterion for admission to the intensive-care unit (icu). [ ] [ ] [ ] moreover, patients with two or more comorbidities have significantly escalated risks of icu admission, invasive ventilation, and mortality as compared with those who had single comorbidity, and even more so as compared with those without any comorbidity. [ ] anews would help as objective criteria for early recognition and escalation of treatment that can be used by less expertized health care workers (hcw) in the event of scarcity of hcws. moreover, when the number of critically ill people would outnumber the icu beds, anews can work as a useful tool for triage of the patients admitted to the emergency department. in such conditions, the patients with anews ≥ and lesser survival benefits like advanced malignancies and end stage organ failure should be given a lesser preference for icu care. respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected. date last accessed cdc covid- response team. severe outcomes among patients with coronavirus disease (covid- ) -united states clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease comorbidity and its impact on patients with covid- in china: a nationwide analysis key: cord- -zadogqiu authors: davido, benjamin; boussaid, ghilas; vaugier, isabelle; lansaman, thibaud; bouchand, frédérique; lawrence, christine; alvarez, jean-claude; moine, pierre; perronne, véronique; barbot, frédéric; saleh-mghir, azzam; perronne, christian; annane, djillali; de truchis, pierre title: nimpact of medical care including anti-infective agents use on the prognosis of covid- hospitalized patients over time date: - - journal: int j antimicrob agents doi: . /j.ijantimicag. . sha: doc_id: cord_uid: zadogqiu introduction: interest of anti-infective agents in covd- showed discrepant results. however, there is no evaluation about the impact in changes of practices on the prognosis over time. methods: single center, retrospective study, conducted from march (th) to april (th) , in adults hospitalized in a medicine ward for a covid- . patient characteristics were compared between periods (before/after march (th)) considering french guidelines issued by learned societies. aim of the study was to evaluate how medical care impacted unfavorable outcome, namely admission in intensive care unit (icu) and/or death. results: one hundred thirty-two patients were admitted, mean age was . ± . years, mean crp level was . ± . mg/l, % had a lymphocyte count< /mm( ). when prescribed, anti-infective agents were lopinavir-ritonavir (n= ), azithromycin (azi) (n= ) and azi combined with hydroxychloroquine (hcq) (n= ). between the periods we noted a significant decrease of icu admission, from % to % (p< . ). delays until transfer in icu were similar between periods (p= . ). pulmonary ct-scan were significantly more performed (from % to %, p< . ), as oxygen-dependency ( % vs %, p= . ) and prescription of azi±hcq (from % to %, p< . ) were greater over time. multivariate analyses showed a reduction of unfavorable outcome in patients receiving azi±hcq (hr= . , %ic [ . - . ], p= . ), especially among an identified category of individuals (lymphocyte≥ /mm( ) or crp≥ mg/l). conclusion: the present study revealed a significant decrease of admission in icu over time probably related to multiple factors, including a better indication of pulmonary ct-scan, of oxygen therapy, and a suitable prescription of anti-infective agents. impact of medical care including anti-infective agents use on the prognosis of covid- hospitalized patients over time introduction: interest of anti-infective agents in covd- showed discrepant results. however, there is no evaluation about the impact in changes of practices on the prognosis over time. methods: single center, retrospective study, conducted from march th to april th , in adults hospitalized in a medicine ward for a covid- . patient characteristics were compared between periods (before/after march th ) considering french guidelines issued by learned societies. aim of the study was to evaluate how medical care impacted unfavorable outcome, namely admission in intensive care unit (icu) and/or death. results: one hundred thirty-two patients were admitted, mean age was . ± . years, mean crp level was . ± . mg/l, % had a lymphocyte count< /mm . when prescribed, anti-infective agents were lopinavir-ritonavir (n= ), azithromycin (azi) (n= ) and azi combined with hydroxychloroquine (hcq) (n= ). between the periods we noted a significant decrease of icu admission, from % to % (p< . ). delays until transfer in icu were similar between periods (p= . ). pulmonary ct-scan were significantly more performed (from % to %, p< . ), as oxygen-dependency ( % vs %, p= . ) and prescription of azihcq (from % to %, p< . ) were greater over time. multivariate analyses showed a reduction of unfavorable outcome in patients receiving azihcq (hr= . , %ic [ . - . ], p= . ), especially among an identified category of individuals (lymphocyte≥ /mm or crp≥ mg/l). conclusion: the present study revealed a significant decrease of admission in icu over time probably related to multiple factors, including a better indication of pulmonary ct-scan, of oxygen therapy, and a suitable prescription of anti-infective agents. management and medical care of covid- pneumonia in hospitalized patients is currently still debated, especially because data regarding an emerging pathogen are constantly evolving over time and across countries. numerous therapies including oxygen, anti-infective agents and corticosteroids have been proposed. historically, gautret et al. [ , ] and million et al. [ ] observed in marseille (france) that a combination therapy using hydroxychloroquine (hcq) and azithromycin (azi) could potentially reduce viral shedding and the incidence of covid- pneumonia. concomitantly, an observational study conducted by mahevas et al. [ ] evaluating hcq alone prescribed in an in-hospital setting, showed no impact of hcq on the transfer rate in intensive care unit (icu) and/or death. this study is concordant with a publication issued in the united states by geleris et al. [ ] who concluded that hcq administration was not associated with a greatly lowered risk of intubation or death. interestingly, although corticosteroids were considered potentially harmful in the early care of covid- infected patients [ ] , the recovery trial (nct ) stated that dexamethasone could reduce mortality rate up to % in severely-ill patients admitted for a covid- pneumonia and revealed no interest of hcq (data not published), meanwhile the azithromycin arm is still being investigated. very recently a multicenter study in the united states reopened the debate concerning the efficacy of hcq with or without azi [ ] . furthermore antiviral therapies, notably lopinavirritonavir, revealed no benefit in comparison to standard of care in a large randomized trial [ ] , whereas remdesivir showed a reduction in time to clinical improvement in trials but no significant impact on mortality [ , ] . overall those reports have raised concerns about the true interest of anti-infective agents in covid- pneumonia in a context where medical practices between these different studies are heterogeneous and have evolved over time. indeed, in the absence of a clear recommendation for treatment initiation, it is difficult to assume or to invalidate the effect of anti-infective agents on the prognosis of covid- patients. to our knowledge, there is no evaluation over time about changes of practices, including anti-infective agents, and their impact on the prognosis of patients admitted in a medical ward for a covid- pneumonia. considering controversies, we retrospectively evaluated the potential factors associated with an unfavorable outcome, namely admission in icu and/or death, during this first wave of the epidemic. we conducted a single center and retrospective study, from march th to april th , regarding adults admitted in our medicine wards in a tertiary university hospital namely hôpital raymond poincaré (ap-hp), garches, france. we included all the adults admitted in medicine for a covid- infection confirmed by sars-cov- rt-pcr and/or a compatible pulmonary ct-scan. exclusion criteria were: i) patients directly admitted in icu; ii) patients discharged from icu to a medicine ward; iii) opposition to collect data expressed by the patient. the following data were collected from patient's medical charts: -patient characteristics: age, sex, diabetes, cardiovascular risk factors, smoking habits, obesity, chronic pulmonary disease, charlson comorbidity index (cci) [ ] , -infection characteristics: delay between onset of symptoms and admission, presence of super-infection, c-reactive protein (crp) and white blood cell count (wbc) at admission, percentage of lung injuries on ct-scan if applicable, positive pcr amplifying the betacoronavirus e gene and the sars-cov- rdrp gene on nasopharyngeal swab or sputum, -treatment characteristics: requiring icu support with invasive ventilation and associated therapeutic strategies (e.g. oxygen, anti-infective agents), -endpoint was defined as unfavorable outcome assessed by the requirement of a transfer in icu for invasive ventilation and/or death within days, -patients were followed-up until hospital discharge. after discharged, patients were monitored during days by the telemedicine through the french covidom platform [ ] , -derived variables: moderate lymphocytopenia was based on a lymphocyte count with a threshold at /mm and high systemic inflammation was defined as a crp threshold ≥ mg/l. all patients who required oxygen received systematically a beta-lactam for at least days, using preferentially ceftriaxone or cefotaxime to treat a potential superinfection. patients were eligible to a supposed effective anti-infective agent against covid- (hcq, azi, lopinavir-ritonavir), independently of biological abnormalities and considering the following indications: i) patient presenting a clinical pneumonia confirmed by sars-cov- pcr, requiring oxygen therapy (independently of the ct scan findings); ii) high suspicion of covid- pneumonia considering the clinical presentation and/or pulmonary ct-scan showing ground-glass opacity affecting ≥ % of the whole parenchyma. patients were categorized as receiving an anti-infective agent once they received at least one dose. patients who received lopinavir-ritonavir were categorized in no treatment group, considering this antiviral drug did not show any benefit for the treatment of covid- [ ] . before hcq or azi initiation, patients had systematically an electrocardiogram (ecg) to evaluate the corrected qt interval using the framingham formula, and monitored times per week during the whole treatment, as well as serum potassium levels. a loading dose at day with mg/day was administered followed by a maintenance dose of mg/day up to mg/day in case of obesity (body mass index (bmi) > ) for a total days. in addition, mg of azithromycin was prescribed the first day, followed by mg for days. patients were informed that hcq and lopinavirritonavir were currently off-label for the treatment of covid- pneumonia until the th of march in france, where the ministerial decree # - authorized the in-hospital prescription of hcq in this particular indication. in case they refused the prescription of hcq or the latter was contraindicated (by ecg or drug interactions), it was noted into their medical chart and patients did not receive hcq. aim of the study was to describe the medical care over time (oxygen therapy, antiinfective agents, pulmonary ct-scan) and to determine whether potential factors were related to an unfavorable outcome (transfer in icu and/or death). descriptive statistics are presented as counts and percentages, or means and standard deviations, with skewed continuous data summarized as medians and interquartile ranges. interactions between treatment and lymphocyte count or crp level were tested and kaplan-meier curves were plotted to assess unfavorable outcome from admission depending on these biological parameters. statistical significance was set at . (two-tailed test). all statistical calculations were performed using r software version . . . all procedures performed in studies involving human participants were in accordance with the ethical standards and with the helsinki declaration and its later amendments or comparable ethical standards. this study has passed the cesrees/health data hub regarding ethics committee approval (mr ) and is registered on clinicaltrials.gov (nct ). as part of an anonymous and retrospective study, a non-opposition and information letter was sent to participants afterwards. greater than mg/l. seventy-two percent of patients were oxygen-dependent at admission, with % of patients with an oxygen flow therapy greater than l/min. among the patients who underwent a pulmonary ct scan, % had lung injuries compatible with covid- greater than % of the whole parenchyma. sars-cov- rt-pcr was positive in . % (n= ) of cases. overall, ( %) patients received one anti-infective agent. among them, ( %) received lopinavir-ritonavir, ( %) azithromycin (azi) and ( %) azi combined with hcq ( during the first period, ( %) patients were hospitalized whereas ( %) were admitted thereafter. there were significantly more oxygen-dependent patients hospitalized during the second period than the first one ( % vs %, p= . ). also, a significant higher number of pulmonary ct scan performed was observed over time between periods of hospitalization from % to % (p< . ), independently of ct-scan severity (table ) . concomitantly, prescription of azi whether or not combined with hcq increased over time, from % to % between the periods (p< . ) (figure ). of note, among patients who did not receive hcq, had cardiac contraindication and refused to be treated with this molecule. during the course of treatment using azi in combination with hcq, we report only patient that presented an adverse event (a prolonged qt interval on ecg without clinical event) that led to discontinuation of hcq within h, and was switched to azithromycin alone. a total of ( %) patients had an unfavorable outcome, among them ( %) were transferred to icu and ( %) died without being transferred in icu. mean delay between hospitalization and admission in icu was . ± . days ( . ± . days during the first period vs . ± . days during the second one, p= . ). a trend towards a lower frequency of admission to icu was observed, from % in the first period to % in the second period (p< . ) (figure ). overall, the risk of death or admission to icu was significantly related to the oxygen flow (p< . ) and to lymphocyte count in a first model (i.e. lymphocyte there was a significant interaction between treatment and crp level (p= . ) and at the limit of statistical significance for the lymphocyte count (p= . ) supporting a subgroup analysis. in univariate analysis, patients who benefited from azi whether or not combined with hcq with a lymphocyte count ≥ /mm , were less likely to have an unfavorable outcome compared to patients without any treatment (p= . ) (fig .a) . concomitantly, patients who benefited from azi whether or not combined with hcq with a crp ≥ mg/l, were less likely to have an unfavorable outcome compared to patients without any treatment (p= . ) (fig .b) . however, these results are not reproducible in patients with a lymphocyte count < /mm (p= . ) and similarly in patients with a crp level < mg/l (p= . ) ( figure s .a, s .b in supplementary data). our study highlights that unfavorable outcome (transfer to icu and/or death) because of lockdown, it looks like patients were admitted later in the second period than during the first period of the epidemic and it might explain why they required more oxygen therapy at baseline. we suggest that in case of a second wave, it could be relevant to introduce telemedicine monitoring of vital signs including pulse oximetry at home. indeed, oxygen therapy at home, as proposed by the french covidom platform in patients discharged from the hospital during the first wave of the epidemic was of interest [ ] . in multivariate analyses, our models adjusted on the lymphocyte count or crp, showed that patients who benefited from azi whether or not combined with hcq were . and . times less likely to have an unfavorable outcome than patients without treatment (p= . ), respectively. this finding suggests that the lymphocyte count which is already known to be closely related to covid- disease severity [ , ] could be also a predictive factor of anti-infective therapy response. indeed, patients with lymphocyte count ≥ /mm might be patients at an early stage of covid- , arguing for the earliest initiation of anti-infective agents, as previously demonstrated with oseltamivir treatment in severely-ill patients with pandemic influenza a (h n ) [ ] . however, we did not study whether there was a relationship between the lymphocyte count and the delay from first onset of symptoms to the admission, because this variable is declarative and thus not reliable. likewise, azi whether or not combined with hcq showed interest in hospitalized patients with a high systemic inflammation (crp level ≥ mg/l), known as the so called -cytokine storm‖. this is one argument pleading for a possible immune-modulator effect of the treatment as previously described by zhao et al. [ ] . interestingly, our study does focus on the potential interest of treatment with azithromycin whether or not combined depending on certain biological parameters. indeed, azithromycin's potential antiviral activity is concordant with previous in vitro studies regarding sars-cov- [ ] or h n -pdm [ ] and one clinical randomized trial in in the prevention of children respiratory infections [ ] . in addition a recent publication emphasized the role of azithromycin against covid- through the cd receptor of stem cell [ ] . moreover, one study published in the jama by rosenberg et al. [ ] highlighted a potential trend to a decreased mortality in patients receiving azithromycin versus hcq or standard of care despite being non-statistically significant (p= . ). moreover, authors discussed that the rapidity with which patients entered the icu (within hours) might have underestimated the treatment efficacy. also, as azithromycin is commonly prescribed for bronchitis and authorized in ambulatory care, a study conducted among general practitioners could be relevant to evaluate early indication of this single therapy for the treatment of covid- in fragile outpatients. in addition, our experience does not report any serious side effect of this combination therapy as long as we take the necessary caution and perform follow-up ecg using a conventional dose of hcq as proposed by borba et al. [ ] . our study has several limitations. the first limitation is the single center nature of the study, describing the experience of a unique center whose results might not be generalizable. however, it was carried out in a hospital specialized for decades in the moreover, considering inherent limitation of a descriptive study with a limited sample size (n= ), we could not infer causality in the association between the use of azi±hcq and the ameliorated prognosis in covid- patients. besides, we also noted that some unforeseen confounders (e.g., pre-hospital medication and delay to admission) may still potentially alter the magnitude of azithromycin effects on the outcome of covid- pneumonia. also, choices in anti-infective agents have differed between the first and second period, notably because prior to march th , hcq was not authorized by the french minister of health and explained partly the common use of lopinavir-ritonavir at this period. finally, we decided to choose a multivariate model rather than a propensity score because the aim of this study was not to evaluate the effect of azi±hcq on the prognosis but to evaluate all factors which could have impacted on medical care. in conclusion, findings from this study showed that rate of admission in icu all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. authors would like to thank pr xavier paoletti for his proofreading of the manuscript and his particular attention to the statistical analyses. ( ) < . azi ± hcq ( ) ( ) † in first period is define between / to / ; ‡in second period is define between / to / ; azi, azithromycin; hcq, hydroxychloroquine; n, number; %, percent; sd, standard deviation; m, men; obesity with body mass index ≥ kg/m²; *cci, charlson comorbidity index; pmn, polymorphonuclear leukocyte; crp, c-reactive protein; ct : computerized tomography; pulmonary ct scan category normal [ %], limited < %, mild % - %, moderate % - %, severe > %; a student test (equal variance) or a welche-satterthwaite t test (unqual variance) was used to analyze the quantitative variables, a mantel-haenszel chi-square test was used to analyze the qualitative variables and the exact test of fisher was used when the sample sizes were small (< ). test significant (p< . ) infection & inflammation-u- centre d'evaluation et de traitement de la douleur-u- handicap neuromusculaire-u- centre d'investigation clinique clinique de la muette clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in covid- patients with at least a six-day follow up: a pilot observational study hydroxychloroquine and azithromycin as a treatment of covid- : results of an open-label non-randomized clinical trial early treatment of covid- patients with hydroxychloroquine and azithromycin: a retrospective analysis of cases in marseille, france clinical efficacy of hydroxychloroquine in patients with covid- pneumonia who require oxygen: observational comparative study using routine care data observational study of hydroxychloroquine in hospitalized patients with covid- clinical evidence does not support corticosteroid treatment for -ncov lung injury treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with covid- a trial of lopinavir-ritonavir in adults hospitalized with severe covid- remdesivir in adults with severe covid- : a randomised, double-blind, placebo-controlled, multicentre trial remdesivir for the treatment of covid- -preliminary report a new method of classifying prognostic comorbidity in longitudinal studies: development and validation assistance publique-hôpitaux de paris' response to the covid- pandemic recommandations d'experts portant sur la prise en charge en réanimation des patients en période d'épidémie à sars-cov : hematological findings and complications of covid- lymphopenia predicts disease severity of covid- : a descriptive and predictive study early versus late oseltamivir treatment in severely ill patients with pandemic influenza a (h n ): speed is life n.d cytokine storm and immunomodulatory therapy in covid- : role of chloroquine and anti-il- monoclonal antibodies outcomes of , covid- patients treated with hydroxychloroquine/azithromycin and other regimens in marseille, france: a retrospective analysis in vitro screening of a fda approved chemical library reveals potential inhibitors of sars-cov- replication azithromycin, a -membered macrolide antibiotic, inhibits influenza a(h n )pdm virus infection by interfering with virus internalization process early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: a randomized clinical trial cd as a target for covid- treatment: suggested effects of azithromycin and stem cell engagement association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with covid- in new york state effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus (sars-cov- ) infection /n number/total; * indicates the reference category no treatment defined as patients who have had no treatment or lopinavir-ritonavir multivariate cox model regression was used to identify the potential factors associated with unfavorable outcome (icu admission or death after icu), adjusted on cci (including age), obesity, oxygen and treatment strategies groups according to crp key: cord- -wm y uwm authors: vargas, maria; de marco, giuseppe; de simone, stefania; servillo, giuseppe title: logistic and organizational aspects of a dedicated intensive care unit for covid- patients date: - - journal: crit care doi: . /s - - -x sha: doc_id: cord_uid: wm y uwm nan logistic and organizational aspects of a dedicated intensive care unit for covid- patients maria vargas * , giuseppe de marco , stefania de simone and giuseppe servillo dear editor, on march, the world health organization (who) reported , confirmed globally confirmed cases of covid- [ ] . covid- cases are dramatically increasing in several countries with heterogenous and unpredictable distributions [ ] . patients with covid- have resulted in high rates of hospitalization and icu admissions [ ] . on april, the worldwide icu admission rate of covid- patients was % ranging from % of total cases in africa to % of total cases in europe [ ] . according to this heterogenous and unpredictable geographic distribution of covid- , several countries are increasing their icu capacity response by converting general icu in dedicated covid- facilities [ ] . dedicated icus for covid- patients were suddenly created on the whole italian territory [ ] . based on the high contagiousness of the novel cov virus [ ] , the logistics and the staff organizations are the fundamental principles to avoid the in-hospital spread of the virus while creating dedicated covid- facilities. from march, our icu is completely dedicated to covid- patients, and actually, it is one of the largest cohorted icu in the south of italy admitting positive critically ill patients (fig. ). the icu is divided into green, yellow, and red areas (fig. ) . each icu bed is equipped with a full monitoring of vital parameters and a mechanical ventilator. each monitor is duplicated in the centralized control unit equipped with microphones and glasses to allow the communications between the staff. inside the icu, we have a laboratory section including two dedicated ultrasound machines, disposable fiberoptic bronchoscopes, video laryngoscopes, point-of-care arterial blood gas and coagulation analyses, transport ventilator, and emergency cart with a defibrillator. during the -h shift, the nursing and medical working is organized as follow: . the most experienced icu physician is the work shift coordinator and stays in the green area to control the compliance of the staff with the procedures and to check the patients from the centralized monitoring area. . medical staff review the medical records of each patient, and then a briefing with the whole staff is made to plan the actions of the shift. . all the therapies are prepared in a dedicated area outside the icu boxes to minimize the time spent inside. . the nursing and medical staff performed the first entry in the icu boxes and stay inside for h. after that, only two nurses and one medical doctor continue to stay inside for an additional h while the other personnel rest themselves and fulfill the medical records. . after that, the nurses and the medical doctor are replaced by other colleagues for another h. . the transition from the red to the green area must be preceded by the staff decontamination in the yellow area. . the disinfection of the different areas is performed three times during the shift. according to our experience, a simple logistic project and clear organizational plan may be the keys to the success of surging the icu capacity with dedicated facilities during the covid- outbreak. fig. upper box-organization of icu before covid- outbreak. before the outbreak of covid- , our icu was equipped with two main boxes including beds each and one box with two beds for the infected patients. we also had several offices for medical and nursing staff. lower box-organization of icu dedicated to covid- patients. the red area is a zone where the full ppe is mandatory. the yellow areas are the zone of decontamination while the green area is a clean one. the entrance of the first icu box was the only entry point for covid- patients. the green area inside the icu is a clean zone where the medical and nursing staff may stay during the -h shift. the green area outside the icu, equipped with shower facilities, clean scrubs, and clean supplies, is dedicated to the staff wash at the end of shift. the yellow areas are the filter of decontamination where the staff must change their scrubs, wash their body with disinfectants, and clean their shoes in the bowls with sodium hypochlorite . to . before accessing the green areas. inside the red area, we set up two contamination filters, equipped with waste management material, mirror, and supply to wash the body and the hand, for doffing after the exiting from the icu boxes coronavirus disease (covid- ) situation report - worldmeters data source aseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region situation update worldwide critical care utilization for the covid- outbreak in lombardy, italy early experience and forecast during an emergency response insights into the recent novel coronavirus (sars-cov- ) in light of past human coronavirus outbreaks publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors' contributions mv, gds, sds, and gs planned the manuscript, collected the data, wrote the manuscript, and approved the final version. none key: cord- -pj lsvsa authors: arabi, yaseen; balkhy, hanan; hajeer, ali h.; bouchama, abderrezak; hayden, frederick g.; al-omari, awad; al-hameed, fahad m.; taha, yusri; shindo, nahoko; whitehead, john; merson, laura; aljohani, sameera; al-khairy, khalid; carson, gail; luke, thomas c.; hensley, lisa; al-dawood, abdulaziz; al-qahtani, saad; modjarrad, kayvon; sadat, musharaf; rohde, gernot; leport, catherine; fowler, robert title: feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with middle east respiratory syndrome coronavirus infection: a study protocol date: - - journal: springerplus doi: . /s - - - sha: doc_id: cord_uid: pj lsvsa as of september , , a total of laboratory-confirmed cases of infection with the middle east respiratory syndrome coronavirus (mers-cov) have been reported to the world health organization (who). at present there is no effective specific therapy against mers-cov. the use of convalescent plasma (cp) has been suggested as a potential therapy based on existing evidence from other viral infections. we aim to study the feasibility of cp therapy as well as its safety and clinical and laboratory effects in critically ill patients with mers-cov infection. we will also examine the pharmacokinetics of the mers-cov antibody response and viral load over the course of mers-cov infection. this study will inform a future randomized controlled trial that will examine the efficacy of cp therapy for mers-cov infection. in the cp collection phase, potential donors will be tested by the enzyme linked immunosorbent assay (elisa) and the indirect fluorescent antibody (ifa) techniques for the presence of anti-mers-cov antibodies. subjects with anti-mers-cov ifa titer of ≥ : and no clinical or laboratory evidence of mers-cov infection will be screened for eligibility for plasma donation according to standard donation criteria. in the cp therapy phase, consecutive critically ill patients admitted to intensive care unit with laboratory-confirmed mers-cov infection will be enrolled and each will receive units of cp. post enrollment, patients will be followed for clinical and laboratory outcomes that include anti-mers-cov antibodies and viral load. this protocol was developed collaboratively by king abdullah international medical research center (kaimrc), gulf cooperation council (gcc) infection control center group and the world health organization—international severe acute respiratory and emerging infection consortium (isaric-who) mers-cov working group. it was approved in june by the ministry of the national guard health affairs institutional review board (irb). a data safety monitoring board (dsmb) was formulated. the study is registered at http://www.clinicaltrials.gov (nct ). the middle east respiratory syndrome coronavirus (mers-cov) was initially identified in september from samples obtained from a saudi arabian patient who developed severe acute respiratory infection and subsequent acute renal failure leading to death (zaki et al. ) . as of september , , a total of cases have been identified with related deaths (world health orgnization ) . to date, there is no specific treatment of proven effect for mers-cov infection. public health england and the international severe acute respiratory and emerging infection consortium (isaric) have published a decision support tool for clinicians managing cases of mers-cov infection. the document suggests that current evidence is strongest for testing convalescent plasma (cp) or other therapeutics which contain neutralizing antibodies (such as hyperimmune immunoglobulin) for treatment of serious mers-cov illness (public health england ) . prior experience in sars and severe influenza suggest that cp may be considered for patients who are deteriorating (despite other specific and supportive therapy) and in whom the virus remains detectable (hung et al. ; luke et al. ; cheng et al. ; kong and zhou ; yeh et al. ) . a recent systematic review of reports from sars and severe influenza concluded that cp therapy appears safe and may reduce mortality, especially if administered early in the illness (mair-jenkins et al. ). an exploratory post hoc meta-analysis showed a statistically significant reduction in the pooled odds of mortality following treatment compared to placebo or no therapy (odds ratio . ; % confidence interval . - . ; i = %) (mair-jenkins et al. ) . citing case series, the authors commented that ( ) patients with severe presentations appeared to demonstrate temporal clinical improvements after treatment with cp and ( ) administration as early as possible in the diseases course appears to be associated with greatest potential clinical effect. one randomized clinical trial (rct) in critically ill influenza a (h n pdm )-infected patients found a survival benefit when hyperimmune globulin was administered within days of symptom onset (hung et al. ) . however, there are no data at present to support the efficacy of cp treatment in mers-cov infection; therefore, it has been recommended to administer cp only in the context of a clinical trial. while an rct will be required to evaluate effectiveness, evaluating effectiveness on clinical endpoints such as mortality will likely require several hundred to several thousand seriously ill mers-cov patients in order to achieve sufficient statistical power, anticipating reasonable potential effect sizes. additionally, cp from different mers-cov survivors will likely contain differing levels of neutralizing anti-mers-cov antibodies. since seriously ill mers-cov-infected patients may have detectable viral rna in various locations that can be sampled (for example lower respiratory tract secretions) for prolonged periods, it might be possible to first determine the relationship between neutralizing antibody dose and antiviral effects on clinical and laboratory features in a small open-label study. this information would be very helpful to design of an rct and in determining the most appropriate neutralizing antibody dose, or dosing range for the study. this may also inform dose selection for follow-on anti-mers-cov antibody preparations currently in preclinical development (for example, neutralizing human monoclonal antibodies, polyclonal human neutralizing immunoglobulin derived from transchromosomic cattle (personal communication, thomas c. luke). therefore, we plan to conduct a -phase study. in the first phase (cp collection phase), we will explore the feasibility of collection of cp from donors who have significant titers of anti-mers-cov antibodies. in the second phase, patients with mers-cov infection will be treated with cp. if the protocol is feasible, safe, and associated with temporal changes in viral load and illness, this pilot study will inform a larger concealed intervention, placebo-controlled rct that is powered to evaluate efficacy of cp on relevant clinical outcomes. the inclusion criteria for screening potential cp donors include individuals from the following cohorts: ( ) healthcare workers (hcws) who had documented exposure to mers-cov, ( ) recovering patients from confirmed or suspected mers-cov infection, ( ) household contacts of known mers-cov infected patients and ( ) other subjects who are willing to donate plasma. females with prior pregnancy will not be included for donation. we will screen consecutive critically ill patients admitted to the intensive care unit or other areas of the hospital where critically ill patients receive care for the following criteria: inclusion criteria . critical illness as defined by one or more of the following: admission to an icu; current receipt of mechanical invasive or non-invasive ventilation; partial pressure of oxygen to fraction of inspired oxygen ratio (pao :fio ) of < mmhg; current receipt of intravenous vasoactive medications to maintain mean arterial pressure > mmhg; new-onset (since development of mers-cov symptoms) receipt of renal replacement therapy or extra-corporeal life support. . laboratory-confirmed mers-cov infection (by realtime reverse-transcription polymerase chain reaction rrt-pcr). . age of more than or equal to years. . symptomatic illness exceeding two weeks ( days) at time of enrollment. . negative rrt-pcr from respiratory secretions or blood within h prior to assessment of eligibility. . history of allergic reaction to blood or plasma products (as judged by the investigator). . known iga deficiency. . medical conditions in which receipt of ml intravascular volume may be detrimental to the patient (e.g., actively decompensated congestive heart failure). the research coordinator and/or physician investigator will explain the objectives of this study and its potential risks and benefits to the donor or patient (or to his/her surrogate decision maker) and will obtain the following consent forms in and as appropriate: cp collection phase . consent for mers-cov serologic testing and mers-cov rt-pcr for donors. . consent for cp donation for those who have elevated anti-mers-cov titers as described below. cp therapy phase . consent for enrollment in the cp therapy phase. . consent for enrollment in the observational study where no intervention will be received, but participants will still have blood (and possibly respiratory) samples taken-for participants not receiving the intervention. for the cp collection phase . eligible candidates for cp donation (as per the inclusion and exclusion criteria above) will be approached to have their blood tested for anti-mers-cov serology (see laboratory methods). subjects who are seropositive will be screened subsequently for mers-cov rrt-pcr to exclude active infection. . critically ill mers-cov patients who meet the above patient eligibility criteria will be approached for consent. . patients will have their blood type determined. cp must be abo compatible with the recipient's blood type. . the trial intervention include the administration of units of cp. each unit of plasma will be given over h with an interval of h between the two units. plasma transfusion will be done in accordance with the standard policies for administration of blood products. the clinical team will have full, independent control of patient management and as such, management other than cp therapy will not be influenced by the intervention or study team. co-interventions, including corticosteroids, ribavirin, intravenous immunoglobulin and interferon, will be documented on the study case report forms. co-enrollment in another study is permissible as long as the enrollment in the other study would not be at moderate to high risk of biologically or analytically confounding the results of this study, as judged by the study management committee and as per the published guidelines. clinical and laboratory data will be collected at baseline, min after first dose, min after second dose, study days , , , , , and . we will explore the feasibility of the study intervention, as measured by ability to screen potential plasma donors, and derive sufficient plasma to enrol patients in a months period. we will also qualitatively describe logistical challenges experienced through the conduct of this study, including ethical, administrative and regulatory challenges. . we will establish safety of the study intervention, as measured by number of serious adverse events related to study intervention (adverse events include development of complications of intravascular volume overload and clinical pulmonary edema by temporally related-shortness of breath, chest radiograph findings and change in oxygenation requirements; development of transfusion-related acute lung injury (trali) or substantial allergy or anaphylaxis). these serious events will be adjudicated by a committee of investigators. . clinical outcomes we will measure ( ) sequential organ failure assessment (sofa) scores on study days , , , , , and ( ) requirement for organ support (oxygen and ventilation; dialysis; vasopressors) after enrollment; ( ) length of stay in icu defined as the number of calendar days between admission and final discharge from icu for the same icu admission of enrollment; and duration of mechanical ventilation, defined as the number of calendar days between start and final liberation from mechanical ventilation for the same icu admission of enrollment and hospital length of stay as defined as the number of calendar days between admission to hospital and final discharge from hospital for the same hospital admission; and ( ) vital outcome (mortality) in icu, hospital and at days. . other clinical outcomes include "icu-free days", defined as the number of days that patients are not in icu in the first days after enrollment. patients who die within days will be counted separately, and not categorised by icu-free days. similarly, "ven-tilator-free days" is defined as the number of days that patients do not receive mechanical ventilation in the first days after enrollment. "renal replacement therapy-free days" and "vasopressor-free days" are defined in a similar way. serial chest radiograph findings, as obtained by the clinical team will also be recording as per case report form, graded as unilateral or bilateral infiltrates, in - quadrants. . laboratory outcomes we will measure the following laboratory outcomes: (a) the serum level of anti-mers-cov antibodies before and after administration of cp. (b) mers-cov viral load (the primary laboratory outcome is viral clearance from all sampled sites by day after administration of cp). mers-cov antibodies will be tested first by the enzyme linked immunosorbent assay (elisa) as a screening test (drosten et al. ; müller et al. ) according to manufacturer's instructions (euroimmun ag, lübeck, germany). results will be reported as the optic density (od) ratio, which is calculated as the od value of the patient's sample divided by the calibrator od value. we will use the cut-off values recommended by the manufacturer: a ratio of < . is considered negative, > . and < . borderline and a ratio of > . is considered positive. confirmation will be done by the indirect fluorescent antibody (ifa, euroimmun ag, lübeck, germany) according to manufacturer's instructions. samples with ≥ : will be considered reactive according to the manufacturer's instructions, subjects will be considered candidate for plasma donation if they have titers of ≥ : ; which is a similar threshold to what has been used in a convalescent plasma trial for h n influenza (hung et al. ) . the primary coordinating study center is the intensive care department at king saud bin abdulaziz university for health sciences (ksauhs) in riyadh, saudi arabia. the study will be conducted in accordance with the ethical principles of the declaration of helsinki and the international conference on harmonization-good clinical practice (ich-gcp) guidelines. several measures will be taken to ensure optimal compliance with the study protocols. before launching the study, icu physicians and nurses will attend the training sessions with special emphasis on any adverse events noted during the intervention. the steering committee, led by the principal investigator, will be responsible for overseeing the conduct of the trial, for upholding or modifying study procedures as needed, addressing challenges with protocol implementation, formulating the analysis plan, reviewing and interpreting the data and preparing the manuscript. the study also has an independent data safety monitoring board (dsmb) which is responsible for reviewing reports submitted to the regarding safety of study patients, protocol adherence and may making recommendations to continue or terminate the study based on safety analysis results. the dsmb, composed of members (who are named at the end of this document) will meet at the beginning of phase ii of the study followed by -monthly or as needed. in the event of an acute transfusion reaction, the transfusion will be stopped immediately and must be reported to the blood bank the principal investigator immediately as well as to the study management committee. all the serious adverse events (sae) adjudicated as related to the study intervention will be reported to the institutional research ethics board and the dsmb. this is an exploratory study, aimed at rectifying the current lack of information on the use of cp to treat mers-cov infection. due to the exploratory nature of this study and the paucity of sequential data on viral rna levels in respiratory tract and blood samples from mers-covinfected patients, and on their clinical progress, the sample size is fixed at , which is a realistic target for a study of months duration. the sample size of is sufficient to reach a conclusion that the -day survival rate significantly exceeds % (p = . , -sided) if or more patients survive for the days of follow-up. this would represent promising evidence to motivate a full-scale comparative clinical trial. . serial mers-cov viral load measurements will be displayed as box and whisker plots for the treated patients against time. . the probability of a patient having an undetectable viral load from all sampled sites by day after administration of therapy will be estimated by the proportion of the treated patients for whom this occurs. an exact, conservative, two-sided confidence interval for this probability will be calculated using the method of clopper and pearson ( ) . . the relationship between log viral load at day and the neutralizing antibody dose received will be characterised by fitting a regression model to the data from the treated patients. the log viral load at baseline will be included in this model. . the relationship between the probability of a patient having an undetectable viral load by day and the neutralizing antibody dose received will be characterised by fitting a log-logistic regression model to the data from the treated patients. the log viral load at baseline will be included in this model. . the sofa score and indicators of whether the patient requires organ support via oxygen and ventilation, dialysis or vasopressors will be plotted against time. . the relationships between the sofa score at day and the neutralizing antibody dose received, and between receipt of any type of organ support during the days of observation and the neutralizing antibody dose received, will be characterised by fitting a logistic regression model to the data from the treated patients. the log viral load at baseline will be included in these models. . the vital status (alive or dead) of each patient will be recorded for all days - . the proportion alive will be plotted against time. . the relationship between the hazard of death and the neutralizing antibody dose received will be characterised by fitting a cox proportional hazards regression model to the data from the treated patients. the log viral load at baseline will be included in this model. . the probability of a patient dying on or before days will be estimated by the proportion of the treated patients for whom this occurs. an exact, conservative, two-sided confidence interval for this probability will be calculated using the method of clopper and pearson ( ) . . the time from infection/exposure and sample collection in days, duration from infection/exposure to cp therapy, length of stay in icu; the number of icu-free days; the duration of mechanical ventilation; the numbers of ventilator-free days, of renal replacement therapy-free days, and of vasopressor-free days; and the length of stay in hospital will be presented as histograms, and suitable summary statistics will be computed. we will conduct exploratory stratified analyes based on ( ) the time between symptom onset and cp therapy initiation, ( ) comorbidities, ( ) co-intervention; and ( ) baseline severity (sofa scores) at treatment initiation. the sas system for windows version . (sas institute, inc., cary, north carolina) and r will be used for all analyses. this protocol was developed collaboratively by king abdullah international medical research center (kaimrc), gulf cooperation council (gcc) infection control center group and the world health organization-international severe acute respiratory and emerging infection consortium (isaric-who) mers-cov working group. it was approved by the ministry of the national guard health affairs institutional review board (irb) (approval number irbc/ / , th june , ) and has been registered at clinicaltrials.gov (nct ). if proven effective, cp therapy is an attractive therapeutic option for mers-cov infection. besides the biologic plausibility of this therapy, it is easy to obtain and administer, relatively inexpensive, and is likely to be acceptable to patients and treating teams. side effects are unlikely to differ from those of transfusion of any other fresh frozen plasma. we believe this study protocol sets the stage to a large efficacy trial. the strengths and weaknesses of the study protocol should be noted. in the cp collection phase subjects will be enrolled from different cohorts, in order to explore all potential donors. it is unknown, at this point, which subjects are likely to have high antibody titers and therefore be cp donors. we are hoping that this feasibility study will help identifying a group of superdonors who have very high titers. by identifying the characteristics of such individuals, a more focused approach for donation can be followed. the cp therapy phase is not designed to establish efficacy; such objective requires an adequately powered randomized controlled trial. however, we believe performing this feasibility study is an essential step to examine the safety, clinical and laboratory effects and the pharmacokinetics of the mers-cov antibody response. the study involves giving critically ill patients this therapy in a controlled monitored setting. however, a recent systematic review suggested that early treatment with cp is likely to be more effective than late treatment (mair-jenkins et al. ) . therefore, if the feasibility study shows that cp is safe and feasible, the next step should be a randomized controlled trial that is sufficiently powered to detect effect on mortality and enrolls patients early in the course of the disease. our study is anticipated to provide information about the feasibility of collecting convalescent plasma in large quantities for therapeutic use in a large numbers of mers-cov patients. the data is anticipated to inform about the relation between the antibody titers in the cp and viral clearance and other laboratory and clinical endpoints. this data will be critical in planning a larger rct to examine the efficacy of cp on patients with mers-cov infection. use of convalescent plasma therapy in sars patients in hong kong ) the use of confidence or fiducial limits illustrated in the case of the binomial transmission of mers-coronavirus in household contacts convalescent plasma treatment reduced mortality in patients with severe pandemic influenza a (h n ) virus infection hyperimmune iv immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe influenza a(h n ) infection successful treatment of avian influenza with convalescent plasma meta-analysis: convalescent blood products for spanish influenza pneumonia: a future h n treatment? the effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis presence of middle east respiratory syndrome coronavirus antibodies in saudi arabia: a nationwide, cross-sectional, serological study middle east respiratory syndrome coronavirus (mers-cov): clinical management and guidance guidelines on assessing donor suitability for blood donation who blood regulators network (brn) ( ) position paper on collection and use of convalescent plasma or serum as an element in middle east respiratory syndrome coronavirus response middle east respiratory syndrome coronavirus experience of using convalescent plasma for severe acute respiratory syndrome among healthcare workers in a taiwan hospital isolation of a novel coronavirus from a man with pneumonia in saudi arabia we would like to thank the dsmb members: the authors declare that they have no competing interests. this trial is funded by kaimrc/ksauhs, riyadh, saudi arabia. the principal investigator (dr. yaseen arabi) declares that the sponsor had no influence on the design of protocol, patient recruitment or data generation and will not have any impact on the analysis of the results or writing of the manuscript. the views expressed by t. c. luke do not necessarily reflect the official policy or position of the department of the navy, department of defense, or the usa government. he is an employee of the us government, and this work was prepared as part of his official duties. title usc. § provides that 'copyright protection under this title is not available for any work of the united states government. title . t. c. key: cord- - fun ze authors: cardoso, filipe s.; papoila, ana l.; machado, rita sá; fidalgo, pedro title: age, sex, and comorbidities predict icu admission or mortality in cases with sars-cov infection: a population-based cohort study date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: fun ze nan previous studies have identified risk factors for severe acute respiratory syndrome coronavirus (sars-cov ) severe outcomes preferentially among hospitalized patients; therefore, they may have understated the denominator of such estimations [ , ] . we aimed to determine pre-hospital risk factors and estimate individual probabilities of sars-cov severe outcomes among a nationwide cohort of cases of sars-cov infection, including those with and without hospitalization. this was a retrospective analysis from a nationwide prospective registry, including confirmed (nasal/pharynx swab real-time polymerase chain reaction) cases of sars-cov infection notified to the directorate-general of health from march until april , , in portugal. primary endpoint was a composite of icu admission or all-cause mortality until april . multivariable analysis was performed with logistic regression. internal validation was performed with bootstrapping. models' performance was studied with calibration plots, c-statistic, and brier score [ , ] . significance level was α = . . informed consent was waived due to the use of anonymized data and the current state of public health emergency. overall, , cases were included in our analyses, following exclusion of ( . %) cases without hospital admission status and ( . %) cases without outcome status. among all cases, median (iqr) age was ( - ) years ( there were ( . %) cases admitted to the icu or deceased (table ) . cases with icu admission or nonsurvivors had higher median age ( vs. years; p < . ) and were more frequently men ( . % vs. . %; p < . ) than those that were not admitted to the icu and survived. cases with icu admission or non-survivors had more frequently any comorbidity than those that were not admitted to the icu and survived ( . % vs. . %; p < . ). all types of comorbidities were more frequently reported in cases with icu admission or non-survivors than those that were not admitted to the icu and survived. in multivariable analysis with logistic regression, higher age (aor . ), male sex (aor . ), or higher number of comorbidities (aor . if one vs. aor . if vs. aor . if ≥ ; p < . for all comparisons) were associated with higher risk of icu admission or all-cause mortality ( table ) . the model's calibration plot showed a very good predictive performance up to estimated probabilities of among cases with sars-cov infection at an early phase of the epidemic in portugal, pre-hospital characteristics like age, sex, and the number of comorbidities were useful to predict icu admission or all-cause mortality [ ] . these findings may inform health policies designed to protect specific subgroups of the population and project allocation of health resources, especially while measures of containment are being eased in many countries. comorbidity and its impact on patients with covid- in china: a nationwide analysis prevalence of comorbidities and its effects in cases infected with sars-cov- : a systematic review and meta-analysis regression modelling strategies: with applications to linear models, logistic regression, and survival analysis bias reduction of maximum likelihood estimates estimating excess -year mortality associated with the covid- pandemic according to underlying conditions and age: a population-based cohort study publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors would like to acknowledge the portuguese directorate-general of health and all staff of the portuguese national health system. dr. cardoso is the guarantor of the paper, taking responsibility for the integrity of the content of the manuscript as a whole, from inception to published article. dr. cardoso conceived and designed the study, performed statistical and data analyses, drafted the manuscript, revised the manuscript, and provided final approval. prof papoila provided significant contribution to data analyses and interpretation, revised the manuscript, and provided final approval. dr. machado provided significant contribution to data acquisition, contributed to the data analysis and interpretation, revised the manuscript, and provided final approval. dr. fidalgo contributed to the conception and design of the study and data analysis and interpretation, contributed to drafting and revision of the manuscript, and provided final approval. the manuscript has been reviewed and approved by all authors. the authors received no funding at all pertaining to this study. the datasets generated and/or analyzed during the current study are not publicly available due to confidentiality but are available from the corresponding author on reasonable request. this study was approved by the ethics committee at curry cabral hospital, central lisbon university hospital center, lisbon, portugal. informed consent was waived due to the use of anonymized data and the current public health state of emergency. not applicable. the authors declare that they have no competing interests.author details intensive care unit, curry cabral hospital, central lisbon university hospital center, nova medical school, nova university, lisbon, portugal. key: cord- -ceur n b authors: hamdan alshehri, hanan; olausson, sepideh; Öhlén, joakim; wolf, axel title: factors influencing the integration of a palliative approach in intensive care units: a systematic mixed-methods review date: - - journal: bmc palliat care doi: . /s - - -y sha: doc_id: cord_uid: ceur n b background: while a palliative approach is generally perceived to be an integral part of the intensive care unit (icu), the provision of palliative care in this setting is challenging. this review aims to identify factors (barriers and facilitators) influencing a palliative approach in intensive care settings, as perceived by health care professionals. method: a systematic mixed-methods review was conducted. multiple electronic databases were used, and the following search terms were utilized: implementation, palliative care, and intensive care unit. in total, articles were screened, of which met the research inclusion/exclusion criteria. a thematic synthesis method was used for both qualitative and quantitative studies. results: four key prerequisite factors were identified: (a) organizational structure in facilitating policies, unappropriated resources, multi-disciplinary team involvement, and knowledge and skills; (b) work environment, including physical and psychosocial factors; (c) interpersonal factors/barriers, including family and patients’ involvement in communication and participation; and (d) decision-making, e.g., decision and transition, goal conflict, multidisciplinary team communication, and prognostication. conclusion: factors hindering the integration of a palliative approach in an intensive care context constitute a complex interplay among organizational structure, the care environment and clinicians’ perceptions and attitudes. while patient and family involvement was identified as an important facilitator of palliative care, it was also recognized as a barrier for clinicians due to challenges in shared goal setting and communication. pandemic shows this very clearly, as many elderly patients with chronic diseases are admitted to the icu due to respiratory failure [ , ] . clearly, the covid- pandemic necessitates the inclusion of responses with a palliative approach, such as active symptom relief, communication and recognition of dying. when chronic conditions lead to deterioration and occur among older adults, the question of the integration of a palliative approach to patient comfort and end-of-life care intensifies. in general, a palliative approach aims to relieve suffering for patients with life-limiting conditions and for those who are dying and to manage symptoms, increase the level of care comfort and provide support to family members [ , ] . despite increasing awareness of integrating a palliative care approach in the icu, there are challenges, given the somewhat contradictory aims of intensive care and palliative care, i.e., in providing lifesaving treatments vs treating dying as a normal process. however, studies have shown the benefits of integrating palliative care into intensive care [ ] [ ] [ ] [ ] , for example, in relieving distress for patients and their families during end-of-life care. nevertheless, a review by kahveci [ ] on attitudes and beliefs pertaining to integrating a palliative approach in the icu shows that there are many challenges, such as sociocultural factors, legal regulations and a lack of awareness of a palliative approach. the integration of a palliative approach has been described as challenged by a lack of resources for symptom management and cultural and societal values and beliefs about death and dying [ ] ; moreover, structural barriers (for example, limited specialties and resources) appear especially difficult to change [ ] . to date, no mixed-methods review has been conducted that integrates both quantitative and qualitative evidence to frame a broader picture of factors that influence the adoption of a palliative care approach in the icu. hence, there is a need to synthesize the findings of quantitative and qualitative research studies on the factors (facilitators and barriers) influencing a palliative approach in the icu from the perspective of allied health professionals. in particular, there is a need to increase knowledge of contextual factors (attitudes, perceptions and structural/organizational) influencing this integration of care perspectives, which could be considered to be exclusively related to each other. to identify factors influencing a palliative approach in intensive care units, as perceived by health professionals. a mixed-methods systematic review was undertaken with the aim of identifying, assessing, analysing and synthesising the current research findings [ ] . the first step in the process was to perform a review protocol (registered in the international prospective register of systematic reviews (prospero) (crd ). second, systematic literature searches were conducted, and relevant literature was selected. third, we performed quality assessments of the included articles [ ] . finally, we analysed and synthesised the articles' findings, taking the assessed quality into consideration. a search guide was developed based on the research concepts and questions within the inclusion and exclusion criteria. the authors used a peo framework (population, exposure, outcome) [ ] and focused on the following: populationallied health care professionals in the icu; exposureintegration or implementation of a palliative approach; outcomefactors (facilitators and barriers) influencing a palliative approach; and. context -icu. two expert medical librarians supported our search process. the inclusion criteria were as follows: ( ) studies focusing on factors influencing the integration of a palliative approach for adult patients admitted to the icu; ( ) studies highlighting health care professionals' experiences or perceptions of the integration or implementation of palliative care in icus; ( ) studies written in the english language; and. ( ) peer-reviewed studies published between january and january . our exclusion criteria were as follows: ( ) non-empirical studies (e.g., editorials, brief reports); ( ) studies in paediatric and neonatal intensive care; ( ) studies reporting the frequency of palliative care in the icu and the effect of palliative care on the mortality rate or length of stay in the icu; and ( ) studies regarding palliative care policy. in this review, we have chosen to use broad concepts and surrogate words and associated definitions. we used the search terms targeting the integration of a palliative approach, such as implementation, palliative care, and intensive care units, as well as synonyms for these terms (see additional file ). the university librarian at the university of gothenburg performed an electronic database search of the following databases: amed, pubmed, embase, psycinfo, sociological abstracts, web of science, scopus and cinahl. in total, citations were identified (amed n = , pubmed n = , embase n = , psycinfo n = , sociological abstracts n = , web of science n = , scopus n = , and cinahl n = ). in total, articles were identified in the initial search, of which were duplicates and were thus deleted before we imported the remaining articles into an web based systematic reviews software for blind screening (rayyan qcri, developed by qatar computing research institute) (see fig. ). two authors (hh, aw) performed blind screening of the articles in rayyan following the inclusion and exclusion criteria (above). in the first round, the article titles and abstracts were screened (in the online tool rayyan). in the second round, eligibility was assessed based on the blind reading of full-text articles by two authors (hh, aw). the authors summarized and documented the reasons for inclusion and exclusion. in the third round, which was unblinded, two authors (hh, aw) compared and discussed the relevant articles, and if there was disagreement, consensus for final inclusion was achieved by consulting all members of the research team. as a result, articles were ultimately included in this systematic review (see fig. ). depending on the type of study, the quality assessment was carried out as follows: nine qualitative studies and one quantitative study with an rct design were evaluated using the critical appraisal skills program (casp). the remaining quantitative studies (n = ) were evaluated using the best evidence topics (best bets) critical appraisal checklists for survey study design. the mixed-methods appraisal tool (mmat) was used to evaluate the studies using a mixed-methods approach (n = ). the researchers evaluated each of the studies and developed scores for all types of tools. for the quality assessment summary (see additional file ). a thematic synthesis approach was selected for the study. thematic analysis has been used in mixedmethods systematic reviews that address questions such as identifying barriers or facilitators from evidence and identifying patterns within the findings [ ] . while thematic synthesis is generally used for the synthesis of qualitative studies, it may also be useful when there is heterogeneity in outcome variables and measurement in quantitative studies. before the beginning of the analysis stages, the first author (hh) read each included article several times, data were extracted, and quality assessments were performed for quantitative and qualitative analyses separately. a three-stage thematic analysis process was undertaken [ ] . in the first stage, the first author (hh) focused on factors influencing a palliative approach in the icu based on results from quantitative data. in the second stage, we focused on factors influencing a palliative approach in the icu based on results from qualitative data. in the third stage, two authors (hh, aw) integrated the analyses using thematic synthesis with a focus on factors influencing a palliative approach in the icu based on results from both quantitative and qualitative data. they also repeatedly checked the analysis against the articles and started to thematize the findings into influencing factors. inconsistencies in preliminary analysis were discussed, and the other authors were consulted (so, jÖ). in this stage, we sought to distinguish the influencing factors into overarching analytical categories (type of factors) and more descriptive categories (specific factors). the similarities and differences between the findings were highlighted and grouped to finalise the development of descriptive categories (factors) and analytical categories (type of factors). all authors were involved in reviewing and checking the accuracy of the final findings. study characteristics and quality assessment summary: fig. shows a standard flow chart reporting the results of the bibliographic search and screening (it follows the guidance of the preferred reporting items of systematic reviews and meta-analyses (prisma). in total, studies were eligible for the review: nine qualitative, nine quantitative and six mixed-methods studies. in total, the articles reported studies with participating allied health professionals. studies were conducted in ten countries worldwide, with most studies conducted in the united states of america (n = ), the united kingdom (n = ), the netherlands ( ), germany ( ), australia ( ), canada ( ), japan ( ) and brazil ( ) . a summary of all included articles and their quality assessments are shown in (see tables , , and ). in total, eight articles were assessed as having either moderate-to-high or high quality, eight articles were assessed as having moderate quality, four articles were assessed as having low-to-moderate quality, and four articles were assessed as having low quality (reference [ , , , ] ) (see additional file ). four types of influencing factors were identified: ( ) organizational structures, ( ) working environment, ( ) patient and family involvement, and ( ) palliative care decision-making. we present the summary of these types of influencing factors below and specific factors with related facilitators and barriers in table below, each of the four influencing factors are presented with specific facilitating and hindering factors. several studies highlighted the lack of protocols and policies for integrating a palliative approach in the icu [ , , , ] . nevertheless, several studies have also revealed that physicians and nurses tend to be resistant to and unaware of the guidelines for a palliative approach in the icu [ , , ] . the number of staff, the standardization of the staffing ratio [ ] , and the time spent by staff with patients were examples of factors influencing the integration of a palliative approach in the icu [ , ] . there was a lack of organizational support, not in the least for junior nurses, who reported a lack of mentoring and support. several studies indicated that poor education and knowledge about a palliative approach created barriers and were due to inadequate education and knowledge among nurses working in the icu [ , ] . one study reported that nurses gained their palliative care experience through trial and error [ ] . other barriers identified were insufficient information [ ] , a lack of awareness of the complexity of and the communication required for a palliative approach in the icu, inadequate training in palliative care decision making [ , ] , and a lack of specialized palliative care teams, which was an obstacle to integrating a palliative approach for patients in the icu [ , ] . a palliative approach was positively enhanced by following standardized tools for dialogue [ ] , bereavement programmes, and adherence to the appropriate policies and procedures [ ] . this approach was also enhanced by the introduction of team meetings [ ] , collaboration with other specialties [ , ] , the involvement of families into the multidisciplinary discussion [ , ] . palliative care training programmes for critical care professionals, or peer-to-peer support programmes, improved the integration of a palliative approach in the icu [ ] , as well as specialized palliative care teams' participation and mentoring within the icu teams [ ] . the physical and psychosocial care environment was more of a barrier than a facilitator for a palliative approach in the icu, and only two studies reported that support through a nurse-adapted bedside environment [ , ] . -simultaneous requirement to care for other patients while staff work with patients' palliative need [ ] . -lack of time to develop and implement strategies [ ] . -lack of training and education as a result of time and resource constraints [ , ] . -lack of spiritual support (assistance is unavailable at weekends) [ , ] . -inadequate support of junior nurses from team leaders [ ] . -absence of palliative care physicians and senior nursing staff in relation to advance directive (ad), orders in icu and difficulties within the palliative care process [ ] . -staff ratios. for example, in icu nurses work in patient/nurse ratios of either one to one or one to two. this allows time to be devoted to dying patients [ ] . -assign a nurse for the patient in late palliative stage, for example, patient and family should be cared for by a nurse who is known to them [ ] . -a bereavement programme to support patients and families (use bereavement material) [ ] . -facilitating palliative care dialogue (standardized tools) [ ] . policies and guidelines -lack of protocol and policies guiding palliative care in icu [ , , ] . -lack of written protocol for palliative care nursing such as pain management, dyspnoea, etc. [ ] . -doctor resistance to applying policy [ , ] . -physicians unfamiliar with the guidelines and resistant to using them, plus difficulties encountered in the removal of all mentors [ ] . -insufficient standardization of care [ ] and the presence of procedural difficulties [ ] . -strong leadership and management team support (supportive factors) [ ] . -guideline recommendations regarding both direct care for palliative patients and palliative care decisions [ ] . employing guidelines and care policy designed for a humanistic approach for example, medication guidelines designed to improve symptom control [ ] . -an integrated care system (clear guidance, reduced paperwork, adequate structure) [ ] . -formulating the physician's strategy [ ] . -open visiting times for family and friends [ ] . knowledge and skills -inadequate education and knowledge of palliative care among nursing staff responsible for delivering care to patients in icu [ , ] . -inadequate training for physicians and nurses regarding communication skills [ ] . -lack of understanding about the complexities involved in providing palliative care in icu [ ] . -lack of requisite knowledge, skills and experience among physicians [ , ] . -lack of skill in the provision of care for dying patients [ ] . -inadequate information relating to palliative care issues within both current nursing curriculums or courses and hospital orientation [ ] . -insufficient preparation for palliative care decision-making (inadequate professional training) [ , ] . -unpreparedness of icu nurses for shifting from curative to palliative care models [ ] . -involving training teams in specialized palliative care while providing care for patients in icu [ ] . -hospital training and the development of a palliative nursing programme [ ] . -specialist palliative nursing coaching [ ] . -training workshop communication programme for bedside nurses [ ] . -trial and error are useful ways to learn from nurses' experiences [ ] . -education and professional support while implementing improvements to guidelines [ ] . multidisciplinary team involvement -lack of nursing staff involvement in palliative care decision making [ , , ] . -lack of palliative care team integration within the icu [ , ] . -involvement of stakeholders from different levels and specialties [ ] . -direct palliative care team involvement in care for patients in icu [ ] . physical environment -absence of infrastructure in the icu to facilitate family involvement in palliative care (insufficient space for meetings) [ , , ] . -inadequate organizational support in promoting humanistic environment in icu [ ] -the challenging, hectic and noisy nature of icu culture [ , , , ] . -inappropriate environments for dying patients [ , ] . -modified bedside environment and use single room for dying patients [ , ] . psychosocial -moral distress acts as barrier to providing palliative care in the icu [ ] . facilities environment -distress experienced by nursing staff due to lack of help from managers [ ] . -colleagues' unwillingness to appreciate the complexity of palliative care (staff compliance with changes) [ , ] . -insufficient emotional support for nurses during and after their providing palliative care for patients in icu [ , ] . conflict -disagreements, unwillingness to discuss them and conflict between families and physicians regarding palliative care process [ , , , ] . -family's refusal of care on the grounds of religious belief [ ] . -to tailor and adapt the object of care in collaboration with the patients and families [ ] . lack of family involvement in any documented wishes that have been expressed by the patient [ ] . -language and culture barriers relating to patients and/or their families [ ] . -lack of understanding and education among patients and family concerning the prognosis and the continuity of palliative care [ , ] . -patient inability to participate in palliative care decision-making [ ] . -patient's wishes regarding palliative care were insufficiently documented prior to their admission to icu [ ] . -family participation and involvement in patient care and decisionmaking (family-centred care [ , , , ] . -patient and family wishes considered prior to actual decision-making [ ] . -the establishment of a patient advocate and medical translation team by nurses involved in family meetings [ ] . -respect for patients' wishes [ ] . information/ communication -lack of effective communication with family members [ , ] . -family's requests for updates on patient's prognosis [ ] . -insufficient information provided to patients and families about death [ ] . -using multiple means to communicate medical information regarding patients' prognoses to their families [ ] . -the allocation of a single point of contact for all family members [ ] . transition of care objectives fragmentation of care objectives by different physicians [ ] . -discrepancies between the care objectives of the medical team and the family [ ] . -disagreement between team members about comfort care decisions and inconsistencies in palliative care [ , ] . -continuation of aggressive and life-supporting treatments [ , ] . -absence of a care plan for palliative care [ ] . -inconsistent attitudes, approaches and beliefs among physicians providing palliative care [ , ] . -icu patient decision-making potentially negated by incapacity [ ] . -clear and defined goals for providing comfort and care [ ] . -consensus regarding objectives among varices involved in health care teams [ ] . -clear information and documentation about patient's history, background, status and prognosis [ ] . -empowered and skilled staff involved in the care process [ ] . -locating physician participation as central during the establishment of comfort care for patients [ ] . -establishing a consensus around decision concerning comfort care [ ] . withholding or withdrawal of lifesustenance -ethical factors influencing doctors' decision-making processes [ ] . -lack of patients' advance directives at the time of admission [ , , , ] . -difficulties with palliative care treatment decisions [ ] . -ethics consultations [ ] . prognostication -lack of understanding concerning the assessment of prognostication efforts and pre-death symptoms [ , ] . -critical delays in palliative care prognostication and decision-making [ ] . -use numeric prognostic scale [ ] . multidisciplinary team communication -lack of communication and team interaction act as core barriers to providing adequate palliative care in icu [ , ] . -inadequate communication about identification of care objectives between icu team members and other clinicians [ ] . -multidisciplinary meetings with families to improve communication [ , ] . -multidisciplinary team meetings [ ] . was effective in the icu [ ] . in many studies, the physical environment or infrastructure of the ward did not facilitate the support and participation of families while integrating a palliative approach for their patients [ , ] . identified barriers included a noisy environment with lack of privacy and confusion regarding who to approach for information [ , , ] . increased moral distress and the need for emotional support to reduce such stress during the integration of a palliative approach in the icu was described in two studies [ , ] , indicating a lack of support from managers, other staff and external support services [ , ] . three studies emphasized that conflict and disagreements between family members and physicians concerning the goals of care were a barrier to the integration of a palliative approach [ , , ] , and other studies highlighted communication challenges with family members [ , ] related to language and culture [ ] , religious beliefs [ ] , and inadequate information about prognosis [ , ] . nevertheless, family involvement in patient care regarding the sharing of information, respect for others' wishes, and cooperation among patients, families and healthcare providers before they decided to change the goals of care towards a palliative orientation was found to be a facilitating factor [ , , ] . studies report that continued intensive care intervention for patients was a barrier to making decisions about the integration of a palliative approach in the goals of care [ , ] , as well as a lack of understanding about how to assess patients' prognostication towards palliative care for dying patients and their family [ , ] . for example, one study found that physicians were unable to identify patients who required a palliative approach to care in the early stage of intensive care [ ] . three studies emphasized that nurses did not contribute to the decision to integrate a palliative approach for their patients in the icu [ , , ] . other identified barriers to decision making were physicians' attitudes and beliefs about palliative care [ , ] , disagreement between physicians [ ] and the icu team regarding the goals of care [ , ] , a lack of standardized care [ ] , and insufficient communication among team members [ , , ] , all of which hampered integration in terms of transitions from lifesustaining interventions to palliative goals (see table ). clarity, agreement and documentation of the palliative goals of care decisions were identified as facilitators [ ] , together with ethical consultation [ , ] and the use of a numeric prognostic scale to support improved prognostication efforts [ ] . in this study, we sought to identify barriers to and facilitators of the integration of a palliative approach in intensive care units. to our knowledge, this study is the first systematic review that combines results based on qualitative and quantitative data to illuminate factors influencing a palliative approach in the critical care environment. our results suggest that the transition from life-sustaining interventions to palliative goals of care in an intensive care context is hindered by both organizational and structural factors (e.g., resources, time constraints, workloads, and work environments) as well as individual factors (e.g., healthcare provider, patient, and family attitudes, communication, interaction and knowledge backgrounds). our quality assessment suggests that the majority of articles (n = ) were assessed to be of either moderate or moderate-to-high quality. the results from the four articles assessed to have low quality were supported by similar results from other studies included. today, a palliative approach to care is characterized by early identification of palliative care needs, adaptation of palliative care knowledge and integration into practice [ ] . given the complex nature of the intensive care context, such knowledge translation may become more challenging. there is no doubt that there is a need for the successful knowledge translation of a palliative approach into the icu; however, the studies reviewed did not explicitly evaluate this. through acknowledgment of the complexities involved, we need explicit knowledge translation research demonstrating valid implementation strategies. one way of moving towards knowledge translation is using the parihs (promoting action on research implementation in health services) model, which provides important insights for supporting knowledge translation into practice by focusing the implementation process on evidence, context and facilitation. according to the parihs model, the context/setting, as well as practice facilitators for change, are as important as the evidence supporting the knowledge. we use this model to discuss the findings from this study. organizational structures appeared in this study to be one of the barriers to the achievement of a palliative approach in the icu. according to the parihs model, the context/setting, as well as practice facilitators for change, are as important as the evidence supporting the knowledge. the parihs framework demonstrates the need to address leadership and organizational aspects by understanding human relationships [ ] . the present study shows that the lack of clinical guidelines and policies for integrating palliative care hinders implementation. nevertheless, there is also evidence that professionals tend to disregard or be unaware of guidelines for a palliative approach in the icu, pointing towards the importance of understanding professional perceptions and attitudes towards a palliative approach. this finding is in line with a review by kahveci [ ] that showed the impact of sociocultural factors and the lack of awareness of a palliative approach. professionals' perceptions and attitudes, leadership and organizational aspects, as well as patients' and relatives' preferences and participation, need to be explored for successful integration. thus, integration is both an organizational challenge as well as an individual challenge, as the organizational culture is created, sustained or changed by the people who work within the organization [ ] . an important aspect of knowledge translation highlighted in the parihs framework is the context of care and its environment. our results found more research emphasizing the challenges that the icu physical work environment imposes on a palliative approach to care [ , , ] . interestingly, we found no articles pinpointing facilitating factors for the psychosocial care environment in the icu. therefore, future research should further investigate the care environment in various situations, such as how to support staff and reduce the stress of the care environment in general in this setting. the present study highlights the importance of both patient and family involvement. the importance of family involvement is in line with the findings of previous literature [ , ] . ineffective communication, a lack of family education, and a lack of healthcare provider awareness were shown to be key issues underlying conflict between family and physicians. patient and family involvement are linked to knowledge and education [ , ] , so it is vital to address family education programmes in the icu. studies show a palliative approach integrated into reduced patient and family distress [ ] [ ] [ ] [ ] . this suggests a need for improved palliative care education and training to assess patients' and families' needs, wishes, and participation in care and goal setting in terms of a palliative orientation. in the present study, decision-making to integrate a palliative approach in intensive care is influenced by healthcare professionals' knowledge and attitudes about the transition from curative-focused to palliative-focused goals of care, which highlights the importance of focusing on healthcare professionals' goal-setting attitudes and abilities in the integration of a palliative approach [ ] . unsurprisingly, having a clear goal of care on admission to the icu seems to support professionals in the palliative decisionmaking process [ ] . however, this cannot be considered in isolation, as many complex related factors can affect it, for example, the wishes of the patient and family and difficulties in defining a patient's prognosis on admission [ ] . studies regarding nurses' involvement in team decisionmaking or consulting the specialized palliative care team were scarce for palliative care in the icus [ , , ] . further studies may explore the impact of nurses' involvement in the decision-making process. in this systematic literature review, we described factors influencing the integration of a palliative approach within the icu. the majority of the included studies were assessed to be of moderate or moderate-to-high quality, with only one of these assessed to be of high quality, and four studies were assessed to be of low quality. the reader should thus acknowledge the heterogeneity of the study designs, as well as the spectrum of quality within the included studies. although the heterogeneity of studies within a mixed-methods review could be acknowledged as a limitation, it is also a strength, as it provides a broad overview of the topic. as in many systematic studies, researchers' language skills are a limitation because we only included literature in english. factors hindering the integration of a palliative approach in an intensive care context are constituting a complex interplay among the organizational structure, the care environment and the clinician's perception and attitudes. while patient and family involvement were identified as an important facilitator of palliative care, it was also identified as a barrier for the clinicians due to challenges in shared goal setting and communication. we suggest that future integration efforts targeting a palliative approach should focus on organizational and educational efforts that strengthen human relationships and partnerships, not in the least regarding patient and family involvement. moreover, there is a need for research evaluating useful strategies for the knowledge translation of a palliative approach in the icu. supplementary information accompanies this paper at https://doi.org/ . /s - - -y. intensive care unit manual ebook integrating palliative care in severe chronic obstructive lung disease palliative care and the quality of life improved short-and long-term outcome of allogeneic stem cell recipients admitted to the intensive care unit: a retrospective longitudinal analysis of patients admission/discharge criterion for acute care surgery patients in the icu: a general review of icu admission and discharge indications. in: intensive care for emergency surgeons facing covid- in italy-ethics, logistics, and therapeutics on the epidemic's front line the toughest triage-allocating ventilators in a pandemic increased access to palliative care and hospice services: opportunities to improve value in health care the distinct role of palliative care in the surgical intensive care unit palliative critical care in the intensive care unit: a perspective evidence-based palliative care in the intensive care unit: a systematic review of interventions palliative care and management of troublesome symptoms for people with chronic obstructive pulmonary disease in their own words: patients and families define high-quality palliative care in the intensive care unit palliative care and intensive care integration barriers to access to palliative care the growth of palliative care in u.s. hospitals: a status report systematic approaches to a successful literature review: sage methods for the thematic synthesis of qualitative research in systematic reviews critical care nurses' values and behaviors with endof-life care: perceptions and challenges a multicenter study of key stakeholders' perspectives on communicating with surrogates about prognosis in intensive care units big picture": communicating with families about end-of-life care in intensive care unit intensive care unit cultures and end-of-life decision making end-of-life care in the intensive care setting: a descriptive exploratory qualitative study of nurses' beliefs and practices use of a supportive care pathway for end-of-life care in an intensive care unit: a qualitative study intensive care unit team perception of palliative care: the discourse of the collective subject. revista da escola de enfermagem da usp the liverpool care pathway in intensive care: an exploratory study of doctor and nurse perceptions a study of the lived experiences of registered nurses who have provided end-of-life care within an intensive care unit efccna survey: european intensive care nurses' attitudes and beliefs towards end-of-life care limiting life-sustaining treatment in german intensive care units: a multiprofessional survey characteristics and outcomes of ethics consultations in an oncologic intensive care unit critical care nurses' perceptions of obstacles, supports, and knowledge needed in providing quality end-of-life care current practices for withdrawal of life support in intensive care units policies of withholding and withdrawal of life-sustaining treatment in critically ill patients on cardiac intensive care units in germany: a national survey palliative care in the intensive care unit: are residents well trained to provide optimal care to critically ill patients? barriers to end-of-life care in the intensive care unit: perceptions vary by level of training, discipline, and institution effectiveness of supporting intensive care units on implementing the guideline 'end-of-life care in the intensive care unit, nursing care': a cluster randomized controlled trial nurses' perceptions of end-oflife care after multiple interventions for improvement resident reflections on end-of-life education: a mixed-methods study of the wishes project palliative care professional development for critical care nurses: a multicenter program improving icu-based palliative care delivery: a multicenter, multidisciplinary survey of critical care clinician attitudes and beliefs respecting the wishes of patients in intensive care units a pilot audit of the process of end-of-life decision-making in the intensive care unit conceptual foundations of a palliative approach: a knowledge synthesis enabling the implementation of evidence based practice: a conceptual framework everyday practices at the medical ward: a -month ethnographic field study end-of-life perceptions among physicians in intensive care units managed by anesthesiologists in germany: a survey about structure, current implementation and deficits publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to acknowledge medical librarians linda hammarbäck and magnus holmberg, whose expertise was helpful in formulating and finalizing the search terms for this review. all authors contributed to the design, conception, and development of the study. hh and aw screened and reviewed all articles. hh drafted the manuscript. hh, aw, so, and jÖ discussed, revised and confirmed the findings. all authors were responsible for the critical revision and finalization of the manuscript. all authors read and approved the final manuscript. open access funding provided by university of gothenburg. hh's phd scholarship is funded by princess nourah bint abdulrahman university, riyadh, saudi arabia; however, the funding body did not have any influence in the design of the study; the collection, analysis, interpretation of the data; or the writing of the manuscript. data sharing is not applicable to this article, as no datasets were generated or analysed during the current study.ethics approval and consent to participate not applicable. not applicable, as it is a systematic review. the authors declare that they have no competing interests.author details key: cord- -p labgd authors: schulman, sam title: coronavirus disease , prothrombotic factors, and venous thromboembolism date: - - journal: semin thromb hemost doi: . /s- - sha: doc_id: cord_uid: p labgd nan coronavirus disease (covid- ) is causing devastating morbidity and mortality worldwide. several studies have shown that the severely ill patients have high or very high ddimer values, and a hypercoagulable state has been described with, in some cases, development of disseminated intravascular coagulation (dic). a few reports have indicated that there seems to be a higher incidence of venous thromboembolism than expected in otherwise severely ill patients. in this article, we will discuss the prothrombotic changes observed and to what extent they are specific for covid- . the incidence of thromboembolic events will be compared with those reported in sepsis and severe influenza a h n . the emphasis is on venous events, which have been the most frequently reported events. finally, the intensity of pharmacological prophylaxis against venous thromboembolism will be discussed. the pandemic of covid- is affecting almost every country in the world, with the number of cases tested and found infected exceeding two million, with an overall mortality of approximately % at the time of writing. there are preliminary reports from china on venous thromboembolism based on a relatively small number of patients. , subsequently, european physicians have reported a higher incidence of thromboembolic events, mainly venous, in patients with covid- pneumonia in the intensive care unit (icu). another manifestation of hypercoagulability is dic, which was not reported in other than the occasional case in the largest published cohorts. [ ] [ ] [ ] on the other hand, abnormalities in the coagulation tests, meeting previously defined criteria for dic, were observed during the terminal days in % of nonsurvivors in another cohort from wuhan, china. these preliminary findings generate several questions, some which are as follows: • what are the indicators of hypercoagulability in covid- infection? • is the hypercoagulability specific for covid- infection? • does the hypercoagulability result in a higher incidence of thromboembolism than in other patients with severe infection in the icu? • if so, is it justified to use higher than standard doses of pharmacological prophylaxis against thromboembolism in these patients? it should be recognized that the data on this infection are rapidly emerging and that information obtained from countries in europe or north america might differ from those in china due to variations in ethnic susceptibility, environmental conditions (e.g., pollution and health care resources availability), diagnostic routines, and prophylaxis regimens. therefore, any assumptions or conclusions drawn in this article can be proven wrong after a short time. several reports have documented increased d-dimer levels, - and these levels were higher on admission in patients who subsequently had to be treated in the icu than in patients not requiring intensive care, as well as higher levels in patients who died in the hospital versus survivors. a meta-analysis of studies and , patients reported that increased d-dimer was associated with severe covid- infection, with a p-value of < . . tang et al found that the d-dimer level on admission was fourfold higher in patients who did not survive the hospitalization compared with survivors ( . vs. . μg/ml; p < . ). on days and of hospitalization, the d-dimer values among the nonsurvivors had increased to ! μg/ml (which was the upper limit of their detection system). fibrin degradation products (fdps) showed a similar pattern. guan et al reported that the platelet count was higher in nonsevere than in severe infection ( vs. .  /l), whereas huang et al found the opposite ( vs.  /l for those without or with icu care, respectively). tang et al observed that in the later stages of their disease, out of nonsurvivors had platelet counts of to  /l and had <  /l, indicating that there was terminal consumption coagulopathy. likewise, the prothrombin time (pt) was in this late stage prolonged by to seconds in and by > seconds in of the nonsurvivors. on admission, the difference in median pt between survivors and nonsurvivors was, however, only seconds, or only . seconds between those requiring or not requiring icu care. the activated partial thromboplastin time was, in the latter study, similar in the two subsets ( . and . seconds for requiring vs. not requiring icu, respectively), whereas tang et al saw a nonsignificant trend in the opposite direction between nonsurvivors and survivors ( . vs. . seconds, respectively). fibrinogen levels did not differ on admission between survivors and nonsurvivors ( . and . g/l, respectively), but in the terminal stage, the nonsurvivors demonstrated fibrinogen levels of around g/l. although antithrombin values were generally in the normal range, they were significantly lower among nonsurvivors than survivors on days , , and although not initially. taken together, the main initial coagulation abnormality is the elevated d-dimer, which is well recognized as an unspecific marker of hypercoagulability. it seems, however, to give already at an early stage an idea of the severity of the infection and is a prognostic indicator of need for icu care and of fatal outcome. furthermore, there is undoubtedly a pronounced inflammatory response in the severely ill patients with high c-reactive protein (crp) and cytokines. , there is also evidence of endorgan damage to the heart, with high-sensitivity cardiac troponin above th percentile in % of patients requiring icu care versus % of those not in icu, and to the liver, with majority of the severe patients demonstrating elevated bilirubin and transaminases, acute kidney injury, and acute respiratory distress syndrome. , this constellation raises concern about cytokine storm and, with lymphopenia and thrombocytopenia in the picture, of a possible secondary hemophagocytic lymphohistiocytosis as well. the inflammatory response will also activate the coagulation system, resulting in thromboinflammation or immunothrombosis. , finally, hypoxia mediated through increased expression of hypoxia-inducible transcription factors can not only increase the inflammatory response but also directly activate platelets and plasma coagulation. direct targets include tissue factor (increased expression), protein s (inhibition), and plasminogen activator inhibitor type (increased levels). the hypoxia in covid- pneumonia is evident and increases with the severity of the disease. the inflammatory response is seen in sepsis in general and is associated with dic and microthrombosis. the mechanisms include activation of monocytes, neutrophils, platelets, and endothelial cells; expression of tissue factor; release of ultralarge von willebrand factor multimers; release of cytokines; and generation of neutrophil extracellular traps. a case report of a patient with severe covid- pneumonia managed with lung transplantation demonstrated hemorrhagic infarctions as well as microthrombosis formation in the lungs. in the former covid severe acute respiratory syndrome, also known as sars, there was pronounced fibrin deposition in the lungs, and the virus was shown to induce transcription of the hfgl prothrombinase gene, which would generate a procoagulant state. in animal models, there was evidence of increased expression in the urokinase pathway involving pro-and antifibrinolytic genes, and in proteomics analyses of the lung, there was increased expression of fibrin and factor viii. lethal doses (but not sublethal) led to increased levels of plasminogen peptides associated with increased urokinase activity. these changes can explain some of the lung pathology but do not necessarily induce venous thromboembolism. there is no clear evidence for a different mechanism for the activation of coagulation in covid- pneumonia compared with severe sepsis, except for the fact that hypoxia may be worse in the former. whether sars-cov- , the microorganism causing sars, triggered increased pe is difficult to know since the focus of the medical staff was on treatment of respiratory failure. computed tomography (ct) of the chest is not performed to diagnose pulmonary embolism (pe), and ct of the pulmonary arteries was rarely performed and was, at the time, performed mainly using less sophisticated equipment than today and therefore may have missed subsegmental emboli. in the xpress (xigris and prophylactic heparin evaluation in severe sepsis) study, , patients with sepsis received activated protein c and were randomized to prophylaxis against venous thromboembolism with heparin or placebo. there were events of venous thromboembolism during the study period with a similar incidence in patients who received unfractionated heparin ( . %), low-molecular-weight heparin (lmwh) ( . %), or placebo ( . %). most of the events were found on screening for deep vein thrombosis (dvt). the protect (prophylaxis for thromboembolism in critical care trial) trial randomized , critically ill patients to dalteparin or unfractionated heparin, and overall the incidence of venous thromboembolism was similar. dalteparin ( , units once daily) was associated with a lower risk of pe ( . vs. . %; hazard ratio: . ; % confidence interval: . - . ), and the risk of dvt was . %, of which . % were proximal and mainly detected by screening with ultrasound. an early review of findings on ct in patients with covid- did not mention pe, but it should be noted that only ct chest was performed, and without performing ct pulmonary angiogram, emboli could have been missed. in another study from china, patients treated in the icu were examined through ultrasonography of the leg veins and ct of the chest. of the patients, ( %) developed dvt. the value of d-dimer was much higher in those who developed seminars in thrombosis & hemostasis vol. no. / thrombosis than among those who did not ( . ae . vs. . ae . μg/ml; p < . ), but it is not stated when samples were taken. furthermore, it is not clear how many, if any, of the patients received prophylaxis against thrombosis. colleagues in italy, spain, and new york city have diagnosed dvt and pe in higher proportions of patients (personal communications), but these are just preliminary, though reliable, observations. at three hospitals in the netherlands, all patients with covid- pneumonia admitted to the icu were evaluated for venous and arterial thromboembolic complications. all patients received prophylaxis with a standard or increased dose of lmwh. it appears from the report that the investigators only performed objective diagnostic imaging in patients with symptoms, raising suspicion of a thromboembolic event, and among those, the composite outcome of all thromboembolism was as high as % or a total of cases. of those, had pe, but there is no information regarding the location of the emboli and how many of those were only subsegmental. of the three cases with dvt, two were catheter-related upper extremity thrombosis and one was a proximal leg vein thrombosis. stroke was verified in three patients, presumably with evidence of acute infarct. these findings are difficult to interpret regarding pe due to the paucity of information and also the difficulty in finding comparable studies on other infections investigated in the same way. a symptomatic dvt rate of per or of catheter-related thrombosis of per is not remarkable. in a recent review of studies on atrial fibrillation in patients with sepsis, new-onset atrial fibrillation was diagnosed in to % of patients, and new strokes were identified in to % of those. stroke was also, albeit at a slightly lower incidence, diagnosed in sepsis patients remaining in sinus rhythm. several retrospective studies showed a high incidence of thromboembolic events in patients hospitalized for the influenza a h n , as shown in ►table . - among patients requiring critical care or with fatal outcome, the incidence was to %, which was dominated by pe without dvt. for patients admitted to the hospital but not requiring icu care, the incidence was to %. the mechanisms behind hypercoagulability in this infection have been reviewed by lippi et al. the data so far are thus not conclusive regarding a truly increased incidence of clinically important thromboembolic events in patients with covid- . there might, however, be a predominance of pulmonary artery thrombi rather than embolism from the leg veins due to the inflammatory reaction in the lungs causing profound local hypercoagulability, as suggested by the h n data (►table ) and as also reviewed recently. dose of low-molecular-weight heparin: standard or increased? in most of the studies from china, it is not reported whether, and in such cases how many, patients received chemoprophylaxis against venous thromboembolism and at what dose. cui covid- , prothrombotic factors, and vte schulman started on therapeutic anticoagulation, the d-dimer values decreased. in a dutch study, two of the three hospitals increased the prophylactic dose of nadroparin during the study period, but it is unclear whether this change led to a reduced incidence of thromboembolism. the american society of hematology has on its website a recommendation to provide the usual thromboprophylaxis unless there is a clear indication for treatment doses, and a similar indication (i.e., enoxaparin - mg every day) has also been recently endorsed by the italian national medicines agency (aifa). there have not been any reports of a pattern of increased bleeding complications in patients with severe covid- infection despite a tendency to develop thrombocytopenia. hemoptysis was reported in of patients with severe disease and in of with nonsevere disease. it is therefore reasonable to assume that there is, in general, hyper-rather than hypocoagulability. nevertheless, this is the case for many other patients admitted to hospital and icu, and increased doses of heparin or lmwh are not recommended for those. increased doses of anticoagulants may always carry a risk of more bleeding events. the only way to resolve this is by performing randomized trials. observational studies will be fraught with a large number of confounders in view of the variety of intensive care procedures performed and the increasing number of experimental therapies introduced to manage severe covid- pneumonia. during the few days between submission and receiving the page proofs, two additional reports of high incidence of venous thromboembolism despite prophylaxis have emerged. in a prospective study of consecutive patients with covid- admitted to icu at two french hospitals, ct of pulmonary arteries was done in case of deteriorating condition or spike in d-dimer. out of examined, ( %) had pe of which only were subsegmental, and patients had dvt. all patients were receiving prophylactic (n ¼ ) or therapeutic (n ¼ ) anticoagulation. a second dutch cohort included admitted patients with ( %) in icu. standard or intermediate lmwh was routine prophylaxis against dvt. after a median observation time of days, patients ( %) were diagnosed with pe (n ¼ , of which subsegmental) or dvt (n ¼ ). most of the events (n ¼ ) were in icu patients and of the events were symptomatic with the remainder found through screening for dvt. these data support unusually high incidence of venous thromboembolism despite lmwh prophylaxis. in severe covid- pneumonia, there are several changes in the prothrombotic direction, and this can be explained by profound inflammatory response as well as hypoxia. many of the changes are similar to what is otherwise seen in sepsis, but hypoxia is likely an aggravating factor in covid- pneumonia. this may result in an increased incidence of pulmonary thrombosis, which may similarly have been the case in critically ill patients with influenza a h n . venous thromboembolism despite chemoprophylaxis in patients in icu is not a new phenomenon, and it is not clear whether this occurs more often with covid- . thus, it seems premature to recommend intermediate or therapeutic doses of heparin or lmwh until we have evidence from randomized clinical trials. coronavirus covid- global cases covid- complicated by acute pulmonary embolism prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia incidence of thrombotic complications in critically ill icu patients with covid- china medical treatment expert group for covid- . clinical characteristics of coronavirus disease in china clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study clinical features of patients infected with novel coronavirus in wuhan, china abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia incidence, clinical characteristics and prognostic factor of patients with covid- : a systematic review and meta-analysis hlh across speciality collaboration, uk. covid- : consider cytokine storm syndromes and immunosuppression thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms blood coagulation in immunothrombosisat the frontline of intravascular immunity the stimulation of thrombosis by hypoxia hypoxia and thrombosis sepsis-induced coagulopathy and disseminated intravascular coagulation clinical pathology of critical patient with novel coronavirus pneumonia (covid- ) seminars in thrombosis & hemostasis the nucleocapsid protein of sars-cov induces transcription of hfgl prothrombinase gene dependent on c/ebp alpha mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury venous thromboembolism in critically ill patients protect investigators for the canadian critical care trials group and the australian and new zealand intensive care society clinical trials group. dalteparin versus unfractionated heparin in critically ill patients chest ct manifestations of new coronavirus disease (covid- ): a pictorial review new-onset atrial fibrillation in sepsis: a narrative review intensive-care patients with severe novel influenza a (h n ) virus infection -michigan pandemic h n influenza infection and vascular thrombosis thromboembolic events in patients with severe pandemic influenza a/h n chest radiographic and ct findings in novel swine-origin influenza a (h n ) virus (s-oiv) infection autopsy findings in eight patients with fatal h n influenza influenza and cardiovascular disease: does swine-origin, h n flu virus represent a risk factor, an acute trigger, or both? pulmonary thrombosis: a clinical pathological entity distinct from pulmonary embolism? covid- and vte/anticoagulation: frequently asked questions high risk of thrombosis in patients in severe sars-cov- infection: a multicenter prospective cohort study incidence of venous thromboembolism in hospitalized patients with covid- prothrombotic factors, and vte schulman dr. schulman reports grants and personal fees from octapharma and boehringer ingelheim, and grants from alnylam, bayer, bristol-myers squibb, daiichi sankyo, and grants from sanofi, outside the submitted work. key: cord- -n nnmlv authors: oliveira, e.; parikh, a.; lopez-ruiz, a.; carrillo, m.; goldberg, j.; cearras, m.; fernainy, k.; andersen, s.; mercado, l.; guan, j.; zafar, h.; louzon, p.; carr, a.; baloch, n.; pratley, r.; silvestry, s.; hsu, v.; sniffen, j.; herrera, v.; finkler, n. title: icu outcomes and survival in patients with severe covid- in the largest health care system in central florida date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: n nnmlv background observational studies have consistently described poor clinical outcomes and increased icu mortality in patients with severe coronavirus disease (covid- ) who require mechanical ventilation (mv). our study describes the clinical characteristics and outcomes of patients with severe covid- admitted to icu in the largest health care system in the state of florida, united states. methods retrospective cohort study of patients admitted to icu due to severe covid- in adventhealth health system in orlando, florida from march th until may th, . patients were characterized based on demographics, baseline comorbidities, severity of illness, medical management including experimental therapies, laboratory markers and ventilator parameters. major clinical outcomes analyzed at the end of the study period were: hospital and icu length of stay, mv-related mortality and overall hospital mortality of icu patients. results out of total of patients with covid- , ( . %) met criteria for icu admission (median age: years [interquartile range {iqr}, . - . ]; . % female). common comorbidities were hypertension ( ; . %), and diabetes ( ; . %). of the icu patients, ( . %) required mv and ( . %) received ecmo. lower positive end expiratory pressure (peep) were observed in survivors [ . ( . - . )] vs non-survivors [ ( . - . ] p= . ]. compared to non-survivors, survivors had a longer mv length of stay (los) [ (iqr - ) vs . (iqr - . ) p< . ], hospital los [ (iqr - ) vs ( - ) p< . ] and icu los [ (iqr - ) vs . (iqr - ), p < . ]. the overall hospital mortality and mv-related mortality were . % and . % respectively. after exclusion of hospitalized patients, the hospital and mv-related mortality rates were . % and . % respectively. conclusions our study demonstrates an important improvement in mortality of patients with severe covid- who required icu admission and mv in comparison to previous observational reports and emphasize the importance of standard of care measures in the management of covid- . coronavirus disease (covid- ) have affected over million of people around the world since december [ ] and in the united states has resulted so far in more than , deaths [ ] . epidemiological studies have shown that to % of patients develop a more severe form of covid- and will require admission to the intensive care unit (icu) due to acute hypoxemic respiratory failure [ ] . most of these patients admitted to icu, will finally require invasive mechanical ventilation (mv) due to diffuse lung injury and acute respiratory distress syndrome (ards). until now, most of the icu reports from united states have shown that severe covid- -associated ards (cards) is associated with prolonged mv and increased mortality [ ] . in fact, retrospective and prospective case series from china and italy have provided insight about the clinical course of severely ill patients with cards in which it demonstrates that extrapulmonary complications are also a strong contributor for poor outcomes [ , ] . in united states, population dense areas such as new york city, seattle and los angeles have had the highest rates of infection resulting in significant overload to hospitals and icu systems [ , , ] . however, tourist destinations and areas with a large elderly population like the state of florida pose a remaining concern for increasing infection rates that may lead to high national mortality. mortality rates reported in patients with severe covid- in the icu range from - % [ , , ] . in patients requiring mv, mortality rates have been reported to be as high as % [ ] . regional experiences in the management of critically ill patients with severe covid- have varied between cities and countries, and recent reports suggest a lower mortality rate [ ] . the regional and institutional variations in icu outcomes and overall mortality are not clearly understood yet and are not related to the use experimental therapies, given the fact that recent reports with the use remdesivir [ ] , hydroxychloroquine/azithromycin [ ] , lopinavir-ritonavir [ ] and convalescent plasma [ , ] have been inconsistent in terms of mortality reduction and improvement of icu outcomes. therefore, the poor icu outcomes and high mortality rate observed during cards have raised concerns about the strategies of mechanical ventilation and the success in delivering standard of care measures. our observational study is so far the first and largest in the state of florida to describe the demographics, baseline characteristics, medical management and clinical outcomes observed in patients with cards admitted to icu in a multihospital health care system. retrospective cohort study conducted at adventhealth central florida division (ahcfd), the largest health system in central florida. ahcfd is comprised of hospitals with a total of beds servicing the million residents of orange county and surrounding regions. all patients with covid- who met criteria for critical care admission from adventhealth hospitals were transferred and managed at adventhealth orlando, a -bed hospital with icu beds and dedicated inhouse / intensivist coverage. this study was approved by the institutional review board of ahcfd. all critical care admissions from march to may , presenting to any one of the ahcfd hospitals were included. all consecutive critically ill patients had confirmed severe acute respiratory syndrome coronavirus (sars-cov- ) infection by positive result on polymerase chain reaction (pcr) testing of a nasopharyngeal sample or tracheal aspirate. due to some of the documented shortcomings of pcr testing early in this pandemic, some patients required more than one test to document positivity. clinical outcomes of the included population were monitored until may , , the final date of study follow-up. all critically ill covid- patients were assigned in icus with a total capacity of beds. patients not requiring icu level care were admitted to a specially dedicated isolation unit at each ahcfd hospital. standardized respiratory care was implemented favoring intubation and mv over non-invasive positive pressure ventilation. the icus employed dedicated respiratory therapists, with extensive training in the care of patients with ards. we considered the following criteria to admit patients to icu: ) oxygen saturation (o sat) less than % on more than liters oxygen (o ) via nasal cannula (nc) or po < mmhg with liters or more o , or respiratory rate (rr) more than per minute on liters o , ) po /fio ratio less than , ) any patient with positive pcr test for sars-cov- already on requiring mv or with previous criteria. we accomplished strict protocol adherence for low tidal volume ventilation targeting a plateau pressure goal of less than cmh o and a driving pressure of less than cmh o. we followed ards network low peep, high fio table in the majority of our cases [ ] . those patients requiring mechanical ventilation were supervised by board-certified critical care physicians (intensivists). intensivist were not responsible for more than patients per hours shift. nursing did not exceed ratios of one nurse to two patients. early paralysis and prone positioning were achieved with the assistance of a dedicated prone team. prone positioning techniques were consistent with the proseva trial recommendations [ ] . the ml/kg crystalloid resuscitation recommendation was applied for those patients presenting with evidence of septic shock and fluid resuscitation was closely monitored to minimize overhydration [ ] . based on recent reports showing hypercoagulable state and increased risk of thrombosis in . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) patients with covid- , deep vein thrombosis (dvt) prophylaxis was initiated by following an institutional algorithm that employed d-dimer levels and rotational thromboelastometry (rotem) to determine the risk of thrombosis [ ] . prophylactic anticoagulation ranged from unfractionated heparin at units subcutaneously (sc) every eight hours or enoxaparin . mg/kg sc daily to full anticoagulation with either an unfractionated heparin infusion or enoxaparin mg/kg sc twice daily. data collected included patient demographic information, comorbidities, triage vitals, initial laboratory tests, inpatient medications, treatments (including invasive mechanical ventilation and renal replacement therapy), and outcomes (including length of stay, discharge, readmission, and mortality). all clinical outcomes are presented for patients who were admitted to the cohort icu during the study period (discharged alive, remained in the hospital or dead). clinical outcomes available at the study end point are presented, including invasive mechanical ventilation, icu care, renal replacement therapy, and hospital length of stay. race data were self-reported within prespecified fixed categories. initial laboratory testing was defined as the first test results available, typically within hours of admission. for initial laboratory testing and clinical studies for which not all patients had values, percentages of total patients with completed tests are shown. the scores apache ivb, mews, and sofa scores were computed to determine the severity of illness and data for these scoring was provided by the electronic health records. the. predicted hospital mortalities were calculated using the equations of apache ivb utilizing principal diagnosis of viral and bacterial pneumonia [ ] . patient characteristics and clinical outcomes were compared based on survival status of covid- positive patients. categorical fields are displayed as percentages and continuous fields . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted august , . . https://doi.org/ . / . . . doi: medrxiv preprint are presented as means or standard deviations (sd) or median and interquartile range. bivariate analysis was performed by survival status of covid- positive patients to examine differences in the survival and non-survival group using chi-square tests and welch's t-test. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted august , . . baseline demographic and clinical characteristics of patients are summarized in table and table respectively. the median age of the patients admitted to the icu was (iqr . - . ). deceased patients were older with a median age of . (iqr - , p < . ). a majority of patients were male ( . %), ( %) were black, and the majority of patients were classified as white and other ( , . %). hypertension was the most common co-morbid condition ( pts, %), followed by diabetes ( , %) and coronary artery disease ( , %). evidence of heart failure, chronic kidney disease (ckd) and dementia were associated with non-survivors. obesity (bmi - . ) was observed in patients ( . %), and ( . %) patients had a bmi of or greater. approximately half of the study population had commercial insurance ( , %) followed by medicare ( , . %), medicaid ( , . %) and uninsured ( , . % ). initial presentation with oxygen (o ) saturation < % (p= . ), respiratory rate > (p= . ) and systolic blood pressure < mmhg (p= . ) were more commonly present in non-survivors. although our study was not designed to assess the effectiveness of any of the above medications, no significant differences between survivors and non-survivors were observed through bivariate analysis. icu outcomes at the end of study period are described in table . of the total amount of patients admitted to icu (n= ), . % (n= ) remained alive at the end of the study period. of those alive patients, . % (n= ) were discharged from the hospital. of these patients who were discharged, ( . %) went home, ( . %) were discharged to skill nurse facilities and ( . %) were discharged to other hospitals. during the study period, patients of the total (n= ) expired ( . % overall mortality). excluding those patients who remained hospitalized (n= [ . % of ] at the end of study period, adjusted hospital mortality of icu patients was . %. higher survival rate was observed in patients younger than years old (p= . ) with the highest mortality rate observed in those patients older than years (p= . ). of the total icu patients who required invasive mechanical ventilation (n= [ . %]), patients ( . %) expired during the study period. when the mechanical ventilation-related mortality was calculated excluding those patients who remained hospitalized, this rate increased to . %. the apache ivb score-predicted hospital and ventilator mortality was % and % respectively for patients . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted august , . . https://doi.org/ . / . . . doi: medrxiv preprint with a discharge disposition. due to lack of risk-adjusted apache predictions specifically for patients with covid -induced acute respiratory failure, we considered acute respiratory failure secondary to usual viral and/or bacterial pneumonia as the principal diagnoses to determine expected rates of mortality. among admissions during the study period, were admitted to our icu ( . %). patients referred to our center from outside our system included patients to be evaluated for extracorporeal membrane oxygenation (ecmo) and patients who experienced delays in hospital level of care due to travel on cruise lines. these patients universally required a higher level of care than our average patient admission and may explain our slightly higher icu admission rate as compared to the literature ( - . %) [ , ] reports of icu mortality due to covid- around the world and in the unites states, in particular, have ranged from - % [ ] . in mechanically ventilated patients, mortality has ranged from - %. observations from wuhan have shown mortality rates of approximately % in covid- patients with ards [ ] . cohorts in new york have shown a mortality rate in the mechanically ventilated population as high as . % [ ] . based on these high mortality rates, there has been speculation that this disease process is different than typical ards, suggesting that standard ards mechanical ventilation strategies may not be as effective in reducing lung injury [ ] . however, both our in-hospital and mechanical ventilation mortality rates were significantly lower than what has been reported in the literature (table ). in fact, our data suggests that covid- -induced ards requiring mechanical ventilation has a similar if not lower mortality than what has been previously observed in ards due to other infectious etiologies [ ] . there are several potential explanations for our study findings. our lower mortality could be partially explained by our lower average patient age or higher proportion of non-african americans as some studies have suggested a higher mortality in the african american population [ ] . however, in countries where the majority population were non-black (china, italy, and other countries in europe), a high mortality rate was also observed. our study population also had a higher rate of commercial insurance, which may suggest an improved baseline health status which has been associated with an overall lower all-cause mortality [ ] . an additional factor to be considered is our geographical location: the warmer climate and higher humidity experienced in central florida, have been associated with a lower mortality of the disease [ ] . it is unclear whether these or other environmental factors could also be associated with a lower virulence for covid- in our region. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted august , . . https://doi.org/ . / . . . doi: medrxiv preprint other relevant factors that in our opinion are likely to have influenced our outcomes were that our healthcare delivery system was never overwhelmed. we were allowed time to adapt our facility infrastructure, recruit and retain proper staffing, cohort all critical ill patients in one location to enhance staff expertise and minimize variation, secure proper personal protective equipment, develop proper processes of care, and follow an increasing number of medical society best practice recommendations [ ] overall, we strictly followed standard ards and respiratory failure management. investigational treatments of uncertain efficacy were utilized when supported by available evidence at the time. ( table ). the majority of our patients throughout march and april received hydroxychloroquine and azithromycin. although the effectiveness and safety of this regimen has been recently questioned [ ] . our observed mortality does not suggest a detrimental effect of such treatment. reported cardiotoxicity associated with this regimen was mitigated by frequent ecg monitoring and close monitoring of electrolytes. potential benefit has been described for remdesivir in reducing the duration of hospital los, but it has not been shown to improve patient survival, especially in the critically ill population [ ] . in addition, % of our patients received tocilizumab and . % where enrolled in a blinded clinical trial of investigational drugs targeting the inflammatory cascade. the theoretical benefit of blocking cytokines, specially interleukin- [il- ], which is one of main mediators of the cytokine release syndrome, has not been shown at this time to improve mortality or other outcomes [ ] . also, of note, . % of our study population received convalescent plasma, and larger studies are underway to understand its role in the treatment of severe covid- [ , ] . another potential aspect that may have contributed to reduce our mv-related mortality and overall mortality is the use of steroids. we are reporting that % of the patients who required mechanical ventilation received methylprednisolone or dexamethasone. this specific population and the impact of steroids in respiratory parameters, ventilator-free days and survival need to be further evaluated. the dose and duration of steroids were based on the study by villar j. et al, that showed an improvement in survival in patients with ards after using dexamethasone [ , ] . interestingly, only . % of our study population was referred for ecmo, however our ecmo mortality was much lower than previously reported in the literature ( % compared to %) [ , ] . this report has several limitations. this was an observational study conducted at a single health care system in a confined geographic area thus limiting the generalizability of our results. as with all observational studies, it is difficult to ascertain causality with icu therapies as opposed to an association that existed due to the patients' clinical conditions. additionally, when examining . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted august , . . multiple factors associated with survival, potential confounders may remain unidentified without a multivariate regression analysis. finally, additional unmeasured factors might have played a significant role in survival. despite these limitations, our experience and results challenges previously reported high mortality rates. in fact, our mortality rates for mechanically ventilated covid- patients were similar to apache ivb predicted mortality, which was based on critically ill patients admitted with respiratory failure secondary to viral and/or bacterial pneumonia. our study demonstrates the possibility of better outcomes for covid- associated with critical illness, including covid- patients requiring mechanical ventilation. our study is the first and the largest in the state florida and probably one of the most encouraging in the united states to show lower overall mortality and mv-related mortality in patients with severe covid- admitted to icu compared to other previous cases series. our study does not support the previously reported overwhelmingly poor outcomes of mechanically ventilated patients with covid- induced respiratory failure and ards. in fact, it is reassuring that the application of well-established ards and mechanical ventilation strategies can be associated with mortality and outcomes comparable to non-covid- induced sepsis or ards. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted august , . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted august , . . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted august , . . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted august , . . https://doi.org/ . / . . . doi: medrxiv preprint coronavirus disease (covid- ) situation report - . epi update. world health organization (who) cdc covid- response team characteristics of and important lessons from coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region covid- in critically ill patients in the seattle region -case series characteristics of hospitalized adults with covid- in an integrated health care system in california characteristics and outcomes of critically ill patients with covid- in washington state clinical course and outcomes of intensive care patients with covid- epidemiology, clinical course, and outcomes of critically ill adults with covid- in new york city: a prospective cohort study remdesivir for the treatment of covid- -preliminary report no evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe covid- infection a trial of lopinavir-ritonavir in adults hospitalized with severe covid- convalescent plasma as a potential therapy for covid- treatment of critically ill patients with covid- with convalescent plasma effect of lung recruitment and titrated positive end-expiratory pressure (peep) vs low peep on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial prone positioning in severe acute respiratory distress syndrome the surviving sepsis campaign bundle: update routine venous thromboembolism prophylaxis may be inadequate in the hypercoagulable state of severe coronavirus disease a study on the efficacy of apache-iv for predicting mortality and length of stay in an intensive care unit in iran incidence, clinical outcomes, and transmission dynamics of severe coronavirus disease in california and washington: prospective cohort study risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease management of covid- respiratory distress past and present ards mortality rates: a systematic review covid- and african americans the relationship of health insurance and mortality: is lack of insurance deadly? effects of temperature variation and humidity on the death of covid- in wuhan innovation and transformation in the response to covid- : seven areas where clinicians need to lead clinical outcomes in covid- patients treated with tocilizumab: an individual patient data systematic review treatment with convalescent plasma for critically ill patients with severe acute respiratory syndrome coronavirus infection poor survival with extracorporeal membrane oxygenation in acute respiratory distress syndrome (ards) due to coronavirus disease (covid- ): pooled analysis of early reports evaluating the efficacy of dexamethasone in the treatment of patients with persistent acute respiratory distress syndrome: study protocol for a randomized controlled trial dexamethasone treatment for the acute respiratory distress syndrome: a multicenter, randomized controlled trial we would like to acknowledge the following adventhealth critical care consortium research key: cord- -hffj s o authors: schmidt, matthieu; hajage, david; lebreton, guillaume; monsel, antoine; voiriot, guillaume; levy, david; baron, elodie; beurton, alexandra; chommeloux, juliette; meng, paris; nemlaghi, safaa; bay, pierre; leprince, pascal; demoule, alexandre; guidet, bertrand; constantin, jean michel; fartoukh, muriel; dres, martin; combes, alain; luyt, charles-edouard; hekimian, guillaume; brechot, nicolas; pineton de chambrun, marc; desnos, cyrielle; arzoine, jeremy; guerin, emmanuelle; schoell, thibaut; demondion, pierre; juvin, charles; nardonne, nathalie; marin, sofica; d'alessandro, cossimo; nguyen, bao-long; quemeneur, cyril; james, arthur; assefi, mona; lepere, victoria; savary, guillaume; gibelin, aude; turpin, matthieu; elabbadi, alexandre; berti, enora; vezinet, corinne; bonvallot, harold; delmotte, pierre-romain; de sarcus, martin; du fayet de la tour, charlotte; abbas, samia; maury, eric; baudel, jean-luc; lavillegrand, jean-remi; ait oufella, hafid; abdelkrim, abdelmalek; urbina, thomas; virolle, sara; deleris, robin; bonny, vincent; le marec, julien; mayaux, julien; morawiec, elise title: extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with covid- : a retrospective cohort study date: - - journal: the lancet respiratory medicine doi: . /s - ( ) - sha: doc_id: cord_uid: hffj s o summary background patients with covid- who develop severe acute respiratory distress syndrome (ards) can have symptoms that rapidly evolve to profound hypoxaemia and death. the efficacy of extracorporeal membrane oxygenation (ecmo) for patients with severe ards in the context of covid- is unclear. we aimed to establish the clinical characteristics and outcomes of patients with respiratory failure and covid- treated with ecmo. methods this retrospective cohort study was done in the paris–sorbonne university hospital network, comprising five intensive care units (icus) and included patients who received ecmo for covid- associated ards. patient demographics and daily pre-ecmo and on-ecmo data and outcomes were collected. possible outcomes over time were categorised into four different states (states – ): on ecmo, in the icu and weaned off ecmo, alive and out of icu, or death. daily probabilities of occupation in each state and of transitions between these states until day post-ecmo onset were estimated with use of a multi-state cox model stratified for each possible transition. follow-up was right-censored on july , . findings from march to may , , patients with covid- were treated in our icus. complete day- follow-up was available for patients (median age [iqr – ] years and [ %] men) who received ecmo. pre-ecmo, ( %) patients had been prone-positioned; their median driving pressure was (iqr – ) cm h o and pao /fio was ( – ) mm hg. at days post-ecmo initiation, the estimated probabilities of occupation in each state were % ( % ci – ) for state , % ( – ) for state , % ( – ) for state , and % ( – ) for state . ( %) patients had major bleeding and four ( %) had a haemorrhagic stroke. patients died. interpretation the estimated -day survival of ecmo-rescued patients with covid- was similar to that of studies published in the past years on ecmo for severe ards. if another covid- outbreak occurs, ecmo should be considered for patients developing refractory respiratory failure despite optimised care. funding none. the outbreak of severe acute respiratory syndrome coronavirus (sars-cov- ) rapidly evolved into a worldwide pandemic, with more than million cases of covid- as of july , . in france, many disease clusters were identified early in march, , with paris and its surrounding area (greater paris) reporting the most cases. covid- can lead to acute respiratory failure requiring intensive care unit (icu) admission and mechanical ventilation. however, its most serious forms can rapidly evolve to severe acute respiratory distress syndrome (ards) with profound hypoxaemia and death, despite lung-protective mechanical ventilation, including prone-positioning. , in , the extracorporeal membrane oxygenation (ecmo) to rescue lung injury in severe ards (eolia; n= ) trial showed that although mortality in the ecmo group was lower at % compared with % in the control group, the difference was not significant (relative risk · [ % ci · - · ]; p= · ). a post-hoc bayesian analysis of eolia data later showed a high likelihood of an ecmo survival benefit for severe ards, as defined by the eolia entry criteria. accordingly, inter national organisations , and experts in the field , recom mended ecmo for patients who were critically ill with covid- following the initial outbreak in china, further stating that it should be provided in high-volume specialised centres, and a mobile ecmo team should retrieve patients on ecmo from other centres. however, survival was very low in chinese case series of ecmo-treated patients with covid- , , raising concerns about the usefulness of ecmo in this setting. we aimed to establish the characteristics and outcomes of patients who received ecmo for laboratory-confirmed sars-cov- infection in the paris-sorbonne university hospital network icus, the principal hospital referral network for icu care in greater paris, including one of the largest european ecmo centres (pitié-salpêtrière hospital). this retrospective cohort study was done in the paris-sorbonne university hospital network icus (three at la pitié-salpêtrière hospital, one in saint-antoine hospital, and one in tenon hospital), which cared for patients with covid- with severe ards. all consecutive adult patients with laboratory confirmed sars-cov- infection, documented by real-time rt-pcr on nasopharyngeal swabs, or lower respiratory tract aspirates, and who received venoarterial-ecmo or venovenous-ecmo for severe ards were included. patients who received ecmo for isolated refractory cardiogenic shock were excluded. ecmo support was provided at pitié-salpêtrière and tenon hospital icus, while saint-antoine hospital icu cared for patients either before ecmo cannulation or after ecmo decannulation. the sorbonne-university ethics committee (cer-su- - ) approved the protocol. in accordance with the ethical standards of french legislation (committees for the protection of human subjects), informed consent for demographic, physiological, and hospital-outcome data analyses was not obtained because this observational study did not modify existing diagnostic or therapeutic strategies. only non-opposition of the patient or their legal representative for use of the data was obtained. in a context of ecmo resource constraints, all ecmo proposals in greater paris were centralised at pitié-salpêtrière hospital. once contacted, indications for ecmo were evaluated in a staff meeting, including at least two intensivists. patients eligible for ecmo had to fulfill ards criteria, and one of the following disease severity criteria, despite ventilator optimisation (fraction of inspired oxygen [fio ] ≥ %, tidal volume set at ml/kg predicted bodyweight, and positive end-expiratory pressure [peep] ≥ cm of water): ( ) partial pressure of arterial oxygen (pao ) over a fio ratio of less than mm hg for more than h; ( ) pao /fio less than mm hg for more than h; or ( ) arterial blood ph less than · with a partial pressure of arterial carbon dioxide (paco ) of mm hg or more for h or more. physicians were strongly encouraged to use neuromuscular blocking agents and prone-positioning before ecmo. ecmo contraindications were: age older than years, severe comorbidities (eg, advanced cardiac, respiratory, or liver failure; metastatic cancer; or evidence before this study covid- can lead to acute respiratory failure requiring intensive care unit (icu) admission and mechanical ventilation. however, its most serious forms can rapidly evolve to severe acute respiratory distress syndrome (ards) with profound hypoxaemia and death, despite lung-protective mechanical ventilation, including prone-positioning. extracorporeal membrane oxygenation (ecmo) efficacy in this setting is unknown. we searched pubmed for full papers in any language published in peer-reviewed journals up to july , , with the terms "ecmo" and " novel coronavirus", " -ncov", "covid- ", or "sars-cov- ". we identified articles that reported cases of patients infected with sars-cov- who received ecmo for acute respiratory failure. however, these studies included only a limited number of patients (n= to n= ), with limited information on patient characteristics, management, and outcomes. very few of them reported patient survival beyond day post-ecmo onset, precluding any conclusion regarding the usefulness of ecmo in this setting. this retrospective study, with patients included and a complete follow-up until day post-ecmo initiation is, to our knowledge, the largest to date reporting the outcomes after rescue ecmo for the most severe forms of covid- ards, in the paris-sorbonne university hospital network (paris, france), the principal hospital referral network for icu care in greater paris, including one of the largest european ecmo centres (pitié-salpêtrière hospital). our patients' pre-ecmo characteristics indicated extreme ards severity (median pao /fio , [iqr - ] mm hg) although % had been prone-positioned before ecmo onset. the estimated probability of death days post-ecmo initiation was % ( % ci - ). ( %) had major bleeding and four ( %) patients had a haemorrhagic stroke. contrary to preliminary results that indicated dismal outcomes with - % mortality of patients with covid- given ecmo, the estimated % probability of day- mortality for our patients on ecmo was similar to those ecmo-treated in the eolia trial or the large prospective lifegard registry. should another covid- wave occur, ecmo should be considered early for patients developing profound respiratory failure, despite optimised conventional care, including pronepositioning. longer-term follow-up of these patients is now needed to evaluate covid- 's potential pulmonary, physical, and psychological sequelae. haematological malignancies), cardiac arrest (except when cardiopulmonary resuscitation was provided immediately and the low-flow time was < minutes), refractory multiorgan failure or simplified acute physiology score (saps) ii more than , irreversible neurological injury, and mechanical ventilation for more than days. once the indication was approved, the pitié-salpêtrière mobile ecmo retrieval team (mert), comprising a cardiovascular surgeon and a perfusionist, was sent to the patient's bedside for ecmo cannulation, as described previously. , our mert was available h per day, days a week. once ecmo had been implanted, the patient was transferred by a service d'aide medicale d'urgence ambulance with the mert to one of the paris-sorbonne university hospital network icus. ecmo cannulation was done percutaneously under ultrasonography guidance by a cardiovascular surgeon wearing full personal protective equipment (ie, respirator ffp or n mask, gown, goggles, and gloves). for venovenous-ecmo, blood drainage with a large cannula ( ) ( ) ( ) ( ) ( ) inserted into the common femoral vein, and returned through the right internal jugular vein was strongly recommended. for venoarterial-ecmo, a venous drainage cannula ( ) ( ) ( ) ( ) ( ) ( ) ( ) was inserted into the common femoral vein, an arterial return cannula ( ) ( ) ( ) ( ) ( ) into the common femoral artery, and an additional anterograde perfusion cannula was systematically inserted into the superficial femoral artery to prevent leg ischaemia. pump speed was adjusted to obtain blood-oxygen saturation at more than %. optimal cannula positioning was verified by ultrasonography and chest x-ray. following early reports of severe covid- associated coagulopathy [ ] [ ] [ ] and frequent thromboembolic events on ecmo, inclu ding massive pulmonary embolism, , we decided to increase the targeted activated partial thromboplastin time for anticoagulation of venovenous ecmo with unfractionated heparin to - s or anti-xa activity · - · iu/ml (respective values were - s or · - · iu/ml in the eolia trial ) before we treated our first patients with covid- ards. plasma-free haemoglobin and plasma fibrinogen concentrations were monitored daily. the haemoglobin threshold for red blood cell transfusion was - g/dl (or ≤ g/dl when hypoxaemia persisted); platelet transfusions were discouraged except for severe thrombocytopenia (< × cells per l) or thrombocytopenia of more than × cells per l with bleeding. to enhance protection against ventilator-induced lung injury, ultraprotective lung ventilation on ecmo was recommended, , by targeting lower mechanical power delivered to the lungs and lower tidal volume, respiratory rate, and airway and driving pressures. early prone-positioning on ecmo was encouraged in the absence of haemodynamic instability and contraindications for prone-positioning (ie, massive haemoptysis requiring an immediate surgical or interventional radiology procedure; deep venous thrombosis treated for less than days, or single anterior chest tube with air leaks). , , patients were assessed daily for possible ecmo weaning with use of the eolia clinical and physiological criteria. , information recorded before ecmo comprised age, sex, body-mass index, comorbidities, saps ii, sequential organ-failure assessment score, respiratory extracorporeal membrane oxygenation survival prediction score, date of first symptoms, and hospital and icu admissions. information collected before ecmo implantation comprised previous rescue therapies, the date mechanical ventilation started, ventilator settings (mode, peep, fio , respiratory rate, tidal volume, plateau pressure [p plat ]), arterial blood-gas parameters, and routine laboratory values. driving pressure (Δp) was defined as p plat minus peep and mechanical power (j/min) was calculated as follows : ventilatory ratio was calculated as : an expanded dataset including mechanical ventilation settings, arterial blood gases, adjuvant therapies on ecmo, and ecmo-related complications was noted daily from day - , then every days until ecmo day , ecmo weaning, or death, whichever occurred first. ecmo-related compli cations and organ dysfunction included major bleeding, blood-cell transfusions, massive haemolysis, ecmo-circuit change, severe thrombocytopenia (< × cells per l, occurring during the first study profile for patients included in this study, and their outcomes at july , . icu=intensive care unit. ecmo=extracorporeal membrane oxygenation. days of ecmo), stroke, renal replacement therapy, proven pulmonary embolism, pneumothorax, ventilatorasso ciated pneumonia, bacter aemia, and cardiac arrest. major bleeding was defined as requiring two or more units of packed red blood cells due to an obvious haemorrhagic event, necessitating a surgical or interventional pro cedure, an intracerebral haemorrhage, or a bleed causing a fatal outcome, while massive haemolysis was defined as plasma-free haemoglobin of more than mg/l associated with clinical signs of haemolysis. patient outcomes comprised the following endpoints: on ecmo, in the icu and weaned off ecmo, alive and out of icu, or died on days , , , , , , and after ecmo implantation. time spent in each state was calculated for the whole population of patients, with right-censoring of patients who did not reach the final absorbing state at later timepoints (day , , or ). other outcomes comprised icu and ecmo-related complications. patient characteristics are expressed as n (%) for categorical variables, mean (sd) for continuous variables, or median (iqr), as appropriate. to better describe patients' trajectories in the icu over time, a multi-state model chronic respiratory disease, copd, or asthma ( %) ( %) time from first symptoms to icu admission, days ( - ) ( - ) ( - ) ( - ) time from first symptoms to intubation, days ( - ) ( - ) ( - ) ( - ) time from intubation to ecmo, days ( - ) ( - ) ( - ) ( - ) states: in the icu and weaned off ecmo and alive and out of the icu. because patients could die at any time during follow-up, either in the icu or after discharge, the died state is the only final absorbing state (the final state that a patient can enter that once entered cannot be left). in this four-state model (appendix p ), each box represents a state and each arrow represents possible transitions from one state to another. after assessing patient status, participants who did not reach the final absorbing state were right-censored at the end of the observation period (july , ). a cox model stratified on each possible transition was fitted to estimate transition (from one state to another) and state occupation (for each of the four states) probabilities over time; the percentages of patients occupying each possible state were represented simultaneously over time with a stacked probability plot and reported with their % ci on days , , , , , , and post-ecmo initiation. another figure (appendix p ) individually displays all possible transition probabilities from one state to another over time. mean state occupation times (ie, the expected length of stay in each possible state of the multi-state model) was also reported at the same timepoints. finally, median on-ecmo time and length of icu stay were established. all the analyses were computed at a two-sided α level of % with r software, version . . . there was no funding source for this study. the corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. among the consecutive patients ( figure ) data are median (iqr) or n (%). ecmo=extracorporeal membrane oxygenation. icu=intensive care unit. pao /fio =ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen. paco =partial pressure of arterial carbon dioxide. resp=respiratory extracorporeal membrane oxygenation survival prediction. sao =arterial oxygen saturation. sofa=sequential organ-function assessment. copd=chronic obstructive pulmonary disorder. *of the patients discharged from the icu, on july , , were still hospitalised or in a rehabilitation centre and returned home. †of the five patients still in the icu, on july , , one remained on ecmo. ‡patients missing data. data missing for - patients, except for lymphocytes (n= ). §defined as haematological malignancies, active solid tumour, or having received specific anti-tumour treatment within year, solid-organ transplant or infected with hiv, long-term corticosteroids, or immunosuppressants. ¶defined as plateau pressure minus positive end-expiratory pressure. ||mechanical power (j/min)= · × tidal volume × respiratory rate × (peak pressure - / × driving pressure). if not specified, peak pressure was considered equal to plateau pressure. saps ii median score ). their pre-ecmo characteristics according to their endpoint state on july , , are reported in table . briefly, pre-ecmo rescue procedures consisted of prone-positioning (n= , %), continuous neuromuscular blockers (n= , %), and nitric oxide (n= , %). median peep was (iqr - ) cm h o, driving pressure was ( ) ( ) ( ) ( ) ( ) ( ) cm h o, and mechanical power was · ( · - · ) j/min. at cannulation, the median pao /fio was (iqr - ) mm hg and paco was ( - ) mm hg. for comparison, detailed characteristics of patients with covid- in our cohort and in the eolia trial group are reported in the appendix (pp - ). femoral-jugular cannulas were inserted in ( %) patients, mostly with a large ( fr) drainage cannula, a median (iqr - ) days after endotracheal intubation. the mert brought ( %) patients from non-ecmo centres. ecmo support successfully lowered tidal volume, respiratory rate, and plateau pressure during the h following its initiation: median · (iqr · - · ) ml/kg for tidal volume, ( - breaths per min for respiratory rate), and ( ) ( ) ( ) ( ) cm h o for plateau pressure (table , appendix pp - ). consequently, the mechanical power delivered to the lungs dropped to · (iqr · - · ) j/min. arterial blood gases also normalised rapidly on ecmo (appendix pp [ ] [ ] . on ecmo, ( %) patients were prone-positioned, ( %) received continuous neuromuscular blockers, five ( %) nitric oxide, and ( %) high-dose corticosteroids (table ) . median activated partial thromboplastin time ratios rose progressively over days - on ecmo: · (iqr · - · ) on day , · ( · - · ) on day , and · ( · - · ) on day . on july , , median follow-up was (range - ) days. complete follow-up on days was available for patients post-ecmo implantation, -day herein, we describe a large case series of patients who received ecmo support for the most severe forms of covid- ards. they were treated in the paris-sorbonne university hospital network icus, comprising five intensive care units, which are experienced in managing ards and ecmo. ecmo indications were based on the eolia trial selection criteria with an upper age limit of years, and patients received highly standardised ecmo care and general icu care. granular information on patients' pre-ecmo characteristics, daily management, and outcomes were analysed. contrary to preliminary results from other studies that indicated dismal outcomes with - % mortality of patients who had covid- and were treated with ecmo, , the estimated % probability of day- mortality for our patients on ecmo was similar to those treated with ecmo in the eolia trial ( % at day ) or the large prospective lifegard registry ( % at day ). the pre-ecmo characteristics of our patients with covid- indicated great ards severity before ecmo support was initiated. their mean pao /fio ( [sd ] mm hg) was lower than for patients in the eolia ( [ ] mm hg) or lifegard ( [ ] mm hg) trials, while pre-ecmo respiratory system compliance, driving pressure, mechanical power, and other respiratory and ventilatory parameters were similar in all three studies. notably, our patients with covid- had lower respi ratory system compliance and higher driving pressure than previously reported for most patients with covid- receiving mechanical ventilation, , indicating extensive sars-cov- -induced alveolar damage. according to guidelines from and for the optimisation of care for the most severe ards forms, , % of our patients benefited from prone-positioning before ecmo (compared with % in eolia and only % in lifegard ). beyond providing adequate oxygenation, high bloodflow ecmo achieves a homogeneous ultraprotective ventilation strategy, most frequently using bilevelpositive airway pressure or airway pressure-release ventilation modes, with tight control of the driving pressure. , our patients' pre-ecmo median mechanical power reached · (iqr · - · ) j/min, although a higher mortality risk for patients with ards whose value exceeded · j/min has been suggested. following ecmo initiation, tidal volume, driving pressure, and respiratory rate were markedly reduced in our patients, resulting in a major decrease of the median mechanical power to · (iqr · - · ) j/min, as previously reported. in addition, ecmo prone-positioning, used for % of our patients with covid- (vs only % of patients treated with ecmo in the eolia trial), sofa score on ecmo day * ( ) ( ) ( ) ( ) ( ) ( ) ( ) sofa score on ecmo day † ( ) ( ) ( ) ( ) ( ) ( ) aptt have contributed to improving their outcomes. indeed, a retrospective series of patients with severe ards showed that on-ecmo prone-positioning obtained higher ecmo weaning and survival rates. an autopsy-based histological analysis of the pulmonary vessels of patients with covid- showed widespread thrombosis with microangiopathy, with alveolar capillary microthrombi being nine times more frequent in patients with covid- than in those with influenza. consistent with other series, , , , we also observed an unusually high on-ecmo rate of proven pulmonary embolism ( %), an event not reported for the patients treated with ecmo in the eolia trial. those thromboembolic events occurred, despite an early increase of our anticoagulation target for patients with covid- receiving venovenous ecmo support, suggesting that other strategies, beyond systemic anti coagulation, are warranted to care for sars-cov- induced lung endothelial injuries. it should also be noted that haemorrhagic stroke occurred in % of our patients, which was more frequent than in the eolia trial ( %). the higher anticoagulation regimen, and specific sars cov- -associated vasculitis and critical illness associated microbleeds could explain this finding. however, the frequency of severe haemorrhagic events requiring transfusion in our study was similar to those of patients treated with ecmo in the eolia trial. compared with the eolia trial of patients with severe ards ( % bacterial and % viral pneumonia) treated with ecmo, has been proposed in patients with septic shock with severe myocardial dysfunction and decreased cardiac index, which was not the case in our patients. lastly, our antibiotic-treated ventilator-associated pneumonia rate was higher ( %) than for patients in the eolia trial ( %), and might reflect the longer mechanical ventilation or specific sars-cov- induced immunoparalysis. it should also be noted that few of our patients received high-dose corticosteroids. we acknowledge several limitations to our study. first, our results have to be considered preliminary, as some patients remained in the hospital and day- post-ecmo outcomes were not available for all patients. however, we used a time-to-event analysis, which allowed estimation of the probabilities of remaining on ecmo, ecmo weaning, icu discharge, or death over time, taking into account the fact that some patients' follow-up was censored. also, on july , , we carefully updated follow-up of all included patients to ensure the absence of informative censoring for unbiased estimations. second, our patients were treated in a high-volume ecmo university hospital network experienced in the care of the most severe forms of ards that might limit the generalisability of our observations. third, indication for ecmo and other selection and information biases might have existed due to the limited size of our cohort of patients. fourth, although the characteristics and outcomes of our ecmo-supported patients with covid- were similar to those reported in a series of ecmo-treated patients with severe ards before the pandemic, we were not able to compare our patients' outcomes to those of patients with covid- who were not ecmo-supported. fifth, only data for thrombo cytopenia occurring during the first days of ecmo were collected, which might have underestimated the actual rate of this complication. lastly, we did not collect data for patients' viral load and cannot ascertain the potential benefits of prone-positioning on ecmo, which might represent areas for future studies. in conclusion, the survival of ecmo-rescued very sick patients with covid- was similar to that reported in studies on ecmo support for severe ards published in the past few years. , should another covid- wave occur, ecmo should be considered at an early stage for patients developing profound respiratory failure, despite optimised conventional care, including prone-positioning. longer-term follow-up of these patients is also needed to evaluate the potential pulmonary, physical, and psychological sequelae of covid- . epidemiology, clinical course, and outcomes of critically ill adults with covid- in new york city: a prospective cohort study baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region extracorporeal membrane oxygenation for severe acute respiratory distress syndrome extracorporeal membrane oxygenation for severe acute respiratory distress syndrome and posterior probability of mortality benefit in a post hoc bayesian analysis of a randomized clinical trial surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) extracorporeal life support organization coronavirus disease interim guidelines: a consensus document from an international group of interdisciplinary extracorporeal membrane oxygenation providers preparing for the most critically ill patients with covid- : the potential role of extracorporeal membrane oxygenation planning and provision of ecmo services for severe ards during the covid- pandemic and other outbreaks of emerging infectious diseases poor survival with extracorporeal membrane oxygenation in acute respiratory distress syndrome (ards) due to coronavirus disease (covid- ): pooled analysis of early reports extracorporeal membrane oxygenation for coronavirus disease -induced acute respiratory distress syndrome: a multicenter descriptive study covid- , ecmo, and lymphopenia: a word of caution clinical management of severe acute respiratory infection when covid- disease is suspected the berlin definition of ards: an expanded rationale, justification, and supplementary material emergency circulatory support in refractory cardiogenic shock patients in remote institutions: a pilot study (the cardiac-rescue program) retrieval of severe acute respiratory failure patients on extracorporeal membrane oxygenation: any impact on their outcomes? systemic inflammatory response syndrome is a major contributor to covid- -associated coagulopathy: insights from a prospective single center cohort study abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia clinical features of patients infected with novel coronavirus in wuhan, china severe pulmonary embolism in covid- patients: a call for increased awareness high risk of thrombosis in patients with severe sars-cov- infection: a multicenter prospective cohort study mechanical ventilation management during extracorporeal membrane oxygenation for acute respiratory distress syndrome. an international multicenter prospective cohort prone positioning and extracorporeal membrane oxygenation for severe acute respiratory distress syndrome: time for a randomized trial a new simplified acute physiology score (saps ii) based on a european/north american multicenter study the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/ failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine predicting survival after extracorporeal membrane oxygenation for severe acute respiratory failure. the respiratory extracorporeal membrane oxygenation survival prediction (resp) score ventilator-related causes of lung injury: the mechanical power physiologic analysis and clinical performance of the ventilatory ratio in acute respiratory distress syndrome tutorial in biostatistics: competing risks and multi-state models clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study covid- pneumonia: different respiratory treatments for different phenotypes? an official american thoracic society/european society of intensive care medicine/ society of critical care medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome formal guidelines: management of acute respiratory distress syndrome extracorporeal life support for adults with respiratory failure and related indications: a review driving pressure and survival in the acute respiratory distress syndrome mechanical power of ventilation is associated with mortality in critically ill patients: an analysis of patients in two observational cohorts pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- confirmation of the high cumulative incidence of thrombotic complications in critically ill icu patients with covid- : an updated analysis pulmonary embolism in patients with covid- : awareness of an increased prevalence venoarterial extracorporeal membrane oxygenation support for refractory cardiovascular dysfunction during severe bacterial septic shock ms, gl, am, gv, dl, eb, ab, jc, pm, sn, pb, pl, ad, bg, jmc, mf, md, and ac were involved in data generation. ms, dh, and ac were involved in analysis of the data. ms, dh, and ac wrote the manuscript. all authors contributed to the revision, and read and approved the final version of the manuscript. ac takes responsibility for the integrity of the work as a whole, from inception to published article. ms reports lecture fees from getinge, drager, and xenios, outside of the submitted work. ad reports personal fees from medtronic, baxter, hamilton, and getinge; grants, personal fees, and non-financial support from philips; personal fees and non-financial support from fisher and paykel; grants from french ministry of health; grants and personal fees from respinor; grants and non-financial support from lungpacer, outside of the submitted work. jmc reports personal fees and nonfinancial support from drager, ge healthcare, sedana medical, baxter, amomed, fisher and paykel healthcare, orion, philips medical, and fresenius medical care, and non-financial support from lfb and bird corporation, outside of the submitted work. md received fees from lungpacer (expertise, lectures). ac reports grants from getinge, personal fees from getinge, baxter, and xenios, outside of the submitted work. gv reports grants and personal fees from biomérieux, grants from sos oxygène, and grants from janssen, outside of the submitted work. all other authors declare no competing interests. individual patient data reported in this article will be shared after de-identification (text, tables, figures, and appendices), beginning months and ending years after article publication, to researchers who provide a methodologically sound proposal and after approval of an internal scientific committee. proposals should be addressed to alain.combes@aphp.fr. to gain access, data requestors will need to sign a data access agreement. the data from this study are not currently part of any other international collection of data. key: cord- -rv fsitx authors: giacobbe, daniele roberto; battaglini, denise; ball, lorenzo; brunetti, iole; bruzzone, bianca; codda, giulia; crea, francesca; de maria, andrea; dentone, chiara; di biagio, antonio; icardi, giancarlo; magnasco, laura; marchese, anna; mikulska, malgorzata; orsi, andrea; patroniti, nicolò; robba, chiara; signori, alessio; taramasso, lucia; vena, antonio; pelosi, paolo; bassetti, matteo title: bloodstream infections in critically ill patients with covid‐ date: - - journal: eur j clin invest doi: . /eci. sha: doc_id: cord_uid: rv fsitx background: little is known about the incidence and risk of intensive care unit (icu)‐acquired bloodstream infections (bsi) in critically ill patients with coronavirus disease (covid‐ ). material and methods: this retrospective, single‐centre study was conducted in northern italy. the primary study objectives were: (i) to assess the incidence rate of icu‐acquired bsi; (ii) to assess the cumulative risk of developing icu‐acquired bsi. results: overall critically ill patients with covid‐ were included in the study. forty‐five episodes of icu‐acquired bsi were registered in patients, with an incidence rate of episodes ( % confidence interval [ci] ‐ ) per patient‐days at risk. the estimated cumulative risk of developing at least one bsi episode was of almost % after days at risk, and possibly surpassing % after days at risk. in multivariable analysis, anti‐inflammatory treatment was independently associated with the development of bsi (cause‐specific hazard ratio [cshr] . with % ci . ‐ . for tocilizumab, cshr . with % ci . ‐ . for methylprednisolone, and cshr . with % ci . ‐ . for methylprednisolone plus tocilizumab, with no anti‐inflammatory treatment as the reference group; overall p for the dummy variable = . ). conclusions: the incidence rate of bsi was high, and the cumulative risk of developing bsi increased with icu stay. further study will clarify if the increased risk of bsi we detected in covid‐ patients treated with anti‐inflammatory drugs is outweighed by the benefits of reducing any possible proinflammatory dysregulation induced by sars‐cov‐ . in a very few months, coronavirus disease (covid- ) has become pandemic, and several countries worldwide are currently dealing with unprecedented epidemic foci of severe acute respiratory infection, a possible presentation of covid- that may require intensive care unit (icu) admission and carries a high case-fatality rate [ ] [ ] [ ] [ ] [ ] . while the demographics, clinical characteristics, and overall survival of patients with covid- admitted to icu have been already extensively characterized by large reports from several parts of the word, little is still known about non-viral infectious complications such as bacterial or fungal bloodstream infections (bsi), that may participate in adversely influencing the outcome of any icu-admitted patient , . in the present study, we aimed to retrospectively assess the incidence rate, cumulative risk, predictors, and survival of icu-acquired bsi in patients with covid- admitted to two icus in a large teaching hospital in northern italy, one of the most affected areas in europe to date . this retrospective study was conducted in two icus ( and beds, respectively) at ospedale policlinico san martino -irccs, a -bed teaching hospital in northern italy. from february th to april th , , all patients with covid- admitted to the participating icus for > h were included in the study. the predefined primary study objectives were: (i) to assess the incidence rate of icu-acquired bsi; (ii) to assess the cumulative risk of developing icu-acquired bsi. predefined secondary objectives were: (i) to describe the clinical characteristics of icu-acquired bsi; (ii) to assess predictors of icu-acquired bsi; (iii) to describe survival of icu-acquired bsi. the collection of anonymized data for the present study was approved by the ethics committee of the liguria region (registry number / ). specific informed consent was waived due to this article is protected by copyright. all rights reserved the retrospective nature of the study. reporting of the study conforms to broad equator guidelines . definitions covid- was defined in the presence of a positive real-time polymerase-chain-reaction (rt-pcr) for sars-cov- on at least one respiratory specimen (nasopharyngeal swab, sputum, and/or lower respiratory tract specimens). icu-acquired bsi was defined in presence of at least one positive blood culture for bacteria or fungi, drawn at > h after icu admission. for coagulase-negative staphylococci and other common skin contaminants, at least two consecutive blood cultures positive for the same pathogen were necessary to define bsi . in patients with multiple blood cultures positive for the same organism, novel bsi events were considered as independent if occurring at least days after the last previous positive blood culture. polymicrobial infections were considered as separate bsi events, one for each causative organism isolated from blood culture. the following data were collected from the patients' electronic medical records as baseline data at the time of icu admission: age in years; gender; hypertension; diabetes mellitus; respiratory disease (defined as asthma or chronic obstructive pulmonary disease); end-stage renal disease (defined as estimated glomerular filtration rate < ml/min/ . m ); moderate to severe liver disease (defined as compensated or decompensated liver cirrhosis); solid cancer; hematological malignancy; human immunodeficiency virus infection; sequential organ failure assessment (sofa) score at icu admission ; antibiotic therapy (yes/no and type of administered antibiotic/s). since they were constantly continued/started at icu admission, possible off-label antiinflammatory treatments for covid- (steroid treatment with intravenous methylprednisolone at mg/kg once daily and/or intravenous tocilizumab at mg/kg single administration or repeated once) were also recorded as dichotomic baseline variables (steroid yes/no; tocilizumab yes/no). the following data were collected related to the onset of bsi episodes (i.e., they were collected the day when the first positive blood culture was drawn): presence of fever this article is protected by copyright. all rights reserved (defined as temperature > . °c); requirement of vasoactive agents; presence of acute kidney injury (defined as at least stage of kdigo [kidney disease: improving global outcomes] classification of acute kidney injury ); source of bsi (defined according to cdc/nhsn criteria ); blood neutrophil count in cells^ - /mm ; blood platelet count in cells^ - /mm ; serum fibrinogen in g/l; serum lactate in mmol/l, serum c-reactive protein in mg/l; serum procalcitonin in ng/ml; causative agents of bsi and susceptibility test results (the vitek- automated system, biomérieux, marcy l'etoile, france, was used for isolate identification and antimicrobial susceptibility testing). finally, the date of the following was collected, whichever came first: death in the icu; discharge from the icu. no sample size calculations were performed a priori for this exploratory, descriptive study. the incidence rate of icu-acquired bsi in the study population was calculated as the number of events per patient-days at risk (defined as the cumulative days of stay elapsed from h after icu admission to death, discharge from icu, or end of study period, whichever came first). the % confidence interval (ci) for the incidence rate estimate was obtained using the mid-p exact test . the cumulative risk of icu-acquired bsi was calculated using the aalen-johansen method, considering the first occurring bsi as the event of interest, death and discharge from the icu as competing events, and length of icu stay equal to days or end of the study period ( apr ) as right- during the study period, patients with covid- admitted to icu for > h were included in the study. their median age was years (iqr - ), and % were males this article is protected by copyright. all rights reserved anti-inflammatory treatment as the reference group; overall p for the dummy variable = . ). in multivariable analysis, only anti-inflammatory treatment (cshr . with % ci . - . for tocilizumab, cshr . with % ci . - . for methylprednisolone, and cshr . with % ci . - . for methylprednisolone plus tocilizumab; overall p for the dummy variable = . ) retained an independent association with development of bsi. as shown in figure , the estimated survival of icu-acquired bsi was of almost % after days (no longer follow-up was available) from the first positive blood culture, although with the important limitation that follow-up after day was available for less than one third of patients at the time of this report. in the present study, we estimated an incidence rate of episodes of icu-acquired bsi per patient-days at risk in critically ill patients with covid- , which is higher than that of - episodes per patient-days registered in other heterogeneous, non-covid- icu populations (even if adjusting for the fact that we considered only patientdays after h from icu admission, see methods) , [ ] [ ] [ ] . it is also of note that our estimation of a cumulative -day risk of developing bsi of more than % is in contrast with the low prevalence of bsi or other bacterial/fungal infections ( - %) reported in other epidemiological reports from china and the us , , . in our opinion, this could be explained by different, non-mutually exclusive reasons. the first is that the number of patients under follow-up in the icu for more than days was limited in our analysis; thus, any generalization of our -day cumulative risk estimate should be made with due caution. on the other hand, the cumulative risk of almost % we estimated at day (based on a larger portion of patients still under follow-up) is already higher than the overall prevalence of bsi registered in critically ill covid- patients in earlier studies , , . in this regard, a possible explanation may be the difficulty of diagnosing bsi in patients receiving anti-inflammatory drugs , which prompted us to collect blood cultures in any case of worsening general conditions in covid- patients, even in the absence of fever and increases in c-reactive protein serum levels. in support of this approach, in the present study, for example, fever was detected only in % of patients with icu-acquired bsi previously treated with tocilizumab. furthermore, serum this article is protected by copyright. all rights reserved c-reactive protein levels were frequently low and other classical inflammatory markers were usually uncharacteristic, making it rather difficult to clinically recognize a bsi event. therefore, we feel the total number of bsi in covid- patients may be underestimated wherever anti-inflammatory drugs are administered but collection of blood cultures remains based on classical clinical and laboratory indicators of bsi. finally, and perhaps most importantly, we found an independent association between receipt of antiinflammatory agents and development of bsi. this effect seems to be mainly driven by steroids rather than tocilizumab, although it is worth noting that the highest instantaneous risk in cox models was registered in patients receiving both steroid and tocilizumab. in another different finding from previous reports is that we found a higher prevalence of gram-positive than gram-negative organisms as causative agents of icuacquired bsi in covid- patients . again, at least two different explanations may be considered. the first is that our sample of bsi events was larger than in previous reports, possibly depicting a more reliable estimate of the true distribution of the relative prevalence of the different causative agents. the second is that, borrowing from the observed microbiological epidemiology (higher prevalence of gram-positive organisms) in patients with severe influenza , and considering the frequent inability we had in rapidly differentiating between primary viral pneumonia and bacterial pulmonary superinfection in icu-admitted covid- patients, most covid- patients in our center were treated with an anti-methicillin-resistant s. aureus cephalosporin (most frequently ceftaroline, see table ) at icu-admission. however, while on the one hand this may be in line with the unusual high relative prevalence of enterococcal bsi (because of the impaired activity of ceftaroline against enterococcus spp., although possible in vitro activity against e. faecalis has been reported ), on the other hand it is also true that this article is protected by copyright. all rights reserved coagulase-negative staphylococci and s. aureus were the other two most prevalent causative agents of bsi in our cohort. from this standpoint, conversely, the true relative prevalence of gram-positive organisms could be even higher than registered in our cohort (because of the anti-staphylococcal and anti-pneumococcal activity of ceftaroline, that could have reduced the prevalence, absolute and relative, of staphylococci and pneumococci as causative agents of bsi). finally, although we apparently observed an improved survival of bsi in comparison with previous large studies conducted in non-covid- icu patients , it should be reminded that our sample size of bsi patients was limited (n = ) and that follow-up was very short. consequently, any related conclusion should be drawn cautiously. other important limitations of our study are its retrospective nature (mainly because of possible information and selection biases), its single-center nature that may impact generalization of results, and the lack of adequate power for exploring possible predictors of improved survival in covid- patients with icu-acquired bsi. in conclusion, in critically ill patients with covid- , the incidence rate of icu- hiv infection ( ) hospital stay before icu admission in days, median (iqr) ( - ) this article is protected by copyright. all rights reserved this article is protected by copyright. all rights reserved enterococcus faecium e ( ) ( ) ( ) ( ) ( ) viridans group streptococci ( ) ( ) ( ) ( ) ( ) pseudomonas aeruginosa g ( ) ( ) ( ) ( ) ( ) enterobacter aerogenes h ( ) ( ) ( ) ( ) ( ) escherichia coli h ( ) ( ) ( ) ( ) ( ) this article is protected by copyright. all rights reserved the novel chinese coronavirus ( -ncov) infections: challenges for fighting the storm clinical characteristics of covid- in new york city baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention covid- : focus on the lungs but do not forget the gastrointestinal tract incidence and outcome of invasive candidiasis in intensive care units (icus) in europe: results of the eucandicu project characteristics and determinants of outcome of hospital-acquired bloodstream infections in intensive care units: the eurobact international cohort study european centre for disease prevention and control (ecdc) a catalogue of reporting guidelines for health research how to discriminate contamination from bloodstream infection due to coagulase-negative staphylococci: a prospective study with patients the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine diagnosis, evaluation, and management of acute kidney injury: a kdigo summary (part ) cdc/nhsn surveillance definition of health careassociated infection and criteria for specific types of infections in the acute care setting epidemiologic analysis with a programmable calculator accepted article this article is protected by copyright. all rights reserved an empirical transition matrix for non-homogeneous markov chains based on censored observations nosocomial bloodstream infection and clinical sepsis population-based assessment of intensive care unit-acquired bloodstream infections in adults: incidence, risk factors, and associated mortality rate nosocomial bacteremia in a medical-surgical intensive care unit: epidemiologic characteristics and factors influencing mortality in episodes epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical features of patients infected with novel coronavirus in wuhan c reactive protein may not be reliable as a marker of severe bacterial infection in patients receiving tocilizumab common infections in patients prescribed systemic glucocorticoids in primary care: a population-based cohort study risk of infections in rheumatoid arthritis patients treated with tocilizumab risk of infectious complications in patients taking glucocorticosteroids balancing evidence and frontline experience in the early phases of the covid- pandemic: current position of the italian society of anti-infective key: cord- -njurbf d authors: romana ponziani, francesca; del zompo, fabio; nesci, antonio; santopaolo, francesco; ianiro, gianluca; pompili, maurizio; gasbarrini, antonio title: liver involvement is not associated with mortality: results from a large cohort of sars‐cov‐ positive patients date: - - journal: aliment pharmacol ther doi: . /apt. sha: doc_id: cord_uid: njurbf d background: severe acute respiratory syndrome coronavirus (sars‐cov‐ ) infection is frequently associated with liver tests abnormalities. aims: to describe the evolution of liver involvement during sars‐cov‐ infection and its effect on clinical course and mortality. methods: data of sars‐cov‐ positive patients were collected at baseline and during follow‐up, last evaluation or death. stratification based on need for hospitalization, severe disease and admission to intensive care unit (icu) was performed. the association between liver tests abnormalities (baseline and peak values) and icu admission or death was also explored. results: liver tests abnormalities were found in ( . %) patients. aspartate aminotransferase (ast), alanine aminotransferase (alt) and gamma glutamyl transferase (ggt) were increased in . %, % and . % of patients, respectively. baseline liver tests abnormalities were associated with increased risk of icu admission (or . [ %ci . ‐ . ], p= . ) but not with mortality (or . [ %ci . ‐ . ], p= . ). conversely, alp peak values were correlated with the risk of death (or . [ %ci . ‐ . ], p= . ) along with age, multiple comorbidities, acute respiratory distress syndrome (ards), icu admission, and c‐reactive protein. alterations of liver tests worsened within days after hospitalization; however, in patients with the longest median follow‐up, the prevalence of liver tests alterations decreased over time, returning similar to that of baseline. conclusions: in sars‐cov‐ positive patients without pre‐existing severe chronic liver disease, baseline liver tests abnormalities are associated with the risk of icu admission and tend to normalize over time. alp peak value seems to be predictive of a worse prognosis. on december , , chinese authorities reported a group of pneumonia cases in wuhan. a zoonotic infection was suspected, and a novel pathogenic human coronavirus (cov) with a certain homology with respect to severe acute respiratory syndrome (sars)-cov and middle east respiratory syndrome (mers)-cov was sequenced and identified as sars-cov- . the human-to-human transmission of sars-cov- was rapid, and due to the increase in the number of cases outside china, the world health organization (who) defined the infection as a pandemic on march , . italy was the second country to be hit after china, but spain, germany, france and other european countries, as well as the united states, are also facing the heavy consequences of this pandemic. during the past sars outbreak, hepatic impairment was described in up to % of patients ( ) , and was associated with elevation of serum transaminases, hypoproteinemia and prolongation of prothrombin time. chinese data on patients with sars-cov- infection report a prevalence of abnormal liver tests as high as . %, while the prevalence in western patients seems to be lower [ ] [ ] [ ] [ ] . however, these studies report baseline or short-term follow-up evaluations. therefore, the evolution of liver involvement, its correlation with patients' mortality or resolution of sars-cov- infection is still unknown. in this paper, we report the experience of a tertiary care center in italy facing the emergency of the sars-cov- infection, describing the prevalence and the evolution of liver involvement over time and its impact on patients' clinical course and mortality. all patients aged > years tested positive for sars-cov- infection at the fondazione policlinico universitario agostino gemelli irccs in rome from march th to april th , were included in this retrospective study. nasopharyngeal swabs for sars-cov- diagnostic testing were obtained according to the who guidelines and analyzed by the microbiology laboratory of our hospital (real-time pcr, this article is protected by copyright. all rights reserved allplextm -ncov assay [seegene] ). to exclude the infection or to confirm its resolution, two negative samples must be obtained at least h apart. according to the italian society for infectious and tropical diseases (simit) guidelines , patients were treated with antivirals (lopinavir/ritonavir or darunavir/ritonavir) plus hydroxychloroquine whereas the anti-interleukin (il- ) agent tocilizumab was used in selected patients. acute respiratory distress syndrome (ards) was defined as the ratio of arterial oxygen partial pressure (pao ) to fractional inspired oxygen (fio ) ≤ mmhg . to investigate the prevalence of liver damage in our cohort of patients, serum aspartate aminotransferase (ast) and alanine aminotransferase (alt), gamma glutamyl transferase (ggt), alkaline phosphatase (alp), total bilirubin and albumin were collected at baseline, then on the date closest to days from the admission. at the same timepoints, lactate dehydrogenase (ldh), c-reactive protein (crp), fibrinogen, d-dimer as inflammatory markers and international normalized ratio (inr), platelets (plts), white blood cells (wbc), neutrophils and lymphocytes counts were also recorded. in a subgroup of patients with a longer follow-up (> month), a third data timepoint was recorded at the last available evaluation. peak values of ast, alt, ggt, alp and bilirubin achieved during the hospitalization were recorded. history of liver disease and comorbidities were also assessed. the study was approved by the institutional ethics committee of the fondazione policlinico universitario agostino gemelli irccs in rome (id number: ) and was conducted according to the principles of the declaration of helsinki. patients' characteristics and laboratory examinations were reported as median and interquartile range (continuous variables) or as frequencies and percentages (categorical variables). baseline serum levels of liver function tests (i.e. ast, alt, ggt), which were the main object of our study, were also stratified according to cut-offs (>uln; >uln but up to x uln) for a better definition of possible alterations. missing data for each variable in the database accounted for < % except for ast ( . %). descriptive and inferential statistics were initially carried out on the overall population, then on three different subgroups identified on the basis of a) need for hospitalization b) severity of the this article is protected by copyright. all rights reserved disease c) admission to intensive care unit (icu the analyses were performed using r statistics program version . . . during the study period, patients tested positive for sars-cov- infection were admitted to the emergency department of our hospital and included in the following analysis ( four-hundred-forty-eight ( %) patients required hospitalization, and, among them, ( . %) presented with ards and ( %) required icu admission. overall, liver tests abnormalities were found in ( . %) patients. increase in ast, alt and ggt above uln was found in . %, % and . %, respectively; these alterations were mild/moderate (lower than x uln), and in only % of cases a more severe increase, above x uln, was observed. relevant alterations in alp or bilirubin serum levels were observed in a minority of patients ( table ). the prevalence of liver tests alteration was higher in patients with ards ( [ . %]) and in those requiring admission to icu ( [ . %]). ast or alt elevation was more frequent than ggt elevation, being present in up to % of those with ards and % of those admitted to icu. conversely, only . % of the patients who were not hospitalized presented liver involvement ( table ). the peak values of liver function tests occurred during hospitalization were the following: ast this article is protected by copyright. all rights reserved after a median follow-up of ( - ) days, ( %) of the hospitalized patients died, ( . %) were discharged and ( . %) were still hospitalized. liver tests alterations at baseline were associated with higher risk of icu admission ], p= . ; table ) but not with death (or . [ %ci . - . ], p= . ; table ). as shown in figure , the cumulative incidence of death or discharge was similar between patients with or without liver tests abnormalities at baseline. older age, the presence of multiple comorbidities, icu admission, high crp and alp peak values were, instead, associated with an increased risk of mortality in our multivariate regression model (table ) . we then analyzed the evolution of liver involvement during hospitalization. liver tests recorded within (± ) days after admission or at the last evaluation for patients who were discharged or died, showed a worsening trend in all groups (table ) this study demonstrates that in patients without severe chronic liver disease liver involvement during sars-cov- infection is usually mild, is not associated with increased risk of icu admission or mortality, and tends to resolve over time. we found a . % prevalence of liver tests abnormalities in patients with sars-cov- infection, which was slightly lower than that reported in previous western , or chinese series . pure cholestatic alterations characterized by the increase of both alp and ggt were extremely rare, whereas ggt elevation was present in . % of patients. noteworthy, all the recorded this article is protected by copyright. all rights reserved alterations were mild, did not require any intervention, except withdrawal of antiviral therapy in a single case. while previous studies mainly addressed liver tests abnormalities at baseline or few days after the admission , , this is the first analysis to include patients with a longer follow-up and to evaluate liver involvement at more than month after the admission. our study revealed that liver tests initially increase during hospitalization and then improve over time, finally reaching values similar to baseline or even lower, as shown in figure by the trend of the proportion of patients with liver tests abnormalities. this was to be expected in a population of patients affected by a viral disease, but the reasons for liver involvement in patients with sars-cov- infection can be multiple. the virus itself may probably exert a direct damage to the liver. post-mortem liver tissue this article is protected by copyright. all rights reserved whereas a parallel decrease in serum albumin is usually observed. although in our population the association between liver tests and indirect markers of inflammation was weak, we recently reported a strict correlation with serum levels of il- , with the highest increase recorded within days after patients' admission . probably, il- serum levels are more sensitive indicators of the persistence of the inflammatory response than non-specific inflammatory parameters. in our series, abnormal liver tests were correlated with icu admission, probably reflecting a more severe evolution of the disease, as previously reported . we also demonstrated that age, multiple comorbid conditions, ards, icu admission and crp serum levels, but not abnormal baseline liver tests, were associated with the risk of death. therefore, the presence of other negative prognostic factors is crucial to increase the risk of mortality during sars-cov- inflammatory syndrome, of which abnormal liver tests are a collateral manifestation. the prognostic significance of alp peak value should be underscored, as also other studies reported an association between clinical deterioration and increased alp serum levels, but not with other liver tests , . as previously discussed, sars-cov- cause cholangiocytes injury in experimental models ; alp peak value could be a marker of virus-related liver injury and, therefore, this event could be associated with an unfavorable prognosis. although this hypothesis is intriguing, multiorgan failure and drug-induced cholangiocellular damage could also explain the association between alp peak values and mortality. this study is one of the few large available series exploring the outcome of liver involvement during sars-cov- infection in western patients. although data were collected in a single center, being a guarantee of their homogeneity and of treatment approach, this study suffers of the generic limitations related to the retrospective collection of data. in particular, the prevalence of chronic liver disease was low in our series, but we cannot exclude that some patients (e.g. those with metabolic comorbidities) could be affected by liver disease. however, patients' records were accurately revised, and based on laboratory examinations, radiological findings and clinical data, we can reasonably rule out that patients with pre-existing advanced liver disease were included in the study group. therefore, our conclusions can only be applied to patients with sars-cov- infection without severe chronic liver disease or cirrhosis, for whom high morbidity and mortality have been reported , . in conclusion, sars-cov- infection is not associated with clinically-meaningful liver injury in western patients without advanced chronic liver disease. baseline liver tests abnormalities can be found in more than % of cases, especially in patients with ards; these alterations are associated with the risk of icu admission but not with mortality, and tend to normalize over time. alp could be a surrogate marker of virus-related liver injury and its peak value seems to be predictive of a worse prognosis. cai this article is protected by copyright. all rights reserved this article is protected by copyright. all rights reserved this article is protected by copyright. all rights reserved this article is protected by copyright. all rights reserved manifestations and prognosis of gastrointestinal and liver involvement in patients with covid- : a systematic review and meta-analysis liver biochemistries in hospitalized patients with covid- clinical characteristics and outcomes of covid- among patients with pre-existing liver disease in united states: a multi-center research network study ards=acute respiratory distress syndrome; ast=aspartate aminotransferase ggt=gamma glutamyl transferase; alp=alkaline phosphatase; wbc=white blood cells laboratory examinations reference range: ast - iu/l; alt - iu/l; ggt - iu/l; alp - iu/l; bilirubin . - . mg/dl crp < mg/l; fibrinogen - mg/dl; d-dimer < ng/ml. ) key: cord- - fvtj a authors: wendel garcia, pedro david; fumeaux, thierry; guerci, philippe; heuberger, dorothea monika; montomoli, jonathan; roche-campo, ferran; schuepbach, reto andreas; hilty, matthias peter title: prognostic factors associated with mortality risk and disease progression in critically ill patients with covid- in europe: initial report of the international risc- -icu prospective observational cohort date: - - journal: eclinicalmedicine doi: . /j.eclinm. . sha: doc_id: cord_uid: fvtj a background: coronavirus disease (covid- ) is associated with a high disease burden with % of confirmed cases progressing towards critical illness. nevertheless, the disease course and predictors of mortality in critically ill patients are poorly understood. methods: following the critical developments in icus in regions experiencing early inception of the pandemic, the european-based, international risk stratification in covid- patients in the intensive care unit (risc- -icu) registry was created to provide near real-time assessment of patients developing critical illness due to covid- . findings: as of april , , critically ill patients with confirmed sars-cov- infection were included in the risc- -icu registry. of these, had deceased or been discharged from the icu. icu-mortality was %, median length of stay (iqr, – ) days. ards was diagnosed in %, with a minimum p/f-ratio of (iqr, – ). prone positioning, ecco r, or ecmo were applied in %. off-label therapies were prescribed in ( %) patients, and % of all bloodstream infections were observed in this subgroup (n = ; rr= · , % ci [ · – · ]). while pct and il- levels remained similar in icu survivors and non-survivors throughout the icu stay (p = · , · ), crp, creatinine, troponin, d-dimer, lactate, neutrophil count, p/f-ratio diverged within the first seven days (p< · ). on a multivariable cox proportional-hazard regression model at admission, creatinine, d-dimer, lactate, potassium, p/f-ratio, alveolar-arterial gradient, and ischemic heart disease were independently associated with icu-mortality. interpretation: the european risc- -icu cohort demonstrates a moderate mortality of % in critically ill patients with covid- . despite high ards severity, mechanical ventilation incidence was low and associated with more rescue therapies. in contrast to risk factors in hospitalized patients reported in other studies, the main mortality predictors in these critically ill patients were markers of oxygenation deficit, renal and microvascular dysfunction, and coagulatory activation. elevated risk of bloodstream infections underscores the need to exercise caution with off-label therapies. in december , a cluster of atypical severe pneumonia was described in wuhan, china, associated with the huanan seafood wholesale market [ ] . the world health organization (who) named the novel virus associated with acute respiratory distress syndrome (ards) as severe acute respiratory syndrome coronavirus investigators are enumerated at the end of the manuscript page . (sars-cov- ), with the associated disease coronavirus disease [ ] . covid- is a symptomatically and asymptomatically transmissible disease, with a presumed incubation period of up to days. during the first months of , a rapid global increase in case numbers and deaths have made this pandemic one of the most critical global health emergencies in modern times [ ] . approximately % of confirmed cases progress to critical illness [ , ] with acute lung failure and, in some cases, multi-organ failure involving the heart, kidney, and gastrointestinal tract, with a high mortality rate [ ] . reported predisposing factors for severe disease include older age, chronic arterial hypertension, and established cardiovascular disease; an underlying virally-triggered endotheliitis has been postulated as a pathophysiological mechanism [ À ] . nevertheless, whilst epidemiological data on critically ill patients have been well described, the understanding of disease progression and indicators for mortality in critical ill patients remains scarce. following the critical spread of the disease in china, italy and spain, on march , the european-based risk stratification in covid- patients in the icu (risc- -icu) registry was launched to allow nearreal time assessment of the main clinical characteristics of critically ill patients during the emerging covid- pandemic. understanding patient characteristics associated with severe forms of covid- is crucial not only for triage and therapeutic selection in these critically ill patients, but also to generate hypotheses based on the pathophysiology of the disease and to support the design of further trials. in the present study, we report the baseline characteristics and status at icu admission of the first european patients with confirmed covid- included in the risc- -icu prospective cohort. disease progression through the initial seven days of intensive care unit (icu) stay and prognostic factors for icu mortality are presented for the patients that had completed their icu stay as of april , . this prospective observational cohort study is based on the data collected in the risc- -icu registry. the registry was deemed exempt from the need for additional ethics approval and patient informed consent by the ethics committee of the university of zurich (kek À , , clinicaltrials.gov identifier: nct ) . the study complies with the declaration of helsinki, the guidelines on good clinical practice (gcp-directive) issued by the european medicines agency as well as the swiss law and swiss regulatory authority requirements, and has been designed in accordance with the strengthening the reporting of observational studies in epidemiology (strobe) guidelines for observational studies [ ] . all collaborating centres have complied with local legal and ethical requirements. a standardized dataset was prospectively collected during the ongoing covid- pandemic for all critically ill covid- patients admitted to the collaborating centres. inclusion criteria for the risc- -icu registry were (i) a laboratory confirmed sars-cov- infection by nucleic acid amplification according to the who-issued testing guidelines [ ] , and (ii) severe manifestation of covid- requiring treatment in an icu or intermediate care unit, defined as a hospital ward specialized in the care of critically ill patients with the availability of organ support therapies including invasive mechanical ventilation and/or non-invasive ventilation. the data was collected through an anonymized electronic case report form managed by the redcap electronic data capture tool hosted on a secure server by the swiss society of intensive care medicine [ ] . the registry has been designed to support a collaborative approach to data analysis by permitting all collaborating centres to request an analysis of the full dataset after approval of a study protocol by the registry board. additionally, code for registry-specific data transformation and statistical analysis has been made available for collaborative development [ ] . as of april , , collaborating centres in countries were contributing to the risc- -icu registry. data were collected on the day of icu admission, and on days one, two, three, five and seven thereafter. data contained in the registry included patient characteristics, treatment modalities and organ support therapies, including the use of mechanical ventilation, prone positioning, vital parameters, arterial blood gas analyses, and laboratory values such as inflammatory, coagulation, renal, liver, cardiac, and other relevant parameters. missing values were accounted for but not imputed for the analysis (suppl. tables and ). ards was defined according to the berlin definition as acute, diffuse bilateral lung infiltrates of non-cardiac origin, characterized by hypoxemia with a pao /fio ratio (p/f ratio) mmhg under positive pressure respiratory support ( cmh o positive end-expiratory airway pressure or continuous positive airway pressure) [ ] . acute kidney injury was diagnosed in accordance with the kdigo criteria as either a serum creatinine increase to more than . x the baseline value, an absolute creatinine increase of . mmol/l, or a urine output of less than . ml/kg/h for À h [ ] . acute cardiac injury was defined according to the fourth universal definition of myocardial infarction, as an elevation in high sensitivity cardiac troponin levels above the th percentile, coupled to the existence of a dynamic change in said levels [ ] . bacteraemia and fungaemia were defined as positive blood cultures for a bacterial or fungal pathogen. for longitudinal analysis of clinical and laboratory parameters, differences between time points and outcome status were tested using linear mixed effects model analysis. as independent variable fixed effects, time point and outcome status were entered into the model, respectively, with and without interaction terms, which were evidence before this study we performed a pubmed search through april , with no date or language limitations using the keywords ("covid- or "sars-cov- ) and "cohort" and "characteristics". baseline characteristics of hospitalized patients were reported in regions such as china, northern italy or specific areas in the united states. two studies that applied multivariable modeling of risk factors for mortality and severe disease in hospitalized patients, respectively, were recently reported in china. we report results from a prospective european cohort of critically ill patients due to covid- . the data include the evaluation of clinical, physiological, and laboratory parameters collected on a daily basis, as well as intensive care unit mortality. our findings accurately characterize severe cases of covid- and identify predictors of mortality at the onset of critical illness. the in-depth characterization of critically ill covid- patients and predictors of treatment outcome presented here complement data from other cohorts to provide crucial information for decision-making during this exceptional public health crisis. retained only if they were found to contribute to the model. as random effects, intercepts for subjects as well as per-subject random slopes for the effect on dependent variables were employed. p values were calculated using a likelihood ratio test of the full model with the effect in question against a "null model" without the effect in question. p values for individual fixed effects were obtained by satterthwaite approximation in a multi-dimensional model comprising time point and outcome status. in patients that have died in the icu or were discharged from the icu, the prognostic value to dichotomize icu survival according to the study variables was analysed using univariable and multivariable cox proportional hazard models; non-normally distributed variables were logarithmically transformed. multivariable analysis was performed by means of an iterative, stepwise, maximum likelihood optimizing algorithm initiated with the seven most significant variables in the univariable analysis, and considering all variables with p< ¢ on the univariable analysis, for the final model. effects of sample size reduction on hazard ratios due to missing values were considered by comparison of the final model to a model excluding the respective variable. censoring was applied to icu survivors at the time of discharge to account for the possibility of an unfavorable outcome during the further hospitalization. receiver operating characteristics (roc) analysis was employed alongside minimal euclidean distance fitting to the ( , ) point to determine the optimal cut-off values for variables included in the final model. icu survival functions were generated by implementing the kaplan-meier estimator. comparisons of population characteristics were performed using paired student's t-test or wilcoxon signed rank test, as appropriate, and the chi-squared test for categorical variables. due to the observational, prospective nature of this cohort study during the ongoing health crisis, no power calculations were performed. statistical analysis was performed through a fully scripted data management pathway using the r environment for statistical computing version ¢ ¢ [ ] . a two-sided p< ¢ was considered statistically significant. values are given as median with interquartile ranges or counts and percentages as appropriate. any intensive care unit or other center treating critically ill covid- patients is invited to join the risc- -icu registry at https://www.risc- -icu.net. while the registry protocol prevents the deposition of the full registry dataset in a third-party repository, analyses on the full dataset may be requested by any collaborating center after approval of the study protocol by the registry board. reproducibility of the results in the present study was ensured by providing code for registry-specific data transformation and statistical analysis for collaborative development on the github and zenodo repositories [ ] . the registry protocol and data dictionary is publicly accessible at https://www.risc- -icu.net. the funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. as of april , , a total of critically ill patients with covid- admitted to european collaborating centres had been included in the risc- -icu registry. the patients were [ À ] years old, predominantly male ( ¢ %), and ( ¢ %) had one or more comorbidities ( table ). the first symptoms of sars-cov- infection were noted [ À ] days before hospital admission, and the patients were hospitalized [ À ] days before admission to the icu. at icu admission, ( ¢ %) patients were intubated and ( ¢ %) met ards diagnosis criteria, with a p/f ratio of [ À ] mmhg and inspiratory oxygen fraction of [ À ]% ( table ) . as of april , , patients had been discharged from and had died in the icu, resulting in an icu mortality of ¢ %; icu length of stay was [ À ] days (table ). in ( ¢ %) of all non-survivors, death was secondary to a failure to stabilize acute organ dysfunction, while life support was withdrawn in non-survivors. the mortality rate in ards patients was % and not correlated to initial disease severity. population characteristics (table ) , organ function, and laboratory values at icu admission ( table ) were stratified by icu mortality. of the patients discharged from the icu or who died, ( ¢ %) patients were mechanically ventilated ( table ). the mortality rate in these patients was %. there was no difference in mortality between patients intubated upon icu admission versus those intubated at a later stage (suppl. figure ). ards was diagnosed in ( ¢ %) patients, with ( ¢ %) presenting severe ards. the lowest median p/f ratio in the cohort was [ À ] mmhg during the initial seven days of icu treatment (table ). prone positioning was applied in ( ¢ %) patients at least once during the icu stay, further ( ¢ %) and ( ¢ %) patients underwent ecco r and ecmo therapy, respectively. vasopressors were prescribed in ( ¢ %) patients during their icu stay. acute circulatory failure occurred in ( ¢ %) patients, resulting in death in % of cases. a total of ( ¢ %) and ( ¢ %) patients suffered acute kidney and acute cardiac injury, respectively; ( ¢ %) required renal replacement therapy. ( ¢ %) of the patients with acute circulatory failure suffered acute cardiac injury, of which died and one of them received ecmo therapy. regarding co-infections, ( ¢ %) patients had positive blood cultures for bacteria and eight patients developed fungaemia. in ( ¢ %) patients, off-label and compassionate use therapies against covid- were prescribed, and ( ¢ %) of these patients received a combination of more than one treatment, with hydroxychloroquine and ritonavir/lopinavir being the most frequent ( ( ¢ %) and ( ¢ %) patients). notably, all but ten ( ¢ %) patients with bloodstream infections with bacteria or fungi were undergoing treatment with off-label therapies, representing a risk ratio (rr) of ¢ with a % confidence interval (ci) of ¢ À ¢ (p < ¢ ). corticosteroid and tocilizumab administration was associated with bloodstream infection in ( ¢ %; rr = ¢ , % ci [ ¢ À ¢ ], p < ¢ ), and hydroxychloroquine in ( ¢ %; rr = ¢ , % ci [ ¢ À ¢ ], p = ¢ ) cases, seven of which were fungaemias. levels of interleukin- (il- ), c-reactive protein (crp), procalcitonin (pct) levels and white blood cell (wbc) count increased over time, peaking between days two and three ( fig. a -b, suppl. table ). in icu non-survivors, the wbc count was persistently higher during the first seven days of icu stay (p< ¢ ). no difference in initial il- (p = ¢ ) and crp (p = ¢ ) levels was observed; however, icu non-survivors were characterized by rising crp dynamics after icu admission (p< ¢ ). the neutrophil to lymphocyte ratio was persistently higher in icu non-survivors (p< ¢ , fig. a , suppl. table ). platelet count increased in all patients, with icu survivors presenting consistently higher counts during the first seven days (p< ¢ , fig. a , suppl. table ). d-dimer (p = ¢ ) and lactate dehydrogenase (ldh) (p< ¢ ) levels remained elevated in patients with unfavorable outcome (fig. a , d, suppl. table ). overall organ dysfunction assessed with the sequential organ failure assessment (sofa) score, albeit initially comparable in icu non-survivors and survivors, diverged after day one and remained consistently worse in icu nonsurvivors (p< ¢ ) (fig. e , suppl. table ). the course of arterial lactate levels (p< ¢ ) and ph (p< ¢ ) further distinctly differentiated patients between non-survivors and survivors (fig. d , c, suppl. table ). pulmonary function, as measured by the p/f ratio (p< ¢ ) and the alveolar-arterial gradient (p< ¢ ), improved within the first week in icu survivors as opposed to non-survivors (fig. c , suppl. table ). troponin t was substantially elevated in icu non-survivors (p = ¢ ). creatinine levels remained consistently elevated (p< ¢ ) and diverged between icu survivors and non-survivors after the third day (p< ¢ , fig. d , e, suppl. table ). in a univariable cox regression model, crude hazard ratios (hr) for parameters were associated with an unfavorable icu outcome (suppl. figure ) . on the multivariable cox proportional hazard regression model the following parameters at admission were independently associated with icu mortality: creatinine, d-dimer, lactate, and potassium levels, p/f ratio and alveolar-arterial gradient, and history of ischemic heart disease ( fig. a) . the inclusion of d-dimer levels into the cox proportional hazards regression model, albeit reducing final model sample size due to missing values (suppl. table ), resulted in hazard ratios similar to the higher sample size model without d-dimers. kaplan-meier survival analysis for all seven parameters demonstrated a distinction between icu survivors and non-survivors for all multivariable independent predictors using the cut-off values resulting from roc analyses (fig. b, suppl. figure ). this prospective, european cohort study provides an initial description of the baseline characteristics, treatments, and outcome of critically ill critically ill covid- patients included in the risc- -icu registry during the peak of the covid- pandemic in early , constituting a near real-time view of a large international cohort. icu admission and treatment data point to a systemic disease characterized by a cytokine and cellular-driven inflammatory and coagulation activation, severe pulmonary oxygenation deficit, and in approximately % of cases progression to multi-organ failure and death. univariable and multivariable cox proportional hazards regression modeling identified several prognostic markers for icu mortality, most notably markers of oxygenation deficit, renal and microvascular dysfunction, and coagulatory activation. in the present study, the demographics and baseline characteristics of patients who became critically ill due to covid- were predominantly male, middle-aged, and with comorbidities. these findings are in concordance with previous case series, most of which had a predominantly regional or national focus [ , , , , ] . the degree of ards severity observed in the present cohort was higher than that reported in other critically ill covid- populations to date [ , , , ] . nevertheless, the incidence of mechanical ventilation in our cohort was lower than that reported in case series from northern italy and the united states [ , ] . by contrast, a considerably higher proportion of patients in our cohort received rescue therapies including prone positioning, inhaled nitric oxide and extracorporeal decarboxylation and oxygenation. these differences may reflect the large variability in therapeutic approaches applied in our cohort related to the international scope of this study. given the relatively low mortality rate in our compared to other reports [ , , , , , ] , together with the lack of clear evidence regarding the optimal respiratory management of critically ill covid- patients, our findings suggest that a wide range of therapeutic approaches-which reflect the particular expertise of the participating hospitals-could be successful strategies in treating critically ill covid- patients. in icu non- organ function apache ii score [ - ] [ - ] [ - ] < saps ii score [ - ] [ - ] [ - ] [ - ] [ - ] ¢ values are given as median [iqr] or count (percent) as appropriate. apache ii, acute physiology and chronic health evaluation ii; saps ii, simplified acute physiology score ii; sofa, sequential organ failure assessment; ards, acute respiratory distress syndrome; niv, non-invasive ventilation; fio , fraction of inspired o ; p/f ratio, pao / fio ratio; a-a gradient, alveolo-arterial gradient; pao , partial pressure of arterial o ; paco , partial pressure of arterial co ; crp, c-reactive protein, pct, procalcitonin; ldh, lactate dehydrogenase; ck, creatine kinase. survivors, the extent of forgoing of life-supporting therapies was found to be similar in this cohort of critically ill covid- patients as previously described in european icus in a non-pandemic setting [ ] . the use of off-label and compassionate use therapies, as well as the combination of multiple empirical drugs, was common in the present cohort, a finding that is consistent with other case series [ , , , ] . as evidenced in recent publications, many of these therapies were initially hypothesized to be effective [ , ] and broadly adopted, but subsequently failed to show clear evidence of effectiveness [ , ] . in this regard, our findings add to previous concerns regarding off-label medication, particularly immunosuppressive therapies [ ] . the high incidence of bloodstream infections in patients treated with off-label therapies in the present cohort, especially those who received corticosteroids and il- anti-body therapies, underscore the who recommendation to limit the use of empirical therapies to the controlled setting of clinical trials [ ] . recently, it has been postulated that multiple parameters may have potential prognostic capacity to discern unfavorable outcomes in general populations of hospitalized covid- patients [ , , , ] . the multivariable cox proportional hazards regression model applied in the present comparatively large, international patient cohort identified several independent predictors of mortality in critically ill covid- patients. while markers of coagulation activation and microvascular dysfunction such as d-dimer and lactate levels, together with markers of renal dysfunction, were positively associated with icu mortality, an inverse association was found for the p/f ratio as a measure of oxygenation deficit. these findings support previous observations of the presence of severe inflammatory reaction [ ] and endothelial dysfunction [ ] in these patients, thereby providing a plausible pathophysiological correlate to the severely decreased p/f ratio due to alveolar fluid accumulation. this would explain the initially highly compliant lungs with severely impaired gas diffusion that is pathognomonic for this disease. [ , ] the persistent inflammatory activation and increased recruitment of neutrophils and nonresolving lymphopenia observed in our study-mainly in non- [ - ] [ - ] [ - ] ¢ values are given as median [iqr] or count (percent) as appropriate. niv, non-invasive ventilation; p/f ratio, pao / fio ratio; ards, acute respiratory distress syndrome; ecmo, extracorporeal membrane oxygenation; igg, immunoglobulin g; icu, intensive care unit. * ( ¢ %) and ( ¢ %) of all bacterial and fungal bloodstream infections developed in patients with off-label therapies. survivors-could explain the transition in certain patients to the classic non-compliant ards phenotype later in the course of disease, as previously suggested [ ] . even though the systemic pro-inflammatory state observed in the present cohort confirms previous data [ , , ] , our findings suggest that il- and pct levels may be less prognostic than previously proposed [ , , ] . in the present study, our focus on severe cases for which outcome data were available for a high proportion of patients, facilitates the systematic investigation of pathophysiologic processes. by contrast, most previous reports have assessed general hospitalized patient populations with only limited outcome data [ , ] . ischemic heart disease was the sole predisposing condition assessed in this study that retained an association with icu mortality on multivariable analysis. similar d-dimer levels were found in critically ill patients with or without this predisposing condition, presenting no obvious link to coagulatory activation. ischemic heart disease has been described in previous studies involving general hospitalized cohorts, including non-critically ill patients [ , ] , where other conditions such as chronic arterial hypertension, diabetes mellitus, age, and body mass index were also implicated. prognostic analyses that conjointly model non-critically and critically ill patients to infer hospital mortality without adjusting for disease severity are ultimately at risk of selection bias. the risc- -icu registry provides the prerequisites for the development of risk scores in critically ill patients, and due to its collaborative nature the data presented here could be combined with databases of similar scope for joint data analysis. the limitations of the present study pertain mainly to the prospective data collection, which was performed in highly variable settings at different collaborating centres at the peak of an unprecedented public health crisis. while missing values due to local differences in laboratory capability or resource availability were present and could potentially have led to effect over-or underestimation, efforts were made to mitigate this variability by rigorous monitoring of data quality and the use of linear mixed model analysis for the descriptive analysis. further, lead-time bias was moderated by alignment of the data collection time points to the onset of critical disease status. survival analysis during an ongoing crisis is associated with a potential survivorship bias in favor of patients with a short icu length of stay with potentially more severe cases still residing in the icu. however, by including into the outcome analysis only patients that had already been discharged from the icu, censoring of the patients that were discharged from the icu alive could be applied in the cox proportional hazards model to account for the possibility of an unfavorable outcome during the further hospitalization and thus reduce kaplan-meier analysis of six of the defining model components (creatinine, d-dimer, lactate and potassium levels, the p/f ratio and ischemic heart disease) demonstrate their effect on icu mortality over time; patients discharged alive from the icu are noted as censored (b). the potential for additional bias. while hospital outcomes and followup assessments may be analysed in a future retrospective analysis, the present study is capable of providing insight during the ongoing pandemic. finally, due to the international study design, the resources, policies and therapeutic approaches utilized in the participating centres and countries presumably were highly heterogeneous, which should be considered when interpreting the results presented here. correction for clustering was not implemented into the statistical models to prevent an increased risk of type ii error in light of the reduced number of patients admitted to certain centres at the time point of analysis as previously described [ ] . this heterogeneity, however, could provide the basis to perform regional or resourcecentered subgroup analyses in the future. in conclusion, the european risc- -icu cohort demonstrates a moderate icu mortality of % in critically ill patients with covid- . despite a high degree of ards severity, the incidence of mechanical ventilation was low and associated with a higher proportion of rescue therapies, which included prone positioning, inhaled nitric oxide and extracorporeal decarboxylation and oxygenation therapies. in contrast to previously reported risk factors for mortality in hospitalized covid- patients, our findings suggest that only creatinine, d-dimer, lactate, potassium, p/f ratio and alveolar-arterial gradient at admission and ischemic heart disease are predictors of mortality in critically ill patients with covid- . the elevated risk of bloodstream infections associated with empirical therapies, especially corticosteroids and tocilizumab, underscores the need to exercise caution with the use of off-label therapies. pdwg, ras, tf, jm, pg, and mph conceived, designed and supervised the registry and this study. pdwg, dmh, frc, and mph acquired and interpreted the clinical data. pdwg and mph processed statistical data. pdwg and mph drafted the manuscript. pdwg, ras, tf, dmh, jm, pg, frc, and mph critically revised the manuscript for important intellectual content. pdwg and mph had full access to the study data and take full responsibility for the integrity and the accuracy of the data analysis. pdwg had full responsibility for the decision to submit the manuscript for publication in eclinicalmedicine. the authors declare no conflicts of interest regarding the present study. austria: department for anesthesiology and intensive care czech republic: klinika anesteziologie perioperacni a intenzivni mediciny france: scpare-intensive care unit germany: department of medicine iii -interdisciplinary medical intensive care hungary: department of anaesthesia and intensive care anesthesia and intensive care, azienda ospedaliero-universitaria di ferrara md); division of anesthesia and intensive care md); department of anesthesiology and intensive care medicine, fondazione policlinico universitario agostino gemelli irccs, rome (maria grazia bocci, md; massimo antonelli, md); department of anesthesia and intensive care medicine, policlinico san marco, zingonia (emanuele rezoagli, md, phd; giovanni vitale, md) medical intensive care unit, hospital clinic de barcelona acute critical cardiac care unit, hospital clinic de barcelona surgery critical care unit, hospital clinic de barcelona liver intensive care unit respiratory intensive care unit, hospital clinic de barcelona hospital verge de la cinta switzerland: klinik für operative intensivmedizin md); department of intensive care medicine division of neonatal and pediatric intensive care, university hospitals of geneva groupement hospitalier de l'ouest lémanique intensivmedizin & intermediate care paediatric intensive care unit, children's hospital of eastern switzerland departement for intensive care medicine spitalzentrum oberwallis united kingdom: harefield hospital a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster the species severe acute respiratory syndrome-related coronavirus: classifying -ncov and naming it sars-cov- coronavirus disease (covid- ): situation report clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study clinical features of patients infected with novel coronavirus in wuhan, china endothelial cell infection and endotheliitis in covid- baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the the strengthening the reporting of observational studies in epidemiology (strobe) statement: guidelines for reporting observational studies laboratory testing for coronavirus disease (covid- ) in suspected human cases: interim guidance, march . world health organization research electronic data capture (redcap)-a metadata-driven methodology and workflow process for providing translational research informatics support hobbes /risc- -icu: registry data transformation v . .. zenodo data repository acute respiratory distress syndrome kdigo clinical practice guideline for acute kidney injury fourth universal definition of myocardial infarction a language and environment for statistical computing clinical characteristics of deceased patients with coronavirus disease : retrospective study characteristics and outcomes of critically ill patients with covid- in washington state clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study end-of-life practices in european intensive care unitsthe ethicus study epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study therapeutic options for the novel coronavirus ( -ncov) remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus ( -ncov) in vitro a trial of lopinavirÀritonavir in adults hospitalized with severe covid- compassionate use of remdesivir for patients with severe covid- treating covid- -off-label drug use, compassionate use, and randomized clinical trials during pandemics clinical management of severe acute respiratory infection (sari) when covid- disease is suspected: interim guidance clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china. intens care med covid- pneumonia: different respiratory treatments for different phenotypes covid- does not lead to a "typical" acute respiratory distress syndrome risk factors of fatal outcome in hospitalized subjects with coronavirus disease from a nationwide analysis in china a tool to early predict severe corona virus disease (covid- ): a multicenter study using the risk nomogram in wuhan and guangdong, china the effect of number of clusters and cluster size on statistical power and type i error rates when testing random effects variance components in multilevel linear and logistic regression models this work is funded and endorsed by the swiss society of intensive care medicine and funded by the institute of intensive care medicine at the university hospital of zurich with an unrestricted research grant. we thank medical writer bradley londres for editorial assistance with this manuscript. finally, we want to thank all physicians and nurses in our collaborating centers for their tireless and brave efforts in patient treatment and care, without you this health care emergency could not be contained. for manuel. supplementary material associated with this article can be found in the online version at doi: . /j.eclinm. . . key: cord- - m ygzn authors: chen, yin-yin; chen, liang-yu; lin, seng-yi; chou, pesus; liao, shu-yuan; wang, fu-der title: surveillance on secular trends of incidence and mortality for device–associated infection in the intensive care unit setting at a tertiary medical center in taiwan, – : a retrospective observational study date: - - journal: bmc infect dis doi: . / - - - sha: doc_id: cord_uid: m ygzn background: device–associated infection (dai) plays an important part in nosocomial infection. active surveillance and infection control are needed to disclose the specific situation in each hospital and to cope with this problem effectively. we examined the rates of dai by antimicrobial-resistant pathogens, and –day and in–hospital mortality in the intensive care unit (icu). methods: prospective surveillance was conducted in a mixed medical and surgical icu at a major teaching hospital from through . trend analysis was performed and logistic regression was used to assess prognostic factors of mortality. results: the overall rate of dais was . episodes per device–days. the most common dai type was catheter–associated urinary tract infection ( . per urinary catheter–days). there was a decrease in dai rates in and rates of ventilator–associated pneumonia (vap, . per ventilator–days) have remained low since then (p < . ). the crude rates of –day ( . %) and in–hospital ( . %) mortality, as well as infection by antibiotic-resistant vap pathogens also decreased. the most common antimicrobial-resistant pathogens were methicillin–resistant staphylococcus aureus ( . %) and imipenem–resistant acinetobacter baumannii (p < . ), which also increased at the most rapid rate. the rate of antimicrobial resistance among enterobacteriaceae also increased significantly (p < . ). after controlling for potentially confounding factors, the dai was an independent prognostic factor for both –day mortality (or . , % confidence interval [ci] . – . , p = . ) and in–hospital mortality (or . , % ci . – . , p < . ). conclusions: the decrease in the rate of dai and infection by resistant bacteria on the impact of severe acute respiratory syndrome can be attributed to active infection control and improved adherence after . surveillance of nosocomial infections (nis) has become an integral part of infection control and quality assurance in many countries. gastmeier et al. reported that effective surveillance could reduce the ni rate on average about - % [ , ] . surveillance programs provide data on the microbes causing specific nis and their resistance to antibiotics. moreover, such programs can guide clinical practices and ni prevention efforts in different geographic regions and clinical settings. the surveillance of device-associated infections (dais) in intensive care units (icus) has become more important owing to the more frequent employment of invasive advanced life support devices, especially after the introduction in of surviving sepsis bundles [ , ] . nevertheless, according to the three largest surveillance systems, the pooled mean rates of dais were: ventilator-associated pneumonia (vap), . - . per ventilator-days; central line-associated bloodstream infection (clabsi), . - . per catheterdays; and catheter-associated urinary tract infection (cauti), . - . per catheter-days [ ] [ ] [ ] . in addition, dais have been associated with significant cost and mortality [ , , ] . the crude mortality rates of icu patients with dai were . - . % [ ] . moreover, as indicated by the message "bad bugs, no drugs" released by the infectious disease society of america in , the emergence of antibiotic resistance threatens to exacerbate the problem of nis in critically ill patients. decreased susceptibility of both gram-positive and gram-negative microbes to antibiotics has been well described in several surveillance studies over the past decade, and increases in the rate of bloodstream infection caused by multi-drug resistant (mdr) gramnegative bacteria have been reported to be -fold [ , [ ] [ ] [ ] [ ] . in addition, both the morbidity and mortality rates have increased [ ] [ ] [ ] . in this study, prospective surveillance was conducted to determine the dai rate and prevalence of antibiotic-resistant isolates at an adult medical-surgical icu (ms icu). our aim was to analyze the secular trend of incidence for different types of dais, determine the common pathogens involved, and determine the rates of antimicrobial resistance and overall -day and in-hospital mortality during the period - . this study was conducted in a -bed adult medicalsurgical icu with more than admissions (age years or older) per year located in a -bed major teaching hospital in the northern part of taiwan. the hospital-wide infection surveillance and control program was established in , with one infection control practitioner (icp) for every beds. all patients admitted to the icu in the period - who developed infections more than hours after admission (i.e., nosocomial infections) were eligible for the study. the protocol of this study was approved by the institutional review board of our teaching hospital. this icu-based surveillance was conducted according to the us centers for disease control and prevention (cdc) procedures. all patients in the unit were monitored for nis that affected particular body sites. infections at more than one site in the same patient were counted as separate infections. the antibiotic susceptibility of each pathogen involved was analyzed. the data were prospectively collected at least once a week in the icu by trained icps according to standardized protocols and definitions of the us cdc national healthcare safety network (nhsn; formerly the national nosocomial infection surveillance system [nnis]) [ ] . all dais of the outcome surveillance component were categorized using standard us cdc nhsn definitions that included laboratory and clinical criteria [ ] . the involved patient demographic information, the dates and sites of infection, device-utilization (du) ratio, pathogens, antimicrobial susceptibilities, invasive procedures, and overall -day mortality and in-hospital crude mortality were recorded. reports of cases of dai were also verified by an infectious disease specialist. data were also collected for each exposed patient in the icu from the prospective hospital database, including demographics and clinical characteristics. pneumonia was defined when a patient had a new or progressive infiltrate, consolidation, cavitation, or pleural effusion on chest radiograph and had the following signs or symptoms: new onset of purulent sputum or change in character of sputum. a vap was categorized as ventilator associated if the patient had been intubated and received ventilation for more than hours prior to the development of pneumonia. to detect vap microorganisms, tracheal aspirates obtained via endotracheal tube suction or tracheostomy tube suction methods were cultured. laboratory-confirmed bloodstream infection (bsi) was defined when a patient had a recognized pathogen cultured from one or more blood cultures and the microorganism cultured from blood was not related to an infection at another site. common skin contaminants (e.g., coagulase-negative staphylococcus [cons]) required culture from two or more blood cultures drawn on separate occasions or at least one blood culture for a patient with intravascular devices and microorganisms of the tip culture identical to those of the blood culture. a clabsi was considered central catheter-associated if a catheter had been in place for more than hours and a secondary site of infection was not present. to detect clabsi micro-organisms, a central catheter were removed aseptically and a -cm segment from the most distal end of the tip of the catheter along with paired peripheral blood samples were cultured. central catheter-tip colonization was defined as isolation of colony-forming units from a central catheter tip by using the roll-plate semiquantitative maki's culture technique. symptomatic uti was defined when a patient had one or more of the following signs or symptoms with no other recognized cause: fever (> °c), dysuria, urgency, frequency, or suprapubic tenderness and ( ) the patient had a positive urine culture, that is, ≥ microorganisms per cm , or urine with no more than two species of microorganisms, or ( ) pyuria (urine specimen with ≥ white blood cells /mm and a positive urine culture of ≥ and < cfu/ml with no more than species of microorganisms. a cauti was a symptomatic uti that occurred in a patient who had an indwelling urinary catheter in place within the hour period before the onset of the uti. to detect cauti organisms, a urine sample was aseptically aspirated from the sampling port of a urinary catheter and cultured quantitatively. pathogens were isolated from blood cultures using the bactec w nr- system (becton dickinson diagnostic instrument systems, spark, md, usa) between and and using the bact/alert d system (bio-mérieux, inc., marcy l'Étoile, france) between and . pathogens were isolated from other specimens using standard methods specified by the clinical laboratory standard institute (clsi) [ ] . antibiotic susceptibilities were determined using disk diffusion tests and interpreted according to the criteria specified by the clsi . the ni rate was defined as the number of nis per , patient-days. patient days were calculated as the number of icu days of the non-ni cohort or the number of icu days after the onset of ni. device-associated infection rates were calculated as the number of deviceassociated infections for a specified body site per , device days. the du ratio was calculated as the number of device-days per number of patient-days. secular trends of du ratio, antimicrobial resistant rates, -day mortality and in-hospital mortality rates were analyzed by chi-square test for linear trend. the overall and site-specific dai rates were analyzed by poisson regression analysis. logistic regression with a stepwise forward approach was used to assess prognostic factors of mortality, while controlling for potentially confounding variables (i.e., demographics, invasive devices, and laboratory data) [ ] . odds ratios (or) and % confidence intervals (ci) were calculated. a p-value < . was defined as statistically significant. statistical analysis was conducted using epi info tm version . . released by us cdc. graphs of secular trends, -day mortality and inhospital mortality rates were created using sigma-plot version . (systat inc., san jose, ca, usa). during the study period, , patient-days and , device-days were evaluated, and , nis and dais occurred in , patients admitted to ms icus with a mean apache ii score of . ± . . the crude mortality rate was . % during the study period. those patients who were admitted to ms icus had a mean age of . ± . years, and male gender accounted for . %. the length of icu stay was . ± . days in average. most patients were admitted due to major medical conditions ( %), such as neoplasms ( . %), digestive system problems ( . %), and respiratory system problems ( . %). patients with serum albumin < . g/dl were . % and blood creatinine > . mg/dl were . %. there were . % patients undergoing hemodialysis during their icu stay. the overall rates of nis and dais were . episodes per patient-days and . episodes per device-days, respectively. the most common dai type was cauti (mean figure ) . a total of , pathogens were isolated from clinical specimens ( table ) . acinetobacter baumannii ( %), pseudomonas aeruginosa ( . %), and staphylococcus aureus ( . %) were the three most common pathogens associated with vap, while s. aureus ( . %), a. baumannii ( . %), and candida albicans ( . %) accounted for the majority of clabsis. in contrast, non-albicans candida (nac) spp. ( %) rather than bacteria were the most common cauti pathogens, followed by enterococci ( . %) and escherichia coli ( . %). the rate of antibiotic resistance every year is presented in table (figures and ) . dai was an independent factor for -day mortality (or . , % ci . - . , p = . ) and in-hospital mortality (or . , % ci . - . , p < . ) by multiple regression analysis. other significant prognostic factors (p < . ) for mortality included apache ii score, service, length of stay after the onset of infection, serum albumin, blood creatinine, neoplasms and hemodialysis (table ). the mean rates of ni and dai in our adult ms icu during the study period were much lower than those reported by the inicc as well as for icus in developing countries [ ] , were similar to those reported by , hospitals in the us through the cdc nhsn [ , ] , and were slightly higher than those indicated by icus in the german surveillance system (icu-kiss) [ ] . reasons for these high dai rates in the inicc report and developing countries may include resource limitations, lack of legal enforcement of the infection control program, and poor adherence to infection control guidelines [ ] . the prospective hospital-wide surveillance and infection control program has been established for nearly years in our hospital, which made a great effort to control infection by implementing infection control bundles and educational programs. the increase of device-related infections is not obvious after , except for cauti. these strategies showed effectiveness in controlling dai rates and suggest the necessity of infection control bundles implementation. the common device-associated pathogens show geographic variation in distribution. a. baumannii, s. aureus, and p. aeruginosa were the three most common vap pathogens in our study, the us cdc nhsn study, and the sentry antimicrobial surveillance study, although their percentages differed between studies [ , ] . the percentage of isolates of mrsa (p = . ) and irpa (p = . ), but not isolates of irab (p < . ) remained relatively constant. however, any variation in these percentages would not be statistically significant and might rather be due to chance than to an actual variation. in contrast, higher rates of a. baumannii and c. albicans isolation compensated for the relatively low rates of cons and enterococcus spp. isolation in cases of clabsi, while c. albicans was replaced by nac spp in cases of cauti. differences in clinical setting, institution, study period, target population, and specific infection type might account in part for differences between studies. cons was less frequently identified in clabsi, because our criteria were slightly different from the us cdc definition for laboratory-confirmed bsi. the cdc defined skin contaminant bsi in and as 'the common skin contaminant (e.g., cons) is cultured from at least one blood culture from a patient with an intravascular line, and the physician institutes appropriate antimicrobial therapy'. however, cons bsis in our study were enrolled if the patient had only one blood culture of cons that was positive but then microorganisms cultured from the tip of the intravascular device that were also cons. the percentage of cons isolates was expected to be at least that of s. aureus isolates reported in previous studies [ , , , ] . however, the frequency of a. baumannii and candida spp. in specimens from patients with clabsi was also reported to be increasing in other hospitals in taiwan as well as several asian countries such as turkey and thailand [ ] [ ] [ ] [ ] [ ] , although the frequency of nac spp. represented by only one candida spp. has also been rising in specimens from patients with cauti. early and empirical usage of broad spectrum antibacterial agents in critically ill patients and preemptive administration of fluconazole are common factors contributing to the increase in frequency of isolation of these relatively resistant pathogens [ , , ] . use of indwelling catheters increases susceptibility to those multi-drug resistant pathogens and is associated with biofilm formation [ , ] . the high prevalence of mrsa is a common problem worldwide, and this situation was much more severe in our institute. our data showed a lower incidence density of s. aureus but a higher proportion of mrsa. the percentage of mrsa infections was . - . % in the inicc report [ ] , . - . % in the us cdc nhsn report [ ] , and, in the asia-pacific region, it was . % in the sentry antimicrobial surveillance program report ( ) ( ) [ ] and - % in the tigecycline evaluation and surveillance trial (test) report [ ] . mrsa rates were decreasing in many european countries but not in usa [ , ] . the more severe illnesses of patients and more frequent use of broad-spectrum antibiotics might account in part for the high rate of mrsa isolation from patients in icu at major teaching hospitals [ , ] . another possible explanation is the clonal spread of resistance genes or resistant strains [ , ] , but molecular analysis will be needed to prove this hypothesis. according to the infection control policies in our icu, when a patient was admitted to the icu, a multi-drug resistant (mdr) checklist was used to inquire about mdr pathogens including mrsa infection or colonization. if mrsa had been isolated, then contact precautions were implemented. furthermore, we have promoted hospital-wide hand-washing activity from to the present. the infection control team also carries on the non-warning investigation of hand-washing and of isolation precautions in each season, and gives feedback of the results to the unit. infectious disease doctors assist in carrying on the infectious disease treatment and the antibiotic use in the icu. mrsa infection rates have been reduced by year from . interestingly, the rates of antibiotic resistance for pathogens other than mrsa was lower at our hospital than those in previously published reports and lower than those for all nis reported by the test and sentry antimicrobial surveillance programs [ , , , ] . however, despite the carbapenems being the most active antimicrobials against acinetobacter species, the increasing development of significant carbapenem resistance among acinetobacter species has been reported [ , , ] . in the present study, the average percentage of a. baumannii isolates resistant to imipenem was . %. the rate of icu patients with irab dai has been rapidly rising (from . % to . %). among enterobacteriaceae, ciprofloxacin-r e. coli and ceftazidime-r k. pneumoniae from , and ceftazidime-r e. coli from , had significant increases. this finding revealed that the resistance of gram-negative bacteria has increased, the development of which should require closely monitored. aside from the fact that dai is an important prognostic factor of mortality., several previous studies have shown that the mortality rate attributed to dai is . - . times higher than that attributed to no infection [ , , ] . our study supports the findings of these published reports. in the present study, the multiple regression analysis indicated that patients with dais (compared to patients with no hai) had significantly increased likelihood of mortality (p < . ). moreover, the annual -day mortality rates of cautis and clabsis had significant changes over the period through . these results may be caused by chance, because this study period did not change substantially in terms of medical care, novelty medical technology, and patient disease severity. in addition to the above-mentioned findings, we used a multiple regression analysis approach to adjust covariables, in addition to demographics, invasive devices, and laboratory investigations. we also identified severity of illness using apache ii scores as a predictor of mortality, with the results indicating that the hazard of mortality is associated with increasing scores. patients who died with dai infection were usually already severely ill and their existing illness, rather than the dai, was often the main cause of death. thus, an important prognostic factor was the severity of their illness, which resulted in an increased likelihood of mortality [ , ] . we also found that patients with blood creatinine over . mg/dl were the highest risk group for dying. excluding an endogenous effect, the reason may be that many patients in this group were receiving hemodialysis with cvcs inserted. the rates of dais of all types decreased during the period - , but this decrease was maintained [ ] [ ] [ ] . some limitations of the present study should be noted. the study was performed at a single medical center. however, the results could be provided to the hospital as a part of the teaching or research mission. this study was a retrospective nine-year survey which might have some potential biases. in the analysis of long-term changes in infection rates or mortality rates, we must consider whether changes in the population, advances in laboratory diagnostic techniques, changes in exposure to risk factors, microbial culture and other factors lead to increased or decreased rates. however, there did not occur any outbreaks of dais during the study period, except for the sars outbreak. we have presented here the secular trend of dais at our institution in northern taiwan, and the great achievement of our infection control and surveillance program, which was the maintenance of a low dai incidence despite high device-utilization ratios. the incidence of dais decreased in . the incidence of vap remained low, and the rate of antimicrobial resistance of the three most common pathogens causing vap decreased. implementation of infection control and traffic control bundles improved adherence to hand hygiene practices and antibiotic stewardship, and the impact of the sars pandemic on adherence to these practices might explain the decrease in dai incidence and rate of antibiotic resistance in . this study also demonstrated that dai was an important independent prognostic factor of mortality. effectiveness of a nationwide nosocomial infection surveillance system for reducing nosocomial infections reproducibility of the surveillance effect to decrease nosocomial infection rates system report, data summary from surviving sepsis campaign guidelines for management of severe sepsis and septic shock international nosocomial infection control consortium (inicc) report, data summary for national healthcare safety network (nhsn) report: data summary for nosocomial infections and multidrug-resistant organisms in germany epidemiological data from kiss (the hospital infection surveillance system) global epidemiology of antimicrobial resistance among community-acquired and nosocomial pathogens: a five-year summary from the sentry antimicrobial surveillance program seminars in respiratory and critical care medicine antipseudomonal activity of piperacillin/tazobactam: more than a decade of experience from the sentry antimicrobial surveillance program ( - ) multidrug resistance among gram-negative pathogens that caused healthcare-associated infections reported to the national healthcare safety network influx of multidrug-resistant, gram-negative bacteria in the hospital setting and the role of elderly patients with bacterial bloodstream infection incidence rate and variable cost of nosocomial infections in different types of intensive care units the attributable cost, length of hospital stay, and mortality of central line-associated bloodstream infection in intensive care departments in argentina: a prospective, matched analysis risk factors and mortality in patients with nosocomial staphylococcus aureus bacteremia cdc/nhsn surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting cdc definitions for nosocomial infections clsi: performance standards for antimicrobial susceptibility testing: eighteen informational supplement nhsn annual update: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the national healthcare safety network at the centers for disease control and prevention microbial etiologies of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia device-associated nosocomial infection rates in turkish medical-surgical intensive care units epidemiology and risk factors of catheter-associated bloodstream infections among intensive care unit patients: an experience from a tertiary care hospital in thailand changing epidemiology of nosocomial bloodstream infections in teaching hospitals in taiwan between and nosocomial bloodstream infections in us hospitals: analysis of , cases from a prospective nationwide surveillance study predominance of gram-negative bacilli and increasing antimicrobial resistance in nosocomial bloodstream infections at a university hospital in southern taiwan a prospective observational study of candidemia: epidemiology, therapy, and influences on mortality in hospitalized adult and pediatric patients prevention and control of biofilm-based medicaldevice-related infections biofilm formation at the solid-liquid and air-liquid interfaces by acinetobacter species antimicrobial susceptibility of gram-positive bacterial isolates from the asia-pacific region and an in vitro evaluation of the bactericidal activity of daptomycin, vancomycin, and teicoplanin: a sentry program risk factors associated with nosocomial methicillin-resistant staphylococcus aureus (mrsa) infection including previous use of antimicrobials relationship between spread of methicillin-resistant staphylococcus aureus and antimicrobial use in a french university hospital prevalence and nosocomial spread of methicillin-resistant staphylococcus aureus in a long-term-care facility in slovenia antimicrobial susceptibility among organisms from the asia/pacific rim, europe and latin and north america collected as part of test and the in vitro activity of tigecycline appropriate antimicrobial treatment in nosocomial infections-the clinical challenges device-associated infection rates and mortality in intensive care units of peruvian hospitals: findings of the international nosocomial infection control consortium device-associated infection rate and mortality in intensive care units of colombian hospitals: findings of the international nosocomial infection control consortium secular trends of healthcare-associated infections at a teaching hospital in taiwan antimicrobial stewardship taiwan's traffic control bundle and the elimination of nosocomial severe acute respiratory syndrome among healthcare workers submit your next manuscript to biomed central and take full advantage of: • convenient online submission • thorough peer review • no space constraints or color figure charges • immediate publication on acceptance • inclusion in pubmed, cas, scopus and google scholar • research which is freely available for redistribution we thank the icps in the department of infection control, taipei veterans general hospital, for data collection during the study period. this study was supported by a part of research grant from taipei veterans general hospital (v b - ), taipei, taiwan. the funding institutes did not have any role in study design, data collection/analysis, the writing of the manuscript and the decision to submit the manuscript for publication. the authors declare that they have no competing interests.authors' contributions yyc participated in the design, data collection and analysis, and drafted the manuscript. lyc participated in the analysis and drafted the manuscript. syl and pc commented on drafts of the manuscript. syl participated in the data collection. fdw conceived of the project, participated in the design and helped to draft the manuscript. all authors approved the final manuscript. key: cord- -jkxioc j authors: mughal, mohsin sheraz; kaur, ikwinder preet; patton, chandler d.; mikhail, nagy h.; vareechon, chairut; granet, kenneth m. title: the prevalence of severe acute respiratory coronavirus virus (sars-cov- ) igg antibodies in intensive care unit (icu) healthcare personnel (hcp) and its implications—a single-center, prospective, pilot study date: - - journal: infection control and hospital epidemiology doi: . /ice. . sha: doc_id: cord_uid: jkxioc j nan to the editor-healthcare personnel (hcp), including practitioners, nursing staff, respiratory therapists, and the pronepositioning team caring for coronavirus disease (covid- ) patients in the intensive care unit (icu) are considered to have a high risk of exposure to severe acute respiratory syndrome coronavirus (sars-cov- ). most patients admitted to the icu are severely sick and need to be intubated. high-risk procedures for droplet dispersion, including tracheal intubation and tracheostomy tube placement, can be performed in the icu. in a community seroprevalence study in los angeles county, the prevalence of antibodies to sars-cov- was . %. to our knowledge, no other study has addressed the prevalence of subclinical seroconversion of sars-cov- among hcp in the icu setting. in this study, we investigated the seroconversion of asymptomatic sars-cov- infection in icu hcp exposed to critically ill covid- patients. this single-center, prospective, pilot study was performed in an icu at a teaching hospital, monmouth medical center in long branch, new jersey. it was approved by our institutional review board. all hcp caring for covid- patients in the icu setting from march , , to april , , were eligible for inclusion in the study. a cross-sectional survey questionnaire was utilized to collect demographic characteristics and to exclude hcp who ( ) tested positive for sars-cov- by reverse transcriptasepolymerase chain reaction assay (rt-pcr), ( ) had symptoms consistent with covid- , or ( ) had covid- exposure in a household setting. in total, icu hcp responded to the survey, and hcp were eligible for sars-cov- -specific igg antibody testing. means and interquartile ranges (iqrs) were used for continuous variables. all participants provided written consent. antibody testing was performed on the sera using a rapid immunochromatography test (standard q covid- igm/igg duo, sd biosensor, suwon-si, korea) by lateral flow in a clinical laboratory improvement amendments certified (clia), high-complexity laboratory. the manufacturer's stated sensitivity and specificity for igg, - days after symptoms onset are . % and . %, respectively. blood specimens were drawn from weeks after the specified period commencing may , , and ending may , . overall, icu hcp responded to the survey: % were women, . % were registered nurses, . % were attending physicians, . % were resident physicians, . % were patient care assistants, . % were respiratory therapists, . % were technicians, and . % were anesthetists. the mean age of the respondents was . years (iqr, - . ). the mean duration of work was . days (iqr, . - . ). of icu hcp eligible staff, were excluded and underwent sars-cov- -specific igg antibody testing. one individual tested positive and test result was inconclusive due to a faulty test kit and was removed from the analysis. in this study, the prevalence of asymptomatic seroconversion was . %. information about the prevalence of asymptomatic seroconversion of sars-cov- in hcp is limited. in a preliminary report released by the centers for disease control and prevention (cdc), nearly , hcp have contracted covid- , and have died. okba et al demonstrated that most pcr-confirmed sars-cov- patients seroconverted after weeks of disease onset. our study revealed a prevalence of . %, which indicates that seroconversion in icu hcp was a rare event. these data indicate that proper education and utilization of personal protective equipment (ppe) is effective. additionally, ventilated patients have less aerosolization and were housed in a negative-pressure environment in the icu isolation rooms, which also may have been factors in avoiding transmission to hcp. our study has several limitations. it was conducted in a single-center icu and did not include long-term clinical or laboratory follow-up. studies with larger sample sizes in different healthcare settings would be useful to validate the clinical impact of our findings. aerosol-generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review seroprevalence of sars-cov- -specific antibodies among adults in characteristics of healthcare personnel with covid- -united states severe acute respiratory syndrome coronavirus −specific antibody responses in coronavirus disease patients effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (sars) acknowledgments. we acknowledge dr violet e kramer md and dr margaret h eng md for their assistance. we acknowledge joann wolfson dnp, msn, ccrn, with critical care services and joseph jaeger, drph, chief academic officer, as well as ali jaffery, for contributing to data collection. we acknowledge barbara mihelic for institutional review board support at monmouth medical center, long branch, new jersey.financial support. no financial support was provided relevant to this article.conflicts of interest. all authors report no conflicts of interest relevant to this article. key: cord- - ih i s authors: pardo, emmanuel; constantin, jean-michel; bonnet, francis; verdonk, franck title: nutritional support for critically ill patients with covid- : new strategy for a new disease? date: - - journal: anaesth crit care pain med doi: . /j.accpm. . . sha: doc_id: cord_uid: ih i s nan before admission and take into consideration the nature and severity of the various organ failures. in these exceptional times, we sought to assess existing recommendations [ ] [ ] [ ] [ ] to optimise nutritional care for patients suffering from covid- (figure ). preliminary data from the territories first affected by the sars-cov- quickly pointed out that older patients with co-morbidities such as hypertension or diabetes were at risk for severe forms of the disease. in addition to being associated with a worse outcome, this population is known to be affected by a high prevalence of sarcopenia. moreover, median time between symptoms onset and severe hypoxia requiring icu admission ranges from to days, during which patients suffer from general (asthenia, fever), digestive (nausea, diarrhea) and otorhinolaryngologic (anosmia) symptoms. these disabling clinical signs associated with an exacerbated systemic inflammatory syndrome may explain the high incidence of dehydration and malnutrition at icu admission and the necessity to provide early adequate nutritional support. existing nutritional assessment such as "global leadership initiative on malnutrition" (glim), "nutrition risk in critically ill" (nutric) or "nutritional risk screening" (nrs) have been validated as pertinent tools associated with the outcome of covid- patients. concerning the nutritional support, enteral nutrition (en) should be preferred to parenteral nutrition (pn) and introduced early after icu admission in the first to hours in the absence of a formal contraindication such as bowel ischemia, active gi bleeding, high flow digestive fistula or abdominal compartment syndrome. enteral nutrition is feasible in patients requiring prone positioning and/or receiving nerve blocking agents, however, a close monitoring for gastric feeding intolerance is advised, associated with the early use of prokinetics and the elevation of the bed in reverse trendelenburg position to at least to °. metoclopramide may be the preferable option compared to erythromycin considering the potential cardiac adverse effects of prokinetics when associated with other arrhythmogenic drugs. systematic measurement of gastric residual volume is not advised as it constitutes a major risk of contamination. a safer alternative to diagnose delayed gastric emptying might be gastric ultrasound, which has proven its effectiveness in the anaesthesia setting; however, evidence is currently lacking. in case of formal contraindication to en or severe feeding intolerance, refractory to prokinetic treatment or post-pyloric tube, total parenteral nutrition should be introduced either early in malnourished patients or at day - in low nutritional risk patients. a sustained attention should be paid to the monitoring of triglycerides, given the high dose of propofol perfusion in covid- patients, and to the provision of vitamins and trace elements. progressive implementation of clinical nutrition should be prescribed; starting at kcal/kg/day and reaching - kcal/kg/day around day- or . these energy targets must also take into account the calories provided by the propofol infusion i.e. around . kcal/ml. the use of energy-dense enteral formulas seems relevant in order to facilitate the achievement of the caloric target while restricting the volume of fluid provided and reducing nurse workload (lower number of bag changes). the use of indirect calorimetry may be indicated in prolonged icu stay (more than days) or with total pn prescription to avoid overfeeding. [ ] progressive protein intake should be prescribed in order to reach . - . g/kg/day at d after icu admission. the target may be raised to g/kg/day in the rehabilitation phase. if a high-protein form is unavailable or out of stock during this critical time of drug shortage, additional parenteral administration of amino-acid solution may be an option. regarding obese patients, guidelines recommend the administration of iso-caloric high protein diet and suggest the use of "adjusted body weight" to prescribe caloric and protein intake. patients who are initially extremely malnourished or who have not received nutritional intake for more than a week are at high risk of developing a refeeding syndrome, which can be potentially life-threatening. expert groups suggest starting, in high risk patients, at % of caloric target, regardless of nutrition route, and increasing slowly while closely monitoring serum phosphate, magnesium and potassium, especially during the first hours of icu stay. in case of uncontrollable metabolic disorders, caloric supply should be decreased until normalisation. sustained vitamin supplementation, thiamine in particular, and provision of j o u r n a l p r e -p r o o f electrolytes and trace elements, especially in total pn patients, completes the tailored nutrition care needed by these specific patients. survivors is the implementation of specific multidisciplinary post-icu rehabilitation care protocols. collaboration with physiotherapists is essential to provide early mobilisation and physical activity, such as resistance-exercise training, in order to limit or reverse the loss of muscle mass. high protein isocaloric diet introduced during icu stay should be continued after discharge as long as oral intake is insufficient. dieticians should be involved in the follow-up of energy intake in the medical wards. due to prolonged mechanical ventilation, dysphagia and swallowing disorders are frequent. their incidence should be looked for and monitored. in conclusion, covid- is a complex disease with a high nutritional risk. the international guidelines issued specifically in this context are clear and offer a pragmatic guidance to all involved healthcare professionals. considering the lack of knowledge about the mediumand long-term consequences of this new pathology, further research focusing on the rehabilitation and functional outcome of covid- survivors is needed. these data could allow us to adjust our practices in the event of a resurgence during the winter season. declarations of interest: ep reports congress reimbursements from nestlé, nutricia, and fresenius. practice. based on [ ] [ ] [ ] [ ] [ ] stratégie de prise en charge nutritionnelle à l'hôpital avis d'experts de la sfncm espen expert statements and practical guidance for nutritional management of individuals with sars-cov- infection nutrition therapy in the patient with covid- disease requiring icu care nutrition management for critically and acutely unwell hospitalised patients with covid- in australia and new zealand nutrition of the covid- patient in the intensive care unit (icu): a practical guidance authors' contributions : all authors listed have made a direct and intellectual contribution to the work and approved it for publication. key: cord- -yoy kdli authors: timsit, jean-françois; perner, anders; bakker, jan; bassetti, matteo; benoit, dominique; cecconi, maurizio; randall curtis, j.; doig, gordon s.; herridge, margaret; jaber, samir; joannidis, michael; papazian, laurent; peters, mark j.; singer, pierre; smith, martin; soares, marcio; torres, antoni; vieillard-baron, antoine; citerio, giuseppe; azoulay, elie title: year in review in intensive care medicine : iii. severe infections, septic shock, healthcare-associated infections, highly resistant bacteria, invasive fungal infections, severe viral infections, ebola virus disease and paediatrics date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: yoy kdli nan this third article for the year in review will report publications from intensive care on severe infections (including endocarditis and peritonitis), septic shock, healthcare and ventilator associated pneumonia, highly resistant bacteria, antimicrobial therapy (including antibiotic stewardship, therapeutic drug monitoring and deescalation), invasive fungal infections, severe viral infections, ebola virus disease and paediatrics. circulatory dysfunction is frequently present in patients admitted to the icu. with the literature on diagnoses, treatment and monitoring of shock updating frequently, it is important to have up-to-date guidelines. an important process to facilitate the establishment of national/local guidelines is the production of a consensus statement of scientific societies. therefore the european society of intensive care medicine formed a taskforce to review literature and expert opinions on the diagnosis, treatment and monitoring in circulatory shock. their report was a long expected update on the publication of the international consensus conference on hemodynamic monitoring in shock in [ ] . the taskforce produced statements using the grade system principles [ ] and included studies published up to october st [ ] . therefore this consensus statement published in december issue of intensive care medicine represents a very up-to-date view on current evidence. the taskforce recommends not using currently recommended preload parameters as a sole target of fluid resuscitation or targeting any ventricular filling pressure or volume. the taskforce recommends to fluid resuscitate patients using more than one single hemodynamic variable and to use dynamic instead of static variables to predict fluid responsiveness whenever possible. this is in sharp contrast with the recently published guidelines on the treatment of sepsis and septic shock from the surviving sepsis campaign (ssc) [ ] . in addition, guiding fluid resuscitation by cvp might even prove to be harmful [ , ] . nevertheless the use of the ssc guidelines has been reported to improve survival from severe sepsis and septic shock [ ] . both the adherence to the resuscitation and the management bundles of the guideline were associated with improved survival. participation of an individual site in the ssc resulted in a significant drop in hospital mortality every months and increases in site compliance with the resuscitation bundle significantly improved icu and hospital length of stay. in the context of the previous part the question arises whether these important clinical effects of the ssc-guideline result from the adequacy of the targets in the guideline or the effect of protocolized and standardized care. most likely it's a combination of effects that warrants further optimization of the sscguideline rather than discarding them [ ] . the adequacy of (fluid) resuscitation in every kind of circulatory failure depends on a good understanding of the physiology of the circulation. three publications have contributed to this important aspect. two publications focused on the understanding of venous return [ ] and hypovolaemia [ ] . these two topics are closely linked as the therapy for hypovolaemia is increasing venous return. the use of cvp in this context would be to assess whether the heart can efficiently handle the increase in venous return rather than using in increase in cvp as an indicator of adequately increased venous return [ ] . in the most challenging circulatory failure (septic shock) where all aspects of the three pillars of the circulation (the vasculature, the volume and the heart) might be affected [ ] the understanding the pathophysiology of cardiac failure is important as is likely to affect your treatment [ ] . important to realize is that the circulation volume is not equal to the total blood volume. this mistake is frequently made my junior doctors and nurses. in a compensated state of hypovolemia, the total blood volume (the sum of stressed and unstressed volume) is decreased while the stressed volume is maintained and therefore cardiac output may be maintained as well. this results from an increased activity of the sympathetic nervous system that translates in clinical practice into decreased peripheral perfusion. an important marker of decreased peripheral perfusion is a prolonged capillary refill time [ ] . many studies have now shown that abnormal peripheral perfusion is an important warning sign in critically ill patients. whether this is abnormal skin color [ ] , abnormal tissue hemoglobin saturation [ ] or increased capillary refill time [ , ] . as abnormal peripheral tissue perfusion can be corrected by specific therapy [ ] the next logical step would be to incorporate the use of peripheral perfusion parameters and specific treatment into diagnostic and therapeutic protocols to define efficacy of the use of these parameters [ ] . although many techniques are available to assess the state of the circulation, echo (cardiography) has gained importance over the last years. the taskforce of the esicm recommends the use of echocardiography as the preferred modality in patients where clinical examination fails to determine the type of shock [ ] . in addition, echocardiography is noninvasive technique to sequentially evaluate cardiac function in patients with circulatory failure and thus preferred over the routine use of a pulmonary artery catheter [ ] . in mechanically ventilated critically ill patients the use of lung ultrasound significantly changes clinical decisions and therapeutic management. in a study of patients, therapy was changed directly in % of the patients [ ] . in patients the combination of lung ultrasound and echocardiography has proven to be superior to using lung ultrasound only [ ] . therefore thoracic echocardiography should be an important competence of the current curriculum of a trainee in intensive care. the role of the hypothalamic-pituitary-adrenal axis (hpa) in critically ill patients remains a subject of interest as the discussion on supporting this axis by use of hydrocortisone and vasopressin remains actual [ ] . the hpa hormones seem to be related to severity of disease in early sepsis and progression to septic shock [ ] . although hydrocortisone has a vasopressor sparing effect, it doesn't seem to affect vasopressin levels nor mortality [ ] . the role of both thus needs more clarification before recommendations for combined treatment can be made [ ] . also the discussion on the use of vasopressin as a hormone substitute or as a vasopressor needs clarification as the use as a vasopressor is associated with serious adverse events not related to vasopressin blood levels but more to the presence of a specific genotype [ ] . the interaction between immune system and infectious organism in not fully understood. in a recent what's new article, douglas et al. [ ] emphasized the role of innate response in sepsis. indeed, innate-like lymphocytes are a recently described subset of the immune response with known antibacterial properties. human trial in critically ill patients provides the first evidence of the drop in mait cells during bacterial sepsis, which compounds the already known immune defects. the persistent depletion and potential for nosocomial infections is an interesting finding and likely to provide fertile grounds for future studies. while it is now well recognized that early appropriate antimicrobial therapy reduces infection-related morbidity and mortality in the critically ill patients, the importance of pharmacodynamic (pd) dosing to optimize drug exposure continues to evolve. since it is well recognized that beta-lactams efficacy is driven by the time the drug concentration exceeds the mic (t [ mic) of the target pathogen, many of these strategies focused on altering infusion times. in the clinical setting, beta-lactam optimization strategies often include the use of a prolonged infusion (i.e., same dose administered over - h) for each dosing interval or as a continuous infusion where the total daily dose is given at a constant rate over h. each of these strategies has been reported to enhance the efficacy when compared to conventional regimens as reported by bassetti et al. [ ] in his editorial. in their interesting and intriguing study, de waele et al. [ ] , using the dali study (a prospective, multi-centre pharmacokinetic point-prevalence study) shown that in critically ill patients receiving different b-lactam antibiotics, antibiotic free drug concentrations remained below the mic during and % of the dosing interval in ( . %) and ( . %) patients, respectively. the use of intermittent infusion was significantly associated with increased risk of non-attainment for both targets; creatinine clearance was independently associated with not reaching the % free time above mic (ft [ mic) target. the study demonstrated that when simulating an empirical setting where a broad range of pathogens at the susceptibility breakpoint is targeted, that target attainment using conventional b-lactam antibiotic dosing was generally inadequate. although several factors play a role, use of intermittent infusion resulted in a three to four fold increase in the likelihood of not reaching the desired pk/pd targets. in another study, de waele et al. [ ] prospectively analyzed the effect of a dose adaption strategy using daily therapeutic drug monitoring (tdm) on the target attainment for meropenem and piperacillin/tazobactam when pneumonia was the primary infectious diagnosis. forty-one patients were included in the study. eighty-five percent of patients in the tdm group needed dose adaptation, required an additional increase. at h, target attainment rates for % ft [ mic and % ft [ mic were higher in the tdm group: vs. % (p = . ) and vs. % (p = . ), respectively. the study supports a strategy of dose adaptation based on daily therapeutic drug monitoring that lead to an increase in pk/pd target attainment compared to conventional dosing in critically ill patients with normal kidney function. aminoglycosides continue to be essential antibiotic in icu. when aminoglycosides are used in critically ill patients, it is crucial that their efficacy is maximized. aminoglycosides are concentration dependent antibiotics, and the peak concentration over mic is the relevant pk/ pd parameter. studies have shown that aminoglycosides have their maximal effect at a c max /mic ratio of - . this means that tdm for efficacy may be helpful to guide therapy. based on these considerations, as well as on the decreasing susceptibility of microorganisms, actual pkguided dosing based on individual plasma concentrations is preferable in critically ill patients. initial therapy (before any mic is known) should use higher doses (amikacin - mg/kg, gentamycin - mg/kg and tobramycin - mg/kg) to compensate for the changes described, and the c max of the previous dose should guide subsequent doses as reported by dimopoulos [ ] in his editorial. under this context, recent studies shed more light on the aminoglycoside pk/pd properties in icu patients. in a prospective study conducted by de montmollin et al. [ ] in a general icu, % of patients that receives a loading dose of amikacin of mg/kg of total body weight (tbw), still had an amikacin c max \ mg/ l. positive -h fluid balance was identified as a predictive factor of c max \ mg/l. low bmi tended to be associated with amikacin underdosing, when tbw was used, suggesting the need for higher doses in patients with a positive -h fluid balance. whether these regimens are associated with improved outcomes is unknown, therefore other prospective randomized controlled studies are warranted to assess the effects of higher loading doses of amikacin on c max , infection control and survival, and its impact on renal and hearing functions. other compound such as tigecyclin has been extensively studied because of potential activities on extensively drug-resistant bacterias. in and , the us food and drug administration (fda) reported an increased risk of mortality associated with tigecycline use in comparison with other drugs in the treatment of serious infections. the analysis used a pooled group of randomized clinical trials including hospital-acquired pneumonia (hap) and ventilator-associated pneumonia (vap), complicated skin and soft tissue infections (cssti), complicated intra-abdominal infections (ciai), and diabetic foot infections. on the basis of the pooled data analysis, the fda recommended that alternatives to tigecycline should be considered in patients with severe infections. in their interesting article montravers et al. [ ] conclude that tigecyclin success rates in patients in icu with severe infections appear comparable to those reported with other antibiotics; the overall success rate was % at the end of treatment, and % days later. furthermore, they report a survival rate of % at day . historically, clinical trials concerning management of critically ill and particularly icu-admitted patients with tigecyclin are limited. despite the obscure vision provided by an impressive number of meta-analyses, tigecyclin is expected to be used more often in approved indications and in off-label combination regimens for the treatment of mdr gram-negative infections in routine clinical practice. this is greatly supported by the montravers study mentioned above. the increased medical need represented by the growing impact of multiresistant infections and the current lack of alternative or new antibiotics suggests that tigecycline benefit-risk continues to be positive. another way to save antimicrobials is to deescalate as often as possible. many important papers have been published in the journal on this field. antimicrobial de-escalation is a clinical approach to empirical antibiotic treatment of serious infections that attempts to balance the need for appropriate initial therapy with the need to limit unnecessary antimicrobial exposure in order to curtail the emergence of resistance. although the concept of antimicrobial de-escalation seems to make intuitive sense, clinicians should ask themselves what the realistic expectations of such a strategy are. intensivists should expect that a de-escalation approach to antimicrobial therapy in critically ill patients will optimize patient's outcomes as said by dr kollef [ ] in his editorial. in his interesting and complete study, garnacho-montero et al. [ ] evaluated patients with severe sepsis or septic shock at icu admission who were treated empirically with broad-spectrum antibiotics. antibiotic therapy was guided by written protocols advocating for de-escalation therapy once the microbiological results became available (day of culture results), although this decision was ultimately the responsibility of the physician in charge of the patient. by multivariate analysis, factors independently associated with in-hospital mortality were septic shock, sofa score on the day of culture results, and inappropriate empirical antimicrobial therapy, whereas de-escalation of antimicrobial therapy was found to be a protective factor for hospital survival. additionally, among patients receiving appropriate therapy the only factor independently associated with mortality was sofa score on the day of culture results, whereas de-escalation therapy was again found to be a protective factor. in the setting of neutropenic patient with severe sepsis or septic shock, use of broad-spectrum antibiotics is recommended. to date, the first study on the safety of deescalation in neutropenic patients has been published in this journal by mokart et al. [ ] . de-escalation of antimicrobial therapy consisted either to delete one of the empirical antibiotic of a combined treatment, or, whenever possible, to use a betalactam antibiotic with a narrower spectrum of activity. cumulative incidence of de-escalation of the empirical antimicrobial treatment among the patients of the cohort, was %, ( % confidence interval, ci - %), including ( %) patients with ongoing neutropenia, while a microbiological documentation was available in ( %) patients. de-escalation did not significantly modify the hazard of death within the first -day [hr = . ( % ci . - . )], nor within the year after icu-discharge [hr = . ( % ci . - . )]. the results of the study are encouraging and impressive: for the first time the authors has shown that, in icu, de-escalation is frequently performed in neutropenic cancer patients with severe sepsis and this approach appears not to affect the outcomes. surprising and apparently not expected results for deescalation therapy were shown by leone et al. [ ] in their multicenter, non-blinded, randomized noninferiority trial included patients with severe sepsis that were randomly assigned to de-escalation or continuation of empirical antimicrobial treatment. the results shown the median duration of icu stay was [interquartile range (iqr) [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days in the de-escalation group and (iqr - ) days in the continuation group, respectively (p = . ). the mean difference was . ( % ci - . to . ). a superinfection occurred in ( %) patients in the de-escalation group and six ( %) patients in the continuation group (p = . ). the numbers of antibiotic days were ( - , - ) and . ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) in the de-escalation group and continuation group, respectively (p = . ). mortality was similar in both groups. the current study casts significant doubt whether the reduction of the spectrum of the antibiotic can be considered safe as a routine measure. the authors demonstrated that deescalation, defined as narrowing the spectrum of the antibiotic, was inferior to continuation of the initial antibiotic therapy with length of stay as the primary outcome parameter. furthermore, antibiotic use was higher in the de-escalation group presumably driven by the number of superinfections in the de-escalation group. a key element in the study of the potential role of deescalation is a uniform definition of de-escalation. deescalation-defined as narrowing the spectrum of an antibiotic treatment-should be cautiously applied, based on each particular patient's clinical status and considering the icu environment as a whole. vallés et al. [ ] prospectively compared the epidemiology, antibiotic therapy and clinical outcomes between patients with community acquired pneumonia (cap), health care acquired pneumonia (hcap) and immunocompromised patients (icp) with pneumonia admitted in spanish icus over a year period. they found that hcap patients had more comorbidities and had a worse clinical status as compared to the two other subgroups and that both hcap and icp more often needed mechanical ventilation and more often underwent tracheostomy. the incidence of gram-negative pathogens, mrsa and pseudomonas aeruginosa was low overall, but higher in hcap and icp. inappropriate empirical antibiotic therapy was . % in cap, . % in hcap and . % in icp while mortality was the highest in icp ( . %) and did not differ between cap ( . %) and hcap ( . %). the authors concluded that empirical antibiotic regimens recommended for cap would be appropriate for % of the patients with hcap and that consequently systematically covering multidrug-resistant pathogens in hcap is not necessary. diagnosis of ventilator-associated pneumonia (vap) is a problem that is not yet fully solved. in fact, there have been no major advances since the last meta-analysis published by the cochrane collaboration [ ] . real major advances will come from rapid pcr point-of-care techniques, but these results are not yet available. in , bos et al. [ ] published an article in the what's new in intensive care section on potential innovations that could improve early recognition of vap. those authors suggested that new techniques are promising in detecting airway colonization and pulmonary infection at the early phase. the first technique would use colorimetric assays inside the endotracheal tubes to detect the type of bacteria and the pattern of resistance. the second technique is based on the detection of volatile compounds (hydrocarbons, alcohols, aldehydes, ketones and, sulfide-containing molecules) released by bacteria that cause vap. these techniques are still in a very early clinical phase and need to be validated. postoperative nosocomial pneumonia is a threatening complication of major surgery (cardiovascular, thoracic and abdominal), with very high morbidity and mortality. all improvements that can help prevent postoperative pneumonia are welcome. preoperative oral care is a nonstandard prophylactic measure. bergan et al. [ ] performed a prospective study implementing several oralhygiene measures, including a dentist visit, brushing teeth and tongue and, oral rinse with chlorhexidine ( . %) twice a day until surgery. with these measures, they were able to reduce pneumonia from an incidence rate of cases to ventilator days in the months period before the study to cases per days of mechanical ventilation during the months following the study. oral chlorhexidine rinsing in the preoperative period (or, ) and on the day of surgery significantly were significantly protective for post-operative pneumonia. oral chlorhexidine rinses and dental hygiene are cheap, easy and effective measures for preventing pneumonia after cardiac surgery. colonization is a better indicator for bacterial dynamics than infection, since colonization only leads to infection in a small group but contributes significantly to the epidemiology of these bacteria. knowledge about the time until clearance of resistant bacteria is of great importance for understanding nosocomial dynamics and for predicting effects of interventions. in his study haverkate et al. [ ] studied all patients screened on admission and twice weekly for resistant bacteria in icus in european countries (mosar-icu trial, - ). unique patients had episodes of colonization and at least one readmission. thirty-two patients were colonized with two or more resistant bacteria. median times until clearance were . months for all resistant strains, . months for highly resistant enterobacteriaceae, less than month for mrsa, and . months for vancomycin resistant enterococci. for all antimicrobial-resistant bacterial species, % of the patients had lost colonization when readmitted two or more months after the previous icu admission. although this study was performed on a selection of hospital patients (i.e., patients admitted to icus), the results are of critical importance since these patients are especially prone to colonization and (subsequent) infection. bacteremia is one of the major causes of nosocomial infection in the intensive care unit (icu), icu-acquired bloodstream infection (icu-bsi) is associated with increased morbidity and length of stay, resulting in excess costs and high mortality of critically ill patients. although there are variations due to heterogeneous information sources and variety of local clinical practices, coagulasenegative staphylococci, staphylococcus aureus, and enterobacteriaceae species are the pathogens most frequently responsible for nosocomial bacteremia. energy deficit in icu patients is mainly caused by reduced intake due to under-prescribed calories and frequent feeding interruptions. cumulated energy deficit build-up during the first days of icu stay appears an independent factor contributing to nosocomial infections. in their interesting study, ekpe et al. [ ] investigated the impact of energy deficit on the microbiological results of the blood cultures of prolonged acute mechanically ventilated patients who experienced a first icu-bsi episode. daily energy balance was compared according to the microbiological results of the blood cultures of consecutive prolonged ([ h) acute mechanically ventilated patients who developed a first episode of icu-bsi. among the icu-bsi, were due to methicillin-resistant staphylococcus aureus (mrsa). the cumulated energy deficit of patients with mrsa icu-bsi was greater than those with icubsi caused by other pathogens. icu admission, risk factors for nosocomial infections, nutritional status, and conditions potentially limiting feeding did not differ significantly between the two groups. patients with mrsa icu-bsi had lower delivered energy and similar energy expenditure, causing higher energy deficits. more severe energy deficit and higher rate of mrsa blood cultures (p = . comparing quartiles) were observed. the conclusions of the study were that early in-icu energy deficit was associated with mrsa icu-bsi in prolonged acute mechanically ventilated patients. results suggest that limiting the early energy deficit could be a way to optimize mrsa icu-bsi prevention. bacteremia is an important cause of mortality, prolonged stay and excess healthcare costs even in paediatric intensive care units (picu). an estimated % of bsis occurring in picu are thought to be related to the use of central venous catheters (cvcs). adherence to full sterile procedures may be compromised when cvcs are inserted as part of emergency resuscitation and stabilisation, particularly outside the intensive care unit. half of emergency admissions to picu in the uk occur after stabilisation at other hospitals. in their study harron et al. [ ] made in uk determined whether bloodstream infection (bsi) occurred more frequently in children admitted to picu after inter-hospital transfer compared to within hospital admissions. multivariable regression showed no significant difference in rates of picu-acquired bsi by source of admission (incidence-rate ratio for inter-hospital transfer versus within-hospital admission = . , % ci . - . ) after adjusting for other risk-factors. rates of inter-hospital transfers decreased more rapidly between and : . % ( % ci . - . % per year) compared with . % ( % ci . - . % per year) for within hospital admissions. the median time to first picu-acquired bsi did not differ significantly between inter-hospital transfers ( days, iqr - ) and within-hospital admissions ( days, . the authors concluded that inter-hospital transfer was no longer a significant risk factor form picu-acquired bsi. given the large proportion of infection occurring in the second week of admission, initiatives to further reduce picu-acquired bsi should focus on maintaining sterile procedures after admission. faecal peritonitis (fp) is a common cause of secondary peritonitis caused by spillage of faecal material from the large bowel into the peritoneum. the genetics of sepsis and septic shock in europe (genosept) project is investigating the influence of genetic variation on the host response and outcomes in a large cohort of patients with sepsis admitted to icus across europe. tridente et al. [ ] reported in their study data for fp patients admitted to centers across countries. the most common causes of fp were perforated diverticular disease ( . %) and surgical anastomotic breakdown ( . %). the icu mortality rate at days was . %, increasing to . % at months. the cause of fp, pre-existing comorbidities and time from estimated onset of symptoms to surgery did not impact on survival. the strongest independent risk factors associated with an increased rate of death at months, included age, higher apache ii score, acute renal and cardiovascular dysfunction within one week of admission to icu, hypothermia, lower haematocrit and bradycardia on day of icu stay. although recent literature is plenty of studies concerning all aspects of infective endocarditis (ie), very few focus on severe ie requiring admission to the icu. in their ''my paper years later'' wolff et al. [ ] affirmed that since the publication of the paper in a lot of information has been accumulated on management of ie. while sets of blood cultures allow the identification of about % of cases, culture negative ie still remains a diagnostic challenge. blood-polymerase chain reaction in valve tissue may yield a microbiologic diagnosis. new imaging techniques such as pet-ct scans have shown additive value in patient with intra-cardiac device or valvular prosthesis. systematic cerebral magnetic resonance imaging can lead to modification of therapeutic plans. the decision to operate and the timing of cardiac surgery should take into account the presence of congestive heart failure, neurological complications, renal failure, and multiorgan dysfunction syndrome. the strongest independent predictor of post-operative mortality was the pre-operative multiorgan failure score. neurological failure also represented a major determinant of mortality, regardless of the mechanism of neurological complication. fungal infections and in particular candida species are responsible for between - % of all bloodstream infections and are the fourth most common cause of nosocomial bloodstream infections in most us population surveys and the sixth or seventh most common cause in european surveys. candida bloodstream infections occur at highest rates in the icu population, with this setting accounting for - % of all candidemias. in their complete and useful review leon et al. [ ] described that a high proportion of icu patients become colonized with candida species, but only - % develop invasive candidiasis. invasive candidiasis and candidaemia are difficult to predict and early diagnosis remains a major challenge. in addition, microbiological documentation occurs often late in the course of infection. delays in initiating appropriate treatment have been associated with increased mortality. in an attempt to decrease candidarelated mortality, an increasing number of critically ill patients without documented candida infections receive empirical systemic antifungal therapy, leading to concern for antifungal overuse. scores/predictive rules permit the stratification and selection of high risk patients who may benefit from early antifungal therapy. however, they have a far better negative predictive value than positive predictive value. new biomarkers [mannan, antimannan, ( , )-b-d-glucan and polymerase chain reaction] are being increasingly used to enable earlier diagnosis and, ideally, to provide prognostic information and/or therapeutic monitoring. although reasonably sensitive and specific, these techniques remain largely investigational, and their clinical usefulness has yet to be established. in their elegant study, lortholary et al. [ ] reported the active hospital-based surveillance program of incident episodes of candidemia in twenty-four tertiary care hospitals in paris area. among adult cases included, candida isolates were collected and species were c. albicans ( %), c. glabrata ( . %), c. parapsilosis ( . %), c. tropicalis ( . %), c. krusei ( . %) and c. kefyr ( . %) . candidemia occurred in icu in patients ( . %). when comparing icu vs. non-icu patients, the former had significantly more frequent surgery during the past days, were more often preexposed to fluconazole and treated with echinocandin, and were less frequently infected with c. parapsilosis. a significant increased incidence in the overall population and icu was found. echinocandins initial therapy increased over time in icu ( . % first year of study, to and - , period ) , and assessed predictors of -day mortality. they reported that -day mortality rate decreased from . % in period - . % in period (p \ . ). predictors of -day mortality by multivariate analysis were older age, period , receipt of corticosteroids and higher apache ii score, while treatment with an echinocandin were associated with a higher probability of survival. the authors concluded that the incorporation of echinocandins as primary therapy of candidemia seems to be associated with better outcome. as in bacterial infections however, adequate treatment remains of paramount importance in treating infections in critically ill patients. also in patients with candida blood stream infections, inadequate source control and antifungal treatment have been associated with increased mortality [ ] . another important phenomenon in the management of candida infections is represented by the emergence of resistance in candida spp. antifungal drug resistance was considered less problematic in candida spp. than in other pathogens, but recent increases in resistance to both echinocandins and azoles have led to clinical failures. in their extensive review maubon et al. [ ] reported that acquired fluconazole resistance is frequent in c. glabrata (from to %), which increasingly displays cross-resistance to voriconazole. so far, multi-drug resistant phenotype against azole and echinocandins, has only been described for c. glabrata and is a matter of serious concern. fluconazole resistance remains uncommon in c. albicans (\ %), but is more prevalent in c. parapsilosis ( - %) and c. tropicalis ( - %), however recent data shows that may reflect geographical differences. acquired resistance to echinocandins is increasingly reported for most of the clinically important candida spp. it remains uncommon in c. albicans (\ %), c. tropicalis (\ %) and c. krusei (\ %), but is now becoming frequent in c. glabrata ( - %) . candida spp. colonization of the airway is frequently reported in mechanically ventilated critically ill patients, and its clinical significance is difficult to evaluate. candida has a low affinity for alveolar pneumocytes and histologically documented pneumonia has been rarely reported. hematogenous dissemination in the context of candidemia may be responsible for multiple pulmonary abscesses and should be viewed as a distinct entity. hence the existence of true candidal pneumonia is doubtful and recovery of candida spp. from the respiratory tract should generally be considered as colonization and does not justify antifungal therapy. in their double-blind, placebocontrolled, multicenter pilot randomized trial, martin et al. [ ] tried to demonstrate a benefit of antifungal therapy in critically ill patients with positive airway secretion specimens for candida spp. they recruited patients into the randomized trial: patients specifically treated with antifungals. markers of inflammation and all clinical outcomes were comparable between placebo and antifungal treatment group at baseline and over time. at baseline, plasma tnf-alpha levels were higher in the patients colonized with candida compared to the observational group (mean ± sd) ( . ± . vs. . ± . pg/ml p = . ) and that these patients had lower innate immune function as evidenced by reduced whole blood ex vivo lps-induced tnf-alpha production capacity ( . ± . vs. . ± . pg/ml p = . ). this study does not provide evidence to support a larger trial examining the efficacy of empiric antifungal treatment in patients with candida in the endotracheal secretions. similar negative impact in duration of mechanical ventilation has been obtained with inhaled amphotericin-b patients with airway colonization with candida sp. ampho-b inhalation therapy was not associated with increased decolonization and might even prolong duration of mechanical ventilation possibly due to the toxicity of the drug on the lungs [ ] . in addition, in a small randomized study on the efficacy of empiric treatment of suspected ventilator associated pneumonia in patients with candida colonization of the respiratory tract did not prove to be effective [ ] . in this study persistent inflammation and immunosuppression were associated with candida colonization of the lung. what to do with respiratory tract colonization in critically ill patients therefore remains an important problem [ ] . for the prevention of fungal infections, oral prophylaxis with nystatin has been recently evaluated and shown to result in a reduction of candida colonization [ ] . the development of the candida colonization index (ci) has been viewed as a major conceptual advance in the characterization of supporting the progression from colonization to infection in surgical patients [ ] . in their ''my paper twenty year later'' eggimann et al. [ ] affirmed that since the publication of the paper in , many centers have used the ci or a methodology derived from its original description to assess the dynamics of candida colonization in different sub-groups of critically ill patients at risk of invasive candidiasis. unfortunately, these data have not been validated in large multicenter trials. several studies have indirectly suggested the validity and potential usefulness of the ci, but almost exclusively in surgical patients. among the pitfalls, it should be emphasized that it is work-intensive with a limited bedside practicability. furthermore, only limited data are available for nonsurgical patients, and its cost effectiveness and usefulness for the management of critically ill patients remain to be proven in large prospective clinical trials. koulenti et al. [ ] analyzed data on epidemiology, clinical aspects and diagnostic novelties in invasive pulmonary aspergillosis (ipa) in icu patients. they concluded that the identification of high-risk profiles for ipa of icu patients without apparent immunosuppression might help in achieving earlier ipa diagnosis as it would lead to a higher level of suspicion and a lower threshold to perform thorough diagnostic work-out for patients at high-risk. epidemiological research with the aim to identify the high-risk patient for ipa is going on (http://www.aspicu .org). in recent years, antineoplastic treatment regimens in hematological patients have intensified. this has led to a significant increase in icu admissions due to severe infectious complications. among these patients, pulmonary infiltrates with a fungal etiology are among the most common findings associated with febrile episodes. the increasing availability of high resolution and multislice ct has rendered the conventional chest radiograph more or less obsolete for diagnosing lung infiltrates in febrile neutropenic patients [ ] . in recent years, viral community-acquired pneumonia (cap) has been reported as a frequent microbial etiology in severe cap. this is due in part to the new diagnostic techniques that allow to detect old and new viruses. middle east respiratory syndrome (mers) is one of these new viral diseases, which is caused by an rna betacoronoravirus. leung and gomersall [ ] described in intensive care medicine the epidemiology, pathogenesis, clinical features, diagnosis, treatment, and implications for intensive care management. the clinical features of this disease are indistinguishable from other viral diseases, including viral pneumonitis. diagnosis is made by means of epidemiological background (middle-east travel) plus the examination of blood, urine, stool, conjunctival swabs and cerebrospinal fluid samples, in which the virus can be found using real-time reverse-transcription pcr. most patients admitted to the icu require mechanical ventilation. shock and renal failure are also frequent. unfortunately, there is no specific antiviral treatment. ebola virus is one of the most virulent human pathogens. since , ebola virus disease (evd) has caused more than outbreaks in africa, with case fatality rates of - %, in the absence of any approved treatment or vaccination. it is transmitted by direct contact through broken skin or mucous membranes with blood, urine, saliva, feces, vomit, and other body fluids of symptomatic infected patients or convalescent persons, or through contaminated needle sticks. the evd outbreak in west africa is a public health emergency of international concern. tattevin et al. [ ] affirmed that every physician active in emergency departments or icu worldwide may turn out to be involved in the care of patients suspected of evd. their take-home messages from this paper were ( ) suspect evd in any patient who presents with fever within three weeks after a stay in guinea, sierra leone, liberia, or nigeria; ( ) while implementing infection control procedures to prevent any secondary cases (in case evd is confirmed), ensure that all plausible differential diagnoses are appropriately considered and managed. even parkes-ratanshi et al. [ ] in their article urgently recommend that health facilities consult national guidelines on evd and develop local action plans. during this epidemic this internet and social media such as twitter are being effectively used to disseminate information by the who, governments and the medical press. as the who are predicting that that the end of the epidemic is far away and it may infect up to , people before it is controlled; it is essential that the global medical community remains informed and vigilant. the critical care teams working with patients who have been evacuated to resource rich settings during the current epidemic must share their best practices as soon as possible. regarding the organ dysfunction, beeching et al. [ ] in their article explained that the pathogenesis of evd shows both similarities with and differences from other causes of viral haemorrhagic fever or bacterial sepsis. systematic prospective observational studies are essential to clarify the pathogenesis and pathophysiology of disease in humans and to inform the development of evidence based clinical scoring systems and management algorithms, as well as the evaluation of novel therapeutic agents. improving access to basic supportive care is essential. the role and possible benefit of more aggressive critical care interventions continue to be debated. deep trouble: unwanted effects of sedation and support we have had a year of notable submissions including novel reviews of large datasets, randomized controlled trials, and state-of-the-art ''what's new'' articles. however, arguably the most compelling piece of paediatric intensive care literature from in icm was the simple but profound recollection of a month spent on a paediatric intensive care unit: 'coma alarm dreams' [ ] . written by a remarkable young man describing his recovery from a gunshot wound to the head, this -word piece provides an uncomfortable insight into our patient's experiences. we may hardly notice monitor alarms; they form the soundtrack of our working lives. but for our patients the experience may be the complete opposite: dreams, nightmares and hallucinations. dr emeriaud and colleagues [ ] from montreal, highlighted another problem during paediatric critical illness that is easily overlooked. they performed repeated estimations of maximal inspiratory diaphragmatic electrical activity (eadimax) in ventilated children. this first systematic description of the natural history of this parameter provides in number of insights; there were frequent periods of little or no detectable diaphragmatic activity during mechanical ventilation; those values that were seen during during full ventilation were much lower than pre-extubation or spontaneous breathing; and patients intubated mainly because of a lung pathology exhibited higher eadi (p \ . ) than did patients supported for other reasons. the authors add to the emerging view that we may be oversedating and oversupporting many of our patients. the possibility of using eadi as a proxy endpoint for clinical trials or as a biomarker for guiding mechanical ventilation is intriguing. ''how to manage ventilation in pediatric acute respiratory distress syndrome'' by kneyber, jouvert and rimensburger [ ] returned to this theme of the limitations of our current practice and the need to recognize the potential harm we might be causing. they present a candid view of the many gaps in our knowledge: is our (new) berlin definition sufficient for selection of patients for randomized trials? is it appropriate to infer guidance from adult studies? does * mls/kg tidal volume really represent our best guess safe and effective ventilation during both acute and recovery phase of lung injury? can we generate clinically meaningful guidance from the bedside tools such as transpulmonary pressure (tpp) measurements and electrical impedance tomography (eit)? perhaps most pressingly, many paediatric intensivists treasure the use of high frequency oscillation in paediatric ards on very limited evidence. surely we need clinical trial data in the face of the results from the oscillate and oscar trials. we are again challenged to provide data to systematise our sedation and weaning policies. drs maclaren, brown and thiagarajan [ ] gave us a view of ''what's new in pediatric ecmo'' from four continents. overall survival after ecmo is improving and therefore other indications are starting to be considered (bridge to lung transplantation anyone?). they highlighted specific area of concerns including the need for more information about advantages of specific pumps or anticoagulant regimens. but above all there is a clear need for long-term follow up. recent reports of very high rates of late death for cardiac ecmo make this point starkly: only % of hypoplastic left heart syndrome cases who received ecmo were alive years later. the impact on the family with high rates of post-traumatic stress, the importance of neurological complications, and the value of neurodevelopment follow-up, as highlighted in the journal in , were noted [ ] [ ] [ ] . at the other end of the spectrum of severity of respiratory failure, we published an important study from kremlin-bicetre hospital in paris, documenting the associations of a change in practice from predominantly invasive ventilation to predominantly nasopharyngeal cpap support in infants with bronchiolitis [ ] . the authors readily acknowledge that they cannot account for potential confounders that might arise from other changes in practice or case mix. that said, the numbers of cases observed (n = ) and the size of the effect: % invasive ventilation falling to % over years with associated significant reductions in length of stay and costs mean that we should not ignore these data. the increasing options and environments in which non-invasive ventilation may be useful was highlighted by dr schlapbach and colleagues [ ] from brisbane australia. high-flow nasal cannula was increasingly used in predominantly aeromedical transports over a median distance of km. the availability of hfnc was associated with a reduced need for intubation when adjusted for pim score, age, and the presence respiratory disease. changes in the case mix received in brisbane do limit the interpretation of these data but they form part of a steady trend towards increasing use of non-invasive support in our speciality. this was reviewed by argent and biban [ ] who asked: ''what's new on niv in the picu: does everyone in respiratory failure require endotracheal intubation''? in this piece they highlighted the very few published randomised studies ( ) and prospective cohort studies ( ) which represent the best data on niv in paediatric critical illness currently available. one of the problems around generating evidence is the variety of techniques, triggering mechanisms, patient interfaces as well as options for patient selection and timing. these combine to make good research in this area difficult. however this is no excuse for not attempting it. argent and biban put it clearly: non-invasive techniques have potential to ''substantially improve the safety of ventilator support for children, and improve access to ventilatory support for both acute and chronic conditions. given that respiratory problems are among the most important cause of childhood deaths across the world, it behoves us to explore the potential and collect the data.'' research on the paediatric airway was a strong theme in this year's icm. dr wakeham and colleagues [ ] used the virtual paediatric intensive care database to document the very wide variability in practice around tracheostomy use on north american paediatric intensive care units. only . % of , admissions underwent tracheostomy at a median length of stay of days. interquartile range was . - . days. tracheostomy rate amongst the larger contributors to the study varied from to . %. the authors right suggest that these differences are unlikely to be attributable to case mix differences alone. this sets paediatric intensivists a serious challenge to remove unhelpful variability on practice. dr baranwal and colleagues [ ] made a valuable contribution to another unknown in paediatric airway management. they asked if -h dexamethasone pretreatment was superior to -h pretreatment for prevention of postextubation airway obstruction in children? they recruited children between the ages of months and years in an elegant randomized double-blind trial. the two groups were similar at baseline. the longer ( h) pre-treatment significantly reduced both the incidence ( h pre-treatment %, / vs. h %, / ; p = . , relative risk . , % ci . - . ) [ ] and duration of post-extubation airway obstruction as assessed by a modified croup score. the longer pre-treatment halved the re-intubation rate ( . , % ci . - . ): but the study was not powered to detect a difference in these relatively rare events (only re-intubations took place in the study). the implications of these data are not clear since pre-treating for h might mean delaying extubation in some scenarios. prince et al. [ ] from london examined the association of 'weight-for-age' and case mix adjusted outcomes in , critically ill children. in addition to the size of this dataset, a strength was the comparison to a healthy reference population in the united kingdom. not surprisingly, critically ill children have lower weight-forage than do their healthly peers. this study confirmed the findings amongst adults and in smaller paediatric studies that children with weight-for-age above the population mean have significantly better case-mix adjusted survival. the similar 'obesity paradox' has been observed in adults with sepsis. indeed the association of weight-for-age and standardised mortality ratio follows a u-shaped distribution (as do many things in intensive care). the accompanying editorial from nadel and argent points out how much more information we need to understand the nutritional needs of our patient [ ] . zinter et al. [ ] described outcomes for , paediatric cancer emergency admissions out of , admissions to the us virtual picu systems database. a diagnosis of leukaemia of lymphoma 'outside of first induction,' still carries a 'high-risk' tariff in the paediatric index of mortality scoring system at icu admission [ ] . but things may be changing. overall survival for paediatric cancer continues to improve with % year survival but % of paediatric cancer patients make at least one visit to the icu. this large series observed only a . % icu mortality to cancer admissions to picu. this figure lower than many series quote for previously healthy children with community-acquired sepsis or acute respiratory distress syndrome (ards) on picu the observed relative risk of picu death with cancer is still highly significant at . ( % ci . - . ), but the truth is that this reflects the overall improvement in picu outcomes more than cancer lagging behind. acute myeloid leukaemia cases had much worse outcome in multiple variant analysis. strikingly a % survival of ecmo in both solid and haematological cancer patients was seen-though the post hematopoietic stem cell transplant group did uniformly badly. in summary, was characterized by two main themes: mining of large datasets to reveal patterns in our care of which we were previously unaware, and observations highlighting the many and varied gaps in our knowledge. conflicts of interest none. hemodynamic monitoring in shock and implications for management clinical meaning of the grade rules consensus on circulatory shock and hemodynamic monitoring. task force of the european society of intensive care medicine surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock association between systemic hemodynamics and septic acute kidney injury in critically ill patients: a retrospective observational study fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality surviving sepsis campaign: association between performance metrics and outcomes in a . year study evaluation of . years of surviving sepsis campaign guidelines understanding venous return understanding hypovolaemia understanding cardiac failure in sepsis peripheral vasoconstriction influences thenar oxygen saturation as measured by near-infrared spectroscopy mottling score predicts survival in septic shock knee area tissue oxygen saturation is predictive of -day mortality in septic shock capillary refill time exploration during septic shock clinical assessment of peripheral perfusion to predict postoperative complications after major abdominal surgery early: a prospective observational study in adults nitroglycerin reverts clinical manifestations of poor peripheral perfusion in patients with circulatory shock clinical significance of monitoring perfusion in non-vital organs impact of lung ultrasound on clinical decision making in critically ill patients integrated use of bedside lung ultrasound and echocardiography in acute respiratory failure: a prospective observational study in icu the interaction of vasopressin and corticosteroids in septic shock: a pilot randomized controlled trial prognostic significance of hypothalamic-pituitary-adrenal axis hormones in early sepsis: a study performed in the emergency department steroids and vasopressin in septic shock-brother and sister or just distant cousins? serious adverse events associated with vasopressin and norepinephrine infusion in septic shock sepsis and the innate-like response what's new in antimicrobial use and resistance in critically ill patients? risk factors for target nonattainment during empirical treatment with b-lactam antibiotics in critically ill patients therapeutic drug monitoringbased dose optimisation of piperacillin and meropenem: a randomised controlled trial what is new in the use of aminoglycosides in critically ill patients? predictors of insufficient amikacin peak concentration in critically ill patients receiving a mg/ kg total body weight regimen tigecycline use in critically ill patients: a multicentre prospective observational study in the intensive care setting what can be expected from antimicrobial deescalation in the critically ill? de-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock de-escalation of antimicrobial treatment in neutropenic patients with severe sepsis: results from an observational study de-escalation versus continuation of empirical antimicrobial treatment in severe sepsis: a multicenter non-blinded randomized noninferiority trial what's new in the clinical and diagnostic management of invasive candidiasis in critically ill patients worrisome trends in incidence and mortality of candidemia in intensive care units prognostic factors and historical trends in the epidemiology of candidemia in critically ill patients: an analysis of five multicenter studies sequentially conducted over a year period resistance of candida spp. to antifungal drugs in the icu: where are we now? candida in the respiratory tract secretions of critically ill patients and the impact of antifungal treatment: a randomized placebo controlled pilot trial (cantreat study) what is new in infection prevention in critical care in ? epidemiology, antibiotic therapy and clinical outcomes of healthcare-associated pneumonia in critically ill patients: a spanish cohort study quantitative versus qualitative cultures of respiratory secretions for clinical outcomes in patients with ventilator-associated pneumonia impact of improvement in preoperative oral health on nosocomial pneumonia in a group of cardiac surgery patients: a single arm prospective intervention study duration of colonization with antimicrobialresistant bacteria after icu discharge methicillin-resistant staphylococcus aureus bloodstream infections are associated with a higher energy deficit than other icu-acquired bacteremia risk of bloodstream infection in children admitted to paediatric intensive care units in england and wales following emergency interhospital transfer patients with faecal peritonitis admitted to european intensive care units: an epidemiological survey of the genosept cohort my paper years later: infective endocarditis in the intensive care unit a multicenter study of septic shock due to candidemia: outcomes and predictors of mortality safety and efficacy of amphotericin-b deoxycholate inhalation in critically ill patients with respiratory candida spp. colonization: a retrospective analysis candida colonization of respiratory tract: to treat or not to treat, will we ever get an answer? candida colonization and subsequent infections in critically ill surgical patients candida colonization index and subsequent infection in critically ill surgical patients: years later what's new in invasive pulmonary aspergillosis in the critically ill what's new in diagnosis and antimicrobial therapy of febrile neutropenic patients with lung infiltrates? middle east respiratory syndrome does this patient have ebola virus disease? ebola in west africa: be aware and prepare understanding organ dysfunction in ebola virus disease coma alarm dreams on paediatric intensive care evolution of inspiratory diaphragm activity in children over the course of the picu stay how to manage ventilation in pediatric acute respiratory distress syndrome? what's new in paediatric extracorporeal membrane oxygenation? years after neonatal ecmo: a nationwide multicenter study neurologic complications in neonates supported with extracorporeal membrane oxygenation. an analysis of elso registry data looking beyond survival rates: neurological outcomes after extracorporeal life support improved clinical and economic outcomes in severe bronchiolitis with pre-emptive ncpap ventilatory strategy high-flow nasal cannula (hfnc) support in interhospital transport of critically ill children what's new on niv in the picu: does everyone in respiratory failure require endotracheal intubation? use of tracheostomy in the picu among patients requiring prolonged mechanical ventilation dexamethasone pretreatment for vs. h for prevention of postextubation airway obstruction in children: a randomized double-blind trial comments on baranwal et al.: dexamethasone pretreatment for h versus h for prevention of postextubation airway obstruction in children weight-for-age distribution and case-mix adjusted outcomes of , paediatric intensive care admissions big babies and big adults surprise us by their outcomes: why? pediatric cancer type predicts infection rate, need for critical care intervention, and mortality in the pediatric intensive care unit optimism and no longer foolishness? haematology/oncology and the picu key: cord- -adqqm n authors: sha, dexuan; miao, xin; lan, hai; stewart, kathleen; ruan, shiyang; tian, yifei; tian, yuyang; yang, chaowei title: spatiotemporal analysis of medical resource deficiencies in the u.s. under covid- pandemic date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: adqqm n coronavirus disease (covid- ) was first identified in december in wuhan, china as an infectious disease, and has quickly resulted in an ongoing pandemic. a data-driven approach was developed to estimate medical resource deficiencies due to medical burdens at county level during the covid- pandemic. the study duration was mainly from february , to may , in the u.s. multiple data sources were used to extract local population, hospital beds, critical care staff, covid- confirmed case numbers, and hospitalization data at county level. we estimated the average length of stay from hospitalization data at state level, and calculated the hospitalized rate at both state and county level. then, we developed two medical resource deficiency indices that measured the local medical burden based on the number of accumulated active confirmed cases normalized by local maximum potential medical resources, and the number of hospitalized patients that can be supported per icu bed per critical care staff, respectively. data on medical resources, and the two medical resource deficiency indices are illustrated in a dynamic spatiotemporal visualization platform based on arcgis pro dashboards. our results provided new insights into the u.s. pandemic preparedness and local dynamics relating to medical burdens in response to the covid- pandemic. coronavirus disease (covid- ) was first identified in december in wuhan, china as an infectious disease, and has quickly resulted in an ongoing pandemic. just before the global pandemic covid- , a report by the global health security index was released, which is the first-ever comprehensive ranking of countries based on their pandemic preparedness, with six categories of questions and indicators [ ] . although national health security is fundamentally weak across the globe, the u.s. scored . / and ranked no. in a a a a a the report. as evidence, there were . critical care beds per , inhabitants in the u.s. by , which is higher than that of any other country [ , ] . however, the u.s. has fewer hospital beds ( . ), and practicing physicians ( . ) per , capita compared to other similar large and wealthy countries [ ] . since the covid- outbreak, it has been estimated that a significant percentage of the u. s. population would test positive for covid- even given a conservative estimation [ ] . for example, a recent aha (american hospital association) webinar on covid- projected that % ( million) of the u.s. population would test positive, with % ( . million) being hospitalized, % ( . million) would be admitted to the intensive care unit (icu), and % ( , ) would require ventilators [ ] . this projection is generally compatible with the characteristics of covid- in wuhan, china, where % of patients required the intensive care unit and . % required a ventilator [ ] . based on a recent cdc survey, the actual weekly hospitalization rate in april was around . - . % for counties across states [ ], which means a large number of infected patients will swarm into hospitals and icus. as a matter of fact, the u.s. had the highest number of confirmed cases of covid- ( , ) in the world on march , , and surpassed italy for the highest national death toll ( , ) on april , [ , ] . are u.s. medical resources enough to handle the worst scenario during this crisis? the society of critical care medicine (sccm) released a report regarding the medical resources both available and needed for a potentially overwhelming number of critically ill patients [ ] . in this report, three fundamental elements or features, i.e. ventilators, icu beds, and critical care staff (ccs) were identified as medical resources to plan for or manage a covid- pandemic, and it would be wise to consider the interconnections among these factors in a spatiotemporal data analysis framework. specifically, the medical resource distribution should be correlated with covid- pandemic statistics in space ( d) and time ( d). so medical resource burden or deficiency can be identified through feature selection, visualization, monitoring, and cluster analysis [ ] . among the three elements mentioned above, an inventory of ventilators is difficult to quantify for estimating critical supply shortages. based on a aha survey, a total of , u.s. acute care hospitals were estimated to have , full-featured mechanical ventilators and , ventilators with limited features [ ] . the strategic national stockpile (sns) had an estimated , ventilators for emergency deployment in , and between , and , ventilators by march , [ - ] . based on these numbers, the ventilator inventory was approximately , - , in the u.s. a model-based analysis suggested that us hospitals could absorb between , to , additional ventilators at the peak of a national pandemic with robust pre-pandemic planning [ ] . since sns can deliver ventilators within - hours after being requested by states and approved by federal organizations, and no reliable database for ventilator inventory exists at county or state level, we will not consider this factor in our spatiotemporal analysis. a recent model-driven study simply assumes one ventilator per critical care bed [ ] and we use this same assumption in our analysis. hospital beds, especially icu beds, are an important factor in evaluating medical resource deficiency during the covid- pandemic, and quantity of beds has been used as a major factor in model-driven predictions of local critical care capacity limit [ , ] . however, safe use of ventilators in icu requires trained personnel. in a previous study, the number of trained medical personnel is assumed to correlate with the number of staffed beds maintained by hospitals [ ] . this assumption is perhaps unrealistic at county level without considering the geographic disparity. for this research, we assumed that a realistic measurement of the medical burden at county level should consider both icu beds and critical care staff (ccs), which will provide reasonable evidence for stakeholder (e.g., hospital, county and state governments policy and decision-making). in this study, we ( ) conduct a medical data analysis, and re-evaluate the spatial distribution of medical resource features (hospital beds, icu beds, and ccs) at county level; ( ) develop two medical resource deficiency indices (mrdi and mrdi d ) by linking positive covid- infections and local medical resources to measure local medical burden; and ( ) develop a data-driven dynamic spatiotemporal framework to visualize and analyze the mrdi /mrdi d trends at the county level. our results provided a new dimension of insight into the u.s. pandemic preparedness and local dynamic medical burden during covid- pandemic. the dataset is open sourced and hosted on github (https://github.com/stccenter/ covid- -data/tree/master/us), and are visualized through arcgis dashboards at: http:// mrd-dashboard.stcenter.net/. a total of , counties and county-equivalents in the u.s. are used as the primary unit of this study, since they are manageable in a gis system and small enough to reflect local geographic discrepancies. the base map was downloaded from the tiger/line products from the u.s. census bureau, which is the most comprehensive spatial dataset designed for gis platforms [ ] . the county vector layer delineates the administrative boundary with land/water area without any demographic data, but it provides geographic entity codes (geoids) for joining with other socio-economic data such as census data. based on the attributes of our collected medical-related datasets, we also prepared state and zip code boundaries for data fusion and integration at county level. in this study, two fundamental features of medical resources in the u.s. were extracted, i.e., hospital beds and critical care staff. besides, the population and + senior population data was extracted at county level from khn online database [ ] , which is used to normalize the local medical data in the subsequent analysis. . . . hospital beds. national public and private online datasets were used to prepare county-level hospital bed counts. hospital data were collected from definitive healthcare [ ] . definitive healthcare consulting services share their hospital dataset to the entire health research community through arcgis online, which cover information of nationwide bed capacity and average yearly bed utilization of hospitals. although it is not a real-time dataset that reflects each hospital's bed capacity during covid- , it can be used as a baseline to estimate the geographic disparity of local health resources. a hospital is defined as a healthcare institution providing inpatient, therapeutic, or rehabilitation services under the supervision of physicians with the capability of inpatient care [ ] . all types of hospitals are included in our study. five types of hospital beds are clearly identified in the definitive healthcare dataset. in our study, two hospital bed capacities were selected and used in the analysis. the first one is the number of licensed beds, which is the potential or maximum number of beds for which a hospital holds a license to operate. the second type of capacity refers to the number of adult icu beds that could be used for covid- . during this crisis, hospitals could use additional intensive care beds to supplement an influx of patients. therefore, adult icu beds include not only internal medical icu beds, but also burn, surgical, and trauma icu beds. however, pediatric, premature or neonatal icu beds are not included because they are mainly for a different target patient population, which has a much lower incidence rate of covid- . two other independent data sources of hospital beds are compared with the data from definitive healthcare. one is from kaiser health news (khn) based on reports of icu beds in - [ ] , and the other is from homeland infrastructure foundation-level data (hifld) for licensed hospital beds updated on october , [ ] . we conducted a regression analysis comparing khn with definitive healthcare in terms of icu beds, and comparing hifld with definitive healthcare in terms of licensed beds, and the coefficients of determination (r ) are . and . , respectively. the results validated the quality of the definitive healthcare dataset. a dataset of critical care staff (ccs) was extracted from the weekly updated national provider identifier registry (npi) database (~ . gb) through structured query language (sql) [ ] . the npi is a unique -digit identification number for each health-care provider issued by the centers for medicare medicaid services through the national plan and provider enumeration system. each health-care provider could have multiple taxonomy codes, which indicate areas of specialization. through consulting with medical researchers and front-line physicians, we extracted detailed ccs data from the npi database released on april , as a medical resource feature (table ). our study identifies , health care providers by searching unique npi records and removing duplicate records. with the development of covid- in the u.s., all these icu-related staff (emergency medicine physician, critical care physicians, anesthesiologists, hospitalists, pulmonologist, infectious disease physician, surgery, anesthesiologist assistant, critical care nurses, nurse anesthetist, and respiratory therapists trained in mechanical ventilation) would become valuable but limited asset for critically ill ventilated patients [ ] . the u.s. centers for disease control and prevention (cdc) published daily covid- confirmed cases on february , . each state got involved soon after and began to report covid- data, including the daily and accumulated test and confirmed case numbers, hospitalization data, and death numbers at state level. however, numbers of discharged or released patients from hospitals are less widely available, e.g., only a few states, such as maryland, colorado, and new york provide some (incomplete) statistics on recovered patients from both hospital and home. this study mainly uses the data collected by the nsf spatiotemporal innovation center (stc) at george mason university. this dataset uses a datacube structure for spatiotemporal data aggregation from multiple sources. the data is cleaned, standardized, and updated daily to solve any data conflicts, and a time-series summary at state and county level is provided for the u.s. [ , ] . the numbers of county-level confirmed positive cases as well as deaths were originally extracted from usa facts based on cdc data [ ] , and compared with local public health agencies for verification. the confirmed and death cases reflect cumulative statistics since january , , the day after the first confirmed cases were reported in washington state. furthermore, state level test and hospitalization data were extracted from the covid tracking project [ ] . however, the current and accumulated hospitalization cases from state health departments are largely incomplete. by april , , a total of states reported both current and accumulated hospitalized patient numbers, states reported only current hospitalized numbers, and states only reported accumulated hospitalized numbers, while washington, d.c., nevada and nebraska did not provide information on the number of hospitalized cases. our analysis was mainly based on the publicly available data of the new confirmed daily cases reported for the u.s. from the th of february until the st of may, . all data were fully anonymized. raw datasets in this study were collected from multiple sources with heterogeneous formats and structures. all data were processed and aggregated at county level based on county federal information processing standard (fips). several aggregation methods were used for each raw dataset, as summarized in fig . first, the hospital data was originally presented as a point location in a coordinate format, and its attribute table includes five types of hospital beds. the spatial point aggregation algorithm was used to integrate the numbers of licensed beds and adult icu beds at county level. the bed numbers per , residents were also calculated at county level. the primary practice addresses of ccs were imported from the npi database, and -digital zip codes were extracted. the total number of ccs within a county was counted based on the county's zip codes through geocoding and the point/ polygon aggregation algorithm. the number of ccs per , residents were also calculated at county level. the accumulated covid- confirmed case numbers were extracted at county level. we used existing hospitalization data to estimate the average length of stay (alos) in acute care, since it is key for estimating the daily hospitalized patients. for a given state, the current hospitalized patients should be equal to the accumulation of hospitalized patients minus the accumulation of deaths and discharged patients within the most recent alos. since no patient discharge data was available, we assumed that the number of discharged patients was zero. therefore, we estimated alos by matching ( ) the accumulation of hospitalized patients minus the accumulation of deaths in most recent days, and ( ) the current number of hospitalized patients, and finally interpolating by two nearest days or accumulation periods. it turns out to be an optimization problem to find a parameter (n) to match the two data sources, as shown in eq ( ). where n h,n is the accumulated number of hospitalized patients in the past n days, n death,n is the accumulated number of deaths in the past n days, and n ch is the number of currently hospitalized patients. state hospitalization data were only available recently (starting from march , in ny) with numerous missing data. by may , , among states that have both current and accumulated numbers of hospitalized patients, eight states (colorado, massachusetts, maine, minnesota, montana, north dakota, new york, oklahoma) had complete data for the most recent days; states (oklahoma, wisconsin, mississippi, maryland, new hampshire, new mexico, oregon, south dakota, virginia, wyoming, rhode island, kentucky) only had data in the most recent - days; and data from arkansas, arizona, and connecticut were abandoned due to poor quality. we calculated the daily alos for these states and pooled the results in fig . the state alos ranges from . (new mexico)- . (mississippi) days. the overall national alos weighted by state hospitalized patients is . days, which is longer than a previous estimation that the alos in acute care were days [ ] . it is worth noting that alos is likely to be underestimated since we assumed no discharged patients. furthermore, alos is subject to change when more hospitalization data become available in the future. finally, we define the covid- hospitalized rate as the ratio of the number of current hospitalized patients and the accumulated confirmed case numbers during the most recent alos. if the hospitalized rate remains the same within a state, the daily hospitalized patient number in a county can be estimated by using the accumulated covid- confirmed case numbers minus deaths in the most recent alos, multiplied by the state average hospitalized rate. if no state alos is available, we use the overall national average alos of . days. this daily hospitalized patient number can be used to evaluate the daily medical burden at county level. the medical resource deficiency indices (mrdi) are defined as an indicator of medical resource burden at county level. we define two forms of mrdi: general mrdi, and local daily mrdi (mrdi d ). where n c is the accumulated number of confirmed covid patients, n death is the accumulated number of deaths, n licbed is the total number of licensed beds, and n ccs is the number of critical care staff. we assumed that n licbed and n ccs were relatively independent at county level, and the product of them represents the interconnection of these two medical resource features or factors. therefore, the mrdi represents the number of accumulated active confirmed cases normalized by the local maximum potential medical resources (total licensed beds and total ccs). mrdi d is represented as where n ca is the accumulated confirmed case numbers during a most recent alos, n da is the accumulated death numbers during the same alos, r h is the state hospitalized rate derived based on arcgis dashboard, we designed a comprehensive operational dashboard for monitoring, analyzing, visualizing, and sharing our medical data and analyzed results. a multistacked map is built at the center of the interface (fig ) , which represents the spatial distributions of covid-related statistics such as mrdi, death rate, and infection rate at county level over the u.s. in addition to visualizing the macro spatial distribution pattern of those statistics results, two lists of counties are displayed. those counties are dynamically filtered by the current map extent in map view and are ranked in real-time by hospitalized rate and death rate to represent the spreading of covid- and the outbreak situation in the selected study area. focusing on a specific county, an indicator and two pie charts are applied to display for each county (fig ) : ) the comparison of active covid- cases and the number of overall beds; ) the percentage of icu beds in overall beds; and ) the proportion of each type of ccs. from the temporal analysis perspective, a time series chart is designed to demonstrate the dynamics of medical resource deficiencies for each county on a daily basis during the pandemic. in the following section, we will use the dashboard components to analyze spatiotemporal distributions of medical resource deficiencies. we will further explore the possible factors relating to the medical resource deficiencies for specific counties and areas as well as the medical resource capacity for non-severe covid- patients, the supplies needed for severe cases, and proportion of each type of ccs. the icu beds per , residents ( fig a) and ccs per , residents ( fig b) are mapped at county level. both maps show that these two medical resources are not homogeneously distributed across the u.s. some midwestern states, such as north dakota, south dakota, nebraska, kansas, and montana have more icu beds, but less ccs. the spatial distribution of ccs shows a checker board pattern, with many gaps or low numbers across the country. the product of icu beds and ccs per , residents is shown in fig a. the darkest green zones represent counties with higher quantities of medical resources including icu beds and ccs. a total of major medical centers represent top ranking healthcare facilities in the u.s. (table ) [ ] . medical centers are conglomerations of health care facilities including hospitals and research facilities that could be affiliated with a medical school. overlaying the locations of these medical centers on the map (purple circles on the map), it seems these counties and medical centers are spatially highly correlated (fig a) . since senior people (aged +) are vulnerable to covid- , we also produced a map of the product of icu beds and ccs per , senior residents (fig b) . this map represents locations where the supply of medical resources for seniors is higher. a regression analysis was conducted to examine the correlation between ccs and adult icu beds at county level (fig ) . if all , counties are included, the coefficient of determination (r ) is . . however, this high r value is quite misleading, since it is heavily influenced by several large counties with rich medical resources (blue dots). removing the top counties, causes the coefficient of determination (r ) to drop to . , which better represents the geographic disparity of these two factors in most ( ) of the u.s. counties, as shown in fig a and b . a total of counties have neither icu beds nor ccs, and are shown in fig . these counties are mainly distributed in less-populated rural areas across the u.s., and they are not included in mrdi or mrdi d calculation to avoid a divide-by-zero error. during the covid- pandemic, individuals requiring a higher level of care in these areas would be sent to the spatiotemporal dynamics of general mdri across the u.s. is illustrated at: http://mrddashboard.stcenter.net/. the general mdri represents the number of accumulated active confirmed covid- cases normalized by local maximum potential medical resources, while the dynamic view provides an insightful alternative visualization of covid- u.s. cases by county. six snapshot maps are illustrated in fig a- f , which demonstrate six time-stamped frames taken on february , march , april , may , june , and july , . a proportional symbol map is used with semi-transparent red circles to represent the general mdri. this visualization technique enhances clustering patterns, and there is a clear trend where the general medical burden shifted from the east coast of the u.s. to midwestern states. as of july , it would seem that louisiana, mississippi, georgia, tennessee, indiana, and iowa are possibly suffering a new wave of medical resource deficiencies due to the rapid increase of accumulated active confirmed cases in some counties. furthermore, the spatiotemporal dynamics of local daily mrdi d is also illustrated in the dashboards. since hospitalization data has been available only recently, we illustrate two frames taken on may , and august , (fig a and b) . the red circle symbols are semi-transparent, and county-level medical resource deficiencies are visually enhanced by searching the reddest clustering patterns in the map. during this covid- infection period, it seems that mississippi, louisiana, tennessee, and indiana were suffering from medical resource deficiencies, which would have required special attention when relocating medical resources if necessary. these hotspots have been partially confirmed from local news reports. for example, there were , known presumptive cases with the total death toll of in mississippi on april , [ ] ; new cases of covid- rose sharply on may in east baton in the center of the dashboard, several map layers could be selected to show the general spatial distribution of mrdi, death rate, infection rate and active cases over licensed beds per capita. after interactive map scaling (by zooming in/out) and moving (by dragging) operations, or using the polygon selection tool, the charts and rank list are linked and self-adapted to the analysis region of interest to a user. by clicking the polygon of a selected county, attribute information about medical resources and covid- related data would popup and the relevant chart is automatically updated in the dashboard. northern tennessee state is presented as a use case to show the possible interactive analysis (fig ) . since western and east coast regions have more medical resources than central regions (fig a) , and the states along the mississippi river in the southern u.s. show a high risk (fig ) , we zoom in on the map and select the nearest region with the largest red bubble in tennessee (fig ) . thirty counties are selected as a result, and relevant numbers are calculated and presented in dashboard charts. the medical bed pie chart shows icu beds are . % in overall licensed beds, and the medical staff pie chart shows the nurses group is the highest ( . %) followed by physicians ( . %), physician assistants ( . %) and therapists ( . %). the line chart shows a time-series trend for mrdi in the northern tennessee area, and we find the index varied greatly between april , to may , , which could be explained by the possible tracing of the virus to a correction center outbreak in trousdale county [ ] . on the right column of the dashboard, the risk factors of medical resource and infection rate is ranked by the selected region. trousdale, davidson, and sumner county are the top with highest infection risks, while trousdale also shows the highest medical resource risk in this region. the case study in fig demonstrates the potential of our developed dashboard for interactive and visual analysis of specific regions of interest for policy makers, other stakeholders, and the general public. in this study, a data-driven approach has been used to estimate the medical resource deficiencies or medical burden at county level during the covid- pandemic across the u.s. specifically, spatiotemporal data analysis methods including feature extraction, database structured query (sql), data fusion or aggregation, linear regression analysis, and spatial statistics were used to extract medical resource features and patient statistics, such as hospital beds, ccs, local population, covid- confirmed case numbers, and hospitalization data at county level. the average length of stay (alos) was then estimated from hospitalization data at state level, and the hospitalized rate were calculated at state and county level. based on these datasets, we developed two medical resource deficiency indices mrdi and mrdi d that measure the local medical burden from two different perspectives. the first index represents the number of accumulated active confirmed cases normalized by local maximum potential medical resources; and the second one represents the number of hospitalized patients that can be supported per icu beds per critical care staff. the related medical resource data, mrdi and mrdi d were visualized and analyzed using a dynamic spatiotemporal platform created through arcgis pro dashboards, which is a convenient way to enhance the clustering patterns and trends. our analysis showed that ( ) the spatial distribution of medical resources (hospital beds, icu beds, and ccs) at county level is highly heterogeneous across the u.s., and icu beds and ccs are not spatially highly correlated; ( ) mrdi and mrdi d can provide new insights into the u.s. pandemic preparedness and local dynamics relating to medical burdens during a peak period in the covid- pandemic; and ( ) a data-driven dynamic spatiotemporal framework is a powerful data visualization tool to illustrate the trends of mrdi / mrdi d and other medical-related statistics. it is worth noting that we have not considered the number of discharged patients due to lack of data, leading to a possible slight underestimate of alos during the covid- rapid infection period. as a result, mrdi d may also be slightly underestimated. we also did not consider the ratio of icu patients and acute hospitalized patients due to lack of data, and assumed all hospitalized patients were treated as icu cases. as a result, mrdi d was possibly overestimated, and the values calculated here should be viewed as the upper limit of local medical burdens. some other uncertainties include ( ) the numbers of registered hospital beds and ccs could be incomplete or not up-to-date, although the most recent definitive healthcare and npi databases have been used, so the medical resources could be underestimated, ( ) critically ill patients in counties without icu beds and ccs would be sent to neighboring counties with sufficient medical resources, ( ) some numbers of experienced icu staff may become ill, ( ) the number of trained professionals may have increased based on emergent recruiting, and ( ) the capacity in icus and emergency rooms may have been expanded during the crisis. however, mrdi d can still serve as a useful indicator to measure the county-level medical resource deficiencies, and this index can be improved once more public health data are available in the future. furthermore, it could provide reasonable evidence for policy makers in local and state governments to assess their medical inventories and staff resources, and provide preparedness for decision of re-opening the economies and public life. in the future, our work can be combined with epidemic models to either provide driving parameters or calibrate the models and predict the local medical burdens. the spatiotemporal analysis used in this study can be extended to include remote sensing data, social media data, and mobile traffic flow data to estimate severity of pandemic or predict the outbreak cases in the u.s. and other counties. conceptualization: dexuan sha, xin miao, yuyang tian, chaowei yang. the variability of critical care bed numbers in europe critical care bed growth in the united states. a comparison of regional and national trends how prepared is the us to respond to covid- relative to other countries? estimating covid- prevalence in symptomatic americans availability for covid- clinical characteristics of coronavirus disease in china an interactive web-based dashboard to track covid- in real time taking the pulse of covid- : a spatiotemporal perspective big spatiotemporal data analytics: a research and innovation frontier mechanical ventilators in us acute care hospitals. disaster medicine and public health preparedness stockpiling ventilators for influenza pandemics ventilator stockpiling and availability in the us strategic national stockpile: overview and ventilator assets assessing the capacity of the us health care system to use additional mechanical ventilators during a large-scale public health emergency flattening the curve before it flattens us: hospital critical care capacity limits and mortality from novel coronavirus (sars-cov ) cases in us counties estimating the maximum capacity of covid- cases manageable per day given a health care system's constrained resources. annals of internal medicine tiger/line shapefiles and tiger/line files where the icu beds are definitive healthcare: usa hospital beds spatiotemporal patterns of covid- impact on human activities and environment in mainland china using nighttime light and air quality data. remote sensing coronavirus locations: covid- map by county and state the covid tracking project: most recent data medical centers in the united states mississippi covid- cases now number more than new confirmed coronavirus cases in east baton rouge, part of sharp rise; see latest statewide data covid- update: april saw rural america's infection rate increase -fold. the daily indiana passes , covid- deaths; lake county reports four more deaths, brings total to large spike in coronavirus cases traced to prison in trousdale county key: cord- - gutb m authors: lapidus, nathanael; zhou, xianlong; carrat, fabrice; riou, bruno; zhao, yan; hejblum, gilles title: biased and unbiased estimation of the average length of stay in intensive care units in the covid- pandemic date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: gutb m background: the average length of stay (los) in the intensive care unit (icu_alos) is a helpful parameter summarizing critical bed occupancy. during the outbreak of a novel virus, estimating early a reliable icu_alos estimate of infected patients is critical to accurately parameterize models examining mitigation and preparedness scenarios. methods: two estimation methods of icu_alos were compared: the average los of already discharged patients at the date of estimation (dpe), and a standard parametric method used for analyzing time-to-event data which fits a given distribution to observed data and includes the censored stays of patients still treated in the icu at the date of estimation (cpe). methods were compared on a series of all covid- consecutive cases (n = ) admitted in an icu devoted to such patients. at the last follow-up date, days after the first admission, all patients but one had been discharged. a simulation study investigated the generalizability of the methods' patterns. cpe and dpe estimates were also compared to covid- estimates reported to date. results: los ≥ days concerned out of the patients ( %), including of the deaths observed. two months after the first admission, ( %) patients had been discharged, with corresponding dpe and cpe estimates of icu_alos ( % ci) at . days ( . – . ) and . days ( . – . ), respectively. series' true icu_alos was greater than days, well above reported estimates to date. conclusions: discharges of short stays are more likely observed earlier during the course of an outbreak. cautious unbiased icu_alos estimates suggest parameterizing a higher burden of icu bed occupancy than that adopted to date in covid- forecasting models. funding: support by the national natural science foundation of china ( to dr. zhou) and the emergency response project of hubei science and technology department ( fca to pr. zhao). the spread of a novel coronavirus (sars-cov- ) has brought about a pandemic referred to as the covid- pandemic [ ] . this pandemic has resulted in a worldwide crisis with unprecedented decisions of restrictive non-pharmacological mitigation interventions taken at local, regional, or national levels. a major aim of these measures is lessening as much as possible the daily number of new individuals requiring an admission in intensive care units (icu) in order to be able to appropriately manage them in the healthcare system and sustain an appropriate management for the rest of the population [ ] . a fast inflow of new admissions in the icu has critical consequences within a short time. for example, between march and april in france, the number of icu beds occupied by covid- infected persons dramatically increased from to [ ] , corresponding to an average daily increase of % additional beds. such a situation requires a massive and rapid increase of icu facilities and the french minister of health announced on march that the nationwide capacity had been increased from to , critical beds [ ] . the underlying mathematics are simple: an average unbalanced increase of % during days implies that at day , the resulting occupancy would be that of day multiplied by a factor . since . ( days) = . . the system is highly sensitive to a sustained unbalance: even an average increase as low as % during weeks, a likely situation after outbreak peak, would nevertheless require increasing occupancy at day by %. the average length of stay (alos) in icu is an important estimate relating to the stability of the healthcare system in terms of icu bed occupancy. for instance, hypothesizing an icu alos of days in patients infected with a new emerging agent, the daily probability of a bed discharge would be / alos = / = . . this implies that whenever the rate of required admissions would exceed the % alos-dependent threshold, the global number of beds occupied or required would increase and possibly overwhelm capacity. this example demonstrates that estimating the icu alos of a population infected by an emergent virus constitutes a very critical information to modelers and decision-makers for guiding adaptations of the local capacities in the context of the outbreak. such an estimate is expected to be provided as soon as possible. however, when examining the situation within a short delay after the beginning of the outbreak, only few cases are likely to be already discharged from the icu. the patients still in icu referred to as censored cases must be considered in any unbiased estimation relating to the length of stay (los). in this study, we present a detailed examination of the timeline of the whole cohort of consecutive covid- patients admitted to a devoted icu of the zhongnan hospital of wuhan university (zhwu) in which we investigated the evolution of the alos estimation according to the accumulation of the cases, using two methods of estimation. our results indicate that even considering a last followup date corresponding to the date when two-thirds of the admitted patients would have been discharged, the icu alos estimated with the biased method would be nearly half of that issued from the unbiased method. in the light of these investigations, the estimates relating to icu los of covid- cases that have been reported to date [ ] [ ] [ ] [ ] , likely underestimate the real values. such estimates being also used in forecasting models [ ] [ ] [ ] [ ] [ ] , the present study has practical implications for improving prediction scenarios to guide public decision. this study was approved by the medical ethics committee, zhwu (clinical ethical approval no. ). the informed consent was waived by the medical ethics committee for emerging infectious disease. as in many locations, the organization of the zhwu (hubei province, people's republic of china) for managing covid- patients was subjected to several changes during the course of the covid- outbreak. first, on december , at a time when the outbreak emerged frankly, two initial icu, one depending on emergency and the other from surgery, were reorganized for constituting a single entity of beds devoted to the management of patients with covid- requiring critical care. second, on march , at a time when the outbreak had declined, all covid- icu patients were transferred to another icu in leishenshan hospital, the largest newly built facility for covid- patients with beds, while icu admissions were reorganized for other pathologies than covid- at zhwu. third, on april , leishenshan hospital was definitively closed and patients initially admitted at zhwu were retransferred to this hospital. all consecutive patients with a confirmed diagnosis of covid- by pcr and initially admitted to the abovementioned icu of beds at zhwu from december to march (n = ) were included in the study. patients admitted to this icu during this period also included consecutive patients for which there was a radiological evidence of viral pneumonia [ ] while rt-pcr test of throat swabs had remained negative for several times, and these patients were also considered as eligible for the study. last follow-up of patients was made on april , and days after the first and the last admission, respectively. the file of each patient along his/ her hospital course was cautiously reviewed, including whenever the patient was transferred to another hospital. the following data were collected for each patient: age, sex, date of admission and discharge in the hospital as well as the vital status at discharge (dead or alive), date of admission and discharge in the icu as well as the vital status at discharge (dead or alive), beginning and end dates of mechanical invasive or noninvasive ventilation procedures. whenever a patient was transferred from the icu in a given hospital to the icu of another hospital, we considered that such a continuum constituted a single icu stay. since the objective of this study was an assessment of the alos in icu of covid- patients, of the abovementioned stays were excluded from the analysis: first, one of the patients with a confirmed rt-pcr positive test had contracted covid- at the hospital while this patient was hospitalized for post-complications after a kidney transplantation, and the record file highly suggested an icu stay relating more to these complications than to covid- infection. conversely, only three of the ten patients with the radiological evidence of viral pneumonia were included in the analysis: seven patients had clinical characteristics suggesting that the icu stay might be not mainly related to covid- (e.g., liver lesions, massive cerebral infarction, …), and were therefore excluded from the study. data are expressed as mean ( % confidence interval (ci)) or median [interquartile range (iqr)], and represented according to the kaplan-meier estimator [ ] . in addition, we examined how the icu alos estimates of covid- patients issued from two estimation methods evolve and compare while the cumulative number of available stays increases along the course of the outbreak. all analyses were made with r statistical software version . . and censored data were fitted with the use of the flexsurv package. the two methods compared were the following. this first method applies a straight-forward calculation: all icu stays of the series for which the discharge date is before or equal to a given follow-up date of interest were considered (and only such stays were considered). reported alos estimate was the mean los of those already discharged patients. reported los median and quartiles were calculated on the same patients. this second method takes into account the inherent censored characteristic of longitudinal data: considering a given follow-up date of estimation, all previously admitted patients were considered, whether or not they were already discharged. a parametric distribution (e.g., exponential, gamma or weibull) was fitted to the whole set of patients. such a method for appropriately analyzing time-to-event censored data belongs to the standard framework of methods of survival analysis [ , ] . reported alos estimates, as well as los medians and quartiles, are predictions based on this parametric model. in order to demonstrate the generalizability of our results, these two methods were also compared using two simulation studies. both considered a -bed icu with as many patients admitted on day and new patients admitted as soon as the previous ones were discharged. in the first study, simulated los were sampled with replacement from the observed los in zhwu. such a simulation allows to be free from the observed schedule in practice, including the order of occurrence of the lengths of stay observed. the simulation forces the icu to be initiated in an already saturated functioning admitting covid- patients. the los of the patient still in the icu at the date of last follow-up was imputed. in the second study, los were sampled from a parametric gamma distribution in order to explore how estimates evolve with time in a situation where the true distribution is known. the median age of the patients was years [iqr - ] and ( %) were men. the time-course of the icu stays of the covid- patients is shown in fig. a . at the date of last follow-up, april , one patient was still in the icu, deaths ( %) had occurred in the icu, and the patients discharged alive from the icu were also all discharged alive from the hospital. invasive mechanical ventilation procedures concerned ( %) patients: stays involving only noninvasive ventilation concerned patients, stays involving only mechanical invasive ventilation concerned patients, and patients had shifted from one type of ventilation to another during the course of their stay. the mean and median estimates for the duration of mechanical invasive ventilation was . days ( % ci . - . ) and . days [iqr . - days], respectively. the corresponding estimates for noninvasive ventilation were . days ( % ci . - . ) and . [iqr . - . ], respectively. figure b shows the cumulative number of admissions and discharges according to time. at the date of last follow-up, over months ( days) had passed since the date of the first admission, january . figure c shows the evolution of dpe and cpe-based alos estimates according to the accumulating data that become available as time passes. exponential, . c evolution of the estimates of icu average los issued from the two methods of estimation according to the date chosen for estimation. the expected estimate is shown together with the corresponding % confidence interval. cpe, method including censored cases; dpe, method considering only stays for which the patient was already discharged from icu at the date of estimation. whenever some patients of the cohort remain treated in the icu at the date of follow-up, c indicates that dpe yields a biased underestimation of alos: discharges observed early are more likely to concern patients with a short los or conversely, the discharges occurring at the end of the process are more likely to concern patients with a long los. b illustrates the latter pattern: nine out of the first occurring discharges concern los < days, while eight out of the last occurring discharges concerned los > days weibull, and gamma distributions led to similar fits of the data-with a delayed convergence for the exponential distribution-and we retained the gamma distribution for reporting cpe. . whenever some patients of the cohort remain treated in the icu at the date of follow-up, dpe yields a biased underestimation of alos: discharges observed early are more likely to concern patients with a short los or conversely, the discharges occurring at the end of the process are more likely to concern patients with a long los. figure b , in which the los corresponding to each discharged patient is indicated along the discharge curve, illustrates this pattern: out of the first occurring discharges concern los < days, while eight out of the last occurring discharges concerned los > days. in the end, the simulations shown in additional file : appendix s demonstrate the generalizability of the biased pattern of dpe, and the unbiased pattern of cpe. figure a presents a kaplan-meier estimator and indicates that the median icu los is around days. the corresponding estimate issued from cpe is slightly higher, at . days, because the corresponding parametric fit is impacted by the substantial frequency of very long stays: fig. b shows the los distribution and out of the patients ( %) had a length of stay ≥ days. the relatively high frequency of such patients with a very long los explains why the expected estimates of alos shown in fig. c requires a substantial delay until remaining stable. interestingly, among the patients with a los ≥ days, had died while the total number of observed deaths in the cohort was . the fact that % ( / ) of the deaths observed occurred in patients who had an icu stay ≥ days also indicates that obtaining a reliable estimate of the mortality rate in the patients admitted to the icu as well as obtaining a reliable alos of the individuals dying in the icu also requires waiting a substantial delay after the beginning of the outbreak. taking the covid- outbreak as an emblematic example of the first outbreak of a threatening pandemic due to a novel infectious agent, the present study demonstrates the importance of obtaining a reliable estimate of the icu alos in such situations. the study also recalls that appropriate methods of estimation require the inclusion of censored cases in the analysis, and we also demonstrate the important bias associated with calculations only based on the stays of already discharged patients. importantly, the bias inherent of the latter method is not at all sensitive to sample size or to the consideration of factors potentially associated with icu alos value (e.g., variability from one center to another). for example, whatever the number of patients and the variability of the numerous centers involved in the studies of guan et al. [ ] based on national data from china and in the study of grasselli et al. [ ] based on hospitals from lombardy mentioned in table , the provided estimates were biased. finally, whenever patients of the population treated in the icu with a long los are observed at a substantial frequency, as was observed in the present reported series, the bias relating to inappropriate methods might be especially important. although the present study shows that alos constitutes an important parameter, we failed to find any observational study of covid- cases published in the early phase of the epidemic that reported alos. nevertheless, several of these studies had reported median estimates of icu los and such a choice is perfectly understandable: since icu los is not normally distributed, a reporting of median and iqr instead of the mean is recommended. the medians of icu los reported [ - , , ] (see table ) often concern a particular sub-population (e.g., patients who died, patients who survived), ranged from days (estimate considering six patients who died in the icu) to days (estimate reported in the same study and based on patients discharged alive from the icu) [ ] , and raise concerns in terms of the potential bias of the reported estimates (see table ). these concerns may be then extended to modeling studies [ , , , , ] that will naturally parameterize their forecasts according to the observational data reported ( table ). the data of the series reported here yielded an estimate of icu alos at . days ( % ci . - . ) and a median icu los at . days [iqr . - . ]. these estimates are well above estimates that were reported in the early phase of the epidemic. they are associated with several strengths. first the whole study time-course lasted days, enough time had passed for allowing a last date of follow-up at which all patients but one were discharged. to our knowledge, such a resulting quasi-complete distribution of the los observed in a given series of covid- cases (see fig. b ) has not been reported to date, and in addition, such a data set is indeed appropriate for assessing estimation methods since the target value of the estimate is nearly perfectly known (only one stay remained censored). second, the high values reported here are based on a reasonable sample size (n = ) and our study demonstrates that an unbiased estimate at a reasonable distance from the beginning of the epidemic is inherently higher than that issued from a biased calculation a short time after the beginning of the outbreak. nevertheless, our study also has some limitations. the study is monocentric and therefore, the extrapolation of our estimates to other settings is questionable. the gamma distribution-based cpe method allowed a reasonable alos estimate at the beginning of the epidemic, but other distributions might better fit data from other settings. because it is unbiased, the cpe method should nevertheless always be preferred, and the choice of associated simple parametric distributions should be favored as compared to more complex distributions whenever corresponding fittings are similar. the estimate issued from wuhan data is also inherently adjusted for many co-factors with a likely influence on icu los that may vary from one place to another and/or with time. for example, one may think about the impact of disease knowledge on triage decisions and on the decision to withdraw early mechanical ventilation based on refinement of prognostic factors (ethical issues), bed availability and pressure of this threatening epidemic on the organization of the healthcare system likely modifies the characteristics of admitted patients as well as various specific characteristics of the units (including cultural behaviors), accumulating experience with covid- patients likely improves management procedures according to time. ideally, estimates for different spatiotemporal settings should be based on observational data directly collected in corresponding settings for guarantying estimates appropriately adjusted with co-factors. however, such generalizability issues relating to estimate variability according to spatiotemporal conditions also stands for most studies reported to date, and devising a universal validated model able to adjust for any spatiotemporal condition worldwide is a very ambitious work, far beyond the object of the present study. the main outcome of this study is alerting the community about three elements. first, all scientists working on covid- must realize that when dealing with data relating to los, they should imperatively use appropriate methods devoted to the analysis of censored data. such methods are not original, they belong to the standard tools used in the domain of survival analysis and are easily available in any statistical software. there is no reason for avoiding their usage, and the reader will find an illustrative computer code in additional file : appendix s . an additional strength of these methods-illustrated in additional file : appendix s -is their ability to fit individual characteristics of patients with multivariable models to predict los adjusted to co-factors explicitly considered in the model formula. such a modeling strategy may for example be deployed for documenting variations between different recruitment settings or for providing estimates in specific strata of the population. a side result of the analyses made in the present study suggests that the fatality rate of covid- patients in the icu might also be underestimated, and on this topic, the present study shares many perspectives with the work of lipsitch et al. on the biases associated with the estimation of case-fatality risks [ ] . second, in the context of the first outbreak of a novel infectious agent, some estimates concerning time-to-event data such as hospital los, icu los, duration of ventilation, time of illness onset to icu admission, etc., constitute a kind of critical food required to feed forecast models and these models are very important in many issues such as exploring and comparing mitigation scenarios, or optimizing preparedness. therefore, enhancing the quality of the above-mentioned estimates is an important concern and our study suggests that there is room for such enhancements in the analyses of covid- epidemic. third and to conclude, whenever the estimates reported in this study would be generalizable to other settings, then this is bad news: long icu los as reported here imply that occupied beds remain unavailable for a long time and this adds additional pressure to the surge in icu beds encountered in many places worldwide. based on this complete series of consecutive cases together with simulated cases, the present work demonstrates that icu_alos estimates used in most models to date may be importantly underestimated. in such a context of novel infectious agent, this work advocates for an urgent application of widespread survival analysis tools to properly estimate icu_alos and other critical parameters relying on censored time-toevent data. accurate estimation of these parameters, on which rely forecast models, is crucial to ensure consistency of mitigation and preparedness scenarios, as attested by the worldwide concern over icu bed occupancy in the current covid- crisis. the funders had no role in: study design; collection, analysis, and interpretation of data; writing of the manuscript; preparation of the manuscript world health organization impact of non-pharmaceutical interventions (npis) to reduce covid- mortality and healthcare demand response team point quotidien infection au nouveau coronavirus (sars-cov- ): nombre de personnes actuellement en réanimation ou soins intensifs pour covid- baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region italy clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan china clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study projecting hospital utilization during the covid- outbreaks in the united states locally informed simulation to predict hospital capacity needs during the covid- pandemic the epidemic calculator modeling covid- spread vs healthcare capacity ihme covid- health service utilization forecasting team, murray cj. forecasting covid- impact on hospital bed-days, icu-days, ventilatordays and deaths by us state in the next months. medrxiv radiological findings from patients with covid- pneumonia in wuhan, china: a descriptive study survival analysis: a self-learning text survival and event history analysis: a process point of view clinical characteristics of coronavirus disease in china clinical features and short-term outcomes of patients with corona virus disease in intensive care unit potential biases in estimating absolute and relative case-fatality risks during outbreaks publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the decision of performing the study emerged from informal discussions involving nl, xz, fc, br, yz, and gh. study conception and design: nl and gh. data acquisition: xz and yz had full access to all of the raw data in the study and can take responsibility for the integrity of the data. analysis: nl and gh. interpretation of data: nl, xz, fc, br, yz, and gh. first draft of the article: nl and gh. all authors read and approved the final manuscript. this study has benefited from the support of the national natural science foundation of china ( to dr. xianlong zhou) and from the emergency response project of hubei science and technology department supplementary information accompanies this paper at https ://doi. org/ . /s - - - .additional file : appendix s . simulation study.additional file : appendix s . unbiased average length of stay estimation-an illustrative example. all data used in this article are explicitly shown in figs. and of the article. any request for additional details must be sent to drs. zhao and zhou. this study was approved by the medical ethics committee, zhwu (clinical ethical approval no. ). the informed consent was waived by the medical ethics committee for emerging infectious disease. not applicable. prof. carrat reports personal fees from sanofi, personal fees from imaxio, outside the submitted work. the other authors have nothing to disclose. key: cord- -c m o l authors: manca, davide; caldiroli, dario; storti, enrico title: a simplified math approach to predict icu beds and mortality rate for hospital emergency planning under covid- pandemic date: - - journal: comput chem eng doi: . /j.compchemeng. . sha: doc_id: cord_uid: c m o l the different stages of covid- pandemic can be described by two key-variables: icu patients and deaths in hospitals. we propose simple models that can be used by medical doctors and decision makers to predict the trends on both short-term and long-term horizons. daily updates of the models with real data allow forecasting some key indicators for decision-making (an excel file in the supplemental material allows computing them). these are beds allocation, residence time, doubling time, rate of renewal, maximum daily rate of change (positive/negative), halfway points, maximum plateaus, asymptotic conditions, and dates and time intervals when some key thresholds are overtaken. doubling time of icu beds for covid- emergency can be as low as - days at the outbreak of the pandemic. the models allow identifying the possible departure of the phenomenon from the predicted trend and thus can play the role of early warning systems and describe further outbreaks. covid- is the most exacting pandemic since the spanish flu of more than a century ago. the fast outbreak of covid- and the wide spread all over the world transformed a local disease, initially located in china, into a global problem; thus the name: pandemic (fauci et al., ) . italy ( . million inhabitants) is one of the most plagued nations by this pandemic with almost official deaths in the hospitals (as of -apr- ) and over icu beds to treat patients at the peak of covid- emergency (livingston & bucher, ; remuzzi & remuzzi, ) . likewise, lombardy ( million inhabitants) is the most crowded region of italy and the most hit and afflicted region of europe with over official deaths in the hospitals and almost icu beds (grasselli et al., a; grasselli et al., b) . before the pandemic, the number of icu beds for any treatments in lombardy was about (grasselli et al., a; manca, a) and in winter months those beds are usually - % occupied (grasselli et al., a) . the pandemic called for doubling that number at an incredible pace to cope with the repeated tsunami waves of very complicated patients affected by dip (i.e. diffuse interstitial pneumonia). those patients required ever-increasing treatments ranging from oxygen masks, to helmet c-pap, to niv, and eventually tracheal intubation (desai & aronoff, ) . in some hospitals, such as the lodi hospital in lombardy (the one where the first covid- italian patient was diagnosed and sheltered in icu, a year-old sporty male with no comorbidities who remained in the icu ward for days before moving to pip, i.e. post-intensive care, for other days) before the pandemic there were icu beds (cutuli, ) . in a matter of few weeks, the beds became and eventually at the peak of the emergency (i.e. . times more). this called for huge efforts in terms of burden on medical doctors, nurses, and managing team that literally transformed the original wards, operating rooms, and recovery rooms to set up and operate that high number of new icu beds. the mathematical models describing the phenomenon dynamics, which are reported in this paper, have allowed understanding the fast evolution and preparing daily for the continuously increasing burden. besides the predicted numbers, those models allowed also forecasting the different phases of the pandemic and quantifying some basic indicators about the daily variations, the key times, the key figures, the expected decrease, the progressive reach of a maximum plateau before facing with the decrease of icu beds for covid- which we are measuring right now. together with the icu beds, which are reported daily by the italian civil protection department every evening at pm cet (dipartimento della protezione civile, ), we also monitored the dynamics of official deaths. official deaths are the ones that occur to patients sheltered in hospitals after they result positive to a nasal swab and possibly to a ct scan. official deaths are important as they measure one of the two possible outcomes of hospital treatment, either success or failure. physicians have to know and somehow forecast not only the daily number of deaths but also the asymptotic value predicted at the end of the pandemic. such a number is a big burden for the psychology of those who struggle for life (e.g., medical doctors, nurses) but it can prepare them to deal with that fatal outcome and somehow find an upper bound of the phenomenon, as shown in the following. as detailed in section , the mathematical models can be incomplete in the sense that further models might describe with the same or even higher efficacy the dynamics of real data. nonetheless, we will show the reliability, robustness, and quality of the suggested models that can describe the phenomenon evolution with a high degree of precision. the object of this paper consists in making the reader aware of the main features of a pandemic in terms of its dynamic evolution based on key points, key intervals, key dates, and key numbers. the mathematical models can be used to get a background of past events, understand the current situation, and forecast the pandemic evolution over either short-term or long-term horizons. the qualitative and quantitative assessment of the pandemic dynamics allows medical decision-makers to plan for the emergency, prepare for severe times, and finally relax the safety measures and revert to standard elective medicine when the pandemic deflates. the models can outline possible deviations of the pandemic from the expected evolutions and therefore play the role of early warning systems in case of new outbreaks. mathematical modeling can be of real help in describing, understanding, and eventually forecasting how a virus diffuses within a domain (e.g., population, province, region, country, and continent). mathematical models feature a set of mathematical equations that include a number of adaptive parameters that can be determined numerically grounding on available real data (panovska-griffiths, ) . once these models are refined and the adaptive parameter computed, one can use these models to understand what happened in the past (e.g., lessons learnt) and even more important to forecast what might happen in the future (e.g., emergency planning, resource allocation) (he et al., ; poston et al., ; steinberg et al., ) . this section focuses on describing the time evolution (i.e. dynamics) of covid- pandemic centering on only two variables that are the most reliable and therefore robust data, namely the number of icu patients (aka icu beds) and official deaths in hospitals. these data are reported daily by the italian civil protection department (dipartimento della protezione civile, ). day is when the first patient was sheltered in the intensive care unit ( -feb- in italy). we chose to describe and follow, but also to predict, the dynamics of those real values with the simplest mathematical models available. such models were carefully chosen by grounding on a keep-it-simple approach. the models are regression-based, which means that they minimize the distance between model predictions and real data. we selected the models that best describe the dynamics of the phenomenon and feature the lowest number of adaptive parameters. indeed, we only used either two or three adaptive parameters to keep the approach simple, avoid overparameterization, and preserve numerical robustness and stability (manca, a (manca, , b . this approach allows implementing those models on any computers without the necessity of relaying on dedicated programming tools. intentionally, we implemented a set of math models that can run on excel as it is widely available on any operating systems (e.g., windows, mac, linux) and works on several platforms (e.g., computers, tablets, mobile phones). in addition, excel (even though it is not a real programming software) requires a lower learning curve respect to other programming tools such as matlab or mathematica or programming languages such as fortran, c/c++, python (just to cite a few). the supplemental material to this manuscript includes an excel file with the proposed models that can be used to extract important information about past, present and future situation, and to draw the diagrams that describe the phenomenon dynamics and allow understanding its qualitative and quantitative evolution. once the models are identified (i.e. regressed respect to real data), they show new values of the adaptive parameters which play a role in quantifying some important indicators about the pandemic. we intentionally did not use any epidemiologic models such as sir, sird, seir, seird models that are based on a set of few differential equations with initial conditions and a number of adaptive parameters as well as strong assumptions and simplifications (c.h. li et al., ; g.h. li & zhang, ; magal et al., ; xia et al., ) . the family of sir models shows a higher detail of description of the phenomenon. however, according to our opinion, their use is good for running parametric predictive scenarios based on a number of assumptions and hypotheses that are quite sensitive to the selection of proper values of the adaptive parameters and functional description. reliable values of those parameters will be available only at the end of the pandemic and depend significantly on the political decisions endorsed at different times and intensity by each country (or even each region locally) on social-distancing measures and more in general on nonpharmaceutical interventions (bayham & fenichel, ; cowling et al., ) . conversely, the math models proposed in this paper can be used daily (by updating the icu and deaths data respectively) and automatically adapt to the evolution of those values. the phenomena behind icu beds and deaths follow two different evolutionary curves in case of a pandemic. icu beds start from zero at the very beginning of the pandemic, they keep on increasing once the pandemic deploys its intensity up to a maximum value. after the plateau, the icu beds start decreasing and reach a final null value when the pandemic expires. conversely, the deaths number continues increasing monotonically and reaches a final value, which is the fatalities toll the country/region has to pay to the pandemic plague. actually, the deaths number is a cumulated value that increases with the daily fatalities. as far as big regions and countries are concerned, the number of icu beds increases monotonically up to the maximum plateau. this is what both lombardy and italy (onder et al., ) dealt with. conversely, small regions in terms of population and/or positive cases may experience non-monotonically increasing trends. for instance, this is the case of umbria a central region in italy with , inhabitants living in small municipalities distributed on its territory, which experimented a trend of icu beds quite different from the most involved italian regions, the northern ones. indeed, umbria saw often the number of icu beds remaining constant for a few days. now and then, that number decreased and then increased again with rather small fluctuations (i.e. few units per day) due to the tiny number of infected people. for this kind of regions/countries, the models and trends discussed in this paper are not recommended and should be avoided. back to lombardy, after the fast explosion of icu patients following an exponential growth (manca, a; remuzzi & remuzzi, ) , it experienced a saturation condition protracted over several days (manca, b) before reaching the maximum plateau and turning into the descent trajectory. that saturation condition was not constant and the healthcare system was flexible enough to increase at a lower extent (than the necessary one) the number of icu beds. the "saturation" term means that the capacity of daily increasing the number of beds, to cope with the tsunami wave of new patients requiring an icu treatment, was lower than the compulsory number of new icu beds. it is worth observing that the continuous creation of new icu beds took to a subtle drift in terms of treatment quality as new beds were created under huge pressure with an above-limited capacity in already existing wards and intensive/step down areas reconfigured in a matter of few days. coupling the saturation condition with the quality of new icu beds had an impact on the treatment quality of icu patients and consequently on the fatalities toll . indeed, there was also a limiting factor played by the number of physicians and nurses subject to over-intensive activities, with shifts of - hours per day, day over day for more than one month, sometimes being themselves hit by covid- (more than medical doctors left their lives due to covid- ) (adnkronos, ). for the sake of simplicity, let us focus first on the qualitative trend of icu patients. the first days of the pandemic see an exponential increase (remuzzi & remuzzi, ). an exponential curve is characterized by a doubling period that remains constant if no external measures or disturbances occur. it is rather easy to show that a phenomenon is exponential when it fits a straight line in a semilogarithmic diagram (i.e. a diagram where x-axis is linear (time, number of days) and y-axis reports the logarithm of the real values (icu beds). it is possible to measure the quality of the fitting curve (i.e. straight-line) respect to real data by means of the determination coefficient ( r ). this is a nondimensional coefficient ranging from to (hahs-vaughn, ). the higher the value, the better the consistency of the model with real data. in case of both italy and lombardy, the first epidemic days saw r values with either two or three nines as decimals, almost equal to , i.e. . , , . r  . the exponential growth remains stable for about - days. for the sake of correctness, every day the slope of the straight line decreases slightly and the intercept increases slightly (i.e. the point where the line cuts the y-axis). this is intrinsic to the epidemic dynamics and shows that the phenomenon starts reducing its momentum, although it remains exponential (see also figure ). there is a time, days - , when new values of icu beds start departing from the straight line and begin to follow a parabola on the semilog plane. this is the case of the so-called exponentially modified gaussian (emg) trend (golubev, ) . on a standard cartesian plane, the phenomenon is well described by two distinct regions. the first one with upward concavity and the second one with downward concavity. the upward concavity reflects the exponential trend that becomes progressively linear at the inflection point where the concavity changes from upward to downward. at the inflection point, the maximum positive velocity of change occurs. in math terms, we say that at the inflection point the first derivative (i.e. maximum daily change of the observed variable, icu beds) has the highest positive slope (i.e. maximum increment). these are the toughest days to stand the tsunami wave as day over day the increment of icu beds is the highest one. in addition, the bigger the region/country with its number of infected patients, the higher its inertia. after the inflection point, the phenomenon continues to increase but at a slower pace. in this phase, the increase is monotonic, which means that the number of icu beds continues to climb, but the daily growth reduces progressively up to a maximum plateau (around days - ). again, the inertia of the system is usually high and instead of having a train at the top of a rollercoaster that quickly starts falling, the plateau remains stable for a few days. that maximum plateau is critical for the whole system as the icu stay is rather long (murthy et al., ) . usually, patients remain in icu wards at least fifteen days (with twenty-day stay the standard value) (cutuli, ) and, respect to covid- emergency, this quite a long time allows describing the whole icu beds inflation period with curves such as the logistic (hosmer et al., ) or the gompertz (panik, ) ones. at the maximum plateau, small oscillations may occur but finally the system starts decreasing (days - ). the reverse trend of the first ascending period occurs in this second descending phase up to a final null value when the pandemic is out. when the descent starts, the concavity is downward and becomes upward after a new inflection point (with negative slope, i.e. downhill). before the inflection point (days - ), the phenomenon increases the velocity of reduction of icu beds. after the inflection, the reduction pace slows down and approaches progressively the final null plateau (days - ). for the sake of simplicity, the two ascending and descending tracts of the overall icu beds phenomenon can be described with two separate segments of suitable models such as (i) exponentially modified gaussian (emg), (ii) logistic, (iii) gompertz curves. all these models ground on either physical or biological foundations. the logistic model (hosmer et al., ) was originally proposed in by pierre françois verhulst to describe the growth of populations where the rate of reproduction depends on both the existing population and the amount of available resources. the gompertz model (panik, ) is similar to the logistic one and was designed by benjamin gompertz in to describe the law of human mortality. the emg model (golubev, ) fits well processes involving normally-distributed inputs and exponentially distributed outputs. emg characterizes the transition probability of cellular cycles and embraces both the deterministic and probabilistic contributions. the same qualitative discussion made to model the inflation period of icu beds may be adapted to model the regional/national fatalities. contrary to icu beds, the deaths curve is only monotonically increasing and finally approaches the maximum plateau once the pandemic expires. the deployment of that curve is longer and shows a lag time respect to the icu curve of about - days in proximity of the first ascending inflection point. it is worth observing that the fatalities curve is a pure cumulative curve (i.e. integral curve) that sums up the single death tolls experienced daily. quantitatively, the inflection point, when the maximum daily fatalities occur, arrives at days - and it takes a total of - days to reach % of the final maximum plateau. mathematically, the logistic and gompertz models predict the practical extinction of deaths after days - . the hiatus between the logistic and gompertz models increases as the pandemic deploys its dynamics. the predicted numbers should be taken with a grain of salt as (i) these are just forecasts when this manuscript was written; (ii) the fatalities phenomenon depends heavily on the social distancing measures enacted by regions and countries together with the very uncertain outcomes that the so-called phase will produce when people progressively reduce social-distancing and start again to live and work as before the pandemic although with a higher awareness about safety and health related risks. only time will tell if these forecasts approach the real phenomenon or further modeling issues should be accounted for. the mathematical description of the exponential model is: the mathematical description of the logistic model is: the mathematical description of the gompertz model is: where t is time, ,, abc are adaptive parameters and . ... e  is the euler's number. y is the dependent variable that is predicted by the model (i.e. icu patients or deaths). the exponential model features two parameters, whilst the logistic and gompertz ones feature three parameters. as discussed in section . the approach to models parameterization is the minimal one and in line with the keep-it-simple philosophy. as far as the independent variable is concerned, t can be considered either continuous or more correctly discontinuous as it corresponds to the number of days since the start of the pandemic in a specific region/country. equation ( ) in semilogarithmic coordinates assumes the form: which is the equation of a line whose slope is b , the intercept is it is straightforward to determine the doubling time of the exponential growth from equation ( ): the higher the slope of the line (equation ), the shorter the doubling time of the exponential phenomenon. the logistic curve (equation ) is symmetric respect to the inflection point and the sigmoid function is a special case of the logistic function (hosmer et al., ) . the gompertz curve is similar qualitatively to the logistic function but it is not symmetric and takes a longer time to reach the final asymptotic plateau. in addition, the gompertz plateau is higher than the logistic one (once the parameters of both curves are identified to minimize the distance from the same set of real data). table shows the analytic formulae that allow computing the inflection and halfway points. the inflection point identifies the time when the rate of change is highest, whilst the halfway point determines the time when the phenomenon reaches a value that is half than the maximum plateau. it is worth observing that the time when the halfway condition occurs does not mean that after an equivalent amount of time the whole phenomenon completes. indeed, the halfway condition refers to the dependent variable ( y ) and not to the independent one ( t ). both the logistic and the gompertz models have the same maximum plateau when t , ya  . for the sake of clarity, each curve has its own a value that is computed by minimizing the sum of the squared distances between the real data (whose cardinality is np ) and the model predictions (equation ) through the following nonlinear regression procedure (hosmer et al., ) : the minimization of equation ( ) is multidimensional and unconstrained even though the optimizing procedure may be eased by specifying that the degrees of freedom (i.e. the adaptive parameters) are positive. once the model is identified, it is possible to answer the following questions: how much time does the phenomenon take to reach a given percentage respect to the maximum plateau? for instance, at what time the death phenomenon will reach % or % of the asymptotic condition (i.e. the maximum final plateau when the pandemic expires)? mathematically one has to solve the following nonlinear algebraic equation: where p is the desired fraction (e.g., . p  if the desired percentage is %). an easier approach to solve equation ( ) consists in reporting in a table the model predictions (e.g., an excel spreadsheet) as a function of time and to search for the first time when the phenomenon overtakes that percentage (as the asymptotic value a is known). equations ( - ) are good at describing the monotonically increasing phase of icu patients and the whole fatalities phenomenon. once the icu phenomenon touches its maximum value it starts decreasing as discussed in section . . the increase-plateau-decrease region can be described by an exponentially modified gaussian (emg) model whose mathematical description is: where c c  is the multiplying factor, bt is the exponential term and at is the gaussian term. equation ( ) is even more flexible as it can be applied to the uphill part of the icu phenomenon (besides the downhill one). for both the uphill and downhill parts, the emg model always showed positive values for , bc and negative values for a which is a mandatory condition for the gaussian contribution. the weak point of emg is that it is rather precise in predicting values over short-time intervals, whilst it is less reliable over longer periods when applied to the uphill portion of the phenomenon. however, across the maximum plateau and the descending section, the emg predictive performance is rather good. the evaluation of the daily rate of change of the phenomenon can be carried out either in a discrete way by computing the difference between two consecutive model predictions (for instance in the excel spreadsheet) or by analytic differentiation ( dy y dt ). the first derivative of the exponential function is:   ln bt y a b   the first derivative of the logistic function is: the first derivative of the gompertz function is: the first derivative of the emg function is: equations ( once the logistic and gompertz curves reach the maximum plateau, they conclude their scope as far as icu beds are concerned. however, their intrinsic monotonic nature can be suitably exploited to describe the descent towards the end of pandemic when icu beds are null. both logistic and gompertz models can be rewritten according to a reverse formulation respect to the original one. it is sufficient to translate them, change their sign, and move the initial condition to the maximum plateau as reported in the following. the mathematical description of the reverse logistic model is: the mathematical description of the reverse gompertz model is: for the sake of clarity, parameters a and t are known as they are the plateau value and the corresponding time when the maximum of icu beds is reached, respectively. consequently, equations ( - ) reduce to two adaptive parameters, , bc. both equations ( - ) exhibit the same final null plateau when the pandemic expires. finally, the first derivatives of the reverse logistic and gompertz models are respectively: the models reported in section . can be selected and used critically according to their performance and consistency with real data published daily in most countries. it is necessary to determine the values of the adaptive parameters by means of an identification procedure that is based on either a linear or a nonlinear regression of real data depending on the mathematical nature of the model (h.h. zhang et al., ) . the good news is that excel implements a multidimensional optimizer, which is capable of solving the minimization problem of equation ( ). any other programming environments can solve as well that same problem provided a multidimensional unconstrained optimization routine is available. the interested reader can refer to the supplemental material to identify the models and their parameters. one of the performance indicators to discriminate the models and find the most representative is rmse , i.e. the root mean square error (equation ). equally, one can evaluate the either the mean ( mae ) or the median ( medae ) absolute errors via equations ( ) and ( ) this section shows how to choose, use, and extract important information from the proposed models. the case study is applied to both italy and lombardy in terms of icu patients and deaths. in the very first days of the pandemic, the phenomenon is purely exponential (equation ). this assumption proved true after observing the linear trend of dependent variables (i.e. icus and deaths) in semilogarithmic coordinates (equation ) and evaluating the determination coefficient. figure shows how, in the first days of the pandemic, the icu beds grow exponentially as the real data lay almost perfectly on a straight line. the linear trend is even stronger after day . it is worth remarking that the y-axis is logarithmic which means that the integer values are powers of ten in linear coordinates. for the sake of clarity, means icu patients, means icus and means icus. the linear trend is confirmed by the determination coefficient r that approximates (i.e. = . r ). as time progresses, the phenomenon leaves progressively the purely linear trend in semilog coordinates and moves towards a quadratic behaviour (in those same semilog coordinates) that is embodied by an emg model (see equations - ). figure shows the high affinity of real data with the emg model, which is also confirmed by the very high value of the determination coefficient (i.e. = . r ). it is not common to have real data (i.e. experimental data) that are so consistent with a model. somehow and to a first sight, data appear tamed or even worst manipulated to make them smoother, although this is absolutely not true. actually, this smoothing effect is the result of large numbers and cumulated curves. in the following, we will illustrate some diagrams, coincides with the logistic predictions and, as a result, it is almost invisible in the diagram. the trend of real data in lombardy fluctuates a bit more than the corresponding italian trend due to the extreme pressure and saturation condition exerted by the covid- emergency on that region. when lombardy exceeded the threshold of - patients in intensive care units, it was a daily struggle with covid- pandemic to create further intensive care beds to shelter the continuously increasing wave of patients requiring icu treatment and tracheal intubation. that was the challenge that absorbed the most from the medical doctors and nurses of intensive care wards (cutuli, ) . consequently, when the first derivative is equal to zero (as for the emg model in figure ) the maximum plateau of the corresponding model occurs. in lombardy, the emg model of figure identifies the maximum plateau of the icu patients' trend at day ( -apr) and the same happens for italy. equally, the minimum values of the first derivatives for the three models of figure occur for lombardy around day - ( - april) and for italy around day - ( - april). these are the days when the highest daily decreases of icu patients are expected. afterward, the daily decrease continues but its intensity lowers and finally becomes negligible in proximity of the null plateau (see also figure ). figure . the red horizontal bottom line shows the % threshold respect to the maximum measured value and identifies the times when most of the icu wards should be empty. last available real data on -apr. equally, the reverse logistic and reverse gompertz models predict that for italy the descent below the % threshold of icu patients will occur on -may and -may respectively (i.e. and days after the maximum plateau, which is also at days and respectively). these values are in line with the predictions for lombardy. equally, the last remaining icu patients would turn out on -jul and -jul for the reverse logistic and reverse gompertz models respectively (i.e. and days after the maximum plateau, which is also at days and respectively, based on -apr real data availability). the description of death dynamics can ground on the same modeling approach based on the logistic, gompertz, and emg curves (equations , , and - respectively). for the sake of brevity, the initial exponential growth (equation ) will not be reported also because the aforementioned models feature in their formulation an initial part where the curve follows the exponential trend. allows also predicting (as of latest data available on april) that the total expected deaths toll will be and that % of that value will be reached on day ( june). it is worth observing that the gompertz curve is not symmetric and that after the inflection point the change of concavity makes it approach the final maximum plateau slower than other curves such as the logistic and emg ones. at the end of june (day ), the gompertz model predicts that . % of the whole phenomenon is manifested and that fatalities remain before the pandemic is out. it is straightforward to remark that these are predictions based on a mathematical model that is subject to the availability of reliable data. the more the real data the better. indeed, every day the national and regional reports release new data and one can carry out forecasts that are more reliable. in addition, the model forecasts ground on the assumption that future values will be registered and made available according to the same boundary conditions in terms of social distancing measures and data collection conditions. it is worth observing that the behaviour of italy in terms of pandemic dynamics all over its territory is not uniform. it would be a huge mistake to assume a uniform distribution of icu patients and fatalities in its regions as the death toll (as of day ) sees more than % the models of section . applied to the case study of lombardy and italy proved their efficiency in reproducing real data and were used to forecast the evolution of key parameters as the number of icu patients and deaths on both short and long-time horizons. the same models can be applied to different countries and regions (hopman et al., ) if reliable and timely data are collected and shared by the public bodies of civil protection and health. the same models can also be applied to describe the dynamics of other variables provided they are reliable and collected according to the same standards and methodologies. for instance, at least in italy, the swabs done to test possibly infected people adopted different approaches in different regions and they are not representative of the expected number of infected people (grasselli et al., b; molinari et al., ) . indeed, a patient initially positive to a swab has to receive two negative in a row results before being declared no more contagious (e.g., a medical doctor of a lombardy hospital was tested with consecutive swabs before being declared negative. he had to wait days from the first positive swab). therefore, the total number of swabs is not representative of the number of people tested. in addition, a large number of probably infected people have not been tested with a swab and nonetheless have to undergo a quarantine of at least days. this happens to a large number of people living together at home with just released patients from hospitals and to asymptomatic or paucisymptomatic individuals (kimball et al., ; nicastri et al., ) . the three main models proposed in this paper (i.e. emg, logistic, and gompertz), either direct or reverse, can be used for qualitative and quantitative purposes in the covid- emergency. they play two separate roles. first, they track real data and allow discriminating among models to find the most reliable one(s) but also they allow understanding if any unexpected trends start occurring. being analytic and fully developed in terms of functional dependency, they are continuous and feature analytic derivatives of any order. this means that not only the cumulated values but also the daily variations can be observed and monitored to understand if any drifts of the phenomenon are occurring. second, these models can be used to predict the evolution of the phenomenon over either short or long-term horizons. during the very first tough days, the most important forecasts are required over short-time intervals to understand the doubling times of icu beds and allocate/prepare suitable resources to cope with the repeated tsunami waves of patients with acute respiratory distress syndrome. when the pressure is at least partially released, the models can be used to predict when some safer thresholds will be reached. in those cases, it will be possible to decrease the number of covid- beds, to close dedicated wards, to reallocate human resources, to restart elective hospital activities that were intentionally shutdown or reduced to the minimum to focus on the demanding emergency. also, the reported models have been exploited for decision making (see figure ) to understand if some extreme decisions in terms of resources allocation would timely meet the dynamics of phenomenon (e.g., reallocation of wards, building new hospitals, moving icu patients to other hospitals and regions/countries). models can be compared for their consistency and precision in describing the phenomenon by evaluating suitable key performance indicators (kpis) as the ones reported in equations ( - ) (k. zhang et al., ) . table and table there is not a clear best-performer among the models used to describe the dynamics of icu patients. however, the gompertz model behaves on average better than the logistic one both uphill and downhill. the emg model can predict the transit across the maximum plateau before leaving the stage to the reverse logistic and gompertz models. the performance of the emg model is better in lombardy than in italy and it is comparable with the uphill and downhill trends of direct and reverse logistic and gompertz models. it is worth remarking that each kpi is characterized by a specific functional dependency and therefore the values of a kpi should be considered just to compare different models belonging to the same region/country (k. zhang et al., ) . for instance, it is reasonable that the kpis of italy are higher than those of lombardy are as the involved numbers are higher for the whole nation respect to that single region. indeed, the maximum plateau counted patients in italy and patients in lombardy. since the unit of measure of all the kpis reported in table and table is the number of icu patients, it is possible to observe that proportionally the same models were a bit less accurate in the predictions of lombardy respect to those of italy. however, the prediction capability of all the proposed models is rather accurate as they describe the allocation of thousands of icu beds and can cope with the intrinsic oscillations of biological and massive organisms (e.g., regions and nations) when they are hit by a pandemic that exerts paramount pressure and burden on their vital resources (livingston & bucher, ) . the comparison of models for the prediction of fatalities is easier as the phenomenon is somehow simpler since it is monotonically increasing and once it passes the inflection point one has to wait only for the final plateau. in case of fatalities, the gompertz model is the clear winner in terms of precision and reliability over the whole horizon of available real data (from the very beginning of pandemic until day , april for italy and lombardy). conversely, the logistic model had to be discarded after day as its predictions were too optimistic and it calculated that final plateau would occur earlier and with a too low fatalities toll. since the number of deaths in lombardy and italy were rather high at day ( and respectively), the kpi values reported in table are pretty low respect to the dimension of the phenomenon (where the expected final number of fatalities was for italy and for lombardy according to the projections of day , april). the paper presented and discussed a few regression models to predict two of the most important variables in a pandemic from the point of view of decision-making and emergency planning. these are the number of icu patients who must be sheltered in dedicated covid- wards and the number of fatalities. these models can be applied to different regions and countries as the pandemic phenomenon has the same qualitative features. the two, maximum three, adaptive parameters allow describing quantitatively the dynamics of those different regions and countries. indeed, every region and every country are characterized by different features bound to their territory nature, population distribution (in terms of age, density, life-styles, human interactions, family habits), and political decisions (in terms of progressive/immediate, relaxed/inflexible lockdowns, social distancing, and other non-pharmaceutical interventions). the mathematics behind the proposed models is rather simple and can be implemented in an excel file that can be used by most decision makers and medical doctors. based on real data that most countries/regions produce daily, these regression models can be identified in terms of their adaptive parameters and used to forecast the trends of icu and deaths on either short or longterm horizons. these same models can also be adapted to track other variables as far as the reliability of those variables is good enough to preserve their consistency. once identified, the models can determine (i) the doubling time of the phenomenon, (ii) the inflection point where the daily increment of the phenomenon is either maximum positive (uphill) or maximum negative (downhill), and (iii) the maximum plateau. in addition, these models can evaluate the time when some conditions occur, such as the achievement of a fraction of the maximum plateau. by monitoring some suitable kpis, the user can assess the performance of the models and understand when they should be quit or if the reverse version of the model (in case of the logistic and gompertz models) would fit better the new real data. the periodic update of these models and the important details that one can extract by observing the diagrams that compare the prediction capabilities respect to real data allow detecting possible drifts of the phenomenon and can play the role of early-warning systems if the pandemic derails from the expected evolution. coronavirus, medici morti in italia impact of school closures for covid- on the us health-care workforce and net mortality: a modelling study. the lancet impact assessment of nonpharmaceutical interventions against coronavirus disease and influenza in hong kong: an observational study covid- : the lodi model (in italian) masks and coronavirus disease (covid- ) covid- italia-monitoraggio situazione covid- -navigating the uncharted exponentially modified gaussian (emg) relevance to distributions related to cell proliferation and differentiation critical care utilization for the covid- outbreak in lombardy, italy: early experience and forecast during an emergency response baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region applied multivariate statistical concepts how to transform a general hospital into an "infectious disease hospital" during the epidemic of covid- managing covid- in low-and middle-income countries applied survival analysis: regression modeling of time to event data applied logistic regression: third edition asymptomatic and presymptomatic sars-cov- infections in residents of a long-term care skilled nursing facility -king county analysis of epidemic spreading of an sirs model in complex heterogeneous networks dynamic behaviors of a modified sir model in epidemic diseases using nonlinear incidence and recovery rates coronavirus disease (covid- ) in italy final size of an epidemic for a two-group sir model analysis of the number growth of icu patients with covid- in italy and lombardy dynamics of icu patients and deaths in italy and lombardy due to covid- sars-cov- : the lombardy scenario in numbers care for critically ill patients with covid- coronavirus disease (covid- ) in a paucisymptomatic patient: epidemiological and clinical challenge in settings case-fatality rate and characteristics of patients dying in relation to covid- in italy growth curve modeling: theory and applications can mathematical modelling solve the current covid- crisis? management of critically ill adults with covid- covid- and italy: what next? the lancet calculated decisions: covid- calculators during extreme resource-limited situations epidemics of sirs model with nonuniform transmission on scale-free networks linear or nonlinear? automatic structure discovery for partially linear models a comparison and evaluation of key performance indicator-based multivariate statistics process monitoring approaches the authors acknowledge the valuable discussions with md piergiorgio villani (lodi hospital), md giovanni mistraletti (san paolo di milano hospital), and md francesco trotta (lodi hospital). key: cord- -w y fjw authors: rodriguez-rubio, miguel; camporesi, anna; de la oliva, pedro title: the role of the pediatric intensivist in the coronavirus disease pandemic date: - - journal: pediatr crit care med doi: . /pcc. sha: doc_id: cord_uid: w y fjw nan response in premature infants with mild-to-moderate respiratory distress. in this regard, we agree with the comment by madney et al ( ) that the experimental period of hours may be considered too short to investigate the full treatment response to a single dose and the possible need for repeat dosing. indeed, after achieving our objective of identifying an appropriate dose of surfactant nebulization for the treatment of respiratory distress in our preclinical setting and demonstrating the safety of the technique using an e-flow nebulizer ( ), we undertook a long-term study to evaluate the efficacy of this technique over the critical period of hours after surfactant administration ( ). our results confirm that the nebulization of mg/kg of poractant alfa is effective in our animal model, given the % lower risk of respiratory failure (requiring intubation and mechanical ventilation) in the first hours after surfactant administration treatment than ncpap alone. unfortunately, we did not test the repeat dosing option in this study setting. finally, the authors raise an important question regarding the translation of the results obtained in our preclinical study to clinical practice. it is known that to better understand the pathophysiology of neonatal rds and verify novel treatment approaches, rds animal models have been extensively used for many years, and we would like to argue are still very much needed today. nonetheless, while it is true that animal models provide a valuable bridge between laboratory research and the clinic, we agree, of course, that translating our results (and indeed the results from any preclinical experimental model) to human infants requires caution. of note, a clinical trial to investigate the safety, tolerability, and efficacy of nebulized poractant alfa has been recently closed european union drug regulating authorities clinical trials database number: - - . more details on the outcomes of this clinical trial, and perhaps other future studies in the field, will be needed to understand the risk-benefit profile for this therapeutic option and, in turn, the potential role of surfactant nebulization in premature infants with rds. drs. rey-santano's, mielgo's, and gomez-solaetxe's institution received funding from chiesi farmaceutici and carlos iii health institute (pi / ), and they disclosed off-label product use of vibrating-membrane nebulizer (eflow-neos). dr. salomone disclosed off-label product use of aerosolized poractant alfa. drs. salomone and bianco received funding from chiesi farmaceutici. t he outbreak of infections by the severe acute respiratory syndrome coronavirus (sars-cov ) was officially declared a public health emergency of international concern by the world health organization (who) on january , , after the initial cases in china continued to rise and new cases started to be reported from several other countries in asia and europe. on march , , with over , cases and almost , deaths in the european region, the who declared the outbreak a pandemic ( ) . to this day, the number of sars-cov infections (coronavirus disease [covid- ]) continues to rise worldwide bringing along an alarming number of deaths. the global preparedness monitoring board of the who, in its "a world at risk report," stated that although progress had been made, worldwide efforts to face a health emergency remained "grossly insufficient" ( ). although icus have had to prepare for pandemic situations in the past and guidance has been provided by professional societies ( ), the current unprecedented situation continues to overwhelm healthcare systems and economies around the world. governments are facing socioeconomic, logistic, and organizational challenges that may change the way our societies and healthcare systems function forever. the availability of icu beds varies greatly among countries ( ) and depends on several factors such as the number of beds per , habitants, the socioeconomic status, the prevalence of chronic illnesses, and overall health status of the population and management choices (i.e., different admission and discharge criteria). during the current pandemic, special attention has been paid to icu bed and ventilator availability. many hospitals in italy, spain, the united kingdom, or the united states have been forced to expand their icus outside of their regular spaces using nonconventional locations like operating theaters, wards, or postoperative care units as icus. these ad hoc spaces commonly lack the complex architecture and resources of a conventional icu making logistics challenging. although healthcare systems around the world have been able to expand their capacity in terms of icu beds, ventilator availability has been a major problem. with a saturated global market that cannot meet the demand of these high-tech devices, physicians and respiratory therapists have turned to alternative management strategies including careful selection of the patients who will benefit the most from invasive ventilatory support, extended use of noninvasive support, off-label use of noninvasive ventilation devices, or anesthesia machines for invasive mechanical ventilation or even ventilator splitting (i.e., using one ventilator to support two or more different patients) ( ). likewise, governments, academic institutions, private companies, and individuals have made an enormous effort to increase the offer of ventilators including, in some cases, homemade devices. with an increased icu bed capacity and ventilator availability, the next challenge arises: critically ill adults with covid- are highly complex patients who have important requirements of specialized icu management, including nursing, respiratory support, and supportive care. the increased complexity along with the elevated number of patients requiring intensive care adds up to the high number of healthcare workers affected by covid- in creating severe staffing problems among institutions worldwide. although goran haglund established the first ever picu in gothenburg, sweden, in , pediatric critical care medicine is a relatively young subspecialty (e.g., the pediatric section of the society of critical care medicine was created in ) that has rapidly evolved into a highly complex field ( ). pediatric intensivists are highly skilled, highly specialized physicians who treat, on a day-to-day basis, severely ill children with life-threatening diseases such as congenital heart disease, trauma, and infectious diseases. picus are high-acuity units where children in a wide range of ages receive state of the art care around the clock, including invasive mechanical ventilation, extracorporeal life support, or continuous renal replacement therapies. covid- seems to somewhat spare children with those who show symptoms rarely evolving to need picu admission ( ). this situation leaves pediatric critical care teams relatively unexposed to the infection and with a maintained or decreased workload. in an unprecedented situation for icus around the world and with healthcare systems suffering severe shortages of equipment and staff, pediatric critical care physicians can be of great value in providing temporary support to adult icus ( ). with advanced knowledge in physiology and, specifically, respiratory support, pediatric intensivist can be integrated into icu teams and under the constant supervision of adult icu consultants can exceptionally perform fellowlevel tasks that may help alleviate the burden these teams are suffering. pediatric teams have been providing resources and logistic support to adult icus in our regions for the last month and a half. this process has been driven by institution-wide protocols and well-meaning improvisation with very little specific guidance, leading to significant heterogeneity in practice. questions remain as to whether admitting adult patients to picus or deploying pediatric intensivists to adult icus should be the preferred model. we encourage professional societies from the critical care field, both adult and pediatric, to develop and distribute consensus statements that at a national level may provide help and support on how to integrate mixed teams in which pediatric intensivists can have clearly defined roles and responsibilities. ( ) highlight an important alternative role for pediatric intensivists outside the picu in supporting adult icus in the fight against the covid- pandemic. pediatric intensivists are comprehensively trained in principles of critical care (e.g., respiratory physiology and mechanical ventilation) which can be easily transposed to adult patients making them qualified to oversee care in an adult icu as described ( ) . our recent perspective ( ) should provide pediatric providers with clinical guidance important in caring for adult patients with covid- and highlight common adult situations rarely encountered in pediatrics. this guidance can be applied in an adult or pediatric hospital. a number of the issues raised by christian and kissoon ( ) can be overcome if pediatric intensivists oversee the care of adults with covid- in a primary adult setting. this appears to be the strategy used in spain and italy ( ) . an interesting alternative recently reported ( ) is the care of adults with covid- within a picu located in a primarily adult hospital. in these situations, the hospitals had in place the supplies and systems needed to care for adults. likewise, there exist academic pediatric hospitals which are connected by halls or bridges to adult centers readily permitting the use of adult consultants and equipment/supplies overcoming many of the challenges pointed out by christian and kissoon ( ) . we agree with these authors that these approaches are preferred prior to bringing adults into a picu where the care of adults is uncommon. in a covid- surge, one must consider whether the scarcity lies in trained personnel or appropriately equipped critical care settings, or both. admitting adults to a picu in a children's hospital is sensible when icu equipped spaces with optimal monitoring, gases, vacuum, etc. are scarce. this avoids creating ad hoc icus in schools or stadiums which have been proposed for surge capacity but have clear limitations. adults brought to a pediatric setting may benefit from services uncommon in adult hospitals such as pet, art, music, and "child life" therapies and rooms designed to permit a family member to remain during the hospitalization. thousands of adults have died in heartbreaking isolation from their loved ones without any form of solace in their final days-a situation rarely permitted in pediatric hospitals. a "one size fits all approach" is unlikely to be universally effective or feasible during this pandemic. however, the pandemic does provide an opportunity to consider related nonpandemic patient care issues such as where and how to care for adults with congenital heart disease, cystic fibrosis, sickle cell, or muscular dystrophies where pediatric providers/hospitals may have greater expertise. we appreciate the innovative approaches and dedication exhibited by our colleagues in spain and italy as they bravely confront this pandemic and prove that pediatric intensivists can save lives regardless of the age. to the editor: w e read with great interest the article by carcillo et al ( ) published in a recent issue of pediatric critical care medicine. studies with biomarkers in adults with sepsis and acute respiratory distress syndrome (ards) have shown that identification of specific subphenotypes could lead to a better identification of patients that could be more responsive to interventions. in ards, a combination of biomarkers and clinical data improved the understanding of the patient profiles and may influence entry criteria of clinical trials. recent trials support that the presence of ards subphenotypes may demand distinct treatment approaches, regarding, for example, fluid management or other specific therapies ( ) . in statins for acutely injured lungs for sepsis study ( ), two subphenotypes (hyper-inflammatory subphenotype or not) were tested for distinct treatment response to statin. although the use of statin did not show treatment effect, hyperinflammatory" subphenotype patients had higher mortality noninvasive surfactant use in the treatment of respiratory distress syndrome world health organization: who announces covid- outbreak a pandemic global preparedness monitoring board: a world at risk: annual report on global preparedness for health emergencies introduction and executive summary: care of the critically ill and injured during pandemics and disasters: chest consensus statement international comparisons of intensive care: informing outcomes and improving standards caring for critically ill adults with coronavirus disease in a picu: recommendations by dual trained intensivists the role of the pediatric intensivist in the coronavirus disease pandemic caring for critically ill adults in picus is not "child's play repurposing a pediatric icu for adults all authors contributed equally to the writing process. the authors have disclosed that they do not have any potential conflicts of interest. the authors have disclosed that they do not have any potential conflicts of interest. we thank all of our colleagues in adult and pediatric critical care around the world for the inspiring high-quality care they continue to provide during this pandemic. key: cord- -ncfxlnpj authors: cillóniz, catia; ewig, santiago; ferrer, miquel; polverino, eva; gabarrús, albert; puig de la bellacasa, jorge; mensa, josep; torres, antoni title: community-acquired polymicrobial pneumonia in the intensive care unit: aetiology and prognosis date: - - journal: crit care doi: . /cc sha: doc_id: cord_uid: ncfxlnpj introduction: the frequency and clinical significance of polymicrobial aetiology in community-acquired pneumonia (cap) patients admitted to the icu have been poorly studied. the aim of the present study was to describe the prevalence, clinical characteristics and outcomes of severe cap of polymicrobial aetiology in patients admitted to the icu. methods: the prospective observational study included consecutive adult patients with cap admitted to the icu within hours of presentation; ( %) patients had an established aetiology. results: polymicrobial infection was present in ( %) cases ( % of those with defined aetiology): cases with two pathogens, and six cases with three pathogens. the most frequently identified pathogens in polymicrobial infections were streptococcus pneumoniae (n = , %), respiratory viruses (n = , %) and pseudomonas aeruginosa (n = , %). chronic respiratory disease and acute respiratory distress syndrome criteria were independent predictors of polymicrobial aetiology. inappropriate initial antimicrobial treatment was more frequent in the polymicrobial aetiology group compared with the monomicrobial aetiology group ( % vs. %, p < . ), and was an independent predictor of hospital mortality (adjusted odds ratio = . , % confidence interval = . to . ; p < . ). the trend for higher hospital mortality of the polymicrobial aetiology group compared with the monomicrobial aetiology group (n = , % versus n = , %), however, was not significantly different (p = . ). conclusions: polymicrobial pneumonia occurs frequently in patients admitted to the icu. this is a risk factor for inappropriate initial antimicrobial treatment, which in turn independently predicts hospital mortality. community-acquired pneumonia (cap) remains a common and potentially life-threatening condition. among patients hospitalised by cap, the rates of severe cap range from . to . % [ ] . the pathogens causing cap may vary according to geographic area and underlying risk factors. appropriate initial antimicrobial treatment has been repeatedly shown to be crucial for the outcome in severe infections. the knowledge of pathogen patterns causing cap as the basis for the selection of such treatment is therefore crucial. some studies have revealed that more than one causative microorganism was present in a considerable amount of cases. one of main problems for the studies on microbial aetiology in cap is that not all microbiological tests are applied systematically for all patients. this limitation could possibly imply that the real frequency of polymicrobial aetiologies in main series is often underestimated. the reported rates for polymicrobial aetiology, however, differ considerably between . and . % [ ] [ ] [ ] [ ] [ ] [ ] . the clinical significance of polymicrobial aetiology in cap patients admitted to the icu has not been specifically addressed. we therefore studied the prevalence, clinical characteristics and outcomes of severe cap of polymicrobial aetiology in icu patients. the study was approved by the ethics committee of our institution, but written informed consent was waived due to the non-interventional design. the present cohort included consecutive adult patients with cap admitted to the icu within hours of admission to the emergency department in an bed tertiary care university hospital (hospital clinic of barcelona, spain) between january and december . the decision for admission to an icu was made by the attending physician in all cases. pneumonia was defined as a new pulmonary infiltrate found on the hospital admission chest radiograph with symptoms and signs of lower respiratory tract infection. we excluded patients with immunosuppression (for example, patients with neutropaenia after chemotherapy or bone marrow transplantation, patients with druginduced immunosuppression as a result of solid-organ transplantation or corticosteroid (> mg/day) or cytotoxic therapy, and all hiv-infected patients) and healthcare-associated pneumonia patients. the following parameters were recorded at admission: age, sex, tobacco use, alcohol and drug consumption, co-morbidities (chronic respiratory disease, including chronic obstructive pulmonary disease, asthma and bronchiectasis among others, diabetes mellitus, chronic cardiovascular disease, neurological disease, chronic renal disease and chronic liver disease), antibiotic treatment in the previous days before hospital admission, treatment with corticosteroids, clinical symptoms and features (fever, cough, pleuritic chest pain, dyspnoea, mental confusion and aspiration), clinical signs (blood pressure, body temperature, respiratory rate and heart rate), arterial blood gas measurements, chest radiograph findings (number of lobes affected, pleural effusion and atelectasis), laboratory parameters (haemoglobin level, white blood cell count, platelet count, serum creatinine level, c-reactive protein level and other biochemical parameters), diagnostic procedures, empiric antibiotic therapy, ventilatory support, pulmonary complications (empyema, acute respiratory distress syndrome (ards) criteria, pleural effusion and surgical pleural draining) and other clinical events (cardiac arrhythmias, septic shock, and acute renal failure). the duration of treatment, length of hospital stay and -day in-hospital mortality were noted. we also calculated the pneumonia severity index (psi) at admission [ ] . microbiological examination was performed in sputum, urine, two samples of blood and nasopharyngeal swabs. pleural puncture, tracheobronchial aspirates and bronchoalveolar lavage (bal) fluid, when available, were collected. conventional tests were used to evaluate the presence of bacterial, parasitic and fungal agents, and of respiratory viruses. sputum, bronchial aspirate sample (bas) and bal specimens were stained using the gram and ziehl-neelsen methods for bacterial and mycobacteria detection, respectively. in bal samples, the following additional stains were used: may-grünwald giemsa for fungal detection and cellular differential count, and gomori methenamine silver for pneumocystis jirovecii. sputum and pleural fluid samples were qualitatively cultured for bacterial pathogens, fungi and mycobacteria. bronchial aspirate sample (bas) and bal samples were homogenised and processed for quantitative culture by serial dilutions for bacterial pathogens; undiluted cultures for legionella spp., fungi and mycobacteria were also carried out. nasopharyngeal swabs and bal specimens were processed for antigen detection by immunofluorescence assay and for isolation of viruses in cell culture (influenza virus a, influenza virus b, human parainfluenza viruses to , adenovirus and respiratory syncytial virus). in addition, two independent multiplex-nested rt-pcr assays able to detect from to copies of viral genomes were performed for the diagnostics of respiratory viruses. one rt-pcr assay detected influenza virus types a, b and c, respiratory syncytial viruses a and b, and adenovirus. another rt-pcr assay studied parainfluenza viruses , , and , coronaviruses e and oc , rhinoviruses and enteroviruses. all positive results were subsequently confirmed by a second independent assay. sputum and blood samples were obtained for bacterial culture before the start of antibiotic therapy in the emergency department. nasopharyngeal swab for respiratory virus detection and urine samples for streptococcus pneumoniae and legionella pneumophila antigen detection were obtained within hours after hospital admission. blood samples for serology of atypical pathogens and respiratory virus were taken at admission and within the third and sixth week thereafter. the aetiology was considered definite if one of the following criteria was met: blood culture positive (in the absence of an apparent extrapulmonary focus); positive bacterial culture of pleural fluid or transthoracic needle aspiration samples; elevated serum levels of igm against chlamydophila pneumoniae (≥ : ), coxiella burnetii (≥ : ) and mycoplasma pneumoniae (any positive titre); seroconversion (that is, a fourfold increase in igg titres) for c. pneumoniae and l. pneumophila > : , c. burnetii > : and respiratory viruses (influenza viruses a and b, parainfluenza viruses to , respiratory syncytial virus and adenovirus); positive urinary antigen for l. pneumophila (binax now l. pneumophila urinary antigen test; trinity biotech, bray, ireland); positive urinary antigen for s. pneumoniae (binax now s. pneumoniae urinary antigen test; emergo europe, the hague, the netherlands); bacterial growth in cultures of tracheobronchial aspirates (≥ cfu/ml), in a protected specimen brush (≥ cfu/ ml) and in bal (≥ cfu/ml); and detection of antigens by immunofluorescence assay plus virus isolation or detection by rt-pcr testing for respiratory virus (influenza viruses a and b, parainfluenza viruses to , respiratory syncytial virus, rhinovirus and adenovirus). the aetiology of pneumonia was classified as presumptive when a predominant microorganism was isolated from a purulent sample (leukocytes > per high-power microscopic field and few epithelial cells < per highpower microscopic field) and the findings of gram staining were compatible. for the purpose of the present study, presumptive and definitive diagnostics were analysed together. polymicrobial pneumonia was defined as pneumonia due to more than one pathogen. severe cap was defined when at least one major criterion or three minor criteria of the infectious disease society of america/american thoracic society (idsa/ats) guidelines were present [ ] . appropriateness of empiric antibiotic treatment was defined when the isolated pathogens were susceptible in vitro to one of the antimicrobials administrated according to current european guidelines for microbiological susceptibility testing [ ] . for pseudomonas aeruginosa infection, adequate treatment needed a combination of two active antibiotics against the isolated strain. categorical variables are described as frequencies and percentages, while continuous variables are presented as means and standard deviations, or as the median and interquartile range for data not normally distributed (kolmogorov-smirnov test). categorical variables were compared with the chi-square test or fisher's exact test where appropriate. continuous variables were compared using the student t test once normality was demonstrated; otherwise, the nonparametric mann-whitney u test was performed. univariate and multivariate logistic regression analyses were performed to identify variables predictive of patients with polymicrobial pneumonia (dependent variable). the independent variables analysed were: age, gender, smoking, alcohol consumption, previous antibiotic, influenza vaccine, pneumococcal vaccine, inhaled corticosteroids, systemic corticosteroids, chronic cardiovascular disease, chronic renal failure, diabetes mellitus, chronic liver disease, neurological disease, chronic pulmonary disease, fever, c-reactive protein level, white blood cell count, creatinine, psi, multilobar infiltration, ards criteria, shock and mechanical ventilation. univariate and multivariate logistic regression analyses were performed to predict day mortality (dependent variable). the independent variables were the previous plus the number of aetiologies and adequacy of empirical treatment, with the exception of ards, shock and mechanical ventilation. variables that showed a significant result univariately (p < . ) were included in the multivariate logistic regression backward stepwise model. the hosmer-lemeshow goodness-of-fit test was performed to assess the overall fit of the model [ ] . all tests were two-tailed and significance was set at %. all analyses were performed with spss version . for windows (spss inc., chicago, il, usa). during the study period, , patients were hospitalised with a diagnosis of cap. of these, ( %) patients were admitted to the icu. the main characteristics of patients and the outcome variables are shown in table . among the patients who had received antimicrobial treatment prior to hospital admission, the median duration of treatment was . days. the types of antibiotics received were: ( %) β-lactams, ( %) fluoroquinolones, six ( %) macrolides and ( %) unknown. the specimens obtained included blood cultures from ( %) patients, urine from ( %) patients, acute and follow-up sera from ( %) patients, sputum from ( %) patients, bronchoscopically obtained lower respiratory secretions from ( %) patients, pleural fluid in ( %) patients, and nasopharyngeal and oropharyngeal swabs from ( %) patients. the aetiology of cap could be established in ( %) icu patients. the proportion of patients with defined aetiology was higher in those with available lower respiratory tract samples, which included sputum and bronchoscopically obtained secretions (table ) . patients with lower respiratory tract samples were more severe, assessed by higher psi risk classes, more frequent septic shock, ards criteria and the need for mechanical ventilation. monomicrobial infection was detected in cases and polymicrobial infection in cases ( % of the overall population and % of those with defined aetiology only), with two pathogens isolated in cases and three pathogens in six cases. as shown in table , the most frequently identified pathogens were s. pneumoniae, respiratory viruses, p. aeruginosa, methicillin-resistant staphylococcus aureus (mrsa), gram-negative enteric bacilli (gneb) and l. pneumophila. patients with polymicrobial aetiology had previously received antibiotics less frequently, had a higher proportion of chronic respiratory and neurological diseases, less frequently presented fever at admission, had higher rates of psi risk class v, had severe cap according to the idsa/ats definition, and fulfilled ards criteria. the length of hospital stay and hospital mortality tended to be higher in these patients ( table ) . as regards the aetiologic pathogens, the proportion of respiratory viruses-particularly influenza a, mrsa, p. aeruginosa, gneb, haemophilus influenzae and moraxella catarrhalis -were more frequently isolated in patients with polymicrobial pneumonia, without differences in the remaining pathogens (table ) . data on antibiotic treatment were available in ( %) patients. the most frequent regimens were fluoroquinolones plus β-lactam (n = , %), β-lactam plus macrolide (n = , %), fluoroquinolone monotherapy (n = , %) and β-lactam monotherapy (n = , %). these regimens were similarly administered in patients with monomicrobial or polymicrobial aetiology. the empirical antibiotic treatment was more frequently inappropriate in patients from the polymicrobial aetiology group (table ). when respiratory viruses were not taken into account, the pathogens most frequently associated with inadequate treatment were mrsa in cases, and s. pneumoniae, p. aeruginosa and gneb in nine cases each. none of our patients received antiviral therapy. several variables were significantly associated with polymicrobial pneumonia in the univariate logistic regression analyses (table ) . among these variables, chronic respiratory disease and ards criteria at hospital admission were independent predictors of polymicrobial aetiology in the multivariate analysis. the univariate logistic regression analyses revealed several variables significantly associated with hospital mortality (table ). although polymicrobial pneumonia (that is, two or more pathogens identified) was associated with increased mortality compared with the absence of defined aetiology, the differences between monomicrobial and polymicrobial aetiology were not significant, as shown in table . among these variables, age ≥ years, neurological disease, chronic liver disease and inappropriate antimicrobial treatment were independently associated with increased hospital mortality in the multivariate analysis. polymicrobial aetiology was found in % of all patients with cap admitted to the icu, % considering those with defined aetiology only. although s. pneumoniae was the most frequent pathogen in both groups, we found mrsa, p. aeruginosa, gneb, h. influenzae, m. catarrhalis and respiratory viruses more frequently identified in polymicrobial pneumonia than in monomicrobial pneumonia. chronic respiratory disease and ards criteria were independent predictors of polymicrobial aetiology. although an independent predictor of hospital mortality such as inappropriate treatment was more frequent in the polymicrobial aetiology group, the trend for higher hospital mortality in patients from this group was not statistically significant. in general populations of hospitalised patients with cap, we have previously reported lower rates of polymicrobial pneumonia ( %) [ , ] than in this series of icu patients. other studies on patients with cap found . % and . % rates of polymicrobial aetiology in their series [ , ] . these wide variations might be explained by differences in the populations studied, epidemiological settings, rate of antimicrobial pretreatment, microbiological workup and definitions of aetiology. a typical limitation of many studies dealing with microbial aetiology in cap is that not all microbiological tests are applied systematically for all patients. this issue means that the real frequency of polymicrobial aetiologies could possibly be higher if a complete microbiological investigation was performed in all cases. in view of these methodological problems, it seems difficult to indicate precisely the extent of the problem of polymicrobial aetiology. analysing the potential impact of polymicrobial aetiology is therefore more important, particularly in the most severely ill patients and in those at highest risk of death. s. pneumoniae was not only the most frequent pathogen but also by far the most frequent co-pathogen in polymicrobial infections. this finding underlines the importance of pneumococcal coverage in any initial antimicrobial treatment regimen. the most frequent polymicrobial pattern was s. pneumoniae and viral infection, particularly influenza virus. pneumococci have been identified as the most frequent bacterial superinfection in both seasonal [ ] and novel h n [ , ] influenza virus-associated pneumonia. interestingly, whereas s. pneumoniae was by far the most frequent single pathogen, the rate of this pathogen was similar among patients with monomicrobial aetiology and those with polymicrobial aetiology. among the pathogens more frequently identified in polymicrobial pneumonia, respiratory viruses were the most frequent. we did not find that polymicrobial aetiology was associated with higher mortality. viruses were the most frequent microorganisms associated with polymicrobial aetiology. except for influenza a h n , viruses are not a cause of excess mortality-as recently pointed out by two recent studies [ , ] . the role of viruses in the aetiology of pneumonia is unclear, since they may be regarded either as primary infection or, with bacteria, as representing superinfection [ ] . none of our patients received antiviral treatment. we feel that at least during the influenza season, however, patients could benefit from antiviral treatment. the role of mrsa in cap is limited in europe, even if patients meeting criteria for healthcare-associated pneumonia remain included [ ] . although for our series we excluded patients with healthcare-associated pneumonia, the frequent association of this pathogen with severe underlying illness [ ] may explain the higher rate of this pathogen in the polymicrobial aetiology group, since these patients were more severe at admission than those with monomicrobial aetiology. the exact role of mrsa in polymicrobial cap is difficult to assess, however, because even a high bacterial load of mrsa may still represent colonisation rather than infection [ ] . the higher rate of p. aeruginosa and gneb in polymicrobial pneumonia may also be related to the higher rate of chronic respiratory diseases in this group, since identification of these pathogens occurs more frequently in those with chronic lung disease [ ] . as for mrsa, the identification of p. aeruginosa does not necessarily mean this is the causative pathogen of acute exacerbation in all chronic obstructive pulmonary disease patients colonised by the pathogen [ ] , and similarly mrsa eventually may represent colonisation rather than infection in patients with pneumonia. we identified chronic respiratory disease and ards criteria as independent predictors of polymicrobial aetiology. in chronic obstructive pulmonary disease, this finding can be explained by the previous colonisation of different bacteria these patients may have in their lower airways. on the contrary, ards may be the consequence of a mixed infection with higher pulmonary insult. in both chronic obstructive pulmonary disease and ards with severe cap, our recommendation is to give a broad empirical antibiotic treatment from the beginning of therapy because mixed infections are more frequent [ , ] . a relevant issue in polymicrobial aetiology of severe cap refers to its potential prognostic implications. we found a strong association between polymicrobial aetiology and initial inappropriate antimicrobial treatment, which in turn was an independent predictor of increased hospital mortality. inappropriate empiric treatment has already been associated with poor outcome in patients with severe infections [ , ] . although crude mortality was near double in patients with polymicrobial aetiology, this difference did not reach statistical significanceprobably due to the insufficient number of patients included. these results indicate that the impact of initial inappropriate antimicrobial treatment is crucial for survival, and that polymicrobial aetiology is an important determinant for such inappropriateness. to the best of our knowledge, this is the first study addressing the issue of multiple aetiologies of cap in a large population of icu patients. we decided to include all patients admitted to the icu regardless of whether they met idsa/ats severity criteria. we think that clinical decisions for icu admission may be valid, while the idsa/ats severity criteria have proven to be overly sensitive [ , ] . several limitations have to be addressed. first, the complete diagnostic workup and microbiological sampling could not be applied in every patient. second, the true incidence of polymicrobial aetiology may be underestimated since % patients had received prior antimicrobial treatment. finally, viral infections may have been missed since paired serology is frequently not available in nonsurvivors. we did not include molecular techniques such as pcr for bacterial detection. we believe that the systematic use of qualitative and quantitative pcr for the diagnosis of respiratory infections may increase substantially the hosmer-lemeshow goodness-of-fit test, p = . . b the p value corresponds to differences between the three groups (none, one or more than one pathogen). the odds ratio and % confidence interval (ci) of monomicrobial and polymicrobial pneumonia are related to cases with no pathogen identified. number of identified bacterial pathogens [ , ] . moreover, these new techniques could play a crucial role in the determination of the clinical impact of polymicrobial aetiology in cap. unfortunately, the use of molecular techniques is not yet part of the routine diagnostic workup in cap. polymicrobial aetiology is a frequent finding in patients with cap admitted to the icu. our data support the potential implication of polymicrobial pneumonia in the outcome of patients related to an increased risk of inappropriate antimicrobial treatment, and suggests the importance of an extensive microbiological testing in very severe cap patients since the cap may be caused by more than one aetiology. the most important clinical implication of the identified predictors of polymicrobial aetiology is to emphasise the use of broad-spectrum antimicrobial treatment in these groups of patients. • polymicrobial aetiology is frequent among patients with cap admitted to the icu and may result in inappropriate empiric antimicrobial treatment. • polymicrobial aetiology of cap should be suspected in the presence of chronic respiratory disease or criteria for ards. • if antimicrobial treatment is appropriate, polymicrobial aetiology does not result in increased hospital mortality from severe cap. abbreviations ards: acute respiratory distress syndrome; bal: bronchoalveolar lavage; cap: community-acquired pneumonia; gneb: gram-negative enteric bacilli; idsa/ ats: infectious disease society of america/american thoracic society; mrsa: methicillin-resistant staphylococcus aureus; pcr: polymerase chain reaction; psi: pneumonia severity index; rt: reverse transcriptase. towards a sensible comprehension of severe community-acquired pneumonia community-acquired pneumonia of mixed etiology: prevalence, clinical characteristics, and outcome mixed community-acquired pneumonia in hospitalised patients multiple pathogens in adult patients admitted with community-acquired pneumonia: a one year prospective study of consecutive patients study of community acquired pneumonia aetiology (scapa) in adults admitted to hospital: implications for management guidelines microbial aetiology of community-acquired pneumonia and its relation to severity value of the polymerase chain reaction assay in noninvasive respiratory samples for diagnosis of community-acquired pneumonia a prediction rule to identify low-risk patients with community-acquired pneumonia infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults applied logistic regression severe community-acquired pneumonia: validation of the infectious diseases society of america/american thoracic society guidelines to predict an intensive care unit admission ewig s: how deadly is seasonal influenza associated pneumonia? the german competence network for community-acquired pneumonia (capnetz) centres for disease control and prevention: bacterial coinfections in lung tissue specimens from fatal cases of pandemic influenza a (h n )-united states community-acquired respiratory cillóniz et al. critical care coinfection in critically ill patients with pandemic influenza a (h n ) virus influenza pneumonia: a comparison between seasonal influenza virus and the h n pandemic insights into the interaction between influenza virus and pneumococcus health care-associated pneumonia requiring hospital admission: epidemiology, antibiotic therapy, and clinical outcomes bts guidelines for the management of community acquired pneumonia in adults: update ventilator-associated tracheobronchitis in a mixed surgical and medical icu population community-acquired pneumonia in chronic obstructive pulmonary disease. spanish multicenter study pseudomonas aeruginosa in adults with chronic obstructive pulmonary disease airway inflammation and bronchial bacterial colonization in chronic obstructive pulmonary disease acute respiratory distress syndrome and pneumonia: a comprehensive review of clinical data initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock appropriate use of antimicrobial agents: challenges and strategies for improvement streptococcus pneumoniae coinfection is correlated with the severity of h n pandemic influenza community-acquired polymicrobial pneumonia in the intensive care unit: aetiology and prognosis the authors are indebted to the nursing staff and the attending physicians of the two icus for their cooperation in this trial. financial support was provided by -sgr- , ciber de enfermedades respiratorias (ciberes cb / / ). authors' contributions cc is the main author of the paper; she reviewed the study data and realised the statistical analysis, edited the main body of the manuscript, and contributed to supervising the collection of clinical, radiological and microbiological data. se contributed to conception of the project and database design. mf contributed to results analysis and interpretation, and to editing the final manuscript. ep contributed to data analysis and drafting the original manuscript, and to supervising the collection of clinical, radiological and microbiological data. ag realised the statistical analysis of the study. jpdlb supervised the microbiological studies. jm supervised the collection of epidemiologic and microbiological data. at led the study group, contributed to conception of the project design and contributed to the final study, being the guarantor of the entire manuscript. all authors read and approved the manuscript for publication. the authors declare that they have no competing interests. key: cord- - gv authors: khan, anas a.; alruthia, yazed; balkhi, bander; alghadeer, sultan m.; temsah, mohamad-hani; althunayyan, saqer m.; alsofayan, yousef m. title: survival and estimation of direct medical costs of hospitalized covid- patients in the kingdom of saudi arabia (short title: covid- survival and cost in saudi arabia) date: - - journal: int j environ res public health doi: . /ijerph sha: doc_id: cord_uid: gv objectives: assess the survival of hospitalized coronavirus disease (covid- ) patients across age groups, sex, use of mechanical ventilators (mvs), nationality, and intensive care unit (icu) admission in the kingdom of saudi arabia. methods: data were retrieved from the saudi ministry of health (moh) between march and may . kaplan–meier (km) analyses and multiple cox proportional-hazards regression were conducted to assess the survival of hospitalized covid- patients from hospital admission to discharge (censored) or death. micro-costing was used to estimate the direct medical costs associated with hospitalization per patient. results: the number of included patients with complete status (discharge or death) was . the overall -day survival was . ( %ci: . – . ). older adults (> years) (hr = . , %ci = . – . ), patients on mvs ( . , . – . ), non-saudi patients ( . , . – . ), and icu admission ( . , . – . ) were associated with a high risk of mortality. the mean cost per patient (in sar) for those admitted to the general medical ward (gmw) and icu was , . ± , . and , . ± , . , respectively. conclusion: the high hospitalization costs for covid- patients represents is a significant public health challenge. efficient allocation of healthcare resources cannot be emphasized enough. coronavirus disease (covid- ) has affected every continent on earth, and the number of confirmed cases has exceeded million worldwide [ ] . as more details about covid- and its associated risk factors have surfaced, the diagnostic and clinical features, treatment, typical clinical course, and monitoring which distinguish the virus that causes covid- , severe acute respiratory syndrome coronavirus (sars-cov- ), have become clear. however, there remain inconsistencies in disease severity among patients and mortality among different countries that hamper the assessment and triage of patients [ ] [ ] [ ] [ ] [ ] . the overall case fatality rate (cfr) of covid- has been estimated be~ . % ( % confidence interval (ci): . - . ) and to range from . % to . % among those under and over years of age, respectively [ ] . moreover, it has been reported that the cfr can reach as high as % in the northern regions of italy [ ] . in china, yan-ni and colleagues estimated the cfr to be . ± . % [ ] . however, the cfr can be as high as % among hospitalized patients [ ] . although the rate of hospitalization among patients confirmed to have covid- is < %,~ % of hospitalized patients in france are transferred to the intensive care unit (icu) [ ] . the median length of l stay (los) for covid- patients has been reported to be ≤ days based on a chinese study; however, larger studies may be needed to better understand the course of covid- after icu admission [ , ] . in addition, the los varied significantly between countries even before the pandemic [ ] . in saudi arabia, the rate of hospitalization among all confirmed covid- cases during march was . % according to alsofayan and colleagues, but the mortality rate was as low as . % [ ] . this high reported rate of hospitalization among covid- cases may exacerbate the cost burden of viral respiratory infections in a country that was deeply affected by the middle east respiratory syndrome (mers) in , and resulted in a huge financial burden with an estimated direct medical cost per patient of sar , . (united states dollars (usd) , . ) [ ] . in light of the high rate of hospitalization among covid- patients in saudi arabia, there is a need to identify different sociodemographic (e.g., age, sex) and medical (e.g., mechanical ventilator (mmv) use, icu admission) status that might increase mortality risk. moreover, the cost of hospitalization should be estimated. providing government officials and clinicians with clear guidance on the risk factors, mortality rate, and how to prioritize screening, testing, isolation or quarantining of covid- cases is imperative to manage this pandemic effectively and efficiently. here, we investigated the survival of hospitalized covid- patients in saudi arabia across age groups, sex, nationality, mv use, and icu admission. furthermore, the average cost of hospitalization due to covid- per patient was estimated. this study protocol was approved by the ethics review board committee of the central ministry of health ( - m) in riyadh, saudi arabia. the data of this study were retrieved from the health electronic surveillance network (hesn) database of the saudi ministry of health (moh) for covid- patients. all symptomatic patients with confirmed covid- after being tested in outpatient settings and confirmed in inpatient settings upon admission in saudi hospitals from march to may were included. the retrieved variables were age, sex, nationality (saudi vs. non-saudi), city, hospital, date of hospital admission, date of discharge from hospital, mv use, inpatient environment (icu vs. general medical ward (gmw)), and final status (discharge vs. death). data on comorbidities were missing for most cases. no re-admissions for the covid- patients were encountered in the retrieved data. all consecutive patients were assumed to receive standardized treatment protocols for covid- as posted on the moh website, and these protocols were (and are still being) updated on a regular basis. the cost of hospitalization was estimated using the micro-costing method as stated in the protocols for covid- management set by the moh. the cost of hospitalization was based on the cost of: all medications (e.g., antivirals, antibiotics, anticoagulants, hydroxychloroquine); personal protective equipment (e.g., n masks, gowns, protective eyewear); oxygen; mvs; isolation-room fees (icu vs. gmw); fees of physicians and other medical staff; laboratory and diagnostic tests (e.g., polymerase chain reaction, complete blood count, liver/cardiac enzymes, swabs, cultures, radiographs and computed tomography of the chest). data on inpatient costs were retrieved from the moh cost center. the cost is presented in saudi riyals (sar). this was a retrospective cohort study upon which covid- patients were followed up retrospectively between march and may from the date of hospital admission to discharge from hospital with final status which was either death or discharged alive (censored). those without any update on their status were excluded. kaplan-meier (km) survival analyses were created to examine the survival probability overall as well as across age groups. moreover, the survival probability was estimated across mv use and sex, nationality (saudi vs. non-saudi), and inpatient environment (icu vs. gmw). comparisons of different strata were adjusted using tukey's method. the hazard ratio (hr) for death was generated using multiple cox proportional-hazards regression that included the variables of: mv use (no vs. yes), age, sex (female vs. male), and inpatient environment (icu vs. gmw). significance was considered at α < . , and the %ci is shown for different strata in all km survival curves and reported for all hrs. statistical analyses were conducted using sas ® v . (sas, cary, nc, usa). the number of patients hospitalized due to covid- between march and may was . however, patients were not listed as having a final status (discharged alive or death) in the hesn database as of may . therefore, only patients with final status (discharged alive or death) were eligible to be included in our analyses ( figure ). the majority of the patients were male ( . %), and between and years of age ( . %). most patients were non-saudi ( . %), and from medina ( . %). only % of patients were admitted to the icu, and mv use was indicated in % (table ) . about % of patients ( patients) died in hospital. the median los was . days, with a maximum los of days. the overall mean survival time from admission to final status (discharged alive or death) for the study cohort was days with differences across different variables (table ). older covid- patients had a significantly shorter mean duration of survival compared with their younger counterparts (p < . ). patients on mvs had a significantly shorter mean duration of survival compared with those not on mvs ( . vs. . days, p < . ). likewise, those admitted in icus had a significantly shorter mean duration of survival compared with those admitted to other inpatient environments ( . vs. . days, p < . ). the survival probability (which was estimated using km curves in all cases) of the overall study cohort from hospital admission up to the second day of hospitalization was estimated to be . figure ). for each -year increase in age, the death risk increased by an estimated . % (hr = . , p < . ). the risk of death among patients on mvs was five-times higher compared with their counterparts who were not on mvs (hr = . , p < . ). the death risk for non-saudi patients was % higher than that of their saudi counterparts (hr = . , p = . ). furthermore, the death risk for patients admitted to the icu was more than twice that of their counterparts admitted to the gmw (hr = . , p < . ). being female was not associated with a lower risk of death (hr = . , p = . ). the adjusted hrs with their %cis are shown in table and figure . the covid- pandemic has had a detrimental effect on global healthcare systems, and affected every aspect of human and economic life [ ] . as of june , the number of covid- cases in saudi arabia has exceeded , , with an estimated case fatality rate (cfr) of . % [ ] . the reported cfr is far below that of france, belgium, spain, italy, and the uk, which have reported a cfr between . % (spain) to % (belgium) [ , , ] . however, the cfr among hospitalized covid- patients is far higher than the population-level cfr. our study (which is the first to report the survival probability across age groups, sex, nationality, mv use, and icu admission among a sample of hospitalized covid- patients in saudi arabia) revealed the cfr to be . %. this cfr is far below the reported cfr among hospitalized patients in the uk ( %) [ ] (docherty et al., ), italy ( %) [ ] , and the usa ( %) [ ] . in addition, the percentage of hospitalized patients treated in the icu or who received invasive ventilation was similar to the one reported in the usa [ ] . the overall -day mortality among our cohort was . %, but the -day mortality ( . %) represented > % of deaths. this finding suggests that the first days of hospitalization are critical for covid- patients, which has also been reported among a sample of hospitalized italian patients with covid- [ ] . the overall -day and -day survival probability (using km curves) was . and . , respectively. this observation is consistent with a study conducted in sichuan province in china, which found that the los was associated with higher risk of death [ ] . older adults were at a significantly higher risk of death compared with those in other age groups, a finding that is in accordance with the work of other scholars [ , ] . this higher risk of mortality among icu patients aligns with the findings of research studies among hospitalized covid- patients [ ] . although most hospitalized patients were male, the risk of mortality was not higher among male patients in comparison with their female counterparts. this finding contradicts the observations of other scholars who showed a higher risk of mortality among hospitalized male patients with covid- [ , ] . patients on mvs had a more than five-times higher risk of death compared with their counterparts not on mvs, a finding that is similar to data from auld and colleagues [ ] . pareek and collaborators reported that ethnicity may have a role in the survival of covid- patients [ ] . we found that hospitalized non-saudi patients were at a slightly higher risk of mortality. this could be attributable to the fact that many non-saudi patients who were hospitalized for covid- did not have legal residence status, and lack health insurance coverage prior to the covid- pandemic. however, this could change if other diseases (e.g., diabetes mellitus, asthma, hypertension, cardiovascular diseases, or chronic renal failure) were controlled for in the analysis. a major concern about the covid- pandemic is the high cost burden to healthcare systems. we calculated the direct medical cost associated with treatment of covid- patients in saudi arabia. the cost of covid- treatment was calculated based on moh treatment protocols and accounted for all health resources used to deliver care to covid- patients. our cost data highlighted differences in resource utilization between patients presenting with moderate-to-severe symptoms versus critical cases who required icu admission. our cost analyses illustrated that the mean direct medical cost of patients with moderate-to-severe covid- symptoms admitted to the gmw was sar . per patient per day, which was much lower compared with the mean cost per patient per day for patients admitted to the icu (e.g., sar . ). however, the difference in the mean cost per patient per day between patients who needed mvs and those who did not need them was sar . and sar . among patients admitted in gmw and icu, respectively. the total direct medical cost per patient was calculated based on the level of care and los. the total direct medical cost per patient for those with moderate-to-severe symptoms admitted to the gmw was sar , . . however, there was an approximate twofold increase in the cost for icu patients (e.g., sar , . ). interestingly, the total cost for patients on mvs was slightly lower in comparison with their counterparts admitted to the gmw but who were not on mvs. this finding was largely attributable to a significantly shorter duration of survival and higher rate of mortality among patients on mvs, which translated to a shorter los and, eventually, lower total cost per patient. however, this finding is not consistent with data from a study by rae and colleagues, who reported that patients on mvs often required a longer hospital stay with a higher cost of healthcare-resource utilization [ ] . there is a dearth of data about the direct medical cost of covid- in the middle east. very few scholars have assessed the financial impact on healthcare systems worldwide. the mean direct medical cost per patient (in usd) has been reported to be in china [ ] , , in canada [ ] and . in india [ ] . a study published recently in the usa reported the mean cost of treatment of patients with mild covid- who were not hospitalized ranged from usd for consultation over the telephone to usd for a clinic visit [ ] . those data are in accordance with our observations because mild cases are often not hospitalized and used medications mainly for relief from fever or pain only. moreover, that usa study estimated the median direct medical cost of caring for patients with moderate covid- symptoms who did not require hospitalization but had to be seen at emergency department was usd , and was usd , for those with more severe symptoms that necessitated hospitalization. based on those estimates, the total direct medical cost in the usa has been projected to range from usd . billion to usd . billion [ ] . in sweden, the total direct medical cost has been projected to reach usd billion [ ] . the mean direct medical cost per patient we estimated was sar , . (usd , . ), which was not significantly different from the one reported for the management of a mers-cov patient in saudi arabia (usd , . ) [ ] . however, the total direct medical cost of covid- far exceeds the one reported for mers-cov due to the high number of covid- infections that are being reported on a daily basis. these variations in cost estimates across countries highlight the challenges in estimating and comparing the direct medical costs globally given the vast differences in the cost of treatment protocols, personnel cost, and utilization rates of healthcare resources and their prices between countries. our study had four main limitations. first, we did not include all hospitalized patients in saudi arabia, which limits the generalizability of our findings. second, variables such as comorbidities (e.g., diabetes mellitus, asthma, cancer, hypertension, chronic kidney disease), smoking status, and occupation were not investigated, which may have changed our findings if they had been controlled for in our analyses. additionally, the study did not control for the changes in the treatment protocols and their potential impact on mortality rates. third, this study was conducted from the perspective of healthcare payers, and did not take into consideration other important costs, such as productivity losses and "lockdown" costs. therefore, the economic impact of covid- would have been much greater. fourth, the outcomes for patients who were discharged alive (censored) cannot be ascertained as some discharged patients may have died or readmitted afterwards. future research should examine the: (i) survival probability for hospitalized covid- patients controlling for comorbidities and other potential confounders; (ii) cost of covid- on other important sectors of the economy; (iii) total direct medical costs of covid- to the saudi arabia healthcare system. an interactive web-based dashboard to track covid- in real time clinical features of patients infected with novel coronavirus in systematic review of covid- in children shows milder cases and a better prognosis than adults the novel coronavirus pneumonia emergency response epidemiology team the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- )-china, case-fatality rate and characteristics of patients dying in relation to covid- in italy clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study case fatality rate analysis of italian covid- outbreak estimating the instant case fatality rate of covid- in china estimates of the severity of coronavirus disease : a model-based analysis intensive care management of coronavirus disease (covid- ): challenges and recommendations clinical characteristics of covid- in saudi arabia: a national retrospective study estimation of direct medical costs of middle east respiratory syndrome coronavirus infection: a single-center retrospective chart review study the socio-economic implications of the coronavirus pandemic (covid- ): a review saudi ministry of health (moh) covid- media center cross-country comparison of case fatality rates of covid- / sars-cov- . osong public health res features of , hospitalised uk patients with covid- using the isaric who clinical characterisation protocol survival of hospitalized covid- patients in northern italy: a population-based cohort study by the ita-covid network the northwell covid- research consortium. presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the survival analysis of hospital length of stay of novel coronavirus (covid- ) pneumonia patients in sichuan, china predictors of mortality for patients with covid- pneumonia caused by sars-cov- : a prospective cohort study predictors of mortality in hospitalized covid- patients: a systematic review and meta-analysis prevalence and risk factors of mortality among hospitalized patients with covid- : a systematic review and meta-analysis gender differences in patients with covid- : focus on severity and mortality. front covid- : the gendered impacts of the outbreak icu and ventilator mortality among critically ill adults with coronavirus disease ethnicity and covid- : an urgent public health research priority potential costs of coronavirus treatment for people with employer coverage. peterson-kff health system tracker website china spends $ on average for each covid- patient effectiveness and cost-effectiveness of public health measures to control covid- : a modelling study rs . lakh spent on each covid- patient in victoria hospital: karnataka minister the potential health care costs and resource use associated with covid- in the united states. health aff covid- health care demand and mortality in sweden in response to non-pharmaceutical (npis) mitigation and suppression scenarios this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license key: cord- -cpjkltsu authors: stubington, thomas j.; mallick, ali s.; garas, georgios; stubington, emma; reddy, chetan; mansuri, mohammed s. title: tracheotomy in covid‐ patients: optimizing patient selection and identifying prognostic indicators date: - - journal: head neck doi: . /hed. sha: doc_id: cord_uid: cpjkltsu background: tracheotomy, through its ability to wean patients off ventilation, can shorten icu length of stay and in doing so increase icu bed capacity, crucial for saving lives during the covid‐ pandemic. to date, there is a paucity of patient selection criteria and prognosticators to facilitate decision making and enhance precious icu capacity. methods: prospective study of covid‐ patients undergoing tracheotomy (n = ) over a ‐week period (march‐april ). association between preoperative and postoperative ventilation requirements and outcomes (icu stay, time to decannulation, and death) were examined. results: patients who sustained fio( ) ≤ % and peep ≤ cm h( )o in the hours pretracheotomy exhibited a favorable outcome. those whose requirements remained below these thresholds post‐tracheotomy could be safely stepped down after hours. conclusion: sustained fio( ) ≤ % and peep ≤ cm h( )o in the hours post‐tracheotomy are strong predictive factors for a good outcome, raising the potential for these patients to be stepped down early, thus increasing icu capacity. coronavirus disease (covid- ) has rapidly evolved into a pandemic since the first report emerged from china in december . with the number of cases rising globally at an exponential rate and with over % of these requiring intensive care unit (icu) admission, demand for critical care increasingly threatens to exceed capacity even among the world's most advanced economies. at present, supportive treatment forms the basis of therapy, with trials currently ongoing to unearth the optimal medicinal treatment regimen and vaccine. tracheotomy, through its ability to wean patients off ventilation, can shorten the icu length of stay and in doing so increase icu bed capacity; crucial for saving lives at a population level. , median icu stay for covid- patients varies widely between countries ranging between and over days. tracheotomy constitutes an aerosol generating procedure (agp), thus potentially exposing the operating surgeon and operating room (or) team to respiratory droplets from the sars-cov- infected patient. with this added risk in mind it is vital that the potential benefits of a reduced icu stay associated with performing a tracheotomy are balanced against the risks to health care professionals. despite a number of authors having already published guidelines to minimize risks to health care personnel when performing tracheotomy in the covid- positive patient, [ ] [ ] [ ] [ ] [ ] there is currently a paucity of literature on patient selection criteria for this procedure and outcomes data for patients who have undergone tracheotomy in these circumstances. to address this, we present our data from the first covid- patients that underwent tracheotomy in our institution, and propose parameters to inform patient selection by identifying those patients who may be more likely to benefit from the procedure. furthermore, we discuss potential predictive factors that may help clinicians identify at an early stage ( hours postoperatively) those patients who are likely to have a positive outcome post-tracheotomy, which may facilitate decisions to step-down patient care and thus improve the availability of critical care resources to those patients that need it most. this was a prospective study of all covid- patients undergoing tracheotomy (n = ) in a head & neck unit in the united kingdom during a -week period (march-april ). anesthesiological processes and surgical steps pretracheostomy and peritracheostomy insertion were standardized to minimize risk to staff and improve patient safety during this crucial part of the procedure (see supplementary material). recordings of the patient's fraction of inspired oxygen (fio ) and peak end expiratory pressure (peep) were obtained for the hours preceding the procedure, and subsequently collected on a daily basis until the patient was either decannulated and discharged from hospital, or died. fluctuations in these values, which occurred due to patient intervention/movement were removed in order to facilitate calculation of representative averages for these values. the number of days that patients were kept under sedation and number of days taken for decannulation were also recorded. following our experience with our first five tracheotomies and in accordance with our local protocol (see supplementary material) and published literature, - we instituted selection criteria for all subsequent tracheotomies as follows: • patients should ideally be at least days post-positive swab result • low oxygen requirements (fio ≤ %), sustained for at least hours • patient able to tolerate clamped tube for minute in icu ("clamp test") • two failed trials of sedation withholding prior to considering tracheotomy • patients that will not require prone ventilation correlation between data sets was determined using the "r" statistical software (v . . , © the r foundation, vienna, austria). data were ranked, and spearman's rank correlation coefficient was calculated to determine association between data sets. in total, covid- patients underwent surgical tracheotomy over a -week period (march-april ), of which two died (patients b and c). patient b had fio values ranging between % and % in the hours before tracheotomy, whilst patient c had their tracheotomy performed days after having a positive swab result. of the remaining patients that survived, patients d and e took the longest to be decannulated, both of whom had preoperative fio values ≥ %, as well as high peep values ( table ). the data suggest that a patient's preoperative status in the hours preceding the procedure may highlight those patients likely to benefit from tracheotomy. figure illustrates each patient's preoperative fio concentration and peep requirements in the format of a bubble plot, which suggests that an fio of ≥ % with a peep of ≥ cm of h o in the hours preceding tracheotomy may be associated with a worse outcome, as the patients that did not fulfill these criteria in the hours preceding tracheotomy either died or had a prolonged wean of ventilation despite the procedure. cumulative data suggested that patients requiring an fio of ≤ % and peep of ≤ cm of h o in the first hours following tracheotomy tended to have a more favorable outcome compared to those exceeding these values. to examine this in greater depth, the proportion of time for each patient at which the peep was ≥ cm h o and the proportion of time fio was ≥ % across all days were calculated regardless of length of follow-up. from this, the average proportion of time that peep was ≥ cm h o and average proportion of time that fio ≥ % were calculated, with the patients subsequently ranked accordingly. these steps were then repeated but with only looking at the data for up to day post-tracheotomy to look for early prognostic indicators (see figures s and s ). the ranks for both parameters were then plotted on a scatter plot (figure ) , which illustrates that rank at day post-tracheotomy strongly correlates with rank from all days, and therefore with the patient's final outcome (ρ = . , p < . ). this is the first report of patient outcomes following tracheotomy in covid- patients, and on the basis of our institutional experience we propose criteria that offer a pragmatic solution to facilitate patient care whilst minimizing risks to health care workers. given the risk that tracheotomy in covid- patients poses to health care workers through aerosolization of sars-cov- virions, it is paramount that these risks are carefully balanced against potential benefits to patient care. concerns around infection in covid- patients stem from previous experience from sars-cov, which posed a particular risk to health care workers as peak viral load tended to occur to days post-infection. in contrast, covid- patients appear to have the highest viral load at the onset of infection and this subsequently declines over time, which may account for the speed at which this novel coronavirus is spreading within the community. furthermore, although it has been shown that sars-cov- rna can be detected in patients up to days or longer post-infection, it is unclear whether this represents patients shedding live virus, or if this reflects shedded virions inactivated by host antibodies. in the context of planning a tracheotomy, this has two important implications; first, a positive test does not reflect the degree of infectivity of a patient, and second, on the basis of current data we can draw a cautious degree of reassurance that patients are likely to be less infectious the further away they are from their initial presentation. thus, we believe that undertaking a tracheotomy at least days following a positive swab result, in conjunction with wearing full personal protective equipment (ppe) and taking all the necessary steps to minimize aerosolization peritracheotomy insertion (see supplementary material) presents a pragmatic solution to minimizing risk to staff. to date, none of the or staff who have been involved with undertaking tracheotomies in covid- patients has tested positive for the disease in our institution. in light of the relative uncertainties that exist in the treatment of patients with covid- , patient selection for tracheotomy will ultimately be refined through experience. the selection criteria proposed in this study (fio ≤ % and peep ≤ cm of h o in the hours prior to the tracheotomy) were derived on the basis of our early experience with the first five covid- tracheotomies; of which, one survived (patient a), two died (patients b and c) and the remaining two had a prolonged wean off the ventilator (patient d, who was taken off ventilation at day post-procedure, and patient e, who continues to be on ventilation at the time of writing). of the four patients who had less favorable outcomes, three had either an fio ≥ % or a peep requirement exceeding cm h o. the "anomaly" was patient c who despite being within an acceptable range for both fio and peep unfortunately died. in retrospect, this patient probably had their tracheostomy too early at day post-intubation; it is thus vital that icu teams liaise closely with surgical teams when identifying potential f i g u r e patient rank according to average proportion of time fio ≥ % and peep≥ cm h o at end of patient follow up ( y-axis) plotted against patient rank according to average proportion of time fio ≥ % and peep ≥ cm h o on day post tracheostomy (x-axis). a higher rank signifies a higher proportion of time spent above the parameters. spearman's rank correlation ( ρ = . , p < . ) candidates for tracheotomy, and put forward those patients who have demonstrated improvement in their clinical course. from this study, two important findings emerge in terms of the prognostic value of ventilation-related parameters prior to tracheotomy. these are an fio requirement ≤ % and peep ≤ cm h o in the hours prior to tracheotomy with all patients exceeding these cut off values either experiencing a prolonged wean and dying or failing to improve and continuing to require icu support. satisfying both the fio and peep criteria is equally important when considering tracheotomy in covid- patients failing trial(s) of extubation. the case of patient d illustrates why consideration of fio requirements alone is not adequate when it comes to covid- patients. even if preoperative fio requirements remain below the % cut off, covid- patients are unlikely to do well following tracheotomy if their peep requirements exceed cm h o. the reason is that the high peep dependence makes them less able to tolerate the combination of a reduction in fio to % during tracheal exposure and the subsequent cessation of ventilation prior to tube exchange, both key recommendation for tracheotomy in covid- patients. furthermore, we have demonstrated that there is a correlation (ρ = . , p < . ) between the proportion of time patients' peep values are ≤ cm h o and their fio values are ≤ % in the first hours following tracheotomy with the respective values (ventilation requirements) across all days of their stay in critical care. this is of clinical importance because it could potentially permit prognostication through early risk-stratification; with those patients whose ventilator requirements consistently remain below the described cut off values (ie, fio ≤ % and peep ≤ cm of h o) for the first two postoperative days to represent a subgroup that can potentially be safely stepped down to another clinical area outside the icu environment at that stage. this has the potential of freeing up intensive care beds as early as day post-tracheotomy for other patients that need it more. furthermore, with the emergence of field hospitals to help cope with the increased patient demand from the covid- pandemic, this could assist in identifying those patients who following tracheotomy are suitable for transfer to such facilities, further enhancing icu capacity, a precious and limited resource in the fight against covid- . prior to concluding, it is important to consider the strengths and limitations of this study. the key limitation relates to the small number of patients (n = ). another relates to the novelty of the disease studied meaning that it is likely that further refinements to the proposed criteria will be needed in the future as our understanding of the pathophysiology of covid- evolves. finally, only two prognostic parameters were studied. despite these limitations, this study also features a number of key strengths. it is the first to look into the development of formal selection criteria for tracheotomy in ventilated patients with covid- and the first to determine early prognostic factors for these patients. moreover, this has been done in a quantitative manner. by providing actual cut off values for pre-tracheostomy and post-tracheotomy ventilatory requirements, it facilitates patient selection, permits risk stratification and in doing so can directly assist clinical decision making and inform policy. in conclusion, this study presents for the first time measurable patient selection criteria for tracheotomy in covid- patients, illustrating that a fio ≤ % and peep ≤ cm h o in the hours prior to tracheotomy are useful markers in helping to identify those patients that are most likely to benefit from a tracheotomy. it has also shown that patients that are able to remain below these threshold values in the first hours following tracheotomy are likely to exhibit a favorable outcome and can thus be stepped down from an intensive care setting at that (early) stage, freeing up vital capacity for other critically ill covid- patients in need of urgent icu care. ali s. mallick https://orcid.org/ - - - georgios garas https://orcid.org/ - - - a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster covid- and italy: what next? lancet systematic review and meta-analysis of studies of the timing of tracheostomy in adult patients undergoing artificial ventilation early versus late tracheostomy for critically ill patients intensive care national audit and research centre icnarc report on covid in critical care aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review tracheostomy protocols during covid- pandemic tracheotomy in the sars-cov- pandemic. head neck tracheostomy guidelines developed at a large academic medical center during the covid- pandemic. head neck clinical progression and viral load in a community outbreak of coronavirusassociated sars pneumonia: a prospective study temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by sars-cov- : an observational cohort study corona-steps for tracheotomy in covid- patients: a staff-safe method for airway management tracheotomy in covid- patients: optimizing patient selection and identifying prognostic indicators key: cord- -hbzbyqi authors: payne, anna; rahman, rafid; bullingham, roberta; vamadeva, sarita; alfa-wali, maryam title: redeployment of surgical trainees to intensive care during the covid- pandemic: evaluation of the impact on training and wellbeing date: - - journal: j surg educ doi: . /j.jsurg. . . sha: doc_id: cord_uid: hbzbyqi objective: : the aim of this study was to evaluate the impact of redeployment of surgical trainees to intensive care units (icus) during the covid- pandemic- in terms of transferrable technical and non-technical skills and wellbeing. design: : this was a survey study consisting of a -point questionnaire. setting: : the study involved surgical trainees that had been redeployed to the (icu) across all hospitals in london during the covid- pandemic. participants: : the survey was sent to surgical trainees who were between postgraduate years two to four. trainees in speciality training programs (> years after graduation) were not included. thirty-two trainees responded to the questionnaire and were included in the study results. results: : all respondents spent between and weeks working in icu. prior to redeployment, % of participants had previous experience of icu or an affiliated specialty, and > % had attended at least one educational course with relevance to icu. there were statistically significant increases in confidence performing central venous cannulation and peripheral arterial catheterisation (p< . ). with regards to clinical skills, respondents reported feeling more confident managing ventilated patients, patients on non-invasive ventilation, dialysis and circulatory failure patients after working in icu. respondents ( %) felt that the experience would be beneficial to their future careers but % felt the redeployment had a negative impact on their mental health. conclusions: : redeployment of surgical trainees to icu led to increased confidence in a number of technical and non-technical skills. however, proactive interventions are needed for training surgeons with regard to their psychological wellbeing in these extraordinary circumstances and to improve workforce planning for future pandemics. the world health organisation declared the coronavirus disease (covid- ) a pandemic on march . the demand for ventilatory support in covid- patients necessitated an expansion of intensive care capacity within weeks. between early march and mid-april , london"s existing hospitals expanded their combined intensive care capacity from to beds. the icu is a challenging working environment, managing complicated medical and surgical patients whilst also preventing further physiological dysfunction. the icu is often only visited fleetingly by surgeons during a ward round or postoperatively, but with the covid- pandemic it became the new working environment for the redeployed. a pandemic like covid- disrupts the sense of routine and control, making working environments stressful. this stress is amplified when the lives of the clinicians caring for patients are at risk. learning how to manage a patient who is critically ill is beneficial to surgeons in training and forms part of the curriculum of core surgical training. completion of the royal college of surgeons of england care of the critically ill surgical patient (ccrisp) course is mandatory prior to specialist training in the uk. the membership examinations (mrcs) which are also a prerequisite for starting specialist surgical training test the candidate on critical care. the aim of this study was to evaluate the impact of the redeployment of surgical trainees to critical care units during the covid- pandemic in terms of transferrable skills, wellbeing and career development. the three core competences assessed in this paper, as per the accreditation council for graduate medical education (acgme), are practice-based learning and improvement, systems-based practice and professionalism. the results may provide insights into how to improve redeployment for future pandemics. this was a survey study conducted using a questionnaire to explore the research aims. participants were recruited from london hospitals. doctors working at postgraduate years two to four who were redeployed from surgical specialties to icu during the covid- pandemic were included. this encompassed core surgical trainees, foundation year doctors and junior clinical fellows. all surgical specialties, and those redeployed for greater than weeks between the months of march and may were included. exclusion criteria included those already in specialty training (postgraduate year +) and those working at registrar (senior clinical fellow) level. all participants received training in both technical and non-technical skills, arranged by the intensive care department, prior to redeployment. the technical skills training included patient proning, insertion of central venous catheters and insertion of peripheral arterial lines in a simulated session. teaching in non-technical skills included breaking bad news and discussion of resuscitation and ceilings of care with patients and relatives. a novel -point survey questionnaire was devised to evaluate trainee experience, clinical skills, procedural skills and non-technical skills (supplement ). practical skill competency was self-assessed by trainees evaluated using an arbitrary scale from - ( being never observed the skill before and being able to perform the skill independently). pre-and postredeployment skills were evaluated by trainees, who were asked to reflect on their skills prior to redeployment as compared to post redeployment. a -point likert scale was utilised to evaluate mental health and wellbeing. the questionnaire was distributed through online and paper format to doctors redeployed to icu in london hospitals as part of the covid- pandemic. normal continuous data are summarised as mean and standard deviation (sd). categorical data are presented as numbers and percentage (%). continuous data were compared between pre-and post-deployment groups using mann-whitney u tests. a p-value of < . was considered statistically significant. statistical analysis was performed using spss v. (spss inc, , chicago, illinois, usa). with the recent guidance from the governance arrangements for research ethics committees (gafrec), the study involves a survey of staff of the services who are recruited by virtue of their professional role, no formal ethical approval is required by the research ethics committee (rec). completion of the questionnaire was taken as implied consent to participate in the study. the response rate was % (n = ). this included males ( %) and females ( %), of whom two were foundation year doctors (fy ), nine were clinical fellows and were core trainees both first and second year (ct and ct ). the surgical specialities of the trainees are shown in figure , including general surgery ( %), orthopaedic surgery ( %), plastic surgery ( %) and trauma ( %). the other surgical specialties made up the remaining %. the duration of redeployment varied from four to eight weeks. ninety-four per cent (n= ) of the respondents were aiming for a career in a surgical speciality. of the remaining six per cent (n= ) one was undecided and the other wanted to pursue a career in general practice. although the majority of participants felt confident breaking bad news and discussing do not resuscitate (dnar) orders before their redeployment, there was a small overall increase in confidence after working in icu. increased confidence was also reported for receiving critical care handover after working in icu. additionally, over % of the respondents felt the redeployment had a negative impact on their mental health (figure ) . the main themes of the areas causing a negative impact on mental health are detailed in figure . the majority ( %) of participants did not feel that they were more likely to pursue icu as their specialty of choice after their redeployment. one participant reported wanting to change from surgery to intensive care medicine and four would consider a career in intensive care medicine as a result of their icu redeployment. surgeons should receive appropriate training and support when working in non-surgical areas. dewey et al recognised "a supportive work culture is vital to maintaining resilience" during stressful times. the perceived lack of support reported by our respondents may have contributed to the negative impact on mental health. this is in addition to the emotional toll of the high mortality witnessed working in covid- units. education was perhaps placed on the back burner as the service needs were the main emphasis, but learning did come from redeployment as shown in this study. support of the wellbeing of trainees is of crucial importance and cannot be overstated. there is significant variation in the delivery of wellbeing support throughout the nhs, even between departments within the same hospital. studies have suggested the introduction of a definition of wellbeing, with tangible outcome measures, may be useful in enabling staff to make better use of the wellbeing resources available to them. the prevalence of psychological morbidity is growing among doctors in the uk , and the report of burnout among doctors before the covid- crisis was between - %. among the surgical workforce poor mental health conditions has been reported to be approximately % but this is possibly an underestimation. burnout is associated with being undervalued and may become more apparent following the pandemic. it is important to assess and address the issues of burnout to mitigate against the potential sequalae of anxiety, depression, substance misuse, poor patient care and clinician suicide. the symptoms of burnout which can become evident are emotional exhaustion and reduced sense of accomplishment. these symptoms should be assessed at regular intervals in surgical trainees during and after the pandemic. surgeons should be encouraged to express their feelings of stress and not supress them in the false perception that it will provide both individual and team benefit. prevention of burnout and mental health sequelae after the pandemic will require leadership from the top down. surgeons need to be more transparent about their psychological needs, and senior leaders should be encouraging and supportive of this. structured leadership programmes should be incorporated into surgical training curricula, rather than courses that trainees are expected to attend of their own accord. shared responsibility to support colleagues and encourage them not to continue working in the face of personal risk as self-less acts is essential. the limitations of this study include the small number of participants resulting in the low response rate. despite this, important aspects of the redeployment of surgical trainees to critical care have been elucidated. the reasons for the non-participation are multifactorial and may be due to fatigue, exhaustion, time constraints or a general decrease in participation. wellbeing has not been extensively explored in this study but highlights areas of concern among surgical trainees. another potential limitation is response bias, particularly in the context of reported improvement in technical and non-technical skills. the dunning-kruger effect may play a role with some respondents whereby there is cognitive miscalibration with individuals overestimating their abilities and reporting more confidence in the presence of less experience. the evaluation of resuscitation skills was difficult to perform in this study as trainees had high levels of supervision and most decisions on clinical management were made by consultant-grade doctors. however, increased understanding of the acute presentations of covid- and the management of its complications were reported. a pandemic with a novel disease, such as covid- , introduces many challenges to healthcare professionals and shifts focus from patient-centred to population-centred care. this includes the redistribution of health care workers in alignment with public health needs. both the technical and non-technical skills developed from the redeployment of surgical trainees to icu will form part of their professional armamentarium for the future. proactive rather than reactive wellbeing interventions are essential for surgeons in training with regards to their psychological health. the long-term impact of covid- pandemic on surgical education is yet to be fully evaluated and more research will be required in the long-term. close monitoring of trainees" surgical development and mental health will be essential in alleviating the effects of this pandemic and improving our response in the future. contributions: ap -conceptualisation, methodology, writing, review and editing, rr -methodology, data collection and analysis, editing, rb -methodology, data collection, editing, sv-conceptualisation, review and editing, maw -conceptualisation, methodology, writing, supervision who. coronavirus disease (covid- ) outbreak improving care by understanding the way we work: human factors and behavioural science in the context of intensive care the surgical high dependency unit: an educational resource for surgical trainees the acgme core competencies: changing the way we educate and evaluate residents governance arrangements for research ethics committees lives on the line? ethics and practicalities of duty of care in pandemics and disasters recovery of surgical services during and after covid- how should complex communication responsibilities be distributed in surgical education settings? non-technical skills in the intensive care unit covid- : good practice for surgeons and surgical teams: royal college of surgeons in england covid- : skin damage with prolonged wear of ffp masks a surgeon's role in fighting a medical pandemic: experiences from the unit at the epicentre of covid- in singapore -a cohort perspective preventing a parallel pandemic -a national strategy to protect clinicians' well-being lessons from covid- : visiting patients at home and assessing comorbidities covid- : doctors must take control of their wellbeing burnout and psychiatric morbidity among doctors in the uk: a systematic literature review of prevalence and associated factors surgeon burnout: a systematic review some good must come out of covid- factors related to physician burnout and its consequences: a review how essential is to focus on physician's health and burnout in coronavirus (covid- ) pandemic? leadership proficiency in surgery: lessons from the covid- pandemic in the st century, what is an acceptable response rate? unskilled and unaware of it: how difficulties in recognizing one's own incompetence lead to inflated self-assessments key: cord- -f n hk authors: khan, hafiz muhammad waqas; parikh, niraj; megala, shady maher; predeteanu, george silviu title: unusual early recovery of a critical covid- patient after administration of intravenous vitamin c date: - - journal: am j case rep doi: . /ajcr. sha: doc_id: cord_uid: f n hk patient: female, -year-old final diagnosis: covid- symptoms: cough • fever • shortness of breath medication: — clinical procedure: — specialty: critical care medicine objective: unusual clinical course background: coronavirus disease (covid- ) continues to spread, with confirmed cases now in more than countries. thus far there are no proven therapeutic options to treat covid- . we report a case of covid- with acute respiratory distress syndrome who was treated with high-dose vitamin c infusion and was the first case to have early recovery from the disease at our institute. case report: a -year-old woman with no recent sick contacts or travel history presented with fever, cough, and shortness of breath. her vital signs were normal except for oxygen saturation of % and bilateral rhonchi on lung auscultation. chest radiography revealed air space opacity in the right upper lobe, suspicious for pneumonia. a nasopharyngeal swab for severe acute respiratory syndrome coronavirus- came back positive while the patient was in the airborne-isolation unit. laboratory data showed lymphopenia and elevated lactate dehydrogenase, ferritin, and interleukin- . the patient was initially started on oral hydroxychloroquine and azithromycin. on day , she developed ards and septic shock, for which mechanical ventilation and pressor support were started, along with infusion of high-dose intravenous vitamin c. the patient improved clinically and was able to be taken off mechanical ventilation within days. conclusions: this report highlights the potential benefits of high-dose intravenous vitamin c in critically ill covid- patients in terms of rapid recovery and shortened length of mechanical ventilation and icu stay. further studies will elaborate on the efficacy of intravenous vitamin c in critically ill covid- . coronavirus disease (covid- ) , which is caused by severe acute respiratory syndrome coronavirus- (sars-cov- ), was first reported on december , in a group of patients who presented with atypical pneumonia in wuhan, hubei province, china [ , ] . since the first report of the disease, more than million cases have been reported worldwide, with the united states as the epicenter of this pandemic, with more than million confirmed cases and more than deaths as of april , [ ] . studies from various countries have reported that covid- is associated with rapid spread, acute respiratory distress syndrome (ards), saturated capacity of intensive care units, and high mortality [ , ] . there are still no targeted therapeutic options available for sars-cov- , and symptomatic management is the mainstay of treatment in ards associated with covid- . the mortality rate associated with ards is up to %, which is almost equal to the % case fatality rate reported in patients with severe covid- disease requiring critical care management [ , ] . multiple studies have found that high-dose intravenous vitamin c reduces systemic inflammation in multiple ways, including attenuation of cytokine surge, and prevents lung injury in severe sepsis and ards [ , ] . we describe a case of covid- with septic shock and ards who received high doses of intravenous vitamin c and was the first case to be able to be taken off of mechanical ventilation (mv) early and recover from the disease at our institute. a -year-old white woman presented to the emergency department with a -day history of low-grade fever, dry cough, and shortness of breath (sob). she had been admitted to another hospital for an elective right total knee replacement week ago, with an uneventful post-operative course. she went to the hospital in a healthy state, stayed in a private room, and denied any recent sick contacts or travel history. upon review of systems, the patient reported pain, redness, and swelling in the right knee, which was unchanged since the surgery. the past medical history was pertinent for essential hypertension, obesity, myasthenia gravis (mg) in remission, and osteoarthritis. the physical examination revealed a body temperature of . °c, blood pressure of / , pulse of beats per minute, respiratory rate of breaths per minute, and oxygen saturation of % while breathing ambient air. lung auscultation revealed bilateral rhonchi with rales. chest radiography (cxr) was performed, which reported patchy air space opacity in the right upper lobe suspicious for pneumonia ( figure ). the remainder of the examination was unremarkable. a rapid nucleic acid amplification test (naat) for influenza a and b was negative. given community transmission of covid- , a nasopharyngeal swab specimen was obtained and sent to the state laboratory for detection of sars-cov- . the patient was admitted to the airborne-isolation unit following the centers for disease control and prevention (cdc) recommendations for contact, droplet, and airborne precautions [ ] . the patient was initially started on broad-spectrum antibiotics with cefepime and levofloxacin for pneumonia in the high-risk setting of recent hospitalization for knee surgery after drawing blood and sputum cultures along with supportive care with l of supplemental oxygen. on day , the patient also developed mild diarrhea, generalized weakness, and fatigue. she was evaluated by neurology and started on g/kg intravenous immunoglobulin for days due to mild mg exacerbation and a pending mg crises. the arterial blood gases (abgs), complete blood count, and basic metabolic profile studies were monitored during hospitalization and are presented in table . the laboratory data on day showed mild absolute lymphopenia and anemia, while the abgs revealed a ph of . , pco of . mmhg, po of . mmhg, and bicarbonate of . mmol/l. on day , the creatinine kinase and lactic acid were normal, while the lactate dehydrogenase, ferritin, and interleukin- were elevated at units per liter, nanograms per milliliter, and picograms per milliliter, respectively. on days through of hospitalization, the patient reported progressively increasing sob, and the oxygen requirements increased up to l high-flow nasal cannula. on day , the nasopharyngeal swab results came back positive for sars-cov- by reverse-transcriptase polymerase chain reaction (rt-pcr). the patient was started on oral hydroxychloroquine mg once and started on mg twice a day, along with azithromycin mg once a day intravenously, zinc sulfate mg times a day, and oral vitamin c g twice a day. the blood and sputum cultures did not grow any organisms and broad-spectrum antibiotics were discontinued. on day , the patient's sob worsened rapidly, and oxygen requirements went up to l. upon physical examination, the patient was drowsy, in moderate distress, and was unable to protect the airways. the blood pressure was / mmhg with the heart rate of beats per minute, temperature °c, and a respiratory rate of breaths per minute. the cxr revealed bilateral alveolar infiltrates due to pneumonia and interstitial edema, consistent with ards ( figure ). given her rapid deterioration, she was intubated on an emergent basis and started on pressure-regulated volume-controlled mechanical ventilation. the patient was started on norepinephrine . mcg/kg/min for septic shock and was titrated accordingly to maintain mean arterial pressure more than mmhg, along with colchicine . mg twice a day to address the cytokine storm given the elevated interleukin- levels. on day [mechanical ventilation (mv) day ], she was started on high-dose vitamin c g per h as a continuous intravenous infusion. her clinical condition started to improve slowly and norepinephrine support was stopped on mv day . the cxr on day showed significant improvement of the pneumonia and interstitial edema (figure ) . a spontaneous breathing trial with continuous positive airway pressure/pressure support (cpap/ps) with the settings of positive end-expiratory pressure (peep) of mmhg, ps above peep of mmhg, and a fraction of inspired oxygen of % was successfully tolerated by the patient. the abgs revealed a ph of . mmhg, pco of . mmhg, po of . mmhg, and bicarbonate of . mmol/l. because of her remarkable clinical and radiological improvement, she was extubated to l of oxygen with a nasal cannula on day of illness (mv day ). her breathing status continued to improve in the following days, with oxygen saturation of % on day of illness while breathing ambient air, and a cxr revealed almost complete resolution of the infiltrates (figure ) . the patient received a total of days of treatment with hydroxychloroquine and azithromycin along with days of colchicine during hospitalization. high-dose vitamin c infusion and oral zinc sulfate were continued for a total of days. she received inpatient physical and occupational rehabilitation after being transferred from the critical care unit to an isolation room. she still positive by rt-pcr for sars-cov- on day of illness and was discharged from the hospital in stable condition with an additional days of quarantine. sars-cov- continues to spread across the world causing severe illness in the form of septic shock, multiorgan failure, ards, and death. the virus was first named -ncov when the initial cases of atypical pneumonia in china were found to be associated with a novel coronavirus [ ] . it was later named sars-cov- as it was found to cause ards, requiring high-support mechanical ventilation and associated high mortality [ , ] . thus far, there are no specific targeted therapies with proven efficacy available for the treatment of critically ill patients with ards. in our case, the patient was treated with high-dose vitamin c as a continuous intravenous infusion and was the first covid- patient to be able to be taken off mechanical ventilation early and recover from the disease at our institution. many decades of research have shown that vitamin c is an essential component of the immune cell function and has a critical role in a variety of immune system mechanisms [ ] . patients with vitamin c deficiency can develop fatal scurvy and are highly susceptible to a variety of infections, including pneumonia [ ] . vitamin c enhances neutrophil motility, phagocytosis, microbial killing by activating reactive oxygen species, and apoptosis, and prevents oxidative damage by its antioxidant properties [ ] . it also promotes b and t lymphocytes proliferation and antibody production [ ] . recent data have shown that vitamin c also prevents the production of pro-inflammatory cytokines, including il- , which causes lung injury and leads to ards; this is a component of the cytokine release syndrome that is observed in critically ill covid- patients [ ] . the attenuation of these immune functions by microorganisms leads to a severe inflammatory state and tissue necrosis resulting in multiorgan failure and ards, requiring mechanical ventilation and icu care. various studies have shown that up to % of critically ill covid- patients require invasive mechanical ventilation in the icu [ , ] . a recent meta-analysis of multiple trials showed that vitamin c reduces the duration of mechanical ventilation and the length of icu stay in patients with severe sepsis and ards [ ] . this finding was also confirmed recently in a randomized clinical trial by fowler et al. involving patients with sepsis and ards who received high-dose intravenous vitamin c up to g per day and showed significant improvement in -day mortality and shortened duration of icu stay [ ] . based on the above data, vitamin c has been increasingly used recently in the treatment of covid- disease, and peng et al., from wuhan university, initiated a phase ii trial to study the efficacy of vitamin c infusion in the treatment of ards associated with sars-cov- , in which patients receive g of intravenous vitamin c per day for a total of days [ ]. vitamin c infusion was not part of the treatment for covid- at our institute as it has not been approved as a standard treatment for sars-cov- . the present patient received high-dose vitamin c infusion due to family request after the development of ards and mv initiation. according to a study by bhatraju et al., who investigated covid- in critically ill patients in the seattle region, the median length of icu stay and duration of mv were and days, respectively [ ] . in our case, the length of icu stay and duration of mv were only and days, respectively. our case was also the first to be able to be taken off of mv early in our covid- icu unit and to recover from the disease at our institute. the length of icu stay and duration of mv in the present patient were also lower than in covid- patients who did not receive vitamin c infusion at our institute. the rest of the hospital course of our case was uneventful and the patient was discharged home in stable condition. vitamin c is a pivotal component of the immune system, with proven antioxidant and anti-inflammatory properties and has been tested in numerous studies for its role in severe sepsis and icu care, especially when used as a continuous high-dose intravenous infusion. high-dose intravenous vitamin c treatment in our case was associated with fewer days on mechanical ventilation, shorter icu stay, and earlier recovery compared to the average length of mechanical ventilation, disease duration, and icu stay in critical covid- patients at our institute. our results show the importance of further investigation of intravenous vitamin c in the form of randomized controlled trials for the treatment of sars-cov- to accurately assess its efficacy in critically ill covid- patients requiring mechanical ventilation and icu care. world health organization: pneumonia of unknown etiology coronavirus covid- global cases dashboard clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study critical care utilization for the covid- outbreak in lombardy, italy: early experience and forecast during an emergency response epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries characteristics and outcomes of critically ill patients with covid- in washington state ascorbic acid attenuates lipopolysaccharide-induced acute lung injury phase i safety trial of intravenous ascorbic acid in patients with severe sepsis novel-coronavirus selected vitamins and trace elements support immune function by strengthening epithelial barriers and cellular and humoral immune responses hemilä h: vitamin c and infections vitamin c and immune function ascorbic acid is a potent inhibitor of various forms of t cell apoptosis caveolin- -mediated internalization of the vitamin c transporter svct in microglia triggers an inflammatory phenotype covid- in critically ill patients in the seattle region -case series clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan vitamin c can shorten the length of stay in the icu: a meta-analysis effect of vitamin c infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the citris-ali randomized clinical trial we thank all the intensive care units (icu) critical care nurses at mclaren-flint/michigan state university hospital for their untiring efforts in taking care of our patient during this difficult period of the pandemic. key: cord- - war j authors: supino, m.; d'onofrio, a.; luongo, f.; occhipinti, g.; dal co, a. title: world governments should protect their population from covid- pandemic using italy and lombardy as precursor date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: war j the covid- pandemic is spreading worldwide. italy emerged early on as the country with the largest outbreak outside asia. the outbreak in northern italy demonstrates that it is fundamental to contain the virus' spread at a very early stage of diffusion. at later stages, no containment measure, even if strict, can prevent the saturation of the hospitals and of the intensive care units in any country. here we show that it is possible to predict when the intensive care units will saturate, within a few days from the first cases of covid- intensive care patients. using early counts of intensive care patients, we predict the saturation for lombardy, italy. governments should use the italian precursor to control the outbreak of covid- and prevent the saturation of their intensive care units to protect their population. the coronavirus disease (covid- ) is a respiratory infectious disease caused by sars-cov- (also known as -ncov), which originated in wuhan, china, in early december . on january rd , wuhan city shut down public transportation and airways; one week later, wuhan and other cities in the province of hubei, imposed strict social distancing measures (closure of school and non-essential work activities), combined with active search and isolation of infective cases and their contacts; on february th , all non-essential companies and manufacturing plants were closed. on february th , france reported the first death from covid- outside asia, while dozens of countries document cases of infection. on february th , three weeks after the lockdown of wuhan and other cities, cases in china have fallen from an average of , daily cases of two weeks before to cases. in the meanwhile, italy emerged as the country with the largest outbreak outside asia. on march th , italy imposed a lockdown of the whole nation. on march th , the world health organization (who) declared the pandemic state, with more than , cases in countries. on march th , while china announced that the incidence was brought to negligible levels and attempts to prudently restart normal life were all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in deaths, surpassing china. in europe, several countries experienced similar exponential growth of cases as italy, with just a few days of delay (fig. ). spain and france imposed a lockdown on march th and on march th , respectively. on march st , italy imposed a full lockdown of the nation, closing all nonessential companies and manufacturing plants. china was able to control the outbreak of covid- in about two months by implementing strong containments measures, such as lockdown of the population ( ). lockdown can appear as an extreme measure, but it is not. mild restrictions, such closure of schools and partial closure of workplaces, can lower the basic reproduction number of infection (r ) but not below the unit. with mild restrictions, the number of infections would grow at the same rate for a period equal to the incubation time (which is below days for % of covid- infections ( )), and would then grow exponentially at a lower rate. therefore, mild restrictions would slow down the epidemic, but not control it ( ) . in this work, we discuss the necessity and efficacy of lockdown measures for controlling the outbreak of covid- , analyzing data from italy, the country with the largest recorded outbreak of the disease today. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in temporally to superpose one on another, so that for all countries day zero represents the onset of covid- outbreak. japan and singapore were able to contain the outbreak at a the very early stage. the chinese region of hubei was able to contain diffusion at a later stage, by imposing a lockdown of the population on january th (red triangle), and a full lockdown of the population on february th (red diamond), closing all non-essential companies and manufacturing plants. italy, spain, france, uk, and the american states of california and new york (referred as us*) display exponential growth of confirmed cases. italy, spain, france and us* imposed a lockdown at similar (relative) times, indicated by the green, gold, blue and purple triangle, respectively. the four countries have comparable population sizes to hubei region, with a minimum of spain ( . m people) and a maximum of france ( . m). italy additionally imposed a full lockdown days afterwards (green diamond). all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in while nhs are prepared to receive a certain number of icu patients distributed during the influenza season, which lasts several months, no nhs can manage an exponentially growing number of covid- patients. to avoid the saturation of the icus, governments need to impose strong containment measures, such as lockdown of the population. acting early is paramount: after containments measures are taken, the number of cases still grows exponentially for at least ten days, due to infections contracted before the measures ( ). the later these containment measures are taken, the stronger these measures need to be to contain diffusion of covid- , and could be anyways insufficient to avoid the catastrophic collapse of the nhs. for example, japan and singapore were able to avoid a lockdown of the population, because the governments implemented a range of measures at a very early stage of the outbreak (fig. ). from the early stage of the covid- outbreak (february th ), italy is providing statistics of the epidemic, through a daily bulletin and an open-access repository ( ). this repository contains daily counts of confirmed cases, hospitalized patients, icu patients, and deceased patients, at the national and regional level (fig. ). this repository represents an important and unique source of information for other countries that the pandemic will reach. the number of icu patients represents a more robust information compared to the number of infected people, which is subject to an under-reporting. the number of infected people strongly depends on the number of performed tests and on the strategy of sampling of the population (e.g. only symptomatic people, random people). testing capability and strategy might largely vary among different countries, while icu patients count is a routine operation performed by all nhss. icu counts are more reliable also compared to deaths counts, since most patients dying with covid- have comorbidities and ascertaining that covid- was the primary cause of death can be complicated. for example, germany reported no cases of death due to sars-cov- until there were all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in covid- outbreak in italy started in codogno, a town of , inhabitants in lombardy region. after ten days from the first icu patient (february, th ), the number of covid- icu patients was all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in ( ) all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in here we show that it is possible to predict the date of saturation of the icus in a region early on, by using the temporal information about the number of available icu beds. we focus on lombardy region. the number of icu patients in the region grew exponentially for the first ten days, starting from february th , and then slowed down as it reached the number of available icu beds. we can predict the date at which the icu beds became saturated by performing a linear regression of the logarithm of the number of icu patients, starting from the first four datapoints (fig. ) . this result shows that monitoring the icus statistics at the beginning of the epidemic allows countries to assess the date of possible saturation of the icu beds early on. monitoring the icus early in the outbreak is paramount: lombardy in italy has one the best nhs in the world ( , ), therefore most countries will face the saturation of their icu beds at earlier stages of the outbreak. it is worth to note that several factors can affect the time to saturate the icu beds. in particular, the saturation time depends on the connectivity of the population: the more people are connected within a region, the faster the infection diffuses ( ) . therefore, the risk of icus saturation is higher for the most developed and connected regions, and lombardy is the most connected region of italy. moreover, if a lock down measure is imposed, the saturation time depends on the incubation time of the disease and on the degree of adherence of the population to the lockdown. here we analyze the effects of the lockdown of the italian population. italy imposed two major containment measures: the lockdown on march th , and a full lockdown on march st , where all non-essential companies and manufacturing plant were closed. these measured helped to avoid the collapse of the whole national health system, yet they could not avoid the saturation of the icu beds in several italian regions (fig. ) . all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the effects of the confinement measures become evident with some delay. specifically, we expect the effect on the number of icu patients to appear within about two weeks (i.e. the maximum incubation time), and on the number of deaths to appear in about three weeks (i.e. the time from infection to death) ( ) . at the current moment, days have passed from the national lockdown, so we expect to see an effect only on the number of icu patients. because of the saturation of the icus in several italian regions, the number of icu patients in italy currently underestimates the number of cases that would require intensive care. therefore, we analyze the data of italy excluding the regions where the icus have saturated. this leaves us with of the regions and excludes about % of the italian population. we find that the recent growth of icu patients is consistent with a linear growth, rather than an exponential growth, suggesting that the lockdown measures have effectively reduced the spread of the infection (fig. ), as it has been for hubei region ( ). specifically, we can obtain a very good fit of the data using an exponential curve (icu patients(t) ∝ exp[r t], t = days), up to five days after the lockdown (equal to the median incubation time of covid- ( )) and a line (icu patients(t) ∝ b t, t = days) for later datapoints. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted march , . . https://doi.org/ . / . . . doi: medrxiv preprint the regional number of icu beds reported before the onset of the epidemics. this number has been increased during the epidemic. at the time we write this manuscript, days after the lockdown declaration, it is still not possible to discriminate between an exponential or logistic trend of the number of icu patients in time. therefore, it is not yet possible to offer a good estimate of the number of icu patients to expect in the near future. however, the growth of icu patients is slower than exponential. governments must consider stronger actions than lockdown, including immediate closing of non-essential companies and manufacturing plants (full lockdown), as italy did on march st . in this work, we analyzed the temporal evolution of covid- outbreak in italy up to march th and we discussed the effects of the national lockdown in containing the diffusion. the saturation of the icus in many italian regions suggests that containment measures were taken too late. using italy as a precursor, other countries should impose these confinement measures at earlier stages of the outbreak to be able to protect their population from covid- . we show that countries can predict the date of saturation of their icus early on, as soon as an exponential growth of intensive care patients is observed, as it was in lombardy region. the italian case demonstrates that a national lockdown is effective in reducing the growth of icu patients. the complete saturation of icus, thus the collapse of a nhs, would be a catastrophe that would affect the entire population of a nation. people would die if, for any reason, intensive care would be needed : no matter being positive or negative to covid- , the age, the richness, or the wellness of the patient. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in we strongly encourage any government to accurately share data, including icu patients; these data will significantly help the understanding of present and future evolution of the covid- pandemic. italy has been the first country in europe in which the pandemic outbreak has been observed, and it has adopted a politics of wide dissemination of open data with detailed spatial structure. unprecedented ms analyzed the data, conceived the manuscript and, together with fl, prepared the figures. all the authors contributed to the interpretation of the data and the discussion of the results. ms and adc wrote the manuscript, and all the authors reviewed it. the authors declare no competing interests. the italian covid- data are available through a github repository managed by the dpc (dipartimento della protezione civile -presidenza del consiglio dei ministri): https://github.com/pcm-dpc/covid- for figure , we used world covid- data published by the eu agency for disease prevention and control: all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted march , . . https://doi.org/ . / . . . doi: medrxiv preprint https://www.ecdc.europa.eu/en/publications-data/download-todays-data-geographic-distribution-covid- for figure , we also used the dataset maintained by the center for systems science and engineering evolving epidemiology and impact of non-pharmaceutical interventions on the outbreak of coronavirus disease the incubation period of coronavirus disease (covid- ) from publicly reported confirmed cases: estimation all rights reserved. no reuse allowed without permission preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted doi: medrxiv preprint and application information-related changes in contact patterns may trigger oscillations in the endemic prevalence of infectious diseases season ): strengths and weaknesses . results of a cohort study in two large italian hospitals measuring health system performance for countries italy: health system review epidemic processes in complex networks incubation period and other epidemiological characteristics of novel coronavirus infections with right truncation: a statistical analysis of publicly available case data this manuscript has been written with the hope that the heroic resistance showed by the city of bergamo, the lombardy region and the whole of italy will not be needed elsewhere.the authors want to thank all the italian nurses, doctors and health-care professionals that are fighting against an invisible enemy as war heroes in dark times. this manuscript is dedicated to the memory of doctor li wenliang, who first tried to warn the world about covid- , and all the healthcare professionals who died fighting against this virus. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in key: cord- - js nudx authors: mac, s.; barrett, k.; khan, y. a.; naimark, d. m.; rosella, l.; ximenes, r.; sander, b. title: covid- demographics, acute care resource use and mortality by age and sex in ontario, canada: population-based retrospective cohort analysis date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: js nudx background: understanding resource use for covid- is critical. we conducted a population-based cohort study using public health data to describe covid- associated age- and sex-specific acute care use, length of stay (los), and mortality. methods: we used ontario case and contact management (ccm) plus database of individuals who tested positive for covid- in ontario from march to september , to determine age- and sex-specific hospitalizations, intensive care unit (icu) admissions, invasive mechanical ventilation (imv) use, los, and mortality. we stratified analyses by month of infection to study temporal trends and conducted subgroup analyses by long-term care residency. results: during the observation period, , covid- cases were reported ( % < years, % female). the proportion of cases shifted from older populations (> years) to younger populations ( - years) over time. overall, % of individuals were hospitalized, of those % were admitted to icu, and % of those used imv. mean los for individuals in the ward, icu without imv, and icu with imv was . , . , . days, respectively. mortality for individuals receiving care in the ward, icu without imv, and icu with imv was %, %, and %, respectively. all outcomes varied by age and decreased over time, overall and within age groups. interpretation: this descriptive study shows acute care use and mortality varying by age, and decreasing between march and september in ontario. improvements in clinical practice and changing risk distributions among those infected may contribute to fewer severe outcomes among those infected with covid- . understanding the local, context specific, epidemiology and resource use implications of covid- is critical to inform mitigation strategies for the second wave and throughout the pandemic. allocating acute care resources appropriately and adequately for all patients and the ability to use targeted public health measures to minimize adverse effects resulting from broad restrictions is a key concern.( - ) ontario population-level studies to date describe several aspects of the first wave: age and sex-specific descriptive studies for testing, cases and outcomes up to may , ,( ) and for hospitalizations up to june , ,( ) mortality using cremation data in a time series up to june , , ( ) and prediction tools using cases up until may , . ( ) however, as the covid- pandemic evolves, current data on health outcomes and acute care resource utilization across stages of the pandemic are warranted. the objective of our study was to describe covid- cases in ontario between march , and september , , and to provide estimates of age-and sex-specific acute care resource utilization (hospitalization, icu admission, invasive mechanical ventilation (imv)), length of stay (los), and mortality. we conducted a population-based cohort study using administrative data collected from ontario's case and contact management (ccm plus) database. we obtained research ethics board approval from the university of toronto. ccm plus is ontario's province-wide population-based dataset on all individuals who test positive for covid- in ontario ( , individuals between january and october , ). ( ) ccm plus includes individual-level data on demographics (e.g., age, sex, region), epidemiology (e.g., likely acquisition), patient characteristics (e.g., co-morbidities), acute care resource utilization (e.g., hospitalization, icu admission, imv), health outcomes (e.g., mortality), and long-term . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint care (ltc) residency. given the evolving nature of the dataset, including addition of variables over time, our analysis was limited to outcomes of interest using fields which were considered complete by the dataset custodian. all variables used for this analysis are described in appendix . we accrued incident cases of laboratory-confirmed covid- cases between march and september , and followed these individuals until october , , ensuring at least days of follow-up. accrual was based on the "accurate episode date" (episode date) field in ccm plus. since % of all cases require up to days for the episode date to be completed (appendix ), and time from episode date to hospitalization is approximately days, we only accrued cases until september , to allow for at least days of follow-up. we examined acute care resource use (hospitalization, icu admission, imv), los at each level of acute care, and mortality. outcomes are examined overall, by age and sex, specific co-morbidities, ltc residence status, and by month based on episode date. we considered three co-morbidities: diabetes, immunocompromised, and renal conditions, which were previously identified as conditions that increase risk of mortality among covid- patients. ( ) we describe overall acute care use by -year age groups, sex, and month based on accurate episode date, which uses a number of dates entered to provide an approximation of onset date. outcomes are calculated as follows: hospitalizations based on the total number of infections, icu admissions based on the total number of individuals hospitalized, and imv based on the total number of icu admissions. we assumed that individuals who were recorded as "intubated" received imv. mortality and los were estimated by acute care level: ) ward (i.e., hospitalized but did not receive icu care or imv), ) icu (i.e. required icu care but no imv) and ) ventilation (i.e., required imv). mortality was also estimated for individuals who were never hospitalized. for these outcomes, we only . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint included individuals with resolved outcomes (resolved or fatal). we assumed death was attributable to the highest level of care (i.e., related to the severity of the disease). for example, if an individual was hospitalized, we do not differentiate whether this individual died during or after their hospitalization. overall mortality was analyzed by month based on episode date. individuals missing data due to lack of follow-up or inaccurate dates (e.g., hospitalization admit dates entered as , , early ) were excluded from the analysis. detailed information on data manipulation and cleaning are described in appendices - . all data was handled and analyzed in microsoft excel . results are reported following the record statement for observational studies (appendix ). ( ) until october , , there were , individuals with laboratory confirmed covid- , of which were excluded due to incomplete data, and , did not meet the accrual period ( pre-accrual, and , post-accrual), resulting in a total of , individuals from march to september , included in this analysis. approximately % of cases were between and years of age, and % were female. approximately % of all cases were years old and older. when cases associated with ltc residency are excluded, the proportion of cases among those age years and over drops to %. among ltc residents, % were years or older, and % were female. characteristics of all cases are summarized in table . figure shows total cases by age group over time overall ( figure a ) and excluding ltc residents ( figure b ). as the pandemic progressed, the proportion of total cases from older population groups (> years) decreased from a high of % in april to % in september, while the proportion of total cases from younger populations (age - years) increased from a low % in april to % in september. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint this trend is still evident in the analysis excluding ltc residents ( figure b ). starting in june, the age groups - years account for the greatest proportion of reported cases, with the proportion of cases in the - year age group increasing from % in april to % in september. analysis of co-morbidities showed a decreasing proportion of cases with the three co-morbidities over time. in march, % of all cases were diabetic vs. % in september, while cases who were immunocompromised or had renal conditions each decreased from % in march to % in september. the proportion of cases with neither of these co-morbidities increased from % in march to % in september. hospitalization, icu admission, and imv use by age and sex are summarized in figure (all data in appendix ). overall hospital admission was %, with males having a slightly higher proportion of hospitalization ( %) compared to females ( %). the proportion of all reported cases of covid- requiring hospitalization decreased over time: it was highest in march at % and decreased to % by the end of september. this trend is apparent for all age groups, among the elderly: to years ( % dropping to %), years or older ( % dropping to %), and also in younger age groups: to years ( % dropping to %). on average, individuals were hospitalized . days after their episode date ( . from symptom onset). hospitalizations for all individuals, and excluding ltc residents, are summarized in table . analysis of the three comorbidities (appendix ) showed that proportion of hospitalization decreased from march to september for cases with diabetes ( % to %), immunocompromised ( % to %), cases with renal conditions ( % to %) and individuals with two or more of these conditions ( % to %). however, proportion of icu admissions were similar or increased in the same period. overall, % of hospitalized patients required admission to the icu, with males being more likely to require icu care ( %) compared to females ( %). icu admission was highest for males and females . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november , . ; between the ages of and years, at % and % respectively. imv was required for % of covid- cases admitted to icu. icu admissions and imv were highest in march at % and %, respectively, and decreased over the course of the pandemic to %, and %, respectively in september. icu admissions and imv, with and without ltc residents, are summarized in appendix . the mean los for those admitted to the ward was . the los distribution for all three levels of acute care are shown in appendices to . among cases designated as resolved, the overall mortality during our observation period was . % ( , deaths out of , resolved cases), and . % ( , deaths out of , resolved cases) when excluding ltc residents. overall mortality is summarized by month in appendix . mortality decreased from a high of % in april to % in september for all individuals, and from % to % when excluding ltc residents. age and sex-specific mortality by highest level of acute care are summarized in table . mortality for individuals not requiring any level of hospitalization, and for individuals requiring acute care was % ( , deaths out of , resolved cases), and % ( , deaths out of , resolved . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint hospitalizations), respectively. excluding ltc residents, these proportions were . % ( deaths out of , resolved cases) and % ( deaths out of , resolved hospitalizations), respectively. overall mortality (excluding ltc) for individuals receiving care only in the ward, individuals receiving care in the icu, and individuals requiring imv were % ( %), % ( %), and % ( %), respectively. among covid- patients admitted to the ward, mortality was highest among individuals age - years ( %) and among those age years and older ( %). mortality for individuals requiring icu admission was highest in individuals age to years ( %), and over years ( %). among patients with covid- who required imv, mortality was similarly highest amongst the older populations: % among those age - years, and % among those over years of age. we provide a descriptive analysis of covid- cases from march , to september , , by age, sex, and ltc residency. the population infected with covid- changed over time: predominantly older age groups in the first three months, and as the summer progressed, infections were predominantly among younger age groups. as the demographics of those infected changed, so too did healthcare resource useolder age groups had a larger proportion of cases requiring admission to hospital, icu, and need for imv. residents represented approximately % of total cases, and the majority of deaths ( %). our results show a decline in the proportion of cases hospitalized, requiring icu resources, and los between march and september. however, the decrease in acute care resource use and mortality was observed overall and within age strata, suggesting that these decreases cannot be entirely explained by changing age distribution over time. there are several potential explanations for these observations. first, changes in clinical practice pattern may have resulted in reduced hospitalizations, utilization of critical care resources and shorter hospital stays. as clinicians gained more experience caring for patients with . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint covid- , they may have become comfortable with expectant management, favouring non-invasive oxygenation and/or ventilation inside and outside the icu, in lieu of early imv, which may lower prolonged hospitalization and decrease mortality from ventilator associated bacterial pneumonia. ( ) ( ) ( ) ( ) further, , data to support the use of prone positioning to improve oxygenation in non-intubated patients, and evidence supporting the use of dexamethasone began to emerge as the pandemic progressed. ( ) ( ) ( ) second, it is possible that mask use or other public health measures including physical distancing, have resulted in lower viral loads among infected individuals, which may be associated with reduced severity of illness. ( ) finally, the finding that there was a decrease in infected individuals who had high-risk comorbidities over time could be a function of greater awareness and protections in place to protect those at higher risk of severe outcomes, thereby decrease the risk level among the infected cases over time and thus the need for hospitalization and icu care. while results from this descriptive study suggest that the proportion of acute care resource use, outcomes (mortality), and los are decreasing, it does not imply that the disease has become less severe and does not capture long-term sequelae. a growing body of evidence describes long-term sequelae experienced by many who had mild acute illness, including memory loss and fatigue months after their initial illness, a condition that is being described as "long-covid". ( , ) our analysis has several limitations. the ccm plus is an administrative dataset and is subject to underreporting and potential misclassification. ( , ) . testing policies and case definitions have changed between march and september in ontario. for example, switch to appointment-only testing in september with stricter criteria means the data may capture more severe cases (and less severe cases), further complicating interpretation of the shifting outcomes. furthermore, since this data has been collated from various sources, it may be more prone to underreporting of outcomes and data entry errors. backfilling of data can result in data being added later, delaying the reporting of outcomes up to two months. while we present september outcomes in our analysis, they should be interpreted with caution . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint as hospitalizations and outcomes are lagging indicators ( ) i.e., the data is right-censored. this would underestimate all outcomes presented, especially los and mortality. some of these trends may be confounded by changing healthcare seeking behaviours, public health interventions, implementing and lifting of restrictions, and individual differences (socioeconomic status, co-morbidities, geography)y. ( ) as such, we presented data descriptively and believe it would be inappropriate to present statistical measures to identify associations without fully adjusting for confounding. despite these limitations, to our knowledge, this study is the first to describe covid- case demographics, acute care use, mortality and los stratified by age and sex over seven months of the pandemic in ontario, canada. we were able to show the demographics and outcomes over time, capturing the different stages of the pandemic. these insights are critical for policy-makers and capacity planners as the pandemic evolves further. centralized public health database like ccm plus can provide timely population data and can be used in the future, especially if linked to other health administrative data (i.e., hospital discharge data) to understand long-term outcomes of covid- infection. further, our findings can be used to inform modeling and other studies estimating the impact of covid- and predicting healthcare resource needs. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november , . ; is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november , . is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november , . is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint figure . distribution of covid- cases by age group from march to september , . figure a ) (top) shows the distribution of cases by age groups including ltc residents. figure b) (bottom) shows the distribution of cases when ltc residents were excluded from analysis. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint *"others" group for all, and age to , to for fig b, fig c are not shown due to small cells . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint covid- -what we know so far about… social determinants of health covid- exacerbating inequalities in the us covid- disproportionately affects those living in poverty. and this impacts us all sex and age specific differences in covid testing, cases, and outcomes: a population wide study in ontario age-dependence of healthcare interventions for sars-cov- infection in ontario, canada . medrxiv an analysis of mortality in ontario using cremation data: rise in cremations during the covid- pandemic. medrxiv derivation and validation of clinical prediction rules for covid- mortality in ontario, canada. open forum infect dis the reporting of studies conducted using observational routinely-collected health data (record) statement covid- : an alert to ventilator-associated bacterial pneumonia covid- in critical care: epidemiology of the first epidemic wave across england, wales and northern ireland improving survival of critical care patients with coronavirus disease in england trends in covid- risk-adjusted mortality rates dexamethasone in hospitalized patients with covid- -preliminary report prone positioning in awake, nonintubated patients with covid- hypoxemic respiratory failure covid- and its implications for thrombosis and anticoagulation association of sars-cov- genomic load with covid- patient outcomes covid: quantitative and qualitative analyses of online long haulers' experiences, emotions and practices in the uk. medrxiv as their numbers grow, covid- "long haulers" stump experts health care claims data may be useful for covid- research despite significant limitations. heal aff blog hospitalizations, deaths will follow ontario's covid- surge, but how many remains unclear length of stay by level of care between months, mean (sd) days includes all individuals with outcome of 'recovered' or 'fatal key: cord- - sogg authors: komaru, yohei; doi, kent; nangaku, masaomi title: urinary neutrophil gelatinase-associated lipocalin in critically ill patients with coronavirus disease date: - - journal: crit care explor doi: . /cce. sha: doc_id: cord_uid: sogg nan to the editor: c oronavirus disease (covid- ), caused by severe acute respiratory syndrome coronavirus (sars-cov- ), was first reported in wuhan in december ( ) and has since spread quickly around the world. this global pandemic urgently needed optimal treatment and management strategies for covid- patients, especially for those critically ill. although sars-cov- predominantly affects the respiratory system, recent publications reported acute kidney injury (aki) as a significant comorbidity in covid- . the reported incidence of aki in covid- patients varies, and most reports from icus presented an incidence of - % ( ). cheng et al ( ) reported a significantly higher in-hospital mortality for covid- patients with severe aki even after adjusting for known confounders. significantly, pei et al ( ) revealed that the mortality of covid- pneumonia was significantly higher in patients with aki than those without. these accumulated observations have indicated that careful management is necessary in the treatment of critically ill patients with respiratory failure and aki as part of covid- . here, we report a retrospective analysis of urinary neutrophil gelatinase-associated lipocalin (ngal) in icu patients with covid- -associated respiratory failure. we included all adult patients admitted to the medical icu of the university of tokyo hospital who were diagnosed with respiratory failure associated with covid- through may , . reverse transcriptase-polymerase chain reaction on specimens obtained via nasopharyngeal swab or endotracheal suctioning was conducted to confirm sars-cov- infection. a treating physician who was independent from this study made all clinical decisions during the icu stay for each patient. the study protocol was approved by the institutional review board of the university of tokyo faculty of medicine (number ). informed consent was waived due to the health record-based, retrospective nature of the study. all clinical data and outcomes were extracted from the electronic health record system of the hospital. the final data extraction was conducted on june , . aki during icu stay was defined in accordance with the serum creatinine and urinary output-based criteria by kidney disease improving global outcomes (kdigo) aki guideline ( ) . the in-hospital clinical laboratory conducted urinary ngal measurements by chemiluminescent immunoassay. clinical outcomes of interest were aki, length of mechanical ventilation, and icu stay. the comparison of continuous values between aki and non-aki group was performed by wilcoxon rank-sum test. correlations between urinary ngal values and outcomes in continuous variables were evaluated using the least squares method. if the regression was statistically significant, the resulting regression line was presented with the coefficient of determination (r ). p values of less than . were considered significant. seventeen consecutive icu patients with covid- associated respiratory failure, who were admitted between march , , and may , , were included in this study. all patients needed oxygen therapy during admission in the icu. table shows a summary of baseline characteristics, laboratory data at icu admission, clinical management, and outcomes. two patients died on icu days and ; both were under treatment-withholding orders since days and , respectively. these two patients were excluded from the analysis on the length of mechanical ventilation and icu stay. the median durations of the ventilation and icu stay were days (interquartile range [iqr], - d) and days (iqr, - d), respectively. one patient was still on a ventilator and two were treated in the icu as of june , . ten patients developed aki during their icu stay. the median duration from icu admission to aki diagnosis was days; two patients met the kdigo aki criteria at icu admission, while the others met criteria within - days from admission. furthermore, patients who developed aki during icu stay (n = ) showed significantly higher urinary ngal level at icu admission compared with those who never fulfilled the aki diagnostic criteria (n = ) ( . vs . ng/ml; p = . ; fig. a ). the area under the receiver operating characteristic curve for aki diagnosis by urinary ngal level at icu admission was . ( % ci, . - . ). the optimal cutoff value of urinary ngal was ng/ml, with sensitivity of . and specificity of . . due to multiple urinary ngal measurements in the first and second days at the icu, we adopted the maximum value of ngal within hours from icu admission as a predictor variable for the length of mechanical ventilation and icu stay. as illustrated in figure b , higher urinary ngal level was correlated with longer length of mechanical ventilation (r = . ; p < . ). higher urinary ngal level was also correlated with longer length of icu stay (r = . ; p < . ). in this study involving critically ill covid- patients, we found that urinary ngal level at icu admission was elevated in patients who went on to develop aki during their icu stay. furthermore, the maximum urinary ngal value in the first hours from icu admission was correlated with length of mechanical ventilation. to the best of our knowledge, this is the first report on urinary ngal measurement in critically ill patients with covid- . our results suggest that urinary ngal may be applicable as an aki biomarker in this patient group. with regard to covid- , several reports indicated that sars-cov- could directly infect the kidneys. the cell surface protein, angiotensinconverting enzyme , which is used by the virus as an entry receptor, is abundantly expressed in renal tubular epithelial cells ( ) . in recent studies on autopsy cases of covid- , electron microscopy revealed viral structures, which were morphologically identical to sars-cov- , in the renal tubular epithelium ( , ) . the direct infection of sars-cov- to renal tubular epithelial cells may enhance the clinical value of urinary ngal as aki marker among covid- patients. another finding in this study was the correlation between urinary ngal level in the early phase of icu stay and the length of mechanical ventilation. this correlation suggested that urinary ngal level might reflect not only the severity of kidney injury but also lung injury in the covid- patients. ngal was reportedly expressed in bronchial goblet cells and alveolar type ii epithelial cells, and the expression was upregulated by inflammation ( ) . further studies on the pathophysiology of lung injury in covid- patients may highlight the efficacy of urinary ngal as a biomarker for respiratory failure beyond its known role in aki diagnosis. as is common with a small cohort study of short duration, this study should be interpreted with caution, as the risk for selection bias and confounding preclude more definitive conclusions. further studies with figure . urinary neutrophil gelatinase-associated lipocalin (ngal) level in icu patients with coronavirus disease associated with acute kidney injury (aki) diagnosis and length of mechanical ventilation. those who developed aki (n = ) manifested significantly higher urinary ngal level at admission than those without aki (n = ) ( . vs . ng/ml; p = . ) (a). lengths of mechanical ventilation are presented against maximum urinary ngal level acquired within hr from icu admission in eight patients who required ventilator during icu stay (b, except one dead patient). there was a significant positive correlation (p < . ) with coefficient of determination (r ) of . . ngal levels were illustrated with logarithmic scale. *p < . . large sample size are urgently warranted to clarify the clinical impact of urinary ngal in the context of treating covid- patients with respiratory failure and aki. in conclusion, the urinary ngal level was significantly associated with aki diagnosis of icu patients. the correlation between urinary ngal level and the length of ventilator dependency suggested that ngal also reflected the severity of lung injury in covid- patients, although this hypothesis should be validated in future studies. china medical treatment expert group for covid- : clinical characteristics of coronavirus disease in china clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a singlecentered, retrospective, observational study kidney disease is associated with in-hospital death of patients with covid- renal involvement and early prognosis in patients with covid- pneumonia kidney disease: improving global outcomes (kdigo) acute kidney injury work group. kdigo clinical practice guideline for acute kidney injury tissue distribution of ace protein, the functional receptor for sars coronavirus. a first step in understanding sars pathogenesis renal histopathological analysis of postmortem findings of patients with covid- in china ultrastructural evidence for direct renal infection with sars-cov- neutrophil gelatinase-associated lipocalin is up-regulated in human epithelial cells by il- beta, but not by tnf-alpha the authors have disclosed that they do not have any potential conflicts of interest. key: cord- - bet e l authors: khan, s. h.; lindroth, h.; perkins, a. j.; jamil, y.; wang, s.; roberts, s.; farber, m. o.; rahman, o.; gao, s.; marcantonio, e. r.; boustani, m.; machado, r.; khan, b. a. title: delirium incidence, duration and severity in critically ill patients with covid- date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: bet e l background delirium incidence, duration and severity in patients admitted to the intensive care unit (icu) due to covid- is not known. methods we conducted an observational study at two large urban academic level trauma centers. consecutive patients admitted to the icu with a positive sars-cov- nasopharyngeal swab polymerase chain reaction test from march st, to april , were included. individuals younger than years of age, without any documented delirium assessments (cam-icu), or without a discharge disposition were excluded. the primary outcomes were delirium rates and delirium duration and the secondary outcome was delirium severity. outcomes were assessed for up to the first days of icu stay. results of consecutive patients with confirmed covid- admitted to the icu, met eligibility criteria and were included in the analysis. delirium occurred in . % ( / ) and delirium or coma occurred in . % ( / ). sixty-three percent of patients were positive for delirium on the first cam-icu assessment. the median duration of delirium and coma was days (iqr: - ), and the median delirium duration was days (iqr: - ). the median cam-icu- score was (iqr: - ) representing severe delirium. mechanical ventilation was associated with greater odds of developing delirium (or: . , %ci: . - . ). mortality was . % in patients with delirium compared to . % in patients without delirium. conclusions . % of patients admitted to the icu with covid- experience delirium that persists for approximately week. invasive mechanical ventilation is significantly associated with odds of delirium. clinical attention to prevent and manage delirium and reduce delirium duration and severity is urgently needed for patients with covid- . the severe acute respiratory syndrome (sars-cov- ) novel coronavirus (covid- ) has emerged as a global pandemic and is associated with rapid spread, severe respiratory failure and significant morbidity and mortality. , as clinical experience with covid- grows, neurologic manifestations of the disease are receiving increased attention. a recently published small case series from france reported delirium occurred in / ( %) of patients admitted to the intensive care unit with covid- . however, the duration and severity of delirium in critically ill covid- patients have not been well described. delirium is a serious neurologic syndrome independently associated with longer duration of mechanical ventilation, prolonged icu and hospital stays, increased mortality, and institutionalization after discharge. [ ] [ ] [ ] [ ] [ ] increasing levels of delirium severity and duration amplify these outcomes, and are independently associated with worsening cognitive and functional outcomes post discharge. [ ] [ ] [ ] [ ] prior to covid- , the prevalence of delirium in mechanically ventilated patients has been decreasing from a historically high rate of % to a range of . - %. [ ] [ ] [ ] [ ] [ ] [ ] [ ] in the setting of the current global health crisis, hospital resources have been stretched to their limits to meet the needs of a large number of critically ill patients. the unintended impact of limited resources on clinical practice has raised concerns that current icu delirium rates have returned to the historically high levels. [ ] [ ] [ ] as of may , , there are . million confirmed covid- cases in the us and approximately % of covid- patients required intensive care unit (icu) level care. , , in this context, delirium is likely to pose a longterm public health challenge if rates in the united states are as high as recently reported in france. therefore, we conducted this study at two large academic health systems in urban midwest to measure incidence of delirium, delirium duration and delirium severity, and investigate risk factors associated with delirium in critically ill patients admitted with covid- . the observational study was conducted at two large, urban, academic, level admitted after april , , patients with no delirium assessments recorded in the electronic medical record for the duration of the follow up period, and those still admitted to the icu or hospital at the end of the study period. we excluded patients remaining admitted to the icu or hospital to accurately identify delirium duration and to prevent confounding of downstream effects of delirium on mortality and length of stay. clinical outcomes were followed up until april , (date inclusive) or until the patient transferred out of the icu. the main exposure variables were patients' demographics, comorbidities, laboratory results and severity of illness at admission. the primary outcomes were rate of delirium and delirium/coma duration during the first days of admission to the icu. delirium/coma duration was defined by the number of days the patient was alive and had documented delirium or coma, representing duration of abnormal cognitive status. patients who were discharged from the intensive care unit prior to days did not have subsequent delirium or coma assessments performed outside the icu. coma was assessed using the richmond agitation sedation scale . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint (rass) and delirium was identified through the confusion assessment method for the icu (cam-icu). coma was defined as a rass score of - or - , making patients ineligible for a cam-icu screening, while patients with a rass score of - or greater were eligible for a cam- hyperactive delirium was defined as a rass score of + to + at the time of positive cam-icu, and hypoactive delirium was defined as a rass score - to with a positive cam-icu score. the secondary outcome of delirium severity was assessed using the confusion assessment method for the intensive care unit- (cam-icu- ) which requires all components of the cam-icu to be assessed for each patient rather than a dichotomous cam-icu positive or negative result. the cam-icu- was implemented into the electronic medical record at eskenazi health in , and is assessed twice daily in the subset of patients receiving care at this hospital site. cam-icu- scores range from to , with - indicating no delirium, - mild to moderate delirium, and - as severe delirium. research assistants familiar with electronic medical systems at the hospitals (cerner powerchart, epic health systems) abstracted study data from the medical record, including cam-icu assessments performed by clinical nurses, and results were entered directly into an electronic redcap database. data obtained from the medical record included patient demographics (age, gender, self-reported race), insurance status, comorbidities, vital signs, . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . health evaluation score (apache-ii) was calculated using laboratory values, vital signs, and neurologic assessments from first hours of icu admission. demographic and clinical characteristics were compared between patients who had delirium positive and those without delirium using two-sample t-tests (normal data) and wilcoxon rank sum tests (skewed data) for continuous outcomes or fisher's exact test for categorical variables. summary statistics including median and inter-quartile range (iqr) were provided for patients with delirium. logistic regression was used including demographic or clinical characteristics that were significantly different between patients with delirium and those without delirium as independent variables to identify factors associated with delirium. two-hundred forty-three consecutive patients with covid- were admitted from march , to april , to the icus at two hospital systems. we excluded patients; did not have any delirium assessments, and remained admitted at the end of the follow up period (see supplementary figure ). in total, patients comprised the study cohort. demographics and clinical characteristics for the cohort are presented in table . the mean . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . age of the cohort was years (sd= . ), . % were female, % african american and . % hispanic, . % utilized commercial insurance, and . % medicare. the median charlson comorbidity index score was (iqr: - ), with hypertension ( . %), obesity ( . %), tobacco use ( . %), and chronic lung disease ( . %) the most frequent comorbid conditions. the median apache-ii score was (iqr: - ), and % of patients in the cohort underwent invasive mechanical ventilation. cerebrovascular accident (ischemic or hemorrhagic) was identified in . % ( / ) of patients. delirium occurred in . % ( / ) of patients in the study, whereas delirium or coma occurred in . % ( / ). forty-four percent of patients experienced coma. of patients with delirium, . % were positive on the first cam-icu assessment, and . % developed delirium on a subsequent cam-icu screening. as shown in table the median duration of delirium and coma was days (iqr: - ) (see table ), and median delirium duration was days (iqr: - ). patients had a median rass of - (iqr: - , ) at the time of icu admission indicating light sedation. figure shows the daily rates of patient's delirium, coma or delirium/coma-free status for up to days of icu admission. in our study . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint cohort, hypoactive delirium occurred in . % of patients on the first cam-icu assessment, and the median duration of hypoactive delirium was days (iqr: - ). details of the subtypes of delirium are shown in table and figure . in the subset of patients with delirium severity assessments (n= ), the median cam-icu- score was (iqr: - ) representing severe delirium. patients with delirium had greater mechanical ventilation days (median . days, iqr: . - . vs. , iqr: - , p< . ) and icu days (median . , iqr: . - . vs. . , iqr: . - . , p< . ) compared to patients without delirium (table ) . we did not find a significant difference in hospital mortality between covid- patients with delirium and those without ( . % vs. . %, p= . ), as shown in table in this observational study of covid- patients admitted to the icu at large hospitals, % of patients experienced delirium, delirium occurred early in the icu course (within the first two days), and the abnormal cognitive states of delirium or coma persisted for median length of one week. in addition, patients with covid- experienced severe delirium, and invasive mechanical ventilation was associated with a marked increase in odds of delirium. while mortality rates did not statistically differ by delirium status likely due to the small sample size of patients without delirium, we found mortality to be % higher in patients with delirium. to the best of our knowledge, our study is the first to describe delirium rates, duration and severity in . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . critically ill patients with covid- using standardized delirium assessment tools. due to the increased risk of mortality and morbidity following delirium, including the development of longterm cognitive impairment and post intensive care syndrome, this study has important implications for clinical practice, the recovery of patients with covid- admitted to intensive care, public health decision making, and even future research priorities. , our study findings represent a significant departure from recently reported trends in rates of icu delirium, including rates of mechanical ventilation ( %), delirium ( . %), and coma ( . %) at our own center during the influenza pandemic occurring in - (see supplementary table ). reductions in the prevalence of icu delirium from a historical high of % to rates of . - % have been reported over the past two years. is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint covid- is increasingly plausible. [ ] [ ] [ ] the possible pathways for neuronal damage due to covid- require additional study. while effective pharmacological therapies for treatment of covid- as well as delirium are not yet available, our study sheds light on an alarming burden of delirium and coma in patients admitted to the icu and the need for continued efforts on delirium prevention. following and implementing evidence-based icu practices (such as the abcdef bundle) to minimize delirium occurrence and severity under the pandemic conditions will likely remain an ongoing challenge. the continued use of screening tools for delirium and delirium severity can also provide bedside clinicians with dynamic assessments to measure the impact of interventions in real-time. , as resources shrink in the face of the pandemic and the health care response disrupts, it is imperative to continue to follow and implement time-tested evidence-based practices. finally, delirium in critically ill patients has been associated with long-term cognitive decline. , if other studies confirm higher rates of delirium in covid- icu patients, longitudinal follow-up will be crucial to understand the full impact of covid- and understand the pathophysiology of covid- related delirium. our study does have important limitations. this analysis is limited by its reliance on data from the medical record including clinician-administered delirium assessments. the limitation of clinician-administered delirium assessments has been minimized by the rigorous implementation and continued education on the cam-icu and cam-icu- at the participating institutions. our analysis also does not include medication exposure data, adherence to the abcdef bundle at the patient level, education levels, baseline functional status, or baseline cognitive function and therefore we are unable to fully explain the rates of delirium seen in our study. our analysis is also limited to delirium and coma assessments performed in the first fourteen days of icu stay, and therefore we are unable to describe the trajectory of delirium and coma for the duration of the hospitalization in this report. strengths of the study include incorporation of delirium severity data, a racially and socioeconomically diverse cohort of . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint patients and protocolized delirium assessments conducted by bedside clinicians at two high volume and high acuity centers. we found that in contrast to recent rates of delirium in icu patients, % of patients with covid- develop delirium which persists for approximately week, and occurs at high severity. invasive mechanical ventilation is significantly associated with delirium development. given these findings, continued attention to prevent and manage delirium is critical. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . white blood cell count x /l . ( . - . ) . ( . - . ) . ( . - . ) glasgow coma scale hypoactive delirium duration days ( - ) hyperactive delirium duration days ( - ) cam-icu- score ( - ) delirium was defined as a positive cam-icu assessment in the patient medical record for up to days during their icu covid- stay. coma was defined by richmond agitation sedation score of - or - . duration of delirium was defined as number of days patient was cam-icu positive on either morning or afternoon assessment for up to days while admitted to the icu. duration of coma was defined as number of days patient had coma by rass score on either morning or afternoon assessment for up to days of icu stay. hypoactive delirium was defined by (rass) of - to - with positive cam-icu, hyperactive delirium was defined by a rass score of + to + with positive cam-icu. delirium severity was measured using the cam-icu- in patients ( - , - : no delirium; - : mild to moderate delirium; - : severe delirium). abbreviations: cam-icu and cam-icu- =confusion assessment method-intensive care unit, icu=intensive care unit, iqr=interquartile range, rass= richmond agitation and sedation scale . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . table describes the clinical outcomes in covid- patients admitted to the icu. the overall cohort is described then divided by delirium status (positive cam-icu). univariate testing was completed to investigate statistical significance. abbreviations: icu=intensive care unit, iqr=interquartile range, los=length of stay . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . daily percentages do not equal % due to incomplete assessments, death, or discharge from intensive care unit. delirium was defined as a positive cam-icu assessment on either morning or afternoon assessment. coma was defined by richmond agitation sedation score of - or - . without delirium or coma was defined by rass greater than - and a negative cam-icu on either morning or afternoon assessment. is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . cam-icu and rass assessments were performed up to twice daily while patient was admitted to the intensive care unit. hypoactive delirium was defined by richmond agitation sedation scale (rass) of - to - with positive cam-icu, hyperactive delirium was defined by a rass score of + to + with positive cam-icu. mixed delirium: patients with both hyperactive and hypoactive delirium assessment on a given icu day. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . clinical characteristics of covid- in covid- in critically ill patients in the seattle region -case series days of delirium are associated with -year mortality in an older intensive care unit population delirium in the icu and subsequent long-term disability among survivors of mechanical ventilation intensive care unit delirium: a review of diagnosis, prevention, and treatment delirium in elderly people delirium in hospitalized older adults delirium severity trajectories and outcomes in icu patients: defining a dynamic symptom phenotype clinical phenotypes of delirium during critical illness and severity of subsequent long-term cognitive impairment: a prospective cohort study quantifying the severity of a delirium episode throughout hospitalization: the combined importance of intensity and duration the confusion assessment method for the delirium severity scale: a novel delirium severity instrument for use in the icu time trends of delirium rates in the intensive care unit evaluation of the e-pre-deliric prediction model for icu delirium: a retrospective validation in a uk general icu differences in -day mortality of delirium subtypes in the intensive care unit: a retrospective cohort study effect of flexible family visitation on delirium among patients in the intensive care unit: the icu visits randomized clinical trial occurrence and practices for pain, agitation, and delirium in intensive care unit patients effect of haloperidol on survival among critically ill adults with a high risk of delirium: the reduce randomized clinical trial intensive care management of coronavirus disease (covid- ): challenges and recommendations tiered staffing strategy for pandemic. online: sccm surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) critical care utilization for the covid- outbreak in lombardy, italy: early experience and forecast during an emergency response evaluation of delirium in critically ill patients: validation of the confusion assessment method for the intensive care unit (cam-icu) covid- : icu delirium management during sars-cov- pandemic impact of sars-cov- infection on neurodegenerative and neuropsychiatric diseases: a delayed pandemic clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the icu staged implementation of awakening and breathing, coordination, delirium monitoring and management, and early mobilization bundle improves patient outcomes and reduces hospital costs caring for critically ill patients with the abcdef bundle: results of the icu liberation collaborative in over , adults the neuroinvasive potential of sars-cov may play a role in the respiratory failure of covid- patients evidence of the covid- virus targeting the cns: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms autopsy findings and venous thromboembolism in patients with covid- psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the covid- pandemic. the lancet psychiatry nervous system involvement after infection with covid- and other coronaviruses long-term cognitive impairment after critical illness key: cord- -f uk m authors: fraser, douglas d.; slessarev, marat; martin, claudio m.; daley, mark; patel, maitray a.; miller, michael r.; patterson, eric k.; o’gorman, david b.; gill, sean e.; wishart, david s.; mandal, rupasri; cepinskas, gediminas title: metabolomics profiling of critically ill coronavirus disease patients: identification of diagnostic and prognostic biomarkers date: - - journal: crit care explor doi: . /cce. sha: doc_id: cord_uid: f uk m objectives: coronavirus disease continues to spread rapidly with high mortality. we performed metabolomics profiling of critically ill coronavirus disease patients to understand better the underlying pathologic processes and pathways, and to identify potential diagnostic/prognostic biomarkers. design: blood was collected at predetermined icu days to measure the plasma concentrations of metabolites using both direct injection-liquid chromatography-tandem mass spectrometry and proton nuclear magnetic resonance. setting: tertiary-care icu and academic laboratory. subjects: patients admitted to the icu suspected of being infected with severe acute respiratory syndrome coronavirus , using standardized hospital screening methodologies, had blood samples collected until either testing was confirmed negative on icu day (coronavirus disease negative) or until icu day if the patient tested positive (coronavirus disease positive). interventions: none. measurements and main results: age- and sex-matched healthy controls and icu patients that were either coronavirus disease positive or coronavirus disease negative were enrolled. cohorts were well balanced with the exception that coronavirus disease positive patients suffered bilateral pneumonia more frequently than coronavirus disease negative patients. mortality rate for coronavirus disease positive icu patients was %. feature selection identified the top-performing metabolites for identifying coronavirus disease positive patients from healthy control subjects and was dominated by increased kynurenine and decreased arginine, sarcosine, and lysophosphatidylcholines. arginine/kynurenine ratio alone provided % classification accuracy between coronavirus disease positive patients and healthy control subjects (p = . ). when comparing the metabolomes between coronavirus disease positive and coronavirus disease negative patients, kynurenine was the dominant metabolite and the arginine/kynurenine ratio provided % classification accuracy (p = . ). feature selection identified creatinine as the top metabolite for predicting coronavirus disease -associated mortality on both icu days and , and both creatinine and creatinine/arginine ratio accurately predicted coronavirus disease -associated death with % accuracy (p = . ). conclusions: metabolomics profiling with feature classification easily distinguished both healthy control subjects and coronavirus disease negative patients from coronavirus disease positive patients. arginine/kynurenine ratio accurately identified coronavirus disease status, whereas creatinine/arginine ratio accurately predicted coronavirus disease -associated death. administration of tryptophan (kynurenine precursor), arginine, sarcosine, and/or lysophosphatidylcholines may be considered as potential adjunctive therapies. objectives: coronavirus disease continues to spread rapidly with high mortality. we performed metabolomics profiling of critically ill coronavirus disease patients to understand better the underlying pathologic processes and pathways, and to identify potential diagnostic/prognostic biomarkers. design: blood was collected at predetermined icu days to measure the plasma concentrations of metabolites using both direct injection-liquid chromatography-tandem mass spectrometry and proton nuclear magnetic resonance. setting: tertiary-care icu and academic laboratory. subjects: patients admitted to the icu suspected of being infected with severe acute respiratory syndrome coronavirus , using standardized hospital screening methodologies, had blood samples collected until either testing was confirmed negative on icu day (coronavirus disease negative) or until icu day if the patient tested positive (coronavirus disease positive). interventions: none. measurements and main results: age-and sex-matched healthy controls and icu patients that were either coronavirus disease positive or coronavirus disease negative were enrolled. cohorts were well balanced with the exception that coronavirus disease positive patients suffered bilateral pneumonia more frequently than coronavirus disease negative patients. mortality rate for coronavirus disease positive icu patients was %. feature selection identified the top-performing metabolites for identifying coronavirus disease positive patients from healthy control subjects and was dominated by increased kynurenine and decreased arginine, sarcosine, and lysophosphatidylcholines. arginine/kynurenine ratio alone provided % classification accuracy between coronavirus disease positive patients and healthy control subjects (p = . ). when comparing the metabolomes between coronavirus disease positive and coronavirus disease negative patients, kynurenine was the dominant metabolite and the arginine/kynurenine ratio provided % classification accuracy (p = . ). feature selection identified creatinine as the top metabolite for predicting coronavirus disease -associated mortality on both icu days and , and both creatinine and creatinine/ arginine ratio accurately predicted coronavirus disease -associated death with % accuracy (p = . ). conclusions: metabolomics profiling with feature classification easily distinguished both healthy control subjects and coronavirus disease negative patients from coronavirus disease positive patients. arginine/kynurenine ratio accurately identified coronavirus c oronavirus disease (covid ) is caused by the severe acute respiratory syndrome coronavirus (sars-cov- ), which continues to spread rapidly worldwide ( , ). diagnosis of covid typically requires polymerase chain reaction for sars-cov- genes or immunoassay for sars-cov- antigens. covid primarily affects lungs, but dysfunction of other organs, such as heart and kidneys, has also been reported ( ) ( ) ( ) ( ) . the severity of covid may involve the excessive release of inflammatory mediators ( - ) together with microvascular thrombi formation secondary to endothelial injury/activation and glycocalyx degradation ( ) . critically ill covid patients are admitted to the icu, where the mortality rate is reported to be - % with standardized icu care ( , ) . although a number of protein mediators have been identified that predict covid -associated death ( , ) , a further characterization of covid -associated processes and pathways is essential for the identification of novel diagnostic/prognostic biomarkers and for improving covid patient outcomes. metabolomics measures a person's metabolite profile (chemicals with an molecular weight < , da), including amino acids, organic acids, biogenic amines, acylcarnitines, glycerophospholipids, sphingolipids, sugars, and many other compounds ( ) . metabolites fall downstream of genetic, transcriptomic, proteomic, and environmental events, thus providing a cohesive measure of a subject's recent phenotype. two complementary analytical methods for metabolomics are proton nuclear magnetic resonance ( h nmr; μm range) spectroscopy and mass spectrometry (ms; nm-pm range). previous studies have demonstrated the diagnostic and prognostic potentials of metabolomics profiling in selecting patient populations (e.g., traumatic brain injury [ ] ). metabolomics profiling of critically ill covid patients over the first days of their icu stay was the overall aim of this exploratory study, thereby identifying potential metabolite candidates and/or combinations as diagnostic/prognostic biomarkers. our specific objectives were: ) to determine/compare the metabolomes between covid positive (+) icu patients and either healthy control subjects or covid negative (-) icu patients, ) to determine specific metabolites that most accurately differentiated covid + from either healthy control subjects or covid -icu patients, and ) to determine whether specific metabolites can predict covid outcome shortly after icu admission. this study was approved by the western university, human research ethics board (hreb). given the unprecedented pandemic situation and the restricted hospital access for substitute decision makers, waived consent was approved for a short, issued march , ) . in keeping with the society for critical care medicine statement on "waiver of informed consent in emergency situations" ( ), the following criteria were considered relevant for hreb approval of waived consent: the subjects were admitted to the icu with a life-threatening condition; the subjects had impaired decisional capacity; the research staff encountered significant obstacles and delays when attempting to contact the absent substitute decision makers; the study risk was minimal; the research knowledge gained on this new, lethal disease offered an eventual chance of benefit; and community consultation had been implemented. given the pandemic circumstances and the waived consent model applied, no further attempts were made to contact the surviving patients and/or substitute decision makers. the last patient enrolled under waived consent was may , . we enrolled consecutive patients who were admitted to our level academic icus at the london health sciences centre (london, on, canada) and were suspected of having covid based on standard hospital screening procedures ( ) . blood sampling began on icu admission for up to days in covid -patients or up to days in covid + patients, with an additional blood draw occurring on day for covid + patients who have not been discharged. covid status was confirmed as part of standard hospital testing by nasopharyngeal swab detection of two sars-cov- viral genes on polymerase chain reaction ( ). patient baseline characteristics were recorded at admission and included age, sex, comorbidities, medications, hematologic labs, creatinine, arterial-partial-pressureto-inspired-oxygen ratio, and chest x-ray findings. we calculated multiple organ dysfunction score ( ) and sequential organ failure assessment score ( ) for both covid + and covid patient groups to enable objective comparison of their illness severity. both patient groups were characterized as having confirmed or suspected sepsis diagnosis using sepsis . criteria ( ) . we also recorded clinical interventions received during the observation period including use of antibiotics, antiviral agents, systemic corticosteroids, vasoactive medications, vte prophylaxis, antiplatelet or anticoagulation treatment, renal replacement therapy, high-flow oxygen therapy, and mechanical ventilation (invasive and noninvasive). final participant groups were constructed by age-and sex-matching covid + patients with covid -patients and healthy controls without disease, acute illness, or prescription medications that were previously banked in the translational research centre, london, on, canada (reb id# e; reissued march , ; "repository of control biological specimens from healthy volunteers for future research purposes"; directed by dr. d. d. fraser; https://translationalresearchcentre.com/) ( , ) . standard operating procedures were used to ensure all samples were treated rapidly and equally. blood was obtained from critically ill icu patients via indwelling catheters in the morning and placed immediately on ice. if a venipuncture was required, research blood draws were coordinated with a clinically indicated blood draw. in keeping with accepted research phlebotomy protocols for adult patients, blood draws did not exceed maximal volumes ( ) . once transferred to a negative pressure hood, blood was centrifuged and plasma was isolated, aliquoted at μl, and frozen at - °c. all samples remained frozen until use and freeze/ thaw cycles were avoided. a targeted quantitative metabolomics approach was used to analyze the samples using a combination of direct injection (di) ms with a reverse-phase lc-ms/ms custom assay. this custom assay, in combination with an absciex qtrap (applied biosystems, foster city, ca/mds sciex, foster city, ca) mass spectrometer, can be used for the targeted identification and quantification of up to different endogenous metabolites including amino acids, acylcarnitines, biogenic amines and derivatives, uremic toxins, glycerophospholipids, sphingolipids, and sugars ( , ) . the method combines the derivatization and extraction of analytes, and the selective mass-spectrometric detection using multiple reaction monitoring pairs. isotope-labeled internal standards and other internal standards were used for metabolite quantification. the custom assay contained a -deep-well plate with a filter plate attached with sealing tape, and reagents and solvents used to prepare the plate assay. the first wells were used for one blank, three zero samples, seven standards, and three quality control samples. for all metabolites except organic acid, samples were thawed on ice and subsequently vortexed and centrifuged at , × g; µl of each sample was then loaded onto the center of the filter on the upper -well plate and dried in a stream of nitrogen. subsequently, phenyl-isothiocyanate was added for derivatization. after incubation, the filter spots were dried again using an evaporator. extraction of the metabolites was then achieved by adding µl of extraction solvent. the extracts were obtained by centrifugation into the lower -deep-well plate, followed by a dilution step with the ms running solvent ( . % formic acid in water, . % formic acid in acetonitrile for biogenic amines and amino acids, and . % formic acid in methanol for all other classes of metabolites). for organic acid analysis, µl of ice-cold methanol and µl of isotope-labeled internal standard mixture were added to µl of serum sample for overnight protein precipitation at - °c, followed by centrifugation at , × g for minutes. a total of µl of supernatant was loaded into the center of wells of a -deep-well plate, followed by the addition of -nitrophenylhydrazine reagent. after incubation for hours, butylated hydroxytoluene stabilizer ( mg/ml) and water were added before lc-ms injection. mass spectrometric analysis was performed on an absciex qtrap tandem ms instrument (applied biosystems/mds analytical technologies, foster city, ca) equipped with an agilent series uhplc system (agilent technologies, palo alto, ca). the samples were delivered to the mass spectrometer by an lc method followed by a di method. data analysis was done using analyst . . (foster city, ca). plasma samples contain a significant concentration of large-molecular-weight proteins and lipoproteins, which affects the identification of the small-molecular-weight metabolites by nmr spectroscopy. a deproteinization step, involving ultrafiltration as previously described ( ) , was therefore introduced in the protocol to remove plasma proteins. prior to filtration, -kda cutoff centrifugal filter units (amicon microcon ym- , burlington, ma) were rinsed five times each with . ml of h o and centrifuged ( , × g for min) to remove residual glycerol bound to the filter membranes. aliquots of each plasma sample were then transferred into the centrifuge filter devices and spun ( , × g for min) to remove macromolecules (primarily protein and lipoproteins) from the sample. the filtrates were checked visually for any evidence that the membrane was compromised, and for these samples, the filtration process was repeated with a different filter and the filtrate inspected again. the subsequent filtrates were collected and the volumes were recorded. if the total volume of the sample was under µl, an appropriate amount from a -mm kh po buffer (ph ) was added until the total volume of the sample was . µl. any sample that had to have buffer added to bring the solution volume to . μl was annotated with the dilution factor and metabolite concentrations were corrected in the subsequent analysis. subsequently, . µl of a standard buffer solution ( % d o: % . -mm kh po ph . v/v containing sodium trimethylsilylpropanesulfonate (dss) [ . -mm , -dimethyl- silcepentane- -sulphonate, . -mm -chloropyrimidine- carboxylate, and . % nan in h o]) was added to the sample. the plasma sample ( µl) was then transferred to a -mm samplejet nmr tube for subsequent spectral analysis. all h-nmr spectra were collected on a -mhz avance iii (bruker, billerica, ma) spectrometer equipped with a -mm hydrogen, carbon, nitrogen z-gradient pulsed-field gradient cryoprobe. h-nmr spectra were acquired at °c using the first transient of the nuclear overhauser effect spectroscopy (noesy) presaturation pulse sequence (noesy dpr), chosen for its high degree of quantitative accuracy ( ) . all free induction decays were zero-filled to k data points. the singlet produced by the dss methyl groups was used as an internal standard for chemical shift referencing (set to ppm). for quantification, all h-nmr spectra were processed and analyzed using an in-house version of the magnetic resonance for metabolomics (magmet)-automated analysis software package using a custom metabolite library. magmet allows for qualitative and quantitative analyses of an nmr spectrum by automatically fitting spectral signatures from an internal database to the spectrum. each spectrum was further inspected by an nmr spectroscopist to minimize compound misidentification and misquantification. typically, all of visible peaks were assigned. most of the visible peaks were annotated with a compound name. it has been previously shown that this fitting procedure provides absolute concentration accuracy of % or better ( ) . medians (interquartile ranges [iqrs]) and frequency (%) were used to report icu patient baseline characteristics for continuous and categorical variables, respectively; continuous variables were compared using mann-whitney u tests (or kruskal-wallis tests, as appropriate), and categorical variables were compared using fisher exact chi-square, with p values of less than . considered statistically significant. receiver operating characteristic (roc) curves were conducted to determine sensitivity and specificity of individual metabolite ratios for predicting a binary outcome. area-under-thecurve (auc) was calculated as an aggregate measure of metabolite ratio performance across all possible classification thresholds. all analyses were conducted using spss version (ibm, armonk, ny). covid analyte data were visualized with a nonlinear dimensionality reduction on the full data matrix using the t-distributed stochastic nearest neighbor embedding (t-sne) algorithm ( ). t-sne assumes that the "optimal" representation of the data lies on a manifold with complex geometry, but with low dimension, embedded in the full-dimensional space of the raw data. for feature selection, the raw data for each subject were ingested within each feature, across subjects. a random forest classifier was trained on the variables to predict covid status or covid outcome ("scikit-learn" module for python . . open source). a random forest is a set of decision trees, and consequently, we were able to interrogate this collection of trees to identify the features that have the highest predictive value. feature selection was not performed in preprocessing. during training, the random forest classifier performed an implicit feature selection; the top features are those that appear highest ranked in the most trees. to reduce overfitting, the number of trees and maximum depth of each tree was limited ( ) ; thus, covid status was determined using a six-fold cross validation with a random forest of trees, whereas patient outcome was determined using a three-fold cross validation with a random forest of trees and a maximum depth of . to remain conservative and to limit the risk of overfitting further, no hyperparameters were tuned or optimized by design and intent. furthermore, to validate the results and ensure no overfitting occurred, a simple linear support vector machine classifier was used to compare the predication accuracies with excellent concordance. we investigated covid + patients (median years of age = . , iqr = . - . ), age-and sex-matched covid -patients (median years of age = . , iqr = . - . ), and ageand sex-matched healthy controls (median years of age = . , iqr = . - . ; p = . ). baseline demographic characteristics, comorbidities, laboratory values, and chest x-ray findings are reported in table . the covid -patients had significantly higher unilateral pneumonia, whereas covd + patients were more likely to have bilateral pneumonia. sepsis was "confirmed" by infectious pathogen identification in only % of covid patients, whereas sepsis was "suspected" in the remaining % ( ) . a mortality rate of % was determined for covid + patients. we measured a total of plasma metabolites using both di-lc-ms/ms and h nmr. in the event of metabolite repeats measured with both techniques ( metabolites), the h nmr metabolite repeat measurements were deleted from the combined metabolite database, yielding a final number of metabolites analyzed. figure a shows a t-sne plot illustrating that the icu day covid + patient metabolome was distinct and easily separable from age-and sex-matched healthy control subjects. in fact, classification accuracy was % when comparing the two metabolomes. we then identified the top eight metabolites underlying these differences between the cohorts, which are shown in figure b with their associated % importance. in the covid + cohort, relative to the healthy control subjects, kynurenine increased . fold whereas arginine decreased . -fold, sarcosine decreased . -fold, and lysophosphatidylcholines (lysopcs) all decreased . -fold on average. the least number of metabolites that were required to maintain a % classification accuracy between the cohorts was then determined, with only arginine (cutoff ≤ . μm) and kynurenine (cutoff ≥ . μm) required. the excellent predictive ability of an arginine/kynurenine ratio for discriminating a covid patient from a healthy control subject (cutoff ≤ . ) is shown with roc analysis in figure c (auc = . ; p = . ). a comparison of covid + and covid -patient cohorts revealed distinct metabolomes. feature classification again identified kynurenine as one of the leading metabolites underlying the differences between the covid + and covid -cohorts ( fig. a) . we then determined that an arginine/kynurenine ratio again showed an excellent discriminative ability to determine covid status on icu day (cutoff ≤ . ) via roc analyses (auc = . ; p = . ; fig. b ). figure c shows an arginine/ kynurenine ratio time plot for the covid + and covid patients over icu days. the cohorts' ratios were significantly different on icu days and (p = . ). figure a shows a t-sne plot for covid + patients that either survived or died, and demonstrates that the outcomes were distinct and separable. to optimize outcome prediction in covid + patients, the number of metabolites was narrowed using feature selection (fig. b) . creatinine was the leading metabolite and could predict death with % accuracy on both icu days (cutoff > μmol/l) and (cutoff > μmol/l). to improve the variation in patient creatinine values, we then tested the ability of a creatinine/arginine ratio to predict death; the corresponding time plot is shown in figure c . death could be predicted with % accuracy on both icu days (cutoff ≥ . ) and (cutoff ≥ . ), as the creatinine/arginine ratios were significantly different between the covid patients that lived or died at both time points (p = . ). the creatinine/arginine ratios normalized by icu day , regardless of eventual outcome. there were no deaths during the icu days. in this study, we measured metabolites in plasma obtained from icu patients, both covid + and covid -, as well as age-and sex-matched healthy control subjects. given the number of metabolites measured, we analyzed the data with the stateof-the-art machine learning. our exploratory data indicate the presence of a unique covid plasma metabolome dominated by changes in kynurenine, arginine, sarcosine, and lysopcs. additionally, we identify that either creatinine alone or a creatinine/arginine ratio predicted icu mortality with % accuracy. despite the exploratory nature of our study, the data generated suggest that these three metabolites (kynurenine, arginine, and creatinine) could be considered for further investigation as continuous data are presented as medians (interquartile ranges) and categorical data are presented as n (%). vte prophylaxis represents the number of patients receiving venous thromboembolism prophylaxis with regular-or low-molecular heparin; new antiplatelets represents the number of patients who were started on aspirin or clopidogrel during icu stay; new anticoagulation represents the number of patients who were started on therapeutic anticoagulation with regular-or low-molecular heparin, or novel oral anticoagulants potential diagnostic and prognostic biomarkers for covid and that they may be useful for patient stratification in clinical interventional trials. our covid + icu patients were similar to those reported in earlier cohorts ( ) ( ) ( ) ( ) with respect to demographics, comorbidities, and clinical presentation. in contrast to covid -icu patients, our covid + icu patients had a higher frequency of bilateral pneumonia. previous work by our study group in these same patients has determined a unique inflammatory profile characterized by elevated tumor necrosis factor and serine proteases ( ) , and a thrombotic profile associated with endothelial activation and glycocalyx degradation ( ). by employing targeted proteomics, figure . a, subjects plotted in two dimensions following dimensionality reduction in their respective metabolites by stochastic neighbor embedding. green dots represent healthy control subjects, whereas orange dots represent age-and sex-matched coronavirus disease positive (covid +) icu patients (icu day plasma). the dimensionality reduction shows that based on the plasma metabolites, the two cohorts are distinct and easily separable. the axes are dimensionless. b, feature classification, demonstrating the top eight plasma metabolites that classify covid + status versus healthy control subjects with their % association. c, receiver operating characteristic analysis of healthy control subjects versus covid + patients, using an arginine/kynurenine ratio, demonstrates an area-underthe-curve (auc) of . (p = . ). the cutoff value is . . the diagonal broken blue line represents chance (auc . ). we also identified six novel protein immune biomarkers that accurately predict covid associated death ( ) . taken together with the data from this study, covid represents a severe illness with a unique pathophysiological signature, as well as a high mortality rate. indeed, in our cohort of covid patients, icu death was % with standardized icu care. our study has identified a unique metabolome in covid + icu patients that is hypothesis-generating for future diagnostic/ prognostic studies. not only have we provided a rank order listing of metabolites important for covid status, we also identified metabolites that accurately determined covid icu outcome. the former represents diverse metabolites that influence immune function and survival, whereas the latter represents compromised renal function early in icu care. importantly, the metabolites required for covid diagnosis (arginine/kynurenine ratio) and outcome (either creatinine alone or creatinine/arginine ratio) can be easily measured using only ms or immunoassay, making their use as covid biomarkers affordable and easily available. point-of-care analyses for these metabolites could be rapidly developed, such as a lateral flow immunochromatographic assay. furthermore, our study raises the possibility that dietary supplementation of tryptophan, arginine, sarcosine, and lysopcs as adjunctive therapies may aid covid outcome. covid status relied heavily on increased plasma kynurenine. the essential amino acid tryptophan is metabolized to elevate the energy-producing cofactor nicotinamide adenosine dinucleotide, with kynurenine as the first stable intermediate to be formed ( ) . increased degradation of tryptophan, with a consequential increase in kynurenine, occurs during an immune response and is driven by the release of interferon-gamma from the activated t-cells. covid caused intense t-cell activation ( , ) with an approximate -fold increase in plasma interferon-gamma in critically ill covid patients when compared with healthy control subjects ( ) . although plasma kynurenine effectively discriminated covid + patients from healthy control subjects, determination of covid status in icu patients required further specificity that was optimally provided by an arginine/kynurenine ratio. arginine, an amino acid precursor for nitric oxide, was significantly depressed in covid + patients. arginine depletion is likely secondary to the intense requirement for nitric oxide signaling and antiviral activity ( ) , as well as consumption by the enzyme arginase that represents a macrophage immunoregulatory mechanism ( ) . as arginine is essential for tissue repair ( ) , its depletion could potentially delay and/or compromise icu recovery. sarcosine, an amino acid that helped discriminate covid + patients from healthy control subjects, was also significantly depressed. although not superior to the arginine/kynurenine ratio for diagnosing covid status, sarcosine sequestration may have a critical role in covid pathology. sarcosine enhances the activity of antigen presenting cells ( ) and activates autophagy ( ) , or the body's removal of damaged cells and their immunostimulatory debris. as a protective catabolic process during covid , autophagy is critical to the antiviral response by direct elimination of virus, the presentation of viral antigens, and the inhibition of excessive inflammation ( ) . sarcosine levels decrease with age ( ) , and the elderly are most susceptible to covid morbidity and mortality. depressed plasma lysopcs also helped discriminate covid + patients from healthy control subjects. the partial hydrolysis of the dimensionality reduction shows that based on the plasma metabolites, the two cohorts are distinct and easily separable. the axes are dimensionless. b, feature classification, demonstrating the top eight plasma metabolites that classify covid + icu patient outcome as alive or dead with their % association. plasma creatinine was the leading outcome predictor metabolite. c, a time plot, demonstrating the creatinine/arginine ratio for covid + icu patients over icu days that either survived (blue dots) or died (orange dots). the two cohorts are significantly different on icu days and (**p = . ). healthy control range values are represented by green shading. phosphatidylcholines by phospholipase a produces lysopcs, which are subsequently implicated in endothelial activation ( ) and phagocytosis of cellular debris ( ) . decreased plasma lysopcs has been observed in sepsis ( ) , where lysopcs may aid pathogen elimination, and therapeutic replacement has been suggested to improve sepsis outcome ( ) . acute renal dysfunction is strongly associated with high mortality in icu patients ( ) . plasma creatinine, a marker of renal dysfunction, was an excellent discriminator for covid patients that either lived or died. in our covid + cohort, two patients had chronic kidney disease and two patients required renal replacement therapy. the angiotensin-converting enzyme receptor that is essential for sars-cov- uptake is highly expressed on tubule epithelial cells ( ) . acute kidney injury is reported to occur in up to % of covid patients ( ) and is secondary to acute tubular injury from direct viral infection ( ) . our data suggest that covid diagnosis (arginine/kynurenine ratio) and outcome (creatinine alone or creatinine/arginine ratio) can be determined with point-of-care measurements of kynurenine, arginine, and creatinine, and that this rapid and affordable biomarker approach may be complimentary to the more expensive and time-consuming diagnostic tools currently employed (e.g., polymerase chain reaction and antigen immunoassay). furthermore, our study raises the possibility that dietary supplementation of tryptophan (kynurenine precursor), arginine, sarcosine, and lysopcs may aid covid outcome as adjunctive therapies. despite the novelty of the metabolite biomarkers discovered, our study has several limitations. first, we only studied critically ill patients and we cannot determine the full metabolome changes associated with icu admissions. second, although our covd study population was limited, we still identified strong associations between the individual metabolites and outcomes and we fulfilled an urgent need for exploratory data to focus future hypothesisdriven studies on larger cohorts. third, we report only mortality as our primary clinical outcome. future studies with larger sample sizes can explore whether reported changes in specific metabolites correlate with additional clinical outcomes such as functional status in survivors. finally, our analyses employed a cross-validation methodology in which the classifier was trained multiple times, each time on a different subset of the data, with the remainder of the data withheld for use only in testing. the reported accuracy is the mean accuracy of all such trials. this is a standard, accepted, technique in the machine learning literature, but should be validated on a larger testing set that is used only once. overfitting was minimized by using a very small number of trees with a limited depth ( ) , and the results verified by training a simple linear vector machine and by identifying concordance between the results. in summary, we report a unique metabolome in covid + icu patients, with identification of three metabolites that appear to be accurate diagnostic/prognostic biomarkers for future studies. given the rapid spread of covid and the critical need for rapid and affordable diagnostics, our data may be invaluable for future testing. in addition, our exploratory data may be useful for guiding resource mobilization and/or goals of care discussion, but only after validation in larger covid + cohorts. furthermore, patient stratification is critically important for future covid interventional trials. world health organization: who director-general's opening remarks at the media briefing on covid- - covid- in critically ill patients in the seattle region -case series clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region into the eye of the cytokine storm uk: covid- : consider cytokine storm syndromes and immunosuppression inflammation profiling of critically ill coronavirus disease patients endothelial injury and glycocalyx degradation in critically ill coronavirus disease patients: implications for microvascular platelet aggregation icu and ventilator mortality among critically ill adults with coronavirus disease novel outcome biomarkers identified with targeted proteomic analyses of plasma from critically ill coronavirus disease patients metabolomics for laboratory diagnostics metabolomics profiling of concussion in adolescent male hockey players: a novel diagnostic method society of critical care medicine: waiver of informed consent in emergency situations centers for disease control and prevention: cdc novel coronavirus (ncov) real-time rt-pcr diagnostic panel -instructions for use external validation of a prognostic model for intensive care unit mortality: a retrospective study using the ontario critical care information system the third international consensus definitions for sepsis and septic shock (sepsis- ) translational research in pediatrics: tissue sampling and biobanking translational research in pediatrics ii: blood collection, processing, shipping, and storage policy: guidelines for limits of blood drawn for research purposes in the clinical center the bovine metabolome chemical composition of commercial cow's milk the human serum metabolome optimization of nmr analysis of biological fluids for quantitative accuracy accurate, fully-automated nmr spectral profiling for metabolomics when do random forests fail? in: proceedings of the nd international conference on neural information processing systems kynurenine pathway metabolites in humans: disease and healthy states marked t cell activation, senescence, exhaustion and skewing towards th in patients with covid- pneumonia e: t cell responses in patients with covid- nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus immunoregulatory interplay between arginine and tryptophan metabolism in health and disease role of arginine and omega- fatty acids in wound healing and infection sarcosine promotes trafficking of dendritic cells and improves efficacy of anti-tumor dendritic cell vaccines via cxc chemokine family signaling sarcosine is uniquely modulated by aging and dietary restriction in rodents and humans digesting the crisis mitochondrial reactive oxygen species mediate lysophosphatidylcholine-induced endothelial cell activation apoptotic cells induce migration of phagocytes via caspase- -mediated release of a lipid attraction signal lipidomic profiling of plasma and erythrocytes from septic patients reveals potential biomarker candidates product inhibition of secreted phospholipase a may explain lysophosphatidylcholines' unexpected therapeutic properties renal failure in the icu: comparison of the impact of acute renal failure and end-stage renal disease on icu outcomes kidney and lung ace expression after an ace inhibitor or an ang ii receptor blocker: implications for covid- acute kidney injury in patients hospitalized with covid- ultrastructural evidence for direct renal infection with sars-cov- key: cord- - ool z s authors: immovilli, paolo; morelli, nicola; antonucci, elio; radaelli, guido; barbera, mario; guidetti, donata title: covid- mortality and icu admission: the italian experience date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: ool z s nan correlation was observed between the cfr and icu admission rate (pearson's r − . , p value . ) and r was . , suggesting an association between mortality and the absence of treatment in icu (fig. ) . the analysis of mortality during an outbreak is no easy feat and a precise evaluation can be obtained only once the outbreak is over. furthermore, the high italian mortality may well be attributable to a large proportion of elderly persons in the italian population, to an ascertainment bias and/or diagnosis bias, leading to an underestimation of the milder cases and mortality overestimation. however, examining the differing outbreak magnitudes in regions with different icu availability evidenced a discrepancy in the percentage of icu-admitted patients. indeed, there was a higher mortality rate in the northern region where fewer patients could be admitted into an icu. these preliminary data evidence the pivotal preventive role played by early lockdown measures to reduce outbreak magnitude and place less pressure on icu beds availability; however, these data should be interpreted with caution because of possible bias: patients could be allowed outside the icu due to various reasons (i.e., age, comorbidities, frailty index), as it occurs in daily clinical practice. covid- in china: ten critical issues for intensive care medicine sostieni l'emergenza corona virs the authors thanks elena marchesi, manuela giovini, ignazio semproni, chiara terracciano, domenica zaino, and eugenia rota for their contribution in reading and reviewing the article and barbara wade for her linguistic advice. received: april accepted: may paolo immovilli, nicola morelli, elio antonucci, guido radaelli, mario barbera, and donata guidetti are responsible for study design and all authors wrote and reviewed the manuscript. the authors read and approved the final manuscript. there was no funding for this article.availability of data and materials data published online by italian civil protection department (http:// opendatadpc.maps.arcgis.com/apps/opsdashboard/index.html#/b c bce cce eaac fe d b ; seen on march , ).ethics approval and consent to participate not applicable. not applicable. the authors have nothing to disclose. key: cord- -ya r h t authors: dobesh, paul p.; trujillo, toby c. title: coagulopathy, venous thromboembolism, and anticoagulation in patients with covid‐ date: - - journal: pharmacotherapy doi: . /phar. sha: doc_id: cord_uid: ya r h t severe acute respiratory syndrome coronavirus (sars‐cov‐ )has led to a world‐wide pandemic, and patients with the infection are referred to as having covid‐ . although covid‐ is commonly considered a respiratory disease, there is clearly a thrombotic potential that was not expected. the pathophysiology of the disease and subsequent coagulopathy produce an inflammatory, hypercoagulable, and hypofibrinolytic state. several observational studies have demonstrated surprisingly high rates of venous thromboembolism (vte) in both general ward and intensive care patients with covid‐ . many of these observational studies demonstrate high rates of vte despite patients being on standard, or even higher intensity, pharmacologic vte prophylaxis. fibrinolytic therapy has also been used in patients with acute respiratory distress syndrome. unfortunately, high quality randomized controlled trials are lacking. a literature search was performed to provide the most up‐to‐date information on the pathophysiology, coagulopathy, risk of vte, and prevention and treatment of vte in patients with covid‐ . these topics are reviewed in detail, along with practical issues of anticoagulant selection and duration. although a number of international organizations have produced guideline or consensus statements, they do not all cover the same issues regarding anticoagulant therapy for patients with covid‐ , and they do not all agree. these statements and the most recent literature are combined into a list of clinical considerations that clinicians can use for the prevention and treatment of vte in patients with covid‐ . impairs the adaptive immune response through inadequate t-cell help to virus-specific cd + cytotoxic t-cells and β-cells. the impaired inf defense, enhanced monocyte/macrophage and neutrophils response producing excessive cytokine and chemokine levels, along with the impaired lymphocyte response produces a hyperinflammatory state that consequentially produces alveolar tissue damage initiating multiple thrombotic processes. this connection between the immune response inflammation and thrombosis has been termed immunothrombosis or thromboinflammation. the clotting cascade is stimulated through both the extrinsic and intrinsic pathways. the extrinsic pathway is initiated by release of tissue factor from cytokine-damaged alveolar endothelial cells. in the setting of significant inflammation, monocytes and macrophages can also express circulating tissue factor. the intrinsic cascade is activated through neutrophil release of neutrophil extracellular traps (nets). these nets contain various bioactive molecules in a process called netosis, which have the ability to stimulate activation of factor xii. nets also contain proteases that are able to inactivate endogenous anticoagulants, and therefore worsen the procoagulant state. the dual activation of the extrinsic and intrinsic clotting cascade leads to significant thrombin generation and thrombosis. the immune function of platelets has been well documented over the last decade. platelets are attracted to the area of cytokine-induced endothelial injury and become activated. through the process of platelet activation, molecules such as platelet factor and neutrophil-activating peptide- are released from platelet α-granules, which are involved in the recruitment and activation of monocytes/macrophages and neutrophils. additional immune actions of activated platelets include being an important source of proinflammatory il- β, as well as the further recruitment of neutrophils accepted article through interaction of platelet surface p-selectin. the impact of platelet on immune function and thrombosis has been specifically documented in patients with patients with covid- also have significant hypoxia, especially in severe disease. hypoxemia triggers expression of hypoxia inducible factors. hypoxia inducible factors can promote thrombosis by directly activating coagulation proteins and platelets and increasing tissue factor expression, as well as inhibiting endogenous protective functions such as increasing plasminogen activator inhibitor- (pai- ) and inhibiting anticoagulant protein s. hypercoagulability is further induced by hypoxia inducible factors due to their ability to promote further inflammation and augmenting blood viscosity. an inflammatory response and activation of thrombotic pathways occurs in a number of severe infections, and is not unique to sars-cov- . normal coagulation responses are often balanced with a fibrinolytic response to prevent fibrin deposition within alveolar tissues. this natural defense mechanism is initiated by the endogenous plasminogen activators, tissue plasminogen activator (t-pa) and urokinase plasminogen activator (u-pa). these are responsible for the conversion of plasminogen to the proteolytic enzyme plasmin, which controls the breakdown of fibrinogen and fibrin deposits into the breakdown products d-dimer and other fibrin degradation products. the increased thrombotic potential in patients with covid- is potentially a result of its interaction with ace . the binding of sars-cov- to ace produces a downregulation of the enzyme and consequentially an increase in at ii. angiotensin ii induces expression of pai- in endothelial cells, which directly inhibits the actions of t-pa and u-pa. therefore, in patients with sars and covid- , the balance between fibrinolysis with t-pa and u-pa is shifted to more hypofibrinolysis and thrombosis due to the excessive at ii and subsequent increase in pai- . the inability to breakdown and remove these fibrin deposits corresponds with poor clinical patient outcome as these deposits reduce normal gas exchange. although most of the direct tissue damage and inflammation occurs in the lung, the impact of thromboinflammation can be systemic. many institutions have reported an uncharacteristically high rate of vte events in both medical ward and icu covid- patients. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] although there is a significant risk of deep vein thrombosis (dvt) in patients with covid- , some evaluations have identified a higher number of pulmonary emboli (pe) than dvt. . . , this discrepancy between accepted article the frequencies of pe and dvt is unusual, since pe without dvt typically occurs in only about % of cases. therefore, in patients with covid- many of the pulmonary thrombotic cases are likely pulmonary thrombi and not pulmonary embolism. this would be consistent with the pulmonary inflammation, alveolar tissue damage, and alveolar fibrin deposits found on autopsy in patients with covid- . [ ] [ ] [ ] [ ] similar to autopsy findings from sars and mers, the primary finding associated with the cause of death is respiratory failure due to diffuse alveolar damage. [ ] [ ] [ ] [ ] [ ] [ ] in contrast to patients with sars and mers, the morphological damage in the lungs and other organs is less severe in covid- , explaining the lower mortality rate. whereas autopsies from cases of sars and mers did demonstrate fibrin deposits in the lungs, this seems to be amplified in cases of covid- . in a series of autopsy cases of patients with severe covid- from brazil, % had a variable number of fibrinous thrombi in small pulmonary arterioles. these thrombi were found in areas of both damaged and more preserved lung parenchyma. in a series of seven covid- cases from belgium, all had intraalveolar fibrin deposits and widespread vascular thrombosis with microangiopathy and occlusion of alveolar capillaries. finally, a series of covid- autopsy cases from austria reported that the most striking finding was obstruction of pulmonary arteries by thrombotic material found at both the microscopic and macroscopic level in all cases. interestingly, of these cases had received pharmacologic vte prophylaxis, and vte was not clinically suspected in any cases before autopsy as a contributor of death. the clinical spectrum of sars-cov- infection has broad presentation including asymptomatic infection, mild upper respiratory tract symptoms, up to severe viral pneumonia requiring mechanical ventilation, and even death (table ) . a number of studies have evaluated characteristics of patients with covid- , as well as those who progress to worse outcomes, such as icu admission, acute respiratory distress syndrome (ards), or death (table ) . , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] although most patients have a favorable prognosis, patients with worse outcomes have a pronounced increase in inflammatory markers, referred to as a "cytokine storm", approximately - days from the onset of initial symptoms. this can coincide with the development of pulmonary thrombosis or pe, which may explain the rapid pulmonary collapse observed in patients suddenly progressing to ards. in general, patients progressing to worse outcome are about to years older and have more this article is protected by copyright. all rights reserved comorbidities such as hypertension, diabetes mellitus, and cardiovascular disease (table ). laboratory findings demonstrate that patients with worse outcomes typically have more liver and renal dysfunction, and significantly lower lymphocyte counts. the sickest patients may also develop elevated procalcitonin and white blood cell counts, but these more likely represent acquired secondary bacterial infection versus caused by sars-cov- itself. patients with covid- often have elevated markers of inflammation. , one study in china reported that il- was elevated in %, ferritin in %, erythrocyte sedimentation rate in %, and c-reactive protein (crp) in % of patients. these numbers are even higher in sicker patients ( table ) . markers of coagulopathy are also present in patients with covid- . although the sars-cov- virus itself does not seem to have intrinsic procoagulant activity, the induced coagulopathy and thromboinflammation extend systemically and impact other organs, such as the kidney, and may eventually lead to multiorgan dysfunction and potentially death. patients with covid- typically have elevated fibrinogen levels, but the extent of increase does not differ based on the severity of disease. antithrombin activity can also be decreased in patients with covid- , but as demonstrated in a study from china, the significantly lower activity ( % in covid- vs. % in healthy volunteers; p< . ) still falls within the normal range (> %). prolongation of the prothrombin time (pt) or activated partial thromboplastin time (aptt) has been demonstrated, but is not a common finding. [ ] [ ] [ ] [ ] tang n and colleagues found that in patients who died of covid- , their pt was prolonged by about seconds compared to those who survived (table ) . a meta-analysis of studies reported an average increase in the pt of about % in patients with although antiphospholipid antibodies have been reported in patients with covid- , and thought to promote the hypercoagulable state, these data should be interpreted with caution. [ ] [ ] [ ] there is a high risk of false positive lupus anticoagulant testing in patients with covid- due to the elevated levels of crp. many assays for lupus anticoagulant are sensitive to crp and give a false positive finding. although most patients with covid- have normal platelet counts, thrombocytopenia has been reported in % to %, and is usually mild. , in a meta-analysis of nine studies, the platelet count was lower by about , x /l in severe cases compared to nonsevere cases, and about , x /l lower in nonsurvivors compared to survivors. these lower platelet counts may not be enough to register as marked thrombocytopenia, but do likely represent platelet recruitment into pulmonary or systemic thrombi. although not as common as other severe infectious diseases, the accepted article occurrence and severity of thrombocytopenia is associated with higher mortality in patients with in a study of patients with covid- , platelet counts of less than x /l occurred in % of patients with critical disease, % in severe disease, and % in those with moderate disease. the odds of death in patients with thrombocytopenia was . ( % ci . - . ). another study of patients with covid- demonstrated increasing mortality in patients with thrombocytopenia, as well as increasing mortality with decreasing platelet counts. nonsurvivors ( %) were significantly more likely to have thrombocytopenia compared to survivors ( . % vs. . %; p< . ), as well as lower nadir platelet counts ( vs . x /l; p< . ), respectively. patients with nadir platelet counts x /l or more had a mortality rate of . %, whereas mortality was . % in those with - x /l, . % in those with - x /l, and . % in those with - x /l. the incidence of a nadir platelet count of - x /l was relatively rare ( %) compared to those with a platelet count of x /l or more ( %). breakdown of fibrin or fibrinogen by u-pa or t-pa produces fibrin degradation products, one of which is d-dimer. an elevated d-dimer is typically a sign of excessive coagulation activation and hyperfibrinolysis. therefore, d-dimer is often used to detect active thrombus with high sensitivity but low specificity. the low specificity is due to other conditions, such as inflammation and infection that can also increase d-dimer in the absence of thrombosis, and are associated with covid- . d-dimer is elevated in % to % of patients with covid- , but is commonly elevated in hospitalized patients. elevations of d-dimer are higher in icu patients and those with worse outcomes by . to -fold (table ). , han h and colleagues found that d-dimer levels were elevated with increasing severity of disease, with levels at ng/ml for patients classified with ordinary disease, , ng/ml in those with severe disease, and , ng/ml in those considered critical, compared to ng/ml in healthy controls. since values are higher in patients with severe disease, d-dimer measurement may be associated with evolution toward worse clinical picture. as would be expected, d-dimer is also elevated in patients with covid- who develop vte. , , , [ ] [ ] [ ] [ ] it has been suggested that d-dimer levels above a certain cut off could be used to predict those with vte if appropriate diagnostic testing is not feasible. , , , , caution should be exercised in this myopic interpretation of elevated d-dimer levels. if elevated d-dimer is mainly due to coagulopathy and increased fibrinolysis of thrombi, this would suggest a consumption coagulopathy. this is supported by a study conducted by tang n and colleagues, where disseminated intravascular coagulation (dic) was more common in nonsurvivors compared to survivors ( . % vs. . %). dic is considered a consumption coagulopathy, with elevated d-dimer levels due to significant fibrinolysis and breakdown of fibrin and fibrinogen. most patients with covid- have elevated fibrinogen levels that is inconsistent with a consumption coagulopathy. the lack of consistent moderate to severe thrombocytopenia and inconsistent prolongation of the pt also are not supportive of dic being a common complication in patients with covid- . therefore, most of the elevations of d-dimer are likely due to the excessive inflammatory state, similar to the elevations in erythrocyte sedimentation rate, crp, and ferritin, and should not be considered to be solely from fibrinolysis. this is supported by data demonstrating that a d-dimer -fold above the upper limit of normal has been used in patients without vte to predict those at highest risk of development of vte. when dic does occur, it is likely in the last stage of covid pneumonia, when there may be increased systemic fibrinolysis and multiorgan failure. hypercoagulability, but not a consumption coagulopathy, is also supported by findings in two thromboelastography studies that evaluated patients with covid- compared to healthy volunteers. , patients with covid- had significantly higher d-dimer and fibrinogen levels compared to healthy controls ( table ), but normal pt and aptt. the first study demonstrated that patients with covid- had significantly shorter clot formation time and higher maximum clot firmness. the shorter clot formation time is reflective of the excessive thrombin generation and higher clot firmness reflects the increased fibrin and fibrinogen in these patients. the other study evaluated intubated icu patients with covid- , most of who were on vte prophylaxis, compared to health volunteers. similar to the previous findings, patients with covid- had a shorter clotting times and firmer clots. all patients with covid- also had reduced clot lysis at minutes. the lack of clot lysis at minutes does not support a hyperfibrinolytic state, which matches the pathophysiologic mechanism of impaired fibrinolysis from ace binding of sars-cov- . , , , in summary, the coagulopathy associated with sars-cov- infection typically presents with elevated d-dimer and fibrinogen levels with normal to slightly lower platelet counts, and normal to slightly elevated pt and aptt. with worsening disease severity, patients will have higher d-dimer levels, lower platelet counts, and eventually elevated pt and aptt. these coincide with increased accepted article markers of inflammation, such as il- and crp, as well as infection (lymphopenia and potentially leukocytosis), and organ dysfunction (renal and liver dysfunction). hospitalized patients with acute medical illness, such as infection, are at increased risk of vte. in general ward patients the rate of vte without prophylaxis ranges from % to % depending on the method of assessment. the use of pharmacologic prophylaxis lowers the rate to . % to %. in icu patients, the risk of vte is higher. rates from one meta-analysis ranged from % to %. another meta-analysis reported a rate of . % for icu patients mainly assessed by compression ultrasound (cus). use of pharmacologic prophylaxis lowers this rate to . % to . %. , a number of studies have reported a higher rate of vte than would be expected in general ward and icu patients with covid- (table ) . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] increased thromboembolic events were also documented with the sars, mers, and influenza a h n viruses. [ ] [ ] [ ] [ ] [ ] [ ] the true risk of vte in patients with covid- is difficult to determine since no placebo-controlled randomized trials have been conducted. rates of vte in general medical ward patients with covid- have been reported to be around % in clinically evaluated patients and as high as almost % in patients screened with cus (table ) . [ ] [ ] [ ] in the early phase of the outbreak, before the thrombotic potential of covid- was appreciated, patients in china did not commonly received vte prophylaxis based on the assumption that they are a lower risk population. in this setting, cui and colleagues screened covid- icu patients for vte with cus, none of which were receiving vte prophylaxis. the rate of dvt was %, which is at the high end of the range for an icu population. another study from china in which only about one-third of screened icu patients received vte prophylaxis had a rate of dvt of %. other trials have evaluated vte rates in cus screened icu patients with covid- receiving pharmacologic prophylaxis with rates as high as % to %, which are higher than reported in typical icu patients (table ) . , most institutions do not routinely screen patients for vte, even in the icu. observational studies on the rates of vte in icu patients with covid- when cus is only done based on clinical suspicion has also been conducted. in patients receiving prophylaxis the rate of vte ranges from % to %, which is -to -fold the rate demonstrated in typical icu patients (table ) . [ ] [ ] [ ] [ ] , [ ] [ ] [ ] , accepted article this article is protected by copyright. all rights reserved there have also been observational trials that have compared rates of vte in covid- patients to historical controls without covid- (table ) . [ ] [ ] [ ] marone and colleagues evaluated general ward patients all receiving cus for clinical suspicion of dvt with covid- to those without covid- at the same time the previous year. the rate of dvt was more than -fold higher in the patients with covid- . poissy and colleagues conducted a similar time frame comparison, but only evaluated patients with clinical suspicion and all received prophylaxis. the rate of pe was -fold higher in covid- patients compared to those without, but was also more than -fold higher than influenza patients specifically during the same time frame. finally, helms and colleagues conduced a matched case control study of ards patients with covid- compared to ards patients in the same icu between and . patients were evaluated based on clinical suspicion and the use of anticoagulation was similar between the groups. patients with covid- had over a -fold higher rate of thrombotic events and more than a -fold higher rate of pe, with no difference in dvt, compared to patients without covid- . most hospitalized patients with covid- are over age years and have a number of risk factors for vte, such as pneumonia, obesity, immobility, respiratory disease, elevated d-dimer levels, as well as potentially underlying heart failure, smoking, varicose veins, cancer, and previous vte. intensity may likely be the best approach. ultimately the optimal approach will depend on the results from several ongoing randomized, controlled clinical trials that will serve to inform clinicians on the best approach (nct , nct , nct , nct , nct , nct , nct ). until results from these trials are available, clinicians must rely on currently available evidence to craft treatment approaches for both the individual patient, as well as over-arching institutional guidelines to help the bedside clinician. typically, hospitalized medically ill patients should be evaluated with a validated risk assessment tool to determine if pharmacologic vte prophylaxis is needed (table ). , hospitalized patients with covid- , whether on the medical ward or icu, do not need to undergo the step of risk assessment. both medical ward and icu patients with covid- have several vte risk factors, known thromboinflammation, and unacceptable high rates of vte despite some form of pharmacologic prophylaxis (table ) . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , consequentially, all hospitalized patients with covid- should receive pharmacologic vte prophylaxis regardless of any risk assessment predictors unless the risk of bleeding is considered high. risk assessment should be performed with symptomatic patients with covid- treated at home, since a number of them may still have several vte risk factors, including immobility, and are at risk of thromboembolic events. , [ ] [ ] [ ] support for the paradigm that a higher intensity of anticoagulation than standard prophylactic doses of heparin comes from previously published evidence from the h n influenza pandemic in . an observational cohort study of critically ill patients with severe ards from h n viral pneumonia demonstrated that empiric systemic heparinization titrated to a goal heparin level of . - . anti-xa units/ml was significantly better at reducing vte rates than standard prophylactic doses of either ufh or lmwh. although these data were obtained only in critically ill patients with ards, they do support the idea that higher intensity anticoagulation may be needed in order to improve outcomes in patients with covid- . the first report evaluating the use of vte prophylaxis (ufh or lmwh) and the impact on mortality came from a retrospective review of patients from wuhan, china. patients with severe covid- in the icu received vte prophylaxis for at least seven days with ufh units two to three times daily (n= ), enoxaparin - mg daily (n= ), or no anticoagulation prophylaxis (n= ). overall, there was no difference in -day mortality between the % of patients that received either ufh or lmwh compared to patients who received no anticoagulation ( . % vs. . %; p= . , respectively). however, when looking at the subset of patients with significant hypercoagulability as defined by a d-dimer level of at least six-fold above the upper limit of normal (> . ng/ml), there was a significant decrease in mortality with the use of heparin compared with no anticoagulation ( . % vs. . %; p= . , respectively). when stratifying patients by a sepsis-induced coagulopathy score of > , there was also a significant reduction in mortality with the use of heparin versus no anticoagulation ( . % vs. . %; p= . , respectively). these same authors compared these patients with covid- in the icu to patients in the icu with non-covid- pneumonia, of which . % received heparin prophylaxis. although there was still no overall reduction in mortality in patients receiving heparin prophylaxis compared with no anticoagulation ( . % vs. . %; p= . , respectively), mortality is half what was seen in the covid- patients. interestingly, there was no difference in mortality between heparin users and non-users even when stratified for d-dimer and sepsis-induced coagulopathy in patients without covid- . although this report was the first to suggest that the use of ufh or lmwh could improve outcomes in severely ill patients with covid- , there are a number of limitations that should be considered. first, the benefit seen with prophylaxis was only demonstrated in a subgroup of the sickest patients evaluated. the observational nature of the study cannot account for potential confounding variables between the groups. in fact, the authors noted that during the time of the study medical resources were strained and mortality rates may have been higher than other parts of the world. the decision of whether to give lmwh or ufh, as well as doses used, were at the discretion of the clinician and were not controlled in the study. there is no information of the impact of actual vte events, as this is also an important endpoint. a second observational study from new york sought to identify the value of full therapeutic anticoagulation in patients hospitalized with covid- . this single center retrospective study evaluated patients with covid- , of which ( %) received therapeutic anticoagulation. overall, in-hospital mortality was not different between patients who received therapeutic anticoagulation vs those that did not ( . % vs. . %, respectively). patients who received therapeutic anticoagulation were more likely to require invasive mechanical ventilation ( . % therapeutic anticoagulation vs. . % no therapeutic anticoagulation; p< . ). consequentially, patients who were receiving mechanical ventilation (n= ) had a reduction of in hospital mortality by accepted article over % with the use of therapeutic anticoagulation compared with those who received no therapeutic anticoagulation ( % vs. %, median survival days vs. days; p< . , respectively). interestingly, major bleeding was not significantly increased in patients receiving therapeutic anticoagulation ( % therapeutic anticoagulation vs. . % no therapeutic anticoagulation; p= . ). in a multi-variate cox proportional hazards model, mortality risk was reduced with longer durations of anticoagulation. similar to the previous study, this report suffers from several limitations such as unaccounted for confounding variables. specific anticoagulant agents used for therapeutic anticoagulation were not specified, the indication for anticoagulation was not provided, and it is unclear if non-anticoagulated patients received prophylaxis dose anticoagulation or nothing. the median length of hospitalization was days and the median duration of anticoagulation was only days. despite these limitations, this report provides at least some insight into the role of higher levels of anticoagulation in the most severe patients with covid- , and support evaluating various levels of anticoagulation intensity in ongoing randomized controlled trials. a number of smaller reports also provide partial insight to the appropriate level of vte prophylaxis needed in patients with covid- . a retrospective observational study of icu patients with covid- evaluated coagulopathy parameters after a nadroparin dose of iu twice daily for vte prophylaxis, and then again after a iu twice daily dose ( iu twice daily in patients with body mass index > ). the increase in dose provided a significant reduction in fibrinogen and ddimer levels and an increase in antithrombin activity. an additional report in patients with severe covid- admitted to the icu reported a higher frequency of vte in patients receiving prophylactic compared to therapeutic anticoagulation ( % prophylactic vs. % therapeutic; p= . ), although all patients ( %) with pe were receiving therapeutic anticoagulation. as discussed previously, a number of observational studies have reported higher than expected rates of vte in critically ill patients with covid- , despite the use of standard dose anticoagulant prophylaxis. [ ] [ ] [ ] [ ] [ ] [ ] , , an important consideration within this area may be augmented renal clearance. augmented renal clearance is a process whereby renal clearance of medications is increased in the setting of critical illness. a report in icu patients with covid- identified patients ( . %) with augmented renal clearance. patients with augmented renal clearance had numerically more dvt ( % vs. %; p= . ) and significantly more pe ( % vs. %; p= . ) compared to those without, respectively. these data, although from a small group of patients, speaks accepted article to the potential need for higher doses of anticoagulant prophylaxis to address both significant hypercoagulability as well as augmented renal clearance. lastly, there is emerging information that standard doses of prophylaxis may be adequate to prevent dvt and pe, but higher doses may be need to prevent primary pulmonary thrombosis. this is consistent with a number of observations that demonstrated a higher rate of pulmonary events than dvt. , , , ultimately data from larger randomized controlled trials will help clarify many of these clinical questions. risk of vte in patients with covid- is unlikely to disappear at the time of hospital discharge. studies in medially ill non-covid- patients have demonstrated a high rate of vte in the days immediately after discharge. this is likely due to patients still recovering and continued immobility. two agents, betrixaban and rivaroxaban, are approved by the united states food and drug administration for extended vte prophylaxis in medically ill patients although betrixaban has recently been removed from the market due to a company acquisition. assuming the appropriate inclusion and exclusion criteria are met (table ) , both agents provided a significant reduction in vte events without significantly increasing major bleeding when used for approximately days post discharge. [ ] [ ] [ ] despite the lack of ability to get betrixaban, applying the criteria from the trial still has merit in appropriate patient selection for extended prophylaxis. if these agents cannot be used due to significant drug interaction or other reason, enoxaparin once daily can be used. although enoxaparin has also demonstrated the ability to significantly reduce vte events in the days post discharge, there is significantly more major bleeding with this regimen. apixaban should not be used since the trial with this agent did not demonstrate efficacy over placebo for thromboprophylaxis in medically ill patients, and it also had significantly more major bleeding. although none of these trials included patients with covid- , vte after hospital discharge has been reported in these patients. patients with covid- have prolonged hospital stays with significant deconditioning, immobility during recovery, high d-dimer levels, and additional risk factors. it is likely that a number of hospitalized patients with covid- would have met criteria to be included in the trials and should realize similar benefit from extended vte prophylaxis (table ) . regardless of the underlying cause, ards has been associated with fibrin deposition in the airspaces along with fibrin-platelet microthrombi at the level of the pulmonary vasculature. these observations have also been noted in the lung microvasculature of patient with covid- . [ ] [ ] [ ] [ ] accepted article conjunction with these findings, patients with covid- can demonstrate hypercoagulable and hypofibrinolysis findings on thrombelastography. , these findings have prompted the hypothesis that fibrinolytic therapy may have a role in managing patients with ards, and more specifically in patients with covid- who develop ards in the setting of a hypofibrinolytic thrombotic coagulopathy. data supporting the role of fibrinolytic therapy in the management of patients with covid- are limited at best. in a case series of three patients on mechanical ventilation, systemic t-pa at a dose of mg over hours followed by another mg administered over the subsequent hours has been evaluated. all three patients were experiencing ards related respiratory failure, and had improvements in their ventilatory parameters and oxygenation following t-pa therapy, however the effects were transient. a second case series of three patients with significantly worsening ventilatory parameters and oxygenation were administered t-pa. one patient received mg over hours ( mg/hr), while the over two received mg over hours . all patients experienced improvement in ventilatory parameters and oxygenation and were discharged alive. a final case series assessed the effects or aerosolized freeze-dried plasminogen in hospitalized patients with covid- . oxygenation and ventilatory parameters were also improved, but only transiently. a report using a markov decision analysis approach to evaluate whether t-pa may improve outcomes in patients with covid- demonstrated the use of fibrinolytic therapy in ards patients was associated with a mortality benefit, although this can be considered hypothesis generating only. given that systemic administration of fibrinolytics in the setting of pe is associated with a % risk of major bleeding and a - % risk of intracranial hemorrhage, additional information from randomized clinical trials is needed to validate whether t-pa has any role in the management of patients with covid- and ards. several trials are underway to address this clinical question (nct , nct ). based on the level of evidence currently available, routine fibrinolytic administration to patients with covid- ards cannot be recommended at this time. several clinical guidance and consensus statements have been developed and disseminated by international organizations to help guide clinicians in the management of the thromboembolic risks associated with covid- (table ). , , - these guidance statements have been developed in the absence of randomized controlled trials in patients with covid- , and hence are largely based this article is protected by copyright. all rights reserved on knowledge regarding the prophylaxis and treatment of vte in patients without covid- , as well as the initial observational publications. as such, some of the recommendations should be considered expert consensus. although these guidance statements attempt to include the most upto-date information, data regarding vte risk, prevention, and treatment in patients with covid- is rapidly evolving. at the time of this writing, data presented in this manuscript cannot be found in many of these guidance documents. also, each of the guidance documents do not address all the clinical issues, and not all of these organizations agree. therefore, a table of clinical considerations has been provided that considers these different guidance documents together, as well as incorporates the most recent published data ( table ) (table ) in the icu setting. for example, a study using standard doses of lmwh prophylaxis in icu patients with covid- reported a failure rate of %, which is -fold higher than prior reports in icu patients without covid- that documented a failure rate of . %. , evidence is also beginning to emerge that escalating the dose of vte prophylaxis in patients who have evidence of thromboinflammation due to a heightened inflammatory state (increased il- , d-dimer, fibrinogen, or teg findings) results in a significant decrease in inflammation and hypercoagulability. in-hospital vte prophylaxis and treatment should be provided with lmwh or ufh instead of a direct oral anticoagulant (doac). both lmwh and ufh have potential anti-inflammatory properties that accepted article may make them beneficial in patients with covid- . [ ] [ ] [ ] these agents also may prevent splitting of the s proteins of sars-cov- , which is necessary for incorporation into the host via ace . the impact of doacs on these properties is unknown. besides patients requiring dialysis, the use of a lmwh is preferred to ufh for both prevention and treatment of vte. prophylaxis with lmwh requires fewer injections per day compared to ufh, and treatment with lmwh can be give once or twice daily, with no need for the frequent monitoring and dose adjustments as is necessary with ufh. use of lmwh instead of ufh will reduce exposure of health care professionals to patients with covid- , as well as preserving personal protective equipment. the preference for lmwh over ufh for prophylaxis is also based on benefit of lmwh over ufh in other high risk patients, such as those with trauma, cancer, and high risk medically ill patients. [ ] [ ] [ ] [ ] [ ] [ ] patients receiving lmwh for vte prophylaxis should have dose adjustments for obesity and renal function. in patients with a bmi of to kg/m or greater, or weighing more than to kg, increased doses of lmwh, such as enoxaparin mg twice daily, mg once daily, or . mg/kg have demonstrated improved efficacy and similar safety to standard doses. , date also is available in patients undergoing bariatric surgery, as well as pregnancy, supporting the notion that doses of prophylaxis should be adjusted upwards based on the presence of elevated body weight. , if ufh is used for vte treatment, monitoring must be done with an anti-xa assay instead of the aptt. the aptt can be elevated or become elevated in patients with covid- , and therefore is unreliable for monitoring ufh. even though bleeding is rare in patients with covid- , the current evidence does not support the use of therapeutic lmwh or ufh for prevention of vte. the use of fibrinolysis outside of patients with hemodynamically compromised pe should also be avoided. the use of doacs in hospitalized patients, especially icu patients with covid- , can be problematic if invasive procedures are needed, requiring longer hold times that may delay procedures. the use of doacs may also be limited by drug interactions with certain antiviral therapies, such as lopinavir/ritonavir. if the perceived need for invasive procedures is low, and no drug interactions exist, doacs could be considered as initial therapy for treatment of vte in non-icu patients. after discharge, patients initiated on injectable therapy in the hospital should be considered for transition to a doac if possible, or warfarin. this article is protected by copyright. all rights reserved as all hospitalized patients with coivd- should receive vte prophylaxis, thrombocytopenia presents a conundrum. platelet count drops to less than x /l may represent the transition of the patient into a consumption coagulopathy, where withdrawal of anticoagulant therapy may worsen the patient's thrombotic potential. it is not uncommon to continue vte prophylaxis until platelet counts get below x /l or even x /l. with the high use of anticoagulation in patients with covid- , heparin-induced thrombocytopenia must also be considered, especially in patients receiving ufh. special attention to the timing and rate of platelet drop needs be considered. since a consumption coagulopathy occurs fairly late in the course of sars-cov- infection in the most severe cases, it is relatively rare, but also difficult to distinguish from the timing of heparin-induced thrombocytopenia. in these cases, switching to an alternative agent such as argatroban or fondaparinux seems prudent. patients with covid- should not only be considered to have a respiratory illness, but a thrombotic condition as well. sars-cov- not only produces an inflammatory and hypercoagulable state, but also a hypofibrinolytic state not seen with most other types of coagulopathy. the rate of vte observed is higher than expected for general ward and icu patients, especially for those receiving prophylaxis. all hospitalized patients with covid- should be considered high risk and receive anticoagulants for vte prophylaxis. although a number of approaches have been observed in the literature, there is unfortunately no high-quality data to help make more definitive recommendations at this time. although guideline statements differ on a number of the clinical issues, such as the best dose of anticoagulant for vte prophylaxis, duration of prophylaxis, and use of fibrinolytics in patients with ards, a number of randomized controlled trials are ongoing to answer these questions. until these randomized controlled trials become available, an understanding of the pathophysiology, coagulopathy, current guideline and consensus statements, and these clinical considerations (table ) are key resources to help clinicians care for patients with covid- . iu once daily to iu bid or iu (or even , iu qd in obese patients) can be considered if dalteparin is the formulary lmwh. adjust doses based on clinical trial data and equal potent anti-xa units. the novel coronavirus originating in wuhan, china: challenges for global health governance timeline of who's response to covid- identification of a novel coronavirus in patients with severe acute respiratory syndrome isolation of a novel coronavirus from a man with pneumonia in saudi arabia summary of probable sars cases with onset of illness from middle east respiratory syndrome coronavirus (mers-cov) clinical characteristics of coronavirus disease in china coagulation disorders in coronavirus infected patients: covid- , sars-cov- , mers-cov and lessons from the past coronavirus spike protein and tropism changes hyerinflammation and derangement of reninangiotensin-aldosterone system in covid- : a novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis the old but new: can unfractionated heparin and low molecular weight heparins inhibit proteolytic activation and cellular internalization of sars-cov by inhibition of host cell proteases? coronavirus disease : the role of the fibrinolytic system from transmission to organ injury and sequelae accepted article this article is protected by copyright. all rights reserved a crucial role of angiotensin converting enzyme (ace ) in sars coronavirus-induced lung injury covid- : consider cytokine storm syndromes and immunosuppression risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study haematological characteristics and risk factors in the classification and prognosis evaluation of covid- : a retrospective cohort study clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china clinical features of patients infected with novel coronavirus in wuhan, china epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study lymphopenia predicts disease severity of covid- : a descriptive and predictive study pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms neutrophil extracellular traps go viral emerging role for platelets as immune and inflammatory cells platelet activation and platelet-monocyte aggregates formation trigger tissue factor expression in severe covid- patients accepted article this article is protected by copyright. all rights reserved . schulman s. covid- , prothrombotic factors and venous thromboembolism angiotensin ii regulates the expression of plasminogen activator inhibitor- in cultured endothelial cells. a potential link between the renin-angiotensinaldosterone system and thrombosis prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia deep vein thrombosis in hospitalized patients with coronavirus disease (covid- ) in wuhan, china: prevalence, risk factors, and outcome extremely high incidence of lower extremity deep vein thrombosis in patients with severe covid- in wuhan high incidence of venous thromboembolic events in anticoagulated severe covid- patients incidence of venous thromboembolism in critically ill coronavirus disease patients receiving prophylactic anticoagulation incidence of thrombotic complications in critically ill icu patients with covid- thromboembolic events and apparent heparin resistance in patients infected with sars-cov- routine venous thromboembolism prophylaxis may be inadequate in the hypercoagulable state of severe coronavirus disease prevalence of venous thromboembolism in critically ill patients with covid- incidence of asymptomatic deep vein thrombosis in patients with covid- pneumonia and elevated d-dimer levels incidence of deep vein thrombosis among non-icu patients hospitalized for covid- despite pharmacological thromboprophylaxis venous thromboembolism in sars-cov- patients: only a problem in ventilated icu patients, or is there more to it? incidence of venous thromboembolism in hospitalized patients with covid- upsurge of deep vein thrombosis in patients affected by covid- : preliminary data and possible explanations pulmonary embolism in covid- patients: awareness of an increased prevalence high risk of thrombosis in patients with severe sars-cov- infection: a multicenter prospective cohort study pulmonary embolism or pulmonary thrombosis in covid- ? is the recommendation to use high-dose heparin for thromboprophylaxis justified? pathological evidence of pulmonary thrombotic phenomena in severe covid- pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- pulmonary arterial thrombosis in covid- with fatal outcome: results from a prospective, single-center, clinicopathologic case series post-mortem examination of covid patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction multiple organ infection and the pathogenesis of sars histopathology of middle east respiratory syndrome coronavirus (mers-cov) infection -clinicopathological and ultrastructural study accepted article this article is protected by copyright. all rights reserved prevention and treatment of venous thromboembolism associated with coronavirus disease infection: a consensus statement before guidelines prominent changes in blood coagulation of patients with sars-cov- infection covid- -related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure hypercoagulability of covid- patients in intensive care unit. a report of thromboelastography findings and other parameters of hemostasis abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia hematological findings and complications of covid- laboratory abnormalities in patients with covid- infection thromboinflammation and the hypercoagulability of covid- coagulopathy and antiphospholipid antibodies in patients with covid- lupus anticoagulant is frequent in patients with covid- coagulopathy of covid- and antiphospholipid lupus anticoagulant (lac) testing in patients with inflammatory status: does c-reactive protein interfere with lac test results? hematologic parameters in patients with covid- infection thrombocytopenia is associated with severe coronavirus disease (covid- ) infections: a meta-analysis accepted article this article is protected by copyright. all rights reserved thrombocytopenia and its association with mortality in patients with covid- d-dimer is associated with severity of coronavirus disease : a pooled analysis the source of elevated plasma d-dimer levels in covid- infection d-dimer as a predictor of venous thromboembolism in acutely ill, hospitalized patients: a subanalysis of the randomized controlled magellan trial pulmonary thrombosis in -ncov pneumonia? the importance of appropriate prophylaxis for the prevention of venous thromboembolism in at-risk medical patients deep vein thrombosis and its prevention in critically ill adults the impact of deep vein thrombosis in critically ill patients: a meta-analysis of major clinical outcomes dalteparin verse unfractionated heparin in critically ill patients failure of anticoagulant thromboprophylaxis: risk factors in medical-surgical critically ill patients emergence of institutional antithrombotic protocols for coronavirus a risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the padua prediction score external validation of the risk assessment model of the international medical prevention registry on venous thromboembolism (improve) for medical patients in a tertiary health system accepted article this article is protected by copyright. all rights reserved covid- and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up acute pulmonary embolism in non-hospitalized covid- patients referred to ctpa by emergency department venous thromboembolism and coronavirus disease in an ambulatory care setting -a report of cases empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill influenza a h n acute respiratory distress syndrome anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy difference of coagulation features between severe pneumonia induced by sars-cov- and non-sars-cov- association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with covid- the procoagulant pattern of patients with covid- acute respiratory distress syndrome low molecular weight heparins in covid- patients: beware of augmented renal clearance extended venous thromboembolism prophylaxis in medically ill patients extended thromboprophylaxis with betrixaban in acutely ill medical patients for the magellan investigators. rivaroxaban for thromboprophylaxis in acutely ill medical patients improved benefit risk profile of rivaroxaban in a subpopulation from the magellan study extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial apixaban versus enoxaparin for thromboprophylaxis in medically ill patients deep venous thrombosis in a non-critically ill patient with novel covid- infection tissue plasminogen activator (tpa) treatment for covid- associated acute respiratory distress syndrome (ards): a case series successful use of tpa for thrombolysis in covid related ards: a case series plasminogen improves lung lesions and hypoxemia in patients with covid- salvage use of tissue plasminogen activator (tpa) in the setting of acute respiratory distress syndrome (ards) due to covid- in the usa: a markov decision analysis thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis prevention, diagnosis, and treatment of vte in patients with covid- : chest guideline and expert panel report thromboembolism and anticoagulant therapy during the covid- pandemic: interim clinical guidance from the anticoagulation forum scientific standardization committee communication: clinical guidance on the diagnosis, prevention and treatment of venous accepted article this article is protected by copyright. all rights reserved thromboembolism in hospitalized patients with covid- covid- and haemostasis: a position paper from italian society on thrombosis and haemostasis anti-inflammatory effects of heparin and its derivatives: a systematic review using heparin molecules to manage covid- the versatile heparin in covid- a comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma unfractionated heparin versus low-molecularweight heparin for venous thromboembolism prophylaxis in trauma evaluation of unfractionated heparin versus low-molecular-weight heparin and fondaparinux for pharmacologic venous thromboembolic prophylaxis in critically ill patients with cancer clinical use of low-molecular-weight heparins in cancer patients: focus on the improved patient outcomes randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease enoxaparin vs. heparin for prevention of deep-vein thrombosis in acute ischaemic stroke: a randomized, double-blind study guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism patients with ards who died (n= ) vs. those with ards who survived (n= ) more liver and renal dysfunction more preexisting htn and dm higher il- higher d-dimer ( vs. ng/ml ards patients who died: older by years ( vs. years; p< . ) more liver and renal dysfunction higher il- ( . vs. . pg/ml higher d-dimer ( vs. ng/ml patients who died (n= ) vs. those who were discharged (n= ) patients who died: older by years ( vs higher sofa scores higher il- ( . vs. . pg/ml higher ldh ( vs. iu/l; p< . ) higher troponin ( vs. pg/ml higher d-dimer ( vs. ng/ml; p< . ) more with d-dimer > ng/ml patients with moderate (n= ) vs. severe (n= ) vs. critical covid- (n= ) moderate vs. severe vs. critical thrombocytopenia ( % vs. % vs. %) patients who died (n= ) vs. those who survived (n= ) patients who died: older by years ( vs higher d-dimer ( vs. ng/ml covid- =coronavirus infection htn=hypertension; dm=diabetes mellitus ldh=lactate dehydrogenase pt=prothrombin time; ards=acute respiratory distress syndrome pe=pulmonary embolism; bid=twice daily; pt=prothrombin time; tid=three times daily; ecmo=extracorporeal membrane oxygenation;ards=acute respiratory distress syndrome. table . vte risk assessment models , padua score † vte=venous thromboembolism; bmi=body mass index † a score of or higher demonstrates high risk of vte and pharmacologic prophylaxis should be used. ‡ patients with local or distant metastases and/or in whom chemotherapy or radiotherapy had been performed in the previous months. § anticipated bed rest with bathroom privileges (either because of patient's limitations or on physician's order) for at least days. ¶ carriage of defects of antithrombin, protein c or s, factor v leiden, g a prothrombin mutation, antiphospholipid syndrome. key: cord- -zzhsrytw authors: rispoli, rossella; diamond, mathew e.; balsano, massimo; cappelletto, barbara title: spine surgery in italy in the covid- era: proposal for assessing and responding to the regional state of emergency date: - - journal: world neurosurg doi: . /j.wneu. . . sha: doc_id: cord_uid: zzhsrytw abstract in december , coronavirus disease (covid- ) was discovered in wuhan, hubei province, from where it spread rapidly across the globe. covid- characteristics – elevated infectivity, rapid spread, and general population susceptibility – pose a great challenge to hospitals. infectious disease, pulmonology, and intensive care units have been strengthened and expanded. all other specialties have been compelled to suspend or reduce clinical and elective surgical activities. the profound effects on spine surgery call for systematic approaches to optimizing the diagnosis and treatment of spinal diseases. here, based on the experience of one italian region, we draw an archetype for assessing the current and predicted level of stress in the health care system, with the aim of enabling hospitals to make better decisions during the pandemic. further, we provide a framework that may help guide strategies for adapting surgical spine care to the conditions of epidemic surge. can cause the severe acute respiratory syndrome coronavirus (sars-cov- ) and represents a potentially fatal disease of enormous public health importance. by the time of the world health organization (who) classification of the novel coronavirus as a global pandemic ( ) , many hospitals in northern italy were already overcrowded by covid- patients, especially intensive care units, where about % of all available icu beds were occupied by covid- patients ( ) . physicians from specialties beyond infectious or respiratory diseases, including neurosurgery, were reassigned to the new covid-wards to rationalize the use of resources ( ) . the covid- pandemic has forced hospitals to progressively reduce surgical volume, both to minimize disease transmission within the hospital and to preserve human resources and personal j o u r n a l p r e -p r o o f protective equipment (ppe) and other resources needed to care for covid- patients ( ) . as the covid- burden on hospitals increased, italian healthcare services responded with new procedures. these include postponing elective surgical procedures until a more appropriate time, putting in place strategies to ensure urgent/emergency operations during the pandemic, defining type of hospital and the assistance pathways, designating covid- operating rooms for urgent procedures with guidance information posted conspicuously to all the professionals, ensuring systematic and correct use of appropriate ppe, controlling and limiting the number of patients' visitors, developing support strategies for healthcare professionals, and treating outpatients through telemedicine (teleorientation, telemonitoring, and teleinterconsultation) ( ) . while the sars-cov- virus and its expression as covid- do not appear to affect the spinal cord or peripheral nerves, except in rare cases ( , ) , the disease impacts spine surgeons and their patients as a consequence of the overall reorganization of health care outlined above. therefore, it is essential to formulate initiatives to help patients and healthcare professionals face this challenging situation. in the context of the pandemic, it is important to underline that most surgical spine procedures do not require intensive care ( ) and the suspension of elective surgeries appears to have a relatively minor impact on icu capacity ( ) . due to uncertainty in the future severity of the outbreak, there is no reliable timeline for the normalization of elective surgical scheduling; estimates range from several weeks to months or longer ( ) . the lombardy regional council, situated at the core of the italian covid- pandemic, decided to reshape the health care system by concentrating all neurosurgical activities that could not be postponed into neurosurgical "hub" hospitals. three hub hospitals guarantee / acceptance of emergency cases. the three hospitals were chosen on geographical bases; all of the other departments have been assigned to one of the three hubs as a "spoke". the fourth "hub" hospital, the regional neuro oncological center, has been re-allocated for urgent oncological patients coming from all the other departments of the region ( ) . this is an example of how one regional health system, overwhelmed by the epidemic wave, reorganized the totality of its hospitals. hospitals in friuli venezia giulia (fvg) responded to the covid- pandemic quickly. on march , the prime minister of italy emanated the rules of a strict lockdown for all regions without j o u r n a l p r e -p r o o f distinction. to increase hospital capacity for future covid- patients, the fvg health system director on march limited elective surgery in general; in particular, elective spine surgery was completely suspended. outpatient access was also reduced: thereafter, only urgent and priority b outpatients could access the medical practice. self-sufficient patients were required to come unaccompanied. our unit was permitted to perform only urgent spine surgical procedures such as spinal trauma and emergency spinal oncological pathology with rapidly evolving spinal cord or roots compression ( ) . in the remainder of this report, we assess trends in the spread of the infection and the pressure it generates on the healthcare system, proposing a modus agendi for optimizing surgical activity. specifically, we build a program to adapt surgical spine care to the ongoing, objectively measured stage of epidemic surge. the university hospital of udine is located in the immediate outskirts of udine and is a hub our approach is to create a scheme in which the health care authorities can rapidly assess the state of the system and provide indications to the surgery clinics in real time. we define three alert levels of the health care system -green, yellow, and red -and identify the surgical procedures appropriate to be undertaken at each level. our view is that two readily available parameters, intensive care occupancy and the estimated doubling time of the number of infected persons, offer the means to compute the stress level of the health care system. these are plotted in figure , along with boundaries which are proposed to divide the space into green, yellow, and red alert levels. first, intensive care occupancy -the number of covid- patients currently in icu divided by the number of beds available in icu under normal conditions -is a proxy for the current level of resources dedicated to covid- patients. as the occupancy increases, from left to right along the green to yellow to red gradient, the health care system is under increasing stress and is less able to allot resources to non-covid- functions. we employed icu occupancy in the index because it is a readily accessible measure that correlates closely with overall health system stress, due to the enormous demand on personnel and materials resources associated with each single icu patient. figure , as the doubling time decreases, from bottom to top along the green to yellow to red gradient, the health care system can expect increasing future stress and is therefore less able to allot resources to non-covid- functions. to illustrate the case of the fvg region, the number of new positive cases was acquired daily from the data released by the protezione civile ( ) . doubling time, t d , in units of days, is where r is daily growth in percent of patients. analyses can be easily carried out in any statistics software; for figure , we used excel. the doubling time measure will be largely independent of regional differences in the policy or availability of covid- testing. two service areas with different testing regimes will each detect some percentage of the true carriers in their respective regions. doubling time within both service areas will be sensitive to changes in the regional daily number of detected positives, and will accurately chart the projected spread of the virus notwithstanding differences in testing across regions. a change in testing policy or capacity within one service area will not affect the derived j o u r n a l p r e -p r o o f doubling time provided the change is effected at a slower timescale than the day-to-day count that yields the doubling time. due to the large orders-of-magnitude ranges covered by the data, it is convenient to assess the health care system status using logarithmic scales. the alert level boundaries intersect at occupancy levels of . (green/yellow), and . (yellow/red). on the ordinate, the green/yellow alert level boundary intersects at doubling time of day. the data used for each point are averaged across the previous days (current date included) to smooth away daily fluctuations and to make temporal trends more reliable. in the fvg region, the baseline count of icu beds is ( ) . occupancy of icu beds was acquired from https://covstat.it/analisi-regioni/#trasmissione-varie-regioni ( ) . note that our scheme allows occupancy to surpass . . this seemingly paradoxical situation occurs when the health system builds new icu facilities in response to epidemic conditions, as occurred in lombardy. when occupancy of icu beds by covid- patients is equal to or greater than . , the alert level is, by definition, red. the proposed decision making grid for spine surgery, shown in table the alert level data points relative to the fvg region of northeast italy are shown in white points in the proposal for prioritizing surgical activities in relation to health care system alert levels is given in all these patients were admitted urgently due to the onset with neurological deficits and, in one case, for early signs of infection. as an example, we report the case of one patient with a facial and cervical trauma, with a facet fracture, on february . we prescribed an x-ray and re-evaluation after weeks. during that period, all the non-urgent radiological exams were suspended. the patient began to experience neck pain and paresthesia. he then started to lose strength in his hands and notwithstanding the lockdown, he went to the emergency room. after a clinical examination, we detected signs of cord compression. x-rays and mri showed a c -c dislocation with cord compression. we operated on the young patient with a double approach. after surgery all the symptoms were resolved. during the first and second yellow alert level pandemic ( - march and april to may ) we performed emergency surgical procedures and programmed with a priority (spinal cord and\or roots impending or chronic but progressive compression, intractable pain, impending deformity). they were subdivided by etiology as follows: oncologic, trauma, acute and subacute with mechanical intractable pain, and degenerative. after the return to green alert level (may to ), we performed surgical procedure programmed, all with a priority. since may we have been allotted hours/week to perform programmed surgery with clinical priority. in our hospital ppe (gloves, gowns, masks, etc), ventilators, ventilator filters, and medications were never lacking. the main factor that led to the reduction or cancellation of elective surgery was the availability of or staff, who were focused on covid- treatment. clinical decisions were made and acted on prior to the formulations represented by figure and table . retrospectively, we can observe that patients operated on during the three alert levels fell into the appropriate categories. for this reason, we can treat the -level decision making grid as the formalization and systematization of practices that had emerged in ipsa hora in "the heat of the battle." the ongoing covid- global pandemic is unprecedented in the last years. it has led to the upheaval of the health care system at all levels and in all specializations. spine surgery triage has its own unique set of challenges and the acuity of cases may be higher than in many other surgical specialties. the spine surgeon has a crucial role to play as provider, conserver of health care resources, and public health advocate. ( ) . recently, the north american spine society (nass) developed a guidance document and the authors' current recommendations for triaging surgical spine cases are largely based on this document ( ) . in lombardy the regional council reorganized the hospitals as described in the introduction. oncological pathology priority has been defined as: patients requiring immediate treatment (class a++: rapidly evolving intracranial hypertension with deteriorating state of consciousness, acute hydrocephalus, spinal cord compression with rapid tetra-or paraparesis), patients requiring treatment within a maximum of - days (class a+: tumors with mass effect or with progressive neurological deficit, without deterioration of consciousness), patients requiring treatment within a month (class a: oncological pathology that appears malignant and determines a neurological j o u r n a l p r e -p r o o f deficit) ( ) . this was made possible with the active collaboration of the expert surgeons who developed protocols for evaluating which operations had to be done urgently and which could be delayed. in this perspective, we propose to incorporate three variables (surge level, etiology of spinal pathologies and clinical presentation) in order to create a dynamic scheme that prioritizes spine surgery. every surgeon can apply this algorithm to any clinical scenario and place the patient in the correct box, as exemplified in table "after this pandemic, nothing will ever be the same" -this oft-heard statement is especially true for healthcare providers and surgeons. in this report have highlighted opportunities to maximize the benefit and minimize the risk of spine surgery during this pandemic and potentially, any future waves. the alert levels of figure allow us to make decisions rapidly and with a solid data base, using infection doubling time to predict the situation in the coming week. one of the benefits of the covid- crisis has been the robust implementation of telemedicine and virtual visits. although it is not meant to replace in-person medical care, telehealth allows for mitigation of patient and avoids exposure to potential contagions by facilitating compliance with home quarantine. in spine surgery, there is the potential to miss a significant neurologic deficit in the course of a telemedicine consultation; spine surgeons must increase the time spent on history acquisition and must be sensitive to descriptors suggestive of a neurological deficit. we think that at the moment telemedicine could be useful for already established patients and long-term postoperative surveillance patients. in conclusion, although there is no single universally agreed plan for recalibrating health systems in the face of the covid- pandemic, we have presented a balanced and succinct description of j o u r n a l p r e -p r o o f rational, safe approaches to all surgical/clinical procedures in case of emergencies that we may encounter in the future. this dramatic, unprecedented experience teaches us to reason in terms of the scarce availability of human and material resources (beds, ventilators gloves, gowns, masks, etc.). faced with limited resources, we are motivated to set priorities that offer the best possible care to patients with spine disease, seeking to preserve their quality of life. when we emerge from the other side of this pandemic, our hope is look back and feel confident that no patient suffered due to the unwise use of health care resources. j o u r n a l p r e -p r o o f table . spine surgery across red/yellow/green alert levels. relationship between clinical presentation, etiology, and alert level to guide spine surgery during covid- pandemic and similar emergencies. the description of the spinal pathology is intended as an example only. a new coronavirus associated with human respiratory disease in china effects of the covid- outbreak in northern italy: perspectives from the bergamo neurosurgery department a novel coronavirus from patients with pneumonia in china current status of epidemiology, diagnosis, therapeutics, and vaccines for novel coronavirus disease (covid- ) acute myelitis after sars-cov- infection: a case report covid infection presenting as motor peripheral neuropathy spinal emergencies in primary care practice cancellation of elective surgery and intensive care unit capacity in new york state: a retrospective cohort analysis when will hospitals recover from covid- ? questions answered neurosurgery in the storm of covid- : suggestions from the lombardy region impact of covid- mitigation measures on patients with spine disease in friuli venezia giulia triaging spine surgery in the covid- era north american spine society. coronavirus nass guidance document neurosurgery during the covid- pandemic: update from lombardy, northern italy cappelletto have made substantial contributions to all of the following: ( ) the conception and design of the study, or acquisition of data, or analysis and interpretation of data sars-cov- : severe acute respiratory syndrome coronavirus who: world health organization icu: intensive care units ppe: personal protective equipment fvg: friuli venezia giulia acs: american college of surgeons cdc: united states centers for disease control and prevention ota: orthopedic trauma association rcs key: cord- - ehuuvnx authors: götzinger, florian; santiago-garcía, begoña; noguera-julián, antoni; lanaspa, miguel; lancella, laura; calò carducci, francesca i; gabrovska, natalia; velizarova, svetlana; prunk, petra; osterman, veronika; krivec, uros; lo vecchio, andrea; shingadia, delane; soriano-arandes, antoni; melendo, susana; lanari, marcello; pierantoni, luca; wagner, noémie; l'huillier, arnaud g; heininger, ulrich; ritz, nicole; bandi, srini; krajcar, nina; roglić, srđan; santos, mar; christiaens, christelle; creuven, marine; buonsenso, danilo; welch, steven b; bogyi, matthias; brinkmann, folke; tebruegge, marc title: covid- in children and adolescents in europe: a multinational, multicentre cohort study date: - - journal: lancet child adolesc health doi: . /s - ( ) - sha: doc_id: cord_uid: ehuuvnx background: to date, few data on paediatric covid- have been published, and most reports originate from china. this study aimed to capture key data on children and adolescents with severe acute respiratory syndrome coronavirus (sars-cov- ) infection across europe to inform physicians and health-care service planning during the ongoing pandemic. methods: this multicentre cohort study involved participating health-care institutions across european countries, using a well established research network—the paediatric tuberculosis network european trials group (ptbnet)—that mainly comprises paediatric infectious diseases specialists and paediatric pulmonologists. we included all individuals aged years or younger with confirmed sars-cov- infection, detected at any anatomical site by rt-pcr, between april and april , , during the initial peak of the european covid- pandemic. we explored factors associated with need for intensive care unit (icu) admission and initiation of drug treatment for covid- using univariable analysis, and applied multivariable logistic regression with backwards stepwise analysis to further explore those factors significantly associated with icu admission. findings: individuals with pcr-confirmed sars-cov- infection were included, with a median age of · years (iqr · – · ) and a sex ratio of · males per female. ( %) had pre-existing medical conditions. ( %) individuals were admitted to hospital. ( %) individuals required icu admission, ( %) mechanical ventilation (median duration days, iqr – , range – ), ( %) inotropic support, and one (< %) extracorporeal membrane oxygenation. significant risk factors for requiring icu admission in multivariable analyses were being younger than month (odds ratio · , % ci · – · ; p= · ), male sex ( · , · – · ; p= · ), pre-existing medical conditions ( · , · – · ; p= · ), and presence of lower respiratory tract infection signs or symptoms at presentation ( · , · – · ; p< · ). the most frequently used drug with antiviral activity was hydroxychloroquine ( [ %] patients), followed by remdesivir ( [ %] patients), lopinavir–ritonavir (six [ %] patients), and oseltamivir (three [ %] patients). immunomodulatory medication used included corticosteroids ( [ %] patients), intravenous immunoglobulin (seven [ %] patients), tocilizumab (four [ %] patients), anakinra (three [ %] patients), and siltuximab (one [< %] patient). four children died (case-fatality rate · %, % ci · – · ); at study end, the remaining were alive and only ( %) were still symptomatic or requiring respiratory support. interpretation: covid- is generally a mild disease in children, including infants. however, a small proportion develop severe disease requiring icu admission and prolonged ventilation, although fatal outcome is overall rare. the data also reflect the current uncertainties regarding specific treatment options, highlighting that additional data on antiviral and immunomodulatory drugs are urgently needed. funding: ptbnet is supported by deutsche gesellschaft für internationale zusammenarbeit. in late december, , who was notified of an unusual cluster of pneumonia cases in wuhan, china. the disease, later termed covid- , spread quickly beyond the borders of china, with the first cases in europe being recorded on jan , . subsequent investigations identified a novel betacoronavirus now designated as severe acute respiratory syndrome coronavirus (sars-cov- ). currently, there are no antiviral treatment options with proven efficacy, but several randomised controlled trials are investigating agents such as hydroxychloroquine, lopinavir-ritonavir, favipiravir, and remdesivir (eg, nct , nct , and nct ). other trials are focusing on immunomodulators, including tocilizumab and anakinra (eg, nct and nct ). to date, data on covid- in children and adolescents remain scarce, despite the number of confirmed covid- cases now exceeding million globally. , most published data originate from china, which cannot necessarily be extrapolated to children in europe and elsewhere. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] also, existing papers from china contain very few clinical data on children, and most lack details regarding supportive measures required by children with covid- . similarly, recent epidemio logical reports from europe and north america contain little clinically relevant information. , determining the level of support required by children is essential for paediatric service planning during the ongoing covid- pandemic. by use of a well established research network, predominately comprising paediatric infectious diseases specialists and paediatric pulmonologists, the aim of this study was to rapidly capture key data on covid- in children in europe on a large scale, to aid physicians in europe and in other geographical locations with service planning and allocation of resources. for this cohort study, european members of the paediatric tuberculosis network european trials group (ptbnet)-which currently includes clinicians and researchers, most of whom are based at tertiary or quaternary paediatric infectious diseases or paediatric pulmonology units, across paediatric health-care institutions in european countries [ ] [ ] [ ] [ ] [ ] [ ] -were invited to contribute cases of confirmed sars-cov- infection that had been managed at or managed remotely by their health-care institution (including individuals admitted to other hospitals or identified during community screening) before or during the study period. any individual aged years or younger with sars-cov- infection confirmed by rt-pcr was eligible for inclusion. a standardised data collection spreadsheet was used by collaborators to record data from their centre. all data were reviewed by three of the investigators (fg, bs-g, and mt), and any inconsistencies and other data queries were clarified with the reporting collaborators. units that did not see any cases before or during the study period were asked to report the absence of cases fulfilling the inclusion criteria at the end of the study period. the study was done over a · -week period, from april to april , . the study was reviewed and approved by the ptbnet steering committee, and the human research ethics committees of the university of bochum, germany ( - -br), the hospital gregorio marañon, spain (ceim hgugm- / ), and the city of vienna, austria (ek - -vk). the study was conducted in accordance with the declaration of helsinki and its subsequent evidence before this study we searched medline on may , , through the pubmed interface to identify publications describing clinical studies in children with covid- . to ensure a broad search, the search terms used were "(child or children or pediatric or paediatric) and covid- ". no additional limits were set. this search yielded papers: case reports or case series; epidemiological reports; guidelines and consensus statements; reviews, perspectives, or editorials without original data; and letters; were unrelated to children with covid- . papers presented original data, but exclusively in adults. only ten papers reported clinical studies in children with covid- : eight papers originated from china, one from spain, and one from italy. the study by tagarro and colleagues was reported in letter format, and only included children with confirmed severe acute respiratory syndrome coronavirus (sars-cov- ) infection in madrid. the study from italy by parri and colleagues was also reported as a letter and included cases across several italian hospitals. however, the study only featured a single patient who required mechanical ventilation, and consequently very few data on children with covid- at the severe end of the disease spectrum. to our knowledge, this study is the first multinational, multicentre study in children with covid- , and provides a detailed overview on sars-cov- infection in children in europe during the initial peak of the pandemic, which was facilitated by a collaboration of units across european countries. the study has several key findings. first, the data show that covid- is generally a mild disease in children, including infants. second, the study found that a substantial proportion ( %) of children develop severe disease, requiring intensive care support and prolonged ventilation. several predisposing factors for requiring intensive care support were identified. third, the study confirms that fatal outcome is rare in children. there was considerable variability in the use of drugs with antiviral activity as well as immunomodulatory medication, reflecting current uncertainties regarding specific treatment options. this study confirms previous reports from china suggesting that the case-fatality rate of covid- in children is substantially lower than in older adult patients. however, some children develop severe disease and require prolonged intensive care support, which should be accounted for in the planning of health-care services and allocation of resources during the ongoing pandemic. finally, the findings highlight that data on antiviral and immunomodulatory drugs are urgently needed from well designed, randomised controlled trials in children, to enable paediatricians to make evidencebased decisions regarding treatment choices for children with severe covid- . amendments. no personal or identifiable data were collected during the conduct of this study. a confirmed case was defined as a patient in whom sars-cov- was detected in any clinical sample (respiratory tract, blood, stool, or cerebrospinal fluid) by rt-pcr. pcr testing was done as part of routine clinical care, and therefore done according to local testing guidelines in place at the time. date of symptom onset was defined as the day when the first symptom or sign occurred, and date of diagnosis as the day when sars-cov- was first detected. pyrexia was defined as a body temperature at least · °c. the index case was defined as the most likely source case based on history; if multiple family members were affected, the person who displayed symptoms first was recorded. diagnosis of upper respiratory tract infection was based on clinical signs and symptoms, encompassing any of the following: coryza, pharyngitis, tonsillitis, otitis media, or sinusitis. lower respiratory tract infection was based on clinical signs and auscultation findings. inotropic support was defined as administration of dopamine, dobutamine, epinephrine, or norepinephrine by continuous infusion. non-parametric two-tailed mann-whitney u tests were used to compare continuous variables and χ² or fisher's exact tests to compare categorical variables, as appropriate. in children younger than years, age was calculated as fraction of a whole year ( days); from years of age, age was rounded to the nearest year. the % ci around the case-fatality rate (cfr) was calculated with the wald method. normality of data distribution was assessed with the shapiro-wilk test. the clinical endpoint was the need for admission to an intensive care unit (icu; either neonatal or paediatric intensive care). the association of baseline characteristics and clinical findings with icu admission was initially evaluated using univariable logistic regression. subsequently, multivariable logistic regression analysis with the backward stepwise method was used to explore variables that were independently associated with icu admission. only variables that were significant in univariable analyses were introduced into the model. factors associated with drug treatment for covid- were also explored with univariable analysis. all probabilities are two tailed. p< · was considered statistically significant. all analyses were done with prism (version . ; graphpad, la jolla, ca, usa) and spss (version . ; ibm, armonk, ny, usa). the funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript. the corresponding author had full access to all the data and had the final responsibility for the decision to submit for publication. cases of sars-cov- infection were reported from health-care institutions located in european countries: austria, belgium, bulgaria, croatia, denmark, estonia, germany, greece, hungary, ireland, italy, lithuania, norway, portugal, slovakia, slovenia, spain, sweden, switzerland, turkey, and the uk (figure ). three cases did not meet the inclusion criteria (one -year-old individual and two individuals diagnosed with covid- based on serological testing, but pcr negative). five participating units in the netherlands, moldova, ukraine, and russia reported not having encountered any cases. individuals with pcr-confirmed sars-cov- infection were included in the final analyses. ( %) were contributed by tertiary or quaternary health-care institutions, whereas ( %) had been diagnosed in secondary and ( %) in primary health-care settings. the median age of the study population was · years (iqr · - · ), ranging from days to years (table) . age was non-normally distributed (w= · ; p< · ), with ( %) participants younger than months (figure ). the sex ratio was · males to every female. the most common source of infection was a parent, considered the index case in ( %) individuals; for ( %) individuals, the most probable index case was a sibling. in the remaining ( %) individuals, the index case was a person outside of the immediate family or unknown. ( %) individuals were admitted to hospital and ( %) required admission to an icu for additional support, corresponding to % of those admitted to hospital. ( %) individuals had no pre-existing medical conditions. among the remaining ( %) individuals, the most common conditions were chronic pulmonary disease ( individuals, of whom had asthma and six bronchopulmonary dysplasia), followed by malignancy ( individ uals, of whom had leukaemia or lymphoma and had solid tumours), neurological disorders ( individuals, of whom nine had epilepsy and eight had cerebral palsy), congenital heart disease ( individuals), chromosomal abnormalities (ten individuals, of whom eight had trisomy ), and chronic kidney disease (nine individuals; table). ( %) individuals had two or more pre-existing medical conditions. ( %) individuals were receiving immunosuppressive medication at the time of covid- diagnosis (table) . three ( %) had a previously diagnosed immunodeficiency, comprising common variable immunodeficiency, congenital neutropenia, and schimke immuno-osseous dysplasia. ( %) individuals were receiving chemotherapy at the time of their diagnosis or had received chemotherapy in the preceding months. three ( %) had previously undergone human stem cell transplant. pyrexia was the most common sign at presentation, observed in ( %) individuals (table). approx imately half had signs or symptoms of upper respiratory tract infection and approximately a quarter had evidence of lower respiratory tract infection; ( %) had gastrointestinal symptoms. ( %) individuals with gastrointestinal symptoms had no respiratory symptoms; the majority ( %; n= ) of these individuals had pyrexia. ( %) individuals were asymptomatic. dates when sars-cov- infection was confirmed by rt-pcr in the study population are summarised in figure . the median interval between symptom onset and diagnosis was days (iqr - ; range - ); in the baseline characteristics in the entire cohort and by requirement of icu admission majority (n= ; %) of cases, the interval was no more than days. in eight cases, sars-cov- infection was confirmed before any signs or symptoms were presentmainly neonates born to sars-cov- -positive mothers and household members of symptomatic adults with confirmed covid- . a chest x-ray was done in ( %) patients. of those, ( %) had changes consistent with pneumonia (table). ten ( %) had changes suggestive of acute respiratory distress syndrome (ards), all of whom required mechanical ventilation. in ( %) patients, additional viruses were detected in respiratory samples, comprising enterovirus or rhinovirus (n= ), influenza virus (n= ), parainfluenza virus (n= ), adenovirus (n= ), respiratory syncytial virus (rsv; n= ), bocavirus (n= ), and coronavirus nl , coronavirus hku , coronavirus oc , and human metapneumovirus (n= each). in patients one virus was detected in addition to sars-cov- ; in six patients, two additional viruses were detected simultaneously; and in one patient, three were detected. patients with one or more viral co-infections were more likely to have signs or symptoms of upper or lower respiratory tract infection at presentation compared with those in whom no additional viral agent was identified (appendix p ). furthermore, individuals with viral co-infection were significantly more likely to require icu admission, respiratory support, or inotropic support. ( %) individuals did not require respiratory support at any stage. ( %) patients required oxygen support: ( %) were started on continuous positive airway pressure (cpap) and ( %) on mechanical ventilation (including who had been managed with cpap initially). the median duration of mechanical ventilation was days (iqr - ; range - ). one (< %) patient was started on extracorporeal membrane oxygenation. ( %) patients required support with inotropes. when comparing individuals by their requirement of icu admission, we found that patients who required icu admission were younger than those who did not (ie, individuals in the community and those admitted to hospital but not needing icu support), but this was not statistically significant (table; figure ). in univariable analysis, being younger than month of age, male sex, pre-existing medical conditions, pyrexia, signs or symptoms of lower respiratory tract infection, radiological changes suggestive of pneumonia or ards, and viral coinfection were associated with icu admission (table) . in multivariable analysis, the factors that remained associated with icu admission were being younger than month (odds ratio [or] · , % ci · - · ; p= · ), male sex ( · , · - · ; p= · ), signs or symptoms of lower respiratory tract infection at presentation ( · , · - · ; p< · ), and presence of pre-existing medical conditions ( · , · - · ; p= · ). the most commonly used drug with antiviral activity was hydroxychloroquine, used in ( %) patients, followed by remdesivir, which was used in ( %) patients. lopinavir-ritonavir was used in six ( %) patients and oseltamivir in three ( %), two of whom had influenza virus co-infection. three ( %) patients received two drugs with antiviral activity and one (< %) patient received three; all four patients had ards on chest x-ray. no patient received chloroquine, favipiravir, zanamivir, or ribavirin. with regard to immunomodulatory medication, ( %) patients received systemic corticosteroids, seven ( %) intravenous immunoglobulin, four ( %) tocilizumab, three ( %) anakinra, and one (< %) siltuximab. in univariable analysis, factors associated with treatment initiation of drugs with antiviral or immunomodulatory activity comprised pre-existing malignancy (or · , % ci · - · ), cardiac disease ( · , · - · ), or respiratory disease ( · , · - · ); immuno suppressive therapy at presentation ( · , · - · ) or recent chemo therapy ( · , · - · ); radiological findings suggestive of pneumonia ( · , · - · ) or ards ( · , · - · ); and viral coinfection ( · , · - · ; all p< · ; appendix p ). four patients, all older than years, had a fatal outcome (cfr · %, % ci · - · ), with death occurring at , , , and days after symptom onset. two patients had no known pre-existing medical conditions; one had a cardiorespiratory arrest before arrival at the hospital and resuscitation was unsuccessful and the other died while being mechanically ventilated in icu. the third patient had undergone human stem cell transplant months earlier. the fourth patient was managed palliatively (without intubation), due to the severity of their pre-existing medical conditions. the remaining patients were alive when the study closed. ( %) individuals never developed clinical symptoms. in ( %) individuals, all symptoms had resolved without apparent sequelae, whereas ( %) were still symptomatic or were requiring respiratory support when the study closed. to our knowledge, this is the first multinational, multicentre study on paediatric covid- , and also the largest clinical study in children outside of china to date. the inclusion of such a substantial number of cases was made possible by involving a large number of specialist centres across europe via a well established collaborative paediatric tuberculosis research network, allowing this study to provide one of the most detailed accounts of covid- in children and adolescents published to date. it is important to highlight that this study has primarily captured data from children and adolescents who were seen or managed within the hospital setting, and that the majority of participating units were part of tertiary or quaternary health-care institutions. consequently, the study population is likely to primarily represent individuals at the more severe end of the disease spectrum. notably, a recent letter summarising pcr-confirmed cases in wuhan suggests that close to % of children and adolescents with sars-cov- infection are asymptomatic. at the time our study was conducted, testing capacity for sars-cov- in many european countries was lower than clinical demand, and therefore many children with symptoms consistent with covid- in the community were not tested and consequently not diagnosed. nevertheless, our data indicate that children and adolescents are overall less severely affected by covid- than adults, particularly older patients. previous, large-scale data suggest that the cfr in adults older than years is close to %, potentially due to immuno senescence. it is reassuring that our data show that severe covid- is uncommon in young children, including infants, despite their immune maturation being incomplete, , with only few requiring mechanical ventilation. it was striking that all children who died in our cohort were older than years. the centers for disease control and prevention (cdc) reported confirmed cases of covid- in individuals younger than years in the usa as of april , , representing only · % of the total number of recorded cases (n= ). the australian health protection agency has reported that children accounted for only % of confirmed covid- cases in australia. unfortunately, in the cdc report, clinical data were only available in a small proportion of patients (n= ; %). in concordance with our observations, fever and cough were the predominant clinical features at presentation (present in % and % of individuals, respectively), with similar rates observed in a study from italy. in our cohort almost a quarter of patients had gastrointestinal symptoms, some of whom had no respiratory symptoms, and a substantial proportion of children were entirely asymptomatic. the cdc report also mentions three deaths, but it is unclear how many patients were still hospitalised by the time of publication, so it is difficult to come to firm conclusions regarding the cfr in us children. our data indicate that the cfr in children and adolescents across europe is less than %. considering that many children with mild disease will never have been brought to medical attention, and therefore not diagnosed, it is highly probable that the true cfr is substantially lower than the figure of · % observed in our cohort. this hypothesis is further supported by an epidemiological study from china, in which the cfr in individuals aged years or younger was only · % (one death in confirmed cases). furthermore, our data indicate that sequelae related to covid- are likely to be rare in children and adolescents. however, after the closure of our study, reports of a hyperinflammatory syndrome affecting children that is temporally, and potentially causally, associated with sars-cov- infection have emerged, which has sub sequently been named paediatric inflammat ory multisystem syndrome temporally associ ated with sars-cov- (pims-ts; sometimes known as mic-s). , further research will be required to characterise this emerging disease entity in detail, and determine the longterm outcome of affected children. importantly, our data show that severe covid- can occur both in young children and in adolescents, and that a significant proportion of those patients require icu support, frequently including mechanical ventilation. a small study from madrid also found that four ( %) of children with sars-cov- infection required admission to icu. in our cohort, being younger than month, male sex, presence of lower respiratory tract infection signs or symptoms at presentation, and presence of a pre-existing medical condition were associated with increased likelihood of requiring icu admission. our results also show that the majority of children who are intubated due to respiratory failure require prolonged ventilation, often for week or more. this contrasts with observations in children with rsv infection who, on average, only require mechanical ventilation for - days, but is not dissimilar to observations in children with influenza. this has important implications for service planning, as although the overall demand for icu support might be lower in children than in adults, each patient is likely to occupy icu space for an extended period of time. at this time of intense strain on health-care services worldwide, it is vital that adequate resources are allocated to paediatric services to sustain the provision of high-quality care for children. the observation that, in our study, individuals with viral co-infection (ie, infected with sars-cov- and one or more other viral agents) were more likely to require icu support than those in whom sars-cov- was the only viral agent identified might have implications for the winter period - , when the incidence of other viral respiratory tract infections, including rsv and influenza virus infections, is bound to increase. this could result in a greater proportion of paediatric patients with covid- requiring icu support than in the cohort described here, as the influenza season - was already over in europe before the study commenced. our data also reflect the uncertainties regarding drug treatment options for covid- . in some countries, including spain and italy, national guidelines were encouraging the use of hydroxychloroquine for selected cases, as reflected in our data, while in other countries, recommendations were more guarded regarding the use of antiviral agents in the absence of robust human data. an expert consensus statement from the usa has emphasised that antiviral treatment should be reserved for patients at the severe end of the disease spectrum, ideally within a clinical trial. overall, the expert panel appeared to favour the use of remdesivir over other agents, based on the currently available data from invitro and animal studies, including in non-human primates, and recent data from compassionate use in humans. , the panel members' opinion was split regarding the use of lopinavir-ritonavir, given the disappointing results of a recently published randomised controlled trial. the main limitation of this study relates to the number of variables for which data were collected. in the context of the ongoing covid- pandemic, to ensure high levels of participation and avoid diverting substantial time away from clinical front-line duties, a decision was made not to collect detailed data on laboratory parameters or icu interventions. a further limitation was that a variety of inhouse and commercial pcr assays were used across different participating centres, precluding an assessment of diagnostic test performance. also, the number of children receiving antiviral or immunomodulatory treatment was too small to draw meaningful conclusions regarding their effectiveness, which will be addressed by the aforementioned randomised trials. a further limitation is that different countries were using different thresholds to screen for sars-cov- at the time the study was done, with some recommending screening of all children admitted to hospital or conducting community screening, whereas others were using more selective testing strategies. despite those limitations, to our knowledge, this study provides the most comprehensive overview on covid- in children and adolescents to date. in conclusion, our data, originating from a large number of specialist centres across europe, show that covid- is usually a mild disease in children, including infants. nevertheless, a small proportion of children and adolescents develop severe disease and require icu support, frequently needing prolonged ventilatory support. however, fatal outcome is rare overall. our data also reflect the current uncertainties regarding specific treatment options, highlighting that more robust data on antiviral and immunomodulatory drugs are urgently needed. mt conceived of the study. fg, bs-g, sbw, mb, fb, and mt designed the study. fg, bs-g, and mt cleaned and analysed the data, constructed the figures, and wrote the first draft of the manuscript. all authors contributed data to the study, contributed to the data interpretation, critically reviewed the manuscript, and approved the final manuscript for submission. fg has received funding from gilead for research related to hepatitis e. bs-g and mt have received assays free of charge from cepheid for tuberculosis diagnostics projects. mt has received assays at reduced pricing or free of charge from cellestis/qiagen for tuberculosis diagnostics projects, has received support for conference attendance from cepheid, and is currently receiving funding from biomérieux as an investigator of an ongoing tuberculosis diagnostics study. uh reports personal fees from cepi for being a member of the speac-cepi meta-data safety monitoring board for covid- vaccine trials, outside of the submitted work. the other authors declare no competing interests. michael buettcher (lucerne children's hospital, lucerne cantonal hospital references who. novel coronavirus ( -ncov) situation report coronaviridae study group of the international committee on taxonomy of viruses. the species severe acute respiratory syndrome-related coronavirus: classifying -ncov and naming it sars-cov- who. novel coronavirus ( -ncov) situation report severe and fatal covid- occurs in young children characteristics of pediatric sars-cov- infection and potential evidence for persistent fecal viral shedding novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- ) in china clinical characteristics and intrauterine vertical transmission potential of covid- infection in nine pregnant women: a retrospective review of medical records clinical characteristics of a case series of children with coronavirus disease severe acute respiratory syndrome coronavirus (sars-cov- ) infection in children and adolescents: a systematic review sars-cov- infection in children epidemiology of covid- among children in china detection of covid- in children in early spread of sars-cov- in the icelandic population cdc covid- response team. coronavirus disease in children-united states performance of immune-based and microbiological tests in children with tb meningitis in europe-a multi-center paediatric tuberculosis network european trials group (ptbnet) study tuberculosis disease in children and adolescents on therapy with anti-tumor necrosis factor-alpha agents: a collaborative, multi-centre ptbnet study use of xpert mtb/rif ultra assays among paediatric tuberculosis experts in europe availability and use of molecular microbiological and immunological tests for the diagnosis of tuberculosis in europe european shortage of purified protein derivative and its impact on tuberculosis screening practices paediatric tuberculosis network european trials group. shortage of purified protein derivative for tuberculosis testing immunosenescence: a review protecting the newborn and young infant from infectious diseases: lessons from immune ontogeny neonatal innate tlr-mediated responses are distinct from those of adults covid- national incident room surveillance team. covid- children with covid- in pediatric emergency departments in italy hyperinflammatory shock in children during covid- pandemic rapid risk assessment: paediatric inflammatory multisystem syndrome and sars-cov- infection in children screening and severity of coronavirus disease (covid- ) in children in high flow nasal cannulae therapy in infants with bronchiolitis characteristics and outcomes of a cohort hospitalized for pandemic and seasonal influenza in germany based on nationwide inpatient data multicenter initial guidance on use of antivirals for children with covid- / sars-cov- compassionate use of remdesivir for patients with severe covid- therapeutic options for the novel coronavirus ( -ncov) a trial of lopinavir-ritonavir in adults hospitalized with severe covid- we express our gratitude to all colleagues and research personnel involved in the data collection for this study, as well as the members of the human research ethics committees and institutional review boards that have kindly fast-tracked this study. we are also grateful for the kind support of the clinical microbiology & infectious diseases department and the covid- group at hospital general universitario gregorio marañón, madrid, spain. this project did not receive specific funding. ptbnet is supported by the deutsche gesellschaft für internationale zusammenarbeit. bs-g is funded by the spanish ministry of health-instituto de salud carlos iii and co-funded by the european union (feder; contrato juan rodés, grant jr / ). an-j was supported by "subvencions per a la intensificacio de facultatius especialistes"-departament de salut de la generalitat de catalunya, programa peris - (slt / / ).editorial note: the lancet group takes a neutral position with respect to territorial claims in published maps and institutional affiliations. key: cord- -l nfd a authors: cammarota, gianmaria; ragazzoni, luca; capuzzi, fabio; pulvirenti, simone; de vita, nello; santangelo, erminio; verdina, federico; grossi, francesca; vaschetto, rosanna; della corte, francesco title: critical care surge capacity to respond to the covid- pandemic in italy: a rapid and affordable solution in the novara hospital date: - - journal: prehospital and disaster medicine doi: . /s x sha: doc_id: cord_uid: l nfd a the rapid insurgence and spread of coronavirus disease (covid- ) exceeded the limit of the intensive care unit (icu) contingency plan of the maggiore della carità university hospital (novara, italy) generating a crisis management condition. this brief report describes how a prompt response to the sudden request of invasive mechanical ventilation (imv) was provided by addressing the key elements of health care system surge capacity from contingency to crisis. in a short time and at a relatively low cost, a structural modification of a hospital aisle allowed to convert the general icu into a covid- unit, increasing the number of covid- critical care beds by %. the coronavirus disease (covid- ) pandemic is now menacing several health systems across the globe. currently, italy has been one of the most affected countries where hospitals are still struggling to deal with the surge of patients. although the majority of patients experiences mild or poor symptoms, in % of cases, a severe acute respiratory failure (arf) may occur leading to intensive care unit (icu) admission. therefore, urgent actions are required to modify icu's capacity to deal with a massive influx of severe arf patients who require intubation. in this regard, the rapid expansion of operational staff, stuff, and structures is paramount for health care system surge capacity. moreover, it has been described that the categorization and implementation of different phases of surge capacity from conventional to contingency to crisis. , this brief report describes the strategy implemented in the maggiore della carità university hospital (novara, italy), the second largest third-level referral hospital of the piedmont region, to provide a prompt response to the steep growing demand for invasive mechanical ventilation (imv) in course of covid- pandemic. , structure figure a depicts the general icu set-up during normal routine: icu stations and a shock room with two dedicated positions for in-and out-of-hospital emergencies are all placed around a central unit for visual control and telemetry monitoring. while covid- was rapidly spreading in the northern italy, the icus were progressively converted into a dedicated, cohorted unit for covid- -positive patients requiring imv. in parallel, all non-covid- icu patients were gradually transferred to an eight-bay post-anesthesia care unit, which was adapted into a general icu. the activation of the hospital contingency plan for massive influx of patients established the interruption of deferrable surgical interventions and the adaptation of five operating rooms into covid- icu stations distributed in different hospital locations. all urgent procedures and non-deferrable oncological interventions were securely maintained. however, during the days, the number of patients with severe arf exceeded the limit of the contingency plan. to meet the unexpected needs, a crisis plan was designed and implemented under the supervision of building engineers. as shown in figure b , an aisle was transformed into an additional critical care area and connected to the principal icu covid- due to its proximity to the emergency department and the computer tomography scanner. lasting only four days of work at a cost of € , ($ , ), the project consisted in a structural modification of the aisle (ie, the realization of medical gases and vacuum supplying circuits, the ad hoc wiring configuration, the improvement of air recirculation system, and the installation of two main doors on both sides of the aisle for isolation). locked from inside, these doors allow patients admittance and discharge, and trash disposal. considering also the additional use of the shock room, this new configuration allowed the rapid creation of additional critical care stations enlarging the principal covid- icu to beds with a small sacrifice in ergonomic workspace. three beds were preserved in one operating room for stabilizing the suspected cases before the admission to the principal icu, where patients can only enter with a confirmed laboratory diagnosis of covid- . wearing personal protective equipment (ppe), icu staff can safely access the so-called "red zone" through a dedicated unidirectional entry/exit pathway (figure b) . within the aisle, all the new icu stations were equipped with standard intensive care equipment (ie, bed, monitor, ventilator, suctioning system, and syringe driver with the appropriate stand). moreover, additional critical care tools (ie, emergency cart, defibrillator, video-laryngoscope, disposable fiberscope, emergency cricothyroidotomy kit, chest drain set, ultrasound machine, refrigerator, and transport ventilator) were rapidly collected and stored in two dedicated areas (the so-called "lab") to allow their rapid accessibility from different zones of the icu (figure b) . the covid- icu was also equipped with an arterial blood gas analyzer, a machine for thromboelastographic assessment, a scialytic lamp, and an x-ray machine. the communication between the red zone and the control unit is allowed by telephones installed ad-hoc in the red zone. the installation of ceiling video cameras in the aisle allows the supervision of the clinical activities from the control unit. also, the icu staff can add clinical notes and make changes in patient therapies through a dedicated software installed on tablets connected to the control unit without exiting the red zone and removing the ppe. the strategy also included an increase of icu staff. while the general icu were progressively converted to covid- unit and the contingency plan was implemented, anesthesiologists, nurses, and other health care professionals, recruited from surgical teams, underwent a specific just-in-time training to improve technical skills in the application of ppe and in the clinical management of mechanically ventilated arf patients. furthermore, the staff was also trained to operate through a dedicated electronic medical records software. once the training had been completed, the new personnel were flanked with highly experienced icu staff ensuring a -day apprenticeship process. the staffing level was set with a : nurse-to-patient ratio and a : physician-to-patient ratio. however, being that the operating rooms converted into covid- icu stations, which were dispersed in different locations distant from the supervision of the control unit, the icu staff had significant difficulties to work as one team and to ensure the same level of care. the structural modification of the aisle eliminated these important limitations homogenizing staff competencies and patient care. the rapid insurgence and spread of covid- exceeded the limit of the icu contingency plan for massive influx of patients generating a crisis management condition. by addressing the key elements of health care system surge capacity from contingency to crisis, a prompt response to the sudden request of imv was provided, converting the general icu into a covid- unit and increasing the number of covid- icu beds by %. in a short time and at a relatively low cost, the structural modification of the aisle allowed to simplify the supervision of the clinical activities and increased the level of quality of care with only a small reduction in ergonomic workspace. correspondence estimation of covid- outbreak size in italy characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention surge capacity for healthcare systems: a conceptual framework refining surge capacity: conventional, contingency, and crisis capacity translating covid- pandemic surge theory to practice in the emergency department: how to expand structure critical care response to a hospital outbreak of the -ncov infection in shenzhen intensive care during the coronavirus epidemic the authors wish to thank all the physicians, nurses, and health operators for their contributions to face covid- outbreak in novara, italy. key: cord- -f hxpat authors: wahlster, sarah; sharma, monisha; lewis, ariane k.; patel, pratik v.; hartog, christiane; jannotta, gemi; blissitt, patricia; kross, erin k.; kassebaum, nicholas j.; greer, david m.; curtis, j. randall; creutzfeldt, claire j. title: the covid- pandemic’s impact on critical care resources and providers: a global survey date: - - journal: chest doi: . /j.chest. . . sha: doc_id: cord_uid: f hxpat background the covid- pandemic has severely impacted intensive care units (icus) and critical care healthcare providers (hcps) worldwide. research question how do regional differences and perceived lack of icu resources affect critical care resource utilization and the well-being of hcps? study design and methods between april rd-may th , we electronically administered a -question survey to interdisciplinary hcps caring for critically ill covid- patients. the survey was distributed via critical care societies, research networks, personal contacts, and social media portals. responses were tabulated by world bank region. we performed multivariate log-binomial regression to assess factors associated with three main outcomes: ) limiting mechanical ventilation (mv), ) changes in cardiopulmonary resuscitation (cpr) practices, and ) emotional distress or burnout. results we included respondents from countries, including physicians ( %), nurses ( %), respiratory therapists ( %) and advanced practice providers ( %). the reported lack of icu nurses was higher than that of intensivists ( % vs %). limiting mv for covid- patients was reported by % of respondents, was lowest in north america ( %), and was associated with reduced ventilator availability (arr: . , % ci: . - . ). overall, % of respondents reported changes in cpr practices. emotional distress or burnout was high across regions ( %, highest in north america), and associated with female gender (arr: . , % ci: . - . ), being a nurse (arr: . , % ci: . - . ), reporting a shortage of icu nurses (arr: . , % ci: . - . ) and powered air-purifying respirators (paprs) (arr: . % ci: . - . ), as well as experiencing poor communication from supervisors (arr: . , % ci: . - . ). interpretation our findings demonstrate variability in icu resource availability and utilization worldwide. the high prevalence of provider burnout, and its association with reported insufficient resources and poor communication from supervisors suggest a need for targeted interventions to support hcps on the front lines. as of august th , the covid- pandemic has resulted in , , confirmed cases worldwide and taken , lives in countries , . with - % of hospitalized covid- patients requiring admission to an intensive care unit (icu) [ ] [ ] [ ] , and - % of critically ill covid- patients requiring mechanical ventilation [ ] [ ] [ ] [ ] , icus around the world have been facing major challenges, including determining the appropriate allocation of resources and balancing the care of covid- and other critically ill patients, while having to restructure workflows and ensure the safety of patients, their families, and healthcare providers (hcps). a better characterization of the pandemics' effects on icu resources (" s: staff, space, stuff" ) and on hcps worldwide is important to identify strategies to support healthcare systems across the world in surmounting this crisis, as well as potential future disasters when rationing of resources may be necessary. with this international survey, we aimed to rapidly assess key concerns of interprofessional hcps on the front lines caring for critically ill covid- patients. negated this question (n= ) were excluded from the analysis, along with particpants who completed only demographic information (n= ). the survey was distributed electronically between april rd -may th , with the intention to capture data during or close to the time of peak surges in many countries. hcps were reached via the following strategies: ( ) patients in the icu were invited to participate and asked to distribute the survey to their colleagues; and ( ) we distributed the link on social media platforms (twitter and facebook) and shared it within intensive/critical care forums focusing on covid- that required medical credentials to approve members. posts were sharable to facilitate widespread distribution. we chose this convenience sampling approach to reach a large number of hcps worldwide in a short time period, accepting that we would not be able to gauge an accurate individual response rates due to various dissemination mechanisms (e.g. critical care societies j o u r n a l p r e -p r o o f sharing the link on various websites and social media portals), and had limited ability to confirm how many respondents saw or received the link within these forums. countries were categorized by world bank region: east asia/pacific (ea/p), europe/central asia (e/ca), latin america/caribbean (la/c), middle east/north africa (me/na), north america (na), south asia (sa), sub-saharan africa (ssa). we categorized countries into pre-/peri-/post-peak of deaths per day , , and calculated an indicator of how much a country was affected by covid- at the time of survey administration ('severity index,' supplementary table ) using the average daily death rate by population , . mortality was chosen as a surrogate for peak and severity index instead of incidence, as mortality is less confounded by testing availability and serves as an indicator of disease burden on icus. descriptive statistics were used to report respondent characteristics and survey outcomes. we utilized univariate binomial regression to assess associations between region, provider type and pre-specified outcomes of interest. we conducted multivariate log-binomial regression to assess predictors of three main outcomes: ) limiting the use of mechanical ventilation (mv) for covid- patients; ) changing policies or practices of cardiopulmonary resuscitation (cpr); and ) reporting emotional distress and burnout. these outcomes were selected as surrogates for icu resource utilization ( and ) and the psychological burden of the pandemic on hcps ( ). exposures considered included provider type, gender, perceived lack of resources (organized by j o u r n a l p r e -p r o o f s: "staff, space, and stuff" ), time from covid- peak, and severity index. exposures that were statistically significant in the univariate regression were considered for inclusion in the multivariate model. we performed a complete case analysis; respondents with missing data were removed from regressions. analyses were conducted using r software - . we identified and approached contacts in countries and received , responses from countries; , respondents from countries were included in the analysis ( % of countries contacted, figure a ). hcps within china reported being unable to access the survey link. reasons for excluding responses are outlined in figure s . detailed respondent characteristics by world bank region are displayed in table . the majority of respondents were from north america ( %) and europe/central asia ( %). the top responding countries (with > respondents per country) were: united states, united kingdom, italy, japan, australia, and germany. survey respondents were: physicians ( %), nurses ( %), rts ( %), and apps ( %). most participants reported working in urban, large teaching hospitals ( %), and % were female. among the ( %) respondents who opted to disclose their institution, different institutions were reported. most respondents listed critical care medicine as a subspecialty ( % of attending physicians, % of physicians in training, % of nurses, table s ). overall, % of respondents (n= ) completed all survey questions. tables and s summarize perceived lack of resources, changes in clinical practice, and hcps concerns by region. while % of respondents reported insufficient numbers of j o u r n a l p r e -p r o o f intensivists to care for critically ill covid- patients, % reported insufficient numbers of icu nurses. regions with the highest report of insufficient numbers of intensivists were sub-saharan africa ( %) and latin america/caribbean ( %), compared to north america ( %). the highest report of insufficient numbers of icu nurses was in south asia ( %) and europe/central asia ( %), compared to north america ( %). figure b and c display the proportion of respondents reporting shortages of intensivists and nurses by country. shortages of icu beds were reported by % of respondents (ranging from % in north america to % in south asia) to care for critically ill covid- patients (figure d ), and by % (ranging from % in north america to % in latin america/caribbean) for other patients requiring icu care. figure s displays reported measures that were implemented to mitigate the impact of icu bed shortages, including the conversion of post-op recovery rooms (reported by %), and operating rooms ( %). testing: the sars-cov -rt-pcr was available for all patients according to % of respondents, and for 'select patients based on symptoms' according to % (table s ). for hcps, the test was available for all according to % of respondents, and for 'select hcps based on symptoms and area of work' according to %. among the respondents that reported testing was available, % indicated that it required hospital approval. few respondents reported absence of testing capabilities for patients ( . %) or hcps ( %). personal protective equipment (ppe): surgical masks and gloves were reported to be 'always available' according to % and % of respondents respectively. other ppe was generally restricted to select hcps or hcps caring for patients with certain characteristics ( figure a ): n masks ( % available for all hcps, % restricted); dedicated eye protection ( % and %); face shields ( % and %). the largest shortage was reported for powered air purifying respirators (papr, % available for all and % restricted), with % of respondents reporting a complete lack of papr in their hospital (least in north america at %). one in four respondents ( %) felt that their hospital's policy on ppe was not appropriate or safe (table s ) one in ( %) respondents reported limiting the use of mv in covid- patients based on clinical severity ( %), comorbidities ( %), age ( %) or health insurance or financial means ( %). in the multivariate regression, the likelihood of limiting mv was - times higher in all other world regions compared to north america (table a) , highest in settings where a lack of ventilators was reported (arr: . , % ci: . - . ), and marginally associated with lack of paprs and caring for > covid- patients. shortages of intensivists, nurses, and icu beds were univariately associated with limiting mv, but these associations disappeared (arr close to ) after adjusting for other covariates. changes in cpr practices due to covid- were reported by % of respondents, with % reporting implementation of a new policy. in multivariate analyses, changes in cpr policy/practices were significantly lower in europe/central asia compared to north america (arr: . , % ci: . - . ), and were not associated with shortage of staff, icu beds, or resources (table b ). the percentage of respondents who reported not performing cpr at all in covid- patients varied by region (from % north america to % in sub-saharan africa). a number of factors were considered when deciding prospectively whether to perform cpr, including: clinical severity ( % of respondents), comorbidities ( %), and patient age ( %). among j o u r n a l p r e -p r o o f those who do perform cpr, respondents were split in their practices whether to base the decision on family or surrogate wishes vs physician determination. north america was the only region in which most respondents ( %) overall, % felt that palliative care consultations have increased during the pandemic ( % in north america vs. % in europe/central asia). the most common concerns among hcps included transmitting infection to their families ( %), emotional distress/burnout ( %), concerns about their own health ( %), and experiencing social stigma from their communities ( %). all hcps concerns were highest in north america. a substantial minority ( %) expressed worries about their financial situation, most commonly in latin america/caribbean ( %) and south asia ( %). most hcps ( %) stated that caring for covid- patients was mandatory at their institution. when not in the j o u r n a l p r e -p r o o f hospital, % of hcps reported relocating to a separate residence from their families to protect them, and an additional % reported taking extra precautions while at home (table s ) . in multivariate regression, emotional distress and burnout was significantly associated with female gender (arr: . , % ci: . - . ) and being a nurse (arr: . ( % ci: . - . ) ( table ). compared to providers who had cared for < covid- patients, those who had cared for - and > patients had a % and % higher risk of burnout, respectively. pandemic severity or time from peak within a respondent's country were not associated with burnout. providers experiencing poor communication from their supervisors had a % higher likelihood of reporting burnout ( % ci: . - . ). limited availability of papr and shortages of nurses were associated with a % and % increased risk of burnout, respectively. providers in europe/central asia were % less likely to report burnout compared to providers in north america ( % ci: . - . ). in this global survey of icu providers during the covid- pandemic, shortages of icu staff and resources were frequently reported, as were emotional distress and burnout. participants reported that the pandemic has changed practices around mv and cpr, in part based on resource availability. in addition, over half of the respondents reported concerns about their own health and their families' health. finally, our results highlight substantial variation across regions. for example, providers in north america reported higher levels of emotional distress or burnout, despite reporting fewer shortages of resources, and were also more likely to base cpr and other critical decisions on family wishes compared to other world regions. our results, which underscore the psychological burden on hcps, complement recent reports about provider wellbeing from china, italy, and the united states amidst the pandemic [ ] [ ] [ ] [ ] , as well as studies before the pandemic ( - % burnout rates across various types of icu providers) [ ] [ ] [ ] [ ] . we found modifiable and non-modifiable predictors of burnout that may inform targeted interventions to improve provider experiences and protect their mental well-being. first, across all regions, female hcps and nurses were more likely to experience burnout. second, provider burnout was independently associated with having cared for a larger number of covid- patients. interestingly, we did not find an association between pandemic severity and burnout. this likely indicates that the number of covid- patients an individual has cared for is a more reliable predictor of this individual's experiences than the number of covid- patients in a given region. finally, burnout was associated with reporting a shortage of icu nurses, insufficient papr availability and poor communication from supervisors. another recently published survey of , icu clinicians from the us found that the perceived need for both ppe masks and icu staffing shortages exceeded all other resource challenges . further analysis j o u r n a l p r e -p r o o f of our data showed that insufficient access to ppe was the strongest predictor of all provider concerns in the us (data not shown). communication in the covid- era poses a major challenge, given the need to constantly adapt and implement new policies while remaining transparent to all affected hcps. strengths of this study include its large sample size consisting of interprofessional hcps at the front line of the pandemic in countries. furthermore, it was conducted during a time when many countries were severely affected by covid- , and we were able to capture the highest number of responses in many of the most affected countries (based on case numbers, mortality and case fatality rates). to our knowledge, this is the first global survey to comprehensively assess of the pandemic's impact in regard to icu resources, practices and provider well-being. several limitations need to be considered. first, the lack of a clearly defined sample introduces a substantial risk of response and sampling bias. we specifically targeted our distribution strategy to reach hcpsworking in icus, but our convenience sampling approach may have limited the generalizability of our results. also, since the survey was anonymous, we cannot exclude the possibility that respondents took the survey more than once. second, the majority of respondents were from north america and europe/central asia, with low representation from low/middle income countries (lmics). future studies will need to specifically target lmics to assess covid- 's effects in the context of resource-constrained health systems. third, our survey was only available in english, and language barriers might have resulted in inaccurate responses and contributed to low numbers of participants in some countries. additionally, responses reflect the views of individual respondents but may not be representative of all hcps in any given country, particularly in countries with few participants. fourth, respondents were mostly from large urban centers, which are likely to have more resources than rural hospitals. however, these regions were also hardest hit in the covid- pandemic. fifth, reported practices during covid- are rapidly changing as icus and hcps continue to adjust to the burden imposed by the pandemic, so responses might differ within the -day time window in which the survey was distributed. also, practices captured in this survey were perceived by the respondents rather than reflecting actual practices. sixth, changes in cpr practices might not purely reflect icu resource utilization, but rather represent measures to ensure the safety of hcps. finally, practice differences within regions, such as involving families in decision-making or limiting life-sustaining therapy, likely reflect cultural and medicolegal differences rather than a differential effect of the pandemic . our findings suggest an important need to create collaborative strategies for ventilatory support in resource limited settings, in particular in anticipation of surges affecting lmics , as well as repeated surges in countries that are currently relaxing their strict measures to mitigate spread. finally, our study emphasizes the personal sacrifices by hcps, especially nurses, on the front lines worldwide, and the need to proactively support them by implementing interventions to promote mental health and well-being. covid- has significantly impacted icu practices, resources and staff. across all regions, the reported lack of icu nurses was higher than that of intensivists, and the use of standard diagnostic tests has been largely limited in covid- patients. high rates of provider emotional distress and burnout are reported across geographic regions. guarantor statement: on behalf of all authors, the corresponding author affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. drs. wahlster, patel, sharma and creutzfeldt had full access to all of the data and take responsibility for the integrity of the data and the accuracy of the data analysis. all authors contributed substantially to the study design, data acquisition and analysis, as well as interpretation. drs. sharma and kassebaum performed the statistical analysis. drs. wahlster and creutzfeldt wrote the manuscript and all authors edited the manuscript. the authors declare no financial disclosures or conflicts of interest. funding sources: the authors of this paper received no direct funding for this publication. ms received support from nimh k mh . ch reports current funding by the federal joint committee innovation funds fkz vsf . cc is supported by ninds ns . we would like to thank all of our colleagues around the world who have taken the time to participate in our survey while being very busy caring for patients in the intensive care unit. we would like to thank the following societies and groups for collaborating in distributing the surveys to their memberships and supporting our study: wficc (drs. janice j o u r n a l p r e -p r o o f tables (below): table : respondent characteristics (all and by world bank region) table summary of data by region table univariate and multivariate predictors of a) limiting mechanical ventilation and b) changes in cpr policy table : univariate and multivariate predictors of emotional distress and burnout mean ( j o u r n a l p r e -p r o o f j o u r n a l p r e -p r o o f † severity index: daily deaths by population during the time of survey administration. physicians in training include residents and fellows. time from peak (mortality) was not associated with outcomes in univariate or multivariate regressions (data not shown). variables not statistically associated with the outcomes in univariate regression or whose inclusion did not improve model fit were not included in the multivariate regression. number of observations for multivariate regressions: mechanical ventilation limited: n = , ; cpr and dnr policies/practice changed since covid- : n = , ; emotional distress and burnout: n = , ." j o u r n a l p r e -p r o o f j o u r n a l p r e -p r o o f slide these is for all respondents, can make regional ones for the supplement british association of critical care nurses (baccn), bangladesh society of critical care medicine, cambia health foundation thai critical care society. we would also like to acknowledge the following colleagues for their input and support in reviewing, testing instituto nacional ciencias neurologicas roop gursahani (hinduja hospital saef izzy (brigham and women's hospital) who coronavirus disease (covid- ) dashboard. accessed johns hopkins coronavirus resource center clinical characteristics of coronavirus disease in china clinical features of patients infected with novel coronavirus in wuhan, china presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area covid- in critically ill patients in the seattle region -case series baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study definitive care for the critically ill during a disaster: current capabilities and limitations: from a task force for mass critical care summit meeting the strengthening the reporting of observational studies in epidemiology (strobe) statement: guidelines for reporting observational studies ihme | covid- projections. institute for health metrics and evaluation world population prospects -population division -united nations mental health outcomes among frontline and second-line health care workers during the coronavirus disease (covid- ) pandemic in italy factors associated with mental health outcomes among health care workers exposed to coronavirus disease critical care clinician reports on coronavirus disease : results from a national survey of , icu providers report high stress in covid- response. society of critical care medicine (sccm) coronavirus disease pandemic measures: reports from a national survey of , icu clinicians nurse burnout in critical care units and emergency departments: intensity and associated factors burnout syndrome in critical care nursing staff communication satisfaction and job satisfaction among critical care nurses and their impact on burnout and intention to leave: a questionnaire study changes in end-of-life practices in european intensive care units from managing covid- in low-and middle-income countries key: cord- -m h hgpb authors: wang, hanyin; poehler, jessica l.; ziegler, jenna l.; weiler, chad c.; khan, syed anjum title: patient care rounds in the intensive care unit during covid- date: - - journal: jt comm j qual patient saf doi: . /j.jcjq. . . sha: doc_id: cord_uid: m h hgpb nan hanyin wang, md ; jessica l. poehler, rn ; jenna l. ziegler, rn ; chad c. weiler, rn ; syed anjum khan, md the situation has posed a considerable difficulty for patient care rounds in the icu. multidisciplinary bedside icu rounds provide a key stage for providers to review patient conditions and communicate a plan of care. given the complex nature of icu patients, who frequently cannot make medical decisions, daily rounds are used to engage family in patient care. , with a visitor restriction policy, families of critically ill patients feel huge anxiety, guilt, and frustration. families are calling icu hours a day, crying and wanting information about their loved ones. another major issue is that families are receiving bits and pieces of information at different times. sometime they perceived mixed messages especially after shift changes or handoffs. the emotional and physical tone of the covid- epidemic is already a huge burden on the staff. on top of that they feel the needs of families are not met. a creative solution for icu rounds is needed in the covid- era. evidence has shown success of telemedicine for icu care. , our hospital recently implemented a telemedicine model for icu rounds that is well perceived by the icu team and patient families. first, providers with direct patient care (including an intensivist physician, midlevel provider, nurse, and respiratory therapist) perform bedside patient evaluations separately before rounds. second, all care team members (including a pharmacist, nutritionist, physical therapist, speech therapist, social worker, charge nurse, and e-icu) call in to an encrypted video conference system at a standard time. the patient"s pre-appointed family member is connected into the conference through a different phone line. third, telerounding is led by a physician following the usual rounding process where the patient"s nurse summarizes overnight events and goes over the icu checklist, followed by each participant giving their recommendation. during virtual rounds, a dedicated staff is assigned to review electronic medical records for any questions and place new orders. family stays on the line for the entire rounds for their loved one, which usually takes minutes. for families with limited english proficiency, a real-time interpretation service is utilized for communication. in the end the physician summarizes key information to the family and answers their questions. if questions remain or other concerns arise, the provider calls the family after rounds. a sample icu daily rounds scripts is provided in the appendix. as a next step, we plan to engage patients in the rounds as appropriate, using a robotic telepresence system. another novel use of the icu rounds being explored by the icu team is student clerkships which were cancelled during the epidemic. this is greatly impacting education for medical students. we are exploring the possibility of providing medical student participation during icu rounds, which would be a huge learning experience in critical care and management of covid- patients. in this challenging time, we hope experience from our center helps the international critical care community to plan for an effective rounding strategy using telemedicine. the authors have no conflicts of interest. a survey of rounding practices in canadian adult intensive care units families" perception of the value of timed daily "family rounds" in a trauma icu a heart-wrenching thing": hospital bans on visits devastate families tele-icu: experience to date robotic telepresence: a helpful adjunct that is viewed favorably by critically ill surgical patients medical students can help combat covid- . don"t send them home key: cord- - lsnv g authors: craig, j.; kalanxhi, e.; osena, g.; frost, i. title: estimating critical care capacity needs and gaps in africa during the covid- pandemic date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: lsnv g objective the purpose of this analysis was to describe national critical care capacity shortages for african countries and to outline needs for each country to adequately respond to the covid- pandemic. methods a modified secir compartment model was used to estimate the number of severe covid- cases at the peak of the outbreak. projections of the number of hospital beds, icu beds, and ventilators needed at outbreak peak were generated for four scenarios (if , , , or % of patients with severe covid- symptoms seek health services) assuming that all people with severe infections would require hospitalization, that . % would require icu admission, and that . % would require mechanical ventilation. findings across the countries included in this analysis, the average number of severe covid- cases projected at outbreak peak was per , (sd: . ). comparing current national capacities to estimated needs at outbreak peak, we found that of countries ( %) do not have a sufficient number of hospital beds per , people if % of patients with severe infections seek out health services and assuming that all hospital beds are empty and available for use by patients with covid- . if only % of patients seek out health services then of countries ( %) do not have sufficient hospital bed capacity. the average number of icu beds needed at outbreak peak across the included countries ranged from per , people (sd: . ) when % of people with severe covid- infections access health services to . per , (sd: . ) assuming % of people seek out health services. even if only % of severely infected patients seek health services at outbreak peak, then of countries ( %) do not have a sufficient number of icu beds per , people to handle projected need. only four countries (cabo verde, egypt, gabon, and south africa) have a sufficient number of ventilators to meet projected national needs if % of severely infected individuals seek health services assuming all ventilators are functioning and available for covid- patients, while other countries require two or more additional ventilators per , people. the majority of countries lack sufficient icu bed and ventilator capacity to care for the projected number of patients with severe covid- infections at outbreak peak even if only % of severely infected patients seek health services. this analysis reveals there is an urgent need to allocate resources and increase critical care capacity in these countries. the covid- pandemic is rapidly emerging across the african continent with over , confirmed cases and over , deaths as of june (world health organization). overall disease prevalence has taken longer to accelerate in growth compared to other regions; however, most african countries are now reporting community transmission, and several countries have started to see week-on-week exponential increases in confirmed cases (dong). estimates of covid- incidence and mortality rates are complicated by low testing capacity in many countries, and it has been suggested that covid- deaths are being under-reported in some areas (kavanagh; maclean) . previous assessments of health systems and critical care capacity, including a covid- readiness survey conducted by the world health organization in march , suggest many african countries are not adequately equipped to cope with surges in demand for hospital beds, intensive care unit (icu) beds, and mechanical ventilators (world health organization). critical care capacity, needs, and overall covid- pandemic readiness in africa remain unclear. a more complete understanding of covid- and local case burden patterns is also needed, given that most countries are at the beginning of their respective outbreaks. measures taken by other countries to mitigate covid- transmission, such as curfews and lockdowns, may not be feasible or effective across africa given various social, economic, political, and demographic factors such as high population density in urban cities, slums, and refugee camps; high proportion of the workforce employed in the informal sector, and high rates of poverty (partnership for evidence-based response to covid- ; hopman; international labour organization). as a result, it has been predicted that the covid- case burden may, at present and in the long term, be higher across africa than in high-income countries (wells; world health organization) . assessing current national health system capacities and future needs in the covid- pandemic context is challenging given the lack of publicly available data. this is further complicated by uncertainties and differences in care-seeking behaviour across the continent. in some cases, even where hospital facilities are available, they may be underutilised due to affordability or safety concerns (nwankwo; wambui) . despite uncertainties around disease transmission and challenges in assessing health systems needs, estimates are essential for public health planners and policymakers to make evidence-based decisions on the distribution of resources in the coming months as covid- progresses across africa. in a previous study, we compiled a database describing various aspects of critical care capacity in africa as relevant to the covid- pandemic (craig). separately, we utilized a previously described secir compartment model to estimate cumulative and peak case burden in all african countries (center for disease dynamics, economics, & policy). in this paper, we combine these analyses and use the best available data on current critical care capacity for african countries and projections for peak case burden to describe national capacity shortages and outline needs for each country to adequately respond to the pandemic. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint data on essential components of critical care capacity relevant to covid- treatment, such as number of hospital beds, icu beds, and ventilators were compiled from various sources including published governmental and non-governmental reports, scientific literature, local and international media, and in-country informants including government or public health officials and other local researchers and healthcare workers, as previously described (craig). a modified susceptible -exposed -contagious -infected -recovered (secir) compartment model was used to predict national covid- case burden for african countries based on current case data and lockdown interventions (dong). the model's parameters and assumptions have been previously described (center for disease dynamics, economics, & policy). briefly, model parameters include a basic reproductive number of . , an incubation period of three days, and a six percent rate of progression to severe disease. in addition, the model assumes an asymptomatic clearance period of days and a symptomatic clearance period of days. duration and timing of lockdown interventions by country were obtained from a review of local and international news media, and country and diplomatic mission reports. peak estimates were based on the assumption that lockdowns decreased covid- transmission by %, and, after lockdown was lifted, disease transmission returned to % of the pre-lockdown value. the parameters used to estimate severe cases in africa were based on hospitalisation rates in regions where most data on covid- epidemiology was available (lin; liu; bi; j. l. wu). the impact of age and comorbidities are not explicitly included in the model but are contained as a function of the estimated number of people who will have severe disease. we estimated the number of hospital beds, icu beds, and ventilators needed during the peak of each country's respective covid- outbreaks assuming changes to disease transmission under the lockdown scenario described above. it was assumed that all people with severe covid- infections would require hospitalization, that . % of severe cases would require icu admission, and that . % of severe cases would require mechanical ventilation (guan; european centre for disease prevention and control; emami; team, severe outcomes among patients with coronavirus disease (covid- ) -united states, february -march , ). the number of cases in need of hospital beds was derived by subtracting the number of cases in need of icu beds from the total number of cases assumed to require hospitalization. given that access to and utilization of health services may be limited across the continent and that patients may opt for home treatment versus inpatient care, we generated estimates of hospital bed, icu bed, and ventilator needs and gaps for four scenarios assuming that , , , . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . or % of patients with severe covid- symptoms will seek health services (akpunne; naanyu; aantjes; hopkins). comoros and lesotho were excluded from all analyses due to lack of covid- case data. dependent territories in the africa region were also excluded. due to lack of data on current national capacities, gaps in hospital bed capacity at outbreak peak were not calculated for two countries (eswatini and south sudan), for icu bed capacity for four countries (benin, equatorial guinea, madagascar, and mozambique), and gaps in ventilator capacity were not calculated for six countries (benin, republic of the congo, eritrea, malawi, mauritius, and the seychelles). however, hospital bed, icu bed, and ventilator needs at outbreak peak were still estimated for these countries. across the countries included in this analysis, the average number of severe covid- cases projected at outbreak peak was per , (standard deviation [sd]: . ) and ranged from per , in sao tome and principe and egypt to per , in equatorial guinea and uganda (appendix ). the average number of hospital beds needed at the peak of respective national covid- outbreaks across countries assuming % of infected patients with severe symptoms seek out health services was . beds per , people (sd: . ) ranging from . per , in egypt to . beds per , in equatorial guinea. the average number of hospital beds needed at the peak of the outbreak was . (sd: . ), . (sd: . ), and . (sd: . ) per , people assuming only , , and % of infected patients seek health services, respectively. hospital bed needs and gaps at the peak of respective national covid- outbreaks are fully described in appendix . comparing current national capacities to estimated needs at outbreak peak, we found that of countries ( %) do not have a sufficient number of hospital beds per , people if % of patients with severe infections seek out health services; if only % of patients seek out health services then of countries ( %) do not have sufficient capacity (figure ). (these estimates assume that all hospital beds are empty and are available for use by patients with mali, madagascar, senegal, niger, and guinea have the largest gap between current hospital bed capacity and predicted need during outbreak peak under the scenario when only % of people with severe covid- infections seek out health services; our findings suggest that senegal, niger, and guinea required more than , additional hospital beds and mali and madagascar more than , additional hospital beds. if % of people with severe infections seek health . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint services at outbreak peak, then each of those countries would require over , additional hospital beds. the average number of icu beds needed at outbreak peak across the included countries ranged from per , people (sd: . ) when % of people with severe infections access health services to . per , (sd: . ) assuming % of people seek out health services. icu bed need at peak was highest in equatorial guinea and uganda and lowest in egypt and sao tome and principe. if % of severely infected patients seek health services at outbreak peak, then of countries ( %) do not have a sufficient number of icu beds per , people to handle projected need (figure ). if % of patients with severe covid- infections seek health services, only countries (botswana, egypt, cameroon, gabon, mauritius, and seychelles) have sufficient icu bed capacity per , to care for covid- patients assuming all icu beds are available while other countries ( %) need more than additional icu beds per , people to adequately care for severely infected covid- patients at the peak of the outbreak. predicted needs and gaps in icu bed capacity at the peak of respective national covid- outbreaks are fully described in appendix . in order to meet the projected icu bed needs at outbreak peak if % of severely infected patients seek health services, our findings suggest drc and ethiopia require approximately , additional icu beds while nigeria would need over , additional beds. across the countries, the average number of ventilators needed when there is a peak number of severe infections ranged from . per , (sd: . ) assuming % of severely infected people seek health services to . per , (sd: . ) assuming % of severely infected people seek health services. projected needs and gaps in current ventilator capacity are fully described in appendix . if % of severely infected individuals seek health services, then only four countries (cabo verde, egypt, gabon, and south africa) have a sufficient number of ventilators to meet national needs, assuming all ventilators are functioning and available for covid- patients, while other countries require two or more additional ventilators per , people. assuming only % of people with severe covid- infections seek health services, then of ( %) still lack sufficient ventilator capacity to respond to projected need at outbreak peak. gaps in current capacity and projected need for the other countries are summarized in figure . guinea-bissau, mali, and mauritania have the highest gaps when comparing the current number of ventilators per , people to projected peak need under all health access scenarios. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . to date, this is the most comprehensive assessment of critical care gaps and needs across african countries under covid- pandemic conditions. however, this analysis has several limitations. first, national critical care estimates may, in some instances, over-or under-represent the true critical care capacity of a country (i.e. estimates from government published reports may only reflect critical care capacity at public sector health facilities designated to care for covid- patients, excluding those from the private sector). in addition, since information on critical care components were collected from different sources and represented estimates from different time points, the number of hospital beds may include a proportion of available icu beds. peak estimates are generated from an secir model which assumes populations are well-mixed and this can lead to overestimation of the peak need. we assume that all hospital beds, icu beds, and ventilators are functioning and available exclusively for people with covid- infections, an assumption which is unlikely to reflect reality. anecdotally, healthcare workers from multiple african countries report that health facilities are seeing significantly fewer patients compared to pre-pandemic months as patients face increased challenges accessing health services or fear becoming infected with the virus at a health facility. data on hospital bed, icu bed, and ventilator distribution were unavailable, and this analysis assumes that they are evenly distributed across populations; in reality, healthcare infrastructure is typically clustered in capital cities and other urban centers (okafor; hoeven; oloyede; world health organization) . in addition, the number of hospital beds, icu beds, and ventilators may not reflect the quality of healthcare; however, these are useful indicators for gauging the capacity of a healthcare system. model assumptions and variations in testing rates across the different countries may partially explain some of the differences between projected and reported cases. estimation of disease severity across africa comes with the challenges of accounting for multiple factors that could have negative or positive effects in the progression of the outbreak. for example, a relatively young population structure could mean that the percentage of severe covid- cases will be lower than that estimated from data from china, europe, and the us as old age has been shown to be an important risk factor for both disease severity and mortality (cdc covid- response team; j. l. wu; cohen). however, despite having a younger population, factors such as high incidence of immunocompromising diseases, malnourishment and limited access to healthcare may increase the vulnerability of the population towards covid- . needs and gaps in current critical care capacity described here consider only the projected burden from those with severe covid- infections. however, the pandemic and subsequent measures to mitigate disease transmission will likely impact all aspects of national health systems; for instance by disrupting bednet campaigns against malaria, reducing access to antiretroviral therapies (art), and stifling essential supply chains thereby potentially increasing malnutrition rates (who africa). it is important to consider that the pandemic is likely to further increase demand for non-covid- health services and will further exacerbate existing gaps in health systems capacities (hogan; anthem). . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . despite the limitations related to these estimates, the overall analysis reveals a lack of coping capacity in the face of the covid- pandemic for many african countries and highlights the immediate need for investment in critical care infrastructure. although the disease seems to be progressing at a slower rate across the african continent, it is predicted to persevere in the coming months, and therefore, rapid improvement of critical care capacity could assist in the treatment of those with severe infections, not only during the current pandemic wave but in the likely second and third waves (world health organization africa). furthermore, for countries where national critical care capacities may be adequate, ensuring equitable access across demographies, geographical locations, and socioeconomic classes is imperative. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint access to lifesaving medical resources for african countries: covid- testing and response, ethics, and politics explaining the bomb-like dynamics of covid- with modeling and the implications for policy characteristics and associations with severity in covid- patients: a multicentre cohort study from jiangsu province, china covid- outbreak in nigeria is just one of africa's alarming hot spots keeping covid- at bay in africa childbirth is not a sickness; a woman should struggle to give birth": exploring continuing popularity of home births in western kenya factors influencing underutilization of government owned health facilitise in mbaukwu community of anambra state, nigeria challenges in critical care services in sub-saharan africa: perspectives from nigeria rural-urban disparities in health and health care in africa: cultural competence, lay-beliefs in narratives of diabetes among the rural poor in the eastern cape province of south africa new who estimates: up to people could die of covid- in africa if not controlled responding to covid- in africa: using data to find a balance severe outcomes among patients with coronavirus disease (covid- ) -united states determinants of health seeking behavior among caregivers of infants admitted with acute childhood illnesses at kenyatta national hospital covid- on the african continent covid- could deepen food insecurity, malnutrition in africa new who estimates: up to people could die of covid- in africa if not controlled who african region covid- readiness status v estimating clinical severity of covid- from the transmission dynamics in wuhan, china nowcasting and forecasting the potential domestic and international spread of the -ncov outbreak originating in wuhan, china: a modelling study key: cord- -zeaqi uc authors: al-ani, fatimah; chehade, samer; lazo-langner, alejandro title: thrombosis risk associated with covid- infection. a scoping review date: - - journal: thromb res doi: . /j.thromres. . . sha: doc_id: cord_uid: zeaqi uc background: infection by the novel coronavirus (covid- ) has been reportedly associated with a high risk of thrombotic complications. so far information is scarce and rapidly emerging. methods: we conducted a scoping review using a single engine search for studies assessing thrombosis and coagulopathy in covid- patients. additional studies were identified by secondary review and alert services. results: studies reported the occurrence of venous thromboembolism and stroke in approximately % and % of patients, respectively. a higher frequency seems to be present in severely ill patients, in particular those admitted to intensive care units. the thrombotic risk is elevated despite the use of anticoagulant prophylaxis but optimal doses of anticoagulation are not yet defined. although and increase of biomarkers such as d-dimer has been consistently reported in severely ill covid- , the optimal cut-off level and prognostic value are not known. discussion: a number of pressing issues were identified by this review, including defining the true incidence of vte in covid patients, developing algorithms to identify those susceptible to develop thrombotic complications and severe disease, determining the role of biomarkers and/or scoring systems to stratify patients' risk, designing adequate and feasible diagnostic protocols for pe, establishing the optimal thromboprophylaxis strategy, and developing uniform diagnostic and reporting criteria. the world health organization (who) declared the novel coronavirus (sars-cov- ) a pandemic on march , . the number of confirmed cases as of may are over . million with over , confirmed deaths (https://www.who.int) . up to % of infected patients sustain interstitial pneumonia, and may evolve to acute respiratory distress syndrome requiring intensive care unit (icu) admission, and may be accompanied by multiorgan failure . recent findings from a pooled analysis suggested a prominent increase in d-dimer levels as a predictor of adverse outcomes was persistently seen in coronavirus disease (covid- ) suggesting the presence of underlying coagulopathy . there is an increasing evidence that severe covid- seems to be associated with pro-hemostatic state with a potential impact on thromboembolism risk, but the nature and extent of these abnormalities is not clear. given the rapid emergence of new evidence we sought to conduct a scoping review of coagulopathy and thrombosis risk associated with covid- infection with the aim of providing an overview of the current knowledge on this topic and potentially inform new areas of research. the review is registered in open science framework and the study protocol is publicly available (https://osf.io/zm gk/). we conducted a literature search using a single search engine through j o u r n a l p r e -p r o o f mg/l in the survivors (p< . ) . similarly, zhou et al. (n= ) reported a significantly higher d-dimer of around -fold was seen in non-survivors as compared to survivors with severe disease ( % vs. %; p< . ) . furthermore, tang et al. reported similar findings with a higher d-dimer being seen in non survivors (n= ) ( . [ . - . ]) compared to survivors (n= ) ( . [ . - . ]) (p< . ) . similarly, d-dimer was associated with disease severity in a study by gao et al . more recently, a study summarized the clinical characteristics of death cases with covid- in wuhan . in of patients where the test readings were available, the last level of d-dimer measured was higher as compared to the first test. finally, a recent irish prospective study that assessed coagulopathy in caucasian patients with covid- suggested the presence of significant coagulopathy in caucasian patients that appears to be similar in magnitude to that previously reported in the chinese cohorts. similarly, d-dimer levels were significantly higher in non-survivors compared to survivors during the disease. overall, the studies consistently reported a significant increase in d-dimer. more importantly, the d-dimer increase was dynamic, meaning it seems to continue to rise as the disease progresses and reflected a prognostic indicator of mortality. however, most of the studies were retrospective except for two prospective studies that included a small number of patients (n= ) , . furthermore, many of those papers were conducted at a single center. limitations of evidence include: ) all studies were limited to a single ethnic population, and extrapolation of this data to other populations might not be accurate, and ) except for the study by tang with regards to association with mortality, zhou and colleagues reported a significantly higher prothrombin time (> seconds) in non-survivors (n= ) compared to survivors (n= ) ( % vs. %; p= · ) . another study echoed that association in which significantly longer prothrombin time found in non-survivors (n= ) compared to survivors (n= ) on admission (p < . ) . moreover, fogarty and colleagues found no significant difference in pt between survivors and no-survivors on admission . unlike chinese studies, no progressive increase in pt was observed in the adverse prognostic group. several studies reported no difference in platelets count between icu and non-icu patients , , . in the study by guan al. around half ( . %) of patients with one or more composite outcomes (icu admission, the use of mechanical ventilation, or death) had a platelet count less than . with regards to mortality, zhou et al. reported that a platelet count of less than was more frequently seen in non-survivors than survivors ( % vs %) . interestingly, researchers also j o u r n a l p r e -p r o o f noted an initial increase in fibrinogen with advanced covid- ; however, the level tended to be significantly lower in non-survivors and was associated with a decrease in antithrombin levels. this observation might indicate that a hypercoagulable status associated with the course of severe covid- infection could be related to prognosis. a second study reported a significantly higher incidence of dic reported among non survivors compared to survivors ( . % vs. , p = . ), however, the study did not provide a dic definition . moreover, in the study by fogarty et al., despite the increased d-dimer level, dic was not evident . another study reported dic in . % of patients, with no bleeding complications but a high mortality ( %) . other studies have reported an association of dic with disease severity but they have serious methodological limitations , . overall, studies have reported marked derangement in hemostasis in non survivors with markedly elevated d-dimers, prolonged prothrombin time, and increase in fibrin degradation products. however, modest degree of thrombocytopenia and high fibrinogen levels were observed with advanced covid- disease as opposed to significant reduction in those levels with dic seen with sepsis . this finding was echoed in a recent italian study in which the pattern of prothrombotic coagulopathy and dic was different from that in sepsis, where platelets count is usually decreased, and the prothrombin time is prolonged with associated hemorrhagic tendency . therefore, dic associated with severe covid- infection could represent a distinct entity of coagulopathy. in case reports of covid- patients, pe was identified in patients with no vte risk factors . a case series of post-mortem autopsy found that venous thromboembolism was present in of ( %) patients with covid- , with pe being the direct cause of death in ( %) . similarly, alveolar damage on autopsy was reported in more studies j o u r n a l p r e -p r o o f was diagnosed in patients ( . %). of these, were critically ill. critically ill patients were defined as being admitted to the icu and requiring mechanical ventilation or requiring at least % fio to maintain oxygen saturation at an acceptable level. in total, patients were defined as critically ill, which meant that in this small sample size, vte was present in % of critically ill patients. all patients who developed dvts did so despite use of routine thromboprophylaxis with either low molecular weight heparin (lmwh) or unfractionated heparin (ufh) . a more recent and larger study reviewed covid- patients admitted to the icu at three centres in the netherlands (n= ) . in this study, patients were enrolled from the time they were admitted to icu. patients were followed until they were discharged from icu, died, or until the study period ended. all patients received standardized doses of subcutaneous nadroparin although the exact dose regimen varied by centre. one centre used , international units (iu) per day, or , iu per day if body weight was greater than kg. the second centre used crude cumulative composite outcome of venous and arterial events was %, or % when adjusting for competing risk of death. authors did note that patients entered the study already on long-term therapeutic anticoagulation (although the exact drug was not specified), and of these, patients developed pe. they also noted that diagnoses were made using ct and ultrasound on basis of suspicion, with no screening. however, ct pulmonary angiogram was used more liberally to investigate patients who were not weaning off the ventilator, especially after the results of the initial study were published . another retrospective study from the netherlands included patients ( in icu, on a medical ward) admitted to the amsterdam university medical centres , . patients were classified as ward patients if they remained stable enough to be on the medical ward, or icu patients if they went to icu at any point during their clinical course. all icu patients required j o u r n a l p r e -p r o o f mechanical ventilation in this study. all icu patients were given thrombosis prophylaxis. at standard or double doses. the primary outcome, which included distal or proximal dvt, pe, or venous thrombus in another site, occurred in patients ( %) with an additional patient developing an extensive thrombophlebitis requiring therapeutic anticoagulation. cumulative incidence calculated using a competing risk model was % at days and % at days. when considering only symptomatic vte, the cumulative incidence was % at days and % at days. the incidence of vte was drastically different when comparing icu vs ward patients ( % versus . %). in this study, patients were investigated for thrombotic events based on clinical suspicion, but also were screened at regular intervals. a third study included covid- patients admitted for ards in france included patients admitted to four icus at two centres of a tertiary care hospital and compared them to a historical database of patients admitted for ards from bacterial and other viral sources using propensity score matching . primary endpoint was any venous or arterial thrombotic event, and secondary endpoint was to compare the primary endpoints, but also to assess thrombosis of renal replacement therapy (rrt) machines and median lifespan of the machines, ecmo oxygenator coagulation, along with assessing for hemorrhagic complications and coagulation parameters. out of the patients initially enrolled, there were ( . %) documented pe and ( %) dvt. after matching, covid- ards patients had statistically significant higher rates of pe ( . % versus . %). there were also higher rates of rrt related thrombotic events. however, other venous and arterial thrombotic events, as well as bleeding, were not significantly different. the results of this study showed an elevated risk of pulmonary embolism in patients with covid- induced ards compared to a population of patients with ards from other causes. this study may have underestimated the rate of vte, given many of the enrolled patients were still intubated at the time the data was reported. this study also demonstrates that the risk of vte is higher despite the use of guideline-recommended thromboprophylaxis. furthermore, the coagulopathy seen in covid- was not related to a true dic, nor was there a high rate of sic. it could mean that the coagulopathy, and coagulation, is due to a different mechanism. the role of antiphospholipid antibodies also remains unclear. a fourth study including covid- patients admitted to the icu reported the occurrence of vte in % of patients, using routine ultrasound screening despite the use of prophylactic or therapeutic anticoagulation . two additional studies from the united kingdom and china reported in % and % of patients, respectively. , . the largest study included patients ( closed cases) of whom were admitted to the icu in milan, italy . the median duration of hospitalization was days this study reported thromboembolic events in . % of closed cases with a cumulative rate of %. the incidence was higher for patients admitted to the icu (proportion . % versus . %; cumulative rate . % versus . %). the authors did note that half of the thromboembolic events were diagnosed within hours of hospital admission, raising speculation that thrombosis may be either an early complication of covid- or a determinant of further deterioration. a study from a tertiary care hospital in france evaluated confirmed covid- patients for presence of pe using ctpa. of the patients, ( %) were found to have pe present on j o u r n a l p r e -p r o o f ctpa and of which were in subsegmental arteries only. patients with pe tended to have higher d-dimer than those who were negative . another french study analyzed data of covid- patients admitted between march to april . ultimately, of these patients had contrast ct pulmonary angiography to investigate for presence of pe. of the patients scanned, ( %) were positive for pe. authors noted patients with pe were more likely to be mechanically ventilated and tended to have their ct scan performed with a longer delay after initial symptom onset. although not a direct comparison, this finding may contradict the findings from lodigiani et al. while all the previous studies included a significant proportion of patients admitted to an intensive care unit, a recent study conducted in northern italy evaluated a group of patients admitted to a non-icu ward. in this study no patient was found to have a dvt, including patients who had routine lower extremity ultrasound screening. the authors did not comment on whether any of these patients developed pe . overall, these studies including patients reported the occurrence of vte in approximately % of patients but with cumulative incidences up to % during hospitalization. there were significant differences in screening strategies and definition of outcomes ( table ) . given the discrepant findings in the reported studies, a post-hoc meta-analysis was conducted (table ) and the results suggested that, a) the proportion of vte is much higher in studies including mostly patients admitted to an intensive care unit and, b) the estimates have a high statistical heterogeneity and there may be a risk for publication bias as suggested by a funnel plot analysis. regarding cerebrovascular disease a case series from new york described patients with sars-cov- , all less than years old, who presented with acute ischemic stroke. only one had a history of prior stroke table . a retrospective study of covid- patients admitted to hospital was conducted in wuhan. six ( . %) patients had acute stroke, of them classified as having "severe" disease. although no definition was provided, patients with "severe" disease had higher frequency of co-morbidities including hypertension and were older on average . reports from other groups are very similar with a reported occurrence of stroke between . % and . % of patients , , , , . overall, all studies included patients with a pooled proportion (random effects model) of . % ( % ci . to . ) with no statistical heterogeneity. a case report highlighted the possibility of cardiovascular arterial thrombosis in a patient presenting with st segment myocardial infarction in whom coronary angiography and optical coherence tomography revealed the presence of thrombus without atheroma, and therefore, it was hypothesized that in-situ thrombosis was responsible for their formationcovid- . findings of cardiovascular thrombosis have been seen in other studies as well . diagnosis of thromboembolic disease can be difficult in patients with sars-cov infection. patients with severe disease requiring hospitalization often have elevated d-dimer levels since it is considered as an acute phase reactant, thus limiting its utility as a screen for venous thromboembolism because, although it has a very high sensitivity for thrombotic disease, its specificity is poor effect of heparin on mortality. given the potential severity of the disease in hospitalized patients, as well as the risk of thrombosis, current guidelines recommend using pharmacological dvt prophylaxis in all patients. however, these recommendations are based on general thromboprophylaxis, and are not specific to covid- , . there is no general agreement on the optimal dosing in this setting, and various papers have suggested heterogeneous protocols. was defined as meeting one of the following criteria: respiratory rate  , arterial oxygen saturation  % at rest, or a p/f ratio  mmhg. a total of severe covid- patients were evaluated in the study. all covid- patients received antivirals and supportive care. ( %) of these patients received either ufh ( , - , units/day) or lmwh (enoxaparin - mg/day). there was no difference in mortality in heparin users vs non-users. however, in a subset of covid- patients who had d-dimer levels > . g/ml (six-fold the upper limit of normal), there was a statistically significant decrease in mortality in heparin users vs non-users although data is sparse, a study from italy data regarding when patients are most at risk of thrombosis are lacking. while some studies seem to suggest thrombosis may be an early finding , others have found thrombotic events occurring even after patients are discharged from hospital . this highlights a need for more research, and whether these events can be more accurately predicted by biomarkers, such as ddimer. several studies suggest substantial coagulation activation with severe covid- infection likely related to sustained inflammatory response due to cytokines release induced by virus invasion. pulmonary vasculature thrombosis is likely to be at least in part a result of the severe hypoxia for hypoxia is a profound stimulant of coagulation . the most prominent coagulation marker is the marked and dynamic elevation of d-dimer levels that has been consistently reported in those studies, potentially representing a prognostic indicator for severity and mortality. the high d-dimer probably indicates a severe inflammatory response accompanied by a secondary hypercoagulable state. in fact, d-dimer is also a marker also of j o u r n a l p r e -p r o o f pulmonary fibrin deposition typical of several lung diseases, notably ards , commonly seen in severe covid- . this is supported by data showing that the time course of d-dimer elevation mirrors that of other inflammatory markers including ferritin, interleukin , troponin i and lactate dehydrogenase . moreover, dic as defined by the isth score demonstrated to be a significant finding among non-survivors indicating that it is an adverse prognostic marker . of note, platelet count seems to be only mildly reduced in general, and prothrombin time showed persistent elevation as opposed to the expected reduced fibrinogen levels seen in dic with sepsis. however, those studies have methodological limitations mainly related to sample size and short incomplete follow up. additionally, it has been demonstrated that d-dimer reagents are not interchangeable when assessing their use for clinical diagnosis of vte , . currently, it is not known whether this would be a limitation for their use in prognostic models in covid- patients. properly conducted prospective studies are needed in this area. the significant and overwhelming inflammatory response in patients with severe covid- infection may increase the likelihood of thromboembolic disease and in turn explain the high frequency of vte, particularly in patients admitted to the icu. however, it is unclear if covid- is more likely to cause venous or arterial thrombosis than other conditions. it has been previously reported that patients with severe sepsis (non-covid- ) or septic shock have a very high incidence of vte of up to % despite the use of guideline-recommended thromboprophylaxis , and it is known that general icu patients frequently fail vte prophylaxis ( . %, . %, . % at , and days, respectively) . inferences on the risk of vte in patients with covid- need to be interpreted in this context, keeping in mind that severe sepsis causes a similar picture with higher rates of vte despite adequate vte prophylaxis although some evidence suggests that indeed covid- has a higher thrombotic risk compared to j o u r n a l p r e -p r o o f patients admitted to the icu for other causes . an important point is the fact that there is no information regarding the risk of thrombosis after hospital discharge. this topic needs to be urgently addressed. an emerging hypothesis worth considering is the possibility that the pathophysiology of the pulmonary thrombotic events in covid- may not be embolic at all which could have major implications for treatment. support for this hypothesis comes from both pathology and clinical data. a review of autopsies of covid- patients ( men, women) found evidence of microthrombi in lung tissue, raising the speculation that in-situ pulmonary thrombosis may be the culprit pathophysiological mechanism . from a clinical perspective, several studies have found that a disproportionate high number of venous clotting events are pulmonary thrombi [ ] [ ] [ ] without an associated increase in deep vein thrombosis . given this data, we and other authors question whether the high number of pe are due to embolic events, or rather, in-situ pulmonary thrombosis and pose the question of whether focusing on anticoagulation is the right approach to decrease the thrombotic risk in covid- patients as treating all patients with higher doses of anticoagulants without a clear indication may be more harmful.. it seems that thrombosis, be it macro or microvascular, is the result of the severe inflammatory response induced bu sars-cov- with its subsequent endothelial dysfunction and procoagulant environment and thus targeting inflammation in conjunction with rational anticoagulant management might be a preferable approach. for this reason, some groups have proposed a staging classification that considers both clinical and laboratory criteria and suggests potential treatments for each stage situation report - : world health organization presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the d-dimer is associated with severity of coronavirus disease : a pooled analysis isth interim guidance on recognition and management of coagulopathy in covid- covid- and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with covid- . thrombosis uk clinical and coagulation characteristics of patients with critical covid- pneumonia and acro-ischemia]. zhonghua xue ye xue za zhi clinical characteristics of coronavirus disease in china abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china clinical features of patients infected with novel coronavirus in wuhan the procoagulant pattern of patients with covid- acute respiratory distress syndrome development and validation of a clinical risk score to predict the occurrence of critical illness in hospitalized patients with covid- clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study diagnostic utility of clinical laboratory data determinations for patients with the severe covid- clinical characteristics of death cases with covid- : a retrospective review of medical records in a single medical center covid- coagulopathy in caucasian patients thrombocytopenia and its association with mortality in patients with covid- coagulopathy and antiphospholipid antibodies in patients with covid- lupus anticoagulant is frequent in patients with covid- laboratory criteria for antiphospholipid syndrome: communication from the ssc of the isth towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation correlation of chest ct and rt-pcr testing in coronavirus disease (covid- ) in china: a report of cases clinical characteristics of fatal and recovered cases of coronavirus disease (covid- ) in wuhan, china: a retrospective study venous and arterial thromboembolic complications in covid- patients admitted to an academic hospital in clinical pathology of critical patient with novel coronavirus pneumonia (covid- ) vander heide rs. pulmonary and cardiac pathology in covid- : the first autopsy series from new orleans acute pulmonary embolism and covid- pneumonia: a random association? autopsy findings and venous thromboembolism in patients with covid- : a prospective cohort study gross examination report of a covid- death autopsy comparison of clinical and pathological features between severe acute respiratory syndrome and coronavirus disease zhonghua jie he he hu xi za zhi = zhonghua jiehe he huxi zazhi = chinese journal of tuberculosis and respiratory diseases risk assessment of venous thromboembolism and bleeding in covid- patients pulmonary embolism in covid- patients: awareness of an increased prevalence incidence of thrombotic complications in critically ill icu patients with covid- confirmation of the high cumulative incidence of thrombotic complications in critically ill icu patients with covid- : an updated analysis incidence of venous thromboembolism in hospitalized patients with covid- high risk of thrombosis in patients in severe sars-cov- infection: a multicenter prospective cohort study diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation high incidence of venous thromboembolic events in anticoagulated severe covid- patients prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia thrombotic complications of patients admitted to intensive care with covid- at a teaching hospital in the united kingdom acute pulmonary embolism in covid- patients on ct angiography and relationship to d-dimer levels acute pulmonary embolism associated with covid- pneumonia detected by pulmonary ct angiography pulmonary embolism or pulmonary thrombosis in covid- ? large-vessel stroke as a presenting feature of covid- in the young neurologic manifestations of hospitalized patients with coronavirus disease multivessel coronary thrombosis in a patient with covid- pneumonia diagnosis, prevention, and treatment of thromboembolic complications in covid- : report of the national institute for public health of the netherlands findings of acute pulmonary embolism in covid- patients. société française d'anesthésie et de réanimation diagnostic evaluation of pulmonary embolism during the covid- pandemic anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with covid- plasminogen improves lung lesions and hypoxemia in patients with covid- direct oral anticoagulant plasma levels' striking increase in severe covid- respiratory syndrome patients treated with antiviral agents: the cremona experience endothelial response to hypoxia: physiologic adaptation and pathologic dysfunction hemostatic abnormalities and leukocyte activation caused by infection in patients with malignant lymphoma during chemotherapy comparison of five d-dimer reagents and application of an age-adjusted cut-off for the diagnosis of venous thromboembolism in emergency department herdoo " clinical decision rule to guide duration of anticoagulation in women with unprovoked venous thromboembolism. can i use any d-dimer? vte incidence and risk factors in patients with severe sepsis and septic shock the cumulative venous thromboembolism incidence and risk factors in intensive care patients receiving the guideline-recommended thromboprophylaxis pathological evidence of pulmonary thrombotic phenomena in severe covid- a proposal for staging covid- coagulopathy. research and practice in thrombosis and haemostasis research (canvector) network; the canvector network. the canvector network receives grant funding from the canadian institutes of health research (funding reference:cdt- ). key: cord- -eln n zb authors: ciminelli, g.; garcia-mandico, s. title: how emergency care congestion increases covid- mortality: evidence from lombardy, italy date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: eln n zb background: the covid- pandemic has caused generous and well-developed healthcare systems to collapse. this paper quantifies how much system congestion may have increased mortality rates, using distance to the icu as a proxy for access to emergency care. methods: we match daily death registry data for almost , municipalities in lombardy, italy, to data on geographical location of all icu beds in the region. we then analyze how system congestion increases mortality in municipalities that are far from the icu through a differences-in-differences regression model. findings: we find that covid- mortality is up to % higher in the average municipality -- which is minutes driving away from the closest icu -- than in a municipality with an icu in town. this difference is larger in areas and in days characterized by an abnormal number of calls to the emergency line. interpretation: we interpret these results as suggesting that a sudden surge of critical patients may have congested the healthcare system, forcing emergency medical services to prioritize patients in the most proximate communities in order to maximize the number of lives saved. through some back-of-the-envelope calculations, we estimate that lombardy's death toll from the first covid- outbreak could have been % lower had all municipalities had ready access to the icu. drawing a lesson from lombardy's tale, governments should strengthen the emergency care response and palliate geographical inequalities to ensure that everyone in need can receive critical care on time during new outbreaks. the first wave of covid- strained healthcare systems in many countries, abounding a series of lessons for governments to prepare for new outbreaks. the principal lesson has highlighted the need to strengthening hospitals and intensive care units (icus) capacity. as such, policies have so far mostly focused on expanding already existing emergency infrastructure and building field hospitals near existing medical centres. while necessary, this does little to reduce geographical inequalities in emergency care coverage. this paper highlights the need of tackling such disparities by quantifying the mortality effects of having communities underserved by emergency care when the system is under severe strain. the analysis focuses on lombardy, which offers a good case to study. the region is one of italy's wealthiest and is also renowned for having one of the best healthcare infrastructures in the country, which itself has fairly high rates of icus per capita. yet, lombardy suffered extremely high mortality rates during its first covid- outbreak, which cannot be explained by traditional epidemiological models, such as sir and seir. , , these models feature an exogenous probability of dying once individuals become infected. however, as noted by favero, if the healthcare system is saturated and infected people cannot access to the icu, such probability increases, becoming endogenous to the level of system congestion. this paper analyzes how much system congestion may have contributed to the high mortality rates observed during lombardy's first covid- outbreak, using distance to the icu as a proxy for access to emergency care. to carry out the analysis, we match highly granular daily death registry data for almost , municipalities to information on geographical location and number of all icu beds across lombardy. we complement the dataset with daily data on the volume of calls to the emergency line, as well as data on a number of co-factors of covid- mortality. we start by showing that, despite its generosity, the region's healthcare system is characterised by significant disparities: the average distance in minutes of driving to the nearest icu is three times as large for municipalities in the mountainous subregion of the alps as for those in the metropolitan area of milan. this is important because, when the system is overwhelmed and there is not enough time to attend everyone in need, emergency medical services may have to prioritize patients in the most proximate communities, at the expense of reducing geographical coverage, in order to maximize the number of lives saved. to test whether distance to the icu has any effect on covid- mortality, we develop a differences-in-differences regression model. we find that mortality is up to % higher in the average municipality -which is minutes of driving away from the closest icu -than in a municipality with an icu in town. of course, distance on its own does not imply that critical patients cannot get to the icu on time. after all, some patients require transportation from remote communities to the icu also in normal times, and usually they get there on time. distance to the icu only becomes a determining factor when the burden on the emergency care system is high, as capacity to serve everyone in need is reduced. we proxy for system congestion using data on calls to the emergency line and find that the additional effects of covid- on mortality in municipalities that are farther away from the icu is stronger in days and areas characterized by an abnormal volume of calls to the emergency line, pointing to system congestion as a plausible explanation. we then quantify how much system congestion may explain the high mortality rates observed in lombardy's first covid- outbreak. to do so, we perform some back-of-theenvelope calculations to compare the number of deaths that occurred in actuality to those that would have occurred in a hypothetical scenario in which all communities had an icu in town. we find that covid- deaths would have been about % less in such as a scenario, meaning that many lives could have been saved through more widespread critical care coverage. the rest of the paper is organized as follows. we close section by putting our analysis in context. section describes the dataset and methodology. section presents the results and section concludes. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint research in context evidence before this study epidemiological models such as sir and seir are at the center of a quickly growing literature assessing how mitigation policies can be optimally set to minimize the burden on the economy while reducing the number of fatalities. however, these models fail to predict the mortality observed in outbreak epicenters, where healthcare systems, and in particular emergency care systems, are overwhelmed. another strand of the literature seeks to understand the causes behind the severity of italy's first covid- outbreak. we contribute to these two strands of work by focusing on the congestion of the healthcare system as an important reason behind the high death toll of lombardy's first covid- outbreak, which cannot be explained by existing epidemiological models. to our knowledge, this is the first study to quantify how an uneven distribution of icus across communities may increase covid- mortality when the health system is overburdened. our resultswhich are robust to controlling for a host of co-factors of covid- mortality -indicate that geographical differences in healthcare coverage, together with overwhelmed healthcare systems, account for a significant fraction of the observed covid- mortality in the region. cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint should also invest in building ambulance capacity and, ideally, mobilize icus more evenly across the territory. all these factors are key to help reducing mortality in the new waves of covid- . we source death registry and census population data at the municipality-level from istat, the italian statistical agency. , census data provide information on the resident population as of january/ st , while death registry data provide information on daily deaths for the january/ st to may/ th period for the years to , for almost all italian municipalities. to measure covid- mortality, we rely on the concept of excess deaths -that is, the difference between deaths for all causes during the covid- epidemic and deaths that would be expected under normal circumstances. we prefer this approach over using official covid- fatality data because these vastly undercount the real number of covid- deaths, as we show in a companion paper. moreover, focusing on excess deaths has the key advantage that underlining data are much more granular than official fatality data, which is crucial for our identification strategy, as it will become clear below. our focus is on the lombardy region, which is universally considered as europe's ground zero for covid- and the epicenter of italy's first outbreak, making up for about % of all fatalities, with less than % of the overall population. the data cover , municipalities, together accounting for almost % of lombardy's population. cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . ; of daily calls to the emergency line, by subregion and reason for the call. these data are taken from l'eco di bergamo. we also source data on location and areas of specialization of each hospital and private clinic from lombardy's institutional database. we use this information to construct a municipality-level variable measuring distance to the nearest icu. if there is an icu in town, we set it to zero. otherwise, the variable measures the distance, in minutes of driving, to the nearest municipality with an icu (taken from istat). admittedly, icu capacity has been strengthened during the covid- epidemic and these additional emergency icu beds are not recorded in our data on health facilities, which provide a snapshot as of end- . however, this does not impact our distance-to-icu measure because capacity expansion was concentrated in municipalities that already had icus (mostly in bergamo, crema, and milan). the dataset is complemented with variables capturing slow-moving socio-demographic, labor market and territorial characteristics that we use to control for potential co-factors of covid- mortality. as most of these variables are not available at a regular frequency, we compute their means over the - period and treat them as time-invariant factors. appendix table a provide detailed information on their sources and coverage. next, we discuss a few stylized facts emerging from the data. before the detection of the first community case, deaths in match very closely deaths in (see appendix figure a ). the severe effects of covid- on mortality is underscored by the exponential increase in deaths following the detection of the first community caseat their peak, roughly a month after detection, deaths in are about four times as large as deaths in . also worth noting, excess mortality reaches particularly high levels in the alps and the po valley subregions (see appendix figure a ). overall, the virus may have contributed to the death of up to . % of the local population in the alps, and about . % . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint in the po valley. we then move on to the emergency care system. figure below characterizes municipalities according to distance to the closest icu. only less than % of all municipalities have an icu in town. as expected, these tend to be the larger municipalities. however, together they only account for less than a quarter of lombardy's population. the average municipality is minutes away from the closest one with an icu in town. but this figure masks large disparities between the subregions. mean distance to the icu is reduced to just . minutes for municipalities in the metropolitan subregion, while about a quarter of all municipalities in the alps subregion are further than minutes away, meaning . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . that an ambulance roundtrip may take more than an hour. calls to the emergency line more than doubled in the alps subregion overall in lombardy, calls for respiratory reasons surge more than four-fold in the month following the detection of the first community case (denoted by the vertical line), from about to almost per , . after peaking, they decrease very slowly, returning to pre-covid- levels only three months following detection (panel a ). the increase in total calls (calls . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint for any reason) is more nuanced and the reversal to pre-covid- levels happens much earlier, likely due to seasonal factors and the fact that the lockdown imposed by the government to contain the epidemic reduced road and workplace accidents (panel a ). panels b and b zoom in on calls received in each of the four subregions. while in the alps calls for respiratory reasons surge more than -fold and total calls double, the increase in calls for respiratory reasons is less than -fold in the po valley and less than -fold in the metropolitan and the lakes subregions. in the latter two the total volume of calls barely increase. all in all, this visual inspection of the data suggests that, although calls for respiratory reasons increased across the board, the alps subregion -which is also the one with the most uneven distribution of icus -may have particularly struggled to cope with the surge in demand for critical care. in what follows we illustrate the methodology used to formally analyze the insights that emerged from this first look of the data. we first quantify the effect of covid- on the mortality rate. to do so, we follow closely the methodology that we developed in two companion papers. , specifically, we rely on a differences-in-differences approach to estimate the dynamic effects on the mortality rate, using the year as counterfactual of what mortality would have been in absence of covid- . the choice of using the year follows from a visual inspection of the data (see appendix figure a ), but the results are robust to using mean - mortality as alternative counterfactual. the equation that we estimate is as follows: where y ijt measures daily deaths per , inhabitants in municipality i, at within-year time t, for year j ; d j is a dummy variable taking value equal to in and otherwise; . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint day t are within-year time effects, taking value in each particular day of the year and otherwise; µ i are municipality fixed effects; and ε ijt is an idiosyncratic error, clustered at the municipality-level. the summation term ranges from - to + since we normalize the within-year time dimension t so that it takes value equal to on the day in which the first community case was detected (february/ st ) and negative (positive) values on days before (after). for the estimation, we use the least squares method with population analytical weights. appendix figure a depicts the effect of covid- on mortality, obtained plotting theβ t coefficients estimated from equation ( ). the effect peaks exactly a month after onset, at slightly below deaths per day per , inhabitants and then slowly decreases, until becoming statistically insignificant days after the peak. these estimates are robust to using average deaths in the five preceding years ( to ) as counterfactual (also reported in appendix figure a ). next, we turn to the congestion of the emergency care system as one potential factor that may have increased mortality. we start by uncovering a positive relationship between daily mortality rates and the variable measuring distance to icu (see appendix figure a ). more precisely, being minutes farther away from the icu is associated with about more death per , inhabitants per day, on average, during the entire epidemic period. this relationship is highly statistically significant. to more formally estimate the effects of the uneven distribution of icus on mortality, we extend equation ( ) by adding an interaction term between the within-year effects, the year dummy and our variable measuring distance to the icu. more specifically, the equation that we estimate is as follows: . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint where dist icu i is the variable measuring distance, in municipality i, to the closest municipality with an icu in town; and the rest of the notation is as before. as for equation ( ) above, the estimation is through ols with standard errors clustered at the municipality-level. up to % higher mortality in municipalities minutes away from the icu the average municipality experiences significantly higher mortality rates than those with an icu in town at the height of the epidemic. at peak, the effect of covid- on the mortality rate reaches deaths per day per , inhabitants in municipalities with an icu in town, while the same effect is about deaths per day per , inhabitants, or over % higher, in the average municipality, which is minutes away from the icu. the divergence in the mortality effect of covid- across these two groups of municipalities match very closely the evolution of calls to the emergency line. particularly, the additional effect in municipalities that do not have an icu in town starts decreasing shortly after that the volume of calls to the emergency care eases up, and it becomes statistically insignificant once emergency calls return to pre-covid- levels. how can we explain the result that covid- mortality rates are higher in communities that are more distant from the intensive care? one possibility is that the emergency care system struggled to cope with a surge in demand. indeed, sorbi reports that waiting times for emergency transportation swelled: to make a trip that usually took only minutes, ambulances were taking an hour, and in some cases, they were not getting in on time. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . ; this begs the question of how many deaths could have been prevented if all communities were readily served by an icu. to answer this question, we use the coefficients estimated in equation ( ) and perform some back-of-the-envelope calculations. first, we calculate the overall number of deaths that can be ascribed to covid- in more than , . then we calculate the number of covid- deaths in a hypothetical counterfactual scenario in which every municipality had an icu in town. we find that deaths would have been slightly less . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . ; than , in this counterfactual scenario. this means that about % of all lombardy's deaths in the first covid- outbreak could have been prevented through better icu coverage. before proceeding further, we check that our results are robust to controlling for other municipality characteristics that may correlate with distance to the icu and that could also have an effect on mortality, such as population density, income, education, the demographic structure, the share of people employed in the healthcare sector, the number of icu beds per capita, the share of people employed in essential sectors, distance from the epicenter and others. we also verify that our results are not driven by outliers and exclude municipalities with abnormal mortality rates and those in which the closest icu is very far away. finally, we check that our estimates are robust to using an alternative variable measuring distance to the icu, in kilometers rather than minutes (taken from istat). all the results from these robustness specifications are shown in appendix figure a . for simplicity, the figure shows the additional effects of being minutes away from the icu, given by theπ t coefficients estimated from equation ( ), and compares it with the same effects estimated from the alternative specifications discussed above. overall, the new estimates are very close to, and not statistically different from, our baseline, thus confirming the validity of our results. larger effects when and where the emergency care system is congested next, we zoom in on the alps subregion, where calls to the emergency line for respiratory reasons increased more than -fold and total calls more than doubled (see figure above), putting particularly high pressure on the emergency care system. if indeed distance to the icu increases mortality when the system is congested, we should find larger effects in the alps than in the other subregions, in which the increase in emergency calls was less pronounced. to formally test this hypothesis, we twist equation ( ) to estimate two distinct sets of coefficients measuring the additional effect of distance to the icu on mortality, one for the alps subregion and the other for the rest of lombardy. figure below shows these newly . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . ; estimated coefficients. for simplicity, the figure only reports the additional effect of covid- on mortality in municipalities that are minutes away from the icu relative to those with an icu in town. ( ), which allows for a differential effect of distance to icu on mortality in the alps subregion vs. the rest of lombardy. blue solid lines denote the estimated effect, shaded areas are % confidence intervals, while dashed black lines depict the daily volume of calls to emergency system. the y-axes report daily deaths and calls to the emergency line per , inhabitants (left and right axes respectively). the x-axis reports days after onset. the extra effect of being distant from the icu on covid- mortality is concentrated in the alps subregion. there, municipalities that are minutes away from the icu experience up to more deaths per day per , inhabitants. for the rest of lombardy, instead, we do not estimate any statistically significant difference in mortality between municipalities that are far from the icu and those with an icu in town. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint looking at the volume of calls to the emergency line, we note that the dynamics of the extra effect of being distant from the icu closely follow the evolution of emergency calls in the alps, reinforcing the interpretation that system congestion may have prevented the transportation of critically ill patients to the emergency room on time. on the other hand, we observe that calls to the emergency line only slightly increase in the rest of lombardy, which suggests that the system did not become congested there and helps rationalizing why more remote communities did not experience higher mortality rates there. we analyzed how emergency care congestion may have contributed to the high mortality rates observed in lombardy during its first covid- outbreak, using distance to the icu as a proxy for access to critical care. we found that covid- -induced mortality was much higher in communities underserved by intensive care. using the estimated coefficients we performed some back-of-envelope calculations to calculate how many deaths can be ascribed to system congestion. we found that more than % of all fatalities of lombardy's first outbreak may have resulted from system congestion. our results suggest that many covid- deaths may have been prevented through better preparedness. drawing a lesson from italy's tale, governments around the world should invest in strengthening their emergency care response. they should improve pre-hospital emergency services, by clarifying the first point of contact for possible covid- cases, expanding capacity to manage large volumes of calls, and improving phone triage to better prioritize care delivery. they should also invest in building ambulance capacity, and, ideally, mobilizing icus more evenly across the territory. all these factors are essential to help reduce mortality during new outbreaks. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint notes: this map characterises excess mortality rates, calculated per , inhabitants. excess mortality rates are calculated by subtracting mortality rates to that in . this method is akin to the empirical method we use for counterfactual estimation of the effects of covid- on mortality (see section ??). lighter (darker) colors denote lower (higher) excess mortality rates associated to covid- . the black lines denote the four different geographical areas under which the emergency care service is organized. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint figure a : the dynamic effects of covid- on the mortality rate notes: the figure shows the effect of covid- on the mortality rate, measured in daily deaths per , inhabitants. coefficients are estimated from equation ( ). the blue solid line show coefficients estimated using as counterfactual, while the blue shaded area depicts % confidence interval. the red line with crosses depicts estimates obtained using - mean mortality as counterfactual. figure a : distance to icu and mortality rates notes: the figure depicts the relationship between distance to icu and observed mortality rates. precisely, it plots the average daily mortality rate per , inhabitants over the february/ / -may/ / period onto distance to icu, measured in minutes of driving for all municipalities in lombardy. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint figure a : robustness checks on baseline estimates notes: the figure shows the additional effect of covid- on the mortality rate in municipalities that are minutes driving away from the closest icu relative to the effect in municipalities with an icu in town. the red solid line depicts our baseline estimates ( × π t from equation ( )). the dotted black line depicts estimates obtained augmenting equation ( ) by adding a set of control variables: share of women in working age population, share of high school graduates in working age population, mean income, share of -plus in population, population density, mean income, external commuting index, number of days in which pm is above limit, per-capita icu beds, per-capita nursing home beds and distance to the outbreak epicenter. the long-dash line depicts estimates obtained using a different distance to icu variable, in kilometeres rather than minutes of driving. the short-dash line depicts estimates obtained by censoring observations with outlier mortality rates or distance to the icu. the y-axis measures daily deaths per , inhabitants, the x-axis measures days since the detection of the first community cases (denoted by a vertical maroon line). . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint are hospitals ready for covid's second wave? bloomberg opinion the countries with the most critical care beds per capita what will be the economic impact of covid- in the us? rough estimates of disease scenarios the macroeconomics of epidemics optimal mitigation policies in a pandemic: social distancing and working from home why is covid- mortality in lombardy so high? evidence from the simulation of a seihcr model raccomandazioni di etica clinica per l'ammissione e trattamenti intensivi e per la loro sospensione decessi del . dataset analitico con i decessi giornalieri indicatori demografici. popolazione residente al °gennaio., . data retrieved on covid- in italy: an analysis of death registry data can telehealth ontario respiratory call volume be used as a proxy for emergency department respiratory visit surveillance by public health? isaia invernizzi. coronavirus, chiamate al giù del % ma l'attenzione resta altainfografica, . retrieved on october letti per struttura sanitaria di ricovero, . open data portal . data retrieved on october business shutdowns and covid- mortality un'ora di attesa per un'ambulanza. ora anche il rischia il collasso elenco rsa accreditate, . open data portal condizioni socio-economiche delle famiglie share of employment in non-essential sectors, % total employment key: cord- -fl yrpzs authors: sayde, george; stefanescu, andrei; conrad, erich; nielsen, nathan; hammer, rachel title: implementing an intensive care unit (icu) diary program at a large academic medical center: results from a randomized control trial evaluating psychological morbidity associated with critical illness date: - - journal: gen hosp psychiatry doi: . /j.genhosppsych. . . sha: doc_id: cord_uid: fl yrpzs background: psychological morbidity in both patients and family members related to the intensive care unit (icu) experience is an often overlooked, and potentially persistent, healthcare problem recognized by the society of critical care medicine as post-intensive care syndrome (pics). icu diaries are an intervention increasingly under study with potential to mitigate icu-related psychological morbidity, including icu-related post-traumatic stress disorder (ptsd), depression and anxiety. as we encounter a growing number of icu survivors, in particular in the wake of the coronavirus pandemic, clinicians must be equipped to understand the severity and prevalence of significant psychiatric complications of critical illness. methods: we compared the efficacy of the icu diary, prospectively written by third parties during the patient's intensive care course, versus education alone in reducing acute ptsd symptoms after discharge. patients with an icu stay greater than h, who were intubated and mechanically ventilated over h, were recruited and randomized to either receive a diary at bedside with psychoeducation or psychoeducation alone. intervention patients received their icu diary within the first week of admission into the intensive care unit. psychometric testing with ies-r, phq- , hads and gad- was conducted at weeks , , and after icu discharge. change from baseline in these scores, obtained within one week of icu admission, was assessed using wilcoxon rank sum tests. results: from september , to september , , our team screened patients from the surgical and medical icus at a single large academic urban hospital. patients were enrolled and randomized, of which patients completed post-discharge follow-up (n = ) in the diary intervention group and (n = ) in the education-only control group. the control group had a significantly greater decrease in ptsd, hyperarousal, and depression symptoms at week compared to the intervention group. there were no significant differences in other measures, or at other follow-up intervals. both study groups exhibited clinically significant ptsd symptoms at all timepoints after icu discharge. follow-up phone interviews with patients revealed that while many were interested in getting follow-up for their symptoms, there were many barriers to accessing appropriate therapy and clinical attention. conclusions: results from psychometric testing demonstrate no benefit of icu diaries versus bedside education-alone in reducing ptsd symptoms related to the intensive care stay. however, our study finds an important gap in care – patients at high risk for pics are infrequently connected to appropriate follow-up care. perhaps icu diaries would prove beneficial if utilized to support the work within a program providing wrap-around services and close psychiatric follow up for pics patients. this study demonstrates the high prevalence of icu-related ptsd in our cohort of survivors, the high barrier to accessing care for appropriate treatment of pics, and the consequence of that barrier—prolonged psychological morbidity. trial registration: nct grant identification: gh- - (arnold p. gold foundation) j o u r n a l p r e -p r o o f patients enduring critical illness carry an increased risk for developing new-onset posttraumatic stress features related to their course in the intensive care unit (icu). this is largely due to the near-death nature of their medical conditions and complicated hospital courses, which often involve acute stress, delirium, and delusional memories. the prevalence of post-traumatic stress disorder (ptsd) in icu survivors is estimated at - % during the first month, and - % during the next - months [ , ]. icu-related psychological sequela, such as ptsd, depression, and anxiety, comprise clinically important components of post-intensive care syndrome (pics). both post-icu ptsd and depression are associated with a significant decrease in patient quality of life after discharge compared to the general population [ , ] . we are thus faced with the challenge of identifying modifiable risk factors in order to prevent the long-term complications of critical care. risk factors related to the development of ptsd in the icu setting include delusional memory formation, poor functional status, use of physical restraints, use of sedation, pre-existing psychiatric history, younger age (less than years), female gender, sepsis, and treatment with benzodiazepines and neuromuscular blockers [ , [ ] [ ] [ ] [ ] . early identification of high-risk patients and subsequent interventions in the forms of social support, administration of self-help manuals, and post-discharge psychiatric consultations have all shown to have a protective effect on the incidence of icu-related ptsd [ , ] . particular genetic polymorphisms regulating corticotropinreleasing hormone are also associated with significantly fewer post-icu depressive and posttraumatic stress symptoms [ ] . in addition, the use of an icu diary, where everyday events can be prospectively recorded by family members and healthcare workers, has been shown in some studies to reduce j o u r n a l p r e -p r o o f new-onset ptsd, anxiety, and depressive symptoms and promote psychological wellbeing in both patients and their families [ , , ] . early interventions, in general, may have the most impact on psychological and cognitive sequela following the icu course. thus, early counseling and planned follow-up with mental health providers appears to be critical for at-risk patients. previous research has shown that patients exhibiting the most severe ptsd symptoms have no factual recall of their icu stay and experience vivid delusional memories of their hospital course, such as memories of staff members trying to kill them [ ] . the icu diary's proposed benefit is based on the idea that -one of the strongest and most consistent predictors of subsequent psychological dysfunction is the memory of what may or may not have happened during the course of critical illness‖ [ ] . the early work of jones, et al. demonstrated benefit of the icu diary as intervention to improve icu-related ptsd outcomes [ , ] ; however, subsequent larger multi-centered studies with randomized control trial (rct) methodology in france have not replicated the early reported benefit [ ] . subjective reports of the secondary benefits of icu diaries have been recognized, especially among caregivers of patients with pics. diaries provide families with a sense of control by allowing them to keep track of general events and to log support and well wishes for their loved one when otherwise unable to communicate. for patients who survive their hospital stay, the diary provides a basic chronology of events and a symbol of the support they received during their icu stay [ ] . prior studies [ , ] involving icu diaries have mostly been implemented in europe, where hospital systems routinely offer diaries to critically ill patients. these trials largely differentiated study groups based on time-to-receiving diaries post-icu discharge, as opposed to randomizing patients from the onset to diary versus no-diary groups. our study examines the j o u r n a l p r e -p r o o f effect of the diary protocol in a new setting where the culture of icu diaries had not previously been implemented. this paper describes our rct at a large, public, level one trauma center in the gulf south to assess the efficacy of a diary versus bedside ptsd education-only on reducing symptoms of new-onset ptsd in patients after their icu course. from september to september , we screened patients at high risk for icurelated ptsd from both the surgical and medical intensive care units of university medical center new orleans, which holds icu beds. inclusion criteria required that patients had an icu stay greater than hours, were intubated more than hours, and did not have pre-existing ptsd, dementia, intracranial injury, or other debilitating neurocognitive conditions (supplemental content, error! reference source not found.). after screening, patients were enrolled and underwent randomization. all patients (and available family members) in our study received ptsd education and referrals at the bedside within one week of admission to the intensive care unit (supplemental content, . ). patients provided informed consent if able to do so on their own behalf. if not able, a legally authorized representative/surrogate decision-maker provided voluntary written consent for participation into the study for the purpose of initiating the diary intervention while the patient was unconscious. surrogates were made aware that their consent for the patient could be overridden by the patient when re-consented by our team upon regaining consciousness. study participants (and respective family members) who received the icu diary were educated on its purpose by a member of our team. this study was approved by our university and hospital j o u r n a l p r e -p r o o f institutional review boards prior to its implementation. our clinical trial registry is found at https://clinicaltrials.gov/ct /show/nct (with study number nct ). for the diaries, we used blank journals, into which we encouraged family and icu healthcare workers write daily events in everyday language. we instructed participants that entries detail daily activities, subjective or hoped for response to treatment, and personal notes of encouragement. diaries remained in the patient's possession after discharge. our study team did not examine or photocopy contents of the personal diaries. patients were visited every two to three days until hospital discharge by a member of our study team, who answered questions and encouraged use of the diary during the intensive care course. we reminded users of the diaries that they were contributing to a public document and cautioned against including personal or sensitive medical information (e.g.: hiv status, details of treatment, substance use history, and other diagnostic information). nursing staff also received educational sessions regarding use of the diaries along with written guidelines of best practices. all family members and healthcare staff involved in diary writing received written instructions adapted from prior studies [ , , ] for consistency (supplemental content, enrolled patients were randomized to either a diary group (intervention group) or an education-only group (control group) (figure ) . randomization was conducted in a : ratio via a computer-generated algorithm. there was some cross-over between groups during the course of the study due to popularity of the idea of using an icu diary among family members. we conducted both an intention-to-treat (itt) analysis maintaining the initial randomization and an as-treated analysis that included the crossover participants originally randomized to the control group in the intervention group. we will present the itt results and discuss key differences between the itt results and as-treated results where differences arose. questionnaire (phq- ), hospital anxiety and depression scale (hads), and generalized anxiety disorder -item (gad- ) within one week of icu admission (baseline) and again at the following time points after icu discharge: week , week , and week . the ies-r assesses the presence and intensity of new-onset ptsd symptoms (range, - ; higher scores indicate more severe symptoms), related to a recent inciting event, and we chose to use this for consistency with prior studies [ , ] . the ies-r also includes sub-scores that reflect the severity of hyperarousal, intrusion, and avoidance symptoms. the phq- identifies the presence and severity of depressive symptoms (range, - ; higher scores correspond to more severe symptoms). the question regarding suicidality on the phq- was omitted. the hads screens for anxiety and depression symptoms in the acute hospital setting (range, - ; higher scores indicate more severe symptoms). the gad- assesses the presence and severity of anxiety symptoms (range, - ; higher scores indicate more severe symptoms). in addition, patient demographic data was collected at baseline: age, sex, race, past medical and psychiatric conditions, reasons for icu admission, hospital diagnosis, and length of icu stay in days. our primary outcome was change in total ies-r score from baseline at week . secondary outcomes included: changes in the other measures and ies-r sub-scores at week , changes in all measures at week , and length of stay (los). moreover, the prevalence of clinically significant ptsd, defined by ies-r total score greater than [ , , ] , was calculated for both groups at all time points. the recruitment target was n = which accounted for a % withdrawal and loss rate, % study power, p-value of . , and -point clinically significant reduction in post-traumatic stress symptoms via the ies-r [ , ] . wilcoxon rank sum tests were used to test group j o u r n a l p r e -p r o o f differences in continuous variables, fisher's exact tests were used for categorical variables, and log rank tests were used for time-to-event variables. all data analyses were conducted using sas . . the screening and enrollment procedures and randomization scheme are summarized in table ) . patients were withdrawn from our study before baseline evaluation, most often due to mortality. reasons for withdrawal included: death, new-onset strokes, hospital elopement, and loss to follow-up after discharge. all patients were withdrawn within one week of enrollment into the study, and complete baseline data was unable to be obtained on these subjects. six participants randomized to the control group were subsequently found to have started diaries on their own, effectively crossing over into the intervention group. five patients randomized to the intervention group never successfully started a diary, thus crossing over into the control group. the results presented below reflect the initial randomization, and key differences with the astreated analysis will be discussed. j o u r n a l p r e -p r o o f changes in ies-r and sub-scores at and weeks can be seen in table . the use of a diary during the icu course was associated with a smaller reduction in ptsd symptoms, as measured by the ies-r, compared to the control group (p = . ). participants in the control group also experienced significantly greater improvements in ies-r hyperarousal sub-scores compared to the intervention group at week (p = . ). changes in other sub-scores and scores at week did not differ significantly between groups. when crossovers were accounted for in an as-treated analysis, there was no longer a significant difference in change from baseline total ies-r score at week between groups. however, the change from baseline in hyperarousal sub-score remained significantly better in the control group than the intervention group (p = . ). changes from baseline in gad- , phq- , and hads-total score and anxiety and depression sub-scores at weeks and are summarized in table . we found a statistically significant reduction in depressive symptoms (as measured by the phq- ) in the control group, compared to the intervention group, at week (p= . ). this difference was not observed in an as-treated analysis, however. our study finds no other significant difference between groups with respect to these secondary measures. length of icu stay did not significantly differ between diary and control groups (table ) . however, the diary group trended towards greater length of stay (supplemental content, error! reference source not found.). the diary intervention group was found to have clinically our analysis indicates that further investigation is warranted before arriving at conclusions regarding the efficacy of diaries in treating icu-related ptsd symptoms. we found no significant benefit attributable to the intervention, consistent with the results of a cochrane review [ ] and a multicenter randomized control trial [ ] studying the use of diaries across icus in france. in fact, our study may indicate harm associated with the use of diaries, which appears to be a new finding. in our sample, the difference in changes of ies-r scores seems to be driven by an effect in the hyperarousal subscore. this may be due to the particular sample we had, especially given its small size. it may also signal that those with significant hyperarousal have a more severe form of icu-related ptsd which may prove to be more persistent and possibly treatment-resistant. both study groups trended towards worsening, clinically relevant ptsd symptoms by weeks after icu discharge. our data demonstrates no benefit to icu-related ptsd with use of an icu diary, but it does suggest that pics is a clinically significant phenomenon that merits attention and improved access to care. our study has several important limitations. we experienced a significant participant withdrawal rate ( . %) within one week of patient enrollment, largely due to loss to follow-up and icu-related morbidity and mortality, which is not uncommon for this study population. initiating practice habits regarding voluntary clinician use of a diary in a hospital without a prior institutional culture of diary stymied staff involvement, and momentum to participate in a novel therapy without direct incentive was difficult to generate. we saw inconsistent family investment at the bedside in utilizing the diary, inconsistent participation among clinicians, and little use of the diary among patients after discharge. for instance, patients who were initially randomized to the intervention group never successfully started a diary, due to lack of family presence and failure to recruit healthcare team involvement. icu diaries are a non-invasive and low-cost intervention, and when adopted by critical care settings, are widely considered to be a way of humanizing an otherwise chaotic, impersonal and sterilized critical care environment. icu diaries are more common in europe where some hospital systems routinely offer diaries to critically ill patients [ , ] . our study endeavored to implement the diaries intervention within a hospital system that was previously not enculturated with the practice of administering icu diaries, and despite efforts at training nurses and clinicians, some diaries received very little attention from staff. if there was no family at bedside for a patient, the intervention for that individual may have been no better than control, which may have contributed to the lack of significant difference we saw between the two groups in the majority of our secondary outcomes. other limitations include our small sample size, which likely explain some of our unexpected results, as small studies are at higher risk of selecting non-representative samples. in addition, the outcomes we measured do not represent all aspects of wellness. it is likely that diaries have benefit in other ways that we did not capture, particularly as patients and families responded positively to them. due to loss to follow-up and our specific study design, we were not able to study the long-term effects that may be associated with the diaries. for instance, j o u r n a l p r e -p r o o f diaries may be effective tools in outpatient therapy long term, leading to faster recovery, rather than preventing ptsd symptoms. our study would not be able to capture this. moreover, we did not look at measures in family members. after an icu experience, family members comprise such an important support system for patients, and the critical illness course can have negative mental health effects on them as well [ ] . the icu diary may have been beneficial for family members and caregivers with regard to certain psychometric outcomes, as shown by jones et al. [ ], and our study did not account for this. many patients and family members in our study population were hesitant towards interacting with mental health providers, largely due to misconceptions about the role and intentions of psychiatrists. this was mostly observed by our study team in the icu rooms during the initial process of consenting patients into our study. multiple patients elicited negative associations, such as forced medications and experimentation, related to the field of mental health. this posed a challenge towards recruitment into our study, along with attempts at bedside education on icu-related psychological complications. in part, these sentiments likely derive from longstanding mistrust towards healthcare providers (due to historical injustices in the medical field in the southern united states and beyond) and the stigmatization of mental illness [ ] . we suspect that underlying mistrust with the mental health care system also affected the willingness of our study participants to present for aftercare. moreover, nearly all of our participants were unaware of their risk for pics that might manifest following an intensive care unit stay when consenting for the study. all of our participants received education on pics. many of our patients who were interviewed after icu discharge required prompting to connect their post-traumatic stress symptoms (e.g., nightmares, j o u r n a l p r e -p r o o f flashbacks, delusional memories) to a mental health condition attributable to their icu course, and many did not recall having been educated about the syndrome while in the icu. this highlights the importance of following up with patients who survive the icu to re-educate about psychological morbidity, which is currently not a routine practice at our institution but perhaps should be. despite follow-ups by phone, only % of our icu survivors in the study presented for mental health follow-up appointments, which is striking given that almost % were reporting impairing symptoms at weeks after discharge. the onus to direct patients toward resources and follow-up care for icu-related psychiatric sequela should not be on the patient and the patient's family alone, but should ideally be absorbed by a system designed to prevent and treat pics. few level one trauma centers in the united states have dedicated pics clinics and case managers, but the awareness of pics as an ongoing disabling syndrome appears to be shifting more research and funding resources toward improving care for those who survive critical illness. as we encounter a growing number of icu survivors, in particular in the wake of the coronavirus pandemic, clinicians must be equipped to understand the severity and prevalence of significant long-term psychiatric complications of critical illnessin an effort to mitigate icurelated symptoms and improve the quality of life of icu survivors [ ] . our icu diary intervention promoted a culture of compassion, collaboration, and humanism among healthcare workers and their critically ill patients and changed the conversation around what can be done, aside from medical care, to improve the psychological j o u r n a l p r e -p r o o f health of those who endure and survive the icu. despite finding no significant improvement in symptoms with use of the diary, our intervention increased awareness of the psychological support available to icu survivors and family members. the intervention also offered a way for staff in a busy teaching hospital to concretize positive sentiments felt toward patients and offer lasting messages of hope. our data demonstrates no benefit in using an icu diary versus bedside education-alone in reducing ptsd symptoms related to the intensive care stay. while our findings with regard to psychometric testing are largely consistent with the available literature [ , ] as a whole, our icu diary intervention for the critically ill proved to be worthwhile to patients and families, and subjectively aided in the recovery process per the feedback of participants and family members. the prevalence of post-intensive care ptsd was staggering in our population. while some patients were connected with pics resources and treatment, this remains an area for improvement: how best to connect patients suffering from symptoms of icu-related ptsd to services? consultant-liaison psychiatrists have a potential role to bridge services in hospitals with icu patients, helping to identify patients at risk for icu-related ptsd, educating patients and families regarding psychological morbidity of icu survival, and building networks of outpatient pics providers for referral. future research with icu diaries may demonstrate benefit in hospital systems with established pics clinics facile in making therapeutic clinical use of these totems from the icu experience. we suspect the true benefit of icu diaries is not in simply making them in the first place but in using them for progressive exposure therapy in the outpatient setting. it remains unclear how diaries may attend to the prevalent and predictive symptoms of delusional traumatic memories, and whether the diaries have the power to replace delusion with factual narrative. further research is required to assess the clinical utility of the icu diary in patients who survive the icu. what is clear from our work is that the psychological needs and pics symptoms of the icu survivor post-discharge are chronic and prevalent and merit improved efforts at prevention, education, treatment, and access to care. j o u r n a l p r e -p r o o f j o u r n a l p r e -p r o o f on behalf of my coauthors, i would like to thank you for the opportunity to revise and resubmit our manuscript ghp-d- - , entitled -implementing an intensive care unit (icu) diary program at a large academic medical center: results from a randomized control trial evaluating psychological morbidity associated with critical illness.‖ we greatly appreciate the thoughtful feedback and suggestions for improvement. we carefully considered and responded to each comment. the recommendations made by the reviewers were successfully incorporated into our revised manuscript. we have clarified elements of our study methods, especially with regard to the early introduction of the icu diary. our discussion and conclusions expand on some of our study's limitations and elaborate on further implications of our findings, as suggested by the reviewers. we highlight the utility of psycho-education, family support and presence at the bedside, and the call for comprehensive post-intensive care services. we have included a response to reviewers in which we address each comment voiced. our responses are highlighted in blue, and prefaced by -author response.‖ corresponding changes are highlighted in the manuscript in the revised file. thank you again for your consideration of our revised manuscript. posttraumatic stress disorder in critical illness survivors: a metaanalysis stress disorders following prolonged critical illness in survivors of severe sepsis patients suffering from psychological impairments following critical illness are in need of information post-intensive care unit psychiatric comorbidity and quality of life intensive care diaries reduce new onset post traumatic stress disorder following critical illness: a randomised, controlled trial posttraumatic stress, anxiety and depression symptoms in patients during the first year post intensive care unit discharge risk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: a prospective cohort study long-term complications of critical care impact of follow-up consultations for icu survivors on post-icu syndrome: a systematic review and metaanalysis a pilot investigation of the association of genetic polymorphisms regulating corticotrophin-releasing hormone with posttraumatic stress and depressive symptoms in medical-surgical intensive care unit survivors intensive care diaries and relatives' symptoms of posttraumatic stress disorder after critical illness: a pilot study evaluation of the effect of prospective patient diaries on emotional well-being in intensive care unit survivors: a randomized controlled trial memory, delusions, and the development of acute posttraumatic stress disorder-related symptoms after intensive care the spectrum of psychocognitive morbidity in the critically ill: a review of the literature and call for improvement precipitants of post-traumatic stress disorder following intensive care: a hypothesis generating study of diversity in care effect of an icu diary on posttraumatic stress disorder symptoms among patients receiving mechanical ventilation: a randomized clinical trial patients' and relatives' opinions and feelings about diaries kept by nurses in an intensive care unit: pilot study developing a framework for implementing intensive care unit diaries: a focused review of the literature psychometric properties of the ies-r in traumatized substance dependent individuals with and without ptsd postintensive care unit psychological burden in patients with chronic obstructive pulmonary disease and informal caregivers: a multicenter study impact of event scale: a measure of subjective stress the impact of event scale-revised: psychometric properties in a sample of motor vehicle accident survivors diaries for recovery from critical illness family response to critical illness: postintensive care syndrome-family why ethnic minority groups are underrepresented in clinical trials: a review of the literature j o u r n a l p r e -p r o o f key: cord- -h q y authors: sisó-almirall, antoni; kostov, belchin; mas-heredia, minerva; vilanova-rotllan, sergi; sequeira-aymar, ethel; sans-corrales, mireia; sant-arderiu, elisenda; cayuelas-redondo, laia; martínez-pérez, angela; garcía-plana, noemí; anguita-guimet, august; benavent-Àreu, jaume title: prognostic factors in spanish covid- patients: a case series from barcelona date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: h q y background: in addition to the lack of covid- diagnostic tests for the whole spanish population, the current strategy is to identify the disease early to limit contagion in the community. aim: to determine clinical factors of a poor prognosis in patients with covid- infection. design and setting: descriptive, observational, retrospective study in three primary healthcare centres with an assigned population of , . method: examination of the medical records of patients with covid- infections confirmed by polymerase chain reaction. logistic multivariate regression models adjusted for age and sex were constructed to analyse independent predictive factors associated with death, icu admission and hospitalization. results: we included patients (mean age . years, % female, ( . %) aged ≥ years): ( . ) were health workers (doctors, nurses, auxiliaries). predictors of icu admission or death were greater age (or = . ; %ci = . to . ), male sex (or = . ; %ci = . to . ), autoimmune disease (or = . ; %ci = . to . ), bilateral pulmonary infiltrates (or = . ; %ci = . to . ), elevated lactate-dehydrogenase (or = . ; %ci = . to . ), elevated d-dimer (or = . ; %ci = . to . ) and elevated c-reactive protein (or = . ; %ci = . to . ). myalgia or arthralgia (or = . ; %ci = . to . ) was protective factor against icu admission and death. predictors of hospitalization were chills (or = . ; %ci = . to . ), fever (or = . ; %ci = . to . ), dyspnoea (or = . ; %ci = . to . ), depression (or = . ; %ci = . to . ), lymphopenia (or = . ; %ci = . to . ) and elevated c-reactive protein (or = . ; %ci = . to . ). anosmia (or = . ; %ci = . to . ) was the only significant protective factor for hospitalization after adjusting for age and sex. conclusion: determining the clinical, biological and radiological characteristics of patients with suspected covid- infection will be key to early treatment and isolation and the tracing of contacts. a a a a a on december , the health authorities of wuhan city (hubei province, china) reported a cluster of cases of pneumonia of unknown aetiology with onset of symptoms on december, including severe cases, with a common exposure identified in a city market [ ], which was closed on january , . on january , the chinese authorities identified a new coronaviridae family virus, initially named coronavirus -ncov and later coronavirus sars-cov- as the causal agent [ ] . the genetic sequence was shared by the chinese authorities on january . on january , the first case was detected in the usa, in washington state [ ] . on january , the world health organization declared the sars-cov- outbreak in china a public health emergency of international concern [ ] . subsequently, the outbreak has spread outside china, with europe especially affected [ ] . the first positive case diagnosed in spain was confirmed on january , on the island of la gomera, while the first death occurred on february in valencia city (the date was confirmed twenty days later). the first confirmed case in barcelona was on february, and from then until june , there have been , confirmed cases in spain [ ] . the most common signs of infection are respiratory symptoms: fever, cough and shortness of breath. in more severe cases, the infection may cause pneumonia, severe acute respiratory syndrome, renal failure and death [ ] . transmission appears to be mainly person-to-person via the airway through respiratory droplets measuring > microns when the patient has respiratory symptoms (cough and sneezing) and contact with fomites [ ] . most estimates of the incubation period of covid- range from to days, with most around five days. evidence on the transmission of the virus before symptom onset is unclear. there is currently no specific treatment for covid- infections. to date, the most important scientific efforts have focused on three areas: strategies to contain the spread of the disease, the initiation of clinical trials with antivirals and multiple therapies, and the design of a new vaccine, which is still unclear. these strategies include some of a community nature, where primary healthcare plays a central role in disease prevention and control [ ] . few studies have described the clinical characteristics of the disease, fewer the predictive factors, and virtually none have described the mediterranean population compared with the rest of the world. therefore, this study aimed to describe the clinical, biological and radiological manifestations, the evolution, treatments and mortality rate of patients with covid- infection in the population of barcelona city and determine the most important predictors of a poor prognosis. a multicentre, observational descriptive study was carried out in three urban primary healthcare centres serving an assigned population of , , with one reference hospital. the study included all consecutive adult patients with covid- confirmed by polymerase chain reaction (pcr) from nasal and pharyngeal samples during the study period of february to april . diagnostic confirmation was made in the hospital laboratories, as pcr is not available in primary healthcare centres. signs and symptoms, the main available haematological and biochemical data and the results of imaging tests were recorded, as were comorbidities, the evolution, the hospitalization rate, intensive care unit (icu) admission and the treatments received. the study population was divided into four age groups: - years, - years, - years and � years. other variables recorded were the type of follow-up, the need for temporary work disability, and the source of possible contacts. the time to first medical visit was defined as the difference (in days) between symptom onset and medical visit by a family physician. the factors that determined a poor prognosis (hospitalization, icu admission, death) were collected. the data were obtained from the electronic medical record. missing data were collected by telephone interviews with patients when possible. patients from nursing homes were excluded, as the rate of infections and mortality has been shown to be much higher than in the non-institutionalized population. the study was approved by the ethics committee of the hospital clinic of barcelona (registration number hcb/ / ). the study was conducted according to the helsinki declaration and spanish legislation on biomedical studies, data protection and respect for human rights. categorical variables are presented as absolute frequencies and percentages (%) and continuous variables as means and standard deviations (sd). predictors of death, icu admission and hospitalization were determined using the student's t test for continuous variables and the chisquare test for categorical variables. logistic multivariate regression models adjusted for age and sex were constructed to analyse independent predictive factors associated with death, icu admission and hospitalization. odds ratios (or) and their % confidence intervals ( %ci) obtained in the adjusted regression analysis were calculated. forest plots were used to represent or and %ci. values of p< . were considered statistically significant. the statistical analysis was performed using the r version . . . for windows. we included patients (mean age . years, % female, ( . %) aged � years). the mean time from symptom onset to the medical visit was . (sd . ) days. clinical characteristics are shown in table ) . comorbidities were presented by ( . %) patients: the most common were hypertension in ( . %), diabetes mellitus in ( . %), and obesity in ( . %) ( table ) . heart disease ( . % vs . %, p = . ), autoimmune disease ( . % vs . %, p = . ), diabetes ( . % vs . %, p < . ), hypertension ( . % vs . %, p < . ) and chronic kidney disease ( . % vs . %, p = . ) were the comorbidities significantly associated with icu admission and death (table ) . autoimmune disease was the only significant predictive comorbidity for icu admission and death after adjusting for age and sex (or = . ; % ci = . to . ) (fig ) . depression was the best predictor of hospitalization among all comorbidities (or = . ; %ci = . to . ) (fig ) . having � comorbidity was associated with icu admission and death (or = . ; %ci = . to . ) and hospitalization (or = . ; %ci = . to . ) independently of age and sex. chest x-ray was necessary in patients ( . %) and showed lobar pulmonary infiltrates in ( . %), bilateral pulmonary infiltrates in ( . %) and an interstitial pattern in ( . %) ( table ) . chest ct was required in patients and pulmonary ultrasound in ( . %). biologically, ( . %) of patients had lymphopenia (< , mm ). likewise, . % had a lactate dehydrogenase (ldh) > u/ml and liver test alterations were common: elevated ast/got in . % and alt/gpt in . %. in ( . %) of cases d-dimer was elevated (> mg/l). the most important factors for icu admission and death were bilateral pulmonary infiltrates (or = . ; %ci = . to . ), elevated lactate-dehydrogenase (or = . ; %ci = . to . ), elevated d-dimer (or = . ; %ci = . to . ) and elevated c-reactive protein (or = . ; %ci = . to . ) (fig ) . significant predictive factors associated with hospitalization, after adjusting for age and sex, were lymphopenia (or = . ; %ci = . to . ) and elevated c-reactive protein (or = . ; %ci = . to . ) (fig ) . this study summarizes the clinical, biological and radiological characteristics, evolution and prognostic factors of patients with covid- disease in primary and community healthcare. to date, we are aware of three published spanish studies [ ] [ ] [ ] . the first reported data from patients on icu admissions in a region where the pandemic was reported early [ ] . the study by borobia et al [ ] describes the first adult patients with covid- consecutively admitted to a university hospital in madrid. the third focuses on the differences by agedependent categories in the clinical profile, presentation, management, and short-term outcomes [ ] . although there have been two systematic reviews and meta-analysis that analyse the clinical characteristics of covid- , they are limited to chinese cohorts or case series [ , ] and a large usa cohort [ ] that did not analyse clinical predictors of a poor prognosis. clinically, the same main symptoms of cough and fever are reported in all series. however, in barcelona city, we have observed diarrhoea, anosmia and dysgeusia, which is hardly reported in the chinese series [ ] which, unlike ours comes principally from hospitals: diarrhoea occurred in . % of cases, very similar to the % in new york [ ] and clearly higher than the . % reported in china. nearly % of patients had anosmia and dysgeusia, similar to the results obtained in french patients [ ] . in contrast, expectoration was found in only %, compared with . % in the chinese series. in bold, statistically significant independent predictive factors associated with hospitalization, death, or icu admission (logistic multivariate regression adjusted for age and sex). † comorbidities with a frequency of < patients were: bronchiectasis (n = ), fibromyalgia (n = ), anaemia (n = ), arthritis (n = ), hiv (n = ), syphilis (n = ) and tuberculosis (n = ). https://doi.org/ . /journal.pone. .t in bold, statistically significant independent predictive factors associated with hospitalization, death or icu admission (logistic multivariate regression adjusted for age and sex). † ( . %) patients had a chest x-ray. the alterations with a frequency < patients were: pneumothorax (n = ) and pleural effusion (n = ). chest x-ray results were not available in patients. ‡ ( . %) patients had a chest cat scan. alterations with a frequency of < patients were: pulmonary thromboembolism (n = ), emphysema (n = ), lobar pulmonary infiltrates (n = ), pneumonia (n = ), atelectasis (n = ) and pleural effusion (n = ). cat scan results were not available in five patients. https://doi.org/ . /journal.pone. .t chinese patients had a mean age of years, ten years lower than our series, and . % of our patients were aged � years, compared with %, % and % in china, germany and the usa respectively, but > % in italy [ , [ ] [ ] [ ] . older age and male sex predisposed to a higher mortality rate in our and all large series [ , ] . in our patients, comorbidities were three times higher than in the chinese cohort [ ] and were similar to the findings of the new york study [ ] . any comorbidity was a risk factor for hospitalization, icu admission and death. depression was an independent risk factor for hospitalization, which has not been observed in other cohorts studied. depression was often accompanied by a vulnerable social situation, which may have justified hospitalization. likewise, autoimmune diseases were independent risk factor for icu admission and death. various hypotheses have been postulated on possible autoimmune alterations in the pathogenic evolution of the disease. with respect to in bold, statistically significant independent predictive factors associated with hospitalization, death, or icu admission (logistic multivariate regression adjusted for age and sex). † complications in < patients were: sepsis (n = ), multiorgan failure (n = ), electrolyte alterations (n = ), hematologic alterations (n = ) and lung cancer (n = ). ‡ treatments with a frequency of < patients, except remdesivir, were: amoxicillin (n = ), interferon (n = ), rituximab (n = ), darunavir (n = ) and entecavir (n = ). treatment, no drug has proved effective against covid- until now. moreover, many treatments were unavailable in the outpatient setting. currently, we are only certain that treatment with tocilizumab showed better survival rates in retrospective cohorts [ ] , although its efficacy has not been tested in randomized clinical trials. therefore, the results on the outcomes associated with treatment should be interpreted with caution. the same comorbidities were identified, with hypertension and diabetes being the two most common, while in the usa and italy, obesity seems to be higher. our results show that obesity was close to being an independent risk factor for hospitalization (or = . ; % ci = . to . ). strikingly, . % of our patients were healthcare workers, compared with . % in wuhan and . % in germany [ , ] . although these studies recognized an important degree of underreporting of cases in health workers, the difference remains important. there are at least two possible explanations: first, the lack of personal protective equipment in the initial phase of the epidemic, a constant revindication of health professionals, who felt undersupplied. secondly, many cases were health professionals from primary healthcare or the reference hospital who reside in the same area where they work. in all reported series, bilateral pneumonia was the most common radiological finding, was present in more than half the cases [ ] and was a factor of a poor prognosis and mortality. in contrast, an interstitial radiological pattern did not confer an increased risk of mortality. the wuhan study reported a cat scan use of . %, compared with . % in barcelona. in contrast, chest x-rays were carried out in . % and . %, respectively: the availability of diagnostic means was higher in china. a recent international consensus states that radiological assessment is not necessary in asymptomatic patients or those with mild disease but is required in patients with moderate or severe disease, regardless of whether a definite diagnosis of covid- has been made [ ] . in addition, simple chest x-rays are preferable in a resourceconstrained environment with difficulties in accessing cat scans [ ] . the possible use of pulmonary ultrasound for the point-of-care diagnosis of covid- pneumonia has not been sufficiently analysed but might be an efficient alternative due to its portability and reliability [ ] . in fact, the regional catalan government has recently acquired ultrasound machines to enable family physicians to make doctors can make point-of-care (home or nursing home) diagnoses of pneumonia [ ] . biologically, lymphopenia and increased crp, ldh and ddimer were usually constant and similar in all series and were associated with an increased risk of mortality. a differential variable in our series is a greater number of alterations in liver tests, which was present in - % of patients, data similar to the usa and italian cohorts, but different from the chinese cohort, where it was % [ ] . we also found hypokalaemia in . % of patients, a factor not reported in other studies. we found a hospitalization rate of . %, compared with - % in the usa and . % in china, and an icu admission rate of %, which was similar to the chinese ( %), usa ( - . %) and german ( %) results. while the protocols of action and admission are similar and depend on the level of clinical involvement, the therapeutic protocols differ between hospitals, cities, and countries. there remain many unknowns in the treatment of covid- . the only truth is that we do not have a vaccine, an etiological treatment or a treatment with sufficient scientific evidence to generalize its use. currently, the systematic review of antiretroviral treatments has not offered conclusive results [ ] and despite in vitro results for hydroxychloroquine, covid- infections are currently intractable [ , ] . the mortality rate in our study was . %, compared with . % in new york ( % in hospitalized patients), . % in china, . % in germany and . % in italy. different information and recording systems, the availability of diagnostic tests, and above all, the organization of national health systems may have contributed to the differences observed. the study had some limitations due to the observational, retrospective design. however, it is sufficiently representative of the population with confirmed covid- to permit better identification of the factors of a poor prognosis of the disease from a clinical perspective. we cannot rule out some heterogeneity in data codification due to observers' interpretations of the medical records. however, this bias is minimal, as most clinical factors included are clearly defined in the electronic medical record. another limitation of this study is the percentage of patients without laboratory parameters (more than %). even though in real clinical practice these percentages may be expected, the results corresponding to laboratory parameters should be interpreted with caution. four months after the declaration of the pandemic, there is not a sufficiently reliable, available and generalizable diagnostic test that can analyse the seroprevalence of covid- , even in the most industrialized countries. given this lack, determining the clinical, biological and radiological characteristics of probable cases of covid- infection will be key to the initiation of early treatment and isolation, and for contact tracing, especially in primary healthcare. visualization: antoni sisó-almirall, belchin kostov, jaume benavent-Àreu. novel coronavirus ( -ncov) situation summary first case of novel coronavirus in the united states world health organization. novel coronavirus situació n del covid- en españa clinical characteristics of coronavirus disease in china enteric involvement of coronaviruses: is faecal-oral transmission of sars-cov- possible? ready for a long fight against the covid- outbreak: an innovative model of tiered primary health care in taiwan sars-cov- in spanish intensive care: early experience with -day survival in vitoria a cohort of patients with covid- in a major teaching hospital in europe clinical presentation and outcome across age categories among patients with covid- admitted to a spanish emergency department clinical characteristics of coronavirus disease (covid- ) in china: a systematic review and meta-analysis clinical, laboratory and imaging features of covid- : a systematic review and meta-analysis presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area clinical characteristics of covid- in new york city utility of hyposmia and hypogeusia for the diagnosis of covid- covid- )-united states the italian coronavirus disease outbreak: recommendations from clinical practice impact of low dose tocilizumab on mortality rate in patients with covid- related pneumonia the role of imaging in novel coronavirus pneumonia (covid- ) the role of chest imaging in patient management during the covid- pandemic: a multinational consensus statement from the fleischner society thoracic ultrasound and sars-covid- : a pictorial essay generalitat de catalunya. darreres mesures systematic review of the efficacy and safety of antiretroviral drugs against sars, mers or covid- : initial assessment should chloroquine and hydroxychloroquine be used to treat covid- ? a rapid review chloroquine and hydroxychloroquine in covid- the authors thank david buss for editorial assistance. conceptualization: antoni sisó-almirall, belchin kostov, jaume benavent-Àreu. key: cord- -q opbz v authors: alharthy, abdulrahman; faqihi, fahad; mhawish, huda; balhamar, abdullah; memish, ziad a.; karakitsos, dimitrios title: configuring a hospital in the covid- era by integrating crisis management logistics date: - - journal: infection control and hospital epidemiology doi: . /ice. . sha: doc_id: cord_uid: q opbz v nan to the editor-the novel coronavirus sars-cov- disease (covid- ) emerged in china and has spread throughout the world. the first case of covid- in saudi arabia was confirmed on march , , and presently almost , people have been infected here. the ministry of health (moh) has responded to the covid- outbreak by designing clusters of governmental hospitals to accommodate the increased flow of patients. although our bed-occupancy rates never exceeded % until , the situation has changed dramatically since march , when the intensive care unit (icu) occupancy rates reached % due to the pandemic. hence, our hospital has been under pressure to upgrade our icu services. we have used crisis management tactics in configuring our medical city (table ) . first, we created a multidisciplinary crisis management team (cmt) to supervise the operations, and we promptly applied a surge plan based on the available scientific evidence. our cmt policies, icu configuration strategy, staff and resource utilization, admission protocols, and therapeutic guidelines have been reviewed continually based on new international updates, emerging therapies, and the recommendations of our national health authorities. [ ] [ ] [ ] [ ] by adjusting, and retrofitting existing icus, and acute wards. we have expanded the icu bed capacity in a stepwise manner: phase , beds; phase , beds; phase , beds). our main challenge has been to install new structures (ie, gas access, power circuits, monitors, and hepa purifiers) in the pop-up units. we could not maintain single-patient occupancy; thus, we isolated cohorts of covid- patients in multiple-occupancy glass rooms. nursing stations have been set up outside these rooms; new circuits have been installed for the transmission of data and alarms; and new procedure carts have been arranged for each new unit. the icu-bed triage and staff governance have been controlled by the cmt. our cmt members have provided coverage hours per day, days per week to arrange the icu admission flow and the transfer of patients to other hospitals based on the daily moh plan. we have followed a tiered strategy in which we allocate experienced inten-sivists and nurses to supervise redeployed noncritical care physicians and nurses, and we also established back-up teams. the refinement of the respiratory and icu care included changing the ventilator circuits and filters based on patient needs, avoiding nebulizers, creating specialized intubation and prone-positioning ventilation teams, and upgrading the oxygen supply system. the latter has been a major problem for our oxygen supply management team. hence, we have promoted awake prone positioning and more oxygen-support therapies (ie, high-flow nasal cannula, and helmet continuous positive pressure ventilation) to avoid mechanical ventilation if possible. interventional therapies (ie, extracorporeal membrane oxygenation and therapeutic plasma exchange) have been carefully screened by expert teams to optimize resource utilization. the icu pharmacy operations have been linked to the moh central stock and supervised by pharmacists of the cmt to facilitate the prompt delivery of medications. infection control measures have been strictly implemented in all hospital areas by creating specific zones and protocols for donning and doffing personal protective equipment, providing sanitizer dispensers, applying strict room-disinfection protocols, and providing safe waste handling. moreover, we have utilized novel transportation capsule isolation technology to minimize the risk of sars-cov- acquisition during inter-and intrahospital transportation. new hospital communication systems have been installed in the pop-up icus. the communication between frontline staff and the cmt is continuous. because visitors were not allowed, family meetings were organized via web-based applications to reduce patient and family stress. training and emotional staff support have been provided on a daily basis. we have utilized daily covid- training sessions to provide additional emotional reassurance (ie, dual training and emotional support strategy). moreover,~ covid- patients have been hospitalized in our icu over the past months. our staff's nosocomial infection rate was~ % during the early stages of the pandemic, and it has decreased to . % since may . as the current wave of covid- subsides, we are focusing on maintaining our costly infrastructure upgrades. these could ensure that a proper set-up would be available to meet future needs. [ ] [ ] [ ] stores of equipment, medications, and technical gadgets remains under cmt supervision. continuous medical education of our staff about covid- by our moh could facilitate the management of future outbreaks. regardless of the limitations in any healthcare system, hospitals should be prepared for future pandemics. clinical characteristics of coronavirus disease in china covid- ) guidelines (revised version . ). saudi ministry of health website hospital preparedness for covid- : a practical guide from a critical care perspective critical care crisis and some recommendations during the covid- epidemic in china covid- in china: ten critical issues for intensive care medicine escalating infection control response to the rapidly evolving epidemiology of the coronavirus disease (covid- ) due to sars-cov- in hong kong novel transportation capsule technology could reduce the exposure risk to sars-cov- infection among health care workers: a feasibility study acknowledgments. we acknowledge all healthcare workers for their hard work and sacrifice in the fight against covid- in saudi arabia.financial support. no financial support was provided relevant to this article. all authors report no conflicts of interest relevant to this article. key: cord- -l hkn li authors: luyt, charles-edouard; bouadma, lila; morris, andrew conway; dhanani, jayesh a.; kollef, marin; lipman, jeffrey; martin-loeches, ignacio; nseir, saad; ranzani, otavio t.; roquilly, antoine; schmidt, matthieu; torres, antoni; timsit, jean-françois title: pulmonary infections complicating ards date: - - journal: intensive care med doi: . /s - - -z sha: doc_id: cord_uid: l hkn li pulmonary infection is one of the main complications occurring in patients suffering from acute respiratory distress syndrome (ards). besides traditional risk factors, dysregulation of lung immune defenses and microbiota may play an important role in ards patients. prone positioning does not seem to be associated with a higher risk of pulmonary infection. although bacteria associated with ventilator-associated pneumonia (vap) in ards patients are similar to those in patients without ards, atypical pathogens (aspergillus, herpes simplex virus and cytomegalovirus) may also be responsible for infection in ards patients. diagnosing pulmonary infection in ards patients is challenging, and requires a combination of clinical, biological and microbiological criteria. the role of modern tools (e.g., molecular methods, metagenomic sequencing, etc.) remains to be evaluated in this setting. one of the challenges of antimicrobial treatment is antibiotics diffusion into the lungs. although targeted delivery of antibiotics using nebulization may be interesting, their place in ards patients remains to be explored. the use of extracorporeal membrane oxygenation in the most severe patients is associated with a high rate of infection and raises several challenges, diagnostic issues and pharmacokinetics/pharmacodynamics changes being at the top. prevention of pulmonary infection is a key issue in ards patients, but there is no specific measure for these high-risk patients. reinforcing preventive measures using bundles seems to be the best option. acute respiratory distress syndrome (ards) regroups a wide range of diseases whose consequence is lung inflammation, alveolar damage and pulmonary edema [ ] . whatever the initial lung injury, patients with ards are prone to develop secondary pulmonary infection, namely ventilator-associated pneumonia (vap). recent data from the center for disease control and prevention suggest that vap rates are not dropping in the usa despite patients with ards exemplify the apparently paradoxical immune state of critically ill patients, whereby activated immune cells mediate organ damage while manifesting impaired antimicrobial defenses [ ] . impaired cellular functions have been identified across both the innate and adaptive arms of the immune system [ , ] , and appear to be stereotyped rather than specific to any precipitating cause of ards [ ] . this apparently paradoxical state is due to the ability of pro-inflammatory and tissue damage molecules to drive immune dysfunction [ , ] . dysfunctional immune cells are found in the lung as well as peripheral blood [ ] . interestingly, lung mucosal immune defects are protracted after the cure from primary inflammation, thus increasing the susceptibility to hospital-acquired pneumonia and ards for weeks after systemic inflammation [ ] . following experimental pneumonia, pulmonary macrophages and dendritic cells demonstrated prolonged suppression of immune functions which increased the susceptibility to secondary infection [ ] . expansion of immuno-modulatory regulatory t cells (t reg ) is also seen and may mediate impaired innate as well as adaptive immune function [ ] . patients with suspected vap, including those with ards, demonstrated impaired phagocytic function of alveolar neutrophils, which interestingly appeared to be mediated by different mediators than those driving dysfunction in the peripheral blood [ ] . while we have a growing understanding of the mediators driving dysfunction, and the intracellular mechanisms which drive them [ ] , we do not as yet have proven therapies although there are multiple potential agents [ ] . when aiming at modulating immunity during inflammation, it is important to differentiate innate and adaptive immune cells responses. while exhaustion and apoptosis seem to be central to lymphocyte defects observed in critically ill patients [ ] , some innate immune cells undergo reprogramming involving epigenetic reprogramming and increased cellular metabolism, a phenomenon so-called trained immunity, resulting in high production of inflammatory cytokines such as il- and tnfα during secondary immune challenge [ ] . while glucocorticoids are classically considered as immunosuppressive drugs, it has been shown that they can prevent the immune reprogramming observed after inflammatory response [ ] , thus limiting the susceptibility of patients admitted to the intensive care unit (icu) to respiratory complications such as pneumonia or ards and improving outcomes of patients with ards [ ] . part of the complexity of pulmonary super-infections arises from the interaction between the injured host with their pulmonary microbiome. although considerably less abundant and diverse than the better studied gastrointestinal microbiome [ ] , the pulmonary microbiome is increasingly well defined and undergoes significant changes during critical illness and ards [ ] . the major role of respiratory microbiota on mucosal immunity and respiratory functions in health suggests that its alterations could be involved in the respiratory complications observed in critically ill patients [ ] . indeed, mechanically ventilated patients experience a reduction in diversity of pulmonary microbes and an increase in enteric-type organisms, even in the absence of overt infection [ ] . early alterations of the lung microbiome, notably increased bacterial burden and biofilm formation, enrichment with gut-associated bacteria and loss of diversity, are associated with the risk of ards and the duration of mv support in critically ill patients [ ] . pre-existing dysbiosis, such as that induced by tobacco smoke, may also influence the development of ards following major trauma [ ] . alongside changes in bacterial species, it is common to find reactivation of latent herpesviridae such as herpes simplex virus (hsv) and cytomegalovirus (cmv) [ ] . the drivers of these changes are incompletely understood but are multi-factorial, with possible mechanisms illustrated in fig. [ , , ] . adding further complexity is the potential for microbes themselves to drive further immune dysfunction [ ] . vap should therefore be conceptualized as less a de novo infection by an exogenous pathogen, but rather a dysbiotic response to critical illness with overgrowth of specific genera of bacteria [ ] . appropriate antibiotic therapy targeting the dominant species, those frequently detected by culture, is key in certain patients but risks exacerbating dysbiosis and further harm to the patient [ ] . what remains to be proven is whether interventions to restore symbiosis, i.e., to increase bacterial diversity rather than only eliminating dominant species, can improve outcomes [ ] . although the experience of fecal transplantation in clostridium difficile associated diarrhea suggests that microbial transplantation may be an effective form of therapy [ ] , negative experience of probiotics in pancreatitis and recent examples of 'probiotic' bacteria causing infections sound a note of caution [ , ] . developing effective therapies for respiratory dysbiosis will require tools to profile the host peripheral pulmonary superinfections in ards patients considerably impact patients' prognosis which is favored by altered local and systemic immune defenses. the poor outcome of ards with pulmonary superinfections is probably related to the lack of early accurate diagnostic methods and difficulties in optimizing therapy. and pulmonary immune cell function and the pulmonary microbiome [ ] . hyperoxia is common in patients receiving mv for ards. a secondary analysis of the lung safe trial [ ] reported that % of the analyzed patients had hyperoxia on day , and % had sustained hyperoxia. while two randomized controlled trials found beneficial effect of avoiding hyperoxia [ , ] , a recent large international multicenter trial demonstrated no effect of conservative oxygen therapy in a cohort of critically ill patients [ ] . however, a subsequent sub-study raised the possibility of clinically important harm with conservative oxygen therapy in patients with sepsis [ ] . oxygen toxicity is mainly related to the formation of reactive oxygen species (ros), especially during hypoxia/ re-oxygenation and long exposure to oxygen. high level of inspired oxygen is responsible for denitrogenation phenomena and inhibition of surfactant production promoting expiratory collapse and atelectasis [ ] . absorption atelectasis occurs within few minutes after pure o breathing. in mechanically ventilated patients, atelectasis seriously impairs cough reflex and mucus clearance resulting in abundant secretions in the lower airways and higher risk for vap. prolonged hyperoxia also impairs the efficacy of alveolar macrophages to migrate, phagocyte and kill bacteria, resulting in decreased bacterial clearance [ ] . hyperoxemia markedly increased the lethality of pseudomonas aeruginosa in a mouse model of pneumonia [ ] . additionally, o can cause pulmonaryspecific toxic effect called hyperemic acute lung injury (hali) (fig. ) . although earlier studies reported a link between high fio and atelectasis, further studies are required to evaluate links between hyperoxia and mortality or vap. in a single center cohort study of patients, among whom ( %) had vap, multivariate analysis identified number of days spent with hyperoxemia [or = . , % ci: ( . - . ) per day, p = . ], as an independent risk factor for vap. however, the study was retrospective, performed in a single center, and the definition used for hyperoxia (at least one pao value > mmhg per day) could be debated [ ] . in the recent hypers s randomized controlled trial [ ] , the percentage of patients with atelectasis doubled in patients with hyperoxia compared with those with normoxia ( % vs. %, p = . ). however, no significant difference was found in vap rate between hyperoxia and control group ( % vs. %, p = . ). however, vap was not the primary outcome of this trial, and there is no clear definition of icu-acquired pneumonia. further well-designed studies are required to determine the relationship between hyperoxia and vap. prone position is recommended in patients with severe ards and is commonly used in this population. there is a rationale supporting a beneficial effect of prone position on the incidence of vap, as it facilitates secretion drainage and allows atelectasis resolution. previous human and animal studies have clearly showed a link between atelectasis and vap, and reported that efficient secretion drainage might result in lower incidence of vap [ ] . on the other hand, prone position might facilitate microorganisms' dissemination and increase microaspiration of contaminated secretions. the results of studies on the relationship between prone position and vap should be interpreted with caution, because of some limitations such as observational design, small number of included patients and confounding factors. five recent studies were performed in patients with protective lung mv, including four randomized controlled studies and one large observational cohort. mounier et al. [ ] reported no significant reduction of vap incidence in a large cohort (n = ) of hypoxemic patients positioned in the prone position, as compared to those who did not receive this intervention [hr . ( % ci . - . )]. one randomized controlled trial reported reduced risk for vap in multiple trauma patients who were subjected to intermittent prone position, as compared to those who did not (p = . ) [ ] . however, the incidence of vap was very high in the control group ( %), and the number of included patients was small (n = ). three other randomized controlled trials reported no significant relationship between prone position and vap [ , , ] . however, these studies lack information on efficient preventive measures of vap, such as the use of subglottic secretion drainage or continuous control of tracheal cuff pressure, and vap was not their primary outcome. in summary, available data do not support a significant relationship between prone position and vap, although it has demonstrated beneficial effects on mortality in severe ards. the diagnosis of lung infections in patients with ards is challenging [ ] . the diagnosis of pneumonia, the dominant respiratory infection of concern in ards, is ultimately a histopathological diagnosis which requires the presence of airspace inflammation and an infecting organism. however, obtaining lung tissue for diagnosis is seldom practical or desirable in ventilated patients [ ] . the clinical features of systemic inflammation and localizing chest signs such as crepitations and bronchial breathing are non-specific and insensitive. while radiological evidence of airspace infiltration is useful, the gold standard of computed tomography is not practical for most patients, leading practitioners to rely on plain radiographs and ultrasound, and even computed tomography cannot always reliably distinguish between infective and non-infective causes of airspace infiltration [ , ] . use of clinical and radiographic criteria alone are likely to significantly overestimate the rate of pneumonia and lead to excessive, potentially harmful, use of antibiotics [ ] . it is also important to recall that pneumonia itself is the commonest precipitant of ards, which, together with the bilateral radiographic alterations in ards patients, creates an additional challenge for the ascertainment of a "new or worsening pulmonary infiltrate", a condition required for clinical diagnosis of vap [ ] . another challenge is the distinction between ventilator-associated tracheobronchitis (vat) and vap. vat is defined as a lower respiratory tract infection without involvement of the lung parenchyma (and therefore without new/progressive chest x-ray infiltrate). the distinction between vat and vap in ards patients remained challenging given the poor accuracy of chest radiograph to detect new infiltrates. obtaining samples from the lungs for microbiological culture is crucial to the establishment of infection. however, there is considerable variability in the timing and type of specimen obtained in practice [ ] . the identification of infection can be complicated by colonization of the proximal airways, which happens rapidly after intubation and is frequent in ards patients [ ] . it is important to differentiate between colonization (presence of bacteria, even at a high burden, in the respiratory tract without lung infection), a harmless phenomenon, and infection. although protected deep lung sampling by broncho-alveolar lavage or protected specimen brush reduces the risk of false positives relative to endotracheal aspirate, this has not been convincingly demonstrated to alter outcomes although observational data suggest they can safely reduce antibiotic use [ ] . although falsepositive results from proximal colonization are a significant problem, intercurrent use of antibiotics is common in ards patients and increases the risk of false-negative culture. this is, increasingly, being addressed by the use of culture-independent molecular technique; however, the utility of the tools available is limited by their restricted range of organisms covered and the risk of over-sensitive detection of irrelevant organisms driving inappropriate use of antimicrobials [ ] [ ] [ ] . physicians should be aware of this particular point and therefore interpret with caution the results of these tests. there are very few prospective studies demonstrating the impact of molecular diagnostics on patient management and the results of forthcoming trials are awaited. antigen detection in the lower respiratory tract can also aid diagnosis, especially with organisms such as aspergillus where culture and pcr are imperfect [ ] . the value of aspergillus sp. and aspergillus fumigatus pcr is promising, but remain to be evaluated in ards patients. in patients with ards and bilateral radiographic infiltrates, there remains a question of which region to sample invasively. while trials have not been undertaken to answer this question definitively, observational data suggest that in the presence of bilateral infiltrates, unilobe sampling is sufficient and minimizes risk of lavage volume and duration of bronchoscopy [ ] . the host response makes up the crucial second component of any infection syndrome, and therefore host biomarkers can be of use in diagnosing infection in ards. laboratory hematological features of inflammation, including leucocytosis, neutrophilia and elevated c-reactive protein, are not specific to infection and can occur in sterile precipitants of ards [ ] . the inflammatory response in pneumonia is highly compartmentalized and alveolar cytokines and other alveolar markers are the most discriminant for pneumonia (table ) [ ] . notably, although alveolar cytokines demonstrated excellent assay performance, measurement of pulmonary cytokines did not alter antimicrobial prescribing in a recent randomized trial [ ] . this illustrates that the challenges in diagnosis lie not only with the technology, but also the behavioral response to results. peripheral blood markers have the advantage of avoiding the need for bronchoscopic sampling and are therefore easier to obtain; however, they are generally less able to discriminate pneumonia from other infections table summary of host-based biomarkers for diagnosis of pneumonia in ards ards acute respiratory distress syndrome, rct randomized controlled trial, strem soluble triggering receptor expressed on myeloid cells, vap ventilator-associated pneumonia, hla human leukocyte antigen interleukin- /interleukin- validated in multi-center cohort [ ] but did not influence practice in an rct [ ] strem- initial report, but not validated in follow-up study [ , ] exhaled breath markers experimental with technical variation currently limiting implementation [ ] pentraxin- meta-analysis suggested alveolar levels superior to plasma levels with moderate diagnostic performance, no rct testing influence on practice [ ] and many lack sensitivity and or specificity for infection (table ). in summary, the diagnosis of pulmonary infection in ards is challenging, and existing techniques are imperfect and risk both inadequate and overtreatment. a combination of clinical, biological and radiological assessment, combined with microbiological sampling from the lungs, remains the current gold standard (fig. ) . the development of molecular diagnostics focusing on both host and pathogen offers great promise, but their impact on patient management and outcomes remains to be convincingly demonstrated. the most common bacterial causes of vap include enterobacterales, pseudomonas aeruginosa, staphylococcus aureus, and acinetobacter among the general population of mechanically ventilated patients [ ] . the pathogens associated with vap in ards are similar to those seen among non-ards patients who develop vap (fig. ) [ , , ] . moreover, patients with ards undergoing extracorporeal membrane oxygenation (ecmo) demonstrate the same breakdown of pathogens with pseudomonas aeruginosa and staphylococcus aureus predominating [ ] . one important element, regardless of the specific causative bacteria seen in vap, is that antibiotic resistance is increasing in vap as well as in other nosocomial infections. in , the tigecycline evaluation and surveillance trial described important european changes in antimicrobial susceptibility between and , with increases in the rates of esbl-positive escherichia coli (from . to . %), mdr acinetobacter baumannii complex (from . to . %), esbl-positive klebsiella pneumoniae (from . to . %), and methicillin-resistant staphylococcus aureus (mrsa) (from . to . %) [ ] . similar worrisome trends for bacterial susceptibility to available antimicrobials have been reported by other investigators as well [ , ] . most worrisome is the increasingly recognized presence of resistance to new antibiotics specifically developed to treat vap [ ] . prior antibiotic exposure and subsequent changes in the host's airway microbiome due to dysbiosis seem to drive the prevalence of antibiotic-resistant bacterial causes of vap (fig. ) [ , ] . the presence of invasive devices such as endotracheal tubes and antibiotic administration promote pathogenic bacterial colonization due to the overwhelming of local defenses, resulting in the development of an intermediate respiratory infection termed vat [ ] . vat represents a compartmentalized host response associated with a better overall prognosis compared to vap, but vat can prolong the duration of mv and icu length of stay [ ] . if the aforementioned response is not compartmentalized, progression to vap is likely and potentially other organ failure including ards may occur [ ] . one of the major fears concerning nosocomial pulmonary infections in ards at the present and into the future is the increasing presence of novel pathogens and infections with microorganisms for which limited treatment options exist. as we increasingly treat older and more immunocompromised hosts with ards, the likelihood for emergence of novel pathogens and infection with pan-resistant microorganisms will increase. early identification of such emerging pathogens in ards is critical. the importance of early identification of novel pathogens is necessary to facilitate epidemiologic surveillance, curtailing pathogen spread, and providing early treatment as illustrated by recent nosocomial outbreaks of middle eastern respiratory syndrome coronavirus, sars-cov- and pan-resistant escherichia coli [ ] [ ] [ ] [ ] . in the future, metagenomic next-generation sequencing should allow earlier and more targeted treatments for novel pathogens causing ards or complicating the course of patients with ards. such technology will allow earlier pathogen identification and accelerate the workup and treatment for both infectious and noninfectious causes of diseases complicating ards [ ] . although the majority of respiratory infections in ards patients are caused by bacteria, icu-induced immunoparalysis may induce infection with unusual pathogens. although invasive pulmonary aspergillosis (ipa) has been reported mainly in immunocompromised patients, lower respiratory tract colonization with aspergillus has been more frequently associated with ards than in other patients invasively ventilated in icu [ ] . the mechanism of damage involves the combination of alveolar damage (induced by ards) and a dysregulation of the local immune response, together with sepsis-induced immunosuppression, innate immunity and antigen presentation impairment, accounting for the development of ipa in previously colonized patients [ , ] . co-infection with influenza has been reported as a risk factor for ipa [ ] . contou et al. reported isolation of aspergillus in the lower respiratory tract in almost % of patients with [ ] . bar graphs depicting the percentages of the most frequently isolated microorganisms in icu-acquired pneumonia episodes for (red bars) and for patients with acute respiratory distress syndrome (ards) (blue bars). total number of isolates , and , respectively ards ( % had putative or proven ipa) [ ] . an important finding from this study was that the median time between initiation of mv and first sample positive for aspergillus spp. was only days. moreover, a post-mortem study in ards patients found that % of deceased patients had ipa manifestations [ ] . if aspergillus is identified as a pathogen in an immunocompetent patient, it is recommended to screen for any kind of immunosuppression (humoral, cellular or combined, complement, etc.). viruses may also be responsible for infection in ards patients. because of immunoparalysis following the initial pro-inflammatory response to aggression, latent viruses such as herpesviridae may reactivate in icu patients [ ] . hsv and cmv are frequently recovered in lung or blood of icu patients (up to %, depending on the case mix), their reactivation being associated with morbidity and mortality [ , , ] . however, the exact significance of these reactivations is debated: these viruses may have a true pathogenicity and cause lung involvement [ , ] , thereby having a direct role in morbidity/mortality observed with their reactivation; or they may be bystanders, their reactivation being only secondary to disease severity or prolonged icu stay. to date, the answer is not known, data regarding a potential benefit of antiviral treatment being controversial. for hsv, the most recent randomized control trial found no increase in ventilator-free days in patients having received acyclovir, but a trend toward lower -day mortality rate (hazard ratio for death within days post-randomization for the acyclovir group vs control was . ( % ci . - . , p = . ) [ ] . for cmv, two recent randomized clinical trials (rcts) were performed: the first one showed that valganciclovir prophylaxis in cmv-seropositive patients was associated with lower rate of cmv reactivation as respiratory microbiome dysbiosis is also demonstrated as a prerequisite for most cases of vap and vt compared to placebo, but not with better outcome [ ] ; and the second one showed that, as compared to placebo, ganciclovir prophylaxis did not lead to lower il- blood level at day , but patients having received ganciclovir had trend toward lower duration of mv [ ] . besides latent viruses, respiratory viruses (rhinovirus, influenza, adenovirus…) have been recently found to be responsible for nosocomial infection in ventilated or non-ventilated patients [ ] . however, like herpesviridae, their true impact on morbidity/mortality is not known. in summary, hsv and cmv may cause viral disease in ards patients, and respiratory viruses may be responsible for hospital-acquired pneumonia; however, the true impact of these viral infections on outcomes remains to be determined. veno-venous extracorporeal membrane oxygenation (vv-ecmo) is now part of the management of refractory ards [ , ] . these very sick patients are at high risk for developing typical icu-related nosocomial infections (e.g., vap or bloodstream infections), in addition to ecmo-specific infections, including localized infections at peripheral cannulation insertion sites. bizzarro et al. reported a high prevalence rate of nosocomial infection of % in a large international registry of ecmo patients [ ] , pulmonary infection being the most frequently reported. this high prevalence may be explained by underlying comorbidities, concomitant critical illness, prolonged mechanical support, mv and icu stay as well as impairment of the immune system by the extracorporeal circuitry through endothelial dysfunction, coagulation cascade, and pro-inflammatory mediators release [ ] . while the rate of pulmonary infection on ecmo has not been thoroughly compared with a population with the same critical illness but in the absence of ecmo, vap was reported in out of patients receiving ecmo ( % vv-ecmo) by grasseli et al. [ ] . among patients who underwent va-ecmo for > h and for a total of ecmo days, ( %) developed nosocomial infections, corresponding to a rate of . infectious episodes per ecmo days. vap was the main site of infection with episodes occurring in patients after a median ± standard deviation of ± days [ ] . vap and resistant organisms are therefore common in that population [ ] [ ] [ ] . the duration of ecmo has been frequently associated with a higher incidence of vap [ , ] , even if a causal relationship is impossible to establish. indeed, longer ecmo runs could be a direct consequence of infectious complications rather than a risk factor. however, it seems clear that ecmo patients who acquired vap had longer durations of mv and ecmo support and a higher overall icu mortality [ , , ] . similarly, immunocompromised patients and older age were consistently found as risk factors associated with infections on ecmo [ , ] . the clinical diagnosis of pulmonary infection in ecmo patients is challenging, since they may have signs of systemic inflammatory response, possibly triggered by the ecmo itself, whereas fever could be absent if the temperature is controlled by the heat exchanger on the membrane. in addition, the common application of an ultraprotective ventilation aiming to rest the lung on vv-ecmo and frequent pulmonary edema on va-ecmo make the interpretation of new infiltrates on chest-x ray, which are commonly used to suspect a vap, difficult. beyond the diagnosis challenge of pulmonary infection on ecmo, the changes of pharmacokinetics/pharmacodynamics (pk/pd) of antimicrobial agents could also contribute to delaying appropriate antimicrobial treatment and consequently increase the burden of infections. an increase in the volume of distribution by ecmo as well as the severity of the underlying illness and drug clearance impairment through renal or liver dysfunctions complicates the management of antibiotics and antifungal therapies [ ] . while waiting for large in vivo studies aiming to report the respective pk/pd of antimicrobial agents on ecmo, avoiding lipophilic agents (i.e., more likely sequestrated on the ecmo membrane) [ ] and therapeutic drug monitoring are warranted. apart from bacteremias/fungemias, most infections are in interstitial or tissue spaces and hence the efficacy of a drug should be related to drug concentrations and actions in those tissues [ ] . drugs will cross the body membranes (move from intravenous compartment into tissue compartments) if there is an intrinsic "carrier mechanism", or if the compound is either a small molecule or is lipophilic [ ] . hydrophilic antimicrobials are found in extravascular lung water, but for relevant lung tissue penetration the lipophilic drugs are most important [ ] [ ] [ ] [ ] . large molecules such as vancomycin, teicoplanin, aminoglycosides and colistin will have poor lung tissue concentrations when given intravenously (elf/plasma concentration ratio << ) [ , ] . betalactams penetrate into lung parenchyma better than other hydrophobic antibiotics [ ] . elf/plasma concentration ratio for glycylcyclines (e.g., tigecycline) is around . lipophilic compounds such as macrolides, ketolides, quinolones, oxazolidinones, antifungals and antivirals will have good lung tissue concentrations (elf/plasma concentration ratio > ) after intravenous administration [ ] . oxazolidinones (linezolid), glycylcyclines (tigecycline) and sulfonamides (cotrimoxazole) may be effective in the treatment of mdr pathogens; however, there is no ards-specific lung pk (elf/plasma concentration) data for these drugs. although newer antimicrobials (ceftolazone-tazobactam, meropenem-vaborbactam, plazomicin) have activity against drug-resistant gram-negative pathogens, there are limited alternatives against drug-resistant acinetobacter baumaniii such as cefiderocol which is undergoing phase clinical trials. the advent of newer generation of delivery devices and mdr organisms has led to a renewed interest in the field of nebulized antimicrobials [ ] , although recent trials in pneumonia have failed to demonstrate clinical benefits [ , ] . ards is often associated with multiple organ dysfunction syndrome. hence, the possibility of achieving high intrapulmonary concentrations with limited systemic side effects is appealing. although recent wellconducted rcts argued against systematic use of nebulized antimicrobials in nosocomial pneumonia [ , ] it may still have a place in the treatment of severe lung infections due to mdr bacteria. in this view, selecting the correct antimicrobial formulation and dosing (table ) is an essential first step, as well as the best device, namely vibrating mesh nebulizer [ ] . clinical pk data available for some nebulized antibacterial, antiviral and antifungals confirm high pulmonary and low systemic exposure [ ] . sputum pk studies report high variability and are difficult to interpret [ ] . however, lung deposition of nebulized antimicrobials is influenced by many factors, including specific ventilator settings. ventilator settings and procedures usually recommended for improving aerosol delivery (high tidal volume, low respiratory rate and low inspiratory flow, systematic changes of expiratory fil-ters…) are difficult to implement in patients with ards, at least those with the most severe forms. ards is a heterogeneous lung condition causing inhomogeneous ventilation distribution potentially affecting drug delivery at the affected site. increased lung inflammation can also increase systemic concentrations by increased diffusion across the alveolo-capillary barrier, thus influencing the nebulized drug dosing [ ] . further pk studies investigating nebulized antimicrobial in ards are required for recommending dosing regimens in this condition. areas of investigation such as pulmonary nanomedicine and targeted delivery using intracorporeal nebulization catheter, while still investigational, have the potential to overcome many of these barriers and enhance lung tissue antimicrobial concentrations [ ] . nosocomial infections may contribute to the mortality related to ards given that such infections are responsible for worsening hypoxemia and causing sepsis. as such, the prevention of these infections must be reinforced to avoid straining the prognosis of patients suffering from ards. however, interpreting the vap prevention literature in this context is challenging because ( ) no studies have been conducted expressly in ards patients; ( ) several preventive measures have been shown to reduce the rate of pulmonary infection, but many less have demonstrated an impact on patient prognosis [ ] . that being said, the general strategy for preventing pulmonary infection applies also in ards patients. however, some preventive measures deserve a special focus in the context of ards patients (fig. ) : ( ) oral care with chlorhexidine is suspected to worsen respiratory failure; ( ) selective digestive decontamination (sdd) deserves to be discussed in such high-risk patients, as it has been proven to be effective in reducing mortality in icu patients and likely lowers vap rates. there is no single preventive measure that will completely avert pulmonary infection in patients suffering from ards and patients must be approached with a package or bundle of preventive measure [ ] provided that an early weaning strategy is part of the bundle [ ] . other preventive measures and notably some expensive medical devices such as automated endotracheal tube cuff pressure monitoring or endotracheal tube allowing subglottic secretion drainage have not been proven effective on patient's outcomes (mortality, duration of mv, antibiotic use), but could be dedicated to these high-risk patients. however, translating research into an efficient bundle of care to prevent pulmonary infection remains a challenge and behavioral approaches to implement the measures are as important as the measures themselves [ ] . chlorhexidine-gluconate (chg) use for oral care in icu patients may be harmful despite previous consistent data showing its beneficial effect in preventing vap [ ] . oral mucosa adverse events with % (w/v) chg mouthwash in icu are frequent, but often transient. adverse events described were erosive lesions, ulcerations, plaque formation (which are easily removed), and bleeding mucosa in of patients ( . %) who received % (w/v) chg [ ] . a systematic review and meta-analysis by labeau et al. in evaluated the effect of oral decontamination with chx [ ] . twelve studies were included (n = ). overall, chx use resulted in a significant risk reduction of vap (rr = . , % ci . - . , p = . ). favorable effects were more pronounced in subgroup analyses for % chx (rr = . , % ci . - . ) and for cardiosurgical patients (rr = . , % ci . - . ). however, a recent metaanalysis suggested that oral chg paradoxically increased the risk of death, which may have resulted from toxicity of aspirated chg in the lower respiratory tract [ ] . consequently, it remains unclear whether using chg for oral care affects outcomes in critically ill patients. selective digestive decontamination (sdd) remains definitely a matter of controversy [ ] . on one hand, it reduces the mortality in mechanically ventilated patients, while on the other hand its use is limited by the potential fig. prevention of pulmonary infections in ards patients: from highly recommended preventive measures to a cautious or even a not recommended use of inducing more bacterial resistance. however, in ards patients at high risk of mortality with high level of bacterial resistance, sdd deserves to be evaluated. the better understanding of ards phenotype may offer an opportunity to develop more selective preventive measures in the future. pulmonary superinfections of ards patients considerably impact patients' prognosis. it is favored by altered local and systemic immune defenses. the poor outcome of ards with pulmonary superinfections is probably related to the lack of early accurate diagnostic methods and difficulties in optimizing therapy. this article reviewed the available knowledge and revealed areas for future investigations in pathophysiology, diagnosis, treatment and prevention. potentials for improvements are numerous in all the fields: to improve knowledge about the host factors (both systemic and local) favoring superinfections. to identify early the disequilibrium between the host and the microbiota that may promote pneumonia in ards patients. to identify early criteria for suspicion of vap and vat. to determine the appropriate time to perform bacteriological samples, and in particular develop a morphological way to unmask areas of pneumonia at the bedside. to identify new diagnostic tests providing accurate and early diagnosis of pneumonia. to develop accurate early methods of pathogen identification and to distinguish patients infected and simply colonized (especially for viruses and fungi). to evaluate the impact of new molecular methods in diagnosing pneumonia in ards patients and improve prognosis. to evaluate the impact of tdm monitoring of antimicrobials on the prognosis of ards patients with pneumonia. to develop non-antibiotic therapies in the future, including vaccines, monoclonal antibodies and phage therapy. evaluate the benefit on antimicrobial consumption and prognosis of the use of sdd in ards patients in icus with a high level of bacterial resistance. acute respiratory distress syndrome changes in prevalence of health care-associated infections in us hospitals ventilator-associated pneumonia and icu mortality in severe ards patients ventilated according to a lung-protective strategy ventilator-associated pneumonia in ards patients: the impact of prone positioning. a secondary analysis of the proseva trial ventilator-associated pneumonia in adults: a narrative review the role of neutrophils in immune dysfunction during severe inflammation immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach cell-surface signatures of immune dysfunction risk-stratify critically ill patients: infect study c a mediates peripheral blood neutrophil dysfunction in critically ill patients trauma-induced damageassociated molecular patterns-mediated remote organ injury and immunosuppression in the acutely ill patient contribution of dendritic cell responses to sepsis-induced immunosuppression and to susceptibility to secondary pneumonia alveolar macrophages are epigenetically altered after inflammation, leading to long-term lung immunoparalysis local modulation of antigen-presenting cell development after resolution of pneumonia induces long-term susceptibility to secondary infections c a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodelling immunosuppression in patients who die of sepsis and multiple organ failure trained immunity and local innate immune memory in the lung dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial harnessing the microbiome for lung health enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome the lung microbiota of healthy mice are highly variable, cluster by environment, and reflect variation in baseline lung innate immunity the dynamics of the pulmonary microbiome during mechanical ventilation in the intensive care unit and the association with occurrence of pneumonia lung microbiota predict clinical outcomes in critically ill patients lung microbiota is related to smoking status and to development of acute respiratory distress syndrome in critically ill trauma patients herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation loss of microbial diversity and pathogen domination of the gut microbiota in critically ill patients antibiotic treatmentinduced secondary iga deficiency enhances susceptibility to pseudomonas aeruginosa pneumonia pathophysiological role of respiratory dysbiosis in hospital-acquired pneumonia antimicrobialassociated harm in critical care: a narrative review duodenal infusion of donor feces for recurrent clostridium difficile probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial genomic and epidemiological evidence of bacterial transmission from probiotic capsule to blood in icu patients hyperoxemia and excess oxygen use in early acute respiratory distress syndrome: insights from the lung safe study effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit: the oxygen-icu randomized clinical trial hyperoxia and hypertonic saline in patients with septic shock (hypers s): a two-bytwo factorial, multicentre, randomised, clinical trial conservative oxygen therapy during mechanical ventilation in the icu conservative oxygen therapy for mechanically ventilated adults with sepsis: a post hoc analysis of data from the intensive care unit randomized trial comparing two approaches to oxygen therapy (icu-rox) adjunct therapies during mechanical ventilation: airway clearance techniques, therapeutic aerosols, and gases inhibition of extracellular hmgb attenuates hyperoxia-induced inflammatory acute lung injury hyperoxia exaggerates bacterial dissemination and lethality in pseudomonas aeruginosa pneumonia hyperoxemia as a risk factor for ventilator-associated pneumonia study of prone positioning to reduce ventilator-associated pneumonia in hypoxaemic patients prone positioning in acute respiratory distress syndrome: a multicenter randomized clinical trial effects of systematic prone positioning in hypoxemic acute respiratory failure: a randomized controlled trial prone positioning improves oxygenation in post-traumatic lung injury-a prospective randomized trial diagnosis of ventilatorassociated pneumonia in critically ill adult patients-a systematic review and meta-analysis a national survey of the diagnosis and management of suspected ventilator-associated pneumonia quantitative versus qualitative cultures of respiratory secretions for clinical outcomes in patients with ventilator-associated pneumonia usefulness of point-ofcare multiplex pcr to rapidly identify pathogens responsible for ventilator-associated pneumonia and their resistance to antibiotics: an observational study s pan-bacterial pcr can accurately identify patients with ventilator-associated pneumonia performance and impact of a multiplex pcr in icu patients with ventilator-associated pneumonia or ventilated hospital-acquired pneumonia invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study pneumonia in acute respiratory distress syndrome. a prospective evaluation of bilateral bronchoscopic sampling the pathogenic involvement of neutrophils in acute respiratory distress syndrome and transfusionrelated acute lung injury diagnostic importance of pulmonary interleukin- beta and interleukin- in ventilatorassociated pneumonia biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia (vaprapid ): a randomised controlled trial and process evaluation microbial cause of icu-acquired pneumonia: hospital-acquired pneumonia versus ventilator-associated pneumonia multicenter prospective study of ventilator-associated pneumonia during acute respiratory distress syndrome. incidence, prognosis, and risk factors. ards study group nosocomial infections in adult cardiogenic shock patients supported by venoarterial extracorporeal membrane oxygenation antimicrobial susceptibility among european gram-negative and gram-positive isolates collected as part of the tigecycline evaluation and surveillance trial geographical and temporal variation in the frequency and antimicrobial susceptibility of bacteria isolated from patients hospitalized with bacterial pneumonia: results from years of the sentry antimicrobial surveillance program ( - ) antimicrobial resistance higher mics (> mg/l) predict -day mortality in patients with lower respiratory tract infections caused by multidrug-and extensively drug-resistant pseudomonas aeruginosa treated with ceftolozane/tazobactam composition and dynamics of the respiratory tract microbiome in intubated patients how can we distinguish ventilator-associated tracheobronchitis from pneumonia? host-pathogen interaction during mechanical ventilation: systemic or compartmentalized response? lower respiratory tract infection and short-term outcome in patients with acute respiratory distress syndrome a candida auris outbreak and its control in an intensive care setting early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia escherichia coli harboring mcr- and blactx-m on a novel incf plasmid: first report of mcr- in the united states middle east respiratory syndrome clinical metagenomic sequencing for diagnosis of meningitis and encephalitis aspergillus in the lower respiratory tract of immunocompetent critically ill patients immune correlates of protection in human invasive aspergillosis increased incidence of co-infection in critically ill patients with influenza aspergillus-positive lower respiratory tract samples in patients with the acute respiratory distress syndrome: a -year retrospective study ards: a clinicopathological confrontation cytomegalovirus reactivation in critically ill immunocompetent patients epidemiology of multiple herpes viremia in previously immunocompetent patients with septic shock cytomegalovirus reactivation in icu patients acyclovir for mechanically ventilated patients with herpes simplex virus oropharyngeal reactivation: a randomized clinical trial safety and efficacy of antiviral therapy for prevention of cytomegalovirus reactivation in immunocompetent critically ill patients: a randomized clinical trial effect of ganciclovir on il- levels among cytomegalovirus-seropositive adults with critical illness: a randomized clinical trial impact of respiratory viruses in hospital-acquired pneumonia in the intensive care unit: a single-center retrospective study formal guidelines: management of acute respiratory distress syndrome extracorporeal membrane oxygenation for severe acute respiratory distress syndrome infections acquired during extracorporeal membrane oxygenation in neonates, children, and adults extracorporeal life support and systemic inflammation nosocomial infections during extracorporeal membrane oxygenation: incidence, etiology, and impact on patients' outcome nosocomial infections in adult cardiogenic shock patients supported by venoarterial extracorporeal membrane oxygenation ventilator-associated pneumonia in patients assisted by veno-arterial extracorporeal membrane oxygenation support: epidemiology and risk factors of treatment failure infections acquired by adults who receive extracorporeal membrane oxygenation: risk factors and outcome six-month outcome of immunocompromised severe ards patients rescued by ecmo. an international multicenter retrospective study pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men the effect of pathophysiology on pharmacokinetics in the critically ill patient-concepts appraised by the example of antimicrobial agents intrapulmonary pharmacokinetics of antibiotics used to treat nosocomial pneumonia caused by gram-negative bacilli: a systematic review penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antibacterial agents a research pathway for the study of the delivery and disposition of nebulised antibiotics: an incremental approach from in vitro to large animal models a randomized trial of the amikacin fosfomycin inhalation system for the adjunctive therapy of gram-negative ventilator-associated pneumonia: iasis trial inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with gram-negative pneumonia (inhale): a doubleblind, randomised, placebo-controlled, phase , superiority trial fundamentals of aerosol therapy in critical care clinical pharmacokinetics of inhaled antimicrobials aerosolized antibiotics for ventilator-associated pneumonia: lessons from experimental studies feasibility and safety of targeted cisplatin delivery to a select lung lobe in dogs via the aeroprobe intracorporeal nebulization catheter ventilator-associated pneumonia and its prevention management of adults with hospital-acquired and ventilator-associated pneumonia: clinical practice guidelines by the infectious diseases society of america and the brief summary of french guidelines for the prevention, diagnosis and treatment of hospitalacquired pneumonia in icu. ann intensive care : changes in knowledge, beliefs, and perceptions throughout a multifaceted behavioral program aimed at preventing ventilator-associated pneumonia prevention of ventilator-associated pneumonia with oral antiseptics: a systematic review and meta-analysis oral mucosal adverse events with chlorhexidine % mouthwash in icu reappraisal of routine oral care with chlorhexidine gluconate for patients receiving mechanical ventilation: systematic review and meta-analysis antipathy against sdd is justified: yes soluble triggering receptor expressed on myeloid cells and the diagnosis of pneumonia soluble triggering receptor expressed on myeloid cells- in bronchoalveolar lavage fluid is not predictive for ventilator-associated pneumonia the potential role of exhaled breath analysis in the diagnostic process of pneumonia-a systematic review diagnostic value of pentraxin in respiratory tract infections: a meta-analysis. medicine (baltimore) :e a biomarker panel (bioscore) incorporating monocytic surface and soluble trem- has high discriminative value for ventilator-associated pneumonia: a prospective observational study the current status of biomarkers for the diagnosis of nosocomial pneumonias maintenance treatment with inhaled ampicillin in patients with cystic fibrosis and lung infection due to methicillin-sensitive staphylococcus aureus use of inhaled ampicillin-sulbactam against multiresistant acinetobacter baumannii in bronchial secretions of intensive care unit patients aerosolized ceftazidime prophylaxis against ventilator-associated pneumonia in high-risk trauma patients: results of a double-blind randomized study aerosolized ceftazidime for prevention of ventilator-associated pneumonia and drug effects on the proinflammatory response in critically ill trauma patients nebulized ceftazidime and amikacin in ventilator-associated pneumonia caused by pseudomonas aeruginosa nebulized imipenem to control nosocomial pneumonia caused by pseudomonas aeruginosa levofloxacin inhalation solution (mp- ) in patients with cystic fibrosis with pseudomonas aeruginosa reduction of bacterial resistance with inhaled antibiotics in the intensive care unit aerosolized antibiotics and ventilator-associated tracheobronchitis in the intensive care unit aerosolized tobramycin in the treatment of ventilator-associated pneumonia: a pilot study for nebulized antibiotics in ventilator-associated pneumonia ( ) ventilator-associated pneumonia caused by multidrug-resistant gram-negative bacteria: understanding nebulization of aminoglycosides and colistin inhaled aztreonam lysine for chronic airway pseudomonas aeruginosa in cystic fibrosis key: cord- -vefgi h authors: bani-sadr, firouzé; hentzien, maxime; pascard, madeline; n'guyen, yohan; servettaz, amélie; andreoletti, laurent; kanagaratnam, lukshe; jolly, damien title: corticosteroid therapy for patients with covid- pneumonia: a before-after study date: - - journal: int j antimicrob agents doi: . /j.ijantimicag. . sha: doc_id: cord_uid: vefgi h background: anti-inflammatory drugs such as corticosteroids may beneficially modulate the host inflammatory response to covid- pneumonia. aims: to evaluate the impact of addition of corticosteroids to the hospital protocol for treatment of suspected or confirmed covid- pneumonia on rates of death or intensive care unit (icu) admission. methods: a before-after study was performed to evaluate the effect of addition of corticosteroids to our institution's covid- treatment protocol on hospital mortality. results: between march (rd) and april (th) , patients with covid- diagnosis were included. as corticosteroids were wide used since march , two periods were considered for the purposes of our study: the before period from march (rd) to (th) (n= ) and the “after period” (n= ) from march (th) to april (th) . the “after” period was associated with a lower risk of death (hr . ; % ci, . - . ; p= . ), and a lower risk of intensive care admission or death before icu admission (hr . % ci . - . ; p= . ) by multivariate analysis adjusted for age, national early warning score and institutionalization status. conclusions: in the “after period”, the addition of corticosteroids to our institution's covid- treatment protocol was associated with a significant reduction in hospital mortality. there is evidence that severe covid- patients present overwhelming inflammatory reactions with high levels of cytokines and inflammatory biomarkers, leading to lung injury [ , ] . anti-inflammatory drugs such as corticosteroids may beneficially modulate the host immune response to covid- pneumonia. with an average of - days between the occurrence of dyspnea and intensive care unit (icu) admission, we postulate that corticosteroid treatment initiated as soon as the patient has shortness of breath or needs oxygen therapy, might be effective in preventing acute respiratory distress syndrome and death [ ] . therefore, since march , we have systematically included corticosteroids in the treatment of patients with covid- pneumonia. prednisone or methylprednisolone at a dose of mg/kg equivalent per day ( . mg/kg for patients also receiving antiviral therapy with ritonavir as coadministration of corticosteroid and ritonavir lead to an increase corticosteroid plasma concentrations and their half-life) for to weeks, according to the severity of pneumonia, with dose tapering over the last week, was added to our initial therapeutic protocol for hospitalized covid- patients [ ] . this protocol included antiviral therapy (lopinavir plus ritonavir or darunavir plus ritonavir) and/or hydroxychloroquine, empiric broad-spectrum antibiotic treatment for days and preventive anticoagulation for to days. the long duration of corticosteroid treatment was chosen by analogy with that recommended for severe pneumocystis pneumonia in order to additionally prevent pulmonary fibrosis [ ] . as lopinavir-ritonavir treatment was not available after mid-march due to a drug shortage in our hospital, most of our patients received another hiv protease inhibitor (darunavir-ritonavir) after this date. in order to evaluate the impact of addition of corticosteroids to the hospital protocol for treatment of suspected or confirmed covid- pneumonia, we compared rates of death (primary outcome) or intensive care unit (icu) admission and/or death before icu admission (secondary outcome) in a before-and-after study, with the introduction of corticosteroids in our therapeutic protocol as the event defining the start of the "after" period. between march rd and april th , patients with covid- diagnosis defined as a positive result on an polymerase-chain reaction testing of a nasopharyngeal sample or presence of characteristic findings on chest ct scan were followed in the university hospital of reims, france [ ] . two periods were considered for the purposes of our study: the first, from march rd to th , corresponded to the "before" period, and the admission of the first cases to our center. during the "before" period, corticosteroid therapy was not recommended. the second period comprised march th through april th , ("after"), with wide use of corticosteroid therapy in this period following our decision to introduce it systematically due to the biological rationale of its use in the inflammatory phase. patients with initiation of corticosteroid therapy during the transition period (from march st to march th ) were not included in the before-after analysis. patients with fewer than days between symptom onset and april th , -that was the end point date of follow up -were not included. individual follow-up was defined as the time from first symptoms to death during hospitalization for the primary outcome and to icu admission or death before icu admission for the secondary outcome. icu admission alone was not considered as an outcome, since we did not exclude patients aged over years and/or with comorbidities, who were less likely to have access to icu care. data are expressed as mean ± standard deviation, or number (percentage), as appropriate. quantitative variables were compared between the two periods using the student t test and qualitative variables using the chi square test or fisher's exact test, as appropriate. for the impact of the period on death and on icu admission and/or death, we constructed kaplan meier curves and compared them using the log rank test. for multivariate analysis, we used cox proportional hazard models systematically adjusted for age, national early warning score and institutionalization status at hospital admission [ ] . at the time of data extraction, a total of patients were included in the cohort, namely patients in the "before" period (until march th , ), patients in the transition period (march st - th), and patients in the "after" period (march th through april th ). eleven patients ( . %) received corticosteroid therapy in the "before period", ( . %) in the transition period and ( . %) in the "after" period. the main characteristics of the patients in the "before" and "after" periods are summarized in table . patients in the "after" period were significantly more frequently nursing home residents, had higher prevalence of dementia, a longer time from symptom onset to hospitalization, less frequently received lopinavir and/or hydroxychloroquine, and more often required oxygen therapy than in the "before" period. patients in the "after" period also had higher serum creatinine. the mean duration of follow-up was . ± . days, and was similar between periods ( . ± . versus . ± . ; p= . ). of note, deceased patients hospitalized in medical ward were older than those who were transferred to icu (mean age . (± . ) versus . (± . ) years). the "after period" was not associated with a lower risk of death (hazard ratio (hr) = . ; % confidence interval (ci), . - . ; p= . ) by bivariate analyses but was associated by multivariate analysis adjusted for age, national early warning score and institutionalization status (hr = . ; % ci . - . ; p= . ). the "after period" was associated with a lower risk of icu admission and/or death before icu admission by bivariate analyses (hr= . ; % ci = . - . ) and by multivariate analysis adjusted for age, national early warning score and institutionalization status (hr = . % ci . - . ; p= . ). in this before-and-after study of hospitalized covid- patients, after adjustment for age, national early warning score and institutionalization status, the "after" period (n= ) -during which corticosteroids were routinely recommended for patients presenting with covid- pneumonia at our institution-was associated with a lower risk of death (hr = . ; % ci . - . ; p= . ), and a lower risk of icu admission and/or death before icu admission (hr = . % ci . - . ; p= . ). to this day, corticosteroids are not recommended by the world health organization for the treatment of covid- pneumonia due to their potential adverse effects, such as secondary infections and prolonged virus shedding [ ] . however, with our improving knowledge of the role played by overwhelming inflammation in severe covid- patients, immunomodulatory drugs such as interleukin- or - blockade or anti-tumor necrosis factor therapy are being evaluated and all are in favor of a beneficial effect of immunomodulatory drugs during the inflammatory phase of covid- infection [ , ] . corticosteroids are old medicines that are inexpensive and accessible to the whole world. in our study, they were associated with a decrease of over % in mortality, and in the rate of death and/or icu admission, even though patients were more dependent and more often required oxygen in the "after" period at the censoring date (although follow-up duration was similar between the two groups). we acknowledge that a before-and-after study yields a low level of evidence, the difference may be the result of overall better patient care with improvements in thrombosis prophylaxis and some of these patients remained hospitalized at end of follow-up and were thus censored for outcomes. furthermore, the favorable outcome observed with corticosteroids may be partly due to the use of concurrent antiviral drugs in our patients. another limitation of our study is that covid- pneumonia diagnosis was more often performed by chest ct scan in patients who received corticosteroids group than in patients who did not. positive reverse transcriptase polymerase-chain reaction is the gold standard for confirming diagnosis of covid- but its performance presents variable sensitivities, ranging from % to % [ ] . although chest ct scan is highly sensitive for detecting covid- pneumonia, overlapping ct image features with others viral pneumonia and other respiratory diseases make an exclusion diagnosis difficult and could be therefore a source of bias in our study [ ] . finally, the unavailability of safety data should be acknowledged as a limitation. nevertheless, these preliminary data support the initiation of clinical trials testing corticosteroids during the inflammatory phase of covid- , and may potentially lead to a change in treatment recommendations. : kaplan meier curves for death before icu admission between patients "before" and "after" implementation of corticosteroids for covid- pneumonia in reims university hospital the use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease (covid- ): the perspectives of clinical immunologists from china covid- : consider cytokine storm syndromes and immunosuppression clinical features of patients infected with novel coronavirus in wuhan influence of antiretroviral drugs on the pharmacokinetics of prednisolone in hiv-infected individuals a controlled trial of early adjunctive treatment with corticosteroids for pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome computed tomographic imaging of patients with coronavirus disease pneumonia with negative virus real-time reverse-transcription polymerase chain reaction test standardising the assessment of acute-illness severity in the nhs clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus trials of antitumour necrosis factor therapy for covid- are urgently needed the role of chest imaging in patient management during the covid- pandemic kaplan meier curves for icu admission and/or death before icu admission between patients "before" and "after" implementation of corticosteroids for covid- pneumonia in reims university hospitalthe "before" period was until march th , and the "after" period began on march th , . log -rank: (p= . ) key: cord- -s m f authors: caillet, anaëlle; coste, charlotte; sanchez, rocio; allaouchiche, bernard title: psychological impact of covid- on icu caregivers date: - - journal: anaesth crit care pain med doi: . /j.accpm. . . sha: doc_id: cord_uid: s m f subject and purpose: just as every pandemic, covid- could lead to emotional and psychological disturbances among caregivers, especially in the intensive care unit (icu), where significant stress related to the influx of patients, exposure to the virus and the lack of documentation on this new sars occurred. the present study aimed at assessing the psychological impact of covid- on the caregivers at the peak of the “crisis period”. materials and methods: a survey using the hospital anxiety and depression scale (hads) and impact of event scale – revised (ies-r) was proposed to the persons working in icus of a french teaching hospital (april to april , ). logistic regression was performed to find independent risk factors for anxiety and post-traumatic stress disorder (ptds). a value of p < . was considered significant. results: the incidence of anxiety and depression were % and %, respectively. ptsd (post-traumatic stress disorder) symptoms were present in % of respondents. the independent risk factors for developing anxiety syndrome were being assigned in covid- + icu (or = . [ % confident interval (ci), . - . )], and not be trained in intensive care medicine, or = . [ % ci, . - . ]. the independent risk factors for ptsd are having a history of burn-out (or = . [ % ci, . - . ] and not being trained in icu, (or = . [ % ci, . - . ]). conclusion: covid- could lead to strong impact on icu workers. these findings should lead to prevention procedures (icu training sessions) in persons at risk. quickly to be operational as soon as possible. all these conditions and changes in professional and personal life could likely impacts the team psychological well-being ( ) . the health care teams have an increased risk of developing psychological disorders during a pandemic such as anxiety, depression, ptsd, anger, fear, guilt, irritability, frustration, and sleep disturbance ( ) . moreover, working in the icu is already a source of stress. indeed, caregivers face death, family distress, end of life, physical and psychological suffering, handling complex therapeutics, sophisticated technical means, etc. ( ) mealer et al. ( ) had already demonstrated a few years earlier that icu nurses were more likely to develop ptsd compared to non-icu nurses. the context of the international health crisis brings many risk factors that can affect the psychological well-being of our caregivers, which is why we must pay special attention to them. the aim of our study was to assess the psychological impact of coronavirus on the entire icu team. ethics committee agreement: this study has obtained the agreement of the ethics committee of nimes (ref . ). no written informed consent was required ( ) . the authors guarantee the anonymisation of all data collected. main objective: the main objective was to analyse the psychological impact (anxiety, depression and ptsd) of covid- on icu staff. questionnaire with data collection: we developed a survey made of one file with four sub-parts. ) characteristics related to the caregiver and the way in which he/she is confined. ) all information concerning his or her professional career. ) two scales: hads and ies-r were proposed ( , ) . surveys were distributed in the department between april and april , , when the influx of patients was the highest in lyon. the entire icu team was invited to fill it out: doctors, nurses, orderlies, students, reinforcements, etc. once the surveys were completed, we proceeded to computer data entry. inclusion criteria were to work in the icu and to be volunteer to complete the survey. the non-inclusion criteria were to refuse to participate in the study. there was a % completion rate. we used the hospital anxiety and depression scale (hads), ( ) validated scale for the evaluation of anxiety and depressive symptomatology and severity of symptoms. the scale has items, assess anxiety and assess depression. all questions have responses, all coded from to . the score ranges go from to . for interpretation purposes, the scores for the anxiety questions ( - - - - - - ) and the depression questions ( - - - - - - ) must be added together to obtain scores that are then added together. -from to : absence of anxiety and depressive disorders -from to : suspected anxiety or depressive disorders -from to : proven anxiety or depressive disorders the thresholds for the overall score are: -from to : no anxiety-depressive syndrome -from to : existence of anxiety-depressive syndrome we used the ies-r validated scale to assess post traumatic stress disorder ( ) . ptsd is a severe or chronic psychological disorder due to a traumatic event and characterised by nightmares, flashbacks, sleep disorders and hypervigilance, which is responsible of many social and personal disturbance ( ) . the scale is composed of items, each statement must be marked with a number between and . items are subdivided into three categories: once the surveys were completed, we proceeded to data anonymisation. for statistical analysis, qualitative data are expressed in absolute numbers (%) and quantitative data are expressed as an average ± sd or median (iqr) depending on their distribution. quantitative data are compared by a student t test or a mann-whitney test; qualitative data are compared by a chi- test or an exact fisher test (sas jmp ). we used logistic regression to find independent risk factors for anxiety and post-traumatic stress. a value of p < . was considered significant. two hundred and eight people completed the surveys ( females, %). one hundred and eight ( %) have no kid. (table ) in the remaining, ( %) reported difficulties with childcare. the "typical" profile of the confined caregiver is as follows: confined with two or more people ( cases, %), for ( %) people, the usual home is the place of confinement, ( %) health care workers live in a house with an outside and ( %) are between and km from their workplace. twenty-eight were physicians ( %) and were nurses ( %). the cohort includes ( %) students who came to help during the crisis. one hundred and five ( %) professionals have less than years' qualifications and the results concerning the depression and anxiety-depressive syndrome was not significative in statistical analysis, so, it will be not shown. table shows responder characteristics associated with more anxiety. being a woman, > years old, having an history of burn-out syndrome, working in a covid- unit, feeling enough trained for working in the icu were associated with more anxiety. being anxious was also associated with more depression and more ptsd. the incidence of anxiety was very high, %, the incidence of depression was at %, and % of caregivers had ptsd symptoms. the independent risk factors for developing anxiety syndrome were being assigned in covid- + icu, and not be trained in intensive care classically, % of icu professionals are anxious and % are depressed ( ) . excluding covid- , % of icu nurses suffer from ptsd ( ) . the present study confirms the findings of different studies reported during the covid- outbreak in asia. j z huang, in china ( ), shows that . % of doctors in contact with the virus are anxious, and anxiety is higher among women, and among nurses. the same is true for ptsd. the professionals exposed to the coronavirus also suffer from depression ( %) and anxiety ( . %). the risk factors were being a woman, a nurse, a front-line caregiver and being between and years old. exposure to the virus has also been shown to be a risk factor as well as experience ( ) . a study carried out in wuhan on the level of anxiety, shows that by having volunteer staff come to work in contact with covid- patients and by having trained this staff beforehand, the level of anxiety is much lower than in other articles in the literature ( ) . a study conducted in singapore during the epidemic found that . % of staff in contact with covid- were anxious, . % were depressed and . % of staff had ptsd. risk factors include being a female, having co-morbidities, and being an elderly person ( ) . all these studies report a strong psychological impact of covid- on caregivers. risk profiles remain similar, even between different countries and/or services. the conclusion is also similar between the different studies: upstream training seems to be the most promising solution. the emergence and global spread of coronavirus have marked the beginning of the year ( ). covid- is a unique, rapidly spreading pandemic with the risk of severe complications, and persons suffering from co-morbidities as well as young people may be severely affected. lack of documentation and treatment is a major stressor ( ). the icus have most often treated patients with a critical and acute form of coronavirus with initial high mortality rate. moreover, the daily lives of icu caregivers have been rapidly disrupted. the challenge for icus has been to increase significantly and rapidly the number of beds available to handle the large influx of patients. in order to increase the number of intensive care beds in france from , to , , it was necessary to postpone all non-j o u r n a l p r e -p r o o f emergency surgical procedures. most of the operating theatre personnel who were not working were subsequently trained by the icu teams. these decisions allowed to double, sometimes triple the icu bed capacity. however, some shortages of equipment and drugs occurred. these conditions associated with the general confinement and distance with family could stressed out the personnel leading to major psychological impact on caregivers, as reported in the present study. during a natural disaster or an epidemic, previous studies have shown that professionals tend to sacrifice their own needs in order to take care of patients and provide assistance ( ) . the emergency and health crisis undermine the emotional and psychological well-being of caregivers. they are on the front line and exposed to the virus almost continuously. the growing influx of patients and the intensity of the working day leads to feelings of helplessness, isolation and physical and mental stress ( ) . all caregivers, regardless of their original service and/or the service to which they were assigned during this health crisis, were exposed to the same psychological risks: fear for being a carrier of the virus and put their family, friends or colleagues at risk, and fear of dying. under these conditions, a feeling of uncertainty prevailed as well as a feeling of stigmatisation ( ) . being a working professional during covid- involves enormous pressure such as being exposed to a risky environment, presenting symptoms of physical and psychological stress that can impact general well-being. caregivers are particularly concerned about contracting the virus and spreading it to others ( ) . front-line health care workers are directly involved in the diagnosis, treatment, and care of covid- patients ( ) . for the first time, many professionals were putting their health, and sometimes their lives, at stake in order to fulfil their duty as caregivers ( ) . prior to covid- , the recommendations during pandemic times were as follows: give staff access to psychological assistance, support groups, and regular updating of knowledge about the pandemic ( ). the psychological consequences of this pandemic should lead us to question the need to offer personalised and psychological care to caregivers ( ) . the present study clearly shows that informing icu caregivers about the covid- outbreak (mode of transmission, prevention procedure) could decrease the associated stress. therefore, managers must be vigilant while dealing with professionals who are prone to psychological disorders discussed above. moreover, training and/or retraining should be considered to prevent psychological repercussions on teams during a new health crisis or a traumatic event. the present study has some limitations. -the covid- impact study was carried out exclusively in lyon in the same hospital. there was non-covid- unit and covid- units. however, the cohort includes all the professionals of the units. the surveys were performed at the peak of the pandemic, which allowed a high response rate ( %). -the ies-r is usually used for a short-time traumatic event and not immediately done right after the event. for instance, those events are likely to occur after car accidents. the scale yet can be considered less suitable for outbreaks such as covid- . indeed, the traumatic event has a longer duration in time. however, we wanted to have the ptsd results during the crisis to have reference data in case of a second remote coronavirus data collection. in clinical practice, the present study shows that covid- has a strong impact on the psychological well-being of caregivers. health managers must be vigilant with people presenting a risk profile. offering training and retraining for staff could be a solution to limit the psychological repercussions of this crisis. ethics committee agreement: this study has obtained the agreement of the ethics committee of nimes, the authors guarantee the anonymization of all data collected. a pneumonia outbreak associated with a new coronavirus of probable bat origin the origin, transmission and clinical therapies on coronavirus disease (covid- ) outbreak -an update on the status investigation of three clusters of covid- in singapore: implications for surveillance and response measures a multinational, multicentre study on the psychological outcomes and associated physical symptoms amongst healthcare workers during covid- outbreak narrative synthesis of psychological and coping responses towards emerging infectious disease outbreaks in the general population: practical considerations for the covid- pandemic stress professionnel en médecine intensive réanimation, de quoi parle-t-on ? méd intensive réa the prevalence and impact of post traumatic stress disorder and burnout syndrome in nurses french legal approach to clinical research validation de contenu de la version francophone du questionnaire impact of event scale-revised selon les critères du dsm- the hospital anxiety and depression scale psychometric properties of the impact of event scale -revised practice guideline for the treatment of patients with acute stress disorder and posttraumatic stress disorder coping with staff burnout and work-related posttraumatic stress in intensive care the cost of caring: emotion, burnout, and psychological distress in critical care clinicians mental health survey of medical staff in a tertiary infectious disease hospital for covid- factors associated with mental health outcomes among health care workers exposed to coronavirus disease work stress among chinese nurses to support wuhan for fighting against the covid- epidemic a qualitative study on the psychological experience of caregivers of covid- patients key: cord- -d kybmz authors: sedes, p. rascado; sanz, m.Á. ballesteros; saera, m. a. bodí; rodríguezrey, l. f. carrasco; ortega, Á. castellanos; gonzález, m. catalán; lópez, c. de haro; santos, e. díaz; barcena, a. escriba; mera, m. j. frade; cano, j. c. igeño; delgado, m. c. martín; estalella, g. martínez; raimondi, n.; gas, o. roca i; oviedo, a. rodríguez; pío, e. romero san; Álvarez, j. trenado; raurell, m.; ferrer roca, ricard; castellanos ortega, Álvaro; trenado Álvarez, josep; tesorero, virginia fraile gutiérrez; tejedor, alberto hernández; gutiérrez, manuel herrera; ramírez galleymore, paula; sanz, m. Ángeles ballesteros; sedes, pedro rascado; de la oliva calvo, leire lópez; delgado, maría cruz martín; torredá, marta raurell; barrio linares, miriam del; garcía, marta romero; garcía, maría teresa ruiz; hito, maría pilar delgado; mondéjar, juan josé rodríguez; arroyo, carmen moreno; arribas, alicia san josé; mera, maría jesús frade title: contingency plan for the intensive care services for the covid- pandemic date: - - journal: nan doi: . /j.enfie. . . sha: doc_id: cord_uid: d kybmz abstract in january , the chinese authorities identified a new virus of the coronaviridae family as the cause of several cases of pneumonia of unknown aetiology. the outbreak was initially confined to wuhan city, but then spread outside chinese borders. on january , the first case was declared in spain. on march , the world health organization (who) declared the coronavirus outbreak a pandemic. on march , there were countries affected. in this situation, the scientific societies semicyuc and seeiuc, have decided to draw up this contingency plan to guide the response of the intensive care services. the objectives of this plan are to estimate the magnitude of the problem and identify the necessary human and material resources. this is to provide the spanish intensive medicine services with a tool to programme optimal response strategies. on january , , the chinese authorities identified a new virus in the coronaviridae family as the cause of an outbreak of pneumonia in the city of wuhan in hubei province. the virus has subsequently been named sars-cov- and the disease, according to data from the european centre for disease prevention and control (ecdc), from december to march the disease had spread to countries, and there were , reported cases, including , deaths. in spain, according to data from the ministry of health, on march at : there were , positive cases, of which were admitted to intensive care units (icu). in this situation, the scientific societies semicyuc, representative of specialists in intensive care medicine, and seeiuc, representative of critical care nurses, are considering the need to develop a contingency plan to respond to the needs that this new disease will entail, with the following objectives: . to provide health authorities, managers and clinicians with a technical document that addresses all aspects related to identifying the care needs of critically ill patients in the face of the new sars-cov- pandemic, for the comprehensive and realistic planning of intensive care services at national, regional and hospital level. . to ensure optimum care for severely ill covid- patients and other critical patients with other diseases. . to limit the nosocomial spread of covid- : • to protect health and non-health workers in all icus. • to prevent hospitals serving as amplifiers of the disease. • to protect non-covid- patients from infection, in order to maintain the capacity to provide essential non-covid- medical care. . to optimise the human resources of intensive care services. . the rational, ethical and organised allocation of limited healthcare resource to ensure the greatest good for the greatest number of people. the proposal for planning possible scenarios is based on flusurge . software. it was developed by the cdc and provides a freely downloadable spreadsheet to estimate the demand for services, in both a moderate and severe pandemic situation. the tool allows changes of the population at risk, the available hospital resources and assumptions on the epidemiological course of the pandemic, and then provides a rough estimate of needs in that context. thus, it estimates the number of hospitalisations and deaths, the number of people hospitalised, the number of patients requiring care in icu, how many of these people will require mechanical ventilation and the degree of saturation of the services available to care for them. it is important to highlight that flusurge . has been specifically designed to assess the possible effect of a pandemic caused by the influenza virus and has been validated only for that purpose. its application to the covid- pandemic should be approached with caution. the calculation of possible scenarios requires several initial assumptions about the characteristics of the pandemic. the estimates used are based on the published series on the chinese outbreak , , the experience in italy and experience with the influenza virus h n . a mean hospital stay of days, a mean icu stay of days, a rate of % of hospitalised patients requiring icu admission and . % requiring mechanical ventilation were considered. considering an attack rate (proportion of persons within a population who become infected with a certain disease) of % and a duration of the pandemic of weeks (data that are adjusted to the progression of the most affected autonomous communities), the following are expected: • , hospital admissions in weeks. • peak demand in week . • the need for more than , icu beds at times of greatest demand. • the need for more than , ventilators in the weeks of greatest demand. the proposed scenario has been designed to plan for needs in the event that containment measures are not sufficient. the following are recommended: • plan according to the actual situation at any given time. • re-evaluate progression in response to containment measures. • elaboration of protocols and contingency plan. • bed availability study. • equipment forecast. • staff training. phase . start of the pandemic • cancellation of elective surgery. • fitting of additional spaces such as icu beds. • completing staff teams. freeing-up of extra-icu activity. • sectorised work teams. phase . saturation of the icu • suspension of all elective activity. • organise shifts. • sectorise covid- patients. • strict admission criteria. phase . collapse of the icu and the hospital • prioritise the care of patients most likely to recover. • nurse: patient ratio based on availability. • prioritise the overall benefit to the individual. page of j o u r n a l p r e -p r o o f the coronavirus committees are working groups at national, regional and local levels (specific to the hospital) that prepare the necessary resources and the action plan for all possible scenarios. the committees have the following objectives: • to define and agree the contingency plan with the administration. • to guarantee the acquisition of material. • complete the necessary protocols. • plan spaces. • define procedures for transfer. • organise the work teams. the role of the intensive care specialist on the committees is essential to: • prepare pathways and areas for critical patient care. • define hospital and out-of-hospital transfer pathways. • report on the situation and the needs of the icu. the following recommendations have been established: • critical covid- patients must be cared for in an icu by specialists in intensive care medicine. • each icu bay or station must be equipped with a ventilator for advanced invasive ventilation. • there must be a transport ventilator for every patients. • all of these aspects must be considered when creating extraordinary icu bays in other areas of the hospital. • cohorting and isolation in cohorts is recommended. • cohorting should take precedence over the concept of closed-door rooms. • if an icu has both open and closed bays, it is recommended that closed bays are used initially. • if necessary, extend the physical space of the icu. a plan for change in care must be made in each centre to include burden sharing, care responsibilities and working hours. the following staffing of intensive care doctors is recommended: ordinary working hours: -one intensive care specialist for every patients. -in the event of saturation, other non-intensive care physicians (including resident physicians) can be included, coordinated by an intensive care specialist. on-call duty: -two intensive care specialists or intensive care specialist plus th / th -year resident for every beds. -in the event of saturation, other non-intensive doctors (including resident doctors) coordinated by an intensive care specialist. the following nursing staffing is recommended : • one nurse per shift for every critical patients. • back-up of nurse for every - beds for support in moments of maximum workload (prone, intubation, transfers...). • one assistant nursing care technician (tcae) for every beds. • back-up per shift every - beds for organisation and cleaning of material, support and replacement. staff training semicyuc will edit the training material: computer graphics, posters, etc. each hospital must organise training sessions with at least the following content: -epidemiology of covid- . -impact on activity. -transmission. -diagnosis of covid- . -personal protection measures: personal protective equipment (ppe), procedures and isolation. we recommend : • establishing an information transfer period. • avoiding close contact during information transfer. • special care in handing off the therapeutic plan and anticipating changes. • undertaking structured hand-offs, e.g. through sbar (status, background, assessment and recommendations). • appropriate completion of clinical history. • in icus where there are cases of covid- , it is recommended that the relatives of all patients admitted to the icu should be informed on a daily basis, as well as when there are no cases, without providing any additional information that could infringe on the privacy of the patient and his/her family. • it is recommended that all family members of patients admitted to an icu where there are covid- cases receive the usual daily information provided by the team outside the unit. • covid- patients will be kept in isolation and accompaniment/visits completely restricted. only in situations reviewed on an individual basis by the care team due to compelling need (e.g. near death) or other clinical, ethical and/or humanitarian considerations, will limited, controlled ,short, supervised visits be permitted on an j o u r n a l p r e -p r o o f exceptional basis, after training the family member how to put on and take off ppe by helping and supervising them. • families are advised to keep the accompaniment of patients, whether or not they have covid- , to a minimum. visits to patients without covid- in units where covid- patients have been admitted will be adapted to the architectural characteristics of the unit. coronaviruses are mainly transmitted by respiratory droplets of more than μm and by direct contact with secretions from infected patients. they may also be transmitted by aerosols in therapeutic procedures that produce them. therefore, we recommend , , , : • precautions for the treatment of all probable or confirmed patients under investigation should include standard, contact and droplet transmission precautions. • strict hand hygiene should be observed. • all professionals should be trained in the use of ppe. • ideally, patients should be isolated in a separate room, if possible, with negative pressure. • priority should be given to cohorting in a specific area. • waste generated is considered class iii waste. • ppe should be removed inside the bay, with the exception of respiratory and eye protection. • clothing and dishes do not require special treatment-personal protective equipment equipment must include : • gloves and protective clothing. • respiratory protection. • eye and face protection. we recommend the following in terms of respiratory protection , : confirmed cases under investigation should wear surgical masks if possible. use high efficiency antimicrobial filters (inspiratory and expiratory branches) in the case of invasive mechanical ventilation. use closed suction systems. for non-invasive ventilation, the use of anti-viral filters and preferably double-tube equipment is recommended. avoid manual ventilation with a bag mask. if this is done, a high efficiency antimicrobial filter should be used. to enter the room or a m perimeter, if procedures that generate aerosols are not going to be performed, it is recommended that the following are used : -gown (can be disposable paper). -mask (surgical or ffp if available and ensuring sufficient stock at all times). -gloves. -anti-splash eye protection. if an aerosol-generating procedure is to be performed, the following are recommended , : -ffp or preferably ffp mask, if available. -tight fitting full frame eye protection or full-face shield. -gloves. -long-sleeved waterproof gown. the current recommendation is to use the mask only once. although there is no clear evidence on this, in the event of a shortage, the masks can be reused by the same practitioner for a maximum period of hours of continuous or intermittent activity. there can be extended use of the mask if it is not stained or wet. optimising the use of ppe j o u r n a l p r e -p r o o f rational use of ppe is necessary and exposure times must be minimised. to this end, the following recommendations should be followed: promote registration, control and monitoring measures that do not require entering the room. • plan tasks and remain in the room for the shortest time possible. • group tasks that require entering the bay. • adjust perfusions to make changes during one programmed entry to the bay. • deliver care, examinations, etc., with the minimum number of people. • do not suction by protocol. • take samples together to prevent unnecessary entries. -prepare the sample for sending inside the bay. -clean the external part of the tube with a surface disinfectant or wipe impregnated with disinfectant. -samples will be transported in person avoiding transport systems such as pneumatic tubes. the professionals responsible for the patient should supervise any action on the patient by non-service personnel. indications for admission to icu due to sars-cov- pneumonia general criteria for admission to icu we recommend using objective criteria for icu admission based on the recommendations of the american thoracic society (ats), the infectious diseases society of america (idsa) and recent evidence from analysis of the sars-cov- (covid- ) epidemic in china (table ) . icu admission will be considered when there is major criterion or or more minor criteria. optimisation in the event of saturation • in a situation of saturation or being overrun, it is necessary to prioritise the care of the cases that are potentially more likely to recover. • icu triage protocols for pandemics should only be activated when icu resources over a wide geographic area are or will be overwhelmed despite all reasonable efforts to expand resources or obtain additional resources. • guidelines for adjusting therapeutic effort are essential. inclusion/exclusion criteria [ ] [ ] [ ] [ ] • a triage instrument that objectively classifies patients is proposed. • the only measure proposed so far, although not validated, is based on the use of sofa. • after the first assessment, patients should be reassessed on days and , when they could be reclassified. the following are exclusion criteria for admission: • poor prognosis despite icu admission. • need for resources that cannot be provided. • not meeting severity criteria • the specific recommendations for admission exclusion criteria in the event of a mass disaster can be applied. the expansion plan includes the transformation and fitting out of additional spaces for the care of the critical patient in the event that icu beds have been overwhelmed and enlarging the team of staff who are experts in critical care. possible sites for critical patients must have , , : • medical gases. • respirators for invasive and non-invasive mechanical ventilation. • possibility of high-flow oxygen therapy. • possibility of advanced monitoring. • points for hand hygiene. • the availability of central monitoring (telemetry) would be desirable. as a guideline, the spaces that can be used to extend icu beds are : • intermediate care units attended by intensive care specialists: nurse:patient ratios need to be adjusted to those of a conventional icu. • resuscitation units and post-anaesthetic recovery units. elective surgery must be suspended. patients must be cared for by specialists in intensive medicine. • critical or intermediate care areas of the emergency services. • make space available near the icu with new equipment. • transform conventional hospitalisation areas, day hospitals or major outpatient surgery areas. • in the event of overcrowding, transfer to another centre with available space should be considered. we recommend that, if % saturation of intensive care services is anticipated, centralisation of resources should be considered. to that end: • develop an inter-hospital transfer procedure. • a critical patient coordinator should be designated in each autonomous community to comprehensively manage all the critical beds in each community. we recommend , : conducting a census of all medical personnel who specialise in intensive care medicine, to also include: -physicians with on-call contracts. -intensive care specialists dedicated to other tasks in the hospital. • conduct a census of other staff physicians or residents who may have the capacity to care for less serious patients, coordinated by the intensive care department. • extending substitution contracts. • carry out a plan for medical staffing and burden sharing in all hospitals. • conduct a census of nursing staff with knowledge and experience in critical patient care. • develop a plan to relocate experienced nurses to critical areas • consider the peak care load in forecasts. • if medical or nursing staff who are not undertaking their usual work are included in critical care activities, they should first receive training. • training should include key areas: intensive care medicine or nursing and infection control. inter-hospital transfer • necessary personnel: attending physician, attending nurse and emergency health technician. • appropriate ppe for the staff in the care cabin is recommended for situations where there is aerosol risk. consider the following during transfer: • the driver must be isolated from the patient's compartment. • family members must not travel in the transport vehicle. • limit the number of care providers in the care cabin. • a protocol for the transfer pathway must be established: itinerary, elevator, number of participants, ppe. block the lift for transfer and disinfection security personnel with a surgical mask will precede the team to clear the area josep trenado Álvarez; vice-secretary, virginia fraile gutiérrez; treasurer, alberto hernández tejedor; president of the scientific committee, manuel herrera gutiérrez; vice-president of the scientific committee Ángeles ballesteros sanz; member for the autonomous societies member for doctors in training, leire lópez de la oliva calvo; former president annex . seeiuc board of directors raurell torredá; vice-president maría pilar delgado hito; member for working groups table . major and minor criteria for admission to the intensive care unit (icu) key: cord- -dw h tp authors: cheng, fu-yuan; joshi, himanshu; tandon, pranai; freeman, robert; reich, david l; mazumdar, madhu; kohli-seth, roopa; levin, matthew a.; timsina, prem; kia, arash title: using machine learning to predict icu transfer in hospitalized covid- patients date: - - journal: j clin med doi: . /jcm sha: doc_id: cord_uid: dw h tp objectives: approximately – % of patients with covid- require hospitalization, and – % may require critical care in an intensive care unit (icu). a rapid surge in cases of severe covid- will lead to a corresponding surge in demand for icu care. because of constraints on resources, frontline healthcare workers may be unable to provide the frequent monitoring and assessment required for all patients at high risk of clinical deterioration. we developed a machine learning-based risk prioritization tool that predicts icu transfer within h, seeking to facilitate efficient use of care providers’ efforts and help hospitals plan their flow of operations. methods: a retrospective cohort was comprised of non-icu covid- admissions at a large acute care health system between february and april . time series data, including vital signs, nursing assessments, laboratory data, and electrocardiograms, were used as input variables for training a random forest (rf) model. the cohort was randomly split ( : ) into training and test sets. the rf model was trained using -fold cross-validation on the training set, and its predictive performance on the test set was then evaluated. results: the cohort consisted of unique patients diagnosed with covid- and admitted to non-icu units of the hospital. the median time to icu transfer was . days from the time of admission. compared to actual admissions, the tool had . % ( % ci: . – . %) sensitivity, . % ( % ci: . – . %) specificity, . % ( % ci: . – . %) accuracy, and . % ( % ci: . – . %) area under the receiver operating characteristics curve. conclusions: a ml-based prediction model can be used as a screening tool to identify patients at risk of imminent icu transfer within h. this tool could improve the management of hospital resources and patient-throughput planning, thus delivering more effective care to patients hospitalized with covid- . with more than million cases and , deaths [ ] by the end of april , the covid- pandemic has rapidly emerged as a serious global health emergency [ ] , testing the ability of health care systems to respond. the burden on health care systems emanates both from the high incidence of covid- and the fact that % to % of patients experience a moderate-to-severe form of the disease-with multi-organ failure, prolonged periods of morbidity and hospitalization, and high mortality [ ] . moreover, from % to % of all patients diagnosed with covid- and up to % of hospitalized patients require supportive critical care in an intensive care unit (icu) [ ] [ ] [ ] . these estimates indicate that the rate of icu transfer of hospitalized patients with covid- is significantly higher than the icu transfer rates of % reported for other hospitalized patients [ , ] . furthermore, the need for icu care may be even higher in specific high-risk groups with covid- , such as older individuals [ ] or those with pre-existing comorbidities [ ] . for example, over % of covid- patients admitted to the icu have one or more pre-existing comorbid conditions [ ] . according to an estimate by the american hospital association, there are just under , icu beds in the united states [ ] , with over % occupancy under normal circumstances [ ] -a potential constraint on resources during a surge in cases. moreover, constraints in the availability of trained manpower [ ] may occur with a rapid surge in covid- hospitalizations. covid- patients admitted to non-icu units often experience rapid clinical deterioration [ ] and, therefore, require frequent clinical assessments. however, with resources stretched thin, frequent assessment is difficult and can increase the risk of exposure among frontline personnel. to efficiently manage these finite resources and personnel, optimal prioritization of patients and efficient use of hospital resources are necessary. icu care may be needed for supportive management of severe covid- -associated pneumonia, acute respiratory distress (ards), sepsis, cardiomyopathy, arrhythmia, and acute renal failure. icu care also may become necessary to manage prolonged hospitalization-associated complications, such as coagulopathy [ ] , secondary infections, gastrointestinal bleeding, and other problems [ ] . determining whether an individual's dynamic risk of clinical deterioration warrants an icu transfer may require analyses of temporal changes in patients' conditions and key indicators of imminent complications of covid- . supervised machine learning approaches may be useful to (a) analyze and interpret patients' clinical and laboratory values and their temporal changes, and (b) quantify their dynamic risk of clinical deterioration and the need for icu transfer. the primary aim of this study is to develop a novel supervised machine learning classifier for predicting the risk of icu transfer within the next h for covid- patients using hospital emr data. we applied a random forest (rf) [ ] approach, which has proven promising in analyzing complex clinical data of multiple types [ ] , has high model generalizability [ ] , and can elucidate high-order interactions between variables without compromising predictive accuracy [ ] . we describe the development and validation of such a model, its predictive performance, and the interpretation of our results. this study was approved by the mount sinai health system institutional research board (irb protocol number: - ); the need for informed consent was waived. the study cohort was comprised of patients years or older who had a covid- diagnosis and were admitted to the mount sinai hospital in non-icu general in-patient beds between february and april . the diagnosis was based on a clinical conclusion of an infectious disease specialist or a positive pcr test (initial or repeat testing). the following data were retrospectively collected from the mount sinai health system covid- registry, sourced from an epic ehr system: demographic information, time-series of the admission-discharge-transfer events, structured and semi-structured clinical assessments, vital signs from nursing flowsheets, and laboratory and electrocardiogram (ecg) results. given the crisis nature of the pandemic, clinicians caring for this cohort collected data such as vital signs, diagnostic labs, ecgs, and nursing assessments based on clinical judgment and resource availability rather than a standard protocol. thus, to create time-series data for each observational variable, we included the three most recent assessments available when the feature vector was created. feature vectors were created daily during each covid- patient's non-icu general bed stay until discharge, icu transfer, or death. missing values for each variable were imputed by using the median value across the cohort [ ] . the primary outcome of this study was icu transfer within h from the time of prediction. labeling of feature vectors followed the following logic: ( ) if the icu transfer was within h of the feature vector creation, we labeled the feature vector as positive; ( ) if the icu transfer occurred after h from the creation of the feature vector, we labeled the feature vector as negative; ( ) if the icu transfer did not occur during the patients' stay, then all feature vectors for that admission were labeled as negative. this process is depicted in figure . the study cohort data were randomly split into a training set used for training the prediction model, and a test set used for testing the model's performance. the training set consisted of percent of the full cohort, and the test cohort consisted of the remaining percent. we randomly split our cohort so that patients were only included in the training or the test set. the non-icu bed to icu transfer rate in our cohort was . percent, which created an extreme class imbalance between the majority class (feature vectors without the occurrence of icu transfer within h) and the minority class (feature vectors with icu transfer within h). we performed random under-sampling [ , ] on the training data set for balancing the majority class (negative label) until both classes were equally balanced. the rf model was trained with -fold cross-validation. the open-source apache spark project machine-learning library [ ] was used. the features included in this study were based on clinical judgments and reports in the covid- literature. we included periodic monitoring of vital signs [ ] , complete blood count, serum biochemical tests [ ] , coagulation profile [ ] , and electrocardiogram results [ ] as relevant input variables. the full list of features used in modeling is provided in table s . features were ranked by using the gini importance [ ] . the model performance was evaluated on the test set. rf model-derived class probabilities [ ] were used to predict icu transfer within h with a default threshold of ≥ . . predictions less than the default threshold were categorized as negative. sensitivity, specificity, accuracy, and area under the receiver operating curve (auc-roc), along with % ci, were estimated for evaluating the screening tool's performance [ ] . performance metrics were computed in the r environment [ ] by using custom scripts and r packages-prroc (v. . . ) [ ] , proc (v. . ) [ ] , and epir (v. . . ) [ ] . cohort characteristics are shown in table . the study cohort yielded feature vectors, which contained data from each day of non-icu hospital stay for unique patients. each individual vector, generated h apart, represented a day of in-patient stay in a non-icu bed for each patient. the split cohort resulted in and feature vectors created from the stays of and patients in the training and test datasets, respectively. after performing majority-class under-sampling, the final training set consisted of feature vectors, representing each non-icu stay of unique patients. the median time to icu transfer from the time of admission was . days. the study cohort included a higher proportion of women, and about two-thirds of the cohort was between and years old. the median duration of hospital stay was . days and ranged between to . days. about one-quarter of the patients in the cohort had more than one comorbidity, including copd, diabetes, hypertension, obesity, or cancer. a total of variables (comprising features) had predictive value using the gini importance metric in training the rf model. hyper-parameters used in the final model are provided in table s . the top predictive variables are summarized in figure . model input variables with their respective sources are listed in table s . our model identified a series of features related to progressive respiratory failure (respiratory rate, oxygen saturation), markers of systemic inflammation (c-reactive protein, white blood cell count), shock (systolic and diastolic blood pressures), renal failure (blood urea nitrogen, anion gap, and serum creatinine), and the pathophysiology of covid- (lymphocyte count). respiratory rate (the earliest recorded value of the latest three assessments) had the highest predictive value in the rf model, and white blood cell count was the second highest. variables included in the final model reflected the importance of temporal changes in vital signs, markers of acid-base equilibrium and systemic inflammation, and predictors of myocardial injury and renal function. the predictive performance of the rf-based model on the test dataset is presented in table . of feature vectors, represented patient-days where icu transfer occurred within h of the prediction time point. the auc-roc of the prediction model is shown in figure . our model provides a tool for dynamic risk quantification for icu transfer within the next h. clinical management of covid- requires frequent monitoring and re-assessment among patients who may suffer rapid deterioration. although deterioration may be evident by corroboration of changes in vital signs, laboratory results, electrocardiograms, and information in nursing notes, frequent review of these important parameters might not be feasible in crisis situations. using machine learning, we developed a model for identifying deteriorating patients in need of icu transfer by using data routinely collected during inpatient care. this model could be easily automated as an alternative to manual clinical review. furthermore, inspection of important features in the model can provide insight into predictors and their plausible links to the pathophysiology of clinical deterioration among patients with covid- . a key advantage of using an rf-based model is that the relative importance of predictive features is available for end users to interpret. our finding that lymphocyte count is a significant predictor of icu transfer correlates with previous reports that identified lymphopenia as a predictor of severe disease and poor prognosis [ , ] . although age is clearly identified as a risk factor for needing icu care among patients with covid- [ ] , patients above years old have lower rates of icu transfer, despite higher mortality [ ] , possibly reflecting a greater preference for palliative or less aggressive care in older patients. we believe that the relatively low rank of age as a risk factor in our model could mean that our model incorporates actual patient data and patterns of clinical practice into its predictions. acute worsening of respiratory rate and oxygen saturation are used for identifying covid- patients at risk of developing acute respiratory distress syndrome [ , ] . the model ranks oxygen saturation with a significantly lower predictive value than respiratory rate. a significant proportion of covid- patients who are hospitalized need supplemental oxygen support. one possible our model provides a tool for dynamic risk quantification for icu transfer within the next h. clinical management of covid- requires frequent monitoring and re-assessment among patients who may suffer rapid deterioration. although deterioration may be evident by corroboration of changes in vital signs, laboratory results, electrocardiograms, and information in nursing notes, frequent review of these important parameters might not be feasible in crisis situations. using machine learning, we developed a model for identifying deteriorating patients in need of icu transfer by using data routinely collected during inpatient care. this model could be easily automated as an alternative to manual clinical review. furthermore, inspection of important features in the model can provide insight into predictors and their plausible links to the pathophysiology of clinical deterioration among patients with covid- . a key advantage of using an rf-based model is that the relative importance of predictive features is available for end users to interpret. our finding that lymphocyte count is a significant predictor of icu transfer correlates with previous reports that identified lymphopenia as a predictor of severe disease and poor prognosis [ , ] . although age is clearly identified as a risk factor for needing icu care among patients with covid- [ ] , patients above years old have lower rates of icu transfer, despite higher mortality [ ] , possibly reflecting a greater preference for palliative or less aggressive care in older patients. we believe that the relatively low rank of age as a risk factor in our model could mean that our model incorporates actual patient data and patterns of clinical practice into its predictions. acute worsening of respiratory rate and oxygen saturation are used for identifying covid- patients at risk of developing acute respiratory distress syndrome [ , ] . the model ranks oxygen saturation with a significantly lower predictive value than respiratory rate. a significant proportion of covid- patients who are hospitalized need supplemental oxygen support. one possible explanation underlying the lower predictive value of oxygen saturation is that in patients with progressive hypoxia, a progressively greater fraction of inhaled oxygen (fio ) is delivered to maintain adequate percutaneous oxygen saturation (spo ) until the patient can no longer maintain normal oxygen saturation despite support from high-flow nasal oxygen or non-invasive ventilation. this makes spo a less sensitive reflection of disease progression until severe respiratory decompensation occurs. we propose to include fio , level of respiratory support, and spo as variables in future versions of this model. c-reactive protein has been reported as a marker of disease severity in early phases of covid- infection and is positively correlated with covid- pneumonia [ ] . patients' vital signs (e.g., pulse rate, blood pressure, and temperature) are among the top predictors in this model and are widely accepted as identifying patients in critical condition who are at risk of deterioration [ ] . hematologic parameters such as red blood cell count, hemoglobin, platelet count, and white blood cell count are conventionally used markers of sepsis in critical care settings [ ] ; thus, it is not surprising that they were predictive of covid- in our model also. abnormalities in potassium, sodium, and calcium also have been associated with severe covid- [ ] . our model has strengths in terms of methodology, utility, and scalability. the labeling approach of feature vectors-using the last observations, rather than the earliest or latest-made it easier to minimize chances of over-fitting despite the low sample size for training. the cohort is diverse in distribution of key variables such as age, race, ethnicity, and length of hospitalization, supporting the generalizability of the model. the model uses input variables mainly comprised of routine laboratory and clinical data, which are commonly available in most streaming data models across the u.s. furthermore, the model can be adopted to different frequencies of assessments and different common input variables. it can be adjusted to use streaming data from the emr and provide frequent predictions for real-time risk prioritization. we use the fast healthcare interoperability resources (fhir) format for facilitating data exchange and retrieval from an epic-supported emr system. this can help to improve the model's scalability in other hospital settings. clinical judgment and resources can play a significant role in data availability. in addition, clinical documentation may not be perfect during crises, when normal documentation standards are relaxed due to the high work burden of clinicians. therefore, unavailable data (as in our case) may be the consequence of either clinical judgement on need for specific assessments or imperfect clinical documentation. despite the non-random pattern of data availability for specific variables, the imputation strategy and the rf model had reasonably high sensitivity. this supports previous reports that found rf models to be highly suitable in situations with missing data [ ] , complex non-linear relationships among input variables, and their potential higher-level interactions [ ] ; thus, an ensemble-based classification approach minimizes overfitting [ ] . an additional asset of this model is that, unlike other models, key discriminatory variables underlying each prediction can be provided. low sample size and class imbalance resulting from low icu transfer rates are major limitations to this version of the model, which resulted in low precision. therefore, we recommend using this version of the model as a prioritization tool, not a tool for clinical decision support. since the model is based on data from a single hospital, its case mix may not be easily generalizable to other settings. for example, in this cohort, rates of hypertension and diabetes were lower than in others reported [ , , ] . variables related to systemic inflammation and the coagulation cascade (e.g., d-dimer, fibrinogen, ferritin, and lactate dehydrogenase) were not available for modeling when this model was generated. while our model provides high sensitivity, we believe that inclusion of these other markers, which have predictive and/or prognostic value [ ] , could improve subsequent iterations of the model. while spo without assessments of fio and level of oxygen support may not be sufficient to capture signs of progressive hypoxia, the inclusion of all three variables in subsequent versions of the model could also further improve its performance. however, given the low sample size of a single medical center in the acute phase of a pandemic, it may be difficult to generate a model with both high sensitivity and precision (positive predictive value). as a screening tool for development of critical illness, this model has multiple opportunities for clinical use. in addition to identifying patients with a potentially increased need for icu transfer within h, the tool can also be used for improving the coordination of patient transfers to the icu. the tool can be used to inform clinicians of patients at higher risk of a greater need for frequent assessments, and thereby can facilitate inclusion of clinicians less familiar with critical care medicine. earlier identification of high-risk patients could potentially reduce the use of invasive mechanical ventilation [ ] , sparing patients from avoidable morbidity and lowering mortality from complications. given the sensitivity of the model, it can effectively identify patients who are likely to be transferred to icu within h, reducing the chance of missing the patients in need of icu care. moreover, clinical implementation of the tool can increase the rates of early icu transfers, which can potentially translate into reduced mortality and shorter lengths of icu stay [ , ] , with favorable consequences on other complications affecting patient outcomes, such as delirium and sleep disorders [ , ] . however, its positive predictive value and precision are limited, and it is not practical to perform labor-intensive interventions for all patients whom the model predicted are at high risk. nonetheless, our model has clinical utility in the setting of a pandemic. the high negative predictive value suggests that those identified as unlikely to require critical care in the next h may be considered for a lower level of monitoring. our rf-based tool can reliably be used for prioritizing covid- patients not in the icu but at risk for deterioration and requiring icu transfer within h. the model shows the importance of respiratory failure, shock, inflammation, and renal failure in the progression of covid- . such a predictive tool may have wide implications and utility in clinical practice and hospital operations. further refinement of the model will yield even higher precision while maintaining sensitivity. more studies are needed to identify other ways to improve patient outcomes by early identification of covid- patients at risk of deterioration. implementing machine learning models has the potential to build capacity within a hospital's continuous learning and quality improvement environment. supplementary materials: the following are available online at http://www.mdpi.com/ - / / / /s , table s : hyperparameters used in the final model, table s world health organization. who covid- dashboard covid- -navigating the uncharted cdc covid- response team. severe outcomes among patients with coronavirus disease (covid- )-united states characteristics of hospitalized adults with covid- in an integrated health care system in california presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the active bed management by hospitalists and emergency department throughput evaluating implementation of a rapid response team: considering alternative outcome measures estimates of the severity of coronavirus disease : a model-based analysis preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease -united states aha annual survey trends in critical care beds and use among population groups and medicare and medicaid beneficiaries in the united states united states resource availability for covid- interim clinical guidance for management of patients with confirmed coronavirus disease (covid- ) abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia iterative random forests to discover predictive and stable high-order interactions an analysis of four missing data treatment methods for supervised learning the class imbalance problem: significance and strategies enhancing the prediction of clinical deterioration in admitted patients through a machine learning model mllib: main guide-spark . . documentation national institute for the infectious diseases "l. spallanzani" irccs. recommendations for covid- clinical management clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study cardiovascular implications of fatal outcomes of patients with coronavirus disease screening tests: a review with examples r: a language and environment for statistical computing computing and visualizing precision-recall and receiver operating characteristic curves in r proc: an open-source package for r and s+ to analyze and compare roc curves epir: an r package for the analysis of epidemiological data evaluation and treatment coronavirus dysregulation of immune response in patients with coronavirus covid- in critically ill patients in the seattle region-case series treatment for severe acute respiratory distress syndrome from covid- c-reactive protein levels in the early stage of covid- monitoring vital signs using early warning scoring systems: a review of the literature the hematologic system as a marker of organ dysfunction in sepsis electrolyte imbalances in patients with severe coronavirus disease (covid- ) laboratory abnormalities in patients with covid- infection lower mortality of covid- by early recognition and intervention: experience from jiangsu province association between intensive care unit transfer delay and hospital mortality: a multicenter investigation an examination of early transfers to the icu based on a physiologic risk score sleep deprivation in intensive care unit-systematic review covid- : icu delirium management during sars-cov- pandemic we acknowledge susan usyal for her editorial assistance. the authors declare no conflict of interest. key: cord- -w iqo q authors: devlin, john w.; o’neal, hollis r.; thomas, christopher; barnes daly, mary ann; stollings, joanna l.; janz, david r.; ely, e. wesley; lin, john c. title: strategies to optimize icu liberation (a to f) bundle performance in critically ill adults with coronavirus disease date: - - journal: crit care explor doi: . /cce. sha: doc_id: cord_uid: w iqo q objectives: the severe acute respiratory syndrome coronavirus pandemic has stretched icu resources in an unprecedented fashion and outstripped personal protective equipment supplies. the combination of a novel disease, resource limitations, and risks to medical personnel health have created new barriers to implementing the icu liberation (“a” for assessment, prevention, and manage pain; “b” for both spontaneous awakening trials and spontaneous breathing trials; “c” for choice of analgesia and sedation; “d” for delirium assess, prevent, and manage; “e” for early mobility and exercise; and “f” for family engagement and empowerment [abcdef]) bundle, a proven icu care approach that reduces delirium, shortens mechanical ventilation duration, prevents post-icu syndrome, and reduces healthcare costs. this narrative review acknowledges barriers and offers strategies to optimize bundle performance in coronavirus disease patients requiring mechanical ventilation. data sources, study selection, and data extraction: the most relevant literature, media reports, and author experiences were assessed for inclusion in this narrative review including pubmed, national newspapers, and critical care/pharmacology textbooks. data synthesis: uncertainty regarding coronavirus disease clinical course, shifts in attitude, and changes in routine behavior have hindered bundle use. a domino effect results from: ) changes to critical care hierarchy, priorities, and icu team composition; ) significant personal protective equipment shortages cause; ) reduced/restricted physical bedside presence favoring; ) increased depth of sedation and use of neuromuscular blockade; ) which exacerbate drug shortages; and ) which require prolonged use of limited ventilator resources. other identified barriers include manageable knowledge deficits among non-icu clinicians unfamiliar with the bundle or among picu specialists deploying pediatric-based bundle approaches who are unfamiliar with adult medicine. both groups have been enlisted to augment the adult icu work force to meet demand. strategies were identified to facilitate bundle performance to liberate patients from the icu. conclusions: we acknowledge current challenges that interfere with comprehensive management of critically ill patients during the coronavirus disease pandemic. rapid response to new circumstances precisely requires established safety mechanisms and protocols like the abcdef bundle to increase icu and ventilator capacity and help survivors maximize recovery from coronavirus disease as early as possible. d uring the current severe acute respiratory syndrome coronavirus pandemic, up to % of patients with coronavirus disease (covid- ) will develop acute respiratory failure. among patients needing icu-level care, nearly % require intubation and mechanical ventilation, often for a prolonged period ( ) ( ) ( ) . these surges inpatient volume, acuity, and icu length of stay may exceed icu resources and bed capacity ( , ) . the prolonged need for mechanical ventilation and the use of deep sedation, with or without use of continuous neuromuscular blockade (nmb), results in a population of covid- patients at high risk for numerous icu and post-icu sequelae including the post-intensive care syndrome ( , ) . in the absence of effective covid- specific therapies, icu clinicians must rely even more heavily on broadbased strategies to mitigate the negative consequences of icu care and subsequent postdischarge morbidity in this population ( ) . the icu liberation campaign using the icu liberation ("a" for assessment, prevention, and manage pain; "b" for both spontaneous awakening trials and spontaneous breathing trials; "c" for choice of analgesia and sedation; "d" for delirium assess, prevent, and manage; "e" for early mobility and exercise; and "f" for family engagement and empowerment [abcdef]) bundle (hereafter referred to as "the bundle") (supplemental table , supplemental digital content , http://links.lww.com/ccx/a ) was launched in by the society of critical care medicine (sccm) to promote the widespread adoption of sccm's pain, agitation, and delirium guidelines ( , ) . the bundle's clearly positive impact on patient outcomes has fostered its global adoption ( ) . the bundle, its use described elsewhere in detail ( ) ( ) ( ) ( ) ( ) , continues to be refined by new practice guidelines ( ) and published evidence ( ) ( ) ( ) . in succinct terms, the bundle strives to optimize pain management, avoid deep sedation, reduce delirium, shorten the duration of mechanical ventilation, minimize icu-acquired weakness, and foster icu patient and family involvement in care processes. although multiple studies demonstrate the salutary impact of bundle use on icu patient care, outcomes, and healthcare costs in non-covid- patients ( ) ( ) ( ) ( ) , important covid- -related issues and barriers may preclude the routine use of the bundle in this population, particularly at centers experiencing a surge of critically ill adults with covid- . the need to adopt social distancing and increased workload demands have pushed interprofessional team (ipt) rounds and collaboration from the ideal that promotes bundle performance ( , ) . this narrative review, which is intended neither as a guideline nor practice statement, is informed by authors with experience in managing critically ill covid- adults admitted to both academic and community centers and builds on other recent covid- papers focused solely on delirium ( , ) . this article does not address factors like clinician fear or ethical issues (e.g., ventilator shortages) that may influence bundle use during the pandemic ( ) . instead, we highlight key barriers to bundle adoption during the pandemic and offer ways to reenvision icu care using evidencebased strategies to optimize bundle application to critically ill adults with covid- requiring mechanical ventilatory support. barriers to bundle delivery in mechanically ventilated adults with covid- can be stratified by those affecting application of the bundle as whole (i.e., global barriers) and those primarily affecting delivery of individual bundle elements. barriers to bundle use, and the solutions to overcome them, are influenced by the degree to which the bundle was implemented prior to the pandemic and the number of covid- icu admissions at any one time relative to institutional icu capacity and staffing. this section of the paper highlights global barriers to bundle use and practical solutions to overcome them. prior to the pandemic, bundle implementation was a major focus of icu critical care quality improvement at many hospitals ( , ) . clinicians should remind themselves of the strong evidence behind the bundle and take the opportunity to ensure the entire ipt refreshes their knowledge surrounding it. in the current crisis, where icu beds and ventilator resources may be limited, the bundle would seem to be tailor made to reduce duration of mechanical ventilation and shorten the icu stay. however, the bundle requires substantial clinician resources and time that many institutions often struggled to provide even before the pandemic ( , ) . although icu delirium assessment/reduction and rehabilitation/mobility are no less important than pain and sedation in optimizing icu liberation and survivorship, it is realistic to assume these two former bundle elements may be especially difficult to apply fully, particularly at centers experiencing a surge in covid- admissions. restrictions on visitation, even to dying patients, has substantially reduced the role of family as part of the icu care team ( ) . the importance of the intensivist-led ipt, in both academic and community hospitals, and its importance in facilitating bundle completion, is well-established ( , ) . however, daily ipt rounds and interactions have been forced to change. the need to adopt social distancing and increased workload demands have pushed ipt rounds and collaboration during the covid- pandemic away from the ideal that promotes bundle performance ( ) . in its place, medical team behaviors have tended to revert back to isolated conversations and patient care decisions that are less informed by the robust input from multiple professionals and their expertise; real-time ipt discussions, an essential component of bundle success, are compromised. maintaining the ipt may require novel approaches. virtual participation by members from other areas of the hospital, or even from home, can augment an approach that facilitates best practice. at many hospitals, the need to expand icu resources has placed the critically ill in noncritical care locations; in these settings, clinicians have variable levels of bundle knowledge and experience. for example, an anesthesiologist, who has been asked to help with ventilator management in the icu but previously practiced solely in the operating room, likely has little familiarity or experience with the bundle. similarly, the focus of training for non-icu registered nurses (rns) has been necessarily focused on immediate tasks; the time for review of strategies and processes of care such as the bundle may be limited. the apparent lower frequency of severe critical illness from covid- among pediatric patients ( ) has resulted in some institutions enlisting picu professionals and resources to expand adult icu capacity. the picu team brings the same skill set to treat and support critically ill patients, just in younger patients with a different range of baseline neurocognitive development and physiology. optimal bundle implementation in the picu patient requires the same strategies of repeated assessments and ipt communication and collaboration needed with adults ( - ) but uses different tactical tools to accomplish these goals (supplemental table , supplemental digital content , http://links.lww.com/ ccx/a ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . established icu ipt members should embrace new team members and prioritize just-in-time training about the bundle. adult icu specialists should partner with their picu colleagues when adults are admitted to picus, both to provide support for adult-specific medicine and also to foster mutual learning about different approaches to bundle element performance. the adult icu team can provide just-in-time training, guidance, and coaching to non-icu or picu clinicians. the amount of training and coaching could be high for a non-icu professional who has never heard of the bundle or low for the picu team member who has experience with the bundle but requires guidance about the chronic medical comorbidities of adults. high quality critical care during a pandemic is predicated by adequate personal protective equipment (ppe); shortages can impact every stage of icu care. initial decisions about how supportive care for acute hypoxemia should be delivered (e.g., noninvasive vs invasive ventilatory support) continue to be clouded by concerns about viral aerosolization ( ) . if the frequency of bedside patient assessments and interventions are reduced, the increased use of hand restraints that invariably results may lead to greater use of deep sedation and nmb therapy outside of usual therapeutic goals. the loss of repeated bedside exams and assessments may force care to become more monitor-based, leaving clinicians to focus more on vital signs, cardiopulmonary status, and laboratory results than on neurologic and musculoskeletal function. restricted ppe availability has also resulted in an overlap of bedside responsibilities among available icu ipt members ( ) ; entry to the patient room by a single icu clinician at a time is more common. as a result, the icu team loses the added layers of safety based on profession-specific education and experience. examples include non-respiratory therapists (rts) making directed ventilator adjustments but without the rt's implicit knowledge of how changes in one ventilator variable might impact another. non-rns may be asked to administer medications but without the rn's ingrained process for cleaning central line hubs to mitigate risk of central line-associated bloodstream infections. the requirement to use ppe at all times also removes the all-important human face-to-face connection and touch of critical care. patients can no longer see the nonverbal cues that convey communication, compassion, and empathy in ways that garbled words behind a n- mask can never hope to replace ( ) . patient fear and anxiety, particularly if delirium is present, may increase and the icu environment becomes that much more foreign. consider repurposing strategies that enhance efficiency of care for patient comfort, rethink the ideal number of in-room team members, and ask front line staff for outside-the-box ideas. adherence to strong ipt communication along with robust justin-time training and coaching can facilitate bundle performance while also promoting judicious use of ppe ( , ) . as patients clinically improve, the bedside frequency of patient monitoring and care may be able to be reduced throughout the day, in a similar fashion to approaches increasingly being used at night to reduce sleep disruption ( ) . icu teams can also reimagine in-room presence to two-person teams that enter the room together and work in tandem to provide "boluses" of patient care. this approach will reduce the time any-one clinician spends in the room, improve efficiency of care, and the in-the-moment clinician-clinician interaction will promote a sense of team rather than isolation. it may also reduce ppe use as the longer a single clinician stays in the room, the more likely they may need to temporarily leave the room to change ppe (e.g., a sweaty n- mask). a number of unique barriers, over and above those already discussed, exist surrounding the performance of individual bundle components in critically ill adults with covid- . this section highlights these potential barriers and offers practical solutions to overcome them. pain assessment of the mechanically ventilated covid- patient may be compromised because patients may be more often deeply sedated and/or receiving nmb therapy and the nurse may be spending less time at the bedside. the risk factors and causes of pain may be different from those of less critically ill adults. prolonged periods of high-dose opioid therapy are common. strategies to overcome these barriers and optimize patient comfort are highlighted in table ( , , , ( ) ( ) ( ) ) . sedation assessment is challenging during nmb therapy and may be reduced if the nurse is less frequently at the bedside. although patients with acute respiratory distress syndrome can often safely be managed at a lighter sedation goal ( ), covid- patients may be maintained at a deep level of sedation for a prolonged period. attempts at spontaneous awakening trials may be reduced due to concerns about patient-initiated device removal (e.g., selfextubation). spontaneous breathing trials may be reduced due to deeper sedation and/or reduced lack of rt presence. strategies to overcome barriers to wakefulness and mechanical ventilation liberation are presented in table ( , , , - , , ) . use of analgesics, sedatives, and nmb, often for prolonged periods and at high doses, coupled with a high prevalence of multiple organ failure, will increase the risk for drug interactions, opioid/ sedative withdrawal effects, and adverse drug events. placement of iv infusion pumps in hallways and reduced room entry by if fentanyl, methadone, and haloperidol are administered, particularly at high doses and/or in combination with other medications known to prolong the qtc interval, monitor the qtc interval regularly coronavirus disease treatment regimens known to be a substrate of one or more cytochrome p isoenzymes (e.g., lopinavir/ritonavir) may reduce fentanyl and midazolam clearance iv acetaminophen may worsen hypotension, particularly in patients requiring vasopressor support nonsteroidal anti-inflammatory drugs should be avoided given their deleterious effects on prostaglandin synthesis and the high prevalence of coagulopathy and acute kidney injury in this population placement of iv infusion pumps in the hallway and frequency of room entry reduced longer lengths of iv extension tubing requires the administration of greater priming amounts when new opioid, sedative, and/or nmb infusion bags/bottles are hung. use of larger bags/bottles will reduce the frequency of priming efforts use greater than normal iv flush volumes when administering opioids or sedatives as an iv bolus bundle oral/enteral medication administration times to preserve personal protective equipment use increased risk for opioid and sedative withdrawal oral/enteral administration of longer-acting opioids (e.g., methadone) and sedatives (e.g., diazepam) may reduce the risk for withdrawal reactions as continuous opioid and sedative infusions are weaned down/ turned off. note: oral/enteral absorption may be unreliable until the gut is deemed to be "moderately functioning" (e.g., vasopressor requirements low and/or tube feeds initiated and being tolerated) frequent use of continuous nmb therapy for prolonged periods to optimize mechanical ventilation/proning and/or to reduce self-extubation risk consider iv bolus dosing for nmb therapy before initiating continuous infusions. note: nmb infusions should be administered using a weight-based approach infusions should be down-titrated (or stopped) at least once daily until ventilator dyssynchrony or some degree of patient movement is observed. note: early use of continuously-infused nmb has not been shown to improve -d mortality in patients with acute respiratory distress syndrome and is associated with safety concerns ( , ) nmb = neuromuscular blocker, pris = propofol-related infusion syndrome. nurses raise important medication administration-related concerns. strategies to optimize analgesic, sedative, and nmb use and reduce safety concerns with their use are presented in the prevalence of delirium in critically ill adults with covid- likely approaches % ( , , ) . delirium screening may be compromised given the high proportion of patients managed at a very deep level of sedation and the reduced frequency of nurses at the bedside. in the potential absence of key ipt members and reduced entry into patient' rooms, challenges to reducing potential modifiable delirium risk factors exist. most covid- patients will have disrupted sleep ( ) ; multiple barriers prevent the routine application of nonpharmacologic strategies known to improve sleep and/or reduce delirium. strategies to help better recognize and reduce delirium in this population are presented in table ( , , , - , , ) . critically ill adults with covid- are at high risk for icu-acquired weakness and compromised post-icu physical function. deep sedation, with or without nmb therapy, precludes out-of-bed rehabilitation ( , ) . physical and occupational therapists may not be present in the icu; the truncated time nurses are at the patient bedside may reduce in-bed rehabilitation efforts. as patients recover, contact precautions may preclude out of icu room mobility efforts. strategies to optimize rehabilitation and mobility in light of these barriers are presented in table ( , , , ( ) ( ) ( ) ) . in the face of contagion, evidence-based strategies known to support family engagement in icu care have generally been abandoned ( ) . there is abundant sharing on social media by family members about their frustration, sadness, and grief over "not being there" for their loved ones. families are rarely present in the hospital and almost never allowed at the bedside. for patients who are wakeful, daily telephone, facetime, or zoom communications with family is encouraged. families should be encouraged to provide the icu with family photos and provide clinicians with the e-stories and music the patient enjoys ( , ) . the number of critically ill adults with covid- requiring mechanically ventilatory support has dramatically affected the way critical care is delivered and has likely prompted a move at many centers away from evidence-based icu practices such as abcdef bundle delivery. despite multiple factors affecting bundle use in icus caring for covid- adults, we have outlined multiple strategies to help operationalize the bundle, regardless of ppe availability, the location of critical care, or patient severity of illness. reemploying the use of evidence-based strategies developed over the past years in critical care research, appropriately adapted for use in this new and trying time of the coronavirus pandemic, may be one of the best mechanisms by which to increase ventilator and icu capacity and help critically ill adults with covid- transition toward recovery and survivorship. supplemental digital content is available for this article. direct url citations appear in the html and pdf versions of this article on the journal's website (http://journals.lww.com/ccejournal). dr. devlin has received research funding from the national institute of aging, national heart, lung, and blood institute, and the canadian institute of health research; he is on the editorial board of critical care medicine. dr. ely has received funding from the national institute of aging and national heart, lung, and blood institute. the remaining authors have disclosed that they do not have any potential conflicts of interest. for information regarding this article, e-mail: j.devlin@neu.edu clinical course and outcomes of critically ill patients with sars-cov-pneumonia in wuhan, china: a singlecentered, retrospective, observational study baseline characteristics and outcomes of patients infected with sars cov- admitted to icus of the lombardy region of italy covid- in critically ill patients in the seattle region -case series introduction and executive summary: care of the critically ill and injured during pandemics and disasters: chest consensus statement united states icu resource availability for covid- the burdens of survivorship: an approach to thinking about long-term outcomes after critical illness improving long-term outcomes after discharge from intensive care unit: report from a stakeholders' conference icu doctors already know how to get covid- patients off ventilators faster the abcdef bundle: science and philosophy of how icu liberation serves patients and families american college of critical care medicine: clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit worldwide survey of the "assessing pain, both spontaneous awakening and breathing trials, choice of drugs, delirium monitoring/management, early exercise/mobility, and family empowerment" (abcdef) bundle critical illness, brain dysfunction and survivorship (cibs) center at vanderbilt university and the nashville veteran's administration hospital icu delirium society of critical care medicine: icu liberation improving health care for critically ill patients using an evidence-based collaborative approach to abcdef bundle dissemination and implementation common challenges to effective abcdef bundle implementation: the icu liberation campaign experience implementing the abcdef bundle: top questions asked during the icu liberation abcdef bundle improvement collaborative clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the icu mind-usa investigators: haloperidol and ziprasidone for treatment of delirium in critical illness anzics clinical trials group and the spice iii investigators: early sedation with dexmedetomidine in critically ill patients nonsedation or light sedation in critically ill, mechanically ventilated patients effectiveness and safety of the awakening and breathing coordination, delirium monitoring/ management, and early exercise/mobility bundle improving hospital survival and reducing brain dysfunction at seven california community hospitals: implementing pad guidelines via the abcdef bundle in , patients caring for critically ill patients with the abcdef bundle: results of the icu liberation collaborative in over , adults staged implementation of awakening and breathing, coordination, delirium monitoring and management, and early mobilization bundle improves patient outcomes and reduces hospital costs university of california, san francisco critical care innovations group: interprofessional care and teamwork in the icu best practices for conducting interprofessional team rounds to facilitate performance of the icu liberation (abcdef) bundle covid- : icu delirium management during sars-cov- pandemic collaborative delirium prevention in the age of covid- doctors fear the coronavirus. is that affecting their medical decisions? washington post. . available at guidelines for family-centered care in the neonatal, pediatric, and adult icu systematic review of covid- in children shows milder cases and a better prognosis than adults picu up!: impact of a quality improvement intervention to promote early mobilization in critically ill children implementation of an icu bundle: an interprofessional quality improvement project to enhance delirium management and monitor delirium prevalence in a single picu changes in provider perceptions regarding early mobility in the picu psychometric properties of the numerical rating scale to assess self-reported pain intensity in children and adolescents: a systematic review the faces pain scale-revised: toward a common metric in pediatric pain measurement the flacc: a behavioral scale for scoring postoperative pain in young children the revised flacc observational pain tool: improved reliability and validity for pain assessment in children with cognitive impairment validity of the richmond agitation-sedation scale (rass) in critically ill children state behavioral scale: a sedation assessment instrument for infants and young children supported on mechanical ventilation a randomized controlled trial of daily sedation interruption in critically ill children restore study investigators and the pediatric acute lung injury and sepsis investigators network: protocolized sedation vs usual care in pediatric patients mechanically ventilated for acute respiratory failure: a randomized clinical trial sedation management in children supported on extracorporeal membrane oxygenation for acute respiratory failure diagnosing delirium in critically ill children: validity and reliability of the pediatric confusion assessment method for the intensive care unit the preschool confusion assessment method for the icu: valid and reliable delirium monitoring for critically ill infants and children cornell assessment of pediatric delirium: a valid, rapid, observational tool for screening delirium in the picu* high-flow nasal cannula may be no safer than non-invasive positive pressure ventilation for covid- patients the-covid- -files-behind-all-the-protection-the-human-touch-fades-away/ reducing deep sedation and delirium in acute lung injury patients: a quality improvement project nutrition therapy in the patient with covid- disease requiring icu care. society of critical care medicine and the american society for parenteral and enteral nutrition incidence of propofol-related infusion syndrome in critically ill adults: a prospective, multicenter study early neuromuscular blockade in the acute respiratory distress syndrome clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient demand for ventilator drugs 'unprecedented repurposing valproate, enteral clonidine, and phenobarbital for comfort in adult icu patients: a literature review with practical considerations the medical letter on drugs and therapeutics: some drugs for covid- . available at clinical drug information the epidemic within the pandemic: delirium. new york times. . available at key: cord- -cwhm v s authors: vergano, marco; bertolini, guido; giannini, alberto; gristina, giuseppe r.; livigni, sergio; mistraletti, giovanni; riccioni, luigi; petrini, flavia title: clinical ethics recommendations for the allocation of intensive care treatments in exceptional, resource-limited circumstances: the italian perspective during the covid- epidemic date: - - journal: crit care doi: . /s - - -w sha: doc_id: cord_uid: cwhm v s nan on february , , the first person-to-person transmission of severe acute respiratory syndrome coronavirus (sars-cov ), the virus causing coronavirus disease (covid- ), was identified in italy. in the following days, despite the restrictive public health measures applied to avoid the spread of the infection [ ] , the number of cases sharply increased. as of march , , italy was the nd most affected country in the world. in one of the largest reports from china, % of covid- patients required admission to the intensive care unit (icu) [ ] . since the beginning of the covid- outbreak, the availability of icu beds has been recognized as one of the major public health concerns in italy, where a total of icu beds ( . / , inhabitants) were reported in [ ] . despite further efforts have been done to contain the number of cases and extraordinary measures have been put in place, the dramatic increase of icu admission abruptly overwhelmed the icu capacity, mostly in lombardy and in the nearby regions of northern italy. from the evidence available so far, a considerable proportion of subjects diagnosed with covid- infection requires ventilatory support due to severe hypoxemia in the context of interstitial pneumonia. the interstitial lung disease is potentially reversible, but the acute course of the disease can last several days, and ventilatory support may be needed for weeks [ ] . these clinical considerations imply that caring for patients with severe pneumonia from covid- can be very demanding in terms of the number of devices and staff required. as of march , , the italian society of anesthesia, analgesia, resuscitation and intensive care (siaarti) issued a series of recommendations [ ] and relevant ethical considerations to better inform the clinicians involved in the care of critically-ill covid- patients, in a setting where a disproportionate number of patients requiring life-sustaining treatments was rapidly saturating both the existing and the newly set-up icu beds. the most relevant recommendations are summarized in table . the emerging epidemic is leading to a substantial increase in the number of patients requiring prolonged ventilatory support for acute respiratory failure, potentially resulting in severe imbalances between the population clinical needs and the overall availability of icu resources. in this scenario, criteria for icu admission (and discharge) may need to be driven not only by the principles of clinical appropriateness and proportionality of care, but also by criteria of distributive justice and appropriate allocation of the healthcare resources, that may be more limited than usual. the primary aim of these recommendations is therefore to supply a common framework for the admission of patients to intensive care treatments in resource-limited circumstances. these recommendations should be shared maximally within all the involved healthcare providers. bioethical reasoning has inspired several operative instructions for the field of disaster medicine. in this area, healthcare providers must be supported during their difficult decision-making process. as an extension of the principle of proportionality of care, in the context of a severe shortage of icu resources, these should be preferentially allocated to patients with the higher possibility of therapeutic success. therefore, the aim is to privilege the greater chance to successfully overcome critical illness with a greater probability to maintain a good quality of life. a single patient's actual need for icu treatments should be therefore integrated with additional criteria for icu admission, taking into account the type and severity of the current disease, comorbidity, the presence and reversibility of organ failures, and the potential for recovery. it follows that within the foregoing context, the "first come, first served" criterion for icu admission does not necessarily have to be followed. because of the rare occurrence of large-scale catastrophic events, the healthcare staff may not be very familiar with the criteria applied for triage during mass casualty events. the availability of resources may not always be part of the clinical decision-making process operated on a single patient, until resources become so limited that it is not possible to treat all patients who may hypothetically benefit from a specific treatment. the application of restrictive (rationing) policies is justifiable only if all the relevant stakeholders ("task forces," hospitals, institutions) have already tried to increase the availability of resources and have already assessed the feasibility and safety to transfer patients to other hospitals. as previously mentioned, a change in the icu admission policy should be shared maximally among the staff involved. moreover, the patients who are affected by the application of new, more stringent criteria of eligibility for icu admission (and/or their proxies) should be allocation of icu resources is a complex and delicate task. criteria for icu admission and discharge under exceptional, resource-limited circumstances must be flexible and should be locally adapted according to the availability of resources, the potential for inter-hospital patient transfer, and the ongoing or foreseen number of hospital and icu admissions. these criteria apply to every patient potentially in need of icu admission, not only to covid- infected patients. triage principles and criteria age, comorbidities, and the functional status of any critically ill patient should carefully be evaluated. a longer and, hence, more "resource-consuming" clinical course may be anticipated in frail elderly patients with severe comorbidities, as compared to a relatively shorter and potentially more benign course in healthy young subjects. the underlying principle would be to save limited resources which may become extremely scarce for those who have a much greater probability of survival and life expectancy, in order to maximize the benefits for the largest number of people. in the worst-case scenario of complete saturation of icu resources, a "first come, first served" criterion is not recommended, as it would ultimately result in denying access to icu care to a large number of potentially curable patients. the presence of advance healthcare directives or advance care planning should be carefully evaluated, especially for patients affected by severe chronic illnesses. these plans should be shared as much as possible between the patient, their proxies, and all the healthcare staff involved in patient care. a decision to deny admission to the icu by applying a "ceiling of care" should always be motivated, communicated, and documented. the decision to withhold invasive mechanical ventilation does not necessarily imply that other, non-invasive, modalities of ventilatory support should also be withheld. the decision to withhold or withdraw life-sustaining treatments must always be discussed and shared among the healthcare staff and, when possible, the patients and/or their proxies. a second opinion (e.g., from regional healthcare coordination centres, or from other recognized or designated experts) may be useful when dealing with particularly difficult or distressing cases. appropriate palliative care must always be provided to hypoxemic patients when a decision to withhold or withdraw life-sustaining treatments is made. palliative care should be provided according to national or international recommendations, as a matter of good clinical practice. every admission to the icu should be considered and communicated as an "icu trial." the appropriateness of life-sustaining treatments should be re-evaluated daily, considering the patient's history, current clinical course, wishes, expected goals, and proportionality of icu care. when a patient is not responding to prolonged lifesustaining treatments, or severe clinical complications arise, a decision to withhold or withdraw further or ongoing therapies should not be postponed in a resource-limited setting during an epidemic. networking and family care networking among healthcare professionals is essential to share clinical expertise. dedicated time and resources should be anticipated for team debriefing and monitoring of burnout symptoms or moral distress among the healthcare staff once time permits. also, the impact of restricted visiting policies on families and proxies should be considered, especially when the death of a loved one occurs during times of complete restriction of family visits. informed of the extraordinary nature of the measures in place, as a matter of duty of transparency and to maintain confidence in the health service. an additional aim of the recommendations is to support the clinicians when dealing with individual patients, as hard and complex decisions may be ethically and emotionally demanding. the response of milan's emergency medical system to the covid- outbreak in italy clinical characteristics of coronavirus disease in china italian ministry for health. statistical report on the national health service clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study siaarti clinical ethics recommendations for the allocation of intensive care treatments in exceptional, resource-limited circumstances springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations all the authors contributed to the draft and the critical revision of the article and provided final approval of the version submitted for publication. the authors did not receive any funding for this project.availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. the authors declare no competing interests.author details key: cord- -qg x pw authors: marshall, andrea p.; austin, danielle e.; chamberlain, di; chapple, lee-anne s.; cree, michele; fetterplace, kate; foster, michelle; freeman–sanderson, amy; fyfe, rachel; grealy, bernadette a.; hodak, alison; holley, anthony; kruger, peter; kucharski, geraldine; pollock, wendy; ridley, emma; stewart, penny; thomas, peter; torresi, kym; williams, linda title: a critical care pandemic staffing framework in australia date: - - journal: aust crit care doi: . /j.aucc. . . sha: doc_id: cord_uid: qg x pw background: pandemics and the large-scale outbreak of infectious disease can significantly impact morbidity and mortality worldwide. the impact on intensive care resources can be significant and often require modification of service delivery, a key element which includes rapid expansion of the critical care workforce. pandemics are also unpredictable, which necessitates rapid decision-making and action which, in the lack of experience and guidance, may be extremely challenging. recognising the potential strain on intensive care units (icus), particularly on staffing, a working group was formed for the purpose of developing recommendations to support decision-making during rapid service expansion. methods: the critical care pandemic staffing working party (n = ), representing nursing, allied health, and medical disciplines, has used a modified consensus approach to provide recommendations to inform multidisciplinary workforce capacity expansion planning in critical care. results: a total of recommendations have been proposed which reflect general recommendations as well as those specific to maintaining the critical care workforce, expanding the critical care workforce, rostering and allocation of the critical care workforce, nurse-specific recommendations for staffing the icu, education support and training during icu surge situations, workforce support, models of care, and de-escalation. conclusion: these recommendations are provided with the intent that they be used to guide interdisciplinary decision-making, and we suggest that careful consideration is given to the local context to determine which recommendations are most appropriate to implement and how they are prioritised. ongoing evaluation of recommendation implementation and impact will be necessary, particularly in rapidly changing clinical contexts. pandemics and the large-scale outbreak of infectious disease can significantly impact morbidity and mortality worldwide with potential to stress intensive care resources [ ] and necessitate change to how services are usually delivered. previous pandemics, such as h n , provide evidence for the need to plan well for increased nursing, allied health, medical, and ancillary staff [ , ] . nevertheless, planning can be challenging owing to the unpredictable and uncertain nature of pandemics [ ] and inability to quickly access skilled staff. we know from experience of respiratory pandemics that pneumonia is a common complication which contributes to the development of critical illness through rapid clinical deterioration [ ] . the impact on intensive care unit (icu) resource can be significant, overwhelming, and unpredictable. with large increases in the number of critically ill patients requiring respiratory support through invasive or noninvasive mechanical ventilation, there will be a concomitant increase in the requirements for nursing, allied health, and medical staff with specific expertise in the management of critical illness. nevertheless, adequate staffing with appropriately trained clinicians who are able to support a surge of critically ill patients can be a major challenge [ ] . this is especially evident in the coronavirus disease (covid- ) pandemic where it has been projected that during maximal surge in australia, an additional registered nursing staff ( % above baseline staffing) and senior medical staff ( % above baseline staffing) may be required [ ] . increases in allied health staffing requirements would also occur, commensurate with service expansion and change in patient profiles. australian federal and state governments' early implementation of travel restrictions and physical distancing measures were initially successful in controlling covid- case numbers [ ] ; however, in the first week of july , nearly new cases of covid- were identified in victoria, almost half of which may indicate community transmission [ ] . while these increases in the rates of transmission are low compared with elsewhere in the world [ ] , the potential for intensive care services to become overwhelmed exists and would require major adjustments in service design and delivery, potentially over a sustained period [ , ] . the purpose of this article is to provide recommendations to inform planning for expansion of multidisciplinary workforce capacity in critical care. the recommendations are provided with the understanding that they will be carefully considered by multidisciplinary teams who take into account local contextual factors and the level of icu surge being experienced. although developed in the context of the covid- pandemic, these recommendations are applicable to most situations in which icu requirements exceed available resources. these recommendations provided herein are underpinned by several tenets: (i) that wherever possible, current staffing recommendations be maintained; (ii) that these recommendations have been developed specifically for the context of critical care practice in australia but may be applicable in other clinical contexts and regions; (iii) that critical care clinical practice in australia has a strong interdisciplinary approach and it is in that spirit that these recommendations have been developed; (iv) that intensive care clinical practice is characterised by rapid changes in response to evidence generation and consequently it is anticipated that these recommendations will be regularly reviewed and updated. updates will be made available on the acccn website (acccn.com.au). an interdisciplinary consultation process was conducted which used a range of methods to engage collaborators who were identified by key nursing, allied health, and medical professional bodies, who comprised the critical care pandemic staffing working party (the working party). at the time of development, we were unable to secure the full range of allied health representation and acknowledge the valuable contributions of social work, occupational therapy and psychology in patient care during, and after recovery from, critical illness. representation and a commitment to securing future input from these groups have been made. recognising the lack of workforce data and research evidence to inform the generation of recommendations, these recommendations are based on both available evidence and expert opinion of a broad interdisciplinary team with experience in both the public and private sectors and expertise in clinical, managerial, and research contexts and built on recommendations in other relevant professional documents (table ) . collaborators contributed to development and iterative refinement of recommendations and, where necessary, consulted more widely within their professional groups. over a -week period in mayejune , collaborators engaged in discipline-specific discussions and wider group consultation through interactive video conferencing telephone consultation written submissions from individuals and organisations. owing to the time-sensitive nature of this exercise, broader consultation was not possible. working party members (n ¼ ) initially developed and contributed recommendations (n ¼ ). these recommendations were reviewed by working party members (n ¼ ) who indicated their level of agreement with each of the recommendations on a -point scale (strongly agree to strongly disagree). a priori, we set the level of agreement to retain a recommendation when % working party members agreed or strongly agreed with the recommendation. recommendations were also iteratively reviewed and refined to achieve clarity, avoid duplication, and determine cross-disciplinary relevance. responses were received from working party members on or before june (response rate: %). working party members' level of agreement was assessed, and all recommendations met the retention criteria of %. however, some duplication was noted and recommendations with a similar focus were grouped, resulting in recommendations; an additional six new recommendations were proposed, and consensus reached for their inclusion, with recommendations included overall. all of the final recommendations met the retention where % working party members agreed or strongly agreed with the recommendation. the majority of recommendations were considered to be broadly applicable across all health professions and were grouped into nine concepts. these included service-level recommendations, maintaining the critical care workforce, expanding the critical care workforce, rostering and allocation of the critical care workforce, nurse-specific recommendations for staffing the icu, education support and training during icu surge situations, workforce support, models of care, and deescalation. specific recommendations for medical practitioners have not been added here and are available within the australian and new zealand intensive care society (anzics) covid- guidelines (version ) [ ] , the minimum standards for intensive care units [ ] , and the statement on managing senior medical workforce in the intensive care during the covid- pandemic [ ] . within the recommendations, critical care nurses refer to registered nurses with experience working in the icu who ideally would also have a postgraduate critical care qualification. allied health professionals are inclusive of, but not limited to, clinical dietitians, clinical pharmacists, physiotherapists, social workers, and speech pathologists. these general recommendations, and the more specific recommendations which follow, are provided with the intent that they be used to guide interdisciplinary decision-making and that careful consideration is given to the local context to determine which recommendations are most appropriate to implement and how they are prioritised. ongoing evaluation of recommendation implementation and impact will be necessary, especially in rapidly changing clinical contexts. . the recommendations outlined in this framework should be considered in conjunction with local, state, and federal emergency response requirements and any recommendations in icuand discipline-specific guidelines to specific pandemics (see table ), which should be monitored frequently for updates. . intensive care services should work collaboratively with hospital-wide services when planning and developing strategies to prepare the broader health service for impact associated with increased icu admissions. . not all recommendations outlined in this document will be universally relevant. when making workforce-related decisions to accommodate anticipated icu surge capacity, the local context should always be considered and multidisciplinary consultation undertaken which examines the potential risk(s) and benefit(s) of each recommendation (acccn workforce standard ) [ ] . . when making any changes to staffing, relevant industrial awards will need to be considered. . health services should consider how they might accommodate redeployment of their critical care nursing and allied health professionals to intrastate or interstate 'hot spots'. . supporting the workforce in surge icus or icus in regional areas could be assisted using new or existing telehealth strategies. these recommendations are made based on the understanding that experienced critical care clinicians who are familiar with their environment will be more confident, adaptable, and able to safely accommodate necessary changes in work practice, including the supervision and support of an expanded critical care workforce, all which contribute to the delivery of safe patient care. . discuss with staff any potential impact they might experience which could influence their ability to attend work. for example, travel restrictions may prevent existing staff from returning to work, or newly appointed staff from travelling to the workplace. existing employees on temporary work visas may need to have visas extended for further work, for example, if they are unable to return home. . review existing and future leave allocations to ensure planned leave is maintained wherever possible to support workforce sustainability. with reference to specific industrial awards, any decisions to change existing and future approved leave should be undertaken in conjunction with the employee and local human resources teams. such decisions should take into consideration icu surge predictions and staffing capacity, the anticipated duration of the pandemic, and need for a sustainable workforce. . where possible, increase the full-time equivalent of parttime staff, ensure all vacancies are filled, revise temporary contracts, and negotiate capacity of casual and agency staff to commit to regular shifts during surge periods. . when planning staffing, consideration should be given for the likely increase in personal, sick, or carer's leave and the potential for some staff to be quarantined. additional strategies to maintain the workforce, such as support with childcare, should be considered. . workforce planning should take into consideration the need to accommodate and support vulnerable staff, for example, by looking after noninfectious critically ill patients who are segregated in a separate clinical area, being deployed to another clinical area or temporary deployment to a nonclinical role. recognising that the degree of vulnerability may vary, such decisions should be made in collaboration with the staff member who should seek independent health advice. it is recognised that icu capacity expansion may be required by using a number of strategies to increase staff members who are able to deliver care to critically ill patients or to support care delivery and logistics in the icu. each strategy will have unique benefits and potential risks, the latter of which should be identified and regularly monitored to optimise patient safety. . expanding the critical care workforce may be achieved through deployment of existing staff with critical care experience from noncritical care to critical care areas. currently employed health professionals with transferrable skills (e.g. those who work in other acute clinical areas with experience in managing patients who require advanced clinical management of complex patients and who are competent in airway management and respiratory support) should be considered for cross-skilling to work in the icu. within health services, early identification of these staff members with critical care experience would be helpful, keeping in mind that deployment to the icu will need to be mutually agreeable [ ] . . health professionals without critical care knowledge and skills could be deployed to support delivery of patient care in the icu under the supervision of a critical care nurse or allied health professional with critical care experience. . strategies to encourage, support, and fast-track health professionals with critical care experience to re-enter the icu workforce should be implemented, for example, the use of flexible education approaches, collaborative organisationwide workforce planning, and streamlined human resource processes. . health professionals without critical care experience who reenter the hospital workforce could be used to support lower acuity patients in the hospital, freeing up staff with acute care experience to support patient care in the icu. . health professionals with critical care experience who are employed external to the health service (e.g,. university partners, private hospitals, industry, armed forces) could be approached to determine their availability to work in either clinical or nonclinical roles. . when expanding the icu workforce, it is essential for the delivery of safe care to determine and communicate to others a clinician's scope of practice. development of a systematic approach to assessment and/or self-assessment of icu capability and competence of newly employed or deployed staff may be helpful. . expansion of nonclinical roles, such as those in education, research, and leadership, may be required to support staff development, service delivery, and data acquisition which are fundamental to the delivery of safe and high-quality clinical care. . where staff members are deployed from nonclinical to clinical roles, the impact on work associated with the nonclinical role should be evaluated and strategies implemented to ensure essential aspects of the role are maintained. . specific to the allied health workforce, each icu should work collaboratively with their allied health departments to review clinical coverage and determine the degree to which expansion and extension of services is required. opportunities exist for allied health workforces to support clinical care requirements and the nursing/medical workforce beyond normal responsibilities but within their scope of practice. we recognise that rostering and allocating the critical care workforce will require careful consideration to minimise risk for staff and patients and to safely achieve optimal patient outcomes. these may assist those responsible for workforce rostering and allocation to make decisions which are in the best interest of patient safety and staff wellbeing. . clearly communicate the processes by which rostering and allocation decisions are made as well as how these will be communicated. the process through which staff members are able to have input into these decisions should also be communicated. . where possible, make informed staffing decisions taking into account the knowledge, skills, experience, strengths, and limitations of individual staff members. knowing the strengths and capabilities of staff will be advantageous when making staffing decisions, specifically when extending icu services beyond what is currently provided (e.g. other areas of the hospital or temporary field hospitals). where possible, try to maintain staff in familiar roles to maintain confidence and minimise uncertainty [ ] . . careful attention to maintaining a balanced skill mix is necessary when allocating staff to rosters. . consider the shift duration and number of consecutive days worked to minimise fatigue. any changes to the usual hours worked, whether this be the number of days or hours per day, should be jointly made with the employee and employer. the aim should be to maximise rest and recuperation times with a view to maintaining the workforce throughout the pandemic. . consider the duration of time health professionals are in personal protective equipment (ppe) and adjust breaks, shifts, or role allocation to minimise physical effects of wearing ppe. following the australian government guidance on the use of personal protective equipment in hospitals during the covid- outbreak is recommended as it relates to the comfortable use of ppe in the icu [ , ] . . use strategies during shifts to minimise staff movement between work areas so that physical distancing and other transmission reduction measures are promoted to reduce the number of staff and patients to which any individual is exposed. . plan rosters and shift duration to take into account prolongation of the shift changeover and breaks owing to the time required to don/doff ppe and debriefing or wellbeing support. registered nurses are responsible for care provision and coordination of critically ill patients. the expectation for : nurse-topatient ratios for critically ill patients means that specific considerations for nurse staffing are required, which may be impacted during a pandemic. . where possible, existing nurse-to-patient ratios and assistance, coordination, contingency, education, supervision, support (access) nurses as recommended in the acccn workforce standards for intensive care nursing [ ] should be maintained. decisions on nurse-to-patient ratios should take into consideration patient safety, acuity, visibility, and staffing skill mix. changes to existing nurse-to-patient ratios should only be considered with maximal surge (tier and of the anzics icu pandemic plan) [ ] . in tier or , the nursing leadership team could consider how nurse-topatient ratios might be maintained with a noncritical care nurse or health professional working under the supervision of a critical care nurse. . the icu patient case mix and unit design (e.g. single rooms) must determine the appropriate nursing service, knowledge, and skills required for the nursing workforce and support staffing of each unit (acccn workforce standard ) [ ] . . any registered nurse who does not have critical care nursing experience should be adequately supported and supervised in the delivery of patient care by a critical care nurse so that patient safety and outcomes are optimised (acccn workforce standard ) [ ] . . staffing models that incorporate direct patient care provided by a nursing student or health professionals other than a registered nurse should only be implemented in extreme situations (tier of the anzics icu pandemic plan) [ ] and should incorporate strategies to ensure effective patient monitoring and review by a critical care nurse. . patient allocation should be done such that there are designated critical care nurses responsible for directing the nursing care of all patients in the icu. where the critical care nurse is responsible for more than one patient, he/she should work in conjunction with, and supervise the care provided by registered nurses without critical care experience, nursing students or other health professionals who are supporting delivery of patient care. such a model of care should be underpinned by clear communication strategies and criteria to escalate concerns to the critical care nurses so that patient safety is maximised (acccn workforce standard ) [ ] . . experienced critical care nurses who routinely undertake collaborative roles such as icu liaison, icu outreach, and/or rapid response maybe required to extend their roles to work more independently in the event of medical shortages. capacity expansion of the icu which may occur during a pandemic will require focused and tailored education, support, and training to maintain high-quality and safe patient care and support optimal organisational performance of the icu. these recommendations are made to assist icu leaders and educators to ensure existing and new staff members are appropriately supported during rapid-learning contexts. . all staff members must have access to and appropriate training in the use of ppe and be aware of strategies being implemented in the workplace to minimise exposure. . alongside review of professional qualifications, assessment of capability and competence should incorporate knowledge, skills, and abilities and be considered across a range of different contexts and not be solely limited to provision of direct patient care. this assessment should subsequently inform decisions about where additional staff members are best placed to support the work of the icu. . situation-specific education and simulation should be provided for existing and newly recruited staff, for example, in preparation for covid- education of health professionals focused on correct use of ppe and patient management strategies including prone positioning. existing staff may also need to assume new and unfamiliar roles for which support and education may be required. . a wide range of education strategies should be used to develop theoretical knowledge, skills, and clinical competency and allow for tailoring of education to individual requirements, which can be informed by self-assessment of individual learning needs. . share high-quality, evidence-based, and peer-reviewed education materials and build on existing education frameworks and learning materials available locally or from regional, state, and national networks, including the use of learning resources from academic and industry colleagues as well as from commercial education providers. . where possible, theoretical education should be supported by supernumerary work to consolidate learning, allow for skill and competency development, and ensure appropriate application of theory to practice. it should be acknowledged that in some instances learning in the workplace without the opportunity for theoretical education or supernumerary support may be required. strategies to maximise learning during supernumerary shifts should be considered. for example, learning may be increased by ensuring exposure to different types of patients, maximising opportunistic learning, and capitalising on 'just-in-time' learning. . when supporting staff to begin or return to work in the icu, consider that longer periods between upskilling and deployment may require staff to be provided opportunities for regular refreshing of newly acquired practices. rapid capacity expansion that may be required during a pandemic will necessitate support of the critical care workforce at the national, state, regional, and local level. support will also be required for health services, hospitals, icus, and specifically for individuals. these recommendations are provided to assist health services, hospitals, icu leaders, and clinicians to consider how organisations, icus, and individuals might be supported to deliver high-quality and safe patient care. . assessment of how changes in staffing, roles, and models of care might disrupt or strain the existing work dynamic may be beneficial to identify areas where additional support may be required. this may be important for staff deployed from the icu to other areas, which may be required for vulnerable staff. assessment should include evaluating the transition experience all staff members undertaking new roles within the icu to determine whether additional support is required. . consider the use of formal and informal debriefing which may be offered at regular intervals (or as required) to all staff members working in the icu during the response to a pandemic; flexibility in when and how debriefing sessions are offered will be needed to maximise participation. staff with debriefing skills should be identified and asked to provide leadership in this area. . as the patient load increases, consideration should be given for simultaneous adjustment to support roles to ensure the ability to maintain services such as, but not limited to, administration, support for patient care, environmental services, and supply of equipment, medications, and consumables (acccn workforce standard ) [ ] . . assess current communication strategies and augment or modify these strategies to accommodate increased frequency of communication to a greater number of staff, ensuring information is able to be easily accessed within or external to the organisation. . streamline communication by providing succinct daily updates to staff which contain key messages specific to the icu as well as that from the broader the health service and the community. in addition to existing infection prevention and control procedures, management of the workspace may be beneficial in promoting adherence to strategies designed to minimise crosscontamination. . review the configuration of shared spaces such as tea rooms, locker areas, and meeting rooms to allow for appropriate physical distancing. for effective implementation, staggered shift start times and breaks might be required. . to minimise potential cross-contamination, consider the use and laundering of hospital-supplied uniforms and access to shower facilities in the workplace. staggered shift finishing times will be required to avoid congestion. existing models of care may require modification to support capacity expansion. it is important that any model of care maintains or improves patient safety and delivery of optimal care while also improving efficiencies. . any proposed changes in models of care should be developed through interdisciplinary collaboration and align with the tiered icu pandemic plan [ ] . . if implementing a team approach to specific tasks, consideration should be given to ensure team members are able to be flexible and provide support in other areas during periods of reduced workload. . team approaches to specific skills or tasks could be considered if there are anticipated gains in efficiencies of care; one example could be the use of proning teams. ensuring that members of the team have the requisite knowledge, skills, and experience to contribute to the collective development of expertise may result in increased efficiency, maximisation of patient safety, and minimisation of risk to the staff. . reconfiguring existing hospital teams (e.g. medical emergency teams or cardiac arrest teams) may be required to minimise workload for icu staff [ ] . where icu expertise is normally provided, this should continue, where possible. . identify models of care delivery that may be implemented to minimise risk and exposure e for example, use of telehealth options or other strategies for collecting information/background history which have normally been done face-to-face. . protocolising the process for transferring patients between departments within the hospital may help ensure appropriately qualified staff members accompany the patient when outside the icu [ ] . . a multidisciplinary team approach to follow up patients recently discharged from the icu should be considered, such as where demand for icu beds is necessitating earlier than anticipated discharge from the icu (acccn workforce standard ) [ ] . this may ensure continuity of specific and/ or complex care such as tracheostomy management, ongoing complex respiratory management, and continuity of rehabilitation and may help to recognise deterioration or prevent readmission to the icu. follow-up of patients discharged to the ward also provides an opportunity for incidental teaching of ward staff. . maintaining a person-centred approach to care delivery, family support, and open communication with families is essential. dedicated support roles such as a family liaison nurse and augmentation of social work support may be helpful strategies to optimise communication with and care of families. telehealth or online collaboration tools (e.g. microsoft teams, zoom, etc) may be effective strategies to connect with families who are either at a distance or unable to visit owing to infection prevention and control measures. decisions to de-escalate from expanded capacity will require careful consideration, particularly where there is potential for fluctuations in capacity which are likely to occur through a pandemic. . retain a portion of the expanded workforce for a period of time to facilitate the ability of staff to access leave or to reduce hours, allowing for rest and recuperation. . as the pandemic eases, identify ways in which staff can be supported through access to leave or reduction in working hours. we recognise the lack of workforce data and research evidence to underpin the development of these recommendations, and this underscores the need for strong interdisciplinary health service research that is specific to the delivery of critical care. a limitation of the study was the inability to gain representation from all allied health professions, for example, by inclusion of occupational therapy, clinical psychology, and social work. however, the role of these professions should similarly be considered alongside other professions contributing to icu management. we attempted to mitigate this limitation by introducing strategies to support the development of recommendations, including the incorporation of current professional and evidence-based guidelines which underpinned some of these recommendations. these strategies include the use of a strong interdisciplinary approach to identify and develop consensus for recommendations, through independent voting, to inform intensive care pandemic staffing that is reflective of the way in which care is delivered in australian icus. in developing these recommendations, we actively engaged the relevant nursing, allied health, and medical professional organisations and ensured the working party members had broad experience in clinical practice, management, education, and research. representation across the public and private sectors, from metropolitan and regional areas, and from a range of states and territories was also ensured. future iterations of this work will be enhanced by broader professional consultation, which is inclusive of consumers. pandemics, which are unpredictable, will continue to be a major global health concern. lessons from past pandemic experiences have helped to inform our preparedness today, and it is important we leverage our learnings from current events to improve future responses. as research and experience continues to inform our understanding of optimal approaches to pandemic management, in particular, how icus can respond to sudden requirements for capacity expansion, it will be important to regularly reflect on, review, and modify these recommendations. covid- : a novel coronavirus and a novel challenge for critical care preparing for the covid- pandemic: our experience in new york the experiences of health care workers employed in an australian intensive care unit during the h n influenza pandemic of : a phenomenological study preparing your intensive care unit for the second wave of h n and future surges influenza epidemiology-past, present, and future preparing icus for pandemics surge capacity of intensive care units in case of acute increase in demand caused by covid- in australia suppressing the epidemic in new south wales coronavirus update for victoria - july melbourne. victoria state government world health organisation. coronavirus disease (covid- ) pandemic geneva. world health organisation covid- bergamo hospital crisis u. adaptations and lessons in the province of bergamo enhancing intensive care capacity: covid- experience from a tertiary center in israel australian college of critical care nurses. workforce standards for intensive care nursing acccn workforce standards for intensive care nursing: systematic and evidence review, development, and appraisal australian and new zealand intensive care society. covid- guidelines. camberwell: vic: anzics; minimum standards for intensive care units covid- critical care coordination collaborative. statement on managing senior medical workforce in intensive care during the covid- pandemic. college of intensive care medicine of australia and new zealand, australian and new zealand intensive care society, australian and new zealand college of anaesthetists facuty of intensive care medicine and the intensive care society. guidelines for the provision of intensive care services physiotherapy management for covid- in the acute hospital setting: clinical practice recommendations nutrition management for critically and acutely unwell hospitalised patients with covid- in australia and new zealand shpa committee of specialty practice in critical care. shpa standards of practice for critical care pharmacy practice speech pathology australia guidance for service delivery, clinical procedures and infection control during the covid- pandemic information/covid- _-_guidance_for_service_delivery/spaweb/about_us/ covid- /guidance_for_service_delivery.aspx?hkey¼fc a -e a - - -a fc d ae royal college of speech language therapists. covid- : maximising the contribution of the speech and langage therapy workforce guidance on the use of personal protective equipment (ppe) in hospitals during the covid- outbreak infection control expert group. the use of face masks and respirators in the context of covid- . canberra: australian government college of intensive care medicine of australia and new zealand. guidelines for transport of critically ill patients. prahran: vic: cicm resources/professional% documents/ic- -guidelines-for-transport-of-critically-ill-patients.pdf we acknowledge the australian college of critical care nurses, the australian and new zealand intensive care society, the college of intensive care medicine, the dietitians association of australia, the society of hospital pharmacists australia, speech pathology australia, and the australian physiotherapy association for providing comment on these recommendations. this document has been reviewed and endorsed by the australian college of critical care nurses, dietitians australia, society of hospital pharmacists australia, and speech pathology australia. the authors have made a commitment to regularly reviewing the recommendations; updates will be available on the australian college of critical care nurses website (acccn.com.au). the authors attest that this work has not been published previously, that it is not under consideration for publication elsewhere, that its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in english or in any other language, including electronically without the written consent of the copyright holder. andrea p marshall, on behalf of all authors, declares that this manuscript is original, has not been published before, and is not currently being considered for publication elsewhere. we confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. we further confirm that the order of authors listed in the manuscript has been approved by all of the authors. we understand that the corresponding author, professor marshall, is the sole contact for the editorial process. she is responsible for communicating with the other authors about progress, submissions of revisions, and final approval of proofs. this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. all persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript. furthermore, each author certifies that this material or similar material has not been and will not be submitted to or published in any other publication before its appearance in australian critical care. andrea p marshall is currently editor-in-chief and emma j ridley is an editor of australian critical care. this manuscript has been managed throughout the review process by a consulting editor, professor gavin leslie. this process prevents authors who also hold an editorial role to influence the editorial decisions made. alison hodak is president, australian college of critical care nurses and anthony holley is president of the australian and new zealand intensive care society. key: cord- -dqmvpqtd authors: pasin, laura; sella, nicolò; correale, christelle; boscolo, annalisa; rosi, paolo; saia, mario; mantoan, domenico; navalesi, paolo title: regional covid- network for coordination of sars-cov- outbreak in veneto, italy date: - - journal: j cardiothorac vasc anesth doi: . /j.jvca. . . sha: doc_id: cord_uid: dqmvpqtd nan in december a novel coronavirus, severe acute respiratory syndrome coronavirus (sars-cov- ) disease (coronavirus- ) was reported in wuhan, china, and it rapidly spread across the world. on february , a -year-old man became the first person in europe to die as a result of covid- in a community hospital in veneto, a region of about , , people located in northeast italy. since then, sars-cov- has become a relentless epidemic in italy with a dramatic increase in the number of patients showing covid- -related acute respiratory failure and hypoxemia. considering the epidemiologic data reported from china, , it was immediately clear that the number of covid- patients requiring hospital and intensive care unit (icu) admission would rapidly overwhelm the total icu capacity, thereby resulting in an unexpected systemic crisis due to the imbalance between increased health care demand and potential of supply. as soon as the first covid- victim in italy was recorded, an emergency technical and scientific committee was promptly formed by the local government of veneto to coordinate the response to the emergency of the sars-cov- outbreak in the region. the task force included experts on infectious diseases, intensive care, and health management. the aim of this article is to describe how the region of veneto dealt with the covid- epidemic crisis and to summarize the urgent measures adopted to prevent the breakdown of the health care system. from the beginning of the sars-cov- outbreak, in addition to the progressively adopted national restrictive measures, the veneto local government immediately acted to limit the spread of the virus among the region. in addition, a covid- -dedicated coordinating center was promptly set up, aiming to manage and strategically organize medical activity. to slow the viral transmission, strict containment measures were adopted immediately. the initial cluster in vo', which is near padua, was isolated through quarantine, and the entire population were administered covid- tests. both inhabitants and health care personnel who came into contact with the first covid- patients without appropriate personal protective equipment (ppe) were isolated until they tested negative for sars-cov- . furthermore, a number of policies aimed at curbing in-hospital contagion were introduced, including the following: progressive suspension of ordinary services, with the exception of urgent and oncological cases; mandatory use of surgical masks for anyone within hospital premises; and restricted access to hospital wards for visitors. in every hospital of the region, a separate access to the emergency department for patients with confirmed or suspected sars-cov- infection was provided to minimize contact among patients. all patients with respiratory symptoms and fever were considered suspected for covid- and were clinically evaluated and screened in new dedicated triage areas, often located outside the emergency department. they were managed with isolation measures until proven clear of sars-cov- , whereas patients positive for infection were discharged home or admitted to the hospital according to the severity of clinical conditions and laboratory tests. dedicated covid- medical wards and icus were established, and a regional network was created to monitor and manage the distribution of covid- patients. health care providers working with covid- patients were equipped with maximum ppe, according to the world health organization guidelines. the type of ppe used when caring for covid- patients varied according to different settings and type of activity, as detailed in the supplemental material (supplemental table ). entry to covid- facilities was restricted to assisting personnel only, and external consulting and patient transfers for examination were strictly limited to essential cases. before the sars-cov- outbreak, the icu capacity in veneto was beds across hospitals, for a total of icu bed every , inhabitants. based on the data arising from the outbreak in china, which reported a % icu admission rate ( . %- %), it became clear that the expected number of critically ill covid- patients would not have been manageable in veneto without increasing icu capacity. as a consequence, additional icu beds were made available immediately, and over the following days, another icu beds were created ex novo, accounting for a % increase of total icu beds (fig ) . such an increase in icu reception capacity would not have been possible by allocating patients exclusively to hub hospitals. therefore, several hospitals also were involved to create a regional icu network. the selected hospitals were required to allocate covid- patients in dedicated icus or in areas separated from the rest of the icu beds and to report every positive critically ill covid- patient to the regional coordinating center. to meet the appropriate number of health care providers (physicians, nurses, and social health operators) required to staff the newly created icu beds, lower-priority surgical procedures were canceled and operating room personnel were reassigned to the icus. basic training and adequate instructions about safe ppe use were guaranteed for beginner icu personnel. moreover, training video tutorials were published online (https://www.youtube.com/channel/ucd rd rjabwkqbvqnwee q/playlists). in parallel, respiratory high-dependency unit capacity was increased by %, by both creating new units and adding supplemental beds to the existing ones. the respiratory high-dependency units are areas where patients can be cared for more extensively than on a normal ward but not to the point of intensive care. respiratory high-dependency units were staffed by pulmonologists already familiar with the treatment of respiratory failure and were dedicated to hypoxemic patients requiring noninvasive respiratory assistance, such as high-flow oxygen therapy and noninvasive ventilation, including continuous positive airway pressure. the patient-to-nurse ratio was less than that of a typical ward but more than that in an icu. the surge of respiratory highdependency units aimed to save icu beds for the most critically ill patients who required invasive mechanical ventilation and multiple organ support therapies. furthermore, this strong enhancement created an intermediate step between the ordinary medical ward and the icu, allowing for a more rapid icu discharge and patient turnover. the number of beds in covid- -dedicated medical wards also was increased and the health care provision was strengthened by instructing personnel on high-flow oxygen therapy and continuous positive airway pressure use. the regional scientific committee developed specific process flows and protocols for the management of covid- patients and shared them with all affiliated hospitals to standardize the therapeutic strategies between hub and spoke hospitals. a decisional algorithm with easily available clinical parameters was adopted to help medical ward physicians choose the proper supplementary oxygen therapy and adequate ventilatory support (supplemental fig ) . furthermore, clear indications for the safe tracheal intubation and protective lung ventilation were provided (supplemental figs and ). extracorporeal membrane oxygenation was considered a rescue therapy for the most critically ill covid- patients for whom lung protective ventilation and pronation strategies failed. [ ] [ ] [ ] [ ] because there were no drugs specifically approved for the treatment of sars-cov- infection nor widely corroborated guidelines, the regional scientific committee proposed a policy whereby antiviral pharmacologic support would escalate in line with the severity of the infection (supplemental table ). on april , , a total of , official covid- patients were registered in italy, , ( . %) of whom were in the region of veneto, where a total of , covid tests were performed. on the same date, , deaths occurred in italy, including in veneto. as the number of infections dramatically increased during weeks, hospital admissions also increased. fortunately, most patients did not need hospitalization. in fact, only , ( . %) required hospital admission, % of whom necessitated treatment in the icu (fig ) until the beginning of march, the number of patients requiring icu admission roughly matched the number of patients discharged or who died in an icu. in the following weeks, however, the number of patients requiring icu admission exceeded the number of deaths or discharged patients (fig ) . nonetheless, the occupancy rate of icus in the region remained constant, consequent to the increase of available beds (figs and ) . the number of icu beds occupied by non-covid- patients decreased over time (see fig ) , which likely can be ascribed to the suspension of ordinary surgical activity with planned postoperative icu monitoring and to the reduction in the number of major traumas as a consequence of the restrictions imposed on everyday life activities. therefore, the usual triage decision-making for icu admission did not need to be modified, and all patients requiring advanced life support therapies were allocated easily. among covid- patients admitted to hospital, ( %) died. among them ( . %) were men. the mortality rate for patients who recovered in ordinary wards was significantly less than that of patients admitted to the icu ( % v %; p < . ). the median age of patients who died in ordinary wards was significantly greater than that of patients who died in the icu veneto was one of the most affected regions in italy by the covid- epidemic. the increase of icu beds associated with the aforementioned measures aimed at treating milder or hypoxemic respiratory failure cases outside the icus allowed for icu bed provision for all patients with indication. overall, the strategies adopted prevented the breakdown of the regional health care system. a novel coronavirus from patients with pneumonia in china clinical characteristics of coronavirus disease in china early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia critical care utilization for the covid- outbreak in lombardy, italy: early experience and forecast during an emergency response rational use of personal protective equipment for coronavirus disease (covid- ) clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china critical care crisis and some recommendations during the covid- epidemic in china extracorporeal life support organization covid- interim guidelines. a consensus document from an international group of interdisciplinary ecmo providers extracorporeal membrane oxygenation (ecmo): does it have a role in the treatment of severe covid- ? poor survival with extracorporeal membrane oxygenation in acute respiratory distress syndrome (ards) due to coronavirus disease (covid- ): pooled analysis of early reports ecmo for ards due to covid- fig . number of newly created intensive care unit beds. icu, intensive care unit blue area, coronavirus- patients managed at home. red area, coronavirus- patients requiring hospital admission. green area, coronavirus- patients discharged from hospital. (b) number of coronavirus- patients in patients discharged from the intensive care unit alive (dashed green line) are distinct from patients who died in the intensive care unit dark red bars, intensive care unit beds occupied by non-coronavirus- patients none. key: cord- - m nnufu authors: ceriello, antonio; standl, eberhard; catrinoiu, doina; itzhak, baruch; lalic, nebojsa m.; rahelic, dario; schnell, oliver; Škrha, jan; valensi, paul title: issues for the management of people with diabetes and covid- in icu date: - - journal: cardiovasc diabetol doi: . /s - - - sha: doc_id: cord_uid: m nnufu in the pandemic “corona virus disease ” (covid- ) people with diabetes have a high risk to require icu admission. the management of diabetes in intensive care unit is always challenging, however, when diabetes is present in covid- the situation seems even more complicated. an optimal glycemic control, avoiding acute hyperglycemia, hypoglycemia and glycemic variability may significantly improve the outcome. in this case, intravenous insulin infusion with continuous glucose monitoring should be the choice. no evidence suggests stopping angiotensin-converting-enzyme inhibitors, angiotensin-renin-blockers or statins, even it has been suggested that they may increase the expression of angiotensin-converting-enzyme- (ace ) receptor, which is used by “severe acute respiratory syndrome coronavirus (sars-cov- ) to penetrate into the cells. a real issue is the usefulness of several biomarkers, which have been suggested to be measured during the covid- . n-terminal-pro-brain natriuretic-peptide, d-dimer and hs-troponin are often increased in diabetes. their meaning in the case of diabetes and covid- should be therefore very carefully evaluated. even though we understand that in such a critical situation some of these requests are not so easy to implement, we believe that the best possible action to prevent a worse outcome is essential in any medical act. in the pandemic "corona virus disease " (covid- ) people with diabetes have a high risk to require icu admission. the management of diabetes in intensive care unit is always challenging, however, when diabetes is present in covid- the situation seems even more complicated. this article discusses the specific problems of managing people with diabetes and covid- in icu. in the recent corona virus disease (covid- ) pandemic people with diabetes are paying a very high price. probably they are not exposed to higher risk of being infected, however, in the case, particularly when the metabolic control is not sufficient, they are more prone to serious complications and to die [ ] [ ] [ ] [ ] [ ] . the rates of severe disease are significantly higher in patients with diabetes compared with non-diabetes ( . % vs. . ) [ ] . similarly, type diabetic patients have higher rates of need for intensive care unit (icu), ( . % vs. . %) [ ] . it is well recognized that the management of people with diabetes in an icu is particularly challenging [ ] . to this situation we have to add that diabetes is very often accompanied by co-morbidities, such as cardiovascular disease, hypertension and obesity, which by themselves worsen the prognosis of people with covid- [ ] [ ] [ ] [ ] [ ] . moreover, there are also several other conditions (described in the course of the article), commonly present in diabetes, which can expose people with diabetes open access cardiovascular diabetology *correspondence: antonio.ceriello@hotmail.it irccs multimedica, via gaudenzio fantoli, / , milan, italy full list of author information is available at the end of the article and covid- at high risk for complications. it seems, therefore, quite clear that people with diabetes may have a particular profile/needs when hospitalized in icu for the covid- . in this article we seek to discuss the specific issues to which people with diabetes can be exposed in icu when having the covid- . it is well recognized that an optimal glycemic control during the stay in icu can improve the prognosis [ ] . however, the optimal glycemic control, particularly in icu involves today several aspects. unfortunately, it is not surprising that patients suffering from covid- with hyperglycemia may have a higher risk and a poorer outcome compared with those with euglycemia [ ] . in particular, very recent reports from the usa have shown that uncontrolled glycemia is exposing people with diabetes and covid- at a very high risk to develop serious complications or to die [ , ] . evidence shows that in icu the more time the patients spend in the normal range of glycemia, the better is their prognosis [ , ] . this is also the case of covid- . it has been reported that a tight glycemic control with insulin infusion had a lower risk of severe disease than patients without insulin infusion [ ] . this aspect might be of immediate understanding, however, it also implies to recognize why acute peaks of glycemia, episodes of hypoglycemia or, even worse, the exposure of the patients to huge glucose variability during the stay in icu are all rather deleterious. acute hyperglycemia produces oxidative stress followed by an enormous production of inflammatory cytokines [ ] , a situation that obviously must be avoided during any stay in icu, but particularly during the stay for covid- . it is well known that during this disease a massive cytokines storm can occur, with severely damaging effects [ ] . hypoglycemia can produce the same effects as acute hyperglycemia and can expose directly people to the risk of dying [ , ] . furthermore, how hypoglycemia is recovered might be dangerous: hyperglycemia post-hypoglycemia is also an issue, leading to an enhancement of inflammation [ ] . finally, there are plenty of reports in the literature that glucose variability is producing a worsening of the prognosis in icu [ , [ ] [ ] [ ] [ ] even when glucose is kept in normal range [ ] . so it seems advisable that glucose variability should be avoided. glucose variability also induces the generation of the oxidative stress and the release of inflammatory cytokines [ ] . is the issue of glycemic control also of importance for people with diabetes and covid- ? it seems, unfortunately, the case, according to reports on how glycemia was managed in several situations during this pandemic [ , ] . when facing high glucose levels due to severe infection per se, it is often required that patients are switched to insulin, with some concerns that insulin treatment might not always be safely managed in such situations, unless insulin is administered intravenously via an exactly dosing perfusion device to avoid subcutaneous absorption irregularities in critically ill patients [ , ] . hyperglycemia is common in the intensive care unit (icu) both in patients with and without a previous diagnosis of diabetes [ ] . the optimal glucose range in the icu population is still a matter of debate. given the risk of hypoglycemia associated with intensive insulin therapy, current recommendations include treating hyperglycemia after two consecutive glucose > mg/ dl with target levels of - mg/dl for most patients [ ] . the optimal method of sampling glucose and delivery of insulin in critically ill patients remains elusive. while point of care glucose meters are not consistently accurate and have to be used with caution, continuous glucose monitoring (cgm) is not standard of care and is not yet generally recommended for inpatient use. the advent of new technologies, such as electronic glucose management, cgm, and closed-loop systems, promises to improve inpatient glycemic control in the critically ill with lower rates of hypoglycemia [ ] . the issue of optimal glycemic control is certainly even more complicated during the management of covid- because high doses of glucocorticoids are often used [ ] . glucocorticoids improve the prognosis of covid- but, of course, induce or worsen hyperglycemia [ ] . in the case keeping normal glycemia may be very challenging [ ] . another challenge in managing glycemia during the stay in icu, particularly during the early phase, is the background anti-hyperglycemia therapy. while for several therapies, such as dipeptidyl-peptidase inhibitors (dpp inhibitors), sodium-glucose-transporter- inhibitors (sglt- inhibitors), pioglitazone, alpha-glucosidase inhibitors, metformin and short-acting glucagon-like-peptide- receptor agonists (glp- ra) (exenatide and lixisenatide) their action is only shortly enduring after they are stopped, this cannot be the case for long-acting insulins but particularly for the long-acting glp- ra (dulaglutide, exenatide la, liraglutide and semaglutide) [ ] . their action will add to that of insulin used during the treatment in icu and must be considered in choosing the insulin dose. on the other hand, many of them show an anti-inflammatory activity, which could be quite helpful during covid- [ ] (fig. ) . another rising problem might be the concomitant use of hydroxychloroquine that, even it is controversial [ ] , sometimes is used for preventing the effect of the "severe acute respiratory syndrome coronavirus " (sars-cov- ) [ ] . hydroxychloroquine has a proven hypoglycemic effect, therefore also in this case the insulin treatment must be very carefully managed in order to avoid episodes of hypoglycemia [ ] . intriguingly, there is also evidence that optimal covid- infection management with tocilizumab is not achieved during hyperglycemia in both diabetic and non-diabetic patients [ ] . increased attention is needed regarding the proper hydration of the diabetic patient with covid- in the icu [ ] . hyperhydration can induce the onset of life-threatening pulmonary oedema due to the severity of lung damage during corona infection. serum k levels are equally important, with a major risk of hypokalaemia, frequently associated with covid- , possibly due to hyperaldosteronism caused by elevated angiotensin [ ] . insulin treatment may worsen hypokalaemia if not corrected in time [ ] . diabetes is very often accompanied by hypertension [ ] . fortunately, the issue of the possible role of angiotensin-converting-enzyme inhibitors and angiotensin-receptor-blockers in favoring the penetration of the sars-cov- , due to the increasing receptor for the virus "angiotensin-converting-enzyme- " (ace ), seems to be over [ ] . new specific data coming from people with the covid- , are certainly reassuring on this point [ , ] . in the coronado study, which included patients with diabetes, neither hypertension nor treatment by renin-angiotensin-aldosterone system blockers were associated with a worse prognosis [ ] . anyhow, the control of blood pressure remains an important point in the management of people in icu and of course this particularly applies to people with diabetes. fig. possible issues in the management of people with diabetes and covid- in icu. several issues are present during the management of people with diabetes and covid- in icu. tight glycemic control, avoiding hypoglycemia and glucose variability improves the prognosis. this goal, to be achieved, needs insulin infusion and continuous glucose monitoring (cgm). *moreover, the achievement of tight glucose control may be influenced by the background anti-hyperglycemic therapy and by the concomitant therapy with hydroxychloroquine (risk of hypoglycemia) or corticosteroids (inducing hyperglycemia). **the evaluation of the meaning of several biomarkers related to the risk of cardiovascular complications, thrombosis and inflammation must be careful, because many of them are already altered by diabetes itself. there is no contraindication, however, to the use of acei or arbs to control blood pressure. acei angiotensin-converting-enzyme inhibitors, arbs angiotensin-receptor-blockers, cv cardio-vascular, cgm continuous glucose monitoring, crp c-reactive protein, hs-troponin high-sensitive troponin, icu intensive care unit, il- interleukin- , nt-probnp n-terminal-pro-brain natriuretic-peptide several biomarkers have been suggested to be helpful in stratification of the risk during the covid- . their value as helpful tools in the case of covid- in people with diabetes needs a careful evaluation. covid- can cause serious acute cardiovascular events [ ] . moreover, people with a previous cardiovascular disease are more prone to a worse prognosis if affected by sars-cov- [ ] [ ] [ ] [ ] [ ] . a pre-existing cardiovascular disease very often accompanies diabetes, therefore, people with diabetes also for this reason may be exposed to a more serious complication when having the covid- . furthermore, a large proportion of people with diabetes has asymptomatic coronary artery disease [ , ] which can increase the risk of acute coronary syndrome, heart failure and arrhythmia during the covid- due to proinflammatory process, hypercoagulability and sympathetic stimulation. qt interval is also often increased in people with diabetes, as a consequence of cardiac autonomic neuropathy [ , ] . qt interval may be further lengthened by hypoglycemia and by drugs used during the covid- and by hypokalemia and needs to be carefully monitored. hs-troponin has been suggested for monitoring the risk of myocardial infarction during the covid- [ , ] . however, in the case of diabetes, increased levels of hs-troponin have been reported [ ] , as signal of an existing chronic heart damage, therefore its use for monitoring heart risk in diabetes during covid- deserves some caution. the situation is not different for heart failure, which again, has been described as a serious complication of covid- [ , ] . the measurement of the "n-terminal-pro-brain natriuretic-peptide" (nt-probnp) to define the risk for heart failure in covid- has been suggested [ ] [ ] [ ] . however, plasma nt-probnp level in a patient with covid- must be seen as a marker of both the presence and extent of pre-existing cardiac disease and the acute haemodynamic stress related to covid- . as for hs-troponin, increased levels of nt-probnp have been often reported in diabetes [ , ] . according to various studies, an asymptomatic heart failure can be present in up to more than % of people with diabetes [ ] [ ] [ ] . this condition is characterized by an increase of plasma nt-probnp. so, again, the usefulness of a marker, in this case the nt-probnp, needs a careful evaluation in the presence of diabetes and covid- . thrombosis has been found to occur very often during the covid- and it is one of the most serious complications [ ] . the measurement of d-dimer is very useful in the prediction of the risk for a thrombotic event and its evaluation has been suggested regarding the management of covid- patients [ , ] . the situation in diabetes looks more complicated. d-dimer is often elevated in diabetes [ , ] . it is just the index of increased thrombophilia, which is highly prevalent in diabetes [ ] . the thrombophilia in diabetes is related to an imbalance between thrombosis and fibrinolysis [ ] . this status suggests in one side that the evaluation of the thrombotic status in diabetes during the admission in icu using the d-dimer should be very careful, but at the same time that an anticoagulation could be very helpful. in this context the role of hyperglycemia also deserves attention. an acute increase of glycemia may activate thrombin formation [ ] , convincingly through the glycation of the antithrombin iii, a phenomenon that can be reversed by a fast control of hyperglycemia or by heparin [ ] . heparin administration is largely suggested in the case of covid- , so it seems true that there is further reason for its use in the presence of diabetes [ ] . finally, it has been recently reported that glucose variability may increase the platelet reactivity [ ] . therefore, regarding the risk of thrombosis, there are good reasons to keep glycemia under a strict control, in association with anticoagulation. markers of inflammation, particularly c-reactive-protein and interleukin- have also been suggested as tools for monitoring the severity of the covid- [ , ] . again diabetes has a particular situation. low-grade inflammation is present in this disease [ ] , therefore, as for thrombosis and heart failure, the significance of altered values of these markers needs a careful evaluation in people with diabetes and covid- . furthermore, as reported above, an acute increase of glycemia as well as glucose variability are accompanied by an increased production of cytokines [ , ] , an effect that must be avoided in the covid- . most of diabetic patients are routinely on lipid-lowering treatment, in particular on statins in accordance with the current diabetes and cardiovascular disease guidelines [ ] . statins have well-known anti-inflammatory effects and improve endothelial function, which may be protective against cardiovascular complications during covid- . however, through various mechanisms statins may enhance compensatory immune signals [ ] . in addition, similar to renin-angiotensin-aldosterone system blockers, experimental studies showed that statins also augment the ace receptor expression [ ] and might thus facilitate the penetration of sars-cov- into the cells. whether statins may be beneficial or harmful during virus-induced acute respiratory distress syndrome is controversial [ , ] . further investigations are urgently required to clarify the interplay of these complex mechanisms with the new coronaviruses. in addition statins may cause myotoxicity. a markedly increase in creatine kinase may be observed in some patients with covid- [ ] . the benefit of statins in cardiovascular prevention is well established in people with diabetes. in this context there is no evidence for withdrawing statins during covid- . however creatin kinase should be carefully monitored and, if increased, statin therapy should be temporarily withheld in order to avoid rhabdomyolysis. probably it is not well recognized that all we have reported above, which is true for type diabetes, applies also and particularly and more seriously to type diabetes [ , ] . type diabetes has the same, albeit not more than type diabetes, risk for cardiovascular events [ ] . moreover, it is important to note that many old people may have today type diabetes. data are reassuring, showing that people with type diabetes are not more exposed to sars-cov- infection [ ] nor to more severe outcomes compared to patients with type diabetes [ ] . however, type diabetes is more complicated to manage and probably deserves a special attention when admitted to icu for covid- . managing people with diabetes in any acute setting is always very difficult. covid- has a very severe prognosis for people with diabetes and evidence shows that a tight glucose control could be very helpful. in the case of covid- people with diabetes are more exposed to cardiovascular complications, which may be more challenging to manage [ , ] . the usefulness of several biomarkers suggested for evaluating/monitoring the severity of the disease might be less evident and their use needs a careful evaluation in the case of diabetes. even though we understand that in such a critical situation some of these requests are not so easy to implement, we believe that the best possible action to prevent a worse outcome is essential in any medical act. china medical treatment expert group for covid- ), et al. clinical characteristics of coronavirus disease in china covid- infection in italian people with diabetes: lessons learned from our future (an experience to be used) clinical characteristics of covid- in new york city clinical characteristics and outcomes of patients with severe covid- with diabetes impact of diabetes mellitus on clinical outcomes in patients affected by covid- improving glycemic control in critically ill patients: personalized care to mimic the endocrine pancreas don't sugar coat it: glycemic control in the intensive care unit diabetes is a risk factor for the progression and prognosis of covid- association of blood glucose control and outcomes in patients with covid- and preexisting type diabetes admission hyperglycemia and radiological findings of sars-cov in patients with and without diabetes adapting to the new consensus guidelines for managing hyperglycemia during critical illness: the updated yale insulin infusion protocol improved outcome of patients with diabetes mellitus with good glycemic control in the cardiac intensive care unit: a retrospective study outcomes in patients with hyperglycemia affected by covid- : can we do more on glycemic control? diabetes care lowering glucose to prevent adverse cardiovascular outcomes in a critical care setting hlh across speciality collaboration, uk. covid- : consider cytokine storm syndromes and immunosuppression association of multiple glycemic parameters at intensive care unit admission with mortality and clinical outcomes in critically ill patients risk factors for hypoglycemia in patients with type diabetes, hospitalized in internal medicine wards: findings from the fadoi-diamond study evidence that hyperglycemia after recovery from hypoglycemia worsens endothelial function and increases oxidative stress and inflammation in healthy control subjects and subjects with type diabetes higher glycemic variability within the first day of icu admission is associated with increased -day mortality in icu patients with sepsis independent association of glucose variability with hospital mortality in adult intensive care patients: results from the australia and new zealand intensive care society centre for outcome and resource evaluation binational registry glycemic variability determined with a continuous glucose monitoring system can predict prognosis after acute coronary syndrome glycemic variability and outcome in critically ill glycaemic variability in diabetes: clinical and therapeutic implications timely blood glucose management for the outbreak of novel coronavirus disease (covid- ) is urgently needed diabetes patients with covid- need better blood glucose management in wuhan intensive insulin therapy in critically ill hospitalized patients: making it safe and effective clinical recommendations for managing the impact of insulin adsorptive loss in hospital and diabetes care glucose management technologies for the critically ill impact of glucocorticoid treatment in sars-cov- infection mortality: a retrospective controlled cohort study systemic steroids in patients with covid- : pros and contras, an endocrinological point of view glucose-lowering therapies in patients with type diabetes and cardiovascular diseases covid- and diabetes management: what should be considered? retraction-hydroxychloroquine or chloroquine with or without a macrolide for treatment of covid- : a multinational registry analysis chloroquine and hydroxychloroquine as available weapons to fight covid- hydroxychloroquine in decompensated, treatment-refractory noninsulindependent diabetes mellitus. a new job for an old drug? negative impact of hyperglycaemia on tocilizumab therapy in covid- patients surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) influence of a strict glucose protocol on serum potassium and glucose concentrations and their association with mortality in intensive care patients trends in blood pressure control in patients with type diabetes: data from the swedish national diabetes register (ndr) covid- , diabetes mellitus and&nbsp;ace : the conundrum renin-angiotensin-aldosterone system inhibitors and risk of covid- association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin ii receptor blockers with mortality among patients with hypertension hospitalized with covid- phenotypic characteristics and prognosis of inpatients with covid- and diabetes: the coronado study cardiovascular implications of fatal outcomes of patients with coronavirus disease (covid- ) predictive value of silent myocardial ischemia for cardiac events in diabetic patients: influence of age in a french multicenter study congestive heart failure caused by silent ischemia and silent myocardial infarction: diagnostic challenge in type diabetes influence of cardiac autonomic neuropathy on heart rate dependence of ventricular repolarization in diabetic patients prediction of mortality using measures of cardiac • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold open access which fosters wider collaboration and increased citations maximum visibility for your research ready to submit your research ? choose bmc and benefit from: autonomic dysfunction in the diabetic and nondiabetic population: the monica/kora augsburg cohort study the science underlying covid- : implications for the cardiovascular system n-terminal pro-b-type natriuretic peptide: an independent marker for coronary artery disease in asymptomatic diabetic patients predictors of early-stage left ventricular dysfunction in type diabetes: results of dyda study performance of high-sensitivity cardiac troponin assays to reflect comorbidity burden and improve mortality risk stratification in older adults with diabetes research digest: cardiac biomarkers for risk prediction covid- and its implications for thrombosis and anticoagulation covid- and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up fibrinogen plasma levels as a marker of thrombin activation in diabetes d-dimer and the risk of stroke and coronary heart disease. the reasons for geographic and racial differences in stroke (regards) study coagulation activation in diabetes mellitus: the role of hyperglycaemia and therapeutic prospects hyperglycemia-induced thrombin formation in diabetes the possible role of oxidative stress low molecular weight heparin restores antithrombin iii activity from hyperglycemia induced alterations incremental role of glycaemic variability over hba c in identifying type diabetic patients with high platelet reactivity undergoing percutaneous coronary intervention inflammageing and metaflammation: the yin and yang of type diabetes acute hyperglycaemia: a 'new' risk factor during myocardial infarction oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type diabetic patients scientific document group: esc guidelines on diabetes, prediabetes, and cardiovascular diseases developed in collaboration with the easd considerations for statin therapy in patients with covid- tissue specific up regulation of ace in rabbit model of atherosclerosis by atorvastatin: role of epigenetic histone modifications effect of pravastatin on the frequency of ventilator-associated pneumonia and on intensive care unit mortality: open-label, randomized study association of elevated plasma interleukin- level with increased mortality in a clinical trial of statin treatment for acute respiratory distress syndrome type diabetes and cardiovascular disease higher glucose variability in type than in type diabetes patients admitted to the intensive care unit: a retrospective cohort study searching the reason of a lower aggressiveness of the coronavirus disease in type diabetes covid- and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options diabetes and cardiovascular disease (d&cvd) easd study group, et al. issues of cardiovascular risk management in people with diabetes in the covid- era publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. key: cord- -sbou vg authors: gonzález-calle, david; villacorta, eduardo; sánchez-serrano, amparo; león, marta; sanchez, pedro l. title: coronavirus disease intermediate care units: containing escalation of icus date: - - journal: crit care med doi: . /ccm. sha: doc_id: cord_uid: sbou vg nan a ccording to the recent publications of sauro et al ( ) and co and hyzy ( ) in critical care medicine, a crucial moment in the care of severely ill patients is the transition from the icus to ordinary hospitalization wards, as significant complications are still frequent. this has become apparent as icus have become overwhelmed during the severe acute respiratory syndrome coronavirus pandemic. in this setting, we believe that intermediate care units (imcus) might play a significant role in a safer transition of patients to ordinary ward. with over , deceased-probably thousands more, considering the patients who have died without a proper diagnosis, in their households or in residencies-spain has been severely hit by the coronavirus disease (covid- ) outbreak. in castile and leon region, with a total population of , , inhabitants, there are over , confirmed cases; , patients have been hospitalized, of them to icus ( % under mechanical ventilation), and , patients have died establishing a mortality rate over %. in order to face this challenging situation, we also transformed our hospitals, working teams, and organization adapting operating rooms and postanesthesia care units into icus in record time ( ). our icus doubled bed capacityfrom to beds-and their occupation increased by % with respect to their regular maximum capacity (fig. ) . to deal with the shortness of icus capacity effectively, our regional healthcare system further put in place covid- imcus infrastructures consisting of a -hour healthcare multidisciplinary team with capacity to perform noninvasive mechanical ventilation in monitored beds ( ) . this covid- imcus were implemented with two major objectives: ) avoiding overwhelmed of icus, concentrating and taking care of candidate patients to icu and ) favoring and incrementing "step-down" from the icus. to date, two covid- imcus are fully implemented and working: one at the university hospital of salamanca, a tertiary public hospital with beds and -extended-bed icu capacity and the second at hospital santa barbara of soria, a secondary public hospital with beds and -extended-bed icu capacity. in our experience, these covid- imcus can significantly reduce mortality when perfectly coordinated with the icu team. we have identified several scenarios in which these units can be of great value. first, there are certain patients-usually at the early stages of the disease-with apparent clinical stability, but with signs of potential severe disease at admission as significant radiological anomalies or mild organ failure in the laboratory analysis. to our knowledge, covid- can be a rapidly progressing disease, and patients might worsen within hours. in these cases, close monitoring helped us in the early identification of patients who needed to be transferred to the icu for mechanical ventilation. second, some patients who presented clinical deterioration and were candidates for invasive ventilatory support were also transferred to our covid- imcus. this allows continuous monitoring and frequent evaluation by the icu team, reducing the delay of the intubation and transfer to the icu when needed. third, these units are an alternative to patients whose icu admission has been initially discarded. some of these patients might benefit from noninvasive mechanical ventilation, as it provides further time for recovery. finally, a very interesting clinical scenario for these units is for patients who have been recently discharged from icus who-in all cases-still need close monitoring. furthermore, in our experience, this last scenario reduced the assistance burden in icus, as some patients could be discharged earlier when this kind of assistance was provided, generating extra icus capacity. with the covid- curve flattening, the creation of covid- imcus has allowed us to build up hospital assistance capacity for severely ill patients, either in tertiary or secondary hospitals. further to act as a "step-up" or "step-down" between the general ward and the icu, we have used these units to provide assistance to patients whose icu admissions were not prioritized. in our opinion, covid- imcus organization should be encouraged in all hospitals as a response to the emerging challenges of this pandemic. dr. sánchez-serrano disclosed work for hire. dr. león disclosed government work. the remaining authors have disclosed that they do not have any potential conflicts of interest. adverse events after transition from icu to hospital ward: a multicenter cohort study lost in transition: a call to arms for better transition from icu to hospital ward introducing an integrated intermediate care unit improves icu utilization: a prospective intervention study key: cord- -f o authors: martin-loeches, i.; lisboa, t.; rhodes, a.; moreno, r. p.; silva, e.; sprung, c.; chiche, j. d.; barahona, d.; villabon, m.; balasini, c.; pearse, r. m.; matos, r.; rello, j. title: use of early corticosteroid therapy on icu admission in patients affected by severe pandemic (h n )v influenza a infection date: - - journal: intensive care med doi: . /s - - -z sha: doc_id: cord_uid: f o introduction: early use of corticosteroids in patients affected by pandemic (h n )v influenza a infection, although relatively common, remains controversial. methods: prospective, observational, multicenter study from june through february , reported in the european society of intensive care medicine (esicm) h n registry. results: two hundred twenty patients admitted to an intensive care unit (icu) with completed outcome data were analyzed. invasive mechanical ventilation was used in ( . %). sixty-seven ( . %) of the patients died in icu and ( . %) whilst in hospital. one hundred twenty-six ( . %) patients received corticosteroid therapy on admission to icu. patients who received corticosteroids were significantly older and were more likely to have coexisting asthma, chronic obstructive pulmonary disease (copd), and chronic steroid use. these patients receiving corticosteroids had increased likelihood of developing hospital-acquired pneumonia (hap) [ . % versus . %, p < . ; odds ratio (or) . , confidence interval (ci) . – . ]. patients who received corticosteroids had significantly higher icu mortality than patients who did not ( . % versus . %, p < . ; or . , ci . – . ). cox regression analysis adjusted for severity and potential confounding factors identified that early use of corticosteroids was not significantly associated with mortality [hazard ratio (hr) . , % ci . – . , p = . ] but was still associated with an increased rate of hap (or . , % ci . – . , p < . ). when only patients developing acute respiratory distress syndrome (ards) were analyzed, similar results were observed. conclusions: early use of corticosteroids in patients affected by pandemic (h n )v influenza a infection did not result in better outcomes and was associated with increased risk of superinfections. by pandemic (h n )v influenza a infection, although relatively common, remains controversial. methods: prospective, observational, multicenter study from june through february , reported in the european society of intensive care medicine (esicm) h n registry. results: two hundred twenty patients admitted to an intensive care unit (icu) with completed outcome data were analyzed. invasive mechanical ventilation was used in ( . %). sixty-seven ( . %) of the patients died in icu and ( . %) whilst in hospital. one hundred twenty-six ( . %) patients received corticosteroid therapy on admission to icu. patients who received corticosteroids were significantly older and were more likely to have coexisting asthma, chronic obstructive pulmonary disease (copd), and chronic steroid use. these patients receiving corticosteroids had increased likelihood of developing hospital-acquired pneumonia (hap) [ . % versus . %, p \ . ; odds ratio (or) . , confidence interval (ci) . - . ]. patients who received corticosteroids had significantly higher icu mortality than patients who did not ( . % versus . %, p \ . ; or . , ci . - . ). cox regression analysis adjusted for severity and potential confounding factors identified that early use of corticosteroids was not significantly [ ] , and argentina ( %) [ ] . the efficacy of systemic corticosteroids has been extensively studied in acute respiratory distress syndrome (ards). while they clearly have a role in situations where ards has been precipitated by a corticosteroidresponsive process (e.g., acute eosinophilic pneumonia), the value of corticosteroid therapy in most other cases remains uncertain [ ] . in the s and early s, empirical corticosteroids were widely used to treat ards; however, corticosteroid therapy in this setting subsequently became less frequent after several studies found that they had no benefit and may actually cause harm [ , ] . since then, several meta-analyses and reviews have been published offering conflicting perspectives regarding corticosteroid treatment for ards [ ] [ ] [ ] [ ] . the most common pulmonary presentation of patients affected by pandemic (h n )v influenza a infection is rapidly progressive viral pneumonia with bilateral alveolar infiltrates on chest radiography, and ards [ ] . the presentation of ards with severe refractory hypoxemia has been particularly common in patients with this disease process and might be linked to an abnormal immune response [ ] . several published reports of pandemic (h n )v influenza a infection [ , ] have reported use of empirical corticosteroid therapy in more than half of these patients, both as primary therapy and as rescue therapy for patients with severe ards. recent guidelines for management of human infection with pandemic (h n )v influenza a infection recommend that corticosteroid therapy should not be used routinely, although low doses may be considered for patients in septic shock who require vasopressors and have suspected adrenal insufficiency [ , ] . data supporting this guidance, however, remain scarce and controversial [ ] . a single prospective interventional study with only patients by quispe-laime et al. [ ] demonstrated that a prolonged low to moderate dose of corticosteroid treatment was associated with significant improvement in lung injury and multiple organ dysfunction scores and reduced hospital mortality rate. the main objective of this study is therefore to assess the effect on survival of early corticosteroid therapy compared with those who did not receive corticosteroids or received them subsequently as rescue therapy, in a cohort of patients hospitalized with severe presentation of pandemic (h n )v influenza a infection in the icu. data for this study were obtained from a voluntary registry instituted by the european society of intensive care medicine (esicm). the registry contains data from patients admitted to the icu with confirmed, probable or suspected pandemic (h n )v influenza a infection. all reports notified before february were eligible for inclusion. ethical approval was sought and obtained where necessary prior to any patients being entered into the registry. all patients enrolled were recorded into the registry in an anonymous format. the need for informed consent was waived due to the observational nature of the study and the fact that this activity was an emergency public health response. the inclusion criteria for this study consisted of: fever ([ °c); acute illness; respiratory symptoms consistent with cough, sore throat, myalgia or influenza-like illness; and acute respiratory failure requiring icu admission with confirmed, probable or suspected pandemic (h n )v influenza a infection, according to case definitions developed by the world health organization (who) [ , ] . a ''confirmed case'' was defined as an acute respiratory illness with laboratory-confirmed pandemic (h n )v influenza a virus infection with real-time reverse-transcription polymerase chain reaction (rt-pcr) or viral culture [ ] . all tests and procedures were ordered by attending physicians. the definitions of community-acquired pneumonia and hospital-acquired pneumonia were based on american thoracic society and infectious disease society of america guidelines [ ] . primary viral pneumonia was defined in patients presenting during the acute phase of influenza virus illness with ards and unequivocal alveolar opacification involving two or more lobes with negative respiratory and blood bacterial cultures. secondary bacterial pneumonia was considered in patients with confirmation of influenza virus infection who showed recurrence of fever, increase in cough, and production of purulent sputum with in addition positive respiratory pathogens or blood cultures [ ] . microbiological confirmation of hap was based on standardized procedures at each investigator site. acute renal failure was defined as need for renal replacement therapy following the international consensus conference [ ] . obese patients were defined as those with body mass index (bmi) over kg/m [ ] . icu admission criteria and treatment decisions for all patients, including determination of need for intubation and type of antibiotic and antiviral therapy administered, were made by the attending physician. the following information was also recorded: demographic data, comorbidities, time of illness onset and hospital admission, time to first dose of antiviral therapy, microbiologic findings, and chest radiographic findings at icu admission. intubation and mechanical ventilation requirements, adverse events during icu stay (e.g., need for vasopressor drugs, or renal replacement techniques), and laboratory findings at icu admission were also recorded. to determine illness severity, the simplified acute physiology score (saps ) [ , ] and the acute physiology and chronic health evaluation (apache) ii score [ ] were determined in all patients within h of icu admission. in addition, organ failure was assessed using the sequential organ failure assessment (sofa) scoring system [ ] . systemic corticosteroid use was considered when dosages equivalent to [ mg/day methylprednisone or [ mg/day prednisone were given at icu admission. patients who received corticosteroid therapy on icu admission were compared with those who did not receive corticosteroid therapy or who received them subsequently as rescue therapy for unfavorable clinical progression. discrete variables are described as counts (%) and continuous variables as mean with standard deviation (sd) or median with th to th interquartile range (iqr), as appropriate. unless otherwise stated, all statistical tests were two sided and p \ . was considered significant. differences in categorical variables were calculated using the two-sided likelihood ratio, chi-square test or fisher's exact test, and the mann-whitney u test or kruskal-wallis test was used for continuous variables, when appropriate. cox proportional-hazards regression analysis was used to assess the impact of independent variables on icu mortality across time. variables significantly associated with mortality on univariate analysis were entered into the model. to avoid spurious associations, variables entered into the regression models were those with a relationship on univariate analysis (p b . ) or a plausible relationship with the dependent variable. results are presented as hazard ratio (hr) and % confidence interval (ci). potential explanatory variables were checked for collinearity prior to inclusion in the regression models using tolerance and variance inflation factor. data analysis was performed using spss . (spss, chicago, il, usa) for windows. two hundred twenty patients with completed outcomes from the esicm h n registry were analyzed in this study. all patients had suspected, probable or confirmed pandemic (h n )v influenza a infection and were being cared for in an icu. one hundred ninety-four were confirmed ( . %), were probable ( . %), and patients were suspected ( . %) for pandemic (h n )v influenza a virus. of these, patients were male ( . %) with median age of (iqr - ) years, and ( . %) were under years of age. the mean saps score was . ± . and the mean sofa score was . ± . on admission. mechanical ventilation was used in ( . %) of the patients, ( . %) with invasive modes and ( . %) noninvasively; ( . %) of the patients having noninvasive modes of ventilation subsequently required invasive ventilation. all patients received antiviral therapy. oseltamivir administration delay after illness onset did not differ between early corticosteroid uses. ards was present in . % patients. comorbidities were present in ( . %) patients. obesity (n = , . %), asthma (n = , . %), and chronic obstructive pulmonary disease (copd, n = . %) were the main comorbidities reported. one hundred twenty-six ( . %) patients received early corticosteroid therapy at icu admission. patients surviving the icu stay and receiving corticosteroids early on icu admission had mean duration of corticosteroid therapy of . ± . days. icu length of stay in survivors did not differ in patients who received early corticosteroids compared with those who did not ( . ± . versus . ± . days, p = . ). patients who received early corticosteroid therapy were significantly older ( [ ( %) versus ( . %), p \ . ] more frequently than patients who did not. patients who received early corticosteroid therapy were sicker than those who did not receive them according to saps data ( . ± . versus . ± . , p = . ). no differences were found between patients who were or were not treated with early corticosteroid therapy regarding prevalence of ards ( . % versus . %, p . ). mechanical ventilation was based on lung protective strategies. for the entire cohort, tidal volume was . (iqr . - . ) ml/kg ideal body weight (ibw). we did not find any differences between tidal volume in patients who received early corticosteroid therapy compared with those who did not [ . (iqr . - . ) versus . (iqr . - . ) ml/kg ibw, p = . ]. additional demographic data and clinical characteristics of patients with pandemic (h n )v influenza a with and without early corticosteroid therapy are presented in table . hospital-acquired pneumonia was clinically suspected in patients ( . %), with microbiological documentation in patients ( . %) patients. patients who received early corticosteroid therapy had hap more frequently than patients who did not [ . % versus . %, p \ . ; odds ratio (or) . , ci . - . ]. since the severity of illness of patients who received early corticosteroid therapy was higher, multivariate regression analysis adjusting for severity was performed and confirmed the higher incidence of hap in patients who received early corticosteroid therapy [or = . %, confidence interval (ci) . - . ; p \ . ]. pseudomonas aeruginosa (n = , . %) was identified as the most prevalent pathogen, followed by acinetobacter baumannii (n = , . %) and streptococcus pneumoniae (n = , . %) ( table ). in total, patients died on the icu ( . %) and ( . %) whilst in hospital. nonsurvivors presented with significantly higher saps score at admission ( . ± . versus . ± . , p \ . ) and higher sofa score ( . ± . versus . ± . , p \ . ) when compared with survivors. the characteristics of the patients who died are shown in table . patients who received early corticosteroid therapy on icu admission had significantly higher icu mortality than those who did not ( . % versus . %; or . , ci . - . ; p \ . ). this association with increased mortality was not present when mortality data were adjusted for increased severity of illness (saps ) and other known confounding variables (age, copd, asthma, and chronic steroid use) [hazard ratio (hr) . %, ci . - . ; p = . ] (fig. ) . similar findings were found when repeating the analysis for only the cohort of patients who presented with ards (hr . , % ci . - . ; p = . ). this analysis of a large, cohort, prospective, multicenter research study suggests that prompt use of corticosteroid therapy on icu admission does not result in a reduction of mortality for critically ill patients admitted with pandemic (h n )v influenza a infection. furthermore, there is also not a beneficial effect of early corticosteroid therapy when given to the more severe end of the spectrum of patients requiring invasive mechanical ventilation for ards. another important finding of this study was that patients receiving early corticosteroid therapy had increased likelihood of developing superadded bacterial infection. endogenous glucocorticoids as end-effectors play a role in inhibiting inflammation [ ] but are not always effective in suppressing the ''cytokine storm'' driven by copd chronic obstructive pulmonary disease systemic inflammation, even though cortisol levels have been correlated with grades of illness severity and mortality [ ] . with the concept of critical-illness-related corticosteroid insufficiency (circi) [ ] and the results of clinical trials showing respiratory immune and hemodynamic benefits, corticosteroid therapy has re-emerged as a promising adjunct for treatment of severe sepsis. severe bacterial pneumonia is associated with relative corticosteroid insufficiency as well as a plethora of other pulmonary and systemic effects [ ] . this inflammatory cascade can be partially blocked by administration of systemic corticosteroid therapy [ ] . the more severe the presentation, the worse the inflammatory crisis, therefore previous authors have suggested that steroid therapy should be more effective in more severely ill patients [ ] [ ] [ ] . this is not what was shown in the present study. recent guidelines for management of community-acquired pneumonia suggest the benefit of systemic corticosteroid therapy for patients with severe presentation [ ] . this has been shown in one small randomized controlled study with hydrocortisone treatment, terminated prematurely due to % mortality in the intervention arm and a significant reduction in length of hospital stay [ ] . more recently, snijders et al. [ ] conducted a randomized controlled trial in hospitalized patients with cap. these patients were randomized to receive either mg prednisolone for days or placebo added to antibiotic therapy. this study did not show any differences in clinical outcomes in either the overall population or those with severe pneumonia. additionally, late clinical failure ([ h after hospital admission) was more common in the prednisolone group than in the placebo group. data supporting use of corticosteroid therapy in patients affected by primary viral pneumonia are limited [ ] [ ] [ ] to the current pandemic. the innate antiviral host response is based on early elevated expression of cxcl , ccl , and ccl in sars-cov and human respiratory syncytial virus (hrsv)-infected patients [ ] [ ] [ ] . use of corticosteroid therapy is a double-edged sword. li et al. [ ] reported that high doses of corticosteroids decrease immunity by reducing cd , cd , and cd levels in patients with sars and result in an increase in secondary infections; moreover, tsang et al. [ ] found an increase in -day mortality in the same subset of patients. nevertheless, the exact mechanism of corticosteroid therapy needs to be further elucidated due to the fact that there is no evidence of benefit in sars in the early phase when sars-cov replication is still ongoing. lee et al. [ ] found that sars-cov load was significantly higher in the second and third week of illness in patients who received initial corticosteroid therapy. recent results from the corticus study [ ] do not support routine use of corticosteroid therapy in patients with septic shock, because they showed only a beneficial effect of stress doses of corticosteroids in decreasing time to shock reversal [ ] but not on -day mortality, an effect at least in part explained by an increased risk of superinfection. use of corticosteroid therapy also exerts a decisive influence on the immune function of macrophages and granulocytes, the main cell host defenses against bacteria [ ] . in the present study there was significant incidence of nosocomial infections that resulted in twofold higher incidence of hospital-acquired pneumonia in patients who received corticosteroid therapy. incidence of hap due to pseudomonas aeruginosa was . % and due to acinetobacter baumannii was . % in the corticosteroid group. additionally, one of the most intriguing observations was that four patients developed ventilator-associated pneumonia (vap) due to aspergillus spp., three of whom were receiving corticosteroid therapy. the present study has several potential limitations that should be addressed. first is that only patients treated with early corticosteroid therapy on icu admission were considered in the treatment group. the control group comprised patients who did not receive early corticosteroid therapy and those who received them subsequently as rescue therapy. use of corticosteroid therapy after icu admission was not considered in the treatment group, since this subgroup of patients would be considered as receiving rescue therapy due to unfavorable clinical progression. no data were available to subanalyze the role of rescue therapy; nevertheless, the multivariate analysis was adjusted for severity as well as other confounding factors to avoid a potential bias that might invalidate our final conclusions. secondly, this is an observational, noninterventional study, in which the participating icus from countries in the world were self-selected. prescription of corticosteroids was chosen in accordance with local protocols. to correct for differences in different corticosteroid therapies, treatment class was homogenized so that systemic corticosteroid use was considered when dosages equivalent to [ mg/day methylprednisone or [ mg/day prednisone were given acutely on icu admission, as reported in previous studies [ ] . thirdly, in spite of the fact that microbiological confirmation based on current infectious disease society of america (idsa)/ american thoracic society (ats) guidelines [ ] would be preferable, bronchoscopic procedures were not performed routinely because of severe hypoxemia complicating ards (h n )v episode and safety concerns regarding generation of aerosols. finally, dosing of oseltamivir was left to the discretion of the attending physician and was not standardized. it is crucial to note that underdosing is a common problem in patients with severe sepsis and mechanical ventilation who have a high volume of distribution and low enteral absorption [ ] . ariano et al. [ ] recently reported that dosage of mg twice-daily achieved plasma levels that were comparable to those in ambulatory patients and were far in excess of concentrations required to maximally inhibit neuraminidase activity of the virus. there is little definitive evidence of either benefit or harm from early corticosteroid use as routine adjunctive treatment in patients affected by pandemic (h n )v influenza a infection. nevertheless, the results drawn from this study show that such early use did not result in better outcomes and may be associated with increased risk of superadded infections. conflict of interest authors declare no conflict of interest regarding the present manuscript. loreto vidaur (hospital donostia antonia socias (hospital son llàtzer) estevão lafuente (uci, ch tâmega e sousa, penafiel), fernando rua (sci, ch do porto alessandro amatu (fondazione irccs policlinico san matteo, rianimazione), giorgio berlot (cattainara (trieste)), federico capra marzani maurizia capuzzo (azienda ospedaliero-universitaria di ferrara) rebecca cusack (southampton), rhiannon jackson (frimley park hospital nhs trust) jeronimo nahuel chaparro fresco marìa fernanda garcía (hospital eugenio-neumologia) gustavo paredes niall kavanagh (st. luke's general hospital) unisa-hospital geral do grajaú), vicente souza dantas elin helset sigurdur e. sigurdsson (fsa) radka valkova (icu infection's department, masaryk's hospital simone rosseau (charité), jens krassler (fachkrankenhaus coswig gmbh alejandro barrionuevo poquet (hospital nacional carlos alberto seguin escobedo) saber barbar yaron barlavie (rambam hospital), moshe hersch (shaare zedek medical center) hervé zender (hôpital neuchâtelois institute for pulmonary diseases of vojvodina), ilons schaffer (hospital health center kikinda) eleni mouloudi (hippokrateion general hospital thessaloniki) critical care services and h n influenza in australia and new zealand pandemic influenza a(h n ) in argentina: a study of patients on mechanical ventilation eosinophilic alveolitis in acute respiratory failure. a clinical marker for a non-infectious etiology ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock high dose corticosteroids in patients with the adult respiratory distress syndrome nonventilatory treatments for acute lung injury and ards steroid treatment in ards: a critical appraisal of the ards network trial and the recent literature do glucocorticoids decrease mortality in acute respiratory distress syndrome? a meta-analysis use of corticosteroid in acute lung injury and acute respiratory distress syndrome: a systematic review and meta-analysis pandemic (h n ) influenza (''swine flu'') in australian and new zealand intensive care th and th hypercytokinemia as early host response signature in severe pandemic influenza critically ill patients with influenza a(h n ) in mexico who guidelines for pharmacological management of pandemic influenza a(h n ) and other influenza viruses clinical aspects of pandemic influenza a (h n ) virus infection corticosteroids for h n associated acute lung injury: is it just wishful thinking? h n influenza a virus-associated acute lung injury: response to combination oseltamivir and prolonged corticosteroid treatment infection prevention and control in health care for confirmed or suspected cases of pandemic (h n ) and influenza-like illnesses. world health organization novel influenza a (h n ) pregnancy working group. h n influenza virus infection during pregnancy in the usa infectious diseases society of america/ american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults viral pneumonia due to influenza and parainfluenza viruses and adenoviruses. in: marrie j communityacquired pneumonia acute renal failure-definition, outcome measures, animal models, fluid therapy and information technology needs saps -from evaluation of the patient to evaluation of the intensive care unit. part : objectives, methods and cohort description saps -from evaluation of the patient to evaluation of the intensive care unit. part : development of a prognostic model for hospital mortality at icu admission apache ii: a severity of disease classification system the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure the hypothalamicpituitary-adrenal axis and immunemediated inflammation a -level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin american college of critical care medicine ( ) recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the american college of critical care medicine role of glucocorticoids on inflammatory response in nonimmunosuppressed patients with pneumonia: a pilot study corticosteroid effects on cell signalling corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review the effects of steroids during sepsis depend on dose and severity of illness: an updated meta-analysis safety and efficacy of corticosteroids for the treatment of septic shock: a systematic review and meta-analysis infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study efficacy of corticosteroid in community-acquired pneumonia-a randomized double blinded clinical trial summary of probable sars cases with onset of illness from epidemiology and cause of severe acute respiratory syndrome (sars) in guangdong, people's republic of china update: outbreak of severe acute respiratory syndrome-worldwide human immunopathogenesis of severe acute respiratory syndrome (sars) interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome fatal outcome of human influenza a (h n ) is associated with high viral load and hypercytokinemia glucocorticoid in the treatment of severe acute respiratory syndrome patients: a preliminary report coronavirus-positive nasopharyngeal aspirate as predictor for severe acute respiratory syndrome mortality effects of early corticosteroid treatment on plasma sars-associated coronavirus rna concentrations in adult patients hydrocortisone therapy for patients with septic shock organ dysfunction/failure in patients with septic shock: results of the corticus study compartmentalized cytokine production within the human lung in unilateral pneumonia effects of systemic steroids in patients with severe community-acquired pneumonia guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcareassociated pneumonia bench-to-bedside review: appropriate antibiotic therapy in severe sepsis and septic shock-does the dose matter? enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (h n ) influenza key: cord- -vvvo t h authors: tempe, dr. deepak k.; khilnani, dr. gopi c.; passey, dr. j.c.; sherwal, dr. bl title: challenges in preparing and managing the critical care services for a large urban area during covid- outbreak: perspective from delhi date: - - journal: j cardiothorac vasc anesth doi: . /j.jvca. . . sha: doc_id: cord_uid: vvvo t h abstract the coronavirus disease- (covid- ) pandemic has put the healthcare services all over the world into a challenging situation. the contagious nature of the disease and the respiratory failure necessitating ventilatory care of these patients has put extra burden on the intensive care unit (icu) services. india has been no exception and by march , the number of covid- patients started increasing in india. this article describes the measures taken and challenges faced in creating the icu beds to cater to the anticipated load of patients in the state of delhi, india. the main challenges faced among others were, estimating the number of icu beds to be created; deciding the dedicated covid hospitals; procurement of ventilators, personal protection equipment and other related material; mobilizing the human resource and their training; and providing isolated in-house accommodation to the staff on duty. the authors acknowledge and agree that the methodology proposed in this article is, but one way of dealing with this difficulty scenario, and that there could be other, perhaps better methods of dealing with such a problem. in december, , many health care facilities in wuhan, china reported patients with symptoms of severe acute respiratory failure, similar to those observed in with severe acute respiratory syndrome (sars-cov). on january , , a novel strain of corona virus sars-cov- was isolated, which confirmed the circulation of a new disease with respiratory illness, coronavirus disease- (covid- ). the virus rapidly spread to several other countries and at the time of writing this article (april , ) the disease has already been reported to have spread to countries, with a total number of reported cases being , , and deaths being , . in india, the first case of covid- was reported from the state of kerala on january, , which originated from china, the number rose to , all were students who had returned from wuhan, china. the government of india initiated several precautionary measures such as screening of the international travelers at the airport and quarantine of the suspected travelers and later on stopping the flights from china, italy and a few other countries. also, bans were imposed in the country on social gatherings, cinema halls, restaurants, functions, conferences, among others. on th march, the chief minister of delhi formulated a "task force committee" (dr. sk sarin as chairman with dkt, gck and other members) with the responsibility to review the current status of the preparedness and to recommend urgent measures for preparedness of delhi for the covid- pandemic. at this time there were covid positive patients in delhi. in the absence of any published data to suggest how many of the exposed get infected (covid test positive), the committee took into account the world health organization (who) estimates and the existing published literature to arrive at a worst-case scenario in delhi. accordingly, it was estimated that delhi may have about % of the million population exposed during the coming months, i.e. around million people may get exposed to covid- . it is not known how many of them may get infected and suffer from the disease. it is known that of those who test positive from covid- , about % have severe disease, % become critical requiring intensive care unit (icu) admission, and . % require mechanical ventilation and . % die. it was a challenging task to estimate the numbers and after deliberating on various aspects, it was proposed that there is a need to be prepared for at least icu beds with ventilation facility in delhi. these numbers may not be needed at one time, and at present preparedness for icu beds with ventilation facility should be considered. the situation would need to be reviewed from time to time. another aspect that was taken into account was the presence of dual healthcare system in delhi. being the capital city, delhi also has large hospitals run by the central government, who would share the burden of these patients. even so, the committee decided to persist with these numbers and preferred to err on the safer side. with this background, a comprehensive plan of requirements for all the aspects of providing care to the covid- patients including among others, infrastructure, equipment, disposables, medicines, human resource and several others was planned, dkt agreed to be the nodal officer for training and supervising the facilities in the icu services at delhi government hospitals. in delhi, there is a perpetual shortage of icu beds, therefore, the biggest challenge was to create sufficient icu beds for an anticipated surge of covid- patients during the next few weeks. initially, the specialists and resident doctors from all the delhi government hospitals from the departments of anesthesiology, pulmonary medicine, and other specialties having an experience in working in the icus will be recruited for managing these icus. in order to meet this challenge, the following fundamental steps were suggested. . one or two major hospitals should be designated as exclusive covid- hospitals. . it was appreciated that best / recommended care may not be possible, if excessive load of patients is received, and plan should be to provide an optimum care in the existing circumstances. . suspension of elective work after initial curtailment in the hospitals designated to cater to the covid- patients. . arrangements to transfer the existing icu patients initially to other icus of the given hospital to make immediate availability of some icu beds (for covid- patients), and later on to other government non-covid hospitals. . rope in all the icus such as general icu, respiratory icu, coronary care units, medical icu, surgical icu, postoperative wards, and any other. . conversion of as many non-icu beds that have the centralized oxygen source into a makeshift icu bed by providing a ventilator and a monitor. . conversion of all the operation theaters (ot, barring one or two, which will be used for covid- patients, if necessary) into icu beds. . urgent purchase of vital equipment such as ventilator and disposables to meet the demands of icu beds created in the above manner. . the above arrangements should be made in a phased manner, as it was realized that all the icu beds cannot be made available in one go. . in case the patient load is increased further, private hospitals may have to be involved in providing icu care to the covid- patients. in the beginning ( th march, ), loknayak hospital (lnh), an bedded tertiary care teaching hospital, and rajiv gandhi super-specialty hospital (rgssh), a bedded recently commissioned hospital were identified for this purpose. however, they were not declared as exclusive covid hospitals, but a part (block/s) of each hospital was to be used for covid- patients. on th march, the situation at lnh was reviewed and beds located at different floors of the emergency block were identified, which could be converted into covid icus. some of these were non-icu beds and were without a ventilator and some were having patients on ventilator, so a decision was taken to transfer out the patients to other areas and mobilize ventilators from some other areas to the identified icu facility. in this manner by the evening of th march, , a total of icu beds were created in the emergency block. however, ventilators were to be arranged for some of these beds. in the mean time, nearly covid- suspect patients were admitted to lnh, of whom were having breathing difficulty and were moved to the newly created covid icu for administering high-flow oxygen therapy. thus, the efforts to create the dedicated covid icu were put to use. likewise, the situation was reviewed at the rgssh, and bedded icu on a single floor was identified and reserved for the covid- patients. rgssh also received about covid- suspect patients, but none of them had breathing difficulty, so did not require icu admission. there was a sudden surge of patients during the first week of april. in anticipation of further surge in numbers, the government decided to convert three hospitals into exclusive covid hospitals, these were, lnh, rgssh, and gb pant institute of postgraduate medical education and research (gipmer). the other hospitals would remain as the non-covid hospitals. on the morning of april , , the situation at the three designated covid hospitals was reviewed in relation to the availability of icu beds. the total number of icu beds identified were; lnh: beds, gipmer: beds, rgssh: beds (total of beds) on the morning of april , , it was appreciated that gipmer is the major super-specialty hospital of the delhi government and by converting it into an exclusive covid hospital, the care provided to the patients suffering from cardiovascular, neurological and gastrointestinal ailments might be affected. hence, the decision to declare gipmer as an exclusive covid hospital was withdrawn. therefore, it was now decided to rope in more icu beds from rgssh (total of ) as this -bedded hospital has oxygen points on almost all the beds. this would be done in two phases of beds each. thus, on the morning of april , , the situation of identified icu beds was; lnh: beds, rgssh beds, (total of beds). admission to the icu would be determined by the severity of disease as defined by the government of india (goi) on th april . only those with severe symptoms (respiratory rate > / min, arterial oxygen saturation (spo ) < % on room air) would be admitted to the icu; those with moderate symptoms (respiratory rate - /min, spo - %) would be admitted to dedicated covid health centers for oxygenation and monitoring. the timeline of various important events is depicted in figure . in this crisis situation, in order to commission as many icu beds as possible, minimum equipment required to make a bed functional as an icu bed was identified. this would entail judicious distribution of available resources and minimizing the requirement of urgent procurement of additional equipment (which was available with difficulty due to shortage) to overcome the deficit of equipment. in this background, it was considered that each icu bed will mandatorily have the (table ) . this would be beneficial to strengthen each icu bed in the coming days as and when the procurement fructifies. the covid- patients are likely to suffer from acute respiratory distress syndrome (ards). it was considered that as a first preference, icu ventilator with the standard modes of ventilation inclusive of airway pressure release ventilation (aprv) mode should be preferred. however, in view of the shortage of ventilators in the market, it was suggested to consider even lower-end icu ventilators including even the transport ventilators which would be used as a backup in a situation when the standard ventilator is not available for the patient. in addition, the patients in the ot should be ventilated with anesthesia ventilators installed on the work station / anesthesia machines. in extreme circumstances, a bed without an oxygen source would be used as an icu bed with the help of a turbine-based transport ventilator that can ventilate with air. bilevel positive pressure ventilation (bipap) and high-flow oxygen therapy would also be a consideration. furthermore, split ventilation was also considered, but would be used in exceptional pressing situations with the consent from the patient / relative. as a general principle, it was considered that salvageable patients should receive a better ventilator as compared to those who are considered difficult to salvage. however, the final decision would be left to the concerned consultant of a particular icu. some agencies came forward with the offers to donate ventilators from their resources, which would be helpful to compensate the deficiency in part. as on date (april , ), the approximate additional requirement of icu ventilators is estimated to be approximately to activate the proposed icu beds. an equal number of multi-parameter monitors was also proposed to be purchased. an inventory of various disposables / small equipment that is required to run the icu was prepared (table ). the list of medicines required to run the various icus was also prepared (table ). in addition, blood banks to be in readiness to fulfill the demand of blood and blood products. a core committee consisting of senior doctors was formed for each hospital to look into the above requirements and prepare the demand that can be submitted to the concerned authorities for urgent procurement. it was appreciated by the committee that the staff will get fatigued quickly while working with the bulky ppe. hence, it was planned to make a -hourly shift for the staff members. (some countries have preferred to make a -hourly shift). it was proposed to constitute a team of staff to look after a - bedded icu. each team will work for a period of one week. the team will be divided into sub-teams to work in shifts of am to pm, pm to pm, pm to am, and am to am. after one week, the team will be replaced by another team. the first team will be quarantined for a period of two weeks before it can be put to work again, if necessary. thus, each team will work for a period of one week and then rested for a period of weeks. in the beginning, three teams should be identified for each - bedded icu so that arrangements are made for the initial weeks. the constitution of each team and the requirement of staff for a period of weeks, if icu patients are admitted is shown in table . the testing protocol for health care professionals (hcps) would be symptom driven, except before termination of the quarantine period, when it would be mandatory. it was emphasized that the safety of health care professionals (hcps) is paramount and therefore, good quality ppes must be provided to each of the hcp. in addition, n/ face masks and sufficient hand scrub antiseptic solution should be readily available to all the staff members. a full complement of ppe inclusive of goggles, face shield, mask, gloves, coverall/gowns (with or without apron), head cover and shoe cover as defined by the goi should be used by the staff working in the icu. it was also appreciated that all the hcps will have to be in isolation after they finish their shift duty. hence, adequate accommodation to the hcps was arranged at the hospital premises. for lnh, accommodation was arranged at the adjacent gipmer by vacating three floors of a special ward, which have separate rooms with attached bath. in addition, rooms were arranged in a nearby hotel. for rgssh, the newly constructed resident doctor's hostel was proposed to be used as accommodation for the staff members. adequate arrangements for serving food to these staff members was also worked out. in the absence of any definite data, and not knowing how effective the complete lock-down would be, it was very difficult to estimate even the probable number of icu beds that are likely to be required during next - weeks. the authors believed that it is safer to assume the worst scenario and err on the safer (higher) side for this purpose. the committee projected to create icu beds, but in the first phase has been able to identify only beds that could be converted into icu beds. one hundred more beds can be created at rgssh in the next phase and for further increase in the beds, the icus of the private hospitals will have to be roped in. since, the situation is dynamic, evaluation will be necessary at regular intervals. it is crucial to identify dedicated covid hospitals exclusively for the covid- patients. in the initial phase, when the number is small, it may be possible to manage covid- patients in an these of course, will vary from place to place and individualization will be necessary due to a sudden increase in the demand of equipment and other disposable materials for managing the covid- patients all around the world and also due to stoppage of import and export of material, there was an acute shortage of these items in the country. although, the government wanted to make bulk purchases of these items, there were not enough supplies to meet the demands. however, efforts on war footing are going on and sufficient supplies are expected soon. on th april, a -plier surgical mask making machine was set up by the delhi government. the machine has a capability to produce , masks per day. likewise, the domestic manufacturing of ppe and medical equipment was ramped up to meet the increasing demand. the defense research and development organization has taken a lead in this matter. in addition, substantial material and equipment supplies is expected from the central government, which will be shared amongst all the states of india. these will be utilized to equip each of the icu beds that has been identified in the two hospitals. due to sudden increase in the number of icu beds, hourly duty roster and a mandatory break of weeks (quarantine period), acute shortage of trained staff should be anticipated. hence, deployment of additional staff who can work in an icu from other hospitals will be necessary. it was suggested that a pool of staff should be created as soon as possible so that as and when the situation worsens, the identified staff is readily available for providing necessary care. it was decided to arrange to provide training to all levels of staff on various aspects related to the management of covid- patients. in particular, the measures and precautions to be taken to avoid the contact and spread of the disease were taken into account. the other training provided the other challenges included creation of facilities to meet the logistic requirements such as signages, partitioning; arranging in-house accommodation for the staff; encouraging and motivating the staff to keep up the morale; arranging to transport patients to and from the covid hospitals, and so on. the covid- endemic has posed several challenges. in essence, it is a fight against a common enemy with unknown transmission pattern with no treatment or vaccine available. the delhi has been relatively slow as compared with other nations. we pray and hope that the strict measures taken and implemented by the government by way of social (physical) distancing and the complete lockdown will show positive results and the preparations will not be actually put to test, however, if they are, it is expected that they will fulfill the requirements. the authors acknowledge and agree that the model proposed in this article is, but one method of dealing with such a difficulty, and there could be other, perhaps better methods of dealing with the problem. also, local circumstances and existing facilities will vary from place to place and have to be taken into account before such plans are prepared elsewhere. conflict of interest: dkt is on the editorial board of the jcva the authors acknowledge the support provided by the political leaders, the administrators, icu team (for - beds) : faculty / consultant- , senior resident- , junior resident- , nurses , technicians - , housekeeping- , sanitation workers - . there will be shifts : am to pm, pm to pm, pm to am, am to am. each team works for hr/day for week, then quarantined for weeks; nd team replaces the first team at the end of the first week. cnbc breaking news kerala defeats coronvirs india's three covid- patients successfully recover clinical characteristics of coronvirus disease in chine preparing for covid- : early experience from an intensive care unit in singapore key: cord- - hdok n authors: hashmi, muhammad daniyal; alnababteh, muhtadi; vedantam, karthik; alunikummannil, jojo; oweis, emil s.; shorr, andrew f. title: assessing the need for transfer to the intensive care unit for coronavirus- disease: epidemiology and risk factors date: - - journal: respir med doi: . /j.rmed. . sha: doc_id: cord_uid: hdok n background: although many patients with coronavirus disease (covid- ) require direct admission to the intensive care unit (icu), some are sent after admission. clinicians require an understanding of this phenomenon and various risk stratification approaches for recognizing these subjects. methods: we examined all covid- patients sent initially to a ward who subsequently required care in the icu. we examined the timing transfer and attempted to develop a risk score based on baseline variables to predict progressive disease. we evaluated the utility of the curb- score at identifying the need for icu transfer. results: the cohort included subjects (mean age . ± . years, . % male) and % were eventually sent to the icu. the median time to transfer was . days. approximately / rd of patients were not moved until day or later and the main reason for transfer ( . %) was worsening respiratory failure. a baseline absolute lymphocyte count (alc) of ≤ . ( )/ml and a serum ferritin ≥ ng/ml were independently associated with icu transfer. co-morbid illnesses did not correlate with eventual icu care. neither a risk score based on a low alc and/or high ferritin nor the curb- score performed well at predicting need for transfer. conclusion: covid- patients admitted to general wards face a significant risk for deterioration necessitating icu admission and respiratory failure can occur late in this disease. neither baseline clinical factors nor the curb- score perform well as screening tests to categorize these subjects as likely to progress to icu care. the coronavirus disease pandemic caused by the sars cov- virus has resulted in substantial morbidity and mortality. this infection has placed considerable burdens on acute care hospitals, generally, and on intensive care units (icus), specifically. prior reports suggest that approximately % of those infected require admission to the hospital while more than % may need care in an icu. ( , ) for those admitted to the icu, the majority undergoes mechanical ventilation (mv) and the prevalence of acute respiratory distress syndrome (ards) is high. ( ) because of the strain placed on icus by the pandemic, multiple public health interventions have focused on containing the spread of sars cov- so as to constrain the exponential demand for icu care. in essence, limitations in icu resources have contributed to the logic underlying the concept of "flattening the curve." as a corollary, understanding the need for icu care in covid- has become a public health priority. hence, a better appreciation of who might require icu admission could facilitate efforts at disease modeling and public health policy. at the same time, identifying variables that identify subjects who require transfer to an icu could also help clinicians risk stratify and triage patients as they present with their acute infections. for many other diseases that regularly necessitate admission to the icu, various risk stratification tools exist. for example, for community-acquired pneumonia, both the pneumonia severity index (psi) and the curb- score represent well-validated paradigms for risk stratification. ( , ) researchers have developed other similar scores for conditions such as congestive heart failure and pulmonary embolism. ( , ) the existence of these tools has substantially facilitated triage decision-making when patients present to the hospital and has helped to insure individuals are sent to the correct level of care. with respect to covid- , several studies have attempted to examine variables associated with need for icu care. ( , ) these models, though, generally evaluate all patients presenting to the hospital. however, a crucial question revolves around identifying patients initially felt stable for admission to the general wards with covid- but who then deteriorate and require an escalation of care and transfer to the icu. to comprehend the actual potential need for icu beds along with the desire to confidently admit subjects to a non-icu floor, physicians require an understanding of the risk for deterioration among covid- subjects sent, on presentation, to a medical ward. to address these issues, we conducted a retrospective study of all subjects with covid- admitted to our hospital in order a) to describe the epidemiology of needing transfer to the icu subsequent to initial admission to the floor and b) to develop a risk tool to categorize these subjects based on variables accessed at time of original hospital presentation. we conducted a retrospective analysis of all consecutively admitted patients to our hospital diagnosed with covid- . covid- was diagnosed based on a combination of appropriate clinical symptoms and the presence of sars-cov- in an upper or lower respiratory specimen. all testing was performed using a real-time reverse-transcriptase polymerase chain reaction (rt-pcr) assay. we excluded patients initially admitted directly to the icu. we also excluded subjects who had a medical order limiting an escalation of care and thus precluding any transfer to a higher level of care. subjects were admitted to our institution between march , and april , . the medstar health research institute institutional review board approved this study. need for transfer to the icu represented our primary endpoint. the decision to admit to the icu was left to a patient's primary physician and the icu triage physician. the need for mechanical ventilation and/or treatment with vasopressors mandated movement to the icu. the timing of admission to the icu after floor admission served as a secondary endpoint as did the reason for transfer. we collected information regarding patient demographics, underlying co-morbid illnesses, and baseline laboratory values. specifically we assembled information regarding age, gender, and race. co-morbidities of interest included the presence of underlying lung disease, such as asthma and/or chronic obstructive pulmonary disease (copd). we also recorded if a patient had hypertension (htn), coronary artery disease (cad), congestive heart failure (chf), or diabetes mellitus (dm). we further noted if a patient was undergoing active chemotherapy for malignancy, carried a diagnosis of human immunodeficiency virus (hiv) infection, or required chronic hemodialysis. with respect to laboratory testing done at the time of hospital admission, we explored the absolute lymphocyte count (alc) along with the erythrocyte sedimentation rate (esr) and c-reactive protein (crp). other variables evaluated included the serum d-dimer, lactate dehydrogenase, and ferritin. each of variables eventually recorded was selected prior to data collection based on a biologically plausible link with a need for escalation of care. we calculated a curb- score for each patient based on clinical and lab values available at presentation. ( ) we defined confusion, in accordance with the approach of others, as a glasgow coma score (gcs) of < . ( ) additionally we developed a novel risk score based on a logistic regression model exploring variables independently associated with an escalation of care. (see below). we compared categorical variables with the fisher's exact test and continuous variables with either student's t-test or the mann whitney u test, as appropriate. all tests were two tailed and a p value of < . was considered to represent statistical significance. to determine factors independently associated with transfer to the icu after admission to the ward, we relied on logistic regression. the regression was a step-wise backwards approach, and we entered all variables significant at the . level in univariate analysis into the model. variables were assessed for co-linearity. we assessed goodness of fit with the hosmer-lemeshow (hl) test. adjusted odds ratios (aors) and % confidence intervals (cis) are presented where appropriate. from the logistic regression findings, we created a predictive scoring tool to identify persons with covid- later admitted to the icu. we converted the β coefficients from the logistic regression into whole integers, after mathematical simplification, representing points and then summed these points to calculate a total score. we then explored the predictive value of the point score at correctly indicating the need for escalation of care via a receiver operating characteristic (roc) curve. we compared the predictive accuracy of the curb- score and our novel risk score via comparing areas under the roc curves (aurocs). all analyses were conducted with spss (v . , ibm, armonk, ny). the final cohort included subjects (mean age . + . years, . % male). subsequent to admission to the floor, patients ( . %) were transferred to the icu. the median time to icu transfer was . days. while more than half ( . %) of patients were moved to intensive care within hours of admission, . % were not transferred until hospital day or j o u r n a l p r e -p r o o f later. the main reason for movement to the icu was progressive respiratory failure ( . %) and did not differ between those moved within hours of presentations or subjects sent to the icu after a floor length of stay of more than days ( . % vs. . %, p= . ). thirty-two ( . %) of those transferred eventually required mechanical ventilation (mv). of these individuals placed on mv, required immediate intubation while failed efforts with either non-invasive ventilation (niv) and/or high-flow oxygen. of the persons moved to the icu who never needed mv, were treated with niv and/or high-flow oxygen. patients sent to the icu from the floor accounted for approximately % of all patients requiring icu care during the study period. table reveals the baseline characteristics of the patients. there was no difference in age or demographic characteristics between patients able to remain on the floor as opposed to needing icu transfer. similarly, in univariate analysis, no co-morbid illness was statistically associated with escalation of care. we did observe a trend in the need for admission to the icu among patients with underlying active malignancy (or: . , % ci: . - . ). in contrast to the results for co-morbidities, we noted several differences in admission lab values (table .) as they relate to the need for moving to a higher level of care. for example, there was a trend towards an alc of < . /ml being more prevalent in persons sent to the icu. we further documented that a high ferritin (> ng/ml) transpired more often (or: . , % ci: . - . , p= . ) as did greater elevations in serum ldh (> u/l) in the cohort moved to an icu. specifically, an elevated ldh occurred times more often in the transferred cohort (or: . ; % ci: . - . , p= . ). a diagnosis of an active malignancy was not retained in the model. table shows the results of the logistic regression. two variables remained independently associated with subsequent icu transfer. patients with a baseline alc < . /ml were twice as likely to be escalated to the icu (aor: . , % ci: . - . , p= . ). an initial serum ferritin > ng/ml also was independently linked to later icu admission (aor: . , % ci: . - . , p= . ). the model had a final hosmer-lemeshow p value of . suggesting good fit. in terms of risk prediction tools, the median curb- score was . figure displays the relationship between initial curb- score and later icu transfer. this relationship was not statistically significant (p= . ). for our novel risk score, one point each was assigned based on the presence of an alc < . /ml and/or a serum ferritin > ng/ml -for a maximum score of . as shown in figure , as this score increased, so too did the risk for icu transfer (p= . ). for example, in those patients with a score of and, thus lacking either criterion, only approximately % were eventually admitted to an icu. alternatively, nearly % of subjects meeting both criteria ultimately needed icu level care. despite this finding, neither scoring paradigm performed well as a screening test for post-admission need for icu transfer. specifically, the auroc for the novel score equaled . ( %ci: . - . ). for curb- , the auroc was . ( % ci: . - . ). these aurocs were not statistically different. this retrospective analysis indicates that nearly one in patients with covid- infection who are admitted to the floor upon hospital presentation will deteriorate and need transfer to the icu. many of those sent to the icu subsequently require mv, even despite efforts to employ niv and/or high flow oxygen. the timing of escalation of care is not confined to the early period following initial hospitalization. rather, it appears that subjects are at risk for declining during the entire length of their stay on a general ward. co-morbid illnesses are not associated with the risk for icu transfer while two initial lab values (alc < . /ml and ferritin > ng/ml ) identify those at higher risk for icu admission. nonetheless, neither a model based on these lab j o u r n a l p r e -p r o o f measures nor the curb- score represents an adequate risk stratification rubric given the limited sensitivity and specificity of these systems. our finding that a significant proportion of patients on the floor will need eventual icu care is important. policy makers and health planners must recognize that estimated icu bed demand will vary not only as a function of patients directly admitted to the icu from the emergency department but also based on the burden of covid- on non-icu wards. ( , ) a strategy that estimates icu bed needs that fails to consider the impact of the floor covid- population will likely misjudge demand and lead to potential crowding and delays in timely icu transfer. similarly, as health systems attempt to load balance and move covid- patients from one institution to another, leaders of these efforts must consider, before shifting patients, the surge capacity of the receiving hospitals' icus --even though these transferred patients are specifically being sent to the wards. not surprisingly, progressive respiratory failure represents the key reason for icu transfer. that this risk does not seem to diminish in the early days after ward admission stresses the need for vigilance on the part of clinicians and underscores that there does not appear to be some window beyond which a patient is free from a need for mv in covid- . our findings emphasize this point in that the use of niv and/or high flow oxygen may not prevent the need for eventual mv in those who become so severely ill as to need care in the icu. at the same time, this observation indicates that planners must consider both having a sufficient number of ventilators but also review potential greater demand for other respiratory support devices such as those that can deliver niv and high flow oxygen. our study is unique in that it looks specifically at those with covid- who are initially thought stable. prior accounts of covid- patients that discuss disease severity have generally addressed those needing either icu care or mv at the time of coming to the hospital. ( , ) for example, huang and colleagues describe outcomes in covid- infection and report the proportion of patients ever needing icu care but do not delineate whether these patients were j o u r n a l p r e -p r o o f directly sent to the icu from the emergency department or later moved after being on the ward. ( ) similarly, in an analysis of patients diagnosed with covid- , chen and co-workers relate disease progression over time. ( ) although they discern that nearly % of the population spent time in their icu, they fail to note the source of these admissions. in a more detailed description of icu subjects, du et al. present information related to cause of death while in the icu but neglect to comment on how or when a patient came to be in the icu. ( , ) in essence, the emphasis of many reports thus far has been either on the initially critically ill population with covid- or those briefly hospitalized who recover quickly. this has left undescribed a core group with covid- who might later come to need more aggressive care. furthermore, hospitalists and others treating covid- outside the icu certainly would benefit from an better awareness of the potential the degree to which such persons might subsequently decline. our results, therefore, help to shed insight on this topic. other analyses have explicitly examined risk factors associated with disease progression in an effort to create risk stratification tools. gong et al, for instance, developed a nomogram based on patients designed to assess progression to severe ) likewise, dong and colleagues constructed a risk score based patient age, co-morbidities, alc, and ldh to estimate onset of severe disease after being classified as "stable." the present analysis contrasts with these two efforts in several ways. first, both gong et al and dong et al do not specifically explore need for icu care. second, their definitions of "severe disease" encompass a diverse set of variables that actually represent a range in disease acuity. ( , ) for example, both sets of investigators consider severe infection present if the patient develops any of the following: a respiratory rate > breath/minute, a resting oxygenation saturation of < %, progresses to mv, or meets the clinical criteria for ards. ( , ) the implications for patient mortality vary greatly with ards vs. having a marginal oxygen saturation while not on a ventilator. therefore, it is unclear if the pooled definition of "severe" employed by these authors is appropriate. additionally, these researchers do not provide a breakdown of how many subjects met the criteria for the "severe" classification based on the unique components of their pooled endpoint. hence, it is difficult to interpret their findings and consider how to apply them. third, since the availability of icu resources varies across the globe, it remains unclear if observations from asia or europe are applicable to the united states and vice versa. hence, our observations help to describe a scenario where there is likely greater icu bed availability. our inability to create a risk score with good sensitivity and specificity is not completely unanticipated. the current understanding of covid- is rapidly changing, and thus there are likely important and nuanced variables that might identify the declining patient which the medical community has yet to appreciate. moreover, that patients appear to be at risk for needing icu care throughout their hospital stays likely explains why factors assessed at presentation have limited predictive value. rather, some dynamic assessment of changes in parameters over time may prove more effective. in that same vein, curb- was created to assess risk for mortality based on initial presentation in community-acquired pneumonia. given that this tool was never calibrated to look at the ensuing need for icu care, it seems logical to conclude that it would not perform well for this purpose. the value of various biomarkers as either stand alone risk stratification tools or their use as part of some risk score is unclear. no biomarker proved effective at predicting need for patient transfer. nonetheless, whether analyzed as a continuous or a categorical variable, all biomarkers were generally worse in those need transfer. perhaps, with a larger sample size, we might have been able to identify one or two laboratory tests that could have facilitated decision making and identified subjects at high risk for decompensation. certainly, future efforts should explore if measures such as d-dimer and the like can aid in the triage decision making process. this study has a number of important limitations. first, its retrospective design exposes it to various forms of bias. we attempted to reduce the impact of bias by looking at specific endpoints where ascertainment is fairly straightforward. concomitantly, the reliance on a stepwise logistic regression raises concerns regarding testimation biase. that we selected candidate variables prior to model creation should have limited the impact of this concern. second, as our findings derive from a single center in a major urban setting in the united states they lack generalizability. third, there are likely patients with covid- who were not included because they presented to the hospital with a syndrome of acute respiratory infection before testing was more prevalent. fourth, our sample size was limited. although comparable in size to other reports thus far, our ability to detect important differences in baseline variables was reduced due to issues of statistical power. larger studies with more diverse populations will be required to create risk stratification schemes. as a corollary, the size of our cohort precluded an effort at internal validation. similarly, we did not perform any external validation as would be needed before the broad adoption of any scoring tool. finally, the decision regarding transfer was otherwise not prospectively standardized and left to individual clinicians. in conclusion, patients with covid- admitted to general medical wards face a significant risk for clinical deterioration necessitating transfer to the icu. neither baseline clinical factors at time of presentation to the hospital nor the curb- score perform well as screening tests to categorize these subjects likely to progress to needing icu care. author contributions: afs and eso are the guarantors of and take responsibility for the data and analysis and all coauthors take responsibility for the content of the manuscript. all authors have made substantial contributions to conception, design, analysis, and interpretation of data; drafted the submitted article or revised it critically for important intellectual content; provided final approval of the version to be published; and have agreed to be accountable for all aspects of j o u r n a l p r e -p r o o f j o u r n a l p r e -p r o o f data sharing statement: the data that support the findings of this study are available from the corresponding author upon reasonable request clinical features of patients infected with novel coronavirus in wuhan risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease a prediction rule to identify low-risk patients with community-acquired pneumonia severity assessment tools for predicting mortality in hospitalized patients with community-acquired pneumonia. systematic review and meta-analysis beyond pulmonary edema: diagnostic, risk stratification, and treatment challenges of acute heart failure management in the emergency department derivation and validation of a prognostic model for pulmonary embolism clinical progression of patients with covid- in swiss society of intensive care medicine. recommendations for the admission of patients with covid- to intensive care and intermediate care units (icus and imcus) prediction for progression risk in patients with covid- pneumonia: the call score key: cord- -snwktcz authors: bansal, agam; singh, achintya d.; jain, vardhmaan; aggarwal, manik; gupta, samiksha; padappayil, rana prathap; nadeem, mahum; joshi, sonya; mian, agrima; greathouse, tyler; wells, david; gupta, mohak; khan, muhammad zarrar title: the association of d-dimers with mortality, intensive care unit admission or acute respiratory distress syndrome in patients hospitalized with coronavirus disease (covid- ): a systematic review and meta-analysis date: - - journal: heart lung doi: . /j.hrtlng. . . sha: doc_id: cord_uid: snwktcz aim: to determine if d-dimers are elevated in individuals with severe acute respiratory syndrome coronavirus (sars-cov- ) infection who have adverse clinical outcomes including all-cause mortality, intensive care unit (icu) admission or acute respiratory distress syndrome (ards). methods: we conducted a systematic review and meta-analysis of the published literature in pubmed, embase and cochrane databases through april , for studies evaluating d-dimer levels in sars-cov- infected patients with and without a composite clinical endpoint, defined as the presence of all-cause of mortality, intensive care unit (icu) admission or acute respiratory distress syndrome (ards). a total of six studies were included in the meta-analysis. results: d-dimers were significantly increased in patients with the composite clinical end point than in those without (smd, . ug/ml ( % ci, . - . ug/ml). the smd of the studies (tang et al, zhou et al, chen et al), which used only mortality as an outcome measure was . ug/ml ( % ci, . - . ug/ml). conclusion: we conclude that sars-cov- infected patients with elevated d-dimers have worse clinical outcomes (all-cause mortality, icu admission or ards) and thus measurement of d-dimers can guide in clinical decision making. . d-dimer levels can discriminate between covid patients with and without worse clinical outcomes (all-cause mortality, icu admission or ards) . elevated d-dimer levels are associated with increased risk of adverse clinical outcomes in patients hospitalized with covid infection . patients who died had higher d-dimer levels than patients who survived . a substantial elevation in d-dimers may be an indicator of progressive disease we carried out an electronic search in medline (pubmed), embase, and cochrane database using the keywords "d-dimer" and "coronavirus " or "covid " or "sars-cov- " or "severe acute respiratory syndrome coronavirus " or " -ncov" between and current date ( th april, ). only the articles published in peer-reviewed journals were included in the analysis. articles were limited to english language publications. we applied the preferred reporting items for systematic reviews and meta-analyses statement (prisma) to the methods for this study ( ) (figure ). after duplications were removed, the title and abstracts were independently screened by two reviewers (ab and vj). the studies reporting the mean or the median d-dimer values in covid patients with and without a composite end point defined as all-cause mortality, icu admission or ards were included in the study. allcause mortality was analyzed as a separate outcome in addition to the composite end-point. we excluded case reports, studies involving pediatric patient population and those not reporting the above-mentioned composite end points. we cross-referenced the research papers to identify additional studies meeting the inclusion criteria. full texts of the included studies were then reviewed by two independent reviewers (ab and vj) and data was extracted. any conflicts were settled by a third author (ads). the following data variables were collected: author name, year published, country where the study was performed, type of study, number of patients, composite end point definition, and mean d-dimer values in patients with and without outcome of interest (all-cause mortality, icu admission and ards). two authors (ab and vj) independently assessed the risk of bias in the included studies using the validated newcastle-ottawa scale. the meta-analysis was conducted with the calculation of standardized mean difference (smd) and % confidence interval ( % ci) of d-dimers in coronavirus patients with and without a composite clinical end point. d-dimers were entered as a continuous variable. the mean and the standard deviation were extrapolated from the sample size, median and interquartile range (q -q ) as per hozo et al ( ) . i statistic was used to assess the heterogeneity between studies with values - %, more than - %, and more than % corresponding to low, moderate, and high degree of heterogeneity, respectively. dersimonian and laird random effects model was used for pooling the studies. the statistical analysis was performed using stata software (stata corp, college station, texas). our systematic electronic search resulted in publications after the initial screening of titles and abstracts. subsequently, studies were excluded, yielding studies that met the inclusion criteria for systematic review. cross-referencing of full-text articles resulted in additional study. therefore, studies were included in the final meta-analysis for association of mean/median d-dimer values with all-cause mortality, icu admission or ards. table elucidates the baseline characteristics and outcomes of the included studies. there were a total of patients with ( . %) patients having a composite clinical end point. the composite end point was defined as defined as mortality in studies ( , , ) , icu admission in studies ( , ) and onset of ards in another study ( ) . zhou et al ( ) ( )), which used only mortality as an outcome measure was . ug/ml ( % ci, . - . ). the heterogeneity of the studies was found to be relatively high (i.e. i statistic %). there were two additional studies which reported higher d-dimer levels in patients with worse outcomes. however, they were not included in our meta-analysis as they did not report the median/mean d-dimer levels. zhang et al ( ) described the characteristics of patients and found that out of the patients having an outcome (icu admission, mechanical ventilation or death), ( %) had d-dimer values > ug/ml. similarly, another study ( ) showed around % of the patients with worse outcome (death, mechanical ventilation or icu admission) having d-dimers > . ug/ml. we performed a systematic review and meta-analysis of studies to assess whether the d-dimer in severe cases of sars-cov- infection, there is an uncontrolled release of pro-inflammatory cytokines (il- , il- , il- , il- , and tnf-a) which lead to upregulation of tissue factor expression on the endothelial cells, resulting in an increased pro-coagulant state. there is increasing evidence that sars-cov- infection is associated with increased risk of venous thromboembolism (vte) and in-situ microvascular thrombosis which has been linked to worse clinical outcomes ( ) . the major limitation of the studies included was lack of information on the timing of the ddimer measurements relative to admission. in addition, there was a significant heterogeneity in the reported results. this was likely due to differences in study size, selection bias, and different stages at which the d-dimer values were measured. also, since all the studies included have been performed in china, the external validity is lacking. the results of this concise meta-analysis suggest that d-dimer is significantly increased in patients having a worse clinical outcome (all-cause mortality, icu admission or ards). further studies are required to assess if the serial measurement of d-dimer plays any role in predicting evolution towards a more critical form of disease. finding a threshold d-dimer level, above which sars-cov- infected patients are at an increased risk of having worse clinical outcomes can assist in following a proactive approach and aid in clinical decision making. also, it will be imperative to know if anticoagulation therapies are of use in patients with severe sars-cov- infection. there were no conflicts of interest world health organization. the coronavirus disease coronavirus covid- global cases by the center for systems science and engineering characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study preferred reporting items for systematic reviews and meta-analyses: the prisma statement estimating the mean and variance from the median, range, and the size of a sample sanchis-gomar f. cardiac troponin i in patients with coronavirus disease (covid- ): evidence from a meta-analysis hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease clinical characteristics of deceased patients with coronavirus disease : retrospective study clinical features of patients infected with novel coronavirus in wuhan, china. the lancet analysis of clinical characteristics and laboratory findings of cases of novel coronavirus pneumonia in wuhan, china: a retrospective analysis clinical characteristics of coronavirus disease in china acute respiratory tract infection leads to procoagulant changes in human subjects serum d-dimer changes and prognostic implication in novel influenza a(h n ) covid- complicated by acute pulmonary embolism. radiology: cardiothoracic imaging correlates of d-dimer in older persons covid- and its implications for thrombosis and anticoagulation key: cord- -v jzvv authors: battaglini, denise; robba, chiara; caiffa, salvatore; ball, lorenzo; brunetti, iole; loconte, maurizio; giacobbe, daniele roberto; vena, antonio; patroniti, nicolò; bassetti, matteo; torres, antoni; rocco, patricia rm; pelosi, paolo title: chest physiotherapy: an important adjuvant in critically ill mechanically ventilated patients with covid- date: - - journal: respir physiol neurobiol doi: . /j.resp. . sha: doc_id: cord_uid: v jzvv in late , an outbreak of a novel human coronavirus causing respiratory disease was identified in wuhan, china. the virus spread rapidly worldwide, reaching pandemic status. chest computed tomography scans of patients with coronavirus disease- (covid- ) have revealed different stages of respiratory involvement, with extremely variable lung presentations, which require individualized ventilatory strategies in those who become critically ill. chest physiotherapy has proven to be effective for improving long-term respiratory physical function among icu survivors. the arir recently reported the role of chest physiotherapy in the acute phase of covid- , pointing out limitation of some procedures due to the limited experience with this disease in the icu setting. evidence on the efficacy of chest physiotherapy in covid- is still lacking. in this line, the current review discusses the important role of chest physiotherapy in critically ill mechanically ventilated patients with covid- , around the weaning process, and how it can be safely applied with careful organization, including the training of healthcare staff and the appropriate use of personal protective equipment to minimize the risk of viral exposure. in late , an outbreak of respiratory disease caused by a novel human coronavirus (sars-cov- ) was identified in wuhan, china. the infection, now known as coronavirus disease , spread rapidly worldwide, and on march , , was characterized as a pandemic by the world health organization (wu et al., ) . the classical routes of infection for sars-cov- are through respiratory droplets and by human-to-human contact. within a few days of infection, a mild febrile illness appears, with dry cough and moderate to severe respiratory distress. at intensive care unit (icu) admission, most covid- patients present with hypoxemic respiratory failure (wu et al., ) , as first step of an awful systemic disease (mods-cov- )(c. robba et al., b) . chest ct scans have revealed different stages of respiratory involvement in covid- , making lung presentations extremely variable (li and xia, ) . thus, different ventilatory strategies may be required for different patients, including early chest physiotherapy (cpt) and rehabilitation. cpt maneuvers are considered essential in patient management during icu stay in general (thomas et al., ) . this also applies to covid- patients, as suggested in a recent paper by the italian association of respiratory physiotherapists (arir) (lazzeri et al., ) . early mobilization and rehabilitation may help prevent or mitigate sequelae related to bed rest, thus improving physical function and outcomes and reducing length of stay by increasing ventilator freedays (kayambu et al., ) . as this is an extremely new topic, the role of cpt in critically ill patients with sars-cov- infection requires investigation (thomas et al., ) . recent manuscripts on respiratory physiotherapy in covid- patients provided general recommendations but did not focus on critically ill covid- cases (lazzeri et al., ; thomas et al., ) . the role of respiratory rehabilitation was reported in three groups of covid- patients : ) acute phase, presenting with critical respiratory impairment (emergency department, first aid, icu, stepdown unit); ) acute phase, with severe respiratory impairment (internal medicine, respiratory, infectious disease, or other wards); and ) post-acute phase (other units, intermediate care facilities, subacute wards). the current review discussed the data regarding the important role j o u r n a l p r e -p r o o f of chest physiotherapy in critically ill patients with covid- , during mechanical ventilation and after weaning process, and how it can be safely applied with careful organization, including the training of healthcare staff and the appropriate use of personal protective equipment to minimize the risk of exposure to sars-cov- . . characteristics. respiratory characteristics of severe covid- include hypoxemia and acute respiratory failure. covid- is associated with peculiar characteristics in terms of respiratory mechanics, with relatively well preserved, high or low respiratory system compliance (li and xia, ) . additionally, chest ct scans of covid- patients have revealed distinct patterns of pulmonary involvement: ) a multifocal, overperfused ground-glass phenotype, with centrilobular nodules, patchy consolidation, and intra-bronchial air bronchogram; ) dilatation and congestion of septal capillaries, followed by exudation into the alveolar space with interstitial edema; ) vascular exudation in the interstitium, with consolidations filled by air bronchogram; ) fibrous exudation with multiple consolidations; and ) thickening of bronchial walls, the interlobular septum, and patchy consolidations (li and xia, ) . this explains why covid- patients present with an extremely variable clinical course, and why individualized ventilatory strategies are required (c. robba et al., a) . accordingly, distinct phenotypes based on both clinical and ct characteristics have recently been identified, as follows: ) phenotype- /l-type: high or normal lung compliance associated with severe hypoxemia. this phenotype is characterized by multiple focal, overperfused ground-glass opacities. treatment should include tidal volume of - ml/kg predicted body weight (pbw) and low to moderate positive end-expiratory pressure (peep) to redistribute pulmonary blood flow and shunt; ) phenotype- /l-type: predominantly characterized by inhomogeneously distributed atelectasis, as well as peribronchial opacities, with hyperperfused ground glass areas. treatment should include tidal volumes of ml/kg pbw and moderate-to-high peep, as well as lateral or prone positioning; ) phenotype- /h-type: patchy acute respiratory distress syndrome j o u r n a l p r e -p r o o f (ards)-like appearance, characterized by alveolar edema and low compliance. treatment should follow standard ards guidelines. steroids, prone positioning, and extracorporeal membrane oxygenation (ecmo) can be considered for the most severe cases(c. robba et al., a; gattinoni et al., ) . in summary, conventional ards is characterized by diffuse alveolar capillary membrane damage, with edema and atelectasis in the dependent lung regions. application of peep or prone position, recruits collapsed lung regions associated with improvement in respiratory mechanics and gasexchange, while no major changes in redistribution of regional pulmonary perfusion. on the contrary in covid- , lesions are compartmentalized with less edema and pneumolysis, alveolar cell infiltration and necrosis. application of peep or prone position result in redistribution of perfusion, but not alveolar recruitment. in this sense, covid- pneumonia represents a "true" primary ards, as defined previously (rocco and pelosi, ) . at the beginning of the pandemic, management of covid- was based on classification of the respiratory involvement as ards-like(c. robba et al., a) , thus consisting of low tidal volume (vt; ml/kg pbw) and plateau pressure (< cmh o), with high peep (fan et al., ) . initial guidelines for the management of covid- patients (alhazzani et al., ) corroborated this strategy, recommending low-vt ventilation ( - ml/kg pbw) with peep levels titrated according to peripheral oxygen saturation (spo ). however, this should only be applied to patients with ards-like covid- (c. robba et al., a; gattinoni et al., ) . continuous positive-pressure ventilation (cpap) or non-invasive ventilation (niv) with vigorous breathing effort may be detrimental in covid- , as it could increase the risk of patient selfinflicted lung injury (p-sili) (telias et al., ) . in fact, as suggested by gattinoni et al. (gattinoni et al., ) , longer periods with non-invasive ventilatory supports should be avoided and intubation prioritized in order to prevent the development of p-sili, which may worsen lung damage. additionally, in non-intubated patients, an esophageal balloon should be inserted to j o u r n a l p r e -p r o o f maintain the pressure below cmh o, thus limiting the risk of p-sili. on the other hand, caution should be adopted with early intubation since endotracheal intubation and mechanical ventilation may also lead to lung damage. therefore, whether to choose early intubation or not should be carefully weighed (tobin et al., ) . the cardiac abnormalities reported in covid- might be distinguished based on patient's phenotype. in the phenotype- /l-type, the right heart impairment is estimated to be less evident than in the phenotype- / h-type due to the expected lower ventilatory pressures and tidal volumes delivered to the lungs (guarracino et al., ) . following increased respiratory effort, phenotype- / l-type may reduce stroke volume as a result of ventricular interdependence with consequent diastolic ventricular septal shift. additionally, high pressures and tidal volumes applied on a poorly recruitable lung, such as observed in this phenotype, may yield haemodynamic instability and fluid retention (gattinoni et al., ) . on the other hand, when positive-pressure ventilation is applied on a phenotype- /h-type, ventricular dilatation, tricuspid insufficiency, reduced right-heart systolic function, and left-heart compression may occur, determining the so called "ventilator-induced heart dysfunction" (guarracino et al., ) . the need for recruitment maneuvers (rms) should be individualized on the basis of each patient's phenotype, since several cases of impaired shunt fraction or poor lung recruitability have been identified(c. robba et al., a) . traditional rms are preferred instead of an incremental peep strategy (alhazzani et al., ) . prone positioning, which redistributes pulmonary blood flow and alveolar ventilation to improve gas exchange, may be considered in the management of mechanically ventilated critically ill covid- patients (guérin et al., ) . evidence of the efficacy of prone positioning in covid- is still lacking, although clinical knowledge suggests reserving this strategy only for those subtypes of patients which should benefit based on chest ct findings(li and xia, )(c. robba et al., a) . however, performing a ct-scan in each patient became unfeasible due to the high turnout of patients (up to - affected patients every day) during the peak of pandemic, limiting the specific phenotype diagnosis and subsequent therapeutic choices. therefore, clinical analysis, chest-x-ray and lung ultrasound (lus) are regarded as better j o u r n a l p r e -p r o o f options to assess covid- phenotypes at bedside (cosentini, ) . the sensitivity and specificity of lus in covid- patients remain to be determined. four basic patterns at lus have been identified: ) normal pattern: a-lines and < b-lines; ) mild disease: ≥ b-lines with some confluents and thickened pleura (phenotype - and l-type); ) b-lines with broken pleural line; ) typical ards pattern with subpleural consolidation (phenotype and h-type). lus cannot be considered as a substitute of ct-scan but can be a valid option when ct-scan is difficult to be done (denault et al., ) . prone positioning has also been used in small cohorts of awake covid- patients during spontaneous or assisted breathing. among patients in one study, tolerated the prone position for more than hour, of whom only six showed increased oxygen saturation, and half of them returned to baseline levels after supine positioning (elharrar et al., ) . larger randomized controlled trials are underway to elucidate whether prone positioning during spontaneous and assisted breathing can be used to reduce the intubation rate (antonelli, ; al-hazzani, ) . if beneficial, it may be further considered as a novel respiratory physiotherapy strategy for awake patients with covid- and ards. finally, a substantial number of covid- patients are able to start the weaning process. traditional criteria for extubation are considered suitable for covid- patients. patients who might be eligible for a spontaneous breathing trial should receive cpt before and after extubation, since improved outcomes have been observed in patients who underwent respiratory physiotherapy around extubation time (lazzeri et al., ; thomas et al., ) . niv, cpap, and high-flow nasal oxygen (hfno) should also be considered for short periods after extubation, until complete respiratory autonomy is reached (lazzeri et al., ) . physiotherapy has proven effective for improving long-term physical function among icu survivors (calvo-ayala et al., ) . however, the true benefit of chest physiotherapy in icu remains controversial, especially in those patients with already established alveolar j o u r n a l p r e -p r o o f damage (lazzeri et al., ; thomas et al., ) . the arir recently published a position paper concerning the role of chest physiotherapy in covid- patients (lazzeri et al., ) , suggesting limitation of some procedures-such as diaphragmatic breathing, bronchial hygiene, lung reexpansion techniques, manual mobilization, respiratory muscle training, nasal washing, and exercise training-in the acute phase of the illness. the literature suggests that physiotherapy maneuvers result in significant changes in respiratory function (cerqueira-neto et al., ) , as well as in changes of cardiovascular and cerebral hemodynamic (cerqueira-neto et al., ) , which could lead to potentially harmful effects. physiotherapy for critically ill patients in general, in critical and post-critical illness, is based on a multisystem approach which comprises not only chest physiotherapy but also musculoskeletal rehabilitation, in order to reduce the incidence of complications, encourage weaning from mechanical ventilation, and facilitate recovery of functional autonomy (thomas et al., ) . few literature is available on physiotherapy during covid- pandemic, especially regarding chest physiotherapy in icu patients (lazzeri et al., ) (simonelli et al., ) conventional chest physiotherapy maneuvers for critically ill patients in general include airway clearance techniques, lung re-expansion through rms, patient-ventilator interactions, inhalational therapies, humidification, and tracheostomy and bronchial aspiration (yang et al., ) . other equally efficient methods, which can replace these techniques, have been recently identified and introduced in clinical practice. since the severe pulmonary illness associated with covid- can lead to long-term mechanical ventilation with a high icu mortality rate, we believe that early physiotherapy and mobilization may be essential for improving outcomes. in the following paragraphs, we describe the chest physiotherapy maneuvers applied in covid- patients in our icu and their rationale. figure summarizes the physiotherapy techniques currently applied in our icu in covid- patients. early physiotherapy, i.e., started during mechanical ventilation, is considered feasible and safe to improve patient performance and long-term quality of life (kayambu et al., ) , although this has not yet been proven in covid- . among chest physiotherapy strategies during mechanical ventilation, mucus clearance and alveolar rms are very commonly applied in clinical practice. sputum production was reported in about % of covid- patients (guan et al., ) , thus suggesting that, by promoting mucus clearance during mechanical ventilation, early physiotherapy interventions (such as subglottic secretion drainage, postural hygiene, and ventilator hyperinflation) may produce beneficial effects in this new critically ill population (thomas et al., ) . before starting chest physiotherapy, we recommend the use of adequate personal protective equipment, limiting healthcare workers in the room to one physician and one physiotherapist, as well as choosing a negative-pressure chamber if available (lazzeri et al., ; thomas et al., ) . rms are transient increases in transpulmonary pressure that may open non-aerated or poorly aerated areas of the lung, while concomitantly increasing the risk of endothelial-cell damage and increased capillary permeability (silva et al., ) . although alveolar recruitment can be obtained through a variety of techniques during mechanical ventilation in critically ill patients in general, whether alveolar rms should be used at all has been widely debated. in experimental ards, "slow" rms showed a more homogeneous inflation of the lung and led to functional impairment with less ventilator-induced lung injury (vili) as compared to "fast" rms (silva et al., ) . in a large, multicenter, randomized controlled trial of ards patients, a strategy based on lung rms and peep titration according to the best respiratory system compliance resulted in increased -day all-cause mortality than a low-peep strategy (cavalcanti et al., ) , thus suggesting this type of recruitment is best avoided. different respiratory phenotypes of covid- have been identified(c. robba et al., a; gattinoni et al., ) . as suggested above, not all phenotypes can benefit from rms(c. robba et al., a) . we suggest the use of lus as well as monitoring of the partial pressure of j o u r n a l p r e -p r o o f oxygen during rms to identify covid- patients who are responsive to alveolar recruitment, as suggested in the literature in critically ill patients in general (tusman et al., ) . figure shows the use of lung ultrasound to evaluate rm in a covid- patient. in intubated and mechanically ventilated critically ill patients in general, the tracheal tube completely bypasses the larynx, facilitating passage of microbes to the lower respiratory tract, which can lead to nosocomial infections such as ventilator-associated pneumonia (vap) and tracheobronchitis (li bassi et al., ) . to date, one of the most fearsome complications of sars-cov- infection is secondary bacterial infection. in a retrospective single-center study, bacterial infections were found in % of elderly patients infected with sars-cov- , and were a strong predictor of overall risk of death (wang et al., ) . similar findings were reported in a case series of covid- patients (dong et al., ) . subglottic secretion drainage (ssd) has been proposed in critically ill patients in general to reduce the risk of vap (lacherade et al., ) . according to a recent meta-analysis of randomized controlled trials (mao et al., ) , ssd reduced vap incidence and shortened the duration of mechanical ventilation in four clinical trials, whereas no differences were found for icu length of stay or for in-hospital and icu mortality. moreover, the use of endotracheal tubes with an incorporated polyurethane cuff and ssd maneuvers helped reduce the risk of early-and late-onset vap as compared to traditional care (lorente et al., ) . the safety of ssd also remains controversial. although ssd reduced vap incidence, a recent meta-analysis of randomized controlled trials found no benefits in terms of duration of mechanical ventilation, icu length of stay, ventilator-associated events, or antibiotic use (caroff et al., ) , raising further controversy as to the use of this technique. although the literature is not conclusive concerning the real clinical benefits of ssd in covid- , we believe that a strategy based on early physiotherapy (including ssd) may reduce the risk of secondary pulmonary infections. nevertheless, the only available paper on cpt in covid- does not suggest that this technique should be started too early, and explains that ssd should be performed only under a j o u r n a l p r e -p r o o f closed aspiration circuit in order to limit droplet dispersion and avoid peep loss (lazzeri et al., ) . based on our direct experience with respiratory physiotherapy in our icu, we propose a novel method to assess this maneuver and reduce the risk of aerosol dispersion. in brief, we perform ssd by reducing the endotracheal cuff pressure, thus providing subglottic aspiration with a closedaspiration circuit, while simultaneously aspirating the oral cavity with another circuit. in our experience, this technique limits airborne dispersion and ensures complete ssd. this technique is depicted in figure . while postural drainage has been abandoned because it requires a considerable time investment and provides only minor clinical benefit, patient positioning is still considered an optimal and quick technique to mobilize secretions and increase lung volumes, perfusion, and oxygenation (li bassi et al., a) . critically ill patients are at high risk of nosocomial infections, and the aspiration of mucus from the endotracheal tube cuff to the lower respiratory tract is the main mechanism for the development of ventilator-associated infections (li bassi et al., a) . patient positioning has been identified as a major contribution to nosocomial infections. in a large, multicenter randomized controlled trial in critically ill patients in general, the incidence of vap was . % in the lateral trendelenburg position and % in the semi-recumbent position (head of bed elevated to - ° above horizontal plane), whereas no differences were found in terms of -day mortality and other secondary outcomes (li bassi et al., b) . although no differences in outcome were found between the two groups in this study, the semi-recumbent position may increase the hydrostatic pressure exerted by bacteria around the endotracheal cuff, thus facilitating gravitational pulmonary aspiration (li bassi et al., a) . another study which compared the semi-recumbent position and supine positions did not find any differences in outcome (van nieuwenhoven et al., ) . finally, a recent meta-analysis of randomized controlled trials compared the semi-recumbent and supine positions, concluding that a higher head position ( - °) reduces the risk of vap . as in ards, some covid- patients require prone positioning to homogenize lung j o u r n a l p r e -p r o o f may reduce the risk of vap by a still-unclear mechanism, which may involve prevention of lung translocation of oropharyngeal pathogens and easier drainage of respiratory secretions (li bassi et al., a) . in a meta-analysis of , ards patients, prone positioning resulted in lower vap incidence. conversely, the most recent study which assessed the use of prone position in ards patients found a higher vap rate in the prone group than in the supine group, and vap occurrence in the prone position group was associated with higher mortality (ayzac et al., ) . the arir position paper on cpt in covid- suggests early implementation of postural changes, although no conclusive data are available for covid- . in summary, the above-mentioned positioning maneuvers may represent an important strategy to reduce the risk of secondary respiratory bacterial infections in mechanically ventilated covid- patients, facilitating mucus clearance and mobilizing secretions, thereby improving lung volumes, perfusion, and oxygenation. ventilator hyperinflation is a technique commonly applied by physiotherapists to promote airway clearance in mechanically ventilated icu patients (thomas, ) . ventilator hyperinflation requires the use of a ventilator generating an expiratory flow rate bias when the peak inspiratory flow rate is less than % of the peak expiratory flow rate, with a minimal difference of l/min and an expiratory flow rate of l/min (volpe et al., ) . recently, ribeiro et al. compared six models of ventilator hyperinflation. volume-controlled ventilation and pressure support ventilation achieved the best effectiveness score (p< . ), with less patient-ventilator asynchronies in pressure support mode (ribeiro et al., ) . however, it is still uncertain whether ventilator asynchronies are associated with a worse outcome (bruni et al., ) . the effectiveness of manual versus ventilator hyperinflation has been compared both in clinical and pre-clinical settings. in an experimental study in pigs, neither manual nor ventilator hyperinflation modified pulmonary parameters. rather, both maneuvers significantly decreased inspiratory flow and increased peak expiratory flow up to l/min (li bassi et al., ) . in summary, the ventilator hyperinflation j o u r n a l p r e -p r o o f technique may be considered for severe covid- patients to promote airway clearance, although its actual beneficial effects have yet to be proven. icu-acquired weakness is a very common global muscle weakness that affects around % of icu patients mechanically ventilated for more than hours (hodgson et al., ) . the risk factors include bed rest, sepsis and multiorgan failure, hyperglycemia, and use of corticosteroids and neuromuscular blockers (shang et al., ) . the literature published to date about critically ill covid- patients has confirmed a need for long-term mechanical ventilation, high doses of neuromuscular blocking agents, and prolonged bed rest(c. robba et al., a; gattinoni et al., ) . moreover, one of the key therapeutic strategies for these patients has been the early use of corticosteroids (battaglini et al., ) , which is another important risk factor implicated in icuacquired weakness (shang et al., ) . the arir position paper (lazzeri et al., ) suggests careful planning of protocols for early mobilization in covid- patients, rather than random application of these techniques. inspiratory muscle training, electrical muscle stimulation, and early mobilization could be considered as key strategies in the prevention of icu-acquired weakness (shang et al., ; nakamura et al., ) , and should be used rationally to help ensure rapid recovery of those who can benefit. a systematic review and meta-analysis concluded that inspiratory muscle training is able to improve maximal inspiratory pressure and weaning success (elkins and dentice, ) . however, improved muscle function and strength have not translated into improved icu outcomes. one randomized controlled trial reported improved quality of life within weeks of interventions, but further studies are needed to confirm these findings (bissett et al., ) . while evidence for these strategies is still limited, early mobilization of critically ill patients is feasible, safe, and proven to reduce icu length of stay (stiller, ) , as recently confirmed by the rehabilitation strategies applied in covid- patients at san raffaele hospital, milan, italy. these were based on a multidisciplinary strategy (iannaccone et al., ) . therefore, it should be considered and implemented early in the course of icu stay in patients with severe covid- (lazzeri et al., ) . as for intubation, the extubation process in critically ill covid- patients should be carefully organized, considering the high risk of aerosol generation (thomas et al., ) . health care workers should begin the process only after donning appropriate personal protective equipment and, if possible, should organize the procedure in a negative-pressure room with an antechamber to minimize exposure (thomas et al., ) . before extubation, an air leak test is recommended. endotracheal suctioning should also be performed, although during cuff deflation and extubation it produces leakage. the application of a cpap of cmh o or pressure support ventilation (psv) at / or / cmh o can also result in lower leakage during the extubation phase (andreu et al., ) . a recent study in critically ill patients demonstrated that using positive-pressure ventilation before extubation reduced the incidence of major complications (andreu et al., ) . alveolar rms, when feasible and necessary, may be considered before extubation to reduce alveolar derecruitment (silva et al., ) . criteria for extubation of covid- patients are the same as for other critically ill patients. a daily awakening trial followed by a spontaneous breathing trial (sbt) is suggested to improve outcomes in critically ill mechanically ventilated patients (girard et al., ) . in , sklar et al. conduced a meta-analysis of randomized controlled trials to evaluate which sbt test determines higher breath effort. pressure support ventilation resulted in lower breath effort when compared to use of a t-piece, while a continuous positive airway pressure of cmh o and t-piece more accurately reflected the post-extubation physiologic condition (sklar et al., ) . it should be noted that sbts can be exhausting, thus reconnecting patients to the ventilator for hour after the sbt before extubation is recommended (fernandez et al., ) . finally, a recent paper proposed a novel technique to limit aerosol generation during extubation of covid- j o u r n a l p r e -p r o o f patients. the authors suggested the so-called "mask over tube" method, which uses a second airway filter to avoid staff exposure(d' silva et al., ) . in figure we propose a comprehensive algorithm of physiotherapy maneuvers for extubation of covid- patients (sklar et al., ) :  use adequate personal protective equipment, limit healthcare workers in the room to one physician and one physiotherapist, choose a negative-pressure chamber if available (lazzeri et al., ; thomas et al., ) ;  bed head elevation and prolonged sitting, recruitment maneuvers (lazzeri et al., ; thomas et al., ) ;  air leak test (schnell et al., ) ;  sbt with cmh o pressure support, peep= cmh o, fio = . for minutes; if the patient passes the sbt (p/f > , vt= ml/kg pbw, spo target, rr< breaths/min) (cabello et al., ) , set a final cycle of pressure support ventilation with cmh o of pressure support and peep= cmh o for at least hour to rest muscles (fernandez et al., ) ;  suction subglottic secretions using a closed-aspiration circuit (lazzeri et al., ; thomas et al., ) ;  choose the next ventilatory support modality (niv, cpap, hfno);  set peep and pressure support < cmh o (to recruit and prevent vili) immediately before extubation (gattinoni et al., ) ;  extubate while aspirating secretions via a closed circuit (lazzeri et al., ; thomas et al., ) ;  be prepared for a rapid, skilled re-intubation if necessary. recent studies have confirmed that cpt in critically ill patients is able to improve respiratory function immediately after extubation (papadopoulos and kyprianou, ; wang et al., ) . as j o u r n a l p r e -p r o o f suggested by the arir position paper (lazzeri et al., ) , cpt may be considered in all covid- patients who require mechanical ventilation, as well as during and after the extubation process. the most common techniques applied after extubation include neuromuscular electrical stimulation, early sitting, airway suctioning, swallow screening, manual hyperinflation, airway cleaning techniques, early mobilization, positive expiratory pressure with an ezpap device, positive expiratory pressure, active cycle of breathing techniques (acbt), intermittent positive pressure breathing, forced expiratory technique, assisted or stimulated cough maneuvers, insufflationexsufflation, cpap, niv, and hfno (lazzeri et al., ) . moreover, we recommend a water swallow test (wst) (brodsky et al., ) to evaluate patients at risk for dysphagia-associated aspiration. the following section provides a brief overview of techniques that could be applied to critically ill covid- patients in the post-extubation phase. these techniques pose a high risk of aerosol generation, which hinders their use (thomas et al., ) . nevertheless, based on our direct experience with covid- patients, we believe that with proper personal protective equipment and airborne precautions, all of these techniques can be safely applied-including those not recommended or even recommended against elsewhere in the literature (lazzeri et al., ; thomas et al., ) . acbts promote airway clearance, thus avoiding sputum retention and inflammation. acbts include the forced expiration technique (fet) and chest expansion exercises (lewis et al., ) . the fet consists of one or two forced expirations followed by relaxed breathing. in a metaanalysis of randomized controlled trials, acbts were associated with higher sputum clearance, vital capacity, and forced expiratory volume in respect to conventional physiotherapy (lewis et al., ) . a meta-analysis of studies concluded that participants prefer autogenic drainage over acbts, which in turn are preferred over airway oscillating devices. no differences were found in term of lung function, disease exacerbations, sputum weight, oxygen saturation, or exercise j o u r n a l p r e -p r o o f tolerance, casting doubt as to the real efficacy of acbts (mckoy et al., ) . no data are available specifically for covid- patients. these maneuvers should only be performed while wearing personal protective equipment in a negative-pressure room (thomas et al., ) . manual hyperinflation is a technique that delivers a high tidal volume up to a peak pressure of cmh o. it starts with a slow inspiration, followed by a -or -second inspiratory hold, followed by a rapid expiration (similar to forced expiration). some techniques include the use of a manual hyperinflation bag with a peep valve, which allows maintenance of peep and thus reduces derecruitment and atelectrauma. the advantage of using manual hyperinflation over ventilator hyperinflation is the proprioceptive feedback from the bag to the operator, while the advantage of ventilator hyperinflation is the safe maintenance of peep and standardization and reproducibility of the technique. in awake patients, use of the manual hyperinflation technique is considered simpler than a ventilator hyperinflation manoeuvre (pathmanathan et al., ) . this technique has not yet been studied in covid- . as for the other techniques mentioned, personnel protective equipment must be worn, and the procedure performed in a negative-pressure room if available. the ezpap is a positive expiratory pressure device that delivers a continuous expiratory pressure through the mouth using airflow delivered from a flowmeter to treat and prevent atelectasis. in a randomized controlled trial of postoperative patients randomly allocated to ezpap or control, spo did not differ between the two groups, whereas the ezpap group restarted oxygen therapy less frequently and had a reduced incidence of postoperative complications. in patients at risk of hypoxemia, the ezpap improved pulmonary oxygenation (rieg et al., ) . another trial compared incentive spirometry to ezpap in postoperative patients, and found no differences between the two strategies in terms of lung expansion or postoperative pulmonary complications (rowley et al., ) . as for other techniques, data are limited in covid- . although the risk for health care workers is higher with such devices, they have proven beneficial j o u r n a l p r e -p r o o f in critically ill patients. thus, using personal protective equipment, disposable circuits, airborne precautions, and placing a filter over the machine and patient is strongly recommended (thomas et al., ) . mechanical insufflation/exsufflation is a device that promotes maximal lung inflation, followed by a negative pressure, in order to simulate cough. this technique is used when the patient is unable to cough or coughs ineffectively. it is particularly efficient when provided in conjunction with assisted cough techniques or thoraco-abdominal trust (pathmanathan et al., ) . no evidence in covid- is available; however, the same recommendations described above may be applied. in our unit, we use a face mask and oral aspiration during the procedure to reduce aerosol dispersal. although sputum induction has not been recommended because of the high risk of aerosol generation (thomas et al., ) , critically ill patients (included those with covid- ) frequently develop neuromuscular weakness and swallowing dysfunction, thus often requiring sputum induction. based on our experience and on clinical evidence, we believe that sputum should be incentivized in covid- patients to reduce the rate of reintubation, but only in case personal protective equipment are guaranteed. as proposed above, early neuromuscular mobilization should be considered to facilitate recovery, particularly in the post-extubation phase, as around % of mechanically ventilated patients develop icu-acquired weakness (hodgson et al., ) . post-extubation respiratory support may be required to reduce the risk of reintubation. in the specific setting of covid- , the risk of extubation also includes health personnel. as suggested by the arir position statement (lazzeri et al., ) , conventional oxygen therapy (such as a nasal cannula) should be avoided in order to reduce droplet dispersion. a face mask with an oxygen flow j o u r n a l p r e -p r o o f up to l/min, a reservoir mask up to l/min, or a venturi mask with . fio may be preferred, and a surgical mask should be placed over the oxygen mask to further reduce dispersion. for patients who require hfno, flows up to l/min and fio up to . should be adopted, again covering the patient's mouth and nose with a surgical mask (thomas et al., ) . the arir suggests that, for patients not admitted to the icu, cpap and niv can be employed for no longer than hour, followed by reintubation if no improvement is observed (lazzeri et al., ) . in our icu experience, -to -hour cycles of niv can be beneficial for covid- patients. among the available interfaces, the helmet is considered the safer choice to minimize risk to health care workers, as it inherently limits droplet dispersion (lazzeri et al., ) ; a viral filter should be placed on the expiratory valve to limit aerosol dispersion. a protocol for a randomized controlled trial comparing early post-extubation respiratory support versus standard care was recently proposed, and the trial is ongoing (casey et al., ) . finally, when considering post-extubation respiratory support strategies, it is worth noting that the peripheral oxygenation target for covid- patients who present with hypoxemic respiratory failure is an spo of % (thomas et al., ) . covid- is a new disease process that has not been completely characterized. although there is still no evidence of the efficacy of chest physiotherapy in the specific setting of covid- , several established physiotherapy techniques can be safely applied in this subgroup of patients to reduce atelectasis and improve outcomes. all physiotherapy interventions should be carefully organized, and personnel must always wear appropriate personal protective equipment to minimize exposure. awake prone position in hypoxemic patients with coronavirus disease (covi-prone): a randomized clinical trial (covi-prone) surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) safety of positive pressure extubation technique effect of applying positive pressure with or without endotracheal suctioning during extubation: a laboratory study prone positioning during high flow oxygen therapy in acute hypoxemic respiratory failure (optiprone) ventilator-associated pneumonia in ards patients: the impact of prone positioning. a secondary analysis of the proseva trial emerging therapies for covid- pneumonia inspiratory muscle training to enhance recovery from mechanical ventilation: a randomised trial screening accuracy for aspiration using bedside water swallow tests: a systematic review and meta-analysis patient-ventilator asynchrony in adult critically ill patients physiological comparison of three spontaneous breathing trials in difficult-to-wean patients interventions to improve the physical function of icu survivors: a systematic review subglottic secretion drainage and objective outcomes: a systematic review and meta-analysis protocolized post-extubation respiratory support to prevent reintubation: protocol and statistical analysis plan for a clinical trial effect of lung recruitment and titrated positive end-expiratory pressure (peep) vs low peep on mortality in distress syndrome -a randomized clinical trial acute effects of physiotherapeutic respiratory maneuvers in critically ill patients with craniocerebral trauma È come un terremoto extubation of patients with covid- a proposed lung ultrasound and phenotypic algorithm for the care of covid- patients with acute respiratory failure eleven faces of coronavirus disease use of prone positioning in nonintubated patients with covid- and hypoxemic acute respiratory failure inspiratory muscle training facilitates weaning from mechanical ventilation among patients in the intensive care unit: a systematic review an official medicine/society of critical care medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome reconnection to mechanical ventilation for h after a successful spontaneous breathing trial reduces reintubation in critically ill patients: a multicenter randomized controlled trial covid- does not lead to a "typical" acute respiratory distress syndrome efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (awakening and breathing controlled trial): a randomised controlled trial clinical characteristics of coronavirus disease in china lung, heart, vascular, and diaphragm ultrasound examination of covid- patients: a comprehensive approach prone positioning in severe acute respiratory distress syndrome early mobilization and recovery in mechanically ventilated patients in the icu: a bi-national, multi-centre, prospective cohort study role of rehabilitation department for adult individuals with covid- : the experience of the san raffaele hospital of milan physical therapy for the critically ill in the icu: a systematic review and meta-analysis subglottic secretion drainage for ventilator-associated pneumonia prevention: an underused efficient measure respiratory physiotherapy in patients with covid- infection in acute setting: a position paper of the italian association of respiratory physiotherapists the active cycle of breathing technique: a systematic review and meta-analysis body position and ventilator-associated pneumonia prevention in-vitro analysis of a novel 'add-on' silicone cuff to improve sealing properties of tracheal tubes short-term appraisal of the effects and safety of manual versus ventilator hyperinflation in an animal model of severe pneumonia randomized, multicenter trial of lateral trendelenburg versus semirecumbent body position for the prevention of ventilator-associated pneumonia coronavirus disease (covid- ): role of chest ct in diagnosis and management influence of an endotracheal tube with polyurethane cuff and subglottic secretion drainage on pneumonia subglottic secretion suction for preventing ventilator-associated pneumonia: an updated meta-analysis and trial active cycle of breathing technique for cystic fibrosis early rehabilitation with dedicated use of belt-type electrical muscle stimulation for severe covid- patients chest physiotherapy after extubation affects vital capacity and inspiratory muscles' strength respiratory physiotherapy in the critical care unit selecting the best ventilator hyperinflation technique based on physiologic markers: a randomized controlled crossover study ezpap® therapy of postoperative hypoxemia in the recovery room : experiences with the new compact system of end-expiratory positive airway pressure distinct phenotypes require distinct respiratory management strategies in severe covid- multiple organ dysfunction in sars-cov- : mods-cov- pulmonary and extrapulmonary acute respiratory distress syndrome: myth or reality? a randomized controlled trial comparing two lung expansion therapies after upper abdominal care cuff leak test for the diagnosis of post-extubation stridor: a multicenter evaluation study on the use of corticosteroids for -ncov pneumonia recruitment maneuvers modulate epithelial and endothelial cell response according to acute lung injury etiology recruitment maneuvers for acute respiratory distress syndrome: the panorama in how the covid- infection tsunami revolutionized the work of respiratory physiotherapists: an experience from northern italy effort to breathe with various spontaneous breathing trial techniques physiotherapy in intensive care: an updated systematic review is the prone position helpful during spontaneous breathing in patients with covid- ? physiotherapy management for covid- in the acute hospital setting: clinical practice the effect of mechanical ventilator settings during ventilator hyperinflation techniques: a bench-top analysis caution about early intubation and mechanical ventilation in covid- ultrasonography for the assessment of lung recruitment maneuvers feasibility and effects of the semirecumbent position to prevent ventilator-associated pneumonia: a randomized study joint statement on the role of respiratory rehabilitation in the covid- crisis: the italian position paper ventilation patterns influence airway secretion movement coronavirus disease in elderly patients: characteristics and prognostic factors based on -week follow-up semi-recumbent position versus supine position for the prevention of ventilator-associated pneumonia in adults requiring mechanical ventilation chest physiotherapy with early mobilization may improve extubation outcome in critically ill patients in the intensive care units risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease chest physiotherapy for pneumonia in adults j o u r n a l p r e -p r o o f authors' contribution: db, literature search, study design, manuscript preparation. cr, sc, lb, key: cord- -jzpgtkai authors: yong choi, sung; shin, joongbo; park, woori; choi, nayeon; sei kim, jong; i choi, chan; ko, jae-hoon; ryang chung, chi; son, young-ik; jeong, han-sin title: safe surgical tracheostomy during the covid- pandemic: a protocol based on experiences with middle east respiratory syndrome and covid- outbreaks in south korea date: - - journal: oral oncol doi: . /j.oraloncology. . sha: doc_id: cord_uid: jzpgtkai background: a subset of patients with covid- require intensive respiratory care and tracheostomy. several guidelines on tracheostomy procedures and care of tracheostomized patients have been introduced. in addition to these guidelines, further details of the procedure and perioperative care would be helpful. the purpose of this study is to describe our experience and tracheostomy protocol for patients with mers or covid- . materials and methods: thirteen patients with mers were admitted to the icu, ( . %) of whom underwent surgical tracheostomy. during the covid- outbreak, surgical tracheostomy was performed in one of seven patients with covid- . we reviewed related documents and collected information through interviews with healthcare workers who had participated in designing a tracheostomy protocol. results: compared with previous guidelines, our protocol consisted of enhanced ppe, simplified procedures (no limitation in the use of electrocautery and wound suction, no stay suture, and delayed cannula change) and a validated screening strategy for healthcare workers. our protocol allowed for all associated healthcare workers to continue their routine clinical work and daily life. it guaranteed safe return to general patient care without any related complications or nosocomial transmission during the mers and covid- outbreaks. conclusion: our protocol and experience with tracheostomies for mers and covid- may be helpful to other healthcare workers in building an institutional protocol optimized for their own covid- situation. in december , a local outbreak of severe acute respiratory syndrome coronavirus (sars-cov- ) occurred in wuhan (hubei, china). the coronavirus disease (covid- ) was highly infectious from the early stage and rapidly spread to several countries. as of may , , covid- has been reported in countries, with more than , , cases and more than , deaths. [ ] since south korea recorded its first case of covid- on january , , the total number of confirmed cases stands at , , which is concentrated mainly in daegu and gyeongsangbuk-do ( . % of all confirmed cases) and the number of the virus-associated deaths has reached people. [ ] most patients are projected to have mild symptoms ( %) and the mortality rate in covid- is relatively low ( . %). [ ] compared with mortality rates of % for severe acute respiratory syndrome (sars) [ ] and % for middle east respiratory syndrome coronavirus (mers) [ ] . however, some infected patients are classified as severe or critical cases, and often require intubation and mechanical ventilation ( . %- . %). [ , ] critically ill patients with prolonged intubation ultimately need tracheostomy for proper airway management and lung care. tracheostomy is a routine surgical procedure, and there has been a debate on the optimal time for tracheostomy in critically ill patients requiring intensive respiratory care. [ ] in general, a timely tracheostomy within seven to ten days after intubation is preferred in terms of minimizing mechanical ventilation time, length of stay in the intensive care unit (icu) and mortality. [ ] however, in this epidemic situation, the risks of exposure and transmission from patients to healthcare workers should be carefully considered when the tracheostomy is planned. it is essential that surgeons and icu staff stay current on the protocols and guidelines for infection prevention during the tracheostomy, and these should be based on real experience and the best available evidence on this topic. in , we experienced the largest in-hospital mers outbreak with laboratory-confirmed mers cases. [ ] although all surgical procedures for mers patients were delayed as long as possible according to our institutional policy, nine cases inevitably required surgical tracheostomy. thus, we developed our own institutional protocol for safe tracheostomy in patients with mers. five years later, as the covid- pandemic rapidly spread, we revised and modified our tracheostomy protocol to prepare for the covid- situation. we applied and tested this protocol in a patient with covid- patient for whom tracheostomy was indicated in march . here we describe our experience and protocol for surgical tracheostomy in patients with covid- in our hospital. this study was a retrospective analysis using clinical and pathological data from patients with mers and covid- who underwent surgical tracheostomy. the study protocol was approved by our institutional review board (no. - - ) and the electronic medical records and interviews of medical staff who cared for patients with mers and covid- who underwent surgical tracheostomy were used for the study. all data were de-identified. the study population included nine patients with mers who had undergone surgical tracheostomy at our institution from may to july (mers outbreak). on the basis of hospital closing date (june ), we defined the early phase of the outbreak (before june ) as phase (two tracheostomies) and the middle phase of the outbreak (after june ) as phase (seven tracheostomies). [ , ] one covid- patient who had undergone surgical tracheostomy at our institution was also included in this study. for mers-cov and sars-cov- pcr tests, either sputum or nasopharyngeal swab samples were collected using a sterile, leak-proof, screw-capped sputum collection container and nasopharyngeal swabs were collected with an eswab ( c, copan diagnostics inc., murrieta, ca, usa). mers samples were tested by rrt-pcr with amplification targeting the upstream e region (upe) and confirmed by subsequent amplification of the open reading frame (orf) a using powercheck™ mers real-time pcr kits (kogene biotech, seoul, korea). [ ] covid- samples were screened by rrt-pcr with amplification targeting the envelope gene (e) and confirmed by subsequent amplification of the rna-dependent rna polymerase gene (rdrp) using powercheck™ sars-cov- real-time pcr kits (kogene biotech, seoul, korea). for serologic surveillance, we used commercial anti-mers-cov enzyme-linked immunosorbent assay (elisa) igg kits (euroimmun, lübeck, germany) to detect antibody response. we used automated fluorescent immunoassay system (afias) covid- ab assay kit for sars-cov- antibody detection (bodi-tech med inc., chuncheon, korea). the perioperative tracheostomy protocol for mers and covid- patients was developed and revised through multidisciplinary discussions led by our in-hospital infection control team during the mers and covid- outbreaks. a multidisciplinary discussion among icu, ent and infection control departments is essential in the decision to perform tracheostomy in an infected patient. when a tracheostomy was planned for a patient with mers, an open surgical tracheostomy was preferred to a percutaneous dilatational tracheostomy (pdt) due to decreased potential for aerosolization. thirteen patients with mers were admitted to the icu, and nine ( . %) of them required surgical tracheostomy. tracheostomy was necessary is one of the seven patients with covid- in our hospital. surgical tracheostomy was also performed in this case not only because the open surgical tracheostomy is considered lower risk in terms of aerosol-generation compared to pdt, but also because a high-riding brachiocephalic (innominate) artery was noted on preoperative computed tomography (ct). thus, preoperative evaluation of neck anatomy is also important to determine the optimal procedure and reduce surgical complications. level of personal protective equipment (ppe) during tracheostomy during phase of the mers outbreak (before june ), two surgical tracheostomies were performed and standard personal protective equipment (ppe) comprising surgical gloves, surgical gowns, eye shields, and n respirators was used by health care workers on the tracheostomy teams. there was no tracheostomy-related mers transmission with this level of ppe, suggesting that standard ppe without papr could be appropriate depending on the situation. however, there were four cases of mers in healthcare workers involved in other procedures in patients with high viral loads (sputum pcr cycle threshold value < ) despite use of this level of ppe. as a result, the infection control department at our institution increased the level of recommended protection, and all members of the tracheostomy team used enhanced ppe, which included coverall clothes including a head cover, shoe covers, two pairs of surgical gloves, powered air purifying respirators (paprs) and n respirators. in addition to enhanced ppe, primary surgeons and surgical assistants used an outer surgical gown and gloves, resulting in double gowning and triple gloving. all members of the tracheostomy team remained free of disease, during and after performing a total of nine tracheostomies for patients with mers, suggesting these protections were successful and safe. thus, enhanced ppe including papr was also used with the patient with covid- (cycle thresholds . for e gene and . for rdrp gene from trans-tracheal aspirates) (supplementary figure ) and there was no perioperative covid- transmission ( table ) . as strict donning and doffing procedures are crucial to prevent operator contamination, institutional training, and education on the proper use of ppe was provided to the surgical teams before they cared for covid- patients ( figure ). on the day of tracheostomy, surgical teams were carefully assisted and closely supervised by skilled nurses in the designated donning and doffing location in the icu ( figures a and b ). during the mers outbreak, we had no permanent negative-pressure icu rooms, and two patients inevitably underwent surgical tracheostomy in an isolated icu created for mers patients. because a negative pressure icu is ideal for surgical procedures to minimize airborne viral spread, isolated icus were temporarily converted to comprise negative-pressure icu rooms to facilitate performing surgical procedures in mers patients. [ ] we performed seven surgical tracheostomies on patients with mers after this icu conversion was completed. based on lessons learned from the mers outbreak, two negative pressure icus with anterooms and negative pressure isolation wards were separately constructed outside the main hospital in . during the covid- pandemic, at the request of the government, a critically ill covid- patient with prolonged intubation was transferred directly to the negative-pressure icu at our hospital in march . one week later, surgical tracheostomy was performed at the bedside in the icu in a negative-pressure room. our institution could not limit the number of team members involved in the tracheostomy procedure and post-operative management at the time of the mers outbreak. two surgeons comprising a primary surgeon and surgical assistant took turns with the icu specialist assisted by a standby nurse in performing tracheostomies. in contrast, the surgical tracheostomy for the covid- patient was performed by one dedicated head and neck surgeon and icu medical staff (two intensivists and one senior nurse), who worked only in the negative pressure room for covid- , and assisted with all procedures (supplementary figure ) . general principles for minimizing aerosolization and surgery time were applied during the tracheostomies. these included complete paralysis to prevent cough and movement, lower positioning, and hyper-inflation of the endotracheal tube cuff, holding ventilation before tracheal incision, and prompt cannula insertion and cuff inflation while withdrawing the endotracheal tube to just above the window. [ ] [ ] [ ] [ ] [ ] performing a tracheostomy with enhanced ppe was not easy. enhanced ppe limited manual tactile sensation (multiple gloves), free surgical motion (double gowns), illumination and visualization. thus, we typically made a relatively wide incision ( - cm) to ensure a clear surgical field and visualization even if additional skin sutures were needed at the end of the procedure. a surgical light was also required for optimal visualization during the procedure. a wearable headlight or headlamp was used in all cases. however, the headlight did not fit a surgeon's head because of the enhanced ppe head cover. instead, surgical assistants (first and second) wore the headlamp and were in charge of illuminating the surgical field ( figure e ). different from many recommendations for avoiding diathermy and suction, we generally used electrical devices including bipolar and monopolar diathermy for hemostasis and to save time and we did not limit suctioning throughout the surgical tracheostomy procedure ( figure d ). nevertheless, there was no transmission caused by using diathermy and suction, suggesting that the possibility of transmission through diathermy producing vapor plumes or suction-related aerosolization is extremely low in the setting of enhanced ppe in a negative pressure room. we did not place stay sutures or a björk flap for any of the mers or covid- patients. instead, we made an oval-shaped tracheal window by removing the tracheal cartilage, which prevented forceful insertion and avoided tracheal damage or false passage. we prepared various sized non-fenestrated cuffed tubes and adjustable tubes on the surgical table to reduce the possibility of a poorly fitted cannula. portex ® "vocalaid" cuffed blue line ® tracheostomy tubes (id . ) were used in six mers patients and vocal aid cuffed mera ® sofit clear tubes (id . ) were used in two mers patients. a portex ® "vocalaid" cuffed blue line® tracheostomy tube (id . ) was used in the covid- patient. these were no accidental decannulation events. after tracheostomy and the associated procedures (e.g., tube insertion, balloon inflation, circuit connection, ventilation resumption and endotracheal removal), peristomal dressing and skin suture using - vicryl (absorbable) performed to minimize the need for tube and dressing changes ( figure e ). during the mers outbreak, the tracheostomy wound was dressed daily by trained icu nurses with enhanced ppe. a tracheostomy tube change was performed three days after the operation, and a subsequent change was performed ten days postoperatively by ent surgeons wearing enhanced ppe. there were no cannula-related complications, including stomal infection and cannula occlusion with a mucous plug (table ) . we subsequently revised the tube management protocols based on other guidelines and experience in our icu system. these revisions included no dressing changes unless there were signs of infection and delaying the first tube change until covid- patients tested negative for viral rna. the first cannula change for the covid- patient was performed by the same surgeon with enhanced ppe at days because that patient had three consecutive negative sars-cov- pcr tests days after tracheostomy. the stoma site and tube lumen were noted to be clean despite the delay. the patients stayed in the negative-pressure icu for an additional three weeks to minimize the risk of nosocomial transmission, and was then transferred to an isolated icu, where decannulation without down-sizing and corking were performed four days after transfer. the patient was transferred to the general ward seven days after decannulation. during the mers outbreak, health care workers involved in tracheostomy and related procedures continued to work with monitoring and were removed immediately from duty if symptoms developed. however, at the end of the mers outbreak in our hospital, all healthcare workers who participated in procedures for the last mers patient were placed in home quarantine for days from the last day of exposure and their sputum was tested by rrt-pcr as a screening test before they returned to general patient care. the pcr results for all associated staff were negative and serologic testing for mers-cov antibody was also negative. [ ] during the covid- pandemic, all members of the team who participated in tracheostomy for the covid- patient were put under active monitoring (checking temperature and symptoms twice a day) while working (table ) . at the end of patient care, icu staff were also placed on seven days of home quarantine and underwent screening by sputum rrt-pcr, and additional pcr screening was performed before they returned to work. the pcr results were all negative. although there was no pcr screening and no quarantine for the primary surgeon, serologic testing was negative for the anti-sars-cov- antibody. several studies related to guidelines or recommendations on surgical tracheostomy for covid- patients have been published. however, the detailed context of the procedure seems inconsistent and varies by the developing group, specialty, hospital and national health care systems. there is a limited number of protocols or recommendations based on real experience on this topic. fortunately, we have clinical experience with tracheostomies for both mers and covid- patients, and we thought it would be helpful to share our experience and protocol with readers. there has been a debate on whether pdt spreads more virus-containing aerosols than surgical tracheostomy. surgical tracheostomy is usually recommended over pdt in most guidelines. [ ] [ ] [ ] ] preoperative evaluation of individual anatomy and patient functional status is critical. this includes particular attention to anatomical variations (a high-riding major artery in our case), obesity, un-extended or short neck, bleeding tendency, or ventilator dependency. in addition to the possibility of aerosol dissemination, surgeons should consider these factors in determining the most appropriate tracheostomy procedure and to reduce surgical complications. some guidelines recommend a double-lumen cannula comprising a non-fenestrated cuffed outer with a disposable inner cannula. [ ] however, the interface between the inner and outer cannulas can vary by manufacturer and ventilation setting, thereby increasing the chance of air leakage. [ ] furthermore, double lumen cannulas tend to be rigid, which can cause mucosal irritation or injury. thus, we prefer to use single lumen non-fenestrated cuffed tubes with or without an adjustable function. this minimizes the risk of viral transmission through air leakage, particularly for infected patients receiving positive pressure ventilation. b virus (hbv) have reported that the plume originating from diathermy contains viable infectious particles that can be transmitted to the upper respiratory tract through inhalation of surgical smoke. [ , ] in this context, some guidelines recommend avoiding or limiting the use of electrocautery to reduce exposure to the surgical plume. [ ] [ ] [ ] however, although the possibility of disease transmission through electrocautery-induced surgical plumes has been recognized, only hpv transmission has been reported in rare cases [ ] ; no prior study has demonstrated that brief exposure to electrosurgical smoke alone causes viral infection. there has been no evidence to indicate that covid- is transmissible through surgical plumes. [ ] additionally, one study reported that none of the blood samples from covid- patients tested positive for rna from sars-cov- , suggesting that the virus may not be present within the smoke produced by electrocautery. [ ] consistent with our study, surgical tracheostomies for covid- patients were preformed using an electrocautery device without any cases of transmission in a recent study. [ ] therefore, we consider the clinical benefits of electrocautery, including reduced operation time, surgical view, and easy bleeding control, to exceed the risk of potential viral transmission. aerosol-generating procedures have highlighted the risk of nosocomial transmission of emerging viruses such as sars-cov. [ ] many medical procedures including bronchoscopy, cardiopulmonary resuscitation (cpr), ventilation, surgery, nebulizers, and suction have been considered potential aerosol-generating procedures. based on these findings, use of suction during tracheostomy is not recommended in recent guidelines. during the sars-cov outbreak, only direct airway-stimulating procedures such as bronchoscopy, cpr, ventilation, and intubation have been reported to be potentially associated with sars-cov transmission. [ ] [ ] [ ] during surgical tracheostomy, exposure of the tracheal lumen is very short and suction can be used to evacuate the diathermy-producing plume. furthermore, enhanced ppe in a negative pressure room minimizes exposure to aerosols and electrocautery-inducing smoke. therefore, we did not limit suction or diathermy in our institutional tracheostomy protocol for mers and covid- patients. complete hemostasis achieved by electrocautery and suction of blood or sputum in surgical fields could contribute to rapid and safe tracheostomy with fewer complications. a stay suture technique, suturing the anterior tracheal wall to the skin after making a tracheal window, facilitates insertion and prevents false passage in accidental decannulation. placing stay sutures or making a björk flap may lead to direct exposure to tracheal secretions through an opened tracheal window in infected patients, thereby increasing the chance of viral particle transmission. thus, we did not use a stay suture or björk flap during surgical tracheostomy in mers and covid- patients. instead, we made a round opening on the tracheal cartilage directly beneath the skin wound. fortunately, our patients did not suffer from false lumen formation or accidental decannulation, even without the stay sutures. one of the major modifications in the covid- tracheostomy protocol at our institution was postoperative management including dressing and cannula changes. during the mers outbreak, there was no difference in cannula dressing and change intervals between infected and non-infected cases. in preparing the covid- tracheostomy protocol, we agreed that daily cannula dressing seems unnecessary and the first cannula change can be delayed until the patient no longer tests positive. additionally, delaying the tube change allows maturation of the skin-to-trachea tract to avoid false passage without a suture or björk flap. our data and recent reports revealed that the rate of negative conversion within days was . % [ ] and the median time from onset of symptoms to mechanical ventilation was . days in covid- patients. [ ] thus, the modified time to cannula change should be within days after tracheostomy. in our patient, the first tracheostomy cannula change was on postoperative day , which was two days after the patient had three negative tests. ultimately, decannulation was possible on day after the first cannula change without any complications. decannulation is a critical process for weaning patients from the tracheostomy. [ ] however, the process includes many aerosol-generating procedures, such as down-sizing, cannula type changes, balloon deflation, airway evaluation, active coughing to prevent aspiration, and repeated capping/uncapping. thus, we chose the abrupt tube removal method for covid- patients to decrease the potential risk of exposures. in response to reports of multiple cases testing positive for sars-cov- after having recovered, the patient stayed for an additional seven days in an isolated icu for close monitoring and to allow the stoma to seal, but this later proved unnecessary as no evidence has suggested that re-positive cases are infective. another stark difference in our revised protocol is the creation of a designated covid tracheostomy team comprised of one highly experienced head and neck surgeon, two attending icu specialist (one to manage ventilator/endotracheal tube, one to assist with the procedures) and a senior icu nurse. during the mers outbreak in , we had to perform eight mersrelated tracheostomies in a short period between june and june without a dedicated team because of limited resources at our institution. as our institution is a tertiary referral center, we are prepared to care for severe cases of covid- requiring intensive medical support. thus, we were able to focus on critically ill covid- patients by preparing medical resources and creating a dedicated team in advance, without any limitations to accessibility or safety for non-covid- patients (figure ). however, if team members in the icu need to be kept to the minimum critical number, an additional icu nurse could be omitted from the tracheostomy team. therefore, the optimal number and composition of covid- tracheostomy teams could vary depending on the medical resources available for each center, region, and country. in addition, we prepared a highly organized infection control system including a negative pressure icu with double anterooms and a validated screening strategy for healthcare workers. as shown in figure a , designated space in a negative pressure icu was created for procedures to minimize potential risk of exposures. it consisted of space for donning ppe and material equipment, one anteroom for entering, a second anteroom for doffing ppe, and a fitting and shower room for personnel protection. every step was guided and supervised by a senior icu nurse ( figure a-e) . we also confirmed the appropriateness of our screening and monitoring strategy (active monitoring and quarantine followed by sputum rrt-pcr) for involved healthcare workers by serologic investigation after the end of the mers outbreak, in which none of the tested sera were positive for mers-cov antibody. [ ] these screening protocols were applied to assigned icu staff (icu specialists and nurses) in the covid- pandemic. however, pcr screening and quarantine for the primary surgeon was omitted as they wear enhanced ppe and are exposed only for a short period of time during the tracheostomy procedure and first cannula change. we had no transmission among healthcare workers who used enhanced ppe during the mers outbreak. [ ] serum collected from the primary surgeon was negative for anti-sars-cov- antibody at the end of our hospital's care of covid- patients, implying that our screening protocol based on clinical situation is effective and practical. these facilities and screening systems for covid- allowed for all associated medical staff to continue their routine clinical work and daily life. to date, we have no cases of transmission from covid- patients to healthcare workers. here we presented our experience with tracheostomy in patients with mers and covid- . the covid- pandemic has escalated and poses a global threat, therefore most hospitals should prepare for performing tracheostomy and perioperative management in patients with covid- . our modified protocol and experience from the mers outbreak and covid- pandemic could serve as one reference to inform the design of protocols unique to other institutions' own covid- situation. there are no conflicts of interest. figures figure . cross-sectional ct image of a covid- patient with tracheostomy. ct scans showed a high-riding innominate artery to the right of the trachea just below the thyroid. supplementary figure . dedicated team for covid- tracheostomy. tracheostomy was performed by one experienced head and neck surgeon and two attending intensivists (one to the manage the ventilator/endotracheal tube, one to assist with the procedure). one icu nurse assisted with the procedure outside the surgical field. all team members used powered air purifying respirators (paprs). table . details of tracheostomies for mers and covid- patients. phase # phase # no. of tracheostomies performing tracheostomy and perioperative management in patients with covid- should be based on real experience and the best available evidence on this topic. our protocol allowed for all associated healthcare workers to continue their routine clinical work and daily life. our protocol guaranteed safe return to general patient care without any related complications or nosocomial transmission during the mers and covid- outbreaks. coronavirus disease (covid- ) pandemic korean center for disease control and prevention. coronavirus disease- characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention summary of probable sars cases with onset of illness from middle east respiratory syndrome coronavirus (mers-cov) clinical features of patients infected with novel coronavirus in wuhan early versus late tracheostomy for critically ill patients timing of tracheostomy in patients with prolonged endotracheal intubation: a systematic review mers-cov outbreak following a single patient exposure in an emergency room in south korea: an epidemiological outbreak study control of an outbreak of middle east respiratory syndrome in a tertiary hospital in korea infection prevention measures for surgical procedures during a middle east respiratory syndrome outbreak in a tertiary care hospital in south korea safe tracheostomy for patients with severe acute respiratory syndrome elective and emergency surgery in patients with severe acute respiratory syndrome (sars) corona-steps for tracheotomy in covid- patients: a staff-safe method for airway management surgical considerations for tracheostomy during the covid- pandemic: lessons learned from the severe acute respiratory syndrome outbreak a framework for open tracheostomy in covid- patients serologic evaluation of mers screening strategy for healthcare personnel during a hospital-associated outbreak elective tracheostomy in mechanically ventilated patients affected by covid- : preliminary case-series from lombardy leakage characteristics of dual-cannula fenestrated tracheostomy tubes during positive pressure ventilation: a bench study surgical plume and its implications: a review of the risk and barriers to a safe work place the dangers of electrosurgical smoke to operating room personnel: a review surgical smoke exposure in operating room personnel: a review safe management of surgical smoke in the age of covid- virological assessment of hospitalized patients with covid- safety and prognosis in percutaneous vs surgical tracheostomy in patients with covid- nosocomial transmission of emerging viruses via aerosol-generating medical procedures aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review transmission of severe acute respiratory syndrome during intubation and mechanical ventilation possible sars coronavirus transmission during cardiopulmonary resuscitation factors associated with negative conversion of viral rna in patients hospitalized with covid- the practice of tracheostomy decannulation-a systematic review none sung yong choi a , joongbo shin a , woori park a , nayeon choi a , jong sei kim a , chan i choi key: cord- -hsh f authors: harris, gavin h.; baldisseri, marie r.; reynolds, benjamin r.; orsino, antoinette s.; sackrowitz, rachel; bishop, jonathan m. title: design for implementation of a system-level icu pandemic surge staffing plan date: - - journal: crit care explor doi: . /cce. sha: doc_id: cord_uid: hsh f background: the current coronavirus disease pandemic is causing significant strain on icus worldwide. initial and subsequent regional surges are expected to persist for months and potentially beyond. as a result of this, as well as the fact that icu provider staffing throughout the united states currently operate at or near capacity, the risk for severe and augmented disruption in delivery of care is very real. thus, there is a pressing need for proactive planning for icu staffing augmentation, which can be implemented in response to a local surge in icu volumes. methods: we provide a description of the design, dissemination, and implementation of an icu surge provider staffing algorithm, focusing on physicians, advanced practice providers, and certified registered nurse anesthetists at a system-wide level. results: the protocol was designed and implemented by the university of pittsburgh medical center’s integrated icu service center and was rolled out to the entire health system, a -hospital system spanning pennsylvania, new york, and maryland. surge staffing models were developed using this framework to assure that local needs were balanced with system resource supply, with rapid enhancement and expansion of tele-icu capabilities. conclusions: the icu pandemic surge staffing algorithm, using a tiered-provider strategy, was able to be used by hospitals ranging from rural community to tertiary/quaternary academic medical centers and adapted to meet specific needs rapidly. the concepts and general steps described herein may serve as a framework for hospital and other hospital systems to maintain staffing preparedness in the face of any form of acute patient volume surge. i n , the national academies of science released the crisis standards of care to provide hospitals with a framework for designing and implementing disaster response plans ( ) . this guidance was the culmination of several years of work examining the h n pandemic, as well as other infectious and natural disasters, which have the potential to overwhelm communities and hospital systems, even those considered well-prepared. subsequently, medical and surgical professional societies have provided special hospital recommendations for preparedness in the case of mass casualty events ( ) ( ) ( ) ( ) ( ) ( ) . in , the centers for disease control and prevention along with the department of health and human services, seeking to standardize approaches, released an updated national influenza pandemic preparedness plan that identified essential domains facilities must address to prepare for future pandemic events ( ) . among many items addressed, the document provided significant guidance for health system preparedness promoting implementation of surge strategies so that patients receive care that is safe and appropriate to their level of need, thereby conserving higher levels of care for those who need it. many types of mass casualty events, such as natural disasters, terrorist attacks, manufacturing or industrial accidents, and infectious pandemics, much like the current coronavirus disease (covid- ) outbreak, will likely result in overwhelming numbers of critically ill patients ( ) . these events create surges in patient volumes that can rapidly supersede baseline bed and staffing capacities and capabilities. this, in turn, may require responses ranging from minor augmentations to a full-scale crisis response. recognizing the uniqueness of individual hospitals regarding physical space, geographic location, and baseline staffing models, it is likely that an internal discrepancy may emerge between local bed capacity and provider staffing capacity and capabilities, especially in the icus in the management of critically ill patients. vital to developing a response to the surge in patient volumes is the ability to determine staffing and space capacity, inclusive of reallocation and augmentation of both space and staff. equally important is the need to assure that the plans for bed capacity augmentation are matched by a proportional expansion of provider capacity. in march , the society of critical care medicine (sccm) conducted a nationwide survey of over , critical care professionals to assess icu preparedness in light of the covid- pandemic. nearly all respondents reported that they had significant concerns about their institution's preparedness, and over half reported expecting or already experiencing staff shortages ( ) . thus, there clearly is a pressing need for critical care disaster planning. with a focus on icu staffing and spatial needs, drawing on the frameworks previously described by both sccm and the american college of chest physicians for disaster planning, we present a system-wide algorithm for optimizing provider staffing needs for icus to align with parallel processes for bed capacity and nursing staffing expansion. this article describes the process undertaken to develop and implement the plan for leveraging system resources and augmenting staffing capabilities in response to the covid- related surge throughout the university of pittsburgh medical center (upmc) system, comprised of community and academic hospitals. it is our hope that this document may serve as a model framework to assist hospital systems in provider staffing (including physicians, advanced practice providers [apps], certified registered nurse anesthetists [crnas]), to assure effective, efficient, and quality care throughout the protracted covid- pandemic and other potential surge events. vital to our initiative, a steering committee was initially assembled to identify the resources provided by various critical care professional societies to guide the creation of our framework. we then designed a strategy prompting individual hospitals within the system to define their current state of operations; identify any critical care resource needs; and create a bed capacity plan to accommodate escalated patient volumes. with this information, we briefed local hospital leadership on this framework, prompting the development of a staffing model for their facility optimizing local resources while simultaneously identifying potential gaps that could be augmented by mobilizing system resources, especially in the instances of staff illness or quarantine. key stakeholders were identified and a core steering team was constructed with the following structure: physician representation from critical care medicine (ccm) and system-wide capacity management; senior leadership from anesthesia and crnas; system-level executive apps leadership; and representation from the upmc icu service center. this center coordinates critical care services across the entire hospital system, focusing on optimizing care delivery and resource utilization, improving patient and family experiences, expansion of telemedicine, and establishment of tertiary-level critical care for underserved populations. as a first step in creating a plan toward augmenting both space and staff, it became necessary to identify the spectrum of surge capacity. this is depicted in figure , an illustration of the escalating imbalance between demand and supply of available resources as an event moves closer to crisis level. additionally, preparedness requires planning for surge capacity of staff, icu space, and supplies across that spectrum of disaster severity from conventional to contingency and to crisis (fig. ) . considering these defined tiered approaches, it was recognized that the current covid- required a similarly tiered approach for staffing and spatial needs that would optimally allow hospitals to adapt to rises in patient volume and demands for icu bed capacity. the sccm provides an effective model to incorporate non-icu trained staff of all disciplines (physicians, nurses, apps, and others) to greatly augment the trained and experienced icu staff in creation of a tiered staffing model. the sccm model also projects that a critical care-trained physician technically should be able to oversee four groups of patients each, all requiring icu-level care and/or mechanical ventilation (fig. ) . various other non-icu physicians who have had prior training but do not regularly provide primary care in icu settings, coupled with experienced icu apps, can be used to make such care effective. the use of telemedicine critical care services was integral to our proposed surge critical care staffing plan. critical care support can be supplemented and supported by using remote telemedicine critical care services, if available. for covid- patients, in general, significant personal protective equipment and specialized training is required. additionally, those requiring icu-level care and mechanical ventilation as a result of severe pneumonia and a form of acute respiratory distress syndrome demand many more human and materiel resources, further putting strain on already finite staffing levels. thus, we asked each hospital icu team to develop contingency plans for potential staffing deficiencies while also acknowledging the more-involved care needs of these icu-level patients. by first defining baseline patient to caregiver ratios, it simplified the task of determining when surge volumes supersede caregiver capabilities, prompting action to augment care delivery. with an appropriate tiered augmentation plan, teams could effectively match capabilities with volumes. our first recommendation to each facility was to identify current staffing resources. we classified all critical care providers currently providing care in icus, as well as telemedicine critical providers as "tier i" providers. all other airway capable providers as well as those with prior critical care training, experience, and skills, as well as nonairway providers that are icu-capable providers (i.e., apps), we classified as "tier ii" providers. last, those providers who do not have previous critical care or acute experience or skills were classified as "tier iii" providers. a separate classification that we identified as a "flex" tier would be those www.ccejournal.org who might comprise a procedure team: providers with skill sets in intubation, bronchoscopy, central line insertion, arterial line insertion, prone positioning, etc. once these staffing tiers were identified and organized, we developed a surge plan utilizing clinical experience caring for covid- patients early in the pandemic, in addition to expert opinion. based on a review of the literature as well as experience, our steering committee came to a consensus that a single tier i provider either as a remote telemedicine resource or on-site should be able to provide oversight care for - covid- positive patients alone or with the help of a dedicated procedure team. once that initial threshold is reached, tier ii providers should be added until a second threshold reached. we identified that with the assistance of two tier ii providers, a tier i provider could be able to provide oversight care for up to covid- icu-level patients (two tier ii providers caring for up to eight patients each). once a second threshold of patients has been reached, an additional eight-patient team may be added for the ultimate threshold for a single tier i provider of patients. by the time the second patient threshold of patients is reached, it is recommended to consider activating tele-icu support to serve as an expert resource. furthermore, each tier ii provider teams can be supplemented by adding a tier iii provider, able to care for up to four covid- positive patients under the direct supervision of a tier ii provider and indirect oversight of a tier i provider. once the ultimate threshold of patients has been reached, additional tier i providers (either remotely or on-site) must be added to extend the algorithm based on patient volumes. a pictorial representation of the algorithm is provided in figure . as not every hospital in the system has trainees, we purposefully excluded them to ensure this framework could be employed at each location. clearly, house-staff can be used interchangeably with tier ii and tier iii providers based upon their specialty and level of competence. we feel that a flexible, easily scalable, on-demand real-time, icu telemedicine service is an integral component of surge staffing, particularly given the uncertainties of critical care individual provider services during an ever-changing pandemic. this design is very consistent with previously described approaches to icu telemedicine, which emphasizes customizing the telemedicine service to local contexts, that is, prioritizing the human (rather than the technological) side of the telemedicine encounter. the work by kahn et al ( ) ( ) ( ) largely suggests that the value of telemedicine is highly sensitive and dependent on implementation strategy, a concept that we fully embraced in our process of surge planning. the upmc hospital system comprises rural, community, and tertiary/quaternary hospitals. senior leadership participating in bed capacity management and surge planning at each facility (including chief medical officers and chief nursing officers) were identified and contacted. initial meetings between the hospital personal and steering committee members were conducted where the needs of facilities and status of preparations were elucidated, the process was explained, and the algorithm was provided. follow-up meetings were subsequently usually held within hours to evaluate the development of surge planning from each facility. parallel processes were designed and implemented for nursing and other essential bedside providers across the system, and this is not discussed in this article since this was not the primary mission of our steering committee. an app operations team was established to support the core mission of the upmc central workforce staffing center (cwsc) in developing strategy to support the needs for app staff for all upmc clinical and nonclinical areas in response to patient care surge related to covid- . the cwsc app operations section provides / support for staffing needs not filled within the local business unit. further, the operations team ensures practice readiness through emergency disaster credentialing, just-in-time critical care training, in-patient electronic health record training, and matching appropriate practice experience and skillset with need. once the appropriate specialty or practice is determined, deployment of the identified app resource is pertinent to geographic proximity to facility as well as credentialing and privileging. requests are processed relative to need (emergent, urgent, and nonurgent) and processed with an app resource that best possess requested acute care/critical care skills or specialty practice experience. recognizing that reassignment of tier ii and tier iii providers from non-icu care platforms to the icu in support of the described tiered staffing model presents a challenge of bridging knowledge gaps, our committee elected to provide all apps throughout the system, as well as hospital leadership teams, the resources assembled by the sccm specifically tailored to address critical care for the non-icu clinician ( ) . these valuable resources provided non-icu providers with the just-in-time training and resources needed to allow them to seamlessly move into the icu and provide direct patient care services under the supervision of more experienced tier i and tier ii providers. because almost half ( . %) of those surveyed in sccm's covid- preparedness report stated that their icus were not equipped with a telemedicine system to help manage covid- patients, this was also identified as a critical pillar of care. additionally, tele-support services could offset the on-site workload, freeing up critical care-trained professionals to perform procedures and to oversee more patients. upmc's tele-icu services were thus robustly created and rapidly expanded using a shared electronic health record and telephonic communication, in the initial absence of an integrated telemedicine infrastructure. upmc has hospitals throughout pennsylvania, new york, and western maryland. it has a bed capacity of roughly , , and a baseline icu bed capacity of beds with the potential to expand to approximately , . as a result of the covid- outbreak, rapid dissemination of our surge staffing plan to all facilities was essential, and requests from individual hospital leadership throughout the system for assistance with provider surge planning were substantial. initially, each of the system's hospitals were required to create a bed capacity plan to accommodate a patient surge of two-fold or an increase to % of their baseline capacity. this space plan allowed our team to guide each hospital leadership team through the process of generating a plan for icu provider staffing using the above model. the concept of a standardized guide for individual facilities to adapt based on their own local resources and identified needs was well received. a myriad of baseline staffing arrangements were encountered throughout the system. the models ranged from full-time intensivist coverage with a full complement of resident and fellow-level trainees, to daytime intensivist accompanied by around the clock app coverage with nighttime tele-icu support, to a high-intensity critical care consultation model in support of hospitalists and surgeons acting in the primary role. our steering committee framed each staffing model using the described tiered model and then assisted in building out the staffing surge plan by identifying local and potential system staffing resources. when gaps were recognized in local staffing capacity, centralized plans were developed to augment individual facilities, whether that included augmentation of existing tele-icu capabilities, deployment of critical care-trained apps, or providing training to non-icu providers, as tier iii providers. application of a standardized framework throughout the system allowed for simultaneous monitoring of patient volumes and targeted deployment of tiered staffing resources to match the individual hospital needs while balancing system demand. figure is a representation of the surge plan that was designed for one of our community facilities. baseline capacity and surge plan were established. staffing model was categorized using the standardized framework. tier i providers consisted of daytime intensivist with nocturnal tele-icu support. tier ii care consisted of resident coverage, both day and night, augmented by procedural support at night by anesthesiology. due to concurrent inpatient pulmonary responsibilities and the presence of established infrastructure to provide tele-icu care, it was determined that surge staffing would consist of tele-icu to provide both daytime and nighttime tier i coverage of the expansion unit. residents' limited number of icu rotations and concurrent clinical responsibilities precluded an expanded resident model from being generated. a gap was identified that would require tier ii staffing from centralized staffing to augment capabilities in the setting of a surge in patient volumes or self-quarantine due to covid- exposure or illness. apps could be deployed to provide tier ii and tier iii support, as volumes demanded. last, a potential need in procedural coverage was identified that could be augmented by local crnas or gap-filled with centralized staffing, if needed. a disaster preparedness credentialing and privileging process allowing providers to move between upmc-system hospitals and provide on-site critical care coverage or deliver telemedical care within the system rapidly was quickly developed and implemented. providers privileges from their primary patient care location were extended throughout the system allowing for rapid activation of credentials to facilitate the deployment of provider workforce. in the early weeks of this pandemic, a robust covid- specific tele-critical care system was designed to augment existing tele-icu infrastructure. intensivists have been staffed hours per day within the upmc operations center, manning telephones with video-response for any of the upmc hospitals. this design drew on the high density of tier i critical care providers located within the pittsburgh-based academic medical centers from the departments of ccm and pulmonary, allergy, and critical care. volunteers from the two departments provided seamless coverage to respond to calls for assistance and guidance for critical care issues related to the covid- outbreak. as the volumes associated with the covid- pandemic varied between hospitals and within hospitals over time, this provider staffing plan became the standard by which upmc hospitals identify specific needs and the system responds to augment provider staffing. this consistency of terminology and role-definition provided an opportunity for rapid deployment of resources that met the individual needs of each situation, especially given the uniqueness of each hospital and situation. the majority of icus have provider staffing that typically function at or near capacity to optimize variable cost structures. further, the number of icu beds is shrinking nationwide resulting in a contraction of provider staffing, especially in nonurban or academic hospitals. the sccm's icu readiness report, conducted in late march to evaluate the state of icu preparedness during the height of the covid- outbreak in the united states showed that % of respondents reported icu resource shortages, including bed capacity, and % reported icu staffing issues ( ) . sixty-one percent reported patient volume surges, and % reported icu staffing shortages. this leaves very little room for expansion and exposes those hospitals that are vulnerable to strain. any surge in volume immediately affects the ability of staff to care for patients. events whether natural, industrial, acts of terror, or infectious pandemics present unique challenges to both individual hospitals or healthcare systems as they generate the potential for large numbers of critically ill patients. to optimally prepare for this, and to ensure that medical and surgical care is delivered in the most reliable, efficient, and safe way based on the resources available, tiered staffing and capacity surge planning is essential and paramount. we have presented a model framework for hospitals across one of the largest systems in the world, ranging from community to tertiary/quaternary academic medical centers, for use to urgently plan for allocation of telemedical services and centralized workforce utilization in the case of large influx of critically ill patients. although initially developed and rapidly disseminated for implementation during the current covid- pandemic, upmc has adopted this icu provider staffing model for rapid assessment and response for staffing requests in response to volume surges secondary to a myriad of increased demands during times of disaster and vulnerability of a healthcare system. furthermore, we hope it may serve as a valuable planning tool for other institutions and health systems to use during those times when mass critical care measure may be demanded. last, it is our hope that in times of future national crisis and regional icu capacity surge that a model such as this one could be used to facilitate coordination between hospital systems to augment patient care capabilities outside the confines of a singular hospital system or region. committee on guidance for establishing crisis standards of care for use in disaster situations, institute of medicine: crisis standards of care: a systems framework for catastrophic disaster response european society of intensive care medicine task force for intensive care unit triage during an influenza epidemic or mass disaster: recommendations for intensive care unit and hospital preparations for an influenza epidemic or mass disaster: summary report of the european society of intensive care medicine's task force for intensive care unit triage during an influenza epidemic or mass disaster task force for mass critical care; task force for mass critical care: surge capacity logistics: care of the critically ill and injured during pandemics and disasters: chest consensus statement task force for mass critical care; task force for mass critical care: surge capacity principles: care of the critically ill and injured during pandemics and disasters: chest consensus statement task force for mass critical care; task force for mass critical care: triage: care of the critically ill and injured during pandemics and disasters: chest consensus statement task force for mass critical care: system-level planning, coordination, and communication: care of the critically ill and injured during pandemics and disasters: chest consensus statement task force for mass critical care; task force for mass critical care: business and continuity of operations: care of the critically ill and injured during pandemics and disasters: chest consensus statement prevention: department of health and human services pandemic influenza plan icu-readiness-assessment-we-are-not-prepared-for/covid- -readiness-assessment-survey-sccm. pdf?lang=en-us icu resource availability for covid- icu telemedicine: from theory to practice determinants of intensive care unit telemedicine effectiveness. an ethnographic study adoption of icu telemedicine in the united states society of critical care medicine: critical care for the non-icu clinician the authors have disclosed that they do not have any potential conflicts of interest.for information regarding this article, e-mail: bishopjm @upmc.edu key: cord- -qn wbnlw authors: kayingo, gerald title: bacteria and viruses: the bogeymen in the intensive care unit date: - - journal: physician assist clin doi: . /j.cpha. . . sha: doc_id: cord_uid: qn wbnlw this article covers the frequently encountered bacteria and viruses in the icu. it focuses on recognition, management, and prevention. emerging and difficult-to-treat organisms are covered in detail. vap is a nosocomial infection of the lung tissue that develops more than hours after intubation in mechanically ventilated patients. critically ill ventilated patients are very susceptible to pneumonia due to an impaired immune system and a breakdown of anatomic barriers that protect the lower respiratory tract. the risk of acquiring vap increases with older age (> years), a history of smoking, alcoholism, prolonged stay in the icu, and chronic comorbid conditions, such as diabetes and chronic obstructive pulmonary disease. there are many etiologic agents for vap. early-onset vap (less than days of mechanical ventilation) is usually caused by haemophilus influenzae, streptococcus pneumoniae, or staphylococcus aureus (methicillin-sensitive). late-onset vap (> days after mechanical ventilation) is usually caused by pseudomonas aeruginosa, acinetobacter species, methicillin-resistant s aureus (mrsa), and multidrug-resistant gram-negative bacilli. clinical signs and symptoms for vap include presence of a new onset of fever, increased productive cough with sputum, leukocytosis, worsening gas exchange, and new pulmonary infiltrates on a chest radiograph. invasive diagnosis with bronchoalveolar lavage is generally recommended to make a definitive diagnosis. for the management of vap, advance practice providers (apps) should direct initial antibiotic therapy against organisms that are known to frequently cause pneumonia in the icu. obtain sputum and blood cultures and initiate appropriate empiric broadspectrum without delay. therapeutic choices include a combination of ceftazidime and ciprofloxacin, when covering p. aeruginosa, and carbapenems, such as imipenem-cilastatin, when covering extended-spectrum b-lactamase (esbl)-producing pathogens, such as klebsiella species. for icus with a high prevalence of mrsa, vancomycin should be used. management of infections in the icu can be challenging due to the rise of multidrugresistant organisms (box ). among the most problematic pathogens are the following: esbl-producing enterobacteriaceae, such as klebsiella species and escherichia coli, which may be resistant to penicillins and cephalosporins for most esbl-producing organisms, carbapenems, such as imipenem and meropenem, are the drugs of choice. p. aeruginosa is one of the leading causes of morbidity in icu patients, especially those with vap. it is also a common cause of icu infections associated with devices and catheters, infections in the urinary tract, and surgical site infections. increasing rates of multidrug resistance have been noted, especially in immunocompromised hosts (box ), those patients with prolonged hospital stays, those patients with invasive devices or mechanical ventilation, and those patients with prior prolonged antibiotic use. risk factors for acquiring pseudomonal infections are age, comorbidities at icu admission (such as anemia and burns), and/or invasive devices. for the treatment of problematic multidrug-resistant pseudomonas, current treatment options include the following combinations: ceftolozane/tazobactam ceftazidime/avibactam piperacillin/tazobactam cefepime, ceftazidime, or a carbapenem plus an additional agent(s), such as colistin, fosfomycin, aminoglycoside, or a quinolone apps working in the icu should optimize dosing, frequency, and longer infusion time. it is good practice to combine time-dependent antibiotics, including piperacillin/tazobactam, cefepime, and imipenem, with concentration-dependent antibiotics, such as ciprofloxacin or levofloxacin. acinetobacter baumannii is also a major cause of vap and bloodstream infections. risk factors include longer icu stay, recent surgery, mechanical ventilation, prior antibiotic exposure. data from the national nosocomial infections surveillance system indicate that resistance of acinetobacter species is on the rise. for the treatment of susceptible isolates of acinetobacter, apps can use broad-spectrum cephalosporins b-lactam-b-lactamase inhibitor combinations carbapenems box antimicrobial resistance and optimizing antibiotic use in the icu the prevalence of multidrug-resistant organisms is increasing in the icu, , leading to increased mortality, longer hospital stays, and higher costs. the emergence of resistance among gram-negative bacteria has significant implications because there are not many therapeutic options. the most encountered resistant pathogens include mrsa, vancomycin-resistant enterococcus, enterobacteriaceae (esbls), p. aeruginosa resistant to imipenem, and fluoroquinolones. features optimizing antibiotic therapy in the icu principles governing antimicrobial therapy in the icu include ensuring adequacy of the initial empiric therapy timing and rapid initiation of empiric broad empiric broad antibiotics source-targeted and tissue-targeted therapy (eg, lungs, urinary tract, catheter, and abdomen) narrow antimicrobial choices based on microbiology and epidemiology data considering host factors, such as immunosuppression and comorbidities initial patient response that should guide need for further work or antibiotic duration treating for the shortest effective duration avoiding unnecessary combination therapy for multidrug-resistant acinetobacter isolates, apps can use polymyxins, such as colistin minocycline tigecycline critically ill and immunocompromised patients are at increased risk for community-acquired, opportunistic, and nosocomial infections. immunocompromised hosts include patients with neutropenia or hematologic malignancy; those patients on corticosteroids and other forms of immunosuppressive therapy; solid transplant patients; patients with hematopoietic stem transplant, hiv/aids, or asplenia; and patients on biologic agents, such as tumor necrosis factor l. the attenuated inflammatory response in these patients make it difficult to make an early diagnosis because clinical signs and symptoms are frequently atypical and nonspecific. because these patients are always put on various prophylactic antimicrobials and have multiple hospitalizations, they are also at increased risk for multidrug-resistant organisms. most infections in the immunocompromised patients present in a hierarchical pattern depending on the level of immunosuppression, neutropenia, and cd counts. because morbidity and mortality are very high, early empiric antimicrobial therapy is universally indicated. bacterial pneumonia, bacteremia, gastrointestinal (gi), and central nervous system infections occur at high frequency in hiv/aids patients, depending on cd levels. common pathogens include mycobacterium tuberculosis, pneumocystis, p. aeruginosa, endemic mycoses, candida species, histoplasma capsulatum, coccidioides species, toxoplasma gondii, and listeria monocytogenes. pathogens frequently encountered when the cd levels less than include mycobacterium avium complex, cryptococcus neoformans, cmv, herpes simplex virus (hsv), and varicella-zoster virus (vzv), although the advent of antiretroviral therapy has reduced the incidence of these pathogens. s aureus, streptococcus pneumoniae, and haemophilus influenzae are the most common fatal bacterial infection in these patients irrespective of cd levels. diarrhea in hiv/aids patients is often caused by protozoa cryptosporidium parvum. immune reconstitution inflammatory syndrome, a life-threatening complication of antiretroviral therapy, may occur, leading to an exuberant inflammatory response against a pathogen that may previously been latent. gram-positive organisms are on the rise in neutropenia patients. these include staphylococcus, streptococcus, enterococcus, and corynebacterium species. gram-negative bacilli include pseudomonas, escherichia, and klebsiella species. empiric therapy covering both gram-negative and gram-positive organisms is recommended for febrile neutropenic patients patients who have undergone solid organ transplantation present with a broad spectrum of infections overtime. during the postoperative period, the common infections include health care-associated pneumonia, urinary tract infections, and catheter-associated and device-associated infections. the risk of opportunistic infections increases over time due to immunosuppressive therapy to prevent organ rejection. viruses are increasingly being recognized as a major cause of morbidity in the icu. table shows the commonly encountered species and their clinical features, workup, management, and prevention. in the icu, viral illness can be community acquired or nosocomial. viruses can lead to multiple organ system complications. the most commonly affected systems are the respiratory, gi, neurologic systems, skin, and mucous membranes, which all eventually may lead to sepsis. viral infections are also a major source of morbidity in the neonatal icus (box ) and are also a leading cause of central nervous system infections (box ). prompt diagnosis and antiviral therapy are key to good outcomes. for long-term and population-wide prevention, immunization, prophylaxis, and infection control should routinely be encouraged. viral community-acquired pneumonia is frequently caused by influenza followed by other respiratory viruses, such as parainfluenza, rhinovirus, adenovirus, rsv, and coronaviruses. the symptoms of viral pneumonia may vary from fever to myalgia to arthralgia headache to shortness of breath to cough and to acute respiratory distress syndrome. apps working in the icu need to recognize viral community-acquired pneumonia early and manage it aggressively to prevent complications and improve outcomes. the diagnosis can be made clinically and then confirmed by serology, polymerase chain reaction (pcr), or culture. treatment is mostly supportive. if the causative agent is influenza, oseltamivir therapy is recommended for adult patients. it can shorten the duration of symptoms and improve outcomes in severe cases. vaccination is the best preventative measure for these viruses. nosocomial viral pneumonia in the icu is frequently caused by herpesviridae family of viruses, which include hsv and cytomegalovirus (cmv). immunocompromised patients are particularly at high risk (see box ). hsv can be detected in the throat and the most common nosocomial bacterial species among neonates are staphylococcus, enterococci, enterobacter, e coli, and group b streptococcus. the bloodstream is among the most frequent site of nosocomial infection followed by nosocomial pneumonia; gi; and eye, ear, nose, and throat sites. the major risk factors are poor umbilical handling and central intravenous catheter use. outbreaks of viral infections in the neonatal icus are commonly caused by rotavirus, rsv, enterovirus, hepatitis a virus, and adenovirus. nosocomial infections can be transmitted via droplet spread, hands of infected hospital personnel and other individuals, contaminated medical equipment, and breast milk from infected mothers. other pathogens, such as hiv, hepatitis b/c, hsv, vzv, and cmv, can be transmitted vertically from infected mothers. the clinical manifestations can be severe requiring mechanical ventilation. complications associated with nosocomial viral infections can be grouped into . respiratory complications, such as rsv, influenza, parainfluenza, adenoviruses, and coronaviruses . gi complications, such as rotavirus (the most common gi virus for infants) . systemic disease, such as enterovirus and parechovirus in critically ill patients, central nervous infections, such as meningitis and encephalitis, cause significant morbidity and mortality if not diagnosed early and treated promptly. bacterial infections can lead to meningitis, brain abscess, subdural empyema, and sepsis. viral infections can also cause meningitis, encephalitis, optic neuritis, and poliomyelitis. meningitis is characterized by the inflammation of the meninges surrounding the brain and the spinal cord. a triad of fever, nuchal rigidity, and altered mental status in most but not all patients cranial nerve palsies, nausea, vomiting, headaches, and photophobia encephalitis is inflammation within the brain parenchyma. clinical presentation is variable depending on the brain cells affected. patients are more likely to present with altered level of conscience or confusion, coma, and focal or generalized seizures. suspected patients should receive neuroimaging before lumbar puncture. bacterial meningitis is confirmed by cerebrospinal fluid (csf). positive findings for bacterial meningitis include elevated opening pressure polymorphonuclear cell predominance decreased glucose concentration elevated protein concentration in viral meningitis, opening pressure is usually normal, there is lymphocyte predominance, and csf glucose is usually normal. the antimicrobial agent of choice must penetrate the blood-brain barrier and should be based on patient age and risk factors. vancomycin plus ceftriaxone is the preferred empiric therapy. ampicillin should be added to the initial empiric therapy in children, immunocompromised hosts, and the elderly (> years). patients with viral encephalitis can be managed with acyclovir. respiratory secretions by pcr. hsv and cmv are responsive to treatment with acyclovir and ganciclovir, respectively. apps should ensure universal control precautions when managing these patients. patients in icus are more prone to infections and are more likely develop multidrugresistant organisms and have poor outcomes. multidrug resistance increases mortality and length of stay and is largely responsible for the escalating health care costs in the united states. , the clinical manifestations of bacterial and viral infections are highly variable in the icu patient, ranging from severe respiratory disease to sepsis (box ). early recognition and empiric therapy are recommended but apps must use antibiotics wisely. icu apps should use appropriate initial empiric therapy and de-escalate once cultures and box dealing with sepsis and systemic inflammatory response syndrome in the icu sepsis is a systemic inflammatory response syndrome that results from an infection. sepsis is described as severe if a patient develops end-organ dysfunction and hypotension that is not responsive to fluid resuscitation. the spectrum of sepsis causing pathogens is rapidly changing from predominantly gramnegative organisms to gram-positive organisms. hemodynamic and tissue perfusion changes in a septic patient may include arterial hypotension hyperlactatemia (> mmol/l) decreased capillary refill when sepsis is suspected, clinicians should rapidly administer broad-spectrum antibiotics. the surviving sepsis campaign bundle recommends the following: measure and monitor lactate level. obtain blood cultures prior to administration of antibiotics. begin rapid administration of crystalloid to manage hypotension and elevated lactate (> mmol/l). apply vasopressors if patient is hypotensive during or after fluid resuscitation to maintain mean arterial pressure mm hg. managing a sepsis patient involves a lot of supportive care. the first few hours should be dedicated to restoring adequate perfusion, providing antibiotics, and optimizing oxygen supply and demand susceptibility data are available. the emerging and re-emerging infectious pathogens as well as drug resistance involving enterobacteriaceae species, acinetobacter baumannii, and pseudomonas should be considered a major threat to public health. there is a need for the development of new and more effective drugs. vaccinations and effective infection control practice should be emphasized globally. international study of the prevalence and outcomes of infection in intensive care units device-associated nosocomial infection rates in intensive care units at cairo university hospitals: first step toward initiating surveillance programs in a resource-limited country the washington manual of critical care critical care medicine e-book: principles of diagnosis and management in the adult comparison of vs days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial infection in solid-organ transplant recipients nosocomial infections among neonates in high-risk nurseries in the united states. national nosocomial infections surveillance system lumbar puncture in pediatric bacterial meningitis: defining the time interval for recovery of cerebrospinal fluid pathogens after parenteral antibiotic pretreatment the high cost of acute health care: a review of escalating costs and limitations of such exposure in intensive care units antibiotics and bacterial resistance in the st century the surviving sepsis campaign bundle: update key: cord- - ij pjjy authors: nopp, stephan; moik, florian; jilma, bernd; pabinger, ingrid; ay, cihan title: risk of venous thromboembolism in patients with covid‐ : a systematic review and meta‐analysis date: - - journal: res pract thromb haemost doi: . /rth . sha: doc_id: cord_uid: ij pjjy background: venous thromboembolism (vte) is frequently observed in patients with coronavirus disease (covid‐ ). however, reported vte‐rates differ substantially. objectives: we aimed at evaluating available data and estimating the prevalence of vte in covid‐ patients. methods: we conducted a systematic literature search (medline, embase, who covid‐ database) to identify studies reporting vte‐rates in covid‐ patients. studies with suspected high risk of bias were excluded from quantitative synthesis. pooled outcome rates were obtained within a random effects meta‐analysis. subgroup analyses were performed for different settings (intensive care unit (icu) vs. non‐icu hospitalization and screening vs. no screening) and the association of d‐dimer levels and vte‐risk was explored. results: eighty‐six studies ( , patients) were identified and ( , patients, mean age: . years, % men, % icu‐patients) were included in quantitative analysis. the overall vte‐prevalence estimate was . % ( %ci . ‐ . ), . % ( %ci . ‐ . ) with ultrasound‐screening and . % ( %ci . ‐ . ) without screening. subgroup analysis revealed high heterogeneity, with a vte‐prevalence of . % ( %ci . ‐ . ) in non‐icu and . % ( %ci . ‐ . ) in icu patients. prevalence of pulmonary embolism (pe) in non‐icu and icu patients was . % ( %ci . ‐ . ) and . % ( %ci . ‐ . ). patients developing vte had higher d‐dimer levels (weighted mean difference . µg/ml ( %ci . ‐ . ) than non‐vte patients. conclusion: vte occurs in . % of patients with covid‐ in the icu, but vte risk is also increased in non‐icu hospitalized patients. patients developing vte had higher d‐dimer levels. studies evaluating thromboprophylaxis strategies in patients with covid‐ are needed to improve prevention of vte. the coronavirus disease , caused by the severe acute respiratory syndrome coronavirus (sars-cov- ) and formally declared a pandemic by the world health organization (who) in march , is an infectious disease with a global impact on public health. it affects primarily the respiratory system, however, involvement of other organ systems may occur, especially with increasing severity of the disease. the high inflammatory burden associated with covid- and inflammation in the vascular system can also result in cardiovascular complications with a variety of clinical presentations. [ ] [ ] [ ] early studies already reported on coagulation abnormalities and coagulopathy with a rather prothrombotic phenotype in patients with ] with the better understanding of covid- and its clinical course, venous thromboembolism (vte), a disease entity covering pulmonary embolism (pe) and deep vein thrombosis (dvt), has been recognized as a particular complication of the disease. initial studies have found alarmingly high rates of pe in patients with severe covid- treated at intensive care units (icu), reporting vte incidences of up to %. [ ] in response to the clinical challenges and the absence of high-quality evidence, experts groups and scientific societies have released guidance statements to address questions concerning diagnosis, prevention, and treatment of vte in patients with covid- which suggest the broad application of thromboprophylaxis in patients with severe covid- in the absence of high bleeding risk. [ , ] in several studies of different design, size, and quality, rates of vte in patients with covid- have been reported. however, a definitive and robust estimate of the vte risk in patients with covid- is currently not available as of the high variability of reported rates. therefore, the true underlying burden of vte in covid- patients is still not fully understood. in the light of the ever-growing infection rates worldwide and the clinical challenges in patient management, understanding of the true frequency of vte in covid- is important and may help to support clinical decision making. we conducted a systematic review of the literature and meta-analysis of available data to determine the prevalence of vte in patients with covid- . our aim was to provide an overall estimate of vte by aggregating reported rates and to thoroughly accepted article explore differences in the vte prevalence according to study design and the health care setting, which may account for the high degree of heterogeneity in reported rates. this article is protected by copyright. all rights reserved we conducted a systematic review of the literature and meta-analysis of published data on the prevalence of vte in patients with covid- . the study protocol was prepared prior to the initiation of the literature research according to the preferred reporting items for systematic review and meta-analysis protocols (prisma-p) [ ] and submitted to prosepero (international prospective register of systematic reviews) on june th , (protocol-id: crd ). the study was conducted according to the "preferred reporting items for systematic reviews and meta-analyses" (prisma) and the guidance for reporting meta-analysis of observational studies in epidemiology (moose) . [ , ] full-text articles, letters, brief reports, editorials, and correspondences published in or with available title and abstract in english were eligible for inclusion. inclusion criteria comprised studies reporting on patients with objectively confirmed covid- in combination with reporting rates of vte as outcome of the study (dvt and/or pe). study designs eligible for inclusion were cohort studies (prospective and retrospective), cross-sectional studies, and interventional studies with vte reported as an outcome or adverse event. study designs that did not allow prevalence estimates such as case reports and case-series including autopsy studies were excluded. we systematically searched embase, medline, and the who covid- research database with distinct predefined search algorithms to identify relevant publications. the exact search protocol is available in the supplementary methods. search for additional studies not identified by the search criteria (e.g. due to pre-print status) was conducted by inquiring databases of pre-print servers (medrxiv) and by manual research of relevant journals. publications in pre-print status were only eligible if they had undergone full peer-review at the date of literature research. duplicate search this article is protected by copyright. all rights reserved results were excluded prior to eligibility screening. two researchers (sn, fm) screened title and abstract of the identified studies and potentially eligible studies underwent fulltext evaluation. the inclusion of a study was based on the consensus of its suitability by the two researchers. where consensus opinion could not be reached, a third reviewer was consulted to make the final decision (ca). all three literature researchers are medical doctors with a thorough research background in the field of thrombosis. the most recent literature research was conducted on august th , . figure displays the process of study identification following a prisma flow-diagram. studies that fulfilled the predefined inclusion criteria and did not meet any exclusion criteria were subjected to data extraction. in the case of multiple studies reporting on the same patient cohort, results were merged and considered only once. data extraction of pre-defined baseline and outcome variables was performed. these included methodological specifics of the studies (study design, health care setting), clinical information of the study population (demographics, comorbidities, disease severity, use of pharmacological thromboprophylaxis, ultrasound screening, and d-dimer levels), and outcome specifics (definition, type, and rate of vte). the full list of extracted variables is provided in the supplementary methods. all data were independently extracted from eligible studies by two authors (sn, fm) to ensure data reliability, with inconsistencies resolved by discussion with a third author (ca). methodology of identified studies was assessed independently by two researchers (fm & sn) . risk of bias of included studies was independently rated with a validated tool for assessing studies reporting prevalence data (joanna briggs institute critical appraisal checklist; supplementary appendix). [ ] this tool consists of categories each classifying the study as low risk of bias, high risk of bias, or unclear. subsequently, an overall evaluation based on these categories was derived. studies with suspected high risk of bias were excluded from the subsequent quantitative data synthesis. potential this article is protected by copyright. all rights reserved publication bias was assessed graphically within a funnel-plot, plotting the prevalence estimate of vte against its' standard error (supplementary figure s a&b) . the primary outcome of the present meta-analysis is vte, defined as dvt (including catheter-related thrombosis), pe, or the composite of both, as defined within the respective study. thrombotic occlusions of mechanical components of extracorporeal devices such as dialysis machines or ecmo devices were not counted as outcome event. the prevalence estimate of the primary outcome is reported stratified by the use of systematic ultrasound screening for thrombosis in the respective studies. secondary outcomes included (i) the pooled prevalence of vte (excluding studies only reporting isolated pe or isolated dvt rates), (ii) the pooled rate of pe, and (iii) the pooled rate of dvt. outcomes of the secondary analyses were reported stratified for icu patients and non-icu hospitalized patients at study baseline and by the performance of dvt screening. the icu cohort comprised patients admitted to the icu, or alternatively those who were defined as being critically ill, or in need of mechanical ventilation at baseline. further, an exploratory analysis of differences between baseline levels of ddimer between patients experiencing vte and those who did not was conducted. outcome definitions throughout the different studies were varying. some studies reported pure incidence, while others reported prevalence, e.g. including patients who have been admitted due to vte and covid- . in this systematic review, we have decided to aggregate the proportion of patients, who have been diagnosed with vte as reported in the included studies. all statistical analyses were performed with the commercially available package stata . (stata corp., houston, tx, usa). summary statistics were aggregated from included studies. pooled prevalence of outcome variables was estimated by aggregating study results within a random-effects meta-analysis utilizing the stata package this article is protected by copyright. all rights reserved metaprop. [ ] the freeman-tukey double arcsine transformation was utilized to normalize variance, and % confidence intervals (ci) were estimated by the score method. heterogeneity of included studies is reported by i as a measure of betweenstudy variability beyond random variation. to explore differences in baseline d-dimer between vte and non-vte patients, mean d-dimer levels and corresponding standard deviation were calculated from reported median, interquartile range (iqr) and sample size according to wan et al. [ ] weighted mean differences (wmd) in baseline d-dimer levels were calculated within a pooled-analysis weighted by corresponding sample sizes. lastly, differences in vte risk according to sex and comorbidities was explored within a random effects meta-analysis utilizing the mantel-haenszel procedure. we identified records upon literature research after the removal of duplicates. title and abstract of these identified studies were screened for conformity with our predefined in-and exclusion criteria and records were subsequently included in the full-text evaluation. from those, studies were included in the qualitative data synthesis. figure displays the screening and selection process, and the reasons for excluding studies. pooled summary characteristics of the eligible studies reporting on vte in covid- patients are displayed in table this article is protected by copyright. all rights reserved a comprehensive summary of each study including the respective study design, demographics, thromboprophylaxis strategy, and outcome rates is presented in tables s & . pooled patient characteristics and comorbidity data are displayed in table . the overall weighted mean age of patients was . years (standard deviation [sd] . ) and % were male. weighted mean age of patients in icu-only studies was . years (sd . ) and . % were male. risk of publication bias was evaluated separately for studies on non-icu hospitalized and icu patients to enhance interpretability. upon visual inspection of the funnel plots, no indication for publication bias was detected, with outliers in the distribution being explained by differences in ultrasound screening strategies. (figures s a&b) secondly, we conducted an exploration of potential time-dependencies in vte rates of published studies suggesting a decrease of vte rates over time upon visual inspection and fitting a regression line of the vte rate and the last patient inclusion date of each respective study. (figure s ) thirdly, a methodological assessment of included studies was conducted in order to evaluate the risk of underlying bias regarding the reported rate of vte. importantly, this evaluation is not to be regarded as a general evaluation of quality and goodness of included studies but rather an evaluation of the generalizability of reported vte rates. in our quality assessment, low risk of bias was attributed to our identified studies in median in of categories (range: - , maximum: low risk of bias in all categories). the results of our structured methodological assessment of all studies are presented in table s . in consensus among the reviewers, studies were excluded from quantitative synthesis upon a strong suspicion of bias in the structured assessment. reasons for exclusion include selection bias ( studies), reporting/information bias ( study), and lack of background information on setting and outcomes ( study). therefore, the remaining studies (including studies reporting on icu patients and studies this article is protected by copyright. all rights reserved reporting on non-icu hospitalized patients) were included in quantitative data synthesis. [ , - ] after excluding studies with a high risk of underlying bias, quantitative results from studies were aggregated within a meta-analysis, including , patients ( , figure shows a forrest plot of vte rates, together with information on health care setting, the performance of screening and outcome definition of respective studies. the rates of vte within our primary analysis strongly differed between studies, depending on the specifics of the study setting, design, and outcome definition. therefore, in order to further explore heterogeneity of the reported vte rates, we conducted detailed subgroup analyses based on the health care setting (non-icu hospitalized vs. icu patients), and the performance of dvt screening (screening vs. no screening). in addition, within these subgroup analyses, we have separately estimated rates of vte, pe, and dvt. available baseline characteristics of patients with vte compared to those without vte were aggregated and analyzed weighted by sample size of the respective study (table ) . mean weighted age of vte and non-vte patients was similar, with a mean age of . years (sd . ) and . years (sd . ), respectively. men were . times more likely to develop vte ( %ci: . - . ), while comorbidities did not differ between the two groups. d-dimer levels at baseline were available in studies, including , patients. patients developing vte had higher baseline d-dimer levels compared to those without vte (weighted mean d-dimer levels: . µg/ml (sd . ) vs. . µg/ml (sd . )) with a wmd of . µg/ml ([ %ci: . - . ], p < . ; i²: . %). (figure ) this article is protected by copyright. all rights reserved in this systematic review and meta-analysis, data from studies reporting on rates of vte in patients with covid- were aggregated to estimate the prevalence of vte. we found that the burden of vte associated with covid- is substantial, with an overall vte prevalence estimate of . % across all identified studies. however, rates of vte varied across different health care settings (icu vs. non-icu hospitalized patients), depending on whether systematic screening was performed or not, and on outcome definitions in the selected studies. in subgroup analysis, rates of vte ranged from . % in non-icu hospitalized patients without ultrasound screening to . % in icu patients undergoing screening strategies. since no pe screening was performed, the pe prevalence of . % in non-icu hospitalized patients and . % in icu patients might provide a robust estimate and strongly highlights the high risk of vte in patients with covid- , especially in those requiring intensive medical care. it is known from large clinical trials in critically ill patients with various underlying diseases that the rate of vte in the icu setting is elevated, with vte rates ranging from to %. [ ] [ ] [ ] [ ] [ ] higher vte rates in covid- patients in the icu and also non-icu this article is protected by copyright. all rights reserved interestingly, autopsy studies in covid- patients revealed severe endothelial injury, endotheliitis, increased angiogenesis, and widespread vascular thrombosis with microangiopathy and occlusion of alveolar capillaries. [ , , [ ] [ ] [ ] based on such findings, the aetiology of the increased pe rates reported in covid- patients has been discussed and two not mutually exclusive pathomechanisms have been proposed. on the one hand, it has been suggested that in-situ pulmonary thrombi, which develop on the basis of diffuse alveolar and local vascular damage, microangiopathy, and inflammation in the pulmonary circulation triggered by the virus, rather than "classical" pe itself may contribute to the high prevalence of pe observed in patients with on the other hand, dvt rates of up to % in studies, where ultrasound screening was performed in icu patients, support the hypothesis of embolism originating from peripheral thrombosis rather than pulmonary in-situ thrombosis largely contributes to the substantial burden of pulmonary artery occlusion observed in patients with covid- . however, the exact role, data on frequency, and clinical consequences of in-situ pulmonary thrombosis in covid- need further investigations. we believe that our meta-analysis is representative of covid- patients requiring hospitalization, as our systematic review confirmed the previously reported sex differences in covid- patients (higher proportion of men among more severe disease). [ ] the sex differences further increased among patients admitted to the icu suggesting that men were more likely to suffer from greater disease severity than women. [ ] correspondingly, men were at higher risk to develop vte, but we observed no association between comorbidities and risk of vte. interestingly, age did not differ between the groups. this suggests that in contrast to the general population, age did not contribute to the vte risk in covid- patients. [ ] similar results have been reported for vte risk in patients with cancer suggesting that the high vte baseline risk of the underlying disease overwhelms general risk factors such as age. [ ] furthermore, explorative analysis has revealed that d-dimer levels were higher in patients developing vte compared to those who remained free from a vte event. our findings support guidance statements from experts and scientific societies which suggest that thromboprophylaxis is a key element in the medical care of patients with covid- , especially in those with severe illness. [ , , [ ] [ ] [ ] however, vte this article is protected by copyright. all rights reserved occurred in many patients despite the use of thromboprophylaxis, and even patients with therapeutic anticoagulation developed vte. therefore, the ideal anticoagulation approach to reduce the high risk of vte in patients with covid- needs to be established. further, the observed higher baseline d-dimer levels in patients who had vte strengthens the idea that d-dimer-guided thromboprophylaxis strategies should be evaluated in prospective randomized-controlled trials. the main limitation of our meta-analysis is the high heterogeneity of included studies with regard to design, clinical setting, local practice (e.g. with respect to thromboprophylaxis strategies), and consequently highly variable event rates. additionally, the disproportionate number of icu studies with higher vte rates than the general ward population may confound the overall estimation of vte prevalence in patients with covid- . to address this issue, we aimed at thoroughly describing the respective clinical settings and provide subgroup analysis, e.g. icu vs. non-icu hospitalized patients or according to diagnostic approaches (studies with screening vs. no screening for dvt) to provide a more precise estimate of vte rates. further, early reports of high vte rates in patients with covid- might have led to the implementation of more specific and intensive thromboprophylaxis approaches over time, which might have confounded the outcomes in subsequently conducted studies. we have analyzed studies according to the date of the last patient recruitment and visual inspection reveals a decrease of vte rates of reported studies over time ( figure s ) . we also provided data on thromboprophylaxis modalities for the respective studies to allow a better interpretation of differences observed in the studies. however, the generalizability of the results of our systematic review and meta-analysis still needs to be interpreted with caution, because only data from patients in north america, europe, and asia were available and included in the meta-analysis. upon visual inspection, vte rates across continents and countries seem to be mainly related to between-study heterogeneity with respect to study design, clinical setting, and local clinical practice with regard to thromboprophylaxis ( figure s ) . given the high mortality especially in icu patients with covid- , competing risk of death might lead to an underdiagnosis of vte. further, the concern of restricting the use of imaging to avoid disease exposure to healthcare worker might further lead to this article is protected by copyright. all rights reserved false-low rates of vte in patients with covid- . these uncontrollable factors in a study level analysis should be considered upon interpreting and generalizing our findings. also, the practice of avoiding imaging due to concerns about healthcare worker exposure should be critically reviewed given the risk of underdiagnosis and consequently undertreatment of patients. furthermore, exploratory analysis of d-dimer levels between patients developing vte and those who did not is limited by the lack of patient-level data and the inability to adjust for between assay variability. therefore, this exploration should be interpreted with appropriate caution and regarded as hypothesis generating. lastly, there is some evidence that non-hospitalized covid- patients are at increased risk of developing vte as well. [ ] as of the unavailability of sufficient data within our meta-analysis, we were unable to provide prevalence estimates for this population of patients and our findings are therefore not representative for the outpatient setting of covid- . in summary, we found a high prevalence of vte in patients with covid- in hospitalized non-icu patients, and especially high vte rates in those being critically ill and requiring intensive medical care. there is a clinical need for further research to better understand the risk and prevent vte in patients with covid- . these findings support the broad use of thromboprophylaxis, specifically in icu patients. future randomized clinical trials are needed to assess whether patients with covid- may benefit from an intensified anticoagulation approach compared to standard thromboprophylaxis or whether a biomarker-based personalized thromboprophylaxis regimen reduces the high prevalence of vte in patients with covid- . this article is protected by copyright. all rights reserved addendum author contributions: s. nopp and f. moik contributed to study design, data collection, data interpretation, statistical analysis, and drafting of the manuscript. c. ay contributed to study design, data interpretation, and critical review of the manuscript. i. pabinger contributed to data interpretation and critical review of the manuscript. s. nopp, f. moik, c. ay are the guarantor of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. all authors have read the manuscript and approved its submission. this article is protected by copyright. all rights reserved pulmonary embolism in covid- patients: awareness of an increased prevalence venous and arterial thromboembolic complications in covid- patients admitted to an academic hospital in acute pulmonary embolism associated with covid- pneumonia detected by pulmonary ct angiography venous thromboembolism in critically ill patients with covid- : results of a screening study for deep vein thrombosis clinical characteristics of covid- in remdesivir for the treatment of covid- -preliminary report impact of anticoagulation prior to covid- infection: a propensity score-matched cohort study anakinra for severe forms of covid- : a cohort study venous thrombosis among critically ill patients with coronavirus disease (covid- ) diagnosis of venous and arterial thromboembolic events in covid- virus-infected patients systematic screening for venous thromboembolic events in covid- pneumonia. th open : companion journal to thrombosis and haemostasis high prevalence of early asymptomatic venous thromboembolism in anticoagulated covid- patients hospitalized in general wards higher intensity thromboprophylaxis regimens and pulmonary embolism in critically ill coronavirus disease patients disease in covid- incidence of deep vein thrombosis among non-icu patients hospitalized for covid- despite pharmacological thromboprophylaxis infanta leonor thrombosis research g. incidence of pulmonary embolism in noncritically ill covid- patients. predicting factors for a challenging diagnosis incidence of thrombosis and hemorrhage in hospitalized cancer patients with covid- prevalence and outcomes of d-dimer elevation in hospitalized patients with covid- . arteriosclerosis, thrombosis, and vascular biology pulmonary embolism and screening for concomitant proximal deep vein thrombosis in noncritically ill hospitalized patients with coronavirus disease . internal and emergency medicine all rights reserved investigators ftcc-f. pulmonary embolism in covid- patients: a french multicentre cohort study pulmonary embolism in hospitalised patients with covid- rate of venous thromboembolism in a prospective all-comers cohort with covid- safety of intermediate dose of low molecular weight heparin in covid- patients the hazard of (sub)therapeutic doses of anticoagulants in non-critically ill patients with covid- : the padua province experience thrombosis in hospitalized patients with covid- in a new york city health system thrombotic complications and anticoagulation in covid- pneumonia: a new york city hospital experience utility of d-dimers and intermediate-dose prophylaxis for venous thromboembolism in critically ill patients with covid- venous thromboembolism in noncritically ill patients with covid- infection characteristics and early outcomes of patients hospitalised for covid- in north zealand, denmark journal of vascular surgery: venous and lymphatic disorders comparison of venous thromboembolism risks between covid- pneumonia and community-acquired pneumonia patients. arteriosclerosis, thrombosis, and vascular biology covid- in critically ill patients in north brabant, the netherlands: patient characteristics and outcomes covid- in patients with rheumatic diseases in northern italy: a single-centre observational and case&#x ;control study deep vein thrombosis in sars-cov- pneumonia-affected patients within standard care units: exploring a submerged portion of the iceberg detection of pulmonary embolism in returning travelers with hypoxemic reunion island early detection of deep vein thrombosis in patients with coronavirus disease : who to screen and who not to with doppler ultrasound factors associated with pulmonary embolism among coronavirus disease frequency and clinical correlates of antiphospholipid antibodies arising in patients with sars-cov- infection: findings from a multicentre study on cases non-overt coagulopathy in non-icu patients with mild to moderate covid- pneumonia pulmonary embolism or pulmonary thrombosis in covid- ? accepted article this article is protected by copyright. all rights reserved is the recommendation to use high-dose heparin for thromboprophylaxis justified? failure of anticoagulant thromboprophylaxis: risk factors in medical burden of illness in venous thromboembolism in critical care: a multicenter observational study a comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome state of knowledge and data gaps of middle east respiratory syndrome coronavirus (mers-cov) in humans pandemic h n influenza infection and vascular thrombosis endotheliopathy in covid- -associated coagulopathy: evidence from a single-centre, cross-sectional study role of von willebrand factor and adamts- in the pathogenesis of thrombi in sars-cov- infection: time to rethink. thrombosis and haemostasis hypercoagulability of covid- patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis covid- and thrombotic complications: pulmonary thrombosis rather than embolism? thrombosis research the vascular endothelium: the cornerstone of organ dysfunction in severe sars-cov- infection immune mechanisms of pulmonary intravascular coagulopathy in covid- pneumonia covid- patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region the epidemiology of venous thromboembolism prediction of venous thromboembolism in cancer patients coagulopathy in covid- and its implication for safe and efficacious thromboprophylaxis covid- and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up prevention, diagnosis, and treatment of vte in patients with covid- : chest guideline and expert panel report /total (%) of patients no./total (%) of icu dyslipidaemia , icu, intensive care unit this study was supported by research funding from the austrian science fund (fwf) this article is protected by copyright. all rights reserved key: cord- -mfde juv authors: li, bo; yang, jing; zhao, faming; zhi, lili; wang, xiqian; liu, lin; bi, zhaohui; zhao, yunhe title: prevalence and impact of cardiovascular metabolic diseases on covid- in china date: - - journal: clin res cardiol doi: . /s - - - sha: doc_id: cord_uid: mfde juv background: studies have reminded that cardiovascular metabolic comorbidities made patients more susceptible to suffer novel corona virus ( -ncov) disease (covid- ), and exacerbated the infection. the aim of this analysis is to determine the association of cardiovascular metabolic diseases with the development of covid- . methods: a meta-analysis of eligible studies that summarized the prevalence of cardiovascular metabolic diseases in covid- and compared the incidences of the comorbidities in icu/severe and non-icu/severe patients was performed. embase and pubmed were searched for relevant studies. results: a total of six studies with patients were included in this analysis. the proportions of hypertension, cardia-cerebrovascular disease and diabetes in patients with covid- were . %, . % and . %, respectively. the incidences of hypertension, cardia-cerebrovascular diseases and diabetes were about twofolds, threefolds and twofolds, respectively, higher in icu/severe cases than in their non-icu/severe counterparts. at least . % patients with covid- suffered the acute cardiac injury. the incidence of acute cardiac injury was about folds higher in icu/severe patients compared with the non-icu/severe patients. conclusion: patients with previous cardiovascular metabolic diseases may face a greater risk of developing into the severe condition and the comorbidities can also greatly affect the prognosis of the covid- . on the other hand, covid- can, in turn, aggravate the damage to the heart. during the past two decades, the outbreak and prevalence of severe acute respiratory infections have been seen as one of the most serious hazards to global health. both two prominent coronaviruses, sars-cov and mers-cov, have markedly affected humans, causing and infections, as well as and deaths, respectively [ , ] . in early december , a series of pneumonia cases with unknown reason emerged in wuhan, hubei, china. highthroughput sequencing from lower respiratory tract samples has revealed a novel coronavirus that was named novel coronavirus ( -ncov) and also named sars-cov- [ ] . as of february th, , , confirmed cases and death cases have been documented in china. -ncov also targets the respiratory tract and shares many similar clinical symptoms with sars-cov and mers-cov [ ] . common symptoms include fever, fatigue, and dry cough, followed always by anorexia, myalgia, dyspnea, and so on bo li and jing yang contributed equally to this article. * bo li libosubmit@ .com * yunhe zhao zhaoyunhe@medmail.com.cn [ ] [ ] [ ] [ ] [ ] . lymphopenia and prolonged prothrombin time are also the most common characteristics [ ] [ ] [ ] . in addition, as cardiologists, we are also concerned about whether patients with cardiovascular disease are at greater risk for -ncov, and whether new coronavirus infections have an impact on the cardiovascular system. previous studies have shown a relationship between cardiovascular metabolic diseases and sars and mers [ ] [ ] [ ] . a systematic analysis of mers-cov cases showed that diabetes and hypertension are prevalent in about % of the patients and cardiac diseases are present in % of the cases [ ] . diabetes was seen as an independent predictor for mortality and morbidity in patients with sars [ ] . with the spread of -ncov and increase of the cases, more and more -ncov infected individuals exhibit comorbidities such as hypertension, diabetes and cardia-cerebrovascular disease. in chen's study of cases, % patients had cardia-cerebrovascular disease [ ] , and in huang's study of cases, % patients had diabetes [ ] . these cardiovascular metabolic comorbidities might render them more susceptible to poor prognosis. given the rapid spread of -ncov, an updated meta-analysis with significantly larger sample sizes by integrating the published studies is urgently warranted. accordingly, the present analysis will not only identify the cardiovascular epidemiological and clinical characteristics of -ncov infection with greater precision but also unravel the impact of the infection on the cardiac injury. preferred reporting items for systematic reviews and meta-analyses of individual participant data (the prisma-ipd) statement was followed for the conduct and reporting of this meta-analysis [ ] . to identify all the studies illustrating the prevalence and impact of cardiovascular metabolic diseases in novel coronavirus infection in china, embase and pubmed were carefully searched from december to february . the following search terms or keywords were used alone or in combination: 'novel coronavirus', 'influenza', 'pneumonia', 'cardiovascular disease', 'hypertension', 'diabetes' and 'cardiac injury'. inclusion criteria are as follows: ( ) comparative studies: randomised controlled trials rcts or non-rcts published in english; ( ) study population: more than ten participants were included in the study; ( ) study intervention: patients in the studies should be confirmed to have been infected by novel coronavirus; ( ) parameters: the comorbidities of cardiovascular metabolic diseases and the outcome of cardiac injury should be given. case reports, non-human studies, studies without adequate information, and studies written in chinese (for the fear of data duplication) were excluded in the present meta-analysis. prevalence of comorbidities including hypertension, cardiovascular and cerebrovascular diseases and diabetes (table and fig. ) together with clinical outcome of cardiac injury (confirmed by elevation of troponin i/t, or the creatine kinase seen as the second choice if troponin i/t were not provided) were extracted from the identified studies (table and fig. ). the primary outcome measure was to compare the prevalence of comorbidities and impact on cardiac injury in icu and non-icu cases (severe and non-severe data as the second choice if icu data was not provided). cochrane collaboration's tool was followed to assess the risk of bias. all analyses were performed using openmeta analyst version . (https ://www.cebm.brown .edu/open_meta) and revman software version . . forest plots were used to illustrate the prevalence of the cardiovascular metabolic diseases in -ncov infection severity from the selected studies as well as the impact of the -ncov infection on the cardiac injury. the results of the included studies were performed with fixed-effect models (mantel-haenszel method) [ ] or random-effect models in cases of significant heterogeneity between estimates [ ] . we used the i statistics to assess the magnitude of heterogeneity: %, %, and % represented low, moderate, and high degrees of heterogeneity, respectively. the chosen of the proper effect model was based on the analysis results: the fixed effect model was used if i < % and the random effect model was used if i ≥ % [ ] . after initially identifying articles, duplicate documents were identified. of the leaving trials, after review of the titles and abstracts, documents of non-human researches, reviews and studies that were not clinical trials were excluded. the leaving studies were carefully and detailed evaluated. at last, six studies were excluded, because the participants of the trials did not meet the criteria we have set. then one study published in medrxiv was added. finally, a total of six studies with patients were included [ - , , , ] (fig. ). all of the selected studies were published in with different sample patient sizes that ranged from to patients ( table summarizes the study characteristics). systematic analysis of studies that described the epidemiological and clinical features of covid- cases and reported the prevalence of cardiovascular metabolic diseases as well as the impact on cardiac injury in the infectious disease, has identified six reports with patients ( table ). the majority of the cases were localized in wuhan, or recent travel to wuhan, or contact people from wuhan. the median ages were, respectively, , , , . , and years old according to the six studies. the infection was diagnosed throughout the whole spectrum of age covering from new born to years old. in all of the studies, men were more likely to be infected than women and the overall proportion of male is . %. meta-analysis for the identified studies showed that the most prevalent cardiovascular metabolic comorbidities were hypertension ( . %, % ci . - . %) and cardia-cerebrovascular disease ( . %, % ci . - . %), followed by diabetes ( . %, % ci . - . %) (fig. ). there was a significant heterogeneity (cochran's q) in the estimates of comorbidities among the identified studies with an i index varied from to % (fig. ). we then compared the difference of the prevalence of the three diseases between severe patients and non-severe patients (or icu patients vs non-icu patients according to the data in the studies). for hypertension and cardia-cerebrovascular disease, the heterogeneity test results were calculated as i = % and %. thus, the fixed-effect model was used for further analyses. the results from the three included studies (with a total amount of patients) showed that hypertension accounted for . % of icu/ severe cases, but . % of non-icu/severe cases. a similar pattern was found in cardia-cerebrovascular disease statistics: it accounted for . % of icu/severe cases, but . % of non-icu/severe cases. the proportion hypertension and cardia-cerebrovascular disease were both statistically significant higher in icu/severe patients compared to the non-icu/severe patients [hypertension: rr = . , % ci ( . , . ), z = . , p < . ; cardia-cerebrovascular disease: rr = . , % ci ( . , . ), z = . , p < . ] (fig. ) . for diabetes, the heterogeneity test showed that i = %, and so the random effect model was used. diabetes accounted for . % of icu/severe cases, but . % of non-icu/severe cases. the result indicated a higher proportion of diabetes in icu/severe patients but without statistical significance [rr = . , % ci ( . , . ), z = . , p = . ] (fig. ) . at last, we focused on the impact of the covid- on the cardiac injury. two studies that gave clear data were statistically analyzed, and the data showed that . % ( % ci . - . %) patients might be suffered from an acute cardiac injury. another two studies only gave the data of creatine kinase, if it can be seen as a biomarker of cardiac injury, the proportion might be . % ( % ci . - . %). when we attempted to compare the differences of cardiac injury incidences between icu/severe patients and non-icu/severe patients, we just included the two studies which specifically identified myocardial injury. the data again showed a significant higher incidence of acute cardiac injury in icu/severe patients compared to the non-icu/severe patients [rr = . , % ci ( . , . ), z = . , p = . ] (fig. ) . the funnel plots demonstrated symmetrical distributions of the effect size of hypertension, cardia-cerebrovascular diseases and cardiac injury on either side of the pooled estimate, but a non-symmetrical distribution of the effect size of diabetes (fig. ). coronaviruses are enveloped rna viruses, which include six species that can cause diseases in humans to our knowledge [ ] . four viruses among them ( e, oc , nl , and hku ) have been reported to cause common cold symptoms in immunocompetent individuals [ ] . however, the two other strains are the infamous sars-cov and mers-cov, which have been linked to fatal illness and caused plagues and large numbers of deaths [ ] . complete genome sequences of -ncov showed that it is identified as a novel betacoronavirus belonging to the sarbecovirus subgenus of coronaviridae family, the same subgenus with sars-cov [ ] . according to previous research on sars-cov, the presence of comorbidities increased the mortality risk, with cardiac disease and diabetes being the most important components to predict adverse outcomes [ ] . cardiac disease and diabetes increase the risk of death by twice as much as other risk factors [ ] . thus, it is necessary for us to evaluate the prevalence of cardiac and metabolic diseases in covid- . the present systematic analysis summarized the data from all of the five studies of covid- . the results demonstrated that the overall proportion of hypertension, cardia-cerebrovascular disease and diabetes were, respectively, . %, . % and . %. according to summary of the report on cardiovascular diseases in china, the morbidities of the hypertension and diabetes were, respectively, . % and . %, and there were about million of cerebrovascular disease patients and million of cardiovascular patients [ ] . therefore, comparing the data to the report, we did not find that people with hypertension and diabetes were more susceptible to -ncov infection. the prevalence of hypertension and diabetes in people infected with the virus is about the same as in the general population, even slightly lower. however, comparing the general population, the incidence of cardia-cerebrovascular disease in patients with covid- is obviously much higher. due to the sample size and limited time so far, data collection is still incomplete, and most of the studies have not analyzed comorbidities in death cases. so the relationship between cardiovascular metabolic diseases and covid- -induced death cannot be determined. but what is assuredly is that patients with hypertension, cardia-cerebrovascular diseases or diabetes are more likely to develop severe/icu cases after -ncov infection. the overall proportion of hypertension, cardia-cerebrovascular diseases and diabetes were about twofolds, threefolds and twofolds, respectively, higher in icu/severe cases than in their non-icu/severe counterparts. although the difference of diseases in the meta-analysis is not statistical, fig. meta-analysis for the proportion of hypertension, cardia-cerebrovascular disease and diabetes in covid- cases. weights are calculated from binary random-effects model analysis. values represent proportions of the diseases in the covid- patients and % ci. heterogeneity analysis was carried out using q test, the among studies variation (i index). forest plots depict the comparison of the incidences of the diseases in icu/severe and non-icu/severe patients ◂ fig. meta-analysis for the incidence of cardiac injury in covid- cases. weights are calculated from binary random-effects model analysis. values represent proportions of the cardiac injury in the covid- patients and % ci. heterogeneity analysis was carried out using q test, the among studies variation (i index). forest plots depict the comparison of the incidences of cardiac injury in icu/ severe and non-icu/severe patients fig. funnel plots of the comparisons of hypertension, cardia-cerebrovascular disease, diabetes and acute cardiac injury between icu/severe and non-icu/severe patients the rr value is about . , and we consider this might because of the sample size of included studies and the algorithm adopts the random effect model which is a more conservative approach. so we speculate the result might reach statistical significance when more researches publish their data. another important finding is the damage the virus did to the heart. according to the present summary, at least . % patients with covid- suffered acute cardiac injury. in chen's report, the first death was a -year old man with no previous chronic underlying disease. after he was admitted by icu, he had developed severe respiratory failure, heart failure, and sepsis, and then experienced a sudden cardiac arrest on the th day of admission and was declared dead [ ] . this case reminded us that patients with a novel coronavirus might develop acute cardiac injury. and further analysis indicates us that the incidence of myocardial injury is much higher in icu/severe patients, about folds more than non-icu/cardiac patients. and furthermore, the observation also reminded us that patients with covid- associated with unstable angina or stemi have poor cardiac reserve, lower tolerance to severe pneumonia, and are more likely to develop cardiac insufficiency, leading to deterioration. according to the information released by shanghai health commission, the first covid- death in shanghai was a patient years old, with a serious history of hypertension, cardiac dysfunction. the analysis of death causes suggested that the patient died of heart failure and systemic multiple organ dysfunction, and in the course of its onset, the ncov infection is only the inducement. the pathogenesis of ncov infection-related acute myocardial injury is still unknown. but according to the clinical presentation and lab data of the disease, as well as the pathogenesis of sars-cov, it can be speculated that -ncov infection may affect the cardiovascular system through multiple mechanisms. first, viral infection directly causes damage to cardiomyocyte. according to oudit's study, sars-cov viral rna was detected in % of autopsied human heart samples from sars-cov infected patients during the toronto sars outbreak [ ] . and they also confirmed that pulmonary infection with the human sars-cov in mice led to an ace dependent myocardial infection [ ] . ace is an important target for sars-cov [ ] , and molecular modelling has shown high structural similarity between the receptor-binding domains of sars-cov and -ncov [ ] . ace expression is highly tissue-specific, mainly expressed in the cardiovascular, renal and gastrointestinal systems, with a small amount expressed in lung cells. therefore, in addition to coronaviruses causing pneumonia through ace receptors in lung epithelial cells, we also need to pay attention to possible viral effects on myocardial tissue. second, hypoxaemia may be also an important reason of cardiac injury. in huang's study, % covid- patients had various degree of hypoxaemia and need required high-flow nasal cannula or higher-level oxygen support. in chen's study, up to % of patients require oxygen therapy. due to severe -ncov infection, the pneumonia may cause significant gas exchange obstruction, leading to hypoxaemia, which significantly reduces the energy supply by cell metabolism, and increases anaerobic fermentation, causing intracellular acidosis and oxygen free radicals to destroy the phospholipid layer of cell membrane. meanwhile, hypoxia-induced influx of calcium ions also leads to injury and apoptosis of cardiomyocytes. third, huang's study noted that high concentration of il- β, ifn-γ, ip- and mcp- could be detected in patients infected with -ncov, which might lead to activated t-helper- (th ) cell responses [ ] . furthermore, they also found that icu patients had much higher concentrations of inflammatory factors than those non-icu patients, suggesting that the cytokine storm was associated with disease severity [ ] . in addition, repeated floods of catecholamines due to anxiety and the side effects of medication can also lead to myocardial damage. in conclusion, patients with previous cardiovascular metabolic diseases may face a greater risk of infection of -ncov and it can also greatly affect the development and prognosis of pneumonia. simultaneously, we should pay close attention to viral infection-related heart damage in the course of disease treatment. sars: prognosis, outcome and sequelae prevalence of diabetes in the influenza a (h n ) and the middle east respiratory syndrome coronavirus: a systematic review and meta-analysis a novel coronavirus from patients with pneumonia in china clinical features of patients infected with novel coronavirus in wuhan, china. lancet clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study the continuing -ncov epidemic threat of novel coronaviruses to global health-the latest novel coronavirus outbreak in wuhan. china clinical characteristics of novel coronavirus infection in china plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with sars cardiovascular complications of severe acute respiratory syndrome prevalence of comorbidities in the middle east respiratory syndrome coronavirus (mers-cov): a systematic review and meta-analysis preferred reporting items for systematic review and meta-analyses of individual participant data: the prisma-ipd statement quantitative methods in the review of epidemiologic literature meta-analysis in clinical trials the effect of statins on microalbuminuria, proteinuria, progression of kidney function, and all-cause mortality in patients with non-end stage chronic kidney disease: a meta-analysis epidemiologic and clinical characteristics of novel coronavirus infections involving patients outside wuhan clinical characteristics of novel coronavirus cases in tertiary hospitals in hubei province epidemiology, genetic recombination, and pathogenesis of coronaviruses origin and evolution of pathogenic coronaviruses short term outcome and risk factors for adverse clinical outcomes in adults with severe acute respiratory syndrome (sars) summary of the report on cardiovascular diseases in china sars-coronavirus modulation of myocardial ace expression and inflammation in patients with sars structure of sars coronavirus spike receptor-binding domain complexed with receptor genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding conflict of interest none declared. key: cord- -bqdvx authors: rice, ken; wynne, ben; martin, victoria; ackland, graeme j title: effect of school closures on mortality from coronavirus disease : old and new predictions date: - - journal: bmj doi: . /bmj.m sha: doc_id: cord_uid: bqdvx objective: to replicate and analyse the information available to uk policymakers when the lockdown decision was taken in march in the united kingdom. design: independent calculations using the covidsim code, which implements imperial college london’s individual based model, with data available in march applied to the coronavirus disease (covid- ) epidemic. setting: simulations considering the spread of covid- in great britain and northern ireland. population: about million simulated people matched as closely as possible to actual uk demographics, geography, and social behaviours. main outcome measures: replication of summary data on the covid- epidemic reported to the uk government scientific advisory group for emergencies (sage), and a detailed study of unpublished results, especially the effect of school closures. results: the covidsim model would have produced a good forecast of the subsequent data if initialised with a reproduction number of about . for covid- . the model predicted that school closures and isolation of younger people would increase the total number of deaths, albeit postponed to a second and subsequent waves. the findings of this study suggest that prompt interventions were shown to be highly effective at reducing peak demand for intensive care unit (icu) beds but also prolong the epidemic, in some cases resulting in more deaths long term. this happens because covid- related mortality is highly skewed towards older age groups. in the absence of an effective vaccination programme, none of the proposed mitigation strategies in the uk would reduce the predicted total number of deaths below . conclusions: it was predicted in march that in response to covid- a broad lockdown, as opposed to a focus on shielding the most vulnerable members of society, would reduce immediate demand for icu beds at the cost of more deaths long term. the optimal strategy for saving lives in a covid- epidemic is different from that anticipated for an influenza epidemic with a different mortality age profile. the united kingdom's national response to the coronavirus disease (covid- ) pandemic has been widely reported as being primarily led by modelling based on work, using an individual based model (ibmic) from imperial college london, although other models have been considered. in this paper, we maintain the distinction between epidemiological "model" (ibmic) and software implementation as "code" (covidsim). the key paper (report : impact of non-pharmaceutical interventions (npis) to reduce covid- mortality and healthcare demand) investigated several scenarios using ibmic with the best parameterisation available at the time. contrary to popular perception, the lockdown, which was then implemented, was not specifically modelled in this work. as the pandemic has progressed, the parameterisation has been continually improved as new data become available. the main conclusions of report were not especially surprising. mortality from covid- is around %, so an epidemic in a susceptible population of million people would cause many hundreds of thousands of deaths. in early march , the case doubling time in the uk might have been around three days, meaning that within a week cases of covid- could go from accounting for a minority of available intensive care unit (icu) beds to exceeding capacity. furthermore, with a disease onset delay of more than a week and limited or delayed testing and reporting in place, there would be little measurable warning of the surge in icu bed demand. one table in report , however, shows that closing schools reduces the reproduction number of covid- but with the unexpected effect of increasing the total number of deaths. in this paper, we reproduce the main results from report and explain why, in the framework of the ibmic model, these counterintuitive results were obtained. we chose not to re-parameterise the model as we wanted to replicate the information available to policymakers at the time, specifically highlighting policies for which suppressing the outbreak and saving lives were conflicting choices. ibmic was developed from an influenza pandemic model. the original code used for report has not been released. however, the team at imperial college london, headed by epidemiologist neil ferguson, collaborated with microsoft, github, and the royal society rapid assistance in modelling the pandemic (ramp) initiative to recreate the model in the covidsim code: this version has been stringently externally validated. we used github tagged version . . plus additional patches dated before june , the full technical details of which are published elsewhere. ferguson et al supplied the input files relevant to report that were included in the github release. covidsim performs simulations of the uk at a detailed level without requiring personal data. the model includes millions of individual "people" going about their daily business-for example, within communities and at home, schools, universities, places of work, and hospitals. the geographical representation of the uk is taken from census data, so the distribution of age, health, wealth, and household size for simulated people in each area is appropriate. the model also includes appropriate numbers, age distribution, and commuting distances of people in the simulated schools and workplaces, each in line with national averages. the network of interactions is age dependent: people interact mainly with their own age group and with family, teachers, and carers. the virus (severe acute respiratory syndrome coronavirus ) initially infects random members of this network of interacting coworkers, strangers, friends, and family. whenever an infected person interacts with a noninfected person, there is a probability that the virus will spread. this probability depends on the time and proximity of the interaction and the infectiousness of the person according to the stage of the disease. infected people might be admitted to hospital and might die, with the probability dependent on age, pre-existing conditions, and stage of the disease. this extremely detailed model is then parameterised using the best available expert clinical and behavioural evidence, with coronavirus specific features being updated as more coronavirus specific data become available from the worldwide pandemic. therefore, the model has the required complexity to consider non-pharmaceutical interventions, which would reduce the number of interactions between simulated people in the model (table ) . to predict policymaking, it is assumed that these interventions are implemented when demand for icu beds reaches a particular "trigger" level. as the model contains far more realistic detail than the data available, the results are averages over many runs with different starting conditions, all of which are consistent with known data. the real epidemic is just one of these possibilities, so the code determines the range of scenarios for which plans should be made. this is particularly important when the numbers of localised outbreaks are low: the prediction that local spikes will occur somewhere is reliable, and the most likely places can be identified, but predicting exactly when and where is not possible with the level of data available. all interventions reduce the reproduction number and slow the spread of the disease. however, a counterintuitive result presented in report (table and table a in that report) is the prediction that, once all other considered interventions are in place, the additional closure of schools and universities would increase the total number of deaths. similarly, adding general social distancing to a scenario involving household isolation of suspected cases (case isolation) and household quarantine of family members, with appropriate estimates for compliance, was also projected to increase the total number of deaths. patients or the public were not involved in the design, conduct, reporting, or dissemination plans of our research. all data used were retrieved from existing public sources, as referenced. we plan to share this on social media, twitter, and blogs. to reproduce the result tables for the scenarios presented in report , we averaged over simulation runs with the same random number seeds as used in the original report. the simulations are run for days, with day being january . the simulated intervention period lasts for three months ( days), with some interventions extended for an additional days. in reality, interventions were in place for rather longer, which delayed the second wave but had little effect on deaths. the mitigation scenarios in report considered reproduction numbers of r = . and r = . . as highlighted by ferguson et al, the results we obtain here are not precisely identical to those in report because they are an average of stochastic realisations, the population dataset has changed to an open source one, and the algorithm used to assign individuals from households to other places such as schools, universities, and workplaces has been modified to be deterministic. we also count deaths in all waves, not just the first. the stochasticity gives a variance of around % in total number of deaths and icu bed demand between different realisations using different random numbers. more important is the uncertainty of the timing of the peak of the infections between realisations, which is around five days. we compared these predictions to the death rates from the actual trajectory of covid- . nhs england stopped publishing data on critical bed occupancy in march , so it was not possible to compare icu data from the model with real world data. table shows the demand for icu beds and table shows the total number of deaths; in both, the same mitigation scenarios as presented in report were used. as in report , for each mitigation scenario we considered a range of icu triggers. in table we report the peak icu bed demand across the full simulation for each trigger, as was presented in report , but we also include the peak demand for icu beds during the period of the intervention (first wave). the latter we define as the period during which general social distancing was in place when implemented. table reports the total number of deaths across the entire simulation as well as the number of deaths at the end of the first wave, again defined as the time at which general social distancing was lifted. table and table present the full simulation numbers, which are essentially the same as those presented in table a in report . table also illustrates the counterintuitive result that adding school closures to a scenario with case isolation, household quarantine, and social distancing in people older than years would increase the total number of deaths across the full simulation. moreover, it shows that social distancing in those over would be more effective than general social distancing. table and table show that in some mitigation scenarios the peak demand for icu beds and most deaths occur during the period when the intervention is in place. there are, however, other scenarios when the opposite is true. the reason for this is illustrated in figure . the mitigation scenarios of "do nothing," place closures, case isolation, case isolation with household quarantine, and case isolation, household quarantine, and social distancing of over s are as presented in figure of report . we also show some additional scenarios (case isolation and social distancing; case isolation, household quarantine, and general social distancing; and place closures, case isolation, household quarantine, and social distancing of over s) that are not shown in figure of report included in table and table and in the tables in report . in the simulations presented here, the main interventions are in place for three months and end on about day (some interventions are extended for an additional days). figure shows that weaker intervention scenarios lead to a single wave that occurs during the period in which the interventions are in place. hence the peak demand for icu beds occurs during this period, as do most deaths. stronger interventions, however, are associated with suppression of the infection such that a second wave is observed once the interventions are lifted. for example, adding place closures to case isolation, household quarantine, and social distancing of over s substantially suppresses the infection during the intervention period compared with the same scenario without place closures. however, this suppression then leads to a second wave with a higher peak demand for icu beds than during the intervention period, and total numbers of deaths that exceed those of the same scenario without place closures. we therefore conclude that the somewhat counterintuitive results that school closures lead to more deaths are a consequence of the addition of some interventions that suppress the first wave and failure to prioritise protection of the most vulnerable people. when the interventions are lifted, there is still a large population who are susceptible and a substantial number of people who are infected. this then leads to a second wave of infections that can result in more deaths, but later. further lockdowns would lead to a repeating series of waves of infection unless herd immunity is achieved by vaccination, which is not considered in the model. a similar result is obtained in some of the scenarios involving general social distancing. for example, adding general social distancing to case isolation and household quarantine was also strongly associated with suppression of the infection during the intervention period, but then a second wave occurs that actually concerns a higher peak demand for icu beds than for the equivalent scenario without general social distancing. figure provides an explanation for how place closure interventions affect the second wave and why an extra intervention might result in more deaths than the equivalent scenario without this intervention. in the scenario of case isolation, household quarantine, and social distancing of over s but without place closures, a single peak of cases is seen. the data are broken down into age groups, showing that younger people contribute most to the total number of cases, but that deaths are primarily in older age groups. adding the place closure intervention (and keeping all other things constant) gives the behaviour shown in the second row of plots. the initial peak is greatly suppressed, but the end of place closures while other social distancing is in place prompts a second peak of cases among younger people. this then leads to a third, more deadly, peak of cases affecting elderly people when social distancing of over s is removed. postponing the spread of covid- means that more people are still infectious and are available to infect older age groups, of whom a much larger fraction then die. one criticism of school closure is that reduced contact at school leads to increased contact at home, meaning that children infect high risk adults rather than low risk children. we investigated this by increasing the infection rate at home to an extremely high level. figure shows that this makes an insignificant difference compared with the overall effect of adding school closures (despite the description of place closure interventions in table of report , university closures are not included in the scenario parameter file representing place closure, case isolation, household quarantine, and social distancing of over s ) to the other interventions. description of a second wave in covidsim although report discusses the possibility that relaxing the interventions could lead to a second peak later in the year, we wanted to explore this in more detail using the newer covidsim code and latest set of parameter files. (summarised in table and table ). the scenario of place closures, case isolation, household quarantine, and social distancing of over s would minimise peak demand for intensive care but prolong the epidemic, resulting in more people needing intensive care and more deaths. these findings illustrate why adding place closures to a scenario with case isolation, household quarantine, and social distancing of over s can lead to more deaths than the equivalent scenario without place closures. doing so suppresses the infection when the interventions are present but leads to a second wave when interventions are lifted. in the model this happened in july , after a day lockdown: in practice the first lockdown was extended into august, so the second wave was postponed to september. the total number of deaths in the scenario of case isolation, household quarantine, and social distancing of over s is , whereas when place closures are included the total number is . similarly, comparing general social distancing with equivalent scenarios without social distancing, the second wave peak in the case isolation, household quarantine, and general social distancing scenario is higher than the first wave peak in the case isolation and household quarantine scenario. icu=intensive care unit; pc=place closures; ci=case isolation; hq=household quarantine; sdol =social distancing of over s; sd=general social distancing the interventions we consider are place closures, case isolation, household quarantine, and general social distancing, which are implemented using the pc_ci_hq_sd parameter file. specifically, we use the parameter file available in the data/param_files subdirectory of the github repository. the only modification was to change the duration of the interventions to days. these interventions start in late march (day ) and last for three months ( days). these simulations are also initialised so that about deaths occur by day ( april) in all scenarios, mostly in people infected before the interventions were implemented. initialisation is done by modifying the "number of deaths accumulated before alert" parameter in the preuk_ . .txt parameter file. this compares with how the report simulations were initialised, which used the reported deaths to march. the results are presented in figure . the top panel shows the cumulative number of deaths, using data from national records of scotland and connors and fordham, whereas the bottom panel shows icu bed demand per people. although our simulations include northern ireland, the available reported data do not. therefore, the simulation results and data presented in figure are only for england, wales, and scotland. we also consider a range of reproduction numbers and find that values higher than those considered in report best reproduce the data, with a value between . and . probably providing the best fit. this is consistent with the analysis presented in flaxman et al, but we acknowledge that the data could also be fitted by changes to the other scenario parameters. in both panels we also show the "do nothing" scenario for a reproduction number of . . the scenarios presented in figure are predicted to substantially reduce the demand for icu beds. the best fit to the code suggests about % infection rate in the first wave. random antibody testing at the time of writing (june ) suggests that about % of the population test positive for antibodies to coronavirus, although the large number of deaths in care homes suggest the post-lockdown first wave was concentrated in the over s age group. interventions are triggered by reaching cumulative intensive care unit cases. after the trigger, all the interventions are in place for days: the general social distancing runs to day and the enhanced social distancing for over s runs for an extra days. results are broken down into age categories, with social distancing of over s interventions affecting the three oldest groups. in the case isolation, household quarantine, and social distancing of over s scenario, a single peak of cases is seen, with greatest infection in the younger age groups but most deaths in the older age groups. in the place closures, case isolation, household quarantine, and social distancing of over s scenario, three peaks occur in the plot of daily cases, with the first peak appearing at a similar time to the other scenario, but with reduced severity. the second peak seems to be a response to the ending of place closure and mostly affects the younger age groups; therefore has little impact on the total number of deaths. the third peak triggered by relaxing social distancing of over s affects the older age groups, leading to a substantial increase in the total number of deaths editorial published in the bmj on september suggests this % could be an underestimate because iga antibodies and t cell immunity were overlooked. ) with only - % immunity after the lockdown, the epidemiological situation at the outset of the second wave is similar to that of march. consequently, the number of second wave infections is predicted to be similar to that of the first wave, with a somewhat lower death rate. in practice, it seems that mandatory and voluntary interventions short of a full lockdown will continue and maintain the reproduction number closer to this will mean slower exponential growth of the second wave and keep the peak demand for icu beds manageable, although since the epidemic is prolonged, the effect on total deaths is smaller. it is worth noting that a reproduction number of is also the value that prolongs the need for interventions for the longest. at this level, the inhomogeneity of transmissions, particularly the unpredictability of superspreading events, becomes critical. despite the level of detail in the model, the data are insufficient to model real people: we observed that for a major national epidemic, insufficient data introduce an uncertainty of about five days in the predictions. at a local level, and with a lower reproduction number, this uncertainty in the timing of the epidemic is greatly increased: it is impossible to predict when a particular town will experience an outbreak (specifically, different towns experience outbreaks in different runs of the code). in this paper we used the recently released covidsim code to reinvestigate the mitigation scenarios for covid- from ibmic presented in mid-march in report . the motivation behind this was that some of the results presented in the report suggested that the addition of interventions restricting younger people might actually increase the total number of deaths from covid- . we find that the covidsim code reliably reproduces the results from report and that the ibmic can accurately track the data on death rates in the uk. reproducing the real data does require an adjustment to the parameters and a slightly higher reproduction number than considered in report and implies an earlier start to the epidemic than suggested by the report. we emphasise that the unavailability of these parameters in early march is not a failure of the ibmic model. we confirm that adding school and university closures to case isolation, household quarantine, and social distancing of over s would lead to more deaths compared with the equivalent scenario without the closures of schools and universities. similarly, general social distancing was also projected to reduce the number of cases but increase the total number of deaths compared with social distancing of over s only. we note that in assessing the impact of school closures, uk policy advice has concentrated on reducing total number of cases and not the number of deaths. the qualitative explanation is that, within all mitigation scenarios in the model, the epidemic ends with widespread immunity, with a large fraction of the population infected. strategies that minimise deaths involve the infected fraction primarily being in the low risk younger age groups-for example, focusing stricter social distancing measures on care homes where people are likely to die rather than schools where they are not. optimal death reduction strategies are different from those aimed at reducing the burden on icus, and different again from those that lower the overall case rate. it is therefore impossible to optimise a strategy for dealing with covid- unless these three desirable outcomes are prioritised. we find that scenarios that are very effective when the interventions are in place, can then lead to subsequent waves during which most of the infections, and deaths, occur. our comparison of updated model results with the published death data suggests that a similar second wave will occur later this year if interventions are fully lifted. more realistically, if the case isolation, household quarantine, and social distancing of over s strategy is followed, alongside other nonpharmaceutical intervention measures such as nonmandatory social distancing and improved medical outcomes, the second wave will grow more slowly than the first, with more cases but lower mortality. since this paper was first written (june ), uk policy has moved to more local interventions. covidsim models the geography of all towns, but only the simulated people are representative of the true population. this uncertainty means that the model cannot reliably predict which town will experience an outbreak. specifically, whereas the timing of the national outbreak is uncertain by days, the timing of an outbreak in a town is uncertain by months. ibmic is the most precise model available, but substantially more personal data would be needed to obtain reliable local predictions. finally, we re-emphasise that the results in this work are not intended to be detailed predictions for the second wave of covid- . rather, we re-examined the evidence available at the start of the epidemic. more accurate information is now available about the compliance with lockdown rules and age dependent mortality. the difficulty in shielding care home residents is a particularly important set of health data that was not available to modellers at the outset. nevertheless, in all mitigation scenarios, epidemics modelled using covidsim eventually finish with widespread infection and immunity, and the final death toll depends primarily on the age distribution of those infected and not the total number. we thank kenji takeda and peter clarke for help with the covidsim code and neil ferguson for advice and sharing data. contributors: kr and bw ported and validated the code across several computer architectures, performed the calculations, and produced the figures. vm supervised the testing and preopensourcing test of the covidsim code. gja designed and supervised the project. all authors contributed to writing the paper. all authors act as guarantors. the corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. funding: this paper was supported by a uk research and innovation grant st/v x/ under covid- initiative. this work was undertaken, in part, as a contribution to the rapid assistance in modelling the pandemic (ramp) initiative, coordinated by the royal society. the funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication. competing interests: all authors have completed the icmje uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from uk research and innovation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. and connors and fordham. bottom panel shows demand for intensive care unit (icu) beds per people, including an unmitigated second wave. a range of reproduction numbers were considered and values higher than that considered in report were found to best reproduce the data. a good fit also requires an assumption that the epidemic started in january , earlier than was previously assumed in report . covidsim is seen to provide a good fit to the data with a reproduction number between . and . and predicts that the demand for icu beds would probably be limited to around per people imperial college london estimating the global infection fatality rate of covid- challenges in control of covid- : short doubling time and long delay to effect of interventions strategies for mitigating an influenza pandemic modeling targeted layered containment of an influenza pandemic in the united states codecheck certificate - covid- covidsim model covid- ) infection survey pilot: england and wales estimating the effects of non-pharmaceutical interventions on covid- in europe antibody prevalence for sars-cov- following the peak of the pandemic in england: react study in adults covid- : do many people have pre-existing immunity? interdisciplinary task and finish group on the role of children in transmission. modelling and behavioural science responses to scenarios for relaxing school closures ethical approval: not required.data sharing: the full simulation and datasets can be accessed and run from github using the sha hash code d c a ab d f f fdd a . code examples and raw data sufficient to reproduce all results in this research are available at https://doi.org/ . /ds/ . the lead author (gja) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.dissemination to participants and related patient and public communities: since this research uses public demographic data for the whole of the uk, there are no plans for dissemination of this research to specific participants, beyond publishing it.provenance and peer review: not commissioned; externally peer reviewed.this is an open access article distributed in accordance with the creative commons attribution non commercial (cc by-nc . ) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. see: http://creativecommons.org/licenses/ by-nc/ . /. key: cord- -z mwzmf authors: rubulotta, francesca; soliman-aboumarie, hatem; filbey, kevin; geldner, goetz; kuck, kai; ganau, mario; hemmerling, thomas m. title: in response date: - - journal: anesth analg doi: . /ane. sha: doc_id: cord_uid: z mwzmf nan in response w e thank esteemed colleagues drs brull and kopman, both well-known experts in the field of neuromuscular monitoring and blockade for their interest in our article and their comments. we would like to start by reiterating that our review was aimed at presenting technologies and techniques for coronavirus disease (covid- ) patients who needed the use of neuromuscular blocking agents (nmba) outside the operating theater. in particular, the editorial focused on severe covid- patients with acute respiratory distress syndrome (ards). nmba were needed for either intubation in the intensive care unit (icu) or emergency room (er) or for sparing these drugs during prolonged invasive mechanical ventilation. the creation of dedicated anesthesia intubation teams during the covid- crisis as well as the increasing engagement of anesthesiologists in the icu setting led us to believe that presenting basic principles of neuromuscular monitoring could be of interest for all readers. we purposely adopted the terminology widely used in the setting of intensive care medicine when we wrote about the train-of-four (tof) monitoring. as a matter of fact, we deliberately referred to the way electric impulses are applied to a motor nerve. the tof stimulation consists of applying electric stimuli each separated by . s. depending on the method of monitoring available, either qualitative-tactile or visual counting-or quantitative monitoring-using a specific monitoring device-is possible. in the former, the tof count can be determined ( - twitches), or a definite ratio of t /t ratio. the tof ratio is the comparison of t (fourth twitch of the tof) to t amplitude, expressed in percentage. we left the choice of using either qualitative or quantitative monitoring to the discretion of the physicians working in the icu because they could be not icu trained. in the operating room, quantitative monitoring devices are recommended as they give a more detailed and precise estimate of neuromuscular blockade (nmb). nmb monitoring is not standard of care in the icu, despite the infusion of nmbas is common for adult with severe ards or during proning maneuvers. the best compromise between practicability, usefulness, and validity of monitoring seems to be the use of qualitative, handheld monitoring devices. handheld monitoring has limited value during intubation outside the icu but it can be easily carried in the physician's pocket, and properly disinfected. monitoring is more frequently used during continuous infusion of nmba and it can be done in seconds using facial or eye muscles, adductor pollicis muscle, or others. the qualitative result can then be noted in the electronic patients' chart. the frequency and the site of placement of such monitoring is also discretion of the treating physician or the icu guidelines. the covid- pandemic peak has significantly increased the workload in most icus and the frequency of tof monitoring has been compromised at times. even if attempted quantitative monitoring in the icu, validity of the results could be questioned because of the lack of standardization. frequently asked questions are: shall one leave stimulating electrodes in the same place? how long could these stay on the skin without causing pressure damages? what position shall be used of the hand when monitoring is performed? in that respect, again facial muscles are easier to monitor but they do not reflect nmb or neuromuscular transmission at the adductor pollicis muscle. we do not recommend the corrugator supercilii as the monitoring site of choice but wanted to point out that it best reflects nmb or neuromuscular transmission at the diaphragm or larynx, anatomic areas of particular interest for icu physicians. drs brull and kopman questioned the recommended target value of nmb in the icu setting. the discussion of whether nmb is at all necessary for mechanical ventilation in the icu is beyond the scope of our article. however, in a recent study, a positive relationship was found between the depth and duration of nmb and icu-acquired weakness. the article entitled "battle of the rsi paralytics" describes the long-standing discussion around the use of succinylcholine versus rocuronium for rapid sequence induction (rsi) from the perspective of emergency medical services. in terms of onset time and intubation conditions, rocuronium in a dose of more than mg/kg and succinylcholine in a dose of mg/kg are equally efficient. covid- patients who need intubation are predominantly suffering from multiple comorbidities. this leaves us with the eternal question which muscle relaxant is better for the "can't intubate can't ventilate situation." despite best efforts of preoxygenation, covid- patients desaturate very quickly during the intubation process to alarming values of % or % or less within seconds. it is therefore important that intubation is provided by a dedicated team and mostly by the very experienced physicians, predominantly using videolaryngoscopy. the procedure can be particularly challenging in covid- patients. naguib et al found a significantly longer objectively measured duration of nmb after mg/kg succinylcholine with minutes versus minutes after . mg/kg rocuronium followed minutes later by mg/kg sugammadex. as to the comments by brull and kopman to the time it takes to get this amount of www.anesthesia-analgesia.org letters to the editor sugammadex is ready, one can easily imagine the fractionated injection of sugammadex by the anesthesiologist, while a second person gets it ready. we argue that the time it takes to get sugammadex ready is not really an issue. however, no one can prove that the risks and benefits ratio of using rocuronium is better for those administering succinylcholine in these situations. even when one looks at clinical parameters, such as a return to spontaneous ventilation, defined as respiratory rate of more than /min at a tidal volume of at least ml/kg for s, the combination of rocuronium/sugammadex is able to achieve this in half the time as succinylcholine. , clarifications on technologies to optimize care of severe covid- patients technologies to optimize the care of severe covid- patients for healthcare providers challenged by limited resources clinical assessment and train-of-four measurements in critically ill patients treated with recommended doses of cisatracurium or atracurium for neuromuscular blockade: a prospective descriptive study monitoring of neuromuscular block towards evidence-based emergency medicine: best bets from the manchester royal infirmary. bet : is rocuronium as effective as succinylcholine at facilitating laryngoscopy during rapid sequence intubation? staff safety during emergency airway management for covid- in hong kong the myth of rescue reversal in "can't intubate, can't ventilate" scenarios rapid sequence induction and intubation with rocuronium-sugammadex compared with succinylcholine: a randomized trial effects of neuromuscular block on systemic and cerebral hemodynamics and bispectral index during moderate or deep sedation in critically ill patients the authors thank umesh patel for editing the content. key: cord- -v by dnp authors: kessler, remi a.; oermann, eric k.; dangayach, neha s.; bederson, joshua; mocco, j.; shrivastava, raj k. title: changes in neurosurgery resident education during the covid- pandemic: an institutional experience from a global epicenter date: - - journal: world neurosurg doi: . /j.wneu. . . sha: doc_id: cord_uid: v by dnp nan to the editor: the first case of the severe acute respiratory syndrome coronavirus (sars-cov- ) and its associated coronavirus disease in new york state was diagnosed on march , . it was declared a global pandemic by the world health organization (who) shortly thereafter on march , . as it rapidly spread across new york city (nyc), the city's major teaching hospitals underwent unprecedented changes to re-organize resources, make space for the massive surge in covid- positive patients who would require hospitalization and ventilatory support, and to re-deploy physicians of all specialties to aid in the effort. given that ny is leading the nation in the number of patients diagnosed with covid- ( , cases as of april , ), coupled with the cancellation of all elective surgeries, the comprehensive redeployment of attending neurosurgeons and residents to assist in covering a covid- intensive care unit (icu) became a necessity. here we present our detailed institutional experience -from an , -bed, tertiary care academic center and six other affiliate hospitals of the mount sinai health system in nyc-on how the re-organization efforts changed our neurosurgical graduate medical education program from the heart of the pandemic. on march , , the department of neurosurgery at mount sinai issued its first version of changes to resident practice. the inciting event for this was the conversion of the new neurosurgical icu (nsicu) into a dedicated -bed covid-icu, requiring full-time staffing from all four of our faculty neuro-intensivist physicians. at this juncture, neurosurgery departmental leadership re-deployed residents and attendings to provide / neuro-critical care coverage, and mid-level providers were assigned to coverage in the emergency department and covid-icu. the old neurosurgical icu was re-activated, and all neurosurgical patients were resident education from the pandemic epicenter transferred there. one of the first changes made was expanded resident coverage to staffing this older neurosurgical icu and junior residents responsible for call every third night. the four chief residents (pgy- s and pgy- s) rotated on a weekly basis between the nsicu, the standard icu and two neurosurgery operating rooms (ors). the nsicu chief supervised the neurosurgical service, neurosurgery floor patients, nsicu patients, oversaw neurosurgery consults, and rounded with the icu team in the morning to build expertise in critical care. they were also responsible for preparing the biweekly radiology conference. the icu chief neurosurgery resident worked closely with the icu physician and rounded in the icu on all patients, supervised icu management day-to-day, and was in-house during the day with home call at night. the first or chief had primary or responsibility, and the second or chief was to remain home unless the second or was running. both pgy- residents were exclusively assigned to the cerebrovascular neurosurgery service and functioned at the fellow level. this change was in response to the seven-fold increase in stroke admissions related to covid- seen at mount sinai within recent weeks. all junior residents were re-assigned to a minimum of six weeks of neurocritical care and six weeks of neurosurgery. the neurocritical care junior residents were scheduled for -hour in-house call every third day. the juniors assigned to the neurosurgery service were scheduled for -hour call every fourth day. their responsibilities include prepping patients for the or, preparing the radiology list, and covering the surgical cases. one other junior resident was considered backup for covering cases, otherwise was to stay at home. interns were assigned to the nsicu through july . the same principles applied to the residents covering the other mount sinai affiliate hospitals. all resident weekly teaching conferences and grand rounds were held virtually via video conferencing. on april , , changes were made to this aforementioned version of the department staffing by introducing a dedicated senior and resident education from the pandemic epicenter junior resident to staffing the covid- icu, due to increased need. the chiefs were also reassigned to four, one-week rotations consisting of the nsicu, the icu, the or, and the hospital floor/neurosurgical consults. the reason for this change was that the low volume of surgical cases did not require a second chief resident and that physician staffing was better utilized in other areas of the hospital dedicated to covid- . the changes to neurosurgery resident education at mount sinai were borne out of a necessity for re-deployment of our physicians to assist in the fight against covid- , given the sheer abundance of positive patients in nyc. the emory university department of neurosurgery reported similar changes for residents covering their neurosurgical service and each resident is to spend one week during the month of april caring for covid- patients. a number of programs have reported reducing resident staffing by % with teams rotating one week at a time, while the rest of the residents remain at home. cases that ultimately go to the or are typically limited to a single resident to both reduce exposure and preserve ppe. the massachusetts general hospital/brigham and women's programs has re-deployed attendings and residents on a voluntary basis. the shutting down of research facilities for residents completing their research years has also led to delays in scientific productivity for those involved in wet bench research. emory, along with many other programs, have similarly used videoconferencing for live-streaming grand rounds, educational didactic sessions, and case conferences. the covid- pandemic has dramatically transformed the clinical neurosurgery residency training program at mount sinai due to the need to treat the unprecedented high numbers of > , covid- positive patients currently admitted to our hospital. the covid- pandemic has required our department to change resident education to an exceptional degree, but we are continuing neurosurgical learning in innovative ways while heeding the call to care for nyc's sickest patients. keywords: resident education, neurosurgery, pandemic, virus who director-general's opening remarks at the media briefing on covid- - cases in u.s. centers for disease control mount sinai neurosurgeon warns of covid- causing sudden strokes in younger patients letter: maintaining neurosurgical resident education and safety during the covid- pandemic impact of covid- on neurosurgery resident training and education covid- and academic neurosurgery impact of covid- on neurosurgery resident research training a neurosurgery resident's response to covid- : anything but routine key: cord- - kiqfy authors: azoulay, elie; fartoukh, muriel; darmon, michael; géri, guillaume; voiriot, guillaume; dupont, thibault; zafrani, lara; girodias, lola; labbé, vincent; dres, martin; beurton, alexandra; vieillard-baron, antoine; demoule, alexandre title: increased mortality in patients with severe sars-cov- infection admitted within seven days of disease onset date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: kiqfy purpose: coronavirus disease (covid- ) is creating an unprecedented healthcare crisis. understanding the determinants of mortality is crucial to optimise intensive care unit (icu) resource use and to identify targets for improving survival. methods: in a multicentre retrospective study, we included covid- patients admitted to four icus between february and april and categorised according to time from disease onset to icu admission. a cox proportional-hazards model identified factors associated with -day mortality. results: median age was years ( – ) and ( %) were men. the main comorbidities included obesity and overweight ( %), hypertension ( . %) and diabetes ( . %). median time from disease onset (i.e., viral symptoms) to icu admission was ( – ) days (missing for three); ( . %) patients were admitted within a week of disease onset, ( . %) between and days, and ( . %) > days after disease onset; day mortality was . % ( – ) and decreased as time from disease onset to icu admission increased, from to % and %, respectively. patients admitted within the first week had higher sofa scores, more often had thrombocytopenia or acute kidney injury, had more limited radiographic involvement, and had significantly higher blood il- levels. age, copd, immunocompromised status, time from disease onset, troponin concentration, and acute kidney injury were independently associated with mortality. conclusion: the excess mortality in patients admitted within a week of disease onset reflected greater non-respiratory severity. therapeutic interventions against sars-cov- might impact different clinical endpoints according to time since disease onset. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. the covid- pandemic has created an unprecedented healthcare crisis. with more than four million confirmed cases worldwide and nearly , deaths during the first months of , the number of patients with severe forms requiring critical care has overwhelmed intensive care units (icus) in many countries. respiratory failure is the main source of morbidity and mortality in severe cases. the causative agent of covid- , sars-cov- (severe acute respiratory syndrome-related coronavirus ) [ , ] , is the third documented spillover of an animal coronavirus to humans in only two decades [ ] . after an incubation period of about days [ ] , clinical viral symptoms such as a fever, cough, sore throat, nasal congestion, myalgia, fatigue, headaches, and/or diarrhoea occur [ , ] . dyspnoea is reported in up to half the patients, and - % of patients require icu admission for acute respiratory failure [ ] . in the earliest descriptions of covid- patients hospitalised in wuhan, china, time from viral symptom onset to dyspnoea was days and time to hospital admission was days [ , ] . understanding the determinants of poor outcomes in covid- patients would help stratify patients at baseline based on a risk assessment to both avoid admitting patients to the icu if they are at low risk for worsening and promptly admit patients likely to require critical care. several studies have identified factors associated with mortality in covid- patients. while advanced age has been recognised as a leading determinant of death in several studies [ , ] , little attention has been paid to outcome differences according to the timing of critical illness onset. a two-step model of lung and systemic injury seems involved, with the aggressive inflammation initiated by the viral replication resulting in a cytokine storm [ , ] . early after infection, sars-cov- binds to angiotensin-converting enzyme receptors, multiplies in the cytoplasm, and leads to type ii pneumocyte apoptosis [ ] . additionally, sars-cov- rna acts as a pathogen-associated molecular pattern that induces a chemokine surge, which causes neutrophil migration and activation [ , ] . the result is destruction of the alveolar-capillary walls and damage to the intra-alveolar space-stroma interface, causing exudative leakage. in addition to massive epithelial apoptosis, the early onset of rapid viral replication triggers endothelial cells to release pro-inflammatory cytokines and chemokines that cause further lung damage together with a systemic insult [ ] . to test the hypothesis that covid- -related critical illness differs according to time from viral symptom onset to icu admission, we assessed patient characteristics and outcomes in a cohort of critically ill patients admitted to four university-affiliated hospitals in paris. this retrospective observational study was performed in four university-affiliated hospitals in paris. consecutive patients with laboratory-confirmed sars-cov- infection admitted to one of the icus between february and april were enrolled. the appropriate ethics committee approved the study and waived the need for informed consent in accordance with french legislation about retrospective studies. laboratory confirmation of sars-cov- was defined as a positive real-time reverse transcriptase-polymerase chain reaction (rt-pcr) assay of nasal and pharyngeal swabs [ ] . the four participating icus applied local (parisian) guidelines regarding icu admission, the provision of standard of care (including sedation, and neuromuscular blockade), the use of non-invasive ventilation, antibiotic treatment, as well as the use of rescue therapies for refractory hypoxemia (prone positioning, ecmo, etc.). these guidelines were approved by all and shared on the health regional agency website (https ://www. ilede franc e.ars.sante .fr/coron aviru s-covid - -infor matio n-aux-profe ssion nels-de-sante ). there were no guidelines regarding the use of anti-viral agents, steroids, or cytokine-blockade that were mostly used in rcts, sometimes through tua (temporary use authorisation) or upon clinician's decisions. data were recorded by the intensivists in each icu. the variables reported in the tables and figures were abstracted from the medical charts and electronic reports. chronic obstructive pulmonary disease was defined as previously reported [ ] and acute kidney injury according to the operational decision [ ] . causes of immunosuppression included solid tumours, haematological malignancies, solid organ transplantation, longterm immunosuppressive therapy (i.e., high-dose steroids (> mg/kg whatever the duration) or any immunosuppressant for more than months), and hiv infection [ ] . obesity was defined as previously reported [ ] . the time from covid- viral symptom onset to icu admission no longer than days is associated with a higher risk of death. a faster onset of critical illness may be associated with kidney and myocardial injury in addition to lung injury, as well as with higher il- concentrations. interventions that are currently used in covid- patients might impact different clinical endpoints according to time since viral symptom onset. sofa score was calculated within h of icu admission [ ] . time from viral symptom onset to icu admission was defined as the number of days between the onset of flulike viral symptoms (fever or chills, cough, sore throat, runny nose, anosmia, muscle pain, body aches, headaches, fatigue, vomiting or diarrhoea) and the day of icu admission. in patients who were intubated and sedated, and unable to respond, relatives were asked to provide the detailed medical history. otherwise, data were retrieved from the medical charts from the emergency department, outpatient consults, general practitioner or medicalised ambulances. time from viral symptom onset to hospitalisation or from hospitalisation to icu admission was calculated as number of days between viral symptom onset or admission to the hospital, and icu admission. patient status at icu and hospital discharge was recorded on may . icu length of stay was recorded. continuous variables are described as median (interquartile range [iqr] ) and compared between groups using the non-parametric wilcoxon rank-sum test. categorical variables are described as frequency (percentages) and compared between groups using fisher's exact test. mortality was assessed using survival analysis. the patients were categorised according to the number of days between disease onset (i.e., the number of days between viral symptoms onset) and icu admission (< , - , and > days). independent risk factors for day- mortality were identified using a cox model. conditional stepwise variable selection was performed with . as the critical p value for entry into the model and . as the p value for removal. interactions and correlations between the explanatory variables, the validity of the proportional hazards assumption, the influence of outliers, and linearity of the relationship between the log hazard and the covariates were carefully checked. for the first step of the variable selection process, age, comorbidities (asthma, diabetes, copd, hypertension, immunosuppression), time from viral symptom onset to icu admission, acute kidney injury, and troponin were included in the model. kaplan-meier graphs were used to express the probability of death from icu admission to day . comparisons were performed using the log-rank test. in a sensitivity analysis, a double adjustment was performed. first, patients were matched on risk factors for icu admission within the first days of covid- . then, a propensity score (ps)-matched analysis was performed on the risk of icu admission within days after viral symptom onset. variables were selected to the ps model if associated with p < . ; they included comorbidities (asthma, hypertension, heart failure), body temperature at admission, and acute kidney injury. casematching was with a : ratio, without replacement, and according to the nearest neighbour method. adequacy of the matching procedure was assessed by plotting ps across groups and computing the standardised mean difference. a univariate analysis was performed, and a cox model was then built with double adjustment on relevant variables that were associated with the outcome and poorly matched. the missing data rate was . % overall and < % for major outcomes or covariates. imputation of missing data was not performed. statistical analyses were performed with r statistical software, version . . (available online at https ://www.rproje ct.org/), using the 'survival' and 'matchit' packages. values of p < . were considered significant. we included patients admitted between february and april . table reports their main features. all but ( . %) patients had at least one comorbidity, and the main comorbidities were obesity and overweight ( . and %, respectively), hypertension ( . %), and diabetes ( . %). time from viral symptom onset to icu admission had a median of [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days. icu, hospital, and day- mortality rates were % (n = ), % (n = ), and % (n = ), respectively. on may , ( %) patients were still hospitalised. as shown in fig. , day- mortality decreased with increasing time from viral symptom onset to icu admission. patients admitted within a week after viral symptom onset had a higher day- mortality rate than did those admitted in the second or third week after viral symptom onset (figs. and ) . tables and compare patient characteristics across the three groups. patients admitted within the first week were more often treated for hypertension and more often febrile at icu admission; also, their radiographic lung involvement was more limited compared to that in the other two groups. patients admitted in the first week less often received high-flow nasal oxygen; they had a higher prevalence of acute kidney injury and more often required renal replacement therapy during the icu stay. among the patients, % had an associate bacterial infection, including . % with a sars-cov , p = . ), normal troponin concentration at admission ( % vs. %, p < . ), need for invasive mechanical ventilation ( % vs. %, p < . ), need for vasopressors ( % vs. %, p = . ), and need for renal replacement therapy ( % vs. %, p = . ). by multivariable cox proportional analysis, factors independently associated with day- mortality were age, copd, immunocompromised status, time from viral symptom onset to icu admission, normal troponin at icu admission, and acute kidney injury (table s ). the total number of patients is as the time between viral symptom onset and icu admission was unavailable for three patients ¥immunocompromised patients included patients with solid tumours, haematological malignancies, solid organ transplantation, or long-term or high-dose steroid therapy £digestive viral symptoms included diarrhoea, abdominal pain, vomiting, and/or occlusion there was no centre effect in this study. for instance, when adding to our final model in the whole population a random effects model for the centre effect, our results were unchanged (hr for time since viral symptom onset - days: . ; % ci . - . ; hr for time > days: . ; % ci . - . ). in the paired matched analysis, patients admitted within the first week after viral symptom onset were matched to controls. day- mortality was . % in the group admitted within a week after disease onset and . % in the group of patients admitted later (fig. s , p = . ) in an exploratory analysis in patients from our cohort (table s ) , concentrations of cytokines including il and il varied significantly across the three patient groups. identifying the determinants of outcomes of critically ill patients with severe covid- is vital to optimise the use of icu and other hospital resources. this study collecting data from covid- patients showed that mortality decreased with increasing time from viral symptom onset to icu admission. mortality was significantly higher in patients admitted to the icu within a week after viral symptom onset, independently from acute illness severity at icu admission. these findings may help to guide the clinical management. they may also be useful for the identification and rational design of effective therapies. interestingly, apart from the prevalence of hypertension, the baseline patient characteristics (age, sex, body mass index, hypoxaemia severity at admission, and inflammation) were mostly similar across the three patient groups defined by viral symptom duration at icu admission. the severity of respiratory failure as assessed by the pao /fio ratio at admission was not significantly different across the three groups. in contrast, the group with early icu admission had a worse sofa score value and a higher prevalence of acute kidney injury, suggesting that the increased mortality was related to early multi-organ dysfunction, as opposed to only severe lung involvement. the significantly smaller number of lung quadrants involved in the early admission group supports this possibility. sars-cov- can bind to many target organs via the angiotensin-converting enzyme receptor. the virus predominantly infects airway and alveolar epithelial cells, but can also infect vascular endothelial cells and macrophages [ ] . sars-cov- viral particles and genome have been detected in monocytes and lymphocytes [ ] . the aggressive inflammation induced by viral replication not only generates type ii pneumocyte apoptosis and severe respiratory distress related to cytokine-induced fluid leakage, but also induces a cytokine storm with multi-organ failure. three lines of evidence seem to support a two-hit model in which an initial insult related to viral replication and responsible for inflammation and injury to multiple organs is followed by a second insult related to exaggerated cytokine production by both epithelial and endothelial cells. first, in a study of patients admitted in wuhan, shanghai, and anhui, the time from viral symptom onset to the first positive rt-pcr test was shorter in the group with critical illness than in the groups with moderate or severe illness [ ] . second, virus-induced alveolar cell death and the accumulation of apoptotic and necrotic cellular debris have been reported to first elicit a pro-inflammatory response from the macrophages then to result in the production of large amounts of eicosanoids, which in turn stimulate the production of pro-inflammatory cytokines by immune cells such as macrophages [ ] . thus, the eicosanoid storm induces a cytokine storm, which promotes further leucocytosis and immune-cell infiltration. last, a study of patients from wuhan showed that the survival time from viral symptom onset to death had two peaks, at about and days, respectively, in keeping with our findings in patients having a length of stay of about days [ ] . strikingly, % of the patients who died had myocardial damage [ ] , a finding consistent with the higher troponin levels in the patients who died compared to survivors in our study. the contribution of fulminant myocarditis to increased mortality in patients admitted within a week of disease viral symptoms deserves further investigation. this study has several limitations. first, the retrospective design limits the interpretation of the findings. however, few data were missing ( . %). moreover, with critically ill patients managed in four centres, this study is among the largest to date. the largest study to date of critically ill covid- patients [ ] emphasised the association of older age with short-term mortality, but did not separate outcomes according to time since viral symptom onset. second, the excess mortality in patients admitted to the icu within days after viral symptom onset was associated with an increased prevalence of non-respiratory injury and, more specifically, of acute kidney and myocardial injury. however, we did not specifically assess causes of death. third, although markers for inflammation were available for all patients, cytokine and lymphocyte typing data were obtained in only patients. our results suggest that targeting il- might be most effective in patients admitted earlier after viral symptom onset. however, this possibility requires further assessment. moreover, sensitivity analyses of the results of ongoing anti-il trials should also explore whether il blockade is most beneficial in those patients admitted to the icu within a week after viral symptom onset. in summary, excess mortality occurred in patients admitted to the icu within a week after covid- onset. this excess mortality was not related to more severe respiratory disease but, instead, to worse dysfunction of other organs and, more specifically, to acute kidney and myocardial injury. studies to investigate the extent of organ injuries at each stage of the disease are warranted. interventions including antiviral, antiinflammatory, or targeted therapies that are currently used in patients with sars-cov- might impact different clinical endpoints according to time since viral symptom onset. the online version of this article (https ://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. the sars-cov- outbreak has been particularly challenging for patients, relatives, healthcare providers, and all others involved. we are indebted to all for their willingness to participate in combatting this health disaster. author contributions ea, ad, avb and mf have designed the study and guided the analyses. all authors have significantly contributed to the research, have discussed the results of the analyses, have edited the final version of the manuscript and have agreed with the submitted version. no funding was received for this study. none of the authors has any conflicts of interest to declare. the total number of patients is as the time between viral symptom onset and icu admission was unavailable for three patients. a new coronavirus associated with human respiratory disease in china a novel coronavirus from patients with pneumonia in china emerging coronaviruses: genome structure, replication, and pathogenesis epidemiological characteristics and incubation period of confirmed cases with coronavirus disease outside hubei province in china clinical features of patients infected with novel coronavirus in wuhan, china clinical characteristics of coronavirus disease in china intensive care management of coronavirus disease (covid- ): challenges and recommendations clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china covid- with different severity: a multicenter study of clinical features baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region hospitalization and critical care of decedents with covid- pneumonia in wuhan, china understanding sars-cov- -mediated inflammatory responses: from mechanisms to potential therapeutic tools cytokine storm intervention in the early stages of covid- pneumonia extracellular hmgb : a therapeutic target in severe pulmonary inflammation including clinical characteristics of refractory covid- pneumonia in wuhan, china targeting potential drivers of covid- : neutrophil extracellular traps detectable serum sars-cov- viral load (rnaaemia) is closely correlated with drastically elevated interleukin (il- ) level in critically ill covid- patients surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) early chronic obstructive pulmonary disease: definition, assessment, and prevention the definition of acute kidney injury and its use in practice acute respiratory failure in immunocompromised adults obesity could shift severe covid- disease to younger ages the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine new understanding of the damage of sars-cov- infection outside the respiratory system pathological inflammation in patients with covid- : a key role for monocytes and macrophages inflammation resolution: a dual-pronged approach to averting cytokine storms in clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china key: cord- -v yrc q authors: al maani, amal; paul, hema; al-rashdi, azza; al wahaibi, adil; al-jardani, amina; al abri, asma m. ali; albalushi, mariam a. h.; al abri, seif; al reesi, mohammed; al maqbali, ali; al kasaby, nashwa m.; de groot, theun; f. meis, jacques; al-hatmi, abdullah m. s. title: ongoing challenges with healthcare-associated candida auris outbreaks in oman date: - - journal: j fungi (basel) doi: . /jof sha: doc_id: cord_uid: v yrc q candida auris has emerged in the past decade as a multi-drug resistant public health threat causing health care outbreaks. here we report epidemiological, clinical, and microbiological investigations of a c. auris outbreak in a regional omani hospital between april and april . the outbreak started in the intensive care areas (intensive care unit (icu), coronary care unit (ccu), and high dependency unit) but cases were subsequently diagnosed in other medical and surgical units. in addition to the patients’ clinical and screening samples, environmental swabs from high touch areas and from the hands of staff were collected. all the positive samples from patients and environmental screening were confirmed using maldi-tof, and additional its-rdna sequencing was done for ten clinical and two environmental isolates. there were patients positive for c. auris of which ( . %) had urinary tract infection, ( . %) had candidemia, and ( . %) had asymptomatic skin colonization. the median age was years ( – ) with ( . %) male and ( . %) female patients. prior to diagnosis, ( . %) had been admitted to the intensive care unit, and ( . %) had been nursed in medical or surgical wards. the crude mortality rate in our patient’s cohort was . . two swabs collected from a ventilator in two different beds in the icu were positive for c. auris. none of the health care worker samples were positive. molecular typing showed that clinical and environmental isolates were genetically similar and all belonged to the south asian c. auris clade i. most isolates had non-susceptible fluconazole ( %) and amphotericin b ( %) minimal inhibitory concentrations (mics), but had low echinocandin and voriconazole mics. despite multimodal infection prevention and control measures, new cases continued to appear, challenging all the containment efforts. the outbreak occurred in a secondary care regional ( -bed) hospital in oman (sohar hospital) with different medical and surgical units. the intensive care department is composed of two units; the intensive care unit (icu), which is an open multi-bed space that can accommodate up to ventilated patients (medical and surgical cases), and the coronary care unit (ccu), which has capacity for patients in single rooms. the department is staffed by intensivists, nurses, and respiratory technicians. all the surgical and medical wards are multi-bed ( cubicles) with shared toilet facilities and some have one or two single isolation rooms. the capacity of each cubicle is - beds which are separated by curtains keeping a minimal space of . m between them. each patient will be attended to by a caregiver who will be usually occupying the space between the patients' beds. any patient admitted to the facility for more than h with a positive screening or clinical sample culture for c. auris was included. the case was stratified as infection versus colonization based on clinical and/or laboratory markers as an evidence of infection. candida auris was isolated by routine microbiology procedures from clinical samples, such as blood, urine, surgical wounds, and catheters, as well as from screening samples (axilla, groin, nasal, throat, and perianal swabs). environmental samples were collected from the icu and high dependency units especially from high touch areas and re-useable devices (including ventilators, patient's cots, steel trolleys, staff and patient lockers, glove boxes, bed lights, racks, sinks, tissue boxes, hand rub dispensers, curtains, floors, head lights, and infusion pumps), using sterile swabs moistened with sterile saline. the first set of environmental samples were collected on october , just before conducting cleaning using a chlorine-based disinfectant ( % sodium hypochlorite with . % sodium chloride) and environmental decontamination with hydrogen peroxide (h o ) fumigation. another set of swabs were collected after cleaning and decontamination of the icu on october . a total of environmental swabs were collected for screening purposes. hand swabs were also collected from health care workers (hcws) in intensive care and high dependency areas. this included nurses, intensivists, respiratory therapists, and medical assistants. all swabs were transported to the laboratory in charcoal transport medium and were inoculated on sabouraud dextrose agar (sda) and incubated at • c for h. all the positive candida isolates processed in the hospital laboratory (clinical or screening) were referred to the central public health laboratory (cphl) for confirmation. the isolates were preliminary identified by phenotypic and biochemical characteristics. biochemical characteristics were analyzed by api c aux (biomerieux). further identification was done using maldi-tof ms (maldi biotyper mbt smart v . . . . , bruker daltoniks, bremen, germany) at canisius wilhelmina hospital, nijmegen, the netherlands [ ] . there were c. auris isolates ( environmental and clinical) examined for further identification and molecular typing at canisius wilhelmina hospital, nijmegen, the netherlands. strains were transferred to fresh glucose-yeast-peptone agar (gypa) plates and incubated at • c for h. dna extraction was performed by the quick ctab (cetyltrimethylammonium bromide) extraction method according to the protocol described by al-hatmi et al. [ ] . briefly, approximately full loop of h cultures was transferred to a ml screw-capped tubes filled with a µl % cetyltrimethylammonium bromide (ctab) buffer and - acid-washed glass beads (diameter . - . mm, sigma). a total of µl proteinase k were added and mixed on a mobio vortex for min, and the mixture was incubated at • c for min. after incubation, µl chloroform:isoamylalcohol ( : ) was added and shaken for min. the tubes were centrifuged for min at , rpm, supernatants were collected in new . ml eppendorf tubes, and~ µl of ice-cold iso-propanol was added followed by centrifugation again at , rpm for min. pellets were washed with ml ice-cold % ethanol, dried using a vacuum dryer, and re-suspended in µl te-buffer. dna concentrations were measured with a nanodrop spectrophotometer (thermo fisher, wilmington, nc, usa). extracted dnas were stored at − • c until use. pcr amplification and sequencing of the rdna internal transcribed spacer region (its) was performed using primers its and its . the internal transcribed spacer region (its) was amplified. the pcr reactions mixture contained µl template dna ( ng), . µl × pcr buffer, µl dntp mix ( . mm), . µl of each primer ( pmol), . µl taq polymerase (biotaq, bioline, germany) ( u/µl), bsa . µl, and water to complete the final volume of . µl. pcr was performed in an abi prism (applied biosystems, foster city, ca, usa). amplifications were performed as follows: • c for min, followed by cycles consisting of • c for s, • c for s and • c for min, as well as a post-elongation step at • c for min. pcr products were visualized by electrophoresis on a % (w/v) agarose gel. sequencing reaction mixtures contained µl template dna ( . pmol), µl primer ( mm), µl of bigdyetm terminator (applied biosystems), µl buffer, and . µl ultra-pure water to µl final volume. sequencing pcr was performed as follows: • c for min, followed by cycles consisting of • c for s, • c for s, and • c for min. dna sequences were edited and consensus sequences were assembled by the seqman package of lasergene software (dnastar, madison, wi, usa). sequences were exported as fasta files. for preliminary identification, a homology search for the sequences of its was done using the blast tool in ncbi and cbs databases down to species level. for conclusive identification, sequences were aligned with mafft (www.ebi.ac.uk/tools/msa/mafft/), followed by manual adjustments with mega v. . and bioedit v. . . . . the ml trees were constructed with mega v. . . maximum likelihood (ml) analysis was done with raxml-vi-hpc v. . . with non-parametric bootstrapping using replicates. for genotyping c. auris a small tandem repeat (str) analysis was employed [ ] . briefly, dna was extracted and purified with the magna pure lc instrument and the magna pure dna isolation kit iii (roche diagnostics gmbh, mannheim, germany), according to the recommendations of the manufacturer. strains were resuspended in µl physiological salt and after addition of u of lyticase (sigma-aldrich, st. louis, mo, usa) and incubation for min at • c, µl physiological salt was added. the sample was then incubated for min at • c and cooled down to room temperature. four multiplex pcr reactions, which amplify str targets with a repeat size of , , or nucleotides, was done for genotyping the omani isolates, which were compared with the global collection [ ] . copy numbers of the twelve markers of all isolates were determined using genemapper software (applied biosystems). relatedness between isolates was analyzed using bionumerics v. . . software (applied maths, kortrijk, belgium) via the unweighted pair group method with arithmetic averages, using the multistate categorical similarity coefficient. in vitro antifungal susceptibility testing of a selection of c. auris isolates (n = ) was performed using the m -a broth microdilution method of clsi (clinical and laboratory standards institute) [ ] . descriptive statistics of the cases were presented as the mean, the median for continuous variables, and percentages for categorical variables. these analyses along with the chart for patient transfer within the hospital were constructed using excel software. the first case of candidemia during this outbreak was identified in june (week ) after a patient died (figure ). a total of patients were identified ( infected and colonized) with c. auris from april to april (table ). there were ( . %) patients with candidemia and ( . %) with urinary tract infection. the affected age group ranged from - years with a median of years. the male to female ratio was : . a total of % (n = ) of affected patients had comorbidities that included diabetes mellitus, hypertension, and cardiovascular, neurological and immunodeficiency diseases. antibacterial usage prior to diagnosis was reported for ( %) patients, and ( . %) patients were on antifungals including fluconazole, voriconazole, and lipid-based formulations of amphotericin b. including: diabetes, hypertension, cardiovascular, neurological, and immunodeficiency diseases; this was calculated as collection date minus admission date; included: cephalosporin, piperacillin/tazobactam, and meropenem; included: fluconazole, voriconazole, and liposomal amphotericin b. among the infected cohort, ( %) patients had been admitted to the icu prior to the diagnosis but ( . %) were in other medical or surgical wards ( figure ). the mean number of admission days prior to developing infection was . . out of the infected patients died ( . %), ( . %) recovered, and ( . %) were still admitted (table ) . the first case of candidemia during this outbreak was identified in june among the infected cohort, ( %) patients had been admitted to the icu prior to the diagnosis but ( . %) were in other medical or surgical wards ( figure ). the mean number of admission days prior to developing infection was . . out of the infected patients died ( . %), ( . %) recovered, and ( . %) were still admitted (table ) . the first case of candidemia during this outbreak was identified in june (week ) after the dead of a patient. cases continued to accumulate intermittently transferring stable emergency cases to other hospitals, and conducting daily infection control rounds to observe health care worker adherence to hand hygiene and care bundles. the above measures resulted in ending the mers-cov transmission but new cases of c. auris continued to occur. among the different isolates collected during this outbreak, were found to be positive after removing duplicates from the same patient. there were seven patients who had c. auris, recovered from more than one site at different episodes during their stay in the hospital. out of swabs collected from environmental surfaces of icu, ccu, and high dependency areas, two swabs from the icu were found to be positive for c. auris (ventilator in bed no. and a steel trolley near bed no. in the icu). repeated swabs after environmental cleaning in the icu were negative. none of the samples collected for screening from health care workers grew candida. the c. auris strains were identified by maldi-tof ms for candida species with confidence log scores > . , indicating correct generic and species identification. a part of the its region was used for identification of positive clinical and environmental isolates. its gene possessed enough polymorphisms and, therefore, was an excellent marker with %- % accuracy for the identification of candida species to be c. auris. for more accurate identification, the phylogenetic position of c. auris was established using maximum likelihood (ml) analysis with raxml-vi-hpc v. . . ( bp) for the its region. candida species within the c. haemulonii complex and other closely related candida species were selected for phylogenetic analyses and sequences of the its gene were aligned among the sequences available from genbank. the its phylogenetic analyses showed that the reported clinical isolates were c. auris and were found to be identical to many other clinical strains of c. auris from all over the world (figure ). by among the different isolates collected during this outbreak, were found to be positive after removing duplicates from the same patient. there were seven patients who had c. auris, recovered from more than one site at different episodes during their stay in the hospital. out of swabs collected from environmental surfaces of icu, ccu, and high dependency areas, two swabs from the icu were found to be positive for c. auris (ventilator in bed no. and a steel trolley near bed no. in the icu). repeated swabs after environmental cleaning in the icu were negative. none of the samples collected for screening from health care workers grew candida. the c. auris strains were identified by maldi-tof ms for candida species with confidence log scores > . , indicating correct generic and species identification. a part of the its region was used for identification of positive clinical and environmental isolates. its gene possessed enough polymorphisms and, therefore, was an excellent marker with %- % accuracy for the identification of candida species to be c. auris. for more accurate identification, the phylogenetic position of c. auris was established using maximum likelihood (ml) analysis with raxml-vi-hpc v. . . ( bp) for the its region. candida species within the c. haemulonii complex and other closely related candida species were selected for phylogenetic analyses and sequences of the its gene were aligned among the sequences available from genbank. the its phylogenetic analyses showed that the reported clinical isolates were c. auris and were found to be identical to many other clinical strains of c. auris from all over the world (figure ). by using str genotyping, the isolates from oman clustered with indian isolates in the south-asia clade (figure ) while isolates from south africa, japan/korea, venezuela, and iran each clustered in the other four major c. auris clades, previously identified via whole-genome sequencing (wgs) [ , ] . j. fungi , , x for peer review of using str genotyping, the isolates from oman clustered with indian isolates in the south-asia clade (figure ) while isolates from south africa, japan/korea, venezuela, and iran each clustered in the other four major c. auris clades, previously identified via whole-genome sequencing (wgs) [ , ] . table summarizes the mic values of eight antifungal drugs against c. auris (n = ). there was a uniform pattern of mics below the ecoff for itraconazole, voriconazole, posaconazole, isavuconazole, anidulafungin, and micafungin [ ] . the highest non-susceptible mics were recorded for fluconazole (mic , > mg/l) and amphotericin b (mic mg/l, mic mg/l). table summarizes the mic values of eight antifungal drugs against c. auris (n = ). there was a uniform pattern of mics below the ecoff for itraconazole, voriconazole, posaconazole, isavuconazole, anidulafungin, and micafungin [ ] . the highest non-susceptible mics were recorded for fluconazole (mic , > mg/l) and amphotericin b (mic mg/l, mic mg/l). with the increasing incidence of candidemia in the intensive care unit, with high mortality, an outbreak team was formed to investigate and manage the situation (figure ) . a retrospective search of one year prior to diagnosis of the first case in the hospital microbiology data base showed no previous isolates of c. auris. some actions were immediately taken, including: creating awareness about c. auris among the health care workers; training all staff of involved units on standard and contact isolation precautions; involving an administration and infection control committee; regular infection control rounds for the affected units, with monitoring of adherence to hand hygiene and other precautions with immediate feedback to staff; implementing screening for c. auris on routine admission to the icu and all contacts of positive cases; and ensuring proper terminal cleaning of rooms and bed spaces. there had been a period of six weeks where no further new cases occurred (weeks - ) but starting from week onwards new cases were diagnosed from different units and wards (figures and ). environmental and health care worker screening was done in the icu where most patients had been identified. this was followed by extensive environmental cleaning with infection control supervision. cleaning was done with a chlorine-based disinfectant ( % sodium hypochlorite with . % sodium chloride), in a ratio of seven tablets per . l of water. this was used for beds and all articles surrounding them and for mopping the floor. different mops were used for each cubicle and aldehyde free alcohol wipes were employed to clean all equipment and monitors. all positive cases were isolated with designated medical equipment and toilet facilities. extensive environmental cleaning and decontamination was done with fumigation with h o . in addition, the implementation of care bundles in all units, strictly enforced adherence to infection control measures, and instituting an antimicrobial stewardship program in the hospital, as well as a competency-based certification course in infection control for all hcws were conducted. all the above measures resulted in earlier detection of cases and improving the outcome of patients, but the incidence of new cases had continued (figure ). we report to the best of our knowledge the largest outbreak in the middle east region from one facility with patients affected and a crude mortality rate of %. in the last three years, six countries in the middle east, including oman (iran, kuwait, ksa, uae, and israel) have reported c. auris in adult patients with several underlying comorbidities [ , ] . the -day crude mortality rates with c. auris infection have been variable in different geographical regions and found to range between % and % [ ] . a recent review from the middle east showed a crude mortality rate of % but in the united kingdom no deaths were directly attributable to c. auris infection. our series showed a crude mortality rate of . %. the high crude mortality maybe a reflection of the comorbidities within the infected population and the diagnostic delay, in addition to the resistant nature of the pathogen [ ] . candida auris is known to affect icu patients, especially those with medical devices (cvcs, urinary catheters, etc.). the latter suggests a potential role for biofilm formation [ , ] . the role of environmental contamination in facilitating c. auris transmission, illustrated in this outbreak, confirms previous similar findings elsewhere, including the oxford university hospitals outbreak where sequenced isolates from reusable equipment were genetically related to isolates from patients [ , ] . environmental screening can be problematic and not cost effective because of transient, sporadic contamination. for example, a report from an icu in india reported less than % environmental contamination [ ] . the same is true for health care workers screening, which usually result in a large number of samples and a very low positivity rate (less than % in the indian [ ] and uk studies [ ] and zero positive out of screened hcws in our study). the single positive hcw in the uk study cared for only one patient, who was heavily colonized with c. auris but was not implicated in any onward transmissions, which further questions the practical implication of screening health care workers [ ] . the intensive care units had been hotspots for c. auris with a great challenge in breaking the vicious cycle of environment/workers contamination-patient contamination infection [ ] . candida auris can persist on different types of surfaces, including moist, dry, and plastic surfaces, with the potential of survival for up to days [ ] [ ] [ ] [ ] [ ] . the success of environmental decontamination was variable in the literature utilizing mostly materials and methods tested earlier against resistant gram-positive and gram-negative pathogens [ , , , ] . the use of high-concentration chlorine solutions in combination with hydrogen peroxide vapor or uv light for terminal decontamination has been suggested to be effective in controlling the transmission in some reports [ , , , ] . the same protocol without uv light was used in our setting twice including when it was used for controlling a mers-cov outbreak, but this failed to have impact on the incidence of new c. auris cases. this could be due to a hidden colonized population or environmental reservoir. the genome analysis of c. auris suggests that there are between and protein-coding sequences, including those for virulence factors such as biofilm formation and acquisition of drug resistance [ , ] . there is also widespread variation between geographic clades, with thousands of single nucleotide polymorphism (snp) differences. at present, c. auris is separated into five geographic clades: the south asian, african, south american, iranian, and east asian clades [ , , , ] . phylogenomic analysis using its sequences and str genotyping show that the omani isolates belong to the south asian clade. most of the omani isolates of c. auris exhibited non-susceptible fluconazole mics (≥ mg/l). some strains of c. auris can be non-susceptible to multiple antifungal classes, severely limiting treatment options and making infection control and prevention guided by rapid detection in healthcare settings essential [ ] [ ] [ ] [ ] . the known characteristics of c. auris (rapid acquisition and spread within affected facilities, high mortality rates, challenging environmental decontamination, and high levels of antifungal resistance) underscore the importance of rapid containment of the spread of this public health pathogen, including developing rapid and accurate diagnostic tools at the point of care [ , ] and investing in infection control and antimicrobial stewardship programs. a high mortality rate and the on-going challenges for containment have been highlighted, with a call for global attention to this growing antimicrobial resistant pathogen, and active research acceleration on intervention modalities. candida auris: a review of the literature candida auris-the growing menace to global health epidemiology, clinical characteristics, resistance, and treatment of infections by candida auris simultaneous emergence of multidrug-resistant candida auris on continents confirmed by whole-genome sequencing and epidemiological analyses increasing prevalence, molecular characterization and antifungal drug susceptibility of serial candida auris isolates in kuwait epidemiologic shift in candidemia driven by candida auris first report of candida auris in america: clinical and microbiological aspects of episodes of candidemia multidrug-resistant candida haemulonii and c. auris first report of candida auris in oman: clinical and microbiological description of five candidemia cases candida auris otomycosis in iran and review of recent literature the first cases of candida auris candidaemia in oman incidence, characteristics and outcome of icu-acquired candidemia in india approach to the investigation and management of patients with candida auris, an emerging multidrug-resistant yeast candida auris: a rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally new clonal strain of candida auris first hospital outbreak of the globally emerging candida auris in a european hospital an outbreak due to candida auris with prolonged colonisation and candidaemia in a tertiary care european hospital investigation of the first seven reported cases of candida auris, a globally emerging invasive, multidrug-resistant fungus-united states recommendations for identification of candida auris clinical spectrum and factors impacting outcome of candida auris: a single center study from pakistan new kid on the block" in hospital-associated infections? candida auris identification and rapid antifungal susceptibility testing against echinocandins by maldi-tof ms maldi-tof and aflp data support fusarium ficicrescens as a distinct species within the f. fujikuroi species complex development of candida auris microsatellite typing and its application on a global collection of isolates reference method for broth dilution antifungal susceptibility testing of filamentous fungi; approved standard-second edition; m -a molecular diagnostics in the times of surveillance for candida auris candida auris: a global fungal public health threat the emerging pathogen candida auris: a focus on the middle-eastern countries a candida auris outbreak and its control in an intensive care setting controlling a possible outbreak of candida auris infection: lessons learnt from multiple interventions the global challenge of candida auris in the intensive care unit survival, persistence, and isolation of the emerging multidrug-resistant pathogenic yeast candida auris on a plastic health care surface environmental surfaces in healthcare facilities are a potential source for transmission of candida auris and other candida species antifungal resistance: specific focus on multidrug resistance in candida auris and secondary azole resistance in aspergillus fumigatus biofilm formation by candida auris isolated from colonising sites and candidemia cases combined antifungal resistance and biofilm tolerance: the global threat of candida auris effectiveness of disinfectants against candida auris and other candida species killing of candida auris by uv-c: importance of exposure time and distance control of candida auris in healthcare institutions. outcome of an isac expert meeting genomic insights into multidrug-resistance, mating and virulence in candida auris and related emerging species draft genome sequence of a fluconazole-resistant candida auris strain from a candidemia patient in india candida auris isolates ( - ) in india: role of the erg and fks genes in azole and echinocandin resistance comparison of eucast and clsi reference microdilution mics of eight antifungal compounds for candida auris and associated tentative epidemiological cutoff values potential fifth clade of candida auris we thank all healthcare workers in sohar hospital, regional and national infection prevention practitioners, and the staff at the mycology section at cphl for their dedicated work and support in the investigation and management of this outbreak. the authors declare no conflict of interest. key: cord- -pre bzne authors: kalligeros, markos; shehadeh, fadi; mylona, evangelia k.; benitez, gregorio; beckwith, curt g.; chan, philip a.; mylonakis, eleftherios title: association of obesity with disease severity among patients with covid‐ date: - - journal: obesity (silver spring) doi: . /oby. sha: doc_id: cord_uid: pre bzne objective: to explore the potential association of obesity and other chronic diseases with severe outcomes, such as intensive care unit (icu) admission and invasive mechanical ventilation (imv), in patients hospitalized with covid‐ . methods: retrospective cohort of patients hospitalized with covid‐ . demographic data, past medical history and hospital course were collected and analyzed. a multivariate logistic regression analysis was implemented to examine associations. results: from february th to april th, consecutive patients were hospitalized with covid‐ . among them, patients ( . %) were admitted to the icu and ( . %) required (imv). the prevalence of obesity was . % ( / ). in a multivariate analysis, severe obesity (bmi ≥ kg/m ) was associated with icu admission (aor . ; % ci: . ‐ . ). moreover, patients who required imv, were more likely to have had heart disease (aor . ; % ci: . ‐ . ), obesity (bmi= ‐ . kg/m ) (aor . ; % ci: . ‐ . ) or severe obesity (bmi≥ kg/m ) (aor . ; % ci: . ‐ . ). conclusion: in our analysis, severe obesity (bmi ≥ kg/m ) was associated with icu admission, while history of heart disease and obesity (bmi ≥ kg/m ) were independently associated with the use of imv. increased vigilance and aggressive treatment of patients with obesity and covid‐ are warranted. in late december , a cluster of patients with pneumonia of unknown origin was first reported in wuhan, china [ ] . since then, coronavirus disease , caused by sars-cov- , has taken the world by storm and was officially declared a pandemic by the world health organization on march , . clinical manifestations of covid- range from asymptomatic or mild infection to severe forms of disease that are life-threatening. among other risk factors, chronic conditions such as chronic lung disease, cardiovascular disease, diabetes mellitus, and hypertension [ ] [ ] [ ] , seem to increase the risk for severe covid- outcomes. in addition, although the role of obesity was initially neglected [ ] , recent reports [ , ] found that obesity is associated with severe covid- outcomes as well. in this study we utilize data from the largest healthcare network in rhode island, usa, with the aim of exploring the potential association of the above-mentioned chronic diseases with severe outcomes such as icu admission and invasive mechanical ventilation (imv) in patients hospitalized with sars-cov- infection. all consecutive adult (≥ years old) patients, who had a laboratory confirmed (using a reverse transcriptase-polymerase chain reaction assay) sars-cov- infection and were admitted to rhode island hospital, the miriam hospital, or newport hospital, in rhode island, usa, between february th and april th , were considered eligible for inclusion. this study was a retrospective electronic chart review and it was approved by the institutional review board of rhode island hospital. a consent waiver was also obtained for the purposes of this study. this retrospective cohort study was performed in line with the strobe (strengthening the reporting of observational studies in epidemiology) statement (table s ). two independent investigators (mk, fs) extracted deidentified demographic, epidemiological, clinical and laboratory data of interest. more specifically, we extracted the following variables: age, gender, race, smoking status, body mass index (bmi), past medical history and hospitalization course. this article is protected by copyright. all rights reserved our primary outcome was to assess if specific risk factors, namely age, race, gender, bmi, diabetes, hypertension, chronic heart disease, and chronic lung disease are associated with icuadmission within the first days of hospital admission with covid- . our secondary objective was to assess if the aforementioned factors are associated with the need for imv during the first days of hospital admission with covid- . for the purposes of statistical analysis, we represented continuous measurements as medians (iqrs) and we compared them using the mann-whitney-wilcoxon test. for categorical data, we used a two-proportion z-test to compare the difference in population proportions between patients admitted to the icu and patients that did not require icu admission. we also examined the association of icu admission and the need for imv with the following variables: age, race, gender, bmi, diabetes, hypertension, heart disease, and chronic lung disease. after examining the associations in a univariate logistic regression model, we performed multivariate logistic regression analysis, where we included all of the above-mentioned variables in the same model. in addition, for the outcome of obesity we show a model that adjusts for potential demographic confounders, but does not include the other chronic disease variables. for our analyses % confidence intervals and p-values are shown. all analyses were performed using stata v . (stata corporation, college station, tx). we identified adult consecutive patients who were admitted with covid- in our hospitals from february th to april th . patients baseline characteristics are depicted on table . the median age of patients was ( - ) years, while patients ( . %) were men. among hospitalized patients with covid- , were non-hispanic white, were hispanic, were non-hispanic black and were non-hispanic asian. the most common comorbidities were hypertension ( %), followed by diabetes ( . %) and heart disease ( . %). the prevalence of obesity was . % among hospitalized patients, . % among patients requiring icu admission and . % among patients who required imv. during the first days of their hospitalization, out of patients were admitted to the icu and of them required imv. both univariate and multivariate logistic regression analyses were used to examine the association of variables with icu admission within the first days of hospital admission ( table ). in univariate models none of the variables was associated with icu admission. we performed a multivariate analysis (adjusted for age, gender and race) to examine the association of obesity this article is protected by copyright. all rights reserved with icu admission and found that severe obesity (≥ kg/m ) was associated with increased risk of icu admission (aor . ; % ci: . - . ). we then extended our multivariate model to include additional chronic diseases. although diabetes, heart disease and lung disease seemed to increase the risk of icu admission, only severe obesity (≥ kg/m ) reached statistical significance (aor . ; % ci: . - . ). as a secondary outcome we examined factors associated with imv within days of hospital admission with covid- (table ). in univariate models, preexisting heart disease and severe obesity were associated with the need for imv. in a multivariate model examining the association of different bmi categories with imv (after adjusting for age, gender and race), severe obesity (≥ kg/m ) was associated with need for imv (aor . ; % ci: . - . ). in our expanded multivariate model, even though diabetes was associated with a trend for imv, only heart disease and obesity reached statistical significance. more specifically, patients who needed imv were more likely to have had a diagnosis of preexisting heart disease (aor . ; % ci: . - . ), or obesity (aor of . and . for bmi - . and ≥ kg/m , respectively). we report one of the first us cohorts that investigates the association of obesity with the severity of covid- . we found that severe obesity (bmi ≥ kg/m ) was associated with icu admission, while history of heart disease and obesity (bmi ≥ kg/m ) were independently associated with the use of imv. a disproportionate impact of covid- on patients with obesity should be anticipated since it has also been previously documented for different viral pathogens including influenza [ ] [ ] [ ] . particularly, rates of hospitalizations and death due to the h n influenza virus during the h n pandemic were greater for adults with both obesity and morbid obesity [ ] . of note, death was associated with obesity (or . ; % ci: . - . ) and morbid obesity (or . ; % ci . - . ) even in patients who had no history of other medical conditions. given that the epicenters of covid- are now north america and europe, the impact of obesity on covid- outcomes might become even more pronounced, since these two continents have the highest prevalence of obesity globally [ ] . relatedly, the first results from france [ ] and new york [ ] are in concordance with our findings and confirm this hypothesis. in a retrospective cohort study with patients from france, simonnet this article is protected by copyright. all rights reserved with a bmi < , patients with a bmi between - . were . and . times more likely to be admitted to acute and critical care, respectively [ ] . although the exact mechanism by which obesity may contribute to severe covid- outcomes is not yet defined, several parameters may play a role. first, patients with obesity have altered respiratory physiology, including decreased functional residual capacity and expiratory reserve volume, as well as hypoxemia and ventilation/perfusion abnormalities [ ] . in addition, obesity has been associated with impaired immune system surveillance and response [ ] , while the levels of ace enzyme expression in adipose tissue, an enzyme for which sars-cov- shows high affinity, may also play a role and need to be further studied [ ] . interestingly, we also found an association between preexisting heart disease (which is often associated with obesity as well [ ] ) and the need for imv. such findings, are in agreement with previous reports which mentioned that patients with cardiovascular diseases had an increased risk for severe outcomes, including death from covid- [ ] . we should also mention that although chronic diseases like diabetes did not reach statistical significance in our analysis, previous reports have found an association with worse covid- outcomes [ ] . thus, future studies with more patients should reassess these findings. our study has some limitations that should be taken into consideration. our confidence intervals were relatively wide, likely because of the small sample size. in addition, there was low statistical power for testing interactions. although the retrospective cohort study design used can estimate associations only; similar to a prospective design, our study does have the strength of certainty in regard to the temporal sequence of the exposures and outcomes. in conclusion, our findings emphasize the need for early detection and aggressive treatment for patients with obesity and covid- , especially in countries like the us, where the prevalence of obesity is over % [ ] . we highlight the need for future studies which will assess the mechanisms behind increased covid- severity in patients with obesity, as well as the need for streamlined prevention and treatment strategies for these patients. declarations ethics approval and consent to participate: the study was approved by the rhode island hospital irb. availability of data and materials: the datasets generated and/or analyzed during the current study are not publicly available due to hipaa restrictions. de-identified summary data are available from the corresponding author on reasonable request. this article is protected by copyright. all rights reserved this article is protected by copyright. all rights reserved a novel coronavirus from patients with pneumonia in china characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease -united states obesity and its implications for covid- mortality obesity in patients younger than years is a risk factor for covid- hospital admission high prevalence of obesity in severe acute respiratory syndrome coronavirus- (sars-cov- ) requiring invasive mechanical ventilation obesity and respiratory hospitalizations during influenza seasons in ontario, canada: a cohort study underweight, overweight, and obesity as independent risk factors for hospitalization in adults and children from influenza and other respiratory viruses. influenza other respir viruses obesity and risk of respiratory tract infections: results of an infection-diary based cohort study morbid obesity as a risk factor for hospitalization and death due to pandemic influenza a(h n ) disease accepted article this article is protected by copyright. all rights reserved world health organization. prevalence of obesity among adults, bmi ≥ , age-standardized estimates by who region altered respiratory physiology in obesity obesity and the risk and outcome of infection obesity reviews : an official journal of the international association for the study of obesity mechanisms linking obesity with cardiovascular disease clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china. intensive care med diabetes is a risk factor for the progression and prognosis of covid- . diabetes/metabolism research and reviews us department of health and human services, cdc. national center for health statistics this article is protected by copyright. all rights reserved key: cord- -puly tyv authors: pak, jamie s.; sayegh, christopher i.; smigelski, michael b.; mckiernan, james m.; cooper, kimberly l. title: a urology department's experience at the epicenter of the covid- pandemic date: - - journal: urology doi: . /j.urology. . . sha: doc_id: cord_uid: puly tyv nan since the first reported case of the novel coronavirus disease in washington state, the united states has become the global epicenter of the pandemic. with many predicting critical shortages of hospital beds, ventilators, and health care providers in new york city (nyc), the newyork-presbyterian hospital and columbia university irving medical center (cuimc) quickly implemented system-wide changes to prepare our response. as of may , , nyc itself had , cases and , deaths, the latter only surpassed by five countries outside the united states. in this correspondence, we summarize the cuimc department of urology's experience at the global epicenter of covid- to guide other departments in the response to this and future pandemics. in early march , our department held twice-weekly phone conferences to address the spread of covid- to nyc. all urology faculty, residents, and administrative personnel participated, allowing all parties to ask questions and give input regarding the frequent changes in protocols. these calls ensured immediacy, transparency, and fidelity of information during a rapidly evolving situation. the volume of covid- patients was quickly increasing and many front-line providers were being quarantined for symptoms and/or exposure. it was clear that redeployment of our staff was imminent. to increase available personnel, equipment, and physical space, all elective surgical cases at cuimc were suspended on march . on the evening of march , our chairman called an emergency phone conference. hospital leadership had declared that our emergency rooms (ers) were overrun and in need of assistanceredeployment had been activated. urology faculty and residents were asked to volunteer on an "opt-in" basis. this was in consideration of the yet unknown roles and risks of redeployment. the hope was that enough willing and able staff would volunteer to fulfill the need, while considering those who may have personal reasons to abstain unless absolutely necessary. our program leadership also emphasized that in the spirit of departmental solidarity, all volunteering urology physicians would be redeployed in pairs of one resident with one attending. this paired team model ensured that we would embark on these challenges together. ultimately, a total of residents, attendings, two nurse practitioners (nps), and three medical assistants volunteered for redeployment. half of the residents continued working in our urologic inpatient services, though they were available for activation should anyone in the redeployment pool need to quarantine (figure ). these separate resident pools were created to minimize the risk of covid- exposure within our department. initially, we were redeployed to two ers at our main university and satellite hospitals, assigned to provide -hour coverage for admitted, "non-covid" patients awaiting bed placement. on the first day of redeployment, our department encountered the overwhelming number of patients, very few of whom were "non-covid." practically every patient in the er was being ruled out for or confirmed to have covid- . our assignment immediately transformed into an undefined ancillary role to serve however needed, including assisting with chest compressions, ensuring empty oxygen tanks were replaced, placing intravenous/arterial lines and foley catheters, and constantly reassessing patients' vital signs. as the cases of suspected/confirmed covid- increased exponentially, many patients in our hospital required icu-level care in the er while awaiting inpatient transfer. our department recognized this gap in care and with the help of our medical colleagues, developed a novel -bed "emergency department-intensive care unit" (ed-icu) to care for these critically ill patients. the team per -hour shift consisted of: ) one medical intensivist or subspecialist as the supervising attending, ) one to two senior medicine icu resident(s) as the team lead(s), ) one icu pharmacist during the day shifts, ) one respiratory therapist, ) ed nurses with prior icu experience, and ) one urology attending/resident pair with or without a urology np. our attending/resident pairs were responsible for entering orders, reviewing labs and imaging, adjusting ventilator settings, contacting consultants, and speaking with patients' families. as the ed-icu gained prominence in the care pathway of covid- patients at cuimc, we also played an instrumental role in onboarding providers from other specialties to the attending/resident pair role. this involved creating an ed-icu manual with a primer on critical care specific to covid- , hosting an online orientation, and taking extra shifts in an oversight role. the volume of critically ill patients in our hospitals continued to increase to unprecedented levels. in order to further increase critical care capacity, several "pop-up" icus were created in various areas throughout the main and satellite hospitals, including many of the pre-operative areas and operating rooms (ors). our roles in these "pop-up" icus were identical to our responsibilities in the ed-icu. at our satellite hospital, with all established icu beds filled to capacity, a "pop-up" icu of six critical care beds was created in the pre-operative area. we began rotating in this new icu on april . given the residents' increasing comfort with caring for critically ill covid- patients, urology residents were redeployed to this icu without an accompanying attending. each -hour shift, the team consisted of: ) one medical intensivist as supervising attending, ) one to two medicine subspecialty fellow(s) as team lead(s), ) one respiratory therapist, ) two to three rns, and ) one urology resident with or without a urology np. at the main university hospital, several of our ors were converted to "pop-up" icus (or-icu), with each or able to accommodate four critically ill patients. on april , the volume of patients in the main hospital ed-icu subsided enough that our department was fully reassigned to the or-icus on april . each bay, consisting of three or-icus (maximum of twelve patients), was covered by one medical intensivist as supervising attending and one senior otolaryngology or anesthesiology resident as team lead. each or-icu was then covered by two rns with prior icu experience and an attending/resident pair from urology or another redeployed specialty. eventually, as the overall volume of critically ill patients with covid- began to subside, our department was informed that we were no longer needed in the or-icus on may and in the satellite hospital "pop-up" icu on may . during the swift and drastic process of redeployment, one of the many concerns was the maintenance of urologic services. residents and attendings who were not in the deployment pools worked in staggered shifts, both in the outpatient and inpatient settings. the vast majority of outpatient visits in both the resident-and faculty-run practices were transitioned to televisits via phone or video, unless an in-person visit was absolutely necessary. the suddenly vacant faculty practice space allowed us to utilize the clinic in another way. to minimize patient and urology consultant exposure to covid- in our ers, our department collaborated with our emergency medicine colleagues to create a new diversion protocol for patients presenting to the er with an acute urologic issue. once a patient was determined to meet certain inclusion and exclusion criteria there have been several sources of anxiety specific to healthcare workers during this pandemic. early on, there were justified concerns about adequate personal protective equipment, potential transmission of covid- to family and friends, and ability to provide appropriate care if redeployed to an unfamiliar setting (i.e., er, icu). as these concerns somewhat dissipated, we encountered the dark realities of critical illness and death from covid- in our patients, colleagues, family, and friends. emotions such as guilt, helplessness, and grief accompanied our anxiety. in response to such concerns, our hospital promoted active working relationships between the housestaff mental health service and our providers. two mental health experts, one who is a psychiatrist and director of mental health services for graduate medical education at cuimc, hosted weekly virtual peer support sessions via zoom, separately for urology residents and faculty. these sessions allowed us to openly express concerns, share common experiences, and discuss coping techniques with our colleagues. in addition, these meetings promoted direct relationships with the mental health staff, who encouraged us to contact them by phone or e-mail at any time. remain open at all times. another unfortunate consequence of the pandemic has been the detrimental effect on urology resident education and training. most urologic surgeries and clinic appointments were cancelled, and anecdotally, inpatient urologic consult requests decreased in number and variety. in addition, weekly multidisciplinary tumor boards and departmental educational conferences were suspended or transitioned to videoconferences. though covid- put a heavy strain on our health care system in general, the changes required to respond to the pandemic led to an overall increased amount of available time for urology residents and faculty. to address this need, our residents and faculty started several educational initiatives. the most prominent of these has been the educational multi-institutional program for instructing residents (empire) lecture series (https://nyaua.com/empire/), sponsored by the new york section of the aua. with inspiration from the "covid" series from the department of urology at the university of california, san francisco, we initiated a multi-institutional lecture series with a focus on resident mentoring, education, and the aua core curriculum given by accomplished speakers across all subspecialties of urology. the schedule of lecture topics was posted at least one week in advance on the empire website, the new york section's twitter account, and via an email listserv. every weekday morning in march and april , two one-hour lectures were given over zoom, with the first ten minutes of each lecture reserved for a q&a session focused on resident career counseling. each day, there were fifty to one-hundred fifty participants, who were encouraged to post questions for the speaker to be answered at the end of each lecture. for those who could not join the live sessions, the lectures were recorded and posted on the empire youtube page. with the empire series covering clinical practice and guidelines, resident surgical training also needed to be addressed. our department therefore initiated the surgical interactive resident curriculum (sirc) and a robotic surgery competition. sirc occurred every afternoon, with a different faculty member hosting an hour-long interactive review of pre-recorded urologic surgeries with cuimc residents and medical students over zoom. this allowed residents to explore the attendings' operative thought processes in terms of steps, techniques, and concerns while obtaining a refresher on relevant anatomy. secondly, the residents, with faculty support, utilized the down time to improve their robotic skills. in order to promote participation and a spirit of competition, a robotic surgery fantasy league was created. residents were split into teams, with an even distribution of post-graduate year experience. every two weeks, three exercises on the da vinci® skills simulator™ were designated and each team member was required to record their best scores during that time period. this approach has resulted in strong resident engagement and improved operative fundamentals, an idea supported in the education literature. a week after our department was relieved from redeployment in early may , the majority of the "pop-up" icus in the ors were vacated. this allowed the space and supporting staff for surgical departments to resume scheduling procedures again, although at limited capacity. this next stage has presented unique challenges of its own. to prioritize surgeries appropriately during decreased or capacity, our department has continued to use our "covid- urologic surgery triage algorithm" (figure ) to prioritize emergent and urgent cases. patients themselves have expressed hesitancy about undergoing surgery at our main hospital in nyc, and therefore have been rescheduled for a later date or at a satellite hospital. this slow process of rescheduling elective surgeries may prolong the detrimental effects of the covid- pandemic on both resident surgical training and patient care. leveraging the aforementioned technologies of videoconferencing and robotic simulation will help to mitigate the effects on resident education. unfortunately, the downstream effects of delay in surgical care will be much more difficult to ameliorate, particularly for patients with cancer. in regards to our outpatient practice, we have reintroduced in-person office visits for select patients, with symptom and temperature checks in the clinic lobby, mask requirements for all patients and visitors, and strict enforcement of six-foot social distancing. though we would like to ensure a "covidfree" space, we recognize that the false-negative rates of the early covid- tests and the presence of asymptomatic carriers make this nearly impossible. given the increased use of televisits during the pandemic, many patients are now more comfortable with the technology, which allows consultation with our providers in the safety and comfort of their homes. similarly to our patients being scheduled for surgeries, those who require in-person visits are being offered appointments at a later date or at a satellite hospital. we foresee that televisits will continue to be a prominent component of our outpatient practice even once the pandemic has subsided. from a big picture perspective, the long plateau of global covid- case numbers highlights the uncertainty of when, if ever, we will return to "normal." though the future remains unclear, our department's unified response to the pandemic has strengthened our sense of solidarity and purpose. our providers volunteered for redeployment, while creating innovative clinical care and educational solutions in a time of need. we have now started performing surgeries and seeing our patients in person again, albeit in much smaller numbers than we had in the pre-covid era. while the recovery first case of novel coronavirus in the united states understanding and addressing sources of anxiety among health care professionals during the covid- pandemic instituting a surgical skills competition increases technical performance of surgical clerkship students over time collateral damage: the impact on outcomes from cancer surgery of the covid- pandemic likely need for imaging (e.g., rule out testicular torsion, suspected renal colic) . likely need for procedural monitoring/sedation (e.g., priapism, abscess incision and drainage) . likely need for admission (e.g., febrile patient with gu chief complaint) key: cord- - cr ph x authors: sarpong, nana o.; forrester, lynn ann; levine, william n. title: what’s important: redeployment of the orthopaedic surgeon during the covid- pandemic: perspectives from the trenches date: - - journal: j bone joint surg am doi: . /jbjs. . sha: doc_id: cord_uid: cr ph x nan in this war, it may be difficult to envision what an orthopaedic surgeon may bring to the battlefield in the hospital emergency room (er) and icu. our roles as orthopaedic surgeons may seem peripheral at best, in contrast to those of our colleagues who practice emergency, internal, and intensive care medicine and are considered front-line workers. however, our hospital's capacity, resources, and health-care personnel are rapidly dwindling as front-line workers are falling ill to covid- or have been redeployed to de novo makeshift icus. the initial hospital response included the reallocation of capacity and resources, with our dedicated orthopaedic surgery operating rooms and suites being converted to icus shortly after the new york state order to cancel all elective surgeries . our department initially focused on the creation of a musculoskeletal urgent care center to offload the surge in the er, along with a % conversion of routine orthopaedic outpatient visits to telehealth visits. however, we quickly recognized that there could be additional ways to help. while the orthopaedic surgeon's knowledge is often deeply specialized, we can also leverage broader strengths, such as intelligence, confidence, grit, and leadership. moreover, as the need to provide subspecialty orthopaedic care has decreased, there is a growing need and opportunity to serve society and our patients. to that end, every available practitioner in our orthopaedic department-including attending surgeons, fellows, residents, nurse practitioners, nurses, physician assistants, medical assistants, and support staff-has been redeployed to another area of the hospital with unmet need, particularly the er and icu. many of us have not worked in the er or icu in years, or have had limited exposure during our training, and we have experienced mixed emotions in the face of this new development. here, we share perspectives on this experience, that of orthopaedic surgery residents and of an attending physician: in our first redeployment shift in the er, we expected the majority of patients to be coughing and dyspneic, and had prepared for a virus-driven cacophony by wearing an n respirator covered by a surgical mask and face shield. to our surprise, however, when we walked into the er, it was quiet. there was no coughing because the majority of patients were intubated. the pace of the er was as fast as ever, but the atmosphere had changed: there was both palpable fear and determination in the room. and the overall volume of patients was actually lower than normal; the only patients were those who were covid- -positive. there were no cases of acute myocardial infarction or acute surgical abdomen. it was eerie. we made rounds with an icu senior resident and our attending physician. we were to act as members of the new er-icu triage team, to help take care of patients who had been admitted to the icu but had not yet been physically moved from the er to the icu. we took care of to patients throughout the day; all but were intubated. two of those patients had tested positive for covid- and were deteriorating, and the icu team was having active, remote discussions with the patients' families regarding appropriate next steps. after rounds, we began to work through our to-do list. we started with the "lowest-hanging fruit," which included obtaining arterial blood gases (abgs) through the femoral artery-appropriate laboratory values are essential in managing intubated and sedated patients. we reviewed the anatomy we knew very well (navel, the mnemonic for the order of the femoral nerve, artery, vein, and lymphatics) and went for it. over the -hour shift, we took turns placing nasogastric tubes, drawing femoral artery abgs, obtaining chest radiographs and other laboratory tests, and helping to transport patients when inpatient beds became available. in the end, we realized we had also effectively completed a crash course in vasopressor medication titration and mechanical ventilator management. as orthopaedic surgery residents, the feeling of intimidation in unfamiliar territory was inevitable, but we were prepared for the challenge. all health-care workers are practicing at the edges or beyond the scope of their training right now and yet continue to strive to learn more and provide compassionate, high-quality care to their patients. during that first redeployment shift and since then, we have been struck by the visible relief on the faces of other residents, attending physicians, nurses, and staff. our redeployment not only allows us to act as care providers to our patients but also allows us to provide care and support to our beleaguered colleagues. during this pandemic, we must remember to not lose sight of the a's of being a successful physician: availability, affability, and ability. although we may be acting in roles that are foreign to us, our role in redeployment as physicians is only part of the picture. we are a part of the broader medical community, and thus are inextricably linked to our colleagues on the front lines of this pandemic. it would be dishonest for us to say that redeploying has made us any less afraid for the safety of our family, friends, patients, and colleagues. however, as orthopaedic surgery residents with valuable skills to offer, we are not afraid of redeployment even in the face of daunting odds. orthopaedic attending surgeon perspective when we started preparing for redeployment nearly weeks ago, it was unclear whether it would truly be necessary. however, as the number of patients who were covid- positive and requiring admission began to double every to days (following the same curve as wuhan in the people's republic of china and italy), it became increasingly clear that we were indeed going to be called on to redeploy. this led to an entire spectrum of emotions from our faculty, including enthusiasm to participate, anxiety, reticence due to comorbidities or relative age, and fear, including fear of transmitting the virus to loved ones. we convened a "redeployment committee," which reviewed the goals and needs of the hospital as well as volunteerism among the faculty, taking into consideration faculty age and comorbidities, any family health concerns, and other relevant information. the committee then delivered a working document to the chairman for his consideration of redeployment. the orthopaedic surgery department was then joined by urology, otolaryngology, and ophthalmology to broaden our provider pool and decrease overall virus exposure for all of those involved. the dean of our institution sent out a note to all indicating that it was expected that % of the faculty and staff would indeed redeploy as needed and as appropriate to areas where their expertise could be best utilized. we have now been redeployed to the er for week and it has been an overwhelming experience. i feel pride in seeing our colleagues put their lives on the line to battle an invisible enemy, which insidiously attacks so many; gratitude to my faculty, fellows, and residents for stepping up and doing whatever necessary to help in a time of extraordinary need; and apprehension and fear, praying that nobody in my department succumbs to this potentially lethal virus. it is our calling to help people, which many of us wrote in our personal statements for medical school, residency, and fellowship. now, we all have the opportunity to do just that. you will be asked to perform procedures that you may not have done in decades (like when i was obtaining abgs the other day!), but as my residents highlighted above, the visceral gratitude demonstrated by our er nurses, respiratory therapists, ward clerks, and physicians will likely have the longest-lasting positive impact on me from this pandemic. in the face of tragedy and crisis, these colleagues were stretched so thin that simply seeing subspecialty surgeons in their personal protective equipment helping to take care of critically ill patients was profoundly appreciated. while redeploying is no doubt a daunting experience, we are left with the indelible sense that it was the right thing to do. if called upon to do so in the future, we will again step up and ask, "when?" and "how can i help?" n coronavirus disease (covid- ) situation report - who director-general's opening remarks at the media briefing on covid- coronavirus fears curtail elective surgeries in nyc amid concern for other patients key: cord- -mhdaov f authors: hong, kyung soo; lee, kwan ho; chung, jin hong; shin, kyeong-cheol; choi, eun young; jin, hyun jung; jang, jong geol; lee, wonhwa; ahn, june hong title: clinical features and outcomes of patients hospitalized with sars-cov- infection in daegu, south korea: a brief descriptive study date: - - journal: yonsei med j doi: . /ymj. . . . sha: doc_id: cord_uid: mhdaov f although some information on the epidemiology of severe acute respiratory syndrome coronavirus (sars-cov- ) and a few selected cases has been reported, data on the clinical characteristics and outcomes of patients hospitalized therewith in south korea are lacking. we conducted a retrospective single-center study of consecutive hospitalized patients with confirmed sars-cov- infection at yeungnam university medical center in daegu, south korea. sixty patients were women ( . %), and the mean age was . ± . years. thirteen patients ( . %) were treated in the intensive care unit (icu). the mean interval from symptom onset to hospitalization was . ± . days. patients who received icu care were significantly older and were more likely to have diabetes mellitus. the national early warning score on the day of admission was significantly higher in patients requiring icu care. acute respiratory distress syndrome ( / patients; %), septic shock ( / ; . %), acute cardiac injury ( / ; . %), and acute kidney injury ( / ; . %) were more common in patients who received icu care. all patients received antibiotic therapy, and most ( / patients; . %) received antiviral therapy (lopinavir/ritonavir). hydroxychloroquine was used in patients ( . %), and glucocorticoid therapy was used in patients ( . %). in complete blood counts, lymphopenia was the most common finding ( / patients; . %). levels of all proinflammatory cytokines were significantly higher in icu patients. as of march , , the mortality rate was . %. here, we report the clinical characteristics and laboratory findings of sars-cov- patients in south korea up to march , . patient electronic medical records were reviewed. clinical data included age, sex, exposure history, comorbidities, symptoms, vital signs, radiologic findings, complications, treatment, clinical outcomes, and laboratory findings. blood samples of some suspected cases were collected for proinflammatory cytokine analysis. the concentrations of cytokines in covid- were determined using commercial enzyme-linked immunosorbent assays. the national early warning score (news) is an early warning score facilitating the early detection of and responses to patient deterioration. news encompasses seven physiological parameters: pulse oximetry, oxygen, pulse, systolic blood pressure, respiration rate, temperature, and central nervous system status. each parameter is assigned a score of to points. the score reflects the extent to which the parameter differs from the standard. acute respiratory distress syndrome (ards) was defined according to the berlin definition. septic shock was defined according to the third international consensus definitions for sepsis and septic shock (sepsis- ). acute cardiac injury was defined as a serum troponin i level above the th percentile upper reference limit or new abnormal electrocardiography and echocardiography findings. acute kidney injury was defined according to the kidney disease improving global guidelines (kdigo) for acute kidney injury. the acute physiology and chronic health evaluation ii (apache ii), a severity of disease classification system, is widely used as an index of illness severity and as a predictor of outcomes. apache ii score is based on age, previous health status, and the initial values of physiological measurements. the sequential organ failure assessment (sofa) scale is a scoring system deigned to evaluate complications in critically ill patients. the sofa scale assigns a score of to to each of six parameters related to organ function (respiration, coagulation, liver, cardiovascular, central nervous system, and renal). continuous variables are expressed as means±standard deviations (sds) and were compared using student's t-test or the mann-whitney u test. categorical variables were compared using the chisquared test or fisher's exact test. in all analyses, a two-tailed p value< . was considered to indicate statistical significance. all statistical analyses were performed using spss software (ver. . ; ibm corp., armonk, ny, usa). table shows the baseline clinical characteristics and radiological findings of patients hospitalized with sars-cov- infection. this study included patients with sars-cov- , ( . %) of whom were treated in the intensive care unit (icu). sixty patients were women ( . %) and their mean age was . ± . years, similar to recently released national epidemiological data for korea. the mean interval from symptom onset to hospitalization was . days. similar to the national epidemiological data, the largest group in our study with a history of exposure was the shincheonji religious group, which comprised patients ( . %). in our study, the proportion of pa-tients over years of age was . %, compared to % in china. the large proportion of women over years of age in our research is thought to be related to the outbreak in the shincheonji religious group whose followers comprise a female majority. more than one comorbidity was present in patients ( . %), of whom ( . %) had hypertension; this was the most prevalent comorbidity. a recent study in china revealed that patients who required icu care were more likely to have hypertension, diabetes, cardiovascular disease, and cerebrovascular disease than patients who did not receive icu care. in our study, diabetes mellitus tended to be more common in icu patients ( . % vs. . %, p= . ). it was difficult to detect meaningful differences in comorbidities between patients treated in the icu and those who were not due to the relatively small number of patients. on admission, about % of the patients had a fever and cough, and one-third had sputum, myalgia, and dyspnea. interestingly, vital signs recorded on the day of admission did not differ between patients who did and did not require icu care. news values on the day of admission was significantly higher in patients requiring icu care ( . ± . vs. . ± . , p< . ). of the news parameters, body temperature, heart rate, and level of consciousness were not associated with icu care. the roy- our study demonstrated that news was more useful than initial vital signs in predicting icu admission in patients with covid- . table shows the complications, treatment patterns, and clinical outcomes of the patients hospitalized with sars-cov- infection. as previously reported in a chinese study, our patients who required icu care had many complications, such as multiple organ failure. ards ( / patients; . %), septic shock ( / ; . %), acute cardiac injury ( / ; . %), and acute kidney injury ( / ; . %) were more frequent in our study than in other chinese studies. [ ] [ ] [ ] it is estimated that the severity of disease in the covid- patients enrolled in this study was higher than that of the patients in chinese studies. the greater disease severity may account for higher rates of use of invasive mechanical ventilation ( . %), extracorporeal membrane oxygenation ( . %), and continuous renal replacement therapy ( . %) than reported in the aforementioned chinese studies. all patients received antibiotic therapy, and most ( . %) received antiviral therapy (lopinavir/ritonavir). hydroxychloroquine was used in ( . %) patients. glucocorticoid therapy was used in patients ( . %); this therapy was used more frequently in patients who required icu care ( . % vs. . %, p< . ). according to a study involving patients in hospitals, . % received systemic glucocorticoids, and . % of patients with severe covid- received systemic glucocorticoids. in our study, . % of all patients received systemic glucocorticoids, and . % of patients in the icu received systemic glucocorticoids. because "severity" was not clearly defined in the chinese study, it is difficult to compare findings. however, the high rate of use of glucocorticoids in our study can be ex-plained by the fact that % of our icu patients received invasive mechanical ventilation versus just . % of the severe covid- patients in the chinese study. wu, et al. reported that treatment with methylprednisolone decreased the risk of death (hazard ratio, . ; % ci, . - . ) in patients with covid- pneumonia who developed ards. the use of glucocorticoids for covid- is beneficial in certain groups of patients, although further investigation is needed to identify the subgroups that can benefit the most. as of march , patients ( . %) had been discharged, and ( . %) had died. six patients (one icu and five general ward patients) were transferred to other tertiary care hospitals because our medical resources were exhausted. all of the other patients are still in the hospital. because our hospital is a tertiary care university hospital, with many patients requiring intensive care, the fatality rate is likely higher than the overall mortality rate in korea. however, the fatality rate in our study was much lower than rates reported in three single-center studies of hospitalized covid- patients in wuhan, china. , , since there will be additional deaths among patients who remain in the hospital, the final fatality rate is expected to increase. table shows the laboratory findings of the patients on admission to hospital. in the complete blood counts, lymphopenia ( . %) was the most common finding, followed by anemia ( . %), neutrophilia ( . %), and thrombocytopenia ( . %). in blood chemistry analyses, increased lactate dehydrogenase ( . %) was common. among infection-related biomarkers, c-reactive protein was elevated in ( . %) patients, while procalcitonin was increased only in ( . %). fig. shows the concentrations of the proinflammatory cytokines interleukin- β (il- β), il- , il- , il- , interferon-γ (ifn-γ), and tumor necrosis factor-α (tnf-α) in the sars-cov- -infected patients [n= (icu, n= )]. levels of all proinflammatory cytokines were significantly higher in icu patients than in non-icu patients in our study. previous studies have demonstrated that increases in proinflammatory cytokine levels are associated with more severe disease in middle east respiratory syndrome and severe acute respiratory syndrome patients. in patients with middle east respiratory syndrome in south korea, il- and cxcl- levels were significantly higher in the severe disease group than in the mild group. in severe acute respiratory syndrome patients, the levels of inflammatory cytokines il- , il- , il- , and ifn-γ were elevated. to prevent organ damage from cytokine release syndrome, it is imperative to develop a drug that targets these cytokines. the severity of respiratory illness and results of arterial blood gas analyses of icu patients on the day of icu admission were also measured. the mean interval from hospital admission to icu admission was . ± . days. on the day of icu admission, the mean apache ii score was . ± . , and the mean sofa score was . ± . . the mean ph, lactate level, mean partial pressure of oxygen/fraction of inspired oxygen ratio, and mean partial pressure of carbon dioxide were . ± . , . ± . mmol/l, . ± . , and . ± . , respectively. a limitation of this study was that it was conducted at a single medical center and included a small number of patients. however, this study identified many predictors of the likely requirement for icu care. we also found that proinflammatory cytokine levels were higher in patients with severe disease. a second limitation was the fact that this study did not include the patients' final clinical outcomes. further analysis will be needed when the covid- pandemic ends and final outcome data are available. this is the first study to describe the clinical characteristics of hospitalized patients with sars-cov- in south korea. in this single-center descriptive study of patients hospitalized with sars-cov- in daegu, south korea, . % of the patients received icu care. as of march , , the mortality rate was . %. clinical features of patients infected with novel coronavirus in wuhan, china clinical characteristics of hospitalized patients with novel coronavirusinfected pneumonia in wuhan, china clinical characteristics of coronavirus disease in china the ability of the national early warning score (news) to discriminate patients at risk of early cardiac arrest, unanticipated intensive care unit admission, and death acute respiratory distress syndrome: the berlin definition the third international consensus definitions for sepsis and septic shock (sepsis- ) kdigo clinical practice guidelines for acute kidney injury apache ii: a severity of disease classification system accuracy and reliability of apache ii scoring in two intensive care units problems and pitfalls in the use of apache ii and suggestions for improvement the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine korean society for antimicrobial therapy; korean society for healthcare-associated infection control and prevention report on the epidemiological features of coronavirus disease (covid- ) outbreak in the republic of korea from epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china clinical progression and cytokine profiles of middle east respiratory syndrome coronavirus infection plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome we thank all of the staff who have helped to care for covid- patients at yeungnam university medical center in daegu, south korea. this study was supported by a research grant from daegu medical association covid- scientific committee. key: cord- -fb gkc f authors: thibault, ronan; seguin, philippe; tamion, fabienne; pichard, claude; singer, pierre title: nutrition of the covid- patient in the intensive care unit (icu): a practical guidance date: - - journal: crit care doi: . /s - - -z sha: doc_id: cord_uid: fb gkc f five to % of the coronavirus sars-cov- -infected patients, i.e., with new coronavirus disease (covid- ), are presenting with an acute respiratory distress syndrome (ards) requiring urgent respiratory and hemodynamic support in the intensive care unit (icu). however, nutrition is an important element of care. the nutritional assessment and the early nutritional care management of covid- patients must be integrated into the overall therapeutic strategy. the international recommendations on nutrition in the icu should be followed. some specific issues about the nutrition of the covid- patients in the icu should be emphasized. we propose a flow chart and ten key issues for optimizing the nutrition management of covid- patients in the icu. the viral epidemic caused by the new coronavirus sars-cov- is responsible for the new coronavirus disease (covid- ) [ ] . up to % of the coronavirus sars-cov- -infected patients are presenting with an acute respiratory distress syndrome (ards) requiring urgent respiratory and hemodynamic support in the intensive care unit (icu) [ ] . the coronavirus sars-cov- is colonizing the respiratory tract but may also invade the gastrointestinal (gi) tract [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , neurological system, and kidneys [ ] . sars-cov- uses the angiotensin-converting enzyme receptor as an entry receptor in the lymphocytes, monocytes, lung alveolar type cells, esophagus epithelial cells, enterocytes, and colonocytes [ ] , creating rapid viral replication and cell damage that induce huge inflammation and increased cytokine secretion. in the most severe cases, it leads to a cytokine storm with high proinflammatory cytokine plasma levels [ ] . lung histopathological changes are compatible with diffuse alveolar damage. this damage is often lethal. the primacy of the resuscitation measures should not obscure the importance of nutritional care. the length of time for recovery for patients who survive covid- is a key factor that nutrition is vital for. icu survivors are staying for long periods [ ] . in seattle, survivor patients were ventilated for days (mean) and stay in hospital for days [ ] . in lombardia [ ] , from patients requiring icu, the median (iqr) icu length of stay was ( - ) days. therefore, it is expected that covid- patients who survived icu would present severe malnutrition and muscle mass loss. the nutritional assessment and the early nutritional care management of covid- patients must be integrated into the overall therapeutic strategy, as with any critical illness and rehabilitation program. as there is a covid- gi and liver involvement [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , it may have an effect on nutrition delivery. this review is intended to help icu health professionals to optimize nutrition management of covid- patients, especially those with ards. this article was written in the emergency of the epidemic by an expert group, based on the international recommendations on nutrition in the icu on march , and will be updated according to new knowledge about the covid- . the covid- patients with the most severe forms as seen in the icu are more frequently elderly and with comorbidities [ ] and therefore at major risk of malnutrition and sarcopenia [ , ] . in the absence of nutritional data specific to covid- , the following considerations are proposed from the data related to severe respiratory infections: -severe respiratory infections induce inflammatory syndrome and hypercatabolism, with increased energy expenditure linked to ventilatory work, in turn responsible for increased energy and protein requirements; -food intake is very reduced by several factors: anorexia secondary to infection, dyspnea, dysosmia, dysgeusia, stress, confinement, and organizational problems limiting attendance at meals. most covid- patients admitted to the icu are at high risk of malnutrition; -infection, hypermetabolism, and physical immobilization expose to rapid muscle wasting. the worsening of malnutrition should therefore be prevented by an appropriate nutritional strategy, including adequate protein-energy delivery and stimulation of physical activity. practical guidance of the nutritional treatment of the patient with covid- in the icu [ ] should be adapted to the covid- epidemic. . indirect calorimetry should be proposed only for patients staying for more than days in the icu or those on full parenteral nutrition (pn) to avoid overfeeding. . refeeding syndrome (rs) [ , , ] and complications related to propofol use must be prevented. . enteral nutrition (en) should be preferred over pn and started within h of admission. . gastric en is generally possible, including in the prone position, and should be preferably performed using a pump with flow regulator. . pn is indicated if en is impossible, contraindicated, or insufficient and should be prescribed using a case-by-case decision making. . the use of en enriched with omega- fatty acids should be preferred in case of ards. fish oilenriched intravenous fat emulsions should be prescribed if pn is required. . after extubation, the nutritional support is promoting patient's recovery and rehabilitation and should be continued until the patient resumes sufficient oral intake. . physical activity should be promoted to preserve muscle mass and function. covid- is a disease at high risk of malnutrition. the most severe cases are encountered in particular, but not exclusively, in patients with a chronic disease (such as organ failure, obesity with body mass index ≥ , type diabetes or cancers), who are elderly, and/or with polypathologies [ , ] . these diseases often mask underlying protein malnutrition (sarcopenia). malnutrition is a factor of poor prognosis and should therefore be actively investigated, even in the absence of specific literature concerning covid- . nutritional evaluation based on the global leadership initiative on malnutrition (glim) [ ] should be adapted to the covid- epidemic the international consensus for malnutrition diagnosis by glim defined new criteria for the diagnosis of malnutrition [ ] . according to the glim criteria, a patient is malnourished if he/she has at least one phenotypic criterion and at least one etiologic criterion. phenotypic criteria are body mass index < (or < if age ≥ years) or weight loss > % within past months or > % beyond months or reduced muscle mass; etiologic criteria are reduced food intake (≤ % in > week or reduced food assimilation (malabsorption or previous history of gi surgery) or acute disease/injury/ chronic disease-related inflammation. in the context of the covid- epidemic, the phenotypic criteria are poorly applicable: -because of the risk of increased viral transmission by patient contacts, weight machine and height chart are difficult to use since they must be decontaminated after each use. icu beds with integrated weight system define body weight difficult to interpret due to the fluid overload, especially in case of severe hypoalbuminemia or shock resuscitation. -similarly, bioelectrical impedance analysis and measurement of muscle strength by handgrip dynamometry are not recommended in covid- patients due to the risk of increased viral transmission by patient contacts. therefore, the nutritional screening at admission should be based on: -patient's or relatives' interview to determine recent weight loss before admission and body mass index. if possible, food intake may also be quickly and easily assessed with semi-quantitative methods: an analogue scale between and / [ ] or consumed portions ( , ¼, ½; ) during the last lunch or dinner, as did in the nutritionday survey [ ] ; taking < / should alert to likely malnutrition [ ] . moreover, two etiologic criteria for malnutrition diagnosis (according to glim recommendations [ ] ) are obvious in the covid- patients: -covid- , as an "acute disease," is associated with acute inflammation. -according to the more recent data [ ] , hypoalbuminemia is associated with a worse prognosis of covid- . indirect calorimetry (ic) should be proposed only for patients staying for more than days in the icu or those on full parenteral nutrition (pn) to avoid overfeeding ic is the reference method to assess the energy requirements in the non-covid- icu patients [ ] . however, in the context of the covid- epidemic, but depending on location, some icus experience massive overload of covid- patients. that context precludes the performance of any sophisticated non-vital methods at the early phase of icu stay. moreover, there is still an uncertainty regarding the safe use of ic, as the usual decontamination procedures cannot be guaranteed in an epidemic context. therefore, committed ic devices and virus filters for covid- patients only should be considered when possible. to avoid exposure to aerosol and potential virus contamination during ic device connection/disconnection, our recommendations are, previous to connection to the ic device, to put the ventilator on standby and to clamp the tube, then connect and when connected to declamp the tube and to restart the ventilator. this way is preventing the potential spread of virus during disconnection/connection. therefore, in these conditions, we propose that ic should be performed to all patients after - days in the icu. depending on staff organization and material availability, patients staying longer than days in the icu or those on full pn should be the priority. indeed, the patients on full pn are the most at risk of developing the serious complications related to overfeeding (hyperglycemia, hypertriglyceridemia, bacteremia, liver injury). alternatively, to determine calorie and protein needs, we propose the use of predictive equations according to weight (fig. ) . introduction of nutrition support should be phased according to day (fig. ) . the ultimate goal is to avoid underfeeding or overfeeding. importantly, obesity is associated with severe forms of covid- . in the icu, obesity is also associated with increased protein catabolism as compared with nonobese patients [ ] . it is therefore even more necessary to avoid restrictive and hypocaloric nutrition in obese patients. underfeeding is more likely in obese patients: obese patients often have increased energy expenditure compared to non-obese [ ] ; initiation of nutritional support is often delayed in obese icu patients [ ] . in obese icu patients, rapid weight loss would be associated with increased loss in muscle mass, weakening the immune defenses and therefore promoting covid- severity. refeeding syndrome (rs) [ , , ] and complications related to propofol use must be prevented the rs is underestimated at icu admission [ ] . covid- patients are often vulnerable (old, polymorbid, malnourished, sarcopenic) [ ] and frequently unwell for - days [ , ] , i.e., presenting fever, asthenia, lack of appetite, reduced food intake, leading to energy deficit before their icu admission. these characteristics promote the risks of electrolyte imbalances (i.e., refeeding syndrome). we propose to detect/prevent the rs in older patients, those with polymorbidity, no/low food intake for > days, preexisting malnutrition, and abnormal electrolytes due to diuretic treatment and dialysis. plasma potassium, phosphorus, and magnesium should be measured within h after nutrition support is started to detect and treat low values. for refeeding guideline, please refer to the uk national institute for health and care excellence (nice) guidelines [ ] https://www.evidence.nhs.uk/search?pa= &q=refeeding+syndrome. specific advices regarding patients under propofol should be stated here. all the sedative drugs, including propofol and benzodiazepines, have immunosuppressive effects [ ] . the "propofol infusion syndrome" (pris) is a rare complication observed when propofol is used for > h and at high doses (> mg/kg/h) and must be evoked in case of hemodynamic degradation or lactic acidosis without any other causative factor. the monitoring every h of arterial gazometry, plasma lactate, creatine phosphokinase, and triglycerides allows anticipating the risk of pris and stop propofol. in the covid- , the cytokine storm could lead to hemophagocytosis that could itself increase plasma triglyceride, independently from propofol use. plasma triglyceride monitoring at least every h is advised in all icu covid- patients. moreover, propofol doses should be controlled and alternative sedation should be used if the doses are too high or the treatment is prolonged. large administration of omega- fatty acids is not recommended in the context of strong inflammatory response to virus load. as usually recommended in the icu [ , ] , en should be preferred over pn. a lack of consensus among international academic societies exists about the best timing to start nutrition support after icu admission. the main reason is the heterogeneity of the icu patients (age, severity of disease, medical versus surgical cares, preexisting malnutrition, chronic diseases). all over the world, icu covid- patients are rather similar in terms of vulnerability (older, chronic diseases, low food intake for - days) [ , ] and likelihood of prolonged icu stay on mechanical ventilation [ , ] . these characteristics support the indication for early (< h after admission) and progressive increase of nutrition support (usually enteral) to reach an energy target by day - days, depending on tolerance (fig. ) . this is in line with the main available international guidelines for nutrition during critical illness and covid- [ ] https://www.nutritioncare.org/ uploadedfiles/documents/guidelines_and_clinical_resources/nutrition% therapy% covid- _sccm-aspen.pdf, https://www.auspen.org.au/auspen-news/ / / /covid- -information. the polymeric standard en formulas should be used like in other icu patients. if polymeric en administration is associated with diarrhea, semi-elemental en can be tested as second line. to our knowledge, there is no specific indication for arginine in icu covid- patients. as a meta-analysis [ ] reported that arginine increases mortality in sepsis and pneumonia patients, arginine should not be used in covid- patients. gastric en is generally possible, including in the prone position, and should be preferably performed using a pump with flow regulator in the context of ards, en is frequently delivered in the prone position. this is associated with an increased risk of gastroparesis and vomiting. all should be done to optimize en (fig. ) . in the context of the use of hydroxychloroquine associated with azithromycin as an antibiotic therapy against the sars-cov virus, the preferable prokinetics is metoclopramide, to avoid any drug side effect and interferences. en during prone position has been shown to be safe in terms of large gastric residue, vomiting, or intolerance [ ] . the prone position per se does not represent a limitation or contraindication for en and is recommended by the espen guidelines [ ] . according to a meta-analysis [ ] , % of the patients with severe covid- had gi symptoms ( % ci, . - . %), in line with other findings [ ] [ ] [ ] [ ] [ ] . in the metaanalysis, stool samples were positive for sars-cov- virus dna in . % of the cases ( % ci, . - . %) [ ] . however, there is no evidence that covid- patients with recent history of diarrhea, abdominal pain, nausea, and vomiting should be contraindicated to en. in case of en intolerance, nutrition delivery should be adapted as described in this section and the "pn is indicated if en is impossible, contraindicated, or insufficient and should be prescribed using a case-by-case decision making" section. according to the severity of gi symptoms, en should be temporarily stopped or reduced or combined/switched to supplemental or total pn. we do not advise the systematic measurement of gastric residual volumes (grv). in ventilated patients, not measuring grv was not associated with an increased risk of ventilator-associated pneumonia [ ] . aspen (https://www.nutritioncare.org/uploadedfiles/doc uments/guidelines_and_clinical_resources/nutrition% therapy% covid- _sccm-aspen.pdf) and aus-pen (https://www.auspen.org.au/auspen-news/ / / / covid- -information) experts are advising measuring grv for all prone patients, those under vasopressors or with gi covid- . however, there is no clear evidence to support this. therefore, as viral load may be present in gastric contents, the number of grv measurements should be reduced. grv may not be measured in those patients with stable hemodynamic or low dose of vasopressors, including those in the prone position. for others, the decisions should be made case by case, in accordance with the usual icu department protocols. feeding tube placement and grv measurement are agp. gastric content and stools can contaminate health professionals. therefore, introduction of nasogastric or postpyloric tube, grv measurement, or handling of stools should be made very cautiously according to strict protection protocols. in ventilated patients with insufficient sedation, it could happen that patients are agitated, coughing, or vomiting during the tube placement procedure. these patients should be better sedated or paralyzed before the feeding tube placement. in case gastric en is complicated with vomiting or gastroparesis, jejunal en may be considered. however, the nasojejunal tube placement is very challenging as it is an agp. therefore, any procedure requiring transfer to radiology suites or endoscopy should be avoided. only bedside introduction of nasoduodenal or nasojejunal tubes may be recommended, but they are not always available or successful. we may rather recommend the use of pn in case en is not tolerated (see the "pn is indicated if en is impossible, contraindicated, or insufficient and should be prescribed using a case-by-case decision making" section). en should be performed as much as possible using a pump with flow regulator. in the event of a shortage of pumps with flow regulator, it is necessary to reserve them as a priority for the icus. in non-intubated patients, it seems preferable to not use en rather than doing it without pumps with flow regulator, because of the risk of aspiration pneumonia. indeed, underfeeding is likely to have less severe consequences than aspiration pneumonia. a recent retrospective study has shown that early en in paralyzed patients was associated with less hospital mortality, and there is no increase in ventilator-associated pneumonia [ ] . however, in this study, paralysis duration was short: h. in covid- patients, paralysis is usually longer. there is no data about how to feed the icu covid- patients who are paralyzed for > h. in our experience, there is no increase in en complications in these patients. therefore, we propose to adapt nutrition support as generally done in case of gi intolerance (see the "pn is indicated if en is impossible, contraindicated, or insufficient and should be prescribed using a case-by-case decision making" section). as there is no data about feeding under vasopressors in the icu covid- patients, we propose to refer to a recent review [ ] and follow the espen recommendations [ ] : "the use of concomitant vasopressors (especially with stable or decreasing doses) should not preclude a trial of en […]. in very unstable patients, en may not have priority." pn is indicated if en is impossible, contraindicated, or insufficient and should be prescribed using a case-bycase decision making as usually recommended in the icu [ , ] , pn is indicated whenever en is impossible or contraindicated or in addition to en as long as it is insufficient (supplemental pn). many patients are still receiving high-flow nasal cannula (hfnc) therapy or non-invasive ventilation in many centers [ , ] . from a practical point of view, based on the chinese experience [ ] , these patients are almost not fed orally or enterally. therefore, we could advocate the use of pn arguing that "being fed by pn" is better than "being not fed." as most severe patients have a central line, pn should be administered through a central venous line. in case there are too many drugs on the central line, peripheral pn could be used. in the specific context of covid- , the use of supplemental pn could be advocated if en in the prone position is associated with vomiting, in case of severe hypoxemia (pao /fio < mmhg with fio > %), or in general, in the situation when the gut is not functioning [ , ] (fig. ) . in that context, supplemental pn should not be started before day [ ] . as a general principle and as the covid- is a new and unknown disease, we also advocate that pn would be prescribed using a case-by-case decision making, always having in mind that pn is at high risk of overfeeding and hyperglycemia over mmol/l that must be avoided [ , ] . mild-to-moderate liver injury, including elevated amino transferases, hypoproteinemia, and prothrombin time prolongation, is a sign of severe covid- [ ] . liver function tests should be monitored like in any other icu patients receiving en or pn. the use of en enriched with omega- fatty acids should be preferred in case of ards. fish oil-enriched intravenous fat emulsions should be prescribed if pn is required a systematic review and meta-analysis on fish oil (fo) enteral supplementation suggests an advantage for eicosapentaenoic acid (epa) and docosahexaenoic acid (dha) acid supplementation in ards patients in terms of length of ventilation and length of icu stay, but not mortality [ ] . however, these conclusions were based on low-quality studies. a cochrane analysis found that enteral epa and dha may improve oxygenation and length of ventilation and length of stay, but these findings were mainly based on low-quality evidence studies [ ] . negative outcome associated with administration of enteral fo has been only observed when administered in a bolus and with a low protein regimen [ ] . the immunoregulator effects of epa and dha may have a beneficial impact in the severe cytokine storm observed in sars-cov- ards. therefore, we suggest that en enriched with . g/day epa and dha can be administered in this disease, not in a bolus. higher amounts up to g/day have been administered safely [ ] . fo-based intravenous lipid emulsions have been extensively analyzed in a meta-analysis [ ] including prospective randomized controlled studies with intervention groups receiving omega- fatty acids compared to standard intravenous lipid emulsions (iles), as a part of pn covering > % of the energy provision. mortality was not decreased significantly, but a significant decrease was observed in relative risk of infection ( % lower) with omega- fatty acid-enriched iles, in icu and in hospital lengths of stay. risk of sepsis was also reduced by %. this latest analysis increases our knowledge on foenriched lipid emulsions. if pn including iles is required in this population suffering from covid- ards, foenriched lipid emulsions should be prescribed. the provision of omega- fatty acids increases the epa and dha plasma levels [ ] . the recommended fo doses are . - . g/kg/day. after extubation, the nutritional support is promoting patient's recovery and rehabilitation and should be continued until the patient resumes sufficient oral intake after extubation, the nutritional strategy must be adapted according to certain situations. after a median of days at hospital [ ] [ ] [ ] ] , patients are likely to be malnourished. in most patients, en should be continued as patients are transitioned to oral diet but not sufficiently to cover their protein-energy needs. this is critical to enhance covid- recovery. post-extubation swallowing disorders are frequent- to % of patients [ ] -and at risk of insufficient oral intake, therefore malnutrition. after extubation, approximately % of elderly patients require en in addition to their oral food intake [ ] . in the context of the covid- epidemic, this proportion would be expected to be higher, due to prolonged resuscitation and the intensity of the inflammatory and catabolic syndrome. based on the espen recommendations [ ] , we propose the following: -in any situation: in case of dysphagia, provide a diet with a suitable texture. the energy and protein intake must be adapted to the needs. a suitable physical activity or muscle strengthening exercising must be offered. -in case of post-extubation swallowing disorders: continue en but assess the risk of aspiration pneumonia. if there is, try to carry out en at the postpyloric site. if en is not possible (e.g., if swallowing rehabilitation may require removal of the feeding tube), propose a temporary pn. -in case of tracheostomy: favor oral, fractional, enriched feeding with oral nutritional supplements. if the energy and protein needs are not covered (< % of the needs), consider supplemental pn by avoiding overnutrition and hyperglycemia > mmol/l. depending on the individual clinical condition, mobilization at bedside will be encouraged to preserve muscle reserves and function and enhance recovery. it will be adapted to the patient's capacity for autonomy, in a context of limited availability and access by physiotherapists for priority respiratory care. mobilization will be intensified as soon as the clinical improvement allows. optimized nutrition care of the icu covid- patients is important to maintain gi tract function, sustain immune defenses, and avoid severe loss of muscle mass and function. as for any other icu patients, the latter is crucial to promote short-and long-term recovery. dedicated studies about the nutrition in the covid- patients are now awaited to enrich our knowledge about the metabolism of this new disease and adapt the nutrition support strategy. a novel coronavirus from patients with pneumonia in china clinical features of patients infected with novel coronavirus in wuhan prevalence and characteristics of gastrointestinal symptoms in patients with sars-cov- infection in the united states: a multicenter cohort study first case of novel coronavirus in the united states clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study evidence for gastrointestinal infection of sars-cov- gastrointestinal manifestations of sars-cov- infection and virus load in fecal samples from the hong kong cohort and systematic review and meta-analysis enteric involvement of coronaviruses: is faecal-oral transmission of sars-cov- possible? covid- : gastrointestinal manifestations and potential fecal-oral transmission the neuroinvasive potential of sars-cov may play a role in the respiratory failure of covid- patients the digestive system is a potential route of -ncov infection: a bioinformatics analysis based on single-cell transcriptomes clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study covid- in critically ill patients in the seattle region -case series baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region are patients with hypertension and diabetes mellitus at increased risk for covid- infection? espen guideline on clinical nutrition and hydration in geriatrics espen guideline on clinical nutrition in the intensive care unit glim criteria for the diagnosis of malnutrition -a consensus report from the global clinical nutrition community measured energy expenditure compared with best-practice recommendations for obese, critically ill patients-a prospective observational study initiation of nutritional support is delayed in critically ill obese patients: a multicenter cohort study use of -point analogue scales to estimate dietary intake: a prospective study in patients nutritionally at-risk decreased food intake is a risk factor for mortality in hospitalised patients: the nutritionday survey clinical and biochemical indexes from -ncov infected patients linked to viral loads and lung injury obesity and the metabolic response to severe multiple trauma in man monitoring nutrition in the icu espen expert statements and practical guidance for nutritional management of individuals with sars-cov- infection refeeding syndrome in the critically ill: a literature review and clinician's guide presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the newyork city area clinical course and risk factors for mortality of adult incovid- patients in wuhan, china: a retrospective cohort study refeeding syndrome: what it is, and how to prevent and treat it immunosuppressive aspects of analgesics and sedatives used in mechanically ventilated patients: an underappreciated risk factor for the development of ventilator-associated pneumonia in critically ill patients guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of critical care medicine (sccm) and american society for parenteral and enteral nutrition should immunonutrition become routine in the critically ill patient? a systematic review of the evidence enteral nutrition in patients receiving mechanical ventilation in a prone position effect of not monitoring residual gastric volume on risk of ventilator-associated pneumonia in adults receiving mechanical ventilation and early enteral feeding: a randomized controlled trial early enteral nutrition in patients undergoing sustained neuromuscular blockade: a propensity-matched analysis using a nationwide inpatient database enteral nutrition can be given to patients on vasopressors novel coronavirus pneumonia diagnosis and treatment plan surviving sepsis campaign on the management of critically ill adults with coronavirus disease (covid- ) early enteral nutrition in critically ill patients: escim clinical practice guidelines parenteral nutrition in the critically ill patient current evidence on ω- fatty acids in enteral nutrition in the critically ill: a systematic review and metaanalysis immunonutrition for acute respiratory distress syndrome (ards) in adults nih nhlbi acute respiratory distress syndrome network of investigators enteral omega- fatty acid, and linolenic acid, and antioxidant supplementation in acute lung injury ω- fatty-acid enriched parenteral nutrition in hospitalized patients: systematic review with meta-analysis and trial sequential analysis four-oil intravenous lipid emulsion effect on plasma fatty acid composition, inflammatory markers and clinical outcomes in acutely ill patients: a randomised control trial (foil fact) publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors' contributions ronan thibault, philippe seguin, fabienne tamion, claude pichard, and pierre singer drafted the article. the author(s) read and approved the final manuscript. availability of data and materials not applicable ethics approval and consent to participate not applicable consent for publication not applicable key: cord- -lq nj j authors: takahashi, nozomi; abe, ryuzo; hattori, noriyuki; matsumura, yosuke; oshima, taku; taniguchi, toshibumi; igari, hidetoshi; nakada, taka-aki title: clinical course of a critically ill patient with severe acute respiratory syndrome coronavirus (sars-cov- ) date: - - journal: j artif organs doi: . /s - - -y sha: doc_id: cord_uid: lq nj j although several studies have reported on the clinical and epidemiological characteristics of the patient with severe acute respiratory syndrome coronavirus (sars-cov- ), clinical course of the most severe cases requiring treatment in icu have been insufficiently reported. a -year-old man traveling on a cruise ship with history of hypertension and dyslipidemia developed high fever, dyspnea and cough after days of steroid treatment for sudden sensorineural hearing loss, and tested positive for sars-cov- in sputa polymerase chain reaction (pcr) examination. his respiratory function deteriorated despite treatments with lopinavir/ritonavir, oseltamivir, azithromycin and meropenem at a regional hospital. he was intubated and transferred to the icu in the tertiary university hospital on day (icu day ). interferon beta- b subcutaneous injection was initiated immediately to enhance anti-viral therapy, and favipiravir on icu day upon availability. progression of organ dysfunctions necessitated inhalation of nitrogen oxide for respiratory dysfunction, noradrenaline for cardiovascular dysfunction and continuous renal replacement therapy for renal dysfunction. his blood samples pcr also tested positive for sars-cov- , indicating viremia, concomitantly with elevated il- levels. vv-ecmo was initiated after sudden exacerbation of respiratory dysfunction on icu day to maintain oxygenation. the sustained excessive inflammatory cytokines in the present case might have led to the exacerbation of the disease, requiring vigorous organ support therapies to allow for survival and recovery from the rapid progression of multiple organ dysfunctions and severe respiratory failure. electronic supplementary material: the online version of this article ( . /s - - -y) contains supplementary material, which is available to authorized users. since the first report on an outbreak of a coronavirus disease (covid- ) from china in december , the disease has rapidly spread across the globe [ ] ; more than , cases were confirmed including more than , death (march , ) [ ] . although several studies have reported on the clinical and epidemiological characteristics of this disease, clinical course of the most severe cases requiring treatment in intensive care unit (icu) have been insufficiently reported. here, we report a critically ill patient with viremia of severe acute respiratory syndrome coronavirus electronic supplementary material the online version of this article (https ://doi.org/ . /s - - -y) contains supplementary material, which is available to authorized users. (sars-cov- ), who developed multiple organ dysfunctions, treated with artificial organ supports including mechanical ventilation, extracorporeal membrane oxygenation (ecmo) and continuous renal replacement therapy (crrt). a -year-old man was transferred to the icu of our hospital for treatment of exacerbating respiratory failure due to covid- . his medical history included hypertension and dyslipidemia. while traveling on cruise ship, he experienced sudden sensorineural hearing loss and prednisone mg was initiated. seven days later, he became febrile and developed dyspnea and cough. due to the outbreak of covid- on the cruise ship, polymerase chain reaction (pcr) test for sars-cov- using sputum sample was performed and turned out to be positive. therefore, he was transferred from the cruise ship to a regional hospital according to the japanese governmental quarantine policy. his respiratory status persisted without supplemental oxygen until day after admission. lopinavir/ritonavir was initiated on day , since progressive ground glass opacity was detected in follow-up chest ct (fig. a , supplemental figure ei ). supplemental oxygen was started on day with l/min. oseltamivir, azithromycin and meropenem was added on day in attempt to treat pneumonia causing deterioration of the respiratory function. his respiratory function slowly deteriorated requiring oxygenation with l/min on day and body temperature persisted at °, while vital signs including consciousness and hemodynamics were stable. he was intubated and transferred to the icu in the tertiary university hospital with ecmo specialists on day (icu day ), due to deteriorating dyspnea and increasing demand for oxygen supplementation. he was transferred with a ventilator equipped with an anti-viral filter to reduce the risk of spreading infectious aerosol particles, and isolated in a negative pressure chamber in the icu. upon icu admission (day from admission, icu day ), atelectasis in the dorsal side of the lung was noted in the chest ct (fig. b , supplemental figure e and e ), while no apparent purulent sputum was observed by bronchoscopy, and presented no evidence of bacterial infection in the gram stain and culture. the pao /fio (p/f) ratio was on cm h o positive end-expiratory pressure (peep) without other organ dysfunctions (fig. , supplemental table e ). lopinavir/ritonavir was continued, and interferon beta- b subcutaneous injection was initiated as anti-viral therapy considering the effect against rna virus; oseltamivir, azithromycin and meropenem were discontinued. various organ support therapies were initiated due to progressive organ dysfunctions, i.e. inhalation of nitric oxide for respiratory dysfunction (icu day ), noradrenaline for cardiovascular dysfunction (icu day ) and continuous renal replacement therapy for renal dysfunction (icu day ). pcr tests for sars-cov- using blood samples were positive (icu day and ), indicating viremia. sustained high blood il- level and sudden exacerbation of respiratory dysfunction on icu day (p/f ratio on cm h o, airway pressure release ventilation) (supplemental figure e ) hls cannula®, maquet getinge, rastatt, germany] in right femoral vein). progressive organ dysfunctions presented the worst condition on icu day . although daily sputum examination proved bacterial infection unlikely, antibacterial agent was switched from cefepime to meropenem to broaden treatment spectrum. on icu day , chest x-ray presented white-out appearance, indicating complete atelectasis with no detectable tidal volume by ventilator ( supplemental figure e ) , and favipiravir supplied by japanese government was initiated to replace lopinavir/ritonavir. the crrt support allowed adjusting the rigorous water balance and vv-ecmo allowed lung rest which avoid pulmonary damage. on icu day , gradual recovery from complete atelectasis was noted in chest x-ray (supplemental figure e ). despite vigorous supportive care including prone positioning, chest ct on icu day showed diffuse alveolar damage depicting irreversible change of the lung (supplemental figure e ). further treatments were withheld and the patient deceased on icu day . here we reported the severe case with viremia of sars-cov- , who admitted to the icu on day . he presented progressive multiple organ dysfunctions with sustained blood il- level and required various artificial organ support therapies (vasopressor [icu day ], crrt [icu day ], vv-ecmo [icu day ]). on icu day , gradual recovery initiated. excessive humoral mediator activity including inflammatory cytokines were suggested to be a key component of the pathophysiology in severe cases of covid- [ ] [ ] [ ] . the present case also presented elevated blood il- levels, which sustained at - pg/ml during initial icu days. high fever persisted with elevated blood il- levels, until temperature management with ecmo. such exaggerated inflammatory reaction might be induced by high viral load, suggested by sustained viremia confirmed by positive blood pcr tests for sars-cov- on icu day and , concomitantly with high il- levels. involvement of viremia has also been reported in a case-series from wuhan of patients including in the icu with laboratory-confirmed -ncov infection, patients ( %) had positive pcr tests for sars-cov- using blood samples [ ] . however, the highest level of il- on icu day might reflect the complication of bacterial infection. favipiravir, an antiviral drug approved as a stockpile against influenza pandemics in japan, was distributed as an option for anti-viral therapy against sars-cov- under government control. the efficacies of antiviral therapies have not been clarified in the clinical course of the patients. however, since the recovery became evident days after favipiravir treatment in the present case, favipiravir may have contributed to the amelioration of the lung lesion. the case was registered in a clinical study of favipiravir, which would provide the efficacy. beneficial effects of ecmo for respiratory failure were reported during the influenza a (h n ) pandemic in [ ] , especially in expert centers with ecmo specialists [ , ] . in japan, a committee of ecmo project was established after the pandemic to promote education of ecmo management and construction of referral network, and has led to an increase in the number of ecmo specialists and better outcomes [ ] . in the present case, the transfer of critical case to the regional icu with ecmo specialists fig. clinical course was well managed by the ecmo network physicians. the implementation of ecmo was performed in the negative pressure isolation room with standard sterile precautions in addition to the full personal protective equipment (ppe) including goggles, n- face mask, hood and gown. poor vision through the goggles and hood, and hot and humid environment induced by full ppe increased the difficulty of ultrasound-guided insertion of the cannula. briefing of the procedures were essential to achieve the safe and smooth ecmo implementation. in the present case, excessive inflammatory cytokines sustained over a week after icu admission, possibly leading to the exacerbation of the disease. vigorous organ support therapies were mandatory to allow for survival and recovery from the rapid progression of multiple organ dysfunctions and severe respiratory failure. author contributions nt, ra, nh, ym, to, tt, hi and tn contributed to study conception, data acquisition, data interpretation, manuscript drafting, and critical revision of the manuscript for important intellectual content. all authors read and approved the final manuscript. funding none. clinical characteristics of coronavirus disease in china who. coronavirus disease (covid- ) situation reports clinical features of patients infected with novel coronavirus in wuhan china covid- : consider cytokine storm syndromes and immunosuppression clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan china extracorporeal membrane oxygenation for influenza a (h n ) acute respiratory distress syndrome association of hospital-level volume of extracorporeal membrane oxygenation cases and mortality. analysis of the extracorporeal life support organization registry referral to an extracorporeal membrane oxygenation center and mortality among patients with severe influenza a (h n ) comparison of extracorporeal membrane oxygenation outcome for influenza-associated acute respiratory failure in japan between conflict of interest the authors have no conflicts of interest to declare. key: cord- -m lkrehi authors: nan title: proceedings of réanimation , the french intensive care society international congress date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: m lkrehi nan introduction: veno-venous extracorporeal co removal (ecco r) is a promising new therapeutic option in the critical care setting. we conducted a prospective observational study of the use of ecco r in selected voluntary centers during years aiming to assess the prevalence of the ecco r use mainly among copd and ards patients. patients and methods: two medical devices: hemolung (alung technologies, pittsburgh, usa) and ila activve (xenios novalung, heilbronn, germany) were selected after literature and medico-economic evaluations. a specific medical and nurses training was provided in table characteristics of patients with known or de novo svv (small-vessel vasculitis) admitted to the intensive care unit for acute respiratory failure (arf) all arf (n = ) immune arf (n = ) non immune arf (n = ) p age , introduction: ineffective triggering is frequent during pressure support ventilation (psv). its occurrence is favored by dynamic hyperinflation that may arise when increasing the pressure support level (psl). decreasing the psl however fails to suppress ineffective triggering in a subgroup of patients that are therefore exposed to refractory ineffective triggering. proportional assist ventilation with load-adjustable gain factors (pav +) decreases the incidence of ineffective triggering in unselected patients but its effect on refractory asynchrony during psv is unknown. the main aim of our study was to assess the effect . the median gain during pav + was % [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the asynchrony index was significantly lower with pav + than psv ( % [ ] [ ] [ ] [ ] [ ] [ ] [ ] vs. % respectively, p = . ). moreover, the asynchrony index decreased in every patient with pav + (fig. ) . noticeably, the tidal volume was already protective in psv and decreased even more during pav + ( . ml kg [ . - . ] vs. . ml [ . - . ] respectively, p = . ); and the neural respiratory rate was high in both modes ( cycles min in psv vs. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in pav + , p = . ). total esophageal pressure-time product (ptpes) did not significantly differ between the two modes but the ptpes proportion that was wasted in ineffective efforts decreased with pav + ( % [ ] [ ] vs. % , p = . ). conclusion: our preliminary data suggest that: ( ) pav + reduces the incidence of refractory ineffective triggering; ( ) patients exposed to refractory ineffective triggering during psv seem characterized by rapid shallow breathing despite high ventilatory support, questioning the tolerance of both ventilatory modes. results with further inclusions will be presented. introduction: the use of alternatives to carbapenems to treat patients with extended-spectrum beta lactamase-producing gram negative bacilli (esbl-gnb) infections remains controversial. their use in patients with severe infections in the icu has been poorly studied. the aim of this study was to compare the outcome of icu patients having received carbapenems to those having received a carbapenem-sparing agent (csa). the charts of patients with esbl-gnb infection hospitalized in our icu between and were retrospectively reviewed. patients treated with betalactam betalactam inhibitor (bl bli), cefepime or quinolones were considered has having received an alternative to carbapenems (csa). patients having received such a csa were compared to those having received a carbapenems. primary outcome was treatment failure at day , defined as esbl-gnb infection recurrence (relapse with same pathogen) or death, whichever first occurred. results: patients with esbl-gnb infection were included. source of infection was the lung for most of them. characteristics of patients are displayed on table . their median saps ii and sofa scores were and [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , respectively, and ( %) were on septic shock. patients received a carbapenem empirically, among whom were switched to a csa agent when antibiogram was available (csa-definite group), whereas carbapenems were pursued in the others (carbapenem-only group), mainly because pathogens were resistant to others antibiotics. among the patients having received a non-carbapenem agent as empirical treatment, pathogen was susceptible to this agent in and they pursued the same treatment (csa-only group), whereas were switched to a carbapenem (pathogens resistant to empirical treatment, carbapenem-definite group). treatment failure were not different among these groups (table ) . globally, patients received a csa as their definite treatment (csadefinite and csa-only groups), whereas received a carbapenems (carbapenems-only and carbapenems-definite groups). whereas duration of antimicrobial treatment was similar ( [ - ] days vs. [ - ] days, respectively, p = ns), treatment failure rate was not higher in the former, as compared to those having received a carbapenems ( vs. %, respectively, p = . ). conclusion: treatment of patients with esbl-gnb severe infection in the icu with a csa seems to be safe when the pathogen is susceptible to this csa. however, mic should be first determined before de-escalating to a csa. larger studies are needed. percentages of samplings which attained the pk pd targets for various crcl with potential suboptimal beta-lactam concentration in critically-ill patients with aki treated either with an early or a delayed rrt strategy. patients and methods: ancillary study in a subset of patients with severe aki (kdigo ), receiving a beta-lactam antibiotic, in a trial comparing two rrt initiation strategies. in this trial, patients from intensive care units were randomly assigned to either an early (immediate rrt) or a delayed (late or no rrt) rrt initiation strategy. beta-lactam residual concentrations were sampled at and h after inclusion. the appropriate concentration was defined as a trough of at least times the minimal inhibitory concentration (clinical breakpoint of eucast). the primary outcome was an adequate plasma concentration of the beta-lactam during the first days. results: among the patients included in the centers participating to this ancillary study, a beta-lactam trough concentration was evaluated in subjects, in the early and in the delayed groups. ninety patients ( . %) had an adequate beta-lactam dosage. rrt initiation strategy had no impact on beta-lactam concentration (p = . ). among the septic shock patients ( % of the sampled patients), ( %) had a correct antibiotic concentration. in contrast, only of the patients without definite sepsis ( . %) had a correct dosage. factors associated with an adequate beta-lactam trough concentration in univariate analysis were admission for a septic shock (p = . ), a higher plasma creatinine level (p = . ), a higher mean arterial pressure (p = . ) and a lower serum bicarbonate level (p = . ) at randomization. a higher sofa score was associated with an adequate beta-lactam concentration near to statistical significance (p = . ). multivariate analysis will be presented. in the context of severe aki, beta-lactam concentration reached a sufficient level in % of septic shock patients. interestingly, rrt initiation strategy was not associated with beta-lactam trough concentration. early rrt did not affect trough concentration of betalactam. we may hypothesize that physicians were highly vigilant and adapted antibiotic administration adequately in these patients. introduction: amikacin infusion requires to target a peak serum concentration (c max ) - times the minimal inhibitory concentration, corresponding to a c max at - mg l − for the least susceptible bacteria. recent study reported that % of critically ill patients do not attain this target with a mg kg dose ( ) . membrane sequestration, alteration of the volume of distribution and lack of data in this population make drugs pharmacokinetics (pk) on ecmo challenging. our study aimed to assess the prevalence of insufficient amikacin c max in critically ill patients on ecmo and to identify relative risk factors. patients and methods: prospective, observational, monocentric study of adult patients on venoarterial (va) or venovenous (vv) ecmo receiving a loading dose of amikacin for suspected gramnegative infections. intravenous amikacin was administered with a loading dose of mg kg of total body weight and c max was measured min after the end of the infusion. independent predicators of c max < mg l − after the first amikacin infusion were identified by mixed model multivariate analysis. results: from january to february , patients (median saps (interquartile range) ( - ); age ( - ) years) under va-ecmo ( %) or vv-ecmo ( %) were included. at inclusion, the sofa score was ( - ) and ( %) patients were on renal replacement therapy. overall icu mortality was %. c max was < mg l − in ( %) of the patients. independent risk factors of amikacin under-dosing were body mass index (bmi) < kg m − (odds ratio (or) . , % confidence interval %ci . - . , p = . ) and a positive h fluid balance (or per ml increment: . , %ci . - . , p = . ) (fig. ). our results were comparable to those observed in patients treated with amikacin without ecmo ( ) . conclusion: this large prospective study suggests that the prevalence and associated risk factors of amikacin under-dosing are similar in critically-ill patients with or without ecmo. the use of a mg kg dose in low bmi patients and in those with a positive -h fluid balance on ecmo is strongly encouraged to obtain adequate therapeutic targets and prevent therapeutic failure. results: fifty patients were included ( with delirium, controls), at day for controls and day for patients with confusion. delirium patients were more severely ill sofa [ ; ] versus [ ; ] (p = . ); with higher rass [ ; ] versus [ ; ] (p = . ). they presented with % bl overdosing versus % in controls (p = . ); with % of bl in therapeutic index: % in controls (p = . ). obesity and renal failure were not associated with bl overdosing but there was a trend with hypoalbuminemia (p = . ). discussion: trend in association of bl overdosing with delirium corresponds to previous studies, and would need a larger scale study to be confirmed. severity differences in groups would need changes in inclusion criteria to obtain homogeneous groups. a possible association of bl underdosing with poor evolution of infection and organ failures would need more precise evaluation. hypoalbuminemia could have an impact on bl overdosing. conclusion: delirium was not associated with bl overdosing but with therapeutic index. a high variability of bl concentrations warrants therapeutic drug monitoring. a larger scale study should include changes in design. feasibility and safety of low-flow extracorporeal co removal with a renal replacement platform to enhance lung protective ventilation in patients with mild to moderate ards schmidt matthieu , jaber samir , constantin introduction: extracorporeal carbon dioxide removal (ecco r) might allow ultraprotective mechanical ventilation with lower tidal volume (vt) (< ml kg ideal body weight), plateau pressure (pplat) (< cm h o), driving pressure, and respiratory rate (rr) to reduce ventilator induced lung injury (vili). the aim of this study was to assess the feasibility and safety of ecco r with a renal replacement platform (rrt) to permit ultra-protective ventilation in patients with mild to moderate acute respiratory distress syndrome (ards). patients and methods: twenty patients with mild (n = ) or moderate ards were included. vt was gradually reduced from to , . and ml kg − and peep adjusted to reach > pplat > cm h o. standalone ecco r (no hemofilter associated on the rrt platform) was initiated when arterial paco increased by more than %. ventilation parameters (vt, rr, peep), respiratory compliance, driving pressure, arterial blood gases, and ecco r system operational characteristics (blood flow, sweep gas flow, and co removal rate) were collected during a minimum of h of ultra-protective ventilation. complications, mortality at day , need for adjuvant therapies and data on weaning from both mechanical ventilation and ecco r were also collected. results: while vt was reduced from to ml kg − and pplat kept below cm h o, peep was significantly increased from . ± . at baseline to . ± . cm h o at vt = ml kg − . as a result, the driving pressure was significantly reduced to . ± . cm h o at vt = ml kg − (p < . ) (fig. ) . no significant differences in rr, pao fio ratio, respiratory system compliance were observed after vt reduction. mean extracorporeal blood, sweep gas flow and co removal were ± ml min − , ± . l min − and ml min − , respectively. mean treatment duration was ± h. main side effects related to ecco r were membrane clotting which occurred in patients after ± h. conclusion: a low-flow ecco r device driven by a rrt platform efficiently removed co while allowing ultra-protective mechanical ventilation settings in patients with mild to moderate ards (clinicaltrials. gov identifier: nct ). morimont philippe , habran simon , desaive thomas , janssen nathalie , amand theophile , blaffart francine , dauby pierre , kolh philippe , defraigne jean-olivier , lambermont bernard introduction: protective lung ventilation (plv) is recommended in patients with acute respiratory distress syndrome (ards) to minimize additional injuries to the lung. however, increased right ventricular (rv) afterload resulting from ards could be enhanced by hypercapnic acidosis resulting from ventilation at lower tidal volume. relative contribution of these factors (ards and plv) in rv afterload is not clearly established. the aim of this study was to compare rv afterload in ards combined with plv to rv afterload in plv alone. patients and methods: this study was performed in an experimental model of severe hypercapnic acidosis performed in series of pigs. in both groups, respiratory tidal volume was decreased by %. in the first group (ards group), an ards (obtained by repeated bronchoalveolar lavage) was performed before reducing ventilation, while in the second group (control group), hypercapnic acidosis was resulting from low tidal volume ventilation alone. results: in both groups, systolic pulmonary artery pressure (paps) significantly increased during plv. this increase was significantly higher in ards group than in control group (fig. ) . severe hypercapnic acidosis occurred in both groups: paco increased from . ± . to . ± . (p < . ) and arterial ph decreased from . ± . to . ± . (p < . ) in ards group while paco increased from . ± . to . ± . (p < . ) and arterial ph decreased from . ± . to . ± . (p < . ) in control group. pao significantly decreased in ards group ( ± to ± . mmhg, p < . ) but did not significantly changed in control group. conclusion: isolated hypercapnic acidosis resulting from plv was clearly responsible for increased rv afterload and this effect was significantly enhanced in ards. pulmonary vasoconstriction resulting from hypercapnic acidosis is strongly enhanced by factors like hypoxia, endothelial injuries or inflammatory mediators in ards. extracorporeal co removal could be the solution to limit afterload burden on the right ventricle when plv is achieved during ards. introduction: prone positioning has been shown to improve mortality in acute respiratory distress syndrome (ards) patients. the respiratory system driving-pressure (dprs) and the transpulmonary driving-pressure (dpl), measured with esophageal manometry, have been shown to be strongly correlated with mortality. the aim of this study was to investigate the evolution of the dpl during prone positioning and its relationship with evolution of oxygenation in ards patients. patients and methods: ten patients with ards equipped with esophageal manometry were enrolled. dprs, dpl and chest wall driving-pressure (dpcw) were measured before and h after prone positioning. respiratory system, pulmonary and chest wall elastance (ers, el, ecw) were calculated at the same time. finally, we studied the correlation between these respiratory variables and oxygenation indicators. patients were classified as responders to prone positioning if the change in the ratio of arterial oxygen partial pressure oxygen inspired fraction (delta.pao /fio ) induced by the manoeuvre was larger than the median value observed in the group. results: in the whole population, median value of delta.pao /fio was . mmhg, and patients were classified as responders and as non-responders. in responders, dpl significantly decreased from . ± . cm h o to . ± . cm h o (p = . ) and el decreased from . ± . cm h o l to . ± . cm h o l (p = . ) after prone positioning. other respiratory variables did not change. in non-responders, respiratory variables did not change. between responders and nonresponders, there was no significant difference between baseline respiratory variables. after prone positioning, delta.pao /fio was not related to baseline respiratory parameters. on the contrary delta. pao /fio induced by prone positioning was strongly correlated with changes in dpl (r = − . , p = . ) and changes in el (r = − . , p = . ). we did not find any correlation between delta.pao /fio and changes in dpcw or changes in ecw. the correlation between delta.pao /fio and changes in dprs (r = − . , p = . ) and changes in ers (r = − . , p = . ) did not reach significance. conclusion: in patients who respond to prone positioning by the highest improvement in oxygenation, dpl significantly decrease after prone positioning. the changes in dpl and the changes in el play a major role in the improvement in oxygenation induced by prone positioning whereas the changes in dpcw and ecw do not. introduction: whereas prone positioning (pp) has been shown to improve patient survival in moderate to severe ards patients, its rate of use was . % in lung safe study. however, lung safe study was not specifically focused on pp. therefore, present study aimed to determine prevalence of use of pp in ards patients (primary endpoint), physiologic effects of and reasons for not using pp (secondary end-points). the apronet study was a prospective international one-day prevalence study performed times in april, july, october and january . at each study day, investigators had to screen every patient staying in icu from to h and to fill electronic crf. for patients with ards (defined from the berlin definition criteria) at each study day oxygenation and ventilator settings were recorded. for those receiving pp these variables were recorded before and at the end of pp session. the reasons for not proning were also collected. values are presented as median ( st- rd quartiles). prevalence rates of pp were compared by using chi square for trend and groups were compared with nonparametric tests. introduction: although acute respiratory distress syndrome (ards) has been largely focused on, few data are available concerning hypoxemia independently of its cause in intensive care unit (icu) patients. a recent prevalence-point-day (ppd) evaluated the patterns and outcomes of hypoxemia in french speaking icus. here, we describe the main etiologies, management and outcomes of the patients of this cohort presenting with severe hypoxemia. patients and methods: a ppd was conducted among french speaking icus during spring . hypoxemia was defined by a pao fio ratio below . we analyzed the data from patients with severe hypoxemia (i.e. with a pao fio ratio < ) and compared their characteristics (causes of hypoxemia, ventilatory and non-ventilatory management) and outcomes to the patients with mild or moderate hypoxemia. results: among the hypoxemic patients the day of the study, ( %) had severe hypoxemia. the main cause of hypoxemia was pneumonia and this diagnosis was more frequent than in mild and moderate hypoxemia. whereas bilateral radiologic infiltrates were present in ( . %) patients, ards was diagnosed by physicians in only ( . %) of them. invasive mechanical ventilation (mv) was used in ( . %) patients. high flow oxygen was administered in ( . %) of them and ( . %) were under non-invasive ventilation (niv) the day of the study. median vt was . ( . - . ) ml kg of ibw. positive end-expiratory pressure (peep) was higher than in mild and moderate hypoxemic patients ( ( - ) vs. ( - ) and ( - ) cm h o respectively, p < . ). median plateau pressure was . ( - . ) and was higher than in mild and moderate groups. median driving pressure was ( - ) cm h o with no difference when compared to other groups. neuromuscular blocking agents were administered in ( . %) patients, inhaled nitric oxide (ino) in ( %) patients and only patients ( . %) were on prone positioning. fourteen ( . %) patients were under extracorporeal membrane oxygenation (ecmo). icu mortality was higher in severe hypoxemic patients as compared to mild and moderate ( . vs. . and . % respectively, p < . ). icu length of stay in icu survivors was not statistically different between groups. conclusion: severe hypoxemia, independently from ards, worsens the prognosis of icu patients. even though ards might be underdiagnosed, a protective ventilation was respected in severe hypoxemic patients. introduction: major changes in septic shock management raise the questions of the relevance of the classical risk factors of nosocomial infections in the current era and the link with the primary infectious insult. we herein investigated the risk factors and the outcomes of icuacquired infections in a recent cohort of septic shock patients. patients and methods: this was a -year ( - ) monocenter retrospective study. all adult patients diagnosed for septic shock within the first h were included. septic shock was defined as a microbiologically proven or clinically suspected infection, associated with acute circulatory failure requiring vasopressors. patients who survived the first three days were eligible for assessment of the risk of the first icu-acquired infections. the diagnosis of nosocomial infections were based on current international guidelines. patients were classified according to the development of pulmonary or non-pulmonary icu-acquired infections. the determinants of icu-acquired infections were addressed in a multivariate logistic regression analysis. results: patients were admitted for septic shock. patients remained alive in the icu after the first three days and could then be evaluated for the risk of icu-acquired infections. hence, patients remained free of secondary infections, patients first developed an episode of nosocomial pneumonia and patients first developed an episode of non-pulmonary infection. the mortality rates of patients with icu-acquired pneumonia, non-pulmonary icu-acquired infections and without secondary infections were , and %, respectively (p = . ). in multivariate analysis, the development of icu-acquired pneumonia was independently associated with male gender (or . , ci % [ . - . ], p = . ), renal replacement therapy (or . , ci % [ . - . ], p = . ), platelet transfusion (or . , ci % [ . - . ], p = . ) and a primary pulmonary infection (or . , ci % [ . - . ], p < . ). the development of non-pulmonary infections was independently associated with renal replacement therapy (or . , ci % [ . - . ], p < . ), fresh frozen plasma transfusion (or . , ci % [ . - . ] , p = . ), healthcare-associated septic shock (or . , ci % [ . - . ], p = . ). conclusion: icu-acquired pneumonia occurs preferentially in patients with septic shock of pulmonary origin. in addition, we identified the transfusion of blood products as a risk factor for pulmonary and nonpulmonary nosocomial infections. introduction: human serum albumin is used for the restoration of blood volume, emergency treatment of septic shock patients. several experimental studies suggested that albumin could have additional protective effects on the vascular wall and more specifically on endothelial functions. however, the in vivo effect of albumin in human endothelium remains unknown. the aim of this study is to assess the effect of albumin or saline infusion on skin endothelial function in septic shock patients requiring volume expansion. we performed a prospective randomized monocentric study in an -bed medical intensive care unit. all patients with septic shock who required fluid administration were included between h and h after vasopressor starting. patients were randomized to receive either ml of saline solution . % or ml of albumin %. norepinephrine dose was not modified h before and during the procedure. endothelium-dependant vasodilatation in the skin circulation was assessed by iontophoresis of acetylcholine before and after fluid administration. the improvement of skin blood flow in response to acetylcholine after fluid administration was compared between groups. for each patient, age, sex, saps ii, site of infection, global hemodynamic parameters and clinical microcirculatory parameters were recorded. results are expressed as mean ± sd. qualitative data were compared using chi- or fisher's exact test while quantitative data comparisons used student t test or mann-whitney as appropriate. results: twenty-two patients were included ( women, age: ± , saps ii: ± ). twelve patients received saline and received albumin. apart from age, no statistical difference was found between groups regarding demographic characteristics and baseline hemodynamic parameters. norepinephrine dose and mean volume of infused fluid before inclusion was not different between groups (table ) . before fluid replacement, endothelial response to acetylcholine iontophoresis was not different between groups (auc vs ; p = . ). volume expansion induced a slight increase of systolic arterial pressure, significantly higher in the albumin group ( vs %; p = . ) with no difference regarding cardiac output variations between groups. next, we compared the variations of endothelium response to iontophoresis before and after fluid infusion. the improvement of endothelial response after acetylcholine challenge was significantly higher in the albumin group ( vs %, p = . ). conclusion: in the early stage of septic shock resuscitation, we showed that albumin infusion had protective endothelial effects. this result has to be confirmed in a larger cohort. ] + all p < . ). we found no correlation between cognitive scores at hospital discharge and the severity of eeg-defined encephalopathy during the days of icu or during the first h after admission. however, sepsis survivors' scores were lower than controls' (p < . ) ( table ) . conclusion: in this study, eeg was more sensitive than clinical tools to detect sae but clinical scales correlated with the eeg grade. encephalopathy was not associated with short-term cognitive function. further study and a larger cohort are needed to determine which early eeg introduction: there is growing evidence that corticotherapy improves survival from septic shock. this observational study aimed at evaluating at bedside resistance to corticosteroids in adults with sepsis. patients and methods: participants-icu adults with septic shock or without sepsis admitted to the raymond poincaré university hospital. we also evaluated healthy controls. intervention-resistance to corticosteroids was assessed using a skin test. µl of dermocorticoid cream (class iii, betamethasone) was applied on a cm surface of the skin. at h, two independent physicians scored the blanching of the skin from to - -no blanching + -< % of surface + - to % of surface + - to % of surface, and -blanching beyond application area. cohen's kappa was used to measure concordance. a mean score of < indicated corticoresistance and a score of indicating normal sensitivity to corticosteroids. we also performed a µg acth test. results: we enrolled patients, patients with septic shock ( males, ) and patients without sepsis ( males, ). overall, ( %) with two measurements patients had concordant evaluation of score by the two physicians + while had a difference of -point in scores, resulting in a kappa of . ( % ci . - . ). in patients with septic shock, ( %) have corticoresistance, i.e. a mean score < , ( %) a score of or , and ( %) has normal sensitivity to corticosteroids. in non-septic critically ill, ( %) have corticoresistance, ( %) a mean score of - , and ( %) have normal sensitivity to corticosteroids. hence, as compared to non-septic patients, patients with septic shock were more likely to have corticoresistance (p = . ). discussion: topic application of corticosteroids on the skin results in activation of glucocorticoid receptors present within the vessels. subsequently, activation of lipocortin may inhibit the activity of phospholipase a , regulator of prostaglandins, leucotrienes and platelet activating factor. then, the coupling of alpha adrenoreceptors to their agonists is potentiated, increasing vessels smooth muscles sensitivity to catecholamines. the subsequent local vasocontriction is reflected by skin blanching. thus, the observed lack of skin blanching in septic patients may reflect altered coupling between gluocorticoids and glucocorticoids receptors. conclusion: roughly one out of two adults with septic shock may develop a resistance to corticosteroids as assessed by a skin blanching test in response to betamethasone. introduction: mild therapeutic hypothermia, currently recommended in the management of cardiac arrests with shockable rhythm could promote infectious complications and especially ventilator-associated pneumonia (vap) (mongardon et al. crit care med ). despite high incidence of vap and retrospective trials suggesting a benefit of shortterm ( h) antibiotics in this setting (davies et al. resuscitation ) , systematic use of antibiotic prophylaxis is not recommended in patients treated with mild therapeutic hypothermia after cardiac arrest. the primary objective was to demonstrate that systematic short-term antibiotic prophylaxis with amoxicillin-clavulanic acid can reduce incidence of early vap (< days) in patients treated with mild therapeutic hypothermia after out-of-hospital cardiac arrest. secondary objectives were its impact on incidence of late vap and on day mortality. patients and methods: multicenter two parallel-group doubleblinded randomized trial. adult patients hospitalized in icu, mechanically ventilated after out-of-hospital resuscitated cardiac arrest related to initial shockable rhythm and treated with mild therapeutic hypothermia were eligible. exclusion criteria were pregnancy, need for extracorporeal life support, ongoing antibiotic therapy or pneumonia, known chronic colonization with multiresistant bacteria, known allergy to beta-lactam antibiotics and moribund patients. patients received either intravenous injection of amoxicillin-clavulanic acid ( g mg) or placebo three times a day for days. the primary endpoint was the onset of early vap. all suspected pulmonary infections were adjudicated by a blinded independent committee. results: out of patients included, were finally analyzed, in treatment group and in placebo group (mean age . ± . years, sex ratio = , sofa score . ± . ). characteristics of cardiac arrest were similar in both groups (no flow = . ± . min vs . ± . min, low-flow = . ± . min vs . ± . min). early vap were confirmed, in treatment group vs in placebo group, with an incidence of . vs . %, respectively (hr = . + ic % = [ . + . ], p = . ) (fig. ). the procedure did not affect occurrence of late vap (> days), respectively vs . day mortality was similar in both arms ( . vs . %, p = . ) and no adverse event was related to study treatment. conclusion: short-term antibiotic prophylaxis with amoxicillin-clavulanic acid significantly decreases incidence of early vap in patients treated with mild therapeutic hypothermia after out-of-hospital cardiac arrest related to shockable rhythm. introduction: immunosuppressed (is) patients are prone to develop respiratory failure and to need ventilatory support. invasive ventilation shared a grim prognosis in the past and non-invasive ventilation had been recommended in these patients, however niv efficacy has been recently challenged and the advent of high flow oxygen therapy had brought even more complexity in the management of such patients. using the data from a recent point-prevalence-day of hypoxemia in icu, we compare the frequency, management and outcomes of hypoxemia in is and immuncompetent (ic) patients. patients and methods: the spectrum study was conducted in french-speaking icus in countries during spring . is was retained in case of malignant hemopathy, hiv positivity, immunosuppressive drugs, recent chemotherapy, neutrophil count < . g l. hypoxemia was defined as a pao fio ratio > and separate into severe (> ), moderate (> ) and mild (> ). we focused on the causes of hypoxemia, the ventilatory management and the outcome. results: among the patients included, ( %) were is out of whom ( %) were hypoxemic, proportion similar to the ic patients. mean age and igs- of hypoxemic patients were similar in is and ic patients. hypoxemia was mild in ( %), moderate in ( %) and severe in ( %) is patients with a similar distribution compared to hypoxemic ic patients. the causes of hypoxemia were also similar pneumonia being the leading cause. ( %) hypoxemic is patients fulfilled the berlin criteria for ards in a similar proportion to ic patients. respiratory support used in hypoxemic is patients was ambient air in , low flow oxygen in , high flow in , niv in and invasive ventilation in patients, with a different distribution from the ic patients (more patients on high flow therapy and less invasively ventilated). the day of the study, thoracic ct scan and echocardiography were performed in a similar proportion in is and ic patients whereas broncho-alveolar lavage was more frequently performed in is patients ( vs %, p < . ). finally, as expected, icu mortality was higher in hypoxemic is patients ( vs %, p < . ). conclusion: immunosuppression in the icu seems not to be associated with hypoxemia, severity of hypoxemia or ards. oxygenation management is slightly different from immunocompetent patients with more frequent use of high flow therapy. ( ) mmhg, ph . ( . ). were included in the l/kg/min group and in the l/kg/min group. no difference was observed between groups for baseline characteristics. failure rate was not different between groups- . vs . % + p = . . no center effect was observed for failure. discomfort was more frequent in the l kg min group- vs % + p = . . the length of stay was shorter in the l kg min group- . ( . ) vs . ( ) days + p = . . intubation occurred in patients in the l/kg/min group vs patients in the l kg min group (p = . ). conclusion: hfnc with a flow rate of l/kg/min did not reduce the risk of failure compared to l/kg/min at the initial respiratory management of avb in young infants. comparison of epinephrine and norepinephrine for the treatment of cardiogenic shock following acute myocardial infarction. optima cc study levy bruno introduction: despite the frequent use of vasopressors which are administered in % of patients in cardiogenic shock (cs), there is only limited evidence from randomized trials comparing vasopressor in cs. hence, the optima cc study was designed to compare epinephrine and norepinephrine in cardiogenic shock following myocardial infarction. patients and methods: multicenter, double-blind, randomized trial in french icu. cardiogenic shock patients due to myocardial infarction treated by pci were randomized to receive epinephrine or norepinephrine to maintain map at mmhg. dobutamine was introduced at the physician discretion according to a combination of parameters-echocardiographic parameters, cardiac index, lactate clearance, svo and swan-ganz derived parameters. results: / patients were ventilated ( %). there were no differences in the duration nor in the maximal dose or cumulated dose of epinephrine or norepinephrine. dobutamine was used in / ( %) in the epinephrine group and in / ( %) in the norepinephrine group. there were no differences in the duration, in the maximal or cumulated dose. arterial pressure evolution was similar. heart rate increased significantly in epinephrine group and did not change in norepinephrine group. cardiac index and cardiac power index increased significantly more in the epinephrine group than in the norepinephrine group. cardiac double product, a surrogate of myocardial oxygen consumption increased in epinephrine group and did not change in norepinephrine group. epinephrine use was associated with a lactic acidosis from h to h while arterial ph increased and lactate level decreased in norepinephrine groupepinephrine was significantly associated with an higher incidence of refractory shock- / ( %) versus / ( %) p = . ). the incidence of arrhythmia was identical (epinephrine- % versus norepinephrine- %, p = . ). ecmo was used in / ( %) in the epinephrine group and in / ( %) in the norepinephrine group (p = . ) mortality was / ( %) in the norepinephrine group and / ( %) in the epinephrine group (p = . ) epinephrine use was associated with a trend to an increased risk of death (p = . ) and an increased risk of death plus ecmo (p = . ) at days. there was a trend for an increased risk of death plus ecmo at j (p = . ). conclusion: in patients with cardiogenic shock following myocardial infarction, epinephrine use was associated with a lactic acidosis, an higher incidence of refractory shock and an increased risk of death plus ecmo at j . high dose immunoglobulins in toxic shock syndrome in children: a pilot randomized controlled study (ighn study) javouhey etienne , leteurtre stéphane , tissières pierre , joram nicolas , wroblewski isabelle , ginhoux tiphanie , dauger stéphane , kassai behrouz hôpital mère enfant, bron, france; hôpital jeanne de flandre, lille, france; hôpital du kremlin-bicêtre, le kremlin-bicêtre, france; chu nantes, nantes, france; chu grenoble, la tronche, france; hospices civils de lyon, bron, france; hôpital robert debré, paris, france; hospices civils de lyon, bron, france correspondence: javouhey etienne -etienne.javouhey@chu-lyon.fr annals of intensive care , (suppl ):co- introduction: superantigen toxins synthesized by s. aureus or by s. pyogenes are responsible for toxic shock syndromes (tss) which lethality can reach %. high dose intravenous immunoglobulins (ivig), able to neutralize these toxins, are frequently used even tough evidence of its efficacy is not supported by randomized controlled study (rct) . moreover, ivig are expensive and possibly harmful. before conducting a rct, a pilot study was first designed to assess the feasibility in the context of pediatric critical care. patients and methods: a double blinded rct was performed comparing g kg of ivig to isovolumic % albumin perfusion within the first h of tss in children aged between month to years. a priori criteria to determine the feasibility were defined as a rate of inclusion among eligible patients > %, a rate of protocol's deviations < % (treatment delivery, non-respect of blinding, premature stop), and by the practical and financial aspects of the protocol. secondary objectives were to assess the efficacy of ivig on organ dysfunction (using pelod- score), on mortality at day and their safety. the study was promoted by the hospices civils of lyon, approved by the cpp sud-est and registered at clinical trial (nct ). inform consent from both parents was required before randomization. this study was funded by csl-behring company. results: during the months study period, patients were included in centers. the inclusion rate was of % ( parent's refusals, parents were absent at admission). two patients were wrongly included (pneumococcal shocks), one patient didn't receive the treatment because he was transferred for ecmo in a non-investigator center, three patients were treated after h, and in two patients one bottle of treatment was missing. the blinding was well respected. missing data on the pelod score and mortality was lower than %, and no premature stop was reported. the ecrf completion was judged easy by investigators. the inclusion of children within the first h was judged challenging. the treatment delivery had to be improved, requiring the help of research assistants. seven serious and one severe adverse events were registered, all patients recovered and no death was reported. conclusion: this pilot study suggested that a rct is feasible. it provides crucial information to improve the recruitment, the respect of the protocol and the correct measure of organ failure. however, inclusion of international centers is necessary to attain the sample size required. indirect calorimetry-based method for the work of breathing assessment when compared to esophageal pressure (pes) measurement and electrical activity of the diaphragm (eadi) during a spontaneous breathing trial in continuous positive airway pressure. patients and methods: a prospective single center study. all intubated and mechanically ventilated children > months and < years old, hospitalized in the pediatric intensive care unit were eligible. patients considered as ready to extubate were included. simultaneous recordings of vo , pes and eadi were performed during steps: before, during and after the spontaneous breathing test in continuous positive airway pressure. results: twenty patients, median . months, were included. half of the patients were admitted for a respiratory reason. predicted resting energy expenditure was overestimated as compared to measured resting energy expenditure ( [ - ] vs [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] kcal kg day, p < . ). spontaneous breathing test was associated with an increase in esophageal pressure-time product from to cm h o s min. the same trend was observed in respiratory drive, assessed by eadi which increased from . [ . - . ] to . [ . - . ] . oxygen consumption obtained by ic was higher during spontaneous breathing test as compared to conventional ventilation ( . [ . - . ] vs . [ . - . ] ml kg min) but non significantly. changes in work of breathing as assessed by vo was poorly correlated with measurements from pes and eadi whereas we found a moderate correlation between pes and eadi values. spontaneous breathing test and extubation were successful in ( %) and ( %) patients, respectively. conclusion: during weaning from mechanical ventilation, spontaneous breathing test in continuous positive airway pressure induced an increase in work of breathing, both in respiratory drive, as measured by eadi and in respiratory mechanics, as measured by pes. oxygen consumption measured by indirect calorimetry does not seem to be a reliable tool to assess work of breathing in mechanically ventilated children. ben gheriba khalil , grimaud marion , heilbronner claire , roy emeline , hadchouel alice , renolleau sylvain , rigourd virginie hôpital necker enfants malades, paris, france correspondence: ben gheriba khalil -bg.khalil@gmail.com annals of intensive care , (suppl ): introduction: during the winter season - we had evaluated breastfeeding disruption after hospitalization for bronchiolitis in our hospital in infants under month (n = ). we observed % of mothers whose breastfeeding was stopped of modified. clinical severity had no impact on breastfeeding but % of mothers stated that lack of support and advice was the first cause of breastfeeding disturbance. we conducted this second phase to evaluate the potential impact of actions to promote breastfeeding on unwanted weaning during hospitalization for bronchiolitis. patients and methods: this is a cross sectional study during two epidemic seasons of bronchiolitis in a tertiary care hospital. all patients aged months or younger hospitalized with acute bronchiolitis and receiving at least partial breastfeeding were eligible for the study. patients discharged at home whose parents accepted to be contacted by phone were included. a bundle of actions to promote breastfeeding in patients with bronchiolitis was implemented (posters, flyers, staff training, equipment with breast pumps) between the two epidemic seasons. the data was extracted from the charts and from a phone survey two weeks after discharge to evaluate breastfeeding in eligible patients in our hospital. phase i (before action) had included patients hospitalized between december and march in all wards hosting patients with bronchiolitis. phase ii (after action) included patients hospitalized from october to december . the data from phase ii was compared with data from phase i. results: fifty patients could be included during the second step of the study, with a mean age of days. breastfeeding was exclusive for % of mothers (vs % in phase i). the median length of stay was days (vs days in phase i). twenty-one ( %) patients spent time in picu vs. % in phase i, needed intubation, received non invasive ventilation for a median length of days (vs. days in phase i). the number of patients needing nutritional support was ( %) during phase ii vs. ( %) during phase i. after implementation of our actions, ( %) mothers kept breastfeeding as before (vs. % in the previous epidemic season, p < . ), mothers ( %) stopped, ( %) switched to partial breastfeeding and ( %) reduced without stopping. conclusion: bronchiolitis is a high risk event for breastfeeding disruption but staff training and correct advices and support for mothers during hospitalization seems to diminish that risk. benefits of using a high temporal resolution database in the automatic real-time pediatric ards screening nardi nicolas introduction: pediatric acute respiratory distress syndrome (pards) is frequent in pediatric intensive care units (picu), potentially lethal and the diagnosis is often missed or delayed (palicc ) . in picu, data are usually recorded between to min which leads to only a minority of the arterial partial pressure of oxygen (pao ) that are usable to calculate a valid oxygenation index (oi). if not available, pao should be replaced by the spo if < % to calculate the oxygen saturation index (osi). using a high temporal resolution (htr) database that records data every - s, we aim to develop a relevant clinical algorithm of mass data aggregation to improve pards screening with the automatic oi and osi calculation. patients and methods: all the patients admitted to our pediatric icu between may and august were included. the htr and the electronic medical records (emr) were queried through structured query language (sql) following these steps-( ) data selection ( ) extraction to a linear format ( ) date and time synchronization ( ) data pivoting ( ) aggregation through a -min moving average ( ) hypoxemia calculation. statistical analysis included proportions, correlations and bland-altman analysis. results: between may and august , patients ( stays) were admitted to the picu. approximately million rows were retrieved from the databases including , pao values. the algorithm was able to calculate , ( % of the pao ) oi and osi. the comparison between oi and osi showed that . % of the results were between the limits of agreements (− . + . ), a bias of − . and a correlation r = . . the comparison between the ois from the htr and emr databases showed that . % of the results were between the limits of agreements (− . + . ), a bias of − . and r = . . conclusion: using a mass data aggregation algorithm on a htr database allows more pao to be used to calculate an oi than the usual emr. the oi results differ slightly between the htr and the emr. the accuracy is probably in favor of the htr because of the shorter timelapse between the oi parameters. the osi is possibly a biased oi surrogate and should be interpreted with caution. our next step will be to measure the impact of the algorithm on the pards real-time diagnosis and pards severity categories. introduction: early administration of appropriate antibiotic therapy with adequate concentration is the cornerstone of the severe sepsis and septic shock's treatment. adult studies showed alteration of distribution and elimination which can lead to insufficient drug concentration in septic patients. in children, studies are lacking and antibiotic dosing may be suboptimal. we aim to describe the plasma concentration of the most used beta-lactam in critically ill children, to describe the rate of patients with suboptimal exposure and associating clinical and biological factors. patients and methods: this was a prospective, single center, observational study designed in beds pediatric intensive care unit (picu) and high dependency care at the necker hospital (paris, france) from january to may . were included, children with severe sepsis or septic shock, aged less than years and weighing more than . kg, and receiving one or more of the following antibiotics-amoxicillin, cefotaxime, cefazolin, ceftazidime, piperacillin-tazobactam, meropenem and imipenem for suspected or proven infection. betalactam plasma concentrations were analysed using high performance liquid chromatography. results: we enrolled children (severe sepsis, n = ( . %) + septic shock, n = ( . %)) with a median age of months ( - . bacteria were identified in patients ( . %). a total of blood samples were analysed at a median of days ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) following the onset of sepsis. twenty-four patients ( . %) had insufficient concentration (cefotaxime ( %) + piperacillin-tazobactam, ( %) + amoxicillin ( %) + meropenem ( %), cefazoline ( %), imipenem ( %) + ceftazidime ( %)). insufficient concentrations were associated with early measurements (< h from the sepsis' onset) (p = . ) and creatinine clearance increase (p = . ). adequate concentrations were associated with small age (p = . ). in conclusion, current standard beta-lactam dosing in children with severe sepsis or septic shock could be inadequate to reach the target concentrations. that could lead to the risk of clinical and bacteriological failures as well as the emergence of bacterial resistance. further pharmacokinetic studies are mandatory to improve antibiotic therapy in this vulnerable population. introduction: intermittent hemodialysis is a key support therapy in icu. despite protocol-based optimization, intradialytic hemodynamic instability (ihi) remains a common complication and could account for mortality and delayed renal recovery. the identification of patients at high risk for ihi is crucial but remains poorly explored. our objective was to test whether tissue perfusion parameters assessed at the bedside (mottling, index capillary refill time (icrt), and lactate) predict ihi and to develop and to validate a predictive score of ihi. patients and methods: prospective observational study in a -bed medical icu in a tertiary university hospital including hemodialysis sessions performed for acute kidney injury. exclusion criteria were patients with dark skin and dialysis performed in extreme emergency. mean arterial pressure (map), mottling score, icrt, and lactate were recorded just before starting hemodialysis. first episode of ihi requiring therapeutic intervention was recorded , , and min after hemodialysis starting. results: ninety-six hemodialysis sessions performed in patients were recorded. half of the patients received vasopressors (n = , %). ihi occurred in ( %) sessions and was more frequent among patients receiving vasopressors ( vs %, p < . ). mottling were more frequent ( vs %, p = . ), lactate levels higher ( . [ . - . ] vs . [ . - . ] mmol l, p < . ) and icrt longer ( . [ . - . ] vs . [ . - . ] s, p < . ) before sessions with ihi compared to sessions without, independently of map (p < . ). the incidence of ihi increased with the number of tissue perfusion alterations ( , , , and % for , , , and alterations, respectively, p < . ). a tissue hypoperfusion score, defined as icrt (seconds) + lactate level (mmol l) + if mottling presence was predictive of ihi independently of map (or . [ . - . introduction: epidemiological data suggest an increased risk of longterm chronic kidney disease after acute kidney injury (aki). in survivors of out-of-hospital cardiac arrest (ohca), aki is frequent and is associated with numerous factors of definitive renal injury. we made the hypothesis that aki after ohca was a strong risk factor of long-term chronic kidney disease (ckd). we aimed to evaluate renal outcome of ohca survivors according the occurrence of aki in icu. patients and methods: we used the cohort of consecutive ohca patients admitted between and in a tertiary medical icu previously described (geri et al. icm. ) . aki was defined by kidney disease improving global outcomes (kdigo) criteria. long-term creatinine level was the last blood creatinine assessment we were able to retrieve. the main outcome was the occurrence of ckd, defined by an estimated glomerular filtration rate (egfr) lower than ml min . m according to the mdrd equation. long-term mortality was evaluated as well. factors associated with ckd occurrence were evaluated by competing risk survival analysis (fine gray and cox cause specific models providing sub-hazard ratio (shr) and cox sub-hazard (csh)). results: among the ohca patients who were discharged alive, we were able to retrieve the outcome of patients (median age [iqr , ] , . % of male) who were included in the analysis. during a median follow-up time of . [ . - . ] years, ckd occurred in ( . %) patients and ( %) patients died. a previous history of arterial hypertension (shr = . [ . + . ], p = . + csh = . [ . + . ], p = . ), aki during icu stay (shr = . [ . + . ], p = . + csh = . [ . + . ] , p = . ) and an age higher than (shr = . [ . + . ] , p = . + csh = . [ . + . ], p = . ) were independently associated with ckd occurrence. aki was not associated with long-term mortality (shr = . [ . + . ], p = . + csh = . [ . + . ], p = . ). in ohca survivors resuscitated from an ohca, ckd was a frequent long-term complication. aki during icu stay was a strong determinant of long-term ckd occurrence. introduction: many critically ill patients have a moderate to high risk of bleeding but they also require prolonged intermittent dialysis to ensure a negative water balance without hemodynamic adverse events. thus, a heparin-free easy-to-use anticoagulation within the dialysis circuit is needed but, to date, usual protocols (iterative saline flushes, heparin grafted membranes) lead to - % of premature clotting and sessions that last greater than min are rarely achievable. we assessed the safety and efficiency of heparin-free regional citrate anticoagulation of the dialysis circuit using a calcium-free citrate-containing dialysate, with calcium reinjected according to ionic dialysance (an online measure of the instantaneous clearance of small molecules available in most of dialyzers). patients and methods: we prospectively reported the clotting events that occurred during all the heparin-free dialysis sessions that were performed with a regional anticoagulation based on calcium-zero citrate-containing dialysate (citrasate, hemotech, france) between january and august in a -beds icu. results: a total of dialysis sessions were performed in patients (mechanical ventilation n = + norepinephrine n = ). median duration of dialysis was min (iqr, - + maximum min), and median ultrafiltration volume was l (iqr . - . ). when assessed, urea and beta -microglobulin reduction rates were . % ± . % and % ± . %, respectively. postfilter ionized calcium was . ± . and . ± . mmol l at and h, respectively, within the extracorporeal circuit. a major clotting event that led to premature termination of the session occurred in only sessions ( . %) . in these five cases, major catheter dysfunction occurred before clotting within the circuit. prefilter ionized calcium remained within narrow ranges (before after change + . ± . mmol l), and total-to-ionized calcium ratio, a surrogate marker for citratemia, was unchanged and always below . . in sessions, no ionized calcium measurement was required. conclusion: dialysis anticoagulation with calcium-free citrate containing dialysate is an easy-to-use, efficient, and inexpensive form of heparin-free regional anticoagulation. calcium reinjection according to ionic dialysance allows prolonged hemodialysis sessions in critically ill patients without the need to systemically monitor ionized calcium. sessions can be safely extended according to the hemodynamic tolerance to ensure an adequate dose of dialysis and a negative water balance, a major point in patients with severe aki. introduction: brain injury is the first cause of death after cardiac arrest (ca) and multimodal neuroprognostication is a cornerstone of postresuscitation care. among the different usable information provide by electroencephalogram (eeg), the aim of this study was to evaluate the predictive value of eeg reactivity regarding neurological outcome at discharge. patients and methods: using our prospective registry of successfully resuscitated patients admitted to a cardiac arrest center between january and , we studied all consecutive comatose patients still alive at h and in whom at least one eeg was performed during coma. in addition to usual clinical findings, we collected eeg (patterns and reactivity, status epilepticus) and somatosensory evoked potentials characteristics. the eeg reactivity was evaluated by a blinded neurophysiologist and was defined as a reproducible change of the tracing (in amplitude or frequency) provoked by an auditory and a nociceptive standardized stimulation. we evaluated the predictive values of persistent lack eeg reactivity and other indicators regarding their respective ability to predict a favorable or unfavorable outcome. recovery of a level or on the cerebral performance category (cpc) scale at discharge was considered as a favorable outcome, as opposed to recovery of a cpc level - (unfavorable outcome). we included patients who were mostly male ( %), with median age of years. ca occurred in a public place in % of cases, and it was witnessed in % of cases. bystander cpr was initiated in % patients and the initial cardiac rhythm was shockable in % patients. median time to eeg was days ( - ) and % of patients were still sedated during the examination. a favorable neurologic outcome was observed in patients ( %). an eeg reactivity was present in patients ( %) with favorable outcome and in patients ( %) with unfavorable outcome. the positive predictive value (ppv) of a persistent eeg reactivity for prediction of favorable outcome was % . by contrast, the ppv of lost eeg reactivity for prediction of unfavorable outcome was % (ic % - ) with a false positive rate (frp) of . % ( . - . ). eeg electroencephalogram, ssep short-latency somatosensory evoked potentials, ppv positive predictive value, npv negative predictive value, fpr false positive rate in this population of post-cardiac arrest patients, the presence of eeg reactivity was poorly predictive of a favorable neurologic outcome. the absence of reactivity was highly predictive of unfavorable outcome. in combination with other indicators, searching for eeg reactivity may have important implications in the neuroprognostication process. conclusion: this subgroup analyses of a randomized controlled trial, found no survival benefit when comparing crystalloids to colloids in critically ill surgical patients. introduction: goal of a fluid challenge (fc) is in fine to increase the stroke volume (sv) or the cardiac index (ci) when an episode of hypovolemia or a preload dependence status are suspected. fc is one of the most common practices in icus, however, the way to assess the response to fc is not standardized. the present study aimed to evaluate whether the trans-thoracic echocardiographic (tte) assessment of the response to fc immediately at the end of the infusion or delayed min later could affect the results of the fc. patients and methods: prospective, observational, multicentre study including all icu patients in septic shock requiring a fc. were excluded patients with-arrhythmias, poor echogenicity and severe mitral or aortic regurgitation. fc was performed administering ml of crystalloids over min. fluid responsiveness was defined as a > % increase in stroke volume (sv). the following echocardiographic parameters were recorded-e wave, a wave, e a ratio, velocity-time integral (vti), ea wave and sa wave. map, hr and tte variables were collected at baseline (t ), at the end of fluid challenge (t ) and (t ) and min (t ) after the end of fluid challenge. quantitative data are expressed as mean and standard deviation (sd) or median and interquartile (iqr), according to their distribution. qualitative data are expressed as absolute number and frequency (%). results: from may th to january th , a total of patients were enrolled in french icus (mean age- ± years, median igs ii- , median sofa score- [ ] [ ] [ ] [ ] [ ] ). among the ( %) patients responders to fc at t , patients were transient responders (tr), i.e. became non-responders at t ( %, % ci = [ - ]) and ( %, % ci = [ - ])) patients were persistent responders (pr), i.e. remained responders at t . among the non-responders (nr) at t , became responders at t , ( %, % ci = [ . - . ] ). in the subgroup analysis, no statistical difference in haemodynamic and echocardiographic parameters was found between non-responders, transient responders and persistent responders (fig. ) . conclusion: the present study shows that, after a % vti increase at the end of the fc, vti returns to baseline at min in half of the responders. blood volume status (normo or hypovolemia) before initiating the fluid infusion could explain the transient or persistent response to fc observed in septic patients. mottling score is a strong predictor of day- mortality in sepsis patients independently of catecholamine dosing and other tissue hypoperfusion parameters dumas guillaume , joffre jérémie , hariri geoffroy , bigé naike , baudel introduction: sepsis is a frequent critical condition. mottling score, an hypoperfusion parameter, is well correlated with outcome. however, uncertainties persist regarding its value not only as a marker of patient severity but also as an independent predictor of mortality and treatment efficacy. we performed a post hoc analysis of four published prospective studies including sepsis patients with or without shock. we analyzed the relationship between the mottling score (from to ) and day- mortality according to other prognosis covariates such as catecholamine dosing, urine output and plasma lactate levels. first, factors associated with outcome were determined by multivariate analysis. second, mottling score-by-covariate interaction was studied to better understand its effect on mortality. finally, effect of mottling score variation at different time point (h -h -h -h ) was assessed. whereas ecmo was successfully weaned in ( %) patients. proportion of perfused vessel (ppv), perfused vessel density (pvd), micro flow index (mfi) and heterogeneity index (hi) were severely impaired before ecmo. re-establishing high and stable peripheral blood flow with va-ecmo led to a rapid decrease in heart rate and vasoactive inotropic support and significantly improved all microcirculation parameters within h. total vessel density and pvd, measured before and after ecmo initiation, were better in patients successfully weaned from ecmo (p < . ) (fig. ) . conclusion: cardiovascular support with ecmo-va rapidly improved macro and microcirculation in refractory cardiogenic shock patients. total vessel density and perfused vessel density were significantly better in survivors h after ecmo initiation and might therefore help to predict outcomes. further studies are now needed to better define the utility of this technology in larger groups of va-ecmo patients. introduction: thyroid storm is a rare but life-threatening disease related to thyrotoxicosis. it can lead to multiple organ failure including cardiovascular disorders or neurological impairment. to date, data on this disease in icu patients are scarce and limited to case reports. we therefore aimed to describe clinical presentation, outcomes and management of thyroid storm in icu patients. patients and methods: local diagnoses coding database (from january to july ) from french icu were interrogated for main and secondary diagnoses codes including thyrotoxicosis based on the international classification of disease th revision. thereafter two investigators reviewed all the medical records selected. inclusion criteria were thyroid storm based on the diagnostic criteria of the japan thyroid association (t. satoh, endocrine journal ). it combines thyrotoxicosis with elevated levels of free triiodothyronine (ft ) or free thyroxine (ft ) with at least two of the following symptoms-central nervous system manifestation, fever, tachycardia > bpm, congestive heart failure, or total bilirubin level more than micromol/l. clinical presentation, therapy used, and outcome were recorded. results: sixty-two patients (median age years (interquartile range - ) + saps ii ( - ) were included. thyroid storm was the first manifestation of thyrotoxicosis in ( %) patients. graves' disease ( %), amiodarone induced thyroiditis ( %), autoimmune thyroiditis ( %), and toxic multinodular goitre ( %) were the main causes of hyperthyroidism. amiodarone, thyroid hormone toxicity, antithyroid drugs withdrawal or infectious trigger were identified in ( %) patients. organ support including mechanical ventilation, catecholamine infusion, renal replacement therapy and veno-arterial ecmo were used in , , , and patients, respectively. main thyroid storm treatments included antithyroid drugs ( %), betablockers ( %), corticosteroids ( %), and plasmapheresis ( %). lastly, icumortality was %, with multiple organ failure responsible of death in all patients. although its incidence appears low, icu physicians should be aware of the multiple clinical features of thyroid storm. our preliminary data reported various specific therapeutic management of this potentially fatal disease. prompt initiation of targeted therapies is required for atypical hemolytic uremic syndrome (ahus) and thrombotic thrombocytopenic purpura (ttp), but no specific therapy is consensual for shiga toxinassociated hemolytic uremic syndrome (stec-hus). thus, rapid differentiation of stec-hus is mandatory to tailor the initial treatment. furthermore, apart from large outbreaks, characteristic features of this syndrome in adults have not been described. in this study, we retrospectively compared the characteristics of stec-hus, ahus and ttp patients at admission in two expert icus. patient were included if they presented with the triad of mechanical hemolytic anemia, thrombocytopenia and organ damage, and tmas were classified using international criteria. other causes than stec-hus, ahus and ttp were excluded. results: amongst tmas admitted between september and january , stec-hus, ahus and ttp were included. stec-hus patients were older ( ) than ahus ( , p = . ) and ttp patients ( , p < . ). they presented with more frequent digestive symptoms ( versus and % for ahus and ttp, p = . and < . ), but bloody diarrhea was rare ( %) and non-statistically different from other tmas. confusion was more frequent in stec-hus ( %) than ahus patients ( %, p = . ). biologically, stec-hus patients displayed elevated fibrinogen levels ( . vs . and . for a hus and ttp, both p < . ) and severe renal failure. forty-two percent required renal replacement therapy and % were treated with plasma exchange before the distinction from other tmas could be made. only ( %) stec-hus patient died in the icu (fig. ) . conclusion: characteristics supposed to identify stec-hus are largely shared with other tmas. in particular, the differential diagnosis between ahus and stec-hus appears to be more difficult than the stereotypical description derived from pediatric studies. severe hyperglycemia in icu patients: a higher mortality rate and a higher incidence of diabetes in a long-term follow-up study . ], p = . ) but not when admitted for coma, sepsis or cardiac arrest. mortality rate was significantly higher in patients with severe hyperglycemia compared to those without, regardless of preexisting diabetes (hnd hd vs. nhnd nhd groups + p < . ). patients with severe hyperglycemia had a higher incidence of type diabetes at ( vs. % + p = . ) and months ( vs. % + p = . ) compared to those who did not. conclusion: severe hyperglycemia occurring in the first days of icu admission was associated with higher mortality rate and an increased risk of diabetes in the following months regardless of preexisting diabetes. introduction: vitamin d deficiency is frequent in northwestern countries and could represent a modifiable risk factor for critically ill patients, in relation with its pleiotropic effects ( ) . some studies reported an association between oh vitamin d ( oh) deficiency, chronic health status and icu-and hospital-related outcomes. however, a large supplementation study have not been found to improve outcome of patients with moderate oh deficiency (< ng ml) ( ) . the aim of the study is to analyze the relationship between the severity of oh deficiency at icu admission, severity of illness and outcomes and ultimately to identify subgroups of patients in whom the likelihood of benefit of supplementation is larger. patients and methods: consecutive patients admitted over a -month period who stayed at least h in a medical surgical -bed icu were included. in these patients, demographic data, charlson comorbidity score, severity scores (saps and sofa) and -oh (chemiluminescence, diasorin) were collected at admission. icu and hospital length of stay (los) and mortality were recorded. correlations were searched between oh and the different scores, and vital outcomes ( - )). hypothyroidism was unknown before icu admission in % patients. median sofa score at icu admission was ( - ). myxedema coma, circulatory failure, respiratory failure, and severe hypothermia were respectively the main admission reason in , , , and % patients. a precipitating factor such as drugs thyroid toxicity, thyroid hormone withdrawal or infection was found out in only ( %) patients. main causes of hypothyroidism were thyroiditis and thyroidectomy. thirtytwo ( %) patients had alteration of consciousness with a median glasgow score at ( - ). in addition, median heart rate at icu admission was ( - ) bpm while hypothermia < °c was noted in ( %) patients. median tsh level at admission was ( - ) mui l, t and t levels respectively ( - . ) pmol l and ( - . ) pmol l. rhabdomyolysis was frequent with median cpk level ( - ) ui l. organ support including mechanical ventilation, catecholamine infusion and, renal replacement therapy were respectively used in , , and % patients. lastly, % patients received oral levothyroxine whereas the intravenous form was used in others. overall icumortality was %. our preliminary data showed that severe manifestations of hypothyroidism leading to icu admission represent de novo hypothyroidism in two-thirds of patients, leading to a high mortality. introduction: when it comes to infections of the central nervous system (cns), the greatest challenge in the emergency department (ed) is to identify patients that have a rare life-threatening diagnosis. alone or in combination, fever, headache, altered mental status encompass a broad differential diagnosis. antibiotics or antiviral therapy should be given as soon as possible, ideally after both blood and cerebrospinal fluid (csf) have been obtained. early treatment is associated with a lower mortality. patients and methods: we present here, a four-year ( - ) retrospective and monocentric study. during the period of the study, we included all adult patients with the diagnosis of cns infection (positive csf culture). we collected and analyzed all clinical, biological, imaging, treatments and evolution datas during the stay. a total of patients with cns infection have been included for statistical analysis. we analyzed a second group (n = ) with suspected cns infection (negative csf) as a control group. results: in the study population, mean age was ± . years old and the sex-ratio was . . there were no difference between the two groups in terms of clinical signs except for more altered mental status in the control group (p = . ). all patients of the study (n = ) benefited of lumbar puncture (lp) in the ed with an average time of ± min after admission. this delay was the same between the two groups (p = . ) but was significantly higher in the encephalitis subgroup (n = , p = . ). patients who had imaging (ct or mri) during the ed stay had more likely a delay in lp realization ( vs min, p = . ). patients where the cns infection diagnosis was firstly evoke by the triage nurse had lp more quickly (p = . ). the median door to-antibiotic-time was min with no difference between the two groups of the study (p = . ). % of all patients were hospitalized for an average length of stay of . ± . days and % of them were admitted in the icu. the inhospital mortality was % in the study population. introduction: there are numerous causes of acute exacerbations of copd (aecopd), the most common of which are bronchial and or pulmonary infections. viral etiologies may account for % of aecopd, but this rate is likely underestimated because of the limited performance of the conventional diagnostic tests. multiplex molecular diagnostic tests may identify several pathogens including viruses and bacteria, from a single respiratory tract sample, with high sensitivity. using these tests, respiratory viruses are identified in to % of cases, according to the series. the objective of this work was to describe the microbial epidemiology, the management and the outcome of patients admitted to the intensive care unit (icu) with moderate to severe aecopd, in the era of multiplex testing. a prospective non interventional multicenter study conducted in two university-teaching hospitals. in addition to the usual samplings, a nasopharyngeal swab was performed for multiplex polymerase chain reaction (pcr), using respiratory panels fil-marray biomérieux ( viruses and bacteria) or eplex automaton ( viruses and bacteria) depending on the center. the preliminary results involve the patients ( males + years ( - )) included in tenon hospital over a -month period. the mean fev was % ( - ) median % [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . drug therapies included anticholinergics (n = + %) and beta- -mimetics (n = + %), inhaled (n = + %) or oral (n = + %) steroids, and azithromycin (n = + %). a respiratory virus was identified in patients ( %), alone or in combination with a bacterium (n = ). a bacterial pathogen was identified alone times ( %). therapeutic interventions did not differ depending on whether a virus was detected or not-exposure to antibiotics ( ± . vs. . ± d + p = . ), administration of oseltamivir ( / vs. / + p = . ), steroids ( / vs. / + p = . ) and mechanical ventilation ( / vs. / + p = . ). the icu length of stay ( . ± . vs. . ± . d + p = . ) was similar. the icu and d-mortality rates were . and . %, respectively. conclusion: respiratory viruses are frequently involved in moderate to severe aecopd. the respiratory multiplex pcr should be performed in this setting and the results should be taken into account to more adequately use the anti-microbial treatments. introduction: prophylactic non-invasive ventilation (niv) is a well established method for prevention of post-extubation acute respiratory failure in hypercapnic patients. however, its role in the postextubation period, in traumatic brain injury patients, is uncertain. especially, because of effects of the brain injury, on respiration and airway control. we perform a study to assess the impact of prophylactic niv after extubation among patients with severe traumatic brain injury. patients and methods: over a period of year, adult patients with isolated severe traumatic brain injury, who were under invasive mechanical ventilation for more than h were eligible for inclusion in the study. they were randomized, after decision of extubation, to receive conventional therapy or conventional therapy associated with niv. conventional therapy consisted of oxygen delivery by facial mask, semi-recumbent position, mucus suctioning and nebulization therapy. the main objective of the study is to assess the impact on reintubation rate. extubation succes was defined by the absence of need for reintubation within the days. the secondary objective is to evaluate the effect on icu length of stay after extubation. the clinical benefit of non-invasive ventilation (niv) in patients with acute hypoxemic respiratory failure (arf) is being called into question. indeed, in a multicenter randomized trial recently conducted in hypoxemic arf patients (pa fi < ), intubation rate in the niv group was % and intensive care unit (icu) mortality rate was %, numbers higher than in the standard-oxygen group ( ) . an excessive tidal volume under niv is a hypothesis to explain these bad outcomes ( ) . our experience does not seem to support these data. therefore we wanted to-investigate the rate of niv success in hypoxemic arf and global in-icu mortality. estimate the average expired tidal volume and identify predictive factors of niv failure. conclusion: though limited by its design, our study seems to show a similar efficacy of niv following ue as compared to planned extubation, with a safety concern for rescue niv and a potential interest for "prophylactic" niv. further data is warranted. which is yet operator dependent and time-consuming, or by invasive methods including esophageal pressure or diaphragmatic electromyogram measurements. the main purpose of this study was to assess the relevance of curvex as a noninvasive diagnostic and classification tool for asynchronism management. this project is based on a prospective physiological tracing data-warehousing program (rea stoc, clinicaltrials.gov # nct ) that aims to record consecutive icu patients, over -years. all consecutive patients were recorded for a -hours period during -h following icu admission. all measurements were recorded with the patient laying supine, with a ° bed angulation. raw ventilatory pressure and flow curves were transferred to a centralized server using a dedicated network. the physician in charge of the study was informed of the online analysis on a routine basis. physiological recordings were associated with metadata collection. asynchronisms detection is based on a non-parametric hypothesis testing (random distortion testing), that requires no prior information on the signal distribution. beside asynchrony index monitoring (ai), five asynchronism's types were qualified-ineffective efforts (ie), short cycles (sc), multiple cycles (mc), prolonged inspiration (pi) and premature cycling (pc introduction: international guidelines recommend ultrasound (us) guidance for central venous catheter (cvc) insertion. however, evidence is lacking for several aspects of guidance such as probe shape or whether the needle has to be in plane (ip) or out-of-plane (oop). we assessed these issues in a randomized trial. success at first pass, number of attempts (needle passes), success, times between skin contact and needle skin penetration and between needle skin penetration and liquid back flow in the syringe were recorded. qualitative and quantitative values are expressed as number (percentage), and median (range), and were compared using the wilcoxon matched pairs test and the fisher exact test, respectively. results: for ijv puncture, first attempt success rate was more than % and was neither influenced by probe shape nor approach (table ) . conversely for rav puncture, using lp with ip approach was more frequently successful at first attempt ( vs %, p = . ). time elapsed between needle skin penetration and liquid back flow was shorter for rav puncture using ip approach ( s vs s, p = . ). time elapsed between probe appliance on skin and liquid back flow was significantly shorter with the linear probe for ijv whatever the approach and for rav using ip approach. rav puncture was more frequently impossible with mcp ( vs %, p = . ). arterial puncture occurred more frequently with mcp ( vs %, p = . ). lp use and ip approach were associated with more free event puncture ( ± ) . minimal ani, reflecting intense stress was . (± . ). objective and subjective stress of each team leader is shown in fig. . there was a significant negative linear correlation between minimal ani and maximal hr (rho = − . , p = . ). there was no significant correlation between self-reported stress vas (neither pre hfs or maximal stress) and minimal ani. conclusion: hrv monitoring is a feasible method to evaluate continuous physiological stress for team leaders in highly stressful simulationteaching. upgrading signal connection by bluetooth . or wi-fi could improve the method. focusing on specific stressful time points might improve stress assessment and its correlation with performance. introduction: simulation training has become available in health sciences faculties and proposed in many specialties. intensive care is one of the fields of development of simulation based training. the aim of the present study was to report the experience of the faculty of medicine of monastir simulation center in training medical students and residents in intensive care and to compare their respective perceptions. this was a descriptive study including students ( th year of the medical curriculum) and residents who received training during the last academic year ( ) ( ) , in the simulation center during their icu traineeship. simulation training was based on high-fidelity mannequins for students and seminars with high fidelity and procedural simulation training for residents. three sessions per group were organized for students and a total of five sessions for residents. we collected participant characteristics and used likert scale (from to ) to assess participant satisfaction, simulation fidelity, impact on clinical practice, stress level and instructor behaviors. chi test was used to compare students' and residents' perception of the simulation based-training. results: during the study period students (of the students' whole promotion) and residents actively participated at least in one of the simulation-based training sessions. median students' and residents' ages were respectively years ( - ) and years ( introduction: hospitals are encouraged to edit local antibiotic therapy guidelines. antibiogarde ® is an electronic antibiotic prescription referential developed by a multidisciplinary team of french physicians, regularly updated, and locally customizable, which has been purchased by more than french hospitals. we compared adequacy fig. team leader's objective (heart rate and ani) and subjective stress (declared vas stress) of initial antibiotic prescription by icu clinicians, antibiogarde ® proposal and national or international guidelines. patients and methods: between january and june , initial antibiotic prescriptions in an icu were retrospectively analyzed when microbiologically documented. antibiogarde ® and guidelines proposals were simulated, considering data available at the time of initial prescription. adequacy was defined when all bacteria responsible for infection were sensitive to at least one prescribed proposed antibiotic. national guidelines were used when published after . otherwise, most recent international guidelines were used. results: initial prescriptions were analyzed ( monotherapy) in patients (median age y, median saps ii , median sofa on prescription , icu mortality %, % immunocompromised). main sources of infection were lung (n = ) and intra-abdominal (n = ). leading isolated bacteria were enterobacteriaceae (n = , antibiotic resistance in ), streptococci (n = ), non-fermenting gram negative bacilli (n = , antibiotic resistance in ) and staphylococci (n = , resistance to methicillin in ). in the clinical settings analyzed, there was a proposal by antiogarde ® in ( %) and a guideline available in ( %) (p = . introduction: intubation is plagued with a high morbimortality, especially in emergency situations. it is now acknowledged that a seated position allows for optimized preoxygenation ( ) . however, there is no guideline concerning the patient's position for intubation. the patient is most often laid in a supine position, leading to a higher risk of aspiration ( ) . face-to-face intubation in sitting position (ftfi) would allow for an easier intubation and a lower morbidity. we focused on learning the ftfi technique using the macintosh laryngoscope and the airtraq videolaryngoscope in simulated difficult intubation situation and comparing the performance of the ftfi with the classic technique. the participants would intubate a high-fidelity manikin (simman g, leardal, norway) configured with a tongue edema (cormack b- ). for each trial, time to intubate (tti), success and complication rate, intubation difficulty and glottis exposure were noted. in classic position, three trials were performed with the airtraq followed by the laryngoscope in order to obtain baseline parameters. in ftfi, at least intubations were performed by each participant for each device. the utilization order was randomized. results: thirty physicians, with an experience of at least intubations each, were included. figure shows the learning curves of the ftfi based on the evolution of the tti measured for the airtraq and the laryngoscope. in classic position, the mean tti with the airtraq was . ± . s versus . ± . s with the laryngoscope (p = ns). in ftfi, once the technique mastered, the tti was ± . s with the airtraq versus . ± . s with the laryngoscope (p < . ). success rate, tti, complication rate, intubation difficulty and glottis exposure were better using ftfi versus classic intubation (p < . ). these parameters were even better with the airtraq than with the laryngoscope (p < . ). the learning profile of ftfi is different between the airtraq and the laryngoscope. it could be due to the participants' lesser familiarity with the airtraq. the better performances in ftfi could be due to better ergonomics allowing easier glottis exposure and learning ( ) . conclusion: face-to-face intubation in sitting position is easy to learn. it provides better performances and fewer complications than the classic intubation technique which might result in a lower morbidity. the airtraq provides even better results than macintosh laryngoscope. all participants recommend their colleagues to be trained in face-toface intubation. among non-invasive respiratory support, niv with bilevel pressure was the most frequent (n = , %) before cpap (n = , %) and high flow oxygen (n = , %). the proportion of patients on niv was up to % in the centres hosting more acs patients. conclusion: despite the absence of evidence from randomized controlled trials niv is nowadays commonly used in picu and hdu for scd patients with acs, especially in centres taking in charge a high number of scd patients. future physiological studies and randomized controlled trials might help to choose between the different ventilatory support options for acs. in transfused patients, the pre-transfusion hemoglobin was . ( . - . ) g dl in moderate pards and . ( . - . ) g dl in severe pards. the evolution of hemoglobin, osi, scvo and lactate after the transfusion is reported in the table . in our picu, a relatively restrictive policy of rbc transfusion was observed even in patients with severe pards. decision to transfuse seemed associated with the general severity status of the patient and with the hemoglobin level. further studies are needed to explore the generalizability of these findings, and to investigate the impact of transfusion on oxygen transport consumption balance in pediatric acute respiratory distress. introduction: pharmacokinetic parameters are altered in critically ill patients. for instance, in adult patients, it has been well demonstrated that augmented renal clearance results in subtherapeutic antibiotic concentrations. our objectives were to build a pediatric population pharmacokinetic model for piperacillin, in order to optimize individual dosing regimen. patients and methods: all children admitted in pediatric intensive care unit, aged less than years, weighing more than . kg, and receiving intermittent piperacillin infusions were included. piperacillin was quantified by high performance liquid chromatography. pharmacokinetics were described using the non-linear mixed effect modelling software monolix. monte carlo simulations were used to optimize dosing regimen, in order to maintain plasma concentration above the minimum inhibitory concentration ( mg l − for pseudomonas aeruginosa) throughout the dosing interval ( % ft > mic). results: we included children with a median (range) post natal age of . ( . - . ) months, median (range) body weight of . ( . - ) kg, median (range) pelod- score of ( - ) and median (range) estimated creatinine clearance of ( - ) ml.min - .m - . a one compartment model with first-order elimination adequately described the data. median (range) values for piperacillin clearance and volume of distribution were respectively ( . - ) l h − and . ( . - . ) l. body weight (allometric relationship), estimated creatinine clearance and pelod- severity score were the covariates explaining the estimated between subject variability. a third of the cohort attained the target, according to our dosing regimen and to the european guidelines. to reach the target and according to the simulated dosing regimens, children with acute kidney injury should receive intermittent infusion every h, administered on min. those with augmented renal clearance should receive a continuous infusion. to reach the target, standard intermittent piperacillin dosing regimen in critically ill children is not appropriate. in addition to body weight, dosing regimens should take into account the creatinine clearance. continuous infusion is adequate for children with augmented renal clearance. piperacillin individualized dosing regimens and therapeutic drug monitoring are mandatory in pediatric intensive care unit. introduction: all data support the need for early recognition, evaluation of pain in the nicu. multiparametric analysis including physiological parameters could be useful to have a more objective evaluation of pain in the nicu compared to scales built on external-evaluation. the newborn infant parasympathetic evaluation (nipe ® ) was developed to assess pain in newborns and infant, from preterm to the age of years. patients and methods: we conducted a monocentric, prospective study to compare the instantaneous nipe ® index value (nipei ® ) to the dan scale during acute procedural pain (picc line insertion) in preterm infants (under gw). the operators and the nurse were blinded to the continuous recording of nipei ® during the entire procedure. dan scale was assessed every min by a third person, trained to this scale and blinded to nipei ® . a direct correlation assessment between the dan scale and the nipei ® was performed by calculating the pearson's linear correlation coefficient. the differences between the nipei ® of non-painful (dan < ) and painful (dan ≥ ) infants were estimated by the wilcoxon-mann-whitney test. the usefulness of nipei ® as a new tool for pain assessment in neonates was estimated by the corresponding roc curve. our study was approved by our local ethic institutional review board. results: thirty-five preterm infants were included, nipei ® data were incomplete in infants. fifty percent of newborns were born before gw, and % had non-invasive respiratory support (continuous positive airway pressure cpap). at the time of the procedure, newborns had a median post-natal age of days and a median weight of grams. there was a moderate correlation between the nipei ® index and the dan scores (r = . + p < . ). the median nipei ® index was for non-painful events vs. for painful events, p < . . the area under the roc curve was . . for a threshold of nipei ® < , the sensitivity was . %, the specificity was %. positive likelihood ratio was . and the negative likelihood ratio was . ( fig. ) . we showed a correlation between the dan scale and the nipei ® index for pain assessment in preterm infants. the nipe ® monitor could be a useful and non-invasive tool for pain assessment in neonates. further studies are needed to confirm our results and to define more precisely the place of such monitors for pain evaluation in daily clinical practice in the nicu. introduction: the aim was to identify factors associated with the occurrence of acute pituitary hormone dysfunction in children with moderate to severe tbi and to describe the impact of this dysfunction on the stability of the children. patients and methods: prospective bicenter study including all children aged between month to years, admitted to picu for a moderate-severe tbi and with an expected stay > days. setting-pediatric intensive care units of grenoble and lyon, from to . endocrine explorations at the second morning following admission and h before discharge were performed-cortisol h cycle with free cortisol and acth dosages every h (or h if no central line) + free h urinary cortisol + tsh and t l, h urinary lh and fsh, blood level of testosterone or estradiol for children aged > years, and igf . patients were classified as having cortisol insufficiency if all the cortisol dosages were < nmol l and all acth were < pg l. tsh deficiency was defined as t l < . pmol l and tsh < . mui l. gonadotropin defciency was defined as urinary lh < . ui h and urinary fsh < . ui h for males + urinary lh < . ui h and urinary fsh < . ui h in female. patients with deficiency (acth and any deficiency) were compared to those without deficiency in terms of hemodynamic instability, respiratory instability, neurological and infectious complications for continuous variables means and % confidence interval were calculated and compared by t student test. chi- test was used to compare proportions. results: among the patients evaluated, had acth deficiency, and had at least one acute pituitary dysfunction. comparison of patients who presented acth deficiency with those who were not deficient found no differences in terms of patients characteristics, cause of tbi, level of severity and level of injury. paitents with acth deficiency required more frequently fluid bolus at day ( vs %, p = . ). all the markers of severity were higher and the need of vasoactive drugs were more frequent but the differences were not statistically significant. table shows comparison between patients with at least one pituitary hormone deficiency to those without deficiency. the same result was found. glycemia levels were lower in the group with deficiency. conclusion: we didn't find any predictive factors of pituitary hormone deficiency in children with moderate-severe tbi justifying a systematic screening of those patients. introduction: most intensive care unit (icu) patients cannot make decisions themselves. familiy members are actively involved in the care process as surrogate decision-makers and judges of care quality. however, family satisfaction with care is complex and is not clearly defined. the aim of this study is to evaluate the different procedures (reception book and staff education for aid and relationship) used in a new icu to improve the family care. patients and methods: we included in our study patients who had spent more than h in our department. a questionnairy, adapted to our population, was performed by our staff and validated by the hygiene and quality care departement. we proceded by phone calls, months after the inauguration of our icu. results: sixty-five questionnaires were included (fig. ). the average of age was ± with a sex ratio of . the average of the simplified acute physiology score (sapsii) was ± . the median stay was days [ - ] with a total mortality rate of %. mostly, we interrogated first-degree parents (n = ). only three families recieved reception book at admission. visit in patient room was autorised only for % (n = ) of family members. only four persons said they were disturbed in visit hours for architectural reasons (tight space). disponibility was found excellent in % (n = ) of cases for medical staff, % (n = ) for paramedicals. informations provided by physicians were clear in . % (n = ) of cases. fifteen of the family members ( %) asked psychology support. patients were followed up via phone calls during year after discharge. characteristics on admission and outcomes after discharge were analyzed stratified by ventilation modality niv vs imv. the overall survival was analyzed on the basis of the kaplan-meier curves. results: during the predetermined period of data collection, the follow-up involved patients. patients were treated by niv (group ) and patients needed imv (group ). there was no difference between the groups in age (p = . ), severity of copd (p = . ), physiological reserve at discharge (p = . ) and icu readmission (p = ). short term outcomes were not different between the groups- -month readmission ( . vs % respectively in niv and imv, p = . ) and -month mortality ( introduction: post-intensive care syndrome (pics) has been recently described as a combination of physical, cognitive and mental impairments appearing during a stay in an intensive care unit (icu). the prevention and detection of pics require the participation of each category of healthcare workers. however, the level of knowledge is unknown. we sought to assess the awareness among our icu staff in preparation for a follow-up consultation. the study used a short multiple-choice survey filled on a voluntary basis. all members of the staff were asked to fill the questionnaire over a one-week period. the assessment was composed by seven structured questions which aimed measure basic knowledge of post-intensive care syndrome and general strategies to diagnose that syndrome and the tests used. results: fifth five workers ( % of the staff ) of the department of intensive care answered the questionnaires ( % nurses, % physiotherapists, % physicians). the estimated ranges of prevalence of psychological problems were very low ( - %) for . %, low ( introduction: drafting a death certificate (dc) is a procedure considered as a part of doctor's daily practice, especially in emergency and intensive care departments. this certificate represents a civil, social, epidemiological and medico-legal act. it can engage the liability of the certifying doctor. the objectives of our study were to examine the content of dc drafted in emergency and intensive care departments, assess the quality of writing, and analyze drafting errors. patients and methods: a prospective study extended over a period of months from january to december , including all dc emanating from emergency and intensive care departments and received in the forensic department of habib bourguiba hospital in sfax. results: during the study period, dc meeting the inclusion criteria were collected. although confidential, the medical part of the dc was sealed by the doctor in onlyone third of cases. in the administrative section, nine socio-demographic parameters were studied. in % of the cases, less than four of the nine criteria were found. in the section concerning the certifying doctor data, parameters were screened. . % of the certifying doctors met at least six criteria. the most frequently missing parameter in this section was the identity of the person to whom the certificate was issued. the identity of the doctor was not mentioned in % of the cases. forensic data ( items) was complete in over three quarters of the certificates. nevertheless, in . % of cases, the medicolegal obstacle to burial box was left empty ( . %) or not ticked even if judicial investigation was required ( . %). the section on causes of death was the source of almost all of the drafting errors. we have classified these errors into six major ones, according the classifications reported in the literature. the percentage of certificate without faults was %. the most common major error was insufficient cause of death found in . % of cases followed by incorrect sequence of causes of death ( . %), medicolegal obstacle to burial not ticked although required ( . %), several causes of death mentioned simultaneously ( . %), unacceptable cause of death ( . %) and mechanism of death mentioned instead of the cause of death ( . %). our study showed that the quality of drafting of dc suffered from several insufficiencies, which encourages us to provide more effort in training doctors and to review the current official model of dc. introduction: septic shock is defined as a sepsis with hyperlactaemia greater than mm after correction of hypovolemia requiring vasopressors to maintain mbp > mmhg [ ] . it can be observed in pre-hospital emergency medicine (phem). the use of a reliable portable device for measuring lactate in phem would allow a better evaluation of septic patient facilitating their orientation towards intensive care unit (icu) or emergency department (ed). this portable delocalized biology device must be validated against the laboratory reference method (nfen iso ) [ ] . the aim of this study was to clarify the validity of a delocalized measure of lactatemia. we performed a prospective study including patients admitted into icu for septic shock (cpp number - - sc). lactate was measured in parallel on samples-one capillary with the portable device (lactate statstrip xpress, nova biomedical) and the other venous on a centrifuge tube for plasma analysis (architect c abbott diagnostics). we evaluated the analytical performance (coefficients of variation (cv) for repeatability and reproducibility evaluated at levels of quality control (qc)- . and . mm) and then the concordance between lactate levels measured by the devices and lactate levels measured by laboratory analyzer. results: at the qc concentrations tested, the cvs were in agreement with the limits set by the french society of clinical biology-cv < % for repeatability and < % for reproducibility. an excellent correlation was observed between the measurements-correlation coefficient r = . , slope = . and ordered at the origin = . . the latter suggested a low positive bias of the device not confirmed by bland-altmann graph analysis and graph of the differences. we verified the analytical performance of the device and showed an excellent correlation with the laboratory measurement. the delocalized measure can be used in phem in patients with suspected sepsis syndrome. this measure should allow a more accurate and early assessment of their severity in order to improve triage and hospital orientation between ed and icu. there is an association between mortality at d and hyperoxia in patients admitted in icu for refractory ohca requiring ecpr. these data underline the potential toxicity of high dose of oxygen and suggest that control of oxygen administration in such patients is an important part of the treatment. a value of pao between and mmhg after starting ecpr seems to be a target during treatment of ohca treated by ecpr. introduction: sepsis has been defined as a dysregulated host response to infection leading to life-threatening organ dysfunction (singer m et al., jama ) . a qsofa score relying on simple clinical criteria (respiratory rate, mental status and systolic blood pressure) has been proposed to better identify septic patients with associated higher mortality outside the intensive care unit (seymour cw et al., jama ) . the study aim was to evaluate the ability of qsofa to predict the development of organ failure and increased -day mortality in patients admitted for suspected sepsis in the emergency department (ed). patients and methods: prospective study conducted over a period of months comparing the prevalence of organ failure and -day mortality according to the value of qsofa at admission to the ed between group a (qsofa > = ) and group b (qsofa < ). as part of routine care, an electronic sepsis form was specifically created to identify prospectively and exhaustively all eligible patients on-line. for the purpose of the study, sepsis diagnosis was independently validated off-line by an adjudication committee which included three physicians who reviewed clinical, biological and microbiological data. for each patient, demographic data, source of infection, qsofa and sofa score, biological data and -day mortality were recorded. seventy-six patients of group a ( %) were hospitalized, of whom were admitted to the intensive care unit ( . %), and -day mortality reached . %. in group b, only patients developed an organ failure ( . %) and -day mortality was . % (table ) . the present study confirmed that the qsofa score is a reliable and practical tool to predict the development of organ failure and higher -day mortality in patients with suspected sepsis in the ed. limits of ct scan criteria and intravascular contrast extravasation to define pelvic angioembolization need: a specific assessment on the risk of false- introduction: opening of the mitochondrial permeability transition pore (ptp), triggered by cyclophilin-d (cypd) binding under stress conditions, plays a key role in ischemia-reperfusion injury. we sought to determine, using transgenic mice, whether cypd deletion (cypd −) would improve resuscitability and survival after experimental cardiac arrest (ca). additionally, we compared the protective effects of cypd deficiency with that of targeted temperature management (ttm). patients and methods: anesthetized mice underwent a min asphyxial ca followed by resuscitation (cardiac massage, resumption of ventilation, epinephrine). four groups of animals were studied-sham, control (ctrl), cypd-ca using mice lacking cypd (knockout mice), and ttm-ca with fast hypothermia induced by external cooling at reperfusion ( °c for h). two hours after ca, the following measurements were carried out (n = - group)-echocardiography, cellular damage markers (including s b protein and troponin ic) and mptp opening in mitochondria isolated from brain and heart. additional mice (n = - group) were included in the same groups for survival follow-up ( h and days). results: characteristics of ca were similar among groups. rate of restoration of spontaneous circulation (rosc) was significantly higher in cypd-and ttm groups compared to controls (p < . ). time to rosc was shorter in cypd-versus ttm and ctrl (p < . ). genetic loss of cypd and ttm prevented to a similar extent ca-induced myocardial dysfunction, increase in blood levels of both s b protein and troponin ic (p < . versus ctrl). ca resulted in a significant increase in ptp opening only in mitochondria isolated from brain (p < . versus sham). cypd deletion as well as ttm limited ca-induced ptp opening in brain (p < . versus ctrl). short-term survival ( h) was significantly improved in the cypd-and ttm groups when compared to controls (p < . ). however, only therapeutic hypothermia improved survival at day (p < . versus ctrl). in our murine ca model, genetic loss of cypd increased resuscitability and short-term survival but, unlike therapeutic hypothermia, failed to improve -day survival. introduction: early prediction of neurological outcome of post-anoxic comatose patients after cardiac arrest (ca) is challenging. prognosis of comatose patient relies on multimodal testing-clinical examination, electrophysiological testing and structural neuroimaging (mainly diffusion mri). this prognostication is accurate for predicting poor outcome (i.e. death) but not sensitive for identifying patients with good outcome (i.e. consciousness recovery). resting state functional mri (rs-fmri) is a powerful tool for mapping functional connectivity, especially in patients with low collaboration. several studies showed that rs-fmri can differentiate states of consciousness in chronically brain-damaged patients. a recent study also showed that functional neuroimaging can early detect signs of consciousness in patient with acute traumatic brain injury. however, rs-fmri has not been assessed for the early prognostication of post-anoxic comatose patient. we assessed whole-brain function connectivity (fc) of post-anoxic comatose patients early after ca using rs-fmri. nine patients ultimately recovered consciousness (good outcome) while eight died (poor outcome). we estimated fc for each patient following a procedure previously described. we statistically compared whole-brain fc between good and poor outcome group, to assess which brain connections differed between them. then, we trained a machine-learning classifier (a support vector machine, svm) to automatically predict coma outcome (good poor) based on wholebrain fc of comatose patients. finally, we compared this outcome prognostication based on functional mri to those using standard structural diffusion mri. results: good and poor coma outcome groups were similar in terms of demographics, except for time to rosc. good outcome group showed significant increase in whole-brain fc between most cortical brain regions + with the strongest changes occurring within and between occipital and parietal, temporal and frontal regions ( fig. ). using whole-brain fc and a svm classifier to predict coma outcome yielded to an overall prediction accuracy of . %(auc . ). interestingly, automatic outcome prognostication using functional neuroimaging achieved better results that structural neuroimaging methods like dwi (accuracy . %). conclusion: we used rs-fmri to predict coma outcome in a cohort of post-anoxic comatose patients early after ca. we deliberately chose to include only patients with indeterminate prognosis after standard multimodal testing, to assess the contribution of rs-fmri in the early prognostication of coma outcome. we found that automatic prediction based on functional neuroimaging yielded much better results than current dwi methods, notably for identifying patients who recovered consciousness. outcomes of post-anoxic comatose patients early after ca, using rs-fmri in rcts comparing treatment of severe pneumonia that may influence their ability to demonstrate differences between studied drugs. clinical cure was the most frequently used endpoint but its definition was highly variable. these results are not surprising as far as even guidance from regulatory agencies on how to evaluate hap vap treatments differ. the aim of this work was to reach a consensus on the most appropriate endpoint to consider in future clinical trials evaluating the efficacy of antimicrobial treatment for hap vap, using delphi method. patients and methods: twenty-six international experts from intensive care, infectious disease and from the industry were consulted using delphi method (four successive questionnaires) from january to january . more than % of similar answers to a question were necessary to reach a consensus. results: according to % the experts, clinical cure was the most desirable primary outcome among those found in the literature but two other endpoints were highly rated-all-cause mortality and mechanical ventilation (mv)-free days. consequently, % of the panelists agreed to use a composite endpoints and even a hierarchical composite endpoint to combine these items together in which clinical cure and mv-free days would be assessed at day and clinical cure at day after end of therapy. for vap, mortality was considered as the most clinically significant item by % of the experts, followed by mvfree days and finally clinical cure (fig. ) . for hap, a dual composite endpoint that only included all-cause mortality and clinical cure was chosen ( fig. ). among the various elements of clinical cure definition found in the literature, only three were retained by the experts-resolution at end of therapy of signs and symptoms present at enrolment, no further antimicrobial treatment needed and resolution or lack of progression of radiological signs of pneumonia. finally, we found a consensus on the signs and symptoms that should trigger the suspicion of pneumonia-worsening of gaz exchange, purulent tracheal secretions, hypotension and or vasopressor requirements and fever or hypothermia. we provide here two consensual endpoints (for vap and hap) that would help addressing the efficacy of antimicrobial molecules for hap vap treatment in future clinical trials. (table) . sm-vap were matched with control patients. in univariate analysis, risk factors for sm-vap weremale gender, chronic heart failure, respiratory, cardiovascular and coagulation sofa scores two days before vap, median number of antibiotics used, percentage of time with antibiotics before vap, parenteral nutrition, dialysis, catecholamine use and exposure to ureido-carboxypenicillin, ciprofloxacin, tazobactam or imipenem-meropenem during the week before vap (table) . patients with sm-vap were less likely to receive initial adequate therapy ( vs %, or . , p = . ). there was no statistical difference for icu or d mortality. d mortality was higher for sm-vap (table) . in multivariate analysis, exposure to imipenem-meropenem during the week before vap, respiratory and coagulation sofa scores two days before vap were independent risk factors for sm-vap. sapsii: simplified acute physiology score; sofa: sofa (sequential organ failure assessment); sofa resp: sofa respiratory score; sofa coag: sofa coagulation score; sofa cardio: sofa cardiovascular score conclusion: sm-vap represented . % of vap. we observed no differences in patients characteristics between the groups. imipenem-meropenem use during the week before vap was the most important risk factor for sm-vap. the higher risk of inadequate initial therapy with sm-vap had no impact on d mortality but d mortality was significantly higher. introduction: education of undergraduate students is key to improve hand hygiene (hh) behavioral changes amongst doctors [ . ] . our aim was to evaluate personal feedback using ultraviolet (uv) light inspection cabinets in a years program. our hypothesis was that its use for alcohol hand rub (ahr) application on first year would increase complete ahr application on nd year. patients and methods: this was a simple blind randomized trial comparing hh training with personal feedback using uv cabinet to a control group. on first year, students had access to a theoretical formation then were convened by groups for a demonstration of the correct execution of world health organization's (who) procedure [ ] . before hh training, each group underwent a cluster randomization. in the control group, the student hand rubbed under visual supervision and advises of a trainer. in the intervention group after the same visual assessment, completeness of ahr hand application was recorded under uv light and shown to the student. he was given free access to the uv cabinet to repeat the technique, until perfect application complete under uv light. an enhancement with a scenario-based learning was proposed to both groups. on second year, every student were asked to hand rub with the fluorescent ahr. a supervisor blinded to the group of randomization assessed the quality of the hh procedure visually, the completeness of hand application under uv light and compliance with the who's opportunities for hh during the simulation. results: after randomization students were included in the intervention group and in the control group. on second year, the rate of complete application of the ahr under uv was increased in the intervention group as compared with the control group ( % versus . % p < . ) ( fig. ) despite that visual assessment of hh procedures was similar between the two groups. in a logistic regression model including gender, intercurrent hh formation, intercurrent uv cabinet use, surgical unit traineeship and report of regular use of ahr, the hazard ratio for the intervention was . (ic . - . ). the rate of perfect compliance with the hh opportunities in the intervention group was increased ( . % versus . % p < . ) and the effect persisted in the logistic regression. conclusion: uv cabinets for undergraduate students' hh education improve the technique and the compliance with hh opportunities. included in a multifaceted education program, it must be considered a key tool for training. results: among the patients who underwent ecmo support for more than h, the bsi prevalence was . cases per ecmo days and microorganisms associated were most frequently gramnegative bacilli. as for positive ta cultures, microorganisms associated were oropharyngeal germs and gram-negative bacilli. two risk factors were associated with nosocomial bacteria occurrence in ta cultures-prior antibiotics and duration of mechanical ventilation more than days. we demonstrated a link between "positive ta culture" and "positive blood culture" and we showed a protective effect of using an antibioprophylaxis on "positive ta culture" and "global positive cultures" development. introduction: delirium in the icu is often under-diagnosed despite its related burden and impact on patients' morbidity, mortality and prolongation of hospital length of stay. the aim of this study was to assess the medical and paramedical community beliefs and practices regarding delirium in tunisian icus. patients and methods: between august st and / , healthcare professionals working at the icus of university hospitals of monastir and mahdia (tunisia) were asked to participate in the survey by completing a questionnaire anonymously (that specified participants' characteristics (age, gender, function, years of experience in icu) and their knowledge and perception of delirium in icu. the questionnaire consisted in questions of different types: likert style (: widespread scale in psychometric questionnaires in which the respondent expresses his or her degree of agreement or disagreement with an assertion), multiple choice, ranking and yes/no). results: during the study period, respondents out of ( % female, nurses: %), aged between - years in %, responded to the questionnaire. healthcare professionals experience in the icu was < year in . %; - years in . %, and > years in . %. participants asserted that the "most characteristic signs of delirium" were: insomnia ( %); confusion ( %); agitation ( %) and aggressiveness ( %). three-quarters of participants said they did not systematically search for signs of delirium in their patients. % thought that delirium was "an insignificant problem" or that "it was not a problem". only one and three participants respectively, said they attended a conference and read an article about delirium in icu the last year. half of the respondents felt that the most appropriate treatment for a patient with delirium was restraint. nearly one-third of participants thought that delirium was an under-diagnosed entity and only % felt that it was associated with long-term neuropsychological deficits. factors considered to be determinant in the occurrence of delirium were ards, shock, age, mechanical ventilation, postoperative status in , , , and %, respectively. conclusion: most tunisian healthcare professionals consider delirium as a common, underdiagnosed, and serious problem in the icu. yet, few participants actually monitor this condition. the influence of sedation choice on the delirium occurrence in critically ill poisoned patients: a randomized controlled trial khzouri takoua introduction: delirium is a common manifestation of acute brain dysfunction in critically ill patients. it is associated with a healthcare cost increase, and extension of the hospital stay length. the present study aimed to explore influence of patient characteristics and analgesicsedation on delirium incidence and to analyze its risk factors. patients and methods: it is a prospective single blind randomized controlled trial, started on the first july in a -bed toxicological intensive care unit, including all mechanically ventilated patients requiring sedation who were admitted for acute poisoning. they were randomly divided into two groups g et g receiving respectevily propofol-remifentanil and midazolam-remifentanil. delirium assessment scores were judged not adapted to our population and we retained the diagnosis of delirium on arguments inspired from diagnostic and statistical manual of mental disorders fourth edition (dsm-iv). results: until the th september , patients were included, with patients in g and in g . the two groups were comparable in terms of epidemiological characteristics. delirium was developed in patients ( %) (n = in g and n = in g ) with an average duration of ± h with no difference between the groups ( ± h for g - ± h for g , p = . ). compared to those without delirium, no differences were found in the patient characteristics among these two groups with regard to sex, age, psychiatric history and severity of illness (apache ii, igs ii score) and even with regard to hypnotic choice ( vs p = . ). delirium was associated to prolonged duration of mechanical ventilation ( ± h vs ± h, p = . ) and length of icu stay ( . h vs . h, p = . ) without significant differences. delirious patients had more hypotension (p = . ), and received more atropine ( . ). multiple logistic regression analysis identified atropine (or . , %cl . - . , p = . ) as an independent risk factor for delirium. the diagnosis and prevention of icu delirium are subjects of multiple ongoing investigations. we carried out this study to detect the risk factors of delirium in order to prevent it. it is important to note that our results are influenced by the studied population and are only preliminary. we rely on the study pursuit and the sample enlargement to better inform us as well on risk factors as protective. introduction: background: severe alcohol withdrawal syndrome is a common cause of hospital admission. delirium tremens is a potentially fatal complication of alcohol withdrawal. in severe delirium, very large dosages of benzodiazepines can be required despite well described side effects, such as coma and hypoxic cardiac arrest, although there is no recommendations for standardized treatments. objective -the aim of this study was to describe outcomes and risk factors for complications in patients with severe alcohol withdrawal syndrome treated in intensive care unit with continous infusion of benzodiazepine (bzd). we retrospectively reviewed the medical records of all patients hospitalized for alcohol withdrawal syndrome between and . only those who received continous-infusion of bzd, associated with close clinical monitoring and the evaluation of rass and cushman scores, without systematic recourse to mechanical ventilation, were included. results: we studied patients hospitalized in icu for severe alcohol withdrawal syndrome. the mean age (sd) was . ± . years, mean icu admission saps (simplified acute physiology score) ii score was ± . . all of them have received continous infusion of midazolam, with a median maximum perfusion velocity of mg h (interquartile range, ( , )). the median duration of treatement was days (interquartile range, ( , ) ). thirteen patients ( %) developed pneumonia, and or required intubation, and ( %) have had seizures. no cardiac arrest and death was observed. icu length of stay (los) was days ( , ) (median, interquartile range). patients who requiried intubation and or developed pneumonia, received substantially more bzd (median total dose, mg of midazolam vs. mg in the non-complicated group + p < . ), and their icu los was higher (median, days vs. days + p < . ). endotracheal intubation and or development of pneumonia were associated with a higher maximum perfusion velocity of midazolam (> mg h) (or . , ic % ( . - . ), p = . ). previous episodes of delirium tremens before icu admission were associated with higher complications such as mechanical ventilation and or pneumonia (or . , ic % ( . - . ), p = . ). in severe delirium, very large dosages of benzodiazepines can be used without systematic mechanical ventilation with a low incidence of complications. introduction: delirium is frequent in intensive care unit (icu) patients and is associated with increased mortality, increased hospital stay, increased cost and long term cognitive impairment in survivors. numerous pharmacological and non-pharmacological strategies have been investigated for delirium treatment without success. therefore delirium prevention strategies are recommended by current critical care practice guidelines. among the potentially modifiable risk factors for delirium, the impact of daylight exposure on delirium incidence and or duration has not been studied. the objective of this study was to investigate whether daylight exposition would reduce delirium burden in critically ill patients. we conducted a prospective study in a -bed medical intensive care unit (icu) over a -year period (january -january ). all consecutive adult patients receiving invasive mechanical ventilation (mv) for days or more were eligible for the study. patients were assigned to a room with windows allowing daylight exposure ("light" group) or without window ("dark" group), depending on bed availability. delirium was evaluated with the intensive care delirium screening checklist (icdsc) for a maximum period of days. delirium was defined by a icdsc score ≥ for two consecutive days. agitation was defined by a rass > or = + . the primary endpoint was cumulative incidence of delirium. data are presented as median (interquartile range) or number (percentage). results: a total of patients were included (age- [ + ] years, saps - [ + ], sofa score- [ + ], medical admission- %). of them, patients were admitted to a "light" group and to a "dark" group. incidence of known risk factors for delirium was similar in the two groups. delirium occurred in ( %) patients in the "light" group and in ( %) patients in the "dark" group (p = . ). the duration of delirium was [ + ] days. patients in the "light" group received significantly less neuroleptics to treat agitation than patients in the "dark" group ( vs. %, p = . ). this protective association persisted after adjustment for confounders in multivariate analysis (odds ratio = . + [ . + . ] + p = . ). daylight exposure does not impact on delirium burden in icu mechanically ventilated patients. however, daylight exposure is independently associated with a reduced prescription of neuroleptics to treat agitation. introduction: patients with convulsive status epilepticus (cse) frequently require mechanical ventilation (mv), either for general anesthesia in case of refractory generalized cse, or for airway protection. guidelines for the management of refractory generalized cse currently recommend general anesthesia for - h, followed by gradual withdrawal. our objective is to evaluate the incidence of refractory generalized cse among patients who required mv during pre-hospital management of status epilepticus, and to describe the management of general anesthesia in intensive care unit (icu). this ongoing multicenter retrospective observational study is conducted in french icus. all patients admitted in icu under mechanical ventilation between - - and - - with disease-code "status epilepticus" are included. exclusion criteria are-age < years, post anoxic se, acute traumatic brain injury, initiation of mv in icu, transfer from another icu, inclusion in a therapeutic trial on se, non-convulsive se. collected data include reason for mv, antiepileptic treatment, dosage and duration of general anesthesia, mode of eeg monitoring. outcomes are-relapse of se, mv duration, in-icu length of stay and mortality. results: among the medical files reviewed, met the inclusion criteria and were analyzed, and were excluded. a minority of patients ( . %) had a refractory generalized cse, most patients ( . %) had a non-refractory generalized cse + the others had mostly partial cse. the main reason for intubation was coma (n = , . %). the duration of general anesthesia was not significantly different in refractory cse patients compared to non-refractory cse patients (p = . ). data regarding main outcomes are summarized below-. these preliminary data suggest that the majority of the patients admitted in icu under mv for cse do not have a refractory status. indication of mv is mainly coma without persistent convulsions. the mean duration of general anesthesia before withdrawal is < h, and thus in discrepancy with guidelines, but does not seem associated with a frequent relapse of se. if this low rate of rse for patients admitted in icu and the safety of rapid withdrawal of ga are confirmed, the recommended - h duration of general anesthesia in icu could be challenged. introduction: induced coma in intensive care patients protect them against pain and neurologic disorders. however, a few of them may present a delayed wake-up when the sedation is interrupted. the aim of this work is to assess brain imaging findings in patients with this condition. patients and methods: retrospective review of imaging data of patients ( males and females), aged between and years, admitted in intensive care unit (icu) between june and september , who had sedation or general anesthesia and presented a delayed wake-up. they were explored either by mri (n = ) or computed tomography (ct) (n = ). patients with traumatic lesions were excluded. results: patients were admitted in the icu because of chronic obstructive pulmonary disease exacerbation (n = ), infectious pneumonia or pleural effusion (n = ), acute respiratory failure (n = ), heart disease (n = ). two patients underwent general anesthesia. septic shock and circulatory collapse occurred in and patients respectively. mri and ct showed lesions that may explain the wake-up delay in of and of patients, respectively. brain anomalies included anoxic lesions (n = ) with basal ganglia involvement (n = ), ischemic or hemorrhagic strokes (n = ), hepatic encephalopathy (n = ) and herpetic encephalitis (n = ). conclusion: brain imaging techniques help diagnosing causes of delayed wake-up after induced coma. anoxic lesions and strokes are mostly behind this condition. mri is more accurate than ct. introduction: gastric tubes are common in intensive care units used for enteral feeding, administration of drugs or aspiration of the digestive tract. these tubes offer an excellent tolerance but malposition may have serious consequences that can lead to patient's death. the actualy gold method to confirm their correct placement is chest x-ray. we report a study which evaluate the performance of gastric ultrasonography for the validation of the good positioning of the gastric tube. we carried out a prospective, monocentric study in a medical intensive care units. for each included patient, we compared the results of a gastric ultrasonography to the interpretation of a chest x-ray. results: one hundred and thirteen gastric ultrasonographies were performed from july to may . in cases, ultrasonography concluded that the gastric tube was correctly positioned, confirmed by chest x-ray. in cases, ultrasonography did not visualize the tube in gastric area. among these cases, only malpositions were detected by the chest x-ray. the sensitivity and specificity of gastric ultrasonography were . [ . + . ] and [ . + ]. positive and negative predictive values were and . , respectively. the ultrasonography was performed min [ . + . ] after the gastric tube placement while the chest x-ray was interpreted min [ . + . ] after this same placement (p < . ). our results suggest a good performance of gastric ultrasonography to check the positioning of the gastric tube. this result must be interpreted with caution because of a low power of the study. we planned a multi-center study to confirm our results. giabicani mikhael introduction: prognosis of cirrhotic patients hospitalized in intensive care unit (icu) remains poor. in many icus, cirrhotic patients are widely admitted and revalued after receiving optimal treatments. little is known about risk factors involved in the evaluation of the prognosis at day , except the persistence of organ failure. this susceptibility to organ failure would be related to an alteration of the regulation mechanisms of the systemic inflammatory response. the blood neutrophil-to-lymphocyte ratio (nlr) is an inflammation biomarker reported to predict clinical outcome in unselected critically ill patients and in patients with stable liver cirrhosis, but has never been studied in critically ill cirrhotic patients. the aim of this study was to evaluate the blood nlr as parameter to predict mortality of cirrhotic patients hospitalized > days in icu. retrospective monocentric study including consecutively cirrhotic patients hospitalized in a medical icu from to . for each patient, clinical and biological data at admission and day were collected. nlr at admission ("nlrd "), at day ("nlrd ") and its variation between admission and d ("delta nlr") were calculated. statistical analysis used appropriate non parametric tests and cox regression for survival analysis. the ability of the variables to discriminate survivors from non-survivors was determined using roc curves and a net reclassification index (nri). results: patients (median child-pugh score = [ - ], median meld score = [ - ]) were hospitalized more than days in icu. the major causes for icu admission were sepsis ( . %), gastrointestinal bleeding ( %) or respiratory failure ( . %). patients were followed up for . d . ( %) patients died- ( %) in icu, ( %) after icu discharge and ( %) after hospital discharge. in univariate analysis, factors significantly associated with mortality wereat d , nlr, meld and sofa scores + and between d and d -delta nlr, delta sofa and delta meld. predictors of death in multivariate analysis are shown in table . area under delta nlr roc curve was . (ci = . - . ). nri revealed that delta nlr was more efficient than delta sofa (nri = . %) to identify patients with a % mortality risk at least. conclusion: nlr is a novel inflammation index known to predict poor clinical outcomes. delta nlr is an independent predictor of mortality in critically ill cirrhotic patients and could be more effective than delta sofa in predicting hospital mortality in these patients. severe liver dysfunction acute liver failure related to exertional heatstroke: outcomes, histological features and role of liver introduction: severe acute liver injury and failure (sali alf) is a grave complication of exertional heatstroke (eh). liver transplantation (lt) may be a therapeutic option, but the criteria for, and timing of, transplantation have not been clearly established. the aim of this study was to define the profile of patients who require transplantation in this context. this was a multicentre, retrospective study of patients admitted with a diagnosis of exertional heatstroke-related sali alf with a prothrombin time (pt) lower than %, with or without hepatic encephalopathy. results: male patients (median age- . years) with ali alf related to exertional heatstroke were studied + nine of them ( . %) were listed for emergency lt. the latter differed from those who were not listed with respect to their more severe liver failure after d , a clear deterioration in their pt and alt values between d and d , and more marked organ dysfunction. four of these nine patients were subsequently transplanted. at the time of lt, all had pt levels lower than %, a marked rise in bilirubin levels and required support for at least one organ (or x organs were involved). histological findings on the explanted livers demonstrated massive or sub-massive necrosis and little potential for effective mitosis with a mitonecrotic appearance. the unlisted patients ( . %) were still alive months later and had not experienced any after-effects. conclusion: survival without liver transplantation in patients with heatstroke-related ali alf reaches . %. the indication for liver transplantation is based on an evolving dynamic. the lack of any signs of an improvement in liver function at or after d , in patients presenting with other organ dysfunctions or failure, means that liver transplantation should be envisaged. the peculiar histological features observed on all the explanted livers, and the aspect of abortive mitoses in hepatocytes could be attributed to the effects of heatstroke. . on admission, the mean pt was . % ( - ), the mean total bilirubin was umol l. paracetamol poisoning was the principal etiology with % of the patients- % in the prometheus group versus % in the standard group (p = . ). the hepatic encephalopathy grade was significantly higher in the prometheus group- versus . in the standard group (p = . ). there was no difference between the two groups concerning mortality on day (p = ) or day (p = . ). there was no difference concerning the length of stay in intensive care unit or in hospital between the two groups. patients ( . %) were transplanted. there was a statistical difference between the two groups concerning liver transplantation (p = . )- transplant ( %) in the prometheus group versus transplant ( %) in the standard medical care group. there was a significant improve of encephalopathy after the prometheus session (p = . ). therapy in our icu were included consecutively and prospectively in the cohort. mars ® therapy performed using a double lumen dialysis catheter in the femoral or jugular vein. we used the monitor mars ® tc (teraklin) coupled with the dialysis machine prismaflex ® (gambro). the albumin dialysate circuit consisted of ml of % human albumin and was regenerated by an anion-exchange column and an uncoated charcoal column (diamars ® ie , diamars ® ac ). results: ninety patients were included for sessions. the mean duration was h min (± h min). the population treated consisted of groups-acute-on-chronic liver failure (aoclf), acute liver failure (alf), post-surgery liver failure (post transplantation, post hepatectomy), refractory pruritus and drug intoxication ( fig. ). regarding biological efficacy-total bilirubin was lowered in aoclf and post-surgery groups (p < . ), also in the alf group although not significatively. meld score was lowered in the aoclf and alf group (p < . ). however clinical variables (glasgow score and encephalopathy) didn't improve significatively. in the refractory pruritus group, pruritus decreased in out of patients (p < . ). bile acid levels decreased to . % of its mean baseline level (p < . ). in the drug intoxication group improvement of the richmond agitation-sedation scale (rass) from deeply sedated (rass < = − ) to minimal sedation (rass > = − ) was obtained in out of patients. out of sessions, catheter-related adverse effects were low ( . %), thrombocytopenia was the main adverse effect ( . %). conclusion: we report our mars ® experience with the largest cohort of patients referred from a single hospital. we showed biological efficacy in all indications, although clinical efficacy was uneven. mars ® therapy in patients with refractory pruritus yielded promising results. tolerance was good and the main adverse effect was thrombocytopenia. global transplantation-free survival was low in patients with liver failure, reinforcing the need for a liver transplantation center when using mars ® . introduction: colonoscopy is crucial for the management of lower gastro-intestinal disorders, but its profitability is discussed in critically ill patients, mainly because of the complexity of colonic preparation. as the profitability of colonoscopy in intermediate or intensive care units (cicu) has been scarcely reported ( ), we investigated its indications and usefulness. patients and methods: retrospective bicenter observational study ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . main endpoint: diagnostic profitability of cicu in unselected critically ill patients. profitability was a priori defined as "high" if cicu led to adapt ongoing therapies; allowed an endoscopic intervention; or participated in the decision to limit therapeutic effort. secondary endpoints: describe the quality of cicu and its preparation; determine its position in diagnosis strategy; describe its morbidity. ) + investigation of a gram negative bacilli sepsis (n = , %) + sigmoid volvulus (n = , %) + and cancer diagnosis (n = + %). cicu profitability was deemed high in % (n = ), with an endoscopic intervention performed in % (n = ). the cicu lead to antimicrobial adaptation (n = ), emergent surgery (n = ), or to limit therapeutics effort (n = ). in cases ( %) the cicu was considered normal. patients' preparation was rated as good in % (n = ) + and the colonoscopy was complete in ( %). the cicu was mainly performed as a nd ( %) or rd ( %) investigation after an abdominal ct-scan or an upper digestive endoscopy (respectively performed in first instance in and %). three cicu were complicated by hemodynamic and respiratory failures, none were fatal. discussion: in our series of unselected critically ill patients, cicu were mainly performed to investigate lower gastro-intestinal bleeding. despite a low rate of good preparation, cicu is safe and its profitability is high in the majority of cases. conclusion: although performed in poor conditions, cicu seems useful in the diagnostic and the therapeutic management of critically ill patients, and not only in gastro-intestinal bleeding. ( ) church, surgical endoscopy . introduction: accurate pain assessment is associated with better outcomes in intensive care unit (icu) patients. specific scales for noncommunicative patients have been developed and validated but their routine use still remains inaccurate and subjective. analgesia nociception index (ani) is based on high-frequency heart rate variability. this study objective was to assess the correlation between the behavioral pain scale (bps) and ani during care procedures in deeply sedated patients. we conduced a french multicentric prospective observational study with blinded continuous recording of ani during h with spotting of care procedures in patients with rass less or equal to − . we compared pain assessment using bps and ani before (t ) and during (t ) each care procedure. the cares analyzed included prick glycaemia, turning, catheter insertion, dressing change and others. a behavioral pain reactivity (bpr) was defined by a bps elevation of at least point. we analyzed minimal ani values and its variations with calculation of deltaani (anit -anit ). because of the analysis of several cares per patient we used a bonferroni's correction in comparison of bpr and no bpr groups with a significant p value < . for this comparison. for others analyses the p value considered as significant was p < . . correlation between ani and bps was analyzed using a spearman correlation rank test. introduction: the pain associated with burn was one of the most painful injuries to treat. pain was induced by therapeutic acts such as wound debridement, dressing and other painful procedures. burn pain caused changes in neurophysiology and pharmacokinetics that may make standard pharmacologic analgesic therapy less effective than usual.virtual reality has been explored as an adjunct therapy for the management of acute pain for a number of conditions. in our study, we attempt to assess the impact of virtual reality on management of burn pain during dressing changes. patients and methods: before the therapeutic procedure (dressing changes), the concept of virtual reality therapy was explained to the patient (technology and equipment used). the video used was snow mountain. during the act, pain was assessed until the end of the procedure. the assessment of pain was based on visual analog scale (vas). for pain intensity, the scale was most commonly anchored by "no pain" (score of ) and "very intense pain" (score of ). results: during the study period, patients were included. the mean age was ± years. % of our patients were adults aged over years. they were men and women. the average burned surface area was ± %. pain was evaluated before the start of the therapeutic procedure. the mean initial pain severity score was . ± . (range to ). the pain assessment after virtual reality condition showed a significant decrease in the intensity of pain (p < . ). the mean pain decreased from . to . ± . with extremes ranging from to . conclusion: our study supports the use of virtual reality, simple noninvasive, as an adjunct therapy in the management of pain associated with dressing changes in burn patients. introduction: hypno-analgesia (ha) is used in the operating room and for complex pain. before implementation of ha in our intensive care unit (icu), most protocols for algogenic procedures included intravenous or epidural morphine and nitrous oxid. since , many caregivers have been trained, ha has been implemented and patient comfort is evaluated using ) a specific analogic scale of comfort ( to ) before and after the procedure + ) at the end of the procedure, a score of patient and caregiver comfort using a five item questionnaire ( to points). this pilot prospective study compares ha versus the standard protocol in the removal of abdominal drains after digestive surgery. the main objective was to evaluate the patient comfort before after the procedure using a scale of comfort + the secondary objectives were to test the patient and caregiver comfort scores and evaluate in the impact on consumption of analgesic. between may and september , two groups were obtained, according whether the procedure was performed by ha-trained or non-hatrained professionals (depending on caregivers availability in the unit). the number of subjects required to compare scales of comfort before vs. after drain removal was , using a nonparametric wilcoxon-mann-whitney test. results: eighty-eight patients were analyzed. the mean note in the comfort scale remained unchanged after vs. before drain removal in patients without ha (n = , + . points, ± . ), while it increased in patients with ha (n = , + . , ± . + p = . ). using our specific five item comfort score, patients and caregivers had a comparable level of satisfaction in ha and non-ha groups (patients . and . + caregivers- in both). a trend was observed in reduction of the consumption of morphine and nitrous oxid with ha, without altering their comfort. discussion: despite its limitations (mainly, its open non-randomized design), this study suggests that-ha may be used for algogenic procedures and is willingly adopted in icu by patients and professionals + specific scales scores, adapted for ha, may be useful to assess the effectiveness + finally, ha seems to be at least as efficient as classical procedures and could reduce the use of analgesic drugs. conclusion: ha adds value to patients and to all caregivers. prospective randomized studies are needed to valid the comfort scores we proposed, and to prove that ha reduces the consumption of analgesic drugs. introduction: pain has long been a focus of concern for doctors and caregivers. in intensive care unit, the inability to verbalize discomfort and pain are major stressors for patients. music therapy has demonstrated in many international studies its effect on the blood pressure and on the respiratory frequency. in this context, we conducted a study to evaluate the effects of standardized musical intervention on pain during painful cares in vigils patients hospitalized in critical care. patients and methods: design-we conduct a prospective, observational, randomised, single blind, mono center study. painful cares were studied and then distributed in two groups (n = with music, n = without music). the patients were equiped with a bose© helmet, and had or not music therapy during the care. our main criteria was the pain, it has been evaluated by a numeric scale before and after the painful care. we also estimated anxiety with the covi's heteroevaluation scale before and after the car. we also noticed if the care were stopped because of the pain, then we used a semi quantative numeric scale in order to estimate the feeling of the caregiver and the patient on the session. results: concerning pain, there is no significant difference between the two groups (p > . ). however, in the music group, pain decreased by % after the care (p < . ). anxiety was way lower in the music group than in the group without music (p < . ). we also noticed a decrease of % of the anxiety in the music group. the patients and the caregivers' feeling were the same in the two groups, with no significant difference (p > . ). on the other hand, caregivers tended to underestimate the difficulty of the session in comparison with the patients' (p < . ) in both groups. conclusion: music therapy did not improve the pain in a significant way, in the music group versus the group without but allowed a decrease of % of the pain after the care. nevertheless, music reduced by two patients'anxiety. introduction: sedation and analgesia is one of the basic themes in icu as complications associated with excessive sedation negatively impact the morbidity and mortality of patients. the objective of this study is to show that the nurse implementation of a sedation and analgesia algorithm is beneficial to the patient in terms of sedative drugs reduction and thus overall decrease in duration of mechanical ventilation (mv) and the morbidity and mortality which is associated with it, without altering patient comfort and tolerance of the environment. patients and methods: a before and after prospective, observational, non-interventional study was conducted in surgical icu in caen university hospital, between november and april . mechanically ventilated patients under sedation predicted to last h or more were included. during the "before" period, sedation and analgesia was managed by the physician, while during the "after" period, it was managed by the nurses according to the protocol. results: intubated and mechanically ventilated patients were admitted during the study period. among the eligible patients, were included during "before" period and during "after" period. the duration of mv after inclusion was significantly shorter in group "after" ( . [ + ] vs [ + . ] days, p = . ), as the duration of target rass (- à ) was significantly longer ( the patients experienced less of ventilator-acquired pneumonia (vap) and delirium during the "after" period ( vs . %, p = . , and vs . %, p = . , respectively). the nurse implementation of a sedation and analgesia algorithm was associated with a trend towards reduction in duration of mv, icu and hospital length of stay. moreover, prevalence of vap and delirium was reduced, in correlation to the significant decrease in sedative drugs. this type of algorithm is necessary to reduce morbidity and mortality associated with mv. introduction: central venous catheter insertion is a common practice for anesthetists and intensivsts. this invasive procedure generates pain and anxiety for patients. we aim to demonstrate that remifentanil improves the analgesia during scheduled central venous catheter insertion in mindful patients. patients and methods: a prospective, randomized, double-blind, controlled study in patients requiring central venous access. patients were randomly assigned to receive ng ml − remifentanil target controlled infusion (tci) and local anesthesia (la) with lidocaine or placebo and la. all patients were monitored in intensive care or postintervention care unit and systematically received oxygen. patients were asked to assess verbal numeric rating pain scale (vnrps) during the procedure. the primary outcome was the maximal vnrps. secondary outcomes were pain at each step, anxiety, patient satisfaction, operator ease and side effects. results: ninety patients were included ( in each group). all patients were analyzed. remifentanil significantly reduced maximal pain-vnrps ( % confidence interval [ci] - ) vs ( % ci - ) in the placebo group p = . (table ) . we did not observe any adverse event during this study, and there were no significant difference between the groups regarding side effects. conclusion: tci remifentanil is a safe procedure to reduce pain during central venous catheter insertion in awake patients. trial registration-clinicaltrials.gov identifier- , remidolcath. introduction: although guidelines on post-resuscitation care recommend the use of short-acting agents for sedation during targeted temperature management (ttm) after cardiac arrest (ca), the potential interests of this strategy have not been clinically demonstrated. patients and methods: before-after study. we compared two sedation regimens (propofol-remifentanil, period p vs midazolamfentanyl, period p ) among comatose ttm-treated ca survivors. management protocol, apart from sedation and neuromuscular blockers use, did not change between the two periods. baseline severity was assessed with cardiac-arrest-hospital-prognosis (cahp) score. time to awakening was measured starting from discontinuation of sedation at the end of rewarming. awakening was defined as delayed when it occurred after more than h. results: patients ( in p , in p ) were included. cahp score in p and p did not significantly differ (p = . ). sixty percent of patients awoke in both periods ( vs , p = . ). median time to awakening was . (iqr - ) hours in p vs. (iqr - ) hours in p . awakening was delayed in % in p vs. % of patients in p (p < . ). after adjustment, p was associated with significantly lower odds of delayed awakening (or . , % ci . - . + p < . ). patients in p had significantly more ventilator-free days, and lower catecholamine-free days between admission and day . survival and favorable neurologic outcome at discharge did not differ across periods. time course for awakening according to sedation period. these figures report the time course of patients included after discontinuation of sedation. at each time point, we report in the upper part, proportion of patients awoken after discontinuation of sedation, in the lower part, patients who died without awakening, and in the middle part (in white), patients still comatose. red dots indicate, for each period, the last patient awakening (after days in p and days in p ). black dots indicate the median time to awakening (too early to appear for period ). conclusion: during ttm following resuscitation from ca, sedation with propofol-remifentanil compared with midazolam-fentanyl was associated with an earlier awakening, and an increase in ventilator-free days. the new recommendations of the french society of anesthesia-intensive care (sfar) on perfusion and medication errors were revised in to promote proper use relating to drug administration with medical devices. to advance that of inquiry, practices of our intensive care unit (icu) were assessed in order to improve drug administration by central venous catheter (cvc). patients and methods: prospective evaluation by pharmacist resident and technical nurse during seven weeks, using a standard evaluation tool, in a bed icu. drug recommendations and sfar documents from were used as referential of conformity. the following parameters were evaluated- central venous lines mounting, drug administration and identification with a focus on narrow therapeutic index (nti) drugs. results: patients with cvc were analyzed between june and july . entered directly in the icu. were hospitalized for surgical reasons. had triple-lumen cvc. regarding the first parameter, no conformity was found due to lack of line identification ( %) or anti-return valve well positioned ( %). perfusion ramp position was above heart level in %, infusion tubing had contact with floor in %, and absence of plug on non-used lines is found in % of cases. regarding second parameter, non-conformities were due mostly to syringe label-absence of drug's concentration ( %), preparator identification ( %), patient identification ( . %), drug identification ( . %, all concerning propofol), date and time of medication preparation ( %), lack of color code of labels ( %). regarding nti, % were not administrated according to the recommendations-absence of dedicated line ( %), absence of administration on the nearest insertion site of the catheter ( %). conclusion: the evaluation highlight some improvement axis such as complete identification on syringes, sensitizing of icu healthcare team, or homogenization of cvc perfusion system. it calls for a second evaluation round after implementation of improvements. introduction: sedation is a corner stone of the care of patients receiving mechanical ventilation in the icu. sedation was associated with increased comfort and adherence to care, but also with increased morbidity, including delirium, increased duration of mechanical ventilation and length of icu stay. previous studies reported beneficial impact of reduced doses of sedative drugs and careful monitoring of patients comfort and consciousness. our goal was to assess the impact of the introduction of a nurses-dedicated sedation protocol in our icu. patients and methods: this monocentre retrospective before-after study included all the patients admitted in our icu, over two threemonth periods, from july and january , treated with invasive mechanical ventilation for more than h and older than yrs. after the first period, all physicians and nurses were trained to a new sedation management protocol. analysis was performed to assess the prescription and application of the protocol, its impact on the use of sedative drugs, icu length of stay, and duration of mechanical ventilation. major complications were also recorded. results: patients were included- before and after the protocol implementation. patients in both groups had similar baseline characteristics (men vs. %, p = . + mean age ± vs. ± years, p = . + weight . ± . vs. . ± . kg p = . + igs ± vs. ± , p = . + medical admission vs. %, p = . ). recordings of rass and bps did not differ between groups ( ± vs ± , p = + ± vs, ± , p = . ). the duration of sedation was significantly shorter after introduction of protocol ( . ± . vs . ± . , p < . ), as was the duration of mechanical ventilation ( . ± . vs . ± . , p = . ) and icu length of stay ( . ± . vs . ± . , p = . ). there was no difference in major icu complications, nor in mortality between groups ( and %). conclusion: although the implantation of a sedation protocol did not translate in increased recording of rass and bps scores, it was associated with improved outcomes. our data suggest that, more than the protocol by itself, beneficial effects reported after the implementation of a sedation protocol may be ascribed to increased awareness of the care givers and thus better management of sedation. introduction: workload affects the quality of care and the prognosis of critically ills patients. measuring workload in intensive care units (icu) has thus become essential for allowing a better matching between the activities required and the management of resources. in march , the medical icu of the university hospital of monastir (tunisia) moved into new buildings (more space and beds, computerbased prescriptions and monitoring, etc.). the aim of the present study is to compare the level of workload before and after the change of the icu buildings. patients and methods: during the two study periods (period -july-september and period -july-september ) adult patients consecutively admitted, for more than h, in the medical icu for arf and or sepsis were included in the analysis. data collected were the demographic characteristics (age, sex, body mass index (bmi), comorbidities, simplified acute physiology score (saps) iii), the nursing workload measured using the therapeutic intervention scoring system (tiss- ) and hospital survival. results: thirty-six patients ( male) were included in the study ( during period and during the second period). the medians of age, saps iii and bmi were respectively (iqr = ) years, (iqr = ) and . (iqr = . ). the main comorbidities were hypertension, copd and neurological disease respectively in , and %. the demographic characteristics were similar during the two periods. nurse workload was characterized by m tiss- = (iqr = ) and time of nurse's care of min (iqr = ). these two workload indicators were significantly higher during the second period (table ) . during the second period, "standard monitoring" and "frequent dressing changes" (> time day) were the activities with significant increase from, respectively to % (p < . ) and from to % (p < . ). the relocation of our icu in in new buildings was associated with a significant increase of the nurse workload with regard to patients with arf and or sepsis. . bland-altman analysis showed excellent accuracy and precision between recorded and collected data for all tested variables within clinically significant pre-defined limits of agreement. however, ( . %) data were missing and a delay was observed between videotaped and collected times. this delay was less than s and remained stable through all data for each patient. we identified that the missing data were due to a limit in the number of data being processed in the database at the same time and the delay between data presentation and data collection in the database was due to different server time settings. both technical issues were corrected. conclusion: our study identified two issues in the data collection process that slightly limited the accuracy of our high resolution electronic database. we recommend the performance of such validation study before using a high resolution database for clinical or research purposes. introduction: fluid overload, and also its variations, is known to jeopardize the outcome of icu patients. however, fluid balance remains difficult to assess accurately. in that context, our study aims to assess the prognostic value of body weight variations (bwv) from day to day on the -day mortality, length of stay (los) and the occurrence of ventilator-associated pneumonia (vap) and bedsore in critically ill patients with shock. patients and methods: adult patients admitted in icu with shock between and , and requiring mechanical ventilation during the first h, were extracted from a prospective multicenter cohort for a retrospective analysis. bwv was defined as the difference between the body weight of the day of interest and the body weight on admission. case mix, severity on admission, and outcomes were collected. fine and gray sub-distribution survival models were used, with icu discharge as competing event, adjusted on comorbidity and illness severity at admission at each landmark, from day to day . the impact of bwv on icu stay duration was estimated through a multivariate negative binomial regression model. the median age and saps score of the included patients were (iqr, - ) years and (iqr, - ), respectively. the bwv increased from . kg (iqr, - . ) on day to kg (iqr, − . to . ) on day . the day in-hospital mortality, the icu occurrence of bedsore and vap were , and . %, respectively. four categories of bwv were defined according to bwv interquartiles: weight loss, stable weight, moderate and severe weight gain. categories of bwv were independently associated with death on day and day (day : shr . ; % . - . p = . ; day : shr . ; % ci . - . , p = . ) (fig. ) . a weight loss tended to be associated with increased occurrence of bedsore, and weight gain with increased occurrence of vap. the extent of bwv increased the duration of icu stay independently of other severity factors. discussion: bwv may be another clinically relevant tool to assess the risk of death, mostly after day . the increased risk of bedsore in case of weight loss deserved to be confirmed. conclusion: body weight should be daily monitored for better prognostication. bwv-based restrictive strategies should be further evaluated. the clinical effectiveness of multi-layer silicone dressings in preventing icu acquired pressure ulcers: a randomised controlled trial introduction: the development of pressure ulcers (pu) in critically ill icu patients result in additional morbidity and may contribute to mortality in some cases. the minimisation of icu acquired pu remain an international challenge. this paper describes australian research that used multi-layer soft silicone sacral and heel dressings to prevent pu in critically ill patients. patients and methods: a total of critically ill patients were enrolled into an -month randomised controlled trial in one of melbourne's trauma centres. patients were randomised on admission to the emergency department and either had standard pu prevention or standard care plus the application of prophylactic sacral and heel dressings. patients were observed daily for pu development for the duration of their icu stay. results: patients in the dressing group has significantly reduced incidence rate of pu development compared to patients receiving standard pu prevention alone ( . vs . %, p < . ). patients in the dressings group had a relative risk reduction of % and a % absolute risk reduction for developing a pu regardless of their critical illness. results indicate the number needed to treat to prevent one pu was . additionally, we calculated the cost-benefit of this intervention and found the patients treated with prophylactic dressings cost . time less than the standard care group for wound care. discussion: the use of prophylactic dressings to prevent pu at our hospital have proved to be very effective in icu and subsequent studies have confirmed our results. it appears that the main mechanism of pu protection provided by these dressings is the reduction of pressure and shear forces leading to tissue distortion and cell death rather than the previously accepted ischaemic model of pu development. our current policy is now to use these dressings on all patients with a high risk of developing pu. the use of prophylactic multi-layer silicone dressings to prevent pu in critically ill patients is effective but it does not replace standard pu prevention methods. the use of these dressings sould be considered complimentary to best practice in pu prevention. iatrogenic events in intensive care unit: incidence, risk factors and impact on outcome ayed samia , merhebene takoua introduction: iatrogenic events (ies) are defined as harm resulting from medical intervention and health care, and not explained by underlying disease. mortality is reported to be as high as . % in cohorts of hospitalized patients experiencing ie. both length of stay and cost of hospitalization are increased by ies occurrence. we perform this study to determine the incidence, risk factors, and impact on outcome of ies in intensive care unit (icu). patients and methods: all patients admitted more than h to the -bed icu of a teaching hospital were prospectively screened. patients were monitored daily for adverse clinical occurrences. time and data about each ie were collected and they were considered as preventable or life-threatening events. for each patient, the followings were recorded-basic demographic data, indication for admission, severity scores on admission (sapsii and apacheii), need and duration of mechanical ventilation (mv), length of stay (los) in icu, intensive care work load score (omega), global mortality and ies related mortality. results: during the months period, patients were included and ( . %) were judged to have developed an ie while hospitalized. we recorded ies over days in icu so a density incidence of ie for patient-day. ies were considered preventable in % of cases and life-threatening in % of cases. ies occurred in a mean delay of ± days. global mortality rate was . % and ies related mortality rate was . %. patients with ies were significantly severe on admission, with a longer duration of mv and los in icu. omega score was significantly higher. multivariate analysis showed that omega score was the independent risk factor of ies occurrence (or . ic % [ . - . ], p < - ). dead patients were significantly severe on admission and experienced more ies than survivors. omega score, duration of mv and los were significantly higher. in multivariate analysis, ies and life-threatening ies were independent factors of mortality (or . ic % [ . - . ], p < - and or . ic % [ . - . ], p < - respectively). conclusion: ies in icu are common and frequent but one-third is preventable. work load icu score is the independent risk factor of their occurrence. ies impact largely the outcome especially the lifethreatening ones. efforts must be focused on preventing programs to reduce ies and improve the outcome. introduction: based on the recent sepsis- definitions, septic shock is defined by the combination of vasopressor requirement and serum lactate level > mmol/l. however hyperlactatemia and lactate kinetics may result from both increased production and impaired clearance in the critically ill, and may therefore not only rely on the severity of circulatory failure. we herein addressed the determinants of hyperlactatemia (> mmol/l) and the factors likely to impact on early lactate clearance in septic shock. patients and methods: this was a -year ( - ) monocentric retrospective study. all adult patients diagnosed for septic shock within the first h were included. septic shock was defined as a microbiologically proven or clinically suspected infection, associated with acute circulatory failure requiring vasopressors. the first lactate value (l ) was measured at the time of icu admission. hyperlactatemia was defined as a first lactate level > mmol/l. the second value (l ) was measured within h following the first measurement. lactate clearance was calculated as (l -l ) l time between l and l measurements) and expressed in mmol hour. parameters associated with initial hyperlactatemia and lactate clearance were investigated using multivariate logistic regression analysis. introduction: cardiac surgery with cardiopulmonary bypass (cpb) induces immunosuppression which has considerable implications for patients. cpb induces a significant increase in circulating neutrophils. neutrophil activation, associated with production of antibacterial peptides, reactive oxygen species (ros), cytokines, and other inflammatory mediators, as well as release of dna into the extracellular milieu (neutrophil extracellular traps (nets)), plays a central role in innate host defense and modulation of inflammation. however, it has been shown that, in septic shock or systemic inflammation as major surgery, immature circulating neutrophils can induce immunosuppression and increase the risk of secondary infections. staphylococcus aureus (sa) is one of the most commonly encountered bacterial pathogen responsible for poststernotomy mediastinitis, and neutrophils alterations may favor postoperative infections. the main objectives of this study were to evaluate the direct effects of cbp on neutrophils functions and to study the impact of different strains of sa on neutrophils bactericidal functions. patients and methods: blood samples were collected before and h after cardiac surgery with cpb and bone marrow samples were harvested directly after sternotomy, before initiation of cpb, and at the end of cpb, before sternal closure. septic patients were included as controls. circulating neutrophils analysis was performed using flow cytometry. we also studied netosis, ros production and bactericidal activity in isolated neutrophils before and after surgery using two strains of sa-one responsible of postoperative mediastinitis and one isolated from nasal carriage. results: blood cell count with differential demonstrated a significant increase in neutrophils h after surgery. flow cytometry analysis of blood samples indicated neutrophils were matures with a significant increase in degranulation marker (cd b). neutrophils life span was also increased after cbp. flow cytometry analysis of bone marrow samples showed no difference in cell composition and maturation before and after cbp. the neutrophil production of ros was significantly higher after cbp. however, cbp did not impact nets formation, phagocytosis and bactericidial function. moreover, there was no difference regarding the phagocytosis and the bactericidial activity when exposed to the two strain of sa. as expected, immature neutrophils count was significantly increased in septic patients compared to cardiac surgery patients. these results indicate that cbp promotes the recruitment of matures neutrophils via a demargination process. cbp does not induce neutrophil dysfunction. neutrophils should not be targeted to decrease postoperative infection after cpb. introduction: protein tyrosine phosphatase b (ptp b) is a negative regulator of both no production and insulin signaling and has been shown to be an aggravating factor in septic shock. stress hyperglycemia frequently occurs in critically ill patients and is associated with poor outcome. experimental studies on transgenic mice have shown that ptp b deletion resulted in a reduced insulin resistance and in a better survival during experimental model of sepsis. the main objective was to study the correlation between the ptp b gene expression and organ failure (through the delta sofa score between day and day ) or insulin resistance. patients and methods: twenty-seven healthy male volunteers have been included in this clinical trial. the product was administered by continuous intravenous infusion (civ). a single ascending dose design with dose levels was used. cohorts and received a -min single dose of motrem ( and mg and one and two volunteers respectively). then, cohorts to received either a -min loading dose (from . mg kg to mg kg) followed by . -hours maintenance dose (from . mg kg h to mg kg h) of motrem or a matching placebo ( - ratio). all volunteers were carefully monitored. before escalation to the next dose level, safety and pk data of the previous dose level were reviewed by a safety review committee. since immune system is at rest in normal individuals and thus trem- pathway is not activated, no pharmacodynamics parameters were analyzed. the main objectives of this trial was then to study the safety and pharmacokinetic profile of motrem. results: no product related changes in vital signs, clinical nor laboratory parameters were observed. no product-related adverse events were reported. the pk of motrem was linear; the main clearance was estimated at l/h/ kg which is higher than the hepatic blood flow in human (i.e., l/h/ kg) and is therefore indicative of an extensive enzymatic metabolism in blood + effective half-life was calculated to be about min. conclusion: motrem was found to be safe and well tolerated up to the highest dose tested ( mg/kg for a -min loading dose and mg kg h for a . -hours maintenance dose). safety and pharmacokinetics of motrem is currently being studied in septic shock patients in a phase iia randomised, double-blind, two-stage, placebo controlled, international, multicenter clinical trial (www.clinicaltrials.gov nct ). - ) is an immunoreceptor expressed on neutrophils and monocytes macrophages whose role is to amplify the inflammatory response driven by toll-like receptors engagement. the pharmacological inhibition of trem- confers protection in several pre-clinical models of acute inflammation. in this study, we aimed to decipher the role of trem- on the endothelium. we evaluated the expression of trem- in vessels and isolated endothelial cells by flow cytometry, qrt-pcr and confocal microscopy. we generated an endothelium-conditional trem- ko mice and submitted them to polymicrobial sepsis through clp. organs and blood were harvested at different time points and analyzed for cellular content, cytokine chemokine concentrations, and vasoreactivity. survival was monitored for week. results: trem- was expressed in aorta and pulmonary vessels from animals, and inducible after lps stimulation or during sepsis. these results were confirmed in human pulmonary microvascular endothelial cells. the pharmacological inhibition of trem- , using the synthetic inhibitory peptide lr , decreased the lps-induced trem- expression. sepsis induced a profound vascular hyporeactivity in wt animals, both in terms of contractility and endothelium-dependent relaxation. although contractility was still impaired in endotrem- -mice, vasorelaxation was completely restored. soluble trem- concentrations, a marker of trem- activation, were markedly increased in the plasma, the peritoneal lavage fluid and the lungs from wt septic mice compared to control. in endotrem- -mice, strem- level was reduced. plasma concentrations of soluble vcam- and il- were also reduced in endotrem- -animals. we observed an accumulation of neutrophils and inflammatory ly chigh monocytes in the lung of wt septic mice. this accumulation was dampened in endotrem- -mice. by contrast, endothelial trem- deletion favored the accumulation of reparative cells (ly clow monocytes). finally, survival was clearly improved in the endotrem- -group as compared to the wt group. conclusion: we reported that trem- is expressed and inducible in endothelial cells and plays a direct role in vascular inflammation and dysfunction. the targeted deletion of endothelial trem- conferred protection during septic shock in modulating inflammatory cells mobilization and activation, restoring vasoreactivity and improving survival. the effect of trem- on vascular tone, while impressive, deserves further investigations including the design of endothelium specific trem- inhibitors. - . ]. patients suffered from pneumonia, from intra-abdominal sepsis. we measured serum levels of total and free thiamine, thiamine mono di and triphosphate (tmp, tdp and ttp respectively), as well as the erythrocyte transketolase activity and arterial lactate at the time of admission. we also recorded the vital status at the end of the icu stay. results: % of our subjects exhibited particularly low levels of free thiamine (< nmol/l). there was no correlation between free (r = − . ; p = . ), or total (r = − . ; p = . ) thiamine concentration and lactate levels. there was no correlation between tmp (r = . ; p = . ), tdp (r = − . ; p = . ), ttp (r = − . ; p = . ) and lactate levels in the whole population. no correlation was found between the concentration of thiamine derivatives and arterial lactate levels in the subgroup of patients exhibiting the highest levels of lactate (> and > mmol/l). total thiamine and tdp concentration at the time of admission were significantly higher in icu survivors than in non-survivors (p = . and p = . ). during sepsis, we did not find any correlation between thiamine and lactate concentration. lower thiamine diphosphate concentration may be associated with icu-mortality. introduction: a positive fluid balance in sepsis is a determining factor for mortality. in previous experimental studies, sodium lactate has been shown to improve hemodynamic and avoid fluid overload ( ). to understand these beneficial effects, we investigated the impact of sodium lactate on capillary leakage, in comparaison to saline on capillary leak in a rat model. the sixteen sedated, mechanically ventilated rats were challenged with intravenous infusion of e.coli lipopolysaccharide ( mg/kg). two groups of eight animals were randomised to receive a continous perfusion ( ml/kg/h) of sodium lactate . % (treatment group) or . % nacl (control group). in order to inject the same caloric load in the two groups, a . ml/kg/h of either water of % dextrose solution were perfused. mean arterial pressure, heart rate, urine ouput were measured over a min period. an echocardiography was then performed and evans blue ( %, mg/kg) was intravenously injected min before sacrifice. organs were withdrawn and organs wet dry ratio and evans blue dye extravasation were measured. results: fluid balance, organs wet dry ratio and evans blue dye extravasation were not significantly improved in sodium lactate group. hemodynamics parameters were not significantly enhanced after sodium lactate infusion. discussion: previously, lactate administration has improves renal perfusion. in our study, the volume of urine output was decreased in the groups reflecting the severity of our model. and the vascular filling ( . ml/kg/h) higher than in the literature could impact our results. ( ) recently, the pressure electricy index-pmus eadi index (pei) has been described. ( ) the purpose of this study was to assess muscular pressure (pmus) using pei with our nava protocol. patients and methods: observational study, patients recovering from pneumonitis and acute respiratory failure. sbt was pressure support ventilation with cmh of assist and no pep. pei was calculated under nava and during sbt from airway pressure drop during end-expiratory occlusions, muscular pressure (pmus) was estimated from pei ( ) . another index, patient ventilator contribution index (pvbc) was also measured using the inspiratory peak of eadi and vt (inspiratory) during assisted and non-assisted breaths. we calculated pvbc-squared because it has been shown that it is more correlated to pmus ptot. results: results are summarized in the introduction: in icu, intubation is a high risk procedure associated with high morbidity. despite procedure's improvement with systematic application of fluid loading, early use of vasopressors and checklist use, morbidity remains high. first pass success is strongly correlated with adverse event occurrence. a recent study by semler et al. concluded than "sniffing" position is better than "ramped" position to increase first pass success even the primary outcome prespecifiedpulse pressure saturation was not different between the two groups. we conducted a post hoc analysis of the randomized clinical trial macgrath mac video laryngoscope or macintosh laryngoscope for intubation in the intensive care unit (macman) to determine the best position for intubation in the icu. patients and methods: macman was a multicentre, open-label, randomized controlled superiority trial. consecutive patients requiring intubation were randomly allocated to either the mcgrath mac videolaryngoscope or the macintosh laryngoscope, with stratification by centre and operator experience. an only inclusion criterion was-"patients must be admitted to an icu and require mechanical ventilation through an endotracheal tube". patients were excluded if-contraindication to orotracheal intubation (e.g., unstable spinal lesion); insufficient time to include and randomize the patient (e.g., because of cardiac arrest); age < years; pregnant or breastfeeding woman + correctional facility inmate; patient under guardianship + patient without health insurance; refusal of the patient or next of kin to participate in the study; previous enrolment in a clinical randomized trial with intubation as the primary end point (including previous inclusion in the present trial). post-hoc analysis was performed to assess association between patient position (sniffing or supine) and first pass success. between-groups baseline difference was adjusted for baseline covariates significantly associated with the group membership (p < . ). results: failure of first pass introduction: during acute exacerbation of copd oxygen should be titrated to avoid both hypoxemia and hyperoxia. the recommendations are not followed and automated oxygen titration may be useful in this population. the aim of this study was to evaluate a new device developed to automatically titrate oxygen based on spo target (freeo , oxynov, canada) and to compare oxygenation parameters with usual administration (manual flowmeter). the study is an observational monocentric study. we prospectively included patients hospitalized for acute exacerbation of copd receiving oxygen. written informed consent was obtained from all patient. in the first part of the study, we evaluated oxygen flowrate and spo during min at baseline based on management of the physicians in charge. the oxygenation parameters were compared with automated titration (freeo during h). in the second part of the study, oxygen was delivered with freeo until oxygen weaning or a maximum of h. we evaluated the oxygenation parameters during prolonged utilization, the duration of oxygen administration, a new bluetooth spo connection compared to wire spo connection (evaluated by visual analog scale - ). results: we present preliminary data of copd patients (sex ratio m f = ). mean age (± sd) was ± years, mean fev (± sd) was . ± . l. oxygenation data in both parts of the study are displayed in the table . time in the spo target was significantly increased with freeo in comparison with manual titration and oxygen flowrate was reduced by half. in the second part of the study, the % of time in the spo target with automated oxygen titration was above % and time with hypoxemia and with hyperoxia were low. in patients, we compared comfort with wire spo connection to bluetooth wireless spo connection. the comfort was significantly increased with wireless connection ( . ± . vs. . ± . , p < . ). duration of oxygen administration after inclusion ( . ± . days) and hospital length of stay after inclusion ( . ± . days). conclusion: automated oxygen titration maintains the patients within predetermined spo target more than % of the time and reduces oxygen flowrate in comparison with manual oxygen titration. the second part of the study demonstrates the feasibility to use automated oxygen titration during several days with similar outcomes as previously reported in similar population. there are several limitations of the study and additional evaluations of this device are required. introduction: hyperoxemia occurs up to % of mechanical ventilation days in the icu [ ] and is associated with increased mortality as compared to patients ventilated in normoxemia [ ] . intellivent-asv is a full closed loop ventilation mode adjusting automatically oxygenation's settings fio and peep according to spo for passive and spontaneously breathing mechanically ventilated patients. this post hoc analysis of a monocentric randomized controlled parallel group study compared frequency of hyperoxemia (pao > mmhg and or spo > %) and hypoxemia (pao < mmhg and or spo < %) and the percentage of ventilation time with spo > % and the percentage of ventilation time with spo < % between intellivent-asv and conventional ventilation mode in mechanically ventilated icu patients. the randomized controlled trial was performed in the general icu of hôpital sainte musse, toulon, france. eligible participants were adult aged or over, invasively ventilated for less than h at the time of inclusion with an expected duration of mechanical ventilation of more than h. exclusion criteria were broncho-pleural fistula, ventilation drive disorder and moribund patients. patients were allocated to intellivent-asv group or to conventional ventilation group (volume assist control and pressure support modes) using blocked randomization. the post hoc analysis was performed by the comparison of all arterial blood gases (abg) performed during the study period-the number of abg with hyperoxemia and hypoxemia, the median pao and spo for these arterial blood gases and fio associated were compared according to group. results: patients were included, patients in each group. the total number od abg was (mode conventional) vs (mode intel-livent-asv) (p = ns). the number of abg with pao > mmhg was respectively versus (p = . ) with sao > % was vs (p = . ) with pao < mmhg was vs (p = . ) + with sao < % was vs (p = . ). the percentage of time of ventilation spent with spo > % was % vs (p = . ), and with sao < % was . vs . (p = . ). the continuous control of oxygenation settings provided by intellivent-asv decreases significantly the number of blood gas with hyperoxemia as compared to manual oxygenation setting without increasing the risk of hypoxemia. introduction: in invasively mechanically ventilated patient, dyspnea is frequent and severe. relying on self-report, its measurement remains challenging in patients unable to communicate. a -item observation scale, namely the intensive care-respiratory distress observation scale (ic-rdos), has been proposed as a surrogate of dyspnea-visual analogic scale (d-vas) self-report in intensive care unit (icu) patients [ ] . however this scale has been validated among non-intubated patients and included one item "supplemental oxygen" not thoroughly adapted for intubated population. we sought to develop a dyspnea observation scale more suitable for intubated patients and to evaluate its performance to detect dyspnea. patients and methods: ancillary analysis of data prospectively collected from icu communicative patients enrolled for the validation of the ic-rdos. factorial principal component analysis was first performed to select variables that mostly contributed to the principal axes, among a set of observable variables with possible clinical relevance. to identify the best correlation between these variables and d-vas, were performed an iterative partial least square regression process (pls). iterative pls procedure identified five variables, of which the combination and weighting allowed optimal correlation with d-vas (r = . ; % ci . to . ; p value < . ), which constitute the ic-rdos [ ] . in a first step, we removed "supplemental oxygen", not relevant in intubated patients. we obtained a -items ic-rdos (r = . introduction: lung ultrasound (lus) has emerged in different clinical settings, such as in intensive care medicine (icm). early diagnosis of ventilator-associated pneumonia (vap) remains a challenge to the intensivist. however, scientific evidence is little available on whether lus reliably improves the diagnosis of vap. the aim of this prospective study was to assess whether lus could be an alternative to pulmonary computerized tomography (ct) for assessing diagnosis of vap in icm. patients and methods: twenty-one patients ventilated for duration more than days suspected of vap were included. lus was performed by a well-trained operator who was blinded of the vap diagnosis. the diagnostic gold standard of vap was on the basis of pulmonary ct and positive culture pulmonary. all clinical criteria for the diagnosis were collected the same day of lus and pulmonary ct. the ultrasound exam included anterior, lateral and posterior views from both sides of the chest with superior and inferior views. we classed patient in groups according diagnosis of vap with pulmonary ct (vap + or vap-) and lus (lus + or lus-). lus characteristics of vap diagnosis included profils-asymetric line b (profil a b), without sliding (profil b'), sub pleural consolidation (profil c), consolidation with punctiforme bronchogram (pb), linear air bronchograms (lb) or dynamic bronchograms (lbd), posteror lateral alveolar pleural suffusion (plaps), pleural effusion pathological (pep), shred sign (ss and complications according to insertion site. the advantage of this method is that it gives a pragmatic view of the real clinical situation. patients and methods: ancillary study of the akiki trial, an open pragmatic randomized controlled trial published in , in which patients with severe acute kidney injury were randomly assigned to either an early or a delayed rrt initiation strategy. the present study involved all patients who underwent at least one rrt session. number of rrt catheters, insertion sites, factors potentially associated with the choice of insertion site, duration of catheter use, reason for catheter replacement, and complications were prospectively collected. results: among the patients included in akiki, received rrt at least once and patients were finally included in the analysis ( missing data), leading to a total of rrt catheters. femoral site was chosen preferentially (n = , %), followed by jugular site (n = , %) and subclavian site (n = , %). investigating center was the sole factor significantly associated with the choice of insertion site in multivariate analysis (p = . ). higher weight did not affect choice of insertion site. mean duration of catheter use was . (+- . ) days without difference according to site. catheter dysfunction was the main reason for replacement (n = , %). suspicion of infection led to replacement of many catheters (n = , %) but was actually seldom proven (n = , % introduction: long standing dialysis (sled or crrt) allows a better hemodynamic tolerance as well as a greater performance to achieve a negative fluid balance in intensive care unit. dialysis alter hemodynamics mainly by short term variation of blood volume. in this study we took advantage of a continuous monitoring of blood volume during dialysis session to decipher the relationship between the variation of relative blood volume (rbv) with mean arterial pressure (map). this study is observational prospective, including all prolonged (> h) dialysis sessions in saint etienne nephrology intensive care unit between january and june . exclusion criteria were ongoing blood transfusion and blood volume controled ultrafiltration. medical records were compiled along with cardiac ultrasonography at the beginning when available. the statistical analysis was perfomed in two parts. the first part studied the performances of the first hour deltarbv (defined by rbv before minus rbv after h of dialysis) to predict a drop of map below mmhg (hypotension). this analysis excluded sessions with hypotension and intervention during the first hour. the second study was the modelization of the relationship between deltarbv and deltamap for every hour of dialysis without any intervention on blood pressure. both analyses were performed using mixed effects linear and generalized models. fig. vancomycin pk during sled results: a total of sessions on different patients were performed during the period. the characteristics of patients were as follows-sex ratio at , age (sd) . ( . ), weight . kg ( . ), sapsii score . ( . ) . patients on were taken in charge for fluid overload. in the first set of analyses (per sessions), sessions were excluded for intervention in the first hour. the adjusted deltarbv did not predict hypotension during the session (generalized mixed effect model, session and patients set as random effects, estimate . , p = . ). in the second set of analyses (per hour without any intervention), h were analyzed. adjusted deltarbv correlated strongly and inversly with deltamap (linear mixed effect model, random effects were sessions, patients and hour order in the session, estimate . , p < . ). conclusion: in our mostly fluid overloaded patients, the drop of rbv correlated with an increase of map. introduction: kidney transplant recipients (ktr) are at risk of icu admission because of prolonged immunosuppressive therapy and a higher risk of cardiovascular events, severe infections or drug-related toxicities. several retrospectives studies reported the short-term outcome of ktr admitted to the icu, but data concerning the risk of chronic kidney disease and anti-hla immunization are scarce. patients and methods: in this retrospective study, we addressed the in-hospital and long-term mortalities of the ktr admitted in a french icu ( beds) between january and june . predictive factors for death, long-term renal function and hla immunization were identified. results: the main causes for admission were acute respiratory failure ( . %), sepsis ( . %), post-operative period (peritonitis, hemorrhage + %). at the admission, mean age, saps and sofa score were ± years, ± and . ± . , respectively. renal replacement therapy, mechanical ventilation and vasopressors were required in ( . %), ( . %) and ( . %) patients. immunosuppressive regimen was modified in patients ( . % + steroids increase %, calcineurin inhibitors or antimetabolites withdrawal and %, respectively). in-hospital mortality was % ( . and . % at months and ). by multivariate analysis, ebv blood proliferation in the months preceding the admission in the icu, and the saps gravity score at admission independently predicted the in-hospital and long-term mortalities. among the patients alive at month after the admission in the icu and with available data, ( . %) and ( . %) progressed to a more severe ckd stage at months and , respectively. both, the severity of the aki and the preexisting ckd predicted the risk of progression of the ckd. last, de novo anti-hla immunization at month was identified in patients ( . %, donor specific antibodies ( . %)) and was significantly associated with the occurrence of acute transplant rejection (p = . ). in five patients who developed anti-hla antibodies, rbc transfusion during the icu stay was the only immunological trigger identified. discussion: outcome of ktr is closed to the general population admitted in icu and better than other immunocompromised patient, like patients from oncohematology. conclusion: worsening of the renal function and hla immunization are frequent and may impact mid to long-term prognosis because of the high risk of transplant rejection, end-stage renal disease and further transplantation contraindication. introduction: acute kidney injury (aki) is associated with a poor prognosis. although pulmonary embolism (pe) may promote aki through renal congestion or hemodynamic instability, its frequency as its impact on the prognosis of patients with acute pe have been poorly studied. patients and methods: using data from the registro informatizado de la enfermedad tromboembolica venosa (riete) registry, we assessed the frequency of aki at baseline, and its influence on the -day mortality rate of patients with objectively confirmed pe. aki was defined according to the "kidney disease-improving global outcomes" definition. we used multivariate analysis to assess whether or not the presence of aki independently influenced the risk for -day death. the study included , patients with acute pe, of whom ( . %) had aki at baseline. of these, patients ( %) were in stage , ( . %) in stage and ( %) in stage . the proportion of patients with high-risk pe in those with no aki, aki stage , aki stage and aki stage was- . , . , . and %, respectively (p < . ). after days, patients ( . %) had died. overall mortality was- % in patients with no aki, . % in aki stage , % in aki stage , % in aki stage , all p < . ). on multivariable analysis, aki was independently associated with an increased risk of death at days (odds ratio = . + % ci . - . ), after adjusting for the initial severity of pe, age > years, chronic heart failure or chronic lung disease, cancer, anemia and liver cirrhosis. conclusion: one in every - patients with acute pe had aki. moreover aki was an independent predictor of poor outcome in pe patients. this study suggests that pe (and its severity) should be considered as a risk factor for aki and aki may deserve to be evaluated as a prognostic factor in patients with acute pe. introduction: metabolic acidosis is frequently observed as a consequence of global ischemia-reperfusion after out-of-hospital cardiac arrest (ohca). we aimed to identify risk factors and assessing the impact of metabolic acidosis on outcome after ohca. patients and methods: we included all consecutive ohca patients admitted between and . using admission data, metabolic acidosis was defined by a positive base deficit and was categorized by quartiles. main outcome was survival at icu discharge. factors associated with acidosis severity and with main outcome were evaluated by linear and logistic regression, respectively. results: patients ( . % male, median age years) were included in the analysis. median base deficit was . [ . , . ] meq/l. male gender (p = . ), resuscitation duration (p < . ), initial shockable rhythm (p < . ) and post-resuscitation shock (p < . ) were associated with a deeper acidosis. icu mortality rate increased across base deficit quartiles ( . , . , . and . %, p for trend < . ) and base deficit was independently associated with icu mortality (p < . ). the proportion of cpc patients among icu survivors was similar across base deficit quartiles ( . , . , . and . %, p = . ) and . % of patients with a base deficit higher than . meq l survived to icu discharge with a good neurological recovery. severe metabolic acidosis is frequent in ohca patients and is associated with poorer outcome, in particular due to refractory shock. however, we observed that about % of patients with a very severe metabolic acidosis survived to icu discharge with a good neurological recovery. introduction: precarious socio-economic status can directly influence health, need for hospitalisation and mortality, according to a previous study performed in european countries. similar findings have been reported from anglo-saxon countries in the setting of intensive care. due to the different structure of the healthcare system in france, we aimed to investigate whether socio-economic status influences initial severity of disease and months mortality in patients admitted to intensive care in france. patients and methods: prospective, multicentre, cohort study including adult patients admitted to one of participating intensive care units (icus) between and , and presenting failure of one or more major organs. patients were considered to have a precarious socio-economic status if they presented at least one criterion of social vulnerability or a high epices deprivation score. results: data on social vulnerability were available for patients, of whom . % were considered to be socially vulnerable. compared to non-vulnerable patients, socially vulnerable patients were younger ( . vs . years, p = . ), more frequently had chronic disease ( . vs . %, p = . respectively for congestive heart failure and . %vs . %, p = . for chronic respiratory disease), had higher levels of physical dependency ( . vs . %, p = . ), and were more often classed as having long-term health conditions ( . vs . %, p < . ). conversely, non-vulnerable patients had greater severity of disease at admission to the icu than those classed as vulnerable, both in terms of saps ii and sofa scores (respectively . vs . (p = . ) and . vs . (p = . )). findings were similar after adjusting for major confounders (adjusted odds ratio (or) . , % confidence interval (ci) [ . - . ], p = . ). mortality at months was not significantly different between socially vulnerable patients and those not considered vulnerable, respectively . vs . % (p = . ), even after adjustment for initial severity. conclusion: despite less severe disease at admission to the icu among patients considered socially vulnerable, -month mortality did not differ significantly between those who were socially vulnerable and those who were not. these findings suggest that the french healthcare system provides good protection for the most disadvantaged members of society, particularly when they are admitted to the icu. introduction: an approach of the quality of care may involve assessing the patients' satisfaction. however, the extended caregiverpatient and family relationship, specific to the critically ill patients, may also require to assess the proxies' satisfaction. the opinionfamily tool was developed to assess the satisfaction of the critically ill patients' proxies, in an anonymous and continuous fashion. we conducted a study in the icu of tenon hospital (paris, france) between mars and august . the opinion-family questionnaire, built with categories ( items each), aimed to measure the proxies' satisfaction regarding their perception of the quality of care. all the proxies were invited to express voluntarily and anonymously his her degree of agreement as a response to a statement by the selection of the corresponding stars (strongly disagree- star, disagree- stars, neither agree nor disagree- stars, agree- stars, strongly agree- stars) using a secure touch screen disposed in the waiting room of the icu. results: altogether, patients were hospitalised during the study period, and proxies completed the questionnaire. all the responders spoke french. only responders ( %) answered more than one time. of the responders, ( %) were the referring person, ( %) were children and ( %) were spouses. during the study period, ( %), ( %), and ( %) responders had visited their relative to times, to times, and more than times, respectively. the different categories assessed by the opinionfamily tool were related to «the family and the patient» (fig. a) , «the family and the environment» (fig. b) , and «the family and the caregivers-availability, trust, support, and information» (fig. c) . the corresponding levels of satisfaction (responses of at least stars) were respectively , , , , , and %. some items were associated with a poor satisfaction (participation to the care, identification and availability of the caregivers). conclusion: the implementation of the opinionfamily tool allowed a continuous evaluation of the satisfaction of the critically ill patients' proxies. a systematic implementation of this tool in the icus may be useful to the caregivers for a better understanding of the needs of the proxies. in addition, this tool may allow rapid changes in icu organizations and behaviours to improve the proxies' satisfaction, which may ultimately, improve the care of patients. many factors influence end-of-life decisions (eol). we describe eol decisions in patients with acute respiratory failure and their impact on patients' prognosis. patients and methods: an international observational study included all patients with acute respiratory distress over a -month period. icu in countries were involved. demographic, clinical and biological data were compared between patients with and without decision of lst limitation. we also compared surviving patients after lst limitation decision to those who eventually died. results: among the patients, mortality was . %. a decision of lst limitation was reported in patients ( . %). in univariate analysis, patients with lst limitation decision were older and more frequently hospitalized for a medical condition, had a lower body weight, a higher sofa score, and presented active neoplasia immunosuppression or chronic liver failure more frequently (p < . for all). patients admitted after trauma, drug overdose or pulmonary contusion were less subject to have an lst limitation decision (p < . ). in contrast, patients with non-cardiogenic shock were more subject to these decisions (p = . ). eol decisions were less frequent in lower-middle income countries as compared to high and middle-high income countries (p < . ). multivariate analysis will be presented. among patients with an lst limitation decision, survived ( . %). mortality was higher in this group than in the whole study population (p = . ). in univariate analysis, death after decision of lst limitation was associated with admission for a medical condition (p = . ), severe ards, higher inspiratory pressure, non-cardiogenic shock, higher sofa score with or without respiratory component and chronic liver failure (p < = . for all). on the contrary, admission for trauma was associated with survival (p = . ). regarding the patients who died during their hospital stay, did not receive a decision of lst limitation ( . %). decision of lst limitation was more frequent in older patients (p < . ) and in high-income countries. conclusion: decisions of lst limitation are frequent in the icu, and are associated with increased age and medical severity. however, a significant percentage of these patients survived. interestingly, almost half of the patients who eventually died during their hospital stay had not been subject of a decision of lst limitation. evaluation of the decision-making process leading to a decision not to readmit a patient to the intensive care unit during a same hospital stay introduction: the risk-benefit ratio of (re-)admission to the intensive care unit (icu) has been widely discussed in the literature. however, the ethics of non-readmission during a single hospital stay have not been widely addressed. a decision not to re-admit a patient to the icu could be seen as a limitation of therapy, thus falling within the scope of the law dated april , by denying the patient access to potentially-available healthcare resources. in this context, we aimed to-( ) investigate whether decisions not to re-admit patients to the icu are taken in accordance with french legislation + and ( ) identify the characteristics of patients concerned by this type of decision. patients and methods: this study was based on data from the prospective, multicentre ivoire cohort (influence of socio-economic vulnerability on initial severity and prognosis of patients admitted to the icu + phrc-ir ). we identified patients included in two large regional university hospitals in the east of france for whom a decision not to re-admit was taken during a single hospital stay. the decisionmaking process was evaluated based on a questionnaire comprising items developed by a sociologist from semi-directive interviews with clinicians. results: among patients discharged from the icu alive, a decision not to re-admit to the icu during a same hospital stay was noted in the medical file of patients ( . %). this decision was primarily made on the day of discharge ( . %), and those involved in the decision included-the family, an outside consultant, and the patient themselves in , . and . % of cases respectively. the decision was justified in medical terms in . % of cases, and the main reasons cited were-( ) therapeutic impasse ( . %) + ( ) comorbidities ( . %) + ( ) degree of dependence of the patient ( . %). patients concerned by decisions of this type were generally older ( vs . years, p < . ), with more comorbidities (median vs , p = . ), greater loss of dependence according to katz's activities of daily living ( vs , p < . ), and longer duration of life-sustaining therapies ( . vs days, p = . ). conclusion: although the profile of the patients identified in this study likely justified the decision not to re-admit the patient to the icu, there is room for improvement in the decision-making process. introduction: most of organ donors are brain dead patients. in some cases, patients are identified as potential donors before brain death and will undergo intubation and mechanical ventilation for the sole purpose of awaiting brain death. the aim of this study is to evaluate the practices of professionals in charge of potential donors. (table ). in this case, the issue of organ donation was addressed to the relatives before intubation by % of icup and % of non icup (p = . ). % of participants never addressed organ donation before the brain death. for the % who have done so at least once, organ harvesting never happened in % of cases. legitimacy and difficulties ( table )- % of respondents felt that when a decision of treatment withdrawal or withholding is taken, the patient should not go to icu for any reason and % think that these patients should be allowed to die "quietly". the prospect of an extubation if brain death does not occur or in case of organ donation refusal is a problem for % of icup and % of non icup (p = . ). % of icup and % of non icup think they would need to receive training. conclusion: this study shows that pursuing mechanical ventilation for the sole purpose of awaiting brain death and organ harvesting is a common practice, and that intubating a patient for this purpose alone is done in most of cases but could still be more generalized. on the other hand, information to the relatives should be improved. - . ] . the effect of pp on the monitored parameters varies significantly between each patient but also between each session for the same patient. in positive responders, the effect continues statistically for to h depending on the parameter studied- . h for vd vt, . for phase slope, for petco and for cdyn. the maximum effect of prone positioning on selected parameters seems to be obtained after h of therapy. the acute respiratory distress syndrome (ards) is characterized by lung infiltration with activated neutrophils. neutrophil extracellular traps (nets) are antimicrobial structures released by neutrophils. nets have also been associated with tissue damage in experimental models of acute lung injury. whether nets are involved in the pathogenesis of human ards and could be a potential therapeutic target is unknown. we aimed to quantify alveolar nets production in patients with pneumonia and ards and assess its relationship with outcomes. patients and methods: prospective monocentric study. patients admitted in the icu in with pneumonia and moderate severe ards were included. immunosuppressed patients were excluded. nets (dnamyeloperoxidase) levels were measured by elisa in broncho-alveolar lavage (bal) fluid and serum samples of ards patients and in those of control patients (n = ). patients with higher and lower bal fluid nets levels were compared using the median as a cutoff value. results: thirty-five patients with bacterial (n = ), viral (n = ) or non-microbiologically documented (n = ) pneumonia and ards were included. nets levels were significantly higher in bal fluid than in blood of ards but not of control patients (fig. introduction: the ratio of arterial oxygen partial pressure to fractional inspired oxygen (pao fio or p f) is daily used to assess patients' evolution under ventilatory support. some studies reported the reliability of percutaneous oxygen saturation (spo ) to appreciate pao easy to get on bedside. thus two equations have been proposed-rice equation and ellis equation. however, no large prospective study assessed the reliability of such equations to estimate the p f at the bedside in real conditions. using the spectrum (severe hypoxemia-preva-lence, treatment and outcome) study, we aimed to evaluate the reliability of spo obtained by rice and ellis equation. this study is a planned companion of spec-trum study, a recent prevalence-point-day conducted by the srlf trial group in french-speaking icu aiming to report the patterns and outcomes of hypoxemic patients (defined by p f < mmhg). we included in the analysis all patients under mechanical ventilation with spo < % (according to limit of the rice study). spo and fio were measured simultaneously to arterial blood gas were drawn. results: among patients of the spectrum study, were on mechanical ventilation and had undergone arterial blood gas with simultaneously recorded spo and fio . of note, p f was < mmhg for + between and for + and between and for . pairwise correlations of truth p f with estimated p f was good (rice-spearman's rho = . , p < . -ellis-rho = . p < . ). bland-altmann test showed an important variability of results (p f vs rice (figure) - . ± . -p f vs ellis- . ± . ). the variability decreased with lower p f. caution may be used to interpret our results because we did not reported the quality of spo signal at the bedside. conclusion: regarding the variability of the results, whatever the used equation, caution may be used to predict the p f by the spo fio ratio in patients under mechanical ventilation. introduction: morbid obesity and ards both affect respiratory mechanics mainly through their respective impacts on chest wall and lung elastances. we present a unique series of patients combining very severe morbid obesity and moderate to severe acute respiratory distress syndrome (ards). we describe the use of trans-pulmonary pressures (tpp) measurements for optimization of external peep setting. patients and methods: the monocentric observational study was performed in morbidly obese patients admitted for moderate to severe ards. we performed an incremental peep trial ( cm h o steps) with tpp measurement (nutrivent probe, sidam, italy) in a semirecumbent position as previously described. a decremental peep trial after a recruitment maneuver was not performed since the safety of such a maneuver in this specific population is largely unknown. we defined two ways for determination of external peep setting-( ) peep necessary to obtain a positive expiratory tpp and ( ) peep necessary to obtain a plateau pressure between and cm h o (maximal alveolar recruitment express strategy). data are expressed as numbers (%) and medians (interquartile range). statistical analysis was made using the xlstat software. results: we enrolled during years morbidly obese patients (bmi (ir - )) admitted for a moderate to severe ards. clinical characteristics are displayed in table . the express strategy indicated a peep setting of cm h o (ir - ) whereas tpp-guided peep was cm h o (ir - ), p = . . driving pressure was higher in the express strategy peep setting ( . cm h (ir - )) than in the tpp-guided peep ( . cm h (ir . - )), p = . . tpp-guided peep setting was higher than indicated by the express strategy in all but one patient. one patient suffered from transient hypotension when external peep was set at cm h o, while no patient displayed an inspiratory tpp higher than cm h o. additional data will be provided during the meeting-pressure-volume curve at zeep ( patients), crf measurements ( patients) and abg and capnometry values at each peep level ( patients) . in our ards patients with extremely severe obesity, an incremental peep trial with tpp measurements appeared to be safe and indicated a peep setting significantly higher than for the commonly-used ards strategies. such an approach deserves further comparisons with other modalities of monitoring, such as crf measurements, eit studies, etc. severe poisoning by cardiotoxic drugs and circulatory assistance: -year experience at french university hospital tardif elsa , conil jean-marie , georges bernard , marcheix bertrand , crognier laure , bounes fanny , delmas clement chu rangueil, toulouse, france correspondence: tardif elsa -tardif.elsa@gmail.com annals of intensive care , (suppl ):f- introduction: toxicity from cardiac drugs is associated with a large number of fatalities, significant morbidity and healthcare consequences. severity of these poisonings can be explained by a refractory cardiogenic shock not responding to optimal conventional treatment. criteria of circulatory assistance indications remain unclear. the aim of the study was to describe and to compare patients intoxicated by cardiotoxic drug treated with or without veno-arterial extracorporeal membrane oxygenation (va ecmo). patients and methods: retrospective cohort study conducted at french university hospital. all patients intoxicated with cardiotoxic drugs between january and march were included. patients were divided into groups-with and without va ecmo. results: among the patients included in the study, patients were treated with va ecmo ( %) and patients with conventional therapies. ecmo was respectively employed for refractory shock and cardiac arrest in and cases, all patient required vasopressor support. in-hospital mortality was . % and was significantly higher in the ecmo group ( . %). beta-blockers with membrane stabilizing activity and non-dihydropyridine calcium channel blockers poisoning were the most commonly reported in the ecmo group. mean time from hospital admission to initiation of ecmo was h and the average ecmo duration was . days [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . no serious adverse reaction was reported during this period. results expressed in median value ± confidence interval conclusion: refractory cardiogenic shock following cardiotoxic drug poisoning requiring circulatory assistance is associated with significant mortality. even if its use seems justified by the literature, the implantation criteria must be specified and this after an optimal conventional treatment to prevent multiple organ failure. the cdv of patients in the edass group was significantly higher (p < . ) at all-time points after the introduction of catecholamines than among those without edass, as early as h from catecholamine initiation (fig. ) . a strategy in two steps (cdv > µg kg at h and or cdv > µg kg at h) was able to predict edass with sensitivity of %, specificity %, positive predictive value % and negative predictive value %. overall, this two-step strategy identified high-risk patients at h, of whom presented edass. conclusion: overall, our results confirm that early death directly attributable to septic shock could be effectively predicted by the cdv in the first hours of treatment. these results will help to select patients eligible for innovative therapies aimed at improving early mortality in septic shock. introduction: in patients with cardiac arrest, end-tidal co (etco ) has been proposed to monitor the efficacy of cardiopulmonary resuscitation (cpr) but uncertainty persists on its interpretation. we hypothesized that exhaled co may also by affected by occurrence of "lung airways" collapse previously noticed during cpr. because this closure may possibly also limit oxygenation + analysis of the entire exhaled co time waveform-may give information of high clinical value to manage cpr. we report preliminary results from a clinical and bench study aimed at describing the pattern of the capnogram during cpr. induces a systemic inflammatory response associated with an immune dysregulation and a significant pulmonary dysfunction which has been well characterized. surprisingly, there are only a few data available on immunological changes induced by ecls. we believe that ecls leads to immune dysfunction that could expose patients to nosocomial infections. patients and methods: a two-phase study was lead. first we analyzed blood cell count with differential (including lymphocyte, neutrophils and monocyte counts) in all patients who received ecls in our institution from to within the first week following ecls initiation. secondly, monocytes, granulocytes, dendritic cells and lymphocytes function were assessed at day , day and day using flow cytometry and functional tests in patients receiving ecls and compared to patients with cardiogenic shock without ecls. results: among patients with elcs we found an early and persistent lymphopenia and a late neutrophilia (found to be associated with poor outcome in critically ill patients). compared to control (n = ), we found in patients who received ecls (n = ) a significant increase in immature granulocytes ( . ± . on day one versus . ± ± , p = . ) and lymphocytes apoptosis. ecls induced changes in myeloid derived suppressors cells proportion ( . % ± . on day three versus . % ± . before ecls, p = . ), which has been recently associated with a higher incidence of nosocomial infections and seems to be major actors of sepsis-induced immune suppression. complement component a receptor (c ar) from the neutrophil cell surface, was also decreased after ecls initiation (ratio of mean fluorescence index . ± . on day one, p = . ) which is a sign of complement-induced neutrophil dysfunction in septic patients. conclusion: ecls induces quantitative and qualitative leukocytes dysfunctions that can lead to a greater susceptibility to nosocomial infections which contribute to the poor outcome observed in several studies. introduction: aspiration pneumonia is a common complication of cardiac arrest. although its real incidence remains undetermined, probabilist antibiotherapy is frequently or even systematically prescribed in these cases. we assessed the incidence of out-of-hospital cardiac arrest-related aspiration pneumonia and the impact of a microbiological documentation in regard to antibiotherapy course. patients and methods: all patients admitted for out-of-hospital cardiac arrest from to were studied. in our icu, aspiration pneumonia is suspected when a clinical syndrome (fever, per resuscitation constatation) and or chest radiography infiltrates were present. in case of suspected aspiration pneumonia, a microbiological documentation was performed before initiation of probabilist treatment with amoxicillin-clavulanate. we retrospectively defined if patients have aspiration pneumonia using the following criteria-per resuscitation constatation, chest radiography infiltrates, fever. the number of microbiological documentation leading to an antibiotherapy modification was recorded as well as pathogens types. data are expressed as numbers (%) and medians (interquartile range). statistical analysis was made as appropriate using the xlstat software. results: patients were studied. clinical characteristics are displayed in table . ( ) received a probabilist antibiotherapy and ( ) were retrospectively considered with aspiration pneumonitia. results of microbiological documentation were ( ) positive microbiological sample and ( ) with a positive threshold whose ( ) were considered colonized (i.e. no clinico-radiological sign). on the entire positive culture sample, ( ) were positive with oropharyngeal flora as unique pathogen, ( ) introduction: this study aimed to assess whether augmented renal clearance (arc) impacts negatively on piperacillin-tazobactam pharmacokinetic pharmacodynamics (pk pd) target attainment in critically ill patients receiving g day by continuous infusion. patients and methods: over an -month period, all critically ill patients treated by piperacillin-tazobactam for a suspected or documented sepsis without renal impairment were eligible. during the first three days of antimicrobial therapy, every patient underwent -hour creatinine clearance (crcl) measurements and therapeutic drug monitoring at steady state. the main pk pd outcome investigated in this study was the rate of empirical target non-attainment using a theoretical target mic of mg l − for piperacillin and mg l − for tazobactam. the secondary clinical outcome was the rate of therapeutic failure in microbiologically documented infections, defined as an impaired clinical response with a need for escalating antibiotics during treatment and or within days after end-of-treatment. over the study period, patients were included in the primary pharmacological analysis and in the secondary clinical analysis. using a mic of mg l − for piperacillin, the rate of empirical target non-attainment in the overall population was %, with a strong association with crcl ( fig. introduction: invasive fungal infections are a major burden in solid organ transplantation, especially in patients receiving liver graft. however, their incidence has decreased thanks to the development of an antifungal prophylaxis in the post-transplantation period. in patients at high risk of invasive fungal infection (ifi), this strategy is recommended, whereas its benefit remains controversial in low-risk patients. however, there is no clear definition of these two patients groups. our aim was to provide recent data on epidemiology, mortality and ifi risk factors in the early post-operative course in a population without any antifungal prophylaxis. results: the number of beta-lactam antibiotics was . of these requests, half were for piperacillin ( . %), and onethird were for amoxicillin ( . %). the other dosages were mainly for cloxacillin, cefepime, cefotaxime and ceftriaxone. the results confirmed that serum concentrations of piperacillin ( . ± . vs . ± . mg l − < . ) and amoxicillin ( . ± . vs ± mg l − < . ) significantly were higher in patients with neurological disorders or wakefulness delays. the roc curves allowed the predictive values associated with the presence of neurological disorders attributable to antibiotic treatment, corresponding to residual serum concentrations of piperacillin of mg l − and amoxicillin of mg l − . a predictive value for neurological disorders of these concentrations is proposed for residual serum concentrations greater than mg l − for both antibiotics ( % specificity and sensitivity). conclusion: our results suggest that there is an association between a residual concentration of piperacillin and amoxicillin greater than mg l − and the occurrence of neurological disorders. pharmacological therapeutic monitoring of beta-lactams in critically ill patients may be a useful intervention to optimize the antibiotic regimens and to avoid antibiotic-related toxicities. ( ) ( ) ( ) ( ) ( ) . patients with a gnb-bsi were included and were divided into two groups according to the resistance (r) profile (bsi due to a r isolate or not). the following resistances were considered-all gnb-bsi including pseudomonas spp., acinetobacter spp., stenotrophomonas spp. and enterobacteriacae (eb) for which the following antimicrobial resistances were considered-ticarcillin and ceftazidime (cefta) (pseudomonas (pa)), third generation cephalosporin ( gc) (eb) and imipenem (all gnb). after variable selection using random forest and univariable mixed logistic regression models, a multivariable analyses using a mixed model with a random effect (center). sub-group analyses were performed according to species (pa and eb) and resistance for eb. results: from , patients admitted in an annual median of french icus, experienced an icu-acquired (> h.) bsi, ( %) bsi due to gnb, including ( %) bsi due to r isolates. pa was identified in ( %) (mdr-pa bsis ( %)) and eb in ( %) (mdr-eb bsis ( ( %)). the raw mortality rate was % in the overall population and % in the patient with gnb bsi. it was significantly higher for r gnb bsi ( vs % for susceptible gnb bsi, p < . ). after adequate adjustment in a multivariate analysis, we showed that r-gnb bsi was significantly associated with mortality compared to susceptible strains (fig. ) . by considering species subgroup, the effect was not significant for resistant pseudomonas aeruginosa (p = . ) but remained significant when considering only eb. considering eb resistance, the impact of gc r showed a trend to an increased mortality risk whatever there was no effect of imi r (n = ( %)) on prognosis. limitation-the absence of information about antibiotic consumption may partly explain the remaining significant center random effect in the final models. conclusion: in a large french database, after adequate adjustment on prognostic factors, resistant bgn-bsi was associated with a higher icu mortality than susceptible one. the effect was mainly due to eb gc r. severely injured group versus . ± . days for the non-severely injured patients (p < . ). in multivariate analysis, heart rate (> min) and vittel score (≥ criterias) were related to the probability of belonging to the severely injured group (p = . ). the -hour mortality rate was . % in the ed and the -day mortality rate was . %. the development of a network in the ed hosting non vital polytraumas remains crucial. its primary goal will be to meet technical and time requirements and establish in-hospital triage algorithms based on clinical variables, in order to detect these patients at an early stage and offer them priority care in our overcrowded eds. introduction: the trauma of traffic accidents and particularly cranial trauma are, due to their frequency and severe consequences in both the short and long term, a real public health scourge on a global scale. studies of the epidemiology of cranial trauma by traffic accidents and their prognosis are rare at least in underdeveloped or developing countries. in addition, the impact of extracranial lesions on cranial trauma prognosis has long been discussed. the purposes of our study were to examine the epidemiological aspects and to determine the factors correlated to the immediate and distant prognosis of isolated cranial trauma. patients and methods: retrospective cohort spread over years (from to ) and including patients with isolated cranial trauma by traffic accidents (mean age . years, sex ratio- ). we proposed to study the factors correlated with a poor prognosis in terms of death in hospital and glasgow outcome scale (gos) at months unfavorable in dual analysis (univariate and then multivariate). for the gos study, patients were divided into groups-gos favorable for patients with good recovery (gos = ), recovery with a light handicap (gos = ), gos unfavorable for those having survived with a severe disability (gos = ), a vegetative or pauci-relational state (gos = ) and those who died (gos class ). results: hospital mortality was % and the gos at months was distributed as follows: death ( . %), vegetative state ( . %), severe disability ( . %), mild disability ( %) and good recovery ( . %). the -month gos was deemed unfavorable in . % of the cases. various after effects were observed in survivors: physical ( %) dominated by headache ( . %), sleep disorders ( . %) and epilepsy ( . %); memory disorders ( . %) or concentration ( . %) and finally emotional after effects ( . %) with irritability ( . %) and aggressiveness ( . %). in multivariate statistical analysis, independent predictors of mortality were arterial hypotension, hypoxia extradural hematoma (edh),, acute subdural hematomas (sdh), diffuse axonal injury and ventilator associated pneumonia. those correlated with an unfavorable gos were an age ≥ years, hypotension, cerebral edema, coma duration ≥ . days, edh and h glucose ≥ . mmol/l. conclusion: although the short-term prognosis of head trauma seems to be improved at present, the long-term consequences of cranial trauma remain fairly frequent, and often underestimated, which underlines the importance of their screening and their proper care. the average age of the survivors ( . ± . years) was lower than the mean age of the deceased ( . ± . ). ra was the cause of the trauma in % of the cases followed by the fall found cat % of the patients. prehospital care only concerned % of patients. the univariate analysis showed that the main factors of occurrence of death were age (p = . ), glasgow score (p = . ) anisocoria (p = . ), shock (p = . ) % of deaths were due to intracranial hypertension, haemorrhagic shock in % of patients and ards in % of polytrauma patients. conclusion: the management of polytrauma can not be improvised. the medical teams must be coordinated by an emergency physician in prehospital, a doctor anesthesiologist-resuscitator at the reception. some systematic gestures such as preparation of the reception allow to optimize the management of the time. introduction: benign cranial trauma is a major public health problem due to both its frequency and the health costs it creates. the aim of this study was to identify relevant clinical factors that could predict the achievement of brain ct and situations at risk for neurosurgical care and for which ct was a necessity. patients and methods: this is a month prospective study, including patients with benign traumatic brain injury (glasgow coma score gcs ≥ ), patients under years of age and patients with gcs < were excluded. epidemiological, clinical, paraclinical, therapeutic and evolutionary parameters were studied. a multivariate and univariate statistical study was carried out to reveal the predictive factors of a ct anomaly and the predictive factors for the neurosurgical care. data were entered and analyzed using spss . and excel software. results: the average age of patients was years with a predominance of male, and sex ratio of . . the cause of the btb was mainly represented by the accidents of the public road in . % of the cases. . % of the patients were asymptomatic, the most common symptomatology was dominated by the initial loss of consciousness ( . %), headache ( . %). the glasgow coma score was distributed as follows-gcs ( . %), gcs ( . %) and ( . %). . % of patients had clinical signs of trauma to the skulland or face. brain ct was performed in . % of patients, and . % had abnormal ct. the use of neurosurgical care was of the order of . %. in univariate analysis-the predictive factors for a ct abnormality were the intoxication during the brain trauma, the gcs < , signs of trauma in the skull face, the vomiting, the initial loss of consciousness, the comitial crisis and the predictive factors of neurosurgical care were the gcs < , the anisocoria, headache, the vomiting, the amnesia, the initial loss of consciousness, the comitial crisis, the anormal ct, the extradural hematoma or the subdural hematomat in multivariate analysis-the predictive factors for a ct abnormality were the gcs < , the initial loss of consciousness and the predictive factors for the use of neurosurgical care were the gcs < , signs of trauma in the skull face, the amnesia, the comitial crisis, the hsd. conclusion: an algorithm must be applied in collaboration between resuscitators and neurosurgeons to improve the quality of benign cranial trauma management. prognostic value of hyperchloremia in patients with traumatic brain injury: a prospective observational study taghouti introduction: background-traumatic brain injuries (tbi) are a major public health problem. they are the leading cause of death among those aged less than years. hyperchloremia is a common electrolyte disturbance in patients with tbi. hyperchloremia has been associated with increased morbidity and mortality in critically ill patients + however, its prognostic significance in tbi patients is poorly documented. the aim of this study is to describe the prevalence and outcomes of hyperchloremia in patients with tbi admitted to the intensive care unit. patients and methods: in a prospective design, we included consecutive patients with tbi ( males + median age- years) admitted to the icu in charles nicolle hospital of tunis from mars to september . adult patients (aged ≥ years) with isolated tbi or associated with minor extra-cranial injuries (defined as all non-head abbreviated injury scale < ) were included. hyperchloremia was defined as a chloride level > meg/l. clinical and laboratory variables were compared between survivors (n = ) and non-survivors (n = ). we assessed the association between hyperchloremia -h post-admission and -day mortality. p < . was taken to indicate statistical significance. results: the median sofa score at t was points and the median igs score was points. the median iss was points. there were cases of mild head injury, moderate head injury and severe head injury. the -day mortality was %. hyperchloremia occurred in patients ( %) and the incidence was significantly different between survivors and non-survivors ( vs. %, respectively, p < . ). in addition to hyperchloremia (p = . ), other laboratory variables were associated with -day mortality-hypernatremia (p = . ) and hypoalbuminemia (p = . ). conclusion: hyperchloremia -h post-admission was associated with -day mortality in patients with tbi. this index could be useful prognostic marker. efforts should focus on the prevention of hypernatremia and hyperchloremia in this vulnerable group of critically ill patients. child traumatic brain injury naili amine blida rp, algÉrie correspondence: naili amine -drnailiamine@yahoo.fr annals of intensive care , (suppl ):p- introduction: brain injury in children is common and mild in most cases, but it remains the leading cause of death and disability in children over year of age worldwide. the peculiarity of the child is that he possesses not mature brain and that the consequences of injuries acquired by traumatic brain injury can lead to the loss of capacities, as well as the non-acquisition of function, but above all the risk impact on learning abilities. the objective of the study is to define the incidence rate of cranial trauma in children as well as the mortality and morbidity of this scourge which presents a major public health problem. patients and methods: it is a descriptive retrospective study of a series of children hospitalized in neuro-resuscitation service during the period january to december , , including children admitted for cranial trauma. clinical, para-clinical, etiological and therapeutic data were collected from hospitalization records. results: in a series of children hospitalized during the defined period, children were admitted for cranial trauma, i.e. a frequency of %. the average age was years [ h of life- years], with a sex ration of among the children, had severe head trauma, a rate of % + whose causes are variable- road accidents, domestic accidents, traffic accidents, and obstetric accident, admitted with a pediatric glasgow score between and , and all required mechanical ventilation of the head trauma, were operated for different lesions- extra-dural hematomas, cranio-cerebral wounds, subdural hematomas, decompressive craniectomy, and embarrure. children had died following severe head trauma, i.e. a mortality rate of %, the morbidity rate of head trauma in the tipaza wilaya was . , children year, the average length of stay in intensive care units was days, with several complications of decubitus, and functional due to the primary and secondary lesions of the cranial trauma. the head trauma of the child is a public health problem, its functional prognosis can be dramatic when it is severe, its management must be early and multidisciplinary. introduction: the aim of the study was to identify factors predicting lung contusion in trauma children. patients and methods: retrospective study conducted for a period of years (january , -december , ) in a medical surgical intensive care unit. all trauma patients younger than years were included. two groups were compared-those with lung contusions (c + group) and those without lung contusions (c − group). results: we included patients. the mean (sd) age was . ( . ) years. chest injury was diagnosed in patients ( . %). all our patients needed mechanical ventilation. lung contusions were diagnosed in patients ( % of all patients and . % of patients with chest trauma). in multivariate analysis, independent factors predicting lung contusion were road traffic accident (odds ratio [or], . + % confidence interval [ci], . - . + p = . ), increased pediatric risk of mortality (prism) score (or, . + % ci . - . + p = . ), hepatic contusion (or . + % ci . - . + p = . ), and pelvic ring fracture (or, . + % ci . - . + p = . ). death occurred in patients ( . %). intensive care unit mortality was significantly higher in the c + group (or, . + % ci . - . + p = . ). however, mortality was not differentbetween the groups after adjusting for prism score (or, . + % ci . - . + p = . ) or after adjusting for injury severity score (or, . + % ci . - . + p = . ). conclusion: lung contusion is common in critically ill children with chest trauma. the diagnosis should be considered in patientswith road traffic accident, increased prism score, hepatic contusion, and pelvic ring fracture. introduction: chest trauma is often associated with pleural effusion (hemothorax and or pneumothorax). drainage of the pleural space by a chest tube is a common intervention in such situations. blunt dissection technique with a kelly clamp is preferred to classical trocar techniques to prevent severe complications, like perforation of thoracic or abdominal organs. despite these precautions, malposition remains the most common complication of tube thoracostomy. we investigated a new technique of bougie-assisted chest tube insertion to prevent chest tube malposition after chest drainage of post traumatic pleural effusion. patients and methods: we performed a controlled before-and-after study to assess the ability of a bougie-assisted chest tube insertion technique, compared to a standard blunt dissection technique, to prevent chest tube malposition. for the bougie-assisted group, we used a disposable eschmann-style bougie, commonly used to guide the endotracheal tube during difficult intubations. technique consisted in blunt dissection until the parietal pleura is opened. thoracostomy tube was preloaded onto the bougie and bougie was advanced alongside the finger, with apical or caudal direction after entering the chest cavity, depending on the type of pleural effusion. thoracostomy tube was then advanced forward utilizing a seldinger technique. the primary end point was optimal position of the chest tube. the tube position was blindly assessed on standard chest x-ray. in pneumothorax, optimal position was apical (above the aortic arch), and in hemothorax or mixed-effusion it was basal ( cm above the diaphragm or lower). results: a total of patients were enrolled (bougie-assistedn = + conventional-n = ). chest tubes were optimally position in ( %) in bougie-assisted group and ( %) in conventional group, or . , ic % = [ . - . ], p < . . efficacy of chest drainage (defined on chest x-ray as the absence of visible pleural line for pneumothorax and as a clear costophrenic angle for hemothorax) was assessed in ( %) in bougie-assisted group and in ( %) in conventional group, or . , ic % = [ . - . ], p < . . average procedure time was s ( % ci - s) for bougieassisted group and s ( % ci - s) for conventional group, p < . . no severe complication was observed in both groups. conclusion: bougie-assisted chest tube insertion technique prevents chest tube malposition, is safe, effective and shortens procedure time for the post traumatic pleural effusion drainage. introduction: infectious complications determine the prognosis of burned patients. however, the emergence of bacterial resistance to antibiotics threatens treatment efficacy, which is due to an inadequate antibiotic consumption inqualitative and quantitative terms. the objective of this study was to describe the profil of consumptionand susceptibility to antibiotics. and, to explore the predictive factors for theemergence of mrb in the service of burns and plastic surgery. patients and methods: it is a retrospective study including severe burnedpatients hospitalized for years in the plastic surgery department of theuniversity hospital ibn rochd from january to december . bacterialecology was described, and the distribution of the seeds by group, by species andby period of time was detailed. the ddd jh (daily defined dosage reportedin days of hospitalization) was used to assess the consumption of antibiotics. p correlation coefficients were calculated to explore the association betweenconsumption of antibiotics and the emergence of the bmr (multiresistantbacteria), and identified predictors of this emergence. results: on samples taken, bacterial and fungal strains were identified, with a predominance of p. aeruginosa ( . %), a. baumani i ( %) and s. aureu s ( %), the number of strains increased with the duration of the stay reaching itsmaximum from days in hospital. the ceftazidine ( . ddd dh), imipenem ( . ddd dh), and amikacin ( . ddd dh) were themost used antibiotics during our study, also + the profile of consumption increasedbetween and . bmr were isolated + the eblse were at the top ( . %) follow up of thecrpa ( . %), followed by the irpa ( . %) follow-up of the crab ( . %) then the irab ( . %) and finally the mrsa with a portion of . %. the profile of bacterial resistance has varied significantly for severalantibiotics bacteria pairs. conclusion: it remains difficult to show correlations between antibioticconsumption and bacterial resistance. however, these data are particularly usefulin the epidemiological surveillance of bacteria to better guide probabilisticantibiotic therapy. introduction: eclampsia is a rare but serious threat to maternal and fetal well-being. the aim of this study was to assess the incidence of eclampsia and its morbidity and mortality. patients and methods: we conducted a retrospective survey in a third level tunisian university teaching hospital from january to december . we included all patients with the diagnosis of eclampsia. results: in study period deliveries were registered. women with eclampsia were identified hence the incidence of eclampsia was . per deliveries. the median gestational age at the time of eclampsia was weeks. no maternal deaths due to eclampsia were recorded. the delivery mode was caesarean section in % of eclamptic patients. the recurrence of eclampsia despite magnesium sulfate prevention was observed in % of patients. severe complications of eclampsia were recorded in . % of patients- posterior reversible encephalopathy syndrome, acute pulmonary edema, and hellp syndrome. . % of new born were preterm. there were stillbirths and neonatal deaths. conclusion: the incidence of eclampsia was very high probably due to center effect. it's essential to raise awareness among mothers in the community regarding early signs and symptoms of preeclampsia eclampsia and to design a better tracking system for antenatal care program. introduction: to monitor maternal mortality which is an indicator of the quality of obstetrical care and anesthesia resuscitation, our country worked to set up several programs targeting maternal and child health. the aim of this work was-to evaluate the maternal mortality rate in our department and its evolution. to identify the cause of death and classify it depending on whether it is preventable or not. to spot the deficiencies either in the care management or the organization of the care system. to propose ways to improve our care and to fill the failures. patients and methods: it was a retrospective study about maternal death, performed at the department of gynecology and obstetrics, over a -year period (from to ) , that have reported cases of maternal death according to the world health organization definition. results: the maternal mortality rate (mmr) was . for every , live births. the average age of our patients was . years. the main risk factors for maternal mortality are unfavorable socioeconomic conditions, high-risk pregnancies, multiparity, primiparity and a poor follow-up of the pregnancy. the main causes of maternal death are represented by direct obstetric causes ( %) allocated as followspostpartum hemorrhage ( %), pregnancy toxemia ( %), acute fat hepatic steatosis ( %), infection ( %) and complications of anesthesia ( %). indirect obstetric causes were found in % of deaths. death was considered avoidable in . % of cases. conclusion: at the end of this work, we were able to pull several recommendations in order to reduce m.m.r. health education. facilitate access to care for the parturient, improve care and conditions of childbirth. continuous training of the medical and paramedical staff. introduction: mechanical ventilation can help improve the prognosis of sepsis. while adequate delivery of oxygen to tissue is crucial, hyperoxemia may be deleterious. invasive out-of-hospital ventilation is often promptly performed in life-threatening emergencies. we propose to determine whether the arterial oxygen pressure (pao ) at intensive care unit (icu) admission affects mortality at day (d ) in patients with septic shock subjected to mechanical out-of-hospital ventilation. patients and methods: we performed a monocentric retrospective observational study on patients with septic shock admitted to the icu. pao was measured at icu admission in patients subjected to invasive ventilation before any hospital admission. the primary outcome was mortality at day (d ). results: forty-nine ( %) patients with septic shock were mechanically ventilated before any hospital admission and transferred to the icu. the mean pao at icu admission was ± and ± mmhg for alive and deceased patients at d , respectively. pao was significantly associated with mortality at d (p = . ). using a roc curve, the corresponding auc was . [ . - . ]. for a pao > mmhg, the or for mortality at d was . [ . - . ] (p = . ), whereas for a pao < mmhg, the or was . [ . - . ] (p = . ). conclusion: in this study, we report a significant association between hyperoxemia at icu admission and mortality at d in patients with septic shock subjected to pre-hospital invasive mechanical ventilation. the adjustment of the pao is a crucial prognosis factor in patients with septic shock subjected to invasive out-of-hospital ventilation to avoid the toxic effects of hyperoxemia. however, blood gazometry is hard to get in a prehospital setting. consequently, alternative and feasible measures are needed, such as pulse oximetry, to improve the management of prehospital invasive ventilation. introduction: nowadays, benefit of enhanced ct-scan in positive diagnosis of acute pulmonary embolism (pe) is well established. it also allows evaluation of pe's burden on the right heart and shows several signs of acute cor pulmonale (acp). objectives -we aimed to assess benefits of control ct-scan h after thrombolysis in acute pe. patients and methods: we retrospectively enrolled patients with confirmed pe whom have been thrombolysed between january and august and controled with an enhanced ct-scan h after thrombolysis. assessement criteria were: qanadli obstruction index; signs of acp-right ventricle diameter left ventricle diameter (rvd lvd) and paradoxical interventricular septum (ivs). non inclusion criteria were: lack of initial or control ct-scan. results: during the study period ( years and months) we admitted patients from whom patients had acute pe ( . %). very severe patients that were thrombolysed as rescue therapy without initial ctscan and those who died before control ct-scan were not included. we enrolled patients-high risk mortality pe (n = , . %) and intermediate high risk pe (n = , . %). mean age was years and sex-ratio was . . at admission, mean severity scores were . ± . for saps ii and . ± . for apache ii. evolution criteria are listed in table . conclusion: control ct-scan is highly useful h after thrombolysis. it allows evaluation of response to pharmacological thrombolysis of acute pe and shows significative resolution of arterial obstruction degree and signs of acp. in december , after cancellation of the budget for a christmas tree, the nurses and caregivers of the night team spontaneously made and hung christmas decorations in our intensive care unit to make patients and their families feel better. the context was difficult with controversies around secularity. the town of paray le monial had been forced to remove a nativity scene and the city of melun had been criticized for setting one up. so we found it important to assess the perception of the approach by patients and relatives. patients and methods: decorations -hand-colored patterns about christmas theme printed on a paper decorations brought by the staff or already possessed by the unit-christmas balls, garlands, silver stardecorations made with service equipment-christmas tree consisting of inflated non-sterile gloves, cardboard, figurative nativity scene without a recognizable figure in a cardboard box with cotton, bed sheet to simulate snow. evaluation -all visitors and conscious patients received an anonymous single choice questionnaire with numerical scale and free fields from december th to december st, . results: answers were received, including-no negative opinion. neutral answer by a person who had not noticed the decorations. positive or extremely positive opinions. no answer without data. the comments pointed out the originality, the good idea, the warm comforting side. some asked for more decorations. others found them sober. the results show the good perception of the spontaneous action by the patients and their relatives. there was no negative response, particularly offend persons. however, it is possible that relatives or patients with negative opinions did not dare to express themselves. the initiative demonstrated a good cohesion of the night paramedical team, encouraging the interns and the day teams to take part in the coloring of the decorations. the initiative was initially aimed at the wellbeing of the patients and their relatives. however it has enabled an activity similar to preventing psychosocial risks among the healthcare team, allowing them to adopt a positive attitude in their approach to care. in addition, no significant costs were incurred thanks to the use of cheap materials, mainly recycled cardboard and standard quality white paper. the spontaneous decoration of our intensive care unit by the night care team was very well received by the patients, their families and their relatives. the initiative also made possible to enhance team cohesion and to value it. the associated costs were negligible. ventricular contractions. bp monitoring revealed a greater diastolic bp throughout h as well as during night-time. systolic bp higher than mmhg during sleep time was observed in % of participants. the frequency of arrhythmias and blood pressure variability are correlated with the increase in work stress and conflicts. conclusion: our results highlight the extent incidence of arrhythmia and blood pressure variability during intensive care unit night's shift probably due to the increased neuroendocrine stress response. ( %) and qrs enlargement ( %). ami was responsible for a significantly deeper coma (p < . ) but fewer seizures than clo (p = . ). three patients ( %) died. based on a univariate analysis, factors associated with death were cardiac arrest onset (p = . ), elevated plasma lactate concentration (p = . ), low arterial ph (p = . ), reduced pao fio ratio (p = . ) and prothrombine ratio (p = . ), increased aspartate aminotransferases (p = . ), alanine aminotransferases (p = . ) and serum creatinine concentration (p = . ) as well as marked catecholamine infusion rate (p = . ). the pharmacokinetic study showed significant increase in ami ( h vs. h) and clo ( h vs. h) elimination half-lives in overdose compared to pharmacological conditions, highlighting the contribution of organ failure to the delayed elimination of both toxicants. conclusion: ami and clo poisonings did not disappear and are still responsible for significant morbidities and mortality. ami was responsible for deeper coma with fewer seizures in comparison to clo. ami and clo elimination half-lives were significantly prolonged in overdose due to organ failure. introduction: severe poisonings and fatalities have been attributed to buprenorphine (bup) despite its ceiling respiratory effects, mainly if abused in co-ingestion with benzodiazepines. we previously showed that diazepam (dzp) bup combination induces severe respiratory depression in the rat, while each drug by itself does not. the objective of this study was to investigate the mechanisms involved in this drug-drug interaction using c-bup pet imaging and diaphragmatic electromyography in the sprague-dawley rat. patients and methods: c-bup was administered intravenously, mg kg unlabeled bup intraperitoneally and mg kg dzp subcutaneously. pet acquisition started with c-bup pet injection, min after dzp or its vehicle (veh + n = group) administration. suv normalized time activity curves (tacs) were generated and c-bup binding potential [bpnd, i.e. the ratio of the total receptor density (bmax) on the equilibrium dissociation constant (kd)] were modeled in different brain regions using a simplified reference tissue model with cerebellum as reference region. dem, implanted under anesthesia days before the experiment, was recorded during min in rats receiving veh veh, dzp veh, veh bup or dzp bup (n = group). after filtering and half-wave rectification, the first min auc of diaphragm contraction and workload were determined and compared between the groups. results: tacs and c-bup bpnd were not different between the dzp bup and the veh bup groups in all studied brain regions. diaphragm contraction was significantly increased in the veh bup group in comparison to the dzp bup group (p < . ). diaphragm workload was significantly increased in the veh bup group in comparison to the dzp veh and the dzp bup group (p < . and p < . respectively). discussion: dzp did not affect the c-bup brain distribution and brain binding suggesting that dzp does not affect bup transport across the blood brain barrier and bup receptors density affinity. bup administration induced an increase in diaphragm contraction and workload. this increase was inhibited in the presence of dzp suggesting that dzp bup combination-induced respiratory depression is mostly related to dzp. conclusion: respiratory depression related to dzp bup combination results from a pharmacodynamic drug-drug interaction. introduction: since the banning of dextropropoxyphene from the market, overdoses and fatalities attributed to tramadol, a who step- opioid analgesic, have increased markedly. tramadol overdose results not only in central nervous system (cns) depression attributed to its opioid properties but also in seizures, possibly related to nonopioidergic pathways, thus questioning the efficiency of naloxone to reverse tramadol-induced cns toxicity. our objective was to investigate the most efficient antidote to reverse tramadol-induced seizures and respiratory depression in overdose. patients and methods: sprague-dawley rats overdosed with mg kg intraperitoneal (ip) tramadol were randomized into four groups to receive solvent (control group), diazepam ( . mg kg ip), naloxone ( mg kg intravenous bolus followed by mg kg h infusion) and diazepam naloxone combination. sedation depth, temperature, number of seizures and intensity, whole-body plethysmography parameters and electroencephalography activity were measured. for each parameter, we compared the areas under the curves using mann-whitney tests for two-by-two comparisons between the four groups. regarding the effects of treatments on seizures, comparisons were performed using two-way analysis of variance followed by multiple comparison tests using bonferroni's correction. results: naloxone reversed tramadol-induced respiratory depression (p < . ) but significantly increased seizures (p < . ) and prolonged their occurrence time. diazepam abolished seizures but significantly deepened rat sedation (p < . ) without improving ventilation. diazepam naloxone combination completely abolished seizures, significantly improved rat ventilation by reducing inspiratory time (p < . ) but did not worsen sedation. based on the eeg study, tramadol-treated rats experienced electro-clinical seizures as soon as min after the injection, characterized by spike-waves and polyspikes with progressive decreased frequencies and inter-critical phases of slow delta waves until the next crisis. after diazepam naloxone injection, eeg waveforms consisted in hz-alpha rhythms and slow-down theta rhythms of drowsiness. none of these treatments significantly modified rat temperature. conclusion: diazepam naloxone combination is the most efficient antidote to reverse tramadol-induced cns toxicity. our experimental data greatly encourage administering this combination rather than naloxone alone as first-line antidote in tramadol-poisoned patients as an alternative to tracheal intubation. introduction: rubigine ® poisoning is a medical emergency that causes a major public health problem in underdeveloped countries, as it is frequently fatal. this poisoning is rare in france, but frequent in the french overseas departments (dom). the rubigine ® , made of fluoride and used as a rust remover, is the main source of poisoning in the caribbean. in martinique, the exact incidence of this intoxication is unknown, as there is no national and regional register. it could represent up to - % of severe acute poisoning. it was not until april that, following a prefectural order on the declaration, classification, packaging and labeling of substances, the composition of rubigine ® was modified to significantly reduce the mortality induced by its ingestion. the objective of our study was to describe the clinical features and complications that can occur after ingestion of rubigine ® as well as to determine the prognostic factors of death. we conducted a retrospective study over years, from to , including all patients admitted to emergency and intensive care units of the university hospital center (martinique) for acute rubigine ® poisoning. the usual demographic and clinical data were collected and comparisons between surviving and deceased patients were performed using a univariate analysis. results: fifty-five patients (mean age- years ( - ) + sex ratio male female- , ) were hospitalized at the university hospital of martinique. one-quarter of patients had no significant history. the average length of stay was . days ( - ). forty percent of patients experienced hypocalcaemia after initial intravenous calcium supplementation. complications included acute respiratory failure requiring invasive mechanical ventilation ( % of patients, duration of ventilation- . days, ( - )), renal failure ( %, of which % required extrarenal treatment, hemodynamic failure ( %), hepatic failure ( %), coagulation failure ( %), neurological failure ( %) and multi-visceral failure ( . %). three patients presented cardiogenic refractory shock requiring va ecmo ( . %) and another patient with digestive perforation ( . %). the mortality was . %, allowing the identification of prognostic factors of death. conclusion: rubigine ® poisoning is responsible for significant morbidity and mortality, despite optimal management. however, its incidence seems to have decreased sharply in recent years thanks to the strong mobilization and awareness of the population following the implementation of an information system by the university hospital 's clinical toxicology and toxico-vigilance unit, and different preventive measures introduced by the health authorities. introduction: since dextropropoxyphene withdrawal from the market, overdoses and fatalities attributed to tramadol, a who step- opioid analgesic drug, have increased markedly. besides central nervous system depression, tramadol overdose may result in seizures, usually included in the related serotonin syndrome. however, the serotoninergic mechanism of tramadol-induced seizures has been recently questioned. we investigated the effects of various specific pretreatments on tramadol-induced seizure onset and alterations in brain monoamines in the rat. patients and methods: sprague-dawley rats were randomized into five groups (n = group) to be pretreated with various agonists antagonists before receiving mg kg tramadol intraperitoneally- . mg kg ip diazepam + mg kg iv bolus followed by mg kg h infusion naloxone + mg kg ip cyproheptadine, and mg kg ip fexofenadine. seizure severity was graded according to the modified racine score ( ). we measured neurotransmitter concentrations in the frontal cortex using high performance liquid chromatography coupled to flurorimetry or radioenzymatic assay, as required. we used positron emission tomography-computed tomography to investigate interactions of tramadol with gaba-a receptors. the effects of treatments on seizures were compared using two-way analysis of variance followed by multiple comparison tests with bonferroni's correction. the areas under the curves of the effects on monoamine concentrations and the binding potentials in the pet-imaging study were compared two-by-two using mann-whitney u tests. results: diazepam abolished tramadol-induced seizures, by contrast to naloxone, cyproheptadine and fexofenadine pretreatments. interestingly, despite seizure abolishment, diazepam significantly enhanced tramadol-induced increase in the brain serotonin (p < . ), histamine (p < . ), dopamine (p < . ) and norepinephrine (p < . ) while no significant modifications were observed with the other tested pretreatments. based on positron emission tomography imaging using c-flumazenil fixation in the rat brain, we demonstrated molecular interaction between tramadol and γ-aminobutyric acid (gaba)-a receptors not related to a competitive mechanism between tramadol and flumazenil on the benzodiazepine binding site. our findings clearly ruled out the involvement of serotoninergic, opioidergic, histaminergic, dopaminergic and norepinephrinergic pathways in tramadol-induced seizures while strongly suggested tramadolinduced specific allosteric change in gabaa receptors that could contribute to seizures onset in overdose. conclusion: tramadol-induced seizures in overdose are mainly related to the gabaergic pathway. introduction: heparin-induced thrombocytopenia (hit) is a serious iatrogenic complication of heparinic treatments. the diagnosis of hit is difficult in the resuscitation environment because thrombocytopenia is a frequent and multifactorial phenomenon. the aim of this work was to study the clinical and biological presentation of patients with hit and the consequences attributable to hit on the evolution of patients in terms of morbidity and mortality and to develop a diagnostic strategy for hit for resuscitation patients. this was a retrospective, monocentric, descriptive and evaluative study conducted in our intensive care unit (icu) over a period of years months. an anti-pf antibody test was performed in patients who developed thrombocytopenia or a % drop in their initial platelet kinetics and the clinical picture. results: the incidence of hit was . % in patients hospitalized in icu. the clinicobiological severity scores, the reasons for admission to resuscitation were similar in both groups (hit+ and hit−) as well as the characteristics of the heparins used. the time of occurrence of thrombocytopenia was similar in the two groups. the diagnosis of hit was more often the only plausible diagnosis in the hit+ group. the t's score was significantly higher in the hit+ group. the evolution of the platelet count was similar in the two groups, in the decay phases as well as in the recuperation phase. hit+ patients showed significantly more thrombosis than hit− patients. there was no significant difference between the transfusion needs of hit+ and hit− patients. mortality was identical in both groups, as was the length of stay in icu. conclusion: hit is a rare disease. there was no evidence of a predisposing factor for the occurrence of the disease in a uniform resuscitation population. the diagnosis of hit is based on a cluster of arguments and not on an isolated event. biological tools are indispensable, in a complementary way to the clinical picture. pulmonary embolism in patients with sickle cell disease in intensive care unit: a challenging diagnosis jamoussi amira , zayet souheil , merhebene takoua results: during the study period, a total of patients with scd were admitted. among them, presented with respiratory distress and chest pain and then benefited first of trans-thoracic echocardiography that often showed right ventricle dilation and systolic pap > mmhg (n = ). all the patients underwent enhanced ct-scan and the diagnosis of pe was finally retained in cases ( . %) and hence colliged. the average age was . years ± . [ - years] with a sexratio = . the mean of apach ii score was . scd were diagnosed at the age of . years ± . [ - years] with a regular follow up in %. the reason for admission was acute respiratory failure in all cases. patients had clinical symptoms of pneumonia: pleuritic chest pain (n = ), dyspnea (n = ) and fever (n = ). all patients had a chest x-ray showing an alveolo-interstitial syndrome in cases ( . %) and an associated pneumonia in cases ( introduction: acute chest syndrome (acs) is the most severe complication of sickle cell disease and its evolution is unpredictable. acute pulmonary hypertension (ph) in acs is associated with an increased mortality, but its mechanism remains poorly known. our hypothesis is that acute ph is associated with a biological state of hypercoagulability in acs. in a prospective single center study, all consecutive scd patients with acs admitted to the intensive care unit (icu) of tenon hospital were included. specialized haemostasis dosages were performed on icu admission. a trans-thoracic echocardiogram was also performed on admission, and was repeated at steady state. results: among patients with acs, had a trans-thoracic echocardiogram and had a high echocardiographic probability of acute ph, including patient with bilateral pulmonary embolism and patient who developed multiple organ failure and died. there were no significant clinical, biological or radiological differences between patients with a low-intermediate probability of acute ph and those with a high probability of acute ph+ their evolution was similar. the exploration of haemostasis did not show between-group differences, regarding each parameter of haemostasis. however, when using a hierarchical cluster analysis, distinct profiles of coagulation were evidenced, defining biological classes. the subset of patients with a high echocardiographic probability of acute ph was more frequent in biological classes and which corresponded to hypercoagulability states. acute ph was transient in patients (n = ) with a repeated echocardiography at steady state. conclusion: acute ph may likely occur in patients with acs and a biological condition of hypercoagulability. further studies are needed to confirm these findings. gorham julie were the two independent predictors of survival after hospital discharge. in lung cancer patients admitted into the icu, the mgps is an independent predictor of survival after hospital discharge but not for mortality during icu stay. this inflammatory score could therefore be used as a long-term prognostic marker in this population of patients and would be more reflective of cancer, than reflecting the acute complication leading to icu admission. prospective and multicentric studies must be carried out to validate these results. introduction: recombinant active factor vii is a pro-hemostatic treatment used in obstetric haemorrhage, but no study has made it possible to specify its exact place in the decision algorithm. the objective of our work is to evaluate the efficacy and the benefit risk ratio of recombinant factor viia in the treatment of severe postpartum hemorrhage. we conducted a prospective study at the ibn jazzar university hospital in kairouan during the period from january , to december , . in total, we collected cases of recombinant factor viia in one postpartum haemorrhage. results: the mean age of our patients was + . years. the rate of childbirth was . %. the caesarean was the mode of delivery chosen for patients. the causes of postpartum haemorrhage in our series were-uterine atony in cases, uterine rupture and cervicouterine tear cases each, retroplacental hematoma and placenta accreta cases for each two and placenta praevia in cases. our patients were treated in an intensive care unit and the average hospital stay was . days. sulprostone was reported in cases ( . %), and all patients received a massive transfusion. the average time to administer rfviia was h min. the mean dose of factor vila recombinant was . ± . μg kg. five patients received a single dose, patients received a second injection and patients received doses. clinical efficacy-after a single injection, clinical efficacy with reduction in bleeding was observed in patients, i.e. %. the most frequent complication was insufficiencyrenal in cases including requiring hemodialysis, civd in cases, oap in cases, a multivisceral failure in cases, a septic shock in case and a mesenteric infarction in case. the progression was favorable in patients, while patients died ( . %). conclusion: it is important that new studies be carried out and shared experiences around the world on this drug appear to be effective and prevent invasive actions in the therapeutic arsenal of postpartum heamorrhage. introduction: post-partum haemorrhage (pph) is a life-threatening complication and remains a leading cause of maternal morbidity worldwide. the woman trial* estabished that early administration of tranexamic acid (ta) reduces mortality due to the bleeding in women with pph. our study purpose was to determine the effects of early administration of ta and fibrinogen concentrate on death, hysterectomy and transfusion in women with severe pph. patients and methods: this retrospective, monocentric study was performed in a third level tunisian hospital providing healthcare for more than pregnant women per year. were included in this study women with diagnosis of severe post partum haemorrhage after a vaginal or caesarean delivery from to . patients who received ta and fibrinogen concentrate were assessed in group (g ) and who not in group (g ). results: the incidence of severe pph was / deliveries. women were retained for data analysis g (n = ), g (n = ). anthropomorphic and obstetrics characteristics were not significantly different between the two groups. there was a significant difference between the two groups regarding to transfused units of red blood cells however, no difference in term of the use of frozen plasma and platelets concentrates was observed. perioperative hemoglobin nadir was significantly higher in g . the frequency of hysterectomy and pelvic packing were higher in g (table ) . no thromboembolic events and no haemorrhage related mortality were observed in the two groups. conclusion: in this retrospective study, early administration of tranexamic acid and fibrinogen reduces risk of hysterectomy transfusion. these encouraging results strongly support the need for a large, international, double-blind study to investigate the potential of the association "ta-fibrinogen concentrate" to reduce maternal haemorrhage related morbidity and mortality. introduction: immunodeficiency, acquired or congenital, is the first comorbidity associated with poor outcome in pediatric patients with acute respiratory distress syndrome (ards). the aim of this study was to describe outcome of pediatric patient with hematologic disease hospitalized in our intensive care unit for respiratory failure and to investigate the clinical variables associated with mortality. patients and methods: it was a retrospective monocentric descriptive study including all immunodeficient pediatric patient (malignant hemopathy, congenital immunodeficiency, bone marrow transplanta-tion…) from hematology hospitalized in our beds pediatric intensive care unit with the diagnosis of respiratory failure between january and february . results: fifty one patients were included corresponding to admissions. nighty percent of the patients met criteria for pediatric ards- % were severe, % moderate and % mild. extracorporeal circulation (ecc) was needed for patients. global mortality rate at picu discharge was %. twenty four patients ( %) received noninvasive ventilation (niv). height of them ( %) did not need invasive mechanical ventilation (imv). in patients who received imv, mortality rate was significantly higher if patients received before niv ( vs. %) p = . . all patients who needed imv after more than h of niv died (n = ). mortality was higher in children with griffon versus host disease ( vs. % p = . ). mortality of patients receiving ecc and renal replacement therapy (rtt) was respectively and %. conclusion: in our study, most of the patients hospitalized for respiratory failure met criteria for pediatric ards. if niv decrease imv requirement, it could be associated with higher mortality rate in case of failure. this result support recent recommendation that immunodeficiency is not a sufficient criteria to delayed imv. . flow and airway pressure were recorded at the asl inlet and mouth pressure into the manikin mouth. we defined "device driving pressure" as the peak mouth pressure minus the tele-expiratory mouth pressure. continuous data are reported as mean ± sd. results: as compared to the oxygen mask, vt increased significantly with m-niv and h-niv whatever the simulated respiratory effort ( ± and ± vs. ± ml respectively with the moderate simulated effort, p < . ; fig. ). hfnc and cpap were associated with a slight but non-significant decrease in vt as compared to the oxygen mask. overall, for a given respiratory effort, vt was influenced by the "device driving pressure", which tended to decrease when using hfnc and cpap and markedly increased with m-niv as compared to the oxygen mask. therefore, vt in m-niv with a simulated low effort was significantly higher than vt in cpap and hfnc with a simulated moderate effort ( ± ml, ± ml, and ± ml respectively, p = . for both comparisons). conclusion: in our bench model, the vt value was significantly influenced by the noninvasive ventilatory device. niv was invariably associated with significantly higher vt than with other devices, even when dividing by two the simulated inspiratory effort during niv. introduction: in icu, intubation is a high risk procedure associated with high morbidity. despite procedure's improvement with systematic application of fluid loading, early use of vasopressors and checklist use, morbidity remains high. several recent trials has been conducted with different metrics choose as primary outcome. however any evidence exists to choose one more than another: time to intubation, first pass success, difficult intubation. first pass success sine hypoxia and hypotension (dash- a) has been highlighted recently and choose by the game program without any scientific evaluation. we conducted a post hoc analysis of the randomized clinical trial macgrath mac video laryngoscope or macintosh laryngoscope for intubation in the intensive care unit (macman) to determine the best metric to choose for primary outcome for the next intubation studies in icu. patients and methods: macman was a multicentre, open-label, randomized controlled superiority trial. consecutive patients requiring intubation were randomly allocated to either the mcgrath mac videolaryngoscope or the macintosh laryngoscope, with stratification by centre and operator experience. an only inclusion criterion was-"patients must be admitted to an icu and require mechanical ventilation through an endotracheal tube". patients were excluded if-contraindication to orotracheal intubation (e.g., unstable spinal lesion) + insufficient time to include and randomize the patient (e.g., because of cardiac arrest) + age < years + pregnant or breastfeeding woman + correctional facility inmate + patient under guardianship + patient without health insurance + refusal of the patient or next of kin to participate in the study + previous enrolment in a clinical randomized trial with intubation as the primary end point (including previous inclusion in the present trial). post-hoc analysis was performed to assess association and prediction of life threatening complication (mild to moderate, severe, mild to severe) by different metric existing-time to intubation, first pass success, difficult intubation, first pass success sine hypoxia and hypotension. each metric was compared with another one. area under curve was built for every metric and all metrics were then compared. results: dash- a was superior to all others metrics included in the analysis for prediction of life threatning complications (all p < . ). failure of first pass conclusion: all metrics are not equal to predict severe life threatening complications during intubation in the icu. in this context, we recommend adoption of definitive airway sine hypoxia or hypotension at first attempt (dash- a) as primary outcome for intubation studies in the icu or as metric indicator tracked in quality improvement program. benbernou soumia introduction: introductionacute respiratory failure (arf) is a common cause of emergency use and one of the major reasons for admission to intensive care unit. it associates a vital risk imposing immediate symptomatic treatments and an etiological approach. [ ] among the etiologies of the arf, acute lung edema (ale), decompensation of chronic obstructive pulmonary disease (copd), chest trauma and pneumonia are the most frequent @it is a life-threatening pathology with a high incidence of mortality, since mortality is reported to be - % [ , ] for arf secondary to cardiogenic ale. the prevalence of arf in algeria remains unknown + the tahina study showed that respiratory diseases were the leading cause of consultation in the hospital [ ] . the the objective of this study is to estimate the frequency of use of the niv and to determine the associated factors of failure of the niv for the adult patients hospitalized for arf in the emergency department of oran hospital from january to november . prevalence of copd was found in the . % of tobacco subjects [ ] . the number of patients hospitalized for chest trauma continues to increase, resulting in an increase in the number of patients admitted for arf secondary to chest trauma. patients and methods: this is an observational and exhaustive study during the month of november, from the files of patients. the population-all subjects over years hospitalized for an arf at the reception and resuscitation units of the emergency department of oran hospital from january to november . results: ninety-seven patients were hospitalized for arf during this period. niv was used for patients. patients were acute lung edema. univariate analysis showed that spo was the only failure factor in this series. the failure rate of this technique was . %. niv is a technique that should be used more in the emergency rooms, which would make it possible to use less intubation specially in indications where the level of proof in the literature is important. demographic characteristics, etiology of exacerbation, comorbidities, the sapsii score, arterial blood gases at admission, respiratory, hemodynamic and neurological parameters, use of noninvasive or invasive ventilation, nosocomial infection, duration of niv, length of stay and mortality. results: during period study patients ( % women with a sapsii score ± ) were included. the etiology of exacerbation was bronchitis in % of cases and pneumonia in %. only patients have niv at home and patients have oxygen. pseudomonas aeruginosa was isolated in cases. twenty percent of the patients had developed a nosocomial infection, acinetobacter baumanii and pseudomonas aeruginosa were isolated in and % respectively. niv was used in patients at admission and the rate of niv failure was %. the duration of mechanical ventilation was ± days and the length of stay was ± days. the mortality was %. niv and oxygen at home were prescribed for patients. in univariate analysis survivors and non-survivors were comparable regarding baseline and clinical characteristics. nosocomial infections ( vs. %), and spassii score were significantly more elevated in non-survivors. in emergency department, the management of hypercapnic acute respiratory failure with hfo is limited. hypercapnia and acidosis remain moderate. patients are old with comorbidities. the mortality rate is high but expected given the number of limitation of active therapy. hfo appears to be effective for a majority of patients, but half of them required niv too. the niv hfo association seems an interesting option. but our methodology is perfectible and would require a randomized control tria. severe chronic obstructive pulmonary disease with chronic respiratory failure in intensive care unit: mortality and prognostic factors arnout chloé , faure morgane , novy emmanuel chu nancy, nancy, france correspondence: arnout chloé -arnout.chloe@gmail.com introduction: last decades, the number of patient with chronic respiratory failure due to chronic obstructive pulmonary disease (copd) admitted in intensive care unit (icu) increased. data about their real prognosis in the icu are lacking. the objective of this study was to evaluate mortality rate at months and to identify prognostic factors of copd patients with chronic respiratory failure, treated with long term oxygen therapy (ltot), admitted in icu. patients and methods: a retrospective cohort study was conducted in the french university hospital of nancy during years - on all copd patients treated with ltot admitted in icu. only the first admission was analysed. patients were included if they had spirometry, blood gas and oxygen flow in the year before admission in icu. other causes of chronic respiratory failure, and patients with tracheostomy before icu admission were excluded of the cohort. hospitalizations were selected using the international classification of diseases, th revision (icd- ). results: one hundred and thirteen patients were included, ( %) died in the first months after icu admission. mortality rate in icu was %. severity of copd was-mean bode score ± . , number of exacerbation per year requiring hospitalization ± . . ltot was used for . ± . years. acute respiratory failure was the main frequent cause- % pneumonia, % acute exacerbation of copd, % acute lung oedema. the sequential organ failure assessment score within the first h of icu admission was ± . need for mechanical ventilation was noted in % of cases and was associated to mortality with an odds ratio of . (ci % [ . - ] p = . ). in presence of other organ failure, mortality rate tends to increase. patients with median pao fio ratio > on first blood gas had a reduced risk of death (or . + ci % [ . - . ], p = . ). conclusion: this is the first study to assess mortality at month of patients with severe copd requiring ltot admitted in icu. severity of hypoxemia and use of mechanical ventilation are two prognosis factor of mortality. the addition of another organ failure seems to increase the mortality rate. severity of the chronic respiratory insufficiency less influenced short and long term outcome. this data have to be included in the global decision to admit a copd patient with ltot in icu. introduction: the remarkable progress in the outpatient care of the asthmatic patient (development and access to inhaled drugs) has made the admission of these patients exceptional in the icu. we have noticed a recent upsurge in asthmatic afmissions in the icu, and are investigating whether this fact was related to modifiable factors (access to adapted drugs) or an increase in the severity of the disease. patients and methods: retrospective, observational, three-center study conducted in three tunisian medical icu from january to july, . were included all consecutive patients admitted for severe acute asthma in three icus. were assessed-patient's demographic characteristics, asthma severity and its actual control based on global initiative for asthma classification (gina) , clinical characteristics of the acute episode, length of icu stay, ventilatory free days and mortality. results: out of the patients admitted within the study period, ( %) had severe acute asthma. the mean age was years (iqr - . ). sex ratio was . asthma was allergic in % with an average ancienty of . years. over all asthma was not very severe with no prior icu admission for acute severe asthma . % were mechanically ventilated at least one time. were classified severe and moderate persistant asthma respectively in . (%) and (%). . % were consideredpoorly controlled. low educational level and socio-economic status are the main determinants of poor control- % of analyzed patients didn't have a social care, and thus no accesse to prescribed anti-asthmatics + % didn't have a regular follow up and . % were jobless. when admitted to the icu- patients ( . %) needed invasive mechanical ventilation, one patient received niv. the mean length of stay was days (iqr . - . ). levels of auto peep and pic pressure at icu admission were respectively (iqr - ) and . (iqr , - . ) cm h o. mortality rate was %. this study suggests that low educational level and socioeconomic status (especially the lack of social care and joblessness) are the main determinants of poor control of asthma and may lead to the increase of rate of icu admission for severe acute asthma requiring mechanical ventilation. introduction: in emergency medicine, the boussignac system (bs) is sometimes used to administer oxygen and continuous positive airway pressure (cpap). in this case, fio value depends on the ratio between o flow and inspiratory flow (if). in some cases, the fio decreases due to the if increase. the aim of this study was to test a modified boussignac system in order to limit the fio decreases during inspiratory flow rate increases. the study was conducted on bench with bs connected to a two compartment adult lung model (dual test lung ® ) (dtl) controlled by a maquet servo i ® ventilator. three minute ventilation (mv- . . l min) with ti ttot = . were investigated. fio and mv measurements were made using an iworx ® ga gas analyzer. with a bs, two peep were analyzed- and cm h o. the bs was supplied by an o flow. in order to increase the fio , we have evaluated the addition of a t piece connected to a nebulizer at the air-room admission of a bs. the aerosol was supplied by an o flow of l min. the o flow was analyzed in continuous with a calibrated mass flow meter (red y vogtlyn ™ ). results: when mv increases, the fio decreases (p < . ). when peep increases, fio increases too (p < . ). the addition of an aerosol (o - l min) to a bs increases the fio (p < . ). however, in this last case, the gap between both fio decreases with increases mv (fig. ) . the addition of an aerosol connected to an o flow rate ( l min) at the entry of a bs limits the fio decreases during the mv increases. introduction: burned patients are at high risk of yeast colonization and thus of invasive fungal infections, particularly to candida (c.) spp., leading to an increase in morbidity and mortality. while pre-emptive antifungal therapy has improved survival, it may lead to an increase in antifungal resistance. the objectives of this work were to describe candida species distribution and to determine the antifungal susceptibility of candida isolates acquired in a burn unit. our study is a retrospective review of severely burned patients admitted to the burn unit of the ben arous traumatology and burns center with one or more positive culture sites for candida, during the -month period from may through august . a total of isolates were thus obtained. the susceptibility to antifungal drugs ( -fluorocytosine, fluconazole, ketoconazole, micronazole, itraconazole, amphotericin b) was determined using the fungitest ® broth dilution method for patients with infected normally sterile body sites or a candida colonization index superior or equal to . . since echinocandin and anidulafungine were recently introduced in tunisia, the susceptibility to these antifungal classes was tested for only one patient from our cohort. results: nasal and buccal sites were the most colonized body sites ( . % each), followed by axillary ( . %) and rectal sites ( . %) and urines ( . %). c. albicans was the predominant species ( . %), followed by c. glabrata ( . %), c. tropicalis ( . %) and c. parapsilosis ( . %). among the strains whose antifungal susceptibility was determined, majority of candida isolates were susceptible to fluconazole ( . %), which is the most frequently used molecule as a pre-emptive treatment in such cases in tunisia due to its availability and its efficiency. on the other hand, . % of the isolates were intermediate and . % were resistant to this antifungal drug, mainly c. glabrata for both groups. as for the other tested azoles, high rates of intermediate strains were noticed ( . % to itraconazole, . % to ketoconazole and . % to miconazole), mostly c. glabrata. only one strain was resistant to amphotericin b, which is not usually used in these cases due to its nephrotoxicity and the frequency of kidney failure in burned patients. our study demonstrates that c. albicans is the most frequent species in burn unit-acquired candidiasis. no major antifungal resistance was observed, apart from high rates of intermediate strains (mainly c. glabrata) to azole class antifungal drugs. introduction: infection, especially bacteremia, is a major cause of morbi-mortality in severely burned patients. mortalityrelated to bacteremia in burn patients was about % [ ] . we performed this study to determine the prevalence, the causative agents and outcomes of bacteremia in burned patients. introduction: carbapenems, the last line of therapy, are now frequently needed to treat nosocomial infections, and increasing resistance to this class of β-lactams limit antibiotic options in critically ill patients especially in burns. the objective of our study was to assess the impact of the detection of carbaménépases in optimizing treatments in burned. patients and methods: a prospective, monocentric study was carried out at the intensive care unit of burn in tunisia over months (march-august ). were included all patients who have had a carbapenemase research. the sample was carried out by rectal swab. all samples were analyzed by polymerase chain reaction (pcr) methods for presence of carbapenemase. during the study period, patients were included. the mean age was ± years. they were men and women. the average burned surface area was ± %. patients were transferred from another hospital structure in % of cases with a delay of h. % of patients had a septic complication with a delay of ± days. antibiotic treatment was empirical in cases. the therapeutic failure rate was %. results of carbame-nepases detected by pcr are detailed in table . in the group of patients pcr (+), the antibiotic treatment was changed in cases. the most association of antibiotics were-tigecycline in combination with colistin or in combination with fosfomycine and fosfomycin in combination with colistin. this leads to reduce therapeutic failure by %. conclusion: detection of carbapenemase in our study was higher ( %), allows us to identify regions with high risk of carbapenemase, improve therapeutic efficacy and strengthen infection control measures by isolation of all carbapenemase producing patient. introduction: icu-acquired bacteraemia is prevalent and poses a grave threat. providing information about the main causative bacterial agents and determination of their susceptibility to antibiotics may improve empiric therapy and early detection of emerging antimicrobial resistance. the aim of this study was to investigate the species distribution and antibiotic susceptibility of isolated strains from blood culture in burn intensive care unit during a five-year period. patients and methods: from january to december , a total of , non repetitive strains were isolated from blood cultures. incubation of blood culture vials and the detection of bacterial growth were performed by the bactec system. all isolated organisms were identified on the basis of standard microbiological techniques. antibiotic susceptibility testing was carried out by the agar disk diffusion method, and susceptibility results were interpreted using clinical breakpoints according to ca-sfm and guidelines. data were analyzed using the sir-system. minimum inhibitory concentrations of colistin, imipenem and vancomycin were determined using the etest ® method (biomérieux). results: of the , strains isolated, the most frequently identified species were staphylococcus aureus ( %), acinetobacter baumannii ( %), klebsiella pneumoniae ( %), and pseudomonas aeruginosa ( %). the rate of methicillin-resistant staphylococcus aureus (mrsa) was %. resistance to tigecycline and linezolid was and %, respectively. all strains were susceptible to glycopeptides. in addition, isolated acinetobacter baumanii strains showed high rates of resistant to all tested antibiotics except colistin. eighty per cent of these strains were resistant to ceftazidime and % to imipenem. resistance to rifampicin was % in , and has increased steadily to % by . similarly, high resistance rates were observed among klebsiella pneumoniae and pseudomonas aeruginosa to ceftazidime ( and % respectively), ciprofloxacin ( and %) and imipenem ( and %). conclusion: this study investigated on the local distribution patterns of causative organisms of bacteraemia in burn patients and the corresponding antimicrobial susceptibility profiles. multidrug-resistant pathogens, especially mrsa and acinetobacter baumanii, were the most frequently isolated organisms. hygiene measures and antimicrobial stewardship should be implemented to prevent the spreading of these resistant strains. introduction: pseudomonas aeruginosa is known opportunistic pathogen frequently causing serious infections in burned patients. multidrug resistance in this pathogen is increasing throughout the world and is a major problem in the management of these pathogens. analysis of serotype and resistance profile to antobiotics of p. aeruginosa help to establish a prompt control and prevention program. the aim of this study was to evaluate the frequency of antimicrobial resistance and the prevalence of pseudomonas aeruginosa serotypes isolated in the burn unit. patients and methods: during a period of years (from to ), strains of pseudomonas aeruginosa were isolated from burned patients. conventional methods were used for identification. antimicrobial susceptibility testing was performed with disk diffusion method and susceptibility data were interpreted according to breakpoints recommended by the french society of microbiology (fsm). serotypes were identified by slide agglutination test using p. aeruginosa o antisera (biorad). the imipenem-resistant strains have benefited from a research of carbapenemase production by the edta test. results: in our study period, bacterial isolates were found among which pseudomonas aeruginosa was the second most frequent bacterium isolated from burned patients ( %) after staphylococcus aureus ( %). the most frequent sites were-cutaneus infection ( %), blood culture ( %) and catheter ( %). the most prevalent serotypes were-o ( %), o ( %), o ( %), o ( %) and o ( %). the survey of antibiotic susceptibilily showed high pourcentage of resistance to the different antibiotics- % of strains were resistant to ceftazidim, % to ticarcillin, % to ciprofloxacin, % to amikacin and % to imipenem. among the imipenem resistant strains, % were metallo-beta-lactamase producers. the antibiotic to which p. aeruginosa was the most susceptible was colistin ( %). multidrugresistance was associated with o serotype in % of the cases. the global frequency of serotypes o , o and o was more than %. multidrug resistance and carbapenemase being associated with serotype o . serotyping of the strains isolated from burned patients will help to guide the first antibiotherapy. the dissemination of carbapenemases strains must be contained by implementation of timely identification, strict isolation methods and better hygienic procedures. and respiratory disorders ( . %)…). the therapeutic management was based on per operative resuscitation, organ failure treatment, probabilistic antibiotic therapy and median laparotomy surgery. the main etiologies of abdominal sepsis were-digestive perforations ( . %), purulent effusion ( %), intestinal necrosis ( %), cholecystitis ( . %). the bacteriological profile was -predominance of bgn ( . %) dominated by e. coli ( %) followed by klebsiella pneumoniae and acinetobacter baumanii ( . %), the mean duration of the hospitalization was . ± . days. the mortality rate was %. the main prognostic factors in our study in univariate analysis were-the advanced age, the diabetes, the organ failure, the increased gravity scores, the time to management, the use of catecholamines and the development of septic shock. the multivariate analysis showed a statistically significant association between the development of septic shock, the stercoral effusion, the peptic ulcer perforation, the operator and the therapeutic descalation. the abdominal sepsis is a serious affection, with great mortality. the improvement of its prognosis is based on a revision of the medical and surgical protocols, and an adapted antibiotic therapy depending on the direct examination of the samples, also of the bacterial ecology of the service. introduction: severe acute respiratory infections (sari) are common in critically ill patients. viruses can be found in immuno-competent patients. however, the main problem for viral infections is the diagnosis, isolation of the pathogen is often difficult and the symptoms not specific. the aims of this study were to describing the epidemiological characteristics of viral respiratory infections, to identify factors predictive of a poor outcome. introduction: in septic shock there are physiological changes with an increase in the volume of distribution, with implications for pharmacokinetics of antibiotics that make recommended doses potentially inadequate for target organisms with highest minimal inhibitory concentrations. to cover these bacteria, peak serum concentration (cmax) target is - pg ml. identification of predictive factors for insufficient cmax, in common practice, would make it possible to target the patients at risk in order to optimize dosage of antibiotic to be administered. objective of this study was to determine predictive factors of amikacin's cmax insufficient independently of the dosage. patients and methods: this was a retrospective study carried out between august and november in icu of our hospital. all adult patient receiving an initial injection of amikacin between and mg kg were included. clinical data collected were-amikacin dosage, body mass index (bmi), mechanical ventilation (mv), mean arterial pressure (map), use of noradrenaline and continuous hemofiltration (cvvh). biological elements were collected and for each, the last result in the h prior to admission and that at the patient's entry into icu were added to analysis. a comparison of this clinical and biological variables was made between two groups-the first one with an ineffective cmax of amikacin (< pg ml) and the second with an effective cmax of amikacin (> pg ml). results: patients were selected for statistical analysis. median dosage was . mg kg for a median cmax at . mg l. for patients, cmax was less than mg l and in patients, it was greater than mg l. there was a statistically significant relationship between a cmax greater than mg l and mv, bmi, pct measured before and after admission, albumin after admission, hemoglobinemia, hematocrit level after admission, the rate of urea after admission (table ) . a low bmi was associated with cmax < mg l. discussion: these results remain comparable to those found by taccone in , with dosages of mg kg having only % of the peaks above mg l + comparable also to montmollin's study in . conclusion: mv, bmi, pre-and post-admission pct, and albumin, hemoglobin after admission, hematocrit and urea after admission seems to be predictive criteria for insufficient amikacin's cmax independently of dosage. our study was limited to one icu, a heterogeneous recruitment, and that all samples have been taken at the right time. introduction: this study aimed to assess whether augmented renal clearance (arc) impacts negatively on ceftriaxone pharmacokinetic pharmacodynamics (pk/pd) target attainment in critically ill patients receiving g day by intermittent infusion. patients and methods: over an -month period, all critically ill patients treated by ceftriaxone for a first episode of sepsis without renal impairment were eligible. during the first days of antimicrobial therapy, every patient underwent -hour creatinine clearance (crcl) measurements and therapeutic drug monitoring at trough concentrations. the main outcome investigated in this study was the rate of empirical target non-attainment using a theoretical target mic of mg/l. results: over the study period, patients were included ( samples analyzed for therapeutic drug monitoring). the rate of pk/pd target non-attainment was %, with a strong association with crcl (p < . ) ( table ). there was no statistical association between pk/ pd target non-attainment and therapeutic failure. conclusion: when targeting %ft > mic of the less susceptible pathogens, patients with crcl > ml/min are at risk of subexposure in ceftriaxone ( g day). these data emphasize the need of therapeutic drug monitoring in patients with arc, especially when targeting less susceptible pathogens or surgical infections with limited penetration of antimicrobial agents. introduction: the septic shock is a major concern of the intensive care unit in the world because of its frequency and especially of its mortality which remains high in spite of the progress made in the optimizing care. the aim of our work is to analyze the prognosis factors related to death among patients with septic shock in the icu of the military hospital avicenna of marrakesh, and to focus on the physiopathological and therapeutic data of the septic shock in the light of last acquisitions in this field. patients and methods: we proceed to a prospective study including all patients with septic shock at admission to icu or secondary, over a -year period (january -december ). prognosis factors related to death in patients with septic shock were studied in univariate and multivariate analysis. results: eighty-six cases of septic shock were collected from icu admissions, the incidence is . %, the mean age was ± . . the sites of infection most often involved were the abdomen and lung ( %), there was a predominance of gram-negative bacilli, the number of organ failure is in average . ± . . the overall mortality was . %. prognosis factors related to mortality retained after logistic regression are cardiovascular organ failure followed by neurological. indeed, the number of patients with or more failures was ( %) in the group of patients who died. as the second factor influencing the high mortality found severity score . ± . , age is also considered a prognosis factor since of patients were over years. the average age of the deceased was ± years versus ± years in survivors (p < . ), yet the mortality according to the infectious agent was not found as factor influencing mortality (p = . ). conclusion: septic shock is a frequent reason for hospitalization in icu. the improvement of prognosis requires an early and adapted management of sepsis as well as increases efforts for control and prevention of nosocomial infection. introduction: vitamin d deficiency is common in critically-ill patients. in addition to its role in the regulation of phosphor-calcic metabolism, vitamin d is of paramount importance for the immune system. the aim of the current study is to assess the prognostic value of vitamin d deficiency in patients with septic shock. patients and methods: retrospective study conducted over months. all the adult patients with septic shock and vitamin d level screening performed within the first h of admission were included in the study. we excluded patients with chronic kidney disease and those receiving vitamin d supply. two groups were compared: those with a serum vitamin d level < ng/ml (g ) and those with higher level (g introduction: since immunity plays a central role in neoplasms surveillance, it is likely that sepsis induced immune dysfunctions may impact on the underlying malignancy. we developed a research project investigating the reciprocal relationships between bacterial sepsis and cancer. we reported that sepsis-induced immune suppression promoted tumor growth in post-septic mice inoculated with cancer. in a reverse cancer-then-sepsis model we observed that sepsis may conversely inhibit tumor growth. this study aimed at investigating the cellular and molecular mechanisms of sepsis-induced tumor inhibition, and most especially the role of monocytes macrophages and toll-like receptor (tlr) signaling. patients and methods: we used c bl j wild-type (wt), tlr -/-, tlr -/-and myd -/-mice. mice were first subjected to tumor inoculation by subcutaneous injection of mca fibrosarcoma cells. fourteen days after, mice were subjected to polymicrobial sepsis induced by cecal ligation and puncture (clp). controls were cancer mice subjected to sham surgery. alternatively, cancer mice were subjected to an i.p. challenge with tlr agonist (lps or heat-killed staphylococcus aureus (hksa)). the distribution of tumor-associated immune cells was assessed by facs at days and following surgery. the activation status of tumorinfiltrating monocytes macrophages was assessed by facs (mhcii, cd , cd , pdl , pd ). f / + cells were purified by facs and we assessed cytokines production (rt-qpcr) and bacteria phagocytosis. we confirmed polymicrobial sepsis dampens tumor growth in wt mice. a similar clp-induced tumor growth inhibition was observed in tlr -/-mice, but neither in tlr -/-nor myd -/-mice. a challenge with lps resulted in a marked anti-tumoral effect, whereas a challenge with hksa had no impact on tumor growth. tumor-infiltrating immune cells analysis retrieved monocytes/macrophages predominance with two different subsets based on f / expression (f / high and f / low). late-onset (day ) tumors from clp-operated mice displayed increased proportions of f / high. as compared to f / low cells, f / high cells displayed a more immature status with a lower expression of cd , mhcii and pdl , and a higher phagocytic activity. interestingly, f / high cells from clp-operated mice exhibited a higher phagocytic activity than those from sham-operated mice. conclusion: polymicrobial sepsis drives a potent antitumoral activity in cancer mice, which is associated with changes in the distribution and functions of tumor-associated monocytes macrophages subsets. our results converge on a critical role of tlr signaling, that should be further investigated. conclusion: post-agressive immunosuppression in icu is not specific to sepsis. in septic shock, the low counts in circulating ilc s could be explained by ilc plasticity (conversion of these cells into ilc s), by migration from the blood or by an exacerbated apoptosis. ilc s expansion, associated with a higher risk of secondary infection, could be promoted by il- , released by tissue injuries. ilc s could activate regulatory t cells via il- . these preliminary results must be confirmed on a larger cohort. they play a suppressive role in the immune system by the secretion of negative regulatory cytokines such as interleukin- or by immune cell contact inhibition. the objective of this pilot study was to develop and test a protocol to determine the breg level in septic patients. the level of breg were measured on whole blood sample by flow cytometry the first day of hospitalisation in septic patients. b cells were identified on the single-parameter expression cd combined with scatter. the breg were identified as subpopulation expressing cd /hicd hi or cd /hicd + (see fig. ). the results were expressed as percentage of the parental lineage gate and absolute value per microliter. this protocol has been optimised in order to be able to transfer technic into clinical practice. results: we include patients hospitalized in intensive care unit with severe sepsis or septic shock. the percentage of cd + cd hic-d hi was . ± . % with a mean of . ± . cells microliter. the percentage of cd + cd hicd + was . ± . % with a mean of . ± . cells microliter. we are able to measure and follow the evolution of breg during severe sepsis or septic shock. because breg could inhibit body immune function, we wish to conduct a prospective study to evaluate the correlation between breg level and the prognosis of patients with sepsis. the neutrophil/lymphocyte ratio (nlr) reflects an inflammatory state. the nlr has recently emerged as a prognostic marker in colorectal cancer patients, acute coronary syndrome and pulmonary embolism (kayrak m, heart lung circ ). the aim of this study was to assess the prognostic value of nlr in patients with septic shock. we performed a prospective observational study in septic shock icu patients within h of admission from january to july in charles nicolle hospital of tunis. exclusion criteria were age < years, pregnancy + oncohematological patients, recent blood transfusion, post-cardiac arrest and brain-death. nlr was measured soon after admission and h, h, and h after. demographic, clinical and biochemical parameters, severity scores, life-support therapies (vasopressors, ventilation), and length of icu stay were recorded. the primary endpoint was -day mortality. results: sixty-five patients ( males, median age, . years) with septic shock were included in the study. the -day mortality was %. the median sofa score at t was points and the median igs score was points. the sources of infection were as follows: the lungs (n = ), the urinary tract (n = ), the central nervous system (n = ), the abdomen (n = ), skin and soft tissue (n = ). the parameters that were identified through univariate analysis to be associated with -day mortality were igs score, lactate level, the nlr elevation at h , h and h . median nlr levels were significantly higher in non-survivors (n = ) than survivors ( introduction: the autonomic nervous system (ans) is highly adaptable and allows the organism to maintain its balance when experiencing stress. heart rate variability (hrv) is a mean to evaluate cardiac effects of ans activity and a relation between hrv and outcome has been proposed in various types of patients. we evaluated the feasibility of a automated hrv monitoring, based on standard electrocardiography monitoring, and investigated the different parameters that should be recorded. this project is based on a prospective physiological tracing data-warehousing program (rea stoc, clinicaltrials.gov # nct ) that aims to record more than icu patients over a -years period. patients and methods: physiological tracings were recorded from the standard monitoring system (intelliview mp philips), using a dedicated network and extraction software (synapse v , ltsi inserm u ) that enables simultaneous recording of different physiological curves, at their native resolution ( hz for ecg, hz for other). raw data were subsequently stored on a dedicated local server, before anonymization and analysis. all consecutive patients were recorded for a -hours period during the -hours following icu admission. all measurements were recorded with the patient laying supine, with a ° bed head angulation. physiological recordings were associated with metadata collection by a dedicated research assistant. hrv parameters were derived from electrocardiography monitoring using kubios hrv premium ( introduction: acute cor pulmonale (acp) is a frequent complication of acute respiratory distress syndrome (ards). it occurs in % of cases and might be associated with an increased mortality rate. it is defined by a ratio of telediastolic surfaces of right ventricular (rv) on left ventricular greater than . and a septal dyskinesia. however, systolic dysfunction defined by the guidelines of the american society of echocardiography has not been well studied in ards and in particular concerning the rv free wall longitudinal strain (rv-fw-ls). the aims of the present study were to identify the prevalence of rv systolic dysfunction and acp in ards, and to evaluate the effects of inhaled nitric oxide (noi) and prone positioning. we prospectively included patients to a mild to severe ards, and proceeded to standardization of ventilation and systematic echocardiography in semirecumbent position, with noi and in prone position. interpretation of examination was blinded to the investigator. we evaluated the presence of acp, systolic dysfunction identified by classical cardiologic criteria (rv fractional area change, rv tei index, tricuspid annular plane systolic excursion, velocity of the tricuspid annular systolic motion) and also by rv-fw-ls. results: sixteen patients were included. thirty-seven percent of patients were in severe ards. the prevalence of acp was % while right ventricular systolic dysfunction was identified in . % of patients with the classic cardiologic criteria and . % with the impairment of rv-fw-ls which represented the most sensitive test for right ventricular dysfunction detection (table ) introduction: the use of extra corporeal membrane oxygenation (ecmo) is increasing. brain complications may occur, resulting in an increased morbidity and mortality. the objective of our study was to analyze the incidence of neurological complications while receiving ecmo, the risk factors, and to describe morbidity and mortality in a large cohort of patients in intensive care unit. patients and methods: this was an observational, mono-centric, -year retrospective study in patients who received ecmo. primary outcome was the occurrence of neurological complication until d after ecmo. results: one hundred and eight patients were included in the analysis. twenty-seven patients ( %) presented a neurological complication. of these, died at d . there were ischemic sequelae ( . %), intracranial haemorrhages ( . %), cerebral edema ( . %) and one other lesion ( . %). the median time before occurence of a neurological complication was days after the implementation of ecmo. multivariate analysis revealed the presence of hyperlactatemia > . mmol l, neurological deficit at the beginning of the management, as well as the history of stroke before the ecmo implementation as predictive factors of neurological complication (or . , . the incidence of neurological complications under ecmo is about % and ischemic sequelae are the most frequent. history of stroke and low cerebral flow associated with ischemia-reperfusion seem to increase the occurrence of these complications and must lead to greater vigilance in these patients. - ] . eighteen patients ( %) survived at icu discharge with a good neurological outcome. by multivariate logistic regression analysis, female sex, initial shockable rhythm, and pre-ecmo arterial blood ph ≥ . were independent predictors of survival with good neurological outcome. all of the patients presenting with cpc score of or at icu discharge had a shockable rhythm and or ph ≥ . before ecls implantation. % of the patients presenting with these criteria had a good neurological outcome at icu discharge. all of the patients presenting with non-shockable rhythm and ph < . before ecls implantation died in the icu. conclusion: about one third of the patients presenting with shockable rhythm and or ph ≥ . before ecls implantation had a good neurological outcome at icu discharge. on the contrary, all of the patients presenting with both non-shockable rhythm and ph < . before ecls implantation died in the icu. these simple parameters might help to identify cardiac arrest patients which could benefit from ecls implantation. radjou aguila introduction: the decrease of lung volume is a keystone for the management of patients under mechanical ventilation in intensive care units. this procedure has not only led to a reduction of morbimortality in ards but also in all patients mechanicaly ventilated in intensive care units as well as in major surjery. nevertheless, the incidence of high volume (vt) on morbimortality is extremely variable (about to %). our main objective is to assess the incidence of high volume ventilation (> ml/kg predicted body weight, pbw) in our hospital intensive care units. moreover we were interested in determining the risk factors of high volume ventilation. we conducted a retrospective observational study from january to march in three intensive care units of a tertiary university hospital. all patients ventilated under sedation in vac mode during the h after admission were included in the study. of the patients admissions during the period, one of them ( %) have no height mentioned in their medical file and were exluded. among the patients considered, ( . %) were ventilated with high vt (fig. ). % of patients had a positive expiratory pressure ≥ cmh o. in multivariable analysis, height (smaller) and weight (lower) are the only associated factors with a high volume ventilation (p < . and p = . , respectively). discussion: the observed incidence on high vt patients is higher than that reported in most papers in literature (jaber et al. %, hess et al. %) . nevertheless, both studies were conducted in operating room with higher vt cut-off ( ml/kg). walkey and al showed that % of patients in ards were ventilated with vt › ml/kg of pbw. moreover, the same associated factors (smaller height and lower weight) have found in the study. older studies revealed higher bmi as factor to high volume ventilation. this difference could be explained by the use of predicted body weight. conclusion: although the growing literature and the recommandations aim to reduce the lung volume between to ml/kg of pbw, still one third of the patients in intensive care units are ventilated with too high lung volume. (fig. ). with either a nc overlap on one nostril or not. results: when the mv increases, the fio decreases. when the mouth opens, the fio decreases. when the prongs are overlapping one nostril the fio decreases slightly (mean ± % in absolute value). statistical differences were found between closed and open mouth and between overlap on one nostril and not (p < . ), except between tmo and cm at two mv ( and l/min) when nc overlap on one nostril (fig. ) . conclusion: when the prongs of nc are not correctly placed in the nostrils, the fio decreases, but this impact is limited in our bench study. the impact of mv increases and mouth opening on the fio values is also important. introduction: the weaning of mechanical ventilation is an essential and delicate phase in the management of a resuscitation patient. the neurosurgical patient presents a number of specific problems, such as impaired control ventilatory control, coughing or the pharyngo-laryngeal intersection. however, it often allows short-term ventilatory withdrawal in the neurosurgical patient, probably largely by the simple fact that it authorizes the definitive cessation of sedation. the objective of the study and demonstrate the place of tracheotomy in neuro-resuscitation patients, and prevent its complications. a retrospective descriptive study of patients hospitalized in the neuro-resuscitation unit during the period january to december , of which patients benefited from surgical tracheotomy, is a frequency of % of all inpatients during this period. clinical, para-clinical, etiological, and therapeutic data were collected from hospitalization records. in a series of hospitalized patients, during the defined period, patients had surgical tracheotomy, a frequency of %, in the literature two studies or the data were extremely variable, with % in the study namen versus . % in the coplin study. of the tracheotomies, were performed by neurosurgeons, and by resuscitators at a frequency of %. the tracheotomy was performed on average days after the intubation of the patients, after verification of the impossibility of the extubation of the latter either for central affection of the ventilatory controls, or reached the mixed nerves and disorders of the laryngo-pharyngeal intersection and according to expert recommendations in -tracheotomy should not be performed in the intensive care unit before the fourth day of mechanical ventilation. different pathologies that patients suffered and required tracheotomy were: post-operative complications of brain tumors (brain stem and mixed nerves) with patients, a rate of %, vascular pathologies (stroke and cvt)), with patients ( %), traumatic pathologies, with patients ( %). cases, %, cases of secondary bleeding of the orifice, cases of tracheal stenosis, and case of tracheomalacia. the decan made after pharyngolaryngeal neurological examination, and according to sfar recommendations experts suggest that a multidisciplinary decanulation protocol available in resuscitation departments. conclusion: tracheotomy in neuro-resuscitation has its place, especially in view of the different complications specific to this type of patient, but no study has demonstrated its improvement in vital prognosis. post-tracheotomy complications can be considerably reduced if the protocols and expert recommendations are applied. introduction: noninvasive ventilation (niv) in intensive care (icu) is associated with the occurrence of frequent asynchronies related to the leaks around the interface, mainly auto-triggering and delayed cycling. their detection requires a respiratory muscles activity monitoring. diaphragmatic ultrasonography is a simple imaging technique available at bedside to assess diaphragm motion. whether diaphragmatic ultrasonography would allow detecting asynchronies due to leaks during niv is unknown. the aim of this study was to assess two methods of diaphragmatic ultrasonography (excursion and thickening), coupled with the airway pressure signal to detect patient-ventilator asynchronies during niv. patients and methods: nine healthy subjects were placed under niv and subjected to intentional inspiratory and expiratory leakage on the ventilator circuit to generate delayed cycling and auto-triggering, respectively. the flow, airway pressure and diaphragmatic electromyogram were collected in order to identify the asynchronies generated by the leaks. in the meantime, an ultrasound recording of the excursion of the right diaphragm and of the thickening of the right diaphragmatic zone of apposition were performed and combined with the display of airway pressure on the ultrasound screen. these records were analyzed a posteriori to define the diagnostic performance [including sensitivity (se), specificity (spe), positive predictive value (ppv), and negative predictive value (npv)] of the excursion and the thickening to detect asynchronies. the experimental setup generated a median of asynchronies per subject (interquartile range - ). auto-triggering was correctly identified by continuous recording of both excursion (se = %, spe = %, ppv = %, and npv = %, fig. a ) and thickening (se = %, spe = %, ppv = %, npv = % + fig. c ). delayed cycling was detected with a slightly lower performance by diaphragm excursion (se = %, spe = %, ppv = %, npv = % + fig. b ) and thickening (se = %, spe = %, ppv = %, npv = % + fig d) . discussion: these encouraging results may be tempered by a variable effectiveness of the technique from one subject to another, in particular concerning the excursion. moreover, their generalization to critically ill patients may depend on several factors including echogenicity, stability and amplitude of the ultrasound signal in this population. conclusion: ultrasound is a simple clinical tool available at the bedside to detect delayed cycling and auto-triggering associated with niv leaks, provided that the airway pressure curve is displayed on the screen of the ultrasound machine. further studies are needed to assess its usefulness in detecting other types of asynchronies and its feasibility in critically-ill patients. introduction: although extra-corporeal co removal (ecco r) is not recommended, strong rational supports the concept. we aimed to describe our single-center experience of ecco r in the setting of mild to moderate acute respiratory distress syndrome (ards) and chronic obstructive pulmonary disease (copd). we performed a retrospective case note review of patients admitted to our tertiary regional intensive care unit (icu) and commenced on ecco r from november to august . demographic data, physiologic data (including ph and partial pressure of carbon dioxide in arterial blood [paco ]) before ecco r starting, and at day were recorded. results: twenty one patients received ecco r. thirteen were managed with hemolung ® device, seven with prismalung ® and one with ila ® . indication for ecco r were copd exacerbation (n = ), mild to moderate ards (n = ), uncontrolled hypercapnia due to pneumonia (n = ), and hypercapnia due to bronchial compression by mediastinal adenopathy (n = ). before starting ecco r, median minute ventilation, ph and paco were respectively . [ . , . conclusion: our observational cohort shows that ecco r therapy is effective to reduce paco and improve ph in the settings of mild ards and copd exacerbation. however, early weaning of sedation and pressure support ventilation might limit the decrease of respiratory rate and tidal volume. introduction: duchenne muscular dystrophy (dmd) is an x-linked recessive genetic disorder, caused by mutations in the dmd gene. respiratory failure is classical in the natural history of this disease. little is known about the diaphragm echographic pattern and the spectrum of patients with diaphragmatic paralysis in this disease. we aimed to assess the relationship between age and diaphragmatic motion and thickening fraction (tf) and to characterize the spectrum of patients with diaphragmatic paralysis. patients and methods: we included retrospectively dmd patients who experienced diaphragmatic echography and spirometry in our institution. diaphragmatic paralysis was defined as a diaphragm with tf < %. results: dmd patients were included in this study. all dmd patients were wheelchair bound. dmd patients had severe respiratory insufficiency with a median vc at % of predicted value [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . . % of patients were on home mechanical ventilation (hmv) and % were invasively ventilated. right diaphragmatic motion at deep inspiration was severely altered with a median of . mm [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . right tf of the diaphragm was severely altered with a median of . % [ . - . ] . . % of patients disclosed a paralyzed diaphragm pattern with a right tf < %. the age was inversely correlated with tf of the diaphragm (r = - . , p . ) and with the right diaphragm inspiration motion (r = − . p < . ). patients with diaphragm paralysis were older with median age at . years [ - . ], with severe respiratory impairment (median sitting cv = %) and median cumulated annual hmv duration at . years. conclusion: in dmd, age is inversely correlated with diaphragm function. diaphragm paralysis is frequent in older adult non-ambulant dmd. . the final probability model included the previous identified factors in addition to age and saps ii score, this model exhibited good calibration (hosmer-lemeshow x , p = . ) and good discrimination (roc-auc, . + % confidence interval, . - . ) (fig. ) . conclusion: our cohort study identified risk factors of icu death, mainly collected at admission among patients with aecopd. the proposed probability model has a good performance in predicting the short-term prognosis. further evaluation in other cohorts is needed. introduction: precarity is a complex notion including several components, and its definition is still debated. it is more subtle than financial poverty alone, and can increase population's health insecurity. we hypothesize that patients with precarity features may have different epidemiologic characteristics and icu outcomes than the general population. the aim of this study was to describe precarity features and outcomes of patients admitted to an icu located in a high poverty rate territory. patients and methods: we conducted a prospective single-center observational study of all patients admitted to icu of the saint-denis general hospital, from february to july . precarity features were classified in categories-absence of health insurance, lack of incomes or minimum allowances, homelessness or social home or hotel, and social isolation (no social link, or associations or neighbors). others social data were collected (speaking fluent french and education level) as well as usual clinical icu data. results: among patients included, precarity features were found in patients ( . %). income precarity was the most common, followed by accommodation precarity, health precarity and relation precarity (table ) . precarity was not associated with hospital mortality ( vs. . %, p = . ). all types of precarity were significantly associated with each other. precarious patients were younger ( vs. years-old, p < . ) and had less comorbidities. we found no differences concerning hospital or icu length of stay ( vs. days, p = . ) or concerning education level between precarious patients and the others. conclusion: our pilot study shows that precarity features are indeed very frequent and are often cumulated. with respect to the small patient sample, precarity does not seems to be associated with hospital mortality or length of stay. further investigations with larger patient samples and multicenter designs are warranted to investigate properly the impact of precarity on icu management and outcomes. introduction: population aging is a global and expanding phenomenon. elderly people are particularly vulnerable, and often need health care. this demographic evolution also affects intensive care units, and years old patient are now frequently admitted-it corresponds to % of admission in france. indeed we have analyzed the change in management of this very elderly people ( years old and more) over the past years in a french medical intensive care unit in a provincial university hospital. patients and methods: a retrospective cohort study was conducted using medical intensive care unit registry for demographic, physiological and diagnostic data from january to december . characteristics and treatment intensity during medical icu stay were specified, and short term and long term mortality were also recorded. results: a total of admissions, including octogenarians and older, were registered during the period. the proportion of very elderly people gradually increase from to %. intensity of treatment (organ support) increased from . from . per patient between the primary and the second part of the period, notably linked to mechanical ventilation ( vs. %, p < . ) and vasopressor infusion ( vs. %, p < . ). even if severity score increased (saps increase from . to . , p < . ), the icu mortality remains constant ( vs. . %). however, we were surprised to observe an increase in year mortality ( to %, p < . ). conclusion: between and , proportion of admission of very elderly people has increased two fold in our icu. although treatment intensity increases for more severe patients, icu mortality remains the same. nevertheless, absence of beneficial effect after year remains questioning. could icu to ward transfers and care course after hospital be optimized? lived alone at home, % in couple or with ther family, ( %) in retirement home and ( %) in nursing home. ( %) had a simplified ald score lower than indicating good functional independence. the more frequent diagnosis were acute pulmonary oedema and exacerbated copd. the mean simplified acute physiology score (saps ii) was ± . the treatment were were invasive mechanical ventilation ( %), only with noninvasive ventilation ( %), vasopressor agents ( %) and ( %) with renal replacement therapy. the average length of stay was . ± . days. after adjustment on sap-sii (without age), those invasive treatments were not associated with mortality no more than age. global mortality rate was %. ( %) were subject of a procedure for limiting therapeutics, among which ( %) died in the unit versus % for the other patients. the decision of therapeutic limitation was associated with severity of illness as measured by the sapsii (p = . ) but not with age. frequency of therapeutic limitation were similar in icu and intermediate care units. the mortality rate is lower than the older studies (s de rooij - %). unlike the study of p. biston ( ) which covers only the most serious cases, the mortality for any type of gravity remains reasonable. the procedure for limiting care were frequent especially for the most severe pathologies but all the patients who a decision of limiting care were stated were not dead. the patients over years old admit in french icu are very chosen. any major treatment appear to enhance mortality. introduction: due to advancements in medical technology and management of illnesses, an increasing proportion of critically ill patients are elderly. few information is available on the prognosis of these patients after icu discharge. the aim of this study was to analyze the clinical characteristics and long-term outcomes of elderly admitted to icu. patients and methods: monocentric, observational prospective study was performed. all elderly survivors (aged ≥ years) after an icu stay in a medical tunisian icu between january and december were included. data collected were: clinical features at admission, acute management procedures, functional characteristics and vital parameters (blood pressure, heart rate, abg's) at icu discharge. patients were followed during year via phone calls. a multivariate regression analysis was used to identify risk factors for one-year mortality. results: during the two-years study period, elderly patients were discharged alive. ( . %) were male. clinical features of elderly survivors were: mean age, . ± . years, median of charlson index, [ - ], chronic respiratory disease, ( . %), hypertension, ( . %) and diabetes ( . %). the most common reason for admission was acute respiratory failure in ( . %) patients and mean saps ii was . ± . . ( . %) patients required invasive ventilatory support, ( . %) vasoactive drugs and ( . %) received renal replacement therapy. the median of icu length of stay was days. the follow up was possible for ( . %) patients. mortality rate at year was . %. predictors of one-year fatal outcome in univariate analysis were as follows-saps ii (p = . ), heart rate at discharge (p = . ), decline in functional status (p = . ), world health organization (who) performance status at discharge (p = . ) and readmission within month (p = . ). multivariate regression showed that saps ii (or, . + % ci [ . - . ] + p = . ), who performance status at discharge (or, . + % ci [ . - . ] + p = . ) and heart rate (or, . + % ci [ . - . ] + p = . ) were independent risk factors of one-year mortality. conclusion: this study suggests that age and comorbidities should not be exclusion criteria for icu admission. in the long-term only saps ii, performance status and heart rate were significantly associated with one-year mortality in the elderly icu survivors. introduction: triage is an act performed at the entrance of emergency departments (ed's), it allows the classification of patients in different categories according to the seriousness and the priorities of treatment. vital emergencies are geared towards resuscitation room. in our ed, triage is not codified and is «done» in most cases by an unqualified staff. the aim of this work is to show the impact of absence of triage on the functionning of the resuscitation room. patients and methods: it's a prospective study, conducted in the ed of a university hospital, over months, including all patients over years old, admitted at the resuscitation room. epidemiological and clinical data of patients, their ccmu classification (classification clinique des malades aux urgences) have been specified, as well as their outcomes. we collected patients. the average age was . years old ( - years), for a sex ratio of . . forty patients ( . %) arrived «standing» at the ed. patients ccmu and represented . % of these admissions. the systolic blood pressure was under mmhg in % of cases, the glasgow coma scale < . in % of cases, and the spo < % in % of cases. mortality was . %. the other patients were admitted at the intensive care unit ( %), at the short stay hospitalization unit ( . %), at the operating room ( . %), or transferred to other departments ( . %). discussion: the patients ccmu and arrived by ambulance, «lying» , were considered as severe. the proximity of the resuscitation room of consultation rooms allows it to be used sometimes in flows' management and as a place of triage. the patients transferred straight to services didn't show signs of vital distress motiving their initial admission at resuscitation room or even at ed. those admitted at the short stay hospitalization unit were steady, but needed complementary examinations, specialized expert advice, or were waiting for a downstream bed. conclusion: a triage system must be introduced at the entrance of our emergency departments. the staff involved in that sorting must be identified, and disposing of a triage scale in order to figure out the degree of priority associated to patients conditions, and direct the ones needing urgent care towards the resuscitation room. results: one hundred patients were included, with average age of . years old ( - ) and sex ratio of . . these patients were brought to emergencies by their family in % of cases. reasons for admissions were varied, severe deterioration of their general condition ( %), alteration of consciousness ( %), respiratory distress ( %), convulsive seizures ( %). therapeutic interventions were cardio-pulmonary resuscitation ( %), fluid volume expansion ( %), mechanical ventilation ( %), administration of vasopressors ( %) and anticonvulsants ( %). mortality at the resuscitation room was %. thirty eight patients were admitted at the intensive care unit, equally at the short stay hospitalization unit (ssu) of ed. two patients returned home at the request of their family. discussion: these results show that ed's remain the last resort in front of oncology patient who is deteriorating, the occurrence of complications, and sometimes, the psychological exhaustion or family's obstinacy. emergencies departments continue admitting patients with terminal cancer, but are not organized for medium and long term care. the creation of a palliative care unit and the organization of home-based care will allow the prevention and treatment of complications as well as a psychological care, thus improving the living quality of these patients and their relatives. refusal of intensive care admission: assessment of a tunisian icu practices merhabene takoua introduction: need of intensive care exceeds its availability in several countries. as a consequence, rationing intensive care unit (icu) beds is common and often leads to admission refusal. purpose-to report refusal determinants and characteristics of patients associated with decisions to deny icu admission. this study was performed at the icu of abderrahman mami hospital, a -bed icu in ariana, tunisia. it was a prospective study enrolled between st january and th december . no predefined admission criteria were determined. decisions to admit are based on a combination of patient-related factors, severity of illness and bed availability. all consecutive patients referred for admission to icu during the study period were included. groups were defined gi-admitted patients and gii-refused patients. the reasons for refusal were categorized as follows: too well to benefit, too sick to benefit, patient or family refusal, necessity of other exploration not available in our institution and unit too busy. results: during the study period, icu admission was requested for patients of whom were admitted ( %). of the patients refused, only were admitted to icu later. refusal of icu admission came in % of cases from the emergency room and wards of our hospital, in % from other hospitals of whom % without icu. reasons of refusal were no beds availability ( . %), too sick to benefit from icu ( %), too well ( . %) and necessity of other exploration ( . %). no differences in demographic characteristic between the two groups were noted. among the refused patients, when compared with admitted patients, we found higher proportions of hematologic malignancies (p < . ) and cardiocirculatory arrest (p = . ). on the other hand, admitted patients were more likely to have cardio-respiratory comorbidities ( / vs. / , p = . ) and more need to mechanical ventilatory support ( vs. , p = . ). conclusion: our study confirms that icu refusal rate still high. it depends on both icu organization and patient characteristics. acute heart failure syndroms in intensive care: clinical features, management and outcome jamoussi amira , ajili achraf , merhebene takoua introduction: classification of acute heart failure (ahf) into clinical scenari (cs) was first proposed to facilitate early management ( ) . a decade after implementation of this approach, epidemiological and evolutive data based on this classification are interesting to investigate. that is why we aim to describe frequencies, management and mortality of each ahf syndrom in intensive care. a prospective study of patients > years with ahf admitted to the medical intensive care unit (icu) of abderrahmen mami hospital from january to august was conducted. patients were classified according to the clinical scenari ( ). clinical, therapeutic and outcome findings were recorded. results: during the study period ( months), we admitted patients in icu from whom ( . %) presented with ahf and then enrolled. the median age was of ± . years and sex-ratio . . a medical history of copd ( . %), hypertension ( . %), diabetes ( . %), ischemic cardiopathy ( %) and valvular cardiopathy ( . %) were noticed. at admission, severity assessement scores were: median apache ii . ± . and median saps ii ± . . clinical and evolutive characteristics according to clinical scenari are listed in table . conclusion: cs and cs are the most frequent ahf syndroms in icu and also have the best outcome. introduction: in cardiac arrest patients resuscitated from an ischemic ventricular fibrillation or tachycardia (vf/vt), both incidence and risk factors of recurrent severe arrhythmia are unclear. whether it is useful to give a prophylactic anti-arrhythmic (aa) treatment during the first hours and days is debated, particularly when a successful coronary reperfusion was provided. we aimed to evaluate the incidence of severe arrhythmia in patients resuscitated from an ischemic vf vt and to identify risk factors for developing arrhythmia during their icu stay. the procat registry captures all data from patients admitted in a tertiary hospital center after a resuscitated cardiac arrest (ca). we selected patients with an initial vf vt caused by an acute coronary syndrome (acs) and who were successfully treated with early percutaneous coronary intervention (pci) on admission. the primary endpoint was the recurrence of major arrhythmia between icu admission and icu discharge. all arrhythmias resulting in ca recurrence and or severe arterial hypotension requiring infusion of vasopressors were classified as major arrhythmias. multivariate logistic regression identified factors associated with the occurrence of major arrhythmias. results: between / and / , consecutive ca patients were included in the analysis. all patients underwent a successful pci of the infarct-related artery on hospital arrival. the only drug used as a prophylactic aa treatment was amiodarone, which was employed in / patients ( %). overall, / patients ( . %) had a major arrhythmia recurrence during their icu stay. a large majority of these major arrhythmia recurrences ( . %) occurred during the first h. characteristics of patients with and without major arrhythmia recurrence are described in the table . in multivariate analysis, public place location (or . [ . - . ], p = . ) and male gender (or . [ . - . ], p = . ) were both associated with a lower risk of major arrhythmia recurrence during the icu stay. prophylactic aa treatment was not associated with a lower risk of recurrences of major arrhythmias (or . [ . - . ], p = . ). conclusion: despite an early coronary reperfusion, more than % of our post-cardiac arrest patients experienced a recurrent severe arrhythmia during the post-resuscitation period, mostly during the first h in the icu. this proportion is much higher than what is reported in common acute coronary syndrome (without cardiac arrest) and further studies are needed to explore protective strategies. introduction: during symptomatic treatment of septic shock, markers of anaerobic metabolism may be used in a goal-oriented strategy. the recent international guidelines for management of sepsis and septic shock suggested guiding resuscitation to normalize lactate as a marker of tissue hypoperfusion. the purpose of this study was to evaluate the kinetics of lactate and other markers during the first three hours and to compare their levels between survivors and non survivors. we conducted a prospective, observational, single-center study of patients admitted to a general icu from the may to august . inclusion criteria were patients age ≥ , intubated and under mechanical ventilation with septic shock as defined by the third international consensus conference. simultaneous sampling of arterial and central venous blood gas were collected at h and h to obtain lactate (mmol/l), and scvo (%). delta pco (mmhg) and delta pco /cavo (mmhg/ml) were computed by our patient data management system and presented as a chart with additional hemodynamic data for clinical decision support. comparisons of values between groups were made by mann-whitney u test as appropriate. p < . was considered statistically significant. all reported p values are two-sided. statistical analysis was performed using systat ver. . . results: we studied intubated septic shock patients aged ± years, saps ii ± , sofa ± . . community pneumonia and peritonitis were the major sources of infection. icu mortality rate was %. all patients received norepinephrine ( . ± . µg/kg/ min), two patients received dobutamine ( . ± . µg/kg/min). the evolution of markers is summarized in table . at h and h , arterial lactate levels were higher in non-survivors than in survivors, but did not decrease at h in both groups. at h there was no statistical difference concerning scvo , delta pco and delta pco /cavo . after three hours of resuscitation, delta pco and delta pco /cavo ratio decreased and scvo increased in survivors. survivors had lower delta pco and delta pco /cavo ratio than non survivors. conclusion: although high lactate level is a key signal of anaerobic metabolism, it did not decrease during the first three hours in this group of severe septic shock patients. instead of using lactate, delta pco and delta pco /cavo kinetics could be integrated in a goaloriented strategy for septic shock resuscitation. introduction: to assess whether, in patients under mechanical ventilation, fluid responsiveness is predicted by the effects of short respiratory holds on cardiac index estimated by oesophageal doppler (cidoppler). patients and methods: in patients, before infusing ml of saline, we measured cidoppler before and during the last seconds of successive -second end-inspiratory occlusion (eio) and endexpiratory occlusion (eeo), separated by min. patients in whom volume expansion increased cardiac index (transpulmonary thermodilution) > % were defined as "fluid responders". results: eeo increased cidoppler more in responders than in nonresponders ( ± vs. ± %, respectively, p < . ) and eio decreased cidoppler more in responders than in non-responders (- ± vs. - ± %, respectively, p = . ). thus, when adding the absolute values of changes in ci observed during both occlusions, cidoppler changed by ± % in responders and ± % in nonresponders. fluid responsiveness was predicted by the eeo-induced change in cidoppler with an area under the receiver operating characteristic (roc) curve of . ( % confidence interval- . - . ) and a threshold value of % increase in cidoppler. it was predicted by the sum of absolute values of changes in cidoppler during both occlusions with a similar area under the roc curve ( . ( . - . )) and with a threshold of % change in cidoppler, which is more compatible with oesophageal doppler precision. in this case, the sensitivity was ( - )% and the specificity was ( - )%. conclusion: if consecutive eio and eeo change cidoppler > % in total, it is very likely that volume expansion will be efficient in terms of cardiac output. the measurement of cardiac output using a signal morphology-based form of impedance cardiography (physioflow ® ) in intensive care unit: comparison with the trans thoracic echocardiography. introduction: in the intensive care units, the cardiac output (co) is one of the main hemodynamic parameters required to manage patients in shock. the physioflow ® is a new non-invasive method using the waveform analysis of the thoracic impedance signal (ti) to assess co. in hemodynamicaly unstable patients, no studies have evaluated the level of agreement between the co estimated by transthoracic echocardiography (co-tte) and that measured using the waveform analysis of thoracic impedance physioflow ® (co-ti). the objective of this study was to evaluate the ability of co-ti relative to co-tte to estimate the absolute co value and detect the expected variation co (v-co) in critically ill patients. patients and methods: fourteen patients sedated and mechanically ventilated, in shock under catecholamines and monitorred with tte and ti physioflow ® were included. hemodynamic datas, stroke volume (sv) and co with two monitoring were performed at baseline min before passive leg raising (plr), s after plr and min after volume expansion (ve) of ml of saline solution. responders were defined by an increase > % of cardiac output (v-co) after plr. results: fourteen pairs of tte and ti measurements were compared. the median (iqr) age was years ( - ), igs was ( - ). only patients were responders after plr. there was a significant correlation between the co-tte and co-ti measurements (r = . , p < . ). the median bias was . l/min and the limits of agreement (loas) were − . and . l/min. there was a significant correlation between v-co-tte and v-co-ti (r = . , p = . ) (fig. ) . the median bias was- . % and the loas for v-co were respectively - . and + . %. conclusion: the co measured with physioflow ® , a signal morphology-based impedance cardiography, is correlated to the co measured with tte. however, the high loa observed in this preliminary study underline the necessity to remain careful and wait for further inclusions. - ] vs. . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days, p = . ). despite imbalancedunderlying characteristics in terms of demographics and comorbidities, in-icu mortality rates were similar between patients ( . vs. %, p = . ). conclusion: prior bb treatment have limited impact on the severity of acute circulatory failure in septic shock and is not associated with increased mortality despite the underlying frailty of patients. introduction: cardiac output monitoring is a key component in the management of critically ill patients. cardiac output estimated by transthoracic echocardiography is documented in patient with atrial fibrillation, but a large part of transpulmonary thermodilution validation studies excluded this specific population. the objective of this study was to evaluate cardiac output mesurement and trend ability by transpulmonary thermodilution relative to transthoracic echocardiography in critically ill mechanically ventilated patients with atrial fibrillation. patients and methods: thirty mechanically ventilated patients requiring hemodynamic assessment were included in a prospective observational study. cardiac output was mesured simultaneously with transpulmonary thermodilution and transthoracic echocardiography. seventy-four pairs of cardiac output measurements were compared. the two measurements were significantly correlated (r = . et p < . ). the mean bias was - . l/min, the limits of agreement were - . and + . l/min, and the percentage error was . %. thirty-four pairs of cardiac output variation measurements were compared. there was no significant correlation between cardiac output variation measurements by transpulmonary thermodilution and transthoracic echocardiography. the mean bias was − . l/ min and the limits of agreement were − . and + . l/min. with a % exclusion zone, the four-quadrant plot had a concordance rate of . %. the polar plot had a mean polar angle of . ° with % confidence interval between − . ° and . °. conclusion: in critically ill mechanically ventilated patients with atrial fibrillation, cardiac output measurements with transpulmonary thermodilution and transthoracic echocardiography are not interchangeable. introduction: basic critical care echocardiography (cce) relies on transthoracic echocardiography (tte). we sought to assess the diagnostic capacity of a next-generation micro-digital broadband beamformer in patients with cardiopulmonary compromise. all patients with acute circulatory respiratory failure underwent two basic tte assessments using successively a next-generation micro-digital broadband beamformer ( elements, - mhz) incorporated in a sector phased array probe with twodimensional, m-mode and color doppler mapping capacities which was connected to a touchscreen interface (lumify, philips), and using a compact full-feature imaging system ( elements, - mhz + cx , philips). tte examinations were independently performed in random order by two intensivists with expertise in cce, within a -min time frame without therapeutic intervention. imaging quality was graded from (no image in the corresponding view) to (clear identification of % of endocardial boarders). the concordance of qualitative data was assessed using the kappa test and agreement of two-dimensional measurements (left ventricular end-diastolic diameter [lvedd], ratio of right ventricular (rv) and lv end-diastolic diameters [rvedd lvedd] + end-expiratory inferior vena cava diameter [dexpivc]) was evaluated using intraclass coefficient correlation (icc). results: thirty consecutive patients were studied, without any exclusion for absence of tte images (age, ± years, sap-sii, ± , % ventilated, % under catecholamines, lactate, . ± . mmol l). the proportion of echocardiographic views eligible for interpretation and mean duration of tte examinations were similar with the miniaturized and full-feature systems ( vs. %, . ± . vs. . ± . min, p = . ). two-dimensional imaging quality grade was lower with the miniaturized system ( system. concordance of two-dimensional measurements was also good-to-excellent (table ) . conclusion: for basic cce use, next-generation micro-digital broadband beamformer appears providing reliable information with good-to-excellent diagnostic capability, accurate two-dimensional measurements, and adapted therapeutic suggestions. these preliminary data require further confirmation. introduction: acute kidney injury (aki) in very old patients (over years) admitted in intensive care unit (icu) is a frequent issue and is known to be associated with a severe prognosis. we aimed at describing the clinical characteristics and prognosis of such a population. the objective of the study was dual: first to evaluate the short and long term mortality of these patients, second to determine the factors associated with a poor outcome. patients and methods: we conducted a descriptive, retrospective and monocentric study based on the hospital records of patients over years with aki admitted in our icu between january and december . the patients were selected according to the kdigo criteria ( ) . survivals at the discharge from hospital, at day and at year were assessed. the factors associated with mortality at year were scrutinized. results: after excluding patients for an initial therapeutic limitation, the data of remaining patients were reviewed. the patients were years old (interquartile range, iqr - ) and were predominantly male gender ( %). saps ii and sofa score at admission were (iqr - ) and (iqr - ) respectively. % of the patients needed for mechanical ventilation and % of them needed for catecholamine use. septic ( %), prerenal ( %), iatrogenic ( %) and cardiogenic injury ( %) were the leading cause of aki. dialysis was performed in % of patients. the overall mortality at the discharge from icu, at day and at year was , and % respectively (fig. ) . neither were the age, the comorbidities, the etiology of aki nor the need for dialysis associated to a significant increase in mortality. a stepwise cox regression analysis revealed saps ii and blood lactate level at icu admission as independent risk factors associated with year mortality. conclusion: aki at admission in icu is associated with a high mortality at year in an elderly population. main long term prognostic factors are linked to the initial severity at icu admission. introduction: the proportion of elderly around the world doesn't stop growing and increases the consumption in health care. however, lots of studies report the impact of the age on the decision to admit a patient to the icu despite no triage recommendation exists. the primary objective was to determine prognostic factors of death for the years and over at admission to the icu and secondly to evaluate their functional prognostic at short and medium term after their exit. patients and methods: prospective and observational study conducted in our icu beds unit from august to february . patients of years and over were listed. the dying patients arriving after a pre-hospital resuscitation for whom no therapeutic plan has been initiated and those admitted for an organ donation were excluded. the primary outcome was the duration between the admission and the potential death during the follow-up. the secondary outcomes were the necessity to entry an healthcare institution or the loss of one autonomy point on the adl french scale after the hospitalization. results: patients of the admissions were included. the igs ii and sofa average scores were respectively . ± . and . ± . . the most common diagnosis were a septic shock ( patients), a cardiopulmonary arrest ( patients), a cardiogenic shock ( patients) and a pulmonary oedema or a lung infection ( patients fig. survival of very old patients with aki in icu (%) each). patients ( . %) died during the follow up- at the icu, during ward and during re-education or after their home return. from a multivariate analysis (table ) , anisocoria, cardiopulmonary arrest and acute kidney injury (aki > ) seem to be independent risk factors of death. patients were alive at the end of the follow up. recovered their previous autonomy, needed a place in a specialized institution. all the other lost a part of autonomy months after their home return with the average loss of one point on the adl autonomy french scale. conclusion: anisocoria, aki and cardiopulmonary arrest seem to be independent risk factors of death for those patients. concerning the survivors, a stay at the icu lead to an increased dependency. other studies have to be led to evaluate which of our patients could have get the best benefit of their stay to prevent from a misuse of the structure. introduction: context-among the severe complications of preeclampsia, acute kidney injury (aki) poses a dilemma if features of thrombotic microangiopathy (tma) are present. although a hellp syndrome is considerably more frequent, ruling out a flare of atypical haemolytic and uremic syndrome (hus) is then of utmost importance. objective-to improve the differential diagnosis procedure in cases of post-partum aki. patients and methods: a hundred and five cases of post-partum aki, admitted in the last years ( ) ( ) ( ) ( ) ( ) in french icu from different regions, were analysed. initial and final diagnosis, renal features, haemostasis and tma parameters were all analysed, paying a special attention to their dynamics within the first days following the delivery. results: the main circumstances of aki were severe preeclampsia (n = ), post-partum haemorrhage (pph, n = ) and primitive tma (n = , including atypical hus and thrombotic thrombocytopenic purpura). among the thirteen cases of renal cortical necrosis, were associated with preeclampsia. congruence between the initial and the final diagnosis was low ( %). thus, none of the women referred to our centers for a suspicion of non-placental tma has received a final diagnosis of non-placental tma (and instead had a pe or a pph). conversely, all women with a final diagnosis of nonplacental tma were referred for a suspicion of pe-related tma, or with a pph which polluted the diagnosis. tranexamic acid was largely used in the context of pph ( %), at a dose up to grams total. taking into account the final diagnosis, we subjectively concluded that plasma exchanges and eculizumab were abusively indicated in and cases, respectively, of typical hellp syndrome. plasma exchanges were in itiated in all cases, a mean h following the admission. dynamics of hemoglobin, haptoglobin, and liver enzymes were poorly discriminant. the dynamic pattern of ldh and of platelets, in contrast, was statistically different between primitive tma-related aki and other groups-at day , platelets increased in preeclamptic women, and in other circumstances, but not in patients with primitive tma. a classification and regression tree (cart) independently confirmed the usefulness of platelets and ldh trajectory in the diagnostic algorithm (fig. ) . conclusion: the trajectory of ldh and platelet count is useful to identify the cause of post-partum aki, and the clinician may reasonably take therapeutic decisions at day post-delivery. introduction: continuous veno-venous hemofiltration (cvvhf) is a common practice in intensive care units (icu). because it is continuous, the choice of anticoagulation is essential-regional anticoagulation fig. analysis of post-partum aki cases with citrate or systemic with unfractionned heparin or low molecular weight heparin (lmwh). filter's lifespan is a major issue regarding filtration's effectiveness and cost. in this study, we compared the filter's lifespan between lmwh and citrate anticoagulation. patients and methods: a monocentric retrospective study was led from january to october . all the cvvhf sessions during this period were included. prismaflex© monitors (hospal) were used. practioners were free to choose between citrate or lmwh defining groups. we aimed a post filter ionized calcemia between . to . mmol/l in citrate group + and a post filter anti xa activity between . to . ui/ml in lmwh. results: cvvhf sessions were included- with lmwh anticoagulation, and with citrate. patients were years old on average, primarly males ( %), with an initial average saps ii score of . icu mortality was %. patients' hemostasis was measured before each cvvhf session, without any significant difference between the groups. global filter's lifespan was h + h in citrate group versus h in lmwh, without significant difference (p = . ) (fig. ) . no serious side effect, especially hemorrhage in the lmwh group, was reported. filtration efficiency, represented by the urea reduction ratio during the first cvvhf session, was similar, % ± % in lmwh group versus % ± % in citrate group (p = . ). conclusion: both anticoagulation-systemic with lmwh or regional with citrate can be used in icu. both methods enable long and comparable filter lifespan, with similar filtration efficiency and without serious adverse events. our results need to be confirmed by a randomized propective study. introduction: arf during the post-partum period is a rare complication. the main etiologies are post-partum haemorrhage (pph) and thrombotic microangiopathy (tma). rrt may be required. the aim of this study was to identify variables associated with rrt in this population admitted in icu. patients and methods: we conducted a study using retrospectively collected data in a cohort of patient with post-partum arf according to the kdigo criteria and requiring icu in the university hospital of lille from until . two groups were compared-rrt and non rrt patients. demographic and obstetrical data as well as data during icu stay and patients' outcome were collected. etiologies of arf, kdigo stage, anuria, hemolysis parameters and biological data at icu admission were studied. comparisons were made using a chi-two or fisher exact test or a mann-whitney u test. odds ratio (or) for the statistically different criteria were studied. results: twenty-two patients requiring rrt were compared to the patients without rrt. the two main etiologies of arf were tma ( . %) and pph ( . %). vaginal delivery was significantly more frequent in the rrt group compared with caesarian delivery (p = . ). use of rtt was significantly increased after pph compared the others etiology of arf (p = . ). in the rrt group, the icu length of stay was longer (p < . ) and igs ii score was higher (p < . ). higher kdigo score was observed in rrt patients (in the rrt group-kdigo = , = %, = %, and without rrt-kdigo = . %, = %, = %, p < . ). anuria h after icu admission was more frequent in cases of rtt ( . % versus . %, p < . ). hemolysis was greater in rrt patients with lower haptoglobin (p = . ) and increased lactate deshydrogenase (ldh) (p = . ). the association with rrt requirement was stronger with the duration of anuria, with an or at h at . [ . - . ] and at h at . [ . - ] . a lower haptoglobin was associated with a higher risk of rtt (or . [ . - . ]), as well as pph (or . [ . - . ] ) and vaginal delivery (or . [ . - . ]). conclusion: hemolysis parameters and anuria seemed useful criteria to identify patients at higher risk of rrt early during their icu admission. introduction: renal replacement therapy (rrt) has three aimsrestoring homeostasis, ensuring survival and preserving the potential for renal recovery. the main indication of rrt in icu is acute renal failure, correlated with a very important rate of mortality despite the progress made in its management. patients and methods: the objective of this work is to take stock of the indications and the objectives of the rrt in icu. through a prospective study, we report a serie of cases, collected at the multipurpose resuscitation unit of the avicenna military hospital in marrakech between september and september . results: the average age of our patients is , ± , years with extremes ranging from to years and a male predominance ( %). the main reasons for admission were hemodynamic distress in . % of cases, followed by septic shock in . % of cases, neurological and respiratory distress were noted in . and . % of cases, respectively. rrt indications were severe acidosis in % of patients, followed by % hyperkalaemia, acute pulmonary edema in %, hemodynamic instability in patients with chronic renal failure in %, acute renal failure in %, and hyperuriaemia in % of cases. the technique chosen is conventional intermittent hemodialysis with a synthetic membrane. the main duration of the sessions was h min ± mn. vascular access was a right internal jugular catheter in . % of patients and left in . %, right femoral catheter in . % of patients and left in . %, arteriovenous fistula (fav) and a tunneled catheter in . and . % of patients. mortality was , %, chronicity progressed in . % of cases and total or partial recovery of normal renal function in % of cases. conclusion: we have a high rate of mortality in our icu that's why we will focus on prevention of risk of renal failure in our patients. introduction: there is limited information on the outcome of acute kidney injury (aki) in patients with traumatic intracranial hemorrhage (tich). tich patient with aki was related high mortality rate. the aim of this study is to estimate the outcome using different renal replacement therapy on the survival rate and rate of long term renal-replacement therapy in adult tich patient. patients and methods: we retrospectively identified a total of tich patients with aki who required glycerol or mannitol therapy admitted to the intensive care unit during a -year period ending dec from the national health insurance research database. demographic data, severity of tich, medication, level of care, type of head surgery were collected. all patients subjects were older than > years. we also excluded patients diagnosed with tich before the cohort entry date, hemodialysis before tich, chronic kidney disease cancer coagulation defects purpura and other hemorrhagic conditions, mortality mechanical ventilation ischemic heart disease before tracking. the primary outcome was overall survival at day . the secondary outcome was the rate of long term hd therapy. results: a total of patients were enrolled. the kaplan-meier estimates of mortality at day did not differ significantly between the continuous veno-venous hemofiltration (cvvh) and hemodialysis (hd) strategies + deaths occurred among patients receiving cvvh-strategy group and deaths occurred among patients receiving hd-strategy group (adjusted hazard ratio: . , % ci . to . ; p = . ). the rate of long term hd was higher in the hd-strategy group than in the cvvh-strategy group ( . vs. . %, p = . ) especially in injury severity score ≥ group (table ) . discussion: in our study, tich patient with aki receving cvvh may have effect on renal blood flow protection or cytokine removal which lower the rate of long term hd. conclusion: these clinical data provides readers interventions to improve outcomes in this population and future study are needed to confirm the result. this study highlights the importance different renal replecement therapy in the tich with aki population (table ) . khaleq khalid , hattabi khalid , bensardi fatima zahra , bouhouri m. a , nciri a , hamoudi d , alharrar r introduction: the combined progress of abdominal surgery and anesthesia lead to more frequent surgical indications, including for fragile patients or serious pathologiespostoperative morbidity and mortality is an element that requires evaluation and analysis in surgical resuscitation. although pathological processes and new therapeutic approaches in surgery are currently well known, data on risk factors for morbidity and mortality are less available. the aim of our work is to evaluate the post-operative morbidity and mortality rate and to identify the main predictive factors. patients and methods: a retrospective-cohort, unicentric study that included all consecutive patients hospitalized in the surgical resuscitation department after abdominal surgery regardless of the operated organ, during years. the structured sheet of data collection included more than items on all perioperative data concerning the patient, the disease, and the operating surgeons. postoperative mortality and morbidity were defined as in-hospital death and complications. a first descriptive analysis of the various parameters collected was carried out a bivariate analysis was then performed to study the factors affecting morbidity and mortality in digestive surgery the comparison was made using the student's t test for quantitative variables and the chi square for the qualitative variables. a difference is considered significant when p < . ( %). results: among patients, the in-hospital death rate was . % and the overall morbidity rate was . %, the mean age was . ± , years with extreme ages of years and years with sex ratio of . . five factors were incriminated in post: operative mortality notably:renal failure p = . , duration of stay p = . , parenteral nutrition p = . , long duration of intubation p = . , perioperative blood transfusion p = . . three factors influencing morbidity were found: duration of stay p = . , parenteral nutrition p = . , long duration of intubation p = . . conclusion: knowledge of the true frequency of both mortality and morbidity is crucial in planning health care and research and identifying risk factors. introduction: tools to quantify and assess bowl management in critically ill are still very limited and often over-looked. with the primary fig. filter's lifespan concern of optimizing patients to preserve life, the problem of bowel care has been given less priority. the aim of this study was to use ultrasonographic measurements of gastric emptying in the critically ill as a tool of measurement of the impact of different specific factors of icu stay on bowl emptying. patients and methods: this is a prospective study conducted in an intensive care unit for months. it included patients. ultrasonic imaging of antral sections was undertaken every min for the first h and every min thereafter until total emptying. correlation analyses were calculated, applying an adjusted significance level (pb < . ) to correct for multiple testing. results: all our patients were above the age of . the median of age was years old . of our patients were male and were female. the total emptying median time was ± min. significant correlation was observed between length of stay and delay in bowl emptying. mechanical ventilation had also significant relation with slower bowl progression and gastric emptying. patients in septic shock had tendencies to earlier delayed bowl emptying compare to others patients included in our study. conclusion: the study we conducted is a pilot study. further studies should be conducted and unltrasonografic gastric assessment could be standardized in protocols to assess clinical decision making and improve nutrition and bowl management in icu patients. introduction: enteral nutrition, via a feeding tube, is often used in intensive care units (icu) to supply artificial nutrition to critically ill patients. the feeding tube is also commonly used to administrate drug therapy as well. however, there is a lack of knowledge of the nurses about this way of administration. this could be a potential source of medicine-related illness. the purpose of this study was first, to evaluate the nurse's knowledge on enteral drug administration, and second, to observe nurses and to evaluate the adequacy of their practices with guidelines, and to report medication-administration errors. patients and methods: this prospective study using the observation technique was conducted in icu (one medical and one surgical). first, a knowledge and practice questionnaire regarding drug administration trough enteral feeding tube was filled by each intensivist nurse. secondly, pharmacist performed observations of nurses during preparation and administration of medications. these practices were compared with the original medical prescription and with the data available in the literature. results: questionnaires were returned. nurses evaluated their knowledge as medium and as inadequate. there was a lack of knowledge on the type of drugs which can be used by feeding tube ( wrong responses). nurses and different drugs were observed during the drug administration phase. no administration totally complied with our institutional protocol, particularly the crush of tablets. when a tablet was crushed, in % an alternative formulation (in syrup for example) existed. the correct administration of drugs in feeding tubes is important and represents a challenge in icu. firstly, crushed tablets is the most frequent cause of obstruction of feeding tubes which have to be changed + secondly, crushed tablets destroys the controlled release of enteric coated dosage forms, resulting in a higher or a lower initial blood level. we have to train nurses for drug administration by feeding tube. on their daily ward, the pharmacist should improve the choice of medication's forms. introduction: acute variceal hemorrhage (avh) is a severe complication of portal hypertension. in addition, the variceal bleeding is still the most common lethal complication of cirrhosis. the most effective modality of treating is based on resuscitation combined with the endoscopic variceal band ligation. the purpose of this preliminary study was to find the factors associated with poor prognosis of avh in cirrhotic patients. patients and methods: this is a retrospective study, spread over months between january and december . are included all consecutive patients with liver cirrhosis hospitalized for variceal bleeding. we exploited the medical records to identify the clinical, biological and endoscopic parameters. results: a total of patients hospitalized for avh occurred during the study period. the mean age at admission was years, and are female. cirrhosis was post viral in % of cases. patients were classified as child-pugh c in % of cases. the median presenting model for end stage liver disease (meld) and clif sofa were respectively and . . twelve ( ) patients received beta-blockers and have required at least one endoscopic variceal band ligation at the time of the bleeding episode. in the acute phase, pharmacological treatment based on vasopressor (sandostatin)) was instituted in all cases and combining with antibiotic prophylaxis (c g or fluoroquinolone) in cases. in cases the endoscopy was made within h, active bleeding at endoscopy was observed in patients. esophageal avarices (ov) were grade i ( patients) grade ii ( patients) and grade iii ( patients). the eradication of varices was obtained in patients ( . % percentage of the cases). the variceal bleeding recurred in of patients ( %of cases) and patients died which within the first days. spontaneous bacterial peritonitis (p . ), hepatic encephalopathy (p . ) and the hemodynamic instability with schok (p . ) are correlated with early mortality at days. hepatic encephalopathy (p . ) and bacteremia (p . ) are corrolated with week motality. non selective betablocker (p . ) and primary use of band ligation when indicated (p . ) are protective factors and parameters of good outcome. conclusion: despite developing of endoscopic tools and respect of actual therapeutic guidelines in avh, the outcome is still poor. the prognosis appears to be dependent on the clinical condition at admission and primary prevention. introduction: the french intestinal stroke center based on a multimodal and multidisciplinary management has been developed to improve survival and intestinal viability. open surgical revascularization was decided for patients unsuitable for radiological revascularization and or suspected of intestinal necrosis. we aimed to study the prognosis of patients suffering from aoami in icu and who have benefited from open revascularization. single-center, observational and prospective study was carried out in a surgical icu of a tertiary center. patients with aoami managed in our intestinal stroke center from to and who underwent open revascularization were included. results: data of patients were collected. patients' characteristics are described in table . all patients had abdominal computed tomography angiography at the diagnosis, and patients ( %) presented signs of intestinal injury. thrombosis was the main mechanism of superior mesenteric artery (sma) occlusion ( patients, %). all patients received antiplatelet therapy, curative unfractionated heparin therapy and digestive decontamination. open revascularization was performed by sma endarterectomy ( patients, %), sma surgical bypass ( patients, %), retrograde open mesenteric stenting ( patients, %) and coeliac artery bypass ( patients, %). three patients ( %) underwent a radiologic endovascular revascularization attempt before open repair. small bowel resection ( cm ) was achieved in patients ( %). four patients ( %) had peritonitis. six patients ( %) had one or more relaparotomy ]), usually for hemodynamic instability ( %). only one patient died in icu ( %). icu lenght of stay was days ] and duration of mechanical ventilation was days [iqr - ]. overall, haemodynamic failure was present in patients ( %). median duration of vasoactive support was days [iqr - ]). severe acute respiratory distress syndrome was observed in patients ( %) and acute kidney injury in patients ( %, including patients who received renal-replacement therapy, %). enteral feeding was initiated in patients ( %) with a delay of . days [ . parenteral nutrition was administered in patients ( %), including patients ( %) without enteral feeding. five patients ( %) were discharged with small bowel syndrome. conclusion: icu patients who underwent open revascularization to treat aoami as part of a multimodal and multidisciplinary management in a dedicated intestinal stroke center have low mortality and intestinal resection rates. larger studies are needed to confirm these results. introduction: precise consequences of late transit in icu remain elusive. we have previously shown that defining late transit by the absence of stool within days after admission was not relevant because it did not identify a group of patients with specific outcome [ ] . to further improve this definition, we investigated the differences in outcome among patients according to their bowel movements frequency. patients and methods: preliminary results of a prospective, two centers, observational study. all patients admitted to icu, with a length of stay (los) of at least h were eligible and included with the following exceptions-abdominal surgery, bowel infection or any baseline condition known to alter transit time. patients were compared according to stool frequency-less than %, between and %, between and % or more than % of icu days. we also tested the former constipation definition of more than days after admission without stool passage. we registered demographic data, time spent under mechanical ventilation (mv), icu los, ventilation associated pneumoniae (vap) and vital status at discharge. results: over months, patients were screened and ( . %) were included, age . ± . years, mean saps ii ± , ( . %) mechanically ventilated. the most frequent exclusion criteria were los < h (n = ). % of the patients had stool less than % of icu days. patients with fewer bowel movements were more likely to be mechanically ventilated, without association with time spent under mv. there was a link between the time to first stool after admission and the stool frequency during icu (p < . vap n(%) ( . ) ( . ) ( . ) ( . ) death n(%) ( . ) ( . ) ( . ) ( . ) discussion: this study is limited by the number of patients leading to an imbalance between subgroups therefore limiting the comparison. conclusion: these preliminary results do not plead for an improvement of the late transit definition based on the frequency of stool. further data is warranted to better define this condition, and the management to provide. introduction: antibiotic therapy during acute exacerbation of copd (aecopd) still controversial and not well supported by clinical evidence. in fact half of these episodes are caused by viruses even during severe episodes with need to ventilator support. procalcitonin is effective to guide antibiotic therapy during acute exacerbation of copd without compromising patients' outcome, its efficacy in the intensive care setting still not well evaluated. we have conducted in a bed icu a before after study. during the first period (january -december ) patients with aecopd were included retrospectively and treated with antibiotics according to anthonisen criteria (control group). in the second period (january -may ) antibiotics were prescribed only if the procalcitonin level was greater than . ng ml (procalcitonin group). results: ninety-two patients were included, in the procalcitonin group and in the control group. antibiotics were administered at icu admission in patients ( %) in the procalcitonin group and in ( %) patients in the control group, p = . . only % of sputum cultures were positive at icu admission. time to recovery was similar between the two groups [ iqr ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) , iqr ( - ), p = . ]. other patients' outcomes did not differ between the control group and the procalcitonin group with respectively: the mortality ( . vs. %, p = . ), the incidence of pavm ( vs. %, p = . ) and niv failure ( vs. %, p = . ). readmission to the hospital at day was significantly higher in the control group ( vs. %, p = . ). conclusion: using procalcitonin to guide antibiotic therapy during severe aecopd can reduce the use of antibiotics without compromising patients' outcomes. our study aimed to assess whether arc impacts negatively on cefazolin pharmacokinetic pharmacodynamics (pk/pd) target attainment and clinical outcome in critically ill patients. patients and methods: over an -month period, all critically ill patients treated by cefazolin for a documented respiratory infection without renal impairment were eligible. patients who underwent an empiric antimicrobial treatment > h before introduction of cefazolin were not included. during the first three days of antimicrobial therapy, every patient underwent -hour creatinine clearance (crcl) measurements and therapeutic drug monitoring at steady state. the main outcome investigated in this study was the rate of pk pd target non-attainment defined by an unbound concentration < µg ml (mic value for inoculum > ufc ml). the secondary outcome was the rate of therapeutic failure, defined as an impaired clinical response with a need for escalating antibiotics during treatment and or within days after end-of-treatment. results: over the study period, patients were included ( samples analyzed for therapeutic drug monitoring). in pharmacological analysis, the rate of pk pd target non-attainment was %, with a strong association with crcl (p = . ) ( table ). in clinical analysis, the rate of therapeutic failure was % ( ), with a strong association with inoculum effect (p = . ). there was a strong association between therapeutic failure, crcl > ml min and pk pd target non-attainment adjusted on the inoculum effect (p = . ). introduction: vancomycin has long been used as the standard therapy of infections due to methicillin-resistant staphylococcus aureus (mrsa). the side effects of this drug as well as the increasing resistance and its pharmacodynamics effects have fostered the development of newly active drugs. nevertheless it is still widely prescribed and it stands as the mostly used comparator in randomized study. an assessment of our medical practice regarding its use may enhance compliance to guidelines so as to promote a better use of vancomycin. patients and methods: in our bed hospital, the incidence rate of mrsa fell from . to . per patient days from to whereas the current proportion of mrsa isolates is about %. vancomycin is the most prescribed empirical or targeted antibiotic therapy covering mrsa in our medical intensive care unit of beds even if a shift towards the use of linezolid in nosocomial pneumoniae has been noticed during the last years. key points regarding the proper use of vancomycin have been implemented in our antibiotic stewardship program. moreover courses concerning this topic are provided to our junior doctors. a retrospective review of the quality of antibiotic use has been carried out in courses of vancomycin therapy and the following criteria have been assessed-indication, dosing schedules, serum levels of vancomycin, duration of antibiotic therapy and the overall degree of conformity of the prescription. results: regarding indication, conformity was observed in cases ( %). the dosing schedule was appropriate in cases ( %) only. of the remaining cases ( %), all of them were not adjusted to the serum concentration and in cases ( %) the general dosing recommendation was not respected. the loading dose was inappropriate in cases ( %) and the proper follow up of serum levels of vancomycin has not been carried out in cases ( %). the duration of antibiotic therapy was in compliance with the protocol in cases ( %) and a slight longer duration was observed in cases ( %). finally the overall degree of conformity of the prescription was observed in cases ( %) only. table . in the sfar srlf guideline, the limitation of the echinocandins use to the benefit of ampho deoxycholate explains most of the poor agreement or consensus rate between investigators. the idsa escmid guideline are more helpful to guide indications of empirical treatment which mainly explains their higher rate of both applicability and agreement rate. the rates of agreement do not reflect whether the choice between different class iii antifungal therapies is the best or not. conclusion: the idsa guideline seems to take a broader spectrum of clinical situations into account, particularly in guiding more precisely indications of empirical treatments. escmid or idsa reach more often consensus at the first reading. ( ), and was discovered during a chest x-ray examination for % ( ). diaphragmatic paralysis was confirmed for all cases with chest ultrasound. % of patients ( ) were receiving mechanical ventilation at the moment of the diagnosis. the paralysed hemidiaphragm was left sided in % ( ), and right sided in % ( ). there was no bilateral diaphragmatic paralysis. hemi-diaphragmatic plication was performed in % of the patients ( ), and median time from cardiac surgery to surgical plication was days (range - days). indications for plication were failure to wean from ventilator ( %, ), and respiratory distress ( %, ). plicatured patients were remarkably younger (median age at cardiac surgery- days, range - days) than non-plicatured patients ( . months, range days- years). the median ventilation time after plication was days (range - days). all patients were asymptomatic after diaphragmatic plication. two patients died ( %). cause of death was independant from surgical plication (cardiogenic shock, septic shock). conclusion: diaphragmatic paralysis is a rare but serious complication of cardiac surgery in children. it commonly occurs after open-heart surgery, and specifically after arterial switch operation. plicatured patients were younger than non-plicatured patients and needed more frequently a ventilatory support. a closer monitoring may be required for young patients and mechanically ventilated patients. indeed, both are more likely to be treated by a diaphragmatic plication, reducing mechanical ventilation and intensive care duration. a prospective study. consecutive children aged between days and -year-old admitted to the picu, intubated and mechanically ventilated were eligible and they reached inclusion if they had at least one chest tube. ppl was directly measured by a pressure transducer connected through a needle inserted into the existing chest tube. pes was measured by both a specific probe (gaeltec probe) and by the feeding tube after mobilization (pes-ft). results: patients (median age months (interquartile + - )) were included and exploitable signals were finally available in patients, who were included in the analysis. most of patients (n = ) were admitted after cardiac surgery and had a spontaneous breathing activity. median pes measured by gaeltec probe and by feeding tube was . (interquartile + . - . ) and . ( . - . ) cm h o, respectively. median ppl measured into the chest tube was . ( . - . ) cm h o. bland-altman plots are represented in the figure. conclusion: both ppl measured into the chest tube, pes measured by the gaeltec probe or by the feeding tube are reproducible methods. . respiratory syncytial virus was identified in infants ( %). an initial caffeine citrate loading dose of mg kg was usually administered, followed by a mg kg day maintenance dose, for a median treatment duration of days [ ] [ ] [ ] [ ] [ ] [ ] . therapeutic management (invasive and non-invasive ventilation, nutrition support) and clinical outcomes (death, length of stay) were similar between groups. there was no difference in potential caffeine adverse effects between groups or within the caffeine exposed group pre and post-caffeine administration. conclusion: caffeine treatment of bronchiolitis related apnea seems to be a standard practice in our picu. our study failed to show any influence of caffeine on clinical outcomes in this indication when compared with a small number of patients. further studies are needed to assess the efficacy and safety of caffeine treatment in this indication as well as the appropriate treatment regimen as pharmacokinetic data suggest that higher dose could be of great interest in this non-prematurely born population. introduction: during the last decade, many authors have raised awareness concerning the increasing rate of venous thromboembolism (vte) in critically ill children [ ] . the presence of central venous catheter (cvc) is one of the most important risk factor for venous thrombosis in children [ ] . the purpose of this study was to analyze incidence and risk factors for catheter-related thrombosis in children admitted in our pediatric intensive care unit (picu). patients and methods: all children aged less than years, admitted in the picu from january to june , and receiving at least one tunneled cvc, were included in our retrospective study. those with venous thrombosis unrelated to cvc placement were excluded. catheter-associated venous thrombosis (cavt) was confirmed using doppler ultrasonography. introduction: weaning from the ventilation is a crucial moment in the icu stay. because of the risks of mechanical ventilation (mv), such as ventilator-associated pneumoniae, it is recommended to begin the weaning process as soon as weaning criteria occurs [ ] . however, extubation is also a hazardous period, with to % of subsequent respiratory failure requiring reintubation, harboring a dismal prognosis [ ] . international guidelines display the criteria triggering the extubation. nevertheless, the physician in charge eventually takes the decision to extubate. in this regard, there could be variations from an individual to another. the main goal of our study was to identify the perceived impediments to mv weaning among physicians, from intubation to extubation. patients and methods: prospective single center study in a bed university icu. all patients admitted between february and may and undergoing mv were included. we daily registered the existence of the criteria recommending a spontaneous breathing trial (sbt), the occurrence of a sbt, the items recommending postponing extubation, and the occurrence of an extubation. the estimated reasons for all the aforementioned decisions were asked to the physician in charge. results: patients were included, gathering days of mv and sbt. the average duration of mv was . ± . days. there was one extubation failure requiring reintubation. there were sbt failures. in cases, sbt was a success but did not lead to extubation because of hypotonia, weak cough, subsequent respiratory failure, hemorrhagic bronchial secretions, hemodynamic instability, absence of weaning criteria, drowsiness (all the aforementioned n = ), post sbt hypercapnia (n = ). out of the sbt ( %) were done while one or several weaning criteria were absent. impediments to weaning trials were different according to the time lag since icu admission, with fluid overload, muscular weakness and persistent need for assist control ventilation settings being the most frequent reasons advocated after days (figure). no objective assessment of muscular or cough strength was performed at any time, neither was monitored the rr vt, vital capacity or inspiratory pressure. . % of patients had otolaryngologist follow-up. the overall mortality of the studied population was . % including mortality related to tracheostomy in patients. the tracheostomy for extended mechanical ventilation was significantly associated with an increase of mechanical ventilation duration before tracheostomy (p < . ), duration of mechanical ventilation (p < . ), length of stay in intensive care unit (p < . ) and mortality rate (p = . ). introduction: acute renal failure complicating surgery has a particularly harmful prognosis, with a mortality of % to %. this high mortality rate is attributed to patient-related factors, the severity of the disease and the type of surgery, but not to the acute renal failure itself. the aim of our study is to elucidate the prognostic factors of acute renal failure in the postoperative sepsis in a series of patients. it is a retrospective analytical descriptive study spread over a period of years (from january to december ), observations of postoperative peritonitis were collected in the service of resuscitation of surgical emergencies of chu ibn rochdof casablanca. the statistical analysis was carried out using the spss software. the results are expressed with or and % confidence intervals (ci at %). the results were considered significant when p is < . . the mean age of the patients was ± years with a sex ratio of . ( m ) . renal failure was the most frequent failure after hemodynamic failure, patients were oliguric, anuriques and patients had a preserved diuresis, patients were divided according to the rifle (r %, i %, f %) and akin (i %, ii %, iii %). the predictive factors of acute renal failure ari were studied in univariate and multivariate analysis, factors were retained including catecholamines-or . + ci at % between . and . + p = . + the surgical site-or . + ci at % between . and . + p = . . conclusion: acute renal failure is an independent factor of mortality in the post-operative sepsis, but remains that its presence is a pejorative prognostic factor. this was a retrospective study performed in a large university hospital. all patients receiving the molecule were included in the analysis. indication for sodium lactate, dose, and modality of administration were collected. we also collected clinical and biological variables before sodium lactate infusion, after h (h ), and after h (h ). an analysis of the evolution of these variables at h and h was performed. results: between january and may , patients, aged years, % males, sofa score [ - ], received an infusion of molar sodium lactate ( ml ). main indications for sodium lactate were hyperchloremic metabolic acidosis ( %), vascular filling ( %), mixed acidosis ( %), and intracranial hypertension ( %). % of the patients presented with a chloride sodium ratio > = . at basal time. sodium lactate was associated with a significant increase of mean arterial pressure at h (p = . ) and h (p = . ), a decrease of catecholamine dose (p = . ) and heart rate (p = . ) at h , and an increase of diuresis in the h period following initiation of the treatment (p = . ). we observed an increase of ph, bicarbonate, base excess, and sodium, at h and h (all p < . ). plasma lactate concentration was increased at h (p < . ), but was not different from basal value at h (p = . ). there were no significant variation of plasma chloride. chloride sodium ratio was significantly reduced. plasma sodium > = mmol l and ph > = . at h were observed in % of the patients. this retrospective study reports the largest number of critically ill patients having received sodium lactate. hemodynamic effects observed in this study are concordant with the data of the literature. the metabolic effects observed in this study, with rapid increase of ph, bicarbonate, and base excess, strongly suggest the potential interest of sodium lactate among critically ill patients presenting with acidosis and increased chloride sodium ratio. introduction: acute kidney injury (aki) is a frequent and severe condition in intensive care unit patients that may require renal replacement therapy, most frequently continuous renal replacement therapy (crrt). although hypoglycemia is a well-known complication of crrt using glucose free solutions, euglycemic ketoacidosis (eka) has never been described in this setting. patients and methods: all anuric patients with glucose free crrt solution induced eka (february -may ) were prospectively included and evaluated. ketoacidosis was deemed possible when nonlactic metabolic acidosis did not improve in patients on crrt. because all patients were anuric, we measured ketonemia and used urinary test strip in the effluent fluid. eka diagnosis was retained when arterial serum bicarbonate was < meg/l despite crrt, in the absence of lactic acidosis and in the presence of ketones in the serum or crrt effluent fluid. results: eighteen patients ( % of our patients under crrt in this period) developed eka during crrt using glucose free solution (phoxilium ® ). time between cvvhdf initiation and ketonemia detection was ( - ) days. patient characteristics are presented in the table . half of them had for a medical history of diabetes ( insulindependent). only patients were receiving insulin and most of them had low glucose or food intake. increasing glucose intake and insulin infusion resolved ketonemia in all cases. discussion: we describe for the first time the occurrence of euglycemic ketoacidosis in critically ill patients under crrt using glucose-free replacement solution. common features of the patients were multiple organ failure with anuria, normal glycemia without insulin infusion and low glucose infusion or food intake. critical illness-induced insulin resistance and starvation could altogether contribute to ketoacidosis even if acidosis is unusual in starvation ketosis. by removing substantial amounts of glucose from the blood, crrt with glucose free solution could worsen this condition, mask hyperglycemia and induce euglycemic ketoacidosis. in critically ill patients on crrt using glucose free solution, euglycemic ketoacidosis is common and should be detected, especially in patients with low glucose intake, no insulin infusion and unexplained metabolic acidosis. importantly, the diagnosis can be missed in anuric patients with normal blood glucose and in the absence of known diabetes. since, cvvhdf-induced ketoacidosis may contribute to persistent acidemia and its adverse effects, serum or crrt effluent fluid ketone level should be measured in this setting. . - ] years. main reasons for admission were hypercalcemia (n = ( . %)), followed by acute encephalopathy (n = ( . %)). median saps ii and sofa scores were [ . - . ] and [ ] [ ] [ ] [ ] [ ] respectively. main causes of hcm were hematological malignancies (n = ( %)), solid tumors (n = ( %)), iatrogenic events (n = ( %)) and endocrinopathies (n = ( %)). median calcium levels at admission, at day and at icu discharge were . [ . - . ], . [ . - . ] and . [ . - . ] mmol l respectively. more than half of the patients (n = ( %)) recovered from hcm days after icu admission. acute kidney injury occurred in ( %) patients and ( . %) patients required dialysis. neurological complications concerned ( . %) patients, mainly delirium (n = , . %). digestive events occurred in ( . %) patients. cardiovascular events concerned ( %) patients and consisted in de novo hypertension in ( %) patients, and ekg disturbances in ( %) patients. during icu stay, ( . %) patients required mechanical ventilation and ( . %) patients required vasopressors. volume resuscitation with crystalloids was the first treatment in ( . %) patients, ( . %) received bisphosphonates and ( . %) received corticosteroids. respective icu and hospital mortality were . and . %. there was no correlation between the degree of hcm and icu mortality (p = . ). icu and hospital mortality were associated with the underlying disease (hematological malignancies (p = . )). conclusion: hcm is associated with high mortality rates. the increased mortality is a consequence of the main mechanism, mainly underlying malignancy rather than hcm per se. the course of hcm may be complicated by organ failures that are most of the time reversible with early icu management. introduction: sepsis is one of the leading cause of death among patients with chronic kidney disease (ckd). the mechanisms of this higher mortality remain poorly understood. sepsis and chronic kidney disease are both conditions associated with a higher plasmatic concentration of bile acids. the farnesoid x receptor (fxr) is a key regulator of the bile acid metabolism and has recently been involved in the regulation of the inflammasome during sepsis. we explored the role of fxr in the prognostic of sepsis in an animal model of ckd. patients and methods: sepsis was provoked by the injection of . mg kg of lps weeks after the creation of ckd. the ckd was created by unilateral nephrectomy associated with contralateral thermocauterisation. the mice (c bl j) were randomly assigned to one of the following groups-sham placebo, ckd placebo, sham lps or ckd lps. a fifth group of ckd lps mice received a treatment with sevelamer (a bile acid sequestrant) during weeks. survival of the animals, serum biochemistry and molecular biology in the kidney were performed after sacrifice. results: whereas the sham lps animals survived, all ckd lps animals died during the h following the injection of lps. the plasmatic urea, il beta and tnfa concentrations increased with the creation of ckd (ckd placebo versus sham placebo animals) and with the creation of sepsis (ckd lps versus sham lps groups). whereas the expression of fxr rna did not changed with the injection of lps in the sham animals (sham lps versus sham placebo), the fxr rna decreased with the creation of sepsis in the ckd animals (ckd lps versus ckd placebo groups). the ckd animals treated with sevelamer weeks before the administration of lps (ckd sev lps group) had a lower plasmatic concentration of il b, tnfa and increased the rna expression of fxr in the kidney compared to the ckd lps group. also, the treatment with sevelamer improved the survival of the ckd lps animals. conclusion: our study demonstrates a relation between fxr and the prognostic of sepsis in ckd animals. the exact link and the potential therapeutic interest of targeting fxr and bile acids metabolism in ckd patients remain to be studied. introduction: dysnatraemia, dyskalaemia and hypomagnesemia are frequent metabolic disorders in intensive care, and their causes represent a major concern for the intensivist, especially in urgent conditions. in the diagnostic approach, we often use the urine analysis. although measurement of -hour urine electrolyte excretion ( -hu) is considered the most reliable method, the great burden and difficulty in collecting complete -hour urine has prompted the search for more practical methods, such as spot urine analysis. the aim of the present study was to compare electrolyte excretion in urine samples collected over different time periods, in comparison with a -hour urine sample collection considered as the gold standard method. patients and methods: this prospective and descriptive study included patients admitted in a tunisian medical icu, between september and december . baseline characteristics, medications and laboratory data including electrolytes and renal function parameters were obtained from all patients. multiple urine specimens for analyzing na + k + mg + urea + ca + phosphate + creatinine + proteins and uric acid were obtained from -hour, -hour and -hour urine samples during day and night time, and results were compared with those obtained from the gold standard method ( -hour urine collection). correlation analysis was performed using the spearman test. results: significant correlation was found for all biochemistry parameters between -hour urine results and those obtained from -hour and -hour samples regardless of day or night sampling. a comparative analysis for sodium and potassium is shown in fig. . conclusion: determination of electrolyte excretion from urine samples taken over different time periods, and h, provides a reliable estimation of -hour urine electrolyte excretion. it appears practical for early understanding of the mechanism of electrolyte imbalance. however, further studies are warranted to confirm the usefulness of this approach. use of the procalcitonin assay in an adult emergencies department: retrospective experience of a general hospital of the suburb of paris ( . - . ). other markers of infectious were poorly recorded (fibrinemia in ( . % + . g l [ . - . ] + immature forms on blood count- . %). only ( . %) had blood cultures in the ed ( patient [ ] [ ] ) and ( . %) other(s) microbiological sample(s), mainly urinary ( patients [ . % + among them % considered as positive]). % of blood cultures were positives, mainly for gram negatives ( %). final diagnosis in the ed was considered as infectious disease (id) in only patients ( . %, including sepsis and septic shocks). ( . %) was considered as non-infected (nid) and final diagnosis remains unprecise in ( . %). pct values was of . ( - . ) in the id vs. ( - . ) in the nid (p < . ), wbc was of . in the id vs. . in the nid (p < . ) and crp was of ( . - . ) in the id vs. ( - ) in the nid (p < . ). no correlation was observed between the pct value and admission to dechocage room admission. . identification of the involved drug was obtained in % of the cases, based on qualitative screening. management was mainly supportive and included sedation ( %), naloxone ( %) and flumazenil ( %). tracheal intubation was required in patients ( . %). one cardiac arrest but no death occurred in the ed. forty-three patients ( %) were transferred to the intensive care unit. conclusion: our dataset provides an interesting insight into the drugs involved in and clinical pattern of toxicity outcome of acute recreational drug toxicity presentations at the ed, despite possible under-declaration and coding. classical recreational drugs were more common ( %) followed by prescription drugs ( %) and nps ( %). and drug ( %) consumers + hiv-infected ( %) and depressive ( %) patients) were admitted to the icu. the main declared compounds were methylenedioxypyrovalerone (mdpv + n = ), -methylethcathinone ( -mec + n = ), -methyl methcathinone ( -mmc + n = ) and -methyl methcathinone ( -mmc + n = ), more frequently used in drug mixtures sold as bath salts or in poly-intoxication with conventional illegal drugs (mainly cocaine and gamma-hydroxybutyrate). nps was used in a recreational ( %), chemsex ( %) or solitary practice ( %). binge ( %) and intravenous ( %) self-administration was remarkable. patients presented acute encephalopathy with psychomotor agitation ( %), confusion ( % + glasgow coma score- [ ]), hallucinations ( %), anxiety ( %), seizures ( %), myoclonus ( %) and stereotypes ( %). ecg typically showed sinus tachycardia ( %), qrs qt abnormalities ( %) and atrio-ventricular block ( %). acute cardiac ischemia ( %) and dysfunction ( %), disseminated intravascular coagulation ( %) and multiorgan failure ( results: during the first and the second study periods and patients were respectively admitted in the icu. total micro-organisms density was and . for patients for the first and the second period, respectively (p < . ). acinetobacter spp and pseudomonas aeroginosa were the predominant isolated microorganisms with a respective density of . and . isolates for patients. figure summarizes the patterns of bacterial ecology and resistance in our icu before and after transfer to new buildings, showing a significant decrease in pseudomonas aeroginosa resistance for ticarcillin and ceftazidim, whereas acinetobacter resistant to carbapenems and enterobacteriacae esbl significantly increased. our study suggests that transfer of icu to the new buildings was associated with a decrease of pseudomonas aeroginosa resistance, whereas acinetobacter spp resistance and esbl enterobacteriacae incidence increased. introduction: infections caused by antimicrobial-resistant bacteria (amrb) are one of the main issues in the spectrum of critically ill patients as they are associated with higher mortality, morbidity, and length of stay. thus, an appropriate initial antimicrobial therapy is decisive for better patient outcomes. the aim of the study is to determine the adequacy of first-line antibiotic therapy guided by weekly amrb screenings. patients and methods: a months prospective study was conducted in -bed micu. were included all patients with more than h of icu stay. an amrb screening was conducted upon admission and on weekly basis for all the patients. the choice of antibiotherapy if indicated, was guided by the most recent colonization results. if the patient has received at least one active in vitro antibiotic against the isolated bacteria, the empiric antibiotherapy was considered appropriate. results: patients were included in the study. mean age and saps ii were respectively ± years and ± . the median length of stay was days. ( %) patients were colonized by amrb upon admission. the most frequent isolated microorganisms were-escherichia coli ( %) and klebsiella pneumonia ( %). were assessed hospital-acquired infections (hai)- ( %) in amrb colonized patients and ( %) in uncolonized ones. the antibiotherapy was considered appropriate in infections ( %). out of the colonized patients, ( %) developed hai. ( %) patients had a concordant colonization body site to the infection. of the nosocomial infections, ventilator-associated pneumonias and central venous catheter infections were the most frequent, both at % (n = and n = ) + followed by urinary tract infections % (n = ) and infective endocarditis % (n = ). ( ). overall, the isolates were-extended spectrum betalactamase productrice-enterobacteria ( %), imipenem resistant-acinetobacter baumanii ( %), and multi resistant-pseudomonas aeroguinosa ( %). ni were documented including caused by mdr bacteria and distributed as follows-ventilator acquired pneumonia-vap (n = ), bacteraemia (n = ), vap with bacteraemia (n = ), catheter related infection-cri (n = ), cri with vap (n = ) and catheter-related bacteraemia-crb (n = ). the performance of mdr bacteria-screening in predicting ni was poor with % of sensitivity, % of specificity, . % of negative predictive value (npv), and % of positive predictive value (ppv). nevertheless, the performance of the nasal swab in the prediction of vap was better with % of sensitivity and . % of npv. conclusion: mdr bacteria-screening is useful as it allows to identifying the mdr bacteria-carriers and helps for a rational use of antibiotics in severe ni. however, its diagnostic contribution in the occurrence of ni is poor except the interest of the nasal swab in the prediction of vap owing to its good npv. we aimed at determining the respective weight of these phenomenon and the physiological determinants of the respiratory variations of the ivc diameter. patients and methods: in mechanically ventilated patients (tidal volume- . ± . ml kg of predicted body weight) haemodynamic, respiratory and the intra-abdominal pressure (iap) signals were continuously computerised. cvp, iap and the ivc diameter (transthoracic echocardiography) were recorded during -second end-inspiratory and end-expiratory occlusions separated by s, before and after the infusion of -ml of saline. patients in whom fluid administration induced an increase in cardiac index (picco- ) > % were defined as "responders". the respiratory variations of the ivc diameter, cvp and iap were calculated as the (end-inspiratory-end-expiratory values) mean value. the compliance of the ivc was estimated by the ratio (end-expiratory-end-inspiratory ivc diameter) (end-expiratoryend-inspiratory cvp). results: fluid administration increased cardiac index by more than % ( . ± . to . ± . l min m , p = . ) in patients. the respiratory variations of the ivc diameter predicted fluid responsiveness (area under the roc curve- . ( % ci . - . ), p < . ). before fluid administration, the ratio of changes in ivc diameter over changes in cvp was not different between responders and non-responders ( . ± . vs. . ± . mm mmhg, p = . ). before fluid administration, the respiratory variations of the cvp tended to be higher in responders than in non-responders ( ± vs. ± %, p = . ). the respiratory variations of the ivc diameter were associated with the respiratory variations of cvp (r = . , p = . ) but not with the respiratory variations of iap (r = - . , p = . ). the respiratory variations of the ivc diameter were not explained by a higher ivc compliance but rather by higher respiratory variations of the cvp in responders than in non-responders. interestingly, it seems that iap, the ivc extramural pressure, was not involved in the respiratory variations of the ivc diameter. inclusions are ongoing. during the hospitalization in icu, there was no significant difference between the two groups regarding the proportion of patients with aki through icu discharge. in the intervention group, % of the patients had a glomerular filtration rate lower than ml min . m compared to . % in the control group (p = . ) at day- . we found no significant difference between the two groups neither on hematopoietic effects of epo or serious adverse events. in patients resuscitated from an ohca of presumed cardiac cause, early administration of erythropoietin compared to standard therapy did not confer any renal protective effect. salvetti marie , and the ratio of end-diastolic areas of both the right and left ventricle in the long axis view of the heart (rveda lveda) were measured. a lvef < % defined lv systolic dysfunction, a ci < l min m defined low cardiac output, and a rveda lveda ratio > . (± associated with a paradoxical septal motion in the short axis of the heart) defined rv dysfunction (± acute cor pulmonale). the preload-dependence was evaluated using deltasvc or deltavmaxao. front-line hemodynamic and metabolic parameters were recorded at the time of tee assessment. results: lvef and ci could be simultaneously measured in of patients ( %). patients ( %) had a low ci related to lv systolic dysfunction (lactate- . ± . mmol l), patients ( %) had a low ci and a preserved lvef related to a rv dysfunction or to a sustained preload-dependence (lactate- . ± . mmol l), patients ( %) had preserved ci and lvef (lactate- . ± . mmol l) including only patients ( %) with a hyperkinetic profile (high ci and lvef > %), and patients ( %) had preserved ci but altered lvef (lactate- . ± . mmol l) due to a marked tachycardia. none of the front-line hemodynamic parameters was discriminatory to identify the circulatory profile identified by tee assessment (table) . introduction: aortic end-systolic pressure (esp) is considered as a reliable index of left ventricular afterload. recently, the effective arterial elastance (ea), i.e., the ratio of esp over stroke volume (sv), has also been proposed as a reliable afterload index. our aim was to document peripheral estimates of ea (eapsap) at the bedside in critically ill patients, and to investigate the haemodynamic mechanisms responsible for ea changes after fluid administration (fa). in the validation study, carotid tonometry (complior) was prospectively performed on haemodynamically stable spontaneously breathing patients equipped with an arterial femoral (n = ) or radial (n = ) catheter. ea was defined as the ( . × csap) sv ratio, where csap was the central systolic arterial pressure directly measured from the calibrated carotid waveform. eapsap was calculated as the ( . x peripheral systolic arterial pressure) sv ratio. sv was obtained by transpulmonary thermodilution or transthoracic echocardiography. in the clinical study, we included patients with invasive haemodynamic monitoring (picco- ), in whom fa was planned. results: in the validation study, the complior allowed estimating ea in all patients (ea = . ± . mmhg ml). the (eapsap-ea) bias was smaller at the femoral than radial artery level ( . ± . vs. . ± . mmhg ml, p < . ) and was strongly related to the systolic pressure amplification between the carotid and peripheral artery (r = . , p < . ). ea was more strongly related to sv (r = − . ) than to esp (r = . ) (each p < . ). the four-quadrant plot analysis indicated that patients ( %) exhibited a concordant low ea high sv pattern or high ea low sv pattern, while only patients ( %) exhibited concordant high ea high esp pattern or low ea low esp pattern (p < . ). there was a negative relationship between changes in eapsap and changes in sv in the whole population, in fluid responders (cardiac index increases > % after fa), in pressure responders (mean arterial pressure increases > % after fa) and in non-responders, while no consistent relationship between eapsap and esp changes was documented. conclusion: ea may be reliably estimated at bedside by using the ( . x femoralsap) sv ratio. ea value and ea changes induced by fa were related to sv rather than to esp. thus, ea should be considered as an index reflecting sv rather than left ventricular afterload in critically ill patients. this study included a sham group (n = ), a cpb group (n = ), an ir group (n = ) and a cpb-ir group (n = ). rats were exposed to min of cec, min of left pulmonary ischemia and min of reperfusion. fonctional endothelial dysfunction was evaluated by measurement of the pulmonary artery reactivity. systemic inflammation was evaluated by the plasma assay of il- beta, il- and tnf-alpha. the endothelial glycocalyx was evaluated by plasma assay syndecan- and electron microscopy. the statistics were performed using an anova test, p < . . we showed that cpb associated with ir induce an endothelial vasorelaxation dysfunction mainly mediated by nitric oxyde (no introduction: during circulatory shock, the goal of increasing cardiac output is to correct tissue hypoxia, which can be manifested by an increase in oxygen consumption (vo ) associated with an increase in oxygen delivery. we hypothesized that, in patients in circulatory shock, veno-arterial co gradients (pv-aco ) could be a good predictor of an increase in vo in fluid responders. patients and methods: we included patients with circulatory shock who received a fluid challenge. circulatory shock was defined by the association of vasopressor requirements to maintain mean arterial pressure (map) and a blood lactate concentration ≥ mmol l. we measured cardiac index (ci) and arterial and central venous blood gases and arterial lactate before and after a volume expansion ( ml of plasmalyte ® ). cardiac index (ci) was measured using a pulse contour analysis method (picco + pulsion, munich, germany). ci responders were the patients in whom ci increased (Δci) by > %. in those patients, vo responders were those in whom vo increased (Δvo ) by > %. receiver operating characteristic (roc) curves were performed. the data was presented as median ( th percentile- th percentile). a p < . was considered as statistically significant. introduction: the autonomic nervous system (ans) is highly adaptable and allows the organism to maintain its balance when experiencing stress. heart rate variability (hrv) is a mean to evaluate cardiac effects of ans activity and a relation between hrv and outcome has been proposed in various types of patients. while electrocardiographic hrv assessment seems to be the gold standard, we evaluated the feasibility of an automated hrv monitoring based on standard photoplethysmographic monitoring. this project is based on a prospective physiological tracing data-warehousing program (rea stoc, clinicaltrials.gov # nct ) that aims to record more than icu patients over a -years period. introduction: diabetic ketoacidosis is an acute complication of diabetes, defined as metabolic acidosis with a high anionic gap, associating hyperglycemia > mmol l ( g l), positive ketonuria, or superior or equal ketonuria to ++, it is a medical emergency which can occur in a known diabetic patient, or not. objective-to describe the clinical therapeutic and prognostic aspects of diabetic ketoacidosis in the intensive pediatric care unit at the ehs canastel oran, algeria. patients and methods: retrospective study carried out over a period of years. from january , to january , , in the intensive pediatric care service. the data was entered and analyzed using excel . results: cases were retained on hospitalizations per year, % of cases had no history with diabetes, % occurred in known diabetics with insulin, but are not followed medically. our patients were aged from months to years, but the average age of these patients was years and months, with a slight female predominance, coma was preceeded by % of cases polydipsy polyuria syndrome and % weight loss, triggered by an infectious syndrome including % of ent cases, % of respiratory infections and % of cases with digestive infections characterized by fever, abdominal pain, vomiting. the delay between diagnosis and admission to ice was - days. at admission % of patients were scored at on the glasgow scale, with presence of the cough reflex, and % were scored at < requiring tracheal intubation and mechanical ventilation of h with signs of dehydration and ionic disorders, namely hypokalemia and hypernatremia, blood glucose at admission varies between . and g l with glycosuria at +++ and ketonesuria between ++ and ++++ in only % of the patients had metabolic acidosis, a cerebral computed tomography (ct) performed in % of cases found a slight cerebral edema. therapeutic management was the rehydration, correction of metabolic disorders and introduction of insulin into sap, with monitoring and subcutaneous relaying due to ketonuria negativity. the outcome was favorable for all patients. conclusion: diabetic ketoacidosis is a major complication of diabetes which can be avoided by a good prevention campaign and systematic screening of any child suspected of diabetes, recognition of risk situations such as infections and clinical manifestations in order not to delay the management. introduction: scorpion sting is a public health problem world wide with a global distribution of species. in algeria, scorpionic envenomation occupies a prominent place in declarations. in , cases were reported. the objective of our study is to describe the epidemiological, diagnostic, therapeutic and evolutionary characteristics of the scorpion sting in children. retrospective study of cases of scorpionic envenomation hospitalized in the pediatric resuscitation department of the ehs canastel oran conducted during the year the inclusion criteria were the presence of traces with at least one locoregional or general clinical signs. the parameters studied-age, sex, city of origin, time of bite, time of management, initial first aid, time limit for admission to pediatric intensive care, and severity criteria. results: % of these cases were boys and % girls. the mediane age . % of the punctures occurred during the day, the site of the injection was the lower limb in % of the cases and there were bites scorpion cases in the west of algeria and exactly in oran and tiaret. of the cases was the upper limb. the delay of the management was from to h for of the cases who were classified in the third classed according to the clinical signs of gravity. the type of the scorpion was not identified. we can classify all the patients that we received in our service into three classes − % in class i, with local signs such as pruritus, redness, abnormalities and local pain. eva - , calmed by the infusion of mg kg iv of paracetamol and application of xylocaine cream at the site of the sting. introduction: the residence of children in intensive care is most often due to the existence of one or more organ dysfunction which requires heavy treatment (intubation, ventilation, drainage, venous tract) and this in a hostile environment which amplifies the aggression organic. the main objective of our work is to study the consequences of hospitalization of children in pediatric resuscitation. patients and methods: this is a descriptive prospective study on the outpatient consultation file of canastel's ehs multipurpose resuscitation. we studied files and assessed memory, perception of contact and nuisance factors felt by sick children. results: out of children seen in post resuscitation. the sex ratio is . . the average age of children is years ( months- years). the average hospital stay is days. the average gos (glasgow out scale) is . ( ) ( ) ( ) ( ) . the average duration of ventilation is days. % of children had central vascular access. three children describe a total memory of the stay, some memory and none. three children have a good perception about the staff, one child dissatisfied and three others indifferent. the nuisance factors described by the children are pain ( ), cold ( ), noise ( ), hunger ( ) and light ( ) . conclusion: consequences of psychological trauma, insufficiently evaluated especially by the staff, which result in the appearance of psychological disorders (nightmares and anxiety) with sometimes even severe post-traumatic neurosis. hence the need to adapt the environment and mainly noise and respect for sleep. [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the median treatment duration time was at ( - ) minutes. femoral vein was used as vascular access ( %) and most of pe procedures ( %) were performed with citrate anticoagulation. median exchange volume was at [ - ] ml and renal replacement fluid was fresh frozen plasma (ffp) in %, % ffp and % human albumin % in % and human albumin only in % of procedures. adverse effects were observed in less than % of procedures and % were lifethreathening including cardiac arrest, heart rhythm disorders, cerebral oedema and hemolysis. other remaining complications were secondary infections %, hemorrhage %, and pulmonary oedema % in all patients. twenty patients deceaded (icu mortality %). icu and hospital lenght of stay was at ± and ± days respectively. of survived patients still underwent pe after their icu discharge + totally recovered whereas ( %) were on partial remission. conclusion: pe is a routine and feasible technique in icu. this study showed that tpp was the most commonly indication of its use and that outcome was fair. adverse effects frequently occured but most of them were not severe. further studies would benefit form larger cohort to improve indications, delay of initiation and practice of this treatment. renal replacement therapy was required in % of elderly versus % (p = . ). frequency of ttp, hus and ahus was similar beetween groups. tma was more frequently associated with ongoing cancer and drug use in elderly ( vs. %, p < . and vs. %, p < . , respectively). gastro-intestinal bleeding during icu occurred more often among elderly ( vs. % (p = . )). icu mortality rate was higher ( vs. %, p = . ). no difference was found concerning plasma-exchange therapy, steroids use, and rescue treatments for refractory-ttp. discussion: increased complication and mortality rates in the elderly group might be ascribed to more cardiovascular morbidity in this population. the association between tma and ongoing cancer suggests a routine oncological workup among elderly. introduction: neutropenia, defined by an absolute count of polymorphonuclear neutrophils less than < mm , exposes patients to infectious complications that can lead to sepsis or septic shock. the mortality risk is higher. the french guidelines published in were formulated to homogenize the clinical practices and improve survival. we performed a monocentric retrospective study including all consecutive patients admitted to the medical icu of a tertiary hospital to a neutropenia with sepsis or septic shock, between the th of december and the th of december . the study protocol was approved by the local ethics committee ( . ce ) and published on clinical trial (nct ). results: patients were admitted in icu during this period. patients ( %) presented a neutropenia with sepsis or septic shock. among these patients, % had hematologic malignancies and % had solid tumour. patients ( %) was treated empirically with antipseudomonal beta-lactam or carbapenem and aminoglycoside. ( %) skin or suspected catheter-related infections were treated with anti-mrsa (methicillin-resistant staphylococcus aureus), vancomycin or linezolid. adequate antibiotics as described in guidelines was performed to patients ( %). patients ( %) received aminoglycoside ( patients received initial dose in icu, patients complement dose) and ( %) received anti-mrsa with antipseudomonal betalactam or cabapenem. patients ( %) had microbiologically documented infections with, % of bacteria ( % of gram-posit cocci, % of gram-negative cocci, % of gram-negative bacillus), % of fungi and % of viral infection ( table ) . among of them, % ( ) of esbl, % ( ) of mrsa and % ( ) of emerging highly resistant bacteria (bhre). the icu-mortality rate was % ( ) with % of -day mortality ( ). the curves of the cumulative incidence of death risk between d and d were no different according to adequate empirical antibiotic treatment as like french guidelines (fig ) . by multivariate analysis, independent factors of adequate antibiotic treatment were septic shock (or, . + % ci . - . ) and febrile neutropenia > days (or, . + % ci . - . ) at icu admission. conclusion: according to the usual clinical practice, septic neutropenic patients was already treated empirically by bitherapy including antipseudomonal or anti-mrsa if there is a skin or suspected catheter-related infection. adjunction of aminoglycoside in of the symptomatology in case of overdose, make the diagnosis difficult, especially since the drug in question is often unspecified and the toxicological analysis is not exhaustive. introduction: carbon monoxide intoxication is a public health problem in tunisia and around the world. currently, it is unclear the impact of this type of poisoning in our country for lack of declarations. we propose in our work to study the epidemiological characteristics of fatal carbon monoxide intoxications collected in the forensic pathology department of the university hospital in sfax, tunisia, to describe the different steps used in forensic diagnosis of fatal carbon monoxide intoxication and to propose preventive measures to reduce the rate of these intoxications. patients and methods: it is a retrospective study of cases of fatal carbon monoxide intoxications collected in the forensic pathology department of the university hospital in sfax, tunisia during years ( january to december ). commemoratives were collected from medical and police records. a forensic autopsy and a toxicological analysis were carried out in all cases. results: fatal carbon monoxide intoxication is the leading cause of toxic death in sfax during the period of our study. we notice a decrease in the incidence of this type of intoxication. the average age of deaths was years and months with male predominance. the peak frequency of intoxication was in cold season. the most frequent form of intoxication was accidental. the source of carbon monoxide was mainly the defective water heater often placed in poorly ventilated areas. the classic carmine red-color of lividity was found in the majority of cases. myocardial distress, favored by hypoxia, has been reported in two subjects with a pathological coronary artery. the mean hbco level was . %. however, account must be taken of the survival time and the time elapsed between death and dosing of hbco. the incidence of fatal carbon monoxide intoxication has decreased since and the victim profile has not changed too much. the fatal carbon monoxide intoxication is still persists as a public health problem in tunisia. the reduction of its frequency requires the implementation of a well-structured prevention plan based on epidemiological data from a national registry. the identification of these data requires mandatory reporting of this type of intoxication in tunisia. introduction: olanzapine is an atypical antipsychotic drug frequently prescribed in the treatement of bipolar disorder and schizophrenia. acute poisoning with this molecule is rarely reported. through this study we aimed to evaluate the incidence and describe the different clinical features of acute olanzapine poisoning. patients and methods: retrospective analysis of all cases of olanzapine intoxication admitted in -bed teaching icu between january and decembre . inclusion criteria were patient age ≥ year, acute olanzapine intoxication, the intoxication severity was assessed by the poisoning severity score (pss) of the european association of poison centres and clinical toxicologists. the evaluation of electrocardiograms was performed in the first day of hospitalization. the durations of qrs and qtc was measured and arrhythmias and conduction disorders was identified. results: patients were included, the mean age was ± years. they were males and females. long term treatment with olanzapine was noted in patients ( %) who suffered from psychiatic desease. the supposed ingestion dose ranged from to mg. the mean consulting time was ± h after the ingestion. olanzapine was co-ingested with others drugs in patients ( %). co-ingested drugs were-benzodiazepine (n = ), levomepromazine (n = ), serotonin recapture inhibitor (n = ), amitriptilyne (n = ) and biperiden (n = ). the pss was moderate in cases ( . %), severe in cases ( %) and fatal in case. the main clinical signs were tachycardia and miosis in % of cases each of them (n = ), agitation in % of cases (n = ). ecg abnormalities has been detected such as prolonged qtc in cases with a mean duration of ± ms. in the group of monointoxication ( patients) the pss was moderate in cases ( . %), severe in cases ( %) and fatal in one case. the coma glosgow scale was < fig. kaplan-meier survival between admission and -day according to adequate empirical antibiotic therapy guidelines (log rank, p = . ) in cases. mechanical ventilation was required in % of cases (n = %) with a mean duration of ± heures. the mean duration of icu stay was of ± h. twenty three patients recovered during the hospitalisation, one patient died with severe poisoning. conclusion: as showed in this study, acute olazapine poisoning could be severe, and lead to death sometimes. introduction: voluntary drug intoxication (vdi) continues to be a major health problem in many developed and developing countries. in algeria, this has become a worrying concern. awareness-raising is launched to prevent the public from these dangers. vdi are intentional or rarely accidental and can be individual or collective and affect all age groups. the vdi represents the first reason for hospitalization in the emergency department university hospital of oran. in algeria there is no national or regional register of voluntary intoxication. knowledge of the causes of drug poisoning should therefore be extrapolated from foreign studies. to draw up an assessment of the imvs, a retrospective study was carried out over the years ( - ) . this survey consisted of collecting data on the nature of the drug, age, sex, major toxidromes, severe imvs requiring hospitalization in icu, mortality, e.t.c scores and glasgo scores. results: cases of acute poisoning were collected, with a predominance in patients aged between and , a percentage of . %. in addition, most patients were female with . %, a sex ratio of . with p < . . the main toxidromes were-opioid syndrome in % of cases and anticholinergic syndrome in % of cases. etc with a score of > % accounted for % of patients. severe vdi requiring resuscitation hospitalization were %. conclusion: acute poisoning remains high and steady in the oran region and the under- age group represents the most affected category. awareness campaigns must be launched throughout the year to better conserve and store medicines, phytosanitary products and other chemicals. improved socio-economic conditions would help to reduce voluntary intoxication. introduction: scorpionic envenomation is unevenly distributed throughout the world and is particularly frequent in some regions of the world, notably north africa. the purpose of this work is to describe the epidemiological profile of the scorpionic envenomations admitted to the resuscitation department of mahres. patients and methods: a prospective study conducted at the mahres intensive care unit over a period of months ( until ), including all patients admitted for scorpion envenomation. results: we collected cases of patients admitted to the resuscitation department of mahres from to , including cases of scorpionic envenomations, i.e. . %. the median age was years with extremes ranging from to years. the sex ratio was . scorpion stings occurred at night in % of patients, % in the first half of the night (between pm and - pm) and % in the second half of the night ( to h). venom inoculation points were in the lower limbs in % of cases, followed by upper limbs ( %). the color of the incriminated scorpion was yellow in %, black in % and unspecified in % of the cases. for admission classes, there were % class i, % class ii and % class iii. the traditional therapeutic gestures practiced by the patients or their entourage were the laying scarification ( %) and the suction ( %). all patients received anti-scorpion serum, an analgesic, serum and tetanus vaccine. the progression was favorable in all cases after an average hospital stay of ± days. conclusion: scorpionic envenomations are indeed a reality in mahres with a non-negligible frequency despite under-reporting of cases treated by traditional medicine or in other hospitals. they mostly affect young people and the associated clinical manifestations often remain benign. introduction: severe pediatric poisoning is defined by the need for intensive care monitoring due to the nature, quantity of the substance and or clinical manifestations. it is one of the frequent reasons for admission to emergency and resuscitation. the purpose of this work is to identify poisoning in children admitted to pediatric intensive care units in order to assess the frequency, identify the products involved, and the clinical and evolutionary aspects. patients and methods: this is a descriptive study over a -month period in the canastel oran multi-purpose pediatric intensive care unit from july to july . we included all children aged - years admitted for ingestion and inhalation of products toxic. results: children admitted to pediatric intensive care, mean age was years, % under years with extremes of months and years, a female predominance of % was observed with a slight predominance of accidental poisoning ( %) compared to voluntary poisoning ( %). in % the toxic is ingested orally. the most frequent toxicants were drugs with cases ( %), mostly antidepressants and antiepileptics, followed by organophosphates with cases ( %), co cases ( %), petroleum products and plants with cases ( %). the main clinical signs were neurological signs ( %) with predominance of coma and convulsions in cases ( %), respiratory distress was present in cases ( %) and digestive signs cases ( %). for therapeutic management gastric lavage, charcoal and antidotes were the most frequent treatments. the evolution was marked by a mortality of % or a death secondary to a poly-medicinal intoxication voluntary in a girl of years. mechanical ventilation in cases ( %) and an average hospital stay of days. conclusion: acute poisoning is a medical emergency that may require resuscitation. young children are most exposed with drugs are the most frequently incriminated. we propose, as a preventive measure, companions of information on the dangers of toxic products and especially of medicines by the surveillance of the child and the regulation of certain products. introduction: the place of neuron specific enolase (nse) dosing remains uncertain as an indicator of neurological prognosis after a cardiac arrest, the threshold value for predicting an unfavorable evolution being variable from one study to another. our objective was to determine a nse cut-off value predictive of poor neurological outcome after a cardiac arrest. patients and methods: we realized a monocentric prospective trial in a medical icu of a french university hospital from january st to december th . all patients over years old hospitalized for a cardiac arrest in medical icu were included. patients who died during the first h or admitted for cardiac arrest with a neurological cause were excluded. serum nse values (elecsys nse test, cobas ® analyzer) were assessed at h and h after cardiac arrest. somatosensory evoked potentials were recorded between h and h . the primary endpoint was neurological outcome at month using the cerebral performance category scale (cpcs). cpcs or was considered as favorable outcome and cpcs higher than as poor outcome. data were collected using cardiologic or neurologic consultations report, or by phone call to the patient. using a roc curve we determined the nse value at h with higher specificity and acceptable sensitivity. results: we included patients. average age was years old. noflow time and low-flow time were respectively . and min. hypothermia was performed in ( %) patients. patients ( %) died in the icu. the -day and -months survival rates were respectively and % with a favorable outcome of % at months. on the roc curve we found a cut-off value of ng ml with specificity of . ci % ( . - . ) and a sensibility of . ci %( . - . ). area under curve was . ci % ( . - . ). out of the patients with a rising nse between h and h had an unfavorable outcome. among patients with nse > ng ml, the cortical n responses were bilaterally present in of them. conclusion: in our study nse value over than ng ml at h was predictive of poor neurological outcome after cardiac arrest. nse may prove to be a useful marker in patients with present n responses, possibly limiting the duration of hospitalization by introducing therapeutic limitation or withdrawal of support. physicians assessment of prognosis in icu patients with brain introduction: outcome prediction in icu patients with severe brain damage is a difficult task with observed heterogeneity in physicians estimation. the aim of the survey was to evaluate the prognostic estimates and treatment recommendation of intensivists in real patients with various causes of severe brain damage. patients and methods: a web anonymous survey including a summarized clinical report of four patients who stayed in the icu was submitted to french intensivists. patient presented with prolonged hypoglycemic coma, patient with intracerebral hemorrhage, patient with central and extra pontine myelinolysis, patient with a brainstem hemorrhage. all these patients received full treatment in the icu and had a -month follow-up. physicians were provided with the four clinical vignettes including clinical history, brain imaging and other relevant exams (csf, eeg,…), evolution of symptoms within the first days of the icu stay. they had to estimate -month outcome using modified rankin scale (mrs) where a score from to was considered as a good outcome and to as a poor outcome. they had to provide a recommendation about care among the following-full treatment, care limitation, care withdrawal. results: physicians completed the survey. there were ( . %) female. ( %) respondents were residents and ( . %) had a > -year of experience. patients and had a good -month outcome with mrs and mrs respectively while patients and had a poor outcome, both with mrs . correct prognosis estimations were ( %), ( . %), ( %) and ( . %) in patients to respectively. care limitation or withdrawal was recommended by ( . %), ( . %), ( %) and ( %) respondents in patients to respectively. of interest, care withdrawal was recommended by ( . %), ( . %), ( . %) and ( . %) respondents in patients to respectively. univariate analysis did not display any factor related with a good prediction of prognosis. conclusion: in this study, overall predictions were pessimistic with important variations among respondents. although decisions to withdraw life sustaining care were relatively low with regard to estimated prognosis, both inappropriate care limitation leading to self-fulfilling prophecies and unreasonable prolonged life supportive care could result from these estimations. introduction: organ harvesting is a national priority because of the shortage of organs, responsible each year for the lengthening of transplant waiting lists. among the identified potential donors, the main cause of non-harvesting is the refusal of organ donation (od), which exceeds % in france and % in paris area. patients and methods: in a network of hopitals, each procedure on a potential donor by the donor co-ordinator is recorded in a report. after selection of the reports with interviews with relatives about od between and , the data in the reports were collected and a multivariate logistic regression was performed to identify the factors associated with the refusal. results: reports with interviews about od was found. the overall opposition rate is . %. among the children ( . % of cases) the opposition rate is . %. among adults, ( . %) expressed their will about od during their lifetime, with an opposition rate of . % and for the ( . %) of them who never expressed their will, the opposition rate is . %. the factors associated with opposition in multivariate analysis are presented in table . when the deceased had never expressed their will, the reasons given by the relatives to justify the refusal are specified in . % of the reports. these are religious grounds ( %), cultural grounds ( %), respect for physical integrity ( %). in % of the cases, relatives believe that the deceased would have been opposed, and in % of the cases, they choose to refuse because they do not know the deceased's opinion. discussion: french law is based on presumed consent. despite this, it is noted that when patients had never expressed their opinion about od (and therefore had not refused it), the opposition rate reached . % and was comparable to the patients who had expressed themselves. conclusion: in our study, factors related to refusal of od are mainly related to the characteristics of the deceased (religion, culture, history of ethylism) and those of relatives (disagreement, presence of a spouse), but little to the way of doing the interview. however, there is a trend for less opposition when the interview is conducted during the day (between - and - ). on the other hand, when relatives first address the issue of od, the opposition rate is lower. introduction: french intensive care society guidelines and the claes-leonnetti law recommend that intensive care teams organize collegiate and multidisciplinary discussions regarding limitation and withdrawal of care decisions. these moments, coined ethical staffs in our unit, require freedom and safety of speech, which can be difficult to obtain when people are caught in hierarchical and or power relations. we sought to assess the representations, perceptions and opinions of icu personnel regarding ethical staffs. patients and methods: a questionnaire, developed by the icu psychologist, was distributed to the entire unit (secretaries, nurses, nursing auxiliaries, doctors) over a period of months. this -question questionnaire covered session organization and power relations between participants. results: among the questionnaires distributed in the icu, were retrieved and analyzed. medical function was associated by respondents with roles linked with power (leading, knowledge, decision, explanation) whereas paramedical function was associated with roles linked with care (perception, account, spokesperson) (fig. ) . regarding representations of decision making, nurses were considered as decision makers in cases ( %) and doctors in cases ( %). discussion: although ethical staffs are presented as a place where each opinion counts, stereotypes representation appear in the different roles assigned-on one side doctors are in charge of explanation and decision, and on the other side, nurses are taking care of patient's feelings and assume a role of spokesperson. these stereotypes correspond to gender stereotypes assigning women to positions of care, empathy and relationship, and men to more intellectual and leading skills. these gender stereotypes attest a hierarchy internalized by each one, as highlighted by social sciences and gender studies. conclusion: our results highlight the existence of a global idea, shared by the majority-doctors are decision makers and therefore are in a power relation regarding paramedical staff. this hierarchical relationship persists in this moment wished egalitarian (each opinion would count equally). these is a linkage between professional power relations and gender power relations, which show an association between doctor and masculine "qualities" and caretakers and feminine "qualities". these power relations are rarely acknowledged but could have a significant impact on the decision process of these meetings, and should be further investigated. results. despite the diary, % had a qspt score > , indicating a higher post traumatic disorders. patients ( %) presented a anxiety score > and patients ( . %) had a depression score > . these results underline the need of psychological support after the stay. conclusion: many survivors of intensive care unit reported a high level of psychological distress. it seems important offer at this patient a psychological support after an intensive care unit stay. most patients needs return in intensive care unit to understand some elements of hospitalization. actually, this support lack to screening and treatment this psychological morbidity. prevalence and description of the complications following a percutaneous coronary intervention for a myocardial infarction in non-cardiac critically ill patients: a retrospective single-center introduction: type myocardial infarction (mi) is an emergency, which immediate invasive strategy by a percutaneous coronary intervention (pci) is based on guidelines for cardiologic patients. conversely, the invasive strategy remains uncertain for patients hospitalized in the intensive care unit (icu) for a primary non-cardiac disease with mi as a complication, given the ischemic and hemorrhagic risks. we aimed to assess the prevalence of-and describe the major adverse cardiac and hemorrhagic events occurring in the icu after an invasive strategy by pci in this context. we conducted a retrospective single-center -year ( - ) study. all the consecutive icu patients with a suspected mi undergoing a coronarography were screened. patients treated with an invasive strategy (pci performed within days of mi) were included. patients hospitalized in icu for cardiac disease were excluded. the major adverse cardiac events (mace) were defined as post-procedure events occurring in the icu, including death from cardiovascular causes, mi recurrence, need for emergent revascularization and stroke. the major adverse hemorrhagic events (mahe) were defined as post-procedure events occurring in the icu, according to the bleeding academic research consortium. results: icu patients suspected of mi underwent a coronarography. patients ( %) had significant coronary lesions. twelve patients were excluded-tri-truncular coronary involvement (n = ), delayed procedure (n = ), cardiogenic shock (n = ). patients were included ( men, years [iqr - - - ], patients mechanically ventilated, patients with sepsis septic shock, median sofa score at the time of mi [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] ). a pci was performed during the first day after diagnosis of mi in patients ( %) (median time- day [iqr - - - ]). a mace occurred in patients ( %), including stroke (n = ) and mi recurrence without revascularization (n = ). no patients deceased from cardiovascular causes in the icu, neither at months post-procedure (table ) . a mahe occurred in patients ( %), of whom had a mace. altogether, the prevalence of major adverse cardiovascular events combining mace and mahe was . ( % ci . - . ). there was no difference between septic and non septic patients regarding the prevalence of mace or mahe. the prevalence of adverse cardiovascular events after an invasive strategy by pci is high in non-cardiac critically ill patients with mi. larger studies are needed to determine which patients may benefit from this procedure. introduction: resuscitated cardiac arrest (ca) lead to immune alteration including lymphopenia, decreased monocyte hla-dr (mhla-dr) expression and dysregulated production of cytokines. in a recent multicenter randomized clinical trial, we tested the hypothesis that cyclosprine a (csa) would limit organ failures following out-of-hospital cardiac arrest (ohca). in a substudy, we aimed to determine the influence of csa on ohca-induced immune dysfunction. this study is a predefined substudy of the randomized cyrus trial (cyclosporine in ca resuscitation). patients with non-shockable ohca randomly received either an intravenous bolus injection of csa ( . mg kg) at the onset of advanced cardiovascular life support (csa group) or no additional intervention (control group). patients from the coordinating center were sampled at admission (d ) and at h (d ). complete blood count, cd + lymphocytes count and mhla-dr were evaluated by flow cytometry. serum levels of il- , il- , il- , il- and tnf&# + were measured by elisa test on frozen samples. results: a total of patients were sampled- patients from the csa group and from the control group. the characteristics of the patients, including resuscitation data, were also similar between the two groups at admission. the severity of organ failure as assessed by the sofa score at admission was similar between groups. all patients introduction: critically ill patients experience major insults that lead to increased protein catabolism and a significant loss of lean body mass with an impact on weaning from the ventilator and muscle recovery. in critically ill patients, severe and persistent testosterone deficiency is very common after icu admission. administration of testosterone may induce skeletal muscle fiber hypertrophy and decreases protein breakdown. the aim of this work is to assess testosterone levels in critical ill patients and to evaluate the safety of testosterone gel administration. this is a single center study realized in a university icu of beds. total testosterone levels were measured in critical ill men with at least one organ dysfunction with sofa > . the study drug was androgel, a formulation of % testosterone in an alcohol-water gel, approved by the ansm for treatment of hypogonadism in men. androgel was applied to the abdomen, shoulders or upper arms once a day at the same time to dry and intact skin during icu stay. the daily dose was mg in men and mg in women daily. patients with history of prostate or breast cancer or psa > ng ml were excluded. results: total testosterone levels were measured in men. median length of stay at the time of measurement was days in icu and days in the hospital. plasma testosterone levels were low in all but patient. median testosterone level was ng dl (normal values - ng dl). testosterone levels were not correlated with score sofa or length of icu stay. we found a moderate positif correlation between testosterone levels and length of hospital stay (r = . =). testosterone gel was administered in men and in women. in these patients, the median score sofa was , icu death occurred in patients ( % icu mortality), median length of ventilation was days and median length of stay in icu days. all patients received mechanical ventilation and vasoactive treatment. patients needed renal replacement therapy. androgel was well tolerated. no ischemic cardiovascular events were described. there was no application site reaction or acne. median length of testosterone gel administration was days. conclusion: critical ill patients have low testosterone levels. testosterone gel may be safely administered during the acute phase in icu. randomized clinical trials are needed to evaluate the impact of testosterone gel on physical performance. introduction: stroke is the leading cause of physical disability and the second leading cause of death worldwide. two thirds of all strokes occur in developing countries and is increasingly a public health problem. the aim of this study was to evaluate the epidemiology of strokes in oran, algeria in order to create a stroke registry. patients and methods: a cross-sectional study was conducted on all patients admitted for stroke at the oran chu between january and september . sociodemographic data, modifiable and nomodifiable risk factors, type of stroke, degree of disability, severity scores (glasgow and nihss) were studied. the spss software, log rank test, was used for data analysis and statistical testing as well as kaplan-meier for survival studies. results: a total of stroke patients were enumerated, aged - years (mean ± sd = . ± . ), . % had an ischemic stroke and % had a haemorrhagic stroke. % of the patients were men and % of the women. high blood pressure, diabetes, emboligenous heart disease and smoking were the most common risk factors. intra-hospital mortality was . % and the overall survival rate at days was %. conclusion: this epidemiological study demonstrates that strokes at oran hospital may be similar to other locations. however, it seems necessary and useful to design a continuous patient registration system. introduction: the prevalence of hyperosmolar states and the relationship with mortality nevertheless remain unquantified and not objectively demonstrated. the aim of this work is to determine whether hyperosmolarity is a prognosis factor, and to assess the impact of hyperosmolarity on the evolution of patients. patients and methods: this is a retrospective descriptive and analytical study performed at the medical intensive care unit at the university teaching hospital ibn rushd in casablanca on the cases admitted during year. we noted epidemiological, clinical, biological and evolutionary parameters of all the patients and divided them into two groups according to their osmolar states, the first non-hyperosmolar group with plasma osmolarity of less than mosm l, called the control group and the second hyperosmolar group, plasma osmolarity greater than or equal to mosm l. results: patients were included. the first group comprised patients ( %) and the second comprised patients ( %). the two groups did not differ significantly about sex and age. hyperosmolar patients had more diabets . %. patients in the two groups did not show significant differences in clinical outcomes, including apache ii and saps ii scores. significant differences are reported between the two groups, in natremia, creatinemia, liver transaminases. the plasma osmolarity was significantly different between the two groups with a mean in the control group of . ± . mol l while in the hyperosmolar group it was . ± . mosmol l (p = . ). the prevalence of hyperosmolar states in the study was % with % mortality. in the control group % were intubated-ventilated + . % received vasoactive drugs and . % received antibiotic therapy. in the control group + %of the patients were complicated by nosocomial infection, . % by septic shock and % diseased by thromboembolic complications. the deceased subgroup used intubation artificial ventilation in . %, vasoactive drugs in %, and antibiotic therapy in . %. in the surviving subgroup, . % only contracted the nosocomial infection. in the subgroup died . % are of mixed hyperosmolar type + . % hyperglycemic hyperuremic + . % hyperglycemic hypernatremic type. conclusion: hyperosmolar states are an independent a prognosis factor. intubation and ventilation, vasoactive drugs and antibiotic therapy increases considerably in hyperosmolar states. furthermore, it induced serious complications as nosocomial infections and septic shocks that further aggravate the prognosis even within hyperosmolar states. introduction: hyperthermia represents a major life-threatening medical emergency, and is also one of the leading causes of death in young athletes worldwide. its incidence is rare and little understood, but its mortality is on the rise. the objective of this study was to describe the population of patients admitted for exertional hyperthermia in martinique and guadeloupe and to determine the prognostic factors. patients and methods: retrospective and prospective study, including all patients admitted for exertional hyperthermia in both emergency and resuscitation services in martinique and guadeloupe from january to june . results were expressed as mean ± sd or %. results: in years, patients were observed (age- ± , men and women), the main antecedents of which were- hypertension, chronic oh, psychoses, stress hyperthermia. ( %) of the patients had seizures initially. the pre-hospital management was < min. nevertheless, ( %) patients were admitted to icu due to organ failure (neurologic %, hemodynamic %, liver %). the progression was favorable, deaths, including fulminant hepatitis and multi-visceral failure. the average length of stay in intensive care units was days (± ). conclusion: despite considerable preventive measures, stress hyperthermia represents a major problem within the military, soldiers and other athletes, with a mortality rate about % in most published series. the most effective method is immersion in ice water. there is an urgent need to provide the region with a clear preventive policy, including a relief action plan, training for doctors, athletes and other health professionals at risk of hyperthermia. chapoutot anne-gaëlle , leteurtre stéphane , chamouine abdourahim ( ) . the university hospital of lille is a pediatric center including several itecus in its pediatric hematology or gastrology departments, and more recently in its pediatric surgical department. moreover, there are - itecu extra-beds within the - bed pediatric intensive care unit (ivecu). the hospital of mayotte has no pediatric ivecu but a polyvalent one for adults, which receives children when necessary, as well as a bed itecu. the aim of this study was to describe prospectively the pediatric population which was admitted in the itecus of lille and mayotte over a one-year period from june to may . patients and methods: in this twin-center, prospective and observational study, data were collected for each patient admitted during the test period in itecus of both lille and mayotte pediatric hospitalsgeneral information about the patient, characteristics of each stay, severity scores on admission, type of treatments implemented, the report of the stay and patient's evolution. a standard declaration was made with an authorization granted by the local commission on informatics and liberty (french commission informatique et liberté, cil). results: during the course of the study, about children were admitted in each center. the collected data allow to describe and compare both populations in terms of severity of each patient's condition. this study based on a very large cohort has permitted to compare the population of a regional hospital with that of a university hospital and to demonstrate that a health-care provision including a pediatric intensive care unit is needed on mayotte island. introduction: simulation in intensive care is an innovative method for teaching. respiratory settings are responsible for some morbi-mortality of our patients. for this reason we develop a simulator of artificial ventilation (simva) and virtual patients. mathematical model resolved differential equations of chest and lung movements in order to match with a clinical data base. the goal of this study was to evaluate and compare virtual patients respiratory mechanic with the results of different protocols of ventilation from large randomised controlled trial-arma ( ) and express ( ). patients and methods: virtual patients had ards, and were defined by different thoracic and pulmonar compliance, total resistance, lung volumes, pressure-volume relation, and pressure and volume recruitment coefficients. ventilatory protocols were high versus low vt (arma study) and max versus min distension according to pep (express study). each virtual patient was titrated on the simulator with the protocols. respiratory frequency was set around cycles minute and adapted to protocols. respiratory mechanic after titration was recorded and compared to results of the studies. results: results are summarised in the table-the difference between virtual and real patients were not significant. vm l/min . ( . ) . ( . ) . ( . ) . ( . ) . ctp: tharacopulmanar compliance (ml/cmh o) discussion: inspiratory plateau pressure and thoraco-pulmonary compliance were able to change according to pep or vt settings within the same range as the large rct studies. mathematical model of recruitment was adapted to create many different results while pep was titrated according to respiratory mechanics with the express protocol. conclusion: simulation of artificial ventilation with a software can be realistic and might be an interesting pedagogical tool to teach interactively and repetidly ventilatory settings and respiratory mechanics interactions in ards without any risk for the patient in our units. introduction: expiratory flow limitation (efl) has previously been investigated in ards patients on zero peep by using negative expiratory pressure (nep) technique on tidal breath. in ards patients with efl peep improved oxygenation from intrinsic peep homogenization rather than lung recruitment. the nep technique is no longer available. as efl should reflect airway closure it is important to assess it. we described a new technique to assess efl. patients and methods: thirty-nine ards patients ( mild, moderate, severe) were investigated at peep and . they were intubated, mechanically ventilated (evita xl) in volume controlled mode (tidal volume ± ml kg predicted body weight) in the semi-recumbent position. airway pressure and flow measured proximal the endotracheal tube were continuously recorded (biopac ). we measured respiratory mechanics by the occlusion technique at each peep and recruited lung volume between peep and by using low flow inflation method associated with measurement in change in end-expiratory lung volume. for the latter, patient was manually disconnected at the end of baseline tidal inflation downstream pneumotachograph to atmosphere til zero flow, then reconnected at previous settings. efl was assessed offline by superimposing flow-volume loops of disconnected and baseline breath. efl was defined if no change in flow occurred over all or part of the disconnected expiration as compared to the baseline breath and no efl (nfl) if any increase in flow during the expiration was present (fig. ) . the percentage of the tidal volume involved in efl was measured. results: efl was present in patients ( %) over % of the tidal expiration. patients with efl had significant higher body mass index ( ± vs. ± kg m , p < . ) and totalpeep at peep ( ± vs. ± cmh o, p < . ) than nfl patients and tended to be more hypoxemic. at peep efl patients had a significant better compliance ( ± vs. ± ml cm h o, p < . ) with no change in recruited lung volume ( ± vs. ± ml) and tended to be more hypoxemic than nfl patients. mortality at icu discharge was % in efl versus % in nfl (p = . ). conclusion: measurement of efl is feasible without the nep technique. at higher peep ards patients with efl markedly improved compliance of the respiratory system not related to lung recruitment. further studies are required to better understand efl in ards patients and to assess its impact on patient outcome. limiting factor being carbon dioxide accumulation and hypercapnic acidosis. extra corporeal carbon dioxide removal (ecco r) intervenes by maintaining ph and pco within physiological ranges. this combination is called ultra-protective ventilation. we report our experience with ecco r in ards and non ards patients with a focus on feasibility and safety. patients and methods: from june to july all patients who have undergone ecco r in our icu were included consecutively and prospectively. venovenous ecco r was used through a dual lumen venous catheter (femoral or jugular). results: nineteen patients underwent ecco r for a total of sessions. ecco r was implemented through a dual lumen venous catheter (femoral or jugular) with different devices-hemolung respiratory assist system ® (alung) (n = ), ila activve ® (novalung) (n = ) and prismalung ® (prismaflex system) (n = ). sessions were (iqr . - . ) days long. catheter diameters were fr (n = ), fr (n = ), fr (n = ) and fr (n = ). thirteen patients suffered from ards and had non ards indications for ecco r, including ultraprotective ventilation. tidal volume decreased during ecco r from . (iqr . - . ) to . (iqr . - . ) ml kg of predicted body weight (p < . ) while ecco r allowed maintaining of ph and pco within acceptable range (fig. ). driving pressure decreased from (iqr - ) to (iqr - ) cm h o (p < . ). the main adverse effect was thrombocytopenia ( patients). six selected patients had no anticoagulation during ecco r because of high bleeding risk. discussion: ultra-protective ventilation was achieved with a decrease of tidal volumes (vt < ml kg) and positive pressures. few data on ecco r are available in patients at high risk of hemorrhagic complications, we report here a subgroup of patients who underwent efficiently ecco r without anticoagulation. six patients underwent ecco r for non ards indications, of them had no structural damages to the lungs which has never been reported and eccor allowed implementing ultra-protective ventilation with no major adverse effect. we report our experience on ecco r for ards and non ards indications. ultra-protective ventilation (vt < ml kg) was safe and feasible. the impact of general practitioners consultation on ards complicating community acquired pneumonia donval ulysse , tadie introduction: community-acquired pneumonia (cap) is a potentially severe infection that results in numerous general practitioner (gp) visits and hospital admissions each year. cap is also the most frequent single cause of acute respiratory distress syndrome (ards). risk factors for development of ards in the course of cap are not clearly defined although prognostic factors associated with mortality have been extensively studied. gp visits, as an early diagnosis and earlier access to antibiotics prescription could significantly affect the course of cap. the aim of the present study was to evaluate the impact of general practitioners consultation on ards complicating cap admitted to our icu. patients and methods: we retrospectively reviewed the medical records of all patients aged over years admitted between october , and december , , for ards complicating community acquired pneumonia with a pao fio ratio < mmhg after at least h of lung protective mechanical ventilation (mv). ventilatory modalities for ards had been protocolized over the study period as our icu was recruiting patients for two consecutive multicenter trials (acurasys and proseva). consequently, the protective ventilatory strategy used in these two clinical trials was applied to every patient with ards. patients were divided into two groups according to whether or not they visited a gp before icu admission. : patients were admitted for ards complicating cap. patients ( %) had visited a gp before admission in icu (gp +) and did not (gp-). analysis of demographic data, respiratory microbiology patterns, ards severity at admission did not show any differences between the two groups. sofa score at admission was significantly higher in gp-compared to gp + patients ( . ( - ) vs. . ( - ) respectively + p = . ) although respiratory sofa scores were not different ( ( - ) vs. ( - ) respectively + p = . ). ( %) gp-( %) and ( %) gp + patients presented septic shock at icu admission (p = . ). multivariate analysis found that gp consultation ( . [ . - . ] + p = . ) with antibiotics prescription ( . [ . - . ] + p = . ) were associated with decreased mortality at day ( fig. ) . in patients admitted to our icu for ards complicating community acquired pneumonia, gp visits prior to icu admission was associated with a better outcome. the beneficial effect may be due to earlier antibiotic prescription which could significantly lowered severe infection and septic shock. introduction: optimal peep level during ards remains controversial because of its beneficial and adverse effects. the optimal level of recruitment and its effect on oxygenation are not well defined and no technique is currently validated. the aim of our study was to evaluate the correlation between the recruited pulmonary volume estimated by a new technique (crf inview ® ) and the evolution of pao as well as the respiratory and hemodynamic tolerance of the application of an increasing levels of peep . patients and methods: a prospective, monocentric study that will last years (january -january ), taking place in the intensive care unit at the military teaching hospital of tunis and including patients if they met standard criteria for ards (berlin criteria). the main criterion for judgment was the correlation between the recruited pulmonary volume estimated by a new technique (crf inview ® ) and the evolution of the pao after application of three increasing levels of peep ( - - ). the other secondary criteria were the respiratory and hemodynamic tolerance of the application of increasing levels of peep measured by the picco ® technique. aimed to investigate the concordance between the onset of three vae tiers and valrti, and their impact on outcomes. we performed a retrospective analysis of prospectively collected data from patients requiring mechanical ventilation for more than days in a -bed mixed icu of a tertiary university teaching hospital, between january and december , . vat and vap episodes were assessed by prospective surveillance of nosocomial infections, according to the american thoracic society criteria. vae were identified retrospectively, according to current cdc definitions. the agreement between vac, ivac, pvap and valrti was assessed by k statistic. the impact of vae and valrti on duration of mechanical ventilation, icu and hospital length of stay and mortality was also assessed for the first episode of vat and vap. results: we included patients ( ventilator days). vap ( . per ventilator-days), vat ( . per ventilator-days) and vae ( . per ventilator-days) were diagnosed. there was no agreement between vat and vae and the agreement was poor between vap and vac (k = . , % ci . - . ), vap and ivac (k = . , % ci . - . ) or vap and pvap (k = . , % ci . - . ). patients who developed vat, vap or vae had significantly longer duration of mechanical ventilation, icu and hospital length of stay, compared to patients who did not, with similar mortality rates. conclusion: vae are not relevant for vat diagnosis and have low agreement with vap, despite their negative impact on ventilation duration, icu and hospital length of stay ( fig. ) . the introduction: post-operative pneumonia (pop) is a frequent and severe complication of major lung resection surgery. in , we changed our surgical antibioprophylaxis protocol from cefamandole to amoxicillin-clavulanate and observed a significant decrease of pop incidence and mortality. in , we additionally implemented in the respiratory intensive care unit (ricu) an antimicrobial stewardship program based on a local antimicrobial guideline and a weekly multidisciplinary review of all antibiotic therapies by ricu physicians, infectious diseases specialists and microbiologists. our objectives were to describe our current epidemiology of severe pop and to assess the quality of antibiotic prescriptions. patients and methods: all patients with severe pop occurring within days after lung resection between january and december were included. we collected data on clinical presentation, results of microbiological investigations, antibiotic regimen and outcomes. the quality of antibiotic use was assessed using indicators previously validated in the literature. results: over patients who underwent major lung resection in our center, matched criteria for severe pop and were included. most were males (n = , %). the median age was years (minimum- + maximum- ). most patients had chronic obstructive pulmonary disease (n = , %) and ( %) a history of non-pulmonary cancer. the resection consisted in lobectomy in % (n = ). the median length of stay in ricu was days ( + ), and -day mortality was % (n = ). respiratory microbiological samples were obtained in all patients, in most cases invasively per bronchoscopy ( %). microorganisms were cultured at a significant level in ( %) patients. predominant species were enterobacteriacae ( %), haemophilus influenzae ( %), staphylococcus aureus ( %) and pseudomonas aeruginosa ( %). microorganisms were sensitive to third generation cephalosporins in ( %) and to piperacillin-tazobactam in ( %). in patients treated empirically, antibiotics were prescribed according to the guideline in % ( ). in documented pop, empiric antibiotics were active against documented micro-organisms in ( %), and were correctly changed to pathogen-directed therapy in ( %). the median duration of antibiotics was of days ( + ). conclusion: ten years after implementation of amoxicillin-clavulanate as surgical antibioprophylaxis, the proportion of enterobacteriacae increased. the -day postoperative mortality rate remained below %. we report high adherence to the guideline for the choice of empirical therapy and treatment duration. the rate of de-escalation to pathogen-directed therapy could however be improved considering the high rate of bacteriologically-documented pop. resistance of pa has reduced between both periods from % to % (p < . ) for ceftazidim, from % to % (p < . ) for cirpofloxacin and from % to % (p < . ) for imipenem. nevertheless, among the cases, the p period did not change the risk of developing an infection (rr = . , ci % . - . ), a vap (rr = . , ci % . - . ), a septicemia (rr = , ci % . - . ) or the mortality rates (rr = . , ci % . - . ). conclusion: colonization and infection with pa are risk factors of increased mortality rates and alos in icu. an antibiotic stewardship program allows to reduce the incidence of patients having a positive sample with pa, and the antibiotic resistance of pa strains, without reducing the infection rate of these patients. impact of a local care protocol on the duration of antibiotic therapy in community-acquired peritonitis: years of experience introduction: the use of antibiotics is a major public health, economic and ecological challenge. in , a french national warning plan was created to manage the use of antibiotics. it advocates monitoring of the prescription of antibiotics and the implementation of measures to assess professional practices. the great majority of guidelines concerning the duration of antibiotic therapy in community-acquired peritonitis are based on studies with low level of evidence. the objective of this study is to evaluate the implementation of a standardized operational report (sor) with a local antibiotic protocol in the management of community-acquired peritonitis at our institution. patients and methods: this is a monocentric, prospective cohort study-before and after the establishment of the sor. the primary endpoint is duration of antibiotic therapy. secondary endpoints are length of hospitalization, infectious complications, mortality, and changes in local bacterial ecology. we have also evaluated retrospectively these different criteria on cohort was constituted since . results: a total of patients were enrolled from january to june and patients from may to may . the duration of antibiotic therapy was decreased by to days in localized peritonitis (p < . ) and to days in generalized peritonitis (p < . ) (figure) . however, the compliance to the protocol was only %, which leads to an increase in the duration of antibiotic therapy and hospital stay when not used (p < . ). the hospital stay decreased from to days in the localized peritonitis (p < . ). amoxicillin clavulanic acid (amc) is the most used antibiotic with an efficiency of %. there was no impact on morbidity and mortality when amc was inadequate. the bacterial ecology was not modified, the rate of extended-spectrum beta-lactamase (esbl) producing enterobacteria (esble) was %. the use of a standardized antibiotic protocol reduced antibiotic therapy duration and hospital stay, particularly in localized peritonitis despite incomplete compliance to the protocol. to achieve full compliance, we need to continue the training of different physicians and continue the spread of the protocol. introduction: bacterial meningitis is an important public health problem because of its frequency and severity. they remain a major cause of mortality and morbidity in developing countries. the aim of our work is to establish the epidemiological characteristics and the prognostic factors . patients and methods: we did a retrospective descriptive and analytical study and we included all the patients admitted for severe meningitis for year in the medical intensive care unit of the university teaching hospital ibn rushd at casablanca-morocco. results: patients were included. the incidence of severe meningtis was . %, the mean age was years old and the sex ratio h f was , . , % were pneumococcal meningitis and % were tuberculosis in univariate analysis, factors influencing mortality significantly-the male sex patients with pulmonary tuberculosis as an antecedent.• a low glasgow score at admission. the presence of a neurological deficit arterial ph, mean (sd) arterial lactate, mean (sd) kidney disease-improving global outcomes chronic kidney disease guideline development work group members. evaluation and management of chronic kidney disease-synopsis of the kidney disease-improving global outcomes clinical practice guideline dramatic increase in venous thromboembolism in children's hospitals in the united states from antithrombotic therapy in neonates and children acute childhood arterial ischemic and hemorrhagic stroke in the emergency department childhood hemorrhagic stroke-an important but understudied problem emergency management of deeply comatose children with acute rupture of a cerebral arteriovenous malformation goulmane mourad -m.goulmane@hotmail.com annals of intensive care we recorded episodes of nosocomial infections-pneumonia (n = , . %), bacteremia (n = , . %), catheter related infections cri (n = , . %) and urinary infections (n = , . %). pathogens isolated were largely dominated by non-fermentent gram-negative bacilli (n = , . %)-acinetobacter baumanii (n = , . %) with % resistance to imipenem and tygecycline, pseudomonas aeruginosa (n = , . %) with . % resistance to ceftazidim and stenotrophomonas maltophila (n = ). other gram-negative bacilli were enterobacteries (n = ), which were wide-spectrum betalactamase secreting (n = ) and carbapenemase (n = ). gram-positive cocci were the second highest (n = , . %)-coagulase negative staphylococcus (n = ) which were resistant to methicilline ( %), enterococcus (n = ) which were resistant to vancomycin (n = , . %), staphylococcus aureus sensitive to methicilline (n = ) and streptococcus (n = ). candida was incriminated in cases of cri we report here that neonates had a reduction in hla-dr expression after cpb, and those with prolonged decreased hla-dr in the early postoperative period (day ) could represent a subpopulation at greatly increased risk of later ni. if confirmed in a larger cohort of patients, our findings could indicate that hla-dr may be a useful biomarker of immunosuppression after cpb in neonates. non-traumatic hemorrhagic stroke (nths) in comatose children: epidemiological features and clinical presentation conclusion: compared to normobaric ltot the fio is lower during niv with the same o flow. compensation for intentional and nonintentional leaks and so an increase of air flow despite a constant o input might explain this. in intermediate care the use of hv for niv may be interesting alternative in which case the clinician must keep in mind that the fio decreases compared to standard oxygen therapy. concerning home usage we hypothesize that this partial removal of o treatment could contribute to the poor results of niv in chronic copd. introduction: in february , we opened a beds-post icu rehabilitation center (service de rééducation post réanimation, «srpr»), dedicated to weaning from mechanical ventilation and global post icu rehabilitation. objectives-description of the characteristics and main outcomes of the patients admitted over the first year of activity. patients and methods: retrospective analysis of data extracted from the medical files. results: patients were admitted times in the unit over its st year, from different icus (median duration of stay in the icu . days (iqr - )). % were ventilated ( % with niv). % had a tracheostomy. % had icu acquired weakness + % were able to walk. an underlying chronic respiratory disease was present in % of cases. % were obese. difficult weaning was found to have one or several respiratory components in % of cases (including post surgery diaphragmatic paralysis), cardiac in %, neurologic in %. significant complications occured in % of cases. median duration of stay was . ( - . ) days. ten patients died in the unit, patients were re-transferred in the icu, where of them died. over half of the patients were discharged at home, in a rehabilitation unit (ssr) or in a hospital ward awaiting a rehabilitation bed. the remaining %, that still needed some form of medical or surgical care were discharged in the ward (fig ) . in intention to treat, successful weaning from invasive ventilation was obtained in % of patients. of the patients discharged alive from the unit after completing the rehabilitation program (n = ), % were completely weaned from mechanical ventilation, % were discharged with niv or cpap + patients ( %) were considered not weanable from invasive ventilation + decanulation of tracheostomy was obtained in % of cases + % of the patients could walk. conclusion: srprs offer a new concept of care for difficult to wean patients, with promising results. introduction: scarce data about patients with prolonged weaning from the mechanical ventilation are available in the literature. patients without successful weaning days after their first weaning attempt were classified in the group of the weaning according new definition (wind) classification ( ) . we here describe specific data concerning weaning and hospital evolution of group patients included in this prospective cohort. among the patients included in the wind study, were classified in the group . additional data concerning comorbidities, cause of weaning failure and hospital evolution were collected for ( %) of these patients. results: these patients had median [interquartile range] duration of invasive mechanical ventilation of [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days and [ ] [ ] [ ] separation attempts. etiology of icu hospitalization was medical in ( %). they had a copd in ( %), hearth disease in ( %) and immusoppression in ( %). we noticed a mean saps ii of ± , a mean sofa d of ± and d of ± . tracheostomy for weaning was performing in ( %). at the end of their follow-up, ( %) were still alive- ( %) were still tracheostomized, still intubated and ventilated, ( %) treated with vni and ( %) were extubated (or decannulated) and breathed without assistance. among the patients still tracheostomized at the end of the follow-up, ( %) were still ventilated (permanently for of them, and partially for ) and ( %) had spontaneous breathing through their tracheostomy. these patients had a total icu length of stay of days. the destination at discharge from the icu is known for only of the survivors- ( %) in medical ward, ( %) in intermediate care units, ( %) in sub acute care, ( %) in icu and in surgical ward. conclusion: a third of the patients of the wind study classified in group and with available additional data died in hospital in months following intubation. at the end of the follow-up, % had spontaneous breathing without assistance, and % were still tracheostomized. among these tracheostomized patients, one third still required mechanical ventilation. ( )-béduneau, g., pham, t. and co ( ) . epidemiology of weaning outcome according to a new definition. the wind study. ajrccm, ( ) , - . introduction: copd patients have often polyglobulia because of associated hypoxemia especially in patients at the stage of chronic respiratory failure. we recently reported that anemia was present in % of patients with severe aecopd admitted to icu without impact on short-term prognosis. the aim of the present study was to assess the long-term impact of haemoglobin (hb) levels on outcomes of aecopd patients. patients and methods: in a prospectively collected database including consecutive patients admitted between and for aecopd in our icu. long-term status of patients following the first icu admission (surviving or deceased) has been verified by consulting the civil status registers. anemia was defined according to who criteria-hb < g dl in males + hb < g dl in females. long-term survival was assessed by kaplan-meier curve. results: the cohort included patients (median age , median ph . , . % males, niv as first ventilator mode in . %). anemia was observed in of the patients ( . %) with median haemoglobin levels at . and . g dl, in patients with and without anemia, respectively. anemia was associated with significantly lower years survival (log rank p = . ) (fig. ). the final model included age, saps ii score, comorbidities, home oxygen therapy, initial ventilatory mode, niv failure and haemoglobin levels. multivariate analysis identified age (or . per year + ic % . - . + p = . ), home oxygen therapy prior to exacerbation (or . + ic % . - . + p = . ), intubation at icu admission (or . + ic % . - . + p < . ), niv failure (or . + ic % . - . + p < . ), and haemoglobin (or . per decrease of g dl + ic % . - . + p = . ) as independently associated factors with years mortality . we conducted a prospective observational study including all patients who visited the sis during the last months. the collection of the usual anonymous demographic, medical and toxicological data was performed by the care-givers and social workers in charge of the drug users. data were declarative and no analytical confirmation was available except for the patients admitted in the icu. results discussion during months, drug users [f m sex ratio . + median age . years ( - ) + patients without resources ( %), without medical insurance ( %), unstable housing homelessness ( %)] visited the sis for drug injection or inhalation, representing , drug use including , inhalations and , injections by drug users day. drug users had no addictology ( %) or sociomedical ( %) follow-up. they were infected by hepatitis virus c ( %) and or hiv ( %). they declared to continue injecting in the public space ( %), sharing material ( %), and needles syringes ( %). the injected inhaled drugs in the sis were skenan ® (morphine, . %), crack ( % including injections), methadone ( . %), buprenorphine ( . %), heroine ( . %), and cocaine ( . %). these drugs were self-administered by polydrug users declaring concomitantly consuming crack ( . %), illicit morphine ( . %), cocaine ( . %), ethanol ( . %), cannabis ( . %), heroin ( . %), illicit methadone ( . %), benzodiazepines ( . %) and illicit buprenorphine ( . %). forty-five patients required a paramedical intervention in the sis resulting in calls to the emergency department and hospital admissions including transfers to the icu in relation to opioid overdose. no cardiac arrest and no death occurred. conclusion: sis visit for recreational drug self-administration rapidly becomes popular among drug users. illicit morphine (skenan ® ) glycemia (mmol/l) . ( - ) . ( - )ketones in the effluent liquid (g/l) . ( . - . ) ( - ) patients and methods: physiological tracings were recorded from the standard monitoring system (intelliview mp philips), using a dedicated network and extraction software (synapse v , ltsi inserm u ) that enables photoplethysmographic recordings from oximetry monitoring at a native resolution of hz. raw data were subsequently stored on a dedicated local server, before anonymization and analysis. all consecutive patients were recorded for a -hours period during the -hours following icu admission. all measurements were recorded with the patient laying supine, with a ° bed head angulation. physiological recordings were associated with metadata collection by a dedicated research assistant.hrv parameters defined in a previous study were derived using kubios hrv premium ( introduction: preventing post liver transplantation (lt) hepatic artery and portal vein thrombosis is challenging and includes enoxaparin administration. enoxaparin pharmacokinetics (pk) has not been investigated in children following lt. between-subject variability and critical illness may alter pk, leading to the risk of subtherapeutic exposure. patients and methods: clinical, biological and kinetic data were retrospectively collected in a single pediatric intensive care unit center from january to july . we described an enoxaparin pk model in children the first week following the lt. anti-xa activity timecourses were analyzed using a non linear mixed effects approach with monolix version r. results: anti-xa activity time-courses were well described by a one-compartment open model with first order absorption and elimination. body weight prior the surgery (bwpreop) and the related postoperative variation (bw(t)) were the main covariates explaining cl and v between subject variabilities. parameter estimates were cli = cltyp*(bwpreop ) + vi = vtyp*(bw(t) ) + where typical clearance (cltyp) and typical volume of distribution (vtyp) were . l h − and . l, respectively. standard dosing regimens of iu kg h were insufficient to reach the target range of anti-xa activity of . to . iu ml. specifically, children ( %) did never attain the target range during the whole period of treatment and all children were at least once under dosed. according to the final results, we simulated individualized dosing regimens within h following the first administration. more than iu kg h are suggested to reach the target range of anti-xa activity of . to . iu ml from the first day. standard enoxaparin dosing regimens is not appropriate to reach the target in pediatric liver transplantation patients. enoxaparin pk modeling should help the physician to achieve the target range from the initial dose and during the maintenance doses. higher dosing regimens, especially in youngest children are suggested to achieve the prophylactic target range. pharmacokinetic analysis of unfractionated heparin in critically ill children during extracorporeal membrane oxygenation: do we achieve the target? introduction: preventing thrombosis in children under extracorporeal membrane oxygenation (ecmo) requiring unfractionated heparin administration. unfractionated heparin pharmacokinetics (pk) has not been well investigated in children under ecmo. we described the unfractionated heparin dosing regimens and resulting anti-xa activities in children with ecmo. patients and methods: this is a single center retrospective study from march to september . were included children (< years old age) who were under ecmo for refractory hemodynamic failure related to (i) myocarditis or (ii) septic shock. anti-xa activity timecourses were analyzed using a non linear mixed effects approach with monolix version r. results: a total of children were included (septic shock, n = + myocarditis + n = with a median age of months ( - ), a median weight of . kg ( . - ) and median admission pelod- score of ( - ). bleeding occurred in children and thrombosis in . an initial bolus of unfractionated heparin ranging from to iu kg was infused and then continued by continuous perfusion with an initial dosing ranging from iu kg h to iu kg h. a total of anti-xa activity measurements were performed between h empirically antibiotics for these patients with severe infection may be recommended. introduction: prognosis of allogeneic hematopoietic stem cell transplant (hsct) recipients admitted to icu has improved with advances in hsct procedures and critical care management, but also with evolution in icu triage policy. our aim was to describe the outcome of hsct recipients admitted to icu according to a wide admission policy. patients and methods: retrospective multicenter study including all consecutive allogeneic hematopoietic stem cell transplant (hsct) recipients admitted to saint-antoine hospital medical icu, paris, france from to january to april . admissions were identified through a systematic review of icu database using icd- codes z and t . data were extracted from medical charts. qualitative and quantitative values are expressed as number and percentage, and median and interquartile range, respectively. comparisons between groups were performed using fisher's exact test and mann-whitney test for qualitative and quantitative variables, respectively. a p-value < . was considered to be significant. results: one hundred seventeen patients- men ( . %), median age [ - ] years-were included in the study. underlying hematological malignancies were: acute myeloid leukemia (n = , . %), myelodysplastic/myeloproliferative neoplasms (n = , . %), acute lymphoid leukemia (n = , . %), lymphoma (n = , . %), other ( . %). complete remission was achieved before hsct in ( %) patients. forty-nine ( . %) patients underwent myeloablative conditioning regimen and ( . %) received haploidentical grafts. twenty-eight ( . %) patients experienced disease relapse after hsct and ( %) graft versus host disease prior icu admission. median saps ii was and sofa score at day one [ - ]. the icu, hospital and -day mortality rates were respectively . , . and . %. in univariate analysis, factors associated with -day mortality were: saps ii (p = . ), invasive mechanical ventilation (p < . ), vasopressors (p = . ) and renal replacement therapy (p = . ). mechanical ventilation was the only independent factor of -day mortality (or . - . ], p < . ) with mortality rate reaching . % and even . % among patients with uncontrolled hematological disease. conclusion: prognosis of unselected hsct recipients admitted to icu remains poor, particurlaly among those receiving mechanical ventilation, and even more if hematological disease is not controlled. these results suggest that the implementation of an icu triage policy determined both by intensivits and hematologists would be helpful to identify good candidates for icu admission. introduction: acute respiratory failure (arf) is a common event in patients with primary malignant brain tumors (pmbt). even if many factors (corticosteroid therapy, swallowing disorders) suggest a specific etiologic spectrum, few data are available regarding its precipitating factors. our first aim was to compare the causes of arf between patients with pmbt and those with other type solid tumors. our second aim was to identify, among pmbt, the factors influencing survival in icu. patients and methods: bicentric case-control study from march to may . patients with pmbt (cases, primary central nervous system lymphoma included) admitted for arf were compared to patients with other kind of solid tumors (controls). the reason for admission "arf" as well as the causes of arf was determined by three experienced respiratory physicians and were required for inclusion: a respiratory rate > cycles/min and a pao /fio < for patients in spontaneous breathing and only a pao /fio < for patients under mechanical ventilation. in both groups were excluded patients with metastatic solid tumors, benign tumors or tumors with more than years of complete remission, recent post-operative patients, and patients with other immunodeficiency. results: a total of cases and controls were included. main patients' characteristics are reported in the table . acute infectious pneumonia was the leading cause of arf in both groups but was more frequent among cases ( vs. %, p < . ). cardiogenic pulmonary edema and exacerbation of chronic respiratory diseases were more frequents in controls ( vs. %, p < . ). pulmonary embolism was similar between the two groups ( vs. %, p = . ). among acute infectious pneumonia, pneumocystis pneumonia (pcp) and aspiration pneumonia were more frequent in cases ( vs. %, p < . and vs. %, p < . respectively). in multivariate analysis cancer progression (or- . %ic [ . - . ], p = . ), need for intubation (or- . %ic [ . - . ], p = . ) and respiratory rate (or- . % ci [ . - . ], p = . ) independently predicted icu mortality of pmbt patients. conclusion: in pmbt patients, the causes of arf differ significantly from other cancer patients. up to % of the admissions was related to preventable causes (pulmonary embolism, pcp) and a curable cause was identified in the majority of cases. our results suggest that pmbt alone is not a relevant criterion for icu recusal. introduction: drug intoxication is a common problem encountered in emergency departments. poisoning remains a major cause of hospitalization for young people, and that of the elderly is constantly increasing. objectives . determine the epidemiological characteristics of addicted patients . know the clinical manifestations of poisoning. patients and methods: a retrospective study of cases of acute poisoning recorded at the university hospital center chuoran between january and december was carried out. seizure on data processing by epi-info version . results: cases of acute poisoning, with an age ranging from to years. female patients predominated with %. people between the ages of and are the people most affected by poisoning. the nature of poisoning is varied. in this series, analgesics were found to be the leading cause of acute intoxication, with cases, % followed by psychotropic drugs ( %), benzodiazepines ( %), neuroleptics ( %), antiepileptics%) and antihistamines ( %). the majority of acute intoxications were managed within an average time of . ± . h with an interval between . and h. in % of cases the poisoning was asymptomatic, there were digestive manifestations in % of patients, % neurological, % cardiovascular and % respiratory. we deplore death in this series secondary to many drug poisoning. conclusion: acute drug poisoning is a common reason for admission to the emergency department of oran university hospital. the large number of drug families offered for sale, as well as the heterogeneity introduction: selective serotonin reuptake inhibitors (ssris) have been considered for their low toxicity comparatively to antidepressant agents. the present study aims to describe clinical features and prognosis of poisoning ssris. patients and methods: a retrospective study of patients admitted to our -bed teaching icu for acute ssris poisoning over a period of years from january to december . ssris poisoning was retained on a history of over dose ingestion, clinical signs and positive urine samples for ssris. results: thirty seven patients were collected, the middle age was ± years with a female predominance ( . %). a psychiatric history with depressive syndrome was noted in . % and a history of suicide in . %. paroxetine was the main invoked drug (n = ), followed by sertaline (n = ), then fluoxetine (n = ), venlafaxine (n = ) citalopram (n = ). the mean supposed ingestion dose was . mg. intoxication was pure in cases and associated with other drugs in cases-benzodiazepines (n = ), klippal (n = ), amisulpride (n = ), non-steroidal anti-inflammatory drug (n = ), prazin (n = ) and promethazine (n = ). neurological examination found drowsiness and mydriasis in % of cases (n = ), coma in . % (n = ), agitation (n = ), tremor (n = ), hyperreflexia (n = ), hypersudation (n = ), fever (n = ) and diarrhea in one patient. the qt was lengthened in five cases. treatment was symptomatic. five patients ( . %) required mechanical ventilation with average of ventilation duration of . h. all patients discharged alive the icu. conclusion: ssris poisoning is mainly manifested by serotonergic syndrome. evolution is favorable in the majority of cases. mechanical ventilation could be required. hemodynamic profile of shocks induced by dihydropyridine calcium channel blocker poisoning khzouri takoua introduction: acute calcium channel blockers (ccb) poisoning remains infrequent despite their increasing use. in our country, dihydropiridines are the most prescribed ones. very few works have studied the hemodynamic profile of acute dihydropyridines poisoning either by invasive means (right cardiac catheterization, transpulmonary thermodilution) or non-invasive (cardiac ultrasound). in this perspective, we carried out this study whose main objective was to illustrate the different hemodynamic profiles of shocks induced by dihydropyridine ccb poisoning. patients and methods: it was an observational retrospective study spread over months from st january to th december in a teaching toxicological icu, including all patients admitted for acute dihydropyridine ccb poisoning, who presented a shock and underwent right hemodynamic exploration.results: during the study period, ccb poisoning accounted for . % (n = ) of all the acute poisoinings requiring hospitalization in our intensive care unit. among them, had taken dihydropyridine which represents . %. four women aged of [ , ] were eligible. all the exposures were single-drug. the dihydropyridines involved were amlodipine in cases with a median value of supposed ingested dose (sid) of . mg and nicardipine in the other two ones, the median sid was mg. the delay of consultation was of . ± h after ingestion. gastrointestinal decontamination was performed in one patient with activated charcoal. the patients developed a shock within h, treated by initial vascular filling on average ml of crystalloids, noradrenaline alone in cases and with a combination of dobutamine in one patient. other adjuvant treatments (high dose insulin, calcium salts) have been used in all patients. their hemodynamic profile evaluation by right-handed catheterization swan-ganz was in favour of vasoplegia in cases with median values of systemic vascular resistances (svr) of dynes.s.cm- , of cardiac output (co) of (l min), and of the arteriovenous oxygen difference of . . the fourth patient's shock had mixed nature with svr of dynes.s.cm- and co of . (l min). all patients were discharged from the icu with a mean length of stay of days. conclusion: the dihydropyridine calcium channel blockers poisoning exposes to the shock risk due to several mechanisms. the clinician must be warned to look for signs of severity and understand its mechanisms by using the hemodynamic study in order to improve its management. goulmane mourad , alachaher djamel , djebli houria introduction: in daily practice, admission to the intensive care unit (icu) usually does not raise any major ethical problems. difficulties arise mainly in acute situations requiring intensive care that have not been anticipated and therefore, not adequately prepared and discussed. we hypothesized that non-admission of a patient to the icu must occur in the following circumstances-( ) with the patient's agreement, expressed either directly or through advance directives (ad), or as relayed by a surrogate or the family + ( ) according to a collegial decision-making process (if the patient is decisionally incapacitated) + and ( ) after seeking the opinion of an external consultant. the decision-making process must be documented in the patient's medical file. patients and methods: prospective, observational study in two hospitals (one large university hospital, one regional non-acamedic hospital) over a period of months. inclusion criteria were-patients aged ≥ years presenting with failure of at least organ that was directly life-threatening and requiring life-sustaining therapies. complete data collection was performed for each patient. results: a total of patients were included ( % from the emergency department and % from medical wards). the decision not to admit the patient to the icu was taken-( ) during night duty for patients ( %) + ( ) by a senior physician in %, and ( ) after clinical examination in ( %). the main reasons justifying the decision not to admit to the icu were-( ) metastatic cancer in patients ( %) + ( ) total loss of autonomy in ( %) + ( ) severe cognitive impairment in ( %) + ( ) premorbid state in ( %) + ( ) chronic organ failure for ( %) + and ( ) presence of ad (written or oral) specifying that the patient did not wish to be admitted to the icu in ( %). this study raises several points concerning the decision-making process for patients requiring intensive care. first, collegiality is observed in almost all situations of non-admission ( %). second, an outside consultant was contacted in around % of cases. third, % of patients had ad. fourth, the family or entourage were consulted in less than % of cases and finally, in around % of cases, the decision-making process was documented. conclusion: this study shows that in emergency situations, it is more difficult to take adequately structured decisions regarding icu admission than, for example, decisions regarding limitation or withdrawal of treatment in the icu. introduction: as known, tracheostomy is performed to improve quality of life (qol) in patients requiring prolonged mechanical ventilation. it is indicated to facilitate care of critically ill patients, in order to minimize risks of oro-tracheal intubation, and enhance recovery, allowing early discharge from icu with home ventilation. we aimed by this study to evaluate long-term survival and qol in tunisian patients discharged from the icu with tracheostomy, as well as related burden assumed by their relatives. patients and methods: patients who were admitted to the icu between and were eligible for inclusion in this retrospective cohort if they had a tracheostomy during their icu stay, and were discharged at home with a tracheostomy canula. for survivors, we used the short form health survey (sf ) to assess their qol at home. we estimated the degree of autonomy using the adl scale. to assess burden assumed by caregivers (family members most of the time) we used the short version of zarit burden interview. exclusion criteria were refusal of the interview or unavailability on the phone call. results: fourteen patients were discharged at home with a tracheostomy canula. only twelve responded to the phone call. four patients died month later. amoung the survivors, the removal of the tracheostomy canula was successful in patients after a mean duration of days. main findings are summarized in table . conclusion: tracheostomy shows good acceptance and acceptable qol. it allowed shorter length of stay in the icu and long-term survival after discharge from the icu, and should be encouraged for tunisian patients. in contrast, the qol of patients' relatives was more affected, with significant burden and work load. introduction: intensive care survivors present often some psychological disorders linked with experience memory loss or nightmares. the use of patient diaries has been developed and implemented by clinical staff to improve the quality of life after intensive care. patients received their diaries at icu discharge. this study was conducted in order to understand the potential benefits for patients the diary on prevalence anxiety, depression and post traumatic disorders during recovery. patients and methods: a structured interview study was administered to adult critical illness survivors who received ≥ h of mechanical ventilation in a medical and surgical intensive care unit. after months, this patients answered at two questionnaire-hospital anxiety and depression scale (had) and a screening instrument for ptsd (qspt). results: from the survivors at months, patients answered the questionnaires. we have two groups- patients had a diary and patients no diary. but these group are so low currently to compare introduction: in ards patients under ecmo common ventilator strategy aims at resting the lung by lowering tidal volume (vt) in the - ml kg predicted body weight range found in the literature analysis. we tested on the bench the not previously explored hypothesis that vt was not delivered in the % accuracy by most of icu ventilators in this low range. patients and methods: pneumatic test lung set at ml/cmh o compliance and cm h o/l/s resistance was attached to any of icu ventilators (v (drager), carescape r (ge healthcare), servo u (maquet), pb (covidien) and g (hamilton)) equipped with heated humidifier (fisher-paykel mr ) set off and adult ventilator circuit (rt evaqua fisher paykel). each icu ventilator was set in btps condition, at peep cm h o and fio . . airway pressure and airflow (hans-rudolph pneumotachograph) were measured (biopac m ) proximal to the lung model. for each ventilator a series of vt ranging from to ml was delivered for breaths each, at then at breaths/min respiratory rate (rr). the relationship of vt measured to vt set was assessed by linear regression over the icu ventilators for each circuit-rr combination. in each model, the change from the mean effect was assessed for each ventilator. for each model we obtained the mean effect of the ventilators then we compared the effect of each ventilator to the mean effect. results: for each combination of f and circuit, the mean slope was significantly lower than indicating that, on average, the set vt was under delivered (table) . there were differences in change in slope from the mean across the ventilators with interaction between ventilators and combinations. as an example, for the adult circuit f , carestation, pb and servo u performed better than g and v . across the combinations, v had consistent negative (greater underestimation than average) slopes and servo u consistent positive (lower underestimation than average) slopes whilst the slope sign in the three others changed direction. biomarkers. yet, hla-dr expression on alveolar monocytes was lower in ards than in controls, consistent with sepsis-induced immunosuppression at the alveolar level. functional differences observed between ards and controls suggested a tolerogenic profile of ards monocytes. introduction: despite their recommendation in the prevention of ventilator-associated pneumonia, oral care is not still clearly standardized. it generally includes a time for oropharyngeal and tracheal suctions which can induce a cough reflex in non-paralyzed patients leading to the mobilization of the endotracheal tube and a consecutively increased risk of tracheal microaspirations. during the oral care procedure, drainage of subglottic secretions at particular times before oro-tracheal suctions is expected to reduce microaspiration. the aim of this study is to assess whether this "optimized" oral care including subglottic drainage can reduce microaspirations. this is an open prospective study, including icu ventilated patients. two procedures have been compared in two randomized cross-over consecutive periods of one day each ( oral cares a day)-on day, they received routine oral care (oral care (o) then tracheal suction (t)) and on the other day they received optimized oral care (subglottic suction (sg ) then o then sg then t). the amylase enzymatic activity has been measured in o, t, sg and sg suctions as a surrogate for the oropharyngeal content. if present in t suctions, it defines microaspiration. since the amylase o content is not similar from a patient to another, the primary outcome was the median amylaset o ratio after routine versus optimized oral care. results: after informed consent, patients were included. were analyzed due to incomplete follow-up in patients. patients (sapsii ± ) were ventilated since . ± . days for a majority of respiratory indications. at day , and patients received routine oral or optimized oral car respectively without significant baseline difference. a trend in the reduction (− %) of amylase t o median ratio was observed after optimized versus routine oral care ( . % [ . - vs. . % [ . - ], p = . . conclusion: despite protection of trachea by the cuff of the endotracheal tube, amylase has been found in tracheal suctions (which represents the last step of oral care). in this pilot study with a limited sample of patients, a trend in the reduction of microaspirations was observed when subglottic suctions were interleaved between oral and tracheal suctions. an increased sample power could show more significant results, but we cannot eliminate that this weak effect could also be due to the inability of subglottic suctions to prevent microaspiration of the oral content. the study has been founded by teleflex. introduction: although necessary, mechanical ventilation can lead to ventilator-induced lung injury (vili) even when using protective ventilation strategies that combine low tidal volume (vt)( ml kg predicted body weight) and plateau pressure (pplat) <= cmh . lower positive pressures and tidal volumes could enhance lung protection + the hla-dr and pd-l expressions were higher on alveolar than on blood monocytes in both ards patients and controls (figure) . yet, hla-dr expression on alveolar monocytes was higher in controls compared to ards patients (p = . ). circulating monocytes had a higher phagocytic activity than alveolar monocytes (p < . ), but no significant difference was observed between ards patients and controls. an lps challenge increased the phagocytic activity of monocytes in controls (p = . ) but not in ards monocytes (p = . ). tnf-α intracellular synthesis was increased after lps exposure in circulating and alveolar monocytes of controls (p < . ) but only tended to do so in ards (p = . ). conclusion: differences in the phenotype of alveolar and circulating monocytes were observed in ards but also in controls, suggesting a physiological lung blood gradient in the expression of these results: until , ten patients were included and analyzed for the study. there was a significant difference between the volumes recruited at the three peep levels (p = . ). the recruitment evaluated was not correlated with pao . there is a significant decrease in cardiac index and pam caused by the increase in peep. conclusion: preliminary results from our study suggest that the estimated recruited lung volume estimated by crf inview ® technology appears to be poorly correlated with measured pao . the hemodynamic repercussions observed should also be considered in order to propose an optimal strategy for the optimal adjustment of peep. were compliant with the re-evaluation. ( %) patients received carbapenems according to the recommendations. a compliant prescription had no impact on hospital or icu length of stay and no impact on duration of mechanical ventilation but seemed associated with increase mortality (p = . ). discussion: the high rate of compliant prescriptions can be explained by the broad indications of carbapenems in the icu, especially in patients with septic shock. the increase mortality of patients with a compliant prescription is probably due to the severity of the infections. in order to achieve % compliance, we could suggested regularly updating the knowledge of carbapenems prescriptions, collaborating with bacteriology and infectiology teams, and establishing a computerized or paper prescription with feedback control. conclusion: the prescription of carbapenems appears most often in accordance with the recommendations in this icu. however, there is a need for improvement. introduction: bacterial infections are frequent triggers for diabetic ketoacidosis and a significant increase in morbimortality is observed in case of delayed antibiotic treatment. however the unnecessary administration of antimicrobial therapy can also lead to bacterial resistance. early sepsis markers are thus particularly useful for patients admitted in icu for diabetic ketoacidosis. patients and methods: we retrospectively studied cases of patients admitted in icu at avicenne french universitary hospital for ketoacidosis defined by ph < . and glycemia > . mmol l. clinical and biological data were analyzed at admission (d ) and on day (d ). results: between and , among patients admitted for diabetic ketoacidosis, were included. twelve out of were infected ( urosepsis, pneumonia, others). demographic data and comorbidities did not significantly differ between the infected and non infected group (ig and nig). antibiotics were administered to patients- ( %) in the infected group versus ( . %) in the non infected group. on d , there was no difference for-ph, temperature, leukocytes, neutrophils-to-lymphocytes count ratio and pct (table ) . on d , temperature, leukocytes, neutrophils-to-lymphocytes count ratio and pct were significantly higher in the ig. in the ig, the biological markers did not vary between d and d , whereas in the nig, leukocytes (p < . ), pnn (p < . ) and neutrophils-to-lymphocytes count ratio (p < . ) significantly decreased. surprisingly average pct levels seem to be particularly high in the nig on do as well as on d . conclusion: at admission, pct as well as other usual markers do not appear to be useful to differentiate infected from non infected patients admitted for ketoacidosis. however, on day , two different patterns can be drawn and help detecting non-infected patients and thus reduce exposure to antibiotics. these results should be confirmed by a prospective study, including a larger number of patients. ventilator-associated events (vae), reflecting worsening oxygenation, are defined as a persistent and significant increase in fio or peep level after a period of stability on the ventilator. vae definition includes ventilator-associated conditions (vac), infection-related ventilatorassociated complications (ivac) and probable ventilator-associated pneumonia (pvap). the relevance of vae for ventilator-associated pneumonia (vap) is low. however, the correlation between the three vac, ivac, and pvap, and the onset of ventilator-associated low respiratory tract infection (valrti), including ventilator-associated tracheobronchitis (vat) and pneumonia (vap), has never been studied yet. we on clinical examination. gravity scores-apache ii and saps ii. for lumbar puncture data, there is the proteinuria, glycorrhaphy resuscitation measures-drug intake and intubationin multivariate analysis, the factors of pejorative evolution-the male sex presence of meningeal syndrome. high proteinorachia. taking vasoactive drugs. the saps ii score. conclusion: according to this work, many factors influence the prognosis of acute meningitis in our population such as severity general scores, hemodynamic state and initial lumbar puncture data. we will need more investigations and prospective multicentric study to have more discrimination parameters. introduction: the emergence of atb-resistant bacteria has become an important public health problem, particularly in resuscitation environments, surveillance and monitoring of atb consumption is essential to combat this threat ecologically and economically. the aim of this work was to evaluate the consumption of atb in surgical resuscitation, to establish the cost, and to list the risk factors for bacterial resistance. patients and methods: it is a retrospective analytical study spread over year, studying patients who have received antibiotic therapy, the data on the consumption of atb were collected from the patient's medical records, the delivered doses were converted into ddd, according to the who standards and the end result is expressed in ddd days of hospitalization. the statistical analysis was carried out by the spss software. results: in our study, the mean age was . ± . , with male predominance + sex ratio . , traumatic pathology is the most common reason for admission, pneumopathy was the most frequent infection. overall atb consumption was . ddd dh, dominated by the class of betalactamins (cephalosporins . ddd dh, carbapenemes . ddd dh), the direct cost of atbs rises to . million dirhams, these are accounting for a large part of the pharmaceutical budget of the ibn rochd university hospital. bacteria found in order of frequency were acinetobacter baummanii, beta-lactamaseproducing enterobacteria, s. aureus and p. aeruginosa. acinetobacter baumannii showed the highest resistance rate. several risk factors for bacterial resistance were studied, notably the correlation between the use of atb and the emergence of resistant strains, only piperacillintazobactam was associated with the emergence of resistant strains of eblse, as well as other factors that were retained as significantly related to bacterial resistance by multivariate analysis-duration of hospitalization and perfusion of albumin. discussion: despite the limited number of studies done on atb consumption, it seemed that our results were similar to other national and foreign studies, the consumption of atbs is increased in hospital giving rise to the appearance of many multi-resistant bacteria. conclusion: in conclusion, resistance to antibiotics is a serious threat to public health both nationally and globally. it is therefore crucial to implement measures to counter this phenomenon + this is only possible through the proper use of atbs and gaits to prevent nosocomial infections. introduction: ventilaor-associated pneumonia (vap), the leading cause of infection in resuscitation, is also the main respiratory complication in cranial trauma. the aim of this study is to determine the specific risk factors for the occurrence of vap in this type of patient in an intensive care unit. patients and methods: we performed a retrospective study in our intensive care unit for an -month period (january , june ). all patients admitted for cranial trauma were included in the study and ventilated more than h in intensive care. vap is defined as late as of the th day of occurrence. the quantitative and qualitative variables studied were recorded at admission and during hospitalization. a univariate and multivariate analysis using the fischer and mann-whitney tests was performed. p is said to be significant if it is < . . results: our study included traumatic brain injury in older adults, of whom ( %) had one or more episodes of vap during their resuscitation. late vap accounted for almost of the cases ( patients). four independent variables were significantly related to the occurrence of vap-advanced age (p = . ), glasgow score (gcs) at admission < (p = . ), diabetes (p = , ), and the use of proton pump inhibitors for the prevention of stress ulcers (p = . ). the duration of intubation ( ± vs. ± days) and on intensive care ( ± vs. ± days) are significantly longer in the case of vap. mortality was significantly higher in vap- versus % (p = . ). the majority of early vap were due to both strepococcus ppneumoniae and haemophilus influenzae. the ecology of late vap was dominated by klebsiella pneumoniae, pseudomonas aeruginosa and acinetobacter baumanii. conclusion: of the four independent risk factors found in our study, glycemic balance and rapid airway safety by orotracheal intubation in the case of initial gcs < represent the relevant prevention axes of vap in traumatic brain injury in older adults. unfortunately, it is accompanied by a significant increase in bacterial resistance to antibiotics, leading to an increase in morbidity and mortality in intensive care units. patients and methods: this is a retrospective study carried out in our intensive care unit, covering all patients hospitalized between january and june and having contracted a nosocomial urinary infection. patients whose hospital stay was less than h and those fig. agreement between vae and lrti diagnostic with a nosocomial urinary tract infection acquired in another service were excluded. results: the study of resistance of the germs responsible for nosocomial urinary tract infection showed that-escherichia-coli was resistant to third generation cephalosporins in % of cases, at imipenem in % of cases, and without resistance to ertapenem and amikacin. pseudomonas was resistant to ceftazidime in % of cases, to imipenem in % of cases and to amikacin in % of cases. acinetobacter baumannii was resistant to imipenem in % of cases and to amikacin in % of cases. enterococcus faecalis had no resistance to vancomycin and ampicillin. staphylococcus aureus was resistant to methicillin in % of cases and without any resistance to vancomycin. mortality directly associated with nosocomial urinary tract infection was %. the comparison with previous studies has shown a significant increase in the bacterial resistance responsible for nosocomial urinary tract infection, which is of interest in monitoring the ecology of intensive care units and the resistance profile as well as the improvement of the management of antibiotics. introduction: nosocomial enterococcus infections are a constant concern in intensive care units due to their increasing frequency and the emergence of resistant strains to vancomycin. the aim of our study was to compare outcome findings of patients with nosocomial enterococcus infections according to their sensibility to vancomycin, and then to investigate predictive factors of mortality. patients and methods: it was a retrospective descriptive study, including all hospitalized patients in intensive care, between january st, and april st, , with nosocomial enterococcus infections. we recorded demographic and clinical findings, severity scores igs ii, apache ii, initial sofa and sofa at the time of infection, microbiological, therapeutic and outcome data. patients infected with vancomycin-susceptible enterococcus (vse) were compared to those having vancomycin-resistant enterococcus (vre) + then we searched for independent risk factors for vre. finally, a multivariate logistic regression was conducted to investigate independent predictive mortality factors. results: during the study period ( years and months), patients presented a nosocomial enterococcus infection with a median age of years [ - ] and a sex-ratio of . . at admission, patients ( . %) had respiratory distress. the median scores of igs ii, apache ii, initial sofa and sofa at the time of infection were respectively + + and . the infection sites were-urinary infection (n = , . %), bacteremia (n = , . %) and central line associated infection (n = , . %). patients had a vre nosocomial infections and vse. a septic shock complicated enterococcus infection in cases including cases of vre and cases of vse (p = . ). vre nosocomial infections were significantly related to arterial (p = . ) and venous (p = . ) femoral catheterization, to a duration of venous femoral catheterization > days (p = . ) and to e. faecium species (p < - ). no independent risk factor of vre was found. the median duration of hospitalization was days and the overall mortality rate was . %. multivariate analysis identified independent predictive factors of attributable mortality-patients in coma (or . + ic % = . - . + p = . ) and the occurrence of septic shock (or . + ic % = . - . + p = . ). conclusion: attributable mortality to nosocomial enterococcus infections was high and independent of the susceptibility of the strain to vancomycin. mortality was independently associated to septic schock occurrence and neurologic dysfonction. introduction: ventilator-associated pneumonia (vap) is defined by a lung infection contracted h after the putting under mechanically assisted breathing. risk factors predisposing to the development of vap among mechanically ventilated patients are many. some are related to the patient as age, history of copd, presence of an altered state of consciousness + others are related to care providing. patients and methods: a prospective nested case control study was conducted from marsh through april . all icu patients mechanically ventilated for more than h with endotracheal intubation or tracheostomy were included. cases of community-acquired pneumonia, non-mechanical ventilated hospital-acquired pneumonia, end-life patients and those aged less than years were excluded. the included patients with vap and those without vap were matched based on the age, the severity score and the comorbidities. for all patients included, preventive measures as assessed by the recent guidelines for preventing vap were applied after an education period of all medical and paramedical staff of the icu. the collected data are-age, comorbidities, admission severity scores, time to onset of vap, prior antibiotic therapy at the onset of vap, need for tracheostomy, duration of mechanical ventilation, length of stay in icu and become. results: during the study period, patients were mechanically ventilated. vap was observed in % of cases. vap was observed in cases with an incidence of % and incidence density of per patient-days of mechanical ventilation (mv). in univariate analysis, significant difference was found between the group with vap and the group without vap regarding admission for poly trauma, acute respiratory failure, the concept of prior antibiotic therapy, the need tracheostomy, the number of days alive without antibiotics and without mv, the duration of mechanical ventilation, length of stay and mortality. multivariate analysis showed that prior antibiotic therapy and the use of tracheotomy were independent factors for developing vap. prolonged duration of mechanical ventilation was an independent predictor of mortality in multivariate analysis with or . + % [ . to . ], p = . . the occurrence of vap was not an independent predictor to mortality. conclusion: the incidence of vap found in our study is similar to that found in the literature. an active strategy of rationalizing the prescription of antibiotics in intensive care units and a well-defined protocol of weaning from mechanical ventilation may reduce the incidence of vap and over-all morbidity and mortality. introduction: hyperoxemia is common in critically ill patients. hyperoxic acute lung injury (hali), reduced bacterial clearance, atelectasis and higher mortality rates were reported in mechanically ventilated patients with hyperoxemia. the aim of our study was to determine the relationship between hyperoxemia and mortality in patients with ventilator-associated pneumonia (vap). this retrospective observational single center study was performed in a -bed mixed intensive care unit (icu) during a -year period, from january to january . all patients with vap were included. vap was defined using clinical, radiological and quantitative microbiological criteria. hyperoxemia was defined as peripheral capillary oxygen saturation-spo ≥ %. spo was hourly collected in all study patients during the whole period of mechanical ventilation. the daily percentage of time spent with hyperoxemia was calculated as the number of hours with hyperoxemia divided by . results: among the patients receiving invasive mechanical ventilation (mv) > h during the study period, the incidence rate of vap was . vap per ventilator-days. patients developed vap and were all included in this study. ( %) vap patients died in the icu. the mean daily time spent with hyperoxemia was %. no significant difference was found in mean percentage of time spent with hyperoxemia between survivors and nonsurvivors at icu admission, before, after or at the vap diagnosis. age, and sequential organ dysfunction assessment (sofa) at the day of vap occurrence were independently associated with icu mortality (or . [ . - . ] per year, p = . + . [ . - . ] per point, p = . + respectively). no significant impact was found of time spent with hyperoxemia before vap occurrence, on mv free days, or icu length of stay (fig. ). discussion: several potential explanations could be provided for the absence of negative impact on mortality of hyperoxemia. first, the definition used for hyperoxemia could be debated, as no consensus exists. however, the definition used in our study was rather stringent and the mean daily time spent with hyperoxemia was in line with that reported by studies. second, the impact of hyperoxemia on mortality could have been confounded by a large number of patients included with pulmonary lesions at admission. third, the number of included patients was small. conclusion: our study found no significant impact of hyperoxemia at icu admission, or during icu stay, on icu mortality in vap patient. results: patients collected during this period. distal protected specimens were performed in patients suspected of vap. the diagnosis of this infection was made. in of them with other diagnostic criteria ( %) which represents an incidence density of . per , days. % of pavm are due to gram negative bacilli. the first germ involved in our series and pseudomonas ( %) followed by klebsielles ( %) followed by acintobacter baumanii ( %) enterobacteries representing the rest. % lung infection with gram-positive cocci (principally sensitive methicillin) pseudomonas was imipenem resistant in . %, baumanii was imipenem resistant in %. the resistance profile of the recovered germs (baumanii and pseudomonas) encourages the utmost rigor in the management of these patients, prevention is better attitude to adopt. introduction: the ventilator associated pneumonia (vap) appear in the second rank of the infections acquired in hospital after the urinary infections. the diagnosis is based on a beam of clinical, biological, radiological and bacteriological arguments. this work consisted of an epidemiologic analysis of the vap and aimed at evaluating of it the frequency, the risk factors, the antibioresistance of the isolated bacteria and the mortality factors. patients and methods: this retrospective study related to patients hospitalized in icu during a period of years from january to december . the study included all patients over years and ventilated more than h and developing vap. results: bgn predominant and represent . % of identified germs, the acinetobacter baumanni leads with . %, followed by klebsiella pneumonia ( . %), followed by pseudomonas aeruginosa ( . %), followed by e. coli ( . %), followed by enterobacter cloacae ( . %) and citrobacter frendi ( . %). the cocci gram positive (cgp) constitue . % of isolated germs of witch . % staphylococcus aureus, . % of non aureus staphylococci, . % streptococcus sp. the polymicrobism was found in % cases. the isolated germs were multiresistants. in this study, we find a very high mortality and a major additional morbidity of the np by prolongation of hospitalization, of mechanical ventilation and a major additional cost.conclusion: it appears in the light of this work that a strategy of prevention based on the strict application of hygiene measurements, the maintenance of the material of ventilation and the respect of care procedures prove to be urgent in our context. introduction: burns induce modification of distribution volume, increased clearance of drugs and decrease of protein binding. amikacin pharmacokinetics (pk) was altered with subthera-peutic serum concentrations. the aim of our study was to assess the pk of amikacin in burns after a loading dose given once a day according to this equation-dose(mg kg) = *pi( * , *dp ) + ( * , * dp ). threshold for therapeutic efficacy was a ratio of ≥ between the concentration achieved h after beginning the infusion (c peak) and the minimal inhibitory concentration (mic) of the isolated pathogen. patients and methods: this study was conducted in burn center in tunis. patients with documented and or suspected infections were included. were excluded pregnant women and patients with renal failure. enrolled patients received amikacin at a loading dose in h infusion. blood samples for pk analysis were assessed during days (total duration of amikacin)-immediately after the end of the first infusion (t ) and min after (t ) at day . for the nd, rd, th and th day, blood samples were taken before the infusion (t ), at the end (t ) and min after the end of it (t ). results: burned patients were included. the mean age was ± years with a body weight of ± kg. the mean dose of amikacin was mg kg day [ - mg kg day]. a peak between and μg/ml was reached in % of cases, corresponding to times the mic, break-points for enterobactericeae and pseudomonas aeuroginosa. total volume of distribution was . l kg ( . - . ) l kg, half-life time (t ) was . h [ . - h] and the amikacin clearance was . l h. a correlation was found between cpeak at day and cpeak at day (r = . ). conclusion: our study shows that an early achievement of an optimal cpeak mic ratio of amikacin was reached in half of cases with a correlation between cpeak in the beginning and at the end of treatment. so, initial cpeak was useful tu adjuste amk therapy in burns and predicts treatment efficacy. *pi-ideal weight + dp -admission weight-ideal weight + dp -actuel weight-admission weight. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -jfx u authors: valdivia, andrés reyes; sanus, enrique aracil; santos, África duque; olmos, cristina gómez; alguacil, sergio gordillo; el amrani, mehdi; guaita, julia ocaña; zúñiga, claudio gandarias title: adapting vascular surgery practice to the current covid- era at a tertiary academic center in madrid. date: - - journal: ann vasc surg doi: . /j.avsg. . . sha: doc_id: cord_uid: jfx u introduction: the epidemic potential of coronavirus infection is now a reality. since the first case detected in late in china a fast-world-wide expansion confirms it. the vascular patient is at a higher risk of developing a severe form of the disease due to its nature associating several comorbid states and thus, some vascular surgery communities from many countries have tried to stratify patients into those requiring care during these uncertain times. methods: observational study describing the current daily vascular surgery practice at one tertiary academic hospital in madrid region, spain; one of the most affected regions worldwide due to the covid- outbreak. we analyzed our surgical practice since march (th) when the lockdown was declared up to date, may (th) ( months). procedural surgical practice, organizational issues, early outcomes and all the troubles encountered during this new situation are described. results: our department is composed of vascular surgeons and trainees. surgical practice has been reduced to only urgent care, totaling repairs on patients during the time period. five surgeries were performed on covid- positive patients. sixty percent were due to cli, % of them performed by complete endovascular approach; whereas less than % of repairs were aorta related. we were allocated to use a total of surgical rooms in different locations, none our usual, as it was converted into an icu room while performing % of those repairs with unusual nursery staff. conclusions: the covid- outbreak has dramatically changed our organization and practice in favor of urgent or semi-urgent surgical care alone. the lack for in-hospital/icu beds and changing nursery staff changed the whole availability organization at our hospital and was a key factor in surgical decision making in some cases. the epidemic potential of coronavirus infection is now a reality. since the first case detected in late in china a fast-world-wide expansion confirms it. the vascular patient is at a higher risk of developing a severe form of the disease due to its nature associating several comorbid states and thus, some vascular surgery communities from many countries have tried to stratify patients into those requiring care during these uncertain times. observational study describing the current daily vascular surgery practice at one tertiary academic hospital in madrid region, spain; one of the most affected regions worldwide due to the covid- outbreak. we analyzed our surgical practice since march th when the lockdown was declared up to date, may th ( months). procedural surgical practice, organizational issues, early outcomes and all the troubles encountered during this new situation are described. our department is composed of vascular surgeons and trainees. surgical practice has been reduced to only urgent care, totaling repairs on patients during the time period. five surgeries were performed on covid- positive patients. sixty percent were due to cli, % of them performed by complete endovascular approach; whereas less than % of repairs were aorta related. we were allocated to use a total of surgical rooms in different locations, none our usual, as it was converted into an icu room while performing % of those repairs with unusual nursery staff. the covid- outbreak has dramatically changed our organization and practice in favor of urgent or semi-urgent surgical care alone. the lack for in-hospital/icu beds and changing nursery staff changed the whole availability organization at our hospital and was a key factor in surgical decision making in some cases. the first reported case in spain was in january st and since then, the rapid spread of the virus has been demonstrated as the numbers of confirmed diagnosis ( ) and deaths ( ) have dramatically increased daily, with the last week reaching the smaller number of deaths per day (less than ). the vascular patient due to its nature associating several comorbid states should be considered at higher risk when compared to other populations . some vascular surgery communities have tried to stratify patients into those requiring urgent care during this pandemic situation, i.e > mm abdominal aortic aneurysms or ruptured aaa, critical limb ischemia (cli) and symptomatic carotid disease . hospital organization strictly depends on the pandemic situation, as in-hospital and intensive care unit beds (icu) availability, surgical rooms disposal and nursery staff. observational study describing the current daily practice at one tertiary academic hospital in madrid region, spain; one of the most affected regions worldwide due to the covid- outbreak. we analyzed our surgical practice since march th when the lockdown was declared up to date ( weeks). procedural surgical practice, organizational issues, early outcomes and all the troubles encountered during this new situation are described. our surgical activity has dramatically been reduced to minimums. we only provided surgical care for urgent cases, and during the last two weeks, as the covid- situation improved and more in-hospital beds and resources are available, we started to provide care to patients requiring a vascular access, limb ischemia with rest pain and one carotid with severe stenosis with unstable plaque. figure shows a pie-chart with those procedures performed during the study period, describing on interventions performed in patients. all surgical procedures were performed outside our usual surgical room. we have changed our surgical room times (like nearly all the other surgical departments) whereas up to % of repairs have been performed without our usual nursery staff. the vast majority of interventions were related to cli revascularization ( %), where nearly % where performed by open means, as shown in figure. . aorta-related disease was required for patients. one patient receiving an axillo- femoral by pass due to aortic-graft thrombosis, was tested positive for covid- and after two re-interventions (one explantation and contralateral axillo-femoral revascularization and one other for acute axillar stump bleeding) died for ards (acute respiratory distress syndrome). three patients received successful tevar treatment for acute aortic syndromes, one case with symptomatic thoracic aortic ulcer, one with intramural hematoma (imh) and the other with post-dissection symptomatic aneurysm. the challenge, as vascular surgeons, was the trouble in decision making on who and how to operate, as we were dealing with our worst situation in terms of lack of resources (limitation of icu beds, in hospital beds, anesthesia team treating patients, nurse staff in other labors, etc.). referral was not an option as this same situation was clearly evident for all private and public hospitals in the region. fortunately, in our center every patient requiring urgent care did receive it at last. with lot of troubles due to a constant change in surgical rooms and nursery team. at the peak of the outbreak, our department was split in two groups, where half of it was in covid- attention and the remaining on specific vascular surgery care. this organization being dynamic depending on in-hospital covid- and/or vascular care at the very beginning of the outbreak, we dealt with a disturbing lack of tests for patients and health care professionals. at some point, and this is already stablished, every patient requiring hospitalization received a pharyngeal swab test for diagnosis. if one needing surgical care was tested positive, one dedicated covid- surgical room was provided. during these weeks, we have performed operations in patients. as shown in figure , those were mainly for cli representing % of our practice. as described previously, covid- patients can associate a pro-coagulant state which can lead either to deep vein thrombosis (dvt) and /or peripheral arterial thrombosis. these patients with acute limb ischemia required most of the times urgent surgery, a situation we dealt with in two cases. pertaining dvt, a previous description of % incidence for covid- patients in icu and % not requiring ventilator demonstrated the importance of such situation in these patients. a national registry (nct ) is currently starting to better understand this situation and provide accurate data in the near interestingly, from those treated for cli, % were treated by open revascularization techniques in our department. this in part due the aforementioned limitations related to organization, as the recommendations standards given by other vascular communities is directed towards total endovascular approach. we also treated patients with aortic diseases, and one of them would have received a different treatment in normal conditions. the decision to perform an axillo-femoral by pass was due to the risk of visceral embolization and absolute lack of icu bed. three other patients received tevar for imh, thoracic pau and enlarging symptomatic taa respectively; despite the limitations, as the open options were extremely risky. the benefits of evar/tevar during the covid- outbreak have been described. two patients were treated for carotid disease, with conventional patch endarterectomy and patients for hemodialysis access (fistula creation) by open means as well. although endovascular procedures are highly recommended during these times being less invasive and needing less in-hospital resources; we needed to adapt our decisions and surgical actions to the changing reality in our hospital, where lack of icu beds and changes in surgical rooms and nursery staffs had a clear incidence in our decisions. finally, from those with positive test for covid- ; were cli with successful repair and the remaining, the abovementioned case of aortic graft thrombosis who unfortunately died for acute respiratory distress syndrome. the increased risk of fatality for a surgical repair in covid- patients is previously described. we are now into the "going back to the normal" process; however, a considerable grade of uncertainty comes for the future where our weakened health system will need to deal with an unprecedent scenario that might surpass again our available resources. the covid- outbreak has dramatically changed our organization and practice in favor of urgent or semi-urgent surgical care alone. the lack for in-hospital/icu beds and changing nursery staff changed the whole availability organization at our hospital and was a key factor in surgical decision making in some cases. cardiovascular examination should also include peripheral arterial evaluation for covid- patients acute limb ischemia in patients with covid- pneumonia characteristics and outcomes of patients hospitalized for covid- and cardiac disease in northern italy vascular surgery activity condition is a common language for uncommon times hypogastric chimney patency in aortic monoiliacal endograft thrombosis: a life saved by collateral pelvic impact of the covid- pandemic on vascular surgery lombardia (italy) during the first month of the covid- outbreak vascular life during the covid- pandemic reminds us to prepare for the unexpected endovasc surg / / endovascular treatment of a ruptured pararenal abdominal aortic aneurysm in a covid- patient: suggestions and case report aortic disease in the time of covid: repercussions on patient care at an academic aortic center surgical practice: unexpected fatality in perioperative period key: cord- -irtdqbeb authors: ackland, g. j.; rice, k.; wynne, b. m.; martin, v. title: the long term predictions from imperial college covidsim report date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: irtdqbeb we present calculations using the covidsim code which implements the imperial college individual-based model of the covid epidemic. using the parameterization assumed in march , we reproduce the predictions presented to inform uk government policy in march . we find that covidsim would have given a good forecast of the subsequent data if a higher initial value of r had been assumed. we then investigate further the whole trajectory of the epidemic, presenting results not previously published. we find that while prompt interventions are highly effective at reducing peak icu demand, none of the pro- posed mitigation strategies reduces the predicted total number of deaths below , . surprisingly, some interventions such as school closures were predicted to increase the projected total number of deaths. the uk national response to the coronavirus crisis has been widely reported as being primarily led by modelling based on the work of ( ), although other models have been considered . the key paper ( ) , which we will refer to as "report ", investigated a number of scenarios using this code with the best parameterisation available at the time. contrary to popular perception, the full lockdown which was then implemented was not specifically modelled in this work. as the pandemic has progressed, the parameterisation has been continually improved with new data as it arrives. the main conclusions of report were not especially surprising. covid has a morbidity around % ( ) , so an epidemic in a susceptible population of m people would cause many hundreds of thousands of deaths. in early-march there may have been a case-doubling time of around days in the uk ( ) , meaning that within a week covid cases could go from accounting for a minority of available icu spaces, to exceeding capacity. furthermore, with an onset delay of over a week, and limited or delayed testing and reporting in place, there would be very little measurable warning of the explosion in icu demand. the original code used for report has not been released, however the ferguson group has led an effort with microsoft, github and the royal society ramp-initiative to recreate the model in the open-sourced covidsim code ( ) . covidsim faithfully replicated the original code, and recently the results presented in report were independently replicated ( ) . covidsim is an individual-based code that includes a detailed geographic network, considers schools, universities, and places of work, and is parameterised using the best available expert clinical and behavioural evidence. the model has the required complexity to consider non-pharmaceutical interventions (npis), specifically home isolation of suspect cases (ci), home quarantine of family members (hq), general social distancing (sd), and social distancing of those over (sdol ). it further considered "place closures" (pc), specifically the closure of schools and universities. more details of these npis are provided in table of report , which we reproduce in appendix figure . report presented both mitigation and suppression strategies, but we focus here on the mitigation strategies. one counter-intuitive result presented in report (their table and table a ) is the prediction that once all other considered interventions were in place, the additional closure of schools and universities would increase the total number of deaths. similarly, adding general social distancing (sd) to a scenario involving case isolation and household quarantine, was also projected to increase the total number of deaths. very recently, the detailed inputs used for report were released. in this paper, we reproduce the main results from report , and explain why, in the framework of the model, these counter-intuitive results were obtained. the covidsim model is developed from an influenza pandemic model( ; ; ). we used the version recovered from github( ), tagged version . . + additional patches dated before - - . input files relevant to report were supplied by ferguson et al. ( ) . we chose not to attempt to re-parameterise the model. covidsim contains a huge number of parameters derived from expert judgement, and so it is not well suited to data-driven re-parameterisation using bayesian inference or related techniques. the epidemiological assumptions underlying our results are identical to those of ferguson et al., the purpose of this paper is to investigate more fully the consequences of those assumption. . cc-by-nc . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the result tables for the scenarios presented in the original report were straightforwardly reproduced by averaging over simulation runs with the same random number seeds as used in report . the simulations are run for days, with day being january . the intervention period lasts for months ( days), with some interventions extended for an additional days. the mitigation scenarios in report considered r = . and r = . , but we initially only considered r = . . as highlighted in ( ) the results we obtain here are not precisely identical to those in report , since they are an average over stochastic realisations, the population dataset has changed to one that is open-source, and the algorithm used to generate the household-to-place network has been modified to be deterministic. the stochasticity gives a variance around % in total deaths and icu demand, which explains the discrepancies with report . more significant is the uncertainty of the timing of the peak of the infections, which is around ± days. we compare these predictions to the death rates from the actual trajectory of the disease( ). we note that nhs england stopped publishing critical bed occupancy in march ( ), so it is not possible to compare icu data from the model with reality. to understand why, for example, closing schools and universities increases total deaths within the model, we consider two possibilities. firstly, reduced contact at school leads to increased contact at home. therefore infection is transferred from low-risk children to high-risk adults. we investigated this by examining the effect of changing the "relative household contact rate after closure" parameter. in figure it is clear that variation due to the value of this parameter is insignificant compared to the overall effect of adding school closures to the other interventions. therefore we reject this hypothesis. secondly, place closures suppress the first wave, but when the interventions are lifted, there is still a large population of people who are susceptible and a substantial number of people who are infected. this then leads to a second wave of infections that can result in more deaths, but at a later time. in table we show the critical care (icu) bed demand, while in table we show total deaths, both using the same mitigation scenarios as presented in report . as in report , for each mitigation scenario we consider a range of icu triggers. in table we report the peak icu bed demand across the full simulation for each trigger, as was presented in report , but also include the peak icu bed demand during the period of the intervention (labelled (int)). the latter we define as the period during which general social distancing (sd) was in place, when implemented. in table we also report the total number of deaths across the entire simulation, and also the number of deaths at the time when the interventions were despite the description of place closure interventions in table of report , university closures are not included in the (pc )ci hq sdol scenario parameter files ( ) . cc-by-nc . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . lifted, again defined as the time at which general social distancing was lifted, if implemented. the full simulation numbers we present in tables and are essentially the same as those presented in table a in report . as discussed earlier, the small difference between our numbers and those presented in report are probably because these are averaged over stochastic realisations, the population dataset is slightly different, and the algorithm for generating the household-toplace network was changed to make it deterministic. table also illustrates the counter-intuitive result that adding pc to ci hq sdol increases the total number of deaths across the full simulation, as does adding sd to ci hq. what's clear from tables and is that in some mitigation scenarios peak icu demand, and most deaths, occur during the period when the intervention is in place. there are, however, other scenarios where the peak icu demand, and total deaths, during the period of the intervention is far smaller than outside this period. the reason for this is illustrated in figure . the solid lines are the same mitigation scenarios as presented in figure of report . we also show some additional scenarios (dashed lines) not shown in figure of report , but which are included in tables and and also in the tables in report . in the simulations presented here, the main interventions are in place for months and end on about day (some interventions are extended for an additional days). figure shows that some intervention scenarios lead to a single wave that occurs during the period in which the interventions are in place. hence, the peak icu bed demand occurs during this period, as do most deaths. . cc-by-nc . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . there are, however, some interventions that suppress the infection so that there is then a second wave once the interventions are lifted. for example, adding place closures to case isolation, household quarantine, and social distancing of those over substantially suppresses the infection during the intervention period when compared to the same scenario without place closures. however, this suppression then leads to a second wave with a higher peak icu bed demand than during the intervention period, and total deaths that exceed that of the same scenario without place closures. we therefore conclude that the somewhat counter-intuitive results presented in report are a consequence of the addition of some interventions suppressing the first wave so that a second wave, occurring after the interventions have lifted, then leads to a total number of deaths that exceeds the total for the equivalent scenario without this additional intervention. a similar effect can be seen in some of the scenarios involving general social distancing (sd). for example, adding general social distancing to case isolation and household quarantine also strongly suppresses the infection during the intervention period, but then leads to a second wave that actually has a higher peak icu demand than for the equivalent scenario without general social distancing. figure provides an explanation for how place closure interventions affect the second wave, and why an extra intervention may result in more deaths than the equivalent scenario without this intervention. in the ci hq sdol scenario, without closures, a single peak of cases is seen. the data is brokendown into age groups, showing that younger people contribute most to the total cases, but that deaths come primarily from older groups. adding the place closure intervention (and keeping all other things constant) gives the behaviour shown in the second row of plots. the initial peak is greatly suppressed, but the end of closures seems to prompt a second peak of cases amongst younger people. this then leads to a third, more deadly, peak of cases affecting the elderly when sdol is removed. the net effect is that there is a postponement in the . cc-by-nc . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . number of infections in the younger age groups, which increases the number of infections, and hence deaths, in the older age groups. figure : comparison of simulation results over time, for the ci hq sdol and pc ci hq sdol intervention scenarios. interventions are triggered by reaching cumulative icu cases. in the scenario including place closure (pc), the value of the relative household contact parameter is varied from . to . . regardless of this variation, the additional pc intervention always leads to an increase in total cases and deaths. although report does discuss the possibility that relaxing the interventions could lead to a second peak later in the year, we wanted to briefly explore this in a bit more detail. given that little data for intialising the model was available when report was released, we use an updated set of parameter files included in the github repository ( ) . the interventions we consider are place closures (pc), case isolation (ci), household quarantine (hq) and general social distancing (sd) which are implemented using the pc ci hq sd parameter file. these interventions start in late march (day ) and last for months ( days). these simulations are also initialised so that there are about deaths by day in all scenarios, presumed to have mostly been infected before the interventions were implemented. . cc-by-nc . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . figure of report . we also include three additional scenarios (dashed lines) not presented in figure of report , but which are presented in their tables and in tables and here. these illustrate why adding place closures (pc) to a scenario with case isolation (ci), household quarantine (hq) and social distancing of those over (sdol ) can lead to more deaths than the equivalent scenario without place closures. doing so suppresses the infection when the interventions are present, but leads to a second wave when they are lifted, which happens on around day . the total number of deaths in the ci hq sdol scenario is , , while for pc ci hq sdol it is , . so the latter has more deaths even though the peak icu bed demand is lower. a similar effect can be seen by comparing scenarios with general social distancing (sd) with equivalent scenarios without sd. for example, the second wave peak in the ci hq sd scenario is actually higher than the first wave peak in the ci hq scenario. the results are presented in figure . the top panel shows cumulative deaths, with data from ( ), while the bottom panel shows icu bed demand per people. we consider a range of r values and find that values higher than those considered in report best reproduce the data, with r = . providing the best fit. this is consistent with the analysis presented in ( ), cc-by-nc . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . figure : simulated values for daily virus cases (left) and deaths (right), for scenarios ci hq sdol (top) and pc ci hq sdol (bottom). interventions are triggered by reaching cumulative icu cases. results are broken down into age categories as indicated, with sdol interventions affecting the three oldest groups. in the ci hq sdol scenario we see a single peak of cases, with greatest infection in the younger age groups but most deaths occurring in the older. in the pc ci hq sdol scenario we see three peaks in the plot of daily cases, with the first peak occurring at a similar time for ci hq sdol above, but with reduced severity. the second peak seems to be a response to the ending of place closure (pc), and most affects the younger age groups, therefore having little impact on the total deaths. the third peak affects the older groups, leading to a significant increase in the total deaths. after the trigger, all the interventions are in place for days the general social distancing runs to day , and the enhanced social distancing for over s runs for an extra days. but we acknowledge that the data could also be fitted by changes to the other scenario parameters. in both panels we also show the "do nothing" scenario for r = . . the icu bed demand for the scenarios presented in figure show that the interventions are correctly predicted to limit icu demand to less than per . however, if interventions are fully lifted, there is a risk that this demand will start increasing again sometime between day and day (i.e., between . cc-by-nc . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . late july and late august). if some interventions were to remain in place, then this might delay, and weaken, this second wave. as illustrated here, and in our analysis of the mitigation scenarios in report , it would seem important to understand how the intervention scenario, and the subsequent relaxation of the imposed interventions, may influence a potentially more deadly second wave that could occur later this year. in this paper we used the recently released covidsim code ( ) to reproduce the mitigation scenarios presented in mid-march in report ( ). the motivation behind this was that some of the results presented in report suggested that the addition of extra interventions may actually increase the total number of deaths. we find that the covidsim code reliably reproduces the results from report- , and that the model underlying covidsim can accurately track the uk deathrate data. to do so does require an adjustment to the parameters, a slightly higher r than considered in report , and results in an earlier start to the epidemic than suggested by report . we emphasize, though, that the unavailability of these parameters in early-march is not a failure of the model. we confirm that adding school and university closures to case isolation, household quarantine, and social distancing of those over would lead to more deaths when compared to the equivalent scenario without school and university closures. similarly, adding general social distancing to a case isolation and household quarantine scenario was also projected to increase the total number of deaths. the qualitative explanation for this is that within all mitigation scenarios in the model, the epidemic ends with herd immunity with a large fraction of the population infected. strategies which minimise deaths involve having the infected fraction primarily in the low-risk younger age groups. these strategies are different from those aimed at reducing the icu burden. a key thing seems to be that scenarios that are very effective when the interventions are in place, can then lead to a second wave during which most of the infections, and deaths, occur. our comparison of updated model results with the published death data suggests that a similar second wave could occur later this year if interventions are fully lifted. finally, we reemphasize that the results in this work are not intended to be detailed predictions for the second wave. rather, we are reexamining the evidence available from covidsim at the start of the epidemic. more accurate information is now available about the compliance with lockdown rules and age-dependent mortality. the difficulty in shielding care-home residents is a particularly important piece of health data that was not available to modellers at the outset. nevertheless, in almost all mitigation scenarios, covidsim epidemics eventually finish with widespread immunity, and the final death toll depends primarily on the age distribution, not the total number, of infections. . cc-by-nc . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . figure : refit of the covidsim march parameterization based on death data through to june. the top panel shows cumulative deaths, with data from ( ), while the bottom panel shows icu bed demand per people. we considered a range of r values and find that values higher than that considered in report best reproduce the data. a good fit also requires us to assume that the epidemic started considerably earlier than was previously suggested in report . we see that covidsim (a) provides a good fit to the data with a value of r = . and (b) correctly predicts that the icu capacity would not be exceeded during the intervention period. . cc-by-nc . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint codecheck certificate - impact of non-pharmaceutical interventions (npis) to reduce covid- mortality and healthcare demand strategies for containing an emerging influenza pandemic in southeast asia strategies for mitigating an influenza pandemic estimating the number of infections and the impact of non covid- covidsim model. github estimating the global infection fatality rate of covid- . medrxiv modeling targeted layered containment of an influenza pandemic in the united states challenges in control of covid- : short doubling time and long delay to effect of interventions. medrxiv we acknowledge support from ukri grant st/v x/ under covid- initiative. this work was undertaken [in part] as a contribution to the rapid assistance in modelling the pandemic (ramp) initiative, coordinated by the royal society. key: cord- -dzmbfp g authors: bi, qifang; hong, chengcheng; meng, juan; wu, zhenke; zhou, pengzheng; ye, chenfei; sun, binbin; kucirka, lauren m; azman, andrew s; wang, tong; chen, jiancong; wang, zhaoqin; liu, lei; lessler, justin; edwards, jessie k; ma, ting; zhang, guoliang title: characterization of clinical progression of covid- patients in shenzhen, china date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: dzmbfp g the covid- pandemic has stressed healthcare care systems throughout the world. understanding clinical progression of cases is a key public health priority that informs optimal resource allocation during an emergency. using data from shenzhen, china, where all cases were monitored in hospital and symptom profiles and clinical and lab results were available starting from early stages of clinical course, we characterized clinical progression of covid- cases and determined important predictors for faster clinical progression to key clinical events and longer use of medical resources. epidemiological, demographic, laboratory, clinical, and outcome data were extracted from electronic medical records. we found that those who progressed to the severe stage, developed acute respiratory distress syndrome, and were admitted to the intensive care unit (icu) progressed on average . days ( %ci . , . ), . days ( %ci . , . ), and . days ( %ci . , . ) after symptom onset, respectively. we estimated that patients who were admitted to icus remained there for an average of . days ( %ci . , . ) and the average time on a ventilator was . days ( %ci . , . ) among those requiring mechanical ventilation. the median length of hospital stay was . days ( %ci, . , . ) for the mild or moderate cases who did not progress to the severe stage, but increased to . days ( %ci, . , . ) for those who required icu admission. clear characterization of clinical progression informs planning for healthcare resource allocation during covid- outbreaks and provides a basis that helps assess the effectiveness of new treatment and therapeutics. the epidemic of coronavirus sars-cov- has led to . million infections and over , deaths over months after the first case was detected , causing severe shortage of essential medical supplies and equipment, medical staff, and hospital beds . complementary to data from covid- epicenters like wuhan (china) or lombardy (italy), data from places where healthcare capacity was not exceeded and patients were treated early and free of charge has the potential to shed light on the near complete clinical trajectory of cases. clear characterization of covid- clinical trajectory under the current standard of care informs planning for healthcare resource allocation during covid- outbreaks and provides a basis that helps assess the effectiveness of new treatment and therapeutics. here, we use rich data on clinical progression of all covid- cases diagnosed and treated in the only designated hospital in shenzhen, china. because all clinically confirmed cases, including a sizable portion detected through contact tracing, were required to be hospitalized for isolation purposes regardless of their clinical presentation and symptom profile, this dataset allows us to examine clinical progression of cases without the considerable selection bias typically seen in hospital-based studies. we estimate time from symptom onset to key clinical events, such as first clinical diagnosis, progression to severe clinical stages, development of acute respiratory distress syndrome (ards), admission to the critical care unit (icu), and discharge. we also estimate duration hospitalized, in the icu, and on ventilators. we determine the key predictors of faster clinical progression to a series of clinical events and longer use of healthcare resources. this single-centre, observational study was conducted at shenzhen third people's hospital, which is the designated hospital to treat all patients with covid- in shenzhen. we prospectively collected data of all patients diagnosed and hospitalized with covid- in shenzhen between january th and march th , regardless of their clinical severity and symptom profile. epidemiological, demographic, laboratory, clinical, and outcome data were extracted from electronic medical records using a standardised data collection form. all information was updated as of april th . data were reviewed by multiple reviewers (bs, jc, jz, pz), and any disagreement between reviewers was resolved by consultation with an attending physician (jm). data from patients with severe or critical clinical assessment were extracted by an attending physician (jm) and reviewed with a reviewer (ch) to ensure data quality. we obtained information on demographic characteristics, mode of detection, and date of onset for each symptom. date of symptom onset before admission was self-reported and date of symptom onset after admission was recorded by an attending physician. clinical severity was defined based on guidelines issued by the national health commission of the people's republic of china, and the severity definition was generally consistent over time (see supplemental table for guidelines in each version) . we recorded clinical severity at initial diagnosis and date of severity progression. clinical severity was assessed daily when mild or moderate and was assessed twice a day when severe or critical. dates of icu admission and discharge were recorded, as well as dates beginning and ending invasive ventilator use. patients were eligible for discharge from the hospital or transfer to a non-covid ward for treatment if they met all of the following: ) no fever for over days, ) drastic improvement in respiratory symptoms, ) pulmonary imaging showing significant reduction in inflammation, and ) two consecutive negative rt-pcr results from respiratory sampling conducted over one day apart . we counted time in non-covid wards for treatment of covid- related complications towards the duration of hospitalization. we recorded patients' self-reported medical history (see table for a list of baseline comorbidities). we reviewed laboratory results and created binary variables indicating presence of any abnormalities and the date when such abnormalities were detected (see table for a complete list of lab indicators and abnormality cutoff). the x-ray computed tomography (ct) results were extracted from radiological examinations. we recorded the lowest cycle threshold values from the available rt-pcr testings and the date when the testing was performed. we also recorded complications developed during hospitalization. the primary endpoints in this study include patients' time from symptom onset to clinical progression beyond the moderate stage, icu admission, invasive ventilator use, and discharge. we also examined other endpoints including time to when pao /fio dropped under mmhg and time to developing ards. we estimated cumulative incidence of developing key clinical events in the presence of competing risks (i.e., death and hospital discharge) using the aalen-johansen estimator , . outcomes included progression to severe stage, low pao /fio ratio, ards, icu admission, use of invasive ventilator, and hospital discharge. we estimated patients' duration of hospitalization by calculating the area above the cumulative incidence of hospital discharge or death, which was estimated using the aalen-johansen estimator , . in addition, we estimated the time patients admitted to the icu ultimately spent in the icu as the area between the cumulative incidence functions for icu entry and icu exit among those who were admitted into icu. we treated death while in the icu and icu discharge as a composite event when estimating cumulative incidence of icu exit. similarly, we estimated the duration of invasive ventilator use among patients requiring ventilation, as the area between . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . . the cumulative incidence functions for ventilator initiation and ventilator discontinuation. we treated death during ventilator use and withdrawal of ventilator support as a composite event when estimating ventilator discontinuation. we compared times in each state estimated using the nonparametric approach described above with times estimated using a parametric accelerated failure time models to examine improvements in precision seen when invoking a parametric approach (see text s for detailed method). we used bootstrap simulation to construct confidence intervals ( bootstrap simulations for time to recovery and time to ards, and bootstrap simulations for time to icu entry/discharge and ventilator use/withdrawal). % confidence intervals were the . th and . th percentiles of the distribution of point estimates from the bootstrap samples. we used competing risk regressions according to the methods of fine and gray to estimate subdistribution hazard ratios comparing the rate of clinical progression between subgroups that were defined a priori (see table for the list of subgroups). we compared the rate of clinical progression to severe stage, icu admission, ards, and hospital discharge between subgroups. except for the models where time to hospital discharge was the outcome, hospital discharge and death were treated as competing events and end of study as administrative censoring for those still in treatment. we used a flexible approach to stratify cases into three risk strata for the purpose of visualizing different clinical trajectories. we constructed a random survival forest model (rsf) and divided cases into low, medium, and high risk groups based on tertiles of rsf out-of-bag predictions. the candidate predictors used in the rsf model included ) demographic information, ) baseline comorbidities, ) symptom profile, lab and ct results within days of any symptom onset. hospital discharge was treated as a competing event. all four deaths occurred after cases progressed beyond the severe stage, thus they were not treated as competing events. we calculated auc over time since symptom onset (tauc), providing a measure of model performance across all possible classification thresholds and based on the observed number of cases entering the severe stage by each time point . we fit trees, considered random splits for each candidate splitting variables, and used the log-rank test as the split function. four-hundred and twenty cases were admitted and hospitalized to shenzhen third people's hospital between january th and march th, ( figure s ). fifteen percent ( / ) of cases were detected through contact tracing (table ) . on average, the first clinical diagnosis occurred . days ( % ci . , . ) and hospitalization occurred . days ( %ci . , . ) after symptom onset. of the cases, there were approximately equal numbers of males ( . %, n= ) and females ( . %, n= ) ( table ) . a large portion ( . %, n= ) were under the age of and the majority ( . %, n= ) were detected through symptom-based surveillance. . % . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint ( / ) of cases had at least one self-reported comorbidity on admission, with hypertension (n= ) and diabetes (n= ) being the most prevalent. fever, cough, sputum production were the most common initial symptoms, with . % ( ) of patients showing fever, . % ( ) with cough, and . % ( ) with sputum production within days of initial symptom onset (see supplemental figure for onset time distribution of each symptom). . % ( ) of patients never had fever, and . % ( ) of patients never had cough. at the initial clinical assessment, patients ( . %) were clinically mild, the vast majority ( . %, n= ) were moderate, and only patients were clinically severe or critical ( figure s ). we estimated the proportion of the initially mild or moderate cases in each stage (mild/moderate, severe, icu, death or discharge) over time following symptom onset, taking into account patients both transitioning into and out of each stage ( figure a ). the total number of patients in the severe stage reached its peak days after symptom onset. among the patients who were classified as mild or moderate at the time of initial assessment, . % ( / ) progressed to the severe stage. . % ( %ci, . %, . %) progressed to the severe stage within days after symptom onset, and . % ( %ci, . %, . %) progressed within days (figure and ) . those who progressed to the severe stage progressed on average . days ( %ci . , . ) after symptom onset. among the patients who were classified as mild or moderate at the time of initial assessment, . % ( / ) developed ards. . % ( %ci . %, . %) developed ards within days from symptom onset, and . % ( %ci . %, . %) within days. those who developed ards developed ards on average . days ( %ci . , . ) after symptom onset. as of april th, patients had been admitted to icu, among which patients required invasive mechanical ventilation support, patients died ( patient died after initial hospital discharge with viral clearance), and patients remained hospitalized in critical condition. we estimated that among the patients who were classified as mild or moderate at the time of initial assessment, . % ( %ci, . %, . %) of patients required icu admission within days from symptom onset (same for patients who required mechanical ventilators support). those who required icu admission were admitted into icu on average . days ( %ci . , . ) after symptom onset. using data from the patients who were admitted into icu, we estimated the average time in icu was . days ( %ci . , . ) ( table ). using data from the patients who required mechanical ventilator support, we estimated the average time on a ventilator was . days ( %ci . , . ). the median length of hospital stay was . days ( %ci, . , . ) for the mild or moderate cases who did not progress to the severe stage, and increased to . days ( %ci, . , . ) for cases who reached the severe stage but did not enter icu and . days ( %ci, . , . ) for the cases who required icu admission. of note, patients in shenzhen were required to . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . be hospitalized for about weeks for isolation; % ( / ) of the cases that were initially mild or moderate were discharged within days from hospitalization, % ( / ) within days. the duration of hospitalization for the mild or moderate cases was likely inflated as a result. all patients who were clinically mild at the time of initial assessment stayed mild until discharge ( figure s ). we then identified a priori-defined patients' characteristics that were associated with faster clinical progression. we found that having hypertension and diabetes at baseline was strongly associated with faster clinical progression to various clinical events, including progression to the severe stage (shr= . , %ci . , . for hypertension and shr= . , %ci . , . for diabetes), to developing ards (shr= . , %ci . , . for hypertension and shr= . , %ci . , . for diabetes), and to icu admission (shr= . , %ci . , . for hypertension and shr= . , %ci . , . for diabetes) ( table ) . having more baseline comorbidities was also associated with a higher rate of clinical progression to these events (table ) . although many lab abnormalities measured within days of symptom onset were strongly predictive of faster clinical progression, including low lymphocyte count, low platelet count, high concentration of creactive protein, and high concentration of d-dimer, notably, a low pao /fio ratio close to symptom onset was very strongly associated with faster clinical progression. we observed a . times ( %ci . , . ) increase in the subdistribution hazard of icu admission among those with early measures of low pao /fio ratio (table ) . older age was one of the most important predictors of faster clinical progression (table ). all four patients who died were male over the age of . about half ( . %, / ) of cases aged or above progressed to the severe or critical stage (table ) . although the vast majority of those under the age of did not progress beyond the moderate stage, % ( / ) of cases in this younger age group became clinically severe or critical and none of them had any known underlying comorbidities. sex was strongly associated with clinical progression of cases, though the difference by sex was mostly driven by the difference among older patients. we did not observe a significant difference in time to icu admission between males and females under the age of (shr = . , %ci . , . comparing males with reference to females; table s , figure b ). however, we observed a noteable difference in progression to require icu admission between males and females aged or above; males in this older age group had a -fold increase in the subdistribution hazard of icu admission compared to females in the same age group (shr= . , %ci . , . ), despite the similar sex-specific age distribution in this age group (males: mean , iqr , vs. females: mean , iqr , ) (table s ). differences in baseline comorbidities between older males and females did not explain the disparity; after adjusting for having any underlying comorbidity, the subdistribution hazard ratio remained unchanged (table s ) . similarly, we found that males aged or above had a lower rate of hospital discharge compared to females in the same age group, and no significant difference by . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . sex in the younger age group (figure c) . however, we did not find significant disparities in clinical progression to severe stage or to developing ards by sex in any age group (table s ) . using linear regression, we found that the minimum rt-pcr cycle threshold values for the severe cases were significantly lower than the mild cases after adjusting for time of sample collection with reference to symptom onset. we observed a general trend of lower minimum cycle threshold values in patients with more severe clinical presentation and in patients in the older age group though the association with age was not statistically significant ( figure s ). based on the random survival forest results, the most important predictors of faster progression to the severe stage were low pao /fio ratio, low platelet count, and high c-reactive protein concentration ( figure s a) . we observed very different clinical trajectories of patients in each risk group (figure b) , highlighting the effectiveness of risk stratification produced by the rsf model. in the low-risk group, no case required icu admission and only % ( %ci, . %, %) of cases became severe within days from symptom onset. whereas in the high-risk group, we estimated that % ( %ci, , ) cases became severe and % ( %ci, %, %) required icu admission within days from symptom onset. all but one case that required icu admission were classified into the high-risk group, and we estimated that the duration in icu for those in the high-risk group was . days ( %ci, . , . ) (table , figure s ). risk stratification produced by a rsf model that excluded lab and ct results from the candidate predictors also differentiated clinical trajectory of patients well ( figure s , figure s c-d) . the analysis of clinical data from covid- patients in shenzhen third people's hospital provides insights into clinical progression of cases starting early in the course of infection. we estimate the proportion of cases in each severity stage over days following symptom onset. we present patient characteristics associated with faster clinical progression and longer use of medical resources. because treatment of covid- was free of charge and hospitalization for all cases was mandatory in shenzhen, we expect that our results are not strongly affected by the selection bias that plagues many hospital-based studies. therefore, our results provide a clear picture of the composition of cases in a city in terms of disease severity and the clinical trajectories of these cases. although healthcare resources in shenzhen were rarely overwhelmed by influx of covid- patients, we show that the trajectory of clinical progression of cases in shenzhen were similar to the trajectory in wuhan, china, with mean time to icu admission and mean time to developing acute respiratory distress syndrome to be around days , . patient characteristics previously reported to be associated with ards and death including hypertension, diabetes, and various lab results were also highly predictive of faster clinical progression to various key clinical events including progression to severe stage, ards, and icu admission. previous studies reported that most cases were males and median age was over , and a higher percentage of men required icu care . we further show differences in clinical progression between males and females that were primarily driven by the stark difference in the older age group independent of differences in baseline comorbidities. this study has a number of limitations. dates of symptom onset were extracted from physicians' notes that were not recorded to explicitly ascertain information on symptom onset. when the date of symptom onset could not be determined, we assumed onset date was the date of initial diagnosis. we performed sensitivity analyses to assess patient characteristics for clinical progression to severe stage and icu admission and the results remained qualitatively the same (table s ) . we also performed the rsf analyses using symptom profile and lab results within days of initial diagnosis as candidate predictors, and the integrated auc remained relatively unchanged ( figure s ). our estimates of duration of icu stay and ventilator use were somewhat imprecise, likely due to the small sample size for those reaching the critical stage. even though estimating duration using our non-parametric approach showed improvement in precision compared to times estimated using parametric accelerated failure time models, the estimated time within subgroups needs to be interpreted with caution because of the small sample size (table s ) . finally, the association presented between clinical progression and patient characteristics should not be interpreted as causal given the variation in treatment and numerous confounders that were not accounted for in this study. we demonstrate that patient characteristics near symptom onset have tremendous potential to inform covid- triage, grouping patients into risk sets with different outlook of clinical progression. while our rsf model performs well based on out-of-bag predictions ( figure s ; text s ), we would be highly cautious of triaging patients in other settings using the important variables identified here due to our limited sample size. however, this is an important first step towards an applicable triage risk screening tool once well recorded data on clinical courses for more patients become available. strategic response and allocation of medical resources for ongoing outbreaks may also benefit from a dynamic risk scoring system that incorporates new patient-level lab and symptom information as it is updated over time. in conclusion, we provided quantitative characterization of the clinical progression of covid- patients beginning from early clinical stages. our estimates form the basis for assessing effectiveness of new treatments and inform planning for healthcare resource allocation during covid- outbreaks. table . demographic characteristics, surveillance method, baseline comorbidity, symptom profile, and lab and ct results by the highest clinical severity assessment. comorbidities were self-reported on admission. table : estimated length of hospital stay, duration in icu, and length of invasive ventilator use. we estimated duration in icu among those who were admitted into icu and estimated duration on ventilator among those who required ventilation. ^three cases whose initial severity was either severe or critical were excluded from estimating risk-group specific duration of hospital stay, duration in icu, and duration on ventilator. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint table : the association of demographic characteristics, baseline comorbidity, initial symptoms, and initial lab results with rate of clinical progression to severe stage, acute respiratory distress syndrome, and icu admission . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint figure : clinical progression within days following symptom onset for a) all cases with mild or moderate initial assessment, and b) cases in each of three risk subgroups obtained from random survival forest (see results for the list of predictors). from the top to the bottom, the four curves show the time-varying proportions of all admitted cases who ) have not been discharged, i.e., still hospitalized or have died in hospital, ) were severe, in the icu, or have died, ) were in the icu or have died, and ) have died. successive differences between the four curves over days from symptom onset were highlighted in distinct colors and show daily composition of cases in each of four stages (mild/moderate, severe, icu, died). . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint figure : cumulative incidence to clinical events and difference by age and sex. a) cumulative incidence of advancing to severe stage, pao /fio dropping below mmhg, requiring icu admission, and developing acute respiratory distress syndrome. b) cumulative incidence of icu admission by age group and sex. c) cumulative incidence of hospital discharge by age group and sex. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint tm were funded by the emergency response program of harbin institute of technology (hiterp ) and emergency response program of peng cheng laboratory (pclerp ). jl and qb were funded by a grant from the us centers for novel coronavirus ( -ncov) situation reports critical supply shortages -the need for ventilators and personal protective equipment during the covid- pandemic clinical features of patients infected with novel coronavirus in wuhan clinical characteristics of coronavirus disease in china risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region nonparametric estimation of partial transition probabilities in multiple decrement models a proportional hazards model for the subdistribution of a competing risk time-dependent roc curves for censored survival data and a diagnostic marker the statistical analysis of failure time data we thank all patients and their families involved in the study; as well as the front line medical staff and public health workers who collected this critical data. gz was funded by the national science and technology major project for control and prevention of major infectious diseases this work was conducted in support of an ongoing public health response, hence was determined not to be human subjects research after consultation with the johns hopkins bloomberg school of public health irb. the study was approved by the ethics committees of shenzhen third people's hospital. key: cord- -w aaalgo authors: mejia-vilet, j. m.; cordova-sanchez, b. m.; fernandez-camargo, d.; mendez-perez, r. a.; morales-buenrostro, l. e.; hernandez-gilsoul, t. title: derivation of a score to predict admission to intensive care unit in patients with covid- : the abc-goals score date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: w aaalgo background. covid- pandemic poses a burden on hospital resources and intensive care unit (icu) occupation. the study aimed to derive a scoring system that, assessed upon patient first-contact evaluation, predicts the need for admission to icu. methods. all consecutive patients admitted to a covid- reference center were prospectively assessed. patients were segregated into a group that required admission to icu during their hospitalization and a group that never required icu admission and was already discharged from hospitalization. three models including clinical, laboratory and imaging findings were derived by logistic regression analysis and internally validated. a score, defined as the abc-goals score was created by assigning values based on the variables weighted odd ratios. results. the study comprised patients, ( %) required icu admission and ( %) were hospitalized and discharged from general wards. the clinical prediction model (abc-goalsc) included sex, obesity, the charlson comorbidity index, dyspnea, arterial pressure and respiratory rate at triage evaluation. the clinical plus laboratory model (abc-goalscl) added serum albumin, glucose, lactate dehydrogenase and s/f ratio to the clinical model. the model that included imaging (abc-goalsclx) added the ct scan finding of > % lung involvement. all three models outperformed other pneumonia-specific scores with area under the curve of . ( . - . ), . ( . - . ) and . ( . - . ) for the clinical, laboratory and imaging model, respectively. conclusion. the abc-goals score is a tool to evaluate patients with covid- at admission to the emergency department that allows to timely predict their risk of admission to an icu and may help optimize healthcare capacities. the presence of a new severe acute respiratory syndrome coronavirus (sars-cov- ) was first reported in china and has subsequently spread to all regions of the world, straining the health systems of many countries . viral pneumonia associated with sars-cov- has been officially denominated as coronavirus disease (covid- ) . approximately to % of patients with covid- pneumonia will be admitted to an intensive care unit (icu) [ ] [ ] [ ] . previous studies have identified several risk factors associated with a severe course of covid- pneumonia and its progression to acute respiratory distress syndrome , . these risk factors may be categorized into patient characteristics obtained through the medical interview (e.g. age, comorbidities, symptoms) - ; vital signs obtained from triage evaluation (e.g. respiratory rate, arterial pressure) , ; laboratory abnormalities including inflammatory, coagulation and organ-specific studies (e.g. lactate dehydrogenase, d-dimer, fibrinogen, cardiac troponins, liver function tests, among others) , , - , ; and lung imaging findings (e.g. number of affected lobes, estimated pneumonia extension) , . in several countries, including mexico, hospital reconversion and temporary care centers have been implemented to cope with the large number of covid- patients . however, many of these centers are prepared to care for patients with supplemental oxygen requirements but just a few patients who require admission to an intensive care unit (icu) and mechanical ventilation. the aim of the study was to derive risk prediction models to anticipate the need for admission to an icu. these models include clinical, laboratory and image findings obtained at the first-contact evaluation to aid triage, decision making and timely referral to maintain healthcare system capacity. this is a prospective observational cohort study. all consecutive adult (> years) patients hospitalized at instituto nacional de ciencias médicas y nutrición salvador zubirán, a referral center for covid- patients at mexico city, were evaluated for this analysis. these patients were hospitalized between march th and april th and followed until may th . the study was approved by the local research and ethics board (cai- - - - ) that waived the use of an informed consent form due to the study's nature. the study population was segregated into two groups: ) patients who required admission to an icu at any time during their hospitalization, and ) patients admitted to general wards who were discharged from hospitalization without ever been considered for admission to an icu. patients were censored for each group once they were admitted to the icu or by the date of discharge from hospitalization, respectively. all patients who remained hospitalized in general wards by the end of the study were discarded for this analysis as it was considered that their risk for icu admission is still active. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / all patients had covid- pneumonia diagnosed by chest computed tomography (ct) and sars-cov- infection confirmed in respiratory specimens using real-time reverse-transcriptase polymerase chain reaction (rt-pcr) assay by local testing and confirmed at a central laboratory. patients were considered positive if the initial test results were positive, or if it was negative but repeat testing was positive. the following variables were obtained by the time of the triage and emergency department (ed) evaluation: demographic variables, previous medical and medication history including smoking; symptoms, physical examination including weight, height and vital signs; laboratory evaluation including arterial blood gas analysis, inflammatory biomarkers, troponin-i levels, complete blood count and blood chemistries; and chest ct-scan findings. all patients underwent chest ctscans that were evaluated by experienced specialists; lung involvement was semi quantitatively classified as mild (< %), moderate ( - %) or severe (> %). for each patient, we calculated the charlson comorbidity index (an index that predicts -year survival in patients with multiple comorbidities) , national early warning score (news) , sequential organ failure assessment (sofa) score , curb- score for pneumonia severity , the mulbsta score for viral pneumonia mortality , the rox index to predict the risk of intubation and the call score model for prediction of progression risk in covid- . all scores were calculated at admission to the ed. although most of these scores were not derived to evaluate the risk of admission to an icu, we evaluated their value if repurposed for this end. the need for admission to critical care was determined by the medical team in charge of the patient and included the need for mechanical ventilation or high-dose vasopressors. patients hospitalized in medical wards were treated with supplementary oxygen (nasal cannula or non-rebreathing oxygen mask) but were never considered for intubation and icu admission. all patients in this group were censored once discharged from hospitalization after improvement. clinical outcomes for patients admitted to icu were monitored up to may th, . the distribution of continuous variables was evaluated by the kolmogorov-smirnov test. variables are described as number (relative frequency) or median (interquartile range [iqr]) as appropriate. characteristics at admission between study groups were compared by the mann-whitney u test. there were less than % missing values for all variables. in the case of missing data, variables were imputed by using multiple imputations . for score derivation, all variables were evaluated by bivariate logistic regression analysis. all variables with p-values < . were considered for the multivariate logistic regression analysis. the best logistic regression analysis model was constructed by the forward stepwise selection method using maximum likelihood estimation and r-square values. three models were constructed: a first model including only clinical variables (abc-goalsc), a second model that included clinical and laboratory variables (abc-goalscl) and a third model that included . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / clinical, laboratory and x-ray findings (abc-goalsclx). the predictive performance of each model was measured by the concordance index (c-index) and internal calibration was evaluated by bootstrap samples. the goodness of fit was evaluated by the hosmer-lemeshow test. to create the final scores, points were assigned by the weighted odd-ratios and approached to the closest integer for each model. the performance of the derived scores as well as for all other scores determined at admission to predict the risk of hospitalization into an icu were assessed by receiver operating characteristic (roc) curves and their % confidence intervals. all analyses were performed with spss version . (ibm, armonk, ny, usa) and graphpad prism . (graphpad software, san diego, ca, usa). a total of patients with covid- pneumonia and sars-cov- positive test were hospitalized during the study period. seventy-nine patients who remained hospitalized in general wards and two patients who were discharged by discharge against medical advice were excluded from the analysis. a total of patients that required icu admission and patients that had been hospitalized and discharged from general wards were finally included for analysis. the median age of the study population was years (iqr - ), ( %) subjects were male with a median charlson comorbidity index of point (iqr - ). there were . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / ( %) subjects with no previous comorbidity. the median days from the start of symptoms to the evaluation at the er were days (iqr - ). all patients received supplementary oxygen. for the group admitted to icu, the median time from er admission to icu admission was days (iqr - days, range to ). the median length of hospitalization for the group hospitalized in general wards was days (iqr - days, range to ). several differences in the admission variables were observed between patients who required critical care and those hospitalized in general wards and are described in table and supplementary table . an extended table with all the results obtained from the bivariate logistic regression analysis is shown in supplementary table . the best predictive models derived from multivariable logistic regression analysis are shown in table . the clinical model included: male sex, the charlson comorbidity index, obesity (bmi> kg/m , not included in the charlson index), referred dyspnea, respiratory rate and systolic arterial pressure at the triage or er evaluation. the clinical plus laboratory model included the same clinical variables plus serum albumin < . g/dl, lactate dehydrogenase above the upper limit of normal and the hemoglobin oxygen saturation to fraction of inspired oxygen ratio < (s/f ratio). the clinical plus laboratory model included all previous variables except for referred dyspnea and serum albumin, and added reported lung involvement > % in the lung ct scan. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / the c-statistics for clinical, clinical plus laboratory, and clinical plus laboratory plus x-ray models were . , . and . , respectively. a predictive point score was constructed based on the weighted or's from each logistic regression model. the derived scores were defined as the abc-goals (arterial pressure, breathlessness, charlson, glucose, obesity, albumin, ldh and s/f ratio) and labeled as clinical (abc-goalsc), clinical plus laboratory (abc-goalscl) and clinical plus laboratory plus x-ray (abc-goalsclx) scores (table ) . by segregating the scores into three levels of risk of admission to icu, the abc-goalsc classified patients into low-( - points, mean risk %, %ci - %), moderate-( - points, mean risk %, %ci - %) and high-risk (≥ points, mean risk %, %ci - %) of admission icu. the respective groups for the abc-goalscl were low-( - points, mean risk %, %ci - %), moderate-( - points, mean risk %, %ci - %) and high-risk (≥ points, mean risk %, %ci - %) for icu admission. finally, the groups for the abc-goalsclx were low-( - points, mean risk %, %ci - %), moderate-( - points, mean %, . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / %ci - %) and high-risk (≥ points, mean %, %ci - %) for icu admission ( table ) . the sensitivity and specificity for selected cutoffs of these scores are shown in table . the abc-goals variants outperformed other scores that were repurposed for the prediction of admission to icu, based on the area under the curve values ( table ). as previously stated, most of these scores were not created to predict this outcome. for practicality, the three abc-goals scores are planned to be implemented into an application for mobile devices. by the end of this study (may th ), all patients from the group that was hospitalized in general wards were discharged to home after improvement. only two patients ( . %) were readmitted and discharged again without admission to icu during the study period. sixty-one ( %) patients from the group admitted to icu have died, ( %) have been discharged to their homes after improvement, and ( %) remain hospitalized. the abc-goalsc, abc-goalscl and abc-goalsclx scores predicted mortality with a sensitivity of %, %, and %, and specificity of %, % and %, respectively, (auc of . , . and . for mortality, respectively). . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint we derived a prognostic score that, evaluated upon patient admission to the ed, helps predict the probability of admission to icu during patient hospitalization. this tool may prove useful for patient assessment at first-contact evaluation and to timely refer patients to other units in case of a lack of or overcrowding of local icus. the abc-goals score predicts the need for admission to an icu with greater accuracy than other scores that were created for the prediction of other outcomes in sepsis or pneumonia, such as mortality. to date, more than million sars-cov- infections have been reported worldwide with almost , total deaths . the fast spread of the disease and the large number of patients admitted to hospitals has strained and overwhelmed local health systems. among hospitalized patients, to % will require admission to an icu and % to % of them will require support with mechanical ventilation - , . an effective evaluation of patients with severe disease may be critical to maintain healthcare system functional for as long as possible. the abc-goals score summarizes many of the previously reported factors that have been shown to independently associate with severe covid- disease. we found that age and comorbidities predictive performance is enhanced when integrated in the charlson comorbidity index. it has been reported in other studies that there may be interactions between age and some comorbidities such as diabetes . also, the charlson comorbidity index offers the advantage of integrating several comorbidities into one score that has been previously associated with survival . among clinical symptoms, dyspnea or shortness of breath is the most . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint consistently reported symptom associated with covid- severity and mortality , , , and was independently associated with icu admission in this study. obesity is a long-recognized factor for severe pulmonary infections and has been consistently associated with adverse outcomes in covid- . low systolic arterial pressure and respiratory rate at triage evaluation complete the clinical abc-goals. among the three derived scores in this study, the clinical abc-goals has an inferior performance and remains to be externally validated, as some reported models based exclusively in demographic (but not physical examination) information have been shown to decrease their performance after external validation . the scores integrating clinical with laboratory (abc-goalscl) and imaging (abc-goalsclx) findings seem to perform better for prediction of admission to an icu. both models include values of glucose, lactate dehydrogenase and oxygenation at admission that have been previously reported to be associated with prognosis in covid- , , , . lactate dehydrogenase has been previously integrated into a predictive model (see below). in contrast to other laboratory tests that may increase during the progression of the disease, such as d-dimer and cardiac troponin levels , , ldh has proved to be the most robust laboratory predictor for admission to icu when evaluated at first-contact. glucose and oxygenation were also included in these models. oxygenation, reflected by the s/f ratio, probably reflects the disease extension along with the imaging findings. it is worth noting that the model that included imaging findings (abc-goalsclx) only mildly improved the model performance, therefore, it may not be necessary to perform imaging in a . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint patient who is planned to be referred based on the clinical plus laboratory model recently, a scoring model to predict covid- progression risk (the call score) was derived from a chinese population . this score includes the presence of any comorbidity, age, lymphocyte count, and ldh levels. the score had a lower performance in our cohort than in the original chinese cohort. most patients in our study presented with lymphopenia below the set cut-off for the call score, therefore reducing the predictive value of this parameter. besides, we found several other independent predictors may that increase the predictive yield for icu admission. we showed that repurposing of other scores employed in pneumonia may not be perform adequately to predict the need for admission to icu in covid- pneumonia. for example, the mulbsta score has been validated for mortality prediction in viral pneumonia, but may have a lower performance in pneumonia. this score points the number of affected lobes by viral pneumonia, however, all patients in our study showed multi-lobar lung infiltrates reducing the performance of this parameter. other variables included in this score, such as bacterial coinfection, may not perform well when evaluated at admission, as bacterial coinfection more frequently occurs later in the disease evolution. finally, although the abc-goals score seems to have a good performance for mortality prediction, this data should be taken with caution as one-fourth of patients admitted to an icu were still on follow-up by the end of this study. therefore, the . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / prognostic performance of this score for mortality prediction should be further evaluated in other studies. the study has some strengths. first, all data were collected prospectively with very few missing data for all collected variables. second, there was an appropriate number of patients in the group that required admission to an icu which allowed the study of multiple predictors. third, the study is reported based on tripod guidelines . there are limitations of this study. the study involves only derivation of the score and therefore, the score still needs further validation in our population as well as external validation in other populations. however, the actual need for a tool to predict icu admission and to timely refer patients compelled us to start using this tool locally and to validate it over the progress of the pandemic. another limitation is that medical practice and admission criteria to icu may vary between institutions and countries, especially in stressed health systems. this score was derived from a population living in mexico city at > feet over the sea level. the mean partial pressure of oxygen at this altitude has been estimated at around mmhg (estimated normal baseline p/f ratio ≈ ) , . we therefore used the s/f ratio to account for respiratory compensation and the right-shift of the hemoglobin dissociation curve that takes place at higher altitudes (higher p values in mexico city). then, local validation is needed for this score. finally, the thresholds set to define the risk groups should be adapted to local needs. in summary, the abc-goals score represents a tool to evaluate patients with covid- at admission to the ed, designed to timely predict their risk of admission . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . to an icu. this score may help early referral and planning of attention during the covid- pandemic. none. all authors declare there is no conflict of interest with the content of this manuscript. the authors want to acknowledge all the health care team at instituto nacional de . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / abbreviations. ckd, chronic kidney disease; ap, arterial pressure; alt, alanine transaminase; ast, aspartate transaminase; bun, blood urea nitrogen; co , total diluted carbon dioxide; pao /fio ratio, ratio of arterial pressure of oxygen to fraction of inspired oxygen; safio /fio , ratio of the percentage of hemoglobin saturation by oxygen to fraction of inspired oxygen; news- , national early warning score ; sofa -pao /fio , sequential organ failure assessment score with respiratory points obtained by pao /fio ratio; sofa-sao /fio , sequential organ failure assessment score with respiratory points obtained by sao /fio . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / abbreviations. or, odds ratio; %ci, % confidence intervals; sbp, systolic blood pressure; ldh, lactate dehydrogenase serum levels; s/f ratio, ratio of percentage of hemoglobin saturation to fraction of inspired oxygen; ct, computed tomography. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / * all scores were obtained at admission to the emergency room. sofa respiratory points were assigned based on the s/f ratio. abbreviations. abc-goalsc, score including only clinical variables; abc-goalscl, score including both clinical and laboratory variables; abc-goalsclx, score including clinical, laboratory and x-ray findings; news- , national early warning score version ; call, comorbidity, age, lymphocyte, ldh score for predicting progression of covid- ; sofa, sequential organ failure assessment score; curb- , confusion, urea, respiratory rate, blood pressure, age> years score for risk of mortality from pneumonia; mulbsta, multi-lobar infiltrate, lymphocyte count, bacterial co-infection, smoking history, hypertension, age> years score for mortality from viral pneumonia; rox index, s/f ratio divided by the respiratory rate to predict the risk of intubation in hypoxemic respiratory failure. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / figure . receiver-operating curves for the three abc-goals scores. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . abbreviations. bmi, body mass index; alt, alanine aminotransferase; ast, aspartate aminotransferase; p/f ratio, ratio of arterial pressure of oxygen to fraction of inspired oxygen; s/f ratio, ratio of oxygen hemoglobin saturation to fraction of inspired oxygen; news- , national early warning score ; sofa -pao /fio , sequential organ failure assessment score with respiratory points obtained by pao /fio ratio; sofa-sao /fio , sequential organ failure assessment score with respiratory points obtained by sao /fio , mulbsta, multi-lobar infiltrate, lymphocyte count, bacterial co-infection, smoking history, hypertension, age> years score for mortality from viral pneumonia; rox index, s/f ratio divided by the respiratory rate to predict the risk of intubation in hypoxemic respiratory failure. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / creatine kinase, u/l u/l), n (%) >uln ( pg/ml), n (%) arterial blood gas analysis ph . pao /fio ratio sao /fio ratio mulbsta score key: cord- -veavzt d authors: ueland, thor; heggelund, lars; lind, andreas; holten, aleksander r.; tonby, kristian; michelsen, annika e.; jenum, synne; jørgensen, marthe j.; barratt-due, andreas; skeie, linda g.; nordøy, ingvild; aanensen fraz, mai sasaki; quist-paulsen e, else; pischke, søren e.; johal, simreen k.; hesstvedt, liv; bogen, mette; fevang, børre; halvorsen, bente; müller, fredrik; bekken, gry kloumann; mollnes, tom e.; dudman, susanne; aukrust, pål; dyrhol-riise, anne m.; holter, jan c. title: elevated plasma stim- levels in severe covid- patients date: - - journal: j allergy clin immunol doi: . /j.jaci. . . sha: doc_id: cord_uid: veavzt d background the pathogenesis of covid- is still incompletely understood, but seems to involve immune activation and immune dysregulation. objective we examined parameters of activation of different leukocyte subsets in covid- infected patients in relation to disease severity. methods we analyzed plasma levels of myeloperoxidase (mpo, neutrophil activation), soluble (s) cd and soluble t cell immunoglobulin mucin domain- (stim- ) (markers of t cell activation and exhaustion) and scd and scd (markers of monocyte/macrophage activation) in covid- infected patients at hospital admission and two additional times during the first days in relation to the need for icu treatment. results our major findings were: (i) severe clinical outcome (icu) was associated with high plasma levels stim- and mpo suggesting activated and potentially exhausted t cells and activated neutrophils, respectively. (ii) in contrast, scd and scd showed no association with need for icu treatment. (iii) scd , stim- and mpo were inversely correlated with the degree of respiratory failure as assessed by p/f ratio and positively correlated with the cardiac marker n-terminal pro-b-type natriuretic peptide. conclusion our findings suggest that neutrophil activation and in particular activated t cells may play an important role in the pathogenesis of covid- infection, suggesting that t cell targeted treatment options and downregulation of neutrophil activation could be of importance in this disorder. patients with severe disease, as compared to those with mild to moderate disease [ ] [ ] [ ] . there are also reports of lymphopenia, and in particular t cell lymphopenia, in those with severe disease , . however, so far the role of the different leukocyte subsets in the pathogenesis of covid- infection has not been fully elucidated. in the present study we examined plasma parameters of activation of different j o u r n a l p r e -p r o o f informed consents were obtained from all patients or next-of-kin if patients were incapacitated of giving consent. the study was approved by the south-eastern norway regional health authority (reference number: ). outcome was defined as the need for treatment at the icu during hospitalization. indication for admission to icu was respiratory failure that required mechanical ventilation support or non-invasive ventilation support that could not be given at the hospital ward. peripheral blood was collected with ml vacutainer ® (bd biosciences, san diego, ca) with edta as anti-coagulant. samples were immediately stored on ice, processed within minutes and plasma was isolated by centrifugation at g for minutes at °c to obtain platelet-poor plasma. plasma were immediately stored at - c in several aliquots until analysis. samples were thawed only once. plasma levels of scd , scd , scd , stim- and mpo were measured in duplicate by cardiac markers and hscrp were measured at department of medical biochemistry at the two centers: ouh: ntprobnp and hscrp were analyzed on cobas (roche diagnostics, basel, switzerland). drammen hospital: hscrp was analyzed on alinity/architect ci (abbott, abbott park, il) and ntprobnp on a cobas e (roche). reference values for nt-probnp: women: < years (y) ≥ ng/l; - y ≥ ng/l; ≥ y ≥ ng/l, men: < y ≥ ng/l; - y ≥ ng/l; ≥ y ≥ ng/l. patient characteristics were compared using student's t-test or chi-square for continuous and categorical variables, respectively (table and (table ) . correlation analysis between selected markers was also performed at individual time-points (pearson, figure ). to limit multiple comparisons, post-hoc testing was only performed on variables where outcome or outcome*time interaction was significant using multivariate regression at each time-point with egfr and age as covariate ( figure ). in addition, we multiplied the pvalues with the number of leukocyte markers assessed, i.e. with five in the overall univariate and partial correlation analysis ( figure and table ) and with three in the post-hoc and individual correlation analysis (figure and ). p-values are two-sided and considered significant when < . . spss release . . . was used for statistical analysis. the sponsor of this study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. the corresponding author had full access to all the data in the study and takes final responsibility for the decision to submit for publication. table . of the covid- patients, were admitted to icu (death n= , due to respiratory failure, due to multi-organ failure related to . the icu patients were characterized by low p/f ratio and lymphocyte counts and high nt-probnp and hscrp levels. no significant differences in age, time from symptoms to admission, major comorbidities or egfr were detected in relation to icu ( table ) . the temporal course of leukocyte markers in relation to icu admission (icu n= ; non-icu n= ) is shown in figure . patients admitted to icu were characterized by high levels of the t cell activation marker scd and stim- in à priori analysis, and for stim- also in posthoc testing. moreover, whereas scd displayed stable levels between samples obtained at - and - days, stim- levels increased until - days in the icu group. finally, scd and stim- levels were markedly higher than control levels at all time-points. the neutrophil marker mpo was significantly higher in the icu group compared with the non-icu group at all time points (figure ). mpo levels in the non-icu patients were comparable to control levels. however, in contrast to the t cell markers, mpo in the icu patients decreased during follow-up. in contrast to the t cell markers and mpo, plasma levels of scd and scd , reflecting activation of monocytes/macrophages, were similar in icu and non-icu patients ( figure ). for the above analysis of outcomes, age and egfr were included as covariates when comparing time-points, but excluding these covariates gave similar results. table shows correlations between leukocyte activation markers and p/f ratio as a marker of respiratory function and nt-probnp as a marker of cardiac involvement during the course of the study. scd , stim- and mpo were negatively correlated with the p/f ratio and positively correlated with nt-probnp. notably, these correlations were consistent with a similar pattern at all time-points, in particular for stim- ( figure whereas mpo levels were positively correlated with neutrophil counts (table ) , none of the t cell markers correlated with lymphocyte counts, of which t cells is the dominating cell subset, suggesting that the increased levels of scd and stim- do not merely reflect altered numbers of t cells. all markers were correlated with kidney function, but importantly, the associations of scd , stim- and mpo with icu admission was seen also after adjustment for egfr. finally, the two markers of t cell activation, scd and stim- , were strongly correlated (r= . , p< . ). with severe clinical outcome, characterized by high levels of inflammatory cytokines and low lymphocyte counts [ ] [ ] [ ] . several studies demonstrate that lymphopenia, and in particular low number of t cells, is an important feature of covid- infection , , , , . we show that despite signs of t cell depletion, severe covid- infection as reflected by icu admission is also characterized by raised levels of stim- suggesting activated and potentially exhausted t cells. there are a few reports of elevated stim- levels in infectious disorders such as hiv , hepatitis b and c , malaria falciparum and pulmonary tuberculosis . this is, however, to the best of our knowledge, the first report on stim- finding may suggest that excessive t cell and neutrophil activation also could be involved. increasing evidence indicate that covid- infected patients are at higher risk of developing cardiac involvement or cv related death , and accordingly, a majority of icu patients had elevated nt-probnp levels in our study. the spectrum of cardiac involvement in covid- infection is ranging from type and type myocardial infarction to myocarditis, and in more general terms, t cells are known to participate in these conditions , the outbreak of coronavirus disease (covid- )-an emerging global health threat hospital surge capacity in a tertiary emergency referral centre during the covid- outbreak in italy a pneumonia outbreak associated with a new coronavirus of probable bat origin a novel coronavirus from patients with pneumonia in china sars-cov- cell entry depends on ace and tmprss and is blocked by a clinically proven protease inhibitor structure, function, and antigenicity of the sars-cov- spike glycoprotein the pivotal link between ace deficiency and sars-cov- infection clinical characteristics of coronavirus disease in china epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study complex immune dysregulation in covid- patients with severe respiratory failure clinical features of patients infected with novel coronavirus in wuhan, china down-regulated gene expression spectrum and immune responses changed during the disease progression in covid- patients retrospective analysis of laboratory testing in patients with severe-or critical-type novel coronavirus pneumonia acute myocardial injury is common in patients with covid- and impairs their prognosis soluble plasma programmed death (pd- ) and tim- in primary hiv infection tim- as a marker of exhaustion in cd (+) t cells of active chronic hepatitis b patients soluble t-cell immunoglobulin mucin domain- is associated with hepatitis c virus coinfection and low-grade inflammation during chronic human immunodeficiency virus infection soluble markers of neutrophil, t-cell and monocyte activation are associated with disease severity and parasitemia in falciparum malaria elevated expression of tim- on cd t cells correlates with disease severity of pulmonary tuberculosis elevated serum levels of checkpoint molecules in patients with adult still's disease soluble plasma programmed death (pd- ) and tim- in primary hiv infection reduction and functional exhaustion of t cells in patients with coronavirus disease (covid- ) t-cell exhaustion in chronic infections: reversing the state of exhaustion and reinvigorating optimal protective immune responses t cells and viral persistence: lessons from diverse infections neutrophil extracellular traps in covid- cardiovascular implications of fatal outcomes of patients with coronavirus disease (covid- ) role of t-cells in myocardial infarction restricted usage of t cell receptor v alpha-v beta genes in infiltrating cells in the hearts of patients with acute myocarditis and dilated cardiomyopathy patients (n= ) women, n (%) ( ) ( ) age, years ± ± time from symptoms, days - . ± . caucasian, n (%) ( ) ( ) current smoker, n (%) ( ) ( ) p/f ratio (kpa) - ± need for oxygen therapy, n (%) - ( ) comorbidities cardiovascular, n (%) ( ) ( ) pulmonary, n (%) ( ) ( ) renal, n (%) ( ) ( )liver, n (%)obesity, n (%) ( ) ( ) diabetes, n (%) ( ) ( ) rheumatic, n (%) ( ) ( ) j o u r n a l p r e -p r o o f key: cord- -zwh xj u authors: al-dorzi, hasan m.; aldawood, abdulaziz s.; khan, raymond; baharoon, salim; alchin, john d.; matroud, amal a.; al johany, sameera m.; balkhy, hanan h.; arabi, yaseen m. title: the critical care response to a hospital outbreak of middle east respiratory syndrome coronavirus (mers-cov) infection: an observational study date: - - journal: ann intensive care doi: . /s - - -z sha: doc_id: cord_uid: zwh xj u background: middle east respiratory syndrome coronavirus (mers-cov) has caused several hospital outbreaks, including a major outbreak at king abdulaziz medical city, a -bed tertiary-care hospital in riyadh, saudi arabia (august–september ). to learn from our experience, we described the critical care response to the outbreak. methods: this observational study was conducted at the intensive care department which covered icus with single-bedded rooms. we described qualitatively and, as applicable, quantitatively the response of intensive care services to the outbreak. the clinical course and outcomes of healthcare workers (hcws) who had mers were noted. results: sixty-three mers patients were admitted to mers-designated icus during the outbreak (peak census = patients on august , , and the last new case on september , ). most patients had multiorgan failure. eight hcws had mers requiring icu admission (median stay = days): seven developed acute respiratory distress syndrome, four were treated with prone positioning, four needed continuous renal replacement therapy and one had extracorporeal membrane oxygenation. the hospital mortality of icu mers patients was . % ( % for the hcws). in response to the outbreak, the number of negative-pressure rooms was increased from to rooms in mers-designated icus. patients were managed with a nurse-to-patient ratio of : . . infection prevention practices were intensified. as a surrogate, surface disinfectant and hand hygiene gel consumption increased by ~ % and n masks were used per patient/day on average. family visits were restricted to h/day. although most icu staff expressed concerns about acquiring mers, all reported to work normally. during the outbreak, . % of nurses and . % of physicians working in the mers-designated icus reported upper respiratory symptoms, and were tested for mers-cov. only / ( . %) icu nurses and / ( . %) physician tested positive, had mild disease and recovered fully. the total sick leave duration was days for nurses and days for physicians. conclusions: our hospital outbreak of mers resulted in patients requiring organ support and prolonged icu stay with a high mortality rate. the icu response required careful facility and staff management and proper infection control and prevention practices. the middle east respiratory syndrome (mers) coronavirus is a recently identified virus that is closely related to the severe acute respiratory syndrome coronavirus (sars-cov) [ ] , causes severe hypoxemic respiratory failure with multiorgan failure and frequently requires admission to the intensive care unit (icu) [ , ] . as of september , , the world health organization (who) reported laboratory-confirmed cases, including related deaths [ ] . the majority (~ %) of mers cases occurred in saudi arabia [ ] , where several hospital outbreaks happened [ , ] with % of all cases taking place within healthcare facilities [ ] . the outbreak in the republic of korea illustrated the global threat of this disease. it started in may and resulted from a case with travel history to the arabian peninsula [ ] . human-to-human transmission occurred to close contacts [family members, other patients and healthcare workers (hcws)] and led to cases of mers-cov infections with % fatality rate. in our hospital, king abdulaziz medical city-riyadh, an outbreak of mers disease occurred in august to september [ ] , led to significant disruption of hospital functions and resulted in mers cases [ ] with patients requiring icu admission. the outbreak was attributed to crowding, movement of infected but undiagnosed patients and breaches in infection prevention and control practices [ ] . details of the hospital outbreak have been published elsewhere [ ] . most of the medical literature on mers has focused on describing the characteristics and outcomes of affected patients. preparedness and the response of the healthcare system at its different levels are crucial to contain this disease and manage its associated outbreaks. nevertheless, little is published about how the healthcare system responded to the disease and hospital outbreaks. the objective of this study was to describe the response of the icu to a hospital mers outbreak, the associated changes in its workflow and the impact on its hcws. this study was an observational study conducted at the intensive care department of king abdulaziz medical city, a -bed tertiary-care referral hospital in riyadh, saudi arabia, that was accredited by the joint commission international. the hospital had an infection prevention and control department. the intensive care department covered units: an -bed trauma icu (unit a), a -bed medical-surgical intensive care unit (unit b), a -bed surgical icu (unit c), an -bed neurologic icu (unit d) and a -bed stepdown unit (unit e). the department also provided coverage to boarding patients in the -bed resuscitation area in the emergency department (ed). the hospital had also an -bed burn icu. the icus were operated as closed units with -h, -day onsite coverage by boardcertified critical care intensivists [ ] . normally, medical teams covered the units during the day with each team consisting of one intensivist consultant, one registrar/ fellow and - residents. the nurse-to-patient ratio in all the icus was mostly : . one certified respiratory therapist covered a maximum of six ventilated patients. additionally, the department had a rapid response team, which covered the hospital wards and was activated according to predefined criteria and is covered by a sixth separate team [ ] . the department has had several ongoing quality improvement projects and indicators. infection prevention and control practices, such as hand hygiene and the ventilator care bundle, were monitored by multidisciplinary icu teams and the infection prevention and control department [ ] . for intubated patients, ventilator care was provided by specialized respiratory therapists and included using closed endotracheal suctioning systems which were changed every h or as clinically indicated [ ] , changing the ventilator circuits in between patients or if they became soiled or damaged [ ] , and using heat and moisture exchangers which were changed every days or when visibly soiled [ ] . due to the high prevalence of multidrug-resistant organisms and prior cases of influenza and mers infection in the hospital, droplet precautions were applied to all icu patients since february [ ] . sporadic cases of mers cases have been managed in our icu since february . the characteristics, management and outcomes of the initial mers cases managed in our unit were described previously [ ] . all hcws were required to undergo fit testing for the n respirators (table ). an infectious disease epidemic plan (idep) was initially released in may and was revised in march . table describes selected plan elements. according to the idep, one unit (unit a) was designated as the primary receiving unit for mers patients, because of its geographic location being away from main hospital traffic and because of its rooms were negative-pressure airborne infection isolation rooms (aiir). the plan was not explicit about which units would be used if the number of cases exceeded the capacity of this unit. however, unit b had negative-pressure rooms. in our hospital, mers was suspected based on clinical presentation and confirmed by laboratory testing as recommended by the who and the saudi ministry of health [ , ] . in our icu, the workup of patients having lower respiratory tract infections was standardized to include bacterial gram stain and culture, mers-cov polymerase chain reaction (pcr), h n pcr, bacterial and viral multiplex pcr on respiratory samples, mycoplasma, chlamydia and legionella serology and, if suspected, tuberculosis workup. the respiratory samples were routinely obtained by blind deep tracheal aspirate in intubated patients. in the hospital biosafety level laboratory, mers-cov screening was performed by real-time reverse-transcription (rrt) pcr on respiratory samples by checking for the upstream e protein genome (roche modular dx coronavirus) and infection confirmation by detecting the open reading frame a genome (mers-cov kit from tib molbiol) [ ] . laboratory workers were fit-tested and applied n respirators while handing respiratory samples. positive samples were sent to the saudi ministry of health reference laboratory for confirmation. viral culture was not performed as biosafety level is needed. we noted mers cases admitted to the icu from july to october , , and collected data on the clinical characteristics, management and outcomes of the affected hcws. we also obtained data about the rrt-pcr performed for icu patients. we identified the physicians and nurses who reported sick leave for respiratory illnesses. as surrogate for infection control practices, we obtained data on the related consumables for units a and b before and during the outbreak (april- september , ) . we also collected qualitatively our own observations and those of other hcws on the icu response during the outbreak using interviews and open discussions. descriptive data were presented as means and standard deviations or frequencies and percentages, as appropriate. the infection prevention and control consumables were compared in the months before (april to july) and the months during (august and september) the outbreak. the plan will be activated by the chair of the outbreak response committee based on the phase definition phase i - cases of suspected or confirmed in the hospital phase ii - cases of suspected or confirmed in the hospital phase iii > cases of suspected or confirmed in the hospital phase i confirmed mers-cov cases requiring intubation will be assigned a negative-pressure room and cohorted in one icu confirmed cases that have been diagnosed with mers-cov in any icu other than the trauma icu (unit a), shall be transferred to the trauma icu (unit a) as soon as possible. phase ii all mers-cov patients will be cohorted in one unit. if the number of patients exceeds its capacity, then other units are identified to receive the additional cases closure of all nonessential hospital functions phase i all services run without interruptions except for certain precautions for mers patients phase ii all elective surgery shall be canceled to free more icu beds phase iii all elective cardiac surgery shall be canceled outpatient clinic visits shall be limited to urgent visits only healthcare worker (hcw) management all hcws shall be aware of . relevant infection prevention and control policies and procedures . their annual influenza immunization status. if not vaccinated, please contact the employee health clinic to arrange for an appointment . their n fit check/test status. if have not been fit-tested, please contact the employee health clinic to arrange for an appointment hcws exposed to a confirmed mers-cov case shall be assessed according to a predetermined protocol hcws requiring isolation at home and happen to share a room with another hcw will be provided a room in the designated accommodation for isolation till cleared by the infection prevention and control department an infection prevention and control officer is available h per day, days per week in july , five cases of acute respiratory failure were referred to the icu team from the ed and wards and were diagnosed to have mers pneumonia. as the number of mers patients increased, the idep was activated on august , and included strict implementation of infection control measures, including airborne and contact isolation for confirmed and probable mers cases, and droplet and contact isolation for suspected cases [ ] . on august , phase iii of the idep was activated (table ) , which included ed closure, elective surgical procedure cancelation and outpatient clinic suspension [ ] . meanwhile, the icu maintained full operations. figure suspected mers cases had rrt-pcr on nasopharyngeal swabs in nonintubated patients and on deep tracheal aspirates in intubated patients. fiberoptic bronchoscopy was not performed for the diagnostic workup of mers or ventilator-associated pneumonia. repeated testing was frequently needed to make the diagnosis. among our critically ill mers patients, the initial mers-cov testing was performed on nasopharyngeal swabs in and deep tracheal aspirates in the rest (n = ). in the first sample, mers-cov was detected in only / ( . %) nasopharyngeal samples and / ( . %) deep tracheal aspirates. after initial negative or equivocal nasopharyngeal swabs (n = ), a second nasopharyngeal swab was performed in patients (positive in . %) and deep tracheal aspirate in (positive in %). our microbiology laboratory extended its working hours and prioritized testing samples coming from the icu and the rest of the hospital. the number of mers-cov tests performed on icu patients went up from an average of . before to . per day during the outbreak with a maximum of tests on september , . in patients with suspected mers and negative rrt-pcr, the test was repeated after - days. there was a general consensus among our intensivists that three negative lower respiratory samples and low clinical pretest probability were needed to exclude mers-cov infection. for patients with confirmed mers, the test was repeated twice weekly until consecutive tests were negative. the mean age of the patients was . ± . years with the majority ( . %) being males. eight hospital workers required icu admission after acquiring mers. table summarizes their characteristics. half of them did not have direct contact with patients. one of them was a pregnant nurse that worked in the ed. all but one required intubation. the medical management of mers patients was largely supportive. most ( . %) mers patients required endotracheal intubation, which was performed by the most experienced available physician with airborne precautions. lung-protective ventilation was implemented for acute respiratory distress syndrome with tidal volumes ( - ml/kg of ideal body weight). to reduce the airborne generating procedures, we discouraged the use of noninvasive ventilation for suspected mers cases. nevertheless, it was used in the initial management of ( . %) patients. these patients were either suspected to have concomitant cardiogenic pulmonary edema or had milder disease. intubation was needed for patients. highflow oxygen therapy was not used as it was unavailable. when needed, bronchodilators were used via metered dose inhalers rather than nebulizers. most ( . %) mers patients required vasopressors. renal replacement therapy was provided for ( . %) patients. for the hospital workers acquiring mers (n = ), cisatracurium infusion was used in ( . %), early prone positioning in ( %), continuous renal replacement therapy in ( %) and extracorporeal membrane oxygenation in ( table ) . none of the patients received ribavirin, interferon therapy or high-dose steroids. the hospital mortality of mers patients was . % with all deaths occurring in the icu. all hospital workers who had mers survived and were discharged to home. the icu and hospital length of stay were prolonged ( . ± . and . ± . days, respectively). during the outbreak, our hospital established a command center, which met twice daily, and oversaw all interventions in accordance to the idep. the intensive care department chairman was a member of the command center and presented daily the number of suspected and confirmed cases in the icu, bed and staff management issues and any challenges. the department chairman attended all morning handover meetings in the icu where he received input from the icu teams and provided feedback from the command center. the hospital provided an intranet page that had educational material on mers, mers management guidelines and proper infection control practices. the page was regularly updated. additionally, the hospital frequently informed staff about the mers outbreak status through emails. staff could communicate with the command center regarding any outbreak-related concern or question. the intensive care department communicated with the medical staff about the saudi ministry of health and who practice guidelines. before and during the outbreak, the who interim guidance for the management of suspected and confirmed mers-cov infection [ ] was circulated to our icu staff. moreover, a letter expressing gratitude and encouragement was sent from the department chairman to all hcws. family visiting to mers patients was restricted from an open visiting policy to h per day during the evening with visitors not allowed to enter patient rooms. visiting outside these hours was allowed in selected cases if the clinical condition required. to update the patients' families, the icu consultant contacted and updated the next of kin by phone every day and addressed the family concerns. a nurse was assigned to screen all staff and visitors entering each unit by asking for symptoms of acute respiratory infection and measuring temperature. staff and family members with symptoms of acute respiratory illness or fever were not allowed to enter. the initial mers cases were admitted to the designated mers unit (unit a). as the number of patients increased, the icu leadership identified other icus as potential placement units. the hospital clinical engineers converted a total of standard rooms in unit b and unit c to negative-pressure rooms by increasing air exhaust more than supply by cubic feet per minute. as the number of suspected and confirmed mers patients increased, unit b and then unit c were used. as the number of our mers patients increased beyond unit a capacity, patients without mers were transferred to other units or hospitals to increase bed capacity. the old pediatric icu, which was recently vacated in june after the opening of a new pediatric hospital, was used to care for stable and long-term patients. during the outbreak, and patients from units a and b, respectively, were transferred to the other icus (units c-e and the old pediatric icu), and patient to another hospital. the care for mers patients was demanding. for example, of the affected hcws required prone positioning for the management of acute respiratory distress syndrome ( table ). also of them required continuous table ) . the care was also associated with significant exposure risk. this can be reflected in the duration of mechanical ventilation for the hcws who required intubation ( - days) and length of icu stay ( - days) ( table ) . during the outbreak, the nurse-to-patient ratio was mostly : except for one patient on ecmo ( : ). additionally, - additional nurses were deployed in each unit to assist in procedures such as prone positioning and to monitor and correct infection control practices. in unit a, for instance, the nurse-to-patient ratio was : . before the outbreak and became : . during the outbreak. we restricted medical management to the attending physicians, senior registrars and critical care fellows. rotating residents were not allowed to work in the icu during the outbreak. entry of nonclinical staff, such as research coordinators, was restricted and the ongoing clinical trials were put on hold, except for mers studies, to reduce staff exposure. during the outbreak, concerns among icu staff were raised about acquiring mers and transmitting the virus to their families; a concern that was substantiated by seeing hospital workers infected and developing critical illness. however, many felt privileged to be part icu team managing the outbreak and taking care of mers patients; none refused to report to work as per schedule. two pregnant icu nurses were redeployed to low-risk units. staff members who developed fever, respiratory symptoms or gastrointestinal illness were asked not to present to work, but rather to report to the ed or the employee health clinic depending on their illness severity. of the bedside nurses covering units a and b, ( . %) nurses had symptoms of acute respiratory infection during the outbreak and consequently had nasopharyngeal swabs obtained for mers-cov; all tested negative. their total sick leave duration was days (range: - days per nurse). in comparison, in the months before the outbreak, ( . %) nurses had sick leaves for a total of days (range - days per nurse). of the nonresident icu physicians, ( . %) physicians received sick leave for a total of days (range - days per physician). in unit c, two nurses ( . %) of nurses who worked in mers units (units a, b and c) and one rotating resident ( . %) out of physicians covering the icus tested positive for mers-cov. the resident and one of the nurses were symptomatic and required hospitalization in a mers ward for approximately week and both recovered fully. in february , long before the mers outbreak, droplet precautions had been added to the standard precautions for all icu patients, mainly to prevent the transmission of influenza. during the outbreak, airborne precautions were added for all confirmed and suspected mers cases. although all staff were required to be fit-tested for the n respirators before the outbreak (table ) , we discovered that many icu staff were not tested. during the outbreak, a clinic was emergently opened to fit test hcws and the results were documented. specific policies and procedures were developed or updated for donning and doffing personal protective equipment (ppe). related visual instructions were provided inside each icu room. outside patient rooms, carts containing ppe were organized to facilitate donning in the correct sequence. during the outbreak, additional training on hand hygiene techniques and ppe application was provided. housekeepers were also retrained on proper cleaning techniques and ppe use. the intensive care department worked closely with the infection prevention and control department on all aspects of infection control. the implementation of such infection control measures required having adequate ppe supplies, such as respirators, goggles, face shields and gowns. table describes the consumption of surface disinfectants, antiseptic alcohol for hand hygiene, n masks and other ppe before and during the mers-cov outbreak. during the outbreak, the consumption of detergent surface disinfectant and ethyl alcohol for alcohol-based hand rub increased by almost % and the use of n masks increased by > times compared to the preceding months. the number of examination gowns per patient per day decreased during the outbreak probably due to staff avoiding unnecessary exposure. twenty-four powered air-purifying respirators were made available to staff who failed the n respirator fit test. they were used by physicians, nurses and respiratory therapists. training sessions on their application were conducted. in this report, we described how the icu responded to a mers-cov outbreak at a tertiary-care hospital. the outbreak led to mers patients requiring prolonged icu care and most received invasive mechanical ventilation, vasopressors and renal replacement therapy. the overall mortality was %, but all affected hospital workers survived. the outbreak management included almost tripling the icu capacity of negative-pressure rooms and intensifying infection prevention and control practices. even though icu staff had significant exposure risk, very small number acquired mers-cov. response to incidents such as an infectious hospital outbreak requires a robust hospital-wide command and control structure that is able to make rapid informed decisions across an institution. as it was the case in our hospital, the control of outbreak may require major interventions such as closing the ed, suspending elective surgeries, preventing inter-facility patient transfers, canceling ambulatory clinics and outpatient diagnostic procedures, preventing hospital staff from working at other institutions and restricting hospital visitors [ ] . our hospital had a preexisting idep, which facilitated managing and containing the mers-cov outbreak. such a plan is mandatory for every hospital. mers infection is associated with several challenges. its presenting symptoms overlap with those of other severe acute respiratory illnesses and include fever ( %), cough ( %), dyspnea ( %) and diarrhea ( %) [ ] , often in older adults with preexisting chronic comorbidities [ , ] . common laboratory abnormalities include leukopenia, lymphocytopenia, thrombocytopenia and elevated serum creatinine, lactate dehydrogenase, and liver enzymes [ ] . the initial chest radiographs show minimal abnormality to extensive bilateral infiltrates [ ] . unfortunately, many frontline physicians are unfamiliar with the mers case definition, probably because cases are sporadic, leading to delayed or even missed diagnosis. delayed recognition may lead to exposing many other patients, visitors and hcws to the infection as it was the case in our hospital. mers-cov nosocomial transmission is thought to be via respiratory droplets, and contact spread is suspected [ ] . in korea, the delayed diagnosis of an infected traveler to the arabian peninsula led to mers cases and resulted in intraand inter-hospital transmission [ ] . in saudi arabia, % of mers cases were acquired in the healthcare setting with % of all cases being hcws [ ] . therefore, taking a detailed history, knowing mers case definitions, standardizing pneumonia workup, obtaining lower respiratory tract specimens [ ] and implementing droplet isolation for suspected cases are crucial interventions to break the transmission chain in the healthcare setting. admitting mers patients in single-bedded negativepressure rooms and cohorting them in selected units are recommended to facilitate providing care and monitoring [ ] . during an outbreak, clinical engineering should have expedient plans to convert standard rooms. retrofitting the rooms with externally exhausted hepa filters may be a solution [ ] . outbreaks can lead to significant increase in the need for icu beds, but may simultaneously reduce the available beds. the sars outbreak in toronto led to -day closures of icu beds, which represented % of the tertiary-care university medical-surgical icu beds in toronto [ ] . hence, hospitals should always have plans to augment icu bed capacity, such as by transforming general wards. the ability of any hospital to deal with an infectious outbreak is decided by the availability of icu beds [ ] . caring for mers patients represents a substantial exposure risk for icu staff because of three reasons: high exposure dose, long daily contact hours and prolonged icu stay with viral shedding. mers-cov patients requiring icu admission have higher viral load than other mers patients [ ] . aerosol-generating procedures, such as noninvasive ventilation, suctioning and bronchoscopy, add to the exposure and transmission risk [ ] . extended bedside care is needed for mers patients due to the requirement of organ support such as mechanical ventilation, vasopressor therapy, continuous renal replacement therapy, prone positioning and extracorporeal membrane oxygenation [ , ] . in this study, we observed an increase in the nurse-to-patient ratio from : . to approximately : . during the outbreak. the sars epidemic was also associated with increases in the nurse-topatient ratio [ ] . stay in the icu can last for weeks [ ] , which we observed. additionally, mers-cov shedding can be prolonged and may last for > days [ ] . the exposure risk to mers-cov can exert significant psychosocial stress on hcws. death has occurred in young hcws who acquired mers-cov infection [ ] , which adds to this fear. during the sars outbreak in toronto, a survey of hcws found that > % of respondents reported sars-related concern for their own or their family's health [ ] . moreover, % of respondents had probable emotional distress [ ] . during our outbreak, many icu staff expressed concerns about acquiring mers. staff safety should be a primary goal in a hospital infectious outbreak. pregnant and immunocompromised staff should be redeployed to lower-risk areas [ ] , which we did. proper exposure management should be pre-planned, which was determined in our idep. n respirator fit testing should be performed at hiring of new staff and done for all other staff before any outbreak. although fit testing was required for all staff, many did not have fit testing done. however, in response to the outbreak, fit testing was performed to all staff and powered air-purifying respirators were provided to those who failed fit testing. strict infection prevention and control practices should be implemented and audited. this was performed in our units. repetitive training is recommended [ ] . despite intensive infection prevention practices, of our icu staff had mers-cov infection during the outbreak likely due to suboptimal ppe use while intubating yet undiagnosed patients. mers management was supportive and largely adhered to the who recommendations [ ] . it included intubation, early prone positioning and neuromuscular blockade for moderate-to-severe acute respiratory distress syndrome as these interventions have been shown to improve the outcomes of ards patients [ , ] . although noninvasive ventilation use was discouraged, it was used in patients. the who considers noninvasive ventilation an option in selected mers cases [ ] . it should be used as a short trial without delaying intubation if unsuccessful [ ] . moreover, high-flow oxygen by nasal cannula may be another option [ , ] ; however, the associated transmission risk as a result of aerosol generation is unknown. systematic corticosteroids, ribavirin and interferon were avoided as they have no proven benefit [ , ] . our mers patients had high mortality ( %). the previously reported mortality of mers patients who had critical illness ranged from to % [ , , ] . none of our hcws who developed mers died, which was gratifying to our staff. our mers-cov hospital outbreak stressed our system to unprecedented limits. we learned many lessons from it ( table ). the successful management of outbreak required integrating icu functions with the hospitalwide plans, having preparedness plans, implementing proper infection control practices and managing staffing and staff exposure. every hospital should have an infectious disease epidemic plan that should govern the response to an infectious disease outbreak. the response should cover organizing patient services, implementing infection control, managing employee exposure and communicating with national health services and with hospital staff hospital leaders should be prepared to increase the capacity of negative-pressure airborne infection isolation rooms in the case of an infectious disease outbreak all healthcare workers should receive training on proper hand hygiene and personal protective equipment application. hand hygiene and personal protective equipment practices should be monitored. education should be repeated periodically all healthcare workers should be fit-tested for n respirators on hire with the result documented in their files. periodic audit of this requirement should be done hospitals should make plans to acutely increase personal protective equipment supplies as consumption increases tremendously during an infectious disease outbreak hospital and icu leaders should have plans to cover healthcare workers who are exposed or become symptomatic to avoid potential staff shortage severe acute respiratory syndrome vs. the middle east respiratory syndrome clinical aspects and outcomes of patients with middle east respiratory syndrome coronavirus infection: a single-center experience in saudi arabia clinical course and outcomes of critically ill patients with middle east respiratory syndrome coronavirus infection middle east respiratory syndrome coronavirus hospital outbreak of middle east respiratory syndrome coronavirus mers-cov outbreak in jeddah-a link to health care facilities the national command control center; ministry of health-kingdom of saudi arabia. mers-cov in ksa notes from the field: nosocomial outbreak of middle east respiratory syndrome in a large tertiary care hospital-riyadh, saudi arabia weekend and weeknight admissions have the same outcome of weekday admissions to an intensive care unit with onsite intensivist coverage impact of an intensivist-led multidisciplinary extended rapid response team on hospital-wide cardiopulmonary arrests and mortality a multifaceted approach to improve hand hygiene practices in the adult intensive care unit of a tertiary-care center comprehensive evidence-based clinical practice guidelines for ventilator-associated pneumonia: diagnosis and treatment ministry of health kingdom of saudi arabia. infection prevention and control guidelines for middle east respiratory syndrome coronavirus (mers-cov) infection assays for laboratory confirmation of novel human coronavirus (hcovemc) infections clinical management of severe acute respiratory infection when middle east respiratory syndrome coronavirus (mers-cov) infection is suspected-interim guidance identification and containment of an outbreak of sars in a community hospital middle east respiratory syndrome: knowledge to date middle east respiratory syndrome coronavirus: a case-control study of hospitalized patients stability of middle east respiratory syndrome coronavirus (mers-cov) under different environmental conditions mers outbreak in korea: hospital-to-hospital transmission an appropriate lower respiratory tract specimen is essential for diagnosis of middle east respiratory syndrome (mers) interim infection prevention and control recommendations for hospitalized patients with middle east respiratory syndrome coronavirus hospital preparedness and sars association of higher mers-cov virus load with severe disease and death, saudi arabia aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review clinical review: sars-lessons in disaster management middle east respiratory syndrome coronavirus (mers-cov) viral shedding in the respiratory tract: an observational analysis with infection control implications middle east respiratory syndrome coronavirus infections in health care workers psychosocial effects of sars on hospital staff: survey of a large tertiary care institution sars and hospital priority setting: a qualitative case study and evaluation infection control in the management of highly pathogenic infectious diseases: consensus of the european network of infectious disease prone positioning in severe acute respiratory distress syndrome neuromuscular blockers in early acute respiratory distress syndrome high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure ribavirin and interferon therapy in patients infected with the middle east respiratory syndrome coronavirus: an observational study none. the authors declare that they have no competing interests. written informed consent was not obtained for publication of these data. the institutional review board of the ministry of national guard health affairs approved the retrospective clinical data collection on mers patients, and no consents were required. abbreviations ed: emergency department; hcw: healthcare worker; icu: intensive care unit; idep: infectious disease epidemic plan; mers: middle east respiratory syndrome; ppe: personal protective equipment; rrt-pcr: real-time reversetranscription polymerase chain reaction; who: world health organization. hmd was involved in conception and design, data collection, statistical analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content and approval of the final version to be published. asa contributed to the analysis and interpretation of data, critical revision of the manuscript for important intellectual content and approval of the final version to be published. rk helped in data collection, analysis and interpretation of data, critical revision of the manuscript for important intellectual content and approval of the final version to be published. sb contributed to the analysis and interpretation of data, critical revision of the manuscript for important intellectual content and approval of the final version to be published. jda helped in data collection, interpretation of data, critical revision of the manuscript for important intellectual content and approval of the final version to be published. aam was involved in data collection, interpretation of data, critical revision of the manuscript for important intellectual content and approval of the final version to be published. smj helped in data collection, interpretation of data, critical revision of the manuscript for important intellectual content and approval of the final version to be published. hhb contributed to data collection, interpretation of data, critical revision of the manuscript for important intellectual content and approval of the final version to be published. yma helped in conception and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content and approval of the final version to be published. all authors read and approved the final manuscript.author details icu and ticu, intensive care department, king abdulaziz medical city, king key: cord- -rog h g authors: franco, cosimo; facciolongo, nicola; tonelli, roberto; dongilli, roberto; vianello, andrea; pisani, lara; scala, raffaele; malerba, mario; carlucci, annalisa; negri, emanuele alberto; spoladore, greta; arcaro, giovanna; tillio, paolo amedeo; lastoria, cinzia; schifino, gioachino; tabbi’, luca; guidelli, luca; guaraldi, giovanni; ranieri, v. marco; clini, enrico; nava, stefano title: feasibility and clinical impact of out-of-icu non-invasive respiratory support in patients with covid- related pneumonia date: - - journal: eur respir j doi: . / . - sha: doc_id: cord_uid: rog h g introduction: the coronavirus (sars-cov- ) outbreak spread rapidly in italy and the lack of intensive care unit(icu) beds soon became evident, forcing the application of noninvasive respiratory support(nrs) outside the icu, raising concerns over staff contamination. we aimed to analyse the safety of the hospital staff, the feasibility, and outcomes of nrs applied to patients outside the icu. methods: in this observational study, data from consecutive patients with confirmed covid- referred to the pulmonology units in nine hospitals between march st and may th, were analysed. data were collected including medication, mode and usage of the nrs (i.e. high-flow nasal cannula (hfnc), continuous positive airway pressure (cpap), noninvasive ventilation(niv)), length of stay in hospital, endotracheal intubation(eti) and deaths. results: forty-two health-care workers ( . %) tested positive for infection, but only three of them required hospitalisation. data are reported for all patients ( . % male), whose mean age was (sd ) years. the pao( )/fio( ) ratio at baseline was ± , and the majority of patients ( . %) were treated with cpap. the overall unadjusted -day mortality rate was . % with %, %, and %, while the total eti rate was % with %, % and %, for hfnc, cpap, and niv, respectively, and the relative probability to die was not related to the nrs used after adjustment for confounders. eti and length of stay were not different among the groups. mortality rate increased with age and comorbidity class progression. conclusions: the application of nrs outside the icu is feasible and associated with favourable outcomes. nonetheless, it was associated with a risk of staff contamination. on february th , coronavirus disease severely hit the northern part of italy. it was reported that, in lombardy, the most populated region of the country, more than patients required intensive care unit (icu) admission over only weeks, largely exceeding the actual capacity ( ) . in the same period, the number of hospital admissions was ( ) . approximately % of these patients experienced acute respiratory failure (arf) requiring any form of respiratory support. a mathematical model of the occupation of intensive care resources in italy predicted saturation of the theoretically available beds in the national territory by mid-april ( ) . under these circumstances, despite extraordinary efforts aimed at increasing the availability of icu resources, the italian societies of respiratory medicine proposed a protocol to provide ventilatory support outside the icu in dedicated respiratory covid units, reinforced by a higher number of nurses and noninvasive monitoring ( ) . this recommendation was somehow in contrast to most of the available guidelines that contraindicated using noninvasive respiratory support (nrs) in these patients due to the major concerns over using bio-aerosol producing techniques, because of possible contamination of the hospital staff ( ) . this "emergency" situation gave us the unique opportunity to challenge the hypothesis that nrs should not be used outside the icu during pandemics. we have therefore analyzed the feasibility and safety, in terms of staff contamination, of nrs applied to severely ill patients outside the icu. patients' characteristics and clinical outcomes were also analyzed. the study was conducted in four out of five hospitals in the area vasta emilia network and in five hospitals in the neighbouring regions, serving a population of approximately million people. institutional review boards reviewed the protocol and authorized prospective data collection. informed consent was waived. a confirmed case of covid- was defined as a patient with a positive result on high throughput sequencing or real-time reverse transcriptase-polymerase chain reaction assay of nasal and pharyngeal swab specimens. data were collected from registries of the respiratory disease units coordinators at the nine hospitals identifying all of the patients receiving nrs outside the icu. excluding standard oxygen administration, patients were treated with three different types of nrs, namely high-flow nasal cannula (hfnc), continuous positive airway pressure (cpap), or noninvasive ventilation (niv), which also represented the three different groups in the analysis. the triage of patients was performed according to the italian respiratory societies joint guidelines based on severity. in particular, the following categories were proposed: a) green (sao > %, respiratory rate (rr)< breaths/min); b) yellow (sao < %, rr> but responds to - l/min oxygen); c) orange (sao < %, rr> but poor response to - l/min oxygen and requiring cpap/niv with very high fio ); d) red (sao < %, rr> but poor response to - l/min oxygen, cpap/niv with very high fio or presenting respiratory distress with pao /fio < and requiring eti and intensive care). patients belonging to these latter two categories were therefore considered eligible for nrs in dedicated respiratory covid areas (see below) set up for the isolation of confirmed cases and arf treatment. these patients were not "usually" treated outside the icu but, given the "emergency" situation, the lack of icu beds and only once multiorgan disfunction was excluded, they still resulted eligible for an nrs trial. the transfer of severely ill patients to the icu for intubation, with compromised haemodynamic parameters, low pao /fio or 'not responding to nrs', was discussed with the intensivists, based on prognosis, and obviously was only possible if beds were available. although not specifically mentioned in the guidelines, hfnc was also used in these two categories, during breaks in ventilation or as a stand-alone support. the use of helmet cpap devices was suggested as first-line treatment, mainly for safety reasons. clearly, this technique requires a sufficient supply of helmet interfaces (which ran out quite rapidly) and a high flow of o (which exceeded the o capacity in some hospitals), so that niv and hfnc were used as alternatives, the first when it was necessary to "save" oxygen, and the second when cpap availability finished. the respiratory covid areas consisted mainly of two different units, both present in all of the hospitals. the first one, formerly a respiratory ward, was an ad-hoc dedicated respiratory monitoring unit consisting of specialized monitored areas with an active full-day shift run by a fixed group of pulmonologists and with a "reinforced" nurse-patient ratio varying from : to : depending on the hospital. the second unit, called respiratory intermediate care units, consisted of a fixed medical team. these had a monitoring system similar to that of the respiratory monitoring units, together with the availability of icu ventilators and a nurse-patient ratio from : to : , where more severely affected patients were usually treated. patients were continuously monitored with electrocardiogram trace, noninvasive blood pressure, arterial oxygen saturation, and respiratory rate (rr). intensive care medicine doctors were eventually available around the clock at the request of the ward teams. great care was taken to keep a distance of > . metres between each bed and to provide natural ventilation and airflow of at least l·s - per patient. concerning staff protection, first of all, courses were quickly organized for staff in the correct use of personal protective equipment (ppe), dressing and undressing. filtering facepiece class (ffp ) or ffp masks, double non-sterile gloves, long-sleeved water-resistant gowns, goggles or face shields were mandatory in the presence of aerosol producing procedures. niv was delivered mainly by dedicated single circuit niv platforms provided with an oxygen blender and ad-hoc filters placed in the single tube circuit before the non-rebreathing devices to minimize bio-aerosol dispersion, or by icu ventilators. hfnc was delivered using standard devices (nasal high flow therapy, fisher and paykel healthcare ltd, new zealand), while helmet cpap dedicated devices, designed for pandemics, were simply activated by connecting them to the o source available in the hospital with blender systems applied to obtain adequate values of delivered fio (intersurgical spa, mirandola, italy and dimar srl, medolla, italy). data were collected prospectively from registries of the respiratory disease units identifying all of the patients receiving nrs outside the icu. variables recorded for each patient were obtained for the period from march st until may th and included the following: demographics (age, sex), comorbidities (type and number), respiratory condition at admission (respiratory rate (rr), pao /fio ratio), medications (type of drugs prescribed), mode and usage of the nrs (ventilatory settings for niv and cpap, and flow rate for hfnc), and stay in hospital (days). the number of patients who died, either in the respiratory unit or in the hospital, and the patients who received endotracheal intubation (eti) within the same time frame were recorded. patients who were still hospitalized at the time of data analysis were excluded. the health status of the staff working in the respiratory unit was closely monitored. all staff with fever or respiratory symptoms underwent chest radiography, and nasal and pharyngeal swab specimens were taken. serology for sars-cov- antibodies and pharyngeal swab was also periodically performed for all staff. no statistical sample size assessment was performed a priori, and sample size was the number of patients treated during the study period in the participant centres. baseline characteristics of patients treated with hfnc, cpap and niv were compared. across the treatment subgroups, continuous variables were expressed as means and standard deviation (sd) and were compared with the kruskal-wallis test and one-way anova test, while categorical variables were expressed as numbers and percentages (%) and were compared using the χ test or fisher's exact test. percentages of available data for the overall study population were based on the total number of patients included in the study, while the distribution of available data over the treatment subgroups was based on the available data for that variable, and the percentages were calculated using the number of available data for that subgroup. the fraction of infected professional health care workers was presented as numerical and percentage values. the association between ventilatory treatment and clinical outcomes was calculated using a logistic regression model. the day mortality rate was calculated adjusted for baseline confounders (age, p/f ratio, steroid usage and number of comorbidities). a total of patients were considered and of these, patients were included and their data analyzed. table lists the patients' characteristics. cpap, as applied by helmet, was used on the majority of patients (supplementary table ). twenty-eight out of ( . %) had a do not intubate (dni) order. figure illustrates the patients' allocation to nrs and clinical outcome. a total amount of patients died at days. twenty of the dni patients died ( % of the total number of deaths). in total, patients died on spontaneous breathing without an expressed written dni order. most of the study patients were male ( . %). hypertension, diabetes, dyslipidemia, obesity and chronic cardiovascular disorders were the comorbidities most represented, evenly distributed among the groups with the exception of obesity, which was more prevalent in the niv group. hydroxychloroquine, methylprednisolone, low molecular weight heparin and tocilizumab were the drugs most used for treatment. the frequency distribution of age and pao /fio ratio in the whole study population are shown in supplementary figure . table , health care workers, including doctors, nurses, and health-care assistants, had been taking care of patients receiving nrs. forty-two of them ( %) tested positive for sars-cov- infection showing symptoms of mild (n= ) or moderate disease requiring hospitalization (n= ). all infected workers recovered well. the overall rate of workers infected, in personnel not specifically involved in the care of covid- patients, in the nine hospitals was . ± . %. outcome measures stratified by pao /fio ratio classes and according to nrs are reported in table . patients with a pao /fio ratio below mmhg presented a higher -day mortality rate and a higher rate of eti (p< . and p< . , respectively). supplementary table . niv was used as much as the patients could tolerate and in a small percentage of cases ( / = %), hfnc was applied during the intervals. patients with bilateral posterior infiltrates were also usually placed in the prone position for few hours a day, in all three nrs groups, with a schedule dependent on their tolerance. this study showed that using nrs devices is feasible in patients with arf due to sars-cov- infection treated outside icus, in newly developed dedicated covid respiratory monitoring units, formerly respiratory wards, and in respiratory intermediate care units. despite using the recommended ppe, a . % contamination rate was observed among healthcare workers treating the infected patients. after adjusting for potential confounders, -day mortality rates using hfnc, cpap and niv were not significantly different. one of the major concerns of using bio-aerosol generating devices is that healthcare workers are at high risk of contracting the infection and therefore most international guidelines recommend being cautious or even contraindicate their use ( ) ( ) ( ) . nevertheless, who advocate using cpap or niv for the management of respiratory failure in covid- patients, provided that appropriate ppe is worn by the personnel ( ) . several studies have found that the maximum exhaled air dispersion via different oxygen administration and ventilatory support strategies is minimal for cpap through an oronasal mask or niv through a helmet equipped with an inflatable neck cushion, and is much less when compared with any kind of oxygen delivery system ( ). interestingly enough, so far, studies have been conducted in negative pressure hospital rooms with at least six air changes per hour (minimum number of air changes recommended by who is per hour). when these rooms were not available, as was the case for most of our patients, alternative hospital areas including rooms with natural ventilation (expressed as the product of room volume and air change rate) of at least l·s - per patient were routinely employed, in keeping with the who statement ( ) . indeed, according to the italian recommendations ( ), the large majority of our study population received cpap (by helmet or face mask), mask-niv, and hfnc with a medical mask over the nasal prongs. taking all these precautions into account and using all of the appropriate protection, the number of health workers who tested positive at serology or pharyngeal swab was still quite high ( . %); however, those who became ill ( / , i.e. . % of the staff involved) were in line with the . % of health care workers requiring hospital admission in china ( ) , the only study so far that has reported this outcome during the covid- outbreak. one may claim that our staff could have been infected in the community rather than by exposure to nrss; however, in the nine hospitals in this study, the overall rate of infection of health workers, in personnel not specifically involved in the care of covid- patients. the dramatic and rapidly increasing wave of the pandemic obliged us to treat a high number of severely hypoxic patients with nrs outside the icu. these patients are usually admitted to "protected" environments. the ats/ers guidelines ( ) for example suggested using niv in de-novo respiratory failure only when managed by an experienced clinical team, and closely monitored in the icu. concerning the first point, all of the units involved had extensive experience in nrs use over a long period, and the nurse-patient ratio was "unusually" high for a ward, since during the outbreak, the nursing staff was reinforced in the locations where the acutely ill patients were admitted. in addition, fully equipped noninvasive monitoring systems were available. this is by far the largest report on the use of nrs outside the icu; however, our covid dedicated respiratory units cannot be considered equivalent to the "usual" respiratory wards. previous studies conducted in icus where nrs use was reported ( , - ) account for patients treated with niv and by hfnc, without showing their characteristics and severity or the outcomes (in all but one study). interestingly, this latter study ( ) showed a very high mortality rate both with niv and hfnc ( % and %, respectively). indeed, only a few patients were treated in the respiratory ward or unit, namely and patients using niv and hfnc respectively, with a poor survival rate ( , ) . despite the fact that comparison among studies is extremely difficult due to the potential heterogeneity of patients included and/or to differing local hospital organization, the failure rate (i.e. mortality and/or eti) was much lower in our population, even when adjusted for potential confounders (see table ), and it was comparable to what was observed ( %) in a large italian study performed in the icu in patients mostly intubated and with a pao /fio ratio similar to ours ( ). in addition, in a recent two-period retrospective case-control study, oranger et al. ( ) demonstrated that cpap could avoid intubation at days and at days, particularly in covid patients with a previous dni decision. the mortality rate was similar with all of the nrs modes used after adjustment for confounders; however, it has to be noted that hfnc was usually applied in less sick patients compared with niv and cpap, and this may reflect the attitude of the clinicians to start these latter two modes in patients where they judged that applying a relatively high level of external positive end expiratory pressure (peep) was more appropriate. it has been suggested that using any form of nrs might unduly delay the start of eti; however, it should be noted that patients received a dni order ( of them died), and that an icu bed was not promptly available at the time of deterioration, as reported in a specific small subset of the patient population. it may also be argued that "only" less than % of patients signed a dni order. in italy, the very large majority of the population are not sufficiently aware of the new advanced directive law ( ), or they do not want to complete in advance any document in this respect. therefore, most of our patients arrived at hospital without any dni or do not resuscitate directives. the reasons for not proceeding to eti in the absence of a written dni order might be explained by: presumed lack of benefit from eti or mechanical ventilation (mv) based on clinical judgement, sudden death, or verbal refusal from the patient at the time of clinical deterioration. however, the majority of patients received "full treatment" when needed. despite the fact that this retrospective analysis in a large population indicates that nrs may help to treat severely affected covid- patients outside the icu, in newly dedicated respiratory areas with experienced staff, it also presents three main limitations. first, the design was retrospective, like most of the studies published during this terrible period. second, the decision to start one of the nrs modes was left to the attending physicians and mainly relied on the actual availability of equipment, so that the proportion of devices used was not evenly distributed. third, as in most reallife studies dealing with the covid- pandemic ( ), missing data may be quite relevant; however, the critical nature of the situation did not always allow detailed information to be collected. to conclude, this is the first observational, large multicentre study showing that the application of noninvasive respiratory devices outside the icu is feasible but is associated with a risk of staff contamination; however, the retrospective study design precludes drawing firm conclusions about its effectiveness despite the fact that the mortality and intubation rates compare favourably with those of previous reports. baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region, italy official bulletin of lombardy region, date march th covid- and italy: what next? managing the respiratory care of patients with covid- . available at www.aiponet.it and www.sipirs.it date last accessed nosocomial outbreak of novel coronavirus pneumonia in wuhan, china intensive care society, association of anaesthetists and royal college of anaesthetists. critical care preparation and management in the covid- pandemic. available at: www.icmanaesthesiacovid- .org date last accessed the australian and new zealand intensive care society covid- guidelines (version surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) clinical management of severe acute respiratory infection (sari) when covid- disease is suspected. interim guidance - protecting healthcare workers from sars-cov- infection: practical indications infection prevention and control during health care when covid- is suspected: interim guidance. available at www.who.int. date last accessed death from covid- of health care workers in china official ers/ats clinical practice guidelines: noninvasive ventilation for acute respiratory failure characteristics and outcomes of critically ill patients with covid- in washington state clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china clinical course and outcomes of intensive care patients with covid- clinical characteristics of deceased patients with coronavirus disease : retrospective study risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china covid- in critically ill patients in the seattle region -case series clinical features of patients infected with novel coronavirus in wuhan, china clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study china medical treatment expert group for covid- . clinical characteristics of coronavirus disease in china continuous positive airway pressure to avoid intubation in sars-cov- pneumonia: a two-period retrospective case-control study the italian law on informed consent and advance directives: new rules of conduct for the autonomy of doctors and patients in end-of-life care key: cord- -jxlrz ce authors: craxì, lucia; vergano, marco; savulescu, julian; wilkinson, dominic title: rationing in a pandemic: lessons from italy date: - - journal: asian bioeth rev doi: . /s - - - sha: doc_id: cord_uid: jxlrz ce in late february and early march , italy became the european epicenter of the covid- pandemic. despite increasingly stringent containment measures enforced by the government, the health system faced an enormous pressure, and extraordinary efforts were made in order to increase overall hospital beds’ availability and especially icu capacity. nevertheless, the hardest-hit hospitals in northern italy experienced a shortage of icu beds and resources that led to hard allocating choices. at the beginning of march , the italian society of anesthesia, analgesia, resuscitation, and intensive care (siaarti) issued recommendations aimed at supporting physicians in prioritizing patients when the number of critically ill patients overwhelm the capacity of icus. one motivating concern for the siaarti guidance was that, if no balanced and consistent allocation procedures were applied to prioritize patients, there would be a concrete risk for unfair choices, and that the prevalent “first come, first served” principle would lead to many avoidable deaths. among the drivers of decision for admission to icus, age, comorbidities, and preexisting functional status were included. the recommendations were criticized as ageist and potentially discriminatory against elderly patients. looking forward to the next steps, the italian experience can be relevant to other parts of the world that are yet to see a significant surge of covid- : the need for transparent triage criteria and commonly shared values give the italian recommendations even greater legitimacy. in late february and early march , while infection rates in china fell, italy became the european epicenter of the coronavirus (sars-cov- ) epidemic. at the beginning of may , italy entered the so called phase two, consisting in a progressive reopening of business and social activities while monitoring the eventual raise of the epidemic curve. "phase two" posed a number of ethical questions, such as finding a new balance between personal liberties and public health, privacy concerns from the use of movement tracking apps, and down the line access to vaccines or improved medications. we think that it is, however, important to look back and determine which lessons can be derived from the way italy confronted the scarcity of medical resources available to confront the epidemic, especially since this experience can prove invaluable for other countries that are still facing the epidemic peak. in the paper, we analyze the features of the italian recommendations, why the raised heated debate and why it is important to have ethical guidelines and balanced and consistent allocation procedures to prioritize patients. the recommendations issued by the italian society of anesthesia, analgesia, resuscitation, and intensive care in march and april , a huge effort was made by the national government to flatten the epidemic surge by enforcing increasingly stringent containment measures, in order to reduce the impact of the outbreak on the health system. despite facing a likely major social and economic crisis, the italian government imposed a nationwide lockdown on march: prohibition of all movements of people within the whole territory, and closure of all non-essential business activities. some think a systematic and strong response arrived too late ; such measures inevitably have a delayed impact, and hospitals were hit by what has been called a medical "tsunami," with high caseload punctuated by a stream of deaths. the enormous challenge for the health system-facing a dramatic shortage of icu beds and staff-has been how to meet the medical needs of patients affected by covid- . even though authorities state that no cases of people who failed to get into intensive care have been reported, many italian physicians working in icus in northern italy have stated otherwise, as has the mayor of bergamo, one of the hardesthit cities (ansa ; nacoti et al. ; rosenbaum ; guerzoni ) . professionals experienced uncertainty and distress about how to allocate the dramatically scarce resources available, as that situation was unprecedented for everyone: in some hospitals, at the peak of the surge, the rationing involved not only ventilators but oxygen as well. at the beginning of march, some hospitals around milan were already collapsing (some of them admitting more than patients with severe respiratory failure every day). as difficult allocation choices were already being made, clinicians (including one of the authors, mv) of the ethics section of the italian society of anesthesia, analgesia, resuscitation, and intensive care (siaarti) were asked to publish guidance on the allocation of limited resources. they worked between shifts to construct the recommendations (box ) that sparked a heated debate immediately after the release. box key elements of siaarti recommendations (vergano et al. a, b) . when the availability of resources is overwhelmed by their need, a decision to deny access to one or more life-sustaining therapies, solely based on the principle of distributive justice, may ultimately be justified . criteria for allocation should be flexible and adapted locally in response to available resources, the potential for patient transfer, and the ongoing or foreseen number of admissions . an age limit for admission to the icu may ultimately need to be set . together with age, the comorbidities and functional status of any critically ill patient should be carefully evaluated . every admission to the icu should be considered and communicated as an "icu trial." the appropriateness of life-sustaining treatments should be re-evaluated daily the recommendations issued by siaarti suggest that, if a choice to ration medical equipment and intervention is needed, the maximum individual benefit in terms of expected life years-likelihood of survival plus remaining likely years of a patient's life-should be prioritized. according to this principle, the recommendations suggested evaluating age, comorbidities, and functional status of any critically ill patient. this was subsequently criticized as ageist, as well as "unconstitutional" and discriminatory against elderly patients (fnomceo ; quotidiano sanità a, b; rodriquez ). it was perceived as not consistent with the values on which the healthcare system is grounded. according to the siaarti guidance, the drivers of decision for admission to icu should be the clinical picture taking into account "biological" (not mere chronological) age, comorbidities, and preexisting functional status. this kind of "soft" utilitarian approach is already applied in italy in specific fields of dramatically scarce resources, such as organ transplants (cillo et al. ) . this approach is justified by the need to maximize the achievable benefit in terms of life years gained, thus optimizing the use of available resources: not only the probability of survival and the "greatest life expectancy" are considered, but also the predicted length of the icu stay and hence the use of intensive care resources. nonetheless, this kind of approach is the opposite of the egalitarianism that pervades the wider italian healthcare system. sometimes in pursuing what is good, we run the risk of forgetting what is fair. in emergencies, the patient-centered "duty to care" needs to be balanced with publicfocused duties to promote equality of persons and equity in distribution of risks and benefits. also, individual allocating decisions must be supported by fair institutional processes that may include strategies such as preparing, conserving, substituting, adapting, re-using, and re-allocating resources (hick et al. ) . in every single country facing covid- emergency, if no ethical guidelines or balanced and consistent allocation procedures are applied to prioritize patients, there is a concrete risk for unfair choices (emanuel et al. ) . should the shortage arise with no rationing plan in action, decisions would be left to the ruling of local healthcare and hospital authorities or to the clinician's judgment in the heat of the moment, resulting in approaches both inconsistent and uncoordinated. one motivating concern for the siaarti guidance was the real chance that the prevalent criterion would be "first come, first served." such an approach appears to remove responsibility for choice over life and death, and can be thought as avoiding having to make ethically fraught choices between patients. we will only point out in passing that from an ethical standpoint, there is no actual difference between action and inaction when they both cause harm and injustice. choosing first come, first served is to be responsible for the foreseeable, avoidable deaths of many people in a pandemic. moreover, this approach would also carry the huge risk of social unrest and riots due to the rush to obtain hospital beds, or at the very least hospital overcrowding, with the ensuing risk of further spread of infection. major inequities would also arise from a "self-made" utilitarian approach by the clinicians left to their own individual intuitions. the risk of arbitrariness and disparities of judgment is only partially reduced by the recommendations that do not set specific thresholds and state that cutoffs "must remain flexible." the aim is to provide a guidance, not a substitution of the individual clinical judgment. last but not the least, individual physicians would be, as it happened in italy, under a tremendous moral distress facing such a terrible task of improvising decisions about whom to treat. they would literally be out on an ethical limb. in italy, as elsewhere in the world, we were dramatically unprepared for such a startling emergency, and not just because we had not enough icu beds, staffing, or funding. we were not prepared at all to face such dramatic choices. in retrospect, the siaarti recommendations might have been written differently. it would have been better to have had a chance to involve members of the wider community in reflection on how to make decisions in the event of such a health emergency, as was done in maryland in the usa in - (daugherty biddison et al. ) . in maryland, multiple forums were held with the general public and with healthcare workers and disaster professionals using a deliberative democracy approach. input from citizens was then fed into policy recommendations developed by an expert working group. this kind of approach would have given the recommendations greater legitimacy and might have provided additional support to clinicians. we do not know what the future will be like after the pandemic, but it is clear that we should try to rethink the whole issue of allocation of scarce resources in emergency conditions, finding out commonly shared and accepted values to construct a contingency plan with sound and consistent ethical guidelines and proper structures-such as triage committees-to help apply guidelines, relieving the individual front-line clinicians of that burden. the approach is similar to other settings, but this is not acknowledged by the general public, or better, by the critics of the triage recommendations. now more than ever, we are aware that a universal, functional, and proactive public healthcare system has the best chances of appropriately facing an unforeseen outbreak of a viral disease. its full functionality is important at the early stage, when no specific immunization or treatment interventions are available, since it guarantees proper infrastructures to mobilize a testing regime that provides the data that health-policy leaders need to make decisions, and it guarantees a fair and consistent access to supportive care. it will become crucial later, when drugs and vaccines will hopefully be available, to define their price and deliver them widely, effectively, and fairly. we do not know yet if this hard time will turn into a global catastrophe, but should learn from the history of past epidemics that one of the highest risks is to give wrong priorities (jones ) (box ). box key lessons from italy . in emergencies, the patient-centered "duty to care" needs to be balanced with public-focused duties to promote equality of persons and equity in distribution of risks and benefits. . in emergencies, when medical resources available are scarce, the first-come-first-served approach should be rejected. . as the development of rapid ethical guidance in emergency is difficult and politically fraught, an advance planning for intensive care-including decision-making in the event of overwhelming demand-is needed. . a political and public engagement/education in the ethics of resource allocation is needed to clarify priorities and values if they are to be reflected in allocation. author contributions lc conceived the paper and constructed a first draft. mv, js, and dw elaborated arguments and contributed to subsequent drafts of the paper. all authors revised the document for critical intellectual input, and all authors approved the final version. funding information js and dw received support from the uehiro foundation on ethics and education, and the wellcome trust via the wellcome centre for ethics and humanities (wt ) and js from the wellcome trust via the responsibility and healthcare project (wt ). through his involvement with the murdoch children's research institute, js was supported by the victorian government's operational infrastructure support program. conflict of interest dr savulescu reports grants from wellcome trust and grants from uehiro foundation on ethics and education, during the conduct of the study. dr vergano reports that he was the lead author on the siaarti covid- clinical ethics recommendations. there are no other declarations. mancano posti in terapia intensiva? non ci risulta on behalf of i-belt (italian board of experts in the field of liver transplantation). . a multistep, consensusbased approach to organ allocation in liver transplantation: toward a too many patients…a framework to guide statewide allocation of scarce mechanical ventilation during disasters fair allocation of scarce medical resources in the time of covid- nostra guida resta ilcodice deontologico coronavirus, gori su twitter: pazienti "lasciati morire duty to plan: health care, crisis standards of care, and novel coronavirus sarscov- . nam perspectives history in a crisis -lessons for covid- at the epicenter of the covid- pandemic and humanitarian crises in italy: changing perspectives on preparation and mitigation lessons from italy's response to coronavirus fnopi sul documento degli anestesisti-rianimatori no a rupe tarpea, la soluzione non è sacrificare gli anziani ci sono un ssn e un sistema paese in grado di dare risposte adeguate facing covid- in italy -ethics, logistics, and therapeutics on the epidemic's front line siaarti recommendations for the allocation of intensive care treatments in exceptional, resource-limited circumstances clinical ethics recommendations for the allocation of intensive care treatments in exceptional, resource-limited circumstances: the italian perspective during the covid- epidemic publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -myaiilra authors: sha, d.; miao, x.; lan, h.; stewart, k.; ruan, s.; tian, y.; yang, c. title: spatiotemporal analysis of medical resource deficiencies in the u.s. under covid- pandemic date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: myaiilra a data-driven approach is developed to estimate medical resource deficiencies or medical burden at county level during the covid- pandemic from february , to may , in the u.s. multiple data sources were used to extract local population, hospital beds, critical care staff, covid- confirmed case numbers, and hospitalization data at county level. we estimate the average length of stay from hospitalization data at state level, and calculate the hospitalized rate at both state and county level. then we develop two medical resource deficiency indices that measure the local medical burden based on the number of accumulated active confirmed cases normalized by local maximum potential medical resources, and the number of hospitalized patients that can be supported per icu beds per critical care staff, respectively. the medical resources data, and the two medical resource deficiency indices are illustrated in a dynamic spatiotemporal visualization platform based on arcgis pro dashboards. our results provide new insights into the u.s. pandemic preparedness and local dynamics relating to medical burdens in response to the covid- pandemic. just before the global pandemic covid- , a report by the global health security index was released, which is the first-ever comprehensive ranking of countries based on their pandemic preparedness, with six categories of questions and indicators [ ] . although national health security is fundamentally weak across the globe, the u.s. scored . / and ranked no. in the report. as evidence, there were . critical care beds per , inhabitants in the u.s. by , which is higher than that of any other country [ , ] . however, the u.s. has fewer hospital beds ( . ), and practicing physicians ( . ) per , capita compared to other similar large and wealthy countries [ ] . since the covid- outbreak, it has been estimated that a significant percentage of the u.s. population would test positive for covid- even given a conservative estimation [ ] . for example, a recent aha (american hospital association) webinar on covid- projected that % ( million) of the u.s. population would test positive, with % ( . million) being hospitalized, % ( . million) would be admitted to the intensive care unit (icu), and % ( , ) would require ventilators [ ] . this projection is generally compatible with the characteristics of covid- in wuhan, china, where % of patients required the intensive care unit and . % required a ventilator [ ] . based on a recent cdc survey, the actual weekly hospitalization rate in april was around . - . % for counties across states [ ], which means a large number of infected patients will swarm into hospitals and icus. as a matter of fact, the u.s. had the highest number of confirmed cases of covid- ( , ) in the world on march , , and surpassed italy for the highest national death toll ( , ) on april , [ , ] . are u.s. medical resources enough to handle the worst scenario during this crisis? the society of critical care medicine (sccm) released a report regarding the medical resources both available and needed for a potentially overwhelming number of critically ill patients [ ] . in this report, three fundamental elements or features, i.e. ventilators, icu beds, and critical care staff (ccs) were identified as medical resources to plan for or manage a covid- pandemic, and it would be wise to consider the interconnections among these factors in a spatiotemporal data analysis framework. specifically, the medical resource distribution should be correlated with covid- pandemic statistics in space ( d) and time ( d), so medical resource burden or deficiency can be identified through feature selection, visualization, monitoring, and cluster analysis [ ] . among these three elements, an inventory of ventilators is difficult to quantify for estimating critical supply shortages. based on a aha survey, a total of , u.s. acute care hospitals were estimated to have , full-featured mechanical ventilators and , ventilators with limited features [ ] . the strategic national stockpile (sns) had an estimated , ventilators for emergency deployment in , and between , and , ventilators by march , [ ] [ ] [ ] ). based on these numbers, the ventilator inventory was approximately , - , in the u.s. a model-based analysis suggested that us hospitals could absorb between , to , additional ventilators at the peak of a national pandemic with robust pre-pandemic planning [ ] . since sns can deliver ventilators within - hours after being requested by states and approved by federal organizations, and no reliable database for ventilator inventory exists at county or state level, we will not consider this factor in our spatiotemporal analysis. a recent modeldriven study simply assumes one ventilator per critical care bed [ ] and we use this same assumption in our analysis. hospital beds, especially icu beds, are an important factor in evaluating medical resource deficiency during the covid- pandemic, and quantity of beds has been used as a major factor in model-driven predictions of local critical care capacity limit [ ] [ ] . however, safe use of ventilators in icu requires trained personnel. in a previous study, the number of trained medical personnel is assumed to correlate with the number of staffed beds maintained by hospitals [ ] . this assumption is perhaps unrealistic at county level without considering the geographic disparity. for this research, we assume that a realistic measurement of the medical burden at county level should consider both icu beds and critical care staff (ccs), which will provide reasonable evidence for stakeholder (e.g., hospital, county and state governments) policy and decision-making. in this study, we ( ) conduct a medical data analysis, and reevaluate the spatial distribution of medical resource features (hospital beds, icu beds, and ccs) at county level; ( ) a total of , counties and county-equivalents in the u.s. are used as the primary unit of this study, since they are manageable in a gis system and small enough to reflect local geographic discrepancies. the base map was downloaded from the tiger/line products from the u.s. census bureau, which is the most comprehensive spatial dataset designed for gis platforms (https://www .census.gov/geo/tiger/tiger /). the county vector layer delineates the administrative boundary with land/water area without any demographic data, but it provides geographic entity codes (geoids) for joining with other socio-economic data such as census data. based on the attributes of our collected medicalrelated datasets, we also prepared state and zip code boundaries for data fusion and integration at county level. in this study, two fundamental features of medical resources in the u.s. were extracted, i.e., hospital beds and critical care staff. besides, the population and + senior population data was extracted at county level from khn online database [ ] , which is used to normalize the local medical data in the subsequent analysis. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. national public and private online datasets were used to prepare county-level hospital bed counts. hospital data were collected from definitive healthcare [ ] . definitive healthcare consulting services shares their hospital dataset to the entire health research community through arcgis online, which covers information of nationwide bed capacity and average yearly bed utilization of hospitals. although it is not a real-time dataset that reflects each hospital's bed capacity during covid- , it can be used as a baseline to estimate the geographic disparity of local health resources. a hospital is defined as a healthcare institution providing inpatient, therapeutic, or rehabilitation services under the supervision of physicians with the capability of inpatient care [ ] . all types of hospitals are included in our study. five types of hospital beds are clearly identified in the definitive healthcare dataset. in our study, two hospital bed capacities were selected and used in the analysis. the first one is the number of licensed beds, which is the potential or maximum number of beds for which a hospital holds a license to operate. the second type of capacity refers to the number of adult icu beds that could be used for covid- . during this crisis, hospitals could use additional intensive care beds to supplement an influx of patients. therefore, adult icu beds include not only internal medical icu beds, but also burn, surgical, and trauma icu beds. however, pediatric, premature or neonatal icu beds are not included because they are mainly for a different target patient population, which has a much lower incidence rate of covid- . two other independent data sources of hospital beds are compared with the data from definitive healthcare. one is from kaiser health news (khn) based on reports of icu beds in - [ ] , and the other is from homeland infrastructure foundation-level data (hifld) for licensed hospital beds updated on october , [ ] . we conducted a regression analysis comparing khn with definitive healthcare in terms of icu beds, and comparing hifld with definitive healthcare in terms of licensed beds, and the coefficients of determination (r ) are . and . , respectively. the results validate the quality of the definitive healthcare dataset. a dataset of critical care staff (ccs) was extracted from the weekly updated national provider identifier registry (npi) database (~ . gb) through structured query language (sql) [ ] . the npi is a unique -digit identification number for each health-care provider issued by the centers for medicare medicaid services through the national plan and provider enumeration system. each health-care provider could have multiple taxonomy codes, which indicate areas of specialization. through consulting with medical researchers and front-line physicians, we extracted detailed ccs data from the npi database released on april , as a medical resource feature (table ) . our study identifies , health care providers by searching unique npi records and removing duplicate records. with the development of covid- in the u.s., all these icu-related staff (emergency medicine physician, critical care physicians, anesthesiologists, hospitalists, pulmonologist, infectious disease physician, all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint surgery, anesthesiologist assistant, critical care nurses, nurse anesthetist, and respiratory therapists trained in mechanical ventilation) would become valuable but limited asset for critically ill ventilated patients [ ] . the u.s. centers for disease control and prevention (cdc) published daily covid- confirmed cases on february , . each state got involved soon after and began to report covid- data, including the daily and accumulated test and confirmed case numbers, hospitalization data, and death numbers at state level. however, numbers of discharged or released patients from hospitals are less widely available, e.g., only a few states, such as maryland, colorado, and new york provide some (incomplete) statistics on recovered patients from both hospital and home. this study mainly uses the data collected by the nsf spatiotemporal innovation center (stc) at george mason university. this all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint dataset uses a datacube structure for spatiotemporal data aggregation from multiple sources. the data is cleaned, standardized, and updated daily to solve any data conflicts, and a timeseries summary at state and county level is provide for the u.s. [ , ] the numbers of county-level confirmed positive cases as well as deaths were originally extracted from usafacts based on cdc data [ ] , and compared with local public health agencies for verification. the confirmed and death cases reflect cumulative statistics since january , , the day after the first confirmed cases were reported in washington state. furthermore, state level test and hospitalization data were extracted from the covid tracking project [ ] . however, the current and accumulated hospitalization cases from state health departments are largely incomplete. by april , , a total of states reported both current and accumulated hospitalized patient numbers, states reported only current hospitalized numbers, and states only reported accumulated hospitalized numbers, while washington, d.c., nevada and nebraska did not provide information on the number of hospitalized cases. raw datasets in this study were collected from multiple sources with heterogeneous formats and structures. all data are processed and aggregated at county level based on county federal information processing standard (fips). several aggregation methods are used for each raw dataset, as summarized in fig . all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. first, the hospital data was originally presented as a point location in a coordinate format, and its attribute table includes five types of hospital beds. the spatial point aggregation algorithm was used to integrate the numbers of licensed beds and adult icu beds at county level. the bed numbers per , residents were also calculated at county level. the primary practice addresses of ccs were imported from the npi database, and digital zip codes were extracted. the total number of ccs within a county was counted based on the county's zip codes through geocoding and the point/ polygon aggregation algorithm. the number of ccs per , residents were also calculated at county level. the accumulated covid- confirmed case numbers were extracted at county level. we used existing hospitalization data to estimate the average length of stay (alos) in acute care, since it is key for estimating the daily hospitalized patients. for a given state, the current hospitalized patients should be equal to the accumulation of hospitalized patients minus the accumulation of deaths and discharged patients within the most recent alos. since no patient discharge data was available, we assumed that the number of discharged patients was zero. therefore, we estimated alos by matching ( ) the accumulation of hospitalized patients minus the accumulation of deaths in most recent days, and ( ) the current number of hospitalized patients, and finally interpolating by two nearest days or accumulation periods. it turns out to be an optimization problem to find a parameter (n) to match the two data sources, as shown in equation ( ). all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. where is the accumulated number of hospitalized patients in the past n days, is the accumulated number of deaths in the past n days, and is the number of currently hospitalized patients. state hospitalization data were only available recently (starting from march , in ny) with numerous missing data. by may , , among states that have both current and accumulated numbers of hospitalized patients, eight states (colorado, massachusetts, maine, minnesota, montana, north dakota, new york, oklahoma) had complete data for the most recent days; states (oklahoma, wisconsin, mississippi, maryland, new hampshire, new mexico, oregon, south dakota, virginia, wyoming, rhode island, kentucky) only had data in the most recent - days; and data from arkansas, arizona, and connecticut were abandoned due to poor quality. we calculated the daily alos for these states and pooled the results in fig . the average state alos ranges from . (new mexico)- . (mississippi) days. the overall national average alos weighted by state hospitalized patients is . days, which is longer than a previous estimation that the alos in acute care were days [ ] . it is worth noting that alos is likely to be underestimated since we assumed no discharged patients. furthermore, alos is subject to change when more hospitalization data become available in the future. finally, we define the covid- hospitalized rate as the ratio of the number of current hospitalized patients and the accumulated confirmed case numbers during the most recent alos. if the hospitalized rate remains the same within a state, the daily hospitalized patient number in a county can be estimated by using the accumulated covid- confirmed case numbers minus deaths in the most recent alos, multiplied by the state average hospitalized rate. if no state alos is available, we use the overall national average alos of . days. this daily hospitalized patient number can be used to evaluate the daily medical burden at county level. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the medical resource deficiency indices (mrdi) are defined as an indicator of medical resource burden at county level. we define two forms of mrdi: general mrdi, and local daily mrdi (mrdid). where is the accumulated number of confirmed covid patients, is the accumulated number of deaths, is the total number of licensed beds, and is the number of critical care staff. we assumed that and were relatively independent at county level, and the product of them represents the interconnection of these two medical resource features or factors. therefore, the mrdi represents the number of accumulated active confirmed cases normalized by the local maximum potential medical resources (total licensed beds and total ccs). mrdid is represented as where is the accumulated confirmed case numbers during a most recent alos, is the accumulated death numbers during the same alos, is the state hospitalized rate derived from state hospitalization data, and is the number of adult icu beds. mrdid represents the local daily medical burden, or the number of hospitalized patients that can be supported per icu beds per ccs. mrdid is large (> ) when local medical resources cannot fully support the hospitalized critically ill patients, or the local medical burden is heavy; and mrdid is small (< ) when local medical resources are sufficient. based on arcgis dashboard, we designed a comprehensive operational dashboard for monitoring, analyzing, visualizing, and sharing our medical data and analyzed results. a multi-stacked map is built at the center of the interface (fig ) , which represents the spatial distributions of covid-related statistics such as mrdi, death rate, and infection rate at county level over the u.s. in addition to visualizing the macro spatial distribution pattern of those statistics results, two lists of counties are displayed. those counties are dynamically filtered by the current map extent in map view and are ranked in real-time by hospitalized rate and death rate to represent the spreading of covid- and the outbreak situation in the selected study area. focusing on a specific county, an indicator and two pie charts are applied to display for each county (fig ) : ) the comparison of active covid - cases and the number of overall beds; ) the percentage of icu beds in overall beds; and ) the proportion of each type of ccs. from the temporal analysis perspective, a time series chart is designed to demonstrate the dynamics of medical resource deficiencies for each county on a daily basis all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint during the pandemic. in the following section, we will use the dashboard components to analyze spatiotemporal distributions of medical resource deficiencies. we will further explore the possible factors relating to the medical resource deficiencies for specific counties and areas as well as the medical resource capacity for non-severe covid- patients, the supplies needed for severe cases, and proportion of each type of ccs. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the icu beds per , residents (fig a) and ccs per , residents (fig b) are mapped at county level. both maps show that these two medical resources are not homogeneously distributed across the u.s. some midwestern states, such as north dakota, south dakota, nebraska, kansas, and montana have more icu beds, but less ccs. the spatial distribution of ccs shows a checker board pattern, with many gaps or low numbers across the country. the product of icu beds and ccs per residents is shown in fig (a) . the darkest green zones represent counties with higher quantities of medical resources including icu beds and ccs. a total of major medical centers represent top ranking healthcare facilities in the u.s. (table ) [ ] . medical centers are conglomerations of health care facilities including hospitals and research facilities that could be affiliated with a medical school. overlaying the locations of these medical centers on the map (purple circles on the map), it seems these counties and medical centers are spatially highly correlated (fig a) . since senior people (aged +) are vulnerable to covid- , we also produced a map of the product of icu beds and ccs per senior residents (fig b) . this map represents locations where the supply of medical resources for seniors is higher. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint a regression analysis was conducted to examine the correlation between ccs and adult icu beds at county level (fig ) . if all , counties are included, the coefficient of determination (r ) is . . however, this high r value is quite misleading, since it is heavily influenced by several large counties with rich medical resources (blue dots). removing the top counties, causes the coefficient of determination (r ) to drop to . , which better all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . a total of counties have neither icu beds nor ccs, and are shown in fig . these counties are mainly distributed in less-populated rural areas across the u.s., and they are not included in mrdi or mrdid calculation to avoid a divide-by-zero error. during the covid- pandemic, individuals requiring a higher level of care in these areas would be sent to neighboring counties with sufficient medical resources, and could result in larger mrdid in the neighboring counties. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint the spatiotemporal dynamics of general mdri across the u.s. is illustrated at: http://mrd-dashboard.stcenter.net/. the general mdri represents the number of accumulated active confirmed covid- cases normalized by local maximum potential medical resources, while the dynamic view provides an insightful alternative visualization of covid- u.s. cases by county. four snapshot maps are illustrated in figs (a)-(d), which demonstrate four time-stamped frames taken on february , march , april , and may , . a proportional symbol map is used with semi-transparent red circles to represent the general mdri. this visualization technique enhances clustering patterns, and there is a clear trend where the general medical burden shifted from the east coast of the u.s. to midwestern states. as of may , it would seem that louisiana, mississippi, georgia, tennessee, indiana, and nebraska are possibly suffering a new wave of medical resource deficiencies due to the rapid increase of accumulated active confirmed cases in some counties. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. furthermore, the spatiotemporal dynamics of local daily mdrid is also illustrated in the dashboards. since hospitalization data has been available only recently, we illustrate a most recent frame taken on may , (fig ) . the red circle symbols are semitransparent, and county-level medical resource deficiencies are visually enhanced by searching the reddest clustering patterns in the map. during this covid- infection period, it seems that mississippi, louisiana, tennessee, and indiana were suffering medical resource deficiencies, which would have required special attention when relocating medical resources if necessary. these newest hotspots have been partially confirmed from local news reports around may , . for example, there were , known presumptive cases with the total death toll of in mississippi on april , [ ] ; new cases covid- rose sharply on may in east baton rouge, louisiana, as deaths approached in the region [ ] ; the nation's highest infection rate was in a county in trousdale county, tennessee, where , cases of covid- were reported, and most of them traced back to a state correction center [ ] ; and indiana passed , covid- deaths on april , [ ] . all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. in the center of the dashboard, several map layers could be selected to show the general spatial distribution of mrdi, death rate, infection rate and active cases over licensed beds per capita. after interactive map scaling (by zooming in/out) and moving (by dragging) operations, or using the polygon selection tool, the charts and rank list are linked and selfadapted to the analysis region of interest to a user. by clicking the polygon of a selected county, attribute information about medical resources and covid- related data would popup and the relevant chart is automatically updated in the dashboard. northern tennessee state is presented as a use case to show the possible interactive analysis (fig ) . since western and east coast regions have more medical resources than central regions (fig a) , and the states along the mississippi river in the southern u.s. show a high risk (fig ) , we zoom in on the map and select the nearest region with the largest red bubble in tennessee (fig ) . thirty counties are selected as a result, and relevant numbers are calculated and presented in dashboard charts. the medical bed pie chart shows icu beds are . % in overall licensed beds, and the medical staff pie chart shows the nurses group is the highest ( . %) followed by physicians ( . %), physician assistants ( . %) and therapists ( . %). the line chart shows a time-series trend for mrdi in the northern tennessee area, and we find the index varied greatly between april , to may , , all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . which could be explained by the possible tracing of the virus to a correction center outbreak in trousdale county [ ] . on the right column of the dashboard, the risk factors of medical resource and infection rate is ranked by the selected region. trousdale, davidson, and sumner county are the top with highest infection risks, while trousdale also shows the highest medical resource risk in this region. the case study in fig demonstrates the potential of our developed dashboard for interactive and visual analysis of specific regions of interest for policy makers, other stakeholders, and the general public. in this study, a data-driven approach has been used to estimate the medical resource deficiencies or medical burden at county level during the covid- pandemic across the u.s. specifically, spatiotemporal data analysis methods including feature extraction, database structured query (sql), data fusion or aggregation, linear regression analysis, and spatial statistics were used to extract medical resource features and patient statistics, such as hospital beds, css, local population, covid- confirmed case numbers, and hospitalization data at county level. and then the average length of stay (alos) was estimated from hospitalization data at state level, and the hospitalized rate were calculated at state and county level. based on these datasets, we developed two medical resource deficiency indices mrdi and mrdid that measure the local medical burden from two different perspectives. the first index represents the number of accumulated active confirmed cases normalized by local maximum potential medical resources; and the second one represents the number of hospitalized patients that can be supported per icu beds per critical care staff. the related medical resources data and mrdi and mrdid were visualized and analyzed using a dynamic spatiotemporal platform created through arcgis pro dashboards, which is a convenient way to enhance the clustering patterns and trends. our analysis showed that ( ) the spatial distribution of medical resources (hospital beds, icu beds, and ccs) at county level is highly heterogeneous across the u.s., and icu beds and ccs are not spatially highly correlated; ( ) mrdi and mrdid can provide new insights into the u.s. pandemic preparedness and local dynamics relating to medical burdens during a peak period in the covid- pandemic; and ( ) a data-driven dynamic spatiotemporal framework is a powerful data visualization tool to illustrate the trends of mrdi /mrdid and other medical-related statistics. it is worth noting that we have not considered the number of discharged patients due to a lack of data, leading to a possible slight underestimate of alos during the covid- rapid infection period. as a result, mrdid may also be slightly underestimated. we also did not consider the ratio of icu patients and acute hospitalized patients due to a lack of data, and assumed all hospitalized patients were treated as icu cases. as a result, mrdid was possibly overestimated, and the values calculated here should be viewed as the upper limit of local medical burdens. some other uncertainties include ( ) the numbers of registered hospital beds and css could be incomplete or not up-to-date, although the most recent all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint definitive healthcare and npi databases have been used, so the medical resources could be underestimated, ( ) critically ill patients in counties without icu beds and ccs would be sent to neighboring counties with sufficient medical resources, ( ) some numbers of experienced icu staff may have become ill, ( ) the number of trained professionals may have increased based on emergent recruiting, and ( ) the capacity in icus and emergency rooms may have been expanded during the crisis. however, mrdid can still serve as a useful indicator to measure the county-level medical resource deficiencies, and this index can be improved once more public health data are available in the future. furthermore, it could provide reasonable evidence for policy makers in local and state governments to assess their medical inventories and staff resources, and provide preparedness for decision of re-opening the economies and public life. in the future, our work can be combined with epidemic models to either provide driving parameters or calibrate the models and predict the local medical burdens. the spatiotemporal analysis used in this study can be extended to include remote sensing data, social media data, and mobile traffic flow data to estimate severity of pandemic or predict the outbreak cases in the u.s. and other counties. the variability of critical care bed numbers in europe critical care bed growth in the united states. a comparison of regional and national trends how prepared is the us to respond to covid- relative to other countries? estimating covid- prevalence in symptomatic americans availability for covid- clinical characteristics of coronavirus disease in china all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity taking the pulse of covid- : a spatiotemporal perspective big spatiotemporal data analytics: a research and innovation frontier mechanical ventilators in us acute care hospitals. disaster medicine and public health preparedness stockpiling ventilators for influenza pandemics ventilator stockpiling and availability in the us strategic national stockpile: overview and ventilator assets assessing the capacity of the us health care system to use additional mechanical ventilators during a large-scale public health emergency flattening the curve before it flattens us: hospital critical care capacity limits and mortality from novel coronavirus (sars-cov ) cases in us counties estimating the maximum capacity of covid- cases manageable per day given a health care system's constrained resources where the icu beds are definitive healthcare: usa hospital beds spatiotemporal patterns of covid- impact on human activities and environment in china using nighttime light and air quality data coronavirus locations: covid- map by county and state the covid tracking project: most recent data medical centers in the united states mississippi covid- cases now number more than new confirmed coronavirus cases in east baton rouge, part of sharp rise; see latest statewide data covid- update: april saw rural america's infection rate increase -fold. the daily indiana passes , covid- deaths; lake county reports four more deaths, brings total to large spike in coronavirus cases traced to prison in trousdale county no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity key: cord- -yk cz hq authors: li, michael; yoo, erika j.; baram, michael; mcarthur, melanie; skeehan, connor; awsare, bharat; george, gautam; summer, ross; zurlo, john; jallo, jack; roman, jesse title: tocilizumab in the management of covid- : a preliminary report date: - - journal: am j med sci doi: . /j.amjms. . . sha: doc_id: cord_uid: yk cz hq importance: pneumonia due to covid- can lead to respiratory failure and death due to the development of the acute respiratory distress syndrome. tocilizumab, a monoclonal antibody targeting the interleukin- receptor, is being administered off-label to some patients with covid- , and although early small studies suggested a benefit, there are no conclusive data proving its usefulness. objective: to evaluate outcomes in hospitalized patients with covid- with or without treatment with tocilizumab. design, setting, participants: retrospective study of , patients with confirmed covid- pneumonia admitted to hospitals within the jefferson health system in philadelphia, pennsylvania, between march , and june , , of which received tocilizumab. exposures: confirmed covid- pneumonia main outcomes and measures: outcomes data related to length of stay, admission to intensive care unit (icu), requirement of mechanical ventilation, and mortality were collected and analyzed. results: the average age was . , with % women; . % were african-american. the average length of stay was days with . % of patients requiring admission to the icu and . % requiring mechanical ventilation. the overall mortality was . %. older age, admission to an icu, and requirement for mechanical ventilation were associated with higher mortality. treatment with tocilizumab was also associated with higher mortality, which was mainly observed in subjects not requiring care in an icu with estimated odds ratio (or) of . (p = . ). tocilizumab treatment was also associated with higher likelihood of admission to an icu (or = . , p < . ), progression to requiring mechanical ventilation (or = . , p < . ), and increased length of stay (or = . , p < . ). conclusion and relevance: our retrospective analysis revealed an association between tocilizumab administration and increased mortality, icu admission, mechanical ventilation, and length of stay in subjects with covid- . prospective trials are needed to evaluate the true effect of tocilizumab in this condition. . % requiring mechanical ventilation. the overall mortality was . %. older age, admission to an icu, and requirement for mechanical ventilation were associated with higher mortality. treatment with tocilizumab was also associated with higher mortality, which was mainly observed in subjects not requiring care in an icu with estimated odds ratio (or) of . (p = . ). tocilizumab treatment was also associated with higher likelihood of admission to an icu (or = . , p < . ), progression to requiring mechanical ventilation (or = . , p < . ), and increased length of stay (or = . , p < . ). tocilizumab administration and increased mortality, icu admission, mechanical ventilation, and length of stay in subjects with covid- . prospective trials are needed to evaluate the true effect of tocilizumab in this condition. since december , the world has grappled with a global pandemic caused by the novel coronavirus sars-cov- . infection with sars-cov- encompasses a continuum of disease from asymptomatic infection to respiratory failure due to the acute respiratory distress syndrome (ards) ( ) . mortality from covid- -related ards in critically ill patients cared for in an intensive care unit (icu) is reported to be in the range of % to % ( ) ( ) ( ) . considering the aggressive nature of the disease, caregivers around the world have opted to try off-label and unproven interventions. hydroxychloroquine, vitamin d, corticosteroids, angiotensin converting enzyme inhibitors, convalescent plasma, and the anti-viral agents lopinavir and ritonavir, among others, have been tested, but none has proven effective and many have potential to cause harm ( ) . to date, only the anti-viral remdesivir has been approved for use in this condition in the u.s. ( ). tocilizumab is another agent that has been used in the management of covid- ( ) . this antibody acts against the interleukin- (il- ) receptor. il- levels have been notably high in some covid- patients and it has been believed to be involved in the exuberant inflammatory response or cytokine storm triggered by sars-cov- infection that might lead to ards ( ) . on this basis, physicians at our hospitals have administered tocilizumab to covid- patients with severe respiratory impairment off-label and outside of a clinical trial hoping to improve outcomes by preventing or ameliorating the development or progression of the covid- related cytokine storm, thereby inhibiting the development of ards in both the intensive care unit (icu) and non-icu settings. considering that the role of tocilizumab in the treatment of patients with covid- remains undefined, and that data from large, well-controlled randomized trials are not available, we retrospectively collected and analyzed data on our patients and report preliminary results that question the usefulness of tocilizumab in this population. this retrospective study was approved by the jefferson institutional review board (figure ) . criteria for inclusion in the tocilizumab treatment group included: ) age of years or older with a clinical presentation consistent with covid- (e.g., fever, respiratory symptoms, and new pulmonary infiltrates), ) laboratory confirmation of sars-cov- infection by an rt-pcr test, and ) outcome data available. subjects without a covid- diagnosis and patients recruited to a formal tocilizumab clinical trial or administered drug for reasons other than for covid- were excluded. most patients were initially hospitalized on the non-icu service cared for by hospitalists or pulmonologists. some were then transferred to the icu if deterioration in clinical picture was noted. for the most part, transfer to the icu was triggered by deterioration of hypoxemia in the setting of increased work of breathing not improved by high flow oxygen supplementation, non-invasive ventilation, and proning (if possible). in other words, significant attempts were made to treat patients non-invasively prior to transfer to the icu for more careful monitoring or mechanical ventilation. a smaller group of patients was directly hospitalized into the icu from the emergency room depending on their level of hypoxemia, hemodynamics, and other parameters. our institution defined the following guideline for considering the administration of tocilizumab to a given patient. the case was to be consulted to infectious diseases and rheumatology or hematology for consideration and ultimately approval of the therapy. consultation of a case was at the discretion of the attending physician. baseline laboratory work to evaluate for inflammatory markers and possible cytokine storm was required. if approved, the patients were given the drug once at - mg/kg intravenously. inpatient mortality was considered the primary outcome variable. we also evaluated mortality in subjects requiring icu care versus non-icu patients. for secondary outcomes, we considered admission to the icu, mechanical ventilation, inpatient length of stay (los), icu los and duration of mechanical ventilation. given that duration outcomes are continuous measures with long tails, we also created dichotomous ( , ) measures to indicate long duration (e.g., days or more vs. shorter duration was chosen arbitrarily); this is a retrospective observational study that evaluated the impact of tocilizumab therapy on mortality and other outcomes for hospitalized patients with severe disease treated in the icu versus those not requiring icu management. use of tocilizumab was analyzed against other parameters such as age, gender, race, icu care, and mechanical ventilation, and length of stay. patient characteristics were compared using fisher exact or chi-square test, and t-test as appropriate. these data include those still hospitalized, or discharged, or those who expired while in the hospital. multivariate logistic regression analysis was performed to predict inpatient mortality, icu admission, los, icu duration, need for ventilation and ventilation duration. we compared baseline characteristics of the tocilizumab treated group (tcz) with the group not treated with tocilizumab (non-tcz) in the overall cohort. categorical variables were compared by using the χ test and continuous variables were compared by using the t-test. the multivariate logistic regression was used for identified factors that predict different bivariate outcome variables with control variables included as appropriate and sample volume allowed. the strengths of associations of the predictors were expressed as the odds ratio (or) estimates, % confidence intervals (cis) and p-value. p < . was considered statistically significant. model discrimination was assessed by using c-statistics, the values of which are equivalent to the area under a corresponding receiver-operating characteristic curve, which measures a model's predicting power with . as no predicting power and . as perfect prediction. all statistical analyses were performed using sas . (sas institute inc., cary, nc). tocilizumab (tcz) was administered in ( . %) of , hospitalized patients with a covid- diagnosis. there were more males ( %) than females ( %) in the overall group, and a higher proportion of males ( %) vs. females ( %) was administered tcz ( table ) . white and asian race groups were more represented in the tcz treated group than in the nontreated group when compared to blacks and hispanics. the average patient age was . , which was similar between the tcz and non-tcz groups. however, a higher percentage of patients in the - age group received tcz treatment when compared to the non-treatment group (pvalue = . ). in genereal, patients over age and, to a lesser degree, younger subjects had relatively less tcz treatments. figure a provides the total covid- patient distribution by icu admission and survival status. as expected, there was higher mortality in the icu group when compared to the non-icu settings (the latter includes patients who received the drug in a non-icu setting, but could have been transferred to an icu later). figure b provides the total covid- patient distribution by their tcz use, icu admission, and survival status. as shown in table the effect of tcz treatment on all covid inpatient mortality was assessed using multivariate logistic regression with gender, age, inpatient length of stay (los), icu admission and ventilation as control variables. the model covariates were selected a priori based on clinical relevance or data availability. we considered los, icu admission, and mechanical ventilation as measures of disease severity. we used male gender, white or caucasian race, and age group of and younger as default for comparison. table shows that tcz therapy had a marginally positive association with mortality (or . , p = . ). age had significant effects on mortality as older age groups had progressively higher odds ratios compared to the baseline age group (less than ). both icu admission and mechanical ventilation had significant positive relationship with mortality (or . and . with p < . ). gender, race and los had no significant effects. when mortality was evaluated in subjects with severe condition (i.e., icu patients) vs. non-severe condition (or non-icu patients), tcz correlation with mortality became much clearer. for icu patients, tcz treatment was not significantly correlated with mortality (p = . ). however, for non-icu patients, tcz treatment was positively correlated with mortality (or . , p = . ). the age effect pattern in both icu and non-icu groups remained similar; i.e., older age groups had bigger odds ratios for mortality. however, for non-icu covid- patients, there were no significant differences in mortality among the three younger age groups, less than , - and - group. for the non-icu group, black race had a marginally negative correlation with mortality (or . , p = . ). using the same multivariate logistic model, we tested tcz treatment effects on several other outcomes in the patient groups. tcz effects on different outcomes are summarized in table measures, we also used the days and days indicator to test the logistic models and reached similar results. finally, it is recognized that multicollinearity between tcz use, icu admission, and mechanical ventilation could affect the association between treatment and mortality, among other variables. therefore, we ran multicollinearity tests on these independent variables. the variance inflation factors of the independent variables were all below , which indicated no multicollinearity concern in the multivariate model. the mortality in patients with covid- requiring hospitalization because of hypoxemia associated with bilateral pulmonary infiltrates has been reported as high as % although more studies that are recent report a lower mortality ( - ); our overall mortality was . %. the development of a cytokine storm leading to ards is considered a major cause of death in such patients. il- is considered an important driver of the cytokine storm and therefore has become a target for intervention. this seemed justified as il- levels were found elevated in patients with severe acute respiratory syndrome (sars), a related disease linked to another coronavirus, and correlated with disease severity ( ) . similar observations have been made in subjects with covid- ( ) . this prompted interest in several agents targeting il- and its receptor. tocilizumab binds to soluble and membrane-bound il- receptors, inhibits il- mediated signaling, and is approved by the federal drug administration for the treatment of rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome ( ) ( ) ( ) . early case reports, case series, and relatively small pilot single-arm non-randomized clinical trials (including a range of to patients) suggested the safety and benefit of tocilizumab in the setting of covid- ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . because of some of these data, the agent was recommended by china's national health commission for use in covid- patients with elevated il- levels ( ) . however, other reports failed to show improved mortality ( ) and highlighted the potential adverse effects of tocilizumab including toxic erythema, candidemia, and bowel perforation ( ) ( ) ( ) . an "interim guidance on management pending empirical evidence report published by the american thoracic society on april , did not make a recommendation in favor of or against tocilizumab considering the limited and conflicting data available ( ) . meanwhile, formal multi-center clinical trials testing the effectiveness of tocilizumab in the treatment of covid- have started (nct and nct ), but data are pending. considering that the role of tocilizumab in the treatment of patients with covid- remains undefined, we felt the need to report data retrospectively collected at our institution in the hope of adding to the accumulating literature regarding this agent in order to assist providers with their management of these patients. consistent with other studies, we confirmed an increase mortality for covid- related to age. however, the main finding from this observational correlation analysis is that tocilizumab treatment may not reduce covid- related mortality, and was associated with increased mortality for non-severe condition (non-icu) covid- patients. our study findings also show that tcz therapy may promote icu admission, progression to requiring mechanical ventilation, and increased los, icu duration, and mechanical ventilation duration. interestingly, tocilizumab was not associated with increased mortality in icu patients, perhaps because of the severity of the condition and duration of disease. although these findings require confirmation in large prospective well-randomized clinical trials, the consistency of the negative impact of tocilizumab on several parameters should prompt pause when considering this agent for all hospitalized covid- patients. il- acts on important physiological processes in many organs including liver, muscle, bone, and kidney, as well as in glucose and lipid metabolism ( ) . in the setting of severe infections, il- appears to drive inflammation as indicated by the now well-known increase in c-reactive protein, a downstream secondary massager for il- ( ). however, il- might only serve as a marker of disease severity, instead of an important driver of disease progression. this concept is consistent with data generated in experimental murine models of sepsis where complete lack of il- was not found to alter mortality ( ) . another consideration is that il- is likely to affect cells in different ways and that targeting this molecule may have simultaneous beneficial and deleterious effects depending on the cell involved. this is highlighted in an animal model of ventilator-associated lung injury where il- from hematopoietic cells appeared to limit alveolar barrier disruption, thereby reducing neutrophil-mediated injury to the endothelium ( ) . this suggests that cell type-specific targeting of il- might represent a better approach in covid- . finally, the dosing of the agent and timing of administration may influence its effectiveness as dosing regimens for covid- have not been standardized and vary considerably in published studies. the retrospective nature of the study has inherent limitations, as it is difficult to include in the analysis differences in practice patterns, which likely affected choice of patients for drug administration, timing of drug administration, considerations for transfer to an icu, and the management of co-morbidities during the hospitalization, among other confounding factors. for example, in our study . % of tcz-treated patients required icu admission compared with only . % of non-tcz-treated patients that speaks to a sicker population and a likely selection bias toward tcz use in the icu group. nonetheless, we found that it is the non-icu patients that seemed to do worse with tcz treatment rather than icu patients. another study confounder was that the inclusion of patients cared for at several hospitals within a single healthcare network might have produced bias as the patients were cared for by different providers. our inability to determine the timing of the drug is an important limitation as it is difficult to ascertain an effect on outcome parameters without this information. another limitation is due to 'bias by indication', which could prompt the administration of an agent to sicker patients. this could not be ascertained with the data available. in conclusion, this preliminary retrospective observational analysis indicates that tocilizumab therapy was not associated with improved inpatient mortality rate for covid- patients. in fact, for non-icu patients, tocilizumab was positively associated with inpatient mortality. this study further indicates that tocilizumab therapy may also be associated with icu acute respiratory failure in covid- : is it 'typical' ards? baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region, italy clinical charateristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china covid- in critically ill patients in the seattle region -case series covid- diagnosis and management: a comprehensive review off-label use of tocilizumab in patients with sars-cov- infection covid- , cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome? clinical and immunologic features in severe and moderate coronavirus disease practical aspects of targeting il- in covid- disease tocilizumab: a review in rheumatoid arthritis use of subcutaneous tocilizumab in patients with covid- pneumonia interleukin- receptor antagonist therapy to treat sars-cov- driven inflammatory syndrome in a renal transplant recipient impact of low dose tocilizumab on mortality rate in patients with covid- related pneumonia tocilizumab therapy reduced intensive care unit admissions and/or mortality in covid- patients tocilizumab for the treatment of severe covid- pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of patients in brescia effective treatment of severe covid- patients with tocilizumab pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe covid- tocilizumab in patients with severe covid- : a retrospective cohort study china approves use of tocilizumab for coronavirus patients tocilizumab for treatment of severe covid- patients: preliminary results from smatteo covid registry (smacore) toxic erythema" and eosinophilia associated to tocilizumab therapy in a covid- patient tocilizumab for cytokine storm syndrome in covid- pneumonia: an increased risk for candidemia? risk of gastrointestinal perforation among rheumatoid arthritis patients receiving tofacitinib, tocilizumab, or other biologics covid- : interim guidance on management pending empirical evidence. from an american thoracic society -led international task force il- biology: implications for clinical targeting in rheumatic disease role of interleukin- in mortality from and physiologic response to sepsis neutrophil-derived il- limits alveolar barrier disruption in experimental ventilator-induced lung injury key: cord- -q trgj authors: robert, rené; kentish-barnes, nancy; boyer, alexandre; laurent, alexandra; azoulay, elie; reignier, jean title: ethical dilemmas due to the covid- pandemic date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: q trgj the devastating pandemic that has stricken the worldwide population induced an unprecedented influx of patients in icus, raising ethical concerns not only surrounding triage and withdrawal of life support decisions, but also regarding family visits and quality of end-of-life support. these ingredients are liable to shake up our ethical principles, sharpen our ethical dilemmas, and lead to situations of major caregiver sufferings. proposals have been made to rationalize triage policies in conjunction with ethical justifications. however, whatever the angle of approach, imbalance between utilitarian and individual ethics leads to unsolvable discomforts that caregivers will need to overcome. with this in mind, we aimed to point out some critical ethical choices with which icu caregivers have been confronted during the covid- pandemic and to underline their limits. the formalized strategies integrating the relevant tools of ethical reflection were disseminated without deviating from usual practices, leaving to intensivists the ultimate choice of decision. in their daily practice, intensivists are used to facing to ethical concerns related to admission or non-admission to icu, to withholding or withdrawing life support and to communication with families. the devastating pandemic that has stricken the worldwide population induced an unprecedented influx of severe ards patients dramatically exceeding icu bed capacities in several areas of many countries. as a result, four new options never applied to date were considered with the common aim of saving a maximum number of lives: to prioritize icu beds for patients with the best prognosis; to increase at all costs the number of icu beds, thereby creating stepdown icus; to organize transfer to distant icus with more beds available, or to accelerate withdrawal of life support in icus. additionally, to protect the patients' relatives, visits for families were prohibited or strongly limited and adequate communication between caregivers and families was disrupted, counteracting more than years of research aimed at improving interaction with families and quality of care during eol [ ] . moreover, since most health care facilities were being used for covid- patients, the situation also raised concerns inside the icu for patients without covid- requiring icu admission. in such a crisis, there are ingredients liable to shake up our ethical principles, sharpen our ethical dilemmas, and lead to situations of suffering for caregivers [ ] . faced with these profound changes in patient management, intensivists were caught off guard, forced by the density of work, the lack of immediately available beds and the possibilities of transferring patients to make painfully experienced choices that were contrary to their basic ethical principles and source of immediate burden [ ] [ ] [ ] . the aim of this paper is to focus on and to discuss the main ethical concerns raised during the pandemic, especially with regard to icus. since there are differences between health organizations in different countries around the world, ethical perception may vary according to legal or societal specificities. however, even though our thinking was based on french management of the crisis, similar approaches were assessed in other countries, especially in europe and ethical questioning is commonly shared by intensivists throughout the world. the massive influx of patients raised questions on the eventual modification of our admission criteria to the detriment of the most vulnerable populations. the decision to refuse admission of a severely ill patient to an icu is a regular part of the intensivist's work. guidelines have been drawn up to guarantee fairness, avoid unreasonable obstinacy and ensure respect for the patient's wishes and transparency with families [ ] . theoretically, even during an epidemic icu patient admission decision-making should be identical to that of a routinely applied decision-making method. however, the number of requests for admission made at a time of extreme scarcity of icu beds dramatically increased. it has been shown that in case of shortage of icu beds, the criteria for patient selection are modified, patients being more frequently considered as necessitating mainly palliative comfort care [ , ] . it is also necessary to underline the increased risk of mortality for patients who cannot be admitted to icu due to lack of beds, whatever the secondary course adopted: delayed admission, transfer to another distant unit or admission to a less specialized unit [ ] . faced with a massive influx of patients and extreme scarcity of icu beds, the theoretical risk of "sacrificing the most vulnerable patients" shakes our ethical convictions. herein, a triage plan with ethical justifications (table ) has been proposed to maximize benefit for the greatest number of people [ , , , ] . were the plan to be applied, utilitarian ethics would take precedence over individual ethics and employ the means least restrictive to individual liberty in view of accomplishing the public health goal. in other words, an unprecedentedly dramatic experience has taken place in which, due to compressed temporality, exacerbated emotional factors and massive influx of patients, a choice in the sorting cursor is made to the detriment of a reasoned strategy. such a situation is likely to contradict our caregiving-based ethical values [ ] . indeed, in addition to the elements linked to the lack of available beds, several factors in the decisionmaking process were sources of concern: reduction of the minimum time necessary to make such occasionally "life-or-death" decisions, decrease due to containment measures in the essential time to be spent with relatives and pressure from the continuous flow of arriving icu patients. in parallel with war medicine or disaster situations, prioritization strategies have been proposed [ , ] . although such prioritization is not supposed to be opposed to the ethical issues of icu access, in a specific epidemic situation this approach is nevertheless in conflict with our principles insofar as it allows utilitarian ethics to take precedence over ethics based on personhood. in this strategy, doing the greatest good for the greatest number may be inadequate insofar as it ignores other ethically relevant considerations. among the ethical principles ( table ) , prediction of number of years to live is posited as the priority selection criterion, which means that the youngest individuals should receive priority, thereby applying the life-cycle principle in allocation decisions [ ] . however, this appears to be only the least bad of existing or proposed justifications. decision trees have been proposed and simplified specific criteria have been requested, so to shorten the previously implemented regulatory period; this is in contradiction with a recommended practice, which privileges clinical contact with the patient. a simple score integrating the sofa score and the estimate of a probability of death at or years has been used, leading to the creation of a three-grade priority standard [ , ] . although numerous studies have demonstrated the relevance of such scores on an overall population scale, their lack of sensitivity or specificity at the individual level has been repeatedly underlined [ ] [ ] [ ] . indeed, the crude auroc for sofa score predicting in-hospital mortality is only . , leaving one out every four patients with an inappropriate decision [ ] . similarly, the ability to predict a given patient's life expectancy or risk of mortality at or years is generally poor. when applied, such first come, first served lottery strategies must assume "mistake of prophecy" and the eventual sacrifice of wrongly predicted patients. similarly, age becomes a potentially easy operational cursor, which we do not know how to place rationally [ ] . however, whatever the angle of attack, we can only make our choices using ethically flawed approaches. thus, shared recommendations including an admission decision-making checklist incorporating frailty score, comorbidities and, quality of life evaluation (table ) , have been developed and published on covid-crisis websites [ , ] helping intensivists to make such decisions. to conclude, rather than promoting unrefined and imprecise outcome prediction, a pragmatic multimodal approach taking into account frailty score and, comorbidity indices while leaving room for physician judgment should be considered as the best possible [ ] . as another application of the societal concept, it has been proposed to prioritize for icu care the caregivers who have become critically ill, not due to their intrinsic quality or for so as to "reward" them, but rather for the possibility, once they are cured, of being returning to the operational caregiving circuit [ ] . this raises at least two issues: first, the illusion of a rapid return to the caregiver circuit after resuscitation care for a severe form of the disease [ ] , and second, the choice of target actors for such prioritization. this appears to be an insoluble brain teaser: why not prioritize other societal actors who may favor the fight against pandemic such as researchers or other professionals helping to maintain the balance of our society in times of acute crisis? and with respect to the ethical principle of distributive justice, how is one to say that one life is worth more than another? moreover, utilitarian theories of emergency icu bed allocation have been criticized in the theoretical literature, especially on the ground of inequity in application of criteria that may disadvantage existing vulnerable populations [ ] . one solution to overcome the shortage of icu beds during a pandemic is to quickly set up new icus. this requires available rooms in the hospital or the rapid construction of new units, as has been done in china. this option effectively increased the number of icu beds by almost % in several countries and facilitated on-the-spot admission of large number of patients requiring mechanical ventilation. it was rendered possible by the dedication of volunteer health care workers (hcws) having agreed to work in a new and singularly stressful environment. however, this option has been associated with a significant risk of reduced quality of care for several reasons associated with the difficulties in meeting nationwide standards for critical care facilities in this type of emergency context. first, rooms converted from intermediate care units or post-operative recovery rooms are not adequately designed for the all the equipment and organization required in critical care. second, volunteer hcws recruited to work in icus may not adequately be trained for specific and sophisticated icu work despite the hastily improvised teaching sessions or "crash courses" organized to help them learn. along with the risk of decreased skill level, insufficient training of these hcws increases the burden of work [ ] . third, in the context of a pandemic, highly sophisticated devices, especially ventilators, are frequently lacking. this leads to use of inappropriate devices for the complex care of severe ards patients. to sum up, while the possibility of quickly setting up "neo-icus" permits admission of a large number of very severe critically ill patients, it also entail a possible risk of downgraded quality level of care and subsequent impaired prognosis, as shown in other situations [ , ] . additionally, this type of organization may imply distributive inequality, with access to icu facilities of heterogeneous efficiency and with a selection criterion recording in the patient's medical file that would be close to first come-first served, which could become first come-best served. epidemic intensity and icu bed availability were reported to vary strongly across countries and also within regions in a single country. to mitigate these "geographic" inequalities, patient transfers from regions with dramatic shortages of icu beds to areas less affected by the outbreak and with a large amount of available icu beds along with including optimal material and icu staff, have been implemented. these transfers require aircrafts, helicopters or trains that have been sophistically adapted to the care of critically ill patients and necessitate the involvement of a large number of dedicated physicians and nurses to ensure adequate organization and optimal patient safety. notwithstanding its complexity, in order to be efficient this transfer strategy should be organized within a short period of time and should allow the transfer of a significant number of patients. it is associated with increased costs that should not be charged to the patient or his or her relatives. the first ethical issue surrounding such transfers is related to the benefit/risk balance. for the patient, the benefit of being in the hands of highly qualified teams is counterbalanced by the risk of clinical worsening during transfer. during patient selection, close attention should be paid to severity status: not too severe (transfer would be too risky), and not too well (to avoid unnecessary transfer). while informed patient consent should theoretically be part of the decision, most of the transferred patients were unconscious and unable to approve such a transfer, thereby ruling out the autonomy principle. informed consent was consequently obtained from their next of kin (patients whose next of kin refused were not transferred). a second ethical issue concerns the icu departments accepting patients from a distant region and possibly aggravating the risk of a suddenly increased epidemic wave in their own area. indeed, covid pandemic experience has shown that we did not have efficient predictive tools to precisely anticipate the kinetics of icu bed requirements. finally, such transfers may be associated with increased suffering and psychological trauma for the relatives. indeed, long distance and limitation of travels for epidemic control will strongly impede if not altogether rule out the presence of relatives at the patient's bedside and prevent adequate communication between them. this could exacerbate pain for the families, especially if specific communications are not developed (see below). it has been proposed to relieve the icu teams in charge of patient care of the responsibility of admission or nonadmission decisions and to entrust this work to a dedicated triage team headed by a triage officer [ , ] . the advantage of this approach is that it relieves the healthcare team of the emotional impact of a potentially painful ethical dilemma [ ] . however, the composition of these triage teams must be specified. mentions of volunteers, leaders recognized by their peers and by the medical community have been put forward [ ] . it should no doubt be specified that the triage leaders will be intensivists recognized for their ethical sensitivity, and an overly "military" strategy should be scrupulously avoided [ ] . if not, the potentially protective role of independent triage teams can be a source of additional injury for caregivers, disappointed with their patient's unfavorable outcome and even blamed for an unshared therapeutic cessation decision or dehumanization of care [ ] . it has been suggested that patient severity assessments be intensified during their progress in icu stay, so that the withdrawal of one patient's mechanical ventilation can benefit another patient [ ] . in this way, withdrawal of artificial ventilation might be decided when the improvement is not fast enough, while hopes of survival may persist. similarly to the triage team, it has been proposed to use triage committee to buffer clinician from potential harm [ , ] . again, the risk of ethical drift must be emphasized. despite an influx of patients and lack of beds, it does not seem ethically acceptable to lose a chance for patients for whom treatment does not seem to be unreasonable obstinacy. moreover, the appreciable time taken to make these decisions is an element that risks being called into question during an epidemic emergency. finally, under the pretext of risk of contamination and need for confinement, exchanges with relatives to share final decisions could be reduced if not eliminated, a factor entering once again into contradiction with basic ethical concepts. it must be admitted that in a crisis situation with an unprecedented influx of patients in icu, no single strategy fully corresponds to our ethical values. whatever the approach adopted, imbalance between societal and individual ethics leads to unsolvable discomforts that caregivers will have to overcome. in other words intensivists would have to consider their own tension between utilitarianism (making icu beds available rapidly, potentially sacrificing patients without rapid improvement for new admissions) and virtue (accept to prolong icu stay for an icu patient even if there is no bed available to admit another patient) ethics. fortunately, the formalized strategies of ethical reflection associated with decision-making for withdrawal of life support therapies have long since been part and parcel of routine practice, leaving the ultimate choice of decision up to the intensivist. the heterogeneity in eol-decision-making is probably huge across hospitals and icu. postponed decision-making or even paralysis at eol may have created excess in mortality due to shortage of icu beds. nevertheless, confidence should be given to icu teams to manage the eventual withdrawal of life support decision through a bedside decision-making process taking into account the exceptional difficulties linked to the epidemic situation. since discrepancies may exist between experts' ethical recommendations and public perception, general public opinion has been investigated based on the basis of deliberative democracy [ , ] . a -participant panel placed in a simulated context of a severe influenza pandemic favored ethical principles of saving the most lives (surviving current illness) and saving the most life-years (living longer) over a first come first serve scenario [ ] . however, a significant number of participants were opposed to the idea of ventilator reallocation [ ] . in this study, subgroup differences associated with age or ethnicity of the participants were pointed out [ ] . in another survey, the pragmatic constraints imposed by an assumption of extreme scarcity were not accepted by the canadian participants, who expressed difficulties in making priority-setting decisions because these were perceived as psychologically burdensome, no-win situations [ ] . transparent communication is also important during such a crisis so as to allow public opinion to be able to better understand place the decisions of icu teams. the covid- epidemic is a threat to family-centered care in icus. during the st weeks of the epidemic, visits were prohibited to ensure that relatives did not contaminate other family members, patients, or healthcare professionals. family members could no longer be at the patient's bedside and the icu team was unable to propose structured communication and support to family members. involvement in decision-making was compromised, and it was felt that this situation was harmful both for patients and family members. indeed, over the last decade, research has shown that post-icu syndrome (pics-f) [ ] in family members is a cause of major concern. the major risk factors for pics-f are poor communication with an icu team, being in a decision-making role, low educational level, and having a loved one who died or was close to death. indeed, many studies have shown that communication with caregivers is one of the most highly valued aspects of care and that impacts-on family members' experience during and after the patient's stay, including in the aftermath of the patient's death [ , ] . communication perceived as inconsistent, unsatisfactory or uncomforting is associated with higher risk of post-icu burden [ ] . risk of ptsd-related symptoms increases when relatives, both non-bereaved and bereaved, feel that the information given is incomplete [ ] . after death in the icu, bereaved family members are at high risk of presenting symptoms that negatively affect their quality of life, such as anxiety, depression, ptsd symptoms [ , ] and complicated grief [ ] . interestingly, family members who witness a relative of theirs suffering from dyspnea are at higher risk of developing ptsd-related symptoms and those who are not able to say goodbye to relative of theirs are at higher risk of developing complicated grief symptoms [ ] . in the context of the covid- pandemic, risk factors for developing post-icu burden are numerous, thereby increasing exposure to anxiety, depression, ptsd and complicated grief. as said in the new york times, "of all the ways the coronavirus pandemic has undermined the conventions of normal life, perhaps none is as cruel as the separation of seriously ill patients and their loved ones, now mandated at hospitals around the world" [ ] . faced with these various difficulties and risks, recommendations have been published regarding communication with family members in this specific context. first, patients and family members should receive clear explanations, both directly (over the phone or when present) and on institutional websites, concerning the imposed restrictive policies: it is important that they understand why they cannot visit their loved one [ ] . in other words, the restriction must have meaning. second, icu teams are encouraged to proactively schedule routine telephone calls with family members to maintain continuity of communication [ ] . the calls must follow a plan so that family members know when to expect contact. the phone calls will not only address the patient's health status, but also provide reassurance regarding comfort and dignity [ ] . conversations are important to help the icu team better understand the patient as a person (values, advance directives, etc.) and to help family members think about possible difficult decisions. in this context, goal-concordant care is particularly important and icu teams must strive to avoid intensive life-sustaining treatments that would be unwanted by patients [ ] . on a parallel track, strategies to reinforce communication between the patient and the family have been developed. icu teams should encourage patient and family to call, text, and videoconference with each other as often as wanted [ ] . they may also help the patient and family members record and send audios, videos, or written messages to one another. if the patient is unconscious, the icu team can print written messages or family photos and stick them in a diary that can then be given to the patient. staying in touch is vital, both for the patient and for the family members. moreover, many icu teams have made visitation policies more flexible. these units have adapted themselves to the influx of patients while respecting a predetermined protocol. the visitor must have a dedicated time appointment and wait in a room where he/she may not meet other visitors. instructions on hygiene are given by the nurses. psychological support for each visit and followup calls by the icu psychologist are also recommended. visiting a loved one in intensive care is very upsetting in the best of times, but when in addition one has been separated for days, perhaps weeks, there is also all the emotional pressure of a long-awaited reunion. in end-of-life (eol) situations, the icu team must avoid depriving family members of the opportunity to say goodbye to the patient [ ] . if visitation is usually forbidden in the icu, it should be made possible in an eol situation. if the family cannot or does not want to come to the icu, letting him/her speak to the patient one last time over the phone is important. family members need to prepare for bereavement, meaning they must understand what is happening: end-of-life family conferences should be organized, remotely if needed [ ] . honest conversations are important, as helping family members prepare for death is an important part of anticipatory grief [ ] . not being prepared is associated with increased risk of complicated grief. when possible, respecting the family's wishes is particularly important in a context where the grief process may be more complex as families are unable to see their loved one's body, to physically share their emotions with other relatives and, sometimes even to attend their loved one's burial. in the current pandemic, sources of psychological disorders for hcws are multiple. they are affected by distress similar to than the general population regarding the effects of lockdown and containment, the risk of personal or families' and friends' illnesses, the uncertainty about pandemic duration and, the lack of effective specific treatment. this dearth of knowledge has given rise to a great deal of contradictory information that has forced health care professionals to constantly readapt and to cope with the experience of powerlessness and personal ineffectiveness [ , ] , and they also experience "front line" specific factors [ ] . the factors include extended workloads, feelings of powerlessness when trying to contain the large number of patients, concerns about the suffering and potential poor outcomes of their patients, preoccupations about potential shortages of intensive care resources (including personal protective equipment), the fear of transmitting the disease to their loved ones, and apprehension about possible involvement in ethically difficult resource allocation decision-making. this situation has created a high level of uncertainty and insecurity that constitutes a risk to the mental health of caregivers [ , ] . to date a few studies have reported a quantification of symptoms amongst hcws. all of them have shown an increase in psychological disorders compared with different control groups providing no direct care to patients: [ , [ ] [ ] [ ] ] . fear was more frequent than anxiety and depression with incidences varying from , , % to , , %, respectively [ , ] . assessments by other scales confirmed two-thirds of mental health disorders, especially in young women [ ] . sleep disorders were also reported [ ] . in some countries, e.g., in italy or in france, healthcare workers are applauded by the population each evening at pm. societal reward and "glorification" [ ] of the caring function appears to be a protective factor in the short term [ ] and in his first address to the nation, the president of france, emmanuel macron, called healthcare workers "the heroes with a white coat". it may be dangerous for healthcare workers to fall into this trap. altruism has long since been recognized as a core value of this profession. moreover, a hero must keep silence about his feelings, a factor which is known to favor burnout [ ] . insecurity and uncertainty are reflected not only at an individual level, but also at a collective level. the covid- epidemic requires reinforcement of the icu teams with new staff members or even reorganization of the unit, weakening the reference points and trust within the team. this context creates a feeling of vulnerability and loss of control for professionals [ , ] . a lack of interaction between caregivers and families induces a feeling of exclusion and even a significant emotional burden when patients die, highlighted in certain cases by a feeling of guilt [ ] . psychological support has been set up for caregivers, as many hospitals have initiated telephone hotlines, psychologists within units, relaxation sessions, meditation, discussion groups, and optimization techniques. these responses should ideally vary according to the phase of the pandemic [ ] . at the early phase, the best way to prevent psychological disorders is to acknowledge staffers' work by providing adequate human resources and material supplies [ ] . both frequency and transparency in hospital communication likewise play a key role [ , ] . concrete measures to set up rest areas, to facilitate the logistics of meals, daily life, and the possibility of having leisure and relaxation time are optimally appropriate to the needs of the caregivers during the crisis. at this stage, this type of collective support could be more effective than individual support. however, individual assessment of mental health may later become relevant. in a study in wuhan, the most valued psychological resources consisted in social media ( %) and psychological guidance books ( %) [ ] . requests for therapist-driven video calls or consultations were less frequent ( %) and rose the question of their availability, given the large number of affected hcws [ ] . similarly, a form of reluctancy, or even an absence of solicitation of the listening units in times of health crisis has been reported [ , ] . to overcome the covid- pandemic, in many places throughout the world, new resources were developed in a short period of time, dramatically increasing the number of icu beds allowing admission of a huge number of critically ill patients. the massive patient influx highlighted numerous ethical concerns that icu caregivers are likely to face. some models have proposed ethical justifications to difficult decision-making, usually based on deontological (or societal) rather than individual ethics. we wished to draw attention to the risk of taking refuge behind ethical alibis notwithstanding the fact that the specific pandemic context there is no single satisfactory solution. in such a situation each option is associated with its own strengths and weaknesses, and intensivists should make their choices in full awareness of intractable ethical dilemmas. in many circumstances, caregivers have no choice but to adopt less than perfect solutions even though the price to be paid consists in undermining patients' , relatives' and caregivers' psychological wellbeing. lessons should be learnt from this experience and ethical reflections should be developed in order to anticipate a potential new pandemic in the close or more distant future. abbreviations eol: end-of-life; hcws: healthcare workers; icu: intensive care unit. guidelines for family-centered care in the neonatal, pediatric, and adult icu a coronavirus cautionary tale from italy: don't do what we did a framework for rationing ventilators and critical care beds during the covid- pandemic triage of scarce critical care resources in covid- an implementation guide for regional allocation factors associated with mental health outcomes among health care workers exposed to coronavirus disease recommendations for end-of-life care in the intensive care unit: a consensus statement by the american college [corrected] of critical care medicine intensive care unit bed availability and outcomes for hospitalized patients with sudden clinical deterioration influence of icu-bed availability on icu admission decisions refusal of intensive care unit admission due to a full unit: impact on mortality surge capacity logistics: care of the critically ill and injured during pandemics and disasters: chest consensus statement fair allocation of scarce medical resources in the time of covid- allocating medical resources in the time of covid- scarce resource allocation during disasters priorisation des traitements de réanimation pour les patients en état critique en situation d'épidémie de covid- avec capacités limitées. société française d' anesthésie réanimation, service de santé des armées too many patients…a framework to guide statewide allocation of scarce mechanical ventilation during disasters understanding articles describing clinical prediction tools. evidence based medicine in critical care group predicting death and readmission after intensive care discharge the proliferation of reports on clinical scoring systems: issues about uptake and clinical utility prognostic accuracy of the sofa score, sirs criteria, and qsofa score for in-hospital mortality among adults with suspected infection admitted to the intensive care unit effect of systematic intensive care unit triage on long-term mortality among critically ill elderly patients in france: a randomized clinical trial décision d'admission des patients en unités de réanimation et unités de soins critiques dans un contexte d'épidémie à covid- clinical ethics recommendations for the allocations of intensive care treatments, in exceptional, resource-limited circumstances long-term outcome after the acute respiratory distress syndrome: different from general critical illness? priority setting of icu resources in an influenza pandemic: a qualitative study of the canadian public's perspectives prepared to respond? exploring personal disaster preparedness and nursing staff response to disasters physician staffing patterns and clinical outcomes in critically ill patients: a systematic review esicm working group on quality improvement, valentin a, ferdinande p. recommendations on basic requirements for intensive care units: structural and organizational aspects the toughest triage-allocating ventilators in a pandemic ventilator triage policies during the covid- pandemic at u.s. hospitals associated with members of the association of bioethics program directors emotional impact of end-of-life decisions on professional relationships in the icu: an obstacle to collegiality? post-intensive care syndrome: an overview in their own words: patients and families define high-quality palliative care in the intensive care unit improving comfort and communication in the icu: a practical new tool for palliative care performance measurement and feedback. qual saf health care family response to critical illness: postintensive care syndrome-family risk of post-traumatic stress symptoms in family members of intensive care unit patients predictors of symptoms of posttraumatic stress and depression in family members after patient death in the icu complicated grief after death of a relative in the intensive care unit family-centered care during the covid- era a -point strategy for improved connection with relatives of critically ill patients with covid- covid-ready communication skills: a playbook of vitaltalk tips the importance of addressing advance care planning and decisions about do-not-resuscitate orders during novel coronavirus (covid- ) not dying alonemodern compassionate care in the covid- pandemic grief during the covid- pandemic: considerations for palliative care providers les professionnels de santé face à la pandémie de la maladie à coronavirus (covid- ): quels risques pour leur santé mentale? l'encéphale a study on the psychological needs of nurses caring for patients with coronavirus disease from the perspective of the existence, relatedness, and growth theory clinician wellness during the covid- pandemic: extraordinary times and unusual challenges for the allergist/immunologist mental health care for medical staff in china during the covid- outbreak psychological impact of the covid- pandemic on health care workers in singapore psychological status of medical workforce during the covid- pandemic: a cross-sectional study online mental health services in china during the covid- outbreak impact on mental health and perceptions of psychological care among medical and nursing staff in wuhan during the novel coronavirus disease outbreak: a crosssectional study social capital and sleep quality in individuals who self-isolated for days during the coronavirus disease (covid- ) outbreak in january in china on behalf of the entire editorial and publishing staff of jama and the jama network. health care heroes of the covid- pandemic an official critical care societies collaborative statement-burnout syndrome in critical care health-care professionals hospital preparedness and sars immediate and sustained psychological impact of an emerging infectious disease outbreak on health care workers timely mental health care for the novel coronavirus outbreak is urgently needed annals for hospitalists inpatient notes-preparing for battle: how hospitalists can manage the stress of covid- protecting healthcare workers during the coronavirus disease (covid- ) outbreak: lessons from taiwan's severe acute respiratory syndrome response publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors wish to thank jeffrey arsham for reviewing and editing the original english-language manuscript. authors' contributions rr: conception and design of the work. rr, nkb, ab, al, jr, ea: drafted the manuscript and revised it. all authors read and approved the final manuscript. not applicable. not applicable. not applicable. not applicable. the authors declare they have no conflict of interest. key: cord- -zp u l authors: quah, pipetius; li, andrew; phua, jason title: mortality rates of patients with covid- in the intensive care unit: a systematic review of the emerging literature date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: zp u l nan mortality rates of patients with covid- in the intensive care unit: a systematic review of the emerging literature pipetius quah * , andrew li and jason phua , the understanding of outcomes in the intensive care unit (icu) for the coronavirus disease (covid- ) remains poor. studies have reported close to % mortality amongst patients requiring mechanical ventilation [ ] , and this together with the hypothesis that covid- may not cause classic acute respiratory distress syndrome (ards) has led to concerns regarding the use of mechanical ventilation [ , ] . we thus aimed to review the outcomes of icu patients with covid- from the existing literature. we searched pubmed for studies published between dec , , and may , , with at least ten icu patients with covid- and reported icu mortality data. we excluded studies that had duplicate patients from other reports, did not provide data on icu survival, enrolled only decedents, and excluded patients who were still hospitalised ( fig. and electronic supplementary material). several lessons can be surmised from table , which outlines the included studies conducted largely in countries worst hit by the pandemic. first, . % of patients were still in the icu at the time of study publication, and attempts to calculate mortality based on a sample of only deceased or discharged patients risk painting a skewed picture of reality [ ] . second, with the prior limitation in mind, the overall icu mortality rate was . %. in china, with . % of patients still in the icu, the mortality rate was . %. these figures are not higher than the mortality rates of to % seen in ards. third, % of the icu patients who died in the chinese studies did not receive mechanical ventilation, and where systems experienced a surge of critically ill patients, up to . % of patients who required icu care were unable to receive it because of resource constraints [ ] . in new york, deaths occurred in hospital wards and outside the icu, compared to deaths in the icu [ ] . we hypothesise that rationing of ventilators and icu beds in overwhelmed health systems may have resulted in attempts at postponing intubation, with a significant minority of patients received high-flow nasal cannula ( . %) and noninvasive ventilation ( . %) based on available data, despite uncertainty surrounding their roles. we conclude that while there is a need for further studies which capture patients' final dispositions, the current preliminary data does not suggest unusually high icu mortality rates for covid- . the poor outcomes seen in various studies may be related to rationing of resources in overwhelmed icus. clinical course and outcomes of intensive care patients with covid- covid- pneumonia: different respiratory treatments for different phenotypes? intensive care med acute respiratory failure in covid- : is it "typical presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area hospitalization and critical care of decedents with covid- pneumonia in wuhan, china publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable.author details division of respiratory and critical care medicine, department of medicine, national university hospital, national university health system, singapore, singapore. fast and chronic programmes, alexandra hospital, national university health system, singapore, singapore.received: may accepted: may additional file . electronic supplementary material. all authors did the literature search. pq and al reviewed the articles and drafted the manuscript, which jp edited and supervised. all authors subsequently revised the manuscript. the author(s) read and approved the final manuscript. this review was not funded by any organisation. the datasets generated during and/or analysed during the current study are available in the pubmed repository. the full list of included studies is available in the electronic supplementary data (appendix). no ethics approval and no patient consent were required for this study. not applicable. all authors declare no competing interests. key: cord- -n ogyxz authors: ip, andrew; berry, donald a.; hansen, eric; goy, andre h.; pecora, andrew l.; sinclaire, brittany a.; bednarz, urszula; marafelias, michael; berry, scott m.; berry, nicholas s.; mathura, shivam; sawczuk, ihor s.; biran, noa; go, ronaldo c.; sperber, steven; piwoz, julia a.; balani, bindu; cicogna, cristina; sebti, rani; zuckerman, jerry; rose, keith m.; tank, lisa; jacobs, laurie g.; korcak, jason; timmapuri, sarah l.; underwood, joseph p.; sugalski, gregory; barsky, carol; varga, daniel w.; asif, arif; landolfi, joseph c.; goldberg, stuart l. title: hydroxychloroquine and tocilizumab therapy in covid- patients—an observational study date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: n ogyxz hydroxychloroquine has been touted as a potential covid- treatment. tocilizumab, an inhibitor of il- , has also been proposed as a treatment of critically ill patients. in this retrospective observational cohort study drawn from electronic health records we sought to describe the association between mortality and hydroxychloroquine or tocilizumab therapy among hospitalized covid- patients. patients were hospitalized at a -hospital network spanning new jersey usa between march , and april , with positive polymerase chain reaction results for sars-cov- . follow up was through may , . among hospitalized patients with covid- there have been deaths ( %), ( %) discharges and ( %) remain hospitalized. ( %) received at least one dose of hydroxychloroquine and ( %) received hydroxychloroquine with azithromycin. after adjusting for imbalances via propensity modeling, compared to receiving neither drug, there were no significant differences in associated mortality for patients receiving any hydroxychloroquine during the hospitalization (hr, . [ % ci, . – . ]), hydroxychloroquine alone (hr, . [ % ci, . – . ]), or hydroxychloroquine with azithromycin (hr, . [ % ci, . – . ]). the -day unadjusted mortality for patients receiving hydroxychloroquine alone, azithromycin alone, the combination or neither drug was %, %, %, and %, respectively. among evaluable icu patients, including receiving tocilizumab in the icu, an exploratory analysis found a trend towards an improved survival association with tocilizumab treatment (adjusted hr, . [ % ci, . – . ]), with day unadjusted mortality with and without tocilizumab of % versus %. this observational cohort study suggests hydroxychloroquine, either alone or in combination with azithromycin, was not associated with a survival benefit among hospitalized covid- patients. tocilizumab demonstrated a trend association towards reduced mortality among icu patients. our findings are limited to hospitalized patients and must be interpreted with caution while awaiting results of randomized trials. trial registration: clinicaltrials.gov identifier: nct a a a a a the global pandemic caused by a novel coronavirus [severe acute respiratory syndrome (sars)-cov- ] and its disease, covid- , has led to infection in over . million individuals and more than , deaths as of july , [ , ] . as there are no approved treatments, management of covid- is largely supportive [ , ] . one empirical treatment for covid- which has received attention is hydroxychloroquine, an antimalarial drug repurposed in recognition of its anti-inflammatory properties in the treatment of autoimmune conditions. hydroxychloroquine and its analogue, chloroquine, demonstrate suppression of sars-cov- replication in vitro, with hydroxychloroquine demonstrating greater potency [ , ] . studies from the original sars-cov virus suggest a mechanism of action involving impairment of the terminal glycosylation of angiotensin converting enzyme (ace ), inhibition of sars-cov viral entry, and rapid elevation of endosomal ph that prevents endosome-mediated viral entry [ ] [ ] [ ] [ ] . the immunomodulatory effects are thought to be due to the accumulation of the drug in lymphocytes and macrophages leading to reduction of proinflammatory cytokines, including type i interferons, tumor necrosis factor alpha, and interleukin- [ ] . other anti-inflammatory effects may be related to inhibition of signaling pathways [ ] . several early small clinical reports have shown conflicting evidence regarding the efficacy of hydroxychloroquine in covid- [ , ] . subsequently, an observational cohort study of hospitalized patients from a new york hospital using propensity modeling found no significant association between hydroxychloroquine use and intubation or death (hazard ratio, . , % confidence interval, . to . ) [ ] . a second observational cohort study of hospitalized patients throughout the new york metropolitan region also found a lack of survival association with hydroxychloroquine with or without concomitant azithromycin (hr . and . respectively) [ ] . a recently reported randomized brazilian trial enrolling hospitalized sars-cov- confirmed patients with mild-to-moderate disease (defined as not requiring significant supplemental oxygen support) found that a -day course of hydroxychloroquine either with azithromycin or alone did not result in better clinical outcomes as measured by a seven-level ordinal scale at days [ ] . as the clinical course of covid- progresses, patients enter a hyperinflammatory phase with dysregulation of adaptive immune responses and a cytokine storm with elevation in plasma levels of pro-inflammatory cytokines including interleukins (il) , , , and , granulocyte-colony stimulating factor (g-csf), interferon-gamma-inducible protein- (ifngamma, il- ), and tumor necrosis factor alpha (tnf-alpha). this cytokine storm results in a pro-thrombotic milieu, cardiomyopathy, and ultimately multi-organ failure [ , ] . tocilizumab, a monoclonal antibody against membrane bound il- receptor inhibiting binding of soluble il- and subsequent signal transduction, has been proposed as a therapeutic candidate for impeding cytokine storm [ ] . small single institution series have suggested benefit among severely ill patients [ , ] . preliminary results from a press release for the french corimu-no-toci trial (nct ), an open-label randomized trial of hospitalized patients with covid- (n = ), noted a reduction in the proportion of participants who died or needed we have included in the supporting information the statistical output that may assist interested readers in understanding the data more fully and could be utilized to assist in independent confirmation. ventilation in the tocilizumab group, although full results of the trial have not yet been released [ ] . an italian observational study involving covid- patients (with % requiring mechanical ventilator support) reported that tocilizumab treatment was associated with a reduced risk of subsequent invasive mechanical ventilation or death [ ] . a michigan usa observational study also noted an associated reduction in mortality among intubated covid- patients [ ] . in the absence of rcts, observational studies may provide useful early insights into effective treatment strategies [ , ] . however in an observational study, treatment allocations are based upon physician judgement, rather than random assignment, increasing the risk of bias and not accounting for known and unknown risk factors. thus, causal inferences on effectiveness of treatments are challenging, but confounding effects can be partially mitigated via statistical methods [ , ] . understanding these limitations, but with the urgency for evaluating potential therapeutic approaches during the current covid- pandemic, we established an observational database within a -hospital network spanning new jersey using an integrated electronic health record (ehr) system (epic; verona, wi). in this observational cohort study we report our survival outcomes with hydroxychloroquine and tocilizumab among hospitalized patients with covid- . this retrospective, observational, multicenter cohort within the hackensack meridian health network (hmh) used ehr-derived data to study hospitalized covid- patient outcomes. our primary objective was to analyze the effect of hydroxychloroquine in hospitalized patients. a secondary, exploratory objective was to investigate the effect of tocilizumab in the icu population. patients were included in the database based on the following inclusion and exclusion criteria: ) positive sars-cov- diagnosis by reverse-transcriptase polymerase chain reaction, ) hospitalized within the time frame of march , until may , , ) non-pregnant, ) not on a randomized clinical trial, and ) did not die during first day of hospitalization, and ) were not discharged to home within hours (fig ) . hackensack meridian health institutional review board approved this study on march , under study # pro - . waiver of consent and hipaa authorization was granted as this retrospective research was a non-interventional protocol utilizing electronic health records to abstract data. no patients were contacted for this study. protected health information was not made available except to investigators. de-identified information was provided to statisticians. the study period was march , until may , . we collected data from hmh's ehr (epic) which is utilized throughout the network. hospitalized patients throughout hmh were flagged by the ehr if sars-cov- testing was positive. these ehr-generated reports served as our eligible cohort to sample. demographic, clinical characteristics, treatments, and outcomes were manually abstracted by research nurses and physicians from the john theurer cancer center at hackensack university medical center. assigning patients to our data team occurred in real-time, and not randomized. to reduce sampling bias, we abstracted of the ( %) possible hospitalized patients by april , (with follow up until may , ), and performed stratification as discussed in our analytic approach. data abstracted by the team was entered using redcap (research electronic data capture) hosted at hmh [ , ] . data abstraction occurred daily from march , until may , . quality control was performed by physicians (ai, slg) overseeing nurse or physician abstraction. demographic information was collected by an electronic face sheet, with gender, race or ethnicity self-reported. academic centers were defined as quaternary referral centers with accredited residency, fellowship, and medical student programs. nursing home or rehabilitation patients, if diagnosed prior to hospital admission, were defined as ambulatory patients. comorbidities were defined as diagnosed prior to hospitalized for covid- . history of hypertension, diabetes, chronic lung disease (copd or asthma), hypertension, cancer, coronary artery disease, cerebrovascular disease, renal failure, and rheumatologic disorder were abstracted from provider notes or medical history sections found within the ehr. if not listed in the patient's record, the comorbidity was recorded as absent. presenting clinical data was abstracted from thorough review of unstructured notes as well as structured data. hospital readmissions were counted as the same admission, with baseline data used from the initial hospitalization. if multiple positive or indeterminate results were found in a patient's record for sars-cov- , the first initial positive test was used as the date of diagnosis. for the effect of hydroxychloroquine, we separated patients into different groups- ) hydroxychloroquine, ) hydroxychloroquine in combination with azithromycin, ) azithromycin alone, and ) neither drug. exposure to hydroxychloroquine or azithromycin was defined as documentation of drug administration in the ehr. dosing, duration, and timing in relation to symptom onset and admission were also collected. if no evidence of administration of drug was found, this was recorded as not having received the drug. for tocilizumab, exposure was defined as receipt of the drug within the icu setting as found in the ehr. if no date of administration was found, this was labeled as insufficient missing data for analysis. if no evidence of administration of the drug was found, this was recorded as not having received the drug. the primary outcome measurement was death with follow-up through may , . mortality was identified on chart review by a provider note announcing time of death or if the ehr labeled the patient as deceased. as death certificates were not readily available, cause of death was identified using the ehr by identifying the most immediate cause(s) documented [ ] . respiratory cause of death included any hypoxic condition related to covid- . cardiac cause of death included cardiac arrest, myocardial infarction, or arrhythmias. infectious cause of death included bacterial sepsis or secondary infections not including covid- . other cause of death included multi-organ failure as well as alternative causes. follow-up occurred until the study cut-off date of may . adverse drug events related to hydroxychloroquine were also described, including discontinuation due to arrhythmia or qt prolongation. this was obtained by provider documentation as well as ekg reports within the ehr. the statistical plan is available in the (s appendix). descriptive analyses of baseline characteristics by hydroxychloroquine exposure were performed using chi-square tests for categorical variables. dose, frequency, timing, and duration of treatment were also summarized. we used propensity-score stratification for the remaining statistical analyses [ , ]. we fit a logistic regression model to the probability of being assigned to the experimental arm (tocilizumab, hydroxychloroquine, or hydroxychloroquine plus azithromycin) compared with the control population (not assigned to the respective treatment). patients are stratified into propensity-score quintiles and these strata are used to adjust treatment effects in a proportional hazards model. the model for selecting factors to be included in propensity scores was a two-stage backward selection approach. we evaluated each of the factors as univariate predictors with factors having p-value less than . included for further consideration. we removed factors sequentially and one at a time from the multivariate model if their p-values were less than . , with largest p-values considered first. we fit the final propensity-scores model using multivariate logistic regression of the selected factors. we then stratified the propensity scores for the entire population into quintiles and used these quintiles as an ordinal ( -degree-of-freedom) variable to adjust the relative treatment comparison in a proportional hazards model (see s appendix, for output). we evaluated the following factors for all propensity-score models: gender, coronary disease, stroke, heart failure, arrhythmia, african american, copd, renal failure, rheumatologic disorder, inflammatory bowel disease, advanced liver disease, age, diabetes mellitus, insulin use prior to hospitalization, asthma, hiv/hepatitis, any cancer, and log ferritin. the final propensity-score model for hydroxychloroquine included the first of these factors. that for hydroxychloroquine plus azithromycin included the first of these factors plus cancer. that for tocilizumab included age, gender, copd, and renal failure. tocilizumab was assigned preferentially for patients in the icu. tocilizumab patients included in our analyses received their first dose of the drug in the icu. control patients were those who were admitted to the icu and who never received tocilizumab either before or after admission to the icu. the start time for analysis was the day of admission to the icu. hydroxychloroquine and hydroxychloroquine plus azithromycin were evaluated from day of hospital admission, whether initially in the icu or not. the control population consisted of patients who never received the respective treatment. we also sought to address the factorial nature of treatment with combination hydroxychloroquine and azithromycin. propensity scores are based on predicting particular an individual therapy and so do not naturally generalize to a factorial setting. for these analyses we averaged the two propensity scores calculated separately for hydroxychloroquine and hydroxychloroquine plus azithromycin. we then stratified into propensity quintiles based on that average and proceeded as indicated above. the raw results of our proportional hazards analyses adjusting for propensity scores is provided (s appendix). patients still alive and in the hospital were censored as of may , . patients who had been discharged from the hospital were censored as of day following hospital admission. we provide hazard ratios of treatment in comparison with control together with corresponding p-values and confidence intervals based on wald tests. we show the unadjusted survival data using kaplan-meier plots from which we identify -day mortality for each treatment. statistical calculations used jmp pro . . . confidence intervals and p-values in this study are descriptive measures of distance between outcomes of treatment groups or distance from hazard ratio . . these measures do not have the same inferential interpretations that are possible for primary end point analyses of rcts. there were , patients flagged in our ehr with positive covid infection within the -hosptial network spanning new jersey, and data was abstracted on , ( %). hospitalized patients met inclusion criteria for this study (fig ) . as indicated in table , the median age of the cohort was years (iqr - ) with a male predominance ( %). nursing home and rehabilitation patients comprised % of the cohort. co-morbidities were common with % having hypertension, % obesity (bmi � ), % diabetes, % coronary arterial disease, % copd/asthma, % cancer, and % having or more chronic conditions. at the time of hospital presentation, fever was present in %, % with dyspnea, % with cough, % gastrointestinal complaints and % had altered mental status. the median time from self-reported onset of symptoms to hospitalization was days (iqr - ). ( %) patients required intensive care unit support during their hospitalization, of which patients were admitted to the icu within the first day. oxygen saturation below % was identified in %. when measured and recorded in the electronic health record, inflammatory markers were elevated with serum ferritin > ng/ml in % and d-dimer > mcg/ml in % of patients. in this non-randomized observational cohort hospitalized patients ( %) received at least one dose of hydroxychloroquine during the study timeframe ( % as single agent and % in combination with azithromycin) (fig ) . dosing and duration was at prescribers' discretion. the majority of patients received mg on day , and mg on day - ( %, n = ), followed by mg tid ( %, n = ) and other ( %, n = ), and missing dosing information ( %, n = ). median duration of hydroxychloroquine was days (iqr - ). the median days of symptoms before hydroxychloroquine administration was (iqr - ), and median days in hospital before first dose was (iqr - ). patients receiving hydroxychloroquine at any time during their hospitalization were younger, less likely to live in a nursing home, but presented later in their clinical course ( days vs days of symptoms prior to hospital admission) with more symptomatic disease (higher incidences of fever, cough, dyspnea, and lower oxygen saturation) ( table ) discontinuation of hydroxychloroquine due to prolongation of qtc or arrhythmias was recorded in the electronic health records in ( %) and ( %) patients. during the entire hospital course, arrhythmias were noted in ( %) hydroxychloroquine patients, compared to ( %) in the non-hydroxychloroquine cohort. cardiomyopathy was described in ( %) treated patients compared to ( %) patients without hydroxychloroquine. among hospitalized patients with covid- there have been deaths ( %), ( %) discharges and ( %) remain hospitalized as of the study cut-off date. in the entire cohort, causes of death included ( %) respiratory, ( %) cardiac, ( %) other, ( %) infectious, and ( %) other. within the hydroxychloroquine treated cohort, of ( %) of deaths were attributed to cardiac causes, compared to of ( %) deaths in the non-hydroxychloroquine cohort. as shown in table , using propensity modeling as described above, there was no significant association between survival and any use of hydroxychloroquine during the hospitalization ( azithromycin alone, the combination or neither drug was %, %, %, and %, respectively (fig ) . toci tocilizumab; hcq hydroxychloroquine; azi azithromycin. toci in icu includes all patients whose first dose of tocilizumab was in the icu or controls who were admitted to the icu and known to not have received tocilizumab during their hospital stay. "in hospital" includes all patients who received the drug at any time during their stay in the hospital. "main effect" is the estimated benefit of the drug whether added to the other drug or not. a drug given "only" means not with the other drug. -day mortality rates are estimated using the corresponding kaplan-meier survival curve at days ( see figs and ). ( %) patients received tocilizumab therapy during their hospitalization. table shows baseline characteristics. patients received their first dose prior to admission to the icu and patients had unknown timing or insufficient data. thus patients with documentation of their first dose of tocilizumab within an icu setting represented the exploratory treatment cohort. patients in the icu never received tocilizumab as of may , and serve as the control cohort. tocilizumab was administered as a single dose in ( %), with the majority receiving mg ( %), followed by mg ( %), mg/kg ( %), mg/kg ( %), and missing dosing ( %). secondary bacteremia occurred in of the ( %) patients in the non-treated group, compared to / ( %) in the treated group. secondary pneumonia occurred in of the ( %) patients in the non-treated group, compared to of the ( %) in the treated group. as shown in table , in the analysis using propensity modeling, there was a trend association between survival and treatment with tocilizumab within the icu setting (hr, . [ % ci, . - . ]). the unadjusted -day mortality favored tocilizumab ( % versus %) (fig ) . this retrospective observational cohort study of hospitalized covid- patients within a -hospital network did not find the empirical use of hydroxychloroquine with or without co-treatment with azithromycin to be associated with a reduction in mortality (adjusted hr, . for any hydroxychloroquine during hospitalization [ % ci, . - . ]). our multi-center findings confirm the recent observational studies from new york [ , ] . our results are also in agreement with the results of a recent randomized controlled study that enrolled patients with only mild-to-moderate disease, a cohort with less severe than our study [ ] . collectively these studies do not support the routine use of hydroxychloroquine outside a clinical trial. furthermore, none of the reported observational studies have addressed the role of hydroxychloroquine among individuals with minimally symptomatic disease in the pre-hospital setting. unlike randomized controlled trials, observational studies have inherent biases in patient allocations that cannot be fully adjusted for during statistical analyses. although we utilized propensity modeling to mitigate known imbalances it is possible that unmeasured confounding factors may still be important. for example, in our series we observed a change in the prescribing patterns of hydroxychloroquine during the study timeframe. similarly dosing and timing of hydroxychloroquine varied throughout the -hospital network. these factors a potentially clinically important finding from an exploratory analysis revealed a favorable association between tocilizumab administration and survival among covid- patients requiring icu support. our study represents one of the largest report of tocilizumab during this pandemic but is subject to all of the concerns of observational studies. however, if confirmed by ongoing randomized clinical trials, tocilizumab would represent the first successful therapy to reduce mortality. multiple ongoing rct's will ultimately determine the efficacy of hydroxychloroquine and tocilizumab in covid- . this observational study has limitations. first, observational studies cannot draw causal inferences given inherent known and unknown confounders. we attempted to adjust for known confounders using our propensity model approach. second, misclassification is possible as we performed manual abstraction of ehr data. third, hydroxychloroquine is a drug that likely has a therapeutic window that requires appropriate dosing, duration, and timing of administration [ ] . we acknowledge our results should be interpreted with caution as significant heterogeneity existed within these factors, although a majority of our patients received the same dose, completed days of treatment, and were given the drug within hours of hospitalization. fourth, low sample size limited our exploratory tocilizumab analysis. fifth, our study focused on patients in new jersey, limiting the applicability to other geographic regions, although the state's population is diverse, and the network included -hospitals (both academic and community) all with differing covid- treatment protocols. lastly, we acknowledge the possibility of sampling bias as we collected data from a convenience sample in attempts to conduct the investigation quickly during this pandemic. this observational cohort study from a multi-hospital system spanning new jersey, when taken together with other studies, does not support the routine (off label and outside of clinical trial) use of hydroxychloroquine to reduce mortality among hospitalized covid- patients. we cannot comment about the efficacy of this agent in the pre-hospital setting. our exploratory review of il- blockade with tocilizumab among icu patients is encouraging and warrants further study. an interactive web-based dashboard to track covid- in real time first case of novel coronavirus in the united states clinical characteristics of coronavirus disease in china covid- ) treatment guidelines. national institutes of health in vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus (sars-cov- ) hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting sars-cov- infection in vitro remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus ( -ncov) in vitro chloroquine is a potent inhibitor of sars coronavirus infection and spread effects of chloroquine on viral infections: an old drug against today's diseases? chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion mechanisms of action of hydroxychloroquine and chloroquine: implicaetions for rheumatology a pilot study of hydroxychlorquine in treatment of patients with common coronavirus disease- (covid- ) hydroxychloroquine and azithromycin as a treatment of covid- : results of an open-label non-randomized clinical trial observational study of hydroxychloroquine in hospitalized patients with covid- association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with covid- in new york state hydroxychloroquine with or without azithromycin in mildto-moderate covid- pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology clinical features of patients infected with novel coronavirus in wuhan, china pathological findings of covid- associated with acute respiratory distress syndrome effective treatment of severe covid- patients with tocilizumab tocilizumab treatment in covid- : a single center experience tocilizumab improves significantly clinical outcomes of patients with moderate or severe covid- pneumonia tocilizumab in patients with severe covid- : a retrospective cohort study tocilizumab for treatment of mechanically ventilated patients with covid- real-world evidence-what is it and what can it tell us? use of electronic health record data in clinical investigations guidance for industry use of real-world evidence to support regulatory decision-making for medical devices: draft guidance for industry and food and drug administration staff framework for fda's real-world evidence program research electronic data capture (redcap)-a metadata-driven methodology and workflow process for providing translational research the authors wish to thank the nurses, data managers, and physicians who after caring for their patients assisted in the abstraction of the clinical data. key: cord- -mmfrqyrc authors: rodríguez, a.; moreno, g.; gómez, j.; carbonell, r.; picó-plana, e.; benavent bofill, c.; sánchez parrilla, r.; trefler, s.; esteve pitarch, e.; canadell, l.; teixido, x.; claverias, l.; bodí, m. title: severe infection due to the sars-cov- coronavirus: experience of a tertiary hospital with covid- patients during the pandemic date: - - journal: nan doi: . /j.medine. . . sha: doc_id: cord_uid: mmfrqyrc objective to describe the clinical and respiratory characteristics of a cohort of patients with covid- after an evolutive period of days. design a prospective, single-center observational study was carried out. setting intensive care. patients patients admitted due to covid- and respiratory failure. interventions none. variables automatic recording was made of demographic variables, severity parameters, laboratory data, assisted ventilation (hfo: high-flow oxygen therapy and imv: invasive mechanical ventilation), oxygenation (pao , pao /fio ) and complications. the patients were divided into three groups: survivors (g ), deceased (g ) and patients remaining under admission (g ). the chi-squared test or fisher exact test (categorical variables) was used, along with the mann-whitney u-test or wilcoxon test for analyzing the differences between medians. statistical significance was considered for p < . . results a total of patients were included (g = [ . %], g = [ . %] and g = [ . %]), with a mean age of years (range - ), % males, apache ii ( - ), sofa ( - ). arterial hypertension ( . %) and obesity ( . %) were the most frequent comorbidities. high-flow oxygen therapy was used in . % of the patients, with failure in %. in turn, % of the patients required imv and % received ventilation in prone decubitus. in the general population, initial pao /fio improved after days ( [ - ] vs. [ - ]; p = . ), in the same way as in g ( [ - ] vs. [ - ]; p = . ), but not in g ( [ - ] vs. [ - ]). no bacterial coinfection was observed. the incidence of imv-associated pneumonia was high ( episodes/ days of imv). conclusions patients with covid- require early imv, a high frequency of ventilation in prone decubitus, and have a high incidence of failed hfo. the lack of improvement of pao /fio at days could be a prognostic marker. march , the world health organization (who) declared a new pandemic as the result of the rapid spread of the sars-cov- virus outside china. patients infected with sars-cov- can develop serious viral pneumonia known as covid- , characterized by severe respiratory failure, and which has placed a heavy burden on spanish intensive care units (icus) and the national healthcare system as a whole. , in europe, the first case of adult acute respiratory distress syndrome (ards) attributable to sars-cov- was diagnosed in italy on february , and a little less one month later the first patient with ards due to covid- was admitted to our icu. the admission of patients with covid- to intensive care varies markedly from one country to another, with prevalences ranging from % in italy to % in china. according to data published by the national epidemiological surveillance network of the instituto de salud carlos iii, on of april , of the total , hospitalized patients in spain, were admitted to the icu ---this representing a proportion of . %. taking into account that both the characteristics of the patients admitted to the icu due to covid- and the care received ---and hence the resulting crude mortality rate ---can differ considerably among different centers and countries, , , --- the present study was carried out to describe the clinical and respiratory characteristics of a series of consecutive patients with severe covid- in a spanish tertiary hospital, differentiating the subjects according to icu outcome after days. a prospective, observational cohort study was made, including all consecutive patients admitted to the department of intensive care medicine (dicm) from march to april with a confirmed diagnosis of sars-cov- infection, based on rt-pcr testing of nasopharyngeal swab and/or bronchial aspirate samples according to the criteria of the who. the rt-pcr tests were made in the reference laboratory (hospital clinic de barcelona) up until march , after which testing was made in our laboratory, which was designated as reference laboratory for the province of tarragona. the study was approved by the clinical research ethics committee of hospital universitario de tarragona joan xxiii (# ceim: / ), and informed consent for secondary use of the automatically compiled data was verbally requested from the patients or their direct relatives, with due reporting of the fact in the electronic case history. the present study was carried out using information stored in the database of the clinical information system (cis) of our center (centricity critical care ® [ccc], general electric). the data are compiled in the cis on a routine basis through manual registries, automated capture from devices and automated integration with the laboratory and the hospital information system (sap) of our center. depending on the source and type of information, the latter is entered in different tables in the cis database. each table contains at least one field or attribute that relates it to another table within the system (relational schema) ---thus allowing integration of all the data through extract, transform and load (etl) processes. the etl process that allowed generation of the cohort from the raw database tables of the cis was fully implemented using free software (python . , jupyter notebook and docker). demographic data were collected, together with severity parameters (apache ii scale), level of organ dysfunction upon admission (sofa score) and comorbidities. recorded. in addition, we considered laboratory test parameters such as hemoglobin concentration, leukocyte count, lactate, c-reactive protein (crp) and procalcitonin (pct). all variables were recorded upon admission and after days for comparative purposes. the indication of orotracheal intubation (oti), hfo or mechanical ventilation (mv) was established by the physician in charge of the patient. there was no specific respiratory management protocol for covid- . due to the recommendation not to use noninvasive ventilation (niv) or hfo because of the risk of aerosol generation, niv was disadvised on the basis of internal consensus, and hfo was indicated in the context of a limited availability of respirators or as a strategy to delay and avoid mv. all the patients with failed hfo were intubated and subsequently received mv. no patients with limitations of life support were considered. the assessment of patient admission to the icu was carried out in abidance with the ethical recommendations of the semicyuc. the patients were divided into three groups according to outcome after days: survivors (group ); non-survivors (group ), and patients still in the icu after days (group ). and corresponding to patients who develop a clinical condition characterized by increased radiological infiltration, changes in appearance of the secretions, and culture positivity (bas or bal sample) for pathogenic microorganisms at concentrations above the cut-off points defined for the technique, in a sample obtained hours after the start of mv. • ventilator-associated pneumonia incidence rate per ventilator days, expressed as density (number of cases per day/person/exposure) and calculated using the formula: incidence rate = number of cases of vap during the study period/total days/person/exposure to mv in the population during the study period * . • failure of hfo: defined as the need for immediate intubation and subsequent mechanical ventilation. the need for oti was based on clinical and blood gas criteria, and was left to the criterion of the physician in charge. • shock upon admission: defined as the need for any dose of noradrenalin within the first hours of admission in order to maintain mean blood pressure, and once the required volume replacement measures have been adopted, based on dynamic parameters or echocardiography. • acute respiratory distress syndrome: classified according to the definition of berlin into two groups: severe/moderate and mild. • acute renal failure was established based on the rifle classification, with three defined categories. previously published criteria were used in reference to the comorbidities and the rest of definitions. in view of the characteristics of the study, no sample size calculation was made. the sample size therefore was the same as the number of patients admitted during the study period. continuous variables were reported as the median and interquartile range (iqr), while categorical variables were reported as frequencies and percentages. differences in distribution of the variables between groups of patients were explored using the chi-square test or the fisher exact test (categorical variables). differences between medians were evaluated using the nonparametric wilcoxon test or mann-whitney u-test. due to the limited number of cases, no multivariate analyses were made. statistical significance was considered for p < . . the spss ® version . statistical package (ibm) was used throughout. from february to april , a total of cases of covid- were diagnosed in our hospital. of these, ( . %) required admission to the icu due to acute respiratory failure, and constituted the subject of the present analysis. seventeen patients ( . %) were admitted from internal medicine, ( . %) were transferred from other hospitals, and ( . %) came from the emergency department of our hospital. although the patients received conventional oxygen therapy and in some cases hfo before admission to our icu, these data were not available for analysis. the median time from arrival in hospital to admission to the icu was one day (iqr: . - . ). the baseline characteristics of the patients are shown in table . at the time of the analysis, patients were discharged live (group = . %), patients died (group = . %) and remained in admission (group = . %). the median number of days to death was (iqr: - ), and only one patient ( . %) died within the first hours of admission. the mean duration of stay in the icu for the patients in group was days (iqr: - ). in general, the patients were young ( years), predominantly males, and with great disease severity as evidenced by the median apache ( ) and sofa scores ( ) . a significant rise (p = . ) in mortality was observed over the increasing age intervals: - years ( %), - years ( . %), - years ( . %) and > years ( . %). the patients over years of age died early, within the first week (fig. ) . forty-four percent of the patients registered no comorbidities. none of the healthcare staff members of our hospital were admitted to the icu due to covid- during the observation period. the main comorbidities were arterial hypertension ( . %) and obesity ( . %), followed by diabetes mellitus ( . %), chronic obstructive pulmonary disease (copd)( . %) and ischemic heart disease ( . %). of the patients with arterial hypertension, ( . %) had a history of drug treatment in the form of angiotensin converting enzyme inhibitors (aceis) (n = ) or angiotensin receptor antagonists (aras)(n = ). only the presence of shock upon admission was more frequent among the non-survivors ( %) than among the survivors (group = . %) ( table ) . the other variables considered showed no statistically significant differences between the groups. the time from symptoms onset to the first antiviral drug dose was considerable, with a median of days (iqr: - ) ---no differences being observed between the groups. lopinavir/ritonavir was administered in cases ( %), with a median duration of only days (iqr: . - ) due to complications related to important transaminase elevation requiring treatment suspension. hydroxychloroquine was used in patients ( . %), with a median duration of days. interferon ß- b was only administered to patients ( . %), due to drug availability problems, and only two patients ( . %) received tocilizumab in other centers, before transfer to our icu (table ). the administration of corticosteroids was not considered among the treatments for covid- . such medication was only used upon admission to the icu in a single patient ( . %) as continuation of preexisting chronic treatment. five patients ( . %) received methylprednisolone as rescue therapy due to persistent lung infiltrations after the second week of stay, and four patients ( . %) received the medication due to other indications such as thrombocytopenia (n = ), hemolytic anemia (n = ) and skin rash (n = ). all the patients required some type of ventilatory support during the first hours of admission to the icu. high-flow oxygen was used as initial treatment for respiratory failure due to covid- in patients ( . %). however, after hours, only four patients responded favorably ---this representing a failure rate of . % ( / ). on day , only two patients maintained hfo, and these were discharged live, with no need for any other type of ventilatory support. the median time to hfo failure was hours (iqr: [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . all the patients in which hfo failed were subsequently intubated and ventilated. invasive mechanical ventilation was used as first treatment option for acute respiratory failure in patients ( . %). however, during the first hours, ( %) of the patients were ventilated, and finally after days, ( %) required imv. of the patients subjected to imv, ( %) required at least one ventilation episode in prone decubitus, with a median of three maneuvers (iqr: - ) per patient ---though some underwent over ventilation periods in prone decubitus. only one patient ( . %) was referred to the reference hospital for ecmo, and this individual finally died. the median number of days a total of % of the patients ( / ) met criteria of ards, which proved moderate/severe in cases ( . %) and mild in ( . %). of the patients with moderate/severe ards, ( . %) received imv after hours, but four ( . %) remained with hfo, and one patient with a face mask and reservoir. all of the patients with mild ards required imv after hours. independently of the ventilatory support received, the median pao /fio upon admission was (iqr: - ), and the ratio increased significantly up until day , reaching (iqr: - ; p = . ). a similar pao /fio behavior was recorded in the survivors, though without reaching statistical significance (p = . ), while the non-survivors showed a discrete decrease in pao /fio after days despite the treatment provided (table ) . a total of . % of the patients (n = ) received antimicrobial treatment (atb) upon admission to the icu due to clinically suspected bacterial co-infection. four patients received ceftriaxone plus a macrolide, and one patient was treated with piperacillin / tazobactam plus a macrolide. no pathogenic microorganisms were isolated from the lower airway samples (bas = ) of these patients. in all subjects, antigen testing in urine for s. pneumoniae and legionella spp. proved negative, in the same way as the bronchoaspirate and blood cultures performed upon admission to the icu. no case of bacterial co-infection was recorded in our series. the median pct concentration upon admission was . ng/ml (iqr: . - . ), while the median c-reactive protein concentration was mg/dl (iqr: - ). on the other hand, of the patients ( . %) developed vap, representing an incidence of . cases/ days of imv. the microorganisms isolated were s. anginosus (n = ), p. aeruginosa (n = ), methicillin-sensitive s. aureus (mssa)(n = ), e. coli (n = ), s. oralis (n = ), k. pneumoniae (n = ), e. fae-calis (n = ) and corynebacterium spp. (n = ). none of the respiratory sample analyzed proved positive for aspergillus spp. our study describes the course of seriously ill patients with covid- during the first four weeks of stay in the icu of a tertiary hospital. despite the limited number of patients, the results obtained are of great interest due to the existing lack of knowledge of the evolution of this new disease and the differences in the characteristics of the patients. one of the main findings of our study was that one of every two admitted patients had no major comorbidities. this observation is consistent with the data reported by other studies --- that describe the absence of comorbidities in over % of the patients. in a way similar to what was seen in the influenza a (h n )pdm pandemic, obesity was very common in our patients. in contrast, obesity was not mentioned in the studies carried out in china or italia, though it is indeed cited in the published experience in vitoria (basque country) and in a recent study in the united states ---where the incidence of obesity was even higher ( . %). this situation could complicate direct extrapolation of the international data, , --- , , since different populations are involved. another relevant finding was that the mortality rate ( . %) in our series was lower than that in the study from vitoria ( %), despite the fact that the patients were of similar age and severity, and presented a similar frequency of imv ( %). different publications also report a higher mortality rate. in the study published by yang et al., the overall mortality rate was . %, though on considering the patients subjected to imv, the figure reached % ( / ) ---which is far higher than the rate obtained in our study ( . %). it should be noted that in the mentioned study, of the critical patients, only ( %) received imv. although the authors did not report the time from failure of other oxy- reported an overall mortality rate of . %. in their study, of the included patients, ( . %) received some type of ventilatory support, though there was a notoriously low incidence of imv ( %), while almost half of the patients ( . %) received nasal cannulas and % were subjected to niv. in turn, grasselli et al., in italy, reported a mortality rate of %. although this study made no mention of severity scales, the included population appears to have been more similar to our own series, since of the subjects, ( %) were admitted to the icu, and of these, % required imv. although the authors associated mortality to the age of the patients, the median age was no different from that of our own series ( versus years). in new york, of patients with covid- , only . % (n = ) were admitted to the icu, and of these individuals ( . %) required imv. the mortality rate in this subgroup was very high ( . %). similar mortality was recorded by arentz et al. in a small population of patients. the high mortality in this series could be related to the fact that the median age was older than in most communications ( years, iqr: - ). in contrast to the above, our mortality rate was markedly higher than in the study published by guan et al. (only . %). in the latter study, most of the patients were not considered to be in serious condition (none required ventilation). in the cases considered to be serious ( . %; / . ), the mortality rate was . %, despite the fact that of these individuals only ( . %) received imv. it is clear that the international studies involve other types of populations and particularly other types of ventilatory support, and this makes it very difficult to extrapolate such experiences to our own setting. the data obtained therefore need to be interpreted with caution. another observation of interest is the fact that despite the contraindications to the use of hfo, the latter was started in over % of the patients as first line treatment. nevertheless, the technique failed in over % of the cases. although the available data do not allow us to evaluate the impact of a delay in intubation upon the patient course, a gap of hours from hfo failure to intubation possibly may have no strong influence upon the clinical course, considering the observed mortality rate. a matter of concern was the high vap rate observed ( % or cases/ days of imv), which more than doubled the usual vap rate in our icu. this incidence was higher than that reported by xang et al. ( . %), though the latter authors did not specify the days of risk exposure ---thereby making it difficult to establish comparisons. the urgency of care during the pandemic, the use of personal protection equipment (ppe), the rotation of scantly trained staff, and a decrease in the vap preventive measures may help explain this increase. nevertheless, such a high incidence must be confirmed by other studies. lastly, our data show that among the non-survivors, pao /fio upon admission did not improve after days despite the treatment provided. in the survivors, however, pao /fio was seen to increase after days. it therefore may be postulated that a lack of improvement in pao /fio after one week of treatment could be a prognostic factor to be considered in future studies. our study clearly has important limitations that need to be mentioned. the first and possibly most important limitation is the small number of patients involved, which may preclude the identification of differences between groups due to type i error. nevertheless, given the novel characteristics of this pandemic, our results do contribute to existing knowledge ---though the findings must be confirmed by studies involving larger patient samples. on the other hand, our results describe the evolution in a special type of icu, and might not be extendable to other areas or icus. it is clear that both the indication of admission to the icu, and the complexity of care of these patients, vary greatly among different centers and countries. such information therefore needs to be analyzed carefully in each study. a. rodríguez et al. in conclusion, although our data describe a not particularly old patient population with a low prevalence of comorbidities, covid- is seen to often require imv due to ards, and is characterized by a high incidence of hfo failure and important mortality. a lack of improvement of pao /fio after one week of active treatment could be regarded as a variable associated to early mortality ---though these data require confirmation in future studies. all the authors approved the final manuscript submitted for evaluation and possible publication. the authors declare that they have no conflicts of interest in relation to the present article. ar has received a research grant from gilead science for the study of nebulized antibiotics, and has received fees for teaching conferences from biomerieux, astellas, pfizer, thermo fisher, msd, gilead, shionogi and brhams. there are no conflicts of interest in relation to the present study, however. the rest of the authors have no conflicts of interest. pandemia por covid- : el mayor reto de la historia del intensivismo plan de contingencia para los servicios de medicina intensiva frente a lapandemia covid- baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region clinical features of patients infected with novel coronavirus in wuhan sars-cov- in spanish intensive care: early experience with -day survival in vitoria clinical characteristics of coronavirus disease in china clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china laboratory testing for novel coronavirus ( -ncov) in suspected human cases recomendaciones éticas para la toma de decisiones difíciles en las unidades de cuidados intensivos ante la situación excepcional de crisis por la pandemia por covid- : revisión rápida y consenso de expertos covid- actualización increased incidence of co-infection in critically ill patients with influenza management of adults with hospital-acquired and ventilator-associated pneumonia: clinical practice guidelines by the infectious diseases society of america and the acute respiratory distress syndrome: the berlin definition. ards definition task force the adqi workgroup acute renal failure ---definition, outcome measures, animal models, fluid therapy and information technology needs corticosteroid treatment in critically ill patients with severe influenza pneumonia: a propensity score matching study impact of obesity in patients infected with influenza a(h n ) presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area characteristics and outcomes of critically ill patients with covid- in washington state the hj -covd- working group thanks all the healthcare staff of hj related to the care of patients with covid- for their unwavering dedication and effort during the period of this study. this article could not have been produced without them.the findings and the conclusions of the present manuscript are the responsibility of the authors, and do not necessarily represent the official position of the catalan health institute. key: cord- - h gzzl authors: calligaro, keith d.; dougherty, matthew j.; maloni, krystal; vani, kunal; troutman, douglas a. title: covid (co-operative vascular intervention disease) team of greater philadelphia date: - - journal: j vasc surg doi: . /j.jvs. . . sha: doc_id: cord_uid: h gzzl we established the covid (co-operativevascularinterventiondisease) team of greater philadelphia because national guidelines may not apply to different geographic areas of the united states due to varying penetrance of the virus. on april , , a ten-question survey regarding issues and strategies dealing with covid- was e-mailed to vss in the greater philadelphia area. fifty-four vss in surgical groups covering hospitals responded. all groups accepted transfers due to continued icu bed availability. thirteen groups were asked to “re-deploy” if the need arose to function outside of the usual duties of a vs. none imposed age restrictions regarding older vss continuing clinical hospital work. the majority restricted non-invasive vascular laboratory studies to those studies where findings might mandate intervention within - weeks, restricted dialysis access operations to urgent revisions of arteriovenous fistulas (avfs)/ grafts that were failing or had ulcerations, converted from in-person to telemedicine clinic interactions, and experienced moderate/severe anxiety or fear about personal covid- exposure in the hospital. the majority of vss in the philadelphia area have dramatically adjusted their clinical practices before the covid- crisis reached peak levels experienced in other metropolitan areas. covid- , also called coronavirus disease, has spread rapidly through the world and the united states with high infection and mortality rates. recently the society for vascular surgery (svs) made a concerted national effort to better educate its members regarding the disease. we philadelphia because ) we believe vascular surgeons (vss) should be the driving force in decisions concerning vascular disease during this crisis and ) national guidelines may not apply to different geographic areas of the united states due to varying penetrance of the virus. the function of the team is to gather opinions and strategies of vss in the philadelphia area to address the impact of covid- . methods on april , , a ten-question survey was e-mailed to vss in the greater philadelphia area regarding issues and strategies for dealing with the coronavirus. response time was limited to three days so results could be analyzed at a specific point in time and re-examined in the future as virus penetrance changes. responses were classified according to individual vss or vs groups depending on the question. surgeons were identified by contacting the chief of each vascular section or division and asking for email contacts for each member of their group. the greater philadelphia area was loosely defined as those medical centers in the city boundaries of philadelphia and inclusion of medical centers within approximately one-hour drive of the city. this area included northeastern, eastern and southeastern pennsylvania and southern new jersey. delaware (table i: six questions) accepted transfers at the time of the survey due to continued icu bed availability. thirteen groups were asked to "re-deploy" if the need arose to function outside of the usual duties of a vs. seven groups needed special permission from the chairman of surgery or other supervisor to schedule urgent or emergent surgery that was not required prior to the pandemic. only one group (private practice) had an office-based laboratory (obl) where endovascular arterial procedures were performed. due to lack of a large sample size, willingness to allow other vss to perform procedures at these non-hospital-based facilities could not be determined. of the university/hospital-employed groups, none expected > % salary reduction whereas all private practice groups had already experienced this drastic decrease in income. none of the groups restricted older vss from performing clinical duties in the hospital. among the vss who responded to the survey (table ii: twenty-percent ( ) continued to perform routine follow-up and diagnostic nivl studies (essentially no change) and % ( ) closed their laboratory. sixty-seven percent ( ) restricted dialysis access operations to urgent revisions of arteriovenous fistulas (avfs) or grafts that were failing or for impending hemorrhage due to skin ulcerations overlying the conduit. seventy-eight percent ( ) converted from in-person office visits to telemedicine clinic interactions. of the vss at teaching hospitals, all had transitioned to digital platforms for educational conferences. philadelphia for two reasons. first, we believed vss should be the driving force in decisions regarding vascular issues during this crisis. vss best understand the complex decision-making regarding emergent, urgent, and non-elective interventions, and the type of interventions, most appropriate to treat vascular disease. for example, vss are best suited to determine timing of elective first-time avfs and grafts if a patient already has a functioning tunneled dialysis catheter, although a discussion with the patient's nephrologist is appropriate. vss can best determine the timing to repair an asymptomatic aaa during the covid- crisis based on the patients' risk factors, aneurysm diameter and morphology, and potential need for an icu bed. vss possess the judgement necessary to determine whether endovascular procedures might be preferable to standard open surgeries in the context of the pandemic. second, national guidelines proposed by the svs and other societies may not be appropriate for different geographic areas of the united states due to varying penetrance of the virus and clinical resource saturation. at the time of the survey in mid-april , % ( / ) of icu beds in the university of pennsylvania health system (seven hospitals) were occupied with covid - patients. this percentage was significantly lower than experienced in other major metropolitan areas such as new york city and seattle, wa. the impact of the virus at local and regional levels might affect attitudes and strategies of vss practicing in those areas more than national data. we wished to examine the availability of icu beds in hospitals in the philadelphia area at varying times of the coronavirus crisis. if certain hospitals were overwhelmed by the virus and could not accept transfers such as ruptured aaas or other vascular patients requiring an icu bed, other hospitals might have available icu beds and be able to accept those patients. by establishing lines of communication among vs groups, the hospitals accepting transfers could be made known to the vascular community. due to the relatively low penetrance of the virus at the time of the survey, all vs groups continued to accept emergency transfers because of continued availability of icu beds. we did not want to wait until our area became so overwhelmed that our collective response was too little too late. hospital administrators asked the majority ( ) of vs groups to "re-deploy" to perform duties other than the usual functions of a vs if the need arose due to an overwhelming number of covid- patients. these duties included placing central venous or peripheral arterial lines and caring for patients in the emergency department or icu. hospital administrators asked of the groups to function as "first-line" responders, meaning vss were as likely to be called as general surgeons or other specialty surgeons, to help deal with the crisis. hospital administrators asked two of the groups to serve as "back-up" responders only if medical and surgical residents, other attending surgeons, anesthesiologists, and icu attendings were unavailable. several vss expressed the concern that if they were "first-line" responders and became infected with the virus, they might not otherwise be available to treat true vascular emergencies. eleven of the vs groups were empowered to schedule urgent or emergent vascular surgery without permission by the chairman of surgery or other supervisors. the argument to allow vss to schedule cases without oversight is because they understand when urgent intervention is indicated, such as for lower extremity rest pain or tissue loss, failing lower extremity bypass, or symptomatic carotid disease. however, the counter-argument of having a chairman of surgery oversee these decisions may be reasonable if there is resource saturation such that triage is necessary. our survey showed that a clear majority of vss did not need this type of permission. our data would support those vss needing permission to approach their chairman and inform that most medical centers do not have this requirement. only one (private practice) of the groups operated an office-based laboratory (obl) that performed arterial endovascular interventions in a non-hospital-based facility. therefore, we could not gather reliable data concerning willingness of vss at obls to allow other interventionalists to perform procedures at their facility. we questioned the financial impact of the virus on vs practices. of the university/hospital-employed groups, none expected more than a % salary reduction, whereas all private practice groups experienced this income reduction by the time of the survey. this reduction was largely due to cancellation of all elective surgical and endovascular interventions. the increasing penetration of the hospital-employed model of practice will likely accelerate as a result of the pandemic. none of the groups imposed age restrictions on older vss performing hospital-based duties. although increased age has clearly been shown to be a significant risk factor in acquiring the virus and experiencing worse symptoms with worse outcomes than younger members of the population, none of the groups adopted these precautions. this attitude "do as i say, not as i do" could prove harmful to older vss, as significant death rates have already been documented among health-care providers. the mantra "stay at home!" does not seem to apply to older vss and may not apply to older health-care providers either. of the vss who answered the survey, elective repair of aaa in a good-risk year- old patient was recommended at a median diameter of . cm (avg = . , range = . - . ) if evar could be performed compared to . cm (avg = . , range = . sixty-seven percent ( / ) restricted dialysis access operations to urgent revisions of arteriovenous fistulas (avfs) or grafts that were failing or for impending rupture due to ulcerations overlying the conduit. some vss continued to place new avfs or grafts in patients with functioning tunneled dialysis catheters [( % ( ) ) and in patients not yet on dialysis [ % ( ) ]. there are two concerns with performing purely elective avfs and grafts during this pandemic. patients with chronic renal failure are immunocompromised and therefore at higher risk of viral infection coming into the hospital for surgery and being exposed to carriers. health-care providers, including vss, are also at greater risk of contracting the infection by exposing themselves to a population that has a higher prevalence of the disease. seventy-eight percent ( / ) of vss had converted from in-person to telemedicine clinic interactions. avoiding direct patient contact in the office-setting is advantageous for patients, office staff, non-invasive vascular laboratory technologists, and vss. even though the penetrance of covid- in the greater philadelphia area was lower than in some other metropolitan areas, the majority of vss quickly adopted this telemedicine strategy. the disadvantage of this approach is the inability to perform a physical examination, and in some cases obtain a nivl study, that may lead to less accurate diagnoses or need for more urgent interventions. it has been noted that there has been an increase in non-covid- cardiovascular mortality in the last two months which may reflect the risk of delayed care . thirty-five percent ( / ) of vss at training programs believed the number of weekly conferences increased since the onset of the crisis, % ( / ) believed the number had decreased, and % ( / ) believed the number remained the same. academic vss realized that continuing to hold teaching conferences seated together in one room was hazardous and quickly converted to digital platforms as a means to continue academic conferences. the fact that teaching conferences did not dramatically decrease during the beginning of the crisis is testament to the flexibility of vss addressing this problem. lastly, % ( / ) of vss experienced moderate or severe anxiety or fear regarding personal covid- exposure in the hospital. vss likely have a high rate of unease and apprehension not only because of concern regarding themselves but also for their family. vss and other health-care providers should acknowledge the emotional impact of dealing with these critically ill patients and understand part of their concern is knowing they might become infected with covid- the next time they enter the hospital. conclusion the majority of vss in the philadelphia area have dramatically adjusted their clinical practices before the covid- crisis reached peak levels experienced in other metropolitan areas. the survey revealed only a modest shift in vss' attitudes regarding recommendations for elective repair of aaas. older vss have not adopted precautionary "stay-at-home" recommendations urged for elderly members of the general population. we will monitor evolving practice strategies as virus penetrance changes. co-operative vascular intervention disease) team of greater philadelphia - abington hospital: danielle pineda capital health system crozer hospital: mark einstein hospital: rashad choudry; evan deutsche; nadia awad covid- guidelines for triage from vascular patients key: cord- -bmppif g authors: girardi, paolo; greco, luca; mameli, valentina; musio, monica; racugno, walter; ruli, erlis; ventura, laura title: robust inference for nonlinear regression models from the tsallis score: application to covid‐ contagion in italy date: - - journal: stat (int stat inst) doi: . /sta . sha: doc_id: cord_uid: bmppif g we discuss an approach of robust fitting on nonlinear regression models, both in a frequentist and a bayesian approach, which can be employed to model and predict the contagion dynamics of covid‐ in italy. the focus is on the analysis of epidemic data using robust dose‐response curves, but the functionality is applicable to arbitrary nonlinear regression models. we aim to discuss a robust approach to model and predict the spread of the coronavirus disease in italy, due to the worldwide epidemic outbreak of the new coronavirus sars-cov- . in particular, we focus on deaths and intensive care unit hospitalizations data, that are expected to aid the detection of the time when the peaks and the upper asymptotes of contagion, both in daily new cases and total cases, are reached, so that preventive measures (such as mobility restrictions) can be applied and/or relaxed. for these data, robust procedures are particularly useful since they allow us to deal with model misspecifications and data reliability, simultaneously. nonlinear regression is an extension of classical linear regression, in which data are modeled by a function, which is a nonlinear combination of unknown parameters and depends on an independent variable. a relevant application of non-linear regression models concerns the modeling of so called dose-response relation, useful in toxicology, pharmacology and in the analysis of epidemic data. in these frameworks, the parameters of the model have a relevant interpretation, such as the upper limit and the inflection point. a normal non-linear regression model is obtained by replacing the linear predictor x t β by a known non-linear function µ(x, β), called the mean function. the model (see, e.g., bates and watts, ) is called a non-linear regression model, where x i is a scalar covariate, β is an unknown p-dimensional parameter, and ε i are independent and identically distributed n( , σ ) random variables. likelihood inference is the usual approach to deal with nonlinear models. the log-likelihood function for θ = (β, σ ) is this article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the version of record. please cite this article as doi: . /sta . and all likelihood quantities (maximum likelihood estimates, tests, confidence intervals, prediction, etc) can be easily derived. using the statistical environment r, the package drc (ritz et al., ) provides a user-friendly interface to specify the model assumptions about the nonlinear relationship and comes with a number of extractors for summarizing fitted models and carrying out inference on derived parameters. a large number of more or less well-known mean functions are available (log-logistic, weibull, gamma, etc, see for instance ritz et al., , table ). these functions are parameterized using a unified structure with a coefficient b denoting the steepness of the curve, c and d the lower and upper asymptotes or limits of the response, and, for some models, e the inflection point. for instance, the five parameter log-logistic curve assumes however, in the presence of model misspecifications or deviations in the observed data from the assumed model, classical likelihood inference may be inaccurate (see, e.g., huber and ronchetti, , farcomeni and ventura, , farcomeni and greco, , and references therein). this paper aims to discuss the use of robust inference on nonlinear regression models. in particular, we discuss a general approach based on the tsallis score (basu et al., , ghosh and basu, , dawid et al., , mameli et al., , giummolé et al., , both in a frequentist and bayesian frameworks. to deal with model misspecifications, useful surrogate likelihoods are given by proper scoring rules (see dawid et al., , and references therein) . a scoring rule is a loss function which is used to measure the quality of a given probability distribution for a random variable y, in view of the result y of y. when working with a parametric model with probability density function f(y; θ), with θ ∈ Θ ⊆ ir d , an important example of proper scoring rules is the log-score, which corresponds to minus the log-likelihood function (good, ) . in this paper, to deal with robustness, we focus on the tsallis score (tsallis, ) , given by the density power divergence dα of basu et al. ( ) is just ( ), with γ = α + , multiplied by /α. the tsallis score gives in general robust procedures (ghosh and basu, ) , and the parameter γ is a trade-off between efficiency and robustness. for the nonlinear regression model ( ), the total tsallis score for θ = (β, σ ) is the validity of inference about θ = (β, σ ) using scoring rules can be justified by invoking the general theory of unbiased m-estimating functions. indeed, inference based on proper scoring rules is a special kind of m-estimation (see, e.g., dawid et al., , and references therein) . the class of m-estimators is broad and includes a variety of well-known estimators. for example it includes the maximum likelihood estimator (mle) and robust estimators (see e.g. huber and ronchetti, ) among others. let s(y; θ) be the gradient vector of s(y; θ) with respect to θ, i.e. s(y; θ) = ∂s(y; θ)/∂θ. under broad regularity conditions (see mameli and ventura, , and references therein), the scoring rule estimatorθ is the solution of the unbiased estimating equation s(θ) = n i= s(y i ; θ) = and it is asymptotically normal, with mean θ and covariance matrix v(θ)/n, where where k(θ) = e θ (∂s(y; θ)/∂θ t ) and j(θ) = e θ (s(y; θ)s(y; θ) t ) are the sensitivity and the variability matrices, respectively. the matrix g(θ) = v(θ) − is known as the godambe information and its form is due to the failure of the information identity since, in general, k(θ) = j(θ). asymptotic inference on the parameter θ can be based on the wald-type statistic which has an asymptotic chi-square distribution with d degrees of freedom. in contrast, the asymptotic distribution of the scoring rule ratio statis- is a linear combination of independent chi-square random variables with coefficients related to the eigenvalues of the matrix j(θ)k(θ) − (dawid et al., ) . more formally, w s (θ)∼ d j= µ j z j , with µ , . . . , µ d eigenvalues of j(θ)k(θ) − and z , . . . , z d independent standard normal variables. adjustments of the scoring rule ratio statistic have received consideration in dawid et al. ( ) , extending results of pace et al. ( ) for composite likelihoods. in particular, using the rescaling factor a(θ) = (s(θ) t j(θ)s(θ))/(s(θ) t k(θ)s(θ)), we have can be obtained by using a parametric bootstrap; see varin et al. ( ) for a detailed discussion of the issues related to the estimation of j(θ) and k(θ). however, for tsallis score ( ) the matrices k(θ) and j(θ) can be derived analytically. indeed, under the same assumptions of theorem . in gosh and basu ( ) , it is possibile to show that . . , n, and ξα and ςα are the same as given in gosh and basu ( ) for the linear regression model (see sect. ), namely ξα = ( π) −α/ σ −(α+ )/ ( + α) − / and ςα = ( π) −α/ σ −(α+ )/ +α ( +α) / . moreover, the computation of j(θ) leads to these matrices can then be used in ( ) to derive the asymptotic distribution ofθ. note thatβ andσ are asymptotically independent. from the general theory of m-estimators, the influence function (if) of the estimatorθ is given by and it measures the effect on the estimatorθ of an infinitesimal contamination at the point y, standardised by the mass of the contamination. the estimatorθ is b-robust if and only if s(y; θ) is bounded in y (see hampel et al., ) . note that the if of the mle is proportional to the score function; therefore, in general, mle has unbounded if, i.e. it is not b-robust. sufficient conditions for the robustness of the tsallis score are discussed in basu et al. ( ) and dawid et al. ( ) . for the tsallis score ( ), straightforward calculation show that the if for the tsallis estimator of the regression coefficients becomes and that the if for the tsallis estimator of the error variance becomes since the functions s exp{−s } and s exp{−s } are bounded in s ∈ ir, than both the influence functions if(y;β) and if(y;σ ) are bounded in y for all γ > . the use of surrogate likelihoods in the bayes formula has received considerable attention in the last decade (see the review by ventura and racugno, , and references therein). paralleling the derivation of posterior distributions based on composite likelihoods, a tsallis posterior distribution can be obtained by using the scoring rule instead of the full likelihood in bayes formula. let π(θ) be a prior distribution for the parameter θ. the proposed sr-posterior distribution is defined as a possible choice of the matrix c is given by giummolé et al. ( ) and references therein. the choice of a prior distribution π(θ) to be used in ( ) involves the same problems typical of the standard bayesian perspective. for instance, for objective bayesian inference the expected α-divergence to the tsallis posterior distribution can be used (giummolé et al., ) , and it is given by π g (θ) ∝ |g(θ)| / . we aim to build a data-driven model that can provide support to policymakers engaged in contrasting the spread of the covid- . in particular, we have applied robust inference for the model ( ) to the available data, which covers the period from february th to april th, . the data sources are the daily report of the protezione civile (https://github.com/pcm-dpc/covid- /). we consider two independent applications to: • daily deaths (dd) for covid- , deaths confirmed by the istituto superiore di sanitá (iss); • intensive care unit (icu) hospitalizations with positive covid- swab; this data can be interpreted as a "department use index". moreover, our analyses are limited to two different geographical extensions: italy and lombardia. however, the proposed methodology has been applied to all the italian regions. we illustrate statistical modelling of cumulative dd and cumulative intensive icu in italy and in the italian region lombardia using the tsallis scoring rule. following dawid et al. ( ) , for dd and icu data the tsallis score ( ) represents a composite scoring rule, based on only marginals. in particular, it can be interpreted as an independent scoring rule (see also varin et al., , for composite likelihoods). figures - display the robust fitted models for italy and lombardia, respectively, for both dd and icu data. here, a three-parameter log-logistic curve has been used, i.e. obtained by setting c = , f = in ( ). in this setting, the parameter e represents the median time. in each plot, the blue points denote the observed data, and the red curves are the estimates/forecasts with our robust nonlinear models. furthermore, the plots on the left show the cumulated data, whereas those on the right give the daily data (new deaths and new hospitalizations, every day). by looking at the plots about cumulative data, we appreciate the characteristic s-shape of the log-logistic curve describing the evolution of total cases. the upper asymptote of the curves represents the expected number of total deaths or intensive care unit hospitalizations due to the covid- outbreak. on the other hand, the inspection of the panels devoted to the evolution of daily data is informative about the peak of daily new cases. the peak in the right panels corresponds to the mode of the distribution of cumulative cases, and it is always dominated by the parameter e due to the right asymmetry. we remark that, in all the figures, the models fit well the observed data. in particular, the plots on the right show that the peak in new cases has already been reached both for dd and icu data, hence highlighting the effectiveness of the restrictions. it is also evident that such counts grew faster at the beginning of the outbreak than they are decreasing after the peak. the plots on the left reveal that the end of the outbreak is still to come, and total numbers are expected to increase. when the cumulative data attain the upper asymptote, then the daily data decrease to zero. the robust fits (tsallis estimates and % confidence intervals) of the parameters e (inflection point) and d (upper asymptote) for the models are summarized in tables and for dd and icu, respectively. for dd italy data, the model predicts an impressive total of more than k deceased at the end of the outbreak. according to the fitted model, the expected number of new deaths will be below counts by the end of june. the inflection point is on april th (day ), whereas the fitted peak is on march th. for what concerns icu, the total expected number of icu occupancy-days is about k, whereas the inflection point is on april th (day ) and the peak on april st. the number of icu will decline at the same level as the end of february, at the very beginning of the outbreak in italy, during the first days of july. moving to lombardia, the model estimates a total of about k deaths at the end of the epidemic, an inflection point on april st (day ), and a peak on march th. for icu counts, the total is about k occupancy-days, the inflection point is on april th (day ), the peak on march st. by the end of may, the death tolls will go below units, whereas by the end of june, the number of icu will be well below . in order to assess the accuracy of the fitted models, some numerical studies have been carried out to investigate the actual sampling distribution of the proposed estimator. to this end, samples have been drawn from the fitted model on italy death data. the sampling distributions of the tsallis estimates for (b, d, e, σ) are displayed in figure . they all exhibit reasonable accuracy and and precision, as confirmed by the comparison with the normal approximation to the distribution of the tsallis estimator based on the fitted model. in the simplest instance of prediction, the object of inference is a future or a yet unobserved random variable z. let p z (z; θ) be the density of z. the basic frequentist approach to prediction of z, on the basis of the observed y from y, consists in using the estimative predictive density function pe(z) = p z (z;θ), obtained by substituting the unknown θ with a consistent estimator, such as the tsallis estimator or the mle. figure reports the estimative predictive densities based on both the estimators for dd and the cumulative icu. note the tsallis estimative predictive density is shifted on the right and exhibits larger variability. to compare the predictive performances of the tsallis method with respect to the mle, a simulation study has been performed, based on n = monte carlo replications. figure mixing the robust procedure with the bayesian approach allows us to include prior information (objective or subjective) on the parameters of the model. moreover, the plots of the posterior distributions for the parameters of the model may be quite useful in practice since they are more informative than a simpler point or interval estimator. for instance, the marginal posterior distributions allow us to assign probabilities to intervals on the parameters. figure gives the violin plots of the marginal posterior distributions for parameters of the model and the expected mean, both for dd and for icu data, using the reference prior (giummolé et al., ) . the posterior medians (the white dots) for the upper asymptotes and the inflection points are consistent with the frequentist robust estimates. note that the classical marginal posterior distribution shows too narrow tails with respect to robust posterior distributions, which, on the contrary, can take into account the actual large uncertainty in the available data. to conclude, we believe that our procedure can constitute a useful statistical tool in modelling italian covid- contagion data. indeed, the tsallis robust procedures allow us to take into account the inevitable inaccuracy of the italian covid- data, which are often underestimated. moreover, an example is those deaths of patients who died with symptoms compatible with covid- but who have not had a tampon, or what has been described by many media regarding the growing number of elderly people who remain in their homes while needing to be hospitalized in intensive care. thus, for these data, robust procedures are particularly useful since they allow us to deal at the same time with model misspecifications (with respect to the normal assumption, independence, or with respect to homoscedasticity) and data reliability. the estimation of the model and, as a consequence, the calculation of the expected asymptote and the inflection point are based on the assumptions that the adopted restrictions will not be subject to change. for these reasons, these fitted models cannot be used for predictive purposes, since it is not possible to predict how the data will change when the restrictions are modified at the end of the lock-down, scheduled for may rd. the day by day monitoring of the model fit stability will allow us to evaluate deviations from the actual lock-down situation with respect to the next reopening. as a final remark, since the variables are daily counts, we will investigate the use of the tsallis scoring rule in the context of nonlinear poisson regression models. updates on the results and on the italian regions may be found in the web page of the robbayes-c research group: https://homes.stat.unipd.it/lauraventura/content/ricerca in this web page also the r codes are available. the reader is also pointed to the work of the statgroup- research group that models the mean function by using the five parameters richards curve (divino et al., ) . the data that support the findings of this study are available in github repository at the italian protezione civile account (pcm-dpc/ and described in morettini et al. ( ) . these data were derived from the following resources available in the public domain: https://github.com/pcm-dpc/covid- /. robust and efficient estimation by minimising a density power divergence nonlinear regression analysis and its applications minimum scoring rule inference an overview of robust methods in medical research robust estimation for independent non-homogeneous observations using density power divergence with applications to linear regression robust bayes estimation using the density power divergence objective bayesian inference with proper scoring rules robust statistics bootstrap adjustments of signed scoring rule root statistics higher-order asymptotics for scoring rules covid- in italy: dataset of the italian civil protection department dose-response analysis using r possible generalization of boltzmann-gibbs statistics an overview of composite likelihood methods pseudo-likelihoods for bayesian inference key: cord- -b yrxkt authors: ahlström, björn; larsson, ing-marie; strandberg, gunnar; lipcsey, miklos title: a nationwide study of the long-term prevalence of dementia and its risk factors in the swedish intensive care cohort date: - - journal: crit care doi: . /s - - -y sha: doc_id: cord_uid: b yrxkt background: developing dementia is feared by many for its detrimental effects on cognition and independence. experimental and clinical evidence suggests that sepsis is a risk factor for the later development of dementia. we aimed to investigate whether intensive care-treated sepsis is an independent risk factor for a later diagnosis of dementia in a large cohort of intensive care unit (icu) patients. methods: we identified adult patients admitted to an icu in to and who survived without a dementia diagnosis year after intensive care admission using the swedish intensive care registry, collecting data from all swedish general icus. comorbidity, the diagnosis of dementia and mortality, was retrieved from the swedish national patient registry, the swedish dementia registry, and the cause of death registry. sepsis during intensive care served as a covariate in an extended cox model together with age, sex, and variables describing comorbidities and acute disease severity. results: one year after icu admission , patients were alive and without a diagnosis of dementia; of these, , ( . %) had a diagnosis of sepsis during intensive care. the median age of the cohort was years (interquartile range, iqr – ). the patients were followed for up to years (median . years, iqr . – . ). during the follow-up, ( %) patients were diagnosed with dementia. dementia was more common in individuals diagnosed with sepsis during their icu stay (log-rank p < . ), however diagnosis of sepsis during critical care was not an independent risk factor for a later dementia diagnosis in an extended cox model: hazard ratio (hr) . ( % confidence interval . – . , p = . ). renal replacement therapy and ventilator therapy during the icu stay were protective. high age was a strong risk factor for later dementia, as was increasing severity of acute illness, although to a lesser extent. however, the severity of comorbidities and the length of icu and hospital stay were not independent risk factors in the model. conclusion: although dementia is more common among patients treated with sepsis in the icu, sepsis was not an independent risk factor for later dementia in the swedish national critical care cohort. trial registration: this study was registered a priori with the australian and new zeeland clinical trials registry (registration no. actrn ). dementia is a common and often detrimental group of diseases with a sharply increasing incidence in the elderly [ , ] . in general, the disease is characterized by memory loss, disturbances in language, altered perception, and other psychological and psychiatric changes. together, these symptoms cause impaired daily functioning [ ] and may severely affect health-related quality of life [ ] . in hospitalized patients, and especially in the intensive care population, sepsis is a common syndrome [ ] defined by a dysregulated host response to an infection [ ] . the systemic inflammation in sepsis has been suggested to have a long-term negative impact on the brain [ ] . both short-and long-term effects of experimental sepsis on brain cells and behavior have been described in rodents [ ] [ ] [ ] . septic encephalopathy and persisting cognitive disturbances have also been reported in human studies [ ] [ ] [ ] . moreover, in patients with an assessment of cognitive function before and after hospitalization, a decline in cognitive function was more pronounced after hospitalization for severe sepsis than after admission for other reasons [ ] . sepsis diagnosis has also been reported to be more common in the history of patients with dementia than age-and sex-matched controls from the health care system [ ] . finally, sepsis is an independent risk factor for dementia in observational studies [ , ] . based on these data, we hypothesized that dementia would develop more commonly in patients admitted for, or developing, sepsis in intensive care compared with other patient groups. however, the prevalence of dementia in the population is relatively low [ ] . additionally, dementia is usually a slowly developing syndrome with a long subclinical period before diagnosis [ ] . dementia also increases the risk of sepsis [ ] , and several comorbidities are risk factors for both dementia and sepsis. we therefore set out to investigate our hypothesis in a large nationwide database with an extended follow-up and accounting for comorbidities. our primary endpoint was the hazard ratio (hr) of sepsis for a diagnosis of dementia adjusting for several potential risk factors. we also investigated the impact of these risk factors and crude dementia incidence in this cohort. this study was approved by the regional ethics committee of uppsala (approval no. / ). since this is a registry-based study, informed consent was waived. the protocol of the study was registered a priori with the australian and new zeeland clinical trials registry (registration no. actrn ). reporting strictly follows the strobe statement [ ] . the swedish intensive care registry (sir) is a national registry to which all general icus in sweden are reporting data on all admissions [ , ] . the national patient register (npr) includes data from all in-patient hospital visits in sweden, and the cause of death registry includes deaths of all swedish residents, including all deaths abroad [ ] . both registries are run by the swedish national board of health and welfare. the swedish dementia registry (svedem) is a national quality registry started in , with primary care and specialized memory units reporting cases in sweden. the svedem had an estimated coverage ratio of - % of dementia incidence in sweden in , partly overlapping with the npr [ , ] . all adult patients aged > years who had at least one episode of intensive care in the sir in to were included. we excluded patients with a diagnosis of dementia at icu admission and patients who died or acquired a diagnosis of dementia during the first year after icu admission. patients in the sepsis diagnosis code cohort (henceforth referred to as the sepsis cohort) were identified by sepsis diagnosis codes registered in the sir. the diagnosis of severe sepsis and septic shock, represented as icd- a . ( - ), r . or r . ( - ), has to be confirmed or negated when registering a patient in the sir. those without sepsis diagnosis codes in sir were included in the no sepsis diagnosis code cohort (hereafter referred to as the no sepsis cohort). during the entire study period, the sir defined the diagnosis of sepsis, severe sepsis, and septic shock according to the second international sepsis definitions conference of [ ] . from the sir, we extracted data on the severity of illness at admission, invasive ventilator support, renal replacement therapy (rrt), icu length of stay (icu-los), and diagnoses relevant to the icu episode. for patients with repeated admissions, we used the first icu episode with a sepsis diagnosis code or, for patients without a sepsis diagnosis code, the first icu episode in the sir. we treated overlapping icu episodes as one episode. the severity of illness was initially reported as acute physiology, age, chronic health evaluation ii (apache ii) in the sir [ ] and, during , gradually substituted with the simplified acute physiology score (saps ) [ ] . death date was extracted from the cause of death registry. from the npr, we derived icd- [ ] diagnosis codes for all inpatient care episodes from years before the icu care episode to december , . the revised charlson comorbidity index (cci) [ ] was calculated using diagnoses from all health care contacts preceding or coinciding with the first icu episode. we defined dementia using the following icd- codes according to the cci [ ] : f x-f x, f , and g x- x. because the inpatient care diagnoses database only includes diagnoses from inpatient care, we incorporated data from the svedem to track down patients with dementia not admitted to the hospital. the date of dementia diagnosis was the first occurrence of the condition in the npr or the svedem. the swedish dementia centre, commissioned by the swedish national board of health and welfare, provides recommendations on the diagnostic process in suspected dementia. in both primary and specialist care, the recommendation is to use the diagnostic criteria of the icd- , especially identifying the importance of symptom stability ( months) and the exclusion of co-existing confusion [ ] . for descriptive statistics, we used counts with percentages, means with standard deviations and medians and interquartile ranges (iqr) as appropriate. we assessed the crude incidence of dementia with kaplan-meier curves using the log-rank test. for the primary analysis, hrs for the risk of dementia were calculated in a cox regression model with mortality censored. the following covariates were chosen from available variables through directed acyclic graph analysis and a literature review: sepsis; age [ ] and sex, all of which have been previously described as independent risk factors for dementia [ ] ; cci; saps box + ; hospital length of stay (h-los); icu-los; invasive ventilator therapy; and rrt. missing data were substituted by redundancy between data sources where possible. missing saps box + was substituted by multiple imputations into five datasets using the multivariate imputation by chained equations (mice) package in r [ ] . the results from the analyses on the imputation datasets were pooled using the harrel miscellaneous (hmisc) package in r. the proportional hazards assumption was deemed fulfilled after visual inspection of plots of scaled schoenfeld residuals against time and the covariates treated as continuous were evaluated for linearity by plots of martingale residuals against the covariate. because of nonlinearity for all continuous covariates, we used cubic splines in the cox model [ ] . seven sensitivity analyses were performed according to the description in additional file . we defined statistical significance as p < . . hrs for which cubic splines were applied were calculated between the th and th percentiles. data management and descriptive statistics were performed in spss for windows version (microsoft inc., il, usa). for inference tests (i.e., regression analyses) and multiple imputations, we used r software version . . (the r foundation for statistical computing, vienna, austria; https://www.r-project.org). of , patients, , ( %) were still alive and without dementia year after icu admission (fig. ) . of those , patients, , ( %) had a sepsis diagnosis code in icu care. the patients were followed for a median of . years (iqr . - . ). saps data were completely missing in . % of the patients in the sepsis cohort and . % in the no sepsis cohort. of patients with missing saps , % had a registration of an apac he ii score in the sepsis cohort and % in the no sepsis cohort. missing saps data were imputed. of all patients admitted to the icu in - , ( . %) emigrated at least once from sweden, and of these, ( . %) had at least one listing in the npr or the sve-dem > year after icu admission. patients in the sepsis cohort were older, had higher saps , and had more comorbidities, expressed as a higher cci score. they also had longer icu-los and h-los and were more commonly treated with invasive ventilation and rrt (table ) . during follow-up, the sepsis cohort had a mean of . episodes of inpatient care, whereas % of these patients had no such episode. the no sepsis cohort had a mean of . episodes of inpatient care, and % of these patients were without any such episode. the patients ultimately developing dementia were older and predominantly female and had higher saps and longer icu-los and h-los than those without dementia ( table ). in addition, those patients who developed dementia were less frequently treated with rrt and invasive ventilator therapy. finally, patients with dementia had a higher rate of acute surgical admissions, but a lower rate of planned surgical admissions. the size of these differences was generally small, however. dementia prevalence and -year mortality increased with age in patients admitted to the icu during the study and alive on the last day of follow-up (december , ) (fig. ) . in the unadjusted analysis, dementia was more common in individuals diagnosed with sepsis during their icu stay (log-rank p < . ) as depicted in the kaplan-meier survival curve (fig. ) . however, after adjusting for age, sex, cci score, saps box + , h-los, icu-los, invasive ventilator therapy, and rrt, sepsis was no longer an independent risk factor for dementia (hr . , % ci . - . ) (fig. ) in any of the pre-specified sensitivity analyses, sepsis was not an independent risk factor for dementia (additional file ). in our nationwide swedish cohort of , patients alive without dementia year after icu admission, sepsis was found to be a crude risk factor for a later diagnosis of dementia. however, after adjusting for baseline characteristics of the patients in our cohort, sepsis was no longer an independent risk factor for dementia. this finding was consistent in all performed sensitivity analyses. in a previous study [ ] , patients having survived a sepsis episode were compared with patients having survived a hospitalization without sepsis. all included individuals underwent at least one prospective cognitive testing. when followed for up to year, the sepsis patients performed worse on repeated cognitive testing. however, it is not clear whether this condition evolves into fulfilling the diagnostic criteria of dementia, and the authors did not control for age, comorbidities, or the degree of acute illness. in the present study, we controlled for several factors expressing both comorbidity and the degree of acute illness besides age. guerra et al. performed two studies on a medicare cohort. in their first study [ ] , the findings seem to confirm the hypothesis that the higher rate of observed cognitive dysfunction after sepsis is evolving into a higher rate of clinically diagnosed dementia in patients treated in the icu with sepsis than in those treated in the icu without sepsis during their hospitalization. however, they were only able to adjust for comorbidities diagnosed in the year preceding the index hospitalization, thereby risking underestimating the comorbidities. in addition, the authors run the risk of overlooking the presence of dementia diagnoses in earlier years that was not registered in the year preceding hospital admission. furthermore, because dementia is a syndrome of a slowly evolving disease [ ] , dementia diagnosed early after the index hospitalization might be an example of a clinically overt disease coming to the attention of the medical system in the convalescence period after hospitalization rather than a consequence of the sepsis episode or acute illness per se. dementia may also be a risk factor for sepsis [ ] . we sought to lessen the effect of both over-diagnosis due to hospitalization and causality problems between sepsis and dementia by excluding dementia diagnoses registered during the first year after icu admission. in the second study by guerra et al. [ ] , patients admitted to the icu with sepsis were compared with non-hospitalized patients matched on age group, sex, and race. sepsis was a significant risk factor for dementia. however, in a model adjusting for comorbid diagnoses associated with dementia during the index hospitalization, the effect of sepsis decreased compared with using the same comorbidities diagnosed before the index hospitalization. moreover, when using comorbidities diagnosed during the index quarter in the model, the effect of sepsis on the risk of dementia disappeared in line with our findings. in a casecontrol study [ ] , the odds ratio for having had a sepsis diagnosis in patients with a dementia diagnosis was higher than in age-and sex-matched controls without dementia. in their design, the authors did not account for the amount of time elapsed from sepsis to the diagnosis of dementia, nor did they adjust for comorbidities diagnosed during the index hospitalization. despite that the patients in the sepsis and the no sepsis cohorts are from the same icu cohort, they were not comparable, i.e., sepsis cohort patients had more chronic illnesses, were older, and had a higher degree of acute illness. hence, it was essential to adjust to these specific factors. our study used the revised cci as a composite fig. dementia prevalence by age interval in patients of the icu cohort alive at st of december and mortality year from icu admission. line thickness represents the number of patients at risk. icu, intensive care unit; n_mort, number at risk of mortality; n_dem, number at risk of dementia measure of the comorbid burden of each patient. we also adjusted for the severity of acute illness, as we presumed that it might mediate the effect of sepsis on dementia development. saps box + , i.e., acute illness severity, was an independent risk factor for dementia. however, in a sensitivity analysis in which saps box + was excluded from the model, sepsis was not a significant risk factor for dementia. this finding implies that saps box + does not modulate the effect of sepsis in the model. as expected, age was a strong risk factor for developing dementia during follow-up in our cohort of icu- for variables treated as continuous: age, icu-los, hospital los, cci score, and saps box + , the hr is of the difference between the th and th percentiles. hr, hazard ratio; ci, confidence interval; icu, intensive care unit; los, length of stay; cci, revised charlson comorbidity index; saps , simplified acute physiology score ; rrt, renal replacement therapy treated patients. intriguingly, in the oldest age category (> years), we observed a lower prevalence of dementia compared with another study on a swedish cohort [ ] . this lower prevalence may be related, in part, to the very high mortality rates in this elderly patient group that have been treated in the icu. surprisingly, the cci score was not an independent risk factor for dementia in the model. we speculate that this finding is due to the small difference between the th and th percentiles of the cci score. a wider range of cci might have yielded another result. for the variables in which cubic splines were applied, the hr was calculated for the difference between values at the th and th percentiles to reduce the risk of false conclusions from the hrs of these splined variables. still, despite this adjustment, results for the splined variables need to be interpreted cautiously. however, their validity as covariates of sepsisthe primary endpoint of the study-in the model is higher after cubic spline application than if we would have categorized these nonlinear variables [ ] . a major strength of this study is that our sample contains virtually all intensive care patients in sweden over years ( to ) , which represents the different socioeconomic groups of a high-income country. another strength is the possibility to follow the patients for an extended period before icu admission. such an approach allows for an accurate assessment of comorbidities in general and pre icu dementia in particular. we believe that the long mean follow-up of > years from year post-icu admission is also an important asset of the study in that most types of dementia are gradually developing diseases [ ] . our study also has by far the largest cohort of icu survivors to study the association between sepsis and dementia. finally, we were able to control for the severity of acute illness. our study has some limitations of note. the major limitation is that we define dementia as a dementia diagnosis at an inpatient visit at a hospital or a dementia diagnosis in the svedem. we thus expect to miss a proportion of patients despite using data from several registries to detect dementia in both hospital-admitted patients and outpatients. however, we have no reason to believe that dementia would be unreported to a larger extent in patients treated for sepsis in the icu as the sepsis cohort patients had more hospital inpatient visits than the no sepsis cohort patients during follow-up. this observation is possibly due to the higher comorbidity burden and higher age in the sepsis cohort patients. moreover, we choose not to include patients that did not live up to year after icu admission, resulting in excluding almost one third of the patients in the analysis. however, we found in a sensitivity analysis that our results did not change after including those patients not surviving up to year after icu admission. another potential shortcoming of the data is the possibility the patients die before they develop dementia, implying that the findings of this study could potentially need to be verified in cohorts with much lower mortality. in a sensitivity analysis, we included only patients with saps in the lowest quartile expecting a lower mortality and thus a smaller risk of dying acting as a competing event, but sepsis was not an independent risk factor in this analysis. finally, the present study is limited because % of the patients emigrated from sweden at some point during the study. however, % of these patients had at least one listing in our data sources during the follow-up, which also were the case in the complete cohort. thus, we chose not to exclude emigrated patients from the main analysis; however, doing so in a sensitivity analysis did not affect our results. because the effect of sepsis on the risk of later dementia development has been shown to be minimal in previous studies and not present at all in our study, we recommend that further research on outcome after sepsis be directed in other directions. in conclusion, although dementia was more common in the whole nation swedish icu cohort for - treatment for sepsis in the icu, sepsis was not a risk factor for later dementia after adjustment for pre-specified, relevant, baseline variables. in our sample, acute illness severity altered the risk of dementia, which might account for a fraction of the apparent causality between sepsis and dementia in icu patients. supplementary information accompanies this paper at https://doi.org/ . /s - - -y. dementia in western europe: epidemiological evidence and implications for policy making the public's perceptions about cognitive health and alzheimer's disease among the u.s. population: a national review dementia: timely diagnosis and early intervention what do we know about quality of life in dementia? a review of the emerging evidence on the predictive and explanatory value of disease specific measures of health related quality of life in people with dementia epidemiology of severe sepsis the third international consensus definitions for sepsis and septic shock (sepsis- ) does infection-induced immune activation contribute to dementia? deterioration of spatial learning performances in lipopolysaccharide-treated mice sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism the additive effect of aging on sepsis-induced cognitive impairment and neuroinflammation septic encephalopathy: relationship to serum and cerebrospinal fluid levels of adhesion molecules, lipid peroxides and s- b protein cognitive impairment in the septic brain persistent cognitive impairment, hippocampal atrophy and eeg changes in sepsis survivors long-term cognitive impairment and functional disability among survivors of severe sepsis association between sepsis and dementia risk factors for dementia after critical illness in elderly medicare beneficiaries risk of a diagnosis of dementia for elderly medicare beneficiaries after intensive care alzheimer' s disease dementia increases the risks of acute organ dysfunction, severe sepsis and mortality in hospitalized older patients: a national population-based study strengthening the reporting of observational studies in epidemiology (strobe) long-term mortality and cause of death for patients treated in intensive care units due to poisoning the swedish board of health and welfare. the national patient register. - no significant difference in cognitive decline and mortality between parkinson's disease dementia and dementia with lewy bodies: naturalistic longitudinal data from the swedish dementia registry sccm/esicm/accp/ats/sis international sepsis definitions conference apache ii: a severity of disease classification system.pdf saps -from evaluation of the patient to evaluation of the intensive care unit. part : objectives, methods and cohort description the swedish board of health and welfare available from: www. socialstyrelsen.se accessed updating and validating the charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from countries coding algorithms for defining comorbidities in icd- -cm and icd- administrative data the swedish dementia centre twenty-year changes in dementia occurrence suggest decreasing incidence in central mice: multivariate imputation by chained equations in r flexible smoothing with b -splines and penalties spurious inferences about longterm outcomes: the case of severe sepsis and geriatric conditions regression modelling strategies. . springer international publishing swizerland measuring cognition and function in the preclinical stage of alzheimer's disease. alzheimer's dement preferred reporting items for systematic reviews and meta-analyses: the prisma statement publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations henrik renlund, the statistician, is gratefully acknowledged for statistical support. authors' contributions ba, gs, iml, and ml conceived and designed the study; ba and ml acquired and analyzed the data; ba and ml drafted the manuscript; and ba, gs, iml, and ml finalized the manuscript. all authors approved the final manuscript as submitted. uppsala university hospital research fund and the centre for clinical research at region dalarna, sweden, funded this research. open access funding was provided by uppsala university. the data used in this study are available from the sir, the npr, and the svedem. however, privacy or ethical restrictions apply to the availability of these data, which were used under license for the current study. thus, these data are not publicly available. the data, however, are available from the authors upon reasonable request and with permission of the sir, the npr, and the svedem. this study was approved by the regional ethics committee of uppsala (approval no. / ). because this is a registry-based study, informed consent was waived by the same ethics committee. not applicable. the authors declare that they have no competing interests. key: cord- - qqpkfd authors: jonmarker, s.; hollenberg, j.; dahlberg, m.; stackelberg, o.; litorell, j.; everhov, a.; järnbert-pettersson, h.; söderberg, m.; grip, j.; schandl, a.; gunther, m.; cronhjort, m. title: dosing of thromboprophylaxis and mortality in critically ill covid- patients date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: qqpkfd background: a substantial proportion of critically ill covid- patients develop thromboembolic complications, but it is unclear whether higher doses of thromboprophylaxis are associated with lower mortality rates. the purpose of the study was to evaluate the association of initial dosing strategy of thromboprophylaxis in critically ill covid- patients and the risk of death, thromboembolism, and bleeding. method: all critically ill covid- patients admitted to two intensive care units in march and april were eligible. patients were categorized into three groups according to initial daily dose of thromboprophylaxis: low ( - iu tinzaparin or - iu dalteparin), medium (> iu but < iu/kilogram, kg, of body weight tinzaparin or > iu but < iu/kg of body weight dalteparin), and high dose ([≥] iu/kg of body weight tinzaparin or [≥] iu/kg of body weight dalteparin). thromboprophylaxis dosage was based on local standardized recommendations, not on degree of critical illness or risk of thrombosis. cox proportional hazards regression was used to estimate hazard ratios with corresponding % confidence intervals of death within days from icu admission. multivariable models were adjusted for sex, age, body-mass index, simplified acute physiology score iii, invasive respiratory support, and initial dosing strategy of thromboprophylaxis. results: a total of patients were included; received low, medium, and high dose thromboprophylaxis. baseline characteristics did not differ between groups. mortality was lower in high ( . %) vs medium ( . %) and low dose thromboprophylaxis ( . %) groups, p{equiv} . . the hazard ratio of death was . ( % confidence intervals . - . ) among those who received high dose, respectively . ( % confidence intervals . - . ) among those who received medium dose, as compared with those who received low dose thromboprophylaxis. there were fewer thromboembolic events in the high ( . %) vs medium ( . %) and low dose thromboprophylaxis ( . %) groups, p{equiv} . , but no difference in the proportion of bleeding events, p{equiv} . . conclusions: among critically ill covid- patients with respiratory failure, high dose thromboprophylaxis was associated with a lower risk of death and a lower cumulative incidence of thromboembolic events compared with lower doses. data on patients' demography, comorbidities (international classifications of diseases, th revision), duration of symptoms, chronic ac therapy, invasive respiratory support, and laboratory values were retrieved from patients' medical records. data was automatically and manually extracted by medical doctors and all charts and events were validated by at least one additional medical doctor. patients were categorized into three groups according to initial treatment doses of subcutaneous low-molecularweight heparin at admission to the icu. daily doses of tinzaparin and dalteparin were defined as low dose thromboprophylaxis ( - international units, iu, tinzaparin or - iu dalteparin), medium dose thromboprophylaxis (> iu but < iu/kg of body weight tinzaparin or > iu but < iu/kg of body weight dalteparin), and high dose thromboprophylaxis(≥ iu/kg of body weight tinzaparin or ≥ iu/kg of body weight dalteparin). patients who received an adjusted dose due to reduced kidney function were classified according to intended dose range. the choice of dosing strategy followed the local recommendations and were modified over time: in march, low dose thromboprophylaxis was recommended for all covid- patients at both icus. in april, the recommendations were altered to medium and then high dose thromboprophylaxis and this was continued throughout the study period in one icu. in the other icu, full dose was only used for one week, and then recommendations were altered to medium dose thromboprophylaxis again. all changes in dose were registered with new dose and date. the primary outcome was -day mortality. days alive and out of icu at day , the cumulative proportion of thromboembolic and bleeding events within days of icu admission, and maximum levels of fibrin-d-dimer were used as secondary outcome measures. thromboembolic events were pe (verified by computed tomography or by clinical suspicion of pe as cause of deterioration combined with findings of acute strain of the right heart on echocardiography), dvt (verified by ultrasound), ischemic stroke (verified by computed tomography), and peripheral arterial embolism (clinical findings of acute peripheral ischemia). bleeding events were categorized according to the world health organization (who) bleeding scale( - ): ) petechiae, tissue hematoma, oropharyngeal bleeding, ) mild blood loss, hematemesis, macroscopic hematuria, hemoptysis, joint bleeding, ) gross blood loss requiring red blood cell transfusion and/or hemodynamic instability, ) debilitating blood loss, severe hemodynamic instability, fatal bleeding, or central nervous system bleeding. baseline laboratory values were obtained from hours before to one hour after icu admission. all rights reserved. no reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint continuous values for baseline and follow-up data are presented in medians with interquartile range (iqr), while categorical or binary data are shown as numbers and proportions. differences over categories of the exposure were tested with kruskal-wallis for continuous data, and fisher's exact for categorical data. in the survival analyses, participants could accrue follow-up time from date of icu-admission, to date of death, or when days had passed since admission, whichever occurred first. in analyses of thromboembolic and bleeding events, the date of that event also led to censoring of follow-up time. kaplan-meier curves were used to estimate the cumulative risk of death, thromboembolic event, and bleeding event, and the log-rank test was used to compare the initial dosing strategies. cox proportional hazards regression was used to estimate hazard ratios (hr) with corresponding % confidence intervals (ci) of death within days from icu admission. multivariable models were adjusted for sex, age, body-mass index (bmi), simplified acute physiology score iii (saps iii), invasive respiratory support (yes/no), and initial dosing strategy of thromboprophylaxis (low, medium and high dose thromboprophylaxis) ( , ). to assess evidence of non-linearity, the second spline transformation equal to zero was tested as the quantitative covariates were modeled with restricted cubic splines at three knots at fixed percentiles ( th , th and th ) of the distribution of that covariate ( ). as there was no such evidence for age (p= . ), or saps iii (p= . ), those variables were adjusted for in a continuous fashion. although no formal evidence, there was an indication of non-linearity between levels of bmi and -day mortality (p= . ), why bmi was categorized as </≥ kg/m with a separate category for missing values (n= ). bmi was flexibly adjusted with restricted cubic splines while missing values were accounted for using chained iterations of multiple imputed data sets (n= ) ( ). although no formal evidence, there was an indication of violation of the assumption of proportional hazards when scaled schoenfeld residuals were regressed against survival time (p= . for high dose thromboprophylaxis). thus, the time-varying effect was fitted by splitting the follow-up time at days from icu-admission, and fitting the time varying covariate as an interaction-term with the main exposure. statistical significance of interaction was tested using the wald test. to account for other possible temporal changes in treatment over inclusion time, sensitivity analysis was performed with additional adjustment for admission date to icu. two-sided p< . was considered statistically significant. analysis was performed using stata . (statacorp), and r v . . (r core team ( ). r: a language and environment for statistical computing. r foundation for statistical computing, vienna, austria.). all rights reserved. no reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. out of critically ill covid- patients treated in the icu due to respiratory failure, remained after exclusion of those with short icu length of stay (n = ), ongoing ac therapy at icu admission due to dvt and/or pe (n = ), or no initial thromboprophylaxis in the icu (n = ) ( figure ). the reason for not giving thromboprophylaxis to four patients was urgent surgery for one and for the other three their prescriptions were likely overlooked; no reason could be found in the medical record. patient characteristics are described in table . the majority of patients included were men ( . %), the median age was years (iqr - ) and the median bmi was . (iqr . - . ). the most common comorbidities were hypertension, obstructive lung disease, and diabetes mellitus. median saps iii-score was (iqr - ) and . % needed invasive respiratory support. the three groups consisted of patients who received low dose thromboprophylaxis, patients who received medium dose thromboprophylaxis and patients who received high dose thromboprophylaxis. demographic and clinical characteristics did not differ between the three groups. all patients were followed-up until death or until the th day after icu-admission. the -day mortality was . % in the group with low dose thromboprophylaxis ( / ), . % with medium ( / ) and . % with high ( / ), ( table ). the hr of death was . ( % ci . - . ) among those who received high dose, respectively . ( % ci, . - . ) among those who received medium dose, as compared with those who received low dose thromboprophylaxis, ( table ). the cumulative proportion of deaths within the first -days from icu-admission differed between the three groups (p log-rank= . ). the risk of death did not differ between groups of exposure until days after admission, after which the proportion of deaths increased in the low dose thromboprophylaxis group compared to the other groups ( figure a ). when follow-up time was split and the time-varying covariate was fitted as an interaction term with the exposure (table ), the hr of high dose thromboprophylaxis was . ( % ci, . - . ) day to , compared with low dose thromboprophylaxis the same time period, while no differences were observed during day to . the interaction term itself was not significant overall (p= . ). among the first half of admissions (before april , ), . % (n= ) received low dose and . % (n= ) high dose thromboprophylaxis. corresponding proportions in the second half of admissions was . % (n= ), respectively % (n= ). in analysis with additional adjustment for median admission date, the hr of death was . ( % ci, . - . ) of high vs low dose thromboprophylaxis, respectively . ( % ci, . - . ) comparing the second to the first half of admissions. all rights reserved. no reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the median number of icu free days alive during the first days were (iqr - ) with low, (iqr - ) with medium and (iqr - ) with high dose thromboprophylaxis, (p= . ). the proportion of thromboembolic events for the three groups was . % with low, . % with medium and . % with high dose thromboprophylaxis, (p= . ). the proportion of bleeding events was . % with low, . % with medium and . % with high dose thromboprophylaxis (p= . ). cumulative proportions of thromboembolic events, and bleeding events, are depicted in figure b , and figure c, respectively. in the low dose thromboprophylaxis group, four patients suffered ischemic stroke, and two had minor intracranial hemorrhage. there were five major or severe bleeding events, three with low and two with medium dose thromboprophylaxis ( table ). dosing of thromboprophylaxis was registered and followed over time as seen in figure . of the patients ( . %) had one or more dose changes during the icu stay and for patients ( . %) the changes included an increase. there were ( . %) patients who had dose adjustments including both increases and reductions and for ( . %) patients the adjustment was a reduction compared to initial dose. the median treatment time before a change in dose was ( - ) days. median duration of thromboprophylaxis was ( - ) days. while there were no differences in fibrin-d-dimer, crp, hemoglobin (hb), platelet count and creatinine values at baseline (table ) , the maximum levels during the first days differed ( table to the best of our knowledge, this is the first study that has compared three different doses of anticoagulants to critically ill patients with covid- in relation to -day mortality, thromboembolism, and bleeding events. our main finding is that we estimated a % decreased risk of death within the first days among those who all rights reserved. no reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint received high, as compared with those who received low dose thromboprophylaxis. also, high dose thromboprophylaxis was associated with a lower incidence of thromboembolic events while no increased risk of bleeding was observed. the -day mortality was . % with low, . % with medium and . % with high dose thromboprophylaxis which could indicate a dose-response relationship. the dose of thromboprophylaxis was based on local standardized recommendations and not on degree of critical illness or risk for thrombosis. this is illustrated by the fact that there were no differences in saps iii score or fibrin-d-dimer and crp levels at baseline, and that patient characteristics were similar between groups. as the local recommendations regarding thromboprophylaxis changed over time . % of patients had a change in dose with the vast majority being increases and only . % having a reduction from initial dose at some point during the icu-stay. this suggests that the observed higher mortality in the groups with lower doses could have been even higher if the initial dosing had been sustained. our results are in congruence with another study where lower mortality was seen when mechanically ventilated covid- patients were treated with higher doses of anticoagulation ( ). in a retrospective study by trinh et al., still in pre-print, outcomes for covid- patients on invasive respiratory support were investigated with respect to dose of thromboprophylaxis. this study reports a % decreased mortality in therapeutic vs prophylactic anticoagulation, but with a trend towards increased risk of bleeding in the therapeutic group, contrary to our findings of similar proportions of bleeding events in all groups. it is still unclear how sars-cov- affects coagulation, and to what degree the hypercoagulable state contributes to the observed respiratory failure, but it is conceivable that early thrombus formation plays an important part in the rapid progression of the pulmonary disease process. subclinical bleeding could potentially impact the safety of high dose thromboprophylaxis. hemoglobin values are known to drop during intensive care. as many as % of patients are anemic after a week's icu care( , ). decreased erythropoiesis, frequent blood sampling and bleeding are known reasons why anemia is common in icu patients ( ). interestingly, no signs were found of more severe anemia in patients with higher doses of anticoagulation, perhaps because covid- patients are hypercoagulable and might not bleed easily despite high dose thromboprophylaxis. there was even a higher proportion of bleeding in the group with low dose, . %, vs high dose, . % but no significant difference. this result differs from a recent report of % incidence of bleeding among critically ill covid- patients, of which had prophylactic dose and had full dose anticoagulation ( ). all rights reserved. no reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint the present study lacks the rigor of a prospective randomized design. the study groups thus reflect the progression from low to high dose thromboprophylaxis based on modifications of local clinical guidelines over time. as the study is observational, other factors might have affected outcome. during the study period the ventilation strategy was changed from a classical acute respiratory distress syndrome strategy with low tidal volumes, fluid restriction, and heavy sedation to a more liberal strategy allowing higher tidal volumes, more fluids and less sedation. however, in analysis with additional adjustment for median admission date, the risk of death was still % lower (although not statistically significant) among those who received high dose compared with low dose prophylaxis. furthermore, patients were grouped according to initial dose of thromboprophylaxis at admission to the icu, and outcomes in relation to total dose thromboprophylaxis received (including changes in dosing strategy during the icu care) have not been analyzed. there was also a lower proportion of patients on invasive ventilation in the group with high dose, though not statistically significant, and this was adjusted for in the statistical analysis. due to the heavy work load during the pandemic, risk of complications during intrahospital transportation of critically ill patients due to respiratory instability, and the risk of viral contamination of radiology suites, it was not always possible to perform computed tomography-scans to diagnose pe. as the number of pe might be underestimated, decision was made to analyze mortality as primary outcome. the results regarding risk of bleeding should be interpreted with caution due to low numbers, limiting statistical power. thus, if high dose thromboprophylaxis is used, it is important to continue to monitor the patients closely for potential bleeding. among critically ill covid- patients with respiratory failure, high dose thromboprophylaxis was associated with a lower risk of death and a lower cumulative incidence of thromboembolic events compared with lower doses. this study suggests that high dose thromboprophylaxis should be tested in a randomized trial in critically ill covid- patients. all rights reserved. no reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint the study was approved by the regional ethical review board in uppsala, sweden, (dnr: - , amendment - ) and informed consent was waived. not applicable the datasets generated and analyzed during current study are not publicly available due to patient records' regulations but can be made available from corresponding author on request. m. cronhjort has honoraria for lectures from b. braun. with this exception the authors declare that they have no competing interests. the study has been fully funded by the authors themselves and their clinical departments. no external funding has been received. all rights reserved. no reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint we would like to thank w. müller for his whole-hearted support in data collection from electronic sources. all rights reserved. no reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september , . preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september , . preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september , . all rights reserved. no reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint all rights reserved. no reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. all rights reserved. no reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. all rights reserved. no reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september , . preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. all rights reserved. no reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint understanding pathophysiology of hemostasis disorders in critically ill patients with covid- venous and arterial thromboembolic complications in covid- patients admitted to an academic hospital in autopsy findings and venous thromboembolism in patients with covid- endothelial cell infection and endotheliitis in covid- pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- incidence of thrombotic complications in critically ill icu patients with covid- adjusted for sex, age (continuously), body-mass index (</≥ kg/m and missing [n= ]), invasive respiratory support (yes/no), and simplified acute physiology score iii (continuously) similar adjustments as in the multivariable model but complete case analysis with bmi flexibly modeled with restricted cubic splines at three knots over the th , th , and th , percentile of the distribution of body-mass index in the population. similar adjustments as in the multivariable complete case model but with body-mass index imputed due to missing values (n= ). follow-up time was split after days and the model was fitted with an interaction between thromboprofylactic strategy and follow-up time (</≥ days). p for interaction with time = . . tinzaparin, ≥ iu/kg of body weight daily, or dalteparin, ≥ iu/kg of body weight daily tinzaparin, > iu daily to < iu/kg of body weight daily, or dalteparin, > iu daily to < iu/kg of body weight daily tinzaparin, - iu daily, or dalteparin, - iu daily all rights reserved. no reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity.the copyright holder for this this version posted september , . preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity.the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint all rights reserved. no reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity.the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint key: cord- -gorp n g authors: hippisley-cox, julia; young, duncan; coupland, carol; channon, keith m; tan, pui san; harrison, david a; rowan, kathryn; aveyard, paul; pavord, ian d; watkinson, peter j title: risk of severe covid- disease with ace inhibitors and angiotensin receptor blockers: cohort study including . million people date: - - journal: heart doi: . /heartjnl- - sha: doc_id: cord_uid: gorp n g background: there is uncertainty about the associations of angiotensive enzyme (ace) inhibitor and angiotensin receptor blocker (arb) drugs with covid- disease. we studied whether patients prescribed these drugs had altered risks of contracting severe covid- disease and receiving associated intensive care unit (icu) admission. methods: this was a prospective cohort study using routinely collected data from general practices in england with . million participants aged – years. we used cox proportional hazards models to derive adjusted hrs for exposure to ace inhibitor and arb drugs adjusted for sociodemographic factors, concurrent medications and geographical region. the primary outcomes were: (a) covid- rt-pcr diagnosed disease and (b) covid- disease resulting in icu care. findings: of patients who had covid- disease, received icu care. ace inhibitors were associated with a significantly reduced risk of covid- disease (adjusted hr . , % ci . to . ) but no increased risk of icu care (adjusted hr . , % ci . to . ) after adjusting for a wide range of confounders. adjusted hrs for arbs were . ( % ci . to . ) for covid- disease and . ( % ci . to . ) for icu care. there were significant interactions between ethnicity and ace inhibitors and arbs for covid- disease. the risk of covid- disease associated with ace inhibitors was higher in caribbean (adjusted hr . , % ci . to . ) and black african (adjusted hr . , % ci . to . ) groups than the white group (adjusted hr . , % ci . to . ). a higher risk of covid- with arbs was seen for black african (adjusted hr . , % ci . to . ) than the white (adjusted hr . , % ci . to . ) group. interpretation: ace inhibitors and arbs are associated with reduced risks of covid- disease after adjusting for a wide range of variables. neither ace inhibitors nor arbs are associated with significantly increased risks of receiving icu care. variations between different ethnic groups raise the possibility of ethnic-specific effects of ace inhibitors/arbs on covid- disease susceptibility and severity which deserves further study. the first cases of infection caused by severe acute respiratory syndrome coronavirus (sars-cov- ) (covid- ) in the uk were confirmed on january . since then the disease has spread rapidly through the population. there are no vaccines, preventative or curative treatments for covid- disease and only one possible diseasemodifying treatment so the government has used social distancing as a population-level intervention to limit the rate of increase in cases. case series of confirmed covid- have identified age, sex, comorbidities and ethnicity as potentially important risk factors for susceptibility to infection, hospitalisation or death due to infection. in addition, chronic use of some medications at the time of exposure has been suggested as a potential risk factor for infection or severe adverse outcomes due to infection, although the evidence is currently too limited to confirm or refute these concerns. understanding this chronic medication use is important because medications could be modified in individuals or at a population scale to alter the likelihood of infection or adverse outcomes. furthermore, associations between medications and improved outcomes, if confirmed from large cohorts, could provide a basis for rapid prioritisation in prospective randomised clinical trials, and might provide important insights into disease mechanisms and pathogenesis. sars-cov- and sars-cov- , which have been responsible for the sars epidemic and for the covid- pandemic, respectively, interface with the renin-angiotensin-aldosterone system (raas) through ace , an enzyme that modulates the effects of the raas but is also the primary receptor for both sars viruses. the interaction between the sars viruses and ace may be one determinant of their infectivity, and there are concerns that raas inhibitors may change ace expression and hence covid- virulence. this hypothesis has been extensively reviewed. ace inhibitors and angiotensin receptor blocker (arb) drugs are recommended by the national institute for health and care excellence as firstline treatment for patients under years of age with hypertension and second-line treatment for those over years of age and for those of african descent. ace inhibitors are also widely used to treat congestive cardiac failure. uncertainty around possible associations of these drugs with covid- disease, and the subsequent risk that patients might special populations stop taking these drugs of proven effectiveness, has led to regulatory and professional bodies issuing statements urging patients to keep taking their regular medications. although several studies have considered the effect in hospitalised patients of drugs acting on the renin-angiotensin on disease course, none has looked at population use of these drugs to determine if they modulate susceptibility. we report a large, population-based study where we examined the drug histories of approximately % of all patients tested positive for coronavirus in england to determine if there was an independent association between ace inhibitor and arb drug prescription and severe covid- disease susceptibility and progression. we undertook a large, open cohort study of all patients aged - years registered with general practices in england contributing to the qresearch database (v. , uploaded march ) linked to covid- rt-pcr test records (updated until april ) and with intensive care records (updated until april ). the protocol is published. we included general practices in england contributing to the qresearch database from which current data were available. qresearch is a high-quality research database established in , which has been extensively used for pharmaco-epidemiological research. qresearch is the largest and most representative general practitioner (gp) practice research database nationally. two national databases were linked to qresearch. the first was the national registry of covid- rt-pcr test positive results held by public health england (phe). since covid- is a notifiable disease, laboratories in england are required to send results of all tests to phe. at the time of analysis, positive covid- test results were available from individuals in england, until april , of whom were aged - years. of these, ( . %) were linked to qresearch patients. the second linked database was the intensive care national audit and research centre (icnarc) case mix programme (cmp) database. this is a high-quality, clinical research database which includes contemporaneous data from icus in england, wales and northern ireland and is widely used for cohort studies, comparative audit and outcome data ascertainment for randomised clinical trials. as of april , there were patients admitted for icu care with covid- disease, of whom were aged - years. of these, ( . %) were linked to qresearch. we identified a cohort consisting of all patients aged - years who were fully registered with the gp practices on the start date ( january ). patients entered the cohort on this date and were censored at the earliest of the date of death, leaving the gp practice, the study end date ( april ) or occurrence of the relevant outcomes of interest. we used all the relevant patients on the pooled database to maximise power and to enhance generalisability of the results. during our study period, over . % of all covid- rt-pcr tests in england were undertaken in a hospital setting for symptomatic patients sufficiently unwell to warrant hospital assessment and admission. our main outcomes for these analyses were: . covid- rt-pcr test positive disease. . covid- -related admission for icu care. we had two main exposures of interest: . ace inhibitors. . arbs. we classified a patient as having had exposure to either medication if they had three or more prescriptions, including a prescription issued in the days preceding cohort entry. we extracted data from the gp record for explanatory and potential confounding variables including variables with some evidence of being risk factors for covid- disease or severe disease as measured by icu admission and variables likely to influence prescribing of ace inhibitors and arb medications. we used the latest information recorded in the gp record on or before study entry as follows: . where quintile is the most affluent and is the most deprived). . geographical region within england, categorised into groups. . body mass index (kg/m ), categorised into five categoriesunderweight (< kg/m ); normal weight ( - . kg/m ); overweight ( - . kg/m ); obese ( - . kg/m ); severely obese (> kg/m ). . smoking status in five categories-never-smoker; exsmoker; light smoker ( - cigarettes/day); moderate smoker ( - cigarettes/day); heavy smoker ( + cigarettes/ day). . gp recorded diagnosis of type or type diabetes. . gp recorded diagnosis of cardiovascular disease. . gp recorded diagnosis of congestive cardiac failure. . gp recorded diagnosis of hypertension. . gp recorded diagnosis of atrial fibrillation. . gp recorded diagnosis of asthma. . gp recorded diagnosis of chronic obstructive pulmonary disease. . gp recorded diagnosis of chronic kidney disease (ckd stage , or ). we also extracted medication use for the following classes of drugs as potential confounding variables. we focused on classes of drugs rather than individual drugs to ensure adequate power. we classified patients as exposed using the same definitions as ace inhibitors and arbs. . drugs to treat type diabetes including sulfonylureas, biguanides and other drugs (thiazolidinediones, gliptins, sodium glucose co-transporter inhibitors, glucagon-like peptide- receptor agonists, meglitinides). . anticoagulant drugs (warfarin and direct oral anticoagulants). . antiplatelet drugs. . calcium channel blocking drugs. . thiazides. . potassium-sparing diuretics. . statins. after conducting univariable analyses, we conducted a multivariable analysis based on patients with complete data. we then used multiple imputation with chained equations to replace missing values for ethnicity, body mass index and smoking status and used these values in our main analyses. we included all exposure and explanatory variables in the imputation model, along with the nelson-aalen estimator of the baseline cumulative hazard, and the outcome indicator. we carried out five imputations. we used cox's proportional hazards models to estimate adjusted hrs for ace inhibitors and arbs adjusting for the confounders. we tested for interactions between ace inhibitors, arbs and ethnicity. we undertook several sensitivity analyses. to further reduce indication biases, additional analyses restricted to patients with hypertension or heart failure to directly compare risks for ace inhibitors and arbs with other antihypertensive drugs. we also undertook analyses adjusted for the number of antihypertensive drugs as a proxy for severity of hypertension (untreated hypertension; monotherapy; dual therapy; triple or more therapy). lastly, we changed the definition of exposure to requiring a prescription within the last days prior to cohort entry. we used p< . (two-tailed) to determine statistical significance, to take account of multiple testing. patient representatives from the qresearch advisory board have advised the whether to undertake this research, on the data linkage, public interest and likely public benefit resulting from the study, dissemination of studies using qresearch data, including the use of lay summaries describing the research and its findings. one thousand two hundred five qresearch practices were included in our analysis. of the patients registered on january , were aged between and years. of these, ( . %) had a covid- rt-pcr positive result and were admitted to an icu. table shows the baseline characteristics of the overall cohort consisting of patients. the median age was years (iqr - ); self-assigned ethnicity was recorded in ( . %). a total of patients ( . % of ) were currently prescribed an ace inhibitor and ( . %) were currently prescribed an arb drug. table shows the proportions of patients prescribed ace inhibitors and arbs by ethnicity and other characteristics. figure a and b show adjusted hrs for each outcome based on the multiply-imputed data. figure a and b show the same for the complete case analysis. ace inhibitors were associated with a significantly reduced risk of covid- disease requiring hospital admission (adjusted hr . , % ci . to . ) but were not significantly associated with risk of icu care (adjusted hr . , % ci . to . ) after adjusting for a wide range of confounders. adjusted hrs for arbs were . ( % ci . to . ) for covid- disease and . ( % ci . to . ) for icu care. the results there were significant interactions with ethnicity for ace inhibitors and arb (both p< . ) for the covid- rt-pcr diagnosed disease outcome. table shows the adjusted hrs for ace inhibitor and arb use for each of the ethnic groups. for ace inhibitors the risks of covid- disease were significantly higher in the caribbean and black african groups than the white group, with a significantly increased risk in the black african group (adjusted hr . , % ci . to . ), although the cis were wide in the non-white ethnic groups. the risks associated with arb use were significantly higher in the other asian, black african, chinese and other ethnic group than the white group. while men were at no greater risk of having covid- diagnosed disease requiring hospital admission than women (adjusted hr . , % ci . to . ), they had a threefold increased risk of icu admission despite adjustment for confounders ( figure b) had an increased risk of covid- disease and icu admission. there were regional variations in the risk of covid- disease and icu admission, the south west had the lowest risk of both outcomes, the north east had the highest risk of covid- disease and london had the highest risk of icu admission. overall, compared with the white ethnic group, all other ethnic groups except chinese and bangladeshi groups were associated with a significantly increased risk of covid- disease. highest risks were found for the other asian group who had a . -fold increased risk; black african ( . -fold increased risk); black caribbean ( . -fold increased risk) and indian ( . -fold increased risk) compared with the white group. the comparative risk of icu admission in these ethnic groups was even higher. compared with the white group, all other ethnic groups had twofold to threefold higher risks of icu admission, but smaller numbers of people in these groups led to some imprecise estimates. the risks of covid- disease and of icu admission were higher in those with increasing bmi. the most pronounced gradient was for icu admission, where being obese was associated with a . -fold increased risk and severe obesity with a . fold increased risk compared with the normal weight group. this was after adjustment for all other variables shown in figure b. there was a small increased risk of both adverse outcomes among ex-smokers compared with never-smokers. we observed a markedly decreased risk of both covid- disease and icu admission in smokers. the apparent protective association was greatest for heavy and moderate smokers and most markedly on the risk of icu admission which was % lower in heavy smokers compared with non-smokers ( figure b) . each of the comorbidities included in the analysis was associated with an increased risk of covid- disease. however, only ckd, hypertension, type and type diabetes were significantly associated with an increased risk of icu admission. figure a shows significantly increased risks of covid- disease associated with anticoagulants, antiplatelets, other diabetes drugs; significantly decreased risks of % for statins, % for thiazides and % for calcium channel blockers and no significant association for biguanides, beta-blockers or sulfonylureas. for icu admission there was a significantly increased risk for calcium channel blockers, but no significant associations with the other drugs (at p< . ). in this very large population-based study, ace inhibitor and arb prescriptions were associated with a reduced risk of covid- rt-pcr positive disease, having adjusted for a wide range of demographic factors, potential comorbidities and other medication. there was no evidence of an increased or reduced risk of icu admission with either drug. there were marked variations in risk of covid- disease and of requiring icu admission by ethnic group, with highest rates among black, asian, and minority ethnic (bame) groups. this association is important and adds to existing knowledge since it is not explained by age, sex, deprivation, geographical region or several comorbidities and intercurrent medications included in our analysis. to date, published studies reporting associations between chronic medication with ace inhibitor or arb drugs and covid- infections are limited to hospitalised patients or those attending a hospital clinic. this allows the study of drug treatment effects on the in-hospital disease course but not effects on disease susceptibility since there is no information on medication use in the uninfected or less severely infected population. most in-hospital studies are relatively small containing low numbers of patients or ace inhibitors of arbs in comparison to our study. however, two were able to correct for the confounding effects of age, gender, comorbidities and in-hospital medications. in one study of patients with hypertension of whom were taking ace inhibitors/arb, in-hospital use of ace inhibitor or arb medication was associated with a lower risk of all-cause in-hospital mortality (adjusted hr . ; % ci . to . ; p= . ). in the larger patient study ( taking ace inhibitors and arbs), ace inhibitors were associated with reduced in-hospital mortality ( . % vs . %; or . ; % ci . to . ) but arbs were not ( . % vs . %; or . ; % ci . to . ). conversely, there was no evidence of reduced risk in outcomes in patients receiving ace inhibitor and arb drugs in initial reports from new york. in our study, prior prescription of ace inhibitor and arb drugs did not have a significant effect on the risk of patients developing covid- disease severe enough to require icu care. in contrast, we found that previously prescribed ace inhibitor and arb drugs are associated with the likelihood of an individual testing positive for covid- in a hospital setting. the effect was similar for both drug classes. this may indicate that drug treatment at the time of exposure altered susceptibility to covid- infection and/or altered the likelihood of an infection progressing to the point where testing is sought. it is also possible that this reflects a 'healthy user' selection bias. there are no other population-based studies of ace inhibitor/arb use and covid- infection. losartan is already being tested in a clinical trial as a treatment of covid- infection. its efficacy may depend on the context in which it is tested. since the recommendations for treatment of hypertension differ according to ethnic groups and age, we considered the possibility that these factors might contribute to the observed association between ace inhibitor or arb use and covid- disease or severity. ace inhibitors are recommended as first-line treatment for hypertension, whereas calcium channel blockers are recommended in patients of black ethnic origin. indeed, there were significant interactions between ethnicity, ace inhibitor and arbs for covid- disease. arbs were significantly less protective in the other asian, black african, chinese and other ethnic group than the white group. ace inhibitors appeared less protective in the caribbean than the white group and were associated with an increased risk of covid- disease in the black african group. this raises the possibility of ethnic-specific effects of ace inhibitors/arbs on covid- disease susceptibility and severity or unmeasured confounding. however, as numbers were relatively small in the non-white ethnic groups so cis were wide, caution is needed in interpreting these results. studies of patients hospitalised with covid- have noted a greater than expected number of patients with hypertension, and hypertension appears to be a risk factor for more severe covid- disease across many studies. in our study, hypertension was a risk factor for being tested positive for covid- in a hospital setting independent of ace inhibitor and arb treatment, but was only modestly associated with likelihood of icu admission. we found an expected association with obesity, with those who are obese or severely obese having higher risk of covid- disease and icu admission. however, we have reported a counterintuitive finding for smoking, with light, moderate and heavy smokers having a lower risk for both covid- disease and icu admission. one systematic review concluded on the basis of limited evidence either there is no difference in risk by smoking status or that there is an increased risk in smokers. however, our data are consistent with very low rates of smoking seen in patients presenting with covid- in wuhan and similar data from the usa and with the findings of a more limited analysis of patients with covid- in france. this may reflect a general immunomodulatory effect, a mechanism that is thought to explain the lower incidence of sarcoidosis, extrinsic allergic alveolitis and ulcerative colitis in current smokers. alternatively, smoking may cause increased ace mrna expression in human lung much as ace inhibitors or arbs are believed to, suggesting a possible common protective mechanism for severe covid- disease. additional possible mechanisms include a direct protective effect of nicotinic receptor stimulation or an association of smoking with another protective factor. this finding arose when including smoking status as a confounder and should be interpreted cautiously. further studies are required to verify the apparent protective association, determine whether it is independent of other risk factors, and investigate potential mechanisms. we have used two high-quality, established large validated research databases (qresearch and icnarc cmp) and linked them to the national register of covid- test results. our study is observational with strengths and inherent limitations since the data were collected as part of routine nhs care. key strengths include the use of highquality, established validated databases, size, representativeness, lack of selection, recall and respondent bias. uk general practices have good levels of accuracy and completeness in recording clinical diagnoses and prescriptions and provide the ability to update analyses as data change over time. it is therefore likely to be representative of the population of england. it has good face validity since it has been conducted in the setting where most patients in the uk are assessed, treated and followed up. we have been able to adjust for a wide range of confounders based on detailed coded information recorded in the patients' electronic medical record. we restricted the sample for these analyses to only include patients with hypertension or heart failure so that all patients, whether treated with ace inhibitors/arbs or not, had the same indication for treatment. this is an important additional analysis as hypertension and heart failure themselves are associated with adverse covid- outcomes, and this restricted analysis reduces their confounding effect and allows for a more direct comparison of the antihypertensive drugs in people with indications for their use. we also accounted for ethnicity and other confounding variables in this restricted analysis which could influence the selection of an antihypertensive treatment and also be associated with covid- outcomes. some systematic differences are still likely between patients who are treated and those who are not, such as severity of hypertension. we have carried out an additional analysis where we adjusted for a proxy measure of severity. there may be some over-ascertainment of exposure to medication since our definition was based on issued prescriptions rather than dispensed medication. our analyses focused on drug classes rather than individual drugs as there were insufficient cases to support an analysis at individual drug level. we have not investigated the relationship between the intensity and duration of exposure and the risk of disease in this early analysis. we investigated the more mechanistically likely and therefore immediately clinically important drug associations. other drug classes can be investigated as numbers accrue. data on community and care home deaths or deaths occurring within hospital but not in icu are not yet available from hospital episode statistics and civil registrations. linkage of the gp data to national registries of outcome data, updated in near real time, will have minimised ascertainment bias relating to laboratory confirmed cases. however, there will be underascertainment of total covid- cases due to the current absence of widespread systematic testing strategy in the uk, and due to false negative tests. as uk health policy during the study period confined testing for covid- to hospitalised patients, our data focus on the incidence of more severe disease, rather than all cases, as most people with probable covid- are not admitted to hospital. some patients deemed to be at high risk of adverse outcomes of covid- will have self-isolated during our study period to reduce their risk of contracting the virus and if effective, may result in a selection bias with such patients less likely to be become infected and subsequently admitted to hospital or icu. not all acutely unwell patients in hospital are admitted to icu and this may result in a selection bias. admission to icu is limited to those who might benefit from this treatment and so varies on the basis of patient demographic and medical characteristics. data on deaths in icu were available to us but a significant proportion of patients admitted to an icu were still being treated in an icu and this varied by region as the pandemic spread. for this reason, icu deaths were not included in the analysis. further analyses of mortality will be undertaken once the relevant data (including out-of-hospital deaths) become available. we have undertaken two new novel data linkages by linking qresearch to both covid- test results and outcomes recorded on the icnarc cmp data. this new linked data asset is a valuable resource for future research projects. in this very large population-based study, ace inhibitor and arb prescriptions were associated with a reduced risk of covid- rt-pcr positive disease in a hospital setting adjusting for a wide range of demographic factors, potential comorbidities and other medication. there was no evidence of an increased or decreased risk associated with either drug for icu admission. there are marked variations in risk of covid- disease and icu admission by ethnic group, with highest rates among bame groups. the strength of this association is greater with the more severe outcome and is not explained by age, sex, deprivation, geographical region or several comorbidities and intercurrent medications included in the analysis. the counterintuitive finding of smokers having a lower risk of covid- disease requiring hospital admission and icu admission deserves further study. what is already known on this subject? ► there is uncertainty about the interaction of ace inhibitor and angiotensin receptor blocker (arb) drugs with covid- disease susceptibility and disease severity. what might this study add? ► in this very large population-based study, treatment with ace inhibitor and arb prescriptions is associated with a reduced risk of covid- rt-pcr positive disease after adjusting for a wide range of variables. ► neither ace inhibitors nor arbs are associated with increased risks of receiving icu care for covid- disease. ► there are significant interactions with ethnicity for ace inhibitors and arbs for covid- disease with higher risks among the non-white ethnic groups particularly black african patients compared with the white group, although the confidence intervals for some analyses are wide; this finding is important and adds to existing knowledge. how might this impact on clinical practice? ► neither ace inhibitors nor arbs are associated with increased risks of covid- rt-pcr positive disease or of receiving icu care for covid- disease. ► variations between different ethnic groups raise the possibility of ethnic-specific effects of ace inhibitors/arbs on covid- disease susceptibility and severity which deserves further study. hopes rise for coronavirus drug remdesivir hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease clinical presentation and initial management critically ill patients with severe acute respiratory syndrome coronavirus (sars-cov- ) infection in brescia, italy does comorbidity increase the risk of patients with covid- : evidence from meta-analysis ethnicity and covid- : an urgent public health research priority association of inpatient use of angiotensinconverting enzyme inhibitors and angiotensin ii receptor blockers with mortality among patients with hypertension hospitalized with covid- renin-angiotensin-aldosterone system inhibitors in patients with covid- hypertension in adults: diagnosis and management nice guideline european society of cardiology. position statement of the esc council on hypertension on ace-inhibitors and angiotensin receptor blockers association of renin-angiotensin system inhibitors with severity or risk of death in patients with hypertension hospitalized for coronavirus disease (covid- ) infection in wuhan, china presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area anticholinergic drug exposure and the risk of dementia: a nested case-control study spatial distribution of clinical computer systems in primary care in england in and implications for primary care electronic medical record databases: a cross-sectional population study admission patterns and survival from status epilepticus in critical care in the uk: an analysis of the intensive care national audit and research centre case mix programme database development and validation of the new icnarc model for prediction of acute hospital mortality in adult critical care imputation is beneficial for handling missing data in predictive models disparities in the risk and outcomes of covid cardiovascular disease, drug therapy, and mortality in covid- association of use of angiotensin-converting enzyme inhibitors and angiotensin ii receptor blockers with testing positive for coronavirus disease (covid- ) losartan for patients with covid- not requiring hospitalization covid- and smoking clinical characteristics of coronavirus disease in china preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease -united states low incidence of daily active tobacco smoking in patients with symptomatic covid- nicotine treatment for ulcerative colitis is smoking beneficial for granulomatous lung diseases? tobacco smoking increases the lung gene expression of ace , the receptor of sars-cov- a nicotinic hypothesis for covid- with preventive and therapeutic implications sources, uses, strengths and limitations of data collected in primary care in england key: cord- -jrz v authors: van arkel, andreas l. e.; rijpstra, tom a.; belderbos, huub n. a.; van wijngaarden, peter; verweij, paul e.; bentvelsen, robbert g. title: covid- –associated pulmonary aspergillosis date: - - journal: am j respir crit care med doi: . /rccm. - le sha: doc_id: cord_uid: jrz v nan netherlands emerged as a hotspot for covid- , and we noticed cases of invasive pulmonary aspergillosis (ipa) occurring in patients with covid- admitted to the icu. here, we describe the clinical characteristics of covid- associated pulmonary aspergillosis (capa) cases and the frequency in our icu. in the first weeks of the outbreak, adult patients with laboratory-confirmed covid- were admitted to the amphia hospital breda, a -bed teaching hospital. of these patients, ( %) required mechanical ventilation on icu. eleven icu patients with covid- developed a secondary infection, of whom six ( . %) were presumed to have ipa. we identified aspergillus fumigatus in five patients, and in three patients, the aspergillus antigen galactomannan (gm) (platelia aspergillus; biorad) was found positive on bal fluid (table ) . three patients had preexisting lung diseases, but none were positive for the european organisation for research and treatment of cancer (eortc) and mycoses study group education and research consortium (msgerc) host factor ( ). three patients received corticosteroids before icu admission; however, either the dose received was , . mg/kg/d or the duration was , weeks. no other immunosuppressive medication was given before capa diagnosis, and all were treated for covid- with chloroquine and lopinavir/ritonavir. there were no significant differences in clinical characteristics between icu patients with covid- with presumed capa and those without presumed capa (table ) . capa occurred after a median of . days (range, - ) after covid- symptom onset and at a median of days (range, - ) after icu admission. chest computed tomographic scan was performed in one patient without apparent signs of fungal infection. in one patient, the bronchoscopy was abnormal, with mucoid white sputum in the left bronchus. serum gm tested negative in three patients. voriconazole and anidulafungin combination therapy was initiated in five patients, and one patient received liposomal amphotericin b. four ( . %) patients died at a median of icu days ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . autopsies were not performed because of concerns for the risk of contamination. we observed a high incidence ( . %) of presumed aspergillosis in our cohort of icu patients, which might indicate that patients with covid- are at risk for developing ipa. secondary fungal infections are increasingly being reported in patients with covid- . studies from wuhan, china, reported secondary fungal infections in of ( . %) patients and in of ( . %) critically ill patients ( , ) . subsequent reports from europe indicate that ipa may be found in association with severe covid- . lescure and colleagues described an icu patient with covid- with antifungal treatment for a. flavus who died on day after symptom onset ( ) . a research letter reports a fatal case of pulmonary aspergillosis coinfection in an immunocompetent patient ( ) . a case series from france reported presumed capa in of ( . %) icu patients with covid- , and a series from germany reported capa in of ( . %) icu patients. allcause mortality was three of nine ( . %) in the french capa series and four of five ( %) in the german series ( , ) . this high incidence of secondary aspergillosis in covid- cases resembles the high rates ( % and %) of influenza-associated pulmonary aspergillosis (iapa) that have been reported in icus in the netherlands and belgium ( ) . one problem is that there is no case definition for capa. however, a case definition for iapa was recently proposed by an expert panel, and this could be used to classify patients with capa ( ) . in the iapa case definition, host factors are not used to classify patients because iapa may develop in any patient with severe influenza. diagnostic criteria include proven influenza infection with clinical symptoms and a gm index of > on bal or > . on serum, or aspergillus spp. cultured from bal ( ). when we apply the iapa case definition to our cases, three (table ) cases could be classified as probable capa on the basis of bal gm detection. the remaining three patients might classify as possible capa, with clinical deterioration and a. fumigatus recovered from tracheal aspirates because bronchoscopy was not performed. however, recovery of aspergillus from upper respiratory samples may represent colonization and not invasive pulmonary disease. although % of patients with iapa had positive bal gm and % had positive serum gm in a retrospective icu study ( ) , the performance of gm in bal and serum of patients with capa remains to be further evaluated, as it may differ from iapa. indeed, in three of our patients with capa, circulating gm was not detected in serum. in one patient, the serum gm index was . , which is borderline negative. including our case series, to date, icu patients have been reported with presumed capa ( ) ( ) ( ) ( ) . only three patients tested gm-positive in serum. it is important to investigate the diagnostic value of serum gm in capa, as there is a general reluctance to perform bronchoscopy in patients with covid- because of the risks for the patient and the pulmonologist. for capa, some clinical characteristics are similar to those of iapa, including early symptom onset after icu admission, absence of eortc/msgerc host factors, and a high icu mortality. invasive aspergillus tracheobronchitis (with plaque formation), which is a common manifestation of iapa, was, however, not registered in these patients. three patients were known to have chronic lung disease, which makes differentiation between ipa and aspergillus colonization challenging. the diagnosis of iapa has controversies because varying frequencies of the infection have been reported in icu influenza studies. geographical differences may explain the observed variations, although differences in diagnostic approaches are also likely to contribute. iapa may remain undiagnosed because respiratory deterioration is considered to be caused by bacterial coinfection rather than fungal infection, and appropriate fungal diagnostics are not performed ( ) . sars-cov- infection might be a risk factor for ipa, and early diagnosis and prompt treatment for capa in icu patients seems warranted because high mortality rates have been reported. in our center, on suspicion of capa, a diagnostic workup is performed that includes serum gm and, if feasible, bronchoscopy with bal for fungal culture and gm. antifungal therapy is started in patients highly suspected of having capa while awaiting results of fungal diagnostics. until the risk of ipa in severe covid- is better understood, infectious disease specialists, icu physicians, pulmonologists, and clinical microbiologists should be aware of this secondary infection. n covid- does not lead to a "typical" acute respiratory distress syndrome clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study revision and update of the consensus definitions of invasive fungal disease from the european organization for research and treatment of cancer and the mycoses study group education and research consortium clinical features of fatal cases of covid- from wuhan: a retrospective observational study detectable serum sars-cov- viral load (rnaaemia) is closely correlated with drastically elevated interleukin (il- ) level in critically ill covid- patients clinical and virological data of the first cases of covid- in europe: a case series prevalence of putative invasive pulmonary aspergillosis in critically ill patients with covid- covid- associated pulmonary aspergillosis. mycosis [online ahead of print fatal invasive aspergillosis and coronavirus disease in an immunocompetent patient. emerg infect dis dutch mycoses study group. influenzaassociated aspergillosis in critically ill patients international expert review of influenza-associated pulmonary aspergillosis in icu patients and recommendations for a case definition influenza-associated pulmonary aspergillosis: a local or global lethal combination? clin infect dis author disclosures are available with the text of this letter at www.atsjournals.org. key: cord- -vof qat authors: jain, vageesh; yuan, jin-min title: systematic review and meta-analysis of predictive symptoms and comorbidities for severe covid- infection date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: vof qat background/introduction covid− , a novel coronavirus outbreak starting in china, is now a rapidly developing public health emergency of international concern. the clinical spectrum of covid− disease is varied, and identifying factors associated with severe disease has been described as an urgent research priority. it has been noted that elderly patients with pre-existing comorbidities are more vulnerable to more severe disease. however, the specific symptoms and comorbidities that most strongly predict disease severity are unclear. we performed a systematic review and meta-analysis to identify the symptoms and comorbidities predictive of covid− severity. method this study was prospectively registered on prospero. a literature search was performed in three databases (medline, embase and global health) for studies indexed up to th march . two reviewers independently screened the literature and both also completed data extraction. quality appraisal of studies was performed using the strobe checklist. random effects meta-analysis was performed for selected symptoms and comorbidities to identify those most associated with severe covid− infection or icu admission. results of the studies identified, were selected after title and abstract analysis, and studies (including covid− patients) were chosen for inclusion. the icu group were older ( . years) compared to the non-icu group ( years), with a significantly higher proportion of males ( . % vs. . %, p= . ). dyspnoea was the only significant symptom predictive for both severe disease (por . , % ci . − . ) and icu admission (por . , % ci . − . ). notwithstanding the low prevalence of copd in severe disease and icu-admitted groups ( . % and . %, respectively), copd was the most strongly predictive comorbidity for both severe disease (por . , % ci . − . ) and icu admission (por . , % ci . − . ). cardiovascular disease and hypertension were also strongly predictive for both severe disease and icu admission. those with cvd and hypertension were . ( % ci . − . ) and . ( % ci . − . ) times more likely to have an icu admission respectively, compared to patients without the comorbidity. conclusions dyspnoea was the only symptom strongly predictive for both severe disease and icu admission, and could be useful in guiding clinical management decisions early in the course of illness. when looking at icu-admitted patients, who represent the more severe end of the spectrum of clinical severity, copd patients are particularly vulnerable, and those with cardiovascular disease and hypertension are also at a high-risk of severe illness. to aid clinical assessment, risk stratification, efficient resource allocation, and targeted public health interventions, future research must aim to further define those at high-risk of severe illness with covid− . the ongoing novel coronavirus outbreak is a public health emergency of international concern (pheic), involving a novel type of coronavirus originally identified in wuhan, china. at the time of writing, there have been , confirmed cases around the world with , deaths ( ) . defining the spectrum of clinical manifestations and the risk factors for severe covid- infections has been identified as an urgent research priority ( , ) . as the virus spreads globally it is likely that government strategies will shift from containment and delay towards mitigation ( ) . this will involve rapidly scaling up healthcare resources including staff, equipment, facilities, and training, to effectively identify and treat patients. to maximise the use of these limited resources it will be imperative that clinicians are able to triage covid- patients likely to recover after a mild illness from those who are not. in order to do this, a better understanding of the symptoms and comorbidities (which are the first and most routinely collected components of patient data) related to covid- severity is required. this can improve patient outcomes through three chief mechanisms: early clinical intervention in high-risk patients, designing appropriate clinical pathways and risk prediction tools, and the efficient allocation of scarce resources and expensive treatments. further still, the early identification of individuals more likely to deteriorate can help direct appropriate public health actions to protect the vulnerable and prevent further spread of infection. a recent meta-analysis of symptoms in , covid- patients from studies found that fever and cough were the most common symptoms, with . % and . % experiencing these, respectively ( ) . it also found that the case fatality rate (cfr) was . %, but the association between individual patient factors and severe infection was not investigated. most reported cases have occurred in adults (median age years) ( ) . according to most recent us centers for disease control and prevention (cdc) guidance, risk factors for severe illness are not yet clear, although older patients and those with chronic all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted march , . . https://doi.org/ . / . . . doi: medrxiv preprint medical conditions may be at higher risk. ( ) the primary aim of this study is therefore to conduct a systematic review and meta-analysis, aggregating all currently available data from published studies, of symptoms and comorbidities predictive for severe illness with covid- . this study was prospectively registered on prospero. identification of relevant existing literature was performed by an online search in three databases: medline, embase and global health, for studies published from st january to th march . the mesh headings (keywords) searched were 'ncov*' or 'coronavirus' or 'sars- -cov' or 'covid*' and 'symptom*' or 'clinical' or 'predict*' or 'characteristic*' or 'co-morbidit*' or 'comorbidit*' or 'condition*'. two reviewers (vg, jmy) independently screened the list of titles and abstracts, and the full text of chosen manuscripts. disagreements on which manuscripts to include during both title and abstract screen, and the subsequent full-text analysis, were discussed until a conclusion was reached. in addition to the medline/embase/global health search, citation tracking was used to identify any remaining relevant published studies, though none were identified. unpublished studies were not retrieved due to uncertain data quality. all studies evaluating individual symptoms and comorbidities in predicting severe infection (as measured by disease severity criteria, or icu admission) were included. all studies of any design, from any time since the outbreak started (in december ) were eligible, except case reports of individual patients or literature reviews. to avoid selection bias, no subjective quality criteria were applied to the studies for inclusion. exclusion criteria included: [ ] studies of exclusively paediatric or pregnant patients, due to the varying presentation of covid- in these groups, [ ] insufficient data on symptoms/comorbidities on admission in either severe or non-severe disease groups (or icu and non-icu all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted march , . . https://doi.org/ . / . . . doi: medrxiv preprint groups), [ ] coronavirus strains other than covid- and [ ] studies not written in english, because of practical limitations with translation. two reviewers independently extracted data from the included studies for both narrative synthesis and statistical analysis. from each study, various details including the study population, investigated predictive symptoms or comorbidities, and the definitions used to measure outcomes, were extracted into microsoft excel. these details are presented by study in table . the number of patients in each study, both with and without each symptom or comorbidity, was extracted for statistical analysis (described below). the symptoms or comorbidities presented were investigated in at least three included studies. where studies measured symptoms ambiguously (including abdominal pain/diarrhea ( ) , myalgia/fatigue ( ) , and nausea/vomiting ( )), this data was excluded. some studies reported heart disease and stroke separately ( ) ( ) ( ) . to allow comparability between studies for meta-analysis, these were grouped into a single predictor (cardiovascular disease). one study was excluded from the analysis of dyspnoea as a predictor of severity, as dyspnoea was part of the definition for severity used by the authors ( ) . for disease severity, the included studies varied in their differentiation of patients' disease status, with classifications of 'mild, moderate, severe and critical' ( ) , 'ordinary and severe/critical' ( ), 'common and severe' ( ) , and 'non-severe and severe', disease ( , ) . the first outcome measure used was severe (including both severe and critical cases) vs. non-severe disease. for icu admission, the included studies varied in their definition of icu admission, with classifications of 'icu, mechanical ventilation or death and non-icu' ( ) , and 'icu and non-icu' ( , ) . the second outcome measure used was icu admission all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in patient numbers were aggregated across all included studies for each group included in the meta-analysis. gender was compared between groups using the chi test in stata ( ). this was not possible for age due to a lack of individuallevel data. the predictive value of symptoms and comorbidities for each of severe disease and icu admission was estimated with random effects meta-analysis in stata. random effects models were used to account for between study heterogeneity ( ) , which was estimated with tau-squared. this provided a pooled odds ratio (por), % confidence intervals, and a p-value, for each symptom or comorbidity. a p-value of < . was used as a marker for evidence of significant association. detailed forest plots of the predictive symptoms and comorbidities common to both disease severity and icu admission are illustrated in the supplementary information file the prisma flow diagram ( figure ) illustrates the process for selection of papers in this study. the initial search on medline, embase and global health produced results. after removing duplicates and applying exclusion criteria, there were papers meeting our criteria from title and abstract analysis. on further review, the majority of these studies did not compare proportions of patients with symptoms or comorbidities between severe (or icu admitted) and non-severe disease (or non-icu admitted) groups. the reasons for all study exclusions are outlined in figure . a total of seven studies were selected for inclusion. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in table shows details of all included studies including reported findings pertaining to symptoms and comorbidities related to disease severity or icu admission. these studies reported on a total of patients. all included studies were retrospective cohort studies in design, conducted between december and february in china, during the novel coronavirus (sars- -cov) outbreak. guan et al ( ) conducted the largest study with covid- patients, whilst huang et al ( ) included patients in their study. the number of symptoms investigated varied from in one study ( ) to in others ( , ) . the range of comorbidities investigated varied greatly with two studies not including any ( , ) and one including comorbidities ( ) . all included studies were retrospective cohort studies, and were critically appraised using the strobe checklist ( ) . the items on the strobe checklist were formulated into individual indicators, against which each study was marked. figure illustrates the proportion of included studies which met each individual appraisal indicator. each paper was assigned an overall quality score based on the percentage of strobe checklist criteria met (< % = -, - % = +, > % = ++), as outlined in table . appraising with the strobe checklist highlighted several major weaknesses in the included studies. firstly, there was no consistent definition on what constituted severe disease. the who-china joint mission on covid- ( ) defined a severe case as tachypnoea (≥ breaths/min) or oxygen saturation ≤ % at rest, or pao /fio < mmhg. critical cases were defined as all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted march , . . https://doi.org/ . / . . . doi: medrxiv preprint respiratory failure requiring mechanical ventilation, shock, or other organ failure that requires intensive care. although the above criteria were used in some included studies, many defined only one out of severe and critical, with one ( ) using a definition for a single severe/critical cohort. one study reported both severity and critical cases ( ), using criteria set by the american thoracic society to judge severity. secondly, the time at which severity of disease was determined was not always clear. severity was assessed on admission in two studies ( , ) , whilst three studies did not specify when severity was assessed ( , , ) . it is possible, therefore, that the non-severe group included patients who went on to later develop severe disease. thirdly, the time point at which symptoms were measured varied from illness onset (via recall) ( , ( ) ( ) ( ) to clinical presentation ( , ) . in the study by li et al, it was not clear when symptoms were measured ( ) . finally, no study specified how each individual symptom or comorbidity was measured. for instance, it was unclear whether fever was objectively measured, and if so, how or by whom. studies may therefore have been susceptible to measurement and reporting bias. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in tables and show the odds ratios, % confidence intervals and p-values for the individual symptoms and comorbidities that were investigated in at least three of the included studies, for both severe disease and icu admission, respectively. a total of seven symptoms were included in the model for severe disease and six for icu admission, as well as four comorbidities in both. the most prevalent symptoms in the severe group were cough ( . %), fever ( . %) and fatigue ( . %); in the icu group these were cough ( . %), fever ( . %) and dyspnoea ( . %). the most prevalent comorbidities in the severe group were hypertension ( . %) and diabetes ( . %) and in the icu group were hypertension ( . %) and cvd ( . %). although no more likely to be in the severe group, men were . times more likely than women to be admitted to icu ( % ci . - . ). dyspnoea was the only symptom significantly associated with both severe disease (por . , % ci . - . ) and icu admission (por . , % ci . - . ), being more strongly associated with the latter. cough was associated with severe disease (por . , % respectively. in contrast, diabetes was not significantly associated with icu admission, although the tau-squared value here was unusually high implying a high level of heterogeneity between studies in this particular case. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in were the most common symptoms found in our analysis. the prevalence of dyspnoea was not investigated in sun's meta-analysis, but we found it to be all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted march , . . https://doi.org/ . / . . . doi: medrxiv preprint relatively low, particularly in non-severe and non-icu groups. the prevalence of dyspnoea in the icu group, however, was . %, compared with . % in the non-icu group. whilst dyspnoea is not a particularly common symptom in covid- patients, its significant association with both severe disease and icu admission may help discriminate between severe and non-severe covid- cases, when present. the findings reported here are in keeping with current knowledge that the elderly and those with comorbidities are more susceptible to severe infection. those with: cardiovascular disease ( . %), diabetes ( . %), chronic respiratory disease ( . %) and hypertension ( . %) ( ) . unlike the china cdc study ( ) that presented case fatality rates for different groups, our findings compare those with particular comorbidities to those without, allowing us to estimate the effect of a particular comorbidity on covid- severity. although we did not investigate death (and included copd rather than chronic respiratory disease), our analysis similarly suggests that comorbidities are not uniform in terms of the risk of severe covid- disease. despite being uncommon in our study population, copd was by far the strongest risk factor for covid- severity, followed by cvd and hypertension. the foremost limitation of this study was an inability to carry out a multivariable analysis to account for the presence of several symptoms, comorbidities and all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted march , . . https://doi.org/ . / . . . doi: medrxiv preprint potential confounders. although this outbreak has seen the evolution of linked data and large datasets ( ) which would be suitable for multivariable analysis, these currently lack the quality of published data: there are large amounts of missing data, a narrow range of collected variables, and uncertainty about data collection methods and consistency. our univariable analysis is therefore valuable in evaluating specific individual symptoms and comorbidities predictive for covid- severity using high-quality evidence in the form of peer-reviewed studies. secondly, the studies included here were all from china, so the generalisability of findings to other countries and populations is not clear. the chinese may differ to other populations in terms of their health-seeking behaviour, symptom reporting, prevalence of different comorbidities, as well as their access to high quality health services. nonetheless, given the current dearth of contextually specific evidence available, our findings will help to inform future research and actions in other countries as the outbreak develops. finally, it was not possible to account for the timing of presentation in the statistical analysis. if a patient presented after many days of being symptomatic, this may have affected disease severity, compared with an earlier clinical presentation. however, this limitation does not apply to comorbidities, and table shows information from individual studies on median duration of symptoms before admission, which appears similar between severe (or icu) and nonsevere (or non-icu) cases. it is therefore unlikely that this will have biased the overall results. by identifying the symptoms and comorbidities predictive for more severe disease, clinicians can better stratify the risk of individual patients, as early as their initial contact with health services. this can lead to practical changes in management, which can improve allocative efficiency as well as clinical outcomes, through the consideration of more intensive environments of care all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted march , . . https://doi.org/ . / . . . doi: medrxiv preprint (e.g. high dependency unit), earlier on, for patients at highest risk of severe infection. these can also be formalised within risk stratification tools to aid clinical decision-making, such as the curb tool for community-acquired pneumonia ( ) . as the number of hospitalised covid- cases continues to increase, hospitals will increasingly need to ration limited resources and improve clinical pathways to effectively prioritise patients with greatest clinical need. this is important, as covid- is already placing increased pressure on icus, and anticipation of future demand, based on local population characteristics, may enable more timely planning and resource mobilisation ( ) . identifying those at the highest risk will also facilitate better-informed discussions between clinicians, patients and patients' families about the anticipated clinical trajectory, allowing more accurate and timely advance care discussions to occur. identifying those at high-risk will aid the public health response in controlling the spread of disease. given the ubiquity of comorbidities in the elderly population, and their increased susceptibility to severe covid- infection ( ), knowledge on the differing prevalence and risk of various conditions may help to focus and tailor public health efforts such as the screening of asymptomatic individuals, risk communication, contact tracing, self-isolation and social distancing. for instance, for copd, which is less common in the general population and very strongly associated with icu admission, a more targeted and intensive health protection strategy may be warranted, compared to other conditions (such as hypertension) that are more difficult to target due to their higher prevalence in the general population. furthermore, if it is found that severity of illness is related to infectivity, as is the case in the closely related sars-cov, then identifying patients who may develop severe illness can help guide precautions to prevent the spread of sars-cov . these include infection control decisions regarding the limited availability of isolation rooms and personal protective equipment (ppe), particularly in more resource-constrained settings. this will be of particular importance as the outbreak develops, if the prevalence of hospitalised covid- patients increases. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in measurement tools used in studies should aim to objectively measure symptoms where possible, and details on how and when symptoms were ascertained should be made clear in all studies. there was also heterogeneity in the range of symptoms and comorbidities recorded by different studies, and some studies grouped various symptoms ( ) ( ) ( ) , limiting the utility of such data. studies investigating covid- severity should avoid using subjective or selfreported criteria (such as dyspnoea) in the definition of severity, as in one study included here ( ) . to ensure consistency between studies and comparability, the who-china joint mission on covid- definition of severe and critical cases should be used. furthermore, the distinction between cases that are severe and critical should be clearly made in studies, to enable more accurate risk stratification of the most unwell patients. for future research on predictors of severity, research should aim to include greater detail on specific conditions, including how well controlled chronic conditions were before and during admission. if the severity of covid- varies according to the severity of underlying comorbidities, there may be a case for optimising routine treatment for healthy, uninfected individuals, as a potential public health action to mitigate risk. multivariable analysis to identify which groups of symptoms or comorbidities are most associated with severe or critical disease will also be valuable. the existing literature on covid- fails to elucidate the specific symptoms and comorbidities most predictive for severe covid- cases. our analysis finds that dyspnoea is the only symptom strongly predictive for both severe disease and icu admission, and could be a useful symptom to help guide clinical management decisions early in the course of illness. the association between comorbidities all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted march , . . https://doi.org/ . / . . . doi: medrxiv preprint and severe disease is not homogenous. whilst copd, cardiovascular disease, and hypertension were all associated with severity, copd was the most strongly predictive. when looking at icu-admitted patients, who represent the more severe end of the spectrum of clinical severity, the difference in effect sizes for copd and the other included comorbidities was large, suggesting copd patients are particularly vulnerable to critically severe disease. as the outbreak develops, future research must aim to substantiate these findings by investigating factors related to disease severity. this will aid clinical assessment, risk stratification, and resource allocation, and allow public health interventions to be targeted at the most vulnerable. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in not in english (n= ) not on covid- ( ) literature review/letter/case report (n= ) data not available for severe and non-severe (n= ) data not available for relevant predictive factors ( ) meta-analysis ( ) not yet reported (n = ) all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted march , . . https://doi.org/ . / . . . doi: medrxiv preprint world health organization. coronavirus disease (covid- ) situation report - epidemiological research priorities for public health control of the ongoing global novel coronavirus ( -ncov) outbreak defining the epidemiology of covid- -studies needed coronavirus action plan: a guide to what you can expect across the uk. clinical characteristics of hospitalized patients with -ncov infection early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia interim clinical guidance for management of patients with confirmed coronavirus disease the clinical and chest ct features associated with severe and critical covid- pneumonia clinical features of patients infected with novel coronavirus in wuhan clinical characteristics of coronavirus disease in china clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china clinical characteristics of patients infected by sars-cov- in wuhan characteristics of covid- infection in beijing clinical and computed tomographic imaging features of novel coronavirus pneumonia caused by sars-cov- statacorp. stata statistical software: release fixed-and random-effects models in meta-analysis the strengthening the reporting of observational studies in epidemiology (strobe) statement: guidelines for reporting observational studies report of the who-china joint mission on coronavirus disease (covid- ) characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study. the lancet respiratory medicine key: cord- -ouukwv authors: frobert, emilie; escuret, v.; javouhey, e.; casalegno, j.s; bouscambert‐duchamp, m.; moulinier, c.; gillet, y.; lina, b.; floret, d.; morfin, f. title: respiratory viruses in children admitted to hospital intensive care units: evaluating the clart® pneumovir dna array, , date: - - journal: j med virol doi: . /jmv. sha: doc_id: cord_uid: ouukwv viruses play a significant part in children's respiratory infections, sometimes leading to hospitalization in cases of severe respiratory distress. the aim of this study was to investigate respiratory infections in children treated in a hospital intensive care unit (icu). assays were performed using the clart® pneumovir dna array assay (genomica, coslada, madrid, spain), which makes it possible to detect genus of respiratory viruses simultaneously. during the winter of – , respiratory specimens collected from children under years of age and admitted to an icu were tested. at least one virus was detected in % ( / ) of the samples. the virological diagnosis was based on single infections in % ( / ) and on multiple infections in % ( / ) of cases. the array assay revealed respiratory syncytial virus (rsv) in . % ( / ) of the samples and rhinovirus in . % ( / ), either on their own or in co‐infections. all viruses identified in single and multiple infections were tested, taking into account clinical features, risk factors, and severity criteria. children with no risk factors presented more multiple infections, up to % of cases, than children with at least one risk factor. rsv seemed to induce severe symptoms by itself as no difference in intubation needs was observed when rsv was detected on its own or in co‐infection. the clart® pneumovir dna array was useful for examining severe viral respiratory infections, when other viruses than those detected by conventional methods could be involved, particularly in an icu. j. med. virol. : – , . © wiley‐liss, inc. viruses play a significant part in children's respiratory infections, sometimes leading to hospitalization in cases of severe respiratory distress. the aim of this study was to investigate respiratory infections in children treated in a hospital intensive care unit (icu). assays were performed using the clart pneumovir dna array assay (genomica, coslada, madrid, spain), which makes it possible to detect genus of respiratory viruses simultaneously. during the winter of - , respiratory specimens collected from children under years of age and admitted to an icu were tested. at least one virus was detected in % ( / ) of the samples. the virological diagnosis was based on single infections in % ( / ) and on multiple infections in % ( / ) of cases. the array assay revealed respiratory syncytial virus (rsv) in . % ( / ) of the samples and rhinovirus in . % ( / ), either on their own or in coinfections. all viruses identified in single and multiple infections were tested, taking into account clinical features, risk factors, and severity criteria. children with no risk factors presented more multiple infections, up to % of cases, than children with at least one risk factor. rsv seemed to induce severe symptoms by itself as no difference in intubation needs was observed when rsv was detected on its own or in coinfection. the clart pneumovir dna array was useful for examining severe viral respiratory infections, when other viruses than those detected by conventional methods could be involved, particularly in an icu. j. med. virol. : - , . ß wiley-liss, inc. acute respiratory diseases are very common in children and a viral etiology can be identified in up to % of cases [mahony, ] . these infections can lead to damage to the lower respiratory tract, including bronchitis, bronchiolitis, pneumonia, and bacterial superinfections. in some cases, particularly for children under years of age, hospitalization in an intensive care unit (icu) may be required in severe cases. respiratory syncytial virus (rsv) is the most frequently reported virus in infants admitted to hospital, but many other viral agents can be associated with acute respiratory infections [mentel et al., ; freymuth et al., ] . rhinovirus (hrv), influenza (flu) virus, and metapneumovirus (hmpv) are also now well known to be involved in such pathologies, with prevalence of emilie frobert and v. escuret contributed equally to this study. conflict of interest: b.l. declares conflicts of interest with argène, biocryst, biomérieux, gsk, medimmune, merck, novartis, plasmair, roche, sanofi-pasteur, and wittycell. e.f., v.e., m.b.d. and f.m. declare conflicts of interest with argène, biomérieux, cepheid, and r-biopharm. d.f. received research grants from biomerieux and merieux foundation. e.y. and y.g. declare no conflict of interest. ethics: this study was conducted during the standard diagnosis of virological parameters and did not require any additional samples. for standard diagnoses, typically no approval by the ethics committee or informed consent from the parents is required. nevertheless, at the hospices civils de lyon, diagnosis is performed in compliance with french laws and hcl guidelines and in accordance with the ethical standards of the declaration of helsinki. around %, %, and %, respectively [bouscambert-duchamp et al., ; freymuth et al., ] . in pediatric icu, the prevalence of viruses may differ, with a larger proportion of dual or mixed infections . viral respiratory diagnosis has traditionally relied on antigen detection and virus isolation. but the lack of sensitivity of antigen detection, the delay in the results with virus isolation and the limitations of detecting only cultivable viruses make the diagnosis of respiratory viruses incomplete. as a consequence, some clinical cases remain virologically negative. molecular technology has better sensitivity and the development of multiplex amplifications makes it possible to detect a broader panel of viruses. adenoviruses (adv), parainfluenza viruses (piv), enteroviruses (ev) but also coronaviruses (hcov) and bocaviruses (hbov) can now be detected by multiplex assays. these assays are based on different types of technology, such as ligation-dependent probe amplification (mlpa ), dual priming oligonucleotide (dpo) technology, targetspecific primer extension (tspe), or target-specific extension (tse) [chun et al., ; mahony et al., ; marshall et al., ; reijans et al., ] . other techniques are based on rt-pcr amplifications followed by microarray analysis, as performed in the present study [li et al., ] . broadening viral diagnosis in this way may help clinicians to decrease prescriptions of antibiotics, implement early antiviral treatments when available, and prevent virus transmission. the aim of the present study was to investigate respiratory infections in children admitted to a hospital pediatric icu. assays were performed with the clart pneumovir dna array assay (genomica, coslada, madrid, spain) which makes it possible to detect genus of respiratory viruses simultaneously. technical aspects, virological, and clinical data were analyzed. seventy-three respiratory samples from children under years of age and admitted to the hospital pediatric icu in lyon were collected between december , and march , . some children were sampled more than once but the samples corresponded to distinct episodes of respiratory disease. in most cases, the samples were nasopharyngeal or tracheo-bronchic aspirates. samples were collected in different clinical contexts: bronchiolitis ( samples), pneumonia ( samples), bronchiolitis associated with pneumonia ( samples). twenty samples were collected in other clinical contexts including isolated apnea ( samples), sepsis ( sample), apnea associated with sepsis ( ), convulsions associated with fever ( ), and asthma ( ). no clinical information was available for samples. risk factors were considered for each patient. of the children, were < days old ( . %), were born prematurely ( . %), had a cardiopathy ( . %), child had chronic respiratory insufficiency, and child was immunodepressed. twenty-one children presented more than one risk factor ( . %) and children had no risk factors at all ( . %). the severity of the respiratory disease was related to intubation requirements. two hundred microliters of samples were treated with. ml of proteinase k at mg/ml (proteinase k pcr grade, roche, diagnostics gmbh, mannheim, germany). rna was then extracted using the automated nuclisens easymag system (biomerieux, sa, mercy l'etoiles, france). elution of the extracted nucleic acids was performed in ml. the clart pneumovir dna array assay (genomica, coslada, madrid, spain) detects and characterizes the most frequent human viruses causing respiratory symptoms in a total of hr after nucleic acid extraction. the viruses analyzed include: rsv a and b; flu virus a, b, c; piv , , , a, b; hmpv a and b; adv ( subtypes), ev ( subtypes), hrv ( subtypes); hcov (subtype e); hbov. this kit is based on the amplification of specific fragments of the viral genome by means of two multiplex rt-pcr or pcr and a subsequent detection by hybridization with specific binding probes. during the -hr rt-pcr/pcr amplification, the amplified products were labeled with biotin. following amplification, hybridization with specific probes immobilized in sites of the micro-array was performed in a second step lasting hr: min. after incubation with a streptavidin-peroxidase conjugate, the addition of tetramethylbenzidine (tmb) induced the appearance of an insoluble product which precipitated at the hybridization sites on the micro-array. student's t-test and person's chi-squared test were used to assess intergroup differences. statistical analyses were performed on epiinfo software (v . . cdc). odds ratio (or) and % confidence interval (ci) were calculated for the likelihood of co-detection and to test the association between multiple infections and risk factors with distress severity. a test was considered to be significant when the p-value was < . . of the samples collected in this study, samples contained at least one virus ( %; table i ). the virological diagnosis revealed single infections in % ( / ) and multiple infections in % ( / ) of the cases (table i) . of the single infections, rsv was found in % ( / ) of cases and hrv in % ( / ). other viruses, such as flu b, adv, piv, hmpv, and hbov were also detected. in multiple infections, rsv was found in co-infection with hrv in % of cases, rsv a with rsv b in . % of cases, hrv with hbov in . % of cases, and rsv a associated with both hrv and adv in . % of cases. eight other viral co-infections were also detected as reported in figure . in total, rsv was detected with at least one other virus in . % of cases, hrv in . % of cases, and hbov in % of cases. respiratory syndrome. clart pneumovir dna array made it possible to diagnose at least one virus in % of the bronchiolitis cases (table ii) . in . % of the cases, rsv was detected as a single infection. multiple infections were also detected in around % of the bronchiolitis cases. they involved mostly rsv a associated with other viruses ( / , . %). hrv and hbov were also detected in coinfections in a proportion of % ( / ) and % ( / ), respectively. in the pneumonia cases ( samples), clart pneumovir dna array detected viruses in . % of cases (table ii) . the implication of rsv in . % ( / ) of the cases was less than in bronchiolitis, with . % ( / ) in single infections and . % ( / ) in multiple infections. other viruses were involved, such as hrv, flu b, adv, and piv in single infections. two cases of hrv associated with hbov were also reported. in total, rsv was implicated in . % ( / ) of the bronchiolitis cases and in . % ( / ) of the pneumonia cases, either in single or multiple infections. hrv was implicated in . % ( / ) of the bronchiolitis cases and in . % ( / ) of the pneumonia cases. risk factors. of the children, presented one risk factor ( . %), presented more than one risk factor ( . %), and children had no risk factors at all ( . %). for the children with no risk factors, viral factors that could have led to the severe respiratory infection were investigated. children with no risk factors presented more multiple infections, up to % of cases, than children with at least one risk factor, even if the difference was not significant, probably because of the low number of patients (n ¼ , p ¼ . ; table iii) . severity. need for intubation was used as a surrogate for the severity of the respiratory distress. nineteen episodes of respiratory disease required intubation and did not. information regarding intubation was missing in two cases. there was no difference in the severity of the distress between single and multiple infections (p ¼ . ). in addition, the detection of rsv in a co-infection did not worsen the respiratory distress, as intubation was required in . % of the cases when rsv was detected alone and in . % of the cases when detected in co-infection with another viral agent. no association was observed between rsv in either single or multiple infections and distress severity (p ¼ . ). rsv seemed to induce severe symptoms on its own. in rsv negative samples, no difference was observed in the distress severity between single and multiple infections (p ¼ . ), probably because of the low number of rsv negative samples. hbov was detected in clinical cases ( in single, in multiple infections) with intubation required in cases (table iv) . interestingly, detection of hbov resulted in an increased likelihood of co-detecting another virus as reflected by an or of > ( % ci: . - ) p ¼ . . but there was no difference in distress severity between single and multiple infections when hbov was detected (p ¼ . ), probably because of the low number of cases (n ¼ ). microarray assay was found to be highly sensitive and made it possible to detect viruses that are not detected otherwise, either with the standard multiplex rt-pcr (piv, adv, ev, hbov, hmpv, hcov) or in culture (hbov, hmpv, hcov) and which may be involved in multiple infections. from a practical point of view, the clart pneumovir array assay is easy to use even if technical training is necessary to avoid false positives because of insufficient washing or overexposure of the arrays. nevertheless, after nucleic acid extraction, the array assay takes hr and is divided into two steps: multiplex rt-pcr followed by hybridization. the main advantages are its high sensitivity and broader detection of respiratory viruses, improving viral diagnosis. however, the detection of multiple infections raises certain questions regarding the pathogenicity of the different viruses. are all the viruses detected responsible for the clinical signs presented by the patient? these multiple viruses can be successive infections and molecular tests could detect a persistent genome in the absence of virus activity. this array assay is only a qualitative technique. however, quantitation should help to identify the predominant viral agent believed to be responsible for an acute respiratory syndrome. different studies have described previously the clinical characteristics of multiple viral infections versus rsv single infection. multiple infections varied from . % to % in children under years of age admitted to hospital [calvo et al., ; miron et al., ] and were associated with higher fever, longer hospitalization, and more frequent use of antibiotics than in the case of infection with rsv alone [calvo et al., ] . infants with multiple infections are at higher risk of being admitted to a pediatric icu richard et al., ] . in the present study, multiple infections were detected by arrays in % of the positive cases. in bronchiolitis, viral co-infection was found in . % of the cases with a predominance of the rsv and hrv co-infection, as described previously . rsv seems to induce severe symptoms on its own. viral co-infections with rsv effectively did not increase the need for intubation in comparison to infections with rsv as a single agent, as recently reported in a study considering duration of ventilation and length of hospitalization [marguet et al., ] . interestingly, children admitted to a pediatric icu with no risk factor were found to present more coinfections than children with risk factors, even if the difference was not significant. rsv prevalence has previously been detected at around % using multiplex rt-pcr in children admitted to the emergency room during winter [freymuth et al., ] . in the population studied, the array assay revealed rsv in % of the samples either alone or in co-infection. this prevalence of rsv may be explained by a higher sensitivity of array assay versus rt-pcr, but this point needs to be evaluated in more detail. it may also suggest that rsv may be responsible for a higher risk of hospitalization in a pediatric icu. the detection of hrv has been greatly improved by molecular techniques [mahony, ] . the prevalence of hrv was previously reported as being around - % with multiplex rt-pcr [freymuth et al., ] . this study reported hrv in % of the samples. this could suggest that infections caused by hrv are less represented in pediatric icu than in other pediatric units. hmpv is an rna virus discovered in and is known to induce symptoms very similar to those caused by rsv [van den hoogen et al., [van den hoogen et al., , . hmpv outbreaks occur predominantly in the winter and spring months, overlapping or following rsv outbreaks [mahony, ] . however, there can be significant differences in the detection of hmpv across seasons from year to year. overall prevalence is around %, ranging from % to % [mahony, ; gaunt et al., ] . only two hmpv infections were detected in this study, probably because the study period missed potential hmpv circulation during the spring season. hbov was discovered in using large-scale molecular viral techniques [allander et al., ] . prevalence, ranging from % to % in respiratory samples from symptomatic patients, has been reported worldwide. in most cases, as in this study, hbov was detected in co-infections with other known viral agents raising the question of its actual pathogenic role [mahony, ] . however, hbov has been associated with low respiratory infections [kesebir et al., ; manning et al., ; fry et al., ] and acute wheezing [allander et al., ] . even if hbov can be found in asymptomatic patients, hbov genome quantitation could help to identify the implication of hbov in lower respiratory tract infections, as a high-hbov load has been reported in patients with lower respiratory tract infections [van de pol et al., ] . in this study, hbov prevalence was around %, higher than the prevalence usually reported [van de pol et al., ] , almost certainly because of the differences in detection techniques, patient recruitment and the seasonal study period. nevertheless, fry et al. [ ] have previously reported up to % of hbov in children under years of age with pneumonia. in conclusion, microarrays have a high level of sensitivity and make broader viral detection possible. however, the relevance of the positive results obtained with this highly sensitive array is not easy to determine, particularly in cases of multiple infections caused by the lack of quantitation. dna array may be useful regarding severe viral respiratory infections, particularly in pediatric icu when no viral diagnosis has been established using conventional techniques that detect the most common viral respiratory pathogens. cloning of a human parvovirus by molecular screening of respiratory tract samples human bocavirus and acute wheezing in children detection of human metapneumovirus rna sequences in nasopharyngeal aspirates of young french children with acute bronchiolitis by real-time reverse transcriptase pcr and phylogenetic analysis multiple simultaneous viral infections in infants with acute respiratory tract infections dual priming oligonucleotide system for the multiplex detection of respiratory viruses and snp genotyping of cyp c gene comparison of multiplex pcr assays and conventional techniques for the diagnostic of respiratory virus infections in children admitted to hospital with an acute respiratory illness human bocavirus: a novel parvovirus epidemiologically associated with pneumonia requiring hospitalization in thailand incidence, molecular epidemiology and clinical presentations of human metapneumovirus; assessment of its importance as a diagnostic screening target human bocavirus infection in young children in the united states: molecular epidemiological profile and clinical characteristics of a newly emerging respiratory virus simultaneous detection and high-throughput identification of a panel of rna viruses causing respiratory tract infections detection of respiratory viruses by molecular methods development of a respiratory virus panel test for detection of twenty human respiratory viruses by use of multiplex pcr and a fluid microbead-based assay epidemiological profile and clinical associations of human bocavirus and other human parvoviruses in very young infants severity of acute bronchiolitis depends on carried viruses evaluation of a multiplexed pcr assay for detection of respiratory viral pathogens in a public health laboratory setting molecular and clinical characteristics of respiratory syncytial virus infections in hospitalized children sole pathogen in acute bronchiolitis: is there a role for other organisms apart from respiratory syncytial virus? mixed respiratory virus infections respifinder: a new multiparameter test to differentially identify fifteen respiratory viruses the impact of dual viral infection in infants admitted to a pediatric intensive care unit associated with severe bronchiolitis key: cord- -oinbicza authors: kormann, raphaël; jacquot, audrey; alla, asma; corbel, alice; koszutski, matthieu; voirin, paul; garcia parrilla, matthieu; bevilacqua, sybille; schvoerer, evelyne; gueant, jean-louis; namour, farès; levy, bruno; frimat, luc; oussalah, abderrahim title: coronavirus disease : acute fanconi syndrome precedes acute kidney injury date: - - journal: clin kidney j doi: . /ckj/sfaa sha: doc_id: cord_uid: oinbicza background: recent data have shown that severe acute respiratory syndrome coronavirus can infect renal proximal tubular cells via angiotensin converting enzyme (ace ) . our objective was to determine whether fanconi syndrome is a frequent clinical feature in coronavirus disease (covid- ) patients. methods: a retrospective cohort of laboratory-confirmed covid- patients without history of kidney disease hospitalized in university hospital of nancy was investigated. patients were admitted to the intensive care unit (icu) (n = ) or the medical department (n = ) and were screened at least once for four markers of proximal tubulopathy. results: the mean (standard deviation) follow-up was . (± . ) days. of the patients, % ( / ) showed at least two proximal tubule abnormalities (incomplete fanconi syndrome). the main disorders were proteinuria ( %, n = ), renal phosphate leak defined by renal phosphate threshold/glomerular filtration rate (tmpi/gfr) < . ( %, n = ), hyperuricosuria ( %, n = ) and normoglycaemic glycosuria ( %, n = ). at the time of the first renal evaluation, icu patients presented more frequent ( versus %, p = . ) and more severe ( ± versus ± mg/g, p = . ) proteinuria, and a trend for an increased number of proximal tubule abnormalities (p = . ). during follow-up, they presented a lower nadir of serum phosphate [median (interquartile range) . ( . – . ) versus . ( . – . ) mmol/l, p = . ] and acute kidney injury (aki) during the hospitalization (p = . ). fanconi syndrome preceded severe aki kdigo stages and in % ( / ) of patients. proximal tubular abnormalities (such as proteinuria, tmpi/gfr and glycosuria in five, two and two patients, respectively) were not detected anymore in recovering patients before hospital discharge. conclusion: incomplete fanconi syndrome is highly frequent in covid- patients and precedes aki or disappears during the recovery phase. starting in wuhan (china) in december , coronavirus disease (covid- ) is a newly ongoing pandemic infection due to a positive-sense rna virus named as severe acute respiratory syndrome coronavirus (sars-cov- ) [ ] . lungs are the first involved organs in the severe form of the disease, as % of patients admitted into intensive care units (icus) suffer from acute respiratory distress syndrome (ards). however, multiorgan damage is relatively frequent [ ] . among laboratoryconfirmed sars-cov- infection death cases, respiratory failure, cardiac failure, haemorrhage, hepatic and renal damage were found in , . , . , . and . % of the patients, respectively [ ] . according to a recent review by naicker ( ), acute kidney injury (aki) could occur in < % of covid- cases; however, renal abnormalities seem to be frequent, with % of cases presenting with proteinuria, . % with haematuria and . % with elevated serum creatinine [ ] . viral infections in immunocompetent hosts can impact kidney function by directly damaging infected kidney cells or as a result of damages from systemic immune responses [ ] or haemodynamic instability [ ] . middle east respiratory syndrome (mers)-coronavirus can induce apoptosis of renal tubular cells through hyperexpression of smad and fibroblast growth factor- [ ] . viral antigens and coronavirus particles were detected in the renal tubular epithelial cells through postmortem renal biopsies in deceased covid- patients [ ] . by light microscopy, diffuse proximal tubule injury with the loss of brush border, non-isometric vacuolar degeneration and even frank necrosis was observed [ ] . it has been reported that ace is a key receptor for sars-cov- entry in cells [ ] . high ace expression was identified in lung type- alveolar cells, gastrointestinal system, heart and kidney, and especially in the proximal tubular epithelial kidney cells [ , ] . we hypothesized that fanconi syndrome may be a clinical feature of infection of proximal tubular epithelial kidney cells in patients hospitalized with a severe form of covid- , and that the most severe patients admitted to icus may develop a more frequent and/or a more severe fanconi syndrome. after clinical and biological signs of proximal tubule injury were detected in three covid- cases, all laboratory-confirmed covid- patients cared for in the university regional hospital (chru) of nancy from to march underwent a systematic screening of tubular function by four clinicians (a.j., m.k., p.v. and s.b.). we retrospectively collected clinical characteristics of laboratory-confirmed covid- patients (aged ! years) from the infectious diseases and icu departments of nancy hospital (chru). a confirmed diagnosis of covid- was defined as a positive result of a real-time reverse-transcriptase-polymerase chain reaction detection in a nasopharyngeal swab or a bronchoalveolar lavage. patients followed for chronic kidney disease (ckd) with golerular filtration rate (gfr) ml/min/ . m and/or kidney transplantation were excluded from the analysis. each included patient was screened for four markers of proximal tubulopathy/fanconi syndrome [proteinuria, renal phosphate threshold/gfr (tmpi/gfr) < . mmol/l, hyperuricosuria and normoglycaemic glycosuria]. if patients were not discharged from hospital or dead, then these specific measures were likely to be repeated during their follow-up. the diagnosis of proximal tubule injury/fanconi syndrome was based on the presence of at least two of the following four abnormalities [ ] . (i) a renal phosphate leak was defined by a ratio of tmpi/ gfr < . mmol/l by bijvoet and majoor [ ] . this ratio was calculated in two steps according to payne as follows [ ] : (a) calculation of the renal tubular reabsorption of phosphate (rtp) with the following formula: rtp ¼ -[phosphate clearance (cpi)/creatinine clearance (ccr)]  and (b) interpretation of rtp value: if rtp . : tmpi/gfr ¼ rtp  plasma phosphate (pp, mmol/l) and if rtp > . : of note, hypophosphataemia was defined as a value under the laboratory threshold of . mmol/l. (ii) a normoglycaemic glycosuria was defined by a glycosuria > . g/l and glycaemia < . g/l. (iii) hyperuricosuria was defined by serum uric acid (sua) levels < mmol/l in men and < mmol/l in women, and a fractional excretion of urate f[(urine uric acid/sua)/(urine creatinine/serum creatinine)]  g > % [ ] . (iv) a urinary protein/creatinine ratio (proteinuria) > mg/ g. data were retrieved from electronic medical records of the nancy university hospital's database. the following demographic and clinical baseline characteristics were collected: age, sex, body mass index (bmi), date of admission, department of admission (icu or medical ward), comorbidities including ckd, a known proteinuria and medications. clinical, biological and radiological characteristics of the covid- infection were also collected, including time of onset of symptoms, initial symptoms at admission and characteristics of the pulmonary injury (radiological features, arterial blood gas results and mechanical ventilation parameters). the other recorded parameters were cardiac and haemodynamic status, liver function, haemodialysis requirement and vital status. aki was defined according to the kdigo criteria [ ] . the severity of icu patients was evaluated using the new simplified acute physiology score (saps) and the sequential organ failure assessment (sofa) score [ , ] . the severity of the respiratory failure was evaluated according to the berlin definition of ards [ ] . all patients admitted to the icu required invasive mechanical ventilation due to respiratory failure and received lungprotective ventilation (low tidal volume and positive end-expiratory pressures set according to severity of hypoxemia) as per the ards management guidelines [ ] . if vasoactive agents were required, then an infusion of noradrenaline was administered. fluid management was conservative as it has been shown that exposure to positive fluid balance is associated with adverse outcomes in critically ill patients [ ] . in the first day of icu stay, the anti-infective therapy included an antiviral and antibacterial treatment. as all patients presented with severe pneumonia during the flu season, oseltamivir [ mg twice daily (b.i.d.), and reduced in cases of altered gfr according to the european medicines agency recommendations] was administered in suspicion of influenza-related ards. treatment was adapted or withdrawn according to microbiology test results. regarding the treatment for covid- , the first patients admitted to the icu were started on lopinavir ( mg b.i.d.) and ritonavir ( mg b.i.d.). this treatment was withdrawn if kidney failure appeared or worsened. the manuscript, entitled 'covid- /acute fanconi syndrome precedes acute kidney injury', was evaluated by the ethical committee of nancy university hospital, where this research was done. this research was carried out in accordance with current french and european ethical standards, as well as with the world medical association international code of medical ethics. the 'nancy biochemical database' is registered in the french national commission for data protection and liberties (cnil no. v ), which supervises the protection of individuals with regard to the processing of personal data [ ] . the analysis was descriptive. quantitative data are presented as mean ( standard devation) or median ( interquartile range). qualitative variables were compared using the fisher's exact test or chi-square test when appropriate. chi-square test for trend was used for the analysis of aki, and to compare the number of abnormalities related to proximal tubule injury between the two groups (icu patients group and other inpatients). quantitative variables were compared using the mann-whitney u-test. all comparisons were two-sided and a p < . was considered significant. analyses were performed using graphpad prism software (san diego, ca, usa). forty-nine patients with a suspected or diagnosed covid- were consecutively included by participating physicians. after excluding seven patients, the analysis was performed on patients. the exclusion reasons were as follows: negative swab (n ¼ ), known estimated gfr (egfr)< ml/min/ . m before hospitalization (n ¼ ) and history of kidney transplantation (n ¼ ). two patients with an incomplete renal assessment for the diagnosis of proximal tubule injury were not excluded in the analysis. twenty-eight patients were admitted to the icu ('icu patients') after . ( . ) days of hospitalization and stayed in the infectious diseases department ('other inpatients'). the mean follow-up was . ( . ) days and was longer in the icu patients than the other inpatients [ . ( . ) versus . ( . ) days, p < . ]. the baseline characteristics are detailed in table . there was no statistically significant difference between the icu patients and the other inpatients regarding the age, gender, bmi, medical history and routine treatments. clinical data on covid- , pulmonary disease, cardiac and hepatic functions and medications are displayed in table . at the end of the follow-up, patients had died ( icu patients versus other inpatient, p ¼ . ) after . ( . ) days, patients had been discharged from the hospital ( icu versus other inpatients, p ¼ . ) and patients were still hospitalized ( icu patients versus other inpatient, p ¼ . ) for . ( . ) days. only patients ( %) had left the icu after . ( . ) days. importantly, icu patients were discharged from hospital later than other inpatients ( . . versus . . days, p < . , respectively). the mean length-of-stay from admission to the first evaluation of proximal tubular injury by the nephrology team was . ( . ) days, and was similar between icu and other inpatients (p ¼ . ). after the first renal evaluation, of patients ( %) had at least two abnormalities related to a fanconi syndrome. urine analyses were not correctly performed in one patient in each group. at this time, five icu patients had stage kdigo aki and two icu patients had stage kdigo aki. all proximal tubular abnormalities are displayed in table . icu patients were more likely than other inpatients to experience a severe fanconi syndrome (p ¼ . ), as shown in figure a , and proteinuria as shown in table . after excluding the two icu patients with glomerular rank proteinuria (> mg/g), other icu patients were more likely to experience a significantly increased tubular proteinuria (mg/g) than other inpatients, as shown in figure b during hospitalization, patients ( in icu versus other inpatients, p ¼ . ) had two or more evaluations of proximal tubular injury during their hospitalization. at the end of followup, of analysable patients ( %) had a diagnosis of fanconi syndrome. the full analysis of proximal tubule injury assessment during hospitalization and associated biological findings are displayed in table . the comparison between the two groups regarding proximal tubular abnormalities during the whole hospitalization is hazardous as the icu patients were more screened. nevertheless, the nadir of serum phosphate during the first days of hospitalization was lower in the icu patients (table ). on the second or third proximal tubular evaluations, the previous abnormalities disappeared in some of the patients. no proteinuria was detectable before hospital discharge in five patients with previous proteinuria. normalization of the tmpi/ gfr was found in two patients. no glycosuria was detectable in two patients with initial normoglycaemic glycosuria. unquantifiable monoclonal bands on serum protein electrophoresis patterns were detected in four patients. a monoclonal gammopathy of undetermined significance was quantified for g/l. in a total of urine protein electrophoresis pattern (upep), tubular proteinuria (albuminuria < %) and glomerulo-tubular proteinuria (albuminuria between % and %) were detected. no light-chain proteinuria was detected in all upep. the serum creatinine at baseline was not different between icu and other inpatients ( versus mmol/l, p ¼ . ). at day , functional stage kdigo aki was retrospectively diagnosed in six icu patients versus two other inpatients (p ¼ . ). taking into account the baseline creatinine or the level of creatinine after hydration in the latter patients, all patients had an egfr by chronic kidney disease epidemiology collaboration > ml/min/ . m , except for two patients (one in each group) with respective egfrs of and ml/min/ . m . these two patients had initial functional aki and were, respectively, aged and years. they were not excluded from analysis because no ckd was known before hospitalization. the mean peak of serum creatinine was ( ) mmol/l in the icu patients versus ( ) mmol/l in the other inpatients (p ¼ . ), respectively at day . ( . ) versus . ( . ) (p ¼ . ). aki during hospitalization stay was very frequent among this population ( %). with ( %) stage , ( %) stage and ( %) stage kdigo aki in the icu patients versus ( %) stage kdigo aki in other inpatients, this condition was more frequent and more severe in the icu patients (p ¼ . ). although the combination of lopinavir and ritonavir was mostly given to the icu patients ( patients) ( table ) , it was not significantly associated with aki (supplementary data, table s ). haemodialysis was required in five icu patients versus zero other inpatients (p ¼ . ) after ( . ) days. one patient was free of dialysis after week, two patients still needed haemodialysis after and days, respectively, and the two other patients died after and days of hospitalization. among seven patients with stage kdigo aki, all patients experienced previous or concomitant incomplete fanconi syndrome with two (n ¼ ), three (n ¼ ) or four (n ¼ ) proximal tubular abnormalities. the patient with stage kdigo aki experienced only proteinuria. among the seven deceased patients, six had aki (three stage and three stage kdigo aki) and fanconi syndrome. the last patient died before urine analysis was performed. this is the first study demonstrating an acute incomplete fanconi syndrome in % patients admitted for mild, moderate or severe lung failure from covid- . this condition was always associated with proteinuria, and irregularly with severe renal phosphate leak that may result in life-threatening hypophosphatemia, hyperuricosuria and glycosuria. if the sensitivity of these four markers of proximal tubulopathy is very high among this population, its specificity to demonstrate a viral infection of proximal tubular epithelial cells needs to be addressed in further studies, as no kidney biopsy or urine viral load was performed in our patients. finding specific biomarkers of kidney injury before aki in covid- is a challenge, and we strongly believe that these four markers taken together will represent a cheap and reproducible method to assess proximal tubular infection by sars-cov- in the future. renal hypokalaemia, salt loss aki and renal tubular acidosis, although classically associated with fanconi syndrome, were not analysed in this study for several reasons. they were indeed infrequent or difficult to diagnose because of potassium supplementation, mechanical ventilation, gfr alterations and/or other unknown factors. in adults, causes of fanconi syndrome are mainly acquired, either exogenous by environmental intoxications (lead, cadmium, aristolochic acid) [ ] [ ] [ ] or by drugs such as cisplatin, tenofovir, adefovir, ifosfamide [ , ] or endogenous with monoclonal gammopathy of renal significance with crystal storing histiocytis [ ] or light chain proximal tubulopathy [ ] . thus, this study identified a novel acquired cause of human proximal tubule injury. we support the hypothesis that the occurrence of acute proximal tubule injury is a predictor of aki. first, % of patients ( / ) with severe stages and kdigo aki experienced proximal tubule injury before aki. secondly, we demonstrate that icu patients were more likely to experience more severe proximal tubule injury, proteinuria and more profound hypophosphataemia during their follow-up. these same icu patients experienced more aki during hospitalization, suggesting a strong association between the severity of proximal tubule injury and a future aki. thirdly, none of the icu patients presented severe haemodynamic instability requiring temporary cardiac support or high doses of vasopressors. they had a relatively low mean sofa score at admission, and had neither multiorgan failure state nor severe haematological, neurological and hepatic failure. finally, the combination therapy of lopinavir/ritonavir is rarely associated with episodes of aki [ ] , but it cannot explain our findings as a whole, as only a quarter patients were treated with this therapy. taken together, we believe that aki observed in the vast majority of our patients is initiated in the proximal tubule. on the other hand, we also observed that many of the patients with initial fanconi syndrome did not develop aki, and were even able to correct their initial tubular proximal abnormalities during their recovery. understanding the other factors necessary to develop aki will require further studies. renal failure is common during viral infections, and several disease mechanisms are involved [ , ] . a common mechanism is the direct cell damage from viral infection with hijacking of host cellular functions, such as in hiv-associated nephropathy or segmental and focal hyalinosis during parvovirus b infection. the second mechanism is a specific immune response to cell infection leading to destruction of infected cells, as in hantavirus nephropathy. finally, the third mechanism is an indirect immune response with complications related to circulating of immune complexes or circulating cytokines, as in hepatitis-b virus-related glomerulonephritis, or membranoproliferative/cryoglobulinaemic hepatitis c virus glomerulonephritis or hiv-associated immune complex kidney disease. the best-documented viral infection targeting the renal tubule structure is puumala hantavirus infection leading to aki due to tubulointerstitial inflammation. very interestingly and alongside the findings of our study, signs of proximal tubular dysfunction (renal glycosuria in dipstick urine test) can appear before aki and predict its severity [ ] . regarding sars-cov- , this novel virus can specifically infect proximal tubular cells by ace [ , ] and we hypothesize that this is leading to proximal tubule injury by hijacking the normal cell machinery, and as a result leading to cell dysfunction. subsequently, viral tubular infection could lead in some patients to a local immune and inflammatory response, leading to acute tubular necrosis [ ] and acute renal failure. the main limitation of this study is a possible patient selection bias in the performance of renal function assessments. further larger and systematic studies should make it possible to evaluate the prevalence of proximal tubule injury in hospitalized and home-care covid- populations. the assessment of tubular proteinuria should require special attention (e.g. retinol-binding protein). aminoaciduria should be assessed to further refine diagnosis. a specific assessment of phosphocalcic metabolism should be carried out to support a vitamin d a-hydroxylase deficiency by proximal tubule in this condition and its outcomes. in conclusion, covid- seems to generate fanconi syndrome leading to life-threatening plasma abnormalities. this tubulopathy precedes aki or disappears during the recovery phase. in future studies, the occurrence and persistence of fanconi syndrome will deserve further attention as a potential prognostic marker of disease severity and as a potential biomarker of proximal tubular epithelial cell infection. characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention clinical characteristics of death cases with covid- the novel coronavirus epidemic and kidneys common mechanisms of viral injury to the kidney kidney diseases associated with parvovirus b , hanta, ebola, and dengue virus infection: a brief review mers coronavirus induces apoptosis in kidney and lung by upregulating smad and fgf renal histopathological analysis of postmortem findings of patients with covid- in china inhibition of sars-cov- infections in engineered human tissues using clinical-grade soluble human ace current antimyeloma therapies in renal manifestations of monoclonal light chain-associated fanconi syndrome: a retrospective series of patients the renal tubular reabsorption of phosphate in thyrotoxicosis renal tubular reabsorption of phosphate (tmp/ gfr): indications and interpretation phenotype and outcome in hereditary tubulointerstitial nephritis secondary to umod mutations kidney disease: improving global outcomes (kdigo) acute kidney injury work group. kdigo clinical practice guideline for acute kidney injury a new simplified acute physiology score (saps ii) based on a european/north american multicenter study use of the sofa score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. working group on "sepsis-related problems" of the european society of intensive care medicine ards definition task force. acute respiratory distress syndrome: the berlin definition formal guidelines: management of acute respiratory distress syndrome fluid overload in the icu: evaluation and management diagnostic accuracy of procalcitonin for predicting blood culture results in patients with suspected bloodstream infection: an observational study of , consecutive patients (a strobecompliant article) biological syndrome simulating de toni-debré-fanconi syndrome during lead poisoning cadmium-induced experimental fanconi syndrome chinese herb nephropathy in japan presents adult-onset fanconi syndrome: could different components of aristolochic acids cause a different type of chinese herb nephropathy? incidence of renal fanconi syndrome in patients taking antiretroviral therapy including tenofovir disoproxil fumarate fanconi syndrome and tenofovir alafenamide: a case report crystal-storing histiocytosis with renal fanconi syndrome: pathological and molecular characteristics compared with classical myelomaassociated fanconi syndrome light chain proximal tubulopathy: clinical and pathologic characteristics in the modern treatment era viral-associated gn: hepatitis b and other viral infections covid- therapeutic options for patients with kidney disease glucosuria predicts the severity of puumala hantavirus infection the authors would like to thank odette agulles md, who greatly contributed to facilitating the connected prescription for renal function assessment using the dxcare software for all physicians managing covid- patients. they acknowledge the contribution of dr zakia ait djafer md, who played a major role in the division of biochemistry of the department of molecular medicine. supplementary data are available at ckj online. none declared. key: cord- -x lng authors: flikweert, antine w.; grootenboers, marco j.j.h.; yick, david c.y.; du mée, arthur w.f.; van der meer, nardo j.m.; rettig, thijs c.d.; kant, merijn k.m. title: late histopathologic characteristics of critically ill covid- patients: different phenotypes without evidence of invasive aspergillosis, a case series date: - - journal: j crit care doi: . /j.jcrc. . . sha: doc_id: cord_uid: x lng purpose: pathological data of critical ill covid- patients is essential in the search for optimal treatment options. material and methods: we performed postmortem needle core lung biopsies in seven patients with covid- related ards. clinical, radiological and microbiological characteristics are reported together with histopathological findings. measurement and main results: patients age ranged from to years, five males and two females were included. time from hospital admission to death ranged from to days, with a mean of ventilated days. icu stay was complicated by pulmonary embolism in five patients and positive galactomannan on bronchoalveolar lavage fluid in six patients, suggesting covid- associated pulmonary aspergillosis. chest ct in all patients showed ground glass opacities, commonly progressing to nondependent consolidations. we observed four distinct histopathological patterns: acute fibrinous and organizing pneumonia, diffuse alveolar damage, fibrosis and, in four out of seven patients an organizing pneumonia. none of the biopsy specimens showed any signs of invasive aspergillosis. conclusions: in this case series common late histopathology in critically ill covid patients is not classic dad but heterogeneous with predominant pattern of organizing pneumonia. postmortem biopsy investigations in critically covid- patients with probable covid- associated pulmonary aspergillosis obtained no evidence for invasive aspergillosis. up to percent of hospitalized coronavirus disease patients are admitted to the intensive care unit (icu) because of acute hypoxemic respiratory failure. [ ] [ ] [ ] [ ] these patients usually present with bilateral patchy ground glass opacities on computed tomography (ct) thorax fulfilling the definition for acute respiratory distress syndrome (ards). often an atypical high compliance phenotype (l-type) is observed during mechanical ventilation in covid- patients in contrast to mechanical ventilation characteristics typically seen in ards with low lung compliance phenotype (h -type). [ , ] during icu stay the radiologic presentation of bilateral patchy ground glass opacities as present at admission often progress to consolidations with or without fibrotic characteristics. [ ] two earlier observed features may play a critical role in the severity of this disease: thromboembolic complications and early onset aspergillosis. the cumulative incidence of venous thromboembolism reported was % in covid- patients admitted to the icu. [ ] presumed pulmonary aspergillosis may be present in as much as % of icu covid- patients. [ ] since the physiology in covid- related ards as well as its complications seems to differ from "typical" ards, an insight into the pulmonary tissue pathology of this new infectious disease is of the utmost importance. the scarcely available pathological data in covid- patients show diffuse alveolar damage, closely related to ards. [ ] [ ] [ ] the clinical relevance of covid- associated pulmonary aspergillosis (capa) as well as survival benefit with antifungal treatment and associated mortality are under debate since histopathological evidence of capa is not obtained. [ ] we examined postmortem obtained lung tissue in seven patients, with covid related ards who needed mechanical ventilation. the histopathologic findings, together with clinical features, radiological all patients with laboratory confirmed severe acute respiratory syndrome coronavirus (sars-cov- ) admitted to the icu due to acute hypoxemic respiratory failure between march and april and with available postmortem needle core biopsy of the lung were eligible for inclusion in this case series. sars-cov- was diagnosed using real-time reverse transcription polymerase chain reaction (rt-pcr) on sputum and/or bronchial aspirates. routine icu management included, among other things, selective digestive tract decontamination (sdd), chloroquine until the dutch national institute for public health and environment advised against its use at the end of march , and high dose anticoagulation with low-molecular-weight heparin (lmwh) (nadroparin ie/kg twice daily). bronchoscopy, with or without lavage, and testing for pulmonary aspergillosis were performed at the discretion of the attending physician. pulmonary aspergillosis was diagnosed using clinical, radiological and mycological data and included galactomannan (serum and sputum), tracheal or bronchial culture. for galactomannan (gm) testing from bronchoalveolar lavage (bal) fluid platelia aspergillis antigen elisa (biorad) was used. recently, a case definition for influenza associated pulmonary aspergillosis (iapa) was proposed by an expert panel, which could be used to classify patients with capa. [ ] diagnostic criteria include proven infection with clinical symptoms and a gm index of ≥ on bal or of ≥ ꞏ on serum; or aspergillus spp. cultured from bal. j o u r n a l p r e -p r o o f during the study period, seven patients underwent postmortem needle core biopsy of the lungs. patients age ranged from to years (median year) and five patients were male. none of the patients had a history of (chronic) pulmonary disease. one patient used immunosuppressive medication before hospital admission, in this case a short course of prednisolone. median time from hospital to icu admission was days (interquartile range - ). time from hospital admission to death ranged from to days. patients deceased at median of (range - ) ventilated days. in five out of seven patients icu stay was complicated by pulmonary embolism. adopting the proposed definition of capa by van arkel et al [ ] , six patients were classified as having probable capa (table ) a -year old female was transferred to our icu due to shortage of icu beds in a nearby hospital. prior to icu admission, she was healthy but complained of diarrhoea and shortness of breath. non-contrast chest ct at initial hospital admission showed multiple bilateral areas of ground-glass opacity along the bronchovascular bundles and periphery. there were some small areas of consolidation in the upper lobes. subtle bronchiectasis were present in affected areas. her respiratory condition required mechanical ventilation in prone position due to ards. after seven days, prednisolone treatment was started because of lack of improvement. repeat chest ct-angiography showed segmental pulmonary emboli in the right lung. ground-glass opacities persisted while the consolidations had disappeared. a reticular pattern combined with ggo was more pronounced with increasing traction bronchiectasis. biopsy specimens showed a pattern of lung injury, that was partially identical to that of case . intra-alveolar depositions of fibroblastic tissue were found, consistent with organizing pneumonia. however, a predominant, diffuse component of fibrinous exudate in the alveoli was present, which was not the case in the aforementioned case with organizing pneumonia. other histologic findings were a chronic inflammatory infiltrate, and mild interstitial changes, including widening of alveolar septa. microthrombi in small septal blood vessels were also observed. neither j o u r n a l p r e -p r o o f remnants hyaline membranes nor prominent eosinophils were present. additional pas-d stain did not show any fungi. the overall histologic pattern of this case was classified as acute fibrinous and organizing pneumonia (afop), figure d. we report pathology in deceased critically ill icu covid patient in the late phase of disease to be heterogeneous. histopathologically, we observed four distinct histopathological patterns: afop, dad, fibrosis and, in four out of seven patients an organizing pneumonia (op). interestingly, our findings are in contrast to previously reported postmortem studies in covid- patients in which dad is the most common predominant pattern. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in two recent autopsy studies of and deceased covid- patients, prevalence of dad was % and % respectively. none of the patients had the postmortem diagnosis of organizing pneumonia [ , ] . in the study of ackermann and colleagues, pulmonary histology of all seven studied patients showed dad [ ] . although the organizing stage of dad may overlap with the histopathological features of op in lung biopsy, the histologic hallmark of dad, namely remnants of hyaline membranes were not present in our four op cases. most plausible explanation for the more common pattern of op in our study population when compared to previous mentioned studies is the difference in length of hospital and icu stay correlating with more advanced disease and longer treatment with mechanical ventilation. in the studies mentioned above the mean hospital stay was six days or less and most of the patients did not receive mechanical ventilatory support. in our present series mean hospital stay of days is significant longer and all patients died in the icu with a mean of days on mechanical ventilation. secondary op can be seen in association with many types of non-specific j o u r n a l p r e -p r o o f lung injury, including viral infections and drug reactions. op is reported following severe influenza infections [ ] [ ] [ ] [ ] [ ] and middle east respiratory syndrome [ ] . most recently, copin et al. reported postmortem biopsies on six patients with covid and reported in five patients with phenotype h and afop histology in contrast to their patient with dad. [ ] estimated elapsed disease time in the afop group was days versus days in the dad patients. in our opinion this supports the theory that pathology changes over time. although the exact pathogenesis of op remains unknown, it is thought that op is a consequence of alveolar epithelial injury. this initial epithelial injury is followed by leakage of plasma proteins, leading to a cascade of host responses with hyperinflammation [ , ] . subsequent fibroblast recruitment and connective tissue and fibroblast organisation is seen within the alveolar space. vascular endothelial growth factor (vegf) and basic fibroblast growth factor (bfgf) play a central role in organizing pneumonia and are highly expressed in intraluminal fibromyxoid lesion in organizing pneumonia. [ ] interestingly, binding to ace receptor is recognized as a critical initial step for sars-cov- to entry alveolar type ii cells, resulting in loss of ace at the membrane. ace is a negative regulator of the renin-angiotensin system (ras) and this depletion of ace upregulates the ras. [ ] an activated ras can induce fibroblastic growth factor. ace also plays a role in regulating the effect of vegf. [ ] therefore, depletion of ace due to the high affinity of sars-co-v to ace might play a role in the pathogenesis of covid related organizing pneumonia. being aware that medication can be the cause of op it is notable is that in our study six out of seven patients received chloroquine, at that time the advised treatment by the dutch national institute for public health and environment. although chloroquine j o u r n a l p r e -p r o o f use is associated with cardiovascular disorders, pulmonary side effects, i.e. drug induced interstitial lung disease, are not described before, and therefore an unlikely cause of the observed histologic op. we found no studies reporting possible relations between antifungal therapy and op. in retrospect, chest ct scans of each of the patients showed a different development during hospital admission, concordant with the histopathological diagnosis (table ). in the presence of an organizing pneumonia. excluding nosocomial infections in such cases is essential. the diversity in histopathological findings correlating with radiological findings is interesting considering possible therapeutic implications and should be subject for further research. although steroids are not routinely recommended to be used in de early phase of sars-cov- pneumonia, they might have a role in the late phase of covid when an organizing pneumonia is suspected. [ ] recently there is increasing awareness and concern for development of secondary infection in covid patients e.g. invasive aspergillus co-infection, a contra-indication for (long-term) systemic steroid therapy. criteria and risk factors for invasive pulmonary aspergillosis are well defined in immunocompromised populations. furthermore it is a well known complication of severe influenza pneumonia with reported incidences of % in icu patients admitted for influenza related acute respiratory failure with high mortality rates. [ ] . in capa case definition is absent although recently an expert panel proposed a classification. [ ] pathophysiology of covid associated pulmonary aspergillosis (capa) consists of lung damage with bilateral alveolar-interstitial damage due to viral replication and cytokine storm in combination with marked low t-lymphocytes cd +t and cd +t cells. [ ] secondary j o u r n a l p r e -p r o o f infection due to lung tissue damage develop within a median of days. [ ] covid associated pulmonary aspergillosis (capa) data are scarce but increasingly reported, although histological confirmation is still absent [ , , , ] . of the first covid- patients admitted to our icu, six where highly suspected for covid- associated pulmonary aspergillosis (capa). [ ] in this case series, bal fluid galactomannan was positive in six out of the seven cases, concluding in the clinical diagnosis of probable capa. to our surprise, none of the lung biopsies showed any presence of invasive aspergillosis. lack of evidence for ipa in our patients with probable capa raises the question whether patients with suspected capa truly develop invasive aspergillosis and require antifungal therapy. for instance, the three deaths in the capa report from france were attributed to bacterial septic shock, and not to aspergillosis. clinical characteristics of coronavirus disease in china clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention covid- does not lead to a "typical" acute respiratory distress syndrome acute respiratory failure in covid- : is it "typical radiological findings from patients with covid- pneumonia in wuhan, china: a descriptive study confirmation of the high cumulative incidence of thrombotic complications in critically ill icu patients with covid- : an updated analysis covid- associated pulmonary aspergillosis autopsy findings and venous thromboembolism in patients with covid- : a prospective cohort study post-mortem examination of covid patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction vander heide rs. pulmonary and cardiac pathology in covid- : the first autopsy series from new orleans diagnosing covid- -associated pulmonary aspergillosis international expert review of influenza-associated pulmonary aspergillosis in icu patients and recommen dations for a case definition clinicopathologic and immunohistochemical findings from autopsy of patient with covid- postmortem lung findings in an asthmatic patient with coronavirus disease pathological findings of covid- associated with acute respiratory distress syndrome covid- autopsies pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- organizing pneumonia in patients with severe respiratory failure due to novel a (h n ) influenza influenza a (h n ) virus-associated pneumonia: high-resolution computed tomography-pathologic correlation organizing pneumonia associated with swine-origin influenza a h n viral infection successful management of refractory respiratory failure caused by avian influenza h n and secondary organizing pneumonia: a case report and literature review glucocorticoid treatment of suspected organizing pneumonia after h n infection: a case report successful treatment of suspected organizing pneumonia in a patient with middle east respiratory syndrome coronavirus infection: a case report time to consider histologic pattern of lung injury to treat critically ill patients with covid- infection covid- : consider cytokine storm syndromes and immunosuppression the pathogenesis and treatment of the "cytokine storm"" in covid- vegf and bfgf are highly expressed in intraluminal fibromyxoid lesions in bronchiolitis obliterans orgnizing pneumonia angiotensin-converting enzyme : sars-cov- receptor and regulator of the renin-angiotensin system: celebrating the th anniversary of the discovery of ace ace antagonizes vegfa to reduce vascular permeability during acute lung injury world health organization . clinical management of covid- invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study covid- associated pulmonary aspergillosis prevalence of putative invasive pulmonary aspergillosis in critically ill patients with covid- ultrasonographic autopsy (echopsy): a new autopsy technique key: cord- -xkb xy k authors: vellieux, geoffroy; rouvel-tallec, anny; jaquet, pierre; grinea, alexandra; sonneville, romain; d'ortho, marie-pia title: covid- associated encephalopathy: is there a specific eeg pattern? date: - - journal: clin neurophysiol doi: . /j.clinph. . . sha: doc_id: cord_uid: xkb xy k nan we report the history of two patients with coronavirus infectious disease (covid- ) whose electroencephalograms (eeg) found a unique pattern, never described up to now. a -year-old man without any previous medical history rapidly displayed a combination of myalgias, headaches, fever and diarrhea. three days later, he complained of dyspnea, chest pain and displayed incoherent speech. he presented to the emergency room with fever up to . °c, polypnea /min and pulse oxymetry in room air (ra) was %. neurological examination showed neck stiffness, and no confusion. two nasopharyngeal swabs for severe acute respiratory syndrome coronavirus (sars-cov- ) were negative and chest computed tomography (ct)-scan did find neither any lung parenchymal abnormalities nor pulmonary embolism, but sars-cov- igm and igg serology was positive. troponin increase, echocardiography and myocardial biopsy led to diagnosis of acute myocarditis due to covid- . all other biological assays in blood and cerebrospinal fluid for etiological investigation of myocarditis and encephalitis were negative. because of refractory cardiogenic shock, he was referred to the icu of bichat-claude bernard hospital (paris, france) where he rapidly required cardiac assistance. the veno-arterial extracorporeal membrane oxygenation (ecmo) was started in the first -hours of arrival. no cardiorespiratory arrest (cra) was experienced during the procedure neither during his whole stay in the icu. continuous long duration eeg was performed for neurological evaluation three days after arrival, under a regimen of sedative drugs composed of propofol mg/h + sufentanyl g/h. eeg recording was performed with system plus evolution, micromed (modigliano veneto, italy) and eight scalp electrodes positioned according to the standard - international system montage. eeg revealed continuous, slightly asymmetric, monomorphic, diphasic, delta slow waves with diffuse projection but greater amplitude over both frontal areas and with a periodic organization with a short period around - s ( figure a ). these slow waves did show any reactivity to neither auditory nor nociceptive stimulation. continuous long duration eeg was repeated one week later under combination of propofol mg/h + sufentanyl g/h and was similar. brain magnetic resonance imaging (mri) with perfusion sequences performed the same day was consistent with hypoxic encephalopathy. a -minutes standard eeg was then performed offsedation after days in the icu and found intermittent occurrence of the pattern described above. the patient was eventually extubated days after admission in icu. at hospital discharge, he displayed only a mild left sensorimotor deficit secondary to right middle cerebral artery infarction without any cognitive symptoms. a -year-old man was admitted to the bichat-claude bernard hospital for acute respiratory failure. his past medical history was marked by arterial hypertension, one episode of acute pulmonary edema, chronic renal failure secondary to suspected nephroangiosclerosis and sleep apnea syndrome. he progressively displayed a combination of fever, chills, hiccup and cough, and then diarrhea and shortness of breath. at hospital admission, he complained of dyspnea with polypnea /min, pulse oxymetry was % ra and temperature was . °c. neurological examination was normal. covid- diagnosis was based on (i) a positive nasopharyngeal swab for sars-cov- and (ii) a typical thoracic ct-scan. initial care consisted on nasal oxygen therapy. his respiratory status rapidly worsened leading to transfer to the icu where he required mechanical ventilation. similarly to the first case, no cra occurred during his stay in the icu before eeg recordings. sedative drugs (propofol mg/h and sufentanyl g/h) were interrupted three weeks later when respiratory failure improved. the first -minutes standard eeg was performed hours after interruption of sedative drugs because of absence of awakening, with the same technical specifications described above. eeg revealed a strictly similar pattern compared to patient # with continuous, symmetric, monomorphic, diphasic (or even triphasic), delta slow waves with diffuse projection but greater amplitude over both frontal areas. these slow waves had a periodic organization with a short period around - s and did show any reactivity to neither auditive nor nociceptive stimulation ( figure b ). another standard eeg performed still off-sedations one week later was similar with still absence of any reactivity. withdrawal of care was decided because of persistent coma three weeks after interruption of sedatives and the patient died. eeg reports are still scarce among literature dedicated to covid- patients and found normal or nonspecific results (filatov et al. ; morassi et al. ; pilotto et al. ). flamand et al. recently reported the case of an -year-old woman with covid- whose eeg successively found frontal status epilepticus, then alterations compatible with toxic/metabolic encephalopathy and finally periodic triphasic activity with short periods of - . s (flamand et al. ). reactivity to stimulation was not mentioned in that report. among the eight patients who underwent eeg reported by helms et al., only nonspecific changes were detected but one patient had diffuse bifrontal slowing (helms et al. ) . morphology, periodicity and reactivity of this bifrontal slowing were not mentioned. the eeg from the patients we presented did not display any usual pattern found in icu patients, such as those seen in post-anoxic, toxic or metabolic encephalopathies and had not been described before. underlying mechanisms of these eeg abnormalities are unknown and perhaps multifactorial. several hypotheses may be suggested, such as direct viral affection of the brain, demyelination and inflammatory lesions secondary to cytokine storm as a post-viral autoimmune process, hypoxic neuronal injuries and/or side effects of pharmacological treatment used in icu. the unusual eeg pattern however pleads against the last two hypotheses. to our knowledge, our report is the first to describe strikingly similar eeg patterns in two patients with covid- , i.e., non-reactive bifrontal monomorphic diphasic periodic delta slow waves, irrespective of sedative drugs. opposite outcomes despite similar eeg patterns of the two present patients suggest that these eeg figures are not predictive for neurological prognosis but may represent a signature of sars-cov- infection. eeg should be more broadly performed in any patients with covid- displaying neurological symptoms. other eeg investigations are absolutely needed from other neurophysiological teams for patients with covid- to evaluate whether the pattern we described is found in other similar patients. gv analyzed eeg and wrote the manuscript. art, pj, ag and rs gave their clinician expertise and revised the manuscript. mpo suggested and revised the manuscript. none. this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. neurological complications of coronavirus -disease (covid- ): encephalopathy pay more attention to eeg in covid- pandemic neurologic features in severe sars-cov- infection stroke in patients with sars-cov- infection: case series steroid-responsive encephalitis in covid- disease key: cord- -dzauzjm authors: guzzi, pietro hiram; tradigo, giuseppe; veltri, pierangelo title: spatio-temporal resource mapping for intensive care units at regional level for covid- emergency in italy date: - - journal: int j environ res public health doi: . /ijerph sha: doc_id: cord_uid: dzauzjm covid- is a worldwide emergency since it has rapidly spread from china to almost all the countries worldwide. italy has been one of the most affected countries after china. north italian regions, such as lombardia and veneto, had an abnormally large number of cases. covid- patients management requires availability of sufficiently large number of intensive care units (icus) beds. resources shortening is a critical issue when the number of covid- severe cases are higher than the available resources. this is also the case at a regional scale. we analysed italian data at regional level with the aim to: (i) support health and government decision-makers in gathering rapid and efficient decisions on increasing health structures capacities (in terms of icu slots) and (ii) define a geographic model to plan emergency and future covid- patients management using reallocating them among health structures. finally, we retain that the here proposed model can be also used in other countries. covid- [ ] is caused by the sars-cov- virus and belongs to the coronaviridae family, which contains many other viruses. only seven of which are known to be responsible for human diseases, e.g., e, nl , oc , hku , mers-cov, sars-cov, and sars-cov- [ , ] . the virus diffused with a surprisingly fast pace, and in one month putting under stress the healthcare resources worldwide, starting from china. italy was the first european country affected by the virus. the high spreading rate and the absence of tailored therapies and vaccines determine a relatively high mortality rate that has been controlled by blocking the virus spreading with severe mobility restrictions to the people of the infected regions [ ] . by the end of march, while the situation in china seems to be under control, the virus is rapidly growing in other countries [ , ] . with different time scales, other countries such as the usa, france, spain and north europe reacted by implementing containment measures. the virus has an initial exponential diffusion which requires: (i) home quarantine for low symptoms, (ii) hospitalisation for part of them and, (iii) hospitalisation in icus requiring respiratory support for severe ones. in some cases, covid- causes severe pneumonia, especially in the presence of co-morbidities [ ] , thus patients need hospitalization in icu where respiratory support (such as mechanical ventilators) are required to keep them alive [ ] . we focus on a disease diffusion model which helps predicting icu resources, for the italian emergency. the model is general enough to foresee its adoption also in other countries. it also scales well at a regional or sub-regional level. data. all data used in this work are provided by italian government on a publicly available web site https://github.com/pcm-dpc/covid- under licence cc-by- . . we start from the analysis of epidemiological data from wuhan city (china, hubey region). as reported in [ , ] about a third of infected patients required icu admission. icu departments need to be well organised to be able to host covid- patients. there is also the need to avoid mixing covid- with other patients in icus [ ] . in italy on march, official data reported , total cases, , people currently infected, deaths and recovered patients. among these: were reported as being treated at home (i.e., not severe illness), hospitalised, and admitted to icus. to react to the exponential growth of infected patients requiring hospitalisation, the chinese government decided to build a large emergency hospital dedicated to covid- patients in a few days. in italy, the plan was to improve existing structures by extending the number of icu resources and beds, as well as using dedicated health structures. for instance, the study reported in [ ] focuses the necessity of acquiring icu resources such as ventilators or breathing support devices. italy has approximately beds in icus, which, by law, are designed to be occupied by patients for the % at any given time. also, these are allocated at a regional level proportionally to its population and are usually managed locally (see table ). many of such icu slots were yet occupied by non-covid- patients while as of march beds are occupied by covid- patients. considering the infection trend, it is reasonable to predict that the number of icus patients will increase. since icu resources are limited, there is the need to know in advance how many will be used. such a decision may regard, for instance, the institution of new icu beds or the movement of people from one region to another. so, it is crucial to correctly estimate the number of patients that will need icu treatment [ ] . we focus on decision strategy to increase number and structures able to treat covid- patients in intensive units, and thus increasing the number of icus. we propose a model able to manage in geographic scale the incoming patients and the icus available places. we cover the a need for the development of a predictive model for helping healthcare administrators in managing structure requirements to improve hospitals and patients managements. we extend a compartmental model for epidemiology, and we derive from italian public data the experimental parameters for simulating the model. literature contains many mathematical epidemiological models for studying the dynamics of infectious diseases [ ] . these models fall in two main classes: deterministic models that are based on differential equations and stochastic models that are based on markov processes. we used a discrete-time markov chain model [ ] and we derived the parameters of the model starting from publicly available data, the same described in section . we use as reference a compartmental model which we adapted from the literature [ ] (see figure ). in figure the covid- diffusion is reported both for italy and china red zones (a "red zone" is a geographical area (e.g., city, region, state) of maximal infection for which the government implements special social rules in order to deal with the emergency: typically restriction of citizens' movements and prohibition to leave or enter the area). we can make the hypothesis of similar trends for different countries (including italy). initial exponential growth of the disease is first identified followed by a logistic regression trend as disease spread slows down. in the last phases of the infection, where the curve becomes logistic, diseases have to be treated, continue managing the fraction of patients that require icus. showing that the initial trend of the infection follows an exponential growth, even though the chinese government rapidly adopted stringent confinement measures. we can thus expect to observe the same initial infection evolution, before arriving to the logistic portion of the curve. the italian national health service is organised on a national and regional scale. the central government controls the distribution of resources and services are arranged at a regional scale. there are regions and two autonomous provinces ( total administrative units). therefore the icus is availability is organised at a regional scale, established by each region. table summarise current icu beds availability per administrative units. patients are admitted into the icus of its region, without considering other criteria, such as free beds into icus of other regions that may be geographically closer. the access is freely guaranteed costs are mapped to citizen with respect to their regions of residence. consequently, some regions may have many available beds while other regions may not. this situation happened in northern italian regions. figure shows the distribution of total icu beds versus occupied icu beds (i.e., in hospitals) for each region in italy whereas figure shows the infected cases for each region. we compare through our model the management of beds in single regions as compartment and the management of places on a nationwide scale (admitting transfers among regions). our findings suggest that the management of icus beds as a whole across regions may improve the overall availability of free beds for covid- patients. figure shows the distribution of total icu beds versus occupied icu beds (i.e., in hospitals) for each region in italy. figure shows the infected cases for each region. we associated the number covid- infections with icu beds occupancy. in particular, the target is to predict the number of icu beds required for a certain amount of infections in a given region, using covid- trend. this is used to relate infections and icus beds (see figure b for lombardia region). we fitted the datapoints from current covid- infection with an exponential function. by using such a fitting we are able to predict infections (y axis of figure a ) for future days (x axis of figure a ). then, we can use such a number (x axis of figure b ) in order to predict the number of icus required in the future (y axis of figure b ). these predictions may be used to plan decision about covid- patients and also to reallocate them in different structures. predicting icu for non-saturated regions. we applied our predicting model to southern italian regions, when the infection trend was at the beginning (i.e., delayed curve and low numbers) with respect to northern ones. during this phase the icu beds capacity was under saturation (see figure ) . we used the predicting model for these regions to early predict saturation phases. in figure a ,b a diffusion of disease and relative connections with icus requirements are reported and refer to a central italian region, i.e., lazio. by using infections vs icu beds trend, we were able to calculate the number of infections for some time point in the future and derive the number of predicted icu beds which will be occupied. similarly, in figure c we report campania region situation at march as south of italy representation. in such case note that the government restrictions rapidly adopted allow a slower diffusion of infectious. note that in a similar way we map all data for all the italian regions. the emergency of covid- is related to an aggressive virus that diffuses rapidly and strongly stresses the resistance of health structures. since the covid- related disease require different non-standard protocols, such as the use of respiratory devices, patients treatment is strictly intertwined with the availability of hospital structure resources (e.g., icu beds). we think that, by using a scalable predictive model, (at regional or district level) may support governments in a better management of the emergency. finally, the presented model is valid during the exponential growth of the infection. furthermore, since the swab tests are not available in sufficient numbers to guarantee a wide screening of the population, they are performed only to hubs (i.e., police officers, healthcare personnel) and people dyeing by covid who were previously hospitalized in icus. hence infection numbers are highly underestimated. we claim that such a model could be used in countries where diffusion is still at the beginning, such as us, france, spain and other european countries (see [ ] where virus diffusion trajectories are reported for different countries). author contributions: g.t. was responsible for data analysis and statistics, and writing of the manuscript. p.h.g. was responsible for data analysis and writing of the manuscript. p.v. was responsible for data analysis and writing of the manuscript. all authors have read and agreed to the published version of the manuscript. funding: this work has been partially funded by project sistabene: sistema di tracciabilità avanzata per il benessere alimentare por calabria fesr-fse - . the coronavirus -ncov epidemic: is hindsight / ? eclinicalmedicine genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding nowcasting and forecasting the potential domestic and international spread of the -ncov outbreak originating in wuhan, china: a modelling study covid- : a new virus as a potential rapidly spreading in the worldwide the effect of travel restrictions on the spread of the novel coronavirus (covid- ) outbreak covid- : italy confirms deaths as cases spread from north critical care management of adults with community-acquired severe respiratory viral infection clinical features of patients infected with novel coronavirus in clinical characteristics of coronavirus disease in china preparing for covid- : early experience from an intensive care unit in singapore covid- and italy: what next? modeling infectious diseases in humans and animals generalized markov models of infectious disease spread: a novel framework for developing dynamic health policies covid- : epidemiology, evolution, and cross-disciplinary perspectives this article is an open access article distributed under the terms and conditions of the creative commons attribution acknowledgments: we thank italian protezione civile for freely providing online data thus allowing studies on covid- . we thank tamer kahveci from university of florida for useful suggestions. the authors declare no conflict of interest. the following abbreviations are used in this manuscript: icu intensive care unit key: cord- -nn rgdw authors: mayorga, lía; garcía samartino, clara; flores, gabriel; masuelli, sofía; sánchez, maría victoria; mayorga, luis s.; sánchez, cristián gabriel title: detection and isolation of asymptomatic individuals can make the difference in covid- epidemic management date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: nn rgdw mathematical modeling of infectious diseases is a powerful tool for the design of management policies and a fundamental part of the arsenal currently deployed to deal with the covid- pandemic. here we present a compartmental model for the disease that can provide healthcare burden parameters allowing to infer possible containment and suppression strategies, explicitly including asymptomatic individuals. the main conclusion of our work is that efficient and timely detection and isolation of these asymptomatic individuals can have dramatic effects on the effective reproduction number and healthcare burden parameters. this intervention can provide a valuable tool complementary to other non-pharmaceutical interventions to contain the epidemic. the covid- pandemic has brought the world to a pause with the sole aim to defeat this worldwide threat, and the scientific community has joined the effort. since its outbreak by the end of , we have been able to learn some about this new sars-cov coronavirus. unfortunately, new facts come with a lag compared to the virus spread and governments are forced to make prompt decisions based on limited evidence which changes at a staggering pace. the fight against a practically unknown enemy has been and still is the major obstacle. aside from studying the virus's biology, infecting mechanisms, probable treatments and of course vaccine development, epidemic mathematical modelling has stepped forward. in a trade-off between simplicity and detail, compartmental modelling strategies provide a sharp suit that allows exploring a variety of scenarios and provides an intuitive understanding of the most critical factors governing disease dynamics. the recent use of s(susceptible)-exposed(e)-infected(i)-recovered(r) models has made a difference for public health care decision making by providing, for example, estimations of the impact of non-pharmaceutical interventions (npi) [ ] . the main challenge is to create a model that predicts plausible scenarios for a disease we have known for only four months. one of the most important barriers for the provision of solid epidemiological parameters has been the different management strategies that each country has taken in response to this outbreak. most evidently, the case fatality rate (cfr) varies largely between countries (i.e. italy %, argentina %, iceland . %). varying cfrs cannot be explained only by the different population age structure or available critical care beds. most importantly, uneven and time-varying testing criteria in different countries make the cfr an inadequate severity parameter. south korea and especially and more recently, iceland's approach to testing massively for covid- has brought us closer to the real infection fatality rate (ifr) which describes more precisely the magnitude of the threat [ ] . better estimates of the ifr have given insights on two aspects. firstly, the asymptomatic or very mildly symptomatic group of individuals is more significant than previously thought [ ] [ ] [ ] since they represent the vast majority of the infected individuals. secondly, these individuals, in most cases, are not detected nor isolated, and therefore appear to be the leading cause of the epidemic's spread. we proposed ourselves to model the strike of the virus locally (mendoza-argentina). anyhow, our model applies to any city or country and available for use and adaptation. argentina, as a developing country, was not going to be able to bear this pandemic without a health care collapse. based on the epidemic behaviour in europe, the government determined a complete lock-down as the primary measure of control for the country as from march th, when argentina's confirmed positive cases were only , mainly located in the capital city buenos aires and mostly imported. many regions from inside argentina had zero confirmed cases, including the authors' hometown, mendoza province. prompt lock-down measures significantly flattened the curve at an early stage. arguably this was an anticipated measure, and it gave time to prepare (at least to some extent) for what was/is coming. as mentioned by ferguson et al. [ ] , the efficiency of mitigation and suppression measures depends on the size of the country or region in which these actions are implemented. different population densities, uneven access to intensive health care, distinguishing age-related communities, all make the epidemic spread distinctively. therefore, a model should be able to take these variables into account. we propose here an seir model for covid- epidemics that incorporates specific compartments that classify infected individuals in several clinical categories. these compartments provide figures that can inform the strategic planning of health care requirements. on the other hand, different regions exchange infectious and exposed individuals through communication routes. consequently, the model can provide the possibility to trigger measures independently for each city and block intercommunications selectively. most importantly, we model asymptomatic individuals as a subset of the infectious compartment. we demonstrate here the significant impact that detecting and isolating these individuals can have on the disease outcome. we augmented the basic seir scheme by modelling symptomatic and asymptomatic individuals separately. symptomatic individuals can move into mild and severe cases which can recover or further evolve into critical care and recover or die. asymptomatic individuals may move into an isolated compartment after a detection lag of variable efficiency. figure shows a connection diagram of the compartments in our model and table provides a detailed description of each. figure shows the possible timelines of the evolution of an initially susceptible individual together with the relevant parameters that determine the flow between compartments. table provides a detailed description of each compartment. cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . table . based on recent calculations on the ifr, of . - . % [ ] , and most recently of . - . % inferred from iceland's statistics [ ] , we adapted the parameters for our model to our country. taking in consideration an ifr of ~ . % and the current cfr in argentina of ~ % we concluded that % of the infected cases were asymptomatic or with very mild symptoms not fulfilling the current argentine criteria for covid- testing (fever & sore throat or cough or respiratory distress). the asymptomatic case percentage is in line with the published data by li et al. [ ] who estimated the undocumented cases in %. argentina's principle to test only highly suspicious cases is leaving out asymptomatic and paucisymptomatic individuals. for our model, we used the complete epidemiological data we found [ , ] that referred to a subset of patients from china for which a similar criterion for covid- testing and hospitalization than argentina was used [ , ] . we adapted it to maintain the cfr of ~ % and ifr~ . %. summarizing, from what is called . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint "symptomatic cases" in argentina today, around % will require hospital care, of those, % will need intensive care unit facilities, and of the latter, % will die. based on european case growth rates, and in agreement with the parameters we set for our model, we presumed a basic reproduction number of [ ] . we assumed that mitigation measures (case-isolation, general social distancing, banning of public gatherings, school closures) lower r to and suppression measures (complete lockdown or quarantine of the whole population except for essential activities) could make r ≤ [ ] . we supposed, as published, that asymptomatic individuals are half as infective as symptomatic patients [ ] . we inferred for these an attenuation factor of . in the basic reproduction number and ⅓-½ the infective time of symptomatic cases [ ]. table shows the parameters we chose and the bibliography that supports our choices. time for which asymptomatic individual is infectious (days) li et al. [ ] time to recover for and cases that do not require icu (days) fang et al. [ ] time to recover for an (days) zhang et al. [ , ] time for to require icu (days) [ ] time for to recover in icu (days) fang et al. [ ] probability of an infected patient to be asymptomatic . li et al. [ ] probability of an infected individual to require hospitalization . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . attenuation factor for asymptomatic patients . li et al. [ ] the seir model depicted in figure gives rise to the following set of ordinary differential equations: where dotted quantities are time derivatives and = ( ), ′ = ( ), = ). probabilistic parameters are adjusted to provide a cfr and ifr of and . % respectively in equilibrium. the quantity represents the probability that . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint an asymptomatic individual is detected and isolated. the mean residence time parameters govern the dynamical evolution of the compartment populations. the model is scaled up to describe different interconnected areas or cities by integrating the ordinary differential equation set for periods of a day and exchanging exposed and infectious individuals at the end of each day according to the following equation: where and stand for the fraction of exposed and infectious individuals in regions and respectively, is the population of area and is the number of people exchanged daily between areas and . infectious individuals include both asymptomatic and symptomatic ones. we divided the mendoza province into regions: north (mostly urban), west (vineyard and mountain zone), east (primarily rural) and south (urban and rural). hospital beds and icu units for each area were added to the model. additionally, an estimate of how many people travel daily between the regions was considered (figure ). use of the regional compartmentalization of the model . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . we set our model to run in zones of the mendoza province considering their respective population, daily mobilization of people between the regions, and health care facilities for each area ( figure ) . as an example of the application of this tool, we simulated an outbreak in the north zone, starting with one infected person and monitored its arrival to the west area. we contemplated two different reproduction numbers; = (no mitigation nor suppression actions installed) or = (moderate containment measures governing the whole province). around people travel every day between these districts. without interfering in the communication routes between zones, it took days (r = ) and days ( = ) for the virus to spread to the west zone. when travelling between the communities was reduced to a tenth, the outbreak reached the west with a -day lag (day ) in the = scenario and a -day delay (day ) for the = scenario (figure ) . as expected, this shows that blocking communication routes between districts is an excellent strategy to delay the entrance of the epidemic. anyhow, this action has more power when combined with other containment measures as shown here by comparing a = versus an = situation. furthermore, in this restricted communication situation, the exponential curves eventually catch up if no other interventions are instated (data not shown in graph). the communication restriction between north and west practically does not modify the north's dynamic, so in figure , we only show the basal state of the northern district. the importance of the asymptomatic group in the model. considering that the asymptomatic or very mildly affected individuals are the majority, as can be expected, to detect and isolate them diminishes the total infectious population and changes the epidemic evolution dynamics. as li et al. have shown [ ] the introduction of an asymptomatic reservoir with a different reproduction number modifies the epidemic evolution in a non-trivial manner. this effect comes into place by a . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint modification of the effective reproduction number when asymptomatic individuals are considered. elaborating on this result, we can add that fast and efficient detection plus the isolation of asymptomatic individuals can indeed control the epidemic. the effective reproduction number of the model shown in figure is significantly altered by fast and efficient detection plus the isolation of asymptomatic individuals, as shown in figure . if the efficiency of detection is % within three days of becoming infectious, the effective reproduction number can be reduced by a half. if this policy is accompanied by other non-pharmaceutical interventions that lower the basic reproduction number such as mitigation and suppression measures then the effective reproduction number can be brought to values lower than one, effectively controlling the epidemic. on the opposite extreme, the effective reproduction number is larger than the parameter when asymptomatics are not isolated and therefore remain infectious until recovery. for details on the calculation of the effective reproduction number please refer to the supplementary information. as can be expected from its influence on the effective reproduction number, the isolation of asymptomatic individuals has a dramatic effect on the duplication time of the epidemic in the exponential growth phase. in a basic reproduction number scenario of , isolating half of the asymptomatic individuals within four days of becoming infectious can effectively double the time it takes for clinical cases to duplicate in the exponential growth phase. this effect is smaller for more significant reproduction numbers reinforcing the statement that other interventions must accompany this policy in order to control the epidemic. the consequence on the effective reproduction number of the removal of asymptomatic individuals from the infectious pool affects both epidemic dynamics and equilibrium values. the result is robust over a wide range of parameters. figure shows the effect of efficient asymptomatic isolation on health capacity burden and overall mortality for the whole population. the plots show medians and interquartile ranges over a sample of . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint sets of parameters. this set was built by sampling residence times from truncated normal distributions between and twice the average value shown in table with a standard deviation of % the average value. we assumed the detection and isolation of % of asymptomatic individuals in day . efficient removal of asymptomatic infectious individuals from circulation has dramatic effects on healthcare burden and fatality over the total population, mainly when r remains at the lower end. once more, this supports the importance to maintain other mitigation actions in combination with asymptomatic detection and isolation. figure : healthcare burden effect of detection and isolation of % of asymptomatic individuals within three days of becoming infectious. the plots show medians and interquartile ranges over a sample of sets of parameters of important healthcare parameters: maximum usage of hospital beds (icu and non-icu), and accumulated fatalities when system reaches equilibrium. considering the hospital beds and icu facilities for each zone, we ventured to see if a zone-specific on-off suppression measure policy was feasible, as suggested by ferguson et al. [ ] . considering the results shown in figure , the communication between all the districts was diminished to a tenth as well. we set a trigger of % icu occupancy (of beds destined to be used for covid- , assuming ~ % of total icu beds were going to be intended to the pandemic) to turn on suppression measures and a stopper of % of icu occupancy to relax these actions. we show results for an = fluctuating with an = and an = combined with an = . considering = as normal activities before this pandemic and = with necessary containment measures . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint but not complete lock-down. an = was considered when complete lock-down or quarantine was ordered. in the first scenario, the exponentiality of an = curve is impossible to stop, even when a complete lock-down is set, and inevitably the sanitary system collapses in all areas, making this undoubtedly a lousy strategy. this evidence supports once more what we said in the previous scheme; life cannot return to normal when suppression measures are relaxed. (figure. ). considering that once the epidemic has struck, social standards are entirely changed, we simulated an alternation of and between and , meaning this that once strict measures are relaxed, there are still essential actions being taken (i.e. social distancing, university and colleges remain closed, etc.). in figure we show that the northern area can stand this situation without a sanitary collapse, needing two quarantines to surpass the epidemic. the other, more rural areas still have an overwhelmed health care system and need much more time in maximum isolation. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint since intensive health care facilities are mainly located in the north, we set our model with the icu beds as a single pool for the whole province. we still maintained the areas separated regarding the rest of the parameters. also, movement between cities remained restricted to a tenth. contemplating this, we ran once more the model between = and an = . this strategy kept the health system below saturation and the quarantine periods were more acceptable for the whole territory. still, in this scenario, . months of lock-down are needed to endure the pandemic and the inconvenience of having to transfer patients throughout the territory yet needs to be taken into account. (figure ) . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint figure : the effect of triggered on-off suppression measures in the whole territory (trigger= % icu occupancy, stopper= % icu occupancy) in a = scenario. icu beds were considered as a single pool for the entire province. dotted lines represent reproduction number fluctuance between = (moderate containment measures installed) and = (lock-down). full lines represent % of icu occupied beds throughout the timeline for which these on-off measures were simulated. since the asymptomatic group is such an essential part of the system, we ventured to see what would happen if one could detect and isolate at least a proportion of them. thus, using the same triggers as before (icu beds %- %), in a synchronized system, we added the detection and isolation of different proportions of asymptomatic individuals. in figure we see that screening for asymptomatic cases diminishes significantly the time needed with complete lock-down. in the ideal assumption that % of the asymptomatics could be detected and isolated, there would be no need for quarantine, and the health care system would not collapse. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint figure : the effect of detecting and isolating different percentages of asymptomatic individuals on a model triggering on-off suppression measures in the whole territory (trigger= % icu occupancy, stopper= % icu occupancy) in a = scenario. icu beds were considered as a single pool for the entire province. dotted lines represent reproduction number fluctuance between = (moderate containment measures installed) and = (lock-down). full lines represent % of icu occupied beds throughout the timeline for which these on-off measures were simulated. argentina was one of the countries that acted fastest and most rigorously very early in the arrival of the pandemic, setting a complete lock-down when only cases had been reported. this policy has indeed "flattened the curve" as it has in many countries around the world for which the growth of clinical cases has changed from exponential to linear in time. the sustainment of drastic suppression measures over months, albeit possibly successful, is not sustainable and alternatives must be considered. to establish a reliable mathematical model for a practically unknown disease was a challenge, but we had the advantage to count with previous epidemiological studies [ , , , ] and modelling proposals [ , , ] . we established a locally inspired mathematical model of the disease, in the ~ , , population province of mendoza-argentina, which can apply to any other city or country. the model we propose provides explicit variables such as the number of patients under intensive care, hospital admissions, mild cases, and asymptomatic individuals. these variables are described dynamically according to the different residence times in each compartment and branching probabilities. we consider this to be a superior alternative to evaluating health burden parameters from a purely probabilistic point of view that does not consider the dynamical nature of the epidemic evolution. furthermore, our model is adapted to the regional realities of small districts, which can be used as a strategy tool for any place in the world. we confirmed that if an outbreak were to burst in one city, blocking circulating routes can as expected, have an essential impact. on the other hand, the health care distribution of mendoza made a regionalized trigger for suppression impractical because of the uneven assignment of intensive care units. still, in other countries or regions, this strategy might be useful. the significant contribution we can make is to suggest that asymptomatic or very mildly ill patients provide a primordial hinge to manage the epidemic. any control upon them exerts a substantial impact on the disease outcome. previously described on-off suppression strategies [ ] become much more effective when combined with the detection and isolation of asymptomatic cases. the association of mitigation measures with detection and isolation of around half of the asymptomatic and paucisymptomatic individuals would not need strict suppressive actions. therefore, massive covid- screening would be an alternative to the province's complete lock-down. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint for low-income countries, like ours, screening by pool-testing could be a helpful strategy if started early in the epidemic. yelin et al. [ ] showed that samples could be examined adequately in pools of , reducing dramatically the costs needed for extensive screening. argentina could use this strategy to detect and isolate as many asymptomatic or very mildly affected individuals as possible to be able to reduce the time span over which strict suppression measures are in effect. our model and its analysis inform that the detection and isolation of all infected individuals, without leaving aside the asymptomatic group is the key to surpass this pandemic. this work was supported by funding from: conicet and universidad nacional de cuyo. no specific grant was used for this work. the global impact of covid- and strategies for mitigation and suppression articles estimates of the severity of coronavirus disease : a model-based analysis global covid- case fatality rates -cebm n estimating the number of infections and the impact of non-pharmaceutical interventions on covid- in substantial undocumented infection facilitates the rapid dissemination of novel coronavirus ( sars-cov ) comparisons of nucleic acid conversion time of sars-cov- of different samples in icu and non-icu patients familial cluster of covid- infection from an asymptomatic impact of non-pharmaceutical interventions (npis) to reduce covid- mortality and healthcare demand clinical characteristics of coronavirus disease in china early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia coronavirus: the hammer and the dance -tomas pueyo -medium n.d evaluation of covid- rt-qpcr test in multi-sample pools the authors thank our affiliation institutions for supporting this work. the authors declare no competing interests. code used in this study is available in the github repository https://github.com/iheminstitute/seir_mendoza key: cord- - xqft authors: rello, jordi; belliato, mirko; dimopoulos, meletios-athanasios; giamarellos-bourboulis, evangelos j.; jaksic, vladimir; martin-loeches, ignacio; mporas, iosif; pelosi, paolo; poulakou, garyphallia; pournaras, spyridon; tamae-kakazu, maximiliano; timsit, jean-françois; waterer, grant; tejada, sofia; dimopoulos, george title: update in covid- in the intensive care unit from the hellenic athens international symposium date: - - journal: anaesth crit care pain med doi: . /j.accpm. . . sha: doc_id: cord_uid: xqft the international web scientific event in covid- pandemic in critically ill patients aimed at updating the information and knowledge on the covid- pandemic in the intensive care unit. experts reviewed the latest literature relating to the covid- pandemic in critically ill patients, such as epidemiology, pathophysiology, phenotypes of infection, covid- as a systematic infection, molecular diagnosis, mechanical ventilation, thromboprophylaxis, covid- associated co-infections, immunotherapy, plasma treatment, catheter-related bloodstream infections, artificial intelligence for covid- , and vaccination. antiviral therapy and co-infections are out of the scope of this review. in this review, each of these issues is discussed with key messages regarding management and further research being presented after a brief review of available evidence. the covid- is an ongoing global pandemic caused by sars-cov- . elderly patients with underlying chronic diseases are considered of high risk for death, like immunocompromised but younger people without major underlying diseases may also present lethal complications [ ] . covid- must be regarded as a systemic disease involving multiple human systems due to the uncontrolled systematic inflammatory response resulting from the release of large amounts of pro-inflammatory cytokines and chemokines by immune effector cells, named "cytokine storm" [ ] . for this reason, we propose the new definition as sars-cov- multiple organ disease syndrome (sars-cov- mods) [ ] . in this situation the treatment with immunomodulatory agents (corticosteroids, tocilizumab, anakinra, sarilumab, etc.) has been widely used, although more laboratory and clinical evidence is required [ ] . a major problem of the coronavirus pandemic is the considerable burden imposed on national health systems worldwide due to the hyperacute outbreak and the proportional increase of patients requiring intensive care unit (icu) support in an extremely limited period of time, while outcomes vary according to the burden of the disease in each country. the pandemic has caused also a major global social and economic disruption while misinformation about the virus has circulated through social and mass media. in this article, through an international webinar meeting which took place in athens greece on september th, , we report an update on information and knowledge on covid- pandemic issues in the icu. j o u r n a l p r e -p r o o f epidemiology infection, caused by sars-cov- , has led to a global pandemic. the clinical and pathological features of acute infection have been extensively published, with a wide spectrum of disease seen, from asymptomatic infection to mild self-limiting symptoms to acute respiratory failure requiring invasive mechanical ventilation (mv) [ ] . the most common clinical finding is fever, cough and fatigue with some laboratory findings such as increased serum ferritin, d dimers and c reactive protein (crp) [ ] . it affects more older adults and there is also a high fatality rate in this subset of patients. acute respiratory distress syndrome (ards) is the primary cause of death in covid- [ ] and a recent scope review found that for covid- , < % of patients were reported as experiencing bacterial/fungal coinfection at admission, but development of secondary infections during icu admission is common [ , ] . patients who do not develop a bacterial infection present high initial crp levels and low procalcitonin (pct) levels, decreasing progressively, with implications on antimicrobial stewardship. therefore, empirical antimicrobial therapy with low serum pct in icu patients should not be indicated. crp does not have predictive value for bacterial infections in icu patients with sars-cov- infection. consideration of superinfection and prompt appropriate use of antibiotics should be considered if pct increase after some days of mv. covid- infection has shown a great variability in terms of mortality in different regions around the globe. an observational study conducted in the us found an excess of , ( % prediction interval, , - , ), more deaths than would typically be expected at the same time of the year [ ] . indirect deaths caused by cardiovascular events, delayed cancer care, or malnutrition may be a serious concern. persistent symptoms after hospital discharge also represent a significant burden after acute covid- in the icu. sars-cov- is an enveloped, positive-sense, single-stranded rna viruses of ~ kb, only able to synthesise proteins but creating a wide variety of signs and symptoms. coronaviruses, and especially sars-cov- , penetrate the epithelial cells via the angiotensin converting enzyme (ace ). the serine transmembrane serine protease in the host cell further promotes viral uptake by cleaving ace and activating the sars-cov- s protein. after entry, sars-j o u r n a l p r e -p r o o f cov- can shut down the effective ifn type antiviral pathway. the virus uses the intracellular machinery to multiply and disseminate into the airway [ ] . the virus mainly spread from the lung but could disseminate to all tissues that express ace (mainly small bowel and colon, brain, heart, kidney and skin); during autopsies, the virus is found in many organs [ ] . critically ill mechanically ventilated patients showed rnaemia for days in median [ ] . the absence of normal th response leads to pyroptosis of the epithelial cell (with massive proinflammatory reactions, recruitment of blood monocytes into the lungs and neutrophils attraction and activation (reactive oxygen species , proteases production and cell death by neutrophil extracellular traps (netosis)), leading to a "cytokine storm" [ ] . the lack of cytokine at a transcriptional level in the blood, contrasting with high level of protein, suggest a compartmentalisation of the response starting into the lung and spreading into other tissues [ ] . the abnormal th response is unable to clear the pathogen and leads to an abnormal activation of cd + t cells with massive decrease, partial differentiation, and exhaustion. the cd + response is anarchic with plasmablast proliferation. the high level of production of sars-cov- antibodies contemporaneously to virus persistence is supposed to enhance the inflammatory reaction and to abrogate the wound healing response (mcp- and interleukin (il)- production and proinflammatory monocytes/macrophage recruitment) [ ] . endothelium is activated, through the ace receptor with expression of tissue factor, platelet activation and increased von willebrand factor (vwf) and factor viii (fviii) levels, all of which contribute to thrombin generation and fibrin clot formation. thrombin, in turn, causes inflammation through its effect on platelets which promote net formation in neutrophils. it also activates endothelium through the protease-activated receptors (par) receptor, which leads to c a release and monocyte activation. vasculitis is associated with a prolonged procoagulant and anti-fibrinolytic states that explain the high risk of arterial and vein thrombosis [ , ] . presentation of covid- is characterised by different clinical phenotypes [ ] , with different severity-of-illness and outcomes, with specific biomarkers. phenotype is characterised by mild symptomatic patients without hypoxemia and radiological abnormalities. phenotype presents as hyper-inflamed and hypovolaemic patients, presenting mild hypoxemia and/or small opacities on chest x-ray. exposed to rapid deterioration risk, close spo j o u r n a l p r e -p r o o f monitoring is needed. manifested as "bronchopneumonia pattern" of jin et al. [ ] these patients have a median il- under pg/ml. phenotype is characterised by greater hypoxemia (pao /fio < ), respiratory rates > per minute, il- values > pg/ml, being a possible progression from type . an "organising pneumonia pattern" of jin and "phenotype " of robba et al. [ ] is present. phenotype and are characterised by severe hypoxemia requiring intubation. phenotype is characterised by hypoxic vasoconstriction, micro-embolic lesions, normal lung compliance, lower lobes oedema with ground glass opacities; consider ino, prostacyclin, normal tidal. computed tomography (ct) scan is consistent with as "progressive organising pneumonia pattern" of jin, "type l" of marini and gattinoni [ ] and "phenotype - " of robba. phenotype represents an advanced stage of ards, typically in patients with delayed intubation; it totally fits the severe ards criteria. patients may benefit from positive end-expiratory pressure (peep) levels > cm h , prone positioning, land low tidal volumes. ct documents the "diffuse alveolar damage pattern" of jin, "type h" of marini and "phenotype - " of robba. a comprehensive categorisation is required, based on physiology, ct scan findings and clinical presentation, to achieve a personalised treatment, indeed. as the ace-ii receptor to which sars-cov- binds is widely found throughout the body, including the lung alveolar epithelial cells, enterocytes of the small intestine, arterial and venous endothelial cells and arterial smooth muscle cells [ ] , it should not be surprising that covid- is a disease more than just the lungs. after the lungs, the heart is the most frequently involved organ. a variety of pathologies can impair cardiac function, both primary (i.e. myocarditis) and secondary (myocardial infarction, arrhythmia, cytokine-induced suppression, etc.) [ ] . assessing the cause of cardiac involvement is complicated by the frequent comorbid heart disease in patients with severe disease and the variety of cardiotoxic medications that have frequently been used in combination (e.g. ritonavir, hydroxychloroquine, alpha interferon, high dose methylprednisolone, etc.) [ ] . however, rates of myocarditis are quite significant and a cause for concern regarding long term consequences in covid- survivors [ ] . widespread thrombotic disease in the venous and arterial system due to the endotheliitis, despite prophylactic low molecular weight heparin therapy [ ] , is the other hallmark of covid- . primary j o u r n a l p r e -p r o o f neurological disease other than stroke is rare, and most renal disease is secondary to systemic insults rather than primary. j o u r n a l p r e -p r o o f the prompt and reliable diagnosis of covid- cases is challenging for several reasons and is mainly based on molecular assays. the aims of real-time rt-pcr are to perform early, rapid and accurate diagnostics and also guide patient care and management as well as epidemiological strategies. the most common specimens used are nasopharyngeal and oropharyngeal samples, while tracheal aspirate, bronchial specimens or bronchoalveolar samples are occasionally collected from intubated patients. the molecular diagnosis nowadays mainly relies on real-time rt-pcr techniques, which are considered reference ones, as they present high sensitivity and specificity and are compatible with automation. in a lesser extent, other pcr assays, such as nested pcr, rt-lamp, rt-iipcr or the genxpert assay may be used [ ] . the rna extraction techniques were initially manual and later evolved to automated, with rt-pcr set up to be prepared manually and rt-pcr to be run in separate thermal cyclers. all these steps were later incorporated in fully automated instruments, such as the sample-to-result instrument neumodx system. a very recent evolution in the molecular diagnosis is the application of real-time rt-pcr in saliva, which can be effectively used for the detection of respiratory viruses [ ] . saliva has the obvious advantages to be easy to collect, unaffected by collection process, advantageous for individuals with physical or mental handicaps, stable at room temperature for extended periods, not dependent on swabs that are in shortage, of low-risk for exposing laboratorians to hazardous samples, can be obtained while social distancing and can reduce the need for personal protective equipment since it is self-collected. the global pandemic manifested as covid- pneumonia has raised important challenges to physicians working in icus. in fact, patients with covid- pneumonia present heterogeneous clinical manifestations; further, significant proportion of these manifestations develop severe hypoxemic respiratory failure requiring invasive mv. different factors have been identified to predict those patients who will require mv, like elevated il- in the serum, deterioration of oxygenation (mainly pao /fio lower than ), presence of heart disease and older age [ ] . at histopathological analysis, early presentation is characterised by lymphocytic alveolitis. recent evidence reported pneumo and vascular lysis, alveolar cell infiltration, alveolar mucinosis, and j o u r n a l p r e -p r o o f further fibrosis [ , ] . it is mandatory to understand better the peculiarities of covid- pneumonia pathophysiology, in order to optimise mv. different radiologic phenotypes have been identified by ct scan [ ] : phenotype with multiple, focal over-perfused ground-glass opacities, associated with normally aerated areas; phenotype , with atelectasis and peri-bronchial opacities, heterogeneously distributed and hypo-perfused, associated with phenotype ; phenotype , with patchy ards-like pattern, heterogeneously distributed, with hyper and hypo-perfused areas, associated with radiologic phenotype . radiologic phenotype is likely to be treated by noninvasive respiratory support, while phenotype , more often needs invasive mv. in icu, among intubated critically ill patients, most of them are characterised by phenotype , and only a minority as phenotype or . in normal lungs, the standard lung weight is around g, while in traditional ards, the lung weight is on average around g, with an excess tissue mass of g. similarly, in covid- patients with phenotype , average lung weight is around g, with an excess tissue mass of g. thus, the excess tissue mass is similar in traditional ards as well as in covid- pneumonia phenotype . in traditional ards, the distribution of regional perfusion is mainly distributed on the dependent lung regions, where atelectasis and the majority of non-aerated lung tissue is located. on the contrary, in covid- pneumonia, the distribution of blood flow is nongravitational, prevalent in non-dependent lung regions, with better aeration. areas of hypoperfusion are distributed mainly in dependent lung non-aerated regions. thus, hypoxia is mainly due to the following mechanisms: first, lower ventilation-perfusion (̇⁄ ), in aerated (non-dependent) and poorly aerated lung regions due to increased perfusion; second, higher shunt in non-aerated lung tissue with micro-thrombosis and vascular lysis effect, which may be even partially protective; and, third, lower alveolar-capillary diffusion. it has been hypothesised that in patients with high compliance and low ̇⁄ , hypoxemia is primarily due to the ̇⁄ mismatch related to the loss of the lung perfusion regulation, with a lower amount of non-aerated tissue and less alveolar recruitability. in contrast, in patients with lower compliance with a major loss of aeration, the recruitability and the response to peep has been suggested to be higher. the application of higher levels of peep is associated with larger recruitment in traditional ards as compared to severe covid- pneumonia, radiological phenotype or , but not with the respiratory mechanics. traditional ards is characterised by a diffuse damage of the alveolar capillary membrane, leading to oedema and atelectasis in the most dependent lung regions, in supine position. thus, traditional ards is characterised by increased excess tissue mass, highly recruitable by increasing levels of pressures. on the contrary, covid- pneumonia is characterised by alveolar infiltration, leading to different increased excess tissue mass, yielding to phenotypes to , less recruitable by increasing pressures. for these reasons, we suggest to minimise lung inflation at end inspiration and expiration, j o u r n a l p r e -p r o o f minimising oxygenation [ ] and optimising the level of haemoglobin, according to the optimal oxygen transport [ ] . severe covid- pneumonia is a typical "primary" ards, with pneumocytes and vascular lysis, to be ventilated at lower pressures both at end inspiration and expiration with minimal oxygenation. in conclusion, "less is more" in ventilating critically ill patients with severe covid- pneumonia. [ ] . progression from lower respiratory tract infection to srf necessitating mv is taking place either through over-production of il- β and development of macrophage activation syndrome or through over-activation of the il- receptor pathway leading to a unique pattern of monocyte dysregulation. in this pattern, the expression of the human leukocyte antigen dr on monocytes is decreased, which is associated with defective antigen presentation and subsequent lymphopenia. in parallel, monocytes maintain their potential for the over-production of pro-inflammatory cytokines [ ] . this leads to the hypothesis that early treatment with a biological that can provide effective blockade of pro-inflammatory responses and enhance anti-inflammatory responses may prevent progression into srf and mv. results of the prospective ana-covid openlabel trial in patients have shown that early treatment with anakinra may achieve this goal [ ] . anakinra is the recombinant receptor of il- . early recognition of the risk of a patient for progression into srf using the biomarker supar (soluble urokinase plasminogen activator receptor) [ ] and start of anakinra to prevent mv is the rational of the on-going save trial (eudract number - - , www.clinicaltrials.gov nct ). tocilizumab which blocks il- receptor is also proposed [ ] with intravenous use being suggested to be superior to subcutaneous administration [ ] . although the roche press release of the first results from the phase iii covacta trial is not favouring early administration in all patients, some systematic reviews suggest potential mortality benefit in some cohorts with acute respiratory failure [ ] . sarilumab is also effective in blocking il- receptors and may have similar effects. promising results were provided with the use of low-dose dexamethasone in the recovery trial. when given at mg once daily either orally or intravenously for days, significant decrease of mortality was found. the recommended patient population is either for patients with severe disease in need for oxygen (e.g. oxygen saturation less than %) or under mv [ ] . the european medicines agency human medicines committee (chmp) endorsed on the th of september the administration of dexamethasone in adults and adolescents (from years of age and weighing at least kg) who require supplemental oxygen therapy (oxygenation requirements to maintain spo above % or who underwent mv). in all cases, the recommended dose is mg once a day up to days. use of intravenous steroids is also recommended in the recent american thoracic and european respiratory society guidance [ ] for patients who underwent mv, require oxygen supplementation or require extracorporeal membrane oxygenation. it is also supported by recent meta-analyses [ ] , although more research is required on the interaction with antivirals, anticoagulation, specific subsets like diabetes or older than years, suggesting the need for a precision prescription approach [ ] to be more selective in reducing potential harm and optimise benefits. finally, interactions between il- r blocking therapy and steroids need to be elucidated. plasma from patients who have overcome covid- infection, referred to as convalescent plasma, is a treatment option, which has been recently approved by the food and drug administration for use in patients with sars-cov- infection [ , ] . this approval was based on preliminary results from clinical studies that showed a significant clinical and biochemical improvement of patients, reduction in hospitalisation days and survival benefit [ ] . in greece, a phase clinical study for the use of convalescent plasma in hospitalised patients with covid- (nct ) has been performed. to date, possible donors were tested for the presence of igg/iga antibodies against the spike protein of sars-cov- (s domain). median time from the day of the first symptom or pcr positivity (for asymptomatic patients) till the day of screening was days. igg antibodies were detected in ( %) donors. plasmapheresis was performed in the first donors, at a median time of days (range: - ) after screening. there was a significant reduction in the titter of igg and iga antibodies between the days of screening and plasmapheresis [ ] . this rapid reduction of anti-sars-cov- antibodies in this cohort has also been described in other studies [ ] and reveals a time pattern of reduction. however, it remains unknown whether neutralising antibodies share the same model or if this reduction affects the host immunity against sars-cov- . this result also suggests that, when indicated, plasmapheresis has to be performed as soon as the patient has recovered from covid- . significant improved clinical outcomes with convalescent plasma therapy has been restricted to patients not requiring mv. [ , ] . as multiple factors interfered with standard hai prevention protocols, it was imperative to quickly recover icu standards of care and "adapt recommendations to exceptional care conditions" [ ] . italian group (siaarti) responded to this challenge with guidance on vascular approach in covid- patients [ ] . the effect of central line bundle enhancement was well demonstrated by swiss researchers back in [ ] . moving forward, taking care of three key elements at all times will probably further minimise hai risk: well-trained people, high compliance to updated evidence-based protocols and utilisation of reliable and easy to use technology. needless to say, maintaining sufficient stock is of paramount importance. scientists and pharmaceutic industry are racing to produce a safe and effective vaccine against sars- science, developed a vaccine based on adenovirus (ad ), which was already given limited approval in china [ ] . the gamaleya research institute has developed gam-covid-vac, using a combination of ad and ad . renamed as sputink-v, it was given limited approval in russia before entering phase iii trials [ ] . johnson  johnson, in partnership with the beth israel deaconess medical center, is testing another ad vaccine. astrazeneca and the university of oxford is testing a vaccine based on a chimpanzee adenovirus called chadox ; safety concerns of potential neurotoxicity (transverse myelitis case) have suspended trials in some countries, whereas in others they resumed [ ] . the artificial intelligence (ai) and data science community has supported the global response to the covid- outbreak, with the number of published ai and machine learning studies related to covid- exceeding thousand. the contribution of ai to the fight against covid- is briefly classified in (i) biomedicine and pharmacotherapy, (ii) modelling of the outbreak (identification, tracking and prediction), and (iii) detection and diagnosis. in biomedicine and pharmacotherapy deep, neural networks were used for dna microarray and genomic sequence analysis, while in the modelling of the outbreak machine learning models like long short-term memory (lstm) have been used [ ] . regarding detection and diagnosis, studies have used machine learning algorithms to predict the criticality of covid- positive patients using clinical features and identifying which of them have statistically significant hazard errors [ , ] . other studies have used cough and/or breath sound data to identify covid- , as in [ ] . the most popular ai-based covid- identification approach is using chest x-ray or ct images with cnn models [ ] . the conducted studies have shown the j o u r n a l p r e -p r o o f contribution of ai and data science to the fight against covid- pandemic, however more standardised datasets and clinical validation of the models' performance are further needed. j o u r n a l p r e -p r o o f management and understanding of sars-cov infection has evolved during the six first months of the pandemic. in spite of early reports calling for icu preparedness [ , ] , many icus in western countries were overwhelmed in march-april , with patients exposed to adverse events due to compassionate administration of drugs with weak evidence [ ] , with need of implementing icu admission triage algorithms [ ] and lack of targeting management based on clinical phenotypes. whereas some icus reported similar mortality to primary influenza pneumonia requiring mv [ ] , these conditions were responsible for a large amount in preventable deaths. better understanding of early micro-thrombosis [ ] , refining strategies of oxygenation and intubation criteria (using high flow nasal therapy with awake prone position), and use of immunomodulatory agents have been associated with a shift in the management of critically ill patients, with a lower burden of deaths among hospitalised patients. further research in form of randomised clinical trials is required to improve the understanding of the interactions between antivirals, steroids and other immunomodulatory agents, and to determine the effects on different subpopulations. clinicians and researchers have focused on the acute phase of severe covid- , but continuing monitoring [ ] after icu and hospital discharge for long-lasting complications is advised. in addition, assessment of anxiety, sleep disturbances, depression and post-traumatic distress syndrome in icu survivors needs to be investigated. clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study clinical features of patients infected with novel coronavirus in wuhan, china multiple organ dysfunction in sars-cov- : mods-cov- complex immune dysregulation in covid- patients with severe respiratory failure characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention the epidemiology and clinical information about covid- estimates of the severity of coronavirus disease : a model-based analysis bacterial and fungal co-infection in individuals with coronavirus: a rapid review to support covid- antimicrobial prescribing biomarkers for antimicrobial stewardship: a reappraisal in covid- times? estimation of excess deaths associated with the covid- pandemic in the united states impaired type i interferon activity and inflammatory responses in severe covid- patients histopathological findings and viral tropism in uk patients with severe fatal covid- : a post-mortem study risk factors for sars-cov- detection in blood of critically ill patients pathological inflammation in patients with covid- : a key role for monocytes and macrophages t cell responses in patients with covid- endothelial cell infection and endotheliitis in covid- clinical phenotypes of sars-cov- : implications for clinicians and researchers a pattern categorization of ct findings to predict outcome of covid- pneumonia distinct phenotypes require distinct respiratory management strategies in severe covid- management of covid- respiratory distress tissue distribution of ace protein, the functional receptor for sars coronavirus. a first step in understanding sars pathogenesis description and proposed management of the acute covid- cardiovascular syndrome covid- : first do no harm outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease (covid- ) confirmation of the high cumulative incidence of thrombotic complications in critically ill icu patients with covid- : an updated analysis diagnostic strategies for sars-cov- infection and interpretation of microbiological results comparison between saliva and nasopharyngeal swab specimens for detection of respiratory viruses by multiplex reverse transcription-pcr. j clinical characteristics, management and in-hospital mortality of patients with coronavirus disease fibrotic progression and radiologic correlation in matched lung samples from covid- post-mortems pneumolysis and "silent hypoxemia" in covid- . open science framework close down the lungs and keep them resting to minimize ventilator-induced lung injury neurological manifestations of severe sars-cov- infection: potential mechanisms and implications of individualized mechanical ventilation settings haematological characteristics and risk factors in the classification and prognosis evaluation of covid- : a retrospective cohort study thrombosis risk associated with covid- infection. a scoping review covid- and coagulation: bleeding and thrombotic manifestations of sars-cov- infection thromboembolism and anticoagulant therapy during the covid- pandemic: interim clinical guidance from the anticoagulation forum prevention, diagnosis, and treatment of vte in patients with coronavirus disease : chest guideline and expert panel report lung and kidney perfusion deficits diagnosed by dual-energy computed tomography in patients with covid- -related systemic microangiopathy characterization of the inflammatory response to severe covid- illness soluble urokinase plasminogen activator receptor (supar) as an early predictor of severe respiratory failure in patients with covid- pneumonia anakinra for severe forms of covid- : a cohort study tocilizumab therapy of covid- : a comparison of subcutaneous and intravenous therapies beneficial and harmful outcomes of tocilizumab in severe covid- : a systematic review and meta-analysis dexamethasone in hospitalized patients with covid- -preliminary report updated guidance on the management of covid- : from an association between administration of systemic corticosteroids and mortality among critically ill patients with covid- : a meta-analysis steroids and covid- : we need a precision approach, not one size fits all convalescent plasma for the treatment of covid- : perspectives of the national institutes of health treatment guidelines panel the emerging role of convalescent plasma in the treatment of covid- effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening covid- : a randomized clinical trial loss of anti-sars-cov- antibodies in mild covid- rapid decay of anti-sars-cov- antibodies in persons with mild covid- impact of sars-cov- on hospital acquired infection rates in the united states: predictions and early results severe covid- and healthcare-associated infections on the icu: time to remember the basics? sustained reduction of catheter-associated bloodstream infections with enhancement of catheter bundle by chlorhexidine dressings over years coronavirus vaccine tracker -the new york times n.d safety, tolerability, and immunogenicity of a recombinant adenovirus type- vectored covid- vaccine: a doseescalation, open-label, non-randomised, first-in-human trial safety and immunogenicity of an rad and rad vector-based heterologous prime-boost covid- vaccine in two formulations: two open, non-randomised phase / studies from russia safety and immunogenicity of the chadox ncov- vaccine against sars-cov- : a preliminary report of a phase / , single-blind, randomised controlled trial an mrna vaccine against sars-cov- -preliminary report artificial intelligence (ai) and big data for coronavirus (covid- ) pandemic: a survey on the state-of-the-arts a machine learning-based model for survival prediction in patients with severe covid- infection early triage of critically ill covid- patients using deep learning exploring automatic diagnosis of covid- from crowdsourced respiratory sound data covid- detection from chest x-rays using transfer learning with deep convolutional neural networks coronavirus disease (covid- ): a critical care perspective beyond china strengthening icu health security for a coronavirus epidemic adult icu triage during the coronavirus disease pandemic: who will live and who will die? recommendations to improve survival sars-cov- in spanish intensive care units: early experience with -day survival in vitoria key: cord- -j l hq h authors: algassim, abdulrahman a.; elghazaly, assem a.; alnahdi, abdulrahman s.; mohammed-rahim, owais m.; alanazi, abdulaziz g.; aldhuwayhi, nawaf a.; alanazi, mashael m.; almutairi, mohammed f.; aldeailej, ibrahim m.; kamli, najeeb a.; aljurf, mahmoud d. title: prognostic significance of hemoglobin level and autoimmune hemolytic anemia in sars-cov- infection date: - - journal: ann hematol doi: . /s - - - sha: doc_id: cord_uid: j l hq h higher levels of d-dimer, ldh, and ferritin, all have been associated with the poor prognosis of covid- . in a disease where there are acute inflammation and compromised oxygenation, we investigated the impact of initial hemoglobin (hgb) levels at emergency department (ed) triage on the severity and the clinical course of covid- . we conducted a cross-sectional study on covid- patients in a covid- national referral center between and june . all adult patients presented at our hospital that required admission or hotel isolation were included in this study. patients admitted to the intensive care unit (icu) had a lower initial hgb than those admitted outside the icu ( . g/dl vs. . g/dl, p = . ) and over the course of admission; the prevalence of anemia (hgb < . g/dl) was % in patients admitted to icu, whereas it was only % in non-icu patients (odds ratio of . , % ci . – . ). anemic icu patients had a higher mortality compared with non-anemic icu patients (hazard ratio = . , log-rank p = . ). a direct agglutination test (dat) for all anemic patients showed that . % of icu patients and % of non-icu patients had autoimmune hemolytic anemia (aiha). aiha patients had significantly longer length of hospital stay compared with anemic patients without aiha ( . days vs. . days, p = . ). lower hgb level at hospital presentation could be a potential surrogate for covid- severity. coronavirus disease (covid- ) is a recently emerged disease caused by the novel severe acute respiratory syndrome coronavirus (sars-cov- ) [ ] . covid- has a wide spectrum of manifestations, from asymptomatic infection to complicated pneumonia with acute respiratory distress syndrome (ards) [ ] together with other extra-pulmonary manifestations [ ] . pneumonia in covid- can be severe resulting in diffuse alveolar damage and disrupting gas exchange [ ] . consequently, arterial oxygenation will be affected, and o desaturation will be ensued [ ] . oxygen saturation is a function of hemoglobin (hgb) concentration, where a decrease in hgb will result in a decrease in the oxygencarrying capacity and subsequently arterial oxygen content (cao ) [ ] . indeed, anemia alone can lead to critical endorgan ischemia [ , ] . as a result, treating anemia will improve cao and subsequently tissue oxygen delivery (do ). accordingly, in some disorders where hemodynamic stability is compromised, treatments achieving higher hemoglobin levels may be required [ , ] . anecdotal evidence has shown that covid- can cause a progressive decrease in hgb [ ] . anemia is a known consequence of acute inflammation [ ] , which results in part from disrupted iron homeostasis and suppression of erythropoietin (epo) [ ] . in covid- patients, iatrogenic active bleeding [ ] or secondary to disseminated intravascular coagulation (dic) can also potentially contribute to anemia [ ] . on the other hand, a plethora of reports showed that sars-cov- infected individuals developed autoimmune hemolytic anemia (aiha) [ ] [ ] [ ] [ ] [ ] . nevertheless, the prevalence and implications of such findings remain to be elucidated. aiha is associated with many infections, particularly viral infections. both warm aiha and cold agglutinin disease (cad) have been well described in the pathogenesis of infectionassociated aiha [ ] , and both forms have been reported in covid- [ ] . all these together, we hypothesized that preexisting low hgb levels are associated with worse covid- disease course. here, we investigate the dynamic relationship between sars-cov- infection and hemoglobin levels at presentation and during the hospital stay in order to determine the consequences of hgb levels on covid- and vice versa. this cross-sectional study was conducted at king saud medical city (riyadh, saudi arabia). institutional review board (irb) approval was obtained. we collected patients' data by retrieving medical records using our electronic health system medisys® his (riyadh, saudi arabia). these include patients' age, gender, vitals, laboratory results, length of hospital stay (los), and status on discharge. statistical analysis and graphing were done using graphpad prism . for continuous variables, mean with standard deviation (sd) or median with interquartile length (iql) was calculated. comparisons and significance were calculated with two-tailed student's t test for normally distributed data; otherwise, mann-whitney u test is used. for normality testing, we used d'agostino-pearson and anderson-darling tests. for graphic expression, we used mean or median with % confidence interval. discrete variables were shown as absolute numbers and percentages and analyzed using fisher's exact test. a simple linear nonparametric correlation between hemoglobin levels and los were done. finally, we used kaplan-meier analyses and compared in-hospital survival for anemic and non-anemic patients using the log-rank test (mantel-cox). a p < · is considered statistically significant. all patients presented to our hospital's emergency department (ed) with signs and symptoms of covid- were swabbed and isolated. patients whose vitals were stable (hr, - ; rr, - ; spo > %) and had appropriate environment for home isolation were sent home for isolation. other than swabbing, no further tests were done. before being sent home, these patients were instructed on when to seek medical care and how to self-isolate if they were tested positive. they were notified with their test result within h. patients whose vitals were stable with unsuitable environment for home isolation were provided with hotel rooms. if they were tested positive for sars-cov- , they continued their hotel isolation for days and received occasional medical visits and laboratory tests, including all those related to this study, during the isolation period. patients whose vitals were unstable were admitted to either general ward (gw) or intensive care unit (icu), depending on the early warning score (ews) [ ] , comorbidities, and laboratory values. between and june , all adult patients with a positive sars-cov- pcr result (n = ) from the aforementioned three severity categories (hotel, gw, and icu) were included in this study. admitted patients were followed for more weeks to review their outcomes. in accordance with the world health organization (who), we defined anemia as having at least one reading of hgb level below . g/dl during hospital follow-up. all patients included in this study were confirmed covid- cases using the rt-pcr cobas® sars-cov- from roche (basel, switzerland). complete blood counts (cbc) was done using the unicel® dxh analyzer. liver function test (lft), renal function test (rft), and d-dimer were performed using the au series clinical chemistry analyzers. ferritin was done using the unicel® dxi immunoassay analyzer. all tests are automated and from beckman coulter (brea, ca). peripheral blood films were made using the hematek system from siemens (munich, germany) and slides examined by (k, na). all covid- patients admitted to the hospital with at least one anemic reading (hgb < . g/dl) and higher than normal ldh levels were screened for igg and c dat using ortho vision® max analyzer from ortho clinical diagnostics (raritan, nj). patients who were positive for dat and with a recent history of blood transfusion, autoimmunity or aiha, or lymphoproliferative disorder were excluded from our analysis. in a total of adult patients confirmed by pcr to be infected with sars-cov- ( fig. ) , the mean hgb level at ed triage for patients requiring admission was significantly lower than that of patients sent to hotel isolation ( . g/dl vs. . g/dl, p = . ) (fig. a) . moreover, among admitted patients, the mean hgb levels were significantly lower in patients admitted to icu than in patients admitted to gw ( . g/dl vs. . g/dl, p = . ) (fig. b ). our findings were in line with other well-described predictors of severity, namely, the triage level of platelets ( × /l vs. × /l p = . ) [ ] (fig. c) , d-dimer ( . mg/l vs. . mg/l, p = . ) [ ] (fig. d) , ldh ( u/l vs. u/l, p = . ) [ ] (fig. e) , and ferritin ( . ng/ml vs. . ng/ml p = . ) [ ] (fig. f) . one hundred sixty-three ( %) of patients admitted to icu had anemic readings, whereas, only ( %) of those admitted to gw had readings below . g/dl ( fig. ) (odds ratio of . , % ci . - . ) (fig. g) . after admission, ( . %) icu patients and ( . %) gw patients developed anemic readings. the drop in hemoglobin levels was more pronounced in icu patients ( . g/dl to . g/dl, p = < . ) compared with gw patients ( . g/dl to . g/dl, p = . ) (fig. h) . there was no statistically significant difference in age or gender between anemic and non-anemic patients ( fig. a and data not shown, respectively). to investigate the potential clinical importance of these findings, we examined los, as an index for outcome. for gw patients, the mean los was significantly longer in anemic patients than in non-anemic patients ( . days vs. . days p = . ) (fig. a) . a significant negative correlation between hgb and los was found (r = − . , p = . ). for patients admitted to icu, because of rapid patients' turnover due to either transfer out of icu or death, we looked at in-hospital mortality as the final outcome. survival analysis showed that the mortality rate was significantly higher in anemic patients ( patients) than in non-anemic patients ( patients) (fig. b ) (log-rank p = . , % ci of hazard ratio . to . ). we also determine the type of anemia based on the mean corpuscular volume (mcv) and found that normocytic anemia was most common among both icu and gw patients ( patients at . % and patients at . %, respectively) (fig. a) . microcytic anemia was more common among gw patients ( in gw . % vs. in icu . %), while macrocytic was more common among icu in patients ( in gw . % vs. in icu . %). because of that, we did a direct agglutination test (dat) for all patients with anemic readings regardless of their initial site of admission. seven patients were excluded for having a history of blood transfusion within the past months (n = ), history of autoimmunity (n = ), or lymphoproliferative disorder (n = ), all of which could be confounding factors for positive dat. among those tested, patients were dat positive (fig. ) , all have met our inclusion and exclusion criteria, patients were initially admitted to gw ( % of gw anemics), and were admitted to icu ( . % of icu anemics) (fig. b) . on determining the type of dat, only one patient had c type alone, while six had both igg and c and had igg only (fig. c ). among patients with anemic readings, the mean triage hgb levels for dat positive patients were lower than that of those with negative dat ( . g/dl vs. . g/dl, p = . ) (fig. d) . indirect bilirubin level was slightly higher in dat positive patients ( . μmol/l vs. . μmol/l); however, the difference was not statistical significance (fig. e) . routine peripheral blood films for dat-positive patients showed spherocytosis, which confirms aiha (fig. f) . no schistocytes were found. finally, dat-positive patients had a higher ldh compared with dat-negative patients ( u/l vs. u/l p = . ) (fig. g) . there was no statistically significant difference in age or gender between dat-positive and dat-negative patients ( fig. a and data not shown, respectively) . we found a mortality rate of . % among dat-positive patients, while it patients with stable vitals were sent for home isolation without further testing whereas those with unstable vitals were admitted. patients without suitable home for isolation were provided with a hotel room and remained under our supervision. a total of patients with confirmed sars-cov- infection were investigated for the presence of anemia (hgb < . g/dl). anemic patients were screened for autoimmune hemolytic anemia was . % among dat-negative patients (fig. b) , which was not statistically significant. however, dat-positive patients had a significantly longer los than dat-negative patients ( . days vs. . days, p = . ) (fig. c ). we demonstrate a relationship between hemoglobin level at presentation and the disease course among covid- patients. a lower hemoglobin level is associated with more severe disease course and a higher mortality rate. we also found a progressive dropping of hgb levels among admitted patients, % of icu patients and % of gw patients developed anemic readings while in the hospital. this drop in hgb can be attributed to inflammation associated with covid- . in acute inflammation, a decrease in the hemoglobin level is expected due to many complicated mechanisms, the best known among which is cytokines-induced iron metabolism dysregulation and inhibition of epo formation [ ] . in covid- patients, there is also a higher propensity to bleed due to either iatrogenic anticoagulation or dic; both can be additional contributing factors for the decrease of hgb. since icu patients have a deeper decline in hgb, our data suggests that the drop is related to the severity of inflammation associated with sars-cov- infection. regardless of the inciting fig. outcomes of anemic patients. a median age of anemic and nonanemic patients. b mean length of hospital stay (los) for patients admitted in gw, anemic indicates patients with hgb < . g/dl. c survival analysis for icu admitted anemic (hgb < . g/dl) and non-anemic patients. *p < . error bars and shaded areas represent % confidence interval causes of anemia, we showed a correlation between hgb levels and los in gw patients and a higher mortality rate among icu anemics. aiha is another potential cause of anemia and has been associated with covid- . to the best of our knowledge, we are the first to report the prevalence of aiha among covid- patients. we found that % of anemic icu patients and % of anemic gw patients had positive dat and spherocytosis. although we did not measure the haptoglobin level for all of our anemic patients, the presence of spherocytes in blood films is a stronger indicator of aiha [ ] . interestingly, not only aiha but also other immune dysregulation phenomena have been reported in covid- patients [ , ] . immune thrombocytopenia (itp) [ ] , guillain-barré syndrome (gbs) [ ] , and the multi-system inflammatory syndrome [ ] , all have been described in covid- patients. in our study, the overwhelming presence of the igg-type rather than the c -type aiha suggests a global immune dysregulation rather than a simple igm cross-reaction [ ] . on that same note, we find hemophagocytic lymphohistiocytosis (hlh) is emerging as a recognizable cause of death in sars-cov- infection [ ] . finally, we showed a mortality rate of % and a longer los among anemic dat-positive patients in comparison with other anemic patients, emphasizing the clinical importance of such a finding. generally, the demonstration of active aiha is an indication to start corticosteroids therapy [ , ] . however, in such a scenario, further investigations are needed. although the drop in hemoglobin levels observed in this large cohort of patients is considered clinically mild to moderate, it is likely to augment the arterial o content (cao ) decrement. indeed, acute parenchymal lung injury due to covid- pneumonia will result in a decrease in arterial partial o pressure (pao ) and arterial o saturation (sao ) [ ] . with that, we can extrapolate decline in arterial o content (cao ) = (hgb × . × sao ) + ( . × pao ). this decline in oxygen content will result in a decrease in oxygen delivery (do ) and subsequent tissue hypoxia. the hgb level is a variable in this equation and will affect its outcome. the hgb concentration is directly proportionate to cao , which is a function of do where do = cao × cardiac output (co) [ ] . based on this mathematical formula, now it is the standard of practice to have a low transfusion threshold when do is compromised. for example, in acute coronary syndrome (acs) and due to co compromise, higher targets of hgb are required to compensate for co deficit as compared with other anemic patients [ ] . those acs patients with anemic readings tend to have a worse prognosis and correcting anemia will mitigate acs severity [ , ] . in acute chest syndrome seen in sickle cell anemia patients, the pathogenesis of do deficit stems from the other variable in the above equation [ ] . rather than the standard restrictive transfusion approach, cao decline in acute chest syndrome is also treated with a liberal blood transfusion in order to achieve a higher hgb target [ , ] . because covid- patients have decreased sao and pao , they therefore have decreased cao and do . moreover, the hgb level is a known important player in do pathology. our study clearly shows that anemic covid- patients have worse prognosis. however, demonstrating that correcting anemia attenuates covid- severity, like in the aforementioned acs and acute chest syndrome patients, is beyond the scope of this study and requires further work. our study provides evidence that lower hemoglobin at presentation is associated with poorer prognosis. early recognition of those at risk might warrant a lower threshold for earlier and more aggressive medical intervention. our work is the basis for future investigations on anemia and covid- where anemia is manageable and reversible. the same goes for aiha where early recognition is necessary as it may require a different approach in management. clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in extrapulmonary manifestations of covid- pulmonary post-mortem findings in a series of covid- cases from northern italy: a two-centre descriptive study. the lancet infectious diseases baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region integrated systems physiology: from molecule to function to disease classification of myocardial infarction: frequency and features of type myocardial infarction assessment and treatment of patients with type myocardial infarction and acute nonischemic myocardial injury anemia as a risk factor and therapeutic target in heart failure a multicenter, randomized, controlled clinical trial of transfusion requirements in critical care hematologic parameters in patients with covid- infection anemia of inflammation weiss gn. dysregulated monocyte iron homeostasis and erythropoietin formation in patients with anemia of chronic disease anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia sars-cov- infection in two pediatric patients with immune cytopenias: a single institution experience during the pandemic autoimmune haemolytic anaemia associated with covid- infection simultaneous onset of covid- and autoimmune haemolytic anaemia cold agglutinin autoimmune haemolytic anaemia associated with novel coronavirus (covid- ) covid- infection associated with autoimmune hemolytic anemia autoimmune hemolytic anemia the impact of the use of the early warning score (ews) on patient outcomes: a systematic review thrombocytopenia and its association with mortality in patients with covid- endotheliopathy in covid- -associated coagulopathy: evidence from a single-centre, cross-sectional study lactate dehydrogenase and susceptibility to deterioration of mild covid- patients: a multicenter nested case-control study covid- : consider cytokine storm syndromes and immunosuppression the trinity of covid- : immunity, inflammation and intervention is covid- a proteiform disease inducing also molecular mimicry phenomena? covid- -associated immune thrombocytopenia guillain-barre syndrome associated with sars-cov- multisystem inflammatory syndrome related to covid- in previously healthy children and adolescents in is molecular mimicry the culprit in the autoimmune haemolytic anaemia affecting patients with covid- ? treatment of autoimmune hemolytic anemias treatment options for primary autoimmune hemolytic anemia: a short comprehensive review physiology of oxygen transport liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease association of hemoglobin levels with clinical outcomes in acute coronary syndromes acute chest syndrome in sickle cell disease: clinical presentation and course. cooperative study of sickle cell disease sickle cell disease: when and how to transfuse effect of transfusion in acute chest syndrome of sickle cell disease publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgments this paper was done with collaborative support from the department of medicine and critical care department at king saud medical city. we acknowledge abdulaziz alrashidi from ed who provided us with data support. abdullah ashlowi rn was a case manager and helped us in logistics and coordination. life science editors edited and proofread the manuscript. authors' contributions a a a provided study design and data analysis manuscript writing. a a e and m d a contributed valuable ideas and consultations throughout the study. a s a, o m r, a g a, and n a a were data collector. m m a, m f a, and i m a were responsible for direct agglutination test. n a k examined blood films for (dat positive) patients. all authors have contributed to manuscript review and editing. conflict of interest the authors declare that they have no conflict of interest.ethical approval all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the helsinki declaration and its later amendments or comparable ethical standards.informed consent informed consent was obtained from all individual participants included in the study. key: cord- - x w authors: piazza, cesare; filauro, marta; dikkers, frederik g.; nouraei, s. a. reza; sandu, kishore; sittel, christian; amin, milan r.; campos, guillermo; eckel, hans e.; peretti, giorgio title: long-term intubation and high rate of tracheostomy in covid- patients might determine an unprecedented increase of airway stenoses: a call to action from the european laryngological society date: - - journal: eur arch otorhinolaryngol doi: . /s - - - sha: doc_id: cord_uid: x w introduction: the novel coronavirus disease (covid- ), caused by the severe acute respiratory syndrome coronavirus , may need intensive care unit (icu) admission in up to % of all positive cases for massive interstitial pneumonia, with possible long-term endotracheal intubation for mechanical ventilation and subsequent tracheostomy. the most common airway-related complications of such icu maneuvers are laryngotracheal granulomas, webs, stenosis, malacia and, less commonly, tracheal necrosis with tracheo-esophageal or tracheo-arterial fistulae. materials and methods: this paper gathers the opinions of experts of the laryngotracheal stenosis committee of the european laryngological society, with the aim of alerting the medical community about the possible rise in number of covid- -related laryngotracheal stenosis (lts), and the aspiration of paving the way to a more rationale concentration of these cases within referral specialist airway centers. results: a range of prevention strategies, diagnostic work-up, and therapeutic approaches are reported and framed within the covid- pandemic context. conclusions: one of the most important roles of otolaryngologists when encountering airway-related signs and symptoms in patients with previous icu hospitalization for covid- is to maintain a high level of suspicion for lts development, and share it with colleagues and other health care professionals. such a condition requires specific expertise and should be comprehensively managed in tertiary referral centers. the novel coronavirus disease (covid- ) is a highly contagious, pandemic zoonosis, caused by an rna betacoronavirus called severe acute respiratory syndrome coronavirus (sars-cov- ). in most patients, the disease takes a mild form with symptoms like fever, cough, nausea, vomiting, and diarrhea, but it can also cause massive involvement of the lower respiratory tract with interstitial pneumonia [ ] . despite the low mortality rate ( . - . %) [ ] [ ] [ ] [ ] and the relatively, low number of patients needing critical care (in the range between and %) [ , , ] , due to its high transmissibility and the sheer number of infected patients, sars-cov- is placing a major burden on health systems globally, causing an unprecedented overwhelming of hospital facilities, especially intensive care units (icu) [ ] . in the recent experience, the median time from symptom onset to the development of pneumonia was approximately days, while the mean time from symptoms onset to icu admission for severe hypoxemia was approximately - days. the cause of severe hypoxemia was essentially correlated to the acute respiratory distress syndrome in - % of cases, followed by shock in %, myocardial dysfunction in - %, and acute renal failure in - % [ ] . covid- patients admitted to the icu often require prolonged mechanical ventilation with high positive endexpiratory pressure through an endotracheal tube, with a frequency reported as high as % in a series of consecutive patients treated at hospitals included in the covid- lombardy icu network, italy [ ] . in pre-covid- settings, tracheostomy performed after - days from endotracheal intubation significantly improved the chance of successful weaning and lowered the risk of complications and mortality when compared to long-term maintenance of the orotracheal tube in place [ ] [ ] [ ] [ ] [ ] [ ] . moreover, in a resource-constrained scenario like that associated to the current pandemic, early tracheostomy would present the advantages of a more rapid weaning and ensuing higher availability of ventilators. despite these pros, the actual clinical practice for covid- patients admitted in several icus worldwide is to try to postpone tracheostomy until the patient no longer needs to be ventilated in the prone position and has been determined to be cleared of the virus with isolation precautions ceasing. this is mainly because of the high risk of accidental decannulation during proning and the chance of cross-infection of healthcare professionals (hcps) due to prolonged duration of tracheal viral positivity compared with the salivary viral load [ , ] . unfortunately, when strictly followed, such a policy may mean that patients remain intubated for up to - weeks. this is clearly far from the usual pre-pandemic standards and a strong effort should be prospectively made to demonstrate that a potential increase in the incidence and severity of laryngotracheal injuries in a given patient is counterbalanced by the potential benefits for him (in terms of reduced risk of accidental decannulation) and to other patients and hcps (in terms of reduced risk of cross-infections). in the meantime, however, as a consequence of the combination of an increased number of long-term intubated, critically ill patients, and delayed tracheostomy, it is probable that, in the near future, an unprecedented rise of iatrogenic sequelae ranging from granulomas, webs, and laryngotracheal stenosis (lts), to tracheomalacia, tracheal necrosis, tracheo-esophageal, and tracheo-innominate fistulae may come to arise [ , ] . the aim of the present paper from the laryngotracheal stenosis committee of the european laryngological society is, therefore, to alert the medical and scientific communities to the possibility of a surge in the number of airway injuries in the short and medium term, to provide a narrative review of the main mechanisms potentially leading to laryngotracheal injuries during prolonged intubation and tracheostomy, and to help in proactively diagnosing and treating lts. airway management, by either endotracheal intubation or tracheostomy/cricothyrotomy placement, must be acknowledged as an hazardous procedure due to the potential sars-cov- airborne cross-infection of hcps and other patients [ ] . consequently, it is of utmost importance that the 'most appropriate' clinician manages the airway to enable its successful establishment in a safe, accurate, and swift manner. the first step for doing this is represented by an accurate plan, taking into account the possibility of difficult airway management, possibly associated to covid- -related laryngitis and laryngeal edema [ ] . difficult intubation is defined by repeated failing attempts to introduce an endotracheal tube, prolonged duration of such maneuvers, or necessity for multiple approaches and/or intubation devices [ ] . it usually refers to the grades iii or iv of the modified cormack-lehane scale [ ] . according to schnittker et al. [ ] , the difficult intubation rate is generally in between . and . % of patients, and in % of these selected unfavorable cases, the procedures can fail. as a consequence, if a 'cannot intubate cannot ventilate' scenario unfolds, airway must be secured by emergent surgery (tracheostomy or cricothyrotomy), under suboptimal conditions with the ensuing risk of large scale viral aerosolization and severe airway damage. to try to predict beforehand these difficulties, different factors have been considered through the years, using various scoring systems, such as the modified mallampati score, or trying to quantify a number of anatomical landmarks alone or in combination (i.e. thyromental distance, sternomental distance, thyromental height test, body mass index, gender, and age) [ ] [ ] [ ] [ ] . nonetheless, up to date, there is no universally recognized objective algorithm that can per se identify a difficult intubation scenario with a sufficiently high sensitivity and specificity. only the anesthesiologist's experience, after a comprehensive patient's evaluation taking into consideration all the available data, can possibly foresee a potentially difficult endotracheal intubation. moreover, a number of devices (i.e. glidescope or transnasal fiberoptic endoscopy) are now available to help anesthesiologists, emergency care, and icu physicians in such a difficult situation, certainly improving the odds of a successful intubation. however, some of these tools may increase the risk of airborne contamination of hcps. for this reason, in a covid- pandemic scenario, guidelines from the british difficult airway society, the association of anaesthetists, the intensive care society, the faculty of intensive care medicine, and the royal college of anaesthetists [ ] recommend to always wear proper personal protective equipment (ppe), and to use the larger cuffed tube possible ( . - . mm internal diameter for women and . - . mm for men), inflating the cuff to seal the airway before starting ventilation. similar guidelines from different countries have followed in the last months, substantially confirming the above-mentioned caveat. in daily clinical practice, acute laryngeal injury may take place as a consequence of endotracheal intubation [ ] . for obvious reasons, use of large caliber tubes exposes the patient to an endolaryngeal (especially at the level of the posterior commissure and subglottis) and/or endotracheal damage, in particular whenever the intubation should be prolonged in time. moreover, it is well known that poor monitoring of tracheal tube cuff pressure, with undue overinflation, may result in further ischemic damage to the airway mucosa (fig. ) . careful use of a manometer is recommended to keep safe cuff pressure values between and cm h o [ ] [ ] [ ] . when the cuff pressure reaches mmhg for min, ischemic injury to the tracheal mucosa invariably occurs. it is possible to find a correlation between excessive tube cuff pressure and presence of tracheal pain, hoarseness, sore throat, and blood-streaked expectoration. however, there is no good correlation between the degree of mucosal damage and the severity of patients' symptoms, since they are always subjective and difficult to collect [ ] . the same injury can occur in the larynx, due to the fact that the endolaryngeal tube lays on the posterior aspect of the larynx, causing a chronic pressure on the cricoarytenoid joints, posterior commissure, and cricoid plate. the mucosal ischemic process may lead to progressive fig. different patterns of lts associated with endotracheal intubation and tracheostomy placement. a bilateral vocal fold immobility caused by still inflamed posterior glottic web. b same condition due to a mature posterior glottic and inter-arytenoid stenosis. c cicatricial stenosis at the junction between the cricoid and trachea due to long-term intubation and tracheostomy. d tracheostomy-related suprastomal collapse. e suprastomal contracture and tracheal stenosis (so called "lambdoid deformity"). f, g tracheal stenoses resulting from tracheostomy cuff injury at different levels of the airay. h complete (grade iv) lts ulceration, possibly causing perichondritis, chondritis and, finally, chondronecrosis and airway malacia or perforation. ulceration at the level of the vocal processes of the arytenoid cartilages can also cause granulomas, occurring within days to weeks after extubation. if bilaterally present, and associated to a posterior commissure ulcerative process, these lesions may merge and evolve into a posterior glottic web which, combining with uni-or bilateral crico-arytenoid fixation, represents the most difficult type of airway stenosis to be successfully managed (fig. a, b) . on the top of this, we currently do not fully appreciate the real role of covid- -induced laryngitis and laryngeal edema in the context of prolonged endotracheal intubation [ ] . only large cohorts of prospectively followed patients will be able to ascertain the possible role of such a pathologic condition on long-term outcomes of the airway managed in the icu. the degree and depth of injury mainly depends on duration of intubation, size of tracheal tube, depth of sedation, patient's general conditions (with cardiovascular diseases, diabetes, and obesity playing an ominous role), and superimposing local infections. this has been commonly described after prolonged mechanical ventilation in the supine position. however, to the best of our knowledge, no precise description on what happens to the laryngotracheal junction of covid- patients ventilated for prolonged time in prone position has been so far produced. in every case, it is always of utmost importance to diagnose and treat these changes as soon as possible to prevent the stabilization of such conditions into irreversible sequelae [ ] . as far as the modalities of tracheostomy is concerned, we are lacking prospective randomized clinical trials comparing different surgical techniques like open tracheostomy vs. various types of percutaneous approaches. however, in a covid- scenario, open tracheostomy seems to pose reduced hazards to the hcps due to the quicker airway entry and lesser aerosolization [ , ] . apart from the proper use of ppe ranging from face shields to powered air-purifying respirators, surgical airway establishment should be performed at bedside to avoid unnecessary transport of patients from icu to the surgical theatre and vice versa. surgical team should be reduced to a minimum and waste disposal and/or decontamination of equipment used during surgery applied to minimize the risk of environmental contamination. common to every surgical or endoscopic attempt to create an artificial airway should be the intent of entering the trachea at the level of the first rings, creating the least disruption as possible in terms of number of rings damaged during tracheal opening and cannula positioning. the smallest possible tracheostomy cannula should be inserted, always bearing in mind the body habitus, neck morphology, and clinical conditions of a given patient. moreover, thick secretions and the need for frequent bronchoscopies to clear the distal airway from mucus plugging may initially prompt to use larger cannula. this, however, should be reduced in size as soon as safe. appropriate antibiotics and careful medication of the stoma would subsequently prevent superinfection with potential drawbacks, as described above. after patient's extubation or decannulation, a few days window period is needed before considering definitive stabilization of the patient's respiratory conditions. usually, lts does not manifest itself in this time frame but, rather, after icu discharge, frequently when the patient is already at home, and not before the third-fourth week or more after normal respiratory conditions re-establish [ ] . every patient with an history of covid- -related icu stay should be followed after discharge by an otolaryngologist or other airway specialist to proactively diagnose early complications at the level of the larynx and trachea. systemic and topical medications, local debridement, endoscopic dilatations or even just surveillance of subclinical conditions may play a fundamental role in avoiding major airway problems to be diagnosed later only after admission in an emergency room (er) for acute dyspnea. as a consequence of the aforementioned potential complications related to long-term endotracheal intubation and tracheostomy in the upcoming months, the medical community must be prepared to face a rise in the number of patients arriving at our attention due to worsening breathless on exertion and at rest, variously associated to hoarseness, stridor, dry cough, and swallowing problems. these are the most common symptoms of presentation of benign lts, usually well known to every otolaryngologist. nevertheless, to maintain a low threshold of suspicion regarding such a diagnosis, we must also elicit such a feeling of urgency among general practitioners, internists, pulmonologists, er specialists, physiotherapists, and other welfare workers seeing patients who have been exposed to covid- -related intubation. prompt referral of patients to tertiary centers with specific expertise in proper evaluation and treatment of lts should follow. of utmost importance is trying to avoid as much as possible that lts be misdiagnosed as asthma or other pulmonary conditions causing dyspnea, thus retarding initiation of the appropriate diagnostic and therapeutic processes. in this sense, one of the most common and useful first-line diagnostic tool, available also in non-specialist clinical settings, is represented by routine lung function tests. it has been demonstrated that the expiratory disproportion index, defined as the ratio of forced expiratory volume in s to peak expiratory flow rate, has a great clinical utility in differentiating lts from other respiratory diseases [ , ] . moreover, its simplicity and non-invasiveness are particularly welcomed in a covid- -related lts screening, before referral to airway specialists for a more detailed evaluation of the underlying condition. to identify the best therapeutic option for acquired lts, an adequate diagnostic work-up should include a thorough preoperative endoscopic and radiologic assessment, associated with an in-depth intraoperative airway evaluation [ ] . an accurate endoscopy provides almost all of the required information; details must be gathered on vocal fold mobility, residual airway inflammation and/or infection, craniocaudal extent of mature scar tissue (with measurement of degree of lts and description or video-documentation of the sites involved), presence of tracheal damage related to the previous or present stoma/cannula, or secondary airway lesions. other clinical conditions such as swallowing difficulties with or without chronic aspiration, obstructive sleep apnea-related issues, severe gastro-esophageal reflux, and eosinophilic esophagitis must be taken into consideration. thorough awake transnasal and/or transoral videolaryngoscopy using flexible and rigid scopes should always be performed first. together with flexible bronchoscopy, it allows gathering the necessary dynamic information on laryngeal mobility, swallowing function, and malacia at the level of the tracheostomy site or distal airway. if lts is apparent, this step should be followed by airway evaluation under general anesthesia to complement the previous picture with the static information needed. in such a situation, to complete the endoscopic diagnostic work-up and have a better visualization of the pharyngo-larynx and subglottis, a suspension laryngoscopy may be of great help. the use of rigid ° and angled telescopes allows to correctly evaluate the site, degree, and length of lts [ , ] . special issues of interest should include differentiating between unilateral vocal cord palsy vs. arytenoid fixation and/or subluxation, and bilateral vocal cords palsy vs. posterior commissure stenosis. manipulation of arytenoids and vocal cords during the procedure using a lindholm vocal cords retractor and angulated probes greatly assists the surgeon in diagnosing the exact cause of vocal cord(s) immobility (recurrent nerve palsy vs. cricoarytenoid joint ankylosis). ct scan of the larynx and trachea (more rarely an mr) can be complementary in evaluating the length of lts in case of complete (grade iv) airway obstruction (fig. h ) and to get a deeper insight of an altered laryngotracheal framework due to its deformity, fracture or collapse [ ] . as an ancillary consideration in a post-covid- clinical scenario, among the potential comorbidities of the patient, pulmonary functions should be thoroughly evaluated in a multidisciplinary environment, and preoperatively considered during appropriate boards with pulmonologists and anesthesiologists. a bronchoalveolar lavage should be considered to definitively rule out residual sars-cov- infection (in case of recent covid- hospitalization), while obtaining bacterial culture and antibiotic sensitivity testing. the majority of patients with airway-related symptoms after covid- management will present to the attention of otolaryngologists with incipient lts as a result of acute or subacute post-intubation/post-tracheostomy airway narrowing, with various degrees of mucosal edema, ulcerations, fibrin, and florid granulation tissue. early diagnosis and treatment of these conditions by gentle debridement, topical application/injection of corticosteroids, and systemic use of antibiotics and anti-inflammatory drugs, when needed, will help in prevention of excessive scar tissue formation. most importantly, the final goal of such an initial clinical evaluation and therapeutic management is to avoid as much as possible a tracheostomy or redo-tracheostomy with further damage to the airway framework [ ] . as a temporary measure to get a partial relief from dyspnea, endoscopic removal of granulation tissue, dilatations by balloon, bougies or rigid bronchoscopic instrumentation, and steroid injection may be applied. a close cooperation with interventional pneumologists is, in this sense, of paramount importance and sometimes allows bridging the gap between an er admittance and definitive treatment. however, if absolutely necessary, tracheostomy should be performed into the already damaged and stenosed crico-tracheal tract not to further compromise the adjacent healthy tracheal rings. after completion of the above-mentioned careful diagnostic work-up, the choice between an endoscopic or openneck approach to the lts must be made. as a general rule, purely intrinsic, short (around cm), low-grade stenoses, limited to just one subsite of the airway, may benefit from endoscopic treatments, such as laser radial incisions or balloon dilatation, alone or in combination [ , , ] . these maneuvers are usually well tolerated even by heavily comorbid patients, may be repeated and, if adequately performed, do not cause additional harm. moreover, as already mentioned, they can play a temporary and symptomatic role while waiting for definitive open surgery. in selected patients with extreme comorbidities (obesity, advanced age, post-covid- severe cardiopulmonary conditions or morbid icu polyneuropathy) in whom extensive surgery and complex postoperative course might represent an overshooting, palliative care could be considered by positioning an endoluminal stent or, if present, leaving the tracheostomy in situ. on the other hand, long, high-grade, and complex lts involving more than one subsites, especially when associated with airway malacia, major laryngeal framework alterations or prior failed endoscopic attempts, can benefit from open-neck surgical techniques. while these can range from laryngotracheal reconstruction with cartilage graft augmentation to (crico-) tracheal resection with end-to-end anastomosis, defining the pros and cons of each of these options is beyond the scope of the present communication. as a general rule, in recent years, a paradigm shift towards a more liberal use of airway circumferential resection and anastomosis techniques has been documented, with reported higher decannulation rates, and lower need for redo-endoscopic or open procedures [ ] . for sure, they represent much more demanding surgical procedures, and the overall general conditions of the patients to be treated in such a way must be adequately assessed. moreover, in this perspective, a quite delicate issue is represented by the anatomy and function of the posterior larynx, potentially affected by long-term intubation as mentioned above (fig. a, b) . the balance between respiration, swallowing, airway hygiene and protection is the result of a healthy cricoarytenoid complex. changes at this level may cause problems, not only related to the airway patency, but to its protective function, potentially facilitating aspiration, and increasing risks of pulmonary complications. therefore, in every respect, lts extended to the posterior commissure and inter-arytenoids area represents the most difficult scenario be effectively solved by every kind of surgical procedure. it is highly probable that in the future months and years, otolaryngologists will be called to manage an increasing number of lts due to the worldwide emerging issues related to the covid- pandemic. apart from every attempt to prevent such an airway complication starting from a good team work in the icus, a low threshold of doubt should be always maintained among general practitioners, er physicians, and other medical professionals to straightforward address these patients to the attention of dedicated tertiary centers with an adequate expertise in the field of airway surgery. comprehensive diagnostic work-up and state-of-art surgical techniques may efficiently solve the majority of these conditions either by endoscopic or open-neck approaches. moreover, centralizing the management of lts represents a unique opportunity for optimizing resources as well as trying to understand if such a cluster of patients presents any specific covid- -related clinical or epidemiological features as a consequence of prolonged icu intubation and/ or tracheostomy. clinical characteristics of coronavirus disease in china characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention clinical features of patients infected with novel coronavirus in wuhan clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan covid- pandemic: effects and evidence-based recommendations for otolaryngology and head and neck surgery practice intensive care management of coronavirus disease (covid- ): challenges and recommendations baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region surgical considerations for tracheostomy during the covid- pandemic: lessons learned from the severe acute respiratory syndrome outbreak tracheostomy practice in adults with acute respiratory failure effect of early versus late or no tracheostomy on mortality and pneumonia of critically ill patients receiving mechanical ventilation: a systematic review and meta-analysis tracheostomy: epidemiology, indications, timing, technique, and outcomes timing of tracheostomy in critically ill patients: a meta-analysis is tracheostomy a better choice than translaryngeal intubation for critically ill patients requiring mechanical ventilation for more than days? a comparison of short-term outcomes recommendations from the cso-hns taskforce on performance of tracheotomy during the covid- pandemic temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by sars-cov- : an observational cohort study multicentric study applying the european laryngological society classification of benign laryngotracheal stenosis in adults treated by tracheal or cricotracheal resection and anastomosis laryngotracheal stenosis: a retrospective analysis of their aetiology, diagnose and treatment consensus guidelines for managing the airway in patients with covid- laryngeal oedema associated with covid- complicating airway management noninvasive ventilation in difficult endotracheal intubation: systematic and review analysis validity of thyromental height test as a predictor of difficult laryngoscopy: a prospective evaluation comparing modified mallampati score, interincisor gap, thyromental distance, neck circumference, and neck extension patient and surgery factors associated with the incidence of failed and difficult intubation risk factors assessment of the difficult intubation using intubation difficulty scale (ids) determinants of success and failure in prehospital endotracheal intubation incidence and outcomes of acute laryngeal injury after prolonged mechanical ventilation endotracheal tube cuff pressure in three hospitals, and the volume required to produce an appropriate cuff pressure endotracheal cuff pressure and tracheal mucosal blood flow: endoscopic study of effects of four large volume cuffs correlations between controlled endotracheal tube cuff pressure and postprocedural complications: a multicenter study classification of laryngeal injury in patients with prolonged intubation and to determine the factors that cause the injury short-and long-term complications of surgical and percutaneous dilatation tracheotomies: a large single-center retrospective cohort study quantifying the physiology of laryngotracheal stenosis: changes in pulmonary dynamics in response to graded extrathoracic resistive loading diagnosis of laryngotracheal stenosis from routine pulmonary physiology using the expiratory disproportion index preoperative assessment and classification of benign laryngotracheal stenosis: a consensus paper of the european laryngological society proposed grading system for subglottic stenosis based on endotracheal tube sizes comorbidities and factors associated with endoscopic surgical outcomes in adult laryngotracheal stenosis posterior glottic laryngeal stenosis systematic review for surgical treatment of adult and adolescent laryngotracheal stenosis publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -w ejgzvu authors: torres-gonzález, ji; arias-rivera, s; velasco-sanz, t; mateos, dávila a; planas pascual, b; zaragoza-garcía, i; raurell-torredà, m title: what has happened to care during the covid- pandemic? date: - - journal: nan doi: . /j.enfie. . . sha: doc_id: cord_uid: w ejgzvu nan what has happened to care during the covid- pandemic? torres-gonzález ji (rn, phd) , arias-rivera s (rn, msn) , velasco-sanz t (rn, phd) , mateos dávila a (rn, msn) , planas pascual b (pt, msc) , zaragoza-garcía i (rn, phd) , raurell-torredà m (rn, phd) oficina regional de coordinación de trasplantes. servicio madrileño de salud. en nombre del grupo de trabajo ecmo de la sociedad española de enfermería intensiva y unidades coronarias (seeiuc) hospital universitario de getafe. en nombre del grupo de trabajo analgesia, sedación, delirio y contenciones (ascyd) de seeiuc hospital clínico san carlos. en nombre del grupo de trabajo bioética de seeiuc hospital universitari sant pau i santa creu. en nombre del grupo de trabajo terapias extracorpóreas de seeiuc hospital universitari vall hebrón. en nombre del grupo de trabajo rehabilitación precoz de seeiuc facultad de enfermería, fisioterapia y podología de la universidad complutense de madrid. en nombre del gt grupo de trabajo de simulación de seeiuc escuela de enfermería de la universidad de barcelona. presidenta seeiuc *correspondencia: raurell-torredà m (mraurell@ub.edu, martaraure@gmail.com) work group (wg) authors, spanish society of intensive nursing and coronary units (seeiuc for its initials in spanish): between the middle of march and the beginning of april, subject to the autonomous community (ac), the intensive care units (icu) reached their occupancy peak. new express icus had to be created with new nurses who had had no training in critical care to attend to the patients diagnosed with covid- , most of whom were extremely seriously ill. also, as suggested by raurell-torredà "this meant that the concept of team had to change and supplant any previous realities". the high risk to the health of healthcare professionals, and the impairment in levels of patient safety led to the emergence of on-line training activities and the use of j o u r n a l p r e -p r o o f simulation which proved to be beneficial on three levels during the pandemic: ) educational: staff were rapidly trained; ) systematic: this helped lead to an understanding and optimization of workflows; ) personal: support for emotional management was offered to the professionals. on an international level different training programmes have been described using simulation and the training of healthcare professions in taking nasopharyngeal secretion samples and online simulation based on the use of videos. in spain we found different initiatives were in place, such as that in the university hospital la paz, where a virtual platform was created using videos with simulated patients. the sadly, despite the efforts to rapidly train new nurses in knowledge and skills which usually require years of post-graduate study, the healthcare reality took over. the care procedures required for patient survival had to be prioritised and strategies which had proven their effectiveness through evidence over the last few years, such as the abcdef control flow and the zero projects remained in the background, due to care overload, lack of training of the new interprofessional icu team members, inadequacy of physical spaces to carry out daily activities and the shortage of the analgesia, sedation, delirium and medical restraint wg (ascyd for its initials in spanish) of the seeiuc, considers that the assessment of appropriate levels of analgesia and sedation were not able to be a priority care issue. as in any intubated patient, analgesia and sedation needs were covered according to their severity, j o u r n a l p r e -p r o o f although in these patients choice of analgesics and sedatives was conditioned by shortages and which ones were available. in the most acute phase, the initial volume of admissions, all extremely severe, led to deep sedation levels which went perhaps beyond what was strictly necessary and due to the impossibility of pain assessment due to high levels of sedation and the administration of muscle relaxants. assessment of sedation depth was further complicated by the recently incorporated professionals' lack of knowledge of sedation scale assessment and the absence of bis® monitors which are useful for assessing sedation in patients with muscle relaxation. aggressive techniques, such as the patient lying in a prone position for a prolonged period or recruitment strategies, have been continuous and have hindered compliance with recommended practices, such as progressing towards more superficial sedation levels or waking up the patient daily. despite the deep sedation levels and high use of muscles relaxants, the use of mechanical medical restraint was high, due to overburden of work, the absence of family members and the fear of not being able to provide a rapid response to an attempt at self-extubation. if expert icu nurses find it difficult to accept that restraint is not the solution, it is impossible to make non expert nurses who feel insecure and clearly out of their depth to understand. how can we risk allowing the patient to remove the tube? all predisposing factors to delirium were present, added to which was the uncertainty of an unknown future prospect for staff and conscious patients, with non invasive respiratory devices or who were in the process of waking up, who faced the prospect of the chaos they observed. patients were often admitted to "field" hospital units, where they were cared for by overstretched healthcare professions, totally covered in ppe, and could see themselves reflected in other seriously ill patients who were beside them, co-existing in dramatic circumstances. in this context, where the patient was socially isolated and facing great uncertainty, instead of a tranquil or secure ambiance delirium was far more likely to ensue. the rehabilitation wg of seeiuc states that the rehabilitation services were reorganized to respond to all patients who required physiotherapy, increasing the number of professionals, with the availability of a specialized physiotherapist in each team. in some cases interconsultation was withdrawn and care was even increased from monday to sunday, aimed at providing recovery to the patients so that they could be discharged as soon as possible. with regards to the treatment administered to the patients, major issues were discussed: j o u r n a l p r e -p r o o f -time in the prone position and with mechanical ventilation, which in some patients was increased and went on for longer than anticipated. -changes in the ventilator parameters and the way in which they could influence early mobilisation and respiratory physiotherapy. -major desaturations prior to active mobilisation and physical exercise, opting for a more progressive therapy, with shorter but more frequent sessions. -sitting, standing and/or verticallisation of the patient and the use of appropriate oxygen therapy systems for carrying out effective treatment of early mobilisation and respiratory physiotherapy, trying to prevent intensifications and trying to prevent the icu acquired weakness (icuaw) which is several cases was highly severe. -management of secretions and distribution of aerosols. all of these questions and the need to resolve them encouraged communication and the active participation of the interprofessional team. this interaction has enabled visibility of the need for definitive integration of the physiotherapist to the icu team, and the highlight that early mobilization is an essential tool in critical care patient approach. according to the bioethics wg, the initial application of strict isolation which involved greater social distancing (restriction of visits), together with the lack of ppe and the need to adapt to new forms of procedures, impeded the inclusion of family members in the care process, leading to greater uncertainty, stress, anxiety, guilt and fear. the establishment of clear, appropriate and regular communication is essential for facilitating adaptation, leading to initiatives which made virtual connection possible. if the patient status allowed it, video-calls were allowed, so as to connect them with their families, and this was one of the most positive aspects for the patients, life-support treatment limitations (lstl) must take into account patient prognosis, futility of treatment and the taking of shared decisions, with participation from the nurse being mandatory to provide the palliative viewpoint leading to the detection of those patients who are going through an end of life process, so that therapeutic obstinacy , may be avoided. what may be a complex decision was greatly simplified with covid- patients because it was highly evident when treatment did not work. when this happened the patient was in a very severe condition. perhaps the greatest ethical conflict was about the patients who were not admitted to the icu, not for lstl criteria, but due to the lack of available resources, leading to a huge emotional burden for healthcare workers. regarding care during continuous replacement therapies, the extracorporeal therapies wg of seeiuc conducted an informal survey among several hospitals in spain, confirming that the incidence of acute kidney failure notably increased. research studies related to corticoid treatments, with chloroquines and other drugs gradually clarified the relationship or non relationship with the apparently increased acute tubular injury in this context. several patients were highly procoagulant, and suffered from significant thrombosis, including with the use of continuous extracorporeal circuit techniques. for icu nurses, whose number had to be increased due to a higher number of beds, caring for patients who were mostly in a prone position with an array of connected purification systems has been a challenge. an attempt was made to insert catheters into the right jugular vein but this was not always possible. the interpretation of the pressure circuit and the sound maintenance of this vital technique with no delayed risks were essential for these patients. the choice of anticoagulation and optimal dose titration was crucial. if all icu had been well provided with staff trained in the use of filter citrate input, the maintenance of this therapy may have been more operative. another difficult issue which was however resolved in most cases, was the availability of consumables. working with filters of a larger or smaller size than desired or without monitors in hospitals which did not usually use these systems so frequently communities resulted in different forms of organization with highly disparate results, both on a regional and institutional level: -benchmark ecmo units with a well defined team (ecmo-team) were able to quickly implement this therapy to a larger number of patients and to adapt care required by this type of patient with the covid pathology. in acs with these ecmo-teams patients were transferred to other hospitals for therapy, since they already had a previously established circuit, complying with the recommendations of ramanathan and collaborators of implementing ecmo in benchmark centres. these benchmark j o u r n a l p r e -p r o o f hospitals with the established ecmo programme specified that during times of high concentrations of cases, the nurses specialised in ecmo worked on shifts outside of their regular hours to guarantee quality of care. -in other centres, expert ecmo nurses were unable to provide care to all the patients with this therapy and were forced to supervise care for these patients carried out by other nurses, as recommended by the elso guideline. however, in other hospitals, the care of these patients fell to nurses with greater experience or expertise. in some hospitals, to minimize the exposure of professionals and optimize the use of the ppe, but maintain patient safety, the presence of ecmo specialists around the pump and the controls were adapted according to the situation of the patients and the icu structure. special attention was given to the coagulation management of these patients. this is in itself complicated, but was made more so by the complexity of the behaviour of this virus for its inflammatory response and the thrombotic changes it provokes. as a scientific society for the care of the critically ill patient, seeiuc requests that healthcare organisations reconsider the urgent need to provide icu staff with a speciality that provides robustness to the nursing profession. theoretical and practical knowledge in care and techniques that are vital to the safety and recovery of these patients must be included. j o u r n a l p r e -p r o o f gestión de los equipos de enfermería de uci durante la pandemia covid- the use of simulation to prepare and improve responses to infectious disease outbreaks like covid- : practical tips and resources from norway, denmark, and the uk effect of implementing simulation education on health care worker comfort with nasopharyngeal swabbing for covid- virtual application of in situ simulation during a pandemic clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the icu prevention of ventilator-associated pneumonia: the multimodal approach of the spanish icu "pneumonia zero" program consejo asesor del programa de seguridad de pacientes críticos del ministerio de sanidad managing the supportive care needs of those affected by covid- recomendaciones sobre acogida de familiares en unidades de cuidados intensivos importancia del abordaje paliativo interprofesional en el paciente crítico nefrología al día ecmo use in covid- : lessons from past respiratory virus outbreaks-a narrative review. crit care extracorporeal life support organization covid- interim guidelines: a consensus document from an international group of interdisciplinary ecmo providers planning and provision of ecmo services for severe ards during the covid- pandemic and other outbreaks of emerging infectious diseases key: cord- -ukoi jyg authors: demkina, a. e.; morozov, s.; vladzymyrskyy, a. v.; kljashtorny, v. g.; guseva, o. i.; pugachev, p. s.; artemova, o. r.; reshetnikov, r. v.; gombolevskiy, v. a.; ryabinina, m. n. title: risk factors for outcomes of covid- patients: an observational study of patients in russia date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: ukoi jyg background several factors that could affect survival and clinical outcomes of covid- patients require larger studies and closer attention. objective to investigate the impact of factors including whether covid- was clinically or laboratory-diagnosed, influenza vaccination, former or current tuberculosis, hiv, and other comorbidities on the hospitalized patients' outcomes. design observational nationwide cohort study. patients all subjects, regardless of age, admitted to , russian hospitals indexed in the federal register of covid- patients between march , , and june , . all included patients for which complete clinical data were available were divided into two cohorts, with laboratory- and clinically verified covid- . measurements we analyzed patients' age and sex, covid- icd- code, the length of the hospital stay, and whether they required icu treatment or invasive mechanical ventilation. the other variables for analysis were: verified diagnosis of pulmonary disease, cardiovascular disease, diseases of the endocrine system, cancer/malignancy, hiv, tuberculosis, and the data on influenza vaccination in the previous six months. results this study enrolled , covid- patients aged from to years, . % females. , patients were excluded due to no confirmed covid- (n= , ) or insufficient and invalid clinical data (n= , ). , participants were included in the study, , ( . %) of them had laboratory-verified covid- , and , patients ( . %) with the clinical verification. influenza vaccination reduced the risk of transfer to the icu (or . ), mechanical ventilation requirement (or . ), and the risk of death (hr . ). tb increased the mortality risk (hr . ) but reduced the likelihood of transfer to the icu (or . ). hiv comorbidity significantly increased the risks of transfer to the icu (or . ) and death (hr . ). patients with the clinically verified covid- had a shorter duration of hospital stay (hr . ) but a higher risk of mortality (hr . ) and the likelihood of being ventilated (or . ). according to the previously published data, age, male sex, endocrine disorders, and cardiovascular diseases increased the length of hospital stay, the risk of death, and transfer to the icu. limitations the study did not include a control group of subjects with no covid- . because of that, some of the identified factors could not be specific for covid- . conclusions influenza vaccination could reduce the severity of the hospitalized patients' clinical outcomes, including mortality, regardless of age, social, and economic group. the other factors considered in the study did not reduce the assessed risks, but we observed several non-trivial associations that may optimize the management of covid- patients. according to the who monitoring, as of october , , the covid- pandemic counted , , million confirmed cases globally, of which , , were fatal [ ] . russia made a significant contribution to these numbers, with , , total cases ( th place out of indexed countries) and deaths ( th place). at the time of writing, russia's incidence rate was cases per , population [ ] , and hospital bed occupancy reached almost % [ ] . despite the high burden on hospitals, the national situation with new coronavirus infection is under control due to available reserve capacities [ ] . there are no plans to reimpose rigid lockdown restrictions, and the russian healthcare system continues to routinely perform testing, monitoring, and contact tracing of new cases. federal recommendations for medical workers on the prevention, diagnosis, and treatment of covid- have been developed to be followed by each hospital [ ] . as our knowledge of the disease grows, causes of possible complications arise that could alter standard treatment guidelines. factors associated with the disease's prognosis and outcome were the objects of several systematic reviews [ ] [ ] [ ] . unfortunately, most of the included studies have limitations associated with small or moderate sample sizes and single-center observations. there are very few publications that enroll large, nationwide, and unbiased cohorts of covid- patients [ ] [ ] [ ] . the published studies agree that the main risk factors associated with critical or mortal outcomes are demographic characteristics (age, sex, bmi) and comorbidities, such as hypertension, diabetes, cardiovascular disease, and respiratory diseases [ ] . there are other not so well-studied but potentially important factors that require closer attention. first, according to who guidelines, there are two different icd- codes for the disease outbreak: u . for covid- confirmed by laboratory testing, and u . assigned to a clinical or epidemiological diagnosis of covid- [ ] . to our knowledge, no comparison was made for clinical outcomes between the two groups of patients. second, marin-hernandes et al. associated higher influenza vaccine uptake in adults aged + years with lower covid- mortality [ ] , which could also benefit other demographic groups. third, there is no clear evidence on covid- complications and mortality for the patients with tuberculosis (tb) [ , ] or hiv [ ] . the objective of this study was to investigate the factors including icd- code, influenza vaccination, tb and hiv comorbidities that could impact on the length of a hospital stay, icu and invasive mechanical ventilation requirements in relation with covid- mortality on a nation-level sample of subjects with completed inpatient treatment. the study was approved by the independent ethics committee of moscow regional office of the russian society of radiologists. the nationwide data from the federal register of covid- patients (the covid- register) were used in this multicenter observational cohort study. the covid- register was established on march , , by the russian government's decision. the covid- register contains the data from all medical clinics and doctor's offices of all constituent regions of the russian federation. the register provides personified records on patients diagnosed with sars-cov- infection, subjects hospitalized with the signs of pneumonia, and those who have been in contact with these persons, including outcomes, form, duration, and extend of medical aid. inclusion and exclusion criteria all patients regardless of age, admitted to hospitals indexed in the covid- register were included in the present study. diagnostic criteria were: (i) laboratory-confirmed sars-cov- infection by reverse transcription polymerase chain reaction (rt-pcr) detection of viral rna (idc code u . ), or (ii) a clinical diagnosis based on the combination of signs of acute respiratory infection (ari) and computed tomography (ct) results (idc code u . ). all included patients were divided into two groups: laboratory-verified covid- (u . cohort) and clinically verified covid- (u . cohort). patients were excluded during data analysis if their clinical records did not contain sufficient data to access at least one of the following outcomes: overall survival, time to full recovery, need of icu treatment or invasive mechanical ventilation (imv) requirements. variables accessed . cc-by-nc . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint we analyzed patients' demographic data (age and sex), icd- code, the length of the hospital stay, and whether they required icu treatment or imv. the other variables for analysis were: verified diagnosis of pulmonary disease, cardiovascular disease, diseases of the endocrine system, cancer/malignancy, hiv, tuberculosis, and the data on influenza vaccination in the previous six months. we report means, standard deviation (sds), medians, interquartile ranges (iqrs), minimum and maximum values for quantitative variables. the total number and proportion (%) of patients in each group were used for categorical variables. the aim of the analysis was to identify the relationship between the accessed variables and the outcomes using multivariable regression models. two types of variables were used for the outcome assessment: (i) time-to-event variables for overall survival and time to discharge and (ii) binary variables for the need for icu treatment and imv. the first type of outcome variables was analyzed with a cox proportional-hazards regression model with the inclusion of all the accessed variables as covariates. the risk ratio (hazard ratio, hr) of the event's occurrence was calculated for each variable. all hrs were estimated with a % confidence interval (ci). for the second type of outcome variables, logistic regression models were created with an estimation of the odds ratio (odds ratio, or) for each variable; ors were also obtained with associated % cis. p-values were determined by the student's t-test with significance threshold set at . . we assessed time-to-event variables as time (in days) from hospital admission to either mortality or complete recovery. patients who were still in hospital by the end of the observational period had their data censored at the latest follow-up date when it was evident that the event did not occur. before the statistical analysis, we performed the dataset's cleansing to remove entries with missing, invalid, and questionable data. role of the funding source there was no funding source for this study. all authors had full access to all the data in the study and had responsibility for the decision to submit for publication. we enrolled , covid- patients aged from to years, . % females, treated in , hospitals between march , , and june , ( figure ). , patients were excluded due to unconfirmed covid- (n= ) or insufficient and invalid clinical data (n= ). in total, participants were included in the study, , ( . %) of them had laboratory-verified covid- , and patients ( . %) had clinical verification only (table ) . . cc-by-nc . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint we observed comorbidities in . % of the study participants: . % with the laboratory-verified covid- and . % with the clinically verified disease. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint the most common were cardiovascular diseases ( . % and . %; from now on, the first value refers to u . patients and the second value corresponds to u . patients), followed by diseases of the endocrine system ( . % and . %) and pulmonary diseases ( . % and . %). among enrolled patients, . % had several comorbidities ( . % and . %, table ). is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint discharge or another outcome (death or transfer to another medical hospital). patients still in hospital at the date of the data cutoff (june , ) were censored for the analysis. in total, the dataset contained , events of discharge and other outcomes. we performed the multivariate regression analysis using as covariates: patient's gender, age, cohort (u . or u . ), the severity of covid- expressed using the "ct - " semi-quantitative grading scale [ ] , whether the patient received the icu treatment or imv, oxygen saturation level, comorbidities, and influenza vaccination status (table ) . hiv comorbidity showed the least association with hospital discharge (hr . , % ci . - . , p < . ). male sex was associated with a slightly longer length of the hospital stay (hr . , % ci . - . , p < . ). age increased for every five years was also associated with a gradual increase in the length of the hospital stay (hr . , % ci . - . , p < . ). the factor most associated with the shorter length of the hospital stay was verified covid- (hr . , % ci . - . , p < . , compared to the laboratory-verified covid- ). is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint the most prominent indicators of the mortality risk. disease progression by one gradation of the "ct - " scale was associated with a five-fold increased risk of death (table ). transfer to the icu, history of tb, hiv, cancer, and male sex were also associated with mortality in descending order. the reduced risk of mortality was revealed in patients with co-existing pulmonary disease (hr . , % ci . - . , p = . ) and those who received imv (hr . , % ci . - . , p < . ) and influenza vaccination (hr . , % ci . - . , p = . ). u . patients had a slightly higher risk of death than u . patients (hr . , % ci . - . , p = . ) ( table ). is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint . , p = . ). there was almost no statistically significant difference between the u . and u . groups (or . , % ci . - . , p = . ) ( table ) . our hypothesis was that influenza vaccination, former or current tb, and hiv could be associated with the severity of covid- outcomes. the results of . cc-by-nc . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint our study revealed that influenza vaccination reduced the risk of icu transfer (or . ), imv requirement (or . ), and the risk of death (hr . ). according to marin-hernandes et al., one of the possible explanations of the negative correlation between influenza vaccination and covid- mortality in the elderly italian population could be a higher vaccine uptake in higher economic groups with better overall health [ ] . we can confidently dismiss this statement due to our results based on vaccinated people of all age, social, and economic groups. the stimulation of innate immunity by an influenza vaccine could be the most feasible explanation of the observed correlation. further research on the relationship between a recent vaccination and covid- outcomes is needed to test this hypothesis. tb increased the mortality risk (hr . ), but at the same time, the presence of tb reduced the likelihood of the icu transfer (or . ). our findings contradict the statement made by motta et al. that covid- contributes to worsening the prognosis of tb patients and that tb might not be a major determinant of covid- mortality [ ] . the observed difference is possibly related to the different composition of the studied cohorts. in the study of motta et al., there were only cases from russia in a cohort of tb patients. our sample included tb patients. according to the estimates of yusunbaeva et al., about % of patients with tuberculosis in russia have multidrug-resistant strains [ ] . in their study of tb patients, the authors showed that the treatment failure could be as high as %, depending on the drug resistance category [ ] . therefore, our findings may be specific for the . cc-by-nc . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint countries with a high proportion of drug-resistant mycobacterium tuberculosis infections, such as russia, south africa, india, and the philippines [ ] . people living with hiv (plwh) are at heightened risk for severe covid- related complications compared to the general population [ ] . while limited data are available on sars-cov- and hiv co-infection, chronic inflammation and immunodeficiency caused by hiv as well as hiv-associated comorbidities in older plwh are associated with poor prognosis [ ] . our results have confirmed these concerns: hiv comorbidity significantly increased the risks of the icu transfer (or . ) and death (hr . ). the revealed fact that hiv infection was associated with a lower risk of imv requires further investigations. there was a statistically significant difference in outcomes between the patients classified with the u . and u . codes. the u . patients had a shorter length of hospital stay (hr . ) but a higher risk of mortality (hr . ) and imv treatment (or . ). according to the federal recommendations on the prevention, diagnosis, and treatment of covid- , a combination of ari symptoms and ct findings was sufficient for the clinical diagnosis of covid- . the "ct - " semi-quantitative grading scale was used to evaluate the severity of the disease; immediate hospitalization was mandatory for the patients with ct and ct grades (pulmonary parenchymal involvement > %). therefore, the u . patients were admitted to hospitals at advanced stages of covid- -associated pneumonia. this fact could explain the shorter length of the hospital stay, imv, and higher mortality. currently, one of the well-investigated risk factors for severe covid- outcomes is the patient's age. a study of laboratory-confirmed covid- patients admitted to tertiary hospitals from provinces in china reported that older age (> years, hr . , % ci . - . , p = . ) was associated with increased odds of composite adverse outcomes such as in-hospital mortality, icu admission, and imv [ ] . these findings were confirmed in a nationwide study of , covid- patients admitted to hospitals in italy [ ] and in the us study of patients [ ] . in some contradiction with that, bello-chavolla et al., in their study addressing covid- patients aged years and older, demonstrated that a combination of age and comorbidities was a better predictor of covid- severity and mortality than age alone [ ] . our study included patients of all age groups, and according to our findings, a five-year increment of the age of enrolled patients increased the length of the hospital stay (hr . ), the risk of death (hr . ), the risk of the icu transfer (or . ), and the risk of imv treatment (or . ). survival analysis revealed that male sex in patients with severe covid- was associated with risk of hospitalization and icu admission [ ] , severe illness (hr . , %ci . - . ) or death (or . , % ci . - . ) [ ] [ ] [ ] . our findings are in good agreement with these data. male sex was associated with the longer length of the hospital stay (hr . ), increased the risk of death (hr . ), icu admission (or . ), and imv requirement (or . ). in accordance with the published data [ ] [ ] [ ] our results show that endocrine disorders and cardiovascular diseases increased the length of the hospital stay, is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint the risk of death, and the icu transfer. endocrine diseases were associated with a higher risk of imv (or . ) than cardiovascular pathologies, cancer or hiv (table ). our results revealed that cancer increases the length of the hospital stay (hr . ) and the risk of death (hr . ) . the impact of concomitant oncological pathology depends on its severity, the presence of metastases, and therapy-induced complications. despite that heterogeneity, our findings indicate that cancer is a significant risk factor that should be taken as a mandatory hospitalization criterion. there was a contradiction regarding the influence of pulmonary diseases on the course of covid- . according to our results, pulmonary diseases' presence reduced the risk of death (hr . ) and increased the risk of transfer to the icu (or . ). however, in previous studies conducted in italy [ ] and china [ ] , chronic obstructive pulmonary disease (copd) was a significant predictor of mortality or factor of reaching the investigated outcomes. contrary to that, bello-chavolla et al. showed that copd was only associated with hospitalization [ ] . one of our study's limitations is that the covid- register does not contain the data on pulmonary disease codes. we believe that a detailed large-scale study is needed to address the effect of pulmonary disease' type on the severity and outcomes of covid- . the other limitation of our study is that the control group of subjects without covid- was absent. due to that, some of the factors that we have identified could not be specific for covid- . despite the limitations, our findings highlight several previously overlooked factors that could reduce the severity of outcomes and mortality and provide aid for the management of covid- patients. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nc . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint coronavirus update (live) the moscow times. russian hospitals near capacity with coronavirus patients moscow ramps up covid hospitals to handle 'big second wave federal recommendations for doctors on the prevention, diagnosis and treatment of covid- (site in russian risk factors for novel coronavirus disease (covid- ) patients progressing to critical illness: a systematic review and metaanalysis risk factors of severe disease and efficacy of treatment in patients infected with covid- : a systematic review, metaanalysis and meta-regression analysis risk factors of critical & mortal covid- cases: a systematic literature review and meta-analysis case characteristics, resource use, and outcomes of patients with covid- admitted to german hospitals: an observational study ethnic and regional variations in hospital mortality from covid- in brazil: a cross-sectional observational study low-dose hydroxychloroquine therapy and mortality in hospitalised patients with covid- : a nationwide observational study of participants world health organization. who -emergency use icd codes for covid- disease outbreak epidemiological evidence for association between higher influenza vaccine uptake in the elderly and lower covid- deaths in italy active tuberculosis, sequelae and covid- co-infection: first cohort of cases tuberculosis, covid- and migrants: preliminary analysis of deaths occurring in patients from two cohorts covid- in patients with hiv: clinical case series chest ct scans with covid- related findings dataset treatment efficacy of drug-resistant tuberculosis in bashkortostan, russia: a retrospective cohort study estimating the future burden of multidrug-resistant and extensively drug-resistant tuberculosis in india, the philippines, russia, and south africa: a mathematical modelling study. the lancet infectious diseases the burden of covid- in people living with hiv: a syndemic perspective covid- and the role of chronic inflammation in patients with obesity risk factors for adverse clinical outcomes with covid- in china: a multicenter, retrospective, observational study baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region older age and comorbidity are independent mortality predictors in a large cohort of covid- patients in michigan, united states unequal impact of structural health determinants and comorbidity on covid- severity and lethality in older mexican adults: looking beyond chronological aging risk factors for severity and mortality in adult covid- inpatients in wuhan clinical characteristics, associated factors, and predicting covid- mortality risk: a retrospective study in wuhan the clinical characteristics and prognosis factors of mild-moderate patients with covid- in a mobile cabin hospital: a retrospective, single-center study age and multimorbidity predict death among covid- patients: results of the sars-ras study of the italian society of hypertension comorbidity and its impact on patients with covid- in china: a nationwide analysis acknowledgements the authors express their gratitude to all doctors of medical organizations of the moscow department of health, fighting the epidemic, and to the team of experts from the moscow department of information technologies for prompt assistance in working with data from umias-eris. the authors declare that they have no conflict of interest. key: cord- -hf ndv f authors: cook, mackenzie; zonies, david; brasel, karen title: prioritizing communication in the provision of palliative care for the trauma patient date: - - journal: curr trauma rep doi: . /s - - -x sha: doc_id: cord_uid: hf ndv f purpose of review: communication skills in the icu are an essential part of the care of trauma patients. the goal of this review is to summarize key aspects of our understanding of communication with injured patients in the icu. recent findings: the need to communicate effectively and empathetically with patients and identify primary goals of care is an essential part of trauma care in the icu. the optimal design to support complex communication in the icu will be dependent on institutional experience and resources. the best/worst/most likely model provides a structural model for communication. summary: we have an imperative to improve the communication for all patients, not just those at the end of their life. a structured approach is important as is involving family at all stages of care. communication skills can and should be taught to trainees. in , the american college of surgeons called upon surgeons to provide high-quality palliative care to all patients with serious illness, not just those approaching the end of their life [ ••] . comprehensive care of the acutely injured and critically ill patient is the defining skill set of the acute care surgeon and an essential part of that skill set is the ability to communicate clearly, effectively, and efficiently with the patient and their family. communicating clearly as part of providing high-quality palliative care in the intensive care unit (icu) is about guiding difficult decisions, defining goals of care, explaining the impact of acute surgical problems on future quality of life, and facilitating transitions to end of life care [ , ] . it is critically important to understand that essential communication skills can be learned and taught [ , ] . the goal of this review is to summarize key aspects of our understanding of communication with injured patients in the icu. we will discuss communication through all phases of trauma care, review specific literature on guiding family meetings, and discuss strategies to teach these skills. the acuity of trauma patients admitted to icus in the usa is very high, with a diversity of pathologies [ ] . roughly one in five americans will die in hospital after receiving icu level care [ ] . when approaching the acutely injured and critically ill trauma patient, it is important to keep in mind the general observation that the seriously ill often value quality of life over extending quantity of their life [ , ] . while individual variation is wide, this point should guide initial approaches to communication with patients and their surrogates. there is a clear clinical need to improve our communication regarding goals and wishes; as even in patients with a stated desire to favor quality over quantity of life, preserving quality of life is not reliably honored [ ] . even in patients with established living wills or advanced directives, fulfillment of end of life wishes in the icu remains inconsistent [ ] . these data emphasize the imperative to improve the communication between patients, their families, and the care team through an earlier consensus on goals of care (goc) [ •] . attending to and this article is part of the topical collection on palliative care in trauma following a patient's goc, even if that includes comfort measures only, do not negatively impact mortality or length of stay [ , ] . this clinical need is matched by an urgent research need. as our ability to care for patients through their initial phases of injury improves, the need to focus on the key communication issues unique to trauma patients in the icu increases [ •, •, •] . this was recently emphasized in by the critical care committee of the american association for the surgery of trauma (aast). their statement on research priorities in adult surgical critical care highlighted addressing goc in the acute care setting as the top research priority [ • ]. there is only limited data specific to the trauma population available to review-with end of life/goc articles comprising just . % of the articles retrieved for the aast statement of research priorities [ •] . while frequently extrapolated, data generated on the optimal communication practices in elective surgical patients and non-surgical icu patients may have incomplete generalizability to trauma. much of the data available on the goc discussions pertained to older patients or those patients with a preexisting life-limiting illness. there is a wide span of injured patients and indeed the leading cause of death between and years old is injury [ ] . in addition to a wide span of ages, trauma patients may be socially marginalized, homeless, have pre-existing mental health and substance abuse disorders, and be estranged from their family and surrogates. the wide diversity of ages and associated medical and social challenges faced by trauma patients are unique. this raises the importance of an organized, consistent, and transparent approach to communication and palliative care in the trauma icu. communication with injured patients can be organized by phases of care and is an ethical imperative that must not be forgotten in the hustle of acute medical interventions [ •] . perhaps most easily organized by the physical location of the patient (prehospital setting, resuscitation bay, icu), communication challenges and priorities during these phases are distinct and build upon each other. a defining feature of trauma care is the unexpected nature of injury and the near instantaneous transition between normal life and high-intensity medical interventions. this temporal uniqueness of trauma care poses a challenge when communicating with families and surrogates. while everyone in medicine hopes that patients have had meaningful conversations with their surrogate decision makers prior to injury, the reality is that few have [ ] . we must help with the sudden news of a major injury while coaching them through a new and potentially uncomfortable role as a surrogate. the prehospital care of an acutely injured patient can be an extraordinarily challenging and time-pressured phase. as physiology is assessed and stabilized, in-depth de novo discussions are neither feasible nor appropriate. it is important, however, that any pre-established advanced directives are retrieved. this takes on critical importance when transporting patients from long-term care facilities, as trauma mortality in the frail elderly can be quite high. prehospital personnel can and do uphold advanced directives and established end of life wishes while managing family emotions near death [ , ] . the role of the hospital trauma service and state trauma system at this point is to support the medics as they seek to obtain and uphold established advanced directives. having access to an advanced directive on a patient's arrival, or shortly thereafter, opens a door to address goc in the resuscitation area and potentially avoid high-intensity interventions that a patient has previously decided are not consistent with their goals [ ] . it should come as no surprise that the presence of a pre-admission do not resuscitate (dnr) order is associated with a high risk of adverse in hospital events and death after injury, likely reflecting the high-risk nature of injury in patients who are already nearing the end of their life [ ] . it is far better to find out that a patient has an advanced directive limiting aggressive care before intubation, and prehospital personnel can help set the trauma team up for success. advanced care plans may be documented in a variety of different ways, including advanced directives, living wills, and durable power of attorney of health care documents. it is not feasible for prehospital personnel to read these documents in the acute setting, although it is helpful to bring them with the patient. what may be applicable in the acute prehospital, however, and can change acute management is a form similar to the physician orders of life-sustaining treatment (polst) form. designed to be portable and applicable across the spectrum of care, including prehospital care, polst forms are medical orders and valid in the states where programs have been established [ ] . they are designed to be easily and rapidly interpreted and honored, regardless of a patient's physical location [ ] . the state of oregon has a robust and easily searchable polst registry, and the presence of an active polst form at the time of contact is associated with a higher chance of dying not at a hospital (i.e., dying in a way concordant with wishes) [ ] [ ] [ ] [ ] . at our institution, trauma activation pages may include information on a pre-existing polst form, and it is not uncommon for a physical poslt form to be given to the attending surgeon by the responding prehospital providers, while the team is completing the primary survey. even in the absence of a physical polst form, a social worker in the emergency department immediately searches the statewide registry and, if a polst exists, it is available to the care team within min of patient's arrival. polst programs fill an important gap where other advanced directive documents fail, namely limiting unwanted resuscitative measures in the urgent/emergent setting if patients are unable to speak for themselves [ , ] . advanced trauma life support (atls) principles are an essential part of trauma care, and when a patient arrives at a trauma hospital, efforts should be focused on efficiently completing the primary and secondary survey. as much as possible, subject to available resources, communication with the patient, family, and surrogate decision makers should proceed in parallel with the trauma resuscitation. this is easier to support with the increasingly robust data on family presence during a trauma resuscitation. having families observe trauma evaluations can result in reduced family anxiety and stress in the short term [ ] . importantly, there were no long-term psychological effects from being at trauma resuscitations, and high-quality trauma care was able to be provided with families present; indeed, all family members present for a trauma resuscitation in one study reported they would choose to be present again [ , ] . having families at the bedside for trauma resuscitations can actually build trust in the health care team as well as fill information needs [ ] . these are concordant data with the findings on family presence during resuscitation from cardiac arrest and in pediatric trauma [ , ] . protocols to allow families to be present during trauma resuscitation do require an institutional commitment as well as support from the physician and nursing staff. a designated person, most frequently a social worker, should be present to provide context, guidance, and support. the trauma resuscitation is also a moment to review polst forms and assure that the care plan is concordant with pre-existing wishes. geriatric trauma patients with a polst specifying limited intervention that was available on admission spent fewer icu days with no change in in-hospital mortality, compared to age-matched controls without limitations on care [ •] . presumably this comes from limiting/focusing icu utilization and care based on a patient's pre-injury goals of care and reflects the sizeable mortality of patients admitted to the trauma system with pre-established limitations on medical interventions. in the absence of a polst, a well informed and empowered surrogate or otherwise well-established preinjury wishes, trauma bay communication with the family is often focused "just" on delivering bad news about the nature of the injury and further planning is left to the icu team. the paucity of data on the provision of high-quality palliative care in the icu is even more significant when the injured patient is considered [ , ] . three key points warrant close attention: clarifying goc, providing goal concordant care and transitioning goals to comfort measures only. given that the vast majority of severely injured trauma patients in the icu have limited abilities to function as their own decision makers, this discussion will primarily focus on the interactions with family and surrogate decision makers as this is the group most in need of high-quality communication [ , ] . the principles outlined below, however, would apply if a patient was competent to and able to make their own decisions. it is important to recognize that efforts to prioritize communication in the icu are difficult and multi-faceted with potentially disparate effects on patients and their families. as an example, among critically ill patients and their surrogates, a family-support intervention delivered by the icu team did not significantly affect the surrogates' burden of psychological symptoms, but their ratings of the quality of communication were higher and the length of stay in the icu was shorter with the intervention than with usual care [ •] . in a similar study, the use of palliative care-led informational and emotional support meetings compared with usual care did not reduce anxiety or depression symptoms and may have increased posttraumatic stress disorder symptoms [ ] . as we seek to advocate for the patient and aim for providing goal concordant care, it is essential to realize that the families and surrogates are under tremendous stress and a consistent, organized, and empathetic approach is likely the optimal approach to decision-making. one of the first questions that must be addressed as we think about communication in the icu setting is who will be primarily responsible for family facing communication, clarifying goc, guiding goal concordant care, and transitioning goals as warranted. this can be thought of both at the team level (trauma surgery, neurosurgery, orthopedics, etc.) and the individual level (attending, fellow, resident, advanced practice provider, etc.). the individual tasked as primary communication point for the family should be experienced enough to provide compassionate, meaningful, and nuanced updates. it is, furthermore, our belief that the primary trauma icu team should be in charge of overall communication with the family as they have the perspective to integrate multiple organ system problems and the recommendations of the whole care team. there are essentially three structural options: primary palliative care by the icu team, integrated subspecialty palliative care into the icu setting, and consult only subspecialty palliative care. there are strengths and weaknesses to each of these designs, and it is likely that the optimal design for any given icu will be dependent upon institutional level resources and culture. with that in mind, we attempt to outline potential benefits and challenges associated with each model. primary palliative care (ppc) is defined as palliative care provided by the primary treating service. this approach emphasizes the co-provision of palliative intensive care and may best integrate palliative communication principles into the icu [ ] . increasingly, this is being viewed as part of the routine job description of an acute care surgeon [ ] . primary palliative care has been shown to promote stronger clinician and patient relationships and reduce the fragmentation of care and can be integrated with other critical care interventions and therapy [ ] [ ] [ ] . the details of how ppc is integrated into routine icu care remain an area of active research, and defining therapeutic goals in a nuanced and sensitive way is essential [ , ] . the primary benefit to the ppc model is that, at least theoretically, all patients have their palliative needs, including communication, addressed on a daily basis. the primarily limitation to the ppc model is that at times of high icu acuity or with an intensive care team with less experience in complex communication, family communication may suffer. a particular challenge may be encountered when interacting with non-critical care surgical colleagues with different understandings of the patient's goals and the attendant conflict [ , ] . this highlights the need for additional subspecialty input which can be accomplished in one of two ways. the first model for providing subspecialty palliative care input in the icu is integrated subspecialty palliative care in the icu [ ] . this is most commonly framed as a subspecialty trained palliative care provider who routinely sees all patients within the icu, either as part of the rounding team or as a scheduled check in-ameliorating the lack of physician contact noted by family members of patients who died in hospital [ , ] . this emphasis on the routine integration of trained palliative care specialists helps to overcome a major barrier to involving palliative care to aid with communication, the initial call [ ] . the routine integration of trained palliative care subspecialists in the icu has been associated with improved quality of life, higher rates of formal advance directives, and greater utilization of hospice service as well as less frequent use of certain non-beneficial life-prolonging treatments for critically ill patients at the end of life [ ] . the challenges of this integrated subspecialty model are limited resources and the concurrent need for subspecialty palliative care across the inpatient and outpatient settings. it is likely that as the ppc skills of the rounding intensivist teams increase, the need for integrated subspecialty palliative care will decrease. the second model for integrating subspecialty palliative care is consultative care. this system works the same way as any other consultant service in the icu. the assumption in this model is that there is a baseline degree of comfort from the icu team with defining goc, providing goal concordant care and transitioning goals to comfort only. additionally, this model presumes a low barrier for the primary team to engage the palliative care consultant when appropriate, providing palliative and surgical care as an integrated whole [ ] . the primary failing of this structure comes if those presumptions are not true and the communication needs of the family and patient are not attended to. when this structure of care is studied, patients with a palliative consult are older, more seriously ill, and more likely to be at the end of life [ ] . palliative care consultations tend to be within the last h of life and are primarily symptom management at the end of life, suggesting an earlier opportunity to involve palliative care [ ] . the risk of late consultation can be mitigated through structured triggers for palliative consultation. demonstrated to increase palliative care involvement in critically ill non-surgical icu patients, triggers are established in only a minority of surgical icus, despite a sizeable identified need for palliative and communication support [ , , ] . as the poor to moderate performance of the "surprise" question in non-cancer diseases demonstrated, established screening systems designed in non-trauma patients have only limited ability to perform well in trauma patients [ ] . within the trauma population, triggers for consultation are poorly defined, beyond injury severity score and profound neurologic injury in older patients [ , ] . within the general geriatric trauma population, the geriatric trauma outcomes score (gtos) is a validated predictive tool that can provide a reliable estimate of in-hospital mortality risk using data available early in a patient's hospital course, allowing palliative consultations for the highest risk patients [ ] [ ] [ ] . predicting patients at risk for death in the year after injury, however, has proven much more challenging despite a clear need to identify patients who survive their hospital stay only to die in the coming year [ ] [ ] [ ] [ ] [ ] . it may be that a sustained focus on changing the culture of an icu unit towards one accepting and supportive of palliative care involvement is a key first step in routinely involving the consultative palliative care service [ ] . the optimal structure to prioritize communication in a given icu is likely dynamic and driven by local expertise and should be tailored to the individual institution's resources. the driving variable here is the quality of intensivist provided ppc as well as the culture of the institution and icu. at an institution where the attending physicians and the medical infrastructure are supportive of early approaches to goc discussions and supportive of a proactive approach to palliative principles, then consulting only subspecialty palliative care can be reserved for only the most difficult or complex cases. in the setting where the attending physicians or the hospital or patient cultures are less open to an early focus on understanding goc and considering less than maximally interventionist care plans, it may be necessary to integrate a palliative care subspecialist into the icu team. this will lower the barrier to integration of palliative care principles, help to prioritize communication, and, over time, will improve the ability of the treating team to provide high-quality primary palliative care in the icu. in the icu setting, communication often occurs with surrogate decision makers-particularly in the most complex patients at highest risk for a poor outcome. when organizing family meetings, we seek to use the broadest definition of "family" as is reasonable-essentially any person of importance in the patient's life who might attend a conference related to their care, as not all family is genetically related. as a general rule, most surrogates are not well prepared for their new, emotionally intense role and can suffer long-term psychological consequences as a result [ , ] . while we hope that all patients have had in-depth discussions about their wishes prior to injury, this is unfortunately not the case. as a result, when communicating with a surrogate in a complex and difficult clinical situation, we have a dual role of not only communicating the medical situation to the surrogates but also preparing them for the role of decision maker. involvement of surrogate decision makers and high-quality communication with them is essential, as physicians tend to systematically underestimate quality of life in favor of life-sustaining treatments, and this can often be mitigated by input from surrogate decision makers [ , ] . a structured communication tool or education program for family members may be helpful in supporting surrogates as they take on their new role. there are several predictable errors that are commonly made while communicating with critically ill patients and their families that can be mitigated by training and a standardized approach. the most common pitfalls are not budgeting appropriate time, entering into communication with family members without adequate information about the prognosis, and harboring a fear of inaction in face of a complex and highrisk scenario [ ] . this last pitfall is all too common among surgeons, who tend to have a "fix-it" mentality-focusing on the disease as an isolated anatomic or physiologic abnormality that can be corrected. this mental model fails in the complex critically ill and, when used to frame a high-risk communication, may lead to overly permissive decision-making that favors intervention even when the chance of the desired outcome is low [ ] . an additional error, more common in junior trainees, is terminating the discussion after a directive to "do everything." such a general statement is difficult to turn into actionable medical decisions. it is very important for the clinician, if asked to "do everything," to not prematurely truncate discussions but rather respond with empathy and explore what is meant, therefore understanding and capturing values that can be used to help guide treatment [ ] . a specific structured tool to help communication in the icu that is gathering a solid evidence base is the "best case/worst case" (bc/wc) model of communication. this model can help facilitate difficult decisions in high-risk scenarios with support from surgeons, patients, and family members [ ] . the bc/wc tool presents a range of possible outcomes ranging from the best case to the worst case, starting from where the patient is now, and using the spectrum to discuss what is possible. when using the tool to facilitate communication, a "most likely" case is marked and then used to make a recommendation that is informed by the patient's values and goc (fig. ) . in an adaptive tool that can be updated with changed in clinical condition, it has been shown to be effective with older patients considering invasive and acute medical treatments as well as high-stakes surgical decisions [ , ] . there are several routine communication scenarios that are frequently used in the icu and can be an opportunity, if correctly done, to build trust, support decision-making, and improve the psychological well-being of family members [ , , ] . communication with families must take the potential for long-term disability, and not just the potential for death, into account when discussing options. the astute surgeon needs to account for media portrayals of trauma care that deemphasize the impact and frequency of long-term physical and neurologic disability [ ] . . the first family meeting is a time to take a breath from the initial icu admission and acute stabilizing interventions. this is an opportunity for the treating icu team to do a comprehensive patient assessment, including not only their anatomic and physiologic status but also their goals, wishes, and values while providing a medical update to the family. this should occur within h of admission in order to optimize the quality of the communication, reduce icu length of stay, and understand patient's preinjury wishes, before proceeding with care that they would not want [ , , ] . early updates to the family and surrogate decision makers have been associated with earlier transition to comfort measured only as well as reduced length of stay, reduced ventilator days, and reduced chance of dying during a medical code (i.e., a dnr order placed for medical futility) [ ] . a proactive discussion regarding the patient's wishes early in the course of an icu admission is vastly preferable to an urgent discussion in the middle of the night following an acute deterioration [ , ] . while there are many ways to structure this first meeting, one of the most effective that we have found is as described by the vitaltalk group using the guide mnemonic [ ••] . get ready: pre-meet, get the right people, find quiet place, and sit down understand: what the patient knows inform: starting with a headline and stop for questions and emotions demonstrate: empathy and respond to emotion equip: the family to understand the next step in care (an opportunity to use the bc/wc tool) it is important to note that within this framework, there is no space reserved for decision-making. this is intentional as the first family meeting is framed as a meeting to deliver bad news and medical updates, gather information, and build relationships. the emotional toll of this meeting can overwhelm surrogates, limiting their ability to make complex decisions. ) the next common meeting type encountered in the surgical icu is the general family meeting, an update or planned check in following the initial meeting. the structure of this meeting can vary somewhat based upon the relationship with family and the urgency and scope of issues to be addressed. however, there are several essential components to the general family meeting. the first is a "pre-meeting"; this should include clinicians only and is an opportunity for multiple consulting teams to share their opinions and come to consensus regarding the medical situation, establish a shared understanding of prognosis, and agree on therapeutic options. it is not effective for clinician disagreements to be sorted out in front of the patient or the family, as discord in the care team often leads to family and patient distress and mistrust [ ] . as referenced earlier, since we are often coaching surrogate decision makers through a new and uncomfortable role, specifically saying things such as "what would they say" or "imagine that they are sitting here with us" to emphasize that we are not asking the surrogate for a decision but rather are seeking to hear the patient's voice. planning next steps together is an essential part of these meetings. the degree and nature of this plan, however, will depend significantly on the scope of the discussion [ ••] . ) clinician anxiety can be understandably high when heading into a meeting to talk about the third specific scenario, transitioning to end of life and comfort measures only. discussions regarding limiting life-sustaining interventions tend to be triggered by clinicians after an acute clinical deterioration and by family after a longer period where the patient fails to improve [ ] . in a study of new york state level trauma centers, advancing age, traumatic brain injury with an advanced directive, preexisting dementia, and pre-existing bleeding disorders are all associated with transition to comfort focused measures after injury [ ] . when discussing end of life issues, it is important to avoid an overly detailed review of clinical data, as this may obscure the overall life-limiting nature of the disease/injury, which is often multifactorial [ ] . similarly, it is essential to integrate patient preferences into medical recommendations, specifically patient preferences regarding quality of life, pain, chances of meaningful neurologic recovery, and anticipated degree of functional recovery [ ] . the bc/wc tool can be very helpful in this setting, particularly when the "best case" is profound disability or impairment. interestingly, fig. a graphical distribution of the use of the best case/worst case communication tool. within a theoretical case of a young man with a severe traumatic brain injury. the tool is used to integrate all available clinical information and estimate the range of future outcomes. the circle represents the absolute best case outcome, while the square represents the absolute worst case outcome and the star represents the clinicians' best judgment about what the future may bring. there is a clinical deterioration between day and day , as manifested by the "most likely" scenario moving closer to the "worst case." this is an original figure using the structure of taylor et al. [ ] while family satisfaction falls with increasing time in the icu, it actually rises when the process of transitioning to comfort only care takes greater than day-suggesting that additional time to adjust to the realities and see the ongoing medical care their loved one is receiving is helpful [ ] . family satisfaction, similarly, is actually higher when their loved one dies than when they survived their icu stay-a difference attributed to the improved patient and family-centered care that dying patients receive [ ] . as with the first family meeting, a structured approach to a "transition of goals" talk is essential, and we have found much success with the remap mnemonic, again supported by vitaltalk [ ••] . reframe: it is important to warn the family that a change in status update is coming and that the clinical scenario duration may have changed from previous updates [ •] . expect emotion and empathize: the nurse (name, understand, respect, support, explore) mnemonic of emotional response can be helpful, as responding to emotions from the family improves information retention [ , , ] . map the future: use an understanding of patient's goals to frame medical recommendations [ ] . the bc/ wc model can be particularly helpful in this setting as alternative approaches (recovery focused vs. comfort focused care) are considered [ ] . it is essential to have bidirectional flow of information when mapping the future as the care team brings medical information and options while the family brings patient values. it is not uncommon to have to make decisions in light of incomplete prognostic information [ ] [ ] [ ] [ ] . align with values: clinicians must align themselves with the family's and patient's values. using "i wish" statements (e.g., "i wish that were different too" or "i wish that was possible") to reflect family requests for clinically impossible options allows clinicians to maintain a therapeutic alliance while not offering false hope. these are difficult decisions for patients and their surrogates and conflict with the care team benefits nobody. plan treatments to match values: a clear statement of the plan moving forward is important, as well as a statement of hope. hope is an essential part of palliative care and even if we cannot hope for survival or recovery, we can still hope for time with family, an opportunity to say goodbye and an end to suffering. when considering the actual transition to comfort only care, specific clinical recommendations from the american college of critical care medicine are pertinent and informative [ ] . we strongly avoid using the words "withdrawal of care" as we never stop caring for patients, and we just shift our goal away from survival and recovery and towards comfort and acceptance of impending death. using "withdrawal of life-sustaining treatments" or "transition to comfort only goals" may be more acceptable. a final tip is to discuss cardiopulmonary resuscitation and code status last. once you have aligned goals and planned transitions of goals with the family, not doing cpr is a foregone conclusion. if, however, you open the meeting with the discussion about chest compressions before setting the ground work, there is a strong likelihood that the entire meeting will derail on this point. it should hopefully go without saying that, as patients transition to comfort measures only, it becomes increasingly important to care for the family [ ] . building and supporting family-clinician relationships and continuing to communicate well in the final hours of a patient's life help the family prepare for their upcoming death [ ] . the limited amount of research as to communication patterns and skills in the icu setting has focused, nearly exclusively, on formal "family meetings." there is, however, a significant amount of information delivery and care planning that occurs outside the structure of formal meetings. this usually happens at the bedside and is based on family and clinician availability-an interaction format that is very poorly studied [ ] . structured communication tools and family may help to improve physician and family relationships and reduce the risk of ptsd in family members [ , ] . difficult communication is a learned skill and must be taught to the next generation of surgical trainees. a cursory education about end of life care and high-stakes communication based on clinical exposure is no longer adequate, and there is very limited education in medical school on this topic [ , ] . as might be expected from the limited efficacy data, there are precious little data on the optimal approach to teaching residents and medical students key communication skills [ , ] . resident self-reported comfort with providing end-oflife care does not correlate well with experience providing end-of-life care, although a formal curriculum may [ ] . residents can effectively learn to use structured communication tools, such as the bc/wc tool, although do need skilled feedback in order to improve [ , ] . in the current medical training environment, it is likely that the clinical education of the vast majority of general surgery residents in high-stakes communication will occur in the surgical icu, where brief intervention can improve self-reported comfort with key communication skills [ ] . as we continue to improve our understanding of the optimal approach to high-stakes communication within injured patients, the educational process should proceed in parallel. families have traditionally and nearly universally been included at the bedside in surgical icus [ ] . as of the writing of this article, the covid- pandemic is raging across the world. as physical distancing becomes ubiquitous and hospitals severely restrict the number of visitors, high-stakes communication is becoming increasingly challenging. technological solutions have provided a bridge, but video conferencing will never be a full replacement for in-person communication and bedside discussions. while we suspect that many of the same principles and structures outlined in this article remain applicable in the current pandemic, adaptations to technological limitations will be required. the weight of the published work, to date, focuses on managing death and dying in the setting of a resource-limited pandemic. much work remains to be done and with families not at the bedside. conversations will need to become more intentional, more structured, and integrated more intentionally into the routine care of patients in the icu. the realities of physical distancing and limited family visitation emphasize the need for rapid and universal acceptance of surgical palliative care principles, particularly structured and empathetic communication in the icu [ •]. communication skills in the icu are an essential part of the care of trauma patients. we have an imperative to improve the communication for all patients, not just those at the end of their life [ ] . the need to communicate effectively and empathetically with patients and identify primary goc is an essential part of trauma care in the icu [ , ] . while the optimal design to support complex communication in the icu will be dependent on institutional experience and resources, a ppc model or integrated palliative care model will allow assessment of every patient's communication needs and may be superior to a purely consult-based format. a structured approach to family meetings may improve our ability to communicate succinctly and clearly in high stress situations. communication skills are teachable and can be improved. in an area of active and dynamic research, we look towards a coming explosion of research on surgical palliative care and complex communication challenges. this is an exciting time to be an acute care surgeon and an exciting time to build palliative and communication capabilities. conflict of interest the authors declare that they have no conflict of interest. human and animal rights and informed consent all reported studies/ experiments with human or animal subjects performed by the authors were performed in accordance with all applicable ethical standards including the helsinki declaration and its amendments, institutional/ national research committee standards, and international/national/institutional guidelines. force on surgical palliative care; committee on ethics. statement of principles of palliative care integrating palliative care in the surgical and trauma intensive care unit: a report from the improving palliative care in the intensive care unit (ipal-icu) project advisory board and the center to advance palliative care - a review and opinion piece that highlights the importance of surgical palliative care as a co-equal part of that makes up acute care surgery shared decision making in oncology practice: what do oncologists need to know? shared decision-making in acute surgical illness: the surgeon's perspective trauma icu prevalence project: the diversity of surgical critical care use of intensive care at the end of life in the united states: an epidemiologic study valuing health at the end of life: a review of stated preference studies in the social sciences literature priority preferences: "end of life" does not matter, but total life does. value health the intensity and variation of surgical care at the end of life: a retrospective cohort study endof-life decision-making for patients with geriatric trauma cared for in a trauma intensive care unit changing the culture around end-of-life care in the trauma intensive care unit impact of advanced directives on outcomes and charges in elderly trauma patients critical care committee of the a. defining the surgical critical care research agenda: results of a gaps analysis from the critical care committee of the american association for the surgery of trauma critical care societies collaborative utfoccr. multisociety task force for critical care research: key issues and recommendations palliative care in surgery: defining the research priorities national center for injury prevention and control. web-based injury statistics query and reporting system (wisqars). (online) completion of advance directives among u.s. consumers decisionmaking in the moments before death: challenges in prehospital care we are strangers walking into their life-changing event": how prehospital providers manage emergency calls at the end of life missed opportunities: integrating palliative care into the emergency department for older adults presenting as level i triage priority from long-term care facilities preadmission do not resuscitate advanced directive is associated with adverse outcomes following acute traumatic injury experiences with polst: opportunities for improving advance care planning: editorial & comment on association between physician orders for life-sustaining treatment for scope of treatment and in-hospital death in oregon injured older adults transported by emergency medical services: one year outcomes by polst status physician orders for life-sustaining treatment (polst): lessons learned from analysis of the oregon polst registry lessons from oregon in embracing complexity in end-of-life care a comparison of methods to communicate treatment preferences in nursing facilities: traditional practices versus the physician orders for life-sustaining treatment program family presence during resuscitation after trauma family presence during trauma resuscitation: ready for primetime? effects of family-witnessed resuscitation after trauma prior to hospitalization experiences of families when present during resuscitation in the emergency department after trauma family presence during trauma resuscitation: family members' attitudes, behaviors, and experiences family presence during cardiopulmonary resuscitation - propensitymatched study showing that polst forms available in the early phases of trauma care do indeed alter the management of patients and that, when specified palliative care interventions for surgical patients: a systematic review structure and function of a trauma intensive care unit: a report from the trauma intensive care unit prevalence project a structured approach to supporting communciation with families in the icu can improve family perceptions of the patient and family centeredness of the care as well as reduce hospital length of stay effect of palliative care-led meetings for families of patients with chronic critical illness: a randomized clinical trial identifying patients in need of a palliative care assessment in the hospital setting: a consensus report from the center to advance palliative care - an outline of the model of palliative care that may be the most successful-primary palliative care from the icu team with subspecialty consultation the costs of waiting: implications of the timing of palliative care consultation among a cohort of decedents at a comprehensive cancer center to operate or not to operate? a multi-method analysis of decision-making in emergency surgery surgeon-reported conflict with intensivists about postoperative goals of care palliative care assessment in the surgical and trauma intensive care unit a model for increasing palliative care in the intensive care unit: enhancing interprofessional consultation rates and communication family perspectives on end-of-life care at the last place of care characterizing the role of u.s. surgeons in the provision of palliative care: a systematic review and mixed-methods meta-synthesis preliminary report of the integration of a palliative care team into an intensive care unit utilization of palliative care consultation service by surgical services characteristics of palliative care consultation at an academic level one trauma center choosing and using screening criteria for palliative care consultation in the icu: a report from the improving palliative care in the icu (ipal-icu) advisory board estimates of the need for palliative care consultation across united states intensive care units using a trigger-based model the "surprise question" for predicting death in seriously ill patients: a systematic review and meta-analysis predicting in-hospital and -year mortality in geriatric trauma patients using geriatric trauma outcome score multicenter external validation of the geriatric trauma outcome score: a study by the prognostic assessment of life and limitations after trauma in the elderly (palliate) consortium estimating geriatric mortality after injury using age, injury severity, and performance of a transfusion: the geriatric trauma outcome score duration of respiratory failure after trauma is not associated with increased long-term mortality statewide data that highlights that, in trauma, discharge is not the end of the mortality risk. when guiding patients, it is important to explain that a bad injury places them or their loved one at an increased risk of how do clinicians prepare family members for the role of surrogate decision-maker? risk of post-traumatic stress symptoms in family members of intensive care unit patients substituted judgment: how accurate are proxy predictions? perceived quality of life and preferences for life-sustaining treatment in older adults pitfalls in communication that lead to nonbeneficial emergency surgery in elderly patients with serious illness: description of the problem and elements of a solution and i think that we can fix it": mental models used in high-risk surgical decision making discussing treatment preferences with patients who want "everything best case/worst case": training surgeons to use a novel communication tool for high-risk acute surgical problems best case/worst case": qualitative evaluation of a novel communication tool for difficult in-the-moment surgical decisions description of the best/worst case tool-one of the best standardized communication tools available at this point. adaptable to the clinical situation and allows easy integration of complex data in a graphical format an intensive communication intervention for the critically ill integrating palliative and critical care: evaluation of a quality-improvement intervention grey's anatomy effect: television portrayal of patients with trauma may cultivate unrealistic patient and family expectations after injury intensity of treatment, end-of-life care, and mortality for older patients with severe traumatic brain injury goals of care discussions for the imminently dying trauma patient advance care planning: beyond the living will care planning for inpatients referred for palliative care consultation an outstanding free and electronic resource for those interested in building their palliative care communication tool box. they have an extensive library of evidence-based communication strategies communicating about end-of-life care with patients and families in the intensive care unit prospective analysis of life-sustaining therapy discussions in the surgical intensive care unit: a housestaff perspective patient characteristics associated with comfort care among trauma patients at a level i trauma center moving from empathy to action in discussing goals of care barriers to goal-concordant care for older patients with acute surgical illness: communication patterns extrinsic to decision aids duration of withdrawal of life support in the intensive care unit and association with family satisfaction family satisfaction in the icu: differences between families of survivors and nonsurvivors informative work that guides an approach to readdressing patient's goals in the setting of a severe illness or injury emotional and informational patient cues: the impact of nurses' responses on recall why should i talk about emotion? communication patterns associated with physician discussion of patient expressions of negative emotion in hospital admission encounters aligning ethics with medical decision-making: the quest for informed patient choice rethinking informed consent: the case for shared medical decision-making patients' expectations about effects of chemotherapy for advanced cancer patients' understanding of treatment goals and disease course and their relationship with optimism, hope, and quality of life: a preliminary study among advanced breast cancer outpatients before receiving palliative treatment recommendations for end-of-life care in the intensive care unit: a consensus statement by the american college [corrected] of critical care medicine family members' perceptions of inpatient palliative care consult services: a qualitative study what constitutes quality of family experience at the end of life? perspectives from family members of patients who died in the hospital communication with patients' families in the intensive care unit: a point prevalence study the effectiveness of interventions to meet family needs of critically ill patients in an adult intensive care unit: a systematic review update communication tools for end-of-life decision-making in the intensive care unit: a systematic review and meta-analysis perspectives on death and dying: a study of resident comfort with end-of-life care palliative care and surgical training: are we being trained to be unprepared? training surgeons and anesthesiologists to facilitate end-of-life conversations with patients and families: a systematic review of existing educational models evaluation of palliative care training and skills retention by medical students resident education in end-of-life communication and management: assessing comfort level to enhance competence and confidence training surgical residents to use a framework to promote shared decision-making for patients with poor prognosis experiencing surgical emergencies surgical palliative care education a brief educational intervention to teach residents shared decision making in the intensive care unit to face coronovirus disease , surgeons must embrace palliative care publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- - rqnu bu authors: nan title: th international symposium on intensive care and emergency medicine: brussels, belgium. - march date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: rqnu bu nan the relationship between systemic glycocalyx degradation markers and regional glycocalyx thickness in non-septic critically ill patients is unclear. conjunctival sidestream dark fieldimaging for the purpose of glycocalyx thickness estimation has never been performed. we aimed to investigate whether changes in glycocalyx thickness in conjunctival and sublingual mucosa are associated with global glycocalyx shedding markers. methods: in this single-centre prospective observational study, using techniques for direct in-vivo observation of the microcirculation, we performed a single measurement of glycocalyx thickness in both ocular conjunctiva and sublingual mucosa in mixed cardio surgical (n= ) and neurocritical patients (n= ) and compared these data with age-matched healthy controls (n= ). in addition we measured systemic syndecan- levels results: in the sublingual and conjunctival region we observed a significant increase of the perfused boundary region (pbr) in both neuro critical and cardiac surgical icu patients, compared to controls ( . ], p< , ). we detected a weak correlation between syndecan- and sublingual pbr(r= . , p= . ) but no correlations between global glycocalyx damage markers and conjuctival glycocalyx thickness. conclusions: conjunctival glycocalyx thickness evaluation using sdf videomicroscopy is suitable and is impaired in non-septic icu patients but only measurements in sublingual mucosa are correlating with systemic glycocalyx shedding markers. global glycocalyx damage is more severe in cardiac comparing to neuro critical patients. introduction: endothelial dysfunction plays a major role in the sepsis related organ dysfunction, and is featured by vascular leakage. amp-activated protein kinase (ampk) is known to regulate actin cytoskeleton organization and interendothelial junctions (iejs), contributing to endothelial barrier integrity. we have already demonstrated its role in defence against sepsis induced hyperpermeability [ ] , but the underlying mechanisms remain unknown. this project aims to identify molecular targets involved in the beneficial action of ampk against endothelial barrier dysfunction. methods: experiments have been performed in human microvascular dermal endothelial cells. α ampk activity has been modulated via the use of a specific sirna or treatment by two pharmacological ampk activators (aicar, ). we have investigated the effect of this modulation on the expression/phosphorylation of connexin (cx ) and heat shock protein (hsp ), two proteins playing a key role in maintenance of iejs and actin dynamics respectively. results: we show that α ampk is required to sustain the level of cx expression as it was drastically reduced in cells transfected with a sirna targeting specifically α ampk. regarding hsp , its expression level was not affected by α ampk deletion. however, both ampk activators increased its phosphorylation on ser , in a α ampkdependent manner, while they had no effect on cx . our results also reveal that hsp phosphorylation concurred with the appearance of actin stress fibers at the periphery of cells, suggesting a beneficial role for phsp as well as f-actin stress fibers in vascular barrier function through reinforcing the endothelial tethering. conclusions: our work identifies the regulation of cx expression and hsp phosphorylation as potential protective responses underlying the beneficial action of ampk against endothelial barrier dysfunction. ampk could consequently represent a new therapeutic target during sepsis. introduction: sepsis induced cardiomyopathy (sic) is a serious condition during sepsis with a mortality rate up to % ( ) . sic is clinically manifested with left ventricle impaired contractility ( ) . melusin is a muscle-specific protein involved in sustaining cardiomyocyte survival thorough the activation of akt signaling pathways ( ) . pi k-akt signaling pathway plays a pivotal role in regulating calcium channel activity ( ) . we hypothesized that melusin overexpression could exert a protective effect on cardiac function during septic injury. methods: animals were treated with an intraperitoneal injection of lipopolysaccharide (lps) at mg/kg. sv strain knockout mice (ko) for melusin gene and fvb strain with cardiac-specific overexpression (ov) of melusin were compared. each group was studied together with a control group (wt). hemocardiac parameters were studied at hour and hours through echocardiography. another cohort of animals was sacrificed hours after mg/kg lps treatment and cardiac tissues and blood sample were harvested for wb analysis to quantify the expression of akt, p-akt and cacna c and elisa analysis for troponin levels. results: sv wt, ko melusin and fvb wt mice groups, fractional shortening (fs) was significantly impaired after lps challenge and was associated with compensatory tachycardia (fig. ) . fvb ov mice group didn't show decrease in fs. consistent with the increased akt phosphorylation observed in ov mice, the expression of cacna c was also significantly higher both at basal levels and after lps treatment in ov mice compared to wt mice (fig. ) . troponin levels didn't differ between mice groups after lps treatment conclusion: melusin has protective role in lps induced cardiomyopathy, likely through akt phosphorylation controlling the cacna c protein density. introduction: liver dysfunction is frequent in sepsis, but its pathophysiology remains incompletely understood. since altered liver function has also been described in icu patients without sepsis [ , ] , the influence of sepsis may be overestimated. we hypothesized that sedation and prolonged mechanical ventilation after abdominal surgery is associated with impaired liver function independent of sepsis. methods: sedated and mechanically ventilated pigs underwent abdominal surgery for regional hemodynamic monitoring and were subsequently randomized to fecal peritonitis and controls, respectively (n= , each), followed by h observation. indocyanine green (icg) retention rate minutes after injection of . mg/kg icg (icg r ) was determined at baseline, and , and h after sepsis induction (si), and at the same time points in controls. concurrent with icg r , plasma volume, total hepatic perfusion (ultrasound transit time), and bilirubin and liver enzymes were measured. anova for non-parametric repeated measurements was performed in both groups separately. results: icg r increased over time without significant differences between groups (table ). there was a parallel increase in bilirubin in septic but not control animals. the other measured parameters were similar in both groups at the end of the experiment. conclusion: liver function was impaired under sedation and prolonged mechanical ventilation after abdominal surgery, even in animals without sepsis. the underlying reasons should be further explored. introduction: previous work has shown the cytoprotective properties of antithrombin-affinity depleted heparin (aadh), by neutralization of cytotoxic extracellular histones [ ] , major mediators of death in sepsis [ , ] . aadh was produced from clinical grade heparin, resulting in preparations that have lost > , % of their anticoagulant activity. to gain insight into the mechanisms and the basic pharmacological aspects of aadh protective properties, we performed a systematic analysis of how aadh is tolerated in mice and ascertained its effects in three different in vivo models of inflammation and infection. methods: dose ranging studies, short term and medium term, were performed in c bl/ mice. the effects of i.v. administration of extracellular histones in the presence or absence of aadh were assessed in mice. we further analysed the effect of aadh in models of concanavalin a-and mrsa-mediated lethality. in all studies we assessed clinical signs, lab parameters and histology. results: aadh was well tolerated in both short term and intermediate term (till days) experiments in mice, in the absence of any signs of tissue bleeding. aadh was able to revert the cytotoxic properties of i.v. administered histones. in a concanavalin a mediated model of sterile inflammation, we confirmed that aadh has protective properties that counteract the cytotoxic effects of extracellular histones. in an in vivo lethal mrsa model, for the first time, aadh was shown to induce a survivalbenefit. conclusions: we conclude that aadh contributes to the overall increased survival by means of neutralization of extracellular histones and represents a promising product for further development into a drug for the treatment of inflammatory diseases and sepsis. introduction: urokinase (uk) and tissue plasminogen activator (tpa) mediate thrombolytic actions by activating endogenous plasminogen. thrombomodulin (tm) complexes with thrombin to activate protein c and thrombin activatable fibrinolysis inhibitor (tafi). activated protein c (apc) modulates coagulation by digesting factors v and viii and activates fibrinolysis by decreasing pai- functionality. methods: the purpose of this study is to compare the effects of rtm and apc on urokinase and tpa mediated thrombolysis utilizing thromboelastography. results: native whole blood was activated using a diluted intrinsic activator (aptt reagent, triniclot). the modulation of thrombolysis by tpa and uk (abbott, chicago, usa) was studied by supplementing these agents to whole blood and monitoring teg profiles. apc (haematologic technologies, vt, usa) and rtm (asahi kasai pharma, tokyo, japan) were supplemented to the activated blood at . - . ug/ml. the modulation of tpa and uk induced thrombolysis by apc and rtm was studied in terms of thromboelastograph patterns. the effect of both apc and rtm on plasma based systems supplemented with tpa was also investigated. patients treated with antibiotic therapy were eligible for inclusion. the plausibility of infection (definite, probable, possible, none) was determined based on the centers for diseases control (cdc) criteria. patients with sepsis (definite/probable/possible infection and a sofa score increase of >= ) were screened for death within days and secondary infections h to days after icu admission, using the cdc criteria. hla-dra and cd mrna expressions were determined by reverse transcription quantitative pcr. results: among icu admissions, a blood sample for rna analysis was collected in cases. two hundred fifty-seven patients met the inclusion criteria and provided written informed consent. sepsis was noted in patients. the sepsis patients experienced death in cases ( %), secondary infection in cases ( %), and death and/or secondary infection in cases ( %). table shows the results of hla-dra and cd expression related to death and secondary infections. conclusions: the mrna expression of hla-dra on icu admission was significantly decreased in patients with sepsis who died or contracted secondary infections within days. cd expression was not significantly decreased in patients with negative outcome. introduction: acid-base disturbances are common in patients with infection admitted to the intensive care unit (icu). more attention is given to hyperlactatemia in this patient population as a prognostic factor, although other acid-base disturbances may also have an impact on patient outcomes. our objective is to describe the acid-base profile of this patient population and determine the association between different acid-base abnormalities and icu mortality. methods: retrospective cohort of patients admitted with infection to an intensive care unit. patients were stratified according to ph (< . ; . - . ; > . ) and, then, according to the standard base excess (sbe) (< - ; - -+ ; > + ). in each of these strata and the whole population, the proportions of acid-base disturbances were quantified during the first hours of icu admission. to assess the association between acid-base disturbances and outcome, a logistic regression model was fit, adjusting for age, sex and saps score. results: patients were analysed. ( %) patients were acidemic and ( %) presented with a normal ph. metabolic acidosis (as assessed by sbe) was observed in all subgroups, regardless of ph levels (ph < ). lactic acidosis was observed in % of the whole population; sig (strong ion gap) acidosis, in %; sid (hyperchloremic) acidosis, in %; metabolic alkalosis, in %; and respiratory acidosis, in % of the patients. introduction: sepsis-induced brain dysfunction has been neglected until recently due to the absence of specific clinical or biological markers. there is increasing evidence that sepsis may pose substantial risks for long term cognitive impairment. methods: to find out clinical and inflammatory factors associated with acute sepsis-induced brain dysfunction (sibd) serum levels of cytokines, complement breakdown products and neurodegeneration markers were measured by elisa in sera of sibd patients and healthy controls. association between these biological markers and cognitive test results was investigated. results: sibd patients showed significantly increased il- , il- , il- and c d levels and decreased tnf-α, il- , c a and ic b levels than healthy controls. no significant alteration was observed in neuronal loss and neurodegeneration marker (neuron specific enolase (nse), amyloid β, tau) levels. increased il- β, il- , il- , il- , tnf-α and decreased c d, c a and ic b levels were associated with septic shock, coma and mortality. transient mild cognitive impairment was observed in of patients who underwent neuropsychological assessment. cognitive dysfunction and neuronal loss were associated with increased duration of septic shock and delirium but not baseline serum levels of inflammation and neurodegeneration markers. conclusions: increased cytokine levels, decreased complement activity and increased neuronal loss are indicators of poor prognosis and adverse events in sibd. cognitive dysfunction and neuronal destruction in sibd do not seem to be associated with systemic inflammation factors and alzheimer disease-type neurodegeneration but rather with increased duration of neuronal dysfunction and enhanced exposure of the brain to sepsisinducing pathogens. introduction: high levels of some aromatic microbial metabolites (amm) in serum are related to the severity and mortality of critically ill patients [ ] . several studies have discussed the imbalance and loss of the diversity of gut microbiota but there are practically no data on the gut microbial metabolites in critical conditions, only a little -in healthy people [ , ] . the aim of this work is to analyze the connection between serum and fecal levels of amm in icu patients. methods: simultaneously serum and fecal samples (sfs) from icu patients with nosocomial pneumonia (group i), sfs from icu neurorehabilitation patients (group ii) and sfs from healthy people were taken for gc/ms analyses. the following amm were measured: phenylpropionic (phpa), phenyllactic (phla), p-hydroxybenzoic (p-hba), p-hydroxyphenyllactic (p-hphla), p-hydroxyphenylacetic (hphaa), p-hydroxyphenylpropionic (p-hphpa) and homovanillic (hva) acids. data were presented as medians with interquartile range (ir, - %) using statistica . results: the sum of the level of most relevant metabolites ( amm) -phla, p-hphla, p-hphaa, and hva -in serum samples from group i and group ii were equal to . ( . - . ) μ m and . ( . - . ) μ m, respectively, and were higher than in healthy people - . ( . - . ) μ m (p< . ). we suppose the presence of the correlation of amm profile in blood and intestine. particularly, sfs of healthy people are characterized by the prevalence of phpa; amm are not detected in feces of non-survivors but only hva dominates in their serum in the absence of other (fig. ) . conclusions: the amm profiles in gut and serum are interrelated; amm in serum probably reflect the violation and loss of biodiversity of the gut microbiota in critically ill patients. introduction: since nitrogen oxide (no) is an essential component of the immune system, the dynamics of plasma no concentration was studied in order to predict the development of sepsis [ , ] . methods: with the permission of the ethics committee included the full-term newborns with respiratory diseases on a ventilator, retrospectively divided into two groups (i, n= -sepsis - days; ii, n= without sepsis), at , - , days was studied by elisa the plasma concentration of no, nos- , nos- , adma (multilabel coulter victor- , finland). to select points "cut-off" used the method of roc-lines. results: the statistical power of the study was . % (α< . ). at admission in patients of groups i and ii decrease the concentration of no and increased adma in plasma (p< . ) relative to healthy newborns. after - days, relatively in patients of groups introduction: sepsis-associated disseminated intravascular coagulation (sac) is associated with decreased platelet counts and formation. the widespread activation of platelets contribute to vascular occlusions, fibrin deposition, multi-organ dysfunction, contributing to a two-fold increase in mortality. the purpose was to measure markers of platelet function in the plasma of patients with clinically established sac and to determine association to disease severity and outcome. methods: plasma samples from adult intensive care unit (icu) patients with sepsis and suspected sac were collected at baseline and on days and . dic scores were calculated using platelet count, d-dimer, inr, and fibrinogen. patients were categorized as having no dic, non-overt dic, or overt dic. plasma levels of cd l, von willebrand factor (vwf), platelet factor- (pf- ), and microparticles (mp) were quantified using commercially available elisa methods. results: markers of platelet activation were significantly elevated in patients with sepsis alone and with suspected dic compared to normal healthy individuals on icu day (p< . ). levels of platelet-associated biomarkers were compared between survivors and non-survivors. pf- was significantly decreased in non-survivors compared to survivors (p = . ). patients were stratified based on platelet count and levels of markers were compared between groups. cd l, vwf, pf , and mp showed significant variation based on platelet count, with all markers exhibiting stepwise elevation with increasing platelet count. conclusions: markers of platelet activation were significantly elevated in patients with sac compared to healthy individuals. pf levels showed significant difference based on dic score or mortality, and differentiated the non-survivors compared to survivors. cd l, vwf, pf , and mp showed significant association with platelet count, increasing in a stepwise manner with increases in platelet count (table ) . prognostic value of mean platelet volume in septic patients: a prospective study a chaari king hamad university hospital, bussaiteen, bahrain critical care , (suppl ):p introduction: mean platelet volume (mpv) has been reported as a valuable marker of inflammatory diseases. the aim of the current study is to assess the prognostic value of mpv in septic patients. methods: prospective study including all patients admitted to the intensive care unit (icu) with sepsis or septic shock. demographic, clinical and laboratory data were collected. the mpv was checked on admission and on day . two groups were compared: survivors and non-survivors. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days in survivors and . [ . - ] days in non-survivors (p= . ). conclusions: the decrease of the platelet count but not the increase of the mpv was associated with increased mortality in critically-ill septic patients. endotoxin activity assay levels measured within hours after icu admission affected patients' severity assessments a kodaira , t ikeda , s ono , s suda , t nagura tokyo medical university, tokyo, japan, introduction: sepsis profoundly alters immune homeostasis by inducing first a systemic pro-inflammatory, then an anti-inflammatory state. we evaluate the prognostic value of ex vivo lipopolysaccharide (lps) stimulation of whole blood in septic patients, at day and after intensive care unit (icu) admission. methods: this prospective cohort study included patients with severe sepsis or septic shock admitted to a surgical icu of a university hospital. blood was drawn on day and day , and stimulated ex vivo with lps for hours. tumor necrosis factor alpha (tnf), interleukin (il) , il and il were measured. twenty-three healthy adults served as controls. outcomes were ventilator and icu-free days, sofa score at day and , and need for dialysis during the course of sepsis. results: forty-nine patients were included (mean age ± years). the blood of septic patients was less responsive to ex vivo stimulation with lps than that of healthy controls, as demonstrated by lower tnf, il , il and il release ( fig. ). at day , patients above the th percentile of il release had significantly fewer ventilator and icu-free days than those in the lower th percentile (fig. ) . in contrast, patients in whom il release increased between day and day had significantly lower sofa scores at day and and need for dialysis, and more icu-free days than patients in whom il release decreased (table ) . conclusions: greater lps-stimulated il release in septic patients at day was associated with poorer clinical outcomes and may reflect the severity of the forthcoming immunoparalysis. however, an increase in il release between day and day was associated with favorable outcomes, perhaps signaling immune restoration. introduction: hyperthermic intraperitoneal chemotherapy with cytoreductive surgery (hipec-crs) is a curative treatment modality for peritoneal carcinomatosis. extensive debulking surgery, peritoneal stripping and multiple visceral resections followed by intraperitoneal installation of heated high-dose chemotherapeutic agents, a process leads to a 'high-inflammatory' syndrome. serum procalcitonin (pct), a biomarker for bacterial sepsis, in the heightened inflammatory state after hipec-crs might be of limited utility. our aim is to determine the trends of pct in the early postoperative phase of hipec-crs and to identify trends in patients with and without bacterial sepsis methods: in a case-control design, we reviewed all patients undergoing hipec-crs over a -month period ( ) ( ) ( ) . patients were divided into groups based on whether they developed bacterial sepsis in the first days after surgery (infected v/s non-infected). summary data are expressed as medians and ranges. two-tailed nonparametric tests were performed and considered significant at p values of less than . results: patients' data was analyzed. infections developed in % ( patients) with escherichia coli as the predominant pathogen isolated ( % isolates). pct levels (ngm/ml) were elevated postoperatively in both infected and non-infected patients; day infected . (iqr . introduction: early outcome in cardiac surgery has been an area of growing interest where the given risks raise several predictive models for assessment of postoperative outcome [ ] . procacitonin (pct) emerges as a possible predictive tool in cardiothoracic intensive care unit (cticu).we aim at testing the predictive power of pct for early morbidity, prolonged ventilation, icu and hospital stay, in patients developing early fever after cardiac surgery methods: a retrospective descriptive study done in tertiary cardiac center, enrolling patients who stayed for more than hours post-operatively in the cticu risk stratification included additive euro score and pct immunoluminometricaly prior to surgery and every hours in response to onset of fever. results: we screened consecutive patients who underwent open heart cardiac, of which patients were enrolled in the study. patients were divided into two groups based on the level of pct, those with value > ng/ml (group ) and those with level < ng/ml (group ). patients in group as compared to group , over the postoperative course was associated with prolonged icu stay (p= . ), length of mechanical ventilation (p= . ), length of hospitalization (p= . ), acute kidney injury (p= . ) and culture positivity (p= . ). multivariate analysis showed that pct > ng/ml was was significantly associated with positive cultures. (p= . ) conclusions: a rise of serum pct carries the signals of early icu morbidity and lengths of ventilation, icu stay and hospital stay methods: patients aged ( - ) days ( - days) underwent cardiac surgery with cardiopulmonary bypass for severe congenital heart disease. in the dynamics levels of pct, mr-proadm, ct-proavp and mr-proanp were measured before surgery and on the , , and days after the operation with the kryptor compact plus analyzer. data are presented as medians with interquartile range. the mann-whitney u-test was used to compare the data. values of p < . were statistically significant. results: patients ( %) required alv for more than hours. in this group statistically significant higher levels of pct, mr-proadm and mr-proanp were found throughout the period ( table ). the level of ct-proavp had increased to statistical significance since the day after the operation. patients were in the icu for more than hours. in this group statistically significant higher levels of pct, mr-proadm were found throughout the whole period ( table ). the higher level of mr-proanp was statistically significant on the st and th days after surgery, mr-proanp had a tendency of increasing values on nd and rd days. ct-proavp increased to statistical significance since the nd day after the operation and persisted throughout the studied period. conclusions: pct, mr-proadm and mr-proanp can be used as predictors of prolonged alv for children of the first year of life after cardiac surgery with cardiopulmonary bypass. the level of ct-proavp can be considered since the day after surgery. pct and mr-proadm may be used to predict the los in the icu. mr-proanp and ct-proavp can be considered since the and days after surgery respectively. introduction: early prediction of the risk of death among patients admitted at the emergency department (ed) remains an unmet need. the prognostic performance of hbp that is secreted by neutrophils was prospectively validated in a series of sequential ed admissions. methods: hbp and elements of qsofa were analyzed prospectively in serial ed admissions (main reasons for admission: acute abdominal pain . %; fever . %; vomiting/diarrhea . %; dyspnea . %; neurologic signs . %; non-specific complaints . %; most patients admitted for more than one reasons). upon ed admission patients were scored as low-risk, intermediate-risk and high-risk at the discretion of the physician. hbp was measured in blood samples upon admission by an enzyme immunosorbent assay. results: hbp was significantly greater among patients who died very early (fig. ). in five out of six of patients dying early hbp was greater than ng/ml. we combined hbp more than ng/ml and the presence of one sign of qsofa into a new score; this had . % sensitivity to predict -day mortality. the respective sensitivity of two signs of qsofa was . % (p: . ). the use of this new score allowed better stratification of patients originally considered at the triage as low-risk into high-risk (fig. ) . conclusions: we propose hbp more than ng/ml and one qsofa sign as an early score for -day mortality at the ed. introduction: despite of our growing knowledge in pathophysiology of septic shock still remain one of the most important factors of hospital mortality. it is thought that early diagnosis and treatment at early stage of septic shock would decrease its mortality. there have been on-going studies in recent years which research the usability of heparin binding protein (hbp) in early diagnosis of sepsis [ ] . to seek the usability of c-reactive protein (c-rp), procalcitonin (pct) and hbp biomarker combination in early diagnosis of septic shock. methods: patients, who have the diagnosis of septic shock, that are expected to stay in intensive care unit more than hours, and aged between - are included in the study. data are collected from the patients' blood samples that are drawn on admission, on the th hour, and on the day of discharge or death. results: it has been found in our study that, best "cut-off" value ng/ml, specificity . and sensitivity . for hbp. compared with other biomarkers, hbp was the best predictor of progression to organ dysfunction (area under the receiver operating characteristic curve (auc) = . ). conclusions: although there have been many biomarkers for early diagnose of septic shock, c-rp and pct are the most common used markers in nowadays' clinical practice. the usability of hbp in early diagnosis of sepsis is still being researched. we concluded that pct, c-rp and hbp biomarker combination is usable to diagnose septic shock at the end of our study. introduction: reduced adamts- and increased von willebrand factor (vwf)/adamts- ratio have been observed in sepsis and are associated with the severity of the disease [ , ] . however, their change during the septic episode and in the event of a change in the clinical status of the septic patients has not been investigated. the aim of the study was to assess the variation of these hemostatic parameters in critically ill patients during the course of a septic episode. methods: we monitored septic patients admitted in the intensive care unit (icu). improved (group a) while deteriorated (group b). we assessed vwf, adamts- and the vwf/adamts- ratio on admission in icu (time point ) and at the time of a change in patients' clinical condition (remission or deterioration, time point ). results: in group a, adamts- and the vwf/adamts- ratio did not significantly change ( . ± . vs . ± . conclusions: hemostatic disorders, as assessed by vwf and adamts- levels were detected in septic patients, while their changes differed according to the evolution of the septic episode. adamts- changes may be associated with outcome. methods: adult patients with at least one sign of qsofa and infection or acute pancreatitis or after operation were prospectively followed-up. blood was sampled the first hours; those with hiv infection, neutropenia and multiple injuries were excluded. sepsis was diagnosed using the sepsis- criteria. soluble urokinase plasminogen activator receptor (supar) was measured by an enzyme immunoassay. results: sixty patients were classified with sepsis using the sepsis- definitions. presence of at least two signs of qsofa had . % sensitivity, . % specificity, . % positive predictive value and . % negative predictive value for the diagnosis of sepsis. the integration of qsofa signs and supar improved the diagnostic performance ( fig. ) . conclusions: conclusions two signs of qsofa have significant positive prognostic value for sepsis but low sensitivity. this is improved after integration with supar. the intelligence- study is supported by the european commission through the seventh framework programme (fp ) hemospec. introduction: sepsis is a frequent reason for admission in the emergency department (ed) and its prognostic mainly relies on early diagnosis. in addition, no validated prognostic tool is currently available. therefore, identification of patients at high risk of worsening in the ed is key. the triage objective was to assess the prognostic value of a blood marker panel to predict early clinical worsening of patients admitted in the ed with suspected sepsis. methods: triage was a prospective, multicenter ( sites in france and belgium) study on biological samples conducted in partnership with biomerieux s.a. patients admitted in the ed with suspected or confirmed community-acquired infection for less than h were included. exclusion criteria were: admission in the ed for more than hours, septic shock at admission, immunodepression, sepsis syndrome days prior to admission. the protocol included clinical and biological time points (h , h , h , h , d ). patients were classified in groups at admission (infection, sepsis, severe sepsis) and divided into evolution/prognosis groups depending on worsening or not from their initial condition to severe sepsis or septic shock and sofa score's evolution. the evolution criteria were centrally evaluated by an independent adjudication committee of sepsis experts including emergency physicians and intensivists. patients were followed up to day for mortality. results: the study duration was years with patients included ( excluded). the centralized analysis is in progress to select the combination of biomarkers with the best prognostic performance comparing both evolution/prognosis groups. currently, patients have been classified as worsening and some results will be available in . conclusions: triage is the largest prospective multicenter study assessing the prognostic value of a panel of blood markers in eds which could help identification of septic patient at risk of worsening at time of admission in the ed and develop specific management. introduction: immune status characterization in intensive care unit (icu) patients presents a major challenge due to the heterogeneity of response. in this study, the filmarray® system was used with customized gene assays to assess the immune profile of critically-ill icu patients compared to healthy volunteers; from within the realism cohort. methods: a customized filmarray® pouch containing assays was designed; target and reference genes. detection and semiquantification of assays from whole blood collected in paxgene tubes occurs in the device within hour. a total of subjects from the realism cohort were tested in duplicates: trauma, septic shock and surgery patients, along with healthy volunteers. the patients' selection was based on hla-dr expression on monocytes, and pha-(phytohaemagglutinin) stimulated t-cell proliferation assay, to have various immune profiles. results: quantification cycle values of the target genes were normalized by the geometrical mean of reference genes to account for the different cell counts among specimens. the number of the cd + cells and hla-dr, determined by flow cytometry, showed good correlation to cd d and cd gene expression, respectively. seven genes showed significant differences in expression levels between the healthy volunteers and patient groups: cd d, cd , ctla & cx cr were down-regulated, while il- , il rn and s a were up-regulated in the patient populations. the use of relative quantitative difference of some markers was able to distinguish and introduction: early, rapid diagnosis is integral to the efficient effective treatment of sepsis; however, there is no gold standard for diagnosis, and biochemical surrogates are of limited and controversial utility. the cytovale system measures biophysical properties of cells by imaging thousands of single cells per second as they are hydrodynamically stretched in a microfluidic channel. this platform has been shown to measure dozens of mechanical, morphological, and cell surface biomarkers of wbc activation simultaneously [ , ] . in this study, we show the performance of the cytovale system in measuring biophysical markers for sepsis detection in the emergency department (ed). methods: we conducted an irb-approved prospective cohort study of emergency department (ed) patients with + sirs criteria and evidence of organ dysfunction. patients were included for analysis. blood samples for the cytovale assay were collected in the ed, and the diagnosis of sepsis was adjudicated by blinded clinician review of the medical record. captured imaging data were analyzed using computer vision to quantify mechanical parameters per cell, and a logistic model was trained to discriminate patients who had sepsis from those who did not. results: we found substantial biophysical differences between cells from septic and non-septic patients as observed at both the single cell level (fig. ) and when looking at the overall leukocyte populations (fig. ) . a multiparameter classification algorithm to discriminate septic from non-septic patients based on biophysical markers currently yields a sensitivity of % with a negative predictive value of %. conclusions: in patients presenting to the ed with of sirs criteria and evidence of organ dysfunction, the cytovale system provides a potentially viable means for the early diagnosis of sepsis via the quantification of biophysical properties of leukocytes. oxidative stress and other biomarkers to predict the presence of sepsis in icu patients v tsolaki, m karapetsa, g ganeli, e zakynthinos icu, larissa, greece critical care , (suppl ):p introduction: early identification of sepsis adds a survival benefit in icu patients. several biomarkers have been evaluated, yet an optimal marker is still lacking [ ] . methods: we prospectively determined oxidative status in patients admitted in a general intensive care unit of the university hospital of larisa. oxidative status was determined measuring the novel static (sorp) and capacity (corp) oxidation-reduction potential markers. other biomarkers (bnp, presepsin, crp) were measured, and the discriminative properties for the detection of sepsis were evaluated. results: oxidative status was evaluated in a hundred and fifty two consecutive patients. patients with severe sepsis and septic shock had significantly higher sorp values than patients without sepsis ( introduction: c-reactive protein (crp), is reported to be an effective marker for the assessment of vascular inflammation activity and acute coronary events prediction [ ] .we hypothesized that preoperative crp elevation is related to the occurrence of postoperative adverse cardiovascular outcomes. methods: we prospectively included patients scheduled to undergo different vascular surgeries from december to september . we assessed demographic data, comorbidities, revised cardiac risk index (rcri) and biomarkers (crp, cardiac troponin high sensitive ths, creatinine and urea) in the preoperative period. we also noted type and duration of surgery, intraoperative blood loss, icu stay and mortality. we evaluated crp as a predictive marker of major cardiovascular events defined as chest pain, ths elevation, electrocardiogram changes, arrhythmia, pulmonary embolism, stroke occuring within postoperative months. results: during our study, patients were scheduled to undergo vascular surgeries. from the patients, % developed adverse cardiac events (table ) . we showed the predictive value of crp in major cardiovascular event in a roc analysis (fig. ) . the cuttoff value of cpr was giving % of sensitivity and % of specificity. conclusions: our study pointed out that crp preoperative elevation could have a very strong predictive value of post-operative cardiovascular events in vascular surgery, this is in line with results showed by previous studies [ ] . introduction: elderly are particularly susceptible to bacterial infections and sepsis, and they comprise an increasing proportion of intensive care unit (icu) admissions. our aim was to evaluate the impact of age on critically ill infected patients. methods: we performed a post-hoc analysis of all infected patients admitted to icu enrolled in a -year prospective, observational, multicenter study involving icus. patients aged < , - and >= years were compared (group a, b, and c). multidrug-resistance (mdr) was defined as acquired non-susceptibility to at least one agent within three or more antimicrobial categories. results: of the patients analyzed, ( . %) were infected on icu admission. of these, ( %) belonged to group a, ( %) to group b and ( %) to group c. group c were more dependent, had higher saps ii and charlson scores (p< . ). icu and hospital length of stay did not differ between groups. microorganism isolation and bacteremia were higher in group b ( % and %, respectively) than groups a ( % and %, respectively) and c ( % and %, respectively; p< . ). septic shock was present in % of patients and was more frequent in groups b ( %) and c ( %) than group a ( %). the most common sources of infections were respiratory and intra-abdominal. isolation of gram-negative bacteria was significantly increased in group b and c (p= . ). the most common isolated bacteria were escherichia coli ( %), staphylococcus aureus ( %) and pseudomonas aeruginosa ( %) for all groups. in total, isolates ( %) corresponded to mdr bacteria, of which % were staphylococcus aureus. age was not a risk factor for infection by mdr. all-cause mortality in icu and hospital was: % and %; % and %; % and % -respectively for groups a, b, and c (p < . ). conclusions: old patients ( - years) were more prone to present with bacteremia, which could account for the increased severity of sepsis and higher all-cause mortality. age was not a risk factor for mdr infection. introduction: the rapid identification of pathogens using patient samples is crucial. delays in this can potentially have serious implications for patients and infection prevention/control [ ] . the aim of this project was to identify the number of microbiology samples sent, the number rejected and reasons for rejection, with the intention to reduce such instances. methods: data was collected retrospectively on icu admissions from january-june to a university hospital in the uk. patients were identified and data collected using the intensive care national audit and research centre (icnarc) database and from electronic patient records. data collected included: demographics, length of stay, microbiology samples sent and details on the rejected samples. results: patients were identified with a total of (median: samples/patient) samples sent to microbiology. were rejected ( %). ( %) patients had at least sample rejected. the median number of samples rejected per patient was (range: - ). the fig. (abstract p ). the area under the curve for crp elevation is . most common samples rejected were urine ( %), blood ( %), faeces ( %) and sputum ( %). ( %) of the samples were resent for testing (median day; range - ). reasons for sample rejection are shown in table . most rejections occurred within -hours of admission ( fig. ) . conclusions: this study confirms a high number of samples are sent to microbiology. although a few are rejected, overall this represents a large number, with most occurring during the first days of admission. reasons for sample rejection are remedial through improved training and vigilance. a bespoke guide to sample collection for microbiology coupled with a training program for healthcare professionals has been introduced with the aim to reduce sample rejections from % to . %. introduction: careful hand hygiene of health-care workers (hcws) is recommended to reduce transmission of pathogenic microorganisms to patients [ ] . mobile phones are commonly used during work shifts and may act as vehicles of pathogens [ , ] . the purpose of this study was to assess the colonization rate of icu hcws' mobile phones before and after work shifts. methods: prospective observational study conducted in an academic, tertiary-level icu. hcws (including medical and nursing staff) had their mobile phones sampled for microbiology before and after work shifts on different days. samples were taken with eswab in a standardized modality and seeded on columbia agar plus % sheep blood. a semiquantitative growth evaluation was performed at and hours after incubation at °c. results: fifty hcws participated in the study ( % of department staff). one hundred swabs were taken from mobile phones. fortythree hcws ( %) reported a habitual use of their phones during the work shift, and of them ( . %) usually kept their mobiles in the uniform pocket. all phones ( %) were positive for bacteria. the most frequently isolated bacteria were coagulase negative staphylococcus, bacillus sp. and mrsa ( %, %, %, respectively). no patient admitted to the icu during the study period was positive for bacteria found of hcws' mobile phones. no difference in bacteria types and burden was found between the beginning and the end of work shifts. conclusions: hcws' mobile phones are always colonized mainly by flora resident on hcw's hands, even before the work shift and irrespective of the microbiological patients' flora. further studies are warranted to investigate the role of mobile phones' bacterial colonization in the icu setting and to determine whether routine cleaning of hcws' mobile phones may reduce the rate of infection transmission in critical patients. methods: sixty samples were collected from aicu (n= ), picu (n= ) and or (n= ) during august to september . samples were randomly selected and taken at the end of the hcws duty with a sterile swab covering all mp surfaces. the inoculation was made into blood sheep and eosyn methilene blue agar for culture. isolated bacteria were identified according to standard microbiological techniques. antibiotic sensitivity testing was performed using disc diffusion method. results: overall mp bacterial colonization rate was %. main results are detailed in table . most common non pathogenic bacteria was staphylococcus epidermidis n= ( %). isolated pathogenic bacteria conclusions: we found high rates of mp colonization with pathogenic bacteria. an educational program is necessary to reduce the contamination and transmission of these high risk microorganisms. introduction: the objective of this study was to evaluate the variability in the dynamics and levels of airborne contamination within a hospital intensive care unit in order to establish an improved understanding of the extent to which airborne bioburden contributes to cross-infection of patients. microorganisms from the respiratory tract or skin can become airborne by coughing, sneezing and periods of increased activity such as bed changes and staff rounds. current knowledge of the clinical microflora is limited however it is estimated that - % of nosocomial infections are transmitted via air. methods: environmental air monitoring was conducted in glasgow royal infirmary icu, in the open ward and in patient isolation rooms. a sieve impactor air sampler was used to collect l air samples every minutes over hour ( : - : h) and hour ( : - : h) periods. samples were collected, room activity logged and the bacterial contamination levels were recorded as cfu/m of air. results: a high degree of variability in levels of airborne contamination was observed over the course of a hour day and a period in a hospital icu. counts ranged from - cfu/m over hours in an isolation room occupied for days by a patient with c. difficile infection. contamination levels were found to be lowest during the night and in unoccupied rooms, with an average value of cfu/m . peaks in airborne contamination showed a direct relation to increased room activity. conclusions: this study demonstrates the degree of airborne contamination that can occur in an icu over a hour period. numerous factors were found to contribute to microbial air contamination and consideration should be given to potential improved infection control strategies and decontamination technologies which could be deployed within the clinical environment to reduce the airborne contamination levels, with the ultimate aim of reducing healthcareassociated infections from environmental sources. new practice of fixing the venous catheter of the jugular on the thorax and its impact on the infection f goldstein, c carius, a coscia quintad'or, rio de janeiro, brazil critical care , (suppl ):p introduction: central line-associated bloodstream infection (clabsi) is an important concern in the icu, mainly in those with a high density of use of central venous catheter. any measures that may have an impact on the reduction of clabsi are important in reducing morbidity and mortality of hospitalized patients. therefore we present a retrospective study comparing the fixation site (neck vs. thorax) of the catheters implanted in the jugular vein, guided by ultrasonography and evaluating its impact on the incidence of clabsi. the purpose of our study was to identify if there is any positive impact on the reduction of clabsi when the catheter is fixated on the thorax. methods: a retrospective unicentric study comparing the infection rates between the year of , when the traditional technique of catheter fixation on the neck was used, and , when % of the catheters were fixated on the thoracic region. the criteria for clabsi were defined by the infection commission of quintad`or hospital and the data on clabsi were provided by the same commission. during this period there were no changes in the team of our unit and the patient's profile was the same. no deep vein catheter impregnated with antibiotics were used in the patients included in the study. the comparison used fisheŕs test as a tool. all the patients hospitalized in the intensive care unit with indication of the central venous catheter of short permanence in the internal jugular vein were included. patients with the central venous catheter of short permanence in other topographies, patients with hemodialysis catheter or with picc were excluded. results: during the year of , internal jugular vein catheters were installed in our unit using the traditional technique, fixing the catheter on the neck. in this period, cases of clabsi were detected. on the other hand, in the year of , internal jugular vein catheters were installed in the same unit, all of them, using the thorax as the point of fixation. although the number of catheters installed this year was higher, there was no case of clabsi. it appears that this position, provides a better fixation of the catheter, avoiding that the bandage gets uncovered. conclusions: during the year of , though there were more patients using deep vein catheters of short permanence, we had less clabsi events on our unity compared to the year of . fisher's exact test identified a p-value of this association of . . fixation of the internal jugular vein catheter in the thorax seems to contribute to the prevention of clabsi. further prospective and randomized studies are required to evaluate the contribution of fixation of the jugular vein catheter in the thorax in the clabsi prevention. introduction: the oral cavity of a patient who has been hospitalized presents a different flora from normal healthy people. after h hours of hospital stay, the flora presents a bigger number of microorganisms that can be responsible for secondary infections, like pneumonia, because of their growth and proliferation. the objective of our study was to assess the dental plaque index on patients on admission to an intensive care unit, and reassess days later, to evaluate the efficacy of oral hygiene. methods: prospective, descriptive and observational study in an intensive care unit of the chp. demographic, admission motive, hospital length of stay, feeding protocol, respiratory support need and oral hygiene protocol data was collected. the greene & vermillion simplified oral hygiene index (iho-s) was used as the assessment tool on the first h and on th day. results: patients were evaluated, of which were excluded for not meeting the minimal dentition. patients had a mean age of , ± , years, , % were males and most of medical and surgical scope ( , % each). mean hospital length of stay was , ± , days. the majority of patients were sedated ( %), under ventilator support ( , %) and with enteric nutritional support, under nasogastric tube feeding. initial iho-s score was , ± , , rising to , ± , (p< , ) days later. conclusions: various studies have proven the importance of a good oral hygiene to avoid bacterial growth and reduce the risk for nosocomial infections. in this study, we've observed a significant worsening of oral hygiene one week after admission. although this could be unimportant for a one week staying patient, it could indicate an increased risk for nosocomial infections for longer staying patients, which could benefit from a more efficient oral hygiene protocol. positive pocket cultures and infection risk after cardiac electronic device implantation-a retrospective observational single-center cohort study p pekić methods: we performed a retrospective observational single-center cohort study on patients who received de novo implantation of pacemaker, cardioverter-defibrillator or cardiac resynchronization therapy device in a two-year period. each patient was implanted using standard aseptic procedure according to local protocol and antibiotic (cefazolin) prophylaxis before the procedure. pocket aspirate was taken after irrigating the wound with normal saline just before device placement. results: we analyzed patients ( . % male, . % female). the most often implanted device was a ddd pacemaker followed by a vvi pacemaker. mean length of hospital stay was . ± . days. there were ( . %) positive cultures with overall ( . %) clinically apparent infections which required prolonged iv antibiotics, removal of device and reimplantation after infection resolution. in regard to microbiology, s. epidermidis ( . %) and coagulase negative staphylococcus ( . %) were the most often finding which is in contrast to the cultures described in the literature. the only statistically significant risk factor for positive pocket culture was male sex and presence of a urinary catheter. invasive vascular devices, previous intrahospital infection, and diabetes were not found to increase the likelihood of positive pocket culture. conclusions: positive pocket cultures after cied implant are a frequent finding mostly due to contamination and colonisation. the risk factors for such a finding differ from the usual and expected clinical circumstances. our results are consistent with those in the literature. it turns out that the most important preventive measure in cied implantation is strict aseptic procedure. introduction: intensive care patients are in constant risk of contamination due to suppression of their immune system, use of invasive procedures and medical equipment and health associated infections (hai). chlorhexidine gluconate (chg) is an antiseptic and disinfectant product. in medical research it has been found that daily chg bathing is affective in reducing levels of skin and central line related infections (climo, ) . it is also referred to in the recommendations of the ministry of health "prevention of septicemia due to central lines" ( ). methods: unit guide lines for patient dry bathing were written in may and thereafter began the implementation and instruction of nursing staff. quality control was inspected by observation. there was a phase questioner that included several categories such as: preparation of the chg solution, staff protection actions, infusions and surgical wound dressings, bathing performance and documentation. results: a gradual rise of %was observed in theperformance ofdry bathing according to the unit guidelines conclusions: % of observed dry baths where performed according to the guide lines. points for improvement: correct care of infusions and surgical wound dressing and verify use of separate wipes for each body part. next we will examine the correlation between the use of dry baths and theextent of infections in the unit. dry baths are nowconsidered an integralpart of the daily nursing routine. they have no substantial costs, help prevent complications from infection and add to the patient's safety. introduction: despite reductions in mortality reported with sdd, concerns about bacterial resistance and alteration of microbiome limit use. a retrospective observational study was conducted into the effect of local sdd protocols on vap rates and resistance patterns. over a -year period, regimens were used dependent on drug availability and hospital antibiotic stewardship concerns. the study was designed to review practice and identify any risks of partial implementation. methods: patients ventilated on a general intensive care were identified via clinical information systems. three periods were reviewed for adherence to sdd protocols, pre sdd (jan -feb ), full (july -sept ) and partial (july -sept ). high-risk patients during both sdd periods also received iv antibiotics for hours. patients admitted with pneumonia or tuberculosis were excluded from vap analysis. remaining patients' records were reviewed and the clinical pulmonary infection score (cpis) calculated for each ventilated day to identify vap rates. positive respiratory microbiological results for all patients admitted to the icu during each time period were reviewed to assess for wider changes in local resistance patterns. results: protocol adherence was assessed in patients during the full sdd period and during the partial ( table ). the number of patients included for analysis of vap rates during each period was pre sdd, during full sdd and during partial sdd. there were no significant changes in resistance patterns or clostridium difficule rates (table ) . conclusions: compliance with the available enteral antibiotics was reasonable but with iv antibiotics was poor. it is accepted that alterations and non-adherence to protocols risk development of resistant bacterial strains. within our unit no decrease in vap rates was seen but reassuringly no increased rates of extended bacterial resistance were identified during the treatment periods. introduction: arterial catheters are commonly used in intensive care units (icu) and are among the most frequently manipulated vascular access devices. our aim was to evaluate the rate of arterial catheterrelated bloodstream infection and colonization. methods: this was a -month, prospective and monocentric cohort study, performed in a multipurpose icu. all arterial catheters, inserted in or presented to the icu, were cultured and assessed for colonization or catheter-related bloodstream infection (crbi). results: we enrolled patients ( . % males, average age ± years, saps ± ) of whom a total of arterial catheters were analyzed for a total of catheter-days. radial arterial catheters were inserted in . % (n= ), femoral arterial catheters in . % (n= ) and other arterial catheters in . % (n= ). signs of dysfunction were found in . % and . %, respectively. radial arterial catheters colonization (n= ) and crbi (n= ) occurred at a rate of . and . / catheter-days. femoral arterial catheters colonization (n= ) and crbi (n= ) occurred at a rate of . and . / catheter-days, respectively. mean catheter time insertion was significantly higher in colonized catheters/crbi ( ± days; % ci: - ) when compared to arterial catheters with negative cultures ( ± days; % ci: - ); p = . ). colonized lines showed acinetobacter baumannii (n= ), staphylococcus epidermidis (n= ), enterococcus spp (n= ) and pseudomonas aeruginosa (n= ). crbi were caused by staphylococcus epidermidis (n= ) and staphylococcus haemolyticus (n= ). conclusions: the incidence of radial arterial catheters colonization and crbi were lower than reported rates in literature. colonization and crbi rates were higher in femoral catheters. femoral catheters showed dysfunction more frequently. prolonged catheterization was associated with colonization and crbi. a multimodality approach to decreasing icu infections by hydrogen peroxide, silver cations and compartmentalization and applying acinetobacter as infection marker introduction: nosocomial infections at the intensive care unit (icu) represent a substantial health threat [ , ] . icu infections are mainly attributed to the extended hospital delay which results in high morbidities and mortalities. methods: a cross sectional study was conducted at the intensive care unit, aseer central hospital, saudi arabia over months period ( ) ( ) . the intervention program included the application of mist of hydrogen peroxide and silver cations, physical separation and compartmentalization of the intensive care unit. the glosair™ system was used to deliver a mist of hydrogen peroxide and silver cations. hydrogen peroxide is an oxidizing agent, which kills microorganisms. results: a total of strains of acinetobacter species were identified from the patients over the months period (fig. ) . the mean infection rates decreased from . in the first three months of the program to in the last three month after continuous. conclusions: the program using the three procedures offered a significant decrease in infections at the icu as measured by acinetobacter count, which is one of the most hazardous nosocomial pathogens. introduction: the efficacy of ß lactam antibiotics is related to the time above mic. continuous or extended infusions can be used to increase the time above mic, especially in patients with normal or increased drug clearance. administering antibiotics by continuous infusion is not a new concept. a review in looks at the outcomes of continuous infusions [ ] . more recently an improvement in mortality has been demonstrated [ ] . our perception was that uptake of this low cost intervention was not common, so we undertook a survey to determine how commonly continuous infusions are used in england. methods: a telephone survey of all intensive care units in england was undertaken. questions included: -are you using continuous or extended antibiotic infusions? -which antibiotics are you using for continuous or extended infusions? -if not currently using has it been considered? data was collected over a week in june . results: there was an % response rate. ( . %) of the units continuously infuse some antibiotics, however . % of those only infuse vancomycin and not ß lactams. only of the total responders ( . %) infuse antibiotics other than vancomycin (i.e. ß lactams). conclusions: the theoretical advantage of continuous infusion of ß lactam antibiotics has been described for over years. there is now evidence that this may improve survival. despite this, uptake in england has been slow. introduction: infections contribute to a significant proportion of morbidity and mortality worldwide. while many infections are successfully managed with antimicrobial therapy, rates of antimicrobial resistance (amr) are increasing. certain patient populations such as those admitted to intensive care units (icu) are at high risk. methods: we conducted a retrospective, observational study of all icu patients at a tertiary referral hospital in rwanda from january through december we collected data on diagnosis, icu length of stay, mortality and hospital length of stay, as well as microorganism, site of culture, amr and antibiotics prescribe. results: overall, patients were admitted to the icu. most patients were admitted from the main operating theater (n= , %).the most common admitting diagnoses were sepsis (n= , %), head trauma (n= , %). a total of samples were collected from patients. the samples were from blood (n= , %), tracheal aspirate (n= , %),. the most common organisms isolated were klebsiella (n= , %), acinetobacter (n= , %), e.coli (n= , %), proteus (n= , %), citrobacter (n= , %), s aureus (n= , %), pseudomonas (n= , %), and other (n= , %). of klebsiella isolates, % and % were resistant to ceftriaxone and cefotaxime, respectively. of e.coli isolates, % and % were resistant to ceftriaxone and cefotaxime, respectively. all acinetobacter isolates were resistant to ceftriaxone and cefotaxime. conclusions: there is an alarming rate of antimicrobial resistance to commonly used antibiotics in the icu. expanding antibiotic options and strengthening antimicrobial stewardship are critical for patient care. the last three days g latten , p stassen zuyderland mc, sittard-geleen, netherlands, introduction: this study provides an overview of the prehospital course of patients with a (suspected) infection in the emergency department (ed). most research on serious infections and sepsis has focused on the hospital environment, while potentially most delay, and therefore possibly the best opportunity to improve treatment, lies in the prehospital setting. methods: patients were included in this prospective observational study during a week period in . all patients aged years or older with a suspected or proven infection were included. prehospital, ed and outcomes were registered. results: in total, patients visited the ed during the study period, of whom ( . %) patients had a (suspected) infection. (fig. ) median duration of symptoms before ed visit was days (iqr - days), with . % of patients using antibiotics before arrival in the ed. most patients ( %) had been referred by a general practicioner (gp), while . % of patients had visited their gp previously during the current disease episode. twenty-two patients ( . %) experienced an adverse outcome (icu admission and/or -day all-cause mortality): these patients were less often referred by a general practicioner (gp) ( . vs. . %, p= . ) and were considered more urgent both by ems and in the ed. conclusions: the prehospital phase of patients with an infection provides a window of opportunity for improvement of care. patients become ill days before the ed visit and . % already visited their gp previously during the current disease episode, while . % is currently using antibiotics. future research should focus on quality improvement programs in the prehospital setting, targeting patients and/or primary care professionals. introduction: worldwide, the prevalence of tetanus has decreased.-however, even if progress has been made in the combat to eradicate tetanus it may be a cause of admission to intensive care.the objectives of our study are to determine epidemiological,clinical and prognostic characteristics for severe tetanus in our unit. methods: we conducted a retrospective study in the medical intensive care unit of ibn rushd hospital in casablanca in morocco from to .we studied the epidemiological,clinical and prognostic characteristics of the patients who were admitted for severe tetanus. results: the incidence of severe tetanus was . % affecting male in %. . % were aged between and years old. in . % there were a integumentary portal of entry. contractures were present in %of the cases. at intensive care unit admission, . % of the patients were sedated. the anti-tetanus vaccination was never updated. according to the dakar score . % of the patients were listed dakar , . % dakar and . % dakar . for the mollaret score, the crude form was found in . %, the acute generalized form was found in . % and the severe form in . % of the cases.mechanical ventilation was necessary in . %. diazepam and baclofen were used in . %, phenobarbital in . % and propofol in . %. a serotherapy was used for all the patients and a preliminary vaccination dose for . %. all the patients received antibiotics, penicillin g . % and metronidazole . %. the mortality was . %. the length of intensive care stay was significantly higher. the need for an intubation,its duration and the occurrence of autonomic dysfunction have significantly influenced the mortality. conclusions: to improve the prognosis in these serious forms of tetanus,it is highly important to identify the warning signs and refer patients in intensive care for early and appropriate management in intensive care. introduction: bloodstream infections (bsis) are associated with increased mortality in the icu. the aim of the study was to evaluate the epidemiology and resistance patterns during the period to . methods: bacteria and fungi isolated from the blood of patients hospitalized in a mixed icu during the study period were retrospectively analyzed. sensitivity testing was performed with disk diffusion (kirby-bauer) and microscan walkaway plus for minimal inhibitory concentrations. results: during the study period patients were hospitalized in the icu. bsis were diagnosed in cases ( . %). the isolated microorganisms were acinetobacter baumannii ( %), klebsiella pneumoniae ( %), other enterobacteriaceae ( %), pseudomonas aeruginosa ( %), stenotrophomonas maltophilia ( %), enterococci ( %), staphylococci ( %) and candida spp. ( %). of the a. baumannii isolates, % were resistant to carbapenems, . % to colistin, and % to tigecycline. of the k. pneumoniae isolates % were resistant to carbapenems, % to colistin, and . % to tigecycline. of the p. aeruginosa species % were resistant to carbapenems and they were all susceptible to colistin. the rate of resistance to vancomycin was % for the e. faecium isolates, . % for the e. faecalis, while the resistance to methicillin of the coagulase negative staphylococci was %. the most commonly isolate species of candida was c. albicans. conclusions: multi-drug resistant isolates, especially a. baumannii and enterobacteriaceae, are a serious problem in our icu. gram positive bacteria are less common, but the resistance of enterococci to vancomycin is significant. antibiotic stewardship and infection control measures should be applied in a more strict way. nosocomial sinusitis in intensive care unit patients i titov introduction: nosocomial sinusitis (ns) is a complication of critically ill patients which develops - h after admission and is mostly linked but not limited to such invasive procedures as nasotracheal intubation and nasogastric tube placement. ns is often overlooked as a source of pyrexia of unknown origin, meningeal manifestations, sepsis and ventilator associated pneumonia in icu patients. ct scanning and sinus puncture are used to confirm the inflammatory process and identify the pathogen behind it. methods: a retrospective case study of . icu patients for a period of - was performed. we have analysed data from the ct scans of paranasal sinuses and bacteriological findings of samples obtained from sinus puncture. results: ( . %) patients were suspected of ns on the - th day of stay in the icu. the ct scan confirmed pathological changes in patients ( . %). hemisinusitis was detected in patients ( . %) and pansinusitis in patients ( . %). there was also an isolated case of maxillary sinusitis in patient ( . %). the pathogenic culture was identified only in ( %) samples, . % of which revealed isolated bacteria and . % a polymicrobial association. gram positive bacteria were detected in . % of cases and gram negative in . %. most cases revealed multiple antibiotic resistance. conclusions: . ns has proved to be largely caused by gram negative bacteria and polymicrobial associations. the use of broad spectrum antibiotics in icu may justify the presence of sterile cultures. .early identification of risk patients in icu as well as the use of screening ct scan may benefit timely diagnosis and adequate treatment of patients. .preventive considerations include: patient's bed head elevation, the use of oral gastric tube in sedated and coma patients on ventilation, nasotracheal intubation only if indicated, removal of nasogastric tube at night, proper hygiene. conclusions: only of , tb patients ( %) required critical care intervention (table ) . those admitted to icu were older and more likely to have pulmonary, cns, miliary or abdominal tb (table ) . mortality was high despite critical care input in a unit familiar with managing tb, and hour access to infectious diseases advice within the trust, likely due to overwhelming organ dysfunction, patient frailty and advanced tb infection. rates of drug resistant tb were low and comparable to uk-wide rates over that period ( % mono-drug resistant, % mdr) thus less likely a contributory factor to the majority of deaths. short term antibiotics prevent early vap in patients treated with mild therapeutic hypothermia after cardiac arrest t daix , a cariou , f meziani , pf dequin , c guitton , n deye , g plantefève , jp quenot , a desachy , t kamel , s bedon-carte , jl diehl , n chudeau , e karam , f renon-carron , a hernandez padilla , p vignon , a le gouge introduction: patients treated with mild therapeutic hypothermia after cardiac arrests with shockable rhythm are at high risk of ventilator-associated pneumonia (vap) [ ] . despite retrospective trials suggesting a benefit of short-term ( h) antibiotics in this setting [ ] , it is not recommended. the primary objective was to demonstrate that systematic antibiotic prophylaxis can reduce incidence of early vap (< days). the impact on incidence of late vap and on day mortality was also assessed. methods: multicenter, placebo-controlled, double-blinded, randomized trial. icu patients > years, mechanically ventilated after out-of-hospital resuscitated cardiac arrest related to initial shockable rhythm and treated with mild therapeutic hypothermia were included. moribund patients and those requiring extracorporeal life supports, with ongoing antibiotic therapy, known chronic colonization with multiresistant bacteria or known allergy to beta-lactam antibiotics were excluded. either iv injection of amoxicillin-clavulanic acid ( g/ mg) or placebo was administered times a day for days. all pulmonary infections were recorded and blindly confirmed by an adjudication committee. results: in intention to treat analysis, patients were analyzed, (treatment group n= ; mean age . ± . years, sex ratio= , sofa score . ± . ). global characteristics of cardiac arrest were similar (no flow= . min vs . min, low-flow= . min vs . min). vap were confirmed incl. early vap, in treatment group vs in placebo group (hr= . ; ic %=[ . ; . ]) (fig. ) . occurrence of late vap ( % vs . %) and day mortality ( . % vs . %) was not affected by the study procedure. conclusions: short-term antibiotic prophylaxis significantly decreases incidence of early vap in patients treated with mild therapeutic hypothermia after out-of-hospital cardiac arrest related to shockable rhythm and should be recommended. introduction: antibiotics are the most commonly prescribed drugs in icu.in the era of antibiotic resistance it is difficult to choose antibiotics during septic episode.the choice antibiotics mainly depends on clinical diagnosis,culture sensitivity and local flora. whether severity of illness really maters is not well known. to study antibiotic prescription pattern and whether the choice of antibiotic varies according to hemodynamic stability in patients admitted in icu.to study of microbiological isolates and their variability according to hamodynamic stability in icu patients. methods: all icu patients of more than years age who received antibiotics and where cultures had been sent were included in the study.patients discharged against medical advice and where treatment had been withdrawn were excluded in this study. this prospective observational study was conducted between july to march .patients were divided into stable and unstable group according to hemodynamic parameter and usage of antibiotics and microbiological isolated were correlated. icu mortality and length of stay were correlated between hemodynamically stable and unstable group. results: sepsis episode were analysed. mean age was years, male predominant, and average apache iv score was (sd ). we had patients in unstable group of which % patients got discharged and % of patients got discharged in stable group. antibiotic combination therapy was used more in hemodynamically unstsble patients(p . ). blbli was used more in stable group. drug resistance in microbiological isolates did not reveal any statistically significant difference among stable or unstable group. conclusions: there is a tendency to administer combination antibiotics in sicker group of patients with hemodynamic instability. prevalence of microbial flora did not show any statistical difference. outcome is worse in hemodynamically unstable patients. the clinical significance of candida score in critically ill patients with candida infection h al-dorzi , r khan , t aldabbagh , a toledo , s al johani , a almutairi , s khalil , f siddiqui , y arabi king abdulaziz medical city, riyadh, saudi arabia, msd, riyadh, saudi arabia, king saud bin abdulaziz university for health sciences, riyadh, saudi arabia critical care , (suppl ):p introduction: candida score (cs) is used to identify patients with invasive candidiasis in the icu, but its clinical use has not become widespread. our objective was to evaluate the clinical significance of cs in a mixed population of icu patients. methods: this was a prospective observational study of critically ill patients who had candida species growth during their stay in any of six different icus of a tertiary-care center. two intensivists classified patients as having candida colonization or invasive candidiasis according to predefined criteria. cs was calculated for each patient on the day of candida species growth as follows: . see text for description point for parenteral nutrition + point for surgery + point for multifocal candida colonization + points for severe sepsis. the receiver operating characteristic (roc) curve was plotted to assess cs ability to discriminate between invasive candidiasis and candida colonization. results: cs was . ± . in patients with candida colonization (n= ) and . ± . in those with invasive candidiasis (n= ) (p< . ). however, only . % of invasive candidiasis cases had cs >= (compared with . % of candida colonization cases; p< . ). the roc curve (fig. ) showed that cs had fair ability to discriminate between invasive candidiasis and candida colonization (area under the curve . , % confidence interval . to . ; p< . ). in patients with invasive candidiasis, cs was similar in hospital survivors and nonsurvivors ( . ± . and . ± . , respectively; p= . ). cs did not discriminate between survivors and nonsurvivors (area under the roc curve . , % confidence interval . to . ; p< . ). conclusions: cs was higher in patients with invasive candidiasis than those with candida colonization. however, its ability to discriminate between these patients was only fair. cs was not associated with hospital mortality. poor reliability of creatinine clearance estimates in predicting fluconazole exposure in liver transplant patients m lugano, p cojutti, f pea asuiud, udine, italy critical care , (suppl ):p introduction: invasive candidiasis (ic) is a frequent complication in liver transplant (lt) recipients, especially during the first - months after lt. fluconazole is a triazole antifungal used for prophylaxis and treatment of ic. due to its renal elimination, dose adjustments are usually based on estimated creatinine clearance (ecrcl). however, the reliability of ecrcl in predicting fluconazole clearance has never been investigated in this population. the aim of this study was to conduct a population pharmacokinetic (poppk) analysis in a cohort of lt patients who underwent therapeutic drug monitoring (tdm) in order to find out which covariates may influence fluconazole pharmacokinetics (pks). methods: this retrospective study included lt patients who were admitted to the intensive care unit of our university hospital between december and may , and who were treated with intravenous fluconazole in the first months after lt. tdm of fluconazole was performed with the intent of attaining the efficacy pharmacodynamic target (auc h/mic > . ). the tested covariates were: age, gender, ckd-epi ecrcl, time from lt, serum albumin and transaminases, saps ii score. poppk was carried out with pmetrics software. results: nineteen patients (mean±sd age, weight and serum creatinine of ± . years, ± . kg, . ± . mg/dl, respectively) with a total of fluconazole trough plasma concentrations were included in the poppk analysis. mean±sd fluconazole distribution volume (vd) and clearance (cl) were . ± . l and . ± . l/h. age and time from lt were the only clinical covariates significantly correlated with fluconazole vd and cl, respectively. conversely, ckd-epi eclcr was unable to predict fluconazole cl. conclusions: ckd-epi eclcr is unreliable in predicting fluconazole exposure in lt recipients. consistently, in this population adaptation of fluconazole dose should be based on measured crcl, and tdm may be helpful in optimizing drug exposure. outcomes of a candidiasis screening protocol in a medical icu m boujelbèn , i fathallah , h kallel , d sakis , m tobich , s habacha , n ben salah , m bouchekoua , s trabelsi , s khaled , n kouraichi introduction: the aim is to determine the incidence, characteristics and risk factors of invasive candidiasis (ic) in critically ill patients by using a weekly screening protocol. methods: a months' prospective study was conducted in a -bed micu. the candidiasis screening consisted of the culture of plastic swabs (from different body sites), urine and respiratory tract samples.it was conducted upon admission and on weekly basis for all the patients. decision to treat was based on clinical and microbiological features. results: patients were included. the colonization rate with candida spp was . %(n= ). screening samples were collected with a positivity rate at . %(n= ). table describes the isolated candida species by site. antifungal resistance was tested in ( %) species. the resistance rate to fluconazole was . %(n= ). the antifungal resistance of candida albicans is detailed in table . ( . %) patients presented an ic with a mean age and mean saps ii at . ± years and ± . respectively. ( %) presented acute renal failure upon admission. . % (n= ) of the patients needed mechanical ventilation. the median length of stay was days [ . - . ] and the mortality rate was . %(n= ). the mean sofa score upon infection was . ± . . the candida score was >= . and the colonization index was >= . in fig. (abstract p ). roc curve for candida score discrimintaing between invasive candidiasis and candida colonization . %(n= ) and . %(n= ) of the patients respectively. only one patient had a positive blood culture. mannan antigen and anti-mannan antibodies were screened only in five patients with a positivity rate at %(n= ). the most isolated species was: candida albicans . %(n= ). multivariate analysis showed that prior use of imipinem more than days was a risk factor for ic (or= . , ci [ . ; . ], p= . ). conclusions: this study showed the ecology and epidemiology of candida species in our micu with an increased ic rate and high mortality. prior imipinem use was a risk factor for ic. introduction: icu-acquired infection is as high as . episodes per patient-days in lower-middle income countries like india (who). almost three times higher than in high-income countries [ ] . candida infection is the rd most commonly acquired nosocomial infection in india burdening the debilitated patient with longer icu stay [ ] . there are no definite guidelines on whether & when to start antifungal treatment, specific to india where ifi risk is high and diagnostic facilities are limited. currently, the intensivists across india are using antifungals, according to their clinical experience and selective application of international guidelines leading to non-uniformity of patient outcomes. in an endeavour to synchronize anti-fungal therapy and educate intensivists from small cities of india, intensivists and infectious disease specialist of international repute were approached to design a module on 'invasive fungal infections -when to start anti-fungals in icu [ fig. ]. the ifi in india was summarised into a compact hour session for dissemination of knowledge using idsa as a reference guideline. intensivists from across india were trained on the module by our faculty. the module was rolled out to intensivists and pulmonologists focussing particularly on the tier- & tier - cities where avenues for learning are limited [ fig. introduction: trichosporon species are fungi found in nature and human normal flora but they can be an opportunistic pathogen, introduction: this study assessed whether empiric combination antibiotic therapy directed against gram-negative bacteria is associated with lower intensive care unit (icu) mortality compared to single antibiotic therapy. methods: retrospective cohort study on prospectively collected data conducted in the icu of a tertiary care hospital in india between july to march . all consecutive infection episodes treated with empiric antibiotic therapy and with subsequent positive culture for gram-negative bacteria were included. primary and secondary outcomes were all cause icu mortality and icu length of stay (los). outcomes were compared between infection episodes treated with single vs.combination antibiotic therapy. results: of total episodes of gram-negative infections . % received combination-antibiotic therapy. baseline demographic and clinical characteristics between single vs. combination therapy groups were similar (mean age: p= . ; sex: p= . ; mean apache iv score: p= . ). overall icu mortality did not significantly differ between single and combination antibiotic groups ( . % vs. %; p= . ). in single antibiotic group, icu mortality was significantly higher for antibiotic-resistant compared to antibiotic-sensitive bacteria ( . % vs. . %, p= . ). in combination group, significantly lower icu mortality was noted if bacteria was sensitive to even one antibiotic compared to pan-resistant bacteria ( . % vs. . %, p= . ). icu los was similar between antibiotic-sensitive bacteria and antibiotic-resistant bacteria, both in single and combination therapy groups (single, antibiotic-sensitive vs. antibiotic-resistant: mean los±sd . ± . vs. . ± days; p= . ; combination, antibioticsensitive vs. antibiotic-resistant: . ± . vs. . days; p= . ). conclusions: irrespective of the number of antibiotics prescribed as empiric therapy, outcome of patients solely depends on the sensitivity pattern of the bacteria isolated. pharmacokinetics of trimethoprim and sulfametrole in critically ill patients on continuous haemofiltration r welte , j hotter , t gasperetti , r beyer , r introduction: the combination of trimethoprim and sulfametrole (tmp-smt, rokiprim®) is active against multi-drug resistant bacteria and pneumocystis jirovecii. in critically ill patients undergoing continuous veno-venous haemofiltration (cvvh), however, its use is limited because of lacking pharmacokinetic data. methods: pharmacokinetics of both drugs were determined after standard doses in patients on cvvh and in critically ill patients with approximately normal renal function. quantification of tmp and smt was done by high pressure liquid chromatography (hplc) and uv detection after pre-purification by solid phase extraction. the total clearance (cltot) was estimated from arterial plasma levels and the haemofilter clearance (clhf) from plasma and ultrafiltrate concentrations. results: six patients on cvvh ( after the first dose, at steady state) and nine patients off cvvh have been enrolled ( after first dose, at steady state). after a single dose, cltot of smt was . ( . - . , median [range]) and . ( . - . ) l/h on and off cvvh, respectively. at steady state, we observed a cltot of . ( . - . ) and . ( . - . ) l/h, respectively, on and off cvvh. steady state trough levels (cmin) of smt amounted to - mg/l in patients on cvvh and - in patients off cvvh. cltot of tmp was . ( . - . ) l/h on cvvh and . ( . - . ) l/h off cvvh after the first dose. at steady state, its cltot amounted to . ( . - . ) and . ( . - . ) l/h on and off cvvh, respectively. cmin was - mg/l on cvvh and - mg/l in patients off cvvh. clhf accounted for - % of cltot of smt and - % of cltot tmp. conclusions: exposure to both antimicrobial agents is highly variable, but comparable in patients on and off cvvh. as considerable amounts of smt and tmp are eliminated by cvvh, no excessive accumulation appears to take place during treatment with standard doses. the positive impact of meropenem stewardship intervention at a brazilian intensive care unit w freitas introduction: loss of colistin as a clinical option has profound public health implications. widespread use of colistin in agriculture and humans has seen the emergence of mcr- mediated resistance amongst south african patients [ ] . we sought to describe the trends of colistin minimum inhibitory concentrations (mic) over two years using data collected by smart. methods: smart monitors the in vitro susceptibility of clinical aerobic and facultative gram-negative bacterial isolates to selected antimicrobials of importance, enabling longitudinal analyses to determine changes over time. the dataset comprised bacterial isolates from four different south african private pathology laboratories and one public sector pathology laboratory from - . the methods used in the study have been described elsewhere [ ] . isolate proportions between years were compared using the chisquared test with yates' continuity correction. ( ) ( ) ( ) ( ) days]; patients underwent renal replacement therapy. the median treatment duration (iqr) was ( - ) days. in . % of cases, antibiotic-therapy therapy combination (phosphomycin and colistin) was chosen. all the patients experienced a clinical response by / hours from the ceftazidime/avibactam commencing. in / bacteraemic patients negativization of blood culture occurred by hours as well as of the rectal swab in / patients. a (b) recurred and a second treatment was given. / ( . %) patients survived, whereas death was caused by multi-organ failure. the susceptibility test of strains showed sensitivity to ceftazidime/avibactam, whereas % of resistance to carbapenems, quinolones and iii/iv generation cephalosporin, tigecycline and piperacillin/tazobactam; . % of susceptibility to fosfomycin and colistin; (v) less than % of suceptibility to aminoglicosides. conclusions: the strains of kp-cp were susceptible to ceftazidimeavibactam despite the high carbapenem-resistance recorded in our icu, because od rare identification of kp-cp vim/ndl +. the preliminary data seems to confirm the efficacy and clinical utility of this antibiotic for the critically ill patients. introduction: multidrug resistant bacteria (mdr) are an increasing problem on intensive care units. lung infections caused by acinetobacter baumannii are frequently difficult to treat. phages have regained attention as treatment option for bacterial infections due to their specificity and effectivity in lysis. the aim of this preclinical study was to determine efficacy and safety of a novel phage preparation in mice. methods: mice were transnasally infected with a mdr a. baumannii strain [ ] and hours later treated intratracheally with a specific phage or solvent. phage acibel [ ] was produced as suspension including efficient depletion of endotoxins. at defined time points, clinical parameters, bacterial burden in lung and bronchoalveolar lavage fluid (balf) and cell influx were determined. further, lung permeability and cytokine release were quantified and histopathological examination was performed. results: mice treated with phages recovered faster from infectionassociated hypothermia. hours after infection, phage treatment led to a reduction in bacterial loads in lungs and balf. in addition, lung permeability and cytokine production were reduced in phagetreated mice. histopathological examination of the lungs showed less spreading of bacteria to the periphery in phage-treated mice, whereas cellular recruitment into the lung was unaffected. no adverse effects were observed. conclusions: for the first time a highly purified phage against a. baumannii was successfully used in vivo. the current preclinical data support the concept of a phage-based therapy against pulmonary a. baumannii infections. introduction: vap is common in critically ill patients and associated with high morbidity and mortality, especially when caused by antibiotic resistant bacteria. recently, phage therapy has emerged as a promising non-antibiotic based treatment of antibiotic resistant bacterial infections. however, proof-of-concept experimental and clinical studies are missing before its wider use in clinical medicine. the goal of this experimental study was to compare the efficacy of phage therapy versus antibiotics for the treatment of mrsa in a rat model of vap. methods: four hours after intubation and protective ventilation, rats were inoculated via the endotracheal tube with - x cfu (ld ) of the mrsa clinical isolate aw . the animals were subsequently extubated. two hours after bacterial challenge, rats were randomised to receive intravenously either teicoplanin (n= ), a cocktail of lytic anti-s. aureus bacteriophages (n= ) or combination of both (n= ). animals served as control (no treatment). survival by hours was the primary outcome. secondary outcomes were bacterial count in lungs, spleen and blood. kaplan-meier estimates of survival were done and multiple comparisons of survival rates performed using the holm-sidak method. results: treatment with either phages, antibiotics or combination of both significantly increased survival ( %, %, % respectively, compared to % survival for controls, p< . ). there were no statistical differences in survival rates between either forms of treatment ( fig. ) . treatments hinder the systemic extension of the infection into the blood and spleen without impacting bacterial counts within the lungs, but the numbers are too small to perform statistical tests (table ) introduction: the aim of the study was comparative evaluation of the clinical and microbiological efficacy of combination of amikacin thru nebuliser aeroneb pro and standard antimicrobal therapy (amtcomb) with standard antimicrobal therapy (amtst) in treatment of ventilator-associated pneumonia (vap) and ventilator-associated tracheobronchitis (vat) caused by multi-drug resistant gram-negative bacteria. methods: in prospective two-center study with retrospective control included patients with vap and vat. in amtst group (retrospective, n= ) we used combination of meropenem g every h iv as continuous infusion, cefoperazon/sulbactam g every h iv as continuous infusion and amikacin g iv every h. in amtcomb group (prospective, n= ) we used combination of amtst and amikacin inhalation mg every h thru nebuliser aeroneb pro. results: in amtcomb clinical cure rate was %, while in amtst . % (p< . ), clinical pulmonary infection score (cpis) on day was ( - ) points in amtst and ( - ) points in amtcomb (p< . ). recurrence of vap/vat was . % in amtst and . % in amtcomb (p= . ). on day infectious agent titer in tracheal aspirate was ( - ) cfu/ml in amtst group, while (no growth- ) cfu/ml in amtcomb (p= . ). microbiological eradication observed in patients in amtcomb vs in patient in amtst and microbiological persistance observed in patients in amtcomb vs patients in amtst (p= . ). in amtcomb on rd day sputum was less purulent (p= . ). amikacin nebulisation didn't led to deterioration of organ dysfunction: on day there was no difference in platelet count, creatinine and bilirubin levels as compared to day (p= . ; p= . , p= . , respectively). conclusions: addition of amikacin inhalation mg every h thru aeroneb pro nebuliser in patients with vap and vat was more efficacious than intravenous standard antimicrobal treatment with comparable safety profile. introduction: the aim of the study was to assess the effectiveness of inhaled colistin (ic) as an adjunct to systemic antibiotics in the treatment of ventilator-associated pneumonia (vap). methods: icu patients with vap were enrolled in this observational study. resolution of vap was assessed as primary endpoint; eradication of pathogens in sputum, weaning time, duration of icu stay and mortality were assessed as secondary outcomes. patients were split into groups: gr. (n = ) -addition of ic to systemic antibiotics without changing the basic regimen; gr. (n = ) -change in systemic antibiotics according to sensitivity. groups were comparable. ic was administered in a dose of million iu tid (xselia pharmaceuticals aps, denmark). statistical analysis was performed using statistica . (m, σ, newman-keuls test; p < . ). results: vap resolution rate was % in gr. (vs. % in gr. , p = . ); eradication of pathogens from sputum by the th day. treatment was achieved in % of gr. and % in the gr. (n = ) (p> . ); in gr. weaning from ventilation was possible earlier than in gr. - . ± . days. in gr. vs. . ± . days. in gr. (p = . ); in gr. duration of icu stay was shorter than in gr. - . ± . days vs. . ± . days. in gr. (p = . ). no mortality differences were detected. conclusions: administration of inhaled colistin million iu tid is effective as an adjunct to systemic antibiotics in the treatment of vap. this modified treatment promotes a more rapid resolution of vap, earlier weaning from ventilator, reduction of the duration of icu stay, with no impact on mortality. the addition of ic to systemic antibiotics should be considered as second-line regimen in vap patients. factors associated with no de-escalation of empirical antimicrobial therapy in icu settings with high rate of multi-drug resistant bacteria c routsi introduction: de-escalation is recommended in the management of antimicrobial therapy in icu patients [ ] . however, this strategy has not been adequately evaluated in the presence of increased prevalence of multidrug-resistant (mdr) bacteria. the aim of this study was to identify factors associated with no de-escalation in icus with high rate of mdr bacteria [ ] . methods: prospective, multicenter study conducted in greek icus over a -year period. patients with laboratory confirmed infections were included. sofa score on admission, on septic episode and thereafter every h over days, infection site(s), culture results, antimicrobial therapy, and mortality were recorded. only the first septic episode was analyzed. in order to assess the factors associated with no de-escalation, a multivariate analysis was performed. results: a total of patients (admission sofa score ± ) were analyzed. % of those had septic episode on icu admission; % patients had an icu-acquired. de-escalation was applied to ( %) patients whereas it was not feasible in patients ( %) due to the recovery of mdr pathogens or it was not applied, although the microbiology results allowed it, in patients ( %). septic shock on the day of septic episode was present in % and % of patients with and without de-escalation, respectively, p= . ). compared to no de-escalation, de-escalation strategy was associated with a shorter duration of shock ( ± vs. ± days, p< . ) and all-cause mortality ( . % vs. . %, p< . ). multivariate analysis showed that the variables associated with no de-escalation were: a deteriorating clinical course as indicated by an increasing sofa score (or . , p< . ) and a lack of de-escalation possibility due to recovery of mdr pathogens (or . , p= . ). conclusions: deteriorating clinical course and mdr pathogens are independently associated with no de-escalation strategy in critically ill patients. conclusions: the qsofa scale in the prognosis of sepsis does not differ significantly from the sirs criteria, but in the prognosis of mortality is significantly better than sirs. qsofa significantly worse in the prognosis of sepsis and death than the sofa scale. the international task force of sepsis- introduced the quick sequential failure assessment (qsofa) score to supersede the systemic inflammatory response syndrome (sirs) score as the screen tool for sepsis. the objective of this study is to prospectively access the diagnostic value of qsofa and sirs among patients with infection in general wards. methods: a prospective cohort study conducted in ten general wards of a tertiary teaching hospital. for a half-year period, consecutive patients who were admitted with infection or developed infection during hospital stay were included. demographic data and all variables for qsofa, sirs and sofa scores were collected. we recorded daily qsofa, sirs and sofa scores until hospital discharge, death, or day , whichever occurred earlier. the primary outcome was sepsis at days. discrimination was assessed using the area under the receiver operating characteristic curve (auroc) and sensitivities or specificities with a conventional cutoff value of . results: of patients (median age, years [iqr, - ]; male, [ %]; most common diagnosis pneumonia, [ %]) who were identified with infection in general wards, ( %) developed sepsis at a median of (iqr, - ) day, patients ( %) and patients ( %) met qsofa and sirs criteria at a median of (iqr, - ) and (iqr, - ) day, respectively. the qsofa performed better than sirs in diagnosing sepsis, with an auroc of . ( % ci, . - . ) vs . ( % ci, . - . ). with a conventional cutoff value of , qsofa had lower sensitivity ( % [ % ci, %- %] vs. % [ % ci, %- %], p < . ) and higher specificity ( % [ % ci, %- %] vs. % [ % ci, %- %], p < . ) than sirs (table ) . conclusions: among patients with infection in general wards, the use of qsofa resulted in greater diagnostic accuracy for sepsis than sirs during hospitalization. qsofa and sirs scores can predict the occurrence of sepsis with high specificity and high sensitivity, respectively. prognostic accuracy of quick sequential organ failure assessment (qsofa) score for mortality: systematic review and meta-analysis introduction: the purpose of this study was to summarize the evidence assessing the qsofa [ ] , calculated in admission of the patient in emergency department (ed) or intensive care unit (icu), as a predictor of mortality. the hypothesis was that this tool had a good prediction performance. methods: systematic review and meta-analysis of studies assessing qsofa as prediction tool for mortality found on pubmed, ovid, embase, scopus and ebsco database from inception until november . the primary outcomes were mortality (icu mortality, inhospital mortality, and -day mortality). studies reporting sensitivity and specificity of the qsofa making it possible to create a x table were included. the diagnostic odds ratio (lndor) was summarized following the approach of dersimonian and laird using the software r ('mada' package). the summary roc curve was created using the reistma model (bivariate model). the revman software was used to organize the data. results: the search strategy yielded citations. of unique citations, met the inclusion criteria ( , patients). the sensitivity and specificity from each study are shown in fig. . the meta-analysis of the dor was . ( % confidence interval (ci): . - . ) and of the lndor was . ( % ic: . - . ) (fig. ) . the pooled area under the summary receiver operating characteristic (sroc) curve was . . the summary estimative of the sensitivity was . and the false positive rate was . , by bivariate diagnostic random-effects metaanalysis. the chi-square goodness of fit test rejects the assumption of homogeneity, and the fit of the model for heterogeneity was better (p-value = . ). conclusions: the qsofa has a poor performance to predict mortality in patients admitted to the ed or icu. introduction: sepsis and septic shock patients are the most common cause of death in intensive care units. [ ] the aim of this study is to quantify the relationship between hours sequential organ failure assessment (sofa) scores change and in-hospital mortality as a treatment outcome in sepsis and septic shock patients. introduction: an outreach team, akin to a rapid response team, is made up of healthcare professionals assembled together for quick and effective reviews in managing of rapidly deteriorating or gravely deteriorated patients [ ] . this study aimed to look at the variety of patient referrals in terms of their severity, patient dynamics, reasons for referral and their subsequent dispositions. methods: patient records were randomly reviewed retrospectively from july to october . data were collated in an excel spreadsheet for comparison and then sorted in accordance with the clinical questions and percentages calculated. results: from the referrals, the severity criteria was done by calculating the national early warning score (news). it was found that % patients had a score of - , % had a score of - , and % scored more or equal to . % of patients were in the age range - years old. % referrals came from the emergency department (ed) where a consultant was involved in the decision of the referral; of this, % were referred during office hours of am to pm where there was greater manpower to aid management. % referrals came from inpatients on the general wards; % were done during office hours. % of referrals were transferred to ic/hd upon review; % were not, from whom died and were later admitted after procedures ( %) or because they deteriorated further ( %). for reasons for referrals and disposition decisions, see fig. . conclusions: despite having no set criteria for outreach team referrals, the accuracy rate was nearly % admissions to ic/hd based on clinician concerns. there was only % re-admission rate having been re-reviewed when the patients had not been deemed suitable for ic/hd admission initially. therefore referrals were done accurately and safely with the protocol of clinician referral openness directly to ic consultants. introduction: prompt recognition of patient deterioration allows early initiation of medical intervention with reduction in morbidity and mortality. this digital era provides an opportunity to harness the power of machine learning algorithms to process and analyze big data, automatically acquired from the electronic medical records. the results can be implemented in real-time. intensix (netanya, israel) has developed a novel predictive model that detects early signs of patient deterioration and alerts physicians. in this study we prospectively validated the ability of the model to detect patient deterioration in real time. methods: the model was developed and validated using a retrospective cohort of consecutive patients admitted to the intensive care unit in the tel-aviv sourasky medical centera tertiary care facility in israel, between january and december . in this study, we tested model performance in real time, on a cohort of patients admitted to the same icu between june and august . significant events that lead to major interventions (e.g. intubation, initiation of treatment for sepsis or shock, etc.) were tagged upon medical case review by a senior intensivist, blinded to model alerts. these tags were then compared with model alerts. [ ] [ ] [ ] [ ] . reviews occurred despite 'low news' (fig. ) . rrt review led to cc admission in ( . %) cases; median [iqr] news [ ] [ ] [ ] [ ] [ ] [ ] . probability of admission increased with higher news (fig. ), however admissions had 'low news'. of these were excluded due to high news trigger in the preceding hrs or post-operative status. the remaining ( . %) represented genuine low news cases; age [ - ], % male, admission apache ii [ - ] and day sofa [ ] [ ] [ ] [ ] [ ] . admission source was emergency department %, medical %, surgical %. diagnoses are shown in table . no low news patients with sepsis were qsofa positive. cc length of stay was [ ] [ ] [ ] [ ] days and icu mortality was . %. conclusions: a high proportion of rrt activity occurs at low levels of abnormal physiology. despite an association between news and cc admission, news fails to trigger for approximately one in ten admitted cases. clinical concern remains an important component of the escalation of acutely ill patients. meanwhile, novel markers of deterioration should be sought and validated. introduction: although rapid response systems are known to reduce in-hospital cardiac arrest rate, their effect on mortality remains debated. the rapid response call (rrc) is a system designed to escalate care to a specialised team in response to the detection of patient deterioration. there are diurnal variations in hospital staffing levels that can influence the performance of rapid response systems and patient outcomes. the objective of this study was to examine the relationship between the time of rrc activations and patient outcome. methods: review of retrospectively collected, linked clinical and administrative datasets, at a private hospital during a -month period. all patients with medical emergency team activation were included. rapid response calls occurring between : - : were defined as 'out of hours'. results: between january and october there were rrc. the trigger for rrcs activation was nurse concern ( ; . %), modified early warning score ( ; . %) and cardiac arrest ( ; . %). rrcs were "out of hours" being the main activation trigger a modified warning score > . "out of hours" patients had higher icu admissions ( . % versus %) and were more likely to have an inhospital cardiopulmonary arrest (or= . , p< . ). conclusions: the diurnal timing of rrcs appears to have significant implications for patient outcomes. out of hours calls are associated to a poorer outcome. this finding has implications for staffing and resource allocation. and septic shock) and severe sepsis (incl. septic shock) using icd- codes coded as primary and secondary discharge diagnoses and procedural ops codes. we assessed incidences and discharge disposition incl. mortality. results: incidences, mortalities and discharge disposition comparing and and the mean annual increase in incidence rates are reported in tables and . conclusions: the annual increase in standardized sepsis incidence rates is greater than in infections, but similar to the increase in infectious disease patients with organ dysfunction, which are less prone to coding incentives than sepsis codes. an increasing number of patients is discharged to nursing homes and hospice. given the alarming increase in sepsis cases and deaths, this analysis confirms sepsis as a key priority for health care systems. introduction: patients with urgent admissions to the hospital on weekends may be subjected to a higher risk of worse outcomes, which may be due to differences in compliance to established processes. because delays to antibiotic administration is an important measure of sepsis protocol efficiency and has been associated to worse outcomes, we aimed to assess the association of the weekend effect (admissions on weekend) with timing to antibiotic administration. methods: patients included in the sepsis protocol in the emergency department (ed) of hospital sao rafael, from january to july were retrospectively evaluated. sepsis protocol is supposed to be activated to every patient with a suspected sepsis diagnosis in the ed. we evaluated the association of weekend (saturday or sunday) admission with timing to antibiotic administration. introduction: current sepsis guidelines emphasize resuscitation of hypotension to a mean arterial pressure (map) of at least mmhg [ ] . a map less than mmhg appears to be associated with poor outcomes in postoperative patients in the intensive care unit (icu) [ ] . however, extent of hypotension in critically ill septic patients during icu stay and its relationship with adverse outcomes is poorly defined. we determined the magnitude of hypotension in icu patients with a diagnosis of sepsis and its association with major complications. conclusions: reduced mortality may be supposed to be correlated to a quicker recovery of organ damage sepsis related. pcrts should be warranted in the future to corroborate these preliminary data. introduction: the pd- /pd-l immune checkpoint pathway is involved in sepsis-associated immunopathy. we assessed the safety of anti-pd-l (bms- , bristol-myers squibb) and its effect on immune biomarkers and exploratory clinical outcomes in participants with sepsis-associated immunopathy. methods: participants with sepsis/septic shock and absolute lymphocyte count <= cells/μ l received bms- i.v. ( - mg; n= ) or placebo (pbo; n= ) + standard of care and were followed for d. primary endpoints were death and adverse events (aes); secondary endpoints were monocyte (m)hla-dr levels and clinical outcomes. methods: this observational study was performed using a prospective, multi-center registry of septic shock. we compared the -day mortality between patients who were excluded from the new definition (defined as < mmol/l after volume resuscitation) and those who were not (lactate level >= mmol/l after volume resuscitation), from among a cohort of patients with refractory hypotension, and requiring the use of vasopressors. results: of patients with refractory hypotension, requiring the use of vasopressors, had elevated lactate levels, while did not have elevated lactate levels (neither initially nor after volume resuscitation), and ( . %) had elevated lactate levels initially, which normalized after fluid resuscitation (fig. ). thus, these patients were excluded by the new definition of septic shock. significantly lower -day mortality was observed in these patients than in those who had not been excluded ( . % vs . %, p= . ). conclusions: it seems reasonable for septic shock to be defined by the lactate levels after volume resuscitation, however due to small sample size further large scale study is needed. results: significant downregulation (p< . ) of about pro-and anti-inflammatory cytokines, including il- , ip- , tnf-a, mip- a, mip- ß, il- , was documented. ifn-g effect on macrophages and dendritic cells was inhibited at the level of phosphorylated stat . ifn-ginduced expression of cxcl and cxcl in macrophages was reduced. patients treated in vivo with higher dosages of apoptotic cells had lower cytokine/chemokine levels compared to those treated with lower levels, and in inverse correlation to agvhd staging. in vitro binding of apoptotic cells to lps was documented. conclusions: the cytokine storm is significantly modified towards homeostasis following apoptotic cell treatment. the mechanism is multifactorial and was shown to include tam receptor triggering, nfkb inhibition, and lps binding. these results together with previous studies showing significantly higher murine survival in sepsis models of lps and cecal ligation puncture suggest that apoptotic cells may be used to treat patients with sepsis. a multicenter clinical trial in septic patients is planned in . moreover, the urine output significantly increased in survival group. conclusions: the present study suggests that cytokine-oriented critical care using pmma-chdf might be effective the treatment of sepsis and ards, particularly,in the treatment of ards associated with aspiration pneumonia in elderly patients. the polymyxin b immobilized fiber column direct hemoperfusion has an effect for septic shock but has no effect on sepsis: a cohort study and propensity-matched analysis k hoshino introduction: overwhelming cytokine release often referred to as "cytokine storm" is a common feature of septic shock, resulting in multiple organ dysfunction and early death. attenuating this cytokine storm early by eliminating cytokines may have some pathophysiological rationale. our aim was to investigate the effects of extracorporeal cytokine removal (cytosorb) therapy on organ dysfunction and inflammatory response within the first hours from the onset of septic shock. methods: patients with: sepsis of medical origin, on mechanical ventilation, noradrenaline > mg/min, procalcitonin > ng/ml and no need for renal replacement therapy, were randomized into cytosorb and control groups. cytosorb therapy lasted for hours. in addition to detailed clinical data collection, blood samples were taken to determine il- , il- ra, il- , il- , il- , tnf-α, pct, crp levels. introduction: blind pericardiocentesis leading to low success rate and high complication rates such as ventricular wall or oesophageal perforations, pneumothorax or upper abdominal organ injury.real time needle visualisation is allowing us to avoid this major complication [ ] . methods: we presented cases of acute traumatic cardiac tamponade secondary to severe chest injury. both patients presented with haemodynamic instability and echocardiographic features of pericardial tamponade. pericardiocentesis under ultrasound guidance at left parasternal area with needle directed from medial to lateral technique were performed (fig. ) . real time needle tip visualisation done throughout the procedure (fig. a) . needle placement in pericardial space was confirmed with agitated saline and guidewire visualisation (fig. b) . pigtail catheter was inserted and blood was aspirated until the patient were haemodynamically improved. repeated ultrasound was done to confirm the absence of ultrasonographic features of tamponade and complications. results: we demonstrated a successful real time needle visualisation ultrasound guided pericardiocentesis in cases acute traumatic pericardial tamponade. procedural time (time from needle piercing the skin to time needle entering the pericardium) in both cases were less than minute. post procedural ultrasound confirmed no major complications. conclusions: the real time needle visualisation using ultrasound was important to reduce major complications during pericardiocentesis. the safety of the highly invasive procedure can be improved with real time needle visualisation. osman a et al. eur j emerg med (in press), introduction: diagnosis of cardiac tamponade post continuous-flow left ventricle assist devices (cf-lvads) is challenging due to missing pulsatility. recent case study of sublingually microcirculation with incident dark-field imaging (idf) provide a new improved imaging for clinical assessment of cardiac tamponade in a patient with cf-lvad. we sought to examine the changes in microvascular flow index (mfi) as a sign of cardiac tamponade following lvad implantation. methods: off-site quantitative analysis of sublingual microcirculation clips with automated vascular analyses software (ava; microvision medical©), and the velocity distributions followed during admission till discharge in patients with end-stage heart failure treated with cf-lvad complicated by cardiac tamponade. results: eleven out of thirty lvad implantations, males, mean age ± years, april to january , (( heart mate (hm ) and heartmate ii (hm ii) (thoratec corp., ca)), were complicated by rethoracotomy due to early postoperative cardiac tamponade within week. there sublingual microcirculation was examined by a novel incident dark-field imaging (idf) before and daily post-lvad implantation. pre-lvad microcirculation was typical for heart failure, characterized by slowly, sludging movement of red blood cells (rbcs), (fig. a arrows) . directly after implantation, a normal microcirculatory flow was seen with a high rbcs velocity (fig. b) . on the day of tamponade the patients were stable except for severe failure of microcirculation as reflected by drop in mfi (fig. c ) and congestion in venules (* in fig. c ). in out of patients there was a significant drop in mfi before tamponade was clinically recognized (p< . ). shortly after rethoracotomy a quick restoration of microcirculatory flow has been found. conclusions: sublingual microcirculation imaging is a simple and sensitive non-invasive tool in early detection of cardiac tamponade. survey on the use of cardiovascular drugs in shock (ucards) - results: a total of physicians responded. as detailed in table , the respondents think that dobutamine is first-line inotrope to increase cardiac pump function (n= , %) and should be started when signs of hypoperfusion or hyperlactatemia despite adequate use of fluids and vasopressors in the context of low left ventricular ejection fraction are present (n= , %). the most accepted target was an adequate cardiac output (n= , %). the combination of noradrenaline and dobutamine was preferred to single treatment with adrenaline mainly due to possibility to titrate individually (n= , %). the main reason for adding another inotrope was to use synergistic effects of two different mechanisms of action (n= , %). according to respondents, phosphodiesterase-inhibitors should be used in the treatment of predominant right heart failure because of prominent vasodilatory effect on the pulmonary circulation (n= , %). they also believe levosimendan is the only inotrope that does not increase myocardial oxygen demand (n= , %). vasodilators are used in cardiogenic shock to decrease left ventricular afterload (n= , %). there is no experience or no opinion about the use of ß-blockers in shock states (n= , %). conclusions: this web-based survey provided latest trends on inotrope use in shock states which showed considerable diversity among respondents in opinions about its use. introduction: recent literature data clearly indicated that in patients with shock the resuscitation of macro-circulation often does not match with microcirculation and tissue perfusion improvement. unfortunately, the bed-side assessment of regional perfusion remains difficult, particulary in critically ill patients. in the last years thermography has been used in different medical fields but no studies have been performed on the use of this technique in critically ill patients. the aim of this study was to evaluate whether thermography is feasible and may provide useful data during resuscitation of patients with septic shock. methods: in patients with septic shock we collected central systemic temperature and infrared images (flir-t digital camera) of limbs at , , and hours after shock occurrence. thermal pattern distribution of the limbs was obtained by a specific analysis of the images (thermacam™researcher p). a systemic to peripheral temperature gradient called "Δ systemic-limb temperature" was calculated for each single temperature data collected. results: macrocirculatory and perfusion parameters improved in all the patients throughout the study period: mean values of noradrenaline dose decreased from . to . γ/kg/min, mean map increased from to mmhg and mean blood lactate decreased from . to . mmol/l. the "Δ systemic-limb temperature" pattern showed an heterogenous time course in the patients with a mean overall increase at and hours (fig. ) . conclusions: as expected, the regional data obtained by thermography did not match with macrocirculatory and systemic perfusion parameters. the significance and the relationship between treatments and data observed will be investigated by appropriate studies. regional differences in the treatment of refractory septic shockan analysis of the athos- data introduction: vasodilatory shock is a common syndrome with high mortality. despite established care protocols, regional differences in treatment remain. we sought to characterize these differences using data from the recently published athos- study [ ] . methods: individual patient data were analyzed at baseline and at h for regional differences in demographics, clinical characteristics, and treatment patterns, and grouped according to four geographical areas: the united states (us), canada (ca), europe (eu) and australasia (au). p-values were calculated by kruskal-wallis tests for continuous data and chi-square tests for categorical data. subsequent temporal analysis compared changes in the treatment of shock, indexed by changes in patient acuity level. results: regional differences existed with respect to bmi (p= . ), albumin (p< . ), cvp (p= . ), meld score (p= . ), apache ii score (p= . ) and sofa score (p= . ). baseline norepinephrine (ne) and ne equivalent doses were significantly higher in eu (p< . and p= . , respectively), and utilization of vasopressin was correspondingly lower (p< . ). at baseline, stress dose steroids were utilized to a greater extent in the us and ca (p= . ). temporal analysis revealed differences in the utilization of vasopressin and steroids with changes in patient acuity: in eu, increasing acuity was associated with a lower utilization of vasopressin, and in ca, increased acuity was associated with a lower utilization of steroids. steroid utilization was higher with increased level of acuity in au and the us. conclusions: significant differences in the treatment of vasodilitory shock exist globally, with important implications: (a) there are introduction: levosimendan is a calcium sensitizer and katp-channel opener exerting sustained hemodynamic and symptomatic effects. in the past fifteen years, levosimendan has been used in clinical practice also to stabilize at-risk patients undergoing cardiac surgery. recently, the three randomized, placebo-controlled, multicenter studies licorn [ ] , cheetah [ ] and levo-cts [ ] have been testing the peri-operative use of levosimendan in patients with compromised cardiac ventricular function. over smaller trials conducted in the past [ ] suggested beneficial outcomes with levosimendan in peri-operative settings. in contrast, the latest three studies were neutral or inconclusive. we aim to understand the reasons for such dissimilarity. methods: we re-analyzed the results of the latest trials in the light of the previous literature to find sub-settings in which levosimendan can be demonstrated harmful or beneficious. results: none of the three latest studies raised any safety concern, which is consistent with the findings of the previous smaller studies. in levo-cts, mortality was significantly lower in the levosimendan arm than in the placebo arm in the subgroup of isolated cabg patients ( fig. ) [ ] . the trend towards both hemodynamic and long term mortality benefits is maintained in recent meta-analyses [ , ] including the three larger recent studies. conclusions: despite the fact that the null hypothesis could not be ruled out in the recent trials, we conclude that levosimendan can still results: patients were included in levosimendan group and in control group. in the whole population, weaning failure incidence and mortality was comparable between the groups (respectively % vs %, pr , and % vs %, pr= , ). higher assistance duration, longer stay under mechanical ventilation and longer duration of stay in critical care unit were observed in levosimendan group. in the post-cardiotomy sub-group (table ) , weaning failure was lower in levosimendan group ( % vs %, pr , ) and levosimendan was an independent protective factor from weaning failure (or , , pr , ). positive impact of levosimendan may be explained in part by his calcium sensitizer effect and by facilitating recovery of myocardial calcium homeostasis in postcardiotomy cardiac stunning. conclusions: levosimendan failed to reduce the incidence of ecmo weaning failure, except for post-cardiotomy population. renal outcomes of vasopressin and its analogues in distributive shock: a systematic review and meta-analysis of randomized trials introduction: venous return (vr) is driven by the difference between mean systemic filling pressure (msfp) and right atrial pressure (rap) and determines the maximum ecmo flow. msfp depends on stressed volume and vascular compliance. it can be modified by absolute blood volume changes and shifts between stressed and unstressed volume. norepinephrine (ne) may increase stressed volume by constriction of venous capacitance and at the same time increase the resistance to systemic flow. we therefore studied the effects of ne on msfp, maximum ecmo flow and the ecmo pressure head (map-rap). methods: msfp was measured with blood volume at euvolemia and ne to ( . , . and . μg/kg/h) in a closed-chest porcine va-ecmo model (n= , central cannulation with left atrial vent and avshunt) in ventricular fibrillation. the responses of rap and vr (measured as ecmo flow, qecmo) were studied at variable pump speeds including maximum possible speed without clinically apparent vessel collapse at constant airway pressure. results: the ecmo pump speed and qecmo showed a strictly linear relationship (r . to . , range over all conditions) despite increased pressure head, indicating that the maximum qecmo was determined by vr alone. ne led to both increases in msfp and qecmo in a dose dependent way, indicating a rightward shift in the vr plot ( fig. ) via recruitment of stressed from unstressed volume ( table , fig. ). this resulted in an increased msfp during ne despite decreased absolute blood volume ( . ± . l vs. . ± . l, p= . ). the reduced blood volume was associated with hemoconcentration suggesting plasma leakage. conclusions: ne shifts the vr curve to the right, allowing a higher maximum ecmo flow. the ne induced increase in msfp results from recruitment of unstressed volume to stressed volume, which may be modified by changes in vascular compliance. the effects on pump afterload were not limiting. introduction: to locate vessels for percutaneous central venous catheterizations, it may be helpful to apply not only real-time ultrasound (us) guidance but also us-assistance vein prelocation. the aim of this study was to evaluate the superiority of two us methods compared to surface landmark methods by reviewing randomized control trials (rcts). methods: as updating an earlier systematic review [ ] , we searched pubmed and central in november . we included rcts which compared the failure rates of internal jugular or femoral venous cannulations among ) real-time us guidance, ) us-assistance vein prelocation and ) surface landmark methods. a frequentist network meta-analysis was conducted using the netmeta package on r. results: out of citations, rcts ( patients) were eligible. the number of studies comparing outcomes between real-time us guidance vs. surface landmark methods, us-assistance vein prelocation vs surface landmark methods and real-time us guidance vs us-assistance vein prelocation was , and . regarding cannulation failure rate, network meta-analysis in a fix-effect model showed that a p-score was lower in the real-time us guidance than us-assistance vein prelocation ( . vs. . ), by reference to surface landmark methods, and also regarding arterial punctures, a p-score was lower in the real-time us guidance than us-assistance vein prelocation ( . vs. . ). conclusions: based on the present network meta-analysis of rcts, pscores of cannulation failure and arterial puncture were lower in the real-time us guidance, suggesting that the us-assistance vein prelocation is superior than the real-time us guidance, both of which achieve lower rates of failure and arterial puncture compared to the landmark methods. we speculates that the inferiority of real-time guidance is associated with difficulties in manipulating the needle together with an echo probe in targeting relatively smaller veins in children. introduction: we present a case report of 'shoshin beriberi' in a young female who was 'fussy with food' that developed an acutely progressive metabolic acidosis and multi-organ failure requiring intensive care support. methods: our patient was a -year-old british woman who presented to the emergency department (ed) with a ten-day history of diarrhea, vomiting and increasing fatigue. she had a past medical history of gastroparesis, polycystic ovary syndrome (on metformin), laparoscopic cholecystectomy and hysteropexy. she lived with her husband and two children who had viral gastroenteritis two weeks previously. results: the patient had a metabolic acidosis (ph . ) with raised lactate (> ) on initial blood gas in the ed. a . % sodium bicarbonate infusion and hemofiltration were commenced overnight. the patient's ph and lactate remained static with an increasing work of breathing over this period. by morning she developed flash pulmonary oedema and hypotension, the first signs of acute cardiac failure. an echocardiogram displayed severely impaired left ventricular function with ejection fraction of %. the patient was intubated and inotropic support was commenced. it was thought that a micronutrient deficiency may have caused a rapid onset cardiac failure. pabrinex (containing ml of thiamine hydrochloride) was commenced and within hours the patient's metabolic acidosis markedly improved ( fig. ). complete reversal of the cardiac failure occurred over hours. conclusions: shoshin is a rare clinical manifestation of thiamine deficiency [ ] . it is an important differential diagnosis to bear in mind after excluding more common aetiologies of heart failure. especially in this case as our patient had no obvious risk factors at the time of presentation. we suggest empiric use of thiamine should be considered in treatment algorithms for young patients presenting with acute cardiac failure. the pateint had provided informed consent for publication. introduction: takotsubo syndrome (ts) is known to be an acute transient cardiac condition accompanied with acute heart failure. ts is often triggered by critical illness but that has been rarely studied in icu practice.therefore, it is known, that the use of catecholamines can directly induce ts, worsen lvot obstruction, and delay spontaneous recovery in ts patients, it is nearly impossible to avoid their administration in critically ill [ ] . methods: we have analyzed medical records from patients with ts, that were revealed during year in our hospital. ts was defined due to mayo criteria, including transient regional wall motion abnormalities, mildly elevated troponin level and no signs of obstructive cad on coronary angiography. results: out of patients who developed ts in icu or iccu, hemodynamic instability occurred in acute phase of ts in ( %) cases. ( %) of patients were admitted to icu in due to septic shock ( patients), major bleeding ( ), cerebral mass lesion ( ) and ards ( ) and required treatment with catecholamines. general mortality rate in ts patients was ( %), and ( %) in critically ill ts patients. mean duration of noradrenalin infusion was , days, dobutamine infusion , days. patients with ts needed more icu resources and longer icu-stay. mortality rate was higher in ts patients ( %) vs the icu-population ( %), p = . . conclusions: ts seems to be an often cause of lv dysfunction and acute heart failure in critically ill. it seems that ts could be a predictor of worse prognosis in critically ill patients. although catecholamine administration may worsen the patient prognosis and induce further ahf in critically ill patients it rearely can be avoided. introduction: previous studies on readmission following lvad implantation have focused on hospital readmission after dismissal from the index hospitalization. since there are very little data existing, the purpose of this study was to examine intensive care unit (icu) readmission in patients during their initial hospitalization for lvad implantation to determine reasons for, factors associated with, and mortality following icu readmission. methods: this was a retrospective, single center, cohort study in an academic tertiary referral center. all patients at our institution undergoing first time lvad implantation from february to march were included. patients dismissed from the icu who then required icu readmission prior to hospital dismissal were compared to those not requiring icu readmission prior to hospital dismissal. results: among lvad patients, ( . %) required icu readmission. the most common reasons for admission were bleeding and respiratory failure (fig. ) . factors found to be significantly associated with icu readmission were preoperative hemoglobin level of less than g/dl, preoperative estimated glomerular filtration rate < ml/min/ . m , preoperative atrial fibrillation, preoperative dialysis, longer cardiopulmonary bypass times, and higher intraoperative allogeneic blood transfusion requirements. mortality at year was . % in patients requiring icu readmission vs. . % in those not requiring icu readmission (age-adjusted or= . , % ci . to . , p= . ). conclusions: icu readmission following lvad implantation occurred relatively frequently and was associated with significant one-year mortality. these data can be used to identify lvad patients at risk for icu readmission and implement practice changes to mitigate icu readmission. future larger and prospective studies are warranted. atrial fibrillation and infection among acute patients in the emergency department: a multicentre cohort study of prevalence and prognosis t graversgaard odense university hospital, odense, denmark critical care , (suppl ):p introduction: patients with infection presenting with atrial fibrillation (af) are frequent in emergency departments (ed). this combination is probably related to a poor prognosis compared to lone af or infection, but existing data are scarce. aim: to describe the prevalence and prognosis for af and infection individually and concomitantly in an ed setting. introduction: its afterload reducing effects make peep the treatment of choice for cardiogenic pulmonary edema. studies indicate that peep may lower coronary blood flow. its effects on left ventricular contractility is unclear. most of the surrogate measures for cardiac contractility are dependent on afterload and contractility assessment under peep may therefore be biased. we have investigated cardiac contractility under peep with the endsystolic pressure volume relationship (espvr) as a load-independent measure of contractility. methods: patients scheduled for coronary angiography were ventilated with cpap and a full face mask at three levels of peep ( , and cmh o) in random order. structural cardiac pathologies were excluded with echocardiography. at every peep level, left ventricular pressure volume loops (millar conductance catheter with inca system, leycom, netherlands) were obtained. the endsystolic elastance was derived from a pv-loop family under preload reduction with an amplatzer sizing balloon in the inferior caval vein. all participants gave written informed consent. the study was approved by the bernese ethics committee. results: women and men with an age ± years were studied. ejection fraction was ± % at baseline. mean espvr at peep levels of , and were . ± . , . ± . and . ± . mmhg/ml (p = . , repeated measurements anova). dp/dt and ejection fraction did not differ between the peep levels (p= . and . ). conclusions: moderate levels of peep did not influence endsystolic elastance. higher peep and patients in cardiogenic shock should be investigated. introduction: we sought to assess the feasibility of d volumetric analysis with transthoracic echocardiography in critically ill patients. we choose a cohort typical of icu where accurate volumetric analysis is important: hypoxic, mechanically ventilated patients. d analysis is enticing in simplicity and wealth of data available. it is accurate in cardiology patients [ ] but has not been assessed in the icu. methods: patients were imaged within hours of admission. inclusion criteria: adult, hypoxic (p:f < ), mechanically ventilated, doppler stroke volume (sv) assessment possible. echocardiography: seimens sc real-time volumetric analysis with standard b-mode and doppler assessment. images unacceptable if > segments unable to be seen in volumetric planes. d left ventricle (lv) and right ventricle (rv) analysis with tomtec imaging and seimens acuson respectively and compared to doppler derived sv. % limit of agreement considered clinically acceptable [ ] . imaging was optimised for volumetric analysis ( - vols/sec). results: patients, in sinus, in af. no significant difference seen between doppler vs d simpson's biplane, d lv or d rv sv estimation. feasibility, sv values and bias are reported in table and fig. . limit of agreement for corrected doppler vs lv d sv = - % to %; rv d sv = - . % to . %. conclusions: d lv and rv volumetric analysis is feasible in majority of patients requiring mechanical ventilation, however lacks agreement with doppler derived stroke volume assessment. although images may appear sufficient, the semi-automated software appears to underestimate stroke volume. further larger studies using thermodilution are warranted. introduction: body position changes such as leg raising are used to determine fluid responsiveness. we hypothesized that the trendelenburg position increases resistance to venous return. together with abolishment of the hepatic vascular waterfall, this may limit the increase in regional blood flow. methods: inferior vena cava (ivc), portal vein (pv), hepatic, superior mesenteric (sma) and carotid artery blood flows and arterial, right atrial (ra) and hepatic (hv) and portal venous blood pressures were measured in anesthetized and mechanically ventilated pigs in supine and °trendelenburg positions. all hemodynamic parameters were measured during end-expiration at cmh o peep, and at inspiratory hold with increasing airway pressures (awp) of , , and cmh o, respectively. paired t test was used to compare pressures and flows in different positions during end-expiration. repeated measures anova was performed to evaluate the effects of awp on hemodynamic parameters. results: trendelenburg position significantly increased ra, hv and pv blood pressures at end-expiration, while qpv and qsma remained unchanged, qha increased and qivc showed a trend to decrease (table ). in both positions, all blood flows decreased with increasing awp, and the difference between ppv and qsma became smaller, indicating splanchnic blood pooling ( table ). in the trendelenburg position, splanchnic blood pooling was less severe compared to supine position. conclusions: trendelenburg position tended to decrease venous return from inferior vena cava. further increases in rap by augmenting awp led to a decrease in all flows and signs of abolished hepatic vascular waterfall. passive manoeuvers to assess fluid responsiveness evoke complex hemodynamic reactions which are not fully understood. introduction: despite of preventive measures, the incidence of deep venous thrombosis (dvt) in icu patients is estimated to range from - %. while clinical diagnostics is unreliable, ultrasound compression test (uct) has proven to be a highly sensitive and specific modality for the recognition of lower extremity dvt [ ] . delegating this competence to icu nurses can increase uct availability and enable preventive dvt screening. therefore, we decided to conduct a clinical study to evaluate the sensitivity and specificity of uct performed by general icu nurse in icu patients compared to an investigation by icu physician certified in ultrasound. methods: prior to the study, each nurse participating in the study completed one-hour training in uct and examined patients under supervision. then, icu patients without known dvt underwent uct in the femoral and popliteal region of both lower extremities performed by trained general icu nurse. on the same day, the examination was repeated by an icu physician. the results of the examinations of each patient were blinded to each other for both investigators until both tests were performed. in case of a positive test, the nurse immediately reported the result to the icu physician. the sensitivity and specificity of the test performed by general nurse was calculated in comparison with the examination by a specialist. results: a total of patients were examined. both lower extremities were examined in all patients. the prevalence of dvt of , % has been found. the overall sensitivity of the examination performed by general nurse was . %, the specificity % with negative predictive value of . %, positive predictive value of % and accuracy of . %. the results of our study have shown that general icu nurses are able to perform bedside screening of dvt by compression ultrasound test with a high degree of reliability after a brief training. methods: a cytosorb® (cytosorbents, new jersey, usa) ha device was inserted within the cpb circuit in ten patients undergoing elective cardiac surgery. one hour after cpb onset, the activity of coagulation factors (antithrombin (at), von willebrand factor (vwf), factors ii, v, viii, ix, xi, and xii) were measured before and after the device. pre and post device measurements were compared using student ttest, a p value < . was considered statistically significant. results: patients' mean age was . ± . years, % were female, the mean euroscore ii was . ± . . procedures were: coronary artery bypass graft (cabg) ( / ), aortic root replacement ( / ) and cabg combined with aortic valve replacement ( / ). mean cpb duration was . ± . min. pre and post ha measurements of coagulation factors activity are presented in fig. . post-device at and fii activity was significantly lower (respectively from . to . , p= . and from . to . , p= . ) compared to predevice measurement. there was no statistically significant difference between pre-and post-ha measurements for all other coagulation parameters conclusions: pre and post ha cytosorb® measurements for coagulation factor activity were not different except for a small decrease in at and fii activity. this might be related with intra-device consumption or adsorption. further analyses accounting for cpb fluid balance, the entire study population and timepoints are pending. introduction: the aim of this study is to evaluate changes in hemodynamics and microvascular perfusion during extracorporeal blood purification with cytosorb in patients with septic shock requiring renal replacement therapy. methods: eight adult patients with septic shock requiring continuous renal replacement therapy for acute renal failure were enrolled and underwent a -hour treatment with the emodasorption cartridge cytosorb. measurements were taken at baseline before starting cytosorb, after h (t ) and h (t ) and included: blood gases, macrohemodynamic parameters (picco ), vasopressor and inotropic dose, plasma levels of cytokines (interleukin [il]- , il , il , il , tumor necrosis factor alpha) and parameters of microvascular density and perfusion (sublingual sidestream dark field videomicroscopy). procalcitonin was measured at baseline and after h of treatment. results: a non-significant decrease in plasma levels of cytokines was observed over time. hemodynamic parameters and vasopressor requirement remained stable. the microvascular flow index increased significantly at t , total vessel density and perfused vessel density increased at t and t ( introduction: objective renal replacement therapy (rrt) with the oxiris filter is used in sepsis septic shock with aki, but few clinical studies compare the adsorbing effect of oxiris filter on the inflammatory mediators to rrt. the aim of this study is -to confirm whether oxiris decreases cytokines and procalcitonin in sepsis septic shock. -this effect is superior to rrt. -this translates in a better cardio renal response. methods: a coohort study and a propensity-matched analysis included patients admitted to three intensive care (aurelia hospital, european hospital, tor vergata -rome) with a diagnosis of septic shock. patients were submitted to rrt with oxiris filter and patients to rrt.il , procalcitonin, the cardiorenal indices and sofa score were compared before (t ) and at the end of the treatments (t ). all data are expressed as mean±sd. anova one way was used to compare the changes of the variables in the time. p< . was considered statistically significant. results: of patients submitted to rrt with the oxiris filter could be matched to septic patients who received rrt. il and procalcitonin decreased in the oxiris group (p< . ) but not in the rrt group.-map increased (p< . ) and noradrenaline dosage decreased in oxiris group (p< . ), but non in rrt group. also pao /fio ratio, diuresis, sofa improved only in the in the oxiris group (p< . ). conclusions: in sepsis/septic shock patients with aki, il and procalcitonin decrease more in the oxirs group then in the rrt group.this is associated with an improvement of the cardio -renal function and the clinical condition.the study confirms that rrt with oxiris filter may be useful in sepsis/septic shock when other convective/diffusive techinques fail. introduction: advos (hepa wash gmbh, munich, germany) is a recently developed ce-certified albumin-based hemodialysis procedure for the treatment of critically ill patients. in addition to the removal of water-soluble and albumin-bound substances, acid-base imbalances can be corrected thanks to an automatically regulated dialysate ph ranging . to . . methods: patients treated with the advos procedure between in the department of intensive care medicine of the university medical center hamburg-eppendorf were retrospectively analyzed. overall treatments in critically ill patients (mean sofa score ) were evaluated. additionally, subgroup analysis for hyperbilirubinemia, respiratory acidosis and non-respiratory acidosis were conducted. results: severe hyperbilirubinemia (> mg/dl) was present in treatments, while and treatments were performed to treat respiratory (paco > mmhg) and non-respiratory (paco < mmhg) acidosis (ph< . ), respectively. mean treatment duration was h. advos procedure was able to correct acidosis and reduce bilirubin, bun and creatinine levels significantly. the subgroup analysis shows an average bilirubin reduction of % per advos multi treatment in the hyperbilirubinemia group ( . mg/dl vs . mg/dl, p< . ). moreover, ph ( . vs. . , p< . ) and paco ( . vs. . mmhg, p< . ) were corrected in the respiratory acidosis group, while in the non-respiratory acidosis group, an improvement in ph ( . vs. . , p< . ), hco ( . vs. . , p= . ) and base excess (- . vs. - . , p= . ) could be observed. there were no treatment-related adverse events during therapy. conclusions: advos is a safe and effective hemodialysis procedure, which is able to remove water soluble and protein bound markers and correct severe acidosis in critically ill patients. score for timely prescribing (stop) renal replacement therapy in intensive care unit -preliminary study of a mneumonic approach introduction: the moment of initiation of renal replacement therapy (rrt) in critically ill patients and a reason for debate, without having objective criteria that indicate it. the objective of this study was to propose a score to help identify the ideal time for the initiation of rrt, and if there is correlation between this score and intensive care unit length of stay and mortality. methods: patients admitted to the intensive care unit, > -yearsold, to whom rrt were indicated by the intensivist. the study protocol was approved by the hospital das forças armadas ethical committe, and written informed consent was obtained from all patients. the stop was assigned according to the presence or not of each of the items (fig. ). they were classified into groups a and b according to fig. , and the group change was recorded. results: patients admitted to icu in the period, excluded for limitation of therapeutic efforts. were admitted to the study, with the mean age of . years; , % males (n= ). distribution among the groups: a (n= , . %), a ( , . %), a ( , . %), b ( , . %), b ( , . %) e b (no patients). there were statistically significant correlation between group change and mortality (p . ), and between the stop and nephrologist agreement (p . ). there was no correlation between stop value and icu los (p , ) or stop and mortality (p . ). conclusions: the stop value is correlated with hemodialysis indication agreement between intensivists and nephrologists, and not correlated with icu los or mortality. the group change was correlated to increased mortality, in the study population. the significance of stop as a tool in determining the moment of initiation of renal replacement therapy remains a work in progress. introduction: liver transplant (lt) in patients with renal dysfunction presents intraoperative challenges and portends postoperative morbidity. continuous renal replacement therapy (crrt) is increasingly used for intraoperative support; however, there is a paucity of data to support this practice. methods: pilot randomized open-label controlled trial in adults receiving cadaveric lt with a modification of end-stage liver disease (meld) score >= and preoperative acute kidney injury (kdigo stage ) and/or estimated glomerular filtration rate < ml/min/ . m . patients were randomized to intraoperative crrt (icrrt) or standard of care. primary endpoints were feasibility and adverse events. secondary endpoints were changes in intraoperative fluid balance, complications, and hospital mortality. analysis was intention-to-treat. results: sixty patients were enrolled, ( %) were randomized ( to icrrt; to control). mean (sd) was age ( ) years, meld was ( ), % (n= ) had cirrhosis; % (n= ) received preoperative rrt; and % (n= ) were transplanted from icu. one patient allocated to icrrt did not receive lt. seven ( %) allocated to control crossed over intraoperatively icrrt ( ( ) min, with only interruptions (all due to access). icrrt fluid removal was . l (range - . ). fluid balance was . l ( . ) for icrrt vs. . l ( . ) for control (p= . ). postoperative crrt was similar ( % vs. %, p= . ). there were no differences in reexploration (p= . ), mechanical ventilation time (p= . ), reintubation (p= . ), sepsis (p= . ), or mortality (p= . ). conclusions: in this pilot trial of high acuity lt patients, icrrt was feasible and safe. these data will inform the design of a large trial to define the role of icrrt during lt. clinicaltrials.gov: nct . the uptake of citrate anticoagulation for continuous renal replacement therapy in intensive care units across the introduction: the purpose of this descriptive study is to report the trend of citrate anticoagulation uptake, used for continuous renal replacement therapy (crrt), in intensive care units (icus) across the united kingdom (uk). citrate anticoagulation has been used in the uk since , but its uptake since then is unknown [ ] . methods: a survey questionnaire targeted pharmacists working in uk adult icus providing crrt. invitations to participate were distributed utilising the united kingdom clinical pharmacy association online forum as a platform for access. survey administration was by self-completion and submissions were accessible over a total of six weeks. basic demographic data, icu specifications, the citrate system in use and implementation details were sought. a descriptive statistical analysis ensued. results: responses were received of which were analysed after duplication removal. trusts, encompassing a total units, in the uk confirmed use of citrate anticoagulation for crrt. units reported a mean of days to implement a citrate system (range to days). prismaflex® (baxter) and multifiltrate (fresenius) were reported as the most commonly used citrate systems; ( . %) and ( . %) units respectively. conclusions: there are icus in the uk [ ] . we conclude that a minimum of units ( %) use citrate anticoagulation for crrt in uk critical care centres. citrate systems of anticoagulation are becoming an increasing popular choice for regional anticoagulation, falling in line with international guidance [ ] . these guidelines were introduced in which corresponds to increase national uptake. introduction: patients requiring renal replacement therapy (rrt) whilst on significant doses of vasoactive medications have often been deemed unsuitable to undergo ultrafiltration (uf). however with better understanding of the pathophysiology of renal injury [ ] in intensive care patients we hypothesise that vasopressor/inotrope requirement will not significantly increase with uf or with a more negative fluid balance (fb). methods: data was retrospectively collected in a general icu/hdu of adult patients requiring acute rrt for acute kidney injury. patients on chronic dialysis were excluded. percentage change in vasopressor index and mean arterial pressure were combined to form the combined percentage change (cpc) which we used as an index of patient stability. results: patients were assessed undergoing a total of rrt sessions. the mean age was with females and males. mean fb for the hours from start of rrt was + mls (range - to + mls). using a model to correct for significant covariates and plotting hour fb against cpc we found no significant effect of fb on stability p= . (fig. ). mean uf volume was mls (range - mls). there was a non linear relationship between uf and stability with moderate volumes improving but larger volumes worsening stability (fig. ). this did not reach statistical significance (p= . ) so may be due to chance but is likely due to a lack of power. conclusions: fluid balance has no effect on cardiovascular stability during rrt in our cohort but there may be a varying effect of uf depending on volume. introduction: exposure of blood to a foreign surface such as a continuous renal replacement therapy (crrt) filter could lead to activation of platelets (plt) and fibrinogen (fib) trapping. thrombocytopenia has been reported in adults on crrt but data in pediatrics are scarce. our institution uses regional citrate anticoagulation (rca) as standard of care with prefilter hemodilution and hf filters (polysulfone, surface area (sa) . m ) regardless of patients' (pts) age and size. as filter sa is relatively larger in younger pts, we aimed to investigate the impact of crrt filter change on hemostasis parameters in infants on crrt in up to first three filter changes. methods: retrospective chart review results: patients < kg were included, age . ( . - ) months, weight . + . kg, with filters. metabolic disease was the most common principal diagnosis ( / , %), liver failure (lf) was the most common comorbidity ( / , %). all patients received prefilter continuous venovenous hemodiafiltration with minimum dose of ml/ . m /h. thrombocytopenia was common at crrt start ( / , %). plts decreased in % filter changes ( / ) by + % (pre vs post plt ( - ) vs ( - ), p< . ). fibrinogen also decreased from ( - ) to ( - ), p< . ; there was no change in ptt, pt, or inr values before and after filter changes. bleeding events were seen in / ( %) of pts ( / of lf pts vs / others, p= . ), but were not more common in pts who had decrease in plts or fib with filter changes ( % with drop in plts vs % without, p= . ; % with drop in fib vs % without, p= . ). conclusions: thrombocytopenia is common in infants on crrt. further decreases in plt and fibrinogen can be seen in with crrt filter changes if the filters are relatively large compared to patient size. bleeding events seems more related to underlying comorbidity, and less to changes in hemostatis parameters observed with filter change but would need to be confirmed with further studies. intensive monitoring of post filter ionized calcium concentrations during cvvhd with regional citrate anticoagulation: is it still required? introduction: the aim of the present study was to evaluate the role of postfilter calcium concentrations (pfca) in terms of safety and efficacy in large retrospective cohort of patients treated with cvvhd and regional citrate anticoagulation. methods: retrospective, observational study at a university hospital with icus. all patients treated with rca-crrt were included in the study. results: among patients treated with rca-cvvh pfca at the start of the cvvhd was available in pts. the pfca concentrations were in target range ( . - . mmol/l) in the majority of patients ( %), whereas % and % of patients had the pfca below or above the target range, respectively. in the further h of cvvhd treatment the propotion of patients with targeted pfca increased to % and remained stable. at the start of the rca-cvvhd there was a significant but weak correlation between the pfca and ionized systemic ca (ica) with a spearman rank-order correlation coefficient (rho) of . (p < . ). the coefficient of variation of pfca concentraions was significantly higher if compared to the coefficient of variation of ica concentration. using per protocol adaptations the incidence of a severe hypocalcemia (< . mmol/l) was low and present only at first hours of therapy: % and % of patients with pfca below the target range and . % and . % of patients with pfca in target range, at h and h respectively (p< . ). there was no correlation between pfca concentrations and filter lifetime. the results of the present study support the previous reports about higher measurements variation of pfca compared to systemic ica ( ). nevertheless due to the weak correlation of ica and pfca as well as a low number of patients with a severe metabolic complication, the results of our study question the necessity of intensive pfca monitoring during rca-crrt. present results need to be validated in further trials. introduction: in critically ill patients, occurrence of pain is frequent and usually correlates with worse outcomes, such as prolonged icu length of stay (los) and mechanical ventilation. in this regard, pain leads to sympathetic activation, inflammatory mediators and therefore, potentially to organic dysfunction. the aim of this study is to evaluate the relationship between acute pain in critically ill patients and their association with acute kidney injury (aki). methods: retrospective cohort with adults patients admitted between june and june , from the icu of hospital sírio libanês hospital in sao paulo (brazil). main exclusion criteria were: length of stay < h, coma and previous aki. the predictor pain was obtained through daily electronic records according to numerical verbal scale ( - ). the outcome was defined as serum creatinine elevation equal to or greater than . mg/dl and/or greater than % increase at any time after the first hours in the icu. the multivariate analysis was performed by binary logistic regression through distinct groups of early or late predictive factors in relation to aki. results: after the exclusion of patients, the incidence of pain with numerical verbal scale equal to or greater than points was . %. the outcome occurred in . % of the cohort. in the binary regression, using the more early predictive factors, sex and pain presented independent relation with the outcome -adjusted or . ( . - . ) and . ( . - . ), respectively (p < . ). in the analysis conclusions: poor management of icu pain is associated to worse outcomes, including increased risk to aki. the search for a better pain management strategy in the icu scenario should therefore be reinforced. introduction: acute kidney injury (aki) is a common complication in hospitalised patients, strongly associated with adverse outcomes [ ] . a lack of baseline incidence and outcome data limits our ability to assess local strategies aimed at improving aki care. methods: in an audit in three linked inner london hospitals we interrogated our electronic patient data warehouse (cerner millennium power insight electronic data warehouse) with a specially written query to identify cases of aki, defined by kdigo creatinine criteria, in patients aged over y admitted for > h during january to june . we excluded palliative care and obstetric patients. in the absence of premorbid baseline (median - d pre-admission) the admission creatinine value was used. end stage renal disease (esrd) and primary sepsis diagnosis was obtained from icd coding. results: of admissions, we excluded with pre-existing esrd (hospital mortality . %) and with fewer than one creatinine result who could not be assigned aki status (mortality . %). of the remaining there were with aki ( . %), with mortality increasing from no aki group ( . %), to aki stage ( . %), and a further increase to aki stages - ( . %) (p< . ) ( table ) . patients with aki were older (p< . ), more likely to be medical than surgical (p< . ), more likely to have a primary sepsis diagnosis (p< . ) and had higher baseline creatinine (median vs p< . ). no known baseline was found in . % of patients with aki, but their mortality did not significantly differ to those with a baseline ( . % vs . %, p= . ). conclusions: an electronic query identified the local burden of aki and it's associated hospital-mortality; such baseline data is essential to assess the effect of quality improvement interventions in aki prevention and care. introduction: acute kidney injury (aki) is a common condition in critically ill patients [ , ] . loop diuretics are generally used as first line treatment. however, controlled trials show controversial results. we ought to search systematically and realize a metaanalysis on the matter. methods: an electronic search of randomized clinical trials in adult patient treated with diuretics for aki compared with standard treatment or a control group was conducted. the primary objective of the analysis was to assess recovery of renal function. secondary endpoints included time to recovery of renal function, need for renal replacement therapy (rrt), mortality in the intensive care unit (icu) and complications. introduction: increased venous pressure is one of the mechanism leading to acute kidney injury (aki) after cardiac surgery. portal flow pulsatility and discontinuous intra-renal venous flow are potential ultrasound markers of the impact of venous hypertension on organs. the main objective of this study was to describe these signs after cardiac surgery and to determine if they are associated with aki. methods: this single center prospective cohort study (nct ) recruited adult patients able to give consent. ultrasound studies were performed before cardiac surgery and repeated on post-operative day (pod) , , and . abnormal portal and renal venous flow patterns are defined in fig. . the association between the studied markers and the risk of new onset of aki in the following hours period following an assessment was tested using logistic regression with a % confidence interval. clinical variables associated with the detection of the signs were tested using generalized estimating equation models. this study was approved by the local ethics committee. results: during the study period, patients were included. the presence of the studied ultrasound signs is presented in fig. . during the week following cardiac surgery, patients ( . %) developed aki, most often on pod ( . %). the detection of portal flow pulsatility and severe alterations in renal venous flow (pattern ) at icu admission (pod ) were associated with aki in the subsequent hours period and was independently associated with aki in multivariable models including euroscore ii and baseline creatinine ( table ). the variables associated with the detection of abnormal portal and renal patterns were associated with lower perfusion pressure, higher nt-pro-bnp and inferior vena cava measurements (table ) . conclusions: abnormal portal and intra-renal venous patterns are associated with early aki after cardiac surgery. these doppler features must be further studied as potential treatment targets to personalize management. introduction: acute kidney injury (aki) is very prevalent after cardiac surgery in children, and associated with poor outcomes [ ] . the present study is a preplanned sub-analysis of a prospective blinded observational study on the clinical value of the foresight nearinfrared spectroscopy (nirs) monitor [ ] . the purpose of this subanalysis was to develop a clinical prediction model for severe aki (saki) in the first week of picu stay. methods: saki was defined as serum creatinine (scr) >/= times the baseline, or urine output < . ml/kg/h for >/= h. predictive models were built using multivariable logistic regression. data collected during surgery, upon picu admission, as well as monitoring and lab data until h before saki onset, were used as predictors. relevant predictors with a univariate association with saki, were included in the models. accuracy of the models was tested using bootstraps, by auroc and decision curves. results: children were enrolled, admitted to the picu of the leuven university hospitals after cardiac surgery, between october and november . patients were excluded. children ( . %) developed saki in the first week of picu stay. a multivariate model with admission parameters (maximum lactate during surgery, duration of cpb, baseline scr, rachs and pim scores), and postoperative measurements (average heart rate, average blood pressure, hemoglobin, lactate), was most predictive for saki ( fig. ) . conclusions: the risk of saki in children after congenital cardiac surgery could be predicted with high accuracy. future models will also include medication data. these models will be compared against and combined with nirs oximetry data to investigate the independent and added predictive value of the foresight monitor. introduction: acute kidney injury (aki) occurs in over % of the patients in the intensive care unit (icu). the predominantly ethiology of aki is septic shock, the most common diagnosis in the icu. aki significantly increases the risk of both morbidity and mortality [ ] . methods: icu patients with septic shock was studied within hrs from admission. patients after cardiac surgery served as control group. all patients were sedated and mechanically ventilated. renal blood flow (rbf) and glomerular filtration rate (gfr) were obtained by the infusion clearance of paraaminohippuric acid (pah) and by extraction of cr-ethylenediamine ( cr-edta). n-acetyl-β -d-glucosaminidase (nag), was measured. results: rbf was % lower, renal vascular resistance % higher and the relation of rbf to cardiac index was % lower in patients with septic shock compared to the control group. gfr ( %, p= . ) and renal oxygen delivery (rdo ) ( %) where both significantly lower in the study group (table ) . there was no difference between the groups in renal oxygen consumption (rvo ) but renal oxygen delivery was almost % lower in septic shock patients. renal oxygen extraction was significantly higher in the study group than in the control group. in the study group, nag was . ± . units/mikromol creatinine more, i.e times the value in patients undergoing cardiac surgery [ ] . conclusions: sepsis related aki is caused by a renal afferent vasoconstriction resulting in a reduced rbf and lowered rdo in combination with an anchanged rvo , this results in a renal oxygen supply/ demand mismatch. introduction: the primary aim was to determine if the addition of daily creatine kinase (ck) measurement was usefully guiding decision making in intensive care units within greater glasgow and clyde. methods: after a change to the daily blood ordering schedule to include ck, a retrospective audit was carried out covering a -month period within intensive care units. all patients with ck > units/ litre were included. basic demographics, apache score and admitting diagnosis were recorded. utility of ck was assessed by determining the associated diagnosis and whether the diagnosis was first considered (diagnostic trigger) due to ck level, clinical suspicion or haematuria. additionally, it was determined if and what actions had been taken based on the raised ck and associated diagnoses. results: data was collected from / / to / / . patients were captured with ck > units/litre from an average combined admission rate of patients/month [ ] . total male patients ( . %) and female ( . %). age range to years (mean . ). apache score range to (mean . ) with estimated mean mortality of . %. patients ( . %) had associated diagnoses with elevated ck including: burns ( . %), compartment syndrome ( . %), myocardial infarction ( . %), myositis/myocarditis ( . %), neuroleptic malignant syndrome ( . %), rhabdomyolysis ( . %), serotonin syndrome ( . %), surgical procedure ( . %). as outlined in fig. the diagnostic trigger was the routine ck measurement in patients ( . %), prior clinical suspicion ( . %), haematuria ( . %) and unclear in ( . %). action was the correlation analysis showed the egfrs from every formula could all to some extent reflect the glomerular function or gfr accurately. the gfr (scys) formula was a quickly and accurate method for estimating gfr and may apply clinically in critically ill patients. perioperative chloride levels and acute kidney injury after liver transplantation: a retrospective observational study s choi introduction: the risk of developing acute kidney injury (aki) after liver transplantation in the immediate postoperative period ranges between to %. most studies in critically ill and surgical patients evaluated the link between chloride-rich resuscitation fluids, not serum chloride levels, and the incidence of aki. the association between preoperative chloride level or difference in perioperative chloride levels and the incidence of postoperative aki after liver transplantation were evaluated. methods: adult patients (>= years old) who underwent liver transplantation at seoul national university hospital between and were included in the retrospective analysis. the difference between preoperative serum chloride level and the immediate postoperative serum chloride level was defined as intraoperative chloride loading. postoperative aki within days of liver transplantation was diagnosed according to the rifle criteria. patients were divided into normochloremia group ( - meq/l), hypochloremia group (< meq/l), or hyperchloremia group (> meq/l) according to their preoperative chloride level. intraoperative chloride loading was defined as the difference between preoperative serum chloride level and immediate postoperative serum chloride level. . ) compared to patients with preoperative normochloremia. meld scores > and age > years were also associated with increased risk of aki. intraoperative chloride loading was not a significant risk factor for aki after liver transplantation. conclusions: preoperative hyperchloremia and hypochloremia were both associated with an increased risk of developing aki in the immediate postoperative period after liver transplantation. introduction: perioperative acute kidney injury (aki) is associated with significant morbidity and mortality [ ] . certain urinary biochemical parameters seem to have a standardized behavior during aki development and may act as surrogates of decreased glomerular filtration rate (gfr) aiding in early aki diagnosis [ ] . aim of this prospective observational study was the evaluation of urinary biochemical parameters as early indicators of aki in a cohort of major surgery patients. methods: patients were studied. aki was defined according to akin criteria within hrs after surgery [ ] . at pre-defined time points (preoperatively, recovery room [rr] and on postoperative days [pod] to ) simultaneous serum and urine samples were analyzed additional studies must confirm these findings and reevaluate these simple parameters as potential aki monitoring tools. urinary liver-type fatty acid-binding protein is the novel biomarker for diagnosis of acute kidney injury secondary to sepsis t komuro, t ota shonan kamakura general hospital, kamakura, kanagawa, japan critical care , (suppl ):p introduction: acute kidney injury (aki) is the predictor of poor prognosis for the patient with sepsis and septic shock. several diagnostic criteria for aki is used on clinical settings, but useful biomarker is not known yet. urinary liver-type fatty acid-binding protein(l-fabp) is associated with kidney function and aki [ ] , but that is not still discussed about aki secondary to sepsis. thus, we conducted the study of the association between urine l-fabp and aki with secondary to sepsis. (fig. ) . the cut-off line of l-fabp was . μg/g cr. conclusions: l-fabp can be the novel biomarker for diagnosis of aki. further investigation need for diagnostic value of l-fabp and usefulness of early intervention for aki used by l-fabp. introduction: biotransformation of -hydroxyvitamin d to active , (oh) d occurs primarily in the kidney. our aim was to explore whether this process was altered in patients with acute kidney injury (aki). methods: consecutive patients admitted to critical care at a tertiary hospital were recruited. the aki group comprised patients with kdigo stage ii or stage iii aki; the non-aki group were patients requiring cardiovascular or respiratory support, but with no aki. vitamin d metabolite concentrations were measured on days , and . statistical analysis included comparison between groups at each time point, and longitudinal profiles of vitamin d metabolites. results: interim analysis of participants ( % of the recruitment target) showed that , (oh) d concentrations were significantly lower in patients with aki at day and day . considering longitudinal changes, -hydroxyvitamin d profiles were not different between the groups ( fig. ) but there was a trend towards a longitudinal increase in , (oh) d in patients without aki, which was not seen in aki patients (fig. ) . conclusions: interim analysis indicates significant differences in concentrations of , (oh) d, but not (oh)d, in critically ill patients with aki. recruitment is ongoing and further results are awaited. introduction: acute renal failure affects from % to % of patients in the intensive care units (icus) and it is associated with excess mortality. hydratation is a useful preventive measure but it is often controindicated in critically ill patients who, on the contrary, often benefit by a strictly conservative strategy of fluid management. fenoldopam, a selective dopamine -receptor agonist, increases renal blood flow and glomerular filtration rate by vasodilating selectively the afferent arteriole of renal glomerulus. the aim of our study is to compare renal effects of fenoldopam and placebo in critically ill patients undergoing a restrictive fluid management. methods: we enrolled patients admitted to our icu. patients were assigned by randomization to study groups: fenoldopam (n= ) and placebo (n= ). fenoldopam was infused continuously at , mcg/kg/ min and equivalent volume for placebo during a period of seven days. creatinine, cystatin c and creatinine clearance were daily measured as markers of renal function. the incidence of aki according to rifle criteria (risk, injury, failure, loss, end stage kidney disease) was also calculated. results: patients with a negative fluid balance at the end of the week (~- ml, p= , ) were included in the analysis, in the placebo group and in the fenoldopam group. there were not significant differences in the trend of creatinine, creatinine clearance, cystatin c and in the incidence of aki between the groups during the week of infusion. conclusions: a continuous infusion of fenoldopam at , mcg/kg/ min does not improve renal function and does not prevent aki in critically ill patients undergoing a strictly conservative strategy of fluid management. introduction: this study aims to evaluate the efficacy of a protocol implemented for dysphagia risk factors [ ] in hospitalized patients in a cicu (coronary intensive care unit). methods: patients hospitalized in the cicu of a medium-sized hospital in presidente prudente, sp, brazil, were subjected to a survey that screened for dysphagia during the period from january of to september of . patients with at least one risk factor for dysphagia were evaluated by a phonoaudiologist and are the subject of this study. the information was statistically analyzed using epi info, version . . . software. considering significant p < . two-tailed, for logistic regressions multivariate estimated in the sample. results: for this study patients were selected, of which . % were male and the mean age was . ± . years. a higher incidence of dysphagia was observed among patients who had at least one of the following risk factors: stroke (odds ratio . p< . ); brain tumor (or . p= . ); chronic obstructive pulmonary disease (copd) (or . p= . ); degenerative diseases (or . p< . ); lower level of consciousness (or . p< . ); ataxic respiration (or . p< . ); aspiration pneumonia (or . p< . ); orotracheal intubation > h (or . p< . ); tracheostomy (or . p< . ); airway secretion (or . p< . ); nasoenteral tube (or . p< . ); gastrostomy (or . p= . ). there was no statistical significance for age > , traumatic brain injury, oropharyngeal surgery and unfavorable dentition. four factors appeared less than times and could not be analyzed (chagas disease, human immunodeficiency virus (hiv), orofacial burn and excess saliva). conclusions: we concluded that the dysphagia triage protocol insertion was effective to identify dysphagic patients and can be used as an additional tool in the intensive care risk management. physiological bases of this age old concept, more recently applied to endotracheal intubation, have never been confirmed by current methods. we therefore decided to study the effects of an apnea oxygenation period under hfnc oxygen therapy by means of a novel modelization of the respiratory system. methods: firstly, an airway model was built with anatomical, physical and physiological attributes similar to that of a healthy subject (fig. ) . this system reproduces the physiological evolution of intrapulmonary gases during apnea by progressively increasing co levels after having cut off previous o supplies (fio %). secondly, the effects of a hfnc apnea oxygenation of l/min with an fio of % were analyzed by collecting intrapulmonary gas samples at regular intervals (fig. ) . results: after minute of apnea oxygenation, intrapulmonary oxygen levels remain stable at %. after minutes, oxygen fraction reaches %, and increases up to % in minutes. regarding co levels, no significant modifications were observed. conclusions: a novel experimental and physiological model of the respiratory system has been developed and confirms the existence of an alveolar oxygen supply as well as the lack of a co washout during hfnc apnea oxygenation. however, these effects are only observed after a delay of about . to minutes. therefore, the clinical interests of this technique to reduce apnea-induced desaturation during intubation of a hypoxemic patient in the icu seem limited without adequate preoxygenation. combination of both preoxygenation and apnea oxygenation by hfnc can most likely explain positive results observed in other clinical studies. effect of % nebulized lignocaine versus % nebulized lignocaine for awake fibreoptic nasotracheal intubation in maxillofacial injuries in emergency department h abbas, l kumar king george's medical university,lucknow,india, lucknow, india critical care , (suppl ):p introduction: topical lignocaine is most commonly used pharmacological agent for anaesthetizing upper airway during fibreoptic bronchoscopy. we compare the effectiveness of two different concentrations, % lignocaine and % lignocaine, in nebulised form for airway anaesthesia during awake fibreoptic nasotracheal intubation in terms of patient's comfort and optimal intubating conditions, intubation time. methods: institutional ethics committee approved the study and written informed consent obtained; patients of either sex, between - years age with anticipated difficult airway planned for intubation were included for this study. patients were randomly allocated into two groups (a and b) based on sealed envelope method; patients and observers were blinded by using prefilled syringes of lignocaine.one group was nebulized with ml of % lignocaine(group a) and other with ml of % lignocaine(group b) in coded syringes via ultrasonic nebuliser for minutes followed by inj midazolam . mg/kg iv and inj fentanyl microgram/kg iv just before the procedure. the fibreoptic broncoscope was introduced via nostril and the other nostril was used for oxygen insufflation ( - l/min). the fibroscope was introduced through the glottic opening and visualising tracheal rings and carina.the endotracheal tube railroaded over the fiberscope and cuff inflated. results: the primary outcome measure was patient's comfort during awake fibreoptic nasotracheal intubation. the mean patient comfort puchner scale score of group a was . ± . and of group b was . ± . . the mean value of puchner scale of group b was significantly higher.the mean procedural time of group b was significantly higher ( . %) as compared to group a (p< . ). the no of intubations attempts did not differ between the two groups. conclusions: % nebulised lidocaine provided adequate airway anaesthesia and optimal intubating conditions, patient comfort, stable hemodynamics. introduction: this systematic review and meta-analysis aims to investigate whether video laryngoscopy (vl) improves the success of orotracheal intubation, when compared with direct laryngoscopy (dl). methods: a systematic search of pubmed, embase, and central databases was performed to identify studies comparing vl and dl for emergency orotracheal intubations outside the operating room. the primary outcome was rate of first pass intubation. subgroup analyses by location, device used, clinician experience, and clinical scenario were performed. the secondary outcome was rate of complications. results: the search identified studies with , emergency intubations. there was no overall difference in first-pass intubation with vl compared to dl. subgroup analysis showed first-pass intubations were increased with vl in the intensive care unit (icu) ( . ( . - . ); p< . ), but not in the emergency department or pre-hospital setting. rate of first-pass intubations were similar with glidescope® and dl, but improved with the cmac® ( . ( . - . ); p= . ). there was greater first-pass intubation with vl than dl among novice/trainee clinicians (or= . ( . - . ); p< . ), but not among experienced clinicians or paramedics/nurses. there was no difference in first-pass intubation with vl and dl during cardiopulmonary resuscitation or trauma. vl was associated with fewer oesophageal intubations than dl (or= . ( . - . ); p= . ), but more arterial hypotension (or= . ( . - . ); p= . ). conclusions: in summary, compared to dl, vl is associated with greater first-pass emergency intubation in the icu and among less experienced clinicians. vl is associated with reduced oesophageal intubations but a greater incidence of arterial hypotension. compared success rate between direct laryngoscope and video laryngoscope for emergency intubation, in emergency department: randomized control trial p sanguanwit, n laowattana ramathibodi hospital, bangkok, thailand critical care , (suppl ):p introduction: video laryngoscope was used as an alternative to intubate in the emergency room, designed for tracheal intubation more success [ , ] . methods: we performed a prospective randomized controlled trial study of patients who had sign of respiratory failure or met indication for intubation from july to june . patients were randomly by snose technique; assigned to video laryngoscope first or direct laryngoscope first. we collect the demographics, difficult intubation predictor, rapid sequence intubation, attempt, cormack-lehane view and immediate complication. primary outcome was first attempt success rate of intubation. results: first attempt success rate of video laryngoscope was . % trend to better than direct laryngoscope was . %, (p= . ), good glottic view (cormack-lehane view - ) of video laryngoscope was . % better than direct laryngoscope . %, and statistically significant (p= . ), no statistical significant in immediate serious complication between direct laryngoscope or video laryngoscope. conclusions: compared to the success rate between using video laryngoscope or direct laryngoscope for intubation, video laryngoscope trend to better success rate, and better glottic view. -year cohort of prehospital intubations and rescue airway techniques by helicopter emergency medical service physicians: a retrospective database study p de jong, c slagt, n hoogerwerf radboudumc, nijmegen, netherlands critical care , (suppl ):p introduction: in the netherlands the pre-hospital helicopter emergency medical service (hems) is physician based and an adjunct to ambulance services. all four hems stations together cover / specialist medical care in the netherlands. in many dispatches the added value is airway related [ ] . as part of our quality control cycle, all airway related procedures were analysed. high quality airway management is characterized by high overall and first pass endotracheal intubation (eti) success [ ] . methods: the hems database was analysed for all patients in whom prehospital advanced airway management was performed in the period - . balloon/mask ventilation, supraglottic airway (sga) devices, total intubation attempts, cormack & lehane (c&l) intubation grades, successful eti, primary and rescue surgical airway procedures and professional background were reviewed. results: in the -year period, there were dispatch calls. in total patients were treated in the prehospital setting by our hems. of those, required a secured airway. eti was successful in of ( . %). in the remaining patients ( fig. ) an alternative airway was needed. rescue surgical airway was performed in . %, . % received a rescue sga, rescue balloon/mask ventilation was applied in . % of cases, was allowed to regain spontaneous ventilation and in . % of patients all airway management failed. hems physicians, ambulance paramedics, hems paramedics and others (e.g. german emergency physicians) had eti first pass success rates of . %, . %, . % and . % respectively (fig. ) . difficult laryngoscopy (no epiglottis visible) was reported in . % of patients (table ) . conclusions: our data show that airway management performed by a physician based hems operation is safe and has a high overall eti success rate of . %. the total success rate is accompanied by a high first pass eti success rate. introduction: incidences associated with endotracheal tubes are frequent during mechanical ventilation (mv) of intensive care unit (icu) patients and can be associated with poor outcomes for patients and detrimental effects on health care facilities. here, we aimed to identify factors associated with event occurrence due to unsafe management of endotracheal tubes (e-umet). methods: a retrospective observational study was conducted in three icus: one surgical icu, one stroke icu, and one emergency department, at a tertiary hospital in japan from april to march . patients requiring mv and oral intubation during their icu stay were included. the primary finding was the incidence rate of e-umet (biting, unplanned extubations, and/or displacement of the endotracheal tube). the patients were divided into two groups: with or without e-umet. to investigate e-umet, potential factors possibly related to its occurrence were obtained from electronic medical records. we conducted univariable and multivariable analyses to investigate e-umet factors. results: of patients, e-umet occurred in ( . %). the mean and standard deviation for age and acute physiology and chronic health evaluation (apache) ii score were ( ) and ( ), respectively. according to a multivariate logistic-regression analysis, significant risk factors associated with e-umet included patients of neurosurgery (odds ratio (or) . ; % ci, . - . ; p= . ), sedative administration (or . ; % ci, . - . ; p< . ), and higher richmond agitation-sedation scale (rass) scores (or . ; % ci, . - . ; p< . ). the use of a restraint (or . ; % ci, . - . ; p= . ) was an independent factor associated with a lower probability of e-umet. conclusions: this study suggests that risk factors associated with e-umet include neurosurgery, higher rass scores, and the administration of sedatives. patients with these factors and longer oral intubation periods might require extra care. introduction: the use of nasal high flow (nhf) as a respiratory support therapy post-extubation has become increasingly more common. nhf has been shown to be non-inferior to niv and reduces escalation needs compared to conventional oxygen therapy. clinical outcomes using nhf in patients with type ii respiratory failure (rf) is less well understood. our aim was to determine if nhf can be used successfully when extubating type ii rf patients compared to type i rf. methods: we conducted a retrospective observational study on the use of nhf as an extubation respiratory support in (n= ) consecutive patients in icu over a -month period. primary outcome was the need for escalation in therapy (niv, intubation and palliation) post extubation. patients were categorised as high risk if they scored >= from: age>= years, bmi>= and >= medical comorbidity. results: analysis was conducted on all fifty-six (n= ) patients. type i rf group was composed of (n= ) patients with a mean age of . (±sd) years. type ii rf group had (n= ) patients with a mean age of . (±sd) years. in type i rf patients ( %) were successfully extubated with nhf compared to patients ( . %) in type ii. in type ii rf the outcomes were more variable with a greater requirement for niv. of these patients % required niv, . % required intubation and . % received nhf therapy for palliation. a higher average bmi ( . vs . kg/m ) was found in unsuccessfully vs successfully extubated patients in type ii rf. in type i rf escalation of therapy was equally distributed with % in each category. conclusions: the use of nhf for respiratory support post-extubation may become standard practice for type i rf in critical care settings. our data suggests that nhf can be used but with caution in type ii rf and clinicians should risk stratify patients to identify those at risk of re-intubation and post-extubation respiratory failure. introduction: pathogenesis of ventilator-associated pneumonia (vap) relies on colonization and microaspiration. oral topical decontamination reduced the vap incidence from to % [ ] . the persistence of antiseptic effect in the oral cavity is questionable; we hypothesize that continuous oral antiseptic infusion may offer a better decontamination. aim of the work: we developed endotracheal tube that allows continuous oral infusion of chlorhexidine (chx), and we want to test the technique versus the conventional on bacterial colonization. (provisional patent: ) methods: a two identical bio models for the upper airways were manufactured by ( dx diagnostics, usa) to adapt the modified and the ordinary endotracheal tubes (ett). the two techniques tested were using six hourly disinfection with chx (group a) versus disinfection through the hours infusion technique (group b). five microorganisms plus mixed bacteria were used and each was tested for five times. normal saline was used constantly to irrigate the biomodels and ten ml aliquot was collected by the procedure end. culturing of the aliquots from decanted broth pre and post disinfection was performed. the time to apply chx by practitioner was also compared. results: there was a trend towards lower bacterial growth in group a in experiments which reach statistical significance only with pseudomonas aeruginosa (p= . ). in one experiment the growth was lower in group b (fig. ) . additionally there was time saving advantage in group b ( ± . versus ± . min, p= . ). conclusions: the novel technique got at least non inferior results, plus time saving advantage. these results may warrant future clinical trial. monitoring airways non invasive online analysing different particle flow from the airways is never done before. in the present study we use a new technology for airway monitoring using mass spectrometric analysis of particle flow and their size distribution (pexa particles in expired air). the exhaled particles are collected onto a substrate and possible for subsequent chemical analysis for biomarkers. our hypothesis was that by analysing the particle flow online, we could optimise the mechanical ventilation. our hypothesis was that a small particle flow would probably be more gentle for the lung than a large particle flow when the lung is squeezed out and the majority of all small airways are open. methods: in the present study we analyse the particle flow from the airways in vivo, post mortem and during ex vivo lung perfusion using different ventilation modes; volume controlled ventilation (vcv) and pressure controlled ventilation (pcv) comparing small tidal volumes( ) versus big tidal volumes( ) at different peep (positive end-expiratory pressure) and after distribution of different drugs in six domestic pigs. results: we found that vcv resulted in a significant lower particle flow than pcv in vivo but in ex vivo settings the opposite was found (fig. ). in both in vivo and ex vivo settings we found that big tidal volume resulted in a larger particle flow than small tidal volumes.air. the opening and the closure of the small airways reflect the particle flow from the airways. we found that different ventilation modes resulted in different particle flow from the airways. we believe this technology will be useful for monitoring mechanical ventilated patients to optimise ventilation and preserve the lung quality and has a high potential to detect new biomarkers in exhaled air. introduction: malaria is a common problem in underdeveloped countries, with an estimated mortality of more than one million people per year. pulmonary involvement is one of the most serious manifestations of plasmodium falciparum malaria. non-invasive ventilation (niv) decreases muscular works and improves gas exchange by recruitment of hypoventilated alveolus. in this context, we analyze the impact of the use of non-invasive ventilation in malaria with pulmonary dysfunction. methods: it's a retrospective cohort study. we analyzed electronic records of patients who were diagnosed with malaria, with acute respiratory failure, who underwent respiratory therapy with niv between - within the intensive care unit (icu). the study variables were: icu mortality, length of hospital stay, niv time and outcome groups. statistical analysis was performed with the pearson correlation coefficient, with significance level of p < . . the statistics were performed using the bioestat . program. results: thirty-one patients were included in the study. four results were analyzed according to table and fig. . % of the patients were discharged from the hospital. pearson's correlation coefficient analysis showed statistical significance in the group (niv/discharge) in the analysis of patients hospitalized versus niv ( % ci = . to . <(p) = . ). conclusions: the use of niv was positive in patients using this resource as first-line treatment of malaria in the fight against respiratory decompensation, with improvement of symptoms. introduction: cpap is used to improve oxygenation in patient with arf. we aimed to determine non-inferiority (ni) of helmet cpap to facemask in arf based on physiological (heart rate (hr) and respiratory rate (rr)) and blood gas parameters (pao and paco ). we also compared patients' perception in dyspnea improvement after cpap using dyspnea scale (visual analogue scale (vas)) and likert score. methods: we randomized patients to helmet (n= ) and facemask (n= ) with . % of arf was due to acute pulmonary edema. cpap was applied for minutes. patients' physiological and blood gas parameters were recorded before and after intervention. patients then marked on dyspnea scale and likert score. ni of helmet would be declared if confidence interval (ci) of mean difference between groups (helmet's mean minus facemask's mean) in improving physiological, blood gas parameters and dyspnea scale was no worse than predetermined non-inferiority margin (nim). secondary outcome was to compare incidence of discomfort and mucosal dryness between groups. methods: this is a single center retrospective study performed in the icu of tel aviv medical center, israel, a tertiary academic referral hospital. using the electronic medical record system and intensix predictive critical care system for analysis, all patients admitted to the icu between . and . were assessed. respiratory deterioration in mv patients was defined as acute adjustment of fio increase > % or peep increase > cmh o that persisted for at least hours. the primary outcome was icu mortality. secondary outcome was length of icu stay (los). a chi square test for trends was used for the significance of mortality data and a one way anova test for los. results: mv patients were admitted to the icu with an overall mortality of . %. mortality and los were tripled in patients who experienced at least one respiratory deterioration when compared to no events ( . % vs. . %, p< . and . vs. . days, p< . respectively) (fig. ) . increased events of respiratory deteriorations showed significant trend of increased mortality (p< . ). conclusions: in mv patients, a single respiratory deterioration event carries a times higher mortality rate and length of stay (los). any additional event further increases both parameters. association of lung ultrasound score with mortality in mechanically ventilated patients j taculod, jt sahagun, y tan, v ong, k see national university hospital singapore, singapore, singapore critical care , (suppl ):p introduction: lung ultrasound is an important part of the evaluation of critically ill patients. it has been shown to predict recruitability in acute respiratory distress syndrome. however, little is known about the application of lung ultrasound in predicting mortality in mechanically ventilated patients. methods: observational study of mechanically ventilated patients admitted to the medical intensive care unit (icu) of a tertiary hospital (national university hospital, singapore) in and . only the first icu admissions of these patients were studied. lung ultrasound was done at six points per hemithorax and scored according to soummer (crit care med ): normal aeration = ; multiple, well-defined b lines = ; multiple coalescent b lines = ; lung consolidation = . the lung ultrasound (lus) score was calculated as the sum of points (score range - ). we analysed the association of lus score with icu/hospital mortality, using logistic regression, adjusted for age and acute physiology and chronic health evaluation (apache) ii score. results: patients were included (age . ± . years; female [ . %]; apache ii . ± . ; sepsis diagnosis [ . %]). icu and hospital mortality were . % and . % respectively. lus score was associated with increased icu (or . , % ci . - . , p= . ) and hospital (or . , % ci . - . , p= . ) mortality, adjusted for age and apache ii score. conclusions: lus score was associated with increased icu/hospital mortality and may be useful for risk stratification of mechanically ventilated patients admitted to icu. introduction: ventilator asynchrony results in morbidities and mortality. the aim of this study was to explore whether and how physicians used patient-ventilator interactions(pvi) to set mechanical ventilators(mv) in thailand. methods: thai physicians treating mv patients were asked to respond to questionnaires distributed in conferences and to e-mails sent. types of asynchronies encountered and frequency of mv adjustment guided by pvi were evaluated. in addition, correlations between physician's knowledge and )confidence to manage asynchronies and )their experience were analyzed. results: two hundred and eleven physicians answered the questionnaires. most of them were medical residents and icu specialists. % of them set and adjusted mv by asynchrony guidance and the majority used waveform analysis to more than a half of their patients. the most and the least common asynchronies encountered were double triggering and reverse triggering, respectively, while the most difficult-to-manage and the most easily managed asynchronies were periodic/?a b show $ #?>unstable breathing and flow starvation, respectively. lack of confidence and knowledge of pvi were the major reasons of physicians who did not perform asynchrony assessment. for knowledge evaluation, more than % of physicians incorrectly managed asynchrony. chest and icu fellows had the greatest skills in waveform interpretation and asynchrony management with the mean score of . from the total , compared with specialist( . ), medical residents( . ), internists( . ) and general practitioner( . ). there were poor correlations between years' experience in mv management and the skill in waveform interpretation (r = . , p= . ) and between physician's confidence in pvi management and the clinical skill (r = . , p< . ) conclusions: the majority of thai physicians realized the importance of pvi, but the skill in asynchrony management was moderate. intensive programs should be provided to improve their clinical performance. methods: six deeply anesthetized swine underwent tracheostomy, thoracostomy and experimental plef with ml/kg of radiopaque saline randomly instilled into either pleural space. animals were ventilated at vt= ml/kg, frequency= bpm, i/e= : , peep= cmh o, and fio = . . quantitative lung computed tomographic (ct) analysis of regional aeration and global frc measurements by nitrogen wash-in/wash-out technique were performed in each of these randomly applied positions: semi-fowler's (inclined °from horizontal in the sagittal plane); prone, supine, and lateral positions with dependent plef and non-dependent plef (fig. ) . results: no significant differences in frc were observed among the horizontal positions, either at baseline (p= . ) or with plef (p= . ) ( fig. a) . however, component sector total gas volume in each phase of the tidal cycle were different within all studied positions with and without plef (p=<. ). compared to other positions, prone and lateral position with non-dependent plef had a more homogenous vt distribution among quadrants (p=. , fig. b ). supine was associated with most dependent collapse (fig. c ) and greatest tendency for tidal recruitment ( % vs~ %, p= . , fig. d ). conclusions: changes in body position in the setting of effusioncaused chest asymmetry markedly affected the internal distributions of gas volume, collapse, ventilation, and tidal recruitment, even when commonly used global frc measurements provided little indication of these important positional changes. of the respondents, % were affiliated with multidisciplinary icus, % with thoracic and/or cardiac icus and % with neuro-icus. most respondents ( %) had completed their specialist training. overall, arterial oxygen tension (pao ) was the preferred parameter for the evaluation of oxygenation (fig. ). the proportions of doctors' preferences for increasing, decreasing or not changing an fio of . in two (out of six) patient categories at different pao levels are presented in table and table . conclusions: this is the largest survey of the preferred oxygenation targets among icu doctors. pao seems to be the preferred parameter for evaluating oxygenation. the characterisation of pao target levels in various clinical scenarios provide valuable information for future clinical trials on oxygenation targets in critically ill icu patients. introduction: sonographic assessment of diaphragmatic excursion and muscle thickening fraction have been suggested to evaluate diaphragm function during weaning trial [ ] . the purpose of this study is to compare these two parameters to predict extubation success. methods: this prospective study was carried out during months from march to november . we enrolled patients who were mechanically ventilated for more than h and met all criteria for extubation. the non inclusion criteria were: age < years, history of neuromuscular disease or severe chronic respiratory failure. we excluded subjects who needed reintubation for upper airway obstruction, neurological or hemodynamic alteration. the scenario involves a patient expected to receive mechanical ventilation for at least hours in the icu. all proportions are percentages of respondents with % confidence intervals. *p < . for comparisons of proportions of "no change" versus adjacent lower pao level (mcnemar's test) introduction: ventilator induced diaphragmatic dysfunction is known to be a contributor to weaning failure. some data suggest that assisted ventilation might protect from diaphragmatic thinning. aims of this study are to evaluate, by ultrasound (us), the change in diaphragm thickness and thickening in patients undergoing controlled and assisted mechanical ventilation (mv) and clinical factors associated with this change. methods: we enrolled patients who underwent either controlled mv (cmv) for cumulative hours or hours of pressure support (psv) if ventilation was expected to last for at least days. patients < years old, with neuromuscular diseases, phrenic nerve injury, abdominal vacuum dressing system and poor acoustic window were excluded. diaphragm thickness and thickening were measured with us as described by goligher and clinical data were collected every hours until icu discharge. results: we enrolled patients, were excluded because they had less than measurements and for low quality images, leaving patients for analysis. as expected, during cmv diaphragm thickening was almost absent and significantly lower than during psv (p< , ). diaphragm thickness did not reduce significantly during cmv (p= . ), but during psv significantly increased (p< . ) (fig. , where "day " represents the first day of psv). during cmv, in / patients diaphragm thickness showed a >= % reduction. they had a significantly higher fraction of days spent in cmv (p= . ) and longer neuromuscular blocking drugs (nbds) infusion (p= . ). during psv, / patients showed an increase in diaphragm thickness >= %. duration of hospital stay was significantly lower for these patients (p . ). differences between the two groups are reported in table . conclusions: longer time spent in cmv and with nbds infusion seems associated with a decrease in diaphragm thickness. assisted ventilation promotes an increase in diaphragm thickness, associated with a reduction in the length of hospitalization. prediction of intrinsic positive end-expiratory pressure using diaphragmatic electrical activity in neutrally-triggered and pneumatically-triggered pressure support f xia nanjing zhongda hospital, southeast university, nanjing, china critical care , (suppl ):p introduction: intrinsic positive end-expiratory pressure (peepi) may substantially increase the inspiratory effort during assisted mechanical ventilation. our purpose of the study was to assess whether electrical activity of the diaphragm (eadi) can be reliably used to estimate peepi in patients undergoing conventional pneumaticallycontrolled pressure support (psp) ventilation and neutrally-controlled introduction: atelectasis develops in critically ill obese patients submitted to mechanical ventilation. the pressure exerted by the abdominal weight on the diaphragm causes maldistribution of ventilation with increased pleural pressure and diminished response to peep. our objective was to analyze the effects of peep in the distribution of ventilation in obese and non-obese patients according to bmi (obese >= kg/m , or non-obese: to . kg/m ), using electrical impedance tomography (eit). methods: we assessed the regional distribution of ventilation of surgical and clinical patients submitted to a decremental peep itration monitored by eit. we calculated the percent ventilation to the nondependent (anterior) lung regions at the highest and lowest peep applied. the highest compliance of respiratory system was consistently observed at intermediate values of peep (between those extreme values), indicating that the highest peep caused pulmonary overdistension, whereas the lowest peep likely caused dependent lung collapse results: were enrolled patients, with non-obese patients ( , ± kg/m ) and obese patients ( . ± . kg/m ). all patients presented progressively decreased ventilation to dependent (posterior) lung regions when peep was lowered (p< . ). obese patients consistently presented higher ventilation to the anterior lung zones (when compared no nonobese), fig. introduction: lung protective ventilation is the mainstay of mechanical ventilation in critically ill patients [ ] . extracorporeal co removal (ecco r) can enhance such strategies [ ] and has been shown to be effective in low flow circuits based on renal replacement platforms [ , , ] . we show the results of a pilot study using a membrane lung in combination with a hemofilter based on a conventional renal replacement platform (prismalung™) in mechanically ventilated hypercapnic patients requiring renal replacement therapy (nct ). methods: the system incorporates a membrane lung ( . m ) in a conventional renal replacement circuit downstream of the hemofilter. mechanically ventilated patients requiring renal replacement therapy were included in the study. patients had to be hypercapnic at inclusion under protective ventilation. changes in blood gases were recorded after implementation of the extracorporeal circuit. thereafter ventilation was intended to be decreased per protocol until baseline paco was reestablished and changes in vt and pplat were recorded. data from patients were included in the final analysis. results: the system achieved an average co removal rate of . ± . ml/min which corresponded to a paco decrease from . ± . to . ± . mmhg (p< . ) and a ph increase from . ± . to . ± . (p< . ) [ fig. ]. after adaption of ventilator settings we recorded a decrease in vt from . ± . to . ± . ml/kg (p< . ) and a reduction of pplat from . ± . to . ± . cmh o (p< . ). these effects were even more pronounced in the "per protocol" analysis [ fig. ]. conclusions: low flow ecco r in combination with renal replacement therapy provides partial co removal at a rate of over ml/min can significantly reduce invasiveness of mechanical ventilation in hypercapnic patients. introduction: in ecco r-crrt, efficiency of co removal is higher positioning the oxygenator (oxy) up-stream than down-stream the haemofilter due to higher blood flow (bf) [ ] . we tested whether this effect was due to lower pre-filter pressure (pfp). methods: ecco r-crrt circuit was tested in-vitro (n= ) with the following settings: l bovine blood; bf ml/min; oxy . m (euroset); cvvh post mode; substitution flow ml/h; uf rate function off; . m haemofilter (diapact®, b.braun avitum); sweep air flow . l/min. pfp was evaluated at baseline, , and hours. co extraction was measured at bf of , and ml/min. sweep air flow/blood ratio was : . co was add to obtain paco of mmhg. co removal rate calculation ( ): co removal rate = (co ecco r inlet-co ecco r outlet)* blood flow (eq. ) co molar volume at °c [l/mol] = ; solubility of co at °c = . mmol/(l*mmhg); hco i = inlet hco concentration [mmol/l]; hco o = outlet hco concentration [mmol/l]; pi co = inlet co partial pressure [mmhg]; poco = outlet co partial pressure [mmhg] equation becomes: co removal rate= x ((hco i + . x pico ) -(hco o + . x poco )) x blood flow (eq. ) results: bf of ml/min was always reached with the up-stream configuration. bf was reduced to ml/min with the down-stream configuration due to high pfp alarm (table ). co removal increased to . ± . to . ± . , and . ± . ml/min, at bf of , and ml/ min (p< . ). conclusions: bf of ml/min can be reached only with the upstream configuration due to lower circuit pfps. bf directly correlates to co removal efficiency. we may speculate that simultaneous use of crrt and lf-ecco r and activation of the uf rate function with the down-stream setting may further increase pfp thus forcing to more enhanced reduction of bf and less effective co -removal. introduction: we describe the use of a novel low-flow ecco r-crrt device (prismalung-prismaflex, baxter healtcare gambro lundia-ab-lund, sweden) for simultaneous lung-renal support. methods: a retrospective review of patients submitted to prismalung-prismaflex due to aki associated to hypercapnic acidosis during the period may -august at prato hospital icu was performed. data collected were: demographic, physiologic, complications, outcome. data were presented as mean ± ds; anova test was used to compare changes of parameters over time; significance was set at p< , . results: we identified patients (mean age ± yr, mean sofa ± ). causes of hypercapnia were moderate ards (n= ) and ae-copd (n= ). in all patients a fr double lumen cannula was positioned and ml/min blood-flow with lt oxygen sweep-gas-flow was maintained; iv-heparin aiming to double aptt was used. haemo-diafiltration (effluent flow ml/kg/hour) was delivered. in all cases prismalung-prismaflex improved respiratory and metabolic parameters (figs. and ) without any complications. all patients survived to the treatment, nevertheless patients ( ae-copd; ards) died during icu stay due to irreversible cardiac complications. in ards cases: patients were successfully weaned from imv, mean duration of the treatment was ± hours, mean duration of imv after ecco r-crrt was ± days. in ae-copd cases: intubation was avoided in patients at risk of niv failure, patients were successfully weaning from imv, mean duration of the treatment was ± hours, mean duration of imv after ecco r-crrt was , ± , days. fig. (abstract p ) . minutes after implementation of the combined renal replacement and ecco r circuit a moderate decrease in paco (- . mmhg) corresponding to a slightly higher ph ( . ) was observed conclusions: the use of prismalung-prismaflex has been safe and effective: it may be argued that it could be due to the low-blood-flow used. the positive results of this preliminary study may constitute the rational for the design of a larger randomized control trial. systemic il- production and spontaneous breathing trial (sbt) outcome: the effect of sepsis introduction: spontaneous breathing trial (sbt), a routine procedure during ventilator weaning, entails cardiopulmonary distress, which is higher in patients failing the trial. an intense inflammatory response, expressed by increased levels of pro-inflammatory cytokines, is activated during sbt. sepsis, a common condition in icu patients, has been associated with increased levels of the pro-inflammatory cytokine il- . il- produced among others by skeletal muscles, has been associated with severe muscle wasting and maybe by icu acquired weakness. we hypothesised that il- increases during sbt, more evidently in sbt failures. we anticipate this response to be more pronounced in formerly septic patients fulfilling the criteria for sbt. methods: sbts of -min duration were performed and classified as sbt failure or success. blood samples were drawn before, at the end of the sbt and hours later. serum il- levels and other inflammatory mediators, commonly associated with distress, were determined and correlated with sbt outcome. subgroup analysis between septic and non-septic patients was performed. )kg/m ) were monitored for . ± . hours. apneas were identified ranging from - s (fig. a) . apneas were observed in % of patients, suggesting low predictability of respiratory insufficiency. the average mv was ± . %mvpred, as patients were often sleeping or mildly sedated. we assessed the effects of each apnea on the temporally associated mv (fig. b) . while apneas ranging in length from - s decrease mv by as much as %, their effect over min is < %. on a min time scale, even s apneas led to lowmv just % of the time (fig. c) . conclusions: while apneas were ubiquitous, they seldom led to lowmv over clinically relevant time scales. large compensatory breaths following an apnea generally restored mv to near pre-apnea levels. nonetheless, some apneas can become dangerous when ignored, as when subsequent sedation decreases compensatory breath size. rvm data provide a better metric of respiratory competence, driving better assessment of patient risk and individualization of care. introduction: diffuse alveolar hemorrhage (dah) is an acute lifethreatening event and recurrent episodes of dah may result in irreversible interstitial fibrosis. identifying the underlying cause is often challenging but is needed for optimal treatment. lung biopsy is often performed in the diagnostic evaluation of patients with suspected dah. however, the role of lung biopsy in this clinical context is unclear. hence, we sought to identify the spectrum of histopathologic findings and underlying causes in patients with dah who underwent lung biopsy, surgical or transbronchial. methods: we identified patients who underwent surgical lung biopsy (n = ) or bronchoscopic biopsy (n = ) in the evaluation of dah over a -year period from to . we extracted relevant clinical pathologic and laboratory data. results: the median age in our cohort was years with % females. serologic evaluation was positive in % of patients (n= ). most common histopathologic findings on surgical lung biopsy included alveolar hemorrhage (ah) with capillaritis in patients of whom six had necrotizing capillaritis, followed by ah without capillaritis in patients. the most common histopathologic finding on bronchoscopic lung biopsy was ah without vasculitis/capillaritis in patients, followed by ah with capillaritis in patients. there were no procedure related complications or mortality observed with either method of lung biopsy. the clinico-pathologic diagnoses in these patients are shown in tables and . conclusions: in patients with dah undergoing lung biopsy alveolar hemorrhage without capillaritis was found to be the most common histopathologic finding followed by pulmonary capillaritis. these histopathologic findings contributed to the final clinico-pathologic diagnoses of granulomatous polyangiitis and microscopic polyangiitis in a substantial portion of cases. future studies are needed to ascertain the benefits vs. risks of lung biopsy in patients with suspected dah. note that, an apnea of -sec will (by definition) drive mv over a -sec window down to , but will only decrease mv over a -sec window down to~ % mvpred and to less than % over a -min window. (c) likelihood of an apnea of specific length to decrease mv below the low mv cutoff over various time windows. note that a single -sec apnea has just a % chance to decrease mv below % in a -sec window and less than % chance to decrease mv below the cutoff over a -min window. even -sec apneas have just % chance of decreasing sustained mv over a -min window below the % mvpred cutoff ( ) granulomatosis polyangitis ( ) ah without capillaritis ( ) antiphospholipid syndrome ( ) microscopic polyangitis ( ) ah with diffuse alveolar damage( ) microscopic polyangitis ( ) ah with pulmonary vascular changes( ) pulmonary hypertension( ) introduction: assessing the sensitivity of the peripheral chemoreflex (spcr), we can predict the likelihood of developing respiratory and cardiovascular disorders. spcr is one of the markers of disease progression and good prognostic marker [ ] . disturbed respiratory mechanics can make it difficult to evaluate. breath-holding test may be helpful in such situation, the results of this test are inversely correlated with peripheral receptor sensitivity to carbon dioxide in healthy people [ ] .the aim of the study was to compare the breath-holding test to single-breath carbon dioxide test in the evaluation of the sensitivity of the peripheral chemoreflex in subjects with copd. methods: the study involved patients with copd with fev /fvc < % of predicted, all participants were divided into two groups depending of disease severity (gold classification, ). in group (mild-to-moderate copd, n= ) all patients had fev >= % and in group (severe-to-very severe copd, n= ) all patients had fev < %. breath-holding test was performed in the morning before breakfast: voluntary breath-holding duration was assessed three times, with min intervals [ ] . a mean value of the duration of the three samples was calculated. the single-breath carbon dioxide test [ ] was performed the next day. the study was approved by the local ethics committee. all subjects provided signed informed consent to both tests. and january . the data was collected from the hospital electronic and paper notes, and data collected was mortality rate, apa-che ii score, icnarc score, type of respiratory support received and whether there was documentation of advanced decisions in case of acute deterioration. results: there were patients admitted to the icu with acute respiratory failure as a complication of pulmonary fibrosis. the median apache ii score was and icnarc standardised mortality ratio was . . nine patients died on icu ( %) and hospital mortality was ten ( %). eight patients ( %) received high flow nasal oxygen, six ( %) received non-invasive ventilation, and two ( %) received invasive ventilation. the median time to death was . days. of patients for whom paper notes were available, no patient had any documented ceiling of care or end of life decisions. conclusions: our study confirmed a very high mortality in this cohort of patients, supporting national guidance that invasive respiratory support has limited value. we advise that frank discussion with patients and their families should happen early after diagnosis, such that end of life plans are already in place in the event of acute deteriorations. introduction: arf is common in critically ill patients. we compared diaphragm contractile activity in medical and surgical patients admitted to icu with a diagnosis of arf. methods: adult medical and major abdominal laparotomic surgical patients admitted to a general icu with a diagnosis of arf were enrolled. arf was defined as a pao /fio ratio<= mmhg/% and need for mechanical ventilation (mv) for at least hours. diaphragmatic ultrasound was realized bedside when the patient was stable and able to perform a trial of spontaneous breathing. a convex probe was placed in right midaxillary line ( th- th intercostal space) to evaluate right hemidiaphragm. diaphragmatic respiratory excursion and thickening were evaluated in m-mode on consecutive breaths and thickening fraction (tf) was calculated. antropometric, respiratory and hemodynamic parameters, saps , sofa score, duration of mv, need for tracheotomy and timing, septic state and site of infection, superinfections, icu and inhospital length of stay (los) and outcome were recorded. patients with trauma and neuromuscular disorders were excluded. p< . was considered significant. results: we enrolled patients: % medical and % surgical, without differences for age, sex, bmi, saps , sofa score, sepsis and superinfections. moderate arf was prevalent in both groups. during diaphragmatic examination, no differences were recorder for respiratory rate, hemodynamic state and fluid balance. surgical patients showed a lower but not significant diaphragm excursion ( . vs . cm), instead tf was significantly reduced ( vs %,p< . ). no differences emerged on duration of mv, but tracheotomy were higher in medical ones ( vs %,p< . ). icu and inhospital los do not differ between medical and surgical patients and mortality rate was respectively % and %. conclusions: in arf, surgical patients showed a lower diaphragm contractility compared to medical ones, maybe due to the combination of anesthetic and surgical effects, but with no influence on outcome. (fig. ) . the slope of the regression line for pes/paw plots was consistently higher for slow compressions ( . ± . ), as compared to fast ones ( . ± . ). a good agreement between Δ pes and Δ paw (fig. ) was found during slow maneuvers, but not during the fast ones. conclusions: slow chest compressions must be used when checking position/inflation of esophageal balloon. the fast maneuver produces hysteresis and underestimation of Δ pes (but not in direct Δ ppl). pes monitoring at high respiratory rates may be problematic. methods: consecutive comatose post cardiac arrest patients were ventilated with volume assist ventilation ( ml/kg ibw, peep cm h o) using elisa eit (lowenstein medical, ge). orogastric tube (nutrivent, sidam, it) was inserted, and eit vest (swisstom ag, ch) was applied in all patients. measurements were performed min after admission and after hrs (fig. ) . optimal peep was defined as lower inflection point using pv curve (pv), positive ptpeep (ptp) and optimal regional stretch/silent spaces (eit) results: methods to determine peep using pv, ptp and eit were comparable in non obese patients (p=ns introduction: the driving pressure of respiratory system (dp) reflects the extent of lung stretch during tidal breathing, and has been associated with mortality in ards patients during controlled mechanical ventilation [ ] . aim of this study was to examine dp during assisted ventilation, and examine if and when high dp occurs in patients in assisted ventilation with pav+. methods: critically ill patients hospitalized in the icu of the university hospital of heraklion, on mechanical ventilation in pav+ mode were studied. continuous recordings of all ventilator parameters were obtained for up to three days using a dedicated software. dp was calculated from the pav+ computed compliance (c) [ ] , and the measured exhaled tidal volume (vt, dp=vt/c). periods of sustained dp above cmh o were identified, and ventilation and clinical variables were evaluated. results: sixty-two patients and hrs of ventilation were analyzed. in half of the patients, dp was lower than cmh o in % of the recording period, while high-dp (> cmh o) more than % of the total time was observed in % of patients. icu non-survivors had more time with high dp than survivors (p= . ). periods of sustained high-dp (> cmh o for > h) were observed in patients. level of assist, minute ventilation, and respiratory rate were not different between the periods of high dp and the complete recordings, while vt was higher and c was lower during the high-dp period compared to the complete recording. the median compliance was below ml/ cmh o during the high-dp period, and above ml/cmh o during the complete recording. conclusions: high dp is not common, but does occur during assisted ventilation, predominantly when compliance is below ml/cmh o, and may be associated with adverse outcome. table summarizes the percent of monitored time with reported data for the two devices. figure depicts mv decrease following propofol and cannula dislodgement fol- fig. (abstract p ) . bland-altman analysis demonstrated that cvp-derived Δppl and Δpes were correlated significantly lowing a jaw thrust. table ) . negative (a-et) pco was strongly associated with good outcome and were significantly associated with overall survival (fig. ) conclusions: in conclusion, the negative arterial to end-tidal co pressure gradient may predict patient survival in some subgroups. introduction: ards may result from various diseases and is characterized by diffuse alveolar injury, lung edema formation, neutrophil-derived inflammation and surfactant dysfunction. various biomarkers have been studied in diagnostics and prognostication of ards. the purpose of the study was to measure the expression of proinflammatory mediators like il- and tnf, a cellular receptor with a role in innate immunity(tlr- ),and a biomarker of fibrogenesis (mmp- ) in different phases of ards patients. methods: we studied patients admitted to our icu with diagnosis of ards during the month of january . six ml of blood were prospectively collected at two times: during the acute phase and in a sub-acute phase before icu discharge. blood samples were centrifuged to obtain the platelet-rich plasma and plasmatic rna (crna) was isolated from platelets.il- , tnf, tlr- and mmp- expression in crna was determined by the droplet digital™ pcr as copies/ml. results: all patient showed a decrease in il- , tnf, tlr and mmp- levels after the acute phase of ards (fig. ) . patient and were affected by influenza a virus (h n ), patient was admitted for pneumococcal pneumonia and patient was affected by legionella. adequate ethiologic treatment was promptly started in patients with bacterial infection. mean duration of mechanical ventilation was . days. all patient survived icu stay and were discharged from hospital. conclusions: il- , tnf, tlr- and mmp- expression detected by extracted platelets rna, may be a novel tool useful for clinicians indicating persistent inflammation with resulting progressive alveolar fibrosis and impaired lung function. more data are necessary to understand the real clinical significance of this biomarkers and their role in fibroproliferation and progression of ards. introduction: although mesenchymal stem cells (mscs) transplantation has been shown to promote lung respiration in acute lung injury (ali) in vivo, its overall restorative capacity appears to be restricted mainly because of low engraftment in the injured lung. ang ii are upregulated in the injured lung. our previous study showed that ang ii increased mscs migration in an angiotensin ii type receptor (at r)dependent manner [ ] . the objective of our study was to determine whether overexpression of at r in mscs augments their cell migration and engraftment after systemic injection in ali mice. methods: a human at r expressing lentiviral vector was constructed and introduced into human bone marrow mscs. we also downregulated at r mrna expression using a lentivirus vector carrying at r shrna to transduce mscs. the effect of at r regulation on migration of mscs was examined in vitro. a mouse model of lipopolysaccharide (lps) induce ali was used to investigate the engraftment of at r-regulated mscs and the therapeutic potential in vivo. results: overexpression of at r dramatically increased ang ii-enhanced human bone marrow msc migration in vitro. moreover, msc-at r accumulated in the damaged lung tissue at significantly higher levels than control mscs h and h after systematic msc transplantation in ali mice. furthermore, msc-at r-injected ali mice exhibited a significant reduction of pulmonary vascular permeability and improved the lung histopathology and had additional anti-inflammatory effects. in contrast, there were less lung engraftment in msc-shat r-injected ali mice compared with msc-shcontrol after transplantation. thus, msc-shat r-injected group exhibited a significant increase of pulmonary vascular permeability and resulted in a deteriorative lung inflammation. conclusions: our results demonstrate that overexpression of at r enhance the migration and lung engraftment of mscs in ali mice and may provide a new therapeutic strategy for the injured lung. introduction: reorganization of endothelial barrier complex is critical for increased endothelial permeability implicated in the pathogenesis of acute respiratory distress syndrome. we have previously shown hepatocyte growth factor (hgf) reduced lipopolysaccharide (lps)-induced endothelial barrier dysfunction. however, the mechanism of hgf in endothelial barrier regulation remains to be unclear. methods: recombinant murine hgf with or without mtor inhibitor rapamycin were introduced on mouse pulmonary microvascular endothelial cells (pmvecs) barrier dysfunction stimulated by lps. then, endothelial permeability, adherent junction protein (occludin), endothelial injury factors (endothelin- and von willebrand factor), cell proliferation and mtor signaling associated proteins were tested. results: our study demonstrated that hgf decreased lps-induced endothelial permeability and endothelial cell injury factors, and attenuated occludin expression, cell proliferation and mtor pathway activation. conclusions: our findings highlight activation akt/mtor/stat- pathway provides novel mechanistic insights into hgf protective regulation of lps-induced endothelial permeability dysfunction. introduction: mechanical ventilation (mv) is a life-saving intervention for critically ill patients, but may also exacerbate pre-existing lung injury, a process termed ventilator-induced lung injury (vili). interestingly, we fig. (abstract p ) . fluorescein isothiocyanate-dextran or fluorescein isothiocyanate-bsa analysis of the effect of hgf on pmvecs permeability fig. (abstract p ) . western blot analysis of hgf on mtor signaling pathway discovered that the severity of vili is modulated by the circadian rhythm (cr). in this study, we are exploring the role of the myeloid bmal , a core clock component, in vili. methods: we employed mice lacking bmal in myeloid cells (lyzmcre-bmal -/-) and lyzmcre mice as controls. at circadian time (ct) or ct , mice were subjected to high tidal volume mv to induce vili. lung compliance, pulmonary permeability, neutrophil recruitment, and markers of pulmonary inflammation were analyzed to quantify vili. to assess neutrophil inflammatory responses in vitro, myeloid cells from bone marrow of wt and bmal -deficient animals were isolated at dawn zt (zeitgeber time ) and dusk (zt ), incubated with dcfh-da and stimulated for min with pma or pbs. neutrophil activation (ly g/cd b expression) and ros production (dcfh-da/ly g+ cells) were quantified. results: injurious ventilation of control mice at ct led to a significant worsening of oxygenation, decrease of pulmonary compliance, and increased mortality compared to ct . lyzmcre-bmal -/-mice did not exhibit any significant differences when subjected to mv at ct or ct . mortality in lyzmcre-bmal -/-mice after vili was significantly reduced compared to lyzmcre controls (ct ). neutrophils isolated from control mice at zt showed a significantly higher level of activation and increased ros production after pma-stimulation compared to zt . ros production of lyzmcre-bmal -/-neutrophils did not differ from zt to zt . conclusions: the lack of the clock gene bmal in myeloid cells leads to increased survival after injurious ventilation and to loss of circadian variations in neutrophil ros production. this suggests that the internal clock in myeloid cells is an important modulator of vili severity. introduction: hemodynamic resuscitation by means of fluids and norepinephrine (ne) is currently considered as a cornerstone of the initial treatment of septic shock. however, there is growing concern about the side effects of this treatment. the aim of this study was to assess the relationship between the hemodynamic resuscitation and the development of the ards. methods: new zealand rabbits. animals received placebo (sham= ) or lipopolysaccharide (lps) with or without (edx-r, n= ; edx-nr, n= ) hemodynamic resuscitation (fluids: ml/kg of ringer's lactate; and later ne infusion titrated up to achieve theirs initial arterial pressure). animals were monitored with an indwelling arterial catheter and an esophageal doppler. respiratory mechanics were continuously monitored from a sidestream spirometry. pulmonary edema was analyzed by the ratio between lung wet and lung dry weight (w/d), and the histopathological findings. results: sham group did not show any hemodynamic or respiratory changes. the administration of the lps aimed at increasing cardiac output and arterial hypotension. in the lps-nr group, animals remained hypotensive until the end of experiment. infusion of fluids in lps-r group increased cardiac output without changing arterial blood pressure, while the norepinephrine reversed arterial hypotension. compared to the lps-nr group, the lps-r group had more alveolar neutrophils and pneumocytes with atypical nuclei, thicker alveolar wall, non-aerated pulmonary areas and less lymphocyte infiltrating the interstitial tissue. in addition, the airway pressure increased more in the group lps-r, and the w/d, although slightly higher in the lps-r, did not show significant differences. conclusions: in this model of experimental septic shock resuscitation with fluid bolus and norepinephrine increased cardiac output and normalized blood pressure but worsened lung damage. obese patients have been excluded from most of the clinical trials testing the effects of peep in ards. we hypothesized that in morbidly obese patients the massive load of the abdomen/chest further increases lung collapse thus aggravating the severity of respiratory failure due to ards. methods: we performed a clinical crossover study to investigate the contribution of lung collapse to the severity of respiratory failure in ards obese patients and to determine the specific contribution of titrated peep levels and lung recruitment to changes in lung morphology, mechanics and gas exchange. patients were studied at the peep (peepicu) levels selected at our institution and at peep levels establishing a positive end-expiratory transpulmonary pressure (peepinc) and at peep levels determining the lowest lung elastance during a decremental peep (peepdec) trial following rm. results: thirteen patients were studied. at peepicu end-expiratory transpulmonary pressure was negative, lung elastance was increased and hypoxemia was present (table ) . regardless the titration technique there was no difference in the peep level obtained. at peepinc level endexpiratory lung volume increased, lung elastance decreased thus improving oxygenation. setting peep according to a peepdec trial after a rm further improved lung elastance and oxygenation. at peedec level after a rm lung collapse and overdistension were minimized (fig. ) . all patients maintained titrated peep levels up to hours without complications. conclusions: in severely obese patients with ards, setting peep according to a peepinc trial or peepdec trial following a rm identifies the same level of optimal peep. the improvement of lung mechanics, lung morphology and oxygenation at peepdec after a rm suggests that lungs of obese ards patients are highly recruitable and benefit from a rm and high peep strategy. introduction: lung protective ventilation (lpv) strategies, principally focused around the use of tidal volumes < ml/kg predicted body weight (pbw) remains an enduring standard of care for ventilated patients. however, implementation of and compliance with lpv is highly variable. we used 'nudge'-based interventions to assess if these can improve lpv. methods: ventilation data analysis over years ( hours in patients) showed patients had been ventilated with a median tidal volume of . ml/kg pbw with a significant proportion receiving over ml/kg pbw (fig. ) , an effect more pronounced in female patients and those with higher bmi. interventions: ) creation of a software tool to easily identify and monitor patients receiving tidal volumes that were too high for their pbw ) attached laminated reference guides to each ventilator to calculate pbw ) presentation, opportunistic education and verbal prompts to relevant clinical care staff regarding importance of lpv and use of pbw rather than actual body weight ) incorporating checking of tidal volumes on a daily ward rounds from junior clinical members results: we collected hourly ventilation data of the patients over a -week period ( hours in patients) following our interventions. there was, overall a statistically significant reduction tidal volume (p< . ). there was improvement in the ventilation of male patients (p< . ) but female patients endured higher tidal volumes. there was a mixed picture in different bmi grades. conclusions: reducing tidal volumes in mechanically ventilated patients can be done through a mix of behavioural and educational interventions, as well as using technological shortcuts. this helps to reduce the effort on the part of clinical staff to adhere to best practices, and ultimately improve patient outcomes. introduction: lung protective ventilation (lpv) using a tidal volume (vt) of - ml/kg ideal body weight (ibw) is recommended in the intensive care unit and theatres to reduce the incidence of pulmonary complications. the aim of this audit was to assess the extent to which lpv is used in theatres in a busy district general hospital and to implement measures to promote adherence to the recommendations. methods: anaesthetists completed questionnaires for all patients undergoing general anaesthesia at northwick park hospital over week. demographics, actual body weight (abw), height, american society of anesthesiologists (asa) score, and procedural information were recorded. ventilatory parameters included the ventilation mode, vt, and positive end expiratory pressure (peep (fig. ) . significantly more females ( %) received vt >= ml/kg than males ( %) (p< . ) (fig. ) . vt was independent of age, asa, bmi, ventilation mode, speciality, and patient position. conclusions: over half of the patients received vt >= ml/kg ibw. females were more likely to be over ventilated. a likely contributing factor is the disparity between abw and ibw in this cohort. we organised staff teaching and constructed ibw charts with the appropriate corresponding tidal volumes to be displayed in all theatres to promote the use of lpv. results: there were significant differences in ards incidence between groups: ards developed in . % of protective mv groups vs. . % of standard mv group (p= . , fisher's exact test). vap patients ventilated in a protective mode presented with lower duration of mv ( . ± . days) and icu stay( . ± . days) than patients with standard mv ( . ± . and . ± . days). there were significant differences in mortality rates between patient groups: . % in protective mv and . % in standard mv (p= . , fisher's exact test). conclusions: protective mv prevents the development of ards in vap septic patients. introduction: reduction of tidal volumes (tv) below ml/kg associated with low driving pressure (dp) might improve lung protection in patients with acute respiratory distress syndrome (ards). the current study tests the combination of coaxial double lumen endotracheal tube (to reduce instrumental dead-space) and moderately respiratory rate (rr) (< bpm) to maintain co at clinically acceptable levels while using ultraprotective tv. the objective is to considerably reduce dp, which has been preconized as an index more strongly associated with survival than tv, per se, methods: juvenile pigs were anesthetized, intubated and mechanically ventilated. severe lung injury (p/f< ) was induced using a double-hit model: repeated surfactant wash-out followed by injurious mechanical ventilation using low positive end-expiratory pressure and high dp (~ cmh o) for hours. then vts of , , and ml/kg were used in random sequence for min each, both using a standard and coaxial endotracheal tube. at each vt level, rr was adjusted to achieve paco = mmhg but not exceeding bpm. lung functional parameters and blood gas analysis were measured at each vt level. statistical analysis was performed using mixed linear model. results: coaxial endotracheal tube, but not the conventional tube, allowed decreasing vt to and ml/kg, while keeping paco at approximately mmhg and rr< bpm, reducing dp of . cmh o and . cmh o, respectively, compared to the conventional vt of ml/kg (fig. ) . conclusions: in this ards model, coaxial tube ventilation associated with moderately high rr allowed ultraprotective ventilation (vt= ml/kg) and reduced dp levels, maintaining paco at acceptable levels. this strategy might have a significant impact on mortality of severe ards patients. the table shows oxygenation and respiratory mechanics. figure : echocardiographically measured right heart function. conclusions: in morbidly obese mechanically ventilated patients with ards an increase in peep by cmh o (from . ± . cmh o to . ± . cmh o) did not impair right heart function, but improved respiratory mechanics and oxygenation. introduction: mechanical ventilation can, while being lifesaving, also cause injury to the lungs. the lung injury is caused by high pressures and mechanical forces but also by inflammatory processes which are not fully understood [ ] . heparin binding protein (hbp) released by activated granulocytes has been indicated as a possible mediator of increased vascular permeability in the lung injury associated with trauma and sepsis [ , ] . we wanted to investigate if hbp levels were increased in bronco alveolar lavage (bal) fluid or plasma in a pig model of ventilator induced lung injury. methods: anaesthetized pigs were surfactant depleted by saline lavage and randomized to receive ventilation with either tidal volumes of ml/kg with a peep of cm h o (controls, n= ) or ml/kg with a peep of cm h o (ventilator induced lung injury (vili) group, n= ). plasma and bal samples of hbp were taken at , , , and hours (fig. ) . results: characteristics of pigs by study group are shown in table . plasma levels of hbp did not differ significantly between pigs in the control and vili group at any time of sampling. hbp levels in bal fluid were significantly higher in the vili group after (p= . ), (p= . ), (p< . ) and (p= . ) hours of ventilation (fig. ) . conclusions: in a model of ventilator induced lung injury in pigs, levels of heparin binding protein in bal fluid increased significantly over time compared to controls. plasma levels however did not differ significantly between groups. (fig. ) . conclusions: this meta-analysis concluded that corticosteroid treatment in ards provided no benefit in decreasing mortality. in addition, this treatment was not associated with increasing risk of nosocomial infection. (fig. ) . the change in the pao /fio ratio was significant [rr( %ci)= . ( . - . ), p= . ] (fig. ) . finally, trial sequential analysis and grade indicated lack of firm evidence for a beneficial effect. conclusions: surfactant administration may improve oxygenation but has not been shown to improve mortality for adult ards patients. large rigorous randomized trials are needed to explore the effect of surfactant to adult ards patients. moderate to severe acute respiratory distress syndrome in a population of primarily non-sedated patients, an observational cohort study l bentsen, t strøm, p introduction: extracorporeal carbon-dioxide removal (ecco r) might allow ultraprotective mechanical ventilation with lower tidal volume (vt) (< ml/kg predicted body weight), plateau (pplat) (< cmh o) and driving pressures to limit ventilator-induced lung injury. this study was undertaken to assess the feasibility and safety of ecco r managed with a renal replacement therapy (rrt) platform to enable ultraprotective ventilation of patients with mild-to-moderate ards. methods: patients with mild (n= ) or moderate (n= ) ards were included. vt was gradually lowered from to , . and ml/kg, and peep adjusted to reach <=pplat<= cm h o. stand-alone ecco r (prismalung, no hemofilter associated with the rrt platform) was initiated when arterial paco increased by > % from its initial value. ventilation parameters (vt, rr, peep), respiratory system compliance, pplat and driving pressure, arterial blood gases, and ecco r-system characteristics were collected during at least hours of ultraprotective ventilation. complications, day- mortality, need for adjuvant therapies, and data on weaning off ecco r and mechanical ventilation were also recorded. results: while vt was reduced from to ml/kg and pplat kept < cmh o, peep was significantly increased from . ± . at baseline to . ± . cm h o, and the driving pressure was significantly reduced from . ± . to . ± . cm h o (both p< . ). the pao / fio ratio and respiratory-system compliance were not modified after vt reduction. mild respiratory acidosis occurred, with mean ph decreasing from . ± . to . ± . from baseline to -ml/kg vt. mean extracorporeal blood flow, sweep-gas flow and co removal were ± ml/min, ± . l/min and ± ml/min, respectively. mean treatment duration was ± hours. day- mortality was %. introduction: there is no consensus on the management of anticoagulation during extracorporeal membrane oxygenation (ecmo). ecmo is currently burdened by a high rate of hemostatic complications, possibly associated with inadequate monitoring of heparin anticoagulation. this study aims to assess the safety and feasibility of an anticoagulation protocol for patients undergoing ecmo based on thromboelastography (teg) as opposed to an activated partial thromboplastin time (aptt)-based protocol. methods: we performed a multicenter, randomized, controlled trial in two academic tertiary care centers. adult patients with acute respiratory failure treated with veno-venous ecmo were randomized to manage heparin anticoagulation using a teg-based protocol (target - minutes of the r parameter, teg group), or a standard of care aptt-based protocol (target . - of aptt ratio, aptt group). primary outcomes were safety and feasibility of the study protocol. results: forty-two patients were enrolled, were randomized to the teg group and to the aptt group. duration of ecmo was similar in the two groups ( ( - ) days in the teg group and ( - ) days in the aptt group, p= . ). heparin dosing was lower in the teg group compared to the aptt group ( . ( . - . ) iu/kg/h versus . ( . - . ) iu/kg/h respectively, p= . ). safety parameters, assessed as number of hemorrhagic or thrombotic events and transfusions given, were not different between the two study groups. as for the feasibility, the teg-based protocol triggered heparin infusion rate adjustments more frequently (p< . ) and results were less frequently in the target range compared to the aptt-based protocol (p< . ). number of prescribed teg or aptt controls (according to study groups) and protocol violations were not different between the study groups. conclusions: teg can be safely used to guide anticoagulation management during ecmo. its use was associated with the administration of lower heparin doses compared to a standard of care apttbased protocol. methods: single-center retrospective study of patients (n= ; ± . years; % males) undergoing vv-ecmo for severe ards. the acp-score ( - ) was calculated immediately before ecmo initiation and at ecmo-day , -day and -day , as follows: pneumonia as cause of ards - point; driving pressure >= cmh o - point; pao /fio ratio < mmhg - point; paco >= mmhg - point. results: longer duration of mechanical ventilation before vv-ecmo was associated with higher acp-scores. patients with higher acp-scores before vv-ecmo also presented longer total duration of mechanical ventilation and hospital stay. after vv-ecmo initiation, acp-scores significantly decreased from . ± . to . ± . , . ± . and . ± . at ecmo-day , -day and -day , respectively. at ecmo-day , patients with higher acp-scores ( - ) presented increased hospital mortality when compared with patients with lower acp-scores ( - ): . vs. . %, respectively (p= . ). at ecmo-day , high driving pressures and low pao /fio ratios were the acp-score determinants that significantly associated with increased hospital mortality. conclusions: in severe ards, vv-ecmo support allowed a significant and sustained acp-score reduction in most patients. this was achieved by artificial lung correction of low pao /fio , hypercapnia and elevated driving pressures. after an initial period of vv-ecmo support, patients with higher acp-scores present higher mortality rates. our results suggest that on-going adjustment of ecmo and ventilation parameters is necessary to maximize outcome. introduction: we sought to use mechanical power to describe "lung rest" in patients with acute respiratory distress syndrome (ards) supported with extracorporeal membrane oxygenation (ecmo). mechanical power describes work done by the ventilator on the patient's respiratory system over time. this concept unifies tidal volume, rate, and total pressure delivered during the ventilatory cycle into a discrete value that may be useful to guide ventilatory support. we hypothesized that initiation of ecmo led to decreased mechanical power delivered to the patient. methods: we reviewed the charts of the three medical intensive care unit patients at our institution supported with ecmo for severe ards. we collected data on plateau pressure, driving pressure, and mechanical power before initiating ecmo, then at < hours, hours, and hours after. we calculated the mechanical power delivered by the ventilator to the patient in joules per minute as . x respiratory rate x tidal volume x (peak pressure -½ x driving pressure) [ ] . results: all patients were alive at discharge and at days. mean pao /fio at ecmo initiation was ± , mean plateau pressure was ± cm water. all patients received neuromuscular blockade at initiation of ecmo. following ecmo initiation, mechanical power decreased by an average of %± % initially, by %± % at hours, and by %± % at hours (fig. ) . by comparison, driving pressure changed by an average value of - . ± . , - . ± . , and - . ± . cm water over those same intervals. average plateau pressure changed by - . ± . , - . ± . , and - . ± . cm water during the same time period (fig. ) . conclusions: in our limited case series, mechanical power decreased significantly following initiation of ecmo in patients with severe ards. we suggest mechanical power may be more useful than changes in driving pressure or plateau pressure when pursuing "lung rest" during ecmo. introduction: it is not clear whether acute respiratory distress syndrome (ards) is independently associated with mortality after controlling for underlying risk factor and baseline severity of illness. we attempted to assess the attributable mortality of ards by performing a systematic review and meta-analysis. methods: we systematically searched pubmed, embase, scopus and reference lists to identify observational studies reporting mortality rates of critically ill patients with and without ards. all included studies were matched for underlying risk factor. primary outcomes were all-cause in hospital-mortality and short-term mortality (combined day-mortality and intensive care unit-mortality). we calculated pooled risk ratios (rr) and % confidence intervals (ci) with a random-effects model. our meta-analysis was registered with prospero. results: of the initially retrieved articles, studies ( cohorts) involving patients were included. the underlying risk factor was sepsis, trauma and other in , and cohorts, respectively. in-hospital mortality was higher in patients with versus without ards ( cohorts; patients; rr . , % ci . - . ; p< . ). we saw a numerically stronger association between ards and inhospital mortality in trauma (rr . , % ci . - . ; p< . ) than sepsis (rr . , % ci . - . ; p= . ). short-term mortality was higher in patients with versus without ards ( cohorts; patients; rr . , % ci . - . ; p= . ). ards was independently associated with mortality in approximately half of the cohorts which controlled for baseline severity of illness using a multivariable analysis. conclusions: the accumulated evidence suggests that ards is independently associated with mortality after controlling for underlying risk factor; the association is stronger for trauma than septic patients. evidence is mixed as to whether ards is independently associated with mortality after controlling for baseline severity of illness. introduction: evidence is mixed as to whether acute respiratory distress syndrome (ards) is independently associated with mortality after controlling for baseline severity of illness, particularly in patients with sepsis. methods: this was an observational study comparing mortality rates of septic patients with and without ards. subjects for the present study were enrolled in ongoing prospective cohorts of critically ill patients hospitalized in medical intensive care unit (icu) in the united states or south korea. ards was defined using the berlin definition for cases after and the american-european consensus conference definition for cases before . sepsis was defined using the sepsis- definition. baseline severity of illness was assessed using a modified sequential organ failure assessment (sofa) after exclusion of the respiratory component. the primary outcome was inhospital mortality. results: of the critically ill patients enrolled in the cohorts, ( . %) had sepsis and comprised the population of the present study. of the septic patients, ( . %) had ards. patients with versus without ards had higher sofa score; both total (median vs ; p< . ) and modified ( vs ; p< . ). the unadjusted mortality of septic patients with ards was higher than septic patients without ards ( . % vs . %; p< . ). after controlling for baseline modified sofa score, both moderate and severe ards remained significant predictors for in-hospital mortality [odds ratio (or) . ; % confidence intervals (ci) . - . ; p< . and or . ; % ci . - . ; p< . , respectively]. in contrast, after controlling for baseline modified sofa score, mild ards was not associated with in-hospital mortality (or . ; % ci . - . ; p= . ). conclusions: among critically ill patients with sepsis, moderate and severe, but not mild, ards are associated with mortality after controlling for baseline severity of illness. a multicenter study on the inter-rater reliability of heart score among emergency physicians from three italian emergency departments introduction: previous studies suggested that the heart (based on history, ecg, age, risk factors, troponin) score could be a valid tool to manage the patients with chest pain at the emergency department (fig. ). our hypothesis was that there could be heterogeneity in the assignment, because of the history and ecg parameters. for this reason, our objective was to test the heart reliability. there are no published studies on this topic. methods: this is a multicenter retrospective study conducted in italian eds between march and october using clinical scenarios. twenty emergency physicians were included, provided that they had undergone a course on heart score. we used scenarios from a medical database with each scenario including demographic and clinical characteristics. each participant assigned scores to the scenarios using the heart. we tested the measure of interrater agreement using the kappa-statistic, the confidence intervals are bias corrected. a p-value of < . was used to define statistical significance. results: the participants' assignment is shown in fig. . the overall inter-rater reliability was good: kappa = . (ci %; . - . ); with a good agreement between the low and high class of risk but a moderate reliability in the medium class: kappa= . , . and . . we have not found differences of inter-rater reliability among the senior (more than yrs in ed) and junior physicians: kappa= . (ci %; . - . ) and . (ci %; . - - ).the heart score showed the worse value of inter-rater reliability in the history and ecg parameters : k inter = . (ci %; . - . ) and . (ci %; . - . ). conclusions: the heart showed a good inter-rater reliability but a fair agreement in the history parameter. the clinical experience doesn't influence the agreement in the assignment. the main limit of this study lies in using scenarios rather than real patients. introduction: the aim of the experiment was to study the efficacy of preconditioning, based on changes in inspiratory oxygen fraction on endothelial function in a model of myocardial ischemia/reperfusion injury in conditions of cardiopulmonary bypass (cpb). methods: the prospective study included rabbits divided into four equal groups: hypoxic preconditioning; hyperoxic preconditioning (hyperp); hypoxic-hyperoxic preconditioning (hhp); control group. animals were anesthetized and mechanically ventilated. we provided preconditioning, then started cpb, and then induced acute myocardial infarction by ligation of left anterior descending artery. after minutes of ischemia we performed minutes of reperfusion. we investigated endothelial function markers (endothelin- (et- ), asimmetric dimethylarginine (adma), nitric oxide metabolites) at stages before ischemia (after preconditioning in study groups), after ischemia and after reperfusion. results: the level of et- after the stage of ischemia increased in all groups, a significant difference was between hhp and control group (p= . ), then et- increased even more after the stage of reperfusion (p= . hhp vs control group). the concentration of nitrite decreased after the stages of ischemia and reperfusion in comparison with the baseline in all groups. however, the level of nitrite after all types of preconditioning was higher than in the control group (p= . ; . ; . ). the total concentration of nitric oxide metabolites in the study groups was higher than in the control group: before ischemia (after preconditioning) p= . ; after ischemia p= . ; after reperfusion, p= . . concentration of adma was lower in the hhp comparing with the control group at the stages after ischemia (p= . ) and after reperfusion (p= . ). conclusions: hyperp and hhp maintain endothelial function: the balance of nitric oxide metabolites and the reduction of et- hyperproduction in a model of myocardial ischemia/reperfusion injury in conditions of cpb. upscaling hemodynamic and brain monitoring during major cancer surgery: a before-after comparison study introduction: hemodynamic and brain monitoring are used in many high-risk surgical patients without well-defined indications and objectives. in order to rationalize both hemodynamic and anesthesia management, we implemented monitoring guidelines for patients undergoing major cancer surgery. methods: early , and for all eligible patients, we started to recommend (standard operating procedure, sop) cardiac output, central venous oxygen saturation, and depth of anesthesia monitoring with specific targets (map > mmhg, svv < %, ci > . l/min/ m , scvo > %, < bis < ). eligibility criteria were pelvic or abdominal cancer surgery expected to last > hours in adult patients. pre-, intra-, and post-operative data were collected from our electronic medical record (emr) database and compared before (from march to august ) and after (from march to august ) the sop implementation. results: a total of patients were studied, before and after the sop implementation. the two groups were comparable in terms of age, asa score, duration and type of surgery, the surgical possum score was higher after than before ( vs , p= . ). the use of cardiac output, scvo and bis monitoring increased from to %, to %, and to %, respectively (all p values < . ). intraoperative fluid volumes decreased ( . vs . ml/kg/h, p= . ), whereas the use of inotropes increased ( vs %, p= . ). the rate of postoperative delirium ( vs %, p= . ) and urinary track infection ( vs %, p= . ) decreased, as well as the median hospital length of stay ( . vs . days, p= . ). conclusions: in patients undergoing major surgery for cancer, despite an increase in surgical risk, the implementation of guidelines with predefined targets for hemodynamic and brain monitoring was associated with a significant improvement in postoperative outcome. introduction: tissue perfusion and oxygen delivery is low in patients with severe preeclampsia, which would explain multiple organ failure and death in these patients. the aim of this study was to determine the relationship between the base deficit and the risk of adverse maternal and perinatal outcomes. methods: retrospective multicenter cohort study included pregnant patients with severe preeclampsia admitted to six intensive care units at tertiary referral centers during a ten years period in colombia. clinical information was gathered from hospital medical records. the correlation of base deficit with adverse maternal outcomes was evaluated using logistic regression analysis. outcomes were maternal death, acute kidney injury, hellp syndrome, transfusion, eclampsia and extreme neonatal morbidity. results: patients were included in the study, we found a total of ( , %) maternal deaths, the median calculated base deficit obtained was - . meq/l. patients with base deficit greater than - . meq/l had significantly higher mortality rates or . (ci . - . ) p , . this group of patients was also associated with a higher probability of developing a class hellp syndrome or . (ci . - . ) p , . a more mild alteration in the base deficit (greater than - . meq/l) was related to the appearance of kidney injury or . (ci . - . ) p . y complete hellp or . (ci . - . ) p . . conclusions: base deficit is related to worse outcomes in patients with severe preeclampsia. according to our results, a cut-off point greater than - meq/l, there is a higher risk of death and worse outcomes such as class hellp syndrome. comparison of two different laser speckle contrast imaging devices to assess skin microcirculatory blood flow g guven, y ince, oi soliman, s akin, c ince erasmus mc, university medical center rotterdam, rotterdam, netherlands critical care , (suppl ):p introduction: laser speckle contrast imaging (lsci) is a common, non-contact and practical method used to assess blood flow of tissue surfaces. we have lack of knowledge about comparability of different lsci devices due to the arbitrary units (au) used to define blood flux. we sought to examine the linearity between skin blood flux, recorded using two different lsci devices. methods: we performed post-occlusive reactive hyperemia test (porh) on the arm and measured blood flux on the hand using two different lsci devices (moor instruments, devon, uk and perimed ab, järfälla, sweden). all volunteers were measured at baseline, during occlusion and after release of occlusion during the hyperemia phase. the third finger and fourth finger nail were selected for recording blood flux and au were used to express values. results: fifteen healthy, non-smoker male volunteers participated in this study. an excellent correlation was found between the two lsci devices (finger: r : . , p< . & finger nail: r : . , p< . ). data were also assessed in terms of the variability at different stages of the porh test (fig. a-d) . correlation of devices was still high at baseline, first minute of occlusion and in the post-occlusion hyperemia phase. however, in the period between minute after start of the occlusion and the beginning of the hyperemia, correlation was lower for the whole finger (r : . , p= . ) and correlation was lost for fingernail (r : . , p= . ) between the two devices. conclusions: skin blood flux measured with two different lsci devices are linearly correlated with each other. however care should be taken when assessing patients with low blood flux such as occurs during shock and ischemic organs. introduction: the aim of this study was to evaluate the effects of hyperoxia and mild hypoxia on microcirculatory perfusion in a rat model. methods: spontaneously breathing anesthetized (isoflurane) male wistar rats (n= ) were equipped with arterial (left carotid) and venous (right jugular) cannulae and tracheotomy. rats were randomized in groups: normoxiainspired oxygen fraction (fio ) of . ; hyperoxia -fio ; mild hypoxia -fio . . the following measurements were taken hourly for hours: blood gases, mean arterial pressure (map), stroke volume index (svi) and heart rate (echocardiography), skeletal muscle microvascular density (sidestream dark field videomicroscopy). results: at hour, arterial o tension was ± mmhg in normoxia, ± mmhg in hyperoxia, ± mmhg in mild hypoxia (p< . ). hyperoxia induced an increase in map (from ± to ± mmhg at h, p< . ) and a decrease in svi (from . ± . to . ± . ml/kg at h, p< . ), while in mild hypoxia map tended to decrease and svi tended to increase (p> . ). microvascular density decreased in hyperoxia and increased in mild hypoxia (fig. ) . conclusions: in anesthetized rats, microvascular density decreased with hyperoxia and increased with mild hypoxia. introduction: the imbalance between oxygen (o ) delivery and o requirement in patients with sepsis can be assessed by central venous oxygen saturation (scvo ). the low or high scvo may indicate cellular hypoxia or inability to utilize the o . this study aims to determine the relationship between high scvo and mortality in patients with sepsis. methods: a retrospective observational cohort study was done by collecting data (i.e., baseline characteristics, severity of infection and vasopressors) from medical records of >= -year-old patients with sepsis and st scvo measurement within hours of sepsis, who were admitted in a university hospital between and . the patients were stratified by st scvo level (< %, - %, > %) and apache-ii score (<= , > ). the primary outcome was inhospital mortality. results: among patients, those with high scvo ( . %) and low scvo ( . %) were associated with adjusted hazard ratios for death of . ( . - . , p= . ) and . ( . - . , p= . ), respectively, while those with normal scvo ( . %) as control. when the patients were stratified by scvo level and apache-ii score, using patients with normal scvo and low apache-ii score as control, those with high scvo and low apache-ii score, and those with low scvo and low apache-ii score had adjusted hazard ratios of . ( . - . , p= . ) and . ( . - . , p= . ). for those with normal, high and low scvo , and high apache-ii score had adjusted hazard ratios of . ( . - . , p= . ), . ( . - . , p= . ), and . ( . - . , p= . ), respectively. conclusions: the scvo > % with apache-ii score > , but not only scvo > %, is independently related to increased mortality in patients with sepsis. introduction: serum lactic acid levels and scvo are useful predictive parameters for patients with sepsis. however, little is known the differences in the impact of lactate levels and scvo on the prognosis of septic patients. in this study, we investigated these differences by analysing septic patients' characteristics and prognosis. methods: this study is a post hoc analysis of data obtained from a multicentre, prospective, randomized controlled trial, which compared two fluid management strategies for septic patients requiring mechanical ventilation. we categorised patients into the following four groups: scvo >= % and lactic acid levels < mmol/l (hh group); scvo >= % and lactic acid levels < mmol/l (hl group); scvo < % and lactic acid levels >= mmol/l (lh group) and scvo < % and lactic acid levels < mmol/l (ll group). sofa score, saps ii score, lactic acid levels, scvo and bnp were evaluated. primary outcome was -day mortality, whereas secondary outcomes were the duration of mechanical ventilation, administration of crrt, duration of catecholamine therapy and length of icu stay. results: in total, patients were included: hh group (n = ), hl group (n = ), lh group (n = ) and ll group (n = ). no significant differences were observed in terms of patient characteristics. further, -day mortality was % in the lh group, . % in the hh group, % in the ll group and % in the hl group, and there was no significant difference in terms of mortality among the groups. furthermore, there were no significant differences in terms of secondary outcomes. on multivariate analysis using the hl group as reference, the odds ratios for -day mortality in the lh, hh and ll groups were . ( %ci, . - . ), . ( %ci, . - . ) and . ( %ci, . - . ), respectively. conclusions: because -day mortality was higher in the hh group than in the ll group, serum lactic acid levels may have bigger impact on the prognosis of septic patients. introduction: in septic shock endothelial damage can lead to failure of microcirculation and low microcirculatory oxygen saturation. in the skin this is seen as mottling and can be quantified using hyper fig. (abstract p ) . changes in microvascular density spectral imaging. there is insufficient data about associations between skin oxygenation, severity of illness, biomarkers of endothelial damage and mortality in patients with septic shock. methods: this single centre observational study was performed in consecutive intensive care patients with septic shock. within hours of admission hyper spectral imaging of knee area skin was performed and blood was sampled for assay of biomarkers of endothelial cell damage (plasminogen activator inhibitor - (pai- ), soluble intercellular adhesion molecule (sicam- ), soluble vascular cell adhesion molecule (svcam- ), thrombomodulin, angiopoetin- ). nonlinear fitting of optical density spectra was used to calculate relative skin oxy/deoxy hemoglobin concentration and obtain oxygen saturation. the association between skin oxygen saturation, biomarkers, sepsis severity (apache ii, sofa) and -day mortality was analyzed. results: the median (iqr) age of patients was years ( to ), and % were males. the median sofa and apache ii scores were ( to ) and ( to ) and -day mortality rate was %. patients ( %) had mottling. there was a relationship between skin oxygenation, plasma biomarkers (thrombomodulin and svcam- ) and sepsis severity assessed by sofa and apache ii scores, p < . . using logistic regression analysis, skin oxygenation and biomarker concentrations were not associated with -day mortality rate. conclusions: in our cohort of patients with septic shock, skin oxygenation and biomarkers of endothelial injury were strongly associated with initial severity of sepsis but poorly predictive of -day mortality. comparison between ultrasound guided technique and digital palpation technique for radial artery cannulation in adult patients: a meta-analysis of randomized controlled trials s maitra, s bhattacharjee, d baidya all india institute of medical sciences, new delhi, new delhi, india critical care , (suppl ):p introduction: possible advantages and risks associated with ultrasound guided radial artery cannulation in-comparison to digital palpation guided method in adult patients are not fully known. previous meta-analyses included both adult and pediatric patients and long axis in-plane technique and short axis out of plane technique in the same analysis, which may have incurred biases [ , ] . methods: pubmed and cochrane central register of controlled trials (central) were searched (from to th november ) to identify prospective randomized controlled trials in adult patients where dimensional ultrasound guided radial artery catheterization has been compared with digital palpation guided technique. for continuous variables, a mean difference was computed at the study level, and a weighted standardized mean difference (smd) was computed in order to pool the results across all studies. for binary outcomes, the pooled odds ratio (or) with % confidence interval ( % ci) was calculated using the inverse variance method. results: data of patients from studies have been included in this meta-analysis. overall cannulation success rate was similar between short axis out of plane technique and digital palpation [p= . ; fig. ] and long axis in-plane technique with digital palpation. ultrasound guided long axis in-plane approach and short axis out of plane approach provides better first attempt success rate of radial artery cannulation in comparison to digital palpation [p= . and p= . respectively; fig. ]. no difference was seen in time to cannulate between long axis and short axis technique with palpation technique. conclusions: usg guided radial artery cannulation may increase the first attempt success rate but not the over all cannulation success when compared to digital palpation technique. introduction: ultrasound guidance may improve the success rate of vascular cannulation. there is lack of data regarding the utility of usg guided arterial cannulation in critically ill patients in shock. we aim to compare the impact of using real time ultrasound guidance versus palpation method in achieving arterial catheterization in critically ill patients in hypotension. methods: a single center, prospective, randomized trial was performed among critically ill patients aged > years, with hypotension (or requiring vasopressor infusion) and on not previous cannulated radial arteries. patients were randomized in a ratio of : to the ultrasound group or palpation group. under aseptic precautions, arterial puncture was performed using appropriate sized leader cath (vygon, ecquen, france), under real time usg guidance using short-axis out-of-plane view with bevel down. data were recorded and compared between two groups. the unpaired student's t-test or mann-whitney u test were used for continuous variables, and the uncorrected chi-squared or fisher's exact test were used for proportions. results: a total of patients with hypotensive shock requiring radial artery catheterization were randomized into palpation (n = ) and ultrasound (n = ) groups. first pass success rate was significantly higher in ultrasound group as compared to palpation group ( % vs %, p< . ). cannulation time was significantly shorter in ultrasound group ( . vs . ,p< . ). early complications were significantly higher in palpation group compared to ultrasound group ( . % vs . %, p< . ). conclusions: in critically ill patients with hypotension (or requiring vasopressors), ultrasound guidance improved first pass success rate, shortened the cannulation time and reduced the rate of early complications in radial artery catheterizations. relationship between inferior vena cava diameter and variability with mean arterial pressure and respiratory effort b kalin, k inci, g gursel gazi university school of medicine, ankara, turkey critical care , (suppl ):p introduction: there is no consensus on the use of vena cava inferior (ivc) diameter and variability in the assessment of fluid response (fr) in spontaneously breathing icu patients. influence from respiratory effort, experience requirement and measurement problems are reasons for not being preferred. the aim of the study is to investigate the relationship between ivc diameter, variability and spontaneous breathing effort and hypotension measured by ultrasonography in spontaneously breathing intensive care patients methods: the maximum and minimum diameters of the ivc were measured and the collapsibility index (ci) was calculated. measurements were made in d mode on cineloop recordings. diaphragm thickening ratio was used as a measure of respiratory effort. correlations between respiratory effort criteria with ivc minimum diameter and ci were calculated by pearson's correlation coefficient. ivc measurement criterias, such as inspiratory diameter of < cm, %, %, % of the ci were compared with chi square test in hypotensive and non-hypotensive patients. we took two mean arterial pressure threshold for hypotension as and mmhg for this calculation. results: patients were included in the study. for both hypotensive threshold values, there was no significant difference in the rates of hypotensive and non-hypotensive patients with and without a minimum ivc diameter of cm below. even there was no significant relationship between the ci higher than %, % and % and hypotension (p> . ). in spontaneously breathing patients, a significant correlation was found between respiratory effort and ivc ci and ivc diameter < cm conclusions: at the end of the study, there was a correlation between spontaneous breathing effort ivc diameter and ci in the intubed patients. additionally the result that ivc ci is not different even between hypotensive and non-hypotensive patients suggests that this method should be used with caution in predicting fr. introduction: fluid responsiveness in icu patients can be assessed using changes in pulse rate and blood pressure following administration of a fluid bolus, assisted if necessary by cardiac output (co) monitors such as the lidcoplus. this uses pulse contour analysis to estimate stroke volume (sv), with > % change in sv following a fluid challenge (fc) signifying overall benefit. there is no evidence that the use of co monitoring improves patient outcomes and it is unclear if it improves clinical decision making. methods: a lidcoplus monitor was set up with the screen covered. a ml fc was administered over minutes. the heart rate, systolic and mean arterial pressures were recorded before and after the fc. the clinician administering the fc was asked to decide if the patient was fluid responsive. following this decision, the sv change was revealed and the clinician asked again to assess fluid responsiveness. results: forty-five fluid challenges were studied. use of the lidco changed the decision made on occasions (fig. ) . in three patients ( %), this change in decision was appropriate and either corrected a misinterpretation of the haemodynamic data or represented a patient whose only marker of fluid responsiveness was a sv change. in four patients ( %), the lidco changed the decision inappropriately from a correct interpretation of the haemodynamic data. in six patients ( %) the sv change was ignored when it should have changed the initial decision. in the remaining patients ( %) the decision made with the haemodynamic data was in agreement with the sv change and unchanged by revealing the lidco data. conclusions: the use of lidco monitoring only appropriately changed the decision made with information from basic haemodynamic monitoring in % of patients. this augmentation of decision making was only seen in patients whose basic haemodynamic parameters did not respond to fluid. it changed a correct decision inappropriately in %. overall, no improvement in the assessment of fluid responsiveness was seen. introduction: there are accumulating evidences suggesting that intraoperative blood pressure affects postoperative outcome including myocardial injury, acute kidney injury, stroke, and mortality. in a patient undergoing laryngeal microsurgery (lms), blood pressure usually rises sharply due to the stimulation on the larynx. since pulse transit time (ptt) has been reported to reflect arterial blood pressure fairly well, it has possibility to be a marker for blood pressure which reflects beat-to-beat changes in blood pressure and is less invasive than arterial catheterization. methods: intraoperative noninvasive blood pressure (nibp), electrocardiogram (ecg), and photoplethysmogram (ppg) of patients undergoing lms were recorded simultaneously. ptt was defined as a time interval between the r-wave peak on ecg and the point which the maximal rising slope appears on the ppg. the mean ptt values for one minute before and after the increase in blood pressure due to the stimulation on larynx were compared. parameters of ppg such as width, height, maximal slope, minimal slope, and area were also compared. then, correlation between blood pressure and each variable was calculated. results: as the larynx was stimulated by lms, nibps have surged (systolic blood pressure, . p< . ) significantly in most of the patients. systolic blood pressure and ptt were inversely correlated (r = - . , p < . ). minimum slope of ppg also showed good negative correlation with systolic blood pressure (r = - . , p < . ). conclusions: ppt showed good correlation with systolic blood pressure and may have potential to be used as noninvasive continuous blood pressure monitor during a surgery in which blood pressure changes abruptly. introduction: aim of this prospective randomized pilot study was to investigate influence of intra operative restrictive volume approach and post operative lung ultrasound (lus)on prevention and early detection of postoperative interstitial syndrome development methods: cardiac patients who underwent non cardiac surgical procedure were randomly assigned for: group a-liberal volume approach or for group b-combination of restrictive intra operative volume approach and small dose of norepinephrine. all patients post operatively received <= . ml/kg/h fluids, mostly crystalloids. lus was performed before surgical procedure and hours after their admission in icu together with arterial blood gases measurements. the ultrasound characteristic of interstitial syndrome was development of b profile results: before surgery all patients had a profile. twenty for hours later in a group significantly higher number of patients / ( . %) vs / ( . %) in b group,had b profile (p< . ).at the same time there were no significant difference between the groups in amount of patients with pao /fio ratio <= ( patients with positive b lines from a group vs patients from group b).(p> . ) conclusions: intra operative fluid restriction is efficient in prevention of post operative cardiogenic pulmonary edema development. lus is a simple non invasive method for early detection of interstitial syndrome even before development of signs of respiratory deterioration. introduction: the peak rate of left ventricular (lv) pressure (dp/dtmax) has been classically used as a marker of lv systolic function. since measuring lv dp/dtmax requires lv catheterization, other surrogates have been proposed using the peripheral arterial waveform. the aim of this study was to test the performance of lv and arterial (aortic and femoral) dp/dtmax for assessing lv systolic function against the gold-standard (the slope of the end-systolic pressure-volume relationship, emax) during different cardiac loading and contractile conditions. methods: experimental study in pigs. lv pressure-volume data was obtained with a conductance catheter and peripheral pressures were measured via a fluid-filled catheter into the aortic, femoral, and radial arteries. emax was calculated during a transient occlusion of the inferior vena cava. the experimental protocol consisted in three consecutive stages with two opposite interventions each: changes in afterload (phenylephrine and nitroprusside), preload (bleeding and fluid bolus), and contractility (esmolol and dobutamine) (fig. ) . measurements were obtained before and after each hemodynamic intervention. results: emax variations and lv, aortic, femoral and radial dp/dtmax changes throughout the study are shown in fig. . all peripheral artery-derived dp/dtmax underestimated lv dp/dtmax. percentage changes in lv and femoral ddp/dtmax were tightly correlated (r = . ; p< . ). both lv and femoral dp/dtmax were affected by preload changes during fluid infusion. all peripheral dp/dtmax estimations allow to detect lv systolic function changes according to emax during isolated variations in contractility. conclusions: femoral and lv dp/dtmax accurately reflected emax changes, although both were affected by preload changes during fluid administration. fig. (abstract p ) . emax, lv dp/dtmax and aortic, femoral and radial dp/dtmax changes. (table , fig. ). concordance was < % and radial loa was ±< °for all devices; mean polar bias was < °for ft only (table , fig. ) . conclusions: cs, ft and pa are not interchangeable with tptd, because of inaccuracy [ ] . when considering limitations they may be used for trending. introduction: about years ago, the german physiologist pflüger stated that the cardio-respiratory system fulfils its physiological task by guaranteeing cellular oxygen supply and removing waste products of cellular metabolism. methods: the study was performed in early postoperative period after major abdominal surgery in patients. the physical condition of patients corresponded to class of asa. the median age was . ( . - . ) years. duration of the surgery was , ( , - , ) hours. surgery was performed under combined epidural anesthesia with mechanical ventilation. the study was conducted in the following stages: -admission from operating room; -in - hours; - - hours; - - hours; -after - hours after the surgery. results: depend on rate of oxygen extraction index (ero ) groups were revealed: group (n= )low ero (< %) followed by recovery to normal levels to stage - (ero = - %), group (n= )normal level ero ( %) in all the stages, group (n= )high levels ero (> %) with recovery to normal levels to stage , group (n= )high ero (> %) in all the stages. oxygen extraction index at admission to icu after surgery can be normal ( . % of patients), reduced ( . % of patients) or high ( . % of patients). when oxygen extraction ratio is reduced metabolic recovery occurs classically after - hours; when ero is elevated -after hours. core temperature improvement is connected with the restoration of oxygen homeostasis. so, under normal and reduced ero even mild central hypothermia after surgery were not observed, and at an elevated ero moderate hypothermia after surgery was observed with only to - hours post-surgery restoration. conclusions: maintaining an adequate tissue oxygenation is the cornerstone of metabolic response and postoperative recovery in patient after major abdominal surgery. (fig. ) . patients with cso < %time above %h had an odds ratio of hospital survival of . ( %ci . - . , p= . ) (fig. ) . conclusions: cerebral oxygen desaturation below % was significantly associated with outcome in patients undergoing vaecmo. in patients with cso < %time above h%, prognosis was especially poor. prospective trials are needed to evaluate if cso is a viable target for therapeutic interventions. introduction: during the second consensus meeting on microcirculatory analysis the exploration of novel parameters related to physiological function of the microcirculation was proposed. capillary hematocrit (chct) is a direct measure of capillary hemodilution, a potential mechanism of microcirculatory dysfunction in states of shock. our hypothesis was that by application of advanced computer vision (i) chct can be reliably measured in given capillaries, and (ii) change in chct reflects capillary hemodilution induced by cardiopulmonary bypass (cpb). methods: in patients undergoing coronary artery bypass surgery sublingual capillary microscopy videos were recorded before and during cpb primed with hes / . . per-capillary chct was estimated as the product of the number of red blood cells (rbc) and an assumed volume of nl, divided by the capillary volume including plasma gaps. rbc number was assessed by manual counting in the first frame of a given video clip, as well as using a novel advanced computer vision algorithm employing blob detection to calculate the mean per-capillary rbc number in all frames of a given video clip (fig. ) . results: capillaries were analyzed, within a total of and frames using manual and algorithmic analysis. a good correlation was found between both methods for chct (r= . , p< . , fig. ). cpb initiation resulted in an decrease in chct from (mean±sem) . ± . to . ± . , p< . and . ± . to . ± . , p= . in manual and algorithm. conclusions: accurate measurement of chct is possible using advanced computer vision, and it reflects hemodilution induced by initiation of cpb. chct further is a determinant of capillary delivery of oxygen. combined with the assessment of functional capillary volume, blood flow velocity, and capillary hemoglobin saturation, chct may enable direct optical quantification of capillary delivery of oxygen as an integrated functional parameter of the microcirculation. fig. (abstract p ) . prognosis of patients with cso < %time above %h was poor fig. (abstract p ) . detection of single erythrocytes using a novel advanced computer vision algorithm in a representative capillary ribbon extracted from a video frame of the sublingual microcirculation fig. (abstract p ) . the area under cso < % was significantly lower in survivors introduction: cardiac function is known to be impacted by sepsis. passive leg raise (plr) is an effective method to predict fluid responsiveness (fr) or cardiac response to preload expansion. preload functional status and trending cardiac output may identify patient phenotypes with varying cardiac reserve, dysfunction and outcome. methods: patient data were analyzed from a currently enrolling prospective randomized controlled study, evaluating the incidence of fr in critically ill patients with sepsis or septic shock (fresh study, nct ). patients randomized to plr guided resuscitation were classified as plr+ (fluid responsive/preload dependent) if stroke volume (sv) increased >= % when measured with a non-invasive bioreactance device (starling sv, cheetah medical). patients were categorized into different phenotypic cohorts based on changing physiology exhibited on plr and trending cardiac output over the initial hours of therapy. results: a total of plr assessments were performed in patients. overall, % ( / ) of assessments indicated a patient was plr+ after receiving initial resuscitation fluid of~ l. most patients ( %) demonstrated a dynamic physiology with changing plr status occurring > time over hours. there were no differences among the groups with respect to age, gender, or qsofa score (fig. ) . patients in group exhibited a significantly decreased icu stay ( . hours) compared to group ( . hours, p= . ) (fig. ) . patients in group exhibited significantly increased echo evidence of lv/rv cardiac dysfunction ( %), compared to group ( %, p= . ) ( table ) . patients in group exhibited % evidence of echo based lv/rv cardiac dysfunction. conclusions: physiological based resuscitation phenotypes identify significantly different patient groups. patients who are initially not plr+, but then become plr+ with no improved co are significantly more likely to have confirmed lv/rv dysfunction and a significantly longer icu stay. introduction: accurate measurement of a patient's intravascular volume status remains an unsolved clinical problem in the icu setting. in particular, septic and cardio-renal patients often receive volume challenges or diuresis, respectively, with little appreciation of baseline bv or the resulting response. this can lead to volume overload and/or depletion and associated increases in morbidity, mortality and hospital length of stay. methods: we tested the performance of a novel, rapid, minimally invasive technique capable of measuring pv, bv and glomerular filtration rate (mgfr) in human subjects. the method consists of a single iv injection of a large ( kda) carboxymethyl dextran conjugated to a rhodamine-derived dye and a small ( kda) carboxymethyl dextran conjugated to fluorescein. plasma and blood volumes were quantified minutes following the injection of the dye based on the indicatordilution principle. results: this phase b study included normal subjects, chronic kidney disease (ckd) stage iii and ckd stage iv subjects. pv and bv varied according to weight and body surface area, with pv ranging from to mls, and both were stable for greater than six hours with repeated measurements. there was excellent agreement ( fig. ) with nadler's formula for pv in normal subjects. a hour repeat dose measurement in healthy subjects showed pv variability of less than +/- %. following an intravenous bolus of ml % albumin solution the mean +/-(sd) measured increase in pv was . ml +/- . ml post infusion (fig. ) . conclusions: this novel bedside approach allowed for rapid and accurate determination of pv, bv, mgfr (data not shown) and dynamic monitoring following clinical maneuvers such as fluid administration, with a high level of safety, accuracy and reproducibility. this approach should assist the intensivist especially with volume administration and removal in septic and cardiorenal patients. introduction: accumulating evidence shows that fluid overload is independently associated with adverse outcome in children and adults with acute lung injury. fluid restriction initiated early in the disease process may prove beneficial, potentially by diminishing the formation of interstitial edema. the main goal of this study was to determine the short-term biophysical effects of intravenous (iv) fluid restriction during acute lung injury in relation to age. methods: infant ( - weeks) and adult ( - months) wistar rats were mechanically ventilated (mv) hours after intratracheal inoculation with lipopolysaccharide to model acute lung injury. both age groups were randomized to either a normal or restrictive iv fluid regimen during hours of mv. thereafter the rats were sacrificed and studied for markers of interstitial edema formation (wet-dry weight ratios), lung permeability (total protein and alpha- macroglobulin (a m) in bronchoalveolar lavage; bal) and local inflammation (cell counts and cytokines in bal). results: restrictive fluid therapy was not associated with worsening of hemodynamic indices during the period of mv in either infant or adult rats. however, as compared to the normal fluid regimen, restrictive fluid therapy led to lower wet-dry weight ratios of the lungs and kidneys in adult rats (p < . ), but not in infants (figs. and ). no difference was found in total protein and a m in bal between the two fluid regimens in both age groups. also, neutrophil influx in the lungs did not differ between fluid regimens in both age categories, nor did the influx of inflammatory cytokines il- and mip- in bal fluid. conclusions: there is an age-dependent effect of early fluid restriction on the formation of interstitial edema in local and distant organs in the disease process of acute lung injury. further investigation of the effects of fluid therapies in experimental models may help steering towards better treatment in critically ill patients. . ) . in a multivariate analysis fb was independently associated with: group c (p< . ), a history of diabetes (p= . ), the acute physiology and chronic health evaluation iii score (< . ) and the duration of aortic-cross clamp (p< . ). the main findings of this study substantiated the hypothesis that the introduction of continuous fb-tracking throughout the entire care process, is associated with a significant reduction in the administration of fluids in post-cardiac surgery patients, independent of differences in their baseline characteristics. demonstrating that certain organizational changes can influence medical behavior beyond the scope of teaching and instruction, and therefore serves to provide awareness to the current issue known as 'knowledge-to-care gap'. using a protocol for fluid resuscitation: how well is it followed? introduction: positive fluid balance in icu patients has been correlated with worse outcomes [ ] . consequently, we developed a protocol to guide fluid resuscitation. the protocol was introduced in and mandates that fluid responsiveness is assessed when administering fluid boluses. once a patient becomes fluid unresponsive, no further resuscitation fluid should be administered. to assess responsiveness, the protocol advises the use of haemodynamic data such as heart rate and blood pressure as well as the change in stroke volume (sv) measured by a lidcoplus monitor. after years of use and a rolling education program this protocol was felt to be well ingrained in our unit culture. we then assessed how well it was being followed. methods: staff performing fluid challenges were asked to fill out a form recording the haemodynamic and sv data measured before and after a fluid challenge. they were also asked to record their interpretation of just the haemodynamic data and then this data combined with the sv data. results: forty five forms were completed. the protocol was not followed on occasions ( %). four patients who should have been assessed as responsive were deemed to be unresponsive. six patients who should have been assessed as unresponsive were assessed as being responsive. the remaining deviations from the protocol represent misinterpretation of the haemodynamic data but correct use of the sv data to reach a correct final assessment. conclusions: despite being a longstanding ingrained practice in our icu, this review suggests that the protocol for fluid resuscitation is being followed incorrectly approximately a third of the time. this could result in inappropriate under or over administration of iv fluid. we plan to review the educational programme and raise awareness of the protocol to try and improve future compliance. introduction: understanding the effects of therapeutics on the left ventricular (lv) loading conditions is of utmost importance in critically ill patients. the effective arterial elastance (ea=esp/sv, where esp is aortic end-systolic pressure and sv stroke volume) is a lumped parameter of arterial load that has been proposed as an index of lv afterload. we aimed at comparing the effects of fluid administration on esp (i.e., the lv afterload in the pressure-volume phase-plane according to the classic "cardiocentric" framework) and on ea. methods: in mechanically ventilated patients, we recorded ea from the femoral peripheral systolic arterial pressure sap (ea=( . ×femoral sap)/sv) before and after the infusion of -ml of saline. patients in whom fluid administration induced an increase in cardiac index (picco- ) >= % were defined as "responders". introduction: the respiratory variations of the inferior vena cava (ivc) diameter in mechanically ventilated patients with preload responsiveness could be explain by a higher compliance of the ivc and/or higher respiratory variations of the ivc backward pressure, i.e., the central venous pressure (cvp).we aimed at determining the respective weight of these two phenomena. methods: in mechanically ventilated patients, haemodynamic, respiratory and the intra-abdominal pressure (iap) signals were continuously computerised. cvp, iap and the ivc diameter (transthoracic echocardiography) were recorded during end-inspiratory and endexpiratory occlusions, before and after the infusion of -ml of saline. patients in whom fluid administration induced an increase in cardiac index (picco- ) >= % were defined as "responders". the respiratory variations of the ivc diameter, cvp and iap were calculated as (end-inspiratory -end-expiratory values)/mean value. the compliance of the ivc was estimated by the ratio between (end-expiratoryend-inspiratory) values of ivc diameter and cvp. results: fluid administration increased cardiac index by more than % in patients. the respiratory variations of the ivc diameter predicted fluid responsiveness (area under the roc curve: . ( %ci: . - . ), p< . ). before fluid administration, the compliance of the ivc was not different between responders and non-responders ( . ± . vs. . ± . mm/mmhg, p= . ), whereas the respiratory variations of the cvp were higher in responders than in nonresponders ( ± vs. ± %, p= . ). the respiratory variations of the ivc diameter were associated with the respiratory variations of cvp (r= . , p= . ) but not of iap (r=- . , p= . ). conclusions: the respiratory variations of the ivc diameter rather depend on the respiratory variations of the cvp than on the ivc compliance. the iap seems to not be involved in the respiratory variations of the ivc diameter. hours and gedi measured at the same time was examined. since the dataset used in this study consists of repeated measurement data, the analysis used the general linear mixed effect model (glmm). the multivariate analysis adjusted with age, cr, and cardiac index was also conducted. results: of the patients with the total bnp measurements conducted for times and gedi measurements for times, the median of age and saps were (iqr - ) and (iqr - ), and the hospital mortality rate was %. the univariable analysis and the multivariable analysis using glmm respectively found statistically significant differences, with regression coefficient at . %ci . - . (p= . ), and . %ci . - . (p< . ). conclusions: while a positive correlation between gedi and bnp was statistically identified, its effect may be minor in clinical terms, and its significant clinical difference remains unclear. introduction: fluids are a cornerstone of the management of critically ill patients who are at risk of multiple organ dysfunction syndrome. however positive fluid balance (fb) is associated with worse morbidity and mortality in this population, so fluid administration needs to be carefully titrated and the nutritional support products must be taken in consideration. objective: evaluate the impact of nutritional support in the fluid balance in a intensive care unit methods: observational prospective study, conducted in eleven portuguese icus of nine general hospitals. patients with years of age or older were eligible if they were ventilated and had a length of stay (los) in icu greater than days. demographic data, fluid balance along type of nutritional support used in the first days and were collected from the selected patients. results: patients were enrolled, . % were male, the median age - ± ( - ), icu los - . ± . days, mortality rate of . % ( ). % of patients were admitted for medical reasons, . % had normal weight, the remaining patients were either overweight or obese. the average daily fb in the eight days was ± ml, being the maximum at day with + ml, slowly trending down reaching a neutral balance at day and reaching - ml at day . in the first days the majority of the intake is due to resuscitation driven fluids, however the nutritional support contribution rises as the days passes, reaching % at day and % at day ( fig. ) . regarding the administration route, the enteral route was responsible to , % of fluids at day compared to , % of parenteral route. the nutritional support is an factor to take into account regarding fluid balance in intensive care units. in this study after the th day the nutritional support, it was responsible for more than % of the total volume that was delivered to the patient and with an higher impact with the increase in los results: we included patients with mean age years, % male, apache ± , saps ii ± , sofa in admission ± , mechanical ventilation %, continuous renal replacement techniques %. the mean total volume administered during the first days was ± l with a mean dcb of ± l and a mean fluid accumulation of % ± . regarding fluid accumulation: % have < %, % between - % and . % > %. th-day mortality and icu mortality were % i % respectively. during the first week, the percentage of fluid accumulation was significantly higher in non-survivors than in survivors ( . ± . l vs. . ± . l, p . ) (fig. ) . cumulative survival was significantly lower (logrank = . , p= . ) in patients with > % of volume gain since the th day (fig. ) . > % volume gain in the th day is a independently associated variable to mortality after adjusting by age, apache and haemodialysis (or = . ; ci % . - . ; p = . ) ( table ) . conclusions: in septic shock patients, fluid overload more than % since -day of evolution is associated with a higher th-day mortality. its early detection may influence the prognosis and survival. introduction: sepsis is defined as a life-threatening organ dysfunction due to a deregulated host response to infection [ ] . fluid infusion is one of the cornerstones of sepsis resuscitation therapies. one of the major adverse effects reported is fluid overload (fo). the objective of this study was to assess influence of fo on sofa score changes from day to day . methods: this study is a retrospective, multicenter, epidemiologic data analysis. it was performed in three french icus. all adult patients admitted for septic shock, caused by peritonitis or pneumonia and mechanically ventilated, were enrolled. delta sofa score was defined as the sofa score measured on admission minus sofa score measured on day . results: patients met the inclusion criteria of the study. fo occurs in about % of the patients. cumulative fluid balance at day was greater in the fo group ( . versus . ml, p < . ) ( table ) . delta sofa score was higher in the no fo group than in the fo group ( . versus . , p = . ) (fig. ). there was a stepwise decrease of delta sofa score when duration of fluid overload was greater (p = . ) (fig. ) . in linear modelling, association between fo status and delta sofa score was confirmed with an adjusted rr of . [ . - . ] (p = . ) ( table ) . conclusions: ) fo patients had more prolonged multi-organ failure during septic shock; ) the longer the fo is the longer the more multi-organ failure last. , (t ) and (t ) minutes later. cardiovascular parameters were also measured at above time points. biomarker change from baseline (fold-change), indexed to hemoglobin, was compared between groups using mixed effects models (bonferroni-holm corrected p< . ). results: minor differences in measures of shock between groups after fluid administration resolved by t . cryst showed increased fold-change in hyaluronan compared to other groups at t (fwb p= . , hes p< . , gelo p< . ), t (fwb p< . ) and t (fwb p< . ) (fig. ) . gelo had increased fold-change in hyaluronan compared to other groups at t (hes p= . ), t (fwb p< . ) and t (fwb p< . , cryst p= . ), as did fwb at t (hes p= . ). cryst showed increased fold-change in il compared to other groups at t (hes p< . , gelo p= . ), t (hes p= . , gelo p= . ,), t (hes and gelo p< . ) and t (hes and gelo p< . ) (fig. ) , of il at t (gelo p= . ), and of kc at shock (fwb p= . , gelo p= . ), t (fwb p= . , gelo p= . ), and t (gelo p= . ). conclusions: rapid large-volume crystalloid given for hemorrhagic shock was associated with increased hyaluronan, a biomarker of endothelial glycocalyx damage, and inflammation, including increased il , il and kc. introduction: a bi-center randomized controlled trial has recently been published that investigates the impact of the type of fluid (crystalloid versus colloid) on patient outcome following major surgery [ ] . the study used a closed-loop fluid delivery system to eliminate the clinician bias when determining when to deliver fluids. the goal of the current analysis is to compare the immediate hemodynamic response to ml fluid boluses of either a crystalloid or a colloid solution. methods: patient consent was obtained prior to transferring the data from [ ] to edwards lifesciences for further post-hoc analysis. the percent change in stroke volume (dsv) following each ml bolus was tabulated and cross-referenced to the type of fluid. the responder rate and the dsv cumulative distribution function (cdf) were determined for each type of fluid administered. a responder was defined as a dsv >= % for a ml fluid challenge. the mean dsv was compared between the two groups using a student t-test. results: from the datasets reported in [ ] , were used in the analysis. descriptive statistics are summarized in table and the cdfs are plotted in fig. . more crystalloid boluses were administered. in both groups, the responder rate was around %. mean dsv was not significantly different between groups (p = . ). we observed similar responder rates and cdfs with the two fluid types, suggesting that the immediate hemodynamic response to ml fluid boluses is independent from the fluid type. we therefore hypothesized that it is the longer intra-vascular persistence of the colloid that explain the lower number of boluses required to achieve the hemodynamic endpoints targeted in the clinical study [ ] . fig. (abstract p ) . cumulative distribution functions of delta stroke volume for crystalloid and colloid fluid boluses the reduction projected to an average annual saving of , usd ( introduction: colloids are widely used for volume resuscitation. among synthetic colloids, hydroxyethyl starch (hes) is commonly administered. in cardiac surgery, priming of the cardiopulmonary bypass (cpb) circuit with colloids minimizes resuscitation volume and results in less pulmonary fluid accumulation. however, the use of hes has been associated with a higher incidence of renal damage and a higher occurrence of coagulopathy. the aim of this study was to investigate the effect of low dose ( - ml/kg) hes % ( / , ) in cpb pump priming on fluid balance, blood loss, transfusion requirement and occurrence of acute kidney injury. methods: in a pre-post design, data from patients undergoing cardiac surgery with cpb were analyzed. in patients, priming solution consisted of ml balanced crystalloids, ml mannitol %, tranexamic acid g and i.e. heparin. for the other patients, ml of the crystalloids were replaced with hes % ( / . ), the other components were the same. patients were matched : with propensity score method. the primary endpoint was intraoperative fluid balance. secondary endpoints were perioperative blood loss, transfusion requirement and the occurrence of acute kidney injury. results: in total, patients were analyzed. the hes group showed less positive fluid balance than the crystalloid group (p< . ). there was no difference in intraoperative blood loss (p= . ) and transfusion requirement (p= . ). the occurrence of acute kidney injury was not significantly different between the two groups (p= , ). conclusions: low-dose administration of - ml/kg hes % ( / . ) to cpb pump priming decreased intraoperative fluid accumulation without increasing perioperative blood loss and transfusion requirement. there was no effect on the incidence of acute kidney injury. priming cpb pumps with a low-dose of hes % ( / . ) is an important component for a restrictive volume strategy and might safely be used in patients with preexisting renal dysfunction. introduction: most crystalloid solutions used in critically ill patients have a greater chloride (cl) concentration than plasma, which may be detrimental. replacing some cl with bicarbonate (hc ) reduces cl, but may increase partial pressure of carbon dioxide (pc ) in blood. such an increase in pc may be harmful [ ] . the main objective was to determine if a hco balanced fluid resulted in increased paco compared to a conventional balanced fluid. methods: single center randomized controlled trial in an adult icu, comparing balanced fluid (sodium,na= mmol/l, chloride,cl= mmol/l, hco = mmol/l) vs conventional fluid (na= mmol/l, cl= mmol/l, hc <= mmol/l). university ethics committee approval:m . we used the absolute difference between the pco and mmhg as a comparison for the fluid groups. betweengroup comparisons of pc from d -d was done by repeated measures anova. a p value < . was considered significant. results: patients were allocated to the conventional group and to the balanced group. at baseline the groups were well matched (p> . ) for age, weight, gender, severity of illness and organ support. there were no significant differences in pc between the two fluid groups, overall or at d , d or d . the balanced group showed a significant improvement in egfr (scr), between d and d (p= . ) while the conventional group exhibited a significant decline (p= . ). there were no significant differences between the groups with respect to fluid requirements, number of positive blood cultures, icu renal replacement utilization, icu length of stay, icu mortality and day mortality. conclusions: the use of a balanced fluid did not result in an increase in pco and appears to be safe. a beneficial effect on renal function was observed. introduction: the effects of crystalloids and colloids on macro-and microcirculation is controversial. our aim was to compare their effects on microcirculation during free flap surgery when management was guided by detailed hemodynamic assessment. methods: patients undergoing maxillo-facial tumour resection and free flap reconstruction were randomized into a crystalloid (ringerfundin, rf, n= ) and a colloid ( % hydroxyethyl starch, hes, n= ) groups. cardiac index (ci), stroke volume (svi) and pulse pressure variation (ppv) were continuously monitored by a non-calibrated device (pulsioflex -pulsion, maquet). central venous oxygen saturation (scvo ), venous-to-arterial pco -gap (dco ), lactate levels and hourly urine output was also measured, and a multimodal, individualized approach based algorhithm was applied [ ] . microcirculation was assessed by laser doppler flowmetry (periflux ldpm, perimed jarfalla, sweden). measurements were performed at baseline and from the start of reperfusion hourly for hours. for statistical analysis, two-way rm anova was used. results: there was no difference between the groups regarding age, sex, length of surgery (whole population: ± min). patients in the rf-group required significantly more fluid in total (rf: ± , hes: ± ml, p= . ). both groups remained hemodynamically stable (ci, svi, ppv, scvo , dco , lactate and urine output) throughout the study. there was no difference between the rf-, and hes-groups in the laser doppler measurements neither on the control site nor in the flap (fig. ) . conclusions: we found that when hemodynamic management is guided by a multimodal assessment and stability is maintained, there was no difference between crystalloids and colloids in macrocirculation and microcirculatory perfusion. introduction: our aim is to evaluate the impact of crystalloid fluids on immune cells. intensive care unit (icu) patients' inflammatory status can switch from an early pro-inflammatory to a late anti-inflammatory phase, which favors infections. they can receive different crystalloids, either normal saline (ns), ringer's lactate (rl) or plasma-lyte (pl). high chloride concentration present in ns has been associated with various complications [ ] , whereas high doses of nacl have inflammatory effects on immune cells [ ] . however, the immune consequences of crystalloids in humans are ill-defined. methods: using our comprehensive immunemonitoring platform, we assessed the immunological phenotype of peripheral blood mononuclear cells (pbmc) in humans. healthy subjects received a liter of ns, rl and pl. blood samples were taken before and h later. pbmc phenotypes were assessed by flow cytometry and cytokine concentrations were measured by a multiplex assay. off-pump cardiac surgery patients were also randomized to receive either ns, rl or pl during surgery and their stay in the icu. blood samples were drawn at various time-points. all leucocytes were analyzed in a similar fashion. we are still recruiting. results: study of healthy subject's pbmc suggested that rl reduced classical monocytes, whereas ns increased lymphocyte activation and il- and mip- b levels. in cardiac surgery patients, our preliminary results suggested that rl and pl reduced classical monocytes and increased non-classical monocytes compared to ns. neutrophils were also affected differently by crystalloids, where ns seemed to activate them more. conclusions: our results suggest that crystalloids have different immune consequences. a better understanding of their immune modulation will lead to personalization of their use according to the inflammatory status of patients to restore their immune homeostasis. this randomised controlled open-label pilot study included patients presenting to an emergency department with suspected infection requiring a fluid bolus. patients received either a single bolus of ml/kg of . % nacl (isotonic group) or ml/kg of % nacl (hypertonic group). blood biomarker concentrations of glycocalyx shedding (syndecan- , hyaluronan), endothelial activation (sicam- , svcam- ) and inflammation (interleukin- , - , - , ngal, resistin) were measured at t (before fluid) and hour (t ), hours (t ) and - hours (t ) later. changes in biomarker concentrations were compared between study groups using mixed regression models, with fold-change from t reported. differences in fluid volumes were compared using the wilcoxon rank sum test. significance was set at p< . . results: syndecan- concentration in the isotonic group decreased from t to t (fold-change . , % ci . - . ), which was significantly different to the hypertonic group (fold-change . , % ci . - . )(p= . )( table ) . interleukin- concentration decreased in the isotonic group from t to t (fold-change . , % ci . - . ), which was significantly different to the hypertonic group (fold-change . , % ci . - . )(p= . ). otherwise, there were no significant differences in change over time between groups for measured biomarkers. total fluid volume administered between t and t was significantly higher in the isotonic group (p< . ) ( fig. ) but not different for subsequent time periods. conclusions: biomarkers of glycocalyx shedding, endothelial activation and inflammation were not different between patients receiving either . % or % saline. also, % nacl did not reduce administration of additional fluids. introduction: acute changes in pco are buffered by non-carbonic weak acids (atot), i.e., albumin, phosphates and hemoglobin. aim of the study was to describe acid-base variations induced by in-vitro pco changes in critically ill patients' blood and isolated plasma, compare them with healthy controls and quantify the contribution of different buffers. methods: blood samples were collected from patients admitted to the icu and controls. blood and isolated plasma were tonometered at and % of co in air. electrolytes, ph, blood gases, albumin, hemoglobin and phosphates were measured. the strong ion difference (sid) was calculated [ ] and non-carbonic buffer power was defined as β=-Δhco -/Δph [ ] . t-tests and linear regression were used for analysis. results: seven patients and controls were studied. hemoglobin, hematocrit and albumin were lower in patients (p< . ), while sid and phosphates were similar. pco changed from ± to ± mmhg, causing different blood ph variations in patients and controls ( . ± . vs. . ± . , p= . ). patients had lower blood and plasma β ( ± vs. ± , p< . and ± vs. ± , p= . , respectively). figure shows changes in [hco -] and sid induced in blood by pco variations. in both populations, ± % of [hco -] change was due to sid variations, while only ± % to changes in atot dissociation. a significant correlation between hematocrit and Δsid was observed in the whole study population (fig. ) . conclusions: the β of icu patients was lower, likely due to reduced albumin and hemoglobin concentrations. similar pco increases caused therefore greater ph variations in this population. electrolyte shifts, likely deriving from red blood cells [ ] , were the major buffer system in our in-vitro model of acute respiratory acidosis. introduction: there is an increasing trend in the incidence of aneurysmal subarachnoid haemorrhage in hong kong and the disease carries high morbidity and mortality rate. electrolyte disturbance is one of the known complications of sah and the outcomes associated with this are not fully understood. the objective of this retrospective local study is to evaluate the pattern of electrolyte disturbances in patients with sah and their impact on the prognostic functional outcome. methods: patients with spontaneous aneurysmal sah who were admitted to icu at pamela youde nethersole eastern hospital, hong kong between st january and st december were included into this retrospective local study. collected data include demographic details, comorbidities, serum electrolyte levels (sodium and potassium) from day to of admission into icu, radiographic intensity of haemorrhage using fisher scale and the clinical grading of sah using wfns. prognosis of these patients was estimated using the glasgow outcome scale at months after initial insult (fig. ) . results: a total of patients were included in this study. the mean age was , with the majority of patients being female ( . %). the most common aneurysm location was in anterior communicating artery, though poor outcomes were shown significant in patients with posterior circulation aneurysms. whilst early-onset hyponatremia was not correlated with poor outcome, late-onset hyponatremia was associated with better outcome. logistic regression analysis identified independent predictors of poor outcome (table ) . patients who underwent interventional radiological procedure treatment was shown to have better outcome. conclusions: hypernatremia after sah is associated with poor outcome. there does not appear to be significant evidence that hyponatremia has an effect on short-term mortality or certain outcome measures such as gos, and its longer-term effects are not well characterized. fig. note logarithmic transformation of los data). we found a statistically significant difference between the two groups when comparing the length of stay (p < . ). conclusions: dean et al demonstrated no significant difference in the mean length of stay using the same definitions of hypo and eunatraemia as in this study [ ] . even though our data appears to contradict their findings, regarding the statistical significance seen, we feel that this is not significant clinically, given the very similar median times for los between the two groups; the unbalanced design may contribute to the statistical significance. fig. (abstract p ) . length of stay between the two groups (note logarithmic scale for los) fig. (abstract p ). gos at months group consisted of patients with mean age . (sd . ) years and mean sodium . (sd . ) mmol/l with a median los of . (iqr . - . ) days. we found no statistically significant difference (p = . ) between the two groups when comparing the length of stay (fig. ) . conclusions: darmon et al demonstrated prognostic consequences of an admission sodium greater than , eliciting hypernatraemia as a factor independently associated with -day mortality [ ] . in contrast, our study suggests that hypernatraemia (as defined) is not associated with the length of stay, however this result is limited by the unbalanced design of this small study. introduction: our aim is to determine whether auscultation for bowel sounds helps in clinical decision making in icu patients with ileus. ileus can be the consequence of an operation, a side effect of drugs or the result of an obstruction requiring direct operative correction. although auscultation for bowel sounds is routinely performed in the icu and a well-established part of the physical examination in patients with suspected ileus, its clinical value remains largely unstudied. methods: a literature search of pubmed, embase and cochrane was performed to study the diagnostic value of auscultation for bowel sounds. results: auditory characteristics (tinkling, high pitched and rushes) were highly variable in postoperative ileus, mechanical ileus and healthy volunteers. the inter-observer variability for the assessment of the quantity, volume and pitch of bowel sounds was high, with a moderate interobserver agreement for discerning postoperative ileus, bowel obstruction and normal bowel sounds (kappa value . ). the intra-observer reliability of duplicated recordings for distinguishing between patients with normal bowels, obstructed bowels or postoperative ileus was % [ ] . no clear relation between bowel sounds and intestinal transit was found (table ) . sensitivity and positive predictive value were low: respectively % and % in healthy volunteers, % and % in obstructive ileus, and % and % in postoperative ileus ( table ) . conclusions: auscultation with the aim to differentiate normal from pathological bowel sounds is not useful in clinical practice. the low sensitivity and low positive predictive value together with a poor inter-and intra-observer agreement demonstrate the inaccuracy of utilizing bowel sounds for clinical decision-making. given the lack of evidence and standardization of auscultation, the critically ill patient is more likely to benefit from abdominal imaging. introduction: stress ulcer prophylaxis has become a standard of care in intensive care unit (icu). however, it has been proposed that enteral nutrition (en) could play preventive role for gastrointestinal bleeding and some studies revealed no added benefit of acid suppressive drugs to patients on en. based on these backgrounds, we use proton pump inhibitor (ppi) as stress ulcer prophylaxis during starvation period, and discontinue it within hours after commencing meals or en. the aim of this study is to evaluate the applicability of our protocol by reviewing the incidence of upper gastrointestinal bleeding (ugib) in our icu. methods: we conducted a retrospective observational study. all consecutive patients admitted to our icu between april and march were reviewed. patients who had ugib within hours after admission, had previous total gastrectomy, or underwent upper gastrointestinal surgery were excluded. the primary outcome was the incidence of overt or clinically important ugib, and the secondary outcome was protocol adherence. we presented descriptive data as number (percentage) and median (interquartile range). results: a total of patients were included. of those, ( . %) were male, median age was ( - ), and median sofa score was ( ) ( ) ( ) ( ) ( ) ( ) ( ) . of all patients, ( . %) had overt bleeding, and ( . %) had clinically important bleeding. both patients who introduction: patients requiring operative procedures admitted under non-surgical specialties typically experience delays in treatment and fail to meet peri-operative standards with regards to the timing of operative intervention. patients admitted from medicine requiring an emergency laparotomy have an increased mortality when compared to those patients admitted from surgery ( . % v . %) [ ] . methods: we undertook a retrospective case note review of patients requiring a non-elective laparotomy at our hospital during a sixmonth period in . patients were identified using the emergency theatre booking system. data were gathered on admission details, peri-operative care and post-operative stay. results: two main investigators reviewed patients to standardise data extraction. six patients presenting with inflammatory bowel disease were excluded from analysis. most patients ( . %) were admitted through the emergency department; ( . %) of whom were initially admitted under medicine, with only . % of these reviewed by a senior clinician prior to admission (table ). there was no statistically significant difference in mortality between the medicine and surgery groups. there was a trend to increased length of stay in icu and in hospital in the medical group (table ) . conclusions: lack of senior decision making may have a direct impact on patient care due to the inappropriate streaming of patients to medicine. the increased mean length of stay in those patients admitted to medicine may reflect a delay in surgical intervention and therefore a prolonged recovery period. we are introducing an acute abdominal pain screening and immediate action tool to improve identification of these high-risk patients and early involvement of senior decision makers. introduction: biomarkers reflecting the extent of surgical tissue trauma should be investigated in an effort to predict and prevent postoperative complications. the aim of the present study was to investigate blood concentrations of selected alarmins in patients after colorectal surgery in comparison to healthy individuals. the secondary aim was to analyze the relationship between alarmins and inflammatory biomarkers during early postoperative period. methods: the prospective, single-center, observational study consisted of non-surgical (ns) group (n= ) and surgical (s) group (n= ) undergoing colorectal surgery. serum levels of selected alarmins (s a and s a ) and inflammatory biomarkers (leukocytes; c-reactive protein, crp; interleukin- , il- ) were analyzed. results: proteins s a an s a had significantly higher serum values in the s-group during all three days after the surgery. the multidimensional model taking into account age, sex, weight, group and days revealed significant differences between study groups for both proteins s a and s a (p< . , p= . , respectively). biomarkers (leukocytes, crp, and il- ) showed significant differences between study subgroups (p< . , p< . , and p< . , respectively). in s-group, moderate positive correlations were found between s a and all biomarkers: leukocytes (r= . ), crp (r= . ), and il- (r= . ). s a had moderate positive correlation with leukocytes (r= . ). levels of s a also positively correlated with intensive care unit and hospital length of stay (r= . , r= . , respectively) conclusions: protein s a might be considered as early biomarker of first wave of immune activation elicited by surgical injury after colorectal surgery. the increase of the alarmins is reflected by the elevation of routine inflammatory biomarkers. introduction: critical illness-induced liver test abnormalities are associated with complications and death in adult icu patients, but remain poorly characterized in the pediatric icu (picu). in the pepanic rct, delaying initiation of parenteral nutrition to beyond day (late pn) was clinically superior to providing pn within h (early pn), but resulted in a higher rise in bilirubin. we aimed to document prevalence and prognostic value of abnormal liver tests and the impact of withholding early pn in the picu. methods: we performed a preplanned secondary analysis of of the pepanic patients aged days to years, as neonatal jaundice was considered a confounder. plasma concentrations of total bilirubin, alt, ast, γ gt, alp were measured systematically during picu stay. analyses were adjusted for baseline characteristics including severity of illness. results: during the first picu days, the prevalence of cholestasis (> mg/dl bilirubin) ranged between . %- . % and of hypoxic hepatitis (>= -fold uln for alt and ast) between . %- . %, both unaffected by the use of pn. throughout the first week in picu plasma bilirubin concentrations were higher in late pn patients (p< . ), but became comparable to early pn patients as soon as pn was started on day . plasma concentrations of γ gt, alp, alt and ast were unaffected by pn. high day plasma concentrations of γ gt, alt and ast (p<= . ), but not alp, were independent risk factors for picu mortality. day plasma bilirubin concentrations displayed a ushaped association with picu mortality, with higher mortality associated with bilirubin concentrations < . mg/dl and > . mg/dl (p<= . ). conclusions: in conclusion, overt cholestasis and hypoxic hepatitis were rare and unrelated to nutritional strategy. however, accepting a large macronutrient deficit during week increased plasma bilirubin. a mild elevation of bilirubin on the first picu-day was associated with lower risk of death and may represent an adaptive stress response rather than true cholestasis. positive fluid balance is an independent risk factor for intensive care unit mortality in patients with acute-on-chronic liver failure introduction: muscle wasting is a common consequence of disuse and inflammation during admission to intensive care with critical illness. limb muscles are known to decrease in size during critical illness, but less is known about muscles of the trunk. in this study, we tracked how psoas muscle area changes at multiple levels, in a group of patients with acute severe pancreatitis. methods: paired computed tomography (ct) scans were obtained from patients admitted to the royal liverpool university hospital's icu with acute severe pancreatitis. the first scan was within days of admission, and the second took place between to days later. for each scan, three slices were identified: the top and bottom plates of l , and the mid-point of l vertebral body. on each slice, the cross sectional area (csa) of the left and right psoas muscle was calculated using imagej. the difference and percentage change in csa between both scans was calculated. white cell counts and c-reactive protein results were obtained, with peak levels correlated against change in muscle size. results: combined csa of the left and right psoas muscle increased from top to bottom plates and was positively correlated with height (r= . , p< . mid l level)) and weight (r= . , p= . , mid l level) at all three levels. at all three levels, there were significant losses of csa between the two scans (see table ). crp was moderately correlated with percentage change in csa (r= - . , p= . ). increasing weight on admission was associated with greater percentage losses in csa (r= - . , p< . ). wcc did not correlate with change in size. in critically ill patients with acute severe pancreatitis, there are significant losses in both psoas muscles throughout the l level. further prospective studies are required to determine if inflammatory markers and cytokines have a role in these losses, and to determine the functional effects of these losses. introduction: the evidence for penta-therapy for hyperlipidemic severe acute pancreatitis (hl-sap) is anecdotal. the purpose of our study is to evaluate the efficacy of penta-therapy for hl-sap in a retrospective study. methods: retrospective study between january and december in a hospital intensive care unit.hl-sap patients were assigned to conventional treatment alone (the control group) or conventional treatment with the experimental protocol (the penta-therapy group) consists of blood purification, antihyperlipidemic agents, lowmolecular-weight heparin, insulin, covering the whole abdomen with pixiao (a traditional chinese medicine).serum triglyceride, serum calcium, apache ii score, sofa score, ranson score, ct severity index, and other serum biomarkers were evaluated. the hospital length of stay, local complications, systematic complications, rate of recurrence, overall mortality, and operation rate were considered clinical outcomes. results: hl-sap patients received conventional treatment alone (the control group) and patients underwent penta-therapy combined with conventional treatment (the penta-therapy group). serum amylase, serum triglyceride, white blood cell count, c -reactive protein, and blood sugar were significantly reduced, while serum calcium was significantly increased with penta-therapy. the changes in serum amylase, serum calcium were significantly different between the penta-therapy and control group on th day after the initiation of treatment. the reduction in serum triglyceride in the pentatherapy group on the second day and th day were greater than the control group. patients in the penta-therapy group had a significantly shorter length of hospital stay. conclusions: this study suggests that the addition of penta-therapy to conventional treatment for hl-sap may be superior to conventional treatment alone for improvement of serum biomarkers and clinical outcomes. average energy expenditure (ee) for all patients was ± kcal/kg (mean ± sd). there was no difference in the average ee between the patients who survived and those who died: ± and ± kcal/ kg (mean ± sd) respectively (p > . ). however, there was a negative correlation between ee and saps score in the non-survivors groupcorrelation coefficient - . , p < . . the energy deficit (computed by subtracting caloric intake from ee measurement) was similar among survivors and non-survivors, . ± vs . ± kcal/kg, respectively (mean ± sd) (p > . ). the patients who survived had received ± kcal/kg while those who died - ± kcal/kg (mean ± sd) (p > . ). the provision of protein was also similar for both groups: . ± . g/kg for survivors and ± . g/kg for nonsurvivors (mean ± sd) (p > . ). there was no statistically significant correlation between provision of calories and protein and outcomes such as length of hospital and icu stay or duration of mechanical ventilation. conclusions: average energy expenditure in critically ill patients with acute severe pancreatitis roughly equals to aspen estimation of kcal/kg and does not differ among survivors and non-survivors. outcomes such as survival, length of hospital and icu stay and duration of mechanical ventilation were unaffected by caloric nor protein provision in this sample. introduction: disturbances in gastrointestinal motility are common in critically ill patients receiving enteral nutrition. slow gastric emptying (ge) is the leading cause of enteral feeding intolerance (efi), which compromises nutritional status and is associated with increased morbidity and mortality. this phase a study evaluated the efficacy, safety and tolerability of acute tak- (previously td- ), a selective agonist of the hydroxytryptamine receptor ( ht ), compared with metoclopramide in critically ill patients with efi. methods: this was a double-blinded, double-dummy study conducted in mechanically ventilated patients with efi (> ml gastric residual volume) randomized to receive either intervention (tak- . mg over hour and . % saline ml injection qid) or control ( . % saline over hour and metoclopramide mg injection qid). within hour of the first dose, patients received a test meal of ml ensure® and ge was measured using scintigraphy. primary objectives were to evaluate the safety and tolerability of tak- and its effect on ge (% retention at mins) vs control. results: a total of patients (intervention, n = ; control, n = ) were studied. the median ages were and years in these groups, respectively. post-treatment, a -fold greater number of patients had normal gastric retention (< % at mins) in the intervention group vs the control group ( vs ; fig. ). in the intervention and control groups, (table ) . no aes led to treatment discontinuation. conclusions: a greater proportion of patients receiving tak- had normal gastric retention after a single dose compared with those receiving metoclopramide. treatment with tak- was not associated with an increase in aes. these results support further evaluation of tak- in critically ill patients with efi. method to assess gastric emptying in the fed state in enterally tube fed patients: comparison of the paracetamol absorption test to scintigraphy j james introduction: the paracetamol absorption test (pat) is the most common and practical approach for assessing gastric emptying (ge) in critically ill patients. however, current methods require that paracetamol be administered to an empty stomach, removing gastric contents and depriving patients of feeding for several hours. the objective of this study was to develop methods to assess gastric emptying in these patients without interrupting feeding. methods: gastric emptying was assessed in the fed state using pat and scintigraphy in healthy volunteers. paracetamol g in ml was ingested immediately before consumption of a test meal of ml ensure plus containing kcal, . g protein, and . g fat plus mbq of mtc-dpta as a scintigraphic agent. comparisons were made between paracetamol absorption and the time to % and % gastric emptying by scintigraphy at baseline and after administration of ulimorelin μg/ kg, a prokinetic agent known to enhance gastric emptying. blood samples for paracetamol were collected for up to h post administration. values for normal gastric emptying were based on the % confidence intervals for pk parameters. sensitivity and specificity were assessed by receiver operating characteristic (roc) analysis before and after treatment. results: the pat correlated with scintigraphy and pk parameters for normal emptying were determined. cmax and auc were the most sensitive and specific parameters for assessing ge with lowest variability and areas under the roc curve of . and . , respectively. a h sampling period appeared sufficient to distinguish normal from abnormal emptying. conclusions: the pat can be used to distinguish normal versus abnormal ge in the fed state. under the conditions used, patients can receive up to ml enteral feeding over a h test period ( ml/hr). this method can be used to distinguish normal from abnormal gastric emptying in enterally tube fed patients without interrupting feedings. introduction: for mechanically ventillated critically ill patients, the effect of full feeding on mortality is stil controversial. we aimed to investigate the relationship of energy intakes with -day mortality, and nutritional risk status influenced this relationship. methods: this prospective observational study was conducted among adult patients admitted to icu and required invasive mechanical ventilation (imv) for more than h. data on baseline characteristics and the modified nutritional risk in critically ill [mnutric] score was collected on day . energy intake and nutritional adequacy was recorded daily until death, discarge or until twelfth evaluable days. patients were divided into groups: a)received < % of prescribed energy b) received >= % of prescribed energy. results: patients ( % male, mean age . ± . years, mean body mass index . ± . kg/m , mean mnutricscore . ± . ) were included. in the univariate analysis, mnutrİc score was associated with -day mortality. in the multivariable logistic regregression analysis, mnutric score(odds ratio, or . , ci . - . , p < o.oo ) was associated with -day mortality. nutritional adequacy was assessed, median nutritional adequacy was . ( . - . ). in patients with high mnutrİc score ( - ), received >= % of prescribed energy was associated with a lower predicted -day mortality; this was not observed in patients with low mnutrİc score ( - ). conclusions: nearly % of imv required patients admitted to icu were at nutritional risk, mnutrİc score is associated with -day mortality. energy adequacy of >= % of prescribed amounts were associated with decreased mortality in patients with a high mnutrİc score. results: patients included in the study were asa iv. four patients died in the first few days after surgery ( ÷ days). mean length of stay in icu was . ± . days. univariate analysis showed a correlation between hypoalbuminemia and the onset of mof (p = . ); reduction of the lymphocyte count and risk of mof (p = . ). sofa score showed a significant correlation with occurrence of pneumonia (p = . ) and mof (p = . ). including the -day mortality among confounders, albumin and lymphocyte count were the strongest predictors of mof. length of stay in icu and ventilation days did not have statistical significance. bmi showed no predictive value of any outcome. conclusions: our sample was poor but results of our study seem to indicate malnutrition as an independent risk factor for elderly patients undergoing emergency surgery. early multidisciplinairy screening of dysphagia at admission to the emergency departmenta pilot study d melgaard, l sørensen, d sandager, a christensen, a jørgensen, m ludwig, p leutscher north denmark regional hospital, hjørring, denmark critical care , (suppl ):p introduction: dysphagia increase the risk of aspiration pneumonia, malnutrition, dehydration and death. this combined with the fact that patients with dysphagia have a longer stay in the hospital makes early prognosis and appropriate treatment important. knowledge about effect of early dysphagia screening is limited. the aim of this study is to examine the prevalence of dysphagia in the emergency department (ed) population. methods: this study included consecutively hospitalized patients in days from pm- pm at the ed of north denmark regional hospital. the screening took place within hours of admission. inclusion criteria were any of the following: age ≥ years, neurological disorders, alcoholism, copd, pneumonia, dyspnoea, diabetes or unexplained weight loss. a nurse screened patients with a water test and with signs of dysphagia tested by an occupational therapist with the v-vst and the meof-ii. results: of eligible patients ( % male, median age years) ( %) were screened. it was impossible to screen patients ( %) to limited time and patients ( %) due to poor health condition and patients ( %) declined participation. the prevalence of dysphagia in the study population was % ( patients). results from the water test were confirmed with v-vst and meof-ii. in patients with lung related diseases or circulatory diseases was the prevalence respectively % and %. patients, not screened due to poor health condition, were tested during hospitalisation and the prevalence of dysphagia was % in this group of patients. conclusions: the prevalence in ed patients was %. patients transferred to other departments due to poor health condition had a prevalence of %. it is possible to screen patients in the ed. the water test is a useful screening tool in an acute setting. introduction: to improve protein and energy delivery in a nutrition delivery bundle was introduced to a level icu. greater protein and energy intake is associated with improved outcomes in the critically ill [ ] [ ] [ ] [ ] , but only % of prescribed protein and energy is delivered in icus worldwide [ , ] . methods: percentage of target protein and energy delivery was measured via participation in the international nutrition survey (ins) before and after a "nutrition delivery bundle" was introduced by the icu dietitian. the nutrition delivery bundle involved all stakeholders in icu nutrition care (fig. ) and included the following quality improvement measures: increased icu dietetic staffing, update of icu enteral feeding protocol with staff education, use of higher protein formulations, earlier patient nutrition assessment, daily calculation of percentage nutrition delivery, increased nutrition communication through more regular discussion of patient care with medical team, expansion of choice of nasojejunal tube available, monthly reporting of key nutrition performance indicators, improved resources for cover dietitian(s) when icu dietitian on leave (fig. ) . results: prior to a nutrition delivery bundle being introduced the mater misericordiae university hospital (mmuh) icu achieved % of protein and % of energy targets over the first admission days of consecutive mechanically ventilated patients in icu > hrs enrolled in the international nutrition survey. this increased to % of protein and % of energy targets in (table ) . conclusions: a % improvement in protein and energy delivery to critically ill patients was seen after the introduction of a dietitian-led nutrition delivery bundle. introduction: the critically ill polytrauma patient with sepsis presents with variable energetic necessities characterized by a proinflammatory, pro-oxidative and hypermetabolic status. one of the challenges the icu doctor faces is adapting the nutritional therapy based on the individual needs of each patient. through this paper we wish to highlight the trend of energy needs in the case of critically ill polytrauma patients with sepsis by using non-invasive monitoring of respiratory gases based on indirect calorimetry (ge healthcare, helsinki, finland). methods: this is a prospective observational study carried out in the anesthesia and intensive care unit "casa austria", emergency county hospital "pius brinzeu", timisoara, romania. we monitored vo , vco , energy demand (ed), and specific clinical and paraclinical data. we measured energy demand values monitored by direct calorimetry with values calculated based on standard formulas. results: values have been recorded in the study. the mean vo was . ± . ml/min/kg, the mean vco was . ± . ml/min/kg. in regard with energy demand, the mean ed obtained through direct calorimetry was . ± . kcal/day, and those obtained by using mathematic formulas were . ± kcal/day (p < . ). moreover, statistically significant differences have been observed regarding the mean difference between energy demand determined using indirect calorimetry and that determined mathematically, respectively between the enteral and parenteral administered ed. conclusions: continuous monitoring of the energy demand in critically ill patients with sepsis can bring important benefits in regard with the clinical prognosis of these patients through the individualization and adaption of intensive therapy for each patient. introduction: cachexia is defined as a complex metabolic syndrome associated with underlying illness, characterized by loss of muscle with or without loss of fat. in cancer cachexia, reduction in muscle size has been demonstrated to be an independent risk factor for mortality. loss of muscle in icu patients is rapid and extensive and is also associated with mortality risk, but methods to measure muscle mass in these patients are lacking. surrogate methods (dexa, ct, ultrasound, total body water) do not measure muscle mass directly methods: the d -creatine (d -cr) dilution method takes advantage of the fact that % of cr is found in muscle and that muscle mass can be assessed by cr pool size. cr is transported into muscle against a concentration gradient and irreversibly converted to creatinine (crn), which is excreted in urine. a single oral dose of d -cr is transported to skeletal muscle, and measurement of d -crn enrichment in a spot urine sample provides an accurate estimate of skeletal muscle mass. results: the method has been validated in preclinical and clinical studies; in a large longitudinal observation study in older men, d -cr muscle mass was strongly associated with habitual walking speed, risk of falls, and incident mobility limitation; dexa failed to show these relationships. the d -cr method is being used in a nicu study to measure changes in muscle mass in neonates (gates foundation grant). further, this method has been incorporated into a trial assessing the treatment effects of a ghrelin agonist in icu patients with enteral feeding intolerance (nct ). in this trial, the d -cr dose is delivered intravenously and a spot urine sample is collected at baseline and postdose. conclusions: the d -cr method provides a non-invasive, accurate way to assess therapeutic agents that may mitigate the loss of skeletal muscle mass; it is of particular utility in clinical settings where changes in muscle mass are consequential, such as muscle loss during an icu admission. introduction: vitamin c, an enzyme cofactor and antioxidant, could hasten the resolution of inflammation, which affects most intensive care unit (icu) patients. while many observational studies have demonstrated that critical illness is associated with low levels of vitamin c, randomized controlled trials (rcts) of high-dose vitamin c, alone or in combination with other antioxidants, yielded contradicting results. the purpose of this systematic review and meta-analysis is to evaluate the clinical effects of vitamin c when administered to various populations of icu patients. methods: eligible trials: rcts comparing vitamin c, by enteral or parenteral routes, to placebo in icu patients. data collection and analysis: we searched medline, embase, and the cochrane central register of controlled trials. after assessing eligibility, data was abstracted in duplicate by two independent reviewers. overall mortality was the primary outcome; secondary outcomes were infections, icu length of stay (los), hospital los, and ventilator days. pre-specified subgroup analyses were conducted to identify more beneficial treatment effects. results: pooling rcts (n= ) reporting mortality, vitamin c was not associated with a lower risk of mortality (risk ratio [rr]: . , % confidence interval [ci]: . - . , p= . , i = %). in a subgroup analysis, trials of lower quality (n= ) were associated with a reduction in mortality (rr . , % ci . , . , p= . ), whereas high quality trials (n= ) were not. no statistical difference existed between subgroups (p= . ). in addition, no effect was found on infections, icu or hospital length of stay, and ventilator days. conclusions: current evidence does not support the hypothesis that vitamin c supplementation improves clinical outcomes of icu patients. introduction: the protein intake for patients who met adequacy for energy was assessed within our cardiothoracic intensive care. nutritional support should aim to provide at least % of calorie requirements to achieve nutritional adequacy with suggested protein requirements of . - g/kg/day [ ] . guidelines highlight the difficulty achieving the correct protein:energy ratio from nutritional support to meet this target especially in the obese population. methods: the audit was registered with clinical governance. data was collected prospectively from patients requiring tube feeding for three or more days from january -october (table ). data included type and volume of feed and calories from other sources. patients who met adequacy for energy (fig. ) introduction: patients admitted to the intensive care unit (icu) are usually at high risk of malnutrition [ , ] . the purpose of our study was to compare the accuracy of nutric score, nrs and sga in predicting los-icu, los-hosp and in-hospital mortality. methods: a total of consecutive patients admitted between march to june in a mixed (medical/surgical) icu were assessed on day of admission using the three screening tools to classify them into high-risk and low-risk of malnutrition. day apache scores and demographic data were recorded. los-icu, los-hosp inhospital mortality and secondary outcomes studied were need for supplemental nutritional support, need for ventilation and need for dialysis in high-risk and low-risk patients by each nutrition assessment tool. results: of the patients studied, ( . %) were males and ( . %) were females. . % males and . % females were found to be at a high risk of malnutrition by at least one of the scores. the mean apache score for patients at high risk (using any one screening tool) was . (sd . ) and . for the low risk group (sd . ; p < . ). the nrs and sga demonstrated statistically significant correlation(p= . ) for length of icu stay for both the high risk and low risk group whereas only the nrs correlated significantly for the length of hospital stay(p= . ). mortality was significantly higher in high risk patients identified using all scores. conclusions: there was a wide difference in the percent of patients identified as high-risk using each of the scores. introduction: nitrogen balance (nb) may be an important tool in the nutritional management of critically ill patients. cancer patients present a special challenge regarding nutrition, due to its peculiar characteristics related to neoplasia and adjuvant treatments. objectives: to evaluate nb in patients with solid cancer in the postoperative period in the icu, analyzing the correlation between nb and the mortality outcome in the icu. methods: retrospective cohort study. we evaluated adult patients (> years) admitted to the icus of two different hospitals, with diagnosis of current cancer in postoperative period (elective or emergency surgeries). patients were excluded if the diagnosis of cancer was not confirmed. nb (measured through analysis of dietary protein intake subtracted from -hour urinary urea plus an estimate of nonurinary losses) was calculated on the st, rd and th icu day. nb was measured only while the patient was in the icu. results: during the study period, patients were included (mean age . , mean apache . , . % male). admission apache ii and abdominal-site surgery were predictors of mortality. the nb of all patients was negative on the st icu day. in the patients who survived, nb of the rd and th day remained stable (negative), whereas in patients who died nb was more positive (fig. ) . there was no difference in the amount of protein ingested on the st day between survivors and deceased patients. conclusions: among adult patients with solid cancer in the postoperative period in the icu, nb was persistently negative in the survivors between st and th icu day, but among the patients who died nb tended to be more positive on the rd day. nb monitoring could allow a more adequate individualization of nutritional management in this group of patients. fig. (abstract p ) . nitrogen balance in st, rd and th icu day introduction: nutritional therapy plays an important role in the treatment of critically ill patients. caloric and protein goals are defined, and artificial nutrition tailored to the targets which are related to outcome [ ] . questions rise about the mean caloric and protein needs of patients, once discharged from icu, and the evolution of body weight, and nutritional adequacy. the aim is to know the ratios between caloric needs and intake of patients with a minimum stay at icu of days. methods: after evaluation of critically ill patients, patients were prospectively followed during their entire hospitalization. data concerning nutritional needs, prescriptions and delivery were collected from the electronic medical file. nutritional calculations of oral intake were done by nubel. ratios were made during the entire stay and body weight was followed up. results: in female and male patients, median age . years (range - year), estimated body weight of . ± kg and actual body weight of . ± kg, a mean caloric need of ± kcal/ day and an effective delivery of ± kcal/day was observed. body weight increased in two patients and decreased in ( %). in ten out of twelve patients, underfeeding was present. one patient with a caloric need of kcal/day received a mean caloric load of kcal/day ( . %). conclusions: the overall observed evolution in body weight was negative in most of the patients. nutritional adequacy was low after icu discharge and never reached target. introduction: severe burn injury can create a rapid-onset, sustained proinflammatory condition that can severely impair all major organs. this massive systemic response has been documented clinically by associated biomarker measurements including dramatic elevations in cytokines such as il- . the severity of multi-organ injury and subsequent development of other systemic complications in burn patients have been well-correlated with il- levels, including the increased risk of sepsis/multi-organ failure and associated morbidity and mortality. considering that estrogen is a powerful and easy to use anti-inflammatory agent, an experimental burn model was created to test the potential value of parenteral β-estradiol (e ) as a feasible and inexpensive early intervention to mitigate the the profound pro-inflammatory response associated with severe thermal injury. methods: male rats (n = ) were assigned randomly into three groups: ) controls/no burn (n = ); ) burn/placebo (n = ); and ) burn/e (n = ). burned rats received a % °tbsa dorsal burn, fluid resuscitation and one dose of e or placebo ( . mg/kg intra-peritoneal) minutes post-burn. eight animals from each of the two burn groups (burn/placebo and burn/e ) were sacrificed at minutes (sham group at days only), with four each of the two burn groups sacrificed at days. tissue samples from major organs and serum were obtained and analyzed by elisa for il- at each of these intervals. results: in the burned rats, β-estradiol decreased the organ levels of il- significantly as measured at both early ( min.) and late ( day) phases post-burn (figs. & . also, sham animal levels were comparable to the estradiol group, conclusions: experimentally, a single, early post-burn dose of estrogen significantly mitigates the associated detrimental inflammatory response in all major organs up to days. in turn, this may present a promising potential therapy to decrease the widespread multipleorgan dysfunction seen in severe burn injury patients. early, single-dose estrogen increases levels of brain-derived neurotrophic factor (bdnf), a neurotrophin for neuronal survival and neurogenesis following indirect brain inflammation caused by severe torso burns introduction: prior studies have found that patients with severe burns may suffer significant neurocognitive changes. while frequently attributed to psycho-social issues, we have found a substantial, rapid and sustained ( min - day) increase in rat brain inflammatory markers (for example, il- ) following remote torso burns that is blunted by a single post-burn dose of estrogen. brain-derived neurotrophic factor (bdnf), one of the most active neurotrophins, protects existing neurons and encourages the growth and differentiation of new neurons and synapses. as estrogens not only blunt inflammation but also exert an influence on cns growth factors, we hypothesized that β-estradiol (e ) might affect levels of bdnf in the post-burn rat brain. methods: male rats (n = ) were assigned randomly into three groups: controls/no burn (n = ); burn/placebo (n = ); and burn/e (n = ). burned rats received a % °tbsa dorsal burn, fluid resuscitation and one dose of e or placebo ( . mg/ kg intraperitoneally) minutes post-burn. eight animals from each of the two burn groups (burn/placebo and burn/e ) were sacrificed at hours and at days, respectively (sham group at days only), with four each of the two burn groups sacrificed at days. brain tissue samples were analyzed by elisa for bdnf. results: mean levels of bdnf were significantly elevated within hours and continued to increase up to days post-injury in burned animals receiving the β-estradiol (> pcg/mg) as compared with the placebo-treated burned animals (< pg/mg) and controls (< . pcg/mg). see fig. . conclusions: early, single-dose estrogen administration following remote severe burn injury significantly elevated levels of bdnf in brain tissue. this finding may represent an extremely novel and important pathway to enhance both neuroprotection and neuroregeneration in burn patients. the value of cortisol in patients with the infection and multiple organ dysfunction. s tachyla, a marochkov mogilev regional hospital, mogilev, belarus critical care , (suppl ):p introduction: hormones changes in patients with infection and multiple organ dysfunction is a topic that hasn't been adequately studied. goal of study: to establish the value of cortisol in patients with infection and multiple organ dysfunction. methods: after approval the ethics committee of the mogilev regional hospital a prospective observational study was performed. the study included patients aged to years. all patients were hospitalized in the intensive care unit with the infection and multiple organ dysfunction. patients with endocrine diseases and receiving glucocorticoids were excluded. cortisol levels were measured on admission and during the course of treatment by radioimmunoassay. in group l (n = ) patients had a low levels of cortisol, in the m group (n = ) -normal cortisol, in group h (n = ) -high cortisol. results: cortisol level was in l-group . ( . , . ) nmol/l, in mgroup . ( . ; . ) nmol/l, in h-group . ( , ; . ) nmol/l. it is found that the mortality was higher in the groups l - . % (p = . ) and h - . % (p = . ), than in the m-group - . %. the mgroup odds ratio equals . at % confidence interval . - . when compared with the h-group. in the m-group in survivors patients (n = ) showed a decrease cortisol with ( . , . ) nmol/l to . ( . , . ) nmol/l (p = . ). while the no survivors patients (n = ) showed increase cortisol with ( . , . ) nmol/l to . ( ; ) nmol/l (p = . ). thus itself cortisol level is not a marker of mortality. receiver operating curve analysis for cortisol was performed: area under the curve equals . at % confidence interval of . - . (p = . ), sensitivity . %, specificity . %. conclusions: in patients with infection and multiple organ dysfunction may be observed disorders in cortisol levels. these disorders require correction to prevent the increased mortality. introduction: the hypothalamic-pituitary-adrenal (hpa) axis is a key regulator of critical illness. cortisol and adreno-corticotrophic hormone (acth) are pulsatile, which emerges from the feed forwardfeedback of the two hormones [ ] . different genes are activated by continuous or pulsatile activation of the glucocorticoid receptor, even when the total amount is the same [ ] . we aimed to characterise the acth and cortisol profiles of patients who were critically ill after cardiac surgery and assess the impact of inflammatory mediators on serum cortisol concentrations. methods: patients with > organ system failure, > days after cardiac surgery were recruited. total cortisol was assayed every min, acth every hour and il , il , il , il , il , tnf-α every hours. cortisol binding globulin (cbg) was assayed at and hrs. the relationship between cortisol and the inflammatory mediators was quantified in individual patients using a mixed regression model. results: all profiles showed pulsatility of both cortisol and acth and there was concordance between the two hormones (see fig. ). one patient died after hours (see fig. ). this patient lost pulsatility and concordance of cortisol and acth. mean cbg was . μ g/ml at the start of sampling and . μ g/ml at the end. there was an association between il (p= . ), il (p< . ), il (p= . ) and serum cortisol levels. there was no association between the other mediators and cortisol. conclusions: cortisol and acth are both pulsatile in critical illness. because pulsatility emerges from the interaction between the two hormones[ ]the premise of a 'disconnect' between the pituitary and adrenal gland is refuted. il , il and il may have roles in the control of cortisol during critical illness. introduction: elevation in plasma cortisol is a vital response to sepsis and partially brought about by reduced cortisol breakdown in which bile acids (bas) may play a role. vice versa, cortisol can also upregulate bas. we hypothesized a central role for the hepatic glucocorticoid receptor (hgr) in cortisol and ba homeostasis and in survival from sepsis. methods: in a mouse model of sepsis, we documented hgr expression and investigated the impact of hepatocyte-specific shrnaknockdown of gr on markers of corticosterone (cort), ba and glucose homeostasis, inflammation and survival. we also compared hgr expression in human septic icu and elective surgery patients. results: in mice, sepsis reduced hgr expression with % (p= . ), elevated plasma cort, bas and glucose and suppressed a-ringreductases. also in human patients, sepsis reduced hgr expression (p< . ), further suppressed by treatment with steroids (p= . ). in septic mice, further and sustained hgr-inhibition increased mortality from % to % (p< . ). at h, hgr-inhibition prevented the rise in total plasma cort, but did not affect a-ring-reductases expression. however, it further reduced cort binding proteins, resulting in elevated free cort equal to septic mice without modified hgr. after days of hgr-inhibition in sepsis, total and free cort were comparable to septic mice without modified hgr, now explained by further reduced a-ring-reductase expression, possibly driven by higher hepatic ba content. hgr-inhibition blunted the hyperglycemic sepsis response without causing hypoglycemia, markedly increased hepatic and circulating inflammation markers and caused liver destruction (p< . ), the severity of which explained increased mortality. conclusions: in conclusion, sepsis partially suppressed hgr expression, which appears to upregulate free cort availability via lowered cort binding proteins and a-ring-reductases. however, further sustained hgr suppression evoked lethal excessive liver and systemic inflammation, independent of cort availability. introduction: cortisol levels have been found to be increased in sepsis patients, and high cortisol levels have been correlated with increased mortality. the purpose of this project is to assess the association of plasma cortisol levels with severity of coagulopathy in a population of patients with sepsis and clinically confirmed dic. methods: citrated, de-identified plasma samples were collected from adults with sepsis and suspected dic at the time of icu admission. platelet count was determined as part of standard clinical practice. pt/inr and fibrinogen were measured using standard techniques on the acl-elite coagulation analyzer. cortisol, d-dimer, pai- , cd l, nlrp , and microparticles were measured using commercially available elisa kits and were performed. dic score was calculated using isth scoring algorithm. results: cortisol showed significant variation based on dic status (kruskal-wallis anova, p < . ). patients with non-overt dic and overt dic exhibited significantly elevated cortisol levels compared to healthy controls (p < . for both groups). cortisol levels showed dic based variations. patients with sepsis and overt dic had elevated cortisol compared to patients with sepsis and no dic (p = . ) (fig. ) . correlations were evaluated between cortisol and hemostatic markers platelets, fibrinogen, inr, d-dimer, and pai- as well as with the inflammatory marker, nlrp and the platelet markers cd l and microparticles. cortisol conclusions: cortisol showed a significant association with hemostatic status in a population of patients with sepsis and welldefined coagulopathy. cortisol levels were significantly elevated in patients with overt or non-overt dic compared to healthy individuals and in patients with overt dic compared to those with sepsis without dic. introduction: in most cases presenting with hypoglycemia in emergency departments (eds), the etiology of the hypoglycemia is almost identified. however, about % of cases, the etiology of hypoglycemia cannot be determined. methods: this is a -year prospective observational study. a total of patients were transported to our ed with hypoglycemia. after the investigation, a rapid acth loading test (synthetic - acth μg iv.) was performed on patients with unexplained hypoglycemia; i.e., μg acth was administered intravenously and blood specimens were collected before loading, at min and min after acth administration. we adopted a peak serum cortisol level < μg/dl or a delta cortisol of < μ g/dl for the diagnosis of adrenal insufficiency. results: among the patients, of ( . %) were using antidiabetic drugs, ( . %) were using hypoglycemia-relevant drugs, ( . %) suffered from digestive absorption failure including malnutrition, ( . %) had been consuming alcohol, ( . %) suffered from malignancy, and ( . %) suffered from insulin autoimmune syndrome. initially, an etiology was unknown in of ( . %) patients. rapid acth test revealed the adrenal insufficiency in ( . %) among them. administration of hydrocortisone in adrenal insufficiency patients promptly improved hypoglycemia. in those patients, serum sodium level was lower (na; vs. meq/l, p< . ) and serum potassium level was higher (k; . vs. . meq/l, p< . ) than in the other hypoglycemic patients, respectively. there was no significant difference in baseline plasma glucose level on ed between the groups of patients ( vs. mg/dl, p= . ). conclusions: the probability of adrenal insufficiency was much greater than that of the better-known insulinoma as a cause of hypoglycemia. when protracted hypoglycemia of unknown etiology is recognized, we recommend that the patient is checked for adrenal function using the rapid acth loading test. introduction: sepsis caused have showed serious alternations of thyroid hormones releasing, causing a nonthyroidal illness syndrome. the aim of the study was to measure thyroid hormone levels in septic patients and analyse its relation with clinical state and outcome. methods: prospective study in a cohort of consecutive septic patients. we studied thyrotropin (tsh), free triiodothyronine fraction (ft ) and free thyroxin fraction (ft ) serum levels, apache ii and sofa score. statistical analysis was performed using spss . . results: we analysed episodes of sepsis ( %) and septic shock (ssh) ( %), the median age of the patients was (inter-quartile range, . - ) years; the main sources of infection were: respiratory tract ( %) and intra-abdomen ( %); . % had medical diseases. apache ii score was [ - ], sofa score was [ . - ] and day mortality was . %. our data shown . % with low levels of tsh (< . uui/ml), . % had low levels of ft (< . ng/dl) and . % low levels of ft (< pg/ml). the tsh ( . vs. . uui/ml) and ft ( . vs . pg/ml) concentration of ssh group were significantly lower than those of sepsis group, whereas ft ( . vs . ng/dl) it was not statistically significantly. correlation of ft to apa-che ii (r = − . , p = . ) and sofa score (r = − . , p = . ). the profile of death patients were men ( . %, n = ), with significantly older ( vs. years; p= , ), as well as clinical severity scores, apache ii ( . vs. . ; p< . ) and sofa ( . vs . ; p< , ). non-survivors had significantly lower tsh . vs. . uui/ ml; p= . , and ft . vs. . pg/ml, p= . , however ft did not show statistical significance . vs. . ng/dl, p=ns. conclusions: conclusions: most of our septic patients present an altered thyroid function. our data suggest that tsh and specially ft may be used as a marker of disease severity and a mortality predictor. observational study to evaluate short and long-term bone metabolism alteration in critical patients. introduction: reduction of bone mineral density and/or muscle mass can be short and long-term complications in critical patients admitted in intensive care unit (icu). the study aims to evaluate, during a -month period, the following parameters: ) the alterations of bone metabolism and quantitative and qualitative parameters of bone tissue, ) the proportion of subjects with bone fragility, and ) the identification of specific risk factors. methods: an observational-longitudinal monocentric study is being conducted in adult patients hospitalized in icu. the evaluations performed at baseline, and month visits include analysis of biochemical and instrumental exams. results: a specific clinical-care pathway was created between bone metabolic diseases unit and icu, in order to perform specific anamnestic collection, biochemical analysis of bone metabolism, and instrumental exams. patients were enrolled and evaluated at the baseline visit. biochemical exams, performed within hours of hospitalization, showed that % (n: ) of subjects had a deficit of ohvitamind < ng/dl, associated with normal corrected serum calcium levels and of these % (n: ) had high pth levels. bone alkaline phosphatase was increased in % (n: ) of patients. conclusions: critical patients are "fragile" subjects, which should be monitored with a short and long-term follow-up. the creation of a clinical pathway that includes specialists of bone metabolism may be a virtuous way to identify patients who report bone mass loss and increased fracture risk. this study will allow to implement the knowledge regarding specific risk factors of bone fragility and the most appropriate therapeutic choices as prevention and treatment. a retrospective analysis of predictors for length of intensive care stay for patients admitted with diabetic ketoacidosis a fung, tl samuels, ae myers, pg morgan east surrey hospital, redhill, uk critical care , (suppl ):p introduction: diabetic ketoacidosis (dka) is one of the most common metabolic causes of admission to the intensive care unit (icu). the incidence of dka is quoted as between . - episodes per patients with diabetes mellitus (dm) [ ] . we aim to establish the factors that affect length of stay (los) on icu. methods: we undertook an analysis of patients admitted to icu over the last years with a primary diagnosis of dka. we assessed whether there was an association between the following factors and an increased length of icu stay: age, gender, body mass index (bmi), systolic blood pressure, heart rate, sodium, potassium, haemoglobin and ph. these factors were assessed using multiple linear backward stepwise regression. results: overall, admissions were identified over the time period from the ward watcher database. the median los was . days (iqr . - . ). our analysis demonstrated that length of icu stay (alpha level < . ) was significantly associated with bmi, low systolic blood pressure, and the presence of hyponatraemia or hypernatraemia. conclusions: we found the variables that affect the los for patients presenting to our unit with dka are bmi, elow systolic bp, low sodium and high sodium. we intend to extend this work to include survival analysis with the same subgroup of patients. maximal glycemic gap is the best glycemic variability index correlated to icu mortality in medical critically ill patients t issarawattna, r bhurayanontachai prince of songkla university, songkla, thailand critical care , (suppl ):p introduction: several evidences shown a correlation of glycemic variability (gv) and icu mortality. however, there have been no report of the correlation between various parameters of gv and mortality in medical icu patients. the aim was to determine the correlation between various parameters of gv and medical icu mortality, as well as, to identify the best gv index to predict icu mortality. methods: a retrospective chart review was then conducted in medical icu at songklanagarind hospital. the patient characteristics, causes of admission, apache ii, blood glucose within the first hours of icu admission and icu mortality were recorded. glycemic variability parameters including maximal glycemic gap, standard deviation, coefficient of variation and j-index of blood glucose were calculated. the correlation of those gv index to icu mortality was determined. the roc and auroc of each gv index were then compare to identify the best gv index to predict icu mortality. results: of patients, patients ( . %) were survived ( table ). all gv indexes were significantly higher in non-survival group (p < . ) ( table ). maximal glycemic gap was independently correlated to icu mortality and give a highest auroc compared to others gv. (maximal glycemic gap auroc . ( %ci . - . vs. coefficient of variation auroc . ( %ci . - . ) vs standard deviation auroc . ( %ci . - . ) vs j-index auroc . ( %ci . - . ), (p< . ) (fig. ) . conclusions: maximal glycemic gap independently correlated to icu mortality and was the best gv to predict icu mortality in medical critically ill patients. reliability of capillary blood glucose measurement for diabetic patients in emergency department h ben turkia, s souissi, a souayeh, i chermiti, f riahi, r jebri, b chatbri, m chkir regional hospital of ben arous, ben arous, tunisia critical care , (suppl ):p introduction: acute glycemic disorders should be early diagnosed and treated in emergency department (ed), especially hypoglycemia. can capillary blood glucose (cg) replace plasmatic glucose (pg). the objective of this study was to compare capillary blood glucose with venous blood glucose methods: patients with type diabetes were included. we realize a capillary blood glucose with a glucose meter (acu-check active-roche) and a concomitant determination of venous blood glucose with laboratory machine (synchrony cx delta system beckman coulter). a correlation study (pearson correlation) between the two measurements was evaluated and linear fitting equation was established. the concordance was checked with bland and altman method. results: during the months of the study, patients were included. the average age was +/- years old, with a sex ratio = . majority of patients ( %,n= ) had type diabetes and % was treated with insulin. we found an excellent correlation between the two techniques with a pearson correlation coefficient r= . .topredict the pg from cg, we can use this equation: pg(g/l)= . cg(g/l)+ . (r = . ; p= . ). we noticed a good concordance between the two techniques especially in case of hypoglycemia and moderate hyperglycemia (fig. ) . however, releases were noted with a pg higher than g/l. conclusions: in ed, the measurement of capillary glucose can exempt from venous blood glucose especially in case of hypoglycemia and moderate hyperglycemia. is frequently found in critically ill patients in icu, especially patients who are treated for a long time. this study aims to analyse the comparison between length of stay and dvt incidents in critically ill patients. methods: a cross-sectional study was employed. we include all patients who were years or older and were treated in icu of dr soetomo public hospital for at least days. data were collected from june until june . the patients were examined with sonosite usg to look for any thrombosis in iliac, femoral, popliteal, and tibial veins and well's criteria were also taken. results: thirty patients were included in this study. this study shows that length of stay is not the only risk factor for dvt in patients treated in icu. in our data, we found out that the length of treatment did not significantly cause dvt. other risk factors such as age and comorbidities in patients who are risk factors may support the incidence of dvt events. the diagnosis of dvt is enforced using an ultrasound performed by an expert in the use of ultrasound to locate thrombus in a vein. conclusions: length of treatment is not a significant risk factor for dvt. several other factors still need to be investigated in order for dvt events to be detected early and prevented. [ ] was used to retrospectively study trends and outcomes of cancer patients admitted to the icu between and . logistic regression analysis was performed to assess predictors of -day and -year mortality. results: out of , icu admissions, , hemato-oncological, , oncological and patients with both a hematologic and solid malignancy were analyzed. hematologic patients had higher critical illness scores, while oncological patients had similar apache-iii and sofa-scores. in the univariate analysis, cancer was strongly associated with mortality (or . , table ). over the -year study period, -day mortality of cancer patients decreased by % (fig. ) . this trend persisted after adjustment for covariates, with cancer patients having significantly higher mortality (or= . , %ci: . , . ). between and , the adjusted -day mortality decreased by % every year. over the decade, -year mortality decreased by %. having cancer was the strongest individual predictor of -year mortality in the multivariate model (or= . , %ci: . , . ) (fig. ) . conclusions: between and , the number of cancer patients admitted to the icu increased steadily and significantly, while longitudinal clinical severity scores remained overall unchanged. although hematological and oncological patients had higher mortality rates than patients without cancer, both -day and -year mortality decreased significantly over the study period. introduction: sepsis was redefined in with the introduction of an increase in sequential organ failure assessment Δsofa) score of >= and the quicksofa (qsofa) as screening tools for sepsisrelated mortality. however, the implementation of these criteria into clinical practice has been controversial and the applicability for hematological patients is unclear. methods: we therefore studied the diagnostic accuracy of different sepsis criteria for sepsis and mortality according to definition criteria in a retrospective analysis of hematological patients in an academic tertiary care hospital. patient characteristics and variables were collected in icuand non-icu patients to determine the systemic inflammatory response syndrome (sirs), Δsofa and qsofa. by applying the definition of sepsis as "life-threatening organ dysfunction caused by a dysregulated host response to infection" [ ] as reference, the scores were evaluated. in patients with sepsis who died, / were sirs-negative, / Δsofa-negative and / qsofa-negative ( fig. and table ). conclusions: in conclusion, these findings suggest that criteria proposed in the sepsis- definition might have limitations as screening fig. (abstract p ) . results of the logistic regression analysis for (a) -day and (b) -year mortality. all covariates were statistically significant except for white race in the -year mortality model. ***p-value< - , **p-value< . , *p-value< . fig. (abstract p ) . longitudinal change in -day mortality for cancer patients (yes) compared with controls (no) over the -year study period. mortality in the cancer group decreased from % to % (- %), while mortality in the control group decreased from to % (- %). enoxaparin pharmacokinetics in patients with augmented renal clearance, preliminary results of a single center study introduction: augmented renal clearance (arc) has being described in some groups of critically ill patients. the aim was to investigate the impact of arc on the pharmacokinetics of enoxaparin. methods: this is a prospective study in a surgical and medical intensive care unit (icu) carried out from august to november . patients < years old, under prophylactic treatment with enoxaparin and normal plasma creatinine, were included. anti-xa activity was measured at second day under treatment. creatinine clearance was calculated from urine sample collected during -hours. arc was defined by a creatinine clearance >= ml/min/ . m . results: thirteen patients aged years old (± . ) were included. six patients developed arc and of them were in therapeutic range. seven patients did not develop arc and of them were in therapeutic range. there was no differences between the two groups in achieving therapeutic range (fisher test, p= . ). we did not observe thromboembolic events. conclusions: we found no relationship between arc and therapeutic failure in patients under prophylactic treatment with enoxaparin. introduction: this study reviewed argatroban use in patients in a tertiary hospital critical care unit. argatroban is a direct thrombin inhibitor approved for use in proven or suspected heparin-induced thrombocytopenia (hit) in patients with renal dysfunction. methods: this was a retrospective cohort study in a medical and surgical icu in a tertiary teaching hospital. data was collected for adult patients treated with argatroban for proven or suspected hit april-august , excluding patients requiring ecmo. we scored patients using the t score and compared this to an elisa immunoassay optical density score which quantifies the pf /h antibody level. also noted was use of continuous haemodialysis and organ failure using the sequential organ failure assessment (sofa), scoring >= defines failure. results: patients were treated with argatroban for proven or suspected hit. / patients had a positive elisa. there was no relationship between t score and elisa optical density (fig. ) . infusions were commenced at either the manufacturer recommended dose of μg/kg/min or a reduced dose of . μg/kg/min. patients receiving the reduced dose had a median of organs failing compared to in the standard regimen. the time taken to the first aptr in range was longer with the reduced dose regimen, however, the time to a stable aptr was less (table ). in patients the dose of argatroban never stabilised. died and was very sensitive to argatroban and required cessation of the infusion for interventions. in the reduced regimen group, there were episodes of bleeding, minor pr bleed in a patient with organs failure and upper gi bleed. conclusions: in this population of icu patients the t score did not correlate with the elisa optical density score, as found previously. patients with multi-organ failure mostly received the reduced starting dose. however, the bleeding events were still confined to this group. this correlates with previous studies that organ dysfunction necessitates a dose reduction for argatroban. results: the mean age in our study group was ± years. the effects of tpe on standard coagulation were increased aptt ( ± to ± s, p= . ) and decreased fibrinogen levels ( ± to ± mg/dl, p= . ). a non-significant decrease in platelet count was observed ( ± to ± /mm , p= . ). on rotem parameters tpe was associated with increased ct in extem ( ± to ± s, p= . ) and intem ( ± to ± s, p= . ) and increased maxvt on extem ( ± to ± s, p= . ) and intem ( ± to ± s, p= . ). all other rotem parameters changed non-significantly. the decrease observed in fibrinogen levels was not associated with a decrease in fibtem mcf ( ± to ± mm, p= . ). conclusions: our results demonstrate that tpe is associated with minimum changes in clot kinetics initiation that do not result in either pro-or anti-coagulant changes. therefore, tpe with fresh frozen plasma can be safely used in normal subjects. introduction: acutely ill patients are prone to critical illness anaemia, a multifactorial condition with potential contribution of iatrogenic anaemia defined as lowered hb due to large/frequent venepunctions. decline in hb is most pronounced in the first days of icu stay. it correlates with the need for rbc transfusion, but the impact on patient outcome is uncertain. the aim of this study was to determine impact of phlebotomy on change in hb (Δhb), and correlation of Δhb with need for transfusion, presence of central venous catheter (cvc) and patient outcome. conclusions: critical illness anaemia is an unexplained phenomenon. impact of phlebotomy is hard to unequivocally determine since there are many confounders. the change in hb levels during icu stay correlates with the need for transfusion that could cause immunomodulation and potentially adverse outcome. every effort should be made to maintain adequate hb levels and lower the risk of iatrogenic anemia. introduction: anemia is prevalent in critically ill traumatic brain injury (tbi) patients and red blood cell (rbc) transfusions are often required. over the years, restrictive transfusion strategies have been advocated in the general critically ill population. however, considerable uncertainty exists regarding optimal transfusion thresholds in critically ill tbi patients due to the susceptibility of the injured brain to hypoxemic damages. methods: we conducted an electronic self-administered survey targeting all intensivists and neurosurgeons from canada, australia and the united kingdom working caring for tbi patients. the questionnaire was developed using a structured process of domains/items generation and reduction with a panel of experts. it was validated for clinical sensibility, reliability and content validity. results: the response rate was . % ( / ). when presented with a scenario of a young patient with severe tbi, a wide range of transfusion practices was noted among respondents, with % favoring rbc transfusion at a hemoglobin level of g/dl or less in the acute phase of care, while % would use this trigger in the plateau phase. multiple trauma, neuromonitoring data, hemorrhagic shock and planned surgeries were the most important factors thought to influence the need for transfusion. the level of evidence was the main reason mentioned to explain the uncertainty regarding rbc transfusion strategies. conclusions: in critically ill tbi patients, transfusion practices and hemoglobin thresholds for transfusion are said to be influenced by patients' characteristics and the use of neuromonitoring in critical care physicians and neurosurgeons from canada, australia and the uk. equipoise regarding optimal transfusion strategy is manifest, mainly attributed to lack of clear evidences and clinical guidelines ( -year) . no significant associations were found between ffp:rbc ratio and mortality rates. patients with higher apache ii score received more platelet transfusions and mortality rates were higher in those who received platelets:rbc ratio > . on multivariate analysis, higher apa-che ii score was an independent predictor of increased mortality. conclusions: the compliance with the recommended : : ratio of blood products was poor. there was no association between transfusion ratios and mortality after adjusting for apache ii score. introduction: the lack of evidence-based medicine supporting the transfusion decision is illustrated by the wide range of blood product use during first-time coronary artery bypass grafting (cabg). use of red blood cells (rbc) ranges from to percent, while the use of platelets range from to [ ] . approximately percent of cabg patients suffer abnormal bleeding, with platelet dysfunction thought to be the most common culprit [ ] . methods: the objective of this study was to evaluate the use of allogeneic blood and blood products among patients undergoing first-time cabg over the past years. the first patients who underwent cabg (on-pump and off-pump) from st of march each year were included for analysis. the percentage of patients receiving rbc, fresh frozen plasma (ffp), platelet and cryoprecipitate during the first hours intra-and postoperatively were analysed. linear regression analysis was performed in each group. results: our analysis shows that the use of rbc decreased over the last years, in contrast to the use of the other investigated products. (see fig. ) the increase of platelets was the most pronounced with a direction coefficient of . and had the least variability (r = . ). (see fig. ) the decrease in rbc was less obvious than the rise in platelet use (direction coefficient of . ) and had a higher variability (r = . ). the consumption of ffp and cryoprecipitate stayed constant (direction coefficient of . and . respectively). the higher incidence of semi-urgent cabg in recent years, which involves continuation of anti-platelet therapy until the day before surgery, can be an explanation for our observed increased use of platelets. the observed decrease in rbc transfusion over the past years might be due to rising awareness of complications associated with red cell transfusion. introduction: red blood cells (rbc) transfusion is frequently required in cardiac surgery and is associated with increased morbidity and mortality rates. the aim of this study is to identify predictors of rbc transfusion for patients undergoing cardiac surgery, emphasizing the use of bioelectrical impedance analysis (bia). methods: this was a retrospective study of patients who underwent elective cardiac surgery between years and in a tertiary reference center. patients' demographic and clinical variables, preoperative bia measurements and postoperative data were analyzed. the univariate and multivariate logistic regression analyses were used to identify the predictors of postoperative rbc transfusion. all of the calculations were performed with ibm spss v. . introduction: red blood cells (rbc) transfusion is a common intervention in cardiac surgery and is associated with higher mortality rates and predisposes serious adverse events. the aim of this study was to determine whether red blood cells (rbc) transfusion is linked to long-term results after cardiac surgery. methods: this observational retrospective study included all of the patients who underwent any of the sts defined elective cardiac surgery types from to . we evaluated - year all-cause mortality rates and secondary postoperative outcomes defined by the sts risk prediction model. patients were categorized according to whether they received rbc transfusions postoperatively; long-term results were compared using cox-regression analysis and kaplan-meier method. introduction: transfusion of packed red cells (prcs) is an important treatment option for patients requiring intensive care but, like all treatments, it is not without risk. these patients, although may be more sensitive to anaemia, are also at increased risk of transfusionrelated complications. we conducted an audit of blood prescribing and administering practices in our intensive care unit. methods: audit proformas were placed in blood prescribing forms for a -month period. all transfusions of prcs were logged over this time, and transfusion triggers, post-transfusion haemoglobin (hb) and whether hb was checked between units was recorded, in addition to other supplementary information. results: over a -month period, transfusion events were recorded, with an average age of the transfused patients of years old (range - years). % of transfusion events were for low hb, % for bleeding and in % of cases the indication was not documented. for patients transfused for a low hb, the mean transfusion trigger was g/l (range: g/l - g/l). only % had a transfusion trigger of g/l or less, and a further % who were transfused for a low hb had a hb of g/l or more. % of transfusion events involved transfusing or more units and, in only % of these cases the hb was checked between units. excluding the two bleeding patients, the mean increase in hb following a single unit transfusion was . g/l (range g/l - g/l), whilst in patients transfused two units, the average increase in hb was g/l per unit transfused (range g/l - . g/l), suggesting single unit transfusions may have greater hb yields. conclusions: our audit demonstrated variability in transfusion triggers and progress needed with administering practices when transfusing multiple units of blood in the non-bleeding patient. we have since implemented measures to meet guidelines in both prescribing prcs with restrictive triggers and in the administration and assessment of hb between units, and will be re-auditing. introduction: there is a perceived increased risk of bleeding in cirrhosis patients undergoing invasive procedures. this lead to a high rate of empirical prophylactic transfusion, which has been associated to increased complications and cost. the best strategy to guide transfusion in these patients remains unclear. our aim was to compare three strategies to guide blood component transfusion prior to central venous catheterization (cvc) in critically ill cirrhosis patients. methods: single center, randomized, double-blinded, controlled clinical trial conducted in brazil [ ] . all cirrhosis patients admitted to the icu with indication for a cvc were eligible. participants were randomized : : to three transfusion strategies based on: ( ) standard coagulation tests (sct), ( ) rotational thromboelastometry (rotem) and ( ) restrictive. the primary outcome was proportion of transfusion of any blood component prior to cvc. secondary outcomes were incidence of major and minor bleeding, icu length of stay (los), and -day mortality. analysis was intention-to-treat. results: participants ( in each group) were enrolled between september and december . most were male ( . %) and listed for liver transplantation. the study ended after reaching efficacy in first interim analysis. there was no significant difference in baseline characteristics among groups. regarding primary endpoint, there was ( . %), ( . %), and ( . %) events in sct, rotem and restrictive groups, respectively (p < . ). there was no difference between sct and rotem groups (p > . ). overall -day mortality was . % and was similar between groups. icu los did not differ between groups. there was no major bleeding. overall minor bleeding occurred in . % with no difference between groups. conclusions: a restrictive strategy is safe and effective in reducing the need of blood component transfusion prior to cvc in critically ill cirrhosis patients. a rotem-based strategy was no different from transfusion guided by sct. introduction: desmopressin (ddavp) is a vasopressin analogue which improves platelet function. its general use as a haemostatic agent is still controversial. the aim of study was to evaluate the effect of prophylactic desmopressin in blood coagulation in patients undergoing heart valve surgery. methods: prospective, randomized, double-blind clinical trial performed at the heart institute of the university of são paulo. a total of adult patients undergoing heart valve surgery were enrolled from february to november . immediately after cardiopulmonary bypass weaning and heparin reversal, patients were randomized in ratio : to intervention group: ddavp ( . μg/kg) or control group. blood samples were drawn at three different times, at baseline (t ), hours (t ) and hours (t ) after study medication. blood coagulation and perioperative bleeding were analysed using laboratorial tests and thromboelastometry, chest tube drainage and requirement of allogenic transfusion within hours. results: a total of patients were allocated to intervention and to control group. blood levels of factor viii at t ( . conclusions: prophylactic use of desmopressin in heart valve surgery does not influence coagulation and thromboelastometric parameters. identifying the impact of hemostatic resuscitation on development of multiple organ failure using factor analysis: results from a randomized trial using first-line coagulation factor concentrates or fresh-frozen plasma in major trauma (retic study) p innerhofer introduction: to clarify how hemostatic resuscitation affects occurrence of multiple organ failure. methods: analysis of secondary endpoints of the retic study [ ] (coagulation factors, activated protein c (apc), thrombin generation, rotem parameters, syndecan- , thrombomodulin (tm) and d-dimer) measured at randomization, and after patients had received ffp or coagulation factor concentrates (cfc) at admission to icu, and hours thereafter. we used factor analysis to reduce the highly interrelated variables to a few main underlying factors and analysed their relation to mof before and after hemostatic therapy. results: the factors concentration, clot and hypoperfusion representing trauma-induced coagulopathy (table ) were comparable between groups at baseline (fig. ) and only high hypoperfusionscore predicted mof, while after therapy a low clot-score also predicted mof. only the changes of the clot-score independently affected occurrence of mof (p= . , adjusted or . , ci . - . ), while changes of concentration (p= . , adjusted or . , ci . - . ) and hypoperfusion (p= . , adjusted or . , ci . - . ) did not. a lower clot-score occurred after ffp transfusion than use of cfc, mainly through persistent thrombocytopenia (platelet count r - ffp vs cfc p< . ) (fig. ) . the higher concentration-score after ffp did not affect mof and ffp had no beneficial effect on fibrinolysis, syndecan- , tm or apc. conclusions: hemostatic resuscitation should augment the factor clot, which is feasible with early fibrinogen administration but not with ffp. the found platelet-saving effect of early fibrinogen administration is important as platelets play a major role in inflammation and transfusion of platelets did not correct thrombocytopenia. introduction: the trauma induced coagulopathy clinical score (ticcs) was developed to be calculable on the site of injury with the objective to discriminate between trauma patients with or without the need for damage control resuscitation (dcr) and thus transfusion [ ] . this early alert could then be translated to in-hospital parameters at patient arrival. base excess (be) and ultrasound (fast) are known to be predictive parameters for emergent transfusion. we emphasize that adding this two parameters to the ticcs could improve its predictability. methods: a retrospective study was conducted in the university hospital of liège. based on the available data in the register (from january st to december st ), the ticcs was calculated for every patient. be and fast results were recorded and points were added to the ticcs according to the ticcs.be definition (+ points if be < - and + points in case of a positive fast). emergent transfusion was defined as the use of at least one blood product in the resuscitation room. the capacity of the ticcs, the ticcs.be and the trauma associated severe hemorrhage (tash) to predict emergent transfusion were assessed. results: a total of patients were included in the analysis. ( %) needed emergent transfusion. the probability for emergent transfusion grows with the ticcs.be value (fig. ) . positive predictive values (ppv) and negative predictive values (npv) of the three scores are displayed in table . conclusions: our results confirm that be and fast results are relevant parameters that can be added to the ticcs for better prediction of the need for emergent transfusion after trauma. fig. (abstract p ) . probability for emergent transfusion with ticcs.be values. fig. (abstract p ) . boxplots show available measurements of extrinsically activated clot firmness at min (exa ), fibrin polymerization at min (fiba ) and platelet count at baseline (r ) and after therapy at admission to icu, and hours thereafter (r to r ) for the cfc (blue, n= ) and the ffp (yellow, n= ) group as well as for patients without (white, n= ) and with (grey, n= ) multiple organ failure. table ) for the cfc (blue, n= ) and the ffp (yellow, n= ) group, as well as for patients without (white, n= ) and with (grey, n= ) multiple organ failure. each factor is given at the measurement time point baseline (r ) and following haemostatic resuscitation at admission to icu, and hours thereafter (r to r ). introduction: the management of the critically ill polytrauma patient is complex and is often a challenge for the intensive care team. the objectives of this study is to analyze the oxidative stress expression in polytrauma cases as well as to evaluate the impact of antioxidant therapy on outcomes. methods: this prospective study was carried out in the clinic for anaesthesia and intensive care "casa austria", form the "pius brînzeu" emergency county hospital, timisoara, romania, with the approval of the hospital's ethics committee. clinicaltrials.gov identifier nct . the patients' selection criteria included an injury severity score (iss) of or higher, and age of or higher. patients were eligible for the study. they were divided in two groups, group a (antioxidant free, control, n= ), and group b (antioxidant therapy, study group, n= ). the antioxidant therapy consisted in continuous iv administration of mg/ h of vitamin c until discharge from icu. the patients included in the study presented with similar characteristics, and no statistically significant differences were shown between group a and b regarding age (p > . ), sex (p > . ), iss upon admission (p > . ), percentage of patients admitted in the icu more than hour post-trauma (p > . ), and associated trauma (p > . ). among patients in group b statistically significant differences were identified regarding the incidence of sepsis (p < . ), multiple organ dysfunction syndrome (p < . ), mechanical ventilation time (p < . ), and mortality (p < . ). no statistically significant differences were shown regarding the time spent in the icu (p > . ). conclusions: following this study we can state that the administration of substances with a strong antioxidant character has positive influences on the outcome of critically ill patients, decreasing the incidence of secondary pathologies as well as mortality rates. icc increased by . %, icd increased by . %, slightly increased ma, and ircl was nearly in the normal range. conclusions: rapid and accurate diagnosis of the coagulation system by lpteg method at different stages of traumatic disease allows for more accurate selection and adjustment of the therapy, which allows improving the prognosis of the disease. introduction: evidence for tranexamic acid (txa) in the pharmacologic management of trauma is largely derived from data in adults [ ] . guidance on the use of txa in pediatric patients comes from studies evaluating its use in cardiac and orthopedic surgery. there is minimal data describing txa safety and efficacy in pediatric trauma. the purpose of this study is to describe the use of txa in the management of pediatric trauma and evaluate efficacy and safety endpoints. methods: this retrospective, observational analysis of pediatric trauma admissions at hennepin county medical center from august to november compares patients who did and did not receive txa. the primary endpoint is survival to hospital discharge. secondary endpoints include surgical intervention, transfusion requirements, length of stay, thrombosis, and txa dose administered. results: there were patients [<=] years old identified for inclusion using a massive transfusion protocol order. twenty patients ( %) received txa. baseline characteristics and results are presented as median (iqr) unless otherwise specified, with statistical significance defined as p < . . patients receiving txa were more likely to be older, but there was no difference in injury type or injury severity score (iss) at baseline (table ) . there was no difference in survival to discharge, need for surgical intervention, or thrombosis (table ) . patients who did not receive txa had numerically higher transfusion requirements and longer length of stay, but these did not reach significance. conclusions: txa was utilized in % of pediatric trauma admissions at a single level i trauma center, more commonly in older patients. though limited by observational design, we found patients receiving txa had no difference in mortality or thrombosis. introduction: the risk of venous thromboembolism (vte) in trauma is greatly increased and one of the leading causes of morbidity and mortality after an accident [ ] . prophylactic measures to prevent vte primarily consist of anticoagulants. in instances in which anticoagulation is contraindicated or inadequate, inferior vena cava (ivc) filters can be used [ ] . however, insertion of ivc filter as a prophylactic measure is controversial as filter-related complications are well documented and increase with treatment time [ ] . the objectives of our study were to evaluate ivc filter insertion indications and filter related complications in pelvic trauma patients. methods: patients with pelvic fractures were operated during the study period / / - / / . all patients who received ivc filter during the period were included into analysis. relevant data was collected from electronic patient journal. results: thirty four patients received retrievable filters during the study period ( males and females) ( table ) . median age of patients was years (range, - ). the predominant indication ( %) was prophylactic insertion. the median indwell time was days (range - days). despite ivc filter insertion one patient experienced lung embolism and another -dvt. in eleven cases ivc filters were tried to be removed at the treating hospital. in two cases filter extraction was unsuccessful and in another two cases filters were left in place due to ivc thrombosis. conclusions: majority of ivc filters were inserted outside guidelines [ ] and proportion of prophylactic indications is significantly higher ( % vs %) than seen in registry studies [ ] . filter related complications were observed in % of patients. more restrictive approach to prophylactic ivc insertion should be exercised. the impact of preinjury antiplatelet and anticoagulant pharmacotherapy on outcomes in patients with major trauma admitted to intensive care unit ( conclusions: patients on preinjury anticoagulants and antiplatelet agents showed an increased mortality; this may be the result of the greater incidence of bleeding, the older age and more comorbidities in this groups. is enzymatic debridement better in critically burned patients? introduction: early debridement of burned tissue reduces infection rate, icu stay and mortality. the use of proteolytic enzymes such as bromelain allows a faster, more effective and selective debridement of denatured tissue, preserving and exposing healthy tissues, reducing debridement times compared to standard of care. methods: retrospective observational study performed in the critical burn unit (march to september ) including patients > years old with a total body surface area (tbsa) burned > % and < %, or > years old with a tbsa burned > %, who underwent enzymatic debridement. mean and standard deviation were used for normal quantitative variables and median and interquartile range in the opposite case. qualitative variables were presented by absolute and relative frequencies. results: mean age was . ± . years old, % males, apache ii (ri - ), absi (ri - ). median tbsa burned was % (ri - %), % (ri - ) were deep dermal or full thickness. time until debridement was hours (ri - ). . % (n= ) had incomplete debridement after first application, % (n= ) received regional anesthesia, % (n= ) didn't need blood transfusion. % of patients who didn't have vasopressors prior debridement, needed the use of it with a mean dose of , mcg/kg/min. % of patients with vasopressors prior treatment, required an increase of dose by a mean of . mcg/kg/min. median icu stay was days. mortality was %. conclusions: topical bromelain allows a fast start of tissue debridement with a low rate of failure. the need for fasciotomy and blood transfusion was very low. topical treatment involved a fast and simultaneous debridement of the tbsa burned, generating an inflammatory response that in some cases required vasopressors. . . / ). the bche activity was measured by using point-ofcare-test system (securetec detektions-systeme ag, neubiberg, germany). levels of the routine inflammation biomarkers, i.e. c-reactive protein (crp) and the white blood cell count (wbcc), were measured during the initial treatment period. measurements were performed at the admission, followed by , and -hour time points. injury severity score (iss) was used to assess the trauma severity. results: the observed reduction in the bche activity was in accordance with the change in the crp concentration and the wbcc. the bche activity measured at the hospital admission negatively correlated with the length of the icu stay in patients with polytrauma (r = - . , spearman's rank correlation coefficient). conclusions: the bche activity might be used as an early indicator for the magnitude of the systemic inflammation following polytrauma. moreover, the bche activity, measured at the hospital admission, might predict the patient outcome and therefore prove useful in early identification of the high-risk patients. pharmacological interventions for agitation in traumatic brain injury: a systematic review introduction: among tbi complications, agitation is a frequent behavioural problem [ ] . agitation causes potential harm to patients and caregivers, interferes with treatments, leads to unnecessary chemical and physical restraints, increases hospital length of stay, delays rehabilitation, and impedes functional independence. pharmacological treatments are often considered for agitation management following tbi. however, the benefit and safety of these agents in tbi patients as well as their differential effects and interactions are uncertain. methods: the major databases and the grey literature were searched. we included all randomized controlled, quasi-experimental, and observational studies with control groups. the population of interest was all patients, including children and adults, who have suffered a tbi. studies in which agitation was the presenting symptom or one of the presenting symptoms, studies where agitation was not the presenting symptom but was measured as an outcome variable and studies assessing the safety of these pharmacological interventions in tbi patients were included. results: we identified references with our search strategy. two authors screened after removal of duplicates. after searching the grey literature and secondary databases, a total of potential articles were identified. eleven studies in which agitation or an associated behavior was the presenting symptom, studies where agitation was not the presenting symptom but was measured as an outcome variable, and studies assessing the safety of these pharmacological interventions were identified. overall, the quality of studies was weak. in studies directly addressing agitation, pindolol and propranolol may reduce assaults and agitation episodes. amantadine and olanzapine may reduce aggression, whereas valproic acid may reduce agitated behavior. conclusions: there is weak evidence to support the use of pharmacological agents for the management of agitation in tbi. impact of decompressive craniectomy on neurological functional outcome in critically ill adult patients with severe traumatic brain injury: a systematic review and meta-analysis p bonaventure, ja jamous, f lauzier, r zarychanski, c francoeur, a turgeon chu de québec -université laval, québec, canada critical care , (suppl ):p introduction: severe traumatic brain injury is associated with high mortality and functional disability. several interventions are commonly used to control the intracranial pressure to prevent secondary cerebral injuries. among them, decompressive craniectomy (dc) is widely performed; however, its impact on functional outcome is still under debate. our objective was to assess the efficacy and safety of this procedure in adult patients with severe traumatic brain injury. methods: we systematically searched in medline, embase, cen-tral, web of science, conference proceedings and databases of ongoing trials for eligible trials. we included randomized controlled trials of adult patients with severe traumatic brain injury, comparing dc to any other intervention. our primary outcome was the neurological function based on the glasgow outcome scale. secondary outcomes were mortality, intensive care unit (icu) and hospital length of stay, intracranial pressure control, and complications. two reviewers independently screened trials for inclusion and extracted data using a standardized form. we used random effect models to conduct our analyses and the i index to assess heterogeneity. results: we identified citations, from which we included trials for a total of patients. we observed no impact on the [ ] . univariate logistic regression analyses were performed to identify predictors associated with the decision for icp monitoring. results: a total of adult patients were included (tables and ). the risk of poor outcome estimated by the impact model was associated to the decision to monitor icp (fig. ) . icp was more often monitored in patients with severe tbi, with one dilated pupil at admission and positive ct findings (in particular, high marshall scores). conclusions: according to our results, the clinician follows a multifactorial reasoning: the main determinants for the decision to monitor icp are gcs, pupils' abnormalities and, above all, ct findings. future studies will be needed to clarify specific indications for the clinicians in the identification of patients who would benefit from invasive monitoring. trajectories of early secondary insults after traumatic brain injury: a new approach to evaluate impact on outcome. introduction: secondary insults (si) occur frequently after traumatic brain injury (tbi). their presence is associated with a worse outcome. we examined the early trajectories of hypotension (sbp< mmhg), hypoxia (spo < %) and pupillary abnormalities from the prehospital settings to the emergency department (ed), and their relationship with -months outcome. methods: in this retrospective, observational study we included all tbi patients admitted to our neuro intensive care unit (nicu) from january to december . we defined the trajectories of si: -"sustained" if present on the scene of accident and at hospital admission, -"resolved" if present on the scene but resolved in ed, -"new event" if absent on the scene and present in ed, -"none" if no insults were recorded. we investigated the association of si trajectories with -months dichotomized outcome (glasgow outcome scale (gos); favorable= - ; unfavorable= - ). results: patients were enrolled in the final analysis. hypoxia and hypotension were related with unfavourable outcome when introduction: guidelines for management of pediatric traumatic brain injury recommend maintaining intracranial pressure (icp) < mmhg [ ] . use of . % sodium chloride (nacl) is considered safe and effective for management of icp in adults, but evidence for concentrations > % in pediatrics is limited. this study will describe the safety and efficacy of . % nacl in reducing icp among pediatric patients. methods: this retrospective study evaluated patients <= years old who received . % nacl and had continuous icp monitoring. cerebral perfusion pressure (cpp), mean arterial pressure (map), icp, and brain tissue oxygenation (pbto ) were recorded hourly and were compared to baseline for hours after each dose. safety outcomes included peak serum sodium, peak serum chloride, and the incidence of stage acute kidney injury (aki) (serum creatinine elevation >= . mg/dl or >= %) [ ] . results: between august and july , eligible pediatric patients received doses of . % nacl; doses were included in the analysis of perfusion parameters. mean age was . +/- years ( months to years), and the median initial glasgow coma scale score was . subjects received a median of four . % nacl boluses, with a mean dose of . +/- . ml/kg. significantly lower icp and higher cpp (p< . ) were observed at all post-treatment time points (fig. ) ; pbto was also significantly increased during of the hours recorded (p< . ). there was no difference in map. peak post-treatment serum sodium and chloride were +/- meq/l and +/- meq/l, respectively (fig. ) . stage aki was observed in . % of patients, and in-hospital mortality was . %. conclusions: our data suggests that . % nacl is a safe and effective therapy for elevated icp in pediatric patients. methods: we performed a prospective study in adult patients with mild head trauma (gcs and ) qualified for acquisition of urgent head ct scan. the clinical symptoms potentially related to intracranial lesion including abnormal vitals, vomiting, headache, persistent dizziness were recorded. ons as well as head ct were then performed. all ons examinations were executed by an experienced sonographer to eliminating interrater bias. head ct findings were dichotomized as positive or negative finding for ich based on formal radiology reports. the patients' disposition including admission, surgery and safe discharge were followed. results: patients were enrolled for the survey. patients had at least one symptom related to potential intracranial lesion ( . %). the mean onsd was ± mm. patients were found to have ich and underwent neurosurgery thereafter. no significant difference of onsd was found between the groups with and without ich, as well as the group receiving surgery or conservative treatment. with introducing a conventional mm threshold of onsd, the sensitivity, specificity, ppv and npv was . , . , . and . , respectively. while incorporating occurrance of at least one positive clinical symptom with the onsd measurement greater than mm as a composite threshold, the sensitivity, specificity, ppv and npv was . , . , . and . , respectively. conclusions: the diagnostic value of ons in mild head trauma is defective. nevertheless, with the supplemental aid of recognition of clinical symptoms relevant to potential intracranial lesion, the overall accuracy would improve. a correlation between ykl- concentrations in cerebrospinal fluid and marshall classification in traumatic brain injurypreliminary results g pavlov , m kazakova , p timonov , k simitchiev , c stefanov , v sarafian medical university -plovdiv, plovdiv, bulgaria, university of plovdiv, plovdiv, bulgaria critical care , (suppl ):p introduction: establishment of prognostic models in traumatic brain injury (tbi) would improve the classification based on predictive risks and will better define treatment options [ ] . in recent years, one of the most intensively studied glycoprotein is ykl- . it is expressed as a consequence of broad spectrum of inflammatory and malignant diseases [ ] . this is study aimed to investigate the level of ykl- in tbi patients and its relationship with several clinical models. methods: we determined plasma and cerebrospinal fluid (csf) ykl- levels in six ( ) patientson the th and th hour after the tbi. each patient was examined by physical and instrumental methods for somatic and neurological status, clinical assessment and prognostic scales (gcs, marshall classification, apache iii). routine haematological and biochemical tests were also performed. as control served the csf of age-matched suddenly deceased healthy individuals (n = ), which was examined post mortem for ykl- levels. results: we found no significant difference between plasma ykl- levels till th and th in all patients (mean difference ± sd: ± ng/ml ) and calculated cerebral autoregulation (ar) as correlation coefficients (pearson) for each ih wave. z-ratios were divided according to binary ar outcome and correlation calculated with intracranial pressure before, during and after the ih waves. results: our preliminary analysis demonstrated a negative correlation between intracranial pressure and z-ratio in the grouped ih waves with preserved ar, but no correlation in the grouped ih waves with impaired ar (table and fig. ). this indicates a decrease in power in the eeg low frequencies ( - hz) and/or an increase in the eeg high frequencies ( - hz) for increased values of intracranial pressure when ar is preserved. conclusions: features of ih waves differ depending on the ability of the injured brain to autoregulate cerebral blood flow. these features might include different signature of eeg frequency changes. the causative links and clinical significance of the different eeg patterns remain unexplored and might represent a signature of neurovascular coupling. introduction: targeted temperature management of patients who have suffered a traumatic brain injury is often used in the hope of preventing further insult to the brain; however, there is no uniform approach to managing temperature either locally, nationally or internationally, and maintenance of goal temperature in this patient population is often challenging due to hypothalamic injury. we sought to evaluate the feasibility and safety of an esophageal heat transfer device (ensoetm, attune medical, chicago, il) to perform temperature management of patients suffering from traumatic brain injury. methods: this was an irb-approved prospective study of patients undergoing temperature management after traumatic brain injury. patients were treated with an esophageal heat transfer device connected to an external heater-cooler, and maintained at target temperature for at least hours. patient temperature obtained via foley catheter was recorded hourly, and the deviation from goal temperature during treatment reported. results: a total of patients were treated from august to may . temperature targets during treatment ranged from . to . degrees c. maintenance of target temperature was successful, with % of readings within +/- degrees c of target, and % of readings within +/- . degrees c of target. one patient developed a small hydrothorax, not attributed to device use. all patients survived to discharge from the icu, with median cpc of (range to ). conclusions: targeted temperature management of patients with traumatic brain injury using an esophageal heat transfer device was feasible and safe, providing a tight maintenance of goal temperature in this challenging patient population. introduction: traumatic brain injury (tbi) represents a serious problem in europe. it still is the principal cause of death in us and europe. every year in italy people on , suffers of tbi and on , dies. disability and incapacity from tbi provides "strong ethicals, medicals, social and health economy imperative to motivate a concerted effort to improve treatment and preventions" methods: our hospital is the hub for modena's county for tbi and we took part in the past year on european project creactive (collaborative researce on acute traumatic brain injury in intensive care medicine in europa) as branch of italian group giviti (gruppo italiano per la valutazione degli interventi in terapia intensiva). our study concerned about patients with tbi dismissed from icu that "personally" or by the family will accepted the consensus to be included in our follow up conducted after months from the dismissal. we collected clinical data from the admission to the dismissale and measured impact of tbi on all day life with gos-e and qolibri-os using telephonical interview. results: we collected data about patients, answered to the telephonical follow-up and only compilated the qolibri-os. we found out that patients admitted with lower gcs has worst outcome in terms of quality of life. it also appears that anisocoria during icu staying represents an odds ratio for death and is connected with worst quality of life after months from the dismissal (tables & ) . inability to re-start a normal work-activity appeared to be the most important factor on the perception that our patient have of their new lives. conclusions: anisocoria seems to be an indicator of severe brain damage. gcs, despite it's simplicity, still represent the best and easiest way to score tbi. work impairment appear to be the most important disability to determine subjective perception of quality of life after tbi, so efforts have to be made to improve work rehabilitation after the dismissal from hospital. introduction: hyperventilation (hv) reduces elevated intracranial pressure (icp) by changing autoregulatory functions connected to cerebrovascular co reactivity. criticism to hv is due to the possibility of developing cerebral ischemia and tissue hypoxia because of hypocapnia-induced vasoconstriction. we aimed to investigate the potential adverse effects of moderate hv of short duration in the acute phase in patients with severe traumatic brain injury (tbi), using concomitant monitoring of cerebral metabolism, continuous brain tissue oxygen tension (pbro ), and cerebral hemodynamic with transcranial color-coded duplex sonography (tccd). methods: a prospective trial was conducted between may and may at the university hospital of zurich. adults (> years), with non-penetrating tbi, first gcs < , icp-monitoring, pbro and/or microdialysis (md)-probes were included within hours after injury. data collection and tccd measurements took place at baseline (a), at the begin of moderate hv (paco - . kpa) (c), after minutes of moderate hv (paco - . kpa) (d), and after return to baseline (e) (fig. ) . repeated measures anova was used to compare variables at the different time points followed by post hoc analysis with bonferroni adjustment as appropriate. p-value < . was considered significant. results: eleven patients were included ( % males, mean age ± years). first gcs was ( - : median and interquartile range). data concerning paco , icp, pbro , mean flow velocity (mfv) in the middle cerebral artery, and md values are presented in table . during hv, icp and mfv decreased significantly. pbro presented a trend of reduction. glucose, lactate and pyruvate did not change significantly ( table ) . conclusions: short episodes of moderate hv have a potent effect on the cerebral blood flow, as assessed by tccd, reduce icp and pbro , and do not induce significant changes in cerebral metabolism. outcome of pediatric patients six months after moderate to severe tbi -results of creactkids study from three picu in israel paco arterial partial pressure of co , cpp cerebral perfusion pressure (mmhg), icp intracranial pressure (mmhg), pbro brain tissue oxygen tension (mmhg), mfv mean flow velocity in the middle cerebral artery introduction: delirium is a major cause of complications in postoperative patient in icu. risk factors for delirium include poor cerebral hemodynamics and peri-operative cerebral desaturations. intraoperative target cerebral oximetry monitoring may decrease the incidence of postoperative delirium in elective major abdominal surgery patients. methods: a single-blinded, randomised controlled trial in patients undergo elective major abdominal surgery who received postoperative care in surgical icu with age more than years were randomised into two groups. the intervention group was received intra-operative target cerebral oxygen monitoring using cerebral oximetry whereas the control group was not. delirium was assessed in both group at , , hour postoperatively. other risk factors for delirium, mechanical ventilator day, length of icu stay, length of hospital stay and post-operative complication were recorded. results: from august -march , patients who met the criteria were randomised to patients in intervention group and patients in control group. overall incidence of delirium was . % (intervention . % vs control . %, p= . ). baseline cerebral oxygen in intervention group was . ± . %. desaturation below % from baseline was found in from patients ( . %) and was the only significant risk factor associated with delirium (p=. , odd ratio . ). there was no significant different in mechanical ventilator day, icu length of stay, hospital length of stay and postoperative complication between both groups. there was no complication associated with application of the cerebral oximetry probe in the intervention group. conclusions: from this preliminary report can not demonstrated the significant different of intra-operative target cerebral oxygen monitoring by using cerebral oximetry in prevention of delirium. however the reduction of cerebral oxygen more than % from baseline in intervention group showed significantly associated with delirium postoperatively. the set score as a predictor of icu length of stay and the need for tracheotomy in stroke patients who need mechanical ventilation introduction: set score was initially developed as an in-house screening tool based on tracheotomy predictors identified in several retrospective studies. it combined the categories of neurological function, neurological lesions, and general organ function/ procedure, and weighed by allocation of certain point values [ ] . in our study it was very interesting to us to find a tool to judge application of early tracheotomy, and as we have a good culprit number from stroke cases so we decided to try to apply this score in our icu after discussion with the inventor of this score. methods: stroke patients were prospectively included in the study as they were ventilated or were very little potential for ventilation and assessed by the stroke-related early tracheotomy score (set score, table ) within the first h of admission (table ) . endpoints were length of stay and ventilation time (vt) after doing early tracheotomy. we examined the correlation of these variables with the set score using standard analytical methods. results: the set score with a value cutoff point of had a significant effect on decision of making tracheotomy and hence decreasing ventilation time and length of stay in icu, which affected outcome (figs. & ) . conclusions: all efforts must be exhausted in neuro intensie care to decrease the secondary changes of brain injury after stroke,early tracheotomy is a good tool to decrease length of stay in icu and ventilation time in these patients.inventing a tool to judge these decisions of doing tracheotomy was a challenge. set score proved to be valuable.further multi center trials are needed. fig. (abstract p ) . specificity for the cutoff point of set score. cut point of is the best to predict tracheostomy with sensitivity of . % and specificity of . %. cut point of is the best to predict early tracheostomy with sensitivity of . % and specificity of . %. since no patients had score so the previous analysis that consider cut-point of should remain the same but just change the number in the text to contraindication for pharmacological vte prophylaxis ( . %). overall, ncc patients were more likely to receive mechanical ( . % icu days) than pharmacological vte prophylaxis ( . % icu days), however pharmacologic was more likely among younger patients with lower apache ii scores. guideline concordant care varied by recommendation; lower for pharmacological and higher for mechanical vte prophylaxis. conclusions: ncc patients uncommonly receive guideline concordant pharmacological vte prophylaxis. collectively, our findings suggest that current vte prophylaxis prescribing practices may reflect uncertainty around risks associated with vte prophylaxis among ncc patients. methods: we retrospectively analysed prospectively collected data from consecutive ich patients that received dvt prophylaxis in a tertiary hospital. he was defined as an increase of > ml measured using the abc/ method or the semiautomatic software based volumetric approach. using multivariate analysis, we analysed risk factors including early dvt prophylaxis for he> h, hospital mortality and poor -month functional outcome ( m modified rankin score> ). results: patients presented with a median gcs of (iqr - ), hematoma volume of ml (iqr - ) and were y old (iqr - ). % received early dvt prophylaxis, % late dvt prophylaxis and % had unclear bleeding onset. hematoma volume was smaller in the early dvt prophylaxis group with . ml (iqr - . ) vs . ml (iqr - ) in the late prophylaxis group (p= . ) without any other significant differences in disease severity. delayed he (n= / , . %) was associated with higher initial hematoma volume (p= . ) and lower thrombocyte count (p= . ) but not with early dvt prophylaxis (p= . ) in a multivariate analysis adjusted for known risk factors. early dvt prophylaxis was not independently associated with m outcome. conclusions: although limited by the retrospective design, our data suggest that early dvt prophylaxis (< h) may be safe in patients presenting with primary ich, which supports the recommendations given by the neurocritical care society. introduction: there is a paucity of literature describing the relationship between clevidipine and its impact on intracranial pressure (icp). the safety of clevidipine in patients with intracranial hemorrhage is often extrapolated from studies using nicardipine, which has demonstrated a neutral effect on icp [ ] . the objective of this study was to determine if there was a relationship between clevidipine initiation and changes to cerebral hemodynamic parameters. methods: this study was a retrospective analysis of adults admitted to hennepin county medical center between july and july . individuals were included if they had intracranial bleeding and icp data recorded prior to initiation of a clevidipine infusion. baseline demographic data was collected, including age, gender, type of injury, and initial glasgow coma score (gcs introduction: aneurysmal subarachnoid hemorrhage (sah) is an acute cerebrovascular event with high mortality and is an important cause of neurologic disability among survivors. many complications in the course of sah, such as hydrocephalus, also play a role in the poor outcome. the aim of the study was to describe the characteristics of patients with sah admitted to the icu to evaluate the factors associated with outcome. methods: this study was conducted in two reference centersone in rio de janeiro and one in porto alegre. from july to september , every adult patient admitted to the icu with aneurysmal sah was enrolled in the study. data were collected prospectively during hospital stay. the primary endpoint was mortality and dichotomized functional outcome (poor outcome defined as glasgow outcome scale to ) at hospital discharge and months. dichotomous variables were analyzed using two-tailed fisher's exact test. results: a total of patients were included. demographic characteristics are presented in table . frequency of clinical and neurological complications are presented in table . in univariate analysis, factors most frequently seen in patients with unfavorable outcome were seizure ( % vs %, p= . ), hydrocephalus ( % vs %, p< . ), meningitis ( % vs %, p= . ), rebleeding ( % vs %, p= . ), vasospasm ( % vs %, p= . ), pneumonia ( % vs %, p< . ), sepsis/septic shock ( % vs %, p< . ), postsurgical neurological deterioration ( % vs %, p= . ) and delayed cerebral ischemia ( % vs %, p< . ). at months, out of patients with follow-up, % had poor outcome. conclusions: sah is associated with high morbidity. both neurological complications as clinical complications were associated with unfavorable outcomes. therapeutic interventions to prevent those may have an impact on clinical outcomes. introduction: brain tissue hypoxia (brain tissue oxygen tension, pbto < mmhg) is common after subarachnoid hemorrhage (sah) and associated with poor outcome. recent data suggest that brain oxygen optimization is feasible and may reduce the time with brain tissue hypoxia to % in patients with severe traumatic brain injury [ ] . little is known about the effectiveness of protocolized treatment approaches in poor-grade sah patients. methods: we present a retrospective analysis of prospectively collected data of poor-grade sah patients admitted to tertiary care centers where pbto < mmhg was treated using an institutional protocol. treatment options were left to the discretion of the treating neuro-intensivists including augmentation of cerebral perfusion pressure (cpp) using vasopressors if necessary, treatment of anemia and targeting normocapnia, euvolemia and normothermia. the dataset used for analysis was based on routine blood gas analysis for hemoglobin data matched to hourly averaged data of continuous cpp, pbto , temperature and cerebral microdialysis (cmd) samples over the first days of admission. results: patients were admitted with a gcs of (iqr - ) and were (iqr - ) years old. overall incidence of brain tissue hypoxia was %. during this time we identified associated episodes of cpp< mmhg ( %), hyperglycolysis (cmd-lacta-te> mmol/l, cmd-pyruvate> μmol/l; %), pco < mmhg ( %), metabolic distress (cmd-lactate-to-pyruvate-ratio> ; %), pao < mmhg ( %), hb< g/dl ( %), and temperature> . °c ( %) (fig. ). of these variables only hyperglycolysis was significantly more common ( %) during episodes of normal pbto ( % of episodes). conclusions: underutilization of ivt despite the overwhelming evidence that support the effectiveness of such therapy can be partly attributed to the fear of hemorrhagic complications. this fear is not justified by current data. the estrangement of the emergency medicine community regarding ivt and the domination of stroke experts in decision making is also a barrier. regional wall motion abnormalities and reduced global longitudinal strain is common in patients with subarachnoid hemorrhage and associated with markedly elevated troponin k dalla sahlgrenska university hospital, gothenburg, sweden critical care , (suppl ):p introduction: stress-induced cardiomyopathy after subarachnoid hemorrhage (sah) is a life-threating condition associated with poor outcome. regional wall motion abnormalities (rwma) is a frequent finding, however, assessment of rwma is known to be difficult. in the present study we hypothesized that global and regional longitudinal strain (gls and rls) assessed with speckle tracking echocardiography can detect myocardial dysfunction indicated by increased levels of the cardiac biomarker troponin (tnt). methods: this prospective study comprised patients with sah. the tnt was followed daily from the admission up to days postadmission and elevated tnt was defined as > ng/l. a transthoracic echocardiography examination was performed within hours after the hospitalization. the peak gls was determined using the three apical projections and presented as the mean of the segments. reduced gls was defined as > - % and reduced rls was considered present when segmental strain was > - % in > adjacent segments. introduction: deviations from strict eligibility criteria for intravenous thrombolysis (ivt) in ischemic strokes regarding either license contraindications to alteplase or relative contraindications to thrombolysis have been reported in international literature, with conflicting results on patients' outcome.the aim of our study was to evaluate safety and efficacy for patients receiving ivt outside standard inclusion criteria. methods: retrospective analysis of our department's thrombolysis database.we compared patients with strict protocol adherence (strict protocol group) [mean age years and national institutes of health stroke scale (nihss) at admission /range - ] and patients with protocol deviations (off-label group) [mean age years and nihss at admission /range - ],in particular patients > years old, patients with mild stroke-nihss< ,and with symptom-to-needle time - . hours ( patients had deviations). results: patients in the off-label group were older but had no difference in baseline severity scores (sapsii, nihss). they had no statistically significant difference on short-term (nihss at days, need for critical care support, primary adverse event) and long-term (mortality,functional outcome at months) outcome measures when compared to standard protocol patients. conclusions: in accordance with international literature,off-label thrombolysis is save and equally effective to standard protocol thrombolysis.thrombolysis strict protocol needs expansion of inclusion criteria. introduction: most scales (gcs,nihss) don't consider the pathway of secondary acute brain failure (sabf). neuron-specific-enolase (nse) could be usefull in diagnostic and treatment pts. with sabf [ , ] . methods: prospective study incl. pts. with abf. pts. were identical in condition, age and comorbidies. in main group, nse examed and choline alfoscerate was used, pts. was divided into subgroups ia (n= ) with acute ischemic stroke(ais) and ib (n= ) pts. with posthypoxic encephalopathy. the control group (n= ) pts. with ais treated by loc.protocol № . clinical, laboratory, and imaging variables were fully compared. pts. examed by abcde algorithm, gcs and nihss. brain ct, carotid doppler performed. considering criteria:nse(days , , ), neurological status, length of stay in icu (icu los). "ss- . "was used. results: the baseline nse was higher and correlated to nihss ( . ± . , ÷ = . ) in all pts. in ia, ib sbgroups nse decreased for - days vs. control group - days (÷ = . ) and correlated with regression neurological deficit. icu los in main group was . ± . days vs. control group . ± . days. sensitivity and specificity of nse as a marker of brain injury in pts. with ais were and % and in posthypoxic pts. were and %, respectively, which showed nse as eligible diagnostic criterion of posthypoxic cerebral edema. in ia (ais) pts. and ib (posthypoxic edema) were confirmed by increasing nse in fold and -fold respectively more vs. pts. who had only brain ct at first day. nse also correlated with regression neurological deficit and improving of the neurological status. although, two pts. in iib group died with nse - ìg/ml conclusions: . nse is an effective marker of the severity of damages even in the sabf, and shoved efficacy efficacy of treatment. . negative outcome can be in pts. with sabf and more -fold increasing nse and increasing up to - ìg/ml is a mortality predictor. . we included nse in local protocols p n-terminal pro-brain natriuretic peptide as a bio-marker of the acute brain injury introduction: the detection of biomarkers levels facilitates an early diagnosis of brain tissues damage, allows assessing the prognosis of the disease and its outcome, and performs the monitoring of the patient treatment. methods: we studied patients ( m, f.). st group comprised patients with severe brain trauma: asurvivors with good outcome (on glasgow outcome scale groups i-ii) (n= ), bdead or severely disabled (on glasgow outcome scale groups iii-v) (n= ). nd group comprises patients with intracranial and sub-arachnoid hemorrhages: assignment to groups a (n= ), b (n= ) was done using the same criteria as group . rd group comprises patients operated in conjunction with brain tumor. assignment to groups a (n= ) and b (n= ) was done using the same criteria as groups and . we tested the level of n-terminal pro-brain natriuretic peptide in blood ( - pg/ml) between st and rd days after severe brain injury and then every - days for the total duration of days. results: : statistical analysis failed to demonstrate noticeable difference in the level of ntprobnp between groups , , . we detected the differences between subgroups (p< . ). patients from groups a, a, a (n= ) ntprobnp level stayed below pg/ml in cases ( %), in the cases ( %) the level was above pg/ml, but by - th day decreased to the normal values. for patients in subgroups b, b, b (n= ) in cases ( %) ntprobnp level was above pg/ml at least once, in cases ( %) level stayed below pg/ ml but remain high for the entire duration of the study without significant decrease. conclusions: all the patients with acute brain injury show the increased level of ntprobnp above normal values, irrespective of ethiology of injury. in case when ntprobnp level increases above pg/ml and/or does not decrease to the normal values it is possible to predict a negative outcome. introduction: cerebrovascular and coronary artery diseases share many of the same risk factors [ ] . cardiac mortality accounts for % of deaths and is the second commonest cause of death in the acute stroke population, second only to neurologic deaths as a direct result of the incident stroke. methods: this is a prospective observational study from july to april done on adult patients (groupi: pts acute ischemic strokes & group ii: pts as control) in kafr-elsheikh general hospital icu. inclusion criteria: all patients with acute ischemic stroke while exclusion criteria: patients with heart or renal failure/sepsis&septic shock/ischemic heart disease or hemorrhagic stroke,full clinical examination&labs including admission quantitative serum cardiac troponin i elisa immunoassay,ecg, d echocardiography&ct brain on day & ,alberta stroke program (asp) early ct (aspect) to predict neurological outcomes and mortality in patient with acute ischemic stroke within days so survivors vs non-survivors in group were divided to g a & g b respectively. results: dyslipidemia, hypertension, diabetes mellitus were significant comorbidities in all ischemic stroke pts.tlc, urea, inr and troponin were significantly higher in case group vs control group.gcs was found to be lower in non-survivors at day &at rd day follow up while aspect was significantly lower only at rd day follow up.troponin level was significantly higher in non-survivors g b, it was also higher in patents who developed convulsion later during their icu stay& it was significantly inversely correlated to gcs and asp. troponin had sensitivity % and specificity % (roc curve analysis) conclusions: troponin level was predictor for mortality in patient with acute ischemic stroke.it is well correlated to gcs and asp on admission.it was a predictor for occurence of convulsions later in icu stay. introduction: based on examination and treatment of hyperkinetic disorder in patients with uws and mcs, we supposed that hyperkinesis manifesting the formation of the generator of pathologically enhanced excitation in cerebral cortex, basal ganglia, which subsequently causes the formation of hyperkinesis. halogencontaining anesthetic sevoflurane had a good clinical effect in patients with prolonged impairment of consciousness. methods: the study included patients with uws ( -hypoxia, -encephalitis) and patients with mcs ( -hypoxia, -encephalitis). hyperkinetic disorder presenting as permanent myoclonus of arms and legs, face. all patients were performed head mri and eeg (before, during and after anesthesia), crs-r assessment, patients -[ f]-fgd pet. initial anesthesia: propofol - mg/kg, rocuronium bromide (esmeron) , mg/kg, fentanyl - mg/kg and clonidine (clophelin) . - . mg/kg. maintenance of anesthesia is carried out due to the following scheme: inhalation anesthesia using sevoflurane ( . - . vol%, mac . - . ). additionally, during the nd - th hours of medical anesthesia was prescribed the intravenous injection using ketamine - mg/kg/hr. the anesthesia is used during hours. the patients were nurtured by balanced mixtures through nasogastric tube. after hours the patients were gradually transferred to the autonomous breathing. the control clinical and instrumental studies to evaluate the therapy effectiveness (eeg, crs-r) were performed. results: in patients ( mcs, uws) was observed the hyperkinetic disorder regression as decrease of hyperkinesis manifestation, patients didn't have a significant dynamics. conclusions: the artificially formed "pharmacological dominant" (using sevoflurane and ketamine) may decrease the activity of pathological system of the brain, which clinically presented as significant decrease of hyperkinesis manifestation in out patients. -year experience of using benzodiazepines in predicting outcomes and targeted treatment of patients in unresponsive wakefulness syndrome (uws). introduction: we accepted a hypothesis that in some patients uws is a consequence of a pathologic system (ps), that limits the brain functional activity. identification of a ps allow to predict consciousness recovery. eeg registration under benzodiazepines test (bt) has become the method of ps identifying in uws patients. methods: we examined uws patients ( -traumatic, -non traumatic). crs scales assessment, eeg with bt, mri of brain were performed for all patients. the midazolamum was administered iv . mg/kg,.in - min after bzd was recorded eeg for min. the test was considered to be positive if against the background of bzd eeg pattern restructuring was observed: the low-amplitude eeg activity was rebuilt with the advent of alpha-and beta-spectrum.in patients with slowwave activity of theta-and delta-spectrum appeared stable fast forms, and in patients with baseline polymorphic eeg pattern was recorded prevalence of alpha activity and (or) the alpha rhythm. in order to confirm the correlation between the bzd effect and eeg pattern restructuring, flumazenil was administrated at rate of . mg every to minutes until the original eeg pattern has been registered again. results: the bt was true positive (recovery consciousness in - month later) in traumatic and non traumatic patients. true negative (permanent uws month later) in traumatic and non traumatic patients. false positive - traumatic, non traumatic. false negative traumatic, non traumatic patients. sensitivity bt to vs/uws = . % sensitivity to mcs = . % conclusions: our data confirmed the correctness of hypothesis that a ps limits the activity of the brain in patients in a uws. we proposed diagnostic method of a ps activity and suppression. apparently, bzd are the drugs of first stage examination choice in the treatment of uws patients. early identification of sepsis-associated encephalopathy with eeg is not associated with short-term cognitive dysfunction introduction: septic-associated encephalopathy (sae) affects approximately % of septic patients. recent studies showed sae is associated with short-term mortality and long-term cognitive disability. however, diagnosis of sae is one of exclusion and its association with short-term cognitive deficit is uncertain. the aim of this study is to evaluate the sensitivity of clinical examination in detecting sae. the association between sae and short-term cognitive impairment is also assessed. methods: prospective observational study enrolling adult septic patients admitted to a mixed icu. exclusion criteria were: encephalopathy from another cause, history of psychiatric/neurologic disease, cardiac surgery. all patients received continuous eeg monitoring and were assessed for sae for up to days after inclusion. we performed a comprehensive consciousness assessment twice daily during the icu (gcs; full outline of unresponsiveness, four; coma recovery scale-revised, crs-r; reaction level scale , rls ; confusion assessment method for the icu, cam-icu). we defined altered brain function as gcs< , no correlation between cognitive function at hospital discharge and severity of eeg alteration was found. conclusions: eeg was more sensitive than clinical assessment in detecting sae. altered eeg was not associated with short-term cognitive function. analysis of the training needs in italian centers that use brain ultrasound in their daily practices: a descriptive, multicenter study r aspide introduction: as mission of siaarti neuroanesthesia and neuroicu group of study, we are mapping out the brain ultrasound training needs in our centers. although brain ultrasound is widely used to study the intracranial vessels and other issues, it is still not clear the homogeneity of the skills required in both neuro and general icu in italy. the aim of this study is to explore the use of us-tcd and validate a collection of criterea which would prove useful in any future national wide survey. methods: starting from sept. the seven center involved (bologna, catania, pisa, verona, bergamo, cesena, roma) collected clinical and sonographic data, basing on a crf of twenty criteria such as: kind of hospital and icu, number of beds and neuro-patients/year, the physicians specialization trained to perform us-tcd, the kind of us doppler device used and the kind of training course followed. as a second step, data were analyzed by coordination team, as third step, during annual siaarti conference, these centers had a deep discussion on these selected items, further modifying and adapting the content of the items. results: the result is a ready list of items, an available tool for all the participant centers, that are going to start with an internal test survey for a final validation. conclusions: there is more than one path to train a physician on brain us in italy and there are new possible applications, even outside of the neuro sub-speciality. from the preliminary discussion, it is clear that in italy we have a inhomogeneous frame of training and use. this group of study believes that among the anesthesiologists/intensivists, it is possible to find a useful number of physicians interested in training on this topic. the main aim is the production of a validated criterea collection, available for eventually future national survey, useful to help map out the real national training needs in italy on us brain. perinatal neurosurgical admissions to intensive care c nestor, r hollingsworth, k sweeney, r dwyer beaumont hospital, dublin, ireland critical care , (suppl ):p introduction: beaumont hospital is the neurosurgical centre for ireland serving a population of . million. we present data on all perinatal patients who required icu admission for neurosurgical conditions over an year period. our data presents an insight into the incidence and outcome of neurosurgical conditions during pregnancy methods: searching our database identified pregnant and recently pregnant patients admitted to icu with neurosurgical conditions. patient data was collected retrospectively by review of charts and of an electronic database. a further pregnant patients were admitted for neurosurgical intervention but did not require critical care. results: intracranial haemorrhage was the most common diagnosis ( subarachnoid haemorrhage and had intra-cerebral haemorrhage). patients presented with intracranial tumours and patient had a traumatic brain injury. patient was admitted post spinal tumour resection. patient was referred with an ischemic stroke after iatrogenic injury to the carotid and vertebral artery. the requirement for organ support in this cohort of patients was high; % required ventilation and % inotropes. patients underwent neurosurgical intervention & medical treatment. maternal deaths occurred at & weeks gestation. the modified rankin score (mrs) on discharge from hospital was <= for of the surviving patients (median= ). of the pregnancies (all singleton) there were foetal deaths. patient miscarried spontaneously at weeks, had a medical termination of pregnancy at weeks to facilitate chemotherapy and foetus died after maternal death at weeks. the remaining patients delivered normal babies. conclusions: neurosurgical disease requiring icu admission during pregnancy is rare; our data suggest an incidence of case per million population. maternal outcomes were mixed with more than half having a mrs> on discharge. foetal outcomes were good with only one miscarriage and good neurological outcome in all surviving infants. stepwise multivariable analyses that included interaction between time of day and arrest location were performed in a stepwise manner. results: prehospital als (adjusted or, . ; %ci, . - . ) but not good-quality of bystander-performed ccs ( . , . - . ) was associated with sustained return of circulation (rosc). neither provison of good-quality ccs nor prehospital als was a major factor associated with on-month survival. however, good-quality of bystanderperformed ccs ( . , . - . ) in addition to shockable rhythm ( . ; . - . ) and bystander-witnessed ohca ( . ; . - . ) were associated with higher chances of neurologically favourable one-year survival, whereas prehospital als ( . ; . - . ) and elderly ohca ( . ; . - . ) were associated with lower chances of the survival (fig. ) . the impact of good quality ccs on survival were preserved in bystander-witnessed ohcas with shockable initial rhythm. noncentral region (adjusted or for good-quality, . ; %ci, . - . ), lack of bls training experience ( . ; . - . ), elderly-only rescuers ( . ; . - . ), cc initiation following dispatcher-assisted cardiopulmonary resuscitation ( . ; . - . ), and female-only rescuer ( . ; . - . ) were associated with poor-quality ccs. cc quality in athome ohcas remained low throughout the day, whereas that in outof-home ohcas decreased during night-time. conclusions: provision of good-quality ccs before ems arrival but not prehospital als was essential for neurologically favourable survival. new protocol for start of chest compressions before definitive cardiac arrest improved survival from out-of-hospital cardiac arrest witnessed by emergency medical service introduction: healthcare providers including emergency medical service (ems) personnel usually confirm absence of carotid pulse before starting chest compressions. at the end of , ishikawa medical control council implemented new criteria for start of chest compressions encouraging ems to start chest compressions when carotid pulse was week and/or < /min in comatose adult patient with respiratory arrest or agonal breathing. methods: data were prospectively collected for out-of-hospital cardiac and respiratory arrests during the period of - . definitive cardiac arrest was recorded when loss of carotid pulse was confirmed by pulse checks performed every min after the early start of chest compressions. the effect of early chest compressions on the proportions of definitive cardiac arrest was analysed in cases with respiratory arrest and circulatory depression in initial patient evaluation. before/after comparison of neurologically favourable -y survival was performed in cases with ems-witnessed ohca. results: the early start of chest compressions did not significantly prevent definitive cardiac arrest that followed respiratory arrest with circulatory depression in the initial patient evaluation (fig. ) . time interval between start of chest compressions and definitive cardiac arrest confirmation (median; iqr) was ; . - min. the survival rate of all ems-witnessed ohcas after the implementation of new criteria was significantly higher than that before the implementation: adjusted or; % ci, . ; . - . (fig. ) . no complications related to early chest compressions were reported during the study period. conclusions: start of chest compressions before definitive cardiac arrest improved survival from out-of-hospital cardiac arrest witnessed by emergency medical service. healthcare providers including ems personnel should be encouraged to provide chest compressions on cases with respiratory arrest and severe cardiovascular depression. introduction: our study sought to determine if there is a difference in time to tracheal intubation between direct and video laryngoscopy during cardiac compressions. guidelines suggest no more than seconds should be taken to perform intubation to minimise any delay in compressions [ , ] . it is unclear if use of video laryngoscopes results in faster intubation times during cardiac arrest. methods: observational trial involving emergency, anaesthesia and intensive care doctors. participants' baseline data obtained by questionnaire. resusci-anne™ manikin with airway trainer™ head [laerdal] with grade airway was utilised. participants intubated the manikin times, once with each of: macintosh size blade, c-mac video laryngoscope (karl storz, germany) with size blade and portable mcgrath mac enhanced video laryngoscope (medtronic, usa) with size blade. order of laryngoscopes was randomised by computer generated sequence. continuous cardiac compressions were performed throughout attempts. results: total participants. there was a statistically significant difference in time to intubation between the devices using friedman test (p< . ). wilcox signed-rank test demonstrated time to intubation with videolaryngoscopy was longer, c-mac (p= . ) and mcgrath (p= . ) compared with direct laryngoscopy. there was no significant difference between the two videolaryngoscopes (p = . ). when controlled for participants level of seniority and previous experience with device, direct laryngoscopy was still significantly faster than c-mac (p = . ) and mcgrath (p = . ) conclusions: our study showed a disadvantage of video laryngoscopy during cardiac compressions. faster intubation times with direct laryngoscopy could result in less pause in compressions and decrease periods without perfusion. direct laryngoscopy is an appropriate first choice for tracheal intubation during cardiac arrest. introduction: the aim of this study was to describe the coronary angiographic findings in relation to specific ecg changes and comorbidity in survivors after cardiac arrest. methods: a retrospective cohort study of out-of-hospital cardiac arrest patients with data retrieved between - from national registries in sweden. unconscious patients with coronary angiography performed within days after return of spontaneous circulation and available ecg were included (fig. ) . results: after exclusion, patients were analyzed (fig. ) , (table ) . ( %) were women and mean age were years. patients without st-elevation were separated into groups with specified ecg changes and comorbidities. differences were observed in the incidence of any significant stenosis, total occlusion and pci performed, between the specified ecg changes, as well as between the comorbidity groups ( introduction: fewer women after return of spontaneous circulation from out-of-hospital cardiac arrest (ohca) are undergoing coronary angiography (cag) with possible percutaneous coronary intervention (pci). the aim was to investigate gender differences in comorbidity, cag findings and outcome after ohca in comatose patients with a shockable first ecg rhythm. methods: a retrospective cohort study of out-of-hospital cardiac arrest patients with data retrieved between - from national registries in sweden (fig. ) . results: there was no difference in age or comorbidity except for men having more ischemic heart disease, . vs . % (p= . ). rates of previous myocardial infarction did not differ, . vs . %. no difference was seen in rates of ecg indicating prompt cag according to guidelines. still, more men underwent cag but no difference in numbers of cag leading to pci was seen (table ) . furthermore, in patients with st elevation or lbbb, no gender difference in cag and subsequent pci was found. men had lower rates of normal cag findings but more triple vessel and left main coronary artery disease ( table ) . year survival did not differ, . vs . %. conclusions: our study suggests, that despite no gender differences in rate of ecg findings indicating a prompt cag, men seems to have a more severe coronary artery disease while women have more frequently normal angiograms. however, this did not influence year survival. introduction: the circadian clock influences a number of cardiovascular physiological processes. a time-of-day variation in infarct size has recently been shown in patients with st segment elevation myocardial infarction. however, there is no clinical evidence of circadian variation in patients with out-of-hospital cardiac arrest (ohca) of cardiac etiology. methods: we performed retrospective analysis using data from japan's nationwide ohca registry from january through december , which includes all ohca patients presented with ventricular fibrillation as first documented rhythm, and consequently confirmed cardiac etiology. in order to eliminate the night and weekend effects, we enrolled only patients suffered ohca in the morning we conduct a retrospective cohort study focusing on the association between ohca outcome and icu bed availability. the ohca data was acquired from a regional emergency operation center, and the icu bed information was obtained from a regional sur it exceeds physiological levels in order to avoid insufficient oxygenation [ ] . hyperoxia has been associated with increased in-hospital mortality, though uncertainty remains about this association. multiwave pulse co-oximetry has safely been studied intraoperatively as a guide to monitor hyper-and hypoxia by calculating an oxygen reserve index (ori) which could add information to pulse oximetry measures when spo is > % [ ] . methods: this is a monocentric prospective study including patients with successful resuscitation following ohca. the aim of our study is to evaluate the feasibility and assess the availability of novel non invasive oxygen and hemodynamic variables. collected data principally concern blood oxygen and circulation such as ori, spo , total hb, perfusion index and pulse rates. recording is ideally started at time of rosc. results: we monitored consecutive patients for a total time of . min during transport from ohca place to the er. spo signal was present for . % of transport time.oxygen reserve index signal was present for . % of the total transport time. pleth variability index (pvi) signal was present . % of the total transport time. sphb signal was present . % of total time from rosc to hospital. the confidence interval for each variable is given in fig. . conclusions: our pilot study shows that noninvasive measurements of hyperoxia, fluid responsiveness and hemoglobin are readily available from the prehospital phase of post-rosc care allowing for early tailored and goal directed interventions. increase in sofa score was associated with € ( % ci - €) increase in the cost per day alive in the first months after ca. the sofa score is a good indicator of disease severity but the overlap between outcome groups does not allow its use for early prognostication in ca patients. the association of sofa and its sub-scores with -month outcome and healthcare costs highlights that in addition to neurologic damage the full spectrum of multiple organ failure affects the survival and morbidity of ca patients. public opinion on cardiopulmonary resuscitation decision and outcome in out-of-hospital cardiac arrest patientsquestionnaire study ty li introduction: metabolomics is a novel approach that can characterize small molecules (metabolites) and has the potential to explore genotype-phenotype and genotype-environment interactions, delivering an accurate snapshot of the subject's metabolic status. in this context, the aim of metabolomics is to improve early diagnosis, classification, and prediction over the development of a pathological condition. to this end, metabolomics have not been used in the characterisation of cardiac arrest (ca), cardiopulmonary resuscitation (cpr) and return of spontaneous resuscitation (rosc). the aim of the present study was to explore whether metabolomics can characterize the ca versus rosc in a swine model of ventricular fibrillation (vf). methods: ten animals were intubated and instrumented and vf was induced with the use of a cadmium battery. vf was left untreated for min and the animals were then resuscitated according to the guidelines. defibrillation was attempted in all animals. venous blood was drown at baseline, min, min, min during untreated ca and finally at min, min, h, h after rosc in order to determine the metabolomic profile during ca and during the early post-resuscitation period. rosc was defined as the presence of an organized cardiac rhythm with a mean arterial pressure of at least mmhg for > min. blood was centrifuged and serum was analysed by high resolution h-nmr spectroscopy. nmr spectral data were submitted to multivariate discriminant analysis. results: eight animals survived the experiment and were included in the analysis. metabolites upregulated in the immediate rosc versus ca were succinate, hypoxanthine, choline and lactate. metabolites upregulated in the hour rosc versus ca were ornithine and alanine. the measured phases are shown in fig. introduction: early outcome prognostication in successfully resuscitated out-of-hospital cardiac arrest (ohca) patients remains challenging. prediction models supporting the early decision to continue with full supportive treatment could be of major interest following ohca. we constructed prognostic models able to predict good neurologic outcome within hours after icu admission. methods: upon icu admission, targeted temperature management at °c, hemodynamic and neuromonitoring (cerebral oxygen saturation measured with near-infrared spectroscopy and bispectral index (bis)) was initiated. prediction models for good neurologic outcome at days post-ca were constructed at hour , , and after admission using variables easily collectable and known to be predictive for outcome. after multiple imputation, variables were selected using the elastic-net method. each imputed dataset was divided into training and validation sets ( % and % of patients, respectively). cut-off probabilities yielding a sensitivity above % were determined and performance of all logistic regression models was assessed using misclassification rates. introduction: in many venues, ems crews limit on-scene care for pediatric out-hospital cardiac arrest (pohca), attempting treatment during transport. hypothesizing that neuro-intact survival can be improved by prioritizing on-site care, strategies were effected to expedite on-scene drug delivery and intubation (with controlled ventilation). methods: from / / to / / , data for pohca cases were collected. in , new training prioritized on-site resuscitation (phase i) using expedited drug delivery and intubation with controlled ventilation (~ breaths/min). training included psychological and skills-enhancing tools to boost confidence in providing on-scene care. in , drugs were prepared while responding (phase ii). american heart association guidelines were used throughout and no other modifications were made. neuro-intact survival in - was compared to phase i & ii outcomes. results: over the . -years, ems faced consecutive pohca cases. the great majority presented in asystole throughout. in those resuscitated, mean time from on-scene arrival to the st epinephrine infusion fell from . min ( - ) to . min (phase i) and . min (phase ii). by , it was min. for resuscitated patients and . min. for all patients. intubation and intraosseous insertion occurred more frequently in phase i/ii, but there were no significant differences in age, sex, etiology, response times, bystander cpr or drug sequencing. neuro-intact survival improved significantly from / in - to . % ( / ) in phase i and . % ( / ) in phase ii (p < . ; -tailed fisher's exact test) (fig. ) . conclusions: although historically-controlled, the sudden appearance of neuro-intact survivors following a renewed focus on rapid on-site care was profound, immediate and sustained. beyond skillsenhancing strategies, physiologically-driven techniques and supportive encouragement from leadership, pre-arrival psychological and clinical tools were also likely contributors to the observed outcomes. fig. (abstract p ) . effecting neurologically-intact survival for children with out-of-hospital cardiac arrest p improved outcomes with a bundled resuscitation technique to enhance venous return out of the brain and into the heart during cardiopulmonary resuscitation pe pepe , ka scheppke , pm antevy , d millstone , c coyle , c prusansky , s garay , jc moore introduction: lowering intracranial pressure to improve brain perfusion during cpr has become a focus for our team. combined with devices that enhance venous return out of the brain and into the thorax during cpr, outcomes have improved using head/chest elevation in the laboratory (fig. ) . this study's purpose was to confirm the safety/clinical feasibility of this new approach involving mechanical cpr at an angle. methods: , consecutive out-of-hospital cardiac arrest (oohca) cases (all rhythms) were studied for . years ( / / to / / ) in an expansive, socio-economically-diverse u.s. county (pop. . mill). in , ems crews used the lucas© and impedance threshold (itd) devices on such patients, but, after april , they also: ) applied o and deferred +-pressure ventilation several min; ) raised the backboard~ °; and ) solidified a pit-crew approach to expedite lucas© placement. neuro-intact survival was not recorded until , so resuscitation by ems to hospital admission was used for consistency. quarterly reports were run to identify any periodic variations or incremental effects during protocol transition (quarter , ). results: no problems were observed with head/torso-up positioning (n= , ), but rates of resuscitation rose steadily during the transition period with an ensuing sustained doubling (fig. ) over the ensuing years when compared to those studied (n= ) prior to the head-up approach (mean . %; range - % vs. . %, range - %; p < . ). outcomes improved across subgroups. response intervals, indications for attempting cpr and bystander cpr rates were unchanged. resuscitation rates in - remained proportional to neuro-intact survival. conclusions: the head/torso-up cpr bundle was not only feasible, but also associated with an immediate, steady rise in resuscitation rates during the transition phase with a sustained doubling of resuscitation rates, making a compelling case that this bundled technique may improve oohca outcomes in future clinical trials. introduction: cardiac arrest (ca) often requires intensive care unit (icu) treatment, which is costly. while there are plenty of data regarding post-ca outcomes, knowledge of cardiac arrest associated healthcare costs is virtually non-existent. methods: we performed a single-center registry-based study to determine expenditure data for icu-treated ca patients between and . healthcare cost evaluation included costs from the initial hospital treatment, rehabilitation costs and social security costs up to one year post-ca. we calculated mean healthcare costs for one year survivors and for hospital survivors who died within the first year after cardiac arrest. we calculated effective costs per independent survivor (ecpis) as an indicator of cost-effectiveness. we adjusted all costs according to consumer price index (cpi) in finland as of . all costs are presented as euros (€). results: we identified , ca patients eligible for the analyses. at one year after ca % of the patients were alive and % were alive and independent in daily activities. one year survival stratified by cardiac arrest location group was % for out-ofhospital ca patients, % for in-hospital ca patients and % for in-icu ca patients. for the whole study population, mean healthcare costs were , € per patient. healthcare costs for hospital survivors were , € per patient and for hospital non-survivors , € per patient. healthcare costs for those who survived to hospital discharge but died within the first year were , € per patient, while for one year survivors they were , € per patient. healthcare costs stratified by ca location are presented in fig. . mean ecpis were , €. conclusions: for icu-treated cardiac arrest patients, the mean ecpis were close to , €. the best prognosis and the lowest costs were observed for out-of-hospital ca patients. introduction: in lithuania the incidence of out-of-hospital cardiac arrest (ohca) is unknown, as there is no official coding for ohca as a cause of death in the national death registry. kaunas emergency medical service (ems) underwent major stepwise changes since , including implementation of medical priority dispatch system and dispatcher-assisted cpr instructions. we sought to describe the epidemiology and outcomes from ohca in kaunas, the second largest lithuanian city. methods: the incidence, demographics and outcomes of patients who were treated for an ohca between st january and st december in kaunas ems, serving a population of almost . million, were collected and are reported in accordance with utstein recommendations. results: in total, ohca cases of ems treated cardiac arrests were reported ( per . of resident population). the mean age was . (sd= . ) years and . % were male. % ohca cases occurred at home and . % were witnessed by either ems or a bystander. in non-ems witnessed cases, . % received bystander cpr, whilst public access defibrillation was not used. medical dispatcher identified ohca in . % of all cases and provided over-the-phone cpr instructions in . % of them. average ems response time ( % fractile) was min. cardiac aetiology was the leading cause of cardiac arrest ( . %). the initial rhythm was shockable (vf or pvt) in % and non-shockable (asystole or emd) in . % of all cases. return of spontaneous circulation (rosc) at hospital transfer was evident in . % and survival to hospital discharge was . %. conclusions: rosc and survival to hospital discharge in kaunas were similar to those reported in united kingdom in [ ] . routine ohca data collection and analysis will allow us to track the efficiency of service improvements and should become a standard practice in all lithuanian regions. outcomes of patients admitted to intensive care following cardiac arrest j mcloughlin, e landymore, p morgan east surrey hospital, surrey, uk critical care , (suppl ):p introduction: patients who have return of spontaneous circulation following a cardiac arrest are haemodynamically unstable and require critical care input. outcomes are often poor, with unadjusted survival to hospital discharge at . %, following an in hospital cardiac arrest [ ] . the aim of the study was to assess the survival of patients admitted to intensive care following a cardiac arrest, reviewing whether age and gender impacted on their outcome. methods: the inarc database for a general intensive care unit (icu) at a district general hospital was reviewed. since , patients were admitted following a cardiac arrest (both in and out of hospital). their age, gender and survival to icu discharge and overall hospital discharge were recorded. results: female patients and male patients of varying ages were admitted to our icu following a cardiac arrest. the mortality for both genders increased with increasing age. overall survival to the time of icu discharge following a cardiac arrest was similar for both females ( . %) and males ( . %). figures (female) and (male) below show the number of patients who survived or died on icu discharge, by age and gender. mortality rates increased when reviewing hospital outcome, as some patients died following discharge to the ward. conclusions: overall mortality in our icu following a cardiac arrest at any age is at least %, with the general trend appearing to rise with increasing age. more male patients were admitted to icu following a cardiac arrest than female, with similar survival rates for both male and female patients. more research could be undertaken to assess whether survival rates following a cardiac arrest have improved since and also to compare outcomes following either an in or out of hospital arrest. introduction: raw simplified eeg tracings obtained by a bispectral index (bis) device significantly correlate with standard eeg [ ] . this study aimed to investigate whether simplified bis eeg tracings can predict poor neurologic outcome after cardiac arrest (ca). methods: bilateral bis monitoring (bis vistatm, aspect medical systems, inc. norwood, usa) was started following icu admission. six, , , , and hrs after targeted temperature management (ttm) at °c was started, raw simplified bis eeg tracings were extracted and reviewed by two neurophysiologists for the presence of burst suppression, cerebral inactivity and epileptic activity. at days post-ca, neurologic outcome was determined using the cpc scale, where a cpc - and cpc - corresponded to good and poor neurologic outcome, respectively. results: of the enrolled ca-patients enrolled, had good and poor neurologic outcome. with a positive predictive value (ppv) of . and a negative predictive value (npv) of . , epileptic activity within - hrs predicted a cpc - with the highest accuracy. epileptic activity within time frames - hrs and - hrs showed a ppv for poor outcome of . and . , respectively. cerebral inactivity within - hrs had a poor predictive power (ppv= . , npv= . ). in contrast, cerebral inactivity between - hrs predicted a cpc - with a ppv of . and a npv of . . the pattern with the worst predictive power at any time point was burst suppression with a ppv of . , . and . at - hrs, at - hrs and at - hrs, respectively. conclusions: based on simplified eeg derived from a bis device, both the presence of epileptic activity at any time as well as cerebral inactivity after the end of ttm can be used to assist with poor outcome prognostication in successfully resuscitated ca patients. the helicopter as first response tool -rio de janeiro fire department experience. (interquartile range= ) min, followed by tih with flights ( %) and median time of (iqr= ) min, and ( %) were neo missions with median time of (iqr= ) min. total time of aircraft usage was higher for tih ( %), followed by neo ( %). evam was the most frequent mission, however it accounted for % of aircraft utilization time, where most victims had traumatic brain injury (tbi) followed by other traumatic injuries ( and cases respectively). tbi victims were predominantly males ( %) with a median age of (iqr= ) years. most commonly, tbi is a consequence of transportation accident ( %), where a motorcycle was involved in %, car collision in % and pedestrian run over % of the cases. conclusions: goa utilizes the air ambulance helicopter as a first response tool in % of total missions, where respect for the trauma golden hour is paramount. traumatic brain injury is the most prevalent diagnosis at the scene of event. therefore, goa training and equipment must be tailored to meet this demand, which translates in stabilization of critical patients outside hospital environment with limited resources. introduction: the intra-hospital transport of critical patients is associated with adverse events and worse outcomes. the objective of this study was to evaluate the safety profile of intrahospital transport after the creation of a specific group for this purpose. methods: evaluated all the transports of critical patients from october to september , in a large hospital, after the creation of a group consisting of intensive care physician, nurse and physiotherapist. clinical and non-clinical complications related to the transport and outcome of the patients were evaluated. results: a total of , transports were performed, . % of the male patients and . % of the patients being hospitalized. . % were under mechanical ventilation and . % under vasoactive drugs. at the time of transport, . % were clinically stable. during transport, . % presented clinical complications, being more frequent hemodynamic instability ( patients) and respiratory failure ( patients). non-clinical complications occurred in patients ( . %), and communication failures were responsible for . % of the occurrences. in cases ( . %) there was worsening of the clinical conditions during transportation, and in only one case this worsening resulted in an increase in the length of stay in the icu and in the hospital, with no correlation with deaths. conclusions: the implantation of a group specialized in critical patients to carry out in-hospital transport made the process safer with complications rates lower than literature and guarantee better quality of care. clinical profile of patients admitted to icu due to acute poisoning mp benitez moreno , e curiel balsera , mc martínez gonzález , s jimenez jimenez intensive care unit, hospital regional universitario carlos haya, malaga, spain; hospital regional universitario carlos haya, málaga, spain critical care , (suppl ):p introduction: patients suffering from acute intoxication, whether voluntarily for autolytic or accidental purposes, often require life support in intensive care units. methods: retrospective observational study of all patients admitted for acute intoxication who required admission to the icu of the regional hospital of malaga between january and august , older than years with admission to the icu for intoxication of any kind. we study patient characteristics in terms of age, sex and medical history, type of toxicity, severity and evolution in our unit. results: we found cases of patients who required admission to the icu due to acute intoxication, of which . % were women. the average age was . (standard deviation . ). the average stay in icu was . (standard deviation . ). . % of patients had a psychiatric history. as other background highlights, . % were addicted to illegal drugs and % were hypertensive. most patients took more than one toxic . % and intoxication was voluntary in . % versus accidental in . % of cases. the toxic was known in %. the most used benzodiazepines in . % of the total. the main cause of admission to the icu was due to neurological deterioration in of the cases registered and mechanical ventilation was necessary in patients. the maximum time in mechanical ventilation was days. the infection occurred in . %, with the majority being respiratory infection. the . % died in icu. the hospital stay presented an average of . days. conclusions: the profile of a patient admitted to the icu due to acute intoxication is that of a woman of middle age and psychiatric history, with voluntary intoxication of several toxic substances and requiring mechanical ventilation for a low level of consciousness for an average of days. the survival is very high and it would be necessary to analyze the possible relapses of these patients. mushroom that break hearts: a case report e karakoc, k demirtas, s ekemen, a ayyildiz, b yelken eskisehir osmangazi university, eskisehir, turkey critical care , (suppl ):p a introduction: because of the high mortality and morbidity mushroom poisoning is a significiant medical emergency [ ] . amanita phalloides (a. phalloides) is responsible for the % of the mortality in adults caused by mushroom poisoning. it causes damage in liver, kidneys and rarely pancreas, causing encephalopathic coma, disseminated intravascular coagulation, hemorrhage, hypovolemic shock and death but its effect on cardiac functions has not been established yet. there are three main groups of toxins;phallotoxins, virotoxins and amatoxins;amatoxin is the common responsible toxin from the fatality. we aimed to present a -year-old woman poisoned by mushroom complicated with hepatic,renal and cardiac toxicity methods: patient with nausea and vomiting started hours after mushroom eating,creatine kinase mb . ng/ml and cardiac troponin i . ng/ml her blood urea nitrogen, creatinine levels and liver enzymes were higher than upper limits in lab tests (table ) ; she was admitted to icu, treated for acute renal failure by hemodialysis.plasmapheresis was applied against potent mushroom toxins. at .day in icu, hypoxemia and severe swelling resistant to ultrafiltration was evaluated as a global left ventricular hypokinesia with ejection fraction(ef) %, end-diastolic diameter of . cm, and systolic pulmonary artery pressure (spap) of mmhg. oxygen was administrated to treatment.urine output improved at .day, three more plasmapheresis sessions were performed. hypoxemia was recovered,liver enzymes and creatinin levels decreased results: at control ef measured was %, end-diastolic diameter of . cm, spap of mmhg.than at the .day patient discharged from the icu.after a year follow up assessment she has no complaints conclusions: one of the major problems for amanita poisoning is diagnosis. patients who had mushroom poisoning should also be evaluated especially in terms of cardiac dysfunction with clinic signs, ecg, cardiac enzyme tests and eco introduction: the characterization of clinical and/or biological variables found in the emergency room predictive of a secondary admission in icu would help to improve the identification of patients at risk of aggravation in order to avoid the associated consequences, such as, an increased mortality and increased hospital stay. methods: this is a retrospective monocentric study of years with patients admitted secondarily to a medical icu within hours of admission to the general wards from the emergency department in the pitié-salpêtrière hospital in paris. each case was matched to controls. different variables were collected in the emergency room. results: patients, of whom were cases and controls were studied. pneumonia is the diagnosis the most frequent in cases followed by sepsis (in and %, respectively). conclusions: the risk of being admitted secondarily to intensive care is higher if patients consult for dyspnea or fever, if they are old smokers, if they have a high igs score, if an arterial blood gas is requested and if an icu medical advice is taken. the meds score under and being an active smoker seems to be protects for the unexpected transfer. introduction: managing the special needs of patients who present with agitation or psychosis can pose a greater challenge to an already busy emergency department as their symptoms can escalate rapidly. traditional antipsychotics used in the ed, such as haloperidol or ziprasidone often do not fully relieve patient's symptoms and may require administration of repeat doses or additional medications such as benzodiazepines to achieve effective results. this can induce excess sedation which can lead to longer length of stay in the ed and requires additional time at the bedside by the ed physicians and staff to manage these patients. adasuve® is an antipsychotic drug that works in a single-use device providing an aerosol form of loxapine that is rapidly absorbed by the lungs which may offer faster symptom relief, allowing subsequent earlier psychiatric evaluation and disposition. methods: to test this hypothesis, data including time of physician assignment and time physician documented discharge disposition and number of hours physician was assigned to the patients was retrospectively collected from patients who arrived to the emergency department presenting with agitation or psychosis that received adasuve or other types of antipsychotic medication such as ziprasidone, haloperidol and benzodiazepines or a combination of the three. results: we found that physicians who administered adasuve spent an average of . hours assigned to their patient compared to . hours when the physician administered any other type of antipsychotic medication. this resulted in a significant . -hour difference (p < . ) between the two groups. conclusions: in conclusion, less time spent assigned to a patient that received adasuve can be attributed to faster symptom relief which allowed the physicians to complete their psychological evaluations and develop dispositions more rapidly than with patients that received other antipsychotic agents. clinical work in language-discordant emergency department introduction: emergency residents are particularly vulnerable to sleep deprivation due to persistent conflicts between work schedule and the biological clock. recent approaches to address fatiguerelated risk mainly focused on reducing work hours and ensuring sufficient recuperation time. such approach has demonstrated its limits due to growing emergency rooms visits and emergency residents' shortage. dawson & mcculloch ( ) introduced the notion of proofing as a complementary approach to manage fatigue-related risk [ ] . fatigue proofing strategies (fps) aim to reduce the likelihood a fatigued operator will make an error, in contrast of reduction strategies (frs) aiming to reduce the likelihood a fatigued operator is working. most formal risk control systems do not encompass the notion of proofing and fps typically develop as informal practices. in this study, we aim to ) identify informal reduction and proofing strategies used by residents and ) to investigate how they relate to fatigue-related risk indicators. methods: first, we organized focus-group with a total of residents in order to identify informal strategies used to manage fatigue-related risk. second, we designed a questionnaire assessing the frequency of use of each reported strategy. introduction: this randomized controlled study assessed the impact of a -hour intravenous medication safety simulation-based learning (sbl) on self-efficacy, stress, knowledge and skills of nursing students. medication administration error is a worldwide concern [ ], that has been linked with a lack of knowledge and skills in safe medication administration among new graduate and student nurses [ ] [ ] [ ] . preventing medication errors could therefore involve training through simulation. methods: participants (n= ) were randomly assigned either to the control group (cg, n= ) or the experimental group (eg, n= ). while cg and eg both had a traditional clinical internship, eg beneficiated in addition the -hour sbl, using standardized patients in the context of an intensive care unit. the two groups were assessed twice: at t and t (four weeks later), through an objective structured clinical examination (osce) and questionnaires. two blinded experts rated the students osce with an evaluation grid. results: mean participants age was , . there were no statistically differences between groups at t . compared to the cg ( %), the eg increased its self-efficacy (+ . %) with a significantly difference (p< . ) at t . the sbl conducted to a greater increase of knowledge and skills in the eg (respectively + %, + %) than in the cg (respectively + % and + %), with a statistically significant difference (p< . ). conclusions: results reinforce the interest of a short sbl using standardized patients to improve medication administration. clinical impact of these observations requires further evaluation to determine potential transfer in clinical settings and retention over time. introduction: medication errors occur frequently in the intensive care unit (icu) and during care transitions. medication reconciliation by a pharmacist could be useful to prevent such errors. therefore, the aim of this study was to determine the effect of medication reconciliation at the icu. methods: a prospective -month intervention study with a pre-and post-phase was performed in haga teaching hospital ( ) and erasmus university medical center ( ). the intervention consisted of medication reconciliation by pharmacists at icu admission and discharge. the severity of potential harm of the medication transfer errors (mte) (pade= ; . ; . ; . ; . ) was scored. primary outcome measures were the proportions of patients with >= mte at icu admission and icu discharge. secondary outcome measures were the proportions of patients with a pade score >= . , the severity of the pades and a cost-benefit analysis. odds ratio and % confidence intervals were calculated. results: table shows patient characteristics. figure shows the primary outcome measures (oradj admission = . [ % ci . - . ] and oradj discharge = . [ % ci . - . ]). the proportion of patients with a pade >= . at icu admission reduced from . % to . % and after icu discharge from . % to . %. the pade reduction resulted in a potential net cost benefit of € per patient. conclusions: medication reconciliation by pharmacists at icu transfers is an effective safety intervention, leading to a significant decrease in the number of errors and a cost effective reduction of potential adverse drug events. introduction: in intensive care unit, administration of numerous drugs in icu patients via a central venous catheter provide a high risk of drugs incompatibilities. it has been reported in experimental studies [ ] that particles issued of drug incompatibilities could induce thrombogenesis, microcirculation impairment and inflammatory response which could aggravate the occurrence of organ dysfunctions [ ] . the objective of this study was to evaluate the occurrence of particles by reproducing in vitro the intravenous system and the drugs combination used in icu for patients suffering either septic shock or acute respiratory distress syndrome (ards). methods: first, we registered during a period of months the most common central venous catheter system used in patients admitted for septic shock or ards in three university hospital in lille. the second part of the study was to reproduce in vitro the previous infusion system in order to quantify the amount of particles generated during a simulated period of hours infusion. the egress of the iv line was connected to a dynamic particle counter qicpic analyser (sympatec inc ; clausthal zellerfeld, germany) (fig. ) . results: the most common intravenous system observed was a three lumen central catheter. the proximal lumen was dedicated for vasoactive agents, the medial lumen for sedation and the distal lumen for the other drugs infused continuously and discontinuously..among the drugs infused via the distal lumen of the central venous catheter, introduction: insufficient identification of possible organ donors in the icu is one of the main factors contributing to the loss of donors after brain death [ ] . up to % of potential donors might not be identified [ ] . the aim of this study was to evaluate how active search of possible brain dead donors affect the potential deceased donor pool. methods: the strategy implemented at university hospital with specialized icus from december to october and data compared to the matching period of the previous year. donor coordinator visited all icus every day and selected patients who met possible brain dead donor criteria: ) gcs <= ; ) severe brain injury. all data registered in original color coded follow-up system according to the patient status. results: a total of patients were identified as possible donors. there was no significant difference of potential donor numbers in study period comparing to previous year ( vs ). main causes of brain death remain intracranial hemorrhage and subarachnoid hemorrhage. the length of hospital stay of potential donors was significantly longer in study period comparing to previous year ( ± . vs . ± . , p= . ). there was no significant difference of donor's demographic data, conversion rates to actual donor or frequency of family refusals and medical contraindications. conclusions: active search of brain dead donors neither increased total number of potential donors nor increased conversion rates and did not change a donor profile in our donor center. longer observational period and more sophisticated follow-up system might be required. a fast hug bid a day keeps the patient ok! e sousa, t leonor, r pinho centro hospitalar de entre douro e vouga, santa maria da feira, portugal critical care , (suppl ):p introduction: regardless the underlying diagnose, providing meticulous supportive care is essential to critically ill patients management. in , vincent jl introduced the fast hug (feeding, analgesia, sedation, thromboembolic prophylaxis, head of bed elevation, ulcer prevention, glucose control) mnemonic for recalling what he considered the key issues to review in daily clinical practice. our intensive care unit (icu) decided to add bid (bowel regimen; indwelling catheter removal; de-escalation of antibiotics) indicators following some published data. since , the adequate use of this mnemonic became an instrument for quality of care evaluation. objectives for each variable were designed; regular annual audits done. the present study aims to audit the use of this mnemonic in a portuguese tertiary hospital icu, in . methods: a prospective observational study was performed. admissions in icu staying at least one h min and h min period, during the first six months of were included. all mnemonic variables were recovered from icu medical record database, as well as demographics, severity scores and clinical information. data was analyzed with microsoft office excel software. results: we included admissions. the predictable global fast hug bid assessment was entries [one per each full day ( h - h ) in the unit, per patient]. the mnemonic was used in about % of the opportunities. the target thresholds were considered as achieved in % of entries (concordance equal or superior to %). looking to individual variables, the best performance was achieved in h and u; worse performance was seen in s. the daily use of this mnemonic aims to revisit important intervention sectors in critical patient. applying the "plan-do-check-act" policy, this study allowed us to identify growth opportunities, reviewing or creating protocols, adopting more frequent training measures and seeking to take this model to other hospital areas. impact of incidents and adverse events in intensive care unit and its characteristics on outcomes e siqueira, l taniguchi, j vieira junior hospital sírio libanês, sao paulo, brazil critical care , (suppl ):p introduction: critically ill patients are usually exposed to adverse events (ae) due to acuity and complexity of care. ae might potentially result in disability or death, and increase in length of stay. our aim was to assess the incidents and ae in a general intensive care unit (icu). methods: this is a prospective cohort study conducted in a private tertiary hospital (hospital sírio-libanês) in são paulo, brazil. all consecutive patients who were admitted to the icu and all incidents and ae reported in the study period were evaluated. univariate and multivariate analysis were used to identify risk factors associated with hospital mortality. results: between may to november we studied patients and reported incidents and ae. overall, patients ( %) experienced some incident or ae during icu stay. we found higher severity of illness (saps of versus ; p< . ), mechanical ventilation (mv), use of vascular lines, drains and catheters, physical restraints, delirium and also an increased length of icu ( vs days; p< . ) and hospital stay ( vs days; p< . ) and hospital mortality ( % vs %; p< . ) among patients who experienced any incident or ae. independent risk factors for hospital mortality in our logistic model were: higher saps , mv and at least one adverse event during the icu stay. mortality was higher among patients who experienced late ae (> hours after icu admission) compared to patients who experienced early ae ( % vs %; p< . ). saps , sofa and mv were predictors of moderate and/or severe ae and a negative correlation between these events and icu occupancy rate was found. conclusions: patients who experienced incident or adverse event during icu stay had poorer outcome. ae, mainly moderate or severe, mv and severity of illness were independent risk factors to mortality. there was a negative correlation between moderate or severe adverse event and icu occupancy rate. monte carlo modelling of patient flow can aid complex intensive care bed and workforce capacity planning. introduction: models for icu populations based on the queuing model use arrival rate, length of stay, and bed number [ , ] . these models lack the complexity of specialised icus with different admission types, and patient subpopulations. results: > % of patients reported satisfaction on all areas except noise, patient facilities for hand hygiene and being informed about timing of operations. staff survey results revealed confusion regarding the interventions that are provided. baseline capacity for new patients was %, bed occupancy varied between and per day (overflow to recovery) with overall capacity at . % and mean length of stay (los) was . days (sd= . , n= , =range - ). following intervention, the los was reduced to . days (sd= . , n= , range - ). new patient capacity was increased to % with a bed occupancy range - . introduction: in clinical practice, when harm or potential harm occurs to patients, this can adversely impact upon the morale of staff involved and thereby affect clinical care delivered to subsequent patients. the personal narratives behind clinical incidents contain learning opportunities and individuals involved may reflect on the course of events and make changes to their practice to avoid recurrence. the aim of this study was to evaluate whether sessions enabling trainees to discuss their mistakes in a confidential environment improved trainee morale and safe clinical practice in an anaesthetic trainee cohort. methods: we conducted a survey amongst anaesthetic trainees in a london teaching hospital before and after a monthly, hour long, confidential, semi-structured, trainee lead "confession session" was introduced. results: initial results demonstrated that % of respondents (n= ) had made a mistake resulting in patient harm with % of these individuals describing negative feelings about themselves as a consequence. additionally, % of respondents had made a mistake causing a near miss, with % of these describing negative feelings as a result. of note, only % of respondents felt comfortable discussing errors with more senior colleagues, whilst % felt comfortable discussing errors with their peers. a follow-up survey identified that % of respondents (n= ) agreed that the session had the potential to improve clinical practice and trainee morale with % agreeing that their own clinical practice had improved from attending the sessions. conclusions: clinical mistakes leading to harm and "near misses" are common and provide opportunities to improve care. this trainee lead "confession session" appears to improve trainee morale and may improve patient care by encouraging trainees to engage in a process that seeks to understand error through sharing stories in a non-judgmental setting. funnel plots for quality control of the swiss icu -minimal data set introduction: a clinical database should be representative of the labelled population and guarantee completeness and accuracy of collected data. without explicit permission of the patients, swiss laws regarding data protection do not allow external audits based on periodic checks of random samples, supposed to give a general pattern of accuracy. to test alternative methods for quality control we introduced the principles of statistical process control to derive funnel plots from the swiss icu -minimal data set (mdsi). the mdsi from all certified adult swiss icus ( and ) was subjected to quality assessment (completeness and accuracy). for the analysis of accuracy, a list of logical rules and cross-checks was developed as e.g. range of saps ii according to age. errors were classified in coding errors (e.g. nems score > points) or implausible data (nems without basic monitoring). we also checked for icus producing significantly more errors -outliers -(> mean ± standard deviations [sd] or > . % confidence interval [ci] of an adapted version of the funnel plots, which allows the presence of trends depending of the icu's size. results: a total of ' patient mdsi ( items/patient; items for trauma patients) from the certified icus.were investigated. we detected ' patients ( . %) with an overall sum of coding errors and ' implausible situations. implausible situations related to supposedly inaccurate definitions (diagnostic and patient's provenance prior to icu admission) and discrepancies in the logical rules between diagnostics and treatments. figure is an example for imprecise coding of the diagnostic: icus declared having treated - % of their patients without a defined diagnosis. conclusions: accuracy of data in mdsi needs further improvement. funnel plots may be useful for meaningful interpretation of data quality and permit to identify icus disproportionately generating inaccurate and/or implausible data. introduction: lung cancer is the leading cause of intensive care unit (icu) admission in patients with the advanced solid tumors. this study was aimed to elucidate the clinical factors associated with icu mortality of advanced lung cancer patients and the effect of intensivist's contribution on their clinical outcomes. methods: we included patients with advanced lung cancer including non-small cell lung cancer (nsclc) with stage iiib or iv and small cell lung cancer (sclc) with extensive stage who admitted to icu from to . multivariate logistic regression analysis was performed to find the variables associated with icu mortality and in-hospital mortality. we applied autoregressive integrated moving average (arima) for time-series analysis of the intenvention of intensivists. results: among total patients with advanced lung cancer, patients ( . %) were admitted icu before introduction of organized intensive care at , and ( . %) were admitted after (fig. ) . the leading cause of admission was the respiratory failure ( . %) and cancer-related event ( . %) in terms of intensivist's and oncologist's perspective. before and after , the -day icu mortality rate was . % and . % (p = . ), and the hospital mortality rate changed from . % to . % (p = . ) (fig. ) introduction: decisions when to refer and to admit patients to the intensive care unit (icu) care are very challenging. demand typically exceeds supply in icu beds, which results in a constant need for evaluation of the processes involved in icu referral and admission with a view to optimising resource allocation and patient outcomes. the aim of this study was to evaluate the theoretical impact of a newly designed triage tool for icu referrals on a cohort of patients referred to icu (fig. ) . methods: we reviewed all patients consecutively referred to our icu, whether admitted or not, in february . demographics, referring speciality, role of the referrer, comorbidities, the presence of advanced disease or terminal illness, the presence of acute organ failure, dnr status, reason for not admitting, and icu mortality were recorded. a retrospective analysis of icu referrals using a pilot triage tool was carried out independently by three authors. results: forty-six patients were referred to our icu over the study period. of these, ( %) were admitted. patients were declined icu if their admission was deemed unnecessary ( %), futile ( %), or were transferred due to bed shortage ( %). of the patients referred, ( %) had an advanced disease or a terminal illness. of those, ( %) were admitted, dnr status was unclear in ( %), family was involved in ( %) and their icu mortality was %. by analysing retrospectively these referrals with the aid of a triage tool, we propose that the overall referrals could have decreased from to ( % percentage difference). dnr status and family involvement would have been clarified in all patients with advanced disease or terminal illness before icu referral. kappa score for inter-rater agreement was . . conclusions: adopting a triage tool for icu referrals could reduce the overall proportion of inappropriate referrals and admissions. end-of-life discussion would also be proactively clarified prior to icu admission. introduction: intensive care unit (icu) admission triage occurs frequently worldwide and often involves decisions with high subjectivity, possibly leading to potentially inappropriate icu admissions. in this study, we evaluated the effect of implementing a decision-aid tool for icu triage on icu admission decisions. methods: urgent icu referrals before (may, to november, , phase ) and after (november, to may, , phase ) the implementation of a decision-aid tool were prospectively evaluated. our primary outcome was the proportion of potentially inappropriate icu referrals (defined as priority b or patients, as described by the or society of critical care medicine [sccm] guidelines) that were admitted to the icu in hours following referral. we conducted multivariate analyses to adjust for potential confounders, and evaluated the interaction between phase and triage priorities to assess for differential effects in each priority strata. results: of urgent icu referrals, ( %), ( %), ( %), ( %) and ( %) were categorized as priorities b, a, , and (sccm ) or ( . %), ( . %), ( %), ( %) and ( %) were categorized as priorities , , , and (sccm ), respectively. overall, ( %) patients were admitted to the icu in hours following referral. the implementation of the decision-aid tool was associated with a reduction of admission of potentially inappropriate icu referrals [adjor ( % ci) = . ( . - . ), p = . ] (fig. ) . there was no difference on hospital mortality for the overall cohort between phase and phase . conclusions: the implementation of a decision-aid tool for icu triage was associated with a reduction of potentially inappropriate icu admissions. introduction: the aim was analyze the icu bed rotation pattern, the epidemiological characteristics of patients and to correlate them with prognostic score after software implementation methods: this is an epidemiological and retrospective study. data were collected between june and november , using epimed® monitor software, applied in an adult icu of a public hospital in bahia/brazil. authorization for collection and use of data was granted by the institution. all patients hospitalized in the period were included regardless of other exclusion criteria. results: during the period evaluated, there were . new hospitalizations, men ( . %) and women ( . %). . % ( ) were in the age group of to years, followed by . % of the patients ( ), who were between and . the mean duration of hospitalization in our unit was approximately , days. during the period covered, . exits occurred: patients ( . %) were introduction: early debriefing after stressful events holds great value in reflection on both an individual and team-based level. our objective was to implement routine structured debriefing sessions for doctors working in intensive care in order to optimise learning and develop strategies to improve practice. methods: % of junior doctors (n= , pre-implementation questionnaire) on the intensive care unit expressed a need for regular debriefing sessions to discuss challenging and complex cases. weekly sessions were implemented and structured using the sharp performance tool [ ] . key learning points were collected and added to a debrief list to track progress and assimilate learning. informal feedback was obtained on a weekly basis with formal feedback assessed following one month of implementation. results: min sessions occurred on a weekly basis supported by a consultant intensivist. desired outcomes included assessment of team performance, identification of key learning points and psychological support. following one month, % doctors involved felt that debriefing sessions were important and should continue. % felt that they left every session with a key learning point applicable to future clinical practice. common themes in perceived benefits included improved team communication and creation of an open environment to address concerns. conclusions: working in intensive care exposes doctors to challenging and stressful situations. implementation of a regular structured debrief session provides an opportunity for clinicians to address concerns, consolidate learning and develop strategies to improve clinical practice. nurse staffing patterns, outcomes and efficiency in resource use in the context of icus with a "low-intensity" nurse staffing: a multicenter study in brazilian icus m soares introduction: studies investigating nurse staffing and outcomes were often conducted in high-income countries with low bed/nurse ratios. our objective was to investigate the association between nurse staffing patterns, outcomes and resource use in brazilian icus. methods: retrospective cohort study in , ( % medical) patients admitted to medical-surgical icus during - . we retrieved patients' data from an icu registry (epimed monitor system) and surveyed participating icus about characteristics related to icu organization. we used multilevel logistic regression analysis to identify factors associated with hospital mortality. we evaluated efficiency in resource use using standardized mortality rates (smr) and resource use (sru) based on saps . results: saps score was ( - ) points and hospital mortality was . %. intensivists were present / in % icus. median bed/ nurse ratio was . ( . - . ) and at least the chief nurse was boardcertified in critical care (bccc) in % icus. bed/nurse technicians ratio was . ( . - . ). adjusting for relevant characteristics at patientlevel (age, admission type, sofa, performance status, comorbidities, hospital days before icu) and icu-level (hospital type, checklist use, / intensivist, protocols), bed/nurse ratio was not associated with mortality [or= . ( % ci, . - . )]. however, mortality was lower in icus with at least the chief nurse bccc [or= . ( . - . )]. in multivariate analysis, bed/nurse ratios <= [or= . ( . - . )] and having the chief nurse bccc [or= . ( . - . )] were associated with higher efficiency. conclusions: in a "low intensity" nurse staffing scenario, bed/nurse ratios were not associated with mortality. however, having at least the nurse chief bccc was associated with higher survival. moreover, bed/nurse ratios <= and presence of chief nurse bccc were associated with higher efficiency in resource use. methods: a systematic search on the value of acute non-physician provider on the icu was conducted. the methodological quality of the included studies was rated using the newcastle ottawa scale (nos). the agreement between the reviewers was assessed with cohen's kappa. results: in total studies were identified. twenty comparative cohort studies were identified which compared non-physicians with either residents or fellows. all studies comprised adult intensive care. most of the included studies were moderate to good quality. a random effects meta-analysis from all studies regarding length of stay and mortality showed no differences between non-physicians and physicians, although there was a trend to better survival when implementing acute non-physician providers in the icu (figs. & ) . mean difference for length of stay on the icu was . ( % ci - . - . ; i = %) and for in hospital - . ( % ci = - . - . ; i = %); while the odds ratio for icu mortality was . ( % ci = . - . ; i = %) and for hospital mortality . ( % ci . - . ; i = ). conclusions: the acute care non-physician provider in the icu seems a promising clinician on the icu with regard to quality and continuity of care. whether they also can reduce mortality remains to be determined by designing studies, which adequately measure the contribution of the non-physician providers in icu care overall and per task. their role in europe remains to be elucidated. burnout and depression in icu staff members n bahgat menoufia university hospital, shibin elkom, egypt critical care , (suppl ):p introduction: family and success in work are the most important sources of person satisfaction in life, chronic prolonged exposure to stressful high workload in intensive care units (icu), create a bad psychological state named burnout syndrome in which person is depressed, exhausted and thinks to leave job. in this study we made a survey on icus staff members in egypt menoufia university hospital to explore and find risk factors increase depression and burnout among nurses and doctor. methods: questionnaires were given to all intensive care staff for estimating the prevalence and associated risk factors of burnout using maslach burnout inventory (mbi) with its three subscales emotional exhaustion (ee), lack of accomplishment (la), and depersonalization (dp). depressive symptoms using the beck depression inventory scale. blood sample was taken for assessing depression biomarkers including il- , tumor necrosis factor (tnf)-alpha, and coenzyme q (coq ), which appears to be one of the most reliable peripheral biomarkers. results: participants were respond in our survey from icu members the response rate was . %, the depression symptoms found increased in nurses more than physicians in icu with more desire to leave the job. there was strong correlation between the degree of depression symptoms and decrease percent of personal accomplishment. impaired personal relationships at work and increased night shifts were major risk factors of burnout syndrome. levels of the proinflammatory cytokine (il and tnf alpha) were elevated in members who recorded sever degree of depression score with decrease in concentration of co-enzyme q . conclusions: the health workers in icu had high liability for depression and burnout syndrome. the risk factors differ between nurses and doctors. il , co-enzyme q and tnf alpha concentrations had god correlation with degree of severity of symptoms. impact of a tailored multicomponent program to reduce discomfort in the icu on post-traumatic stress disorder: a casecontrol study p kalfon , m alessandrini , m boucekine , m geantot , s renoult , s deparis-dusautois , o mimoz , j amour , e azoulay , c martin , t sharshar , m garrouste-orgeas , k baumstarck , p auquier introduction: reducing discomfort during the icu stay should be beneficial on long-term outcomes. the aim of this study was to assess the impact of the implementation of a tailored multicomponent program to reduce discomfort in the icu [ ] on the occurrence of posttraumatic stress disorder (ptsd) months after discharge from the icu. methods: design: case-control study; the cases were patients hospitalized in the icus which implemented the tailored multicomponent program; the controls were patients hospitalized in the icus which did not implement the program. exposition: the tailored multicomponent program consisted of assessment of icu-related self-perceived discomforts by using the iprea questionnaire, immediate and monthly feedback to healthcare teams, and tailored site-targeted measures under control of a duo of local champions. general procedure: eligible patients were recalled months after the icu stay. data collection: sociodemographics, clinical data related to the icu stay, discomfort's levels assessed the day of discharge from the icu, life situation (home/care center), pstd (ies-r) and anxiety-depression symptoms (hads) months after the icu discharge. results: from the eligible cases and eligible controls, cases and controls were included (reason for exclusion: deaths after discharge from the icu, lost to follow-up, patient refusal, cognitive incapacity). a total of . % of the cases and . % of the controls presented certain symptoms of ptsd at months (p= . ). after adjustment for age, gender, iprea score, mccabe score, presence of invasive devices during the icu stay and considering anxietydepression symptoms at months, cases are less likely to have ptsd symptoms than controls. conclusions: our tailored multicomponent program for discomfort reduction in the icu can reduce long-term outcomes as ptsd. diffusion of such a program should be enhanced in the icus paving the way for a new strategy in care management. introduction: cognitive dysfunction is a major factor leading to disability and poor quality of life in icu survivors. in order to identify patients at risk for developing cognitive dysfunction due to critical illness or icu treatment, one has to discriminate between patients with pre-existing cognitive dysfunction and those developing new cognitive dysfunction or worsening of cognitive function during icu treatment. we investigated the incidence of pre-existing cognitive dysfunction in icu patients using the informant questionnaire on cognitive decline in the elderly (iqcode) and its relation with delirium during icu treatment. methods: patients relatives were asked to fill in the iqcode on admission. an overall score on cognitive dysfunction was calculated by the average of the score on each item of the questionnaire. the incidence of delirium was based on the cam-icu score. statistical analysis was performed using the fisher's exact test. p-values of less then . were deemed significant. results: in total consecutive patients admitted to our icu were analyzed, of whom . % (n= ) showed decline in cognitive function prior to icu admission. cognitive function was divided in four groups; no change . % (n= ), slight decline . % (n= ), moderate decline . % (n= ) and severe decline . % (n= ) (fig. ). incidence of delirium is shown in fig. . patients with moderate to severe cognitive dysfunction showed significant more delirium during icu treatment than patients with no change in cognition ( . % and . % respectively, (p= . )). conclusions: almost half of the patients admitted to the icu have cognitive dysfunction prior to icu admission. to assess ones cognitive function after icu treatment one has to take in to account the patients pre-existing cognitive functioning. patients with a moderate to severe pre-existing cognitive dysfunction develop significantly more delirium during icu treatment. introduction: our aim was to identify and analyse patients treated for pocd admitted to a thoracics/urology intensive care unit at university college london, uk. pocd is rising in the ageing high-risk surgical patient. early identification of those at risk and timely intervention could help reduce associated morbidity and mortality [ ] . methods: we identified patients treated with haloperidol, midazolam, lorazepam, olanzapine, clonidine or chlordiazepoxide from our electronic data system. these pharmacological interventions were used as surrogate markers of primarily hyperactive pocd, acknowledging other forms of delirium may be unaccounted for. of admissions ( . %) were shortlisted from august to july . patients were excluded if the drugs had been used for other indications. prevalence of known pocd risk factors were then detailed. on these data we performed a cluster analysis using r. results: of the patients ( . %) suitable for analysis, the mean age was . patients underwent elective procedures. were male and were female. % patients had thoracic surgery. the mean pain score in the first hours post-op was . (sd= . ), (with = no pain, = very severe pain). % had evidence of poor sleep and % evidence of anxiety. in the hours prior to evidence of pocd, the mean pain score remained . (sd= . ), % had evidence of poor sleep and % had evidence of anxiety. % of our population was septic during their itu admission. conclusions: our analysis demonstrates pocd is highly prevalent in male patients over undergoing thoracic procedures. we will now develop a pocd pathway targeting improved postoperative management of pain, sleep, anxiety and infection in this patient population. introduction: our objective was to determine the feasibility of employing family-administered tools to detect delirium in the critically ill. the use of family-administered delirium detection tools has not been assessed in the icu where patients are critically ill and frequently intubated. family members may be able to detect changes in patient cognition and behavior from pre-illness levels earlier than unfamiliar providers. these tools may be a valuable diagnostic adjunct in the icu. methods: consecutive patients and family members (dyads) in the largest adult icu in calgary, canada were recruited (aug. -sept. , ). inclusion criteria were: patients with a richmond agitation sedation scale (rass) >=- ; no primary brain injury and glasgow coma scale score of < ; ability to provide informed consent (patient/ surrogate); and remain in icu for hours. data were collected for up to days. family-administered delirium assessments were completed once daily (family confusion assessment method & sour seven). to assess feasibility, we assessed proportion of eligible patients and percent family member enrollment. barriers to enrollment were categorized. results: of admitted patients with family, ( %) met inclusion criteria and ( %) dyads consented. % of admitted patients did not have family and were thus ineligible. % of enrolled dyads assessed delirium at least once, with a median of (of total) assessments. the most common reason for non-enrollment was refusal by the family, who commonly reported feeling overwhelmed by the icu environment. barriers with nursing staff were encountered, including not providing access to patients and patient exclusion. conclusions: these data suggest that employing family-administered delirium detection tools in the icu is feasible for a subset of the population. future studies will validate the use of these tools in the icu, decrease modifiable barriers to enrollment, and test strategies to overcome attitudinal barriers towards employing these tools. introduction: psychological impact of critical illness and icu stay on patients can be severe and frequently results in acute distress as well as psychological morbidity after discharge [ ] . however, the stressful experience in icu and its influence on patient recovery, remain relatively understudied. we assessed patients in icu for acute distress and psychological symptoms with validated tools. methods: we conducted an observational study in a group of awake icu adult patients admitted in a tertiary centre for at least hours, from january until october , with mixed diagnosis on admission. we collected demographic factors, saps ii at admission, mechanical ventilation, day of sedation, history of psychopathological disorder. un-sedated and alert, critical care patients were assessed with tools such as intensive care delirium screening checklist (icdsc), hospital anxiety and depression scale (hads) and intensive care psychological assessment tool (ipat). results: patients were recruited, (mean age . ± . years, . % males). saps ii at admission was . ± . , . % was mechanically ventilated (mean duration . ± ), mean duration of sedation was . ± . days and a rate of . % had an history of psychopatological disorder. . % of the sample had clinical delirium (icsdc> ) and was not assessed with others tools, . % had subclinical delirium (icsdc <= ). regarding psychological outcomes, . % (mean score . ± . ) reported a score (>= ) on hads that indicates a possible diagnosis of anxiety and . % (mean score . ± . ) of depression. a rate of . % reported a score >= on ipat suggesting an acute distress. conclusions: the study's key finding was that acute psychological distress was high in awake icu patients. further work is needed to determine the efficacy of early psychological interventions to reduce the incidence of acute distress and psychological outcomes after icu stay. introduction: a high percentage of polytrauma patients require surgery within the first hours to stabilize primary traumatic injuries. one of the main intraoperative complications in this type of patients is due to hemodynamic instability [ ] . thus, it is necessary to implement multimodal monitoring involving both hemodynamic monitoring and monitoring of general anesthesia. the objectives of this study were to identify the possible implications of entropy monitoring on hemodynamic stability in critically ill polytrauma patients. methods: prospective observational study, deployed in the clinic of anesthesia and intensive care, emergency county hospital "pius brinzeu" timisoara, romania. clinicaltrials.gov identifier. there were two groups, group a (n = ), in which the depth of hypnosis was monitored through entropy (ge healthcare, helsinki, finland) and group b (n = ). results: the incidence of hypotension and tachycardia episodes was statistically significantly lower in group a, unlike the control group (p < . ). moreover, a statistically significant (p < . ) consumption of inhaled anesthetic agent was recorded in group a compared with group b. consumption of vasopressor was also lower in group a (p < . , difference between means . ± . , % confidence interval . - . ) conclusions: deploying monitoring for the depth of hypnosis in general anesthesia using entropy can significantly increase the hemodynamic stability of critically ill polytrauma patients. introduction: the use of methadone as a potent analgesic has been gaining ground in the intensive care setting, such as where it is possible to properly select the group of patients who will benefit from the drug, as well as monitoring of possible complications. the objective of this study is to evaluate the safety of the use of methadone in critically ill patients in a large hospital. methods: a retrospective analysis of all patients who used methadone in a neurological intensive care unit for a period of four months and the results were evaluated. results: in the four-month period, patients used methadone during intensive care. % of the patients were male, with a medical age of . ± . years. the main indication for the use of the medication was for analgesia in patients who were weaned from mechanical ventilation. the mean time of use was . days. in all cases evaluated, analgesia was effective, with methadone being used alone or in combination with other drugs, according to an institutional protocol. among the complications found, patients presented hypotension ( %); presented bradycardia ( %); presented constipation ( %); had excessive sedation ( %) and had other complications. all complications were reversible. patients of the studied population died, however, without correlation with the use of methadone. conclusions: the use of methadone, in the studied group, was effective in the control of analgesia, with no impact on patient safety when used in a monitored way. introduction: renal colic is a common disorder which presents with dramatic acute pain. providing rapid relief, using effective pain control medications is the clinical priority to treat the patients. this study aims to compare the effect of iv ketorolac versus morphine in releasing renal colic pain by measuring pain severity and duration and also the need for additional doses. methods: we performed a clinical pilot cohort study from during on patients with the clinical diagnosis of renal colic who recruited from the emergency department (ed) of rasool-e-akram hospital and firoozgar hospital. participants who were candidate to receive either morphine or ketorolac were divided into two groups who received either mg ketorolac iv or mg morphine. the pain was evaluated using the visual analog scale (vas) at four time points: before drug injection (vas- ), minutes (vas- ), minutes (vas- ), and minutes (vas- ) after injection. in cases when the pain was not controlled with the first injection of drug beyond minutes; additional doses (rescue) were injected. statistical analyses were performed using spss . results: one-hundred-fifty patients treated with morphine and ones with ketorolac were studiedthe group treated with morphine scored on average . before the injection, which was roughly . points higher than ketorolac. morphine reduced patients' vas scores more intensely (median: , iqr: versus median: , iqr: ; p value< . ). in general, patients treated with morphine were more likely to need a second (rescue) dose, when compared to ketorolac group ( . % vs %, p value= . ). conclusions: morphine is a better option for pain release in cases of renal colic. ketorolac released the pain to an acceptable level; but, because of its slower action time, we recommend it in cases with moderate than severe pains. effect of analgesics on cardiovascular and hormonal response to operative trauma d loncar stojiljkovic, mp stojiljkovic sgh, , serbia critical care , (suppl ):p introduction: objective of this study was to compare the effects of two analgesic regimens, one opioid and one non-opioid, on cardiovascular and hormonal reaction of patients undergoing elective surgery under general endotracheal anaesthesia. methods: a total of elderly patients, asa , scheduled for elective abdominal surgery were assigned to receive on induction a single dose of either fentanyl ( . mg, + . mg) or a fix combination of etodolac and carbamazepine (novocomb, dose mg+ mg iv bolus). haemodynamic parameters and concentrations of prolactin cortisol and growth hormone (gh) [ ] were determined at critical points and h after operation. results: both fentanyl and novocomb blocked the hypertensivetachycardic response to surgical trauma. cortisol was a more appropriate endocrine marker of stress than prolactin or gh since fentanyl as an opioid analgesic increased secretion of prolactin [ ] , while carbamazepine from novocomb did the same with gh [ ] (figs. & ) . conclusions: cortisol plasma concentration correlates positively with cardiovascular parameters in patients undergoing elective abdominal surgery who received fentanyl or novocomb as intraoperative analgesic. its suppression is better marker of analgesia than prolactin and gh. volatile anaesthetic consumption and recovery times after long term inhalative sedation using the mirus system -an automated delivery system for isoflurane, sevoflurane and desflurane introduction: the new mirus system as well as the anaconda uses a reflector to conserve volatile anaesthetics (va) [ , ] . both systems can be paired with icu ventilators, but mirus features an automated control of end-tidal va concentrations (etva). we compare feasibility and recovery times for inhalational long term sedation with isoflurane (iso), sevoflurane (sevo) or desflurane (des). methods: asa ii-iv patients undergoing elective or emergency surgery under general anaesthesia were included. patients were randomized into three equal groups iso, sevo and des. the mirus system was started with a targeted etva of . mac. we used the puritan bennett icu ventilator and performed a spontaneous breathing trial. if successful, the target concentration was set to mac and recovery times measured. results: patients were comparable in demographics, tidal volume, respiratory rate and sedation time (total h: iso ± h; sevo ± h; des ± h; p= . ). in all patients, a mac of . was reached. conclusions: mirus could automatically control end-tidal va concentrations in ventilated and spontaneously breathing patients. the recovery times are only prolonged in the iso group and could be shortened by removing the reflector. the higher etva required for a . mac using des and sevo were associated with an increased va consumption. introduction: intranasal analgesia is increasingly used in order to relieve pain in the emergency department. this non-invasive approach avoids discomfort, stress and risks related to the parenteral route of administration. the objective is to compare intranasal (in) fentanyl versus any parenteral opioid (intravenous, subcutaneous, intramuscular) for the effectiveness of acute pain relief in an adult population. methods: the systematic review was registered in prospero (crd ). the research of articles was conducted through embase, central, and medline databases. randomized clinical trials comparing the effectiveness of in fentanyl to any parenteral opioid for acute pain relief (<= days) in an adult population (>= years old) were considered for inclusion. studies on breakthrough cancer pain were excluded. two different reviewers extracted data and analyzed the quality of the selected articles. the main outcome was the difference between pain levels before and after analgesia. the effect size was approximated using the inverse of variance of standardized mean differences, based on a random-effect model. heterogeneity was quantified using a test of i . results are presented with % confidence interval. results: eight randomized clinical trials with cohorts and a total of patients were selected ( in fentanyl vs control group). selected articles contained a low risk of bias. there is no significant difference between the average levels of pain before and after analgesia comparing the two groups (smd . [ic % - . à . ], p= . ; i = %) (fig. ) . conclusions: in fentanyl is as effective as other parenteral opioid to relieve pain during the first hour of treatment. introduction: the aim of this study is to underline the importance of sedation protocol when performing the pegj procedure in advanced parkinson's disease (pd) patients. research about the use of sedation in endoscopy is getting more and more widespread as to answer to the increasing grade of complexity and duration of endoscopic procedures as to offer comfort to the patient in terms of analgesia, tolerability, and amnesia. sedation is also a way to assure quality and safety examination and to improve its outcome [ ] . methods: this observational retrospective study includes pd patients scheduled for pegj procedure (fig. ) in order to start therapy with duodopa gel. we propose an anesthetic technique (table ) to support pegj with both local anesthesia and moderate sedation so as to provide analgesia and patient's comfort. this technique ensures mean duration of pegj procedure was '± '. mean stay time in recovery room '± '. compared to our old experience, we collected lack of patient's discomfort, anxiety, and memory, high procedure compliance and improvement of the quality of procedure without use of opioids. conclusions: based on our experience, we consider this sedation protocol effective for different reasons: to relieve or abolish patient's discomfort, anxiety, and memory, to ensure compliance with the procedure, to ensure patient's analgesia and patient's safety and, finally to assure procedure's quality and rapid discharge. anyways, a multicentric study should be done to test our protocol. introduction: studies have shown that icu survivors exhibit longterm neurocognitive impairment and perceived reduction in quality of life after icu discharge, but studies examining sleep architecture and sleep disordered breathing (sdb) in icu survivors after icu discharge are scanty. the aim of our study was to assess sleep architecture and sbd in icu survivors. methods: icu survivors were screened for eligibility. inclusion criteria were: age - yrs, mechanical ventilation >= hours, gcs of at the time of hospital discharge. patients with a history of sbd, chronic neuromuscular disorders, chronic restrictive lung disease, congestive heart failure and respiratory failure at hospital discharge were excluded. patients were evaluated within one week after hospital discharge and months later. at both visits patients completed health related quality of life questionnaires (sf and epworth sleepiness scale), underwent a physical examination, lung function tests including maximum inspiratory and expiratory mouth pressures, and an overnight full polysomnography (psg). results: sleep quality at days of hospital discharge is poor, characterized by severe disruption of sleep architecture and excessive sdb, mainly of obstructive type which in % of patients was classified as moderate or severe. although at six months after hospital discharge sleep quality remained relatively poor, significant improvement in n stage and ahi was observed, with more patients to be classified as normal or mild sdb. both at hospital discharge and months later quality of life was reduced but there was no relationship between the health related quality of life and sleep disturbances. conclusions: icu survivors experience significant deterioration in their quality of life status with minor improvement months later and a variety of sleep disturbances that seems to start getting better months later. introduction: disrupted sleep in critically ill patients may be associated with delirium, prolonged stay in icu and increased mortality. polysomnography (psg), the criterion standard method of sleep monitoring, is challenging in icu due to interpretation difficulties, as the patterns defined by the standard classification for scoring sleep are absent in many critically ill patients. the aim of this study was to investigate if the presence of atypical patterns in critically ill patients' psg is associated with poor outcome measured by -days mortality in conscious critically ill patients on mechanical ventilation. methods: psgs (median duration hours) recorded in conscious critically ill mechanically ventilated patients were scored by an expert in sleep medicine blinded to patient characteristics. standard sleep scoring classification was used if possible. otherwise, modified classification for scoring sleep in critically ill patients proposed by watson et al. was applied [ ] . the association of sleep patterns (normal or atypical) and micro-sleep phenomena (sleep spindles and kcomplexes) with days mortality was assessed using weibull model by calculation of hazard ratios (hr). results: hr analysis showed twice as high mortality risk in case of atypical sleep compared to normal sleep; this was however not significant (hr . ; % ci . - . ; p= . ). the presence of sleep spindles in psg significantly reduced mortality risk to / (hr . ; % ci . - . ; p= . ). the presence of k-complexes in psg reduced mortality risk to ½, though not significantly (hr . ; % ci . - . ; p= . ). conclusions: the absence of normal sleep characteristics in psg in conscious critically ill patients on mechanical ventilation is associated with poor short-term outcome. antipsychotics (aps) prescribing in critically ill delirious patients, the reported versus the perceived practice e almehairi , g davies , d taylor introduction: aps are the most commonly prescribed drugs in hyperactive/mixed delirium and agitation in critical care (cc) [ ] . yet evidence in cc is scant, there are known adverse effects (ade) and prescription is out with the european license. meticulous observation of ap selection, prescribing and safety, alongside delirium assessment/plan is essential to gain new knowledge and patients. when accompanied by prescribing clinicians perspective of delirium ap treatment results are more interpretable. we conducted a two-part single centre cohort study that aimed to describe/compare real to perceived delirium assessment/plan, aps prescribing and safety in cc adult patients at gstt. methods: part : a prospective survey, of cc prescribing clinician's beliefs and attitudes to delirium assessment/plan, aps prescribing and safety over previous months. part : a meticulous audit of aps prescribing and safety and delirium/agitation assessment and plan, over period of months. results: part survey. of prescribers ( . %) completed survey. % of reported using aps to treat delirium, with % selecting atypical aps as first option. part audit. there were admissions to cc. aps were prescribed in . % ( prescription), . % ( prescription) were in delirium/agitation patients (table ) . survey (vs.) audit: in the survey % reported daily delirium screening whereas only . % undertook daily screening in audit (fig. ) . higher quetiapine and lower iv haloperidol maximum daily dose were prescribed in audit in comparison with survey reported doses ( table ) . lead ecg was used to monitor ap ade. in survey % reported assessing ecg once or more daily. audit revealed only % actually did so (fig. ) . conclusions: authors believe perceived vs actual can identify key areas for quality improvement (qi). major differences were in delirium assessment/plan and safety monitoring sedation practices in turkish icus, the aim was to provide knowledge on this matter. methods: an electronic survey form was generated with google forms. first part of the form included questions about demographics, and choices and routines of sedation administration. this part mostly contained multiple choice questions, which more than one choice could be indicated. second part was comprised of some statements to investigate the attitudes of physicians, which were indicated on a five-point likert scale. the link for the survey was posted to all email addresses registered in the turkish society of intensive care member database. results: of members, ( %) completed the survey form. demographics are given in table . sedation was generally applied by the physicians ( %). the indications were mechanical ventilation ( %), agitation ( %), seizures ( %), anxiety ( %), delirium ( %). drug choices of the respondents are shown in fig. . sedation level was evaluated daily by % of respondents, mostly using ramsay scale ( %). daily established sedation level was indicated in . %, and daily interruption of sedation was indicated in . % answers. sedation protocol was not used in . % of the answers. analgesics applied commonly, while % routinely evaluated pain and visual analogue scale (vas) was the preferred method in % of the answers. . % of physicians indicated routine use of neuromuscular blockers. in . % answers routine evaluation for delirium was indicated, mostly using cam-icu.when the knowledge of sccm guideline pain, agitation and delirium management, % indicated a positive answer.the respondents indicated their opinion for some comments on sedation, the answers are shown in the table . conclusions: it may be concluded sedation practices may need to be improved by increasing awareness on novel concepts in this area. fig. (abstract p ) . the prediction-corrected vpc plots for dexmedetomidine pk. the vpc plots show the simulation-based % confidence intervals around the th, th, and th percentiles of the pk data in the form of blue ( th) and gray ( th and th) areas. the corresponding percentiles from the prediction corrected observed data are plotted in black color methods: a prospective multinational cohort study was performed in icus in sweden, denmark and the netherlands. all adult patients with an icu stay >= hours were screened for inclusion. primary outcome was psychological problems three months after discharge from the icu, assessed with the questionnaires hospital anxiety and depression scale (hads) and post-traumatic stress symptoms checklist- (ptss- ). a subscale score > in the hads and a score > in the ptss- part b indicate clinically significant symptoms of depression, anxiety and pts and was considered an adverse outcome. we collected data on known risk factors for psychological problems post-icu. univariable and multivariable logistic regression modelling of risk factors was performed in order to create an instrument to be used bedside, predicting individual risk for adverse psychological outcome. results: patients were included and ( %) returned follow-up questionnaires. % of patients scored above the predefined cut-offs having symptoms of depression, anxiety or pts. age, lack of social support, depressive symptoms and traumatic memories at discharge remained significant after multivariable modelling and constituted the screening instrument ( table ) . the predictive value of the instrument was fairly good with an area under the receiver operating characteristics curve (auroc) of % (fig. ) . we developed an instrument to be used at icu discharge, predicting individual patients' risk for psychological problems three months post-icu. the instrument can be used as a screening tool for icu follow-up and enable early rehabilitation. improving the patients hospitalization experience in an intensive care unit by contact with nature w yacov , y polishuk , a geal-dor , g yosef-hay kaplan medical center, rehovot, israel; kaplan medical center, rehovot, israel critical care , (suppl ):p introduction: the intensive care unit is characterized by a noisy and threatening work environment using multi tecnologic equipment.the staff works very intensively caring for very complicated and unstable patients.whilst caring for the patients physical needs one must not forget the patients mentally needs.the improvement of the patients hospitalization experience by changing the environment improves the mood and responsiveness to treatment gives hope for healing to the patient and family. methods: a quality questionare with open questions relating to the subjective sensory experience of the patients and their families. the patients were transferred to the "sun balcony" for a period of - minutes having their families alongside. music was transmitted and the patients were offered food and drinks if their condition allowed. results: the patients reported a significant improvement of hospilizaton experience following their exposure to the "nature environment". patients described the sensory experience as a positive, pleasant, quiet and relaxing experience. the contact with the sun, wind, sky and grass and being outside on the "sun balcony" allows a disconnection from the threatening icu environment. conclusions: the "sun balcony" gave the patients a sense of hope and wish for healing. mobilizing complicated patients to the "sun balcony" is a big challenge which requires planning and preparation by the staff. yet by the proactive and creative thinking of the staff the patients are tranferred to the "sun balcony" to give them encouragement, a feeling of well being and hope for recovering. this intervention is costless and a routine procedure in the intensive care unit. introduction: long-term psychological outcomes of patients(pts) discharged from icu represent an emergent relevant matter of concern.systematic reviews refer prevalence of %- % for anxiety, %- % for depression and %- % for posttraumatic symptoms in ards patients.the onset of psychiatric symptoms after discharge, might be associated with patient's competence to process memories related with hospitalization and with memories. methods: we selected ards pts in icu of a tertiary centre (jan -dec ) at least hour, for months follow-up and pts for months follow-up after discharge. the psychopathological assessment was performed using scale as: impact event scale-revised (ies-r), hospital anxiety and depression scale (hads), icu memory tool (icu-mt). results: mean age was . ± . at months follow-up and , ± , at months. ptsd symptoms was fund respectively in % and . % pts at and months; anxiety symptoms % and . % of pts;depression symptoms in % and . %. significant correlations were fund between psychopathology at months and memories of icu: hads anxiety with delusion memories (r . ,p< . ); hads depression with factual (r . ,p< . ), feeling (r . ,p< . ) and delusion memories (r= . ,p< . ); feeling (r . ,p< . ). at months significant correlations was fund between hads anxiety and feeling memories (r . ,p< . ); ies-r and factual (r . ,p< . ), feeling (r . ,p< . ) and delusion memories (r . ,p< . ). the results of the study confirmed the importance of assessing psychopathology after discharge from icu. the onset of these symptoms appeared to be mediated by specific traumatic memories related with icu hospitalization. the main clinical recommendation emerging from this study is to investigate psychiatric history and develop psychological strategies to manage frightening or delusional experiences during icu stay. introduction: the aging of the population is a fact. the subgroup of very old (>= years (ys)) is the one that increases the most rapidly. intensive care unit (icu) admission of these patients is an ongoing discussion worldwide. our icu has designed the voolcano aiming its characterization and reviewing outcomes, to find some predictive indicators. the purpose of this first analysis is to evaluate specifically the group of very old patients (volds) admitted to a tertiary portuguese hospital icu. methods: retrospective observational study was preformed, included all volds admitted in icu during years ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . demographic data, admission diagnosis, severity scores, charlson comorbidity index, length of stay and outcomes were considered. data analysis used spss software. results: we found a total of admissions. the median age was . ys with iqr ; mostly male with medical admission diagnosis (sepsis and respiratory failure due to infection). there was a median acute physiology and chronic health evaluation ii of (iqr ) and simplified acute physiology score ii of (iqr ). median charlson comorbidity index was . (iqr ). median length of stay was . days (iqr . ). concerning outcomes, we found intra-icu mortality of %; intra-hospital after icu discharge mortality of % and mortality after hospital discharge of %. identified as predictors of intra-hospital mortality the use of mechanical ventilation (p < . ), urgent surgical admission or medical admission versus schedule surgical admission (p < . ) and the absence of oncologic disease (p = . ). on multivariate analysis, only mechanical ventilation (p = . , hr . , % c.i. . - . ) and urgent surgical admission versus schedule surgical admission (p = . , hr . , % c.i. . - . ) remain significant. conclusions: recognizing the need to understand what is the biologic|funcional age (opposed to chronologic age) would be beneficial in the selection of volds to icu admission. organ failure and return to work after intensive care s riddersholm , s christensen , k kragholm , cf christiansen , bs rasmussen aalborg university hospital, aalborg, denmark; aarhus univeristy hsopital, aarhus, denmark critical care , (suppl ):p introduction: organ failure is associated with an unfavorable prognosis. nevertheless, the association with capability to return to work remains unclear. therefore, we investigated the association between organ support therapy as a proxy for organ failure and return to work in a nationwide cohort of icu survivors. methods: we linked danish registry-data on icu-and hospitalsurvivors working prior to hospital admission during - , - years of age, with an icu length of stay > hours and not previously treated with dialysis, to data on return to work. we reported cumulative incidences (chance) of return to work with death as competing risk, and compared rate of return to work in adjusted cox regression-models by number of organ support therapies including renal replacement therapy, cardiovascular support and mechanical ventilation and stratified on primary hospital-admission diagnosis. results: of , patients - years of age, % ( , ) survived to hospital discharge (tables and ). among these, the chance of return to work was . % ( % ci [ . - . ]) within two years (fig. (fig. ) . when stratified an increasing number of organ support was associated with a decreased chance of return to work among patients with infection, respiratory failure or trauma but not among patients with neoplasms or endocrine, gastrointestinal and cardiovascular diagnoses. introduction: mortality rates among people with moderate to severe learning disabilities (ld) are times higher than in the general population [ ] [ ] [ ] . this study was designed to examine critical care admissions with learning disabilities in terms of mortality, demographics and reason for admission. methods: data was retrieved for adult patients (> years old) between sept and . the ward watcher database for icus within surrey and sussex healthcare nhs trust was interrogated using search words including, learning disability, cerebral palsy, down's syndrome and autism. results: there were episodes ( . % of all admissions) of patients admitted with ld. % of the ld patients had more than admission. respiratory is the most common system affected ( %). logistic regression suggests survival is highest in those with a neurological reason for admission (p= . ). proportionally ld patients were young compared to the total population (fig. ) . we found that mortality appears to increase rapidly in those over years of age and overall mortality is greater in those with ld (fig. ) . conclusions: from april all uk trusts will be required to complete a detailed review for patients with ld who die whilst in hospital care. this follows mencap's report 'death by indifference' which exposed deficiencies in the care of people with lds who died whilst in nhs care and the subsequent confidential inquiry into premature deaths of people with learning disabilities. in our population, ld patients have an earlier death than the general population and the overall mortality from critical illness is greater. a multidisciplinary approach at the emergency department to admit potential organ donors for introduction: the aim of the present study is to improve the recognition of potential organ donors by implementing a multidisciplinary approach for organ donation at the emergency department (ed) [ ] . methods: in a prospective intervention study, we implemented this approach in six hospitals in the netherlands. when the decision to withdraw life sustaining treatment was made at the ed in patients with a devastating brain injury without contra indications for organ donation, an intensive care unit (icu) admission for end-of-life care was considered. every icu admission for end-of-life care was evaluated. interviews were conducted with emergency physicians, neurologists and icu physicians according to a standardized questionnaire. this interview focused on medical decisions that were made and difficulties arising during hospitalization. results: from january to november data were collected on the number of patients admitted to the ed with acute brain injury. in total, potential organ donors were admitted to the icu for end-of-life care. donation was either requested in the ed ( %), icu ( %), neurology department ( %), or donation was not requested ( %). out of donation requests, families ( %) consented to donation. this led to successful organ transplantations. in four of these patients family consent was obtained to intubate them solely for the purpose of organ donation. the most important points raised during the interviews were: explaining the non-therapeutic icu admission to the family, the location where donation should be requested (ed/icu) and utility of icu resources. conclusions: a close collaboration between the ed, neurology department and icu is necessary and achievable in order not to miss potential organ donors in patients with acute brain injury with a futile prognosis in the ed. introduction: there is a relationships between intensive care patients losing the ability to speak and negative emotions [ ] . nursing care is challenging when patients are unable to verbalise and factors like pain and comfort are misjudged.. our intensive care unit has introduced a communication tool intelligaze grid which enables patients with primary motoric disorders to communicate their needs. a quality improvement study reviewed the methods of communication and interactions that our nurses use for patients who are ventilated. the objective of the study was to promote areas of improvement with communication in the icu. methods: we used a mixed-methods qualitative and quantitative study to evaluate the communication tools used by our nursing staff to interact with ventilated patients. a convenient data sample for all nurses working on particular dates was collected which is % of the nursing workforce. the study has been approved as a quality assurance project by the human research ethics committee of nepean hospital. results: sixty registered nurses ( %) participated in the study. the most common communication tool used with patients was closed yes/no questions( %), followed by hand gestures( %), magnetic writing board( . %), lip reading( . %) and alphabet board( . %). the descriptive analysis identified challenges were levels of sedation, weakness, non-english speaking patients and delirium. a significant finding was that only % of nurses identified the patients message being understood and % acknowledged listening as effective communication. conclusions: communication is a vital aspect of icu nursing and is achieved through dialogue and specialised skills. the study concluded that icu nurses find it difficult to communicate effectively with ventilated patients. the introduction of intelligaze grid has improved patient communication and promotes holistic nursing care. p withdrawn introduction: substantial variability in eolp occurs around the world [ ] . differences in eolp were previously reported in europe in the ethicus i study [ ] . methods: icus worldwide were invited to participate through their country societies. consecutive admitted icu patients who died or had treatments limitations during a month period from . . to . . were prospectively studied. regions included north, central and southern europe (ne, ce, se), north and latin america (na, la), asia (as), australia (au) and africa (af). previous eolp definitions were used [ ] . results: icus in countries participated enrolling , patients. figure shows differences in eolp by region and figure in patient competency by region. conclusions: worldwide differences included more cpr in af, la, and se and less cpr in ne, au and na. there was more withdrawing (wd) in ne and au and less wd in la and af. more patients were competent in au and ne and less were competent in af, se and la. introduction: the decision of end-of-life care in the icu is very tough issue because the law, ethics, traditions and futility should be concerned involving family's will. especially, stop or withdraw therapy is a quite difficult operation in japan because of our traditions. recently there are few legal issues due to some guidelines. our hypothesis is some difference over time exists in thoughts about end-of-life care in the icu. the purpose of this study is to know changing methods: a questionnaire survey, which consists of questions with optional answers related to the thoughts of participants about end-of-life care of hopeless or brain death patients, was performed to nurses and doctors in our icu. the questions were; whether accept to withdraw therapy or not and with family's will, whether positive or not to donate of organs from brain death patient, necessary of icu care for brain death patient, feel guilty and stress for doing stop or withdraw therapy. the optional answer has gradations from 'yes' to 'no' for all questions. it was guaranteed to be anonymous for them in the data analysis. we conducted entirely same survey in . the answers between in and in were fig. (abstract p ) . patient mental compentency by region kidney disease: improving global outcomes acute kidney injury working group references nice clinical guidelines: idiopathic pulmonary fibrosis in adults: diagnosis and management references . zambon et al annual update in inten care references references references damage control management in the polytrauma patient crash- trial collaborators guidelines for the management of severe traumatic brain injury references references references . soar et al; european guidelines for resuscitation we acquired the confirmed date of death from the finnish population register centre database and gross -month healthcare costs from the hospital billing records and the database of the finnish social insurance institution. results: a total of patients were included in the study and were alive at months. median (interquartile range, iqr) -hour sofa score was ( - ) in -month survivors and ( - ) in non-survivors. the sofa score had an area under receiver operating characteristic curve of . ( % ci . - . ) for predicting -month mortality. in multivariate regression model with age and gender, sofa score had an odds ratio, or ( % confidence interval, ci) of . ( . - . ) for predicting -month mortality. all except cardiovascular sub-score also had p predictive factors for secondary icu admission within hours after hospitalization in a medical wards from the emergency room m cancella de abreu hôpital saint antoine p acquired neuromuscular weakness in eldery patients with femoral bone fracture, could we decrease the incidence? d pavelescu, i grintescu, l mirea emergency hospital floreasca p adasuve enables quicker dispositions of acute psychiatric patients in the emergency department k hesse , e kulstad , k netti , d rochford isi web of science and clinicaltrials.gov. data extraction: eligible studies were case reports and randomised controlled trials (rcts) that evaluated the effects of drug incompatibilities in critically-ill patients on morbidity or mortality as primary or secondary outcomes, or adverse events. two investigators independently reviewed the eligibility of the study from abstracts or manuscript data. data synthesis: twelve articles met the selection criteria (fig. ). the six articles reporting rcts concern only four rcts. rcts were single-centre studies comparing infusion with or without filter. two of them included adult patients. the others included pediatric and neonatal intensive care unit patients. primary endpoints were systemic inflammatory response syndrome (sirs), organ failure, overall complication rate, bacteremia, sepsis, phlebitis and length of stay. results: the results are mixed with one rct reporting a reduction in sirs, organ failure and overall complication rate, two studies in disagreement over the occurrence of sepsis and one study reporting no impact on length of stay. the six articles on case reports show different drug incompatibility situations european directorate for the quality of medicines & healthcare of the council of europe. guide to the quality and safety of organs for transplantation p current status and problems of organ transplantation before and after the enactment of the revised organ transplant law in p morale: introducing the anaesthetic trainee confession session results: of total patients admitted during study period, were eligible for study; . % were males and ( %) patients were transferred during after-hour. mean age of two groups (daytime vs. after-hour . ± . vs. . ± . years) was similar(p= . ) methods: retrospective analysis of prospectively collected data between october to february of a tertiary care icu in india. patient data collected on all consecutive icu admissions. primary and secondary outcomes were icu los and hospital mortality respectively. icu patients payer status were categorized as self-paid, corporate (paid-fully or partially-by-employer), and insurance (paid-fully or partially-by-third-party-payer). all analyses were adjusted for illness severity and icu support (vasopressor use, mechanical or noninvasive ventilation, blood transfusion). results: of patients admitted during study period significantly higher number of patients received icu support in self-paid and corporate groups compared to insured group ( . %and . % vs. . %; p= . ) braden scale is predictive of mortality in critically ill patients, independent of its efficiency as a predictive tool of pressure ulcer risk d becker , tc tozo discharged and died ( . %). the turnover rate of the icu was . . the occupancy rate calculated during the period was . %. there were only readmissions ( . %) within hours of admission. regarding the hospital evolution of these patients we had exits in this period, ( . %) were discharge and ( . %) were deaths, of these, ( . %) were after discharge from the icu. the mean saps score was . (ranging from to ). the probability of death, according to the standard equation was . % and the adjusted for latin america of . %. conclusions: the icu has a high occupancy rate and rotation turnover, as well as a higher mortality than predicted by the score. these indicators show the great population demand that we have and alert to the impact on the sustainability of the unit and patient safety methods: research/ethics approvals were obtained. surveys, interviews, round tables, targeted delphi exercises and non-participant observation were conducted across four adult critical care units, involving professionals. these methods were used to describe the baseline 'paper-based' workflow/inter-professional communication systems; and semi-quantitative quality improvement measures. secondly, critical care services worldwide were visited to generate a database of experience, lessons and models of optimised informatics delivery. results: key challenges at baseline in relation to workflow/communication information transfer between different healthcare professionals site visits revealed the importance of human resources; lead time technology advances; the prioritisation of nursing workflow and pharmacy medicines/prescribing database creation/testing and the importance of the hardware interface and ergonomics. improvements included patient safety/experience p work-related stress amongst doctors and nurses in intensive care, a&e, acute medicine, anaesthetics and surgery i lever *, h nawimana introduction: work-related stress is associated with anxiety, depression, days off-work, errors and 'near misses' [ ]. our objective was to references . kerr et al p pre-existing cognitive dysfunction in critically ill patients and the incidence of delirium during icu treatment p validation of the sos-pd scale for assessment of pediatric delirium: a multicenter study e ista , b van beusekom children's hospital, rotterdam, netherlands; umc groningen -beatrix children's hospital p introduction: delirium in critically ill children has gained attention in the last few years and the incidence seems higher than anticipated before. the sophia observation withdrawal symptoms-pediatric delirium (sos-pd) was developed to combine assessment of delirium with iatrogenic withdrawal syndrome, two conditions with overlapping symptoms. the current study evaluates the measurement properties of the pd component (pd-scale) of the sos-pd scale. methods: in a multicenter prospective observational study in four dutch picus, patients aged months to years and admitted for more than hours were included. these patients were assessed with the pd-scale three times a day. criterion validity was established: if the pd total score was or higher the child psychiatrist was consulted to confirm the diagnosis of pd using the diagnostic and statistical manual-iv criteria as the "gold standard". the child psychiatrist was blinded to outcomes of the pd-scale. in addition, the child psychiatrist assessed a randomly selected group of patients to establish false-negatives the pediatric delirium scale had an overall sensitivity of . % and a specificity of . % for a cut off score of points. the positive predictive and the negative predictive value were respectively, . % and . %. the icc of paired nurse-researcher observations was . ( % ci . - . ). in total patients were diagnosed with delirium during the picu stay. conclusions: the pd scale shows a good validity for early screening of pd. so, the pd scale is a valid and reliable tool for nurses to assess delirium in critically ill children p frequency, risk factors and symptomatology of iatrogenic withdrawal from opioids and benzodiazepines in critically ill neonates, children and adults: a systematic review of clinical trials ma duceppe , m perreault we also examined the grey literature. we included studies reporting frequency, risk factors or symptomatology of iatrogenic withdrawal of opioids, benzodiazepines (or both) in critically ill patients. we considered all study designs except case reports and case series. pairs of reviewers independently abstracted data and evaluated methodological quality using the cochrane collaboration tool, newcastle-ottawa or quadas- . pros-pero (registration number: crd ). results: we identified unique citations through database search and full-texts were assessed for eligibility. thirty-three studies were included; the majority were observational and only a few included adults proportion of perfused small vessels at to p use of methadone in critically ill patients p the use of intranasal fentanyl versus parenteral opioid for acute pain relief in adults: systematic review and meta-analysis p sleep disorders in icu survivors c alexopoulou, a proklou p impact of dexmedetomidine on the duration of invasive mechanical ventilation in pediatric intensive care patients -dexped trial m genest peri-operative dexmedetomidine in high risk cardiac surgerymulticentre randomized double blind placebo controlled pilot trial y shehabi we compared vasopressors, inotropes, pacing and cardiac complications for safety and severe acute kidney injury (aki), dialysis and death (major adverse kidney events make) for efficacy. methods: adults patients undergoing cardiac surgery [combined (valve + coronary bypass) or complex] or with preoperative glomerular filtration rate (egfr) < mls/min/ . m were included. salvage or transplant surgery, dialysis, egfr < mls/min/ . m and those on extracorporeal support were excluded. dex ( . ug/kg/hr) was started at induction of anaesthesia and continued up to hours after surgery. equivalent volume of saline was given to control group. standard intra and post-operative care was provided. results: we randomized patients in the dex group and in the placebo (pgp). the mean(sd) age . ( . ) and egfr . ( . ) in all patients. no significant differences at baseline. in the dex, . % underwent complex surgery vs . % pts in the pgp. the mean(sd) bypass time and aortic clamp was comparable ( ) and ( ) min. the vasopressor requirements methods: nine tracheostomized copd patients ready to be weaned from ventilation were enrolled.for each patient, the sleep architecture was studied by polisomnography (sleep profiler-advanced brain monitoring) performing recordings:basal registration, continuos infusion of propofol or dexmetomidine from pm to am. rass target was - /- . results: the mean dose was . mg/kg/h for propofol and . mcg/ kg/h for dexmedetomidine.quantitative analysis showed, a statistically significant longer total sleep time (tst) and less sleep fragmentation (awakenings/hour) using dexmedetomidine. qualitative analysis showed non statistical differences between the two regimens: longer n and n stage with propofol and a longer n and rem phase with dexmetedomidine. furthermore, a reduced number of dosage adjustment was needed during dexmedetomidine sedation methods: a -year prospective observational cohort analysis was performed. all patients consecutively admitted to the medical or surgical icu or burn unit of a university hospital with an icu-los of >= days were included. qol was assessed at baseline (bl) and at months (m), year (y) and lt (median . years (iqr . - . )) after icu discharge with eq- d and sf- surveys. at lt, questions about daily life were added. in subanalysis, we compared groups (g and g ) based on median icu-los. results: patients ( % men) with a median age of , an apa-che ii score of and a sofa score of at icu admission were included. patients ( . %) were lost to follow-up. median icu-los in the cohort, g and g was (iqr - ), (iqr - ) and days (iqr - ) respectively. during icu stay, g had significantly more and longer need for any type of organ supportive therapy (p< . ) and had higher maximum sofa scores (p< . ). icu, hospital, m, y and lt-mortality rates in the cohort were , , , and % respectively. these rates were similar in g and g and the outcomes were assessed by telephone interviews at month after discharge. factors associated with readmission and post icu mortality are presented as odds ratios. results: during the study period, elderly patients were discharged alive. the follow up was possible for ( . %) patients. predictors of one-month readmission in univariate analysis were coronary disease (p= . ), sapsii (p= . ) and decline in functional status (p= . ). in multivariate analysis ) were the independent predictors of early readmission. mortality rate at month was . %. risk factors of onemonth mortality in univariate analysis were sapsii (p= . ), heart rate at discharge (p= . ), world health organization(who) performance status at discharge (p= . ) and decline in functional status (p= . ). in multivariate analysis p= . ), decline in functional status (or, . ; %ci comorbidities don't have an important impact on short term outcome after critical illness, which is most strongly predicted by severity of illness and physiological reserve at discharge. p characteristics and outcome of elderly patients in intensive care unit i coelho health inequalities & people with learning disabilities in the uk: emerson & baines cipold p comparison of home and clinic follow-up visits after hospital discharge for post-icu patients: a cross-sectional study r rosa , c robinson , p berto , p cardoso , l biason in a post-icu follow-up service which is reference for tertiary hospitals in southern brazil. post-icu patients with a icu stay > h (for medical and emergency surgical icu admissions) or > h (for elective surgical icu admissions) who were discharged alive from the hospital were invited by telephone to participate in a clinic-based multidisciplinary appointment months after icu discharge. home visits were offered to patients who claimed impossibility to attend the clinic appointment due to the severity of their disabilities graph of total mortality in ld vs all patients fig. (abstract p ). graph of admission age in ld vs all patients references p evaluation of family satisfaction instrument in multicultural middle eastern critical care units a p breaking bad news in the emergency department: a randomized controlled study of a training using role-play simulation i bragard , jc servotte , i van cauwenberghe p introduction: this is a randomized controlled study aiming to assess the impact of an e-learning and a -hour role-play training in breaking bad news (bbn) each assessment included a video-recorded role-play with two actors playing the role of relatives, and questionnaires. two blinded experts rated the videos. results: out of participants, % were trainees and % were anaesthesia residents. eg (n= ) and cg (n= ) were not different at baseline on the several variables. there were significant group and time interaction effects. only eg increased their selfefficacy p deficits of end-of-life care (eolc) perceptions among physicians in intensive care units managed by anesthesiologists in germany m weiss , a michalsen , a toenjes p ethicus end-of-life practices (eolp) in worldwide intensive care units (icus)-the ethicus ii study a avidan p multidisciplinary team perceptions about terminal extubation in a teaching hospital in brazil s p changing thoughts about end-of life care in the icu; results of a survey the feel guilty for withdraw therapy in nurses was also significantly decreased in years ( % vs. %, p< . ). conclusions: some of end-of-life thoughts in the icu were shown differences in nurses compared with years ago introduction: workload resulting from in-flight emergencies has not been quantitatively analysed in the literature. for hospitals local to major airports, this may have significant financial implications. methods: review was carried out of all cases admitted to east surrey hospital from gatwick airport over a year period beginning in . data were collected by interrogating the icnarc database. demographics, presenting pathology and length of stay for each patient were recorded. in addition, the cost of care for patients admitted during was calculated using recent median figures for intensive care admission (local ccg rates). results: since , patients were admitted from gatwick airport. this was approximately % of our critical care admissions. the mean (sd) age was . ( . ) years, and the median [iqr] length of stay [ . - . ] days. around % of these patients were non-uk or eu nationals and therefore not entitled to nhs care. reasons for admission included cardiac ( . %), respiratory ( . %), central nervous system ( . %), and gastrointestinal issues ( %). during , patients were admitted resulting in a total of . patient days in critical care. the total cost attributable to this group of patients was calculated to be £ , . conclusions: there is a substantial additional financial burden on hospitals that regularly receive admissions from major airports simply due to their geographical location. there is no additional funding available for providing this service. the pattern of presenting conditions in our population is similar to that seen in previous reports describing inflight emergencies [ ]. given the increasing accessibility of air travel and the economic pressures on healthcare providers, further analysis of the financial impact of this patient group on certain hospitals would be welcome. methods: we developed a monte-carlo simulation [ ] with separate referral rates for emergency, elective, and ventilated patients. bed occupancy is classified according to admission type with a conversion to prolonged ventilated stays at a rate of % [ ]. we used data from our neurointensive care unit to complete the parameters required for the model e.g. beds and , referrals/day. outcome measures were bed occupancy, and failed admissions. we tested two scenarios: increased referral rate ( . /day), and increasing to beds. results: the model simulated our intensive care where we have a high occupancy rate. increasing referral rate led to a consumed icu and an increase in failed admissions (fig. ) . lastly, increasing bed numbers eased pressures with fewer failed admissions. conclusions: we recommend a personalised icu monte-carlo population model for specialist units for a more accurate representation of icu bed occupancy. these icu specific models should be more useful for predicting staff, bed and financial requirements in specialist units where healthcare resources are changing e.g. increasing geographical referral radius. conclusions: better patient flow increased occupancy and standards. staff education and clear protocols are needed to improve patient booking and efficiency. assess stress levels and causes of stress among doctors and nurses at university hospital lewisham and queen elizabeth hospital woolwich. we surveyed staff using uk health and safety executive's management standards (hsems), a -question validated tool which identifies stressful work conditions requiring intervention. methods: we conducted an anonymous survey of doctors and nurses working in intensive care, accident and emergency (a&e), acute medicine, anaesthetics and surgery over six weeks. results were analysed using the hsems analysis tool and broken down into seven areas: job demands, managers' support, peer support, relationships, role, level of control and possibility of change. each area was scored from - ( represents lowest stress). we compared the trust's results against national standards. results: healthcare professionals completed the survey. intensive care had the lowest stress levels and scored above average in all areas (n= , mean . , s.d. . ). this was followed by a&e (n= , mean . , s.d. . ), anaesthetics (n= , mean . , s.d. . ), surgery (n= , mean . , s.d. . ) and acute medicine (n= , mean . , s.d. . ) which had the highest stress levels. when compared to hsems targets peer support exceeded national standards. however, there is a clear need for improvement in staff's ability to control and change their working environment. conclusions: stress levels on intensive care were reassuringly low when compared to other departments as well as national standards. we identified areas that need improvement and with the support of hospital management we will initiate hsems-validated measures to reduce stress. p tools for sepsis-associated mortality in hematological patients and should be studied in larger cohorts.conclusions: our results present clinical data of protocolized pbto -targeted therapy and show that there is room for further optimization. a larger cohort with predefined interventions is needed to proof the effect on longterm outcome after sah. impact of phone cpr on rosc outcome a giugni , s gherardi , l giuntoli introduction: early cardiopulmonary resuscitation (cpr) improves survival in out-of-hospital cardiac arrest, and phone-cpr instructions can increase the number of victims receiving cpr before emergency medical service (ems) arrival. little is known about the impact of cpr phone instructions on the outcome of patients (pts) with return of spontaneous circulation (rosc). the target of this study is to investigate the impact of phone instructions on mortality, and on neurological outcomes of patients who survived an out-of-hospital cardiac arrest. methods: we enrolled pts admitted to icu after rosc following out-of-hospital-cardiac-arrest, from / / to / / ; pts younger than , in-hospital cardiac-arrest-victims, pts who underwent cardiac arrest in health facilities, and missing data records were excluded. written informed consensus was obtained for all pts during follow up. data about comorbility, mortality, neurologic outcome, cpr timing according to utstein style, complications in icu, metabolic state on er admission, were collected. study population was divided into two groups for statistical analysis: pts with immediate cpr guided by phone instructions (phone-cpr group) and those who did not underwent immediate cpr by laic bystanders. data were extracted from icu, ems databases and registered ems phone calls. results: pts met study criteria. phone cpr were given in cases, % of the whole study population. results are summarized in tables and conclusions: phone-cpr significantly reduced cpr-free interval. it correlates with a significative increase in shockable rhythms on ems arrival. there is no significative reduction in mortality and in disability, even if a decrease trend can be observed. phone-cpr seem to be a promising, effective and easy to use tool to improve survival and disability in rosc, and should be widely applied. early hemodynamic complications in cardiac arrest patients-a substudy of the tth- study j hästbacka introduction: our aim was to determine the incidence and severity of hemodynamic complications during therapeutic hypothermia and analyze whether these complications can be predicted from data available on admission. methods: this is a substudy of the tth- study, where cardiac arrest (ca) patients were randomized to receive therapeutic hypothermia treatment for either or h [ ] . hypotension within four days from admission was recorded and defined as mild, moderate, severe or circulatory failure. arrhythmias were recorded and classified as mild, moderate or severe. we calculated the incidence and distribution of severity of the events. we used multivariate logistic regression analysis to test association of admission data with any hypotension or any arrhythmia. results: of all patients, . % had hypotension which was mild in . %, moderate in . %, severe in . % cases. . % had circulatory failure. an arrhythmia was present in % of patients. of these, . % were mild, % moderate and . % severe. bradycardia (n= ), new ca (n= ) and circulatory shock (n= ) were hemodynamic reasons for preterm rewarming. in multivariate analysis age (p= . , or . ) and admission map (p= . , or . ) were significantly associated with hypotensive complications. only use of mechanical compressions was significantly associated with risk for arrhythmia (p= . , or . ). conclusions: hypotension and arrhythmias were frequent in cardiac arrest patients during days - from admission, but mostly mild or moderate in severity. age and admission map were associated with hypotension. only the use of mechanical compressions was independently (negatively) associated with arrhythmias. introduction: in a retrospective study from the pittsburgh clinic, which analyzed survival data from patients admitted to a hospital with a cardiac arrest outside the hospital, it was found that patients with opioid overdose showed significant improvements in neurological status when discharged from the hospital compared with patients who did not receive opioids [elmer j. et al., ] . methods: after local ethic committee approval case-records of patients with cardiac arrest and subsequent resuscitation for the period - in the clinic of traumatology and orthopedics in astana were analyzed. criteria for inclusion in the study were hospital cardiac arrest, trauma to the musculoskeletal system. results: out of case-records, ( . %) patients with out-ofhospital cardiac arrest were excluded. among all hospital stops of blood circulation, we found only successful cpr ( . %). among the patients who were successfully resuscitated, groups were identified: i - patients ( %) who received ketamine or/and opioids before the blood circulation stopped ( - minutes); ii - patients ( %) who did not receive these medicines. the mean age in group i of patients was . ± . years, in group ii - . ± . years (p> . ). patients of the second group had an average life expectancy of . ± . days, with a maximum postresuscitation life of days. patients of the first group were in the hospital for . ± . days (p < . ), with a maximum period of days. in the first group, the final neurologic evaluation according to the glasgow scale was . ± . points, while in the second group it was . ± . points (p < . ). conclusions: a retrospective analysis revealed a better survival and neurological outcome in patients who received ketamine or/and opioids before circulatory arrest.introduction: the revised organ transplant law was enacted in japan in . under the revised law, it is now possible to donate organs with the consent of the family even if the intention of the potential donor is unknown. organs from brain-dead children under the age of can also be donated. methods: the aim of this study was to assess how to provide prompt transplant medical care and improve the donor's condition. this was achieved by clarifying the problems encountered in the process leading to brain-dead organ transplantation at our institute before and after the enactment of the revised organ transplant law. there were cases of organ donation at our institute from january to june . among them, the background factors of cases leading to organ donation were examined. results: the causes of the brain-dead condition were cerebrovascular disease (n = ; subarachnoid hemorrhage, intracerebral hemorrhage), trauma (n = ), suffocation (n = ), cardiopulmonary arrest on arrival (n = ), suicide by hanging (n = ), cardiomyopathy (n = ), and lethal arrhythmia (n = ). the organs donated for transplantation were kidneys, eyes, lungs, livers, hearts, and tissues (i.e., heart valve, bone, and skin). the time lapses were as follows. the number of days from informed consent to family acceptance was . days before the enactment of the revised organ transplant law and . days after the revision. the number of days from informed consent to organ removal was . days before the revision and . days after the revision. even after the enactment of the revised organ transplant law in japan, it still takes about days from informed consent to organ removal, with no current initiatives to shorten the time to organ removal. conclusions: although years have passed since the enactment of the revised organ transplant law in japan, there are still administrative and management problems that need to be addressed to achieve optimal organ transplantation. the financial impact of proximity to a major airport on one critical care unit introduction: in septic patients, increased plasma levels of cell-free hemoglobin (free-hb) are associated with a reduction of perfused vessel density (pvd) of sublingual microcirculation and to adverse outcomes caused by hemoprotein-mediated lipid peroxidation. recent studies show that acetaminophen protects from damage due to lipid peroxidation in sepsis [ ] . the aim of this study is to detect changes in sublingual microcirculation after the infusion of a standard dose of acetaminophen in febrile septic patients. methods: prospective observational study on adult septic patients admitted to our intensive care unit. pre-infusion (t ), minutes (t ) and hours (t ) after the end of the infusion of acetaminophen, sublingual microcirculation was assessed with incident dark field illumination imaging; vital signs, plasma levels of acetaminophen and free-hb were assessed. results: preliminary descriptive analysis on the first patients shows a median sequential organ failure assessment (sofa) score of (interquartile range iqr - ) and baseline temperature of , c°( iqr . - °c). an increase of the proportion of perfused vessels (ppv) was evident both at t and t ( introduction: in common sedation is required during mri for adult uncommunicative patients or those with different psychiatric disorders [ ] . although it can be challenging to obtain the deep sedation level required to prevent the patient's movement while maintaining respiratory and hemodynamic stability. limited access to the patient may pose a safety risk during mri. objectives: to compare efficacy and safety of dexmedetomidine sedation versus propofol during mri in adults.methods: this prospective randomized study was conducted at department of anesthesiology and intensive care at postgraduate institute of bogomolets national medical university (kyiv, ukraine) during - . uncommunicative conscious patients with acute ischemic stroke were included in the study and randomly allocated to groupsdexmedetomidine (d) and propofol (p). the sedation goal was the same in the both group (rass to - ). patients in group d receive dexmedetomidine infusion in dose . conclusions: in this prospective randomized study dexmedetomidine comparing to propofol was associated with higher sedation quality and lower incidence of complication during acute ischemic stroke patients sedation for mri. the usefulness of dexmedetomidine after lung transplantation in intensive care unit. introduction: dexmedetomidine (dex) showed some advantages in the sedation of patients in intensive care unit (icu) [ ] . other studies described efficacity of dex in icu delirium [ ] . the aim of this study was to evaluate the efficacity and safety of dex after lung transplantation in icu. methods: we conducted a prospective monocentric study in our surgical icu between november at november . in the first part of the study (november at november ), lung recipients did not received dex; in the second part of the study dex was used for the sedation in mechanically ventilated patients after lung transplantation. we compared the duration of mechanical ventilation in the two groups and the occurence of adverse effects. results: in total lung recipients were enrolled. there was no difference between the two groups in demographic data, one or double-lung transplants, the cause of lung transplantation and the use of epidural infusion. in the dex group, mechanical ventilation support was hours versus . hours in the other group (p= . ). there was no difference between delirium in the two groups ( / , p= . ). the occurence of adverse events like hypotension and bradycardia was significantly higher in the dex group ( / for hypotension, p= . ; / for bradycardia, p= . ). conclusions: the use of dex after lung transplantation in icu was not more efficience for the mechanical ventilator weaning. lung recipients delirium was significantly the same in the two groups. the most notable effect was the occurence of bradycardia and hypotension in the dex group.introduction: dexped evaluated the impact of a prolonged exposure (>= hours) to dexmedetomidine on the duration of invasive mechanical ventilation (imv), length of picu and hospital stay and use of other sedative agents. methods: dexped is a retrospective cohort study that included patients aged to years, admitted to the picu of the montreal children's hospital between november st and april th , requiring imv and sedative agents for >= hours. patients exposed to dexmedetomidine during imv (n= ) were compared to non exposed patients (n= ) using a propensity score analysis ( : ratio). , and received more opioids and benzodiazepines. however, a secondary analysis redefining exposure as initiation of dexmedetomidine within the first hours from intubation suggested that exposure was associated with a greater short-term probability of extubation, although this study was not powered to perform this analysis. conclusions: dexmedetomidine was associated with a longer duration of imv. however, the association was inversed when patients received dexmedetomidine as a primary sedative agent. it is uncertain whether this difference of associations is due to immortal time bias or clinical features. timing of initiation of dexmedetomidine in relationship to other sedatives may impact patient outcomes and should be considered in the planning of future trials. is an α -agonist which has been increasingly used for analgosedation. despite of many papers published, there are still only a few concerning the pk of the drug given as long-term infusion in icu patients. the aim of this study was to characterize the population pharmacokinetics of dex and to investigate the potential benefits of individualization of drug dosing based on patient characteristics in the heterogeneous group of medical and surgical patients staying in icu. methods: all the subjects were sedated according to modified ramsay sedation score of - . blood samples for dex assay were collected on every day of the infusion and at the selected time points after its termination. the dex concentrations in the plasma were measured using lc-ms/ms method. the following covariates were examined to influence dex pk: age, sex, body weight, patients' organ function (sofa score), catecholamines and infusion duration. non-linear mixed-effects modelling in nonmem (version . . , icon development solutions, ellicott city, md, usa) was used to analyse the observed data. results: concentration-time profiles of dex were obtained from adult patients ( table ). the dex pk was best described by a twocompartment model (fig. ) . the typical values of pk parameters were estimated as l for the volume of the central compartment, . l for the volume of the peripheral compartment, . l/h ( . ml/min/kg for a kg patient) for systemic clearance and . l/h for the distribution clearance. those values are consistent with literature findings. we were unable to show any significant relationship between collected covariates and dex pk. conclusions: this study does not provide sufficient evidence to support the individualization of dex dosing based on age, sex, body weight, sofa, and infusion duration. seems to reduce the wakefulness time and the sleep fragmentation but, while we haven't found differences in sleep architecture using dexmedetomidine or propofol. introduction: the early mobilization program during intensive care hospitalization presents numerous benefits related to the outcome of the patient. the objective of this study is to evaluate the safety of the implementation of an early mobilization protocol within the first hours of admission and its impact on high functional status of the icu. methods: retrospective study, from march to may , evaluating patients admitted to the neurological icu, assessing the hemodynamic, respiratory and neurological variables in patients submitted to the early mobilization program, consisting of progressive therapeutic activities, including sedestation and orthostatism assisted on the board and evaluated the impact on the functional status/degree of high muscle strength of the icu. results: from march to may , , patients were admitted to a neurological intensive care unit, of whom , were included in the early mobilization program. the mean age of the patients was . years, with saps of . points (estimated mortality risk of . %) and real mortality of . %. during the program, % presented clinical instability, which was promptly reversed in all situations. ninety-one percent of the patients presented maintenance or gain of muscle strength/functional status. conclusions: the application of an early mobilization program within hours of patient admission was shown to be safe, positively influencing the rehabilitation of neurological patients. introduction: given the worldwide rapidly aging of the population, the demand of critical care for elderly is increasing. data on short -term outcomes of elderly patients after icu discharge are sparse. the objective of our study was to assess short term outcomes of elderly after icu discharge and their potential risk factors.introduction: patients aged years or older presently account for approximately - % [ ] of all intensive care unit (icu) admissions in europe. the major challenge nowadays is to admit those elderly patients who will benefit from icu treatment. the objective of this study is to describe the characteristics and outcomes of patients >= years old admitted to the icu. methods: retrospective observational study of all patients aged >= years admitted for > h in . demographic data, admission diagnosis, apache ii and saps ii scores, use of icu resources and mortality were collected. results: patients ( %) were included, with a mean age of , . female gender was more prevalent ( . %). mean length of stay was , days with mean saps ii and apache ii scores of , and , respectively. the most prevalent type of admission was medical, , % (n= ) and from these the main reasons for admission were respiratory disease (n= ; , %) and sepsis (n= ; %). icu mortality rate was , % (n= ), whereas -month mortality was , % (n= ).survival rate was often related with cardiovascular ( [ , %], p<. ) and respiratory diseases ( [ %], p=. ), whereas nonsurvivors were admitted due to sepsis and neurologic causes. mortality rate was independent from the mean length of stay, noninvasive ventilation and renal replacement therapy, but dependent for previously comorbidities. mechanical ventilation was an independent predictive factor of icu mortality (p<. ) and -month mortality (p=. ). conclusions: nearly % of patients aged >= years were discharged alive from icu, and less than % survived months after icu admission.our study revealed a better prognosis for admissions due cardiovascular and respiratory diseases. efforts should be done to identify earlier septic and neurological patients that benefit icu treatment, and reevaluate the critical patient pathway, in this special population.conclusions: more than % of icu-survivors returned to work. overall, the chance of return to work within two years was independent of the number of organ support therapies in patients with at least one organ support therapy. however, in subgroups, the chance of return to work decreased with increasing number of organ-support therapies. factors associated with non-return to work among general icu survivors: a multicenter prospective cohort study r rosa introduction: critical care patients may develop long-term health problems associated to their illness or icu treatments, which may affect their work capacity. unfortunately, studies evaluating the impact of critical illness on work-related outcomes are scarce.therefore, we aimed to investigate factors associated with non-return to work among icu survivors. methods: a prospective cohort study involving icu survivors of brazilian tertiary hospitals was conducted from may to august . patients with a icu stay > h (for medical and emergency surgical icu admissions) or > h (for elective surgical icu admissions) who were discharged alive from the hospital were evaluated through a structured telephone interview months after discharge from the icu. a stepwise multivariate poisson regression analysis adjusted by age, gender and years of education was used to evaluate the association of sociodemographic-and icu-related variables with nonreturn to work. results: in total icu survivors completed the -month follow-up. of these, ( %) were working before icu admission. only of patients ( %) returned to work within the first months after discharge from the icu. percentage of risk of death at icu admission (relative risk [rr], . ; % confidence interval [ci], . - . ), decrease in physical functional status in relation to the pre-icu period measured by barthel index (rr, . ; % ci, . - . ), not having a introduction: the aim of this study was to assess the accuracy of physician's prediction of hospital mortality in critically ill patients in an intensive care unit (icu) scarcity setting. methods: prospective cohort of acutely ill patients referred for icu admission in an academic, tertiary hospital in brazil. physicians' prognosis and other variables were recorded at the moment of icu referral. results: there were analyzed referrals. physician's prognosis was associated to hospital mortality. there were ( . %), ( . %) and ( . %) deaths in the groups ascribed a prognosis of survival without disabilities, survival with severe disabilities or no survival, respectively (p< . ) (fig. ) . sensitivity was %, specificity was % and the area under the roc curve was . for prediction of mortality. after multivariable analysis, severity of illness, performance status and icu admission were associated to an increased likelihood of incorrect classification, while worse predicted prognosis was associated to a lower chance of incorrect classification. physician's level of expertise had no effect on predictive ability. conclusions: physician's prediction was associated to hospital mortality, but overall accuracy was poor, mainly due to low sensitivity to detect mortality risk. icu admission was associated to increased incorrect classification, but there was no effect of physician's expertise on predictive ability. what are physicians in doubt about? an interview study in a neuro-intensive care unit. introduction: inescapable prognostic uncertainty, lack of decisionmaking capacity, risk of death or disability and long recovery trajectories complicate decision-making after traumatic brain injury. methods: to elicit experienced physicians' perspective we interviewed neurosurgeons, intensive care-and rehabilitation physicians from oslo university hospital about being in doubt about whether to offer, continue, limit or withdraw life-sustaining treatment and on how such cases were approached. interviews were audiotaped and transcribed verbatim, coded and analysed using systematic text condensation by a clinician (ar) and a medical ethicist (rf). results: the difficulty of decision-making when there is prognostic uncertainty was acknowledged, leading to adaptive approaches; willingness to change and adjust plans along the way. to have access to different opinions within the physician group was seen as constructive. time-critical decisions were based on team discussions and physician's discretion. none-time critical decisions were reached through a process of creating common ground between the medical team and family. themes physicians where in doubt about or expressed different opinions towards: ) appropriate aggressiveness of treatment in a given situation. ) if and when to initiate discussions on appropriateness of treatment. some believed that even addressing the issue in young patients or if small improvements were seen was inappropriate due to the possibility of late recovery. physicians questioned the value of previously expressed patient's wishes in this context. ) optimal timing and type of decisions. the need for nuanced individualized plans was recognized. to have a plan as opposed to just "wait and see" was seen as especially important in medical unstable patients. conclusions: physicians expressed different views on appropriateness and optimal timing of level of care discussions and decisions in traumatic brain injury. a need for a more structured approach was exposed. fig. (abstract p ) . association of physician's prognosis with hospital mortality (p< . ).introduction: this cross sectional study was designed to investigate the level of family satisfaction in intensive care units in a tertiary hospital in the united arab emirates (uae), which is a multicultural society methods: family members of patients who were admitted to intensive care unit for more than hours or over were included in the study. families were approached with a validated fs -icu family satisfaction survey questionnaire [ ] . one hundred questionnaires were collected over a period of months from january to march in our pediatric medical surgical and cardiac, adult cardiac and adult medical/surgical intensive care units. results: the overall level of satisfaction rate was comparable to other high-income and developed countries with total satisfaction score, medical care score and decision making score of . ± . , . ± . , and . ± . respectively (table ) . conclusions: this is the very first study from the uae demonstrating a high level of patient family satisfaction in both adult and pediatric intensive care units. this study also highlighted areas where further improvement needed to occur.introduction: in order to apprehend the structural aspects and current practice of end-of-life care (eolc) in german intensive care units (icus) managed by anesthesiologists, a survey was conducted to explore implementation and relevance of these items. methods: in november , all members of the german society of anesthesiology and intensive care medicine (dgai) and the association of german anesthesiologists (bda) were asked to participate in an online survey to rate items. answers were grouped into three categories: category reflecting high implementation rate and high relevance, category low implementation and minor relevance, and category low implementation and high relevance. results: five-hundred and forty-one anesthesiologists responded, representing just over / of anesthesiology departments running icu's. the survey revealed new insights into current practice, barriers, perceived importance, relevance, and deficits of eolc decisions. only four items reached >= % agreement as being frequently performed, and items were rated "very" or "more important". items attributed to category , to category , and to category , representing a profound discrepancy between current practice and attributed importance. items characterizing the most urgent need for improvement (category ) referred to desirable quality of life, patient outcome data, preparation of health care directives and interdisciplinary discussion, advanced care planning, distinct aspects of changing goals of care, standard operating procedures, implementation of practical instructions, continuing eolc education, and inclusion of nursing staff and families in the process. conclusions: the survey generated awareness about deficits in eolc matters in critical care. consequently, already available eolc tools have been made available through the website of the german society of anesthesiology and intensive care medicine (dgai): http:// www.ak-intensivmedizin.de/arbeitsforen.html.introduction: this study evaluated differences in eolp after years in european icus that also participated in the ethicus i study [ ] . methods: all previous ethicus i centers were invited to participate in the ethicus ii study. consecutive admitted icu patients who died or had treatment limitations during a month period from . . to . . were prospectively studied. previous eolp and region definitions were used [ ] . eolp in the different regions of the ethicus i study [ ] were compared to the same icus in the ethicus ii study. results: of the original icus participated again in this study. figure shows the differences in eolp by region. figure notes differences in patient mental competency at the time of decision, information about patient's wishes and patient discussions in both ethicus studies. conclusions: changes included less cpr (especially in the south) with more withholding and withdrawing therapies. there was a greater number of competent patients with discussions and knowledge of their wishes.introduction: palliative extubation is performed in patients with terminal ilnesses in which mechanical ventilation might prolong suffering. even though the procedure involves nurses, respiratory therapists and doctors, some professionals feel unconfortable performing a palliative extubation. the concept of withdrawing life support can be easily confounded with euthanasia, specially in low income countries, where there is usually less education on palliative care. methods: a questionary containing open ended questions concerning a hypotetical case of intracerebral hemorrhage and prolonged coma, with potential indication for palliative extubation was applied to members of an emergency department intensive care unit staff ( doctors, nurses, respiratory therapists (rt). results: more than half of the professionals ( %) had never participated in a palliative extubation. four professionals ( %) believed palliative extubation is euthanasia. when asked about their own preferences in such a situation, only two ( %) would like to be tracheostomized. symptoms anticipated by most professionals were dyspnea and respiratory secretions. four ( %) would feel very uncomfortable performing palliative extubation because they either felt to be killing the patient or unable to manage symptoms conclusions: most professionals in this tertiary emergency intensive care unit never witnessed a palliative extubation. however, most of believe this procedure is beneficial. some still cannot understand the difference between palliative extubation and euthanasia. education in palliative care and withdrawal of life support can be helpful to clear concepts and relieve moral distress in the team. key: cord- -o hr mox authors: nan title: proceedings of réanimation , the french intensive care society international congress date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: o hr mox nan rationale: expiratory muscles has recently been stated as the «neglected component» in mechanically ventilated patient. several authors stated these muscles importance in cough capacity, contractile efficiency of the diaphragm or reduction of hyperinflation. however, few studies reported potential factors leading to expiratory muscle weakness and its importance on weaning success or survival after mechanical ventilation. patients and methods: this study is a secondary analysis of our previously described cohort of patients ventilated for at least h assessed for respiratory muscles function. maximal expiratory pressure (mep) measurement was carried out during spontaneous breathing trial using a manometer with an unidirectional valve. mep diagnostic accuracy to predict icu-aw (icu acquired weakness), weaning success and sursvival within days were assessed using expiratory muscle strength as absolute values (cmh o), as %predicted values and as %lower limit of normal. results: due to the paucity of data reporting threshold value for expiratory muscle weakness, we considered our median value ( cmh o (iqr )) as the threshold value for expiratory muscle weakness group (mep ≤ cmh o) and normal expiratory muscle group (mep > cmh o). patients with low mep received more catecholamines (p = . ) and a higher duration of mechanical ventilation (p = . ). inversely, higher body mass index was associated with higher mep. patients with low mep presented more icu-aw compared to normal mep patients ( % vs. %; p = . ). no other outcomes were different between groups. mep was statistically able to predict icu-aw but area under (auc) receiving operating curves showed weak predictive ability (auc: . ( % ic . - . ; p < . ) for a threshold value ≤ cmh o. expiratory muscle weakness was unable to predict critical outcomes when adjusting mep to the %predicted or lower limit of normal. discussion: possible explanation is that contrary to inspiratory muscle weakness, cough inefficacy after weaning from mechanical ventilation could be managed with cough supplementation techniques (i.e. mechanical in-exsufflation). conclusion: in our cohort, mep was not associated with mechanical ventilation weaning or death. despite our results, different clinical techniques for quantifying expiratory muscle weakness may provide more beneficial results. compliance with ethics regulations: yes rationale: venoarterial extracorporeal membrane oxygenation (va-ecmo) is used to support tissue perfusion during extracorporeal cardiopulmonary resuscitation (e-cpr). shock, resuscitation and the extracorporeal circuit may trigger a capillary leakage and a vasoplegic shock. currently, in these situations, high doses of norepinephrine (ne) are required. because high ne doses may have significant cardiovascular side effects, alternative options to support arterial blood pressure are needed. in recent years, several approaches to decrease the administration of high ne doses have been tested, one of them is the administration of vasopressin (avp). randomized trials have shown that avp infusion increases arterial pressure and systemic vascular resistance, decreases catecholamine requirements in patients with or at high risk of vasoplegic syndrome and attenuates vascular dysfunction. currently, no data are available for the study of the effects of avp in shock state in post refractory cardiac arrest. patients and methods: pigs were randomized into two groups, in order to receive avp or ne. a refractory cardiac arrest of ischemic origin was surgically created and va-ecmo was started after a min period of cardio-pulmonary resuscitation. then, resuscitation lasted h in each randomization group. the evolution of the consequences of the shock was evaluated by lactatemia and microcirculation (sdf and nirs) at baseline hour, h (when ecmo starts), h and h . renal and hepatic functions were assessed. results: experimental conditions were met for animals (avp, n = ; ne, n = ). the groups were comparable on the shock impact and its severity. no significant differences were found between populations for ecmo flow and map. there was a significant difference on fluid volume resuscitation amount ( [ . - . ] ml in the ne group versus ml in the avp group, p < . ) (fig. ). no significant difference between the ne and avp groups for lactate clearance between h and h ( . [− . to . ]% vs . [ . - . ]%, p = . ). we did not find any significant for sublingual microcirculation indices and nirs values. renal and liver function evolution were similar in the two groups during the protocol. conclusion: avp administration in refractory cardiac arrest resuscitated by va-ecmo when compared to ne is associated with less fluid volume for similar global and regional hemodynamic effects. compliance with ethics regulations: yes. patients and methods: a single-center prospective study. patients younger than months with severe bronchiolitis and supported by niv or hfnc were included. niv/hfnc was discontinued according to the local practices and no protocol existed. exceptt the principal investigator, the attending team was blinded to the study. weaning failure was defined as the need to reinstate niv/hfnc in the h after discontinuation. ethical approval was not necessary for this study in accordance with the french data protection autority methodology reference number mr- . results: a total of patients (median age days, ( %) males) were included. respectively, ( %) and patients ( %) were supported by niv and hfnc at admission (fig. ) . regarding the mode of niv, a bilevel mode was used in patients ( %) (fig. ). in patients supported by hfnc, the ventilatory support was discontinued progressively by decreasing air flow in patients ( %) while it was stopped abruptly in ( %). in patients supported by niv, the respiratory support was stopped abruptly in ( %) of them while hfnc was used as a weaning method for ( %) patients. a total of ( %) patients experienced a weaning failure. patients supported by niv/ hfnc who experienced a prompt weaning had a lower pediatric intensive care unit (picu) length of stay as compared to patients in whom hfnc was used as a weaning method ( ± h versus ± h, p = . ). however, the hospital length of stay was similar according to the weaning method ( ± days versus ± days for prompt and progressive methods respectively, p = . ). the duration of the weaning process did not differ according to the bed-availability in picu. in patients with severe bronchiolitis, a prompt weaning from niv/hfnc was associated with a lower length of stay in picu. however, the hospital length of stay was similar according to the weaning method. we suggest that a prompt weaning should be preferred in order to reduce the risk of picu related complications. compliance with ethics regulations: yes. information and incitation to open a twitter account and to follow critical care journal feeds) or group (control group). ict were interrogated on their recent medical literature knowledge at and month on trials published in pre-selected journals. results: during the study period, on the french ict contacted, agree to participate: were already on twitter, were randomized to twitter incitation and to control group. at month, there were who answered electronic questionnaire. self-declaration of article knowledge was not different between groups (p = . ). knowledge of primary outcome of each trial was not significantly better in groups (p = . ). in per-protocol analysis of ict on twitter or not, knowledge of article and primary outcome were also not significantly different (respectively p = . and p = . ). short incitation to open a twitter account and follow major medical journals with specific focus on cardiac arrest did not improve knowledge of medical literature by intensive care trainees at month. further trials are needed to better imply intensive care trainees in scientific medical literature. compliance with ethics regulations: yes. - . ] ; p = . ) as independently associated with in-hospital mortality ( fig. ). discussion: triple therapy is the recommended first-line treatment of caps. however, herein, it was not significantly associated with better survival in critically ill, thrombotic aps patients. for the subgroup of "definite/probable caps" patients, double and triple regimens were associated with survival. but the bivariable analyses including the day- saps ii showed that survival was linked to in-icu anticoagulation and corticosteroids-not ivig or plasmapheresis. our findings indicate that corticosteroids should probably be added to in-icu anticoagulation to treat "definite/probable caps". frequent fever and elevated c-reactive protein in all thrombotic aps patients suggest a marked inflammatory state that could explain corticosteroid efficacy. neither plasmapheresis nor ivig impacted the prognosis of "definite/ probable caps", but that finding could be explained by a lack of power compared to caps registry data. conclusion: in-icu anticoagulation was the only aps-specific treatment independently associated with survival for all patients. doublebut not triple-therapy was independently associated with better survival of "definite/probable caps" patients. in these patients, double therapy should be used as first-line therapy while the role of triple therapy requires further evaluation. compliance with ethics regulations: yes. motor deficiency ( %) ( %) ( %) . cognitive impairment ( %) ( %) ( %) . intra-individual relationships between Δpdi and tfdi for mechanically ventilated (mv) patients (a) and healthy subjects (c). relationships between Δpdi and tfdi when breathing cycles were averaged for all participants during each condition for mv patients (b) and healthy subjects (d). − %: initial settings minus % inspiratory help, + %: initial settings plus % more inspiratory help, pep : zero positive end-expiratory pressure, sbt: spontaneous breathing trial. healthy subjects performed spontaneousbreathing (sb) and ventilation against inspiratory threshold at , , , and % of maximal inspiratorypressure (mip) groups. airway closure occurrence increased with bmi ( %, % and %, p = . ). when present, airway opening pressure was . cmh o ( . - . ) and similar between the groups. with increasing bmi, total peep increased from . to . cmh o between groups (p = . ). all values of esophageal pressure increased with bmi. endexpiratory esophageal pressure was strongly correlated with bmi (rho = . , p < . ), as illustrated in fig. . consequently end-expiratory transpulmonary pressure decreased from − . to − . cm h o with increasing bmi (p = . ). the ratio of eelv to predicted functional residual capacity was negatively correlated with end-expiratory pressure (rho = − . , p = . ), but not with bmi. driving pressure and elastance of the respiratory system, chest wall and lung were similar across all ranges of bmi. likewise, eelv was similar between groups. conclusion: in ards, increasing bmi is associated with increased occurrence of airway closure and increased values of esophageal pressure. conversely, chest wall elastance is not influenced by bmi, as well as lung elastance. including bmi in interpreting respiratory mechanics in ards patients can provide additional information for the clinical management. compliance with ethics regulations: yes. rationale: low tidal volume is the cornerstone of protective ventilation inthe initial phase of ards ( ) . whether such low tidal volume can still be achieved when the patient is allowed to breathe spontaneously under pressure support ventilation (psv) is unknown. in moderate-tosevere ards patients receiving neuromuscular blockade, we assessed the tidal volume and its potential association with the outcome during the "transition period" following neuromuscular blockade. patients and methods: retrospective observational study in two university intensive care units. patients fulfilling moderate-to-severe ards criteria less than h after intubation and receiving neuromuscular blockers were included upon entry in the "transition period". we defined the "transition period" as the h following neuromuscular blockers cessation. ventilatory and hemodynamic parameters were recorded every h during the "transition period". primary outcome was the association between mean tidal volume under pressure support ventilation (psv) during the "transition period" and the -day mortality after adjustment for confounding factors. data are reported as median [ st- rd quartile] or number (percentage). results: one hundred nine patients were included, with a pao /fio ratio of mmhg at intubation and mmhg at inclusion and a sofa score at [ . - ] . patients had been ventilated days [ - . ] before inclusion. during the "transition period", patients ( . %) were switched to psv. the median duration of psv was h . the mean tidal volume under psv was significantly lower in survivors than in non survivors at day ( . ml/kg [ . - . ] vs. . ml/kg [ . - . ] respectively, p = . ). by multivariate analysis (cox proportional hazards regression model), mean tidal volume during psv remained independently associated with the -day mortality after adjusting for sofa score and immunosuppression. patients with a mean tidal volume above ml/kg under psv during the "transition period" had a lower cumulative probability of survival at day as compared with others (log rank test, p = . ) (fig. ) . conclusion: in patients with moderate-to-severe ards, a higher tidal volume under psv within the h following neuromuscular blockers cessation is independently associated with the -day mortality.compliance with ethics regulations: yes. kaplan-meier estimate of the cumulative probability of survival according to the mean tidal volume (vt)-lower of higher than ml/ kg-under pressure support ventilation (psv) during the "transition period" transfusion is associated with adverse events, and equipoise remains on the optimal transfusion strategy in oncologic patients in surgical setting. patients and methods: this is a retrospective, single center study. all adults admitted to the intensive care unit (icu) after oncologic surgery from january to december were eligible. the following types of surgery for cancer or metastasis resection with a high risk of bleeding were eligible: thoracic, abdominal, neurosurgery, gynecologic, urologic, otorhinolaryngology or spinal surgery. the primary outcome was a composite outcome including post-operative complications (respiratory, cardiac, renal, thromboembolic, infectious and/or hemorrhagic) and/or hospital mortality. results: of the patients included, patients ( . %) had anemia (based on the who definition: hemoglobin level - . g/dl for female; hemoglobin level - . g/dl for male), patients ( %) had moderate anemia (hemoglobin level: - . g/dl) and patients ( . %) severe anemia (hemoglobin level < g/dl). fifty-six patients ( . %) received at least one rbc transfusion during their hospital stay. patients exposed to moderate and severe anemia required more often renal replacement therapy (rrt) for acute kidney injury (aki) ( . % vs. . %; p = . ), had more surgery-related infections ( . % vs. . %; p = . ). patients who received rbc had more often aki with rrt ( . % vs. . %; p < . ), thromboembolic events ( . % vs. . %; p = . ), sepsis ( . % vs. . %; p = . ), pneumonia ( . % vs. . %; p = . ), surgical site infections ( . % vs. . ; p < . ) and second surgery for infection ( % vs. . %; p = . ). the multivariate analysis found an association between moderate and severe anemia (moderate anemia: or . [ . - . ] ; severe anemia: or . [ . - . ]; p = . ) and severe post-operative complications (fig. a) . there was also an association between rbc transfusion and severe post-operative complications ]; p < . ) (fig. b) . conclusion: anemia was frequent in oncologic surgical patients. anemia, including moderate anemia, was independently associated to patient outcomes; however, rbc transfusion also negatively impacts on patients' prognosis. our study highlights the need for further research to identify the optimal hemoglobin threshold for rbc transfusion in surgical oncologic patients. compliance with ethics regulations: yes. rationale: right ventricular (rv) failure is a common complication in moderate to severe acute respiratory distress syndrome (ards). rv failure is exacerbated by hypercapnic acidosis and overdistension induced by mechanical ventilation. veno-venous extracorporeal co removal (ecco r) might allow ultraprotective mechanical ventilation strategy with a low tidal volume (vt) and plateau pressure (pplat). this study investigated if ecco r therapy could have beneficial effects on rv function. patients and methods: this prospective monocentric pilot study was conducted in a french icu from january to march . patients with moderate to severe ards with pao /fio ratio between to mmhg were enrolled. ventilation parameters, arterial blood gases, echocardiographic parameters performed by transthoracic echocardiography (tte), low-flow ecco r system operational characteristics, outcomes and adverse events were collected during the protocol. primary end point was evolution of rv echocardiographic parameters with ultraprotective ventilation strategy at ml/kg pbw during the -h following the start of ecco r. results: eighteen patients were included. efficacy of ecco r allowed an ultraprotective strategy in all patients. we observed a significant improvement of rv systolic function parameters assessed by tte (fig. ). tricuspid annular plane systolic excursion (tapse) increased significantly under ultraprotective ventilation compared to baseline (from . to . mm; p < . ). systolic excursion velocity (s') also increased after -day protocol (from . m/s to . m/s; p < . ). a significant improvement of aortic velocity time integral (vtiao) under ultraprotective ventilation settings was observed. there were no significant differences in the values of systolic pulmonary arterial pressure (spap). when patients were separated in two groups according to baseline paco level above or under mmhg, we showed the deleterious effect of hypercapnia on rv function, and observed in both groups a beneficial impact of an ultraprotective ventilation strategy on tapse. no severe adverse events directly related to ecco r were observed in our small cohort. conclusion: the low-flow ecco r allows ultraprotective ventilation strategy and improve rv function in moderate to severe ards patients. similarly to prone positioning, ecco r could become a strategy that enables to reconcile lung protective approach with rv protective approach in ards patients. large-scale clinical studies, including patients with severe rv dysfunction, will be required to confirm these results and to assess the overall benefits, in particular the best timing of beginning ecco r in ards patients. compliance with ethics regulations: yes. rationale: bronchoalveolar lavage (bal) is usually deemed to allow the diagnosis of a large array of pulmonary diseases and is usually considered as well tolerated in intensive care unit (icu) patients. however, recent data suggest that the diagnostic yield of bal could be rather low ( ) , and may question its innocuity ( ) . the present study aimed at assessing the benefit-to-risk balance of bal in icu patients. patients and methods: the study was approved by the appropriate ethics committee and registered with clinicaltrials.gov (nct ). in icus, from april to october , we prospectively collected adverse events (ae) during or within h after bal and assessed the bal input for decision-making in consecutive adult patients. aes were categorized in grades of increasing severity. the occurrence of a clinical ae at least of grade , i.e. sufficiently severe to need therapeutic action (s), including modification (s) in respiratory support, defined poor bal tolerance. the bal input for decision-making was declared satisfactory if it allowed to interrupt or initiate one or several treatments. results: we included bal in patients (age yrs ; female gender: [ . %]; simplified acute physiology score ii: ; immunosuppression [ . %], chronic pulmonary disease [ / ( . %)]). bal was performed either in non-intubated patients receiving standard o therapy (n = [ . %]), or noninvasive ventilation (n = [ . %]), or high-flow nasal cannula o therapy ( [ . %]), or in patients under invasive mechanical ventilation (n = [ . %]). a total of aes were observed in ( . %) patients. sixty-seven ( . %) patients reached the grade of ae or higher. the main predictor of poor bal tolerance identified by logistic regression was the association of a bal performed by a non-experienced physician (non-pulmonologist, or intensivist with less than years in the specialty or less than bal performed) in non-intubated patients (or: . [ % confidence interval . - . ] ; p < . ). ordinal regression also showed that when bal was performed by a non-experienced physician in a non-intubated patient, this was associated with an increased risk of ae of any grade (or: . [ . - . ]). a satisfactory bal input for decision-making was observed in ( . %) cases and was not predictable using logistic regression. conclusion: adverse events related to bal in icu patients are frequent, and sometimes serious. our findings call for an extreme caution when envisaging a bal in icu patients and for a mandatory accompaniment of the less experienced physicians. compliance with ethics regulations: yes. meningitis is a rare complication of critically ill patients with severe pneumococcal community-acquired pneumonia paul jaubert, julien charpentier, jean-daniel chiche, frédéric pene, alain cariou, guillaume savary, marine paul, jean-paul mira, mathieu jozwiak cochin, paris, france; mignot, versailles, france correspondence: paul jaubert (paul.jaubert@gmail.com) ann. intensive care , (suppl ): rationale: severe pneumococcal community-acquired pneumonia (pcap) is a frequent infection requiring intensive care unit (icu) admission. pneumococcal meningitis associated with pcap has been reported and could worsen the prognosis of patients. however, this complication is difficult to predict and lumbar puncture is not systematically performed, regardless the severity of pcap. thus, we investigated the characteristics of patients with pcap associated with pneumococcal meningitis. patients and methods: we retrospectively included all patients admitted for pcap in our icu between (inception of our electronic medical sheet) and the end of . community-acquired pneumonia was defined according to the criteria of the american thoracic society. we excluded all patients admitted in icu with initial suspicion of meningitis. variables regarding epidemiology, clinical and microbiological characteristics, management and prognosis of these patients were collected and analyzed. results: among the patients admitted for pcap ( ± years old, saps ii ± , % of men), % of the patients required mechanical ventilation and % vasopressors infusion. the icu mortality was %. s. pneumoniae was documented by a positive antigen test in % of the patient and/or by a positive sputum smear, tracheal aspirate or distal protected airway specimen in % of the patients, and/or by pleural aspirate in % of the patients and/or by positive blood culture in % (n = ) of the patients. a lumbar puncture was performed in % (n = ) of the patients with bacteriemia and in % (n = ) of the patients without bacteriemia, with a median delay of h [interquartile range: after the onset of antibiotherapy. alllumbar punctures (n = ) were performed for neurological signs: % of coma, % of confusion and % of seizures. when a lumbar puncture was performed, meningitis was diagnosed in % (n = ) of the patients with bacteriemia and in % (n = ) of the patients without bacteriemia (p < . ). the icu mortality ( % vs. %, respectively), age ( ± vs. ± years old, respectively), saps ii ( ± vs. ± , respectively) or icu length of stay ( ± vs. ± days, respectively) were not different between patients with and without meningitis (each p = ns). conclusion: meningitis is a rare complication of pcap and is more frequent in patients with bacteriemia. suprisingly, meningitis is not associated with higher icu mortality. further analyses are ongoing to identify independent risk factors of meningitis in patients with pcap. compliance with ethics regulations: yes. rationale: shock is the clinical expression of a circulatory failure that results in inadequate cellular oxygen utilization. whereas the host response to septic shock has been extensively described, knowledge of the pathogenesis of non-septic shocks remains limited. we aimed to characterize the systemic host response in shock related to non-septic conditions (nssh) as compared with septic shock (ssh). patients and methods: we performed a prospective study in two intensive care units (icus) in patients admitted for ssh (n = ) or nssh (n = ). immune responses were determined upon icu admission by measuring plasma biomarkers reflecting host response pathways implicated in the pathogenesis of critical illness (in ssh and nssh patients), and by applying genome-wide blood mrna expression profiling (in ssh and nssh patients). results: compared with nssh, patients with ssh had more chronic comorbidities, greater disease severity (apache iv score vs. , p < . ) and worse outcomes resulting in higher mortality rates up to one year after icu admission ( . % vs. . %, p < . ). plasma biomarker analysis revealed severely disturbed host responses in both ssh and nssh patients. however, ssh patients displayed more prominent inflammatory responses, endothelial cell activation, loss of vascular integrity and a more pro-coagulant state relative to nssh patients. blood leukocyte genomic responses were more than % common between ssh and nssh patients relative to health (fig. a) , comprising overexpression of innate pro-and anti-inflammatory pathways, and underexpression of lymphocyte and antigen-presentation gene sets. direct comparison of ssh to nssh patients matched for severity (fig. b) showed overexpression of genes involved in mitochondrial dysfunction and specific metabolic pathways, and underexpression of lymphocyte, nf-κb and cytokine pathways. conclusion: patients with ssh and nssh present with largely similar host response aberrations at icu admission; however, patients with septic shock show more dysregulated inflammatory and vascular host responses, as well as specific leukocyte transcriptome alterations consistent with greatermetabolic reprogrammingand more severe immune suppression. compliance with ethics regulations: yes. rationale: aki is associated with short and long term mortality and morbidity. although recovery has been demonstrated to be associated with outcome of critically ill patients, interpretation of available data is limited by time dependent nature of recovery and by competing risks. our objective was to describe renal recovery, pattern of recovery according to adqi definitions and risk factor of this later. monocenter retrospective cohort study. adult patients admitted in our icu from july to december were included. aki was defined according to kdigo criteria and recovery according to adqi definition. incidence of recovery at each time point was depicted using competing risk survival analysis. risk of transition between aki and no-aki was assessed by a semi-markov model. last, a trajectoire analysis was performed to depict most frequent recovery patterns. results are reported as n (%) or median (iqr). results: patients were included with a median age of ( - ). median sofa score at admission was [ ] [ ] [ ] [ ] [ ] [ ] . at icu admission, patients ( . %) had an aki stage , patients ( . %) an aki stage and patients ( . %) an aki stage . according to adqi criteria, aki was defined as rapidly reversed in patients ( . % of aki patients), persistent aki in patients ( . %) and as acute kidney disease (akd) in patients ( . %), remaining patients couldn't be classified (n = ). risk of recovery was of % per day until day then % per day (fig. a) . fine and gray model, taking into account death as competing risk, identified risk factors negatively associated with renal recovery, namely sofa score (shr = . per point; % ic = [ . - . ]), preexisting hypertension (shr = . ; % ic = [ . - . ]) and aki severity (stage vs. stage shr = . ; % ic = [ . - . ]). risk of de novo aki was maximal during the first days and ranged from to % per day. trajectoire model identified clusters of patients ( fig. b) , closely associated with patients' outcome: a) low patients' severity and no or mild aki (n = ; hospital mortality: %); b) moderate to severe aki but little associated organ dysfunction (n = , hospital mortality: . %); c) severe aki and multiple organ failure (n = ; hospital mortality: . %). conclusion: this study, assessing aki recovery patterns, is the first to our knowledge using adqi definition. despite the high rate of early recovery and of rapidly reversed aki, up to % of aki patients had not recovered at day and could therefore be classified has having akd. compliance with ethics regulations: yes. rationale: sepsis is the most frequent cause of acute kidney injury (aki). the "acute disease quality initiative workgroup" recently proposed new definitions for aki, classifying it as transient or persistent. we aimed to determine the incidence, attributable mortality and host response characteristics of transient and persistent aki in patients with sepsis. patients and methods: we performed a prospective observational study comprising consecutive admissions for sepsis in intensive care units (icus) in the netherlands, stratified according to the presence and evolution of aki. attributable mortality fraction (excess risk for dying with persistent aki relative to transient aki) was determined using a logistic regression model adjusting for confounding variables. in a subset of sepsis patients, plasma biomarkers indicative of major pathways involved in sepsis pathogenesis were measured. in a second subset of patients, whole-genome blood-leukocyte transcriptomes were analyzed. results: sepsis patients were included. aki occurred in . % (n = ), of which . % (n = ) was transient and . % (n = ) persistent. patients with persistent aki had higher disease severity scores on admission than patients with transient aki or without aki and more frequently had severe (injury of failure) rifle aki-stages on admission (n = , . %) than transient aki patients (n = , . %, p < . ). persistent aki, but not transient aki, was associated with increased mortality by day- (adjusted or . , % ci . - . ; p = . ) ( figure) and up to -year (adjusted or . , % ci . - . ;p = . ). the attributable mortality of persistent relative to transient aki by day- was . % ( % ci . - . %). persistent aki was associated with enhanced and sustained inflammatory and procoagulant responses during the first days, and a more severe loss of vascular integrity compared with transient aki. baseline blood gene expression showed minimal differences with respect to the presence or evolution of aki. conclusion: persistent aki is associated with higher sepsis severity, sustained inflammatory and procoagulant responses, and loss of vascular integrity as compared with transient aki, and independently contributes to sepsis mortality. compliance with ethics regulations: yes. rationale: to address the paucity of data on the epidemiology of patients admitted to intensive care units (icus) with in-hospital cardiac arrest (ihca), we examined key features, mortality and trends in mortality in a large cohort of patients admitted in french icus over the past years. patients and methods: from to database of the collège des utilisateurs de bases de données en réanimation (cub-réa), we determined temporal trends in the characteristics of ihca, patients' outcomes and predictors of icu mortality. results: of the icu admissions, ( . %) were cardiac arrests and were ihca ( . %). during the study period, the age of ihca patients increased by . years (p = . ) and patients presented more comorbidities (chronic heart disease, chronic kidney disease and cancer). patients were also more critically ill over the period as reflected by the increase of saps-ii by . % (p < . ). paradoxically, in-hospital management became lighter through the time with reduced respiratory support (p < . ), renal support (p < . ) and use of vasoactive drugs (p < . ). crude in-icu mortality decreased from % to . % over the past eighteen years (p < . ), fig. rationale: in surgery, prophylaxis antibiotic aims at preventing the occurrence of post-operative infections. for adults, it is currently recommended to only use prophylactic antibiotic therapy during the time of the intervention. but in pediatric cardiac surgery, there is no consensus around the optimal duration of use of antibiotic prophylaxis. the protocol was modified in in the icu and its time reduced to h. we aimed to determine whether h of post-sternotomy antibiotic prophylaxis was not less effective than h treatment to help prevent care-associated infections. patients and methods: after agreement of the ethics committee of our institution, we performed a retrospective non inferiority study, with an inferiority margin to %. the primary objective is to compare the incidence of care-related infections between a second-generation cephalosporin (c g) antibiotic prophylaxis during h and a -h protocols. the secondary objectives are to determine the infection's incidence, to identify the risk factors for nosocomial infections and to compare the incidence of multidrug-resistant infections. results: between january and july , children underwent cardiac surgeries with sternal opening. received h of c g antibiotic prophylaxis and received h of c g treatment. five previously infected children have been excluded. both groups were demographically and surgically similar. the median age was months (range a few hours of life to . years old) and the median weight was . kg. in the intent-to-treat analysis, incidence of care-related infections is at . % in the c g- h group and . % in the c g- h group. a multivariate analysis shows that the shorter -h time antibiotic prophylaxis is not inferior regarding infection prevention compared to h of antibiotic prophylaxis, p = . . as in the per protocole analysis, the c g- h group rate was . % and . % for the g g- h group. conclusion: it demonstrates that shortening the antibiotic prophylaxis treatment time to h does not affect or increase the rate of infections after a pediatric sternotomy surgery compared to -h protocole. prophylaxis in pediatric cardiac surgery should be short-lived. a multicenter prospective study would allow a consensus and confirm this decision. compliance with ethics regulations: yes. rationale: the use of "big data" is getting increasingly popular in the medical field, especially in intensive care where large amounts of data are continuously generated. however, big data can be misleading when essential clinical data are missing. the adequate adjustment for potential confounding factors (e.g., severity of respiratory distress) should be the key procedure in the big data analyses; however, it is challenging to capture the clinical severity within large electronic databases. bronchiolitis is one main reason for admission to pediatric intensive care unit (picu). the modified wood's clinical asthma score (mwcas) is widely used to assess the severity of bronchiolitis. the objective of the study is to build an automated mwcas (a-mwcas) to continuously assess the severity of respiratory distress in critically ill children. this retrospective study included all infants < years old with a clinical diagnosis of bronchiolitis, ventilated with non-invasive neurally adjusted ventilatory assist, in a canadian picu, between october and june . we developed an algorithm, using python . , which was directly connected to the electronic medical record. the components of the score were collected using structured query language (sql) queries and processed to derive the a-mwcas. for validation, the a-mwcas score was compared to the mwcas manually computed by a clinical expert (m-mwcas) . results: sixty-four infants were included in the study, for which of a-mwcas and m-mwcas were generated respectively. the cohen's kappa coefficient was applied to estimate the agreement between the two scores which was . ( % confidence interval) ( table ) which corresponds to . % of complete agreement. . % of the a-mwcas scores were within ± . of the m-mwcas. the kappa coefficient for the each score component were: . for the oxygen saturation, . for the expiratory wheezing, . for the inspiratory breath sounds, . for the use of accessories muscles and . for the mental status, respectively. discussion: the largest discrepancy was observed in the mental status, which clinical evaluation is relatively subjective and varies among care team members (doctor, nurse, respiratory therapist…). the automated score likely decreases this variability by consistently using the same source (respiratory therapist), but its validity should be confirmed in a prospective study. the a-mwcas provides a valid estimation of the mwcas that is fast and robust. after external prospective validation, it may help to add some clinical sense within large electronic databases, with improved assessment of the respiratory distress. compliance with ethics regulations: yes. rationale: in paediatric intensive care units (picu), survival rates have dramatically improved. this has been accompanied by increased morbidity, including psychological morbidity. these new impairments, that can affect the survivors and their families have been conceptualized under the frame of post-intensive care syndrome (pics) and picsfamily. the aim of this study was to explore the experience of critically ill children parent's during the stay in picu, and its impact on the family. patients and methods: we planned a prospective, single centre study for months. we collected qualitative written data from parents whose child had been admitted to the picu for the first time, for at least two nights. results: fifty-seven questionnaires were analysed from thirty-seven admissions. picu admissions were mostly unplanned. among parents % experienced very painful memories during admission and % have feared for their child's life. during the stay, noise has bothered % of parents, and many have described difficulties to rest at night. % had the sensation that their child was suffering, mostly from pain, tiredness, anxiety or fear. during picu stay, % of parents had to stop working, and siblings schooling was impacted in % of cases, % of parents considered themselves to be useful for their child and % have participated to nursing care. more than % were satisfied about information given and communication, % appreciated empathy and support from care givers. parents received support from family, friends, and also from other parents of hospitalized children. parents expressed relief ( %) and serenity ( %) to leave picu, % of them were in demand to meet picu staff again after discharge. conclusion: picu parent's experience is tough, and the impact on family is clear. these are known risks factors for pics. on a very positive note, parents seemed to be satisfied by family-centred care, and were able to preserve their parental role. however, there is still room for improvement of practices. compliance with ethics regulations: yes. the gut has been suspected to be involved in multiple organs dysfunction syndrome (mods) in the intensive care unit (icu). studies suggested a link between gastrointestinal dysfunction (gid) and outcomes. but these studies included very few patients and most of them were retrospective. patients and methods: this study is a secondary analysis of data from a previous study that included patients from french icus. gid is defined as the association of vomiting and constipation or diarrhea during the first week after icu admission. patients included were treated with vasopressors and mechanical ventilation. the first goal was to determine if gid is a risk factor of -day mortality in this population. secondary goals were to assess the impact of gid on nosocomial infections. results: among included patients, ( . %) had gid. by day- , ( %) of the patients with gid and ( %) of the patients without gid had died (odds ratio . [ . - . ]; p = . ). multivariable regression model did not show any association between gastrointestinal dysfunction and increased risk of -day mortality in patients (odds ratio . [ . - . ], p = . ). gastrointestinal dysfunction was strongly associated with other secondary outcomes ( table ). patients with gid had longer ventilation duration, icu length of stay and hospital length of stay. they also had more nosocomial infections, in particularly ventilator-associated pneumonia. this association still existed in a multivariable regression model for prediction of nosocomial infection including the same variables than the previous model (odds ratio . [ . - . ], p = . ). no association with day- mortality was observed. conclusion: gastrointestinal dysfunction was not a risk factor of day- mortality but was associated with an increased risk of nosocomial infection and an increased length of stay. this study is observational and no causality link can be done. however, our data suggest further studies on strategies aimed to limit gid. compliance with ethics regulations: yes. rationale: acute cholangitis (ac), a bacterial infection related to an obstruction of the biliary tree, may be responsible for life-threatening organ failure. however, little is known about the outcome and the predictive factors of mortality of critically ill patients admitted in icu for acute cholangitis. we aimed to describe characteristics of patients admitted in icu for ac and to analyze predictive factors of in-hospital mortality including the time to biliary drainage procedure. patients and methods: retrospective study of all cases of acute cholangitis admitted in french icus ( tertiary hospitals and non-ter- [ . ; . ] µg/l. % of patients (n = ) have positive blood culture, mostly gram negative bacilli ( %) and % producing extended spectrum beta lactamase enterobacteriaecae. at icu admission, persisting obstruction was frequent ( %) and therapeutic endoscopic retrograde cholangiopancreatography was performed in % of them. in a multivariable analysis, at icu admission, several factors were significantly associated with in-hospital mortality: sofa score (or = . [ % ic . ; . ] by point, p = . ), arterial lactate (or = . [ . ; . ] by mmol/l, p < . ), total serum bilirubin (or = . [ . ; . ] by umol/l, p < . ), obstruction nonrelated to gallstones (p < . ) and ac complications (liver abcess and/or pancreatitis) (or = . [ . ; . ] p = . ). in addition, time > h between icu admission and biliary drainage was associated to in-hospital mortality (adjusted or = . [ . ; . ] p = . ). conclusion: acute cholangitis is responsible for high mortality in icu. organ failure severity, causes and local complications of cholangitis are predictive factors of mortality as well as delayed biliary drainage. compliance with ethics regulations: yes. the united kingdom) were included (n = ). predictors of one-year mortality were retrospectively screened and tested on a single center training cohort. a predictive score was developed and tested on an independent multicenter cohort. results: four independent pre-transplantation risk factors were associated with one-year mortality after transplantation in the training cohort: age ≥ years (or = . , % ci = . - . , p = . ), pre-transplantation arterial lactate level ≥ mml/l (or = . , % ci = . - . , p = . ), mechanical ventilation with pao / fio ≤ mmhg (or = . , % ci = . - . , p = . ) and pretransplantation leukocyte count ≤ g/l (or = . , % ci = . - . , p = . ). a simplified version of the model was derived by assigning point to each risk factor: the transplantation for aclf- model (tam) score. a cut-off at points distinguished a high-risk group (score > ) from a low-risk group (score ≤ ) with one-year survival of . % vs. . % respectively (p < . ). the model and its simplified version were validated on the independent multicenter cohort. there was a significant difference between the high-risk and low-risk group with one-year survival of % vs. . % respectively (p < . ). conclusion: liver transplantation can be an effective treatment for critically ill cirrhotic patients with hepatic and extra hepatic organ failure provided patients are carefully selected and that they are transplanted at the optimal time in the intensive care. the tam score can help stratify post-transplantation survival and assist clinicians in the transplantation decision-making process at the bedside of aclf- patients. compliance with ethics regulations: yes. rationale: trans-thoracic echocardiography (tte) is commonly used in the initial management of patients with shock in icu. there is little published evidence for any mortality benefit. we compared the effect of echocardiography protocol versus standard care for survival and clinical outcomes. patients and methods: this randomized controlled trial included selected shocked patients (systolic blood pressure < mm hg and signs of organ hypoperfusion) randomized to early tte plus standard care versus standard care without tte. the primary outcome measure was survivalto days. secondary outcome measures included initial treatment and vasopressor weaning. results: consecutive subjects with circulatory shock (low systolic arterial blood pressure (sap) and signs of organ hypoperfusion) at the time of icu admission are included in the study. in the tte group: fluid prescription during the first h was significantly lower rationale: both the negative prognostic value and reversibility of left ventricular (lv) diastolic dysfunction in septic patients remain debated. the excess of mortality in septic shock patients with hyperdynamic profile has only been reported by small-size studies. accordingly, the primary objective of the prodiasys study was to assess the impact of lv diastolic dysfunction (and its severity) and of lv hyperkinesia echocardiographically identified during the initial phase of septic shock on -day survival. the secondary objective was to assess the potential link between lv diastolic dysfunction, cumulative water balance (on day ), and outcome. patients and methods: this was a multicenter, prospective, observational, cohort study. patients older than years hospitalized in icu for septic shock (sepsis- definition) were eligible. exclusion criteria were administration of inotropes, severe left valvular disease, constrictive pericarditis and moribund patients. in each patient, echocardiography was first performed within h after the diagnosis of septic shock and then daily until day , after vasopressor discontinuation, at icu discharge and on day or at hospital discharge, whichever occurred first. vital and biological parameters usually monitored for septic shock management were collected at each echocardiographic assessment. vital status was collected on day . associations between lv diastolic dysfunction or lv hyperkinesia and day- mortality were analyzed using a chi test. adjusted analyses were performed using logistic regression models, including variables known to be linked with the prognosis of septic shock (e.g., severity scores, delay of antibiotherapy). the relationship between the grade (i to iii) of lv diastolic dysfunction and -day survival were analyzed using a logistic regression model. the relationship between the presence of lv diastolic dysfunction and cumulated water balance on day were analyzed using a linear regression model adjusted on the body weight on admission. the relationship between the grade of lv diastolic dysfunction and cumulated water balance on day were analyzed using a linear regression model. diaphragm dysfunction and weaning induced pulmonary edema are two frequent causes of weaning failure but their coexistence and interaction have been poorly investigated. we hypothesized that diaphragm dysfunction may not induce a sufficient decrease in intra-thoracic pressure to increase venous return and generate a weaning induced pulmonary edema. we therefore investigated whether weaning induced pulmonary edema and diaphragm dysfunction are or not associated and evaluated the effect of diaphragm dysfunction on cardiac function and lung aeration during a spontaneous breathing trial (sbt). patients and methods: patients with readiness to wean criteria who had failed a first sbt were eligible. before and after a second sbt, diaphragm function was assessed by measuring the change in tracheal pressure induced by a bilateral phrenic nerve stimulation (ptr, stim), cardiac function (cardiac output, systolic pulmonary arterial pressure) was evaluated with echocardiography and lung aeration was estimated from the lung ultrasound score (lus). plasma protein concentration and hemoglobin were also sampled before and after the sbt. diaphragm dysfunction was defined by ptr, stim < − cmh o and weaning induced pulmonary edema was diagnosed in case of sbt failure associated with ) increase in plasma protein concentration or hemoglobin > % during the spontaneous breathing trial and/or ) early (e) over late peak diastolic velocity ratio > . or e over peak diastolic velocity ratio > . . results: fifty-three patients were included and / ( %) failed the sbt. diaphragm dysfunction was present in / ( %) of patients with weaning induced pulmonary edema, in / ( %) patients with sbt success and in / ( %) patients with other causes of sbt failure (p < . ). during the sbt, diaphragm dysfunction induced a significant increase in systolic pulmonary arterial pressure but no change in cardiac output. patients with diaphragm dysfunction had a higher lus as compared to their counterparts ( ± vs. ± , respectively, p < . ). conclusion: diaphragm dysfunction induces a loss of lung recruitment and a significant increase in systolic pulmonary arterial pressure during the sbt. coexistence of diaphragm dysfunction and weaning induced pulmonary edema is common in case of sbt failure but weaning induced pulmonary edema appears more likely to be involved than diaphragm dysfunction. compliance with ethics regulations: yes. rationale: diaphragmatic weakness in the intensive care unit (icu) is associated with poor outcome. prolonged mechanical ventilation is associated either with a decrease (atrophy) or an increase (supposed injury) in diaphragmatic thickness, both associated with prolonged weaning. shear wave elastography is a non-invasive technique that measures diaphragm shear modulus (sm), a surrogate of its mechanical properties. the aim of this study was to describe the diaphragm shear modulus during the icu stay and to describe its relation with diaphragm thickness. patients and methods: this prospective and monocentric study included all consecutive critically ill patients. ultrasound examination of the diaphragm (aixplorer; supersonic-imagine, aix-en-provence, france) was obtained by two investigatorsevery other day until icu discharge. demographics, diaphragm thickness, sm and outcomes were collected. a mixed model regression was used to study the relation between sm and diaphragm thickness. results: we enrolled patients from december st to june st, being invasively mechanically ventilated during the stay. diaphragm ultrasound evaluation was feasible in / ( %) patients. the duration of mechanical ventilation during the icu stay was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days with [ ] [ ] [ ] [ ] [ ] days spent on controlled mechanical ventilation. sm was . ± . kpa and diaphragm end-expiratory thickness was . ± . cm upon icu admission. increase and decrease ≥ % during icu stay occured in and percent of the patients respectively for diaphragmatic thickness, and in and percent of the patients respectively for diaphragmatic sm. diaphragm thickness over time was inversely correlated with diaphragm sm and with time spent under mechanical ventilation (table) . diaphragm sm over time was correlated with time spent under pressure support ventilation or under spontaneous breathing (compared to controlled ventilation) and with time spent under deep sedation. diaphragm sm was inversely correlated with age, sepsis, exposition to steroids (table) . no association was found between diaphragm sm and outcomes. discussion: our results are in line with the myotrauma concept, suggesting alteration in diaphragm mechanical properties associated with increased diaphragm thickness in critically ill patients. we hypothesize that this observation most likely reflects muscle injury and tissue infiltration with edema and inflammatory cells. conclusion: shear wave ultrasound elastography suggests that in critically ill patients, the increase in diaphragmatic mass is associated with an alteration in diaphragm mechanical properties as measured by sm. compliance with ethics regulations: yes. rationale: diaphragm dysfunction and intensive care unit (icu) acquired weakness (icu-aw) are associated with poor outcomes in the icu but their long term impact on prognosis and health-related quality of life (hrqol) is poorly established. this study sought to determine whether diaphragm dysfunction is associated with negative long-term outcomes and whether the coexistence of diaphragm dysfunction and icu-aw has a particular impact on two-year survival and hrqol. patients and methods: we used a previous cohort study conducted in our institution to follow up mechanically ventilated patients in whom diaphragm and limb muscle functions were investigated at the time of liberation from mechanical ventilation. diaphragm dysfunction was defined by tracheal pressure generated by phrenic nerve stimulation < cmh o and icu-acquired weakness was defined by medical research council (mrc) score < . hrqol was evaluated with the sf- questionnaire. results: sixty-nine of the patients enrolled in the original study were included in the survival analysis and were interviewed. overall two-year survival was % ( / ): % ( / ) in patients with diaphragm dysfunction, % ( / ) in patients without diaphragm dysfunction, % ( / ) in patients with icu-acquired weakness and % ( / ) in patients without icu-acquired weakness. patients with concomitant diaphragm dysfunction and icu-acquired weakness had a poorer outcome with a -year survival rate of % ( / ) compared to patients without diaphragm function and icu-acquired weakness ( % ( / ) (p < . )). hrqol was not influenced by the presence of icu-acquired weakness, diaphragm dysfunction or their coexistence. conclusion: icu-acquired weakness but not diaphragm dysfunction has a strong negative impact on two-year survival of critically ill patients. the presence of diaphragm dysfunction appears more likely to be a determinant of early prognosis and does not appear to have a significant impact on long-term survival. compliance with ethics regulations: yes. rationale: influenza can lead to severe condition with acute respiratory failure and acute respiratory distress syndrome due to a massive pulmonary inflammatory in response to the viral invasion. lung bacteriobiota has been described to be associated with pulmonary inflammation in chronic respiratory diseases such as chronic obstructive pulmonary disease or cystic fibrosis. lung mycobiota has been poorly investigated despite the well-known role for fungi in numerous respiratory diseases. the aim of our study was to assess the prognostic value of lung bacteriobiota and mycobiota among critically ill influenza patients. patients and methods: we prospectively included influenza patients admitted to icu. sputum were stored a - °c. bacterial and fungal dna were extracted thanks to qiaamp ® powerfecal ® pro dna kit. s rrna gene v -v regions and its regions were amplified by pcr and sequenced on illumina miseq ® . taxonomic assignation was obtained by dada pipeline and microbiota analysis were performed according to day- mortality by the mean of phyloseq package on r . . software. results: thirty-nine patients were admitted to icu for influenza with sputa available and finally dna samples available after extraction. bacteriobiota alpha diversity was significantly lower among non-survivors than survivors when expressed by the mean of shannon index, simpson index or evenness (respectively p = . , p = . , p = . ). area under the curve to predict day- mortality was . , ci [ . ; . ] for shannon index, . ci [ . ; . ] for simpson index and . ci [ . ; . ] for evenness. β-diversity analysis also demonstrated significant differences between survivors and non-survivors (adjusted permutational multivariate anova, p = . ). nonsurvivors had a higher abundance of staphylococcus, haemophilus, streptococcus and moraxella. none of the fungal alpha-diversity index nor beta-diversity were significantively different between survivors and non-survivors. non-survivors had a higher proportion of candida albicans and malassezia but not of aspergillus. conclusion: the lung bacteriobiota profile, but not the mycobiota one, of critically ill influenza patients is associated with day- mortality and may be used to identify subjects with a poor prognosis at the time of admission. compliance with ethics regulations: yes. that takes into account the interaction between multiple cellular pathways. the pathway profiles between moderate and severe influenza were then compared to delineate the biological mechanisms underpinning the progression from moderate to severe influenza. results: patients ( severe and moderate influenza patients) and healthy control subjects were included in the study. severe influenza was associated with upregulation in several neutrophilrelated pathways, including pathways involved in neutrophil differentiation, migration, degranulation and neutrophil extracellular trap (net) formation. the degree of upregulation in neutrophil-related pathways was significantly higher in severely infected patients compared to moderately infected patients. severe influenza was also associated with downregulation in immune response pathways, including pathways involved in antigen presentation, cd + t-cell co-stimulation, cd + t cell and natural killer (nk) cells effector functions. apoptosis pathways were also downregulated in severe influenza patients compared to moderate and healthy controls. conclusion: these findings showed that there are changes in gene expression profile that may highlight distinct pathogenic mechanisms associated with progression from moderate to severe influenza infection. compliance with ethics regulations: yes. rationale: herpesviridae reactivation among non-immunocompromised critically ill patients is associated with impaired prognosis, especially during acute respiratory distress syndrome (ards). however, few is known about herpes simplex virus (hsv) and cytomegalovirus (cmv) reactivation occurring in patients with severe ards under venovenous extracorporeal membrane oxygenation (ecmo). we tried to determine the frequency of herpesviridae reactivation and its impact on patients'prognosis during ecmo for severe ards. patients and methods: we conducted an observational, retrospective study in a medical icu (ards and ecmo referee center) between and . patients with a severe ards requiring a venovenous ecmo for days or more were included. hsv and/or cmv reactivation occurring after ecmo insertion was screened for these patients. patients with immunosuppression, antiviral therapy against hsv and/ or cmv prior to inclusion, or hsv/cmv reactivation known at the time of ecmo insertion were excluded. hsv reactivation was defined by a positive qualitative throat sample (virocult ® ) pcr or positive bronchoalveolar lavage (bal) pcr. cmv reactivation was defined by a positive quantitative blood or bal pcr. results: during a five-year period, non-immunocompromised patients with a severe ards necessitating a veno-venous ecmo were included. sixty-seven ( %) experienced hsv and/or cmv reactivation during ecmo course ( viral co-infection, hsv alone and cmv alone). hsv reactivation occurred earlier than cmv after the beginning of mv ( ( - ) vs. ( - ) days; p < . ) and after ecmo implementation ( ( - ) vs. ( - ) days; p < . ). in univariate analysis, hsv/cmv reactivation was associated with a longer duration of mechanical ventilation ( ( - . ) vs. . ( - ) days; p < . ), a longer duration of . ) vs. ( - ) days;p < . ), and a prolonged vs. ( - ) days; p < . ) and hospital stay ( ( - . ) vs. ( - ) days; p < . ). however, in multivariate analysis, viral reactivation remained associated with prolonged mv only. when comparing patients having cmv (alone or combined with hsv) vs. hsv reactivation alone, cmv positive patients had a longer mechanical ventilation duration and fewer ventilator-free days at day- and a longer icu and hospital length of stay. conclusion: herpesviridae reactivation is frequent among patients with sevre ards under veno-venous ecmo and is associated with a longer duration of mechanical ventilation. cmv seems to have a proper negative role on pulmonary fiunction as compared to hsv alone. hsv and cmv deserve to be researched in severe ards patients under ecmo. compliance with ethics regulations: yes. charlotte vandueren , benjamin zuber , eve garrigues , antoine gros , nicolas epaillard , guillaume voiriot , yacine tandjaoui rationale: respiratory syncytial virus (rsv) is a common cause of pediatric bronchiolitis and influenza-like illness in adults. its involvement in severe infections in adults remains unclear. the captif study aimed at comparing characteristics and prognosis of icu patients infected with rsv and influenza, assuming that, based on the limited evidence, the mortality of rsv infection would be lower than the influenza related one. patients and methods: multicenter franco-belgian retrospective study. adults admitted to icus between /nov/ and / apr/ with respiratory rsv infection were included and matched : to influenza patients on center and icu admission date. patients' characteristics, clinical presentation, and outcome were compared between groups using univariate and multivariable analyses. results: we report here the results for the first cases among included patients. mean age was . ( . ) years and saps- score was ( ), not different between groups. compared to influenza patients, rsv patients more frequently had chronic respiratory failure ( % vs %, p < . ) or immune suppression ( vs %, p = . ). frequencies of cardiac, renal and hepatic chronic diseases were similar. almost all patients had respiratory symptoms (> %), extrarespiratory symptoms were more frequent in influenza patients ( vs %, = . ). rsv patients more frequently had bronchospasm ( vs %, p = . ). clinical presentation such as ards ( %), shock ( %) and pulmonary coinfection ( %) were similar, however sofa score was higher in rsv patients ( . ( . ) vs . ( ), p = . ). the p/f ratio was around mmhg in both groups, paco was higher in rsv patients ( vs mmhg, < . ). respiratory assistance at diagnosis tended to differ (p = . ), rsv patients receiving more non invasive ventilation ( vs %) and less high flow oxygen therapy ( vs %) but invasive ventilation was required similarly ( vs %). during icu stay, ards was more frequent in rsv patients ( vs %, p = . ), accordingly prone position ( . vs . %) and ecmo ( . vs . %) were more frequently needed. length of mechanical ventilation ( days ( - ) ) and icu los ( days ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ) were not different. icu mortality was similar in rsv and influenza patients ( . % and . %), the multivariate analysis did not find an association between type of virus and mortality. conclusion: rsv infection is frequent in adult icu patients. it presents more frequently than influenza as an acute on chronic respiratory failure with bronchospasm. despite difference in case mix and clinical presentation, vrs severity and burden appear similar to influenza justifying effort to prevent and treat it. compliance with ethics regulations: yes. rationale: mortality in acute stroke patients requiring mechanical ventilation ranges from to % at year. studies evaluating indicators of outcome in these patients have limitations, including singlecenter, retrospective designs and no adjustment for withholding/ withdrawal of life-sustaining treatments (wlst). our objective was to identify factors associated with -year survival in acute stroke patients requiring mechanical ventilation. patients and methods: retrospective analysis of a prospective multicenter database between and . icu stroke patients entered in the database and requiring mechanical ventilation within h were included. were excluded patients with stroke of traumatic origin, subdural hematoma or venous cerebral thrombosis. factors associated with -year survival were identified using a cox model stratified on inclusion center, adjusted on wflst occurring during the first h. data are presented as median [q -q ] or percentages. cox model results are presented as hazard ratios (hr) and % confidence intervals (ci). results: we identified patients from icus, aged [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] years and % males. on admission, the glasgow coma score (gcs) was [ ] [ ] [ ] [ ] [ ] [ ] and the saps score was . types of strokes were ischemic ( %), hemorrhagic ( %) and subarachnoid hemorrhage (sah) ( %). ischemic stroke patients received thrombolysis or thromboaspiration in / ( %) cases, and hemorrhagic stroke/ sah patients received neurosurgery or embolization in / ( %) cases. reasons for endotracheal intubation were coma ( %), acute respiratory failure ( %), seizures ( %), cardiac arrest ( %) and elective procedure ( %). sixty-five ( %) patients received a decision of wflst in the first h. one-year survival year was %. variables independently associated with -year survival were stroke type (ischemic as reference, hemorrhagic hr . (fig. ) . inclusion period ( inclusion period ( - inclusion period ( / inclusion period ( - inclusion period ( / inclusion period ( - or having a stroke unit on site was not associated with -year survival. conclusion: in acute stroke patients requiring mechanical ventilation, the reason for intubation and the opportunity to receive a specific stroke therapy are independently associated with long-term survival. these variables should be integrated in the decision process regarding initiation of mv in acute stroke patients. compliance with ethics regulations: yes. rationale: international guidelines recommend targeted temperature management (ttm) between ° and °c for out-of-hospital cardiac arrest (ca) patients. however, it is unknown if this treatment is effective whatever the severity of the insult. we aimed to examine the association between ttm and long-term neurological outcome according to the risk evaluated at time of admission in intensive care unit (icu) using a dedicated and validated score. patients and methods: we used data prospectively collected in the sudden death expert center (sdec) registry (great paris area, france) between may and december and in the resuscitation outcome consortium-continuous chest compression (roc-ccc) between june and may . we used a modified version of the cardiac arrest hospital prognosis (mcahp) score to assess the risk of poor outcome at icu admission in each of datasets. we finally studied the association between ttm use and long-term neurological prognosis according to mcahp score at icu admission divided into tertiles of severity in each of the datasets. results: there were patients analyzed in the french dataset and in the north-american dataset. the mcahp identified categories: low risk (score < points, % of unfavourable outcome), medium risk ( ≤ score < , % of unfavourable outcome) and high-risk group (score > , % of unfavourable outcome). according to the mcahp score at icu admission, ttm was associated with a better long-term neurological prognosis in patients with low risk (aor = . [ . - . rationale: acute ischaemic stroke is associated with a high risk of mortality, morbidity and healthcare-related costs. over the last decades new treatments, such as thrombolysis and thrombectomy, have been introduced. because of their further improvement, complications have been decreasing. this also led to extending indications for treatment to patients who were previously not eligible. the impact of this evolution on long-term outcome and cost-effectiveness has mainly been assessed in clinical trials and simulation studies. patients and methods: this single-centre retrospective study included patients treated for stroke between january and february . functional outcome at days was assessed by the modified rankin scale (mrs). cost data were retrieved from individual invoices of patients. undiscounted total healthcare costs were calculated for the index hospital stay, capped at days. contribution of cost categories to total costs was analysed. mrs at days was used as a proxy for utilities to define quality-adjusted life years (qalys). multivariate analysis was done for gender, age, charlson comorbidity index, pre-stroke mrs, stroke severity (nihss) and treatment modality (thrombectomy, thrombolysis, thrombectomy + thrombolysis, no intervention). incremental cost-effectiveness ratios (icers), associated to each treatment modality, were calculated. results: no intervention was done in patients ( . %). patients ( . %) required thrombolysis, ( . %) thrombectomy and ( . %) the combination. total costs were mean , eur ) . hospitalisation costs (mean , eur, iqr - , ) represented % of total costs, compared with drug costs ( eur, iqr - ), procedural costs ( eur, iqr - ), honoraria ( eur, iqr - ), lab ( eur, iqr - ) and imaging ( eur, iqr - ). mean total costs differed between treatment modalities: , (iqr - , ) eur for no intervention, , ) eur for thrombolysis, , (iqr , ) eur for thrombectomy and , (iqr , ) eur for the combination (p < . ). drivers for total costs were treatment modality (p < . ) and nihss-stroke severity (p < . ). utility scores were . rationale: emergency endotracheal intubation (eti) in the intensive care unit (icu) often concerns hypoxemic patients with hemodynamic instability. a cardiovascular collapse (cvc) after eti is a life-threatening complication. french guidelines suggested systematic fluid loading prior to eti. our study aimed to predict cvc after eti, while using echocardiography, and to evaluate the impact of fluid loading. patients and methods: a prospective study of consecutive intubations was performed from june to november in three icus. patients were selected if mean blood pressure measurements ≥ mmhg before eti. cvc was defined as mean blood pressure < mmhg within min following eti. four echocardiographic examinations were performed: - min before and - min after eti (or when a cvc occurred); -after passive leg raising; - h following eti. patients were classified as fluid responders when the left ventricular outflow tract velocity-time integral increased by at least % compared with baseline. results: echocardiographic examinations were performed. cvc occurred in / procedures ( %). in cvc group, mean dose of diprivan, used for fast sequence induction, was higher ( . ± mg/kg vs . ± . mg/kg, p = . ). in the cvc group, fluid responsiveness was considered in % patients and left ventricular (lv) systolic dysfunction %. lv diastolic dysfunction did not concern any patient in the cvc group. systolic blood pressure (sbp) < mmhg was the sole independent risk factor for cvc occurrence in multivariate analysis: or . ci % . - . , p = . . fluid responsiveness independent risk factors for cvc patients was sbp < mmhg (or . , ci % . rationale: the autonomic nervous system is highly adaptable and allows the organism to maintain its balance when experiencing stress. heart rate variability (hrv) is a mean to evaluate cardiac effects of autonomic nervous system activity and a relation between hrv and outcome has been proposed in various types of patients. we attempted to evaluate the best determinants of such variation in survival prediction using a physiological data-warehousing program (reastoc clinicaltrials identifier nct ). patients and methods: physiological tracings were recorded at hz from the standard monitoring system (intelliview philips mp ) using the synapse software (ltsi inserm umr ), for a h period, during the h following icu admission. all measurements were recorded while patients were laying in bed, with the head at ° and without any medical intervention. physiological data were associated with metadata collection by a dedicated research assistant. hrv was derived using kubios hrv, in either temporal ( (sdnn), (rmssd) and triangular index (ti)), frequency ( (lf), (hf)), non-linear domains (poincaré plotting) and entropy. results: consecutive patients were recorded between may and april . a lower lf/hf (< . ) and sd /sd (< . ) ratios on admission were associated with a higher icu mortality. multivariate analysis enabled to develop a mortality predictive model (bicus) associating spo /fio and hrv parameters (lf/hf and shannon entropy) with an auc = . (p < . ) for a bicus value > (fig. ) . conclusion: hrv measured on admission enables to predict prognosis in the icu, independently of the admission diagnosis, treatment and mv requirements. bicus may help predict prognosis on a real time basis, using parameters derived from standard routine monitoring. compliance with ethics regulations: yes. rationale: stroke, in the context of type diabetes (t d) is associated with a worse outcome than in non-diabetic conditions, reflected by an increased ischemic volume and more intracerebral hemorrhage. an unbalanced diet is one of major risk for developing t d. we aimed at creating a reproducible mouse model of stroke in impaired glucose tolerance condition induced by high fat diet. patients and methods: adult c bl mice ( male and female) were fed for months with either high fat diet (hfd, % lipids, % proteins, % carbohydrates) or a normal diet (nd, . % lipids, . % proteins, . % carbohydrates) . we used a model of middle cerebral artery occlusion (mcao) by a monofilament for min. oral glucose tolerance test and insulin tolerance test were used for evaluating the pre-diabetic state. mice were euthanized h after reperfusion. systemic inflammation, cerebral infarct volume and hemorrhagic transformation were determined. results: hfd was associated with an increased glycaemia following the oral glucose tolerance test. plasma leptinlevels in stroke conditions were significantly higher in hfd vs nd group. the hfd group presented a significant increase of infarct volume (hfd: . ± . mm vs nd: . ± . mm p = . ) and hemorrhagic transformation (hfd: . ± . vs nd: . ± . p = . ) (fig. ) compared to nd group. discussion: in humans, one of the mechanisms leading to insulin resistance is low-grade inflammation. hfd increases gut permeability, which leads microbiota dysbiosis, thereby promoting metabolic endotoxaemia and a low-grade inflammation state. experimental mouse models available for diabetes studies use leptin receptor deficient mice which develop t d or destruction of pancreatic beta cells by streptozotocine injection (t d). studies using diet-induced insulin resistance models generally feed the mice for weeks or more. however, metabolic disorders could appear earlier such as increase inflammatory markers. in our model, a short exposition to hfd ( weeks) leads to an increase of the pro-inflammatory markers as plasma leptin and a more severe stroke status (infarct and hemorrhagic transformation). conclusion: two months of hfd in adult mice altered hyperglycemia control. this metabolic disorder was associated with significantly higher leptin production, increased infarct volume and hemorrhagic complications than in normal-fed mice. this new model is particularly relevant to study stroke under pre-diabetic conditions induced by hfd. compliance with ethics regulations: yes. eight weeks of hfd increase ischemic volume and hemorrhagic transformation. (a)-infarct volume (v) h after reperfusion, all value are mean ± sem, hfd: v = . ± . mm , n = , nd: v = . ± . mm , n = , *p = . (b)-hemorrhage transformation (ht) score h after mcao. all value are mean ± sem hfd: ht score = . ± . , n = , nd: ht score = . +/+ . , n = *p = . rationale: cardiac arrest (ca), as massive ischemia reperfusion (ir), is an universal health issue. medication taken at the time of the ca could have prognosis consequences. no medication has proven its benefit on ca prognosis. pharmacological pre-or postconditioning aims to reduce ir injury but with disappointing results. metformin (met) is a worldwide-prescribed antidiabetic drug, and several clinical reports plead for a potential protective effect in various settings of sterile and non sterile inflammation, including ir. our hypothesis is that met act as a preconditioning drug against ca-induced ir. patients and methods: retrospective single academic medical center survival study (french west indies) on resuscitated ca in icu (institutional ethical committee approval). data were extracted from medical charts, pmsi, and laboratory dbsynergy ™ software. anonymized data were entered on a excel ™ and transferred to ibm ® -spss ® software (v . . . ) for analysis. univariate study (chi- , fisher exact tests, student-t test, mann-whitney u-test if required) was followed by a multivariate model (odd ratio or and % ic: kaplan-meier estimator and non parametric logrank test-mantel cox model). assuming an overall in-hospital mortality for ca in icu of % with an expected mortality decrease of % by met, the number of patients to be included is . results: the inclusion period was to , with included patients ( diabetic patients among whom took met). the d mortality was % in met+ patients (n = ) versus % in nomet patients (n = ), p < . . comparing alive (n = ) versus deceased (n = ) at d in univariate then multivariate analysis, asystole on the first ekg, number of iterative cardiac arrest,sofa, no-flow, lactate, low-flow and sapsii appear as independent criteria associated with d mortality.conversely, met intake showed up as a protective criterion (or . , ci . - . ). the survival curve, including strata of low-flow duration at the cut-off min, is reported on the fig. . among diabetic patients (n = ), the mortality of patients in the met+ (n = ) was % versus % in the nomet (n = ), p = . . conclusion: in diabetic patients suffering of massive ir related to resuscitated ca, a current treatment by met is associated with a better survival. these results support a protective effect of met and are important to initiate prospective evaluations, because of millions diabetic people around the world and the potential benefit of met. the potential benefit in non diabetic patients and in sterile as well as non sterile inflammation should be addressed. compliance with ethics regulations: yes. rationale: during systemic inflammation, the accumulation of misfolded proteins in the endoplasmic reticulum (er) induces er stress (ers). in animal models, the inhibition of ers reduces inflammatory response and organ failure. cardiopulmonary bypass (cpb) induces a significant systemic inflammatory response but ers expression has never been described in cardiac surgery patients. our objective was to describe the variations of the glucose related protein of kda (grp ), the final effector of the ers, during cpb. patients and methods: we conducted a prospective monocenter study including patients undergoing cardiac surgery with cpb. two samples (paxgene ® tube + edta tube) were taken at three times: before cpb, h after the end of cpb (h -cpb) and h after (h -cpb). after rna isolation and reverse transcription, we performed a quantitative polymerase chain reaction to evaluate the expression of gene encoding for grp and determined the plasma level of grp using enzyme-linked immunosorbent assay. our main objective was to study the variation of grp between pre-cpb and h -cpb samples. our secondary objectives were to evaluate the association of ers with morbi-mortality: organ failure at h (catecholamines and/or invasive ventilation and/or acute renal failure), troponinemia and pao /fio ratio (lung damage control). fig. ). we found an inverse correlation between grp plasma level and troponinemia at h (r = − . ; % ci[− . ; − . ]; p = . ) and a correlation between the pao /fio ratio and grp plasma level at h (r = . ; % ci[ . ; . ]; p = . ). we showed a significant relationship between the variation in plasma concentration of grp and post-operative organ failure after cpb. further studies are needed to better understand the molecular mechanisms of ers in acute inflammatory organ failure in humans. compliance with ethics regulations: yes. patients and methods: in a retrospective monocentric study ( / - / ) conducted in cardio-vascular surgical intensive care unit (icu) in henri mondor teaching hospital, all consecutive adult patients who underwent peripheral va-ecmo were included, with exclusion of those dying in the first h. diagnosis of acute mesenteric ischemia was performed using digestive endoscopy, abdominal ct-scan or fist-line laparotomy. significative results in the univariate analysis were analyzed in a multivariate analysis using logistic regression. results: va-ecmo were implanted. median age was ( - ) years and median . va-ecmo was implanted after a cardiotomy in % of the cases and for a medical reason in % of the cases including % of refractory cardiac arrest. patients characteristics are reported in the table. acute mesenteric ischemia was suspected in patients, with a delay of ( - ) days after ecmo implantation. digestive endoscopy was performed in patients, ctscan in five patients and first-line laparotomy in three patients. acute mesenteric ischemia was confirmed in patients, i.e. an incidence of %. laparotomy was performed in six of the patients, two having a stage i colitis ischemitis with stable conditions and being considered too severe to undergo futile surgery. overall mortality was %. all the patients with acute mesenteric ischemia died in the icu. independent risk factors of developing acute mesenteric ischemia were renal replacement therapy , p = . )) and onset of a second shock state within the first days of icu stay (or . ( % ic . - . , p = . )). conversely, early enteral nutrition was negatively associated with acute mesenteric ischemia (or . ( % ic . - . ), p . ). conclusion: acute mesenteric ischemia is a relatively frequent condition among patients under va-ecmo for cardiogenic shock. its extremely poor prognosis requires low threshold of suspicion. compliance with ethics regulations: yes. ( ). it allows the computation of trans-pulmonary pressure ( ) and can be used to set positive end-expiratory pressure (peep) ( . ) . prone position(pp) can reduce mortality in patients with acute respiratory distress syndrome (ards), but peep selection in pp is controversial. in human ards end-expiratory pes at zero flow (peept,es) was not different between supine (sp) and pp at same peep ( ). as no study measured ppl in sp and pp in ards we aimed at comparing peept,es and end-expiratory ppl at zero flow (peept,ppl) in this condition. our hypothesis was that peept,es was close to dorsal peept,ppl (peept,ppldorsal) in sp and to ventral peept,ppl (peept,pplventral) in pp. in eight female pigs of kgs intubated, sedated, paralyzed and mechanically ventilated, ards was induced by repeated saline lavage until pao /fio < mmhg under fio and peep cmh o. pes was measured by nutrivent catheter. ppl was measured by custom-made pouch sensors inserted surgically into the right anterior and posterior sixth intercostal space. ppl sensors were filled with air. after ards induction animals were randomly assigned to sp or pp. in each position, a recruitment manoeuver was performed and peep decreased from to cmh o by steps of cmh o lasting min each, then the animals were crossed over into the alternate position where the same procedure was done. at the end of each step nonstressed volume and correct position (baydur maneuver) were determined for pes and ppl sensors, then a -s end-expiratory occlusion was performed and pes and ppl recorded. linear mixed model was used to compare the value of pes and ppl at each peep and position. results: box-and-whisker plots of pes and ppl in sp and pp are shown in fig. . there is marked dorsal-to-ventral gradient in ppl at each peep in sp, which is reverted in pp at peep and only. there was no interaction between pressures and peep or position. with increasing peep pes increased significantly from peep in sp and pp. peept,pplventral was significantly lower than peept,es in sp but not in pp. (medtronic) , carescape (ge)) were set in pressure support cmh o, peep cmh o, fio % and equipped with the same double limb ventilator circuit (intersurgical) without any humidification device. asl bench model was set with inspiratory/expiratory resistance (r) and compliance (c) combinations: r / -c , r / -c and r / -c mimicking normal, ards and copd conditions, respectively ( ) . inspiratory effort generated by asl consisted of consecutive breaths obtained from the esophageal pressure in a real patient at the time of a spontaneous breathing trial. for each icu ventilator and rc combination, two steps were performed: in the first, atc was not activated and ventilator attached to asl without ett (atc-ett-); in the second, atc was set on at % compensation for an ett mm id and such an ett (shiley hi contour, covidien) joined icu ventilator to asl (atc+ ett+). the null hypothesis is that vtatc+ ett+ minus vtatc-ett-is . primary end point was the breath by breath paired difference betwen atc+ ett+ and atc-ett-. it was tested to zero for each ventilator in each rc condition. results: median vt was ml. table displays mean (± sd) difference in vt (ml) between atc+ ett+ and atc-ett-: a negative value means that atc under delivers and a positive value that atc over delivers vt for a given patient's inspiratory effort and rc. in four ventilators (c , s , elisa and ) atc almost systematically under delivered vt. in several instances under compensation was greater than % median vt. by contrast atc performed better with the other three ventilators (evita xl, v and carescape ). conclusion: atc tended to under deliver vt. furthermore, there were marked differences between icu ventilators the clinician should be aware of when using the atc option. compliance with ethics regulations: na. rationale: during the last decades, identification of factors associated with ventilation-induced lung injury has led to improved survival in patients with ards. the mechanical power of ventilation is the total energy transmitted from the ventilator to the respiratory system per unit of time and comprises three different components: elastic related to peep, elastic related to tidal volume and resistive. this integrative variable has been recently proposed as an useful predictor of ventilationinduced lung injury and death among ventilated patients. our goal was to determine the respective impact of the total mechanical power and its three components on the outcome of patients with ards. patients and methods: we performed a post hoc analysis of a randomized, controlled study of patients with ards with a pao /fio ratio < . themechanical power at inclusion and averaged on the first days after inclusion (total and its three different components) was computed according to the following equation: powerrs (j/ min) = . respiratory rate tidal volume [peep ( ) + ½ driving pressure ( ) + (peak pressure-plateau pressure) ( )], where the ( ), ( ) and ( ) parts correspond respectively to the elastic related to peep, elastic related to tidal volume and resistive components. the association between each of these four types of mechanical power evaluated during the first days after inclusion and mortality at d was assessed one after the other through multiple logistic regression, allowing control for potential confounding variables at inclusion (age, igs score without age, group of randomization, pao /fio , arterial ph). results: data from patients were analyzed, among which ( . %) died before d . there was no difference concerning the mechanical power at inclusion between survivors and non survivors (either total or its three components). among the four different types of mechanical power tested during the first days after inclusion, the elastic component related to tidal volume was the only one that was independently associated with mortality at d (or . ; % ci . - . ; p = . ) (figure) . conclusion: our study shows that only the elastic component of the mechanical power related to tidal volume independently predicted mortality at d among patients with ards, whereas the total mechanical power, its elastic component related to peep and its resistive component did not. further studies are needed to better define how the mechanical power of ventilation could be useful to synthetize the risk of ventilation-induced lung injury. compliance with ethics regulations: yes. probability of death at d as a factor of mean value (on d -d ) of the elastic component related to tidal volume of the mechanical power. to examine the effect of early-stage mechanical ventilation (mv) on diaphragmatic contractility. in the nd step, if a diaphragmatic dysfunction was detected, we assessed its influence on the weaning from ventilator. patients and methods: we measured prospectively the ultrasounddiaphragmatic thickening fraction (dtf) between groups: a study group versus a control group (n = for each). the study group included all adult patients receiving mv, in whom, the dtf was measured within a minimum of h and a maximum of days of mv. for the control group, were enrolled after their approval for participation, adult volunteers in spontaneous ventilation (sv). patients with factors affecting the diaphragmatic contractility (neuromuscular disease, severe obesity, and neuromuscular blockers…) were excluded. the ultrasound measurements were obtained at the zone of apposition of the right hemithorax. teleinspiratory and telexpiratory diameters (tid/ ted) were taken on the medio-axillary lines: posterior, median and anterior. the dtf was calculated as following: dtf = (tid-ted/ted) x . at the st step, the dtfs were compared and at the nd step: the relationship between dtf and weaning was analysed. results: our groups were comparable in corpulence and co morbidities. the sv group was younger ( vs. years, p < . ) with a predominant female composition. the diaphragmatic exploration concluded that in the mv group, the mean tid tended to be higher but without significant difference ( . + versus . + mm, p = . ), the mean ted was significantly higher ( . + versus . + . mm, p = . ) and dtf was significantly lower ( . + . % versus + . %, p = . ). the ventilation mode had no effect on dtf ( . + % for control volume vs. . + % for psv mode, p = . ). fourteen among ventilated patients had a successful weaning with a mean duration of days. a negative correlation was found close to significance between dtf and weaning duration (rho = − . and p = . ). a dtf value > % wasassociated with weaning success (or = , % ci = [ . - . ] and p = . ) with sensitivity = . %, specificity = %, ppv = % and npv = %. conclusion: the diaphragmatic contractile function was altered from the first days of mv. weaning duration seemed to be negatively correlated with dtf, and a dtf at the first days of mv greater than % was predictive of weaning success. compliance with ethics regulations: yes. rationale: mechanical ventilation is a life-saving treatment that is however associated with lung injury and/or diaphragm dysfunction. the optimal ventilator settings to provide lung protective ventilation while maintaining safe diaphragm activity are difficult to determine. a noninvasive and bedside evaluation of the diaphragm activity could be helpful in this context. the present study investigated whether changes in diaphragm shear modulus (i.e. stiffness, Δsmdi) assessed by ultrasound shear wave elastography (swe) may be used as a surrogate of changes in transdiaphragmatic pressure (Δpdi) in mechanically ventilated patients. patients and methods: patients had to be ventilated for at least h without contraindications for the placement of an oeso-gastric catheter. pdi was monitored continuously and smdi was measured at the zone of apposition of the right hemi-diaphragm, at hz sampling rate. measurements were performed twice under initial ventilator settings and at the end of a weaning trial. pearson correlation coefficients (r) were computed to determine within-individual correlations between pdi and smdi and changes in pdi and in smdi occurring between initial ventilator settings and the end of the sbt were compared by a paired test. results: twenty-five patients were enrolled and displayed a significant correlation between Δsmdi and Δpdi (mean r = . , range = . - . , all p < . ) (fig. a ). compared to their counterparts, patients with significant within correlations had a lower respiratory rate ( . ± . vs . ± . breath/min. respectively; p < . ) and a significant increase in Δsmdi ( . ± . kpa vs . ± . kpa. p < . ) between initial ventilator settings and the sbt. patients without Δsmdi-Δpdi correlation only displayed an increase in Δpdi ( . ± . vs . ± . cmh o, p < . ) at the end of the sbt with no concomitant significant increase in Δsmdi ( . ± . kpa vs . ± . kpa, p > . ). (fig. b) . conclusion: smdi obtained by swe appears as a promising technique to assess diaphragm activity in mechanically ventilated patients but technological improvements are necessary to increase swe sampling rate before enabling its generalization in the icu. compliance with ethics regulations: yes. rationale: end-inspiratory (eip) and end-expiratory (eep) pauses are commonly used during volume assist control ventilation to assess plateau pressure and total positive end-expiratory pressure (peeptot). they can also be used during assisted ventilation (av) for muscle pressure assessment. it requires ventilators able to perform eip during av. plateau pressure (pplat) usually increases in av during eip due to "hidden" inspiratory effort. pressure muscular index (pmi) is equal to pplat minus the sum of peeptot (measured during an eep) and set pressure support (ps); it theoretically reflects patient's effort without esophageal pressure (pes) monitoring. pes is the gold standard method to assess inspiratory muscle pressure (pmus, difference of pes drop at neural end-inspiration and correction factor for chest wall elastance and tidal volume). we aimed to illustrate the feasibility of measuring pmi using a standard icu ventilator at the bedside and study the correlation between pmus and pmi. patients and methods: measurements were recorded in icu patients. pes was measured using an nasogastric probe (equipped with an esophageal balloon) inserted for advanced monitoring (severe acute respiratory distress syndrome-ards) or for a study protocol (difficult weaning after copd exacerbation). recorded eip, eep and pes were used for post hoc analyses. results reported as ranges and median [iqr] . correlation between pmus and pmi tested with spearman correlation test. results: out of eip and eep duos could be analyzed ( -esophageal spasm/ -calibration error). ventilator mode was pressure support ventilation (ps - cmh o). cmh o, pmus = . [ . - . ] cmh o, pmi = . [ . - . ]. for all recordings, spearman r coefficient between pmus and pmi was . (p = . ). conclusion: muscular effort can be assessed in av using eip and eep using icu ventilators. however, recordings can be influenced by expiratory muscles contraction. patient's ability to follow directions during the maneuvers is an important factor to obtain reliable values. there seem to be a correlation in our small sample between muscular pressure assessed without and with pes. compliance with ethics regulations: yes. rationale: severe pneumonia can culminate in acute respiratory distress syndrome (ards). an uncontrolled inflammatory response is a key feature favoring transition towards ards. however, the underlying mechanisms remain poorly understood. in this context, the contribution of "innate t cells" (itc) -a family of non-peptide reactive t cells comprising nkt cells, mucosal associated invariant t (mait) cells and γδt cells-has never been explored. itc have emerged as key players in orchestration of the host response during infections and inflammation processes. for these reasons, these cells are already seen as potential therapeutic targets in other medical fields (especially oncology). here, we hypothesized that a tight regulation of their functions could be paramount to control the inflammatory response and to prevent ards development. patients and methods: to explore this, we combined a murinemodel of influenza a virus (iav) infection mimicking ardssymptoms and a clinical study recruiting patients admitted in icu for severe pneumonia. using flow-cytometry approaches, we investigated ( ) the abundance and dynamics of itc in various compartments, ( ) their pattern of activation/regulation markers (respectively cd and pd- ) and ( ) their cytokine production. results: during experimental iav pneumonia, itc were transiently recruited into the airways. unlike γδt and nkt, mait cells phenotype was largely changed, displaying a progressive cd overexpression and increased il- a production. during the resolution phase, up to % of pulmonary maits expressed pd- (versus < % in controls), which can suggest emergence of regulatory functions. last, using gene-targeted mice, we suggested that mait cells confer a protective effect during pneumonia. in the ongoing clinical study, the proportion of circulating mait cells in patients was markedly decreased compared to controls ( . ± . % versus . ± . % of t cells), but not for nkt or γδt cells. notably, some patients with severe ards presented detectable levels of maits in their respiratory fluids. in addition, circulating mait cells in patients overexpressed cd and pd- ( . % and % respectively), but with a reduced proportion able to produce il- and ifnγ, compared to healthy controls. lastly, proportion of activated (cd +) mait cells significantly decreased with clinical improvement. conclusion: this translational approach combining in vivo animal experiments and clinical samples with ex vivo experiments indicates a preferential modulation in mait cells functions during severe pneumonia. these data justify an in-depth analysis of mait cells activation mechanisms and functions in this context, in order to further explore a potential use as a disease-progression marker and -in a long term perspective-as a potential therapeutic target. compliance with ethics regulations: yes. representative flow-cytometry dot-plots of mait cells labelling using fluorophore-conjugated mr tetramers loaded with -op-ru from lungs of an infected mouse (a) and blood sample of a patient with pneumonia (b). c: frequency of mait cells, proportion of cd and pd- + mait cells in bronchoalveolar lavage during experimental murine pneumonia. d: blood frequency of mait cells in patients with pneumonia compared with healthy controls (as % of total t cells) rationale: immune paralysis following hyperinflammatory states increases the risk of secondary infections and death. reversing t-cells exhaustion using recombinant il or immune checkpoints inhibitors may improve the prognosis of patients with sepsis admitted to the icu. however, there is an unmet need to better characterize the state of t-cells exhaustion in these patients, its reproducibility and its correlation with the outcomes before implementing immunotherapy in the therapeutic armamentarium against sepsis. patients and methods: prospective observational cohort study performed in two tertiary-care icus in a university hospital. peripheral blood mononuclear cells were collected at day in adult patients with sepsis admitted to the icu. the level of cd + and cd + t-cells exhaustion was quantified using multi-color flux cytometry targeting the following exhaustion markers: pd- , b and cd . cd + regulatory t-cells (cd + cd + cd hi cd lo cells) were also assessed. results: the patients included in the study could be split in five clusters according to their dominant pattern of exhaustion markers on cd + t-cell (i.e. no markers, pd- +, b +, b + cd + and b + pd- +) and independently of their underlying morbidities. no patients harbored a fully exhausted triple-positive pattern. by multivariate analysis, saps gravity score at day (p = . ), a dominant b and/or pd- cd + pattern (p = . ) and lung sepsis (p = . ) where associated with the risk of death at day , whereas hemoglobin level was associated with survival (p = . ). no cd + or cd + exhaustion pattern independently predicted the risk of secondary infections. neither the level of cd + regulatory t-cells nor the dominant cd + exhaustion pattern was associated with the outcomes. rationale: there is growing use of multiplex polymerase chain reaction (mpcr) for respiratory virus testing in patients with communityacquired pneumonia (cap). data on one-year outcomes in patients with severe cap of bacterial, viral and unidentified etiology are scarce. patients and methods: a single-center retrospective study was performed in intensive care unit (icu) patients with known one-year survival status who had undergone respiratory virus testing for cap by mpcr. one year after icu admission, mortality rates and functional status were compared in patients with cap of bacterial, viral or unidentified etiology. results: there were ( . %) patients in the bacterial group, ( . %) in the viral group and ( . %) with unidentified etiology. one-year mortality was . % (n = / ), % (n = / ) and . % (n = / ), respectively (p = . ). in multivariate analysis, one-year mortality was higher in the bacterial group than in the viral group (hr . , % ic . - . , p = . ), had a trend to be higher in the bacterial group compared to the unidentified etiology group (hr . , % ic . - . , p = . ) and was not different between the viral and unidentified etiology groups (hr . , % ic . - . , p = . ). severe dyspnea (mmrc score = or death), major adverse respiratory events (new homecare ventilatory support or death) and severe autonomy deficiencies (adl katz score ≤ ordeath) were observed in / ( . %), / ( . %) and / ( . %) patients, respectively, with no difference between groups. conclusion: cap of bacterial origin was associated with a poorer prognosis than viral or unidentified etiology. impaired functional status was observed in a substantial proportion at one-year, irrespective of the causative microorganisms involved. compliance with ethics regulations: yes. interest of unyvero multiplex pcr (curetis) for bal rapid microbiologic and antibiotic susceptibility documentations in immunocompromised patients under antibiotic therapy jean-luc baudel , jacques tankovic , redouane dahoumane , salah gallah , laurent benzerara , jean-remy lavillegrand , razach abdallah , geoffroy hariri , naike bige , hafid ait-oufella , nicolas veziris , eric maury , bertrand guidet rationale: our aim was to evaluate the interest of the unyvero rapid ( . h) multiplex pcr assay (performed on bronchoalveolar lavage [bal] samples) for the management of immunocompromised patients already treated with antibiotics and diagnosed with pneumonia (according to clinical and radiological findings). we thus performed an observational study that compared the results (and the length of time to obtain them) of routine microbiological evaluation and unyvero assay. patients and methods: from july to january and from april to august , we examined bal samples from immunocompromised patients (coming from hematology, oncology, hepatology, gastroenterology, internal medicine, and neurology units) diagnosed with pneumonia (based on clinical and radiological findings), and already receiving antibiotic treatment. the following data were collected: age, gender, saps score, lung ct scan ( %) or x-ray ( %) results, duration and content of prior antibiotic therapy, direct examination, culture, antibiogram and unyvero results, secondary confirmation of pneumonia or not, possible changes in antibiotic therapy that could have been made after obtention of unyvero results. informed consent was obtained from all patients. results: bal samples were analyzed in immunocompromised patients (m/f ratio . , saps . ± . ) mostly with hematologic ( %) or oncologic ( %) diseases. the patients received either corticosteroids ( %), or chemotherapy ( %), or immunotherapy ( %). % of the patients were under mechanical ventilation, % under optiflow. % presented a shock, % had aplasia or neutropenia, % were allografted, % were autografted. the duration of prior antibiotic therapy at the time of bal were . ± . days. direct examination was positive in . % of the cases, culture (both above and under the classical threshold of cfu/ml) in %, unyvero in . %. a retrospective analysis of all the cases confirmed the initial diagnosis of pneumonia in only % of the cases. compared to culture, the sensitivity of unyvero was %, its specificity %. unyvero could permit to rapidly deescalate antibiotic therapy in % of the cases and to rapidly stop it in %. the unyvero assay on bal samples is useful in this specific population for rapid obtention of microbiological results and also for confirmation of the negativity of cultures and thus permits a better management of antibiotic therapy, leading to a reduction of antibiotic resistance selection pressure in the icu. compliance with ethics regulations: yes. do not underestimate rsv pneumonia among critically ill patients erwan begot , suzanne champion , charline sazio , benjamin clouzeau , alexandre boyer , hoang-nam bui , marie-edith lafon , camille ciccone , julia dina , didier gruson , renaud prével chu bordeaux, medical intensive care unit, bordeaux, france; chu bordeaux, virology laboratory, bordeaux, france; national reference center for measles mumps and rubella, chu de caen, caen, france correspondence: erwan begot (erwan.begot@chu-bordeaux.fr) ann. intensive care , (suppl ):f- rationale: respiratory syncitial virus (rsv) is a well-known cause of respiratory failure among neonates but its pathogenicity in adults is now emerging as a potential cause of viral pneumonia. data are limited with conflicting results regarding rsv pneumonia severity in adults. data are lacking about critically ill rsv patients' characteristics and outcomes. the aim of this study is to compare rsv patients' characteristics, care and outcomes to influenza patients' ones. patients and methods: patients diagnosed with rsv and influenza pneumonia admitted to our medical icu were included. data were retrospectively recorded. quantitative data are expressed by median and interquartile range and compared by use of mann-whitney test. qualitative data are expressed by number and percentages and compared by use of fischer exact t-test. rsv strains were prospectively collected. results: eighteen critically ill patients with rsv pneumonia and with influenza pneumonia were included. rsv and influenza patients had the same characteristics at admission except for age (respectively yo [ ; ] and acute respiratory distress syndrome rates (respectively / ( %) vs / ( %), p = . ). they received similar treatment as suggested by oro-tracheal intubation rates (respectively / ( %) vs / ( %), p: . ) and antibiotics prescription (respectively / ( %) vs / ( %), p: . ). rsv and influenza patients also had the same rates of bacterial co-infections ( / ( %) vs ( %), p: . ). invasive aspergillosis remained a rare event but also occurred among rsv patients ( / ( %) vs / ( %), p: . ). acute coronary syndromes were as frequent in both groups (respectively / ( %) vs / ( %), p = . ). day- mortality was similar between rsv and influenza patients (respectively / ( %) rationale: respiratory distress from seawater drowning is commonly considered multifactorial. etiologies are debatable and include heart failure, infection and acute respiratory distress syndrome (ards). documented bacterial infections seems mostly related to the site of drowning. data in this regard are scarce with prospective studies lacking. the objective of our study was to describe prospectively the characteristics and determinants of respiratory distress from seawater drowning. patients and methods: all patients admitted for seawater drowning to seven intensive care units (icu) on the french riviera in the summers of and were prospectively included. recorded data included clinical features on examination, personal history, chest x-rays, echocardiography and biological results obtained within the first h. a paired student's t-test was used to study statistical differences between quantitative variables on admission and during early evaluation (i.e. first h). results: forty-eight patients were admitted to seven centers of which ( %) were diagnosed as having ards, ( %) early pneumonia and ( %) acute cardiogenic pulmonary edema. twenty-one ( %) respiratory samples were collected but bacterial culture was positive in only cases. multidrug-resistant bacteria were not observed, and amoxicillin-clavulanate as first-line treatment was effective in all cases. echocardiography performed in ( %) patients was normal and unable to identify specific patient profiles. the median clinical pulmonary infection score (cpis) on admission was (iqr, - ) and decreased rapidly and significantly (p < . ) within h to (iqr, - ) (fig. ) . conclusion: data from this multicenter cohort suggest that respiratory distress following seawater drowning can mimic bacterial pneumonia during the first h with subsequent rapid clinical improvement in patients admitted to the icu. probabilistic antibacterial therapy should therefore be limited to the most severe patients. isolate ards is often the only etiology found and is resolutive within h. this prospective cohort is the largest of its kind and gives a better insight into the limited impact of cardiogenic and infectious processes on sea drowning-related respiratory distress. compliance with ethics regulations: yes. rationale: patients treated with "extracorporeal membrane oxygenation" (ecmo) are at a higher risk of developing nosocomial infections and they are consequently often treated with beta-lactams. french guidelines recommend obtaining beta-lactam trough concentrations above four times the minimal inhibitory concentration (mic) of the causative bacteria. the ecmo device may alter the pharmacokinetics of these medications, which may result in underexposure to beta-lactam antibiotics. patients and methods: this observational, prospective, multicenter, case-control study was performed in the intensive care units of two tertiary care hospitals in france. ecmo patients with sepsis treated with piperacillin-tazobactam were enrolled. control patients were matched according to sofa score and creatinine clearance. the pharmacokinetics of piperacillin was described based on a population pharmacokinetic model, allowing to calculate the time spent above × the mic breakpoint for pseudomonas aeruginosa susceptibility after the first dose and at steady state between two piperacillin infusions. results: forty-two patients were included. the median age was years [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , the sofa score was [ ] [ ] [ ] [ ] [ ] [ ] , and median creatinine clearance was ml/min . there was no significant difference in the time above x mic in patients treated with ecmo and controls during the first administration (p = . ) and at steady state (p = . ). there was no significant difference between the trough at steady state (p = . ), with / patients ( %) exhibiting concentrations of piperacillin lower than x mic. ecmo support was not associated with a steady state trough concentration below x mic (or = . [ . - . ], p = . ). the only variable independently associated with this risk was a creatinine clearance ≥ ml/min, (or = . [ . - . ], p = . ). conclusion: ecmo support has no significant impact on piperacillin exposure. intensive care unit patients with sepsis are, however, frequently underexposed with piperacillin, which suggest that therapeutic drug monitoring should be strongly recommended for severe infections. impact of a visual support dedicated to prognosis of patients on symptoms of stress of family members rationale: family members commonly have inaccurate expectations of patient's prognosis. adding to classic oral information a visual support, depicting day by day the evolution of the condition of the patient, improves the concordance in prognosis estimate between physicians and family members. the objective of this study was to evaluate the impact of this support on symptoms of anxiety/depression of family members. patients and methods: we conducted a bi-center prospective beforeafter study. all consecutive patients admitted in the two icus were eligible. in the before period ( months), family members received classic oral information. in the after period ( months) , in addition to classic oral information, the visual support ( fig. ) was available for family members in the patient's room from the day of admission until discharge from the icu. at day and from admission, symptoms of anxiety/depression of referent family member were evaluated by hospital anxiety and depression scale (hads). results: patients and their referent family members were included ( in period before and after). characteristics of patients of the two groups were similar regarding age, reason for admission, saps ii at admission and sofa score at day . also characteristics of referent family members were comparable in terms of age, sex ratio, type of relationship with the patient and number of visits since admission. at day , total had score was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in the group before without the support and [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in the group after with the support (p = . ). the prevalence of symptoms of anxiety (had-a score > ) and depression (had-d score > ) was similar in the two groups (respectively . % and . % in the group before, and . % and . % in the group after (ns)). at day , total had score was in the group before [ - ] and [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in the group after (p = . ). by multivariate analysis the following factors were significantly associated with total had score > at day : age of patient ]), number of visits of referent ) and previous or current treatment of referent for anxiety or depression . ]). conclusion: in this study, the use of a visual support dedicated to prognosis of patients did not modify the level of stress of family members. compliance with ethics regulations: yes. rationale: the use of sedation and opioids at the end of life is a topic of considerable ethical debate. incidence of discomfort during the end-of-life of icu patients and impact of sedation on discomfort are poorly known. patients and methods: post-hoc analysis of an observational prospective multicenter study comparing terminal weaning vs. immediate extubation for end-of-life in icu patients, aimed at assessing the incidence of discomfort events according to levels of sedation. discomforts including gasps, significant bronchial obstruction or high behavioral pain scale score, were prospectively assessed by nurses from mechanical ventilation withdrawal until death. level of sedation was assessed using the richmond agitation sedation scale (rass). results: among the patients included in the original study, ( %) experienced discomfort after mechanical ventilation withdrawal. patients with discomfort received lower doses of midazolam and equivalent morphine, and less frequently had deep sedation (rass - ) than patients without discomfort ( % vs %, p < . ). after multivariate logistic regression, immediate extubation was the only factor associated with discomfort whereas deep sedation and administrations of vasoactive drugs were two factors independently associated with no discomfort. death occurred less rapidly in patient with discomfort than in those without discomfort ( . h [ . - . ] vs . [ . - . ], p < . ) (figure) . long-term evaluation of psychological disorders in family members of dead patients did not differ between those with discomfort and the others. discussion: despite the theoretically expected anticipatory titrated doses of opioids and benzodiazepines to alleviate any discomfort after withdrawal of mechanical ventilation, half of the patients did not receive sedation or opiate when the decision to withdraw mechanical ventilation was taken. a major point that could interfere with the continuous deep sedation practice until death is the fear of potentially hastening death, and there is much controversy regarding its proper use in end-of-life care. conclusion: discomfort was frequent during end-of-life of icu patients and was mainly associated with terminal extubation and less profound sedation. compliance with ethics regulations: yes. rationale: bereavement in intensive care unit (icu) is associated with psychiatric disorders on relatives called post-intensive care syndrome family (pics-f). no isolated intervention (such as condolence letter) has shown a positive effect on these disorders, despite a well acceptance by relatives. we thought that a more integrated bereavement program should be considered. the goal of this study is to evaluate a combined psychologist-physician post-death meeting (pdm) in a bereavement program to evaluate needs and adhesion of relatives, and the effect on symptoms of anxiety and depression. patients and methods: monocentric, prospective study focused on relatives of patient admitted > h and deceased in icu. during patient's stay, relatives' presence was allowed on a h-basis and they could meet a clinician psychologist. formal meeting between relatives and the staff was realized at patient's admission and after important decision-making treatment. two weeks after patient's death, the psychologist called relatives to offer emotional support and to invite to a pdm. pdm occurs weeks after patient's death with the psychologist and the physician in charge of the patient. the objectives of the meeting were to provide emotional support, to answer medical question, and to detect symptoms of anxiety and/or depression with the hospital anxiety and depression scale (hads). we hypothesized that pmd would be able to alleviate pics-f at months. we aimed to enroll families to detect a % lowering of hads. results: the rate of pdm acceptance was lower than expected. after inclusions, only relatives accepted the pdm, whereas the phone call was well perceived ( %). main association with acceptance of pmd was a short duration of icu stay ( . days [ - . ] vs . days [ . - . ] p = . ) and icu admission for acute respiratory failure ( . % vs . %, p = . ) ( table ) . we found no relation between the number of in icu meeting (psychologist of medical staff) and pmd acceptance. for relatives who accept pmd we found a high proportion of symptoms of anxiety and depression ( % and %) with a hads at . [ - . ] (median, iqr). no evaluation was performed at months. conclusion: post death contact appears well perceived by relatives but pmd quite useless. this result may be explained by the inclusion of only late death (> h) where psychologist and medical staff had the opportunity to support relatives. further study should focus on early death (< h). compliance with ethics regulations: yes. rationale: pediatric intensivists frequently question themselves on the issue of limitation or termination of life-sustaining treatments (llst) carried out on children. such a decision comes under the claeys-leonetti law which forbids doctors from applying unreasonable treatment however, every so often, parents oppose themselves to a collegial llst decision that the medical and paramedical team had taken. such cases can even end up in court. in order to sort out this problem, this study focused on the factors that underlie the disagreement and the solution brought forward by pediatricians whenever parents demand to persue treatments although considered as unreasonable obstinacy. patients and methods: we carried out a qualitative study involving three multipurpose pediatric critical care unit. all pediatricians operating within these units were contacted. those who volonteered were met individually for a semi-directed interview. every interview was recorded and entitled to a complete hand-written retranscription. the interviews were analysed following the phenomenological interpretive analysis method and were subject to dual listing. results: pediatricians out of took part in the study. / claimed they would increase treatments or carry out cardiopulmonary resuscitation acts if asked to do so by parents, even if this went against the initial collegial decision. / claimed they would persue treatments although not beyond the current level. / said they would oppose themselves to parents concerning blood transfusion for comfort reasons. several key factors were identified as leading a doctor to the non-application of a llst decision: the certainty regarding the child's death on a short or mid-term basis ( / ), the litigiousness risk ( / ), the apprehension of mediatic pressure ( / ), the fear of a violent reaction from parents ( / ), other self-interest positions within the medical team ( / ), empathy towards parents ( / ), the uncertainty concerning the neurological prognosis ( / ), the lapse of time needed to fully accept the application in force of a decision ( / ). pediatricians out of admitted their own-suffering when confronted to the situation. conclusion: this study points out that pediatricians tend to follow parents' position when confronted to parental opposition. in such situations, pediatricians go against their own decision in order to safeguard the parental alliance even if it leads to unreasonable obstinacy, thus conflicting with medical deontological code obligations. compliance with ethics regulations: yes. rationale: end-of-life management strategies are clearly a worldwide issue of major importance that intensivists have to deal with on a daily basis. advance directives may be the solution sought to guide physicians to take such difficult decisions. yet, health care directives are not legislated in tunisia. the objective of this project was to draw a general descriptive overview to assess patients' wishes in tunisia. patients and methods: data were collected from a -item-questionnaire based on the french intensive care society's form for advance directives which was filled by people of general population in tunisia, including doctors and paramedics, from may to mid-september . all people included were or older and well informed of the form's utility. results: a total of participants were included. the mean age was . ± . years with extremes of and and a sex ratio of . . fourty-one ( . %) were either doctors or nurses and ( %) did suffer from a severe medical condition. among all the participants, ( . %) thought that end-of-life decisions were up to the doctor. for the rest, they willingly chose to be hospitalized in an icu, to undergo cardiopulmonary rescuscitation and to have ventilation support with orotracheal intubation or tracheostomy respectively in ( . %), ( . %) and ( . %) of the cases. only ( . %) refused temporary dialysis. when asked about sequelae they can live with, participants accepted hemiplegia in . % and paraplegia in . % of the cases. on the contrary, ( . %) refused to live in permanent coma and ( . %) disagreed to undergo tracheostomy and ventilation for life. moreover, ( . %) found that serious un aesthetic sequelae was a fatal consequence they could not survive. as well, only ( . %) consented to live with deep intellectual deficiency. regarding palliative care, ( . %) participants wished to be profoundly sedated until death, ( . %) prefered to die home over ( . %) in hospital. sixtytwo ( . %) desired to see a representative of their religion. furthermore, ( %) were for organ donnation. gender, being a health care professional and age under versus equal or over were not significant in dependent factors (p > . ). conclusion: it is our duty ashealth care professionals to spread advance directives awareness and education. nevertheless, the law should keep the pace with ethics evolution. compliance with ethics regulations: yes. rationale: adapted organ support techniques are needed to enhance reliability of preclinical animal experiments in the intensive care setting (guillon, annals of intensive care- ). a few renal replacement therapy (rrt) models have already been developed in rats, mostly hemodialysis in chronic kidney disease models or hemofiltration techniques in sepsis experiments. mounting evidence from clinical (gaudry, nejm- ) and histopathological studies suggest that rrt for acute kidney injury (aki) could impair renal recovery by acting as a 'second hit' leading to a maladaptive repair of tubular epithelium. we aimed to study this hypothesis in a hemodialysis model in rats with septic aki. patients and methods: on day , sprague-dawley rats were injected with lipopolysaccharide or placebo (nacl . %) intraperitoneally. on day , anesthetized rats underwent femoral artery catheterization for hemodynamic parameters monitoring. at the same time, one femoral vein and one carotid artery were catheterized for arterio-venous sterile extracorporeal circulation with or without passing through a miniature sterile polyester sulfone hemodialyzer ( cm surface, kda pores, microkros ® ) filled with dialyzate liquid in the outer compartment (table ) . vessels were ligated after the procedure and rats allowed to awaken. on day , rats were sacrificed. results: all rats injected with lipopolysaccharides o :b mg/kg survived at day . anesthesia was much challenging: ketamine + xylazine and tiletamine-zolazepam + xylazine required induction and maintenance intraperitoneal injections. these medications induced important hemodynamic parameters fluctuations and high mortality. isoflurane gas inhalation enabled better stability, less hypothermia and quick awakening. adequate temperature was controlled with a heating pad during the procedure and an incubator after. supine position was maintained. the whole circuit was anticoagulated with ml of heparinized saline ui/ml, since clots occurred in the absence of anticoagulation and bleeding when higher dosing was used. circuit (< . ml including dialyzer) was filled with saline solution before initiation, and total restitution of blood at the end of the experiment prevented any blood transfusion requirement. hematocrit was determined at beginning ( %) and end of experiment ( %). a peristaltic pump provided a blood flow rate of . ml/min, (higher rate was not tolerated) for h. of note, rats who underwent sham procedure (vessels ligature only) survived and did not display aki. circulation of a counterflow dialysate in the dialyzer is planned but has not been performed yet. conclusion: this hemodialysis system for rats is feasible at a reasonable price and might help research involving rrt in either ckd or aki. compliance with ethics regulations: yes. there were no significant relationship between rri and past medical history or severity score. we observed a significant negative correlation between rri and diastolic arterial pressure (p = . ) and heart rate (p = . ) as it could be expected by rri formula. an increased rri was associated with higher potassium (p = . ) and higher creatinine levels (p = . ). although not significant, we found a higher rate of subsequent rrt in the high rri group ( % vs %, p = . ). over the first days, fluid balance was significantly different between groups ( ml vs - ml respectively for low and high rri group, p = . ). since standard of care were similar, this suggests different fluid volume status between the two groups. in the low rri group, the cause of aki could predominantly be prerenal since positive fluid balance was not explained by more severe aki with refractory oliguria as shown by the low rrt rate. nevertheless, we did not observed any relationship between rri and the evolution of serum urea or creatinine levels, nor with the presumed aetiology of aki. conclusion: when focussing on the first rri measurement once stage aki was reached, rri ≤ . seems to be in favour of prerenal and transient renal dysfunction even if this is not supported by creatinine serum evolution. compliance with ethics regulations: yes. rationale: critically ill patients are at higher risk of bleeding but also dialysis filter clotting (inflammatory state). intermittent hemodialysis with calcium-free citrate-containing ( . mmol/l) dialysate (cafcit-ihd) recently emerged as a new safe and simple alternative to continuous renal replacement therapy allowing heparin-free extended dialysis sessions (> h). in this study, we aimed to answer to two issues still unresolved: (i) can citrate contained in the dialysate accumulate and lead to citrate intoxication in patients with liver disorders, and (ii) can citrate be avoided using citrate-and calcium-free dialysate (ccf-ihd)? patients and methods: monocentric retrospective study. among the sessions performed with cafcit-ihd, the ihd sessions ( critically ill patients) with citrate measurement available before and after the dialysis filter were reviewed. estimation of the liver clearance was performed using the picco lemon ® system (pulsion). in addition, sessions performed using ccf-ihd were reviewed. results: all the patients had liver disorders (post-liver transplantation period n = ; cirrhosis with child > a ). among the eighteen cafcit-ihd patients, fifteen ( %) and six ( %) received mechanical ventilation or vasopressive drugs, respectively. the median time of the dialysis session was h [ ] [ ] [ ] [ ] , with hourly ultrafiltration rate of ml (one premature termination not related to dysfunctional catheter). in all patients, ionized calcium (ica) decreased below . mmol/l after the filter, whereas post-filter calcium reinjection according to ionic dialysance led to a stable pre-filter (i.e. patient) ica. median citrate concentrations were all below . mmol/l after the filter (minimal concentration to obtain anticoagulation mmol/l) and all except one below the normal value (< µmol/l) before the filter. during all the sessions, ionized to total calcium ratio was below . and the strong ionized gap decreased. when available (n = ), no correlation could be identified between serum citrate concentration and liver clearance. last, in ccf-ihd sessions performed in critically ill patients, no premature termination occurred (median time of the sessions h) and post-filter ica also decreased below . mmol/l. no citrate accumulation could be identified in critically ill patients (even with liver disorders) and receiving extended dialysis sessions ( h or more) using calcium-free citrate containing-ihd. interestingly, we demonstrated that citrate is not required to obtain optimal regional anticoagulation (i.e. post-filter ica < . mmol/l), and a citrate-and calcium-free dialysate could be a safe alternative. compliance with ethics regulations: yes. rationale: ventilator induced diaphragmatic dysfunction is highly prevalent in adult critical care and associated with worse outcomes. specificities in pediatric respiratory physiology suggest that critically ill children may be at high risk of developing this complication, but no study has described the evolution of diaphragmatic function in critically ill children undergoing mechanical ventilation. this study aims to validate a method to quantify diaphragmatic function in mechanically ventilated children. in this prospective single-center observational study, children between week and years old intubated for elective ent surgery and without pre-existing neuromuscular disease or recent muscle paralysis were recruited. immediately after intubation, diaphragmatic function was evaluated using brief airway occlusion maneuvers during which airway pressure at the endotracheal tube (paw) and electrical activity of the diaphragm (eadi) were simultaneously measured for consecutive spontaneous breaths, while the endotracheal tube was occluded with a specific valve. occlusion maneuvers were repeated times. in order to account for central respiratory drive and sedation use, we recorded the neuromechanical efficiency ratio (nme, paw/eadi), in addition to the maximal inspiratory force (mif). in order to determine the optimal measure of nme during an occlusion, the variability over the three occlusion maneuvers of different variables (first breath, last breath, breath with maximal paw deflection, breath with maximal nme value, and median nme value) was assessed using coefficients of variation and repeatability coefficients. results: patients had a median age of . years (interquartile range . - . ), a median weight of kg ( - ), and were male ( %). the median evolution of paw, eadi, and nme ratio over the occluded breaths are represented on fig. . nme values corresponding to the last breath and the breath with maximal paw deflection were the least variable, with median coefficient of variation of % and % and repeatability coefficients of . and . , respectively. conclusion: brief airway occlusions can be used to assess diaphragmatic function in intubated children through both mif and nme ratio, and the latter should ideally be computed on the last breath or the breath with the largest pressure deflection to improve repeatability and decrease variation. compliance with ethics regulations: yes. epidemiology is poorly understood due to the rare use of validated diagnostic tools. the main objective of the study was to determine, by systematically calculating the wat- score, the incidence of ws in our surgical picu. the secondary objective was to analyze the risk factors, consequences and management modalities of ws. patients and methods: following institutional review board approval, we conducted a prospective monocentric study between july and january . all consecutive mechanically ventilated children admitted in our surgical picu with sedation/analgesia by continuous intra-venous (iv) benzodiazepines (bzd) and/or opioids for at least h were included. as soon as sedation was decreased and during h following their total discontinuation, wat- score was assessed twice a day. ws was defined by a wat- score > . the search for risk factors and consequences associated with ws was performed by univariate analysis (mann-whitney and chi test). ethical standards were satisfied and the lack of opposition from patients and their parents was systematically checked. results: the incidence of ws was % among the patients of our cohort including % of children admitted postoperatively and % after severe traumatic brain injury (tbi). significant results are reported in table . our results show that even for sedation time less than days, children could develop ws ( / patients). on the other hand, age, severity (pelod score), number of previous surgeries and severe tbi were not associated with ws. our study also demonstrated that cessation of sedation and prevention of ws was not uniform in our unit. the high incidence of withdrawal syndrome in our study, even in children sedated for less than days, and its consequences require thinking about prevention. we suggest a systematic monitoring of the occurrence of this adverse event using a validated score, from days of continuous iv sedation/analgesia. compliance with ethics regulations: yes. rationale: severe traumatic brain injury (tbi) is a major healthcare problem. amplitude and duration of intracranial hypertension is highly associated with patient outcome. the intracranial pressure (icp) is therefore one key parameter to monitor in the acute phase. when icp is monitored with an external ventricular drain, the pressure recorded by the monitor does not always correspond to the real icp, depending on the status (open/closed) of the -way tap. misleading values could therefore be sent to the patient medical record. our hypothesis is that a machine-learning algorithm will be able to identify automatically and in real time the reliable and non-reliable values of the icp signal. we retrospectively studied pediatric patients having an external ventricular drain between july and july , in a single pediatric intensive care unit. the icp signals were extracted from a high-frequency database ( hz) and pre-processed adequately. to train the algorithms, an annotated database was manually created with two classes: reliable icp vs. non-reliable icp (drain system opened to allow cerebrospinal fluid removal). eleven signal characteristics were compared between the two classes (mann-whitney test), and significantly differing variables were tested in the algorithms. we compared the performance of two machine-learning algorithms: the k-nearest neighbors (knn) and the support vector machine (svm). using -fold cross-validation method, % of the data was used to train the algorithms and % was used for testing. the best classifier was further validated by simulating a real-time icp analysis, using a s sliding-window approach with % overlap. the study was approved by the localresearch ethics committee. results: sixteen patients were included in the study. the training database created from patients, contained segments (of s duration) per class and per patient. eight signal variables were identified and kept to define the segments. the knn algorithm, with k = , led to the best performance, with a mean of % (mean ± sd: % ± . %). the knn was then visually validated on icp signals from the remaining two patients ( figure) . by simulating a real-time icp extraction, our algorithm was able to efficiently identify the reliable icp segments, and to display a mean value only for valid segments. university hospital picu (paris). all consecutive children ( month- years) admitted for acute encephalitis were included and diagnosis was confirmed using the consensus conference criteria's. data regarding clinical, biological and radiological presentations were collected as well as data on the therapeutics used and outcomes at discharge and at the last medical consultation. results: patients were included with a mean age of . years (range . to years old). infectious causes were identified in % (n = ), autoimmune causes in % (n = ) and acute demyelinating encephalomyelitis in % (n = ) of cases. etiology remained undetermined in % of cases (n = ). the most common pathogens were, in order of frequency, influenzae virus, mycoplasma pneumoniae and epstein-bar virus. the main clinical features were fever ( % n = ); epileptic seizures ( % n = ) and coma ( % n = ). regarding therapeutics, % of patients required mechanical ventilation and % of patients required hemodynamic support. % received corticosteroids, % intravenous immunoglobulins and % plasmatic exchanges. the use of these specific treatments was heterogeneous, especially in infectious and undetermined encephalitis, where respectively % and % received boluses of corticoids. the mean length of stay in picu was . days (range - days). the mortality rate was % and the overall rate of sequelae at discharge was % and % at distance, with % considered as severe (gose-ped score > ). the use of mechanical ventilation and young age at diagnosis were risk factors associated with poor prognosis at discharge. the etiology of acute encephalitis remains indeterminate in more than % cases with a clear predominance of infectious causes when an etiology is found. this is a severe pathology responsible for significant mortality and morbidity requiring long-term follow-up. compliance with ethics regulations: yes. rationale: preserving neurological outcome of children under extracorporeal membrane oxygenation (ecmo) remains challenging. acute brain injury (abi) is a frequent complication of ecmo that could be prevented by continuous neuromonitoring. cerebral near infrared spectroscopy (nirs) is routinely used for detecting cerebral complications of cardiac surgery. in adults and infants under prolonged ecmo, cerebral hypoxia is associated with poor neurological outcome. the aim of this study was to assess the value of an impaired cerebral oxygenation on mortality and occurrence of an abi in children under ecmo. patients and methods: children under years old were included in this observational retrospective monocentric study if they needed veno-venous (v-v) or veno-arterial (v-a) ecmo for respiratory and/ or circulatory failure and had concomittant nirs monitoring. cerebral desaturation was defined as a rsco value under % or under % from the baseline; cerebral hyperoxia was defined as a rsco value above %. proportion of time in cerebral desaturation and hyperoxia were recorded. neurological lesions were identified on imaging (mri or scan) by blinded radiologist and classified as major or minor. abi was defined as any hemorragic or ischemic lesion on cerebral imaging, including brain death. results: patients were included. ecmo duration was [ ; ] days. the mortality rate was ( . %), and the proportion of abi was ( %) including brain deaths, ( . %) major lesions, and ( . %) minor lesions. mean rsco was ± % in the right hemisphere, and ± % in the left hemisphere. there was no significant difference in cerebral hypoxia between survivors and non survivors, and between patients with and without an abi. cerebral hyperoxia was associated with a better survival (p = . in the right hemisphere, and p = . in the left hemisphere). in v-v ecmo and at the right conclusion: in our study, cerebral hypoxia was not associated with poor neurological outcome, but cerebral hyperoxia seems to be protective especially in v-v ecmo. this is the first study assessing the value of cerebral oxymetry in all age ranges pediatric ecmo. in this population, multimodal monitoring might be better than nirs alone to predict neurological impairment. further prospective studies are needed to assess first the feasibility, then the impact of such a monitoring. compliance with ethics regulations: yes. cerebral autoregulation impairment is associated with acute neurological events during pediatric extracorporeal membrane rationale: children supported by extracorporeal membrane oxygenation (ecmo) present a high risk of adverse neurological complications. as some animal studies have shown, cerebral autoregulation (ca) impairment after exposure to ecmo, may be a key factor. our main objective was to investigate the feasibility of ca continuous monitoring during ecmo treatment. the second objective was to analyze the relationship between ca impairment and neurological outcome. patients and methods: an observational prospective study including children treated by ecmo in centers was conducted. a correlation coefficient between the variations of regional cerebral oxygen saturation (rsco ) and the variations of mean arterial blood pressure(map) was calculated as an index of ca (cerebral oxygenation reactivity index, cox) during ecmo. a cox > . was considered as indicative for dysautoregulation. cox values were averaged inside mmhg-map bins, allowing determining optimal map (mapopt) and lower (lla) and upper (ula) limits of autoregulation in -h periods. neurological outcome was assessed by the onset of an acute neurologic event (ane) defined by occurrence of hemorrhagic or ischemic stroke and/ or clinical or electrical seizure and/or brain death during the ecmo treatment. rationale: myocardial ischemia reperfusion (ir) injury is the leading cause of perioperative morbi-mortality. protective effect of pharmacologic preconditioning such as anesthetic preconditioning (apc) with sevoflurane (sev) has been widely demonstrated in animal and human models. apc seems to protect myocardial cells from apoptosis, a programmed process of cell death tightly controlled by bcl- family proteins. however, the involved mechanisms in apc have yet to be characterized. we hypothesized that apc protects against myocardial apoptotic cell death by regulating bcl- anti-apoptotic members. to study the sev-induced apc mechanisms against myocardial ir, we used a validated in vitro model reproducing ir injury. rat cardiomyoblast cells h c were cultivated in . % o hypoxia in the presence of ischemia-mimicking medium. after min of ischemia, the reperfusion injuries are induced by replacing the culture medium with a krebs-henseleit normoxic medium for min. apc was performed by adding sev directly into the culture medium at an initial concentration of mm, prior to ischemia, for min. we then used another preconditioning agent, metformin (met), to explore the same signaling pathways. apoptotic cell death was measured by caspase activity assay and western blotting (expression of cleaved caspase ) under ir and apc conditions. results: our model faithfully reproduced the protective effect of apc which results in a significant decreased apoptosis under ir ( % reduction of the caspase enzymatic activity, correlated with a decrease of caspase cleavage). we showed that sev induces overexpression of the anti-apoptotic protein bcl-xl, which is responsible for the protective effect of apc. furthermore, these observations were confirmed in vivo in mouse heart lysates. we demonstrated that bcl-xl overexpression was due to the activation of the protein kinase akt. interestingly, we were able to show that preconditioning with met reproduces the protective effect of sev by inducing an akt-dependent bcl-xl overexpression. indeed, sev and met, which are both complex inhibitors of mitochondrial respiratory chain, seem to share a common reactive oxygenated species-dependent protective mechanism responsible for bcl-xl protein regulation. rationale: despite early endovascular treatment with successful recanalization, % of acute ischemic stroke (ais) patients experience a poor functional outcome after a large vessel occlusion. sepsis is frequent at the acute phase of stroke and is associated with poorer short and long term outcomes. we aimed to investigate the cerebral consequences of sepsis after recanalized ais and explore possible mechanisms involved. patients and methods: male c bl mice were randomly assigned to a x factorial plan to one of the following groups: ) a -minute middle cerebral artery (t-mcao) transient occlusion under inhaled general anesthesia, followed min after recanalization by intraperitoneal (i.p.) sepsis (lps, µg/g diluted in µl of nacl . %), (tmcao/ lps group); ) t-mcao followed by i.p. placebo ( µl of nacl . %) (tmcao/placebo group); ) sham operation (cervicotomy without carotid catheterization) followed by i.p. lps. (sham/lps group); ) sham operation followed by i.p. placebo, (sham/placebo group). in all groups, animals received subcutaneous fluid resuscitation ( µl nacl . %) immediately after the procedure and h later. twenty-four hours after recanalization, animals were scored for sepsis features and neurological deficit (on the modified neurological severity scale), (mnss) before sacrifice. the primary outcome measurement was a composite of death and hemorrhagic transformation at h. secondary outcome measurements included neurological deficit, sepsis features, neutrophil activation reflected by plasmatic myeloperoxydase (mpo) levels, stroke volume, and microglial activation in brain parenchyma (infarct core, perilesional area, controlateral hemisphere). results: t-mcao/lps animals had higher mnss ( . fold, p = . ) and sepsis ( fold, p = . ) scores at h with increased plasma mpo levels at h ( . fold, p < . ) and h ( . fold, p < . ), as well as, lower temperature ( . °c reduction, p = . ) and glycemia ( . g/l reduction, p = . ) as compared to tmcao/placebo animals. t-mcao/lps animals had a higher risk of unfavorable outcome at h ( -group comparison: p = . ; x analysis: t-mcao/lps, / − %vs. t-mcao/placebo / - %-, p < . ), whereas stroke volumes were not significantly different between groups. detailed results are presented in table . compared to t-mcao/placebo group, t-mcao/ lps animals had . fold increase (p = . ) in the mean number of microglial cells in the hemisphere controlateral to t-mcao, whereas no significant difference was observed in infarct core or peri-infarct parenchyma. conclusion: early sepsis after experimental ais worsens outcome and neurological deficit, without impacting stroke volume. early sepsisinduced systemic activation of neutrophils and increased microglial activation in the hemisphere contralateral to ischemia may have an important role on neurological outcomes observed in this setting. compliance with ethics regulations: yes. rationale: extracellular vesicles (evs) regulate diverse cellular and biological processes via facilitating intercellular cross-talk. several studies have suggested an association between lung injury and the generation of evs derived from platelets, neutrophils, monocytes, lymphocytes, red blood cells, endothelial cells, and epithelial cells. every year more than , patients require cardiac surgery with cardiopulmonary bypass (cpb). this cpb allows a substitution of the heart pump function and an oxygenation of the blood permitting a stop of the mechanical ventilation (mv). stopping mv during cpb is responsible for lung damage, leading to postoperative systemic inflammation while maintaining mv with positive expiratory pressure (peep) diminished the occurrence of atelectasis and the postoperative inflammatory response. in addition, this surgery is marked by immune dysfunction, leading to real immunosuppression of patients in postoperative care. a link between pulmonary injury and postoperative immunosuppression has been established, however, the mechanisms underlying this association are not fully known and evs may have a role in this post-operative immunosuppression. the purpose of this study is to investigate whether lung injury induced during cardiac surgery with cpb lead to the emergence of evs. the effect of mv during cpb on the production of these evs has also been studied. patients and methods: patients were prospectively divided into two groups: without mv during cpb and dead space mv with positive end-expiratory pressure during cpb. pao (arterial oxygen tension)/ fio (inspired oxygen fraction) ratio, biological markers of lung injury (cxcl , ccl , tnf-α, il- β, il- , rage, il- ) and blood cell count were collected before, h and days after surgery. the quantification of plasma evs was performed using turnable resistive pulse sensing and characterization of evs was performed using flow cytometry before, h and days after surgery. rationale: the benefit of prone positioning (pp) during moderate to severe acute respiratory distress syndrome (ards) may be related to its impact on the inflammatory response to ventilator-induced lung injuries. [ c]-pk is a positron emission tomography (pet) radiotracer that allows the non-invasive quantification of macrophages. we aimed to evaluate the effects of pp on [ c]-pk lung uptake in animals with experimental ards. patients and methods: experimental ards (by hydrochloric acid) was induced in pigs in supine position (sp), to obtain a pao / fio < mmhg. animals were under general anesthesia, neuromuscular blockade, and ventilated with a ml kg − tidal volume, and cmh o of positive end-expiratory pressure (peep). immediately after experimental ards, animals were randomized to be prone positioned, or to remain in sp. pet and computerized tomography (ct) were acquired h after randomization (h ). [ c]-pk uptake was measured on the whole lungs, and by dividing the lungs into regions or slices-of-interest (soi) along the ventro-dorsal axis, and was quantified by the standardized uptake value (suv), corrected for lung tissue density. results: pp was performed in animals, and sp in . after ards induction, pao /fio was [iqr, [ . - . ] in sp animals (p = . ). in pp animals, [ c]-pk suv was significantly lower in ventral soi, compared to sp, and significantly increased in dorsal soi ( fig. , *: p < . between groups in a given soi). in univariate analysis, [ c]-pk regional suv was positively associated with regional ct-measured peep-related increase in gas volume, and negatively with peep-related lung recruitment, but not with regional tidal volume. conclusion: during experimental ards, pp redistributed lung macrophage recruitment estimated by [ c]-pk uptake from ventral lung regions to dorsal regions, without affecting global macrophage influx. the intensity of macrophage recruitment was associated with peep-related lung inflation. compliance with ethics regulations: yes. rationale: acute respiratory distress syndrome (ards) is a pleiomorphic disease characterized by a severe respiratory failure associated with an increased mortality. nowadays, predicting clinical outcome of patients suffering from ards remains difficult. therefore, identifying new biomarkers to predict patient outcome, to evaluate response to therapy and to identify new potential pathways of interest are highly needed. exosomes are extracellular vesicles involved in cell-cell communication by transferring micrornas (mirnas) from donor to recipient cells. thus, exosomal mirnas can significantly affect biological pathways within recipient cells resulting in alterations of cellular function and the development of a pathological state. as biomarkers are highly needed in the particular field of ards, we realized a monocentric and prospective study to identify a new potential biomarker of interest. therefore, a prospective plasma sampling at the diagnosis of moderate to severe ards according to the definition of "berlin" has been performed. we analysed mirna content of exosomes from plasma ards patients compared to healthy subjects (hs) in order to identify new potential predictive biomarkers in ards. during one-year period, patients hospitalized in the icu of chu sart tilman suffering from infectious moderate-to-severe ards have been included. the ethical committee review boards of the hospital approved the research protocol (b , ref: / ), and informed consents were obtained. exosomes were isolated from plasma samples of ards patients and hs with standard ultracentrifugation protocol. exosomal mirna content was analyzed using small rna sequencing method, and diseases/biological processes associated to altered mirs were determined by bioinformatic analysis. results: for the first time, exosomal mirna expression modifications were studied in patients with moderate-to-severe infectious ards. we identified a new signature statistically significant composed of three up-regulated mirnas (mir- , mir- a and mir- ) and one downregulated (mir-let- b). conclusion: we identified potential biomarkers for ards from plasma exosomes. our findings may thus lead to predict ards outcome but also a better understanding about the roles of these mirs in the pathogenesis of ards and thus open new avenues for therapeutic approaches. in particular, exploit and develop the pro-fibrotic pathway induced by down-expression of mir-let- b. but also confirm in the future the current interest about mir- in its ability to restore pulmonary integrity after trauma. compliance with ethics regulations: yes. rationale: diabetic ketoacidosis (dka) is a life-threatening emergency. microvascular hyporeactivity was reported in these patients and was completely reversibly when ph was corrected with treatment: aggressive rehydration, electrolyte replacement and insulin therapy ( ) . red blood cell (rbc), a component of the microcirculation, showed alterations oftheir shape in diabetic patients ( ) but no data were available concerning the time course of the rbc deformability during treatment for dka. we aimed to assess the rbc deformability during dka treatment in icu patients. patients and methods: after approval by the ethics committee, rbcs deformability was assessed, in all icu patients admitted for dka and without infection, by ektacytometry technique (laser-assisted optical rotational red cell analyzer-lorrca): at icu admission, + h, + h and at the end of the icu stay ( - h). elongation index (ei) was defined as (l − w)/(l + w), where l is the length and w is the width. at °c, ei values were determined in the function of shear stress (ss) in a range of . - pa, based upon the laser diffraction pattern changes. a higher ei indicates greater rbc deformation. rbc deformability from patients with dka was compared at icu admission to healthy volunteers (v) and to diabetic patients followed in consultation (d). we also studied the evolution of deformability during treatment. results: icu dka patients compared to d and v were studied. as expected, glycemia and glycated hemoglobin were significantly higher in dka compared to d (respectively: glycemia: ( - ) vs ( - ) mg/dl and . % ( . - . ) vs . ( . - . ); all p < . ). dka patients received ( - ) ml of fluids and . ui/ kg bw ( . - . ) of insulin during their first h of icu stay. rbcs deformability from dka patients was significantly more altered at icu admission compared to others groups ( fig. ) and these alterations persists despite treatment. no correlations were observed between these alterations and quantity of fluids or insulin received, glycemia, glycated hemoglobin, ph, natremia, age or length of diabetes history. conclusion: in contrast of reversible microvascular hyporeactivity, rbc deformability from dka patients was already altered at icu admission and remains altered despite treatment. these alterations could contribute to the blood flow abnormalities observed in these patients. compliance with ethics regulations: yes. rationale: sepsis remains the first cause of acute circulatory failure in the emergency department (ed). standardized fluid resuscitation may not be adapted in certain patients, especially those with early sepsisinduced cardiac dysfunction in whom excessive fluid administration could be deleterious. information on early hemodynamic profile of septic patients in the ed are scarce. accordingly, we aimed at describing hemodynamic profiles encountered in septic patients assessed shortly after their ed admission using focused echocardiography. patients and methods: we prospectively enrolled adult patients with sepsis (qsofa score ≥ ) from january to july in the ed (nct ). focused echocardiography were performed by emergency physicians previously trained to ecmu level. each patient was evaluated according to a standardized protocol based on a limited number of simple binary clinical questions. investigators interpreted on-line the echocardiographic examination, determined the hemodynamic profile based on simple yet robust criteria (hypovolemia, left ventricular [lv] or right ventricular [rv] failure, vasoplegia with hyperdynamic state, tamponade, severe mitral or aortic regurgitation, or apparently normal profile), and recorded any substantial change in planned therapeutic management (surviving sepsis campaign ). data were digitally stored and validated off-line by an expert in critical care echocardiography. results: focused echocardiography were performed in patients (mean age: ± years; men: %; source of infection: pulmonary %, urinary %, abdominal %) after a median fluid loading of ml (iqr: - ml). according to sepsis- definition, patients had sepsis and sustained septic shock. mean sofa score was . ± . (hemodynamic failure %, respiratory failure %, renal failure %), mean lactate reached . ± . mmol/l, icu admission involved % of patients and overall -day mortality reached %. hemodynamic profile was hypovolemia in patients ( %), vasoplegia in patients ( %), cardiac failure in patients ( %) (lv failure: n = ; rv failure: n = ) and without relevant hemodynamic abnormality in patients ( %). ongoing therapy was altered based on early echocardiographic assessment in % of cases. mortality rate was not significantly different between groups (p = . ). conclusion: although hypovolemia was predominantly identified in patients presenting to the ed with sepsis during hemodynamic assessment, early ventricular dysfunction involved one-quarter of patients. these results suggest that early focused echocardiographic assessment promises to help the front-line physician tailoring the therapeutic management of septic patients in ed, especially regarding fluid resuscitation. compliance with ethics regulations: yes. right ventricular failure in septic shock characterization, incidence and impact on fluid-responsiveness guillaume geri , amélie prigent , xavier repessé , marine goudelin , gwenael prat , bruno evrard , cyril charron , philippe vignon , antoine vieillard-baron ambroise paré hospital, boulogne-billancourt, france; ambroise paré hospital, medical icu, aphp, boulogne-billancourt, france; chu limoges, limoges, france; chu brest, brest, france correspondence: guillaume geri (guillaume.geri@aphp.fr) ann. intensive care , (suppl ):f- rationale: right ventricular (rv) failure was defined by rv dilatation with systemic congestion. tricuspid annular plane systolic excursion (tapse) could be of limited value. we report the incidence of rv failure in patients with septic shock, its potential impact on the response to fluids, as well as tapse values. patients and methods: ancillary study of the hemopred prospective multicenter study including patients under mechanical ventilation with circulatory failure. with septic shock were analyzed. patients were classified in groups based on central venous pressure (cvp) and rv size (rv/lv end-diastolic area, eda). in group , patients had no rv dilatation (rv/lveda < . ). in group , patients had rv dilatation (rv/ lveda ≥ . ) with a cvp < mmhg (no venous congestion). rv failure was defined in group by rv dilatation and a cvp ≥ mmhg. passive leg raising (plr) was performed. results: % of patients were in group , % in group and % in group . in group and , rv/lv eda was higher than in group , . [ . ; . ] versus . [ . ; . ]. cvp was [ ; . ] mmhg in group . a correlation between rv size and cvp was only observed in group . higher rv size was associated with a lower response to plr (figure) . a large overlap of tapse values was observed between the groups. . % of patients with rv failure had an abnormal tapse. conclusion: rv failure is frequent in septic shock and alters fluid responsiveness. tapse was not accurate enough to diagnose rv failure. compliance with ethics regulations: yes. rationale: weaning-induced pulmonary oedema (wipo) is a leading cause of weaning failure in high-risk patients (heart failure, copd, obesity). we hypothesized that hypervolemia associated with positive fluid balance facilitates wipo in high-risk patients. patients and methods: in this prospective, observational, singlecenter study, patients with copd and/or heart failure with reduced ejection fraction (< %) were studied. exclusion criteria were nonsinus rhythm, severe mitral valve disease and inability to obtain adequate echocardiographic views. echocardiography was performed immediately before and during spontaneous breathing trial (sbt, -min t-tube). patients who failed sbt were treated according to echocardiographic results before undergoing a second sbt. fluid balance and body weight were collected at each sbt. shows interesting performance to predict fluid responsiveness in spontaneously breathing patients. nevertheless, measurement sites of inferior vena cava (ivc) diameters remain controversial for that purpose. the aim of the study was to test the accuracy of different measurement sites of civc to predict fluid responsiveness in spontaneously breathingpatients. this study is a post hoc analysis of two prospective cohorts. we included spontaneously breathing patients without mechanical ventilation presenting with sepsis-related acute circulatory failure and considered for volume expansion (ve). we assessed hemodynamic status at baseline and after a fluid challenge (fc) induced by a min-infusion of ml-gelatin %. the ivc diameters were measured off-line with ultrasonography using the bi-dimensional mode on a subcostal long-axis view. the civc was calculated as [ (expiratory-inspiratory)/expiratory] diameters during standardized (civc-st) and unstandardized breathing (civc-ns) conditions. breathing standardization consisted of a deep inspiration with concomitant control of buccal pressures and passive exhalation. patients were referred to be responders to fc (i.e. fluid responsive) when the stroke volume increased by ≥ %. results: among the patients included in the study, ( %) were responders to fc. the accuracy of civc-st and civc-ns before fc to predict fluid responsiveness differed significantly by measurement sites (interaction p value < . and < . , respectively). measuring ivc diameters cm from the junction of the ivc and the right atrium provided the best accuracy to predict fluid responsiveness ( fig. ). at cm caudal to the right atrium, civc-st was significantly better than civcns to predict fluid responsiveness: area under roc curve . ( % ci . - . ) versus . ( % ci . - . ), p < . . at cm, a civcst ≥ % and a civc-ns ≥ % predicted fluid responsiveness with sensitivity of % and %, and specificity of % and %, respectively. conclusion: accuracy of civc to predict fluid responsiveness in spontaneously breathing patients depends on both measurement sites of ivc diameters and breathing conditions. measuring ivc diameters during a standardized inspiration maneuver at cm caudal to the right atrium is the most relevant mean to optimize civc performance to guide ve. compliance with ethics regulations: yes. rationale: intermittent hemodialysis (ihd) is increasingly used in patients admitted to intensive care unit (icu) with acute kidney injury (aki) requiring renal replacement therapy (rrt). however, this technique is associated with nearly % of episodes of perdialytic hemodynamic instability (hi), a common cause of increased morbidity and mortality. at the same time, trans-thoracic echocardiography (tte) has become widely used in intensive care units and is now one of the hemodynamic monitoring methods used daily in the icu setting. patients and methods: search for one or more pre-dialysis tte criteria predictive of perdialytic hi, defined by a systolic blood pressure (sbp) lesser than mmhg or a suddain decrease in sbp of more than mmhg. prospective, observational study of standard care in a medical icu. collection of demographic, clinical and pre-dialysis echocardiographic data from included patients. results: twenty-five patients with a total of sessions of ihd between november and november were included in the study. tte was performed for each patient before each ihd session. hi occurred in hemodialysis sessions. in univariate analysis, the existence of prior heart disease ( % vs %, p = . ), a greater diameter of the left atrium ( . vs . cm, p = . ), a lower cardiac output ( . vs . l/min, p = . ), a right dysfunction assessed by lowered tapse and s-wave ( vs mm, p < . and . vs . cm/s, p = . , respectively) and an increase in paps ( vs mmhg, p = . ) were significantly associated with the occurrence of perdialytic hi (fig. rationale: several transthoracic echocardiography (tte) parameters of left (lv) and right ventricular (rv) systolic function are available. we compared the ability of these different parameters to track changes in lv or rv systolic function and to detect lv or rv systolic dysfunction in critically-ill patients. in patients ( mechanically ventilated and with atrial fibrillation), tte examinations were performed before and after i) infusion of -ml of saline (n = ), ii) changes in norepinephrine (n = ), iii) or in dobutamine (n = ) dosage. for the lv systolic function, we compared the mitral annular plane systolic excursion (mapse), the systolic (s') peak velocity of the lateral mitral annulus and the global longitudinal strain (glslv) to the lv ejection fraction (lvef), considered as the gold standard. for the rv systolic function, we compared the tricuspid annular plane systolic excursion (tapse), the systolic peak (s) velocity of the tricuspid annulus and the global longitudinal strain (glsrv) to the rv fractional area change (fac), considered as the gold standard. results: after pooling all values, lvef ( ± % at baseline) was better correlated to glslv (r = . ) than to mapse (r = . ) and s' wave (r = . ) (each p < . ). the concordance rate between changes (in %) in lvef and in the other parameters of lv systolic function was % for glslv, % for mapse and % for s' wave. both mapse and s' wave could not reliably detect moderate ( % ≤ lvef ≤ %) or severe (lvef < %) lv dysfunction. conversely, a glslv > − % predicted moderate lv dysfunction with a sensitivity of % ( % ic: - %) and a specificity of % ( % ic: - %) and a glslv > − . % predicted severe lv dysfunction with a sensitivity of % ( % ic: - %) and a specificity of % ( % ic: - %). after pooling all values, fac ( ± % at baseline) was better correlated to glsrv (r = . ) than to tapse (r = . ) and s wave (r = . ) (each p < . ). the concordance rate between changes (in %) in fac and in the other parameters of rv systolic function was % for glsrv, % for tapse and % for s wave.both tapse and s wave could detect rv dysfunction (fac ≤ %) with moderate reliability only. conversely, a glsrv > − % detected rv dysfunction with a sensitivity of % ( % ic: - %) and a specificity of % ( % ic: - %). in critically-ill patients, glslv and glsrv seem to be the best tte parameters of lv and rv systolic function. enrolments are still ongoing, which may allow further analysis. compliance with ethics regulations: yes. rationale: passive leg raising (plr), pulse pressure variation (ppv), and the -second end-expiratory occlusion test (eexpo) are frequently used to assess preload responsiveness. however, there are conditions in which they are not valid or feasible, which may preclude their applicability in the daily clinical practice. the aim of this study was to estimate the prevalence of such conditions in critically ill patients with acute circulatory failure. between january and april , all patients of a -bed medical icu were daily screened and those with acute circulatory failure, defined by norepinephrine infusion or fluid therapy > l during the previous h, were included. in each of them, we screened the criteria of validity/feasibility of ppv, plr and eexpo. results: eighty-four patients ( % with septic shock, % with cardiogenic shock, % with hypovolemic shock, % with non-septic vasoplegic shock) were enrolled in the study. among them, norepinephrine infusion was ongoing at the time of enrolment in % of the patients whilst % were under mechanical ventilation, and % with acute respiratory distress syndrome. plr was not applicable in % of cases. this was mainly due to venous compression stocking ( % of cases), intra-abdominal hypertension ( % of cases), and either an absence of cardiac output monitoring or impossibility to perform echocardiography ( % of cases). among the intubated patients, ppv was applicable in % of cases, including cases with high ppv under conditions generating false negatives (low tidal volume or lung compliance) or low ppv values under conditions generating false positives (spontaneous breathing, cardiac arrythmias). however, ppv was not interpretable in % of cases. this was mainly due to low tidal volume ventilation ( % of cases), spontaneous breathing activity ( % of cases), while the remaining non-interpretable cases ( %) had more than one reason. in the intubated patients, eexpo was not applicable in % of cases. this was due to impossibility for patients to sustain a -s hold of mechanical ventilation in % of cases, and either an absence of cardiac output monitoring or the impossibility to perform echocardiography in % of cases. plr and eexpo were both valid and feasible in % of the patients, and the three tests were all feasible in only % of patients. rationale: comorbid association between chronic respiratory diseases and sleep apnea syndrome (sas) revealed frequent with systematic search in icu following icu stay. this association carries prognosis impact depending whether specific treatment is implemented or not. nosas and stop bang scores are proposed for screening of sas in general population. the aim of the present study is to report the prevalence of sas in icu patients admitted for hypercapnic respiratory failure and compare association of nosas and stop bang score with sas severity. the study was conducted between january and september . patients consecutively admitted in the icu for hypercapnic respiratory failure had calculation of a no sas and stop bang scores at admission. in survivors nocturnal polygraphic records was performed to weeks following icu discharge. the association between the number of apnea-hypopnea episodes, bmi, and clinical variables suggestive of sas, was tested by poisson regression model. results: during the study-period, patients (mean age: ± years, ph . ± . , paco ± ) were admitted for hypercapnic respiratory failure. non invasive ventilation was used in % and death occurred in six patients. polygraphic records were performed in ( lost to follow-up) mean apnea-hypopnea index was ± with a minimum of and a maximum of . poisson logistic regression showed that no sas (p = . ) but not stop bang (p = . ) was associated with the level of apnea-hypopnea index. rationale: patients with severe acute exacerbations of chronic obstructive pulmonary disease (copd) may benefit from high-flow nasal oxygen regarding its physiological effects and good tolerance. bronchodilator vibrating mesh nebulization through high-flow nasal oxygen circuit has been described to induce similar effect to standard facial mask jet nebulization in stable copd patients. we aim to evaluate whether vibrating mesh nebulization of salbutamol through highflow nasal oxygen circuit is efficient in unstable patients with copd. patients and methods: we conducted a monocenter non-randomized physiological prospective cross-over study, between january and september , including icu patients with severe acute exacerbation of copd and respiratory acidosis treated by salbutamol nebulization. spirometry and airway resistances records were performed after a -h wash-out period without bronchodilator, before and after vibrating mesh nebulization of mg salbutamol through high-flow nasal oxygen circuit. the primary endpoint was forced expiratory volume in s after salbutamol nebulization. secondary endpoints included other spirometry parameters, clinical parameters, dyspnea assessed by a borg scale. results: fourteen consecutive patients were included, forced expiratory volume in s increased significantly after salbutamol nebulization through high-flow nasal oxygen ( ± ml, p = . ), as well as forced vital capacity ( ml ± , p = . ). airway resistances were not significantly changed after nebulization (− . ± . , p = . ) as well as peak expiratory flow (+ ml ± , p = . ). no difference was observed on borg scale (p = . ) and respiratory rate (p = . ) after salbutamol nebulization, while heart rate increased significantly (p = . ). discussion: salbutamol nebulization using vibrating mesh nebuliser placed on high-flow nasal oxygen circuit induces a significant but moderate bronchodilation in patients with severe acute exacerbation of copd. moreover, improvement of forced vital capacity after salbutamol nebulization suggests a reduction of dynamic hyperinflation. conclusion: salbutamol vibrating mesh nebulization through highflow nasal oxygen circuit increases significantly forced expiratory volume in s. compliance with ethics regulations: yes. t-piece versus sub-therapeutic pressure support for weaning from invasive mechanical ventilation in patients with chronic obstructive pulmonary disease: a comparative prospective study amira jamoussi, fatma jarraya, samia ayed, takoua merhabene, jalila ben khelil, mohamed besbes abderrahmen mami hospital, tunis, tunisia correspondence: amira jamoussi (dr.amira.jamoussi@gmail.com) ann. intensive care , (suppl ):f- rationale: the best weaning strategy for patients with chronic obstructive pulmonary disease (copd) remains unknown. the spontaneous breathing trial (sbt) represents a crucial step of weaning, but the choice between the t-piece (sv-tube) or the sub-therapeutic setting of the level of pressure support without positive expiratory pressure (psv) is still a matter of debate. we aimed to compare the success of extubation between two groups of copd patients according to the sbt type (vs-tube vs psv). patients and methods: it was a prospective and comparative study, from april to march , at the abderrahmen mami hospital's intensive care unit (icu). copd patients who underwent invasive mechanical ventilation (mv) for at least h and met the criteria for weaning were included and randomized to sv-tube or psv. a multivariate analysis was performed to determine the association between the sbt modality and the success of extubation (no re-intubation during the h following extubation). results: during the two years' study, patients were included. the mean age was ± years, the sex-ratio was . . weaning process was simple in patients ( %), difficult in patients ( %) and prolonged in patients ( %). fifteen and patients were respectively randomized to the sv-tube and psv groups. the mean duration of mv before randomization was comparable between the groups (sv-tube . ± . days vs psv . ± . days, p = . ). mean weaning time (days) was . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] for the sv-tube group and . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] for the psv group. the mean total mv duration (days) was higher in the sv-tube group than in the psv group ( . vs . , p = . ). the number of re-intubated patients within h following extubation was higher in the psv group ( / vs / , p = . ) as well as the overall reintubation rate ( . % vs %, p = . ). in multivariate analysis, the sbt's trial was independently associated to the success of extubation (or = . , ic [ . - . ], p = . ) in favor of sv-tube' modality. the median length of stay in intensive care was days [ ; ]. the mortality was higher in the psv group ( / vs / , p = . ). extubation failure was a factor associated with mortality (or = . , ci [ . , . ], p = . ). conclusion: ventilation weaning was easy in % of intubated copd patients. sv-tube as sbt modality was associated to success of extubation in patients with copd. mortality in intensive care was significantly higher in re-intubated patients. compliance with ethics regulations: yes. rationale: non-invasive ventilation has become the mainstay in hypercapnic respiratory failure. delaying intubation and invasive ventilation is associated with a worse outcome in these patients. although a predictive score of niv failure has been validated for hypoxemic respiratory failure no such score exists in hypercapnic respiratory failure. the aim of our study is to compare the performance of two scores in the predictive niv failure hypercapnic respiratory failure. patients and methods: consecutive patients admitted between january and july for hypercapnic respiratory failure, were included. hacor score and rox score were calculated in each patient at admission. in patients ventilated non-invasively, the outcome (niv success or failure) was noted. the area under curve (auc) and operative characteristics were computed for both scores. results: during the study-period, out of patients admitted for hypercapnic respiratory failure received niv as the primary ventilatory mode. these patients were mainly men ( / ), had a mean age of . ± years and had the following pulmonary disease: copd exacerbation . %, obesity-hypoventilation syndrome . %, bronchiectasis . %, and other diseases: . %. niv failure occurred in patients ( . %) and icu mortality in . %. mean hacor score and rox score were . ± . and . ± , respectively. the auc under roc was higher for hacor than rox ( . and . respectively) ( fig. ). the hacor score (cut-off ) had a sensitivity of . and specificity of . . conclusion: hacor score seems more accurate in predicting niv failure in hypercapnic respiratory failure. further prospective validation is needed. compliance with ethics regulations: na. rationale: published data on outcomes in respiratory weaning centers are limited and seem to depend on the organisation of healthcare systems and patient case-mix. the weaning center of our university hospital (post intensive care rehabilitation unit) admits for weaning and rehabilitation patients from medical and surgical intensive care units without severe neurological pathologies. the aim of this study was to describe patient's characteristics and outcome (weaning outcomes and survival) and to compare in subgroups according to the initial medical, surgical or cardiac surgical context. patients and methods: we conducted a monocentric retrospective observational study between / / and / / . «successful outcome» was defined by the association of survival and weaning from invasive ventilation. factors associated with evolution were investigated by uni-and multivariate analysis. survival after discharge was analysed according to the initial context and according to the type of ventilation at discharge. results: among patients included, ( . %) had a successful outcome with high use of non-invasive ventilation (niv) ( %). respiratory history (p = . ), female gender (p < . ), igs score at admission to the srpr (p = . ) and non-cardiac surgical setting (p < . ) were associated with an adverse course. the -month survival rate was % in discharged patients. the outcome was not different in the tree subgroups. niv rate at discharge was high in the subgroup of cardiac surgery patients. a multidisciplinary and personalised approach by a specialized weaning unit can provide a successful service model for patients who require liberation from prolonged invasive mechanical ventilation. compliance with ethics regulations: yes. rationale: high-dose insulin euglycemic therapy (hiet) is recommended as first line therapy for calcium channel blockers (ccbs) poisoning because of its inotropic effect. our first objective was to study its hemodynamic impact. we performed a retrospective cohort study of all consecutive patients admitted for ccbs poisoning treated with hiet, in one icu at the university hospital of lille between january and july . the hemodynamic impact was studied through mean arterial pressure (map), vasoactive-inotropic score (vis) and map/vis ratio during the h following hiet initiation. metabolic parameters were also collected. results: patients admitted for ccbs poisoning. patients treated with hiet in icu ( patients without circulatory shock, patients with shock after hiet and patients with shock at baseline before hiet). among shocked patients at baseline (n = ), no hemodynamic improvement was found except an increased map/vis ratio at h (p < . ). on the contrary, an initial worsening of vis ( [ rationale: ketamine is used in the induction and maintenance of general anesthesia. recently, there were concerns regarding its liver toxicity. we conducted a study to investigate the link between ketamine use and liver dysfunction (ld) in intensive care unit (icu) patients. patients and methods: data were extracted from the [anonymized] study, a randomized controlled trial designed to evaluate the effect of cisatracurium on -day mortality rate in moderate and severe acute respiratory distress syndrome (ards) patients. the main endpoint was the occurrence of a ld defined as a total serum bilirubin superior or equal to micromol/l. a matched case-control cohort was created: cases, receiving at least day of continuous ketamine infusion, were paired for with controls according to treatment with cisatracurium, hepatic and cardiovascular sofa sub-score, total serum bilirubin level at the time of inclusion, age, sex, ards from septic origin, shock anytime after inclusion. an analysis was also made on the whole cohort comparing the patients receiving at least day of continuous ketamine infusion to all patients who did not fulfill this criterion. results: cases were identified and matched to controls. in the ketamine group, the median ketamine duration was ( - ) days, and median total cumulative dose . ( . - . ) g. the occurrence of ld was higher in the ketamine group than in the matched control group ( . % versus . %, p = . , fig. ). the hazard ratio (hr) for ld in the ketamine group was . ( % ci . - . , p = . ). there was an increased risk of ld of . % per day of exposure to ketamine (hr . , % ci . - . p = . ) and of . % per gram of ketamine infused (hr . , % ci . - . , p = . ), with a risk starting to be statistically significant after days and gr. in multivariate analysis on the whole cohort, ketamine exposure (hr . , % ci . - . , p = . ), cumulative dose in gram (hr: . , % ic: . - . , p = . ) and ketamine exposure in days (hr: . , % ic: . - . , p < . ) remained independent risk factors for ld occurrence. conclusion: ketamine use in critically ill patients treated for ards is associated to a higher risk of liver dysfunction, assessed by total serum bilirubin. this risk is dose-dependent and increases with duration of treatment. the prescription of high doses or prolonged treatment with ketamine should probably be avoided in critically ill patients. compliance with ethics regulations: yes. rationale: ciguatera is one of the most common cases of marine poisoning associated with fish consumption in the world. the incidence of this intoxication is largely unreported. in martinique, the incidence of this intoxication seems constantly increasing. during the last years, numerous cases of large collective poisonings have been reported in martinique, especially during summer. the spectrum of clinical manifestations is large including gastrointestinal, neurological andcardiovascular symptoms. ciguatoxin, the toxin responsible for ciguatera fish poisoning is considered as a sodium channel agonist with cholinergic and adrenergic activity. it is rarely fatal and management of poisoned patients is essentially based on supportive care. the objective of this study was to describe the clinical characteristics and complications of ciguatera poisoning in martinique, focusing on the cardiovascular ones. observational, retrospective, single-center study covering six-year period from october to september , including all patients admitted to the emergency department of the university hospital of martinique (chu), and all patients who were declared to the regional health agency (ars) for ciguatera intoxication. results: one hundred and forty-nine patients ( ) who were ciguatera-affected were included. the incidence rate found was to be . cases per . patient-years in martinique over the period. about % of patients had gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdominal pain; % neurological disorders and % cardiovascular symptoms including, bradycardia, hypotension and interventricular block. ingestion of carangue fish was related to a major risk of chronic signs. conclusion: the incidence of ciguatera in martinique is increasing, with . cases/ . patient-years. the clinical presentation is defined mainly by digestive signs, followed by peripheral neurological disorders and cardiovascular symptoms. ciguatera fish poisoning in martinique presents similar clinical presentation to that of the other caribbean islands. there is no specific treatment. acute ciguatera poisoning is responsible for significant cardiovascular complications. physicians should be aware of the potential cardiovascular risk of ciguatera poisoning. compliance with ethics regulations: yes. rationale: pesticides have represented the most incriminated products in severe acute poisonings, in the developing countries, due to the availability of these products. organophosphate poisoning accounts for million poisonings/year worldwide. organophosphate (op) pesticides are used mainly as insecticides in agriculture. the moroccan anti-poison and pharmacovigilance centrer shows that op poisoning are responsible for % of all poisonings combined. the aim of our study: epidemiological, clinical, management and prognostic factors. patients and methods: a retrospective study was conducted on patients with op poisoning admitted to our nine-bed medical intensive care unit between january and december . inclusion criteria were: all patients over years of age and the exlusion criteria were: pesticide poisoning other than op, alcohol poisoning, drug poisoning, scorpionic poisoning and snake bites. statistical analysis was performed with spss software. results: forty patients were admitted for acute op poisoning. in morocco, organophosphores are available over-the-counter in several forms: rodentocides, malathion, cockroach trap, baygon insecticide ( fig. ). the average age was years with a female prévalence of . %. the intoxications were mostly intentional ( %). the symptomatology was determined by the three syndromes: central syndrome in %, muscarinic syndrome in %, nicotinic syndrome in %. rhythm disorders in %, and cardiovascular collapse in %. the symptomatic treatment was applied to all patients, antidotic treatment was administered in % of patients. the average length of hospitalization was days. conclusion: acute op poisoning is a real public health problem. its associated symptomatic treatment (respiratory and neurological resuscitation) and antidotic treatment. the mortality remains high in our context, therefore, we must attach great importance to the prevention. compliance with ethics regulations: yes. ( ). over an -month period, health officials in guadeloupe and martinique reported more than . such cases. assault of these brown algae represents not only an environmental and economic disaster, but also a threat for human health. after h on seashore, large amounts of toxic gas are produced by matter decomposition, including hydrogen sulfide (h s) and ammoniac (nh ). the acute effects on humans after exposure to high concentrations of h s are well described and of increasing severity with concentration, leading to potentially fatal hypoxic pulmonary, neurological and cardiovascular injuries (table ) ; however, the association of long-term exposure to sargassum and health events is unknown. although less documented, long term exposures may result in conjunctiva and upper airways irritation, headaches, vestibular syndrome, memory loss, and modification of learning abilities. in the absence of any available antidote, management of h s intoxication relies on supportive care and prevention using individual protection. the objective of this study was to evaluate the clinical characteristics and consequences of long-term exposure to sargassum among the local population. we conducted a prospective observational cohort study including all patients admitted to the emergency department at the university hospital of martinique from march to december due to exposure to sargassum. patients were managed according to the protocol established by the research group on sargassum in martinique. we assessed the patients exposure to sargassum and air pollutants using monitor located near of the patient's residence. demographics and clinical data (including cardiovascular, neurological and respiratory events) were collected. data are presented as mean ± sd or %.comparisons were performed using univariate analysis. results: in months, patients were included (age: ± years, m/ w, past history: hypertension (n = ), diabetes (n = ), asthma ( ). patients arrived with referral letter from their general practitioner ( %) and presented headaches ( %), developed gastrointestinal disturbances ( %), dizziness ( %), skin lesions ( %), cough ( %) and conjunctivitis ( %). not all patients were clinically symptomatic. in the patients presented in june ( %), symptoms more frequently occurred in the workplace or at home (p < . ). initial lung function tests were normal ( %). three patients were admitted in intensive care unit. conclusion: our study indicates that the magnitude of health effects following long-term exposure to sargassum may be larger than previously recognized. efforts to limit long-term exposure are mandatory. compliance with ethics regulations: yes. rationale: liver consequences of out-of-hospital cardiac arrest (ohca) have been poorly studied. the aim of this study was to describe the characteristics of ohca-induced acute liver dysfunction and its association with outcomes. we analyzed all consecutive ohca patients admitted to two academic centers between and . patients treated with vitamin k antagonist were not included. acute hepatocellular insufficiency (ahi), liver failure (lf) and hypoxic hepatitis (hh) were defined as a prothrombin (pt) ratio < %, a hepatic sofa sub-score > and an increase in transaminases > times the normal values, respectively. indocyanine green (icg) clearance was used as the reference measure of liver function in a subset of patients. multivariate logistic regression was used to identify potential risk factors for day mortality. rationale: neuron-specific-enolase (nse) is commonly used as a biomarker reflecting the extent of brain injury in different settings. in post-cardiac arrest patients, previous clinical studies reported that an increase in nse was predictive of a poor outcome but did not specifically focused on neurological outcome. in this prospective study, we aimed to determine the nse performance for prediction of severe brain damage in post-cardiac arrest patients. patients and methods: all consecutive patients admitted in our icu after cardiac arrest between january and february that were still comatose at h and had at least one measurement of serum nse were included. blood samples for nse measurement were serially collected at (h ) and h (h ) after cardiac arrest and serum nse levels were measured within h. we used the following criteria for the definition of severe brain damage (primary endpoint): cerebral performance categories (cpc) or level at discharge, brain death or withdrawal of life-sustaining treatments (wlst) based on neurological status. we also assessed the predictive value of serum nse using allcause mortality as a secondary endpoint. results: during the study period, patients were available for the analysis. they were mostly male ( . %), with an age of . years. among these patients, ( . %) had a good neurologic outcome (cpc - ) and patients were classified as having a severe brain damage ( wlst based on neurological status, brain deaths and survivors with . in univariate analysis, patients with severe brain damage less frequently received bystander cpr, had longer duration of no-flow, less initial shockable rhythm, more post-resuscitation shock and higher nse values: mean at h were . versus . ; and . versus . at h (p < . ). nse levels at h and h were strong predictors of severe brain damage (auc of . and . respectively, figure ) and also predicted all-cause mortality (auc of . and . respectively). to predict severe brain damage with % specificity, best nse cutoff values at h and h were . and . µg/l, with a sensitivity of . and . % respectively. conclusion: a high serum nse measured at h and h after cardiac arrest accurately predicted severe brain damage with a high specificity. our results support the use of nse for neuroprognostication after cardiac arrest, in combination with other predictors. compliance with ethics regulations: yes. rationale: the psychological care of patients, their relatives and of healthcare workers is a major issue in the intensive care unit (icu). psychologists may provide emotional support during trying times. the intervention of a psychologist may alleviate long term mental health issues such as post-traumatic stress disorder. the main objective of our study was to describe the availability of psychologists in french-speaking icus. patients and methods: internet survey conducted between march and may using surveymonkey (san mateo, usa). survey consisting of questions sent to subscribers of the srlf mailing list via mailchimp software (atlanta, usa). frequencies and percentages were determined for categorical variables and median and interquartile range for continuous variables. the icus with or without psychologist were compared using nonparametric fisher exact test. stata used (lakeway drive, te, usa). results: responses were obtained from unique icus in france (n = ), belgium (n = ), switzerland (n = ), algeria (n = ), morocco (n = ) and tunisia (n = ). ( %) icus were part of public hospitals, ( %) of private facilities. ( %) icus cared for adult patients, ( %) for children. the median number of beds was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . ( %) icus were open to visitors / , ( %), to visitors > h/day and ( %) to visitors < h/day. psychological consults were established in ( %) wards ( icus did not answer). pediatric icus employed more psychologists than adult icus (p = . ). comparison of icus based on the presence or not of a psychologist appears in table . in icus where a consulting psychologist is available, their effective availability is . [ . - ] full time equivalent. consults are delivered to: patients ( %), families ( %) or healthcare workers ( %). out of the icus without a psychological consult, responders from ( . %) icus believe that a psychological consult is undesirable. out of the icus without psychological consult, ( %) responders cannot obtain a psychological consult, whatever the circumstances, ( %) can require an outside psychological consult when needed, while ( %) can require assistance from a psychologist working in another unit (several answers possible for each respondent). conclusion: psychologists consult in only half of adult icus but in almost all pediatric icus. % of icus are unable to provide a psychological consult. psychological consults are delivered in similar proportions to patients, their family and to a lesser extent to healthcare workers. responders from . % icus without an established psychological consult believe that the availability of a psychologist is undesirable. compliance with ethics regulations: na. rationale: comfort of patients in intensive care unit (icu) is now a real concern for the healthcare teams. perceived patient discomfort assessment is a daily practice for our staff. the primary objective of our study was to assess whether the overall discomfort score reported by patients hospitalized in a separate intermediate care unit differs from that reported by patients hospitalized in icu. a tailored multicomponent program consisting of assessment of icu-related self-perceived discomforts with a -item questionnaire, immediate and monthly feedback to healthcare teams and site-specific tailored interventions, was applied in our department, located in a general hospital, and comprising a -bed icu and a separate -bed intermediate care unit rationale: the transition period surrounding the discharge from icu to hospital ward is a critical period in the course of the patient. handoff of complex patients is at high risk for communication failures between providers, inaccurate cares and icu readmission. a transition program including a post icu follow-up has been proposed to improve handoff quality. post icu consults by icu team represent, also, an opportunity for improving feedback on the quality of icu cares. the goal of the present study is to assess the feasibility and the impact of a systematic early post-icu consult (epicuc) program on handoff quality in a bed mixed icu. patients and methods: before the development of the epicuc program, standardized handoffs were already applied including identified day and hour of discharge and both verbally communicate and written medical and nurse information for receiving team. from st march to th october , all patients who were discharged to the ward of our hospital were candidates for epicuc. epicuc were performed by icu staff (at least one icu physician) within the days following discharge. the epicuc consisted of a face-to-face discussion with the receiver team to assess the accuracy, completeness and understanding of passing information and of a patient visit. a standardized form was used for collecting data. the impact of epicuc on handoff quality was assessed by the number of communication failures and the number of patients in whom epicuc resulted in a management change. personal feeling of epicuc providers on its usefulness was assessed by a - rating scale. results: among the candidates for epicuc, were dead and already discharged alive from hospital at epicuc time. epicuc were performed in patients ( %) within ± days after icu discharge. epicuc ( %) were performed by both, nurse and icu physician. ( %) patients and receiver teams ( %) were available at epi-cuc time. epicuc duration was ± min. a communication failure was identified in epicuc ( %), either a rectification of passing information (n = ; %) and/or a change in patient management (n = ; %). the usefulness of the epicuc was rated at ± and ± by icu physicians and nurses, respectively. conclusion: the time spent for epicuc appears reasonable. epi-cuc identified a communication failure in one-third of handoffs and allowed care readjustment in one quarter of patients. factors associated with handoff failures will be presented during the congress. compliance with ethics regulations: yes. rationale: surviving a critical illness is a challenging condition for patients and relatives. the psychological aspects are directly affected by physical status and performance. patients can feel depressed or anxious facing difficulties during recovery time. the aim of this study was to correlate patients' perceptions of his health status and his clinical performance measured after icu discharge. patients and methods: this is a prospective pilot study of an icu follow-up clinic conducted in a single center from january to july . this clinic is multidisciplinary and includes two visits at and months after icu discharge. patients with more than days of icu los were eligible. all patients at and -m visit were evaluated with sf- , mwt, mrc and time-up-and-go test. we conducted an analysis comparing clinical performance data and qualitative data between and months after icu discharge. the investigation included patients who had at least days of icu length of stay. patients attended the consult at -m and patients attended the consult both times. the median age (iqr) was ( - ) and % were men. %, % and % of patients had medical, scheduled surgical and emergency surgical admission causes respectively, with median (iqr) saps iii score ( - ). %, % and % of patients had sepsis, delirium and mechanical ventilation as a support. the physical status was progressively increased overtime likewise the physical capacity assessed by sf- score with p-value . between and -m. however, no significant difference between the subjective dimension of sf- , which analyses the perception of the patient about his physical capacity, assessed at -m and at -m was demonstrated (p . ). in this pilot-phase of following a cohort of critically ill patients, the natural physical improvement does not seem to change the patient's perception of their performances. this paradigm rouses a different perspective that should take into account when setting up rehabilitation programs. compliance with ethics regulations: yes. post-traumatic stress disorder after discharge from an acute medical unit basma lahmer , naoufel madani , , jihane belayachi , , redouane abouqal rationale: post-traumatic stress disorder (ptsd) occurs after exposure to a traumatic event and comprises of symptoms of repeated re-experiencing of the said event, avoidance of reminders, emotional numbing and persistent hyperarousal. in individuals exposed to "medical stress", various studies found evidence of ptsd occurring after the onset, diagnosis, or treatment of physical illness. our study aims to determine ptsd's risk factors in patients of an acute medical unit (amu) after their discharge. patients and methods: it was a prospective, analytical study conducted over a period of months at an acute medical unit. we collected sociodemographic and clinical data, patients' medical history, and evaluated the symptoms of anxiety and depression during their stay using the hospital anxiety and depression scale (hads). the prevalence of severe ptsd symptoms was assessed with the impact of events scale-revised (ies-r) at weeks and months using a cutoff of . associations between ptsd as evaluated by ies-r at months and patients' characteristics, including hads scores at admission were investigated using unadjusted linear regression, for univariate and multivariate regression analysis. statistical analyses were carried out using spss for windows (spss, inc., chicago, il, usa). we included patients in our study with a mean age of . ± . . in our population, . % of patients scored higher than a ies-r cutoff at weeks compared to . % at months. the mean hads-anxiety score is . ± and that of the hads-depression score is . ± . . on one hand, higher hads-anxiety score during the stay in the amu was linked to higher ies-r scores at months β: rationale: objective of critical care includes restoration of functional capacities. prompt identification of muscle acquired weakness (icu-aw) is crucial to target efficient rehabilitation. in published literature, data of quadriceps strength (qs) cannot be compared because of insufficient standardization of measurement protocols. we recently validated a highly standardized protocol of qs measurement. in order to build basic and comparable knowledge and to identify the weakest patients, this study aimed to describe qs of critically ill (ci) patients during their short-term evolution, and to compare them to surgical (s) and healthy (h) subjects. patients and methods: this observational study included ci patients who spent at least days in icu, patients scheduled for elective colorectal surgery (s) and young healthy volunteers (h). maximal isometric qs was assessed using a handheld dynamometer (microfet ® ) and expressed in newton/kg (n/kg). dominant leg was tested in supine position using a highly standardized procedure. ci and s patients were tested at t (as soon as collaborative in icu) and month after discharge (m rationale: the post intensive care syndrome (pics) gathers various disabilities, associated with a substantial healthcare use. however, patients' comorbidities and active medical conditions prior to intensive care unit (icu) admission may partly drive healthcare use after icu discharge. to delineate the relative contribution of critical illness and pics per se to post-critical illness increased healthcare use, as opposed to pre-existing comorbidities, we conducted a population-based evaluation of patients' healthcare use trajectories. patients and methods: using discharge databases in a . -million-people region in france, we retrieved, over three years, all adult patients admitted in icu for septic shock or acute respiratory distress syndrome (ards), intubated at least days and discharged alive from hospital. healthcare use (days spent in healthcare facilities) was analyzed two years before and two years after icu admission. healthcare trajectories were next explored at individual level: patients were assembled according to their individual pre-icu healthcare use trajectory by clusterization with the k-means method. results: eight-hundred and eighty-two ( ) patients were included. median duration of mechanical ventilation was days (interquartile ranges [iqr] ; ), mean saps was , and median hospital length of stay was days (iqr ; ). prior to icu admission, we observed, at the scale of the whole study population, a progressive increase in healthcare use. however, clusterization of individual according to pre-icu healthcare trajectories identified patients with elevated and increasing healthcare use (n = ), and two main groups with low (n = ) or no (n = ) pre-icu healthcare use. patients with high healthcare use had significantly more comorbidities than those with low healthcare use. in icu, however, saps , duration of mechanical ventilation and length of stay were not different across the groups. interestingly, analysis of post-icu healthcare trajectories for each group revealed that patients with low or no pre-icu healthcare (which represented % of the population) switched to a persistent and elevated healthcare use during the two years post-icu. conclusion: for % of ards/septic shock survivors, critical illness appears to have a pivotal role in healthcare trajectories, with a switch from a low and stable healthcare use prior to icu, to a sustained higher healthcare recourse two-years after icu discharge. this underpins the hypothesis of long-term critical illness and pics-related quantifiable consequences in healthcare use, measurable at a population level. compliance with ethics regulations: yes. ( ) to describe the pre-hospital grading protocol developed by the northern french alps emergency network (trenau) for children, ( ) to evaluate its quality to detect the most severe trauma patients and ( ) to assess the accuracy of this procedure to perform an adequate triage. patients and methods: our regional trauma system included hospitals categorized as level i, ii or iii pediatric trauma centers. eachpatient was graded a, b or c by an emergency physician, according to the seriousness of their injuries at presentation on scene. the triage was performed according to this grading and the categorization of centers. this study is a registry analysis of an -year period ( to ). results: a total of children (mean age years, % were boys) with severe trauma were included in the cohort. fifty-seven, % and % of patients were admitted to a level i, ii and iii, respectively. road accident was the main mechanism of injury ( % of patients). thirtysix percent of patients had a severe trauma, defined as an injury severity score (iss) higher than . one quarter of patients had at least severe lesions and one-third of patients had a trauma brain injury. the pre-hospital gradation was closely related with injury severity score (iss) and intra-hospital mortality rate. the triage protocol had a sensitivity of % and a specificity of % to predict adequate admission of patients with iss more than . using a specific trauma score (including occurrence of death, an admission in intensive care unit and the need for urgent surgery), sensitivity and specificity reached and %, respectively. fourty-six percent of patients were not graded at the scene (non-graded group). undertriage rate was significantly reduced in the graded group compared with the non-graded group, ( % versus %), without significant modification of the overtriage rate ( % versus %). overall, mortality at discharge from hospital was %, but % in grade a patients. conclusion: implementation of a regional pediatric trauma system with a specific pre-hospital triage procedure was effective in detecting severe pediatric trauma patients and in lowering the rate of prehospital undertriage. compliance with ethics regulations: yes. rationale: critically ill children suffer from pathophysiological changes, leading to large between-subject variability in drug clearance. since piperacillin is eliminated mainly via the kidney, changes in renal function go along with a modified elimination, and possible subtherapeutic or toxic drug concentrations. we aimed to determine the most accurate glomerular filtration rate (gfr) estimation formula for assessing piperacillin clearance in critically-ill children. patients and methods: all children hospitalized in pediatric intensive care unit and receiving piperacillin were included. piperacillin was quantified by high performance liquid chromatography. pharmacokinetics were described using the non-linear mixed effect modeling software monolix. in the initial pharmacokinetics model, gfr was estimated according to the schwartz formula. in the study, gfr was estimated with additional formulas, developed with plasma creatinine and/or cystatin c. biases, precisions, spearman's rank correlation coefficient and normalized prediction distribution error (npde) were used to assess the models. results: we included children with a median (range) postnatal age of . ( . - ) years, body weight of . ( . - ) kg and estimated gfr according to the schwartz formula of . ( - ) ml min- . . m . piperacillin concentrations were best predicted with the model using the creatinine clearance. the correlations were most accurate: r = . between the population-predicted and the observed concentrations, r = . and r = . for the npde versus population-predicted concentrations and time, respectively. concerning the individual predicted concentrations, bias and precision were respectively − . mg l − and . mg l − . gfr estimations based on serum creatinine were higher than those based on cystatin c (p = . ). conclusion: in summary, the -h creatinine clearance is the best predictor of piperacillin clearance and this could be investigated for drugs with renal elimination. as a whole, literature and our findings strongly suggest using creatinine clearance to also estimate gfr in critically ill children. the gap between the gfr estimations is large depending on the formulas, with higher estimations with equations based on serum creatinine. compliance with ethics regulations: yes. rationale: acute pancreatitis (ap) incidence have increased dramatically over the past years. new guidelines in were recently published in order to standardize the definition and management of ap. the aim of this study is to describe the management of children that were diagnosed with ap from the pediatric intensive care unit (picu) in two french hospitals. patients and methods: this retrospective cohort study included children aged under years old, who were admitted to the picu of robert-debré hospital and trousseau from to with a discharge diagnosis of ap. data collected included management, severity and outcomes. we have also obtained data on clinical, biological and radiological presentation. results: sixty patients were included, the median age was years ( - ) and % had a co-morbidity mainly hematologic ( / ). most of the ap were moderate ( %) or severe ( %). hemodynamic failure was the main reason for picu admission requiring a median fluid resuscitation ml/kg complemented by a median intravenous fluid therapy of ml/kg/h ( - ) during the first h. twenty patients ( %) required mechanical ventilation. fasting has been instituted in patients ( %) for a median of days ( - ), whereas patients ( %) received parenteral nutrition, only patients ( %) received enteral nutrition. antibiotic therapy was given to patients ( %) including % for curative therapy. the median length of stay in picu was days ( ) ( ) ( ) ( ) ( ) . the mortality rate was %. conclusion: this is the first french study which precisely described the management of patients with ap in picu. it highlighted the differences withthe new international guidelines. this study could improve the management of pa in picu and open research perspectives. compliance with ethics regulations: yes. rationale: apheresis and therapeutic plasma exchange (tpe) for children diseases has been poorly investigated in mostly small-uncontrolled studies. the purpose of this study is to describe indications and safety of tpe in children. patients and methods: in this single center and retrospective study, we included patients who underwent tpe with an age < years old in the pediatric center of necker-enfants-malades hospital from january to december . data were retrospectively collected in an electronic case report form via a web-based data collection system. results: patients with a median age of . years [range . ; . ] were selected. they achieved a total number of procedures. indications were antibody-mediated rejection (n = ; %) or desensitization therapy (n = ; %) for solid organ or hematopoietic transplantations; microangiopathy (n = ; %); renal diseases (n = ; %) and pediatric inflammatory diseases (n = ; %); or hyperviscosity syndrome (n = ; %). each patient had an average of procedures for the first session [range ; ] with a median volume of ml [range ; ml] corresponding to a median (rang) total plasma volume (tpv) equivalent of . l/m [ . - . ]. within days since the beginning of sessions, patients ( %) present a total of adverse events (aes) potentially related to tpe. there was a median (range) of aes/patients [ - ]. there was no association between aes and diseases, severity of patients, venous access, plasma substitute and body weight. few of aes (n = for patients) were potentially life-threatening and concerned mostly critically ill children. allergic reactions represented only aes for patients (grade i n = ; grade ii n = ; grade iii n = ). at the months endpoint, ( %) patients died and ( %) patients had severe persistent disease. no death had been related to the tpe process. we describe one of the largest retrospective pediatric cohort updated to the last international recommendations. tpe in children is performed for specific and potentially refractory disease. it is feasible without a major risk of life threatening adverse events. compliance with ethics regulations: yes. yacine benhocine university hospital nedir mohamed, tizi-ouzou, algeria correspondence: yacine benhocine (yacine @yahoo.fr) ann. intensive care , (suppl ):f- rationale: although analysis of literature data shows that implantable chamber catheters (iccs) are less at risk of infectious complications than other central venous catheters, these complications can be serious, which may differ from ongoing treatments such as chemotherapy, and may lead to the removal of the implanted device. the literature on preventing these infections is quite disparate, as practices. purpose: to evaluate the incidence of infections, to identify responsible germs and to measure the impact of preventive measures. patients and methods: prospective, descriptive, mono-centric study, from january to january . all patients under the age of who have benefited from an implantable chamber catheter, whose insertion procedure is as follows: local anesthesia, surgical asepsis (polyvidone iodine) in an operating room, double disinfection, no antibiotic prophylaxis, routes used: subclavian ( %), internal jugular ( %) by anatomic registration. the main criteria of judgment are: the incidence of local and general infections, their time of onset, responsible microorganisms. statistical analysis used the statistical package for the social sciences software. results: patients were included, the average incidence density of early infection is . / day-catheters. the time of onset of infection is essentially between the nd and rd week post-exposure, of which % is general infection. ablation involved % of infected catheters. the causative organisms are mainly gram-positive cocci ( . %), gram-negative bacilli are less involved ( . %), with a significant number of candida infections ( %). discussion: higher incidence of data from the literature. to remedy this requires the implementation of additional hygiene measures: antiseptic showers preoperatively, chlorhexidine??, and practice changes: echo guidance, antibiotic prophylaxis or locks? second generation catheters? our practices are disparate especially since the recommendations specifically concerning the prevention of infectious risk associated with internationally published iccs are rare. conclusion: at the end of this work, our perspectives are to: update the procedure, highlight risk factors on which it is possible to act, the adhesion of the different staff to the protocols. compliance with ethics regulations: yes. rationale: the sepsis and septic shock pediatric guidelines advise to treat patients using care bundles. in the first hour, the «resuscitation bundle» contains an appropriate fluid resuscitation, a broad-spectrum antibiotics administration after blood cultures, and initiation of inotrope if needed. the objectives were to evaluate the resuscitation bundle compliance in a cohort of septic children with cardiovascular dysfunction, and to analyze the effect on severity and outcome in pediatric intensive care unit (picu). patients and methods: retrospective analysis of the diabact iii study. this study analyzed the care course of children with severe community-acquired bacterial infection, hospitalized in picus in france's west departments, between august and january . children with severe sepsis and cardiovascular dysfunction were retrospectively included. results: we included children of whom ( . %) had compliant bundled care. the severity scores at picu's admission were similar between groups (p = . for the prism score and . for the pelod ). there was the same proportion of fluid-refractory shock (p = . ), mechanical ventilation (p = . ), neurological dysfunction (p = . ) and cardiac arrest (p = . ). in the «resuscitation bundle compliant» group, . % died versus . % in the other group (p = . ). we highlighted a severity bias: the sickest patients were more likely to receive compliant bundled care. conclusion: in our cohort, the resuscitation bundle's compliance was low. we did not show some effect on morbidity nor mortality. however, this study helps understand the factors associated with resuscitation bundle's compliance. rationale: nosocomial infections with extended-spectrum β-lactamase (esbl) producing gram-negative bacilli (gnb) are an important cause of hospital morbidity and mortality. the objective of this study was to determine the incidence and risk factors of nosocomial esbl-producing gnb infections in a paediatric intensive care unit (picu). patients and methods: a prospective surveillance study was performed from january through march in a picu. all patients hospitalized for more than h were included. centers for disease control and prevention criteria were applied for the diagnosis of nosocomial infection. results: during the study period, patients (median age: ± days) were included. the average length of stay was ± days with a total of , days of hospitalization. newborns accounted for . % of patients. sixty-two per cent of patients were colonized with multi drug resistant gram-negative rods, on admission or during their stay in the picu. one hundred and nineteen bacterial infectious episodes were registered ( . / patient days). one hundred infectious episodes were caused by a gnb and ( . %) by esbls producing gnb with an incidence of . / patient days (bloodstream infections: episodes, ventilator acquired pneumonia: episodes). esbls producing gnb infection had a specific incidence of . per catheter-days, and . per mechanical ventilation-days. fifty-nine percent of patients infected with esbls producing gnb had a prior digestive colonization with a multidrug-resistant gnb. forty-one episodes ( %) occurred in patients with central venous catheters. klebsiella pneumoniae was the most frequently isolated bacteria ( . %). mortality in the esbls producing gnb group was high ( . %). associated factors of nosocomial esbls producing gnb infection were mechanical vrntilation (p < . ), central venous catheterization (p < . ) and colonization with multiple drug-resistant gram-negative bacteria (p < . ). conclusion: nosocomial esbl-producing gnb infection had an incidence of . per patient days in our unit and seems to increase the mortality rate. factors associated with this infection were identified. marie lemerle , aline schmidt , valérie thepot-seegers , achille kouatchet , valérie moal , mélina raimbault , corentin orvain , jean-francois augusto , julien demiselle chu angers, médecine intensive réanimation, angers, france; chu angers, maladie du sang, angers, france; chu angers-ico, angers, france; chu angers, pharmacie, angers, france; chu angers, labora-toire de biochimie, angers, france; chu angers, néphrologie dialyse transplantation, angers, france correspondence: marie lemerle (marielemerle@yahoo.fr) ann. intensive care , (suppl ):f- rationale: acute kidney injury (aki) is associated with high morbidity and mortality in the setting of tumor lysis syndrome (tls). thus, strategies aimed at preventing aki occurrence represent a major goal to improve prognosis of patients with tls. the role of hyperphosphatemia as a risk factor of tls has been poorly analyzed. the aim of this study was to study the association between hyperphosphatemia and aki, and to determine whether a cut-off value of phosphatemia or phosphatemia's variation was associated with aki development during tls. patients and methods: in this retrospective and monocentric study, we included all patients with tls and whithout aki at admission, admitted to hematology, nephrology and intensive care units of the university hospital of angers between / / and / / . results: one hundred and thirty tls episodes were identified in patients. aki developed during episodes of tls ( %). hospital mortality was much higher in aki patients ( . % versus . %, p = . ). phosphate maximal values ( . ± . versus . ± . ) and ldh maximal values ( . ± . versus . ± . ) were higher in tls with aki, before aki occurrence (p = . and p = . , respectively). we found no association between the other biological parameters of tls and aki (serum calcium, uric acid and potassium). after adjustment for cofounders, there was a strong association between a rise in phosphate level of . mmol/l (hr . ic % [ . - . ], p < . ), exposure to platinum salts (hr . ic % [ . - . ], p = . ) and increasing maximal ldh value (hr per ui/l increase . ic % [ . - . ], p = . ) with aki. conclusion: this study highlights the utmost importance of serum phosphate in the setting of tls: phosphate is an early relevant biomarker for the risk of aki development. further studies are needed to assess whether aggressive prophylactic treatment to control serum phosphate concentration, such as renal replacement therapy before aki onset, constitutes a valuable approach. compliance with ethics regulations: yes. retrospective cohort of patients admitted to the medical icu of university affiliated hospital after carts treatment between august and august . results: of the patients treated by carts in the haematology department, ( %) were subsequently admitted to icu. median age was [ . - . ] years, and ( . %) were female. carts were indicated for r/r lymphoma. the median time between carts injection and icu admission was [ . - . ] days. all patients had cytokine release syndrome (crs), and ( . %) developed car-related encephalopathy syndrome (cres). median sofa score and saps were [ - . ] and [ . - . ], respectively. four ( . %) patients had hypotension treated by fluid bolus (n = ) or vasopressors (n = ), and ( . %) had acuterespiratory failure requiring oxygen therapy (n = ) or mechanical ventilation (n = ). six ( . %) patients had neurological symptoms (impaired consciousness n = , confusion n = , transient aphasia n = ), of whom one developed refractory convulsive status epilepticus afterwards. all patients received broad spectrum antibiotics, of whom ( . %) had documented infections. six ( . %) patients received interleukin- inhibitor (single dose n = , multiple doses n = ), and ( . %) received intravenous dexamethasone. one patient died in the icu from septic shock. median icu and hospital length of stays were [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and [ . - . ] days, respectively. two ( . %) patients died from relapsing malignancy before hospital discharge. three months after icu admission, four ( . %) patients were alive in complete remission. conclusion: more than % of patients treated with carts required icu admission for the management of a crs or a cres. early icu admission, close collaboration between haematologists and intensivists, and prompt administration of appropriate therapy (il- inhibitor and/or dexamethasone) and supportive care resulted in a good prognosis. compliance with ethics regulations: yes. rationale: tisagenlecleucel (ctl ) is a chimeric antigen receptor t cell therapy that reprograms autologous t cells to target cd + leukemia cells, approved in the us since august and in the eu since august for children and young adult (< years old) with relapsed/refractory b-cell acute lymphoblastic leukemia (b-all). this study reports the experience of picu management of ctl toxicity in patients treated in robert-debré university hospitals. patients and methods: all patients (age < years old) treated by tisagenlecleucel infusions between march , and september , , included in sponsored-clinical trials or treated within the french compassionate program or with the commercial product, were retrospectively analyzed. results: twenty-four patients were infused and patients ( %) were managed in picu for stays. ( stays: n = and stays: n = ). median age at picu admission was . years old [ . ; . ] with a median delay after car-t cells infusions of days [ . ; ] . the median length of stay in picu was days [ . ; ] with a max at days. cytokine release syndrome (crs) was the main indication of picu hospitalization ( . %, n = ) with grade (n = ) and grade (n = ) according to american society for transplantation and cellular therapy (astct) consensus grading system and treated by corticosteroid (n = . ) and tocilizumab (n = , only one infusion). norepinephrine was the only vasopressor used. the median vaso-inotrope score (vis) for grade was [ . ; . ] with a maximum at . neurologic toxicity was observed in patients with a grade (status epilepticus) and grade (focal edema on neuroimaging with depressed level of consciousness) according to immune effector cell-associated neurotoxicity syndrome (icans) grading system from astct consensus. the status epilepticus was managed with anti-epileptic drugs without mechanical ventilation. the focal edema was related to hhv and toxoplasmosis encephalitis. evolution was positive with foscavir and ganciclovir and days of mechanical ventilation. one patient was hospitalized for septic shock secondary to gram-negative central line bloodstream infection in aplasia, with a vis score at . evolution was favorable with antibiotics and central line removal. no death in picu from severe tisagenlecleucel toxicity was observed since the beginning of the car-t cells program. conclusion: toxicity profile of tisagenlecleucel required frequent and early picu hospitalization after infusions for severe crs and icans management. compliance with ethics regulations: yes. rationale: car-t cell (chimeric antigen receptor t) therapy is a promising treatment in refractory acute lymphoid leukemia (all) and diffuse large b cell lymphoma (dlbcl). the main complication consists in a cytokine release syndrome (crs) leading to an inflammatory state that can be very severe with life-threatening organ failure. neurological toxicity is also reported. we aim to describe car-t cells-related complications in icu patients. patients and methods: this is a single-center prospective study conducted between july and august . all the patients who have received car-t cells and who required icu admission were included. crs grading was defined according to the most recent classification of the asbmt and neurological toxicity was assessed with the cartox scale. each admission is considered independent and therefore corresponds to one patient. results: admissions, representing patients ( men and women), were considered. the median age was years . twothirds of the patients have been diagnosed with dlbcl (n = , %) and one-third with all (n = , %), months [ - ] ago. they had received lines [ ] [ ] of chemotherapy and had a high tumor burden ( % of lymphomas classified stage iv). the majority of the patients was admitted because of hemodynamic failure (n = , %) or respiratory failure (n = , %), days [ ] [ ] [ ] [ ] [ ] after car-t cells infusion. sofa at admission was [ ] [ ] [ ] [ ] [ ] . all the patients presented at least one complication ( figure) , the most common being crs (n = , %) with a median grade of [ ] [ ] . neurological toxicity was reported in ( %) patients (worst grade at [ ] [ ] [ ] ). documented bacterial infection involved % of the patients and consisted in catheter-related infections for half of the cases. in the icu patients were managed with fluid resuscitation (n = , %) during the first day, vasopressors (n = , %) and broad spectrum antibiotics ( %). a single patient required mechanical ventilation and two patients underwent dialysis. tocilizumab (anti-il receptor) was given to patients ( % of crs) in a median time of . h [ . - . ] after icu admission. patients ( %) received corticosteroids. the median icu length of stay was . days [ ] [ ] [ ] [ ] . patients ( %) died in the icu and hospital mortality was %. the -fluorouracil ( -fu)-induced hyperammonemic encephalopathy is a rare but serious -fu adverse drug reaction, which could require the admission of patients in intensive care unit (icu). given the paucity of data regarding this -fu adverse drug reaction, we performed a retrospective national survey from the french pharmacovigilance database to better characterize -fu-induced hyperammonemic encephalopathy and its management. patients and methods: since the inception of the french pharmacovigilance database, we identified all patients that experienced -fu-induced encephalopathy. variables regarding epidemiology, characteristics, management and prognosis of these patients were collected and analyzed. results: from from to years-old, % of women) were included. overall mortality was % (n = ) and % (n = ) of patients were admitted in icu. the -fu-induced hyperammonemic encephalopathy started [ ] [ ] [ ] [ ] days after the onset of -fu infusion. the most common neurological disorders were consciousness impairment, confusion and seizures. abnormalities in ct scan, mri, electroencephalogram and lumbar puncture were found in %, %, % and % of the whole population respectively, similar in icu and non-icu patients. ammonemia was dosed in % of the whole population and in % of icu patients. hyperammonemia tended to be higher in icu than in non-icu patients ( [ - ] vs. [ - ] µmol/l, respectively, p = ns) and in patients with the lowest glasgow outcome scale, but was not different between survivors and non-survivors. among icu patients, % required mechanical ventilation and % anti-epileptic drugs administration. besides -fu discontinuation, lactulose intake, renal replacement therapy or ammonium chelators were used to decrease hyperammonemia in %, % and % of patients respectively. a complete neurological recovery was observed in up to % of icu and non-icu patients within a delay of [ - ] days. a dihydropyrimidine deshydrogenase (dpd) deficiency was found in % of tested patients. a -fu rechallenge was considered in % (n = ) of patients with complete neurological recovery, including a patient with a partial dpd deficiency, within a delay of [ - ] days after recovery. a -fu-induced hyperammonemic encephalopathy relapse was observed in % of patients with -fu rechallenge. no relapse was observed when -fu rechallenge was performed with a decreased -fu dosage. conclusion: we report the first national survey and the largest cohort of patients with -fu-induced hyperammonemic encephalopathy so far. this serious -fu adverse drug reaction must be known by intensivists, since more than half of patients are admitted in icu and specific treatments are available. compliance with ethics regulations: yes. immune related adverse events: a retrospective look into the future of oncology in the intensive care unit adrien joseph , annabelle stoclin , antoine vieillard-baron , guillaume geri , jean-marie michot rationale: immune checkpoint inhibitors (ici) represent a paradigmatic shift in oncology. with their new position as a mainstay in cancer treatment, new toxicities called immune related adverse events (iraes) have emerged. patients and methods: retrospective study including patients admitted in the icu within days after treatment with an ici in french hospitals. patients were classified into groups according to the reason for admission: irae, intercurrent adverse event (intae) or event related to tumor progression (tumprog). results: patients were admitted during the course of an ici treatment, including irae, intae and tumprog, with a significant increase between (n = ) and (n = patients, p for trend < . ). irae included pneumonitis, colitis, diabetes complications, hypophysitis, nephritis, myocarditis and cardiac disorders, hepatitis or allergic reaction and meningitis. the immune related nature of the complication was known before admission in only ( %) cases. mean age was (± ) years and % had a performance status of - . primary tumors were melanomas ( , %), non-small cell lung cancers ( , %) , urothelial carcinomas ( , %) and hodgkin lymphomas ( , %) . ici at the time of admission included anti-ctla ( , %), anti-pd /pdl ( , %) and anti-ctla /anti-pd combination in ( %) patients. mean duration of stay in the icu was . (± ) days. three patients required vasopressor therapy alone, with mechanical ventilation and one with extracorporeal membrane oxygenation. three patients required non-invasive ventilation and renal replacement therapy alone. six required only endocrine or electrolytic equilibration and others did not receive any form of organ support. icu mortality was %. compared with other admissions, anti-ctla or anti-ctla /anti-pd combination treatments were associated with irae diagnosis (or = . [ . - . ] , p = . for anti-ctla and . [ . - . ] for anti-ctla /anti-pd , p = . ) and so was the diagnosis of melanoma ( . [ . - . ] , p = . ). there was no difference in terms of icu and post-icu survival between irae (median post-icu survival months [ -na]), intae ( . [ . -na]) and ). six patients admitted for an irae were rechallenged with the same ici after icu discharge and achieved complete response. conclusion: we conducted the first study describing patients admitted in the icu for iraes. their specific and heterogeneous profile, along with the expected increase in the number of admissions, underlines the need for an in-depth knowledge for icu physicians in order to take part in the multidisciplinary care required by these patients. compliance with ethics regulations: yes. rationale: patients with advanced-stage non-small-cell lung cancer have high mortality rates in the intensive care unit (icu). in this context, acute respiratory failure due to cancer involvement is the worst situation. in the last two decades, targeted therapies have changed the prognostic of patients with lung cancer outside the icu. unlike cytotoxic chemotherapy, the fast efficacy of targeted therapies led some intensivists to use them as rescue therapy for icu patients. we sought to investigate the outcomes of patients with lung cancer involvement responsible for acute respiratory failure and who received tyrosine kinase inhibitor during icu stay. patients and methods: we performed a national multicentric retrospective study with the participation of the grrroh (groupe de recherche en réanimation respiratoire en onco-hématologie). all patients with non-small-cell lung cancer admitted to the icu for acute respiratory failure between and were included in the study if a tyrosine kinase inhibitor was initiated during icu stay. cases were identified using hospital-pharmacies records. we collected demographic and clinical data in icu charts. vital status was assessed at the time of study completion (august ). the primary outcome was overall survival days after icu admission. results: twenty-nine patients (age: ± years old) admitted to a total of icus throughout france were included. seventeen patients ( %) were nonsmoker. the most frequent histological type was adenocarcinoma (n = , %) and a majority had metastatic cancer (n = , %). epithelial growth factor receptor mutation was the most common oncologic driver identified (n = , %). during the icu stay, ( %) patients required invasive mechanical ventilation, ( %) catecholamine infusion, ( %) renal replacement therapy and one ( %) extracorporeal membrane oxygenation. in addition to tyrosine kinase inhibitor, ( %) patients received steroids (beyond . mg/kg/day) and ( %) cytotoxic chemotherapy during icu stay. seventeen patients ( %) were discharged alive from icu and ( %) were still alive after days (see kaplan-meier curve figure) . moreover, patients ( %) were alive one year after icu discharge. conclusion: despite a small sample size this study showed that, in the context of lung cancer involvement responsible for acute respiratory failure, the use of tyrosine kinase inhibitor should not be refrained in patients with severe condition in icu. compliance with ethics regulations: yes. rationale: acute respiratory failure is the leading reason for intensive care unit (icu) admission in immunocompromised patients and the need for invasive mechanical ventilation has become a major clinical end-point in randomized controlled trials (rct). however, data are lacking on whether intubation is an objective criteria that is used unbiasedly across centers. this study explores how this outcome varies across icus. patients and methods: hierarchical models and permutation procedures for testing multiple random effects were applied on both data from observational cohort (the trial-oh study: patients, icus) and randomized controlled trial (the high trial: patients, icus) to characterize icu variation in intubation risk across centers. results: the crude intubation rate varied across icus from % to % in the observational cohort and from to % in the rct. this center effect on the mean icu intubation rate was statistically significant, even after adjustment on individual patient characteristics (observational cohort: p-value = . , median or . [ . - . ]; rct: p-value: . , median or . [ . - . ]). two icu-level characteristics were associated with intubation risk (the annual rate of intubation procedure per center and the time from respiratory symptoms to icu admission) and could partly explain this center effect. in the rct that controlled for the use of high-flow oxygen therapy, we did not find significant variation in the effect of oxygenation strategy on intubation risk across centers, despite a significant variation in the need for invasive mechanical ventilation. conclusion: invasive mechanical ventilation has become an important endpoint in immunocompromised patients with acute respiratory failure. however, we found significant variation in intubation risk across icu in both an observational cohort and a randomized controlled trial. our results highlight the need to take into account center effect in analysis because it could be an important confounder. reasons for heterogeneity are various (case-mix differences, center practices). this gives opportunities to future improvement in care management and study design. compliance with ethics regulations: yes. rationale: influenza virus (iv) infection is a major cause of ards that has been the focus of attention since the pandemic h n (h n pdm ) iv. although iv-mediated damage of the airway has beenextensively studied emphasizing specificity compared to other causes of ards, the impact of iv infection on the prognosis of ards patients, compared to the other causes of ards, has been few assessed. patients and methods: systematic detection of iv in times of epidemic using rt-pcr in respiratory specimen is routine practice in our icu along with prospective data collection of patients admitted to our icu for ards with pao /fio ratio ≤ mmhg. all patients received lung-protective ventilation, the sequential organ failure assessment (sofa) score was calculated on the first days of mechanical ventilation. the primary endpoint compared the -day survival from the diagnosis of ards between patients with and without iv infection. results: from october, to may, , patients (pts) [median saps ii score = ( - ); age years ( - ); pao / fio ≤ mmhg, n = ( %)] were admitted to our icu for ards with pao /fio ratio ≤ mm/hg, including pts ( %) with iv infection (h n pdm iv a, n = ; h n a virus, n = ; b virus, n = ; associated bacteria, n = ). other main causes of ards were bacterial pneumonia without iv ( %), aspiration ( %), non-pulmonary sepsis ( %). ( %) received prone positioning, and ( %) extra-corporeal membrane oxygenation. the overall mortality rate at day- for the entire population was % ( pts ( %) with iv infection versus pts ( %) without iv infection, p = . ). kaplan-meier survival curves showed that survival was significantly higher in patients with iv infection than in those without iv infection. iv infection remained independently associated with a better prognosis at day- when entered as dichotomous variable (iv infection, yes/no) (adjusted hazard ratio (hr) = . , % ci . - . , p = . ) and when iv infection only was distinguished from other causes of ards including mixed infection iv plus bacteria (adjusted hr = . , % ci . - . , p = . ). of note, within the first days of mechanical ventilation, non-pulmonary sofa scores were significantly lower in iv patients although similar pulmonary sofa scores. conclusion: our results suggest that patients with iv related ards have less severe non-pulmonary organ dysfunctions than those with ards from other and a lower mortality at day- despite similar ards severity. compliance with ethics regulations: yes. rationale: acute respiratory distress syndrome (ards) remains frequent in intensive care unit (icu) with % to % mortality. according to joint theater trauma system, ards occurs among % of war casualties: direct lung trauma, blast lesions, burn, massive transfusion and systemic inflammatory response syndrome lead to ards development. however, there is no data reporting ards among french evacuated casualties from forward environment. our study's aim is to describe ards incidence and its severity concerning medical evacuations from war theater. patients and methods: this is an observational retrospective multicentric study analyzing all evacuated patient from war theater and admitted in icu. all patients developing ards according to berlin definition have been included. study has been approved by local ethic committee. primary study endpoint was ards developing. second study endpoints were ards severity, duration of invasive ventilation, ards treatments, icu length of stay and mortality. results: patients have been admitted in icu between and . have been excluded. a total of patients have been analyzed. % (n = ) were military aged ( - ) years. % (n = ) developed ards. we found % (n = ) war casualties, % (n = ) trauma not related to war and % (n = ) medical patients. among severe trauma, median iss was ( - ), ais thorax ( ) ( ) ( ) , and % benefited from surgery on forward environment and % (n = ) received massive transfusion. % (n = ) suffered from mild ards, % (n = ) moderate ards and % (n = ) severe ards. evacuation time was ( - ) h. at admission in icu, pao /fio ratio was ( - ) (fig. ). all patients were intubated. ards treatments used were curarization ( %, n = ), prone position ( %, n = ), inhaled nitric oxide (noi) ( %, n = ), almitrine ( %, n = ) and extracorporeal life support (ecls) ( %, n = ). invasive ventilation duration was ( - ) days, length of stay ( - ) days, and -month mortality % (n = ). conclusion: according to our study, ards among french evacuated patients from war theaters remains frequent: it occurs on % among icu admitted patients. % suffer from severe ards with % global mortality. those datas are consistent with us studies. also, we wonder if we must adapt our treatment capacities on forward environment for the most severe patients. in us army, a specialized team (acute lung rescue team) is trained to care the most hypoxemic war casualties with more treatment options as noi, ecls. compliance with ethics regulations: yes. rationale : we recently reported that septic shock patients with pneumonia exhibit a high risk of icu-acquired pneumonia, suggesting that a primary pulmonary insult may drive profound alterations in lung defence towards secondary infections ( ) . given their importance in lung immune surveillance, alveolar macrophages (am) are likely to play a pivotal role in this setting. the objective of this experimental study is to address the impact of primary pulmonary or non-pulmonary infectious insults on lung immunity. patients and methods: we established relevant double-hit experimental models that mimic common clinical situations. c bl/ j mice were first subjected either to polymicrobial peritonitis induced by caecal ligation and puncture (clp), or to bacterial pneumonia induced by intra-tracheal instillation of staphylococcus aureus or escherichia coli. respective control mice were subjected to sham laparotomy or intratracheal instillation of phosphate-buffered saline. seven days later, mice that survived the primary insult were subjected to intra-tracheal instillation of pseudomonas aeruginosa (pao strain). we assessed survival and pulmonary bacterial clearance of post-septic animals subjected to p. aeruginosa pneumonia, as well as the distribution and functional changes in alveolar macrophages. results: when compared to sham-operated mice, post-clp animals exhibited increased susceptibility to secondary p. aeruginosa pneumonia as demonstrated by defective lung bacterial clearance and increased mortality rate ( % vs. %, p < . ). in contrast, all postpneumonia mice survived and even exhibited improved bacterial clearance as compared to their control counterparts. when addressing whole-lung immune cell distribution at the time of second hit (day ), amounts of am were decreased in post-clp mice while preserved or even increased in post-pneumonia mice. antigen-presenting functions of am appeared similar in all conditions. percentages of apoptotic (annexinv + ) and necrotic ( -aad + ) am were comparable at day and day after the first hit. interestingly, both ly c high and ly c low monocytes were sustainably increased in the lungs of post-clp mice, while only transiently expanded following pneumonia, suggesting that differences in am counts could be related to modulated turnover from precursor monocytes. conclusion: using clinically relevant double-hit experimental models, a primary pulmonary infection conferred resistance to secondary bacterial pneumonia. ongoing investigations are aimed at addressing the antibacterial am functions, as well as the turnover-driving mechanisms.compliance with ethics regulations: yes. rationale: little is known on the role of exit-site signs in predicting intravascular catheter infections. the current study aimed to describe the association between local signs at the exit-site and catheter-related bloodstream infection (crbsi), which factors substantially influenced local signs and which clinical conditions may predict crb-sis if inflammation at insertion site is present. patients and methods: we used individual data from multicenter randomized-controlled trials in intensive care units (icus) that evaluated various prevention strategies regarding colonization and crbsi in central venous and arterial catheters. we used univariate and multivariate logistic regression stratifying by center in order to identify variables associated with redness, pain, non-purulent discharge, purulent discharge and ≥ local sign and subsequently evaluate the association between crbsi and local signs. moreover, weevaluated the role of thedifferent local signs for developing crbsi in subgroups of clinically relevant conditions. results: a total of patients, , catheters ( , catheterdays) and crbsi ( . %) from icus withdescribed local signs were included. redness, pain, non-purulent discharge, purulent discharge and ≥ local signs at removal were observed in ( . %), ( . %), ( . %), ( . %) and ( . %) episodes, respectively. the sensitivity of ≥ local sign for crbsi was by . %, whereas the highest specificities were observed for pain ( . %) and purulent discharge ( . %). positive predictive value (ppv) was low for redness ( %), pain ( %), non-purulent discharge ( %) and ≥ local sign ( %), but increased for purulent discharge ( . %). negative predictive values were high for all local signs. after adjusting on confounders, crbsi was associated with redness, non-purulent discharge, purulent discharge and ≥ local sign (fig. ). conditions independently associated with ≥ local sign were age ≤ years old (or . , % ci . - . , p < . ), sofa score (sofa < or . , % ci . - . , p < . ), non-immunosuppression (or . , % ci . - . , p < . ), catheter maintenance > days (or . , % ci . - . , p < . ) and insertion site (or for subclavian site . , % ci . - . , p < . ). however, the presence of ≥ local sign was more predictive for crbsi in the first days of catheter maintenance (or . , % ci . - . vs. > catheter-days or . , % ci . - . , p heterogeneity = . ). conclusion: this post hoc analysis showed that local signs were related to crbsis in the icu. local signs were independently associated with specific patient's and catheter's conditions. in the first days of catheter maintenance, local signs were predictive for crbsi. compliance with ethics regulations: yes. rationale: pneumococcal meningitis (pm) is the leading cause of bacterial meningitis in adult patients requiring icu admission and is associated with a high case fatality rate (cfr), ranging from to more than % ( ) ( ) ( ) . patients with pm may develop sepsis or septic shock that may impact management and outcomes. we aim to describe the epidemiology and outcomes of pm associated with sepsis in adult patients in france. we analysed the occurrence of pm with sepsis from to in adult patients, using the national french hospital database pmsi (programme de médicalisation des systèmes d'information). for all analyses, only the first hospital admission was considered. cases were identified using a combination of a diagnosis code for pm plus a diagnosis code for sepsis (either a code for organ failure or a procedure code for organ support). data recorded included comorbidities ( ), characteristics of the hospital stay, severity of the patients including major intracranial complications and characteristics of the infection. costs and endpoints were determined at the end of all the hospital stays related to the first admission for pm with sepsis. standardized incidence, hospital mortality, and cfr were estimated. temporal trends were assessed using cochran armitage tests of trends and linear trend analyses. results: a total of pm with sepsis aged ≥ years were hospitalized in france during - . the incidence of pm decreased from . to . per m inhabitants (p < . ) (fig. ) . most of them came from home ( %), were admitted in an academic institution ( %) and benefited from icu ( %). their median age was [ ; ] years. twothird of them had at least one comorbidity. the initial neurological presentations included coma ( %), focal signs ( %), seizures ( %) and brain stem involvements ( %). the saps ii score was [ ; ] points. the main neurological complications were cerebrovascular complications ( %), cerebral abscess ( %) and hydrocephaly ( %). pm was associated with pneumococcal septicaemia or pneumococcal pneumonia in % and % of cases respectively. the length of icu and hospital stays were [ ; ] and [ ; ] days respectively and only icu length of stay decreased over time (p < . ). the prognosis was poor since only . % of the patients were discharged to home. indeed, . % of them died and % were transferred to rehabilitation units. no temporal trends could be observed for these outcomes. the average hospital costs per case were , € [ . ; . ] . conclusion: pm with sepsis in adult in france remained a real burden associated with a high mortality rate, and disability. compliance with ethics regulations: na. rationale: mucormycosis is an emerging fungal infection, especially in patients with hematological malignancies. although this infection may lead to multi organ failure, no study has been dedicated to critically ill patients with hematological malignancy. the primary objective was to assess outcome in this setting. the secondary objective was to assess prognostic factors. patients and methods: this retrospective cohort study was performed in icus. critically ill adult patients with hematological malignancies and mucormycosis were included between and . mucormycosiswas classified as "probable"or "proven" regarding eortc criteria. variables are reported as median [iqr] or number (%). adjusted analysis was performed using cox model. results: twenty-six patients were included with a median age of years [iqr, . acute leukemia was the most frequent underlying disease (n = , %). nine patients ( %) were allogeneic stem cell transplantation (sct) recipients. nineteen patients ( %) had neutropenia and patients ( %) had received steroids. the main reason for admission was acute respiratory failure (n = , %) followed by shock (n = , %). the median sofa score at admission was [iqr, - ] points. only patients ( %) had received prior anti-fungal prophylaxis effective against mucorales. mucormycosis was "proven" in patients and "probable" in patients. diagnosis was made by histopathologic examination in patients, direct microscopy or culture in , and polymerase chain reaction in . rhizopus and mucor were the most frequent documented species. seven patients ( %) had concurrent aspergillus infection. mucormycosis was diagnosed day [− to + ] after icu admission. ten patients ( %) had pulmonary involvement whereas five patients ( %) had rhino-cerebral involvement. infection was disseminated in eight patients ( %). twenty-two patients ( %) were treated with liposomal amphotericin b. twelve patients ( %) received antifungal combination including posaconazole in . eight patients ( %) underwent curative surgery. multiple organ failure was frequent, patients ( %) requiring invasive mechanical ventilation (imv), ( %) vasopressors, and ( %) renal replacement therapy. icu and hospital mortality rates were % and %, respectively. only two patients were alive at day . three variables were associated with mortality in a cox model including allogeneic sct . ]; figure), sofa score (hr . [ % ic . - . ]) and dual therapy (hr . [ % ic . - . ]) (fig. ) . conclusion: mucormycosis is associated with a high mortality rate in patients with hematological malignancies, especially in allogeneic sct recipients. futility of icu management in these patients is to be considered and strategies aiming to improve these patients' outcome are urgently needed. compliance with ethics regulations: yes. rationale: sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. several mediators, alone or in combination, were proposed to characterize individual response, but none was proven to have good external validity. the aim of this work was to establish whether some combinations are linked to clinical phenotypes in patients with presumed sepsis, using the data collected in the captain multicenter cohort which methods and first results were previously published (parlato, icm ). patients and methods: patients were prospectively included at the time of sepsis criteria, ( %) of whom with a secondary confirmed infection. community acquired pneumonia was causal in % of infections. saps score = points [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , age = years , male sex = %. patients were followed for more than days, in whom usual icu clinical and biological parameters were collected, as well as plasma biomarkers and leucocyte associated rnas. patients were clinically classified according to their acute severity (sofa score, serum lactate), confirmed initial infection, outcome (secondary infection occurrence, icu survival). non-supervised principal component analysis of the maximal values of biomarkers assessed on first days of sepsis, and varimax rotation technique of the selected components using sas software. results: patients, med sofa day = pts, med serum lactates day = . meq/l, bacterial infection = ( %), enterobacteriaceae infection = ( %), vap and/or bacteremia after day = ( %), alive at icu d/c = ( %). five components explain % of the variance of the biomarkers. the first component ( % of the variance) was not linked to the clinical predetermined phenotypes. the second component ( % of the variance) was principally made of hla-dr rna, cd rna and cx cr rna, and linked to a lower initial severity (r = − . , p = . ), a less frequent confirmation of initial infection (p = . ), a lower occurrence of pneumonia or bacteremia (p = . ) or death (p = . ). conclusion: in our cohort, using non supervised analysis, we could separate a biomarker association linked to lower initial severity, lower rate of a bacterial cause to sepsis, and better outcome. the markers found are among those which are regularly considered as describers of the peripheral alteration of the immune system observed during sepsis (pachot, ccm ; friggeri, cc ; peronnet icm ) . compliance with ethics regulations: yes. ( ) compared a standard of care to a procalcitonin (pct) oriented use of antimicrobials for sepsis in icus. serial blood samples were biobanked in / icus ( / patients enrolled for pro-adrenomedullin (proadm) and pct concentrations). patients and methods: the aim of the study was to evaluate the respective impact of serial pct and proadm measurements in predicting relapse or superinfection and death on day *. relapse was defined as the growth of one or more of the initial causative bacterial strains (i.e., same genus, species) from a second sample taken from the same infection site at h or more after stopping of antibiotics, combined with clinical signs or symptoms of infection. superinfection was defined as the isolation from the same or another site of one or more pathogens different from that identified during the first infectious episode, together with clinical signs or symptoms of infection [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] points at amission, medical admission: ( %), immunocompromised: ( %), on mechanical ventilation ( %), pct and proadm at inclusion were [ . - . ] ng/ml and . [ . - . ] nm/l respectively. ( %) patients developed a first episode of recurrence or supereinfection after a median delay of days [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and ( %) died before d . the hr maximization process proposed an optimal cut point of ng/ml for pct and nm/l for pro adm to predict d death. in the multivariate cox model, both pct and proadm were associated with death but not with relapse or superinfection (table ) . conclusion: conclusion: both serial measurements of pct and proadm are independent predictors of death in patients treated for sepsis in icu. our study confirmed the use of nm/l as a good prognosis cut point for proadm. . compliance with ethics regulations: yes. rationale: the performance of serum ( - )-β-d-glucan (bdg) and its evolution to predict the occurrence of invasive fungal infection (ifi) in a high risk non immunocompromized population remains to be determined ( ). in a post hoc analysis of the empiricus randomized clinical trial ( ), we aimed to assess the prognostic value of repeated measures of bdg on the occurrence of invasive fungal infections. patients and methods: non-neutropenic, non-transplanted, critically ill patients with icu-acquired sepsis, multiple candida colonization, multiple organ failure, exposed to broad-spectrum antibacterial agents, and enrolled between july and february in french icus were included. bdg were collected in icu at day , , , and after inclusion. a value time of more than pg/ ml, pg/ml and an increase by more than % from the previous measurement (threshold of measurement error) were assessed at baseline and overtime. for that purpose, we conducted cause specific hazard models with death as a competing risk. we also planned subgroup analyses on the placebo and the micafungin groups. cumulative risk (cumrisk) of ifi at day were derived from models. [ . ; . ] ). neither a bdg > pg/ml, nor an increase by % of bdg over time were associated with the occurrence of ifi. similar results were found in the placebo subgroup. conclusion: among high risk patients, a first measurement of bdg over pg/ml was highly associated with the occurrence of ifi. neither a cut-off of pg/ml, nor repeated measurements of bdg over time seemed to be useful to predict the occurrence of ifi. the cumulative risk of ifi in the placebo group if bdg > pg/ml is . % questioning about the potential interest of empirical therapy in this subgroup. compliance with ethics regulations: yes. rationale: since the sepsis- conference, the distinction between sepsis and septic shock is based on blood lactate value. septic shock may be encountered in the pre-hospital setting. in order to reduce the mortality, the precocity of treatments implementation has been emphasized, particularly early antibiotic administration. prior antibiotic administration, and blood culture drawing must be performed. the aim of this survey was to clarify the capabilities of french prehospital emergency service (pems) to measure blood lactate and to draw blood culture prior to hospital admission for septic shock. patients and methods: we performed an electronic survey of auto-questions addressed to the deputy chair of the french pems in . results: sixty pems ( %) participated in the survey. twenty-five percent are able to measure blood lactate and % are able to draw blood culture in the prehospital setting. ninety-five percent declared lactate measurement is helpful in assessing severity. ninety percent claimed that the lactate value influences the hospital facility, emergency department vs. intensive care unit. twenty-eight percent believe that the impossibility to draw blood culture precludes prehospital antibiotic administration. sixty-three percent estimate that a protocol for septic shock management would be beneficial. conclusion: few french pems are able to measure lactate and draw blood culture in the prehospital setting. the impact of blood lactate measurement and blood culture drawing by pems on septic shock outcome requires further studies. compliance with ethics regulations: yes. rationale: head injury is a common cause of morbidity and mortality in the first four decades of life, accounting for approximately , annual hospital admissions in the united kingdom. the majority of patients recover without intervention, however some may develop a long-term disability or even die. the early detection of pathology is therefore absolutely critical in determining patients' prognosis, helping to provide appropriate timely management. the national institute for health and care excellence (nice) adult head injury guidelines, recommend that head injuries with specific risk factors should have a ct scan within h of risk factors being identified. furthermore the provisional report should be made available within h of the scan. this audit assessed the compliance of staff to the nice adult head injury guidelines. patients and methods: the previous adult ct head scans, requested due to head injury, from the emergency department (ed) at london north west healthcare nhs trust were analysed for compliance to the nice guidelines. the standards measured were: ( ) time from request of scan to completion of scan should be within h; ( ) time from completion of scan to publication of provisional report should be within h. the locally agreed target for both standards was %. results: on review of the ct scans, ( %) were completed within h of request. from the scans ( %) not completed within the hour, were due to porter unavailability, due to an uncooperative patient and the remaining reasons were not clear from documentation. following completion of the scan, scans ( %) were provisionally reported within h. conclusion: this study highlighted a good compliance by hospital staff in ensuring patients with head injuries are managed appropriately, following detection of risk factors indicating a ct head scan. having said that, the locally agreed targets were just short of being met. one factor resulting in delayed scans was porter availability. an intervention recently introduced is the use of the "e-portering" application, which will endeavour to save time for referrers requesting porters and allow patient tracking. it is also worth educating porters, via email bulletins, on the importance of priority scans, such as ct head following injury. furthermore, the findings of the audit were relayed to the radiology department to help improve reporting times and to the ed to re-emphasize prompt requesting of ct head scans when clinically indicated. compliance with ethics regulations: yes. rationale: continuous insufflation of oxygen (cio) performed with specific endotracheal tube during cardiopulmonary resuscitation (cpr) is as effective as intermittent ventilation on endotracheal tube. experimental data suggest that cio improves the efficacy of external cardiac massage and reduces gastric dilatation. as endotracheal intubation is a cause of cpr interruption and requires skilled staff, a specific device has been developed to perform cio without intubation. this device has been implemented progressively in our fire department since . we evaluated this practice. patients and methods: longitudinal study comparing the patients with out-of-hospital cardiac arrest managed by our fire department with cio or bag-valve ventilation between january and april . patients who received mechanical chest compression were excluded. the main outcome was hospital survival. secondary outcomes were the return of spontaneous circulation (rosc) and cpr quality. univariate and multivariate analysis was performed in the whole cohort and in the sub-groups of patient with shockable and non-shockable rhythms to take into account factors associated with survival (shockable rhythm, witness, age). results: among the patients included, have been ventilated with cio and with valve-bag. the mortality was similar in the two groups (cio: . % valve-bag: . % p . ). mortality and rosc were not associated with cio in the multivariate analysis (odds ratio or . %-confidence interval ci [ . - . ] and . [ . - . ], respectively). cpr quality was better with cio than with valve-bag regarding cpr fraction (ratio of duration of chest compressions on total duration of cpr, versus % p < . ) and adequacy to the guidelines of the rhythm and depth of chest compressions ( % vs % p < . and % vs % p < . , respectively). in both subgroups of patients, cpr quality was still better with cio than with valve-bag. in the subgroup of patients with shockable rhythm, univariate analysis showed a lower mortality among the patients with cio than among the patients with valve-bag ( . % vs . % p < . ) but this difference was not confirmed by the multivariate analysis (or . ci [ . - . ], p . ). conclusion: cio without intubation is associated with an improvement of cpr quality but neither with mortality nor return of spontaneous circulation in case of out-of-hospital cardiac arrest. compliance with ethics regulations: yes. rationale: cardiovascular accidents are a leading cause of death. a cardiopulmonary resuscitation (cpr) of quality has well shown that can reduce the mortality; despite this, survival rate has not changed significantly during last years. the aim of this study is to test a new wearable glove to provide lay people with instructions during out-ofhospital cpr. patients and methods: we performed a blinded, controlled trial on an electronic mannequin ambuman to test the performance of adult volunteers, non-healthcare professionals performing a simulated cpr both, without and with glove, following the glove instructions. the group without glove, also called "no-glove" is intended as control group. each compression performed on the electronic mannequin ambuman was recorded by a connected laptop computer, drawing a depth frequency curve over the time. primary outcome was to compare the accuracy of the two simulated cpr sessions in terms of depth and frequency of chest compressions performed by the same lay volunteers. secondary outcome was to compare the decay of performance and percentage of time in which the candidate performed accurate cpr. finally, the participants were asked if the glove was useful for cpr maneuvers. the difference between the two groups in regard to change in chest compression depth over time due to fatigue, defined as decay were also analyzed. results: chest compressions were included: in control group, in glove group (table ) . mean depth of compression in the control group was . mm versus . mm in the glove-group (p = . ). compressions with an appropriate depth were not statistically different ( . % vs . %, p = . ). mean frequency of compressions in the group with glove was . rpm vs . rpm in the control group (p < . ). the percentage of compression cycles with an appropriate rate (> rpm) was . % in the group with the glove versus % in the control group, with an observed difference of . % between the two groups, which was statistically significant (p < . ,ci = %). a mean reduction over time of compressions depth of . mm (sd . ) was observed in the control group versus a mean reduction of . mm in the group wearing the glove (sd . ), but this mean difference in the decay of compressions delivery was not statistically significant (f-ratio = . , ss = . , df = , ms = . , p = . ). conclusion: the visual and acoustic feedbacks provided by the device were useful in dictating the correct rhythm for non-healthcare professionals, translating in a significantly more accurate cpr. compliance with ethics regulations: yes. rationale: neuroprognostication after cardiac arrest (ca) is a crucial issue and current guidelines recommend delayed multimodal approach. we aimed to describe reasons for death in a prospective cohort of ca patients and evaluate the diagnostic accuracy of early combined neurological prognostication tools such as automated pupillometry (ap), continuous amplitude electroencephalography (aeeg) and cardiac arrest hospital prognosis (cahp) score performed h after return of spontaneous circulation (rosc). we set up a monocentric prospective cohort of adult ca patients admitted in icu after sustained rosc and collected data according to utstein style recommendations. reasons for death were described under recently proposed classification: withdrawal of life-sustaining therapies (wlst) for neurological reasons, wlst due to comorbidities, refractory shock or recurrence of sudden ca or respiratory failure. for patients who kept abnormal neurologic state after rosc with glasgow coma scale < , we analysed accuracy of early neuroprognostication tools (ap, aeeg and cahp score) to predict poor neurological outcome, i.e. cerebral performance category (cpc) > at hospital discharge. results: patients were admitted after sustained rosc from ca during the period ( . . to . . ). in-hospital mortality was %. neurological wlst was the first reason for death ( %). exhaustive early neuroprognostication with ap, aeeg and cahp score was available for patients. among them, poor neurological outcome at hospital discharge (cpc > ) was observed for patients ( % (fig. ) . this strategy would falsely misclassificate % of patients in a good neurologic outcome category. other survivors ( %) should then be investigated with further classical delayed neuroprognostication tools. compliance with ethics regulations: yes. rationale: management delay is one of the determining factors in the assessment of emergency department quality of care. asking for a specialized advice seems to increase the time of delay. our study aimed at measuring the delays in obtaining specialized advice and identify their major causes. patients and methods: we conducted a prospective study over the period of month. we included all adult patients presenting to the emergency department who required specialized advice. data of all patients was collected. waiting times and influencing factors were studied. results: a total of patients were included. the main reason for calling for a specialized advice was to ask for a department transfer in % of cases. the time of the day when specialized advice was solicited (n (%)): in the morning ( ); in the afternoon ( ); in the evening ( ). the main solicited specialties were (n (%)): visceral surgery ( ), trauma medicine ( ), cardiology ( ), urology ( ), and pulmonology ( ). the average waiting time between calling for and getting the specialized advice was ± min. seventy-five percent of the specialized advice was obtained within h. the causes of the delay were (n (%)): physician busy in the operating room ( ), unreachable physician ( ), physician in the outpatient clinics ( ). the impact of the waiting time was (n (%)): conflict ( ), worsening patient state ( ). the average time between calling for the specialized advice and reaching a management decision was ± min. conclusion: the increasing length of stay of patients in the ed is strongly correlated to the delay in obtaining specialized advice. the implementation of a strategy to reduce the waiting time is necessary to avoid overcrowding the emergency departments and provide optimal care. compliance with ethics regulations: yes. rationale: hypnoanalgesia has been used since few years to reduce icu-patients physical and psychological discomfort during invasive procedures. however, feasibility of overall well-being management of intubated patients with hypnosis has not been described. patients and methods: we report here the hypnotic accompaniment of a -year old patient without significant medical history hospitalized in our icu for a severe gbs during months. the gbs was diagnosed by electrophysiological study and immunologic markers. patient had nearly complete paralysis of all extremities, but no facial or bulbar muscles. he received mechanical ventilation during days, including weaning time. tracheotomy was performed at day . sedative drugs were stopped days after intubation. hypnosis sessions were startedvery early after intubation by one of our trained intensivist. eight hypnotic sessions of hypnoanalgesia or hypnotherapy were performed after approval of the patient and his parents. time distribution is reported in fig. . first and second sessions were performed in order to induce relaxation and reduce anxiety. following sessions were dedicated to: ) decrease pain intensity (initially neuropathic, then induced by physiotherapy), ) attenuate the negative perception of paralysis, ) reduce the discomfort of tracheotomy ) promote the belief in healing ) facilitate swallowing exercises. furthermore the patient was quickly trained to use self-hypnosis in order to dissociate him from pain, anxiety and icu pollutions. results: feasibility of hypnosis was judged satisfactory by the operating physician, despite mechanical ventilation. after extubation, final debriefing with the patient indicates that the most efficient sessions were those focused on anxiety disorders (using the suggestion of a safe place) and suggestions of mobility (using a mangas metaphor). the patient reported very positive perception of hypnosis use. he explained that self-hypnosis was effective to reduce many discomfort. he used it frequently (generally twice a day) for a puff of anxiety or before enoxaparin injection. our observation suggests that hypnosis seems feasible in icu-awake patients and may be an interesting way to improve their icu lived experience in combination with validated measures. further investigations are needed to evaluate its effects on post-traumaticstress disorder. compliance with ethics regulations: yes. rationale: there is little medical reference for hypnosis in the intensive care field. closed specialties such as anesthesia, emergency medicine can help and refer to hypnosis for certain technical procedures. objective: to propose landmarks for a successful implementation of hypnosis by intensivists within the intensive care unit. patients and methods: this monocentric prospective observational study was performed from february to june in the -bed medical icu of brest university hospital. collected data were: characteristics of patients and hypnosis sessions performed, demographic data, physiological parameters (heart and respiratory rates) and objective and subjective evaluation of hypnosis sessions quality. results: patients were included (mean age . ± years, saps ii . ± points). hypnosis sessions were performed, of which / under mechanical ventilation. patterns of hypnosis sessions were: anxiety/comfort ( %), during a technical procedure ( %): toe, cvc placement, thoracic drainage, upper digestive or bronchial endoscopy), initiation of noninvasive ventilation or before intubation. most of time, the hypnotic trance was permitted by formal hypnosis techniques with travel and nature themes suggestion. efficacy was qualitatively assessed and rated as "total effectiveness" for % of sessions. qualitative evaluation by hypnotherapist, technical operator and observers was respectively . ± . , . ± . and ± / . heart rate decreased from ± to ± bpm and respiratory rate/min decreased from ± to . ± rpm during sessions. discussion: after a meeting, the healthcare team carried out a brainstorming to propose hypnosis in our unit. several difficulties were observed to explain implementation failures such as: finding competent patient, respiratory assistance, difficult communication, noisy environment, many nursing care, unexpected emergencies, etc.…). this experience allowed writing a vademecum to perform hypnosis in intensive care. our aims are to get more trained caregivers and to integrate hypnosis during our postresuscitation consultation, especially for post-traumatic stress. conclusion: hypnotic tools can facilitate technical procedures and improve patients' and caregivers' quality of life within the icu. compliance with ethics regulations: yes. effect of a musical intervention during central venous catheterization in an intensive care unit: the music cat prospective randomized pilot study sophie jacquier, brice sauvage, gregoire muller, thierry boulain, mai-anh nay chr, orléans, france correspondence: sophie jacquier (sophie.jacquier@chr-orleans.fr) ann. intensive care , (suppl ):f- rationale: evaluate the effect of a musical intervention on patient anxiety during a central venous access or a dialysis catheter implantation in an intensive care unit. patients and methods: the music cat study was a prospective, single-centre, controlled, open-label, two-arm randomized trial, conducted from february to february . central venous catheterization with musical intervention was compared to standard care, i.e., the usual procedure of central venous catheterization without listening to music. eligible patients had to be able to hear, understand explanations and consent. randomisation was stratified according to ventilation type (mechanical ventilation or not) and catheter site (superior vena cava or femoral vein). the music care ® (paris, france) application was used to make the patients listen to music through headphones. each patient chose his/her musical topic on a digital tablet, just before the catheterization. the primary outcome was the change in anxiety visual analogic scale (vas) between the beginning and the end of the catheterization procedure (t -tf anxiety vas). secondary outcomes included the patient's pain vas at the end of the procedure (tf pain vas). results: patients were included in the standard care group versus in the musical intervention group. main reasons for admission were the need of central catheter for chemotherapy ( , %), and sepsis and/or shock in both groups ( , %). catheters were inserted in the internal jugular vein in most cases ( , %) and about one-third were tunnelled in both groups. there was no between-group difference regarding median t -tf anxiety vas: [iqr:− to ] in the standard care group versus − [− to ] in the music intervention group (p = . ) (fig. ) , with no significant interaction between the variables of stratification or the operator experience and the intervention. the median tf pain vas was not statistically different between groups: [ to . ] in standard care group and [ to ] in music intervention group (p = . ), with no significant interaction between the variables of stratification or the operator experience and the intervention. conclusion: in this first randomized pilot study of musical intervention for central venous catheterization in awake patients in the intensive care unit, the musical intervention did not reduce patients' anxiety as compared to usual care. as the study may have been underpowered, larger size trials are needed. compliance with ethics regulations: yes. rationale: sleep is markedly altered in icu-patients under mechanical ventilation and may be due to noise, light, patient-care activities, patient-ventilator asynchronies, or the result of acute brain dysfunction induced by sedative drugs. to our knowledge, sleep has never been studied at icu admission before any sedation. our study aimed at assessing sleep quality of non-intubated sedation-free patients admitted to icu for acute respiratory failure. patients and methods: observational study performed in a single centre of a teaching hospital. patients admitted to icu for acute respiratory failure (respiratory rate ≥ breaths/min and pao / fio < mm hg under high-flow nasal oxygen) could be enrolled. patients with hypercapnia, central nervous disease, intubated early after admission and those with a do-not-intubate order were excluded. sleep was evaluated by complete polysomnography (psg) that started in the afternoon following admission and was continuously performed until the next morning. results: over a -year period patients were screened and patients were included. among them, patients were excluded for the following reasons: patient was intubated shortly after psg initiation, psg was lost, and eeg recordings ( %) were stopped before midnight (electrodes turned off or loss of signal). therefore, patients in whom psg was complete during the nocturnal period were retained in the analysis ( rationale: convulsive status epilepticus (cse) is a common neurological emergency associated with high mortality and morbidity rates. there are strong experimental data suggesting a potential impact of secondary brain insults (sbi) on outcome after cse. however, there is no clinical proof to support this hypothesis. our objective was to evaluate the association between sbi (mean arterial blood pressure, arterial partial pressure of carbon dioxide, arterial partial pressure of oxygen, temperature, natremia, and glycemia) at day and neurological outcomes days after cse. patients and methods: this was a post hoc analysis of the hyber-natus multicenter open-label clinical trial randomized critically ill patients with cse requiring mechanical ventilation to either therapeutic hypothermia ( - °c for h) plus standard care or standard care alone. patients still alive at day after inclusion were enrolled from march to january in french medico-surgical icus. the primary outcome was favourable outcome days after cse defined as a glasgow outcome scale score of . results: median age was of years . a previous history of epilepsy was noted in ( %) patients. most episodes ( / , %) occurred out-of-hospital, and ( %) were witnessed from their onset. cse was refractory in ( %) patients and total seizure duration was min ( - ). a favorable -day outcome occurred in ( %) patients. maximal glycemia value and hyperglycemia > . mmol/l at day were the only sbi variables associated with outcome in univariate analysis. by multivariate analysis, age > years (or, . ; % ic, . - . ; p = . ), refractory cse (or, . ; % ic, . - . ; p = . ), and primary brain insult (or, . ; % ic, . - . ; p = . ) were associated with an increased risk of poor outcome, and a bystander-witnessed onset of cse (or, . ; % ic, . - . ; p = . ) was associated with a decreased risk of poor outcome. conclusion: in our population, secondary brain insults were not associated with outcome in critically ill patients with convulsive status epilepticus; whereas age, bystander-witnessed onset of status epilepticus, refractory status epilepticus and primary brain insult were identified as strong predictors of -day functional impairment. further studies are warranted to confirm our findings. compliance with ethics regulations: yes. rationale: acute stroke (as) is a leading cause of morbidity and mortality worldwide. however, data on the prognosis andfunctional outcome of patients with as requiring icu management is limited. our purpose was to identify factors associated with good outcome (defined by a modified rankin score (mrs) of - ) months after icu admission. patients and methods: retrospective cohort of patients admitted to the medical icu of a university-affiliated hospital between january and december and coded for acute stroke using the icd- criteria. patients with traumatic stroke and isolated subarachnoid hemorrhage were excluded. results: we identified patients. median age was [ . - ] years and ( . %) were males. main reasons for icu admission were coma ( %), hemodynamic instability ( . %), acute respiratory failure ( %), and cardiac arrest ( . %). glasgow coma score at icu admission was [ ] [ ] [ ] [ ] [ ] [ ] [ ] and points. types of stroke were hemorrhagic in ( . %) patients and ischemic in ( . %). mechanical ventilation was required in patients ( . %). seizures occurred in . % of the patients and convulsive status epilepticus in . %. pneumonia was diagnosed in ( . %) patients (aspiration pneumonia n = , ventilator associated pneumonia n = ). thrombolysis or thromboaspiration were performed in ( %) patients with ischemic stroke. surgical evacuation of expanding hematoma was performed in ( . %) patients, ( . %) had craniectomy, and ( . %) had external shunt for hydrocephalus. icu and hospital mortality were . % and %, respectively. six months after icu admission, ( . %) patients had a good outcome (mrs - ), ( . %) had significant disability (mrs - ), and ( . %) were deceased (lost follow-up n = , . %). on multivariable analysis, age (or . per year ( . - . ), p = . ), saps (or . per point ( . - . ), p = . ), and hemorrhagic stroke (or . ( . - . ), p = . ) reduced the likelihood of good outcome (mrs - ) months after icu admission. conclusion: in our study, prognosis of acute stroke requiring icu admission was poor and a good functional outcome occurred in less than % of the patients at months. age, severity at icu admission, and type of stroke predicted outcome. compliance with ethics regulations: yes. rationale: in intensive care units, severe spontaneous hemorrhagic brain injuries have a poor prognosis for mortality and functional outcomes. affected patients face particular ethical issues regarding the difficulty of anticipating their eventual recovery. in this context, prognostic scores can help clinicians in patients/relatives counseling and therapeutic decisions. the previous reviews pointed out many prognostic tools for intracranial hemorrhage and subarachnoid hemorrhage but did not focus on injuries explicitly severe nor assessed the methodological limitations of the models. our systematic review aimed to assess methodologically prognostic tools for functional outcomes in severe spontaneous haemorrhagic brain, with particular attention to their clinical utilities. patients and methods: following prisma recommendations, we queried medline, embase, web of science, and the cochrane by february , . we included multivariate prognostic models explicitly developed or validated on adults with severe intracranial or subarachnoid haemorrhage. we evaluated the articles following the charms recommendations (checklist for critical appraisal and data extraction for systematic reviews of prediction modelling studies) and the tri-pod statements (transparent reporting of a multivariable prediction model for individual prognosis. results: our review confirmed the multiple publications of prognostic scores, as we found articles aiming to develop or validate prognostic tools. relying on guidelines, we discarded articles due to the lack of prognostic capacities, validation, or predictor selection. articles developed and validated a prognostic tool and externally validated existing models (fig. ) . no score was of good methodological quality in intracranial hemorrhage. we highlighted two prognostic scores in subarachnoid hemorrhages: the sahit predicting unfavorable outcome or mortality at months and the fresh predicting unfavorable outcome at months. conclusion: although prognostic studies on haemorrhagic brain injuries abound in the literature, they generally lack of methodological robustness or show incomplete reporting. with the numerous published scores, we believe that it is time to stop developing new scores. ongoing validation, recalibration, and impact studies would keep improving existing good tools. the use of "patient-centered" approaches could also enhance them, and be more appropriate to inform patients and families about their long-term potential recovery. these considerations should drive future research in the modern era of neurocritical care prognosis. compliance with ethics regulations: na. rationale: respiratory pattern analysis by a visual examination is an important part of clinical assessment but is dependent on caregiver expertise and is subjective. furthermore, there is no easy medical device used in picu to measure tidal volume (vt) and minute ventilation (mv) in spontaneous breathing patients. the clinical research unit in critical care of chusj and ets have developed a non-invasive computerized d video analyzing system (retract system) to detect and perform a video analysis of respiratory status in children. the aim of this study is to test the reliability of the retract system to monitor respiratory distress in critically ill children. the retract system is detailed in reference . in summary, cameras reproduce in d the thorax and abdomen of a subject. the respiratory status (respiratory rate (rr), tidal volume (vt), minute ventilation (mv)) assessed by the retract system was compared on a bench test (high-fidelity mannequin) and in critically ill children, to the ventilator measurements and clinician expert evaluation (gold standard). bland-altman plots were used for comparison. results: we observed a significant agreement, on mannequin, between retract system and gold standard method in estimating vt, rr and mv, i.e. % of the paired differences were within the limits of agreement in bland-altman plots, as illustrated in fig. . in critically ill children (n = ), the correlation between the pairs of measures was also high (r > . , p < . ) and thecoefficient of determination with a high fit ( . < r < . , p < . ). for good correlation, the retract system needed to have a visual access to thorax and abdomen in a quiet subject. the retract system measurements of vt, rr and mv for respiratory distress monitoring in patients seems reliable. more testing are required to validate this method in usual practice and to develop the retractions signs video analysis. compliance with ethics regulations: yes. rationale: severe bronchiolitis requires hospitalization in paediatric intensive care unit (picu). non-invasive ventilation (niv) has been demonstrated to treat them since twenty years, its use is well defined but there is no consensus for the weaning. this study evaluated the application of a nurse-driven niv weaning protocol in hospitalized infants with severe bronchiolitis and verified its safety. this was a retrospective monocentric study in a picu of robert debré hospital-paris, france. in the epidemic period of bronchiolitis between and , all patients under one year old with severe bronchiolitis and requiring niv were included. two groups were compared: one group using the nurse-driven niv weaning protocol and one group without using this protocol. occurrences of complications, duration of ventilatory support and length of stay (los) in picu and total los were compared. results: patients were included in the study, in the no-protocol group, and in the protocol group. the nurse-driven protocol was using at the rate of % (n = / in the protocol group (p = . ). picu los were . days [ ] [ ] [ ] in the no-protocol group versus days [ - . ] in the protocol group (p = . ), hospital los was days [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in the no-protocol group versus days [ ] [ ] [ ] [ ] [ ] [ ] in the protocol group (p = . ) (fig. ) . the use of this first nurse-driven niv weaning protocol was feasible and simple with a very good application rate. its utilization was safe. the occurrence of complications did not increase by the use of this protocol. it would allow an optimal niv weaning without prolonging the ventilatory support duration nor picu los or hospital los. the professional practices appeared to be coordinated and the nurses appeared to be more autonomous. compliance with ethics regulations: yes. no-protocol and protocol groups comparison: cpap duration ( ), ventilatory support duration ( ), picu los ( ), hospital los ( ) rationale: first-line management of severe acute bronchiolitis in infants is mainly based on non-invasive ventilation (niv) and high-flow nasal cannula (hfnc) therapy. however, pediatric data regarding weaning from niv/hfnc are lacking. this study aims to identify the weaning practices from niv/hfnc in children with severe bronchiolitis. the weaniv-survey is a cross-sectional survey. a questionnaire was sent to french-speaking physicians with key roles in pediatric intensive care units. results: a total of % ( / ) of french university hospital were represented in the study. only % of pediatric centers used a protocol for weaning from niv/hfnc and nurses were considered as key-actors of the weaning process for half of participants. continuous positive airway pressure (cpap) was the mode of ventilation mainly used as the first-line therapy in clinical practice. the main criteriaconsidered toinitiate weaning process were: noor slight respiratory distress, a fio < %, a respiratory rate < /min and no significant apnea. three strategies to discontinue niv/hfnc were identified: /gradual decrease of ventilatory parameters (pressure or flow), /abrupt discontinuation and /gradual increase in off-ventilation time. abrupt weaning strategy was the most commonly used, no matter the mode of ventilation. a significant level of respiratory distress, the presence of apneas, an increase in oxygen requirement, and a respiratory rate > / min were identified as weaning failure criteria by most pediatric intensive care physicians. conclusion: in most centers, the weaning process does not follow any protocol. abrupt weaning seems to be commonly used as weaning strategy in children with severe bronchiolitis supported by niv/hfnc. based on the study findings, we suggest that criteria for weaning initiation and for weaning failure must be defined and weaning protocols generated. compliance with ethics regulations: yes. complications secondary to prone positioning occured for patients ( . %). conclusion: this first study, which evaluate prone positioning efficacy in severe p-ards shows evidence that prone positioning improves oxygenation parameters and survival rate. these results highlight the necessity to develop a multicentric prospective randomized study to confirm these conclusions. compliance with ethics regulations: yes. ( vs ) and vasoactive-inotropic score (vis) ( vs ) were significantly higher in the non-survivor group. cannulation was veno-venous ( %) or veno-arterial ( %) and patients ( %) were finally not initiated on ecmo. we observed an increase of patients cannulated in our picu over time (fig. ). there was no significant difference in mortality between patients transported on ecmo after cannulation in our picu and those who were transported to be cannulated in a referral ecmo center. the median time between the decision and the cannulation was . h and the median time taken in charge by picu transport team was approximately h. these periods were not significantly different between cannulation on site or in an ecmo center and between survivors and not-survivors. conclusion: in our study, multiple organ dysfunction, particularly hematologic and acuterenal failures, seems to be a risk factor of mortality. the delay between decision and management is similar whatever the cannulation site. specific ecmo mobile team and picu transport team seem to be essential, fast and trained to transfer these patients. it would be interesting to compare our cohort with children requiring ecmo already hospitalized in a referral ecmo center. compliance with ethics regulations: yes. rationale: life expectancy in patients with metastatic breast cancer (mbc) has substantially improved over the last decade. life threatening complications result from advanced diseases, infection and treatment-related toxicity. only few studies have assessed outcomes in this setting. we performed a hospital-wide study to investigate how icu resources are needed in patients with mbc. patients and methods: all patients with mbc managed at our hospital between and were retrospectively included. the primary outcome was overall survival (os). factors associated with icu mortality were identified using a multivariable cox proportional hazard model with sensitivity analysis. results are expressed as median [interquartile ranges] unless stated otherwise. results: among the patients managed at our hospital, ( %, including male) were admitted to the icu ( [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] patients per year). age was [ - ] years. patients were receiving their nd [ st- rd] line of treatment and had [ ] [ ] metastatic sites. sofa score at admission was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . main reason for icu admission was sepsis (n = , %), acute respiratory failure (n = , %), coma (n = , %) and metabolic disorder (n = , %). invasive mechanical ventilation was required for patients ( %) and renal replacement therapy for ( %). sixteen ( %) patients died in icu. following icu discharge, median os was . months ( % ci [ . - . ]) and / ( . %) patients died within months. an antineoplastic treatment was resumed for / ( %) patients alive after icu discharge. factors independently associated with mortality were performance status ≥ (hr . , % ic [ . - . ] ) and sofa score at day (hr . per point, % ic [ . - . ] ). after sensitivity analysis, the number of treatment lines at icu admission was not associated with mortality. conclusion: icu admission is required in the course of the mbc disease for % of the patients. determinants of short term outcomes rely on performance status and disease severity but not on the characteristics of the underlying disease. ongoing analyses will assess whether icu survivors reach life expectancy of patients never admitted to the icu. compliance with ethics regulations: yes. hubert gheerbrant , jean-françois timsit , nicolas terzi , stephane ruckly , mathieu laramas , matteo giaj levra , emmanuelle jacquet , loic falque , denis moro-sibilot , anne-claire toffart chu grenoble alpes, grenoble, france; aphp, paris, france; outcom-erea, bobigny, france correspondence: hubert gheerbrant (hgheerbrant@chu-grenoble.fr) ann. intensive care , (suppl ):p- rationale: the prognosis of critically ill cancer patients admitted in intensive care unit (icu), remains an issue. our objective was to assess the factors associated with -and -month survival of icu cancer survivors. patients and methods: based on the french outcomerea ™ database, we included solid cancer patients discharged alive, between december and november , from the medical icu of the university hospital in grenoble, france. patient characteristics and outcome at and months following icu discharge were extracted from available database. results: of the cancer patients with unscheduled admissions, ( %) were discharged alive from icu. the main primary cancer sites were digestive ( %) and thoracic ( %). the -and -month mortality rates were % and %, respectively. factors independently associated with -month mortality included ecog performance status (ecog-ps) of [ ] [ ] . . - . ). interestingly, cancer chemotherapy prior to icu admission was independently associated with lower -month mortality (or, . ; % ic: . - . ). among patients with an ecog-ps - at admission, % (n = ) and % (n = ) displayed an ecog-ps - at and months, respectively. at months, ( %) patients received anticancer treatment, ( %) were given exclusive palliative care. discussion: factors associated with -month mortality are almost the same as those known to be associated with icu mortality. we highlighted that most patients recovered an ecog-ps of - at and months, in particular those with a good ecog-ps at icu admission, and could benefit from an anticancer treatment following icu discharge. conclusion: these results should be taken into account when deciding upon icu admission. it is of paramount importance to have an evaluation of both patient's general condition and anticancer treatment opportunities following icu discharge. compliance with ethics regulations: yes. rationale: the decision to urgently initiate medical anti-cancer treatment in cancer patients admitted to intensive care unit for cancerrelated organ failure is an issue. we currently lack criteria to select patients who may benefit from the treatment initiation. the purpose of our exploratory study was therefore to evaluate the characteristics of patients whose medical anti-cancer treatment is initiated in icu and to identify prognostic factors for in-hospital mortality. in these patients. patients and methods: we analyzed retrospectively, over a period of years ( / / to / / ), cancer patients over -year old admitted to our icu bordet and in whose anti-cancer medicaltreatment was initiated during in-icu stay. to identify prognostic factors for in-hospital mortality, we carried out a multivariate analysis of the factors influencing this mortality, considered as a binary. we also analyzed the long term survival of patients alive after their hospital stay (from the day of going out of hospital). results: overall, patients were included, men ( %) and women ( %), with a median age of years ( - ). of these, patients ( %) had a solid tumor and ( %) had a hematological tumor. in-icu mortality is % ( % ci - %) and in-hospital mortality % ( % ci - %). the prognostic factors for in-hospital mortality were age (mean vs in those who survived), the sofa score (median vs ), the saps ii score (mean vs ), the charlson score (mean vs. . ), the number of organ failure (mean . vs . ) and the presence of a therapeutic limitation (ntbr stated within h: % vs %). survival at year of patients who survived the hospital stay was % and median survival time was estimated to be . year ( % ci . - . ). in patients with a solid tumor, -year survival was % and % in those with a hematological tumor (p < . ). conclusion: we observed, in selected cancer patients admitted to the icu for a cancer-related complication, that the initiation of an anti-cancer medical treatment is feasible and can lead to interesting results, particularly in patients with a hematological tumor. compliance with ethics regulations: yes. rationale: considerable progress in the management of onco-hematology (oh) malignancies led to an increase in the number of patients proposed for intensive care unit (icu) admission. several guidelines offer decision models for icu transfer of these patients. we aimed to describe prognosis, adequacy of icu admission and denial in oncohematology patients. we included all oh patients proposed for icu admission in a tunisian medical icu, between january and july . from an admission proposal registry, were collected patient underlying condition, functional status, malignancy and predicted prognosis, acute critical illness and its reversibility, adequacy of icu rationale: cancer patients frequently need intensive care support for a life-threatening condition due to the underlying neoplasm or an adverse therapy-related event. however, there are poor data on their characteristics and outcomes in the intensive care setting. the aim of the present study was to describe clinical characteristics and to identify factors associated with in-icu mortality in critically ill cancer patients. patients and methods: it is a retrospective study conducted in the medical icu of farhat hached teaching hospital between january and december . all cancer patients with complete records were included. baseline characteristics, clinical parameters, severity of illness, primary tumor location and outcomes were collected. univariate and multivariate regression analyses were carried out to identify factors independently associated to poor prognosis. rationale: prognostic impact of underlying malignancy seems limited in most studies assessing outcome of critically ill cancer patients [ ] . however, only limited number of characteristics, namely disease progression status and preexisting stem cell transplantation, were usually assessed [ ] . primary objective of this study was to assess influence of hematological malignancy aggressiveness on hospital outcome. secondary objective was to assess influence hematological malignancy aggressiveness on type of infection. patients and methods: post-hoc analysis of prospective multicenter cohort performed in hospitals in france and belgium and including critically ill adults with underlying hematological malignancy admitted in icu from jan to may . a cox model was used to adjust for confounding variables then a propensity score matching on characteristics associated with underlying malignancy aggressiveness was performed. results: of the included patients, ( . %) had low grade malignancy (lg), the most frequent being myeloma (n = ), chronic lymphocytic leukemia (n = ), and myelodysplasia (n = ). patients with lg malignancy were older, underwent more frequently autologous stem cell transplantation (sct) and had less frequently altered performans status. they had more severe organ failure at icu admission (sofa score [ ] [ ] [ ] [ ] [ ] [ ] vs. [ ] [ ] [ ] [ ] [ ] [ ] , p = . ). before adjustment, mortality was % (n = ) and . % (n = ) respectively in patients with and without lg malignancy (p = . ). after adjustment for confounder using a cox model, a higher mortality was associated with nonlow grade malignancy (or . ; % ic . - . ). a propensity score then allowed a : matching upon variable associated with malignancy aggressiveness. after matching unadjusted mortality was % (n = ) in patients with lg malignancy and . % (n = ) in patients with high grade malignancy (p = . ) (figure) . in the matched cohort and after adjustment for confounder, high grade malignancies were associated with lower mortality (or . ; % ic . - . ). risk of fungal infection was unchanged by underlying malignancy before adjustment ( % vs. . % of patients with and without lg malignancy; p = . ) or after adjustment (hr . ; % ic . - . ). conclusion: despite anti-cancer advances, aggressiveness of hematological malignancies is associated with overall icu outcome. lowgrade malignancies displaying a better prognosis than non-low grade. aggressiveness of the underlying malignancy is not associated with risk of fungal infection. compliance with ethics regulations: yes. rationale: guillain-barré syndrome is the most common cause of acute flaccid paralysis and is associated with pulmonary embolism due to the mobility limitation. the aim of this study is to describe the incidence, the severity of pulmonory embolism in patients admitted to an intensive care unit (icu) for guillain-barre syndrome (gbs). patients and methods: twenty-eight adults patients with confirmed diagnosis of gbs were admitted to the icu in our university hospital center over a -year period and they were all included. prevalence, risk factors and course of vte were analyzed in icu patients with various forms and severity of gbs. results: during the study period, adult gbs patients were included. five ( . %) developped pulmonary embolism. the mean age was . ± . years and the sex ratio was . . the comparaison betewen the groups with and without pe showed that factors associated with the development of this complication were: respiratory failure requiring mecanical ventilation (p = . ), infectious complications (p < . ), blood pressure lability (p = . ), the delay of icu admission (p = . ), the delay to treatment initiation (p = . ), the sofa score (p = . ) and the presence of quadriplegia (p = . ). conclusion: pulmonary embolism is a frequent complication in patients with gbs. factors associated with this complication were: respiratory failure requiring mecanical ventilation, infectious complications, the delay of icu admission, the delay to treatment initiation, a high sofa score and the presence of quadriplegia. preventive measures in this category of patients have to be improved. rationale: acute respiratory distress syndrome (ards) is a life-threatening pathology associated with very high morbidity and mortality ( - %) in intensive care units (icu) and with even higher mortality among the severly burned patients worldwide ( à %). the aim of our study was to describe in tunisia burn patients with ards and to identify prognosis factors. patients and methods: we conducted a descriptive retrospective study between - - to - - , in burns icu, in ben arous, in tunisia. all burns who presented an ards, according to the berlin definition, during their stay in the icu, were included. when clinical or gasometric data was uncomplete, these patients were excluded. results: during the study period, patients were admitted to our burn unit including ventilated patients. fifty patients presented an ards: fifteen patients were excluded for lack of information, and patients were retained. the sex ratio was . . patients had a mean age of ± years, an average burned area of % ± %, an average unit of burn skin score (ubs score) of ± and an average sequential organ failure assessment score (sofa score) of . none of the patients had a history of cardiovascular or pulmonary diseases. the average time of onset of ards was ± days. ards was mild in case, moderate in and severe in . the etiology of ards was pulmonary in cases ( %) and extra-pulmonary in ( %). the pulmonary ards had as cause pneumonia isolated in patients, an isolated pulmonary burn in patients and a combination of pneumonia and lung burns in patients. extra-pulmonary ards were all due to sepsis and mainly to bacteremia. septic shock was associated with ards in patients ( %). the treatment was a conventional treatment based on protective ventilation, curarization and prone positioning in addition to the etiological treatment. the average length of stay in icu was days and mortality was % in these patients. conclusion: mortality from ards in burns in tunisia, is important especially in those with pulmonary burns as well as those with sepsis. the introduction of new treatments, such as extracorporeal membrane oxygenation, remains essential to improve the prognosis of burn patients. compliance with ethics regulations: yes. rationale: aspiration pneumonia (ap) is common in intensive care unit (icu). the incidence of ap among adults hospitalized with pneumonia ranges between and . %. usually one or more risk factors are identified to be involved in ap. the aim of this study was to determine the risk factors and predictors of mortality on patients with ap. patients and methods: we retrospectively included patients aged more than years and who were hospitalized in our icu for ap. patients were excluded if they had history of tuberculosis, if they have bronchiectasis or metastatic brain tumor. results: a total of patients were included. history of diabetes, hypertension, epilepsy and ischemic stroke were found respectively in . %, . %, . %, and . % of cases. the reason of icu admission were coma ( %), acute respiratory failure ( %), poisoning ( %) and cardiac arrest ( %). the incidence of acute respiratory distress syndrome (ards) was %. the most common organism isolated was staphylococcus aureus ( cases). risk factors for ap were epilepsy ( %), swallowing disorders ( %), ischemic stroke ( %), copd ( %) and degenerative neurological disease ( %). the mortality rate was . %. the median duration of mechanical ventilation was days [iqr - ]. in multivariate logistic regression analysis; saps ii score (or = . , % ic [ . - . ], p = . ) and ards (or = . , % ic [ . - . ], p = . ) were independently associated with mortality. conclusion: risk factors for aspiration pneumonia were epilepsy, swallowing disorders and ischemic stroke. ards and saps ii score were independent predictive factors of mortality. compliance with ethics regulations: yes. undetermined. the aim of this study was to evaluate the impact of hyperoxia on morbidity and mortality. patients and methods: this was a prospective study performed in the icu of abderrahmen mami hospital during a -month period. all patients admitted in icu during the study-period were included. those who didn't need oxygen therapy or in end of life stage were excluded. arterial blood gases were analyzed daily and each day with at least one value of oxygen arterial saturation (sao ) > % was considered as a day with hyperoxia. for each patient included, the number of times and days spent in hyperoxia was recorded as well as complications during the icu stay and the outcome. results: during the study-period, patients were included but only were eligible. mean age was ± years. acute on chronic respiratory failure was the most frequent reason of admission ( %). non-invasive ventilation was required for % of patients and invasive mechanical ventilation was necessary in % of cases. overall mortality was %. hyperoxia was observed in % of cases, with an average of ± times during the icu stay and ± days. a statistically significant association was observed between a long duration of hyperoxia and the occurrence of ventilator acquired pneumonia (p < - ), ventilator acquired bronchitis (p = . ), acute respiratory distress syndrome (p < - ), atelectasis (p < - ), septic shock (p < - ), rythm disorders (p = . ), reintubation (p < - ) and tracheostomy (p = . ). on multivariate analysis, independent factors of mortality were: simplified acute physiology score ii, cardiac failure, need for invasive mechanical ventilation and septic shock. hyperoxia was not independently associated with mortality. conclusion: hyperoxia is frequent in icu. it is significantly associated with icu complications but not independently associated with mortality. compliance with ethics regulations: yes. experience of the practice of prone position in patientswith acute respiratory distress syndrome in intensive care (chu oran) nabil ghomari, soumia benbernou, djebli houria faculté de medecine d'oran, oran, algeria correspondence: nabil ghomari (nabilghomari@hotmail.fr) ann. intensive care , (suppl ):p- rationale: mechanical ventilation (mv) in the prone position (pp) and low tidal volume have become recommendations with a high level of scientific evidence in recent years. the pp has been practiced for years in the chu oran emergency resuscitation service. we wanted to report the service experience in the practice of pp in patients with ards. patients and methods: retrospective study performed in patients with severe hypoxia ards with spo < % under fio > % or pao /fio < during the period march to december . results: patients received ventilation in pp. ards was secondary to thoracic trauma in % of patients, septic shock in % and aspiration pneumonitis in %. analysis of the success factors and improvement of oxygenation found that lobar ards, the delay < h and a duration of pp ≥ h were statistically significant. conclusion: the pp must be integrated into the arsenal of care of the patients in ards especially in our country where we do not have all the therapeutic options. compliance with ethics regulations: yes. julien goutay, nicolas cousin, thibault duburcq, erika parmentier-decrucq chu de lille, pôle de réanimation, hôpital salengro, lille, france correspondence: julien goutay (julien.goutay@gmail.com) ann. intensive care , (suppl ):p- rationale: in veno-venous extracorporeal membrane oxygenation (vv-ecmo) therapy, blood flow is the main determinant of arterial oxygenation and should be - ml/kg/min in adults. this flow rate is determined by several factors including the size of the inflow cannula. the impact on clinical outcomes of arterial cannula's size in veno-arterial ecmo (va-ecmo) has already been studied, and showed no difference for survival to discharge, weaning success rate and initial flow rate between a small cannula group and a larger one. our first objective was to describe the impact of inlet cannula size on the assistance flow rate in patients treated with vv-ecmo. secondary objectives were to analyze its impact on ecmo weaning, mechanical ventilation characteristics and mortality. patients and methods: we retrospectively reviewed all cases of respiratory failure treated with vv-ecmo admitted in the medical intensive care unit (icu) of lille's teaching hospital from january st, through march st, . inlet cannula size was collected and divided into two groups: the "small cannula" group had inlet cannula less than or equal to fr, while "large cannula" were larger than fr. primary endpoint was the initial flow rate according to the inlet cannula size, and its changes during the first h of assistance. secondary endpoints were the analysis of predictive factors associated with the choice of a larger inlet cannula, and the impact of its size on clinical outcomes such as successful ecmo weaning. results: patients treated with vv-ecmo were admitted in our hospital. eleven ( %) were cannulated with a large inlet device. mean initial ecmo flow rate was statistically higher in the "large cannula" group than in the "small cannula" one: . l/min (± . ) versus . (± . ) respectively, p < . . the difference was also significant during the first h of assistance. we found no difference between the two groups on clinical outcomes such as ecmo weaning time. in univariate analysis, weight was heavier in the "large cannula" group [ (± ) kg] than "small cannula" [ (± )], p < . . conclusion: ecmo initial flow rate was higher in a "large inlet cannula" group (internal diameter more than fr) compared with a "small cannula" group. we found no correlation with cannula-related haemorrhagic or thrombotic complications. inlet cannula size did not influence ecmo weaning, and duration time, but this may be a lack of statistical power. further prospective studies should confirm this results. compliance with ethics regulations: yes. rationale: burn patients are at risk of multidrug-resistant (mdr) bacterial infections with high mortality rate. therefore, monitoring the emergence of mdr pathogens in these vulnerable patients is important. this study aimed to assess digestive colonization with carbapenemase-producing gram-negative bacilli (cp-gnb) in patients admitted to the burn intensive care unit. patients and methods: our study was prospective and conducted over a one-year period (january to december ). every admitted patient was subjected to the screening. a double swab set was used to collect rectal swab specimens. one swab was used for mdr screening by disk diffusion method on selective media; the other for multiplex real-time pcr (cepheid's genexpert ® ) allowing detection of the most common carbapenemase-encoding genes (ceg) (blaoxa- , blakpc, blandm, blavim and blaimp). results: among the studied patients, ( . %) were detected positive at admission for cp-gnb by the genexpert ® carba-r assay. eleven patients, initially not colonized, acquired positive faecal carriage subsequently during their hospital stay. forty-two colonized patients ( . %) developed cp-gnb infection during their hospitalization. the ceg blandm quantitatively dominated by far with detections; either alone ( cases) or associated with other ceg ( cases). the second most frequent gene was blaoxa- . it was detected alone eight times and in association with other ceg times. forty-three patients carried blavim gene, usually in association with other ceg ( %). however, only one patient carried blakpc gene. the parallel screening by classical microbiology methods (disk diffusion on selective media) detected the presence of cp-gnb in all molecular positive samples. conclusion: our study describes the characterization of carbapenemase in burn patients and highlights their alarming spread. this emphasizes the importance of an active surveillance program by early detection of cp-gnb carriers and an isolation policy to limit the mdr infections expansion. compliance with ethics regulations: yes. rationale: invasive fungal infections are increasingly observed in the icus especially in burn units. inthe absence of simple and accessible techniques for early microbiological diagnosis, the use of antifungal treatment is increasing. little is known about the extent of the problem of antifungal prescription in burn icus. we aimed to evaluate the antifungal prescription in major burn patients. patients and methods: during the study period ( - ), all prescriptions of antifungals were analysed. analysis concerned demographics, clinical circumstances, as well as the basis of antifungal prescribing (targeted vs. empiric). among the patients admitted in this period, patients were treated with antifungals (sex ratio: . ; mean age: ± years, with low associated comorbidity). the tbsa was . % [ . - . ], ubs was [ . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . most of the patients ( . %) were transferred from another hospital structure within ± h. antifungal treatment was started at the average of the seventh day post wound injury, more often on an empiric basis. sofa score at the beginning of the treatment was ± . . lymphopenia was present in % and thrombopenia was present in %. index of colonisation was positif only in cases. the average candida score was . ± . . microbiological results were tardily collected, within weeks, in %. fungal urine infections were found in cases. candidemia and catheter-related infections were considered only in cases. the risk factors of fungal infection as described in literature were found in most of the patients including mechanical ventilation ( . %), length period of stay ( days [ . - . ]), central venous line ( %), severe sepsis or septic shock ( %), large-spectrum antibiotherapy for more than days ( %). conclusion: the management of antifungal infections in major burn patients is still challenging. antifungal prescription is based on clinical presumption. the empirical prescription reflects the lack of efficient laboratory support and late microbiological results prompting physicians to rely on clinical informations. the management of fungal infections is based on the improvement of mycological investigations. compliance with ethics regulations: na. rationale: invasive candidiasis is a widespread and alarming infection in intensive care units (icu) patients. its diagnosis is often difficult because of the lack of specificity of clinical signs and the low sensitivity of blood cultures. while the candida albicans species remain the most common cause of bloodstream infections, non-albicans are emerging. these infections are serious, associated with high mortality rate and requiring early diagnosis and appropriate treatment. in tunisia, few data are available. we aimed to determine the epidemiological profile of a series of candidemia in icu, the risk factors associated with the occurrence of candidemia and to describe the modalities of the mycological diagnosis of candidemia and their etiological profile. patients and methods: a retrospective longitudinal descriptive study conducted in the parasitology-mycology laboratory with the collaboration of the medical icu of la rabta hospital-tunis over a -year period from january , to december , . all hospitalized icu patients with at least one candida-positive blood culture were included. results: forty-three patients among hospitalized patients during the study period had at least one candidemia infection. the main risk factors for development of candidemia infection include invasive procedures, a prior use of antibiotics and parenteral nutrition. c. albicans was the most common species, detected in . % of patients. nonalbicans candida species were prominent ( . %), represented by c parapsilosis, followed by c. tropicalis and c. krusei then c. glabrata and finally c. lusitaniae. all the isolates tested were sensitive to the common antifungal agents. the mortality rate of our patients was high ( . %), and the detection of the albicans species in blood cultures was the only prognostic factor identified (or = . [ . - . ], p = . ). conclusion: candidemia in the medical icu patients is common and is associated with high mortality rate. despite the progress of biological tools, the diagnosis is difficult and needs to take into account the risk factors of the patients as well as scores based on clinical and microbiological parameters. a better identification of risk patients may help to early initiate empirical antifungal treatment. compliance with ethics regulations: yes. necrotizing soft-tissue infections in the intensive care unit: a retrospective hospital-based study kais regaieg, sabrine nakaa, arnaud mailloux, madjid boukari, johana cohen, dany goldgran-toledano groupe hospitalier intercommunal le raincy-montfermeil, montfermeil, france correspondence: kais regaieg (kais.regaieg@gmail.com) ann. intensive care , (suppl ):p- rationale: the objective of our study is to describe the epidemiological and clinical characteristics of necrotizing soft-tissue infections (nsti) and to improve therapeutic management. we conducted a retrospective observational study that included patients admitted in the intensive care unit (icu) of general hospital between september and aout with a primary or secondary diagnosis of nsti. we collected demographic and clinical data, cultured pathogens, lengths of stay, and in-icu mortality. results: during the study period, a total of patients admitted to the icu were diagnosed with nsti ( . % of the total number of patients). the mean of age was years. the sex ratio (m/w) was . . ten patients ( %) were directly admitted to the icu, others were transferred from medical or surgical wards. the mean of saps ii was . ( . ). the main indication to admission in icu was shock ( %). the most common comorbidity was diabetes ( %). the other co-morbidities associated with nsti were cardiovascular diseases ( %), obesity ( %) and carelessness ( %). the sites most commonly affected were extremities in patients ( %) and abdomen/ano-genital in patients ( %). in icu, a total of patients ( %) were mechanically ventilated [ (median duration: . days ( . )], patients ( %) were given vasopressors, and patients ( %) underwent renal-remplacement. all patients underwent one or more chirurgical intervention. patients ( %) underwent radical necrosectomy. in cases, an amputation was necessary. polymicrobian infection was seen in patients ( %). in patients ( %), we used vacuum assited closure therapy, which in patients was followed by definitive reconstruction by split skin grafts. the mortality in icu was %. the mean stay in icu was days . the mean duration of hospitalization of the patients who survived was days ( - ). on the basis of a univariate analysis, higher saps ii score and lactate levels were associated with increased mortality (p < . ). conclusion: ntsi is rare in icu but it's a life-threatening and disabling disease with a high mortality requiring a multidisciplinary management. early diagnosis and adequate treatment are necessary to improve clinical outcome and must be known by everyone. more studies are needed to estimate the interest and delay of new strategies such as negative pressure therapy. compliance with ethics regulations: yes. rationale: nosocomial infections remain a major cause of mortality and morbidity in burn patients. providing information about the main causative bacterial agents and determination of their susceptibility to antibiotics may improve empiric therapy and early detection of emerging antimicrobial resistance. the aim of our study was to investigate the species distribution and antibiotic susceptibility of isolated strains from a burn intensive care unit (icu). patients and methods: this study was performed retrospectively on all bacteriological samples taken from the burn icu at the trauma and burn center in tunisia during a seven year period (from january to december ). all isolated microorganisms were identified on the basis of standard microbiological techniques. antibiotic susceptibility testing was carried out by the agar disk diffusion method, and susceptibility results were interpreted using clinical breakpoints according to ca-sfm guidelines. minimum inhibitory concentration of colistin was determined using the e-test ® method (biomérieux), then using the eucast broth micro-dilution method (umic, biocentric ® ) since may . results: during the study period, the most frequent identified species were pseudomonas aeruginosa ( . %), staphylococcus aureus ( %), klebsiella pneumoniae ( . %) and acinetobacter baumannii ( %). these strains have been mainly isolated from blood cultures ( %) and skin samples ( . %). pseudomonas aeruginosa resistance to ceftazidime increased from . % in to . % in and resistance to imipenem and ciprofloxacin was . % and . %, respectively. four strains were resistant to colistin. rationale: community-acquired peritonitis is a heterogeneous condition characterized by peritoneum inflammation in response to a bacteria injury. the aim of our study is to describe the epidemiological, clinical, bacteriological, etiological, therapeutic characteristics of community peritonitis, and to evaluate the prognostic factors. patients and methods: this is a retrospective descriptive and analytical study spanning three years (between january and december ) involving cases of community peritonitis, hospitalized in the surgical emergency resuscitation department p ibn rochd casablanca university hospital. our study included adult patients with community-acquired peritonitis who underwent medical and surgical management. the studied parameters are the demographic data, the clinical and paraclinical signs, the care taken and the evolution of the patients. the study showed that the mean age was . ± . years, with a sex ratio of . . patients medical history included tobacco ( . %), extra-abdominal signs [hemodynamic failure ( %), renal failure (n = , %), hematological disorders (n = , %) and respiratory disorders (n = , %)]. therapeutic management was based on perioperative resuscitation, treatment of organ failure, probabilistic antibiotic therapy and median laparotomy surgery. the main etiologies of community peritonitis were: digestive perforation ( . %), purulent effusion ( %), intestinal necrosis ( . %), cholecystitis ( . %). intraoperative bacteriological specimens yielded the following bacteriological profile: predominance of ngb ( . %) dominated by e. coli ( . %) followed by klebsiella pneumoniae and enterobacter cloacae ( . %) the mean hospital stay was . ± . days. the mortality rate was . %. conclusion: improvement in the prognosis of community-acquired peritonitis can only be achieved by constant assessment of very early diagnosis and initiation of appropriate resuscitation and antibiotic therapy associated with a complete surgery carefully codified according to guidelines. compliance with ethics regulations: yes. rationale: klebsiella pneumoniae carbapenemase (kpc)-producing bacteria are a group of emerging highly drug-resistant gram-negative bacilli causing infections associated with significant morbidity and mortality. the aim of our study is to point out the incidence of bloodstream infections (bsi) caused by kpc in icu patients, its clinical presentation and course. patients and methods: we conducted a retrospective descriptive study. all patients hospitalized in the icu of our hospital who developed bsi caused by kpc from january , to december , were included. results: during the study period, patients were included. the mean age was . ± . years ranging from to years. sex ratio (m/f) was . trauma was the major cause of hospitalization in cases ( %). the most common past medical diseases were arterial hypertension in patients ( %). length of hospital stay prior to icu admission was ± . days. at infection onset, mean saps ii was ± . , mean sofa was . ± . and mean apache ii was . ± . . during icu hospitalization, all patients required invasive mechanical ventilation during . ± . days, had a central venous catheter (cvc) and an indwelling urinary catheter in place, patients ( . %) had tracheotomy, ( %) underwent surgery, ( %) presented acute kidney failure and ( %) needed hemodialysis. before the isolation of kpc, all patients presented infections. antibiotics prescript were: colistin in patients ( %), carbapenems in patients ( %), amoxicillin/clavulanic acid in patients ( %), cephalosporins in patients ( %), fluoroquinolones in patients ( %), tigecycline in patients ( %), aminosids in patients ( %), rifampicin in patients ( %), fosfomycin in patients ( %), glycopeptides in patients ( %). the delay for kpc-bsi onset was . ± . days. the most common infection sources responsible of kpc-bsi were: cvc in patients ( %) and pneumonia in patients ( %). kpc infection was responsible of septic shock in patients ( %). resistance rates were: gentamycin ( %), amikacin ( %), colistin ( %), fosfomycin ( %) and tigecycline ( %). antibiotics used to treat kpc bloodstream infection were resumed in table . the mean length of icu stay was . ± . days. out of the included patients, patients died (the mortality rate was %). death was related to kpc infection in patients. conclusion: the high prevalence of kpc-bsi in icu patients dictates the importance of implementation of infection control measures and strict antibiotic policies. compliance with ethics regulations: not applicable. we identified episodes of nosocomial infections in patients, representing a cumulative incidence rate of . per exposed patients. the incidence density was . infections per days of hospitalization. the prevalence of pneumonia was . %, followed by urinary tract infections . %, central venous catheterization infections . %, bacteriemia . %, meningitis . % and surgical site infections . %. the incidence rate of intubation-related pneumonia was . / day of exposure. the incidence rate of bladder-related urinary tract infection was . / day of exposure. the incidence rate of positive culture of the central venous catheter was . / day of exposure. the incidence rate of bacteremia related to stay was . / day of exposure. the mortality rate was . % with a significant difference between infected and uninfected patients (p = . ). microorganisms were gram negative bacteria in % of cases. conclusion: epidemiological surveillance of healthcare-associated infections is needed to establish prevention plans. compliance with ethics regulations: not applicable. in the prehospital setting, early identification of septic shock (ss) with high risk of mortality is essential to guide hospital orientation (emergency department (ed) or intensive care unit (icu)) prior to early treatment initiation. in this context, the severity assessment is most of the time restricted to clinical tools. in this study, we describe the association between prehospital shock index (si) and mortality at day of patients with ss initially cared for in the prehospital setting by a mobile intensive care unit (micu in this study, we reported an association between prehospital si and mortality of patients with prehospital ss. a si > . is a simple tool to assess severity and to optimize prehospital triage between ed and icu of patients with ss initially cared for in the prehospital setting by a micu. the association of si with biomarkers may be helpful to improve the screening for ss and decision making of ss in the prehospital setting. compliance with ethics regulations: yes. the failure rate and complications were comparable between the groups, but the ultrasound-guided internal jugular catheter appears to be faster to insert and requires fewer punctures, so it could be an alternative to the femoral one in emergency situations. rationale: neuromyelitis optica (nmo) is a rare but severe disease. the prognosis of treated nmo attacks remains unclear. we evaluated our practice, the early evolution and the prognosis of nmo patients. patients and methods: an observational study was performed on patients with nmo attacks presenting with visual or medullar symptoms admitted for plasma exchange (pe) therapy from january to august . treatment efficiency was defined as a negative shift of the visual or motor disability score (edss). nonparametric mann-whitney and fisher exact tests were used for statistical analysis as required. results: twenty-four patients had pe sessions. characteristics of the cohort are described in table . ( . %) died from complications of nmo attacks. treatment had an effect in ( . %) patients. the shift in the ambulatory and visual edss was respectively − . + . and − . + . . the non-survivor patients had all aqp antibodies (p < . ). residual edss was higher in the non-survivor group ( . + . vs . + . , p < . ). pulse steroids were administered in ( %) patient in the non-survivor group vs ( %) patients in the survivor group (p < . ). twelve ( %) patients previously given pulse steroid therapy responded to pe. discussion: we assessed the handling of nmo attacks and identified our flaws. we concluded that pulse steroid therapy should not be withheld or replaced by lower dosage. we also need to find a way to make attacks identified by physicians earlier to shorten the delay between its onset and patient's admission in a specialized care unit. we observed that the mean improvement is modest during the early phase of our treatment. but a modest improvement in the edss can have a great impact in the patient's quality of life and even survival. conclusion: nmo attacks remain a threatening disease despite aggressive treatment. shortening the delay of treatment and ensure adequate pulse steroid therapy coupled to pe could be a way to improve the prognosis. compliance with ethics regulations: yes. rationale: acute kidney injury in trauma patients is a problem that has been little studied in the intensive care unit (icu). its occurrence has been shown to be associated with high morbidity and mortality. we aim to determine the outcome of icu trauma patients with acute kidney injury (aki), including the incidence of death in the icu, of nonreversible renal impairment and icu complications. patients and methods: this is a prospective study, conducted in the department of emergencies and icu, including trauma patients with a minimum icu stay of days. renal failure was defined based on the new kdigo classification. predictors of mortality and poor outcome were identified using univariate and then multivariate analysis. results: one hundred and fifty patients were admitted during the study period for the management of post-traumatic injuries, among which patients were included. the incidence of aki in the studied population was % ( cases) with ( %) diagnosed with stage one, ten ( %) with stage two and ten ( %) with stage three. the overall mortality of patients with post-traumatic aki was . % ( patients) with a mean icu lengh of stay (los) at ± days and of days on ventilator at ± . eight patients ( . %) needed renal replacement therapy and thirty-four had non-reversible renal impairement ( %). during icu stay, eight patients ( %) were diagnosed with pulmonary embolism. on univariate analysis, the following variables were associated to mortality in patients with post-tramatic aki including; age, hemodynamic instability on the day of diagnosis and bilirubin levels on the day of aki diagnosis. besides, according to our analysis, the use of renal replacement therapy and the non-reversibility of renal impairment during icu stay were also associated to icu mortality. among these factors, the non-reversibility of renal impairment in the icu was a predictor of mortality on multivariate analysis (p = . , or = , . in this cohort, the following variables were predictive of non-reversible renal impairment during icu stay; including age (with a best cut-off of years old), medical history of hypertension, higher iss and diuretics' administration. on multivariate analysis, the age (p = . , or = . , ci . - . ) and use of diuretics (p = . , or = , ci . - ) were associated to non-reversible aki in the icu. conclusion: our study confirms that post-traumatic aki in the icu is associated to high morbidity and mortality. the identification of outcome predictors could be valuable to guide the management of aki. compliance with ethics regulations: yes. rationale: the occurrence of acute kidney injury (aki) in trauma patients is a problem that has been little studied to date. its presence has been shown to be associated with an increased risk of morbidity and mortality in affected individuals. to determine the incidence of post-traumatic aki and identify its predictive risk factors that could be eventually prevented. patients and methods: this is a -month long prospective cohortstudy, conducted in the department of emergencies and intensive care unit (icu) of a university hospital, including trauma patients with a minimum icu stay of days. renal failure was defined based on the new kdigo classification. predictors of aki were identified using univariate and then multivariate analysis. results: one hundred thirty patients were admitted during the study period for the management of post-traumatic injuries, among which patients were included. the incidence of aki in the studied population was % ( cases) with ( %) diagnosed with stage one, ten ( %) with stage two and ten ( %) with stage three. on univariate analysis, older age and medical history of diabetes or hypertension were predictors of aki. injury assessment found traumatic brain injury (ais > ), glasgow (gcs) on admission, and the diagnosis of fat embolism to be associated to post-traumatic aki. moreover, hemodynamic instability on admission and during icu stay, shock-index on admission, the amount of fluid administered the use of vasoactive drugs, sepsis, hyperbilirubinemia, p/f ratio and acute respiratory distress syndrome (ards) were also associated to post-traumatic aki. among these factors, ards (p = . , or = , ci - ), fat embolism (p = . , or = , ci . ) without preload-dependence, and were unclassified. multivariate analysis (using variables collected prior to hypotension) identified the following variables as risk factors for the occurrence of hypotension associated with preload-dependence: preload-dependence before hypotension (odds ratio = . , p < . ), fluid removal rate by crrt (or = . per increase in sd, p < . ), and lactate levels (or = . per increase in sd, p < . ). in this single center study, preload dependence-associated hypotension was slightly more frequent than hypotension without preload dependence in icu patients undergoing crrt. testing for preload dependence to adjust fluid removal could help prevent hypotension incidence during crrt. rationale: few studies report the relation between functionnal brain alterations during and after icu stay and abnormalities of cbf displayed on tcd. using vti as hemodynamic parameter is unusual for evaluation of cbf. the purpose of this preliminary study was to compare the values of vti of healthy controls (c) versus icu (p) with usual parameters (i.e. diastolic (vd) and mean velocities (vm), resistance (ir) and pulsatility index (ip)). rationale: accurate diagnosis of the level of consciousness is a challenge and different states such as coma, vegetative state (vs) or minimally conscious state (mcs) are often confused while they convey meaningful prognostic information. this distinction rely on the coma recovery scale-revised (crs-r) gold-standard. however, this clinical scale is imperfect since unresponsive patients can exhibit genuine signs of consciousness using advance neuroimaging techniques. expanding the range of behaviors indexing consciousness at bedside is thus of decisive importance. patients and methods: we designed and proposed a new clinical sign of mcs, the habituation to auditory startle reflex (asr), based on the blink response to repeated sounds: either inhibition of the automatic asr response (extinguishable) or nohabituation (inextinguishable response). we prospectively tested this new sing in patients suffering from disorders of consciousness after severe brain injury and first compared its diagnostic performances with the current gold-standard (crs-r) using standard discrimination metrics (auc, sensitivity, specificity, likelihood ratios) and their % confidence interval. we then investigated the correlates of this new sign on two validated neuroimaging diagnostic procedures (multivariate eeg-based classification of the state of consciousness and fdg-pet metabolic index of the best preserved hemisphere) using an anova with the state of consciousness and the asr response as independent variable. rationale: although continuous electroencephalography (ceeg) is commonly recommended in neurocritical care patients, implementation of this monitoring in routine is facing the need for a specific training of professionals. we evaluated the effectiveness of a training program for the basic interpretation of ceeg to critical care staffs in a prospective multicentre study. patients and methods: after completion of a pre-test, participants (physicians and nurses) recruited in french intensive care units (icu) received a face-to-face eeg learning course, followed by additional e-learning sessions at day- (post-course), day- , day- and day- , based on training tests followed by illustrated and commented answers. each test was designed in order to evaluate knowledge and skills through correct recognition of predefined eeg sequences covering the most common normal and abnormal patterns. the primary objective was to achieve a success rate of more than % of correct answers at day- in at least % of participants. results: among participants, ( . %) completed the full training program and of these ( . %) full-training participants achieved at least % of correct answers at day- . paired comparisons between scores obtained at each evaluation demonstrated a statistically significant increase over time. at day , rates of correct answers were greater than % for all predefined usual eeg sequences, excepted for the recognition of periodic and burst-suppression patterns and reactivity, which were identified in only . % ( % ci . - . ) and . % ( . - . ) and . ( . - . ) tests, respectively. discussion: this multicentric prospective study, which evaluated a training program for the basics of electroencephalography offered to critical care teams, provides interesting information about the training process and its impact on learners according to their different characteristics. we believe that participants reflect the heterogeneity of the various use of ceeg in the critical care setting. participants came from university and non-university icus, and whereas some of them used to monitor patients with ceeg, others were in an implementation process when the last monitored neurocritical care patients with intermittent eeg. in accordance with previous studies, we focused to the entire medical and nursing icu staffs. conclusion: a -months training program aiming to teach the basic interpretation of continuous eeg in the intensive care units was associated with a significant attrition in participation over time. however, participants who received the full training program were capable to accurately recognize the vast majority of eeg patterns that are encountered in critically ill patients. compliance with ethics regulations: yes. mourad goulmane oran hospital and university center, oran, algeria correspondence: mourad goulmane (goulmane.mourad@univ-oran . dz) ann. intensive care , (suppl ):p- rationale: cerebral venous thrombosis (cvt) is a rare but very serious disease with various clinical and etiological aspects. unlike ischemic arterial accidents, epidemiological studies are limited. the aim of our work was to study the clinical, etiological and evolutionary features of cvt in the algerian population from a sample of patients. patients and methods: this is a retrospective observational study conducted in the neurology department of the chu d'oran between january and december . in a clinical context suggestive of cvt, the diagnosis of certainty was provided by brain mri coupled with mra. all subjects benefited from a complete etiological assessment. the anticoagulant treatment was based on the low molecular weight heparin relayed by the anti-vitamin k. the duration of the follow-up was months. results: the mean age was . ± . years, the sex ratio was ( f/ h), the onset was subacute in % of cases. the main early signs were headache ( . %), visual disturbances ( %), epileptic seizures ( . %) and motor deficit ( . %). thrombosis predominated in the upper sagittal sinus and lateral sinuses; parenchymal lesions were associated in / of the cases. gynecologic obstetric causes were by far the most frequent. the evolution was favorable in . % of the cases. discussion: cvt is characterized by its clinical polymorphism, its predominance in young women, and its most often favorable evolution. the causes are multiple and often intricate requiring the realization of a systematic etiological assessment even if the cause seems obvious. the treatment of choice remains early anticoagulation, based on heparinotherapy even in case of hemorrhagic softening. the characteristics of cvt in the algerian population are distinguished by a high frequency of gynecological obstetric causes. awareness campaigns for women of childbearing age are useful. compliance with ethics regulations: not applicable. rationale: the ct-dragon score was developed to predict longterm functional outcome after acute stroke in the anterior circulation treated by thrombolysis. its implementation in clinical practice is hampered by the plethora of variables included. in addition, the score has not been validated in important subgroups such as stroke patients undergoing thrombectomy. given these limitations, the current study was designed to evaluate the use of a simplified score based on machine learning, as a possible alternative. this single-centre retrospective study included patients treated for stroke, in the anterior and posterior cerebral circulation, between - and - . at days, favourable (modified rankin scale (mrs): - ) and miserable outcome (mrs: - ) were predicted by ct-dragon. machine learning selected the aim was to describe the adherence rates to gold guidelines in critically ill copd patients and to identify predictors of low adherence. patients and methods: a prospective cohort study conducted from december to april in a -bed medical intensive care unit of farhat hached hospital. all adult patients admitted for aecopd during the period of the study were included. demographic and clinical data were recorded. adherence to gold was evaluated. univariate and multivariate regression analyses were carried out to identify factors independently associated to non-adherence to gold guidelines. results: seventy-seven patients were recruited. patients' characteristics were : mean age, . ± years; male ( . %); median duration of the disease, [ - ] years; mmrc scale ≥ , ( . %); health insurance coverage rate, ( %); pulmonologist follow up, ( , %); frequent exacerbator (≥ exacerbations in the last year), ( . %); median exacerbations episodes, [ ] [ ] [ ] . long-term oxygen use and home mechanical ventilation were respectively used in ( . %) and ( . %). eight ( . %), ( . %) and ( . %) belonged to copd groups b, c and d, respectively. pharmacological treatment included: saba-ics combination, ( . %), laba-ics, ( . %), laba-lama, ( . %) and lama-laba-ics, ( . %). overall adherence to gold guidelines treatment recommendations for the different stages of copd was ( . %). two patients ( . %) were over treated and ( . %) were undertreated. inappropriate treatment rate was ( %) in gold b, ( . %) in gold c and ( . %) in gold d. univariate analysis identified two factors associated with non-adherence to gold : the absence of pulmonologist follow-up ( % vs. . %; p = . ) and the low income ( . % vs. . %; p = . ). in multivariate analysis only the lack of pulmonologist follow-up was identified as an independent risk factor associated with gold guidelines discrepancies (or, ; % ci [ . - . ]; p = . ). there is a lack of adherence to gold guideline treatment recommendations in tunisian copd patients. this may lead to severe exacerbations. discrepancies were due to the poor access of severe copd patients to an appropriate pulmonologist follow-up. compliance with ethics regulations: yes. the operating theaters concerned were: the otolaryngology block, ophthalmology, vascular and thoracic surgery, and gynecological surgery. all patients over years of age were enrolled using the clinical parameters of difficult intubation (arne score > ), which will benefit from orotracheal intubation. the main judgment criteria were: first-pass success rate, intubation time, which is defined as the time between inserting the slide into the patient's mouth and obtaining the capnography curve, the cormack-lehane score and the pogo score (percentage of opening of the glottis). statistical analysis used spss software. results: a total of patients were included. no cases of failure with this device were observed, the duration of intubation was on average . s (only cases required more than min). the cormack-lehane score and involved patients ( . %), and the pogo score greater than % involved patients ( . %). one case required the features of the simplified score. discrimination, calibration and misclassification of both models were tested. results: % had proximal anterior stroke, % proximal posterior stroke and % lacunar infarcts in either circulation. in % no thrombus was objectivated. % of patients were treated with thrombectomy, % received thrombolysis and % underwent both thrombolysis and thrombectomy. % only received anti-platelet therapy. the area under the receiver-operating-characteristic curve (auc-roc) for ct-dragon was . ( % ci . - . ) for favourable and . ( % ci . - . ) for miserable outcome. r ofct-dragon was . and . for favourable (lack of fit, p = . ) and miserable (lack of fit, p = . ) outcome respectively. misclassification rate was % for favourable and % for miserable outcome with ct-dragon. selection of predictors from the ct-dragon was done by logistic regression, bootstrap forest and decision tree analysis. nih stroke scale, pre-stroke mrs and age were identified as the strongest contributors to favourable and miserable outcome, and included in the simplified score. auc-roc was . ( ci% . - . ) and . ( ci% . - . ) for the prediction of favourable and miserable outcome respectively. r was . and . for the prediction of favourable (lack of fit p = . ) and miserable (lack of fit p = . ) outcome respectively. misclassification rate was % for favourable and % for miserable outcome with the simplified score. the simplified score had better discriminative power than ct-dragon for both outcomes (both p < . ). the ct-dragon score revealed acceptable discrimination in our cohort of both anterior and posterior circulation strokes, receiving a variety of treatment modalities. the simplified score had a better discrimination, while maintaining comparable and good specificity and misclassification rate for miserable outcome. the simplified score needs further validation in a prospective, multi-centre study. compliance with ethics regulations: yes. rationale: the gold report represents a major revision to gold strategy guidelines. it brings new recommendations regarding diagnosis, severity assessment, and both pharmacologic and non-pharmacologic treatment of copd. however, adherence to evidence-based therapeutic guidelines is often poor in low-income developing countries and represents a significant barrier to optimal management. the setting up of an lma-fastrach (desaturation). a case of glottic edema has been noted. discussion: this study shows a very high success rate with this technique ( . % in the first trial and . % in the second trial), in the context of a predictable difficult intubation. the video-airtraq allows a very good visualization of laryngeal structures, a shortening of the duration of intubation, and is rarely responsible for immediate or secondary complications. all the data in the literature go in the same direction. conclusion: at the end of this work, our perspectives are to update the difficult intubation procedure, integrating the video-airtraq into our algorithm, as well as into our difficult intubation trolley. to take into consideration the cost of this device to eventually generalize it to all our structures. compliance with ethics regulations: yes. ) and beds of continuous monitoring. the activity of the cp is organized in a medical visit in the morning and in conducting projects in the afternoon. the activity is presented using a -years balance sheet results: the activity of pharmaceutical interventions (pi) or answers to requests from teams is shown in table . the solicitations doubled the second year. the cp is involved in the conduct of internal or polar projects (set up of cooperative sedation, nutrition…), the good use of health products (relay iv/po, infusion, crushed tablets and compatibility with gastric probe, drug incompatibilities, proton pump inhibitors…), the efficiency of the drug circuit (link with the pharmacy, reflection on the improvement of the circuit, regular meetings with nurses), medico-economic analysis of health products spending and the formalization of actions by protocolisation. he is also very involved in clinical research: patient screening, clinical study setup: blipic study (beta-lactam's dosing in pneumonia in icu in patients treated by continuous renal replacement therapy; clinicaltrials nct ) or in candiarea project (invasive infections to candida and preemptive treatment guided by biomarkers; in progress). a satisfaction survey submitted at months to nurses ( answers/ ) or to doctors/ residents ( / ) reported cp competence in the accompaniment of teams (> %) [in medico-economical, contribution of knowledge, vigilance reflex…], relevance of information transmitted (> %) [administration of drugs, dosage adjustments, …] and his relationship adapted to the units (> %) [communication, availability] . the development of clinical pharmacy in icu involves mastery of the specificities of icu by the cp, requiring a learning period and relationships adapted to clinical situations and teams. many health products projects specific to critical care are coordinated by the cp and made possible by medical and paramedical involvement. the cp appears as a vector of good use both in medical (reasoned prescription) and paramedical (good practices) with increasing solicitation of teams since his arrival. this reception has been facilitated by an innovative approach of clinical pharmacy deployment in our icu on an impulse of the clinical pole compliance with ethics regulations: yes. predicting models such as the news has been developed in the emergency department, but it has only been fewly evaluated in the icu. heart rate variability (hrv) reflects the autonomic nervous system response in various pathological situations and may vary according to patients' physiological status. the rox index, which reflects the acute respiratory failure severity, seems to be a good predictor of high-flow nasal canula failure. the aim of this study was to evaluate the potential value of news, hrv and irox (inversed rox) as poor outcome predictors, using artificial intelligence and machine learning. a retrospective analysis of a prospective datawarehousing project (reastoc clinicaltrials identifier nct ) on icu patients who did not require invasive ventilation. physiological parameters were collected on admission, within a -h delay. news, hrv (in time, frequency, and non-linear domains), and irox were computed and integrated into the prediction model. analysis was performed using medcalc and matlab machine-learning work-package. results: one hundred and twelve patients were included. patients who died in the icu (n = ) had highest news as compared with icu survivors ( . [ . - . ] vs. . [ . - . ] respectively; p = . ). the irox was higher ( . [ . - . ] vs. . [ . - . ], p = . ) and most hrv parameters also depicted higher values for icu survivors. considering a composite icu prognostic outcome parameter (mortality and/or need for any form of respiratory assistance and/or an icu los > median los), there was also a difference for news, hrv and irox (p < . ). the best value to predict icu mortality for news was (auc = . , p = . ), irox > . (auc = . , p = . ) and hrv (shannon entropy) > . (auc = . , p = . ). the best model to predict the need fo respiratory assistance combines irox and hrv (sd /sd ; auc = . , p = . ). adding shannon entropy on this model predicts either the need for respiratory assistance and icu survival (respectively auc . , p = . and auc . , p = . ). in icu spontaneously breathing patients, news, irox and hrv are different in between survivors and patients who died. the best model to predict the need for respiratory assistance combines irox and hrv (sd /sd ). compliance with ethics regulations: yes. rationale: sepsis is known for its important mortality in critically ill patients. the last guidelines defined sepsis as life threatening organ dysfunction. it rejected the concept of systemic inflammatory response syndrome (sirs) associated to suspected or confirmed infection, and considered the concept of dysregulated response to infection. actual guidelines recommend the quick sequential organ failure assessment score (qsofa) to identify patients with sepsis especially when outside intensive care unit. thus, outcomes have mainly to judge the value of sirs in the sepsis- era. the purpose of our study was to compare whereas qsofa score or the sirs criterion are superior to predict in-hospital mortality, shock and mechanical ventilation use in sepsis. our study includes patients in whom the sepsis- definition is met. therefore, this inclusion was retrospectively performed throughout emergency department (ed) admission cases for clinically suspected infection. we collected patients admitted to ed for sepsis. mean age was years ± with bornes of and . men were % of the patients. death occurs in . % of patients, sepstic shock in % and the use of mechanical ventilation in . %. qsofa ≥ has a significant association with in-hospital mortality (p < . ) but not sirs ≥ ( . ). neither qsofa ≥ nor sirs ≥ has association with the use of mechanical ventilation (p = . vs. p = ). whereas, both have a significant association for prediction of septic shock. the absolute sensitivity and negative predictive value in our study can be explained by the small size of our sample. this needs confirmation with literature data about the fact that sirs criterion are superior in term of sensitivity and npv than qsofa to predict septic shock. despite the weak odds ratio (or) of sirs before that of qsofa and the poor specificity and positive predictive value (ppv), we can conclude that sirs according to its sensitivity and npv, seems to persist useful in the sepsis- era as a reliable prognostic tool in the ed. this may need more large studies for confirmation. conclusion: despite sirs has no significant association with mortality in sepsis, it has largely higher sensitivity and superior npv to predict septic shock than qsofa in ed. compliance with ethics regulations: yes. our study aimed to determine the predictive factors of mortality in our patients. retrospective study over years in the intensive care unit of the hospital august. all patients with septic shock were included. a p value < . was considered significant. results: patients were collected. the age ranged from to years old. the average duration of hospitalization in pre-intensive care was days. the reasons for admission: (febrile respiratory distress: % of cases, polytrauma: % and % for sepsis), the most frequent infections: pulmonary ( %) and blood ( %). % received prior antibiotic therapy and % were immunocompromised. the overall mortality was %. the analytical study of the data shows that the age, the length of stay before admission in intensive care and that in intensive care, fever, hypothermia, slimming, hypotension, collapse, failures (respiratory, hematological, renal, hepatic and neurological) and the use of catecholamines are correlated with mortality, whereas sex, chest pain, tachycardia or bradycardia and mottling are not predictive of mortality. conclusion: despite improved techniques for the diagnosis and treatment of patients with septic shock, mortality remains high, especially in the presence of certain risk factors, hence the value of prevention in immunocompromised patients and the reduction in their length of stay in a hospital setting. compliance with ethics regulations: yes. conclusion: p. mirabilis is among the leading bacteria responsible for nosocomial infections in icu. they are emerging highly drug resistant pathogens whose incidence is rapidly increasing in icu. so that, it early identification with in vitro testing is of paramount importance to the success of infectioncontrol efforts. compliance with ethics regulations: not applicable. rationale: influenza is a potential lethal disease causing dozens of thousands excess deaths per year both in europe and in the united states. besides hygiene procedures, vaccination is a cornerstone of influenza prevention and guidelines recommend for vaccination among health workers (hw), especially if they are in close contact with frail people. despite these recommendations, the vaccination coverage is low among health workers both in europe and in the us. the relevance of a mandatory vaccination for health workers is currently a hot topic but data are scarce regarding intensive care unit health workers' opinion. patients and methods: health workers from medical, surgical and polyvalent icus received a link to the electronic record of the survey. results: among the icus, icu health workers (hw) (medical: and paramedical: ) were questioned. three hundred and forty-one icu ( %) answered, ( %) medical health workers (mhw) and ( %) paramedical health workers (phw) (p < . ). among mhw / ( %) were vaccinated vs only / ( %) phw (p < . ). discrepancies exist between medical and paramedical icu health workers' opinions and beliefs about vaccination for influenza and its acceptance. medical health workers were more prone to consider influenza as a potentially lethal disease occurring not only among frail people but also in healthy people, to consider the vaccine efficient and safe. to agree with "vaccination for influenza is mostly related with gain for pharmaceutical industry" (or: [ . - ] ) and to disagree with "the risk of guillain-barré syndrome is higher after an episode of influenza than after vaccination for influenza" (or: . [ . - ] ) were independently associated to the disagreement with a mandatory vaccination for icu hw. conclusion: vaccination for influenza should be strongly recommended as a tool of individual protection for icu health workers as for general population. as confidence in vaccine efficacy and concerns about vaccine side-effects impact the vaccination rate, objective information should be provided to icu health workers about the efficacy and the side effects of vaccination for influenza. compliance with ethics regulations: yes. rationale: intra-abdominal infections are a major cause of morbidity and mortality. sfar recommendations on this topic were published in february . the purpose of this work was to evaluate whether our antibiotic therapy was adequate for these recommendations and whether they were adapted to our unit. the secondary objectives were to look for different risk factors for mortality, to evaluate the impact of inappropriate antibiotic therapy, to evaluate the relevance of carbapenem prescription. this is a single-center retrospective observational study of secondary peritonitis in the tourcoing intensive care unit. for each peritonitis, the epidemiological data and the co-morbidities of the patients were collected. bacteriology and anti-infectious therapies were described to determine the rates of adaptation of our antibiotic therapy and that recommended by sfar. the adequacy of our treatments to the recommendations was also quantifiable. the description of the stay, the occurrence of a death was specified. results: peritonitis were included. the rate of adaptation of the sfar antibiotic therapy was %. the rate of adaptation of our antibiotic therapy was % and its adequacy rate of %. the main differences in prescriptions concerned over-prescription of antifungals, molecule against gram positive bacillus and a sub-prescription of aminoglycosides and beta-lactams, in particular carbapenems. the different mortality risk factors found were sofa score > (or . % ci . - . ), the charlson score > (or . % ci . - . ), the hollow organ perforation (or . % ci . - . ). a comparison of the appropriate or not antibiotic groups did not reveal a significant difference in mortality, number of surgical revision and length of stay. in % of nosocomial peritonitis, antibiotic therapy with carbapenem was recommended. after recovery of microbiological data, it was only necessary for . % of cases. conclusion: our work showed a low rate of compliance with sfar recommendations. these recommendations are applicable to our service by providing a particular reflection for fungal infections. our study does not show a correlation between mortality and inadequate antibiotic therapy, surgery remaining the major treatment. compliance with ethics regulations:yes. rationale: acinetobacter baumannii is a gram-negative opportunistic bacteria that has gained several drug resistance mechanisms over the last decades. analysis of a. baumanii's resistance profile helps to establish a prompt control and a prevention program. the aim of this study was to evaluate the epidemiology and antimicrobial resistance of a. baumannii isolates in a trauma and burn center in tunisia. patients and methods: retrospectively, we studied all strains of acinetobacter baumannii isolated over a -year period (from january to december ). conventional methods were used for identification. antimicrobial susceptibility testing was performed with the disk diffusion method, and susceptibility results were interpreted using clinical breakpoints according to ca-sfm guidelines. data were analyzed using the sir-system. minimum inhibitory concentration (mic) of colistin was determined using the e-test ® method (biomérieux), then using the eucast broth micro-dilution method (umic, biocentric ® ) since may . results: during the study period, non-repetitive strains of acinetobacter baumannii were isolated representing . % of all isolates, % of gram-negative bacilli (gnb) and . % of non-fermenting gnb. in our center, infections due to a. baumannii were endemic with epidemic peaks. a. baumannii was mainly isolated from burn intensive care unit ( %) and anesthesiology department ( . %). the most frequent sites of isolation were blood cultures ( . %), catheters ( %), respiratory specimens ( . %) and skin samples ( % sampling duration is also reduced, improving workflow. evaluators consider that bronchosampler rationalizes the cumbersome sampling process and that the closed system design reduces the risk of losing sample or sample contamination. the set-up, the suction capacity, the sampling quality and quantity have all been evaluated better or far better than that usually observed with usual sampling techniques and devices. finally, ( %) of users prefer bronchosampler to commonly used method. conclusion: this satisfaction survey shows that with its simple but revolutionary design, bronchosampler brings a real effective benefit in sampling procedure enabling the clinician to perform it alone, and ( %) of the survey evaluators consider that bronchosampler should replace their current practice. compliance with ethics regulations: yes. rationale: the possibility of having a sensitive, specific and prognostic biological marker for bacterial infections is a considerable challenge. a step was taken with the discovery of pracalcitonin. patients and methods: this is a prospective observational cohort study of patients in the medical resuscitation department of the university hospital of casablanca during the -month period, including patients in whom the pct was dosed. the data collected allowed us to form two groups according to the pct value: pct+ group with pct > ng/ml and pct− group with pct < ng/ml. the statistical analysis of these different data was carried out using epi info software version . . . results: % of our patients had a bacterial infection and % did not have one. we also distinguished community infections ( % of i+ patients) and nosocomial infections ( % of i+ patients). we found that the highest rates of pct were in nosocomial infections and the lowest pct rates were found in community-acquired infections. then, in each type of organ involvement we tried to vary the pct thresholds to . - and ng/ml in order to find the best threshold for which pct allowed to diagnose bacterial infection, justifying our choice of departure. we concluded that the best pct cut-off value in general was ng/ml, because it gave us the best sensitivity/specificity ratio ( % and % respectively) with a positive predictive value of % and a negative predictive value of %. the link between pct and bacterial infection was moderate (yule q-factor at . ). by analyzing the different therapeutic aspects, we showed that % of our patients had been treated with atb before the pct assay and that the broadest spectrum antibiotics available to our service were used in patients with pct levels the highest. finally, concerning the evolution, the higher the rate of pct, the higher the death rate, especially since % of patients with pct > ng/ml died. conclusion: procalcitonin is considered to be one of the best markers of systemic bacterial infection. indeed, its elevation is earlier than that of crp and its specificity is better compared to il- and il- . the rate of procalcitonin remains low in the presence of viral infection. procalcitonin is also a prognostic marker, its elevation is correlated with the severity of the infection, and its decrease is a good indicator of the effectiveness of antibiotic therapy. compliance with ethics regulations: not applicable. rationale: due to induction immunosuppression infection is the most common cause of mortality within the first year after lung transplantation (ltx). the management of perioperative antibiotic therapy is a major issue, but little is known about worldwide practices. we sent by email a survey to ltx centers around the world dealing with daily clinical vignettes concerning perioperative antibiotic therapy. we considered perioperative period as the period of the transplant surgery (per operative) and the postsurgery time before any infection occurrence (postoperative). after general questions on local practices, we asked each center for colonization definition and their diagnostic methods for microbial screening in recipients and donors. the clinical cases were related to specific issues concerning the management of antibiotic therapy in different clinical situations, including no prior colonization, prior colonization with sensitive or multi-drug resistant (mdr) microorganisms including prior colonization with mdr bacteria not sensitive to beta-lactams. the invitation and a weekly reminder were sent to lung transplant specialists for a single consensus answer per center between june and september . we received a total of responses from countries, mostly from western europe (n = ) and the usa (n = ), (fig. ) . systematic screening for bronchial colonization before ltx was mostly performed with sputum samples ( %), regardless of the underlying lung disease. definition of colonization was very heterogeneous and the delay between the last bacterial isolation in pre-transplant and the ltx to consider if the therapy should target these bacteria varied between week and more than year. in recipients without colonization, antibiotics with activity against gram-negative bacteria resistant strains (piperacillin/tazobactam, cefepime, ceftazidime, carbapenems) were reported in % of the centers, and antibiotics with activity against methicillin-resistant staphylococcus aureus (mainly vancomycin) were reported in % of the centers. for these recipients, the duration of antibiotics reported was days ( %) or less ( %) or stopped when cultures of donor and recipients were reported negatives ( %). in recipients with pre-transplant colonization, antibiotics were adapted to the susceptibility of the most resistant strain isolated in pre-transplant samples and given for at least days ( %). conclusion: practices vary widely around the world, but resistant bacterial strains are mostly targeted even if no colonization occurs. the antibiotic duration reported was longer for colonized recipients. compliance with ethics regulations: not applicable. the vancomycin was therefore considered as justified or not and appropriate or not. occurrence of nephrotoxicity and supratherapeutic exposure in this study group was compared to critically ill children control group. results: thirty one children receiving vancomycin lines of treatment whose ( %) observed a risk of acute kidney injury (aki) (n = ) and an aki (n = ) during the vancomycin treatment period were included. there was a trend to inversed relationship between plasmatic concentrations of vancomycin and estimated creatinine clearance (r = . ). seven patients observed a nephrotoxicity related to vancomycin, they had a higher plasmatic concentration of vancomycin (p = . ). seven patients ( %) had a supratherapeutic exposure to vancomycin. nephrotoxicity and supratherapeutic exposure were higher in children with or combined liver-kidney transplantation than in comparative critically ill children group. we found blood stream infection due to the central catheter and blood stream infections probably due to the central catheter. one hundred thirtyfive bacteria were identified of which ( %) were staphylococcus coagulase negative. nineteen ( %) lines of vancomycin were appropriate and ( %) were justified. conclusion: vancomycin could have been avoided in one third of children with liver or combined liver-kidney transplantation during the early phase of postoperative stage. vancomycin is associated with a risk of both nephrotoxicity and supratherapeuric exposure. vancomycin should be used with caution, appropriate indications and dosing in this vulnerable population. compliance with ethics regulations: yes. rationale: early bacterial infection is a major and severe complication occurring within the first month after pediatric liver transplantation (lt). the rise of antimicrobial resistance, especially extended-spectrum beta lactamase producing enterobacteriaceae (esbl-pe), is henceforth a concern for these patients. this study aimed to assess the epidemiology of early bacterial infections, including those caused by multidrugresistant (mdr) pathogens, and to identify the risk factors for infection. rationale: the number of cancer patients admitted to emergencies is clearly increasing and digestive oncology is the leading cause of consultation. the aim of this work is to identify the epidemiological factors, the therapeutic modalities as well as the predictive factors of mortality and to compare them with the data of the literature. patients and methods: patients admitted to visceral emergencies for an urgent syndrome revealing or complicating a primary or secondary digestive cancer, and who required immediatemedical and/or surgical intervention and who had stayed at the surgical resuscitation level in our hospital center for a duration of years. several data were entered on excel and analyzed using the spss version software.-epidemiological, concerning age and sex; -clinics including risk factors, history, general condition of the patient and clinical examination data; -para-clinical, interesting biological assessments, and morphological examinations-medical and surgical therapeutics; -postoperative follow-up-treatment results. the three most frequent sites were rated in order of increasing frequency: colo-rectum ( %), pancreas ( %), and stomach ( %). the age group most found was age over years with % of cases, % of patients had under years. this series includes men and women with a sex ratio of , . the installation method was mostly gradual with % of cases. our patients have consulted for urgent clinical presentations mainly occlusive syndrome noted in % of patients. abdominal ct was the first examination performed, followed by abdominal ultrasonography in % and %, respectively. the therapeutic management was medico-surgical. the surgery done in % of patients, % for palliative indication: % were operated for an ostomy discharge, % for a digestive bypass, % for a palliative resection and % for a stoma feeding. postoperative outcomes were % morbidity and % mortality. the main cause of death was septic shock in % of cases, thanks to multivariate statistical analysis three factors were deduced significantly related to mortality: the asa score: p = . ; or = . ; ic: [ . ; . icu and hospital mortality rates were % (n = ) and . % (n = ), respectively. ten patients were alive months after with a median rankin score at [ - ]. more than half of the patients without stupor had a favorable neurological outcome (fig. ) . in univariate analysis, mechanical ventilation and stupor were correlated with mortality, whereas dic and apl were not. by multivariate analysis stupor was the only factor significantly associated with a higher mortality (hr: . [ . - . ] ). conclusion: intracranial hemorrhage is associated with a high mortality rate in al patients, stupor at the onset of intracranial bleeding being independently associated with poor outcome. up to one third of patients will nevertheless survive and experience a favorable neurological outcome. compliance with ethics regulations: yes. neurological outcome assessing by modified rankin scale according to stupor or coma at intracranial hemorrhage diagnosis (blank reflect missing data) rationale: sinusoidal obstruction syndrome (sos, previously known as veno-occlusive disease) is a complication of high dose chemotherapy, frequently occurring during bone marrow transplantation (bmt). severe sos is associated with a high mortality rate, related to multi-organ failure (mof). defibrotide being the only available option for prevention and treatment. prognosis of patients with sos requiring intensive care unit (icu) admission remains unknown. the primary objective was to assess the outcome of these patients. secondary objective was to assess risk factors associated with hospital mortality. patients and methods: retrospective study conducted between january and july in french icus. critically ill adult patients with sos (according to ebmt classification) who received defibrotide were included. results are reported as median [iqr] or number (%). adjusted analysis was performed using cox model. results: seventy-one patients were included with a median age of years . underlying hematologic diseases were acute myeloid leukemia ( %), lymphoma ( %),myelodysplasia/myeloproliferative neoplasm ( %) or acute lymphoid leukemia ( %). sos occurred during myeloablative allogeneic bmt ( %), reduced conditioning allogeneic bmt ( %), autologous bmt ( %) or chemotherapy ( %, including gemtuzumab ozogamycin in patients). median sofa score at icu admission was ]. ebmt prognostic score was often "very severe" ( %). main reasons for icu admission were respiratory failure (n = ), acute renal injury (n = ), shock (n = ), liver failure (n = ), coma (n = ) and monitoring (n = ). median bilirubin level at icu admission was µmol/l [iqr - ] and platelets count g/l . mechanical ventilation (mv), vasopressors, and renal replacement therapy (rrt) were required in % (n = ), % (n = ) and % (n = ) of patients, respectively. sixteen patients receiving defibrotide experienced bleeding events. icu and hospital mortality rates were % and % respectively, mainly related to organ dysfunction. in univariate analysis, delayed defibrotide initiation, bilirubin level, organ supports, sofa, and ebmt scores were associated with hospital mortality. cox model identified older age (hr . , % ci . - . ), mv (hr . , % ci . - . ), rrt (hr . , % ci . - . ), as associated with mortality. prophylactic defibrotide was correlated with a better outcome (hr . , % ci . - . ). similar results were observed after adjustment for center effect. conclusion: when organ support is required, icu management is associated with high mortality. organ support (namely rrt and mv) and older age were associated with poor outcome. prophylactic defibrotide was associated with survival either due to selection process or to efficacy in this setting. additional studies are needed to confirm these results. compliance with ethics regulations: yes. rationale: prognosis of critically ill immunocompromised patients (ciip) has improved over time. neutropenia is common and is found in one third of these patients. prognostic impact of neutropenia remains controversial and little data focus on ciip admitted in a context of acute respiratory failure (arf). primary objective was to assess prognostic impact of neutropenia on outcome of these patients. secondary objective was to assess etiology of arf according to neutropenia. patients and methods: retrospective analysis of prospective multicenter multinational dataset. adults immunocompromized patients with arf were included. adjusted analyses included ( ) a hierarchical model with center as random effect; ( ) propensity score (ps) matched cohort; and ( ) adjusted analysis in the matched cohort. results: overall, patients were included in this study. median age was [iqr - ] and patients ( . %) were of female gender. median sofa score was [ ] [ ] [ ] [ ] [ ] [ ] [ ] and ps was [ ] [ ] [ ] [ ] . main immune defect were hematological malignancy in patients ( %), solid tumor in ( %), systemic disease in ( . %), and other immunosuppressive drugs in ( %). neutropenia at admission was observed in patients ( %). initial oxygenation strategy was oxygen in patients ( %), high flow nasal oxygen in ( %), non-invasive ventilation in ( %) and invasive mechanical ventilation in ( %). before adjustment, hospital mortality was significantly higher in neutropenic patients ( % vs. % in non-neutropenic patients; p = . ). after adjustment for confounder in a mixed model, neutropenia was no longer associated with outcome (or . , % ci . - . ). after ps matching, neutropenic and non-neutropenic patients were compared. hospital mortality was similar in both groups ( % vs. % respectively; p = . ). after adjustment for variables associated with mortality, neutropenia was not associated with hospital mortality (or . , % ci . - . ). arf etiologies were distributed similarly in both neutropenic and non-neutropenic patients (fig. ) , main etiologies being bacterial pneumonia ( % vs. %), invasive fungal infection ( % vs. %), pneumocystis jiroveci pneumonia ( % vs. . %), and undetermined etiology ( % vs. %) (p = . ). conclusion: neutropenia at icu admission is not associated with hospital mortality in this cohort of ciip admitted for arf. surprisingly, arf etiology did not differ despite the multiplicity of observed immune defects. compliance with ethics regulations: yes. rationale: hepatic dysfunction (hd) is commonly observed in patients with hematologic malignancies and associated with an increased mortality in allogeneic hematopoietic stem cell transplantation patients. we aimed to assess incidence, risk factors and prognostic impact of hd in a large multicenter cohort study of critically ill patients with hematologic malignancies. patients and methods: this research was a post hoc analysis of a franco-belgian multicenter prospective study assessing the prognosis of patients with hematologic malignancies admitted to intensive care unit (icu) between january and may . hd was defined as serum total bilirubin ≥ µmol/l at icu admission. for patients with hd, a review of medical hospital records was performed by an expert panel to assess management of hd by attending physicians. results: among the patients with hematologic malignancies admitted to icu, were included in the study, mainly patients with non-hodgkin lymphoma ( . %) or acute myeloid leukemia ( . %). hd at icu admission occurred in patients ( . %). factors independently associated with hd were the use of cyclosporine (or = . , % ci . - . , p < . ) and antimicrobial treatment (or = . , % ci . - . , p = . ) before icu admission, abdominal symptoms at icu admission (or = . , % ci . - . , p < . ), ascites (or = . , % ci . - . , p = . ), hepatic charlson comorbidity (or = . , % ci . - . , p = . ), increased creatinine at icu admission (or = . , % ci - . , p = . ), neutropenia (or = . , % ci . - . , p = . ) and myeloma (or = . , % ci . - . , p = . ). hospital mortality was . % and . % in patients with hd and patients with no hd respectively (p < . ). hd appeared as an independent factor of hospital mortality after adjustment with other organ failure (oradj = . , % ci . - . , p = . ). factors independently associated with hospital mortality among patients with hd at icu admission are reported in table . etiologic diagnoses for hd by physicians were undetermined for patients ( . %) including ( . %) for whom the existence of hd has not even been mentioned in the medical record. investigations were performed in % and only % of patients received a specific treatment for hd. conclusion: hd at icu admission is common, underestimated, poorly investigated, and impairs outcome in critically ill patients with hematologic malignancies. hd should be considered and managed as other organ dysfunctions. it raises the importance of an early severity assessment of hd and a development of diagnosis strategies to get therapeutic options, in close collaboration between hematologists and intensivists. compliance with ethics regulations: yes. rationale: acute respiratory failure (arf) is the main cause for admission to the icu for patients with hematological malignancies (hm). viral pneumonia is poorly described in this population. respiratory viruses pcr is a rapid and sensitive diagnostic tool. thoracic ct allows to guide the diagnosis but is also poorly described. the primary objective was to describe ct features suggesting viral pathogenicity. secondaryobjectives were to assess risk factors associated with the use of invasive mechanical ventilation (imv) and icu mortality. rationale: high-dose methotrexate (hd-mtx) is commonly used in the treatment of solid tumours and hematological malignancies. severe toxicities are frequent, leading to organ dysfunction, multiple organ failure and death. outcome of these patients when critical illness occurs is poorly studied. this study aims to describe mtx-induced toxicities and to assess outcome in critically ill patients. in this retrospective study conducted in the icu of one university hospital between january and december , all the patients who were given hd-mtx (single dose greater than mg/m ) in the icu were included. results are presented as median [interquartile range] and number (percent). results: patients ( men and women) aged years [ - ], were included. b-cell lymphoma had been diagnosed in patients (burkitt, n = ; diffuse large b cell lymphoma with cns (central nervous system) involvement, n = ; primary cns lymphoma, n = ) and t-cell lymphoma in two patients. patients were mainly admitted for coma (n = ; %) or acute kidney injury (n = ; %). mtx was administered at a median dose of . g [ - ] . fourteen patients had concomitant medication interacting with mtx. median mtx clearance was days [ ] [ ] . frequent mtx-related complication were mucositis (n = , %), diarrhea (n = , %) or hepatic failure (n = , %). during icu stay, patients experienced acute kidney injury (kdigo stage . [ ] [ ] ). two patients received carboxypeptidase and three underwent dialysis. overall, patients ( %) required mechanical ventilation, ( %) vasopressors. hospital mortality was % (n = ). cox model identified mtx concentration h after administration higher than . µmol/l as associated with hospital mortality (hr . , % ci . - . ) (fig. ) . conclusion: to our knowledge this is the first study assessing characteristics and outcome of critically ill patients receiving hd-mtx. mtx concentration at h was associated with hospital mortality. despite underlying malignancy, icu support of these patients was associated with a meaningful survival. compliance with ethics regulations: yes. rationale: high-dose methotrexate ( g/m ; hdmtx) is the cornerstone of chemotherapy in acute lymphoblastic leukemia (all) and several high-grade non-hodgkin lymphoma (hnhl). despite standardized prevention, acute kidney injury (aki) and other life-threatening complications still occur. given the cost of glucarpidase, an enzyme that metabolizes mtx in few minutes, and the complexity of hematological patients admitted to the icu, a better comprehensive view of the factors that predict hdmtx toxicity, as well as the role of glucarpidase as rescue therapy in patients with organ failure, is mandatory. patients and methods: retrospective monocenter study including all the adult patients referred for all or hnhl in a french university hospital, and who received hdmtx. aki was defined according to the kdigo classification. univariate analysis (fischer exact or mann-withney tests) followed by multivariate analysis (stepwise logistic regression) were used to identify before hdmtx the clinical and biological predictive factors of aki. outcomes following glucarpidase were also addressed. results: from dec- to sept- , patients received hdmtx (median dose g/m ; all n = , hnhl n = ), totalizing hdmtx pulses. sixty-nine patients ( . %) developed aki after a median time of days (stage n = , stage n = , stage n = including one requiring dialysis in the first week). by multivariate analysis, only age, body mass index and a diagnosis of all were significantly and independently associated with the risk to develop aki. mtx exposure (maximal serum concentration at h - ) was also associated with aki (auc . , p < . ). glucarpidase was used in patients ( %) that differed by a higher age and bmi, and a lower basal egfr. glucarpidase was followed by a rapid renal improvement but serum creatinine did not return to baseline ( vs. micromol/l). thirty patients with aki or delayed mtx elimination did not receive glucarpidase but none required renal replacement therapy and egfr was only slightly but not significantly reduced at the end of follow-up. extra-renal adverse-events (rbc and platelets transfusions, neutropenia, hepatitis, severe diarrhea, mucitis) were more frequent in patients that developed aki. eighteen patients were admitted to the icu, including and that required mechanical ventilation or vasopressor drugs, respectively. conclusion: few actionable factors predict the development of aki after hdmtx, suggesting additional genetic factors. aki was reversed by glucarpidase but progression toward ckd was the rule. further studies will have to identify patients that will actually beneficiate from glucarpidase. compliance with ethics regulations: yes. khaoula ben ismail, sana khedher, ameni khaled, nassereddine foudhaili, mohamed salem usi digestif-service de gastroenterologie-eps charles nicolles.tunis-tunisie., tunisia, tunisia correspondence: khaoula ben ismail (khaoula @hotmail.fr) ann. intensive care , (suppl ):p- rationale: infection is common and accounts for major morbidity and mortality in cirrhosis. patients with cirrhosis are immunocompromised and have increased susceptibility to develop spontaneous bacterial infections, hospital-acquired infections, and a variety of infections from uncommon pathogens. we aimed to evaluate the impact of infection on hepatic encephalopathy. patients and methods: this is a prospective study, conducted over a period of years from january to december . consecutive patients with approved decompensated cirrhosis admitted to our department are included. all clinical and biological data were collected from the medical records. univariate and multivariate analysis were used to identify the impact of infection on hepatic encephalopathy. results: a total of patients diagnosed with decompensated cirrhosis were enrolled in this study. mean of age was years ( - ). sex ratio was . . hcv ( %) was the main etiology of cirrhosis. the reasons of hospitalization were: oedema with ascitic syndrome ( % of cases), digestive bleeding ( % of cases), fever ( % of cases), and encephalopathy ( % of cases). patients with infection seemed to have a high incidence of hepatic encephalopathy with % versus % when the patients are none infections. the results also showed that in those with hepatic encephalopathy, an effective antibiotic treatment accelerates significantly wakefulness under h with a rate of % vs. % (p < . ) . in addition, the infection does not influence mortality or length of stay compared to other complications such as digestive bleeding. conclusion: we found that infection caused more episodic hepatic encephalopathy than other complication and an effective antibiotherapy accelerate wakefulness. compliance with ethics regulations: yes. rationale: hepatic encephalopathy (he) is a common cause of hospitalization in patients with cirrhosis. pharmacologic treatment for acute (overt) he has remained the same for decades. to compare polyethylene glycol electrolyte solution (peg) and lactulose treatments in patients with cirrhosis admitted to the hospital for he. we hypothesized that rapid catharsis of the gut using peg may resolve he more effectively than lactulose. patients and methods: this is a prospective study, conducted over a period of years. from janury to december , we have been interested in cirrhotic patients with hepatic encephalopathy. all clinical and biological data were collected from the medical records. univariate and multivariate analysis were used to identify the difference beteween peg and lactulose in the treatement of hepatic encephalopathy. results: a total of patients diagnosed with decompation of cirrhosis were enrolled in this study. mean of age was years ( - ). sex ratio was . . hcv ( %) was the main etiology of cirrhosis. the hospitalization reasons were: edematous-ascitic syndrome in %, gastro-intestinal bleeding %, fever in %, and encephalopathy was present in % of cases. a total of patients were randomized to each treatment arm. baseline clinical features at admission were similar in the groups. twelve of patients in the standard therapy arm ( %) had an improvement of or more in hesa score, thus meeting the primary outcome measure, compared with of evaluated patients receiving peg ( %) (p < . ). the mean ± sd hesa score at h for patients receiving standard therapy changed from . ± . to . ± . compared with a change from . ± . to . ± . for the peg-treated groups (p = . ). the median time for he resolution was days for standard therapy and day for peg (p = . ). adverse events were uncommon, and none wasdefinitely study related. conclusion: we found that peg led to more rapid he resolution than standard therapy, suggesting that peg may be superior to standard lactulose therapy in patients with cirrhosis hospitalized for acute he. compliance with ethics regulations: yes. acute pancreatitis and pregnancy janati adnane, lina berrada obstetric intensive care unit, casablanca, morocco correspondence: janati adnane (adnanejanati@gmail.com) ann. intensive care , (suppl ):p- rationale: the association of acute pancreatitis and pregnancy is rare but not negligible, it often cause a diagnostic problem given the gravidal context that can lead to serious repercussions. the objective of our study is to assess the particularities in the diagnosis, management and prognosis of acute pancreatitis during pregnancy patients and methods: this is a retrospective study about cases of acute pancreatitis occurred during pregnancy over a -year period ( - ) at the obstetric intensive care unit of the meriem maternity hospital in the chu ibn rochd casablanca. a retrospective analysis of the medical files of these patients was carried out, considering epidemiological and etiological criteria, the treatments administered and maternal/fetal fate. we found cases during this period, with an incidence of / . the average age of onset was years, % of cases occurred in the rd trimester. epigastric pain and vomiting were the common symptomatology. ultrasound showed biliary lithiasis in % of cases with increased pancreas size in % of cases. maternal mortality was zero. uncomplicated benign forms are the most common ( %). severe hypokalemia was found in % of patients. neonatal morbidity was marked by six premature deliveries. among them, a newborn died at day- of life discussion: the association of acute pancreatitis and pregnancy is rare, more frequent during the rd trimester, it mainly affects the young woman. lithiasic biliary pathology remains by far the most frequent etiology. the diagnosis is clinical most often represented by epigastralgia with vomiting and biological via lipasemia and amylasemia dosage. uncomplicated benign forms are the most common. hydroelectrolytic disorders are often found. abdominal ultrasound allows the etiological diagnosis. the treatment is above all symptomatic whose objective is the digestive rest, the correction of the hydroelectrolyte disorders but first of all relieve the pain. conclusion: acute pancreatitis is a rare event in pregnant women, but can have a maternal and fetal prognosis. it must be systematically evoked in front of the acute abdominal pains of the pregnant woman because the confirmation of the diagnosis is easy and the maternal results depend mainly on therapeutic management. prematurity remains the predominant factor in neonatal morbidity. compliance with ethics regulations: not applicable. rationale: aclf is a clinical concept defined in patients with chronic liver disease who presented organ failure(s) secondary to an acute decompensated event. liver transplantation in this indication showed good results in selected patients. the aim of this prospective study was to evaluate the outcome and the factors associated with a favorable selection to liver transplantation in this population. patients and methods: all consecutive patients admitted to the icu with cirrhosis and aclf, were recruited. patient with age < years or with fulminant hepatitis were excluded. results: between july and february , cirrhotic patients were admitted to icu. mean age was . ± . years ( . % male). cirrhosis was due to alcohol in . % of the patients. aclf grading at admission was: . % aclf (n = ), . % aclf (n = ), . % aclf (n = ), and . % aclf (n = ). of the patients, . % (n = ) were considered to be eligible for a transplant project and were assessed for liver transplantation. the main reasons were alcohol abuse ( . %, n = ), death within days after admission ( . %, n = ) and rapid improvement of the liver disease. of the eligible patients, % were transplanted with a mean time between admission to icu and liver transplantation of . ± . days. twelve patients died on the waiting list ( % of the listed patients), mainly of septic shock. among those who were assessed for liver transplantation but not listed (n = ), . % died before the listing (n = ) and . % were not listed because of severe comorbidities (n = ). the global mortality rate was . % (n = ). the and days rate mortality were respectively . % and . %. the overall -month patient survival was respectively % and % in the transplant and non-transplant group (p < . ) for the entire cohort. among eligible patients, factors associated with the absence of liver transplantation, in the multivariate analyses, were mechanical ventilation (hr . , % ci rationale: body composition is known to be a prognostic factor in cirrhotic patients. however, the link between this and the prognosis of patients in intensive care unit (icu) is unknown. the computed tomography offer accurate estimations of muscle mass by analysing a cross-section usually going through the third lumbar vertebrae. this retrospective study aimed to assess the feasibility of body composition (bc) analysis in cirrhotic patients with septic shock, using computed tomography (ct) and evaluate the impact of bc (muscle mass, subcutaneous and visceral fat) on outcome. patients and methods: this retrospective study included cirrhotic patients with septic shock hospitalized in icu who underwent an abdomino pelvic ct scan within h of admission. we collected the surface areas of muscle mass and adipose tissue on the ct scans. we compared bc data with mortality and with the number of organ failures. the average age was years . the average child and meld scores were respectively . [ - ] and . . the prevalence of sarcopenia was %. it was not associated with a higher mortality rate at day (p = . ) or with a higher number of organ failures at day (p = . ). we observed a higher subcutaneous adiposity index in patients who died at day (p = . ) and in patients with renal insufficiency at admission (p = . ). there was a trend (p = . ) towards more visceral fat in patients who died in icu. the assessment by ct of body composition reveal evaluation of bc using ct is feasible and reproducible and may constitute a promising tool to evaluate in cirrhosis critically ill patients. visceral fat mass seems associated with poor outcome in cirrhotic patients with septic shock compliance with ethics regulations: yes. rachid jabi, mohammed bouziane chu mohammed vi, oujda, morocco correspondence: rachid jabi (jabirachid@gmail.com) ann. intensive care , (suppl ):p- rationale: the infection of the necrosis constitutes a pejorative element in the management of the necrotico-haemorrhagic pancreatitis, in the absence of the drainage the mortality approaches %. the morbidity and mortality of surgery can be avoided with minimally invasive treatments. purpose: to compare the morbidity and mortality of the two groups of post-ercp pancreatitis and the other etiologies. patients and methods: a retrospective study over years between and and a comparison between pancreatitis secondary to post-ercp and other etiologies of pancreatitis. a p value of . is considered significant. the surgical treatment used in cases of superinfection post ercp against seven cases of other etiologies of pancreatitis. high mortality in post-ercp pancreatic arm % vs. % (p = . ). high morbidity in the operated group % vs. % (p = . ) represented mainly digestive haemorrhages. duration of stay was significantly longer in the operated group vs. days (p = . ). thrombocytopenia and beta-lactamase-producing enterobacteria have further complicated management in the post-ercp infected pancreatitis arm. the antibiotic resistance of infected pancreatitis in post-ercp patients is . % for ciprofloxacin, . % for imipenem and % for amikacin. conclusion: pancreatitis the most common adverse effect of ercp with significant morbidity and mortality. the collaboration between the intensive care unit gastroenterologist and the surgeon improves management since the risk factors are mainly related to the patient and can not be modified. compliance with ethics regulations: yes. gautier nitel, aghiles hamroun, anne bignon, gilles lebuffe chru lille, lille, france correspondence: gautier nitel (gautier.nitel@gmail.com) ann. intensive care , (suppl ):p- rationale: liver transplantation (lt) has been recently experiencing an expansion of its indications, allowing patients with potentially more co-morbidities to access to transplantation. in our era of graft shortage, we should focus on the identification of the best lt candidates. the aim of our work is to study the determinants of early morbidity and mortality after lt from three angles: occurrence of a major cardiovascular event (mace) or acute renal failure (kdigo stage - aki) in the first days postoperative, and death in the year following lt. retrospective study investigating the occurrence of mace or aki (kdigo - ) within days post-operative and mortality at year after lt, including patients who received a first lt between january and december in our center. analysis of risk factors by a multivariate step-by-step analysis. statistical significance for p < . . data presented in odds ratio (or) rationale: infectious complications are frequently reported in critically ill patients supported by veno-arterial extracorporeal membrane oxygenation (va-ecmo) for refractory cardiogenic shock, but their diagnosis is challenging. no study has specifically studied bloodstream infection (bsi) in this population and some recommendations suggest performing systematic blood culture (bc). in our unit, systematic bc are daily sampled. we investigated the interest of systematic bc to detect bsi under va-ecmo. patients and methods: in a retrospective analysis ( - ), and after exclusion of patients dying within h, all adult patients from cardio-vascular intensive care unit supported by va-ecmo were included. systematic daily and "on demand" bc (at the physician's discretion) performed from va-ecmo implantation to days after withdrawal were analyzed. bsi was defined as at least one bc positive to a pathogen (except for contaminants bsi which required at least two positive bc with the same bacteria in h). multivariable logistic regression was performed to identify risk factors for positivity of systematic bc. rationale: fungal infections are constantly increasing in hospitals. indeed, the increase in these infections and especially candida yeast infections is almost parallel to the increase in the widespread use of a wide range of implanted medical devices such as catheters. for this reason, we have been investigating, isolating and identifying candida yeast colonizing vascular catheters and studying the epidemiological and clinical characteristics of patients with colonized catheters. patients and methods: it is a prospective, transversal study conducted at the intensive care and neurosurgery services of the sétif university hospital, evaluating the fungal colonization of vascular catheters. these are collected from hospitalized patients for a period of months. a culture of the distal end of the catheter is performed directly after its ablation. the results obtained showed that among the samples taken, six are colonized by the yeasts, the incidence is %. six yeast of candida spp were isolated, % of them were candida albicans species, . % candida parapsilosis and . % were candida glabrata. conclusion: it appears that colonization of catheters occurs most frequently in patients with the following characteristics: extreme ages of life, male sex, antibiotic therapy and length of hospitalization or prolonged catheterization. compliance with ethics regulations: yes. rationale: the threat of emergent extensively drug-resistant bacteria (exdr) dissemination worldwide is real. it has become a global public health issue. in fact, glycopeptides-resistant enterococcus faecium (gre) and carbapenemase-producing enterobacteriaceae (cpe) are the lead microorganisms in the high resistant bacteria category. the aim of our study was to characterize the molecular mechanisms and to determinate the antimicrobial susceptibility profiles of gre and cpe isolated from burn patients. patients and methods: prospectively, we studied all cpe and gre strains isolated from burn patients between january and december . all isolated microorganisms were identified on the basis of conventional microbiological techniques. antibiotic susceptibility testing was carried out by the agar disc diffusion method, and susceptibility results were interpreted using clinical breakpoints according to ca-sfm guidelines. molecular characterization was performed by multiplex real-time pcr (cepheid, genexpert ® ) allowing detection of the most prevalent carbapenemase encoding genes (blavim, blandm, blaimp, (blaoxa- and blakpc) as well as the genes vana and vanb of gre. results: during the study period, exdr were isolated from burn patients. the most frequent sites of isolation were blood cultures ( %) and skin samples ( . %). cpe represented . % of isolated exdr ( strains). among them, the most frequently identified species was klebsiella pneumoniae ( . %) followed by enterobacter cloacae ( %). twenty-four cpe ( . %) expressed the blandm gene. the blaoxa- gene was found in strains ( . %) and ten strains ( . %) carried both genes. of the cpe, . % revealed ertapenem mic > mg/l whereas most strains were susceptible to imipinem and meropenem with . % and . % of susceptibility, respectively. the antibiotics showing the highest resistance rates were cefotaxime ( . %), piperacillin-tazobactam ( . %), ciprofloxacin ( . %) and amikacin ( . %). the most active agents were colistin and fosfomycin with . % of resistance for each. seven strains of gre were isolated ( . % of exdr). all of them expressed the vana gene, with vancomycin mic > mg/l. however, teicoplanin mics ranged from to mg/l. all gre strains were beta-lactam resistant and highly resistant to aminosides. linezolid and tigecycline were the only active antibiotics. the dissemination of these extensively drug-resistant bacteria must be contained by implementation of strict isolation methods and better hygienic procedures in order to limit their economical and health consequences. compliance with ethics regulations: yes. rationale: stenotrophomonas maltophilia has emerged as an important pathogen that induces nosocomial infections. it is a non-fermentative, gram-negative bacillus that causes severe infectious diseases, particularly bacteremia in the hospital setting. morbidity and mortality due to stenotrophomonas maltophilia seems to be high, particularly in critically ill patient. the aim of this study was to describe the clinical features, management and outcome of patients with stenotrophomonas maltophilia infections. patients and methods: this was a retrospective analysis of prospectively collected data of patients hospitalized in intensive care unit (icu) between january and december . collected data were: age, gender, comorbidities, severity scores on admission, prior infections, use of antibiotics, use of invasive devices (urinary tract catheter, or mechanical ventilation), microbiological data, and antimicrobial therapy and outcome. results: during the study period, patients with stenotrophomonas maltophilia infection were included, with a mean age of ± years. the simplified acute physiology score ii and acute physiology and chronic health evaluation ii on admission were respectively ± and ± . bacteremia caused by stenotrophomonas maltophilia was observed in patients ( %) and ventilator acquired pneumonia in two patients ( %). twenty four episodes were classified as primary bacteraemia and only one as secondary bacteraemia due to urinary infection. four patients ( %) developed septic shock. mean sofa on the day of stenotrophomonas maltophilia infection was ± . prior antibiotic use was observed in % including an antipseudomonal agent in % of cases. infection due to stenotrophomonas maltophilia was considered in cases. empiric antibiotic therapy was administered to patients ( %) and had included an appropriate agent in only five cases ( %). after adapting antibiotics, monotherapy was the choice for six ( %) patients while a combination of two antibiotics was indicated in the others ( %). the most used antibiotic was the colistin in episodes ( %). intensive care mortality was %. univariate comparison between dead and survivors showed a significant difference in prior nosocomial infection and respiratory comorbidities. no independent risk factor of mortality was found in multivariate analysis. rationale: thrombocytopenia is a frequent disorder in critically ill patients, and several studies have reported its correlation with poor prognosis. considering the major role of platelets in hemostasis, a significant drop in platelet count is an alarming sign in septic patients. the aim of this study was to show the relationship between thrombocytopenia and platelet level changes and mortality in septic patients. patients with criteria for septic shock (based on the third international consensus definitions for sepsis and septic shock) at admission or at any time during hospitalization were included in a prospective study conducted for a period of months (january -august , ) in a medical surgical intensive care unit. patients hospitalized for less than h were excluded. thrombocytopenia was defined as a platelet count less than . /mm , and recovery was defined as returning to levels more than . /mm after presenting thrombocytopenia. we assessed the platelet count during the hospitalization and its outcomes. we included patients. the mean ± sd age was . ± . years. sex ratio was . . thrombocytopenia during sepsis (group ) was found in patients ( %) with a mortality rate at %. the mortality rate among patients not showing thrombocytopenia (group ) was significantly lower % (p = . ). the receiver operating characteristic showed that in (group ), a drop in the platelet count (from admission to septic shock day) more than % was associated with poor outcome (sensibility = %, specificity = %, auc = . ). among the (group ), % showed recovered platelet counts. the mortality was significantly higher in the patients with uncovered thrombocytopenia ( % vs. %, p = . ). conclusion: thrombocytopenia was shown to be an indicatorof poor prognosis in our study. in addition, drops of > % and failure to recover the platelet counts were further determinants of unfavorable outcomes. compliance with ethics regulations: yes. mehdi gaddas , sarra dhraief , karim mechri , imen jami , amenallah messaadi , lamia thabet rationale: pseudomonas aeruginosa is known as an opportunistic pathogen frequently causing serious infections. multidrug resistance in this bacterium is increasing worldwide and poses a major problem in the treatment of infections due to this microorganism. analysis of resistance profile to antibiotics of p. aeruginosa helps to establish a prompt control and prevention program. the aim of this study was to evaluate epidemiological profile and antimicrobial resistance of p. aeruginosa isolates in a trauma and burn center. patients and methods: retrospectively, we studied all p. aeruginosa isolates over a -year period (from january to december ). conventional methods were used for identification. antimicrobial susceptibility testing was performed with disk diffusion method and susceptibility results were interpreted using clinical breakpoints according to ca-sfm guidelines. data were analyzed using the sirsystem. minimum inhibitory concentration of colistin was determined using the e-test ® method (biomérieux), then using the eucast broth micro-dilution method (umic, biocentric ® ) since may . results: during study period, non-repetitive strains of p. aeruginosa were isolated, representing % of all isolates. in our center, infections due to p. aeruginosa were endemic with epidemic peaks. p. aeruginosa was mainly isolated from burn intensive care unit ( . %) and anesthesiology department ( . %). the most frequent sites of isolation were skin samples ( . %), blood cultures ( . %), catheters ( . %) and urines ( . %). the survey of antibiotic susceptibility showed high percentage of resistance to the different antibiotics: . % of strains were resistant to ceftazidime, % to ticarcillin, . % to pipercaillin-tazobactam, % to imipenem, . % to ciprofloxacin and % to gentamicin. resistance to colistin was rare. it concerned only four strains, isolated from burn patients. the survey of antibiotic susceptibility evolution have shown a global increase of resistance to commonly prescribed antibiotics between and : from % to . % to imipenem, from . to . % to ticarcillin-clavulanate, from . % to % to ceftazidime and from . to % to gentamicin. whereas ciprofloxacin resistance rate have decreased from . to %. antibiotic resistant strains were mainly isolated from burn intensive care unit, with % of resistance to imipenem and . % to ceftazidime. the dissemination of multidrug-resistant strains of p. aeruginosa in our center must be contained by the implementation of strict isolation methods and better hygienic procedures. compliance with ethics regulations: yes. acinetobacter baumanii: therapeutic impasse sabah benhamza, mohamed lazraq, abdelhak bensaid, youssef miloudi, najib el harrar réanimation de l'hôpital du août, casablanca, morocco correspondence: sabah benhamza (benhamzasabah @gmail.com) ann. intensive care , (suppl ):p- rationale: acinetobacter baumanii (ab) is frequently responsible for nosocomial infection in the intensive care units, and its resistance to antibiotics continues to increase. the objective of our study is to determine the epidemiological profile and antibiotic sensitivity of isolated bacteria in the intensive care unit august , in order to optimize the probabilistic antibiotherapy of bacteremia in intensive care. patients and methods: this is a retrospective study performed in the intensive care unit of the hospital august , , spread over a period of years from january to january . results: the incidence of ab infection in our department was . % for all patients admitted to intensive care. the average age was years ± , male predominance (sex ratio . ). the average time to onset of infection was days. during the study period, ab strains were isolated, % of which were pulmonary, % blood, and % urinary. resistance to c g reached % in , % in and % in . for imipenem resistance was % in , % in , % in . for amikacin, resistance was % in , % in , and % in . for fluoroquinolones resistance was % in , % in and % in . cotrimoxazole resistance was around % in the last years conclusion: the resistance of ab to antibiotics has reached very alarming levels, especially for carbapenems. this requires resuscitators to change their antibiotic prescription behavior and to invest in the prevention of nosocomial infections. compliance with ethics regulations: yes. this is a prospective observational study conducted at the ed during the period of year. data of all patients admitted with suspected infection of any cause were collected. poor outcomes were defined as death and transfer to an icu within h. results: during the study period, a total of patients with a mean age of ± were included. % were male. within h of management in the ed, % of patients were transferred to the icu and % died. independent predictors of icu-transfer and death included low systolic blood pressure, fever and tachycardia. a prediction model containing these independent predictors had a good predictive accuracy with an area under the curve of . ( % ci . - . ). sensitivity was %, specificity %, positive predictive value % and negative predictive value %. conclusion: assessing readily available clinical variables at arrival to the ed can aid in predicting poor outcomes. [ ] [ ] [ ] [ ] [ ] [ ] . the most common co-morbidities were chronic respiratory failure (crf, n = ) and hypertension (n = ). respiratory distress (n = ) and coma (n = ) were the major indications for iv. us diaphragmatic exploration was performed at a median delay of iv at days [ ] [ ] [ ] [ ] [ ] [ ] . % of patients received sedation and . % received neuromuscular blockers. the ventilator mode was control volume in patients via endotracheal tube (n = ) and tracheostomy cannula (n = ). no major incident was detected during the turning of patients. both tid and ted decreased from the sp to the pp (fig. ) : tid (mm) ( in sp vs. . in pp, p = . ), ted (mm) ( . in sp vs. in pp, p = . ). the observed dtf was lower in the pp but without significance ( . vs. . %, p = . ). no difference was showed when the comparison between sp-dtf and pp-dtf was adjusted on the ventilator mode, obesity, neuromuscular blockers and crf. the positioning in pp in ventilated patients reduces both tele-inspiratory and tele-expiratory diameters of the diaphragm but not altered its contractile function. compliance with ethics regulations: yes. significance was considered at p < . . results: results are presented in the table below. discussion: nebuliser type influences the efficiency of aerosol delivery, with the vmn delivering a significantly higher % aerosol dose than the jn at the two circuit positions (p = . on inspiratory limb; p = . at the dry side of humidifier). in agreement with previous reports using bias flow, for both nebulisers, the location within the circuit has a significant effect, with the nebuliser on the dry side of the humidifier delivering more aerosol than on the inspiratory limb (p = . for vmn; p = . for jn). conclusion: for a mechanically ventilated adult tracheotomy patient, the type of nebuliser and the location of the nebuliser within the circuit influences aerosol delivery. rationale: automatic tube compensation (atc) is a mode available in most icu ventilators. it compensates for the resistive pressure into endotracheal tube/tracheostomy canula by continuously providing a pressure assistance based on internal diameter of a new endotracheal tube/tracheostomy tube. its use in icu is unclear. we designed a survey to further explore this. patients and methods: the survey was endorsed by the acute respiratory failure section and the clinicaltrials group of the european society of intensive care medicine (esicm). the pool was sent out via an email on june to the esicm members worldwide. the following closed questions were: country, years in icu, kind of icu, kind of hospitals, kind of respirators, atc use (never, always or in some patients), reasons to or not to use atc, ventilatory mode in which atc was used. the database was frozen on august st after two reminders. we used the gross national income per capita (usd) provided by the world bank to transform the respondent's country into a geographical-economical variable with levels: high-europe, high-noneurope and middle ( ) . atc use was coded as yes or no. the primary end-point was atc rate of use and the hypothesis was that less than % of the respondents do use it. variables were expressed as counts. groups were compared by chi square test. a logistic regression analysis was performed to explore the contributing factors to atc use. we received responses without any doublons, of which six were empty, from countries. four-hundred and nine respondents used atc always or in some patients ( % atc rate of use). this rate was not different between economical-geographical regions, icu, hospitals and years in icu. for those respondents who did not use atc the reasons were: atc mode not available in icu ventilators ( . %), atc not helpful mode ( . %), atc not known ( . %) and atc provides too much pressure assistance ( . %). for those respondents who used atc the reasons were: helpful in weaning ( . %), set by default ( . %) and physiological benefit ( . %). they used atc during spontaneous breathing trial ( . %), with any assisted mode ( . %) and with specific modes ( . %). we found no risk factor for atc use in the logistic regression model (fig. ) . the atc rate of use was unexpectedly high in this survey. this may result from respondents selection bias or from an a priori underestimation of its use. compliance with ethics regulations: yes. rationale: during pressure support ventilation (psv), adjusting the level of assistance mainly aims at maintaining the patient's respiratory effort within a normal range. however, respiratory effort measurement is impeded in clinical routine by the need of esophageal pressure recording. in this study, we evaluated the accuracy of assessing the respiratory effort from the flow and airway pressure signals using several machine learning algorithms based on the equation of motion of the respiratory system. patients and methods: using the asl simulator (ingmar medical) connected to a pb ventilator (medtronic) set in psv, we simulated a massive number of different respiratory cycles. each simulated cycle represented a unique combination of compliance and resistance of the respiratory system, duration and intensity of the muscle pressure (pmus), positive end-expiratory pressure (peep) and pressure support levels. using least squares regression methods, the flow waveform was fitted according to the equation of motion of the respiratory system to determine the compliance and resistance of the respiratory system, and the pmus. the hypothesis used (alone or in combination) to constrain the system were: linearity of pmus at the onset of the inspiratory effort, nullity of pmus at the end of insufflation, and nullity of pmus during expiration. thus, nine methods were built and tested. calculated and actual peak pmus values were compared using the bland-altman method. the nine methods of pmus assessment were evaluated using different simulated cycles. by limiting the analysis to selected cycles with a predefined applicability criterion (intrinsic peep less than cmh o), a limited inspiratory effort (peak pmus less than cmh o) and a high quality of fitting (r > . ), the method using the three hypothesis together to constrain the system was characterized by a bias of . cmh o and limits of agreement of - . and . cmh o. however, when widening the analysis to all the simulated conditions, no method allowed an accurate estimation of the peak pmus : the best one exhibited a bias of - . cmh o and limits of agreement of − . and . cmh o. conclusion: among the nine machine learning methods tested, some provided an accurate estimate of the respiratory effort in selected cycles but none allowed such accuracy across all simulated conditions. this incites to assess automated methods using a more complex physiological and physical model. compliance with ethics regulations: not applicable. rationale: there is a growing interest in esophageal pressure monitoring in mechanically ventilated patients. esophageal pressure can be measured with a specific nasogastric catheter equipped with esophageal balloon and connected to a pressure transducer. it is used as a surrogate for pleural pressure and may be considered as a corner stone in advanced care of ventilated patients to better assess lung and chest wall mechanics and easily detect patient-ventilator asynchronies. however, this promising technique is still seldom used in clinical practice. trained icu nurses may perform oesophageal pressure measurements which may help facilitate its implementation in the usual patient care. this study aimed at assessing whether a specific educational program to train nurses to perform esophageal pressure monitoring allowed reliable measurements. this was a prospective monocenter study performed in an academic icu. written informed consent was obtained from the nurses before inclusion in the study. the specific educational program consisted of a -min online theoretical course, a -h group theoretical teaching and a -min simulation training on a mannequin. then each participating nurse performed three esophageal pressure measurements (using nutrivent ® catheters and an icu monitor connected to arterial line pressure transducers system) on three different mechanically ventilated paralysed patients under supervision. a knowledge assessment was performed with a short written mcq test. the skill evaluation was by two trained experts. concretely the trained nurses performed an esophageal pressure measurement without assistance. their ability to control the esophageal balloon position by an occlusion test, to measure the inspiratory and expiratory airway and transpulmonary pressures and to calculate of respiratory system, lung and chest wall compliances was assessed at the bedside using a standardized evaluation form. we present here the preliminary results of the first nine included nurses. the written knowledge assessment was considered as rationale: several modalities of ventilatory support have been proposed to gradually withdraw patients from mechanical ventilation. we conducted this study to compare t-piece and pressure support ventilation (psv) ( cmh and peep ) in the process of weaning of mechanical ventilation in burns. patients and methods: it was a prospective randomized trial in burn icu in tunisia during months. mechanically ventilated patients who met standard weaning criteria were included [ ] . patients were randomized into two groups: group under t-piece and group under psv. duration of the test: - min. the tolerance of the vs test should be judged on clinical criteria. stopping the test if occurred: agitation, tachypnea > cycles/ min, tachycardia > / min, spo < %. successful withdrawal was defined as the ability to maintain spontaneous respiration for h after extubation. results: thirty patients were included, randomized into two groups. the mean age was ± years with a ratio sex of . the average tbsa was ± %. the cause of mechanical ventilation was essentially a face neck burned ( %). the following table shows the weaning outcome of both modalities. eighty percent of succeeded extubation for both groups (n = / ). the cause of failure of extubation was secretion retention and clutter in majority of cases followed by neurological and cardiac distress. the duration of mechanical ventilation does not influence the outcome of the weaning test (p < . ), with a mean of duration of ± days. conclusion: our study did not show any difference between the two weaning modalities in the matter of outcome of extubation. the choice of weaning test of mechanical ventilation is to be judged by the clinician according of the state of his patient. compliance with ethics regulations: not applicable. rationale: when expiratory tidal flow does not go up after increasing expiratory driving pressure expiratory flow limitation (efl) occurs. it is thought that efl heralds airway closure (ac). we investigated the role of chest wall elastance (ecw) in both efl and ac in acute respiratory distress syndrome (ards) patients. our hypothesis was that the lower the ecw to lung elastance (el) ratio the higher the likelihood of efl and ac. patients and methods: twenty-five moderate to severe ards patients were prospectively included in two centers. mechanical ventilation was delivered in volume-controlled mode with tidal volume ml/kg predicted body weight at positive end-expiratory pressure cmh o in semi-recumbent position. airway (paw) and esophageal (pes) pressures and flow were continuously recorded during min by a data logger (biopac ). then, end-expiratory and end-inspiratory occlusions were performed for s, then respiratory system was slowly inflated at constant flow. finally, patient was allowed to breathe out freely to atmosphere by using a three-way stop lock by-passing expiratory valve. ac and airway opening pressure (aop) were determined according to chen et al. ( ) . efl was assessed by the atmospheric method ( ) . dynamic elastance of chest wall (edyn,cw) and lung (edyn,l) were obtained from least square linear regression method over consecutive breaths. static elastance (est,cw and est,l) were determined by classic formulas and also by taking into account aop (est,cw_aop and est,l_aop, respectively). the performance of ecw/el ratio to predict efl and ac was assessed by the area under receiver operating characteristic (aucroc) curve. results: efl was observed in patients ( %) and ac in ( %). median aop was . cmh o ( % ci . - . ) . aucrocs for ecw/el ratios to detect efl and ac are shown in table . edyn,cw/edyn,l ratio was better to detect efl than est,cw/est,l ratio with edyn,cw/edyn,l ≤ . % sensitivity and % specificity. correction for aop made the performance of est,cw/est,l ratio as good as that of the edyn ratio. ac was poorly predicted by edyn and est ratios but its prediction greatly improved with aop correction. however, with the est,cw/ est,l_aop the critical ratio was . (sensitivity %, specificity %) and . (sensitivity and specificity %) for predicting efl and ac, respectively. conclusion: efl and ac are frequent in ards at peep cmh o. edyn,cw/edyn,l ratio lower than best predicted efl occurrence. once ac is taken into account est,cw/est,l ratio greater than accurately predicts ac. efl and ac are two distinct phenomena. compliance with ethics regulations: yes. rationale: anesthesia outside the operatingroom (aoor) in a pediatric environment was giving increasingly increasing indications and a lot of progress because of its interest in carrying out diagnostic and/or therapeutic explorations: % of the acts of anesthesia are performed outside the operating room. the objective of our study is: to clarify the importance and the frequency of the practice of the ahbo, to define its particularities, as well as an evaluation of the ratio: benefit/risk in order to reduce the morbidity and mortality. patients and methods: we report in this study the experience of the service of the resuscitation mother-child on the gestures of aoor. this is a prospective observational study, spread over a period of months: from / / to / / , dealing with acts performed for endoscopic digestive and bronchial procedures, cures in dermatology and radiotherapy, and medical imaging (ct and mri). results: of the procedures performed: were performed for ct, for mri, for arteriography and for endoscopic digestive procedures, for bronchoscopies, for radiotherapy treatments, for laser treatments in dermatology. anesthesia techniques use intravenous induction in % of cases using: hypnotics (propofol, midazolam, ketamine), morphine (remifentanyl, fentanyl), inhalation induction in % of cases (sevoflurane, halothane) and curare for cases of bronchoscopy (rocuronium). this anesthesia was marked by the occurrence of accidents in order of frequency: cardiac in % of cases (tachycardia, hypotension and rhythm disorders), and then respiratory in % of cases. the most serious accidents were admitted in reality and are represented by cases, of which required an intubation (bronchoscopy), a case of cardiorespiratory arrest recovered, cases of severe hypoxia associated with bradycardia and which required the ventilation with the mask (radiotherapy), and cases of bronchospasm requiring the deepening of the anesthesia (absence of tci). a good knowledge of the patient and the intervention, and difficulties specific to each specialty is necessary, as well as a preanesthetic consultation. the aoor must obey the same safety rules as in the operating theater and that in terms of: equipment, monitoring (integrate the capnograph to respiratory monitoring whenever deep sedation and when the continuous control of vas is difficult), anesthetic technique (tcbi) and post-procedure wakefulness management that must meet the same requirements as the sspi, especially for prolonged sedation. compliance with ethics regulations: yes. umbilical vein catheterization through wharton's jelly: a possibility for a fast and safe way to deliver treatments in the delivery room? suzanne borrhomée hôpital rené dubos, france correspondence: suzanne borrhomée (suzanne.borrhomee@gmail. com) ann. intensive care , (suppl ):p- rationale: a fast and safe venous access can be a critical issue in the delivery room during neonatal cardiopulmonary resuscitation, or before endotracheal intubation. here, we describe a new method to inject drugs using the umbilical vein, directly punctured through wharton's jelly. this method was performed in newborns between november and may . umbilical vein was identified and punctured easily and a reflux was obtained in all patients. the first step was antisepsis, and then the umbilical vein was punctured. the puncture was made approximately to cm above the navel. after checking for blood reflux, the nurse injected the treatment. the cannula was left in the vein during the injection and removed as soon as the intervention was over (intubation was performed, or the heart rate had increased). results: here, we report ten cases of emergency injection in the delivery room using this method: -four cases of cardiopulmonary resuscitation using this method to deliver epinephrine. cardiac massage was performed on all patients.-six cases of intubations in the delivery room using this method to administer the premedication. in all patients, the umbilical vein was identified easily. the equipment was the one usually used for venous injection in our unit and was manipulated and handled with ease. venous access was obtained in a matter of seconds, and blood reflux was observed in all patients. the treatments were efficient in all but two patients, which was imputable to the method in one patient. discussion: although this method has been known in our nicu for several years, there has been no publication regarding this method in neonates. inserting an umbilical vein catheter in the delivery room has been validated for resuscitation but this technique is lengthy and requires some sterility conditions that makes it even longer, and thus non-fitting for an emergency tracheal intubation. our method is fast and can be performed easily with no specific training. the whole manipulation procedure, from the beginning of the puncture to the end of the flush-out takes to s. we only identified few specific risks related to this method, mostly infectious, and the risk of drug diffusion. we describe a new route for administration of drugs in the delivery room that was successfully used in nine neonates. umbilical vein needle catheterization is not only safe and efficient, but is also fast and easy to perform without any special training. compliance with ethics regulations: yes. rationale: liver transplantation (lt) is the only option for children with end stage liver disease. recent advances in surgical procedure and immunosuppression have permitted a better patient and long term graft survival. however, acute cellular rejection remains a frequent complication occuring in to % of the cases according to different studies. it is more likely to occur during the first weeks post lt. many predictive factors of acute rejection have been described in litterature and results differ from one study to another. pediatric studies regarding this topic are few. the aim of this work is to study acute cellular rejection prevalence in the days following lt and to determine predictive factors. rationale: sedation practices for pediatric magnetic resonance imaging (mri) are highly heterogenous. the main challenge is to keep children immobile while being alone in a traumatizing environment for a long time. clinicians have to ensure hemodynamic and respiratory stability in this isolated environment while minimizing sedation neurologic adverse effects. in this series, we report the potential usefulness, feasibility, efficacy and safety of dexmedetomidine sedation for pediatric mri. patients and methods: a single center retrospective review of six children sedated with dexmedetomidine for mri in an emergency context. all children were hospitalized in the pediatric intensive care unit of a university hospital at the time of mri. results: data on six patients aged months to years is reported. five patients received dexmedetomidine by intravenous route (bolus of - µg/kg over min, followed by a continuous infusion of µg/ kg/h). one child received dexmedetomidine by intranasal route ( µg/ kg with atomization device). one child experienced bradycardia that did not require any intervention. very few movements were recorded during the mris for which images were rated as good quality. conclusion: dexmedetomidine seems a promisingly useful sedation agent for pediatric mri, thanks to its efficient sedative properties and good tolerability without respiratory compromise. compliance with ethics regulations: yes. rationale: computational models, or virtual patients, could be used to teach cardiorespiratory physiology and ventilation, determine optimal ventilation management as well as forecast the effect of various ventilatory support strategies. currently, there is no virtual patient specifically designed for modelling children cardiorespiratory system. thus, our research team has developed a cardiorespiratory simulator for children called "simulresp©". according to summers et al., the quality of a physiologic model is evaluated by three specific criteria: qualitatively, which relates to the model's ability to provide directionally appropriate predictions; quantitatively in steady states and in dynamics, which is the ability of the model to provide accurate predictions in steady state situations as well as dynamic transitions. the purpose of this study was to evaluate the quality ofsimulresp© according to these criteria. this study consisted in a prospective evaluation of the simulresp©'s predictions with simulated healthy subjects. the tests were performed with patients from to years old ( , , , , , years), with different characteristics; gender (m, f) and weight ( th, th and th percentile). blood gas values (ph, pco , po and spo ) were simulated for several virtual healthy patients with different characteristics. this study was conducted for both spontaneously breathing and mechanically ventilated patients. simulresp©'s quality and reliability were evaluated in terms of accuracy, robustness, repeatability and reproducibility. results: simulresp©'s validation procedures are ongoing. we intend simulresp© to be accurate when simulating healthy spontaneously breathing patients. but we hypothezised that simulresp© would not be able to simulate accurate blood gas values of mechanically ventilated patients conclusion: simulresp© is a promising computational model that will serve to perform calibration and validation procedures of clinical decision support systems and help clinican to determine optimal respiratory support strategies at bedside. further calibration procedures are yet required. compliance with ethics regulations: yes. the isthmic surgical tracheostomy, which was performed in the operating room by otolaryngologist under general anesthesia. the cutaneous incision was transversal in all cases.the choice of the cannula was adapted to the age, and the decanulation was carried out according to the evolution of the underlying disease. complications associated with tracheotomy are diverse, and common complications are such as careassociated pneumonia ( . %), tracheostomy tube obstruction ( . %), accidental decannulation ( . %), pneumothorax ( . %) and cases of tracheal stenosis ( . %). the mortality rate amounted to . %, where in most cases was due to the poor prognosis of the underlying diseases. the main factors of evolution are the patient's previous condition, cranial trauma, guillain-barré syndrome, tracheostomy time, prolonged tracheal intubation and the presence of complications. conclusion: regardless of the indication, the tracheotomy is an act of survival whose usefulness and effectiveness are certain. rationale: aspiration pneumonia (ap) is a frequently suspected complication of drug overdose requiring mechanical ventilation (mv) and admission to intensive care unit (icu). in the absence of reliable biomarkers for distinguishing between aspiration pneumonia and aspiration pneumonitis, antibiotic therapy is frequently prescribed. latest studies suggest that a care protocol could better select patients requiring antibiotic therapy. the objective was to determine the impact of a care protocol on the antibiotic prescription among patient admitted to icu for toxic coma with mv. we conducted a prospective observational cohort study in four icu. we included all patients admitted for toxic coma with mv. in the university-affiliated icu, a care protocol was applied. in the three others icu, physicians declared that they did not follow formalized conduct within the service and did as usual. results: we included patients in care protocol group and in control group. the mean saps ii was . (± . ) with a mean glasgow coma scale score at . (± . ) before intubation. within the total population, patients ( %) had a pulmonary bacteriologic sample (pbs), mostly because purulent tracheobronchial aspirate and new infiltrates on the chest x-ray (respectively . % and . % of the population with a bacteriological sample). among the patients with a bacteriological sample, ( %) were culture positive. the incidence of probabilistic antibiotherapy did not differ between the care protocol group (n = ) and the control group (n = ) . there was no difference for the incidence of pbs ( in each group). the others secondary outcomes did not differ either (table ) . conclusion: our study does not show that a care protocol allows a reduction of antibiotic prescription among patient admitted to icu for toxic coma with mv. our incidence of antibiotic prescription is lower than the previous studies. the absence of difference can be explain by two reasons: some of the physicians of the control group had been trained in the university-affiliated icu in the last years and may follow a management approach similar to that of the control group; despite our precautions, the existence of the study could have modify the practices in the control group. compliance with ethics regulations: yes. rationale: pancreatic surgery is associated with high morbidity, mostly due to infectious complications, so that many centers introduce post-operative antibiotics for all patients. such systematic prescriptions are not consensual and often rely on local practices. the aims of the study were to describe the occurrence of surgical site infection (ssi) and the antibiotic (atb) prescription after pancreatic surgery, and to determine the risk factors of post-operative surgical site infection, in order to better define the clinical indications for the prescription of antibiotics after major pancreatic surgery. patients and methods: all patients undergoing a scheduled major pancreatic surgery from january to november were included in the study. patients were classified in four groups according to the occurrence of a surgical site infection and to the post-operative antibiotic prescription as follows (ssi+/atb+; ssi-/atb+; ssi+/atb-, ssi-/ atb-). in addition, risk factors (fever and pre-operative biliary prosthesis) associated with the occurrence of a surgical site infection and with the antibiotic prescription, were analyzed using a logistic regression model. results: data from patients ( pancreaticoduodenectomies and splenopancreatectomies) were analyzed and classified as presented in the table. thirty patients ( . %) experienced a surgical site infection and ( . %) received post-operative antibiotics. we did not find any difference on post-operative antibiotic prescriptions ( . % versus . %, p = . ) between patients who developed a surgical site infection and those who did not. amongst the patients who were not prescribed antibiotics post-operatively, ( . %) did not develop a surgical site infection while ( . %) did. in-icu mortality did not differ between infected and non-infected patients ( versus %, p = . ). post-operative fever was different between ssi+ and ssi-( . versus . %, p < . ), while the prevalence of pre-operative biliary prosthesis was similar ( . versus . %, p = . ). amongst patients who did not develop a surgical site infection, antibiotic prescription was not associated with fever (p = ), but associated with a higher prevalence of preoperative biliary prosthesis ( . versus . %, p = . ). conclusion: non-systematic antibiotic prescription after major pancreatic surgery allowed to appropriately spare antibiotics in ( %) patients at the cost of under prescription in ( . %) patients. these results suggest that systematic post-operative antibiotic prescription could be excessive. fever appears to be a relevant clinical sign for individual-based prescription, whereas the presence of a biliary prosthesis does not. compliance with ethics regulations: yes. ( , ) . however, there is little evidence to support those recommendations ( ) . we aimed to describe care paths of pm with sepsis in french hospitals and to assess outcomes depending on their hospital trajectory. we conducted a retrospective analysis of the french medico administrative (pmsi) database of consecutive patients with pm and sepsis admitted to french hospitals, between and . only the first hospital admission was considered. cases were identified using a combination of a diagnosis code for pm plus a diagnosis code for organ failure or a procedure code for organ support. hospital trajectories were determined from the first admission to death or discharge, taking into account all potential transfers. costs and endpoints were determined at the end of patients' trajectories. five groups of patients were defined, according to care pathways: direct icu admission ( sticu); secondary icu admission, after initial admission to another unit including wards (ward ndicu) rationale: new-onset atrial fibrillation (af) is a common complication in patients with sepsis and is associated with increased mortality and morbidity rates. this condition results from a complex chain of events in response to infection, involving immunologic, humoral and cellular process and sympathetic overactivity. landiolol, the new injectable beta-blocker, with high beta selectivity and minimal impact on arterial blood pressure, may have beneficial effects in such a context. in this study, we aimed to investigate whether landiolol decrease the newonset of atrial fibrillation in a mice model of endotoxin-induced sepsis. patients and methods: thirty c bl/ male mice were randomly allocated to the following groups: sham (administration of µl of isotonic saline intraperitoneally-ip), septic (administration of µl of isotonic saline with mg/kg of lipopolysaccharide-lps-of e. coli o :b ip) and septic + landiolol (administration of isotonic saline with mg/kg of lps and, two hours later mg/kg of landiolol ip). four hours later, an attempt of af occurrence was triggered by a transesophageal electric pacing at fixed rate (as previously reported) in all mice previously anesthetized by isoflurane %. ekg was continuously recorded. results: ten mice per group (mean weight: ± g) have been included and analyzed. among the sham group the mean heart rate was at bpm versus bpm in the septic group. among the septic + landiolol group the mean heart rate was at bpm (p < , ). after transesophageal stimulation, none mice in the sham group had af, seven mice ( %) in the septic group had an af, and mice ( %) in the septic + landiolol group had an af. landiolol decreased the incidence of new-onset, sepsis-induced atrial fibrillation in mice (p = . ). conclusion: landiolol seems to have a protective effect against sepsis-induced af in mice. however, the mechanisms, including sympathetic activation and inflammasome pathways, should be investigated before drawn definitive conclusion regarding to efficiency of landiolol to prevent new-onset af during sepsis. compliance with ethics regulations: yes. - mg/l at or h, proportion of patients with a vancomycin serum concentration < mg/l, previously associated with resistance emergence and assessment of mortality and test of cure. results: a serum vancomycin concentration between - mg/l was reported in out of included patients ( %). a serum vancomycin concentration < ml/l and > mg/l were reported in patients ( %) and patients ( %), respectively. vancomycin serum concentrations during follow-up are shown in fig. . in multivariate regression analysis, a longer time between admission and initiation of vancomycin was the only parameter associated with a serum vancomycin out of this target, while acute kidney injury (aki) was associated with a lower incidence of subtherapeutic concentration. acute kidney injury rate was significantly higher in patients with a serum vancomycin concentration > mg/l. discussion: an adequate therapeutic target of serum vancomycin concentration was reached in % patients with nearly % < mg/l, which was similar to previous studies. aki and rrt requirement were higher in patients with serum vancomycin concentration > mg/l, whereas it is hardly to know whether it is a cause or a consequence. conclusion: these findings highlight the importance of a larger loading dose, vancomycin monitoring and measured creatinin clearance to improve vancomycin dosing protocol. compliance with ethics regulations: yes. rationale: suicide is a global phenomenon and one of the leading causes of death in the world. tunisia ranks second in the suicide rate in the maghreb, with . cases of suicide per , inhabitants. the aim of this study was to reconstruct the state of suicidal subjects before the act in order to identify their psychiatric profile. patients and methods: a -year prospective observational singlecenter ( -bed intensive care unit) study including all patients hospitalized for suicide attempt (sa). psychiatric evaluation of patients and contact with their families were done before intensive care unit discharge. results: seventy-one patients were enrolled with female predominance (sex ratio . ). mean age was ± years. familial or personal history of mental illness were found in ( %) and cases ( %) respectively. personal mental disorders were depression ( %), bipolar disorder ( %), schizophrenia ( %) and border line personality disorder ( %). twenty-five per cent had prior sa. sixty-three per cent were single, % married and % divorced. the common methods of suicide included drug ( %), chloralose ( %) and pesticide ( %) poisoning. mean igs ii and apache ii scores were ± and ± respectively. on admission, % of all patients were in coma, % had shock and % developed aspiration pneumonia. mechanically ventilation was done in % of all cases with mean duration of days. the mean length of stay in intensive care unit was days. mortality rate was %. psychiatric evaluation and contact with families deduced that the main precipitating factors for suicide were traumatic events. in fact: relationship problems (familial, marital or breakups), school failure and mourning were found in %, % and % of all cases respectively. reactional sa accounted for %. rationale: poisoning is a worldwide problem, associated with high morbidity and moratlity. in tunisia, the rate of fatal poisoning has been increasing in the last years, with emergence of new toxic substances. regardless of the toxic, fatal poisining is considered as a non natural death, that requires medico-legal investigation, to assess whether it is suicidial, crimnal or accidental death. this study aimes to determine the epidemiological characteristics of the cases of fatal poisoning in south, to identify the toxics used in oder to deduce the preventive measures. patients and methods: we conducted a retrospective study of all cases of fatal poisoning recorded in the forensic department of habib bourguiba university hospital in sfax, tunisia, over a -years period ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . results: during the study period, cases of fatal poisoning were autopsied. the number of victims recorded per year varied between and cases with an average of cases per year. the average age was years with extrems ranging from months to years. nearly half ( . %) were younger than years. a male predominance was noted with a sex-ratio of . . the majority of victims were single, loweducated and from rural origin. personal antecedent of psychiatric pathology was found in . % of cases. psychotic disorders (schizophrenia) and depression were the most common pathologies. in our study we noticed that death occured every weekday without significant difference between days. however, the frequency of fatal poisoning was slightly higher in cold seassons ( . %). in . % of cases, victims were found dead at home. accidental fatal poisoning was the most common ( %). no criminal cases have been observed. we noted a male predominance in accidental forms and a female predominance in suicidal forms. carbon monoxide poisoning was the most common ( cases) followed by the organophosphorus poisoning which was noted in cases. conclusion: decreasing the mortality rate from poison ingestion requires increasing public awareness about poisons and improving emergency service equipment and health personnel training. compliance with ethics regulations: yes. severe acute poisoning by organophosphate pesticides: report of cases at the oran hospital and university center mourad goulmane hospital and university center of oran, oran, algeria correspondence: mourad goulmane (goulmane.mourad@univ-oran . dz) ann.intensive care , (suppl ):p- rationale: organophosphate pesticides are synthetic organic pesticides widely used in agriculture mainly as an insecticide, nemacid or acaricide. these are the agricultural products, the most incriminated in poisoning in our context. the objective of this work was to determine the clinical, paraclinical, and progressive characteristics of this poisoning in a resuscitation environment. patients and methods: retrospective study of cases admitted to intensive care (january -december ). inclusion criteria were clinical, para-clinical, therapeutic and progressive. results: cases were identified: women and men, mean age = . ± years. the suicide attempt was the main reason for the intoxication ( cases). the glasgow coma score averaged ± . the central syndrome was present in % of our patients, followed by muscarinic syndrome % and nicotinic syndrome in % of cases. therapeutic management consisted of mechanical ventilation in % of cases, the use of vasoactive drugs in % of cases and the administration of antidotal treatment in % of cases. the overall mortality was . %. conclusion: organophosphate pesticides intoxication is a real health problem in algeria. it is a serious condition dominated by the respiratory and neurological distress that causes most deaths. it concerns in our context especially young women who ingest the product for the purpose of autolysis. the diagnosis is based on the clinical and dosage of cholinesterase activity in the plasma. treatment combines symptomatic measures that rely primarily on respiratory and neurological resuscitation to antidotal treatment. the clinical course in this type of intoxication is generally favorable under treatment with regression of signs in a few days. mortality is high in our context, so it should be considered a diagnostic and therapeutic emergency. the commercial availability of these products is worrisome, justifying the use of a broad prevention program to inform the public and authorities of the danger of organophosphate pesticides compliance with ethics regulations: not applicable. . the clinical examination revealed that five patients met the criteria for serious intoxication with the following signs: coma in four patients requiring the use of mechanical ventilation, seizures (n = ), rhabdomyolysis (n = ), shock (n = ), toxic takotsubo (n = ) and hepatocellular failure (n = ) leading to patient's death. the use of mechanical ventilation was necessary in patients. the analysis of the severity factors did not show a statistically significant association between severity, age (p = . ), sex (p = ) and chronic consumption of psychoactive substances (p = . ). on the other hand, we did not find a statistically significant association between serious intoxication, the number of tablets ingested (p = . ), the apacheii score (p = . ) and the average length of stay (p = . ). conclusion: ecstasy acute poisoning is becoming more common in our country and can potentially be very serious regardless of age, sex, medical history or number of tablets ingested. on the other hand, the concentration of nmda could be the only factor to be taken into consideration upon admission. compliance with ethics regulations: yes. quarter of early trauma-related mortality, in some series. early identification of poor outcome predictors could be valuable to guide the most appropriate care. we aim to determine factors associated to mortality in patients with severe non-penetrating chest trauma admitted to the icu. patients and methods: this is a prospective cohort study, including all patients with isolated severe blunt chest trauma (abbreviated injury scale ais > ) admitted to the intensive care unit of a university hospital, over a one-year period. the primary objective was to analyse risk factors associated to death and poor outcome using univariate and multivariate analysis. results: one hundred-thirty patients were admitted to the icu for blunt chest trauma among them were diagnosed with severe isolated chest trauma and were included. the mean age was at ± , mean iss at ± and mean tts at ± . twenty-eight ( %) patients were diagnosed with acute respiratory distress syndrome, ( %) with post-traumatic acute kidney injury and fourteen ( %) with post-traumatic pulmonary embolism. the mean length of icu stay (los) was at ± days and mean number of days on ventilator was at ± days. thirty-two ( %) patients underwent elective tracheostomy for prolonged intubation. thirty-seven patients ( %) developed infections, among them thirty ( %) were diagnosed with pulmonary infection and seven ( %) with non-thoracic infections. overall mortality had an incidence of . % ( patients rationale: early hyperglycaemia in traumatic brain injury (tbi) is a part of the stress response. it is an important indicator of severity and a reliable predictor of prognosis. we aimed to describe the epidemiological, clinical and paraclinical characteristics and to assess the prognostic impact of this hyperglycaemia on the tbi. we conducted a retrospective study in the intensive care unit (icu) of our hospital between and . were included all patients with tbi and blood glucose > mmol/l at the first h post-trauma. results: during the study period, patients were hospitalized in our icu with tbi. early hyperglycemia (> mmol / l) was found in patients ( . %). in univariate analysis, glycaemia > . mmol/l (= mg/dl) at admission was significantly associated with mortality (p = . ). we observed that glycaemia > . mmol/l at h , > . mmol/l at h , > . mmol/l at h and > . mmol/l at h was significantly associated with mortality (p = . ; p < . ; p = . and p = . , respectively). the risk factors significantly associated with mortality were age > years (p < . ), saps ii > (p < . ), initial shock (p < . ), glasgow coma scale (gcs) < / (p < . ), coma period > days (p = . ). the ct scan lesions statistically associated with mortality were: subdural hematoma (p < . ), cerebral oedema (p < . ), intra cerebral haemorrhage (p = . ), cortical contusion (p = . ), contusion of cerebral trunk (p = . ), contusion of the corpus callosum (p = . ), thalamus contusion (p = . ). in multivariate analysis, independent risk factors statistically associated with mortality were age > years old (or = . ic [ . - . ]; (p = . )), glycaemia > . mmol/l at admission (or = . ic [ . - . ]; (p = . )),gcs < / (or = . ic [ . - . ]; p < . ), intracerebral hematoma (or = . ic [ . - . ]; p = . ). we recommend a mandatory control of the blood glucose levels during a tbi with a target between . and . mmol/l in the acute phase. compliance with ethics regulations: not applicable. the fat embolism syndrome (fes) is a set of clinical, biological and radiological signs resulting in the obstruction of microcirculation by micro-droplets of insoluble fats.the clinical signs of the fes are not very specific, the diagnosis is difficult and the risk of misunderstanding this syndrome is very real.the fes appears after a trauma, often few days later. however, it sometimes occurs without previous trauma; and it is particularly difficult to recognize in these cases. the aim of this work is to define the epidemiological profile, the clinical and para-clinical features of this syndrome and its therapeutic management. rationale: sedative and analgesic treatment administered to critically ill patients with mechanical ventilation need to beregularly assessed to ovoid complications of oversedation mainly in elderly patients. our objective is to evaluate our sedation practice in the elderlyin our unit patients and methods: it was a prospective observational study, including elderly patients over years of age without acute brain injury requiring sedation more than h of hospitalization in the intensive care unit of our university hospital between april and december . thirty patients were included. the aged was . years, the sex ratio was . . respiratory distress was the most common reason for hospitalization %. the most accepted diagnoses were the decompensation of copd in % of cases and septic shock in % of cases. the saps ii averaged ± points, sofa averaged ± . points. renal failure was found in patients ( %), hepatic impairment was noted in patients ( %), hypoproteinemia was marked in patients ( %). midazolam was used in % of patients. it was in combination with fentanyl in % of cases and remifentanyl in % of cases. the median ramsay score . ± . on the first day of sedation and . ± . on the second day of sedation. the median rass scale was − . ± . on the first day of sedation and − . ± . on the second day of sedation. the median bps scale . ± . on the first day of sedation and . ± . on the second day of sedation. the mean wake up time was ± , days. neuromyopathy of resuscitation was suspected in seven patients ( %), withdrawal syndrome was observed in two patients ( %) and acute cognitive dysfunction in two patients ( %). the median duration of sedation was . days ± . days, the median duration of mechanical ventilation was . ± . days, the median length of stay was . ± . days. ventilator-associated pneumonia was diagnosis among % of patients. the mortality in intensive care was %. conclusion: sedation analgesia in the elderly person should be adapted according to age, ideal weight and renal and hepatic function by decreasing the initial doses. it should be evaluated by the recommended scores by setting a sedation objective according to the pathology. compliance with ethics regulations: not applicable. rationale: more than original articles are newly indexed in pub-med every day. journal club (jc) is one way to cope with this abyssal amount of medical information. we aimed at ( ) describing journals and articles analyzed during our jc sessions ( ), reporting the proportion of published articles being analyzed during jc sessions and ( ) assessing the clinical impact on our daily practices for each journal. patients and methods: a retrospective analysis of prospectively collected data over a -year period from to in a universityaffiliated icu. jc sessions were scheduled weekly and participants were free to choose and expose orally an article recently published in any medical journal (general, icu or non-icu specialized). clinical impact of a journal was retrospectively and independently assessed by two attending intensivists (dc, hm) and was defined by the ratio of articles considered as having a direct impact on our daily practices over the number of articles of the same journal read during the same period. results: from august to august , jc sessions were held and articles-mostly original (n = / ; %)-from journals were analyzed, accounting for . % of the articles ( . % of the original articles) referenced in pubmed during the same period. median number of articles exposed per session was [ ] [ ] [ ] [ ] . median number of doctors attending each session was [ ] [ ] [ ] (attendings: [ ] [ ] , fellows: [ ] [ ] , residents: [ ] [ ] ). general, icu and non-icu specialized journals accounted for %, % and % of the exposed articles, respectively. most of the reported articles dealt with intensive care (n = , %) especially infectious diseases (n = / ; %), hemodynamics (n = / ; %) or icu-organization (n = / ; %). compared to general and non-icu specialized journals, the proportion of read-over-published articles was higher for icu-specialized journals ( . % vs. . % vs. . %, respectively; p < . ). among original articles, only ( . %) [interventional (n = / ; %); observational (n = / ; %) studies] were considered as having a clinical impact on our daily practices. compared to icu and non-icu specialized journals, general journals had a higher clinical impact ( . % vs. . % vs. . %, respectively; p = . ). data regarding the most read general, icu and non-icu specialized journals are detailed in table . in a french university-affiliated icu with regular jc sessions, the proportion of read-over-published articles and the clinical impact of medical journals appear minor. in the ocean of medical literature, general medical journals appear more worth reading by intensivists than icu-specialized journals. compliance with ethics regulations: yes. rationale: the world's population is aging and the and over's age group is growing fast (+ . % per year). this aging population is impacting intensive care units with exponential rates of elderly patients ( . % in , % in ) , associated with significant mortality (from % to %). the evolution and the prognostic factors of these elderly patients in intensive care are therefore a public health issue for optimal management. patients and methods: we included all patients aged and over who were operated and admitted to surgical resuscitation in our center, with a duration of stay greater than h, from april to july . the data collected were: general characteristics of this population, mortality in intensive care, at day and at months and the prognostic factors guiding their evolution in intensive care and at months. results: of the patients included in our study, mortality was . % in intensive care, . % at day and . % at months. the prognostic factors in the intensive care unit were the average dose of noradrenaline at day (threshold at . mg/h), the sofa score at day (threshold at points) and the igs score (threshold at points). the prognostic factors at months were ventilatory autonomy on day (spontaneous ventilation, non-invasive ventilation, invasive ventilation), the reason for admission to intensive care (acute respiratory distress or septic shock) and the fragility score (clinical failure scale with a threshold at ). conclusion: the mortality of patients aged and over is influenced by prognostic factors easily obtained daily at patient's bed. these prognostic factors could be an aid for the resuscitation teams to evaluate the relevance of the care undertaken in elderly or even very elderly patients admitted in an acute situation. compliance with ethics regulations: not applicable. assessing patient safety culture perception in the intensive care unit in tunisia oussama jaoued, chaoueh sabrina, sik ali habiba, wael chemli, gharbi rim, fekih hassen mohamed, elatrous souheil hôpital taher sfar, mahdia, tunisia correspondence: oussama jaoued (oussamajaoued@gmail.com) ann. intensive care , (suppl ):p- rationale: in tunisia health care system, patient safety has become a priority of quality assessment. the aim of our study was to describe the safety culture perception of the intensive care unit staff. patients and methods: the safety attitude questionnaire (saq-icu) was distributed to all intensive care unit staff by email. the questionnaire explores safety culture domains: "team work", "safety climate", "job satisfaction", "stress recognition", "perception of the hospital and intensive care unit management" and "work condition". results: eighty participants responded to the questionnaire, % of them were women. participants were doctors in . %. the coordination between physicians and nurses was very good only in %. thirtynine participants thought that the workload was high and % like their work. medical errors are handled appropriately in % of cases and it was difficult to discuss errors in % of cases. the hospital is a good place to work in % of participants, % of participants were less effective at work when there were tired. the hospital did a good effort of training new personal in % of cases. the number of medical staff was lower than expected in % of cases. half of participants would feel safe being treated as patients in their respective units. all domains explored by saq-icu could be improved according to attendants. conclusion: safety culture perception among intensive care unit staff had several deficiencies, mainly the working conditions, the ignorance of medical error reporting procedures and the lack of communication. rationale: the simplified acute physiology score ii (saps ii) is an icu scoring system used to predict the mortality risk in patients presenting at the icu. however the majority of critically ill patients present initially at the ed and their transfer to the icu may be delayed for hours. therefore, the ability to accurately assess mortality risk at ed may have a great impact. the purpose of this study was to evaluate the performance of saps ii in predicting early and late mortality in ed patients. patients and methods: this prospective study was conducted at the ed during a -month period. data for adult ed patients were evaluated. saps ii score was used to predict early and late mortality rates at -h and -day respectively. discrimination was evaluated by calculating the area under the receiver operating characteristic curve (auroc). results: during the study period patients were enrolled. the mean age was ± years, % of the patients were men. the mean saps ii was . the early mortality rate was % and late mortality rate was %. saps ii was efficient in predicting early mortality, with an auroc of . ( % ci . - . ). however, it demonstrated no value in predicting late mortality with an auroc of . ( % ci . - . ) conclusion: in this study, saps ii score was accurate in predicting early mortality, however this tool appears less suitable for predicting late mortality. compliance with ethics regulations: yes. oussama jaoued, chaoueh sabrina, sik ali habiba, yosri ben ali, fekih hassen mohamed, elatrous souheil hôpital taher sfar, mahdia, tunisia correspondence: oussama jaoued (oussamajaoued@gmail.com) ann. intensive care , (suppl ):p- rationale: the aging of the population increased the number of hospitalizations in icu. the aim of our study was to determine the impact of hospitalization of patients over the age of on morbi-mortality and consumption of care (omega score). patients and methods: this is a retrospective study carried out in the icu in the hospital of taher sfar in mahdia over a period of years. all patients hospitalized in the icu were included in this study. two groups of patients were individualized: g : patients over years old, g : patients under years old. results: during the study period, patients ( < years old and ≥ years old) with a mean age ± years and with a mean sapsii ± were included. the common reason for hospitalization was acute respiratory failure in % of cases. comparing the two groups, the severity score sapsii was higher among patients older than years ( ± vs ± , p < . ). the use of mechanical ventilation was more common in the first group ( % vs. %, p < . ). the incidence of nosocomial infections was similar in both groups ( % in the group g and % in group g , p = . ) and the use of renal replacement therapy was also similar in tow groups ( % in the g group and % in the g group, p = . ). the duration of mechanical ventilation and length of stay were similar between the two groups. workload evaluated by the omega score was higher in the first group ( rationale: icu outcome depends on quality of pre-icu care. we aimed to assess the chain of care of deteriorating ward patients (dwp), through evaluation of preadmission severity and delays before admission, and association with outcome. patients and methods: retrospective observational study in a single center ( beds general hospital) for year-may th of to . all adult patients admitted in the icu from the wards were included, except for scheduled surgery, or unexpected event in the operative theater. preadmission severity was assessed through levels of national early warning score (news ): group with news inferior to , group with news between and , and group with news superior to . these scores were established from vital signs during the h before icu admission. patterns of patients, including sofa and saps , knaus index, charlson comorbidity score, cause of admission and technics used in the icu, length of stay in the icu and in the hospital, limitations of life-supporting care, and mortality at and days after icu stay. satistical analysis was performed through chi and fisher tests on qualitative parameters, and with kruskal-wallis, student and mann-whitney tests for quantitave data. results: sixty-eight patients were studied: in group , in group and in group . most patients (all except ) had not respiratory rate monitoring before icu admission. icu mortality was associated with rising preadmission severity (group : . %; group : . %; group : . %). base patterns (charlson comorbidity score, knaus index) did not differ between the groups, and . % of patients presented with sepsis. main causes of admission were respiratory ( . %), hemodynamic ( %) or neurologic ( . %) failures. all patients admitted after cardiac arrest resuscitation ( patients) belonged to group . acute severity scores (sofa and saps ) followed preadmission severity. limitation or withdrawing of life support in the icu was higher in group ( . %) than in groups ( %) and ( . %) . median delay between first news equal or superior to and icu admission was h, and h between news equal or superior to . diffrences in delays were not associated with outcome. discussion: our study outlines weaknesses in the chain of care of dwp. emphasis should be put on respiratory rate monitoring and better assessment of severity. rationale: access to critical care is controversial in older patients for reasons: lack of available icu-beds and speculation on induced costs. in contrast, admission of young patients aged or under is infrequently questioned even though they develop catastrophic multiple-organ failure requiring full care. in addition, emotive reaction triggered in staff by these patients often represents a heavy psychological burden when icu-stay is < h. information on the epidemiology, clinical information and induced costs regarding such patients is lacking. patients and methods: this study retrospectively assessed the records of patients aged or under, and admitted from january to august . cost-related expenses charged to care-payers were obtained from our medical information department. data (number, percentages or medians) were reported and discussed by comparison with those of nonagenarians during the same period. results: of , icu-admissions, were aged or under ( %), of whom ( . %) died within the icu, with ( %) dying within h of admission despite full intensive care. the latter represent our study population ( . % of the screened population). the median age was . years , male gender was prevalent ( %). half the patients (n = , %) were referred from the emergency department, ( . %) from hematology, from oncology ( . %), from medical intermediate care units ( . %), and one from digestive surgery ( . %). the first diagnosis at admission was septic shock (n = , . %), followed by post-anoxic encephalopathy (n = , . %), coma (n = , . %), acute respiratory failure (n = , . %) and cardiogenic shock (n = , . %). sapsii was . all patients were ventilated and infused norepinephrine. two patients underwent ecmo, and others mars. mean (± sem) retribution per stay was , ± €, and mean retribution per "day of stay" €. discussion: full care of these icu-patients, with early mortality has a financial impact similar to that of nonagenarians at , ± , €; the cost per "day of stay" is therefore on average % higher than that of nonagerians (mean length of stay: . days), and, in our experience, % higher than that of average patients. conclusion: icu-patients aged or under represent a small percentage of admissions and display half our overall mortality: one third of them die within h of admission with a not insignificant financial impact for cost-payers. septic shock is the first cause of referral, followed by unexpected cardiac arrest. compliance with ethics regulations: yes. rationale: severity scores in patients with sepsis are useful for triaging and predicting mortality. mortality in emergency department sepsis (meds) score is validated in patients with sepsis in the emergency department. curb- is validated in patients with communityacquired pneumonia but not in sepsis. curb- is a simple bedside tool that has many common elements with new sepsis identification score-q sofa. the study aimed to assess the accuracy of curb- score in predicting icu admittance and mortality compared to meds score. patients and methods: this prospective study was conducted at the ed during a -month period. we enrolled all adult patients with sepsis admitted to the ed. meds and the curb- scores were calculated at admission. patients were studied using curb- score and their icu admission and in-hospital mortality were ascertained. results: a total of patients were enrolled. the mean age was ± years. % of the patients were men. % of patients had a curb- score ≥ points with a mean meds score of %. among these patients, % were admitted to icu and % died. the curb- score,was efficient in predicting both icu admittance and in-hospital mortality with an auroc of . ( % ci . - . ) and . ( % ci . - . ), respectively. conclusion: a higher curb- score was correlated with higher rates of icu admittance and mortality in patients with sepsis due to any cause. compliance with ethics regulations: yes. abderrahim achouri, hadil mhadhbi, khedija zaouche, hamida maghraoui, radhia boubaker, kamel majed university hospital center rabta of tunis, tunis, tunisia correspondence: abderrahim achouri (achouryabderrahim@gmail. com) ann. intensive care , (suppl ):p- rationale: sepsis is a major cause of mortality. in other hand, preexistent chronic diseases seem to worsen outcomes among critically ill patients. the acknowledgement of this fact may motivate studies in this type of situations in order to improve survival in sepsis. on that purpose, our study tried to check the impact of chronic pre-existent illnesses on outcomes in this type of emergency patients. patients and methods: we have included patients in whom the sepsis- definition was met throughout emergency department admission cases for infection. in this study, considered outcomes were in-hospital mortality, shock occurence and the use of mechanical ventilation. results: we collected patients admitted to ed for sepsis. mean age was years ± with bornes of and . men were % of the patients. cormorbidities were: insulin dependent diabetes mellitus in . % of patients, non insulin dependent diabetes mellitus in . %, chronic obstructive lung disease in . %, chronic renal failure in . % with % in chronic replacement therapy from total patients, coronary artery disease in . %, with stent in . % and . % with aortic coronary graft from total patients, arterial hypertension in %, chronic heart failure in . %, atrial fibrillation in . %,. death occurs in . % of total patients, septic shock in % and the use of mechanical ventilation in . %. we did not find any association between comorbidity and the use of mechanical ventilation, but association with in-hospital mortality was found in pre-existent coronary artery disease (p = . ) and in patients with coronary artery stent (p = . ). odds ratio (or) was respectively . ( % ic = [ . - . ]) and . ( % ic = [ . - . ] ). we found significant association between chronic heart failure and shock (p = . ) with or = . ( % ic = [ . - . ] ). discussion: the small size of our sample may enlimit the contibution of other comorbidities on outcomes in sepsis such chronic renal failure, especially with renal replacement therapy and diabetes mellitus. whereas, we can conclude that cardiac diseases have the most important impact on outcomes in sepsis. outcomes in sepsis can be affected by comorbidities, especially cardiac diseases. therefore, that needs large studies to check it. compliance with ethics regulations: yes. micafungin population pk analysis in critically ill patients receiving continuous veno-venous hemofiltration or continuous veno-venous hemodiafiltration nicolas garbez , litaty mbatchi , steven c. wallis , laurent muller , jeffrey lipman , jason a. roberts , jean-yves lefrant , claire roger chu nîmes, nîmes, france; university of queensland, brisbane, australia correspondence: nicolas garbez (nicolas.garbez@umontpellier.fr) ann. intensive care , (suppl ):p- rationale: to compare the population pharmacokinetics (pk) of micafungin in critically ill patients receiving continuous veno-venous hemofiltration (cvvh, ml/kg/h) to those receiving equidoses of hemodiafiltration (cvvhdf, ml/kg/h + ml/kg/h). critically ill patients in septic shock undergoing continuous renal replacement therapy (crrt) and receiving mg micafungin once daily were eligible for inclusion. total micafungin plasma concentrations were analyzed using pmetrics ® . probability of target attainment (pta) was calculated from monte carlo simulations using -hour area under curve/minimum inhibitory concentration (auc - /mic) cut-offs (c. parapsilosis), (all candida species) and (c. non parapsilosis). daily dosing regimens of , and mg were simulated for the first days of treatment. results: eight patients were included in the study. micafungin concentrations were best described by a two-compartmental pk model. no covariate, including crrt modality (cvvh and cvvhdf), was retained in the final model, confirmed by internal validation. the mean parameter estimates (standarddeviation) were . ( . ) l/h for clearance, . ( . ) l for the volume of the central compartment, . ( . ) /h and . ( . ) /h for rate constants. the standard mg daily dosing was unable to reach % of pta for all candida species except c. albicans on the second day of therapy (fig. ) . conclusion: there was no difference in micafungin pk between equidoses of cvvh and cvvhdf. a dose escalation to mg is suggested to achieve the pk/pd target of candida species with mics exceeding . mg/l in this population. these "off-label" dosing regimens should be further investigated in clinical trials knowing the favourable toxicity profile and the post-antifungal effect of micafungin in order to ensure efficacy and to prevent the emergence of resistance due to an inadequate initial antifungal dosing regimen. compliance with ethics regulations: yes. rationale: sepsis is an important cause of morbidity and mortality in hospitalized patients. recognizing and responding to patients who experience clinical deterioration remains challenging in daily practice. our purpose was to assess the ability of the quick sequential organ failure assessment (qsofa) score to identify, among patients reviewed by an intensivist, those at risk of adverse outcomes. patients and methods: retrospective cohort of patients with suspected infection reviewed by an intensivist in a university-affiliated hospital between january and june . outcomes of interest were hospital mortality and a combined criterion of hospital mortality or icu stay of days or more. results: during the study period, patients were reviewed by an intensivist, of whom ( . %) had suspected infection according to the sepsis- criteria. at the time of review, ( . %) patients with suspected infection were qsofa positive (≥ ) and ( . %) were qsofa negative ( - ). following the review, ( . %) patients were admitted to the icu, among whom ( . %) had a prolonged stay (≥ days). in-hospital mortality was . %, and . % of the patients met the combined criterion of in-hospital mortality or prolonged icu stay. qsofa positive patients required more frequently mechanical ventilation ( . % vs. . %, p = . ) and vasopressor support ( . % vs. . %, p < . ) than qsofa negative patients. moreover, qsofa positive patients had higher hospital mortality than qsofa negative patients ( . % vs. . %, p = . ). for the prediction of in-hospital mortality, a positive qsofa had a predictive positive value (ppv) of %, and a negative predictive value (npv) of %. for the prediction of in-hospital mortality or prolonged icu stay, a positive qsofa had a ppv of % and a npv of %. conclusion: hospitalized patients with suspected infection for whom a review by an intensivist was requested, are at high risk of hospital mortality. although the accuracy of qsofa for identifying patients at risk of adverse outcomes is limited, its integration in a multimodal risk assessment approach may help distinguish the subset of patients who will benefit from an escalation of care. compliance with ethicsregulations: yes. rationale: according to the sepsis- consensus, sepsis is identified as an increase of at least points in the sepsis-related organ failure assessment (sofa) score in patients who presented infection. the quick sofa or qsofa is considered as a predictive tool of sepsis and mortality when it is equal to points or more. systemic inflammatory response syndrome (sirs) criteria are of limited utility because of their low sensitivity. hyperlactatemia, as known is a determinant of tissue hypoperfusion. our objective was to evaluate the prognostic value of sofa > , sirs > , qsofa > and lactate level > mmol/l in infected patients. nine-month prospective cohort study. patients aged years or older who had a proven or suspected infection were included. sofa score, sris criteria, sofa q and lactate levels were determined within the first h of infection. the primary endpoint was hospital mortality at days. the predictive power of the studied parameters was determined using using the area under the receiver operating characteristic curve (auroc). results: a cohort of cases was studied with mean age at . years. bacterial pneumonia was the most common infection site ( %). in the first h of onset of infection the medians [iqr - ] of the sofa, sris, and sofa scores and lactate levels were respectively [ ] [ ] [ ] [ ] [ ] [ ] [ ] , [ ] [ ] , [ - ] and . [ . - . ] . the progression to severe septic status was observed in patients ( %) and norepinephrine was introduced in cases. median length of stay was days [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and mortality was %. overall, the accuracy in predicting mortality of the studied parameters was poor. an increase of sofa score by at least points had greater accuracy with auroc = . [ . - . ], sensitivity = % and specificity = %. conclusion: in infected patients, the sofa score had greater prognostic accuracy than the sirs criteria, the qsofa score or the lactate level. these results suggest that sirs, qsofa, and high lactate level may be useful in screening for sepsis, but this utility is limited in predicting mortality. compliance with ethics regulations: yes. rationale: quick sequential organ failure assessement (qsofa) has been validated for patients with presumed sepsis and others in general emergency department (ed) population. however, it has not been validated in specific subgroups of patients with a high mortality. the aim of this study is to evaluate the ability of qscore to predict prognosis in patients with decompensated liver cirrhosis. patients and methods: this is a retrospective study, conducted over a period of years from january to december . consecutive patients with decompensated cirrhosis, admitted in our department are included. data of all patients were collected and the qsofa score was calculated at admission. the main study endpoints were length of stay, complications and in-hospital mortality. results: a total of patients diagnosed with decompensated cirrhosis were enrolled. mean of age was years ( - ). sex ratio was . . hcv ( %) was the main etiology of cirrhosis. the reasons of hospitalization were: oedema with ascitic syndrome in % of cases, digestive haemorrhage ( % of cases), fevers ( % of cases), and hepatic encephalopathy was present in % of cases. the mean duration of stay was days ± . in-hospital mortality rate was % and mean score qsofa was . .the qsofa score was significantly correlated with length of stay (p = . ) and complications(p = . ) but not with in-hospital mortality (p = . ). conclusion: the qsofa score was not useful for predicting in hospital mortality in patients with decompensated liver cirrhosis but it was significantly correlated to the length of stay and complications. compliance with ethics regulations: yes. angioedema associated with thrombolysis for ischemic stroke: analysis of a case-control study clara vigneron , aldéric lécluse , thomas ronzière , sonia alamowitch , olivier fain , nicolas javaud médecine interne, centre de référence associé sur les angioedèmes à kinines (créak), hôpital saint-antoine, aphp, paris, france; neurologie, chu angers, angers, france; neurologie, chu pontchaillou, rennes, france; neurologie, hôpital saint-antoine, aphp, paris, france; urgences, centre de référence associé sur les angioedèmes à kinines (créak), hôpital louis mourier, aphp, colombes, france correspondence: clara vigneron (claravigneron@hotmail.fr) ann. intensive care , (suppl ):p- rationale: bradykinin-mediated angioedema is a complication associated with thrombolysis for acute ischemic stroke. risk factors are unknow and management is discussed. the aim of this study was to clarify risk factors associated with bradykinin-mediated angioedema after thrombolysis for acute ischemic stroke. patients and methods: in a case-control study conducted at a french reference center for bradykinin angioedema, patients with thrombolysis for acute ischemic stroke and a diagnosis of bradykinin-mediated angioedema, were compared to controls treated with thrombolysis treatment without angioedema. two matched control subjects were analyzed for each case. results: thrombolysis-related angioedema were matched to control subjects. the sites of attacks following thrombolysis for ischemic stroke mainly included tongue ( / , %) and lips ( / , %). the upper airways were involved in ( %) cases. three patients required mechanical ventilation. patients with bradykinin-mediated angioedema were more frequently women ( ( %) vs. ( %); p = . ), had higher frequency of prior ischemic stroke ( ( %) vs ( %); p = . ), hypertension ( ( %) vs. ( %); p = . ), were more frequently treated with angiotensinconverting enzyme inhibitor ( ( %) vs. ( %); p < . ) and were more frequently hospitalized in intensive care unit ( ( %) vs. ( %); p = . ). in multivariate analysis, factors associated with thrombolysisrelated angioedema were female sex (odds ratio [or], . ; % confident interval [ci], . - . ; p = . ) and treatment with angiotensin-converting enzyme inhibitors ([or], . ; % [ci], . - . ; p < . ). discussion: because of theretrospective case-control design and the lack of the total number of thrombolysis for ischemic stroke, the incidence of this complication could not be evaluated in our study. previous studies reported an incidence of . to . % of angioedema in patients treated with a thrombolytic therapy for acute ischemic stroke. our case-control study permits for the first time to analyse more cases to evaluate associated risk factors of this rare complication. conclusion: this case-control study points out angiotensin-converting enzyme inhibitors and female sex as risk factors of bradykininangioedema associated with thrombolysis for ischemic stroke. compliance with ethics regulations: yes. rationale: patients with inflammatory bowel disease (ibd), frequently treated by immunosuppressive drugs, are more susceptible to be admitted to the intensive care unit (icu). however, outcome and predictive factors of mortality are little known. therefore, we aimed to assess the outcome and prognostic factors for critically ill ibd patients. patients and methods: we retrospectively studied data of consecutive ibd (i.e. crohn's disease and ulcerative colitis) patients admitted in icus between and . in-icu and one-year mortalities were estimated and predictive factors of in-icu mortality were identified by univariate and multivariate analysis. results: seventy-six patients (male: %, median age: . [ . - . ] years, charlson index: [ . - . ]) entered the study. ibd type was largely represented by crohn's disease ( . %) and its localization was mostly extensive: l ( . % of crohn's disease) or e ( % of ulcerative colitis) according to the montreal classification. twenty-seven patients ( . %) were treated with corticosteroids and ( %) with immunosuppressive therapy (azathioprine: . % and anti-tnfα: %). reasons for admission were shock/sepsis ( . %) and acute respiratory failure ( . %). icu diagnoses were infection ( %), ibd flare-up ( . %) or both ( . %), and pulmonary embolism ( . %). at admission, sofa score was [ . - . ] and . fifty-three patients ( . %) required mechanical ventilation, ( . %) vasoactive drugs, and ( . %) renal replacement therapy. twenty-three patients underwent emergency surgery ( . %) and six urgent endoscopic treatment ( . %). in-icu and one-year mortality rate were . % and . %, respectively. prognostic factors of in-icu mortality were sofa score (hr . , % ci [ . - . ], p < . ) and azathioprine treatment before icu admission (hr . , % ci [ . - . ], p < . ) (fig. ) . previous immunosuppressive treatment with anti-tnf did not alter the prognosis and even the type of ibd. conclusion: our study showed that more than % of ibd critically ill patients were discharged alive from the icu and a majority of them survived after one-year ( . %). we also found that sofa score and previous azathioprine immunosuppressive treatment worsened icu outcome. higher severity of the acute event affected short-term prognosis and should be taken into account for best icu triage and management. intensivists should pay particular attention to patients treated by azathioprine. compliance with ethics regulations: yes. fig. outcome of ibd patients admitted to the icu according to precious treatment with azathioprine status all aps patients with any new thrombotic manifestation(s) admitted to icus. results: one hundred and thirty-four patients (male/female ratio: . ; mean age at admission: . ± . years), who experienced caps episodes, required icu admission. the numbers of definite, probable or no-caps episodes (fig. ) , respectively, were: ( . %), ( . %) and ( . %). no histopathological proof of microvascular thrombosis was the most frequent reason for not being classified as definite caps. overall, / ( . %) episodes were fatal, with comparable rates for definite/probable caps and no caps ( % vs. . % respectively, p = . ). the kaplan-meier curve of estimated probability of survival showed no between-group survival difference (log-rank test p = . ). discussion: our results suggest that the caps criteria do not sufficiently encompass all the parameters responsible for thrombotic aps patients' disease severity in the icu. the absence of items referring to organ dysfunction/failure in the caps criteria probably limited their ability to predict mortality. albeit useful for the retrospective classification and comparison of patients, the caps criteria may be too stringent and not yet ready-to-use for the management of icu patients. for physicians outside expert aps centres, the absence of caps criteria could be misleading and lead to rejection of the diagnosis for near-caps patients, thereby preventing them from receiving the appropriate aggressive treatment they indeed require. we think that, when confronted with a critically-ill thrombotic aps patient, caps criteria should be interpreted with caution and should not be the only elements taken into account to decide the intensity of the therapeutic management. rationale: % of resuscitation patients develop anemia during their stay, it can worsen the prognosis, prolong the length of stay and lead to transfusions that can be the cause of complications. the objective of our work is to specify the incidence of anemia in our unit, its etiologies and its therapeutic management. patients and methods: we conducted a descriptive and analytical retrospective study within the surgical emergency resuscitation department of ibn rochd university hospital of casablanca, over a period of years from to . we included all anemic patients. statistical analysis was performed with spss statistics . p < . was considered significant. results: we included patients with an estimated incidence of %, the average age was years, the sex ratio h / f was . . % of admissions were for traumatic pathology and % postoperative digestive surgery. % had hypotension at admission and the mean temperature was . % .the onset of anemia and its depth were related to length of stay with . % of patients who were anemic beyond the th day of hospitalization with a hemoglobin level that became < . g / dl beyond the th day. % of the patients had a normochromic normocytic anemia becoming microcytic with the lengthening of the duration of stay. ferritinemia dosed in % of patients and was normal. % of our patients had exclusive parenteral nutrition while % had an enteral / parenteral combination. % were transfused in red blood cells (rbc) and % of patients were transfused more than once. % received between and rbc units. in patients who received transfusion episodes costing euros, the transfusion was inappropriate. the total cost of the transfusion was estimated at around , euros. % were supplemented with oral iron with an increase in hemoglobin in % of them. % of the patients came out of the intensive care unit with a hemoglobin level < g/dl/l. the mortality rate of our patients was % with as predictive factors in multivariate analysis, hyperthermia, coagulopathy, the transfusion appears as a factor of good prognosis. the prevention of blood spoliation and the fight against inflammation and nosocomial infection remain the pillars of the management of anemia in intensive care but in view of our results and the protective role of transfusion it would be interesting to see again the transfusion thresholds in our context. compliance with ethics regulations: yes. (fig. ). discussion: we described a series of patients with severe acute viral myopericarditises associated with anti-rnapol autoantibodies, an association that has never been reported previously. the fortuitous association of these autoantibodies with acute myopericarditis is highly unlikely. acute myocarditis is a very rare disease with a reported incidence of / , inhabitants. anti-rnapol -antibody detection is also very rare: . % positive tests (including the patients in this series) out of samples during a -year period in our immunology laboratory. this % proportion of patients with proven influenza-virus infections suggest that such severe infections could trigger anti-rnapol autoantibody production. however, influenza is a common disease and anti-rnapol autoantibodies are very rare. furthermore, no anti-rnapol autoantibodies were detected in the patients with severe influenza-related ards. last, anti-rnapol autoantibodies remained detectable several months after the viral infection had been cured. conclusion: this previously unknown association between severe acute viral myopericarditis and anti-rnapol autoantibodies is probably not fortuitous. anti-rnapol antibody detection in acute myopericarditis patients could imply individual susceptibility to severe viral infection. further studies are needed to investigate the pathophysiological mechanisms involved in this entity and potential specific therapeutic strategies. fig. relative frequencies of digestive manifestations in critically ill tma patients rationale: arrhythmia-induced cardiomyopathy has been recognized for several decades, but most severe forms, i.e. cardiogenic shock and refractory cardiogenic shock requiring mechanical circulatory support, were rarely described in adults. in this retrospective study, we described patients admitted in our tertiary care center for non-ischemic acute cardiac dysfunction (or worsening of previously known cardiac dysfunction) and recent onset supraventricular arrhythmia who developed cardiogenic shock requiring veno-arterial ecmo (va-ecmo). results: in a years period, patients had va-ecmo for acute non ischemic cardiac dysfunction and recent onset supraventricular arrhythmia (table ). fourteen ( %) patients had known nonischemic cardiomyopathy and ( %) known paroxystic atrial fibrillation. cardiogenic shock was the first manifestation of the disease in patients. atrial fibrillation was the main cause of arrythmia ( % of cases). at ecmo implantation, sofa score was [ - ], inotropic score , lvef % [ - ] and lactate level was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] mmol/l. twelve patients had sustained successful reduction after amiodarone and/or electric shock, all were weaned from ecmo and survived without transplantation nor long term assist device. among the patients with failure of reduction, underwent an atrio-ventricular ablation while on ecmo and had atrial tachycardia ablation; all were weaned from ecmo and survived. among the remaining patients without reduction and without ablation procedure, only the patients who were bridged to heart transplantation or left ventricular assist device survived. in univariate analysis, factors associated with unfavorable outcome were previously known heart disease, heart rate, renal replacement therapy, nt-probnp level, failure of rhythm reduction after amiodarone load and/or electric shock. among the patients who recovered and survived ( with successful reduction and with successful ablation), lvef increased from [ - ]% before ecmo implantation to [ - ]% at long term follow-up. discussion: this is the largest cohort of arrhythmia induced cardiomyopathies on va-ecmo and the first description of atrio-ventricular node ablation with favorable outcome in this setting. conclusion: arrhythmia induced cardiomyopathy is probably underrecognized and should be considered in any patient with nonischemic acute cardiac dysfunction and recent onset supraventricular arrhythmia. recovery is possible in the most severely ill patients on va-ecmo, even with severe left ventricular dilation. aggressive rate control by av-node ablation may be warranted in case of failure of reduction, and may allow recovery and favorable outcome. compliance with ethics regulations: yes. rationale: diagnosis of sepsis is a major challenge in intensive care units and is associated with a high morbidity and mortality. sepsis identification is even more difficult in patients with extracorporeal membrane oxygenation (ecmo) because of many confounding factors. the primary objective was to study the ability of c-reactive protein (crp) and procalcitonin (pct) values measured at ecmo support initiation (day ) to predict the occurrence of early sepsis in patients undergoing venoarterial ecmo (va-ecmo) or venovenous ecmo (vv-ecmo). the secondary objectives were to study the association between these biomarkers and mortality rate during ecmo support and in-hospital mortality rate. furthermore, we investigated the relationship between early sepsis and mortality. patients and methods: we performed a retrospective, monocentric study in the cardiovascular intensive care unit of the university hospitals of lille, france. between november , and december , , we included patients over years old, who underwent an ecmo support for a medical or surgical indication, and for whom biomarkers (crp and pct) levels were available for at least the first days of admission. biomarkers and blood cultures were daily assessed for the first ecmo support days. early sepsis was defined by sepsis diagnosis in the first days after circulatory assistance initiation. in-hospital mortality rate was censored at days. after univariate analysis, a cox multivariate regression model was used to assess if the association between biomarkers levels and early sepsis or mortality rate was independent. a kaplan-meier survival plot was used to describe the association between early sepsis and mortality. results: among patients included, underwent va-ecmo and underwent vv-ecmo. an early sepsis diagnosis was made in . % of va-ecmo patients and in % of vv-ecmo patients. pct and crp levels on day were significantly associated with early sepsis diagnosis (fig. rationale: fluids are one of the most prescribed drug in intensive care, particularly among patient with circulatory failure. yet, very little is known about their pharmacodynamic properties and this topic has been left largely unexplored. several factors may impact the haemodynamic efficacy of fluids among which the infusion rate. the aim of this study was to investigate the influence of the rate of fluid administration on the fluid pharmacodynamics, in particular by studying mean systemic pressure (pms). we conducted a prospective observational study in patients with septic shock to compare two volume expansion strategies. a fluid bolus, ml of normal saline were administered and several haemodynamic variables were recorded continuously: cardiac output (co), arterial pressure (ap), mean systemic pressure (pms, estimated from ci, pvc and map). infusion rate was left at the discretion of the attending physician. a "slow" and a "fast" groups were determined based on the median of the infusion duration. fluids effect was measured by the area under the curve (auc), maximal effect (emax) and time to maximal effect (tmax) for each haemodynamic variable. the effects of fluid on psm disappeared in one hour on average. compared to patients of the "slow" group, those of the "fast" group had a shorter tmax and a higher emax for pms (p = . and . respectively). the auc for pms was identical between group, while in case of similar effect of infusion rates, it should be larger in the "slow" group. regarding co, tmax was also shorter in the "fast" than in the "slow" group (p = . ). the decreasing slope from maximal effect was comparable between groups, for pms as for co. the effect of a ml fluid bolus with normal saline in septic shock patients vanished within one hour. a faster infusion rate increased the maximal and total effect of the fluid bolus and shortened the delay to reach the maximal effect. rationale: significant hypotension following spinal anesthesia is a common issue in everyday clinical practice. toavoid this potentially harming situation, an empirical fluid administration is usually performed before the procedure. inferior vena cava (ivc) ultrasound has been demonstrated effective in guiding fluid therapy in critical care patients. the purpose of this study was to evaluate the ivc ultrasound guided volemic status optimization in order to decrease post-spinal hypotension rate. patients and methods: in this prospective, controlled, randomised study, consecutive patients were recruited and patients were randomly assigned to a control group, consisting of pre-anesthesia empirical fluid administration (itt), an ivc ultrasound group in which fluid management was based on an ivc ultrasound evaluation, and a passive leg raising test (plrt) group in which volume optimization was performed following the above mentioned test. primary outcome was the hypotension rate reduction after spinal anaesthesia following fluid optimization therapy between the groups. secondary outcomes were the total fluid amount administered, the total vasoactive drug amount used and the time needed to realize the whole anaesthetic procedure in all three groups. results: % reduction in hypotension rate ( % ci - %, p = . ) was observed between the echocardiography group and the control group, and there was a reduction of hypotension rate by % (ci % - %, p = . ) between the echocardiography group and the plrt group. the total fluid amount administered was significantly greater in the ultrasound group than in the control group ( ml; sd ml, versus ml; sd ml, p = . ). the total amine consumption was % in control group, % in ivc group and % in plrt group. an increased of total study time was observed for the echocardiography group min (sd min) in comparison with the control group min (sd min) and ptlr group min (sd min), (p < . ). the study showed a faint but positive trend toward the use of ivc-ultrasound to identify patients in spontaneous breathing needing fluid optimization before spinal anesthesia compliance with ethics regulations: yes. rationale: we performed a systematic review and a meta-analysis of studies investigating the ability of the end-expiratory occlusion (eexpo) test to predict preload responsiveness, through the changes in cardiac output (co) or its surrogates, in adult patients. this meta-analysis was prospectively registered on prospero (crd- ). we screened pubmed, embase and cochrane database to identify all original articles published between and evaluating the ability of the eexpo test to predict a significant increase in co or surrogate, compared to the one induced by a subsequent volume expansion or by passive leg raising (plr). the meta-analysis determined the pooled area under the receiver operating characteristics curve (auroc) of eexpo testinduced changes in co to detect preload responsiveness, as well as pooled sensitivity and specificity and the best diagnostic threshold. subgroup analysis and sensitivity analysis were planned to investigate potential sources of heterogeneity. results: thirteen studies ( patients) were identified and included in the analysis. nine studies were performed in the intensive care unit and four in the operating room. preload responsiveness was defined according to co changes induced by fluid administration in studies (fluid-induced increase in co ≥ % or ≥ %) and according to co changes induced by plr in one study. the duration of the respiratory hold ranged between and s. for the eexpo test-induced changes in co, the pooled sensitivity and specificity were [ - ]% and [ - ]%, respectively, while the pooled auroc curve was . ± . (fig. ) . the corresponding best diagnostic threshold was . ± . %. when changes in co were monitored through pulse contour analysis compared to other methods the accuracy of the test was significantly higher ( ( ). continuing (decrease to % of peak level) or modification (decrease < %) of antibiotic therapy was guided by a serum pct assay from the third day of treatmentand every h until antibiotic was stopped. this last was stopped when pct levels had decreased of % from the initial value. results: a total of patients had been diagnosed as sepsis (n = , %) and septic shoc (n = , %). mean age was years ± . an average ubs and absi score of % and . the average length of stay in icu was days. patients were assigned into two groups: group a (favorable evolution, n = ); group b (unfavorable evolution, n = ). the therapeutic attitude according to the kinetics of the pct are presented in the table . we found a significant difference between patients with unfavorable evolution compared to those with a favorable evolution (in whom we stopped antibiotics) (p < . ), in terms of hemodynamic state, pct concentration and renal clearance. pctguided antibiotic treatment has been proven to significantly reduce length of antibiotic therapy in our patients. the average duration of antibiotic was . ± days. conclusion: pct measurement may help with the decision to initiate antibiotic therapy in low risk acuity of infection and allows more judicious antibiotic use by reducing antibiotic exposure. compliance with ethics regulations: not applicable. rationale: reducing the risk of severe hypoxemia during endotracheal-intubation (eti) is a major concern in intensive care unit but little attention was paid to co variations during this period. we conducted a prospective observational study to describe transcutaneous co (ptcco ) throughout intubation in patients who received preoxygenation with standardoxygen therapy (sot), non-invasive ventilation (niv), or high flow nasal cannula oxygen therapy (hfncot). patients and methods: patients over years undergoing eti in icu were continuously monitored for ptcco during intubation and the following h under mechanical ventilation (mv). haemodynamics and respiratory parameters were also recorded as well as arterial partial pressure of co (paco ) to evaluate reliability of the transcutaneous measure. results: two hundred and two patients were included in the study. we found a strong correlation between ptcco recorded at preoxygenation and the last paco available before intubation (r = . , p < . ). in % of patients ptcco values recorded at initiation of mv were out of - mmhg ranges. ptcco recorded at eti, at initiation of mv, min and h of mv were significantly higher than ptcco during preoxygenation (p < . by anova). variations of ptcco were significantly different according to the preoxygenation method (p < . for interaction in anova). lastly, a decrease in ptcco higher than mmhg within half an hour after the beginning of mv was independently associated with postintubation hypotension (pih) (odds ratio = . , % confident interval . - . , p = . ). conclusion: ptcco is a valuable tool to record paco variation in patients requiring invasive mechanical ventilation and could be useful to prevent pih. compliance with ethics regulations: yes. rationale: intubation in intensive care unit (icu) is a critical procedure which leads to serious adverse event in to % of cases. several recent trials were conducted to help physicians to choose medications, devices and modality of intubation. especially, videolaryngoscope (vl) led to several publications in the last few years, with increasing tools marketed and spread use (difficult airway management, routineintubation). we designed an online survey to take a picture of intubation process and devices availability in france. toolbox. it was positioned as a first line laryngoscope for every intubation in critically ill patients to reinforce the vl skill training. present study was performed using prospectively collected data from a continuous quality improvement database about airway management in a -beds french teaching hospital medical icu. all consecutive intubation procedure performed with vl from september to june were included. "first attempt success" group and "first attempt failure" group were compared by univariate and multivariate analysis in order to analyze the first attempt intubation success rate according to the level of operators' expertise, identify factors associated with first pass intubation failure and describe the intubation related complications. results: we enrolled consecutive endotracheal intubations. overall first attempt success rate was ( %). comorbidities, junior operator, the presence of cardiac arrest and coma were associated with a lower first attempt success rate. the first attempt success rate was less than % in novice operators ( - previous experiences with vl, independently of airway expertise with direct laryngoscopies) and % in expert operators (greater than previous experiences with vl) (fig. rationale: tracheostomy in intensive care unit (icu) has many advantages. but only patient comfort and shorter icu and hospital stay were demonstrated. the timing of this procedure is still debated. the aim of this study was to determine the impact of early tracheostomy on prognosis. we performed a retrospective study in a medical icu ( beds unit) from january to november . the technique of tracheostomy was exclusively surgical in the operating room made by the surgeon. the primary endpoint was mortality in icu. the secondary outcomes were post-tracheostomy incidence of ventilator acquired pneumonia, duration of mechanical ventilation and length of stay in icu. these criteria were assessed in relation to timing of the tracheostomy defined as early when performed before day of mechanical ventilation. results: forty-two patients were enrolled during the study period. mean age of patients was ± years. median length of stay in icu was of days. mortality rate was of %. comparing the two groups, early vs late tracheostomy, no difference was found with respect to mortality ( % vs. %, p = . ), vap occurrence ( % vs. %, p = . ), post-tracheostomy duration of mechanical ventilation ( ± d vs. ± d, p = . ), or length of stay in icu ( ± d vs. ± d, p = . ). in multivariate analysis, the only factor independently related to mortality was the sofa score patient on tracheostomy day with p = . and or = . (ci % [ . - . ] ). conclusion: tracheostomy in the intensive care unit remains a justified alternative despite the discordant data in the literature. in our study, the delay of the procedure didn't interfere with the evolution. however, the patient severity as attested by sofa score at the day of tracheostomy, was the only independent prognostic factor. those results should be confirmed by other large prospective studies. compliance with ethics regulations: not applicable. sabah benhamza, mohamed lazraq, youssef miloudi, abdelhak bensaid, najib el harrar réanimation de l'hôpital du août, casablanca, morocco correspondence: sabah benhamza (benhamzasabah @gmail.com) ann. intensive care , (suppl ):p- rationale: many unknowns remain as to the place of tracheostomy in intensive care. reluctance to perform a tracheotomy is numerous, especially when pre-exists chronic respiratory failure, but some data suggest benefits. we report in this work our experience in tracheotomy in the intensive care unit of the august hospital, casablanca. patients and methods: this is a retrospective descreptive study over years (january to january ) including all patients that have been tracheostomized in the intensive care unit of the august hospital . results: during the study period, patients were tracheostomized with a prevalence of . % in years, the predominance was male (sex ratio . ). the average age was ± years old. the indication for tracheostomy was prolonged ventilation in % of cases, extubation failure in % of cases, and intubation failure in % of cases. tracheostomy was performed on average on the th day of intubation. all patients were tracheostomized in the operating room by ent surgeons. the main complications attributable to tracheotomy were hemorrhage of the tracheostomy orifice in patients ( %) immediately resumed, cases of subcutaneous emphysema ( %), case of pneumothorax ( %), cases of orifice infection ( %). no patient died of a tracheostomy related cause. the tracheotomy in intensive care is still a subject of debate especially concerning the time of its realization. however it seems to reduce the duration of mechanical ventilation, facilitates the care and also the ventilatory weaning. compliance with ethics regulations: yes. rationale: hfnco is a frequently used device providing heated and humidified high flow oxygen with several advantages: decreased work of breathing, decreased dead space, increased end expiratory lung volume (eelv), more stable fio . the increase in eelv is relying of the positive expiratory effect generated by the device. the level of generated pep seems however to largely depend on whether the mouth is open or not. this study was aimed to assess the impact of mouth opening on eelv increase induced by hfnco using electric impedance tomography. patients and methods: the following hfnco trial was proposed to healthy subjects who used hfnco on a regular basis for patients care. oxygen flow was set successively during min periods at , and l/min (optiflowtm; fisher & paykel healthcare, auckland, nz). these three conditions were tested in semi recumbent and supine position chosen at random. measurement started in supine position with no flow (baseline) and each period was separated from the following by a wash out period on min during which the subject could breath normally with no supplemental oxygen. electric impedance tomography (pulmovista ® , dräger medical gmbh, lündbeck, germany) was performed applying a electrodes belt placed between the th and th intercostal space, including a reference electrode located on the abdomen. as no spirometer was used, the data of eelv computed on the eit device were expressed as percentage of variation of the value measured in supine or semi recumbent position with no flow. demographic data were expressed as median and extreme values. comparisons were performed using u mann whitney test. [ . - . ] accepted to participate to the study. when subjects received hfnco with open mouth (whatever position) no modification of eelv was observed (table ) . conversely, a significant increase in eelv was noted with closed mouth, whatever position. in the semi recumbent position the increase in eelv was even more important with l/min. conclusion: electrical impedance tomography illustrates the impact of mouth closure on eelv increase among healthy subjects receiving hfnco. compliance with ethics regulations: yes. rationale: in stable copd patients, nasal high flow oxygen (nhf) use can be associated with reduction in respiratory rate (rr) and minute ventilation (mv). in thesepatients, paco remains stable or decreases under nhf. this suggests a possible dead space reduction related to a washout effect of nhf. the aim of this study was to assess the physiological effects of nhf in hypercapnic patients with acute copd exacerbation. patients and methods: crossover study in hypercapnic patients suffering from acute copd exacerbation and treated with intermittent non-invasive ventilation (niv). nhf l/min or standard oxygenotherapy (stand o ) were randomly administered during h between niv treatments. rr, tidal volumes (vt), mv and corrected mv (cormv = mv x paco / ) variations were recorded during the last min of each study period using a respiratory inductive plethysmography vest. blood gas analysis was performed at the end of each oxygen administration period. visual analogic dyspnea score (vas) quoted from to was assessed by the patient after and min. results given as median [iqr] . wilcoxon tests were used to compare data between stand o and nhf. results: twelve patients were included and data could be recorded in ( (fig. ). dyspnea scores were not different between the modalities. conclusion: in case of acute copd exacerbation, using nhf between niv treatments was associated with paco and rr decrease. mv concomitantly decreased suggesting a deadspace volume reduction related to a washout effect of nhf. corrected mv decreased in all the patients except one. these results suggest that nhf could be used to deliver oxygen between niv treatments to copd patients suffering from acute exacerbation and could contribute reducing paco . compliance with ethics regulations: yes. rationale: the role of atypical micro-organisms in acute exacerbation of chronic obstructive pulmonary disease (copd) that require mechanical ventilation is poorly none. the aim of this study was to determine the role of atypical pathogens in severe acute exacerbation of copd. patients and methods: in this prospective study we included all patients admitted for acute exacerbation of copd requiring mechanical ventilation. atypical pathogens (chlamydophila pneumoniae and mycoplasma pneumoniae) were searched by serological diagnosis and by culture of sputum samples. in this study we included patients aged ± years. sixty-eight percent of sputum culture were considered significant. six cultures were positive with different microorganisms. neither chlamydophila pneumoniae nor mycoplasma pneumoniae were found. the prevalence of chlamydophila pneumoniae was . % (positive igg serum). the demographic characteristics was similar between patients with and without positive culture. the rate of noninvasive ventilation (niv) failure was % in positive serology group versus % in negative serology group (p = . ). the mortality was similar in both groups. in multivariate logistic regression analysis only positive serology (or = . ; % ic [ . - . ], p = . ) was an independent factor of niv failure. conclusion: a positive serology of chlamydophila pneumoniae was a predictive factor of niv failure without an impact on the morbidity and mortality of copd patient treated with mechanical ventilation. compliance with ethics regulations: yes. rationale: emergency departments (ed) receive a growing up number of patients with acute exacerbation of chronic obstructive pulmonary disease (copd) .non-invasive ventilation (niv) could be a good alternative to achieve a respiratory support, avoiding as much as possible the complications of invasive ventilation. the study aimed to assess the clinical outcomes of using niv in acute exacerbation of copd at ed and to identify whether clinical variables present at admission are predictive of niv failure. we conducted a prospective study conducted at the ed over a period of one year. data of all patients admitted for acute exacerbation of copd for all causes and requiring non-invasive ventilation were collected. niv failure was defined as need for endotracheal intubation or death. results: during the study period, a total of patients with a mean age of years (± ) were included. acute exacerbation of copd was due to bronchitis in %, to pneumonia in % of cases. % of patients had no apparent etiology of acute exacerbation of copd. bilevel positive airway pressure was performed on all patients, during a mean period of h (± ). clinical niv success was observed in patients ( %). the predictors of niv failure were advanced age, tachycardia, and hypercapnia. conclusion: the efficiency of niv in the management of acute exacerbations of copd at ed is well documented. this is further supported by our study which showed a clinical success in % of patients with acute exacerbation of copd. compliance with ethics regulations: yes. rationale: non invasive ventilation (niv) is often performed in elderly patients with acute respiratory failure (arf) at emergency department (ed). this technique may be subject to many difficulties, due to the presence of frequent co-morbidities. the aim of this study was to identify the predictive factors of niv failure in elderly patients with arf at ed. patients and methods: this was a retrospective study conducted at ed on year and months including patients aged more than years and who required the use of niv for an arf. all data were collected and analyzed using the spss software. patients were divided into two groups: niv failure and niv success. niv failure was defined by inhospital mortality, requirement of intubation or hospitalization at intensive care unit. results: during the study period, a total of elderly patients that required niv for arf were included. median age was years (min = , max = ) and sex ratio was . . the median charlson index was (min = , max = ). the etiological diagnoses of arf were acute decompensation of chronic obstructive pulmonary disease ( %), acute heart failure ( %), pneumonia ( %) and pulmonary embolism ( %). the arf was hypercapnic in % of cases and nonhypercapnic in %. niv failure concerned %. predictive factors of niv failure were clinical signs of right heart dysfunction (p < . ), c reactive protein (p = . ), initial ph (p = . ) and kidney dysfunction (p < . ). conclusion: in our study, niv failure in elderly patients with arf at ed was influenced by clinical signs of right heart dysfunction, c reactive protein, initial ph and kidney dysfunction. these clinical and biological factors could be useful to identify the most critical elderly patients and to better guide therapeutic decisions. compliance with ethics regulations: yes. rationale: the interest of ecco r in the management of very severe acute asthma exacerbations is still unclear. since it could help to control respiratory acidosis and /or to limit dynamic hyperinflation, its clinical benefits are uncertain, even in mechanically ventilated patients. the rexecor observatory is a prospective ecco r cohort in the great paris area. tencases of severe asthma treated by ecco r were retrospectively reviewed. mainly, arterial blood gases (abg), duration of ecco r and imv were collected and in-icu mortality were assessed. data are reported as median (iqr). results: ten patients ( men, age: (ic: - ) years, bmi: . (ic: . - . ) kg/m , fev- : . (ic: . - . ) l, ( (ic: - ) %), saps : . (ic: . - . ) points) were included. one patient suffered from cardiac arrest before admission and one had pneumothorax at icu admission. nine patients were under imv (started on the day of admission for ). before ecco r, patients received systemic corticosteroids, paralyzing agents, epinephrine and salbutamol. two patients suffered from pneumonia. ecco r was started (ic: - . ) days after intubation. venous vascular access was achieved via the right internal jugular route in patients and via the femoral route in . the hemolung device was used in patients, the ila activve in and the prismalung in . abg before and after day of ecco r are reported in table . duration of ecco r was (ic: . - ) days and patients were weaned from imv under ecco r. for the remaining patients, duration of imv after ecco r was (ic: - . ) days. icu stay was . (ic: - . ) days. the only one niv patient was not intubated. ecco r as stopped in patients because of complications (one hemolysis, one internal bleeding and one membrane clotting). one patient died in icu after limitation of life-sustaining therapy decision. we report a preferential use of ecco r in imv patients, contrasting with a marginal use in only one niv patient to prevent intubation. the mortality rate was low, in line with previous case series of severe acute asthma with ecmo or ecco r support. more studies are needed ( ) to better delineate the pathophysiological benefits of ecco r in asthma patients and ( ) to confirm strong clinical benefits. compliance with ethics regulations: not applicable. rationale: acute exacerbations of chronic obstructive pulmonary disease (aecopd) are the most important events characterizing respiratory illness progression. their management often needs noninvasive or invasive ventilation (iv). data of literature confirm that the mortality of aecopd requiring iv is high but are discordant about prognostic factors. the aim of our study was to describe the epidemiologic and clinical features of patients admitted for aecopd requiring iv, the treatment and the evolution in intensive care unit in order to deduce the independent factors of mortality. patients and methods: a -year retrospective analytic observational single-center study including patients hospitalized for aecopd requiring iv. results: fifty-eight patients were enrolled. mean age was ± years with sex-ratio of . . eighty one percent were smokers and % were classified gold stage . history of intensive care hospitalization and prior iv were found in % and % of all cases respectively. mean apache ii score was ± . the predominant precipitating factor for aecopd was respiratory tract infection ( % of all cases). twenty two percent of all patients presented septic shock. iv was initiated on admission in % of all cases and after noninvasive ventilation failure in % of all cases. forty-eight per cent of all patients developed septic shock as evolutionary complication. mortality rate was %. in univariate analysis: male gender (p = . ), duration of respiratory disease progression (p = . ), annual exacerbations frequency (p < − ), gold stage (p = . ), prior iv (p < − ), duration of symptoms before hospitalization (p = . ), apache ii score (p = . ), ph (p = . ), shock on admission (p = . ) and septic shock as evolutionary complication (p = . ) were predictors of mortality in our study. besides; shock on admission (p = . ) and as evolutionary complication (p = . ) were the two independent prognostic factors in multivariate analysis. conclusion: vital and functional prognosis of aecopd requiring iv depends on the severity of the underlying respiratory illness, the severity of the exacerbation and the quality of an early management. this emphasizes the importance of controlling modifiable risk factors including smoking cessation, basic treatment improvement and early appropriate treatment of these exacerbations. compliance with ethics regulations: yes. medical background, biological parameters, death-rate and outcome of patients have been compared. results: in total, patients have been included in the "hlh" population. death-rate in intensive care unit was % in the "hlh" group compared to % in the "not hlh" group (p = . ). we used more extrarenal cleansing in the "hlh" group ( % vs. %, p < . ), the duration of assisted ventilation was longer ( . days vs. . days, p < . ), as well as the duration of extrarenal cleansing ( . days vs. . days, p < . ) and those of amines ( . days vs. . days, p = . ). the average time of hospitalization was significantly longer in the "hlh" group ( . days vs. . days, p < . ). the secondary hlh to sepsis in intensive care unit, not well known and understudied, seems to have a different profile and a more serious outcome but no change in death-ratehas been found considering the pairing with the sofa. further studies are needed to plan a better therapeutic strategy within this population. compliance with ethics regulations: not applicable. serum and peritoneal exudate concentrations after high doses of ß-lactams in critically ill patients with severe intra-abdominal infections: an observational prospective study lisa leon, philippe guerci, elise pape, nathalie thilly, amandine luc, adeline germain, anne-lise butin-druoton, marie-reine losser, julien birckener, julien scala bertola, emmanuel novy chru nancy, vandoeuvre les nancy, france correspondence: lisa leon (lisaleon @gmail.com) ann. intensive care , (suppl ):p- rationale: critically ill patients with severe intra-abdominal infections (iais) requiring urgent surgery may undergo several pharmacokinetic alterations that can lead to ß-lactam under dosage. the aim of this study is to measure serum and peritoneal exudate concentrations of ß-lactams after high doses and optimal administration schemes. patients and methods: this observational prospective study included critically ill patients with suspicion of iai who required surgery and a ß-lactam antibiotic as empirical therapy. serum and peritoneal exudate concentrations were measured during surgery and after a h steady-state period. the pharmacokinetic/pharmacodynamic (pk/ pd) target was to obtain ß-lactam concentrations of % ƒt> x mic (minimum inhibitory concentration) based on a worst-case scenario (highest ecoff value) before bacterial documentation (a priori) and redefined on the mic of the isolated bacteria (a posteriori). results: forty-eight patients were included with a median [iqr] age of [ - ] and a saps ii score of . septic shock occurred in % of cases. the main diagnosis was secondary nosocomial peritonitis. piperacillin/tazobactam was the most administered ß-lactam antibiotic ( %). prior to bacterial documentation, patients ( . %) achieved the a priori pk/pd target. iai was documented in patients ( %). enterobacteriaceae were the most isolated bacteria. based on the mic (n = ) of isolated bacteria, % of the patients achieved the pk/pd target ( % ƒt> xmic). in the fig. we presented serum ß-lactams pk/pd target attainment and observed total concentrations of piperacillin-tazobactam at each timepoint in serum and peritoneal exudate. in critically ill patients with severe iais, high doses of ß-lactams ensured % ƒt> xmic in % of critically ill patients with severe iais within the first h. a personalized ß-lactam therapeutic scheme with a pk/pd target based on local ecology should be warranted. compliance with ethics regulations: yes. rationale: intensive care unit acquired bloodstream infections (icu-bsi) are frequent, and associated with high morbidity and mortality rates. the objective of our study was to describe the epidemiology and the prognosis of icu-bsi in our icu (cayenne general hospital). secondary objectives were to search for factors associated to icu-bsi caused by esbl-pe, and those associated with mortality at days. patients and methods: we retrospectively studied icu-bsi in the medical-surgical intensive care unit of the cayenne general hospital, during months (january to june ). we assessed survival at days from the diagnosis of icu-bsi. results: icu-bsi was diagnosed in . % of admissions giving a density incidence of . icu-bsi/ days. the median delay to the first rationale: necrotizing soft tissue infections (nsti) are a heterogenous group of severe infections. among them, group a streptococcal (gas) infection represent a subgroup that could benefit from specific therapies targeting the toxinic pathway, such as intravenous immunoglobulins or clindamycin. nevertheless, previous trials evaluating these treatments suffered from a low rate of gas infection among the study population. early identification of patients at high risk of gas infection would allow for assessing targeted treatment strategies. patients and methods: we conducted a secondary analysis of a previously published cohort of patients admitted to our tertiary center for surgically proven nsti between and . admission characteristics and microbiological documentation based on surgical samples, blood cultures or subcutaneous puncture were recorded. we compared patients with a documented gas infection to all other patients regarding admission characteristics. a generalized linear regression model was used to identify admission characteristics associated with a subsequent documentation of gas infection. results: among patients, ( %) had a gas infection, which was monomicrobial in ( %) cases. admission characteristics associated with gas infections by univariate analysis were nsaid treatment before admission ( ( . %) for gas infections vs ( . %) for others, p = . ) and leukocytosis as a continuous variable ( , /mm [ , - , ] vs. , [ - , ], p = . ). those inversely correlated with gas infections were immunodeficiency ( ( %) vs. ( . %), p = . ), and an abdominoperineal topography ( ( . %) vs. ( . %), p > . ). after multivariate analysis only immunodeficiency (or = . [ . - . ], p = . ) and an abdominoperineal infection (or = . [ . - . ], p = . ) remained associated with the absence of gas infection. using these criteria allowed for identifying subgroups of patients with increased likelihood of gas infections: from % overall (n = ) to % for non-abdominoperineal infections (n = ), % for patients without immunodeficiency (n = ) and % for both non abdominoperineal infections in patients without immunodeficiency (n = ). a sensitivity analysis for monomicrobial gas infections yielded similar results with the addition of younger age and non-nosocomial infections as predictors. conclusion: upon admission, the absence of immunodeficiency and of an abdominoperineal infection in nsti patients were covariables associated with gas infection. compliance with ethics regulations: yes. rationale: sickle-cell disease is the most common genetic disorder in the world. a complication of this disease is the acute chest syndrome (acs) which is associated with a high risk of death. respiratory tract infections are often mixed up and the introduction of betalactam antibiotics is recommended. glomerular hyperfiltration is common and responsible of a high risk of underdosing. this study compares cefotaxim continuous infusion to intermittent bolus in adult patients with acs. patients and methods: this observational retrospective monocentric study included acs admitted in intensive care unit and treated by cefotaxim with at least one plasmatic dosing between may and august . results: thirty patients received bolus administration while the others received continuous infusion. we observed patients ( %) and patients ( %) with a cefotaxim trough level ≥ mg/l in the bolus and continuous group, respectively (p < . ). the median residual concentration was mg/l [ - ] and . mg/l [ . - . ] in the bolus and continuous group, respectively (p < . ). there was no toxic effect induced by overdosing of cefotaxim. conclusion: compared to intermittent bolus infusion, continuous cefotaxim administration maximizes the pharmacokinetics parameters by obtaining a plasmatic concentration times above the minimal inhibitory concentration of usual germs associated with acs. continuous infusion of time-dependant antibiotics seems to decrease the risk of underdosing in patients with sickle cell disease. compliance with ethics regulations: not applicable. (n = , %), followed by esophageal varices rupture (n = , %), ulcer bleeding (n = , %) and diverticular hemorrhage (n = , %). infectious diseases were diagnosed in three patients ( %), including one clostridium colitis, one erosive gastritis with helicobacter pylori and one esophageal candidiasis. conclusion: gib is associated with a high mortality rate in immunocompromised patients, especially in patients with hematological malignancies. specific malignant lesions were the main etiology and may be difficult to treat. comparison with critically ill non-immunocompromised patients with gib will help physicians to provide specific therapeutic strategies in this population. compliance with ethics regulations: yes. risk factors for delayed defecation and impact on outcome in critically ill patients: a multicenter prospective non-interventional study benoît painvin ,* , arnaud gacouin , antoine roquilly , claire dahyot-fizelier , sigsimond lasocki , chloe rousseau , denis frasca , philippe seguin anesthésie-réanimation/chu rennes, rennes, france; réanimation médicale/chu rennes, rennes, france; réanimation chirurgicale/ chu nantes, nantes, france; réanimation chirurgicale/chu poitiers, poitiers, france; anesthésie-réanimation/chu angers, angers, france; centre investigation clinique/chu rennes, rennes, france; anesthésie-réanimation/chu poitiers, poitiers, france; réanimation chirurgicale/chu rennes, rennes, france correspondence: benoît painvin (painvinbe@gmail.com) ann. intensive care , (suppl ):p- rationale: delayed defecation is very common in intensive care units (icu) and it increases length of mechanical ventilation (mv), icu length of stay (los) and possibly mortality. the objective of this prospective multicenter study was to determine risks factors for constipation in icu and to evaluate their impact on mortality. patients and methods: it was a prospective multicenter non-interventional trial performed in university icus in france from january to october . all patients ≥ years old who had an expected los of days and mechanically ventilated for at least days were eligible. defecation was defined as the time of the first stool passage. results: patients were included in the analysis. a stool passage was observed in % of the patients during their icu stay with a mean delay of ± days. in multivariate analysis, risk factors for delayed passage of stool were non-invasive ventilation use and time spent under invasive ventilation whereas alcoholism, laxative treatment (before and after icu admission) and nutrition ≤ h favoured passage of stool (table ) . no relations between constipation and mortality were found. conclusion: we highlighted new and important independent factors for constipation in critically ill patients leading to a better prevention of this phenomenon.. compliance with ethics regulations: yes. rationale: community peritonitis is a frequent medical-surgical emergency of the adult, acquired by the patient in a non-hospital setting. careful multidisciplinary care is essential, involving surgeons, anesthetists, microbiologists and radiologists. the objective of our study is to determine the bacteriological aspects of intra-abdominal sepsis, to describe their sensitivity profiles and to propose treatment regimens for the management of community peritonitis. we conducted a descriptive retrospective study spanning a period of two years from january to january involving cases of community abdominal sepsis operated in the operating room of surgical emergencies of our hospital. we included in our study adult patients admitted for suspected or confirmed abdominal sepsis who had undergone bacteriological examinations on the abdominal collections. samples taken are sent directly to the bacteriology laboratory for bacteriological analysis of the results. the studies showed the mean age is . years old, with a sex ratio of . . we found positive results mainly of peritoneal origin with a percentage of . % peritonitis, dominate by intestinal peritonitis . % followed by the appendicular origin . % then peritonitis by perforation of ulcer. the most incriminated organism in intraabdominal sepsis is e. coli with a percentage of . % of the total germs found, followed by streptococcus spp . %, enterococci . %, non-fermenting bgn composed mainly of pseudomonas aeruginosa . %, staphylococci . % and acinetobacter baumanii . %. note also the presence of bacteroides fragilis is %. e. coli had a very low sensitivity profile for amoxicillin/clavulanic acid ( . %), unlike ceftriaxone, gentamicin, amikacin and ertapenem, which had a sensitivity of . %, respectively. . %, %, . %. conclusion: knowledge of the bacterial ecology of intraabdominal sepsis is important in the choice of probabilistic antibiotherapy, pending bacteriological findings. no data are yet available about nutritional management and risk of malnutrition in tunisian medical intensive care units (icu). the purpose of this study was to describe nutritional management in medical intensive care patients and to evaluate the risk of malnutrition. patients and methods: we conducted a prospective observational cross-sectional study in medical icus all around the tunisian country on the th september . all participant units received a questionary form about routine nutritional management and data of all patients hospitalized in icu on the study day. collected data were: demographic characteristics, reason for admission, severity scores and subjective evaluation of nutritional status on admission, type and volume of nutritional support on the study day and the day before, nutritional status, nutric score and biological data on the study day, reasons for nutritional interruption and other supports prescribed. results: thirteen icu all around tunisia participated to the study. no icu had a nutrition team and only one had a written nutrition protocol. four icus evaluated systematically the nutritional status on admission. all icus were aware and practiced early enteral nutrition in patients unable to maintain oral intake with a systematic supplementation of oligoelements and minerals. neither target energy nor protein intake were calculated. on the study day, patients were hospitalized with an occupation rate of %. mean age was ± years. mean body mass index was ± and % of patients were judged well nourished. enteral nutrition support was prescribed on admission in % of cases with a mean caloric intake of ± kcal/day. the mean caloric target on the study day was ± kcal/day with a mean caloric intake of ± kcal/day and a mean caloric gap of ± kcal/day. the mean nutric score and body mass index on the study day were ± and ± respectively. twenty patients were judged malnourished by the nutric score and twenty two by clinical evaluation. a good correlation was found between nutric score and clinical evaluation of nutritional status (k = . ). conclusion: tunisian icus don't have nutrition team or nutritional written protocol. early enteral feeding and supplementation is common. a good correlation exists between nutric score and clinical nutrition status evaluation. compliance with ethics regulations: yes. rationale: whether more intensive glycemic control (gc) is beneficial or harmful forcritically ill patient has been debated over the last decades. gc has been shown hard to achieve safely and effectively in intensive care. the associated increased hypoglycemia and glycemic variability is associated with worsened outcomes. however, modelbased risk-based dosing approach have recently shown potential benefits, improving significantly gc safety and performances. the stochastic targeted (star) gc framework is a model-based controller using a unique risk-based dosing approach. star identifies modelbased patient-specific insulin sensitivity and assesses its potential variability over the next hours. these predictions are used to assess hypoglycemic risks associated with a specific insulin and/or nutrition intervention to reach a specific target band. this study analyzes preliminary clinical trial results of star in a belgian icu compared to the local standard protocol (sp). the mean age in our series was . years with a male predominance (sex ratio = . ). the main revealing symptoms were epigastralgia, weight loss and vomiting. subtotal gastrectomy was performed in . % of cases and total gastrectomy in . % of cases. curative resection could only be performed in . % of cases. operative mortality was . % and morbidity was . %. the main factor influencing operative mortality was age greater than years. in univariate analysis the main prognostic factors; tumor size, degree of parietal invasion, presence of ganglionic invasion, presence of more than ganglia invaded, presence of metastases, locally advanced tumor, tumor stage and curative nature of resection. patient-related factors such as age associated blemishes and biological factors have a significant influence on the patient's prognosis. the prognosis of gastrectomies, although it has improved overall, remains mediocre. the only way to improve the prognosis remains the early diagnosis with an effective surgical management and the introduction of an adapted resuscitation. compliance with ethics regulations: yes. efficacy of multiple second line agents in refractory status epilepticus in a pediatric intensive care unit lea savary, claire le reun chu tours, tours, france correspondence: lea savary (lea.savary@hotmail.com) ann. intensive care , (suppl ):p- rationale: convulsive status epilepticus (cse) is the most common neurological emergency in children. refractory status epilepticus (rse) occurs whenseizures are not controlled with first-and secondline agents. in adults, rse requires pharmacological induced coma. in pediatric patients, association of second line treatment is often used to avoid general anesthesia although there is currently no data on the efficacy of this association. we performed a monocentric retrospective study to assess the efficacy of multiple second line agents in pediatric rse. all children admitted to clocheville hospital (tours) between january and december with a diagnosis of rse were included. our population was divided into two groups: need of general anesthesia (midazolam+) or not (midazolam-). results: children were included ( in group midazolam+, in group midazolam−) during the study period. among the patients with multiple second line agents, % did not need general anesthesia (n = ). in group midazolam+, cse was % longer in patients treated with multiple second line agents ( rationale: drowning is an acute respiratory failure resulting from immersion or submersion in a liquid. patients and methods: we report cases of drowning collated in the pediatric reanimation department during a period from to . the aim of our retrospective study was to analyze and compare the different epidemiological, clinical, parcalinical, therapeutic and evolutionary of drowning in our study. results: our study contains boys and girls, with a sex ratio (m/f) of , in an age between months and years. for cases studied, no one was classified stage i, . % classified stage ii, % stage iii, and . % stage iv. all cases collected by ou service were victim of accidental drowning, . % were secondary to the lack of parental supervision. among cases, had respiratory complications, cases of hydroelectrolytic disorders, case with infectious complications, cases of neurological and cases of cardiac or hypothermic complication. in our study, cases recovered well and cases died. the survival of the drowned person depends on the speed and efficiency of the intervention, which in thefirst place is prehospital, thus ensuring the first actions at the scene of the accident, which will have repercussions on the hospital care. this has an equal share in the improvement of the victim's prognosis. compliance with ethics regulations: not applicable. epidemiology of severe pediatric trauma following winter sport accidents in the northern french alps emilien maisonneuve , nadia roumeliotis , pierre bouzat , guillaume mortamet chu grenoble, grenoble, france; chu sainte-justine, montréal, canada correspondence: emilien maisonneuve (emilienmaisonneuve@orange. fr) ann. intensive care , (suppl ):p- rationale: this study describes the epidemiology of severe injuries related to winter sports (skiing, snowboarding and sledding) in children, and assesses potential preventive actions. we did a single-center retrospective study in our pediatric intensive care unit in the french alps. we include all patients less than years old, admitted to the intensive care unit following a skiing, snowboarding or sledding accident from to . results: we included patients (mean age . years and % were male); of which ( %), ( %) and ( %) had skiing, snowboarding and sledding accidents, respectively. the average iss (injury severity score) was . the major lesions were head (n = patients, %) and intra-abdominal (n = patients, %) injuries. compared to skiing and snowboarding, sledding accidents affected younger children ( vs. years, p < . ); most of whom did not wear a helmet ( % vs. %, p < . ). severity scores were similar amongst winter sports (iss = for skiing, for snowboarding and for sledding accident, p = . ). rationale: best strategies for the management of severe pediatric traumatic brain injury (tbi) are still not clearly established and wide variations among professional practices have been reported in the literature. unfortunately, these variations in practice have an impact on the patient's outcome. the objectives of this work were to assess the adequacy of professional practices to the guidelines for the management of severe head injury and to assess the level of agreement of respondents in the absence of guideline. patients and methods: a practice survey was conducted in frenchspeaking hospitals in canada, belgium, switzerland and france from april st to june th, . the survey was conducted as a progressive clinical case with questions based on guidelines and the literature from to . the questions related to the assessment and management of tbi during the acute and intensive care phase. results: seventy-eight questionnaires were included. the adherence to guidelines was good, with items out of obtaining an adherence rate of more than % regardless of the annual number of tbi managed by the centre. there was strong agreement among clinicians on the intracranial pressure (pic) (> %) and cerebral perfusion pressure (> %) thresholds used according to age. guidelines for indication of pic monitoring were almost perfectly followed in the case of glasgow score < and abnormal brain ct scan (n = , %). on the other hand, the natremia and glycemia thresholds and the role of transcranial doppler were not consistent. strong adherence to recent recommendations was achieved: seizure prophylaxis with levitracetam (n = / , %) and capnia threshold (n = , %). assessment of o pressure in brain tissue (n = , %) and autoregulation (n = ; %) was not a common practice. conclusion: overall, practices for the management of tbi appear to be standardised. variations persist in areas where there is a lack of literature and guidelines in paediatrics, so clinicians seem to refer to adult guidelines. compliance with ethics regulations: yes. choubeila guetteche chu constantine, constantine, algeria correspondence: choubeila guetteche (cguetteche@gmail.com) ann. intensive care , (suppl ):p- rationale: ingesting a coin cell is a common household accident in children, which can have serious consequences. the goal is to determine prognostic factors to improve management and reduce complications. patients and methods: we conducted a retrospective study including children under admitted in pediatric intensive care between january and may for ingestion of button cells, with epidemiological, clinical and paraclinical data collection. results: twenty-six children boys ( %), and girls ( %) were included, with an average age of months ( - ), increased incidence in recent years. clinical signs indicative were dysphasia with hyper-sialorrhea in cases, cervical pain in one case, respiratory distress in one case, the cell was located in the upper third of the esophagus in cases, third average in cases, third inferior in cases, the mean time before extraction was h. complications: cases of mediastinitis, cases of oesotracheal fistula, a case of perforation. conclusion: the young age of the child, the diameter of the battery, and especially the time of care are risk factors for the occurrence of complications, the prevention passes through the education of the general public and creation of channel of taking into account fast charge. compliance with ethics regulations: not applicable. yacine benhocine university hospital center nedir mohamed, tizi-ouzou, algeria correspondence: yacine benhocine (yacine @yahoo.fr) ann. intensive care , (suppl ):p- rationale: inhalation of foreign bodies is a common and serious accident in children, especially between and years old. at this age, children use their mouth to explore their environment. asphyxia is the immediate risk and respiratory sequelae may appear secondarily. the severity of this incident has been considerably reduced due to the progress of the instrumentation and anesthesia which condition the smooth running of the therapeutic act. aim: to evaluate the anesthetic modalities of the extraction of the foreign bodies of the airways in children, in order to optimize our care with a maximum of security. a prospective, mono-centric, descriptive study from january to november of patients treated for inhalation of foreign bodies in the airways. study population wasdefined by: age, sex, hospitalization context, physical and radiological examination data, anestheticmanagement. results: the average age of the patients was . months, the male predominated ( %), and the hospitalization context was polymorphic. general anesthesia was necessary in all cases, sevoflurane mainly for narcosis; the combination of an opioid in . % of cases and a curare in . %. spontaneous ventilation is desirable, but % was manually broken down intermittently between extraction attempts. cases of desaturation, bronchospasm, bradycardia, and pneumothorax have been reported. . % had a good evolution. discussion: the results of the epidemiological data are consistent with those of the literature. the penetration syndrome is very revealing. the chest x-ray is the key examination, the diagnosis is often based on indirect signs. in case of asphyxia by foreign body enclosed above or between the vocal cords, laryngoscopy and oxygenation is the first step to perform. in other cases, a rigid bronchoscopy is performed under general anesthesia; inhalation induction with sevoflurane is the technique of choice for many experienced authors. controlled ventilation is used in the majority of cases because spontaneous ventilation is not often not possible. the heterogeneity of anesthetic practices accounts for the multiplicity of clinical situations. conclusion: the inhalation of a foreign body is a diagnostic and therapeutic emergency. extraction of the foreign body takes place under general anesthesia, which is difficult and at risk. compliance with ethics regulations: yes. non-invasive neurally adjusted ventilatory assist (nava) in infants with bronchiolitis: a retrospective cohort study alex lepage-farrell, sally al omar, atsushi kawaguchi, sandrine essouri, philippe jouvet, guillaume emeriaud chu sainte justine, université de montréal, montréal, canada correspondence: alex lepage-farrell (alex.lepage-farrell@umontreal.ca) ann. intensive care , (suppl ):p- rationale: bronchiolitis is one main reason for admission to pediatric intensive care unit. most infants are successfully managed with nasal cpap or high-flow nasal cannula, but about a third of these patients are not sufficiently supported and require an alternative support. non-invasive neurally adjusted ventilatory assist (niv-nava) improves patient-ventilator interactions and could therefore improve the effectiveness of non-invasive support. our hypothesis is that niv-nava is feasible in infants with bronchiolitis and that it reduces the respiratory effort. patients and methods: we retrospectively studied all patients under years of age with a clinical diagnosis of bronchiolitis ventilated with niv-nava in our pediatric intensive care unit, between october and june . patients characteristics, respiratory and physiologic parameters, including diaphragmatic electrical activity (edi) were extracted from an electronic medical database (data collected every s). respiratory effort was estimated using the modified wood clinical score for asthma (mwcas) and the inspiratory peak edi, and -h periods before and after niv-nava initiation were compared (wilcoxon rank test). the study was approved by the local research ethics committee. results: during the study period, patients were admitted with bronchiolitis; infants ( boys) with a median ( th- th percentile) age of ( - ) days were treated with niv-nava after a failure of other non-invasive support methods, and all were included. twentyfive subjects ( %) had at least one comorbidity. the interfaces used were predominantly face masks ( %). the maximum ventilatory settings were nava level of . ( . - . ), peep of ( - ) cmh o, fio of % ( - ) and maximal pressure of ( - ) cmh o. total duration of non-invasive ventilation was ( - ) hours, including ( - ) hours in niv-nava. as detailed in the table , mwcas significantly decreased after niv-nava initiation, from . ( . - . ) to . ( . - . ), p < . . a decrease in inspiratory peak edi was also observed, which was particularly clinically relevant in infants with high baseline edi (> mcv). capillary blood ph and pco also significantly improved after niv-nava introduction. six patients ( %) needed escalation to endotracheal intubation. conclusion: this study confirms the feasibility of niv-nava in infants with bronchiolitis after failure of first line non-invasive support, with a low failure rate. niv-nava initiation was followed by a decrease in respiratory effort and an improvement in blood gases. this observational study supports the needs for prospective interventional trial. compliance with ethics regulations: yes. rationale: the use of blood transfusion is frequent in pediatric intensive care units and has increased significantly since . considered as therapeutic, it requires an assessment of the benefit / risk balance before making the transfusion decision. the aim of our study is to describe the transfusion practices in the pediatric resuscitation department of the ehs canastel, algeria. patients and methods: a retrospective observational study over a -month period from january of any blood transfusion performed in hospitalized patients, in the pediatric intensive care unit. we studied : the age, the sex, the history of blood transfusion, the indication of transfusion, the haemodynamic and respiratory parameters, the transfusional accidents, the length of stay in intensive care, the evolution after a blood transfusion. results: these included transfusion patients out of hospitalizations during the -month period, mean age was months.all patients had no transfusion history, % of patients had their anemia admission and % developed it during their stay. the reason for hospitalization was respiratory distress in %, convulsive condition in %, polytrauma in %, and head trauma in %. the indication of the transfusion was placed on a hb inferior or equal to g / dl in % of cases, in % on an hb superior to g / dl in addition to the clinical criteria of intolerance to anemia; in % of the cases no clinical or biological criteria found, the nature of the blood products was of the red cell in % of the cases and of the plasma concentrate in / of the cases and pfc in %. % received a+, % of a-, % of b+, % of o+ and % of o-. % of the patients had a transfusion-like reaction at min after the start of the transfusion; % of the patients were under artificial ventilation and % were under hemodynamic support, % under diuretic.the average length of stay was days; the favorable outcome was % of the patients after the transfusion with an increase in the hb level beginning, % of the patients had complications of their pathology and the death in % of the cases. conclusion: current transfusion practices in children often do not reflect the implementation of our current knowledge of the need for transfusion. hence the need to review the protocols and practice other transfusion alternatives to avoid complications and improve the quality of care. compliance with ethics regulations: not applicable. rationale: bacterial multi drug resistance is medical actuality nowadays, because of its morbidity and mortality especially in intensive care, it constitutes a real problem in our hospitals. we conducted a retrospective descriptive study, to identify bacterial drug resistance profile of patients with cross infections in the department of intensive care in august hospital. this study included patients hospitalized between st january and st december . the data was collected from medical records of this unit as from the register of the bacteriology service of ibn rochd university hospital. results: patients were hospitalized in the resuscitation service, of which had nosocomial infection, an incidence of . %. the mean age of the patients was years with male predominance (sex ratio . ), the average stay in intensive care was days. the site of infection was pulmonary in % of cases, blood in % of cases, urinary in % of cases, central catheter in %, neuro-meningeal in . % of cases. the germs isolated were: acinetobacter baumanii in . % of cases, pseudomonas aeroginosa in . % of cases, klebsiella pneumonia in . % of cases, enterococcus feacalis in . % of cases, e.coli in . % of cases and staphylococcus aureus in % of cases. acinteobacter baumanii showed resistance rates of up to % for the impenem and % for amikacin. regarding pseudomonas, it was resistant to impenem in % of cases and in % of cases to amikacin. compared to klebsiella, resistance to imipenem was % and % for amikacin. the mortality rate of infected patients was % conclusion: in the light of this work, we found that important emergence of multidrug resistance bacteria in intensive care unit is related to not only the immunocompomised state of patients but also to daily bad practices of health professionals such as the misuse of antibiotics. compliance with ethics regulations: yes. overnight culture of escherichia coli, klebsiella pneumoniae, staphylococcus aureus and pseudomonas aeruginosa, was also sequenced. results: twenty-four samples and the pc were analyzed. amplicon sequence analyses found similar results with the two primer pairs in % of cases. cultured pathogen was found in % ( / ) for human primer pair and in % ( / ) for earth primer pair. for each eta, ngs revealed bacteria unknown as pathogen globally identified as oropharyngeal flora in conventional microbiology (table ) . alpha diversity decreased for all vap patients overtime, average shannon . ( ; . ) versus ( . ; . ), and was higher in upper respiratory tract (os) versus lower respiratory tract (eta): average shannon . ( . ; . ) vs. . ( . ; . ) (ns). conclusion: this pilot study highlights the impact of s rdna amplification procedures (especially oligonucleotide sequences) used on the results in microbiome research. concordance between ngs and bacterial culture, as well as similar evolution of the alpha diversity than previously described ( ), enables us to validate our methodology using the "gut primers" pair f- r. these findings allow furthers major studies on the pulmonary microbiome of icu ventilated patients including comparison according to the occurrence of a vap or not. compliance with ethics regulations: yes. rationale: in the field of intensive care only few studies have explored bacterial microbiota whereas virome remained hardly considered. it appears essential to describe both evolution in mechanically-ventilated patients to improve the pathophysiological understanding of ventilator-associated pneumonia (vap) development. to date no study had been simultaneously conducted on lower respiratory tract with a single nucleic acid extraction before metagenomics analysis of bacterial microbiota and virome. we conducted a preliminary study to validate our methodology based on a common automated extraction of nucleic acids. patients and methods: twelve mechanically ventilated patients were selected: five who developped (vap) and seven controls (c) who did not. endotracheal aspirate (eta) were collected between intubation and day (or dvap for vap patients). conventional bacterial microbiology and multiplex respiratory viruses pcr were also performed. total nucleic acids were extracted using nuclisens easymag extractor. for the bacterial microbiota, region v of the s rrna genes was amplified. for the virome, the nextera dna xt kit (illumina) and rna seq trio kit (nugen) protocols were used to prepare viral dna and rna libraries. libraries underwent paired-end sequencing on the illumina miseq (bacteria) or nextseq- (virus) platform. after bioinformatics analysis we compared the performance of metagenomics analysis with conventional bacterial culture and other common viral detection methods. results: for culturable bacteria, concordance between conventional microbiology and sequencing was found in % ( / table . our preliminary results confirm the feasability of exploring both bacterial microbiota and virome on the same sample using a common extraction method. data from metagenomics were highly concordant with conventionnal detection methods for known pathogenic viruses and bacteria in lower tract respiratory sample and enables identification of other microorganisms. this is the first step for a large cohort study that aims to compare evolution of global lung microbiome in patients at risk of vap and assess how bacteria and virus interplay. compliance with ethics regulations: yes. references . clancy department of medical and toxicological critical care, lariboisière hospital one microorganism was isolated in . % and two in . % of cases. the main isolated microorganism were enterobacteriaceae in . % of patients. they were esbl-producers in . % of cases. initial antibiotic therapy was appropriate in . % of cases. factors independently associated with esbl-pe as the causative microorganism of icu-bsi were esbl-pe carriage prior to icu-bsi the sensitivity of esbl-pe carriage to predict esbl-pe as the causative microorganism of icu-bsi was . %, and specificity was . %. mortality at days was . % in the general population in multivariable analysis, there was no parameter which was independently associated to mortality at day from the occurrence of icu-bsi. conclusion: icu-bsi complicates . % of admission to icu and was associated with % in-hospital mortality assessing and applying individualized treatment for group a streptococcal necrotizing soft-tissue infection is possible service de réanimation médicale intensive care decompressive craniectomy in traumatic brain injury: about cases karama bouchaala sex ratio of . . the mean (sd) length of stay in icu was . ± . days. the mean glasgow coma score (gcs) (sd) was . ± . and gcs ≤ in . %. sofa score > was found in patients ( . %) and sapsii score ≥ in patients ( . %). the cerebral ctscan at admission showed acute subdural hematoma (asdh) in ( . %), cerebral oedema ( . %) and cerebral contusions ( %) teaching: fresenius medical care; patent or product inventor: gml czech republic banydeen rishika: no conflict of interest baptiste amandine: no conflict of interest baptiste olivier: no conflict of interest barbar saber davide: no disclosure barbier françois: no disclosure barbierlouise: trainings, teaching: ethicon, astellas; invitation to national or international congresses: sandoz, astellas barnerias christine: no disclosure baron aurore: no disclosure baron elodie: no conflict of interest barr att -due andreas: no disclosure barrau stephanie: no disclosure barraud damien: no disclosure barraud helene: no disclosure barrois brigitte: no conflict of interest baruchel andré: no disclosure bastide marie anaïs: no conflict of interest baudel jean-luc: no conflict of interest baudin florent: invitation to national or international congresses: dr baudin has received speaking fees from maquet critical care (epnv teaching: drager; invitation to national or international congresses: msd; hill rom beganton frankie: no conflict of interest begot erwan: no disclosure beinse guillaume: research support/scientific studies: association pour la recherche contre le cancer ion and fresenius kabi bensaid abdelhak: no disclosure bensardi fatimazahra: no disclosure benyamina mourad: no disclosure benzerara laurent: patent or product inventor: aphp benzerdjeb nazim: research support/scientific studies: amarape, icap; consultancy, expert: alphasights, msd; trainings, teaching: msd beqiri erta: no disclosure bÉranger agathe: no conflict of interest berard emilie: no conflict of interest berdai adnane: no disclosure berger patrick: no disclosure bernal william: no disclosure bernardin gilles: no disclosure berrada lina: no conflict of interest berthaud romain: no conflict of interest berthet guillaume: no conflict of interest berti enora: no conflict of interest bertoli sarah: no disclosure bertrand pierre-marie no conflict of interest besbes lamia: no disclosure besbes mohamed: no conflict of interest besch camille: invitation to national or international congresses: abbvie no conflict of interest boisseau chloé: no disclosure boissel nicolas: no disclosure boissier florence: no conflict of interest boivin alexandra: no conflict of interest bonacorsi stéphane: no conflict of interest bongiovanni filippo: no conflict of interest bonnardel eline: no conflict of interest bonnefoy-cudraz eric: no disclosure bonnet sixtine: no conflict of interest bonnevie tristan: research support/scientific studies invitation to national or international congresses: fresenius kabi and fresenius medi-calcare bucur petru: no disclosure buetti niccolo: research support/scientific studies: swiss national science foundation research grant and bangerter rhyner foundation supporting my postdoc bui hoang-nam: no disclosure burelli gabrielle: no conflict of interest burgel pierre-régis: no disclosure burghi g: no conflict of interest bustarret olivier: no conflict of interest butin-druoton anne-lise: invitation to national or international congresses expert: astra-zeneca; invitation to national or international congresses expert: hamilton medical; invitation to national or international congresses: hamilton medical chemli wael: no conflict of interest chenouard alexis: no conflict of interest cherkab rachid: no conflict of interest chevret sylvie: no disclosure chhun stephanie: no conflict of interest chiche jean-daniel: no disclosure chicoisneau maxence: no conflict of interest chlilek abdelaziz: no disclosure chocron richard: consultancy, expert: aspen chommeloux juliette: no conflict of interest chomton maryline: no conflict of interest chosidow olivier: no disclosure chouchana laurent expert: biotest; invitation to national or international congresses: sanofi research support/scientific studies: fresenius medical care; consultancy, expert: fresenius medical care; invitation to national or international congresses: xenios novalung, heilbronn, germany dachraoui fahmi: no disclosure dahoumane redouane: no conflict of interest dahyot-fizelier claire: no disclosure daix thomas: no conflict of interest daly foued: no conflict of interest damonti lauro: no conflict of interest dantan etienne: no conflict of interest darmon michaël: research support/scientific studies: msd no disclosure das vincent: no disclosure daubin cedric: no conflict of interest daubin delphine: no conflict of interest daudon michel: no disclosure daufresne pierre: no conflict of interest dauger stéphane: no conflict of interest daviet florence: invitation to national or international congresses: sandosz de courson hugues: no conflict of interest de jong audrey: trainings, teaching: baxter, medtronic; invitation to national or international congresses teaching: cardiosleep delhaes laurence: no disclosure delignette marie-charlotte: no conflict of interest dellamonica jean: trainings, teaching: medtronic; invitation to national or international congresses: msd, general electrics delpierre clément: no conflict of interest delville marianne: no conflict of interest demailly zoé: research support/scientific studies: srlf demarest elsa: no disclosure demaret pierre: no conflict of interest demiselle julien: no conflict of interest demondion pierre: no conflict of interest demoule alexandre: research support/scientific studies: drager, philips; consultancy, expert: baxter, respinor, lungpacer; trainings, teaching: fisher & paykel, hamilton, baxter; invitation to national or international congresses: fisher & paykel denis manon: no conflict ofinterest depeyre fanny: invitation to national or international congresses: pfizer deplante yvon: no conflict of interest dequin pierre-françois: research support/scientific studies: medimmune combioxin ferring pharmaceuticals a/s asahi kasei pharma america corporation derauglaudre lucie: no conflict of interest derbel karim: no disclosure derkaoui ali: no disclosure dervin krystel: no conflict of interest desaive thomas: no conflict of interest desguerre isabelle: research support/scientific studies: ptc inc, avexis; consultancy, expert: avexis, ptc inc, biogene; trainings, teaching: roche, ptc inc, avexis; invitation to national or international congresses: sarepta, biogen, avexis, biomarin desnos cyrielle: no conflict of interest desroys du roure françois: no conflict of interest detollenaere charles: no conflict of interest devaquet jérôme: invitation to national or international congresses expert: lungpacer; invitation to national or international congresses: lungpacer dreyfuss didier: research support/scientific studies: grant from french ministry of health drouot xavier: no disclosure du cheyron damien: no conflict of interest dubÉ bruno-pierre: consultancy, expert: novartis, gsk dubert marie: no conflict of interest dubost baptiste: no conflict of interest dubost jean-louis: no conflict of interest duburcq thibault: no conflict of interest duchemann boris: consultancy, expert: bms, msd, roche; invitation to national or international congresses no conflict of interest frÉrou aurélien: no conflict of interest fritz caroline: no disclosure fromentin mélanie: research support/scientific studies: msd; invitation to national or international congresses: msd frouin antoine: no conflict of interest frugier alexandre: no disclosure gaboriau louise: no conflict of interest gaci rostane: invitation to national or international congresses: bard gacouin arnaud: no disclosure gaddas mehdi: no conflict of interest gaillard arnaud: trainings, teaching: zoll medical gaimard sophie: no conflict of interest gainnier marc: no conflict of interest galbois arnaud: no conflict of interest galerneau louis-marie: invitation to national or international congresses: agir À domicile galicier lionel: consultancy, expert: novartis, eusapharma; trainings, teaching: baxalta, pfizer; invitation to national or international congresses no conflict of interest ichaÏ philippe: no conflict of interest imen sioud: no conflict of interest ioos vincent: no disclosure iserin franck: no disclosure issa nahema: no conflict of interest jaber samir: consultancy, expert: drager, fisher-paykel; medtronic; baxter xenios fresenius; invitation to national or international congresses: drager no conflict of interest jacq gwenaëlle: no conflict of interest jacquet emmanuelle: research support/scientific studies: unicancer (esme and storm studies invitation to national or international congresses: pfizer université laval-qc-ca labbe vincent: no disclosure labro laura: no disclosure lacaille florence: no conflict of interest lacampagne alain: no disclosure lacan claire: no conflict of interest lacherade jean-claude: no conflict of interest ladjemi maha-zohra: no conflict of interest lafon charles: no conflict of interest lafon marie-edith: no disclosure lafon thomas: no conflict of interest lagache laurie: invitation to national or international congresses advertising documents: philips; trainings, teaching: novartis, gsk, astra zeneca, boeringher; invitation to national or international congresses: chiesi, astra zeneca, sos oxygene, novartis, boeringher lamoth frédéric: consultancy, expert: gilead, msd, basilea; invitation to national or international congresses: msd expert: norgine; trainings, teaching: fujifilm, boston scientific lebreton guillaume: no disclosure lebrun-vignes benedicte: research support/ scientific studies: novartis; consultancy, expert: ansm lebuffe gilles: no disclosure leclerc maxime: no conflictof interest lÉcluse aldéric: research support/scientific studies: pgrx avc study; consultancy, expert: bms-pfizer, boerhinger ingelheim, bayer; invitation to national or international congresses: bms-pfizer, boerhinger ingelheim ledoux didier: no disclosure lefebvre francois: no conflict of interest macloughlin ronan: research support/scientific studies: aerogen ltd no conflict of interest mari arnaud: no conflict of interest marie damien: no conflict of interest marijon eloi: no disclosure mariotte eric: consultancy, expert: sanofi-aventis marjanovic nicolas: no disclosure marjanovic zora: no disclosure maroni arielle: no conflict of interest marot benoit: no conflict of interest marque sophie: no conflict of interest marti teaching: zambon, chiesi; invitation to national or international congresses no conflict of interest matusik elodie: no conflict of interest mauchien benedicte: no conflict of interest maury eric: research support/scientific studies: doran international, drager; trainings, teaching: vygon maxime virginie: no conflict of interest mayaux julien: invitation to national or international congresses stock shareholder: tanderev; patent or product inventor: tanderev mercat alain: research support/scientific studies: fisher-paykel, general electric; consultancy, expert: faron pharmaceuticals no disclosure merhabene takoua: no conflict of interest merle jean-claude: no disclosure mesotten dieter: no conflict of interest messaadi amenallah: no conflict of interest messika jonathan: invitation to national or international congresses: cslbehring; fisher&paykel metaxa victoria: no disclosure metogo mbengono junette arlette: no conflict of interest meunier anne: no conflict of interest meurice jean-claude: no disclosure meybeck agnes: consultancy, expert: janssen, gilead; invitation to national or international congresses teaching: msd no conflict of interest morimont philippe: no conflict of interest moro-sibilot denis: no disclosure mortamet guillaume: no conflict of interest mosbah nabil: no conflict of interest moschietto sebastien: no conflict of interest moucadel virginie: research support/scientific studies: biomérieux moulaire rigollet valérie: no disclosure mouliade charlotte: no conflict of interest moulin florence: no disclosure mounir yousfi: no conflict of interest mourabit karima: no disclosure mourvillier bruno: trainings, teaching: msd research support/scientific studies: aerogen; advertising documents: aerogen; patent or product inventor: aerogen musiari michele: no conflict of interest n'guyen quang-thang: no conflict of interest n'guyen tran: no disclosure nabil mosbah: no disclosure naccache lionel: no disclosure naimi skander: no conflict of interest nakaa sabrine: no disclosure nallet-amate megan: no conflict of interest natalis eloïse: no disclosure naudin jérôme: invitation to national or international congresses: novartis nay mai-anh: no conflict of interest nemlaghi safaa: no conflict of interest neofytos dionysios: research support/scientific studies: msd; consultancy, expert: msd, gilead, pfizer; invitation to national or international congresses: gilead, pfizer nesseler nicolas: no conflict of interest neviere remi: no disclosure nguyen alexandre: no disclosure nguyen khoa thao: no conflict of interest nicolau-travers marie-laure: no disclosure niÉrat marie cécile: no conflict of interest nieszkowska ania: no disclosure nigeon olivier: no conflict of interest nitel gautier: no conflict of interest nodea elena madalina: no conflict of interest noel marine: no conflict of interest nogier marie-béatrice: no disclosure noorah zaid: no disclosure nouira wiem: no conflict of interest noumeir rita: stock shareholder: softmedical noury norbert: no conflict of interest novy emmanuel: research support/scientific studies: msd; invitation to national or international congresses: pfizer expert: air liquide medical system ollivier veronique: no conflict of interest onimus thierry: no conflict of interest oppenheimer anne: invitation to national or international congresses: gedeon richter orkisz maciej: no conflict of interest orliaguet gilles: research support/scientific studies research support/scientific studies: oxynov; patent or product inventor: oxynov patrier juliette: no conflict of interest paugam catherine: no disclosure paul marine: no conflict of interest paul-bellon rachel: no disclosure paulo nicolas: no conflict of interest pavot arthur: invitation to national or international congresses: fresenius medical care france pehlivan jonathan: no conflict of interest peigne vincent: invitation to national or international congresses: air liquide pÉju edwige: no conflict of interest pene frédéric: consultancy, expert: alexion pÉpin-lehalleur adrien: invitation to national or international congresses: chiesi pere morgane: no conflict of interest pereira bruno: no disclosure perez didier: no disclosure perez pierre: no disclosure perez yonatan: no conflict of interest perier françois: no disclosure perin nicolas: no conflict of interest biomerieux robin emmanuel: no conflict of interest robin nicolas: no disclosure robineau olivier: no disclosure roch antoine: no disclosure roche anne: no conflict of interest roger claire: consultancy, expert: pfizer, fre-senius medical care; invitation to national or international congresses: msd,pfizer rolle amélie: no conflict of interest rondeau eric: no disclosure ronziÈre thomas: no disclosure roquilly antoine: no disclosure rosselli sylvène: no disclosure rouby jean-jacques: no disclosure rouis sana: no conflict of interest rouleau stéphane: no conflict of interest roulet sylvie: no disclosure roulland charlotte: no disclosure roumeliotis nadia: no conflict of interest rousse natacha: no disclosure rousseau anne-françoise: invitation to national or international congresses no disclosure sagnier anne: no disclosure saillard colombe: trainings,teaching: amgen, novartis; invitation to national or international congresses no conflict of interest schmidt aline: no disclosure schmidt matthieu: consultancy no disclosure schultz marcus: no conflict of interest schwebel carole: invitation to national or international congresses: pfizer scicluna brendon: no disclosure sculier jean-paul: no conflict of interest see perrine: no conflict of interest seghboyan jean-marie: no disclosure seguin amelie: no conflict of interest seguin philippe: consultancy, expert: lfb; invitation to national or international congresses: astellas sejourne caroline: no conflict of interest sellami walid: no conflict of interest sendid boualem: research support/scientific studies: allfun project, fp european commission; invitation to national or international congresses: pfizer senhadji lahcen: no conflict of interest serbouti rita: research support/scientific studies: fresenius medical care; consultancy, expert: fresenius medical care; trainings, teaching: fresenius medical care; invitation to national or international congresses: fresenius medical care serfaty lawrence: no disclosure sÉrie mathieu: no conflict of interest shaw geoffrey m.: no conflict of interest shi rui: no conflict of interest shimi abdelkrim: no disclosure shojaei maryam: no disclosure si-tahar mustapha: consultancy, expert: cynbiose respiratory; stock shareholder: cynbiose respiratory siami shidasp: no conflict of interest silva daniel: research support/scientific studies: fresenius medical care france; consultancy, expert: fresenius medical care france; invitation to national or international congresses: xenios novalung, heilbronn no conflict of interest sirault bruno: no disclosure sirodot michel: no disclosure slama michel: no disclosure slim amine: no disclosure smielewski peter: no disclosure soares marcio: stock shareholder: epimed solutions teaching: gilead; invitation to national or international congresses: pfizer spagnoletti marco: no conflict of interest steckelmacher claire: no disclosure stockx luc: research support/scientific studies: phenox, medtronic; consultancy no conflict of interest voiriot guillaume: research support/scientific studies: biomérieux, sos oxygène, janssen; consultancy, expert: biomérieux; invitation to national or international congresses: biomérieux von kietzell matthias: invitation to national or international congresses expert: aguettant; invitation to national or international congresses: vifor yacoubi wejden: no conflict of interest yager hélène: no conflict of interest yahya yosra: no conflict of interest yakini khalid: no disclosure yakouben karima: no disclosure yonis hodane: invitation to national or international congresses: lvl medical et pfizer younan romy: no conflict of interest youssoufa atika: no disclosure zacharia mahi: no disclosure zafrani lara: research support/scientific studies: jazz pharmaceuticals zambon olivier: no disclosure zaouak nadia: no conflict of interest zaouche khedija: no conflict of interest zarrougui wafa: no conflict of interest ze minkande jacqueline: no disclosure zeghdoud dalila: no disclosure zerbib yoann: no conflict of interest zerhouni amel: no conflict of interest zerhouni amine: no conflict of interest zerimech farid: no conflict of interest zerouali khalid: no disclosure zheng yi: no conflict of interest zimmerli stefan: research support/scientific studies: msd, pfizer, gilead; consultancy, expert: msd, pfizer; trainings, teaching: gilead; invitation to national or international congresses springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations farhat hached hospital, sousse, tunisia; yassminet regional hospital, ben arous, tunisia; habib bougatfa regional hospital, bizerte, tunisia; larabta hospital, tunis, tunisia; carthagene private hospital, tunis, tunisia; regional hospital of zaghouan, zaghouan, tunisia; regional hospital of tozeur, tozeur, tunisia; habib thameur hospital, tunis, tunisia correspondence: samia ayed (samia.ayed@yahoo.fr) ann. intensive care , (suppl ):p- geoffroy hariri, kyann hodjat-panah, laurene blum, jean-rémi lavillegrand, idriss razach, naike bige, jean-luc baudel, bertrand guidet, eric maury, hafid ait-oufella médecine intensive-réanimation, hôpital saint-antoine, paris, france correspondence: geoffroy hariri (geoffroyhariri@hotmail.com) ann. intensive care , (suppl ):p- rationale: hemolytic anemia (ha) is a common condition in intensive care unit but its diagnosis remains challenging. free hemoglobin (and heme) degradation leads to co release that can bind to hemoglobin to form carboxyhemoglobin (hbco). we hypothesized that hbco concentration could be used as a reliable diagnosis tool for ha. patients and methods: we performed a monocentric retrospective study in a -bed intensive care unit at st antoine hospital, paris, between and . all patients hospitalized for ha with arterial hbco dosage at admission were included. arterial hbco was measured in routine in our department with an il system ph/ blood gas analyzer. demographic and biological data were collected. a group control of patients with non-hemolytic anemia (hb < g/ dl) (nha) was also included. finally, we analyzed patients outcome according to hbco changes during icu stay. results: between and , patients with ha were included. nha patients were included in the control group. patients with ha were younger than patients with nha ( [ ; ] vs. [ ; ] years old, p = . ) but admission sofa was not different between groups ( [ ; ] , vs. [ ; ] , p = ns). among patients with ha, % had thrombotic microangiopathy, % had autoimmune hemolytic anemia and % had sickle cell disease. at icu admission, ha patients had higher hbco level than patients with nha ( . [ . ; . ] vs. . [ . ; . ] %; p < . ). hbco was a reliable biomarker of hemolysis (auc . ( . ; . ) p < . ). an hbco level threshold at . % identify hemolysis with a sensitivity ( - ) % and a specificity ( - ) %. in ha group, hbco was negatively correlated to hb level (r = . ; p < . ). in ha patients, changes of hbco level during icu management were associated with outcome, decreasing in survivors ( . [ ; . ] vs. . [ . ; . ] ; p = . ) but not in non-survivors ( . [ . ; . ] vs. . [ . ; . ] %; p = . ). conclusion: carboxyhemoglobin is a reliable diagnosis and prognosis biomarker for hemolytic anemia in icu compliance with ethics regulations: yes. rationale: thrombocytopenia is the most commonly hemostatic disorder encountered in intensive care, present in to % of patients. the mortality associated with this thrombocytopenia, the numerous pathological contexts associated with resuscitation and the lack of a recommended management strategy led to the establishment of these guidelines. the aim of our study was to determine the incidence, causes and risk factors associated with the occurrence of thrombocytopenia, as well as the impact of thrombocytopenia on the mortality and length of stay in the icu ibn medical resuscitation unit. rochd de casablanca, over a period of months. patients and methods: this was a prospective study, carried out in the medical resuscitation department of ibn rochd university hospital in casablanca over a period of months. there were two groups: ''sick'' group with thrombocytopenia with a platelets count < , / mm , and a ''control'' group without thrombocytopenia. patients with previous platelet disorders, hematologic malignancies, and patients undergoing chemotherapy were excluded. of the patients included, episodes of thrombocytopenia were identified, anoverall incidence of . %. sepsis was incriminated times ( . %), followed by ards in patients ( . %), massive filling in patients ( . %), disseminated intravascular coagulation in patients ( . %), and massive transfusion in patients ( . %). the drug origin was incriminated in patients ( . %). it was due to quinolones and imipenem. the mortality rate was deaths ( . %) which was inversely proportional to the lowest platelet count in the thrombocytopenia group, compared to deaths ( %) in the control group. the mean duration of stay in the thrombocytopenia group was ± days with extremes ranging from to days. conclusion: thrombocytopenia was a common abnormality in the intensive care system, it occured in many pathological situations and was a factor of morbidity and excess mortality. the most common etiology in this study was sepsis. the diagnostic and therapeutic approach depended on the particular clinical context in which thrombocytopenia occurs. its onset may constitute a hematological emergency, particularly when there is a major mucocutaneous and / or visceral hemorrhagic syndrome, which necessitates a rapid etiological diagnosis, and the establishment of an effective treatment, both symptomatic and specific. compliance with ethics regulations: not applicable. marc pineton de chambrun , romaric larcher , frédéric pene , laurent argaud , alexandre demoule , rémi coudroy , elie azoulay , yacine tandjaoui-lambiotte , stanislas faguer , alain combes , charles-edouard luyt , zahir amoura sorbonne université, aphp, hôpital la pitié-salpêtrière, institut de cardiométabolisme et nutrition (ican), service de médecine intensive-réanimation, paris, paris, france; rationale: catastrophic antiphospholipid syndrome (caps), the most severe manifestation of antiphospholipid syndrome (aps), is characterised by simultaneous thromboses in multiple organs. diagnosing caps can be challenging but its early recognition and management is crucial for a favourable outcome. this study was undertaken to evaluate the frequencies, distributions and ability to predict mortality of "definite/probable" or "no-caps" categories of thrombotic aps patients requiring admission to the intensive care unit (icu rationale: septic acute kidney injury (s-aki) is a frequent complication in critically ill patients and is associated with high morbidity and mortality. it is well known that chronic kidney disease increases the risk of pulmonary embolism (pe), but few studies have investigated the relationship between acute kidney injury (aki) and pe occurrence in septic patients. the aim of this study is to determine whether patients with aki are at increased risk of developing pe. patients and methods: were included, in a prospective study conducted over months (january -june , ) in a medical surgical intensive care unit, all the patients older than years with septic shock at admission or during hospitalization. two groups were compared: patients with kidney injury (aki+ group) and patients without kidney injury (aki− group). we studied the occurrence of pe in these two groups. results: we included patients. the mean (sd) age was . ( ± ) years. sex ratio was . . thirty one ( . %) patients developed pe. the occurrence of pe was significantly higher in (aki + group) [ patients ( %) vs. patients ( %); p = . ]. the incidence of pe according to kidney injury severity was patients ( %) kdigo i, patients ( %) kdigo ii, patients ( %) kdigo iii. in the aki+ group, pe was significantly associated with increased sofa score at admission ( points vs. points; p = . ), lower platelets count ( , vs. , ; p = . ), higher lacatatemia at septic shock day [ . vs. . mmol/l; p = . ] and higher c reactive protein level [ mg/l vs. mg/l; p = . ]. in a multivariate analysis the pe risk factors in (aki+ group) were thrombopenia (odds ratio = . ; ci [ . - . ], p = . ) and c-reactive protein value (odds ratio = . ; ci[ . - . ], p = . ). discussion: the increased risk for pe with aki may be due to endothelial involvement, vascular injury and the related changes found in procoagulant proteins (increased levels of fibrinogen, factor vii, factor viii, von willebrand factor, and plasminogen activator inhibitor- ). in our study, lower platelet and higher c reactive protein level were found in patients with pe, suggesting the participation of disseminated intravascular coagulation. these factors may contribute to increase pe risk. conclusion: the risk of pe is higher in septic patients with aki than in those with normal kidney function. therefore, because of paucity of evidence, larger studies are needed to understand pe pathway in septic aki and to establish efficient prophylaxis protocols. compliance with ethics regulations: yes. and of these patients ( . %) required intensive care. the lasted were males ( %) and a majority ( %) were younger than years of age. in intensive care patients, only ( . %) had nosocomial infection, majority were community acquired infections ( . %) with ( %) pneumoniae, ( . %) profound abscess, pyelonephritis ( . %), ( %) meningitidis. patients( %) required mechanical ventilation for days ( % ci - ), length of stay in icu was days ( % ci - ) and mortality rate was %. conclusion: hmkp infections lead young patients in intensive care unit in one third of case with a majority of pneumoniae requiring mechanical ventilation and with a high rate of mortality. furthers studies are needed to investigate the role of this particular strain in severity. compliance with ethics regulations: yes. rationale: infections secondary to snakebite occur in a number of patients, and are potentially life-threatening. bothrops lanceolatus bites in martinique average thirty cases per year and may result in severe thrombotic and infectious complications. we aimed to investigate the infectious complications related to bothrops lanceolatus bite. patients and methods: a retrospective single-center observational study over seven years ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) was carried out, including all patients admitted to the hospital due to bothrops lanceolatus bite. clinical and biological data were reported using the dx care, x-plore et cyberlab softwares of the emergency medicine and analyzed. one hundred and seventy snake-bitten patients ( males and females) were included. thirty-nine patients ( %) presented grade or envenoming. twenty patients ( %) developed wound infections. the isolated bacteria were aeromonas hydrophila ( cases), morganella morganii ( cases), group a streptococuss, and group b streptococcus (one case each). patients were treated empirically with third-generation cephalosporin (or amoxicillin/clavulanate), aminoglycoside and metronidazole combinations. outcome was favorable. the main factor significantly associated with the occurrence of infection following snakebite was the severity of envenoming (p < . ). our findings clearly point towards the frequent onset of infectious complications in b. lanceolatusbitten patients presenting with grade and envenoming. conclusion: infectious bite-related complications of bothrops lanceolatus account for approximately % of the cases, with a strong predominance for grade iii and iv. thus, based on the bacteria identified in the wounds; we suggest that empiric antibiotic therapy including third-generation cephalosporin should be administered to those patients on hospital admission. compliance with ethics regulations: yes. rationale: endocrine abnormalities have been reported with varying frequencies, following traumatic brain injury (tbi). few studies have examined the clinical features and outcomes of isolated acute thyrotropic hormone deficiencies after tbi. theaim of the study was to evaluate the early changes in thyrotropic hormone levels after traumatic brain injury (tbi) and to evaluate whether hormone changes are related to outcome patients and methods: we conducted a months long prospective cohort, including all patients admitted to a university hospital icu with moderate to severe traumatic brain injury (tbi), defined as a glasgow coma scale below twelve (gcs < ). blood samples for basal hormone values of thyroid-stimulating hormone (tsh) and free thyroxine (ft ) were obtained on days , , and . tsh serum concentrations were considered normal at > . mu/l; ft at > pmol/l. a thyrotropic insufficiency was defined as low ft and low tsh plasma levels. all patients were screened with a brain mri. patients were also monitored for neurological deterioration, including cognitive decline, convulsive seizures, increase in cerebral edema and brain herniation that were simultaneous to the diagnosis. results: during our study period's, trauma patients were admitted to our icu and met the inclusion criteria. on admission, our patients had a mean age at . ± , a mean injury severity score (iss) at ± , a mean abbreviated injury severity (ais) of the head at . ± . and a mean gcs at ± . of the patients a thyrotropic insufficiency was diagnosed in patients ( %) during the first days. the median delay to thyrotropic insufficiency diagnosis was days. in three of ( %), the thyrotropic insufficiency was nonrecovering during the patient's icu stay and was transient for the rest. none of the patients with acute thyrotropic insufficiency had direct hypothalamic or pituitary lesions on the brain mri. factors associated to the occurrence of acute thyrotropic insufficiency were: the ais of the head ( . ± . vs. ± . , p = . ), cerebral contusions ( % vs. %, p = . ), subarachnoid haemorrhage ( % vs. %, p = . ) and subdural haematoma ( % vs. %, p = . ). thyrotropic insufficiency was associated to neurological deterioration (p = . ) on the day of diagnosis but did not affect icu mortality ( % vs. %, p = . ). in this study, low pituitary-thyrotropic axis hormone levels were found in the acute phase of tbi and were associated to neurological deterioration but with no perceived effect on icu mortality. compliance with ethics regulations: yes. rationale: acute diabetes insipidus following head injury and its effect on patients outcome have not been sufficiently evaluated in large prospective studies. the aim of this study was to determine the incidence of acute cdi, delay of onset predictive factors and its impact on tbi patients. we conducted a prospective cohort, including all patients admitted to icu with moderate to severe tbi, defined as a glasgow coma scale (gcs) below twelve. for each tbi patient plasma sodium was measured daily, and if abnormally high, urine specific gravity and osmolality were measured. cdi was diagnosed using the seckl and dunger criteria. acute cdi was defined as cdi diagnosed in the first week following injury. all patients were screened with a brain mri. results: during our study's period, trauma patients were admitted to our icu, presented with moderate to severe tbi and were included. on admission, our patients had a mean age at . ± , a mean injury severity score (iss) at ± , a mean abbreviated injury severity (ais) of the head at . ± . and a mean gcs at ± . twenty-three percents ( patients) of the patients developed hypernatremia and % ( patients) were diagnosed with acute cdi. in of ( %), the cdi was nonrecovering. the median delay to develop transient cdi was h and for non-recoviring cdi was h (p = . ). none of the patients with acute cdi had direct hypothalamic or pituitary lesions. factors associated to the occurrence of acute cdi were: younger age ( ± vs ± , p = . ), neuro-surgery ( % vs. %, p < . ), hemorrhagic shock ( % vs. %), p < . ), cerebral edema ( % vs. %), p < . ), and fractures to the base of the skull ( % vs. %, p = . ). patients who developed cdi had a significantly higher mortality than those who did not ( of ( %) vs. of ( %), p < . ). there were no difference in terms of mortality between non-recovering and transient cdi ( % vs. %, p = . ), similarly the onset of cdi did not affect mortality ( h vs. h, p = . ). patients with acute cdi had poor glasgow outcome scale ( ± . vs. . ± . , p < . ) and longer icu los ( ± vs. ± , p = . ). conclusion: acute cdi is associated with higher mortality and poor outcome. therefore it is essential to diagnose and treat it promptly and correctly. compliance with ethics regulations: yes. acute glucocorticoid deficiency following traumatic brain injury mariem dlela, rania ammar zayani, abir bouattour, najeh baccouche, mounir bouaziz habib bourguiba hospital, sfax, tunisia correspondence: mariem dlela (mariem @gmail.com) ann. intensive care , (suppl ):p- rationale: published data demonstrates that long-term hypopituitarism could be common after traumatic brain injury (tbi).however, few studies focused on radiological, clinical, and repetitive endocrine assessment in the acute phase. the aim of the study was to evaluate the early changes in the adrenal axis following (tbi) and to evaluate whether hormone changes affect patient's outcome. we conducted a prospective study, including all patients admitted to a university hospital icu with moderate to severe traumatic brain injury (tbi), defined as a glasgow coma scale below twelve (gcs < ). each patient underwent sequential measurement of plasma cortisol (pc) on days , , and after tbi. we defined adrenal insufficiency as pc less than ng/ml. patients who received glucocorticosteroid therapy were excluded. outcome was measured by incidence of death, and glasgow outcome scale (gos) on day thirty. souhila sadat, dalila zeghdoud, dalila bougdal, kamel guenane ehs salim zemirli, alger, algeria correspondence: souhila sadat (sadatsouhila@hotmail.fr) ann. intensive care , (suppl ):p- rationale: the renewed interest in the pathophysiology of severe traumatic brain injury (tcg), allowed the understanding of the pathophysiological mechanisms leading to neuronal death.the non-invasive, easy, patient-based technical dtc allows evaluation of cerebral blood flow. purpose of the study: to determine the contribution of transcranial doppler (dtp) in the prevention of post-traumatic ischemia. patients and methods: a monocentric, observational, prospective study over a period of years, including tcg in the monitoring of cerebral blood flow (dsc) was provided by the dtc. we collected the following data: age, gender, lesion mechanism, lesion association, glasgow score at admission, time to perform the initial scan, time to perform the initial doppler, various abnormalities found at the initial dtp, the analysis of the level of map according to each situation of cerebral blood flow, the proposed therapies, the time to obtain a correct dtc. ( %), the statistical analysis showed no difference between the delay in setting up a hypohemia and the presence of a correct cerebral blood flow (p = . ), the statistical analysis of the map in the dtc group hypohemia compared to the correct dtc group objectified the absence significant difference between the two groups. the realization of dtp allowed therapeutic prioritization, the introduction of norepinephrine was in % of cases, osmotherapy in % of cases, optimization of sedation in . % of cases, the introduction of penthotal in . % of cases and the completion of decompressive in . % of cases. statistical analysis of mortality showed a significant difference in mortality (p = . ) in the hypohemic dtc group compared with the correct doppler . conclusion: ttc is an essential monitoring tool of cerebral hemodynamics, which may in prove the neurologic outiome of tcg. compliance with ethics regulations: yes. rationale: hyponatremia is a frequent electrolyte disturbance in hospitalized patients. it is particularly common in brain-injured patients with significantly elevated morbidity and mortality. the aim was to study the prevalence of hyponatremia in the acute phase of post-traumatic cerebral aggression, its degree of severity, its predictive factors as well as its prognostic impact in the population of post-traumatic brain injury. patients and methods: this is a retrospective study, carried out over a period of years about all traumatized head patients who developed hyponatremia during the first h of their stay. the descriptive part treated all patients who developed hyponatremia by detailing its different stages of severity.the analytical part treated the patients who developed a hypo-osmolar hyponatremia with a threshold of mmol/l retained to define the severity. during the study period, the incidence of hyponatremia in head trauma patients was . %. the occurrence of hyponatremia was associated only with the occurrence of early seizures (p = . ).severe hyponatraemia was associated with paroxysmal occurrence (p = . ), mass effect (p = . ), and hemostasis disorders. the multivariate study revealed that severe hyponatremia was associated with the glasgow score (p < . ) and pupillary changes (p = . ). on the other hand, it is the initial variation in serum sodium that was associated with both the severity of the initial neurological examination; glasgow (p < . ), saps (p = . ), pts (p = . ) and prism scores (p = . ), haemodynamic instability (p = . ) and neurovegetative disorders (p = . ). lesional features have also been found.regarding the prognosis, the occurrence of initial hyponatremia had a protective effect: a more favorable gos score p = . and a lower mortality (p = . ). a poor neurologic prognosis as well as a high mortality were associated with the most severe hyponatraemia and particularly with the initial variation of the sodium level (p = . ;). the mortality was . %. it was also particularly related to the initial change in sodium levels (p < . , . ). we concluded that there is no association between post traumatic early hyponatremia and the severity of the initial clinical presentation. however, the depth of hyponatremia and especially the initial change in sodium levels have been associated with more severe clinical pictures and a more limited prognosis. compliance with ethics regulations: yes. rationale: post-traumatic epilepsy (pte) is one of the complications described in the aftermath of headtrauma. its incidence is variable in the literature because of its clinical polymorphism. objectives of the study was to analyze the epidemiological profile (clinico-biological, radiological, therapeutic and evolutionary) of the patients having presented pte and to determine the risk factors for this pathology by comparing them with the rest of the traumatized brain patients. patients and methods: our study was retrospective. it was conducted in the intensive care unit (icu) of our university hospital between and . were included in our study all patients admitted to the service with brain injury and a glycaemia above mmol/l during the first h post-trauma. results: the incidence of pte was . %. ( among ) the average age was . ± . years. the sex ratio was . . the average of gcs was . ± . . three ( . %) patients had initial motor impairment. seizures were observed in ( . %) patients during the first h of hospitalization. the mean delay of occurrence of pte was ± . months. pte was diagnosed before the end of the first post-traumatic year in patients ( % of cases). the most commonly observed brain lesions were cortical brain contusions ( rationale: electrolytic disorders are common in neuro-resuscitation, especially dysnatremias and dyskalemias. hyponatremias are the most frequent, including the main etiologies: the syndrome of inappropriate secretion of antidiuretic hormone (siadh) and the "cerebral salt wasting" syndrome (csw). diabetes insipude of central origin secondary to a lack of dha secretion is the second most common disorder. patients and methods: it is a prospective study, analysing all the brains injured admitted to the a intensive care unit of chu hassan in fez, morocco. study spread over a -month period from / / to / / . the objective of the study is to detect the most frequent hydro-electrolytic disorders and to evaluate the therapeutic effectiveness of the service protocols. results: all these brains injured have caused he disorders over a period of time varying between d and d : * cases of hyponatremia ( %)/ cases of hypernatremia ( %), * cases of hypokaliemia ( %)/ cases of hyperkaliemia ( %), * cases of hyperchloremia, or %/ cases of hypochloremia ( %). * cases of diabetes insipidus, or . %. * cases without he disorder ( . %). the treatment for these disorders was: *for hypona; it reached mmol/l, initially corrected by a -hour water restriction, followed by an increase in the basic ration and furosemide boluses according to the ecv, even sodium loads for a single case of salt loss syndrome, while the main etiology remains the siadh. *for hyperna, it has reached mmol/l, evaluated by the extracellular volume, corrected by enteral tap water after calculation of the hydric deficit. if hperna is associated with polyuria greater than cc/kg/h; we speak of: *insipude diabetes, with polyuria up to cc/kg/h, compensated with potassium-containing solutions and blood ionogram monitored every h. desmopressin was used in titration, by bolus of . µg, with a diuresis objective between and . ml/kg/h. *for hypokalemia, up to . g/dl, observed mainly in the acute phase of brain aggression, corrected by increase in br for a k between . and g/l, and by potassium loads if k below . g/l. the evolution: deaths or . % ( cases of uncorrected diabetes insipidus), the restriction of disorders were corrected. conclusion: a knowledge of the hydroelectrolytic disorders encountered in this context is essential, as well as the implementation of a diagnostic and therapeutic protocol, which will reduce the time required to correct these disorders. compliance with ethics regulations: yes. . ] u/h). however, workload was increased under star ( vs. measurements per day), as expected from measurement interval difference between star ( -hourly) and the sp ( -hourly). conclusion: this unique patient-specific risk-based dosing approach gc framework was successful in controlling all patients safely and effectively. these preliminary results are encouraging and show gc can be achieved safely and effectively at lower target bands. in turns, these improved gc outcomes could improve patient outcomes. compliance with ethics regulations: yes. rationale: although its incidence has declined in recent years, gastric cancer remains common worldwide and is the leading cause of gastrectomy. his treatment is mainly surgical, but his prognosis remains poor. many studies on survival and prognostic factors have been carried out in foreign series. patients and methods: this is a retrospective study covering a period of three years from january to december interesting patients who had a gastrectomy and hospitalized in emergency resuscitation department surgical uhc ibnou rochd from casablanca. the statistical analysis of the different clinical, paraclinical and therapeutic data was carried out thanks to an exploitation sheet. rationale: gram-negative bloodstream infections (gnbsi) require timely appropriate antimicrobial therapy in intensive care units (icu) patients. conventional techniques usually take - h for antimicrobial susceptibility testing (ast). innovative approaches (accelerate pheno ™ system) provide pathogen identification in ~ h and ast including minimal inhibitory concentrations (mics) in ~ h. we report, in icu patients with gnbsi, results of implementation of the accelerate pheno ™ in our laboratory. we prospectively screened all gnbsi episodes reported in adult icu patients between september and september . to allow integration into the laboratory workflow, the accelerate pheno ™ was run on blood bottles positive before am (day ), in parallel with routine procedures: maldi-tof identification after short incubation on solid media (day ), β lacta (bio-rad ® ) test (day ) and disk diffusion method for ast (day+ ). for each episode, antimicrobial regimen was reassessed by a multidisciplinary team of bacteriologists, infectious diseases and icu physicians by the end of day . we measured: (i) concordance of accelerate pheno ™ results with conventional techniques, (ii) number of antibiotic adaptations on day and (iii) number of patients within the therapeutic range (free fraction over x mic and below concentration at risk of adverse events), based on real-time measurement of beta-lactams concentrations. results: of patients reported with gnbsi over the study period, were included. mean age was of ± . years, / were males. main sources of gnbsi were pulmonary (n = ) and digestive (n = ). bacterial identification of the accelerate pheno ™ was concordant with standard techniques in ( %): enterobacteriacae (n = ), pseudomonas aeruginosa (n = ). overall categorical agreement for ast was of % ( errors including very major errors). by the end of day , the antibiotic regimen was de-escalated in ( %) patients, which was appropriate in ( %). in cases, de-escalation was possible, but not fulfilled by icu physicians. twenty patients had beta-lactams concentrations measurements: were in the therapeutic range, below and over. conclusion: accelerate pheno ™ provided rapid and accurate results for most microorganisms isolated in blood cultures of icu patients with gnbsi. however, in a laboratory with routine maldi-tof early identification and β lacta test performed on day , the impact on early adaptation of the antibiotic regimen was evident in around patient over . compliance with ethics regulations: not applicable. jean-luc baudel , jacques tankovic , redouane dahoumane , jean-remy lavillegrand , razach abdallah , geoffroy hariri , naike bige , hafid ait-oufella , nicolas veziris , eric maury , bertrand guidet service bactériologie, hôpital saint-antoine, paris, france; service réanimation médicale, hôpital saint-antoine, paris, france correspondence: jean-luc baudel (jean-luc.baudel@aphp.fr) ann. intensive care , (suppl ):p- rationale: evaluation of the accurateness of the accelerate phenotest bc kit for rapid analysis ( . h for microorganism identification and additional hours for antibiotic susceptibility testing) of positive blood cultures from icu and hematology patients. patients and methods: from february to august , we included patients from the icu and hematology units with positive blood cultures. the following informations were collected : gender, age, duration of prior antibiotherapy, source of the infection, results obtained by conventional microbiological methods and by phenotest (data obtained and time to obtention of results). informed consent was obtained from all patients. results: blood cultures were analyzed in patients (m/f ratio . , age . ±, from the icu and from hematology). % of the patients were receiving antibiotics at the time of blood culture collection (mean duration : . days). the source of infection was unknown in % of cases, urinary in %, catheter-related in %, ascites in %, pneumonia in %. in cases ( %), there was a perfect match between phenotest and conventional results (identification and antibiotic susceptibility testing). in cases ( %), the bacterium responsible was not present in the phenotest panel. in cases ( %), phenotest identification was correct, but some discrepancies were observed regarding antibiogram. in cases ( %) phenotest identification was again correct but no antibiogram was available. in cases ( %), where two bacteria were present, phenotest could not identify one of them. in cases, phenotest did not provide bacterial identification because too few bacteria were present in the blood culture bottle. conclusion: the phenotest panel covered % of the bacteria implicated in this study. when the bacterium responsible was present in the panel, the results given by the phenotest correlated in % of cases with those of conventional methods. some rare discrepancies were observed regarding antibiotic susceptibility testing that have to be analyzed further. in the remaining % of cases, where too few bacteria or two different bacteria were present in the blood culture bottle, technical limitations did not permit to correctly identify microorganism(s) present or to obtain an antibiogram. compliance with ethics regulations: yes. mélanie fromentin, antoine bridier-nahmias, constance vuillard, jean-damien ricard, damien roux inserm umr iame infection antimicrobials modelling evolution, paris, france correspondence: mélanie fromentin (mel.fromentin@wanadoo.fr) ann. intensive care , (suppl ):p- rationale: studying human lower respiratory tract microbiota by using ngs (new generation sequencing) method is complex because of many unexpected biases due to dna extraction and amplification procedures. lung microbiota evolution under mechanical ventilation evolution may be highly informative to evaluate the actual risk of vap (ventilator-associated pneumonia) development. before starting a large study on the lung microbiome of ventilated icu patients, a methodological study was mandatory. patients and methods: five control and three vap patients were selected. endotrachealaspirate (eta) and oropharyngeal swab (os) were collected at icu admission for control patients and, days before and on the day of vap diagnosis for vap patients. after automated extraction of total dna, hypervariable region v of the s rdna genes was amplified with two different pairs of primers f- r: oligonucleotides from the earth microbiome project (earth primer pair) and from the gut microbiome project (gut primer pair), followed by sequencing on illumina miseq plateform. after bioinformatics analysis with mothur ® software, we compared the performance of ngs alongsideconventional bacterial culture. differences in alpha diversity (microbial diversity in a sample), expressed as the shannon index, across respiratory tract site (upper or lower) and across time (before and at vap time) has been investigated. a positive control (pc), rationale: colistin is used as a last-line treatment to combat multidrug-resistant (mdr) gram-negative bacilli (gnb). worryingly, colistin resistance in klebsiella pneumoniae, pseudomonas aeruginosa and acinetobacter baumannii is increasingly reported worldwide. we hereby report the prevalence of colistin resistance among gnb isolated from burn patients in tunisia. the study was carried out on strains of gnb isolated from microbiological samples of burn patients hospitalized in the intensive care unit between october and december . identification was performed by conventional methods. antimicrobial susceptibility was tested by disk diffusion method and the results were interpreted according to ca-sfm guidelines. minimum inhibitory concentration (mic) of colistin was determined using the eucast broth micro-dilution method (umic, biocentric ® ) results: pseudomonas aeruginosa was the most frequently isolated bacteria ( strains), followed by acinetobacter baumannii ( strains) and klebsiella pneumoniae ( strains). the most common sites of isolation were blood cultures ( %), catheters ( %) and skin samples ( %). most of p. aeruginosa isolates were multidrug-resistant with high levels of resistance to imipenem ( . %), ceftazidime ( %) and ciprofloxacin ( . %). however, all of them were susceptible to colistin. in fact, mics of colistin against all p.aeruginosa isolates were less than or equal to . mg/l. a. baumannii strains had high resistance rates to beta-lactams : % to ceftazidime and % to imipenem. only one strain was resistant to colistin with a mic equal to mg/l. all k. pneumoniae isolates were resistant to extended-spectrum cephalosporins. one third of these strains were resistant to imipenem and more than half ( . %) were resistant to amikacin. two strains were resistant to colistin with high mics (> mg/l). both were carbapenemase-producers, carrying oxa- and ndm carbapenemase encoding genes. conclusion: these data suggest that colistin-resistant or pan-drug resistant gnb clinical isolates are still relatively rare. however, they have important global public health implications because of the therapeutic problems they present, especially for vulnerable populations such as severely burned patients. hence the need to test colistin regularly in the laboratory and to set up a monitoring program for mdr pathogens. compliance with ethics regulations: yes. rationale: descending necrotizing mediastinitis (dnm) are medicosurgical emergencies whose forecast is closely related to the precocity of the therapeutic assumption. the purpose of our work is to profile these patients as well as the therapeutic and evolutionary aspects. patients and methods: retrospective study over years in the intensive care unit of the hospital august. all patients with dnm on cervicofacial cellulitis were included. results: cases were collected, % of cellulitis, incidence of . patients / year. average age , sex ratio of . . smoking, chronic alcoholism and diabetes are the most common antecedents. the favoring factors were: (poor dental conditions: % of cases, non steroidien anti-inflammatory drugs: %, diabetes: %). in % of cases the front door was dental. average time taken to take care of days. c-reactive protein and procalcitonin were positive in all patients. in % the chest x-ray was normal. all patients received tri-antibiotic therapy. intubation were difficult in all patients, we used nasofibroscope in % of cases and a rescue tracheotomy in one patient. only one patient had a cervico-thoracic surgical approach; for all the others she was cervical alone. streptococcus was the most isolated germ. the complications were (septic shock: %, ards: %). the average hospital stay was days with a mortality rate of %. conclusion: dnms are poorly prognostic. the best treatment remains prevention by better management of dental abscesses and tonsillar phlegmons. rationale: the initial, empirical antibiotic therapy of ventilator-associated pneumonia (vap) is often based on timing of its occurrence in relation to the onset of mechanical ventilation. this is due to reported differences between causal pathogens associated with early-onset (e-vap < - days of mechanical ventilation) compared to late-onset vap (l-vap ≥ - days of mv). e-vap is most often reported to be due to antibiotic-sensitive pathogens while l-vap is frequently attributed to antibiotic-resistant pathogens. however, there is emerging evidence that the isolated microorganisms may be similar regardless of onset time. the aim of our study was to compare the clinical outcomes of critically ill patients developing e-vap and l-vap and to compare the causative pathogens of the two groups. patients and methods: all the patients with the diagnosis of vap admitted between january and december were retrospectively included. vap was suspected on the basis of clinical and chest x-ray findings. the identification of the causative organisms was performed with endotracheal aspirate (eta) cultures. results: ninety patients developed vap. e-vap was observed in patients ( , %), whereas patients ( , %) developed l-vap. among patients with early-onset vap, % received antibiotics prior to the development of pneumonia, compared to % with late-onset vap (p = . ). otherwise, no differences (sociodemographic factors, antecedents, severity score, length of stay, length of mv) between the two groups were observed. the most common pathogens associated with e-vap were enterobacter species ( . %), pseudomonas aeruginosa ( . %) and oxacillin-resistant staphylococcus aureus (orsa , %). enterobacter species ( . %), acinetobacter baumannii ( . %) and pseudomonas aeruginosa ( %) were the most common pathogens associated with l-vap. no difference was noted in the contribution of multidrug resistant bacteria mdr ( % vs. %). hospital mortality was significantly greater for patients with l-vap caused by mdr ( %) compared to patients with e-vap ( %) (p = . ). conclusion: this classification is no longer helpful for empirical antibiotic therapy, since both early-onset and late-onset vap were caused by mdr bacteria. this justifies the need of intensive care unit-specific knowledge of causal agents associated with vap to reduce the rate of administration of inadequate antimicrobial therapy. compliance with ethicsregulations: yes.